[{"rthcId":"RTHC-00001","title":"Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion.","authors":"Benowitz, N L; Jones, R T","year":1975,"journal":"Clinical pharmacology and therapeutics, 18(3), 287-97","doi":null,"pmid":"1164818","tags":["cardiovascular","tolerance"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Single doses of THC speed up heart rate and raise blood pressure. But when hospitalized volunteers took THC continuously over an extended period, the opposite happened: heart rate slowed and blood pressure dropped.\n\nThe researchers observed impaired circulatory responses to standing, exercise, and cold exposure, pointing to reduced sympathetic nervous system activity. All subjects gained substantial weight during the study, linked to fluid retention and plasma volume expansion.\n\nTolerance developed to the drop in blood pressure upon standing (possibly from the expanded blood volume), but blood pressure while lying down stayed low throughout. The psychological high and heart rate increase from smoked marijuana also diminished almost completely during ongoing THC intake.","whyItMatters":"This 1975 study was among the first to document that THC has opposite cardiovascular effects depending on whether exposure is acute or chronic. The finding that the body adapts to some effects (heart rate increase, orthostatic hypotension) but not others (sustained blood pressure lowering) shaped decades of follow-up research on cannabis tolerance and cardiovascular safety.","specificNumbers":"- Heart rate: tachycardia with single doses reversed to bradycardia with prolonged use\n- Blood pressure: significant lowering in supine position persisted without tolerance\n- Tolerance to psychological effects of smoked marijuana developed nearly completely\n- All subjects experienced marked weight gain from fluid retention","methodology":"Hospitalized volunteers received prolonged oral THC in a controlled clinical setting. Researchers tracked heart rate, blood pressure, circulatory responses to physical challenges (standing, exercise, cold pressor test, Valsalva maneuver), weight changes, and electrocardiogram readings throughout the study period.","limitations":"The study used a small number of hospitalized volunteers in a controlled setting that does not reflect real-world cannabis use. Only oral THC was administered for the prolonged phase. The specific doses and duration are not detailed in the abstract. Results from the 1970s may not directly apply to modern cannabis products with different potency and delivery methods."},{"rthcId":"RTHC-00002","title":"Cannabis intoxication: effects of monetary incentive on performance, a controlled investigation of behavioural tolerance in moderate users of cannabis.","authors":"Casswell, S","year":1975,"journal":"Perceptual and motor skills, 41(2), 423-34","doi":null,"pmid":"1187298","tags":["cognition","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Cannabis produced dose-related impairment on four out of five tasks testing short-term memory, goal-directed behavior, and reaction times. But when participants were offered money for better performance, they showed less impairment than unmotivated participants on three of those tasks.\n\nExperienced cannabis users performed no differently than first-time users, contradicting the common assumption that regular users develop behavioral tolerance to cognitive effects.","whyItMatters":"This study raised an important question that remains relevant: how much of cannabis impairment is pharmacological versus motivational? The finding that external incentives can partially offset drug effects has implications for understanding impairment in real-world settings where stakes vary, from driving to workplace performance.","specificNumbers":"- Dose-related impairment found on 4 of 5 tasks\n- Motivated subjects showed less impairment on 3 of 5 tasks\n- No performance difference between experienced and naive cannabis users\n- Two dose levels tested against placebo","methodology":"Experienced cannabis users and cannabis-naive participants smoked placebo material and two different doses of cannabis in a controlled setting. Motivated participants received monetary incentives for task performance. Their results were compared to matched non-motivated groups across five cognitive and motor tasks.","limitations":"The abstract does not specify sample sizes, exact doses, or the magnitude of the motivation effect. The tasks used in the 1970s may not reflect modern cognitive testing standards. The study cannot determine whether motivation fully eliminates impairment or merely reduces it."},{"rthcId":"RTHC-00003","title":"Reduction in T-lymphocytes forming active rosettes in chronic marijuana smokers.","authors":"Cushman, P; Grieco, M; Gupta, S","year":1975,"journal":"International journal of clinical pharmacology and biopharmacy, 12(1-2), 217-20","doi":null,"pmid":"1080754","tags":["inflammation","cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared immune cell counts in 23 marijuana smokers and 23 non-smoking controls. B-lymphocyte levels were normal in both groups. However, T-lymphocytes that form active rosettes (a measure of T-cell function) were significantly lower in marijuana smokers.\n\n39% of smokers had active rosette counts more than two standard deviations below the control group average, suggesting altered T-cell function in a substantial portion of chronic users.","whyItMatters":"This was one of the earliest studies to document immune system changes in marijuana smokers. While it could not establish whether the T-cell differences had clinical consequences, it opened a research line into cannabis and immune function that continues today.","specificNumbers":"- 23 marijuana smokers vs. 23 controls\n- B-lymphocyte rosettes: normal in both groups\n- T-lymphocyte active rosettes: significantly lower in smokers\n- 39% of smokers had values below 2 standard deviations of the control mean","methodology":"Cross-sectional comparison of peripheral blood T- and B-lymphocyte rosette formation between 23 chronic marijuana smokers and 23 normal controls.","limitations":"Small sample size of 23 per group. Cross-sectional design cannot establish causation. No control for other substances, lifestyle factors, or health conditions. Rosette formation assays from the 1970s are not used in modern immunology. The clinical significance of reduced active rosettes is unclear."},{"rthcId":"RTHC-00004","title":"Marijuana smoking and reduced pressure in human eyes: drug action or epiphenomenon?","authors":"Flom, M C; Adams, A J; Jones, R T","year":1975,"journal":"Investigative ophthalmology, 14(1), 52-5","doi":null,"pmid":"1089090","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"After smoking a dose of marijuana containing 12 mg of THC, normal eye pressure decreased in light-to-moderate users. The pressure reduction occurred only in participants who reported experiencing a substantial high and a state of peaceful relaxation.\n\nThis pattern suggested the eye pressure lowering was an indirect effect tied to the relaxation state rather than a direct pharmacological action of THC on the eye. The researchers noted that similar relaxation from non-drug sources could theoretically produce the same result.","whyItMatters":"Marijuana is often cited as a potential glaucoma treatment. This early study complicated that narrative by suggesting the eye pressure reduction might stem from generalized relaxation rather than a direct drug effect on the eye, raising questions about whether cannabis offers any specific advantage over other relaxation methods for lowering intraocular pressure.","specificNumbers":"- Dose: 12 mg THC delivered via marijuana cigarette\n- Eye pressure reduced in light-to-moderate users\n- Effect occurred only in participants reporting substantial high and relaxation\n- No reduction observed in users who did not achieve relaxation","methodology":"Participants smoked a marijuana cigarette delivering 12 mg of THC, and intraocular pressure was measured. The relationship between subjective drug effects (high, relaxation) and pressure changes was analyzed.","limitations":"The abstract does not report exact sample size or the magnitude of pressure reduction. Only one dose level was tested. The study examined only immediate effects, not long-term glaucoma management. The indirect mechanism hypothesis (relaxation) was not tested against a relaxation-only control."},{"rthcId":"RTHC-00005","title":"Delta-9 -tetrahydrocannabinol and decreased macrophage migration inhibition activity.","authors":"Gaul, C C; Mellors, A","year":1975,"journal":"Research communications in chemical pathology and pharmacology, 10(3), 559-64","doi":null,"pmid":"1135516","tags":["inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"When immunized rats received THC by injection at doses ranging from 0.31 to 1.25 mg per kg body weight, the activity of macrophage migration inhibition factor (MIF) dropped significantly. MIF is a signal that keeps immune cells at sites of infection or inflammation. The suppression was most pronounced 15 hours after THC injection.\n\nThe researchers linked this finding to observations of impaired cellular immunity in regular cannabis users, suggesting THC may weaken one arm of the immune defense system.","whyItMatters":"This animal study provided early mechanistic evidence for how THC might suppress immune function. By showing that THC reduces a specific immune signaling molecule, it moved beyond simple observations of reduced immune cell counts toward understanding the pathway involved.","specificNumbers":"- Dose range: 0.31 to 1.25 mg/kg body weight\n- Route: intraperitoneal injection\n- Peak suppression: 15 hours after injection\n- MIF activity in peritoneal exudates was depressed","methodology":"Immunized rats received intraperitoneal injections of THC at varying doses. Macrophage migration inhibition factor activity was measured in peritoneal exudates at different time points after injection.","limitations":"Animal study using injected THC, which does not mirror how humans consume cannabis. Doses may not translate to human-relevant exposures. The study measured one immune marker in isolation. Rat immune systems differ from human immune systems in important ways."},{"rthcId":"RTHC-00006","title":"Depressant effect of marihuana smoke on antibactericidal activity of pulmonary alveolar macrophages.","authors":"Huber, G L; Simmons, G A; McCarthy, C R; Cutting, M B; Laguarda, R; Pereira, W","year":1975,"journal":"Chest, 68(6), 769-73","doi":null,"pmid":"1192853","tags":["respiratory","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Lung immune cells (alveolar macrophages) harvested from rats were exposed to marijuana smoke at increasing doses and then challenged with Staphylococcus bacteria. Control cells killed 78% of the bacteria. After marijuana smoke exposure, killing ability dropped in a clear dose-dependent pattern: 67% at the lowest dose down to just 11% at the highest dose.\n\nThe toxic component was found in the gas phase of the smoke and was water-soluble. Critically, purified THC and THC-extracted marijuana did not impair the macrophages, meaning the lung damage came from other components of marijuana smoke, not from THC itself.","whyItMatters":"This study made a critical distinction that remains relevant: the lung damage from marijuana smoke comes from combustion byproducts, not THC. This finding supports the modern understanding that the route of administration (smoking vs. other methods) determines respiratory risk, not the cannabinoid content.","specificNumbers":"- Control macrophage kill rate: 78.0% (+/- 5.0%)\n- 2 ml smoke exposure: 66.7% (+/- 7.1%)\n- 4 ml: 23.7% (+/- 7.0%)\n- 6 ml: 20.5% (+/- 7.0%)\n- 8 ml: 11.4% (+/- 7.6%)\n- THC concentration: 2.2%","methodology":"Alveolar macrophages were harvested from rat lungs via bronchopulmonary lavage and incubated in vitro with Staphylococcus albus and standardized marijuana smoke (2.2% THC content) at graded doses (2, 4, 6, and 8 ml). Differential filtration identified the toxic component. Purified THC and THC-extracted marijuana were tested separately.","limitations":"In vitro study using rat cells exposed directly to smoke, which does not replicate the complexity of smoke exposure in living lungs. The doses used may not correspond to human smoking patterns. Only one bacterial species was tested. The specific gas-phase compounds responsible were not identified."},{"rthcId":"RTHC-00007","title":"Effects of delta-9-tetrahydrocannabinol on mouse spleens.","authors":"Lefkowitz, S S; Chiang, C Y","year":1975,"journal":"Research communications in chemical pathology and pharmacology, 11(4), 659-62","doi":null,"pmid":"1101329","tags":["inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice immunized with sheep red blood cells and given THC showed a marked reduction in plaque-forming cells, which are the spleen cells responsible for producing antibodies. This suppression occurred alongside a general loss of spleen cellularity, meaning the overall number of cells in the spleen decreased.\n\nThe results pointed to THC having substantial effects on antibody synthesis, the process by which the immune system produces the proteins that target specific pathogens.","whyItMatters":"While the previous studies in this era focused on T-cells and macrophages, this study showed THC also affects the antibody-producing arm of the immune system. Together, these early animal studies painted a picture of THC broadly suppressing multiple components of immunity.","specificNumbers":"- Marked suppression of plaque-forming cells (exact numbers not provided in abstract)\n- General loss of spleen cellularity\n- Model: mice immunized with sheep erythrocytes","methodology":"Mice were immunized with sheep erythrocytes and administered delta-9-THC. Plaque-forming cell response (a measure of antibody production) and overall spleen cellularity were measured.","limitations":"Animal study with injected THC at doses that may not reflect human exposure. Abstract does not report specific doses, timing, or magnitude of suppression. Mouse immune systems differ from human immune systems. No clinical outcomes were measured."},{"rthcId":"RTHC-00008","title":"Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy.","authors":"Sallan, S E; Zinberg, N E; Frei, E","year":1975,"journal":"The New England journal of medicine, 293(16), 795-7","doi":null,"pmid":"1099449","tags":["cancer","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a double-blind, randomized, placebo-controlled trial, oral THC was tested as an anti-nausea treatment for cancer patients receiving chemotherapy drugs known to cause severe vomiting. The results were stark: THC produced an antiemetic effect in 14 of 20 total courses (and 12 of 15 courses in patients who completed the study). Placebo produced zero antiemetic responses in 22 courses.\n\nA notable observation: no patient vomited while experiencing a subjective high from THC. The study was published in the New England Journal of Medicine, lending significant credibility to cannabis as a potential chemotherapy support medication.","whyItMatters":"Published in the New England Journal of Medicine in 1975, this was one of the first rigorous clinical trials demonstrating that THC has genuine antiemetic properties. It helped launch the medical marijuana movement for chemotherapy support and eventually contributed to the development of synthetic THC drugs like dronabinol (Marinol) for this indication.","specificNumbers":"- 22 patients enrolled, 20 evaluable\n- THC antiemetic effect: 14 of 20 courses (70%)\n- Completers: 12 of 15 THC courses (80%) vs. 0 of 14 placebo courses (0%)\n- P < 0.001\n- Zero vomiting episodes during subjective high","methodology":"Double-blind, randomized, placebo-controlled crossover trial. Twenty-two cancer patients receiving chemotherapy known to cause central nausea and vomiting were enrolled. Each patient served as their own control, receiving both oral THC and placebo in separate courses. Twenty patients were evaluable.","limitations":"Small sample of 22 patients with only 20 evaluable. The abstract does not specify the THC dose. Crossover design means carryover effects are possible. Published in 1975, before modern antiemetic drugs (ondansetron, etc.) were available, so the comparator is placebo rather than current standard of care."},{"rthcId":"RTHC-00009","title":"Marijuana and T lymphocyte rosettes.","authors":"Cushman, P; Khurana, R","year":1976,"journal":"Clinical pharmacology and therapeutics, 19(3), 310-7","doi":null,"pmid":"1083326","tags":["inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In a comparison of 35 chronic marijuana smokers and 34 controls, smokers produced significantly fewer early (active) T-lymphocyte rosettes. However, late rosettes (which capture total T-cells) were similar between groups.\n\nThis pattern meant that marijuana smokers had normal numbers of T-cells in their blood, but a subpopulation of those cells functioned differently. The researchers suggested that marijuana smoke may alter T-cell membranes, affecting their ability to quickly bind to targets without reducing their overall count.","whyItMatters":"This study refined the earlier finding from Cushman and Gupta (1975) by distinguishing between T-cell number and T-cell function. The conclusion that cannabis affects how T-cells work rather than how many exist was an important nuance for understanding cannabis immunology.","specificNumbers":"- 35 chronic marijuana smokers vs. 34 controls\n- Early (active) rosettes: significantly fewer in smokers\n- Late (total) rosettes: similar between groups\n- Interpretation: functional impairment, not numerical reduction","methodology":"Cross-sectional study comparing sheep cell rosette formation in both early (active) and total (cold-enhanced) T-lymphocytes between 35 chronic marijuana smokers and 34 non-smoking controls.","limitations":"Cross-sectional design cannot prove causation. No adjustment for other substance use or lifestyle factors. Rosette assays are outdated. The clinical significance of altered early rosette formation is unclear. Sample size is modest."},{"rthcId":"RTHC-00010","title":"Effects of marihuana-dextroamphetamine combination.","authors":"Evans, M A; Martz, R; Rodda, B E; Lemberger, L; Forney, R B","year":1976,"journal":"Clinical pharmacology and therapeutics, 20(3), 350-8","doi":null,"pmid":"782773","tags":["cardiovascular","drug-interactions","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In two double-blind, randomized studies, researchers tested the combination of marijuana and dextroamphetamine. Heart rate and blood pressure increases were additive when both drugs were taken together. EKG changes were nonspecific and associated with marijuana.\n\nFor cognitive and motor performance, impairment tracked with marijuana only. Adding amphetamine to marijuana did not worsen or improve psychomotor performance compared to marijuana alone. Subjective effects measured by a modified symptom questionnaire also showed only additive patterns, with no synergistic interaction.","whyItMatters":"This is one of the earliest controlled drug interaction studies involving cannabis. The finding that cardiovascular effects were additive but cognitive effects were not is practically important for understanding polydrug use. It suggested that mixing cannabis with stimulants increases cardiac strain without counteracting the mental impairment from cannabis.","specificNumbers":"- Amphetamine dose: 10 mg/70 kg\n- THC dose: 50 mcg/kg (Study 1), 25 mcg/kg (Study 2)\n- Heart rate and blood pressure: additive effects from combination\n- Psychomotor impairment: attributable to marijuana only\n- Subjective effects: additive, no synergistic interaction","methodology":"Two separate double-blind, randomized, complete block design studies. Study 1: placebo or 10 mg/70 kg dextroamphetamine orally, followed 1.5 hours later by a marijuana cigarette delivering 50 mcg/kg THC. Cardiovascular measures tracked. Study 2: same amphetamine dose with marijuana delivering 25 mcg/kg THC. Psychomotor performance evaluated.","limitations":"Small sample size (not specified in abstract). Only one dose combination was tested in each study. Short-term, single-session design. Conducted in the 1970s with lower-potency cannabis than is available today. The amphetamine dose was relatively low."},{"rthcId":"RTHC-00011","title":"Alcohol and marijuana effects on ocular tracking.","authors":"Flom, M C; Brown, B; Adams, A J; Jones, R T","year":1976,"journal":"American journal of optometry and physiological optics, 53(12), 764-73","doi":null,"pmid":"797262","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Researchers tested experienced substance users on a visual tracking task where participants followed a small moving dot with their eyes. The dot oscillated faster and faster until smooth tracking broke down.\n\nAlcohol consistently degraded smooth eye tracking, reducing the frequency at which participants could maintain smooth pursuit. It also increased the time the brain needed to initiate saccadic (jumping) eye movements. These effects appeared dose-dependent.\n\nCannabis, by contrast, produced no measurable impairment on either smooth or saccadic tracking compared to placebo. The researchers attributed alcohol's effects to disruption of central processing in brainstem and cerebellar regions that coordinate eye movements.","whyItMatters":"Eye tracking is used as a proxy for neurological impairment because it reflects how quickly the brain processes and responds to visual information. This study suggested cannabis and alcohol affect different neural pathways, with alcohol targeting brainstem and cerebellar structures involved in eye movement coordination while cannabis left those systems intact.","specificNumbers":"The tracking test ranged from 0.5 to 3.0 Hz over 40 seconds. The visual field span was 7.5 degrees. Alcohol reduced both smooth and saccadic cutoff frequencies; cannabis did not differ from placebo on either measure.","methodology":"Experienced alcohol and cannabis users tracked a horizontally oscillating dot while eye movements were recorded. The dot's frequency increased from 0.5 to 3.0 Hz over 40 seconds. Researchers measured the frequency at which smooth tracking and saccadic tracking broke down under alcohol, cannabis, and placebo conditions.","limitations":"The study used experienced users who may have developed tolerance. The sample size was small. Only one type of visual tracking was tested, which does not capture all aspects of visual-motor coordination. The cannabis dose and route of administration were not detailed in the abstract."},{"rthcId":"RTHC-00012","title":"The combined effect of marihuana and dextroamphetamine.","authors":"Forney, R; Martz, R; Lemberger, L; Rodda, B","year":1976,"journal":"Annals of the New York Academy of Sciences, 281, 162-70","doi":null,"pmid":"798521","tags":["cognition","cardiovascular","drug-interactions"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In mice, THC enhanced locomotor activity and amplified the stimulant effects of methamphetamine. But in human participants, the picture was different.\n\nWhen young adult males smoked cannabis (25 micrograms/kg THC) and took oral dextroamphetamine (10 mg/70 kg), their psychomotor performance and subjective effects were not significantly different from cannabis alone. The amphetamine did not rescue cannabis-induced impairment in standing steadiness or attentive motor performance.\n\nDextroamphetamine alone, even at doses that raised blood pressure, produced no significant performance impairment. But participants themselves believed their driving ability was impaired under the combination, a judgment the researchers noted was supported by their lab measurements.","whyItMatters":"Polysubstance use is common, and understanding how cannabis interacts with stimulants matters for assessing real-world impairment. This study suggested amphetamines do not counteract cannabis-induced motor impairment, which challenges the assumption that stimulants might \"cancel out\" depressant effects.","specificNumbers":"THC doses: 3, 6, or 9 micrograms/kg via smoking. Dextroamphetamine doses: 5, 10, or 15 mg/70 kg orally. Combination dose: 25 micrograms/kg THC + 10 mg/70 kg d-AMP. Systolic blood pressure was elevated at the 15 mg d-AMP dose.","methodology":"The study combined animal experiments (mice, locomotor activity) with human testing. Young adult males received graded THC doses via marijuana smoking (3, 6, or 9 micrograms/kg) and dextroamphetamine (5, 10, or 15 mg/70 kg). Performance was measured via standing steadiness, attentive motor tasks, delayed auditory feedback, and subjective evaluations.","limitations":"The doses used were described as \"modest.\" The sample consisted only of young adult males. Animal and human results diverged, highlighting species differences. The study did not assess cognitive effects beyond psychomotor performance."},{"rthcId":"RTHC-00013","title":"Intact humoral and cell-mediated immunity in chronic marijuana smoking.","authors":"Rachelefsky, G S; Opelz, G; Mickey, M R; Lessin, P; Kiuchi, M; Silverstein, M J; Stiehm, E R","year":1976,"journal":"The Journal of allergy and clinical immunology, 58(4), 483-90","doi":null,"pmid":"135011","tags":["cognition","harm-reduction"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Twelve healthy adults smoked cannabis daily for 64 consecutive days in a controlled hospital setting while researchers tracked multiple immune markers.\n\nB-cell counts, initially lower than controls, increased to normal levels over the study period. T-cell counts followed the same pattern, starting significantly below controls and rising to normal by day 63. The ability of lymphocytes to respond to immune challenges (PHA stimulation and allogeneic cell response) was normal at baseline and remained unchanged throughout.\n\nImmunoglobulin levels (IgG, IgA, IgM) stayed within normal ranges. Four subjects showed increased IgE levels, though none showed signs of allergic reactions. The researchers concluded that short-term chronic cannabis use did not produce substantial adverse effects on either B or T cells in young healthy adults.","whyItMatters":"Earlier lab studies using isolated cells had suggested cannabis might suppress immune function. This study tested that hypothesis in living humans under controlled conditions and found no meaningful immunosuppression, an important counterpoint to the in vitro evidence.","specificNumbers":"Baseline T cells: 951 cells/mm3 (controls: 2,010). By day 63: 1,875 cells/mm3. Baseline B cells by surface immunoglobulins: 338 cells/mm3 (rose to 485). IgG: 1,064, IgA: 166, IgM: 96, all within normal ranges. Duration: 64 consecutive days of daily use.","methodology":"Twelve healthy adults who were experienced cannabis smokers were hospitalized and smoked cannabis daily for 64 consecutive days. Researchers measured B and T cell subpopulations, lymphocyte proliferative responses to PHA and allogeneic cells, and serum immunoglobulin levels at multiple time points.","limitations":"Only 12 participants, all healthy young adults who were already experienced cannabis users. The 64-day window may not capture effects that emerge over years of use. Baseline immune values were already lower than controls, raising questions about pre-existing differences."},{"rthcId":"RTHC-00014","title":"Differential association between chronic cannabis use and brain function deficits.","authors":"Soueif, M I","year":1976,"journal":"Annals of the New York Academy of Sciences, 282, 323-43","doi":null,"pmid":"1071386","tags":["cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers administered 12 objective tests measuring psychomotor speed, distance and time estimation, memory, and visuomotor coordination to 850 regular cannabis users and 839 non-users.\n\nCannabis users performed significantly worse than controls on most measures. But a striking pattern emerged: the size of the performance gap depended heavily on who was being tested.\n\nAmong literate, urban, younger participants, the difference between users and non-users was large and consistent. Among illiterate, rural, older participants, the gap nearly disappeared. The researchers proposed a working hypothesis: the lower someone's baseline level of cognitive proficiency, the smaller the measurable deficit associated with cannabis use.\n\nThey suggested cortical arousal as the underlying mechanism, with literacy, urbanization, and age all correlating with different baseline arousal levels.","whyItMatters":"This was one of the largest early studies of chronic cannabis use and cognition, and it introduced an important idea: that the measurable impact of cannabis on cognitive performance depends on the baseline cognitive demands of the population being studied. This concept has implications for how we interpret cannabis research across different demographic groups.","specificNumbers":"850 cannabis users vs. 839 non-users. 12 tests generating 16 variables. Three moderating dimensions analyzed: literacy vs. illiteracy, urban vs. rural, and age groups. Most test variables showed significant group differences.","methodology":"Cross-sectional comparison of 850 male regular cannabis users and 839 male non-users in Egypt. Twelve objective tests generated 16 variables measuring psychomotor speed, distance estimation, time estimation, immediate memory, and visuomotor coordination. Results were analyzed across literacy, urban/rural residence, and age dimensions.","limitations":"Cross-sectional design cannot determine whether cannabis caused the cognitive differences or whether pre-existing differences led some people to use cannabis. Only male participants were studied. The cannabis used in 1970s Egypt may differ substantially from modern products. Cultural and educational factors may confound the literacy and urbanization variables."},{"rthcId":"RTHC-00015","title":"Adverse effects of intravenous cannabis tea.","authors":"Mims, R B; Lee, J H","year":1977,"journal":"Journal of the National Medical Association, 69(7), 491-5","doi":null,"pmid":"875075","tags":["cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Four youths prepared a tea by boiling cannabis seeds, then injected the liquid directly into their veins. The consequences were immediate and severe.\n\nAll four developed nausea, vomiting, abdominal pain, watery diarrhea, chills, and fever within moments of injection. They progressed to hypovolemic shock with dangerously low blood pressure and temporary kidney failure.\n\nAdditional complications included persistent low blood sugar, rapid heart rate, gastrointestinal bleeding, bleeding in the whites of the eyes, jaundice, enlarged spleen, muscle pain, joint pain, motor weakness, and EKG changes indicating cardiac ischemia.\n\nAll four survived, with symptoms reversing over the following weeks, but the researchers emphasized that these effects had been potentially fatal.","whyItMatters":"This case report documents an extremely dangerous route of cannabis administration that introduces plant material, particulates, and contaminants directly into the bloodstream. The severity of the reactions underscores that the route of administration fundamentally changes the risk profile of any substance.","specificNumbers":"Four patients. All experienced hypovolemic shock and transitory renal failure. EKG showed ischemic changes. Recovery occurred over weeks.","methodology":"Case report of four youths who presented with acute adverse reactions after intravenous injection of aqueous cannabis-seed tea. Clinical findings were documented including vital signs, laboratory values, and EKG results.","limitations":"Case report of only four individuals. The exact composition of the injected tea is unknown, and contaminants from the preparation process likely contributed to the reactions. No way to separate effects of THC from effects of injecting plant particulates and other seed compounds."},{"rthcId":"RTHC-00016","title":"Cannabis, 1977.","authors":"","year":1978,"journal":"Annals of internal medicine, 89(4), 539-49","doi":null,"pmid":"358885","tags":["medical-cannabis","cardiovascular","respiratory"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized the state of cannabis science as of 1977, covering both therapeutic potential and health concerns.\n\nOn the therapeutic side, cannabis showed promise for reducing eye pressure in glaucoma and for bronchodilation in asthma. The reviewers anticipated these findings might drive development of synthetic cannabinoid derivatives with better safety profiles.\n\nOn the risk side, the most concrete short-term concern was cardiovascular: cannabis use predisposed patients with coronary artery disease to angina during exercise. Even in healthy people, smoking marijuana decreased peak exercise performance, likely because it increased heart rate to maximum levels at lower workloads.\n\nFor long-term effects, the reviewers noted preliminary evidence suggesting impaired lung function and immune responses, but emphasized that no conclusive evidence for lasting biological consequences existed at that time.","whyItMatters":"This review captures a snapshot of medical understanding at a pivotal moment when cannabis was transitioning from primarily a recreational concern to a subject of serious pharmacological investigation. Many of the research directions it identified remain active today.","specificNumbers":"No specific numeric data provided in the abstract beyond the publication timeframe (research through 1977).","methodology":"Narrative review of published cannabis research through 1977, covering immunoassay detection methods, therapeutic applications, and short- and long-term health effects.","limitations":"As a narrative review from 1978, it reflects limited evidence available at that time. The cannabis landscape has changed dramatically in terms of product potency, consumption methods, and the volume of research available."},{"rthcId":"RTHC-00017","title":"A critical review of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol.","authors":"Cocchetto, D M; Cook, L F; Cato, A E","year":1981,"journal":"Drug intelligence & clinical pharmacy, 15(11), 867-75","doi":null,"pmid":"6271519","tags":["medical-cannabis","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"By 1981, both government and industry had invested substantial effort in isolating cannabis compounds with medical potential. THC's ability to reduce nausea and vomiting during cancer chemotherapy had emerged as one of the most active areas of investigation.\n\nThis review critically evaluated the clinical trial evidence for THC as an antiemetic, finding that while the drug showed efficacy, the evidence base had significant weaknesses. The reviewers identified deficiencies in understanding THC's basic clinical pharmacology, including absorption, metabolism, and dose-response relationships, that complicated evaluation of its safety and effectiveness.","whyItMatters":"This review came at a critical juncture when THC was being seriously considered as a prescription medication. Its identification of pharmacological knowledge gaps helped shape the research agenda that eventually led to FDA approval of dronabinol (synthetic THC) in 1985.","specificNumbers":"The review covered six years of research activity (approximately 1975-1981) across both government and private sector investigations.","methodology":"Critical review of published clinical studies evaluating delta-9-THC as an antiemetic in cancer chemotherapy patients. The review assessed both efficacy and safety data.","limitations":"The review itself acknowledged that the evidence base had significant deficiencies. As a review from 1981, it predates decades of subsequent antiemetic research including modern serotonin antagonists that now dominate nausea management."},{"rthcId":"RTHC-00018","title":"The California program for the investigational use of THC and marihuana in heterogeneous populations experiencing nausea and vomiting from anticancer therapy.","authors":"Dow, G J; Meyers, F H","year":1981,"journal":"Journal of clinical pharmacology, 21(S1), 128S-132S","doi":null,"pmid":"6271818","tags":["medical-cannabis","cancer","youth","seniors"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Recognizing that existing THC studies left major questions unanswered, California established a statewide program combining therapeutic access with structured research.\n\nFour protocols were designed to address specific gaps: optimal oral THC dosing in adults on cyclic chemotherapy, optimal dosing in children, dosing for adults on chronic chemotherapy or radiation therapy, and optimal dosing for smoked marijuana. Each protocol would track side effects and efficacy by chemotherapy agent, cancer type, age, and sex.\n\nThe program was notable for its scale, involving over 200 investigators, and for explicitly studying populations often excluded from cannabis research: pediatric patients, elderly patients, and the very ill. The researchers acknowledged the substantial challenges of running a large collaborative study with community practitioners while maintaining scientific rigor.","whyItMatters":"This was one of the first large-scale, government-sponsored efforts to study therapeutic cannabis use in real-world medical settings. Its inclusion of children, elderly patients, and multiple cancer types addressed critical gaps in the evidence base that small academic studies had not covered.","specificNumbers":"Four separate protocols. Over 200 investigators. Populations included: adults on cyclic chemotherapy, children, adults on chronic chemotherapy or radiotherapy, and smoked marijuana users.","methodology":"Description of a multi-protocol statewide research program. Four separate protocols covered different patient populations and administration routes. Over 200 investigators participated across community practice settings.","limitations":"The abstract describes the program design rather than results. Phase III collaborative studies across community practices inherently involve less control than academic clinical trials. The emphasis on broad access may have complicated rigorous data collection."},{"rthcId":"RTHC-00019","title":"Clinical relevance of cannabis tolerance and dependence.","authors":"Jones, R T; Benowitz, N L; Herning, R I","year":1981,"journal":"Journal of clinical pharmacology, 21(S1), 143S-152S","doi":null,"pmid":"6271820","tags":["tolerance","withdrawal","addiction","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Drawing on data from 120 research subjects, this review documented how the body adapts to repeated cannabis exposure and what happens when use stops.\n\nTolerance developed to multiple effects: cardiovascular changes, lowered eye pressure, sleep disruption, mood changes, and behavioral effects. This tolerance was acquired rapidly under consistent dosing and was also lost rapidly when dosing stopped. The mechanisms appeared primarily functional (the brain adapting its response) rather than metabolic (the body breaking down THC faster).\n\nWithdrawal symptoms emerged after as little as seven days of THC administration. The syndrome included irritability, restlessness, insomnia, loss of appetite, nausea, sweating, increased salivation, elevated body temperature, tremor, weight loss, and changes in both sleep and waking brain wave patterns. While described as \"mild and transient\" in the 120 subjects studied, the syndrome resembled withdrawal from sedative drugs.\n\nThe review raised a clinically important concern: if tolerance develops to therapeutic effects, chronic medical use could become less effective over time.","whyItMatters":"This review established that cannabis tolerance and withdrawal were real, measurable phenomena, countering claims in both directions: that cannabis was completely non-addictive, or that it produced severe dependence. The finding that therapeutic tolerance could undermine medical use remains relevant to modern medical cannabis prescribing.","specificNumbers":"120 research subjects studied. Withdrawal appeared after as few as 7 days of THC use. Tolerance development rate depended on dose and dosing schedule.","methodology":"Review of clinical data from 120 research subjects who received THC under controlled conditions. The review synthesized findings on tolerance acquisition and loss, withdrawal symptoms, and clinical implications.","limitations":"Data from controlled research settings may not reflect real-world usage patterns. The 120 subjects likely represented a relatively homogeneous population. Withdrawal was described as mild and transient, which may underestimate severity in heavier or longer-term users."},{"rthcId":"RTHC-00020","title":"Topical delta 9-tetrahydrocannabinol and aqueous dynamics in glaucoma.","authors":"Merritt, J C; Perry, D D; Russell, D N; Jones, B F","year":1981,"journal":"Journal of clinical pharmacology, 21(S1), 467S-471S","doi":null,"pmid":"6271841","tags":["medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"THC was known to lower eye pressure when administered systemically, either by smoking marijuana or taking oral capsules. But systemic THC also lowered blood pressure, an unwanted side effect. Topical eye drops seemed like an obvious solution.\n\nIn laboratory animals, topical THC in light mineral oil successfully reduced eye pressure. But when the same approach was tested in six human patients with primary open-angle glaucoma using 0.05% and 0.1% THC solutions, it failed to lower eye pressure.\n\nThe researchers offered an important insight: light mineral oil has an affinity for corneal epithelium, making it an optimal vehicle for drugs that work locally within the eye. But if THC's pressure-lowering mechanism is systemic rather than local, this delivery approach would not work. They recommended future research focus on marijuana strains with minimal THC and on alternative local delivery systems for the specific cannabinoid compounds that act directly on the eye.","whyItMatters":"This study demonstrated a critical pharmacological principle: a drug that works systemically does not necessarily work locally, even at the same target organ. It redirected glaucoma research away from simple THC eye drops toward understanding which specific cannabinoids act locally within the eye.","specificNumbers":"Six patients with primary open-angle glaucoma. Two concentrations tested: 0.05% and 0.1% topical THC. Vehicle: light mineral oil. Marijuana strains with less than 0.4% THC recommended for future research.","methodology":"Randomized, balanced, double-masked protocol testing 0.05% and 0.1% topical THC in light mineral oil on six subjects with primary open-angle glaucoma. Previous animal studies using the same formulation served as comparison.","limitations":"Only six patients tested. Only two concentrations used. Only one vehicle (light mineral oil) was tested. The animal-to-human translation failure could reflect species differences, dose differences, or formulation issues rather than a fundamental mechanistic problem."},{"rthcId":"RTHC-00021","title":"Treatment of human spasticity with delta 9-tetrahydrocannabinol.","authors":"Petro, D J; Ellenberger, C","year":1981,"journal":"Journal of clinical pharmacology, 21(S1), 413S-416S","doi":null,"pmid":"6271839","tags":["medical-cannabis","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Spasticity, the involuntary tightening of muscles, is a common and disabling symptom in conditions like multiple sclerosis, stroke, cerebral palsy, and spinal cord injury. Some patients had reported improvement after smoking cannabis, and animal studies showed THC inhibited certain reflex pathways.\n\nIn this double-blind trial, patients received either 10 mg THC, 5 mg THC, or placebo. The blinded examiner correctly identified THC trials in seven of nine cases. At the 10 mg dose, THC significantly reduced spasticity as measured by clinical assessment (P < 0.01). EMG recordings confirmed reduced muscle activity in four patients whose spasticity primarily involved extensor muscles.\n\nIn a separate group of eight patients with spasticity from various central nervous system lesions, responses varied. Three of three patients with \"tonic spasms\" benefited, but patients with cerebellar disease saw no improvement.","whyItMatters":"This was among the earliest controlled trials demonstrating THC's antispastic effects in humans, providing clinical evidence for what patients had reported anecdotally. The finding that tonic spasms responded well while cerebellar conditions did not suggested THC acts on specific neural pathways rather than producing generalized muscle relaxation.","specificNumbers":"10 mg THC significantly reduced spasticity (P < 0.01). Blinded examiner correctly identified THC in 7 of 9 cases. Three of three patients with tonic spasms benefited. Zero benefit in patients with cerebellar disease.","methodology":"Double-blind, placebo-controlled trial with oral administration of 5 mg THC, 10 mg THC, or placebo. Muscle tone, reflexes, strength, and EMG were measured before and after dosing. An additional open-label group of eight patients with various CNS conditions was also treated.","limitations":"Very small sample size. The additional eight patients were treated in an open-label fashion without blinding. The study assessed short-term effects without tracking longer-term outcomes or tolerance development."},{"rthcId":"RTHC-00022","title":"THC therapeutic research by independent and state-sponsored investigators: a historical review.","authors":"Scigliano, J A","year":1981,"journal":"Journal of clinical pharmacology, 21(S1), 113S-121S","doi":null,"pmid":"6271816","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The path from cannabis prohibition to medical research was shaped by three key pieces of federal legislation: the Marihuana Tax Stamp Act of 1937, the Controlled Substances Act of 1970, and the Federal Food, Drug and Cosmetic Act of 1962.\n\nStarting in 1968, Congress directed initial studies toward understanding long-term cannabis use in humans. By the early 1970s, research expanded to include medical applications. This shift was driven by several converging forces: anecdotal reports from patients finding relief from chemotherapy nausea and glaucoma, lobbying from advocacy groups pushing for legalization, and the passage of Controlled Substances Therapeutic Research Acts by 25 states.\n\nThe review documented approved investigational new drug (IND) applications across four therapeutic categories and mapped the components of the research laws passed by all 25 states that enacted them.","whyItMatters":"This review documents a critical transition period in American cannabis policy. Understanding how therapeutic research authorization developed, through the interplay of federal law, state legislation, patient advocacy, and scientific interest, provides context for the much larger medical cannabis movement that followed.","specificNumbers":"25 states passed Controlled Substances Therapeutic Research Acts. Four therapeutic categories had approved INDs. Key legislative dates: 1937, 1962, 1968, 1970.","methodology":"Historical and legislative review covering U.S. cannabis policy from the 1937 Marihuana Tax Stamp Act through 1981. Included a listing of approved INDs, comparative chart of 25 state research laws, and bibliography.","limitations":"As a historical review focused on the U.S. regulatory landscape, it does not evaluate clinical evidence directly. The 25-state comparison covers legal frameworks, not research outcomes."},{"rthcId":"RTHC-00023","title":"Antagonism by chlornaltrexamine of some effects of delta 9-tetrahydrocannabinol in rats.","authors":"Tulunay, F C; Ayhan, I H; Portoghese, P S; Takemori, A E","year":1981,"journal":"European journal of pharmacology, 70(2), 219-24","doi":null,"pmid":"6266844","tags":["neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers administered chlornaltrexamine (beta-CNA), a long-acting irreversible opiate receptor blocker, to rats before giving them THC. The opiate blocker inhibited several key THC effects: pain relief (analgesia), body temperature reduction (hypothermia), the development of tolerance to hypothermia, and the development of physical dependence.\n\nThese results suggested that some of THC's effects in the brain are mediated through opioid-related mechanisms, meaning cannabis and opiates share common features in how they interact with the central nervous system.","whyItMatters":"This study provided early pharmacological evidence for cross-talk between the cannabinoid and opioid systems in the brain. This connection has since become a major area of research, with implications for pain management, addiction treatment, and understanding why cannabis and opioids can sometimes substitute for each other.","specificNumbers":"Beta-CNA inhibited four measured THC effects: analgesia, hypothermia, hypothermia tolerance, and physical dependence.","methodology":"Animal study in rats using chlornaltrexamine (beta-CNA), a selective irreversible opiate antagonist, administered before THC. Measured analgesia, hypothermia, hypothermia tolerance, and physical dependence.","limitations":"Animal study in rats; results may not translate directly to humans. Chlornaltrexamine is not perfectly selective, so some effects could involve non-opioid mechanisms. The study did not identify which specific opioid receptor subtypes were involved."},{"rthcId":"RTHC-00024","title":"Randomised clinical trial of levonantradol and chlorpromazine in the prevention of radiotherapy-induced vomiting.","authors":"Lucraft, H H; Palmer, M K","year":1982,"journal":"Clinical radiology, 33(6), 621-2","doi":null,"pmid":"6754212","tags":["medical-cannabis","cancer"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Cannabinoid antiemetics had shown promise in chemotherapy, but their use in radiation therapy was largely untested. This trial compared levonantradol, a synthetic cannabis derivative, against chlorpromazine, a standard antiemetic, in patients receiving palliative single-fraction radiation to sites known to cause nausea.\n\nTwo doses of levonantradol (0.5 mg and 0.75 mg) were tested against 26 mg chlorpromazine. In both the pilot study and the randomized trial, the frequency of vomiting was similar across all three groups. Both drugs were well tolerated, with most patients treated as outpatients.","whyItMatters":"While cannabinoid antiemetics showed advantages in chemotherapy settings, this study showed they were not superior for radiation-induced nausea. This distinction matters because different treatments cause nausea through different mechanisms, and a drug that works for one may not work for another.","specificNumbers":"Levonantradol doses: 0.5 mg and 0.75 mg. Chlorpromazine dose: 26 mg. Vomiting frequency was similar across all three groups in both the pilot and randomized phases.","methodology":"Pilot study followed by a randomized trial comparing chlorpromazine (26 mg) with levonantradol at two doses (0.5 and 0.75 mg) in patients receiving palliative single-fraction radiotherapy to sites likely to cause nausea and vomiting.","limitations":"The study used palliative single-fraction radiation, which may produce different nausea patterns than multi-fraction regimens. Sample size details were not provided in the abstract. Only two doses of levonantradol were tested."},{"rthcId":"RTHC-00025","title":"Cannabis and cancer chemotherapy: a comparison of oral delta-9-THC and prochlorperazine.","authors":"Ungerleider, J T; Andrysiak, T; Fairbanks, L; Goodnight, J; Sarna, G; Jamison, K","year":1982,"journal":"Cancer, 50(4), 636-45","doi":null,"pmid":"6284334","tags":["medical-cannabis","cancer"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Two hundred fourteen cancer patients were randomized in a double-blind crossover design to receive either THC (dosed by body surface area) or prochlorperazine (Compazine, a standard antiemetic) before chemotherapy.\n\nBoth drugs were equally effective at reducing nausea and vomiting across a wide range of chemotherapy regimens and tumor types. Neither drug was superior for appetite or food intake.\n\nTHC produced more side effects: reduced concentration (P < 0.01), less social interaction (P < 0.05), and reduced activity (P < 0.05). However, these side effects did not reduce patients' preference for the drug and were actually associated with better nausea reduction (P < 0.05).\n\nAn interesting pattern emerged: patients who correctly identified when they were receiving THC responded better to it than those who could not tell the difference (P < 0.05). Past marijuana experience and age did not affect how well either drug worked.","whyItMatters":"This was one of the largest and best-designed early trials of THC as an antiemetic. The finding of equivalence rather than superiority was clinically important: it meant THC was a legitimate alternative but not necessarily better than existing options. The \"unblinding\" effect, where patients who recognized THC responded better, raised important questions about expectation and placebo effects in cannabinoid research.","specificNumbers":"214 patients evaluated. 75% had previously received prochlorperazine. THC doses: 7.5 mg (BSA < 1.4), 10 mg (BSA 1.4-1.8), 12.5 mg (BSA > 1.8). THC reduced concentration (P < 0.01), social interaction (P < 0.05), and activity (P < 0.05).","methodology":"Double-blind, crossover design with 214 subjects. THC was dosed by body surface area (7.5, 10, or 12.5 mg). Prochlorperazine was 10 mg fixed dose. Both given orally one hour before chemotherapy then every four hours for four doses. Assessed nausea, vomiting, appetite, mood, activity, concentration, and social interaction.","limitations":"Crossover design means each patient received both treatments, which may introduce carryover effects. The \"unblinding\" finding suggests the double-blind was not perfect, potentially biasing results. The study used oral THC with its variable absorption."},{"rthcId":"RTHC-00026","title":"Review of cannabinoids and their antiemetic effectiveness.","authors":"Vincent, B J; McQuiston, D J; Einhorn, L H; Nagy, C M; Brames, M J","year":1983,"journal":"Drugs, 25 Suppl 1, 52-62","doi":null,"pmid":"6301800","tags":["medical-cannabis","cancer","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized the growing body of evidence on cannabinoid antiemetics. THC, isolated in 1964 and first used for chemotherapy nausea in the 1970s, had accumulated enough clinical trial data for meaningful assessment.\n\nIn controlled trials, THC was superior to both placebo and prochlorperazine (a standard antiemetic). A notable finding was that antiemetic effectiveness correlated with the subjective \"high\" experienced by patients. THC worked across multiple chemotherapy regimens, including high-dose methotrexate and the doxorubicin-cyclophosphamide-fluorouracil combination, though cisplatin-based regimens were more resistant.\n\nTwo synthetic alternatives showed promise: nabilone, which was more active than prochlorperazine even against cisplatin regimens, and levonantradol, which could be given intramuscularly as well as orally, offering flexibility for outpatient use. Side effects for all three cannabinoids were generally well tolerated but could be dose-limiting, particularly dysphoria in elderly patients.","whyItMatters":"This review consolidated the evidence that moved cannabinoid antiemetics from experimental curiosity to clinical reality. The finding that effectiveness correlated with the \"high\" raised important mechanistic questions about whether the antiemetic and psychoactive effects could be separated.","specificNumbers":"THC isolated in 1964, first used for nausea in the 1970s. THC superior to placebo and prochlorperazine. Nabilone more active than prochlorperazine including against cisplatin. Marijuana used medicinally for over 2 centuries.","methodology":"Narrative review of controlled clinical trials evaluating THC, nabilone, and levonantradol as antiemetics for cancer chemotherapy. Covered mechanisms of action, efficacy data, and side effect profiles.","limitations":"Narrative review format means no systematic quality assessment of included studies. The correlation between \"high\" and efficacy could reflect unblinding rather than a true mechanistic link."},{"rthcId":"RTHC-00027","title":"Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure of the rabbit.","authors":"ElSohly, M A; Harland, E C; Benigni, D A; Waller, C W","year":1984,"journal":"Current eye research, 3(6), 841-50","doi":null,"pmid":"6329602","tags":["medical-cannabis","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers systematically tested 32 different cannabinoid compounds for their ability to reduce intraocular pressure (IOP) in rabbits. The tested compounds included derivatives and metabolites of both delta-9-THC and delta-8-THC, other natural cannabinoids, synthetic cannabinoids, and even some non-cannabinoid compounds found in the cannabis plant.\n\nMost compounds were tested intravenously, with a few also tested topically in mineral oil. Water-soluble derivatives of delta-9-THC and delta-8-THC were synthesized specifically for topical testing in aqueous solution.\n\nThe key findings: certain THC derivatives were more active at lowering eye pressure than the parent THC compounds. Additionally, compounds other than THC and its derivatives also demonstrated IOP-lowering activity, broadening the range of potential therapeutic candidates for glaucoma.","whyItMatters":"This study expanded the therapeutic search beyond THC itself. By identifying non-THC cannabinoids with IOP-lowering activity, it opened the door to developing glaucoma treatments that might avoid the psychoactive side effects of THC.","specificNumbers":"32 different cannabinoids tested. Included delta-9-THC and delta-8-THC derivatives, metabolites, natural cannabinoids, and synthetic compounds. Some derivatives were more active than parent compounds.","methodology":"Screening study in rabbits testing 32 cannabinoid compounds for intraocular pressure reduction. Most compounds were administered intravenously; selected compounds were tested topically in mineral oil or as water-soluble aqueous solutions.","limitations":"Animal study in rabbits; IOP responses may differ in humans. Most compounds were tested intravenously, which does not reflect a practical route of administration for glaucoma patients. Topical testing was limited to a few compounds."},{"rthcId":"RTHC-00028","title":"Ethanol, marijuana, and other drug use in 600 drivers killed in single-vehicle crashes in North Carolina, 1978-1981.","authors":"Mason, A P; McBay, A J","year":1984,"journal":"Journal of forensic sciences, 29(4), 987-1026","doi":null,"pmid":"6502125","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers tested blood samples from all 600 drivers killed in single-vehicle crashes in North Carolina between 1978 and 1981 for alcohol, THC, barbiturates, cocaine, opiates, phencyclidine, amphetamines, and methaqualone.\n\nAlcohol dominated the findings: detected in 79.3% of drivers, with 85.5% of alcohol-positive drivers having blood concentrations at or above 1.0 g/L (substantially above legal limits). Of all drivers tested, 67.8% had blood alcohol at or above this level.\n\nTHC was detected in 7.8% of drivers, methaqualone in 6.2%, and barbiturates in 3.0%. Other drugs were rarely detected. Critically, when drugs other than alcohol were found, the concentrations were usually within or below therapeutic ranges, and most drug-positive drivers also had high blood alcohol levels.\n\nThe researchers concluded that among the substances tested, alcohol was the only drug that appeared to have a significantly adverse effect on driving safety in this population.","whyItMatters":"This was one of the first large-scale studies to systematically test for cannabis alongside alcohol and other drugs in fatal crashes. Its finding that THC detection was relatively rare and usually accompanied by high alcohol levels helped contextualize cannabis's role in driving fatalities relative to alcohol.","specificNumbers":"600 fatal crashes analyzed. Alcohol detected in 79.3% of drivers. THC detected in 7.8%. Methaqualone in 6.2%. Barbiturates in 3.0%. 67.8% of all drivers had blood alcohol at or above 1.0 g/L.","methodology":"Comprehensive toxicology screening of blood specimens from an inclusive population of 600 single-vehicle operator fatalities in North Carolina, 1978-1981. All specimens were tested for ethanol, THC, barbiturates, cocaine, opiates, and phencyclidine. Subsets were tested for amphetamines and methaqualone.","limitations":"Detection of THC in blood does not prove impairment at the time of the crash. THC metabolites clear the blood relatively quickly, so some cannabis-impaired drivers may have tested negative. The study could not isolate cannabis-only crashes because most THC-positive drivers also had alcohol. Blood collection timing after death may affect detection rates."},{"rthcId":"RTHC-00029","title":"Cannabinoids in blood and urine after passive inhalation of Cannabis smoke.","authors":"Mørland, J; Bugge, A; Skuterud, B; Steen, A; Wethe, G H; Kjeldsen, T","year":1985,"journal":"Journal of forensic sciences, 30(4), 997-1002","doi":null,"pmid":"2999292","tags":["harm-reduction","driving"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Five healthy volunteers who had never used cannabis sat in a small closed car (approximately 1,650 liters of air) while other people smoked marijuana or hashish for 30 minutes.\n\nImmediately after exposure, THC was detectable in the blood of all five passive smokers at concentrations ranging from 1.3 to 6.3 nanograms per milliliter. Total cannabinoid blood levels exceeded 13 ng/mL in four of the five volunteers. Both THC and total cannabinoid concentrations dropped to near the detection limits of the assays within two hours.\n\nCannabinoids were also detectable in urine using both radioimmunoassay and EMIT testing methods. The researchers concluded that detecting cannabinoids in blood or urine is not unequivocal proof that someone actively smoked cannabis.","whyItMatters":"This study had direct implications for drug testing in workplaces, law enforcement, and forensic settings. It demonstrated that positive drug tests could result from passive exposure rather than active use, raising questions about the validity of drug test results as proof of cannabis consumption.","specificNumbers":"Five volunteers. 30-minute exposure. Car air volume: approximately 1,650 L. Blood THC range: 1.3 to 6.3 ng/mL immediately after exposure. Blood levels fell near detection limits within 2 hours. Urine positive by both RIA (above 13 ng/mL) and EMIT (above 20 ng/mL).","methodology":"Prospective study with five cannabis-naive volunteers passively exposed to cannabis smoke in a closed car (approximately 1,650 L air volume) for 30 minutes. Blood and urine were collected at multiple time points and tested using GC-MS for THC and RIA/EMIT for total cannabinoids.","limitations":"The exposure conditions were extreme: a small closed car with active smoking for 30 minutes. This does not represent typical secondhand exposure in normal indoor or outdoor environments. Only five participants. The study did not assess whether the absorbed THC levels produced any psychoactive effects."},{"rthcId":"RTHC-00030","title":"Therapeutic issues of marijuana and THC (tetrahydrocannabinol).","authors":"Ungerleider, J T; Andrysiak, T","year":1985,"journal":"The International journal of the addictions, 20(5), 691-9","doi":null,"pmid":"2995262","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"By 1985, sufficient clinical evidence had accumulated to assess cannabis and THC across three primary medical applications.\n\nFor chemotherapy-induced nausea and vomiting, THC had demonstrated efficacy in multiple controlled trials. For glaucoma, cannabis consistently lowered intraocular pressure, though delivery and side effect challenges remained. For multiple sclerosis spasticity, preliminary evidence suggested benefit.\n\nThe review noted that the primary barriers to medical cannabis were not scientific but moral and ethical, reflecting the broader cultural controversy around marijuana that complicated both research and clinical access.","whyItMatters":"Published the same year dronabinol received FDA approval, this review captures the state of medical cannabis evidence at a watershed moment. Its observation that the barriers were primarily moral and ethical rather than scientific foreshadowed decades of ongoing debate about medical cannabis access.","specificNumbers":"Three therapeutic applications reviewed: nausea/vomiting, glaucoma, and MS spasticity.","methodology":"Narrative review summarizing clinical evidence for medical cannabis across three therapeutic areas: antiemetic use in chemotherapy, intraocular pressure reduction in glaucoma, and spasticity reduction in multiple sclerosis.","limitations":"The abstract describes a summary review without methodological details. The three conditions covered represent only a portion of the therapeutic claims made for cannabis."},{"rthcId":"RTHC-00031","title":"Open label evaluation of cannabidiol in dystonic movement disorders.","authors":"Consroe, P; Sandyk, R; Snider, S R","year":1986,"journal":"The International journal of neuroscience, 30(4), 277-82","doi":null,"pmid":"3793381","tags":["cbd","medical-cannabis","neuroscience"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"In this preliminary open-label study, five patients with dystonic movement disorders received oral CBD at escalating doses from 100 to 600 mg per day over six weeks, alongside their standard medications.\n\nAll five patients showed dose-related improvement in their dystonia, ranging from 20% to 50%. Side effects were mild: low blood pressure, dry mouth, psychomotor slowing, lightheadedness, and sedation.\n\nHowever, a notable adverse finding emerged. Two patients who had Parkinson's features alongside their dystonia experienced worsened hypokinesia (slowed movement) and resting tremor at doses above 300 mg/day. This suggested CBD has both antidystonic and Parkinsonism-aggravating effects, a dual action with significant clinical implications.","whyItMatters":"This was one of the earliest clinical studies of CBD for a neurological movement disorder. The finding that CBD helped dystonia but worsened Parkinsonism highlighted that cannabinoid effects on movement are complex and condition-specific, not uniformly beneficial.","specificNumbers":"Five patients. CBD doses: 100 to 600 mg/day over 6 weeks. Improvement range: 20-50% in dystonia. Parkinsonism worsened in 2 of 5 patients at doses above 300 mg/day.","methodology":"Open-label pilot study with five dystonia patients. Oral CBD was escalated from 100 to 600 mg/day over 6 weeks alongside existing medications. No placebo control or blinding.","limitations":"Open-label design with no placebo control means improvement could reflect placebo effects or natural variation. Only five patients. CBD was added to existing medications, making it difficult to isolate its specific contribution."},{"rthcId":"RTHC-00032","title":"Health aspects of cannabis.","authors":"Hollister, L E","year":1986,"journal":"Pharmacological reviews, 38(1), 1-20","doi":null,"pmid":"3520605","tags":["youth","respiratory","cardiovascular","cognition","pregnancy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This extensive review examined cannabis health effects across virtually every organ system and population group.\n\nThe review's central concern was youth: regular cannabis use might stunt emotional growth in adolescents, though whether the drug caused these effects or whether at-risk youth were drawn to use remained unclear. Evidence for an \"amotivational syndrome\" was largely anecdotal.\n\nFor adults, the picture was more reassuring on several fronts. Brain damage had not been proven. Physical dependence was rare in typical social use patterns. No clinical consequences had been documented from effects on immune response, chromosomes, or cell metabolites. Fears about dangerous accumulation in the body were unfounded.\n\nRisks were identified in specific contexts: chronic smoking caused bronchitis (though emphysema and lung cancer had not been documented), cardiovascular effects were harmful for those with pre-existing heart disease, the drug was likely harmful during pregnancy, and driving impairment seemed obvious but was hard to prove definitively. The review singled out herbicide spraying of marijuana crops as the clearest danger to health.","whyItMatters":"Published in one of pharmacology's most prestigious journals, this review represented the mainstream scientific consensus on cannabis health effects in the mid-1980s. Its nuanced conclusions, acknowledging both real risks and unfounded fears, stood in contrast to more extreme positions on both sides of the debate.","specificNumbers":"No specific numeric data highlighted in the abstract beyond noting that nabilone was the only approved synthetic cannabinoid at the time of publication.","methodology":"Comprehensive narrative review published in Pharmacological Reviews, covering cannabis effects on the brain, behavior, endocrine system, lungs, cardiovascular system, immune system, reproduction, and driving performance.","limitations":"Reflects evidence available through the mid-1980s. Cannabis potency, usage patterns, and the volume of research have all changed dramatically. The review's reassurance about lung effects preceded modern research on the topic."},{"rthcId":"RTHC-00033","title":"Marijuana effects on immunity: suppression of human natural killer cell activity of delta-9-tetrahydrocannabinol.","authors":"Specter, S C; Klein, T W; Newton, C; Mondragon, M; Widen, R; Friedman, H","year":1986,"journal":"International journal of immunopharmacology, 8(7), 741-5","doi":null,"pmid":"3023245","tags":["neuroscience","cancer"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Natural killer (NK) cells are immune cells that identify and destroy abnormal cells, including tumor cells. Researchers tested whether THC could affect this critical immune function.\n\nTHC was toxic to peripheral blood lymphocytes at 20 micrograms/mL but not at 10 micrograms/mL or below. At concentrations down to 5 micrograms/mL, THC inhibited NK cell activity against K562, a human tumor cell line.\n\nThe suppression of NK function depended on both the concentration of THC and how long the cells were exposed to it before encountering tumor targets. However, the suppression was independent of the ratio of NK cells to tumor cells, meaning more NK cells did not overcome the THC-induced impairment. Prostaglandins, which mediate some other forms of immune suppression, were not involved in this effect.","whyItMatters":"NK cells are a frontline defense against cancer cells. This study demonstrated that THC could suppress this defense in laboratory conditions, raising questions about whether cannabis use might affect cancer surveillance in living people.","specificNumbers":"THC toxic at 20 micrograms/mL. Not toxic at 10 micrograms/mL or less. NK suppression observed down to 5 micrograms/mL. Suppression was dose-dependent and time-dependent.","methodology":"In vitro study testing THC's effect on human natural killer cell function against K562 tumor cells. Variables included THC concentration, pre-incubation time, and effector-to-target cell ratios. Prostaglandin involvement was also assessed.","limitations":"In vitro study using isolated cells in a dish, which does not account for the complex regulatory environment of the intact immune system. The THC concentrations tested may exceed physiologically relevant levels during typical cannabis use. The study tested isolated NK cells, not the coordinated immune response."},{"rthcId":"RTHC-00034","title":"Possible risk of invasive pulmonary aspergillosis with marijuana use during chemotherapy for small cell lung cancer.","authors":"Sutton, S; Lum, B L; Torti, F M","year":1986,"journal":"Drug intelligence & clinical pharmacy, 20(4), 289-91","doi":null,"pmid":"3009125","tags":["respiratory","cancer","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with small cell lung cancer was using illegally obtained marijuana to control nausea during combination chemotherapy. During treatment, the patient developed invasive pulmonary aspergillosis, a serious and potentially fatal fungal lung infection.\n\nMarijuana samples have been shown to contain bacterial and fungal contaminants, including Aspergillus species. When an immunocompromised patient, whose immune defenses are already weakened by chemotherapy, inhales contaminated marijuana smoke, those contaminants gain direct access to vulnerable lung tissue.\n\nThe researchers acknowledged the patient had multiple risk factors for aspergillosis beyond marijuana use, including chemotherapy-induced immunosuppression. They could not definitively attribute the infection to marijuana alone. However, they emphasized that the infectious potential of inhaled marijuana in immunocompromised patients is a real and underrecognized risk.","whyItMatters":"This case report highlighted a specific harm-reduction concern: marijuana contamination with fungi poses minimal risk to healthy users but potentially serious risk to immunocompromised patients. This distinction became increasingly relevant as medical marijuana programs expanded to include cancer patients.","specificNumbers":"One patient with small cell lung cancer. Multiple risk factors for aspergillosis. Marijuana obtained illicitly (unregulated, untested for contaminants).","methodology":"Case report of a single patient who developed invasive pulmonary aspergillosis while using illicitly obtained marijuana during cancer chemotherapy. Clinical findings and risk factors were documented.","limitations":"A single case report cannot establish causation. The patient had multiple risk factors for aspergillosis. The marijuana was not tested for contaminants. No control comparison was possible."},{"rthcId":"RTHC-00035","title":"Effect of cannabinoids on spasticity and ataxia in multiple sclerosis.","authors":"Meinck, H M; Schönle, P W; Conrad, B","year":1989,"journal":"Journal of neurology, 236(2), 120-2","doi":null,"pmid":"2709054","tags":["medical-cannabis","pain"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 30-year-old man with chronic multiple sclerosis experienced acute improvement in his motor symptoms while smoking a marijuana cigarette. Recognizing the opportunity for objective measurement, researchers quantified the effect using three methods.\n\nClinical rating showed improvement in spasticity. Electromyographic (EMG) recordings of leg flexor reflexes confirmed reduced spastic reflexes. Electromagnetic recording of hand action tremor showed reduced ataxia (uncoordinated movement).\n\nThe researchers concluded that cannabinoids produced \"powerful beneficial effects\" on both spasticity and ataxia, two of the most disabling symptoms of MS, and called for further evaluation.","whyItMatters":"While anecdotal reports of cannabis helping MS symptoms were common, this case study was notable for its objective, quantitative documentation of improvement. The use of EMG and electromagnetic recordings moved beyond subjective reports to measurable physiological changes.","specificNumbers":"One patient, age 30. Single marijuana cigarette. Three objective measurement methods confirmed improvement in both spasticity and ataxia.","methodology":"Single-patient case study with quantitative assessment of motor function before and after smoking cannabis. Three measurement methods: clinical rating, EMG of leg flexor reflexes, and electromagnetic recording of hand action tremor.","limitations":"A single patient without placebo control. Acute effects of one session may not predict sustained benefit. The patient's expectation of improvement could influence clinical ratings, though the EMG and electromagnetic recordings are less susceptible to placebo effects."},{"rthcId":"RTHC-00036","title":"The importance of the orientation of the C9 substituent to cannabinoid activity.","authors":"Reggio, P H; Greer, K V; Cox, S M","year":1989,"journal":"Journal of medicinal chemistry, 32(7), 1630-5","doi":null,"pmid":"2738895","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used molecular mechanics calculations to study six cannabinoid compounds with varying levels of psychoactive potency: three active (delta-9-THC, delta-8-THC, and 11-beta-hexahydrocannabinol), one minimally active (11-alpha-HHC), and two inactive (delta-7-THC and delta-9,11-THC).\n\nAfter optimizing the three-dimensional structures and analyzing ring conformations, they found that all six molecules had nearly identical positions of the key hydroxyl group. The critical difference was in the conformation of the carbocyclic ring, which determined the orientation of the C9 substituent relative to that hydroxyl oxygen.\n\nActive cannabinoids shared a specific geometric relationship between the C9 substituent and the hydroxyl oxygen. When this relationship was disrupted by different ring conformations, the compound became inactive. This suggested that psychoactive potency depends on a precise molecular shape that enables binding to whatever receptor recognizes cannabinoids.","whyItMatters":"This study provided fundamental insight into the structure-activity relationship of cannabinoids before the cannabinoid receptors were even discovered (CB1 was identified in 1990). Understanding which molecular features produce psychoactivity is essential for designing therapeutic cannabinoids that separate medical benefits from psychoactive effects.","specificNumbers":"Six cannabinoid compounds analyzed. Three active, one minimally active, two inactive. Multiple torsion angles measured including C10-C10a-C1-O, C8-C7-C1-O, C11-C9-C1-O, and C9-Q-C1-O.","methodology":"Computational molecular mechanics study using the MMP2(85) program. Six cannabinoid structures were optimized and their conformations analyzed. Energy profiles for ring conformations and hydroxyl rotations were calculated.","limitations":"Computational modeling predicts molecular shapes but cannot confirm actual biological binding mechanisms. The study predated the discovery of cannabinoid receptors, so the target of interaction was unknown. Only six compounds were analyzed."},{"rthcId":"RTHC-00037","title":"Age-related suppression of murine lymphoid cell blastogenesis by marijuana components.","authors":"Pross, S H; Klein, T W; Newton, C; Smith, J; Widen, R; Friedman, H","year":1990,"journal":"Developmental and comparative immunology, 14(1), 131-7","doi":null,"pmid":"2159920","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers exposed mouse lymphoid cells to THC and its active metabolite 11-OH-THC, then measured how well those cells could proliferate in response to immune stimulation.\n\nAdult thymus cells were more readily suppressed than adult spleen cells. When comparing across ages, splenocytes from young mice were more susceptible to suppression than those from older mice.\n\nThe findings suggest that the immunosuppressive effects of cannabinoids are not uniform across the immune system. Age and tissue type both influence how strongly THC dampens immune cell activity, raising questions about whether developmental stage matters for cannabis-related immune effects.","whyItMatters":"This study provided early evidence that cannabinoid-induced immune suppression is not a blanket effect. The finding that younger immune cells were more vulnerable raised important questions about whether cannabis exposure during development might carry different immunological risks than exposure in adulthood.","specificNumbers":"Adult thymus cells showed greater suppression than adult spleen cells. Young mouse splenocytes were more readily suppressed than older mouse splenocytes. Both THC and 11-OH-THC produced suppressive effects.","methodology":"Researchers isolated lymphoid cells from the thymus and spleen of mice at different ages. These cells were cultured with THC or 11-OH-THC at various concentrations, then stimulated with mitogens to trigger proliferation. Blastogenesis (cell division response) was measured to quantify suppression.","limitations":"This was an animal study using isolated cells in culture, which does not replicate the complexity of a living immune system. Mouse immune responses differ from human immune responses. The concentrations of THC used may not reflect physiologically relevant levels from normal cannabis use."},{"rthcId":"RTHC-00038","title":"In vivo metabolism of the ethyl homologues of delta-8-tetrahydrocannabinol and delta-9-tetrahydrocannabinol in the mouse.","authors":"Brown, N K; Harvey, D J","year":1991,"journal":"Biological mass spectrometry, 20(5), 324-8","doi":null,"pmid":"1653028","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers synthesized two THC variants with ethyl side chains (ethyl-delta-8-THC and ethyl-delta-9-THC) and administered them to mice to study how the liver processes these modified cannabinoids.\n\nSix metabolites were identified from ethyl-delta-8-THC. The metabolism pattern was similar to natural THC and higher homologues, with one metabolite, ethyl-delta-8-THC-11-oic acid, accounting for approximately 95% of the total metabolic fraction. No side-chain hydroxylated metabolites were detected.\n\nFive metabolites were identified from ethyl-delta-9-THC. Its metabolism was also similar to higher homologues, but with less metabolism at the C-8 position and a higher percentage of the 11-oic acid metabolite. Minor metabolites included dihydroxylated compounds and hydroxylated derivatives.","whyItMatters":"Understanding how the body processes different cannabinoid structures is essential for predicting the behavior of both natural and synthetic cannabinoids. The finding that modified THC variants follow similar metabolic pathways to natural THC helps predict drug interactions and detection windows.","specificNumbers":"Six metabolites from ethyl-delta-8-THC. Five metabolites from ethyl-delta-9-THC. The 11-oic acid metabolite accounted for approximately 95% of ethyl-delta-8-THC metabolism.","methodology":"Animal pharmacokinetics study in male Charles River CD-1 mice. Synthetic cannabinoids were administered and liver metabolites were extracted, isolated by chromatography, and identified by gas chromatography/mass spectrometry using multiple derivative techniques.","limitations":"Mouse metabolism may differ from human metabolism. Only two synthetic variants were tested. The study focused on liver metabolites and did not assess brain or other tissue distribution."},{"rthcId":"RTHC-00039","title":"Controlled clinical trial of cannabidiol in Huntington's disease.","authors":"Consroe, P; Laguna, J; Allender, J; Snider, S; Stern, L; Sandyk, R; Kennedy, K; Schram, K","year":1991,"journal":"Pharmacology, biochemistry, and behavior, 40(3), 701-8","doi":null,"pmid":"1839644","tags":["cbd","medical-cannabis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Based on encouraging preliminary findings, researchers conducted a rigorous controlled trial of CBD in 15 Huntington's Disease patients who were not taking neuroleptic medications.\n\nPatients received either oral CBD (10 mg/kg/day, averaging about 700 mg/day) or placebo (sesame oil) for six weeks each in a double-blind, randomized crossover design. The primary outcome was chorea severity, the involuntary jerking movements characteristic of HD.\n\nCBD produced no significant differences from placebo on chorea severity or any other therapeutic outcome measure. It was also not toxic: clinical lab tests, a cannabis side effect inventory, and other safety measures showed no significant differences from placebo.\n\nPlasma CBD levels were consistent across the six weeks (mean range 5.9 to 11.2 ng/mL), confirming patients were absorbing the drug. The conclusion was straightforward: at this dose and duration, CBD was neither helpful nor harmful for HD.","whyItMatters":"This was one of the first rigorous controlled trials of CBD for a neurodegenerative disease. While the negative result was disappointing, it was scientifically important: it demonstrated that CBD does not universally benefit all neurological conditions and established a safety profile at high doses.","specificNumbers":"15 patients. CBD dose: 10 mg/kg/day (approximately 700 mg/day). Duration: 6 weeks per phase. Plasma CBD: 5.9 to 11.2 ng/mL. No significant differences on any outcome (P > 0.05).","methodology":"Double-blind, randomized crossover trial in 15 neuroleptic-free Huntington's Disease patients. CBD (10 mg/kg/day) and placebo (sesame oil) were each administered for 6 weeks. Weekly assessments included chorea severity, therapeutic outcomes, side effects, clinical lab tests, and plasma CBD levels by GC/MS.","limitations":"Fifteen patients is a small sample. Six weeks may be too short to detect slowly developing benefits. The crossover design assumes no carryover effects. Plasma CBD levels were relatively low despite high oral doses, suggesting poor bioavailability."},{"rthcId":"RTHC-00040","title":"Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans.","authors":"Consroe, P; Kennedy, K; Schram, K","year":1991,"journal":"Pharmacology, biochemistry, and behavior, 40(3), 517-22","doi":null,"pmid":"1666917","tags":["cbd","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers developed and validated a method to measure CBD in blood plasma, then used it to track CBD levels in 14 Huntington's Disease patients receiving high-dose oral CBD (10 mg/kg/day, approximately 700 mg/day) for six weeks.\n\nDespite the high oral dose, mean plasma CBD levels ranged from only 5.9 to 11.2 ng/mL across the six weeks. This represented poor oral bioavailability, meaning most of the ingested CBD was not reaching the bloodstream.\n\nOne week after stopping CBD, plasma levels averaged 1.5 ng/mL and were virtually undetectable thereafter. The elimination half-life was estimated at 2 to 5 days. There were no gender differences in either CBD levels or elimination half-life.\n\nImportantly, no delta-1-THC (the major psychoactive cannabinoid) was detected in any patient's blood, confirming CBD did not convert to THC in the human body at this dose.","whyItMatters":"This study revealed a critical pharmacological challenge for oral CBD: very low bioavailability. Patients taking 700 mg/day achieved plasma levels well below concentrations shown to be active in laboratory studies. This has major implications for CBD dosing and product formulation.","specificNumbers":"Fourteen patients. CBD dose: 10 mg/kg/day (approximately 700 mg/day). Plasma levels: 5.9-11.2 ng/mL over 6 weeks. One week post-cessation: 1.5 ng/mL. Elimination half-life: 2-5 days. Assay sensitivity: 500 pg/mL. No gender differences.","methodology":"Pharmacokinetic study within a double-blind crossover trial. Plasma CBD levels were measured weekly using trimethylsilyl derivatization, capillary gas chromatography, and ion trap mass spectrometry in positive ion chemical ionization mode. Assay sensitivity: approximately 500 pg/mL. Precision: approximately 10-15%.","limitations":"Fourteen patients is a small pharmacokinetic sample. Patients had Huntington's Disease, which could affect drug metabolism. Only oral CBD was tested; other routes of administration would produce different pharmacokinetic profiles."},{"rthcId":"RTHC-00041","title":"Marijuana as antiemetic medicine: a survey of oncologists' experiences and attitudes.","authors":"Doblin, R E; Kleiman, M A","year":1991,"journal":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 9(7), 1314-9","doi":null,"pmid":"2045870","tags":["medical-cannabis","cancer"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In 1990, researchers surveyed a random sample of 2,430 members of the American Society of Clinical Oncology about their experiences and attitudes toward medical marijuana. The 43% response rate yielded 1,035 completed surveys.\n\nThe results revealed a striking gap between medical practice and drug policy. More than 44% of responding oncologists reported having recommended illegal marijuana use to at least one chemotherapy patient for nausea control. Nearly half (48%) said they would prescribe marijuana if it were legal.\n\nOncologists who expressed an opinion rated smoked marijuana as somewhat more effective than the legally available oral dronabinol (Marinol) and roughly as safe. A majority (54%) believed marijuana should be available by prescription.\n\nThe researchers noted that oncologists' experience with medical marijuana was more extensive, and their opinions more favorable, than regulatory authorities appeared to have believed.","whyItMatters":"This survey provided the first large-scale evidence that practicing cancer doctors were already widely recommending an illegal drug to their patients, revealing a disconnect between drug policy and clinical reality that would fuel the medical marijuana movement throughout the 1990s.","specificNumbers":"2,430 surveys mailed. 1,035 responses (43% rate). 44% had recommended marijuana to patients. 48% would prescribe if legal. 54% favored prescription availability. Smoked marijuana rated more effective than oral dronabinol.","methodology":"Random-sample anonymous survey mailed to approximately one-third of U.S.-based American Society of Clinical Oncology members (N=2,430). Response rate: 43% (1,035 responses). Measured attitudes, experiences, and opinions regarding antiemetic use of marijuana.","limitations":"The 43% response rate means non-respondents may have held different views. Anonymous surveys may elicit more candid responses about illegal recommendations but cannot be verified. Oncologists' subjective comparisons of smoked marijuana versus dronabinol may reflect bias rather than controlled observation."},{"rthcId":"RTHC-00042","title":"Influence of chronic oral intake of cannabis extract on oxidative and hydrolytic metabolism of xenobiotics in rat.","authors":"Khanna, P; Gupta, M B; Gupta, G P; Sanwal, G G; Ali, B","year":1991,"journal":"Biochemical pharmacology, 41(1), 109-13","doi":null,"pmid":"1986734","tags":["drug-interactions","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats fed cannabis extract for three weeks at escalating doses showed selective changes in liver enzyme activity. Several enzymes that break down drugs and chemicals (carboxylesterases and amidases) were significantly boosted, with increases ranging from 60% to 125%.\n\nThe most concerning finding involved aromatic hydrocarbon hydroxylase (AHH), which processes benzo(a)pyrene, a carcinogenic compound found in smoke. This enzyme was induced approximately three-fold. Since AHH activation of benzo(a)pyrene is a step in its cancer-causing pathway, increased AHH activity could theoretically increase cancer risk from smoke exposure.\n\nMost enzyme changes reversed within seven days of stopping cannabis. However, one cytosolic enzyme (thiacetazone N-deacetylase) remained substantially elevated even after withdrawal, suggesting some metabolic changes persist longer.","whyItMatters":"This study demonstrated that chronic cannabis use could alter how the liver processes other substances, which has implications for drug interactions. The induction of AHH, which activates carcinogens, is particularly relevant to understanding cancer risk in cannabis smokers.","specificNumbers":"Acetanilide N-deacetylase: +125%. NPA esterase: +64%. ASA esterase I: +82%. ASA esterase II: +60%. AHH: approximately 3-fold increase. Most effects reversed within 7 days of stopping. Thiacetazone N-deacetylase remained elevated at 62% after withdrawal.","methodology":"Animal pharmacology study in rats. Petroleum ether extract of cannabis leaves was administered orally at escalating doses (158, 250, and 500 mg/kg over three weeks). Liver and kidney enzyme activities were measured during treatment and after withdrawal.","limitations":"Rat metabolism may differ from human metabolism. The cannabis extract used is not equivalent to modern cannabis products. Doses were high and escalating. The relevance of in vitro enzyme activity changes to actual in vivo drug metabolism is uncertain."},{"rthcId":"RTHC-00043","title":"Neurotoxicology of cannabis and THC: a review of chronic exposure studies in animals.","authors":"Scallet, A C","year":1991,"journal":"Pharmacology, biochemistry, and behavior, 40(3), 671-6","doi":null,"pmid":"1666926","tags":["neuroscience","cognition","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Multiple laboratories had reported that chronic exposure to THC or marijuana extracts produced persistent changes in the rat hippocampus, a brain region critical for learning and memory.\n\nThe review identified two critical factors determining whether neurotoxic effects appeared: age during exposure and duration of exposure. At least three months of cannabinoid administration (representing 8-10% of a rat's lifespan) was needed to produce neurotoxic effects in young rats. Scaled to humans, this would correspond to roughly seven to ten years of exposure.\n\nStudies in monkeys were less conclusive. Up to 12 months of daily THC exposure had not consistently produced neurotoxicity in primates, and longer exposures had not been studied. The review emphasized that experimental design choices, including dose, route, duration, age at onset, species, withdrawal period, and choice of outcome measures, critically affected results.","whyItMatters":"This review provided important context for interpreting claims about cannabis and brain damage. By showing that neurotoxicity required prolonged exposure during a specific developmental period, it suggested that occasional or short-term use was unlikely to produce the structural brain changes observed in chronic animal studies.","specificNumbers":"Three months minimum exposure needed in rats (8-10% of lifespan). Human equivalent: approximately 7-10 years. Monkey studies: up to 12 months daily exposure without consistent neurotoxicity.","methodology":"Literature review of chronic cannabis exposure studies in animals, examining neurotoxicity endpoints across different species, doses, durations, and ages of exposure.","limitations":"Animal models have inherent limitations for predicting human neurotoxicity. Dose scaling between species is imprecise. The review predated the discovery of cannabinoid receptors in the hippocampus, so mechanisms were speculative."},{"rthcId":"RTHC-00044","title":"Effects of long-term cannabis use on selective attention: an event-related potential study.","authors":"Solowij, N; Michie, P T; Fox, A M","year":1991,"journal":"Pharmacology, biochemistry, and behavior, 40(3), 683-8","doi":null,"pmid":"1806953","tags":["cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers recorded brain event-related potentials (ERPs) from nine long-term cannabis users and nine non-user controls during a complex listening task. Participants heard a random sequence of tones varying in location, pitch, and duration, and had to respond only to specific target tones.\n\nCannabis users performed significantly worse on the task overall. But the brain recordings revealed something more specific about why. Users showed greatly enhanced early processing of non-target stimuli that partially matched the target, engaging in unnecessary pitch processing of tones that only matched on location.\n\nThis pattern indicated that cannabis users had difficulty setting up an accurate attentional filter. Rather than efficiently screening out irrelevant information early in processing, their brains were allocating resources to evaluating stimuli that should have been dismissed. The data pointed to a dysfunction in how attentional resources are allocated and how stimulus evaluation strategies are organized.","whyItMatters":"This was one of the first studies to use brain recordings to identify a specific mechanism behind cannabis-related cognitive impairment. Rather than simply showing \"worse performance,\" it demonstrated that cannabis users' brains were processing information differently, allocating attention to irrelevant details.","specificNumbers":"Nine cannabis users vs. nine controls. Three stimulus dimensions (location, pitch, duration). Cannabis users showed significantly worse task performance and enhanced early processing negativity to partially matching non-targets.","methodology":"Cross-sectional comparison using event-related potentials (ERPs). Nine long-term cannabis users and nine non-user controls performed a complex auditory selective attention task while brain electrical activity was recorded. Stimuli varied on three dimensions: location, pitch, and duration.","limitations":"Very small sample (9 per group). Cross-sectional design cannot determine whether cannabis caused the attentional differences or whether people with pre-existing attentional differences were drawn to cannabis use. No information on recency of last use or current intoxication status."},{"rthcId":"RTHC-00045","title":"Neurobiology of marijuana abuse.","authors":"Abood, M E; Martin, B R","year":1992,"journal":"Trends in pharmacological sciences, 13(5), 201-6","doi":null,"pmid":"1604713","tags":["neuroscience","addiction","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review highlighted a puzzling disconnect in cannabis research. Marijuana was one of the most widely used psychoactive substances, yet the standard laboratory measures of addiction potential painted an unusual picture.\n\nAnimals would not reliably self-administer THC, a behavior seen with most other drugs of abuse. Evidence that marijuana stimulated brain reward pathways (the dopamine circuits implicated in addiction) was minimal. While marked tolerance developed to marijuana's effects, demonstrating physical dependence had been difficult.\n\nThe review noted that until recently, the mechanisms by which cannabinoids produced their behavioral effects were poorly understood. The development of new synthetic cannabinoid analogs had enabled the characterization and cloning of the cannabinoid receptor, opening the door to understanding how marijuana actually works in the brain.","whyItMatters":"This review captured a turning point in cannabis neuroscience. The disconnect between widespread human use and the failure to demonstrate traditional addiction markers in animals suggested cannabis operated through different mechanisms than classical drugs of abuse, a hypothesis that the cannabinoid receptor discovery was beginning to illuminate.","specificNumbers":"No specific numeric data in the abstract beyond noting marijuana's \"long history of abuse.\"","methodology":"Narrative review of animal behavioral pharmacology studies, self-administration paradigms, brain reward pathway research, and the emerging cannabinoid receptor literature.","limitations":"Published at the very beginning of the cannabinoid receptor era. Many of the puzzles identified were later resolved by endocannabinoid system research. The review's characterization of limited reward pathway stimulation was later revised by more sensitive experimental techniques."},{"rthcId":"RTHC-00046","title":"Isolation and structure of a brain constituent that binds to the cannabinoid receptor","authors":"Devane, William A.; Hanus, Lumir; Breuer, Aviva; Pertwee, Roger G.; Stevenson, Lesley A.; Griffin, Graeme; Gibson, Dale; Mandelbaum, Arnon; Etinger, Alexander; Mechoulam, Raphael","year":1992,"journal":"Science, 258(5090), 1946-1949","doi":"10.1126/science.1470919","pmid":"1470919","tags":["neuroscience","foundational","endocannabinoid-system"],"studyType":"animal-study","evidenceStrength":"strong","keyFinding":"Arachidonylethanolamide (anandamide), an arachidonic acid derivative, was isolated from porcine brain tissue by screening lipid extracts for compounds that bind the cannabinoid receptor. Its structure was determined by mass spectrometry and NMR spectroscopy, confirmed by chemical synthesis. Functionally, anandamide competitively displaced a radiolabeled cannabinoid probe from synaptosomal membranes and produced concentration-dependent inhibition of the electrically evoked twitch response in mouse vas deferens — a classic cannabinoid bioassay. These results identified anandamide as the first known endogenous ligand for the cannabinoid receptor.","whyItMatters":"This paper answered one of the most important questions in neuropharmacology: why does the brain have receptors for a plant molecule? The answer — because the brain makes its own cannabinoid — established the existence of the endocannabinoid system, now recognized as one of the most important regulatory systems in human physiology. It governs mood, pain, appetite, memory, immune function, and dozens of other processes. Every subsequent discovery in endocannabinoid research traces back to this paper.","specificNumbers":"- 1992: first report of an endogenous cannabinoid receptor ligand isolated from mammalian brain\n- Source tissue: porcine brain synaptosomal membranes used for receptor binding assays\n- Functional assay: concentration-dependent inhibition of mouse vas deferens twitch, a hallmark cannabinoid effect\n- Binding mode: competitive displacement of a radiolabeled cannabinoid probe from receptor sites","methodology":"Lipid extracts from porcine (pig) brain tissue were screened for compounds that bind the cannabinoid receptor using a radiolabeled probe displacement assay. A compound that competitively bound the receptor was isolated and its structure was determined using mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. The proposed structure was confirmed by synthesizing the compound from scratch and showing the synthetic version had identical properties. Biological activity was validated using the mouse vas deferens preparation, a standard cannabinoid bioassay where cannabinoid receptor agonists inhibit electrically stimulated muscle contractions in a concentration-dependent manner.","limitations":"This was an animal study using pig brain tissue, not human tissue. The paper demonstrated receptor binding and one functional bioassay (vas deferens) but did not characterize anandamide's effects in living animals or determine its physiological role. No potency values, receptor subtype selectivity data, or in vivo outcomes were reported. The initial characterization as a cannabinoid receptor ligand was correct but incomplete — anandamide was later found to also bind TRPV1 vanilloid receptors and PPARα/γ nuclear receptors."},{"rthcId":"RTHC-00047","title":"The age of alcohol onset and alcohol, cigarette, and marijuana use patterns: an analysis of drug use progression of young adults in New York State.","authors":"Yu, J; Williford, W R","year":1992,"journal":"The International journal of the addictions, 27(11), 1313-23","doi":null,"pmid":"1446964","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined the \"gateway theory\" by analyzing substance use patterns among 16- to 24-year-olds in New York State. Using statistical modeling, they traced how the age of first alcohol use related to subsequent use of cigarettes and marijuana.\n\nAlcohol use increased the probability of using both cigarettes and marijuana. The combined use of alcohol and cigarettes further increased the likelihood of marijuana use, suggesting a sequential pattern.\n\nThe timing of alcohol onset was critical. Early initiation of alcohol use during a proposed critical period between ages 13 and 16 had the strongest impact on current use of both alcohol and other substances. Starting to drink before or after this window had less influence on subsequent drug use patterns.","whyItMatters":"This study extended the gateway hypothesis beyond simple sequencing to identify a specific developmental window when substance initiation has maximum impact. The finding that ages 13-16 represented a critical period for alcohol's influence on later drug use suggested vulnerability during early-to-mid adolescence.","specificNumbers":"Age range studied: 16-24 years. Critical age period for alcohol onset: 13-16 years. Three substances tracked: alcohol, cigarettes, marijuana.","methodology":"Cross-sectional survey analysis of young adults aged 16-24 in New York State. Logit analysis was used to estimate the impact of alcohol onset age on subsequent drug use progression across alcohol, cigarettes, and marijuana.","limitations":"Cross-sectional data cannot establish causation. The gateway pattern could reflect shared risk factors (genetics, environment, personality) rather than a causal progression. Data relied on self-reported substance use. The study did not account for substance availability or peer influences."},{"rthcId":"RTHC-00048","title":"Characterization of a region of steric interference at the cannabinoid receptor using the active analog approach.","authors":"Reggio, P H; Panu, A M; Miles, S","year":1993,"journal":"Journal of medicinal chemistry, 36(12), 1761-71","doi":null,"pmid":"8510104","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Building on their earlier work on cannabinoid structure-activity relationships, researchers used the \"active analog approach\" to model a previously unknown feature of the cannabinoid receptor.\n\nBy comparing the three-dimensional shapes of four active cannabinoids with two inactive ones, they identified a region of \"steric interference\" near the receptor, essentially a physical space where extra molecular bulk prevents a compound from binding. They termed this the \"receptor essential volume\" (REV).\n\nThe REV was located near the top of the carbocyclic ring on the bottom face of the cannabinoid molecule. Active compounds had conformations that cleared this zone; inactive compounds could not avoid it.\n\nThe model was validated by testing it against additional cannabinoids: a minimally active classical cannabinoid, an active benzofuran cannabinoid, and the nonclassical cannabinoid CP-47,497. In each case, the compound's activity could be explained by whether its accessible conformations could clear the REV.","whyItMatters":"This study provided a molecular-level explanation for why some cannabinoid compounds are active and others are not, knowledge essential for designing new therapeutic cannabinoids with specific properties.","specificNumbers":"Four active cannabinoids, two inactive cannabinoids used to define the model. Three additional compounds used for validation. The REV was mapped in three-dimensional space near the carbocyclic ring.","methodology":"Computational molecular mechanics study using MMP2(85) for structure optimization and Chem-X MAP facility for calculating the receptor essential volume. Four active and two inactive cannabinoids were used to define the model, with three additional compounds used for validation.","limitations":"Computational modeling predicts but does not directly observe receptor interactions. The cannabinoid receptor structure was not yet experimentally determined at this time. Only a small set of compounds was used to define and test the model."},{"rthcId":"RTHC-00049","title":"Prospective study of factors predicting outcome of transdermal nicotine treatment in smoking cessation.","authors":"Gourlay, S G; Forbes, A; Marriner, T; Pethica, D; McNeil, J J","year":1994,"journal":"BMJ (Clinical research ed.), 309(6958), 842-6","doi":null,"pmid":"7950614","tags":["quitting","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 1,481 heavy smokers (averaging 32 cigarettes per day) through a 26-week smoking cessation program using transdermal nicotine patches and brief behavioral counseling.\n\nOverall, 21.3% successfully quit. Several factors predicted success: being male, age 40 or older, living with a partner, high motivation, and concern about weight gain. But marijuana use emerged as one of the most powerful negative predictors.\n\nSmokers who also used marijuana had an adjusted odds ratio of 0.4 for quitting, meaning they were roughly half as likely to succeed compared to non-marijuana users. Having other smokers in the household also reduced success (odds ratio 0.8).\n\nAnother striking finding: 96% of participants who smoked three or more cigarettes in the first four weeks of treatment eventually relapsed to regular smoking, making early lapse the strongest predictor of long-term failure.","whyItMatters":"This is one of the few large studies to identify marijuana use as a specific barrier to tobacco cessation. For the millions of people who use both substances, this finding suggests that addressing cannabis use may be important for successful tobacco quitting.","specificNumbers":"1,481 subjects. Mean 32 cigarettes/day. 21.3% quit rate at 26 weeks. Marijuana use odds ratio: 0.4 (half the chance of quitting). 96% of those smoking 3+ cigarettes in the first 4 weeks relapsed.","methodology":"Prospective cohort study of 1,481 subjects recruited by media who smoked 15+ cigarettes per day. Twelve weeks of transdermal nicotine with monthly behavioral counseling. Outcome: sustained cessation for 28 days before week-26 visit, verified by expired carbon monoxide. Logistic regression identified predictors.","limitations":"Marijuana use was self-reported and not the primary study outcome. The study did not control for the type, frequency, or quantity of marijuana use. It cannot determine whether marijuana use causally impeded quitting or was a marker for other factors (impulsivity, higher addiction severity) that predicted failure."},{"rthcId":"RTHC-00050","title":"Marijuana as an antiemetic drug: how useful is it today? Opinions from clinical oncologists.","authors":"Schwartz, R H; Beveridge, R A","year":1994,"journal":"Journal of addictive diseases, 13(1), 53-65","doi":null,"pmid":"7503819","tags":["medical-cannabis","cancer"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed two groups of practicing oncologists about their antiemetic preferences, receiving completed surveys from 141 physicians (78% response rate). The results revealed a notably cooled enthusiasm compared to earlier surveys.\n\nMarijuana (in any form) ranked ninth for mild-to-moderate nausea and sixth for severe chemotherapy-induced symptoms. Most oncologists (65%) had prescribed marijuana or oral THC ten times or fewer in their careers. Only 3.5% had prescribed it more than 100 times.\n\nOncologists who had prescribed marijuana estimated it effectively relieved nausea in about 50% of patients, with unpleasant side effects in about 25%. Only 6% said they would prescribe it \"much more frequently\" if legal barriers were removed.\n\nThis was a marked shift from an earlier survey where 44% of oncologists had recommended illegal marijuana. By 1994, with better antiemetics emerging, cannabis had moved down the preference list.","whyItMatters":"This survey showed that as better antiemetics became available, oncologists' interest in marijuana declined substantially. It provided evidence that cannabis was useful but not uniquely effective, a finding relevant to medical marijuana policy debates.","specificNumbers":"141 respondents (78% response rate). Marijuana ranked 9th for mild nausea, 6th for severe. 65% prescribed it 10 times or fewer. 3.5% prescribed it 100+ times. Estimated 50% efficacy, 25% adverse effects. Only 6% would prescribe more if legal.","methodology":"Mailed questionnaire survey to two groups: a systematic sample from ASCO membership (N=120) and all adult oncologists in metropolitan Washington, D.C. (N=60). 78% response rate (141 respondents). Conducted before ondansetron approval.","limitations":"Conducted just before ondansetron approval, so respondents had limited experience with the newer antiemetics. Response rates, while good, may still introduce selection bias. Oncologists' estimates of efficacy and side effects are subjective."},{"rthcId":"RTHC-00051","title":"Testing the abstinence violation effect construct with marijuana cessation.","authors":"Stephens, R S; Curtin, L; Simpson, E E; Roffman, R A","year":1994,"journal":"Addictive behaviors, 19(1), 23-32","doi":null,"pmid":"8197890","tags":["addiction","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tested the Abstinence Violation Effect (AVE) theory with marijuana users. The AVE proposes that how someone interprets their first lapse after attempting to quit determines whether they return to regular use.\n\nSeventy-five adults who completed either relapse prevention or social support treatment for marijuana dependence subsequently lapsed. The study examined how their attributions for the lapse related to outcomes.\n\nThose who attributed the lapse to internal causes (their own fault), stable causes (permanent factors), and global causes (affecting all areas of life) were significantly more likely to report concurrent relapse. Perceived loss of control during the lapse also predicted relapse.\n\nFurther, internal and global attributions predicted marijuana use over the subsequent six months, suggesting these thinking patterns had lasting effects on behavior. Notably, the relapse prevention treatment, which was designed to modify these attributions, did not successfully change how participants reacted to their lapses.","whyItMatters":"This study demonstrated that cognitive patterns around relapse, specifically how people explain their slip-ups, play a meaningful role in marijuana cessation outcomes. The finding that relapse prevention treatment failed to modify these patterns identified a gap in existing treatment approaches.","specificNumbers":"75 adults who lapsed. Two treatment conditions: relapse prevention and social support. Three attribution dimensions measured: internal, stable, global. Follow-up: 6 months post-lapse.","methodology":"Prospective analysis within a treatment trial. Seventy-five adults who lapsed after completing either relapse prevention or social support group treatment for marijuana cessation. Attributions, guilt, and perceived control were assessed at the time of lapse. Marijuana use was tracked for six months following the lapse.","limitations":"Relatively small sample. The assessment of attributions at the time of lapse may have been influenced by current use status. The study cannot determine whether attributions caused relapse or whether imminent relapse shaped how people explained their lapse."},{"rthcId":"RTHC-00052","title":"An efficient new cannabinoid antiemetic in pediatric oncology.","authors":"Abrahamov, A; Abrahamov, A; Mechoulam, R","year":1995,"journal":"Life sciences, 56(23-24), 2097-102","doi":null,"pmid":"7776837","tags":["medical-cannabis","cancer","youth"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Researchers administered delta-8-THC, a cannabinoid with lower psychoactive potency than the more familiar delta-9-THC, to eight children with hematologic cancers. The children ranged from 3 to 13 years old and were receiving various chemotherapy drugs.\n\nDelta-8-THC was given orally in edible oil at a dose of 18 mg/m2 body surface area, starting two hours before each chemotherapy session and continuing every six hours for 24 hours. Some children received treatment for up to eight months.\n\nThe results were striking: vomiting was completely prevented across all 480 total treatments. The side effects observed were described as negligible. The researchers highlighted delta-8-THC as an efficient cannabinoid antiemetic for pediatric oncology, noting its advantage of lower psychoactive potency compared to delta-9-THC.","whyItMatters":"This study demonstrated 100% efficacy against chemotherapy-induced vomiting in children with minimal side effects, a remarkable result that was particularly notable because it used delta-8-THC, a less psychoactive cannabinoid that could potentially offer antiemetic benefits without the psychoactive burden of delta-9-THC.","specificNumbers":"Eight children aged 3-13. Dose: 18 mg/m2 in edible oil. 480 total treatments. Up to 8 months of treatment. 100% vomiting prevention. Negligible side effects.","methodology":"Open-label pilot study with eight pediatric patients aged 3-13 with various hematologic cancers. Delta-8-THC (18 mg/m2) given orally in edible oil starting 2 hours before chemotherapy and continuing every 6 hours for 24 hours. Treatment duration: up to 8 months.","limitations":"Open-label design without placebo control. Only eight patients. The \"negligible\" side effects were not described in detail. The study was conducted by researchers who included the scientist who first identified THC (Mechoulam), which adds credibility but also potential bias."},{"rthcId":"RTHC-00053","title":"The relationship of tobacco and marijuana smoking characteristics.","authors":"Simmons, M S; Tashkin, D P","year":1995,"journal":"Life sciences, 56(23-24), 2185-91","doi":null,"pmid":"7776848","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers analyzed smoking patterns in 467 people who regularly used tobacco, marijuana, or both. The goal was to understand how concurrent use of both substances related to tobacco consumption patterns.\n\nPeople who smoked both tobacco and marijuana tended to have lower cumulative tobacco exposure, measured in pack-years. They also reported smoking fewer cigarettes per day compared to those who only smoked tobacco.\n\nAcross the sample, smoking habits either decreased or remained stable over the observation period, suggesting that adding marijuana to a tobacco habit did not accelerate cigarette consumption.","whyItMatters":"Understanding how tobacco and marijuana smoking habits interact is relevant for public health, particularly as marijuana legalization expands. If marijuana use is associated with lower tobacco consumption, that complicates simple assumptions about dual use being universally more harmful to the lungs.","specificNumbers":"467 regular tobacco and marijuana users were analyzed. Dual users had fewer pack-years and fewer cigarettes per day than tobacco-only smokers. Smoking habits decreased or remained stable over time.","methodology":"This cross-sectional study surveyed 467 regular tobacco and marijuana smokers, collecting data on daily cigarette counts, pack-years of tobacco exposure, and patterns of concurrent use. Researchers compared smoking characteristics between dual users and tobacco-only smokers.","limitations":"As a cross-sectional study, this cannot determine whether marijuana use caused people to smoke fewer cigarettes or whether lighter tobacco smokers were simply more likely to also use marijuana. Self-reported smoking data is subject to recall bias. The study predates modern vaping and high-potency cannabis products."},{"rthcId":"RTHC-00054","title":"Differential impairments of selective attention due to frequency and duration of cannabis use.","authors":"Solowij, N; Michie, P T; Fox, A M","year":1995,"journal":"Biological psychiatry, 37(10), 731-9","doi":null,"pmid":"7640328","tags":["cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Building on their earlier ERP work, researchers studied long-term cannabis users while sober and identified two dissociable cognitive deficits that were affected by different patterns of use.\n\nThe ability to focus attention and filter out irrelevant information, measured by frontal brain processing negativity, worsened progressively with the number of years of cannabis use but was unrelated to how often someone used. This suggested a cumulative, long-term effect that builds over time.\n\nInformation processing speed, measured by the latency of the parietal P300 brain wave, was delayed with increasing frequency of use but was unaffected by total duration. This suggested a more acute, dose-related effect.\n\nThe researchers interpreted these findings as evidence that cannabinoids produce both short-term impairments (related to how much is in the system) and long-term impairments (related to cumulative exposure), through different mechanisms.","whyItMatters":"This was one of the first studies to separate different dimensions of cannabis use (duration vs. frequency) and link them to distinct cognitive deficits. This nuance is important because it suggests that reducing frequency might improve processing speed while not addressing the cumulative attentional filtering deficit.","specificNumbers":"Two distinct ERP measures affected: frontal processing negativity worsened with years of use; P300 latency increased with frequency of use. Users were tested while sober.","methodology":"Cross-sectional ERP study of long-term cannabis users in the unintoxicated state. Two ERP measures of distinct attentional components were analyzed: frontal processing negativity (attentional filtering) and parietal P300 latency (processing speed). Both were correlated with years and frequency of use.","limitations":"Cross-sectional design cannot establish causation. Pre-existing cognitive differences might predispose both to longer cannabis use and poorer attentional filtering. Sample size was not specified in the abstract. Users were sober but \"sober\" timing was not detailed."},{"rthcId":"RTHC-00055","title":"Self-efficacy and marijuana cessation: a construct validity analysis.","authors":"Stephens, R S; Wertz, J S; Roffman, R A","year":1995,"journal":"Journal of consulting and clinical psychology, 63(6), 1022-31","doi":null,"pmid":"8543705","tags":["quitting","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers examined self-efficacy, the confidence in one's ability to avoid marijuana use, in 212 adults seeking marijuana cessation treatment.\n\nSelf-efficacy measured after treatment completion was more meaningfully connected to theoretically predicted sources (mastery experiences, social modeling, emotional states) than pre-treatment efficacy, suggesting the treatment experience itself shaped these beliefs.\n\nCognitive-behavioral relapse prevention treatment produced marginally greater self-efficacy than a non-behavioral social support treatment, but the link between specific coping skill training and efficacy was ambiguous.\n\nThe most nuanced finding: self-efficacy predicted frequency of post-treatment marijuana use better than it predicted complete abstinence. In other words, people's confidence in their ability to avoid marijuana was related to how often they used, but was less useful for predicting the binary outcome of whether they quit entirely.","whyItMatters":"This study refined understanding of how psychological constructs predict cannabis cessation. The finding that self-efficacy predicted frequency of use better than abstinence suggests that treatment success may be better measured by reduction in use rather than all-or-nothing quitting.","specificNumbers":"212 total participants (161 men, 51 women). Two treatment conditions: relapse prevention vs. social support. Self-efficacy predicted frequency of use better than abstinence status.","methodology":"Construct validity analysis with 161 men and 51 women seeking marijuana cessation treatment. Self-efficacy was measured before and after treatment. Relationships were examined between efficacy, theoretically proposed sources of efficacy judgments, treatment type, and post-treatment marijuana use outcomes.","limitations":"Self-efficacy was self-reported and may reflect optimism rather than actual capability. The relapse prevention treatment produced only marginally greater self-efficacy. The study could not determine whether self-efficacy caused reduced use or whether reduced use boosted self-efficacy."},{"rthcId":"RTHC-00056","title":"A survey of adolescent smoking patterns.","authors":"Dappen, A; Schwartz, R H; O'Donnell, R","year":1996,"journal":"The Journal of the American Board of Family Practice, 9(1), 7-13","doi":null,"pmid":"8770804","tags":["youth","addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 154 students aged 14 to 20 at two vocational high schools about their smoking habits, with objective laboratory verification.\n\nSixty-five percent of the sample smoked at least 10 cigarettes daily and had begun by age 13. They easily purchased tobacco over-the-counter. The strongest predictors of smoking were having a close friend, parent, or sibling who smoked.\n\nSmokers had significantly poorer academic performance and higher rates of alcohol and marijuana use compared to non-smokers. Despite knowing the health risks (awareness exceeded 95%), 70% of smokers were unconcerned. More than half had tried to quit multiple times and failed, with rapid relapse common. However, one-third remained motivated to try quitting.\n\nExhaled carbon monoxide proved more immediate, sensitive, and cost-effective than salivary cotinine for detecting smokers.","whyItMatters":"This study documented the clustering of substance use in adolescents, with tobacco, alcohol, and marijuana use co-occurring alongside academic problems. The finding that most adolescent smokers had tried and failed to quit by their mid-teens underscores how quickly dependence develops.","specificNumbers":"154 students surveyed. 65% smoked 10+ cigarettes/day. Most started by age 13. Health knowledge exceeded 95%. 70% were unconcerned about health risks. More than 50% had tried to quit and failed. 33% remained motivated to quit.","methodology":"Cross-sectional survey of 154 vocational school students aged 14-20. A 23-item questionnaire for all students; smokers (N=99) completed an additional 55-item questionnaire on patterns, addiction criteria, health concerns, and quitting experiences. Exhaled CO and salivary cotinine were measured.","limitations":"Vocational school students may not represent all adolescents. The sample was relatively small. Cross-sectional data cannot determine whether smoking led to marijuana/alcohol use or vice versa. The study did not control for socioeconomic factors."},{"rthcId":"RTHC-00057","title":"The short-term consequences of early onset cannabis use.","authors":"Fergusson, D M; Lynskey, M T; Horwood, L J","year":1996,"journal":"Journal of abnormal child psychology, 24(4), 499-512","doi":null,"pmid":"8886945","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed a New Zealand birth cohort to examine what happened to children who began using cannabis before age 15. Early users showed dramatically elevated risks across multiple domains.\n\nCompared to non-users, early cannabis users had higher rates of subsequent substance use, conduct and oppositional disorders, juvenile offending, severe truancy, school dropout, anxiety, depression, and suicidal ideation. The odds ratios ranged from 2.7 to 30.8 times higher.\n\nHowever, a critical nuance emerged: most of these elevated risks were explained by pre-existing characteristics. Early cannabis users already had family disadvantages, early childhood adjustment problems, and strong connections to substance-using or delinquent peers before they started using cannabis.\n\nAfter statistically adjusting for these confounding factors, one association remained: early onset cannabis use independently predicted increased risk of later cannabis use, suggesting a self-reinforcing pattern.","whyItMatters":"This study delivered an important methodological lesson: associations between early cannabis use and negative outcomes can be misleading if pre-existing risk factors are not accounted for. The finding that most associations disappeared after controlling for confounders challenged simplistic narratives about cannabis causing these problems.","specificNumbers":"Odds ratios: 2.7 to 30.8 for various outcomes before adjustment. Most associations attenuated after controlling for family disadvantage, early adjustment problems, and delinquent peer affiliation. Cannabis use before age 15 independently predicted later cannabis use even after adjustment.","methodology":"Longitudinal birth cohort study following children from birth through ages 15-16 in New Zealand. Early onset cannabis use (before age 15) was the exposure variable. Outcomes included mental health disorders, substance use, behavioral problems, and educational outcomes. Extensive confounders were controlled including family disadvantage, early adjustment problems, and peer affiliations.","limitations":"Observational cohort study cannot fully establish causation even with extensive confounder adjustment. Some confounders may be unmeasured. The study covered outcomes only through age 15-16, missing longer-term consequences. The New Zealand cohort may not generalize to all populations."},{"rthcId":"RTHC-00058","title":"The perceived effects of smoked cannabis on patients with multiple sclerosis.","authors":"Consroe, P; Musty, R; Rein, J; Tillery, W; Pertwee, R","year":1997,"journal":"European neurology, 38(1), 44-8","doi":null,"pmid":"9252798","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This was the first survey specifically asking people with MS about their cannabis use. One hundred twelve respondents (53 from the UK, 59 from the USA) reported using cannabis for symptom management.\n\nThe percentage reporting improvement ranged from 97% for the top-ranked symptom down to 30% for the lowest. In descending order, respondents reported cannabis improved: spasticity, chronic pain of extremities, acute paroxysmal phenomenon, tremor, emotional dysfunction, anorexia/weight loss, fatigue, double vision, sexual dysfunction, bowel and bladder dysfunction, vision dimness, walking and balance dysfunction, and memory loss.\n\nThe researchers noted that MS patients had specific, identifiable therapeutic reasons for using cannabis and recommended the findings be used to guide the design of controlled clinical trials.","whyItMatters":"This survey provided systematic patient-reported evidence that cannabis helped multiple MS symptoms, not just the spasticity that had been the focus of earlier case reports. The breadth of symptoms reportedly improved suggested cannabinoids might have multiple therapeutic mechanisms in MS.","specificNumbers":"112 respondents (53 UK, 59 USA). 14 symptoms assessed. Improvement rates ranged from 97% to 30%. Top-ranked: spasticity and chronic pain.","methodology":"Anonymous questionnaire survey of 112 people with MS (53 UK, 59 USA) who used cannabis. Respondents rated whether cannabis improved various MS symptoms. This was described as the first questionnaire specifically on cannabis use and MS.","limitations":"Self-selected respondents who chose to use cannabis and believed it helped. No placebo control or blinding. Survey responses are subjective and subject to recall bias. Sample size was small and self-selected."},{"rthcId":"RTHC-00059","title":"Reading and language in 9- to 12-year olds prenatally exposed to cigarettes and marijuana.","authors":"Fried, P A; Watkinson, B; Siegel, L S","year":1997,"journal":"Neurotoxicology and teratology, 19(3), 171-83","doi":null,"pmid":"9200137","tags":["pregnancy","youth","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers examined reading and language abilities in 131 children aged 9-12 who were part of a longitudinal study tracking prenatal drug exposure from a predominantly middle-class population.\n\nPrenatal cigarette exposure showed a dose-dependent association with lower language and reading scores, even after controlling for potential confounders. The effects were strongest on auditory-related aspects of reading, consistent with earlier findings linking prenatal cigarette exposure to altered auditory functioning.\n\nPrenatal marijuana exposure was not significantly related to either reading or language outcomes at this age.\n\nAn additional finding: while the mother's own passive smoke exposure during pregnancy did not affect outcomes, the child's postnatal secondhand smoke exposure was associated with poorer language scores.","whyItMatters":"This study provided important comparative data: prenatal cigarette exposure, not marijuana exposure, was the substance linked to cognitive effects in this age group. The finding has implications for risk communication to pregnant women and for understanding which prenatal exposures carry the greatest developmental risk.","specificNumbers":"131 children aged 9-12. Prenatal cigarette exposure: dose-dependent association with lower reading and language. Prenatal marijuana exposure: not significantly related to outcomes. Postnatal secondhand smoke: associated with poorer language scores.","methodology":"Longitudinal study of 131 children aged 9-12 from a low-risk, predominantly middle-class sample. Prenatal exposure to marijuana and cigarettes was ascertained prospectively. Reading and language were assessed using multiple measures. Discriminant Function Analysis controlled for potential confounders.","limitations":"Predominantly middle-class sample may not generalize to higher-risk populations. The absence of a significant marijuana association does not prove safety, as the study may have been underpowered to detect small effects. Self-reported prenatal substance use may be inaccurate."},{"rthcId":"RTHC-00060","title":"Comparative effects of alcohol and marijuana on mood, memory, and performance.","authors":"Heishman, S J; Arasteh, K; Stitzer, M L","year":1997,"journal":"Pharmacology, biochemistry, and behavior, 58(1), 93-101","doi":null,"pmid":"9264076","tags":["cognition","driving"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Five male volunteers received three doses each of alcohol and marijuana under double-blind conditions across seven sessions, using technology that controlled puffing and inhalation parameters for precise marijuana dosing.\n\nAt the highest doses, perceived impairment was identical for alcohol and marijuana. Both drugs comparably impaired digit-symbol substitution (a measure of processing speed) and word recall (memory). Neither drug affected time perception or reaction time.\n\nAlcohol slightly impaired number recognition performance while marijuana did not, representing the only clear difference between the two drugs.\n\nBlood alcohol concentrations ranged from 10-90 mg/dL, while THC levels reached 63-188 ng/mL, confirming dose-dependent drug delivery.","whyItMatters":"By using controlled dosing for both substances, this study enabled the first precise comparison of alcohol and marijuana impairment profiles. The finding of similar impairment patterns challenges the common assumption that one substance is inherently more impairing than the other.","specificNumbers":"Five subjects, seven sessions. Alcohol: 0.25-1.0 g/kg (BAC 10-90 mg/dL). Marijuana: 4-16 puffs of 3.55% THC (blood THC 63-188 ng/mL). Identical perceived impairment at high doses.","methodology":"Double-blind, placebo-controlled, within-subjects design with 5 male volunteers. Three doses each of alcohol (0.25, 0.5, 1.0 g/kg) and marijuana (4, 8, 16 puffs of 3.55% THC). Controlled puffing technology for marijuana. Measures included subjective ratings, digit-symbol substitution, word recall, number recognition, time perception, and reaction time.","limitations":"Only five male participants. Controlled laboratory conditions do not reflect real-world use patterns. The marijuana used (3.55% THC) is substantially weaker than modern products. The narrow range of cognitive tests may miss domain-specific differences."},{"rthcId":"RTHC-00061","title":"Importance of the C-1 substituent in classical cannabinoids to CB2 receptor selectivity: synthesis and characterization of a series of O,2-propano-delta 8-tetrahydrocannabinol analogs.","authors":"Reggio, P H; Wang, T; Brown, A E; Fleming, D N; Seltzman, H H; Griffin, G; Pertwee, R G; Compton, D R; Abood, M E; Martin, B R","year":1997,"journal":"Journal of medicinal chemistry, 40(20), 3312-8","doi":null,"pmid":"9379452","tags":["neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Separating the mood-altering effects of cannabinoids from their therapeutic effects has been a long-standing goal. This study found that modifications at the C-1 position of classical cannabinoid structures produced compounds with selectivity for the CB2 receptor over the CB1 receptor.\n\nA series of cyclic ether THC derivatives were synthesized and tested. Analogs containing an oxygen attached to C-9 showed the highest CB2 affinity and selectivity, with one compound achieving a CB2 binding affinity of 5.8 nM and a selectivity ratio of 4.5.\n\nThe compounds produced dose-dependent effects in tissue assays that were blocked by a CB1 antagonist. In live animals, one analog produced pain relief with reduced activity in three other behavioral measures, suggesting partial separation of therapeutic and psychoactive effects.","whyItMatters":"This study identified a specific molecular position for achieving CB2 receptor selectivity, which is important because CB2 activation may produce anti-inflammatory and pain-relieving effects without the psychoactive effects mediated by CB1. This work advanced the goal of creating therapeutic cannabinoids without the \"high.\"","specificNumbers":"Best CB2 compound: Ki(CB1) = 26 nM, Ki(CB2) = 5.8 nM, selectivity ratio 4.5. Another compound: Ki(CB1) = 90 nM, Ki(CB2) = 23 nM, selectivity ratio 3.9.","methodology":"Medicinal chemistry study synthesizing five C-9 analogs of O,2-propano-delta-8-THC. Compounds were evaluated using radioligand displacement assays for CB1 and CB2 receptor affinity, mouse vas deferens tissue assays, and the mouse behavioral tetrad for in vivo cannabinoid activity.","limitations":"The selectivity ratios achieved (3.9-4.5) were modest. Mouse behavioral assays may not predict human pharmacology. Only a small series of analogs was tested."},{"rthcId":"RTHC-00062","title":"Marijuana. Respiratory tract effects.","authors":"Van Hoozen, B E; Cross, C E","year":1997,"journal":"Clinical reviews in allergy & immunology, 15(3), 243-69","doi":null,"pmid":"9358987","tags":["respiratory","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review consolidated the evidence on marijuana's effects on the respiratory system, drawing careful comparisons with tobacco.\n\nDaily marijuana smoking clearly produced bronchitis symptoms (cough, wheeze, sputum) similar to tobacco smoking, along with measurable declines in pulmonary function. However, the review estimated that a marijuana-only smoker would need to consume 4-5 joints daily for at least 30 years to develop overt COPD, assuming no alpha-1-antitrypsin deficiency.\n\nMarijuana smoke's mutagenic and carcinogenic properties were well-established in laboratory tests. Several case reports and observational series documented laryngeal, oropharyngeal, and possibly bronchogenic (lung) cancer in marijuana smokers. However, a quantified relative risk ratio had not been established.\n\nAn intriguing pattern emerged: case reports of upper airway cancers were more common than lung cancer reports, suggesting marijuana smoke might disproportionately affect the upper respiratory tract, though this remained speculative.","whyItMatters":"This review provided the most detailed assessment of respiratory risks from marijuana smoking available at the time. The practical estimate that severe lung disease would require decades of heavy daily use helped contextualize the risk for typical users, while the cancer evidence raised legitimate concerns.","specificNumbers":"Estimated threshold for COPD: 4-5 joints/day for 30+ years. Mutagenic/carcinogenic properties established in lab tests. Relative risk for cancer not yet quantified. More case reports for upper airway than lower airway cancers.","methodology":"Comprehensive narrative review of published studies on marijuana's respiratory tract effects, covering pulmonary function, respiratory symptoms, mutagenicity, carcinogenicity, and clinical case reports.","limitations":"Narrative review format without systematic quality assessment. Cancer risk estimates were based on case reports, not controlled epidemiological studies. The COPD threshold estimate was extrapolated from tobacco data and may not be accurate for marijuana."},{"rthcId":"RTHC-00063","title":"Medicinal applications of delta-9-tetrahydrocannabinol and marijuana.","authors":"Voth, E A; Schwartz, R H","year":1997,"journal":"Annals of internal medicine, 126(10), 791-8","doi":null,"pmid":"9148653","tags":["medical-cannabis","cancer","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Following the passage of ballot initiatives in California and Arizona making marijuana accessible to patients, the authors reviewed all relevant research from 1975 to 1996 on medical applications of THC and marijuana.\n\nThe evidence supported selective use of pure THC preparations for two conditions: nausea associated with cancer chemotherapy and appetite stimulation. Evidence was less convincing for glaucoma and spinal cord spasticity.\n\nHowever, the authors drew a sharp distinction between pharmaceutical THC and crude marijuana. They cited THC toxicity delivered in any form while supporting its clinical use, and concluded that the evidence did not support reclassifying crude marijuana as a prescribable medicine. They argued for the pharmaceutical pathway (pure, standardized compounds) over the herbal one.","whyItMatters":"Published in the Annals of Internal Medicine at a pivotal moment when two states had just passed medical marijuana ballot initiatives, this review represented a mainstream medical position that supported therapeutic cannabinoids but opposed crude marijuana prescribing. This distinction between \"medicine\" and \"marijuana\" shaped the medical establishment's response to the growing medical cannabis movement.","specificNumbers":"Twenty-one years of research reviewed (1975-1996). Two supported therapeutic applications: chemotherapy nausea and appetite stimulation. Two insufficient applications: glaucoma and spasticity.","methodology":"Literature review of research published between 1975 and 1996 on medical applications of delta-9-THC and crude marijuana, covering nausea, glaucoma, appetite stimulation, and spasticity. Legal precedents were also reviewed.","limitations":"The review was explicitly positioned against crude marijuana reclassification, which may have influenced the framing of evidence. Published before the wave of clinical trials on whole-plant cannabis that followed state legalization. The \"toxicity\" framing did not include comparison with other approved medications' risk profiles."},{"rthcId":"RTHC-00064","title":"Drugs and immunity: cannabinoids and their role in decreased resistance to infectious disease.","authors":"Cabral, G A; Dove Pettit, D A","year":1998,"journal":"Journal of neuroimmunology, 83(1-2), 116-23","doi":null,"pmid":"9610679","tags":["neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized the evidence on THC and immune function, finding consistent immunosuppressive effects across multiple experimental models.\n\nTHC decreased host resistance to bacterial, protozoan, and viral infections in lab and animal studies. The primary immune cells affected were macrophages (first-line defenders), T lymphocytes (adaptive immunity coordinators), and natural killer cells (which target infected and cancerous cells).\n\nHowever, the review drew an important distinction: definitive data directly linking marijuana use to increased susceptibility to infection in living humans was currently unavailable. The evidence was extrapolated from in vitro and animal studies, which supported the hypothesis that similar effects would occur in humans but had not confirmed it.","whyItMatters":"This review highlighted a persistent gap in cannabis immunology: extensive laboratory evidence of immunosuppression but limited clinical confirmation in humans. This gap remains partially unfilled, making it one of the longest-standing unanswered questions in cannabis research.","specificNumbers":"Three major immune cell types affected: macrophages, T lymphocytes, natural killer cells. Three categories of infection with reduced resistance: bacterial, protozoan, viral.","methodology":"Narrative review of experimental studies examining THC effects on immune function across in vitro models, animal studies, and human data. Covered macrophage, T cell, and NK cell responses and host resistance to various infectious agents.","limitations":"The review acknowledged that definitive human data was unavailable. Animal and in vitro models use different doses, routes, and exposure durations than human cannabis use. The THC concentrations used in lab studies often exceed physiological levels."},{"rthcId":"RTHC-00065","title":"Abuse potential of dronabinol (Marinol).","authors":"Calhoun, S R; Galloway, G P; Smith, D E","year":1998,"journal":"Journal of psychoactive drugs, 30(2), 187-96","doi":null,"pmid":"9692381","tags":["addiction","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers investigated the abuse potential of dronabinol (Marinol), a prescription oral THC product, through literature review, surveys, and interviews with addiction specialists, oncologists, HIV researchers, and law enforcement.\n\nThe findings were consistently negative across all measures of abuse potential. No evidence of abuse or diversion was found. Prescription tracking showed patients stayed within therapeutic dose ranges over time. Healthcare professionals detected no \"scrip-chasing\" or \"doctor-shopping.\" Cannabis-dependent populations showed no interest in abusing dronabinol.\n\nThe explanation was pharmacological: dronabinol has a slow, gradual onset of action, is at most weakly reinforcing, and most users described its effects as dysphoric and unappealing. There was no street market for dronabinol and no evidence of diversion for sale as a street drug.","whyItMatters":"This study directly addressed concerns that pharmaceutical THC would become a drug of abuse. The finding that even cannabis-dependent individuals had no interest in dronabinol demonstrated that the pharmaceutical formulation's slow onset and dysphoric effects made it fundamentally different from smoked cannabis in terms of abuse potential.","specificNumbers":"Zero evidence of abuse or diversion across all data sources. Prescription tracking confirmed therapeutic-range dosing over time. No street market detected. Most users reported dysphoric, unappealing effects.","methodology":"Multi-method assessment including literature review, surveys, and interviews with addiction medicine specialists, oncologists, cancer and HIV researchers, and law enforcement. Prescription tracking data was also reviewed.","limitations":"The study was conducted among legitimate patients and healthcare providers. Surveillance systems may not capture all forms of diversion. The relatively small patient population using dronabinol at the time may have limited detection of rare abuse events."},{"rthcId":"RTHC-00066","title":"The use of cannabis as a mood stabilizer in bipolar disorder: anecdotal evidence and the need for clinical research.","authors":"Grinspoon, L; Bakalar, J B","year":1998,"journal":"Journal of psychoactive drugs, 30(2), 171-7","doi":null,"pmid":"9692379","tags":["mental-health","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The authors presented case histories of bipolar disorder patients who used cannabis therapeutically. The patterns were varied but consistently positive from the patients' perspective.\n\nSome patients used cannabis specifically for mania, others for depression, and some for both phases of the illness. Several reported cannabis was more effective than conventional medications. One woman found it curbed her manic rages and became an advocate for medical cannabis access.\n\nOther patients described using cannabis as a supplement to lithium, either allowing reduced lithium doses or relieving lithium's side effects. The authors noted that medical cannabis users faced legal risk, with one case illustrating how children were encouraged by drug prevention programs to report their parents.\n\nThe authors drew a provocative parallel to lithium in the early 1950s, when its effect on mania had been discovered but no controlled studies existed. They argued that legal barriers had made controlled cannabis studies for bipolar disorder nearly impossible.","whyItMatters":"This paper raised the possibility that cannabis might have mood-stabilizing properties, a hypothesis that remains largely untested in controlled trials. The comparison to lithium's early history highlighted how legal and regulatory barriers can prevent scientific evaluation of potentially useful treatments.","specificNumbers":"Multiple case histories presented. Applications included mania, depression, and both phases. Some patients used cannabis as a lithium adjunct or substitute.","methodology":"Case series presenting anecdotal patient histories of cannabis use for bipolar disorder. No controlled comparisons or systematic assessment.","limitations":"Entirely anecdotal case histories. No controlled data. Patients who report benefit are not representative of all bipolar patients who use cannabis. Selection bias is extreme: only positive experiences are reported. Cannabis may worsen bipolar symptoms in many users who are not represented here."},{"rthcId":"RTHC-00067","title":"Comment on 'Health aspects of cannabis: revisited' (Hollister).","authors":"Johnson, Bankole A.","year":1998,"journal":"The international journal of neuropsychopharmacology, 1(1), 81-82","doi":null,"pmid":"11281948","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This commentary responded to a review of cannabis health effects, placing it in the context of growing medical marijuana advocacy in the United States.\n\nThe author noted that following California's Proposition 215 in 1996, cannabis was being used medicinally for conditions including pain, glaucoma, chemotherapy nausea, AIDS-related symptoms, and multiple sclerosis spasticity. Of these, the evidence for nausea treatment and appetite stimulation appeared most promising.\n\nHowever, the commentary emphasized that definitive controlled clinical studies were typically lacking for most proposed medical uses. There was concern that any therapeutic advantage might be offset by harmful effects. The author argued that evaluating the risk-versus-benefit profile was essential for rational prescribing, particularly as public health implications of increased cannabis use were becoming apparent.","whyItMatters":"This commentary represented the mainstream medical establishment's cautious response to the medical marijuana movement: acknowledging therapeutic potential while insisting on controlled evidence before widespread adoption.","specificNumbers":"Proposition 215 passed November 5, 1996. Multiple medical conditions mentioned: pain, glaucoma, nausea, AIDS wasting, MS spasticity.","methodology":"Published commentary responding to a health review, contextualizing cannabis therapeutic evidence within the post-Proposition 215 policy landscape.","limitations":"A brief commentary rather than a systematic review. Reflects one perspective within the medical establishment. Does not present original data."},{"rthcId":"RTHC-00068","title":"Cannabis use, abuse, and dependence in a population-based sample of female twins.","authors":"Kendler, K S; Prescott, C A","year":1998,"journal":"The American journal of psychiatry, 155(8), 1016-22","doi":null,"pmid":"9699687","tags":["genetics","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers interviewed 1,934 women from female twin pairs, including 485 identical (monozygotic) and 335 fraternal (dizygotic) pairs, about their lifetime cannabis use.\n\nNearly half (47.9%) had used cannabis at least once. Rates of heavy use (6.7%), abuse (7.2%), and dependence (2.2%) were lower but substantial.\n\nThe twin analysis revealed a striking pattern. Whether someone ever tried cannabis was influenced by both genetic and family-environmental factors, meaning shared upbringing and home environment played a meaningful role in initial use decisions.\n\nBut for the progression from use to heavy use, abuse, and dependence, the picture changed dramatically. These more severe outcomes were driven primarily by genetic factors, with heritability estimates ranging from 62% to 79%. Family and social environment had little influence on whether cannabis use escalated to problematic levels.","whyItMatters":"This study fundamentally reframed the understanding of cannabis use disorder. It showed that the factors leading someone to try cannabis (largely social and environmental) are different from the factors that determine whether use becomes problematic (largely genetic). This has implications for both prevention and treatment approaches.","specificNumbers":"Lifetime cannabis use: 47.9%. Heavy use: 6.7%. Abuse: 7.2%. Dependence: 2.2%. Heritability of heavy use and abuse: 62-79%. 1,934 twins from 485 MZ and 335 DZ pairs.","methodology":"Population-based twin study using a registry of female-female twin pairs. 1,934 individual twins (485 MZ pairs, 335 DZ pairs) were interviewed by phone. Lifetime cannabis use, heavy use, abuse, and dependence were assessed using DSM-IV criteria. Biometric model fitting was performed.","limitations":"Female-only sample may not generalize to men. Self-reported cannabis use measures. Twin studies assume equal environments for identical and fraternal twins, which may not hold perfectly. The study cannot identify which specific genes are involved."},{"rthcId":"RTHC-00069","title":"Marijuana, immunity and infection.","authors":"Klein, T W; Friedman, H; Specter, S","year":1998,"journal":"Journal of neuroimmunology, 83(1-2), 102-15","doi":null,"pmid":"9610678","tags":["neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized 25 years of research across three major areas of cannabinoid immunology.\n\nFirst, cannabinoids affected the function of all major immune cell types: T and B lymphocytes, natural killer cells, and macrophages. The effects were consistently immunomodulatory across human studies, animal models, and cell culture experiments.\n\nSecond, cannabinoids altered host resistance to specific infections. Herpes simplex virus, murine retrovirus, and bacteria including Staphylococcus, Listeria, Treponema, and Legionella were all affected. The secondary immune response (the body's enhanced response to a previously encountered pathogen) appeared particularly vulnerable.\n\nThird, cannabinoids modulated the cytokine network, the chemical messaging system that coordinates immune responses. Both acute-phase and immune cytokines were affected, along with the helper T cell balance (Th1 vs. Th2).\n\nDespite these extensive findings, the review concluded that more studies were needed to determine both the actual health risk of marijuana abuse and the role of the endocannabinoid system in immune regulation.","whyItMatters":"This review established the endocannabinoid system as a significant player in immune regulation, not just an immunosuppressive nuisance. The dual recognition that cannabinoids can both enhance disease processes and potentially serve regulatory functions opened the door to therapeutic immunomodulation research.","specificNumbers":"Twenty-five years of research reviewed. Four immune cell types affected: T cells, B cells, NK cells, macrophages. Multiple pathogens studied: HSV, murine retrovirus, Staphylococcus, Listeria, Treponema, Legionella.","methodology":"Comprehensive narrative review covering 25 years of cannabinoid immunology research across in vivo (human and animal) and in vitro models. Covered immune cell function, host resistance to infection, and cytokine network modulation.","limitations":"Narrative review format. The diversity of experimental models, doses, and endpoints across 25 years of research makes synthesis challenging. The translation from lab findings to human health risk remains uncertain."},{"rthcId":"RTHC-00070","title":"Breastfeeding and the use of recreational drugs--alcohol, caffeine, nicotine and marijuana.","authors":"Liston, J","year":1998,"journal":"Breastfeeding review : professional publication of the Nursing Mothers' Association of Australia, 6(2), 27-30","doi":null,"pmid":"9849117","tags":["pregnancy","harm-reduction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined the evidence on four commonly used recreational substances and their effects on breastfeeding, combining published research with reports from breastfeeding counselors.\n\nAll four substances, alcohol, caffeine, nicotine, and marijuana, enter breast milk. Each can potentially affect milk production, volume, composition, and the milk ejection reflex. Each can also directly affect the infant.\n\nThe review recommended that breastfeeding mothers restrict their intake of all four substances. However, the authors acknowledged the practical challenge: the postpartum period is stressful, and mothers may need support and practical strategies rather than simple prohibitions to limit infant exposure.","whyItMatters":"By reviewing marijuana alongside alcohol, caffeine, and nicotine, this paper contextualized cannabis exposure during breastfeeding within the broader picture of commonly used substances. The practical, supportive approach to harm reduction was notable for its era.","specificNumbers":"Four substances reviewed: alcohol, caffeine, nicotine, marijuana. All enter breast milk. All can affect milk production and the infant.","methodology":"Narrative review combining published literature with anecdotal reports from Nursing Mothers' Association breastfeeding counselors. Covered alcohol, caffeine, nicotine, and marijuana effects on breastfeeding.","limitations":"Combined published evidence with anecdotal counselor reports without distinguishing between them. Did not quantify the relative risk of each substance. The marijuana-specific evidence was particularly limited. Did not address dose-response relationships."},{"rthcId":"RTHC-00071","title":"Medical marijuana.","authors":"Marmor, J B","year":1998,"journal":"The Western journal of medicine, 168(6), 540-3","doi":null,"pmid":"9656007","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Writing in the Western Journal of Medicine as California patients were self-medicating with marijuana under Proposition 215, the author assessed the state of medical marijuana evidence and policy.\n\nClinical studies suggested medical utility for some conditions, but the scientific evidence was described as weak. The author identified several key issues. The regulatory system needed modification to remove barriers to clinical research. Marijuana should be held to the same safety and efficacy standards as other drugs (a flaw in Proposition 215) but should not need to be proven better than existing medications.\n\nThe therapeutic window for marijuana and THC between desired effects and unpleasant side effects was narrow, which was a major reason patients discontinued use. The NIH panel recommended high priority for developing a controlled inhaled form of THC. The existence of a natural cannabinoid receptor system in the brain suggested that selective THC analogs could enhance therapeutic effects while minimizing adverse ones.","whyItMatters":"This review articulated a middle-ground position that influenced subsequent policy: support research, apply standard evidence requirements, but remove unnecessary regulatory barriers. The observation about the narrow therapeutic window identified a core challenge that still affects cannabis medicine.","specificNumbers":"NIH identified several conditions meriting further research. The therapeutic window between effect and side effects was described as narrow. Proposition 215 cited as lacking proper efficacy standards.","methodology":"Commentary and review assessing medical marijuana evidence and policy in the context of California's Proposition 215. Referenced NIH panel recommendations.","limitations":"A single author's perspective rather than a systematic review. The characterization of evidence as \"weak\" may have been overstated for some conditions. The focus on pharmaceutical approaches may have undervalued whole-plant preparations."},{"rthcId":"RTHC-00072","title":"Endocannabinoids.","authors":"Mechoulam, R; Fride, E; Di Marzo, V","year":1998,"journal":"European journal of pharmacology, 359(1), 1-18","doi":null,"pmid":"9831287","tags":["neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review, authored by Raphael Mechoulam and colleagues who played central roles in discovering the endocannabinoid system, described two molecules the body produces naturally that activate the same receptors as THC.\n\nAnandamide and 2-arachidonoyl glycerol (2-AG) were identified as the principal endocannabinoids. The review covered their chemical structures, how structural modifications affect their activity, their levels in unstimulated tissues and cells, and how the body makes, releases, and breaks them down.\n\nA key concept introduced was the \"entourage effect\": companion compounds that do not directly activate cannabinoid receptors but modify the activity of anandamide and 2-AG, potentially amplifying or modifying their effects. The review also described their signaling mechanisms within cells and their effects when administered to animals.","whyItMatters":"This review documented one of the most significant biological discoveries of the 1990s. The finding that humans have an endogenous cannabinoid system reframed the entire field: cannabis was not introducing foreign chemistry but rather hijacking a natural signaling system. This transformed both therapeutic research and our understanding of brain function.","specificNumbers":"Two principal endocannabinoids identified: anandamide and 2-arachidonoyl glycerol (2-AG). The entourage effect concept was introduced.","methodology":"Comprehensive review by key researchers in the field, covering endocannabinoid discovery, structure-activity relationships, biochemistry (biosynthesis, release, inactivation), the entourage effect, signaling mechanisms, and animal pharmacology.","limitations":"The field was young and many details were still being worked out. Some conclusions from this era were later refined or revised. The clinical significance of endocannabinoid biology was still largely theoretical."},{"rthcId":"RTHC-00073","title":"Comment on 'Health aspects of cannabis: revisited' (Hollister).","authors":"Mechoulam, R.; Golan, D.","year":1998,"journal":"The international journal of neuropsychopharmacology, 1(1), 83-85","doi":null,"pmid":"11281949","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Raphael Mechoulam, who first synthesized THC and later co-discovered the endocannabinoid system, responded to a cannabis health review with specific concern about the therapeutic dimension.\n\nHe highlighted a notable divergence between British and American medical authorities on cannabis for multiple sclerosis. The British Medical Association \"strongly recommended carefully controlled trials of cannabinoids in patients with chronic spastic disorders which have not responded to other drugs\" and stated such trials \"merit a high priority.\" In contrast, the US National Multiple Sclerosis Society did not support cannabis use for MS.\n\nMechoulam expressed regret that the reviewed paper did not revisit the therapeutic aspects of cannabis, noting it would be valuable to hear analysis of the \"medical marijuana\" debate, the relative clinical advantages of marijuana versus THC, and the specific question of cannabis in MS, which patients were already widely using.","whyItMatters":"Coming from the scientist who first synthesized THC and co-discovered anandamide, this commentary carried unique authority. His call for clinical trials, particularly for MS, helped validate patient experiences and push for the research that eventually led to nabiximols (Sativex).","specificNumbers":"British Medical Association recommended \"high priority\" for cannabis clinical trials in spastic disorders. US National MS Society did not support cannabis use.","methodology":"Published commentary by Raphael Mechoulam responding to a health review article, drawing on his expertise as a pioneer of cannabinoid chemistry and endocannabinoid discovery.","limitations":"A brief commentary rather than a systematic analysis. Reflects one scientist's perspective, though from a uniquely authoritative voice in the field."},{"rthcId":"RTHC-00074","title":"Cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana.","authors":"Porcella, A; Casellas, P; Gessa, G L; Pani, L","year":1998,"journal":"Brain research. Molecular brain research, 58(1-2), 240-5","doi":null,"pmid":"9685662","tags":["medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used molecular techniques to measure cannabinoid receptor levels across different structures of the rat eye. CB1 receptor mRNA was found at significantly higher levels in the ciliary body (the structure that produces aqueous humor, the fluid that determines eye pressure) compared to the iris, retina, and choroid.\n\nThe CB2 receptor, associated primarily with immune function, was undetectable in any eye structure.\n\nThis distribution pattern provided the first molecular evidence for a specific mechanism by which cannabinoids could lower eye pressure: by acting on CB1 receptors in the ciliary body, cannabinoids could potentially reduce the production of aqueous humor, directly lowering intraocular pressure.","whyItMatters":"For decades, researchers knew cannabis lowered eye pressure but did not understand the mechanism. This study identified where the receptors are concentrated, pointing to a local mechanism in the ciliary body rather than a purely systemic effect, potentially reviving interest in topical cannabinoid eye drops.","specificNumbers":"CB1 mRNA in ciliary body: 0.84% of reference gene. Iris: 0.34%. Retina: 0.07%. Choroid: 0.06%. CB2: undetectable in all structures.","methodology":"RT-PCR measurement of CB1 and CB2 receptor mRNA in four rat eye structures: ciliary body, iris, retina, and choroid. Levels were normalized to the reference gene beta-2 microglobulin.","limitations":"Rat eye anatomy may differ from human. mRNA levels do not necessarily correspond to functional protein levels. The study did not demonstrate that activating these receptors actually reduced aqueous humor production."},{"rthcId":"RTHC-00075","title":"Analysis of the medical use of marijuana and its societal implications.","authors":"Taylor, H G","year":1998,"journal":"Journal of the American Pharmaceutical Association (Washington, D.C. : 1996), 38(2), 220-7","doi":null,"pmid":"9654850","tags":["medical-cannabis","addiction","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review from a pharmacist's perspective assessed marijuana across pharmacology, risks, and therapeutic potential.\n\nFor risks: acute intoxication featured euphoria, short-term memory loss, sensory enhancement, and impaired linear thinking. Depersonalization and panic attacks were adverse effects. Chronic high doses might cause subtle cognitive impairments of unknown duration. Marijuana was flagged as a risk factor for underlying mental illness.\n\nFor dependence: marijuana caused dependence but compared to cocaine, alcohol, heroin, and nicotine, it had \"little addictive power\" and produced only mild withdrawal symptoms.\n\nFor therapeutic potential: clinical promise was identified for glaucoma, nausea and vomiting, pain relief, spasticity, multiple sclerosis, and AIDS wasting syndrome.\n\nThe review concluded with a balanced position: as a recreational drug, marijuana posed dangers particularly to adolescent development; as a medical drug, it should be available for patients who do not respond to existing therapies.","whyItMatters":"Coming from a pharmaceutical perspective, this review provided a notably balanced assessment at a time when most publications took strong positions either for or against medical marijuana. The comparison of marijuana's addiction potential to other substances was particularly useful for contextualizing risk.","specificNumbers":"Six conditions with clinical promise: glaucoma, nausea/vomiting, pain, spasticity, MS, AIDS wasting. Addiction potential ranked below cocaine, alcohol, heroin, and nicotine.","methodology":"Literature review using MEDLINE searches with multiple therapeutic and pharmacological search terms, supplemented with interviews of cannabinoid researchers.","limitations":"A single-author review without systematic methodology. The characterization of cognitive impairments as \"subtle\" may understate effects found in subsequent research. The comparison of addiction potential is qualitative rather than quantitative."},{"rthcId":"RTHC-00076","title":"The effects of cannabinoids on the brain.","authors":"Ameri, A","year":1999,"journal":"Progress in neurobiology, 58(4), 315-48","doi":null,"pmid":"10368032","tags":["neuroscience","cognition","dopamine","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This extensive review covered the full spectrum of cannabis effects on the brain, from molecular mechanisms to behavioral consequences.\n\nA striking finding was that recent research had revealed THC-induced cell death in the hippocampus, with neuron shrinkage and DNA fragmentation, effects the review stated had been \"underestimated for a long time.\" Cognitive deficits, particularly in concentration and memory, appeared to persist after withdrawal.\n\nAt the receptor level, the review detailed how CB1 receptors mediate THC's effects through G proteins, inhibiting calcium channels and stimulating potassium channels. The CB2 receptor, found in immune tissue, provided the molecular basis for immunosuppression.\n\nCritically, the review established that cannabinoids increase dopaminergic neuron activity in the mesolimbic pathway, the same reward circuit activated by morphine, alcohol, and nicotine. This shared \"final common pathway\" was interpreted as underlying marijuana's reinforcing and abuse properties.","whyItMatters":"This review integrated the emerging understanding of cannabinoid neuroscience into a coherent picture for the first time: from receptor to cell death, from endocannabinoids to behavioral effects, from acute intoxication to withdrawal. The finding that cannabis shares a dopamine reward pathway with other drugs of abuse was particularly influential.","specificNumbers":"CB1 and CB2 receptors described. CB1 highest in hippocampus, cerebellum, striatum. CB1 and CB2 share 44% nucleotide sequence identity. Two endocannabinoids detailed: anandamide and 2-AG.","methodology":"Comprehensive narrative review published in Progress in Neurobiology, covering cannabinoid receptors, endocannabinoids, signaling mechanisms, neurotoxicity, cognitive effects, and reward pathways.","limitations":"The hippocampal cell death findings were from animal studies with high-dose exposure and have been debated in subsequent research. The review's characterization of cannabis toxicity as \"underestimated\" reflects one interpretation of evolving evidence. The shared reward pathway does not necessarily mean cannabis has the same addiction potential as other substances."},{"rthcId":"RTHC-00077","title":"Specific attentional dysfunction in adults following early start of cannabis use.","authors":"Ehrenreich, H; Rinn, T; Kunert, H J; Moeller, M R; Poser, W; Schilling, L; Gigerenzer, G; Hoehe, M R","year":1999,"journal":"Psychopharmacology, 142(3), 295-301","doi":null,"pmid":"10208322","tags":["cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers hypothesized that cannabis exposure during a critical brain development period around puberty could cause lasting neural changes. They selected 99 healthy individuals from a pool of 250 regular cannabis users, choosing only those with no other drug use, psychiatric history, or medical conditions.\n\nParticipants completed computerized tests of visual scanning, alertness, divided attention, flexibility, and working memory. Among multiple potential predictors, including current age, current intoxication level, and estimated lifetime dose, only one factor predicted impaired performance: the age at which cannabis use began.\n\nEarly-onset users (before age 16, N=48) showed significantly impaired reaction times specifically in visual scanning. Late-onset users (after age 16, N=51) performed identically to non-user controls (N=49). The impairment was specific to visual scanning, a cognitive function known to undergo major maturation between ages 12 and 15.\n\nNeither the amount of cannabis consumed over a lifetime nor current intoxication level predicted the deficit.","whyItMatters":"This study provided some of the strongest early evidence for a vulnerable period during brain development when cannabis exposure could cause lasting changes. The specificity of the finding, only visual scanning affected and only in early-onset users, made it more convincing than general claims about cannabis and cognition.","specificNumbers":"99 cannabis users (48 early onset, 51 late onset) vs. 49 controls. Early onset: before age 16. Visual scanning maturation period: ages 12-15. Only onset age predicted impairment; not current intoxication, age, or lifetime dose.","methodology":"Cross-sectional study of 99 pure cannabis users (no polydrug use) selected from 250 candidates after physical exam, lab work, drug screening, MMPI, and interview. Compared with 49 controls on computerized attention battery. Predictors analyzed: age, onset age, acute THC levels, total life dose.","limitations":"Cross-sectional design cannot prove cannabis caused the deficit; pre-existing differences between early and late starters could be responsible. Self-reported age of onset may be inaccurate. The specificity to visual scanning could reflect the choice of tests rather than a genuinely narrow effect."},{"rthcId":"RTHC-00078","title":"Growth from birth to early adolescence in offspring prenatally exposed to cigarettes and marijuana.","authors":"Fried, P A; Watkinson, B; Gray, R","year":1999,"journal":"Neurotoxicology and teratology, 21(5), 513-25","doi":null,"pmid":"10492386","tags":["pregnancy","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tracked weight, height, and head circumference from birth through early adolescence in children whose prenatal marijuana and cigarette exposure had been documented.\n\nPrenatal cigarette exposure produced clear effects at birth, with lower weight, but these differences disappeared within the first few years as children caught up. By age six, children of heavy smokers were actually heavier than controls. Interestingly, the catch-up appeared related to bottle-feeding or shorter breastfeeding duration among smoking mothers.\n\nPrenatal marijuana exposure showed a different and more subtle pattern. No significant growth differences were visible at birth. However, a trend toward smaller head circumference was observed at all ages, and this reached statistical significance among early adolescents born to heavy marijuana users. Head circumference is used as a proxy for brain size, making this finding potentially concerning.","whyItMatters":"The delayed emergence of the head circumference finding is important: prenatal marijuana effects may not be visible at birth but could manifest as development progresses. This pattern of \"sleeper effects\" became a recurring theme in prenatal cannabis exposure research.","specificNumbers":"Prenatal cigarette effects on birth weight reversed within first few years. By age 6, heavy smokers' children were heavier. Prenatal marijuana: no growth effects at birth, but smaller head circumference reached significance in early adolescence among heavy users.","methodology":"Longitudinal study tracking children from a low-risk, predominantly middle-class sample from birth through early adolescence. Prenatal marijuana and cigarette exposure was ascertained prospectively. Growth measures (weight, height, head circumference) were tracked at multiple time points.","limitations":"Head circumference is an imprecise proxy for brain development. The effect reached significance only among heavy users in the early adolescent subgroup. Self-reported prenatal substance use may be inaccurate. The predominantly middle-class sample may not represent higher-risk populations."},{"rthcId":"RTHC-00079","title":"Chronic (-)-delta9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats.","authors":"Gorriti, M A; Rodríguez de Fonseca, F; Navarro, M; Palomo, T","year":1999,"journal":"European journal of pharmacology, 365(2-3), 133-42","doi":null,"pmid":"9988095","tags":["psychosis","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers investigated whether chronic cannabis exposure could sensitize the brain to psychosis-like effects, using amphetamine-induced behavior in rats as a model.\n\nThree patterns emerged across different exposure conditions. Acute THC antagonized amphetamine's stimulant effects, essentially blocking the amphetamine response. During chronic THC treatment (14 days), tolerance developed to this blocking effect on some measures, while amphetamine-induced stereotypies (repetitive behaviors) were actually potentiated.\n\nMost significantly, 24 hours after stopping 14 days of THC, rats showed sensitization to amphetamine's effects. The animals became hyperresponsive to amphetamine's ability to increase locomotion, exploration, and stereotypies. This sensitization pattern parallels what is seen in animal models of psychosis.\n\nSince CB1 receptors are densely located in limbic and basal ganglia circuits where amphetamine enhances dopamine and serotonin, these findings supported a role for the cannabinoid system in regulating the monoaminergic circuits implicated in psychosis.","whyItMatters":"This study provided a mechanistic model for how cannabis use might increase vulnerability to psychosis. By demonstrating that chronic THC exposure sensitizes the dopamine system, it connected two previously separate observations: clinical reports of cannabis-associated psychosis and the dopamine hypothesis of schizophrenia.","specificNumbers":"Two THC doses: 0.1 and 6.4 mg/kg. Fourteen days of chronic treatment. Sensitization observed 24 hours after last dose. Three behavioral measures showing sensitization: locomotion, exploration, stereotypies.","methodology":"Animal behavioral pharmacology in male rats. Three conditions: acute THC, chronic THC (14 days), and 24-hour withdrawal after chronic THC. Two doses of THC (0.1 and 6.4 mg/kg). Amphetamine responses measured on a hole-board assessing locomotion, exploration, inactivity, and stereotypies.","limitations":"Animal model using forced drug administration, not voluntary use. The amphetamine-psychosis model is an approximation of human psychosis, not a direct equivalent. The 24-hour withdrawal timepoint may represent an acute withdrawal state rather than lasting sensitization."},{"rthcId":"RTHC-00080","title":"Cancer cachexia and cannabinoids.","authors":"Gorter, R W","year":1999,"journal":"Forschende Komplementarmedizin, 6 Suppl 3, 21-2","doi":null,"pmid":"10575285","tags":["cancer","appetite","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Anorexia and cachexia (severe weight loss) are diagnosed in more than two-thirds of cancer patients with advanced disease and independently increase illness and death risk. Patients often rate nausea and appetite loss as more detrimental to quality of life than even severe pain.\n\nTHC was licensed as an antiemetic in 1986 and had shown significant appetite stimulation and weight gain in clinical studies of HIV and cancer patients. However, the psychoactive side effects of pure THC limited its tolerability.\n\nThe review highlighted a key insight: whole cannabis appeared to be better tolerated than THC alone because it contains additional cannabinoids, particularly CBD, which counteract THC's psychoactive effects without inhibiting the appetite-stimulating effect. The authors proposed comparing whole-plant cannabis extracts to THC alone in controlled studies.","whyItMatters":"This review articulated the \"entourage effect\" hypothesis in a clinical context: that whole cannabis containing multiple cannabinoids might have a better therapeutic profile than isolated THC. This concept drove the development of whole-plant cannabis medications.","specificNumbers":"More than two-thirds of advanced cancer patients develop cachexia. THC licensed as antiemetic in 1986. Appetite stimulation and weight gain demonstrated in HIV and cancer studies.","methodology":"Narrative review of cancer cachexia literature and cannabinoid appetite stimulation research, proposing a research agenda for whole-plant extracts versus pure THC.","limitations":"The review presented a hypothesis for testing rather than established evidence. The \"strong indications\" that cannabis is better tolerated than THC alone were largely anecdotal at the time. The proposed controlled studies were not yet completed."},{"rthcId":"RTHC-00081","title":"History of alcohol or drug problems, current use of alcohol or marijuana, and success in quitting smoking.","authors":"Humfleet, G; Muñoz, R; Sees, K; Reus, V; Hall, S","year":1999,"journal":"Addictive behaviors, 24(1), 149-54","doi":null,"pmid":"10189984","tags":["quitting","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers examined how alcohol and drug histories affected smoking cessation in 199 clinic patients. Nearly a quarter (23%) had a history of alcohol or drug problems, 79% used alcohol, and 21% used marijuana during treatment.\n\nHistory of substance abuse did not predict cessation outcomes. But current substance use patterns diverged sharply. Alcohol use, even at low-to-moderate levels, predicted smoking at every follow-up assessment. Participants who used any alcohol during treatment had significantly lower quit rates.\n\nMarijuana use told a different story. Neither baseline marijuana use nor marijuana use during treatment predicted smoking outcomes. Marijuana users quit smoking at the same rates as non-marijuana-users.\n\nThis finding was surprising given previous research linking marijuana to smoking cessation failure, suggesting the relationship may be more nuanced than earlier studies indicated.","whyItMatters":"This study challenged the assumption that marijuana use necessarily undermines tobacco cessation. By separating alcohol and marijuana effects, it showed that alcohol was the primary substance-use barrier to quitting smoking, while marijuana was neutral.","specificNumbers":"199 participants. 23% had alcohol/drug problem history. 79% used alcohol. 21% used marijuana during treatment. Alcohol predicted smoking at all follow-up points. Marijuana predicted nothing.","methodology":"Prospective study of 199 smokers in a cessation clinic. History of alcohol/drug problems, current alcohol use, and current marijuana use were assessed. Abstinence was measured at multiple follow-up points.","limitations":"Relatively small sample (199). Marijuana use was self-reported and the 21% rate may reflect varying use levels. The study may not have been powered to detect smaller marijuana effects. The clinic population may not represent all smokers."},{"rthcId":"RTHC-00082","title":"Recent advantages in cannabinoid research.","authors":"Mechoulam, R","year":1999,"journal":"Forschende Komplementarmedizin, 6 Suppl 3, 16-20","doi":null,"pmid":"10575284","tags":["neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Writing 35 years after his group first isolated THC, Mechoulam described the trajectory from an isolated plant molecule to a complete biological system.\n\nThe path was: THC isolation, receptor discovery (CB1 and CB2), and identification of endogenous ligands (anandamide and 2-AG). THC was officially used against chemotherapy vomiting and AIDS-related appetite loss. Illegally, patients used smoked marijuana for MS symptoms, pain, and various other conditions.\n\nA synthetic cannabinoid, HU-211, was in advanced clinical trials for brain damage from closed head injury, with potential applications for stroke and other neurological diseases. This represented a new frontier: cannabinoids as neuroprotectants.\n\nMechoulam's insider perspective highlighted the irony that while the scientific understanding of cannabinoids had become sophisticated, the legal framework remained prohibitive.","whyItMatters":"Coming from the scientist who started the field, this review provided unique historical perspective and identified neuroprotection as an emerging therapeutic frontier. HU-211 represented an attempt to develop cannabinoid-based treatments for acute brain injury.","specificNumbers":"Thirty-five years since THC isolation. Two receptors: CB1 and CB2. Two principal endocannabinoids: anandamide and 2-AG. HU-211 in advanced clinical trials for head injury.","methodology":"Review by the principal discoverer of THC and co-discoverer of endocannabinoids, covering the 35-year arc from THC isolation through receptor and endocannabinoid discovery to clinical applications.","limitations":"A brief review from a specific perspective. HU-211 (dexanabinol) ultimately did not complete its clinical development for head injury. The review does not systematically assess all therapeutic applications."},{"rthcId":"RTHC-00083","title":"Cannabis in movement disorders.","authors":"Müller-Vahl, K R; Kolbe, H; Schneider, U; Emrich, H M","year":1999,"journal":"Forschende Komplementarmedizin, 6 Suppl 3, 23-7","doi":null,"pmid":"10627163","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoid CB1 receptors are densely concentrated in the basal ganglia output nuclei (globus pallidus and substantia nigra), the brain circuits that control voluntary movement. The endocannabinoid system interacts with these circuits by increasing GABA transmission, inhibiting glutamate release, and affecting dopamine uptake.\n\nMost movement disorders, both hyperkinetic (too much movement) and hypokinetic (too little), result from dysfunction in these same basal ganglia circuits. This overlap suggested the endocannabinoid system might participate in movement control and could be a therapeutic target.\n\nLimited clinical trials in humans showed evidence that cannabinoids could help reduce tics in Tourette syndrome, levodopa-induced dyskinesia in Parkinson's disease, and some forms of tremor and dystonia. The review speculated that cannabinoid antagonists (receptor blockers) might help in conditions involving chorea (Huntington's disease) and hypokinetic Parkinson's syndromes.","whyItMatters":"This review connected the neuroanatomy of the endocannabinoid system to the pathophysiology of movement disorders, providing a rational basis for therapeutic trials. The identification of both agonist (Tourette, dyskinesia) and antagonist (chorea, Parkinsonism) applications was particularly sophisticated.","specificNumbers":"CB1 receptors dense in globus pallidus and substantia nigra. Clinical evidence for four movement disorders: Tourette tics, levodopa-induced dyskinesia, tremor, and dystonia.","methodology":"Narrative review of cannabinoid receptor distribution in basal ganglia, endocannabinoid interactions with other neurotransmitter systems, and clinical trial evidence for cannabinoids in movement disorders.","limitations":"The clinical evidence reviewed was \"limited\" and mostly from uncontrolled studies. The speculation about cannabinoid antagonists for chorea and Parkinsonism remains largely untested. Receptor distribution does not guarantee therapeutic utility."},{"rthcId":"RTHC-00084","title":"Cannabis and cannabinoids: pharmacology and rationale for clinical use.","authors":"Pertwee, R G","year":1999,"journal":"Forschende Komplementarmedizin, 6 Suppl 3, 12-5","doi":null,"pmid":"10575283","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review provided a comprehensive pharmacological roadmap for cannabinoid therapeutics. Two CB1 agonists, THC and nabilone, were already in clinical use as antiemetics and appetite stimulants.\n\nThe review identified additional CB1 agonist applications: suppressing muscle spasm and spasticity in MS and spinal cord injury, relieving chronic pain, and managing glaucoma and asthma. But it also proposed the opposite approach: CB1 antagonists might serve as appetite suppressants, and could potentially help manage schizophrenia and cognitive or memory disorders.\n\nCB2 receptor ligands and drugs that boost endocannabinoid levels indirectly represented another therapeutic avenue.\n\nA practical concern was highlighted: oral THC had variable absorption and a narrow therapeutic window, making dosing unpredictable. This pointed to the need for better formulations and administration routes.","whyItMatters":"This review mapped a complete therapeutic strategy: agonists for some conditions, antagonists for others, and indirect approaches that boost endocannabinoids. This framework guided cannabinoid drug development for the following two decades.","specificNumbers":"Two receptor types: CB1 and CB2. Two drugs in clinical use: THC and nabilone. Multiple proposed applications for agonists, antagonists, and indirect approaches.","methodology":"Pharmacological review covering cannabinoid receptor subtypes, endocannabinoid system, clinical applications of agonists and antagonists, and formulation challenges.","limitations":"A forward-looking review based on available evidence that was largely preclinical for many proposed applications. The therapeutic window problem remained unsolved for many applications."},{"rthcId":"RTHC-00085","title":"Medical marijuana: legal considerations.","authors":"Schouten, J T","year":1999,"journal":"STEP perspective, 99(2), 5","doi":null,"pmid":"11366751","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This review examined the legal framework created by Washington State Initiative 692, passed in 1998. The law allowed patients to possess marijuana for medical purposes with documentation from a physician.\n\nQualifying conditions included HIV/AIDS, cancer, multiple sclerosis, and epilepsy. Patients could legally possess up to a 60-day supply.\n\nThe article explored the practical legal considerations for both patients and healthcare providers navigating this new framework, including the tension between state law and ongoing federal prohibition of marijuana.","whyItMatters":"Washington was among the earliest states to pass medical marijuana legislation. Understanding these early legal frameworks helps contextualize how the patchwork of state-level cannabis laws evolved and why inconsistencies between state and federal law continued to create uncertainty for patients and providers.","specificNumbers":"Initiative 692 passed in Washington State. A 60-day supply was the possession limit. Qualifying conditions included HIV, cancer, MS, and epilepsy. Physician documentation was required.","methodology":"This was a legal review and analysis published in a medical perspectives journal. The author examined the text and implications of Washington State Initiative 692, discussing its provisions, qualifying conditions, and practical considerations for medical providers and patients.","limitations":"This review reflected the legal landscape as of 1999 and did not predict subsequent legislative changes. It focused on a single state's law and may not apply to other jurisdictions. The article did not evaluate clinical evidence for marijuana's medical effectiveness."},{"rthcId":"RTHC-00086","title":"One-year prospective prediction of marijuana use cessation among youth at continuation high schools.","authors":"Sussman, S; Dent, C W","year":1999,"journal":"Addictive behaviors, 24(3), 411-7","doi":null,"pmid":"10400279","tags":["youth","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tracked 566 current marijuana users at continuation high schools (alternative schools for at-risk youth) over one year. Quitting was defined as not having used in the last 30 days and having no intention to use in the future.\n\nThirty-one percent of baseline users met this definition of quitting one year later, a substantial rate of self-initiated cessation. Four factors predicted quitting: being slightly older, receiving relatively less peer approval for drug use, holding relatively unfavorable personal attitudes about drug acceptability, and reporting less victimization in the past year.\n\nThe finding that social attitudes and peer approval were the strongest modifiable predictors suggested that prevention efforts focused on increasing the social unacceptability of marijuana use could support self-initiated quitting.","whyItMatters":"This was one of the first large studies of naturalistic marijuana cessation among adolescents. The 31% quit rate showed that adolescent marijuana use is not uniformly persistent, and the identification of modifiable predictors (peer attitudes, personal beliefs) provided targets for prevention programming.","specificNumbers":"566 adolescent marijuana users. 31% quit within one year. Four significant predictors: older age, less peer approval, unfavorable drug attitudes, less victimization.","methodology":"One-year prospective study of 566 current marijuana users at continuation high schools. Social, attitudinal, intrapersonal, violence-related, drug-use-related, and demographic baseline measures predicted cessation at one-year follow-up.","limitations":"Self-reported quitting without biochemical verification. Continuation high school students are a specific at-risk population. The 30-day abstinence criterion may not reflect sustained cessation. Attrition between baseline and follow-up may bias results."},{"rthcId":"RTHC-00087","title":"Marijuana mania.","authors":"Syracopoulos, T","year":1999,"journal":"STEP perspective, 99(2), 2-3, 6","doi":null,"pmid":"11366748","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This review surveyed the history of marijuana as a medical substance and the state of cannabis research at the close of the 20th century. It highlighted the longstanding tension between marijuana's widespread historical use and the legal barriers that had constrained modern scientific investigation.\n\nA notable development was NIDA's 1999 decision to begin selling research-grade marijuana to private researchers, ending the agency's monopoly on who could study the substance. This policy change was expected to accelerate clinical research.\n\nThe article identified pain management, AIDS-related wasting syndrome, and chemotherapy-induced nausea as the most promising therapeutic targets for cannabis-based treatments.","whyItMatters":"By 1999, medical marijuana laws were spreading across states, but rigorous clinical research remained scarce due to federal restrictions on cannabis supply. NIDA's policy shift represented a meaningful reduction in one of the biggest barriers to studying marijuana's medical potential.","specificNumbers":"NIDA began selling research marijuana to private researchers in 1999. Pain, AIDS wasting, and chemotherapy-induced nausea were identified as primary therapeutic targets.","methodology":"This was a narrative review published in a perspectives journal. The author surveyed historical uses of marijuana, summarized the contemporary regulatory landscape, and identified areas of therapeutic promise based on existing preliminary evidence and clinical interest.","limitations":"This was an opinion and perspectives piece rather than a systematic review. It did not evaluate the strength of existing clinical evidence for any therapeutic indication. The research landscape it described has changed substantially since 1999."},{"rthcId":"RTHC-00088","title":"Factors in marijuana cessation among high-risk youth.","authors":"Weiner, M D; Sussman, S; McCuller, W J; Lichtman, K","year":1999,"journal":"Journal of drug education, 29(4), 337-57","doi":null,"pmid":"10786412","tags":["youth","quitting","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 842 students at eleven continuation high schools in southern California about marijuana use and cessation using both questionnaires and focus groups.\n\nApproximately 70% were current marijuana users. Interest in quitting was high, and over half of users had tried to quit at least once and failed. However, students expressed little confidence in the effectiveness of formal marijuana cessation programs.\n\nStudents believed either self-help approaches or punitive methods (legal consequences, school discipline) were the most effective cessation strategies. Several positive social images remained associated with marijuana use, which competed with motivations to quit.\n\nThe reasons for continuing use centered on stress relief, while motivations for wanting to quit included legal consequences, vocational concerns, and health effects. The high rate of failed quit attempts suggested that effective cessation programs were genuinely needed, even as students doubted their value.","whyItMatters":"This study revealed a gap between adolescent desire to quit marijuana and their ability to do so successfully, while also showing that existing programs were not meeting their needs. The finding that stress relief was the primary reason for continued use pointed to the need for alternative coping strategies in cessation programs.","specificNumbers":"842 students across 11 schools. 70% current marijuana users. Over 50% had tried to quit and failed. Self-help and punitive methods viewed as most effective.","methodology":"Mixed-methods study with open-ended and multiple-choice surveys plus health educator-led focus groups. Two separate samples from eleven continuation high schools in southern California. Total N=842.","limitations":"Continuation high school students represent a specific high-risk population. Self-reported data without verification. The belief that punitive methods work does not necessarily mean they do. Focus groups may amplify dominant opinions."},{"rthcId":"RTHC-00089","title":"Cannabinoids control spasticity and tremor in a multiple sclerosis model.","authors":"Baker, D; Pryce, G; Croxford, J L; Brown, P; Pertwee, R G; Huffman, J W; Layward, L","year":2000,"journal":"Nature, 404(6773), 84-7","doi":null,"pmid":"10716447","tags":["medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"strong","keyFinding":"Using a mouse model of MS (chronic relapsing experimental allergic encephalomyelitis) that produces spasticity and tremor similar to human MS, researchers tested multiple cannabinoid compounds.\n\nFour different cannabinoid receptor agonists, including THC, all quantitatively reduced both tremor and spasticity in the diseased mice. This was the first objective, quantitative demonstration in an animal model.\n\nThe more revelatory finding came from the antagonist experiments. When cannabinoid receptors were blocked (particularly CB1), spasticity and tremor worsened. This meant the body's own endocannabinoid system was already actively working to control these symptoms. Cannabinoid drugs were not introducing a new effect but rather augmenting an existing natural defense mechanism.\n\nThis provided the scientific rationale for MS patients' reports that cannabis helped their symptoms and established a framework for developing more selective cannabinoid treatments.","whyItMatters":"Published in Nature, one of science's most prestigious journals, this study provided the strongest preclinical evidence yet for cannabis in MS. The finding that blocking cannabinoid receptors worsened symptoms was particularly important because it revealed an active endocannabinoid tone controlling spasticity, a previously unknown function.","specificNumbers":"Four cannabinoid agonists tested, all effective. Two antagonists tested: CB1 blockade notably worsened symptoms. Both tremor and spasticity were quantitatively measured and improved.","methodology":"Controlled animal study using CREAE mice (MS model). Tested four cannabinoid agonists (R(+)-WIN 55,212, THC, methanandamide, JWH-133) and two antagonists (SR141716A targeting CB1, SR144528 targeting CB2). Spasticity and tremor were quantitatively measured.","limitations":"Mouse model of MS, not human MS. CREAE captures some but not all features of human MS. Quantitative measures in mice may not predict clinical significance in humans. Short-term drug effects measured without long-term follow-up."},{"rthcId":"RTHC-00090","title":"The ethics of medical marijuana: government restrictions vs. medical necessity.","authors":"Clark, P A","year":2000,"journal":"Journal of public health policy, 21(1), 40-60","doi":null,"pmid":"10754797","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This ethics review examined the medical marijuana controversy through the lens of biomedical ethics.\n\nThe factual foundation was established by the 1999 Institute of Medicine report, in which eleven independent scientists found medical marijuana effective for controlling some pain, alleviating chemotherapy-induced nausea and vomiting, treating AIDS-related wasting, and combating MS-related muscle spasms. The report also found no evidence that marijuana was a \"gateway\" drug or that medical use would increase illicit use.\n\nDespite this evidence, the DEA refused to reclassify marijuana from Schedule I (no accepted medical use) to Schedule II (medical use with restrictions).\n\nApplying the principle of double effect, a foundational framework in medical ethics for evaluating treatments that have both good and bad effects, the author concluded there was proportionate reason for allowing physicians to prescribe marijuana. The ethical argument was straightforward: seriously ill patients have a right to effective therapies, and denying access denies them dignity and respect.","whyItMatters":"This was one of the first formal bioethics analyses of medical marijuana policy. By framing the issue as one of patient rights and dignity rather than pharmacology alone, it introduced ethical arguments that proved influential in subsequent policy debates.","specificNumbers":"Eleven IOM scientists. Four conditions with evidence: pain, chemotherapy nausea, AIDS wasting, MS spasticity. IOM found no evidence of gateway effect.","methodology":"Ethics review applying the principle of double effect to scientific evidence from the Institute of Medicine report and other sources, examining the tension between drug policy and patient rights.","limitations":"The ethical analysis assumed the IOM evidence was definitive, though some of the evidence was preliminary. The principle of double effect, while established in ethics, involves subjective judgments about proportionality. The review did not fully address potential harms of medical marijuana access."},{"rthcId":"RTHC-00091","title":"Substance dependence and other psychiatric disorders among drug dependent subjects: race and gender correlates.","authors":"Compton, W M; Cottler, L B; Ben Abdallah, A; Phelps, D L; Spitznagel, E L; Horton, J C","year":2000,"journal":"The American journal on addictions, 9(2), 113-25","doi":null,"pmid":"10934573","tags":["addiction","mental-health","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers interviewed drug-dependent individuals in treatment using a structured diagnostic tool. The rates of co-occurring psychiatric disorders were striking.\n\nLifetime prevalence rates included: alcohol dependence (64%), antisocial personality disorder (44%), phobic disorders (39%), major depression (24%), dysthymia (12%), and generalized anxiety disorder (10%). These rates far exceeded general population prevalences.\n\nRace and gender differences were significant. Caucasians had higher rates of cannabis, alcohol, hallucinogen, opiate, and sedative dependence, plus higher rates of depression, dysthymia, and anxiety compared to African-Americans. Men had higher cannabis dependence rates than women, while women had higher rates of depression, dysthymia, panic, and OCD.\n\nThe racial differences in treatment populations contrasted with community surveys, suggesting differential treatment-seeking patterns rather than true prevalence differences.","whyItMatters":"This study documented the extensive psychiatric comorbidity among cannabis and other drug-dependent individuals, showing that substance use disorders rarely exist in isolation. The racial differences in treatment populations versus community surveys highlighted important disparities in access to or willingness to seek treatment.","specificNumbers":"Alcohol dependence: 64%. ASPD: 44%. Phobic disorders: 39%. Major depression: 24%. Dysthymia: 12%. GAD: 10%. Caucasians and males had higher cannabis dependence rates.","methodology":"Cross-sectional diagnostic study using the NIMH Diagnostic Interview Schedule to assess DSM-III-R disorders in drug treatment patients. Stratified by race and gender.","limitations":"Treatment-seeking populations may not represent all drug-dependent individuals. Race was used as a category, which may oversimplify complex social and cultural factors. DSM-III-R criteria are now outdated. The cross-sectional design cannot determine which conditions preceded which."},{"rthcId":"RTHC-00092","title":"Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from 1980-1997.","authors":"ElSohly, M A; Ross, S A; Mehmedic, Z; Arafat, R; Yi, B; Banahan, B F","year":2000,"journal":"Journal of forensic sciences, 45(1), 24-30","doi":null,"pmid":"10641915","tags":["potency"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Researchers analyzed 35,312 cannabis preparations confiscated in the United States between 1980 and 1997, categorizing them as marijuana, sinsemilla, hashish, hash oil, Thai sticks, or ditchweed.\n\nMore than 82% of confiscated samples were marijuana in every year. The potency story was clear: marijuana THC content rose from under 1.5% in 1980 to approximately 3.3% in 1983-84, fluctuated around 3% through 1992, then began a continuous rise reaching 4.2% by 1997.\n\nThe average THC concentration across all cannabis samples showed a gradual rise from 3% in 1991 to 4.47% in 1997. Hashish and hash oil showed no specific potency trends.\n\nOther major cannabinoids, CBD, CBN, and CBC, showed no significant concentration changes over the 18-year period, meaning the increasing potency was specific to THC, not a general increase in all cannabinoid concentrations.","whyItMatters":"This was the definitive documentation of rising marijuana potency in the United States. The finding that THC was rising while CBD was not meant the ratio of psychoactive to potentially therapeutic cannabinoids was shifting, a trend that continued dramatically in subsequent decades.","specificNumbers":"35,312 samples analyzed over 18 years. THC: under 1.5% (1980) to 4.2% (1997). Continuous rise since 1992. CBD, CBN, CBC: no significant change. Over 82% of samples were marijuana category.","methodology":"Systematic analysis of 35,312 confiscated cannabis preparations from U.S. law enforcement seizures, 1980-1997. Samples were categorized by type and analyzed for THC and other major cannabinoids.","limitations":"Confiscated samples may not represent all marijuana available. Law enforcement seizure patterns could bias which products are captured. The analysis covers only through 1997; subsequent increases were even more dramatic."},{"rthcId":"RTHC-00093","title":"Impaired cognitive performance in drug free users of recreational ecstasy (MDMA).","authors":"Gouzoulis-Mayfrank, E; Daumann, J; Tuchtenhagen, F; Pelz, S; Becker, S; Kunert, H J; Fimm, B; Sass, H","year":2000,"journal":"Journal of neurology, neurosurgery, and psychiatry, 68(6), 719-25","doi":null,"pmid":"10811694","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared cognitive performance across three carefully matched groups of 28 participants each: ecstasy users (who also used cannabis), cannabis-only users, and non-users. The ecstasy users had typical recreational use patterns, not extremely heavy use.\n\nEcstasy users performed normally on simple attention tests but showed significant impairment on complex attention tasks, memory and learning, and aspects of general intelligence. Heavier ecstasy and cannabis use correlated with poorer performance within the ecstasy group.\n\nThe cannabis-only group did not differ significantly from non-users on any cognitive measure.\n\nThe researchers attributed the cognitive decline primarily to ecstasy's known neurotoxic effects on the serotonin system, suggesting that even typical recreational doses may cause sufficient neurotoxicity to impair cognition in otherwise healthy young people. A working memory impairment was proposed as the common denominator.","whyItMatters":"By including a cannabis-only comparison group, this study could separate ecstasy effects from cannabis effects. The finding that cannabis-only users showed no cognitive impairment relative to non-users (while ecstasy users did) suggested that cannabis was not the driver of cognitive problems in polydrug-using populations.","specificNumbers":"Three groups of 28. Ecstasy users impaired on complex attention, memory, and intelligence. Cannabis users not different from non-users. Heavier ecstasy and cannabis use correlated with worse performance in ecstasy group only.","methodology":"Cross-sectional comparison of three matched groups of 28: abstinent ecstasy+cannabis users, cannabis-only users, and non-users. Comprehensive cognitive battery assessing attention, memory, learning, and intelligence. All participants were drug-free at testing.","limitations":"Small sample (28 per group). Cross-sectional design. The ecstasy group used cannabis concurrently, so additive or interactive effects cannot be fully separated. Self-reported drug histories. \"Cannabis-only\" may still include unreported other drug use."},{"rthcId":"RTHC-00094","title":"Cannabis, vulnerability, and the onset of schizophrenia: an epidemiological perspective.","authors":"Hambrecht, M; Häfner, H","year":2000,"journal":"The Australian and New Zealand journal of psychiatry, 34(3), 468-75","doi":null,"pmid":"10881971","tags":["psychosis","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"From a German population of 1.5 million, researchers identified 232 first-episode schizophrenia patients and carefully mapped the timeline of cannabis abuse relative to the onset of psychotic symptoms.\n\nThirteen percent had a history of cannabis abuse, double the rate in matched controls. Male sex and early symptom onset were major risk factors.\n\nThe timing analysis revealed three approximately equal groups. Group 1 had been using cannabis for several years before any signs of schizophrenia. Group 2 started cannabis and experienced first symptoms within the same month. Group 3 began cannabis use after schizophrenia symptoms had already started.\n\nThe researchers proposed different mechanisms for each: Group 1 might reflect cannabis gradually eroding the vulnerability threshold. Group 2 might represent cannabis as the precipitating stress in already-vulnerable individuals. Group 3 likely represents self-medication, with patients using cannabis to cope with symptoms, particularly negative and depressive symptoms.","whyItMatters":"By carefully timing the onset of both cannabis use and psychotic symptoms, this study moved beyond the simple question of \"does cannabis cause psychosis\" to reveal multiple distinct pathways. This nuanced framework influenced subsequent research and clinical thinking.","specificNumbers":"232 first-episode patients. 13% had cannabis abuse history (2x controls). Three equal groups: cannabis first, simultaneous onset, symptoms first. Male sex and early onset were risk factors.","methodology":"Population-based first-episode study from a German catchment area of 1.5 million. 232 schizophrenia patients interviewed with the Retrospective Assessment of the Onset of Schizophrenia. Onset timing of cannabis abuse and schizophrenic symptoms (including prodromal symptoms) compared. Relatives validated patient reports.","limitations":"Retrospective timing of symptom and drug use onset is subject to recall bias. The three groups are approximate and the boundaries between them may be artificial. The sample included only those who developed schizophrenia, missing individuals who used cannabis without developing psychosis."},{"rthcId":"RTHC-00095","title":"An approach to the medical marijuana controversy.","authors":"Hollister, L E","year":2000,"journal":"Drug and alcohol dependence, 58(1-2), 3-7","doi":null,"pmid":"10669050","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Writing in Drug and Alcohol Dependence, Leo Hollister (a highly respected pharmacologist) proposed a practical solution to the medical marijuana impasse.\n\nThe evidence supporting therapeutic marijuana use was insufficient for FDA approval, yet many patients maintained it was necessary for their treatment. His proposed interim solution: a structured 6-month program of legal marijuana availability, similar to the previous \"compassionate IND\" program, combined with post-marketing surveillance techniques to collect quantitative data.\n\nFour conditions were prioritized for data collection: nausea and vomiting from chemotherapy or other causes, weight loss from debilitating illnesses, spasticity from neurological diseases, and chronic pain syndromes.\n\nThis approach would simultaneously provide patient access and generate the structured clinical data needed for regulatory decisions.","whyItMatters":"This proposal from a respected establishment researcher represented a pragmatic middle ground: providing access while generating evidence. The framework anticipated the structure that many state medical marijuana programs eventually adopted, though without the rigorous data collection component.","specificNumbers":"Six-month program proposed. Four priority conditions: nausea/vomiting, wasting, spasticity, chronic pain. Model based on compassionate IND precedent.","methodology":"Commentary proposing a policy framework combining compassionate access with structured data collection. Referenced the historical compassionate IND model and post-marketing surveillance methodology.","limitations":"A policy proposal rather than a research study. The practicality of collecting quantitative data from a compassionate access program was not demonstrated. The proposal did not address regulatory and legal barriers to implementation."},{"rthcId":"RTHC-00096","title":"Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins.","authors":"Kendler, K S; Karkowski, L M; Neale, M C; Prescott, C A","year":2000,"journal":"Archives of general psychiatry, 57(3), 261-9","doi":null,"pmid":"10711912","tags":["genetics","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers interviewed 1,198 male-male twin pairs (708 identical, 490 fraternal) from a population registry about lifetime use, heavy use, abuse, and dependence on six drug classes including cannabis.\n\nTwin resemblance was consistently greater in identical twins than fraternal twins across all measures. For any drug use and for cannabis specifically, both genetic and family-environmental factors contributed. But for heavy use, abuse, and dependence, resemblance was caused almost entirely by genetic factors, with heritability typically ranging from 60% to 80%.\n\nThis mirrored earlier findings in female twins by the same research group. In both men and women, the family environment influenced whether someone tries drugs, but genetics overwhelmingly determines who progresses to problematic use.","whyItMatters":"Combined with the earlier female twin study (RTHC-00068), this established that the genetic architecture of substance use disorders is remarkably similar across sexes: environment shapes initiation, but genetics shapes escalation.","specificNumbers":"1,198 twin pairs (708 MZ, 490 DZ). Heritability of heavy use, abuse, and dependence: 60-80%. Six drug classes studied. Family environment contributed to initiation but not escalation.","methodology":"Population-based twin study with 1,198 male-male twin pairs (708 MZ, 490 DZ). Personal interviews assessed lifetime use, heavy use, abuse, and dependence for cannabis, sedatives, stimulants, cocaine, opiates, and hallucinogens. Biometric model fitting estimated genetic and environmental contributions.","limitations":"Twin studies assume equal environments for MZ and DZ twins. Lifetime assessments are retrospective and subject to recall bias. The registry-based sample may not represent all populations. Specific genes were not identified."},{"rthcId":"RTHC-00097","title":"Detection of cannabis in oral fluid (saliva) and forehead wipes (sweat) from impaired drivers.","authors":"Kintz, P; Cirimele, V; Ludes, B","year":2000,"journal":"Journal of analytical toxicology, 24(7), 557-61","doi":null,"pmid":"11043659","tags":["driving","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers collected blood, urine, saliva, and forehead sweat simultaneously from 198 injured drivers in Strasbourg, France. Of 22 drivers who tested positive for cannabis metabolites in urine, 14 had detectable THC in saliva and 16 had detectable THC in forehead sweat.\n\nSaliva THC concentrations ranged from 1 to 103 ng per collection device, while forehead wipe concentrations ranged from 4 to 152 ng per pad. Neither metabolite (11-OH-THC and THC-COOH) was detected in saliva or sweat, only the parent compound THC.\n\nThe advantage of saliva and sweat over urine is that they detect THC itself rather than metabolites, better indicating recent use and likely current impairment. The non-invasive collection was practical for roadside situations. However, limitations included smaller specimen volumes and the absence of sufficiently sensitive immunoassays for roadside screening.","whyItMatters":"This study advanced the development of non-invasive cannabis impairment testing for drivers. By detecting parent THC rather than metabolites, saliva and sweat testing better reflects recent use than urine, where metabolites can persist for days to weeks after last use.","specificNumbers":"198 drivers. 22 urine-positive. 14 saliva-positive (64%). 16 sweat-positive (73%). Saliva THC: 1-103 ng. Sweat THC: 4-152 ng.","methodology":"Cross-sectional study of 198 injured drivers at a Strasbourg emergency hospital. Four specimen types collected simultaneously. GC-MS analysis for THC in saliva (Salivettes) and forehead wipes (cosmetic pads).","limitations":"Only 22 cannabis-positive drivers in the sample. Saliva and sweat missed some urine-positive drivers (36% and 27% false negative, respectively). No immunoassay suitable for field screening existed at the time. THC can deposit in the oral cavity from smoking, confounding the distinction between systemic and local contamination."},{"rthcId":"RTHC-00098","title":"The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis.","authors":"Malfait, A M; Gallily, R; Sumariwalla, P F; Malik, A S; Andreakos, E; Mechoulam, R; Feldmann, M","year":2000,"journal":"Proceedings of the National Academy of Sciences of the United States of America, 97(17), 9561-6","doi":null,"pmid":"10920191","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"strong","keyFinding":"Using two mouse models of rheumatoid arthritis, researchers tested CBD given after clinical symptoms had already appeared, mimicking how patients would actually use the treatment.\n\nCBD effectively blocked arthritis progression in both acute and chronic relapsing models. It worked whether given by injection or orally, an important practical finding. The dose-response curve was bell-shaped, with an optimal effect at 5 mg/kg injected or 25 mg/kg orally.\n\nJoint protection was confirmed: CBD-treated animals showed less joint damage than controls. The mechanism involved multiple immune pathways: decreased proliferation of disease-causing immune cells, reduced production of the inflammatory cytokine IFN-gamma, reduced tumor necrosis factor from joint tissue cells, suppressed lymphocyte proliferation, and blocked inflammatory oxidative bursts.\n\nCBD also blocked the systemic inflammatory response to bacterial toxins, demonstrating broad anti-inflammatory potential.","whyItMatters":"Published in PNAS and co-authored by Mechoulam, this study provided the strongest preclinical evidence for CBD as an anti-arthritic agent. The combination of multiple anti-inflammatory mechanisms and the finding that oral administration was effective supported CBD's therapeutic potential for autoimmune joint diseases.","specificNumbers":"Optimal dose: 5 mg/kg i.p. or 25 mg/kg oral. Bell-shaped dose response. Joint protection confirmed histologically. Multiple immune markers suppressed.","methodology":"Controlled animal study using two murine collagen-induced arthritis models (acute and chronic relapsing). CBD administered i.p. and orally after symptom onset. Outcomes: clinical disease scores, joint histology, lymph node cell proliferation, cytokine production, oxidative burst, and systemic TNF response.","limitations":"Mouse arthritis models do not perfectly replicate human rheumatoid arthritis. The bell-shaped dose curve means finding the right human dose is complex. Long-term effects were not assessed. Translation from mouse to human doses is imprecise."},{"rthcId":"RTHC-00099","title":"Cognitive performance amongst recreational users of \"ecstasy\".","authors":"Rodgers, J","year":2000,"journal":"Psychopharmacology, 151(1), 19-24","doi":null,"pmid":"10958112","tags":["cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared cognitive function across three groups of 15 young people: regular ecstasy users, regular cannabis users who had never taken ecstasy, and drug-free controls.\n\nReaction times (visual, auditory, complex) were similar across all three groups. Visual memory, attention, and concentration also showed no differences.\n\nVerbal memory was impaired in both cannabis users and ecstasy users compared to controls. However, delayed memory (the ability to recall information after a time gap) was impaired only in ecstasy users, distinguishing their cognitive profile from cannabis users.\n\nA notable secondary finding: despite objective cognitive impairments, neither user group reported more cognitive failures in daily life than controls on the Cognitive Failures Questionnaire. Users were not aware of their own deficits.","whyItMatters":"Unlike the previous ecstasy-cannabis comparison (RTHC-00093) which found no cannabis effects, this study found verbal memory impairment in both groups. The discrepancy highlights how study design, tests used, and population characteristics affect findings. The lack of self-awareness of deficits is clinically important.","specificNumbers":"Three groups of 15. Verbal memory impaired in both user groups. Delayed memory impaired only in ecstasy users. Reaction times unaffected in all groups. No subjective awareness of cognitive deficits.","methodology":"Cross-sectional comparison of three groups of 15: ecstasy users, cannabis-only users, and non-users. Wechsler Memory Scale (revised) and computerized reaction time tasks administered while drug-free. Cognitive Failures Questionnaire assessed subjective cognitive complaints.","limitations":"Very small groups (15 each). Cannabis users varied in frequency and duration of use. Self-reported drug history without verification. Cross-sectional design cannot determine causation. The ecstasy group may have differed from cannabis group in other unmeasured ways."},{"rthcId":"RTHC-00100","title":"The impact of substance abuse on the course of bipolar disorder.","authors":"Strakowski, S M; DelBello, M P; Fleck, D E; Arndt, S","year":2000,"journal":"Biological psychiatry, 48(6), 477-85","doi":null,"pmid":"11018221","tags":["mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 50 new-onset bipolar disorder patients over time, tracking the temporal relationship between substance abuse symptoms and mood episodes.\n\nA striking dissociation emerged between alcohol and cannabis. The duration of alcohol abuse during follow-up was associated with the amount of time patients experienced depression. In contrast, the duration of cannabis abuse was associated with the duration of mania.\n\nSeveral subgroups with different temporal relationships could be identified, suggesting the relationship between substance use and bipolar symptoms is not uniform across all patients. The effects may involve both direct pharmacological actions on mood and indirect effects through impaired treatment compliance.","whyItMatters":"The differential association, alcohol with depression and cannabis with mania, suggested these substances interact with different aspects of bipolar pathophysiology. This has implications for treatment: addressing alcohol use might help depression, while addressing cannabis use might help mania.","specificNumbers":"50 new-onset bipolar patients. Alcohol abuse duration correlated with depression duration. Cannabis abuse duration correlated with mania duration. Multiple subgroups identified.","methodology":"Longitudinal follow-up study of 50 new-onset bipolar disorder patients. Regression and time-series correlative methods were used to examine associations between alcohol and cannabis abuse symptoms and affective symptoms over time.","limitations":"Small sample (50 patients). Correlation does not establish causation. Cannabis could trigger mania, or manic episodes could increase cannabis use, or both. The subgroup analysis was exploratory and sample sizes per subgroup were small."},{"rthcId":"RTHC-00101","title":"Marijuana and medicine: assessing the science base: a summary of the 1999 Institute of Medicine report.","authors":"Watson, S J; Benson, J A; Joy, J E","year":2000,"journal":"Archives of general psychiatry, 57(6), 547-52","doi":null,"pmid":"10839332","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Responding to public pressure, the Office of National Drug Control Policy funded a comprehensive study by the Institute of Medicine. The resulting report used scientific reviews, public hearings, and expert evaluation.\n\nThe key findings: cannabinoids showed therapeutic potential for pain, chemotherapy nausea, and appetite stimulation. But the report recommended against smoked marijuana as medicine due to the health risks of smoking.\n\nInstead, the IOM recommended developing a medical cannabinoid inhaler that would deliver the rapid onset of smoking without combustion-related harm. For patients with immediate needs, compassionate use of marijuana under carefully reviewed protocols was recommended.\n\nThe report called for major research investment in cannabinoid biology, careful clinical trials, psychological effects analysis, and evaluation of heavy use consequences. On addiction and gateway concerns, the report found limited evidence that medical cannabinoid use would lead to widespread abuse or serve as a gateway to other drugs.","whyItMatters":"The IOM report was the most authoritative and comprehensive assessment of medical marijuana by a major scientific institution. Its conclusions influenced federal and state policy for decades and became the most-cited reference in medical marijuana debates.","specificNumbers":"Therapeutic potential identified for pain, nausea, and appetite. Limited gateway and addiction risk. Recommended: cannabinoid inhaler development, research investment, compassionate use under protocols.","methodology":"Comprehensive systematic evaluation by the Institute of Medicine, incorporating scientific literature reviews, public hearings, agency reports, and expert evaluation.","limitations":"The report was constrained by the evidence available through the late 1990s. Its recommendation against smoked marijuana was partly superseded by vaporizer technology. The compassionate use recommendation was narrower than what state programs eventually implemented."},{"rthcId":"RTHC-00102","title":"Cannabis abuse as a risk factor for depressive symptoms.","authors":"Bovasso, G B","year":2001,"journal":"The American journal of psychiatry, 158(12), 2033-7","doi":null,"pmid":"11729021","tags":["depression","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers leveraged a 15-year follow-up of the Baltimore Epidemiologic Catchment Area study to test a crucial question: does cannabis cause depression, or do depressed people self-medicate with cannabis?\n\nThe answer was one-directional. Among 849 people with no depression at baseline, those with cannabis abuse were four times more likely to develop depressive symptoms over the follow-up period, after adjusting for age, gender, antisocial symptoms, and other covariates. The depressive symptoms included suicidal ideation and anhedonia (inability to feel pleasure).\n\nCritically, the reverse direction was not supported. Among 1,837 people with no cannabis abuse at baseline, depression did not significantly predict future cannabis abuse. This asymmetry argued against the self-medication hypothesis and suggested cannabis abuse is a genuine risk factor for depression rather than a consequence of it.","whyItMatters":"The bidirectional analysis was methodologically powerful: by testing both directions of the association and finding that only cannabis-to-depression was significant, the study provided some of the strongest evidence that cannabis abuse genuinely increases depression risk rather than merely co-occurring with it.","specificNumbers":"1,920 participants. 15-year follow-up. Cannabis abusers: 4x more likely to develop depression. Suicidal ideation and anhedonia specifically elevated. Reverse direction (depression to cannabis): not significant.","methodology":"Prospective cohort study using the Baltimore ECA dataset. 1,920 participants assessed in 1980 and reassessed 1994-1996 (15-year follow-up). Two cohorts analyzed: those without depression at baseline (N=849) and those without cannabis abuse at baseline (N=1,837). Diagnostic Interview Schedule assessed symptoms.","limitations":"The 15-year gap between assessments means intervening variables could explain the association. Cannabis \"abuse\" is a specific diagnostic category that may not represent all use patterns. The baseline assessment was in 1980 with different cannabis potency. Adjusted for several confounders but residual confounding is possible."},{"rthcId":"RTHC-00103","title":"Treating the substance-abusing suicidal patient.","authors":"Cornelius, J R; Salloum, I M; Lynch, K; Clark, D B; Mann, J J","year":2001,"journal":"Annals of the New York Academy of Sciences, 932, 78-90; discussion 91-3","doi":null,"pmid":"11411192","tags":["mental-health","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Studies of suicidal substance abusers are extremely rare because suicidality is typically an exclusion criterion for treatment studies. This review described one of the only double-blind, placebo-controlled studies addressing this population.\n\nThe study involved 51 patients with comorbid major depression and alcohol dependence, of whom 39% had attempted suicide in the current episode, 61% had a lifetime attempt, and 90% reported suicidal ideation. Fluoxetine decreased both depressive symptoms (including suicidal ideation) and alcohol consumption, though it did not eliminate either problem entirely.\n\nSecondary analyses revealed additional findings: fluoxetine also significantly reduced marijuana use in a subgroup with cannabis abuse, and the magnitude of improvement was described as \"robust.\" The benefits of fluoxetine for depression and drinking persisted at one-year follow-up. However, cocaine abuse predicted poor outcomes for both depression and alcohol use.","whyItMatters":"This is one of the very few studies to include suicidal substance users, who are normally excluded from treatment research. The finding that treating depression with fluoxetine also improved substance use, including marijuana, supports the importance of treating psychiatric comorbidities alongside substance use disorders.","specificNumbers":"51 patients in controlled study. 39% current suicide attempt. 61% lifetime attempt. 90% suicidal ideation. Fluoxetine reduced depression, suicidal ideation, alcohol, and marijuana use. Cocaine predicted poor outcome.","methodology":"Review of one open-label study (12 patients) and one double-blind placebo-controlled study (51 patients) of fluoxetine in suicidal substance abusers, plus secondary analyses and one-year follow-up data.","limitations":"Only one controlled study with 51 patients. The marijuana finding was a secondary analysis of a subgroup. Fluoxetine reduced but did not eliminate symptoms. The study population was specific (comorbid depression + alcohol dependence) and may not generalize."},{"rthcId":"RTHC-00104","title":"Delta9-tetrahydrocannabivarin as a marker for the ingestion of marijuana versus Marinol: results of a clinical study.","authors":"ElSohly, M A; deWit, H; Wachtel, S R; Feng, S; Murphy, T P","year":2001,"journal":"Journal of analytical toxicology, 25(7), 565-71","doi":null,"pmid":"11599601","tags":["driving","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Because synthetic THC (Marinol) and natural marijuana produce identical urinary metabolites, drug tests cannot tell them apart. This creates a problem: people testing positive for cannabis can claim they were using a prescription.\n\nResearchers identified a solution: delta-9-tetrahydrocannabivarin (THCV), a natural compound present in marijuana but absent from synthetic Marinol. THCV is metabolized to THCV-COOH, which can be detected in urine.\n\nFour subjects received, in randomized order: oral Marinol (15 mg), smoked THC in a placebo marijuana cigarette (16.88 mg), or smoked marijuana (2.11% THC, 0.12% THCV). Urine was collected for one week.\n\nTHCV-COOH was detected only after smoking actual marijuana. Neither oral Marinol nor smoked pure THC produced THCV-COOH in urine. This confirmed THCV-COOH as a reliable marker to distinguish marijuana use from Marinol use.","whyItMatters":"This study solved a practical problem in drug testing: distinguishing between legal prescription THC and illegal marijuana use. The THCV-COOH marker has since been used in forensic and workplace drug testing when this distinction matters.","specificNumbers":"Four subjects, three sessions. Marinol: 15 mg oral. Smoked THC: 16.88 mg. Smoked marijuana: 2.11% THC, 0.12% THCV. Detection limit: 1.0 ng/mL. THCV-COOH only positive after marijuana.","methodology":"Three-session, within-subject, crossover design with four subjects. Each received oral Marinol, smoked THC in placebo cigarette, and smoked marijuana in randomized order. GC-MS analysis of urine for THC-COOH and THCV-COOH.","limitations":"Only four subjects. THCV content varies among marijuana varieties, so very low-THCV marijuana might not produce detectable THCV-COOH. The study predates the availability of many modern cannabis products. Detection window for THCV-COOH may be shorter than for THC-COOH."},{"rthcId":"RTHC-00105","title":"The role of cannabinoids in neurodegenerative diseases.","authors":"Glass, M","year":2001,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 25(4), 743-65","doi":null,"pmid":"11383976","tags":["neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized the rapidly growing understanding of the endocannabinoid system's role in neurological disease.\n\nThe endocannabinoid system, consisting of two receptors (CB1, CB2) and two endogenous ligands (anandamide, 2-AG), is involved in normal movement control, memory formation, and appetite regulation. As this physiological role became clearer, evidence emerged that the system may be disrupted in several neurological diseases.\n\nFor Huntington's disease, loss of CB1 receptors in the basal ganglia occurs early and may contribute to the characteristic involuntary movements. For Parkinson's disease, endocannabinoid levels appear altered, and cannabinoids may help treat levodopa-induced dyskinesia. For schizophrenia, the interaction between cannabinoid and dopamine systems may contribute to psychotic symptoms. For tremor, cannabinoids showed direct therapeutic potential.\n\nThe review identified an array of potential therapeutic approaches: cannabinoid agonists, antagonists, and compounds that modify endocannabinoid synthesis, uptake, or metabolism.","whyItMatters":"This review reframed neurodegenerative diseases through the lens of the endocannabinoid system, suggesting that cannabis-based medicines might not just treat symptoms but address underlying pathophysiology in some conditions.","specificNumbers":"Two receptors (CB1, CB2). Two endogenous ligands (anandamide, 2-AG). Four diseases reviewed: Huntington's, Parkinson's, schizophrenia, tremor.","methodology":"Comprehensive narrative review of endocannabinoid system involvement in four neurological conditions, covering receptor distribution, endocannabinoid levels, and potential therapeutic targets.","limitations":"Much of the evidence was preclinical at the time of publication. The therapeutic applications proposed were largely theoretical. The complexity of the endocannabinoid system means that simple agonist or antagonist approaches may have unintended effects."},{"rthcId":"RTHC-00106","title":"Allowing the medical use of cannabis.","authors":"Hall, W D; Degenhardt, L J; Currow, D","year":2001,"journal":"The Medical journal of Australia, 175(1), 39-40","doi":null,"pmid":"11476203","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis had been advocated as a treatment for nausea, vomiting, wasting, pain, and muscle spasms across cancer, HIV/AIDS, and neurological conditions. However, cannabinoid drugs were not registered for medical use in Australia, and the authors noted that a smoked plant product was unlikely to meet registration standards.\n\nA New South Wales Working Party recommended a middle path: granting exemption from prosecution for patients who were medically certified to have specified conditions. The authors argued this approach deserved consideration by other Australian state and territory governments.","whyItMatters":"This piece captured a moment when Australia was grappling with the gap between patient demand for cannabis as medicine and the regulatory frameworks that prohibited it. The recommendation for prosecution exemptions rather than full legalization represented a cautious, incremental approach that many countries would later adopt in various forms.","specificNumbers":"No quantitative data were presented in this editorial.","methodology":"This was a short editorial commentary reviewing the state of cannabis policy in Australia and the recommendations of a New South Wales government working party. It did not involve original data collection or systematic review methodology.","limitations":"This was an opinion piece, not a systematic analysis of evidence. It represented the views of three authors and did not provide comprehensive data on efficacy or safety. The short format (two pages) limited the depth of policy analysis."},{"rthcId":"RTHC-00107","title":"Cannabinoids - from plant to patient. 5 April 2001, London, UK.","authors":"Holdcroft, A","year":2001,"journal":"IDrugs : the investigational drugs journal, 4(7), 773-5","doi":null,"pmid":"15995932","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The conference highlighted several emerging findings in cannabinoid medicine. Whole cannabis plant constituents, including cannabinoids and possibly flavonoids, appeared more effective than a single isolated cannabinoid in reducing muscle spasticity in an animal model of multiple sclerosis. This suggested that interactions between multiple compounds in the plant contributed to therapeutic effects.\n\nSynthetic cannabinoids with high receptor affinity were available, and pharmaceutical products targeting the endocannabinoid system through uptake and metabolism blockade were being developed. Government and charity-funded clinical trials were proceeding in acute pain, chronic pain, and multiple sclerosis across the UK.","whyItMatters":"This report captured the state of cannabinoid medicine at a pivotal moment when the field was transitioning from preclinical research to large-scale clinical trials. The observation that whole-plant extracts outperformed single cannabinoids would become an important concept in cannabis pharmacology, later termed the \"entourage effect.\"","specificNumbers":"No specific quantitative data were reported in this conference summary.","methodology":"This was a conference proceedings report summarizing presentations at a scientific meeting on cannabinoids held in London in April 2001. It compiled findings from multiple presenters rather than reporting original research.","limitations":"Conference proceedings provide a snapshot of presented findings without the rigor of peer-reviewed original research. The animal model findings on whole-plant superiority may not directly translate to human outcomes. Specific data and effect sizes from the presentations were not included."},{"rthcId":"RTHC-00108","title":"Medicinal use of cannabis: history and current status.","authors":"Kalant, H","year":2001,"journal":"Pain research & management, 6(2), 80-91","doi":null,"pmid":"11854770","tags":["medical-cannabis","pain","respiratory"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"THC and several analogues showed significant therapeutic benefits for nausea, vomiting, and appetite stimulation in patients with wasting syndrome. Recent evidence demonstrated analgesic and anti-spasticity effects that the author considered likely to become clinically useful.\n\nHowever, cannabinoid effects on intraocular pressure in glaucoma and bronchodilation in asthma were not sufficiently strong, long-lasting, or reliable for therapeutic use. Cannabidiol showed promising anticonvulsant effects warranting further clinical trials.\n\nThe author argued that for all established and probable future uses, pure cannabinoids administered orally, rectally, or parenterally were effective and avoided the risks of chronic airway inflammation and upper respiratory cancer associated with smoking crude cannabis.","whyItMatters":"This review provided one of the more balanced and thorough assessments of the medical cannabis evidence base at the time. By sorting conditions into those with strong evidence (nausea, appetite), emerging evidence (pain, spasticity), and weak evidence (glaucoma, asthma), it helped establish a framework for prioritizing clinical research that largely held up over subsequent decades.","specificNumbers":"THC doses of 5-10 mg were referenced for therapeutic applications. The review covered multiple conditions but did not provide pooled statistical analyses.","methodology":"This was a narrative review that assessed the literature on therapeutic uses of cannabis and cannabinoids. Studies were evaluated by design type, data quality, independent replication, effect size, comparison with other treatments, and adverse effects. Results were compared with major international reviews from the preceding five years.","limitations":"As a narrative review rather than a systematic review or meta-analysis, the study selection and interpretation reflected the author's judgment. Long-term pharmacokinetic data and drug interaction information were acknowledged as major gaps. The review predated many of the large clinical trials conducted in subsequent years."},{"rthcId":"RTHC-00109","title":"The cannabinoids: an overview. Therapeutic implications in vomiting and nausea after cancer chemotherapy, in appetite promotion, in multiple sclerosis and in neuroprotection.","authors":"Mechoulam, R; Hanu, L","year":2001,"journal":"Pain research & management, 6(2), 67-73","doi":null,"pmid":"11854768","tags":["medical-cannabis","cbd","neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review traced cannabinoid science from historical use in Assyria and China through to the identification of CB1 and CB2 receptors and the discovery of endogenous cannabinoids. THC had established clinical utility as an anti-vomiting and appetite-enhancing agent. Clinical work in multiple sclerosis was advancing toward potential drug approval.\n\nCBD, described as a non-psychotropic constituent, was showing promise in preclinical studies. Recent animal model work on CBD in rheumatoid arthritis suggested potential clinical applications. A synthetic cannabinoid called HU-211 (Dexanabinol) was in advanced clinical trials as a neuroprotectant for head trauma.","whyItMatters":"Written by the researcher who first isolated and synthesized THC in 1964, this review carried unique authority. It documented the state of cannabinoid science at a transitional moment when the basic pharmacology was established but clinical applications were still being developed. The mention of CBD for rheumatoid arthritis and synthetic cannabinoids for neuroprotection pointed toward research directions that would expand significantly.","specificNumbers":"No specific statistical data were presented in this overview.","methodology":"This was a narrative review by Raphael Mechoulam, one of the founding researchers in cannabinoid science, covering the historical, pharmacological, and clinical landscape of cannabinoid research. It synthesized findings from preclinical and clinical studies across multiple therapeutic areas.","limitations":"As a broad overview by a single researcher, this paper provided perspective rather than systematic analysis. The review covered many therapeutic areas briefly rather than deeply. Some of the promising research directions described did not pan out as anticipated."},{"rthcId":"RTHC-00110","title":"Influence of treatment of Tourette syndrome with delta9-tetrahydrocannabinol (delta9-THC) on neuropsychological performance.","authors":"Müller-Vahl, K R; Koblenz, A; Jöbges, M; Kolbe, H; Emrich, H M; Schneider, U","year":2001,"journal":"Pharmacopsychiatry, 34(1), 19-24","doi":null,"pmid":"11229617","tags":["medical-cannabis","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 12 adult Tourette syndrome patients given a single dose of 5-10 mg THC or placebo, researchers found no significant differences in verbal memory, visual memory, reaction time, intelligence, sustained attention, divided attention, vigilance, or mood. The only notable finding was a potential worsening of obsessive-compulsive behavior measured by one questionnaire, though the authors cautioned this particular instrument had known limitations for measuring that outcome.\n\nA trend toward increased phobic anxiety was also observed, which the researchers attributed to the single-dose design that prevented gradual dose titration. The authors concluded that, unlike findings in healthy recreational cannabis users, therapeutic THC doses did not cause cognitive impairment in Tourette syndrome patients.","whyItMatters":"One of the major concerns about using THC therapeutically is the potential for cognitive side effects. This study provided early evidence that cognitive impairment observed in recreational users may not apply to patients using THC for specific medical conditions, potentially because the therapeutic context, dose, and patient population differ from recreational use scenarios.","specificNumbers":"Twelve patients participated. THC doses ranged from 5.0 to 10.0 mg as a single administration. No significant differences were found across any of the primary cognitive measures between THC and placebo conditions.","methodology":"This was a randomized, double-blind, placebo-controlled crossover trial. Twelve adult Tourette syndrome patients received either a single dose of THC (5-10 mg) or placebo, then crossed over to the other condition. A comprehensive battery of neuropsychological tests assessed multiple cognitive domains. The Symptom Checklist 90-R was used to assess behavioral and mood changes.","limitations":"The sample size of 12 patients was small and limited statistical power to detect subtle cognitive effects. Only a single dose was tested, so the cognitive safety of longer-term THC treatment remains unaddressed by this study. The crossover design, while efficient, can be complicated by carryover effects. The increase in obsessive-compulsive behavior scores is difficult to interpret given the acknowledged limitations of the assessment tool used."},{"rthcId":"RTHC-00111","title":"Effects of chronic Delta(9)-tetrahydrocannabinol treatment on hippocampal extracellular acetylcholine concentration and alternation performance in the T-maze.","authors":"Nava, F; Carta, G; Colombo, G; Gessa, G L","year":2001,"journal":"Neuropharmacology, 41(3), 392-9","doi":null,"pmid":"11522331","tags":["cognition","neuroscience","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats given chronic THC treatment (5 mg/kg twice daily for two weeks) continued to show reduced hippocampal acetylcholine levels and impaired T-maze performance without developing tolerance to either effect. This was notable because tolerance develops to many other effects of THC with repeated use.\n\nThe study also found that the cognitive and cholinergic effects operated on different timescales. Memory impairment in the T-maze appeared within 20 minutes of THC administration, while the reduction in hippocampal acetylcholine did not appear until 80 minutes after treatment. Both effects were completely blocked by the CB1 receptor antagonist SR 141716A, confirming CB1 receptor involvement.","whyItMatters":"Tolerance is a key factor in both the therapeutic potential and abuse liability of any drug. The finding that tolerance did not develop to THC's cognitive and cholinergic effects, even while tolerance develops to other THC effects like sedation, suggested that these impacts on memory could be persistent with ongoing use. The different timescales also indicated that memory impairment and acetylcholine reduction, while both CB1-mediated, may involve distinct neural mechanisms.","specificNumbers":"THC was administered at 5 mg/kg intraperitoneally, twice daily for 14 days. Memory impairment appeared at 20 minutes post-dose. Acetylcholine reduction appeared at 80 minutes post-dose.","methodology":"This was an animal study using rats treated with chronic THC (5 mg/kg intraperitoneally, twice daily for two weeks). Researchers measured hippocampal extracellular acetylcholine concentrations using microdialysis and assessed spatial memory using T-maze alternation tasks. The CB1 antagonist SR 141716A was used to confirm receptor specificity.","limitations":"Animal studies using injected THC at fixed doses do not directly replicate human cannabis use patterns. The two-week treatment period may not capture longer-term tolerance development. Rat cognitive tests like T-maze alternation assess a limited form of spatial memory that does not encompass the full range of human cognitive functions."},{"rthcId":"RTHC-00112","title":"The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies.","authors":"Porcella, A; Maxia, C; Gessa, G L; Pani, L","year":2001,"journal":"The European journal of neuroscience, 13(2), 409-12","doi":null,"pmid":"11168547","tags":["medical-cannabis","neuroscience"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"The synthetic CB1 receptor agonist WIN 55212-2, applied topically to the eye, reduced intraocular pressure in 8 patients with glaucoma resistant to conventional therapies. At the 25-microgram dose, pressure decreased by 15% within 30 minutes and reached a maximum reduction of 20% at 60 minutes. At the 50-microgram dose, pressure decreased by 23% within 30 minutes and reached a maximum reduction of 31% at 60 minutes.\n\nThe researchers had previously demonstrated the presence of CB1 receptor mRNA and protein in the human ciliary body, establishing a biological mechanism for the pressure-lowering effect. These results confirmed that CB1 receptors directly regulate human intraocular pressure.","whyItMatters":"While cannabis has long been known to lower eye pressure, its use for glaucoma has been limited by short duration of effect and systemic side effects. This study demonstrated that a topical synthetic cannabinoid could achieve meaningful pressure reduction directly in the eye, potentially avoiding systemic effects. The fact that it worked in treatment-resistant patients made it particularly significant.","specificNumbers":"Eight patients were treated. At 25 micrograms: 15% pressure reduction at 30 minutes, 20% maximum at 60 minutes. At 50 micrograms: 23% reduction at 30 minutes, 31% maximum at 60 minutes.","methodology":"This was a small clinical study in which 8 patients with glaucoma resistant to conventional therapies received topical application of the synthetic CB1 agonist WIN 55212-2 at doses of 25 or 50 micrograms. Intraocular pressure was measured at 30-minute and 60-minute intervals after application.","limitations":"The study included only 8 patients with no placebo control group. Duration of the pressure-lowering effect beyond 60 minutes was not reported. Long-term safety and efficacy of repeated dosing were not assessed. The study did not compare results with existing topical glaucoma medications."},{"rthcId":"RTHC-00113","title":"Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review.","authors":"Tramèr, M R; Carroll, D; Campbell, F A; Reynolds, D J; Moore, R A; McQuay, H J","year":2001,"journal":"BMJ (Clinical research ed.), 323(7303), 16-21","doi":null,"pmid":"11440936","tags":["medical-cannabis","cancer"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Across 30 randomized trials with 1,366 patients, cannabinoids (nabilone, dronabinol, and levonantradol) outperformed conventional antiemetics for chemotherapy-induced sickness. For complete nausea control, the number needed to treat was 6; for complete vomiting control, it was 8. In crossover trials, patients preferred cannabinoids for future cycles by a wide margin (NNT 3 for preference).\n\nHowever, cannabinoids also produced significantly more side effects. Dizziness occurred frequently (NNT 3), along with dysphoria or depression (NNT 8), hallucinations (NNT 17), paranoia (NNT 20), and low blood pressure (NNT 7). Some side effects were considered potentially beneficial, including feeling \"high\" (NNT 3), sedation (NNT 5), and euphoria (NNT 7). Patients on cannabinoids were more likely to withdraw due to side effects (NNT 11).","whyItMatters":"This was one of the most rigorous early systematic reviews of cannabinoids for chemotherapy-induced nausea and vomiting. By quantifying both benefits and harms with numbers needed to treat, it provided clinicians with practical data for decision-making. The finding that patients strongly preferred cannabinoids despite side effects suggested the anti-nausea benefit was highly valued by people undergoing chemotherapy.","specificNumbers":"NNT 6 for complete nausea control. NNT 8 for complete vomiting control. NNT 3 for patient preference. Side effects: dizziness NNT 3, \"high\" NNT 3, sedation NNT 5, euphoria NNT 7, low blood pressure NNT 7, dysphoria NNT 8, withdrawal due to side effects NNT 11, hallucinations NNT 17, paranoia NNT 20. Relative risk for efficacy vs. conventional antiemetics: 1.38 for nausea, 1.28 for vomiting.","methodology":"This was a quantitative systematic review with comprehensive searching across Medline, Embase, the Cochrane Library, and bibliographies in any language through August 2000. Thirty randomized comparisons with dichotomous efficacy and harm data were included, covering 1,366 patients. All tested oral nabilone, oral dronabinol, or intramuscular levonantradol against placebo or conventional antiemetics. No study used smoked cannabis.","limitations":"None of the included trials used smoked cannabis, so results apply only to oral and intramuscular pharmaceutical cannabinoids. The comparator antiemetics were older drugs; no trials compared cannabinoids with newer 5-HT3 antagonists. Follow-up lasted only 24 hours. The trials were conducted primarily in the 1970s-1990s with varying quality standards."},{"rthcId":"RTHC-00114","title":"Workplace drug testing in Europe.","authors":"Verstraete, A G; Pierce, A","year":2001,"journal":"Forensic science international, 121(1-2), 2-6","doi":null,"pmid":"11516880","tags":["workplace","legalization"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Workplace drug testing in Europe lacked the standardized infrastructure found in the United States. There was no specific legislation and no generally accepted guidelines across Europe. Many companies established drug policies with little or no actual testing provisions. When testing was performed, it was often done on-site by occupational physicians with minimal quality control, no systematic confirmation of positive results, no chain of custody, and no adulteration testing.\n\nTesting was growing in the UK and Scandinavian countries but remained uncommon elsewhere in Europe. The most frequently tested substances were amphetamines, cannabinoids, cocaine, opiates, and alcohol. Cannabis was the drug most frequently detected. Positive test rates appeared to decrease in the years following the introduction of workplace drug testing programs.","whyItMatters":"This review documented a significant gap between European and American approaches to workplace drug testing at a time when cannabis policy was diverging internationally. The finding that cannabis was the most commonly detected drug in European workplace testing raised questions about whether these programs disproportionately captured cannabis users, given cannabis's longer detection window compared to other substances.","specificNumbers":"No specific prevalence data or positive rates were reported in detail. The review noted that positive rates generally decreased after workplace drug testing programs were introduced.","methodology":"This was a descriptive review of the state of workplace drug testing practices across Europe, including information about legislation, testing procedures, quality standards, and recent organizational developments such as the founding of the European Workplace Drug Testing Society (EWDTS).","limitations":"This was a descriptive overview rather than a systematic review. Specific data on testing rates, positive rates, and outcomes across European countries were sparse. The review reflected the state of practice in 2001 and much has changed since then in both regulation and technology."},{"rthcId":"RTHC-00115","title":"Testing Gateway Theory: do cigarette prices affect illicit drug use?","authors":"Beenstock, Michael; Rahav, Giora","year":2002,"journal":"Journal of health economics, 21(4), 679-98","doi":null,"pmid":"12146597","tags":["addiction","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The researchers used variation in cigarette prices across birth cohorts in Israel as a natural experiment to test gateway theory. By treating cigarette prices as an external factor that randomly influenced smoking rates, they could examine whether changes in smoking rates caused corresponding changes in cannabis use, and whether cannabis use in turn caused hard drug use.\n\nThe data supported the first link: cigarette smoking appeared to cause cannabis use. However, the evidence for the second link, that cannabis use caused hard drug use, was much weaker. These results held across multiple statistical methods including two-stage logit, bivariate probit, and frailty analysis for survival data.","whyItMatters":"Gateway theory, the idea that softer drugs lead to harder ones, has been one of the most influential and contested concepts in drug policy. This study's use of econometric methods and natural experiments brought a different analytical approach to a question usually studied through correlational survey data. The finding that the cigarettes-to-cannabis link was stronger than the cannabis-to-hard-drugs link challenged the simplistic version of gateway theory often used to justify cannabis prohibition.","specificNumbers":"Specific effect sizes and price elasticities were not detailed in the abstract. The study used Israeli data across multiple birth cohorts.","methodology":"This was an observational study using econometric methods applied to Israeli population data. The researchers used cigarette prices as an instrumental variable, exploiting the fact that price variation across birth cohorts created a natural experiment that randomly influenced smoking rates. Multiple statistical approaches (two-stage logit, bivariate probit, frailty analysis) were used to test causal relationships in the drug use sequence.","limitations":"The study relied on Israeli data and may not generalize to other countries with different drug markets and cultural contexts. Using cigarette prices as an instrumental variable assumes that price variation affects only drug use through smoking behavior, which may not hold perfectly. The abstract did not provide detailed effect sizes or confidence intervals."},{"rthcId":"RTHC-00116","title":"Precipitation and determination of the onset and course of schizophrenia by substance abuse--a retrospective and prospective study of 232 population-based first illness episodes.","authors":"Bühler, Babette; Hambrecht, Martin; Löffler, Walter; an der Heiden, Wolfram; Häfner, Heinz","year":2002,"journal":"Schizophrenia research, 54(3), 243-51","doi":null,"pmid":"11950549","tags":["psychosis","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"People experiencing their first episode of schizophrenia were twice as likely as controls to have a lifetime history of substance abuse (alcohol abuse: 23.7% vs 12.3%; drug abuse: 14.2% vs 7.0%). Among patients who abused drugs, 88% used cannabis. Sixty-two percent of patients with drug abuse began using before the first sign of their disorder.\n\nA striking finding was that drug abuse onset and illness onset occurred within the same month in 34.6% of cases, suggesting a temporal connection. However, no temporal correlation was found between abuse onset and the onset of the first psychotic episode specifically. Over five years of follow-up, patients with early substance abuse showed more positive symptoms, less affective flattening, and worse outcomes in treatment compliance, rehabilitation, and employment.","whyItMatters":"This study addressed one of the most debated questions in psychiatry: whether cannabis and other substance use can trigger schizophrenia. The finding that drug abuse often preceded illness onset, and that onset timing frequently coincided, suggested a possible precipitating role. However, the researchers were careful to conclude that only a \"small proportion\" of schizophrenias might have been precipitated by substance abuse.","specificNumbers":"Alcohol abuse: 23.7% in schizophrenia vs 12.3% in controls. Drug abuse: 14.2% vs 7.0%. Cannabis was used by 88% of drug abusers. Drug abuse preceded illness onset in 62% of cases. Drug abuse and illness onset coincided within the same month in 34.6% of cases.","methodology":"This was a population-based study using both retrospective and prospective designs. The retrospective component assessed 232 first-episode schizophrenia cases using the IRAOS interview compared with controls. The prospective component followed a subsample of 115 patients over five years with six cross-sectional assessments from first admission.","limitations":"The retrospective component relied on patient recall, which may be unreliable especially regarding the timing of first symptoms. The correlation between drug use onset and illness onset does not prove causation. Some patients may have been self-medicating early prodromal symptoms with drugs. The study could not definitively separate substance-precipitated psychosis from psychosis with comorbid substance use."},{"rthcId":"RTHC-00117","title":"Reversal of cannabinoids (delta9-THC) by the benzoflavone moiety from methanol extract of Passiflora incarnata Linneaus in mice: a possible therapy for cannabinoid addiction.","authors":"Dhawan, Kamaldeep; Kumar, Suresh; Sharma, Anupam","year":2002,"journal":"The Journal of pharmacy and pharmacology, 54(6), 875-81","doi":null,"pmid":"12079005","tags":["withdrawal","addiction","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice given THC (10 mg/kg twice daily for 6 days) along with a benzoflavone compound from Passiflora incarnata developed significantly less tolerance and dependence compared to mice receiving THC alone. When withdrawal was artificially triggered using the CB1 antagonist SR-141716A on day 7, typical withdrawal effects like paw tremors and head shakes were significantly reduced in mice that had received the passionflower compound alongside THC.\n\nEven when given acutely (single dose of 20 mg/kg) to mice already experiencing severe withdrawal symptoms, the benzoflavone compound significantly attenuated withdrawal effects. This suggested the compound could both prevent and treat cannabinoid withdrawal.","whyItMatters":"At the time of this study, there were no pharmacological treatments for cannabis withdrawal. The finding that a compound from a traditionally used medicinal plant could reduce both tolerance development and withdrawal symptoms in an animal model represented a novel therapeutic approach grounded in ethnobotanical knowledge.","specificNumbers":"THC dose: 10 mg/kg twice daily for 6 days. Benzoflavone doses: 10 or 20 mg/kg twice daily for 6 days (prevention) or 20 mg/kg single dose (acute treatment). Withdrawal was precipitated with SR-141716A at 10 mg/kg on day 7.","methodology":"This was an animal study in which mice received THC (10 mg/kg twice daily for 6 days) either alone or with concurrent benzoflavone from Passiflora incarnata (10 or 20 mg/kg twice daily). Cannabinoid withdrawal was precipitated on day 7 using SR-141716A (10 mg/kg). Locomotor activity, paw tremors, and head shakes were measured as withdrawal indicators.","limitations":"Animal models of cannabis withdrawal do not directly replicate human withdrawal experiences. The doses of THC used were high relative to typical human consumption. The mechanism of action of the benzoflavone compound was not elucidated. No human studies have tested this approach. The six-day dependence induction period was very short."},{"rthcId":"RTHC-00118","title":"Cannabis use and psychosocial adjustment in adolescence and young adulthood.","authors":"Fergusson, David M; Horwood, L John; Swain-Campbell, Nicola","year":2002,"journal":"Addiction (Abingdon, England), 97(9), 1123-35","doi":null,"pmid":"12199828","tags":["youth","depression","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Across annual assessments from ages 14 to 21, more frequent cannabis use was significantly associated with property and violent crime, depression, suicidal ideation, suicide attempts, and other illicit drug use. Statistical controls for both fixed and time-varying confounders substantially reduced but did not eliminate these associations.\n\nA key finding was age-related variation: younger cannabis users (14-15 years old) showed stronger associations with crime, suicidal behaviors, and other drug use than older users (20-21 years old). However, the association between cannabis use and depression did not vary by age. The strongest and most persistent association was between cannabis use and other illicit drug use.","whyItMatters":"This study was influential because of its long follow-up period, population-based design, and sophisticated approach to confounding. The finding that younger users were disproportionately affected provided empirical support for age-specific drug policies and reinforced concerns about adolescent cannabis exposure during brain development.","specificNumbers":"The cohort included 1,265 children followed for 21 years. Cannabis use was assessed annually from ages 14-21. Associations remained significant (P < 0.05) for all outcomes after adjustment. Younger users (14-15) showed stronger associations than older users (20-21) for crime, suicidal behavior, and other drug use.","methodology":"This was a 21-year longitudinal birth cohort study following 1,265 children born in Christchurch, New Zealand. Annual assessments of cannabis use frequency were obtained for ages 14-21, alongside measures of crime, depression, suicidal behaviors, and other drug use. Statistical models controlled for both fixed confounders (childhood factors) and time-dynamic confounders (changing circumstances).","limitations":"Observational studies cannot definitively establish causation, even with sophisticated confound adjustment. Unmeasured confounders such as genetic vulnerability or peer network effects may partly explain the associations. Self-reported cannabis use may be underreported. The cohort was from a single city in New Zealand and may not generalize to all populations."},{"rthcId":"RTHC-00119","title":"Delta-9-tetrahydrocannabinol (THC) in the treatment of end-stage open-angle glaucoma.","authors":"Flach, Allan J","year":2002,"journal":"Transactions of the American Ophthalmological Society, 100, 215-22; discussion 222-4","doi":null,"pmid":"12545695","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Despite 20 approved ophthalmologist investigators and strong initial interest, only 9 patients enrolled in the Cannabis Therapeutic Research Program. All patients showed an initial decrease in intraocular pressure, and treatment goals were met in 4 of the 9 patients. However, the pressure reductions were not sustained over time, and every patient elected to discontinue treatment within 1 to 9 months.\n\nReasons for discontinuation were varied but related to the development of tolerance to the pressure-lowering effect and significant systemic side effects. The authors concluded that while cannabinoids can lower eye pressure, tolerance and toxicity appeared to limit their usefulness as a glaucoma treatment.","whyItMatters":"This real-world program provided a rare look at what happened when glaucoma patients actually tried cannabinoid treatment over months rather than in single-dose laboratory studies. The finding that all patients voluntarily stopped treatment due to tolerance and side effects was a powerful practical counterpoint to the common belief that cannabis is an effective glaucoma treatment.","specificNumbers":"Twenty ophthalmologists were approved as investigators. Nine patients enrolled. Four of nine met the investigator's therapeutic goal initially. All nine discontinued treatment within 1 to 9 months.","methodology":"This was an uncontrolled, unmasked, nonrandomized study conducted under the California Cannabis Therapeutic Research Program. Patients with end-stage glaucoma unresponsive to conventional treatments received either oral THC capsules or inhaled marijuana alongside their existing treatment regimen. The program was designed for compassionate access rather than rigorous clinical investigation.","limitations":"The uncontrolled, unmasked design prevents definitive conclusions about efficacy. The very small sample (9 patients) limits generalizability. The program enrolled only end-stage, treatment-resistant patients who may not represent typical glaucoma cases. No standardized outcome measures or dosing protocols were described."},{"rthcId":"RTHC-00120","title":"Shared genetic risk of major depression, alcohol dependence, and marijuana dependence: contribution of antisocial personality disorder in men.","authors":"Fu, Qiang; Heath, Andrew C; Bucholz, Kathleen K; Nelson, Elliot; Goldberg, Jack; Lyons, Michael J; True, William R; Jacob, Theodore; Tsuang, Ming T; Eisen, Seth A","year":2002,"journal":"Archives of general psychiatry, 59(12), 1125-32","doi":null,"pmid":"12470129","tags":["genetics","depression","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among male veteran twins, the heritability estimates were 69% for antisocial personality disorder, 56% for alcohol dependence, 50% for marijuana dependence, and 40% for major depression. Genetic effects on antisocial personality disorder accounted for substantial portions of the total genetic variance in risk for the other disorders: 38% for depression, 50% for alcohol dependence, and 58% for marijuana dependence.\n\nAfter controlling for genetic effects on antisocial personality disorder, the genetic correlations between depression and both alcohol and cannabis dependence were no longer statistically significant. This suggested that antisocial personality traits were a key genetic link connecting depression to substance dependence.","whyItMatters":"This study provided a mechanistic explanation for why depression and substance dependence so often co-occur. Rather than depression causing substance use or vice versa, the shared genetic risk was largely channeled through antisocial personality traits. This has implications for treatment: addressing antisocial features may be important when treating comorbid depression and substance dependence.","specificNumbers":"Sample: 3,360 twin pairs (1,868 MZ, 1,492 DZ). Heritability: ASPD 69%, AD 56%, MJD 50%, MD 40%. ASPD genetic effects accounted for 38% of MD genetic variance, 50% of AD genetic variance, 58% of MJD genetic variance.","methodology":"This study used the Vietnam Era Twin Registry, analyzing data from 3,360 male twin pairs (1,868 monozygotic and 1,492 dizygotic). Lifetime DSM-III-R diagnoses were obtained through telephone diagnostic interviews. Structural equation modeling estimated additive genetic, shared environmental, and nonshared environmental effects common and specific to each disorder.","limitations":"The sample was limited to male veterans, who may not represent the general population. The Vietnam Era Twin Registry overrepresents men exposed to military service during a specific historical period. Telephone diagnostic interviews have limitations compared to in-person clinical assessment. The study could not identify specific genes involved."},{"rthcId":"RTHC-00121","title":"Cannabinoids on the brain.","authors":"Irving, Andrew J; Rae, Mark G; Coutts, Angela A","year":2002,"journal":"TheScientificWorldJournal, 2, 632-48","doi":null,"pmid":"12805989","tags":["neuroscience","cognition","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review synthesized research on how cannabinoids interact with the brain across multiple systems. CB1 receptors mediated most central nervous system effects, though evidence suggested a new, unidentified brain cannabinoid receptor also existed. In the hippocampus, cannabinoids influenced learning and memory. In the basal ganglia, they modulated locomotor activity and reward pathways. In the hypothalamus, they played a role in appetite control.\n\nThe endocannabinoid system was shown to modulate synaptic transmission and plasticity throughout the brain. Cannabinoids also demonstrated neuroprotective properties against neurodegeneration and brain damage, and exhibited anticonvulsant activity. Some analgesic effects of cannabinoids involved brain sites rather than only peripheral mechanisms.","whyItMatters":"This review provided a brain-region-by-region map of how cannabinoids exert their effects, helping explain why cannabis produces such a wide range of cognitive, motor, appetitive, and emotional effects. The description of the endocannabinoid system as a widespread modulator of brain function helped establish it as a major target for drug development.","specificNumbers":"No specific quantitative data were presented in this overview review.","methodology":"This was a comprehensive narrative review covering cannabinoid receptor signaling, synaptic transmission, regional brain effects, and the endocannabinoid system. It synthesized findings from pharmacological, electrophysiological, and behavioral studies.","limitations":"As a broad review, individual findings were described without detailed critical appraisal. The field was rapidly evolving at the time, and some conclusions were based on limited data. The review focused primarily on basic science rather than clinical applications."},{"rthcId":"RTHC-00122","title":"Cardiovascular system effects of marijuana.","authors":"Jones, Reese T","year":2002,"journal":"Journal of clinical pharmacology, 42(S1), 58S-63S","doi":null,"pmid":"12412837","tags":["cardiovascular","tolerance"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis and THC increased heart rate, slightly increased blood pressure when lying down, and occasionally caused marked drops in blood pressure upon standing. Cardiac output increased while peripheral vascular resistance and maximum exercise performance decreased. Tolerance to most cardiovascular effects developed rapidly with repeated use.\n\nWith continued exposure, blood pressure while lying down decreased slightly, standing blood pressure drops disappeared, blood volume increased, and heart rate slowed. These changes were consistent with reduced sympathetic and enhanced parasympathetic nervous system activity. For most young, healthy users, these effects were not associated with serious health problems. However, occasional myocardial infarction, stroke, and other adverse cardiovascular events had been reported, and smoking cannabis posed particular risks for people with existing cardiovascular disease due to increased cardiac workload, catecholamine levels, and carbon monoxide exposure.","whyItMatters":"This review provided a comprehensive account of how cannabis affects the cardiovascular system, distinguishing between effects in healthy young users (generally benign) and risks in people with heart disease (potentially dangerous). The description of rapid tolerance development to cardiovascular effects was clinically relevant for understanding both recreational and medical cannabis use.","specificNumbers":"No specific numerical data were presented in the abstract, though the review described characteristic patterns of heart rate increase and blood pressure changes.","methodology":"This was a narrative review of the cardiovascular pharmacology of cannabis, covering human and animal studies of acute and chronic effects, tolerance development, and clinical safety considerations. It addressed both receptor-mediated and endocannabinoid system mechanisms.","limitations":"As a narrative review, the evidence was synthesized without systematic methodology. Most data came from studies in young, healthy subjects and may not apply to older or medically compromised populations. The mechanisms of rare but serious cardiovascular events were not fully elucidated."},{"rthcId":"RTHC-00123","title":"Cannabis use in the last year in a US national sample of twin and sibling pairs.","authors":"Kendler, K S; Neale, M C; Thornton, L M; Aggen, S H; Gilman, S E; Kessler, R C","year":2002,"journal":"Psychological medicine, 32(3), 551-4","doi":null,"pmid":"11990000","tags":["genetics"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Twin and sibling resemblance for cannabis use in the past year was substantial. Monozygotic (identical) twin pairs showed much higher concordance than dizygotic (fraternal) twin pairs, and dizygotic twins showed similar resemblance to non-twin siblings. Modeling suggested heritability of at least 60% for last-year cannabis use.\n\nFamily environmental factors possibly contributed to resemblance as well, but no evidence was found for a special twin-specific environment influencing cannabis use. The finding that dizygotic twins and non-twin siblings showed similar resemblance strengthened the interpretation that shared genes rather than shared twin-specific experiences drove the familial pattern.","whyItMatters":"This was the first nationally representative US twin study of cannabis use, addressing a limitation of three prior twin studies that used non-representative samples. The high heritability estimate (60%+) established that genetic factors substantially influence who uses cannabis, independent of cultural and environmental factors.","specificNumbers":"Heritability was estimated at a minimum of 60%. The study included both monozygotic and dizygotic twin pairs plus sibling pairs from a national probability sample.","methodology":"This was a twin study using a US national probability sample of twin and sibling pairs. Cannabis use in the past year was assessed by self-report questionnaire. Biometrical twin analyses compared monozygotic twins, dizygotic twins, and non-twin siblings to partition variance into genetic, shared environmental, and non-shared environmental components.","limitations":"The study assessed only last-year cannabis use, not lifetime use, frequency, or dependence. Self-report questionnaires may underestimate cannabis use. Twin studies estimate heritability for a specific population at a specific time and may not generalize across cultural contexts where cannabis availability and norms differ."},{"rthcId":"RTHC-00124","title":"Safety, tolerability, and efficacy of orally administered cannabinoids in MS.","authors":"Killestein, J; Hoogervorst, E L J; Reif, M; Kalkers, N F; Van Loenen, A C; Staats, P G M; Gorter, R W; Uitdehaag, B M J; Polman, C H","year":2002,"journal":"Neurology, 58(9), 1404-7","doi":null,"pmid":"12011290","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In this randomized, double-blind, placebo-controlled crossover study, 16 patients with severe multiple sclerosis spasticity received oral THC, cannabis plant extract, and placebo in different periods. Both active treatments were considered safe, but adverse events were more common with plant extract.\n\nNeither THC nor plant extract reduced spasticity compared to placebo. Perhaps most notably, both active treatments worsened patients' global impression of their condition, suggesting that any potential benefits were outweighed by side effects experienced during the treatment periods.","whyItMatters":"This study stood out because it found no benefit, directly contradicting the narrative from some other trials and patient reports suggesting cannabinoids help MS spasticity. The finding that patients actually felt worse overall on cannabinoid treatment highlighted the importance of controlled trials over anecdotal reports and raised questions about publication bias in cannabinoid research.","specificNumbers":"Sixteen patients with severe MS spasticity were enrolled. The study used a twofold crossover design testing THC and plant extract against placebo.","methodology":"This was a randomized, double-blind, placebo-controlled, twofold crossover study. Sixteen patients with MS and severe spasticity received oral THC, cannabis sativa plant extract, and placebo in a crossover design. Spasticity was measured using standardized assessments, and patients rated their global impression of change.","limitations":"The sample of 16 patients was small and may have been underpowered to detect modest benefits. Only patients with severe spasticity were included, which may represent a population less responsive to cannabinoid treatment. The specific doses and titration schedule were not detailed in the abstract."},{"rthcId":"RTHC-00125","title":"Endocannabinoids in cognition and dependence.","authors":"Lichtman, A H; Varvel, S A; Martin, B R","year":2002,"journal":"Prostaglandins, leukotrienes, and essential fatty acids, 66(2-3), 269-85","doi":null,"pmid":"12052042","tags":["neuroscience","cognition","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review synthesized evidence from two approaches: pharmacological blockade of CB1 receptors using SR141716A, and genetic knockout mice lacking the CB1 receptor. Both approaches consistently showed enhanced performance across a variety of memory tasks, indicating that the endocannabinoid system normally acts to constrain or modulate cognitive function.\n\nCannabinoid intoxication produced cognitive deficits accompanied by changes in glutamatergic, GABAergic, and cholinergic systems in the hippocampus, each implicated in memory. The review also described evidence that the endocannabinoid system modulated opioid dependence, and that cannabis withdrawal produced a constellation of mild effects in dependent individuals.","whyItMatters":"The finding that blocking or removing the endocannabinoid system improved memory suggested that this system normally acts as a brake on memory formation. This had dual implications: it helped explain why cannabis impairs memory, and it suggested that CB1 antagonists might enhance cognition, a concept that was explored therapeutically.","specificNumbers":"No specific quantitative data were presented in the abstract.","methodology":"This was a narrative review synthesizing findings from pharmacological studies using the CB1 antagonist SR141716A, behavioral studies in CB1 receptor knockout mice, neurochemical studies of hippocampal systems, and research on cannabinoid-opioid interactions in dependence.","limitations":"Much of the evidence came from animal studies using artificial interventions (complete receptor blockade or genetic knockout) that may not reflect the subtler modulation that occurs with normal endocannabinoid signaling. The review did not address potential negative consequences of blocking the endocannabinoid system."},{"rthcId":"RTHC-00126","title":"Treatment of Tourette's syndrome with Delta 9-tetrahydrocannabinol (THC): a randomized crossover trial.","authors":"Müller-Vahl, K R; Schneider, U; Koblenz, A; Jöbges, M; Kolbe, H; Daldrup, T; Emrich, H M","year":2002,"journal":"Pharmacopsychiatry, 35(2), 57-61","doi":"10.1055/s-2002-25028","pmid":"11951146","tags":["medical-cannabis","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"THC significantly reduced tics (p=0.015) and obsessive-compulsive behavior (p=0.041) compared to placebo. Examiner ratings showed significant improvement in complex motor tics (p=0.015). The therapeutic effect correlated with blood levels of 11-OH-THC rather than THC itself, suggesting the liver metabolite may be the active therapeutic agent.","whyItMatters":"This was the first randomized controlled trial demonstrating that THC reduces tics in Tourette syndrome. The correlation between tic improvement and 11-OH-THC levels provided pharmacological insight into which compound drives the therapeutic effect, potentially enabling more targeted drug development. It launched a 20-year research program that has fundamentally changed how the field approaches cannabinoid treatment for tic disorders.","specificNumbers":"Twelve patients received 5.0, 7.5, or 10.0 mg THC. Tic improvement p=0.015 (self-rating). OCB improvement p=0.041. Complex motor tics p=0.015 (examiner). Five patients had mild transient side effects.","methodology":"Randomized, double-blind, placebo-controlled, crossover, single-dose trial. Twelve adult Tourette syndrome patients received THC (5.0, 7.5, or 10.0 mg based on body weight) or placebo. Tics assessed using self-rating (TSSL) and three examiner scales (Shapiro, YGTSS, Tourette Syndrome Global Scale). Blood levels of THC, 11-OH-THC, and THC-COOH measured at multiple time points and correlated with clinical outcomes.","limitations":"Small sample of 12 patients. Single-dose design cannot assess sustained treatment effects. Crossover with a single dose limits detection of effects that emerge with dose optimization or repeated dosing. The dose range (5-10mg) was based on weight but not individually optimized."},{"rthcId":"RTHC-00127","title":"Cannabinoids and multiple sclerosis.","authors":"Pertwee, Roger G","year":2002,"journal":"Pharmacology & therapeutics, 95(2), 165-74","doi":null,"pmid":"12182963","tags":["medical-cannabis","pain","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Clinical evidence from 8 trials in MS patients and 1 in spinal cord injury showed that cannabis, THC, and nabilone produced objective or subjective relief from spasticity, pain, tremor, and nocturia. Animal models using mice with chronic relapsing experimental allergic encephalomyelitis (CREAE) strongly supported cannabinoid receptor involvement in these effects.\n\nEndocannabinoid concentrations were elevated in the brains and spinal cords of mice with spasticity, suggesting the body's own cannabinoid system was responding to the disease. Spasticity could be reduced by inhibiting endocannabinoid breakdown, pointing toward a therapeutic strategy that would enhance the body's natural response rather than introducing external cannabinoids.","whyItMatters":"This review was published at a critical moment when large-scale clinical trials of cannabinoids for MS were being planned. The convergence of patient reports, small clinical trials, and robust preclinical evidence helped justify the investment in larger trials that would ultimately lead to the approval of Sativex.","specificNumbers":"Eight clinical trials in MS and 1 in spinal cord injury were reviewed. Both CB1 and CB2 receptors were implicated in the therapeutic effects.","methodology":"This was a narrative review synthesizing clinical trial data from 9 trials, questionnaire-based anecdotal evidence, and preclinical research using CREAE mouse models of MS. It evaluated both the clinical evidence and the biological mechanisms underlying cannabinoid effects on MS symptoms.","limitations":"The clinical trials reviewed were small, and the review acknowledged that more conclusive evidence was needed. Animal models of MS do not perfectly replicate human disease. The review did not systematically assess the quality of the included trials."},{"rthcId":"RTHC-00128","title":"Cannabinoids inhibit excitatory inputs to neurons in the shell of the nucleus accumbens: an in vivo electrophysiological study.","authors":"Pistis, Marco; Muntoni, Anna Lisa; Pillolla, Giuliano; Gessa, Gian Luigi","year":2002,"journal":"The European journal of neuroscience, 15(11), 1795-802","doi":null,"pmid":"12081659","tags":["neuroscience","addiction","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Synthetic cannabinoids (WIN 55212,2 and HU-210) and THC all strongly inhibited the firing of neurons in the shell of the nucleus accumbens when those neurons were activated by inputs from the basolateral amygdala or medial prefrontal cortex. This inhibition was completely blocked by the CB1 antagonist SR141716A, confirming it was CB1 receptor-mediated.\n\nNeither dopamine receptor antagonists nor the opioid antagonist naloxone could reverse the cannabinoid effect, demonstrating that this mechanism was independent of both dopamine and opioid signaling. This was significant because the nucleus accumbens is a critical site for the rewarding properties of drugs of abuse.","whyItMatters":"The nucleus accumbens is central to how the brain processes reward and motivation. This study revealed that cannabinoids had a direct, receptor-specific effect on this region's excitatory inputs, separate from the dopamine system that most drugs of abuse target. This provided a mechanistic explanation for why cannabis has both rewarding properties and the potential for dependence.","specificNumbers":"WIN 55212,2 doses: 0.062-0.25 mg/kg IV. HU-210: 0.125-0.25 mg/kg IV. THC: 1.0 mg/kg IV. SR141716A (CB1 antagonist): 0.5 mg/kg IV fully blocked the effect.","methodology":"This was an in vivo electrophysiology study in anesthetized rats. Extracellular recordings were made from neurons in the nucleus accumbens shell while electrically stimulating the basolateral amygdala or medial prefrontal cortex. Various cannabinoid agonists and antagonists, along with dopamine and opioid receptor blockers, were administered intravenously.","limitations":"The study was performed in anesthetized rats, which may alter neural dynamics. The doses used were administered intravenously, differing from typical human cannabis use. The relationship between inhibition of excitatory inputs to the nucleus accumbens and subjective reward experience was inferred rather than directly demonstrated."},{"rthcId":"RTHC-00129","title":"Evidence that anandamide-signaling regulates human sperm functions required for fertilization.","authors":"Schuel, Herbert; Burkman, Lani J; Lippes, Jack; Crickard, Kent; Mahony, Mary C; Giuffrida, Andrea; Picone, Robert P; Makriyannis, Alexandros","year":2002,"journal":"Molecular reproduction and development, 63(3), 376-87","doi":null,"pmid":"12237954","tags":["pregnancy","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Anandamide, an endocannabinoid, was detected in human seminal plasma, mid-cycle oviductal fluid, and follicular fluid. Human sperm expressed cannabinoid receptors with specific, saturable binding. A metabolically stable anandamide analogue produced dose-dependent effects on sperm: at higher concentrations (2.5 nM) it inhibited hyperactivated motility, while at lower concentrations (0.25 nM) it stimulated it.\n\nBoth the anandamide analogue and THC inhibited acrosomal changes needed for fertilization at remarkably low concentrations. Sperm fertilizing capacity in the Hemizona Assay was reduced 50% by just 1 nM of the anandamide analogue. These findings suggested that the endocannabinoid system plays a natural regulatory role in fertility, and that cannabis use could disrupt this regulation.","whyItMatters":"This study provided the first evidence that the endocannabinoid system was present and active in human reproductive fluids and sperm. The finding that very low concentrations of cannabinoids could significantly impair sperm fertilizing capacity raised important questions about cannabis use and male fertility.","specificNumbers":"Cannabinoid receptor binding: KD 9.71 nM on sperm. Anandamide analogue: inhibited hyperactivated motility at 2.5 nM, stimulated at 0.25 nM. Acrosomal changes inhibited at IC50 of 5.9 pM (analogue) and 3.5 nM (THC). Fertilizing capacity reduced 50% at 1 nM.","methodology":"This was a laboratory study using human reproductive fluids analyzed by HPLC/mass spectrometry to detect anandamide. Cannabinoid receptor binding on human sperm was characterized using radioligand binding assays. Functional effects of cannabinoid agonists and THC on sperm capacitation, hyperactivated motility, acrosomal changes, and fertilizing potential were assessed in vitro.","limitations":"All functional experiments were conducted in vitro and may not directly reflect conditions in the reproductive tract. The concentrations of anandamide in reproductive fluids and the concentrations of THC that would reach sperm after cannabis use may differ from those tested. The study did not assess female fertility parameters."},{"rthcId":"RTHC-00130","title":"Cannabinoids in the treatment of pain and spasticity in multiple sclerosis.","authors":"Smith, Paul F","year":2002,"journal":"Current opinion in investigational drugs (London, England : 2000), 3(6), 859-64","doi":null,"pmid":"12137404","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review acknowledged substantial evidence that cannabinoids could reduce muscle spasticity and pain through CB1 receptor mechanisms. However, in the specific context of multiple sclerosis, the evidence for superiority over existing treatments was questionable. For spasticity, too few controlled trials existed to draw reliable conclusions. For pain, most available trials suggested cannabinoids were not superior to existing treatments, though few had examined chronic pain syndromes relevant to MS.\n\nThe author argued that synthetic cannabinoids targeting specific receptor subtypes would likely prove more therapeutically useful than THC itself, which activates both CB1 and CB2 receptors broadly. Non-smoked delivery methods (such as aerosol) were recommended to avoid respiratory risks.","whyItMatters":"This review provided a more cautious assessment than many contemporaneous reviews, emphasizing that demonstrating an effect is not the same as demonstrating superiority over existing treatments. The argument for synthetic, receptor-selective cannabinoids over whole-plant cannabis represented a pharmacological perspective that would influence drug development efforts.","specificNumbers":"No specific quantitative data were highlighted in the abstract.","methodology":"This was a narrative review evaluating clinical trial evidence, preclinical data, and pharmacological considerations for cannabinoid use in MS-related pain and spasticity.","limitations":"As a narrative review, the assessment reflected the author's interpretation of limited evidence. The review did not use systematic review methodology. The evidence base at the time was dominated by small trials."},{"rthcId":"RTHC-00131","title":"Current perspectives on smoking cessation among substance abusers.","authors":"Sullivan, Maria A; Covey, Lirio S","year":2002,"journal":"Current psychiatry reports, 4(5), 388-96","doi":null,"pmid":"12230968","tags":["addiction","quitting"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Nicotine dependence was extremely prevalent among people with alcohol or other substance use disorders, and many patients in treatment programs expressed interest in quitting smoking. The review identified several key findings from clinical trials: people with past but not current alcohol dependence had similar smoking cessation success rates as non-alcoholics; quitting tobacco did not increase alcohol relapse; continued smoking adversely affected treatment for marijuana dependence; cocaine and nicotine use patterns were interrelated; and smoking cessation rates among opioid-dependent individuals were several times lower than in the general population.\n\nThe authors concluded that smoking cessation was indicated for people already in recovery from substance dependence and might actually protect against relapse to the primary drug of abuse.","whyItMatters":"This review challenged the prevailing clinical wisdom that people in substance abuse treatment should not attempt smoking cessation simultaneously because it might trigger relapse. The finding that quitting smoking actually supported rather than undermined recovery from other substances was clinically significant and helped shift treatment approaches toward addressing nicotine dependence as part of comprehensive substance abuse care.","specificNumbers":"Smoking cessation rates among opioid-dependent individuals were described as \"several times lower\" than in the general US population.","methodology":"This was a narrative review of clinical trials and survey data examining smoking cessation among people with various substance use disorders, including alcohol, marijuana, cocaine, and opioid dependence.","limitations":"The review covered a heterogeneous set of substance use disorders with varying evidence quality. The interaction between tobacco and cannabis treatment was noted but not extensively analyzed. The review did not provide a systematic assessment of all available evidence."},{"rthcId":"RTHC-00132","title":"Cannabis-based medicines--GW pharmaceuticals: high CBD, high THC, medicinal cannabis--GW pharmaceuticals, THC:CBD.","authors":"","year":2003,"journal":"Drugs in R&D, 4(5), 306-9","doi":null,"pmid":"12952500","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"GW Pharmaceuticals was developing distinct cannabis-based prescription medicines using three delivery systems: sublingual spray, sublingual tablet, and inhaled (non-smoked) forms. Four formulations were being tested: High THC, THC:CBD (narrow ratio), THC:CBD (broad ratio), and High CBD.\n\nCompleted phase III trials demonstrated that THC:CBD (narrow ratio) produced statistically significant reductions in neuropathic pain in MS patients and other conditions, with improvements in additional MS symptoms observed. Phase II trials across MS, spinal cord injury, neuropathic pain, peripheral neuropathy, rheumatoid arthritis, and perioperative pain all provided positive results with excellent safety profiles. Bayer AG was licensed for UK commercialization under the Sativex brand name.","whyItMatters":"This review documented a watershed moment in cannabinoid medicine: the first pharmaceutical company successfully developing standardized cannabis-based prescription drugs through the conventional regulatory pathway. The development of Sativex demonstrated that cannabis could meet pharmaceutical standards for quality, safety, and efficacy.","specificNumbers":"Five phase III trials underway. One trial included more than 100 patients with cancer pain. Phase II trials completed across 6 therapeutic areas. UK commercialization licensed to Bayer AG. IND approval for US phase II trials received.","methodology":"This was a pharmaceutical industry review documenting the development program for GW Pharmaceuticals' cannabis-based medicines, including summaries of completed and ongoing clinical trials across multiple indications.","limitations":"This was an industry-produced review that presented the company's development program in favorable terms. Detailed trial data and methodology were not provided. The review was written before most trial results were published in peer-reviewed form."},{"rthcId":"RTHC-00133","title":"The therapeutic potential of cannabis.","authors":"Baker, David; Pryce, Gareth; Giovannoni, Gavin; Thompson, Alan J","year":2003,"journal":"The Lancet. Neurology, 2(5), 291-8","doi":null,"pmid":"12849183","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review drew parallels between the cannabinoid and opioid research fields, noting that in both cases, study of drug-producing plants led to discovery of endogenous control systems with central roles in neurobiology. While clinical claims were being formally tested in disorders like MS spasticity and pain, basic research was uncovering new properties of cannabinoid compounds, most notably neuroprotection.\n\nThe authors argued that even if ongoing large clinical trials produced disappointing results for traditional indications like spasticity and pain, the field was only beginning to appreciate the broader therapeutic potential of cannabinoid compounds.","whyItMatters":"Published in one of the most prestigious neurology journals, this review signaled mainstream medical acceptance that cannabinoids deserved serious therapeutic investigation. The emphasis on neuroprotection as a potentially more important application than symptom relief anticipated research directions that continue to be explored.","specificNumbers":"No specific quantitative data were presented in the abstract.","methodology":"This was a narrative review published in Lancet Neurology synthesizing the state of clinical and basic cannabinoid research, with emphasis on emerging evidence for neuroprotective properties.","limitations":"The review was forward-looking and speculative in nature. Neuroprotective claims were based primarily on preclinical data. The review did not provide systematic analysis of existing evidence."},{"rthcId":"RTHC-00134","title":"The time course and significance of cannabis withdrawal","authors":"Budney, Alan J.; Moore, Brent A.; Vandrey, Ryan G.; Hughes, John R.","year":2003,"journal":"Journal of Abnormal Psychology, 112(3), 393-402","doi":null,"pmid":"12943018","tags":["withdrawal","addiction","anxiety","appetite"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"After heavy users stopped, a consistent withdrawal pattern emerged across mood, sleep, and physical symptoms. Participants reported aggression, anger, anxiety, irritability, restlessness, shakiness, sleep problems, stomach pain, decreased appetite, and measurable weight loss. Symptoms typically began between Days 1 and 3 after cessation, peaked between Days 2 and 6, and for most people subsided within 4 to 14 days. The ex-user comparison group, assessed in parallel, did not show the same time-locked pattern. The authors judged the size and timing of the cannabis withdrawal syndrome to be comparable to tobacco and other recognized withdrawal syndromes.","whyItMatters":"In 2003, whether cannabis produced a clinically meaningful withdrawal syndrome was debated. This study mapped a timeline that aligned with other substance withdrawal patterns, which helped clarify why stopping heavy use can be difficult and informed later diagnostic criteria.","specificNumbers":"- Sample: 18 current heavy users plus 12 ex-users, followed for 50 days\n- Onset of withdrawal: 1–3 days after stopping\n- Peak severity: Days 2–6 after stopping\n- Typical duration: 4–14 days before most symptoms eased","methodology":"Researchers followed 18 current heavy cannabis users through a 5-day smoking-as-usual baseline followed by 45 days of instructed abstinence. A comparison group of 12 ex-users was assessed on the same schedule. Symptoms were tracked repeatedly across the 50-day window in an outpatient setting. There was no randomization or blinding, and abstinence verification methods were not described in the abstract. The design allows within-person observation of symptom change after cessation but remains observational and subject to expectancy and reporting biases.","limitations":"Only 30 participants were studied, and just 18 underwent abstinence monitoring. The outpatient design relies on participant adherence and self-report. The abstract does not state whether abstinence was biochemically verified. Ex-users may differ from current users in ways that affect symptom reporting. No dose, potency, or product-type details were provided, so generalizability to different patterns of use is unclear."},{"rthcId":"RTHC-00135","title":"Therapeutic potential of cannabinoids in CNS disease.","authors":"Croxford, J Ludovic","year":2003,"journal":"CNS drugs, 17(3), 179-202","doi":null,"pmid":"12617697","tags":["medical-cannabis","neuroscience","pain","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review mapped cannabinoid therapeutic potential across multiple CNS conditions. For MS, cannabinoids alleviated tremor and spasticity in animal models with clinical trials underway. For Parkinson's disease, cannabinoids could potentially inhibit excitotoxic glutamate and counter oxidative damage to dopaminergic neurons. Cannabinoid inhibition of reactive oxygen species, glutamate, and tumor necrosis factor suggested potent neuroprotective properties, with Dexanabinol in clinical trials for traumatic brain injury and stroke.\n\nFor pain, animal models showed cannabinoid effectiveness across mechanical, thermal, and noxious pain, with clinical trials confirming superiority over placebo though not necessarily over existing treatments. Dronabinol was established for HIV wasting syndrome, and cannabinoid receptor antagonists were being explored for obesity. Non-psychoactive cannabinoids like CBD and Dexanabinol offered the possibility of separating therapeutic effects from unwanted psychoactivity.","whyItMatters":"This review provided one of the most comprehensive surveys of cannabinoid therapeutic potential across neurology, organized by condition and mechanism. By systematically cataloging both the evidence and the gaps, it served as a roadmap for future clinical research.","specificNumbers":"Nabilone was noted as currently licensed for chemotherapy-induced nausea. Dronabinol was established for HIV wasting. Multiple clinical trials were referenced across MS, pain, and neuroprotection.","methodology":"This was a comprehensive narrative review covering the pharmacology of the endocannabinoid system and its therapeutic implications across multiple CNS disorders, integrating preclinical evidence, clinical trial data, and pharmacological analysis.","limitations":"The review covered a very broad scope, limiting depth on any single topic. Many of the therapeutic claims were based on preclinical or early clinical data. The pain comparison with existing therapies was acknowledged as unfavorable for cannabinoids."},{"rthcId":"RTHC-00136","title":"Microbial infections, immunomodulation, and drugs of abuse.","authors":"Friedman, Herman; Newton, Catherine; Klein, Thomas W","year":2003,"journal":"Clinical microbiology reviews, 16(2), 209-19","doi":null,"pmid":"12692094","tags":["medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review described how multiple drugs of abuse, including marijuana, modulated the immune system. For marijuana and opiates, immunosuppressive effects were receptor-mediated, occurring both directly through receptors on immune cells and indirectly through receptors in the nervous system. Cocaine and nicotine showed similar receptor-mediated immunomodulatory effects.\n\nThe immunosuppressive properties of these drugs increased susceptibility to opportunistic infections, which became an urgent public health concern with the AIDS epidemic. The review noted a long-recognized relationship between drug abuse and increased infection levels, with mechanistic research providing explanations for this clinical observation.","whyItMatters":"Understanding how cannabis affects the immune system has dual significance: it explains increased infection susceptibility in cannabis users and points toward potential therapeutic applications of cannabinoid immunomodulation in autoimmune and inflammatory conditions. The receptor-mediated nature of these effects suggested they could potentially be targeted pharmacologically.","specificNumbers":"No specific quantitative data were presented in the abstract.","methodology":"This was a narrative review covering the immunomodulatory mechanisms of marijuana, opiates, cocaine, nicotine, and alcohol, synthesizing evidence from basic science, immunology, and clinical observations of infection susceptibility.","limitations":"The review covered five different drug classes broadly, limiting depth on cannabis specifically. Much of the evidence was from in vitro and animal studies. The clinical significance of cannabinoid immunosuppression in otherwise healthy users remained unclear."},{"rthcId":"RTHC-00137","title":"Cardiovascular manifestations of substance abuse: part 2: alcohol, amphetamines, heroin, cannabis, and caffeine.","authors":"Frishman, William H; Del Vecchio, Alexander; Sanal, Shirin; Ismail, Anjum","year":2003,"journal":"Heart disease (Hagerstown, Md.), 5(4), 253-71","doi":null,"pmid":"12877759","tags":["cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review compared cardiovascular effects across five categories of substances. Cannabis posed fewer cardiovascular risks than opiates (which could cause arrhythmias and pulmonary edema), amphetamines (which shared cocaine's acute and chronic cardiovascular toxicities), and alcohol (associated with cardiomyopathy, hypertension, and arrhythmia). However, the review noted that major cognitive disorders could accompany chronic cannabis use.\n\nAlcohol was unique among these substances in having possible protective effects against coronary artery disease and stroke when used in moderate amounts. Caffeine's role in hypertension and coronary disease remained controversial.","whyItMatters":"By placing cannabis cardiovascular risks in the context of other commonly used substances, this review provided perspective often missing from single-substance analyses. The finding that cannabis posed relatively lower cardiovascular risk compared to other drugs of abuse was informative for both clinical risk assessment and public health messaging.","specificNumbers":"No specific quantitative data were presented in the cannabis section of the abstract.","methodology":"This was a narrative review comparing the cardiovascular manifestations of alcohol, amphetamines, heroin, cannabis, and caffeine, serving as part 2 of a two-part series on substance abuse and cardiovascular disease.","limitations":"The review covered five substance classes in a single paper, limiting depth on each. The cardiovascular effects of cannabis were not extensively detailed in the abstract. The cognitive effects mentioned were outside the cardiovascular focus."},{"rthcId":"RTHC-00138","title":"Pharmacokinetics and pharmacodynamics of cannabinoids.","authors":"Grotenhermen, Franjo","year":2003,"journal":"Clinical pharmacokinetics, 42(4), 327-60","doi":null,"pmid":"12648025","tags":["medical-cannabis","neuroscience","tolerance"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review provided a detailed account of how THC and other cannabinoids are absorbed, distributed, metabolized, and eliminated. When inhaled, THC reached peak plasma concentration within minutes, with psychotropic effects starting within seconds to minutes, peaking at 15-30 minutes, and tapering off within 2-3 hours. Oral ingestion delayed effects by 30-90 minutes, with peak effects at 2-3 hours lasting 4-12 hours depending on dose.\n\nAt therapeutic doses, cannabis typically produced enhanced well-being and relaxation with intensified sensory experiences. The most important acute adverse effects from overdosing were anxiety, panic attacks, increased heart rate, and blood pressure changes. Regular use could lead to dependency and a mild withdrawal syndrome. The review listed therapeutic properties including analgesia, muscle relaxation, immunosuppression, appetite stimulation, antiemesis, bronchodilation, neuroprotection, and induction of apoptosis in cancer cells.","whyItMatters":"This review became a standard reference for cannabinoid pharmacokinetics. Understanding how different routes of administration affect onset, peak, and duration of effects is critical for both medical dosing and understanding recreational use patterns. The pharmacokinetic differences between inhalation and oral routes explain many of the practical challenges in cannabinoid therapeutics.","specificNumbers":"Inhalation: peak plasma within minutes, effects peak 15-30 min, duration 2-3 hours. Oral: onset 30-90 min, peak 2-3 hours, duration 4-12 hours.","methodology":"This was a comprehensive pharmacokinetic and pharmacodynamic review published in Clinical Pharmacokinetics, covering absorption, distribution, metabolism, and elimination of cannabinoids across all routes of administration, along with therapeutic and adverse effects.","limitations":"Pharmacokinetic parameters vary substantially between individuals based on body composition, tolerance, metabolism, and other factors. The review was published before many modern cannabis products (concentrates, edibles with precise dosing) existed. Long-term effects were described as controversial at the time."},{"rthcId":"RTHC-00139","title":"Cannabinoids: potential anticancer agents.","authors":"Guzmán, Manuel","year":2003,"journal":"Nature reviews. Cancer, 3(10), 745-55","doi":null,"pmid":"14570037","tags":["cancer","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Beyond their established palliative effects in cancer patients (preventing nausea, vomiting, pain, and stimulating appetite), cannabinoids had been shown to inhibit tumor cell growth in cell cultures and animal models. These anti-tumor effects occurred through modulation of key cell-signaling pathways. Importantly, cannabinoids were generally well tolerated and did not produce the generalized toxic effects seen with conventional chemotherapies.\n\nThe review posed the question of whether cannabinoids could be developed into new anticancer therapies, marking one of the first times this question was seriously raised in a top-tier cancer research journal.","whyItMatters":"Publication in Nature Reviews Cancer gave significant visibility and credibility to cannabinoid anticancer research. The observation that cannabinoids could inhibit tumor growth while being well tolerated contrasted sharply with the toxicity of conventional chemotherapy and stimulated further investigation.","specificNumbers":"No specific quantitative data were provided in the abstract.","methodology":"This was a review article published in Nature Reviews Cancer evaluating the evidence for anticancer properties of cannabinoids from cell culture and animal model studies.","limitations":"The evidence was entirely preclinical (cell cultures and animal models). Tumor inhibition in the lab does not necessarily predict clinical anticancer efficacy. The mechanisms by which cannabinoids affected tumor growth were not fully elucidated."},{"rthcId":"RTHC-00140","title":"Medical marijuana initiatives : are they justified? How successful are they likely to be?","authors":"Hall, Wayne; Degenhardt, Louisa","year":2003,"journal":"CNS drugs, 17(10), 689-97","doi":null,"pmid":"12873153","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"THC was moderately effective for nausea and vomiting, appetite loss, and acute and chronic pain. Oral THC (dronabinol) and nabilone were registered in the US and UK but not widely used because patients found dose titration difficult. Several jurisdictions had attempted different policy approaches: US states legislated medical cannabis but faced federal opposition; the UK recommended prescription but governments rejected the recommendation; Canada allowed prosecution exemptions and was moving toward prescription access.\n\nThe authors argued that full legalization would violate international drug treaties and was electorally unpopular. They concluded the best prospects were non-smoked THC delivery methods and synthetic cannabinoids with fewer psychoactive effects. As an interim measure, they suggested prosecution exemptions for patients with specified conditions.","whyItMatters":"This review captured the medical cannabis policy landscape at a pivotal moment when multiple countries were experimenting with different regulatory frameworks. The analysis of why each approach succeeded or failed provided a comparative framework that policymakers continue to reference.","specificNumbers":"Alberta MS prevalence: 217 per 100,000 (cited as among the highest in the world). Various policy approaches across US, UK, Australia, and Canada were compared.","methodology":"This was a policy review examining the evidence for medical cannabis effectiveness alongside the various legislative and regulatory approaches being attempted internationally.","limitations":"The review reflected the evidence and policy landscape of 2003, which has changed substantially. The authors' preference for synthetic cannabinoids over plant cannabis was not borne out by market dynamics. The analysis may have underestimated patient and voter support for medical cannabis."},{"rthcId":"RTHC-00141","title":"Cannabis and the brain.","authors":"Iversen, Leslie","year":2003,"journal":"Brain : a journal of neurology, 126(Pt 6), 1252-70","doi":null,"pmid":"12764049","tags":["neuroscience","cognition","psychosis","tolerance"],"studyType":"review","evidenceStrength":"strong","keyFinding":"All known central effects of THC were mediated through CB1 receptors, with particularly high expression on GABAergic interneurons in the hippocampus, amygdala, and cerebral cortex. The endocannabinoids anandamide and 2-AG acted as retrograde synaptic mediators. Central effects included disruption of psychomotor behavior, short-term memory impairment, intoxication, appetite stimulation, pain relief (particularly neuropathic pain), and anti-emetic effects.\n\nWhile signs of mild cognitive impairment were observed in chronic cannabis users, there was little evidence that such impairments were irreversible or accompanied by drug-induced brain pathology. Some users developed tolerance and dependence. Some studies linked chronic use to increased psychiatric illness risk, but the review found little evidence for a causal link. Medical applications for MS were being tested in clinical trials.","whyItMatters":"Published in one of neurology's most prestigious journals, this review carried significant weight. The careful conclusion that cognitive impairments appeared reversible and that psychiatric links lacked causal evidence was influential in shaping the medical and scientific consensus about cannabis safety. The review balanced acknowledgment of risks with proportionate assessment of evidence.","specificNumbers":"No specific quantitative data were presented in the abstract, but findings were synthesized from the broader literature.","methodology":"This was a comprehensive review published in Brain, one of the leading neurology journals, covering cannabinoid receptor neurobiology, endocannabinoid function, central effects of cannabis, cognitive impacts, dependence, psychiatric associations, and therapeutic potential.","limitations":"Published in 2003, the review predated several large longitudinal studies that provided stronger evidence for cannabis-psychosis links. The assessment of irreversibility of cognitive effects was based on limited data available at the time."},{"rthcId":"RTHC-00142","title":"Auditory-evoked potentials and selective attention: different ways of information processing in cannabis users and controls.","authors":"Kempel, P; Lampe, K; Parnefjord, R; Hennig, J; Kunert, H J","year":2003,"journal":"Neuropsychobiology, 48(2), 95-101","doi":null,"pmid":"14504418","tags":["cognition","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Using event-related potentials during a complex auditory attention task, the study found that controls showed shorter latencies for negative brain wave peaks (at 200 and 300 ms) to target tones compared to non-targets, while cannabis users showed no clear difference between targets and non-targets. Users also displayed reduced P3 amplitude to target tones, a brain wave component associated with attention allocation and cognitive processing.\n\nThe reduced P3 was more pronounced in early-onset cannabis users. No significant differences were found between groups on standard neuropsychological tests of memory or executive function, suggesting that brain wave measures detected subtle processing differences that behavioral tests missed.","whyItMatters":"This study demonstrated that electrophysiological measures could detect subtle differences in information processing that standard neuropsychological tests missed. The finding that early-onset users showed greater effects supported the hypothesis that the developing brain is more vulnerable to cannabis effects. The suggestion that cannabis users employed different attention strategies rather than simply performing worse added nuance to the cognitive impact discussion.","specificNumbers":"Twenty-one cannabis users and 13 controls were tested. Brain wave components at 200 and 300 ms were analyzed. P3 amplitude was significantly reduced in users, more so in early-onset users.","methodology":"This was a cross-sectional study comparing 21 cannabis users (divided by age of onset) with 13 controls matched for age, IQ, and educational background. Event-related potentials were recorded during a complex auditory selective attention task. Standard neuropsychological tests of executive function and memory were also administered.","limitations":"The sample was small (21 users, 13 controls). Cross-sectional design cannot determine whether the brain wave differences preceded or resulted from cannabis use. Cannabis users also consumed more alcohol, which could contribute to the findings. The study could not distinguish between acute residual effects and chronic changes."},{"rthcId":"RTHC-00143","title":"Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial.","authors":"Müller-Vahl, Kirsten R; Schneider, Udo; Prevedel, Heidrun; Theloe, Karen; Kolbe, Hans; Daldrup, Thomas; Emrich, Hinderk M","year":2003,"journal":"The Journal of clinical psychiatry, 64(4), 459-65","doi":null,"pmid":"12716250","tags":["medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In this 6-week randomized, double-blind, placebo-controlled trial, THC (up to 10 mg/day) produced significant improvements or trends toward improvement across multiple tic rating scales. Using patient self-ratings, there was a significant difference between THC and placebo across 10 treatment days. The overall ANOVA also demonstrated a significant difference (p=0.037).\n\nSeven of 24 patients dropped out or were excluded, but only one due to side effects. No serious adverse effects occurred. This was the first controlled trial to demonstrate THC effectiveness for tics over a sustained treatment period rather than a single dose.","whyItMatters":"This was the landmark trial that moved cannabinoid treatment for Tourette syndrome from promising single-dose studies to evidence of sustained efficacy. The 6-week treatment period with multiple assessment tools and a robust study design provided the strongest evidence to date that THC could be an effective treatment for tics.","specificNumbers":"Twenty-four patients enrolled, 17 completed. THC dose up to 10 mg/day. Treatment duration: 6 weeks with 6 assessment visits. Overall ANOVA p=0.037. One dropout due to side effects.","methodology":"This was a randomized, double-blind, placebo-controlled parallel study. Twenty-four patients with Tourette syndrome (DSM-III-R criteria) were treated for 6 weeks with up to 10 mg/day THC or placebo. Tics were rated at 6 visits using 5 different assessment tools: TS-CGI, STSSS, YGTSS, TSSL (self-rated), and a videotape-based rating scale.","limitations":"The sample of 24 patients (17 completers) was still relatively small. The 29% dropout rate, while only partly due to side effects, reduces the interpretability of results. Multiple assessment tools were used, with significance reached on some but not all scales, which could raise concerns about multiple comparisons."},{"rthcId":"RTHC-00144","title":"Cannabinoid receptor activation in the rostral ventrolateral medulla oblongata evokes cardiorespiratory effects in anaesthetised rats.","authors":"Padley, James R; Li, Qun; Pilowsky, Paul M; Goodchild, Ann K","year":2003,"journal":"British journal of pharmacology, 140(2), 384-94","doi":null,"pmid":"12970095","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers activated CB1 cannabinoid receptors in a specific brainstem region called the rostral ventrolateral medulla oblongata (RVLM) of anesthetized rats. This region is critical for controlling both cardiovascular function and breathing.\n\nCB1 activation produced dose-dependent increases in sympathetic nerve activity and blood pressure. Strikingly, it also completely abolished phrenic nerve activity, the nerve output responsible for driving diaphragm contractions during breathing.\n\nThis was the first demonstration that cannabinoid receptors in this particular brainstem region could simultaneously affect both cardiovascular and respiratory control, suggesting a previously unknown mechanism through which cannabinoids might influence vital autonomic functions.","whyItMatters":"The brainstem regions controlling blood pressure and breathing are fundamental to survival. Discovering that CB1 receptors in this area can dramatically alter both systems provided a new mechanism to investigate regarding cannabinoid effects on cardiovascular and respiratory function, including potential risks.","specificNumbers":"CB1 activation produced dose-dependent increases in sympathetic nerve activity and blood pressure. Phrenic nerve activity was completely abolished. Effects were localized to the rostral ventrolateral medulla oblongata.","methodology":"Researchers used anesthetized rats and directly applied a CB1 receptor agonist to the rostral ventrolateral medulla oblongata via microinjection. They simultaneously recorded sympathetic nerve activity, blood pressure, and phrenic nerve discharge to measure dose-dependent cardiorespiratory effects.","limitations":"This was an acute animal study using direct brain microinjection in anesthetized rats, which does not replicate how cannabinoids reach the brain during normal cannabis use. Anesthesia itself affects autonomic function. The doses and delivery method have no direct human equivalent."},{"rthcId":"RTHC-00145","title":"Cannabis use as described by people with multiple sclerosis.","authors":"Page, S A; Verhoef, M J; Stebbins, R A; Metz, L M; Levy, J C","year":2003,"journal":"The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 30(3), 201-5","doi":null,"pmid":"12945941","tags":["medical-cannabis","pain","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 420 MS patients who completed the survey (62% response rate), 96% were aware that cannabis could potentially be therapeutically useful for MS and 72% supported legalization for medical purposes. Forty-three percent had tried cannabis at some point, and 16% had used it specifically for medicinal purposes.\n\nPatients who used cannabis medicinally reported improvements in anxiety and depression, spasticity, and chronic pain. The main reasons for not trying cannabis were its illegal status, concern about side effects, and not knowing how to obtain it. The sample ranged from mildly to severely impaired, with a mean age of 48 years and 75% women.","whyItMatters":"This was one of the larger surveys of cannabis use among MS patients and provided important data about patient perspectives at a time when clinical trials were underway. The finding that illegality was the primary barrier to use highlighted how drug policy directly affected patient access to a treatment many believed was helpful.","specificNumbers":"420 respondents from 673 eligible (62% response). Mean age 48 years, 75% women. 96% aware of potential therapeutic use. 72% supported medical legalization. 43% had ever tried cannabis. 16% used medicinally.","methodology":"This was a cross-sectional survey study. Questionnaires were mailed to 780 adults with MS in southern Alberta, Canada, with 420 of 673 eligible subjects responding (62% response rate). The survey assessed beliefs, practices, and experiences related to cannabis use.","limitations":"Self-reported symptom improvement was subjective and not verified by clinical assessment. The 62% response rate, while reasonable, may have introduced selection bias if cannabis users were more motivated to respond. Alberta's high MS prevalence may limit generalizability to lower-prevalence regions."},{"rthcId":"RTHC-00146","title":"Cannabinoids inhibit neurodegeneration in models of multiple sclerosis.","authors":"Pryce, Gareth; Ahmed, Zubair; Hankey, Deborah J R; Jackson, Samuel J; Croxford, J Ludovic; Pocock, Jennifer M; Ledent, Catherine; Petzold, Axel; Thompson, Alan J; Giovannoni, Gavin; Cuzner, M Louise; Baker, David","year":2003,"journal":"Brain : a journal of neurology, 126(Pt 10), 2191-202","doi":null,"pmid":"12876144","tags":["medical-cannabis","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Using experimental allergic encephalomyelitis (EAE), an animal model of MS, researchers demonstrated that the cannabinoid system was neuroprotective. Mice lacking the CB1 receptor tolerated inflammatory and excitotoxic insults poorly and developed substantial neurodegeneration following immune attack. Conversely, administering CB1 receptor agonists provided significant neuroprotection in an experimental uveitis model of inflammatory CNS disease.\n\nThese findings suggested that beyond symptom management (spasticity, pain), cannabis might actually slow the neurodegenerative processes that lead to chronic disability in MS, a fundamentally different and potentially more important therapeutic role.","whyItMatters":"This study shifted the conversation about cannabinoids and MS from symptom management to disease modification. If cannabinoids could protect neurons from the inflammatory damage that drives MS progression, they could potentially change the course of the disease rather than just making symptoms more bearable. This was a conceptually significant advance.","specificNumbers":"CB1 knockout mice developed substantial neurodegeneration compared to normal mice. Exogenous CB1 agonists provided significant neuroprotection in the uveitis model.","methodology":"This was an animal study using CB1 receptor knockout mice in the EAE model of MS. Neurodegeneration was compared between normal and CB1-deficient mice following immune-mediated CNS attack. Exogenous CB1 agonists were tested for neuroprotection in an experimental uveitis model. The study was published in Brain.","limitations":"Animal models of MS do not perfectly replicate human disease. The EAE model has limitations in modeling the chronic progressive phase of MS. Results from CB1 knockout mice may not directly predict what happens when cannabinoids are added to an intact system."},{"rthcId":"RTHC-00147","title":"Reduced binocular depth inversion in regular cannabis users.","authors":"Semple, David M; Ramsden, Fiona; McIntosh, Andrew M","year":2003,"journal":"Pharmacology, biochemistry, and behavior, 75(4), 789-93","doi":null,"pmid":"12957220","tags":["cognition","psychosis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Ten regular cannabis users showed significantly higher scores on the binocular depth inversion illusion (BDII) for inverted images compared to 10 matched controls. This was not due to basic visual processing problems, as there was no difference for normal image depth perception. The BDII impairment did not correlate with time since last dose, suggesting it reflected chronic rather than acute effects.\n\nStandard neuropsychological tests of memory and executive function showed no significant differences between groups. The BDII appeared to be a more sensitive tool for detecting subtle visual information processing changes. The pattern of reduced BDII is also seen in schizophrenia patients with positive symptoms and in other altered states including alcohol withdrawal and sleep deprivation.","whyItMatters":"The overlap between the BDII pattern seen in cannabis users and schizophrenia patients was intriguing, as it raised questions about whether cannabis-related visual processing changes shared underlying mechanisms with psychotic states. The finding that standard tests missed what the BDII detected supported the use of more specialized assessments in cannabis research.","specificNumbers":"Ten cannabis users and 10 controls. BDII scores significantly higher for inverted images in users. No significant differences on standard memory or executive function tests. Cannabis users consumed significantly more alcohol.","methodology":"This was a cross-sectional study comparing 10 regular cannabis users with 10 healthy controls matched for age, sex, and premorbid IQ. The binocular depth inversion illusion task, standard neuropsychological tests, and personality measures (EPQ-R) were administered.","limitations":"The sample was very small (10 per group) and cross-sectional, preventing causal conclusions. Cannabis users also used more alcohol, which could confound results. Pre-existing perceptual differences could explain the findings rather than cannabis effects. The BDII, while sensitive, is a specialized measure with limited clinical applicability."},{"rthcId":"RTHC-00148","title":"Cannabinoids: reward, dependence, and underlying neurochemical mechanisms--a review of recent preclinical data.","authors":"Tanda, Gianluigi; Goldberg, Steven R","year":2003,"journal":"Psychopharmacology, 169(2), 115-34","doi":null,"pmid":"12827346","tags":["addiction","dopamine","neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Strong and persistent THC self-administration was demonstrated in squirrel monkeys at doses matching those humans self-administer when smoking marijuana, providing the first reliable direct measure of THC's reinforcing effects. Synthetic CB1 agonists were also self-administered by rats and mice, and genetically modified mice lacking cannabinoid receptors provided models for exploring mechanisms.\n\nTHC and synthetic CB1 agonists could induce conditioned place preferences or aversions depending on dose and timing, could reduce intracranial self-stimulation thresholds under certain conditions, and served as discriminative stimuli. Major functional interactions existed between endocannabinoid, opioid, and dopamine systems across analgesia, dependence, tolerance, and reward, suggesting opportunities for developing drugs with therapeutic benefits but reduced abuse potential.","whyItMatters":"For decades, the inability to demonstrate reliable THC self-administration in animals was cited as evidence against cannabis addiction. This review documented the breakthrough demonstration of THC self-administration in monkeys, fundamentally changing the scientific understanding of cannabis reward. The identification of cannabinoid-opioid-dopamine interactions opened new avenues for understanding and treating drug dependence.","specificNumbers":"THC self-administration was demonstrated at doses matching human marijuana smoking. Both rats and mice self-administered synthetic CB1 agonists.","methodology":"This was a comprehensive review of preclinical models of cannabinoid reward and dependence, published in Psychopharmacology, covering self-administration studies, conditioned place preference, intracranial self-stimulation, drug discrimination, and neurochemical mechanism studies.","limitations":"Animal self-administration models may not fully capture the complexity of human drug-seeking behavior. The dose-dependent nature of conditioned place preferences and aversions complicated interpretation. Most studies used intravenous administration, which differs from typical human use."},{"rthcId":"RTHC-00149","title":"Marijuana and tobacco: a major connection?","authors":"Tullis, Laura Michelle; Dupont, Robert; Frost-Pineda, Kimberly; Gold, Mark S","year":2003,"journal":"Journal of addictive diseases, 22(3), 51-62","doi":null,"pmid":"14621344","tags":["addiction","youth"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"While gateway theory traditionally described progression from tobacco to cannabis to harder drugs, this review proposed a reversal: cannabis might serve as a gateway to tobacco smoking. Research with university students was suggesting that cigarette smoking initiation often followed or coincided with marijuana use, rather than preceding it as traditional gateway theory predicted.\n\nThe review noted that while short and long-term consequences of marijuana use were well documented, the relationship between tobacco and marijuana use patterns had received less attention. The authors argued that understanding this bidirectional relationship was important for youth health education and prevention efforts.","whyItMatters":"This review challenged the unidirectional framing of gateway theory and raised important practical concerns: if cannabis use leads some young people to start smoking tobacco, then cannabis prevention might also be tobacco prevention, and cannabis education should address the tobacco connection directly.","specificNumbers":"No specific quantitative data were presented in the abstract.","methodology":"This was a narrative review combining literature analysis with preliminary research findings from university student populations regarding the temporal relationship between tobacco and cannabis use initiation.","limitations":"The review's own research findings from university students were described as preliminary and suggestive rather than definitive. Selection bias in university samples limits generalizability. The temporal relationship between cannabis and tobacco initiation may vary by cultural context and smoking practices."},{"rthcId":"RTHC-00150","title":"A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms.","authors":"Wade, Derick T; Robson, Philip; House, Heather; Makela, Petra; Aram, Julia","year":2003,"journal":"Clinical rehabilitation, 17(1), 21-9","doi":null,"pmid":"12617376","tags":["medical-cannabis","cbd","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 24 patients with neurological conditions (18 MS, 4 spinal cord injury, 2 other) whose symptoms had not responded to standard treatments, sublingual cannabis extracts produced significant pain relief. Both THC-containing and CBD-containing extracts improved pain significantly compared to placebo. Some patients also experienced improvements in bladder control, muscle spasms, and spasticity.\n\nThe extracts were self-administered by sublingual spray at doses patients titrated based on symptom relief, ranging from 2.5 to 120 mg per 24 hours. Three patients experienced transient hypotension and intoxication with rapid initial dosing, but unwanted effects were generally predictable and well tolerated.","whyItMatters":"This was one of the early clinical trials of what would become Sativex, testing sublingual delivery of standardized cannabis extracts. The finding that both THC and CBD provided significant pain relief in treatment-resistant neurological conditions helped build the evidence base for subsequent approval of Sativex.","specificNumbers":"Twenty-four patients enrolled. Doses ranged from 2.5 to 120 mg per 24 hours via sublingual spray. Two-week treatment periods for each condition. Three patients experienced transient hypotension.","methodology":"This was a series of double-blind, randomized, placebo-controlled, single-patient crossover trials with two-week treatment periods. Twenty-four patients received whole-plant extracts of THC, CBD, 1:1 CBD:THC, or placebo via sublingual spray. Patients recorded daily symptom, well-being, and intoxication scores using visual analogue scales.","limitations":"The sample was small (24 patients) and heterogeneous in terms of underlying conditions. The single-patient crossover design, while appropriate for early-stage investigation, limits generalizability. The wide dose range (2.5-120 mg) suggests substantial individual variation that requires further characterization."},{"rthcId":"RTHC-00151","title":"Established and potential therapeutic applications of cannabinoids in oncology.","authors":"Walsh, Declan; Nelson, Kristine A; Mahmoud, Fade Aziz","year":2003,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 11(3), 137-43","doi":null,"pmid":"12618922","tags":["medical-cannabis","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Two uses for the synthetic cannabinoid dronabinol were established: chemotherapy-induced nausea and vomiting, and AIDS-related anorexia. Beyond these, the review identified several potential applications relevant to cancer patients: pain relief, antitumor effects (through cannabinoid receptors in immune and neural tissue), mood elevation, muscle relaxation, and insomnia relief.\n\nTwo cannabinoid receptor types had been identified: CB1 (mainly central and peripheral nervous system) and CB2 (mainly immune cells). The discovery of both receptors and endocannabinoids had opened new research avenues for pharmaceutical applications.","whyItMatters":"This review helped frame cannabinoid therapeutics in the oncology context, where patients often deal with multiple symptoms simultaneously. The argument that cannabinoids could address several cancer-related symptoms (nausea, pain, appetite, mood, sleep) with a single class of medications was appealing for patients dealing with polypharmacy.","specificNumbers":"No specific quantitative data were presented in the abstract.","methodology":"This was a narrative review published in Supportive Care in Cancer evaluating established and potential therapeutic applications of cannabinoids specifically for oncology patients.","limitations":"The review was primarily descriptive without systematic evidence assessment. Many of the \"potential\" applications lacked clinical trial support. The distinction between established and speculative applications could have been more clearly delineated."},{"rthcId":"RTHC-00152","title":"Medicinal cannabis: is delta9-tetrahydrocannabinol necessary for all its effects?","authors":"Wilkinson, J D; Whalley, B J; Baker, D; Pryce, G; Constanti, A; Gibbons, S; Williamson, E M","year":2003,"journal":"The Journal of pharmacy and pharmacology, 55(12), 1687-94","doi":null,"pmid":"14738597","tags":["medical-cannabis","cbd","epilepsy"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"In a mouse model of MS, whole cannabis extract (SCE) and pure THC inhibited spasticity to comparable levels, but the extract produced faster onset of muscle relaxation and shorter time to maximum effect. THC-free extract and pure CBD did not reduce spasticity, confirming THC was necessary for this effect.\n\nIn an epilepsy model using rat brain slices, the whole extract was both more potent and faster-acting as an anticonvulsant than isolated THC. The THC-free extract also exhibited anticonvulsant activity in this model, though CBD alone did not. This demonstrated that some therapeutic effects of cannabis were enhanced by or even independent of THC, with unidentified plant compounds contributing.","whyItMatters":"This study provided some of the clearest early evidence that cannabis extracts contained therapeutically active compounds beyond THC and CBD. The finding that THC-free extract had anticonvulsant properties independent of CBD was particularly intriguing and suggested unidentified plant constituents with therapeutic potential.","specificNumbers":"Cannabis extracts were compared at matched THC concentrations. Both spasticity and epilepsy models were tested with four preparations: full extract, THC alone, THC-free extract, and CBD alone.","methodology":"This was a preclinical study comparing standardized cannabis extract (SCE), pure THC, THC-free extract, and CBD in two models: a mouse model of MS spasticity (CREAE) and an in vitro rat brain slice model of epilepsy (oxotremorine-M-induced seizures). All extract concentrations were matched for THC content.","limitations":"Both models were preclinical (animal and in vitro). The specific compounds in THC-free extract responsible for anticonvulsant activity were not identified. The mouse spasticity model and brain slice epilepsy model may not fully predict human therapeutic responses."},{"rthcId":"RTHC-00153","title":"Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.","authors":"Zajicek, John; Fox, Patrick; Sanders, Hilary; Wright, David; Vickery, Jane; Nunn, Andrew; Thompson, Alan","year":2003,"journal":"Lancet (London, England), 362(9395), 1517-26","doi":null,"pmid":"14615106","tags":["medical-cannabis","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In this landmark trial of 667 MS patients across 33 UK centers, neither oral cannabis extract nor THC improved spasticity as measured by the Ashworth scale (primary outcome, p=0.40). However, patient-reported spasticity improvement was significantly better with both active treatments compared to placebo (p=0.003): 61% on cannabis extract, 60% on THC, and 46% on placebo reported improvement.\n\nObjective mobility measures also improved in the treatment groups. The trial raised important questions about whether the Ashworth scale, a clinician-rated measure, adequately captured the spasticity improvements that patients experienced.","whyItMatters":"The CAMS study was the largest randomized trial of cannabis for MS at the time and remains one of the most important. The disconnect between negative objective spasticity results and positive patient-reported outcomes sparked a major debate about outcome measurement in spasticity research and whether clinician-rated scales adequately capture patient experience.","specificNumbers":"667 patients enrolled, 630 treated, 611 followed for primary endpoint. Cannabis extract: n=211, THC: n=206, placebo: n=213. Primary outcome p=0.40 (not significant). Patient-reported improvement: 61% cannabis extract, 60% THC, 46% placebo (p=0.003). Trial duration: 15 weeks at 33 UK centers.","methodology":"This was a randomized, placebo-controlled trial enrolling 667 patients with stable MS and muscle spasticity at 33 UK centers. Patients received oral cannabis extract (n=211), THC (n=206), or placebo (n=213) for 15 weeks. The primary outcome was change in Ashworth scale spasticity scores. Analysis was by intention to treat. Patient-reported outcomes and objective mobility measures were secondary endpoints.","limitations":"The primary outcome was negative, and the study technically failed to demonstrate efficacy. Some unmasking occurred (patients could tell they were on active treatment), potentially biasing patient-reported outcomes. The 15-week duration may have been insufficient for full therapeutic effect. Oral dosing required dose titration that some patients may not have optimized."},{"rthcId":"RTHC-00154","title":"Cannabis and other illicit drugs: comorbid use and abuse/dependence in males and females.","authors":"Agrawal, Arpana; Neale, Michael C; Prescott, Carol A; Kendler, Kenneth S","year":2004,"journal":"Behavior genetics, 34(3), 217-28","doi":null,"pmid":"14990863","tags":["addiction","genetics"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using data from 1,191 male and 934 female same-sex twin pairs, researchers tested 13 genetically informative models of comorbidity between cannabis and other illicit drug use. The correlated liabilities model, which posits shared genetic and environmental risk factors, provided a good fit for both drug use and abuse/dependence.\n\nThe pure gateway model (in which cannabis use directly causes other drug use) did not adequately explain the data. However, there was some evidence that among high-risk cannabis users, cannabis use might increase the likelihood of other drug use. For abuse and dependence specifically, a model including causal pathways between cannabis and other drug liability also fit well, suggesting the relationship may be more complex for problematic use than for casual use.","whyItMatters":"This study provided some of the strongest genetic evidence against a simple gateway model of drug progression. By using twins to separate genetic from environmental influences, it showed that shared vulnerabilities, rather than cannabis exposure itself, largely explained why cannabis users were more likely to use other drugs.","specificNumbers":"1,191 male and 934 female same-sex twin pairs. Thirteen models tested. Correlated liabilities model fit best for both use and abuse/dependence.","methodology":"This was a twin study using 1,191 male and 934 female same-sex twin pairs. Thirteen genetically informative structural equation models were compared, including gateway models, correlated liabilities models, and hybrid models. Models were fit separately for use and abuse/dependence in both sexes.","limitations":"Twin studies estimate genetic effects at the population level and cannot identify specific genes. The cross-sectional design limited the ability to establish temporal relationships. The finding that some gateway-like effects might exist for abuse/dependence complicated the interpretation."},{"rthcId":"RTHC-00155","title":"Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse","authors":"Allen, John H.; de Moore, Guy M.; Heddle, Roger; Twartz, John C.","year":2004,"journal":"Gut, 53(11), 1566-1570","doi":null,"pmid":"15479672","tags":["addiction","withdrawal","quitting","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Nine closely followed patients with long-term heavy cannabis use had a repeating vomiting illness. In every case, cannabis use started before the vomiting began. Seven of the nine who stopped using cannabis saw their vomiting stop during follow up. Three people who restarted after a symptom-free break relapsed, a pattern consistent with a drug-related syndrome. A striking behavioral clue showed up too. Nine of ten patients, counting one previously published case they compared against, reported abnormal washing behavior during episodes, which in later literature was described as prolonged hot bathing or showers that temporarily eased symptoms.","whyItMatters":"Published in 2004, this paper helped define the clinical pattern that later came to be called cannabinoid hyperemesis syndrome. At the time, many patients with recurrent vomiting cycled through emergency departments without an explanation. An abstinence and rechallenge pattern plus the hot bathing behavior gave clinicians a recognizable profile to consider when standard tests were unrevealing.","specificNumbers":"- 19 identified patients with heavy cannabis use and cyclic vomiting. 10 proceeded to analysis including one earlier published case\n- 7 of 9 observed cases: vomiting stopped after stopping cannabis during follow up\n- 3 of 3: vomiting returned after restarting cannabis following a symptom-free period\n- 9 of 10: reported abnormal washing behavior during active episodes, later characterized as prolonged hot showers or baths","methodology":"This was a case series from South Australia. Nineteen patients with heavy, chronic cannabis use and cyclic vomiting were identified. For ethical and legal reasons, all were counseled to stop using cannabis. Serial urine drug screens and regular clinic visits tracked use and symptoms over time. Five patients declined consent and were lost. Five more were excluded due to confounders. The authors present nine cases in detail and compare them to a previously published case labeled psychogenic vomiting. Outcomes focused on whether vomiting episodes resolved with abstinence and recurred with cannabis rechallenge.","limitations":"This is a small, uncontrolled case series. Half of the initially identified patients did not contribute to the main analysis because five were lost to follow up and five were excluded for confounders that are not detailed in the abstract. There was no control group and no blinding, so expectation effects from counseling could influence reporting. Reliance on self-reported symptom timing introduces recall bias, although urine drug screens strengthened the abstinence verification. Product type, dose, potency, and duration of abstinence before recovery were not standardized or fully reported."},{"rthcId":"RTHC-00156","title":"'You can't go without a fag...you need it for your hash'--a qualitative exploration of smoking, cannabis and young people.","authors":"Amos, Amanda; Wiltshire, Susan; Bostock, Yvonne; Haw, Sally; McNeill, Ann","year":2004,"journal":"Addiction (Abingdon, England), 99(1), 77-81","doi":null,"pmid":"14678065","tags":["addiction","youth","quitting"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Among 145 young smokers in Scotland (ages 15-19), cannabis use was regarded as an important and enjoyable part of their lives. Cannabis and cigarette smoking were described as inextricably linked. Several participants reported that smoking joints (which in the UK typically contain tobacco) was their gateway to cigarette smoking, reversing the traditional gateway direction.\n\nWhile most wanted to quit smoking cigarettes, their cannabis use reinforced their tobacco dependence, and few wanted to stop using cannabis. This created a significant barrier to tobacco cessation: stopping cigarettes was difficult while continuing to smoke cannabis mixed with tobacco.","whyItMatters":"This study highlighted a public health problem that was largely overlooked: the way cannabis smoking (especially when mixed with tobacco, as is common in the UK) reinforced tobacco dependence among young people. For teens who wanted to quit smoking, their continued cannabis use made it nearly impossible. This has direct implications for how smoking cessation programs should address cannabis use.","specificNumbers":"99 participants in paired interviews (ages 16-19). 46 participants in focus groups (ages 15-16). Total: 145 young smokers.","methodology":"This was a qualitative study using two approaches: semi-structured paired interviews with 99 smokers aged 16-19, and eight focus groups with 46 smokers aged 15-16, all in Scotland. The research explored the role of smoking in participants' lives and how it related to cannabis use.","limitations":"Qualitative research with 145 Scottish teenagers cannot be generalized to all young people or all cultural contexts. The UK practice of mixing cannabis with tobacco is less common in North America and some other regions. The findings may not apply where cannabis is consumed without tobacco."},{"rthcId":"RTHC-00157","title":"Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial.","authors":"Berman, Jonathan S; Symonds, Catherine; Birch, Rolfe","year":2004,"journal":"Pain, 112(3), 299-306","doi":"10.1016/j.pain.2004.09.013","pmid":"15561385","tags":["medical-cannabis","cbd","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 48 patients with chronic nerve pain from brachial plexus root avulsion, both Sativex (THC:CBD approximately 1:1) and a THC-only extract delivered by oral spray produced statistically significant improvements in pain severity compared to placebo during two-week treatment periods. Sleep measures also improved significantly.\n\nHowever, the primary outcome (mean pain severity over the last 7 days) did not fall by the two points defined in the study hypothesis as clinically meaningful, placing this in the category of statistically significant but not clinically significant by the researchers' own predefined standard. The medications were generally well tolerated, with most adverse events being mild to moderate.","whyItMatters":"Brachial plexus avulsion pain is an excellent model of central neuropathic pain because the injury is anatomically uniform. All patients had intractable symptoms on current analgesics, making this a treatment-resistant population. The finding of statistical significance despite the predefined clinical threshold not being met raised important questions about outcome definition in chronic pain research.","specificNumbers":"Forty-eight patients enrolled. Baseline pain score 4+ on 11-point scale. Two-week treatment periods. Both active treatments showed statistically significant improvement. Predefined two-point clinical significance threshold not met.","methodology":"This was a randomized, double-blind, placebo-controlled, three-period crossover study. Forty-eight patients with at least one avulsed brachial plexus root and baseline pain score of 4+ (out of 11) received placebo, Sativex (THC:CBD), or THC-only extract via oromucosal spray in random order, each for two weeks following a two-week baseline.","limitations":"Two-week treatment periods may have been too short for full therapeutic effect in chronic pain. The predefined two-point threshold for clinical significance was ambitious for a pain population already on analgesics. The crossover design could be affected by carryover effects."},{"rthcId":"RTHC-00158","title":"An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis.","authors":"Brady, C M; DasGupta, R; Dalton, C; Wiseman, O J; Berkley, K J; Fowler, C J","year":2004,"journal":"Multiple sclerosis (Houndmills, Basingstoke, England), 10(4), 425-33","doi":null,"pmid":"15327041","tags":["medical-cannabis","cbd"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"In 15 evaluable MS patients with refractory lower urinary tract symptoms, cannabis extracts delivered by sublingual spray produced significant improvements across multiple bladder measures. Urinary urgency, number and volume of incontinence episodes, frequency, and nocturia all decreased significantly (p<0.05). Pain, spasticity, and sleep quality also improved significantly, with pain improvement persisting to a median of 35 weeks.\n\nPatients first received THC:CBD extract (2.5 mg each per spray) for 8 weeks, then THC-only extract for 8 weeks, followed by a long-term extension. Few troublesome side effects were reported.","whyItMatters":"Bladder dysfunction affects the majority of MS patients and significantly impacts quality of life. Standard treatments often provide inadequate relief. This study was one of the first to specifically evaluate cannabis-based medicines for MS bladder symptoms, finding improvements across multiple urinary measures that had been resistant to other treatments.","specificNumbers":"Twenty-one patients recruited, 15 evaluated. THC:CBD extract: 2.5 mg each per spray. Treatment: 8 weeks THC:CBD, then 8 weeks THC. Pain improvement persisted to median 35 weeks. All primary bladder measures improved significantly (p<0.05).","methodology":"This was an open-label pilot study in 21 recruited patients (15 evaluable). Patients with advanced MS and refractory bladder symptoms received sublingual spray extracts: THC:CBD for 8 weeks, then THC-only for 8 weeks, with option for long-term extension. Assessments included urinary frequency/volume charts, incontinence pad weights, cystometry, and visual analogue scales.","limitations":"This was an open-label study without placebo control, so expectation effects cannot be ruled out. The sample was small (15 evaluable patients). Daily total voided volume and incontinence pad weights also decreased, which complicates the interpretation of reduced incontinence episodes. The sequential design (THC:CBD then THC) makes it difficult to compare the two formulations directly."},{"rthcId":"RTHC-00159","title":"Review of the validity and significance of cannabis withdrawal syndrome","authors":"Budney, Alan J.; Hughes, John R.; Moore, Brent A.; Vandrey, Ryan","year":2004,"journal":"American Journal of Psychiatry, 161(11), 1967-1977","doi":"10.1176/appi.ajp.161.11.1967","pmid":"15514394","tags":["withdrawal","addiction","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Across human laboratory studies and clinical reports, a reproducible cluster of symptoms showed up after discontinuing chronic heavy cannabis or THC use. The most common complaints were emotional and behavioral, with changes in mood and sleep often described, alongside appetite change, weight loss, and general physical discomfort. The timing tracked with other substance withdrawals, emerging soon after cessation, peaking, then resolving. Severity was judged substantial in a meaningful minority of cases, enough for the authors to argue the syndrome carries clinical importance. The paper closed by proposing formal diagnostic criteria for cannabis withdrawal.","whyItMatters":"In 2004, many clinicians still questioned whether cannabis had a withdrawal syndrome at all. This review pulled together laboratory and clinical evidence showing a consistent pattern after cessation and offered a diagnostic framework that later shaped how health systems talk about cannabis-related problems.","specificNumbers":"- Study type: narrative review of animal, human laboratory, and clinical studies\n- Core result: a consistent withdrawal syndrome followed cessation of chronic heavy cannabis or THC use\n- Symptom profile: primarily emotional and behavioral, with appetite change, weight loss, and physical discomfort also reported\n- Clinical significance: severity judged substantial in enough cases to matter for care planning","methodology":"This was a narrative review. The authors summarized animal experiments briefly and focused on human evidence from controlled laboratory abstinence studies and clinical samples. They assessed whether symptoms appeared reliably after cessation, how severe they were, and how the time course compared with other withdrawals. No pooled meta-analysis was reported in the abstract, and no single sample size applies because multiple study types were included.","limitations":"This was a narrative review from 2004 without a quantitative meta-analysis. Much of the human evidence came from small, controlled laboratory abstinence studies and clinical samples of heavy users, which limits generalizability. Product potency, cannabinoid profiles, and precise dosing were often underreported. Symptom measurement tools were not standardized across studies. Animal findings cannot be assumed to predict human experiences. Publication bias is possible, and the abstract does not detail funding or conflicts of interest."},{"rthcId":"RTHC-00160","title":"Medical marijuana: emerging applications for the management of neurologic disorders.","authors":"Carter, Gregory T; Ugalde, Vivian","year":2004,"journal":"Physical medicine and rehabilitation clinics of North America, 15(4), 943-54, ix","doi":null,"pmid":"15458761","tags":["medical-cannabis","neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis contains over 60 different cannabinoids with capacity for neuromodulation through direct, receptor-based mechanisms at many levels within the nervous system. The review identified seven key therapeutic properties: antioxidation, neuroprotection, analgesia, anti-inflammation, immunomodulation, modulation of glial cells, and tumor growth regulation.\n\nThese properties were described as potentially applicable to the treatment of various neurological disorders, representing a shift in perspective for rehabilitation medicine, which traditionally focused on physical and occupational therapy rather than pharmacological intervention with cannabis-based medications.","whyItMatters":"The publication of a cannabinoid therapeutics review in a rehabilitation medicine journal signaled growing mainstream medical acceptance. By framing cannabinoids through the lens of neuromodulation and specific mechanisms rather than simply \"medical marijuana,\" it helped legitimize cannabinoid research within conventional medical practice.","specificNumbers":"Over 60 different cannabinoids identified in cannabis. Seven therapeutic properties cataloged.","methodology":"This was a narrative review published in Physical Medicine and Rehabilitation Clinics of North America, examining current and emerging research on the physiological mechanisms of endogenous and exogenous cannabinoids and their applications in neurological disease management.","limitations":"The review was broad in scope, listing many potential applications without extensively evaluating the evidence quality for each. The distinction between established and speculative therapeutic properties could have been clearer."},{"rthcId":"RTHC-00161","title":"Patterns of cannabis use among patients with multiple sclerosis.","authors":"Clark, A J; Ware, M A; Yazer, E; Murray, T J; Lynch, M E","year":2004,"journal":"Neurology, 62(11), 2098-100","doi":null,"pmid":"15184623","tags":["medical-cannabis","pain","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 220 MS patients surveyed in Halifax, Nova Scotia, 36% reported ever using cannabis for any purpose and 14% were currently using it for symptom treatment. Medical cannabis use was associated with being male, using tobacco, and having a history of recreational cannabis use.\n\nThe symptoms most commonly reported as effectively relieved were stress, sleep disturbances, mood problems, muscle stiffness/spasms, and pain. This range of symptoms suggested patients were finding cannabis useful for quality-of-life issues beyond just the physical symptoms typically studied in clinical trials.","whyItMatters":"This study added Canadian data to the growing body of survey evidence documenting substantial cannabis use among MS patients. The finding that stress, sleep, and mood were among the most effectively relieved symptoms suggested patients valued cannabis for psychological benefits as much as physical symptom relief.","specificNumbers":"220 patients surveyed. 72 (36%) ever used cannabis. 29 (14%) currently using for symptoms. Most relieved symptoms: stress, sleep, mood, spasticity, pain.","methodology":"This was a cross-sectional survey of 220 MS patients at a single center in Halifax, Nova Scotia. The survey assessed prevalence and patterns of cannabis use, associated demographics, and self-reported symptom relief.","limitations":"Single-center survey with potential selection bias. Self-reported symptom relief is subjective and unverified. The association between medical cannabis use and recreational use history makes it difficult to separate medical from recreational motivation. Small numbers limited subgroup analysis."},{"rthcId":"RTHC-00162","title":"Towards cannabis and cannabinoid treatment of multiple sclerosis.","authors":"Croxford, J Ludovic; Miller, Stephen D","year":2004,"journal":"Drugs of today (Barcelona, Spain : 1998), 40(8), 663-76","doi":null,"pmid":"15510238","tags":["medical-cannabis","pain","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review identified a gap between promising preclinical evidence and disappointing clinical results. Animal models of MS showed clear efficacy for cannabinoids in controlling spasticity, tremor, and clinical disease severity. Patient self-reports and anecdotal evidence also strongly suggested benefit. However, the translation to clinical proof was incomplete.\n\nOnly ten published clinical reports involving 78 patients existed at the time, with equivocal results. The somewhat better-designed studies had failed to demonstrate objective improvement on standard measures, even while patients reported subjective benefit. This disconnect between objective and subjective outcomes was a major challenge for the field.","whyItMatters":"This review captured the frustrating state of the field in 2004: compelling biological rationale and patient reports, but clinical trial results that did not convincingly demonstrate objective benefit. The honest assessment of this gap helped identify the need for better outcome measures and larger trials.","specificNumbers":"Ten published clinical reports involving 78 individuals worldwide at the time of review.","methodology":"This was a narrative review covering the endocannabinoid system, preclinical evidence from animal models, and clinical trial evidence for cannabinoid treatment of MS symptoms.","limitations":"The review was written before the full results of the CAMS trial and other large studies were available. The small number of clinical reports (10, involving only 78 patients) limited the conclusions that could be drawn."},{"rthcId":"RTHC-00163","title":"Self-reported psychopathological symptoms in recreational ecstasy (MDMA) users are mainly associated with regular cannabis use: further evidence from a combined cross-sectional/longitudinal investigation.","authors":"Daumann, Jörg; Hensen, Gernot; Thimm, Bastian; Rezk, Markus; Till, Bianca; Gouzoulis-Mayfrank, Euphrosyne","year":2004,"journal":"Psychopharmacology, 173(3-4), 398-404","doi":null,"pmid":"14722704","tags":["mental-health","cognition","anxiety"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"At baseline, ecstasy users reported significantly more psychological complaints than controls. However, when the analysis accounted for concurrent drug use, self-reported psychopathology was mainly associated with regular cannabis use rather than ecstasy use.\n\nThe 18-month follow-up strengthened this finding: subjects who had stopped using ecstasy showed no different symptom levels from those who continued, while subjects who regularly used cannabis during the follow-up period reported more anxiety, interpersonal sensitivity, and obsessive-compulsive behavior than cannabis-abstinent users. Higher levels of depression, anxiety, phobic anxiety, paranoid ideation, and obsessive-compulsive behavior were all significantly correlated with the duration of regular cannabis use during the follow-up period.","whyItMatters":"Much of the research attributing psychiatric symptoms to ecstasy use had not adequately controlled for concurrent cannabis use. This study demonstrated that cannabis, not ecstasy, was the primary driver of psychological complaints in this population. This has implications for both drug policy messaging and clinical assessment of polydrug users.","specificNumbers":"Sixty ecstasy users and 30 controls at baseline. 38 ecstasy users at 18-month follow-up. Anxiety, interpersonal sensitivity, obsessive-compulsive behavior, depression, phobic anxiety, and paranoid ideation all correlated with cannabis use duration.","methodology":"This study combined cross-sectional and longitudinal designs. At baseline, 60 recreational ecstasy users and 30 matched controls completed self-rating scales for impulsivity, sensation seeking, and psychological complaints. At 18-month follow-up, 38 of the original ecstasy users were re-examined.","limitations":"The sample was relatively small and self-selected. Self-reported symptom measures may not capture clinical diagnoses. Cannabis users may differ from non-users in ways not captured by the study, introducing confounding. The 18-month follow-up had some attrition."},{"rthcId":"RTHC-00164","title":"Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol.","authors":"Ghafouri, Nazdar; Tiger, Gunnar; Razdan, Raj K; Mahadevan, Anu; Pertwee, Roger G; Martin, Billy R; Fowler, Christopher J","year":2004,"journal":"British journal of pharmacology, 143(6), 774-84","doi":null,"pmid":"15492019","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The study systematically tested analogues of the endocannabinoid 2-AG for their ability to inhibit two key enzymes: monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), which break down the body's own cannabinoids. Several compounds were identified that inhibited these enzymes without directly activating CB1 receptors, meaning they could potentially enhance endocannabinoid signaling without producing psychoactive effects.\n\nCompounds alpha-Methyl-1-AG, O-2203, and O-2204 were identified as promising leads for developing selective MAGL inhibitors, as they only weakly interacted with CB1 receptors and showed no central cannabinoid receptor activation in vivo at tested doses.","whyItMatters":"Rather than introducing external cannabinoids (like THC), this research aimed to enhance the body's own cannabinoid system by preventing the breakdown of endocannabinoids. This approach could potentially provide therapeutic benefits without psychoactive effects, representing a fundamentally different strategy for cannabinoid-based medicine.","specificNumbers":"2-AG IC50: 13 micromolar for MAGL. Lead compounds: alpha-Methyl-1-AG, O-2203, O-2204 with Ki values of 1.8, 3.7, and 3.2 micromolar for CB1 (vs 0.24 for 1-AG). No central effects at doses up to 30 mg/kg IV.","methodology":"This was a pharmacological study using in vitro enzyme assays and in vivo animal testing. Analogues of 2-AG were tested for inhibition of MAGL and FAAH using cytosolic and membrane-bound preparations. CB1 receptor binding was assessed in CHO cells, and in vivo cannabinoid activity was tested at doses up to 30 mg/kg IV.","limitations":"In vitro enzyme inhibition does not guarantee in vivo therapeutic efficacy. The compounds were tested only in acute settings; chronic effects were not assessed. The selectivity between MAGL and FAAH was modest for most compounds tested."},{"rthcId":"RTHC-00165","title":"Pharmacology of cannabinoids.","authors":"Grotenhermen, Franjo","year":2004,"journal":"Neuro endocrinology letters, 25(1-2), 14-23","doi":null,"pmid":"15159677","tags":["medical-cannabis","neuroscience","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"THC acts as an agonist at both CB1 and CB2 receptors distributed across the central nervous system and peripheral tissues including spleen, leukocytes, reproductive and urinary tracts, endocrine glands, arteries, and heart. Five endogenous cannabinoids had been identified, with anandamide and 2-AG best characterized. Evidence suggested additional cannabinoid receptor subtypes and vanilloid receptors were involved in cannabinoid functions.\n\nThe review cataloged therapeutic properties: analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, mood improvement, appetite stimulation, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection, and antineoplastic effects. Strategies to enhance endocannabinoid activity included inhibiting reuptake and degradation.","whyItMatters":"This review provided a comprehensive pharmacological reference for the expanding field of cannabinoid therapeutics. By mapping receptor distribution across the body and linking it to specific therapeutic properties, it helped explain the broad therapeutic potential of cannabinoids and guide drug development.","specificNumbers":"Two receptor subtypes (CB1, CB2) cloned. Five endocannabinoids identified. Thirteen therapeutic properties cataloged.","methodology":"This was a pharmacological review covering cannabinoid receptor distribution, endocannabinoid biology, therapeutic properties, and pharmacological strategies for modulating the endocannabinoid system.","limitations":"The broad scope limited depth on individual therapeutic applications. The review was primarily descriptive rather than critically evaluating evidence quality for each application."},{"rthcId":"RTHC-00166","title":"Marijuana withdrawal in humans: effects of oral THC or divalproex.","authors":"Haney, Margaret; Hart, Carl L; Vosburg, Suzanne K; Nasser, Jennifer; Bennett, Andrew; Zubaran, Carlos; Foltin, Richard W","year":2004,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 29(1), 158-70","doi":null,"pmid":"14560320","tags":["withdrawal","addiction","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In two controlled studies with heavy marijuana users (6-10 joints per day), oral THC (10 mg five times daily) administered during marijuana abstinence decreased anxiety, misery, trouble sleeping, chills, and craving, and reversed large decreases in food intake. Importantly, these therapeutic effects occurred at doses that were subjectively indistinguishable from placebo, meaning patients did not feel high.\n\nIn contrast, divalproex (1500 mg/day) decreased marijuana craving during abstinence but increased anxiety, irritability, and tiredness, worsened cognitive performance, and increased food intake regardless of marijuana condition. The authors concluded that oral THC but not divalproex may be useful for treating marijuana dependence.","whyItMatters":"This was an early demonstration of the concept of agonist replacement therapy for cannabis dependence, analogous to methadone for opioid dependence or nicotine replacement for tobacco. The finding that oral THC could relieve withdrawal without intoxication suggested a practical clinical approach to cannabis dependence treatment.","specificNumbers":"Seven participants per study. 6-10 marijuana cigarettes per day at baseline. Oral THC: 10 mg five times daily. Divalproex: 1500 mg/day. THC reduced craving without intoxication; divalproex reduced craving but worsened mood and cognition.","methodology":"Two placebo-controlled, within-subject studies. Study 1 (n=7): 15-day inpatient/5-day outpatient/15-day inpatient design testing oral THC (10 mg, 5x daily) during marijuana abstinence. Study 2 (n=7): 58-day outpatient/inpatient design testing divalproex (1500 mg/day). Participants smoked 6-10 joints daily and were not seeking treatment.","limitations":"Very small samples (7 per study) in a controlled laboratory setting. Participants were not seeking treatment, which may limit applicability to treatment-seeking populations. The short abstinence periods may not capture the full withdrawal trajectory."},{"rthcId":"RTHC-00167","title":"Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling.","authors":"Hiley, C Robin; Ford, William R","year":2004,"journal":"Biological reviews of the Cambridge Philosophical Society, 79(1), 187-205","doi":null,"pmid":"15005177","tags":["cardiovascular","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review documented multiple mechanisms by which cannabinoids affect the cardiovascular system. CB1 receptors are present in the heart and blood vessels, and endocannabinoids act through them to regulate cardiovascular function. Anandamide also activates vanilloid VR1 receptors on sensory nerves, releasing the vasodilatory peptide CGRP.\n\nImportantly, evidence suggested endocannabinoids had protective roles in pathological conditions such as shock and myocardial infarction. Some cardiovascular effects appeared to involve receptors beyond the currently identified CB1 and CB2, and the cannabinoid receptor family appeared related to a broader family of lipid receptors linked to similar signaling pathways.","whyItMatters":"While much attention focused on the risks of cannabis for cardiovascular health, this review highlighted the other side: the endocannabinoid system appeared to play protective roles during cardiovascular emergencies. This suggested that understanding and modulating this system could lead to new treatments for heart disease and shock.","specificNumbers":"No specific quantitative data were highlighted in the abstract.","methodology":"This was a comprehensive review published in Biological Reviews covering cannabinoid receptor pharmacology, endocannabinoid signaling, and cardiovascular effects including potential protective mechanisms in pathological conditions.","limitations":"Much of the evidence was from animal models and isolated tissue preparations. The clinical significance of endocannabinoid cardioprotection in humans remained unclear. The complexity of multiple receptor types and signaling pathways made simple therapeutic applications difficult."},{"rthcId":"RTHC-00168","title":"Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study.","authors":"Kanayama, Gen; Rogowska, Jadwiga; Pope, Harrison G; Gruber, Staci A; Yurgelun-Todd, Deborah A","year":2004,"journal":"Psychopharmacology, 176(3-4), 239-47","doi":null,"pmid":"15205869","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using functional MRI, 12 heavy cannabis users (6-36 hours after last use) showed increased activation in brain regions typically used for spatial working memory (prefrontal cortex, anterior cingulate) compared to 10 controls. Users also recruited additional brain regions not typically used for this task, including areas in the basal ganglia.\n\nDespite performing the task adequately, cannabis users needed more widespread brain activation to do so. Brain activation did not significantly correlate with years of education, verbal IQ, lifetime cannabis use episodes, or urinary cannabinoid levels at scanning. The researchers concluded that recent cannabis users compensated for subtle neurophysiological deficits by \"working harder,\" calling on additional brain regions to meet task demands.","whyItMatters":"This study revealed that cannabis effects on cognition may be more nuanced than simple impairment. Rather than failing at tasks, cannabis users appeared to compensate by recruiting additional brain resources. This \"neural compensation\" pattern has been observed in other conditions and suggests a subclinical inefficiency that standard behavioral tests might miss.","specificNumbers":"Twelve cannabis users and 10 controls. Users tested 6-36 hours after last use. Increased activation in prefrontal cortex, anterior cingulate, and basal ganglia in users.","methodology":"This was a cross-sectional fMRI study comparing 12 long-term heavy cannabis users (6-36 hours after last use) with 10 controls during a spatial working memory task. Regional brain activation was analyzed using statistical parametric mapping. Results were re-analyzed with age as a covariate.","limitations":"Small sample (12 users, 10 controls). Cross-sectional design cannot determine whether brain differences preceded cannabis use. Users were tested 6-36 hours after last use, so residual acute effects could contribute. Heavy users may differ from controls in other ways that affect brain activation."},{"rthcId":"RTHC-00169","title":"Cannabinoids in multiple sclerosis: do they have a therapeutic role?","authors":"Killestein, Joep; Uitdehaag, Bernard M J; Polman, Chris H","year":2004,"journal":"Drugs, 64(1), 1-11","doi":null,"pmid":"14723555","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"While the identification of cannabinoid receptors and endocannabinoid ligands, along with animal model efficacy, generated excitement about cannabinoid treatment for MS, the clinical evidence was described as equivocal. Only ten published clinical reports involving 78 individuals worldwide existed, and the results were mixed.\n\nFrom the studies specifically examining spasticity, the somewhat better-designed ones failed to demonstrate objective improvement. The authors noted that researchers faced significant difficulties in designing clinical studies with cannabinoids, including blinding challenges and outcome measure selection. The review characterized the overall evidence as \"still lacking\" for convincing demonstration of cannabinoid efficacy in MS.","whyItMatters":"This review provided a necessary counterpoint to the often optimistic framing of cannabinoid research. By highlighting the gap between receptor biology enthusiasm and clinical trial results, it reinforced the importance of rigorous evidence standards and identified specific challenges that needed to be addressed.","specificNumbers":"Ten published clinical reports involving 78 individuals worldwide. Better-designed studies failed to show objective improvement.","methodology":"This was a narrative review critically assessing the clinical evidence for cannabinoids in MS, published in the pharmacology journal Drugs, covering receptor biology, animal models, and clinical trial results.","limitations":"The review was published before many larger trial results were available. The critical stance may have underweighted patient-reported benefits. The focus on objective measures aligned with traditional evidence standards but may not have captured the full clinical picture."},{"rthcId":"RTHC-00170","title":"Major depressive disorder, suicidal ideation, and suicide attempt in twins discordant for cannabis dependence and early-onset cannabis use.","authors":"Lynskey, Michael T; Glowinski, Anne L; Todorov, Alexandre A; Bucholz, Kathleen K; Madden, Pamela A F; Nelson, Elliot C; Statham, Dixie J; Martin, Nicholas G; Heath, Andrew C","year":2004,"journal":"Archives of general psychiatry, 61(10), 1026-32","doi":null,"pmid":"15466676","tags":["depression","genetics","youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 277 twin pairs discordant for cannabis dependence, the cannabis-dependent twin had 2.5 to 2.9 times higher odds of suicidal ideation and suicide attempt compared to their non-dependent co-twin. This association persisted even when controlling for shared genetic and environmental factors, suggesting cannabis dependence itself may contribute to suicidal behavior.\n\nIn contrast, the association between cannabis dependence and major depressive disorder was found only in dizygotic twins (who share ~50% of genes), not in monozygotic twins (who share 100%), suggesting shared genetics explained the depression-cannabis link. Early cannabis use (before age 17) was associated with 3.5 times higher odds of subsequent suicide attempt but not depression or suicidal ideation.","whyItMatters":"By comparing twins discordant for cannabis dependence, this study could control for shared genetic and environmental factors in a way that observational studies cannot. The finding that the suicide link persisted while the depression link did not suggested fundamentally different causal pathways for these outcomes.","specificNumbers":"277 twin pairs discordant for cannabis dependence. 311 pairs discordant for early cannabis use. Suicidal ideation OR: 2.5-2.9. Early-onset suicide attempt OR: 3.5 (95% CI 1.4-8.6). Median age: 30 years.","methodology":"This was a cross-sectional survey of 277 same-sex twin pairs discordant for cannabis dependence and 311 pairs discordant for early-onset cannabis use (before age 17) from a general population twin registry. DSM-IV lifetime diagnoses of MDD, suicidal ideation, and suicide attempt were assessed by self-report.","limitations":"Cross-sectional design limits causal inference despite the twin design. Self-reported diagnoses may not match clinical assessment. The study examined cannabis dependence rather than use, so findings may not apply to non-dependent users. Twin designs assume equal environmental sharing between MZ and DZ twins."},{"rthcId":"RTHC-00171","title":"Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults.","authors":"Nicholson, Anthony N; Turner, Claire; Stone, Barbara M; Robson, Philip J","year":2004,"journal":"Journal of clinical psychopharmacology, 24(3), 305-13","doi":null,"pmid":"15118485","tags":["sleep","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 8 healthy volunteers given sublingual cannabis extracts before sleep, 15 mg THC alone had no effect on nocturnal sleep architecture but produced next-day sedation, impaired memory, and reduced sleep latency (indicating increased sleepiness). When 15 mg CBD was combined with 15 mg THC, it increased wakefulness during sleep and decreased stage 3 (deep) sleep.\n\nThe lower dose combination (5 mg THC + 5 mg CBD) improved reaction time on a next-day memory task. The findings suggested that CBD at 15 mg had alerting properties, counteracting THC's residual sedation. THC alone appeared sedating, while CBD appeared to promote wakefulness.","whyItMatters":"This was one of the first controlled studies to demonstrate that CBD had alerting rather than sedating properties, and that it could modify THC's effects on sleep. This has significant implications for how cannabis products are formulated for sleep versus daytime use.","specificNumbers":"Eight volunteers. Four treatments: placebo, 15 mg THC, 5+5 mg THC:CBD, 15+15 mg THC:CBD. THC alone: sedating next day. High-dose CBD+THC: increased wakefulness during sleep.","methodology":"This was a double-blind, placebo-controlled, 4-way crossover study in 8 healthy volunteers (4 male, 4 female, ages 21-34). Treatments were placebo, 15 mg THC, 5 mg THC + 5 mg CBD, and 15 mg THC + 15 mg CBD via oromucosal spray at 10 PM. EEG was recorded during sleep (11 PM - 7 AM). Next-day assessments at 8:30 AM measured performance, sleep latency, and mood.","limitations":"Very small sample (8 volunteers). Single-night assessments in each condition may not reflect chronic effects. Healthy young volunteers may respond differently from patients. The oromucosal spray delivery may produce different effects from other routes."},{"rthcId":"RTHC-00172","title":"Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies.","authors":"Notcutt, William; Price, Mario; Miller, Roy; Newport, Samantha; Phillips, Cheryl; Simmons, Susan; Sansom, Cathy","year":2004,"journal":"Anaesthesia, 59(5), 440-52","doi":null,"pmid":"15096238","tags":["medical-cannabis","cbd","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Thirty-four patients with chronic, mainly neuropathic, pain used three cannabis-based sublingual sprays (THC, CBD, and 1:1 THC:CBD) over 12 weeks in individual randomized crossover trials. THC-containing extracts proved most effective for symptom control. A wide range of dosing requirements was observed across patients, and structured regimens for using the sublingual spray emerged from patient experience.\n\nSide effects were common, reflecting a learning curve for both patients and the study team, but were generally acceptable and similar to those seen with other psychoactive medications used for chronic pain. The study established practical parameters for using cannabis-based medicines in pain management.","whyItMatters":"This study provided practical clinical experience with cannabis-based medicines that was crucial for the development of dosing guidelines. The finding that THC was the primary active ingredient for pain, and that a wide dose range was needed, influenced how Sativex was subsequently prescribed.","specificNumbers":"Thirty-four patients studied individually over 12 weeks each. Three extract formulations tested. THC-containing extracts most effective. Wide dosing range observed. Side effects common but generally acceptable.","methodology":"These were 34 individual \"N of 1\" trials using sublingual cannabis extracts. After an initial open-label period, the three extracts (THC, CBD, THC:CBD 1:1) were tested in randomized, double-blind, placebo-controlled crossover format over 12 weeks per patient.","limitations":"N-of-1 trials, while rigorous for individual patients, have limited generalizability. The open-label period may have biased subsequent randomized periods. Side effects described as \"common\" raises questions about long-term tolerability."},{"rthcId":"RTHC-00173","title":"Spontaneous cannabinoid withdrawal produces a differential time-related responsiveness in cannabinoid CB1 receptor gene expression in the mouse brain.","authors":"Oliva, José M; Ortiz, Sergio; Palomo, Tomás; Manzanares, Jorge","year":2004,"journal":"Journal of psychopharmacology (Oxford, England), 18(1), 59-65","doi":null,"pmid":"15107186","tags":["withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"When cannabinoid-tolerant mice stopped receiving the cannabinoid CP-55,940, they developed a time-dependent withdrawal syndrome peaking on day 1: motor activity increased 140%, rearings increased 170%, while grooming decreased 57%. Symptoms progressively returned to normal by day 3.\n\nCB1 receptor gene expression changed differentially across brain regions during withdrawal: it increased 20-30% in the caudate-putamen, hypothalamus, central amygdala, and hippocampal CA1 region, but decreased 15-20% in the hippocampal CA3 field. This region-specific pattern suggested that different brain areas undergo distinct adaptations during cannabis withdrawal.","whyItMatters":"Understanding the molecular changes that occur during cannabis withdrawal helps explain why withdrawal symptoms occur and could guide the development of medications to treat them. The finding that CB1 receptors upregulate in some regions but downregulate in others during withdrawal revealed a more complex picture than simple receptor normalization.","specificNumbers":"Motor activity increased 140% on day 1. Rearings increased 170%. Grooming decreased 57%. CB1 upregulation: 20-30% in caudate-putamen, hypothalamus, amygdala, CA1. CB1 downregulation: 15-20% in hippocampal CA3. Symptoms normalized by day 3.","methodology":"This was an animal study in mice treated chronically with the synthetic cannabinoid CP-55,940 to induce tolerance, followed by cessation and measurement of behavioral withdrawal signs and CB1 receptor gene expression across multiple brain regions at different time points.","limitations":"Animal studies using synthetic cannabinoids may not perfectly model human cannabis withdrawal. The relatively short treatment and withdrawal periods may not capture long-term adaptations. Gene expression changes may not directly translate to receptor protein levels or function."},{"rthcId":"RTHC-00174","title":"Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons.","authors":"Pistis, Marco; Perra, Simona; Pillolla, Giuliano; Melis, Miriam; Muntoni, Anna Lisa; Gessa, Gian Luigi","year":2004,"journal":"Biological psychiatry, 56(2), 86-94","doi":null,"pmid":"15231440","tags":["youth","dopamine","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"After just 3 days of cannabinoid treatment followed by a 2-week washout, adolescent-treated rats showed long-lasting changes in how their dopamine neurons responded to other drugs. Dopamine neurons in the reward pathway (mesoaccumbens) became less responsive to morphine, cocaine, and amphetamine, meaning these drugs produced weaker activation of the reward system.\n\nCritically, this cross-tolerance to other drugs developed only in rats treated during adolescence, not in those treated during adulthood. Both age groups showed tolerance to the cannabinoid itself, but only the adolescent group showed the broader cross-tolerance to other drug classes.","whyItMatters":"This study provided a neurobiological mechanism for why adolescent cannabis exposure might have different long-term consequences than adult exposure. The finding that adolescent cannabinoid exposure altered subsequent responses to multiple drug classes through the dopamine reward system has implications for understanding vulnerability to substance use disorders.","specificNumbers":"Three days of cannabinoid treatment. Two-week drug-free interval before testing. Cross-tolerance to morphine, cocaine, and amphetamine observed only in adolescent-treated group.","methodology":"This was an animal electrophysiology study. Rats were treated with the cannabinoid agonist WIN55212.2 for 3 days during either adolescence or adulthood, then allowed a 2-week drug-free interval. Single-unit recordings from identified mesoaccumbens dopamine neurons measured responses to cannabinoid, morphine, cocaine, and amphetamine stimulation.","limitations":"Animal models may not directly translate to human experience. The synthetic cannabinoid used (WIN55212.2) is more potent than THC. Only 3 days of treatment were used, which is very brief. The 2-week washout period, while showing lasting effects, does not confirm permanence."},{"rthcId":"RTHC-00175","title":"Mechanisms for impaired effector function in alveolar macrophages from marijuana and cocaine smokers.","authors":"Roth, Michael D; Whittaker, Katherine; Salehi, Ken; Tashkin, Donald P; Baldwin, Gayle C","year":2004,"journal":"Journal of neuroimmunology, 147(1-2), 82-6","doi":null,"pmid":"14741433","tags":["respiratory","inflammation"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Alveolar macrophages (lung immune cells) from marijuana smokers showed limited antimicrobial activity against Staphylococcus aureus compared to nonsmokers and tobacco smokers. The mechanism involved suppression of inducible nitric oxide synthase (iNOS) expression, reducing nitric oxide production that normally kills bacteria.\n\nImportantly, this impairment was specific to marijuana and crack cocaine smokers. Tobacco smokers maintained normal macrophage killing ability. However, the impaired cells from marijuana smokers could be restored to normal function by treatment with GM-CSF or interferon-gamma, suggesting the impairment was reversible with appropriate immune stimulation.","whyItMatters":"This study identified a specific mechanism by which marijuana smoking impairs lung immunity. The finding that marijuana but not tobacco smoke suppressed this immune defense was surprising and clinically important, suggesting marijuana smokers may be at increased risk for lung infections through a mechanism distinct from tobacco damage.","specificNumbers":"Four groups compared: nonsmokers, tobacco smokers, marijuana smokers, crack cocaine smokers. Staphylococcus aureus killing assessed. iNOS and nitric oxide production measured. GM-CSF and interferon-gamma restored macrophage function.","methodology":"This was an observational study comparing alveolar macrophages recovered from nonsmokers, tobacco smokers, marijuana smokers, and crack cocaine smokers. Cells were tested for bacterial killing capacity, nitric oxide production, and iNOS expression. Restoration of function with GM-CSF and interferon-gamma was also tested.","limitations":"The study compared groups of smokers rather than following individuals longitudinally. Differences between marijuana and tobacco smokers beyond smoking habits could contribute. The in vitro bacterial killing assay may not perfectly predict in vivo immune function."},{"rthcId":"RTHC-00176","title":"Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?","authors":"Russo, Ethan B","year":2004,"journal":"Neuro endocrinology letters, 25(1-2), 31-9","doi":null,"pmid":"15159679","tags":["medical-cannabis","pain","appetite"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review proposed a novel medical theory: clinical endocannabinoid deficiency (CECD). It argued that migraine, fibromyalgia, and irritable bowel syndrome display common clinical, biochemical, and pathophysiological patterns suggesting an underlying deficiency in endocannabinoid function.\n\nThe evidence included: anandamide is tonically active in the periaqueductal gray matter (a migraine-generating brain region); cannabinoids modulate multiple pain pathways relevant to fibromyalgia; and cannabinoid receptors are densely expressed in the gastrointestinal system. The theory explained why these conditions frequently co-occur, resist conventional treatment, and respond to cannabis-based medicines.","whyItMatters":"The CECD hypothesis was influential because it provided a unifying framework for understanding why certain treatment-resistant conditions co-occur and respond to cannabis. If validated, it could explain why some patients find cannabis uniquely helpful and could guide the development of targeted endocannabinoid-based therapies.","specificNumbers":"Three primary conditions examined: migraine, fibromyalgia, irritable bowel syndrome. Five endogenous cannabinoids identified in the system.","methodology":"This was a theoretical review and hypothesis paper examining the relationships between endocannabinoid function and three treatment-resistant conditions. It synthesized evidence from neuropharmacology, clinical observations, and endocannabinoid research to propose the CECD concept.","limitations":"This was a hypothesis paper rather than an empirical study. The CECD concept remains unproven and difficult to test directly, as measuring endocannabinoid levels in living patients is technically challenging. The conditions examined have complex multifactorial origins that may not reduce to a single deficiency."},{"rthcId":"RTHC-00177","title":"Effects of prenatal marijuana on response inhibition: an fMRI study of young adults.","authors":"Smith, Andra M; Fried, Peter A; Hogan, Matthew J; Cameron, Ian","year":2004,"journal":"Neurotoxicology and teratology, 26(4), 533-42","doi":null,"pmid":"15203175","tags":["pregnancy","cognition","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using fMRI, 31 young adults from the Ottawa Prenatal Prospective Study showed that greater prenatal marijuana exposure was associated with increased neural activity in bilateral prefrontal cortex and right premotor cortex during response inhibition tasks. Activity in the left cerebellum was attenuated. Prenatally exposed participants made significantly more commission errors (failures to inhibit responses), though all performed above 85% accuracy.\n\nThese findings persisted when controlling for current marijuana use and prenatal exposure to nicotine, alcohol, and caffeine, suggesting the effects were specifically attributable to prenatal cannabis exposure and lasted into young adulthood.","whyItMatters":"This was one of the first fMRI studies to demonstrate lasting neural effects of prenatal cannabis exposure into adulthood. The finding that prenatally exposed young adults needed more brain activation to perform impulse control tasks suggested persistent, subtle neurological changes from in-utero exposure.","specificNumbers":"Thirty-one participants aged 18-22 from the OPPS. Increased activation in bilateral prefrontal cortex and right premotor cortex. Decreased activation in left cerebellum. More commission errors in exposed group, all above 85% accuracy.","methodology":"This was a longitudinal study using fMRI within the Ottawa Prenatal Prospective Study (OPPS), which had followed participants from birth for over 20 years. Thirty-one participants aged 18-22 performed a Go/No-Go task during fMRI scanning. Analyses controlled for current drug use and prenatal exposure to other substances.","limitations":"The OPPS cohort is relatively small and non-randomly selected. Self-reported prenatal drug use may be inaccurate. The cross-sectional fMRI assessment cannot prove the brain differences were caused by prenatal exposure rather than other factors. Controlling for current drug use does not eliminate all confounding."},{"rthcId":"RTHC-00178","title":"Medicinal cannabis extracts for the treatment of multiple sclerosis.","authors":"Smith, Paul F","year":2004,"journal":"Current opinion in investigational drugs (London, England : 2000), 5(7), 727-30","doi":null,"pmid":"15298068","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review contrasted two approaches to cannabis-based MS treatment. Orally administered THC had failed to demonstrate objective spasticity reduction in placebo-controlled trials. However, sublingually administered cannabis extracts containing approximately equal concentrations of THC and CBD were claimed to produce statistically and clinically significant spasticity reduction, though this claim needed further validation.\n\nThe author noted that preclinical evidence continued to support the involvement of the endocannabinoid system in regulating spasticity and pain, maintaining the theoretical basis for cannabinoid treatment even as clinical results were mixed.","whyItMatters":"This review highlighted an important distinction between formulations: oral THC alone versus sublingual THC:CBD. The suggestion that the combination formulation and delivery method mattered was clinically significant and aligned with the development of Sativex (which is sublingual THC:CBD).","specificNumbers":"No specific quantitative data were presented in the abstract.","methodology":"This was a critical review evaluating the most recent clinical trial evidence for cannabis extracts in MS pain and spasticity, comparing oral THC with sublingual THC:CBD formulations.","limitations":"The review was published before all major trial results were available. The critical assessment reflected one author's interpretation of limited data. The claim that sublingual THC:CBD was superior to oral THC was not yet thoroughly validated."},{"rthcId":"RTHC-00179","title":"Five-year prospective prediction of marijuana use cessation of youth at continuation high schools.","authors":"Sussman, Steve; Dent, Clyde W","year":2004,"journal":"Addictive behaviors, 29(6), 1237-43","doi":null,"pmid":"15236829","tags":["quitting","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 339 teenage marijuana users at continuation high schools, 42% had quit marijuana use (no use in the past 30 days) at the 5-year follow-up. After controlling for all predictor variables, only four factors remained significant direct predictors of continued use: heavier baseline marijuana use, male gender, being unmarried as a young adult, and having friends who used marijuana (marginally significant).\n\nNotably, social, attitude, intrapersonal, and violence-related variables did not independently predict quitting after accounting for these primary factors. The authors suggested that reducing psychological dependence and increasing social unacceptability of use across genders could increase quit attempts.","whyItMatters":"This study provided practical information about natural recovery from teen marijuana use. The finding that 42% quit within 5 years suggested that many teen users spontaneously reduce or stop use as they mature into adult social roles. The specific predictors identified could help target prevention and cessation interventions.","specificNumbers":"339 teen marijuana users followed for 5 years. 42% had quit at follow-up. Four significant predictors: baseline use level, male gender, marital status, friends' use.","methodology":"This was a 5-year prospective study of 339 teenage marijuana users from continuation high schools. Baseline measures included social, attitudinal, intrapersonal, violence-related, drug use, and demographic variables. Young adult social role variables were added as predictors. Three-step regression analysis identified independent predictors of quitting.","limitations":"Continuation high school students may not represent typical teen marijuana users. Self-reported quitting was defined as no use in the past 30 days, which may not capture intermittent use or recent relapse. The 5-year follow-up may miss those who quit and relapsed or vice versa."},{"rthcId":"RTHC-00180","title":"Substance misuse at presentation to an early psychosis program.","authors":"Van Mastrigt, Sarah; Addington, Jean; Addington, Donald","year":2004,"journal":"Social psychiatry and psychiatric epidemiology, 39(1), 69-72","doi":null,"pmid":"15022049","tags":["psychosis","addiction","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers examined the first 357 consecutive admissions to a comprehensive early psychosis program in Canada. They found that 44% of patients met diagnostic criteria for substance abuse or dependence at the time they first presented for treatment.\n\nThe substances most commonly involved were alcohol and cannabis. The rate of substance misuse in this group was significantly higher than in the general population.\n\nSubstance misuse was significantly associated with male gender, younger age, and younger age of onset. These patterns held across different assessment measures including the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia.","whyItMatters":"First-episode psychosis represents a critical window for intervention. Understanding how common substance use is at this stage, and which substances are most involved, helps clinicians design treatment programs that address both psychosis and substance use simultaneously rather than treating them as separate issues.","specificNumbers":"357 consecutive admissions studied. 44% met criteria for substance abuse or dependence. Cannabis and alcohol were the most commonly used substances. Substance misuse was significantly associated with male gender and younger age of onset.","methodology":"This was a cross-sectional study of the first 357 consecutive admissions to a comprehensive early psychosis program. Patients were assessed using standardized tools including the Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, Quality of Life Scale, Case Manager Rating Scale, and Premorbid Adjustment Scale. Substance misuse was assessed using diagnostic criteria for abuse and dependence.","limitations":"The cross-sectional design cannot determine whether substance use preceded or followed the onset of psychosis. The study assessed substance use at the time of first presentation, which may not reflect lifetime patterns. The single-site design limits generalizability to other populations and healthcare systems."},{"rthcId":"RTHC-00181","title":"Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study.","authors":"Vaney, C; Heinzel-Gutenbrunner, M; Jobin, P; Tschopp, F; Gattlen, B; Hagen, U; Schnelle, M; Reif, M","year":2004,"journal":"Multiple sclerosis (Houndmills, Basingstoke, England), 10(4), 417-24","doi":null,"pmid":"15327040","tags":["medical-cannabis","cbd","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers enrolled 57 MS patients with poorly controlled spasticity into a randomized, double-blind, placebo-controlled crossover study during inpatient rehabilitation. Patients received capsules standardized to 2.5 mg THC and 0.9 mg CBD each, escalated from 15 to a maximum of 30 mg THC per day.\n\nIn the full intention-to-treat analysis of 50 patients, there were no statistically significant differences between cannabis extract and placebo. However, trends favoring active treatment appeared for spasm frequency, mobility, and getting to sleep.\n\nIn the 37 patients who took at least 90% of their prescribed dose (the per-protocol analysis), improvements in spasm frequency (P = 0.013) and mobility (P = 0.01) reached statistical significance. Minor adverse events were slightly more frequent during active treatment but were generally mild.","whyItMatters":"The split between intention-to-treat and per-protocol results highlights a common challenge in cannabis research: dosing compliance matters. When patients took enough of the medication, measurable benefits emerged. This distinction is important for understanding how cannabis-based medicines might work in clinical practice.","specificNumbers":"57 patients enrolled. 50 included in intention-to-treat analysis. 37 completed per-protocol analysis (took 90%+ of dose). Capsules contained 2.5 mg THC and 0.9 mg CBD each. Spasm frequency improvement P = 0.013 in per-protocol set. Mobility improvement P = 0.01 in per-protocol set.","methodology":"This was a prospective, randomized, double-blind, placebo-controlled crossover study conducted during inpatient rehabilitation. Fifty-seven MS patients received standardized cannabis extract capsules (2.5 mg THC and 0.9 mg CBD each) with dose escalation from 15 to 30 mg THC daily. Outcomes included daily self-reported spasm frequency, Ashworth Scale, Rivermead Mobility Index, 10-m timed walk, nine-hole peg test, and cognitive tests.","limitations":"The intention-to-treat analysis did not show significant benefits. The per-protocol analysis, while positive, excludes patients who could not tolerate the full dose, potentially inflating the apparent benefit. The crossover design during inpatient rehabilitation may not reflect real-world use. Sample size was relatively small."},{"rthcId":"RTHC-00182","title":"Cannabis use and age at onset of schizophrenia.","authors":"Veen, Natalie D; Selten, Jean-Paul; van der Tweel, Ingeborg; Feller, Wilma G; Hoek, Hans W; Kahn, René S","year":2004,"journal":"The American journal of psychiatry, 161(3), 501-6","doi":null,"pmid":"14992976","tags":["psychosis","youth","mental-health","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers conducted a population-based, first-contact incidence study in The Hague, Netherlands, examining 133 schizophrenia patients. They looked at three milestones: first social/occupational dysfunction, first psychotic episode, and first negative symptoms.\n\nMale patients reached all three milestones at significantly younger ages than female patients. Cannabis-using patients also reached these milestones significantly younger than non-users.\n\nIn multivariate analysis, cannabis use, but not gender, independently predicted the age of first psychotic episode. Male cannabis users were a mean of 6.9 years younger at illness onset than male non-users. However, gender rather than cannabis use predicted the age of first social/occupational dysfunction and the risk of developing negative symptoms before treatment.","whyItMatters":"The finding that cannabis use independently predicted earlier onset of psychosis, even after controlling for gender differences, adds to evidence of a specific relationship between cannabis and the timing of psychotic episodes. The 6.9-year difference is clinically substantial, as earlier onset is generally associated with worse long-term outcomes.","specificNumbers":"133 schizophrenia patients studied. Male cannabis users were 6.9 years younger at first psychotic episode than male non-users. Cannabis use, but not gender, independently predicted age at first psychotic episode in multivariate analysis.","methodology":"Population-based, first-contact incidence study conducted in The Hague, Netherlands. One hundred thirty-three patients were interviewed using the Comprehensive Assessment of Symptoms and History. Key informants were interviewed with the Instrument for the Retrospective Assessment of the Onset of Schizophrenia. Multivariate analyses controlled for the independent effects of gender and cannabis use on three illness milestones.","limitations":"The cross-sectional design cannot establish causation. Cannabis use was assessed retrospectively, which introduces recall bias. The study cannot determine whether cannabis use precipitated psychosis in individuals who would not have developed it otherwise or simply accelerated onset in those already predisposed."},{"rthcId":"RTHC-00183","title":"Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.","authors":"Wade, Derick T; Makela, Petra; Robson, Philip; House, Heather; Bateman, Cynthia","year":2004,"journal":"Multiple sclerosis (Houndmills, Basingstoke, England), 10(4), 434-41","doi":null,"pmid":"15327042","tags":["medical-cannabis","cbd","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers recruited 160 MS outpatients experiencing significant problems with spasticity, spasms, bladder issues, tremor, or pain across three centers. Patients received either matched placebo or whole-plant cannabis extract (Sativex) containing equal amounts of THC and CBD at doses of 2.5 to 120 mg each daily via oromucosal spray.\n\nThe primary outcome, a visual analogue scale (VAS) score for each patient's most troublesome symptom, improved in both groups but did not reach statistical significance between them.\n\nHowever, spasticity VAS scores were significantly reduced by Sativex compared to placebo (P = 0.001). There were no significant adverse effects on cognition or mood, and intoxication was generally mild.","whyItMatters":"While the primary outcome was negative, the significant improvement in spasticity specifically (P = 0.001) suggested that Sativex may be effective for this particular MS symptom. This trial contributed to the evidence base that eventually led to Sativex receiving regulatory approval for MS spasticity in multiple countries.","specificNumbers":"160 MS patients across three centers. Sativex dose range: 2.5-120 mg THC and CBD daily. Primary symptom VAS: not significant between groups. Spasticity VAS: significantly reduced (P = 0.001). No significant cognitive or mood adverse effects.","methodology":"Parallel group, double-blind, randomized, placebo-controlled study across three centers. One hundred sixty MS outpatients experiencing problems with spasticity, spasms, bladder issues, tremor, or pain received oromucosal spray of placebo or Sativex (equal THC and CBD, 2.5-120 mg daily). Primary outcome was VAS score for each patient's most troublesome symptom. Secondary outcomes included VAS scores for other symptoms, disability, cognition, mood, sleep, and fatigue.","limitations":"The primary endpoint did not reach significance. The wide dose range (2.5-120 mg) means individual dosing varied substantially. The study grouped patients with different primary symptoms together, which may have diluted the overall treatment effect."},{"rthcId":"RTHC-00184","title":"Neural substrates of faulty decision-making in abstinent marijuana users.","authors":"Bolla, Karen I; Eldreth, Dana A; Matochik, John A; Cadet, Jean L","year":2005,"journal":"NeuroImage, 26(2), 480-92","doi":null,"pmid":"15907305","tags":["cognition","addiction","neuroscience","dopamine"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers used PET imaging during the Iowa Gambling Task to study decision-making in 11 heavy marijuana users after 25 days of supervised abstinence at an NIH inpatient unit, compared to 11 non-drug users.\n\nThe marijuana group showed greater activation in the left cerebellum and less activation in the right lateral orbitofrontal cortex and right dorsolateral prefrontal cortex compared to controls.\n\nWhen the marijuana group was split by usage level, heavy users (53-84 joints/week) showed less activation in the left medial orbitofrontal cortex and greater cerebellar activation than moderate users (8-35 joints/week). However, moderate users performed similarly to controls, suggesting a threshold effect where only very heavy use produces lasting deficits.","whyItMatters":"The finding of a potential threshold effect is significant. Moderate marijuana users showed brain activity and task performance comparable to non-users after 25 days of abstinence, while very heavy users did not. This suggests the level of use matters considerably for whether lasting cognitive effects emerge.","specificNumbers":"11 marijuana users vs. 11 controls. 25 days supervised abstinence. Moderate users: 8-35 joints/week. Heavy users: 53-84 joints/week. Heavy users showed less orbitofrontal cortex activation and worse Iowa Gambling Task performance. Moderate users performed similarly to controls.","methodology":"Eleven heavy marijuana users and 11 non-drug using controls were studied using PET H2O15 imaging during the Iowa Gambling Task. Marijuana users resided in an NIH/NIDA inpatient research unit for 25 days prior to testing to ensure abstinence. Users were subdivided into moderate (8-35 joints/week) and heavy (53-84 joints/week) groups for dose-response analysis.","limitations":"Very small sample size (11 per group). The study cannot determine whether brain differences preceded cannabis use or resulted from it. The threshold for \"moderate\" use (8-35 joints/week) is still substantial. Only male participants were included based on the study description. The Iowa Gambling Task is one measure of decision-making and may not capture all relevant cognitive domains."},{"rthcId":"RTHC-00185","title":"Recent developments in the therapeutic potential of cannabinoids.","authors":"Corey, Susan","year":2005,"journal":"Puerto Rico health sciences journal, 24(1), 19-26","doi":null,"pmid":"15895873","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review identified 15 independent, qualifying clinical trials (randomized, double-blind, placebo-controlled) of cannabinoid therapeutics published since 1997. Only three of the 15 had more than 100 patients.\n\nTwo large trials found cannabinoids significantly better than placebo for managing MS spasticity, though patients reported greater improvement than objective measures confirmed. Smaller trials showed significant objective improvement for tics in Tourette's disease and for neuropathic pain. A new non-psychotropic cannabinoid also showed analgesic activity for neuropathic pain.\n\nNo significant improvement was found for levodopa-induced dyskinesia in Parkinson's disease or post-operative pain. A large trial found no difference from active placebo for cachexia management. Quality of life assessments were made in only 3 of the 15 trials.","whyItMatters":"This review provides a snapshot of where cannabinoid research stood in the mid-2000s and helps distinguish conditions where evidence was emerging (spasticity, tics, neuropathic pain) from those where trials were negative (cachexia, Parkinson's, post-operative pain). The low number of large trials highlights how early clinical cannabinoid research was at this point.","specificNumbers":"15 qualifying clinical trials identified. Only 3 had more than 100 patients. Quality of life assessed in only 3 of 15 trials. Positive findings: MS spasticity (2 large trials), Tourette's tics, neuropathic pain. Negative findings: Parkinson's dyskinesia, post-operative pain, cachexia.","methodology":"Literature review searching publications since 1997 using terms including cannabinoid, marijuana, THC, and various medical conditions. Qualifying studies were randomized, double-blind, and placebo-controlled. Selected open-label studies and surveys were also discussed. Fifteen qualifying clinical trials were identified.","limitations":"Only 15 qualifying trials existed, most with small sample sizes. The review was limited to studies since 1997. Self-reported improvement in MS trials exceeded objective measures, raising questions about placebo effects. The distinction between different cannabinoid formulations and delivery methods was not always clear."},{"rthcId":"RTHC-00186","title":"Cannabinoids and the immune system: potential for the treatment of inflammatory diseases?","authors":"Croxford, J Ludovic; Yamamura, Takashi","year":2005,"journal":"Journal of neuroimmunology, 166(1-2), 3-18","doi":null,"pmid":"16023222","tags":["inflammation","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Since the discovery of cannabinoid receptors on immune system cells, researchers have investigated how cannabinoids affect immune function. This review compiled evidence from chronic cannabis smokers, animal studies, and in vitro experiments on immune cells including T cells and macrophages.\n\nThe evidence shows cannabinoids can modulate both the function and secretion of cytokines from immune cells. These immunomodulatory effects operate through cannabinoid receptors and suggest potential therapeutic applications for inflammatory diseases.\n\nThe review highlighted the role of endogenous cannabinoids (endocannabinoids) as natural ligands that also demonstrate immunomodulatory properties, supporting the idea that the endocannabinoid system plays a role in regulating immune responses.","whyItMatters":"Understanding how cannabinoids interact with the immune system is foundational for developing targeted treatments for autoimmune and inflammatory conditions. The presence of cannabinoid receptors on immune cells suggests the endocannabinoid system naturally participates in immune regulation.","specificNumbers":"Two cannabinoid receptor subtypes (CB1, CB2) identified on immune cells. Evidence compiled from chronic cannabis smoker studies, animal models, and in vitro immune cell experiments.","methodology":"Narrative review article compiling evidence from studies on chronic cannabis smokers, animal models, and in vitro experiments on immune cells (T cells, macrophages). Examined the function and role of cannabinoid receptors within immunological cellular function.","limitations":"Much of the evidence comes from cell culture and animal studies, which may not directly translate to humans. Studies from chronic cannabis smokers involve confounding factors. The review covers a broad range of inflammatory conditions without deep evidence for any specific one."},{"rthcId":"RTHC-00187","title":"Tobacco-reporting validity in an epidemiological drug-use survey.","authors":"Fendrich, Michael; Mackesy-Amiti, Mary Ellen; Johnson, Timothy P; Hubbell, Amy; Wislar, Joseph S","year":2005,"journal":"Addictive behaviors, 30(1), 175-81","doi":null,"pmid":"15561458","tags":["addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared self-reported tobacco use with saliva cotinine testing in 627 respondents from an epidemiological drug-use survey. While outright underreporting of tobacco was relatively rare, self-report sensitivity was below the 90% level established in prior reviews, even after adjusting for passive smoke exposure.\n\nA key finding was that underreporting of marijuana use showed a strong association with underreporting of tobacco use. Race and ethnicity also predicted tobacco underreporting.\n\nThe study used Audio Computer-Assisted Self-Interview (ACASI) to minimize social desirability bias, and also tested hair, urine, and oral fluid for illicit drugs including marijuana, cocaine, heroin, and amphetamines.","whyItMatters":"If people who underreport marijuana use also underreport tobacco use, it suggests that drug survey data may systematically underestimate use in certain populations. This has implications for interpreting all cannabis research that relies on self-reported use data.","specificNumbers":"627 respondents via multistage sampling. Self-report sensitivity was below the 90% threshold from prior reviews. Marijuana underreporting strongly predicted tobacco underreporting. Biological tests included saliva (cotinine), hair, urine, and oral fluid.","methodology":"Cross-sectional epidemiological study using multistage sampling of 627 respondents. Participants completed household surveys via Audio Computer-Assisted Self-Interview (ACASI) and provided saliva samples for cotinine testing. Hair, urine, and oral fluid were tested for illicit substances. Self-report sensitivity was calculated by comparing reported use against biological confirmation.","limitations":"The study cannot determine why respondents underreported. The single geographic sample may not generalize to other populations. Passive cotinine exposure complicates the comparison between self-report and biological testing. The study focused on tobacco reporting validity with cannabis as a predictor, not the reverse."},{"rthcId":"RTHC-00188","title":"Cannabinoid tolerance and dependence: a review of studies in laboratory animals.","authors":"González, Sara; Cebeira, Maribel; Fernández-Ruiz, Javier","year":2005,"journal":"Pharmacology, biochemistry, and behavior, 81(2), 300-18","doi":null,"pmid":"15919107","tags":["tolerance","addiction","neuroscience","withdrawal"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This extensive review compiled evidence from laboratory animal studies on cannabinoid tolerance and dependence. Five key conclusions emerged.\n\nFirst, prolonged exposure to cannabinoid agonists consistently produces tolerance to most pharmacological effects. Second, tolerance primarily results from pharmacodynamic changes, specifically down-regulation and desensitization of cannabinoid receptors, with some pharmacokinetic contributions.\n\nThird, spontaneous withdrawal symptoms rarely appear when chronic cannabinoid treatment stops, likely because cannabinoids are eliminated slowly from the body. However, when cannabinoid CB1 receptors are pharmacologically blocked in tolerant animals, withdrawal responses do emerge. Fourth, these withdrawal responses include somatic signs and molecular changes similar to those seen with other drugs, but the magnitude is generally smaller. Fifth, cannabinoid-tolerant animals do not appear more vulnerable to the reinforcing properties of morphine.","whyItMatters":"This review helps explain why cannabis withdrawal is different from withdrawal from drugs like alcohol or opioids. The slow elimination of cannabinoids from the body masks physical dependence that becomes apparent only when receptors are pharmacologically blocked. This has implications for understanding both addiction potential and treatment approaches.","specificNumbers":"Tolerance develops through CB1 receptor down-regulation and desensitization. Spontaneous withdrawal is rare but can be precipitated by receptor blockade. Withdrawal magnitude is generally smaller than with other drugs. No increased vulnerability to morphine reinforcement was found.","methodology":"Comprehensive review article compiling evidence from published laboratory animal studies on cannabinoid tolerance and dependence. Covered studies using plant-derived, synthetic, and endogenous cannabinoid agonists. Examined both pharmacodynamic (receptor-level) and pharmacokinetic mechanisms of tolerance.","limitations":"All evidence comes from animal models, which may not fully translate to human experience. The review notes that results have been controversial in various aspects. The pharmacokinetic differences between animal and human cannabinoid metabolism may affect the applicability of withdrawal findings."},{"rthcId":"RTHC-00189","title":"Cannabis and endocannabinoid modulators: Therapeutic promises and challenges.","authors":"Grant, Igor; Cahn, B Rael","year":2005,"journal":"Clinical neuroscience research, 5(2-4), 185-199","doi":null,"pmid":"18806886","tags":["medical-cannabis","neuroscience","pain","epilepsy"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined the endocannabinoid signaling system, including CB1 receptors (heavily represented in the central nervous system), CB2 receptors (localized to immune cells), and their endogenous ligands anandamide and 2-arachidonoyl glycerol.\n\nA key insight was that endocannabinoid system activation can enhance or dampen neural circuit activity depending on the circuit's existing state of activation. This suggests a fundamental role in maintaining physiological steady state, essentially acting as a biological balancing mechanism.\n\nThe therapeutic implications include potential applications for neuroprotection, certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control. Both botanical cannabis and synthetic molecules acting as agonists, antagonists, or modulators of endocannabinoid metabolism show therapeutic promise.","whyItMatters":"The concept of endocannabinoids as a physiological balancing system helps explain why cannabinoids can have seemingly contradictory effects in different contexts. This framework guides research into developing targeted therapeutics rather than relying on whole-plant cannabis.","specificNumbers":"Two established receptor types: CB1 (CNS and other tissues) and CB2 (immune cells). Two main endogenous ligands: anandamide and 2-arachidonoyl glycerol. Therapeutic targets identified: neuroprotection, pain, epilepsy, spasticity, eating disorders, inflammation, blood pressure.","methodology":"Narrative review examining current understanding of CB1, CB2, and other possible cannabinoid receptors, their endogenous ligands, and physiological roles. Reviewed evidence for therapeutic applications of botanical cannabis and synthetic cannabinoid molecules.","limitations":"This is a broad overview rather than a deep dive into any single therapeutic application. Most therapeutic evidence at the time was preclinical. The review acknowledges addiction potential as a concern alongside therapeutic promise."},{"rthcId":"RTHC-00190","title":"Cannabinoids.","authors":"Grotenhermen, Franjo","year":2005,"journal":"Current drug targets. CNS and neurological disorders, 4(5), 507-30","doi":null,"pmid":"16266285","tags":["medical-cannabis","neuroscience","pain","appetite","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review covered 15 years of research since the discovery of the endocannabinoid system. It detailed two G-protein coupled cannabinoid receptors (CB1 and CB2), endocannabinoids produced \"on demand\" from membrane lipids, and the distribution of cannabinoid receptors across the central nervous system and peripheral tissues including immune, reproductive, gastrointestinal, cardiovascular, and endocrine systems.\n\nTherapeutic properties of CB receptor agonists identified include analgesia, muscle relaxation, immunosuppression, anti-inflammation, antiallergic effects, mood improvement, appetite stimulation, antiemesis, lowered intraocular pressure, bronchodilation, neuroprotection, and antineoplastic effects.\n\nClinical research at the time focused on chronic pain and neurological disorders. CB receptor antagonists were under investigation for obesity and nicotine addiction, with additional potential proposed for alcohol and heroin dependency, schizophrenia, Parkinson's disease, and Alzheimer's disease.","whyItMatters":"This review provides one of the most complete snapshots of cannabinoid pharmacology as of 2005, documenting the remarkable breadth of biological processes influenced by the endocannabinoid system. The fact that both agonists and antagonists show therapeutic potential highlights the complexity of this signaling system.","specificNumbers":"Two receptor subtypes: CB1 and CB2. Main endocannabinoids: anandamide and 2-AG. Receptors found in: CNS, immune system, reproductive tract, GI tract, sympathetic ganglia, endocrine glands, arteries, lung, heart. Therapeutic properties cataloged: 12+ distinct actions.","methodology":"Comprehensive narrative review covering 15 years of research on the endocannabinoid system, cannabinoid receptors, endogenous ligands, synthetic modulators, and therapeutic applications. Covered pharmacology, receptor distribution, and both agonist and antagonist therapeutic potential.","limitations":"As a narrative review, it does not systematically evaluate the quality of evidence for each therapeutic application. Many therapeutic claims were based on preclinical data. The rapid pace of research means some conclusions were quickly superseded."},{"rthcId":"RTHC-00191","title":"Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation.","authors":"Gruber, Staci A; Yurgelun-Todd, Deborah A","year":2005,"journal":"Brain research. Cognitive brain research, 23(1), 107-18","doi":null,"pmid":"15795138","tags":["cognition","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers used fMRI and diffusion tensor imaging (DTI) to study heavy cannabis smokers and matched controls during a Stroop task, which measures impulse control and interference processing.\n\nCannabis smokers showed significantly lower anterior cingulate cortex activity and higher midcingulate activity compared to controls. Controls showed increased right dorsolateral prefrontal cortex (DLPFC) activation during the interference condition, while cannabis smokers showed a more diffuse, bilateral pattern of DLPFC activation.\n\nBoth groups performed the task within normal limits, but cannabis smokers made more errors of commission during the interference condition. DTI measures showed no differences in white matter directional coherence but increased overall diffusivity in cannabis smokers' frontal regions. The findings suggest cannabis smokers recruit different cortical processes to achieve comparable task performance.","whyItMatters":"The finding that cannabis smokers achieved normal task performance through different brain activation patterns suggests the brain may compensate for cannabis-related changes by recruiting alternative or additional neural pathways. This has implications for understanding how chronic cannabis use affects brain function even when performance appears normal.","specificNumbers":"Cannabis smokers showed lower anterior cingulate and higher midcingulate activity. Controls used right-lateralized DLPFC; smokers used bilateral DLPFC. Both groups performed within normal limits. Cannabis smokers made more commission errors. DTI: no fractional anisotropy differences but increased trace (diffusivity) in smokers.","methodology":"Pilot investigation using functional MRI and diffusion tensor imaging. Heavy cannabis smokers and matched controls performed a modified Stroop task during scanning. Brain activation patterns, error rates, and white matter integrity measures (fractional anisotropy and trace) were compared between groups.","limitations":"This was a pilot investigation with a small sample size. The cross-sectional design cannot determine whether brain differences preceded or resulted from cannabis use. The Stroop task is one specific cognitive measure that may not capture all relevant domains. Current cannabis use was not controlled for (participants were chronic smokers, not abstinent)."},{"rthcId":"RTHC-00192","title":"Cannabinoids and cancer: causation, remediation, and palliation.","authors":"Hall, Wayne; Christie, MacDonald; Currow, David","year":2005,"journal":"The Lancet. Oncology, 6(1), 35-42","doi":null,"pmid":"15629274","tags":["cancer","medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review addressed three distinct relationships between cannabinoids and cancer.\n\nFirst, regarding cancer causation: case reports linked cannabis smoking to upper respiratory tract cancers in young adults, but epidemiological evidence from cohort and case-control studies was inconsistent.\n\nSecond, regarding anti-tumor effects: some lab studies showed THC and synthetic cannabinoids had antineoplastic effects, while others showed THC impaired immune responses to cancer. No evidence existed that cannabinoids have anticancer effects in humans.\n\nThird, regarding symptom management: evidence supported THC for improving appetite, reducing nausea and vomiting, and alleviating moderate neuropathic pain in cancer patients. The main challenge was developing safe delivery methods that provide therapeutic effects without adverse psychoactive effects.","whyItMatters":"This review separated three commonly conflated questions about cannabis and cancer into distinct evidence evaluations. The distinction between cannabis potentially causing cancer through smoking, potentially fighting cancer at the cellular level, and treating cancer symptoms is critical for informed decision-making.","specificNumbers":"Three relationships examined: causation (inconsistent evidence), anti-tumor effects (mixed in vitro/in vivo, none in humans), and symptom management (positive evidence for appetite, nausea, neuropathic pain).","methodology":"Narrative review published in The Lancet Oncology examining three categories of evidence: epidemiological studies on cannabis smoking and cancer risk, preclinical studies on cannabinoid anti-tumor effects, and clinical evidence on symptom management in cancer patients.","limitations":"Epidemiological evidence on cancer causation was limited and inconsistent at the time. Anti-tumor evidence was entirely preclinical with contradictory findings. The review was narrative rather than systematic."},{"rthcId":"RTHC-00193","title":"Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids.","authors":"Ilan, A B; Gevins, A; Coleman, M; ElSohly, M A; de Wit, H","year":2005,"journal":"Behavioural pharmacology, 16(5-6), 487-96","doi":null,"pmid":"16148455","tags":["cognition","neuroscience","cbd","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-three healthy marijuana users (12 men, 11 women) participated in four sessions where they smoked marijuana cigarettes under blinded conditions. Participants were assigned to low (1.8%) or high (3.6%) THC groups and received cigarettes with varying levels of CBC (0.1% vs 0.5%) and CBD (0.2% vs 1.0%).\n\nCompared to placebo, active THC cigarettes produced expected effects on mood, behavior, and brain activity. EEG and ERP measures showed decreased performance, reduced EEG power, and attenuated attention-related ERP components during working memory and episodic memory tests.\n\nMost effects were not dose-dependent between the two THC levels. Critically, varying the concentrations of CBC and CBD did not change any outcome measures, supporting the conclusion that THC and its metabolites are the primary active constituents of marijuana.","whyItMatters":"The finding that CBC and CBD concentrations did not modulate the effects of smoked marijuana challenges the \"entourage effect\" hypothesis at these dose levels. It also validates the use of neurophysiological measures (EEG, ERP) as biomarkers for THC effects in research settings.","specificNumbers":"23 participants (12 men, 11 women). Four sessions each. THC groups: 1.8% vs 3.6%. CBC: 0.1% vs 0.5%. CBD: 0.2% vs 1.0%. No dose-dependent THC effects on most measures. No CBC or CBD effects on any measures.","methodology":"Randomized, blinded study of 23 healthy marijuana users across four sessions. Participants smoked placebo or active cigarettes with varying THC (1.8% vs 3.6%), CBC (0.1% vs 0.5%), and CBD (0.2% vs 1.0%) concentrations. Measures included subjective reports, cognitive task performance, EEG, and event-related potentials during working memory and episodic memory tasks.","limitations":"The CBD and CBC concentrations tested were relatively low compared to some cannabis preparations. The study used only two THC dose levels that may not have been different enough to detect dose-dependent effects. The sample size was modest at 23 participants. Only acute effects were measured."},{"rthcId":"RTHC-00194","title":"Endocannabinoids in the regulation of appetite and body weight.","authors":"Kirkham, T C","year":2005,"journal":"Behavioural pharmacology, 16(5-6), 297-313","doi":null,"pmid":"16148436","tags":["appetite","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compiled evidence on the endocannabinoid system's role in appetite and body weight regulation. Endocannabinoids acting at CB1 cannabinoid receptors in the brain stimulate appetite and eating behaviors, partly through interactions with established hunger and satiety signals.\n\nKey brain structures sensitive to endocannabinoid appetite stimulation include the nucleus accumbens and hypothalamic nuclei. Endocannabinoid activity in these regions varies with nutritional status and feeding behavior.\n\nBehavioral studies revealed endocannabinoids increase eating motivation through two mechanisms: enhancing the incentive salience of food (making food more attractive) and enhancing hedonic evaluation (making food taste better). Beyond appetite, endocannabinoids also play a role in energy metabolism and fuel storage. CB1 receptor antagonists showed potential clinical benefits for managing obesity.","whyItMatters":"Understanding exactly how the endocannabinoid system drives appetite explains the well-known \"munchies\" phenomenon at a neurobiological level. More importantly, it identified endocannabinoid receptors as a viable drug target for both increasing appetite (in wasting conditions) and decreasing it (in obesity).","specificNumbers":"CB1 receptors identified as the key receptor for appetite stimulation. Key brain regions: nucleus accumbens and hypothalamic nuclei. Two mechanisms: incentive salience (food wanting) and hedonic evaluation (food liking). Endocannabinoid activity varies with nutritional status.","methodology":"Narrative review compiling evidence from animal behavioral studies, receptor pharmacology, brain imaging, and clinical trials on the role of endocannabinoids in appetite, eating behavior, and body weight regulation.","limitations":"Much of the evidence comes from animal studies. The complexity of appetite regulation means endocannabinoid effects interact with many other signaling systems. Clinical translation of CB1 antagonists later encountered problems with psychiatric side effects."},{"rthcId":"RTHC-00195","title":"Recent cannabis abuse decreased stress-induced BOLD signals in the frontal and cingulate cortices of cocaine dependent individuals.","authors":"Li, Chiang-Shan Ray; Milivojevic, Verica; Constable, R Todd; Sinha, Rajita","year":2005,"journal":"Psychiatry research, 140(3), 271-80","doi":null,"pmid":"16290108","tags":["addiction","neuroscience","cognition","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers used fMRI to compare stress-induced brain activation in two groups of abstinent cocaine-dependent individuals: eight who had recently also abused cannabis and 18 who had not. All subjects were abstinent for at least 15 days with confirmed drug-free urine screens.\n\nDuring a guided imagery stress task, the cannabis-using group showed significantly reduced activation (hypo-activation) in frontal cortical areas, including the perigenual anterior cingulate cortex. No brain regions showed increased activation in the cannabis-using group.\n\nThe group difference in the anterior cingulate persisted even after controlling for lifetime cocaine and alcohol consumption, suggesting the effect was specifically related to cannabis use rather than overall drug exposure.","whyItMatters":"The finding that cannabis use was associated with blunted frontal cortex stress responses in cocaine-dependent individuals raises questions about how cannabis use might affect emotional regulation and stress processing in the context of addiction, potentially affecting recovery outcomes.","specificNumbers":"8 cocaine-dependent subjects with recent cannabis abuse vs. 18 without. All abstinent 15+ days. Cannabis users showed hypo-activation in frontal cortex and perigenual anterior cingulate during stress. Effect persisted after controlling for lifetime cocaine and alcohol consumption.","methodology":"Observational fMRI study comparing 8 abstinent cocaine-dependent subjects with recent cannabis abuse to 18 matched cocaine-dependent subjects without recent cannabis abuse. All abstinent for 15+ days with confirmed urine screens. Brain activation measured during script-guided emotional stress imagery versus neutral imagery at 1.5T.","limitations":"Very small cannabis-using group (n = 8). Cross-sectional design cannot determine if brain differences preceded or resulted from cannabis use. The groups may differ in unmeasured ways despite demographic matching. All participants were cocaine-dependent, limiting generalizability to cannabis users without cocaine dependence."},{"rthcId":"RTHC-00196","title":"Drugs and driving: the Finnish perspective.","authors":"Lillsunde, P; Gunnar, T","year":2005,"journal":"Bulletin on narcotics, 57(1-2), 213-29","doi":null,"pmid":"21338023","tags":["driving","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined drug-impaired driving from a Finnish and European perspective. It reported that the prevalence of illicit drug use among the general driving population in Europe ranged from 1-5%, while licit drugs affecting driving (particularly benzodiazepines) had a prevalence of 5-10%.\n\nDrugs identified as most concerning for driving impairment included amphetamines, cocaine, cannabis, opiates, and benzodiazepines. The review discussed evolving legal frameworks, noting that some countries had introduced zero-tolerance per se laws that prohibit driving with any detectable level of illicit drugs or metabolites, regardless of demonstrated impairment.\n\nThe review also discussed advancing roadside testing technology, including oral fluid (saliva) testing. Legislation in Victoria, Australia already allowed oral fluid testing for cannabis and methamphetamine, though blood testing remained the most common form of evidentiary testing in most jurisdictions.","whyItMatters":"As cannabis legalization has expanded since this review, the question of drug-impaired driving has become increasingly important. The distinction between zero-tolerance approaches (any detectable level) and impairment-based approaches (demonstrated functional impairment) remains a central policy debate.","specificNumbers":"Illicit drug prevalence in European general driving population: 1-5%. Licit drug prevalence affecting driving: 5-10%. Most concerning drugs: amphetamines, cocaine, cannabis, opiates, benzodiazepines. Some countries adopted zero-tolerance per se laws.","methodology":"Review article examining drug-impaired driving from a Finnish perspective, covering prevalence data, legal frameworks across countries, detection methods (blood, oral fluid, urine), and enforcement approaches. Drew on epidemiological data from drivers, offenders, and crash-involved populations.","limitations":"The review focused on the Finnish and European context, which may not generalize to other regions. Data on drug prevalence among drivers varied in quality across countries. The review did not establish specific impairment thresholds for individual drugs."},{"rthcId":"RTHC-00197","title":"Cognitive consequences of cannabis use: comparison with abuse of stimulants and heroin with regard to attention, memory and executive functions.","authors":"Lundqvist, Thomas","year":2005,"journal":"Pharmacology, biochemistry, and behavior, 81(2), 319-30","doi":null,"pmid":"15925403","tags":["cognition","addiction","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compared cognitive consequences across different drug classes using neuroimaging and neuropsychological evidence.\n\nCannabis acutely causes loss of internal control and cognitive impairment, particularly in attention and memory. Heavy cannabis use is associated with reduced attentional/executive function, including decreased mental flexibility, increased perseveration, and reduced ability to shift and sustain attention.\n\nAmphetamine and methamphetamine users showed deficits in learning, delayed recall, processing speed, and working memory. MDMA users had difficulties encoding information into long-term memory and focusing attention on complex tasks. Chronic cocaine users displayed impaired attention, learning, memory, reaction time, and cognitive flexibility.\n\nHeroin addiction showed a negative effect on impulse control and selective processing. For all substances, the degree of impairment increased with severity of use, and impairments were relatively lasting over time.","whyItMatters":"By comparing cognitive effects across multiple substances, this review helps contextualize what cannabis does to cognition relative to other drugs. The finding that cannabis primarily affects attention and memory, while stimulants primarily affect processing speed and flexibility, suggests different drugs target different cognitive systems.","specificNumbers":"Cannabis: impaired attention, memory, mental flexibility, increased perseveration. Amphetamine/meth: impaired learning, delayed recall, processing speed, working memory. MDMA: impaired long-term memory encoding, attention focus. Cocaine: impaired attention, learning, memory, reaction time, cognitive flexibility. Heroin: impaired impulse control.","methodology":"Narrative review comparing cognitive consequences of cannabis, stimulants (amphetamine, methamphetamine, MDMA, cocaine), and heroin. Drew on brain imaging studies and neuropsychological test results to compare attention, memory, and executive function effects across drug classes.","limitations":"The review compared evidence from different studies using different methodologies, which limits direct comparisons. Polydrug use is common and complicates attribution of specific effects to specific substances. The review does not clearly distinguish acute from chronic effects for all substances."},{"rthcId":"RTHC-00198","title":"From cannabis to endocannabinoids in multiple sclerosis: a paradigm of central nervous system autoimmune diseases.","authors":"Malfitano, Anna Maria; Matarese, Giuseppe; Bifulco, Maurizio","year":2005,"journal":"Current drug targets. CNS and neurological disorders, 4(6), 667-75","doi":null,"pmid":"16375684","tags":["medical-cannabis","inflammation","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review compiled evidence on cannabinoids and endocannabinoids in the context of MS as a central nervous system autoimmune disease. Evidence suggests cannabinoids can benefit MS through multiple mechanisms.\n\nOn the immune side, cannabinoids down-regulate the production of pathogenic T helper 1 (Th1) cytokines while enhancing protective T helper 2 (Th2) cytokines. This Th1-to-Th2 shift has been associated with therapeutic benefit in MS.\n\nOn the neurological side, cannabinoids exert neuromodulatory effects on neurotransmitters and hormones involved in the neurodegenerative phase of the disease.\n\nAnimal studies using experimental allergic encephalomyelitis (EAE), an established model of MS, suggest that increasing circulating levels of endocannabinoids could have therapeutic effects. The review proposed that agonists of endocannabinoids with low psychoactive effects could open new treatment strategies for MS.","whyItMatters":"MS is an autoimmune disease where the immune system attacks the nervous system. The finding that cannabinoids can shift immune responses from harmful to protective patterns while also providing neuroprotection suggests a dual therapeutic mechanism that addresses both the cause and consequences of MS.","specificNumbers":"Cannabinoids down-regulate Th1 cytokines and up-regulate Th2 cytokines. EAE animal model studies show increased endocannabinoid levels have therapeutic effects. Endocannabinoids with low psychoactive effects proposed as treatment candidates.","methodology":"Narrative review examining evidence from immune cell studies, animal models of MS (experimental allergic encephalomyelitis), and clinical observations on how cannabinoids and endocannabinoids interact with the immune system and nervous system in the context of MS.","limitations":"Most evidence comes from cell studies and animal models (EAE), which do not perfectly replicate human MS. The review proposes therapeutic strategies rather than demonstrating clinical efficacy. The psychoactive effects of many cannabinoids remain a barrier to clinical development."},{"rthcId":"RTHC-00199","title":"Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract.","authors":"Nadulski, Thomas; Pragst, Fritz; Weinberg, Gordon; Roser, Patrik; Schnelle, Martin; Fronk, Eva-Maria; Stadelmann, Andreas Michael","year":2005,"journal":"Therapeutic drug monitoring, 27(6), 799-810","doi":null,"pmid":"16306858","tags":["cbd","medical-cannabis","drug-interactions"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-four volunteers (12 male, 12 female) received soft-gelatin capsules of either 10 mg THC alone, cannabis extract containing 10 mg THC plus 5.4 mg CBD, or placebo in a crossover design. Blood samples were collected over 24 hours and analyzed for THC, 11-OH-THC, THC-COOH, and CBD.\n\nDespite large individual variation in the data, evidence emerged that CBD partially inhibits the CYP 2C enzyme that hydroxylates THC to 11-OH-THC. This inhibition is likely most relevant for oral intake because THC and CBD reach relatively high liver concentrations and because of THC's substantial first-pass metabolism.\n\nHowever, the effect of CBD was small compared to variability from other factors. A notable secondary finding was that women had significantly higher peak concentrations (Cmax) and total exposure (AUC) of THC, and reached peak levels faster (shorter tmax) than men.","whyItMatters":"The finding that CBD partially inhibits THC metabolism has implications for dosing cannabis-based medicines. If CBD reduces THC conversion to its active metabolite, the ratio of THC to CBD in a product could affect the pharmacological profile. The sex difference finding also suggests men and women may need different dosing considerations.","specificNumbers":"24 volunteers (12 male, 12 female). Doses: 10 mg THC alone or 10 mg THC + 5.4 mg CBD. Blood sampled at 9 time points over 24 hours. CBD partially inhibits CYP 2C-mediated THC hydroxylation. Women had significantly higher Cmax and AUC for THC than men.","methodology":"Double-blind, placebo-controlled, crossover study in 24 volunteers (12 male, 12 female, age 18-45). Three conditions at weekly intervals: 10 mg THC capsules, cannabis extract (10 mg THC + 5.4 mg CBD), or placebo. Blood samples at 9 time points over 24 hours. THC and metabolites measured by solid phase extraction, derivatization, and GC-MS. Pharmacokinetic parameters compared statistically.","limitations":"Large individual variation in pharmacokinetic data made it difficult to detect definitive effects. The doses used (10 mg THC, 5.4 mg CBD) may not represent all clinical scenarios. The study concluded the pharmacokinetic interaction is unlikely to explain clinical differences between pure THC and cannabis extract at these doses. Only single-dose pharmacokinetics were assessed."},{"rthcId":"RTHC-00200","title":"Passive cannabis smoke exposure and oral fluid testing. II. Two studies of extreme cannabis smoke exposure in a motor vehicle.","authors":"Niedbala, R Sam; Kardos, Keith W; Fritch, Dean F; Kunsman, Kenneth P; Blum, Kristen A; Newland, Gregory A; Waga, Joe; Kurtz, Lisa; Bronsgeest, Matth; Cone, Edward J","year":2005,"journal":"Journal of analytical toxicology, 29(7), 607-15","doi":null,"pmid":"16419389","tags":["driving","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers conducted two studies where four non-smoking subjects sat alongside four active cannabis smokers in an unventilated eight-passenger van. In Study 1, smokers used 5.4% THC cannabis mixed with tobacco; in Study 2, they used 10.4% THC pure cannabis.\n\nIn Study 1, where oral fluid samples were collected inside the smoky van, passive subjects showed THC concentrations up to 7.5 ng/mL. However, collection devices exposed to the smoke-filled air without being in anyone's mouth also contained 3-14 ng/mL, revealing environmental contamination of the collection devices themselves.\n\nIn Study 2, where all collections occurred outside the van, every passive subject tested negative at both screening and confirmation cutoff concentrations throughout the entire study. Active smokers had peak THC concentrations approximately 100-fold greater than passive subjects.","whyItMatters":"This research directly addresses the \"secondhand smoke\" defense in drug testing. By showing that positive results from passive exposure were actually caused by environmental contamination of the collection device rather than systemic absorption, the study supports the validity of oral fluid drug testing when proper collection procedures are followed.","specificNumbers":"Passive subjects in smoky van: up to 7.5 ng/mL THC. Exposed collection devices (no mouth contact): 3-14 ng/mL. Passive subjects tested outside van: all negative. Active smokers: approximately 100-fold higher concentrations than passive subjects. Screening cutoff: 3 ng/mL. Confirmation cutoff: 1.5 ng/mL.","methodology":"Two controlled exposure studies in an unventilated eight-passenger van. Four passive subjects alongside four active smokers per study. Study 1: 5.4% THC cannabis/tobacco blend, collections inside van. Study 2: 10.4% THC pure cannabis, collections outside van. Oral fluid analyzed by immunoassay screening and GC-MS-MS confirmation. Urine also collected for verification.","limitations":"The extreme exposure conditions (unventilated van with four simultaneous smokers) may not represent typical passive exposure scenarios. Only oral fluid testing was examined. The sample size of passive subjects was small (four per study). The studies did not assess impairment or subjective effects in passive subjects."},{"rthcId":"RTHC-00201","title":"The endocannabinoid system and the treatment of obesity.","authors":"Pagotto, Uberto; Vicennati, Valentina; Pasquali, Renato","year":2005,"journal":"Annals of medicine, 37(4), 270-5","doi":null,"pmid":"16019725","tags":["appetite","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review detailed how the endocannabinoid system contributes to obesity through two parallel mechanisms. In the brain, CB1 receptors in the hypothalamus and mesolimbic system regulate appetite by modulating hunger signals and the reward value of food. CB1 activation stimulates food intake, particularly of palatable foods, through dopamine release in the nucleus accumbens.\n\nIn peripheral tissues, CB1 receptors were found to be present in adipose tissue and the gastrointestinal system. In fat cells, CB1 activation directly stimulates lipogenesis (fat production). Animal models showed that genetically obese animals have permanently overactive endocannabinoid systems, which may help maintain obesity.\n\nCB1 blockers showed dual benefits: increasing adiponectin production in fat cells (which promotes fatty acid burning) and reducing appetite centrally. CB1 receptors were also found to be upregulated in fat cells from obese animals.","whyItMatters":"The discovery that endocannabinoids act on fat cells directly, not just on brain appetite circuits, changed the understanding of how the cannabinoid system contributes to obesity. It also explained why CB1 blockers might produce weight loss effects beyond simple appetite reduction.","specificNumbers":"CB1 receptors found in hypothalamus, mesolimbic system, adipose tissue, and GI tract. CB1 activation stimulates lipogenesis in fat cells. CB1 blockers increase adiponectin production. CB1 is upregulated in obese animal adipocytes. Genetically obese animals show chronic endocannabinoid overactivation.","methodology":"Narrative review examining evidence from molecular biology, animal models of obesity, and early clinical data on the role of CB1 receptors in central appetite regulation and peripheral energy metabolism. Covered both brain and adipose tissue endocannabinoid signaling.","limitations":"Much evidence came from animal models that may not fully translate to humans. The review was published before long-term clinical trial data on CB1 blockers was available. The complexity of endocannabinoid signaling means blocking CB1 affects many systems beyond appetite and fat storage."},{"rthcId":"RTHC-00202","title":"Sativex for the management of multiple sclerosis symptoms.","authors":"Perras C","year":2005,"journal":"Issues in emerging health technologies, 1-4","doi":null,"pmid":"16317825","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Sativex, containing THC and CBD in a 1:1 ratio delivered as an oromucosal spray, was one of the first cannabis-based medicines to undergo conventional clinical development and receive prescription approval. Five randomized controlled trials compared Sativex with placebo in a total of 368 patients with various neurological conditions including MS.\n\nIn some trials, Sativex significantly reduced neuropathic pain, spasticity, muscle spasms, and sleep disturbances. The most common adverse events were dizziness, sleepiness, fatigue, feeling of intoxication, and bad taste.\n\nSativex was approved in Canada as adjunctive treatment for neuropathic pain in MS patients. It is regulated as a narcotic. Long-term safety and the potential for dependence, abuse, misuse, and diversion remained unknown at the time of this review.","whyItMatters":"Sativex represented a milestone in cannabis medicine: the first cannabis-derived pharmaceutical to achieve regulatory approval through standard clinical trial processes. Its approval validated the concept that cannabis-based medicines could meet the same standards as conventional pharmaceuticals.","specificNumbers":"5 RCTs reviewed. 368 patients total. THC:CBD ratio: 1:1. Each spray delivers 2.7 mg THC + 2.5 mg CBD. Approved indication: neuropathic pain in MS. Significant improvements in: neuropathic pain, spasticity, muscle spasms, sleep disturbance.","methodology":"Health technology assessment reviewing five randomized controlled trials comparing THC:CBD oromucosal spray with placebo. Total of 368 patients with various neurological conditions including MS. Assessed benefits and harms across trials.","limitations":"Only 368 patients across all five trials, limiting the power to detect rare adverse events. Long-term safety data was not available. The review noted that potential for dependence, abuse, and diversion was unknown. Only neurological conditions were studied."},{"rthcId":"RTHC-00203","title":"Comorbidity: cannabis and complexity.","authors":"Raphael, Beverley; Wooding, Sally; Stevens, Garry; Connor, Jason","year":2005,"journal":"Journal of psychiatric practice, 11(3), 161-76","doi":null,"pmid":"15920390","tags":["psychosis","addiction","anxiety","depression","youth","withdrawal"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered multiple dimensions of cannabis health effects and comorbidity. The physiological and neurological effects of cannabis were reviewed alongside prevalence data and the gateway drug hypothesis.\n\nThe review found strong support for a link between cannabis and the development and exacerbation of psychosis. Links to anxiety and depression were also supported, though the evidence was less definitive.\n\nRegarding dependence, the review supported the existence of a cannabis withdrawal syndrome with diagnostic criteria. The question of whether cannabis serves as a \"gateway\" to harder drugs was discussed but not definitively resolved.\n\nThe authors called for further research into the neurochemical processes underlying cannabis-mental health relationships, the social factors driving increasing youth cannabis use, and systematic evaluation of prevention and treatment programs through randomized controlled trials.","whyItMatters":"By addressing the full spectrum of cannabis health risks in a single review, this paper provided a comprehensive resource for clinicians and policymakers. The emphasis on cannabis being potentially more harmful than traditionally perceived, particularly regarding mental health, reflected a shift in research consensus in the mid-2000s.","specificNumbers":"Strong evidence for cannabis-psychosis link. Support for cannabis withdrawal syndrome as a diagnosable condition. Cannabis identified as one of the most commonly used illicit drugs globally.","methodology":"Narrative review examining published literature on cannabis physiological effects, prevalence, gateway hypothesis, dependence criteria, withdrawal syndrome, and comorbidity with psychosis, anxiety, and depression. Also reviewed public health prevention and treatment programs.","limitations":"As a narrative review, it did not systematically grade the quality of evidence for each claim. The causal direction of the cannabis-mental health relationship was acknowledged as uncertain. Prevention program evidence was limited."},{"rthcId":"RTHC-00204","title":"Human studies of cannabinoids and medicinal cannabis.","authors":"Robson, P","year":2005,"journal":"Handbook of experimental pharmacology, 719-56","doi":null,"pmid":"16596794","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review traced the arc of medicinal cannabis from its prominence in 19th century Western medicine through its early 20th century prohibition and 1960s recreational explosion, to the current state of clinical research.\n\nThe author identified major methodological challenges that had kept clinical evidence weak: studies tended to be small, imperfectly controlled, and often used synthetic cannabinoid analogs or smoked herbal material with uncertain composition and irregular bioavailability.\n\nNew research opportunities were emerging from three developments: the discovery of the endocannabinoid system, expanding knowledge of cannabinoid pharmacology, and a more sympathetic political environment in several countries. Future therapeutic targets were expected to extend beyond symptom relief into disease modification, with cannabinoids showing particular promise for inflammatory and neurodegenerative conditions.","whyItMatters":"This review honestly assessed the gap between thousands of years of anecdotal evidence for medical cannabis and the thin base of rigorous clinical research. By identifying why research had lagged, including the \"pariah drug\" status and methodological challenges, it helped set the agenda for more rigorous future studies.","specificNumbers":"Cannabis medicinal use documented across several thousand years and multiple cultures. Most clinical studies described as small and imperfectly controlled. Future targets identified: inflammatory and neurodegenerative conditions.","methodology":"Comprehensive narrative review covering the historical development and current status of medicinal cannabis research. Examined legal controls, existing clinical trial evidence across multiple conditions, safety considerations, and future research directions.","limitations":"As a broad historical and contemporary review, it could not deeply evaluate evidence for any specific condition. The assessment of research quality was qualitative rather than systematic. The review reflected the state of evidence as of 2005."},{"rthcId":"RTHC-00205","title":"Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis.","authors":"Rog, David J; Nurmikko, Turo J; Friede, Tim; Young, Carolyn A","year":2005,"journal":"Neurology, 65(6), 812-9","doi":null,"pmid":"16186518","tags":["medical-cannabis","cbd","pain","sleep"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Sixty-six MS patients with central pain (59 with dysesthetic pain, 7 with painful spasms) participated in a 5-week randomized, double-blind, placebo-controlled trial of a THC:CBD oromucosal spray. Each spray delivered 2.7 mg THC and 2.5 mg CBD, with patients self-titrating up to 48 sprays per day.\n\nSixty-four patients (97%) completed the trial. In week 4, those on the active medication used an average of 9.6 sprays daily compared to 19.1 for placebo, suggesting participants recognized the active treatment and adjusted their dosing.\n\nThe cannabis-based medicine was significantly superior to placebo for both pain intensity (mean change -2.7 vs -1.4, P = 0.005) and sleep disturbance (mean change -2.5 vs -0.8, P = 0.003) on 11-point rating scales. The treatment was generally well tolerated, with dizziness, dry mouth, and somnolence being more common in the active group. Cognitive side effects were limited to long-term memory storage.","whyItMatters":"Central pain in MS is common and often resistant to existing treatments. This trial demonstrated clinically meaningful pain relief and sleep improvement with a cannabis-based medicine, with the high completion rate (97%) indicating good tolerability. Published in Neurology, it provided high-quality evidence for regulatory decisions.","specificNumbers":"66 patients enrolled. 64 (97%) completed. 34 received active treatment. Mean daily sprays: 9.6 active vs 19.1 placebo. Pain reduction: -2.7 vs -1.4 (P = 0.005). Sleep improvement: -2.5 vs -0.8 (P = 0.003). Side effects: dizziness, dry mouth, somnolence.","methodology":"Single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial. Sixty-six MS patients with central pain received THC:CBD oromucosal spray (2.7 mg THC + 2.5 mg CBD per spray) or placebo as adjunctive analgesic treatment. Self-titration up to 48 sprays/24 hours. Pain and sleep measured daily on 11-point numerical rating scales.","limitations":"Single center with 66 patients. The large difference in placebo spray usage (19.1 vs 9.6 daily sprays) suggests possible unblinding, as active treatment participants may have recognized the drug effects. Four-week treatment period may not capture long-term efficacy or safety. Published in Neurology, a high-impact journal."},{"rthcId":"RTHC-00206","title":"The safety of cannabinoids for the treatment of multiple sclerosis.","authors":"Smith, Paul F","year":2005,"journal":"Expert opinion on drug safety, 4(3), 443-56","doi":null,"pmid":"15934852","tags":["medical-cannabis","cbd","psychosis","pregnancy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review assessed the safety profile of cannabis-based medicinal extracts (CBMEs) for MS treatment. Clinical trial data showed adverse effects were generally mild: dry mouth, dizziness, somnolence, nausea, and intoxication. No cases of toxicity developed.\n\nDespite evidence that cannabinoids can disrupt cognitive function and promote depression in recreational users, these adverse effects appeared unlikely with CBMEs based on available data. Effects on balance, motor control, and immune function also appeared clinically insignificant.\n\nHowever, the review identified two populations warranting concern: people predisposed to psychosis, given growing evidence of cannabis-psychosis links, and pregnant women, given increasing evidence of adverse fetal effects. The author concluded that given the modest therapeutic benefits demonstrated so far and the risk of unknown long-term effects, caution was warranted.","whyItMatters":"This review provided an honest assessment of both the safety and the limitations of cannabis-based MS medicines. The identification of specific at-risk populations (psychosis-prone individuals and pregnant women) helped guide clinical decision-making about who should and should not use these treatments.","specificNumbers":"Common adverse effects: dry mouth, dizziness, somnolence, nausea, intoxication. No toxicity in any trial. Most trials ran only months long. Specific concerns: psychosis-predisposed individuals and pregnant women.","methodology":"Safety review of clinical trial data on cannabis-based medicinal extracts for MS. Evaluated adverse effect profiles, cognitive impacts, effects on balance and motor control, immune function, psychosis risk, and reproductive safety.","limitations":"Most clinical trials were relatively short (months), limiting knowledge of long-term safety. The review noted that unknown adverse effects could develop with longer use. The assessment of psychosis and pregnancy risks drew partly from recreational cannabis research, which may not directly apply to pharmaceutical preparations."},{"rthcId":"RTHC-00207","title":"Smoked marijuana as a cause of lung injury.","authors":"Tashkin, D P","year":2005,"journal":"Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, 63(2), 93-100","doi":null,"pmid":"16128224","tags":["respiratory","cancer","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review by a leading pulmonologist examined the lung effects of marijuana smoking. While THC causes short-term bronchodilation, regular smoking produces chronic cough, sputum, widespread airway inflammation, and dysregulated growth of respiratory epithelial cells that may be cancer precursors.\n\nMarijuana smoke contains many of the same toxic gases and particulates as tobacco smoke. The pulmonary consequences may be amplified by the way marijuana is smoked: deeper inhalation and longer breath-holding deposit more particulates in the lungs, even though fewer joints are smoked daily than cigarettes.\n\nTHC itself may contribute to lung injury through augmenting oxidative stress, causing mitochondrial dysfunction, and inhibiting apoptosis (programmed cell death). However, despite these concerning cellular findings, epidemiological evidence that marijuana smoking leads to COPD or respiratory cancer was limited and inconsistent.\n\nMarijuana smoking was also associated with impaired alveolar macrophage function, including reduced ability to kill microbes, potentially increasing susceptibility to lung infections.","whyItMatters":"The disconnect between concerning cellular findings (inflammation, precancerous changes) and the lack of clear epidemiological evidence for serious lung disease is one of the more puzzling aspects of cannabis respiratory research. This review highlighted this paradox and called for further studies.","specificNumbers":"Marijuana smoke deposits more particulates per cigarette than tobacco due to smoking technique. THC causes short-term bronchodilation. Regular use produces chronic cough and airway inflammation. Epithelial cell dysregulation identified. Alveolar macrophage microbial killing impaired.","methodology":"Narrative review by D.P. Tashkin, a prominent pulmonary researcher, examining laboratory, clinical, and epidemiological evidence on the respiratory effects of marijuana smoking. Covered airway inflammation, cellular changes, immune function, and cancer risk.","limitations":"Most evidence came from observational studies of self-reported marijuana smokers. Distinguishing marijuana from tobacco effects is difficult since many users smoke both. Epidemiological studies were limited by small numbers of heavy, long-term marijuana-only smokers."},{"rthcId":"RTHC-00208","title":"Cannabis withdrawal in adolescent treatment seekers.","authors":"Vandrey, Ryan; Budney, Alan J; Kamon, Jody L; Stanger, Catherine","year":2005,"journal":"Drug and alcohol dependence, 78(2), 205-10","doi":null,"pmid":"15845324","tags":["withdrawal","youth","addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Adolescents presenting for outpatient substance abuse treatment with cannabis as their primary drug completed questionnaires about withdrawal symptoms during past periods of abstinence.\n\nNearly two-thirds reported experiencing four or more withdrawal symptoms. Over one-third reported four or more symptoms at moderate or greater severity. The severity of withdrawal was positively correlated with current emotional and behavioral symptoms and self-reported problems with cannabis use.\n\nThe prevalence and magnitude of withdrawal symptoms were lower than those observed in a similar study of adult treatment seekers (Budney et al., 1999), suggesting that adolescents may experience less severe withdrawal, potentially due to shorter duration or lower levels of use.","whyItMatters":"This was among the few published studies examining cannabis withdrawal specifically in adolescents. The finding that a majority of treatment-seeking teens experienced withdrawal symptoms supports the reality of cannabis dependence in this age group, with implications for treatment planning and expectations during quitting.","specificNumbers":"Nearly two-thirds reported 4+ withdrawal symptoms. Over one-third reported 4+ symptoms at moderate or greater severity. Withdrawal severity correlated with emotional/behavioral symptoms and self-reported cannabis problems. Rates lower than in adult treatment seekers.","methodology":"Cross-sectional questionnaire study of adolescents presenting for outpatient substance abuse treatment with cannabis as their primary substance. Participants reported presence and severity of withdrawal symptoms during past periods of abstinence. Correlations were examined between withdrawal severity and current emotional, behavioral, and substance use problems.","limitations":"Retrospective self-report of withdrawal symptoms is subject to recall bias. The sample was limited to treatment seekers, who may not represent all adolescent cannabis users. No biological confirmation of abstinence periods. The absence of a comparison group of non-treatment-seeking adolescent users limits generalizability."},{"rthcId":"RTHC-00209","title":"Cannabinoids and the regulation of ingestive behaviour.","authors":"Vickers, S P; Kennett, G A","year":2005,"journal":"Current drug targets, 6(2), 215-23","doi":null,"pmid":"15777191","tags":["appetite","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compiled evidence on how cannabinoids regulate eating behavior, covering both exogenous (plant-derived) and endogenous cannabinoids. In multiple species including humans, cannabinoid administration leads to robust increases in food intake and can promote weight gain, mediated through CB1 receptor activation.\n\nSelective CB1 receptor antagonists demonstrated reductions in food intake and body weight with repeated administration. Weight loss was greater in obese animals than lean ones, suggesting the endocannabinoid system is more active in obesity. The reductions appeared to result from dual effects on both food intake and metabolic processes.\n\nThe most advanced CB1 antagonist, rimonabant (Acomplia/SR-141716), showed significant reductions in body weight, waist circumference, and improvements in lipid and glucose metabolism in early Phase III results with overweight and obese humans.","whyItMatters":"This review captured the excitement around rimonabant as a potentially transformative obesity treatment. The dual mechanism of action, reducing both appetite and metabolic dysfunction, was particularly promising for addressing the complex pathophysiology of obesity.","specificNumbers":"CB1 antagonists produced greater weight loss in obese vs. lean animals. Rimonabant Phase III results: significant reductions in body weight and waist circumference, improved lipid and glucose metabolism in overweight/obese humans. Dual mechanism: appetite reduction + metabolic improvement.","methodology":"Narrative review examining evidence from animal behavioral studies, receptor pharmacology, and early Phase III clinical trial data on cannabinoid regulation of food intake and body weight. Covered both agonist (appetite-stimulating) and antagonist (appetite-suppressing) effects.","limitations":"The review was published before full Phase III safety data was available. The optimistic tone did not anticipate the psychiatric side effects that later emerged. Animal data showing greater effects in obese subjects may not directly translate to human outcomes."},{"rthcId":"RTHC-00210","title":"Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up.","authors":"Zajicek, J P; Sanders, H P; Wright, D E; Vickery, P J; Ingram, W M; Reilly, S M; Nunn, A J; Teare, L J; Fox, P J; Thompson, A J","year":2005,"journal":"Journal of neurology, neurosurgery, and psychiatry, 76(12), 1664-9","doi":null,"pmid":"16291891","tags":["medical-cannabis","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"This was the 12-month follow-up to the main Cannabinoids in Multiple Sclerosis (CAMS) study, the largest RCT of cannabinoids for MS at the time. Six hundred thirty patients from 33 UK centers had been randomized to oral THC, cannabis extract, or placebo in the initial 15-week study, which had not found significant Ashworth score changes.\n\nEighty percent of patients continued into this blinded follow-up. At 12 months, intention-to-treat analysis revealed a small but significant treatment effect for THC on the Ashworth spasticity scale (mean reduction 1.82 for THC vs. -0.23 for placebo, P = 0.01 adjusted for ambulatory status and center). Cannabis extract showed a smaller, non-significant effect.\n\nThere were suggestive findings for THC benefits on some aspects of disability. No major safety concerns emerged over the 12-month period. Patients generally reported feeling the drugs were helpful.","whyItMatters":"The finding that THC produced a significant spasticity benefit at 12 months, when the initial 15-week study had not, suggests that cannabinoid effects on spasticity may take time to develop or that the Ashworth scale may be insensitive to early changes. This result was important for the broader case that cannabinoids have a role in MS management.","specificNumbers":"630 patients from 33 UK centers. 80% followed for 12 months. THC Ashworth reduction: 1.82 (n=154). Cannabis extract: 0.10 (n=172). Placebo: -0.23 (n=176). P = 0.01 adjusted. No major safety concerns.","methodology":"Double-blind follow-up study extending the original 15-week CAMS trial. Six hundred thirty MS patients from 33 UK centers originally randomized to oral THC, cannabis extract, or placebo. Eighty percent followed for 12 months. Primary outcome: change in Ashworth spasticity scale. Secondary outcomes: Rivermead Mobility Index, timed walk, disability scores, quality of life.","limitations":"The treatment effect, while statistically significant, was small. Cannabis extract did not show a significant effect, complicating interpretation. Eighty percent follow-up means 20% were lost, potentially biasing results. The Ashworth scale has known limitations as a measure of spasticity."},{"rthcId":"RTHC-00211","title":"The genetic epidemiology of cannabis use, abuse and dependence.","authors":"Agrawal, Arpana; Lynskey, Michael T","year":2006,"journal":"Addiction (Abingdon, England), 101(6), 801-12","doi":null,"pmid":"16696624","tags":["genetics","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined twin, family, and adoption studies investigating genetic and environmental influences on cannabis use. Key findings emerged across multiple study designs.\n\nThere is a genetic basis to each stage of cannabis involvement: initiation of use, progression to regular use, and development of abuse and dependence. However, some genetic factors influencing each stage appear to be stage-specific, meaning the genes that influence whether someone tries cannabis may differ from those influencing whether they become dependent.\n\nMultivariate analyses exploring relationships between cannabis and other substances found that common genetic and environmental factors influence liability to cannabis, alcohol, tobacco, and other drug involvement. This suggests overlapping genetic vulnerability across substances rather than cannabis-specific genetic risk.","whyItMatters":"Establishing a genetic basis for cannabis dependence has important implications: it means vulnerability to cannabis problems is partly biological rather than purely a matter of choice. It also supports research aimed at identifying specific genes involved, which could inform prevention and treatment strategies.","specificNumbers":"Genetic basis found for each stage: use initiation, regular use, and dependence. Some stage-specific genetic factors identified. Common genetic factors influence cannabis, alcohol, tobacco, and other drug involvement.","methodology":"Review of genetically informative studies including family studies, twin studies, and adoption studies examining genetic and environmental contributions to cannabis use, abuse, and dependence. Included multivariate analyses examining genetic relationships between cannabis and other substance use.","limitations":"Twin studies have inherent assumptions (equal environment assumption) that may not fully hold. Heritability estimates vary across populations and cannot be directly applied to individuals. The review predated genome-wide association studies that could identify specific genetic variants."},{"rthcId":"RTHC-00212","title":"Implication of cannabinoids in neurological diseases.","authors":"Alsasua del Valle, Angela","year":2006,"journal":"Cellular and molecular neurobiology, 26(4-6), 579-91","doi":null,"pmid":"16699878","tags":["medical-cannabis","neuroscience","pain"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This brief review summarized how recent advances in understanding THC's pharmacological properties and the endocannabinoid system have created new therapeutic opportunities.\n\nPotential therapeutic applications for CB1 receptor agonists include managing spasticity and tremor in MS and spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation in advanced cirrhosis.\n\nCB1 receptor antagonists were identified as having therapeutic potential for Parkinson's disease, based on the rationale that blocking endocannabinoid activity in the basal ganglia could improve motor function.\n\nThe review also noted the contributions of Dr. Julius Axelrod to research on the neuroprotective actions of cannabinoids.","whyItMatters":"This concise review highlighted the breadth of neurological conditions that might benefit from cannabinoid-based treatments, emphasizing that both activating and blocking cannabinoid receptors could have therapeutic value depending on the condition.","specificNumbers":"CB1 agonist targets: spasticity, tremor, pain, inflammation, glaucoma, asthma, cancer, cirrhosis. CB1 antagonist target: Parkinson's disease.","methodology":"Brief narrative review summarizing recent advances in cannabinoid pharmacology and therapeutic potential for neurological and psychiatric diseases. Referenced both agonist and antagonist therapeutic applications.","limitations":"Very brief review that provides limited detail on the evidence for each therapeutic application. Many listed applications were based on preclinical rather than clinical evidence. The review format was more a summary of possibilities than a critical evaluation."},{"rthcId":"RTHC-00213","title":"New insights into endocannabinoid degradation and its therapeutic potential.","authors":"Bari, M; Battista, N; Fezza, F; Gasperi, V; Maccarrone, M","year":2006,"journal":"Mini reviews in medicinal chemistry, 6(3), 257-68","doi":null,"pmid":"16515464","tags":["neuroscience","medical-cannabis","cancer","anxiety"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review focused on the enzymes responsible for endocannabinoid synthesis and degradation. Two endocannabinoids, anandamide (AEA) and 2-AG, are produced on demand and their activity is terminated by specific enzymes: fatty acid amide hydrolase (FAAH) for anandamide and monoacylglycerol lipase (MAGL) for 2-AG.\n\nThese enzymes are pivotal regulators of endocannabinoid levels in the body. Specific inhibitors of FAAH, MAGL, or the anandamide membrane transporter (AMT) could serve as therapeutic targets by boosting the body's own cannabinoid signaling rather than introducing external cannabinoids.\n\nThe review also described the biosynthetic enzymes NAPE-PLD and DAGL that produce endocannabinoids. Animal studies of endocannabinoid degradation inhibitors showed promise for treating anxiety, cancer, and neurodegenerative disorders.","whyItMatters":"Inhibiting endocannabinoid breakdown is a fundamentally different approach from administering THC or other cannabinoids. By boosting the body's own cannabinoid signaling at specific sites, this approach could provide therapeutic benefits with fewer psychoactive side effects, since endocannabinoid levels would only increase where they are naturally being produced.","specificNumbers":"Key enzymes: FAAH (degrades anandamide), MAGL (degrades 2-AG), AMT (transports anandamide), NAPE-PLD (synthesizes anandamide), DAGL (synthesizes 2-AG). Therapeutic targets tested in animal models: anxiety, cancer, neurodegenerative disorders.","methodology":"Review of molecular biology research on endocannabinoid synthesis and degradation pathways. Covered enzyme characterization, inhibitor development, and animal model studies of therapeutic applications.","limitations":"All therapeutic evidence was from animal models. The complexity of endocannabinoid signaling means inhibiting degradation enzymes affects multiple biological systems. The review was published before significant human clinical data was available."},{"rthcId":"RTHC-00214","title":"Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain.","authors":"Barnes, Michael Philip","year":2006,"journal":"Expert opinion on pharmacotherapy, 7(5), 607-15","doi":null,"pmid":"16553576","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered the clinical development of Sativex, one of the first cannabis-based medicines approved through conventional pharmaceutical pathways. As an oromucosal spray allowing flexible, individualized dosing, patients typically self-titrate to approximately 8-12 sprays per day.\n\nAt this dosing, patients receive approximately 22-32 mg THC and 20-30 mg CBD daily. Clinical development focused on MS symptoms (spasticity and neuropathic pain) and neuropathic pain from other causes.\n\nPositive results from placebo-controlled trials demonstrated efficacy and tolerability as add-on therapy for these conditions. Sativex had been approved in Canada for neuropathic pain due to MS, with further approvals expected for spasticity and broader neuropathic pain indications based on ongoing studies.","whyItMatters":"The self-titration approach to dosing, where patients adjust their own dose based on response and tolerability, became a model for other cannabis-based medicines. The typical daily dose range provides useful reference points for clinical practice.","specificNumbers":"Each spray: 2.7 mg THC + 2.5 mg CBD. Typical daily dose: 8-12 sprays. Daily THC: approximately 22-32 mg. Daily CBD: approximately 20-30 mg. Approved in Canada for MS neuropathic pain.","methodology":"Clinical review of the Sativex development program, covering pharmacology, dosing, clinical trial results, and regulatory status. Focused on placebo-controlled trials for MS symptoms and neuropathic pain.","limitations":"This review is from the manufacturer's perspective and focuses on positive results. The self-titration dosing approach means controlled dosing comparisons are difficult. Long-term safety data beyond the trial periods was limited."},{"rthcId":"RTHC-00215","title":"Comorbid substance use and age at onset of schizophrenia.","authors":"Barnes, Thomas R E; Mutsatsa, Stanley H; Hutton, Sam B; Watt, Hilary C; Joyce, Eileen M","year":2006,"journal":"The British journal of psychiatry : the journal of mental science, 188, 237-42","doi":null,"pmid":"16507965","tags":["psychosis","addiction","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers studied 152 people recruited to the West London First-Episode Schizophrenia Study. Sixty percent were smokers, 27% reported alcohol problems, 35% reported current substance use (excluding alcohol), and 68% reported lifetime substance use, with cannabis and psychostimulants most commonly used.\n\nCannabis use and gender had independent effects on age at onset of psychosis, even after adjusting for alcohol misuse and use of other drugs. This means the cannabis-earlier onset association was not explained by general substance use patterns.\n\nThe authors noted the bidirectional nature of the finding: the strong association between cannabis use and earlier psychosis onset could mean either that cannabis precipitates schizophrenia or that early-onset symptoms are themselves a risk factor for cannabis use.","whyItMatters":"This UK inner-city study replicated findings from other countries showing cannabis use is associated with earlier schizophrenia onset. The careful adjustment for alcohol and other drugs strengthens the case that cannabis has a specific association with onset timing rather than being a marker of general substance use.","specificNumbers":"152 patients studied. 60% smokers. 27% alcohol problems. 35% current substance use. 68% lifetime substance use. Cannabis and psychostimulants most common. Cannabis and gender independently predicted earlier onset after adjusting for alcohol and other drugs.","methodology":"Cross-sectional study of 152 participants in the West London First-Episode Schizophrenia Study. Self-reported data on drug and alcohol use collected alongside information on age at onset. Mental state, cognition (IQ, memory, executive function), and social function were assessed.","limitations":"Cross-sectional design cannot determine causation or temporal sequence. Self-reported drug use may underestimate actual use. Inner-city London sample may not represent other populations. The study could not determine whether cannabis precipitated psychosis in people who would not otherwise have developed it."},{"rthcId":"RTHC-00216","title":"Experience with the synthetic cannabinoid nabilone in chronic noncancer pain.","authors":"Berlach, David M; Shir, Yoram; Ware, Mark A","year":2006,"journal":"Pain medicine (Malden, Mass.), 7(1), 25-9","doi":null,"pmid":"16533193","tags":["medical-cannabis","pain","sleep"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This report described clinical experience with off-label nabilone (a synthetic cannabinoid approved only for chemotherapy nausea) for chronic non-cancer pain at a Canadian pain clinic from 1999 onward.\n\nTwenty adult patients with chronic non-cancer pain were followed for an average of 1.5 years. Prior to nabilone, patients had used a wide range of other therapies, and 11 had previously used cannabis.\n\nFifteen of 20 patients (75%) reported subjective overall improvement. Nine specifically reported reduced pain intensity. However, the main reasons patients continued using nabilone were benefits for sleep and nausea rather than pain relief alone. Three patients experienced intolerable side effects: palpitations, urinary retention, and dry mouth.","whyItMatters":"This early clinical experience suggested nabilone might be useful for chronic pain management, but interestingly the main perceived benefits were improved sleep and reduced nausea rather than direct pain relief. This pattern, where cannabinoids improve overall symptom burden more than pain scores alone, has been seen in other studies.","specificNumbers":"20 patients followed for average 1.5 years. 11 had previously used cannabis. 15/20 (75%) reported overall improvement. 9/20 reported reduced pain. 3/20 had intolerable side effects. Main benefits: sleep and nausea improvement.","methodology":"Retrospective clinical case series of 20 adult chronic non-cancer pain patients treated with off-label nabilone at a Canadian pain clinic. Average follow-up of 1.5 years. No control group or randomization. Outcomes assessed by clinician review of medical records.","limitations":"No control group, no randomization, no blinding. Only 20 patients. Retrospective assessment introduces bias. Subjective outcomes without standardized measures. The 75% improvement rate may reflect selection bias since patients who tolerated the drug stayed on it."},{"rthcId":"RTHC-00217","title":"Development of the first potent and specific inhibitors of endocannabinoid biosynthesis.","authors":"Bisogno, Tiziana; Cascio, Maria Grazia; Saha, Bijali; Mahadevan, Anu; Urbani, Paolo; Minassi, Alberto; Appendino, Giovanni; Saturnino, Carmela; Martin, Billy; Razdan, Raj; Di Marzo, Vincenzo","year":2006,"journal":"Biochimica et biophysica acta, 1761(2), 205-12","doi":null,"pmid":"16466961","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers developed and screened new synthetic compounds as inhibitors of DAGL-alpha, the enzyme responsible for producing the endocannabinoid 2-arachidonoyl glycerol (2-AG). They also tested for inhibitors of MAGL, the enzyme that breaks down 2-AG.\n\nThe most potent and selective DAGL-alpha inhibitors were compounds O-3640 (IC50 = 500 nM) and O-3841 (IC50 = 160 nM). These compounds were highly selective: they were nearly inactive against MAGL, rat liver lipase, the anandamide synthesis enzyme, FAAH, and cannabinoid CB1 and CB2 receptors.\n\nAdditional compounds were identified that inhibited both DAGL-alpha and MAGL with similar potency, providing different pharmacological tools for studying endocannabinoid biology.","whyItMatters":"Before this work, researchers could boost endocannabinoid signaling by blocking degradation, but could not specifically reduce 2-AG production. These selective DAGL inhibitors provided the first tools to study what happens when endocannabinoid synthesis is blocked, fundamental to understanding the system's biological roles.","specificNumbers":"O-3640 IC50: 500 nM against DAGL-alpha. O-3841 IC50: 160 nM against DAGL-alpha. Both nearly inactive on MAGL, liver lipase, NAPE-PLD, FAAH, CB1, and CB2. Reference compound orlistat: IC50 approximately 60 nM but non-selective.","methodology":"In vitro enzyme inhibition study using membranes from COS cells over-expressing recombinant human DAGL-alpha and cytosolic fractions from wild-type COS cells for MAGL. Screened known compounds and new phosphonate derivatives of oleic acid and fluoro-phosphinoyl esters. Selectivity tested against multiple related enzymes and receptors.","limitations":"All testing was in vitro using recombinant enzymes, not in living animals or humans. The selectivity profile was tested against a limited panel of related enzymes. The compounds may behave differently in biological systems where additional factors affect drug availability and metabolism."},{"rthcId":"RTHC-00218","title":"Clinical trial of abstinence-based vouchers and cognitive-behavioral therapy for cannabis dependence","authors":"Budney, Alan J.; Moore, Brent A.; Rocha, Higgins L.; Higgins, Stephen T.","year":2006,"journal":"Journal of Consulting and Clinical Psychology, 74(2), 307-316","doi":null,"pmid":"16649875","tags":["addiction","withdrawal","quitting","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Three groups were compared for 14 weeks: cognitive-behavioral therapy (CBT) alone, abstinence-based voucher incentives alone, and the combination. Vouchers were effective at producing extended runs of continuous abstinence during the treatment window. CBT by itself did not improve these during-treatment abstinence runs.\n\nWhere CBT mattered was after treatment stopped. Participants who received CBT plus vouchers maintained abstinence better across the 12-month follow-up than those who received vouchers without CBT, according to the authors. The pattern suggests a division of labor: incentives helped people achieve abstinence during treatment, while CBT supported keeping it going when the external rewards ended.","whyItMatters":"Cannabis dependence has far fewer tested interventions than other substance use disorders. This trial put two widely used approaches head to head and in combination, clarifying that contingency management can drive short-term abstinence during active treatment, while CBT may help preserve gains after incentives stop. Programs that separate the short-term and maintenance phases can plan with better expectations about what each component delivers.","specificNumbers":"- Sample: 90 adults with cannabis dependence, randomized to CBT, vouchers, or both\n- Treatment length: 14 weeks of active intervention\n- Follow-up: 12 months after treatment ended\n- During treatment: vouchers produced longer runs of continuous abstinence than CBT alone","methodology":"Randomized controlled trial of 90 treatment-seeking adults diagnosed with cannabis dependence. Participants were assigned to one of three arms for 14 weeks: CBT, abstinence-contingent voucher incentives, or both combined. Outcomes were assessed for 12 months after treatment. The abstract does not report the country, verification method for abstinence, voucher values, therapist training, or attrition rates.","limitations":"Only 90 participants and a single trial. The abstract does not report exact abstinence rates, effect sizes, or how abstinence was verified. Voucher amounts, schedule, and CBT content are not detailed, making replication and real-world translation difficult. All participants were treatment-seeking adults, which may not generalize to people who are not seeking treatment. Published in 2006, before major shifts in cannabis potency, product types, and policy environments."},{"rthcId":"RTHC-00219","title":"Influence of the anabolic-androgenic steroid nandrolone on cannabinoid dependence.","authors":"Célérier, Evelyne; Ahdepil, Therese; Wikander, Helena; Berrendero, Fernando; Nyberg, Fred; Maldonado, Rafael","year":2006,"journal":"Neuropharmacology, 50(7), 788-806","doi":null,"pmid":"16443242","tags":["addiction","neuroscience","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers examined whether the anabolic steroid nandrolone affects THC's pharmacological and behavioral effects in mice. Nandrolone was administered either as a 14-day pre-exposure or co-administered with each THC injection.\n\nNeither nandrolone treatment affected THC's acute effects (pain relief, temperature drop, reduced movement) or tolerance development. However, nandrolone pre-exposure produced several notable behavioral changes: it blocked THC-induced conditioned place preference (a measure of reward), blocked food reward, and increased the physical withdrawal symptoms precipitated by the CB1 antagonist rimonabant.\n\nNandrolone pre-exposure also reduced THC's anxiety-relieving effects at low doses without affecting the anxiety-producing effects at high doses. Importantly, CB1 receptor binding and G-protein activation were not changed by nandrolone treatment, suggesting the interaction occurs downstream of the receptor.","whyItMatters":"The combination of anabolic steroid and cannabis use is not uncommon, particularly among young males. Finding that nandrolone blocks the rewarding effects of THC while worsening withdrawal suggests that steroid use could complicate cannabis cessation and alter the experience of cannabis use.","specificNumbers":"Nandrolone pre-exposure: 14 days before THC. THC reward (place preference): blocked. Food reward: blocked. Withdrawal symptoms: increased. Anxiolytic effects of low-dose THC: reduced. CB1 receptor binding: unchanged. G-protein activation: unchanged.","methodology":"Mouse behavioral pharmacology study using two nandrolone treatment protocols (14-day pre-exposure and co-administration). Assessed THC acute effects, tolerance, conditioned place preference, withdrawal (rimonabant-precipitated), anxiety (lit/dark box, open field, elevated plus-maze), and CB1 receptor binding and GTP-binding protein activation.","limitations":"Mouse study results may not translate to humans. The doses and administration routes differ from typical human use patterns. Nandrolone also blocked food reward, suggesting a general reward-blunting effect rather than a cannabis-specific interaction. Only one anabolic steroid was tested."},{"rthcId":"RTHC-00220","title":"Changes in cannabis use and its consequences over 3 years in a remote indigenous population in northern Australia.","authors":"Clough, Alan R; Lee, Kim S Kylie; Cairney, Sheree; Maruff, Paul; O'Reilly, Bridie; d'Abbs, Peter; Conigrave, Katherine M","year":2006,"journal":"Addiction (Abingdon, England), 101(5), 696-705","doi":null,"pmid":"16669903","tags":["psychosis","cognition","youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers conducted a 3-year follow-up in remote Aboriginal communities in Arnhem Land, Northern Territory, Australia. A randomly selected sample of 161 people (aged 13-36) was assessed in 2001 and reassessed in 2004, with an additional opportunistic sample of 104.\n\nThose who used cannabis at both time points were at significantly greater risk than never-users of experiencing auditory hallucinations, suicidal ideation, and imprisonment.\n\nIn the randomly selected cohort, cannabis use decreased significantly from baseline to follow-up (P = 0.003). The reduction was evident in females generally (P = 0.008) and older males aged 16+ at baseline (P = 0.007). Among continuing users, fewer reported withdrawal-type symptoms including fragmented thoughts, memory problems, difficulty controlling use, and hallucinations. The reductions may reflect enhanced supply control and broader socio-political changes in the communities.","whyItMatters":"This is one of very few longitudinal studies of cannabis use in an indigenous population. The finding that persistent use was associated with hallucinations, suicidal thoughts, and imprisonment underscores the real-world consequences of heavy cannabis use in a vulnerable population, while the overall decline in use suggests that community-level interventions can be effective.","specificNumbers":"161 randomly selected participants (13-36 years). 3-year follow-up. Cannabis use declined (P = 0.003). Decline in females (P = 0.008) and older males (P = 0.007). Persistent users: higher rates of auditory hallucinations, suicidal ideation, and imprisonment vs. never-users.","methodology":"Longitudinal cohort study with 3-year follow-up. Randomly selected sample (n=161) and opportunistic sample (n=104) from Aboriginal communities in Arnhem Land, NT, Australia. Cannabis and substance use assessed by combining proxy assessments from Aboriginal health workers, medical records, and interview data. Changes analyzed using McNemar's test and Wilcoxon signed rank test.","limitations":"Relatively small sample from a specific remote population, limiting generalizability. Cannabis use was assessed through combined proxy, medical, and self-report methods rather than biological testing. The observational design cannot determine whether cannabis caused the psychiatric symptoms or shared risk factors explain both. The decline in use may reflect specific local factors not applicable elsewhere."},{"rthcId":"RTHC-00221","title":"Reductions in heroin use are not associated with increases in other drug use: 2-year findings from the Australian Treatment Outcome Study.","authors":"Darke, Shane; Williamson, Anna; Ross, Joanne; Teesson, Maree","year":2006,"journal":"Drug and alcohol dependence, 84(2), 201-5","doi":null,"pmid":"16580792","tags":["addiction","harm-reduction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 615 heroin users recruited for the Australian Treatment Outcome Study at 3, 12, and 24 months. The proportion reporting weekly heroin use declined significantly at all time points.\n\nReductions in heroin use were associated with less frequent use of other opioids, cocaine, amphetamine, and benzodiazepines. Alcohol use remained stable throughout. Cannabis and alcohol use were unrelated to changes in heroin use.\n\nLonger periods in residential rehabilitation were associated with declines across all drug classes. Maintenance treatment was associated with declines in other opioid and alcohol use specifically. The study found no evidence for drug substitution, directly challenging the concern that reducing heroin use would push people to other substances.","whyItMatters":"The fear that treating one addiction simply shifts people to another substance is a common concern that can discourage treatment-seeking. This study provides evidence against that substitution hypothesis, showing that successful heroin reduction tends to coincide with reduced use of most other substances as well.","specificNumbers":"615 heroin users followed for 24 months. Weekly heroin use declined at all time points. Use of other opioids, cocaine, amphetamine, and benzodiazepines also declined. Cannabis and alcohol use were unrelated to heroin changes. Residential rehab associated with declines across all drug classes.","methodology":"Longitudinal cohort study with follow-up at 3, 12, and 24 months. Six hundred fifteen heroin users in New South Wales, Australia. Assessed frequency of use across multiple substance categories at each time point.","limitations":"Limited to treatment-seeking heroin users in one Australian state, which may not generalize to other populations. Self-reported drug use may underestimate actual consumption. The study cannot determine whether reduced use of other drugs was caused by heroin treatment or by general lifestyle changes associated with treatment engagement."},{"rthcId":"RTHC-00222","title":"Drug testing in oral fluid.","authors":"Drummer, Olaf H","year":2006,"journal":"The Clinical biochemist. Reviews, 27(3), 147-59","doi":null,"pmid":"17268583","tags":["driving","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered a decade of developments in oral fluid drug testing. For basic drugs like amphetamines, cocaine, and some opioids, oral fluid concentrations are similar to or higher than plasma levels, making saliva testing straightforward.\n\nTHC from cannabis presented unique challenges. During the elimination phase, oral fluid THC concentrations are similar to blood. However, immediately after smoking, there is significant local absorption of THC in the oral cavity, creating a depot effect that temporarily inflates oral fluid concentrations far above what blood levels would indicate.\n\nSimilar depot effects occur with other drugs introduced through routes allowing oral absorption, such as smoked cocaine, amphetamines, and sublingual buprenorphine. Screening techniques were adapted to emphasize parent drug detection since metabolites are less prevalent in oral fluid. Confirmatory techniques increasingly used liquid chromatography-mass spectrometry due to low sample volumes and detection limit requirements.","whyItMatters":"Understanding why THC oral fluid testing behaves differently from other drugs is critical for interpreting results in workplace and roadside testing. The depot effect means a positive oral fluid test shortly after smoking reflects both systemic levels and local mouth contamination, complicating the interpretation of impairment.","specificNumbers":"THC oral fluid concentrations similar to blood during elimination phase. Significant depot effect from oral cavity absorption after smoking. Screening emphasis on parent drugs (not metabolites) in oral fluid. LC-MS becoming dominant confirmatory technique.","methodology":"Comprehensive review of developments in oral fluid drug testing over the previous decade. Covered drug pharmacokinetics in oral fluid, collection methods, screening and confirmatory analytical techniques, and applications in workplace, roadside, and clinical settings.","limitations":"Review focused on analytical and pharmacokinetic aspects rather than clinical correlation with impairment. Collection methods can affect results, including stimulation of saliva production. Drug concentrations in oral fluid can be affected by food, drink, and other factors."},{"rthcId":"RTHC-00223","title":"Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement.","authors":"Esposito, Giuseppe; De Filippis, Daniele; Maiuri, Maria Chiara; De Stefano, Daniela; Carnuccio, Rosa; Iuvone, Teresa","year":2006,"journal":"Neuroscience letters, 399(1-2), 91-5","doi":null,"pmid":"16490313","tags":["cbd","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested CBD's effects on neuronal cells (PC12) stimulated with beta-amyloid (1-42), a protein associated with Alzheimer's disease. Exposure to beta-amyloid for 36 hours caused a significant increase in nitrite production, a marker of nitrosative stress.\n\nCBD inhibited both nitrite production and iNOS protein expression in a concentration-dependent manner. The mechanism was traced to two specific pathways: CBD inhibited the phosphorylation of p38 MAP kinase and blocked activation of the transcription factor NF-kappaB, both key mediators of inflammatory responses.\n\nThis built on previous work showing CBD has anti-oxidant and anti-apoptotic effects that protect neurons from beta-amyloid toxicity. The finding that CBD also blocks the nitrosative stress pathway adds another potential neuroprotective mechanism.","whyItMatters":"Neuroinflammation is a major component of Alzheimer's disease pathology. Finding that CBD can block specific inflammatory pathways triggered by beta-amyloid protein in neurons adds to the evidence for CBD's potential neuroprotective properties, though this is limited to cell culture observations.","specificNumbers":"CBD concentrations tested: 10^-6 to 10^-4 M. Beta-amyloid stimulation: 1 microgram/mL for 36 hours. CBD inhibited iNOS expression and nitrite production concentration-dependently. Mechanism: p38 MAP kinase and NF-kappaB pathway inhibition.","methodology":"In vitro cell study using differentiated PC12 neurons. Cells were stimulated with beta-amyloid (1-42) at 1 microgram/mL for 36 hours. CBD tested at concentrations of 10^-6 to 10^-4 M. Nitrite production measured as an indicator of nitric oxide production. iNOS protein expression, p38 MAP kinase phosphorylation, and NF-kappaB activation assessed.","limitations":"In vitro cell line study that may not translate to the complex environment of the living brain. The concentrations of CBD used may not be achievable in brain tissue. PC12 cells are a simplified model that does not capture the full complexity of Alzheimer's pathology."},{"rthcId":"RTHC-00224","title":"Scopolamine and MK801-induced working memory deficits in rats are not reversed by CBD-rich cannabis extracts.","authors":"Fadda, Paola; Robinson, Lianne; Fratta, Walter; Pertwee, Roger G; Riedel, Gernot","year":2006,"journal":"Behavioural brain research, 168(2), 307-11","doi":null,"pmid":"16406104","tags":["cbd","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Previous research had shown that CBD-rich cannabis extracts could reverse working memory deficits caused by THC in a dose-dependent manner. This follow-up study tested whether CBD could also reverse memory impairments caused by different mechanisms.\n\nScopolamine (0.2 mg/kg, an anticholinergic drug) and MK801/dizocilpine (0.1 mg/kg, an antiglutamatergic drug) both impaired working memory in rats at delays of 30 seconds and 4 hours in a spatial water maze task.\n\nTwo doses of CBD-rich extract (5 and 10 mg/kg), which did not affect memory when given alone, were unable to reverse the deficits when co-administered with either scopolamine or MK801. This indicates that CBD's memory-protective effects work specifically through the cannabinoid system and cannot compensate for cholinergic or glutamatergic dysfunction.","whyItMatters":"Understanding the specificity of CBD's memory-protective effects is important for realistic expectations about its therapeutic potential. The finding that CBD only reverses cannabinoid-system-mediated memory problems, not cholinergic or glutamatergic ones, narrows the conditions where CBD might be helpful.","specificNumbers":"CBD-rich extract doses: 5 and 10 mg/kg. Scopolamine: 0.2 mg/kg. MK801: 0.1 mg/kg. Memory deficits at 30-second and 4-hour delays. CBD failed to reverse either scopolamine or MK801 deficits.","methodology":"Rat behavioral study using a spatial delayed matching to position task in an open-field water maze. Working memory assessed at 30-second and 4-hour delays. CBD-rich cannabis extracts (5 and 10 mg/kg) tested against scopolamine (0.2 mg/kg) and MK801 (0.1 mg/kg) induced memory deficits.","limitations":"Animal study using a specific behavioral paradigm. Only two doses of CBD-rich extract were tested. The extract contained some residual THC as a contaminant, complicating interpretation. Results may not generalize to other cognitive tasks or to humans."},{"rthcId":"RTHC-00225","title":"The effects of concurrent cannabis use among ecstasy users: neuroprotective or neurotoxic?","authors":"Fisk, John E; Montgomery, Catharine; Wareing, Michelle; Murphy, Philip N","year":2006,"journal":"Human psychopharmacology, 21(6), 355-66","doi":null,"pmid":"16915582","tags":["cognition","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers reanalyzed data from multiple studies to test whether using cannabis alongside ecstasy (MDMA) might protect against ecstasy-related cognitive damage, based on evidence that cannabinoids can be neuroprotective under certain conditions.\n\nThey compared three groups: people who typically use cannabis and ecstasy at the same time, people who use ecstasy without concurrent cannabis, and non-ecstasy users. Testing covered processing speed, random letter generation, verbal and visuospatial working memory, reasoning, and associative learning.\n\nThe two ecstasy-using groups did not differ from each other on any measure. Both ecstasy groups performed significantly worse than non-ecstasy users on associative learning, verbal and visuospatial working memory, and reasoning. Cannabis co-use provided no measurable cognitive protection.","whyItMatters":"The idea that cannabis might protect against ecstasy neurotoxicity had theoretical support from cannabinoid neuroprotection research. This study provides a practical reality check: in actual human use patterns, combining cannabis with ecstasy did not result in better cognitive outcomes.","specificNumbers":"Three groups compared across 6+ cognitive domains. No significant differences between the two ecstasy groups on any measure. Both ecstasy groups significantly worse than controls on associative learning, verbal working memory, visuospatial working memory, and reasoning.","methodology":"Reanalysis of data from previous studies comparing three groups: concurrent cannabis/ecstasy users, ecstasy-only users, and non-ecstasy controls. Assessed processing speed, random letter generation, verbal and visuospatial working memory span, reasoning, and associative learning.","limitations":"Cross-sectional design cannot establish whether pre-existing differences between groups explain the results. Self-reported drug use patterns may be inaccurate. The reanalysis combined data from studies with potentially different methodologies. Users may differ in unmeasured ways."},{"rthcId":"RTHC-00226","title":"The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS).","authors":"Freeman, R M; Adekanmi, O; Waterfield, M R; Waterfield, A E; Wright, D; Zajicek, J","year":2006,"journal":"International urogynecology journal and pelvic floor dysfunction, 17(6), 636-41","doi":null,"pmid":"16552618","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"This was a substudy of the large Cannabinoids in Multiple Sclerosis (CAMS) trial, which had randomized 630 MS patients across 33 UK centers to cannabis extract, THC, or placebo. Participants completed incontinence diaries.\n\nAll three groups showed significant reductions in urge incontinence episodes from baseline to end of treatment. However, both active treatments were significantly superior to placebo: cannabis extract reduced episodes by 38% (P = 0.005 vs. placebo), and THC reduced episodes by 33% (P = 0.039 vs. placebo), compared to placebo's 18% reduction.\n\nNotably, this positive finding contrasted with the main CAMS study result, where no difference was seen in the primary outcome of spasticity (Ashworth scale). The authors suggested this indicated a genuine clinical effect of cannabis on bladder function in MS.","whyItMatters":"Urinary incontinence is a common and debilitating MS symptom with limited treatment options. Finding significant benefits from both cannabis extract and THC in this large, rigorous trial setting provided stronger evidence than most previous studies, particularly since the main trial's primary outcome (spasticity) was negative.","specificNumbers":"630 patients in main CAMS study. Incontinence episode reduction: cannabis extract 38%, THC 33%, placebo 18%. Cannabis extract vs. placebo: P = 0.005. THC vs. placebo: P = 0.039.","methodology":"Substudy of the multicenter CAMS RCT. From 630 MS patients randomized to oral cannabis extract, THC, or placebo across 33 UK centers. Participants completed incontinence diaries. Episode rates adjusted for baseline imbalance.","limitations":"This was a substudy, not the primary analysis. Not all 630 patients completed incontinence diaries. The adjustment for baseline imbalance was necessary but adds analytical complexity. The mechanism of cannabinoid effects on bladder function was not directly studied."},{"rthcId":"RTHC-00227","title":"Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors.","authors":"Gelfand, Eli V; Cannon, Christopher P","year":2006,"journal":"Journal of the American College of Cardiology, 47(10), 1919-26","doi":null,"pmid":"16697306","tags":["appetite","cardiovascular","addiction","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review from the Journal of the American College of Cardiology summarized clinical trial evidence for rimonabant, the first selective CB1 cannabinoid receptor blocker developed for cardiometabolic risk management.\n\nAcross four large trials, rimonabant 20 mg daily produced greater weight loss and waist circumference reduction compared to placebo after one year. The drug also improved serum lipid profiles and glycemic control in both prediabetes patients and type 2 diabetics.\n\nAt the same dose, rimonabant significantly increased cigarette smoking quit rates compared to placebo. The primary side effect was mild nausea. The review positioned rimonabant as a potential adjunct to lifestyle modification for managing multiple cardiometabolic risk factors simultaneously.","whyItMatters":"The concept of treating multiple cardiometabolic risk factors with a single drug by targeting the endocannabinoid system was groundbreaking. The fact that a cannabinoid receptor blocker could simultaneously improve weight, metabolic markers, and smoking rates illustrated how deeply the endocannabinoid system is involved in these interconnected health behaviors.","specificNumbers":"Four large RCTs reviewed. Rimonabant 20 mg daily vs. placebo. Outcomes: greater weight loss, reduced waist circumference, improved serum lipids, improved glycemic control, increased smoking quit rates. Primary side effect: mild nausea.","methodology":"Clinical review summarizing results from four large randomized controlled trials (the RIO program) of rimonabant for cardiometabolic outcomes. Evaluated weight, waist circumference, lipids, glycemic control, and smoking cessation.","limitations":"This review was published before the full safety signal emerged. The optimistic framing of \"mild nausea\" as the primary side effect did not capture the psychiatric risks that became apparent with wider use. The one-year trial duration may have been insufficient to detect longer-term risks."},{"rthcId":"RTHC-00228","title":"Cannabis use and expression of mania in the general population.","authors":"Henquet, Cécile; Krabbendam, Lydia; de Graaf, Ron; ten Have, Margreet; van Os, Jim","year":2006,"journal":"Journal of affective disorders, 95(1-3), 103-10","doi":null,"pmid":"16793142","tags":["mental-health","psychosis"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers followed 4,815 individuals aged 18-64 years in a longitudinal population-based study with assessments at baseline, one year, and three years. Cannabis use at baseline increased the risk of developing manic symptoms during follow-up (adjusted odds ratio 2.70, 95% CI: 1.54-4.75).\n\nThis association held after adjusting for age, sex, education, ethnicity, marital status, neuroticism, use of other drugs, alcohol use, depressive symptoms, and manic symptoms at baseline. Importantly, the cannabis-mania association was independent of psychotic symptoms, meaning it was not simply a manifestation of cannabis-related psychosis.\n\nThere was no evidence for reverse causality: manic symptoms at baseline did not predict the onset of cannabis use during follow-up (OR = 0.35, 95% CI: 0.03-3.49), arguing against the self-medication explanation.","whyItMatters":"While the cannabis-psychosis link is well-studied, much less was known about cannabis and mania/bipolar disorder. This study provided some of the strongest prospective evidence that cannabis use increases the risk of manic symptoms specifically, independent of psychosis, and that this is not explained by self-medication.","specificNumbers":"4,815 adults followed for 3 years. Cannabis use increased mania risk: adjusted OR 2.70 (95% CI: 1.54-4.75). Association independent of psychotic symptoms. No reverse causality: baseline mania did not predict future cannabis use (OR = 0.35).","methodology":"Longitudinal population-based cohort study. 4,815 individuals aged 18-64 assessed with the Composite International Diagnostic Interview at baseline, 1-year, and 3-year follow-up. Assessed substance use, manic symptoms, psychotic symptoms, and potential confounders. Adjusted odds ratios calculated for prospective associations.","limitations":"Three years is relatively short for detecting long-term effects on bipolar disorder risk. Self-reported cannabis use may be underestimated. The Composite International Diagnostic Interview assesses symptoms rather than clinical diagnoses. The study population was from the Netherlands, which may not generalize to all populations."},{"rthcId":"RTHC-00229","title":"A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management.","authors":"Holdcroft, Anita; Maze, Mervyn; Doré, Caroline; Tebbs, Susan; Thompson, Simon","year":2006,"journal":"Anesthesiology, 104(5), 1040-6","doi":null,"pmid":"16645457","tags":["medical-cannabis","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Patients were given a single dose of 5, 10, or 15 mg of oral cannabis extract (Cannador) for post-operative pain after stopping patient-controlled analgesia. The dose-response relationship was clear and significant.\n\nAll 11 patients (100%) receiving 5 mg requested rescue analgesia. At 10 mg, 15 of 30 patients (50%) needed rescue medication. At 15 mg, only 6 of 24 patients (25%) needed rescue (log rank test for trend P < 0.001). The number needed to treat to prevent one rescue request was 2.0 for 10 mg and 1.3 for 15 mg, comparable to many routinely used analgesics.\n\nHowever, there were significant trends for increasing sedation (P = 0.03) and more adverse events (P = 0.002) at higher doses. The study was terminated after a serious vasovagal adverse event in a patient receiving the 15 mg dose.","whyItMatters":"The clear dose-response relationship and competitive number needed to treat values provided strong evidence for cannabinoid analgesic efficacy. However, the safety-related termination highlights the challenge of finding the right dose: effective pain relief required doses that also produced more adverse events.","specificNumbers":"5 mg: 100% needed rescue (11/11). 10 mg: 50% needed rescue (15/30). 15 mg: 25% needed rescue (6/24). Trend: P < 0.001. NNT to prevent rescue: 2.0 (10 mg), 1.3 (15 mg). Increasing sedation: P = 0.03. More adverse events: P = 0.002. Study terminated: serious vasovagal event at 15 mg.","methodology":"Multi-center dose-escalation study. Patients aged 18-75 received a single dose of 5, 10, or 15 mg Cannador after stopping patient-controlled analgesia for at least moderate pain. Dose escalation based on rescue analgesia requests and adverse effects. Pain relief, pain intensity, and side effects recorded over 6 hours.","limitations":"Study terminated early due to adverse event, limiting the total evidence base. Single-dose design cannot assess effects of repeated dosing. The dose-escalation design means treatment groups were not concurrent. The vasovagal event may or may not have been drug-related."},{"rthcId":"RTHC-00230","title":"The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells.","authors":"Holland, M L; Panetta, J A; Hoskins, J M; Bebawy, M; Roufogalis, B D; Allen, J D; Arnold, J C","year":2006,"journal":"Biochemical pharmacology, 71(8), 1146-54","doi":null,"pmid":"16458258","tags":["cancer","drug-interactions","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether cannabinoids affect P-glycoprotein (P-gp), a transporter that pumps anti-cancer drugs out of cancer cells and is a major cause of multidrug resistance.\n\nShort-term (1-hour) exposure to cannabinol, CBD, THC, and a synthetic cannabinoid did not inhibit P-gp drug efflux in either human leukemia cells or mouse cells with the MDR1 gene. This was different from the known P-gp inhibitor PSC833, which did block efflux.\n\nHowever, prolonged (72-hour) exposure to THC and CBD decreased P-gp protein expression in leukemia cells, similar to the flavonoid curcumin. This reduction in P-gp correlated with increased intracellular drug accumulation and enhanced sensitivity to vinblastine, an anti-cancer drug normally pumped out by P-gp.","whyItMatters":"Multidrug resistance is a major obstacle in cancer chemotherapy. If cannabinoids can reduce expression of the drug resistance transporter P-gp, they might enhance the effectiveness of conventional chemotherapy drugs when used in combination. This is a fundamentally different mechanism from any direct anti-cancer effect.","specificNumbers":"Short exposure (1h): no P-gp inhibition by any cannabinoid. Prolonged exposure (72h): THC and CBD decreased P-gp expression comparable to curcumin. Result: increased intracellular drug accumulation and enhanced vinblastine sensitivity.","methodology":"In vitro cell study using a drug-resistant human leukemia cell line (CEM/VLB100) and MDR1-transfected mouse fibroblasts. Short-term (1 hour) and prolonged (72 hour) cannabinoid exposures. P-gp function measured by Rhodamine 123 efflux. P-gp expression, drug accumulation, and vinblastine sensitivity assessed.","limitations":"In vitro cell line study. The concentrations and exposure times may not be achievable in patients. Only one drug-resistant cell line was tested in detail. The interaction between cannabinoids and chemotherapy drugs in vivo could be more complex than this simplified model suggests."},{"rthcId":"RTHC-00231","title":"Long-term effects of frequent cannabis use on working memory and attention: an fMRI study.","authors":"Jager, Gerry; Kahn, Rene S; Van Den Brink, Wim; Van Ree, Jan M; Ramsey, Nick F","year":2006,"journal":"Psychopharmacology, 185(3), 358-68","doi":null,"pmid":"16521034","tags":["cognition","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers used fMRI to compare 10 frequent cannabis users (after one week of abstinence) with 10 non-using controls matched for age, gender, and estimated IQ. Both groups performed verbal working memory and visuoauditory selective attention tasks during scanning.\n\nCannabis users performed equally well on both tasks and showed no differences in overall patterns of brain activity in the regions typically involved in these cognitive functions.\n\nHowever, a more specific region-of-interest analysis revealed that cannabis users displayed significantly altered brain activity in the left superior parietal cortex during working memory processing. The authors interpreted this as evidence that frequent cannabis use may affect brain function in subtle ways even when behavioral performance is intact.","whyItMatters":"This study focused on relatively moderate cannabis users rather than extremely heavy users, making it more relevant to typical recreational use patterns. The finding that performance and most brain activity was normal after one week of abstinence, with only subtle regional differences, suggests moderate use may have limited lasting cognitive impact.","specificNumbers":"10 cannabis users vs. 10 matched controls. 1 week abstinence. No behavioral differences on working memory or attention tasks. No overall brain activity pattern differences. Altered activity found in left superior parietal cortex during working memory.","methodology":"fMRI study comparing 10 frequent cannabis users (abstinent 1 week) and 10 matched non-using controls. Verbal working memory and visuoauditory selective attention tasks performed during scanning. Both whole-brain and region-of-interest analyses conducted.","limitations":"Very small sample size (10 per group) limits statistical power and generalizability. One week of abstinence may not be sufficient for full recovery. The definition of \"frequent but moderate\" use was not precisely quantified. Self-reported abstinence was not biologically verified."},{"rthcId":"RTHC-00232","title":"Illicit psychoactive substance use, abuse and dependence in a population-based sample of Norwegian twins.","authors":"Kendler, Kenneth S; Aggen, Steven H; Tambs, Kristian; Reichborn-Kjennerud, Ted","year":2006,"journal":"Psychological medicine, 36(7), 955-62","doi":null,"pmid":"16650346","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers assessed lifetime use, abuse, and dependence across five illicit drug categories (cannabis, stimulants, opiates, cocaine, psychedelics) in 1,386 young adult Norwegian twin pairs. Only 6.4% reported significant lifetime use (10+ times) of any illicit substance, reflecting Norway's low drug use prevalence.\n\nDespite the low prevalence, twin model fitting consistently found that resemblance between twins was due largely or entirely to genetic factors rather than shared environment. Best-fit models included only genetic and individual-specific environmental effects, with heritability estimates ranging from 58% to 81% across all analyses.\n\nMeaningful abuse/dependence analyses were only possible for cannabis and for any substance combined, as too few twins met criteria for individual substance dependence diagnoses. The genetic findings replicated results previously reported from the US and Australia.","whyItMatters":"Replicating the heritability of drug use in Norway, a country with very different drug policies and much lower prevalence than the US or Australia, strengthens the conclusion that genetic vulnerability is a robust finding across cultural and legal contexts, not an artifact of specific social environments.","specificNumbers":"1,386 twin pairs studied. Only 6.4% reported significant lifetime illicit drug use (10+ times). Heritability estimates: 58-81% across analyses. Best-fit models: genetic + individual environmental factors only (no shared environmental contribution). Replicated US and Australian findings.","methodology":"Twin study of 1,386 complete young adult twin pairs from the Norwegian Institute of Public Health Twin Panel. Personal interviews assessed lifetime use, DSM-IV abuse/dependence symptoms and diagnoses for five drug categories. Twin model fitting using Mx statistical package compared genetic, shared environmental, and individual environmental contributions.","limitations":"The low prevalence of drug use in Norway limited statistical power, particularly for individual substance dependence analyses. Twin studies assume equal environments for identical and fraternal twins. The young adult age of the sample means some participants may not yet have developed substance problems."},{"rthcId":"RTHC-00233","title":"Cannabinoid-induced immune suppression and modulation of antigen-presenting cells.","authors":"Klein, Thomas W; Cabral, Guy A","year":2006,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 1(1), 50-64","doi":null,"pmid":"18040791","tags":["inflammation","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how the endocannabinoid system, originally discovered through neuroscience research, also regulates immune function. Studies showed that cannabinoid-based drugs suppress many cellular and cytokine mechanisms in the immune system.\n\nThe review focused particularly on effects on antigen-presenting cells, which are critical for initiating immune responses. Cannabinoids affected these cells' ability to present foreign molecules to T cells, potentially dampening the immune cascade at its earliest stage.\n\nThe breadth of immunosuppressive effects led to the hypothesis that cannabinoid-based drugs could be valuable for managing chronic inflammatory diseases, where overactive immune responses cause tissue damage.","whyItMatters":"Antigen-presenting cells are the gatekeepers of immune responses. Finding that cannabinoids can modulate these cells suggests a mechanism for broad immunosuppressive effects that could be therapeutically useful in autoimmune and chronic inflammatory conditions.","specificNumbers":"Two receptor types: CB1 (brain, most abundant G protein-coupled receptor) and CB2 (mainly immune cells). Cannabinoids affect antigen-presenting cell function and cytokine production.","methodology":"Review of cannabinoid ligand and receptor biology, immune suppression mechanisms with emphasis on antigen-presenting cells, and preclinical and clinical models of cannabinoid-based drug therapeutic potential.","limitations":"Much evidence from animal and cell studies. The balance between therapeutic immunosuppression and harmful immune compromise is not well defined. The review does not provide clinical trial evidence for treating specific inflammatory conditions."},{"rthcId":"RTHC-00234","title":"The cannabinergic system as a target for anti-inflammatory therapies.","authors":"Lu, Dai; Vemuri, V Kiran; Duclos, Richard I; Makriyannis, Alexandros","year":2006,"journal":"Current topics in medicinal chemistry, 6(13), 1401-26","doi":null,"pmid":"16918457","tags":["inflammation","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how modulating the endocannabinoid system affects immune function. Research demonstrated that regulating endocannabinoid signaling can impact virtually every major function of the immune system.\n\nNumerous novel molecules targeting the endocannabinoid system were tested for immune effects, and results suggested therapeutic potential for multiple inflammatory conditions: multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, allergic asthma, and autoimmune diabetes.\n\nThe breadth of conditions reflects the widespread distribution of cannabinoid receptors across immune and inflammatory tissues. The development of new synthetic compounds expanded the toolkit beyond plant-derived cannabinoids.","whyItMatters":"The range of inflammatory conditions potentially treatable through endocannabinoid modulation is remarkably broad. This review helped establish the endocannabinoid system as a major therapeutic target in inflammation research, not just an aspect of recreational drug pharmacology.","specificNumbers":"Diseases with therapeutic potential identified: multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, allergic asthma, autoimmune diabetes. Novel synthetic compounds expanded the pharmacological toolkit.","methodology":"Review of cell-based experiments and in vivo animal testing examining the effects of endocannabinoid system modulation on immune function. Covered novel synthetic compounds alongside plant-derived cannabinoids and their effects on inflammatory disease models.","limitations":"Evidence primarily from cell and animal studies. Clinical translation for most conditions discussed remained distant. The review does not distinguish between the strength of evidence for different conditions. Systemic effects of endocannabinoid modulation may limit clinical utility."},{"rthcId":"RTHC-00235","title":"Targeting the CB2 receptor for immune modulation.","authors":"Lunn, Charles A; Reich, Eva-Pia; Bober, Loretta","year":2006,"journal":"Expert opinion on therapeutic targets, 10(5), 653-63","doi":null,"pmid":"16981823","tags":["inflammation","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined the CB2 cannabinoid receptor's role in immune regulation. Unlike CB1, which is primarily in the brain and mediates psychoactive effects, CB2 is associated with immune cells. Researchers sought to develop CB2-specific compounds that could provide immunomodulatory benefits without marijuana's psychoactive effects.\n\nThe review focused on CB2's role in regulating immune cell recruitment, the process by which immune cells are directed to sites of inflammation. This function is central to inflammatory diseases where excessive immune cell recruitment causes tissue damage.\n\nEvidence was highlighted for CB2-specific effects in experimental autoimmune encephalomyelitis (an animal model of MS) and in influencing bone density, adding skeletal health to the list of potential CB2-mediated therapeutic targets.","whyItMatters":"The CB2 receptor represents one of the most promising paths to cannabis-derived medicines without psychoactive effects. By targeting CB2 on immune cells rather than CB1 in the brain, treatments could modulate immune responses while leaving brain function unaffected.","specificNumbers":"CB2 receptor primarily on immune cells. Involved in immune cell recruitment regulation. Evidence in experimental autoimmune encephalomyelitis model and bone density regulation.","methodology":"Review of CB2 receptor biology with emphasis on immune cell recruitment regulation. Examined CB2-specific compound effects in autoimmune disease models and bone metabolism.","limitations":"Evidence primarily preclinical. CB2 selectivity of tested compounds varied. The assumption that CB2 activation avoids all psychoactive effects may be oversimplified, as emerging evidence suggests CB2 may have some brain effects. The review is more of a rationale than a comprehensive evidence evaluation."},{"rthcId":"RTHC-00236","title":"A validation of event-related FMRI comparisons between users of cocaine, nicotine, or cannabis and control subjects.","authors":"Murphy, Kevin; Dixon, Veronica; LaGrave, Kathleen; Kaufman, Jacqueline; Risinger, Robert; Bloom, Alan; Garavan, Hugh","year":2006,"journal":"The American journal of psychiatry, 163(7), 1245-51","doi":null,"pmid":"16816231","tags":["neuroscience","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"A critical concern in brain imaging research on drug users is whether drugs' effects on blood vessels could alter the fMRI signal, making comparisons with non-users unreliable. This study directly tested this concern.\n\nCocaine, nicotine, and cannabis users along with control subjects performed a simple finger-tapping task during fMRI scanning. Activation measures did not differ between any of the groups using two different analytical methods. The shape of the hemodynamic response was also identical across groups.\n\nAdditionally, comparing cocaine users during intravenous saline versus intravenous cocaine conditions showed no difference in the basic brain response, further confirming that acute drug effects do not corrupt the fMRI measurement.","whyItMatters":"This methodological validation is foundational for the entire field of addiction neuroimaging. By demonstrating that drug use does not alter the basic fMRI signal, it means that activation differences reported between drug users and controls in other studies can be confidently attributed to actual brain function differences rather than measurement artifacts.","specificNumbers":"Four groups compared: cocaine, nicotine, cannabis users, and controls. Two analytical methods tested. No group differences in activation measures. No hemodynamic response shape differences. Saline vs. cocaine comparison in cocaine users: null result.","methodology":"Event-related fMRI study comparing four groups (cocaine users, nicotine users, cannabis users, controls) performing a simple finger-tapping task. Two analytical methods used. Hemodynamic response shape compared across groups. Additional within-subject comparison of saline vs. cocaine conditions in cocaine users.","limitations":"Only one simple task was tested (finger-tapping). More complex cognitive tasks might reveal different patterns. The study only assessed basic hemodynamic response validity, not all possible confounds. Sample sizes for each group were not reported in the abstract."},{"rthcId":"RTHC-00237","title":"Results of hair analyses for drugs of abuse and comparison with self-reports and urine tests.","authors":"Musshoff, F; Driever, F; Lachenmeier, K; Lachenmeier, D W; Banger, M; Madea, B","year":2006,"journal":"Forensic science international, 156(2-3), 118-23","doi":null,"pmid":"16410161","tags":["addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared self-reported drug use with urine immunoassay and hair analysis by GC-MS in a group of drug abusers. Self-reports indicated opiate abuse most commonly (89%), followed by cannabis (55%), cocaine (38%), and methadone (32%).\n\nExcept for opiates, the correlation between self-reported use and urine analysis at admission was low. Hair tests revealed drug consumption in more cases than either self-report or urine, demonstrating the longer detection window of hair analysis.\n\nCocaine hair testing was particularly effective, identifying past use even when urine tests were negative. However, hair lacked sensitivity for cannabis detection. Reliable cannabis identification through hair required detecting the metabolite THC carboxylic acid at very low concentrations (lower picogram range), which is technically challenging.","whyItMatters":"The finding that drug use is \"dramatically underreported\" has implications for all drug research relying on self-report data. The differential sensitivity of hair testing across substances (excellent for cocaine, poor for cannabis) is important for forensic and clinical applications.","specificNumbers":"Self-reported use: opiates 89%, cannabis 55%, cocaine 38%, methadone 32%. Hair tests detected more use than urine or self-report. Cocaine hair testing highly sensitive/specific even with negative urine. Cannabis hair testing less sensitive; requires THC-COOH detection in lower picogram range.","methodology":"Cross-sectional comparison of three drug detection methods in drug abuse patients: self-reported interview data, urine immunoassay screening, and hair analysis by gas chromatography-mass spectrometry. Tested for opiates, cocaine, amphetamines, methadone, and cannabinoids.","limitations":"Study population was known drug abusers, limiting generalizability to general population drug testing. Hair testing sensitivity varies with hair type, color, and cosmetic treatments. The comparison between detection methods is complicated by their different detection windows."},{"rthcId":"RTHC-00238","title":"Post-traumatic stress disorder, survivor guilt and substance use--a study of hospitalised Nigerian army veterans.","authors":"Okulate, G T; Jones, O B E","year":2006,"journal":"South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 96(2), 144-6","doi":null,"pmid":"16532084","tags":["ptsd","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers assessed hospitalized Nigerian army veterans evacuated from peacekeeping operations in Liberia and Sierra Leone (1990-1994). The prevalence of PTSD was 22%, and survivor guilt was found in 38% of respondents.\n\nPTSD was significantly associated with long duration of stay in the mission area, current alcohol use, lifetime use of an alcohol/gunpowder mixture (a local practice), and lifetime cannabis use. Survivor guilt was associated with avoidance of trauma-related stimuli but not with duration of combat exposure.\n\nThe authors concluded that PTSD might be common but undetected among Nigerian military personnel, and recommended deliberate screening and primary prevention efforts regarding alcohol and cannabis use.","whyItMatters":"This study documented PTSD and substance use in a military population rarely studied in the research literature. The association between PTSD and cannabis use in Nigerian veterans parallels findings in Western military populations, suggesting the PTSD-substance use relationship crosses cultural boundaries.","specificNumbers":"PTSD prevalence: 22%. Survivor guilt: 38%. PTSD significantly associated with: long deployment, current alcohol use, alcohol/gunpowder mixture use, lifetime cannabis use.","methodology":"Cross-sectional study of hospitalized patients from military operations at the 68 Nigerian Army Reference Hospital, Lagos. Socio-demographic questionnaire, PTSD checklist, and WHO substance use survey instrument administered to all physically capable patients over a 4-year period.","limitations":"Cross-sectional design cannot determine whether cannabis use preceded or followed PTSD development. The hospitalized sample may not represent all veterans. The specific military context (peacekeeping operations) and cultural context (Nigeria) may limit generalizability. Assessment was over a broad 4-year period."},{"rthcId":"RTHC-00239","title":"The emerging role of the endocannabinoid system in endocrine regulation and energy balance.","authors":"Pagotto, Uberto; Marsicano, Giovanni; Cota, Daniela; Lutz, Beat; Pasquali, Renato","year":2006,"journal":"Endocrine reviews, 27(1), 73-100","doi":null,"pmid":"16306385","tags":["appetite","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review published in Endocrine Reviews detailed the endocannabinoid system's emerging role in regulating hormonal function. CB1 receptors in the hypothalamus and pituitary gland modulate all endocrine axes.\n\nThe system influences the stress response through the hypothalamic-pituitary-adrenal (HPA) axis and controls reproductive function by modifying gonadotropin release, fertility, and sexual behavior.\n\nRegarding energy balance, the endocannabinoid system operates through multiple modes: controlling the rewarding properties of food via mesolimbic brain areas, regulating appetite through hypothalamic circuits, and acting directly on peripheral tissues. In adipocytes (fat cells), CB1 activation stimulates lipogenesis. In genetically obese animals, the endocannabinoid system shows chronic overactivation that may help maintain obesity.","whyItMatters":"Published in a premier endocrinology journal, this review established the endocannabinoid system as a fundamental part of hormonal regulation, not just a receptor for recreational drugs. This reframing was important for legitimizing cannabinoid research within the endocrinology community.","specificNumbers":"CB1 present in hypothalamus and pituitary. System modulates: all endocrine axes, HPA stress axis, gonadotropin release, fertility, sexual behavior. Energy balance via: mesolimbic reward, hypothalamic appetite, peripheral metabolism (adipocytes, hepatocytes, GI tract, skeletal muscle).","methodology":"Comprehensive review published in Endocrine Reviews covering the endocannabinoid system's role in endocrine regulation across the HPA axis, reproductive axis, and metabolic function. Integrated evidence from molecular biology, animal models, and emerging clinical data.","limitations":"The breadth of the review means individual topics could not be covered in great depth. Much evidence was from animal studies. The review was published during the early enthusiasm for rimonabant, before its psychiatric side effects became apparent."},{"rthcId":"RTHC-00240","title":"Combined cannabinoid therapy via an oromucosal spray.","authors":"Perez, Jordi","year":2006,"journal":"Drugs of today (Barcelona, Spain : 1998), 42(8), 495-503","doi":null,"pmid":"16969427","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered the clinical development of Sativex as a combined cannabinoid medicine (THC and CBD) delivered via oromucosal spray. The spray delivery system was designed to maintain therapeutic levels while minimizing psychoactive effects.\n\nSativex had been shown to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical trials demonstrated efficacy across a range of conditions: intractable chronic neuropathic pain, brachial plexus nerve injury pain, allodynic peripheral neuropathic pain, advanced cancer pain, rheumatoid arthritis, and MS symptoms (bladder problems, spasticity, central pain).\n\nNotably, trials reported no significant intoxication-like symptoms, no development of tolerance, and no withdrawal syndrome upon discontinuation.","whyItMatters":"The absence of tolerance, withdrawal, and significant intoxication addressed three major concerns about cannabis-based medicines. If patients can use a cannabinoid medicine long-term without needing escalating doses or experiencing withdrawal when stopping, it makes the treatment more practical and reduces concerns about dependence.","specificNumbers":"Conditions with demonstrated efficacy: intractable neuropathic pain, brachial plexus injury pain, allodynic neuropathic pain, advanced cancer pain, rheumatoid arthritis, MS bladder problems, MS spasticity, MS central pain. No significant intoxication, tolerance, or withdrawal reported.","methodology":"Clinical review of Sativex development program covering pharmacology, delivery system, healthy volunteer studies, and clinical trials across multiple pain and neurological conditions.","limitations":"This review was written from a perspective favorable to the product. Individual trials for some conditions had small sample sizes. The absence of tolerance and withdrawal may partly reflect the relatively short duration of most trials. The optimistic framing may not capture all safety concerns."},{"rthcId":"RTHC-00241","title":"Brain neuroimaging in cannabis use: a review.","authors":"Quickfall, Jeremy; Crockford, David","year":2006,"journal":"The Journal of neuropsychiatry and clinical neurosciences, 18(3), 318-32","doi":null,"pmid":"16963581","tags":["neuroscience","cognition"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This systematic review examined both structural and functional neuroimaging studies of cannabis use. The key finding was a disconnect between structure and function: structural abnormalities generally have not been identified with chronic cannabis use.\n\nFunctionally, regular users show reciprocal changes in brain activity globally and in cerebellar and frontal regions. Abstinence results in decreased brain activity, while cannabis administration increases activity in correlation with subjective intoxication.\n\nDuring cognitive tasks, chronic use and acute cannabis administration result in either attenuated brain activity in task-relevant regions or activation of compensatory regions, suggesting the brain adapts to maintain performance. Findings partially correlate with neuropsychological data.","whyItMatters":"The absence of consistent structural brain damage despite functional changes is an important finding. It suggests cannabis affects how the brain works rather than its physical structure, which has implications for the reversibility of cannabis-related cognitive effects.","specificNumbers":"No consistent structural abnormalities identified. Functional changes found in cerebellar and frontal regions. Brain activity correlates with intoxication levels. Compensatory activation observed during cognitive tasks.","methodology":"Systematic review of structural and functional neuroimaging studies of cannabis use. Covered both MRI/CT structural studies and fMRI/PET functional studies. Evaluated findings during both intoxication and abstinence.","limitations":"Generalization was limited by the lack of diagnostic criteria use, inconsistent neuropsychological testing pairing, and poor quantification of cannabis use and abstinence across studies. Study quality and methodology varied widely."},{"rthcId":"RTHC-00242","title":"Cognition and motor control as a function of Delta9-THC concentration in serum and oral fluid: limits of impairment.","authors":"Ramaekers, J G; Moeller, M R; van Ruitenbeek, P; Theunissen, E L; Schneider, E; Kauert, G","year":2006,"journal":"Drug and alcohol dependence, 85(2), 114-22","doi":null,"pmid":"16723194","tags":["driving","cognition","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Twenty recreational cannabis users participated in a double-blind, placebo-controlled, three-way crossover study with single doses of 0, 250, and 500 micrograms/kg THC by smoking. Performance tests measuring driving-related skills were conducted from 15 minutes to 6 hours post-smoking.\n\nTHC concentrations in serum and oral fluid showed a strong linear relationship. However, the linear relationship between THC concentration and performance impairment was weak, meaning blood levels alone poorly predicted the degree of impairment.\n\nA more useful approach emerged from examining the proportion of observations showing impairment at each THC level. Initial significant impairment appeared at 2-5 ng/ml serum THC. At 5-10 ng/ml, 75-90% of observations showed significant impairment. Above 30 ng/ml, 100% of observations showed significant impairment in every test.","whyItMatters":"This study directly addressed one of the most important practical questions in cannabis policy: at what blood THC concentration does impairment begin? The finding of a 2-5 ng/ml threshold has been influential in establishing legal per se limits for drug-impaired driving in several jurisdictions.","specificNumbers":"20 participants. Doses: 0, 250, 500 micrograms/kg THC. Impairment threshold: 2-5 ng/ml serum THC. 75-90% impaired at 5-10 ng/ml. 100% impaired above 30 ng/ml. Strong linear relationship between serum and oral fluid THC. Weak linear relationship between THC and impairment magnitude.","methodology":"Double-blind, placebo-controlled, three-way crossover study. 20 recreational cannabis users. Single doses of 0, 250, and 500 micrograms/kg THC by smoking. Tests: Critical tracking task (perceptual-motor control), Stop signal task (motor impulsivity), Tower of London (cognitive function). Blood and oral fluid collected throughout.","limitations":"Only 20 participants, all recreational users (tolerance may affect results). Only smoked cannabis tested. Only three cognitive tasks used, which may not capture all driving-relevant skills. Laboratory setting does not replicate actual driving conditions."},{"rthcId":"RTHC-00243","title":"The acute effects of cannabinoids on memory in humans: a review.","authors":"Ranganathan, Mohini; D'Souza, Deepak Cyril","year":2006,"journal":"Psychopharmacology, 188(4), 425-44","doi":null,"pmid":"17019571","tags":["cognition","neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This comprehensive review of human studies found that acute THC administration impairs immediate and delayed free recall of information presented after drug administration but does not affect recall of information learned before THC was given.\n\nThe effects are dose-dependent and delay-dependent, with greater impairment at higher doses and longer delays. THC particularly increases intrusion errors (recalling items that were not actually presented). The effects are most robust with inhaled and intravenous routes and correspond to peak drug levels.\n\nThe profile of effects suggests THC impairs all stages of memory: encoding (getting information in), consolidation (storing it), and retrieval (getting it out). Multiple mechanisms are involved, including effects on long-term potentiation/depression and inhibition of GABA, glutamate, acetylcholine, and dopamine release.","whyItMatters":"The finding that THC impairs memory for new information but not previously learned information has practical implications: using cannabis does not erase existing memories but makes it harder to form new ones. The dose-dependence means the effect scales with how much is consumed.","specificNumbers":"Memory impairment is dose-dependent, delay-dependent, and route-dependent. Inhaled and IV routes produce strongest effects. Impairment corresponds to peak drug levels. Intrusion errors particularly increased. All memory stages affected: encoding, consolidation, retrieval.","methodology":"Comprehensive review of human studies on acute cannabinoid effects on memory. Covered dose-response relationships, route of administration effects, timing parameters, and multiple memory domains. Discussed human findings against preclinical research.","limitations":"The review noted significant methodological issues across studies: inconsistent doses, variable routes of administration, small sample sizes, poor selection criteria, uncontrolled other drug use, tolerance effects, and varying test sensitivity. An expanding gap between human and preclinical literature was identified."},{"rthcId":"RTHC-00244","title":"A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol.","authors":"Russo, Ethan; Guy, Geoffrey W","year":2006,"journal":"Medical hypotheses, 66(2), 234-46","doi":null,"pmid":"16209908","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This review synthesized clinical evidence on why combining CBD with THC produces better therapeutic outcomes than using either cannabinoid alone. The authors argued that CBD acts as a functional antagonist to several of THC's unwanted side effects.\n\nSpecifically, CBD appeared to reduce THC-induced intoxication, sedation, and rapid heart rate (tachycardia). At the same time, the combination maintained or enhanced therapeutic effects for conditions including spasticity, pain, and symptoms of multiple sclerosis and cancer-related pain.\n\nThe authors proposed that cannabis-based medicines should be formulated with both cannabinoids to optimize the balance between efficacy and tolerability, an approach already reflected in the drug Sativex (nabiximols), which uses a roughly 1:1 THC:CBD ratio.","whyItMatters":"This paper helped establish the scientific rationale for why whole-plant cannabis extracts or balanced THC:CBD formulations might be preferable to pure THC products. It influenced how researchers and clinicians think about cannabinoid medicine design and contributed to the concept of the entourage effect.","specificNumbers":"CBD counteracted THC side effects including intoxication, sedation, and tachycardia. Therapeutic benefits were demonstrated for spasticity, neuropathic pain, cancer pain, and MS symptoms. Sativex uses an approximately 1:1 THC:CBD ratio.","methodology":"This was a narrative review examining preclinical and clinical data on THC and CBD interactions. The authors compiled evidence from multiple studies on conditions including spasticity, neuropathic pain, cancer pain, and multiple sclerosis to build the case for combined cannabinoid therapy.","limitations":"As a narrative review, this paper selectively compiled evidence to support its hypothesis. The clinical studies cited varied in quality and sample size. The optimal THC:CBD ratio likely differs by condition, and the review did not systematically address this variability."},{"rthcId":"RTHC-00245","title":"Cannabis and sport.","authors":"Saugy, M; Avois, L; Saudan, C; Robinson, N; Giroud, C; Mangin, P; Dvorak, J","year":2006,"journal":"British journal of sports medicine, 40 Suppl 1(Suppl 1), i13-5","doi":null,"pmid":"16799094","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This review examined the rationale behind cannabis prohibition in competitive sports and the practical challenges of enforcing that ban. The authors found no scientific evidence that cannabis enhances athletic performance.\n\nDespite the lack of ergogenic effects, cannabis remained on the World Anti-Doping Agency's prohibited list based on other criteria, including the argument that it violates the spirit of sport and poses health risks to athletes.\n\nA major practical challenge was THC's unusually long excretion time. Because THC is fat-soluble and stores in body tissue, it can be detected in urine for days or weeks after use, long after any psychoactive effects have worn off. This made it difficult to distinguish recent use from past use and raised fairness questions about testing thresholds.","whyItMatters":"The disconnect between cannabis's lack of performance-enhancing effects and its continued prohibition in sports reflects broader debates about drug policy. The detection challenges highlighted here remain relevant as more jurisdictions legalize cannabis and athletes advocate for policy reform.","specificNumbers":"No proven performance enhancement was identified. THC's fat-soluble nature causes protracted excretion times that complicate drug testing interpretation.","methodology":"This was a narrative review published in a sports medicine journal. The authors surveyed the scientific literature on cannabis and athletic performance, examined anti-doping policies, and analyzed the pharmacokinetic properties of THC that complicate detection and testing.","limitations":"The review was published in 2006, before many jurisdictions legalized cannabis and before WADA raised its urinary THC threshold in 2013. Limited research existed on cannabis effects during athletic performance specifically. The review did not address potential recovery or anti-anxiety benefits some athletes report."},{"rthcId":"RTHC-00246","title":"Effects of prenatal marijuana on visuospatial working memory: an fMRI study in young adults.","authors":"Smith, Andra M; Fried, Peter A; Hogan, Matthew J; Cameron, Ian","year":2006,"journal":"Neurotoxicology and teratology, 28(2), 286-95","doi":null,"pmid":"16473495","tags":["pregnancy","cognition","neuroscience","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers scanned 31 participants from the Ottawa Prenatal Prospective Study (16 prenatally exposed to cannabis, 15 non-exposed) at age 18-22 using fMRI during a visuospatial working memory task. This longitudinal study had tracked participants for over 20 years, providing detailed prenatal drug history and controlling for other exposures.\n\nPerformance on the memory task did not significantly differ between exposed and non-exposed groups. However, as the amount of prenatal marijuana exposure increased, there was significantly more neural activity in the left inferior and middle frontal gyri, left parahippocampal gyrus, left middle occipital gyrus, and left cerebellum, and significantly less activity in right inferior and middle frontal gyri.\n\nThe pattern suggests prenatal exposure alters the neural circuits used during memory processing in adulthood, even when behavioral performance appears intact.","whyItMatters":"This is one of the few studies to examine prenatal cannabis exposure effects into young adulthood using brain imaging. The finding that neural functioning is altered 18-22 years after prenatal exposure, even without behavioral deficits, suggests long-lasting effects on brain development that may become apparent under more demanding conditions.","specificNumbers":"31 participants from OPPS (16 exposed, 15 non-exposed). Age 18-22. 20+ years of longitudinal data. No performance differences. Increased left-hemisphere activation and decreased right-hemisphere activation associated with more prenatal exposure.","methodology":"Longitudinal cohort study from the Ottawa Prenatal Prospective Study (OPPS). 31 participants (16 prenatally exposed, 15 non-exposed) aged 18-22. fMRI during visuospatial 2-back working memory task. Multiple regression analyses controlled for potentially confounding drug exposure variables using 20 years of collected data.","limitations":"Small sample size (31 participants). Cannot rule out all confounding factors despite extensive controls. The 2-back task may not be challenging enough to reveal behavioral deficits. Prenatal exposure was self-reported by mothers. Results may not generalize to all levels of prenatal exposure."},{"rthcId":"RTHC-00247","title":"Cannabis and neurodevelopment: implications for psychiatric disorders.","authors":"Sundram, Suresh","year":2006,"journal":"Human psychopharmacology, 21(4), 245-54","doi":null,"pmid":"16783814","tags":["neuroscience","youth","pregnancy","sex-differences"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Across human observational studies, prenatal exposure through maternal use was associated with small, domain-specific cognitive differences later in life, especially visuospatial skills, along with higher rates of impulsivity, inattention, hyperactivity, depressive symptoms, and substance use disorders. Adolescent use was linked to longer-term difficulties in cognition and mood, elevated risk of schizophrenia, and higher odds of later substance use disorders.\n\nAnimal work mapped out potential mechanisms rather than real-world behavior. Perinatal cannabinoid exposure in animal models altered motor control systems, neuroendocrine function, and nociception. Fetal and early-life exposure was reported to affect the development of dopamine and opioid neurotransmitter systems, offering biological pathways that could help explain human associations.\n\nSex-specific patterns appeared in both human and animal studies, suggesting interactions between cannabinoids and sex hormones during neurodevelopment.","whyItMatters":"Debates about cannabis and youth often hinge on whether the developing brain is uniquely sensitive. This review helped shape that conversation by organizing early evidence that linked exposure in pregnancy and adolescence to later cognitive and psychiatric outcomes, while also pointing to biological systems in development that cannabinoids could influence.","specificNumbers":"- Publication year: 2006, an early synthesis before widespread legalization and high-potency retail markets\n- Developmental windows covered: 2 (perinatal, adolescence)\n- Human outcomes associated with exposure: visuospatial cognitive deficits, impulsivity/inattention/hyperactivity, depressive symptoms, schizophrenia, substance use disorders\n- Animal domains affected: motor control, neuroendocrine function, nociception","methodology":"This was a narrative review published in 2006 summarizing human observational and animal experimental studies on cannabis exposure during two windows: the perinatal period and adolescence. Human evidence largely came from cohort and cross-sectional designs that measured maternal use during pregnancy or self-reported adolescent use and then assessed later cognitive and psychiatric outcomes. Animal studies investigated how early cannabinoid exposure altered neural development and physiology. No pooled effect sizes or trial counts were reported in the abstract, and sample sizes for included studies were not specified.","limitations":"This was a narrative review without a formal systematic search or meta-analysis. Human findings were mostly observational and vulnerable to confounding by factors such as tobacco and alcohol co-use, socioeconomic context, and family history. Exposure measurement often relied on self-report with limited detail on dose, potency, or timing. Animal results cannot be assumed to predict human behavior. Effect sizes, sample sizes, and study quality assessments were not reported in the abstract, making it hard to judge the magnitude or reliability of specific associations. The evidence base reflects studies available up to 2006, before current high-potency products and widespread vaping."},{"rthcId":"RTHC-00248","title":"Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study.","authors":"Tomida, Ileana; Azuara-Blanco, Augusto; House, Heather; Flint, Maggie; Pertwee, Roger G; Robson, Philip J","year":2006,"journal":"Journal of glaucoma, 15(5), 349-53","doi":null,"pmid":"16988594","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Six patients with ocular hypertension or early primary open angle glaucoma received single sublingual doses of 5 mg THC, 20 mg CBD, 40 mg CBD, or placebo in a randomized, double-masked crossover design.\n\nTwo hours after THC administration, intraocular pressure (IOP) was significantly lower than after placebo (23.5 mmHg vs. 27.3 mmHg, P = 0.026). The effect was temporary, returning to baseline by 4 hours.\n\nCBD at 20 mg did not reduce IOP at any time point. The higher CBD dose (40 mg) actually produced a transient elevation of IOP at 4 hours (from 23.2 to 25.9 mmHg, P = 0.028). One patient experienced a transient mild panic reaction after THC administration.","whyItMatters":"This study clarified that while THC can lower eye pressure, its effect is brief (about 2 hours). More importantly, it showed CBD does not share this property and may actually raise eye pressure at higher doses, cautioning against assuming all cannabinoids help with glaucoma.","specificNumbers":"6 patients. THC 5 mg: IOP reduced from 27.3 to 23.5 mmHg (P = 0.026). Effect lasted about 2 hours. CBD 20 mg: no effect. CBD 40 mg: transient IOP increase at 4 hours (P = 0.028). 1 patient had mild panic reaction with THC.","methodology":"Randomized, double-masked, placebo-controlled, 4-way crossover study at a single center. Six patients received sublingual doses of 5 mg THC, 20 mg CBD, 40 mg CBD, or placebo. IOP measured as primary outcome. Visual acuity, vital signs, and psychotropic effects monitored.","limitations":"Very small sample (6 patients). Single-dose study cannot assess tolerance or sustained effects. The crossover design with only one dose level per cannabinoid limits dose-response analysis. Sublingual delivery may not achieve optimal bioavailability."},{"rthcId":"RTHC-00249","title":"Unheated Cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways.","authors":"Verhoeckx, Kitty C M; Korthout, Henrie A A J; van Meeteren-Kreikamp, A P; Ehlert, Karl A; Wang, Mei; van der Greef, Jan; Rodenburg, Richard J T; Witkamp, Renger F","year":2006,"journal":"International immunopharmacology, 6(4), 656-65","doi":null,"pmid":"16504929","tags":["inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers compared the immune effects of unheated (raw) cannabis extract, containing primarily THCa (tetrahydrocannabinoid acid), with heated cannabis extract, which converts THCa to the psychoactive THC.\n\nBoth unheated extract and purified THCa inhibited TNF-alpha production from stimulated macrophages in a dose-dependent manner. However, the effects differed from THC in a critical way: THCa inhibition persisted over longer exposure periods, whereas prolonged THC exposure actually induced TNF-alpha production.\n\nTHCa and THC also had opposite effects on the enzyme PC-PLC: THCa inhibited it dose-dependently while THC induced it at high concentrations. These results suggest THCa and THC exert their immunomodulatory effects through different metabolic pathways, and the effects are not mediated through CB1 and CB2 receptors.","whyItMatters":"This study challenges the assumption that decarboxylation (heating cannabis to convert THCa to THC) is necessary for therapeutic effects. Raw cannabis acid has distinct anti-inflammatory properties that may be useful without the psychoactive effects of THC.","specificNumbers":"THCa inhibited TNF-alpha dose-dependently. THC inhibited TNF-alpha initially but induced it with prolonged exposure. THCa inhibited PC-PLC activity. THC induced PC-PLC activity at high concentrations. Effects not mediated by CB1/CB2 receptors.","methodology":"In vitro cell study using U937 macrophages and peripheral blood macrophages. Compared unheated cannabis extract (THCa-rich), heated extract (THC-rich), purified THCa, and purified THC. Measured TNF-alpha production after LPS stimulation and PC-PLC enzyme activity.","limitations":"In vitro cell study only. THCa bioavailability and metabolism in living organisms may differ from cell culture conditions. The non-CB1/CB2 receptor mechanism was suggested but not fully characterized. Only one inflammatory marker (TNF-alpha) and one enzyme (PC-PLC) were studied."},{"rthcId":"RTHC-00250","title":"Nicotine and cannabinoids: parallels, contrasts and interactions.","authors":"Viveros, Maria-Paz; Marco, Eva M; File, Sandra E","year":2006,"journal":"Neuroscience and biobehavioral reviews, 30(8), 1161-81","doi":null,"pmid":"17049986","tags":["addiction","youth","cognition","anxiety","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the pharmacological interactions between nicotine and cannabis, two drugs increasingly used in combination, especially by adolescents and young adults.\n\nAnimal studies suggested that the reinforcing effects of both drugs may be enhanced by joint consumption. Anxiety-reducing effects may also be amplified when used together, which could be particularly appealing to adolescent girls.\n\nHowever, the two drugs have contrasting effects in other domains: cannabis increases appetite while nicotine suppresses it; cannabis impairs cognition while nicotine may enhance certain cognitive functions. The review highlighted the adolescent period as requiring urgent further investigation, with sex differences emerging as an important variable.","whyItMatters":"Cannabis and tobacco are frequently co-used, often mixed together in joints. Understanding their pharmacological interactions is critical because enhanced reinforcement from combining them could accelerate addiction to both substances, particularly during the vulnerable adolescent period.","specificNumbers":"Two of the most widely used drugs of dependence. Increasingly combined, particularly among adolescents. Animal studies suggest enhanced reinforcement and anxiolytic effects from co-use. Opposite effects on appetite and cognition.","methodology":"Comprehensive narrative review examining nicotine and cannabinoid system interactions. Covered addiction processes, gateway theories, adolescent effects, anxiety, food intake, and cognition. Drew on animal behavioral studies, human observational data, and pharmacological evidence.","limitations":"Much evidence from animal studies that may not directly translate to human use patterns. The review identifies concerns about adolescent co-use but notes the area is \"in urgent need of further investigation.\" Sex differences are emerging but not well characterized."},{"rthcId":"RTHC-00251","title":"Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis.","authors":"Wade, D T; Makela, P M; House, H; Bateman, C; Robson, P","year":2006,"journal":"Multiple sclerosis (Houndmills, Basingstoke, England), 12(5), 639-45","doi":null,"pmid":"17086911","tags":["medical-cannabis","cbd","withdrawal"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Following a 10-week placebo-controlled study, 137 MS patients entered this open-label trial and used Sativex for an average of 434 days (range 21-814 days). The improvements and dosage established during the initial study remained stable throughout long-term use, suggesting no development of tolerance.\n\nFifty-eight patients (42.3%) withdrew over the study period: 24 for lack of efficacy, 17 for adverse events, and the rest for other reasons. Of 292 reported unwanted effects, 86% were mild to moderate, most commonly oral pain, dizziness, diarrhea, and nausea. Four patients experienced first-ever seizures.\n\nA planned sudden 2-week interruption of Sativex in 25 patients (of 62 approached) did not produce a consistent withdrawal syndrome, although 46% reported at least one symptom (tiredness, sleep interruption, mood changes, reduced appetite). Twenty-two of 25 (88%) restarted Sativex after the interruption.","whyItMatters":"Long-term cannabis-based medicine use data is critical for clinical decision-making. The finding that benefits were maintained without dose escalation (no tolerance) and that stopping produced only mild, inconsistent symptoms (no major withdrawal) addresses two key concerns about long-term cannabinoid therapy.","specificNumbers":"137 patients. Average follow-up: 434 days (range 21-814). 42.3% withdrew (24 lack of efficacy, 17 adverse events). 292 unwanted effects, 86% mild-moderate. 4 first-ever seizures. Withdrawal test: 25 patients, no consistent syndrome, 46% had at least one symptom, 88% restarted.","methodology":"Open-label extension study following a 10-week placebo-controlled trial. 137 MS patients. Average follow-up 434 days. Assessments every 8 weeks using VAS and diary scores. Planned 2-week treatment interruption in a subset of patients to assess withdrawal.","limitations":"Open-label design (no placebo comparison for long-term efficacy). The 42% dropout rate limits conclusions about long-term tolerability for the full population. Only 25 of 62 approached patients agreed to the withdrawal test, introducing selection bias. The seizure finding needs further investigation."},{"rthcId":"RTHC-00252","title":"Cannabis use, cognitive performance and mood in a sample of workers.","authors":"Wadsworth, E J K; Moss, S C; Simpson, S A; Smith, A P","year":2006,"journal":"Journal of psychopharmacology (Oxford, England), 20(1), 14-23","doi":null,"pmid":"16204329","tags":["cognition","workplace"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis users and controls completed laboratory cognitive tests before and after work at the start and end of a working week, along with daily workplace performance diaries.\n\nCannabis use was associated with lower alertness and slower response organization across testing sessions. Users experienced working memory problems at the start of the working week (suggesting a \"hangover\" effect from weekend use) and psychomotor slowing and poorer episodic recall at the end of the working week (suggesting fatigue-related vulnerability).\n\nDespite these laboratory-measured impairments, cannabis users reported no more workplace errors than controls in their daily diaries. The pattern suggested two types of effects: a hangover effect that may increase with frequency of use, and a subtle cognitive effect more apparent under cognitive load or fatigue.","whyItMatters":"This is one of the few studies to examine cannabis effects in a real-world work context rather than just a laboratory. The finding that measurable cognitive impairments did not translate to more workplace errors suggests either compensation strategies or that the tests are more sensitive than job demands.","specificNumbers":"Cannabis users showed: lower alertness, slower response organization, working memory problems (start of week), psychomotor slowing and poorer episodic recall (end of week). No more self-reported workplace errors than controls.","methodology":"Observational study comparing cannabis users and controls on laboratory cognitive tasks (mood, cognitive function) administered pre- and post-work at the start and end of a working week. Daily workplace diaries tracked self-reported performance errors.","limitations":"Self-reported workplace errors may not accurately capture actual performance differences. Cannabis use patterns were not precisely controlled or verified. The sample size is not specified in the abstract. The studies occurred over a single working week, limiting conclusions about longer-term effects."},{"rthcId":"RTHC-00253","title":"Evaluation of herbal cannabis characteristics by medical users: a randomized trial.","authors":"Ware, Mark A; Ducruet, Thierry; Robinson, Ann R","year":2006,"journal":"Harm reduction journal, 3, 32","doi":null,"pmid":"17101054","tags":["medical-cannabis","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Eight experienced and authorized medical cannabis users with chronic pain evaluated four different herbal cannabis preparations varied by grind size, THC content, and humidity in a randomized crossover trial at a licensed clinical facility.\n\nSeven subjects completed the study. The product rated highest overall had the highest THC content (12%), highest humidity (14%), and largest grind size (10 mm). Significant differences were noted between preparations on overall appearance and color (P = 0.003).\n\nParticipants evaluated products on appearance criteria (smell, color, humidity, grind size, ease of preparation, overall appearance) and smoking characteristics (burn rate, hotness, harshness, taste).","whyItMatters":"Valid clinical trials of herbal cannabis require products that patients will actually use consistently. Understanding patient preferences for product characteristics helps researchers design studies with better adherence and more reliable results.","specificNumbers":"8 medical cannabis users. 7 completed. 4 preparations varied by THC (up to 12%), humidity (up to 14%), and grind size (up to 10 mm). Significant differences on overall appearance and color (P = 0.003). Preferred product: highest THC, humidity, and grind size.","methodology":"Randomized controlled crossover trial of 4 different herbal cannabis preparations. 8 experienced medical cannabis users with chronic pain. Products varied in grind size, THC content, and humidity. Evaluation using 5-point Likert scales for appearance and smoking characteristics.","limitations":"Very small sample (8 patients, 7 completers). Results may not generalize to inexperienced cannabis users. Only smoked cannabis was evaluated. Product preference may reflect THC content preference rather than other physical characteristics. The number of preparations (4) was limited."},{"rthcId":"RTHC-00254","title":"Cannabidiol lowers incidence of diabetes in non-obese diabetic mice.","authors":"Weiss, L; Zeira, M; Reich, S; Har-Noy, M; Mechoulam, R; Slavin, S; Gallily, R","year":2006,"journal":"Autoimmunity, 39(2), 143-51","doi":null,"pmid":"16698671","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested CBD in non-obese diabetic (NOD) mice, a standard animal model for type 1 (autoimmune) diabetes. CBD treatment significantly reduced diabetes incidence from 86% in untreated controls to 30% in treated mice.\n\nThe mechanism involved immune system modulation: CBD significantly reduced pro-inflammatory cytokines IFN-gamma and TNF-alpha while increasing anti-inflammatory cytokines IL-4 and IL-10. This represents a shift from Th1-associated (destructive) to Th2-associated (protective) immune responses.\n\nHistological examination showed significantly reduced insulitis (immune cell infiltration of the pancreatic islets) in CBD-treated mice. The authors had previously shown CBD could suppress autoimmune joint destruction in a rheumatoid arthritis model, and this study extended the findings to autoimmune diabetes.","whyItMatters":"Reducing diabetes incidence from 86% to 30% is a dramatic effect. The clear immunomodulatory mechanism (Th1 to Th2 shift) provides a biological explanation and suggests CBD might have broader applications in autoimmune diseases. Importantly, CBD is non-psychoactive, making it more clinically feasible.","specificNumbers":"Diabetes incidence: 86% untreated vs. 30% CBD-treated. Pro-inflammatory cytokines (IFN-gamma, TNF-alpha) significantly reduced. Anti-inflammatory cytokines (IL-4, IL-10) increased. Pancreatic insulitis significantly reduced.","methodology":"Animal study using non-obese diabetic (NOD) mice. CBD treatment compared to untreated controls. Assessed diabetes incidence, plasma cytokine levels (IFN-gamma, TNF-alpha, IL-4, IL-10), in vitro T-cell and macrophage cytokine production, and pancreatic histology for insulitis.","limitations":"Animal model results may not translate to human type 1 diabetes. NOD mice are a specific genetic model that may not represent all forms of autoimmune diabetes. CBD dosing, timing, and bioavailability in mice differ from potential human use. No human clinical trials for this application were conducted."},{"rthcId":"RTHC-00255","title":"Survey of medicinal cannabis use among childbearing women: patterns of its use in pregnancy and retroactive self-assessment of its efficacy against 'morning sickness'.","authors":"Westfall, Rachel E; Janssen, Patricia A; Lucas, Philippe; Capler, Rielle","year":2006,"journal":"Complementary therapies in clinical practice, 12(1), 27-33","doi":null,"pmid":"16401527","tags":["pregnancy","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 84 female medical cannabis users recruited through two compassion societies in British Columbia, Canada. Of the 79 who had experienced pregnancy, 51 (65%) reported using cannabis during their pregnancies.\n\nSeventy-seven percent of those who had been pregnant experienced nausea and/or vomiting during pregnancy. Of the 40 women (68% of those with nausea) who used cannabis to treat the condition, 37 (over 92%) rated it as \"extremely effective\" or \"effective\" for their symptoms.\n\nThe authors noted that 1-2% of women suffer from hyperemesis gravidarum, a life-threatening condition, and called for further investigation into cannabis therapy for severe pregnancy nausea.","whyItMatters":"Morning sickness affects the majority of pregnant women, and severe cases (hyperemesis gravidarum) can be life-threatening. While the survey shows high self-reported effectiveness, the safety of cannabis during pregnancy is a separate and critical concern that this study does not address.","specificNumbers":"84 female medical cannabis users surveyed. 79 had been pregnant. 51 (65%) used cannabis during pregnancy. 77% experienced pregnancy nausea. 40 used cannabis for nausea. 37/40 (92%) rated it extremely effective or effective.","methodology":"Cross-sectional survey of 84 female medical cannabis users recruited through two compassion societies in British Columbia, Canada. Self-reported data on cannabis use during pregnancy and effectiveness ratings for pregnancy-related nausea and vomiting.","limitations":"Self-selected sample of existing medical cannabis users, introducing strong selection bias. No control group or blinding. Retrospective self-assessment of effectiveness is subject to recall bias and placebo effects. The study does not address safety for the fetus. Recruited from compassion societies, limiting generalizability."},{"rthcId":"RTHC-00256","title":"Effects of delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid in marijuana, on human sperm function in vitro.","authors":"Whan, Lynne B; West, Mhairi C L; McClure, Neil; Lewis, Sheena E M","year":2006,"journal":"Fertility and sterility, 85(3), 653-60","doi":null,"pmid":"16500334","tags":["pregnancy","sex-differences"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers exposed human sperm from 78 men to THC at concentrations equivalent to therapeutic (0.032 microM), moderate recreational (0.32 microM), and heavy recreational (4.8 microM) plasma levels for 3 hours.\n\nIn the best-quality sperm fraction (90% density), progressive motility decreased by 2-21% dose-dependently (P < 0.05 to P < 0.001). In the poorer-quality fraction (45% density), the effects were more dramatic: motility decreased by 28% at the lowest concentration and 56% at the highest (P = 0.004 and P = 0.01).\n\nTHC also significantly reduced the acrosome reaction, the essential process by which sperm penetrate the egg. Spontaneous acrosome reactions were reduced by 17-35% (P = 0.004 to P < 0.001), and when artificially induced, THC at the highest concentration inhibited the reaction by 57% (P < 0.001).","whyItMatters":"The dose-dependent effects on both sperm motility and the acrosome reaction (essential for fertilization) suggest THC could directly impair male fertility. The finding that even therapeutic-level THC concentrations had measurable effects raises concerns for both recreational and medical cannabis users trying to conceive.","specificNumbers":"78 male patients. THC concentrations: 0.032, 0.32, 4.8 microM. Best sperm: motility reduced 2-21%. Poorer sperm: motility reduced 28-56%. Swimming speed reduced approximately 10%. Acrosome reaction reduced 17-35% (spontaneous) and 57% (induced at highest dose).","methodology":"In vitro laboratory analysis of sperm from 78 male patients at an assisted reproductive technology unit. Sperm separated into 90% (best) and 45% (poorer) quality fractions. Exposed to three THC concentrations matching plasma levels from therapeutic to heavy recreational use. Motility assessed by computer-assisted semen analysis. Acrosome reaction assessed by fluorescent staining.","limitations":"In vitro study: sperm exposure to THC in a lab dish may not fully replicate in vivo conditions. Sperm were exposed for only 3 hours at fixed concentrations. The study does not account for THC metabolites, which also have biological effects. Real-world fertility outcomes were not assessed."},{"rthcId":"RTHC-00257","title":"Genetic and environmental vulnerabilities underlying adolescent substance use and problem use: general or specific?","authors":"Young, Susan E; Rhee, Soo Hyun; Stallings, Michael C; Corley, Robin P; Hewitt, John K","year":2006,"journal":"Behavior genetics, 36(4), 603-15","doi":null,"pmid":"16619135","tags":["genetics","addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers studied 645 monozygotic twin pairs, 702 dizygotic twin pairs, 429 biological sibling pairs, and 96 adoptive sibling pairs, all aged 12-18 years. They examined genetic and environmental contributions to both substance use and problem use (1+ DSM-IV abuse/dependence symptoms).\n\nProblem use was more heritable than simple use for all substances, confirming the hypothesis that progressing to problematic use has a stronger genetic component than initial experimentation. Heritability was significant for use and problem use of all substances except alcohol use alone.\n\nMultivariate analyses found significant genetic correlations between all substances for both use and problem use, supporting common genetic vulnerability. However, shared environmental correlations were significant only for use (not problem use), suggesting family and peer influences drive experimentation but genetics drives progression to problems.","whyItMatters":"The distinction between genetics driving problem use and environment driving experimentation has important implications. Prevention efforts targeting the environment (peer pressure, availability) may effectively reduce experimentation, while identifying genetic vulnerability could help target interventions toward those most likely to develop problems.","specificNumbers":"645 MZ twin pairs, 702 DZ twin pairs, 429 bio sibling pairs, 96 adoptive pairs. Ages 12-18. Heritability significant for all substances except alcohol use. Problem use more heritable than simple use. Genetic correlations significant across all substances. Shared environmental correlations significant for use only, not problem use.","methodology":"Twin, sibling, and adoptive sibling study of 12-18 year olds from community samples. Structured psychiatric interviews assessed repeated use and problem use (1+ DSM-IV symptoms) for tobacco, alcohol, and marijuana. Univariate and multivariate biometrical model fitting with age- and sex-specific thresholds.","limitations":"Cross-sectional assessment of a developmental process (adolescence). Twin assumptions may not fully hold for substance use (peers may differ for MZ vs. DZ twins). Age range 12-18 means some participants may not yet have developed substance problems. Cannabis-specific analyses were limited by lower prevalence."},{"rthcId":"RTHC-00258","title":"A latent class analysis of illicit drug abuse/dependence: results from the National Epidemiological Survey on Alcohol and Related Conditions.","authors":"Agrawal, Arpana; Lynskey, Michael T; Madden, Pamela A F; Bucholz, Kathleen K; Heath, Andrew C","year":2007,"journal":"Addiction (Abingdon, England), 102(1), 94-104","doi":null,"pmid":"17207127","tags":["addiction","mental-health","depression","anxiety"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using latent class analysis of the National Epidemiological Survey on Alcohol and Related Conditions (43,093 participants), researchers identified five distinct patterns of illicit drug abuse/dependence.\n\nThe largest class (92.5%) had no drug abuse/dependence. Cannabis abuse/dependence only was the most common drug problem (5.8%). Three smaller classes were identified: stimulants/hallucinogens (0.6%), prescription drugs including sedatives, tranquilizers, and opiates (0.6%), and polysubstance abuse/dependence (0.5%).\n\nEach class had a distinct psychiatric profile. The polysubstance class had the strongest associations with major depression and nicotine dependence. The prescription drug class had the strongest association with anxiety disorders. All drug classes (2-5) were associated with alcohol abuse/dependence and antisocial personality disorder compared to the no-abuse class.","whyItMatters":"Identifying distinct patterns of drug abuse rather than treating all illicit drug use as one category allows for better-targeted prevention and treatment. The finding that cannabis-only abuse is by far the most common pattern (5.8% vs. 0.5-0.6% for other patterns) and has the mildest psychiatric profile informs risk stratification.","specificNumbers":"43,093 participants. Class 1: no abuse/dependence (92.5%). Class 2: cannabis only (5.8%). Class 3: stimulants/hallucinogens (0.6%). Class 4: prescription drugs (0.6%). Class 5: polysubstance (0.5%). Polysubstance: strongest link to depression. Prescription drugs: strongest link to anxiety.","methodology":"Latent class analysis of 43,093 participants from the National Epidemiological Survey on Alcohol and Related Conditions. Multinomial logistic regression examined associations between drug abuse classes and psychiatric disorders (DSM-IV diagnoses of depression, anxiety, panic, social phobia, antisocial personality).","limitations":"Cross-sectional design cannot determine whether drug abuse preceded or followed psychiatric disorders. Self-reported drug use in a national survey may underestimate prevalence. The latent class solution depends on the analytic approach and sample characteristics."},{"rthcId":"RTHC-00259","title":"Parental alcoholism predicts suicidal behavior in adolescents and young adults with cannabis dependence.","authors":"Arendt, Mikkel; Sher, Leo; Fjordback, Lone; Brandholdt, Jack; Munk-Jorgensen, Povl","year":2007,"journal":"International journal of adolescent medicine and health, 19(1), 67-77","doi":null,"pmid":"17458326","tags":["addiction","depression","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers assessed 119 heavy cannabis users recruited from 19 substance treatment centers in Denmark. Depression, suicidal ideation, and suicidal behavior were highly prevalent: 46% had lifetime depression, 42% reported suicidal ideation, and 23% had engaged in suicidal behavior.\n\nThese problems were more common among females and were significantly associated with adverse childhood experiences and parental alcoholism. Critically, comorbid alcohol or other drug use did not independently increase the risk.\n\nParental alcoholism remained significantly associated with depression (P < 0.009), suicidal ideation (P < 0.001), and suicidal behavior (P < 0.03) even after adjusting for multiple potential confounders. Physical abuse during childhood independently predicted suicidal ideation (P < 0.01).","whyItMatters":"This study suggests that the high rates of depression and suicidality seen among heavy cannabis users may be driven more by childhood adversity and family factors than by cannabis use itself. This has implications for treatment: addressing underlying trauma and family history may be more important than focusing solely on cannabis cessation.","specificNumbers":"119 heavy cannabis users from 19 treatment centers. Depression: 46%. Suicidal ideation: 42%. Suicidal behavior: 23%. Parental alcoholism predicted: depression (P < .009), suicidal ideation (P < .001), suicidal behavior (P < .03). Physical abuse predicted suicidal ideation (P < .01).","methodology":"Cross-sectional study of 119 subjects from 19 Danish substance treatment centers. Structured questionnaires and SCAN psychiatric assessment, Beck Depression Inventory, Addiction Severity Index, CIDI, and AUDIT administered.","limitations":"Treatment-seeking population may not represent all heavy cannabis users. Cross-sectional design cannot establish causation. Self-reported childhood experiences may be affected by current mental state (depressed individuals may recall more negative experiences). The sample was entirely from Denmark."},{"rthcId":"RTHC-00260","title":"Marijuana as a trigger of cardiovascular events: speculation or scientific certainty?","authors":"Aryana, Arash; Williams, Mark A","year":2007,"journal":"International journal of cardiology, 118(2), 141-4","doi":null,"pmid":"17005273","tags":["cardiovascular","harm-reduction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review compiled case reports and studies from the previous three decades documenting cardiovascular complications associated with marijuana use. The physiologic effects of marijuana on the cardiovascular system and supportive evidence for marijuana as a trigger of adverse events were discussed.\n\nReported cardiovascular complications included tachyarrhythmias (rapid abnormal heart rhythms), acute coronary syndrome (heart attacks), vascular complications, and potentially congenital heart defects with prenatal exposure.\n\nThe review raised particular concern about the aging population of long-term marijuana users from the 1960s-70s, as cardiovascular risks may compound with the typical cardiovascular risk factors that increase with age.","whyItMatters":"As long-term marijuana users from earlier decades age into the period of highest cardiovascular risk, and as medical and recreational cannabis use expands, understanding the cardiovascular effects of marijuana becomes increasingly important for clinical practice.","specificNumbers":"Case reports spanning three decades. Cardiovascular events documented: tachyarrhythmias, acute coronary syndrome, vascular complications, congenital heart defects. Concern heightened for aging long-term users.","methodology":"Narrative review of published case reports and studies documenting cardiovascular events associated with marijuana use. Covered physiologic mechanisms and clinical case evidence across three decades.","limitations":"Largely based on case reports, which cannot establish causation. Many patients with cardiovascular events also had other risk factors (tobacco, age, pre-existing conditions). The prevalence of cardiovascular events relative to the large number of marijuana users was not established. Publication bias favors reporting unusual adverse events."},{"rthcId":"RTHC-00261","title":"Cannabinoid control of neuroinflammation related to multiple sclerosis.","authors":"Baker, D; Jackson, S J; Pryce, G","year":2007,"journal":"British journal of pharmacology, 152(5), 649-54","doi":null,"pmid":"17891167","tags":["medical-cannabis","inflammation","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review from the British Journal of Pharmacology examined whether cannabinoids can modify the neuroinflammatory process driving MS, beyond just controlling symptoms.\n\nExperimental studies revealed two mechanisms: synthetic cannabinoids can indirectly suppress the immune response through CB1 receptor signaling in nerve centers that control systemic immunosuppression, and can directly inhibit lymphocyte and macrophage/microglial function through CB2 receptors.\n\nHowever, the review concluded that these immunosuppressive effects, which could reduce relapsing attack frequency, would probably not be achieved clinically through medical cannabis use due to dose constraints: the doses needed for immunosuppression would likely cause unacceptable psychoactive effects.\n\nA more promising avenue was cannabinoid modulation of the glial response within damaged CNS tissue, which could slow the progressive neurodegeneration accounting for disability accumulation in MS.","whyItMatters":"This review honestly assessed the gap between what cannabinoids can do experimentally and what they can achieve clinically. The distinction between achievable symptom control and unachievable immunosuppression (at tolerable doses) is important for realistic expectations about cannabis-based MS treatments.","specificNumbers":"Two mechanisms: CB1-mediated indirect immunosuppression via nerve signaling, CB2-mediated direct immune cell inhibition. Both require doses beyond clinical feasibility. Glial response modulation more promising at tolerable doses.","methodology":"Review published in the British Journal of Pharmacology examining experimental evidence for cannabinoid effects on neuroinflammation in MS. Covered CB1 and CB2 receptor-mediated mechanisms, clinical dose feasibility, and potential for disease modification versus symptom control.","limitations":"Based largely on experimental (animal model) data. The prediction about dose constraints for immunosuppression is theoretical and has not been directly tested in clinical trials. The neuroprotective potential of cannabinoids at clinical doses remains to be proven."},{"rthcId":"RTHC-00262","title":"Critical enzymes involved in endocannabinoid metabolism.","authors":"Basavarajappa, Balapal S","year":2007,"journal":"Protein and peptide letters, 14(3), 237-46","doi":null,"pmid":"17346227","tags":["neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review provided an integrative overview of the enzymes controlling endocannabinoid levels. Anandamide (AEA) biosynthesis involves multiple pathways including NAPE-PLD, secretory PLA2, and PLC. The endocannabinoid 2-AG is produced through phosphatidic acid phosphohydrolase, diacylglycerol lipase (DAGL), PI-PLC, and lyso-PLC.\n\nCellular uptake of endocannabinoids involves a putative membrane transporter or facilitated diffusion. Degradation is handled by FAAH (for anandamide) and both FAAH and MAGL (for 2-AG).\n\nThe review discussed therapeutic interventions targeting these metabolic enzymes, including applications for addiction treatment. By modulating the enzymes rather than the receptors, researchers could fine-tune endocannabinoid levels with potentially greater selectivity than directly activating or blocking cannabinoid receptors.","whyItMatters":"Understanding the full metabolic machinery of the endocannabinoid system is essential for developing targeted drugs. Each enzyme in the pathway represents a potential drug target that could raise or lower endocannabinoid levels in specific ways, offering more precision than administering cannabinoids directly.","specificNumbers":"AEA synthesis: NAPE-PLD, PLA2, PLC pathways. 2-AG synthesis: DAGL, PI-PLC, lyso-PLC, phosphatidic acid phosphohydrolase. Degradation: FAAH (AEA), MAGL and FAAH (2-AG). Transport: putative membrane transporter.","methodology":"Integrative review of published research on endocannabinoid biosynthesis, transport, and degradation enzymes. Covered enzyme characterization, metabolic pathways, and potential therapeutic applications.","limitations":"Rapidly evolving field where new enzymes and pathways were still being discovered. Some proposed pathways were based on limited evidence. The putative membrane transporter remained controversial. Therapeutic applications were largely preclinical."},{"rthcId":"RTHC-00263","title":"Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review).","authors":"Bifulco, Maurizio; Laezza, Chiara; Gazzerro, Patrizia; Pentimalli, Francesca","year":2007,"journal":"Oncology reports, 17(4), 813-6","doi":null,"pmid":"17342320","tags":["cancer","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review highlighted an emerging area of endocannabinoid cancer research beyond the previously known effects on tumor cell growth and death. New evidence showed endocannabinoids can also suppress angiogenesis (the formation of new blood vessels that tumors need to grow), inhibit cancer cell migration, and block metastasis (tumor spreading) across different cancer types.\n\nThe endocannabinoid system was positioned as a potential therapeutic target that acts on multiple aspects of cancer progression simultaneously. Unlike many anti-cancer drugs, cannabinoids have a favorable safety profile with low toxicity, and are already used in cancer patients for symptom management (appetite stimulation, anti-nausea, pain relief).\n\nThe dual utility of cannabinoids, potentially fighting cancer while also managing cancer treatment side effects, was noted as particularly appealing.","whyItMatters":"The ability to block tumor blood supply and spreading represents a fundamentally different anti-cancer mechanism from direct cell killing. If endocannabinoid-based treatments can slow tumor vascularization and metastasis while being well-tolerated, they could complement existing cancer therapies.","specificNumbers":"Endocannabinoids shown to inhibit: cancer cell growth, apoptosis induction, angiogenesis, cell migration, metastasis. Multiple cancer types studied. Existing clinical use for: appetite stimulation, anti-nausea, pain relief.","methodology":"Narrative review of emerging research on endocannabinoid effects on tumor angiogenesis, cell migration, and metastasis. Covered in vitro and in vivo studies across multiple cancer types.","limitations":"Evidence primarily from cell culture and animal models. No clinical evidence that endocannabinoids or cannabinoids treat cancer in humans. The \"good safety profile\" comparison is against cytotoxic chemotherapy, setting a low bar. Anti-tumor doses may differ from symptom management doses."},{"rthcId":"RTHC-00264","title":"A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.","authors":"Blankman, Jacqueline L; Simon, Gabriel M; Cravatt, Benjamin F","year":2007,"journal":"Chemistry & biology, 14(12), 1347-56","doi":null,"pmid":"18096503","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Using proteomic techniques on mouse brain tissue, researchers identified three enzymes primarily responsible for breaking down 2-arachidonoylglycerol (2-AG), one of the brain's main endocannabinoids.\n\nMonoacylglycerol lipase (MAGL) accounted for approximately 85% of total 2-AG hydrolysis in the brain. The remaining 15% was split between two previously uncharacterized enzymes called ABHD6 and ABHD12.\n\nNotably, each of these three enzymes showed different subcellular distributions within neurons. This spatial separation suggests they may regulate distinct pools of 2-AG rather than serving redundant roles, potentially offering more precise targets for future drug development.","whyItMatters":"Understanding which enzymes control 2-AG levels in the brain is essential for developing drugs that target the endocannabinoid system. Since 2-AG activates the same receptors that THC does, manipulating its breakdown could theoretically produce therapeutic effects without requiring external cannabinoids.","specificNumbers":"MAGL accounted for approximately 85% of brain 2-AG hydrolase activity. ABHD6 and ABHD12 together accounted for most of the remaining 15%.","methodology":"The researchers used activity-based protein profiling (ABPP), a functional proteomics approach, to identify and quantify all enzymes capable of hydrolyzing 2-AG in mouse brain homogenates. They used selective inhibitors to confirm the relative contributions of each enzyme and mapped their subcellular locations.","limitations":"This was conducted entirely in mouse brain tissue, and enzyme distribution or relative activity could differ in human brains. The study examined brain tissue homogenates, which may not fully capture the dynamics of 2-AG metabolism in living, functioning neural circuits."},{"rthcId":"RTHC-00265","title":"A comparison of symptoms and family history in schizophrenia with and without prior cannabis use: implications for the concept of cannabis psychosis.","authors":"Boydell, J; Dean, K; Dutta, R; Giouroukou, E; Fearon, P; Murray, R","year":2007,"journal":"Schizophrenia research, 93(1-3), 203-10","doi":null,"pmid":"17462864","tags":["psychosis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The study examined 757 people experiencing their first episode of schizophrenia, of whom 182 (24%) had used cannabis in the year before their first presentation.\n\nAfter controlling for age, sex, and ethnicity, researchers found no statistically significant differences in any measured symptom between cannabis users and non-users. This included bizarre behavior, thought disorder, negative symptoms, delusions of reference, paranoid delusions, and first-rank symptoms.\n\nThere were two borderline findings among cannabis users: a non-significant trend toward better insight and fewer abusive or accusatory hallucinations. Family history of schizophrenia did not differ between the two groups.","whyItMatters":"There has been long-standing debate about whether cannabis causes a distinct form of psychosis that differs from \"typical\" schizophrenia. This study's finding of minimal symptom differences argues against a separate \"cannabis psychosis\" and suggests that cannabis-associated schizophrenia is clinically indistinguishable from other forms.","specificNumbers":"757 first-episode schizophrenia cases examined. 182 (24%) had used cannabis in the prior year. Loss of insight: OR 0.65 (p=0.055). Fewer abusive hallucinations: OR 0.65 (p=0.049, borderline).","methodology":"Researchers used the Camberwell case register containing 757 cases of first-onset schizophrenia. They completed the OPCRIT checklist on all patients and used chi-square tests followed by logistic regression to compare symptoms between cannabis users and non-users, controlling for age, sex, and ethnicity.","limitations":"Cannabis use was self-reported and measured only in the year before first presentation, which may not capture lifetime use patterns. The study was cross-sectional, so it could not determine whether cannabis played a causal role. Symptom assessment occurred at first presentation only."},{"rthcId":"RTHC-00266","title":"Does occasional cannabis use impact anxiety and depression treatment outcomes?: Results from a randomized effectiveness trial.","authors":"Bricker, Jonathan B; Russo, Joan; Stein, Murray B; Sherbourne, Cathy; Craske, Michelle; Schraufnagel, Trevor J; Roy-Byrne, Peter","year":2007,"journal":"Depression and anxiety, 24(6), 392-8","doi":null,"pmid":"17096386","tags":["anxiety","depression","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a randomized trial of 232 adults with anxiety and panic disorders, researchers examined whether occasional cannabis use affected treatment outcomes.\n\nParticipants receiving a combined cognitive-behavioral therapy (CBT) and medication intervention showed similar improvements in anxiety regardless of cannabis use frequency. Monthly cannabis users' anxiety outcomes were comparable to those who used less frequently.\n\nFor depression specifically, monthly cannabis users in the active treatment group improved just as much as less frequent users. However, monthly users who received only usual care had significantly worse depressive symptoms than their less-frequent-using counterparts, suggesting the structured intervention may have been particularly beneficial for cannabis users.","whyItMatters":"Clinicians often worry that cannabis use undermines mental health treatment. This study found the opposite pattern for depression: cannabis users benefited from structured treatment at least as much as non-users, while those receiving only usual care fared worse if they used cannabis monthly.","specificNumbers":"232 adults participated. Monthly cannabis users in usual care had significantly more depressive symptoms than less-than-monthly users. In the CCAP intervention group, no significant difference by cannabis use frequency.","methodology":"This was a secondary analysis of the Collaborative Care for Anxiety and Panic (CCAP) study, a randomized effectiveness trial at six university-based primary care clinics. 232 adults were randomized to either the CCAP intervention (combined CBT and pharmacotherapy) or usual care. Cannabis use frequency was assessed and used as a moderating variable.","limitations":"Cannabis use was self-reported and categorized broadly (monthly vs. less than monthly). The study was not designed or powered specifically to test cannabis use as a moderating variable. The relatively small sample limits subgroup analyses."},{"rthcId":"RTHC-00267","title":"Dysregulation of the endogenous cannabinoid system in adult rats prenatally treated with the cannabinoid agonist WIN 55,212-2.","authors":"Castelli, M Paola; Paola Piras, A; D'Agostino, Antonella; Pibiri, Fabio; Perra, Simona; Gessa, Gian Luigi; Maccarrone, Mauro; Pistis, Marco","year":2007,"journal":"European journal of pharmacology, 573(1-3), 11-9","doi":null,"pmid":"17644084","tags":["pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Pregnant rats received daily doses of WIN 55,212-2 (a potent synthetic cannabinoid) from gestational day 5 through 20. Their adult male offspring showed significant alterations in the endocannabinoid system compared to controls.\n\nIn the striatum (a brain region involved in movement and reward), adult offspring had increased anandamide levels, reduced FAAH enzyme activity (which breaks down anandamide), and enhanced NAPE-PLD activity (which produces anandamide). In limbic areas (involved in emotion), the opposite pattern emerged.\n\nCB1 receptor sensitivity was altered in the hippocampus (reduced by 26%) and striatum (increased by 27%), despite receptor numbers remaining unchanged. Notably, the animals' ambulatory activity appeared normal despite these neurochemical changes.","whyItMatters":"This study demonstrated that prenatal cannabinoid exposure can produce permanent, region-specific changes in the brain's endocannabinoid system that persist into adulthood. These changes occurred in brain areas critical for learning, memory, motor function, and emotional behavior.","specificNumbers":"CB1 receptor sensitivity changed: hippocampus -26%, striatum +27%. Striatal anandamide levels increased with reduced FAAH and enhanced NAPE-PLD activity. Limbic areas showed opposite changes.","methodology":"Pregnant rats were treated daily with WIN 55,212-2 (0.5 mg/kg) or vehicle from gestational day 5 to 20. Adult male offspring underwent radioligand binding assays and GTPgammaS functional assays to measure CB1 receptor density, affinity, and function across multiple brain regions. Anandamide levels and enzyme activities were also quantified.","limitations":"WIN 55,212-2 is a synthetic cannabinoid more potent than THC, so findings may not directly translate to cannabis use during pregnancy. Only male offspring were studied. Behavioral testing was limited to ambulatory activity and did not assess cognitive or emotional function."},{"rthcId":"RTHC-00268","title":"Functional imaging studies in cannabis users.","authors":"Chang, Linda; Chronicle, Edward P","year":2007,"journal":"The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry, 13(5), 422-32","doi":null,"pmid":"17901252","tags":["neuroscience","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the existing neuroimaging literature on cannabis users, covering both acute THC administration studies and chronic use studies.\n\nAcute THC studies (mostly using PET) consistently found that THC increases brain activation in frontal, paralimbic, and cerebellar regions, matching the drug's known behavioral effects.\n\nFor chronic users, the picture was different. Structural imaging studies showed only equivocal evidence of brain changes. However, functional MRI studies consistently found altered activation patterns during higher cognitive tasks. These changes appeared as neuroadaptation, where chronic users recruited brain networks differently to accomplish the same tasks as non-users.\n\nWhether these functional changes reverse with abstinence remained unclear at the time of the review.","whyItMatters":"This review established an important distinction in the cannabis neuroscience field: chronic cannabis use may not cause detectable structural brain damage, but it does appear to change how the brain works during complex cognitive tasks. Whether this represents harm, adaptation, or compensation remained an open question.","specificNumbers":"The review covered multiple PET and fMRI studies. THC acutely increased activation in frontal, paralimbic, and cerebellar regions. Chronic users showed altered activation during higher cognitive tasks despite largely normal structural scans.","methodology":"The authors reviewed published neuroimaging studies of cannabis users, including PET studies of acute THC effects and fMRI studies of chronic users. They organized findings by imaging modality (structural vs. functional) and by acute vs. chronic exposure.","limitations":"As a narrative review, it did not include formal meta-analytic methods. The studies reviewed used varying methodologies, sample sizes, and definitions of \"chronic use.\" Most available studies at the time had relatively small samples."},{"rthcId":"RTHC-00269","title":"Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis.","authors":"Collin, C; Davies, P; Mutiboko, I K; Ratcliffe, S","year":2007,"journal":"European journal of neurology, 14(3), 290-6","doi":null,"pmid":"17355549","tags":["medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In this double-blind trial, 189 people with multiple sclerosis and spasticity were randomized to receive either a cannabis-based mouth spray containing THC and CBD (n=124) or placebo (n=65) for six weeks.\n\nThe primary analysis showed the active preparation was significantly superior to placebo (p=0.048) in reducing daily spasticity scores recorded by patients. All secondary measures, including the Ashworth spasticity scale and subjective spasm assessment, favored the active treatment, though they did not reach statistical significance individually.\n\nIn a responder analysis, 40% of patients on the active treatment achieved at least 30% improvement, a rate significantly higher than placebo (p=0.014). Six patients on the active spray and two on placebo withdrew due to adverse events.","whyItMatters":"MS spasticity is often difficult to manage with existing medications. This trial provided evidence that a standardized cannabis-based medicine could offer meaningful relief for a significant proportion of patients, contributing to the eventual approval of nabiximols (Sativex) in multiple countries.","specificNumbers":"189 patients randomized (124 active, 65 placebo). Primary outcome: p=0.048 favoring active treatment. 40% of active group achieved 30% or greater improvement (p=0.014). 8 withdrawals due to adverse events (6 active, 2 placebo).","methodology":"This was a randomized, double-blind, placebo-controlled trial. 189 MS patients with spasticity received daily doses of either a standardized oromucosal (mouth spray) cannabis-based medicine containing THC and CBD, or placebo, for 6 weeks. The primary endpoint was change in a daily patient-recorded numerical rating scale of spasticity.","limitations":"The 6-week duration may not capture long-term efficacy or safety. The 2:1 randomization ratio gave less statistical power to detect differences. Secondary endpoints did not reach significance, and the primary endpoint p-value was close to the threshold."},{"rthcId":"RTHC-00270","title":"On the pharmacological properties of Delta9-tetrahydrocannabinol (THC).","authors":"Costa, Barbara","year":2007,"journal":"Chemistry & biodiversity, 4(8), 1664-77","doi":null,"pmid":"17712813","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered the pharmacological landscape of THC as of 2007, drawing on clinical trials, animal studies, and anecdotal reports.\n\nThe evidence supported THC's therapeutic applications across several areas including pain relief, nausea suppression, appetite stimulation, neuroprotection, and anti-tumor effects. The discovery of the endocannabinoid system (CB1 and CB2 receptors and their natural ligands) had enabled more targeted research into these applications.\n\nHowever, the review noted persistent barriers: psychoactive effects in patients, adverse reactions reported in human trials, tolerance development with repeated use, and potential dependence. These issues pushed researchers toward alternative strategies, including drugs that modulate the endocannabinoid system indirectly rather than activating cannabinoid receptors directly.\n\nIntriguingly, emerging evidence suggested that whole cannabis extracts sometimes outperformed isolated THC, hinting at synergistic effects between cannabis compounds.","whyItMatters":"This review captured a pivotal moment in cannabinoid pharmacology when the field was shifting from studying THC in isolation toward understanding the broader endocannabinoid system and whole-plant preparations. The observation that whole extracts sometimes work better than pure THC foreshadowed the \"entourage effect\" concept.","specificNumbers":"The review covered applications in pain, nausea, appetite, neuroprotection, and cancer. Whole cannabis extract showed benefits beyond those of isolated THC in some comparisons.","methodology":"This was a narrative review of the published literature on THC pharmacology, covering cellular and molecular mechanisms, animal model results, and clinical trial data. The author organized findings by therapeutic application and discussed limitations and future directions.","limitations":"As a narrative review, it did not use systematic search methods or meta-analytic techniques. The evidence base in 2007 included many small studies and animal models with limited human clinical trial data."},{"rthcId":"RTHC-00271","title":"Targeting astrocytomas and invading immune cells with cannabinoids: a promising therapeutic avenue.","authors":"Cudaback, Eiron; Stella, Nephi","year":2007,"journal":"Molecular neurobiology, 36(1), 36-44","doi":null,"pmid":"17952648","tags":["cancer","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined the accumulating evidence that cannabinoids could be effective against astrocytomas, particularly high-grade brain tumors that remain among the most difficult cancers to treat.\n\nThe authors summarized in vitro (cell culture) evidence showing cannabinoids could inhibit tumor cell proliferation, induce programmed cell death (apoptosis), and reduce tumor invasiveness. Animal studies had demonstrated that cannabinoids could slow the growth of implanted brain tumors in mice.\n\nBeyond direct anti-tumor effects, the review highlighted cannabinoids' potential to modulate the immune cells that infiltrate brain tumors, which could either help or hinder tumor growth depending on the immune response. The authors argued that cannabinoids' combined anti-tumor and immunomodulatory properties warranted serious investigation as complementary or alternative treatments for brain cancers.","whyItMatters":"High-grade brain tumors (glioblastoma and other astrocytomas) remain among the deadliest cancers, with limited treatment options. The identification of cannabinoids as having anti-tumor properties in laboratory and animal settings opened a new avenue for research into these difficult-to-treat cancers.","specificNumbers":"The review covered multiple in vitro and animal studies showing anti-proliferative, pro-apoptotic, and anti-invasive effects of cannabinoids on brain tumor cells.","methodology":"This was a narrative review of published in vitro and in vivo studies examining cannabinoid effects on brain tumor cells and tumor-associated immune cells. The authors synthesized evidence across multiple study types and proposed mechanisms of action.","limitations":"All evidence was preclinical (cell cultures and animal models) at the time of review. Tumor models in animals don't fully replicate human brain cancer biology. The psychoactive effects and other systemic impacts of cannabinoids complicate their potential clinical use."},{"rthcId":"RTHC-00272","title":"Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury.","authors":"Durst, Ronen; Danenberg, Haim; Gallily, Ruth; Mechoulam, Raphael; Meir, Keren; Grad, Etty; Beeri, Ronen; Pugatsch, Thea; Tarsish, Elizabet; Lotan, Chaim","year":2007,"journal":"American journal of physiology. Heart and circulatory physiology, 293(6), H3602-7","doi":null,"pmid":"17890433","tags":["cbd","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers induced heart attacks in rats by temporarily blocking the left anterior descending coronary artery for 30 minutes, then treated them with CBD (5 mg/kg) or vehicle for 7 days.\n\nCBD-treated rats showed significantly better preserved heart function, with shortening fraction declining from 48% to 39% compared to 44% to 32% in controls. Most strikingly, infarct size was reduced by 66% in CBD-treated animals, despite nearly identical areas of tissue at risk.\n\nThe protective effect was associated with reduced inflammation: CBD-treated hearts showed less myocardial inflammation and dramatically lower IL-6 levels (254 vs. 2,812 pg/ml). However, when the experiment was repeated in isolated hearts (removed from the body), no protective effect was observed, suggesting CBD's cardioprotection depends on systemic processes rather than direct effects on heart tissue.","whyItMatters":"CBD had no known cardiovascular applications before this study. The finding that it dramatically reduced heart attack damage in rats, apparently through anti-inflammatory mechanisms, opened a new area of CBD research and raised questions about its potential in cardiovascular medicine.","specificNumbers":"Infarct size reduced by 66% with CBD. Heart function (shortening fraction): CBD group 48% to 39%, controls 44% to 32% (p<0.05). IL-6 levels: CBD 254 pg/ml vs. controls 2,812 pg/ml (p<0.01). CBD dose: 5 mg/kg daily for 7 days.","methodology":"For in vivo studies, rats underwent 30-minute coronary artery ligation and received CBD (5 mg/kg intraperitoneally) or vehicle for 7 days. Heart function was assessed by echocardiography. Infarcts were examined morphometrically and histologically. In ex vivo studies, CBD was administered 24 and 1 hour before hearts were harvested for isolated heart experiments.","limitations":"This was an animal study with a small sample size. The heart attacks were surgically induced, which differs from natural heart attacks in humans. The CBD dose and route of administration may not translate directly to human use. The ex vivo finding limits understanding of the mechanism."},{"rthcId":"RTHC-00273","title":"Carpal tunnel syndrome, diabetic neuropathy, fibromyalgia, glucosamine and chondroitin, hypnosis in pain management, marijuana for pain.","authors":"Fishman, Scott M","year":2007,"journal":"Journal of pain & palliative care pharmacotherapy, 21(2), 61-7","doi":null,"pmid":"17844729","tags":["pain","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This publication used a question-and-answer format designed for patients, covering multiple pain management topics including carpal tunnel syndrome, fibromyalgia, glucosamine and chondroitin, hypnosis, and marijuana.\n\nThe marijuana section addressed common patient questions about cannabis for pain in accessible language. However, the format prioritized breadth over depth, covering marijuana as one of several topics rather than providing a comprehensive analysis of the evidence.\n\nAs a patient education piece, it offered general information rather than new research findings.","whyItMatters":"Patient-oriented publications play a role in making medical information accessible, though they typically provide less rigorous evidence analysis than peer-reviewed research articles.","specificNumbers":"No specific quantitative data on marijuana and pain was presented in this format.","methodology":"This was a patient-education article written in question-and-answer format, covering multiple pain management topics. It was not a systematic review or original research study.","limitations":"This is a patient education piece covering multiple topics, not a focused research study. It does not include original data or systematic evidence review on marijuana and pain."},{"rthcId":"RTHC-00274","title":"Cannabidiol, unlike synthetic cannabinoids, triggers activation of RBL-2H3 mast cells.","authors":"Giudice, Elda Del; Rinaldi, Luciano; Passarotto, Marzia; Facchinetti, Fabrizio; D'Arrigo, Antonello; Guiotto, Adriano; Carbonare, Maurizio Dalle; Battistin, Leontino; Leon, Alberta","year":2007,"journal":"Journal of leukocyte biology, 81(6), 1512-22","doi":null,"pmid":"17339608","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using a rat mast cell line (RBL-2H3), researchers found that CBD at concentrations of 3-10 micromolar increased the release of beta-hexosaminidase, a marker of mast cell activation. This occurred in both stimulated and unstimulated cells.\n\nThis effect was the opposite of what synthetic cannabinoids WIN 55,212-2 and CP 55,940 produced. Those compounds inhibited mast cell activation, while CBD enhanced it.\n\nCBD's activating effect was associated with a robust increase in intracellular calcium levels. Importantly, this was not mediated through known G-protein coupled cannabinoid receptors or vanilloid VR1 receptors (tested using capsaicin, which had no effect on these cells). THC mimicked CBD's activating effect, suggesting natural cannabinoids interact with as-yet-unidentified receptors or ion channels.","whyItMatters":"CBD is widely described as \"anti-inflammatory,\" but this study showed it could actually activate mast cells, key players in inflammatory responses. The finding that natural cannabinoids (CBD and THC) behaved opposite to synthetic cannabinoids suggests undiscovered receptors or mechanisms for cannabinoid action.","specificNumbers":"CBD at 3-10 micromolar increased mast cell activation marker release. Calcium channel blockers clotrimazole and nitrendipine (10-30 micromolar) reduced the CBD effect. Capsaicin (vanilloid VR1 agonist) had no effect.","methodology":"Researchers used the RBL-2H3 rat mast cell line to measure beta-hexosaminidase release (a marker of cell activation) and intracellular calcium levels in response to CBD, THC, and synthetic cannabinoids. They used pharmacological tools to probe which receptors and signaling pathways were involved.","limitations":"The study used a single rat cell line, which may not represent how mast cells behave in living tissues or in humans. The concentrations used may not reflect physiologically achievable levels of CBD. In vitro mast cell activation may not translate to systemic inflammatory effects."},{"rthcId":"RTHC-00275","title":"Functional correlates of verbal memory deficits emerging during nicotine withdrawal in abstinent adolescent cannabis users.","authors":"Jacobsen, Leslie K; Pugh, Kenneth R; Constable, Robert T; Westerveld, Michael; Mencl, W Einar","year":2007,"journal":"Biological psychiatry, 61(1), 31-40","doi":null,"pmid":"16631130","tags":["youth","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared 20 adolescent cannabis-and-tobacco users with 25 tobacco-only users. During nicotine withdrawal, the cannabis users showed deteriorated verbal recall that did not occur in the tobacco-only group.\n\nFunctional MRI revealed that during high-demand verbal memory tasks, nicotine withdrawal selectively increased activation in posterior brain regions among cannabis users. More importantly, it disrupted the functional connectivity between frontal and parietal brain areas, the neural circuit that normally supports working memory.\n\nThese findings suggest that cannabis use during adolescence may compromise the brain circuits responsible for verbal memory, but that these deficits are normally masked when nicotine is present. Nicotine withdrawal removed a compensatory effect, unmasking the underlying vulnerability.","whyItMatters":"Most adolescents who use cannabis also use tobacco, but the interaction between these substances on the developing brain is poorly understood. This study revealed that nicotine may temporarily compensate for cannabis-related memory circuit disruption, hiding deficits until nicotine use stops.","specificNumbers":"20 adolescent cannabis+tobacco users vs. 25 tobacco-only users. Verbal recall deteriorated during nicotine withdrawal specifically in cannabis users. fMRI showed increased posterior activation and disrupted frontoparietal connectivity in cannabis users during withdrawal.","methodology":"Twenty adolescent tobacco-and-cannabis users and 25 adolescent tobacco-only users underwent verbal learning and memory testing during nicotine withdrawal. A subset performed a verbal working memory task during functional MRI scanning to examine brain activation patterns and functional connectivity.","limitations":"The cross-sectional design cannot determine whether cannabis caused the observed differences or whether pre-existing differences led to cannabis use. The sample was small. The study could not separate the effects of chronic cannabis use from acute withdrawal effects."},{"rthcId":"RTHC-00276","title":"Effects of frequent cannabis use on hippocampal activity during an associative memory task.","authors":"Jager, Gerry; Van Hell, Hendrika H; De Win, Maartje M L; Kahn, Rene S; Van Den Brink, Wim; Van Ree, Jan M; Ramsey, Nick F","year":2007,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 17(4), 289-97","doi":null,"pmid":"17137758","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Twenty frequent cannabis users and 20 matched non-users underwent functional MRI while performing an associative memory task (learning to link pairs of items together).\n\nCannabis users showed significantly lower activation in the parahippocampal regions and right dorsolateral prefrontal cortex compared to non-users. Despite this reduced brain activity, their actual task performance was statistically normal.\n\nStructural analysis using voxel-based morphometry (VBM) revealed no differences in hippocampal brain tissue composition between users and non-users. The reduced activation was not related to any detectable structural changes, leading the authors to suggest it might reflect altered cerebral blood flow or differences in vigilance rather than cognitive impairment.","whyItMatters":"This study complicated the narrative that altered brain activation in cannabis users necessarily means impairment. Users performed normally despite different brain activity patterns, raising the question of whether the changes represent damage, compensation, or simply a different but functional way of processing information.","specificNumbers":"20 frequent cannabis users vs. 20 matched non-users. Lower activation found in parahippocampal regions and right dorsolateral prefrontal cortex. No structural differences detected by VBM. Task performance was statistically equivalent between groups.","methodology":"Researchers matched 20 frequent cannabis users with 20 non-users on age, gender, and IQ. Both groups underwent fMRI during an associative learning task. Structural brain differences were assessed using voxel-based morphometry focused on the hippocampal and parahippocampal regions.","limitations":"The cross-sectional design cannot determine causation. The sample was relatively small. Cannabis users may have compensated through unmeasured strategies. The associative memory task may not have been challenging enough to reveal performance differences."},{"rthcId":"RTHC-00277","title":"Suppressive effects of cannabidiol on antigen-specific antibody production and functional activity of splenocytes in ovalbumin-sensitized BALB/c mice.","authors":"Jan, Tong-Rong; Su, Shu-Ting; Wu, Hsin-Ying; Liao, Mei-Hsiu","year":2007,"journal":"International immunopharmacology, 7(6), 773-80","doi":null,"pmid":"17466911","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice received a single dose of CBD (5-20 mg/kg) before being sensitized with ovalbumin (a common allergen used in immunology research). Seven days later, researchers measured immune responses.\n\nThe highest CBD dose (20 mg/kg) significantly reduced IgM antibody levels, while all three doses (5, 10, and 20 mg/kg) suppressed IgG1 and IgG2a antibody production. Immune cells from CBD-treated mice produced less IL-2, IL-4, and IFN-gamma when stimulated, and T-cell proliferation was markedly suppressed.\n\nImportantly, these effects were confirmed both in vivo (in the living mice) and in vitro (when immune cells were directly exposed to CBD), demonstrating a direct immunosuppressive action rather than an indirect systemic effect.","whyItMatters":"This study provided dose-response evidence that CBD has significant immunosuppressive properties. While this could be beneficial for autoimmune conditions or allergies, it also raises questions about whether regular CBD use might compromise normal immune function.","specificNumbers":"CBD 20 mg/kg suppressed IgM production. All doses (5, 10, 20 mg/kg) suppressed IgG1 and IgG2a. Splenocyte proliferation and cytokine production (IL-2, IL-4, IFN-gamma) were markedly reduced at 5 and 20 mg/kg.","methodology":"BALB/c mice received a single intraperitoneal dose of CBD (5, 10, or 20 mg/kg) before ovalbumin sensitization. Serum antibodies were measured 7 days later. Splenocyte function was assessed through cytokine production and proliferation assays both ex vivo and in vitro.","limitations":"This was a mouse study using intraperitoneal injection, a route not used by humans taking CBD. A single dose before sensitization is a specific scenario that may not reflect typical CBD use patterns. The ovalbumin model is standard but may not predict effects on natural immune challenges."},{"rthcId":"RTHC-00278","title":"Targeted modulators of the endogenous cannabinoid system: future medications to treat addiction disorders and obesity.","authors":"Janero, David R; Makriyannis, Alexandros","year":2007,"journal":"Current psychiatry reports, 9(5), 365-73","doi":null,"pmid":"17915075","tags":["addiction","neuroscience","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review outlined how the endocannabinoid system regulates reward-driven behaviors that underlie both addiction and obesity. Both conditions involve endocannabinoid system hyperactivity, where the brain's internal cannabinoid signaling is turned up too high.\n\nThe authors described how CB1 cannabinoid receptor modulators, drugs that can either block or fine-tune CB1 activity, represented a rational therapeutic approach. The review discussed rimonabant, a CB1 blocker that had shown promise for both smoking cessation and weight loss, as a proof of concept.\n\nThe key insight was that rational drug design targeting specific components of the endocannabinoid system (receptors, enzymes, transporters) could potentially produce medications that address the reward-seeking component of addiction and obesity without the broad side effects of older approaches.","whyItMatters":"Both substance abuse and obesity are major public health challenges with limited pharmacological options. This review articulated a scientific rationale for targeting the endocannabinoid system, which regulates both food intake and drug reward through overlapping neural circuits.","specificNumbers":"The review covered endocannabinoid system components including CB1 and CB2 receptors, endogenous ligands (anandamide, 2-AG), and metabolic enzymes (FAAH, MAGL). Rimonabant was discussed as the primary CB1 modulator in clinical development.","methodology":"This was a narrative review synthesizing the scientific literature on endocannabinoid system pharmacology as it relates to addiction and obesity. The authors focused on translational research connecting basic science to potential clinical applications.","limitations":"As a narrative review, it did not systematically assess evidence quality. The review was written before rimonabant's psychiatric side effects led to its market withdrawal, so it presented a more optimistic picture than later evidence supported."},{"rthcId":"RTHC-00279","title":"Acute effects of Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity.","authors":"Juckel, Georg; Roser, Patrik; Nadulski, Thomas; Stadelmann, Andreas M; Gallinat, Jürgen","year":2007,"journal":"Schizophrenia research, 97(1-3), 109-17","doi":null,"pmid":"17884351","tags":["psychosis","cbd","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a double-blind, placebo-controlled crossover study, 22 healthy volunteers received either pure THC, a standardized cannabis extract containing both THC and CBD, or placebo on separate occasions.\n\nThe cannabis extract (THC + CBD) produced significantly greater mismatch negativity (MMN) amplitudes at central brain electrodes compared to both placebo and pure THC. MMN is an automatic brain response that reflects auditory information processing and is often reduced in schizophrenia.\n\nPure THC alone did not significantly alter MMN amplitudes compared to placebo. Since the main difference between the two active conditions was the presence of CBD in the extract, the authors suggested that CBD may contribute to enhanced cortical activation and cognitive processing, potentially through neuroprotective or anti-psychotic mechanisms.\n\nMMN amplitudes at central electrodes correlated with blood levels of 11-OH-THC, a psychoactive THC metabolite.","whyItMatters":"Reduced MMN is a biomarker of schizophrenia and reflects impaired automatic auditory processing. This study provided experimental evidence in humans that CBD may counteract some of THC's effects on brain function, supporting the hypothesis that CBD has neuroprotective or antipsychotic properties.","specificNumbers":"22 healthy volunteers. Cannabis extract with CBD significantly increased MMN amplitude at central electrodes (p significant). Pure THC showed no significant effect on MMN. 11-OH-THC levels correlated with MMN amplitudes at central electrodes.","methodology":"This was a prospective, double-blind, placebo-controlled crossover study in 22 healthy volunteers. Each participant received THC, standardized cannabis extract (THC + CBD), and placebo on separate occasions. Auditory mismatch negativity was recorded using 32-channel EEG with 1000 standard (1000 Hz) and deviant (1500 Hz) stimuli.","limitations":"The sample was small (22 participants). The study examined only one aspect of cognitive function (auditory mismatch negativity). The cannabis extract contained other compounds besides CBD that could contribute to the difference. Acute effects may not predict chronic use outcomes."},{"rthcId":"RTHC-00280","title":"Mutation studies of Ser7.39 and Ser2.60 in the human CB1 cannabinoid receptor: evidence for a serine-induced bend in CB1 transmembrane helix 7.","authors":"Kapur, Ankur; Hurst, Dow P; Fleischer, Daniel; Whitnell, Rob; Thakur, Ganesh A; Makriyannis, Alexandros; Reggio, Patricia H; Abood, Mary E","year":2007,"journal":"Molecular pharmacology, 71(6), 1512-24","doi":null,"pmid":"17384224","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers mutated two serine residues in the human CB1 cannabinoid receptor to determine their roles in ligand binding.\n\nThe Ser7.39 mutation (S7.39A) completely abolished high-affinity binding of CP55,940, a widely used synthetic cannabinoid, and dramatically reduced binding of HU210 and AM4056 (50- to 100-fold). Their activation potency dropped by over 200-fold.\n\nRemarkably, the same mutation had virtually no effect on WIN55,212-2 binding, demonstrating that this structurally different cannabinoid binds to a distinct site on the receptor. The Ser2.60 mutation had no effect on any tested ligand.\n\nMolecular modeling suggested that Ser7.39 induces a bend in the receptor's transmembrane helix 7, creating a docking space specifically required by CP55,940-type compounds.","whyItMatters":"Understanding exactly how different cannabinoids interact with the CB1 receptor at the molecular level is essential for designing targeted drugs that activate specific aspects of cannabinoid signaling while avoiding unwanted effects.","specificNumbers":"S7.39A mutation: complete loss of CP55,940 binding; 50-100 fold reduction in HU210 and AM4056 affinity; >200-fold reduction in HU210/AM4056 potency. WIN55,212-2 binding: unaffected. S2.60A mutation: no effect on any ligand.","methodology":"Researchers created mutant human CB1 receptors (S7.39A and S2.60A) stably expressed in human kidney cells. They tested radioligand binding and GTPgammaS functional assays with four different cannabinoid ligands (CP55,940, WIN55,212-2, HU210, AM4056). Molecular modeling was used to explain the structural basis of the findings.","limitations":"The study used an artificial expression system (human kidney cells), which may not fully represent how CB1 receptors behave in neurons. Only four ligands were tested. Molecular modeling predictions need experimental validation."},{"rthcId":"RTHC-00281","title":"Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1.","authors":"Martini, Lene; Waldhoer, Maria; Pusch, Margareta; Kharazia, Viktor; Fong, Jamie; Lee, Josephine H; Freissmuth, Clarissa; Whistler, Jennifer L","year":2007,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 21(3), 802-11","doi":null,"pmid":"17197383","tags":["neuroscience","tolerance","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Agonist exposure led CB1 receptors to internalize, then get degraded rather than recycled back to the surface. Disrupting the G-protein-coupled receptor-associated sorting protein GASP1 shifted this postendocytic fate, implicating GASP1 as a key director of CB1 receptor degradation. The pattern appeared both in HEK293 cells engineered to express CB1 and in primary cultured neurons with endogenous CB1. This cellular pathway offers a mechanistic explanation for receptor down-regulation that is often observed after prolonged cannabinoid exposure.","whyItMatters":"CB1 trafficking influences signaling strength. If activated receptors are routed to degradation, surface levels drop and signaling capacity falls, which aligns with receptor down-regulation seen after repeated agonist exposure. Identifying GASP1 as a major director of CB1's postendocytic fate gives a concrete, testable mechanism for how cellular tolerance could develop at the receptor level.","specificNumbers":"- Experimental models: HEK293 cells overexpressing CB1, plus primary cultured neurons with endogenous CB1\n- Outcome: cannabinoid agonists drove CB1 internalization followed by degradation\n- Mechanism: GASP1 played a major role in directing internalized CB1 to degradation rather than recycling\n- Study type: mechanistic cell and neuron culture work, not an in vivo or clinical study","methodology":"Researchers used two model systems: HEK293 cells stably expressing CB1 and primary cultured neurons that naturally express CB1. They applied cannabinoid agonists known to trigger receptor internalization, then tracked where the receptors went and what happened to them. By interfering with GASP1 function, they tested whether this sorting protein determined whether internalized CB1 receptors were recycled or degraded. Endpoints included receptor localization and loss consistent with degradation after endocytosis.","limitations":"This was done in vitro using HEK293 overexpression and primary neuron cultures. Cell systems may not mirror receptor trafficking in intact brain circuits. Sample size details and time courses are not in the abstract. Agonists were not specified, so it is unclear how general the effect is across different cannabinoid ligands or potencies. The study links GASP1 to CB1 degradation in cells, but it does not test whether this pathway governs tolerance in living animals or people."},{"rthcId":"RTHC-00282","title":"Cannabinoids:their role in pain and palliation.","authors":"McCarberg, Bill H","year":2007,"journal":"Journal of pain & palliative care pharmacotherapy, 21(3), 19-28","doi":null,"pmid":"18032352","tags":["pain","medical-cannabis","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the evidence for cannabinoid use in pain management and palliative care across several conditions.\n\nThe author described how the endocannabinoid system works alongside the opioid system as a retrograde neuromodulatory network. Clinical trial evidence suggested cannabinoid formulations could be useful for chronic pain, with delivery method and formulation playing critical roles in determining the risk-benefit profile.\n\nA key theme was opioid-cannabinoid synergy: co-administration appeared to produce opioid-sparing effects, extend pain relief duration, and potentially reduce opioid tolerance and dependence. Beyond pain, cannabinoids addressed multiple symptoms simultaneously, including sleep disturbance, appetite loss, muscle spasm, and nausea.\n\nThe review also noted emerging evidence for anti-cancer and neuroprotective properties that could be particularly relevant in aging and terminally ill populations.","whyItMatters":"Palliative care patients often manage multiple symptoms with multiple medications. A single class of drugs that addresses pain, nausea, appetite, sleep, and muscle spasm simultaneously could reduce medication burden and improve quality of life in serious illness.","specificNumbers":"The review covered clinical trials of synthetic and plant-based cannabinoids across multiple conditions, with a focus on pain, cancer, neurodegenerative disease, and HIV/AIDS symptom management.","methodology":"This was a narrative review covering the mechanism of action of cannabinoids, marketed agents and those in clinical trials, and their therapeutic applications across chronic pain, cancer, neurodegenerative diseases, and HIV/AIDS.","limitations":"As a narrative review, it did not systematically grade the evidence. The clinical trial evidence available in 2007 was relatively limited. The review may have presented an optimistic perspective on cannabinoid therapy."},{"rthcId":"RTHC-00283","title":"Workplace drug testing in a military organization: results and experiences from the testing program in the Finnish Defence Forces.","authors":"Meririnne, Esa; Mykkänen, Sirpa; Lillsunde, Pirjo; Kuoppasalmi, Kimmo; Lerssi, Risto; Laaksonen, Ilmo; Lehtomäki, Kyösti; Henriksson, Markus","year":2007,"journal":"Forensic science international, 170(2-3), 171-4","doi":null,"pmid":"17630234","tags":["workplace"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"The Finnish Defence Forces conducted a drug testing program from 2002 to 2005, testing soldiers, civilian personnel, and military students. Testing occurred during application/enrollment and through annual random testing of 5% of personnel.\n\nOver 2,000 urine samples were analyzed for cannabis, opiates, amphetamines, and cocaine. Only one person, a civilian job applicant, tested positive for amphetamine and cannabis. Seven other samples showed codeine and morphine, all attributed to prescribed medications rather than drug abuse.\n\nThe program encountered no significant operational difficulties. The authors attributed the extremely low positive rate partly to the military's broader anti-drug strategy, of which testing was one component. They noted the program's financial costs and called for controlled studies to determine whether testing programs actually improve workplace safety.","whyItMatters":"This study provided data on the actual yield of workplace drug testing in a military setting, finding that the rate of illicit drug use was extremely low. This raises questions about the cost-effectiveness of broad testing programs when baseline prevalence is already very low.","specificNumbers":"Over 2,000 urine samples tested from 2002-2005. 1 positive for illicit drugs (amphetamine and cannabis). 7 positives for prescription opioids (not abuse). 5% of personnel randomly tested annually.","methodology":"Cross-sectional analysis of a workplace drug testing program. Over 2,000 urine samples collected from 2002-2005 were analyzed in an accredited laboratory for cannabis, opiates, amphetamines, and cocaine. Results were compiled alongside operational and financial data from the program.","limitations":"The study describes one military in one country with generally low drug use rates, limiting generalizability. The deterrent effect of the testing program itself may explain the low positive rate, making it impossible to know what the rate would be without testing. No control group existed."},{"rthcId":"RTHC-00284","title":"Suicidal ideation and associated factors among in-school adolescents in Zambia.","authors":"Muula, A S; Kazembe, L N; Rudatsikira, E; Siziya, S","year":2007,"journal":"Tanzania health research bulletin, 9(3), 202-6","doi":null,"pmid":"18087900","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using data from the 2004 Zambia Global School-Based Health Survey, researchers analyzed responses from 1,970 in-school adolescents regarding suicidal ideation and behavioral risk factors.\n\nOverall, 31.3% of students reported having seriously considered suicide in the past 12 months, with no significant difference between males (31.1%) and females (31.4%). A striking 35.9% reported having ever smoked marijuana.\n\nIn logistic regression analysis, ever having used marijuana was positively associated with suicidal ideation (OR=1.18, 95% CI 1.17-1.19). Other associated factors included having been drunk, feeling worried, and feeling sad or hopeless. Being male and being under 14 years old were also positively associated.\n\nUnexpectedly, loneliness appeared protective (OR=0.92), which the authors noted was counterintuitive and may reflect methodological issues.","whyItMatters":"This study provided data from sub-Saharan Africa, a region underrepresented in cannabis and mental health research. The high rate of both suicidal ideation (31.3%) and marijuana use (35.9%) among Zambian school students highlights the scale of these issues in this population.","specificNumbers":"1,970 adolescents surveyed. 31.3% reported suicidal ideation in past 12 months. 35.9% had ever used marijuana. 40.8% were current drinkers. Marijuana association with suicidal ideation: OR=1.18 (95% CI 1.17-1.19). Alcohol intoxication: OR=1.28.","methodology":"Cross-sectional analysis of the 2004 Zambia Global School-Based Health Survey, a school-based self-report questionnaire administered to 1,970 adolescents. Backward logistic regression was used to assess associations between risk factors and suicidal ideation.","limitations":"Cross-sectional design cannot determine whether marijuana use contributes to suicidal ideation or whether both share common underlying causes. Self-report data from adolescents may be unreliable. The \"ever used\" marijuana measure doesn't capture frequency or recency. Non-response bias may affect the suicidal ideation results."},{"rthcId":"RTHC-00285","title":"Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.","authors":"Nurmikko, Turo J; Serpell, Mick G; Hoggart, Barbara; Toomey, Peter J; Morlion, Bart J; Haines, Derek","year":2007,"journal":"Pain, 133(1-3), 210-20","doi":null,"pmid":"17997224","tags":["pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In a five-week randomized trial, 125 patients with peripheral neuropathic pain received either Sativex (THC:CBD mouth spray) or placebo while continuing their existing pain medications.\n\nPatients on Sativex experienced significantly greater pain reduction: -1.48 points vs. -0.52 points on a 0-10 pain scale (p=0.004). The treatment also improved sleep (p=0.001), reduced both dynamic and punctate allodynia (pain from normally non-painful touch), and lowered pain-related disability (p=0.003).\n\nPatient-reported global improvement strongly favored Sativex (p<0.001). However, 18% of Sativex patients withdrew due to side effects (mainly sedation and GI issues) compared to 3% on placebo.\n\nAn open-label extension study showed that pain relief was maintained for 52 weeks without dose escalation or toxicity, suggesting no tolerance developed.","whyItMatters":"Neuropathic pain is notoriously difficult to treat, and allodynia (pain from gentle touch) is one of its most debilitating features. This trial showed Sativex addressed both general neuropathic pain and allodynia specifically, with sustained benefit over a year.","specificNumbers":"Pain reduction: -1.48 vs. -0.52 points (p=0.004). Sleep improvement: p=0.001. Dynamic allodynia: p=0.042. Punctate allodynia: p=0.021. Disability index: p=0.003. Withdrawal due to adverse events: 18% Sativex vs. 3% placebo. 52-week extension showed maintained benefit.","methodology":"Randomized, double-blind, placebo-controlled, parallel design trial over 5 weeks. 125 patients with peripheral neuropathic pain self-titrated their Sativex dose while maintaining existing analgesics. Primary outcome was change in daily pain intensity on a 0-10 numerical rating scale. An open-label extension followed for up to 52 weeks.","limitations":"The five-week controlled phase was relatively short. The open-label extension lacked a placebo control, so sustained benefit could partly reflect placebo effects or natural disease fluctuation. The 18% withdrawal rate on Sativex suggests tolerability challenges for some patients."},{"rthcId":"RTHC-00286","title":"Combined immunomodulating properties of 3,4-methylenedioxymethamphetamine (MDMA) and cannabis in humans.","authors":"Pacifici, Roberta; Zuccaro, Piergiorgio; Farré, Magí; Poudevida, Sandra; Abanades, Sergio; Pichini, Simona; Langohr, Klaus; Segura, Jordi; de la Torre, Rafael","year":2007,"journal":"Addiction (Abingdon, England), 102(6), 931-6","doi":null,"pmid":"17523988","tags":["inflammation","drug-interactions"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed three groups over one year with assessments at baseline, 6 months, and 12 months: 37 people who used both MDMA and cannabis, 23 cannabis-only users, and 34 non-using controls.\n\nThe MDMA-cannabis group showed significantly decreased IL-2 (a pro-immune cytokine) and increased TGF-beta1 (an anti-inflammatory marker), along with reduced total lymphocytes, CD4 cells, and natural killer cells. The cannabis-only group showed intermediate changes between the MDMA-cannabis users and controls.\n\nThese immune alterations persisted across all three time points, suggesting they were sustained rather than acute effects. Regular MDMA-cannabis users had significantly more mild infections (colds, respiratory issues) than occasional users or controls.\n\nNo difference was found between regular and occasional MDMA users for the immune markers, though infection rates were higher in regular users.","whyItMatters":"Most drug interaction research focuses on acute effects. This study showed that combined MDMA and cannabis use produced immune system changes that persisted over at least a year and translated into measurable health consequences (more infections).","specificNumbers":"37 MDMA+cannabis users, 23 cannabis-only users, 34 controls. Decreased: IL-2, total lymphocytes, CD4 cells, NK cells. Increased: TGF-beta1. Higher mild infection rate in regular MDMA+cannabis users. Immune changes sustained over 12 months.","methodology":"Longitudinal prospective study with three cross-sectional evaluations at baseline, 6 months, and 1 year. Cell-mediated immune function was assessed through cytokine panels and immune cell counts. Infection history was documented through self-report and medical records.","limitations":"Polydrug users often use additional substances not accounted for in this study. Self-reported drug use may be inaccurate. The observational design cannot confirm that drug use caused the immune changes rather than pre-existing differences. Sample sizes were relatively small."},{"rthcId":"RTHC-00287","title":"High suicide risk after the development of cognitive and working memory deficits caused by cannabis, cocaine and ecstasy use.","authors":"Pompili, Maurizio; Lester, David; Girardi, Paolo; Tatarelli, Roberto","year":2007,"journal":"Substance abuse, 28(1), 25-30","doi":"10.1300/J465v28n01_04","pmid":"19263559","tags":["mental-health","cognition"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The authors described a 30-year-old man who used cannabis, MDMA (ecstasy), and cocaine for at least three years and subsequently developed significant cognitive and working memory deficits.\n\nThese cognitive problems led to increasing difficulties in his professional and personal life. As his functioning declined, he developed depressive symptoms including hopelessness and helplessness, which progressed to active suicidal ideation and ultimately a suicide attempt.\n\nThe authors proposed a causal chain: polysubstance use caused cognitive deficits, which caused functional decline, which caused depression, which caused suicidal behavior. They highlighted this pathway as an underrecognized mechanism linking substance use to suicide risk.","whyItMatters":"This case report proposed a specific mechanism by which substance use could lead to suicidality: through cognitive decline and functional impairment rather than through direct pharmacological effects on mood. This pathway may be underrecognized in clinical practice.","specificNumbers":"One 30-year-old male patient. At least 3 years of polysubstance use (cannabis, MDMA, cocaine). Cognitive deficits in working memory and executive function. One suicide attempt documented.","methodology":"This is a single case report describing one patient's clinical course. The authors assessed cognitive function, reviewed substance use history, and documented psychiatric symptoms and the suicide attempt.","limitations":"A single case report cannot establish causation. The patient used multiple substances, making it impossible to attribute cognitive deficits to any single drug. Pre-existing vulnerabilities (cognitive, psychiatric) may have preceded substance use. No objective baseline cognitive testing was available."},{"rthcId":"RTHC-00288","title":"Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors.","authors":"Pryce, G; Baker, D","year":2007,"journal":"British journal of pharmacology, 150(4), 519-25","doi":null,"pmid":"17220914","tags":["medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers tested cannabinoid effects on spasticity in both normal mice and mice genetically lacking CB1 receptors, all with experimental autoimmune encephalomyelitis (a model of MS).\n\nSome CB2-selective agonists (like RWJ400065) appeared to reduce spasticity. However, when tested in CB1-deficient mice, this anti-spastic effect completely disappeared, revealing that the seeming \"CB2\" effect was actually due to cross-reactivity with CB1 receptors.\n\nNon-selective cannabinoid agonists (WIN55,212-2 and CP55,940) also lost their anti-spastic effects in CB1-knockout mice. This provided definitive genetic evidence that CB1, not CB2, is the receptor responsible for cannabinoid control of spasticity.\n\nThe authors noted a significant clinical implication: since CB1 also mediates the psychoactive effects of cannabinoids, truly separating therapeutic anti-spastic effects from unwanted psychological effects would be difficult.","whyItMatters":"There had been hope that CB2-selective drugs could provide the anti-spastic benefits of cannabinoids without psychoactive side effects. This study eliminated that possibility for spasticity, showing that even apparently CB2-selective drugs worked through CB1 cross-reactivity.","specificNumbers":"RWJ400065 (CB2-selective agonist) reduced spasticity in wildtype mice but had zero effect in CB1-knockout mice. WIN55,212-2 and CP55,940 (non-selective agonists) also lost anti-spastic effects in CB1-deficient mice.","methodology":"Spasticity was induced in wildtype and CB1-deficient mice through relapsing experimental autoimmune encephalomyelitis. Hindlimb spastic stiffness was measured by resistance to flexion against a strain gauge following administration of various CB1 and CB2 receptor agonists.","limitations":"Mouse models of MS do not fully replicate human MS spasticity. The limited specificity of available cannabinoid compounds was acknowledged by the authors. Genetic knockout models can develop compensatory changes that might affect results."},{"rthcId":"RTHC-00289","title":"Behavioural and neurochemical effects of combined MDMA and THC administration in mice.","authors":"Robledo, Patricia; Trigo, Jose M; Panayi, Fany; de la Torre, Rafael; Maldonado, Rafael","year":2007,"journal":"Psychopharmacology, 195(2), 255-64","doi":null,"pmid":"17684733","tags":["drug-interactions","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested how THC and MDMA interact when given together to mice, using reward-based behavioral tests and brain dopamine measurements.\n\nAt low doses, THC and MDMA produced a synergistic reward effect: combining sub-effective doses of both drugs (THC 0.3 mg/kg + MDMA 3 mg/kg) produced place preference, while neither alone did at those doses. THC pretreatment also enabled mice to self-administer a sub-threshold MDMA dose.\n\nAt higher MDMA doses, the pattern reversed: THC combined with a fully effective MDMA dose (10 mg/kg) actually decreased place preference, suggesting a biphasic interaction.\n\nIn the brain's reward center (nucleus accumbens), THC alone increased dopamine release, while low-dose MDMA alone did not. When MDMA was given before THC, dopamine levels dropped relative to THC alone. The order of administration mattered for the neurochemical effects.","whyItMatters":"Cannabis and MDMA are frequently co-used recreationally. This study showed their interaction on reward pathways is not simply additive but complex and dose-dependent, with low doses enhancing each other's rewarding effects and higher doses producing different patterns.","specificNumbers":"THC 0.3 mg/kg + MDMA 3 mg/kg produced CPP; neither alone did at these doses. MDMA 10 mg/kg + THC 0.3 mg/kg decreased CPP vs. MDMA 10 mg/kg alone. THC alone increased dopamine in nucleus accumbens. MDMA before THC reduced dopamine relative to THC alone.","methodology":"Mice underwent conditioned place preference (CPP) testing and operant self-administration with various THC/MDMA combinations. In vivo microdialysis measured dopamine outflow in the nucleus accumbens. The study examined dose-dependent and order-dependent interactions.","limitations":"Mouse reward behavior may not directly translate to human subjective experience. The doses used were chosen for experimental precision and may not reflect typical recreational use patterns. Only acute interactions were studied."},{"rthcId":"RTHC-00290","title":"Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial.","authors":"Rog, David J; Nurmikko, Turo J; Young, Carolyn A","year":2007,"journal":"Clinical therapeutics, 29(9), 2068-79","doi":null,"pmid":"18035205","tags":["pain","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This open-label extension followed 63 MS patients with central neuropathic pain for up to 917 days (over 2.5 years) of Sativex (THC/CBD mouth spray) treatment.\n\nOf the 63 patients who entered the extension, 34 (54%) completed more than one year, and 28 (44%) completed the full follow-up. Among these 28 completers, mean pain scores decreased from 3.8 (end of the original trial for the treatment group) to 2.9 in the final week, suggesting continued improvement over time.\n\nCritically, the mean number of sprays remained stable throughout, providing no evidence of tolerance. Intoxication ratings also remained stable, not increasing over time.\n\nHowever, 92% of patients experienced at least one adverse event (dizziness 27%, nausea 18%, feeling intoxicated 11%), and 25% withdrew specifically due to adverse events. Two serious adverse events (cardiac) occurred in one patient but resolved after stopping treatment.","whyItMatters":"One of the biggest concerns about long-term cannabinoid use is tolerance, where patients need escalating doses for the same effect. This study showed no tolerance over approximately two years, which was unusual and encouraging for the field.","specificNumbers":"63 patients entered extension. 28 (44%) completed full follow-up (mean 839 days). Mean pain score at completion: 2.9/10. 92% experienced adverse events. 25% withdrew due to adverse events. Dizziness (27%), nausea (18%), intoxication (11%). 2 serious cardiac events (1 patient, resolved).","methodology":"Uncontrolled, open-label extension of a previous 5-week randomized trial. 63 MS patients with central neuropathic pain self-titrated Sativex dosing. Primary endpoint was adverse event monitoring. Pain scores, drug usage, and intoxication levels were tracked as secondary endpoints.","limitations":"No placebo control in the extension phase, so sustained benefit could reflect placebo effects, natural disease changes, or selection bias (patients who benefited were more likely to continue). The 56% dropout rate means results represent only the most successful patients."},{"rthcId":"RTHC-00291","title":"Medical marijuana and the developing role of the pharmacist.","authors":"Seamon, Matthew J; Fass, Jennifer A; Maniscalco-Feichtl, Maria; Abu-Shraie, Nada A","year":2007,"journal":"American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 64(10), 1037-44","doi":null,"pmid":"17494903","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review outlined the pharmacological, therapeutic, and legal landscape of medical marijuana for pharmacists as of 2007.\n\nThe authors identified five general indications with varying levels of evidence: chemotherapy-induced nausea, weight loss from debilitating illness (HIV, cancer), spasticity from neurological diseases, pain syndromes, and other uses including glaucoma.\n\nThe review cataloged known adverse effects across psychiatric, cardiovascular, respiratory, and immunologic domains, and highlighted potential drug-drug interactions and disease-state interactions that pharmacists should be aware of.\n\nA key practical challenge was noted: since marijuana remained a Schedule I controlled substance under federal law, patients using state-legal medical marijuana might never interact with a pharmacist, creating a gap in patient safety.","whyItMatters":"This review highlighted a unique problem in medical marijuana: it occupied a legal gray zone where patients used it medicinally but without the pharmaceutical infrastructure (pharmacist counseling, interaction screening, quality control) that exists for other medications.","specificNumbers":"Over 460 active chemicals and 60+ unique cannabinoids in marijuana. 11 US states had legalized medical marijuana as of 2007. Five general medical indications were identified.","methodology":"Narrative review of published literature on marijuana pharmacology, therapeutic uses, safety profile, drug interactions, and legal status. Organized as a practical reference for pharmacists.","limitations":"As a narrative review from 2007, the evidence base was limited. The legal landscape has changed dramatically since publication. Drug interaction data for cannabis remained sparse and largely theoretical."},{"rthcId":"RTHC-00292","title":"The association between conduct problems and the initiation and progression of marijuana use during adolescence: a genetic analysis across time.","authors":"Shelton, Katherine; Lifford, Kate; Fowler, Tom; Rice, Frances; Neale, Mike; Harold, Gordon; Thapar, Anita; van den Bree, Marianne","year":2007,"journal":"Behavior genetics, 37(2), 314-25","doi":null,"pmid":"17131199","tags":["youth","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using data from 1,088 adolescent twin pairs in Wales and England, researchers examined how genetic and environmental factors influence the path from childhood conduct problems to adolescent marijuana use.\n\nMarijuana use initiation (whether someone tried it) was influenced by genetic factors, shared environment, and unique environment. Marijuana use progression (how frequently someone used after trying it) was influenced by genetic and unique environmental factors, but not shared environment.\n\nFor conduct problems, the presence or absence of problems was largely heritable, while the severity of problems was more environmentally influenced.\n\nMultivariate modeling showed that childhood conduct problems made a small but statistically significant contribution to marijuana use risk 8 years later, suggesting some shared genetic vulnerability between behavioral problems and later drug use.","whyItMatters":"The finding that genetics partly explain the link between conduct problems and marijuana use challenges the assumption that bad behavior simply leads to drug use. Some of the same genetic factors that predispose to behavioral problems may also predispose to marijuana use, independent of a direct causal path.","specificNumbers":"1,088 adolescent twin pairs. 8-year follow-up (1996-2004). Marijuana initiation influenced by genetics + shared + unique environment. Marijuana progression influenced by genetics + unique environment only. Conduct problems contributed a small but significant genetic risk to later marijuana use.","methodology":"Prospective longitudinal twin study (CaStANET cohort). Conduct problems assessed in 1996 via parent and teacher reports. Marijuana use self-reported in 2004. Novel modeling approach separated marijuana use initiation from progression. Genetic, shared environmental, and unique environmental influences were estimated.","limitations":"Self-reported marijuana use in adolescents may be unreliable. The 8-year gap between assessments leaves the developmental pathway largely unobserved. The \"small but significant\" contribution suggests many other factors are involved. The sample was predominantly white British."},{"rthcId":"RTHC-00293","title":"Symptomatic treatment of multiple sclerosis using cannabinoids: recent advances.","authors":"Smith, Paul F","year":2007,"journal":"Expert review of neurotherapeutics, 7(9), 1157-63","doi":null,"pmid":"17868014","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review surveyed the rapidly expanding clinical trial landscape for cannabinoids in multiple sclerosis, covering THC, dronabinol, Sativex (THC:CBD), CT-3, nabilone, and other cannabis extracts.\n\nThe author noted a shift from earlier conflicting evidence to emerging consensus: the majority of recent studies suggested cannabinoids were useful for at least some MS patients with pain and spasticity. The adverse side effect profile was generally described as mild compared to other drugs used for these symptoms.\n\nHowever, two concerns remained: potential long-term psychiatric side effects and effects on fetal development. The review emphasized that the field was moving from whether cannabinoids work in MS to identifying which patients benefit most and optimizing formulations.","whyItMatters":"This review captured a turning point in the field: by 2007, the evidence had shifted from uncertain to generally supportive of cannabinoids for MS symptoms. This consensus eventually led to regulatory approvals.","specificNumbers":"Multiple cannabinoid formulations reviewed: THC, dronabinol, Sativex (THC:CBD), CT-3, nabilone. Multiple clinical trials surveyed. Side effects generally rated as mild compared to alternatives.","methodology":"Narrative review of recent clinical trials investigating cannabinoids for MS symptom management. The author compared findings across different cannabinoid formulations, study designs, and outcome measures.","limitations":"As a narrative review, it did not formally assess bias or evidence quality across studies. The \"subset of individuals\" who benefit was not well characterized. Long-term safety data remained limited."},{"rthcId":"RTHC-00294","title":"Expression of endocannabinoid synthetic enzyme mRnas is correlated with cannabinoid 1 receptor mRNA in the mouse brain.","authors":"Tsuyama, Shoichiro; Oikawa, Daichi; Yamasaki, Yasuko; Takagi, Sayuri; Ando, Hironori; Furuse, Mitsuhiro","year":2007,"journal":"Nutritional neuroscience, 10(1-2), 45-50","doi":null,"pmid":"17539482","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers investigated whether feeding mice arachidonic acid (AA), the fatty acid building block of endocannabinoids, would change the expression of endocannabinoid-related genes in the brain.\n\nMice received varying amounts of AA-rich oil (0, 100, 200, or 300 microliters) orally for 7 days. Despite this dietary manipulation, no changes in brain gene expression were detected for any endocannabinoid-related enzyme or the CB1 receptor.\n\nHowever, the study revealed a significant correlation: CB1 receptor expression was positively correlated with the expression of PLD (which makes anandamide), FAAH (which breaks down anandamide), and DAGL (which makes 2-AG). This coordinated expression suggests the endocannabinoid system is tightly regulated as a unit rather than having independently controlled components.","whyItMatters":"The finding that endocannabinoid enzymes and their receptor are co-regulated suggests the system maintains internal balance. The lack of dietary influence on gene expression indicates the brain's endocannabinoid system is robust against short-term nutritional changes.","specificNumbers":"Four AA dose groups (0, 100, 200, 300 microliters). 7 days of treatment. CB1 receptor mRNA positively correlated with PLD, FAAH, and DAGL expression. No dose-dependent changes in any measured gene.","methodology":"Male mice received oral AA-rich oil at four dose levels for 7 days. Whole brain mRNA expression of PLD, FAAH, DAGL, MAGL, and CB1 receptor was measured and analyzed for dose-response effects and inter-gene correlations.","limitations":"Whole brain homogenates were used, which could mask region-specific changes. The 7-day treatment period may be too short to observe dietary effects. Only mRNA was measured, not protein levels or enzyme activity. Small sample typical of mouse studies."},{"rthcId":"RTHC-00295","title":"Differential regulation of endocannabinoid synthesis and degradation in the uterus during embryo implantation.","authors":"Wang, Haibin; Xie, Huirong; Sun, Xiaofei; Kingsley, Philip J; Marnett, Lawrence J; Cravatt, Benjamin F; Dey, Sudhansu K","year":2007,"journal":"Prostaglandins & other lipid mediators, 83(1-2), 62-74","doi":null,"pmid":"17259073","tags":["pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers mapped the endocannabinoid system in the mouse uterus during embryo implantation, focusing on both anandamide and 2-AG.\n\n2-AG was present at levels one order of magnitude (roughly 10x) higher than anandamide in the uterus, but both showed the same spatial pattern: lower levels at implantation sites and higher levels at interimplantation sites.\n\nThese gradients were created by region- and stage-specific expression of four key enzymes: NAPE-PLD and FAAH (for anandamide synthesis and breakdown) and DAGLalpha and MAGL (for 2-AG synthesis and breakdown). The enzymes were expressed in precise patterns to create lower endocannabinoid levels exactly where embryos needed to implant.\n\nGenetic evidence showed FAAH was the primary anandamide-degrading enzyme, while 2-AG metabolism involved MAGL, COX-2, and to some extent COX-1. Disrupting these pathways compromised pregnancy outcomes.","whyItMatters":"This study demonstrated that successful pregnancy depends on precise endocannabinoid regulation in the uterus. Since THC and other cannabinoids can disrupt this system, the findings raised concerns about cannabis use during early pregnancy and implantation.","specificNumbers":"2-AG levels were approximately 10x higher than anandamide in the uterus. Both showed lower levels at implantation sites vs. interimplantation sites. FAAH was the primary anandamide degrader. MAGL, COX-2, and COX-1 participated in 2-AG metabolism.","methodology":"Researchers measured anandamide and 2-AG levels at implantation and interimplantation sites in pregnant mouse uteri. They mapped enzyme expression (NAPE-PLD, FAAH, DAGLalpha, MAGL) by region and stage. Genetic knockout mice were used to confirm enzyme roles in endocannabinoid metabolism.","limitations":"Mouse reproductive biology differs from human in important ways. The study focused on enzyme expression and endocannabinoid levels rather than directly testing cannabis exposure effects. The precise endocannabinoid thresholds for successful implantation were not established."},{"rthcId":"RTHC-00296","title":"Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample.","authors":"Agrawal, Arpana; Hinrichs, Anthony L; Dunn, Gerald; Bertelsen, Sarah; Dick, Danielle M; Saccone, Scott F; Saccone, Nancy L; Grucza, Richard A; Wang, Jen C; Cloninger, C Robert; Edenberg, Howard J; Foroud, Tatiana; Hesselbrock, Victor; Kramer, John; Bucholz, Kathleen K; Kuperman, Samuel; Nurnberger, John I; Porjesz, Bernice; Schuckit, Marc A; Goate, Alison M; Bierut, Laura J","year":2008,"journal":"Drug and alcohol dependence, 93(1-2), 12-20","doi":null,"pmid":"17942244","tags":["genetics","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using large multi-generational families from the COGA study, researchers scanned the genome for regions linked to substance dependence using 1,717 genetic markers.\n\nFor alcohol dependence, significant linkage signals appeared on chromosomes 1, 2, and 10 (highest LOD score 3.7 on chromosome 10). For cannabis dependence, a notable signal appeared on chromosome 14 (LOD 1.9). For any illicit drug dependence, signals appeared on chromosomes 10 and 13.\n\nWhen alcohol and drug dependence scores were combined, the strongest signals were on chromosomes 2 (LOD 3.2) and 10 (LOD 2.4 and 2.6 at different locations). The overlap on chromosome 10 for both alcohol-specific and broader substance dependence phenotypes suggested this region may harbor genes influencing general addiction vulnerability rather than substance-specific risk.","whyItMatters":"Identifying chromosomal regions linked to substance dependence is a step toward finding specific genes that influence addiction risk. The overlap between alcohol and drug dependence signals supports the idea that some genetic factors create a general vulnerability to addiction rather than risk for specific substances.","specificNumbers":"Alcohol dependence: LOD 3.7 on chr 10 (60 cM), 3.4 on chr 2 (234 cM). Cannabis dependence: LOD 1.9 on chr 14 (95 cM). Any drug dependence: LOD 2.4 on chr 13 (64 cM). Combined: LOD 3.2 on chr 2, LOD 2.6 on chr 10.","methodology":"Quantitative genome-wide linkage analysis using 1,717 SNP markers in large families from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-IV criteria counts for alcohol dependence, cannabis dependence, and any illicit drug dependence were analyzed individually and in combination.","limitations":"Linkage analysis identifies broad chromosomal regions containing many genes, not specific causal variants. The COGA families were selected for high alcoholism rates, which may limit generalizability. LOD scores for cannabis dependence specifically did not reach genome-wide significance."},{"rthcId":"RTHC-00297","title":"Corpus callosum damage in heavy marijuana use: preliminary evidence from diffusion tensor tractography and tract-based spatial statistics.","authors":"Arnone, D; Barrick, T R; Chengappa, S; Mackay, C E; Clark, C A; Abou-Saleh, M T","year":2008,"journal":"NeuroImage, 41(3), 1067-74","doi":"10.1016/j.neuroimage.2008.02.064","pmid":"18424082","tags":["neuroscience","cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Using diffusion tensor imaging (DTI), researchers compared the corpus callosum (the major white matter tract connecting the brain's left and right hemispheres) in 11 heavy marijuana users who started in early adolescence and 11 age-matched controls.\n\nMean diffusivity (MD), a measure of structural integrity, was significantly increased in marijuana users in the region of the corpus callosum where fibers pass between the prefrontal lobes. Increased MD indicates compromised white matter structure.\n\nThere was a trend toward a positive correlation between MD and length of use, suggesting possible cumulative damage over time. The trend also suggested that younger age at first use might predispose to greater structural damage.\n\nFractional anisotropy (FA), which measures tract coherence, showed trends toward reduction but did not reach significance in all regions.","whyItMatters":"This was early evidence that heavy marijuana use beginning in adolescence may cause structural damage to brain white matter, specifically in the fibers connecting the prefrontal cortices. This region is critical for decision-making, planning, and impulse control.","specificNumbers":"11 heavy marijuana users vs. 11 controls. Significantly increased mean diffusivity in prefrontal corpus callosum fibers. Trend toward correlation between MD and length of use. Users started in early adolescence.","methodology":"Diffusion tensor imaging (DTI) was obtained in 11 heavy marijuana users (onset in early adolescence) and 11 age-matched controls. The corpus callosum was mapped using tractography and tract-based spatial statistics (TBSS). Mean diffusivity and fractional anisotropy were compared between groups.","limitations":"The sample was very small (11 per group). Cross-sectional design cannot determine whether marijuana caused the changes or whether pre-existing differences led to marijuana use. Users likely had other substance exposures. The correlation with length of use was a trend, not significant."},{"rthcId":"RTHC-00298","title":"Sequencing of substance use and affective morbidity in 166 first-episode bipolar I disorder patients.","authors":"Baethge, Christopher; Hennen, John; Khalsa, Hari-Mandir Kaur; Salvatore, Paola; Tohen, Mauricio; Baldessarini, Ross J","year":2008,"journal":"Bipolar disorders, 10(6), 738-41","doi":"10.1111/j.1399-5618.2007.00575.x","pmid":"18837869","tags":["mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 166 first-episode bipolar I disorder patients for an average of 4.7 years, tracking the timing of substance use relative to mood episodes on a quarterly basis.\n\nCannabis use selectively and strongly preceded and coincided with mania and hypomania. This association was specific: cannabis was not similarly associated with depressive episodes.\n\nAlcohol use showed the opposite pattern: it preceded or coincided with depressive episodes but was not specifically linked to mania.\n\nImportantly, substance use did not tend to follow mood episodes. This temporal direction (substance first, then mood episode) suggests substance use may trigger mood episodes rather than being a consequence of them, though the observational design cannot prove causation.","whyItMatters":"The selective association between cannabis and mania (not depression) and between alcohol and depression (not mania) suggests these substances interact with distinct mood circuits. This has clinical implications for counseling bipolar patients about which substances may be most destabilizing for their specific symptom patterns.","specificNumbers":"166 first-episode bipolar I patients. Mean follow-up: 4.7 years. Cannabis use selectively preceded/coincided with mania. Alcohol use preceded/coincided with depression. Substance use did not follow mood episodes in the preceding quarter.","methodology":"Prospective follow-up (mean 4.7 years) of 166 first-episode DSM-IV bipolar I disorder patients. Standardized assessments provided quarterly data on alcohol use, cannabis use, manic/hypomanic episodes, and depressive episodes. Generalized estimating equation regression modeling examined temporal relationships.","limitations":"Observational design cannot prove cannabis causes mania. Quarterly assessments may miss finer-grained temporal patterns. Self-reported substance use in psychiatric patients may be unreliable. Other substances and medication changes were not fully controlled for."},{"rthcId":"RTHC-00299","title":"The endocannabinoid system and multiple sclerosis.","authors":"Baker, David; Pryce, Gareth","year":2008,"journal":"Current pharmaceutical design, 14(23), 2326-36","doi":null,"pmid":"18781983","tags":["medical-cannabis","neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the dual potential of the endocannabinoid system in MS: symptom management and disease modification.\n\nFor symptom relief, the evidence showed that spasticity is tonically (continuously) regulated by the endocannabinoid system, and clinical trials suggested cannabis can relieve pain, spasms, and spasticity. However, since CB1 receptors mediate both therapeutic and psychoactive effects, some unwanted effects are unavoidable.\n\nMore intriguingly, the review presented evidence that the endocannabinoid system is altered at MS lesion sites, with local perturbations in both animal models and human MS tissue. Boosting endocannabinoid activity locally at lesion sites, through increased synthesis or decreased degradation, could provide therapeutic effects while minimizing psychoactive side effects by targeting the damage site rather than the whole brain.\n\nAdditionally, CB1 and CB2 receptor stimulation showed anti-inflammatory and neuroprotective effects, suggesting cannabinoids might reduce the neurodegeneration that causes progressive disability in MS.","whyItMatters":"Most MS medications either treat symptoms or modify the disease course, but rarely both. This review articulated how the endocannabinoid system could potentially do both, and proposed a strategy (local endocannabinoid enhancement) to achieve therapeutic effects while minimizing psychoactive side effects.","specificNumbers":"The review covered evidence from EAE models, human MS tissue, and multiple clinical trials. Local endocannabinoid system changes documented at MS lesion sites in both animal models and human tissue.","methodology":"Narrative review of preclinical and clinical evidence on the endocannabinoid system in MS, covering experimental autoimmune encephalomyelitis models, human MS tissue studies, and clinical trials.","limitations":"Much of the disease-modification evidence was preclinical. Clinical trials had focused on symptom relief rather than disease progression. The proposed local targeting strategy was theoretical and had not been tested in humans."},{"rthcId":"RTHC-00300","title":"Cannabis smoking and risk of lung cancer in men: a pooled analysis of three studies in Maghreb.","authors":"Berthiller, Julien; Straif, Kurt; Boniol, Mathieu; Voirin, Nicolas; Benhaïm-Luzon, Veronique; Ayoub, Wided Ben; Dari, Iman; Laouamri, Slimane; Hamdi-Cherif, Mokhtar; Bartal, Mohamed; Ayed, Fahrat Ben; Sasco, Annie J","year":2008,"journal":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 3(12), 1398-403","doi":"10.1097/JTO.0b013e31818ddcde","pmid":"19057263","tags":["respiratory","cancer"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Researchers pooled data from three hospital-based studies in Tunisia, Morocco, and Algeria, regions with high cannabis consumption.\n\nAmong 430 male lung cancer cases, 15.3% had ever smoked cannabis, compared to 5% of 778 controls. After adjusting for age, country, tobacco smoking, and occupational exposure, the odds ratio for lung cancer among cannabis smokers was 2.4 (95% CI: 1.6-3.8).\n\nThe association remained after adjusting for lifetime tobacco pack-years (OR=2.3, 95% CI: 1.5-3.6). Among current tobacco smokers, the combination of tobacco plus cannabis carried an OR of 18.2 compared to 10.9 for tobacco smoking alone.\n\nLung cancer risk increased with joint-years (cumulative exposure) but not with the dose or duration of cannabis smoking independently, suggesting total lifetime exposure matters most.","whyItMatters":"While the relationship between cannabis smoking and lung cancer has been debated, this pooled analysis from a high-prevalence region found a significant association even after careful tobacco adjustment. The combined effect of tobacco plus cannabis was notably higher than tobacco alone.","specificNumbers":"430 cases, 778 controls. 15.3% of cases vs. 5% of controls ever smoked cannabis. Adjusted OR for cannabis smoking: 2.4 (95% CI: 1.6-3.8). Tobacco-only OR: 10.9. Tobacco + cannabis OR: 18.2. Risk increased with joint-years of cannabis exposure.","methodology":"Pooled analysis of three hospital-based case-control studies in Tunisia, Morocco, and Algeria. 430 male lung cancer cases and 778 male controls. Logistic regression adjusted for country, age, tobacco smoking (pack-years), and occupational exposure.","limitations":"All cannabis smokers were also tobacco users, making it difficult to fully separate the effects. Residual confounding by tobacco despite statistical adjustment is possible. The Maghreb smoking style (often mixing cannabis with tobacco) may differ from other regions. Self-reported cannabis use may be underreported. Hospital-based controls may not represent the general population."},{"rthcId":"RTHC-00301","title":"Sleep disturbance in heavy marijuana users","authors":"Bolla, Karen I.; Lesage, Suzanne R.; Gamaldo, Charlene E.; Neubauer, David N.; Funderburk, Frank R.; Cadet, Jean Lud; David, Philip M.; Verdejo-Garcia, Antonio; Benbrook, Ashley R.","year":2008,"journal":"Sleep, 31(6), 901-908","doi":null,"pmid":"18548836","tags":["sleep","withdrawal"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Across two consecutive lab nights immediately after stopping, heavy users slept less and spent less time in slow wave sleep than matched drug-free controls. On the second night, differences widened. Heavy users showed worse sleep efficiency, took longer to fall asleep, and entered REM sleep sooner than controls. In typical sleep studies, the second night often looks better due to adaptation to the lab environment. Here, the heavy-use group did not show that pattern. Reported withdrawal symptoms, craving, and depression scores did not account for these sleep differences in this sample.","whyItMatters":"Many people report sleep problems when they stop heavy cannabis use. This study used gold-standard sleep recordings rather than self-report and found that early abstinence was associated with disrupted sleep architecture and continuity. Sleep disruption during cessation could complicate behavior-change efforts and help explain why the first days of quitting are challenging.","specificNumbers":"- Sample: 31 young adults, 17 heavy cannabis users vs 14 drug-free controls, ages 18–30\n- Nights recorded: 2 consecutive nights immediately after stopping for the user group\n- Total sleep time: lower in heavy users on both nights, meaning they slept fewer minutes overall\n- Slow wave sleep: less in heavy users on both nights, indicating reduced deep, restorative sleep","methodology":"Observational case-control design in a core sleep laboratory. Researchers enrolled 17 heavy cannabis users, ages 18 to 30, who discontinued use just before testing, and matched them to 14 drug-free controls of similar age. Urine screens in the user group were positive only for cannabis metabolites, and alcohol use was negligible in both groups. Participants completed questionnaires before cessation, then underwent two consecutive nights of in-lab polysomnography measuring total sleep time, sleep stages, sleep efficiency, sleep onset latency, and REM latency.","limitations":"Small, single-site sample of young adults. Only two nights of recording, so the trajectory beyond 48 hours is unknown. No pre-cessation polysomnography, which makes baseline differences impossible to rule out. Product types, potencies, duration of heavy use, and timing since last use were not detailed in the abstract. Although withdrawal, craving, and depression did not appear to drive the findings, the study may have been underpowered to detect subtle effects. Laboratory sleep can be influenced by the first-night effect, and adaptation patterns differed between groups."},{"rthcId":"RTHC-00302","title":"Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition.","authors":"Borgwardt, Stefan J; Allen, Paul; Bhattacharyya, Sagnik; Fusar-Poli, Paolo; Crippa, Jose A; Seal, Marc L; Fraccaro, Valter; Atakan, Zerrin; Martin-Santos, Rocio; O'Carroll, Colin; Rubia, Katya; McGuire, Philip K","year":2008,"journal":"Biological psychiatry, 64(11), 966-73","doi":"10.1016/j.biopsych.2008.05.011","pmid":"18589404","tags":["cognition","cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Fifteen healthy volunteers performed a Go/No-Go task (requiring them to withhold a response on certain trials) under three conditions: THC, CBD, or placebo, in a double-blind crossover design with fMRI.\n\nTHC attenuated activation in the right inferior frontal gyrus and anterior cingulate cortex, two brain regions well established as critical for response inhibition (the ability to stop an action once initiated).\n\nCBD produced a different pattern entirely: it deactivated the left temporal cortex and insula, regions not typically associated with response inhibition.\n\nImportantly, these brain changes were not explained by differences in anxiety, intoxication, sedation, or psychotic-like symptoms between conditions, suggesting direct pharmacological effects on brain function rather than secondary consequences of feeling impaired.","whyItMatters":"Response inhibition, the ability to stop yourself from doing something, is a fundamental aspect of self-control that is impaired in many psychiatric conditions. This study showed THC specifically weakens the brain's inhibitory control network, while CBD acts on entirely different neural circuits.","specificNumbers":"15 healthy volunteers. THC attenuated right inferior frontal gyrus and anterior cingulate cortex activation. CBD deactivated left temporal cortex and insula. Effects were independent of subjective measures (anxiety, intoxication, sedation, psychotic symptoms).","methodology":"Double-blind, pseudo-randomized, placebo-controlled, repeated-measures, within-subject design. 15 healthy volunteers received THC, CBD, or placebo on separate occasions. fMRI was recorded during a Go/No-Go motor inhibition task. Behavioral performance and subjective state measures were assessed.","limitations":"The sample was small (15 subjects). Only one dose of each compound was tested. The Go/No-Go task is one specific measure of inhibition and may not capture all aspects of self-control. The study examined acute effects in healthy volunteers, not chronic users."},{"rthcId":"RTHC-00303","title":"N-arachidonyl maleimide potentiates the pharmacological and biochemical effects of the endocannabinoid 2-arachidonylglycerol through inhibition of monoacylglycerol lipase.","authors":"Burston, James J; Sim-Selley, Laura J; Harloe, John P; Mahadevan, Anu; Razdan, Raj K; Selley, Dana E; Wiley, Jenny L","year":2008,"journal":"The Journal of pharmacology and experimental therapeutics, 327(2), 546-53","doi":"10.1124/jpet.108.141382","pmid":"18682568","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested N-arachidonyl maleimide (NAM), a potential MAGL inhibitor, for its ability to enhance the effects of the endocannabinoid 2-AG in mice.\n\nNAM unmasked 2-AG activity across a standard battery of cannabinoid tests: reduced locomotion, catalepsy, hypothermia, and pain insensitivity. Without NAM, 2-AG was rapidly degraded before it could produce these effects.\n\nNAM increased 2-AG's potency in biochemical assays but did not affect anandamide (the other major endocannabinoid), confirming selectivity for the MAGL pathway.\n\nA surprise finding emerged: the effects of 2-AG enhanced by NAM were only partially blocked by the CB1 antagonist SR141716A and were only partially reduced in CB1 knockout mice. This provided evidence for the existence of non-CB1, non-CB2 cannabinoid receptors that respond to 2-AG.","whyItMatters":"This study demonstrated that MAGL inhibition could be a viable therapeutic strategy for enhancing endocannabinoid signaling. The finding of non-CB1/non-CB2 cannabinoid activity also suggested the cannabinoid receptor system is more complex than previously thought.","specificNumbers":"NAM unmasked 2-AG effects across all four tetrad measures. Effects were partially (not fully) blocked by SR141716A and partially reduced in CB1-knockout mice. NAM increased brain 2-AG levels in vitro. NAM enhanced 2-AG potency but not anandamide potency.","methodology":"Mice received NAM followed by 2-AG or anandamide, and were assessed using the standard cannabinoid tetrad (locomotion, catalepsy, body temperature, pain sensitivity). CB1-knockout mice and the CB1 antagonist SR141716A were used to determine receptor involvement. In vitro assays measured brain 2-AG levels and receptor activation.","limitations":"NAM may have off-target effects beyond MAGL inhibition. The partial CB1-dependence of effects complicates interpretation. Mouse endocannabinoid pharmacology may differ from human. Only acute effects were examined."},{"rthcId":"RTHC-00304","title":"Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice.","authors":"Capasso, R; Borrelli, F; Aviello, G; Romano, B; Scalisi, C; Capasso, F; Izzo, A A","year":2008,"journal":"British journal of pharmacology, 154(5), 1001-8","doi":"10.1038/bjp.2008.177","pmid":"18469842","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers tested CBD's effects on both normal and inflamed mouse intestines. In healthy mice, CBD had no effect on gut motility, meaning normal digestive movement was unaffected.\n\nHowever, in mice with croton oil-induced intestinal inflammation, CBD normalized the excessive gut motility (hypermotility) that accompanies inflammation. This selectivity, affecting only abnormal movement while leaving normal function intact, is a desirable property for any potential medication.\n\nThe anti-hypermotility effect was blocked by the CB1 receptor antagonist rimonabant but not by the CB2 antagonist, opioid antagonist, or alpha2-adrenergic antagonist, indicating a CB1-mediated mechanism. CBD's effect was also abolished when FAAH (the enzyme that breaks down anandamide) was inhibited, suggesting CBD works by enhancing anandamide levels through FAAH.\n\nIn isolated intestinal tissue, CBD inhibited acetylcholine-induced contractions from both normal and inflamed intestines, showing it has direct smooth muscle effects as well.","whyItMatters":"Inflammatory bowel diseases cause painful gut hypermotility. Most anti-motility drugs (like loperamide) reduce all gut movement, including normal digestion. CBD's selective action on only inflamed, hyperactive intestines suggests it could relieve symptoms without causing constipation.","specificNumbers":"CBD normalized croton oil-induced hypermotility. Effect blocked by rimonabant (CB1 antagonist). Effect NOT blocked by CB2 antagonist, naloxone (opioid), or yohimbine (alpha2-adrenergic). Effect abolished by FAAH inhibition.","methodology":"In vivo gut motility was measured by tracking an orally administered fluorescent marker through the small intestine. Inflammation was induced with croton oil. Various receptor antagonists and enzyme inhibitors were used to identify the mechanism. In vitro contractility was measured in isolated ileum.","limitations":"Mouse intestinal inflammation models don't fully replicate human IBD. The doses used may not correspond to achievable human doses. Only acute effects were examined. The croton oil model is a chemical irritant, not an immune-mediated model like Crohn's disease."},{"rthcId":"RTHC-00305","title":"Cannabis: a trigger for acute myocardial infarction? A case report.","authors":"Cappelli, Francesco; Lazzeri, Chiara; Gensini, Gian Franco; Valente, Serafina","year":2008,"journal":"Journal of cardiovascular medicine (Hagerstown, Md.), 9(7), 725-8","doi":"10.2459/JCM.0b013e3282f2cd0d","pmid":"18545075","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The case report described a young man who experienced a heart attack (ST-elevation myocardial infarction, or STEMI) after smoking marijuana. Cardiac catheterization revealed acute thrombosis (blood clot) in the left anterior descending artery, which was successfully treated with primary coronary angioplasty (balloon and stent).\n\nThe authors noted that while cannabis has well-established effects on the cardiovascular system (increased heart rate, changes in blood pressure), the link between cannabis and heart attack remains limited and controversial. They positioned this case as additional evidence that cannabis may trigger acute cardiac events, possibly through effects on blood clotting, coronary artery spasm, or increased myocardial oxygen demand.","whyItMatters":"Heart attacks in young people are unusual and often have identifiable triggers. While this case cannot prove cannabis caused the heart attack, the temporal association adds to a small but growing body of case reports linking cannabis use to acute cardiac events.","specificNumbers":"One young male patient. ST-elevation myocardial infarction. Acute thrombosis of the left anterior descending coronary artery. Successful primary angioplasty.","methodology":"Single case report with clinical documentation of the cardiac event, coronary angiography findings, and treatment. The temporal relationship between marijuana smoking and symptom onset was documented.","limitations":"A single case report cannot establish that cannabis caused the heart attack. The patient may have had undetected risk factors. The temporal association (marijuana then heart attack) does not prove causation."},{"rthcId":"RTHC-00306","title":"The effects of perceived quality on the behavioural economics of alcohol, amphetamine, cannabis, cocaine, and ecstasy purchases.","authors":"Cole, Jon C; Goudie, Andrew J; Field, Matt; Loverseed, Anne-Claire; Charlton, Sarah; Sumnall, Harry R","year":2008,"journal":"Drug and alcohol dependence, 94(1-3), 183-90","doi":"10.1016/j.drugalcdep.2007.11.014","pmid":"18201842","tags":["addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Eighty polydrug users completed a simulated purchasing task where drug prices stayed fixed but perceived quality changed for alcohol, amphetamine, cannabis, cocaine, and ecstasy.\n\nAlcohol demand was \"quality inelastic,\" meaning users kept buying the same amount regardless of quality, and alcohol quality changes didn't affect purchases of other drugs.\n\nCannabis demand was \"quality elastic,\" meaning purchases dropped as quality decreased, and alcohol substituted for cannabis as its effective unit price rose. Similarly, cocaine demand was quality elastic, with alcohol, cannabis, and ecstasy substituting for it. Ecstasy showed the same pattern, with alcohol and cocaine as substitutes.\n\nThe key finding was that drug markets behave like economic markets: when one product becomes less appealing, consumers switch to substitutes rather than simply using less.","whyItMatters":"Understanding how drug users respond to quality changes has direct implications for drug policy. If cannabis quality decreases (through regulation, contamination, or enforcement), users may shift to alcohol or other substances rather than reducing total substance use.","specificNumbers":"80 polydrug users. Alcohol: quality inelastic. Cannabis: quality elastic, alcohol substitutes. Cocaine: quality elastic, alcohol/cannabis/ecstasy substitute. Ecstasy: quality elastic, alcohol/cocaine substitute.","methodology":"Cross-sectional behavioral economics study. 80 polydrug users completed questionnaires (DAST-A, SDS, AUDIT, HADS) and a simulated drug purchasing task where price remained fixed but quality varied, effectively changing the unit price.","limitations":"Simulated purchasing tasks may not reflect real-world behavior. The sample of 80 polydrug users may not represent all drug-using populations. The study examined stated preferences rather than actual purchases."},{"rthcId":"RTHC-00307","title":"Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8.","authors":"De Petrocellis, Luciano; Vellani, Vittorio; Schiano-Moriello, Aniello; Marini, Pietro; Magherini, Pier Cosimo; Orlando, Pierangelo; Di Marzo, Vincenzo","year":2008,"journal":"The Journal of pharmacology and experimental therapeutics, 325(3), 1007-15","doi":"10.1124/jpet.107.134809","pmid":"18354058","tags":["neuroscience","cbd","pain"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers tested six plant cannabinoids (CBD, THC, CBD acid, THC acid, cannabichromene/CBC, and cannabigerol/CBG) on two ion channels involved in pain sensing: TRPA1 and TRPM8.\n\nAll six cannabinoids activated TRPA1 channels (which detect chemical irritants and contribute to inflammatory pain). CBC was by far the most potent, with an EC50 of just 60 nanomolar, making it more potent than mustard oil, the standard TRPA1 activator. CBG and CBD acid were the least potent.\n\nFor TRPM8 (the cold-sensing channel linked to menthol and icilin sensitivity), all cannabinoids except CBC blocked the channel's activation. CBD, CBG, THC, and THC acid were equipotent blockers at 70-160 nanomolar.\n\nThese findings demonstrated that cannabinoids interact with ion channels completely separate from the CB1 and CB2 cannabinoid receptors, potentially explaining some of cannabis's pain-relieving and anti-cancer effects.","whyItMatters":"This study revealed that plant cannabinoids act on pain-related ion channels (TRP channels) at very low concentrations, independent of the traditional CB1/CB2 receptor system. This provides a molecular explanation for some of cannabis's analgesic effects that couldn't be explained by cannabinoid receptor activity alone.","specificNumbers":"TRPA1 activation: CBC EC50 = 60 nM (most potent), CBG/CBD acid EC50 = 3.4-12 micromolar. TRPM8 blockade: CBD, CBG, THC, THC acid IC50 = 70-160 nM. CBC did not block TRPM8.","methodology":"Researchers used HEK-293 cells overexpressing TRPA1 or TRPM8 channels and measured intracellular calcium responses. Results were confirmed in rat dorsal root ganglia (DRG) sensory neurons that naturally express these channels. Six phytocannabinoids were tested across concentration ranges.","limitations":"Cell line overexpression systems may not reflect natural channel density or behavior. DRG neuron results showed lower potency than the cell line results. The study examined isolated channels, not the complex pain processing of whole organisms."},{"rthcId":"RTHC-00308","title":"Auditory event-related potentials (P3) and cognitive performance in recreational ecstasy polydrug users: evidence from a 12-month longitudinal study.","authors":"de Sola, Susana; Tarancón, Thais; Peña-Casanova, Jordi; Espadaler, Josep María; Langohr, Klaus; Poudevida, Sandra; Farré, Magí; Verdejo-García, Antonio; de la Torre, Rafael","year":2008,"journal":"Psychopharmacology, 200(3), 425-37","doi":"10.1007/s00213-008-1217-5","pmid":"18581098","tags":["cognition","drug-interactions"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed three groups for one year: 14 ecstasy polydrug users, 13 cannabis-only users, and 22 drug-free controls, measuring cognitive performance and brain event-related potentials (P300/P3).\n\nAfter one year, ecstasy users showed significant cognitive deficits compared to controls in word fluency, processing speed, and memory recognition. Lifetime ecstasy use specifically correlated with poorer memory recognition.\n\nNo significant cognitive differences emerged between ecstasy users and cannabis users, or between cannabis users and controls, though this may reflect the small sample sizes.\n\nA paradoxical finding emerged in the brain recordings: higher lifetime cannabis use was associated with faster P3 latency (faster brain processing), opposite to what would be expected if cannabis caused cognitive impairment. No P3 differences were found between any groups.\n\nThe authors suggested that the dynamic interaction between ecstasy and cannabis effects may account for the cognitive patterns observed.","whyItMatters":"This study attempted to disentangle the cognitive effects of ecstasy and cannabis in polydrug users. The finding that cognitive deficits were attributed more to ecstasy than cannabis, combined with the paradoxical P3 finding, suggests cannabis's cognitive effects may be more nuanced than simple impairment.","specificNumbers":"14 ecstasy users, 13 cannabis users, 22 controls. 1-year follow-up. Ecstasy users showed deficits in word fluency, processing speed, and memory recognition. Cannabis use correlated with faster (not slower) P3 latency. No P3 group differences.","methodology":"Longitudinal study with two evaluations one year apart. Auditory P300 event-related potentials and a cognitive test battery were administered to 14 ecstasy polydrug users, 13 cannabis users, and 22 controls.","limitations":"Very small sample sizes limit statistical power and generalizability. Ecstasy users were polydrug users, making attribution difficult. Self-reported drug use may be inaccurate. The paradoxical cannabis P3 finding needs replication."},{"rthcId":"RTHC-00309","title":"Current status of cannabis treatment of multiple sclerosis with an illustrative case presentation of a patient with MS, complex vocal tics, paroxysmal dystonia, and marijuana dependence treated with dronabinol.","authors":"Deutsch, Stephen I; Rosse, Richard B; Connor, Julie M; Burket, Jessica A; Murphy, Mary E; Fox, Fiona J","year":2008,"journal":"CNS spectrums, 13(5), 393-403","doi":null,"pmid":"18496477","tags":["medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The authors presented a case of a 52-year-old woman with multiple sclerosis complicated by paroxysmal dystonia (sudden abnormal muscle contractions), complex vocal tics, and marijuana dependence.\n\nWhen started on dronabinol (synthetic THC capsules normally prescribed for chemotherapy nausea), she reported multiple improvements: dramatic reduction in craving for marijuana and illicit use, improved sleep quality with fewer nighttime awakenings, decreased vocal tics and associated tension, reduced anxiety, and fewer episodes of dystonia.\n\nNotably, she reported not experiencing the \"high\" from the prescribed dronabinol that she experienced from smoked marijuana. This may reflect the different pharmacokinetics of oral versus smoked delivery, or the controlled dosing versus self-titrated smoking.\n\nThe case was presented alongside a review of current evidence for cannabis-based MS treatments.","whyItMatters":"This case illustrated several important points: prescription THC can potentially replace illicit marijuana use in MS patients, oral delivery may produce therapeutic effects without the euphoric \"high,\" and cannabinoids may address multiple MS symptoms simultaneously including unusual ones like tics and dystonia.","specificNumbers":"One 52-year-old female patient with MS. Multiple symptom improvements on dronabinol. Reduced craving and illicit marijuana use. Improved sleep, reduced tics, reduced dystonia, reduced anxiety. No reported \"high\" from prescription THC.","methodology":"Single case report with clinical observations. The patient was started on an empirical trial of dronabinol (oral synthetic THC) and outcomes were documented. A literature review of cannabis in MS accompanied the case.","limitations":"Single case reports cannot establish efficacy or generalizability. Placebo effects may account for some improvements. The patient's self-report of reduced craving and no \"high\" is subjective and unverified."},{"rthcId":"RTHC-00310","title":"Direct suppression of autoreactive lymphocytes in the central nervous system via the CB2 receptor.","authors":"Dittel, B N","year":2008,"journal":"British journal of pharmacology, 153(2), 271-6","doi":null,"pmid":"17922025","tags":["inflammation","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review focused on the CB2 cannabinoid receptor's role in controlling autoimmune inflammation in the central nervous system.\n\nWhile THC activates both CB1 (mainly brain) and CB2 (mainly immune system) receptors, the generation of mice lacking specific cannabinoid receptors has allowed researchers to separate these functions. Studies using CB2-specific approaches showed that this receptor directly regulates T cell effector functions, particularly the autoreactive lymphocytes that attack myelin in MS.\n\nEndogenous cannabinoids (endocannabinoids) also bind CB2 and exert immune-modulatory effects, suggesting the body has a built-in system for regulating autoimmune responses through cannabinoid signaling.\n\nThe review argued that CB2-targeted therapies could potentially suppress the autoimmune component of MS without causing the psychoactive effects mediated by CB1 receptors in the brain.","whyItMatters":"If CB2 receptors can suppress the autoimmune attack in MS without affecting brain CB1 receptors, it could lead to cannabinoid-based treatments that modify MS disease progression without causing intoxication or cognitive effects.","specificNumbers":"CB2 is primarily expressed on immune cells. Studies used CB1 and CB2 knockout mice to discriminate receptor-specific functions. THC binds both CB1 and CB2. Endocannabinoids also activate CB2.","methodology":"Narrative review of preclinical research on CB2 receptor function in autoimmune CNS inflammation, drawing primarily on knockout mouse studies and in vitro immune cell experiments.","limitations":"Most evidence was from animal models. Translating mouse immune findings to human MS is uncertain. No CB2-selective drugs had been tested in MS clinical trials at the time of the review."},{"rthcId":"RTHC-00311","title":"Delta9-Tetrahydrocannabinol-induced cognitive deficits are reversed by olanzapine but not haloperidol in rats.","authors":"Egashira, Nobuaki; Ishigami, Noriko; Mishima, Kenichi; Iwasaki, Katsunori; Oishi, Ryozo; Fujiwara, Michihiro","year":2008,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 32(2), 499-506","doi":null,"pmid":"18029074","tags":["cognition","psychosis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether two different antipsychotic medications could reverse the spatial memory impairment caused by THC in rats using an eight-arm radial maze.\n\nTHC (6 mg/kg) impaired spatial memory and decreased acetylcholine (ACh) levels in the dorsal hippocampus, a brain region critical for spatial memory.\n\nOlanzapine (0.1 mg/kg), an atypical antipsychotic, reversed both the memory deficit and the acetylcholine decrease caused by THC. Haloperidol (0.03-0.3 mg/kg), a typical antipsychotic, had no effect on either measure at any dose tested.\n\nThe results suggest olanzapine's ability to restore hippocampal acetylcholine release may underlie its reversal of THC-induced cognitive impairment, potentially relevant to treating cannabis-related cognitive effects in patients with psychosis.","whyItMatters":"Many patients with schizophrenia use cannabis, which can worsen their cognitive symptoms. This study suggested that olanzapine (but not haloperidol) may counteract cannabis-induced cognitive impairment, potentially guiding antipsychotic selection for cannabis-using patients.","specificNumbers":"THC dose: 6 mg/kg. Olanzapine 0.1 mg/kg reversed memory deficits and ACh decrease. Haloperidol 0.03-0.3 mg/kg had no effect. THC decreased ACh in dorsal hippocampus.","methodology":"Rats were tested in an eight-arm radial maze task after receiving THC (6 mg/kg i.p.) with or without olanzapine or haloperidol pretreatment. Extracellular acetylcholine levels in the dorsal hippocampus were measured by in vivo microdialysis.","limitations":"Rat spatial memory tasks may not translate to human cognitive function. The THC dose was relatively high. Only one dose of olanzapine was effective. The clinical relevance for humans requires clinical trial confirmation."},{"rthcId":"RTHC-00312","title":"Cannabis withdrawal in the United States: results from NESARC.","authors":"Hasin, Deborah S; Keyes, Katherine M; Alderson, Donald; Wang, Shuang; Aharonovich, Efrat; Grant, Bridget F","year":2008,"journal":"The Journal of clinical psychiatry, 69(9), 1354-63","doi":null,"pmid":"19012815","tags":["withdrawal","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), researchers examined cannabis withdrawal among 2,613 frequent users (three or more times per week) and a subset of 1,119 \"cannabis-only\" users who didn't binge drink or use other drugs frequently.\n\nWithdrawal was common: 44.3% of the full sample and 44.2% of the cannabis-only subset experienced two or more symptoms. About 34% experienced three or more symptoms. The nearly identical rates in the cannabis-only subset confirmed these symptoms were specific to cannabis, not other substances.\n\nThe symptoms clustered into two distinct factors: (1) a \"weakness\" factor including weakness, excessive sleep, and psychomotor retardation, and (2) an \"anxiety\" factor including anxiety, restlessness, depression, and insomnia.\n\nBoth symptom types were associated with significant distress or impairment. Psychiatric disorders predicted anxiety-type withdrawal, family drug problems predicted weakness-type withdrawal, and depression was associated with both types.","whyItMatters":"This study provided some of the strongest evidence that cannabis withdrawal is a real, clinically significant phenomenon. The identical rates in the cannabis-only subset eliminated the argument that withdrawal symptoms were caused by other substances. These findings influenced the addition of cannabis withdrawal to DSM-5.","specificNumbers":"2,613 frequent users examined. 44.3% experienced 2+ withdrawal symptoms. 34.4% experienced 3+ symptoms. Cannabis-only subset (n=1,119) showed 44.2% and 34.1% respectively. Two symptom factors identified: weakness/hypersomnia and anxiety/insomnia.","methodology":"Analysis of NESARC data (2001-2002), a nationally representative survey. 2,613 frequent cannabis users and 1,119 cannabis-only subset assessed via structured in-person interviews covering substance history, DSM-IV disorders, and withdrawal symptoms after cessation.","limitations":"Cross-sectional survey data relies on retrospective self-report. The definition of \"frequent use\" (3+ times/week) may include a wide range of use patterns. Withdrawal symptoms were assessed through structured interview rather than clinical observation."},{"rthcId":"RTHC-00313","title":"Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism.","authors":"Hayakawa, Kazuhide; Mishima, Kenichi; Hazekawa, Mai; Sano, Kazunori; Irie, Keiichi; Orito, Kensuke; Egawa, Takashi; Kitamura, Yoshihisa; Uchida, Naoki; Nishimura, Ryoji; Egashira, Nobuaki; Iwasaki, Katsunori; Fujiwara, Michihiro","year":2008,"journal":"Brain research, 1188, 157-64","doi":null,"pmid":"18021759","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested CBD at multiple doses (1-50 mg/kg) alone and in combination with THC in mice, measuring effects on movement, body temperature, catalepsy, and spatial memory.\n\nCBD alone, even at doses up to 50 mg/kg, had no effect on any measure. However, when high-dose CBD (10 or 50 mg/kg) was combined with low-dose THC (1 mg/kg), it exacerbated THC's effects: greater reduction in locomotion, greater hypothermia, and greater spatial memory impairment.\n\nThe mechanism was unexpected: CBD at 50 mg/kg combined with THC at 1 mg/kg increased CB1 receptor expression in the hippocampus and hypothalamus. This receptor upregulation could explain why THC's effects were amplified, as more receptors meant more targets for THC to activate.\n\nThis contradicted the common notion that CBD always counteracts THC's effects.","whyItMatters":"This study challenged the widespread assumption that CBD inherently opposes THC. Under certain dose conditions, CBD actually amplified THC's pharmacological effects. This has implications for cannabis product formulation and the assumption that high-CBD products are always \"safer.\"","specificNumbers":"CBD alone (1-50 mg/kg): no behavioral effects. CBD 10 or 50 mg/kg + THC 1 mg/kg: enhanced hypoactivity, hypothermia, and memory impairment. CBD 50 mg/kg + THC 1 mg/kg: increased CB1 receptor expression in hippocampus and hypothalamus.","methodology":"Mice received various CBD and THC doses alone or combined. Behavioral measures included locomotor activity, catalepsy-like immobilization, rectal temperature, and eight-arm radial maze spatial memory. CB1 receptor expression was measured in four brain regions using immunohistochemistry.","limitations":"Mouse pharmacology may not translate to humans. The CBD:THC ratios used (10:1 to 50:1) are higher than many cannabis products. Only acute effects were studied. The CB1 upregulation mechanism needs further confirmation."},{"rthcId":"RTHC-00314","title":"Neurobiology of cannabis addiction.","authors":"Jain, Raka; Balhara, Yatan Pal Singh","year":2008,"journal":"Indian journal of physiology and pharmacology, 52(3), 217-32","doi":null,"pmid":"19552052","tags":["addiction","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review summarized the neurobiological basis of cannabis addiction, covering several key themes.\n\nThe discovery of cannabinoid receptors (CB1 and CB2) and their endogenous ligands (anandamide and 2-AG) provided a molecular framework for understanding how cannabis produces dependence. The endocannabinoid system is involved in reward, motivation, and stress response, all relevant to addiction.\n\nAnimal studies had demonstrated that chronic cannabis exposure produces neuroadaptive changes including receptor downregulation, tolerance, and withdrawal. Human studies showed that a significant proportion of regular users develop dependence meeting clinical criteria.\n\nThe review noted that the earlier characterization of cannabis as relatively benign had been challenged by accumulating clinical and research evidence showing multiple physical and mental effects.","whyItMatters":"Understanding the brain mechanisms behind cannabis dependence is essential for developing treatments. This review synthesized the transition in scientific thinking from viewing cannabis as non-addictive to recognizing it as a substance that can produce genuine neurobiological dependence.","specificNumbers":"CB1 and CB2 receptors identified. Endogenous ligands: anandamide and 2-AG. Chronic exposure produces receptor downregulation and tolerance in animal models.","methodology":"Narrative review of published animal and human studies on the neurobiological basis of cannabis dependence, covering receptor pharmacology, neuroadaptation, and clinical evidence.","limitations":"As a narrative review, it did not systematically assess evidence quality. Some referenced studies were in animals, limiting direct human applicability. The review was published before some of the largest human studies on cannabis dependence."},{"rthcId":"RTHC-00315","title":"The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT).","authors":"Kaplan, Barbara L F; Springs, Alison E B; Kaminski, Norbert E","year":2008,"journal":"Biochemical pharmacology, 76(6), 726-37","doi":"10.1016/j.bcp.2008.06.022","pmid":"18656454","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Building on previous findings that CBD suppresses IL-2 production, researchers investigated the mechanism and found CBD has broad immunosuppressive effects on T cells.\n\nCBD suppressed production of IL-2 and IFN-gamma (key immune signaling molecules), inhibited T cell proliferation, reduced surface expression of the activation marker CD25, and suppressed antibody production in response to a standard immune challenge.\n\nThe mechanism involved suppression of two critical transcription factors: AP-1 and NFAT, which are essential regulators of T cell activation and cytokine production.\n\nCritically, these immunosuppressive effects persisted in splenocytes from mice completely lacking both CB1 and CB2 receptors, proving CBD's immune effects operate through an entirely different pathway than traditional cannabinoid signaling. However, the CB1/CB2 knockout mice had a generally weaker immune response, showing these receptors do play a role in baseline immune function.","whyItMatters":"This study identified a specific molecular mechanism for CBD's immune suppression (NFAT/AP-1 deregulation) and proved it doesn't require either known cannabinoid receptor. This has implications for autoimmune disease treatment but also raises questions about whether regular CBD use could compromise immune function.","specificNumbers":"CBD suppressed IL-2 and IFN-gamma production, CD25 expression, T cell proliferation, and anti-sRBC IgM antibody responses. Effects persisted in CB1/CB2 double-knockout mice. AP-1 and NFAT transcriptional activity were suppressed.","methodology":"Murine splenocytes and purified T cells were treated with CBD and assessed for cytokine production, proliferation, surface marker expression, and antibody responses. Transcription factor activity was measured. CB1/CB2 double-knockout mice were used to determine receptor involvement.","limitations":"In vitro mouse immune cell studies may not predict human immune responses. The CBD concentrations used may not reflect achievable human tissue levels. Only acute exposure was examined."},{"rthcId":"RTHC-00316","title":"Mapping the structural requirements in the CB1 cannabinoid receptor transmembrane helix II for signal transduction.","authors":"Kapur, Ankur; Samaniego, Patrick; Thakur, Ganesh A; Makriyannis, Alexandros; Abood, Mary E","year":2008,"journal":"The Journal of pharmacology and experimental therapeutics, 325(1), 341-8","doi":"10.1124/jpet.107.133256","pmid":"18174385","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used site-directed mutagenesis to study two adjacent amino acid positions in the CB1 receptor's second transmembrane helix.\n\nMutating the charged residue Asp2.63 to asparagine (removing the charge) reduced the potency of four different cannabinoid agonists for receptor activation without changing their ability to bind the receptor. The charge-conserved mutation (D2.63E) behaved like the normal receptor.\n\nThe Ile2.62 mutation alone similarly affected activation potency without altering binding affinity.\n\nThe dramatic finding was that combining both mutations (I2.62T-D2.63N double mutant) produced a synergistic approximately 50-fold increase in the concentration needed for agonist-mediated activation. This synergistic loss of function, far beyond what either mutation caused alone, showed these two residues work together as a critical switch for signal transduction.","whyItMatters":"Understanding exactly how the CB1 receptor converts ligand binding into cellular activation is essential for designing drugs that can bind the receptor but modulate its activity in specific ways, potentially separating therapeutic from unwanted effects.","specificNumbers":"D2.63N: reduced agonist potency without affecting binding. I2.62T: similar effect. Double mutant I2.62T-D2.63N: approximately 50-fold increase in EC50 (synergistic loss). D2.63E (charge-conserved): behaved like wild type.","methodology":"Site-directed mutagenesis of the human CB1 receptor stably expressed in HEK-293 cells. Mutant receptors were assayed for ligand binding affinity (radioligand binding) and agonist-induced activation (GTPgammaS binding) with four structurally diverse cannabinoid agonists.","limitations":"In vitro receptor studies in cell lines may not capture the full complexity of receptor behavior in neurons. Only four agonists were tested. The functional significance of the identified residues in physiological contexts was not examined."},{"rthcId":"RTHC-00317","title":"Endocannabinoids and the neurochemistry of gluttony.","authors":"Kirkham, Tim","year":2008,"journal":"Journal of neuroendocrinology, 20(9), 1099-100","doi":"10.1111/j.1365-2826.2008.01762.x","pmid":"18624929","tags":["appetite","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This brief review outlined how the endocannabinoid system drives overeating through two complementary mechanisms.\n\nFirst, endocannabinoids acting at CB1 receptors in the brain increase appetite by enhancing both food craving (wanting) and food enjoyment (liking). This explains the well-known \"munchies\" effect of cannabis.\n\nSecond, the endocannabinoid system promotes energy storage as fat in adipose (fat) tissue, meaning it doesn't just increase food intake but also directs where that energy goes.\n\nThese dual actions, increasing intake and promoting storage, raised the possibility that CB1 receptor blockers could address obesity from both directions: reducing appetite and decreasing fat deposition.","whyItMatters":"Understanding that the endocannabinoid system drives both overconsumption and fat storage explained why cannabis users often experience intense food cravings and why the CB1 blocker rimonabant showed weight loss effects in clinical trials.","specificNumbers":"Endocannabinoids activate CB1 receptors in brain (appetite) and peripheral tissues (fat storage). CB1 antagonists were identified as potential anti-obesity agents.","methodology":"Brief narrative review or editorial summarizing the current understanding of endocannabinoid system involvement in appetite regulation and energy storage.","limitations":"This is a brief editorial rather than a systematic review. It summarizes the concept without detailed evidence assessment."},{"rthcId":"RTHC-00318","title":"Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis.","authors":"Machado Rocha, F C; Stéfano, S C; De Cássia Haiek, R; Rosa Oliveira, L M Q; Da Silveira, D X","year":2008,"journal":"European journal of cancer care, 17(5), 431-43","doi":"10.1111/j.1365-2354.2008.00917.x","pmid":"18625004","tags":["medical-cannabis","cancer"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"This systematic review and meta-analysis examined 30 randomized clinical trials from over 12,000 initially identified papers, comparing cannabinoids to conventional anti-emetics and placebo for chemotherapy-induced nausea and vomiting.\n\nFive meta-analyses were conducted. Dronabinol significantly outperformed neuroleptic anti-emetics (RR=0.67, NNT=3.4), meaning only 3-4 patients needed treatment with dronabinol instead of neuroleptics for one additional patient to benefit. Dronabinol versus placebo showed a trend favoring dronabinol (RR=0.47) but didn't reach significance.\n\nNabilone and levonantradol showed similar but non-significant trends against neuroleptics.\n\nThe most striking finding was patient preference: across 1,138 patients, the preference for cannabinoids over other drugs was overwhelming (RR=0.33, NNT=1.8), meaning nearly every other patient preferred the cannabinoid.\n\nHowever, adverse effects were more frequent and intense with cannabinoids than conventional drugs.","whyItMatters":"This was one of the most comprehensive meta-analyses of cannabinoids for chemotherapy nausea at the time. The clear superiority over neuroleptic anti-emetics and overwhelming patient preference provided strong evidence for cannabinoids in this indication.","specificNumbers":"30 RCTs from 12,749 papers. Dronabinol vs. neuroleptics: RR=0.67, NNT=3.4. Patient preference for cannabinoids: RR=0.33, NNT=1.8 (n=1,138). Adverse effects more common with cannabinoids.","methodology":"Systematic review of PUBMED, EMBASE, PSYCINFO, LILACS, and Cochrane databases through December 2006. From 12,749 papers, 30 randomized clinical trials met inclusion criteria. Five meta-analyses were performed using relative risk and number needed to treat.","limitations":"Many included trials were from the 1980s-1990s and used outdated comparator drugs (neuroleptics rather than modern anti-emetics like ondansetron). Some individual trials had small samples. The increased adverse effects of cannabinoids are clinically significant. Publication bias may favor positive results."},{"rthcId":"RTHC-00319","title":"Expression of the endocannabinoid system in fibroblasts and myofascial tissues.","authors":"McPartland, John M","year":2008,"journal":"Journal of bodywork and movement therapies, 12(2), 169-82","doi":"10.1016/j.jbmt.2008.01.004","pmid":"19083670","tags":["pain","inflammation","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Using bioinformatics analysis of publicly available gene expression data, the researcher found that fibroblasts, myofibroblasts, chondrocytes, and synoviocytes all express CB1 receptors, CB2 receptors, and the enzymes that make and break down endocannabinoids.\n\nFibroblast CB1 levels were notably high, nearly matching adipocyte (fat cell) levels. CB1 expression increased when fibroblasts were exposed to inflammatory cytokines or mechanical stretching.\n\nThe endocannabinoid system in these tissues was found to affect fibroblast remodeling (through lipid rafts at focal adhesions), reduce cartilage destruction by decreasing metalloproteinase enzymes, and modulate pain and inflammation in myofascial tissues.\n\nThe author suggested this system may help explain the biological basis of myofascial trigger points and fibromyalgia symptoms, and that manual therapies, diet modifications, and pharmaceutical approaches can all influence endocannabinoid activity.","whyItMatters":"The discovery that connective tissue cells have a functional endocannabinoid system provides a biological framework for understanding how cannabis-based treatments might address musculoskeletal pain, and why manual therapies like massage may work partly through endocannabinoid mechanisms.","specificNumbers":"Fibroblast CB1 levels nearly equaled adipocyte levels. CB1 upregulated by inflammatory cytokines and mechanical stretching. CB1, CB2, and endocannabinoid enzymes detected in fibroblasts, myofibroblasts, chondrocytes, and synoviocytes.","methodology":"Bioinformatics review using microarray data from the GEO database (NCBI) to characterize endocannabinoid system expression in fibroblasts and related cells. Combined with a narrative review of endocannabinoid system biology relevant to bodywork and manual therapy.","limitations":"The endocannabinoid system expression was identified through database mining of microarray data, not direct tissue measurements. The connections to trigger points and fibromyalgia were speculative. The claims about bodywork upregulating endocannabinoids were not directly tested."},{"rthcId":"RTHC-00320","title":"A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions.","authors":"Moir, David; Rickert, William S; Levasseur, Genevieve; Larose, Yolande; Maertens, Rebecca; White, Paul; Desjardins, Suzanne","year":2008,"journal":"Chemical research in toxicology, 21(2), 494-502","doi":null,"pmid":"18062674","tags":["respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers prepared marijuana and tobacco cigarettes identically and analyzed their smoke under two standardized smoking conditions, comparing both mainstream (inhaled) and sidestream (environmental) smoke.\n\nMainstream marijuana smoke contained ammonia at levels up to 20-fold higher than tobacco. Hydrogen cyanide, nitric oxide, and certain aromatic amines were found at 3-5 times higher concentrations in marijuana smoke.\n\nHowever, some polycyclic aromatic hydrocarbons (PAHs), known carcinogens, were actually lower in mainstream marijuana smoke compared to tobacco. The pattern reversed for sidestream smoke, where marijuana had higher PAH concentrations.\n\nThe overall composition was qualitatively similar between marijuana and tobacco smoke, meaning they contained the same types of chemicals, but in different quantities.","whyItMatters":"While tobacco smoke chemistry is extensively documented, marijuana smoke had received limited analysis. This systematic comparison provided the first comprehensive side-by-side data, revealing both reassuring findings (lower PAHs in mainstream smoke) and concerning ones (much higher ammonia and HCN).","specificNumbers":"Ammonia: up to 20x higher in marijuana smoke. Hydrogen cyanide, NO, NOx, aromatic amines: 3-5x higher in marijuana. PAHs: lower in mainstream marijuana but higher in sidestream marijuana smoke.","methodology":"Marijuana and tobacco cigarettes were prepared identically and machine-smoked under two standardized conditions. Both mainstream and sidestream smoke were analyzed for the complete suite of chemicals routinely tested in tobacco smoke, including ammonia, hydrogen cyanide, nitrogen oxides, aromatic amines, and PAHs.","limitations":"Machine smoking may not replicate human smoking behavior (marijuana users typically inhale more deeply and hold longer). The study analyzed chemicals but did not measure health outcomes. Marijuana cigarette composition varies widely in the real world."},{"rthcId":"RTHC-00321","title":"The metabolic implications of long term cannabis use in patients with psychosis.","authors":"Mushtaq, Farrah; Mondelli, Valeria; Pariante, Carmine M","year":2008,"journal":"Epidemiologia e psichiatria sociale, 17(3), 221-6","doi":null,"pmid":"18924561","tags":["psychosis","appetite","cardiovascular"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This narrative review examined how cannabis use might affect metabolic health in people with psychosis, a population already at elevated risk for cardiovascular and metabolic disease.\n\nIn the general population, cannabis's short-term appetite-stimulating effects through the endocannabinoid system are well documented. However, the long-term metabolic effects of chronic cannabis use remain unclear, with conflicting results from the few studies conducted.\n\nIn patients with psychosis specifically, only one study had examined this question at the time of the review. That study found cannabis use was associated with increased body weight and blood glucose levels, suggesting cannabis may compound the metabolic risks already elevated in this population (due to both the illness itself and antipsychotic medications).\n\nThe authors noted that psychosis patients already have reduced life expectancy partly due to metabolic and cardiovascular disease, and cannabis use could be an additional contributing factor.","whyItMatters":"People with psychosis have higher rates of metabolic syndrome, diabetes, and cardiovascular disease. Understanding whether cannabis use adds to these risks is important for clinical care, especially since cannabis use is common in this population.","specificNumbers":"One study in psychosis patients found cannabis use associated with increased body weight and blood glucose. Psychosis patients have reduced life expectancy partly due to metabolic/cardiovascular disease.","methodology":"Narrative review of the literature on cannabis effects on appetite, weight, and metabolic parameters in both the general population and patients with psychosis.","limitations":"Only one study directly examined cannabis metabolic effects in psychosis patients at the time of review. The general population evidence on long-term cannabis metabolic effects was conflicting. The narrative review format did not systematically assess evidence quality."},{"rthcId":"RTHC-00322","title":"Deficits in learning and memory: parahippocampal hyperactivity and frontocortical hypoactivity in cannabis users.","authors":"Nestor, Liam; Roberts, Gloria; Garavan, Hugh; Hester, Robert","year":2008,"journal":"NeuroImage, 40(3), 1328-39","doi":"10.1016/j.neuroimage.2007.12.059","pmid":"18296071","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Two experiments examined learning and memory in cannabis users. In the first, 35 cannabis users performed significantly worse than 38 controls on learning, short-term memory, and long-term memory in a face-name association task.\n\nIn the second experiment, 14 cannabis users and 14 controls performed a modified version of the task during fMRI. Despite similar performance in this smaller group, the brain activation patterns differed dramatically.\n\nCannabis users showed significantly lower activation (hypoactivity) in the right superior temporal gyrus, right and left superior frontal gyrus, and right middle frontal gyrus during learning. Simultaneously, they showed significantly higher activation (hyperactivity) in the right parahippocampal gyrus.\n\nThe authors interpreted the frontal hypoactivity as a functional deficit and the parahippocampal hyperactivity as a compensatory mechanism, where the memory encoding region works harder to make up for inadequate frontal support.","whyItMatters":"This study revealed that cannabis users' brains show a push-pull pattern: some regions underperform while others overcompensate. This helps explain why cannabis users sometimes perform normally on simple tests but may struggle with more demanding real-world cognitive tasks.","specificNumbers":"Experiment 1: 35 users vs. 38 controls, significant deficits in learning and memory. Experiment 2: 14 users vs. 14 controls, frontal/temporal hypoactivity and parahippocampal hyperactivity during learning (no performance difference).","methodology":"Experiment 1: 35 cannabis users vs. 38 controls on behavioral face-name association task. Experiment 2: 14 cannabis users vs. 14 controls performed modified task during fMRI. Groups were well-matched on demographic variables.","limitations":"Cross-sectional design cannot determine causation. The fMRI sample was small (14 per group). Cannabis users may differ from non-users in unmeasured ways. The lack of performance differences in Experiment 2 limits the ability to link brain changes to functional impairment."},{"rthcId":"RTHC-00323","title":"Activation of the endocannabinoid system by organophosphorus nerve agents.","authors":"Nomura, Daniel K; Blankman, Jacqueline L; Simon, Gabriel M; Fujioka, Kazutoshi; Issa, Roger S; Ward, Anna M; Cravatt, Benjamin F; Casida, John E","year":2008,"journal":"Nature chemical biology, 4(6), 373-8","doi":"10.1038/nchembio.86","pmid":"18438404","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers discovered that certain organophosphorus compounds (normally studied as nerve agents) simultaneously inhibit both MAGL and FAAH, the two main enzymes that break down endocannabinoids in the brain.\n\nThis dual blockade produced greater than 10-fold increases in brain levels of both 2-AG and anandamide and caused robust CB1-dependent behavioral effects (reduced movement, catalepsy, hypothermia, pain insensitivity) that mirrored those of directly administering THC.\n\nThis was strikingly different from blocking FAAH alone, which produces only analgesic and anxiolytic effects without cognitive impairment or cannabinoid-like intoxication.\n\nAn unexpected finding: brain arachidonic acid levels decreased by amounts equivalent to the 2-AG increases, revealing that endocannabinoid and eicosanoid (inflammatory lipid) signaling pathways are coordinately regulated in the brain.","whyItMatters":"This study made two important contributions: it showed that blocking both endocannabinoid enzymes simultaneously produces very different effects than blocking either alone, and it revealed an unexpected connection between the endocannabinoid and inflammatory lipid systems.","specificNumbers":"Greater than 10-fold increases in both brain 2-AG and anandamide. CB1-dependent behavioral effects matching THC. Arachidonic acid decreased by amounts equivalent to 2-AG increases. FAAH inhibition alone: analgesia/anxiolysis without CB1-like behavioral effects.","methodology":"Selected organophosphorus agents were administered to mice. Brain endocannabinoid levels (anandamide and 2-AG) and arachidonic acid levels were measured. Behavioral effects were assessed using the cannabinoid tetrad. CB1 receptor involvement was confirmed using antagonists.","limitations":"Organophosphorus agents have multiple mechanisms of action beyond endocannabinoid enzyme inhibition (notably acetylcholinesterase inhibition), complicating interpretation. The doses used may not reflect typical environmental or occupational exposures."},{"rthcId":"RTHC-00324","title":"Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism.","authors":"Ortar, Giorgio; Bisogno, Tiziana; Ligresti, Alessia; Morera, Enrico; Nalli, Marianna; Di Marzo, Vincenzo","year":2008,"journal":"Journal of medicinal chemistry, 51(21), 6970-9","doi":"10.1021/jm800978m","pmid":"18831576","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers synthesized 21 analogues of tetrahydrolipstatin (THL, the active ingredient in the weight-loss drug orlistat) and tested them as inhibitors of 2-AG metabolism.\n\nThree compounds (11, 13, and 15) inhibited DAGLalpha (the enzyme that produces 2-AG) with IC50 values below 50 nanomolar, making them 20 times more potent than the parent compound THL. Critically, they were 23- to 375-fold selective for DAGLalpha over MAGL (which breaks down 2-AG), CB1/CB2 receptors, and FAAH.\n\nOne compound (8) was a potent inhibitor of MAGL-like activity (IC50 = 0.41 micromolar) with approximately 7-fold selectivity over other targets.\n\nThese selective tools allowed researchers to separately manipulate 2-AG production and degradation, enabling more precise studies of endocannabinoid function.","whyItMatters":"Selective pharmacological tools are essential for understanding which aspects of endocannabinoid signaling produce specific biological effects. These compounds allowed researchers to ask whether reducing 2-AG production versus enhancing it by blocking breakdown produces different outcomes.","specificNumbers":"Compounds 11, 13, 15: DAGLalpha IC50 < 50 nM (vs. THL IC50 = 1 micromolar). Selectivity: 23-375 fold vs. MAGL, CB1/CB2, FAAH. Compound 8: MAGL IC50 = 0.41 micromolar, 7-fold selective.","methodology":"Medicinal chemistry study synthesizing 21 THL analogues. Compounds were tested against DAGLalpha, MAGL, CB1, CB2, and FAAH in standardized biochemical assays to determine potency and selectivity.","limitations":"These are tool compounds, not drug candidates. In vitro potency and selectivity may not translate to in vivo utility. No behavioral or physiological testing was reported. Long-term safety profiles were not assessed."},{"rthcId":"RTHC-00325","title":"Behavioral pharmacology of cannabinoids with a focus on preclinical models for studying reinforcing and dependence-producing properties.","authors":"Panagis, George; Vlachou, Styliani; Nomikos, George G","year":2008,"journal":"Current drug abuse reviews, 1(3), 350-74","doi":null,"pmid":"19630731","tags":["addiction","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review examined preclinical (animal) evidence for the reinforcing and dependence-producing properties of cannabinoids.\n\nThe central finding was that cannabinoids behave differently from other drugs of abuse in standard laboratory paradigms. While opioids, stimulants, alcohol, and nicotine reliably produce self-administration and conditioned place preference in animals, cannabinoids do so only under narrow, specific experimental conditions.\n\nThis inconsistency in animal models contrasted with the clear subjective rewarding effects cannabis produces in humans, leading to cannabinoids being classified as \"atypical\" drugs of abuse.\n\nThe review also covered endocannabinoid system modulators (FAAH inhibitors, endocannabinoid transport inhibitors) and their reinforcing properties, finding these generally lacked abuse liability compared to direct CB1 agonists like THC.","whyItMatters":"The gap between animal and human evidence for cannabis reward has been a longstanding puzzle in addiction research. Understanding why cannabinoids are \"atypical\" helps explain their unique addiction profile: relatively low but non-zero addiction potential compared to many other drugs.","specificNumbers":"Cannabis is the most widely used illicit drug globally. Cannabinoids produce reinforcement in animals only under \"particular experimental conditions.\" Endocannabinoid modulators generally showed lower abuse liability than direct CB1 agonists.","methodology":"Comprehensive narrative review of preclinical behavioral pharmacology studies examining cannabinoid reward, reinforcement, and dependence, including self-administration, conditioned place preference, intracranial self-stimulation, and physical dependence paradigms.","limitations":"Narrative review format. Animal models may miss important aspects of human addiction. The conditions under which cannabinoids are reinforcing in animals may reveal something about cannabinoid pharmacology or may reflect limitations of the animal models themselves."},{"rthcId":"RTHC-00326","title":"Does cannabis use lead to depression and suicidal behaviours? A population-based longitudinal study.","authors":"Pedersen, W","year":2008,"journal":"Acta psychiatrica Scandinavica, 118(5), 395-403","doi":"10.1111/j.1600-0447.2008.01259.x","pmid":"18798834","tags":["mental-health","depression","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This population-based longitudinal study followed 2,033 Norwegians over 13 years from early adolescence to their late twenties.\n\nCannabis use in early adolescence showed no associations with later depression or suicidal behaviors. However, cannabis use in participants' twenties was significantly associated with suicidal ideation and suicide attempts.\n\nThe strongest finding emerged for frequent users: those who used cannabis 11 or more times in the past year had an adjusted odds ratio of 2.9 (95% CI: 1.3-6.1) for later suicide attempts, even after controlling for confounding factors.\n\nNotably, the study found no independent association between cannabis and depression, suggesting the link to suicidal behavior may operate through pathways other than mood disorders.","whyItMatters":"This study separated two commonly conflated outcomes: depression and suicidal behavior. The finding that cannabis was linked to suicide attempts but not depression challenges the assumption that cannabis causes depression which then leads to suicidality, suggesting a more direct or alternative pathway.","specificNumbers":"2,033 participants followed for 13 years. Frequent cannabis use (11+ times/year): OR 2.9 (95% CI: 1.3-6.1) for later suicide attempts after adjusting for confounders. No association with depression.","methodology":"Prospective longitudinal study using the Young in Norway cohort. 2,033 participants were followed from early teens to late twenties over 13 years. Cannabis use, depression, suicidal ideation, and suicide attempts were assessed with adjustment for potential confounders.","limitations":"Observational design cannot prove causation. Self-reported cannabis use and suicidal behavior may be unreliable. Confounders may not be fully controlled despite adjustment. The specific pathways linking cannabis to suicidality were not identified."},{"rthcId":"RTHC-00327","title":"The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.","authors":"Pertwee, R G","year":2008,"journal":"British journal of pharmacology, 153(2), 199-215","doi":"10.1038/sj.bjp.0707442","pmid":"17828291","tags":["pharmacology","cbd","medical-cannabis","foundational"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Delta-9-THC functions as a CB1 and CB2 receptor partial agonist, with its efficacy depending on receptor expression levels and ongoing endocannabinoid tone. Cannabidiol (CBD) displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists — not activating the receptors but blocking them. Delta-9-THCV behaves as a potent CB2 receptor partial agonist in vitro while antagonizing cannabinoid receptor agonists in CB1-expressing tissues at low doses, but acting as a CB1 agonist at higher doses. All three compounds also interact with non-cannabinoid targets including TRPV1, 5-HT1A, and GPR55 receptors. The review additionally covers THC tolerance development, dose-response relationships, and therapeutic implications of each distinct pharmacological profile.","whyItMatters":"This review established that plant cannabinoids are not pharmacologically interchangeable — the same plant produces molecules with completely different, sometimes opposite, receptor pharmacology. This insight underpins the entire regulatory distinction between THC and CBD, explains why different cannabis preparations produce different effects, why CBD modulates the THC high, why synthetic full agonists (K2/Spice) are more dangerous than plant-derived THC, and why THCV is being developed for metabolic conditions. Without this pharmacological framework, cannabis medicine is guesswork.","specificNumbers":"THC: partial agonist at CB1 and CB2. CBD: potent antagonist at CB1 and CB2. THCV: CB2 partial agonist, CB1 antagonist (low dose) or agonist (high dose). All three also interact with non-cannabinoid targets.","methodology":"Comprehensive pharmacological review synthesizing published receptor binding data, functional assay results (including the mouse vas deferens bioassay), in vivo behavioral studies, and clinical observations for three major phytocannabinoids. The author integrated evidence from transfected cell lines, native tissue preparations, knockout mouse studies, and clinical pharmacology to characterize each compound's receptor interaction profile.","limitations":"As a review, this paper synthesizes existing pharmacological data rather than generating new experiments. Much of the characterization was performed in cell lines and isolated tissue preparations — the in vivo pharmacology is more complex due to polyvalent receptor interactions, metabolite effects, and pharmacokinetic variables. The CBD characterization as an antagonist was later refined to \"negative allosteric modulator\" (Laprairie 2015). THCV dose-response data was primarily from animal models with limited human clinical confirmation at the time of publication."},{"rthcId":"RTHC-00328","title":"Effects of acute oral Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers.","authors":"Roser, Patrik; Juckel, Georg; Rentzsch, Johannes; Nadulski, Thomas; Gallinat, Jürgen; Stadelmann, Andreas M","year":2008,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 18(8), 569-77","doi":"10.1016/j.euroneuro.2008.04.008","pmid":"18544469","tags":["cognition","cbd","psychosis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a double-blind crossover study, 20 healthy volunteers received pure THC, a standardized cannabis extract containing THC and CBD, or placebo on separate occasions.\n\nAs expected, pure THC significantly reduced P300 amplitude at frontal, central, and parietal electrodes. P300 is a brain wave that reflects attention and working memory capacity, and its reduction mirrors the pattern seen in schizophrenia.\n\nUnexpectedly, the cannabis extract containing both THC and CBD also reduced P300 amplitude. CBD did not prevent or reverse THC's effect on this measure, contrary to the hypothesis that CBD counteracts THC's cognitive effects.\n\nThe authors speculated this could reflect an insufficient CBD dose or that the P300 is generated by neurotransmitter systems not influenced by CBD. No correlations were found between blood cannabinoid levels and P300 parameters.","whyItMatters":"While many studies suggest CBD counteracts THC, this study found one important measure where it did not. This complicates the narrative that CBD universally protects against THC's cognitive effects and suggests the interaction is task-specific and dose-dependent.","specificNumbers":"20 healthy volunteers (10 male, mean age 28.2). THC significantly reduced P300 amplitude at midline frontal, central, and parietal electrodes. Cannabis extract (THC+CBD) also reduced P300. No correlation between blood cannabinoid levels and P300.","methodology":"Prospective, double-blind, placebo-controlled crossover study. 20 healthy volunteers received THC, standardized cannabis extract (THC+CBD), or placebo on separate occasions. P300 event-related potentials were recorded during a choice reaction task.","limitations":"Relatively small sample (20 subjects). Only one dose ratio was tested. The CBD dose may have been insufficient. P300 is one specific measure that may not capture all cognitive effects."},{"rthcId":"RTHC-00329","title":"Cannabinoids in the management of difficult to treat pain.","authors":"Russo, Ethan B","year":2008,"journal":"Therapeutics and clinical risk management, 4(1), 245-59","doi":null,"pmid":"18728714","tags":["pain","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review by Ethan Russo comprehensively covered the evidence for cannabinoid use in pain management as of 2008.\n\nSativex (THC:CBD oromucosal spray) had been approved in Canada for MS central neuropathic pain (2005) and intractable cancer pain (2007). The US FDA had approved an Investigational New Drug application for advanced cancer pain trials in 2006.\n\nThe review covered multiple mechanisms of cannabinoid analgesia: endocannabinoid system modulation, non-receptor mechanisms, anti-inflammatory effects, and synergy with opioids. Clinical trial evidence supported efficacy in central and peripheral neuropathic pain, rheumatoid arthritis, and cancer pain.\n\nAdverse effects were generally well tolerated, and the adjunctive use of cannabinoids alongside existing pain treatments showed \"great promise.\" The review positioned cannabinoids as complementary additions to the pain medicine toolkit rather than standalone treatments.","whyItMatters":"This review captured the state of cannabinoid pain research at a time when the first cannabinoid medicines were receiving regulatory approval. It provided a comprehensive evidence-based framework that influenced clinical practice and further research.","specificNumbers":"Sativex approved in Canada: MS neuropathic pain (2005), cancer pain (2007). US FDA IND approved for cancer pain (2006). Multiple RCTs demonstrated safety and efficacy across pain types.","methodology":"Comprehensive narrative review of endocannabinoid system biology, non-receptor analgesic mechanisms, and randomized clinical trials of cannabinoids for pain.","limitations":"Narrative review without systematic methodology. Many trials were industry-sponsored. Long-term safety data was limited. The evidence was strongest for neuropathic pain, with less robust data for other pain types."},{"rthcId":"RTHC-00330","title":"Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?","authors":"Russo, Ethan B","year":2008,"journal":"Neuro endocrinology letters, 29(2), 192-200","doi":null,"pmid":"18404144","tags":["medical-cannabis","pain","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Ethan Russo proposed the concept of Clinical Endocannabinoid Deficiency (CECD), arguing that migraine, fibromyalgia, and irritable bowel syndrome (IBS) may share a common underlying cause: insufficient endocannabinoid system function.\n\nThe evidence included: all three conditions involve central sensitization and hyperalgesia (amplified pain processing); they frequently co-occur in the same patients; they respond to cannabis-based treatments in clinical reports; and endocannabinoid system components interact with pathways relevant to each condition.\n\nFor migraine specifically, anandamide modulates serotonin receptors, is active in the periaqueductal gray (a migraine generator region), and cannabinoids have anti-inflammatory and glutamate-modulating effects relevant to migraine pathophysiology.\n\nThe review proposed testing this hypothesis through cerebrospinal fluid endocannabinoid measurement and neuroimaging studies.","whyItMatters":"The CECD concept offered a unifying explanation for conditions that often co-occur, respond poorly to conventional treatment, and share features of central sensitization. If validated, it would provide a rational basis for treating these conditions with cannabinoid medicines.","specificNumbers":"Three conditions proposed as CECD-related: migraine, fibromyalgia, IBS. These frequently co-occur. Anandamide potentiates 5-HT1A and inhibits 5-HT2A receptors. THC modulates glutamatergic NMDA receptors.","methodology":"Literature review examining shared clinical, biochemical, and pathophysiological patterns among migraine, fibromyalgia, and IBS, with analysis of endocannabinoid system involvement in each condition.","limitations":"The CECD hypothesis was largely theoretical when proposed. Direct measurement of endocannabinoid levels in these conditions was limited. The shared features could be explained by other common mechanisms. The review did not include systematic evidence assessment."},{"rthcId":"RTHC-00331","title":"Effect of illicit recreational drugs upon sleep: cocaine, ecstasy and marijuana.","authors":"Schierenbeck, Thomas; Riemann, Dieter; Berger, Mathias; Hornyak, Magdolna","year":2008,"journal":"Sleep medicine reviews, 12(5), 381-9","doi":"10.1016/j.smrv.2007.12.004","pmid":"18313952","tags":["sleep"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compared the sleep effects of three illicit drugs.\n\nCannabis: Acute use facilitated sleep onset and increased Stage 4 (deep) sleep while reducing REM sleep. Cannabis withdrawal produced insomnia, strange dreams (possibly reflecting REM rebound), longer sleep onset, reduced slow-wave sleep, and increased REM sleep. These withdrawal sleep disturbances were among the most consistently reported withdrawal symptoms.\n\nCocaine: Acute use increased wakefulness and suppressed REM sleep. Withdrawal was associated with sleep disturbances and unpleasant dreams. Objectively measured sleep actually worsened during sustained abstinence even though patients reported sleep improvement.\n\nEcstasy (MDMA): Heavy use was associated with persistent sleep disturbances. Abstinent heavy users showed altered sleep architecture on polysomnography, consistent with MDMA's effects on the serotonin system.","whyItMatters":"Sleep disturbance is a major factor in substance use relapse. Understanding how each drug specifically alters sleep helps clinicians address sleep problems during treatment and withdrawal.","specificNumbers":"Cannabis: increased Stage 4 sleep, reduced REM sleep acutely. Cannabis withdrawal: insomnia, vivid/strange dreams, REM rebound. Cocaine: increased wakefulness, REM suppression. MDMA: altered sleep architecture in abstinent heavy users.","methodology":"Narrative review of published polysomnography studies and clinical reports examining the effects of cannabis, cocaine, and MDMA on sleep architecture during use and withdrawal.","limitations":"Many studies had small samples. Polysubstance use complicates attribution. Duration of sleep effects after cessation varied across studies. The review predated many larger studies on cannabis and sleep."},{"rthcId":"RTHC-00332","title":"Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure.","authors":"Schneider, Miriam","year":2008,"journal":"Addiction biology, 13(2), 253-63","doi":"10.1111/j.1369-1600.2008.00110.x","pmid":"18482434","tags":["youth","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review assembled evidence from human and animal studies showing puberty is a uniquely vulnerable period for cannabis exposure.\n\nThe endocannabinoid system undergoes significant maturation during puberty, with changes in CB1 receptor density, endocannabinoid levels, and enzyme expression across brain regions. These developmental processes are essential for adult behavioral and cognitive capacities but simultaneously create vulnerability to disruption.\n\nEvidence from human studies showed early-onset cannabis use was associated with lasting cognitive deficits, increased risk for neuropsychiatric disorders (particularly psychosis), greater likelihood of progressing to other illicit drugs, and higher rates of cannabis dependence compared to adult-onset use.\n\nAnimal studies confirmed greater sensitivity: pubertal animals showed more severe acute effects and more lasting behavioral changes from the same cannabinoid doses that produced milder, reversible effects in adults.","whyItMatters":"This review provided a biological explanation for why early-onset cannabis use is associated with worse outcomes: the developing endocannabinoid system during puberty is especially vulnerable to disruption, and interference during this critical period can have lasting consequences.","specificNumbers":"Endocannabinoid system undergoes major maturational changes during puberty. Early onset associated with: lasting cognitive deficits, increased psychosis risk, greater progression to other drugs, higher dependence rates.","methodology":"Narrative review of human epidemiological studies, human neuroimaging research, and animal studies examining the effects of cannabis/cannabinoid exposure during the pubertal period.","limitations":"Human studies were primarily observational and cannot prove causation. Selection effects (risk-prone teens being more likely to use cannabis early) may explain some associations. The specific developmental windows of vulnerability were not precisely delineated."},{"rthcId":"RTHC-00333","title":"Acute and chronic cannabinoid treatment differentially affects recognition memory and social behavior in pubertal and adult rats.","authors":"Schneider, Miriam; Schömig, Edgar; Leweke, F Markus","year":2008,"journal":"Addiction biology, 13(3-4), 345-57","doi":"10.1111/j.1369-1600.2008.00117.x","pmid":"18782382","tags":["youth","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers gave pubertal rats (postnatal day 40-65) and adult rats (postnatal day 80+) daily injections of the synthetic cannabinoid WIN 55,212-2 for 25 days and tested behavior at three time points: immediately after the first dose, 24 hours after stopping, and 15 days after stopping.\n\nPubertal-treated rats showed persistent deficits in both object and social recognition memory, indicating impaired short-term information processing. They also showed lasting disturbances in social behavior, social play, and self-grooming, even 15 days after treatment stopped.\n\nAcute cannabinoid effects (after the first dose) were also more pronounced in pubertal rats than adults. The same dose that caused severe behavioral disruption in pubertal rats produced milder effects in adult animals.\n\nThe authors attributed the heightened vulnerability to an overactive endocannabinoid system during puberty combined with ongoing maturation of interacting neurotransmitter systems.","whyItMatters":"This study provided direct experimental evidence that the same cannabinoid exposure produces more severe and longer-lasting effects in pubertal animals than adults, supporting the human epidemiological observation that early-onset cannabis use carries greater risk.","specificNumbers":"25-day cannabinoid treatment. Pubertal rats: persistent memory and social deficits at 15 days post-cessation. Adult rats: milder effects. Acute effects more pronounced in pubertal vs. adult rats for the same dose.","methodology":"Pubertal (pd 40-65) and adult (>pd 80) rats received daily WIN 55,212-2 (1.2 mg/kg) or vehicle for 25 days. Behavioral testing (object/social recognition memory, social interaction, spontaneous social behavior) at three time points: acute, 24 hours post-cessation, 15 days post-cessation.","limitations":"WIN 55,212-2 is a synthetic cannabinoid more potent than THC. Only one dose was tested. Rat puberty differs from human puberty. 15 days post-cessation may not predict truly permanent effects."},{"rthcId":"RTHC-00334","title":"Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet.","authors":"Starowicz, Katarzyna M; Cristino, Luigia; Matias, Isabel; Capasso, Raffaele; Racioppi, Alessandro; Izzo, Angelo A; Di Marzo, Vincenzo","year":2008,"journal":"Obesity (Silver Spring, Md.), 16(3), 553-65","doi":"10.1038/oby.2007.106","pmid":"18239598","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers fed mice standard or high-fat diets for up to 14 weeks and mapped the endocannabinoid system in their pancreatic and fat tissues.\n\nIn the pancreas, they found that CB1 receptors and endocannabinoid-producing enzymes were primarily located in alpha cells (which make glucagon), while degrading enzymes were in beta cells (which make insulin). A high-fat diet caused endocannabinoid-producing enzymes to appear in beta cells and reduced FAAH (a degrading enzyme), resulting in elevated pancreatic endocannabinoid levels.\n\nIn subcutaneous fat tissue, the opposite occurred: endocannabinoid levels decreased, with lower expression of producing enzymes and higher expression of FAAH.\n\nVisceral fat showed no diet-induced enzyme changes. Cannabinoid receptor levels remained unchanged in all tissues regardless of diet.\n\nThis tissue-specific dysregulation suggests the endocannabinoid system's role in metabolic disease is more complex than simply being \"overactive.\"","whyItMatters":"Understanding how obesity and high-fat diet alter the endocannabinoid system in metabolically active tissues is essential for developing targeted treatments. The finding that changes are tissue-specific and bidirectional complicates the simple \"endocannabinoid overactivity\" model of obesity.","specificNumbers":"Pancreas: endocannabinoid levels increased on high-fat diet, with enzyme redistribution to beta cells. Subcutaneous fat: endocannabinoid levels decreased. Visceral fat: no enzyme changes. Receptor levels unchanged in all tissues.","methodology":"Mice were fed standard or high-fat diet for up to 14 weeks. Endocannabinoid system components (CB1, CB2, NAPE-PLD, DAGLalpha, FAAH, MAGL) were mapped in pancreas and adipose tissue by immunohistochemistry. Endocannabinoid levels (2-AG, anandamide) were measured by LC-MS.","limitations":"Mouse metabolism differs from human. Only one high-fat diet composition was tested. The functional consequences of enzyme redistribution were not directly tested. Immunohistochemistry provides semi-quantitative data."},{"rthcId":"RTHC-00335","title":"Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.","authors":"Vandevoorde, Séverine","year":2008,"journal":"Current topics in medicinal chemistry, 8(3), 247-67","doi":null,"pmid":"18289091","tags":["neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review cataloged and compared all known synthetic inhibitors of FAAH and MAGL, the two primary enzymes that break down the endocannabinoids anandamide and 2-AG.\n\nFAAH inhibitors fell into two groups: substrate-inspired compounds (mimicking the fatty acid chains of anandamide, oleamide, or PEA) and structurally novel compounds (carbamates, oxazolopyridines, imidazolidines, and even some NSAIDs). The substrate-inspired group was extensive and included highly selective compounds.\n\nMAGL inhibitors were far fewer in number and most lacked selectivity, meaning they also inhibited other enzymes. This disparity reflected the earlier characterization of FAAH and the greater research attention it had received.\n\nThe review provided detailed comparisons of synthetic pathways, potencies, selectivities, and mechanisms of inhibition to facilitate research tool selection.","whyItMatters":"Selective enzyme inhibitors are essential tools for understanding endocannabinoid function and for developing therapeutics. This catalog highlighted the urgent need for better MAGL inhibitors, a gap that has since been addressed.","specificNumbers":"FAAH inhibitor families: substrate-inspired (arachidonoyl, oleoyl, palmitoyl chains) and novel (carbamates, oxazolopyridines, etc.). MAGL inhibitors: few members, most lacking selectivity. FAAH was cloned nearly simultaneously with MAGL but received far more pharmacological attention.","methodology":"Comprehensive review of published literature on FAAH and MAGL inhibitor chemistry, covering synthetic pathways, potencies (IC50 values), selectivities, and mechanisms of action for all known inhibitor families.","limitations":"As a chemistry-focused review, it did not cover in vivo efficacy or safety in detail. The field was evolving rapidly, and new inhibitors were being developed. Some potency comparisons across studies using different assay conditions must be interpreted cautiously."},{"rthcId":"RTHC-00336","title":"Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome.","authors":"Vemuri, V Kiran; Janero, David R; Makriyannis, Alexandros","year":2008,"journal":"Physiology & behavior, 93(4-5), 671-86","doi":null,"pmid":"18155257","tags":["appetite","neuroscience","cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review detailed the pharmacological rationale for targeting the endocannabinoid system in obesity and metabolic syndrome.\n\nThe endocannabinoid system promotes food intake (through brain CB1 receptors) and energy storage as fat (through peripheral CB1 receptors). In obesity, this system is hyperactive, creating a vicious cycle of overconsumption and fat accumulation.\n\nRimonabant, the first approved CB1 antagonist/inverse agonist, demonstrated weight loss and improvements in metabolic markers (blood lipids, blood sugar, waist circumference) in clinical trials. However, psychiatric side effects (depression, anxiety, suicidality) limited its clinical utility.\n\nThe review highlighted an emerging concept: \"neutral CB1 antagonists\" that block the receptor without the inverse agonist activity that may cause psychiatric effects. Preclinical data suggested these could provide metabolic benefits with a better safety profile.\n\nBeyond weight loss alone, effective CB1 modulation could address type 2 diabetes, atherosclerosis, inflammation, and immune disorders associated with metabolic syndrome.","whyItMatters":"Obesity is a global pandemic with limited pharmacological options. This review articulated both the promise and the challenges of the endocannabinoid approach, and pointed toward the next generation of potentially safer drugs.","specificNumbers":"Rimonabant: approved in some markets for weight management. Multiple CB1 antagonists in preclinical or clinical development. Neutral CB1 antagonists proposed as superior to inverse agonists for safety profile.","methodology":"Comprehensive review of endocannabinoid system pharmacology as it relates to obesity and metabolic syndrome, covering preclinical mechanisms, clinical trial results, and emerging drug development strategies.","limitations":"Written before rimonabant's market withdrawal. The review presented the field optimistically. The \"neutral antagonist\" concept was based on limited preclinical data at the time."},{"rthcId":"RTHC-00337","title":"Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions.","authors":"Aggarwal, Sunil K; Carter, Gregory T; Sullivan, Mark D; ZumBrunnen, Craig; Morrill, Richard; Mayer, Jonathan D","year":2009,"journal":"Journal of opioid management, 5(3), 153-68","doi":null,"pmid":"19662925","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review traced the arc of medical cannabis from ancient Chinese use (c. 2737 BCE) through its US history to the emerging science of the endocannabinoid system.\n\nCannabis was criminalized in the US in 1937, notably against the formal advice of the American Medical Association presented to Congress. This effectively ended medical use and research for decades.\n\nThe discovery of the endocannabinoid system transformed the field. Endocannabinoids were found to control pain, muscle tone, mood, appetite, and inflammation. Cannabis contains over 100 cannabinoids with the capacity for analgesia through neuromodulation, neuroprotection, and anti-inflammatory mechanisms.\n\nMajor institutions (NIH, Institute of Medicine, American College of Physicians) had issued statements supporting further research. The review focused on applications in chronic pain, muscle spasticity, cachexia, and other debilitating problems.","whyItMatters":"This review placed the modern medical cannabis movement in historical context, showing that the current resurgence is not a new phenomenon but a return to pre-prohibition norms, now supported by modern neuroscience.","specificNumbers":"Cannabis use documented since c. 2737 BCE. Criminalized in US in 1937. Over 100 cannabinoids identified. NIH, IOM, and ACP issued support statements for research.","methodology":"Historical and scientific narrative review covering the chronology of medical cannabis in the US, the endocannabinoid system, and current/emerging research on therapeutic applications.","limitations":"Narrative review format without systematic methodology. Historical claims about ancient cannabis use are difficult to verify. The review presented a predominantly pro-medical-cannabis perspective."},{"rthcId":"RTHC-00338","title":"Characteristics of patients with chronic pain accessing treatment with medical cannabis in Washington State.","authors":"Aggarwal, Sunil K; Carter, Gregory T; Sullivan, Mark D; ZumBrunnen, Craig; Morrill, Richard; Mayer, Jonathan D","year":2009,"journal":"Journal of opioid management, 5(5), 257-86","doi":null,"pmid":"19947069","tags":["pain","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers reviewed charts of 139 patients legally authorized for medical cannabis in Washington State, seen at a university pain clinic.\n\nThe patient population was complex: 88% had more than one pain syndrome. The most common diagnoses were myofascial pain (82%), neuropathic pain (64%), discogenic back pain (52%), and osteoarthritis (27%). Other conditions included diabetic neuropathy, fibromyalgia, HIV neuropathy, phantom limb pain, and cancer pain.\n\nMales (63%) and females (37%) accessed medical cannabis at approximately equal rates with similar authorization durations (median 1.12 years, range 11 days to 8.3 years).\n\nA striking 37% of patients faced documented access barriers: prior physicians unwilling to authorize use, legal problems related to medical cannabis, and difficulties finding affordable, consistent supply. Despite these barriers, the majority of records documented significant symptom alleviation.","whyItMatters":"This was one of the earliest detailed profiles of medical cannabis patients in the US. It revealed that these were complex pain patients, not recreational users seeking access, and that significant barriers existed even in a state with legal medical cannabis.","specificNumbers":"139 patients (87 male, 52 female). Median authorized use: 1.12 years. 88% had 2+ pain conditions. Myofascial pain: 82%. Neuropathic pain: 64%. Discogenic back pain: 52%. 37% faced major access barriers.","methodology":"Retrospective chart review of 139 patients at a university-based pain clinic in Washington State. All were legally authorized for medical cannabis. Records were scored for demographics, diagnoses, McGill Pain scores, functional status, analgesic use, and access barriers.","limitations":"Retrospective chart review with inherent limitations in data quality. Single clinic in one state may not represent all medical cannabis patients. Self-selection bias (only patients reaching a university pain clinic). No control group for symptom outcomes."},{"rthcId":"RTHC-00339","title":"Candidate genes for cannabis use disorders: findings, challenges and directions.","authors":"Agrawal, Arpana; Lynskey, Michael T","year":2009,"journal":"Addiction (Abingdon, England), 104(4), 518-32","doi":"10.1111/j.1360-0443.2009.02504.x","pmid":"19335651","tags":["genetics","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized the genetic research on cannabis use disorders, covering both linkage studies (mapping chromosomal regions) and candidate gene association studies.\n\nFour linkage studies identified regions on chromosomes 1, 3, 4, 9, 14, 17, and 18. Notable candidates within these regions included MGLL (monoglyceride lipase, on chromosome 3) and a novel gene ELTD1 on chromosome 1.\n\nCandidate gene studies examined two categories: cannabis-specific genes (CNR1/CB1 receptor, CB2, FAAH, MGLL, TRPV1, GPR55) and general addiction genes from dopamine (DRD2), GABA (GABRA2), and opioid (OPRM1) systems.\n\nThe review highlighted four major challenges: understanding biological complexity including gene-gene and gene-environment interactions; choosing between diagnostic and quantitative phenotypes; distinguishing which stage of cannabis involvement (use, misuse, dependence) genes influence; and problems of sample composition.","whyItMatters":"Understanding the genetic basis of cannabis use disorders could lead to better prediction of who is at risk and potentially targeted prevention strategies. The review mapped the landscape of genetic knowledge and identified critical research gaps.","specificNumbers":"Regions on chromosomes 1, 3, 4, 9, 14, 17, and 18 identified. Cannabis-specific candidate genes: CNR1, CB2, FAAH, MGLL, TRPV1, GPR55. Non-specific candidates: GABRA2, DRD2, OPRM1.","methodology":"Review of peer-reviewed linkage and candidate gene association studies related to cannabis use disorders, organized by study type and gene system.","limitations":"Most candidate gene studies had small samples prone to false positives. Linkage studies identify broad regions, not specific genes. The review predated GWAS era. Gene-environment interaction studies were largely absent."},{"rthcId":"RTHC-00340","title":"Developing a quantitative measure of alcohol consumption for genomic studies on prospective cohorts.","authors":"Agrawal, Arpana; Grant, Julia D; Littlefield, Andrew; Waldron, Mary; Pergadia, Michele L; Lynskey, Michael T; Madden, Pamela A F; Todorov, Alexandre; Trull, Timothy; Bucholz, Kathleen K; Todd, Richard D; Sher, Kenneth; Heath, Andrew C","year":2009,"journal":"Journal of studies on alcohol and drugs, 70(2), 157-68","doi":null,"pmid":"19261227","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers developed a quantitative alcohol consumption factor score using four measures: maximum typical consumption, maximum drinks in 24 hours, frequency of 5+ drinks per day, and frequency of intoxication.\n\nThe composite score showed good psychometric properties: factor loadings of 0.60-0.90, measurement invariance across two samples and genders, and 50% heritability. Individual component measures were 34-47% heritable.\n\nImportantly for substance use research, the alcohol factor correlated with nicotine and cannabis use measures similarly across samples and genders, supporting construct validity and suggesting shared genetic influences across substances.\n\nThe genetic variance in the composite factor accounted for a majority of the genetic variance in each individual measure, meaning the factor captured the common genetic influence underlying different aspects of alcohol consumption.","whyItMatters":"Better measurement tools for substance use improve the ability to identify genetic variants. The correlation with cannabis use supported the idea of shared genetic vulnerability across substances.","specificNumbers":"3,787 female twins + 489 college sample. Factor loadings: 0.60-0.90. Heritability of composite score: 50%. Individual measures: 34-47% heritable. Correlated with nicotine and cannabis use.","methodology":"Twin study using 3,787 young adult twin women and 489 men and women from a college drinking study. Factor analysis, measurement invariance testing, construct validation against tobacco/cannabis use, and genetic psychometric modeling were performed.","limitations":"The primary sample was all female. Cross-validation with the college sample was helpful but limited in size. Cannabis use was examined as a correlate, not as the primary focus."},{"rthcId":"RTHC-00341","title":"Simultaneous cannabis and tobacco use and cannabis-related outcomes in young women.","authors":"Agrawal, Arpana; Lynskey, Michael T; Madden, Pamela A F; Pergadia, Michele L; Bucholz, Kathleen K; Heath, Andrew C","year":2009,"journal":"Drug and alcohol dependence, 101(1-2), 8-12","doi":"10.1016/j.drugalcdep.2008.10.019","pmid":"19081202","tags":["addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using data from 3,427 young women, researchers distinguished between co-occurring use (using both substances in one's life) and simultaneous use (using cannabis and tobacco on the same occasion).\n\nRegular cigarette smokers were 4.5-9.5 times more likely to also use cannabis and progress to cannabis abuse or dependence compared to non-smokers.\n\nAmong the 1,073 women who used both substances, those who used them simultaneously were 1.6 times more likely to meet criteria for DSM-IV cannabis abuse, even after controlling for early risk factors and prior cannabis use stages.\n\nTwin analysis revealed that simultaneous use was not heritable (0% genetic influence) but was partly explained by shared environmental factors (31%), suggesting that peer groups and social contexts, rather than genetics, drive the behavior of combining these substances.","whyItMatters":"This study identified simultaneous cannabis-tobacco use as a marker for more severe cannabis outcomes. The finding that this behavior is environmentally (not genetically) driven suggests it may be modifiable through peer-based or contextual interventions.","specificNumbers":"3,427 women total. Regular smokers: 4.5-9.5x more likely to use cannabis. 1,073 co-occurring users. Simultaneous users: 1.6x more likely to have cannabis abuse (OR 1.6). Heritability of simultaneous use: 0%. Shared environment: 31%.","methodology":"Cross-sectional analysis of 3,427 young adult women from a twin registry. Distinguished co-occurring from simultaneous cannabis-tobacco use. Logistic regression examined associations with cannabis outcomes. Twin modeling estimated genetic and environmental contributions to simultaneous use.","limitations":"Cross-sectional design cannot establish causation. Only women were studied. Self-reported simultaneous use may be imprecise. The cannabis-tobacco interaction mechanism was not investigated."},{"rthcId":"RTHC-00342","title":"The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.","authors":"Ahrens, Jörg; Demir, Reyhan; Leuwer, Martin; de la Roche, Jeanne; Krampfl, Klaus; Foadi, Nilufar; Karst, Matthias; Haeseler, Gertrud","year":2009,"journal":"Pharmacology, 83(4), 217-22","doi":"10.1159/000201556","pmid":"19204413","tags":["cbd","pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers investigated whether CBD interacts with glycine receptors, which are the main inhibitory neurotransmitter receptors in the adult spinal cord and are important for pain processing.\n\nCBD showed a positive allosteric modulating effect on alpha1 and alpha1-beta glycine receptors at low micromolar concentrations (EC50 of 12.3 and 18.1 micromolar). This means CBD enhanced the receptors' response to their natural activator.\n\nAt higher concentrations (above 100 micromolar), CBD directly activated the receptors independently (EC50 of 132.4 and 144.3 micromolar).\n\nSince loss of glycinergic inhibition in the spinal cord is a key mechanism in the development of chronic pain following inflammation or nerve injury, CBD's ability to restore or enhance glycine receptor function could explain some of its pain-relieving properties through a non-cannabinoid receptor mechanism.","whyItMatters":"This study identified a specific non-cannabinoid receptor mechanism for CBD's pain effects. Since glycine receptor dysfunction is implicated in chronic pain development, CBD's ability to enhance glycinergic transmission provides a mechanistic explanation for clinical pain relief.","specificNumbers":"Allosteric modulation EC50: alpha1 = 12.3 micromolar, alpha1-beta = 18.1 micromolar. Direct activation EC50: alpha1 = 132.4 micromolar, alpha1-beta = 144.3 micromolar.","methodology":"Whole-cell patch clamp electrophysiology on cells expressing alpha1 or alpha1-beta glycine receptors. CBD effects were measured as changes in glycine-evoked currents (allosteric modulation) and as direct current induction (direct activation).","limitations":"In vitro electrophysiology on expressed receptors may not reflect in vivo conditions. The concentrations needed for direct activation (>100 micromolar) may not be achievable in the spinal cord with typical CBD dosing. Only two receptor subtypes were tested."},{"rthcId":"RTHC-00343","title":"A critical review of the cannabinoid receptor as a drug target for obesity management.","authors":"Akbas, F; Gasteyger, C; Sjödin, A; Astrup, A; Larsen, T M","year":2009,"journal":"Obesity reviews : an official journal of the International Association for the Study of Obesity, 10(1), 58-67","doi":"10.1111/j.1467-789X.2008.00520.x","pmid":"18721231","tags":["appetite","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This critical review assessed how close CB1 cannabinoid receptor antagonists were to being ideal anti-obesity drugs.\n\nThe mechanisms were sound: CB1 antagonists reduced food intake centrally (brain) and may increase energy expenditure peripherally (thermogenesis in animal studies).\n\nHowever, the clinical reality was disappointing. Despite these dual mechanisms, the weight loss achieved by rimonabant and taranabant (the two most advanced compounds) did not exceed that of already-approved anti-obesity medications.\n\nMore concerning, both compounds were associated with potentially severe psychiatric adverse effects including depression, anxiety, and suicidal ideation, which significantly limited their clinical utility.\n\nThe review noted several new CB1 antagonists in development and questioned whether they would differ meaningfully in efficacy and safety.","whyItMatters":"This review provided a reality check on the anti-obesity cannabinoid approach. While the mechanism was elegant, the clinical outcomes were underwhelming and the safety concerns were serious, leading to rimonabant's withdrawal and the shelving of other programs.","specificNumbers":"Rimonabant and taranabant: weight loss did not exceed existing medications. Psychiatric adverse effects limited clinical use. Multiple new CB1 antagonists in development at the time.","methodology":"Critical narrative review of CB1 receptor antagonist mechanisms of action, clinical trial efficacy data, and safety profiles, compared to existing approved anti-obesity medications.","limitations":"Published during a period of active drug development, so the review could not assess compounds that were not yet in clinical trials. The comparison to existing anti-obesity drugs depended on the specific comparators chosen."},{"rthcId":"RTHC-00344","title":"Factors associated with psychoactive substance use among a sample of prison inmates in Ilesa, Nigeria.","authors":"Amdzaranda, P A; Fatoye, F O; Oyebanji, A O; Ogunro, A S; Fatoye, G K","year":2009,"journal":"The Nigerian postgraduate medical journal, 16(2), 109-14","doi":null,"pmid":"19606190","tags":["addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"All inmates of a Nigerian medium-security prison who consented were interviewed about substance use before and during imprisonment.\n\nCurrent use rates were: tobacco (13.7%), hypnosedatives (11.4%), alcohol (10.7%), stimulants (9.6%), cannabis (7%), and smaller percentages for opioids, inhalants, cocaine, and heroin. Notably, these rates were only slightly lower than pre-imprisonment rates for most substances, indicating continued access within prison.\n\nAmong current cannabis users, 71.4% were classified as \"heavy users,\" the highest heavy-use proportion of any substance. Cannabis use was specifically associated with previous arrests for drug offenses, previous imprisonment, and being held for a major offense, suggesting a link between cannabis use and criminality patterns.\n\nAn unexpected finding was the emergence of pethidine/morphine use (2.3%), suggesting injecting drug use may be developing among Nigerian prisoners.","whyItMatters":"This study provided data from a non-Western setting where substance use patterns differ from those typically studied. The finding that drug use rates barely decreased during imprisonment highlighted the need for drug prevention programs within the Nigerian criminal justice system.","specificNumbers":"Current use rates: tobacco 13.7%, hypnosedatives 11.4%, alcohol 10.7%, stimulants 9.6%, cannabis 7%. Cannabis heavy use: 71.4%. Pethidine/morphine: 2.3% (emerging). Rates similar to pre-imprisonment.","methodology":"Cross-sectional survey of all consenting inmates at Ilesa medium-security prison, Nigeria. Structured interviews covered sociodemographic information, substance use history before and during imprisonment, and imprisonment-related factors.","limitations":"Single prison in one Nigerian city may not represent national patterns. Self-reported drug use in prison may be underreported due to consequences. The cross-sectional design cannot establish causal relationships. Small numbers for some substances limit analysis."},{"rthcId":"RTHC-00345","title":"Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study.","authors":"Aragona, Massimiliano; Onesti, Emanuela; Tomassini, Valentina; Conte, Antonella; Gupta, Shiva; Gilio, Francesca; Pantano, Patrizia; Pozzilli, Carlo; Inghilleri, Maurizio","year":2009,"journal":"Clinical neuropharmacology, 32(1), 41-7","doi":"10.1097/WNF.0B013E3181633497","pmid":"18978501","tags":["medical-cannabis","psychosis","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Seventeen cannabis-naive MS patients were randomized in a double-blind crossover trial to receive Sativex or placebo for 3-week periods, with comprehensive psychological and cognitive assessments.\n\nNo significant differences were found between the Sativex and placebo phases on any measured psychological or cognitive variable. Sativex did not cause psychopathology (measured by SCL-90-R), anxiety (Zung scale), cognitive impairment (PASAT), or quality of life changes.\n\nNo abuse tendencies or direct withdrawal symptoms were reported. One subject did report increased desire for Sativex with secondary depression after discontinuation.\n\nHowever, a correlation was found between blood THC levels and scores on interpersonal sensitivity, aggressive behavior, and paranoid tendencies subscales. This suggested that at higher doses than used therapeutically, psychological symptoms might emerge, though the correlation needs confirmation in larger studies.","whyItMatters":"Safety concerns about psychiatric effects are a major barrier to cannabinoid medicine use. This study in cannabis-naive patients (the most potentially vulnerable group) found Sativex was psychiatrically safe at therapeutic doses, addressing clinician concerns about prescribing cannabinoid medicines.","specificNumbers":"17 cannabis-naive MS patients. 3-week crossover design. No significant differences between Sativex and placebo on any psychiatric or cognitive measure. THC blood levels correlated with interpersonal sensitivity, aggression, and paranoid tendency scores.","methodology":"Eight-week randomized, double-blind, placebo-controlled, parallel-group crossover trial. 17 cannabis-naive MS patients assessed at baseline and after each 3-week treatment phase with SCL-90-R, Self-rating Anxiety Scale, MSFC/PASAT, VAS quality of life, MSIS-29, and Fatigue Severity Scale.","limitations":"Very small sample (17 patients). Three-week treatment periods may be too short to detect longer-term psychiatric effects. The THC-symptom correlation was exploratory and needs replication. Cannabis-naive patients may not represent all potential users."},{"rthcId":"RTHC-00346","title":"Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis.","authors":"Bhattacharyya, Sagnik; Fusar-Poli, Paolo; Borgwardt, Stefan; Martin-Santos, Rocio; Nosarti, Chiara; O'Carroll, Colin; Allen, Paul; Seal, Marc L; Fletcher, Paul C; Crippa, José A; Giampietro, Vincent; Mechelli, Andrea; Atakan, Zerrin; McGuire, Philip","year":2009,"journal":"Archives of general psychiatry, 66(4), 442-51","doi":"10.1001/archgenpsychiatry.2009.17","pmid":"19349314","tags":["neuroscience","cognition","psychosis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In a double-blind crossover study, 15 healthy men received 10 mg THC, 600 mg CBD, or placebo before completing a verbal learning task during fMRI scanning.\n\nTHC increased psychotic symptoms and anxiety while disrupting normal brain activation patterns. Specifically, THC caused the parahippocampal gyrus to remain highly active across repeated learning blocks instead of showing the normal decrease in activation that occurs with repeated exposure.\n\nTHC also altered ventrostriatal activation during word retrieval, and this change correlated directly with the severity of psychotic symptoms participants experienced.\n\nCBD produced none of these effects. Neither drug significantly affected actual learning performance on the task.","whyItMatters":"This study identified specific brain regions where THC may interfere with learning and produce psychotic symptoms. The finding that ventrostriatal disruption correlated with psychotic symptoms suggests a potential neural mechanism for cannabis-related psychosis.","specificNumbers":"15 participants completed all three sessions. THC dose was 10 mg oral. CBD dose was 600 mg oral. THC augmented parahippocampal activation during learning blocks 2 and 3, eliminating the normal linear decrease.","methodology":"This was a double-blind, randomized, placebo-controlled, within-subject crossover study. Each of the 15 participants completed three separate fMRI scanning sessions, receiving THC (10 mg oral), CBD (600 mg oral), or placebo on different occasions. During scanning, they performed a verbal paired-associate learning task.","limitations":"The sample included only 15 healthy men with very limited cannabis experience (15 times or fewer lifetime). Results may not generalize to regular users, women, or people with psychiatric conditions. A single oral dose may not reflect typical cannabis use patterns."},{"rthcId":"RTHC-00347","title":"Cannabinoids, endocannabinoids, and related analogs in inflammation.","authors":"Burstein, Sumner H; Zurier, Robert B","year":2009,"journal":"The AAPS journal, 11(1), 109-19","doi":"10.1208/s12248-009-9084-5","pmid":"19199042","tags":["inflammation","cbd","medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined five years of research on the anti-inflammatory properties of cannabinoids across several categories: plant-derived cannabinoids (THC, CBD), synthetic analogs (ajulemic acid, nabilone), endocannabinoids (anandamide and related compounds), and non-cannabinoid cannabis components.\n\nAll classes demonstrated anti-inflammatory activity. The authors proposed a specific mechanism: cannabinoids increase the production of eicosanoids that promote the resolution of inflammation, rather than suppressing the eicosanoids that initiate inflammation (which is how COX-2 inhibitors work).\n\nThis distinction is important because promoting resolution is fundamentally different from blocking initiation, potentially offering a different therapeutic approach.","whyItMatters":"The proposed mechanism, promoting inflammation resolution rather than blocking initiation, distinguishes cannabinoids from conventional anti-inflammatory drugs like COX-2 inhibitors and suggests they may work through a complementary pathway.","specificNumbers":"The review covered roughly 5 years of published research across phytocannabinoids, synthetic cannabinoids, endocannabinoids, and non-cannabinoid cannabis components.","methodology":"This was a narrative review covering research published between approximately 2004 and 2009 on all classes of cannabinoids and their anti-inflammatory effects.","limitations":"As a narrative review, this paper did not systematically assess study quality or risk of bias. The proposed mechanism involving resolution-promoting eicosanoids, while supported by evidence, was not definitively established."},{"rthcId":"RTHC-00348","title":"Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis.","authors":"Centonze, Diego; Mori, Francesco; Koch, Giacomo; Buttari, Fabio; Codecà, Claudia; Rossi, Silvia; Cencioni, Maria Teresa; Bari, Monica; Fiore, Stefania; Bernardi, Giorgio; Battistini, Luca; Maccarrone, Mauro","year":2009,"journal":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 30(6), 531-4","doi":"10.1007/s10072-009-0136-5","pmid":"19768368","tags":["medical-cannabis","cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Twenty MS patients used Sativex (a THC/CBD oromucosal spray) and were assessed for changes in spasticity and endocannabinoid system markers.\n\nSativex failed to improve clinically measured spasticity. It also did not change stretch reflex excitability, a neurophysiological marker of spasticity.\n\nOn the biochemical level, Sativex did not affect the synthesis or degradation of the endocannabinoid anandamide. It also did not change the expression of CB1 or CB2 cannabinoid receptors on various types of peripheral lymphocytes.","whyItMatters":"While Sativex has been approved for MS-related pain in some countries, this study found no objective improvement in spasticity, suggesting the drug may not address all MS symptoms equally.","specificNumbers":"20 MS patients were studied. Sativex contains both THC and CBD. No significant changes were found in any measured outcome.","methodology":"This was an observational study of 20 MS patients receiving Sativex. Researchers measured clinical spasticity, stretch reflex excitability (neurophysiological), anandamide metabolism, and cannabinoid receptor expression on peripheral lymphocytes.","limitations":"Small sample of only 20 patients. The study did not include a placebo control group. Peripheral lymphocyte markers may not reflect what is happening in the central nervous system."},{"rthcId":"RTHC-00349","title":"Cannabis and anxiety: a critical review of the evidence","authors":"Crippa, Jose Alexandre S.; Zuardi, Antonio Waldo; Martin-Santos, Rocio; Bhattacharyya, Sagnik; Atakan, Zerrin; McGuire, Philip; Fusar-Poli, Paolo","year":2009,"journal":"Human Psychopharmacology: Clinical and Experimental, 24(7), 515-523","doi":null,"pmid":"19693792","tags":["anxiety","mental-health","cognition","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Acute anxiety reactions and panic attacks were commonly reported during cannabis intoxication. Across observational studies, two patterns showed up repeatedly: frequent cannabis users had higher rates of anxiety disorders, and people with anxiety disorders reported higher rates of cannabis use. The review could not show that cannabis use leads to persistent anxiety disorders. Explanations ranged from neurobiology to environment and social context, including self-medication, shared vulnerability, and confounding by stress and other substance use. The bottom line in 2009 was correlation in both directions without a clear causal pathway.","whyItMatters":"Anxiety is one of the most commonly cited reasons people discuss cannabis, and also one of the most frequently reported adverse reactions during intoxication. This review mapped what was known in 2009, separating acute panic-like reactions from questions about longer-term anxiety disorders, and highlighted how easily co-occurrence can be misread as causation.","specificNumbers":"- Databases searched: 3 (Medline, PsycLIT, EMBASE)\n- Publication year: 2009, before today’s higher-potency products and concentrates were widespread\n- Causality: 0 studies in the review established a definitive causal link to chronic anxiety disorders\n- Pattern observed: elevated anxiety rates among frequent users, and elevated cannabis use among people with anxiety disorders, reported across multiple observational samples","methodology":"A systematic search of Medline, PsycLIT, and EMBASE gathered human studies on cannabis and anxiety. Designs were mostly observational or cross-sectional, with some experimental work focused on acute effects. The review synthesized patterns qualitatively. It did not report a pooled effect size, did not specify the number of included studies, and did not establish temporal ordering between cannabis exposure and the onset of anxiety disorders.","limitations":"The review period predates widespread legal markets and high-potency concentrates. Most included studies were observational or cross-sectional, which cannot establish temporal order or causality and are vulnerable to confounding. Specific product types, THC-to-CBD ratios, dose, frequency, and timing of last use were rarely characterized. Anxiety was measured with varying tools, and acute intoxication effects were sometimes conflated with chronic disorders. Publication bias and unmeasured comorbidities, including alcohol and tobacco, were likely."},{"rthcId":"RTHC-00350","title":"Adolescent tobacco use and substance abuse treatment outcomes.","authors":"de Dios, Marcel A; Vaughan, Ellen L; Stanton, Cassandra A; Niaura, Raymond","year":2009,"journal":"Journal of substance abuse treatment, 37(1), 17-24","doi":"10.1016/j.jsat.2008.09.006","pmid":"19004603","tags":["youth","addiction","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 1,779 adolescents in substance abuse treatment, categorizing them by cigarette smoking status: persistent smokers, nonsmokers, quitters, and those who started smoking during the study period.\n\nPersistent smokers and those who started smoking had significantly greater odds of relapsing on both alcohol and marijuana compared with those who quit smoking. These two groups also had shorter periods before marijuana relapse.\n\nThe results held after controlling for intake substance use levels and demographic and treatment characteristics.","whyItMatters":"This finding suggests that tobacco cessation should be integrated into adolescent substance abuse treatment programs, as continued cigarette use appears to be associated with worse outcomes for other substances.","specificNumbers":"1,779 adolescents were followed. Four smoking status groups were compared. Persistent smokers and smoking initiators had significantly greater odds of alcohol and marijuana relapse, plus shorter time to marijuana relapse.","methodology":"Data came from the Drug Abuse Treatment Outcomes Study for Adolescents (DATOS-A). Participants were classified into four groups based on change in cigarette smoking status from intake to 12-month follow-up. Logistic regression predicted likelihood of relapse to alcohol, marijuana, and other drugs, controlling for baseline substance use and demographics.","limitations":"This is observational data, so the relationship between smoking and relapse could reflect a shared underlying vulnerability rather than a causal connection. Self-reported substance use may be unreliable in adolescents."},{"rthcId":"RTHC-00351","title":"The analgesic potential of cannabinoids.","authors":"Elikkottil, Jaseena; Gupta, Pankaj; Gupta, Kalpna","year":2009,"journal":"Journal of opioid management, 5(6), 341-57","doi":null,"pmid":"20073408","tags":["pain","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the history, pharmacology, and clinical data on cannabinoids as pain treatments.\n\nClinical and experimental studies showed that cannabis-derived compounds act as antiemetic, appetite-modulating, and analgesic agents. However, the effectiveness of individual products varied depending on the route of administration.\n\nA key finding was that cannabinoids act synergistically with opioids, functioning as \"opioid-sparing agents\" that allow patients to use lower opioid doses with fewer side effects. With opioids being the primary therapy for severe pain at the time of publication, this synergistic potential was highlighted as particularly significant.","whyItMatters":"The opioid-sparing potential of cannabinoids was an early articulation of what would become a major research theme as the opioid crisis intensified in subsequent years.","specificNumbers":"The review covered preclinical and clinical studies without specifying exact counts. Route of administration was identified as a key variable affecting analgesic efficacy.","methodology":"This was a narrative review covering the history of medical cannabis, cannabinoid signaling pathways, and preclinical and clinical data on cannabinoid analgesic effects.","limitations":"As a narrative review, no systematic quality assessment was performed. The clinical evidence at the time was limited, and many findings were preclinical. The review emphasized potential without fully addressing the variable and sometimes disappointing clinical trial results."},{"rthcId":"RTHC-00352","title":"Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa.","authors":"Feng, B-J; Khyatti, M; Ben-Ayoub, W; Dahmoul, S; Ayad, M; Maachi, F; Bedadra, W; Abdoun, M; Mesli, S; Bakkali, H; Jalbout, M; Hamdi-Cherif, M; Boualga, K; Bouaouina, N; Chouchane, L; Benider, A; Ben-Ayed, F; Goldgar, D E; Corbex, M","year":2009,"journal":"British journal of cancer, 101(7), 1207-12","doi":"10.1038/sj.bjc.6605281","pmid":"19724280","tags":["cancer","respiratory"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Researchers interviewed 636 nasopharyngeal carcinoma (NPC) patients and 615 matched controls across Algeria, Morocco, and Tunisia.\n\nCigarette smoking and snuff were associated with differentiated NPC but not with undifferentiated carcinoma (UCNT), the dominant type in these populations.\n\nMarijuana smoking significantly elevated NPC risk independently of cigarette smoking. Statistical analyses (stratified permutation test and conditional logistic regression) confirmed this was an independent effect, suggesting cannabis and tobacco may cause cancer through different mechanisms.\n\nDomestic cooking fumes from charcoal ovens during childhood also increased risk. Neither alcohol nor water pipe smoking was associated with NPC.","whyItMatters":"This was one of the first studies to identify cannabis as an independent risk factor for a specific cancer type in a large population, separate from tobacco effects.","specificNumbers":"636 NPC patients and 615 controls from Algeria, Morocco, and Tunisia. Cannabis effect was independent of cigarette smoking. Childhood cooking fume exposure (from charcoal ovens) also elevated risk.","methodology":"This case-control study enrolled 636 NPC patients and 615 controls from three North African countries (2002-2005), frequency-matched by center, age, sex, and childhood household type. Conditional logistic regression evaluated lifestyle associations with NPC risk, controlling for socioeconomic status and dietary factors.","limitations":"Case-control design relies on participants accurately recalling past cannabis use. North African cannabis use patterns (kif smoking) may differ from patterns in other regions. NPC is a relatively uncommon cancer with specific regional risk factors that may not apply broadly."},{"rthcId":"RTHC-00353","title":"Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing.","authors":"Fusar-Poli, Paolo; Crippa, José A; Bhattacharyya, Sagnik; Borgwardt, Stefan J; Allen, Paul; Martin-Santos, Rocio; Seal, Marc; Surguladze, Simon A; O'Carrol, Colin; Atakan, Zerrin; Zuardi, Antonio W; McGuire, Philip K","year":2009,"journal":"Archives of general psychiatry, 66(1), 95-105","doi":"10.1001/archgenpsychiatry.2008.519","pmid":"19124693","tags":["neuroscience","anxiety","cbd","psychosis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Fifteen healthy men received THC (10 mg), CBD (600 mg), or placebo before viewing faces expressing different levels of fear during fMRI scanning.\n\nTHC increased anxiety, intoxication, sedation, and psychotic symptoms. CBD showed a trend toward reducing anxiety.\n\nThe drugs had clearly opposite effects on physiological responses to intensely fearful faces. THC increased skin conductance fluctuations while CBD decreased them.\n\nCBD specifically attenuated activation in the amygdala (a key fear-processing region) and the anterior and posterior cingulate cortex. The suppression of amygdala and anterior cingulate responses correlated with the concurrent reduction in skin conductance.\n\nTHC mainly affected frontal and parietal brain areas rather than the limbic system.","whyItMatters":"This study provided a neural explanation for why THC can increase anxiety while CBD may reduce it. The finding that CBD calms the amygdala (the brain region most associated with fear processing) offered a biological basis for CBD anxiety research.","specificNumbers":"15 participants. THC: 10 mg oral. CBD: 600 mg oral. CBD reduced amygdala, anterior cingulate, and posterior cingulate activation. Amygdala suppression correlated with reduced skin conductance.","methodology":"Double-blind, randomized, placebo-controlled crossover study. Fifteen healthy men with minimal cannabis experience completed three fMRI sessions, receiving THC (10 mg oral), CBD (600 mg oral), or placebo. They viewed faces expressing varying levels of fear while brain activation and skin conductance were measured.","limitations":"Only 15 male participants with minimal cannabis experience. Single acute doses may not reflect chronic use effects. The emotional processing task (viewing faces) is artificial compared to real-world anxiety triggers."},{"rthcId":"RTHC-00354","title":"Naturally occurring and related synthetic cannabinoids and their potential therapeutic applications.","authors":"Galal, Ahmed M; Slade, Desmond; Gul, Waseem; El-Alfy, Abir T; Ferreira, Daneel; Elsohly, Mahmoud A","year":2009,"journal":"Recent patents on CNS drug discovery, 4(2), 112-36","doi":null,"pmid":"19519560","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered the landscape of naturally occurring cannabinoids (phytocannabinoids) and their synthetic analogs, focusing on patents filed between 2003 and 2007.\n\nThe review noted that while psychotropic effects of cannabis are mainly attributed to THC, cannabinoids also affect the cardiovascular, immune, and endocrine systems through interactions with CB1 and CB2 receptors.\n\nThe FDA had approved synthetic THC (dronabinol/Marinol) in 1985 for chemotherapy-related nausea and in 1992 as an appetite stimulant for AIDS patients. The patent literature from 2003-2007 showed expanded research interest in isolation methods, purification techniques, chemical synthesis routes, and new therapeutic applications.","whyItMatters":"This review captured the state of cannabinoid pharmaceutical development at a pivotal moment, documenting the expanding commercial and research interest in cannabis-derived medicines.","specificNumbers":"Marinol (synthetic THC) was FDA-approved in 1985 for chemotherapy nausea and in 1992 for AIDS-related appetite stimulation. Patent review covered 2003-2007.","methodology":"Patent review covering methods for cannabis compound isolation, chromatographic purification, synthesis, and therapeutic applications described in patents from 2003 to 2007.","limitations":"Patent reviews describe what companies and researchers claim, not what has been clinically validated. Many patented compounds and methods never reach clinical use."},{"rthcId":"RTHC-00355","title":"Biological effects of THC and a lipophilic cannabis extract on normal and insulin resistant 3T3-L1 adipocytes.","authors":"Gallant, M; Odei-Addo, F; Frost, C L; Levendal, R-A","year":2009,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 16(10), 942-9","doi":"10.1016/j.phymed.2009.02.013","pmid":"19345076","tags":["medical-cannabis","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested a lipophilic (fat-soluble) cannabis extract on mouse fat cells (3T3-L1 adipocytes) in several experiments.\n\nWhen applied during fat cell development, increasing THC concentrations reduced the rate of adipogenesis (fat cell formation) while simultaneously increasing insulin-stimulated glucose uptake.\n\nWhen cells were made insulin-resistant using TNF-alpha (a molecule linked to inflammation and insulin resistance), the cannabis extract restored insulin-stimulated glucose uptake in these resistant cells.\n\nGene expression analysis showed effects on glucose transporter (GLUT-4) and insulin receptor substrate (IRS-1 and IRS-2) genes.","whyItMatters":"Type 2 diabetes affects millions worldwide, and insulin resistance is a key driver. Finding that a cannabis extract could improve glucose uptake in insulin-resistant cells suggested a potential mechanism for the anecdotal reports of cannabis lowering blood glucose in diabetics.","specificNumbers":"Type 2 diabetes affects approximately 150 million people worldwide. Insulin-induced glucose uptake increased with increasing THC concentration. Adipogenesis decreased with increasing THC concentration.","methodology":"Cell culture study using mouse 3T3-L1 adipocytes. Cells were differentiated over 3 days, then exposed to a lipophilic cannabis extract with and without insulin. Insulin resistance was induced using TNF-alpha. Lipid content, glucose uptake, and gene expression (GLUT-4, IRS-1, IRS-2) were measured using RT-PCR.","limitations":"Cell culture results cannot be directly translated to living organisms. The extract contained multiple compounds beyond THC, making it impossible to attribute effects to a single compound. Mouse fat cells may respond differently than human fat cells."},{"rthcId":"RTHC-00356","title":"Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine.","authors":"Garzón, Javier; de la Torre-Madrid, Elena; Rodríguez-Muñoz, María; Vicente-Sánchez, Ana; Sánchez-Blázquez, Pilar","year":2009,"journal":"Molecular pain, 5, 11","doi":"10.1186/1744-8069-5-11","pmid":"19284549","tags":["tolerance","neuroscience","pain","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Injecting CB1 receptor agonists into the brain ventricles of mice produced dose-dependent pain relief, then a long-lasting drop in analgesic effect that persisted for more than 14 days. This desensitization happened after a single exposure. It was not explained by loss of CB1 receptors at the surface or by uncoupling from standard G proteins.\n\nThe tolerance carried over to opioids. Morphine’s supraspinal analgesia was reduced in mice previously exposed to a CB1 agonist, indicating cross-tolerance between the cannabinoid and opioid systems. By contrast, a single morphine exposure produced only a short tolerance window of about 3 days and did not alter CB1 receptor function.\n\nMechanistically, both CB1 receptors and mu opioid receptors engaged a HINT1–RGSZ signaling module that regulates pertussis toxin-insensitive Gz proteins. Mice with reduced Gz protein levels did not develop the long-lasting CB1 desensitization or morphine cross-tolerance. Enhancing Gz signaling flipped the script for opioids. A single morphine dose then produced long-lasting mu receptor tolerance beyond two weeks and also blunted cannabinoid analgesia.","whyItMatters":"Cannabinoids and opioids interact in the brain, and users often encounter tolerance and reduced benefit over time. This mouse work isolates a supraspinal mechanism in which neural Gz proteins bridge CB1 and mu opioid receptor signaling, aligning with a pattern where tolerance at one system tracks with diminished response at the other.","specificNumbers":"- Duration of cannabinoid-induced tolerance: more than 14 days in mice after a single intracerebroventricular dose\n- Duration of morphine-induced tolerance: about 3 days after a single dose, with no change to CB1 receptor function under baseline Gz conditions\n- Gz pathway manipulation: reducing Gz blocked CB1 desensitization and opioid cross-tolerance; enhancing Gz made a single morphine dose produce more than 2 weeks of mu receptor tolerance and reduced cannabinoid analgesia\n- Agonists tested: WIN55,212-2, ACEA, methanandamide","methodology":"This was an animal study in mice using intracerebroventricular administration to target supraspinal CB1 receptors while minimizing CB2 involvement in the brain. CB1 agonists included WIN55,212-2, ACEA, and methanandamide. Analgesia and tolerance were assessed after single exposures. Receptor abundance and coupling were examined to rule out receptor loss or generic G protein uncoupling. The team manipulated Gz pathway activity indirectly, studied mice with reduced Gz proteins, and evaluated interactions between CB1 and mu opioid receptors via the HINT1–RGSZ complex. The study did not report sample sizes in the abstract.","limitations":"All experiments were in mice. The exposure route was intracerebroventricular, which does not reflect inhaled, oral, or smoked cannabis. Agonists included synthetic and stabilized compounds that differ from plant THC. Sample sizes and detailed dosing parameters were not reported in the abstract. Analgesia was the main behavioral endpoint, so the breadth of functional effects is unknown. Replication status was not stated."},{"rthcId":"RTHC-00357","title":"Metabolism of 2-acylglycerol in rabbit and human platelets. Involvement of monoacylglycerol lipase and fatty acid amide hydrolase.","authors":"Gkini, Eleni; Anagnostopoulos, Dimitris; Mavri-Vavayianni, Mary; Siafaka-Kapadai, Athanasia","year":2009,"journal":"Platelets, 20(6), 376-85","doi":null,"pmid":"19811221","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers investigated how platelets (blood cells involved in clotting) break down 2-arachidonoylglycerol (2-AG), an endocannabinoid signaling molecule.\n\nThey found that both MAGL (monoacylglycerol lipase) and FAAH (fatty acid amide hydrolase) contributed to 2-AG breakdown in rabbit platelets. When FAAH was blocked with specific inhibitors, 2-OG (a related compound) hydrolysis decreased by up to 55%, confirming FAAH involvement.\n\nMAGL was characterized for the first time in platelets, showing Michaelis-Menten kinetics with specific parameters. The enzyme was present in both the cytosolic and membrane fractions of platelets.\n\nHuman platelets showed higher 2-acylglycerol hydrolysis rates and different sensitivity to inhibitors compared to rabbit platelets. Immunoblot analysis confirmed MAGL protein (approximately 33 kDa) in both species.","whyItMatters":"Understanding how endocannabinoids are broken down in blood cells is important for developing drugs that target the endocannabinoid system. Platelets are accessible blood cells that could serve as biomarkers for endocannabinoid system function.","specificNumbers":"MAGL Km = 0.11 microM, Vmax = 1.32 nmol/min per mg protein. FAAH inhibitor URB597 IC50 = 129.8 nM. AM374 IC50 = 20.9 nM. FAAH inhibition reduced 2-OG hydrolysis up to 55%. MAGL molecular mass approximately 33 kDa.","methodology":"Biochemical study using rabbit and human platelets. Radiolabeled 2-AG and 2-OG were used to measure hydrolysis rates. FAAH inhibitors (URB597 and AM374) were used to separate MAGL and FAAH contributions. Subcellular fractionation, kinetic characterization, and immunoblot analysis were performed.","limitations":"This was a purely biochemical study in isolated platelets. The physiological significance of platelet endocannabinoid metabolism in whole-blood signaling was not established. Species differences between rabbit and human platelets were noted."},{"rthcId":"RTHC-00358","title":"Impaired error awareness and anterior cingulate cortex hypoactivity in chronic cannabis users.","authors":"Hester, Robert; Nestor, Liam; Garavan, Hugh","year":2009,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 34(11), 2450-8","doi":"10.1038/npp.2009.67","pmid":"19553917","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Sixteen active chronic cannabis users and 16 controls performed a Go/No-go response inhibition task during fMRI scanning. The task measured both the ability to stop a response (inhibitory control) and awareness of errors when they occurred.\n\nCannabis users performed equally well at inhibiting responses, but they showed a significant deficit in awareness of their own commission errors.\n\nThis reduced error awareness was associated with reduced activity (hypoactivity) in the anterior cingulate cortex (ACC) and right insula, two brain regions critical for monitoring behavior and interoceptive awareness.\n\nIncreased hypoactivity in both regions significantly correlated with error awareness rates in the cannabis group but not in controls.","whyItMatters":"Error awareness is fundamental to self-monitoring and behavior change. A reduced capacity to notice mistakes could contribute to continued problematic behavior patterns, including ongoing drug use.","specificNumbers":"16 cannabis users and 16 controls. Inhibitory control was equivalent between groups. Error awareness was significantly reduced in cannabis users. ACC and right insula hypoactivity correlated with error awareness deficits in the cannabis group.","methodology":"Cross-sectional fMRI study comparing 16 active chronic cannabis users to 16 matched controls. Participants performed a Go/No-go task that separately measured inhibitory control and error awareness. Brain activation was measured with event-related fMRI.","limitations":"Small sample (16 per group). Cross-sectional design cannot determine whether reduced error awareness preceded cannabis use or resulted from it. Participants were active users, so acute intoxication effects cannot be fully separated from chronic effects."},{"rthcId":"RTHC-00359","title":"Hyperlocomotion and paw tremors are two highly quantifiable signs of SR141716-precipitated withdrawal from delta9-tetrahydrocannabinol in C57BL/6 mice.","authors":"Huang, Peng; Liu-Chen, Lee-Yuan; Unterwald, Ellen M; Cowan, Alan","year":2009,"journal":"Neuroscience letters, 465(1), 66-70","doi":"10.1016/j.neulet.2009.08.073","pmid":"19733208","tags":["withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"C57BL/6 mice received THC (25 mg/kg) or vehicle twice daily for 4.5 days. The CB1 receptor antagonist SR141716 (rimonabant) was then administered to precipitate withdrawal.\n\nTHC-treated mice showed dramatically increased locomotor activity: total activity was 4.1 times, ambulatory activity 3.3 times, and stereotypic activity 3.8 times that of vehicle-treated controls.\n\nPaw tremors were even more dramatic: THC-treated mice showed 111 paw tremors in 45 minutes versus only 1.1 in controls.\n\nInterestingly, scratching behavior showed the opposite pattern: vehicle-treated mice scratched 182 times versus only 17 times in THC-treated mice.\n\nThis was the first study to demonstrate hyperlocomotion as an explicit THC withdrawal sign in mice.","whyItMatters":"Establishing reliable, quantifiable withdrawal signs in animal models is essential for studying the mechanisms of cannabis dependence and developing potential treatments.","specificNumbers":"THC dose: 25 mg/kg twice daily for 4.5 days. Total locomotor activity: 4.1x control. Ambulatory activity: 3.3x. Stereotypic activity: 3.8x. Paw tremors: 111 vs 1.1 in 45 minutes. Scratching: 17 vs 182 (reversed direction).","methodology":"C57BL/6 mice received twice-daily subcutaneous THC (25 mg/kg) or vehicle for 4.5 days. Four hours after the last dose, SR141716 (15 mg/kg) was administered to precipitate withdrawal. Locomotor activity and specific behaviors were recorded for 2 hours.","limitations":"Animal withdrawal was precipitated by an antagonist rather than occurring naturally through abstinence. THC doses were much higher relative to body weight than typical human use. Mouse behavior may not directly model human withdrawal experiences."},{"rthcId":"RTHC-00360","title":"Cognitive and psychomotor effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg delta-9-tetrahydrocannabinol (THC).","authors":"Hunault, Claudine C; Mensinga, Tjeert T; Böcker, Koen B E; Schipper, C Maarten A; Kruidenier, Maaike; Leenders, Marianne E C; de Vries, Irma; Meulenbelt, Jan","year":2009,"journal":"Psychopharmacology, 204(1), 85-94","doi":"10.1007/s00213-008-1440-0","pmid":"19099294","tags":["cognition","driving","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-four non-daily male cannabis users smoked cannabis cigarettes containing 0, 29.3, 49.1, or 69.4 mg THC in a four-way crossover design.\n\nResponse time slowed linearly across all cognitive tasks (simple reaction time, visual-spatial attention, sustained attention, divided attention, and short-term memory) as THC dose increased. Motor control also worsened linearly with dose.\n\nErrors increased significantly with higher doses in short-term memory and sustained attention tasks specifically.\n\nHowever, some participants showed no motor impairment even at THC blood concentrations above 40 ng/mL, suggesting substantial individual variability in susceptibility to THC-induced impairment.","whyItMatters":"With cannabis potency increasing, this study directly tested how high-THC products affect cognitive and motor function. The linear dose-response relationship and individual variability have implications for traffic safety and impairment testing.","specificNumbers":"24 participants, 2-9 joints per month. THC doses: 0, 29.3, 49.1, and 69.4 mg (up to 23% THC). Response time and motor impairment increased linearly with dose. Some participants showed no motor impairment even above 40 ng/mL blood THC.","methodology":"Double-blind, placebo-controlled, randomized, four-way crossover study. 24 non-daily male cannabis users (2-9 joints/month) smoked cannabis cigarettes at four THC doses (0, 29.3, 49.1, 69.4 mg) on separate occasions. Cognitive tasks and motor control were assessed.","limitations":"Only 24 non-daily male users were studied. Experienced daily users might show different dose-response patterns due to tolerance. The controlled smoking protocol may not reflect real-world consumption. Individual variability was noted but not fully characterized."},{"rthcId":"RTHC-00361","title":"Cannabidiol-induced lymphopenia does not involve NKT and NK cells.","authors":"Ignatowska-Jankowska, B; Jankowski, M; Glac, W; Swiergel, A H","year":2009,"journal":"Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 60 Suppl 3, 99-103","doi":null,"pmid":"19996489","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Male rats received daily CBD injections (2.5 or 5 mg/kg) for 14 days.\n\nAt the higher dose (5 mg/kg), CBD caused a significant decrease in total white blood cells and in the numbers of T cells, B cells, T helper cells, and T cytotoxic cells.\n\nHowever, this immunosuppressive effect did not affect NK or NKT cells, which are responsible for nonspecific antiviral and antitumor immune responses.\n\nAt the lower dose (2.5 mg/kg), CBD actually increased NKT cell numbers and the percentage of NK cells.\n\nThe results suggest CBD may suppress adaptive (specific) immunity while sparing or enhancing innate (nonspecific) antiviral and antitumor defenses.","whyItMatters":"Understanding how CBD affects different branches of the immune system is important for evaluating its potential in autoimmune conditions (where suppressing specific immunity could help) and in cancer (where preserving NK cell function is desirable).","specificNumbers":"Doses: 2.5 and 5 mg/kg daily for 14 days. At 5 mg/kg: significant decrease in total leukocytes, T cells, B cells, T helper, and T cytotoxic cells. NK and NKT cells were spared. At 2.5 mg/kg: NKT cells increased.","methodology":"Fourteen-day repeated-dose animal study. Male Wistar rats received daily intraperitoneal CBD injections at 2.5 or 5 mg/kg or vehicle. Blood was collected one hour after the last injection. Three-color immunofluorescent staining was used to identify T, B, NK, NKT, T helper, and T cytotoxic lymphocyte subsets.","limitations":"Rat immune systems differ from human immune systems. CBD was administered by injection, not orally. The doses and duration may not correspond to typical human CBD use. Blood sampling at a single time point may not capture the full immune response dynamics."},{"rthcId":"RTHC-00362","title":"Reduced memory and attention performance in a population-based sample of young adults with a moderate lifetime use of cannabis, ecstasy and alcohol.","authors":"Indlekofer, F; Piechatzek, M; Daamen, M; Glasmacher, C; Lieb, R; Pfister, H; Tucha, O; Lange, K W; Wittchen, H U; Schütz, C G","year":2009,"journal":"Journal of psychopharmacology (Oxford, England), 23(5), 495-509","doi":"10.1177/0269881108091076","pmid":"18635709","tags":["cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers tested 284 young adults (ages 22-34) drawn from a large epidemiological study, avoiding the recruitment biases common in drug research.\n\nEcstasy and cannabis use were both significantly related to poorer episodic memory function in a dose-related manner, meaning more use was associated with more impairment.\n\nAttentional measures showed small but significant effects. Error rates increased in alertness, selective attention, and vigilance tasks, suggesting a tendency toward attention lapses rather than overall slowing. Reaction times were not significantly affected.\n\nImportantly, participants had only moderate lifetime drug experience, and effects were still detectable, though small in size.","whyItMatters":"Most studies of cannabis and cognition recruit participants through advertisements, which can introduce bias. By using a population-based sample, this study provided a more representative estimate of cognitive effects associated with moderate drug use.","specificNumbers":"284 participants aged 22-34. Effects were dose-related and statistically significant for episodic memory. Attentional decrements were small in effect size. Reaction times were not significantly different.","methodology":"Cross-sectional study with 284 participants (ages 22-34) sampled from a large epidemiological study. This population-based sampling avoided the advertisement-based recruitment that introduces bias in most drug cognition research. Participants completed neuropsychological tests of verbal learning, memory, and attentional functions. Linear regression examined relationships between lifetime drug use and cognitive performance.","limitations":"Cross-sectional design cannot determine whether cognitive differences preceded or resulted from drug use. Cannabis and ecstasy use often co-occur, making it difficult to isolate effects of each substance. Effect sizes were small and may not be clinically meaningful."},{"rthcId":"RTHC-00363","title":"Cannabidiol: a promising drug for neurodegenerative disorders?","authors":"Iuvone, Teresa; Esposito, Giuseppe; De Filippis, Daniele; Scuderi, Caterina; Steardo, Luca","year":2009,"journal":"CNS neuroscience & therapeutics, 15(1), 65-75","doi":"10.1111/j.1755-5949.2008.00065.x","pmid":"19228180","tags":["cbd","neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the evidence for CBD as a treatment for neurodegenerative diseases, which involve progressive neuron loss and are among the leading causes of death in industrialized countries.\n\nInflammation was identified as a common factor across diverse neurodegenerative conditions, contributing to the progressive nature of neurodegeneration.\n\nPreclinical evidence showed CBD has both neuroprotective and anti-inflammatory properties. Unlike THC, CBD does not produce psychotropic effects, making it more practical for therapeutic development.\n\nThe review argued that combined neuroprotective and anti-inflammatory strategies are needed because isolated treatments targeting only one pathway have limited effectiveness. CBD was highlighted as potentially offering both in a single compound.","whyItMatters":"Neurodegenerative diseases have few effective treatments. A compound that offers both neuroprotection and anti-inflammatory effects without psychotropic side effects could address an enormous unmet medical need.","specificNumbers":"Neurodegenerative diseases were described as among the main causes of death in industrialized countries. The review covered preclinical data without specifying exact numbers of studies reviewed.","methodology":"Narrative review examining preclinical research on CBD neuroprotective and anti-inflammatory mechanisms relevant to neurodegenerative diseases.","limitations":"The evidence was primarily preclinical. Many compounds show promise in cell culture and animal models but fail in human trials. The review did not systematically assess study quality or provide a quantitative synthesis."},{"rthcId":"RTHC-00364","title":"Cannabis abuse and addiction: a contemporary literature review.","authors":"Iyalomhe, G B S","year":2009,"journal":"Nigerian journal of medicine : journal of the National Association of Resident Doctors of Nigeria, 18(2), 128-33","doi":null,"pmid":"19630315","tags":["addiction","dopamine","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized recent developments in understanding cannabis abuse and addiction, with particular focus on neurobiological mechanisms.\n\nRecent advances identified dopamine and serotonin (5-HT) as key neuronal substrates responsible for the rewarding effects of cannabis and the addictive process. Prolonged cannabis exposure was found to produce long-lasting effects in both cognitive and drug-rewarding brain circuits.\n\nThe review characterized chronic cannabis effects as including impaired cognitive functions, perception, reaction time, learning, memory, concentration, social skills, and emotional control. Severe effects could include panic reactions, hallucinations, paranoid states, and acute psychosis.\n\nBased on this evidence, the review endorsed the view of addiction as a chronic brain disease rather than simply a behavioral choice.","whyItMatters":"Framing cannabis addiction as a brain disease rather than a moral failing has implications for treatment approaches and public health policy, emphasizing the need for medical rather than purely behavioral interventions.","specificNumbers":"The review cited effects on cognitive functions, perception, reaction time, learning, memory, concentration, social skills, and emotional control. Complications could include psychosis, panic reactions, hallucinations, and paranoia.","methodology":"Literature review using manual search and electronic databases (Medline and HINARI) covering recent neurobiology of cannabis abuse and addiction.","limitations":"The review presented a somewhat one-sided view emphasizing negative effects. The Nigerian context may have influenced the framing, as cannabis policy and attitudes vary greatly by region. The literature search methodology was not systematic."},{"rthcId":"RTHC-00365","title":"Functional consequences of marijuana use in adolescents","authors":"Jacobus, Joanna; Bava, Sunita; Cohen-Zion, Mairav; Mahmood, Omar; Tapert, Susan F.","year":2009,"journal":"Pharmacology, Biochemistry and Behavior, 92(4), 559-565","doi":null,"pmid":"19348837","tags":["youth","cognition","neuroscience","sleep"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Across the studies reviewed, adolescents who used marijuana heavily tended to score lower on attention, learning, and processing speed. The gaps were detectable but generally modest.\n\nBrain imaging work pointed to subtle structural differences and a functional pattern where teens who used heavily showed greater activation during cognitive tasks while keeping performance on par with non-users. That is consistent with a compensatory response, where the brain recruits more resources to achieve the same result.\n\nSleep was another signal. Objective measures indicated poorer sleep quality among users. Timing mattered too. Some abnormalities appeared to persist beyond one month of abstinence, while several reports suggested they could resolve within about three months if abstinence continued.","whyItMatters":"Adolescence is a period of rapid brain development, and marijuana exposure is common in high school. This review pulled together cognitive, neural, and sleep data in one place, creating an early foundation for how researchers think about heavy adolescent use and day-to-day functioning.","specificNumbers":"- 12th graders who had tried marijuana: nearly half (about 1 in 2 seniors)\n- 12th graders using daily: 6% (roughly 1 in 17)\n- Persistence window: some differences reported beyond 1 month of abstinence\n- Potential recovery: several studies suggested normalization by ~3 months of continued abstinence","methodology":"This was a narrative review of human studies on adolescent marijuana use. It summarized findings from neuropsychological testing, structural and functional brain imaging, and both subjective and objective sleep assessments. Most included studies were observational, often cross-sectional, with varied definitions of heavy use and heterogeneous abstinence windows. Co-use of alcohol, nicotine, and other drugs was common and not always fully controlled. No meta-analytic effect sizes were reported in the abstract.","limitations":"Evidence was dominated by small, cross-sectional samples that cannot establish temporal order. Abstinence periods varied widely, making persistence and recovery timelines uncertain. Co-use of alcohol, nicotine, and other substances was common and not consistently accounted for. Product potency and cannabinoid profiles were rarely characterized, and sleep outcomes were not uniform across studies."},{"rthcId":"RTHC-00366","title":"Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain.","authors":"Kinsey, S G; Long, J Z; O'Neal, S T; Abdullah, R A; Poklis, J L; Boger, D L; Cravatt, B F; Lichtman, A H","year":2009,"journal":"The Journal of pharmacology and experimental therapeutics, 330(3), 902-10","doi":"10.1124/jpet.109.155465","pmid":"19502530","tags":["pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers tested whether blocking the enzymes that degrade endocannabinoids could reduce neuropathic pain in mice with sciatic nerve injury.\n\nFAAH inhibitors (URB597 and OL-135), which increase anandamide levels, reduced both mechanical and cold allodynia. This effect required both CB1 and CB2 receptors but not TRPV1 or opioid receptors.\n\nThe MAGL inhibitor JZL184, which increases 2-AG levels, also reduced allodynia but only through CB1 receptors, not CB2.\n\nCritically, neither FAAH nor MAGL inhibition produced the behavioral side effects typically associated with direct cannabinoid receptor agonists (like THC).\n\nBrain and spinal cord measurements confirmed that URB597 increased anandamide while JZL184 increased 2-AG in these tissues, but endocannabinoid levels did not differ between nerve-injured and control mice.","whyItMatters":"This study demonstrated that boosting the body's own cannabinoids through enzyme inhibition could reduce neuropathic pain without the psychoactive and behavioral side effects of THC, providing a promising therapeutic strategy.","specificNumbers":"FAAH inhibition increased brain and spinal cord anandamide. MAGL inhibition increased 2-AG. FAAH anti-allodynic effects required both CB1 and CB2. MAGL effects required CB1 only. Neither opioid nor TRPV1 receptors were involved.","methodology":"Mice underwent chronic constriction injury of the sciatic nerve to model neuropathic pain. FAAH inhibitors (URB597, OL-135) and the MAGL inhibitor (JZL184) were administered acutely. Mechanical and cold allodynia were measured. Receptor involvement was tested using selective antagonists. FAAH knockout mice and endocannabinoid tissue levels were used to confirm specificity.","limitations":"Animal model of neuropathic pain may not fully represent human conditions. Acute dosing was tested; chronic treatment effects and potential tolerance were not examined. The precipitating nerve injury model is only one type of neuropathic pain."},{"rthcId":"RTHC-00367","title":"Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review.","authors":"Lakhan, Shaheen E; Rowland, Marie","year":2009,"journal":"BMC neurology, 9, 59","doi":"10.1186/1471-2377-9-59","pmid":"19961570","tags":["medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Six randomized controlled trials of combined THC and CBD extracts for MS-related spasticity were systematically reviewed.\n\nA consistent trend of reduced spasticity in treated patients was observed across studies. However, the pattern of results differed between measurement types.\n\nObjective measures of spasticity (clinical scales, physiological tests) showed improvement trends but no statistically significant changes.\n\nSubjective assessments of symptom relief often showed statistically significant improvement.\n\nAdverse events were reported in every study, but combined THC/CBD extracts were generally considered well-tolerated.","whyItMatters":"The disconnect between subjective and objective spasticity measures raises important questions about what outcomes matter most. Patients may experience meaningful relief even when clinical scales do not detect significant changes.","specificNumbers":"Six RCTs were included. All six reported adverse events. Subjective measures often showed significant improvement. Objective measures showed trends but no significant changes.","methodology":"Systematic review of MEDLINE/PubMed, Ovid, and CENTRAL databases for randomized controlled trials using combined THC and CBD extracts with pre- and post-treatment spasticity assessments. Six studies met inclusion criteria.","limitations":"Only six studies met inclusion criteria. Variation in outcome measures across studies made direct comparison difficult. The review was limited to combined THC/CBD extracts, excluding other cannabinoid preparations."},{"rthcId":"RTHC-00368","title":"The future of endocannabinoid-oriented clinical research after CB1 antagonists.","authors":"Le Foll, Bernard; Gorelick, David A; Goldberg, Steven R","year":2009,"journal":"Psychopharmacology, 205(1), 171-4","doi":"10.1007/s00213-009-1506-7","pmid":"19300982","tags":["appetite","medical-cannabis","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Rimonabant, the first clinically available CB1 receptor antagonist, showed promise for treating obesity, metabolic syndrome, and potentially drug addiction. However, it was linked to increased risk of anxiety, depression, and suicidality.\n\nThe European Medicines Agency called for its withdrawal in October 2008. Shortly after, several major pharmaceutical companies (Sanofi-Aventis, Merck, Pfizer, Solvay) announced they would stop clinical research on this drug class entirely.\n\nThe authors argued against abandoning the field, suggesting that the endocannabinoid system has therapeutic potential for many conditions beyond obesity. They made recommendations for continuing research with improved safety measures to protect patients and clinical trial subjects.","whyItMatters":"The rimonabant story illustrates the risks and complexities of targeting the endocannabinoid system. The psychiatric side effects highlighted that blocking cannabinoid receptors can have serious mental health consequences, influencing how the field approached subsequent drug development.","specificNumbers":"Rimonabant was withdrawn in October 2008. At least four major pharmaceutical companies stopped CB1 antagonist research: Sanofi-Aventis, Merck, Pfizer, and Solvay.","methodology":"Commentary/review discussing the rimonabant withdrawal and providing recommendations for the future of endocannabinoid-targeted clinical research.","limitations":"This was a commentary piece rather than original research. The recommendations were opinion-based, though informed by the clinical evidence that led to rimonabant withdrawal."},{"rthcId":"RTHC-00369","title":"Substitution profile of Delta9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Delta9-tetrahydrocannabinol.","authors":"Lile, Joshua A; Kelly, Thomas H; Pinsky, David J; Hays, Lon R","year":2009,"journal":"Psychopharmacology, 203(2), 241-50","doi":"10.1007/s00213-008-1393-3","pmid":"19018520","tags":["neuroscience","dopamine"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Eight healthy moderate cannabis users learned to distinguish 25 mg oral THC from placebo under double-blind conditions, achieving at least 80% accuracy over four consecutive sessions.\n\nOnce trained, they were tested with multiple doses of THC, the sedative triazolam (a benzodiazepine), the opioid hydromorphone, and the stimulant methylphenidate (Ritalin).\n\nAll tested drugs produced measurable subjective effects on self-report questionnaires. However, only THC itself substituted for the training dose. Neither the opioid, nor the sedative, nor the stimulant was mistaken for THC.\n\nThis suggests the subjective experience of THC is distinct from the effects produced through opioid, GABA, and dopamine systems.","whyItMatters":"Understanding whether THC shares subjective properties with other drug classes helps clarify its unique pharmacology and abuse potential. The finding that no tested drug mimicked THC suggests cannabinoid effects are pharmacologically distinct.","specificNumbers":"8 subjects completed the study. Training dose: 25 mg oral THC. Discrimination criterion: 80%+ accuracy for 4 consecutive sessions. Only THC substituted for itself; triazolam, hydromorphone, and methylphenidate did not.","methodology":"Double-blind, placebo-controlled drug discrimination study. Eight moderate cannabis users were trained to identify 25 mg oral THC. Once discrimination was acquired (80%+ accuracy for four sessions), multiple doses of THC, triazolam, hydromorphone, and methylphenidate were tested for substitution.","limitations":"Very small sample (8 participants). Only oral THC was tested, which has a different pharmacokinetic profile than smoked cannabis. The drugs tested represent only a few neurotransmitter systems; other mechanisms were not examined."},{"rthcId":"RTHC-00370","title":"Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo.","authors":"Long, Jonathan Z; Nomura, Daniel K; Vann, Robert E; Walentiny, D Matthew; Booker, Lamont; Jin, Xin; Burston, James J; Sim-Selley, Laura J; Lichtman, Aron H; Wiley, Jenny L; Cravatt, Benjamin F","year":2009,"journal":"Proceedings of the National Academy of Sciences of the United States of America, 106(48), 20270-5","doi":"10.1073/pnas.0909411106","pmid":"19918051","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers developed JZL195, a drug that simultaneously blocks both FAAH and MAGL, the enzymes that break down the endocannabinoids anandamide and 2-AG.\n\nJZL195 produced analgesia, reduced movement, and catalepsy, covering a broader range of cannabinoid-like effects than blocking either enzyme alone.\n\nCritically, in drug discrimination tests (where animals indicate whether a drug feels like THC), dual FAAH/MAGL blockade produced THC-like responses, but inhibiting either enzyme alone did not.\n\nThis revealed that anandamide and 2-AG pathways have both unique and overlapping functions. Some behaviors (like reduced movement) are regulated mainly by the 2-AG/MAGL pathway, while others (like drug-related responses) require both pathways working together.","whyItMatters":"This study explained why individual FAAH or MAGL inhibitors produce only a subset of THC-like effects. The finding that both pathways must be disrupted to fully mimic THC has important implications for understanding cannabis pharmacology and developing endocannabinoid-based therapies.","specificNumbers":"JZL195 produced analgesia, hypomotility, and catalepsy. Only dual blockade (not FAAH or MAGL inhibition alone) substituted for THC in drug discrimination. All effects were reversed by a CB1 antagonist.","methodology":"Preclinical study using the novel dual FAAH/MAGL inhibitor JZL195 in mice. Behavioral effects were measured using the tetrad test (analgesia, hypothermia, catalepsy, hypomotility) and drug discrimination. Results were compared to selective FAAH and MAGL inhibitors. CB1 antagonist reversal confirmed cannabinoid receptor involvement.","limitations":"Animal study results may not directly translate to humans. The dual inhibitor was novel and its specificity and safety profile were not fully characterized. Long-term effects were not examined."},{"rthcId":"RTHC-00371","title":"Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.","authors":"Long, Jonathan Z; Li, Weiwei; Booker, Lamont; Burston, James J; Kinsey, Steven G; Schlosburg, Joel E; Pavón, Franciso J; Serrano, Antonia M; Selley, Dana E; Parsons, Loren H; Lichtman, Aron H; Cravatt, Benjamin F","year":2009,"journal":"Nature chemical biology, 5(1), 37-44","doi":"10.1038/nchembio.129","pmid":"19029917","tags":["neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers developed JZL184, the first potent and selective inhibitor of MAGL, the enzyme that breaks down the endocannabinoid 2-AG.\n\nWhen administered to mice, JZL184 raised brain 2-AG levels eightfold without altering anandamide levels, confirming that MAGL is the primary enzyme responsible for 2-AG degradation in the brain.\n\nMice treated with JZL184 exhibited analgesia, hypothermia, and reduced movement, all classic cannabinoid effects that were blocked by a CB1 receptor antagonist, confirming they were mediated through the cannabinoid system.\n\nThese findings established that 2-AG endogenously modulates several behavioral processes traditionally associated with cannabis pharmacology.","whyItMatters":"This was the first demonstration that selectively raising 2-AG levels produces a broad array of cannabinoid-like effects, establishing 2-AG as a major player in endocannabinoid signaling and opening new therapeutic possibilities.","specificNumbers":"Brain 2-AG increased 8-fold. Anandamide levels were not altered. JZL184 produced analgesia, hypothermia, and hypomotility. All behavioral effects were CB1-dependent.","methodology":"Preclinical pharmacological study. JZL184 was characterized biochemically for selectivity and potency against MAGL. Brain endocannabinoid levels were measured after administration. Behavioral effects (analgesia, hypothermia, hypomotility) were assessed and confirmed as CB1-dependent using a selective antagonist.","limitations":"Animal study using acute dosing only. Long-term effects and potential tolerance development were not examined. The relationship between mouse behavioral effects and human therapeutic outcomes is uncertain."},{"rthcId":"RTHC-00372","title":"Cannabidiol reverses the reduction in social interaction produced by low dose Delta(9)-tetrahydrocannabinol in rats.","authors":"Malone, Daniel Thomas; Jongejan, Dennis; Taylor, David Alan","year":2009,"journal":"Pharmacology, biochemistry, and behavior, 93(2), 91-6","doi":"10.1016/j.pbb.2009.04.010","pmid":"19393686","tags":["cbd","psychosis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Pairs of rats were tested in an open field after receiving CBD or vehicle followed by THC or vehicle.\n\nLow-dose THC (1 mg/kg) significantly reduced social interaction between rat pairs. CBD alone had no effect on social behavior.\n\nHowever, pretreatment with CBD (20 mg/kg) reversed the THC-induced decrease in social interaction, restoring normal social behavior.\n\nAt higher doses, the pattern was different. High-dose THC (10 mg/kg) alone did not significantly reduce social interaction. But combining high-dose CBD with high-dose THC significantly reduced both social interaction and locomotor activity, suggesting the impairment at high combined doses may have been partly due to sedation.","whyItMatters":"This preclinical evidence supports the idea that CBD can counteract some negative effects of THC, relevant to understanding why different cannabis strains (with varying THC:CBD ratios) may produce different social and psychological effects.","specificNumbers":"Low-dose THC (1 mg/kg) reduced social interaction. CBD (20 mg/kg) reversed this reduction. High-dose THC (10 mg/kg) alone had no significant effect on social interaction. High CBD + high THC reduced both social interaction and locomotion.","methodology":"Pairs of male rats received CBD or vehicle followed by THC or vehicle and were observed in an open field for 10 minutes. Social interaction time and locomotor activity were measured across multiple dose combinations.","limitations":"Animal behavior models of social withdrawal are limited analogies for human social functioning. The inverted-U dose response of THC (low dose reduced social interaction but high dose did not) complicates interpretation. Rat social behavior may not predict human experiences."},{"rthcId":"RTHC-00373","title":"An endocannabinoid signal associated with desire for alcohol is suppressed in recently abstinent alcoholics.","authors":"Mangieri, Regina A; Hong, Kwang-Ik A; Piomelli, Daniele; Sinha, Rajita","year":2009,"journal":"Psychopharmacology, 205(1), 63-72","doi":"10.1007/s00213-009-1518-3","pmid":"19343330","tags":["addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared endocannabinoid responses in 11 healthy social drinkers and 12 recently abstinent alcoholics during guided imagery of alcohol cues, stress, and neutral relaxation.\n\nIn social drinkers, alcohol cue imagery specifically increased circulating anandamide levels (neutral and stress imagery did not). Baseline anandamide was negatively correlated with craving, while cue-triggered anandamide increases were positively correlated with craving and heart rate changes.\n\nIn abstinent alcoholics, no imagery condition triggered anandamide mobilization. Their baseline anandamide levels were markedly reduced compared to healthy drinkers and showed no correlation with craving or heart rate.\n\nThis suggests the endocannabinoid system participates in normal alcohol desire but becomes dysregulated in alcoholism.","whyItMatters":"This was one of the first studies to directly link endocannabinoid levels to alcohol craving in humans, suggesting the endocannabinoid system may be a target for treating alcohol use disorders.","specificNumbers":"11 social drinkers and 12 abstinent alcoholics. Alcohol cue imagery increased anandamide in social drinkers but not alcoholics. Baseline anandamide was markedly reduced in alcoholics.","methodology":"Laboratory study using guided imagery procedures (stress, alcohol cue, neutral) in 11 healthy social drinkers and 12 treatment-engaged abstinent alcoholics. Blood anandamide levels, alcohol craving, heart rate, and anxiety were measured.","limitations":"Very small sample sizes (11 and 12). Cross-sectional design cannot determine whether low anandamide preceded alcoholism or resulted from it. Plasma anandamide may not reflect brain endocannabinoid levels. Recently abstinent alcoholics may differ from active drinkers."},{"rthcId":"RTHC-00374","title":"A placebo-controlled trial of buspirone for the treatment of marijuana dependence.","authors":"McRae-Clark, Aimee L; Carter, Rickey E; Killeen, Therese K; Carpenter, Matthew J; Wahlquist, Amy E; Simpson, Stacey A; Brady, Kathleen T","year":2009,"journal":"Drug and alcohol dependence, 105(1-2), 132-8","doi":"10.1016/j.drugalcdep.2009.06.022","pmid":"19699593","tags":["addiction","quitting","anxiety"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Fifty participants with marijuana dependence received either buspirone (up to 60 mg/day) or placebo for 12 weeks alongside motivational interviewing.\n\nIn the full intent-to-treat analysis, the buspirone group had 18 percentage points more negative urine drug screens than placebo, though this did not reach statistical significance (p=0.071).\n\nSelf-reported marijuana-free days did not differ between groups (45.2% vs 51.4%).\n\nHowever, among participants who completed all 12 weeks, buspirone produced a significantly higher percentage of negative drug tests (p=0.014) and a trend toward reaching the first negative test sooner (p=0.054).\n\nRetention in the study was a major challenge, limiting statistical power.","whyItMatters":"No FDA-approved medication exists for cannabis use disorder. This was an early exploration of whether an anti-anxiety medication could help, based on the idea that anxiety contributes to continued cannabis use.","specificNumbers":"23 buspirone, 27 placebo. 12-week trial. 18 percentage point difference in negative drug tests (not significant, p=0.071). Among completers: significant difference (p=0.014). Self-report showed no difference.","methodology":"Randomized, double-blind, placebo-controlled trial. 23 participants received buspirone (maximum 60 mg/day) and 27 received placebo for 12 weeks. Both groups received motivational interviewing. Outcomes included urine drug screens and self-reported use.","limitations":"Small sample with high dropout rates. The completer analysis showing significance is subject to selection bias. Self-report and urine test results conflicted. Buspirone dose was variable up to 60 mg/day."},{"rthcId":"RTHC-00375","title":"Protracted cannabinoid administration elicits antidepressant behavioral responses in rats: role of gender and noradrenergic transmission.","authors":"Morrish, Anna C; Hill, Matthew N; Riebe, Caitlin J N; Gorzalka, Boris B","year":2009,"journal":"Physiology & behavior, 98(1-2), 118-24","doi":"10.1016/j.physbeh.2009.04.023","pmid":"19414024","tags":["depression","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Male rats received the CB1 receptor agonist HU-210 for 10 days and then underwent the forced swim test, a standard measure of depressive-like behavior.\n\nHU-210 reduced immobility and increased struggling, matching the effects of the antidepressant desipramine. This effect was blocked by both alpha- and beta-adrenergic receptor antagonists, indicating the antidepressant response involves the noradrenergic (norepinephrine) system.\n\nThe same effect occurred in both male and female rats, demonstrating it is not sex-specific.\n\nWhen the CB1 antagonist AM251 was given before the test (precipitating withdrawal), the antidepressant effect was eliminated, confirming it depends on ongoing cannabinoid receptor activation rather than being a lasting neuroadaptation.","whyItMatters":"This study identified a specific mechanism (noradrenergic involvement) through which cannabinoid receptor activation produces antidepressant effects, and showed the effect is present in both sexes but dependent on continued receptor activation.","specificNumbers":"HU-210 dose: 0.1 mg/kg for 10 days. Desipramine: 10 mg/kg. Prazosin (alpha1 blocker) at 1 mg/kg and propranolol (beta blocker) at 2.5 mg/kg both attenuated the antidepressant effect. Effect present in both sexes.","methodology":"Three experiments using the forced swim test in rats. Experiment 1: 10-day HU-210 vs desipramine vs vehicle. Experiment 2: Same protocol with noradrenergic antagonists to test mechanism. Experiment 3: Males and females, with CB1 antagonist AM251 to test withdrawal effects.","limitations":"The forced swim test is a limited model of human depression. HU-210 is a synthetic cannabinoid much more potent than THC. The finding that withdrawal reversed the effect raises questions about therapeutic utility. Animal depression models have significant limitations."},{"rthcId":"RTHC-00376","title":"Endocannabinoid system: An overview of its potential in current medical practice.","authors":"Mouslech, Zadalla; Valla, Vasiliki","year":2009,"journal":"Neuro endocrinology letters, 30(2), 153-79","doi":null,"pmid":"19675519","tags":["neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This extensive review covered the endocannabinoid system (ECS) across multiple body systems.\n\nIn the brain, CB1 receptors are concentrated in areas controlling motor function, emotional responses, motivated behavior, and energy balance. Endocannabinoids act as retrograde messengers at synapses, modulating both inhibitory (GABA) and excitatory (glutamate) neurotransmission.\n\nIn the periphery, CB1 receptors are expressed in adipose tissue, pancreas, liver, GI tract, skeletal muscle, heart, and reproductive organs. CB2 receptors are mainly found on immune cells.\n\nThe review covered the ECS role in food intake regulation, cardiovascular function, gastrointestinal motility, immune regulation, behavioral responses, cell proliferation, and reproduction. It also discussed the rimonabant story and emerging evidence linking the ECS to fertility and spermatogenesis.","whyItMatters":"This review provided a snapshot of how broadly the endocannabinoid system was understood to function across the body by 2009, highlighting its involvement in nearly every major physiological system.","specificNumbers":"The two main endocannabinoids are anandamide (AEA) and 2-AG. Two primary receptors: CB1 (brain, peripheral organs) and CB2 (mainly immune system). Two main degradation enzymes: FAAH and MAGL.","methodology":"Comprehensive narrative review covering endocannabinoid system anatomy, physiology, and pathophysiology across central and peripheral tissues.","limitations":"As a comprehensive overview, the review covered many topics at a surface level rather than providing deep analysis of any single area. Some claims about therapeutic potential were speculative at the time."},{"rthcId":"RTHC-00377","title":"Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats.","authors":"Napimoga, Marcelo H; Benatti, Bruno B; Lima, Flavia O; Alves, Polyanna M; Campos, Alline C; Pena-Dos-Santos, Diego R; Severino, Fernando P; Cunha, Fernando Q; Guimarães, Francisco S","year":2009,"journal":"International immunopharmacology, 9(2), 216-22","doi":"10.1016/j.intimp.2008.11.010","pmid":"19070683","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers induced periodontal disease in rats using ligatures around the lower first molars and treated them with CBD (5 mg/kg daily) or vehicle for 30 days.\n\nCBD-treated animals showed significantly less alveolar bone loss compared to untreated animals with periodontal disease.\n\nThe protective effect was associated with lower expression of RANKL/RANK, molecules that drive bone resorption. CBD-treated gingival tissue also showed decreased neutrophil migration and reduced levels of the pro-inflammatory cytokines IL-1beta and TNF-alpha.","whyItMatters":"Periodontal disease affects a large proportion of the global population and leads to tooth loss through inflammatory bone destruction. An anti-inflammatory compound that also reduces bone resorption could address both aspects of the disease process.","specificNumbers":"CBD dose: 5 mg/kg daily for 30 days. CBD reduced alveolar bone loss, RANKL/RANK expression, neutrophil migration (MPO), IL-1beta, and TNF-alpha in gingival tissues.","methodology":"Rat periodontal disease model using ligature placement around mandibular first molars. Three groups: healthy control, ligature + vehicle, ligature + CBD (5 mg/kg daily). After 30 days, bone loss was measured morphometrically, RANKL/RANK expression was assessed, and neutrophil migration (MPO) and cytokine levels (IL-1beta, TNF-alpha) were measured in gingival tissue.","limitations":"Animal model of periodontal disease using ligatures is an artificial induction method. CBD was administered systemically rather than locally to the gums. Rat periodontal anatomy and healing differ from humans."},{"rthcId":"RTHC-00378","title":"Deficient mental own-body imagery in a neurological patient with out-of-body experiences due to cannabis use.","authors":"Overney, Leila S; Arzy, Shahar; Blanke, Olaf","year":2009,"journal":"Cortex; a journal devoted to the study of the nervous system and behavior, 45(2), 228-35","doi":"10.1016/j.cortex.2008.02.005","pmid":"18632094","tags":["medical-cannabis","neuroscience"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A multiple sclerosis patient with tetraplegia (paralysis of all four limbs) and severe sensory loss developed repeated out-of-body experiences (OBEs) after starting cannabis treatment for spasticity with painful cramps.\n\nThe OBEs occurred daily and were consistently triggered by cannabis use. Researchers tested the patient on a body imagery task before and after cannabis consumption.\n\nBefore cannabis, the patient showed an unusual pattern: he was less accurate for back-facing body stimuli compared to front-facing, the opposite of what healthy people show. The researchers attributed this to his frequent OBEs, which typically involve viewing one's body from behind and above.\n\nAfter cannabis consumption, performance on back-facing stimuli (matching the OBE perspective) specifically improved while front-facing performance remained unchanged.\n\nThe researchers proposed that cannabis interfered with own-body imagery, but only in the context of existing brain damage.","whyItMatters":"This case report connected cannabis use with altered body representation in a neurologically vulnerable patient, suggesting that cannabis can interact with pre-existing brain damage to produce unusual perceptual phenomena.","specificNumbers":"One patient with MS and tetraplegia. OBEs occurred daily. Performance on back-facing body stimuli improved after cannabis. Six control subjects showed the typical pattern (better for back-facing than front-facing).","methodology":"Single case study of a tetraplegic MS patient. Mental body imagery was assessed using a validated own-body transformation task with front- and back-facing schematic figures, administered before and after cannabis consumption. Six healthy control subjects served as comparison.","limitations":"Single case report with no ability to generalize. The patient had multiple factors (MS, tetraplegia, severe sensory loss, spinal cord involvement) that could contribute to OBEs. Cause-and-effect between cannabis and OBEs cannot be established definitively."},{"rthcId":"RTHC-00379","title":"Emerging strategies for exploiting cannabinoid receptor agonists as medicines.","authors":"Pertwee, Roger G","year":2009,"journal":"British journal of pharmacology, 156(3), 397-411","doi":"10.1111/j.1476-5381.2008.00048.x","pmid":"19226257","tags":["medical-cannabis","neuroscience","pain","pharmacology"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Five strategies for improving cannabinoid therapeutics while reducing psychoactive side effects: (1) peripheral restriction — drugs that cannot cross the blood-brain barrier; (2) tissue-specific delivery — intrathecal, transdermal, topical routes; (3) receptor upregulation — exploiting disease-induced increases in receptor density; (4) CB2 selectivity — targeting immune receptors that don't cause intoxication; (5) multi-targeting — synergistic combinations, especially cannabinoid-opioid at sub-effective doses.","whyItMatters":"Published three months after rimonabant's worldwide withdrawal for psychiatric side effects, this review reframed the narrative: the cannabinoid system is targetable if you avoid global CB1 blockade in the brain. The five strategies became a roadmap for the next decade of cannabinoid drug development, with multi-targeting/opioid-sparing proving most clinically viable.","specificNumbers":"Three approved cannabinoid medicines reviewed: Cesamet (nabilone), Marinol (dronabinol), and Sativex (THC + CBD). Five therapeutic strategies outlined.","methodology":"Narrative review synthesizing preclinical and early clinical evidence supporting five pharmacological strategies for improving the therapeutic profile of cannabinoid receptor agonists. Published in the British Journal of Pharmacology.","limitations":"Highly optimistic about timelines — most strategies have taken far longer to translate than the review implied. CB2-selective pharmacology proved more complex than expected (species differences, protean agonism). Receptor upregulation strategy remains largely theoretical in clinical practice. Multi-targeting faces regulatory challenges requiring separate efficacy proof for each component."},{"rthcId":"RTHC-00380","title":"Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents.","authors":"Pisanti, Simona; Malfitano, Anna Maria; Grimaldi, Claudia; Santoro, Antonietta; Gazzerro, Patrizia; Laezza, Chiara; Bifulco, Maurizio","year":2009,"journal":"Best practice & research. Clinical endocrinology & metabolism, 23(1), 117-31","doi":"10.1016/j.beem.2009.02.001","pmid":"19285265","tags":["cancer","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the growing evidence for cannabinoids in cancer treatment, covering both established palliative uses and emerging anti-tumor evidence.\n\nPreclinical studies showed that cannabinoid receptor agonists can limit cell proliferation and induce tumor-selective cell death. Predominantly inhibitory effects were described on tumor growth, migration, blood vessel formation (angiogenesis), metastasis, and inflammation.\n\nHowever, the review noted a complicating factor: synthetic cannabinoids could also have pro-tumor effects in living organisms due to their immunosuppressive properties, creating a tension between anti-tumor and immune-suppressive effects.\n\nThe authors suggested that cannabinoid receptor agonists expressed by tumor cells may offer a novel therapeutic strategy and proposed exploring cannabinoids not just as palliative agents but as potential curative treatments.","whyItMatters":"While cannabinoids have been used for cancer-related symptoms (nausea, pain, appetite), the preclinical evidence for direct anti-tumor effects suggested a fundamentally different role in cancer treatment.","specificNumbers":"The review covered multiple cannabinoid types and cancer models. Inhibitory effects were described on tumor growth, migration, angiogenesis, metastasis, and inflammation.","methodology":"Narrative review of preclinical research on cannabinoids and cancer, covering anti-proliferative effects, apoptosis induction, anti-angiogenic properties, anti-metastatic effects, and immunological considerations.","limitations":"Evidence was primarily preclinical (cell culture and animal studies). The immunosuppressive properties of cannabinoids could theoretically promote tumor survival. Human cancer is far more complex than animal models suggest."},{"rthcId":"RTHC-00381","title":"Cannabis and suicide: longitudinal study.","authors":"Price, Ceri; Hemmingsson, Tomas; Lewis, Glyn; Zammit, Stanley; Allebeck, Peter","year":2009,"journal":"The British journal of psychiatry : the journal of mental science, 195(6), 492-7","doi":"10.1192/bjp.bp.109.065227","pmid":"19949196","tags":["mental-health","depression","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers followed 50,087 men conscripted for Swedish military service over 33 years, during which 600 suicides or deaths from undetermined causes occurred.\n\nCannabis use measured at conscription was associated with increased suicide risk in the crude analysis (OR 1.62, 95% CI 1.28-2.07).\n\nHowever, after adjusting for confounding factors, including markers of pre-existing psychological and behavioral problems, the association was completely eliminated (adjusted OR 0.88, 95% CI 0.65-1.20).\n\nThe authors concluded that cannabis use is unlikely to have a strong direct effect on suicide risk. The initial association was explained by the fact that people who used cannabis also tended to have pre-existing psychological vulnerabilities.","whyItMatters":"This study addressed a critical question with unusual rigor: a large population, 33-year follow-up, and objective outcome measurement (completed suicide, not just ideation). The finding that confounding fully explained the association challenges claims that cannabis directly causes suicide.","specificNumbers":"50,087 men followed for 33 years. 600 suicides or deaths from undetermined causes (1.2% of cohort). Crude OR for ever-use: 1.62 (95% CI 1.28-2.07). Adjusted OR: 0.88 (95% CI 0.65-1.20).","methodology":"Longitudinal cohort study of 50,087 Swedish military conscripts with cannabis use measured non-anonymously at conscription. Suicides were identified through 33 years of follow-up using the National Cause of Death Register. Logistic regression with adjustment for psychological and behavioral confounders.","limitations":"All-male military conscript cohort may not generalize to women or non-military populations. Cannabis use was measured at a single time point (conscription) and may not reflect lifetime use patterns. Confounders may not capture all relevant factors."},{"rthcId":"RTHC-00382","title":"Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling.","authors":"Puighermanal, Emma; Marsicano, Giovanni; Busquets-Garcia, Arnau; Lutz, Beat; Maldonado, Rafael; Ozaita, Andrés","year":2009,"journal":"Nature neuroscience, 12(9), 1152-8","doi":"10.1038/nn.2369","pmid":"19648913","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers discovered that THC activates the mTOR/p70S6K pathway in the mouse hippocampus, a signaling cascade that controls new protein synthesis.\n\nThis activation correlated with THC-induced memory impairment. When researchers blocked mTOR with rapamycin (at non-amnesic doses), or blocked protein synthesis with anisomycin, THC could no longer impair memory.\n\nThe memory-impairing effect was specifically mediated by CB1 receptors on GABAergic interneurons (inhibitory neurons). In mice genetically engineered to lack CB1 receptors on these interneurons (GABA-CB1R knockout mice), both the memory impairment and mTOR pathway activation were reduced.\n\nThe mechanism involved NMDA glutamate receptors, as blocking them also prevented THC-induced mTOR activation.","whyItMatters":"This study identified a specific molecular mechanism for THC-induced memory impairment, opening the possibility of developing interventions that block the amnesic effects of THC without blocking its other properties.","specificNumbers":"THC transiently activated the mTOR/p70S6K pathway. Non-amnesic doses of rapamycin or anisomycin blocked THC memory impairment. Effects were reduced in GABA-CB1R knockout mice. NMDA blockade also prevented the effect.","methodology":"Preclinical study using pharmacological and genetic tools in mice. THC-induced mTOR/p70S6K activation was measured in hippocampus. Memory was tested using object recognition and spatial memory tasks. Rapamycin (mTOR blocker), anisomycin (protein synthesis inhibitor), GABA-CB1R knockout mice, and NMDA blockade were used to dissect the mechanism.","limitations":"Mouse memory tasks are limited models of human memory. The specific role of mTOR signaling in human THC-induced memory impairment has not been confirmed. Rapamycin has its own significant effects on the brain and immune system."},{"rthcId":"RTHC-00383","title":"Intermittent marijuana use is associated with improved retention in naltrexone treatment for opiate-dependence.","authors":"Raby, Wilfrid Noel; Carpenter, Kenneth M; Rothenberg, Jami; Brooks, Adam C; Jiang, Huiping; Sullivan, Maria; Bisaga, Adam; Comer, Sandra; Nunes, Edward V","year":2009,"journal":"The American journal on addictions, 18(4), 301-8","doi":"10.1080/10550490902927785","pmid":"19444734","tags":["addiction","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Sixty-three opioid-dependent patients were enrolled in a naltrexone trial and classified by their cannabis use during treatment: abstinent, intermittent, or consistent users.\n\nIntermittent cannabis users showed dramatically superior treatment retention: median 133 days compared to just 35 days for both abstinent and consistent cannabis users. This difference was highly significant (p=0.002).\n\nThe effect remained after adjusting for baseline heroin use and cocaine use during treatment. Intermittent cannabis users also took their naltrexone medication more consistently.\n\nIntensive behavioral therapy appeared to moderate the poor prognosis in the consistent cannabis use group.\n\nImportantly, this replicated a previous finding from an independent sample.","whyItMatters":"Naltrexone is theoretically promising for opioid dependence but plagued by poor adherence. Finding that intermittent cannabis use predicts dramatically better retention challenges the assumption that all concurrent substance use is detrimental in addiction treatment.","specificNumbers":"63 patients. Intermittent cannabis users: median 133 days retention (mean 112.8). Abstinent: median 35 days (mean 47.3). Consistent users: median 35 days (mean 68.3). Log rank test: p=0.002.","methodology":"Secondary analysis of a randomized trial comparing two behavioral therapies with naltrexone for opioid dependence (N=63). Participants were classified into three cannabis use groups based on biweekly urine tests. Cox proportional hazards model adjusted for baseline heroin and in-treatment cocaine use.","limitations":"Observational classification within a clinical trial (not randomized to cannabis use). Intermittent cannabis users may differ from abstainers and heavy users in ways not captured by the analysis. Small sample size. Association, not causation."},{"rthcId":"RTHC-00384","title":"Suicidal ideation induced by episodic cannabis use.","authors":"Raja, Michele; Azzoni, Antonella","year":2009,"journal":"Case reports in medicine, 2009, 321456","doi":"10.1155/2009/321456","pmid":"19707477","tags":["mental-health","depression"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report described a patient who experienced suicidal ideation on exactly two occasions, both immediately following acute cannabis intoxication. The patient had only used cannabis on these two occasions.\n\nTwo aspects were highlighted as clinically significant:\n\nFirst, the suicidal ideation appeared abruptly after episodic (not chronic) cannabis use, suggesting an acute pharmacological trigger rather than a cumulative effect.\n\nSecond, the suicidal ideation appeared independent of mood depression, external stressors, or life events. This suggested that suicidality can emerge as a distinct psychological phenomenon rather than necessarily being a consequence of depression.","whyItMatters":"The temporal specificity (suicidal thoughts appearing only with cannabis use, on both occasions the patient used it) raises important questions about acute psychiatric effects of cannabis in vulnerable individuals.","specificNumbers":"Two separate occasions of cannabis use. Both followed immediately by suicidal ideation. No intervening depression, stressors, or life events.","methodology":"Single case report documenting clinical observations of suicidal ideation temporally linked to two separate episodes of cannabis intoxication in the same patient.","limitations":"Single case report cannot establish causation. The patient may have had underlying psychiatric vulnerability not fully characterized. Coincidence cannot be ruled out. No information about cannabis potency or composition."},{"rthcId":"RTHC-00385","title":"Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users.","authors":"Ramaekers, J G; Kauert, G; Theunissen, E L; Toennes, S W; Moeller, M R","year":2009,"journal":"Journal of psychopharmacology (Oxford, England), 23(3), 266-77","doi":"10.1177/0269881108092393","pmid":"18719045","tags":["cognition","tolerance","driving"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twelve occasional cannabis users and 12 heavy users smoked THC (500 mcg/kg) or placebo in a double-blind crossover design, with performance tested at intervals over 8 hours.\n\nOccasional users showed significant impairment on perceptual motor control (critical tracking), divided attention processing, and motor inhibition (stop signal task) after THC.\n\nHeavy users showed no impairment on any task except the stop signal task, where only stop reaction time increased, and only at high blood THC concentrations.\n\nImportantly, baseline (sober) performance comparisons between heavy and occasional users showed no persistent performance differences, arguing against residual THC impairment in heavy users.\n\nThese results demonstrated that cannabis use history strongly determines the behavioral response to a given THC dose.","whyItMatters":"This study directly demonstrated functional tolerance to THC cognitive effects, which has major implications for driving laws, workplace testing, and clinical use of cannabinoid medicines.","specificNumbers":"12 occasional users, 12 heavy users. THC dose: 500 mcg/kg smoked. Occasional users impaired on 3 of 4 tasks. Heavy users impaired only on stop reaction time at high THC concentrations. No baseline performance differences between groups.","methodology":"Double-blind, placebo-controlled, two-way mixed model design. 12 occasional and 12 heavy cannabis users smoked 500 mcg/kg THC or placebo. Tests included critical tracking, divided attention, stop signal task, and Tower of London, administered at regular intervals from 0-8 hours post-smoking.","limitations":"Small sample (12 per group). A single THC dose was used; tolerance patterns might differ at other doses. Heavy users may have developed compensatory strategies rather than true neurological tolerance. Selection criteria for \"heavy\" and \"occasional\" may not capture the full spectrum."},{"rthcId":"RTHC-00386","title":"Cannabis as a substitute for alcohol and other drugs.","authors":"Reiman, Amanda","year":2009,"journal":"Harm reduction journal, 6, 35","doi":"10.1186/1477-7517-6-35","pmid":"19958538","tags":["harm-reduction","medical-cannabis","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 350 patients at a Berkeley, California medical cannabis dispensary about their substance use patterns and substitution behaviors.\n\nSubstitution was common: 40% had used cannabis as a substitute for alcohol, 26% for illicit drugs, and 66% for prescription drugs.\n\nThe most frequently cited reasons for substituting cannabis were fewer adverse side effects (65%), better symptom management (57%), and less withdrawal potential (34%).\n\nThe sample was predominantly male (68%), with a mean age of 39. Most (71%) reported a chronic medical condition, 52% used cannabis for pain, and 75% for a mental health issue. Just 16% had previous substance abuse treatment.","whyItMatters":"The finding that two-thirds of patients used cannabis as a substitute for prescription drugs challenges the narrative that cannabis is purely an additional substance of abuse and supports its consideration within a harm reduction framework.","specificNumbers":"350 patients surveyed. 40% substituted for alcohol. 26% for illicit drugs. 66% for prescription drugs. Top reasons: fewer side effects (65%), better symptom management (57%), less withdrawal potential (34%).","methodology":"Anonymous cross-sectional survey of 350 patients at a single medical cannabis dispensary in Berkeley, California. Data collected on demographics, substance use patterns, and substitution behaviors.","limitations":"Self-selected sample from a single dispensary. No verification of medical conditions or prescription histories. Self-report of substitution behavior may not reflect actual outcomes. Berkeley, California population may not be representative."},{"rthcId":"RTHC-00387","title":"Nicotine and Delta(9)-tetrahydrocannabinol withdrawal induce Narp in the central nucleus of the amygdala.","authors":"Reti, Irving M; Han, Sungho; Miskimon, Matthew; Rosen, Jeffrey B; Baraban, Jay M","year":2009,"journal":"Synapse (New York, N.Y.), 63(3), 252-5","doi":"10.1002/syn.20586","pmid":"19084905","tags":["withdrawal","neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers had previously found that the immediate early gene Narp (which encodes a protein that interacts with AMPA glutamate receptors) is induced in the central nucleus of the amygdala during opiate withdrawal.\n\nThis study showed that Narp is also induced in the same brain region during withdrawal from both nicotine and THC.\n\nThe central nucleus of the amygdala is known to play a key role in mediating aversive responses to drug withdrawal, responses that are thought to drive continued drug use.\n\nThe finding that Narp induction is common across opiate, nicotine, and THC withdrawal suggests it is part of a shared transcriptional response to drug withdrawal rather than being specific to any single substance.","whyItMatters":"Identifying molecular components shared across different drug withdrawals could lead to treatments that address the unpleasant withdrawal experience regardless of which drug is involved.","specificNumbers":"Narp was induced in the central nucleus of the amygdala by withdrawal from three different drug classes: opiates (previously shown), nicotine, and THC.","methodology":"Animal study examining Narp gene expression in the central nucleus of the amygdala following precipitated withdrawal from chronic nicotine and chronic THC administration in rodents.","limitations":"Precipitated withdrawal (using antagonists) rather than spontaneous abstinence was used. Gene expression changes do not necessarily translate to functional significance. The study did not establish whether Narp induction is necessary or sufficient for withdrawal symptoms."},{"rthcId":"RTHC-00388","title":"Learning and memory deficits in ecstasy users and their neural correlates during a face-learning task.","authors":"Roberts, Gloria M P; Nestor, Liam; Garavan, Hugh","year":2009,"journal":"Brain research, 1292, 71-81","doi":"10.1016/j.brainres.2009.07.040","pmid":"19631624","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Twenty recreational ecstasy users, 14 cannabis users, and 20 controls completed a face-learning task during fMRI scanning.\n\nEcstasy users performed significantly worse at learning and remembering face-name associations compared to both controls and cannabis users.\n\nBrain imaging revealed ecstasy-specific patterns: hyperactivity in bilateral frontal, temporal, parietal, and occipital regions, and hypoactivity in the right dorsal anterior cingulate cortex and left posterior cingulate.\n\nSome brain activation changes overlapped between ecstasy and cannabis groups: both showed decreased activation in the right medial frontal gyrus, left parahippocampal gyrus, left dorsal cingulate, and left caudate.\n\nThese results identified both ecstasy-specific and shared ecstasy-cannabis neural effects, with the ecstasy-specific effects potentially related to neurotoxic damage to serotonergic brain regions.","whyItMatters":"By including a cannabis user comparison group, this study could separate effects attributable specifically to ecstasy from those that might be explained by concurrent cannabis use, a common confound in ecstasy research.","specificNumbers":"20 ecstasy users, 14 cannabis users, 20 controls. Ecstasy users performed significantly worse than both other groups. Ecstasy-specific hyperactivity in frontal, temporal, parietal, and occipital regions. Shared ecstasy-cannabis hypoactivity in four brain regions.","methodology":"Cross-sectional fMRI study comparing 20 ecstasy users, 14 cannabis users (from a previously published study), and 20 controls on a face-name learning task. Conjunction analysis identified drug-specific and shared neural changes.","limitations":"Cross-sectional design cannot determine causation. The ecstasy group likely used multiple drugs. Cannabis user data came from a separate study. Groups may have differed in unmeasured ways. Relatively small sample sizes."},{"rthcId":"RTHC-00389","title":"Subjective effects to cannabis are associated with use, abuse and dependence after adjusting for genetic and environmental influences.","authors":"Scherrer, Jeffrey F; Grant, Julia D; Duncan, Alexis E; Sartor, Carolyn E; Haber, Jon R; Jacob, Theodore; Bucholz, Kathleen K","year":2009,"journal":"Drug and alcohol dependence, 105(1-2), 76-82","doi":"10.1016/j.drugalcdep.2009.06.014","pmid":"19628344","tags":["addiction","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using data from 464 cannabis-using offspring of twins from the Vietnam Era Twin Registry, researchers identified four classes of subjective response to cannabis: high responders (39%), positive responders (28%), mixed/relaxed (22%), and low responders (11%).\n\nCompared to low responders, all other groups used more heavily (odds ratios 3.0 to 11.8). High responders were significantly more likely to develop cannabis abuse and dependence compared to mixed/relaxed and positive responders.\n\nCritically, these associations persisted after adjusting for familial (genetic and shared environmental) risk for substance use disorders, psychopathology, and demographics. This means the way cannabis affects you subjectively predicts your risk above and beyond your genetic vulnerability.","whyItMatters":"Identifying individual risk factors for cannabis dependence beyond genetics is important for prevention. If how you respond to cannabis the first few times predicts later problems, this could be a useful screening tool.","specificNumbers":"464 cannabis users analyzed. Four response classes: high (39%), positive (28%), mixed/relaxed (22%), low (11%). Heavy use ORs vs low responders: 3.0-11.8. High responders had greatest abuse/dependence risk.","methodology":"Offspring-of-twins design using 725 twin members of the Vietnam Era Twin Registry, 839 biological offspring (ages 12-32), and 427 mothers. Latent class analysis identified four groups based on 13 subjective cannabis effects. Logistic regression tested associations with use severity, controlling for familial risk.","limitations":"Retrospective recall of subjective effects may be influenced by later use patterns. The twin-offspring design controls for many confounds but cannot fully establish causation. The classification of \"high responders\" may partly reflect heavier use rather than purely predicting it."},{"rthcId":"RTHC-00390","title":"Heroin as an attachment substitute? Differences in attachment representations between opioid, ecstasy and cannabis abusers.","authors":"Schindler, Andreas; Thomasius, Rainer; Petersen, Kay; Sack, Peter-Michael","year":2009,"journal":"Attachment & human development, 11(3), 307-30","doi":"10.1080/14616730902815009","pmid":"19455456","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared attachment representations across four groups: 22 heroin users, 31 ecstasy users, 19 cannabis users, and 22 non-clinical controls.\n\nHeroin users were primarily fearful-avoidant in their attachment style. Ecstasy users showed a mix of insecure styles (preoccupied, fearful-avoidant, and dismissing-avoidant). Cannabis users were mainly dismissing and secure. Controls were mainly secure.\n\nThe groups also differed in psychosocial functioning (cannabis users > ecstasy users > heroin users), but attachment differences remained even after controlling for this.\n\nThe authors interpreted these patterns through the self-medication hypothesis: heroin may serve as an emotional substitute for people lacking coping strategies, while cannabis may support existing emotional distancing strategies.","whyItMatters":"Understanding why people gravitate toward specific substances could improve treatment by addressing the underlying emotional needs rather than just the substance use.","specificNumbers":"22 heroin users, 31 ecstasy users, 19 cannabis users, 22 controls. Cannabis users had highest psychosocial functioning among substance groups. Attachment differences persisted after controlling for functioning.","methodology":"Cross-sectional comparison using the Family Attachment Interview and Bartholomew & Horowitz attachment measure. Four groups compared: heroin users (n=22), ecstasy users (n=31), cannabis users (n=19), and non-clinical controls (n=22). Global Assessment of Functioning (GAF) was controlled.","limitations":"Small sample sizes in each group. Cross-sectional design cannot determine whether attachment patterns preceded substance choice. Cannabis users may represent a less severe population. The groups may differ in other unmeasured ways."},{"rthcId":"RTHC-00391","title":"Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice.","authors":"Schlosburg, Joel E; Carlson, Brittany L A; Ramesh, Divya; Abdullah, Rehab A; Long, Jonathan Z; Cravatt, Benjamin F; Lichtman, Aron H","year":2009,"journal":"The AAPS journal, 11(2), 342-52","doi":"10.1208/s12248-009-9110-7","pmid":"19430909","tags":["withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers tested whether increasing endocannabinoid levels could ease THC withdrawal in dependent mice.\n\nBoth the FAAH inhibitor URB597 (which raises anandamide) and the MAGL inhibitor JZL184 (which raises 2-AG) significantly attenuated withdrawal signs precipitated by the CB1 antagonist rimonabant in THC-dependent mice.\n\nImportantly, subchronic URB597 administration did not itself produce cannabinoid dependence, and neither inhibitor impaired motor coordination on the rotarod test.\n\nInterestingly, FAAH knockout mice (born without the enzyme) showed identical withdrawal responses as normal mice, suggesting that constitutive absence of FAAH throughout the development of dependence does not affect withdrawal, while acute FAAH inhibition during withdrawal does.","whyItMatters":"No FDA-approved medication exists for cannabis withdrawal. This study showed that boosting endocannabinoid levels could reduce withdrawal severity without creating new dependence, supporting a novel treatment strategy.","specificNumbers":"Both URB597 (FAAH inhibitor) and JZL184 (MAGL inhibitor) significantly reduced withdrawal. Subchronic URB597 did not produce dependence. Neither drug impaired motor coordination. FAAH knockout mice showed normal withdrawal.","methodology":"THC-dependent mice received FAAH inhibitor URB597, MAGL inhibitor JZL184, or vehicle before rimonabant-precipitated withdrawal. FAAH knockout mice were also tested. Subchronic URB597 was tested for dependence induction. Motor coordination was assessed on the rotarod.","limitations":"Precipitated withdrawal differs from spontaneous withdrawal. Mouse models may not predict human withdrawal experiences. The finding that FAAH knockout mice showed normal withdrawal complicates the interpretation of acute FAAH inhibitor effects."},{"rthcId":"RTHC-00392","title":"The effect of cannabis compared with alcohol on driving.","authors":"Sewell, R Andrew; Poling, James; Sofuoglu, Mehmet","year":2009,"journal":"The American journal on addictions, 18(3), 185-93","doi":"10.1080/10550490902786934","pmid":"19340636","tags":["driving","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compared the driving-related effects of cannabis and alcohol.\n\nBoth substances impaired driving skills in a dose-related fashion, but the patterns were fundamentally different. Cannabis impaired highly automatic driving functions (lane tracking, routine reactions) more than complex tasks requiring conscious control. Alcohol showed the opposite pattern, impairing complex decision-making more than automatic functions.\n\nCritically, cannabis users tended to recognize their impairment and compensate by driving slower, increasing following distance, and using other behavioral strategies. This compensation did not occur with alcohol.\n\nHowever, combining cannabis and alcohol eliminated the ability to compensate effectively, resulting in impairment even at individually insignificant doses of each drug.\n\nEpidemiological studies were inconclusive about whether cannabis alone increased accident risk, while alcohol use unanimously increased crash risk.","whyItMatters":"Understanding how cannabis and alcohol differ in their driving effects is essential for drug-impaired driving policy, which has largely been modeled on alcohol impairment assumptions that may not apply to cannabis.","specificNumbers":"Drunk drivers involved in 25% of motor vehicle fatalities. Cannabis effects varied more between individuals than alcohol due to tolerance, smoking technique, and absorption differences. Combination eliminated compensatory driving.","methodology":"Narrative review of experimental and epidemiological research comparing cannabis and alcohol effects on driving-related skills, on-road driving performance, and crash risk.","limitations":"The review included studies with varying methodologies and doses. Compensatory behavior in laboratory settings may not reflect real-world driving decisions. Epidemiological evidence was described as inconclusive."},{"rthcId":"RTHC-00393","title":"Do cannabinoids reduce multiple sclerosis-related spasticity?","authors":"Thaera, Greg M; Wellik, Kay E; Carter, Jonathan L; Demaerschalk, Bart M; Wingerchuk, Dean M","year":2009,"journal":"The neurologist, 15(6), 369-71","doi":"10.1097/NRL.0b013e3181bf5572","pmid":"19901724","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"A structured critical appraisal examined whether cannabinoids improve MS-related spasticity.\n\nThe largest randomized placebo-controlled trial of oral cannabinoid therapy found no improvement on the Ashworth scale (an objective spasticity measure). However, patients reported significant improvement in spasticity (p=0.01), spasms (p=0.038), sleep quality (p=0.025), and pain (p=0.002) without worsening depression, fatigue, irritability, or walking.\n\nA second RCT confirmed the same disconnect between objective and subjective outcomes.\n\nThe authors concluded that this raises important questions about whether current objective instruments are sensitive or valid enough to capture the clinical benefits patients experience.","whyItMatters":"The consistent disconnect between what objective scales measure and what patients experience suggests a measurement problem rather than a drug problem, with implications for how clinical trials should evaluate cannabis-based medicines.","specificNumbers":"Ashworth scale: no significant improvement. Subjective spasticity: p=0.01. Spasms: p=0.038. Sleep: p=0.025. Pain: p=0.002. No worsening of depression, fatigue, irritability, or walk time.","methodology":"Critically appraised topic developed by neurologists, epidemiologists, and MS specialists. Structured literature search and critical appraisal of the best available randomized controlled trial evidence.","limitations":"Limited number of high-quality RCTs available. The Ashworth scale is known to have inter-rater variability. Subjective improvement could be influenced by psychoactive effects rather than true spasticity reduction."},{"rthcId":"RTHC-00394","title":"Does cannabis use affect treatment outcome in bipolar disorder? A longitudinal analysis.","authors":"van Rossum, Inge; Boomsma, Maarten; Tenback, Diederik; Reed, Catherine; van Os, Jim","year":2009,"journal":"The Journal of nervous and mental disease, 197(1), 35-40","doi":"10.1097/NMD.0b013e31819292a6","pmid":"19155808","tags":["mental-health","psychosis","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In an observational study of 3,459 bipolar disorder patients (both inpatient and outpatient), researchers tracked the influence of cannabis use on treatment outcomes over one year.\n\nCannabis users exhibited less medication compliance and higher levels of overall illness severity, mania, and psychosis compared to non-users throughout the 12-month treatment period.\n\nCannabis users also experienced less life satisfaction and had a lower probability of being in a relationship.\n\nThere was little evidence that these associations were explained by third variables (mediators), suggesting an independent impact of cannabis on clinical outcomes in bipolar disorder.\n\nThe impact on psychopathological outcomes was pronounced, while the impact on social outcomes was more modest.","whyItMatters":"With a large sample and mediation analysis finding little evidence of confounding, this study provided relatively strong evidence that cannabis independently worsens bipolar disorder outcomes.","specificNumbers":"3,459 bipolar patients followed for 12 months. Cannabis users had higher overall illness severity, mania, psychosis, lower treatment compliance, less life satisfaction, and lower relationship probability.","methodology":"Observational longitudinal study (EMBLEM) enrolling 3,459 bipolar in- and outpatients. Cannabis exposure was assessed and clinical/social outcomes were tracked over 12 months. Mediation analysis tested whether third variables explained the cannabis-outcome associations.","limitations":"Observational design cannot definitively establish causation. Cannabis users may have more severe illness at baseline. Self-reported cannabis use may be unreliable. The study did not quantify cannabis use amounts."},{"rthcId":"RTHC-00395","title":"Measurement of affective state during chronic nicotine treatment and withdrawal by affective taste reactivity in mice: the role of endocannabinoids.","authors":"Wing, Victoria C; Cagniard, Barbara; Murphy, Niall P; Shoaib, Mohammed","year":2009,"journal":"Biochemical pharmacology, 78(7), 825-35","doi":"10.1016/j.bcp.2009.06.017","pmid":"19540830","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used taste reactivity (reactions to sweet and bitter tastes) to measure emotional state in mice during chronic nicotine treatment and withdrawal.\n\nChronic nicotine itself did not change taste reactions, and neither did spontaneous nicotine withdrawal.\n\nHowever, the CB1 receptor blocker AM251 had clear effects: it decreased positive reactions to sucrose (sweet) and increased negative reactions to quinine (bitter), suggesting that endocannabinoids normally contribute to positive emotional state.\n\nIn nicotine-treated mice, the effects of AM251 were modified: the decrease in positive reactions was attenuated while the increase in negative reactions was enhanced, suggesting chronic nicotine exposure alters endocannabinoid emotional regulation.","whyItMatters":"This study revealed that endocannabinoids contribute to normal emotional state and that chronic nicotine exposure changes how the endocannabinoid system regulates emotion, potentially relevant to understanding tobacco-cannabis co-use patterns.","specificNumbers":"Nicotine dose: 12 mg/kg/day. AM251 doses: 1, 3, 10 mg/kg. AM251 decreased positive sucrose reactions and increased negative quinine reactions. Chronic nicotine modified both AM251 effects.","methodology":"Mouse study using intraoral taste reactivity to measure affective state. Mice received chronic nicotine (12 mg/kg/day via osmotic minipump) or vehicle. The CB1 antagonist AM251 (1, 3, 10 mg/kg) was administered during chronic nicotine to test endocannabinoid involvement.","limitations":"Taste reactivity is an indirect measure of emotional state. Mouse emotional responses may not translate to human subjective experiences. The nicotine doses and administration method (continuous infusion) may not model typical human smoking patterns."},{"rthcId":"RTHC-00396","title":"Withdrawal phenomena and dependence syndrome after the consumption of \"spice gold\".","authors":"Zimmermann, Ulrich S; Winkelmann, Patricia R; Pilhatsch, Max; Nees, Josef A; Spanagel, Rainer; Schulz, Katja","year":2009,"journal":"Deutsches Arzteblatt international, 106(27), 464-7","doi":"10.3238/arztebl.2009.0464","pmid":"19652769","tags":["synthetic-cannabinoids","withdrawal","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 20-year-old patient smoked Spice Gold daily for 8 months, developing classic signs of dependence: tolerance with dose escalation to 3 grams per day, continuous drug craving, continued use despite cognitive impairment, and neglect of professional duties.\n\nOn hospital days 4-7 after cessation, he developed withdrawal symptoms: inner restlessness, drug craving, nightmares, profuse sweating, nausea, tremor, headache, elevated blood pressure (180/90 mmHg), and tachycardia (125 bpm).\n\nThe patient reported experiencing a similar syndrome during a previous involuntary abstinence period, which resolved when he resumed use.\n\nUrinary drug screens were negative, as standard tests did not detect synthetic cannabinoids. The withdrawal syndrome closely resembled cannabis withdrawal.\n\nThe authors attributed the syndrome to synthetic cannabinoids (JWH-018, CP 47497) that had been found in Spice products and were banned in Germany in January 2009.","whyItMatters":"This was among the earliest clinical documentation of dependence and physical withdrawal from synthetic cannabinoid products, which had been marketed as \"legal\" and \"natural\" alternatives to cannabis.","specificNumbers":"Age 20. Daily use for 8 months. Dose escalated to 3 g/day. Blood pressure peak: 180/90 mmHg. Heart rate: 125 bpm. Withdrawal days 4-7. Urine drug screens negative.","methodology":"Single case report documenting clinical features of dependence and withdrawal from Spice Gold, a herbal product containing undeclared synthetic cannabinoids. Clinical observations included vital signs, subjective symptoms, and drug screening.","limitations":"Single case report. The exact synthetic cannabinoids in the patient's Spice Gold supply were not analytically confirmed. Individual variation in withdrawal severity is expected. Cannabis withdrawal itself was still debated at the time."},{"rthcId":"RTHC-00397","title":"Functional MRI evidence for inefficient attentional control in adolescent chronic cannabis abuse.","authors":"Abdullaev, Yalchin; Posner, Michael I; Nunnally, Ray; Dishion, Thomas J","year":2010,"journal":"Behavioural brain research, 215(1), 45-57","doi":"10.1016/j.bbr.2010.06.023","pmid":"20600341","tags":["cognition","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Fourteen young adults with chronic adolescent cannabis use were compared to 14 matched non-users on two attention tasks during fMRI scanning.\n\nOn the Attention Network Task, cannabis users performed worse (slower reaction times and more errors) specifically on trials requiring executive attention (processing conflicting information). Performance on alerting and orienting components was normal.\n\nfMRI showed that cannabis users activated the right prefrontal cortex more strongly than controls during executive attention trials, despite performing worse.\n\nThe same pattern appeared on a use-generation task: cannabis users showed stronger right prefrontal activation.\n\nThe authors interpreted increased activation with worse performance as evidence of inefficient attentional processing: cannabis users needed more brain resources to resolve conflict but still performed worse.","whyItMatters":"Adolescence is a critical period for brain development. Finding that adolescent cannabis use is associated with lasting inefficiency in attentional control suggests potential long-term consequences for the developing brain.","specificNumbers":"14 cannabis users, 14 controls. Impairment specific to executive attention (conflict resolution). Stronger right prefrontal activation in users on both tasks. No differences in alerting or orienting attention.","methodology":"Cross-sectional fMRI study comparing 14 young adults with chronic adolescent cannabis use to 14 matched non-users. Two tasks assessed attention networks: the Attention Network Task (alerting, orienting, executive attention) and a use-generation task.","limitations":"Small sample (14 per group). Cross-sectional design cannot determine whether attentional inefficiency preceded or resulted from cannabis use. Adolescent cannabis users may differ from non-users in other ways not controlled for."},{"rthcId":"RTHC-00398","title":"Treatment of cannabis use among people with psychotic or depressive disorders: a systematic review.","authors":"Baker, Amanda L; Hides, Leanne; Lubman, Dan I","year":2010,"journal":"The Journal of clinical psychiatry, 71(3), 247-54","doi":"10.4088/JCP.09r05119gry","pmid":"20331929","tags":["mental-health","psychosis","depression","quitting"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"From 1,713 initial articles, only 7 randomized controlled trials reported cannabis use outcomes from pharmacological or psychological interventions in mental health patients.\n\nThe limited evidence suggested two key findings:\n\n1. Effectively treating the mental health disorder with standard pharmacotherapy was associated with reduced cannabis use.\n\n2. Longer or more intensive psychological interventions appeared more effective than brief interventions, particularly for heavier cannabis users and those with more chronic mental disorders.\n\nMotivational interviewing and cognitive-behavioral therapy appeared most promising, though specific recommendations about type and length of psychological treatment could not yet be made.","whyItMatters":"Cannabis use is common among people with psychosis and depression and worsens outcomes. Identifying effective treatments for concurrent cannabis use in these populations addresses a critical clinical gap.","specificNumbers":"1,713 articles screened. 7 RCTs met inclusion criteria. Brief interventions appeared insufficient. Longer interventions and medication treatment of the primary disorder showed promise.","methodology":"Systematic review of PubMed and PsychINFO databases from inception through December 2008. Searches combined cannabis use, mental disorders, and pharmacotherapy/treatment terms, limited to RCTs in humans.","limitations":"Only 7 RCTs met criteria, severely limiting conclusions. Studies varied in design, populations, and outcomes. Most evidence was short-term. No specific treatment could be definitively recommended."},{"rthcId":"RTHC-00399","title":"Chronic use of cannabis and poor neural efficiency in verbal memory ability.","authors":"Battisti, Robert A; Roodenrys, Steven; Johnstone, Stuart J; Respondek, Colleen; Hermens, Daniel F; Solowij, Nadia","year":2010,"journal":"Psychopharmacology, 209(4), 319-30","doi":"10.1007/s00213-010-1800-4","pmid":"20217055","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Twenty-four chronic cannabis users (mean 17 years of near-daily use) and 24 non-using controls were tested on a verbal memory task while brain electrical activity (ERPs) was recorded.\n\nCannabis users showed poorer recall. Their brain activity during memory encoding showed a specific pattern of dysfunction: attenuation of the N4 component and an increase in the late positive component of the subsequent memory effect (SME).\n\nThe SME normally predicts whether information will be successfully remembered. Its alteration in cannabis users suggests disrupted neural processes during the initial encoding of memories.\n\nDuration of cannabis use and age of initial use were significantly correlated with the degree of SME alteration. Longer use and earlier onset were associated with greater changes, suggesting cumulative or developmental effects.","whyItMatters":"By examining the subsequent memory effect, this study identified disrupted neural processes during memory formation itself, not just at retrieval. This suggests chronic cannabis use alters the brain machinery that creates memories.","specificNumbers":"24 users (mean 17 years near-daily use), 24 controls. N4 component attenuated and late positive component increased in users. Duration and age of onset correlated with SME alterations.","methodology":"Cross-sectional study comparing 24 chronic cannabis users (unintoxicated, mean 17 years near-daily use) with 24 non-using controls. Event-related potentials were recorded during a verbal word list learning task. ERPs were averaged based on whether words were later recalled or not (subsequent memory effect).","limitations":"Cross-sectional design cannot establish causation. Seventeen years of near-daily use represents very heavy exposure; effects may not generalize to moderate users. The correlation between use duration and brain changes could reflect age effects or other confounds."},{"rthcId":"RTHC-00400","title":"Chronic cannabis users show altered neurophysiological functioning on Stroop task conflict resolution.","authors":"Battisti, Robert A; Roodenrys, Steven; Johnstone, Stuart J; Pesa, Nicole; Hermens, Daniel F; Solowij, Nadia","year":2010,"journal":"Psychopharmacology, 212(4), 613-24","doi":"10.1007/s00213-010-1988-3","pmid":"20721538","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Twenty-one chronic cannabis users (mean 16.4 years near-daily use, unintoxicated) and 19 controls completed a Stroop color-naming task while ERPs were recorded.\n\nCannabis users made significantly more errors specifically on incongruent trials (where the word meaning conflicts with the ink color, like \"RED\" written in blue). Performance on congruent and neutral trials was normal.\n\nAn earlier age of onset of regular cannabis use predicted worse incongruent trial performance.\n\nERP analysis showed altered expression of a late sustained potential related to conflict resolution. Cannabis users showed opposite patterns of brain activity between trial types at certain electrode sites, along with altered relationships between brain activity and behavioral performance not seen in controls.","whyItMatters":"Conflict resolution is essential for self-regulation, decision-making, and behavior control. Impaired conflict processing could contribute to difficulty controlling substance use and making decisions that require overriding automatic responses.","specificNumbers":"21 users (mean 16.4 years near-daily use), 19 controls. Increased errors on incongruent trials only. Earlier age of onset predicted worse performance. Altered late sustained potential in users.","methodology":"Cross-sectional ERP study comparing 21 chronic cannabis users (unintoxicated, mean 16.4 years near-daily use) with 19 non-using controls on a discrete-trial Stroop color-naming task.","limitations":"Cross-sectional design cannot establish causation. Very heavy use sample may not generalize. Brain activity differences are correlational and could reflect pre-existing differences. Unintoxicated state does not rule out residual THC effects."},{"rthcId":"RTHC-00401","title":"Altered parahippocampal functioning in cannabis users is related to the frequency of use.","authors":"Becker, Benjamin; Wagner, Daniel; Gouzoulis-Mayfrank, Euphrosyne; Spuentrup, Elmar; Daumann, Jörg","year":2010,"journal":"Psychopharmacology, 209(4), 361-74","doi":"10.1007/s00213-010-1805-z","pmid":"20300735","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Forty-two cannabis users underwent fMRI while encoding and retrieving face-profession associations. They were compared across three dimensions of use: duration, frequency, and age of onset.\n\nHigh-frequency users showed significantly stronger activation in the left parahippocampal gyrus during encoding compared to low-frequency users. This finding was confirmed by linear regression analysis.\n\nNeither the duration of cannabis use nor the age of first use was associated with parahippocampal activation differences.\n\nThe authors interpreted the increased parahippocampal activation as possible functional compensation: the brain working harder to maintain cognitive performance in the face of frequent cannabis exposure.","whyItMatters":"Understanding which aspect of cannabis use is most important for brain function helps focus prevention messages. If frequency matters more than total duration, reducing how often you use may be more protective than simply limiting total years of use.","specificNumbers":"42 cannabis users. High-frequency users showed stronger left parahippocampal activation during encoding. Duration and age of onset groups showed no significant differences in this region. Linear regression confirmed frequency as the key predictor.","methodology":"Cross-sectional fMRI study of 42 cannabis users divided by duration (longer vs shorter), frequency (higher vs lower), and onset age (earlier vs later). Region of interest analysis focused on hippocampal and parahippocampal function during face-profession association learning.","limitations":"No non-using control group, limiting interpretation of whether increased activation represents compensation or dysfunction. Cross-sectional design. Self-reported use parameters may be inaccurate. Only parahippocampal function was examined."},{"rthcId":"RTHC-00402","title":"The impact of early-onset cannabis use on functional brain correlates of working memory.","authors":"Becker, Benjamin; Wagner, Daniel; Gouzoulis-Mayfrank, Euphrosyne; Spuentrup, Elmar; Daumann, Jörg","year":2010,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 34(6), 837-45","doi":"10.1016/j.pnpbp.2010.03.032","pmid":"20363277","tags":["cognition","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Twenty-six early-onset cannabis users (first use before age 16) and 17 late-onset users (first use at 16 or later) were compared on a verbal working memory task during fMRI.\n\nEarly-onset users showed significantly increased activation in the left superior parietal lobe during the task. Correlational analysis confirmed that earlier onset was associated with greater activation in this region.\n\nImportantly, cumulative dose, current frequency of use, and time since last use were not significantly associated with brain activation, suggesting that age of onset has a specific impact independent of total exposure.","whyItMatters":"The finding that onset age affects brain efficiency independently of how much cannabis was used overall supports the idea that the adolescent brain is particularly vulnerable to cannabis effects during its development.","specificNumbers":"26 early-onset users (before age 16), 17 late-onset users (16+). Increased left superior parietal activation in early onset. Neither cumulative dose, frequency, nor time since last use predicted brain activation.","methodology":"Cross-sectional fMRI study comparing early-onset (before 16, n=26) and late-onset (16+, n=17) cannabis users on a verbal working memory task. No non-using control group. Region of interest and correlational analyses examined the effect of onset age versus other use parameters.","limitations":"No non-using control group makes it impossible to determine whether late-onset users also differ from non-users. Cross-sectional design. Early-onset users may differ from late-onset users in other ways (e.g., family environment, other drug use). The authors explicitly note alternative interpretations cannot be excluded."},{"rthcId":"RTHC-00403","title":"Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.","authors":"Bhattacharyya, Sagnik; Morrison, Paul D; Fusar-Poli, Paolo; Martin-Santos, Rocio; Borgwardt, Stefan; Winton-Brown, Toby; Nosarti, Chiara; O' Carroll, Colin M; Seal, Marc; Allen, Paul; Mehta, Mitul A; Stone, James M; Tunstall, Nigel; Giampietro, Vincent; Kapur, Shitij; Murray, Robin M; Zuardi, Antonio W; Crippa, José A; Atakan, Zerrin; McGuire, Philip K","year":2010,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 35(3), 764-74","doi":"10.1038/npp.2009.184","pmid":"19924114","tags":["neuroscience","cbd","psychosis","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a two-part study, 15 healthy men completed four tasks during fMRI after receiving THC (10 mg), CBD (600 mg), or placebo.\n\nTHC and CBD had opposite effects on brain activation across all four tasks:\n- In the striatum during verbal recall\n- In the hippocampus during response inhibition\n- In the amygdala while viewing fearful faces\n- In the superior temporal cortex during speech processing\n- In the occipital cortex during visual processing\n\nIn a second experiment with 6 volunteers, CBD pretreatment prevented the acute psychotic symptoms normally induced by intravenous THC.\n\nThis demonstrated that the two main cannabis compounds have fundamentally opposing brain effects, and that CBD can actively block THC-induced psychosis.","whyItMatters":"This landmark study demonstrated that THC and CBD have opposing brain effects across multiple cognitive domains and that CBD can prevent THC-induced psychosis, with major implications for cannabis product composition and potential therapeutic applications.","specificNumbers":"15 men in fMRI experiment. 6 men in CBD-blocks-psychosis experiment. THC: 10 mg oral. CBD: 600 mg oral. Opposite effects documented in striatum, hippocampus, amygdala, temporal cortex, and occipital cortex.","methodology":"Two experiments. Experiment 1: Double-blind, placebo-controlled crossover with 15 healthy men receiving oral THC (10 mg), CBD (600 mg), or placebo before fMRI during verbal memory, response inhibition, sensory processing, and emotional processing tasks. Experiment 2: 6 volunteers received IV THC after CBD or placebo pretreatment.","limitations":"Small samples (15 and 6). Only healthy men with minimal cannabis experience. Single doses only. The second experiment (CBD blocking THC psychosis) had only 6 participants. IV THC has different kinetics than smoked cannabis."},{"rthcId":"RTHC-00404","title":"Methamphetamine neurotoxicity increases brain expression and alters behavioral functions of CB₁ cannabinoid receptors.","authors":"Bortolato, Marco; Frau, Roberto; Bini, Valentina; Luesu, William; Loriga, Roberta; Collu, Maria; Gessa, Gian Luigi; Ennas, M Grazia; Castelli, M Paola","year":2010,"journal":"Journal of psychiatric research, 44(14), 944-55","doi":"10.1016/j.jpsychires.2010.03.002","pmid":"20378129","tags":["neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats were exposed to a neurotoxic methamphetamine regimen (4 doses of 4 mg/kg in one day) and examined three weeks later.\n\nMeth-exposed rats showed significantly increased CB1 receptor expression in the prefrontal cortex, caudate-putamen, basolateral amygdala, hippocampal CA1 region, and perirhinal cortex.\n\nBehavioral responses to the cannabinoid agonist WIN 55,212-2 were altered: it produced anxiolytic (anti-anxiety) effects in meth-exposed rats but anxiogenic (anxiety-inducing) effects in controls. Meth-exposed animals also showed reduced cannabinoid effects on exploration and short-term recognition memory.\n\nSome cannabinoid effects (locomotor reduction, acoustic startle) were not altered by meth exposure.","whyItMatters":"Cannabis is the most common secondary drug among meth users. Understanding how meth neurotoxicity alters the cannabinoid system could explain different cannabis responses in meth users and has implications for dual-use populations.","specificNumbers":"Meth regimen: 4 mg/kg x 4 doses in one day. CB1 increased in prefrontal cortex, caudate-putamen, basolateral amygdala, CA1, and perirhinal cortex. Cannabinoid agonist produced opposite anxiety effects in meth-exposed vs control rats.","methodology":"Rats received a neurotoxic meth regimen (4 mg/kg x 4, 2 hours apart). Three weeks later, CB1 receptor expression was measured by immunohistochemistry in multiple brain regions. A separate group was tested with the cannabinoid agonist WIN 55,212-2 in behavioral paradigms (open field, object recognition, startle reflex).","limitations":"Animal study using a specific neurotoxic meth protocol that may not reflect typical human meth use patterns. Three-week post-exposure timepoint may not reflect longer-term changes. Rats were drug-naive before the experiment."},{"rthcId":"RTHC-00405","title":"Cannabinoid-Induced Hyperemesis: A Conundrum-From Clinical Recognition to Basic Science Mechanisms.","authors":"Darmani, Nissar A","year":2010,"journal":"Pharmaceuticals (Basel, Switzerland), 3(7), 2163-2177","doi":null,"pmid":"27713347","tags":["medical-cannabis","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids are clinically used as anti-nausea medications (preventing chemotherapy-induced vomiting through CB1 receptor stimulation), making the recently recognized cannabinoid hyperemesis syndrome (CHS) a paradox.\n\nCHS is characterized by repeated cyclical vomiting and compulsive hot water bathing in chronic cannabis users. Though initially considered rare, increasing case reports suggested it was more common than thought.\n\nThe review proposed multiple potential mechanisms:\n\nPharmacokinetic: THC long half-life and fat solubility leading to accumulation, individual variation in metabolism/excretion, and buildup of emetogenic (vomiting-causing) metabolites.\n\nPharmacodynamic: THC switching from partial agonist to antagonist at certain levels, CB1 receptor desensitization or downregulation with chronic exposure, alterations in endocannabinoid concentrations, and differential effects in the brain versus the gut.\n\nThe review also noted that chronic exposure may not be necessary to trigger vomiting but is required for the intensity of emesis.","whyItMatters":"Understanding why an anti-emetic drug can paradoxically cause vomiting has implications for both clinical use of cannabinoid medications and for the millions of chronic cannabis users who could potentially develop this syndrome.","specificNumbers":"International case reports were increasingly being published at the time. Multiple pharmacokinetic and pharmacodynamic mechanisms were proposed.","methodology":"Narrative review examining basic science mechanisms that could explain cannabinoid-induced hyperemesis, integrating pharmacokinetic, pharmacodynamic, and clinical data.","limitations":"No single mechanism has been definitively established. The review was based on case reports and basic science reasoning rather than direct experimental testing of proposed mechanisms. CHS prevalence was uncertain."},{"rthcId":"RTHC-00406","title":"Evaluating the drug use \"gateway\" theory using cross-national data: consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys.","authors":"Degenhardt, Louisa; Dierker, Lisa; Chiu, Wai Tat; Medina-Mora, Maria Elena; Neumark, Yehuda; Sampson, Nancy; Alonso, Jordi; Angermeyer, Matthias; Anthony, James C; Bruffaerts, Ronny; de Girolamo, Giovanni; de Graaf, Ron; Gureje, Oye; Karam, Aimee N; Kostyuchenko, Stanislav; Lee, Sing; Lépine, Jean-Pierre; Levinson, Daphna; Nakamura, Yosikazu; Posada-Villa, Jose; Stein, Dan; Wells, J Elisabeth; Kessler, Ronald C","year":2010,"journal":"Drug and alcohol dependence, 108(1-2), 84-97","doi":"10.1016/j.drugalcdep.2009.12.001","pmid":"20060657","tags":["addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using data from WHO World Mental Health Surveys across 17 countries with widely varying drug use prevalence, researchers tested whether the standard gateway sequence (alcohol/tobacco to cannabis to other illicit drugs) reflects a causal chain or other factors.\n\nThe likelihood of progression from \"gateway\" substances to other illicit drugs varied based on the background prevalence of gateway substance use in each country. In countries where gateway substances were more commonly used, the conditional probability of progression was different.\n\nCross-country differences in substance use prevalence also corresponded to differences in the likelihood of non-normative sequences (people starting with \"harder\" drugs before \"softer\" ones).\n\nThe authors concluded that the gateway pattern at least partially reflects unmeasured common causes (like drug availability, cultural attitudes, and socioeconomic factors) rather than causal effects of specific drugs promoting subsequent use.\n\nThe implication: preventing use of specific gateway drugs may not lead to major reductions in later drug use.","whyItMatters":"The gateway theory has profoundly influenced drug policy for decades. This large cross-national study provided evidence that the theory oversimplifies the relationship between substance use progression, suggesting policy should focus on common underlying causes rather than specific gateway substances.","specificNumbers":"17 countries surveyed. Initiation sequence varied with background substance use prevalence. Non-normative sequences (skipping gateway drugs) were more common in some countries.","methodology":"Cross-national analysis using WHO World Mental Health Surveys conducted in 17 countries with consistent instruments and procedures. Patterns and order of initiation of alcohol, tobacco, cannabis, and other illicit drug use were compared across populations with varying drug prevalence.","limitations":"Cross-sectional surveys rely on retrospective recall of drug initiation timing. The study could not directly test causal mechanisms. \"Common causes\" were inferred from patterns rather than measured directly."},{"rthcId":"RTHC-00407","title":"Implicit and explicit affective associations towards cannabis use in patients with recent-onset schizophrenia and healthy controls.","authors":"Dekker, N; Smeerdijk, A M; Wiers, R W; Duits, J H; van Gelder, G; Houben, K; Schippers, G; Linszen, D H; de Haan, L","year":2010,"journal":"Psychological medicine, 40(8), 1325-36","doi":"10.1017/S0033291709991814","pmid":"19917142","tags":["psychosis","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Seventy patients with recent-onset psychotic disorder and 61 healthy controls with varying cannabis use levels were tested on both implicit (automatic) and explicit (conscious) associations toward cannabis.\n\nSurprisingly, there were no differences in implicit associations between patients and controls. Both groups showed strong negative implicit associations toward cannabis.\n\nHowever, patients scored significantly higher on explicit negative affect expectancies, meaning they were more consciously aware of negative consequences of cannabis use.\n\nDespite this, explicit relaxation expectancies were the strongest predictors of actual cannabis use and craving in both groups. The expectation that cannabis would help them relax appeared to override their negative associations.\n\nThe finding that users had strong negative implicit associations suggested they were engaging in a behavior they did not implicitly \"like.\"","whyItMatters":"Understanding why schizophrenia patients continue using cannabis despite knowing it worsens their illness could improve treatment approaches. The dominance of relaxation expectancies suggests targeting these specific beliefs in therapy.","specificNumbers":"70 psychotic disorder patients, 61 healthy controls. Both groups showed strong negative implicit cannabis associations. Patients had stronger explicit negative expectations. Explicit relaxation expectancies were the strongest predictor of use and craving.","methodology":"Cross-sectional study using three Single-Category Implicit Association Tests (relaxed, active, negative) and an explicit expectancy questionnaire in 70 patients with recent-onset psychotic disorder and 61 healthy controls with varying cannabis use levels.","limitations":"Cross-sectional design. Implicit measures may not capture all aspects of automatic processing. The study cannot determine whether relaxation expectancies drive use or are post-hoc justifications. Different levels of cannabis use between groups may confound comparisons."},{"rthcId":"RTHC-00408","title":"Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds.","authors":"Dresen, Sebastian; Ferreirós, Nerea; Pütz, Michael; Westphal, Folker; Zimmermann, Ralf; Auwärter, Volker","year":2010,"journal":"Journal of mass spectrometry : JMS, 45(10), 1186-94","doi":"10.1002/jms.1811","pmid":"20857386","tags":["synthetic-cannabinoids","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers analyzed over 140 samples of \"herbal incense\" products (marketed as legal cannabis alternatives) between June 2008 and September 2009.\n\nInitially, products contained CP-47,497-C8 and JWH-018. After Germany banned these compounds in February 2009, manufacturers quickly switched to JWH-073, then to JWH-250 and JWH-398.\n\nThe composition of many products changed repeatedly over time in direct response to legal restrictions. This meant neither sellers nor consumers could predict what was actually in the products.\n\nOne herbal product marketed as containing \"kratom\" was found to contain the synthetic opioid O-desmethyltramadol, demonstrating that the practice of spiking \"natural\" products with dangerous synthetic chemicals extended beyond cannabinoids.","whyItMatters":"This study documented in real-time how the synthetic cannabinoid market responded to regulation, demonstrating a cat-and-mouse dynamic that made harm reduction nearly impossible for consumers.","specificNumbers":"Over 140 samples analyzed over 15 months. Compounds identified: CP-47,497-C8, JWH-018 (banned February 2009), JWH-073 (appeared after ban), JWH-250, JWH-398. One product contained undeclared synthetic opioid.","methodology":"Analytical chemistry study monitoring over 140 commercially available herbal incense products for synthetic cannabinoid content from June 2008 to September 2009 in Germany.","limitations":"German market may not reflect products in other countries. Analytical methods may not have detected all possible adulterants. The study could not assess health consequences of the identified compounds."},{"rthcId":"RTHC-00409","title":"Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting.","authors":"Duran, Marta; Pérez, Eulàlia; Abanades, Sergio; Vidal, Xavier; Saura, Cristina; Majem, Margarita; Arriola, Edurne; Rabanal, Manel; Pastor, Antoni; Farré, Magí; Rams, Neus; Laporte, Joan-Ramon; Capellà, Dolors","year":2010,"journal":"British journal of clinical pharmacology, 70(5), 656-63","doi":"10.1111/j.1365-2125.2010.03743.x","pmid":"21039759","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Sixteen cancer patients with persistent nausea and vomiting despite standard anti-emetic treatment were randomized to a THC/CBD oral spray (7 patients) or placebo (9 patients) for the 120-hour post-chemotherapy period.\n\nThe cannabis-based medicine group showed a dramatically higher complete response rate: 71.4% (5 of 7) versus 22.2% (2 of 9) with placebo, a difference of 49.2 percentage points. The benefit was primarily in the delayed nausea period.\n\nOnly one patient in the cannabis group withdrew due to adverse events. While the overall incidence of adverse events was higher in the cannabis group (86% vs 67%), none were serious.\n\nThe mean daily dose was 4.8 sprays in both groups.","whyItMatters":"Delayed CINV remains a significant problem despite advances in anti-emetic therapy. This pilot trial suggested that a cannabis-based medicine could provide additional relief when standard treatments are insufficient.","specificNumbers":"7 CBM patients, 9 placebo. Complete response: 71.4% vs 22.2% (difference 49.2%, 95% CI 1%-75%). Mean daily dose: 4.8 sprays. One withdrawal for adverse events. No serious adverse events.","methodology":"Pilot, randomized, double-blind, placebo-controlled phase II clinical trial. Sixteen patients with chemotherapy-induced nausea and vomiting (CINV) refractory to standard anti-emetics were randomized to a whole-plant cannabis-based medicine (THC + CBD) or placebo as add-on therapy.","limitations":"Very small sample (16 patients total). Pilot study not powered for definitive efficacy conclusions. The 95% confidence interval for the primary outcome was wide (1%-75%). Higher adverse event rate in the treatment group."},{"rthcId":"RTHC-00410","title":"FAAH-/- mice display differential tolerance, dependence, and cannabinoid receptor adaptation after delta 9-tetrahydrocannabinol and anandamide administration.","authors":"Falenski, Katherine W; Thorpe, Andrew J; Schlosburg, Joel E; Cravatt, Benjamin F; Abdullah, Rehab A; Smith, Tricia H; Selley, Dana E; Lichtman, Aron H; Sim-Selley, Laura J","year":2010,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 35(8), 1775-87","doi":"10.1038/npp.2010.44","pmid":"20357755","tags":["tolerance","withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Repeated THC dosing shifted dose–response curves further to the right for classic cannabinoid effects in mice. That means it took more THC to achieve the same level of pain relief, catalepsy, and body temperature drop after a subchronic regimen. Anandamide produced smaller shifts under the same testing conditions in FAAH knockout mice, which are engineered so anandamide is not rapidly broken down.\n\nBrain measures lined up with behavior. THC reduced CB1 receptor signaling capacity and receptor availability, shown by lower agonist-stimulated [35S]GTPγS binding in brain and spinal cord and reduced [3H]WIN55,212-2 binding in brain. Anandamide-treated mice showed less CB1 desensitization and downregulation.\n\nDependence signals diverged too. Giving the CB1 blocker rimonabant after repeated dosing precipitated a much smaller withdrawal syndrome in anandamide-dosed mice than in THC-dosed mice.\n\nCross-tolerance tests pointed to pharmacology at the receptor as a key driver. THC is a lower efficacy CB1 agonist than anandamide. When CB1 receptors were partially lost or desensitized, the behavioral effects of the lower efficacy drug dropped off more. The study argues that what you observe as tolerance during testing depends heavily on the intrinsic activity of the ligand being tested.","whyItMatters":"The study separates two ways of engaging the endocannabinoid system in mice. Repeated direct CB1 agonism with THC produced stronger tolerance, more receptor downregulation, and a clearer withdrawal signal. Elevating signaling via an endogenous ligand, anandamide, produced milder adaptations under parallel conditions in a model designed to keep anandamide from being rapidly degraded. For drug development that targets endocannabinoid tone rather than directly pushing the receptor, this mechanistic contrast is central.","specificNumbers":"- Tolerance pattern: larger rightward shifts in THC dose–response curves than in anandamide curves for pain relief, catalepsy, and hypothermia. A rightward shift means a higher dose is needed to get the same effect.\n- CB1 signaling: agonist-stimulated [35S]GTPγS binding was significantly reduced after repeated THC in brain and spinal cord. This indicates receptor desensitization.\n- CB1 availability: [3H]WIN55,212-2 binding fell after repeated THC in brain, consistent with receptor downregulation.\n- Dependence signal: rimonabant precipitated markedly smaller withdrawal in anandamide-dosed FAAH knockout mice than in THC-dosed mice.","methodology":"Male FAAH knockout mice, which have impaired breakdown of anandamide, received subchronic dosing with either anandamide or THC at equi-active, maximally effective doses. Tolerance was quantified as rightward shifts in dose–effect curves for antinociception, catalepsy, and hypothermia. CB1 receptor function and density were assessed using agonist-stimulated [35S]GTPγS binding in brain and spinal cord and [3H]WIN55,212-2 binding in brain. Dependence was probed by precipitating withdrawal with the CB1 antagonist rimonabant after repeated dosing. Cross-tolerance experiments compared how prior exposure altered responses to each ligand. The abstract does not report sample size, dosing route, or exact dosing schedules.","limitations":"This is an animal study in a genetically modified model where FAAH is absent. That elevates anandamide and other FAAH substrates in ways that do not mirror typical physiology. Only males were studied. The abstract does not report sample sizes, dosing routes, or exact dosing intervals, which makes it hard to gauge effect sizes and reproducibility. Behavioral outcomes were limited to the classic rodent tetrad, which captures only a slice of cannabinoid effects. Withdrawal was defined by antagonist-precipitated signs, an operational model that may not map onto other dependence measures. Anandamide and THC differ in more than efficacy, including metabolism and signaling kinetics, which could contribute to the adaptation differences."},{"rthcId":"RTHC-00411","title":"Individual and additive effects of the CNR1 and FAAH genes on brain response to marijuana cues.","authors":"Filbey, Francesca M; Schacht, Joseph P; Myers, Ursula S; Chavez, Robert S; Hutchison, Kent E","year":2010,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 35(4), 967-75","doi":"10.1038/npp.2009.200","pmid":"20010552","tags":["genetics","addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Thirty-seven regular marijuana users who had been abstinent for 3 days underwent fMRI while exposed to marijuana cues. They were grouped by genotype on two gene variants previously linked to cannabis dependence.\n\nCarriers of the CNR1 rs2023239 G allele showed significantly greater activation in reward-related brain areas (orbitofrontal cortex, inferior frontal gyrus, anterior cingulate) when viewing marijuana cues.\n\nFAAH rs324420 C/C homozygotes showed greater activation in the orbitofrontal cortex, anterior cingulate, and nucleus accumbens compared to A-allele carriers.\n\nThe total number of risk alleles across both genes was positively correlated with neural response in the orbitofrontal cortex and nucleus accumbens, showing an additive genetic effect on brain reward activation.","whyItMatters":"This study identified a biological mechanism through which genetic variations in the cannabinoid system could increase vulnerability to cannabis dependence: enhanced brain reward responses to drug cues.","specificNumbers":"37 participants, 3 days abstinent. Two SNPs tested: CNR1 rs2023239 and FAAH rs324420. Both independently associated with greater reward-area activation. Additive effect of risk alleles on OFC and NAc response.","methodology":"Cross-sectional neurogenetics study. Thirty-seven 3-day-abstinent regular marijuana users were genotyped for CNR1 rs2023239 and FAAH rs324420 SNPs. fMRI was collected during a cue-elicited craving paradigm. Between-group comparisons and correlation analyses examined genetic effects on brain activation.","limitations":"Small sample for a genetics study (37 participants). Cross-sectional design. Only two SNPs examined from a complex polygenic trait. No non-using control group. Three days of abstinence may not eliminate all acute withdrawal effects."},{"rthcId":"RTHC-00412","title":"Lack of positive allosteric modulation of mutated alpha(1)S267I glycine receptors by cannabinoids.","authors":"Foadi, Nilufar; Leuwer, Martin; Demir, Reyhan; Dengler, Reinhard; Buchholz, Vanessa; de la Roche, Jeanne; Karst, Matthias; Haeseler, Gertrud; Ahrens, Jörg","year":2010,"journal":"Naunyn-Schmiedeberg's archives of pharmacology, 381(5), 477-82","doi":"10.1007/s00210-010-0506-9","pmid":"20339834","tags":["pain","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Loss of inhibitory glycine signaling in the spinal cord plays a key role in chronic pain. Recent research suggested that cannabinoids might relieve pain partly by modulating glycine receptors, independent of cannabinoid receptors.\n\nResearchers tested three non-psychotropic cannabinoids (ajulemic acid, CBD, and HU210) on glycine receptors with a specific mutation: serine to isoleucine at position 267 in the transmembrane domain.\n\nThis single amino acid change completely abolished the ability of all three cannabinoids to co-activate or directly activate glycine receptors.\n\nThis demonstrated that position 267 in the TM2 domain is crucial for cannabinoid-glycine receptor interactions, providing insight into the molecular basis of cannabinoid pain relief through non-CB1/CB2 mechanisms.","whyItMatters":"Understanding how cannabinoids relieve pain through non-cannabinoid receptor mechanisms (like glycine receptors) could lead to pain medications that work through the cannabinoid-glycine interaction without producing psychoactive effects.","specificNumbers":"One amino acid mutation (S267I) abolished all cannabinoid-glycine receptor interactions. Three cannabinoids tested: ajulemic acid, CBD, HU210. All effects eliminated by the mutation.","methodology":"In vitro electrophysiology study. Mutated alpha1(S267I) glycine receptors were expressed in HEK293 cells and studied using whole-cell patch clamp technique. Three cannabinoids (ajulemic acid, cannabidiol, HU210) were tested for their ability to modulate glycine receptor currents.","limitations":"In vitro study using recombinant receptors in cell lines, not native neurons. The mutation may affect receptor function in ways beyond cannabinoid interactions. Whether this mechanism contributes significantly to pain relief in living organisms was not tested."},{"rthcId":"RTHC-00413","title":"Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol.","authors":"Fusar-Poli, Paolo; Allen, Paul; Bhattacharyya, Sagnik; Crippa, José A; Mechelli, Andrea; Borgwardt, Stefan; Martin-Santos, Rocio; Seal, Marc L; O'Carrol, Colin; Atakan, Zerrin; Zuardi, Antonio W; McGuire, Philip","year":2010,"journal":"The international journal of neuropsychopharmacology, 13(4), 421-32","doi":"10.1017/S1461145709990617","pmid":"19775500","tags":["anxiety","cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Fifteen healthy men received CBD (600 mg), THC (10 mg), or placebo before viewing fearful faces during fMRI. Advanced computational modeling (dynamic causal modeling) was used to examine how brain regions influence each other during emotional processing.\n\nUnder placebo, the best-fitting brain model showed the anterior cingulate cortex driving responses, with forward connectivity from the amygdala to the anterior cingulate.\n\nCBD specifically disrupted this forward connectivity between the amygdala and anterior cingulate during processing of intensely fearful faces. This was the first study to show CBD affects the functional connections between fear-processing brain regions rather than simply changing activation levels.\n\nTHC did not disrupt this specific connectivity pattern.","whyItMatters":"This study moved beyond simply showing where CBD acts in the brain to showing how it changes the communication between brain regions during anxiety-related processing, providing a more sophisticated neural mechanism for CBD anxiolytic effects.","specificNumbers":"15 participants. CBD: 600 mg. THC: 10 mg. CBD disrupted amygdala-to-anterior cingulate forward connectivity during fearful face processing. THC had no effect on this specific connection.","methodology":"Double-blind, randomized, placebo-controlled crossover fMRI study. Fifteen healthy men received CBD (600 mg), THC (10 mg), or placebo on separate occasions. Dynamic causal modeling (DCM) and Bayesian model selection analyzed effective connectivity between the amygdala and anterior cingulate cortex during fear face processing.","limitations":"Very small sample (15 men). Only healthy volunteers with minimal cannabis experience. Single acute dose. Dynamic causal modeling makes assumptions about the brain model that may not be fully accurate."},{"rthcId":"RTHC-00414","title":"Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.","authors":"Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo","year":2010,"journal":"Recent patents on CNS drug discovery, 5(1), 46-52","doi":null,"pmid":"19832688","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered the pharmacology, therapeutic uses, and toxicology of cannabis-derived medications.\n\nExisting clinical applications included Sativex (THC/CBD extract) for MS symptoms, nabilone and dronabinol for chemotherapy-induced nausea, and dronabinol for appetite stimulation. THC extracts had also been used for glaucoma.\n\nHowever, the severe side effects and high abuse liability of THC-based agents represented serious limitations. Diversion for recreational use was also a concern.\n\nThe review highlighted emerging alternatives: synthetic cannabinoid receptor agonists and agents that activate the endocannabinoid system indirectly (FAAH and MAGL inhibitors), which were being developed with the hope of providing therapeutic effects with better safety profiles.","whyItMatters":"This review captured the tension between the therapeutic potential and practical limitations of cannabis-based medicines, and the search for safer alternatives that maintain efficacy.","specificNumbers":"Clinical cannabinoid medicines reviewed: Sativex, nabilone, dronabinol. Key concern areas: side effects, abuse liability, diversion risk.","methodology":"Narrative review of recent studies and patents focused on cannabinoid system agonists for CNS disorders.","limitations":"Narrative review without systematic methodology. Focus on agonists may have underrepresented other approaches. Some therapeutic claims were based on limited clinical evidence."},{"rthcId":"RTHC-00415","title":"Can the prevalence of high blood drug concentrations in a population be estimated by analysing oral fluid? A study of tetrahydrocannabinol and amphetamine.","authors":"Gjerde, Hallvard; Verstraete, Alain","year":2010,"journal":"Forensic science international, 195(1-3), 153-9","doi":"10.1016/j.forsciint.2009.12.011","pmid":"20045272","tags":["driving"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers compared five methods for estimating how many people in a population have high blood THC concentrations based on oral fluid (saliva) testing.\n\nThe methods ranged from simple calculations (dividing saliva concentration by an average ratio) to complex Monte Carlo simulations.\n\nDividing by the oral fluid/blood regression coefficient gave the best balance of accuracy and precision, making it the recommended method.\n\nMonte Carlo simulations could give better accuracy but required good data on the distribution of oral fluid/blood ratios, which is not always available.\n\nNone of the methods worked well when fewer than 15% of the population had high blood drug concentrations.","whyItMatters":"Roadside saliva testing for drugged driving is more practical than blood testing. If saliva THC levels can reliably estimate blood levels, it could improve drug-impaired driving enforcement.","specificNumbers":"311 cannabis users and 197 amphetamine users. Five estimation methods compared. Best method: dividing by regression coefficient. Accuracy acceptable only when 15%+ of population had high blood levels.","methodology":"Methodological study comparing five estimation methods using data from 311 cannabis users and 197 amphetamine users from the Rosita-2 Project. Methods included simple ratio calculations and Monte Carlo simulations.","limitations":"The relationship between oral fluid and blood THC concentrations is highly variable between individuals. No single method was highly accurate. The 15% prevalence threshold limits applicability in low-use populations."},{"rthcId":"RTHC-00416","title":"Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists.","authors":"Greineisen, William E; Turner, Helen","year":2010,"journal":"International immunopharmacology, 10(5), 547-55","doi":"10.1016/j.intimp.2010.02.012","pmid":"20219697","tags":["inflammation","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the immunological effects of cannabinoids in the context of their clinical applications.\n\nBoth endogenous and exogenous cannabinoids were shown to be \"potently immunoactive.\" The review argued that these immune effects are not incidental side effects but are highly relevant to the conditions for which cannabinoid therapeutics are prescribed.\n\nFor cannabinoid receptor agonists (used for pain, nausea, appetite, spasticity), immunosuppressive effects could be beneficial in inflammatory conditions but harmful in infections or cancer.\n\nFor CB1 receptor antagonists (developed for obesity), immune activation could either help or harm depending on the patient's immune status.\n\nThe central argument was that immunological effects should be considered with each prescribing decision, not treated as secondary concerns.","whyItMatters":"As cannabinoid medicines become more widely prescribed, understanding their immune effects is essential. Immunosuppression could worsen outcomes in patients with infections or cancer, while it might benefit those with autoimmune conditions.","specificNumbers":"Both CB1 and CB2 receptor signaling have documented immunological effects. Agonists tend to be immunosuppressive. Antagonists can have immune-activating effects.","methodology":"Narrative review synthesizing evidence on immunological effects of cannabinoid receptor agonists and antagonists, organized by therapeutic application.","limitations":"Narrative review without systematic methodology. Much of the immunological evidence was preclinical. The clinical significance of cannabinoid immune effects in typical prescribing scenarios was not always clear."},{"rthcId":"RTHC-00417","title":"Involvement of 2-arachidonoyl glycerol in the increased consumption of and preference for ethanol of mice treated with neurotoxic doses of methamphetamine.","authors":"Gutierrez-Lopez, M D; Llopis, N; Feng, S; Barrett, D A; O'Shea, E; Colado, M I","year":2010,"journal":"British journal of pharmacology, 160(3), 772-83","doi":"10.1111/j.1476-5381.2010.00720.x","pmid":"20590579","tags":["drug-interactions","neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice exposed to a neurotoxic methamphetamine regimen showed increased alcohol consumption and preference seven days later.\n\nBiochemical analysis of the limbic forebrain revealed that while CB1 receptor density and activity were unchanged, 2-AG (endocannabinoid) levels were significantly elevated. This increase was associated with reduced MAGL (the enzyme that breaks down 2-AG) activity.\n\nAs expected, dopamine levels and dopamine transporter density were decreased (reflecting meth neurotoxicity).\n\nThe CB1 receptor antagonist AM251 prevented the meth-induced increase in alcohol consumption. Conversely, a MAGL inhibitor (which raises 2-AG) increased alcohol consumption in both meth-treated and control mice.\n\nThis suggested that increased endocannabinoid tone following meth neurotoxicity drives increased alcohol seeking.","whyItMatters":"This study identified an endocannabinoid mechanism linking methamphetamine neurotoxicity to increased alcohol consumption, suggesting that meth use could change brain chemistry in ways that promote polysubstance use.","specificNumbers":"Meth: 4 mg/kg x 4 doses. 7 days later: increased 2-AG, decreased MAGL activity, decreased dopamine, decreased dopamine transporters. CB1 receptor density/activity unchanged. AM251 blocked increased drinking. MAGL inhibitor increased drinking.","methodology":"Mice received neurotoxic methamphetamine (4 mg/kg x 4, 2 hours apart) and were tested for alcohol consumption 7 days later with increasing ethanol concentrations (3-20%). Limbic forebrain was analyzed for CB1 density/activity, 2-AG levels, MAGL activity, dopamine levels, and dopamine transporter density. CB1 antagonist and MAGL inhibitor were tested for effects on drinking.","limitations":"Animal model using a specific neurotoxic meth protocol. Human meth use patterns differ. The 7-day timepoint may not reflect longer-term changes. Alcohol preference in mice may not directly model human alcohol-seeking behavior."},{"rthcId":"RTHC-00418","title":"Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence.","authors":"Hanson, Karen L; Winward, Jennifer L; Schweinsburg, Alecia D; Medina, Krista Lisdahl; Brown, Sandra A; Tapert, Susan F","year":2010,"journal":"Addictive behaviors, 35(11), 970-6","doi":"10.1016/j.addbeh.2010.06.012","pmid":"20621421","tags":["cognition","youth","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Nineteen adolescent marijuana users (ages 15-19) and 21 non-using controls were tested at three time points: after 3 days, 2 weeks, and 3 weeks of confirmed abstinence.\n\nMarijuana users performed significantly worse on verbal learning (p<0.01), verbal working memory (p<0.05), and attention accuracy (p<0.01) compared to controls.\n\nVerbal learning improved after 2 weeks of abstinence, and working memory improved after 3 weeks, suggesting these deficits can recover.\n\nHowever, attention accuracy remained impaired throughout the entire 3-week abstinence period, suggesting more persistent effects on prefrontal cortex function.\n\nAbstinence was verified through decreasing THC metabolite levels on serial urine drug screens.","whyItMatters":"This study provided the first longitudinal evidence of cognitive recovery patterns in adolescent marijuana users, showing that some deficits resolve relatively quickly while others persist, information critical for teens considering quitting.","specificNumbers":"19 users, 21 controls, ages 15-19. Verbal learning improved by week 2. Working memory improved by week 3. Attention accuracy remained impaired through week 3.","methodology":"Longitudinal study of 19 adolescent marijuana users and 21 controls. Participants completed neuropsychological testing at 3 days, 2 weeks, and 3 weeks of abstinence. Abstinence verified by serial urine drug screens showing decreasing THC metabolite levels.","limitations":"Small sample (19 users). Three weeks may not be enough time for full recovery. Practice effects from repeated testing could mask or enhance recovery patterns. Participants had limited alcohol and other drug use but these could still confound results."},{"rthcId":"RTHC-00419","title":"Cannabis and hyperemesis.","authors":"Harris, Ella; McDonagh, Michael; Kennedy, Noel","year":2010,"journal":"Irish journal of psychological medicine, 27(1), 47-48","doi":"10.1017/S0790966700000938","pmid":"30282296","tags":["medical-cannabis","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report described cannabinoid hyperemesis syndrome (CHS) in a psychiatric patient, noting that while the syndrome had been documented since 2004, it had never been reported in psychiatric settings.\n\nThe clinical presentation included cyclical vomiting associated with chronic cannabis use and compulsive bathing behavior, consistent with the CHS profile identified in earlier reports.\n\nThe authors noted that despite cannabis's established anti-emetic properties, chronic use can paradoxically cause cyclical vomiting, and this condition may be underrecognized, particularly in psychiatric populations where cannabis use is common.","whyItMatters":"Cannabis use is highly prevalent among psychiatric patients. If CHS is underrecognized in this population, patients may undergo unnecessary investigations and treatments for their vomiting before the correct diagnosis is made.","specificNumbers":"First reported case of CHS in a psychiatric patient. CHS was originally described by Allen et al. in 2004.","methodology":"Single case report documenting clinical presentation of cannabinoid hyperemesis syndrome in a psychiatric patient.","limitations":"Single case report. Cannot establish prevalence of CHS in psychiatric populations. Limited clinical details provided in the brief report."},{"rthcId":"RTHC-00420","title":"Correlates of smoking cessation at pregnancy onset among Hispanic women in Massachusetts.","authors":"Haskins, Amy; Bertone-Johnson, Elizabeth; Pekow, Penelope; Carbone, Elena; Chasan-Taber, Lisa","year":2010,"journal":"American journal of health promotion : AJHP, 25(2), 100-8","doi":"10.4278/ajhp.090223-QUAN-77","pmid":"21039290","tags":["pregnancy"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined factors associated with quitting smoking at pregnancy onset in 351 Hispanic (predominantly Puerto Rican) women from Massachusetts.\n\n45% of women quit smoking when they learned they were pregnant.\n\nWomen who used marijuana before pregnancy were significantly less likely to quit smoking (23-49% less likely in multivariate analyses). Other factors associated with continued smoking included high stress, higher pre-pregnancy cigarette consumption (20+ per day), and having previous children.\n\nFactors associated with quitting included being born outside the United States, having a family history of diabetes, and being non-Puerto Rican Hispanic.","whyItMatters":"Smoking during pregnancy is a major preventable risk factor. Understanding why some women do not quit when they become pregnant can help design targeted interventions, particularly for populations where marijuana co-use is a barrier.","specificNumbers":"351 Hispanic women. 45% quit at pregnancy onset. Marijuana users were 23-49% less likely to quit. Heavy smokers (20+ cigarettes/day) had RR 0.44 for quitting vs light smokers.","methodology":"Cross-sectional analysis of baseline data from a prospective cohort study (Latina Gestational Diabetes Mellitus Study). 351 Hispanic prenatal care patients who smoked in the year before pregnancy were analyzed. Logistic regression with backward elimination identified independent predictors of quitting.","limitations":"Cross-sectional design at enrollment. Self-reported smoking and marijuana use. Predominantly Puerto Rican sample may not generalize to other populations. Marijuana use was measured as any use, without quantifying amount or frequency."},{"rthcId":"RTHC-00421","title":"Enhancement drugs: are there limits to what we should enhance and why?","authors":"Hesse, Morten","year":2010,"journal":"BMC medicine, 8, 50","doi":"10.1186/1741-7015-8-50","pmid":"20682058","tags":["harm-reduction","potency","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This commentary made two specific harm-reduction proposals:\n\nFor alcohol: adding dissolved oxygen could reduce accident risk and liver damage.\n\nFor cannabis: strong evidence indicated that reducing THC content and increasing CBD content could reduce the risk of psychosis and addiction associated with cannabis use.\n\nThe author argued that public health interventions should focus on reducing concrete harms rather than making moral judgments about which human experiences should or should not be enhanced through substance use.\n\nThe central proposition was that responsible regulation should not be limited to preventing or reducing use, but should include strategies to reduce the burden of illness associated with substance use.","whyItMatters":"This commentary articulated a regulatory philosophy that has gained traction: rather than debating whether people should use cannabis, focus on making the available products less harmful through compositional standards.","specificNumbers":"Two substances discussed: alcohol (dissolved oxygen proposal) and cannabis (THC reduction, CBD increase). Evidence cited for CBD reducing psychosis and addiction risk.","methodology":"Commentary/editorial presenting evidence-based harm reduction proposals for alcohol and cannabis, arguing for regulatory approaches focused on specific harm reduction.","limitations":"Commentary piece rather than original research. The practical feasibility of regulating cannabis composition was not fully addressed. The dissolved oxygen/alcohol proposal had limited evidence."},{"rthcId":"RTHC-00422","title":"Anxiety-like effects of SR141716-precipitated delta9-tetrahydrocannabinol withdrawal in mice in the elevated plus-maze.","authors":"Huang, Peng; Liu-Chen, Lee-Yuan; Kirby, Lynn G","year":2010,"journal":"Neuroscience letters, 475(3), 165-8","doi":"10.1016/j.neulet.2010.03.071","pmid":"20363293","tags":["withdrawal","anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Male mice received THC (10 mg/kg) daily for 10 days. Four hours after the last dose, the CB1 antagonist SR141716 was administered to precipitate withdrawal, and mice were tested on the elevated plus-maze 30 minutes later.\n\nIn vehicle-treated mice, SR141716 had no significant effect on behavior.\n\nIn THC-treated mice, SR141716 produced a significant reduction in open arm exploration, a well-validated measure of anxiety-like behavior. At the highest dose (3.0 mg/kg), SR141716 significantly reduced percentage of open arm entries, percentage of open arm time, and absolute time in open arms.\n\nClosed arm entries and total arm entries were not affected, confirming that the reduced open arm exploration reflected anxiety rather than altered motor activity.\n\nThis was the first evidence that cannabinoid withdrawal produces anxiety-like effects in mice.","whyItMatters":"Anxiety is one of the most commonly reported symptoms of cannabis withdrawal in humans. Having an animal model of withdrawal-induced anxiety allows researchers to investigate the neural mechanisms and test potential treatments.","specificNumbers":"THC: 10 mg/kg daily x 10 days. SR141716: 0.3, 1.0, 3.0 mg/kg. At 3.0 mg/kg: significant reduction in % open arm entries, % open arm time, and absolute open arm time. No changes in closed or total arm entries (no motor effect).","methodology":"Male ICR mice received daily THC (10 mg/kg) or vehicle for 10 days. SR141716 (0.3, 1.0, or 3.0 mg/kg) precipitated withdrawal 4 hours after the last dose. The elevated plus-maze was administered 30 minutes post-SR141716 for 5 minutes.","limitations":"Precipitated rather than spontaneous withdrawal. Single mouse strain and sex (male ICR mice). The elevated plus-maze measures a specific aspect of anxiety that may not fully represent the human experience. SR141716 doses may be clinically irrelevant."},{"rthcId":"RTHC-00423","title":"Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain.","authors":"Johnson, Jeremy R; Burnell-Nugent, Mary; Lossignol, Dominique; Ganae-Motan, Elena Doina; Potts, Richard; Fallon, Marie T","year":2010,"journal":"Journal of pain and symptom management, 39(2), 167-79","doi":"10.1016/j.jpainsymman.2009.06.008","pmid":"19896326","tags":["pain","medical-cannabis","cancer","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"One hundred seventy-seven cancer patients whose pain was inadequately controlled by opioids were randomized to THC/CBD extract spray (60 patients), THC-only extract spray (58 patients), or placebo (59 patients) for two weeks.\n\nThe THC/CBD group showed statistically significant pain improvement compared to placebo (mean change -1.37 vs -0.69 on a numerical rating scale). The THC-only group showed improvement (-1.01 vs -0.69) but did not reach significance.\n\nTwice as many THC/CBD patients achieved clinically meaningful pain reduction (30% or more): 43% versus 21% on placebo. The THC-only group response rate (23%) was similar to placebo.\n\nOpioid background medication doses did not change across groups, confirming the cannabinoid effect was additive rather than opioid-replacing.\n\nOne negative finding: THC/CBD worsened nausea and vomiting scores compared to placebo (p=0.02).","whyItMatters":"This was one of the strongest clinical trials supporting cannabinoids as adjunctive pain therapy in cancer patients already on opioids. The finding that THC/CBD was effective but THC alone was not highlighted the importance of CBD in the formulation.","specificNumbers":"177 patients. THC/CBD pain reduction: -1.37 vs placebo -0.69 (significant). THC alone: -1.01 (not significant). 30% responders: THC/CBD 43% vs placebo 21% (significant). THC alone 23% (not significant). Nausea worsened with THC/CBD (p=0.02).","methodology":"Multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. 177 patients with advanced cancer pain inadequately controlled by chronic opioids. Two-week treatment with THC/CBD extract, THC extract, or placebo spray. Primary outcome: change in mean pain NRS score.","limitations":"Two-week trial may not reflect long-term outcomes. The THC-only group's failure to reach significance raises questions about why CBD was necessary. Nausea worsening with THC/CBD is a significant concern. Open-label extension data were not reported in this paper."},{"rthcId":"RTHC-00424","title":"ST segment elevation myocardial infarction due to slow coronary flow occurring after cannabis consumption.","authors":"Karabulut, Ahmet; Cakmak, Mahmut","year":2010,"journal":"Kardiologia polska, 68(11), 1266-8","doi":null,"pmid":"21108208","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient who had consumed cannabis regularly over a long period presented with an inferior myocardial infarction (heart attack) showing ST segment elevation on ECG.\n\nCoronary angiography revealed slow coronary flow (SCF), defined as slow movement of contrast dye through the coronary arteries in the absence of significant arterial blockages.\n\nThe patient lacked the common cardiovascular risk factors typically associated with heart attacks, suggesting cannabis use may have contributed to the coronary event.\n\nThe authors noted that recent research had linked cannabis consumption to increased coronary heart disease risk and acute coronary syndromes, particularly in young individuals without standard risk factors.","whyItMatters":"While cannabis is generally not associated with coronary artery disease, this case adds to a small but growing number of reports linking cannabis use to acute cardiac events, potentially through mechanisms like vasospasm or slow coronary flow.","specificNumbers":"One patient. Regular long-term cannabis use. Inferior MI with ST elevation. Slow coronary flow on angiography. No significant coronary artery stenosis.","methodology":"Single case report documenting ST-elevation myocardial infarction with slow coronary flow on angiography in a chronic cannabis user.","limitations":"Single case report cannot establish causation. Other contributing factors may not have been fully evaluated. Slow coronary flow has multiple causes beyond cannabis. The temporal relationship between cannabis use and the cardiac event was not specified."},{"rthcId":"RTHC-00425","title":"Nicotine: alcohol reward interactions.","authors":"Lajtha, A; Sershen, H","year":2010,"journal":"Neurochemical research, 35(8), 1248-58","doi":"10.1007/s11064-010-0181-8","pmid":"20499168","tags":["addiction","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the neurochemical interactions between nicotine and alcohol, two substances whose use frequently co-occurs.\n\nChronic nicotine altered multiple brain systems: nicotinic receptors (subunit composition changes), catecholamine, glutamate, GABA levels, and opiate and cannabinoid receptors. Similarly, chronic alcohol affected many of the same systems.\n\nKey interactions included:\n- The two substances reduced each other's negative withdrawal symptoms, which may reinforce combined use\n- Some brain changes from combined use were additive, while others were opposing\n- Effects were sex- and age-dependent, with adolescents generally more sensitive\n- Endocannabinoid content was among the systems affected by both substances\n\nThe authors noted that the mechanisms by which one drug increases preference for another are complex, multi-component, and likely differ depending on the direction of the interaction.","whyItMatters":"Smoking and drinking co-occur at very high rates. Understanding the neurochemical basis for this co-use could lead to treatments that address both substances simultaneously rather than treating them separately.","specificNumbers":"Brain systems affected: nicotinic receptors, catecholamines, glutamate, GABA, opioid peptides, cannabinoid receptors, endocannabinoid content. Effects were sex- and age-dependent.","methodology":"Narrative review examining neurochemical changes induced by chronic nicotine and alcohol, focusing on mechanisms of cross-drug preference enhancement.","limitations":"Narrative review without systematic methodology. Many findings were from animal studies that may not translate to human experience. The complexity of multi-system interactions makes specific conclusions difficult."},{"rthcId":"RTHC-00426","title":"Suicidal ideation among young French adults: association with occupation, family, sexual activity, personal background and drug use.","authors":"Legleye, S; Beck, F; Peretti-Watel, P; Chau, N; Firdion, J M","year":2010,"journal":"Journal of affective disorders, 123(1-3), 108-15","doi":"10.1016/j.jad.2009.10.016","pmid":"19892406","tags":["mental-health","depression","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 4,075 French adults aged 18-30 about suicidal ideation, substance use, and psychosocial factors.\n\nSuicidal ideation in the previous year affected 5.7% of men and 4.9% of women.\n\nDepression was the strongest predictor for both sexes (adjusted OR approximately 8). Among men, other significant predictors included homosexual intercourse (OR 3.37), absence of sexual activity (OR 2.83), living alone, daily tobacco smoking, unemployment, and parental relationship quality.\n\nAmong women, forced sexual intercourse (OR 5.37) and illicit drug use other than cannabis (OR 4.01) were significant predictors.\n\nNotably, cannabis use in the previous month was not independently associated with suicidal ideation in the adjusted models for either sex. Other illicit drugs (not cannabis) were significant for women only.","whyItMatters":"This large population-based study found that cannabis was not independently associated with suicidal ideation after accounting for depression and other psychosocial factors, consistent with the Swedish longitudinal study (RTHC-00381) finding that confounding explains the cannabis-suicide association.","specificNumbers":"4,075 adults, ages 18-30. Suicidal ideation: 5.7% men, 4.9% women. Depression OR: ~8 (both sexes). Cannabis: not significant in adjusted models. Non-cannabis illicit drugs: OR 4.01 for women.","methodology":"Cross-sectional analysis of 4,075 French adults aged 18-30 from a random national telephone survey in 2005. Depression assessed with CIDI-SF. Alcohol abuse assessed with AUDIT-C. Logistic regression with comprehensive adjustment for sociodemographic, health, and behavioral factors.","limitations":"Cross-sectional design. Self-reported data via telephone survey. Cannabis use measured only in the previous month. French cultural context may limit generalizability. Telephone survey may miss marginalized populations."},{"rthcId":"RTHC-00427","title":"The effects of cannabis and alcohol on simulated arterial driving: Influences of driving experience and task demand.","authors":"Lenné, Michael G; Dietze, Paul M; Triggs, Thomas J; Walmsley, Susan; Murphy, Brendan; Redman, Jennifer R","year":2010,"journal":"Accident; analysis and prevention, 42(3), 859-66","doi":"10.1016/j.aap.2009.04.021","pmid":"20380913","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-five experienced and 22 inexperienced drivers completed nine simulated driving conditions combining three cannabis doses (placebo, low, high) with three alcohol doses (placebo, low, high).\n\nHigh cannabis doses caused decreased mean speed, increased speed and lateral position variability, increased headways, and longer reaction times. Cannabis impairment was greater at higher doses.\n\nAlcohol at the tested doses (approximately 0.4 and 0.6 g/kg) had relatively few effects and was associated with a slight increase in speed (opposite to cannabis, which decreased speed).\n\nSurprisingly, combining cannabis and alcohol did not produce synergistic effects beyond what each drug produced alone. Both substances increased speed and lateral position variability.\n\nThe driving environment included varied workload conditions and a secondary task to test demand effects.","whyItMatters":"This study directly compared cannabis and alcohol effects on driving in the same participants, providing a within-subject comparison. The finding that cannabis slowed drivers while alcohol slightly sped them up illustrates fundamentally different impairment profiles.","specificNumbers":"25 experienced, 22 inexperienced drivers. 9 conditions. Cannabis: 19 mg THC cigarettes. Alcohol: 0, 0.4, 0.6 g/kg. High cannabis: decreased speed, increased variability, longer reaction time. Low-moderate alcohol: few effects.","methodology":"Counterbalanced nine-condition study (3 cannabis x 3 alcohol doses) in 25 experienced and 22 inexperienced drivers using a driving simulator with arterial road environment. Cannabis: pre-rolled cigarettes with 19 mg THC. Alcohol: approximately 0, 0.4, 0.6 g/kg.","limitations":"Driving simulator does not fully represent real-world driving. Alcohol doses were relatively low (0.4-0.6 g/kg) and may not have reached impairment-producing levels. Cannabis was a single high dose (19 mg). The absence of synergy at these doses does not rule out synergy at higher doses."},{"rthcId":"RTHC-00428","title":"Substitution profile of the cannabinoid agonist nabilone in human subjects discriminating δ9-tetrahydrocannabinol.","authors":"Lile, Joshua A; Kelly, Thomas H; Hays, Lon R","year":2010,"journal":"Clinical neuropharmacology, 33(5), 235-42","doi":"10.1097/WNF.0b013e3181e77428","pmid":"20838217","tags":["addiction","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Six cannabis users learned to identify 25 mg oral THC under double-blind conditions. They were then tested with multiple doses of nabilone (a synthetic cannabinoid prescription drug), THC, and methylphenidate.\n\nNabilone shared discriminative-stimulus effects with THC: participants identified it as feeling like their training dose. It also produced comparable subjective effects and increased heart rate.\n\nMethylphenidate (a dopamine stimulant) did not produce THC-like effects, serving as a negative control.\n\nThe authors noted that since agonist replacement therapy has been relatively successful for opioid (methadone), tobacco (nicotine replacement), and stimulant dependence, nabilone could potentially serve as a similar replacement therapy for cannabis use disorders.","whyItMatters":"No FDA-approved medication exists for cannabis dependence. If nabilone feels like THC to users, it could serve as a controlled substitute during treatment, similar to how methadone is used for opioid dependence.","specificNumbers":"6 participants. Nabilone: 1, 2, 3, 5 mg tested. THC: 5, 10, 15, 25 mg. Methylphenidate: 5, 10, 20, 30 mg. Nabilone substituted for THC. Methylphenidate did not.","methodology":"Double-blind drug discrimination study. Six cannabis users learned to discriminate 25 mg oral THC from placebo. Multiple doses of nabilone (1-5 mg), THC (5-25 mg), and methylphenidate (5-30 mg) were tested for THC substitution, subjective effects, and physiological measures.","limitations":"Very small sample (6 participants). Drug discrimination measures subjective similarity, not treatment efficacy. Whether nabilone actually reduces cannabis use has not been tested in this study. The analogy to methadone may not hold for cannabis dependence."},{"rthcId":"RTHC-00429","title":"Cannabis-derived substances in cancer therapy--an emerging anti-inflammatory role for the cannabinoids.","authors":"Liu, Wai M; Fowler, Daniel W; Dalgleish, Angus G","year":2010,"journal":"Current clinical pharmacology, 5(4), 281-7","doi":null,"pmid":"20925645","tags":["cancer","inflammation","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"While previous cannabinoid-cancer research focused primarily on direct anti-tumor effects (inducing cancer cell death through disrupting signaling pathways like ERK and PI3-K), this review highlighted a newer perspective: cannabinoids as anti-inflammatory agents in cancer.\n\nChronic inflammation has long been associated with cancer development and progression. The review argued that reducing inflammation could be a mechanism through which cannabinoids impact cancer, distinct from direct cell-killing effects.\n\nThe review also noted established clinical uses of cannabinoids in cancer care as anti-emetics and appetite stimulants for cachexia.\n\nThe anti-inflammatory approach was described as emerging, with the relationship between chronic inflammation and cancer providing a new therapeutic rationale for cannabinoid use in oncology.","whyItMatters":"Recognizing anti-inflammatory effects as a separate mechanism for cannabinoid anti-cancer activity opens new therapeutic avenues and could explain benefits that direct tumor-killing mechanisms alone cannot account for.","specificNumbers":"Key signaling pathways disrupted by cannabinoids: ERK, PI3-K. Established clinical uses: anti-emetic, appetite stimulation. Emerging application: anti-inflammatory role in cancer.","methodology":"Narrative review examining the evolving relationship between cannabinoids and cancer, with particular focus on anti-inflammatory mechanisms alongside established pro-apoptotic and anti-proliferative effects.","limitations":"The anti-inflammatory anti-cancer mechanism was described as emerging, with limited direct clinical evidence. Anti-inflammatory effects observed in preclinical settings may not translate to clinical cancer outcomes. Immunosuppressive effects could theoretically promote some cancers."},{"rthcId":"RTHC-00430","title":"Cannabis and psychiatric disorders.","authors":"Loga, Slobodan; Loga-Zec, Svjetlana; Spremo, Mira","year":2010,"journal":"Psychiatria Danubina, 22(2), 296-7","doi":null,"pmid":"20562767","tags":["psychosis","depression","youth","mental-health"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The authors identified associations between cannabis use and multiple psychiatric outcomes in young people. These included what the literature describes as \"cannabis psychosis,\" depression, panic attacks, and suicidal ideation.\n\nThe review noted that negative effects could stem from specific pharmacological actions of cannabis or from stressful experiences during intoxication. The authors highlighted what they called a \"very dangerous\" frequency of suicidal ideation among cannabis users.","whyItMatters":"The review provided a concise summary of psychiatric concerns linked to cannabis use in young people, drawing attention to suicide risk as an area of clinical concern.","specificNumbers":"The review was a brief commentary-style piece and did not report specific numerical findings or effect sizes.","methodology":"This was a brief narrative review published in Psychiatria Danubina examining existing literature on cannabis and psychiatric disorders, with a focus on adolescent populations.","limitations":"The piece was extremely brief (two pages) and did not include systematic search methodology, inclusion criteria, or detailed analysis of the studies cited. The strength of associations and potential confounding factors were not discussed."},{"rthcId":"RTHC-00431","title":"Learning and memory performances in adolescent users of alcohol and marijuana: interactive effects.","authors":"Mahmood, Omar M; Jacobus, Joanna; Bava, Sunita; Scarlett, Anthony; Tapert, Susan F","year":2010,"journal":"Journal of studies on alcohol and drugs, 71(6), 885-94","doi":null,"pmid":"20946746","tags":["cognition","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers tested memory and learning in 130 adolescents aged 15 to 19. Among those who did not use marijuana, greater alcohol hangover and withdrawal symptoms predicted significantly worse verbal learning and verbal memory scores.\n\nSurprisingly, among heavy marijuana users with similar levels of alcohol involvement, this relationship was not observed. Alcohol hangover symptoms did not predict poor verbal memory in the marijuana-using group.\n\nVisual memory was not affected by alcohol hangover symptoms in either group.","whyItMatters":"The finding that marijuana use appeared to buffer against alcohol-related verbal memory deficits was unexpected and raised questions about potential neuroprotective properties of cannabinoids, though the cross-sectional design limited causal conclusions.","specificNumbers":"The study included 130 adolescents (ages 15.7 to 19.1). Greater alcohol hangover symptoms predicted worse verbal learning (p < .05) and memory (p < .05) in non-marijuana users but not in marijuana users.","methodology":"This cross-sectional study included 130 adolescents: 65 with histories of heavy marijuana use and 65 non-marijuana-using controls. Participants completed neuropsychological tests (California Verbal Learning Test, Second Edition) and interviews about substance use, hangover/withdrawal symptoms, and diagnostic criteria. Regression models tested whether alcohol hangover symptoms predicted memory performance, moderated by marijuana use status.","limitations":"The cross-sectional design could not determine causation. The apparent \"buffering\" effect could reflect other differences between groups rather than a true neuroprotective mechanism. Selection bias may have influenced which teens used both substances versus alcohol alone."},{"rthcId":"RTHC-00432","title":"Endogenous cannabinoid and opioid systems and their role in nicotine addiction.","authors":"Maldonado, Rafael; Berrendero, Fernando","year":2010,"journal":"Current drug targets, 11(4), 440-9","doi":null,"pmid":"20017727","tags":["addiction","neuroscience","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review detailed how the endogenous cannabinoid and opioid systems interact with dopamine-driven reward pathways that underlie nicotine addiction. Both systems were found to play modulatory roles across multiple aspects of tobacco dependence.\n\nThe endocannabinoid system participated in nicotine's rewarding properties, the development of physical dependence, and relapse to nicotine-seeking behavior. Similarly, the opioid system contributed to nicotine reward processing.\n\nPreclinical evidence supported the use of cannabinoid or opioid receptor antagonists as potential treatments for nicotine addiction, and early clinical trials showed promise.","whyItMatters":"Understanding how multiple neurotransmitter systems contribute to nicotine addiction could open new treatment pathways beyond traditional nicotine replacement therapy.","specificNumbers":"The review synthesized findings across multiple preclinical and clinical studies but did not report pooled statistics.","methodology":"This was a narrative review published in Current Drug Targets synthesizing behavioral and biochemical data on the roles of endocannabinoid and opioid systems in nicotine addiction, including both preclinical animal studies and early clinical trial data.","limitations":"As a narrative review, the evidence was not systematically evaluated. The clinical trial data available at the time was limited, and the translation from animal models to human outcomes remained uncertain."},{"rthcId":"RTHC-00433","title":"Neuroimaging in cannabis use: a systematic review of the literature.","authors":"Martín-Santos, R; Fagundo, A B; Crippa, J A; Atakan, Z; Bhattacharyya, S; Allen, P; Fusar-Poli, P; Borgwardt, S; Seal, M; Busatto, G F; McGuire, P","year":2010,"journal":"Psychological medicine, 40(3), 383-98","doi":"10.1017/S0033291709990729","pmid":"19627647","tags":["neuroscience","cognition","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Researchers systematically reviewed 66 brain imaging studies, of which 41 met inclusion criteria. Among the 33 functional imaging studies, resting brain blood flow in the prefrontal cortex was consistently lower in cannabis users compared to non-users.\n\nWhen THC or marijuana was administered acutely, the pattern reversed: resting brain activity increased, and frontal and anterior cingulate cortex activation rose during cognitive tasks.\n\nAmong the 8 structural imaging studies, only 3 found any differences between cannabis users and controls. The overall conclusion was that cannabis primarily affected brain function rather than brain structure.","whyItMatters":"This comprehensive review provided an evidence snapshot showing that while cannabis use was associated with measurable changes in brain function, structural brain changes were minimal based on available imaging technology at the time.","specificNumbers":"66 studies identified, 41 met inclusion criteria. 33 functional imaging studies and 8 structural studies reviewed. Only 3 of 8 structural studies found differences between users and controls.","methodology":"Systematic review searching Medline, EMBASE, LILACS, and PsycLIT through January 2009. Identified 66 studies, of which 41 met inclusion criteria (33 functional studies using SPECT/PET/fMRI and 8 structural studies using volumetric MRI/DTI). Heterogeneity across studies precluded meta-analysis.","limitations":"High heterogeneity across studies prevented meta-analysis. Imaging technology available through 2009 may have been insufficient to detect subtle structural changes. Many studies had small sample sizes and varied methodologies."},{"rthcId":"RTHC-00434","title":"Reducing endocannabinoid metabolism with the fatty acid amide hydrolase inhibitor, URB597, fails to modify reinstatement of morphine-induced conditioned floor preference and naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance.","authors":"McCallum, Amanda L; Limebeer, Cheryl L; Parker, Linda A","year":2010,"journal":"Pharmacology, biochemistry, and behavior, 96(4), 496-500","doi":"10.1016/j.pbb.2010.07.010","pmid":"20643159","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether URB597, which increases endocannabinoid levels by blocking the enzyme FAAH, could prevent relapse to morphine-seeking behavior in rats. Two experiments were conducted.\n\nIn the first, rats developed a conditioned floor preference after morphine pairings. After extinction training, a morphine prime reinstated the preference, but URB597 pretreatment did not reduce the reinstated preference.\n\nIn the second experiment, rats developed conditioned avoidance of a floor associated with morphine withdrawal. After extinction, a withdrawal prime reinstated the avoidance, but again URB597 did not reduce the reinstatement.\n\nThe results suggested that while endocannabinoid activation promotes extinction of learned associations, it does not prevent relapse when triggered by drug re-exposure.","whyItMatters":"The findings distinguished between the role of endocannabinoids in extinction learning versus relapse prevention, an important distinction for potential addiction treatments.","specificNumbers":"Experiment 1 used 4 conditioning trials and showed morphine reinstated floor preference regardless of URB597. Experiment 2 used 2 conditioning trials and 14 extinction trials with the same result for withdrawal-induced avoidance.","methodology":"Two controlled animal experiments using male rats. Experiment 1: morphine-induced conditioned floor preference with 4 conditioning trials, extinction, then reinstatement with URB597 or vehicle pretreatment. Experiment 2: naloxone-precipitated withdrawal-induced conditioned floor avoidance with 2 conditioning trials, 14 extinction trials, then reinstatement testing.","limitations":"Animal model findings may not translate directly to human addiction. Only one dose of URB597 was tested. The floor preference paradigm captures only one aspect of addiction-related behavior."},{"rthcId":"RTHC-00435","title":"Pediatric cannabinoid hyperemesis: two cases.","authors":"Miller, Joseph B; Walsh, Mark; Patel, Pankaj A; Rogan, Michael; Arnold, Cliff; Maloney, Megan; Donnino, Michael","year":2010,"journal":"Pediatric emergency care, 26(12), 919-20","doi":"10.1097/PEC.0b013e3181fe9189","pmid":"21131803","tags":["youth","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Two adolescent patients presented with severe nausea and uncontrollable vomiting (hyperemesis) in the setting of chronic marijuana use. Both underwent extensive gastrointestinal workups that failed to identify any other cause.\n\nIn both cases, symptoms resolved when the patients stopped using marijuana. Both patients also displayed compulsive bathing behavior, a hallmark feature of cannabinoid hyperemesis syndrome (CHS) that had been consistently reported in adult cases.\n\nThese represented the first documented cases of CHS in pediatric patients, as the syndrome had previously been described only in adults.","whyItMatters":"This report expanded recognition of cannabinoid hyperemesis syndrome to include adolescent patients, suggesting clinicians should consider CHS in younger patients with unexplained cyclic vomiting and marijuana use history.","specificNumbers":"2 pediatric patients. Both had extensive GI workups with no identified cause. Both exhibited compulsive bathing. Both improved with cannabis cessation.","methodology":"Case report of two pediatric patients presenting to the emergency department with severe cyclic vomiting and chronic marijuana use histories. Both received extensive gastrointestinal evaluations. Symptom resolution was documented after cannabis cessation.","limitations":"Case reports cannot establish causation and represent only two patients. The mechanism of CHS remained poorly understood at the time."},{"rthcId":"RTHC-00436","title":"Comparison of urine results concerning co-consumption of illicit heroin and other drugs in heroin and methadone maintenance programs.","authors":"Musshoff, Frank; Trafkowski, Jens; Lichtermann, Dirk; Madea, Burkhard","year":2010,"journal":"International journal of legal medicine, 124(5), 499-503","doi":"10.1007/s00414-009-0361-8","pmid":"19672612","tags":["addiction","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers analyzed urine samples from patients in a heroin maintenance program (HMP) and a methadone maintenance program (MMP) at one month before and 6 and 12 months into treatment.\n\nIllicit heroin co-use was detected in 50% of HMP patients, significantly lower than the 71% rate in MMP patients. This higher detection rate compared to previous reports resulted from testing for multiple markers of illicit heroin beyond just acetylcodeine.\n\nCocaine use was similar between groups and decreased during treatment. Benzodiazepine use also decreased over time. Cannabis use remained high in both groups throughout treatment. Amphetamine use was minimal in both programs.","whyItMatters":"The finding that cannabis use remained persistently high during opioid addiction treatment raised questions about whether cannabis serves a functional role for patients in these programs.","specificNumbers":"Illicit heroin co-use: 50% in HMP vs 71% in MMP (significant difference). Cocaine and benzodiazepine use decreased during treatment in both groups. Cannabis use remained high in both groups.","methodology":"Observational comparison study analyzing urine samples chromatographically for heroin markers and immunochemically for cannabinoids, cocaine metabolites, amphetamines, MDMA-type substances, and benzodiazepines. Samples collected at 1 month pre-treatment, 6 months, and 12 months.","limitations":"Observational comparison between programs without randomization. Differences between programs may reflect patient selection rather than treatment effects. Single center study."},{"rthcId":"RTHC-00437","title":"A cannabinoid CB(1) receptor antagonist ameliorates impairment of recognition memory on withdrawal from MDMA (Ecstasy).","authors":"Nawata, Yoko; Hiranita, Takato; Yamamoto, Tsuneyuki","year":2010,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 35(2), 515-20","doi":"10.1038/npp.2009.158","pmid":"19829291","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice received MDMA (ecstasy) daily for 7 days. On the 7th day of withdrawal, recognition memory was significantly impaired in a novel object recognition test.\n\nThe cannabinoid CB1 receptor antagonist AM251 blocked this memory impairment when given either before the test or alongside MDMA during the treatment period. CB1 receptor protein levels increased significantly in the hippocampus during MDMA withdrawal, but not in the prefrontal cortex or striatum.\n\nCo-administration of AM251 with MDMA prevented the hippocampal CB1 receptor increase. Additionally, CB1 receptor knockout mice showed no recognition memory impairment during MDMA withdrawal, confirming the role of CB1 receptors in this effect.","whyItMatters":"The study identified the endocannabinoid system as a key mediator of memory impairment during MDMA withdrawal, potentially opening therapeutic targets for cognitive recovery in ecstasy users.","specificNumbers":"MDMA dose: 10 mg/kg daily for 7 days. Memory tested at withdrawal day 7. CB1 protein increased significantly in hippocampus but not prefrontal cortex or striatum.","methodology":"Controlled animal study in mice. MDMA (10 mg/kg i.p.) administered daily for 7 days. Novel object recognition test performed on withdrawal day 7. CB1 receptor protein measured by western blotting. Multiple experimental conditions tested: AM251 before testing, AM251 co-administered with MDMA, and CB1 knockout mice.","limitations":"Mouse model using high daily MDMA doses that may not reflect human recreational use patterns. The novel object recognition test captures only one type of memory. Withdrawal period was limited to 7 days."},{"rthcId":"RTHC-00438","title":"Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users.","authors":"Nestor, Liam; Hester, Robert; Garavan, Hugh","year":2010,"journal":"NeuroImage, 49(1), 1133-43","doi":"10.1016/j.neuroimage.2009.07.022","pmid":"19631753","tags":["dopamine","neuroscience","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Fourteen chronic cannabis users and 14 non-using controls completed a monetary incentive delay task during fMRI brain scanning. Despite no behavioral performance differences, cannabis users showed significantly greater right ventral striatum (reward center) activation when anticipating rewards.\n\nThis heightened reward anticipation response correlated significantly with lifetime cannabis use and total joints consumed. No correlations with abstinence duration were found.\n\nCannabis users also showed reduced left insula activation in response to loss and loss avoidance outcomes, suggesting diminished sensitivity to negative financial outcomes.","whyItMatters":"The findings suggested cannabis users may have a heightened sensitivity to rewards generally (not just drug rewards) while being less sensitive to losses, a pattern relevant to understanding risk-taking behavior and continued drug use.","specificNumbers":"14 cannabis users vs 14 controls. Reward anticipation: significantly greater right ventral striatum BOLD response in users, correlated with lifetime use. Loss outcomes: reduced left insula cortex activation in users.","methodology":"Cross-sectional fMRI study comparing 14 chronic cannabis users to 14 drug-naive controls during a monetary incentive delay (MID) task measuring brain activation during reward and loss anticipation and outcome delivery.","limitations":"Small sample size (14 per group). Cross-sectional design could not determine whether brain differences preceded or followed cannabis use. Cannabis users may differ from controls in ways beyond drug use."},{"rthcId":"RTHC-00439","title":"Cellular mechanisms underlying the interaction between cannabinoid and opioid system.","authors":"Parolaro, D; Rubino, T; Viganò, D; Massi, P; Guidali, C; Realini, N","year":2010,"journal":"Current drug targets, 11(4), 393-405","doi":null,"pmid":"20017730","tags":["neuroscience","addiction","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review synthesized evidence for three main mechanisms through which the cannabinoid and opioid systems interact:\n\n1. Cannabinoids can trigger the release of opioid peptides, and opioids can trigger endocannabinoid release, creating bidirectional communication between the systems.\n\n2. When CB1 and opioid receptors are expressed on the same cells, direct receptor-receptor interactions occur, potentially through receptor heteromerization.\n\n3. The intracellular signaling pathways activated by each receptor type converge and interact within cells.\n\nImportantly, the interaction differed between brain reward networks and those involved in pain, emotion, and cognition, as well as between central nervous system and peripheral tissues.","whyItMatters":"Understanding how cannabinoid and opioid systems interact at the cellular level could enable combination therapies that use lower doses of each, potentially reducing side effects while maintaining pain relief or other benefits.","specificNumbers":"The review covered three distinct interaction mechanisms across multiple tissue types and brain regions, synthesizing findings from numerous preclinical studies.","methodology":"Narrative review synthesizing biochemical and molecular studies on cannabinoid-opioid interactions, examining evidence from both central nervous system and peripheral tissue research.","limitations":"Primarily preclinical evidence from cell culture and animal studies. Translation to human clinical applications remained uncertain. The complexity of the interaction made simple therapeutic approaches challenging."},{"rthcId":"RTHC-00440","title":"Catechol-O-Methyltransferase (COMT) Val158Met variations and cannabis use in first-episode non-affective psychosis: clinical-onset implications.","authors":"Pelayo-Terán, José María; Pérez-Iglesias, Rocío; Mata, Ignacio; Carrasco-Marín, Eugenio; Vázquez-Barquero, José Luis; Crespo-Facorro, Benedicto","year":2010,"journal":"Psychiatry research, 179(3), 291-6","doi":"10.1016/j.psychres.2009.08.022","pmid":"20493536","tags":["psychosis","genetics","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers examined 169 patients with first-episode schizophrenia spectrum disorders, looking at how the COMT gene (which regulates dopamine) interacted with cannabis use to affect when psychosis first appeared.\n\nCannabis users had significantly earlier onset of psychosis compared to non-users. The Met/Met genotype of COMT was associated with later onset, but only among patients who did not use cannabis.\n\nAmong cannabis users, the COMT genotype had no effect on onset timing. The authors concluded that cannabis use may override the protective delay effect of the Met allele, essentially eliminating the genetic advantage that would otherwise delay psychosis onset.","whyItMatters":"This was among the first studies to demonstrate gene-environment interaction between COMT and cannabis in the timing of psychosis onset, suggesting cannabis may neutralize genetic factors that would otherwise delay disease onset.","specificNumbers":"169 Caucasian patients with first-episode psychosis. Cannabis-COMT interaction was significant for both DUP and age of onset. COMT genotype differences in onset were present only in non-users.","methodology":"Cross-sectional study of 169 Caucasian patients with first-episode schizophrenia spectrum disorder. COMT Val158Met polymorphism was typed using PCR. Cannabis use was classified as regular versus sporadic/non-user. Multivariate ANCOVA tested effects on age of onset and duration of untreated psychosis (DUP), with gender as covariate.","limitations":"Cross-sectional design examining only patients who already developed psychosis (no healthy controls). Cannot determine whether cannabis caused earlier onset or whether earlier-onset patients were more likely to use cannabis. Self-reported cannabis use may be unreliable."},{"rthcId":"RTHC-00441","title":"Diffusion tensor imaging in the early phase of schizophrenia: what have we learned?","authors":"Peters, Bart D; Blaas, J; de Haan, Lieuwe","year":2010,"journal":"Journal of psychiatric research, 44(15), 993-1004","doi":"10.1016/j.jpsychires.2010.05.003","pmid":"20554292","tags":["psychosis","neuroscience","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined diffusion tensor imaging (DTI) studies in first-episode schizophrenia patients and people at high risk for psychosis. Several key patterns emerged.\n\nSome white matter abnormalities appeared to convey liability for psychosis, existing even before disease onset. Additional abnormalities emerged around the onset of psychosis itself. However, findings in first-episode patients were less consistent than in chronic patients.\n\nProgression of white matter disturbances appeared to occur in early-course patients with poor outcomes. The review also noted that adolescent cannabis use had specific, measurable effects on DTI measures of white matter integrity, adding an environmental factor to the neurodevelopmental picture.","whyItMatters":"Identifying that white matter changes exist before psychosis onset and that cannabis use adds measurable effects provided a more complete picture of how schizophrenia develops and which factors contribute.","specificNumbers":"The review synthesized findings across multiple DTI studies but did not report pooled statistics. Findings in first-episode patients were described as less robust than in chronic patients.","methodology":"Narrative review of DTI (diffusion tensor imaging) studies in first-episode schizophrenia patients and high-risk individuals, discussing timing, location, and progression of white matter abnormalities, underlying pathology, and environmental influences including cannabis use.","limitations":"Narrative review without systematic methodology. DTI findings were heterogeneous across studies. The underlying pathology of DTI abnormalities remained unclear, and combining DTI with other imaging methods was recommended."},{"rthcId":"RTHC-00442","title":"Daily marijuana users with past alcohol problems increase alcohol consumption during marijuana abstinence.","authors":"Peters, Erica N; Hughes, John R","year":2010,"journal":"Drug and alcohol dependence, 106(2-3), 111-8","doi":"10.1016/j.drugalcdep.2009.07.027","pmid":"19783385","tags":["withdrawal","addiction"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Twenty-eight daily marijuana users who were not trying to quit completed three phases: 8 days of normal use, 13 days of verified marijuana abstinence, and 7 days of return to normal use.\n\nOverall, marijuana abstinence did not produce a significant increase in alcohol consumption. However, having a past diagnosis of alcohol abuse or dependence was a powerful moderator.\n\nParticipants with past alcohol problems increased alcohol consumption by 52% during marijuana abstinence. Those without alcohol history showed only a 3% increase. Increases in marijuana withdrawal discomfort and alcohol craving during abstinence both correlated with greater alcohol consumption.\n\nNo increases in cigarettes, caffeine, or other illicit drugs were observed during marijuana abstinence.","whyItMatters":"This was one of the first studies to provide empirical evidence for drug substitution among marijuana users, finding it occurred specifically in a subgroup with previous alcohol problems rather than universally.","specificNumbers":"28 daily marijuana users. Past alcohol problems group: 52% alcohol increase during abstinence. No alcohol history group: 3% increase. No increases in cigarettes, caffeine, or other drugs.","methodology":"Within-subjects prospective study of 28 daily marijuana users through three phases: 8-day baseline (normal use), 13-day marijuana abstinence (verified by urine testing twice weekly), and 7-day return-to-baseline. Daily self-report of all substance use.","limitations":"Small sample size (28 participants). Participants were not seeking treatment, so results may differ in clinical populations. Self-reported substance use aside from urine-verified marijuana abstinence."},{"rthcId":"RTHC-00443","title":"Processing dynamic facial affect in frequent cannabis-users: evidence of deficits in the speed of identifying emotional expressions.","authors":"Platt, Bradley; Kamboj, Sunjeev; Morgan, Celia J A; Curran, H Valerie","year":2010,"journal":"Drug and alcohol dependence, 112(1-2), 27-32","doi":"10.1016/j.drugalcdep.2010.05.004","pmid":"21036306","tags":["cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared emotion recognition between heavy cannabis users and non-using controls using dynamic facial expressions that gradually changed from neutral to increasingly intense emotional displays.\n\nCannabis users were significantly slower at identifying all three emotional expressions (sadness, anger, and happiness). This was not due to general cognitive slowing, as users showed no delay in identifying neutral-to-neutral facial changes.\n\nCannabis users also had a more liberal response criterion for recognizing sadness, meaning they were more likely to identify an expression as sad even at low intensities.\n\nThe findings suggested a generalized deficit in reading basic emotions during social interactions.","whyItMatters":"Difficulty reading emotions in others could contribute to interpersonal problems reported by cannabis users and may relate to the observed association between heavy cannabis use and mental health difficulties.","specificNumbers":"Cannabis users were significantly slower at identifying all three emotional expressions. No difference in neutral-to-neutral recognition speed, ruling out general cognitive slowing.","methodology":"Cross-sectional study comparing heavy cannabis users to non-using controls on a dynamic emotion recognition task. Facial expressions morphed from neutral to increasingly intense emotions. Reaction times and accuracy were recorded. Participants also completed measures of theory of mind, depression, and impulsivity.","limitations":"Cross-sectional design cannot determine whether cannabis caused the deficits or whether people with existing emotion recognition difficulties were more likely to use cannabis heavily. The study did not control for all potential confounders."},{"rthcId":"RTHC-00444","title":"Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.","authors":"Rajesh, Mohanraj; Mukhopadhyay, Partha; Bátkai, Sándor; Patel, Vivek; Saito, Keita; Matsumoto, Shingo; Kashiwaya, Yoshihiro; Horváth, Béla; Mukhopadhyay, Bani; Becker, Lauren; Haskó, György; Liaudet, Lucas; Wink, David A; Veves, Aristidis; Mechoulam, Raphael; Pacher, Pál","year":2010,"journal":"Journal of the American College of Cardiology, 56(25), 2115-25","doi":"10.1016/j.jacc.2010.07.033","pmid":"21144973","tags":["cbd","cardiovascular","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested CBD in a mouse model of type I diabetic cardiomyopathy and in human heart cells exposed to high glucose conditions.\n\nIn diabetic mice, the heart showed declining function, increased oxidative stress, elevated inflammatory markers (NF-kB activation, TNF-alpha, adhesion molecules), fibrosis markers, and enhanced cell death. CBD treatment significantly attenuated all of these pathological processes.\n\nIn human cardiomyocytes (heart cells) exposed to high glucose, CBD reduced reactive oxygen species generation, NF-kB activation, and cell death.\n\nThe authors noted that CBD's established safety profile in humans made it a strong candidate for further investigation in diabetic cardiovascular complications.","whyItMatters":"Diabetic cardiomyopathy is a serious complication of diabetes with limited treatment options. The finding that CBD addressed multiple pathological pathways simultaneously (inflammation, oxidative stress, fibrosis, cell death) was notable.","specificNumbers":"CBD attenuated: NF-kB and MAPK activation, adhesion molecule expression (ICAM-1, VCAM-1), TNF-alpha, fibrosis markers (TGF-beta, CTGF, fibronectin, collagen-1, MMP-2/9), and caspase 3/7 activity. Results were significant across multiple markers.","methodology":"Preclinical study using a type I diabetic mouse model. Left ventricular function measured by pressure-volume system. Oxidative stress, cell death, and fibrosis assessed by molecular biology techniques, electron spin resonance spectroscopy, and flow cytometry. Also tested in primary human cardiomyocytes exposed to high glucose.","limitations":"Animal model (type I diabetes in mice) may not fully replicate human diabetic cardiomyopathy. The in vitro human cell work used isolated cells rather than whole organ systems. No clinical data on CBD for diabetic heart disease was available."},{"rthcId":"RTHC-00445","title":"Cannabis and the lung.","authors":"Reid, P T; Macleod, J; Robertson, J R","year":2010,"journal":"The journal of the Royal College of Physicians of Edinburgh, 40(4), 328-3; quiz 333-4","doi":"10.4997/JRCPE.2010.417","pmid":"21132143","tags":["respiratory"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined evidence on respiratory effects of cannabis smoking, noting that mental health concerns had dominated cannabis research while lung effects received relatively little attention.\n\nThe authors found emerging concern that habitual cannabis smoking may contribute to chronic obstructive pulmonary disease (COPD), pneumothorax (collapsed lung), and respiratory infections including tuberculosis.\n\nRegarding lung cancer, the review noted that biological plausibility existed for an association (cannabis smoke contains carcinogens and causes cellular changes), even though epidemiological evidence had not yet definitively established the link. The authors suggested biological evidence may precede epidemiological confirmation.\n\nThe review emphasized that cannabis research was complicated by confounding from concurrent tobacco use and other social factors.","whyItMatters":"The review highlighted a gap between public perception of cannabis as safe and emerging evidence of respiratory harms, particularly relevant as cannabis smoking was widespread among young people.","specificNumbers":"The review discussed qualitative evidence across multiple respiratory conditions but did not report pooled risk estimates.","methodology":"Narrative review by chest physicians examining epidemiological and biological evidence for respiratory effects of cannabis smoking, published in the Journal of the Royal College of Physicians of Edinburgh.","limitations":"Narrative review without systematic methodology. Many referenced studies were confounded by concurrent tobacco smoking. Epidemiological evidence for lung cancer specifically was acknowledged as incomplete."},{"rthcId":"RTHC-00446","title":"Precipitated withdrawal counters the adverse effects of subchronic cannabinoid administration on male rat sexual behavior.","authors":"Riebe, Caitlin J; Lee, Tiffany T; Hill, Matthew N; Gorzalka, Boris B","year":2010,"journal":"Neuroscience letters, 472(3), 171-4","doi":"10.1016/j.neulet.2010.01.079","pmid":"20138966","tags":["neuroscience","withdrawal"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Male rats received the potent CB1 agonist HU-210 daily for 10 days. Sexual behavior was then assessed under three conditions: continued drug use, spontaneous withdrawal, and precipitated withdrawal (induced by the CB1 antagonist AM251).\n\nBoth continued drug use and spontaneous withdrawal resulted in impaired sexual activity, with reduced intromission and ejaculation frequency.\n\nSurprisingly, precipitated withdrawal (rapidly blocking CB1 receptors with AM251) reversed the sexual impairment, restoring ejaculation frequency. This contradicted the expectation that withdrawal itself caused the dysfunction.\n\nThe authors concluded that the impairment was likely due to neuroadaptive changes from repeated drug exposure rather than withdrawal effects.","whyItMatters":"The finding that rapidly blocking CB1 receptors restored sexual function while gradual withdrawal did not suggested the dysfunction was maintained by persistent receptor adaptations rather than withdrawal itself.","specificNumbers":"HU-210: 0.1 mg/kg/day for 10 days. AM251: 1 mg/kg for precipitated withdrawal. Both intromissions and ejaculations reduced under drug maintenance and spontaneous withdrawal. Ejaculations restored under precipitated withdrawal.","methodology":"Controlled animal study in male rats. HU-210 (0.1 mg/kg/day) for 10 days. Three conditions tested: drug maintenance, spontaneous withdrawal, and precipitated withdrawal with AM251 (1 mg/kg). Sexual behavior assessed by intromission and ejaculation frequency.","limitations":"Animal model using a synthetic cannabinoid (HU-210) at doses that may not reflect human cannabis use. Short treatment period (10 days). Sexual behavior in rats may not translate directly to human sexual function."},{"rthcId":"RTHC-00447","title":"Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.","authors":"Rieder, Sadiye Amcaoglu; Chauhan, Ashok; Singh, Ugra; Nagarkatti, Mitzi; Nagarkatti, Prakash","year":2010,"journal":"Immunobiology, 215(8), 598-605","doi":"10.1016/j.imbio.2009.04.001","pmid":"19457575","tags":["inflammation","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review catalogued how cannabinoids mediate immunosuppression through four broad mechanisms:\n\n1. Apoptosis (programmed cell death) of immune cells, primarily through CB2 receptor activation\n2. Inhibition of immune cell proliferation\n3. Suppression of cytokine and chemokine production\n4. Induction of regulatory T cells (Tregs) that dampen immune responses\n\nCB2 receptors, predominantly expressed on immune cells, emerged as the key therapeutic target. The authors noted that cannabinoids had shown beneficial effects in models of multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma.\n\nImportantly, CB2-targeted therapies could achieve immunosuppression without the psychoactive effects mediated by CB1 receptors in the brain.","whyItMatters":"The identification of CB2 receptor-targeted immunosuppression offered a pathway to develop anti-inflammatory therapies without the psychoactive effects of cannabis, potentially benefiting patients with autoimmune and inflammatory conditions.","specificNumbers":"Four immunosuppressive pathways identified. Beneficial effects demonstrated in models of at least five autoimmune/inflammatory conditions.","methodology":"Narrative review focusing on mechanisms of cannabinoid-induced apoptosis in immune cells, synthesizing laboratory findings on CB2 receptor-mediated immunosuppression across multiple immune cell types and disease models.","limitations":"Primarily based on preclinical and in vitro studies. Translation to human autoimmune disease treatment remained speculative. The immunosuppressive effects could theoretically increase infection susceptibility."},{"rthcId":"RTHC-00448","title":"Evidence of increased activation underlying cognitive control in ecstasy and cannabis users.","authors":"Roberts, Gloria M P; Garavan, Hugh","year":2010,"journal":"NeuroImage, 52(2), 429-35","doi":"10.1016/j.neuroimage.2010.04.192","pmid":"20417713","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Twenty recreational drug users (predominantly ecstasy and cannabis) and 20 healthy controls completed a GO/NOGO impulse control task during fMRI scanning.\n\nDespite no differences in behavioral performance (both groups performed equally), drug users showed significantly elevated brain activation in frontal and parietal regions during successful response inhibition. During errors, users showed hyperactivity in temporal, frontal, and cingulate regions.\n\nDrug users also showed reduced deactivation of the default-mode network during task performance. The default-mode network normally deactivates when the brain focuses on external tasks.\n\nThe pattern of compensatory hyperactivation suggested drug users needed greater neural resources to achieve normal performance levels.","whyItMatters":"The finding that drug users achieved normal performance through increased brain effort suggested a compensatory mechanism that might break down under more demanding conditions, even when standard tests show no deficits.","specificNumbers":"20 drug users (10 female) vs 20 controls. No behavioral performance differences. Elevated frontal and parietal BOLD during inhibitions. Temporal, frontal, and cingulate hyperactivity during errors. Reduced default-mode network deactivation.","methodology":"Cross-sectional fMRI study comparing 20 current recreational drug users (10 female, predominantly ecstasy/cannabis) to 20 healthy controls during a GO/NOGO response inhibition task. BOLD signal measured during successful inhibitions and commission errors.","limitations":"Cannot separate effects of ecstasy from cannabis since most users took both. Cross-sectional design cannot determine whether brain differences preceded drug use. Current drug use status was not verified biochemically."},{"rthcId":"RTHC-00449","title":"The effect of social isolation on rat brain expression of genes associated with endocannabinoid signaling.","authors":"Robinson, Stephanie A; Loiacono, Richard E; Christopoulos, Arthur; Sexton, Patrick M; Malone, Daniel T","year":2010,"journal":"Brain research, 1343, 153-67","doi":"10.1016/j.brainres.2010.04.031","pmid":"20430015","tags":["neuroscience","psychosis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats raised in social isolation from weaning to adulthood (a model that produces schizophrenia-like behavioral changes) showed widespread changes in endocannabinoid system gene expression.\n\nCB1 receptor mRNA was significantly higher in multiple brain regions of isolated rats, particularly prefrontal areas and cortical layers. Enzymes for synthesizing endocannabinoids (DAGL-alpha, DAGL-beta, NAPE-PLD) were also elevated in many regions.\n\nConversely, FAAH (the enzyme that breaks down the endocannabinoid anandamide) was significantly lower in prefrontal regions, cortical layers, and caudate putamen. Lower FAAH would lead to higher anandamide levels.\n\nDAGL-beta mRNA was notably higher in the substantia nigra and ventral tegmental area, brain regions critical to dopamine signaling and reward.","whyItMatters":"The findings provided further evidence linking endocannabinoid system dysregulation to psychosis-like states, and identified specific molecular changes that could underlie the behavioral abnormalities seen in social isolation models of schizophrenia.","specificNumbers":"Social isolation from day 21 for 8 weeks. CB1, DAGL-alpha, DAGL-beta, MAGL, NAPE-PLD mRNA significantly higher in isolated rats across multiple regions. FAAH mRNA significantly lower in prefrontal and striatal regions.","methodology":"Controlled animal study comparing rats housed individually versus in groups of 6 from postnatal day 21 for 8 weeks. CB1, DAGL-alpha, DAGL-beta, MAGL, NAPE-PLD, and FAAH mRNA measured using in situ hybridization histochemistry across multiple brain regions.","limitations":"Animal model of social isolation is an approximation of psychosis, not a direct equivalent. Gene expression changes (mRNA) may not perfectly reflect protein levels or functional receptor activity. Rat brain organization differs from human."},{"rthcId":"RTHC-00450","title":"Cannabis use and cognitive functioning in first-episode schizophrenia patients.","authors":"Rodríguez-Sánchez, José Manuel; Ayesa-Arriola, Rosa; Mata, Ignacio; Moreno-Calle, Teresa; Perez-Iglesias, Rocío; González-Blanch, César; Periañez, José Antonio; Vazquez-Barquero, José Luis; Crespo-Facorro, Benedicto","year":2010,"journal":"Schizophrenia research, 124(1-3), 142-51","doi":"10.1016/j.schres.2010.08.017","pmid":"20826079","tags":["psychosis","cognition","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers compared cognitive functioning between cannabis-using and non-using patients with first-episode schizophrenia. The results contradicted expectations.\n\nCannabis-using patients (47 users) performed better on attention and executive function tests than non-users (57 non-users) both at initial assessment and after one year of treatment. Both groups improved similarly over the follow-up period.\n\nCannabis users also had better social premorbid adjustment, particularly during early life stages. The amount of cannabis consumed and duration of use did not correlate with cognitive performance.\n\nThe authors concluded that cannabis-using schizophrenia patients may represent a distinct subgroup with better baseline cognitive abilities and social functioning prior to illness onset.","whyItMatters":"The finding challenged the assumption that cannabis always worsens cognitive outcomes in schizophrenia, suggesting instead that cannabis-using patients may have had better functioning to begin with.","specificNumbers":"104 patients (47 cannabis users, 57 non-users) and 37 healthy controls. Cannabis users performed better on attention and executive function at baseline and 1-year follow-up. Amount and duration of cannabis use did not predict cognitive performance.","methodology":"Longitudinal study of 104 first-episode non-affective psychosis patients (47 cannabis users, 57 non-users) and 37 healthy controls. Cross-sectional and one-year longitudinal cognitive assessments with clinical and premorbid adjustment measures.","limitations":"Observational design cannot determine causation. Better cognition in users may reflect selection effects (higher-functioning people being more socially engaged and thus more exposed to cannabis). Cannabis use was assessed prior to illness onset only."},{"rthcId":"RTHC-00451","title":"Common genetic contributions to alcohol and cannabis use and dependence symptomatology.","authors":"Sartor, Carolyn E; Grant, Julia D; Bucholz, Kathleen K; Madden, Pamela A F; Heath, Andrew C; Agrawal, Arpana; Whitfield, John B; Statham, Dixie J; Martin, Nicholas G; Lynskey, Michael T","year":2010,"journal":"Alcoholism, clinical and experimental research, 34(3), 545-54","doi":"10.1111/j.1530-0277.2009.01120.x","pmid":"20028363","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Researchers analyzed data from 6,257 Australian twins aged 24 to 36 to understand genetic and environmental contributions to alcohol and cannabis use and dependence.\n\nGenetic factors accounted for over 60% of variance in alcohol consumption, cannabis use, and cannabis dependence symptoms. For alcohol dependence symptoms, genetics explained just under 50%. Shared environmental factors did not contribute significantly to any of the four measures.\n\nGenetic correlations between alcohol and cannabis were substantial: 0.68 for use patterns and 0.62 for dependence symptoms. This meant about two-thirds of the genetic liability was shared between the two substances.\n\nHowever, substance-specific genetic influences still accounted for the majority of genetic variance in cannabis phenotypes, meaning cannabis-specific genes exist beyond the shared addiction genetics.","whyItMatters":"The large-scale twin design provided robust estimates of heritability, confirming that both substance-specific and shared genetic factors influence cannabis use and dependence.","specificNumbers":"6,257 individuals. Genetic variance: >60% for cannabis use and dependence, ~50% for alcohol dependence. Genetic correlations: 0.68 (use) and 0.62 (dependence) between alcohol and cannabis. Shared environment was not significant.","methodology":"Twin study of 6,257 individuals (2,761 complete twin pairs and 735 singletons) from the Australian Twin Registry. Telephone diagnostic interviews assessed alcohol consumption, cannabis use frequency, and DSM-IV dependence symptom counts. Quadrivariate genetic model estimated heritability and cross-substance genetic overlap.","limitations":"Australian sample may not generalize to all populations. Self-reported substance use. Twin studies estimate broad heritability but do not identify specific genes. The age range (24-36) may miss later-onset patterns."},{"rthcId":"RTHC-00452","title":"A comparison of psychosocial and cognitive functioning between depressed and non-depressed patients with cannabis dependence.","authors":"Secora, Alex M; Eddie, David; Wyman, Bertram J; Brooks, Daniel J; Mariani, John J; Levin, Frances R","year":2010,"journal":"Journal of addictive diseases, 29(3), 325-37","doi":"10.1080/10550887.2010.489444","pmid":"20635282","tags":["depression","cognition","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared 54 cannabis-dependent individuals with comorbid depression to 54 with cannabis dependence alone.\n\nAs expected, the depressed group showed significantly more psychosocial impairment on the Addiction Severity Index, with greater difficulties in social and daily functioning.\n\nHowever, contrary to the hypothesis that depression would compound cognitive deficits, the depressed group actually performed better on some computerized cognitive assessment modules. The \"additive\" effect of depression and cannabis dependence appeared limited to psychosocial domains and did not extend to cognitive functioning.","whyItMatters":"The counterintuitive finding that depression was associated with better cognitive scores in cannabis-dependent individuals challenged assumptions about how comorbid conditions compound impairment.","specificNumbers":"108 participants total: 54 cannabis dependent only, 54 cannabis dependent plus depressed/dysthymic. Depressed group showed more psychosocial impairment but less cognitive impairment on some measures.","methodology":"Cross-sectional comparison of 108 cannabis-dependent individuals: 54 with comorbid depression/dysthymia and 54 without depression. Cognitive performance measured by California Computerized Assessment Package. Psychosocial functioning measured by Addiction Severity Index.","limitations":"Cross-sectional design. Moderate sample size. The cognitive finding was opposite to the hypothesis and may reflect characteristics of the depressed subgroup rather than a protective effect of depression."},{"rthcId":"RTHC-00453","title":"New approaches in the management of spasticity in multiple sclerosis patients: role of cannabinoids.","authors":"Smith, Paul F","year":2010,"journal":"Therapeutics and clinical risk management, 6, 59-63","doi":null,"pmid":"20234785","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined clinical trial evidence for cannabis-based medicinal extracts (CBMEs) in treating spasticity associated with multiple sclerosis (MS).\n\nPatients consistently reported subjective improvement in spasticity when using CBMEs. However, objective measurements using the Ashworth scale (a clinical rating of muscle resistance) generally showed no significant effect. The authors noted that the validity of the Ashworth scale itself had been questioned.\n\nSide effects were generally mild, including dry mouth, dizziness, drowsiness, nausea, and intoxication. Most clinical trials ran for only months, and long-term safety data were limited.\n\nThe review flagged particular caution for adolescents, people predisposed to psychosis, and pregnant women.","whyItMatters":"The disconnect between patient-reported improvement and objective clinical measures highlighted a challenge in evaluating cannabis-based medicines and raised questions about which outcome measures best capture treatment benefits.","specificNumbers":"Mild adverse effects reported: dry mouth, dizziness, somnolence, nausea, intoxication. Most trials ran for months. Ashworth scale generally showed no significant effect despite patient-reported improvement.","methodology":"Narrative review of clinical trial data examining cannabis-based medicinal extracts for MS-related spasticity, published in Therapeutics and Clinical Risk Management.","limitations":"Narrative review without systematic methodology. Reliance on subjective outcomes. Limited long-term safety data. The Ashworth scale limitations make it difficult to assess true objective efficacy."},{"rthcId":"RTHC-00454","title":"Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications.","authors":"Snider, Natasha T; Walker, Vyvyca J; Hollenberg, Paul F","year":2010,"journal":"Pharmacological reviews, 62(1), 136-54","doi":"10.1124/pr.109.001081","pmid":"20133390","tags":["neuroscience","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review focused on an underappreciated aspect of endocannabinoid biology: the oxidation of anandamide by cytochrome P450 enzymes.\n\nWhile FAAH is the primary enzyme that breaks down anandamide, several P450 enzymes (CYP3A4, CYP4F2, CYP4X1, and the highly variable CYP2D6) also metabolize anandamide into structurally diverse lipid products.\n\nCritically, one P450-derived epoxide of anandamide was found to be a potent agonist at CB2 receptors. This meant that blocking FAAH alone (the approach being developed for pain treatment) might not fully control endocannabinoid signaling because alternative metabolic pathways would still produce active compounds.\n\nThe genetic variability in CYP2D6 across individuals could lead to different responses to endocannabinoid-targeting drugs.","whyItMatters":"Understanding that multiple enzyme systems process anandamide into bioactive products was essential for developing effective endocannabinoid-targeting drugs, particularly FAAH inhibitors being developed for pain and inflammation.","specificNumbers":"Four P450 enzymes identified: CYP3A4, CYP4F2, CYP4X1, CYP2D6. One P450-derived epoxide was a potent CB2 agonist. CYP2D6 is highly polymorphic across populations.","methodology":"Comprehensive review published in Pharmacological Reviews examining the cytochrome P450-mediated oxidation pathways of anandamide, their physiological significance, and implications for drug development.","limitations":"Much of the evidence came from in vitro enzyme studies. The physiological relevance of P450-mediated anandamide metabolism in vivo required further investigation. The clinical implications were still theoretical."},{"rthcId":"RTHC-00455","title":"The cannabis hyperemesis syndrome characterized by persistent nausea and vomiting, abdominal pain, and compulsive bathing associated with chronic marijuana use: a report of eight cases in the United States.","authors":"Soriano-Co, Maria; Batke, Mihaela; Cappell, Mitchell S","year":2010,"journal":"Digestive diseases and sciences, 55(11), 3113-9","doi":"10.1007/s10620-010-1131-7","pmid":"20130993","tags":["appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Eight patients with cannabinoid hyperemesis syndrome (CHS) were identified at a single US hospital between January and August 2009. The syndrome had previously been described mainly in Australian patients.\n\nPatients averaged 32.4 years old, and the mean interval between first cannabis use and development of recurrent vomiting was 19 years. The burden on healthcare was substantial: patients averaged 7.1 emergency room visits, 5 clinic visits, and 3.1 hospital admissions for this syndrome. All had visited at least one other hospital.\n\nAll patients experienced vomiting every 3 hours on average, took about 5 baths or showers per day (totaling 5 hours of bathing daily), and had abdominal pain. Seven took hot baths and seven experienced excessive thirst.\n\nFour of five patients who stopped cannabis recovered. The three who continued using despite medical advice continued to have symptoms. One recovered patient who resumed cannabis experienced symptom recurrence.","whyItMatters":"This US case series confirmed that CHS was not limited to Australian populations and documented the extensive healthcare utilization and long latency period before symptom onset.","specificNumbers":"8 patients, mean age 32.4 years. Mean 19 years from first cannabis use to symptoms. Mean 7.1 ER visits, 5.0 clinic visits, 3.1 admissions. Vomiting every 3 hours. 5 baths/showers per day (5 hours total). 4/5 who quit recovered.","methodology":"Retrospective case series of 8 patients identified at William Beaumont Hospital (Michigan) from January to August 2009 based on chronic cannabis use, unexplained recurrent vomiting, and compulsive bathing. Chart review with follow-up from subsequent visits and patient interviews.","limitations":"Small case series from a single hospital. Retrospective design with potential recall bias. No comparison group or prevalence estimate. Self-reported cannabis use history."},{"rthcId":"RTHC-00456","title":"Altered architecture and functional consequences of the mesolimbic dopamine system in cannabis dependence.","authors":"Spiga, Saturnino; Lintas, Alessandra; Migliore, Michele; Diana, Marco","year":2010,"journal":"Addiction biology, 15(3), 266-76","doi":"10.1111/j.1369-1600.2010.00218.x","pmid":"20477755","tags":["dopamine","addiction","neuroscience","withdrawal"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers examined brain structure changes during cannabinoid withdrawal in rats treated with two different cannabinoid agonists (THC and CP55940).\n\nDuring both spontaneous and precipitated withdrawal, dopamine-producing neurons in the ventral tegmental area (VTA) showed significant morphological shrinkage. This shrinkage was specific to the VTA and did not occur in the substantia nigra.\n\nIn the nucleus accumbens (the brain's reward center), dendritic spine density decreased in the shell subdivision but not the core. These structural changes were mirrored when the CB1 antagonist SR141716A was given to control rats, producing similar abnormalities.\n\nA computational model predicted that these structural changes would significantly reduce the excitability of the affected neurons, resulting in decreased signaling output. The findings supported the concept of a \"hypodopaminergic state\" as a feature of the addicted brain.","whyItMatters":"This was among the first studies to provide direct morphological evidence that cannabinoid dependence physically alters the structure of reward-circuit neurons, supporting the concept that addiction involves tangible brain changes.","specificNumbers":"Significant morphometrical reductions in VTA (but not substantia nigra). Decreased spine density in nucleus accumbens shell (but not core). Computational model predicted strong reduction in action potential output from structurally altered neurons.","methodology":"Controlled animal study using rats treated chronically with THC or CP55940. Brain tissue analyzed with tyrosine hydroxylase immunostaining for VTA neurons and Golgi-Cox staining with confocal microscopy for nucleus accumbens dendritic spines. Computational modeling predicted functional consequences of structural changes.","limitations":"Animal model with synthetic cannabinoid doses that may not reflect human use patterns. Structural changes were measured at single time points; recovery over longer abstinence was not assessed. Computational model predictions require experimental validation."},{"rthcId":"RTHC-00457","title":"Rimonabant-induced Delta9-tetrahydrocannabinol withdrawal in rhesus monkeys: discriminative stimulus effects and other withdrawal signs.","authors":"Stewart, Jennifer L; McMahon, Lance R","year":2010,"journal":"The Journal of pharmacology and experimental therapeutics, 334(1), 347-56","doi":"10.1124/jpet.110.168435","pmid":"20375197","tags":["withdrawal","tolerance","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Monkeys receiving chronic THC were trained to discriminate the cannabinoid antagonist rimonabant (which precipitates withdrawal) from vehicle. The withdrawal discrimination was dose-dependent.\n\nSeveral drugs were tested for their ability to block the withdrawal signal. THC and the cannabinoid agonist CP55940 fully blocked it. The cannabinoid agonist WIN 55212-2 and the alpha-2 adrenergic agonist clonidine partially blocked it. Diazepam (a benzodiazepine) and cocaine did not block it.\n\nSimply stopping THC treatment also triggered the withdrawal discrimination, along with physical signs like head shaking and increased nighttime activity.\n\nThe drug discrimination approach was more pharmacologically selective than observing physical withdrawal signs, as head shaking was reduced by all test compounds including those that did not block the subjective withdrawal experience.","whyItMatters":"The study suggested that cannabinoid agonist replacement therapy (analogous to methadone for opioids) and possibly clonidine could help manage the subjective experience of cannabis withdrawal, informing potential treatment development.","specificNumbers":"Chronic THC: 1 mg/kg every 12 hours. Rimonabant discrimination ED50: 0.25 mg/kg. THC and CP55940 fully attenuated; WIN 55212-2 and clonidine partially attenuated; diazepam and cocaine did not attenuate withdrawal discrimination.","methodology":"Controlled primate study using drug discrimination under a fixed-ratio schedule of stimulus-shock termination in rhesus monkeys receiving chronic THC (1 mg/kg every 12 hours). Multiple agonist and non-cannabinoid drugs tested for ability to attenuate withdrawal discrimination.","limitations":"Primate model with small numbers of animals. The discriminative stimulus paradigm measures one aspect of withdrawal. Rimonabant-precipitated withdrawal may differ from natural withdrawal. Clinical translation not yet tested."},{"rthcId":"RTHC-00458","title":"Spice drugs as a new trend: mode of action, identification and legislation.","authors":"Vardakou, I; Pistos, C; Spiliopoulou, Ch","year":2010,"journal":"Toxicology letters, 197(3), 157-62","doi":"10.1016/j.toxlet.2010.06.002","pmid":"20566335","tags":["synthetic-cannabinoids","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review examined the emerging problem of synthetic cannabinoids sold as \"Spice\" herbal products. Key findings included:\n\nSynthetic cannabinoids in these products bound to cannabinoid receptors more strongly than natural cannabis. Chronic abuse was linked to signs of addiction and withdrawal symptoms similar to those observed with cannabis.\n\nThe products were marketed as \"herbal highs\" despite containing entirely synthetic compounds. It remained unclear where or how production took place, but manufacturers were knowingly risking consumer health.\n\nMajor challenges included difficulty identifying the specific synthetic compounds in products, lack of reference standards for laboratory testing, and the speed at which new compounds appeared on the market. Several European countries, the US, and Canada had begun banning specific synthetic cannabinoids.","whyItMatters":"The review served as an early warning about a rapidly growing public health problem that would later produce numerous emergency department visits and deaths from novel synthetic cannabinoid products.","specificNumbers":"Synthetic cannabinoids described as stronger than natural cannabis at cannabinoid receptors. Multiple countries in Europe plus the US and Canada had banned some compounds by 2010.","methodology":"Narrative review searching multiple literature databases for information on psychoactive properties, safety profiles, clinical data, and detection problems related to synthetic cannabinoids in \"Spice\" products.","limitations":"Limited clinical and safety data available at the time. The rapidly evolving nature of the products meant that information was quickly outdated. Most evidence was from case reports rather than systematic research."},{"rthcId":"RTHC-00459","title":"Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies.","authors":"Verweij, Karin J H; Zietsch, Brendan P; Lynskey, Michael T; Medland, Sarah E; Neale, Michael C; Martin, Nicholas G; Boomsma, Dorret I; Vink, Jacqueline M","year":2010,"journal":"Addiction (Abingdon, England), 105(3), 417-30","doi":"10.1111/j.1360-0443.2009.02831.x","pmid":"20402985","tags":["genetics","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Researchers conducted a meta-analysis of 28 twin studies on cannabis initiation and 24 on problematic use, weighting results by sample size.\n\nFor cannabis use initiation, genetics explained 48% of variance in males and 40% in females. Shared environment (family, peers) accounted for 25% in males and 39% in females. Unique environment explained 27% and 21% respectively.\n\nFor problematic cannabis use, genetics explained 51% in males and 59% in females. Shared environment dropped to 20% in males and 15% in females. Unique environment accounted for 29% and 26%.\n\nA notable pattern emerged: shared environment was more important for initiation than for problematic use, especially in females. This suggested that family and peer influences may determine whether someone tries cannabis, but genetic factors become more important in determining who develops problems.","whyItMatters":"By pooling data across many twin studies, this meta-analysis provided the most precise estimates available at the time for the genetic and environmental contributions to cannabis use and dependence.","specificNumbers":"Initiation: A=48%/40% (M/F), C=25%/39%, E=27%/21%. Problematic use: A=51%/59%, C=20%/15%, E=29%/26%. 28 initiation studies, 24 problematic use studies analyzed.","methodology":"Meta-analysis of twin studies identified through systematic literature search. 28 studies on cannabis initiation and 24 on problematic use. Heritability (A), shared environment (C), and unique environment (E) estimates averaged across independent cohorts, weighted by sample size.","limitations":"Twin studies estimate broad heritability without identifying specific genes. Meta-analysis combined studies with varying definitions of \"problematic use.\" Most twin registries were from Western countries, limiting generalizability."},{"rthcId":"RTHC-00460","title":"Heritability of cannabis initiation in Dutch adult twins.","authors":"Vink, Jacqueline M; Wolters, Liselot M C; Neale, Michael C; Boomsma, Dorret I","year":2010,"journal":"Addictive behaviors, 35(2), 172-4","doi":"10.1016/j.addbeh.2009.09.015","pmid":"19793625","tags":["genetics","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined cannabis initiation in 3,115 Dutch twins with a mean age of 27.4 years. The Netherlands permits small-scale cannabis use, providing a natural experiment to test whether liberal drug policy changes the genetic-environmental balance.\n\nGenetic influences accounted for 44% of individual differences in cannabis initiation. Shared environmental factors (family, peers, neighborhood) explained 31%, and unique environmental factors explained 24%.\n\nThese proportions were remarkably similar to those found in the United States, Australia, and United Kingdom, where cannabis policies were more restrictive. The authors concluded that the relative importance of genetic and environmental factors was not meaningfully different in a country with more liberal cannabis policy.","whyItMatters":"The finding that heritability proportions were similar regardless of legal context suggested that genetic vulnerability to cannabis use operates independent of policy environment.","specificNumbers":"3,115 twins, mean age 27.4 (SD 4.7). Heritability: 44%. Shared environment: 31%. Unique environment: 24%. Results comparable to US, Australia, and UK estimates.","methodology":"Twin study of 3,115 twins (mean age 27.4) from the Netherlands Twin Register. Standard genetic modeling to estimate additive genetic (A), shared environmental (C), and unique environmental (E) contributions to cannabis initiation.","limitations":"Single-country study with self-reported cannabis use. The Netherlands policy specifically applies to small amounts; results might differ under full legalization. Twin studies assume equal environments for identical and fraternal twins."},{"rthcId":"RTHC-00461","title":"The abuse potential of the synthetic cannabinoid nabilone.","authors":"Ware, Mark A; St Arnaud-Trempe, Emmanuelle","year":2010,"journal":"Addiction (Abingdon, England), 105(3), 494-503","doi":"10.1111/j.1360-0443.2009.02776.x","pmid":"20402993","tags":["medical-cannabis","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers conducted a comprehensive evaluation of whether the synthetic cannabinoid nabilone (approved in Canada since 1981 for chemotherapy nausea) was being abused, particularly as off-label pain management prescribing increased.\n\nThe scientific literature and popular press contained very little reference to nabilone abuse. Internet searches revealed only rare, isolated instances of recreational use. Law enforcement database review showed some seizures and thefts in Canada (particularly Ontario) but most officers reported no encounters with nabilone abuse. The drug had no known street value.\n\nSeveral factors limited abuse potential: nabilone produced more undesirable side effects than smoked cannabis, had a slower onset of action, and cost more. Medical professionals did not perceive nabilone as a concern for abuse.","whyItMatters":"The finding of negligible abuse potential after nearly 30 years of availability was reassuring for clinicians prescribing nabilone for pain management, while still recommending ongoing monitoring.","specificNumbers":"Nabilone approved in Canada since 1981. Some seizures and thefts documented, primarily in Ontario. No known street value. Law enforcement and medical professionals reported minimal concern.","methodology":"Multi-source investigation including systematic searches of scientific literature, popular press, and internet databases, plus focused interviews with medical professionals and law enforcement agencies across Canada.","limitations":"Absence of evidence is not evidence of absence. Nabilone prescribing was relatively limited in 2010. Under-reporting of abuse is possible. The study predated the expansion of nabilone use for pain."},{"rthcId":"RTHC-00462","title":"The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial.","authors":"Ware, Mark A; Fitzcharles, Mary-Ann; Joseph, Lawrence; Shir, Yoram","year":2010,"journal":"Anesthesia and analgesia, 110(2), 604-10","doi":"10.1213/ANE.0b013e3181c76f70","pmid":"20007734","tags":["sleep","pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-nine fibromyalgia patients with chronic insomnia completed a crossover trial comparing nabilone (0.5-1.0 mg at bedtime) to amitriptyline (10-20 mg at bedtime), each for two weeks with a two-week washout period.\n\nNabilone was significantly superior to amitriptyline on the Insomnia Severity Index (difference = 3.2 points, 95% CI: 1.2-5.3). Nabilone was also marginally better for restfulness on the Leeds Sleep Evaluation Questionnaire.\n\nHowever, neither drug improved pain, mood, or quality of life during the two-week treatment periods. Adverse effects were more common with nabilone and were mostly mild to moderate: dizziness, nausea, and dry mouth.","whyItMatters":"The study provided randomized controlled evidence that a cannabinoid could improve sleep in fibromyalgia more effectively than a commonly used first-line treatment, supporting cannabinoid consideration for sleep-related symptoms.","specificNumbers":"29 completers (26 women, mean age 49.5). Nabilone dose: 0.5-1.0 mg. Amitriptyline dose: 10-20 mg. ISI difference: 3.2 points (95% CI: 1.2-5.3) favoring nabilone. No significant effects on pain, mood, or quality of life.","methodology":"Randomized, double-blind, active-control, equivalency crossover trial. 31 enrolled, 29 completed (26 women, mean age 49.5). Each treatment period was 2 weeks with 2-week washout. Primary outcome: sleep quality (Insomnia Severity Index, Leeds Sleep Evaluation Questionnaire). Secondary outcomes: pain, mood, quality of life, adverse events.","limitations":"Small sample size (29). Short treatment duration (2 weeks each). Predominantly female sample. No placebo arm (only active comparator). Crossover design may have carry-over effects despite washout."},{"rthcId":"RTHC-00463","title":"Cannabinoid hyperemesis.","authors":"Wild, Kim; Wilson, Hugh","year":2010,"journal":"BMJ case reports, 2010","doi":"10.1136/bcr.01.2010.2605","pmid":"22778182","tags":["appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 21-year-old woman presented with four weeks of sudden-onset vomiting, nausea, and appetite loss. She had smoked cannabis heavily for 7 years. All other causes were ruled out through extensive testing.\n\nBlood work showed mild metabolic derangement (low potassium and bicarbonate) consistent with prolonged vomiting. Urine tested positive for cannabinoids. All other investigations (blood counts, kidney and liver function, ECG, pregnancy test, CT head scan) were normal.\n\nSymptoms resolved with IV fluids, antiemetics, and cannabis abstinence. However, since discharge she experienced several relapses, each directly related to resuming cannabis use and each resolving again with abstinence. She was seeking cognitive behavioral therapy to achieve permanent abstinence.","whyItMatters":"This case illustrated the recurring nature of CHS and the difficulty of maintaining abstinence, demonstrating why some patients require behavioral therapy support to avoid relapse.","specificNumbers":"Age 21, 7 years of heavy cannabis smoking. Low potassium and bicarbonate. Multiple relapses, each resolved with abstinence.","methodology":"Single case report of a 21-year-old woman presenting to hospital with 4 weeks of vomiting. Standard workup to exclude other causes. Follow-up documented multiple relapse-remission cycles correlated with cannabis use and abstinence.","limitations":"Single case report. Cannot determine prevalence or risk factors. Self-reported cannabis use history."},{"rthcId":"RTHC-00464","title":"Conventional and alternative matrices for driving under the influence of cannabis: recent progress and remaining challenges.","authors":"Wille, Sarah M R; Ramírez-Fernandez, Maria Del Mar; Samyn, Nele; De Boeck, Gert","year":2010,"journal":"Bioanalysis, 2(4), 791-806","doi":"10.4155/bio.10.29","pmid":"21083274","tags":["driving"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined different biological samples used for detecting cannabis in driving-under-the-influence (DUID) cases. Each test matrix provided different information.\n\nBlood and urine were the most widely used for DUID legislation, with blood THC levels more closely correlated with recent use and potential impairment. Oral fluid testing was gaining popularity for roadside screening because it was less invasive and easier to collect.\n\nHowever, each matrix had limitations. Blood THC levels drop rapidly, potentially missing impairment. Urine detects metabolites that persist long after impairment ends. Oral fluid concentrations could be affected by collection methods and did not have standardized cut-off values.\n\nThe review discussed the challenges of setting appropriate cut-off levels, sample stability during storage, and the need for standardized proficiency testing across laboratories.","whyItMatters":"As more countries adopted cannabis-impaired driving laws, the choice of biological testing matrix had direct legal and practical consequences for enforcement and for drivers.","specificNumbers":"Several countries had adopted DUID legislation with varying approaches. Blood, urine, and oral fluid were the three primary matrices compared. No universally standardized cut-off values existed.","methodology":"Narrative review of literature on cannabis detection methods for DUID enforcement, covering screening techniques, laboratory confirmation methods, and practical aspects of implementing DUID legislation.","limitations":"Narrative review of a rapidly evolving field. No systematic comparison of diagnostic accuracy across methods. The relationship between THC concentrations and actual impairment remained poorly defined."},{"rthcId":"RTHC-00465","title":"Adverse effects of cannabis.","authors":"","year":2011,"journal":"Prescrire international, 20(112), 18-23","doi":null,"pmid":"21462790","tags":["mental-health","psychosis","youth","cardiovascular","respiratory","driving"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review examined multiple categories of cannabis adverse effects using systematic methodology.\n\nAcute effects included mental slowness, impaired reaction times, and occasionally heightened anxiety. Serious psychological episodes occurred with high intoxication levels. Cannabis doubled the risk of fatal road accidents, though alcohol played an even greater role.\n\nRegarding psychosis, several longitudinal cohort studies showed statistical associations between cannabis use and psychotic illness, but methodological problems (including unreliable self-reporting) prevented establishing a causal relationship. Notably, Australia's marked increase in cannabis use was not accompanied by increased schizophrenia incidence.\n\nCannabis dependence was described as usually psychological, with withdrawal symptoms (irritability, anxiety, sleep difficulties) appearing within 48 hours and resolving within 2-12 weeks. The review found inconclusive evidence on memory effects, depression, and suicide.\n\nThe overall conclusion was that adverse effects of low-level recreational use were generally minor, with cannabis harms appearing less serious than alcohol's.","whyItMatters":"The comparative framing (cannabis versus alcohol harms) and the conclusion about limited evidence for causation in the psychosis relationship were significant for public health policy discussions.","specificNumbers":"Cannabis doubled fatal road accident risk. Withdrawal symptoms within 48 hours, resolving in 2-12 weeks. Australia's cannabis increase did not produce matching schizophrenia increase.","methodology":"Review conducted using Prescrire's standard systematic methodology, examining evidence across multiple outcome domains including neuropsychological effects, psychosis, dependence, driving, cardiovascular effects, cancer, and hepatitis C.","limitations":"The review acknowledged difficulty evaluating long-term effects due to confounding by tobacco, alcohol, and lifestyle factors. Evidence for several outcomes (cancer, hepatitis C, memory) was described as inconclusive."},{"rthcId":"RTHC-00466","title":"A genome-wide association study of DSM-IV cannabis dependence.","authors":"Agrawal, Arpana; Lynskey, Michael T; Hinrichs, Anthony; Grucza, Richard; Saccone, Scott F; Krueger, Robert; Neuman, Rosalind; Howells, William; Fisher, Sherri; Fox, Louis; Cloninger, Robert; Dick, Danielle M; Doheny, Kimberly F; Edenberg, Howard J; Goate, Alison M; Hesselbrock, Victor; Johnson, Eric; Kramer, John; Kuperman, Samuel; Nurnberger, John I; Pugh, Elizabeth; Schuckit, Marc; Tischfield, Jay; Rice, John P; Bucholz, Kathleen K; Bierut, Laura J","year":2011,"journal":"Addiction biology, 16(3), 514-8","doi":"10.1111/j.1369-1600.2010.00255.x","pmid":"21668797","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers conducted the first genome-wide association study (GWAS) specifically targeting DSM-IV cannabis dependence. They compared 708 cannabis-dependent individuals to 2,346 cannabis-exposed but non-dependent controls.\n\nNone of the 948,142 single nucleotide polymorphisms (SNPs) tested reached the strict threshold for genome-wide significance (P < 10^-8). The strongest signals were two SNPs on chromosome 17 (rs1019238 and rs1431318) in the ANKFN1 gene, with P values at 10^-7.\n\nDespite the null headline finding, the study represented an important first step because twin studies consistently showed 50-70% heritability for cannabis dependence, meaning specific genetic variants must exist even if this study was underpowered to detect them.","whyItMatters":"While the null result was initially disappointing, it demonstrated that cannabis dependence is likely influenced by many genes of small individual effect, requiring much larger samples to detect, rather than a few genes of large effect.","specificNumbers":"708 cases, 2,346 controls. 948,142 SNPs tested. Lowest P values at 10^-7 (chromosome 17, ANKFN1 gene). None reached genome-wide significance (10^-8).","methodology":"Genome-wide association study (GWAS) using logistic regression in PLINK. 708 DSM-IV cannabis-dependent cases versus 2,346 cannabis-exposed non-dependent controls. 948,142 SNPs tested for association with dependence.","limitations":"Likely underpowered given the expected small effect sizes of individual genetic variants. Single-ancestry sample may miss variants important in other populations. Cannabis dependence is genetically complex, requiring much larger samples."},{"rthcId":"RTHC-00467","title":"The Cannabis Withdrawal Scale development: patterns and predictors of cannabis withdrawal and distress.","authors":"Allsop, David J; Norberg, Melissa M; Copeland, Jan; Fu, Shanlin; Budney, Alan J","year":2011,"journal":"Drug and alcohol dependence, 119(1-2), 123-9","doi":"10.1016/j.drugalcdep.2011.06.003","pmid":"21724338","tags":["withdrawal","addiction","sleep"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers developed and validated the Cannabis Withdrawal Scale using 49 dependent cannabis users who provided daily symptom scores during one baseline week and two weeks of abstinence.\n\nThe scale demonstrated excellent psychometric properties: internal reliability (Cronbach's alpha = 0.91) and test-retest stability (average intra-class correlation = 0.95).\n\nNightmares and strange dreams were the most statistically valid withdrawal indicator (Wald chi-squared = 105.6) but caused relatively little distress. Angry outbursts were both intense (Wald chi-squared = 73.69) and highly distressing (Wald chi-squared = 45.54). Difficulty falling asleep was also intense (Wald chi-squared = 42.31) and distressing (Wald chi-squared = 47.76).\n\nScores on the Severity of Dependence Scale predicted the severity of cannabis withdrawal symptoms.","whyItMatters":"Having a validated withdrawal measure was essential for clinical trials of cannabis dependence treatments and for establishing cannabis withdrawal as a clinically recognized condition.","specificNumbers":"49 dependent cannabis users. Cronbach's alpha = 0.91. Intra-class correlation = 0.95. Nightmares: Wald chi-squared = 105.6. Angry outbursts: Wald chi-squared = 73.69. Sleep onset difficulty: Wald chi-squared = 42.31.","methodology":"Prospective validation study with 49 dependent cannabis users providing daily Cannabis Withdrawal Scale scores during 1 week of baseline use and 2 weeks of monitored abstinence. Psychometric analysis included internal reliability, test-retest stability, content validity, and predictor analysis.","limitations":"Volunteer sample of 49 participants may not represent all cannabis-dependent populations. Two weeks of abstinence may not capture the full withdrawal timeline. Self-reported symptoms."},{"rthcId":"RTHC-00468","title":"Association between substance use and psychosocial characteristics among adolescents of the Seychelles.","authors":"Alwan, Heba; Viswanathan, Bharathi; Rousson, Valentin; Paccaud, Fred; Bovet, Pascal","year":2011,"journal":"BMC pediatrics, 11, 85","doi":"10.1186/1471-2431-11-85","pmid":"21985036","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"A school survey of 1,432 students aged 11-17 from all secondary schools in the Seychelles examined associations between substance use and psychosocial characteristics.\n\nSubstance use (cigarette smoking, alcohol drinking, and cannabis use) was more prevalent in boys and increased with age. After adjusting for age, several individual-level risk factors were associated with substance use, including suicidal ideation and truancy.\n\nAt the family level, poor parental monitoring was associated with substance use. The authors emphasized that substance use clustered with other risk behaviors, suggesting health promotion programs should address multiple behaviors simultaneously.","whyItMatters":"This study from a developing small island state provided data from an under-represented region, showing that the association between substance use and psychosocial risk factors was consistent across diverse cultural contexts.","specificNumbers":"1,432 students aged 11-17. All secondary schools sampled. Boys had higher prevalence. Substance use increased with age. Suicidal ideation, truancy, and poor parental monitoring were significant correlates.","methodology":"Cross-sectional school survey using the Global School-based Health Survey (GSHS) methodology. Representative sample of 1,432 students aged 11-17 from all secondary schools. Self-administered anonymous questionnaire. Adjusted analyses accounted for classroom clustering effects.","limitations":"Cross-sectional design cannot establish causation. Self-reported anonymous questionnaire may be subject to social desirability bias. Cannabis use may be underreported in an African island context."},{"rthcId":"RTHC-00469","title":"Medial temporal structures and memory functions in adolescents with heavy cannabis use.","authors":"Ashtari, Manzar; Avants, Brian; Cyckowski, Laura; Cervellione, Kelly L; Roofeh, David; Cook, Philip; Gee, James; Sevy, Serge; Kumra, Sanjiv","year":2011,"journal":"Journal of psychiatric research, 45(8), 1055-66","doi":"10.1016/j.jpsychires.2011.01.004","pmid":"21296361","tags":["youth","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared hippocampal brain structure between 14 heavy cannabis-using adolescents (averaging 5.8 joints per day) and 14 matched controls using high-resolution MRI, after an average of 6.7 months of supervised abstinence.\n\nHeavy cannabis users had significantly smaller right (p < 0.04) and left (p < 0.02) hippocampal volumes compared to controls. No significant differences were found in the amygdala.\n\nIn controls, larger hippocampal volumes correlated significantly with better verbal learning and memory scores. This normal brain-cognition relationship was absent in cannabis users.\n\nSmaller right hippocampus volume was correlated with greater prior cannabis use (r = -0.57, p < 0.03), suggesting a dose-response relationship.","whyItMatters":"The persistence of hippocampal volume differences after nearly 7 months of abstinence suggested that heavy adolescent cannabis use may produce lasting structural brain changes, particularly in a region critical for memory and learning.","specificNumbers":"14 cannabis users (5.8 joints/day average) vs 14 controls. Mean 6.7 months abstinence. Smaller left (p < 0.02) and right (p < 0.04) hippocampi. Right hippocampal volume correlated with use amount (r = -0.57, p < 0.03).","methodology":"Cross-sectional MRI study comparing 14 treatment-seeking adolescents (aged 18-20) with heavy cannabis history to 14 demographically matched controls. High-resolution 3D MRI and California Verbal Learning Test administered after average 6.7 months of supervised drug abstinence.","limitations":"Small sample size (14 per group). Cross-sectional design cannot determine whether smaller hippocampi preceded or resulted from cannabis use. Treatment-seeking adolescents may not represent all cannabis users. No pre-use baseline imaging."},{"rthcId":"RTHC-00470","title":"Effects of chronic bhang (cannabis) administration on the reproductive system of male mice.","authors":"Banerjee, Arnab; Singh, Ajit; Srivastava, Puneet; Turner, Helen; Krishna, Amitabh","year":2011,"journal":"Birth defects research. Part B, Developmental and reproductive toxicology, 92(3), 195-205","doi":"10.1002/bdrb.20295","pmid":"21678546","tags":["pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adult male mice received oral bhang (cannabis extract) at 3 or 6 mg/kg daily for 36 consecutive days. The chronic exposure produced multiple reproductive impairments.\n\nSperm count, viability, and motility all declined significantly. Circulating testosterone levels dropped due to reduced activity of a key steroidogenic enzyme (3-beta-HSD) in the testes.\n\nThe study also confirmed that CB1 and CB2 cannabinoid receptors and the endocannabinoid-degrading enzyme FAAH were present in mouse testes. Bhang exposure significantly altered the levels of these proteins.\n\nBoth in vivo and in vitro experiments showed bhang directly affected testicular function by reducing luteinizing hormone receptor expression, suggesting effects beyond just hormonal disruption from the brain.","whyItMatters":"The study demonstrated that cannabis can directly affect testicular function through the endocannabinoid system, not just indirectly through hormonal disruption, expanding understanding of how cannabis affects male fertility.","specificNumbers":"Bhang doses: 3 or 6 mg/kg/day for 36 days. Significant reductions in sperm count, viability, motility, and testosterone. Significant changes in CB1, CB2, and FAAH protein levels in testes.","methodology":"Controlled animal study in adult male Parkes strain mice. Bhang administered orally at 3 or 6 mg/kg/day for 36 days. Sperm parameters, testosterone levels, enzyme activity, and protein expression measured by immunohistochemistry. In vitro testicular tissue exposure also performed.","limitations":"Mouse model with oral bhang administration that may differ from human cannabis consumption patterns. Doses and duration may not be directly comparable to human use. Fertility outcomes (actual mating success) were not tested."},{"rthcId":"RTHC-00471","title":"The manifold actions of endocannabinoids on female and male reproductive events.","authors":"Bari, Monica; Battista, Natalia; Pirazzi, Valentina; Maccarrone, Mauro","year":2011,"journal":"Frontiers in bioscience (Landmark edition), 16(2), 498-516","doi":null,"pmid":"21196184","tags":["pregnancy","neuroscience","sex-differences"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review traced the role of endocannabinoids in reproductive biology across the evolutionary spectrum from invertebrates to mammals.\n\nIn females, chronic THC exposure was found to disrupt the menstrual cycle, suppress egg development (oogenesis), and impair embryo implantation and development. The endocannabinoid system played a critical role in signaling fertility windows and regulating the uterine environment for embryo attachment.\n\nIn males, THC was associated with increased ejaculation problems, reduced sperm count and motility, loss of libido, and impotence. Endocannabinoids normally regulated sperm capacitation and the acrosome reaction needed for fertilization.\n\nThe review noted that endocannabinoid system components responded to fertility hormones and interacted with cytokines and other signaling molecules in reproductive tissues.","whyItMatters":"The review established that the endocannabinoid system is deeply integrated into reproductive biology at every level, meaning cannabis exposure can disrupt fertility through multiple mechanisms simultaneously.","specificNumbers":"THC effects documented: disrupted menstrual cycle, suppressed oogenesis, impaired implantation (females); reduced sperm count and motility, ejaculation problems, libido loss (males).","methodology":"Comprehensive narrative review synthesizing evidence from invertebrate to mammalian studies on the endocannabinoid system's roles in female and male reproduction, published in Frontiers in Bioscience.","limitations":"Much of the evidence came from animal studies and in vitro work. Human reproductive effects of cannabis were less well documented. The review drew on evolutionary comparisons that may not always translate directly to human biology."},{"rthcId":"RTHC-00472","title":"Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients.","authors":"Bergamaschi, Mateus M; Queiroz, Regina Helena Costa; Chagas, Marcos Hortes Nisihara; de Oliveira, Danielle Chaves Gomes; De Martinis, Bruno Spinosa; Kapczinski, Flávio; Quevedo, João; Roesler, Rafael; Schröder, Nadja; Nardi, Antonio E; Martín-Santos, Rocio; Hallak, Jaime Eduardo Cecílio; Zuardi, Antonio Waldo; Crippa, José Alexandre S","year":2011,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36(6), 1219-26","doi":"10.1038/npp.2011.6","pmid":"21307846","tags":["cbd","anxiety"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-four treatment-naive SAD patients were randomized to CBD 600 mg (n=12) or placebo (n=12), with 12 healthy controls. CBD significantly reduced anxiety (p=0.012), cognitive impairment (p=0.009), and discomfort (p=0.029) during public speaking versus placebo. Negative self-statements were \"almost abolished\" by CBD. No significant differences between CBD and healthy controls on most measures (SSPS-N, cognitive impairment, discomfort, alertness subscales of VAMS). Statistical power: 0.996 for primary anxiety measure.","whyItMatters":"This study provided the clearest evidence to date that CBD could normalize clinical anxiety to healthy control levels without sedation or cognitive impairment — differentiating it from benzodiazepines. Combined with companion neuroimaging showing CBD reduces limbic brain activity, it established CBD as a serious anxiolytic candidate with a plausible mechanism. It became the foundational citation for the entire CBD anxiety research field and the CBD wellness market.","specificNumbers":"24 SAD patients (12 CBD, 12 placebo) + 12 healthy controls. CBD dose: 600 mg, single dose. Significant reductions in anxiety, cognitive impairment, discomfort, and negative self-statements. CBD group scores were similar to healthy controls.","methodology":"Double-blind, randomized, placebo-controlled study with healthy control group. 2,319 undergraduates screened with MINI-SPIN; 24 treatment-naive SAD patients confirmed by SCID-CV. CBD group received 600 mg (~99.9% pure) in gelatin capsules 90 min before Simulated Public Speaking Test (4-min speech, videotaped). Measured: Visual Analogue Mood Scale (VAMS — 4 factors), Negative Self-Statement Scale (SSPS-N), Bodily Symptoms Scale (BSS), heart rate, blood pressure, skin conductance at 6 time points. FAPESP-funded. Repeated-measures ANOVA with Bonferroni correction.","limitations":"Only 12 patients per group. Single-dose study with no information on repeated dosing, tolerance, or durability. 600 mg dose is impractical and expensive for real-world use. Simulated public speaking does not capture daily social anxiety. Young Brazilian university student sample limits generalizability. Treatment-naive patients may respond differently than typical treatment-seeking patients. No adverse event power with 12 subjects."},{"rthcId":"RTHC-00473","title":"Cannabis use among military veterans after residential treatment for posttraumatic stress disorder.","authors":"Bonn-Miller, Marcel O; Vujanovic, Anka A; Drescher, Kent D","year":2011,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 25(3), 485-91","doi":"10.1037/a0021945","pmid":"21261407","tags":["ptsd","addiction","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tracked 432 male military veterans admitted to residential PTSD rehabilitation, examining whether treatment response predicted subsequent cannabis use.\n\nLower levels of PTSD symptom improvement between intake and discharge significantly predicted greater cannabis use frequency at 4-month follow-up, even after controlling for pre-treatment cannabis use and length of stay.\n\nSpecifically, less improvement in avoidance/numbing symptoms and hyperarousal symptoms drove this relationship. These are the PTSD symptom clusters most associated with emotional regulation difficulties.\n\nImportantly, this relationship was specific to cannabis. The same pattern was not observed for alcohol or opiates, suggesting veterans may have been selectively using cannabis to manage residual PTSD symptoms.","whyItMatters":"The cannabis-specific finding suggested that veterans may have been self-medicating residual PTSD symptoms with cannabis, highlighting the need for both more effective PTSD treatments and integrated substance use management.","specificNumbers":"432 male veterans, mean age 51. Lower PCL-M change scores predicted greater cannabis use at 4 months (p < .05). Effect was specific to cannabis, not alcohol or opiates. Avoidance/numbing and hyperarousal symptom clusters drove the relationship.","methodology":"Prospective cohort study of 432 male military veterans (mean age 51 years) with primary PTSD diagnosis. PCL-M (PTSD Checklist-Military) scores at intake and discharge compared to substance use frequency at 4-month follow-up. Controlled for treatment duration and baseline substance use.","limitations":"All-male veteran sample limits generalizability. Self-reported cannabis use. Observational design cannot prove cannabis was used specifically for PTSD symptom relief. No data on whether cannabis actually helped manage symptoms."},{"rthcId":"RTHC-00474","title":"Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition.","authors":"Cippitelli, Andrea; Astarita, Giuseppe; Duranti, Andrea; Caprioli, Giovanni; Ubaldi, Massimo; Stopponi, Serena; Kallupi, Marsida; Sagratini, Gianni; Rodrìguez de Fonseca, Fernando; Piomelli, Daniele; Ciccocioppo, Roberto","year":2011,"journal":"PloS one, 6(11), e28142","doi":"10.1371/journal.pone.0028142","pmid":"22140525","tags":["addiction","neuroscience","withdrawal"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats made dependent on nicotine via transdermal patches for 7 days showed both physical and emotional withdrawal symptoms when patches were removed.\n\nPhysical (somatic) withdrawal signs appeared at 16 hours and emotional (affective) signs at 34 hours after patch removal. The researchers found that spontaneous nicotine withdrawal was accompanied by significant fluctuations in anandamide (an endocannabinoid) levels across the amygdala, hippocampus, hypothalamus, and prefrontal cortex. Levels of 2-AG, the other major endocannabinoid, were not significantly altered.\n\nThe FAAH inhibitor URB597, which boosts anandamide levels, reduced withdrawal-related anxiety at both doses tested (0.1 and 0.3 mg/kg) on two different anxiety measures. However, URB597 did not reduce physical withdrawal signs.","whyItMatters":"The selective effect of endocannabinoid enhancement on emotional but not physical nicotine withdrawal suggested that boosting the endocannabinoid system could specifically target the anxiety component that often drives relapse.","specificNumbers":"Nicotine: 5.2 mg/rat/day for 7 days. Somatic signs at 16 hours, affective signs at 34 hours. URB597 at 0.1 and 0.3 mg/kg reduced anxiety. Anandamide fluctuated in amygdala, hippocampus, hypothalamus, and prefrontal cortex.","methodology":"Controlled animal study in Wistar rats. Nicotine dependence induced via transdermal patches (5.2 mg/rat/day for 7 days). Withdrawal assessed by somatic signs, anxiety tests (elevated plus maze, shock-probe defensive burying), locomotion, and weight. Brain endocannabinoid levels measured by mass spectrometry. URB597 tested at 0.1 and 0.3 mg/kg i.p.","limitations":"Animal model using transdermal nicotine delivery that may differ from human smoking. Only one week of dependence induction. Brain endocannabinoid measurements were at specific time points. Translation to human smoking cessation uncertain."},{"rthcId":"RTHC-00475","title":"Medical marijuana: medical necessity versus political agenda.","authors":"Clark, Peter A; Capuzzi, Kevin; Fick, Cameron","year":2011,"journal":"Medical science monitor : international medical journal of experimental and clinical research, 17(12), RA249-61","doi":null,"pmid":"22129912","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined the conflict between federal marijuana classification (Schedule I, no accepted medical use) and accumulating scientific evidence.\n\nStudies showed medical marijuana was effective for controlling chronic non-cancer pain, alleviating chemotherapy-associated nausea and vomiting, treating AIDS wasting syndrome, and controlling MS muscle spasms. Benefits outweighed negative effects in patients who had failed other therapies.\n\nAt the time of publication, 16 states and the District of Columbia had legalized medical marijuana, creating a direct conflict with federal zero-tolerance policy.\n\nThe authors argued from bioethical principles that patients had a right to beneficial treatments, and denying physicians the ability to prescribe marijuana to suffering patients who had exhausted other options violated principles of beneficence and nonmaleficence.","whyItMatters":"The review framed the medical marijuana debate in ethical terms, arguing that the gap between evidence and policy constituted a violation of patient rights and medical ethics.","specificNumbers":"Medical marijuana was legal in 16 states plus DC at the time. Evidence supported efficacy in 4 major conditions. Federal classification remained Schedule I.","methodology":"Narrative review of scientific evidence for medical marijuana efficacy combined with analysis of regulatory status and ethical framework based on bioethical principles.","limitations":"Advocacy-oriented review rather than systematic evidence synthesis. Did not quantify the strength of evidence for each condition. Did not address potential harms in depth."},{"rthcId":"RTHC-00476","title":"Pre-illness cannabis use and the early course of nonaffective psychotic disorders: associations with premorbid functioning, the prodrome, and mode of onset of psychosis.","authors":"Compton, Michael T; Broussard, Beth; Ramsay, Claire E; Stewart, Tarianna","year":2011,"journal":"Schizophrenia research, 126(1-3), 71-6","doi":"10.1016/j.schres.2010.10.005","pmid":"21036542","tags":["psychosis","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers examined how pre-illness cannabis use related to the course of early psychosis in 109 first-episode patients.\n\nSurprisingly, patients who used cannabis by age 15 had better early adolescent social functioning than those who had not used cannabis. However, those who used cannabis by age 18 had significantly poorer late adolescent academic functioning.\n\nCannabis use before psychosis onset did not affect whether patients experienced a prodromal phase or the number of prodromal symptoms. However, mode of onset differed dramatically: 42% of daily cannabis users had an acute onset of psychosis versus only 20% of those without prior daily use.\n\nNicotine and alcohol use were also examined but did not show the same pattern of associations.","whyItMatters":"The finding that daily cannabis use was associated with acute psychosis onset (rather than gradual) had clinical implications for early detection and intervention strategies.","specificNumbers":"109 first-episode patients. Cannabis by age 15: better early social functioning (p=0.02). Cannabis by age 18: poorer late academic functioning (p<0.001). Daily cannabis users: 42% acute onset vs 20% non-daily users (p=0.04).","methodology":"Cross-sectional study of 109 first-episode patients hospitalized in public-sector settings. Assessments included ages at substance initiation, Premorbid Adjustment Scale, Symptom Onset in Schizophrenia inventory, and consensus-based mode of onset classification.","limitations":"Cross-sectional and retrospective design. Self-reported substance use before illness. Hospitalized patients may not represent all first-episode cases. Temporal relationships between cannabis and premorbid changes are uncertain."},{"rthcId":"RTHC-00477","title":"Effects of chronic, heavy cannabis use on executive functions.","authors":"Crean, Rebecca D; Tapert, Susan F; Minassian, Arpi; Macdonald, Kai; Crane, Natania A; Mason, Barbara J","year":2011,"journal":"Journal of addiction medicine, 5(1), 9-15","doi":"10.1097/ADM.0b013e31820cdd57","pmid":"21643485","tags":["cognition","quitting","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The case described a cannabis-dependent person entering a 12-week abstinence-based research program. Executive function was tested at three time points: after 24 hours, 4 weeks, and 12 weeks of abstinence.\n\nThe case illustrated the trajectory of cognitive recovery during sustained cannabis abstinence, with particular focus on executive functions including planning, decision-making, inhibitory control, and cognitive flexibility.\n\nThe report was accompanied by commentary from two clinical psychologists and a psychiatrist, discussing the clinical implications of executive function impairment for treatment participation and sustained recovery.","whyItMatters":"Executive functions are critical for treatment engagement and maintaining recovery. Understanding the timeline of cognitive recovery informed how treatment programs should be structured and when patients might be best able to benefit from cognitive-behavioral interventions.","specificNumbers":"Testing at 24 hours, 4 weeks, and 12 weeks of abstinence. Progressive executive function improvement documented over the 12-week period.","methodology":"Clinical case report documenting neuropsychological assessment at 24 hours, 4 weeks, and 12 weeks of monitored abstinence in a cannabis-dependent individual participating in a research program. Expert commentary provided clinical context.","limitations":"Single case report cannot establish generalizable recovery timelines. Individual variation in recovery is expected. No comparison to non-using controls or other substances."},{"rthcId":"RTHC-00478","title":"Factors associated with alcohol and drug use among traffic crash victims in southern Brazil.","authors":"De Boni, Raquel; Bozzetti, Mary Clarisse; Hilgert, Juliana; Sousa, Tanara; Von Diemen, Lisia; Benzano, Daniela; Menegon, Guilherme; Holmer, Barbara; Duarte, Paulina do Carmo Arruda Vieira; Pechansky, Flavio","year":2011,"journal":"Accident; analysis and prevention, 43(4), 1408-13","doi":"10.1016/j.aap.2011.02.016","pmid":"21545873","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Emergency room data from two Porto Alegre hospitals over 45 days identified 609 traffic crash victims. Key findings:\n\nDrivers were mostly male (p<0.001) with higher rates of binge drinking (p=0.003) and marijuana use (p=0.005) compared to pedestrians and passengers. Cannabis prevalence was 13.3% among drivers.\n\nPositive blood alcohol was found in 7.8% of drivers and 9.2% of pedestrians. The variables most associated with alcohol-related crashes were binge drinking in the prior year (OR 2.4) and coming from a party or bar (OR 8.7).\n\nAlcohol abuse or dependence increased the odds of an additional substance-related crash by 5.2 times, indicating that alcohol problems substantially increased the risk of polysubstance-impaired driving.","whyItMatters":"The 13.3% cannabis prevalence among crash-involved drivers in Brazil highlighted cannabis as a significant traffic safety concern beyond alcohol alone.","specificNumbers":"609 victims, 72% male, median age 29. Cannabis positive: 13.3% of drivers. BAC positive: 7.8% of drivers. Binge drinking: OR 2.4. Coming from party/bar: OR 8.7. Alcohol dependence increased other substance-related crash risk 5.2-fold.","methodology":"Cross-sectional study with consecutive sampling of non-fatal traffic crash victims at two emergency rooms over 45 days. Structured interview, breathalyzer, and salivary drug testing. Multinomial logistic regression for associated factors.","limitations":"Cross-sectional emergency room sample (no comparison to non-crash drivers). Salivary testing may detect cannabis from days prior. Cannot determine whether cannabis caused or contributed to the crash."},{"rthcId":"RTHC-00479","title":"Endocannabinoid pathways and their role in multiple sclerosis-related muscular dysfunction.","authors":"Di Marzo, Vincenzo","year":2011,"journal":"Expert review of neurotherapeutics, 11(4 Suppl), 9-14","doi":null,"pmid":"21449854","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined the role of endocannabinoids in MS-related muscular dysfunction and the therapeutic potential of Sativex (nabiximols), containing equal parts THC and CBD.\n\nEndocannabinoid levels were found to be altered in both animal models of MS and in cerebrospinal fluid samples from MS patients. Anandamide and 2-AG levels changed in different and sometimes opposing ways, suggesting complex regulatory involvement.\n\nIn an experimental mouse model of MS-related spasticity, Sativex dose-dependently improved hind limb flexion and stiffness. At 10 mg/kg, Sativex was as effective as baclofen at 5 mg/kg, the most widely used anti-spasticity medication.\n\nThe author noted that Sativex acted as an \"endocannabinoid system modulator\" rather than simply activating cannabinoid receptors.","whyItMatters":"Demonstrating that a cannabis-based medicine could match the effectiveness of established anti-spasticity treatment in an animal model provided strong preclinical support for clinical development.","specificNumbers":"Sativex at 10 mg/kg was as effective as baclofen at 5 mg/kg for MS-related spasticity in mice. THC:CBD ratio was 1:1.","methodology":"Expert review examining endocannabinoid pathways in MS-related spasticity, including animal model data and patient cerebrospinal fluid studies, with focus on Sativex preclinical efficacy data.","limitations":"Mouse model of spasticity may not perfectly replicate human MS. Single expert review perspective. The \"modulator\" mechanism was described conceptually rather than with detailed molecular evidence."},{"rthcId":"RTHC-00480","title":"Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring.","authors":"DiNieri, Jennifer A; Wang, Xinyu; Szutorisz, Henrietta; Spano, Sabrina M; Kaur, Jasbir; Casaccia, Patrizia; Dow-Edwards, Diana; Hurd, Yasmin L","year":2011,"journal":"Biological psychiatry, 70(8), 763-769","doi":"10.1016/j.biopsych.2011.06.027","pmid":"21820648","tags":["pregnancy","dopamine","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"This study combined human fetal tissue analysis with a rat model to investigate how prenatal cannabis exposure affects the developing brain's reward system.\n\nIn human fetal subjects, prenatal cannabis exposure specifically decreased dopamine D2 receptor (DRD2) gene expression in the nucleus accumbens, the brain's key reward region. Other dopamine and opioid genes were not significantly affected by cannabis (though cigarettes affected prodynorphin and alcohol affected multiple genes).\n\nIn rats, prenatal THC exposure produced epigenetic changes at the D2 receptor gene that persisted into adulthood. Specifically, repressive epigenetic marks increased while activating marks decreased at the DRD2 gene locus. Adult offspring had fewer D2 receptor binding sites and were more sensitive to opiate reward.\n\nThis was direct evidence that prenatal cannabis exposure could alter gene regulation through epigenetic mechanisms, with lasting consequences for addiction vulnerability.","whyItMatters":"This was among the first studies to demonstrate a specific epigenetic mechanism by which prenatal cannabis exposure could permanently alter reward circuit development and increase addiction vulnerability in offspring.","specificNumbers":"THC dose: 0.15 mg/kg during pregnancy. DRD2 mRNA decreased in human fetal nucleus accumbens. Increased 2meH3K9 (repressive) and decreased 3meH3K4 (activating) marks at Drd2 gene in adult rat offspring. Reduced D2R binding sites and increased opiate sensitivity.","methodology":"Combined human fetal tissue study and rat model. Human: gene expression analysis in striatal tissue from cannabis-exposed (and cigarette/alcohol-exposed) fetuses. Rat: pregnant rats exposed to THC (0.15 mg/kg), offspring assessed at postnatal day 2 and adulthood by chromatin immunoprecipitation, receptor binding assays, and opiate reward sensitivity tests.","limitations":"Human fetal tissue sample sizes were not reported in the abstract. Rat THC doses may not reflect typical human cannabis exposure during pregnancy. Epigenetic changes are complex and other genes may also be affected."},{"rthcId":"RTHC-00481","title":"Age moderates non-genetic influences on the initiation of cannabis use: a twin-sibling study in Dutch adolescents and young adults.","authors":"Distel, Marijn A; Vink, Jacqueline M; Bartels, Meike; van Beijsterveldt, Catharina E M; Neale, Michael C; Boomsma, Dorret I","year":2011,"journal":"Addiction (Abingdon, England), 106(9), 1658-66","doi":"10.1111/j.1360-0443.2011.03465.x","pmid":"21489006","tags":["genetics","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined 6,208 twins and 1,545 siblings from 3,503 Dutch families to understand how the genetic-environmental balance for cannabis initiation changed with age.\n\nAt the median age of 16.5, genetic factors explained 40% of individual differences in cannabis initiation. Twins resembled each other more than non-twin siblings, even after accounting for age differences.\n\nEnvironmental influences increased with age across all categories. Factors shared only between twins accounted for 47% of variance, factors shared by all siblings in a family for 24%, and individual-specific factors for 13%. All of these environmental components grew larger as young people aged.\n\nThe result was that heritability was proportionally higher in adolescents than in young adults, not because genetic influence decreased, but because environmental exposure opportunities expanded with age.","whyItMatters":"The finding that environmental influences on cannabis initiation grew with age helped explain why prevention efforts targeting social environments may be increasingly important for older adolescents and young adults.","specificNumbers":"7,753 total participants from 3,503 families. At age 16.5: genetic = 40%, twin-shared environment = 47%, family-shared = 24%, unique environment = 13%. All environmental components increased with age.","methodology":"Twin-sibling study using genetic structural equation modeling. 6,208 twins (ages 13-20) and 1,545 siblings (ages 11-25) from 3,503 families in the Netherlands Twin Register. Self-reported cannabis use from the Dutch Health Behavior Questionnaire. Age moderation of genetic and environmental variance components tested.","limitations":"Dutch sample where cannabis is relatively accessible, potentially affecting environmental component estimates. Self-reported cannabis use. Cross-sectional age comparisons rather than longitudinal tracking."},{"rthcId":"RTHC-00482","title":"Cannabinoids and innate immunity: taking a toll on neuroinflammation.","authors":"Downer, Eric J","year":2011,"journal":"TheScientificWorldJournal, 11, 855-65","doi":"10.1100/tsw.2011.84","pmid":"21479354","tags":["inflammation","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review connected two important biological systems: the cannabinoid system and the Toll-like receptor (TLR) system, which mediates innate immunity in the brain.\n\nTLRs are pattern recognition receptors that detect threats and trigger inflammatory responses. They have emerged as important players in the neuroinflammatory processes underlying various CNS diseases including Alzheimer's, multiple sclerosis, and Parkinson's disease.\n\nCannabinoid receptors and endocannabinoids are present on immune cells and brain glial cells (microglia and astrocytes). The review highlighted evidence that cannabinoids could reduce neuroinflammation specifically by dampening TLR-mediated signaling events.\n\nThis interaction provided a molecular framework for understanding why cannabinoids showed anti-inflammatory effects in neurological disease models.","whyItMatters":"Identifying the TLR pathway as a target of cannabinoid anti-inflammatory action provided a specific molecular mechanism that could guide the development of targeted therapies for neuroinflammatory conditions.","specificNumbers":"TLRs constitute a major family of pattern recognition receptors. Cannabinoid receptors and endocannabinoids detected on immune cells and brain glia.","methodology":"Narrative review synthesizing evidence on the interaction between cannabinoid system components and Toll-like receptor signaling pathways in neuroinflammation.","limitations":"Primarily based on in vitro and animal model data. The complexity of TLR signaling pathways means that cannabinoid effects may vary depending on which TLR is involved and what disease state is present."},{"rthcId":"RTHC-00483","title":"Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement.","authors":"Esposito, Giuseppe; Scuderi, Caterina; Valenza, Marta; Togna, Giuseppina Ines; Latina, Valentina; De Filippis, Daniele; Cipriano, Mariateresa; Carratù, Maria Rosaria; Iuvone, Teresa; Steardo, Luca","year":2011,"journal":"PloS one, 6(12), e28668","doi":"10.1371/journal.pone.0028668","pmid":"22163051","tags":["cbd","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers investigated whether CBD's neuroprotective effects in Alzheimer's disease (AD) models worked through the PPARgamma receptor, recently identified as a potential CBD binding site.\n\nIn rat AD models exposed to beta-amyloid (the toxic protein in Alzheimer's), CBD reduced reactive gliosis (brain immune cell activation) and subsequent neuronal damage. Blocking the PPARgamma receptor significantly blunted these protective effects, confirming PPARgamma was essential for CBD's mechanism.\n\nAdditionally, CBD stimulated hippocampal neurogenesis (the growth of new brain cells) through its PPARgamma interaction. This was particularly significant because the hippocampus is the brain region most affected by Alzheimer's.\n\nThe findings identified PPARgamma as the critical receptor mediating CBD's anti-inflammatory and neurogenic actions in AD models.","whyItMatters":"Identifying PPARgamma as CBD's mechanism of action provided a specific molecular target for understanding and potentially optimizing CBD's neuroprotective properties in Alzheimer's disease.","specificNumbers":"PPARgamma blockade significantly reduced CBD's anti-inflammatory and neuroprotective effects. CBD stimulated hippocampal neurogenesis through PPARgamma activation.","methodology":"Preclinical study using rat Alzheimer's disease models with beta-amyloid-induced neurotoxicity. CBD effects tested in the presence and absence of PPARgamma antagonists. Reactive gliosis, neuronal damage, and hippocampal neurogenesis assessed.","limitations":"Rat model of Alzheimer's with artificially introduced beta-amyloid, which may not fully replicate human disease progression. In vivo relevance of PPARgamma-mediated neurogenesis requires further validation. No clinical data available."},{"rthcId":"RTHC-00484","title":"Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life.","authors":"Fiz, Jimena; Durán, Marta; Capellà, Dolors; Carbonell, Jordi; Farré, Magí","year":2011,"journal":"PloS one, 6(4), e18440","doi":"10.1371/journal.pone.0018440","pmid":"21533029","tags":["pain","medical-cannabis","sleep"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared 28 fibromyalgia patients who used cannabis to 28 matched non-users. Demographics and clinical profiles were similar between groups.\n\nCannabis users consumed the drug through smoking (54%), oral ingestion (46%), or combined routes (43%), with variable amounts and frequencies. Within 2 hours of cannabis use, visual analogue scale scores showed statistically significant improvements in pain, stiffness, relaxation, drowsiness, and feeling of well-being (all p<0.001).\n\nOn the SF-36 quality of life measure, cannabis users had significantly higher mental health component scores (p<0.05) than non-users. However, no significant differences were found in other SF-36 domains, the Fibromyalgia Impact Questionnaire, or the Pittsburgh Sleep Quality Index.","whyItMatters":"This was one of the first studies to document specific symptom relief from cannabis in fibromyalgia patients using validated measurement tools, though the observational design limited causal conclusions.","specificNumbers":"28 cannabis users, 28 non-users. Routes: 54% smoking, 46% oral, 43% combined. At 2 hours post-use: significant reductions in pain and stiffness (p<0.001). Mental health SF-36 scores significantly higher in users (p<0.05).","methodology":"Cross-sectional study comparing 28 fibromyalgia cannabis users to 28 non-users. Cannabis effects measured by VAS at baseline and 2 hours post-use. Quality of life, fibromyalgia impact, and sleep quality compared between groups using FIQ, PSQI, and SF-36.","limitations":"Observational study without blinding or placebo control. Self-selected cannabis users may differ from non-users in ways beyond cannabis use. The 2-hour measurement window captured acute effects only. Small sample size."},{"rthcId":"RTHC-00485","title":"Associations of social phobia and general anxiety with alcohol and drug use in a community sample of adolescents.","authors":"Fröjd, Sari; Ranta, Klaus; Kaltiala-Heino, Riittakerttu; Marttunen, Mauri","year":2011,"journal":"Alcohol and alcoholism (Oxford, Oxfordshire), 46(2), 192-9","doi":"10.1093/alcalc/agq096","pmid":"21245062","tags":["anxiety","youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed Finnish adolescents aged 15-16 at baseline over two years to examine how anxiety related to substance use.\n\nAnxiety preceded substance use, but no reciprocal effect was found (substance use did not predict anxiety). Depression mediated the relationship between anxiety and substance use.\n\nGeneral anxiety increased the incidence of frequent alcohol use and cannabis use. However, social phobia had a different pattern: it did not elevate substance use incidence and actually decreased the persistence of frequent alcohol use. The authors suggested social phobia may \"protect\" from substance use because socially anxious teens avoid the social situations where substance use typically occurs.\n\nFrequent drunkenness was less strongly associated with anxiety than regular alcohol use or cannabis use.","whyItMatters":"The contrasting effects of general anxiety versus social phobia on substance use had direct implications for prevention, suggesting that different types of anxiety require different intervention approaches.","specificNumbers":"Baseline age 15-16 with 2-year follow-up. Anxiety preceded substance use (no reciprocal effect). Depression mediated the anxiety-substance use link. Social phobia decreased persistence of frequent alcohol use.","methodology":"Longitudinal cohort study using the Adolescent Mental Health Cohort Study, a school-based Finnish survey. Baseline assessment at ages 15-16 with 2-year follow-up. Associations between social phobia, general anxiety, and substance use (alcohol, drunkenness, cannabis) analyzed for prevalence, incidence, and continuity.","limitations":"Finnish adolescent sample may not generalize to all cultures. Self-reported substance use and anxiety symptoms. Cannabis use was described as smoked hashish of unknown composition. Two-year follow-up may miss longer-term patterns."},{"rthcId":"RTHC-00486","title":"Cannabinoid hyperemesis syndrome.","authors":"Galli, Jonathan A; Sawaya, Ronald Andari; Friedenberg, Frank K","year":2011,"journal":"Current drug abuse reviews, 4(4), 241-9","doi":null,"pmid":"22150623","tags":["appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review synthesized existing knowledge about cannabinoid hyperemesis syndrome (CHS), describing a paradox: cannabis is well-established as an anti-emetic, yet chronic use could cause severe cyclic vomiting.\n\nThe clinical course was divided into three phases. The prodromal phase involved morning nausea and fear of vomiting. The hyperemetic phase featured severe nausea, vomiting, and abdominal pain, typically ceasing within 48 hours. The recovery phase saw symptom resolution with cannabis cessation.\n\nCompulsive hot bathing was identified as a learned behavior that provided temporary symptom relief, with patients often spending hours in hot water. The mechanism remained unknown, though the review discussed opposing effects of THC, CBD, and cannabigerol on the emesis response.\n\nCHS was frequently misdiagnosed due to overlapping symptoms with cyclic vomiting syndrome, leading to unnecessary diagnostic workups.","whyItMatters":"The comprehensive characterization of CHS phases, hallmark features, and differential diagnosis helped clinicians recognize and diagnose the condition more efficiently, potentially reducing unnecessary testing.","specificNumbers":"Three phases identified: prodromal, hyperemetic (ceases within 48 hours), recovery. Three cannabinoids with opposing emesis effects: THC, CBD, cannabigerol.","methodology":"Narrative review synthesizing case reports, clinical series, and pathophysiological hypotheses about cannabinoid hyperemesis syndrome.","limitations":"Knowledge was largely based on case reports and small series. Mechanism remained unknown. Epidemiology was poorly characterized. No validated diagnostic criteria existed at the time."},{"rthcId":"RTHC-00487","title":"Antagonist-elicited cannabis withdrawal in humans.","authors":"Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A","year":2011,"journal":"Journal of clinical psychopharmacology, 31(5), 603-12","doi":"10.1097/JCP.0b013e31822befc1","pmid":"21869692","tags":["withdrawal","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Ten male daily cannabis smokers received around-the-clock oral THC (40-120 mg/day increasing over 8 days) to standardize cannabis dependence in a closed research unit. On day 9, they received double-blind placebo or rimonabant (a CB1 receptor antagonist) at 20 or 40 mg.\n\nUsing the prespecified criterion (150% increase in at least 3 withdrawal visual analog scales within 3 hours), only 3 of 5 subjects in the 20-mg group and 1 of 3 in the 40-mg group met the withdrawal threshold. No placebo subjects met the criterion.\n\nThere were no significant associations between withdrawal symptoms and rimonabant plasma levels. The study was terminated prematurely because rimonabant was withdrawn from clinical development (due to psychiatric side effects in other studies).\n\nThe authors noted that higher rimonabant doses might produce more reliable withdrawal, but these could not be tested.","whyItMatters":"This was the first and only study to attempt antagonist-elicited cannabis withdrawal in humans, an important methodology for understanding cannabis dependence physiology.","specificNumbers":"10 completers (14 enrolled). THC: 40-120 mg/day over 8 days. Rimonabant: 20 mg (n=5+1 placebo) or 40 mg (n=3+1 placebo). 3/5 met withdrawal criterion at 20 mg, 1/3 at 40 mg, 0/2 at placebo.","methodology":"Double-blind, placebo-controlled study in 10 daily cannabis smokers on a closed research unit. 8 days of escalating oral THC to standardize dependence, followed by single-dose rimonabant or placebo on day 9. Withdrawal assessed by visual analog scales, heart rate, and blood pressure for 23.5 hours. Rimonabant and THC plasma levels quantified by mass spectrometry.","limitations":"Very small sample (10 completers). Prematurely terminated. Rimonabant doses may have been too low. Oral THC dosing may not perfectly replicate smoked cannabis dependence. No longer possible to replicate with rimonabant."},{"rthcId":"RTHC-00488","title":"Does the EQ-5D measure quality of life in schizophrenia?","authors":"Halling Hastrup, Lene; Nordentoft, Merete; Hjorthøj, Carsten; Gyrd-Hansen, Dorte","year":2011,"journal":"The journal of mental health policy and economics, 14(4), 187-96","doi":null,"pmid":"22345360","tags":["psychosis","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether the EQ-5D (a widely used generic health measure recommended for economic evaluations) adequately captured quality of life in patients with schizophrenia and cannabis abuse.\n\nThe EQ-5D showed only moderate correlation with the Manchester Short Assessment of Quality of Life (MANSA), a psychiatric-specific measure (rho = 0.358). Three of the five EQ-5D dimensions (Mobility, Self-Care, and Pain/Discomfort) were not sensitive in this population.\n\nOnly the \"Usual Activities\" and \"Anxiety/Depression\" dimensions showed moderate correlation with MANSA. Both measures correlated moderately with clinical scales (PANSS, GAF, WHO-DAS).\n\nThe authors recommended using EQ-5D alongside psychiatric-specific quality of life measures, as mental health interventions often target domains (relationships, finances, employment, housing) that EQ-5D does not capture.","whyItMatters":"Health economic evaluations using only generic measures could undervalue mental health interventions, particularly those addressing social functioning, relationships, and community integration in patients with dual diagnoses.","specificNumbers":"103 patients with schizophrenia and cannabis abuse. EQ-5D vs MANSA correlation: rho = 0.358. Mobility, Self-Care, and Pain/Discomfort dimensions were insensitive. Both measures correlated moderately with PANSS, GAF, and WHO-DAS.","methodology":"Cross-sectional analysis of 103 patients with schizophrenia and cannabis abuse from a randomized controlled trial. Correlation analysis between EQ-5D and MANSA using Spearman's coefficient, with additional correlations to PANSS, GAF, and WHO-DAS.","limitations":"Relatively small sample (103 patients). Specific to schizophrenia with cannabis comorbidity. Correlation analysis cannot establish which measure better captures true quality of life changes."},{"rthcId":"RTHC-00489","title":"Expecting innovation: psychoactive drug primes and the generation of creative solutions.","authors":"Hicks, Joshua A; Pedersen, Sarah L; Friedman, Ronald S; McCarthy, Denis M","year":2011,"journal":"Experimental and clinical psychopharmacology, 19(4), 314-20","doi":"10.1037/a0022954","pmid":"21480729","tags":["cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers tested whether substance-related cues (images, words) could enhance creative performance through the power of expectation alone, without any actual drug consumption.\n\nIn Study 1, participants were briefly exposed to either marijuana-related or neutral stimuli. Those who expected marijuana to enhance creativity performed significantly better on a creative problem-solving task after seeing marijuana cues. The same pattern was found with alcohol cues in a separate sample.\n\nIn Study 2, alcohol cues improved performance on a divergent thinking task (generating multiple creative ideas), but only for participants with creativity-related alcohol expectations. This improvement was specific to creative tasks and did not affect performance on non-creative measures.\n\nNo drugs were consumed. The creative enhancement came entirely from the activation of existing expectations about substance effects.","whyItMatters":"The finding that expectations alone (without drug consumption) could enhance creativity raised important questions about how much of cannabis's reported cognitive effects are pharmacological versus psychological.","specificNumbers":"566 total participants across studies. Marijuana cues enhanced creative problem-solving (Study 1). Alcohol cues enhanced divergent thinking (Study 2). Effects were specific to creative tasks and moderated by pre-existing expectations.","methodology":"Two experimental studies with 566 total participants. Brief exposure to substance-related or neutral stimuli followed by creative problem-solving or divergent thinking tasks. Substance expectancies measured. Study 2 included a non-creative control task.","limitations":"Laboratory creative tasks may not reflect real-world creative production. Expectancies were measured, not manipulated, so pre-existing individual differences may contribute. Brief cue exposure may differ from sustained environmental priming."},{"rthcId":"RTHC-00490","title":"Effects of cannabis on cognitive function in patients with multiple sclerosis.","authors":"Honarmand, Kimia; Tierney, Mary C; O'Connor, Paul; Feinstein, Anthony","year":2011,"journal":"Neurology, 76(13), 1153-60","doi":"10.1212/WNL.0b013e318212ab0c","pmid":"21444900","tags":["cognition","medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared 25 MS patients who used cannabis to 25 matched MS non-users using a comprehensive neuropsychological battery designed specifically for MS.\n\nCannabis users performed significantly worse on information processing speed, working memory, executive functions, and visuospatial perception. They were twice as likely to be classified as globally cognitively impaired.\n\nImportantly, there were no differences in depression, anxiety, or lifetime psychiatric diagnoses between the groups, meaning the cognitive differences were not explained by mood disorders.\n\nThe authors noted that whatever subjective benefits patients derived from cannabis (pain or spasticity relief) should be weighed against these cognitive costs, particularly since MS already causes cognitive deterioration.","whyItMatters":"Since MS already impairs cognition, the finding that cannabis compounded these deficits was clinically significant for the many MS patients using cannabis for symptom relief.","specificNumbers":"25 cannabis users vs 25 non-users. Cannabis users twice as likely to be globally cognitively impaired. Significantly worse on processing speed, working memory, executive function, and visuospatial perception. No mood differences between groups.","methodology":"Cross-sectional study of 50 MS patients (25 cannabis users, 25 non-users). Minimal Assessment of Cognitive Function in MS battery, Hospital Anxiety and Depression Scale, and SCID-I administered. Group-matching and regression controlled for age, sex, education, premorbid intelligence, disability, and disease characteristics.","limitations":"Cross-sectional design cannot determine whether cannabis caused the cognitive deficits or whether more cognitively impaired patients were drawn to cannabis use. \"Street cannabis\" was used, not standardized pharmaceutical products. Small sample size."},{"rthcId":"RTHC-00491","title":"Cannabinoids lead to enhanced virulence of the smallpox vaccine (vaccinia) virus.","authors":"Huemer, Hartwig P; Lassnig, Caroline; Bernhard, David; Sturm, Sonja; Nowotny, Norbert; Kitchen, Maria; Pavlic, Marion","year":2011,"journal":"Immunobiology, 216(6), 670-7","doi":"10.1016/j.imbio.2010.11.001","pmid":"21131094","tags":["inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers found that a single dose of cannabis resin was equally effective as pure THC at increasing the severity and duration of vaccinia virus (smallpox vaccine virus) infection in mice.\n\nIn vitro, cannabis resin was more potent than THC alone at inhibiting immune cell proliferation, suggesting additional cannabis compounds beyond THC contributed to immunosuppression. Sub-fractions containing cannabidiol and cannabinol (also found in cigarette smoke) were also inhibitory.\n\nThe immunosuppressive effects were distinct from direct cell-killing (apoptotic) effects, as drug-treated immune cells retained their ability to produce cytokines when stimulated.\n\nThe authors noted a recent case of unusually severe cowpox infection in a young drug user, and concluded that cannabis could increase risk of acquiring poxvirus infections or experiencing worse vaccine side effects.","whyItMatters":"The finding that cannabis enhanced viral infection severity had implications for immunocompromised individuals and vaccination programs, suggesting cannabis users might face increased infection risks.","specificNumbers":"Single dose of cannabis resin or THC enhanced vaccinia symptoms. Cannabis resin was superior to THC alone at inhibiting immune cell proliferation in vitro. CBD and CBN fractions also showed inhibitory effects.","methodology":"Animal study and in vitro experiments. Mice infected with vaccinia virus after cannabis resin or THC administration. In vitro immune cell proliferation assays with human and mouse spleen cells and PBMCs. Sub-fractionation of cannabis resin to identify active components.","limitations":"Mouse model with vaccinia virus, which has limited relevance to most modern infections. Single-dose exposure protocol. In vitro immune effects may not fully translate to in vivo immune function."},{"rthcId":"RTHC-00492","title":"Marijuana-induced mania in a healthy adolescent: a case report.","authors":"Iskandar, Joseph W; Griffeth, Benjamin; Sharma, Taral","year":2011,"journal":"General hospital psychiatry, 33(6), 640.e3-4","doi":"10.1016/j.genhosppsych.2011.04.007","pmid":"21749837","tags":["psychosis","youth","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"An adolescent with no known prior psychiatric history developed manic symptoms following marijuana use. Previous case reports of marijuana-induced mania had been documented only in adult patients.\n\nThe case was notable because the adolescent had no identifiable psychiatric vulnerability before the marijuana exposure. The report was contextualized against nationwide usage data showing 11.8% of 8th graders, 26.7% of 10th graders, and 32.8% of 12th graders had used marijuana at least once in the prior year.","whyItMatters":"The case extended the recognized age range for marijuana-induced mania to adolescents and suggested that even individuals without psychiatric vulnerabilities could develop acute manic symptoms.","specificNumbers":"First documented adolescent case. Usage rates in 2009: 11.8% of 8th graders, 26.7% of 10th graders, 32.8% of 12th graders.","methodology":"Case report with retrospective review of published literature on marijuana-induced mania. No psychiatric history identified in the patient prior to the marijuana-associated manic episode.","limitations":"Single case report. Cannot establish causation or estimate how commonly marijuana triggers mania. Undetected pre-existing vulnerability is possible despite no identified psychiatric history."},{"rthcId":"RTHC-00493","title":"Subjective and physiological effects after controlled Sativex and oral THC administration.","authors":"Karschner, E L; Darwin, W D; McMahon, R P; Liu, F; Wright, S; Goodwin, R S; Huestis, M A","year":2011,"journal":"Clinical pharmacology and therapeutics, 89(3), 400-7","doi":"10.1038/clpt.2010.318","pmid":"21289620","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Nine cannabis smokers received five treatments in randomized, double-blind fashion: placebo, low and high doses of oral synthetic THC, and low and high doses of Sativex (1:1 THC:CBD oromucosal spray).\n\nAt therapeutic doses, Sativex and oral THC produced similar, clinically insignificant increases in heart rate, anxiety, and \"good drug effects.\" No serious adverse events occurred with either treatment.\n\nContrary to the hypothesis that CBD would attenuate THC-induced side effects, no substantial CBD-induced modulation of THC's effects was evident at these dose levels. Oral and oromucosal THC delivery had slower absorption and lower brain delivery rates compared to smoked cannabis, resulting in fewer adverse events.\n\nThe authors concluded that Sativex had a safety profile comparable to oral THC at low, therapeutic doses.","whyItMatters":"The finding that CBD did not noticeably reduce THC effects at therapeutic doses challenged a key marketing claim about Sativex and had implications for how combination products were understood and prescribed.","specificNumbers":"9 participants. Sativex low: 5.4 mg THC + 5.0 mg CBD. Sativex high: 16.2 mg THC + 15.0 mg CBD. Oral THC: 5 and 15 mg. Similar effects across equivalent THC-dose conditions. No serious adverse events.","methodology":"Randomized, double-blind, placebo-controlled, five-session crossover study in 9 cannabis smokers. Treatments: placebo, 5 and 15 mg oral THC, low-dose Sativex (5.4 mg THC + 5.0 mg CBD), high-dose Sativex (16.2 mg THC + 15.0 mg CBD). Pharmacodynamic assessments over 10.5 hours.","limitations":"Very small sample (9 participants). Cannabis smokers may have different sensitivity than naive users. Only therapeutic doses tested; CBD modulation might emerge at higher doses. Single-dose sessions only."},{"rthcId":"RTHC-00494","title":"Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration.","authors":"Karschner, Erin L; Darwin, W David; Goodwin, Robert S; Wright, Stephen; Huestis, Marilyn A","year":2011,"journal":"Clinical chemistry, 57(1), 66-75","doi":"10.1373/clinchem.2010.152439","pmid":"21078841","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers measured plasma levels of cannabinoids after administering Sativex (THC+CBD) and pure oral THC to determine whether CBD alters THC pharmacokinetics.\n\nNine cannabis smokers received five treatments in randomized, double-blind sessions: placebo, low and high oral THC, and low and high Sativex doses. Blood was drawn at multiple time points over 10.5 hours.\n\nThere were no significant differences in peak plasma THC concentration, time to peak, or total THC exposure between equivalent oral THC and Sativex doses. Relative bioavailability calculations showed oral THC at 5 and 15 mg was 92.6% and 98.8% of Sativex, respectively, nearly identical.\n\nThese data demonstrated that whatever effects CBD has on THC are not due to pharmacokinetic interactions (changing absorption or metabolism) at therapeutic doses.","whyItMatters":"Ruling out pharmacokinetic interaction meant that any CBD modulation of THC effects would have to be pharmacodynamic (at the receptor level), which informed the design of future combination products.","specificNumbers":"9 completers. THC bioavailability: 92.6% (5 mg) and 98.8% (15 mg) of equivalent Sativex doses. No significant differences in Cmax, Tmax, or AUC between oral THC and Sativex.","methodology":"Randomized, double-blind, placebo-controlled, five-session crossover study. 9 cannabis smokers. CBD, THC, 11-OH-THC, and THC-COOH quantified in plasma by 2D GC-MS. Lower limits of quantification at 0.25 mcg/L or below.","limitations":"Very small sample (9 participants). Only therapeutic doses tested. Cannabis smokers may metabolize cannabinoids differently than naive users. Single-dose pharmacokinetics may differ from steady-state with chronic dosing."},{"rthcId":"RTHC-00495","title":"Effects of the cannabinoid-1 receptor antagonist rimonabant on psychiatric symptoms in overweight people with schizophrenia: a randomized, double-blind, pilot study.","authors":"Kelly, Deanna L; Gorelick, David A; Conley, Robert R; Boggs, Douglas L; Linthicum, Jared; Liu, Fang; Feldman, Stephanie; Ball, M Patricia; Wehring, Heidi J; McMahon, Robert P; Huestis, Marilyn A; Heishman, Stephen J; Warren, Kimberly R; Buchanan, Robert W","year":2011,"journal":"Journal of clinical psychopharmacology, 31(1), 86-91","doi":"10.1097/JCP.0b013e318204825b","pmid":"21192149","tags":["psychosis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Fifteen overweight patients with schizophrenia on second-generation antipsychotics were randomized to rimonabant (20 mg/day) or placebo for 16 weeks. The trial was terminated early when rimonabant was withdrawn from the European market.\n\nSurprisingly, rimonabant was associated with significantly greater reduction in overall psychiatric symptom scores compared to placebo (BPRS difference -1.9, p=0.02). This was driven by improvements in anxiety/depression (p=0.0004) and hostility (p=0.02) subscales.\n\nNo significant differences were found for weight, blood pressure, fasting lipids, glucose, depression scale scores, or negative symptoms. Rimonabant was well tolerated with no significant adverse events in this small sample.\n\nThe authors concluded that the endocannabinoid system remained a promising target for schizophrenia pharmacotherapy despite the trial's premature termination.","whyItMatters":"The unexpected psychiatric benefits of a CB1 antagonist in schizophrenia patients suggested the endocannabinoid system played a role in psychiatric symptoms beyond psychosis itself, though the very small sample size limited conclusions.","specificNumbers":"15 randomized (7 rimonabant, 8 placebo), 5 completed per group. BPRS total difference: -1.9 (p=0.02). Anxiety/depression: -1.4 (p=0.0004). Hostility: -0.7 (p=0.02). No weight or metabolic effects.","methodology":"Randomized, double-blind, placebo-controlled, 16-week trial. Target enrollment was 60 but terminated at 15 participants (7 rimonabant, 5 completed per group). Overweight criteria: BMI 27+ with dyslipidemia or BMI 30+. Weekly exercise and dietary counseling offered.","limitations":"Extremely small sample (15 randomized, 10 completers). Premature termination limits conclusions. No weight loss observed despite this being the primary outcome target. Multiple comparisons in a small trial increase false positive risk."},{"rthcId":"RTHC-00496","title":"Altered brain activation during visuomotor integration in chronic active cannabis users: relationship to cortisol levels.","authors":"King, George R; Ernst, Thomas; Deng, Weiran; Stenger, Andrew; Gonzales, Rachael M K; Nakama, Helenna; Chang, Linda","year":2011,"journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience, 31(49), 17923-31","doi":"10.1523/JNEUROSCI.4148-11.2011","pmid":"22159107","tags":["cognition","neuroscience","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Thirty cannabis users (16 men, 14 women) and 30 matched controls were tested with neuropsychological assessments and fMRI during a finger-sequencing task.\n\nMale, but not female, cannabis users had significantly slower psychomotor speed. As a group, cannabis users showed greater activation in a motor planning region (BA 6) but reduced activation in a primary visual area (BA 17) compared to controls.\n\nThis shift from visual processing regions to executive/attentional control areas suggested cannabis users relied on more effortful, less automated motor control. Cannabis users also had significantly higher salivary cortisol levels (p=0.002).\n\nThe authors proposed that elevated cortisol from chronic cannabis use may mediate the altered brain activation patterns and reduced motor efficiency.","whyItMatters":"The sex-specific finding (males affected, females not) and the cortisol elevation provided mechanistic insights into how chronic cannabis use may disrupt motor function through stress hormone pathways.","specificNumbers":"30 cannabis users vs 30 controls. Male users significantly slower on psychomotor tests. Greater BA 6 activation, reduced BA 17 activation in users. Salivary cortisol significantly higher (p=0.002) in cannabis users.","methodology":"Cross-sectional study comparing 30 chronic active cannabis users (16M, 14F, ages 18-45) to 30 non-drug-using controls (16M, 14F, ages 19-44). fMRI during visually paced finger sequencing at 2 and 4 Hz. Salivary cortisol measured. Neuropsychological motor tests administered.","limitations":"Cross-sectional design. Cannot determine whether cannabis caused the cortisol elevation or brain changes. Active cannabis users were tested, so acute intoxication effects cannot be fully separated from chronic effects."},{"rthcId":"RTHC-00497","title":"Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice.","authors":"Kinsey, Steven G; Nomura, Daniel K; O'Neal, Scott T; Long, Jonathan Z; Mahadevan, Anu; Cravatt, Benjamin F; Grider, John R; Lichtman, Aron H","year":2011,"journal":"The Journal of pharmacology and experimental therapeutics, 338(3), 795-802","doi":"10.1124/jpet.110.175778","pmid":"21659471","tags":["neuroscience","inflammation","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"NSAIDs (common painkillers like ibuprofen) frequently cause stomach bleeding and ulcers. Researchers tested whether boosting levels of the endocannabinoid 2-AG by inhibiting its breakdown enzyme MAGL could protect the stomach.\n\nIn mice given the NSAID diclofenac, the MAGL inhibitor JZL184 significantly prevented gastric hemorrhages, as effectively as the proton pump inhibitor omeprazole (a standard gastroprotective drug) and THC.\n\nJZL184 also completely blocked diclofenac-induced increases in pro-inflammatory cytokines (IL-1-beta, IL-6, TNF-alpha) in stomach tissue. The protective effect worked through CB1 receptors specifically, as shown by both pharmacological blockade and genetic knockout experiments.\n\nImportantly, the gastroprotective effects of JZL184 persisted with repeated administration, showing no tolerance development.","whyItMatters":"NSAIDs cause significant GI complications. A gastroprotective agent based on the endocannabinoid system could potentially be combined with NSAIDs to prevent stomach damage while maintaining pain relief.","specificNumbers":"JZL184 matched omeprazole and THC effectiveness. Completely blocked diclofenac-induced increases in IL-1-beta, IL-6, TNF-alpha, and G-CSF. Gastroprotection mediated by CB1 (not CB2). No tolerance with repeated dosing.","methodology":"Controlled animal study in mice. Diclofenac-induced gastric hemorrhage model. JZL184 (MAGL inhibitor), omeprazole, and THC tested as interventions. Inflammatory cytokines measured. CB1 and CB2 receptor involvement tested using antagonists and knockout mice. Repeated dosing tested for tolerance.","limitations":"Mouse model. JZL184 is a research tool not approved for human use. Only one NSAID (diclofenac) tested. Long-term safety of MAGL inhibition in the GI tract is unknown."},{"rthcId":"RTHC-00498","title":"Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.","authors":"Kinsey, Steven G; O'Neal, Scott T; Long, Jonathan Z; Cravatt, Benjamin F; Lichtman, Aron H","year":2011,"journal":"Pharmacology, biochemistry, and behavior, 98(1), 21-7","doi":"10.1016/j.pbb.2010.12.002","pmid":"21145341","tags":["anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether boosting either of the two main endocannabinoids could reduce anxiety-like behavior in a marble-burying test, a model relevant to compulsive behaviors in disorders like OCD.\n\nThe FAAH inhibitor PF-3845 (which boosts anandamide) and the MAGL inhibitor JZL184 (which boosts 2-AG) both reduced marble burying at doses that did not impair locomotor activity. The benzodiazepine diazepam also reduced burying.\n\nIn contrast, THC did not consistently reduce marble burying without also causing profound decreases in locomotor activity, meaning its apparent anxiolytic effect was inseparable from sedation.\n\nThe CB1 antagonist rimonabant blocked the anti-burying effects of both FAAH and MAGL inhibitors but not diazepam, confirming a CB1 receptor mechanism.","whyItMatters":"The separation of anxiolytic effects from sedation was a key advantage of endocannabinoid-boosting drugs over direct cannabinoid agonists like THC, supporting their development as potential anxiety treatments.","specificNumbers":"PF-3845, JZL184, and diazepam reduced marble burying without affecting locomotion. THC reduced burying only at doses that also impaired movement. Rimonabant blocked FAAH/MAGL inhibitor effects but not diazepam.","methodology":"Controlled animal study in mice using the marble burying assay. FAAH inhibitor PF-3845, MAGL inhibitor JZL184, diazepam, and THC tested at multiple doses. Locomotor activity measured concurrently. CB1 receptor involvement confirmed with rimonabant.","limitations":"Mouse model with a single behavioral measure. Marble burying is only one model of anxiety/compulsive behavior. Translation to human anxiety disorders is uncertain."},{"rthcId":"RTHC-00499","title":"Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice.","authors":"Kozela, Ewa; Lev, Nirit; Kaushansky, Nathali; Eilam, Raya; Rimmerman, Neta; Levy, Rivka; Ben-Nun, Avraham; Juknat, Ana; Vogel, Zvi","year":2011,"journal":"British journal of pharmacology, 163(7), 1507-19","doi":"10.1111/j.1476-5381.2011.01379.x","pmid":"21449980","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used an experimental autoimmune encephalomyelitis (EAE) model in mice, the standard animal model for multiple sclerosis. CBD treatment beginning at disease onset reduced the severity of clinical signs.\n\nCBD's benefits were accompanied by reduced axonal damage, less inflammation, decreased microglial activation, and reduced T-cell recruitment in the spinal cord.\n\nIn laboratory tests, CBD directly inhibited the proliferation of myelin-attacking T cells at both low and high concentrations of the myelin antigen. This effect was not mediated through CB1 or CB2 cannabinoid receptors, indicating CBD worked through a different, non-cannabinoid mechanism.\n\nThe non-psychoactive nature of CBD made it a potentially safer alternative to THC-based treatments for neuroinflammatory conditions.","whyItMatters":"The finding that CBD worked through non-cannabinoid receptor mechanisms expanded the understanding of how CBD exerts therapeutic effects and suggested it could complement existing MS treatments.","specificNumbers":"CBD ameliorated EAE clinical signs. Reduced axonal damage, inflammation, microglial activation, and T-cell recruitment in spinal cord. Inhibited MOG-specific T-cell proliferation at low and high antigen concentrations. Effects independent of CB1 and CB2 receptors.","methodology":"Preclinical study using EAE induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. CBD administered at disease onset. Immunocytochemistry and cell proliferation assays evaluated effects on microglial activation and T-cell proliferation. CB1 and CB2 receptor independence confirmed.","limitations":"Mouse EAE model does not perfectly replicate human MS. CBD was given at disease onset, not after established disease. The non-CB1/CB2 mechanism was not fully identified."},{"rthcId":"RTHC-00500","title":"Cannabis use amongst patients with inflammatory bowel disease.","authors":"Lal, Simon; Prasad, Neeraj; Ryan, Manijeh; Tangri, Sabrena; Silverberg, Mark S; Gordon, Allan; Steinhart, Hillary","year":2011,"journal":"European journal of gastroenterology & hepatology, 23(10), 891-6","doi":"10.1097/MEG.0b013e328349bb4c","pmid":"21795981","tags":["medical-cannabis","pain","appetite"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 100 ulcerative colitis (UC) and 191 Crohn's disease (CD) patients at a specialty clinic about cannabis use.\n\nLifetime cannabis use was similar between groups: 51% of UC and 48% of CD patients. Current use was 12% for UC and 16% for CD. Among lifetime users, 33% of UC and 50% of CD patients reported using cannabis specifically for IBD symptom relief, including abdominal pain, diarrhea, and reduced appetite.\n\nPatients more likely to use cannabis for symptom relief had a history of abdominal surgery (60% vs 32%, p=0.002), chronic analgesic use (71% vs 31%, p<0.001), complementary medicine use (55% vs 32%, p=0.01), and lower quality of life scores (45.1 vs 50.3, p=0.03).\n\nCannabis users were significantly more interested in hypothetical clinical trials (43% vs 10%, p<0.001).","whyItMatters":"The high prevalence of cannabis use for symptom relief among IBD patients, particularly the sickest patients, highlighted the need for controlled research on therapeutic cannabinoids in this population.","specificNumbers":"291 IBD patients. Lifetime use: 51% UC, 48% CD. Current use: 12% UC, 16% CD. Symptom relief use: 33% UC users, 50% CD users. Prior surgery: 60% vs 32% among users vs non-users. Interest in cannabis trial: 43% users vs 10% non-users.","methodology":"Cross-sectional questionnaire study of 291 IBD patients (100 UC, 191 CD) at a tertiary-care outpatient clinic. Cannabis use patterns, symptom relief, socioeconomic factors, disease history, and quality of life (short-IBD questionnaire) assessed.","limitations":"Cross-sectional self-report design. Tertiary care patients may not represent all IBD patients. Cannabis use was self-reported and may be underreported. No objective efficacy assessment."},{"rthcId":"RTHC-00501","title":"Effects of smoking cannabis on lung function.","authors":"Lee, Marcus H S; Hancox, Robert J","year":2011,"journal":"Expert review of respiratory medicine, 5(4), 537-46; quiz 547","doi":"10.1586/ers.11.40","pmid":"21859273","tags":["respiratory"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review noted that despite cannabis being the most widely used illicit drug, respiratory effects were surprisingly under-researched. Key findings:\n\nConsistent evidence showed cannabis smoking was associated with large airway inflammation, bronchitis symptoms, increased airway resistance, and lung hyperinflation.\n\nHowever, the evidence that cannabis leads to COPD features (airflow obstruction and emphysema) was \"not convincing.\" While case reports described bullous emphysema in cannabis smokers, systematic studies had not confirmed this association. These cases likely represented uncommon adverse effects in very heavy users.\n\nThe assumption that cannabis smoking would have similar effects to tobacco smoking appeared to be incorrect. Cannabis had quite different effects on lung function.\n\nEvidence for respiratory malignancies was described as \"controversial\" and \"inconclusive.\"","whyItMatters":"The finding that cannabis and tobacco have different lung effects challenged assumptions and had implications for harm reduction messaging and clinical assessment of cannabis smokers.","specificNumbers":"Consistent findings: large airway inflammation, bronchitis symptoms, increased airway resistance, lung hyperinflation. Not convincing: COPD-like obstruction, emphysema. Inconclusive: lung cancer.","methodology":"Expert review of observational studies examining the effects of cannabis smoking on respiratory function, including studies of lung function parameters, airway inflammation, and cancer risk.","limitations":"Inherent difficulty studying an illegal habit. Confounding by concurrent tobacco use in many studies. Limited long-term prospective data. Publication bias toward positive findings."},{"rthcId":"RTHC-00502","title":"Benign and time-limited visual disturbances (flashbacks) in recent abstinent high-potency heavy cannabis smokers: a case series study.","authors":"Lerner, Arturo G; Goodman, Craig; Rudinski, Dmitri; Bleich, Avi","year":2011,"journal":"The Israel journal of psychiatry and related sciences, 48(1), 25-9","doi":null,"pmid":"21572239","tags":["cognition","potency"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Eight patients seeking outpatient detoxification for cannabis dependence reported visual disturbances both during intoxication and persisting after they stopped using cannabis. None had any history of LSD or other hallucinogen use.\n\nSeven categories of visual disturbances were described: visual distortions, distorted distance perception, illusions of movement in stationary objects, color intensification, dimmed color, dimensional distortion, and blending of patterns and objects.\n\nPatients reported 2-5 different categories of flashbacks that persisted for 3-6 months after cannabis cessation. All were high-potency heavy cannabis smokers meeting DSM-IV-TR criteria for cannabis dependence.\n\nThe authors interpreted these as time-limited benign side effects occurring in some individuals who used large amounts of high-potency cannabis, likely involving a combination of individual vulnerability and product potency.","whyItMatters":"This report linked high-potency cannabis use to a specific perceptual phenomenon (visual flashbacks) previously associated mainly with hallucinogens, raising awareness among clinicians treating heavy cannabis users.","specificNumbers":"8 patients. 7 categories of visual disturbances. 2-5 types per patient. Duration: 3-6 months after cessation. All high-potency heavy users. No prior LSD use.","methodology":"Case series of 8 cannabis-dependent patients reporting visual disturbances during routine psychiatric interview at an outpatient detoxification clinic. All met DSM-IV-TR cannabis dependence criteria. Visual phenomena categorized by type and duration.","limitations":"Uncontrolled case series with subjective symptom reports. \"High-potency\" was not objectively quantified. Small sample. Cannot determine prevalence or establish cannabis as the definitive cause."},{"rthcId":"RTHC-00503","title":"Cannabis and its derivatives: review of medical use.","authors":"Leung, Lawrence","year":2011,"journal":"Journal of the American Board of Family Medicine : JABFM, 24(4), 452-62","doi":"10.3122/jabfm.2011.04.100280","pmid":"21737770","tags":["medical-cannabis","pain","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review provided a practical update for family physicians on medical cannabis, covering several key points.\n\nClinical trials demonstrated benefits for alleviating chronic and neuropathic pain, though significant psychotropic and physical side effects accompanied use. The addiction potential was acknowledged.\n\nRecent laboratory data highlighted synergistic interactions between cannabinoid and opioid receptors. These interactions had two important implications: potential reduction in drug-seeking behavior and opioid-sparing effects (lower opioid doses needed when combined with cannabinoids).\n\nThe legal landscape was changing, with certain US states permitting medical marijuana, and family physicians needed practical knowledge about the pros, cons, legal implications, and future developments.","whyItMatters":"As the front line of patient care, family physicians needed balanced, practical information about medical cannabis to counsel patients appropriately in a changing legal landscape.","specificNumbers":"The review covered clinical trial evidence for chronic and neuropathic pain without reporting specific pooled effect sizes.","methodology":"Narrative review for the Journal of the American Board of Family Medicine, synthesizing clinical trial evidence, pharmacology, and sociological context of medical cannabis for primary care physicians.","limitations":"Narrative review for a clinical audience, not a systematic evidence synthesis. The legal and regulatory landscape described was specific to 2011 and has changed substantially."},{"rthcId":"RTHC-00504","title":"Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial.","authors":"Levin, Frances R; Mariani, John J; Brooks, Daniel J; Pavlicova, Martina; Cheng, Wendy; Nunes, Edward V","year":2011,"journal":"Drug and alcohol dependence, 116(1-3), 142-50","doi":"10.1016/j.drugalcdep.2010.12.010","pmid":"21310551","tags":["addiction","quitting","withdrawal"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This was the first clinical trial testing an agonist substitution strategy for cannabis dependence, similar to how methadone is used for opioid dependence.\n\n156 cannabis-dependent adults were randomized to dronabinol (20 mg twice daily) or placebo for 12 weeks, with all participants receiving weekly therapy. There was no significant difference in the primary outcome: 17.7% of dronabinol patients achieved 2 weeks of abstinence versus 15.6% on placebo.\n\nHowever, dronabinol showed two significant secondary benefits. Treatment retention at the end of the maintenance phase was significantly higher with dronabinol (77%) compared to placebo (61%, p=0.02). Withdrawal symptoms were also significantly lower on dronabinol (p=0.02).\n\nBoth groups reduced marijuana use over time, but there were no between-group differences in overall reduction.","whyItMatters":"While dronabinol did not increase abstinence, the improved retention and withdrawal management established proof of concept for agonist substitution in cannabis dependence, informing future medication development.","specificNumbers":"156 participants. Abstinence: 17.7% dronabinol vs 15.6% placebo (not significant). Retention: 77% vs 61% (p=0.02). Withdrawal symptoms lower on dronabinol (p=0.02). Dose: 20 mg BID.","methodology":"Randomized, double-blind, placebo-controlled, 12-week trial. 156 cannabis-dependent adults. 1-week placebo lead-in, then dronabinol 20 mg BID or placebo for 8 weeks maintenance, 2-week taper. Weekly motivational enhancement and relapse prevention therapy for all. Timeline followback for marijuana use assessment.","limitations":"Abstinence rates were low in both groups. Dronabinol dose may have been insufficient. Relapse often occurred during the taper/post-taper period. Self-reported marijuana use as primary outcome."},{"rthcId":"RTHC-00505","title":"Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials.","authors":"Lynch, Mary E; Campbell, Fiona","year":2011,"journal":"British journal of clinical pharmacology, 72(5), 735-44","doi":"10.1111/j.1365-2125.2011.03970.x","pmid":"21426373","tags":["pain","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Researchers systematically reviewed randomized controlled trials of cannabinoids for chronic non-cancer pain. Of 18 trials meeting inclusion criteria, 15 demonstrated a significant analgesic effect compared to placebo.\n\nThe review included studies of smoked cannabis, oromucosal cannabis extracts, nabilone, dronabinol, and a novel THC analogue. Pain conditions included neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain.\n\nOverall trial quality was described as \"excellent.\" Several studies also reported significant improvements in sleep alongside pain relief.\n\nThere were no serious adverse effects across the trials. Most commonly reported side effects were generally well tolerated, mild to moderate in severity, and rarely led to study withdrawal.\n\nThe authors concluded there was evidence that cannabinoids were \"safe and modestly effective\" for neuropathic pain, with preliminary evidence for fibromyalgia and rheumatoid arthritis.","whyItMatters":"This was one of the most influential systematic reviews establishing cannabinoids as modestly effective analgesics for chronic pain, with 83% of high-quality trials showing significant benefit.","specificNumbers":"18 RCTs met inclusion criteria. 15 of 18 (83%) showed significant analgesic effects. No serious adverse effects. Conditions: neuropathic pain, fibromyalgia, rheumatoid arthritis, mixed chronic pain. Multiple cannabinoid formulations studied.","methodology":"Systematic review conducted according to PRISMA guidelines. Randomized controlled trials of cannabinoids for chronic non-cancer pain identified and evaluated for quality and outcomes.","limitations":"Studies were heterogeneous in cannabinoid type, dose, duration, and pain condition. \"Modest\" effectiveness means the effect sizes were not large. Longer-term safety data were lacking."},{"rthcId":"RTHC-00506","title":"Interactions between endocannabinoid and serotonergic systems in mood disorders caused by nicotine withdrawal.","authors":"Mannucci, Carmen; Navarra, Michele; Pieratti, Antonella; Russo, Giuseppina A; Caputi, Achille P; Calapai, Gioacchino","year":2011,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 13(4), 239-47","doi":"10.1093/ntr/ntq242","pmid":"21324836","tags":["addiction","neuroscience","depression"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers investigated how the endocannabinoid and serotonin systems interact during nicotine withdrawal in mice.\n\nNicotine-dependent mice showed decreased serotonin 5-HT1A receptor levels in the diencephalon. The CB1 receptor antagonist AM251 reduced physical withdrawal signs, while the endocannabinoid transport inhibitor AM404 reduced depression-like behavior (immobility in the forced swimming test) in a dose-dependent manner.\n\nCritically, the antidepressant-like effects of AM404 were blocked by both the CB1 antagonist AM251 and the 5-HT1A receptor antagonist WAY 100635. This demonstrated that both the cannabinoid and serotonin systems were required for the antidepressant effect.\n\nThis cross-system interaction suggested that targeting the endocannabinoid system could address the mood component of nicotine withdrawal through serotonergic mechanisms.","whyItMatters":"Mood disturbances during nicotine withdrawal are a major driver of relapse. Identifying a cannabinoid-serotonin interaction suggested new pharmacological targets for smoking cessation.","specificNumbers":"Nicotine: 2 mg/kg, 4 injections daily, 15 days. AM251 (0.5-2 mg/kg) reduced abstinence signs. AM404 (0.5-2 mg/kg) dose-dependently reduced immobility. Both AM251 and WAY 100635 blocked AM404's antidepressant effect.","methodology":"Controlled animal study. Nicotine dependence induced by subcutaneous injection (2 mg/kg, 4x daily, 15 days) in mice. AM404, AM251, and WAY 100635 tested for effects on abstinence signs, forced swimming test, and locomotor activity. Diencephalic 5-HT1A expression measured.","limitations":"Mouse model of nicotine dependence using injection rather than inhalation. The forced swimming test is a limited model of depression. Clinical translation is uncertain."},{"rthcId":"RTHC-00507","title":"Early intervention for psychosis.","authors":"Marshall, Max; Rathbone, John","year":2011,"journal":"The Cochrane database of systematic reviews, CD004718","doi":"10.1002/14651858.CD004718.pub3","pmid":"21678345","tags":["psychosis","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This Cochrane systematic review examined whether early intervention could improve outcomes in psychosis across 18 RCTs with 1,808 participants.\n\nFor psychosis prevention in prodromal patients: olanzapine showed little benefit, CBT was similarly inconclusive, risperidone plus CBT showed short-term benefit at 6 months but not 12 months, and omega-3 fatty acids showed a promising but unreplicated result.\n\nFor first-episode psychosis treatment: specialized early intervention teams showed some benefit for treatment retention and independent living at 5 years. Phase-specific cannabis and psychosis therapy did not show significant benefit (RR for cannabis use 1.30, CI 0.8-2.2). Vocational intervention improved employment.\n\nThe largest and highest quality study showed specialized teams reduced dropout and improved treatment compliance, with better independent living at 5 years but not at 1 year.","whyItMatters":"The finding that cannabis-specific psychosis therapy did not show measurable benefit was important for treatment planning, while the broader finding that early intervention services had emerging support informed mental health policy.","specificNumbers":"18 RCTs, n=1808. Cannabis-psychosis therapy: RR 1.30 (0.8-2.2), not significant. Specialized teams: reduced dropout RR 0.59 (0.4-0.8), NNT 9. Independent living at 5 years: RR 0.42 (0.21-0.8), NNT 19.","methodology":"Cochrane systematic review of RCTs for preventing psychosis in prodromal individuals or improving outcomes in first-episode psychosis. 18 RCTs identified (n=1808). Risk ratios with 95% CIs calculated. NNT/NNH computed where possible.","limitations":"Studies were diverse, mostly small, and conducted by pioneering researchers with methodological limitations. Meta-analysis was inappropriate for most comparisons. Cannabis-psychosis therapy data came from a single small trial (n=47)."},{"rthcId":"RTHC-00508","title":"Cannabinoids in oral fluid following passive exposure to marijuana smoke.","authors":"Moore, Christine; Coulter, Cynthia; Uges, Donald; Tuyay, James; van der Linde, Susanne; van Leeuwen, Arthur; Garnier, Margaux; Orbita, Jonathan","year":2011,"journal":"Forensic science international, 212(1-3), 227-30","doi":"10.1016/j.forsciint.2011.06.019","pmid":"21763088","tags":["driving"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Ten non-marijuana-smoking volunteers spent 3 hours in two Dutch coffee shops where others were actively smoking marijuana. Oral fluid samples were collected before, during, and after exposure.\n\nTHC was detectable in all oral fluid specimens taken 3 hours into exposure. At the 3-hour point, 50% of volunteers exceeded the recommended immunoassay screening cut-off of 4 ng/mL THC, and 70% exceeded the proposed confirmatory cut-off of 2 ng/mL.\n\nCritically, the metabolite THC-COOH was not detected in any specimens from passively exposed individuals. Since THC-COOH can only be produced by the body metabolizing absorbed THC, its absence was a reliable indicator that the person had not actively consumed marijuana.\n\nThe authors recommended that oral fluid testing for DUID should include THC-COOH analysis to distinguish active use from passive exposure.","whyItMatters":"The finding that passive exposure could produce false-positive oral fluid results had direct implications for workplace drug testing, DUID enforcement, and forensic toxicology.","specificNumbers":"10 volunteers. 3-hour exposure. At 3 hours: 50% exceeded 4 ng/mL THC screening cut-off, 70% exceeded 2 ng/mL confirmatory cut-off. 0% positive for THC-COOH at any time point.","methodology":"Prospective study of 10 healthy non-marijuana-smoking volunteers. 3-hour exposure in two Dutch coffee shops. Oral fluid collected at 6 time points during exposure and at 12-22 hours after. Immunoassay screening plus GC-MS confirmation for THC, CBN, CBD, and 2D GC-GC/MS for THC-COOH.","limitations":"Small sample (10 volunteers). Dutch coffee shop exposure may be more intense than typical passive exposure. Only oral fluid tested, not blood. Duration of detectable THC after exposure not fully characterized."},{"rthcId":"RTHC-00509","title":"Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment.","authors":"Morris, Claudia V; DiNieri, Jennifer A; Szutorisz, Henrietta; Hurd, Yasmin L","year":2011,"journal":"The European journal of neuroscience, 34(10), 1574-83","doi":"10.1111/j.1460-9568.2011.07884.x","pmid":"22103415","tags":["pregnancy","neuroscience","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined molecular mechanisms through which prenatal cannabis and cigarette exposure disrupted brain development.\n\nPrenatal cannabis exposure specifically altered dopamine D2 receptor gene expression in the fetal brain's reward center (nucleus accumbens), potentially through epigenetic mechanisms including DNA methylation and histone modification. These changes could persist into adulthood and enhance vulnerability to psychiatric disorders.\n\nPrenatal cigarette exposure affected different gene targets, including the opioid peptide prodynorphin in the striatum. Alcohol exposure produced broader gene expression changes across the dorsal striatum.\n\nThe review emphasized that epigenetic pathways (DNA methylation, histone modification) could maintain abnormal gene regulation established during fetal development throughout life, explaining how a brief exposure period could produce permanent behavioral consequences.","whyItMatters":"Understanding the molecular mechanisms explained how brief prenatal drug exposure could produce lifelong neuropsychiatric vulnerability, strengthening the evidence base for avoiding substance use during pregnancy.","specificNumbers":"Prenatal cannabis: decreased DRD2 expression in nucleus accumbens. Prenatal cigarettes: reduced prodynorphin in striatum. Prenatal alcohol: broad changes in dorsal striatum. Epigenetic mechanisms: DNA methylation and histone modification.","methodology":"Narrative review synthesizing human fetal brain tissue studies and translational animal model research on molecular consequences of prenatal cannabis and cigarette exposure, with focus on epigenetic mechanisms.","limitations":"Much evidence came from limited human fetal tissue samples supplemented by animal models. Epigenetic mechanisms are complex and not fully characterized. The specific contribution of cannabis versus concurrent substance use was difficult to isolate."},{"rthcId":"RTHC-00510","title":"Regulation of nausea and vomiting by cannabinoids.","authors":"Parker, Linda A; Rock, Erin M; Limebeer, Cheryl L","year":2011,"journal":"British journal of pharmacology, 163(7), 1411-22","doi":"10.1111/j.1476-5381.2010.01176.x","pmid":"21175589","tags":["medical-cannabis","cbd","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review pulled together decades of research on how the endocannabinoid system regulates nausea and vomiting. CB1 receptor activation consistently suppressed vomiting across multiple animal species, while CB1 inverse agonists (like rimonabant) actually promoted it.\n\nCBD showed anti-nausea effects within a limited dose range, apparently working through serotonin 5-HT1A receptors in the brainstem rather than cannabinoid receptors directly. This is a different mechanism than THC uses.\n\nAnimal research suggested cannabinoids may be particularly effective against anticipatory nausea, the type that develops when patients begin to feel sick before chemotherapy even starts. This form of nausea responds poorly to standard anti-emetic drugs.","whyItMatters":"Standard anti-nausea medications work well for acute chemotherapy-induced vomiting but perform poorly against anticipatory nausea. This review identified cannabinoids as a potential tool for that gap, with CBD offering a non-intoxicating option.","specificNumbers":"CB1 agonists suppressed conditioned gaping (nausea proxy) in rats. CBD was effective within a limited dose range. FAAH inhibitor URB-597 also suppressed nausea responses.","methodology":"This was a narrative review synthesizing preclinical and clinical evidence on cannabinoid regulation of nausea and vomiting. The authors examined studies across emetic species (ferrets, shrews) and rodent models using conditioned gaping reactions as a proxy for nausea.","limitations":"Much of the evidence came from animal models. Rats and mice cannot vomit, so researchers used conditioned gaping as a proxy for nausea, which may not perfectly translate to human experience. Clinical trial data in humans was limited at the time of review."},{"rthcId":"RTHC-00511","title":"Cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety.","authors":"Pickering, Elspeth E; Semple, Stephen J; Nazir, Muhummad S; Murphy, Kevin; Snow, Thomas M; Cummin, Andrew R; Moosavi, Shakeeb H; Guz, Abraham; Holdcroft, Anita","year":2011,"journal":"Chronic respiratory disease, 8(2), 109-18","doi":"10.1177/1479972310391283","pmid":"21436223","tags":["medical-cannabis","cbd","respiratory"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Nine subjects (five healthy, four with COPD) received sublingual cannabis extract or placebo in a crossover design. Standard breathlessness measurements using visual analogue scales showed no differences between drug and placebo in either group.\n\nHowever, when COPD patients were asked to describe their breathlessness using specific descriptors, those who received the cannabis extract chose \"air hunger\" less frequently compared to placebo. This suggested the drug might change the qualitative experience of breathlessness without altering its perceived intensity.\n\nThe study found no respiratory depression with cannabis extract, supporting the hypothesis that cannabinoids could ease breathlessness sensation without suppressing breathing.","whyItMatters":"Breathlessness in COPD is difficult to treat. If cannabinoids can change the subjective quality of breathlessness without suppressing respiratory drive, they could fill a treatment gap where opioids carry respiratory depression risk.","specificNumbers":"9 total subjects (5 normal, 4 COPD). Maximum dose: 10.8 mg THC and 10 mg CBD sublingual. Measurements taken at baseline and 2 hours post-administration.","methodology":"Double-blind, randomized, placebo-controlled crossover study with two test days. Five normal subjects and four COPD subjects received sublingual cannabis extract (up to 10.8 mg THC and 10 mg CBD) or placebo. Breathlessness was induced using fixed carbon dioxide loads.","limitations":"Extremely small sample size (only 4 COPD patients). Single-dose design. The carbon dioxide challenge may not adequately replicate real-world breathlessness experiences. The study was underpowered to detect meaningful differences."},{"rthcId":"RTHC-00512","title":"Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice.","authors":"Ramesh, Divya; Ross, Gracious R; Schlosburg, Joel E; Owens, Robert A; Abdullah, Rehab A; Kinsey, Steven G; Long, Jonathan Z; Nomura, Daniel K; Sim-Selley, Laura J; Cravatt, Benjamin F; Akbarali, Hamid I; Lichtman, Aron H","year":2011,"journal":"The Journal of pharmacology and experimental therapeutics, 339(1), 173-85","doi":"10.1124/jpet.111.181370","pmid":"21719468","tags":["neuroscience","drug-interactions","withdrawal","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Morphine-dependent mice challenged with naloxone displayed jumping, paw tremors, diarrhea, and weight loss. The researchers tested two strategies to boost endocannabinoids: blocking MAGL (which breaks down 2-AG) and blocking FAAH (which breaks down anandamide).\n\nThe MAGL inhibitor JZL184 reduced most withdrawal symptoms in a dose-dependent manner through CB1 receptors. It also reduced spontaneous withdrawal signs, not just those triggered by naloxone.\n\nThe FAAH inhibitor PF-3845 reduced jumping and paw tremors through CB1 receptors but did not help with diarrhea or weight loss. This suggested 2-AG and anandamide play different roles in opioid withdrawal.","whyItMatters":"Opioid withdrawal is a major barrier to quitting. These findings suggested that boosting the body's own cannabinoids, rather than using external cannabis, could reduce withdrawal severity while potentially avoiding the side effects of direct cannabinoid agonists.","specificNumbers":"JZL184 dose-dependently reduced most withdrawal symptoms. PF-3845 reduced jumping and paw tremors but not diarrhea or weight loss. Both effects were blocked by CB1 antagonist rimonabant, confirming the mechanism.","methodology":"Morphine-dependent mice received naloxone to precipitate withdrawal. Researchers tested MAGL inhibitor JZL184 and FAAH inhibitor PF-3845 at multiple doses, using CB1 and CB2 antagonists to confirm receptor mechanisms. An isolated ileum preparation tested gut-level effects.","limitations":"Mouse study only. The doses and routes of administration may not translate to humans. Naloxone-precipitated withdrawal is more abrupt than natural withdrawal. Long-term effects of endocannabinoid enzyme inhibition were not assessed."},{"rthcId":"RTHC-00513","title":"Marijuana dependence: not just smoke and mirrors.","authors":"Ramesh, Divya; Schlosburg, Joel E; Wiebelhaus, Jason M; Lichtman, Aron H","year":2011,"journal":"ILAR journal, 52(3), 295-308","doi":"10.1093/ilar.52.3.295","pmid":"23382144","tags":["addiction","withdrawal","tolerance"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review compiled evidence that prolonged cannabis use produces genuine physical dependence in both humans and laboratory animals. Withdrawal symptoms included anger, aggression, irritability, anxiety, decreased appetite, restlessness, and sleep difficulties with vivid dreams.\n\nA key point was that THC's long half-life delays withdrawal onset, creating a disconnect between stopping use and feeling symptoms. Because people do not immediately connect their discomfort to cannabis cessation, the withdrawal syndrome goes under-recognized by both users and clinicians.\n\nThe review also examined potential pharmacotherapies including oral THC (to taper), antidepressants, and lithium, though none had been approved for cannabis dependence at the time.","whyItMatters":"The perception that cannabis is not addictive led to under-recognition of dependence. This review compiled decades of evidence showing dependence is real, measurable, and may contribute to continued use even when people want to quit.","specificNumbers":"Withdrawal symptoms documented: anger, aggression, irritability, anxiety, decreased appetite/weight loss, restlessness, sleep difficulties with strange dreams. No approved medications for cannabis dependence existed.","methodology":"Narrative review of 30 years of preclinical and clinical research on cannabis dependence, withdrawal, and potential treatments. Covered both human clinical studies and animal models of cannabinoid dependence.","limitations":"This was a narrative review, not a systematic review with predefined search criteria. The authors were researchers in cannabinoid pharmacology, and the review focused heavily on preclinical models. Treatment options discussed were largely untested in large clinical trials."},{"rthcId":"RTHC-00514","title":"Prevalence and psychosocial correlates of prior incarcerations in an urban, predominantly African-American sample of hospitalized patients with first-episode psychosis.","authors":"Ramsay, Claire E; Goulding, Sandra M; Broussard, Beth; Cristofaro, Sarah L; Abedi, Glen R; Compton, Michael T","year":2011,"journal":"The journal of the American Academy of Psychiatry and the Law, 39(1), 57-64","doi":null,"pmid":"21389167","tags":["psychosis","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In a sample of 109 patients hospitalized for first-episode psychosis in an urban setting, 57.8% reported previous incarceration. Among those with incarceration history, 58.1% had been incarcerated more than once, averaging 2.9 incarcerations.\n\nPatients who had been incarcerated had completed fewer years of education, reported earlier cannabis use initiation, and were more likely to meet criteria for cannabis and alcohol dependence or abuse. They also had more psychosocial problems and more severe general psychopathology symptoms.\n\nThe study highlighted that many individuals with psychotic disorders first encounter the criminal justice system rather than the mental health system.","whyItMatters":"The finding that most first-episode psychosis patients in this sample had already been incarcerated suggests the mental health system is reaching many people too late. Earlier cannabis use was one of several risk factors associated with incarceration.","specificNumbers":"57.8% of 109 patients had prior incarceration history. Among incarcerated patients, 58.1% had multiple incarcerations, with a mean of 2.9 incarcerations. Earlier cannabis use initiation was associated with incarceration history.","methodology":"Cross-sectional study of 109 urban, low-income, predominantly African-American patients hospitalized for first-episode psychosis. Researchers compared those with and without prior incarceration on demographic, clinical, and substance use variables.","limitations":"Cross-sectional design cannot establish whether cannabis use contributed to incarceration or psychosis. The sample was predominantly African-American and urban, limiting generalizability. Self-reported incarceration and substance use data may be affected by recall or reporting biases."},{"rthcId":"RTHC-00515","title":"Abuse potential and psychoactive effects of δ-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine.","authors":"Robson, Philip","year":2011,"journal":"Expert opinion on drug safety, 10(5), 675-85","doi":"10.1517/14740338.2011.575778","pmid":"21542664","tags":["medical-cannabis","cbd","addiction","tolerance"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compiled safety data from all published Sativex clinical trials, including the integrated safety analysis for multiple sclerosis patients. Intoxication scores were consistently low. Only 2.2% of patients reported euphoria.\n\nTolerance did not develop over extended use, meaning patients did not need increasing doses for the same effect. When patients stopped Sativex abruptly, no formal withdrawal syndrome occurred. No cases of abuse or diversion were reported.\n\nA separate formal abuse liability study in recreational cannabis users showed Sativex had some abuse potential at higher doses compared to placebo, but scores were consistently lower than equivalent doses of pure THC (dronabinol).","whyItMatters":"Any THC-containing medicine raises concerns about abuse potential. This evidence suggested that the 1:1 THC:CBD formulation and oromucosal delivery route of Sativex produced substantially less abuse liability than pure THC or smoked cannabis.","specificNumbers":"Euphoria reported by 2.2% of patients. No tolerance development. No withdrawal syndrome on abrupt cessation. Abuse liability scores consistently lower than equivalent THC doses.","methodology":"Review of all published clinical trial data for Sativex, plus GW Pharmaceuticals' integrated safety database for MS patients. Also referenced a formal abuse liability study comparing Sativex to dronabinol in recreational cannabis users.","limitations":"Review compiled by a single author associated with cannabis medicine research. Clinical trial populations (MS patients) may differ from recreational users in their responses. The formal abuse liability study used recreational users, which represents a high-risk population."},{"rthcId":"RTHC-00516","title":"Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults.","authors":"Rubio, Marina; Villain, Hélène; Docagne, Fabian; Roussel, Benoit D; Ramos, José Antonio; Vivien, Denis; Fernandez-Ruiz, Javier; Ali, Carine","year":2011,"journal":"PloS one, 6(8), e23690","doi":"10.1371/journal.pone.0023690","pmid":"21886913","tags":["neuroscience","drug-interactions","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using an in vitro model of chronic alcohol exposure and withdrawal, researchers found that alcohol withdrawal increased sensitivity to NMDA-induced neuron death, likely by altering the balance of NMDA receptor subtypes (GluN2A vs GluN2B).\n\nThe cannabinoid agonist HU-210 reduced NMDA-induced neuronal death, but only in alcohol-withdrawn neurons, not control neurons. This protection appeared to work by reducing calcium influx after NMDA stimulation.\n\nBy contrast, the CB1 antagonist rimonabant during alcohol withdrawal increased neuronal death. Chronic rimonabant administration increased toxicity in both withdrawn and control neurons. The authors concluded that stimulating the endocannabinoid system is protective during alcohol withdrawal while blocking it is \"highly counterproductive.\"","whyItMatters":"Alcohol withdrawal can cause brain damage through excitotoxicity. This study suggested the endocannabinoid system naturally helps protect against this damage, and that drugs blocking CB1 receptors (like rimonabant, which was being tested for addiction treatment) could worsen outcomes.","specificNumbers":"HU-210 decreased NMDA-induced death exclusively in ethanol-withdrawn neurons. Rimonabant increased death of withdrawn neurons. Chronic rimonabant increased toxicity in both withdrawn and control neurons.","methodology":"In vitro study using cortical neuron cultures exposed to chronic ethanol followed by withdrawal and excitotoxic challenge with NMDA. Tested cannabinoid agonist HU-210 and CB1 antagonist rimonabant. Measured neuronal death and calcium influx.","limitations":"In vitro study using isolated neuron cultures, which do not capture the full complexity of brain circuitry. The alcohol exposure protocol may not replicate human patterns of chronic drinking and withdrawal. Results may not directly translate to clinical situations."},{"rthcId":"RTHC-00517","title":"Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.","authors":"Russo, Ethan B","year":2011,"journal":"British journal of pharmacology, 163(7), 1344-64","doi":"10.1111/j.1476-5381.2011.01238.x","pmid":"21749363","tags":["medical-cannabis","cbd","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review, which became one of the most cited papers in cannabis science, examined how non-cannabinoid plant compounds, particularly terpenes, might contribute to the therapeutic effects of whole-plant cannabis beyond what THC or CBD alone can do.\n\nRusso cataloged eight major cannabis terpenes (limonene, myrcene, pinene, linalool, beta-caryophyllene, caryophyllene oxide, nerolidol, and phytol) and their documented pharmacological effects. He mapped potential synergies between specific cannabinoid-terpene combinations for conditions including pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, and infections.\n\nThe review also presented evidence that some terpenes could serve as \"antidotes\" to THC intoxication, potentially increasing THC's therapeutic index by reducing unwanted psychoactive effects while preserving medical benefits.","whyItMatters":"This paper formalized the concept of the \"entourage effect\" and provided the scientific framework for why whole-plant cannabis extracts might work differently than isolated THC. It influenced cannabis product development, strain selection, and regulatory discussions for years afterward.","specificNumbers":"Eight major terpenes reviewed: limonene, myrcene, alpha-pinene, linalool, beta-caryophyllene, caryophyllene oxide, nerolidol, phytol. Terpenes noted as pharmacologically active at serum levels in single-digit nanograms per milliliter.","methodology":"Comprehensive narrative review synthesizing pharmacological data on cannabis terpenes and phytocannabinoids. The author mapped theoretical synergies between specific compounds based on their known mechanisms of action.","limitations":"Much of the synergy evidence was theoretical, based on known mechanisms rather than direct clinical testing of combinations. The review proposed synergies that had not been confirmed in human trials. Some critics argue the entourage effect remains insufficiently proven."},{"rthcId":"RTHC-00518","title":"Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease.","authors":"Sagredo, Onintza; Pazos, M Ruth; Satta, Valentina; Ramos, José A; Pertwee, Roger G; Fernández-Ruiz, Javier","year":2011,"journal":"Journal of neuroscience research, 89(9), 1509-18","doi":"10.1002/jnr.22682","pmid":"21674569","tags":["medical-cannabis","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats given 3-nitropropionate (3NP), which produces Huntington's disease-like damage, were treated with combinations of THC- and CBD-enriched botanical extracts. The 1:1 combination (as in Sativex) attenuated GABA deficiency, neuronal loss, CB1 receptor downregulation, and calpain overexpression in the striatum.\n\nThe protective effects appeared to be independent of CB1 and CB2 receptors, since selective antagonists for both receptor types could not block the benefits. This suggested the neuroprotection came from the antioxidant properties of both phytocannabinoids rather than their cannabinoid receptor activity.\n\nThe combination also reversed inflammatory markers (inducible nitric oxide synthase) in a malonate lesion model, indicating anti-inflammatory neuroprotection.","whyItMatters":"Huntington's disease has no disease-modifying treatments. These findings suggested cannabinoid combinations could slow neurodegeneration through antioxidant rather than receptor-dependent mechanisms, a distinction that matters for drug development.","specificNumbers":"1:1 THC:CBD ratio tested (as in Sativex). Neuroprotection markers: reversed SOD-1 reduction completely, attenuated calpain overexpression, reduced GABA deficiency, preserved Nissl-stained neurons.","methodology":"Two rat models of Huntington's disease: 3NP intoxication and malonate lesions. Rats received various combinations of THC- and CBD-enriched botanical extracts. CB1 and CB2 antagonists were used to test receptor dependence. Multiple neuroprotection markers were measured.","limitations":"Chemical models of Huntington's disease do not fully replicate the human genetic disease. Rat brains differ from human brains in important ways. The study did not assess functional outcomes like motor behavior. Translation to human disease is uncertain."},{"rthcId":"RTHC-00519","title":"THC and CBD oromucosal spray (Sativex®) in the management of spasticity associated with multiple sclerosis.","authors":"Sastre-Garriga, Jaume; Vila, Carlos; Clissold, Stephen; Montalban, Xavier","year":2011,"journal":"Expert review of neurotherapeutics, 11(5), 627-37","doi":"10.1586/ern.11.47","pmid":"21456949","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compiled clinical trial evidence for Sativex oromucosal spray in MS-related spasticity. Randomized controlled trials reported reductions in spasticity severity when Sativex was added to existing treatments, along with improved ability to perform daily activities.\n\nBoth patients and caregivers perceived functional improvement. Common adverse events included dizziness, diarrhea, fatigue, nausea, headache, and somnolence, but these were generally mild to moderate and could be substantially reduced by gradually increasing the dose rather than starting at full dose.\n\nThe review positioned Sativex as a useful add-on therapy when existing spasticity medications provided insufficient relief.","whyItMatters":"MS spasticity significantly impacts quality of life, and existing drug treatments often provide limited benefit with poor tolerability. Sativex offered an additional option, particularly for patients who had not responded adequately to conventional anti-spasticity medications.","specificNumbers":"Common adverse events: dizziness, diarrhea, fatigue, nausea, headache, somnolence. Side effects were mild-to-moderate intensity. Gradual uptitration markedly reduced adverse event incidence.","methodology":"Review of published randomized controlled trials and clinical experience data for Sativex in MS spasticity. Included the GW Pharmaceuticals integrated safety analysis.","limitations":"Review focused on initial clinical trial data. Long-term safety and efficacy data was still accumulating. The subjective nature of spasticity measurement makes blinding challenging. Industry data was included."},{"rthcId":"RTHC-00520","title":"Cannabinoid hyperemesis syndrome: an underreported entity causing nausea and vomiting of pregnancy.","authors":"Schmid, Seraina M; Lapaire, Olav; Huang, Dorothy J; Jürgens, Frank Edwin; Güth, Uwe","year":2011,"journal":"Archives of gynecology and obstetrics, 284(5), 1095-7","doi":"10.1007/s00404-010-1811-8","pmid":"21170540","tags":["pregnancy","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report described a 26-year-old patient admitted at 10 weeks of pregnancy with severe nausea and vomiting unresponsive to standard antiemetic drugs. The key diagnostic clue was that compulsive hot bathing provided relief, a hallmark of cannabinoid hyperemesis syndrome (CHS).\n\nCHS is a paradoxical reaction in long-term cannabis users where the drug that typically reduces nausea instead causes cyclic severe vomiting. The authors emphasized that before pursuing expensive medical workups for therapy-resistant hyperemesis in pregnancy, clinicians should ask about hot bathing behavior and cannabis use.\n\nThis was reported as the first documented case of CHS presenting during pregnancy.","whyItMatters":"CHS can be misdiagnosed as hyperemesis gravidarum (extreme pregnancy nausea), leading to unnecessary and expensive testing. Recognizing CHS in pregnant patients allows appropriate treatment and avoidance of unnecessary interventions.","specificNumbers":"Patient age: 26. Gestational age: 10 weeks. This was described as the first reported case of CHS in pregnancy.","methodology":"Single case report of a 26-year-old patient at 10 weeks gestation presenting with therapy-resistant vomiting. Clinical history, examination, and response to hot bathing were documented.","limitations":"Single case report. Cannot determine how common CHS is among pregnant cannabis users. The mechanisms underlying CHS were not well understood at the time."},{"rthcId":"RTHC-00521","title":"Cocaine withdrawal reduces group I mGluR-mediated long-term potentiation via decreased GABAergic transmission in the amygdala.","authors":"Schmidt, Kady; Krishnan, Balaji; Xia, Yan; Sun, Anyang; Orozco-Cabal, Luis; Pollandt, Sebastian; Centeno, Marjorie; Genzer, Kathy; Gallagher, Joel P; Shinnick-Gallagher, Patricia; Liu, Jie","year":2011,"journal":"The European journal of neuroscience, 34(2), 177-89","doi":"10.1111/j.1460-9568.2011.07769.x","pmid":"21749491","tags":["addiction","neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers studied how cocaine withdrawal altered brain circuitry in the amygdala, a region central to emotional learning and drug-cue associations. After 14 days of cocaine withdrawal, rats showed reduced mGluR1-mediated long-term potentiation (a form of synaptic plasticity) in the pathway from the basolateral amygdala to the central amygdala.\n\nThis reduction was associated with decreased GABAergic (inhibitory) signaling. Endocannabinoid signaling was also altered: CB1 and CB2 receptor protein levels were increased, but normal CB1-mediated modulation of plasticity was disrupted.\n\nThe disrupted plasticity could bias behavior toward drug-seeking by altering how the brain processes environmental cues associated with cocaine use.","whyItMatters":"Understanding how cocaine withdrawal rewires the amygdala helps explain why environmental cues trigger relapse weeks after drug cessation. The endocannabinoid system changes suggest it may be a therapeutic target for preventing cue-induced relapse.","specificNumbers":"mGluR1-LTP was reduced at both 2-day and 14-day withdrawal timepoints. CB1 and CB2 protein levels were increased in cocaine-withdrawn rats. GABAergic synaptic inhibition was reduced in CeLc neurons.","methodology":"Rats underwent cocaine conditioned place preference, then 14-day withdrawal. Brain slice electrophysiology measured synaptic plasticity in the amygdala pathway. CB1 and CB2 receptor levels were quantified by Western blot. Pharmacological tools tested endocannabinoid contributions.","limitations":"Rat model of cocaine dependence may not fully replicate human addiction. Brain slice recordings capture isolated circuit activity rather than whole-brain dynamics. The specific behavioral consequences of the plasticity changes were not directly tested."},{"rthcId":"RTHC-00522","title":"A randomized, double-blind, placebo-controlled, crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a history of recreational cannabis use.","authors":"Schoedel, Kerri Alexandra; Chen, Nancy; Hilliard, Annie; White, Linda; Stott, Colin; Russo, Ethan; Wright, Stephen; Guy, Geoffrey; Romach, Myroslava K; Sellers, Edward M","year":2011,"journal":"Human psychopharmacology, 26(3), 224-36","doi":"10.1002/hup.1196","pmid":"21671456","tags":["medical-cannabis","cbd","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This crossover study gave 23 recreational cannabis users single doses of Sativex (at three dose levels), dronabinol (at two dose levels), or placebo. At the lowest dose (10.8 mg THC), Sativex was not significantly different from placebo on primary abuse potential measures.\n\nAt the medium dose (21.6 mg THC), Sativex showed some abuse potential on certain measures. At the highest dose (43.2 mg THC), Sativex showed significant effects on most abuse measures, roughly comparable to dronabinol 40 mg.\n\nCritically, at every dose comparison, Sativex scores were numerically equal to or lower than equivalent dronabinol doses. This confirmed that adding CBD and using oromucosal delivery did not increase abuse potential beyond that of pure THC.","whyItMatters":"This study directly addressed the regulatory concern about whether a THC-containing medicine could be abused. By showing Sativex had no greater abuse potential than already-approved dronabinol, it supported the case for regulatory approval.","specificNumbers":"23 recreational cannabis users. Sativex 10.8 mg: not different from placebo on primary measures. Sativex 43.2 mg and dronabinol 40 mg: generally not statistically different from each other. Sativex scores consistently equal to or lower than equivalent dronabinol.","methodology":"Single-dose, randomized, double-blind, crossover study. 23 recreational cannabis users received Sativex (10.8, 21.6, and 43.2 mg THC), dronabinol (20 and 40 mg), and matching placebos. Subjective and cognitive measures were assessed over 24 hours post-dose.","limitations":"Single-dose design does not capture repeated-use patterns. Recreational cannabis users represent a high-risk population, so abuse potential in pain or MS patients may be lower. The study was funded by GW Pharmaceuticals, Sativex's manufacturer."},{"rthcId":"RTHC-00523","title":"MDMA & cannabis: a mini-review of cognitive, behavioral, and neurobiological effects of co-consumption.","authors":"Schulz, Sybille","year":2011,"journal":"Current drug abuse reviews, 4(2), 81-6","doi":null,"pmid":"21696342","tags":["drug-interactions","cognition","neuroscience","dopamine"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined 23 articles on the combined effects of MDMA (ecstasy) and cannabis. Human retrospective studies pointed to additive negative effects on different types of memory in long-term co-users, with cannabis-independent decreases in learning and decision-making among MDMA users.\n\nAnimal studies showed that acute co-administration of MDMA and cannabinoid agents affected body temperature, conditioned reinforcement, and presumed neurotoxicity. The neural mechanisms involved interactions between the CB1 receptor and serotonergic and dopaminergic systems in the prefrontal cortex, nucleus accumbens, and hippocampus.\n\nThe review noted that despite MDMA-cannabis co-use being very common among recreational drug users, surprisingly few studies had specifically examined the combination.","whyItMatters":"MDMA and cannabis are frequently used together in recreational settings, but most drug research examines each substance in isolation. Understanding their interaction helps predict risks for the large population of co-users.","specificNumbers":"23 articles reviewed (2002-2010). Brain regions involved: prefrontal cortex, nucleus accumbens, hippocampus. Neurotransmitter systems: CB1, serotonin, dopamine.","methodology":"Mini-review of 23 articles published between 2002 and 2010 specifically examining combined MDMA and cannabis/cannabinoid effects. Included human retrospective cognitive studies and animal behavioral and neurobiological experiments.","limitations":"Most human studies were retrospective, meaning they could not prove the drugs caused the observed cognitive deficits. Polydrug use makes it difficult to isolate specific drug combination effects. Few studies examined chronic co-administration in animals."},{"rthcId":"RTHC-00524","title":"Behavioral effects of fatty acid amide hydrolase inhibition on morphine withdrawal symptoms.","authors":"Shahidi, Siamak; Hasanein, Parisa","year":2011,"journal":"Brain research bulletin, 86(1-2), 118-22","doi":"10.1016/j.brainresbull.2011.06.019","pmid":"21763761","tags":["addiction","withdrawal","drug-interactions","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats made dependent on morphine through 7 days of daily injections received URB597, a FAAH inhibitor that boosts anandamide levels, before naloxone-precipitated withdrawal. URB597 at doses of 0.1 to 1 mg/kg reduced most withdrawal symptoms including jumping, teeth chattering, paw tremor, wet dog shakes, face grooming, and weight loss.\n\nOnly the lowest dose tested (0.03 mg/kg) failed to produce significant effects. The broad dose-response range suggested robust endocannabinoid involvement in opioid withdrawal modulation.\n\nThe results demonstrated that endocannabinoids interact with the opioid system during withdrawal, and that boosting endocannabinoid tone through enzyme inhibition could be a therapeutic strategy for managing morphine addiction.","whyItMatters":"Opioid withdrawal is a primary driver of continued opioid use. Finding that boosting natural endocannabinoids reduces withdrawal opens a potential treatment path that avoids the psychoactive effects of directly using cannabinoid drugs.","specificNumbers":"URB597 effective at 0.1, 0.3, 0.5, and 1 mg/kg. Ineffective at 0.03 mg/kg. 10 withdrawal symptoms measured over 30-minute observation period. 7-day morphine dependence protocol.","methodology":"Morphine dependence was induced by 7 consecutive days of morphine injections in rats. URB597 (0.03, 0.1, 0.3, 0.5, 1 mg/kg) was administered before naloxone-precipitated withdrawal. Ten different withdrawal symptoms were recorded during 30 minutes after naloxone injection.","limitations":"Rat model of opioid dependence. Naloxone-precipitated withdrawal is more abrupt than natural withdrawal. Only acute URB597 administration was tested. Long-term safety of FAAH inhibition was not assessed."},{"rthcId":"RTHC-00525","title":"Acute effects of delta-9-tetrahydrocannabinol on performance monitoring in healthy volunteers.","authors":"Spronk, Desirée; Dumont, Glenn J H; Verkes, Robbert J; de Bruijn, Ellen R A","year":2011,"journal":"Frontiers in behavioral neuroscience, 5, 59","doi":"10.3389/fnbeh.2011.00059","pmid":"22046151","tags":["cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Ten healthy volunteers completed a speeded Flankers task (a test of accuracy under time pressure) after receiving THC or placebo vapor in a double-blind crossover design. EEG recordings showed the error-related negativity (ERN), a brain signal that fires immediately after making a mistake, was significantly reduced after THC.\n\nDespite this reduced error-detection signal, behavioral performance on the task was not significantly different between THC and placebo conditions. This disconnect suggested THC impaired the brain's internal monitoring system without immediately degrading task performance in this simple paradigm.\n\nThis was the first study to directly demonstrate cannabinoid effects on the ERN.","whyItMatters":"Performance monitoring is essential for catching and correcting mistakes. A reduced ERN means the brain is less aware of its own errors, which could have implications for driving, complex decision-making, and other tasks where error detection matters.","specificNumbers":"10 healthy volunteers. ERN was significantly reduced after THC compared to placebo. Behavioral accuracy on the Flankers task was not significantly different between conditions.","methodology":"Double-blind, randomized, placebo-controlled crossover design. 10 healthy volunteers inhaled THC or placebo vapor. EEG was recorded during a speeded Flankers choice-reaction-time task. Error-related negativity was measured on error trials.","limitations":"Very small sample size (10 volunteers). Single acute dose design. The Flankers task was not optimized to detect behavioral effects. The disconnect between ERN reduction and preserved behavior might not hold in more demanding real-world tasks."},{"rthcId":"RTHC-00526","title":"Association between a cannabinoid receptor gene (CNR1) polymorphism and cannabinoid-induced alterations of the auditory event-related P300 potential.","authors":"Stadelmann, Andreas M; Juckel, Georg; Arning, Larissa; Gallinat, Jürgen; Epplen, Jörg T; Roser, Patrik","year":2011,"journal":"Neuroscience letters, 496(1), 60-4","doi":"10.1016/j.neulet.2011.04.003","pmid":"21513772","tags":["genetics","cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Twenty healthy volunteers received oral THC, cannabis extract (THC + CBD), or placebo in a controlled study. Both THC and cannabis extract reduced P300 amplitudes (a brain wave associated with attention and working memory), with no difference between the two cannabinoid conditions.\n\nHowever, when participants were grouped by their CNR1 gene variant (an AAT repeat polymorphism), those with the >10/>10 genotype showed a significant P300 amplitude decrease and latency prolongation specifically under pure THC, but not under cannabis extract containing both THC and CBD.\n\nThe number of AAT repeats correlated with P300 changes under THC, suggesting the cannabinoid receptor gene directly influenced sensitivity to THC's cognitive effects.","whyItMatters":"This was early evidence that genetic variation in the cannabinoid receptor gene could explain why people respond differently to cannabis. The finding that CBD in the extract appeared to buffer the genetic sensitivity to pure THC was also notable.","specificNumbers":"20 healthy volunteers. CNR1 (AAT)n repeat polymorphism genotyped. >10/>10 genotype showed significant P300 changes under THC but not cannabis extract. Number of AAT repeats correlated with THC-induced P300 changes.","methodology":"Study of 20 healthy volunteers genotyped for the CNR1 (AAT)n polymorphism. Participants received oral THC, cannabis extract (THC + CBD), or placebo. EEG P300 was recorded during an auditory choice reaction task.","limitations":"Very small sample size (20 volunteers) limits genetic analysis power. A single genetic variant was examined. The study could not determine whether the genotype effect has real-world cognitive consequences beyond EEG changes."},{"rthcId":"RTHC-00527","title":"Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania.","authors":"Valvassori, Samira S; Elias, Guilherme; de Souza, Bruna; Petronilho, Fabrícia; Dal-Pizzol, Felipe; Kapczinski, Flávio; Trzesniak, Clarissa; Tumas, Vitor; Dursun, Serdar; Chagas, Marcos Hortes Nisihara; Hallak, Jaime E C; Zuardi, Antonio W; Quevedo, João; Crippa, José A S","year":2011,"journal":"Journal of psychopharmacology (Oxford, England), 25(2), 274-80","doi":"10.1177/0269881109106925","pmid":"19939866","tags":["cbd","neuroscience","mental-health"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used two experimental models in rats. In the reversal model, rats received amphetamine daily for 14 days (to mimic mania), then received CBD (15, 30, or 60 mg/kg) from day 8 to 14. In the prevention model, CBD was given first, followed by amphetamine from day 8 to 14.\n\nIn the reversal model, CBD at 15 mg/kg reversed amphetamine-induced oxidative damage in the hippocampus and increased brain-derived neurotrophic factor (BDNF) at 30 mg/kg. In the prevention model, CBD at 30 or 60 mg/kg prevented oxidative protein damage in the prefrontal cortex, and all CBD doses prevented damage in the hippocampus and striatum.\n\nNotably, CBD did not reduce amphetamine-induced hyperactivity in either model, suggesting its neuroprotective effects were independent of behavioral changes.","whyItMatters":"Bipolar disorder involves oxidative stress and reduced BDNF in the brain. If CBD can protect against these changes, it might function as a neuroprotective adjunct to standard mood stabilizers, addressing brain health rather than just symptom control.","specificNumbers":"CBD 15 mg/kg reversed hippocampal oxidative damage. CBD 30 mg/kg increased BDNF. CBD 30-60 mg/kg prevented prefrontal cortex damage. All doses (15, 30, 60 mg/kg) prevented hippocampal and striatal damage in the prevention model.","methodology":"Two rat models of mania: reversal (CBD given during ongoing amphetamine) and prevention (CBD given before amphetamine). CBD at 15, 30, and 60 mg/kg was administered twice daily. Oxidative damage markers, BDNF levels, and locomotor activity were measured.","limitations":"Amphetamine-induced hyperactivity is a limited model of bipolar mania. CBD did not reduce hyperactivity, raising questions about behavioral relevance. Rat brain responses may not translate to human bipolar disorder. Dosing and timing may not apply clinically."},{"rthcId":"RTHC-00528","title":"Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study.","authors":"van Hell, Hendrika H; Bossong, Matthijs G; Jager, Gerry; Kristo, Gert; van Osch, Matthias J P; Zelaya, Fernando; Kahn, René S; Ramsey, Nick F","year":2011,"journal":"The international journal of neuropsychopharmacology, 14(10), 1377-88","doi":"10.1017/S1461145711000526","pmid":"21489346","tags":["neuroscience","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-three subjects underwent pharmacological MRI after receiving THC or placebo. Using arterial spin labeling to measure blood flow, researchers found THC increased perfusion in the anterior cingulate cortex, superior frontal cortex, and insula, while reducing it in the post-central and occipital regions.\n\nResting-state fMRI showed increased baseline brain activity (measured by signal fluctuation amplitude) in the insula, substantia nigra, and cerebellum after THC. Frontal cortex perfusion changes were negatively correlated with \"feeling high\" ratings.\n\nThe insula findings were particularly notable because this region processes interoceptive awareness, the brain's perception of internal body states. The authors proposed that THC-induced changes in the insula may be central to the subjective experience of \"feeling high.\"","whyItMatters":"Understanding the neural basis of the cannabis \"high\" helps explain both its recreational appeal and potential therapeutic mechanisms. The insula's role in interoceptive awareness connects the subjective experience to a specific brain mechanism.","specificNumbers":"23 subjects. THC increased perfusion in anterior cingulate, superior frontal cortex, and insula. Reduced perfusion in post-central and occipital regions. Increased resting-state activity in insula, substantia nigra, and cerebellum.","methodology":"Pharmacological MRI study with 23 subjects. Combined arterial spin labeling (for perfusion) and resting-state fMRI (for baseline activity). THC was compared to placebo. Subjective \"feeling high\" ratings were correlated with imaging measures.","limitations":"Acute single-dose design. The sample was healthy volunteers, not regular cannabis users. ASL perfusion measurement has lower signal-to-noise ratio than traditional fMRI. Heart rate effects of THC can confound blood-flow-based imaging."},{"rthcId":"RTHC-00529","title":"Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal.","authors":"Vandrey, Ryan; Smith, Michael T; McCann, Una D; Budney, Alan J; Curran, Erin M","year":2011,"journal":"Drug and alcohol dependence, 117(1), 38-44","doi":"10.1016/j.drugalcdep.2011.01.003","pmid":"21296508","tags":["sleep","withdrawal","medical-cannabis","cognition"],"studyType":"cross-over","evidenceStrength":"preliminary","keyFinding":"When participants stopped cannabis for three nights and took placebo at bedtime, objective sleep quality dropped. They spent less of their time in bed asleep (lower sleep efficiency) and slept fewer total minutes. It took longer to fall asleep. Sleep architecture shifted, with less Stage 1 and Stage 2 sleep, shorter REM latency, and more time spent in REM. Subjective sleep quality also worsened compared to nights when participants were using cannabis.\n\nDuring the parallel abstinence period with extended-release zolpidem at bedtime, many of these changes were dampened. Sleep efficiency returned to pre-abstinence levels, and broader architecture disruptions were attenuated. One exception stood out: zolpidem did not shorten sleep latency, so time to fall asleep remained prolonged. Across study nights, zolpidem was not linked to significant side effects or next-day cognitive performance deficits on the tests used.","whyItMatters":"Sleep disturbance is one of the most common withdrawal symptoms reported by regular cannabis users. This study moved past self-report to measure sleep with polysomnography during early abstinence and tested whether a standard hypnotic changed those signals.","specificNumbers":"- Sample: 20 daily cannabis users in a within-subject, placebo-controlled crossover\n- Abstinence windows: 3 nights per condition (placebo vs extended-release zolpidem at bedtime)\n- Placebo-abstinence vs cannabis use: lower sleep efficiency and total sleep time; longer time to fall asleep; less Stage 1 and Stage 2; shorter REM latency; more time in REM; worse subjective sleep\n- Zolpidem during abstinence: sleep efficiency normalized; architecture disruptions attenuated; no change in sleep latency","methodology":"Within-subject, placebo-controlled crossover. Twenty daily cannabis users alternated between periods of ad libitum cannabis use and short abstinence windows of three days. During one abstinence period they received placebo at bedtime, and during the other they received extended-release zolpidem at bedtime. Each day included overnight polysomnography to quantify sleep stages and efficiency, subjective sleep ratings, and next-day cognitive testing. The abstract does not report dose, setting, or country.","limitations":"Small sample (N=20). Only three nights of abstinence per condition, so no insight into longer withdrawal courses. No dose information for zolpidem in the abstract. Cannabis potency, product type, and timing of last use were not reported. Potential order or carryover effects are not detailed. Outcomes were limited to sleep architecture, subjective ratings, and short next-day cognitive tests, not clinical endpoints like craving or return to cannabis use."},{"rthcId":"RTHC-00530","title":"Increased blood pressure after abrupt cessation of daily cannabis use.","authors":"Vandrey, Ryan; Umbricht, Annie; Strain, Eric C","year":2011,"journal":"Journal of addiction medicine, 5(1), 16-20","doi":"10.1097/ADM.0b013e3181d2b309","pmid":"21359104","tags":["cardiovascular","withdrawal","quitting"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Thirteen daily cannabis users participated in an inpatient study alternating between ad libitum cannabis smoking and supervised abstinence. Vital signs were measured three times daily over 11 inpatient days.\n\nBlood pressure increased significantly during abstinence compared to cannabis-use periods. In a subset of 6 participants, the increases were substantial: up to 22.8 mmHg systolic and 12.3 mmHg diastolic. Heart rate was not significantly affected overall, though morning resting heart rate showed a slight increase during abstinence.\n\nThe authors noted that abrupt cessation of heavy cannabis use may cause clinically significant blood pressure increases, particularly concerning for users with preexisting hypertension.","whyItMatters":"Cannabis withdrawal is typically described in terms of mood, sleep, and appetite changes. This study identified a cardiovascular component that could be dangerous for people with existing high blood pressure who suddenly stop heavy cannabis use.","specificNumbers":"13 daily cannabis users. Subset of 6 showed mean increases up to 22.8 mmHg systolic and 12.3 mmHg diastolic. 11 inpatient days. Vital signs measured 3 times daily.","methodology":"Within-subjects ABAC crossover design with inpatient monitoring. 13 daily cannabis users (11 men, 8 African American) alternated between ad libitum cannabis smoking (A) and abstinence (B/C). Vital signs taken 3 times daily over 11 days.","limitations":"Small sample size (13 participants). The clinically significant increases were seen in only a subset of 6. Short observation period means the time course of blood pressure normalization is unknown. All-male sample limits generalizability."},{"rthcId":"RTHC-00531","title":"Sativex(®) (tetrahydrocannabinol + cannabidiol), an endocannabinoid system modulator: basic features and main clinical data.","authors":"Vermersch, Patrick","year":2011,"journal":"Expert review of neurotherapeutics, 11(4 Suppl), 15-9","doi":null,"pmid":"21449855","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review summarized data from three pivotal randomized controlled trials of Sativex for MS-related spasticity. The first trial (189 patients, 6 weeks) showed a significant spasticity score reduction with Sativex versus placebo (-1.18 vs -0.63, p=0.048). The second trial (337 patients, 15 weeks) confirmed the finding (-1.3 vs -0.8, p=0.035).\n\nThe third trial used an innovative design: 572 patients first tried Sativex openly, and the 47% who responded (20% or greater improvement) were then randomized to continue Sativex or switch to placebo. Responders who continued Sativex maintained their improvement, while those switched to placebo worsened (p=0.0002).\n\nNo tolerance, withdrawal syndrome, or evidence of misuse or abuse was reported across trials. Side effects were mild-to-moderate and transient, primarily dizziness, fatigue, and somnolence.","whyItMatters":"This represented the strongest clinical trial evidence at the time for any cannabis-based medicine. The enriched enrollment design of the third trial was particularly important because it demonstrated that identifying responders first could improve treatment efficiency.","specificNumbers":"Trial 1: 189 patients, 6 weeks, p=0.048. Trial 2: 337 patients, 15 weeks, p=0.035. Trial 3: 572 patients, 47% initial responders, p=0.0002 for sustained efficacy. No tolerance or withdrawal reported.","methodology":"Review of three pivotal randomized, placebo-controlled clinical trials of Sativex oromucosal spray in MS patients with resistant spasticity. Combined enrollment exceeded 1,000 patients. Primary endpoint was the 0-10 NRS spasticity score.","limitations":"Review by a single author. The NRS spasticity scale is subjective. The enriched enrollment design in trial 3, while practical, selects for patients who respond and may overestimate effect size for the general MS population."},{"rthcId":"RTHC-00532","title":"Pharmacological treatment of cannabis dependence.","authors":"Weinstein, A M; Gorelick, David A","year":2011,"journal":"Current pharmaceutical design, 17(14), 1351-8","doi":null,"pmid":"21524266","tags":["addiction","withdrawal","quitting"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review surveyed the landscape of pharmacological treatments for cannabis dependence, a condition with rising treatment admissions but no approved medications. Three categories of medications had been studied: those targeting withdrawal symptoms, those acting on cannabinoid receptors, and those with efficacy for other addictions or psychiatric conditions.\n\nBuspirone, an anti-anxiety medication, was the only drug that had shown efficacy in a controlled clinical trial. Dronabinol (oral THC), the COMT inhibitor entacapone, and lithium showed promise in smaller studies or laboratory settings.\n\nPreclinical research suggested newer targets including FAAH inhibitors like URB597, endocannabinoid-metabolizing enzymes, and nicotinic alpha-7 receptor antagonists, but none had reached clinical trials.","whyItMatters":"The majority of people entering treatment for cannabis dependence struggled to achieve and maintain abstinence. Without effective medications, treatment relied entirely on behavioral interventions, which have limited success rates for substance use disorders.","specificNumbers":"Buspirone: only medication with controlled trial efficacy. Dronabinol, entacapone, lithium: promising in smaller studies. No medications approved by any national regulatory authority for cannabis dependence.","methodology":"Narrative review of clinical trials, human laboratory studies, open-label trials, and preclinical research on medications for cannabis dependence. Covered both published and emerging data.","limitations":"Narrative review without systematic search methodology. The field was young with mostly small studies. Many promising preclinical findings had not yet been tested in humans."},{"rthcId":"RTHC-00533","title":"Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study.","authors":"Winton-Brown, Toby T; Allen, Paul; Bhattacharyya, Sagnik; Borgwardt, Stefan J; Fusar-Poli, Paolo; Crippa, Jose A; Seal, Marc L; Martin-Santos, Rocio; Ffytche, Dominic; Zuardi, Antonio W; Atakan, Zerrin; McGuire, Philip K","year":2011,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36(7), 1340-8","doi":"10.1038/npp.2011.17","pmid":"21412224","tags":["psychosis","cbd","neuroscience","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Fourteen healthy volunteers were scanned with fMRI on three occasions after receiving THC (10 mg), CBD (600 mg), or placebo. During auditory processing, THC decreased activation in bilateral temporal cortices, while CBD increased activation in the right temporal cortex.\n\nThe most striking finding was in the right posterior superior temporal gyrus, the right-hemisphere counterpart to Wernicke's area (critical for language comprehension). THC and CBD had directly opposite effects in this region. THC's attenuation of activation here correlated with its tendency to induce psychotic symptoms.\n\nDuring visual processing, THC both increased and decreased activation in different visual areas. CBD produced anxiety or psychotic symptom increases in no participants, while THC increased anxiety, intoxication, and positive psychotic symptoms.","whyItMatters":"The finding that THC-induced changes in a language-related brain area correlated with psychotic symptoms provided a neural mechanism linking cannabis use to psychosis risk. CBD's opposite effect suggested it might counteract this specific vulnerability.","specificNumbers":"14 volunteers, 3 sessions each. THC: 10 mg oral. CBD: 600 mg oral. THC and CBD had opposite effects at coordinates 61, -15, -2 (right posterior superior temporal gyrus).","methodology":"Double-blind, pseudo-randomized crossover design with 14 healthy volunteers. Each participant received 10 mg THC, 600 mg CBD, or placebo on separate occasions. fMRI was recorded during passive listening to words and viewing a radial checkerboard.","limitations":"Small sample size (14 volunteers). Single acute doses may not represent chronic use patterns. The tasks were passive (listening, viewing) and may not capture the full range of perceptual effects. CBD dose (600 mg) was much larger than typical consumer doses."},{"rthcId":"RTHC-00534","title":"delta(9)-Tetrahydrocannabinol-dependent mice undergoing withdrawal display impaired spatial memory.","authors":"Wise, Laura E; Varvel, Stephen A; Selley, Dana E; Wiebelhaus, Jason M; Long, Kelly A; Middleton, Lisa S; Sim-Selley, Laura J; Lichtman, Aron H","year":2011,"journal":"Psychopharmacology, 217(4), 485-94","doi":"10.1007/s00213-011-2305-5","pmid":"21559804","tags":["cognition","withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats received the cannabinoid agonist WIN55,212-2 daily during late adolescence (postnatal days 45-60) and were tested at 24 hours, 10 days, 30 days, and 75 days after the last injection. Short-term memory in the water maze and object recognition tasks, and synaptic plasticity in the brain's reward pathway, recovered by 10 or 30 days after stopping.\n\nHowever, hippocampal-dependent spatial memory (tested with the object location task) remained impaired at all timepoints including 75 days, the latest measurement taken. This suggested a specific vulnerability of location-based memory to chronic adolescent cannabinoid exposure.\n\nThe researchers interpreted the recoverable deficits as likely due to residual cannabinoids in the brain or acute withdrawal effects, while the persistent spatial memory deficit reflected a more fundamental change in hippocampal function.","whyItMatters":"The distinction between temporary and persistent effects matters for adolescent cannabis users. Some cognitive deficits cleared with abstinence, but spatial memory impairment persisted well beyond the drug clearance period, suggesting lasting brain changes.","specificNumbers":"Treatment: postnatal days 45-60 (late adolescence equivalent). Water maze and object recognition: impaired at 24 hrs and 10 days, recovered by 30 days. Object location (spatial memory): still impaired at 75 days.","methodology":"Rats received WIN55,212-2 (1.2 mg/kg i.p.) daily for 2 weeks during late adolescence. Cognitive testing included Morris water maze, object recognition, and object location tasks at 24 hours, 10 days, 30 days, and 75 days post-treatment. Synaptic plasticity (LTP) was measured electrophysiologically.","limitations":"Used a synthetic cannabinoid agonist (WIN55,212-2), not THC. Rat adolescence does not perfectly map to human adolescence. The dosing regimen was high and consistent, unlike typical human use patterns. Only male rats were used."},{"rthcId":"RTHC-00535","title":"Role of cannabinoids in multiple sclerosis.","authors":"Zajicek, John P; Apostu, Vicentiu I","year":2011,"journal":"CNS drugs, 25(3), 187-201","doi":"10.2165/11539000-000000000-00000","pmid":"21323391","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered both the endocannabinoid system biology and clinical evidence for cannabinoids in MS. For symptoms, the evidence was strongest for spasticity/muscle spasms, neuropathic pain, and sleep disturbance. Trials for tremor and nystagmus (involuntary eye movements) showed no benefit.\n\nSafety profiles were generally acceptable, with slow dose titration improving tolerability. No serious safety concerns had emerged across the clinical trial program.\n\nBeyond symptom management, emerging experimental evidence suggested cannabinoids might have disease-modifying properties, with preclinical data showing anti-inflammatory effects, encouragement of remyelination, and neuroprotection. Clinical trials were underway to test whether cannabinoids could reduce disability progression.","whyItMatters":"This review distinguished between confirmed symptomatic benefits and speculative disease-modifying potential. The gap between strong preclinical neuroprotection data and unproven clinical disease modification remained an important research question.","specificNumbers":"Cannabinoids effective for: spasticity, pain, sleep, bladder disturbance. Not effective for: tremor, nystagmus. No serious safety concerns identified.","methodology":"Comprehensive narrative review of cannabinoid receptor biology, the endocannabinoid system, and clinical evidence for cannabinoids in MS. Covered both symptom management trials and preclinical disease modification research.","limitations":"Narrative review by authors in the field. The disease modification evidence was entirely preclinical at the time. Symptom assessment in MS is inherently subjective, making trial results harder to interpret."},{"rthcId":"RTHC-00536","title":"What place for ▾ cannabis extract in MS?","authors":"","year":2012,"journal":"Drug and therapeutics bulletin, 50(12), 141-4","doi":"10.1136/dtb.2012.11.0150","pmid":"23241565","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This Drug and Therapeutics Bulletin evaluation reviewed the clinical evidence for Sativex (cannabis extract containing THC and CBD) for MS-related spasticity. MS affects about 60,000 people in England and Wales, with a lifetime UK risk of 1 in 1,000.\n\nSpasticity was described as a common symptom requiring complex drug combinations that were often only partially effective with unacceptable side effects. Sativex was the first licensed cannabinoid preparation for medical use, approved specifically for patients with moderate-to-severe spasticity who had not responded adequately to other anti-spasticity medications.\n\nThe license required patients to demonstrate clinically significant improvement during an initial trial period before continuing treatment.","whyItMatters":"Independent drug evaluation bulletins help clinicians make prescribing decisions. This assessment from a source without industry ties provided a balanced perspective on where Sativex fits in the treatment pathway.","specificNumbers":"MS affects ~60,000 people in England and Wales. UK lifetime risk: 1 in 1,000. Sativex licensed for moderate-to-severe spasticity after other treatments fail.","methodology":"Drug evaluation review by the Drug and Therapeutics Bulletin, an independent UK publication that critically appraises medicines. Reviewed published clinical evidence for Sativex in MS spasticity.","limitations":"Brief review format. Limited critical detail on the magnitude of treatment effects. The publication predated longer-term efficacy and safety data."},{"rthcId":"RTHC-00537","title":"Short- and long-term cognitive effects of chronic cannabinoids administration in late-adolescence rats.","authors":"Abush, Hila; Akirav, Irit","year":2012,"journal":"PloS one, 7(2), e31731","doi":"10.1371/journal.pone.0031731","pmid":"22348124","tags":["cognition","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats received the cannabinoid agonist WIN55,212-2 daily during late adolescence and were tested at multiple timepoints. Short-term memory in the water maze and object recognition recovered by 10-30 days after stopping. Synaptic plasticity in the ventral subiculum-nucleus accumbens pathway also recovered.\n\nHowever, hippocampal-dependent spatial memory (object location task) remained significantly impaired at 24 hours, 10 days, 30 days, and 75 days after the last injection. This persistent deficit was specific to the spatial domain, suggesting the hippocampus was particularly vulnerable to lasting cannabinoid effects during adolescent development.\n\nThe authors proposed that the recoverable deficits were caused by residual drug or acute withdrawal, while the persistent spatial memory impairment reflected genuine neurodevelopmental changes.","whyItMatters":"The finding that spatial memory was selectively and persistently impaired while other cognitive functions recovered has implications for understanding which brain functions are most vulnerable during adolescent cannabis exposure.","specificNumbers":"Treatment window: postnatal days 45-60. Recovery of water maze and object recognition: by 10-30 days. Object location deficit: persisted through 75 days. LTP in vSub-NAc pathway: recovered.","methodology":"Rats received WIN55,212-2 (1.2 mg/kg i.p.) daily during postnatal days 45-60. Behavioral testing (water maze, object recognition, object location) and electrophysiology (LTP in vSub-NAc pathway) were conducted at 24 hours, 10 days, 30 days, and 75 days post-treatment.","limitations":"Used synthetic cannabinoid agonist, not THC. Only late-adolescent exposure was tested. Male rats only. The highest timepoint (75 days) may not be the final recovery point."},{"rthcId":"RTHC-00538","title":"Quantifying the clinical significance of cannabis withdrawal","authors":"Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molber, Anna; Budney, Alan J.; et al.","year":2012,"journal":"PLOS ONE, 7(9), e44864","doi":"10.1371/journal.pone.0044864","pmid":"23049760","tags":["withdrawal","addiction","quitting","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"People who felt that withdrawal was getting in the way of normal activities reported higher withdrawal severity, and those two measures moved together with a strong statistical signal. Participants with more severe dependence before stopping reported more disruption from withdrawal once they tried to abstain.\n\nDuring the two-week abstinence window, relapse was associated with greater interference from a subset of withdrawal symptoms among those with high dependence. Looking beyond the quit attempt, higher levels of withdrawal-related functional impairment during abstinence statistically predicted higher cannabis use at the one-month follow-up. These are associations in a small, volunteer sample, not proof that withdrawal caused relapse or later use.","whyItMatters":"At the time, there was debate about whether cannabis withdrawal meaningfully affects daily life. This study quantified interference with normal activities and found that higher disruption tracked with relapse during abstinence and with heavier use a month later. It frames withdrawal not just as a list of symptoms, but as something that can be tied to everyday functioning and the course of a quit attempt.","specificNumbers":"- Sample: 49 non-treatment seeking adults with DSM-IV cannabis dependence\n- Timeline: 1-week baseline, 2 weeks of monitored abstinence, 1-month follow-up\n- Withdrawal interference and symptom severity moved together (p=0.0001), indicating a strong statistical link\n- Greater dependence severity at baseline tracked with more withdrawal-related interference during abstinence (p=0.03)","methodology":"Prospective observational study. Forty-nine non-treatment seeking adults who met DSM-IV criteria for cannabis dependence completed a one-week baseline, followed by two weeks of monitored abstinence and a one-month follow-up. Each day, they rated how much withdrawal symptoms interfered with normal activities, producing a 'functional impairment' score. Analyses tested links between impairment, symptom severity, dependence severity at baseline, relapse during abstinence, and use at one month. There was no control group and impairment was self-reported.","limitations":"Small sample (49) limits precision. Non-treatment seeking volunteers may not resemble people seeking help. Relapse analyses drew on a small subgroup, raising the risk of unstable estimates. Outcomes relied on self-reported daily interference without objective verification. The study was observational with no control group, so it cannot establish causality. Product types, potencies, ages, and sex distribution were not detailed in the abstract. Country was not specified."},{"rthcId":"RTHC-00539","title":"Steppingstone and gateway ideas: a discussion of origins, research challenges, and promising lines of research for the future.","authors":"Anthony, James C","year":2012,"journal":"Drug and alcohol dependence, 123 Suppl 1(Suppl 1), S99-S104","doi":"10.1016/j.drugalcdep.2012.04.006","pmid":"22572210","tags":["addiction","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The author examined the origins of \"steppingstone\" and \"gateway\" ideas about cannabis and other drug use, tracing references from American law and epidemiology as far back as 1858. Cannabis, opium, tobacco, alcohol, cocaine, and other substances had all been discussed as potential gateways at various points in history.\n\nA central critique was that most gateway research uses between-individual designs (comparing people who used cannabis to those who did not), which are vulnerable to uncontrolled confounding. People who try cannabis early may differ from those who do not in many ways beyond their drug use.\n\nThe author highlighted epidemiologic case-crossover designs and prevention research experiments as potentially more valuable approaches, because they better control for the individual characteristics that confound between-person comparisons.","whyItMatters":"The gateway theory has been one of the most influential ideas in drug policy. This paper argued that the research methods commonly used to support it are fundamentally limited, and that better designs exist but are underutilized.","specificNumbers":"Historical references traced from 1858 to present. Substances discussed as potential gateways: cannabis, opium, tobacco, alcohol, cocaine, kava, heroin.","methodology":"Discussion paper reviewing the historical origins and research methodology of steppingstone/gateway hypotheses. Critiqued between-individual designs including co-twin and imaging studies. Proposed alternative research approaches.","limitations":"This was a discussion paper, not a systematic review. It primarily critiqued existing research rather than presenting new data. The proposed alternative designs have their own limitations."},{"rthcId":"RTHC-00540","title":"Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis.","authors":"Asbridge, Mark; Hayden, Jill A; Cartwright, Jennifer L","year":2012,"journal":"BMJ (Clinical research ed.), 344, e536","doi":"10.1136/bmj.e536","pmid":"22323502","tags":["driving"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Researchers searched 19 databases without language or year restrictions and identified 9 observational studies meeting inclusion criteria. Cannabis use while driving was associated with a significantly increased collision risk (odds ratio 1.92, 95% CI 1.35-2.73, p=0.0003).\n\nRisk estimates were higher in studies of fatal collisions (OR 2.10) than non-fatal ones (OR 1.74, not statistically significant). Case-control studies showed higher estimates (OR 2.79) than culpability studies (OR 1.65).\n\nHeterogeneity among studies was high (I-squared 81%), indicating substantial variation in results across different study designs and populations.","whyItMatters":"This was one of the most comprehensive meta-analyses of cannabis-impaired driving risk. The near-doubling of crash risk provided a clear evidence base for policy on drug-impaired driving.","specificNumbers":"Overall OR: 1.92 (95% CI 1.35-2.73). Fatal collisions: OR 2.10 (1.31-3.36). Non-fatal: OR 1.74 (0.88-3.46). Case-control studies: OR 2.79. Culpability studies: OR 1.65. I-squared: 81%.","methodology":"Systematic review and meta-analysis. Searched 19 electronic databases with no year or language restrictions, plus manual searches and unpublished studies. Included observational studies with appropriate control groups measuring recent cannabis use by blood toxicology or self-report. Used Newcastle-Ottawa scale for bias assessment and random effects models.","limitations":"High heterogeneity between studies. Observational designs cannot prove causation. Different studies used different measures of cannabis exposure (blood THC vs self-report). Publication bias was possible. The analysis could not determine a dose-response relationship."},{"rthcId":"RTHC-00541","title":"Nicotine-induced anxiety-like behavior in a rat model of the novelty-seeking phenotype is associated with long-lasting neuropeptidergic and neuroplastic adaptations in the amygdala: effects of the cannabinoid receptor 1 antagonist AM251.","authors":"Aydin, Cigdem; Oztan, Ozge; Isgor, Ceylan","year":2012,"journal":"Neuropharmacology, 63(8), 1335-45","doi":"10.1016/j.neuropharm.2012.08.016","pmid":"22959963","tags":["neuroscience","addiction","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used novelty-seeking (high-responder) rats that are predisposed to nicotine sensitization. After chronic adolescent nicotine exposure, these rats showed lasting behavioral sensitization and social anxiety even after 3 weeks of abstinence.\n\nThe CB1 antagonist AM251 was tested during abstinence. It successfully reversed locomotor sensitization to nicotine challenge even after prolonged abstinence. However, it completely failed to reverse nicotine-induced anxiety. When given later in abstinence (late phase), AM251 actually augmented anxiety and worsened associated molecular changes in the amygdala.\n\nThe amygdala showed persistent imbalances in neuropeptide Y and CRF systems, increased BDNF, and elevated spinophilin after nicotine, and AM251 did not correct these changes, instead worsening BDNF and spinophilin changes in the basolateral amygdala.","whyItMatters":"This study cautioned against using CB1 antagonists/inverse agonists for nicotine-related anxiety, even though they could reverse some addiction-related behaviors. The divergent effects on sensitization versus anxiety highlighted the complexity of cannabinoid system involvement in addiction.","specificNumbers":"AM251 dose: 5 mg/kg. Short abstinence: 1 week. Long abstinence: 3 weeks. AM251 reversed locomotor sensitization but worsened anxiety during late abstinence.","methodology":"Rat model using high-responder (novelty-seeking) phenotype. Chronic intermittent nicotine during adolescence. AM251 (CB1 antagonist, 5 mg/kg) administered during early (1 week) or late (3 weeks) abstinence. Measured locomotor sensitization, social anxiety, and amygdala neuropeptide/neuroplastic markers.","limitations":"Animal study with a specific genetic phenotype (high-responder rats). Single dose and timing protocol for AM251. The novelty-seeking model may not generalize to all individuals. Only nicotine was tested."},{"rthcId":"RTHC-00542","title":"The biology that underpins the therapeutic potential of cannabis-based medicines for the control of spasticity in multiple sclerosis.","authors":"Baker, David; Pryce, Gareth; Jackson, Samuel J; Bolton, Chris; Giovannoni, Gavin","year":2012,"journal":"Multiple sclerosis and related disorders, 1(2), 64-75","doi":"10.1016/j.msard.2011.11.001","pmid":"25876933","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review connected the biology of MS to the biology of the endocannabinoid system, explaining why cannabis-based medicines work for spasticity at a fundamental level. MS damages myelin and impairs neurotransmission. Cannabinoid receptors and endocannabinoids naturally regulate neurotransmission, making them logical therapeutic targets.\n\nThe review traced the path from MS patients self-medicating with street cannabis, through preclinical validation in animal models of MS, to the approval of cannabis-based medicines. The endocannabinoid system was positioned not just as a symptomatic treatment target but as potentially relevant to the accumulation of progressive disability in MS.","whyItMatters":"Understanding why cannabis-based medicines work, not just that they work, helps guide further drug development and identifies which patients might benefit most.","specificNumbers":"Cannabis-based medicines approved for pain and spasticity in MS at time of publication.","methodology":"Review article connecting MS disease biology to endocannabinoid system biology. Integrated preclinical animal model data with clinical approval evidence for cannabis-based medicines.","limitations":"Review by authors in the field. The disease modification argument was largely preclinical. The biological rationale, while logical, does not guarantee clinical efficacy for all applications."},{"rthcId":"RTHC-00543","title":"Headaches related to psychoactive substance use.","authors":"Beckmann, Yeşim Yetimalar; Seçkin, Mustafa; Manavgat, Ali İlhan; Zorlu, Nabi","year":2012,"journal":"Clinical neurology and neurosurgery, 114(7), 990-9","doi":"10.1016/j.clineuro.2012.02.041","pmid":"22424726","tags":["pain","addiction","withdrawal"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 1,015 consecutively admitted substance users about headaches. Cannabis was the most commonly used substance (80.5%), followed by alcohol (74.6%) and methamphetamine (18.7%).\n\nOverall, 27% reported headaches. Critically, 94.5% of those with headaches said they began after substance use started, suggesting a potential link. Among individual substances, benzodiazepine, methamphetamine, cocaine, heroin, and volatile solvent users had higher headache rates than cannabis users alone.\n\nFor cannabis specifically, younger age at first use and longer duration of use were associated with higher headache incidence. This correlation was not seen with other substances. Migraine was more prevalent in this population than in previously reported community samples. Notably, 78% of headache sufferers had never sought medical help.","whyItMatters":"Headache is an underappreciated symptom in substance users, and 78% had never sought help for it. The specific association between cannabis use duration and headache incidence, not seen with other substances, raised questions about chronic cannabinoid effects on pain pathways.","specificNumbers":"1,015 patients. Cannabis use: 80.5%. Alcohol: 74.6%. Headache prevalence: 26.9%. Headache after substance use onset: 94.5%. Never sought help for headache: 78%.","methodology":"Cross-sectional study of 1,015 consecutively admitted psychoactive substance users. All completed a detailed headache questionnaire. Headache onset timing relative to substance use was recorded. This was a single-group study without a non-user comparison group.","limitations":"No control group of non-substance users. Self-reported headache timing is subject to recall bias. Polydrug use was the norm (most used multiple substances), making it impossible to attribute headaches to cannabis specifically. The population was from a single treatment center."},{"rthcId":"RTHC-00544","title":"The underdiagnosis of cannabis use disorders and other Axis-I disorders among military veterans within VHA.","authors":"Bonn-Miller, Marcel O; Bucossi, Meggan M; Trafton, Jodie A","year":2012,"journal":"Military medicine, 177(7), 786-8","doi":null,"pmid":"22808884","tags":["addiction","ptsd","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared structured clinical interview diagnoses with VA electronic medical record diagnoses for 84 military veterans with confirmed cannabis use disorders. The structured interviews, considered the gold standard, found significant underdiagnosis of cannabis use disorders and PTSD in the VA system.\n\nOther anxiety disorders were also underdiagnosed. In contrast, mood disorders and other substance use disorders were overdiagnosed compared to structured interview results. This pattern suggested clinicians were recognizing some conditions (depression, other substance problems) more readily than others (cannabis dependence, PTSD).\n\nThe findings indicated that routine clinical assessment was missing cannabis use disorders and trauma-related diagnoses at concerning rates.","whyItMatters":"Underdiagnosis means undertreated conditions. If clinicians are not identifying cannabis use disorders and PTSD in veterans, these conditions go unaddressed, potentially worsening outcomes and complicating treatment for the conditions that are identified.","specificNumbers":"84 military veterans with confirmed cannabis use disorders. Cannabis use disorders: significantly underdiagnosed. PTSD and other anxiety disorders: significantly underdiagnosed. Mood disorders and other substance use disorders: overdiagnosed.","methodology":"Cross-sectional study comparing structured clinical interviews (gold standard) with retrospective electronic medical record review for 84 military veterans with cannabis use disorders. Diagnosis rates were compared between the two methods.","limitations":"Small sample size (84 veterans). All participants had cannabis use disorders, so the findings may not generalize to all veterans. Single VA site. The direction of the diagnostic bias may reflect clinical priorities rather than inability to diagnose."},{"rthcId":"RTHC-00545","title":"A placebo-controlled study to assess Standardized Field Sobriety Tests performance during alcohol and cannabis intoxication in heavy cannabis users and accuracy of point of collection testing devices for detecting THC in oral fluid.","authors":"Bosker, W M; Theunissen, E L; Conen, S; Kuypers, K P C; Jeffery, W K; Walls, H C; Kauert, G F; Toennes, S W; Moeller, M R; Ramaekers, J G","year":2012,"journal":"Psychopharmacology, 223(4), 439-46","doi":null,"pmid":"22581391","tags":["driving","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty heavy cannabis users participated in a placebo-controlled study where they smoked cannabis (400 micrograms/kg THC) with or without alcohol. Standard Field Sobriety Tests (SFST) were only mildly sensitive to cannabis-induced impairment.\n\nCannabis alone significantly affected performance on the one-leg stand test (p=0.037), but the overall SFST battery was poor at detecting impairment. The combination of cannabis and alcohol affected horizontal gaze nystagmus (p=0.029), but this test is primarily validated for alcohol.\n\nFor roadside drug detection, the Drager Drug Test 5000 demonstrated high sensitivity for detecting THC in oral fluid, while the Securetec Drugwipe 5 had low sensitivity. The results suggested different tools are needed for detecting cannabis impairment versus detecting cannabis presence.","whyItMatters":"Field sobriety tests are the primary roadside tool for detecting impaired drivers. Their poor sensitivity to cannabis impairment means officers may not identify cannabis-impaired drivers, creating a gap in road safety enforcement.","specificNumbers":"20 heavy cannabis users. THC dose: 400 micrograms/kg. Cannabis significantly affected one-leg stand (p=0.037). Cannabis + alcohol affected horizontal gaze nystagmus (p=0.029). Drager 5000: high THC sensitivity. Drugwipe 5: low sensitivity.","methodology":"Double-blind, placebo-controlled study with 20 heavy cannabis users (15 males, 5 females, mean age 24.3). Participants received THC (400 micrograms/kg) with alcohol (targeting BAC 0.5 or 0.7 mg/mL) or placebo combinations. SFST performance and oral fluid THC detection were assessed.","limitations":"Heavy users were tested, and tolerance likely reduced observable impairment. Time between cannabis use and testing may have affected results. The study could not determine whether the lack of SFST sensitivity reflected tolerance or genuine limitations of the tests for detecting cannabis effects."},{"rthcId":"RTHC-00546","title":"Medicinal Δ(9) -tetrahydrocannabinol (dronabinol) impairs on-the-road driving performance of occasional and heavy cannabis users but is not detected in Standard Field Sobriety Tests.","authors":"Bosker, Wendy M; Kuypers, Kim P C; Theunissen, Eef L; Surinx, Anke; Blankespoor, Roos J; Skopp, Gisela; Jeffery, Wayne K; Walls, H Chip; van Leeuwen, Cees J; Ramaekers, Johannes G","year":2012,"journal":"Addiction (Abingdon, England), 107(10), 1837-44","doi":"10.1111/j.1360-0443.2012.03928.x","pmid":"22553980","tags":["driving","tolerance","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-four participants (12 occasional users, 12 heavy users) received dronabinol (10 mg and 20 mg) or placebo in a crossover design, then drove on actual roads. Occasional users showed significant increases in lane weaving (SDLP, p=0.008) and slower reaction times in car-following (p=0.011).\n\nHeavy users also showed impairment that exceeded the threshold associated with blood alcohol of 0.05%, but to a lesser degree than occasional users, consistent with tolerance. Notably, both groups reported similar levels of subjective \"high\" despite the behavioral difference.\n\nCritically, the Standard Field Sobriety Test failed to distinguish between dronabinol and placebo conditions in either group, meaning it would not identify these impaired drivers at a traffic stop.","whyItMatters":"This study used actual on-the-road driving, the most ecologically valid measure of driving impairment. The finding that medicinal THC doses impaired driving more than a BAC of 0.05% was directly relevant to patients prescribed dronabinol.","specificNumbers":"12 occasional + 12 heavy users. Dronabinol doses: 10 mg, 20 mg. SDLP increase significant (p=0.008) in occasional users. Impairment exceeded BAC 0.05% equivalent in both groups. SFST did not discriminate between conditions.","methodology":"Double-blind, placebo-controlled, randomized, three-way crossover study. 12 occasional and 12 heavy cannabis users received placebo, 10 mg, or 20 mg dronabinol. Primary outcome was SDLP (lane weaving) in on-the-road driving. Car-following reaction time and SFST performance were secondary measures.","limitations":"Sample size of 24. Dronabinol (oral THC) has different pharmacokinetics than smoked cannabis. The on-road driving course, while realistic, was conducted under controlled conditions. Tolerance assessment was between-group (occasional vs heavy) rather than within-subject."},{"rthcId":"RTHC-00547","title":"Blurred boundaries: the therapeutics and politics of medical marijuana.","authors":"Bostwick, J Michael","year":2012,"journal":"Mayo Clinic proceedings, 87(2), 172-86","doi":"10.1016/j.mayocp.2011.10.003","pmid":"22305029","tags":["medical-cannabis","legalization","addiction","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This extensive review covered the full landscape of cannabis issues circa 2012. Historically, cannabis was widely prescribed by American physicians from the mid-19th century until federal restrictions began in the 1930s, culminating in Schedule I classification in 1970.\n\nOn the medical side, the discovery of the endocannabinoid system in the 1990s opened numerous pharmaceutical possibilities, but federal research restrictions hampered clinical trials. On the risk side, growing evidence showed marijuana's addictive potential, particularly in young people, and its ability to induce and exacerbate psychotic illness in susceptible individuals.\n\nThe review noted the unusual situation where public approval drove medical legalization without the scientific data normally required for a new medication.","whyItMatters":"This review captured a pivotal moment when medical marijuana legalization was advancing rapidly while scientific evidence lagged behind. It provided clinicians with a balanced assessment of both potential and risks.","specificNumbers":"16 states had legalized medical cannabis at time of publication. THC isolated in 1964. Endocannabinoid system appreciated in the 1990s. Schedule I classification since 1970.","methodology":"Comprehensive narrative review using PubMed searches across multiple cannabinoid-related keywords, with hand-searched bibliographies. Covered endocannabinoid system biology, clinical therapeutics, addiction, psychosis, and legislative history.","limitations":"Single-author review from a clinical perspective. The broad scope necessarily sacrificed depth on individual topics. Published during a rapidly evolving legal landscape that has changed substantially since."},{"rthcId":"RTHC-00548","title":"Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates.","authors":"Chang, Jae Won; Niphakis, Micah J; Lum, Kenneth M; Cognetta, Armand B; Wang, Chu; Matthews, Megan L; Niessen, Sherry; Buczynski, Matthew W; Parsons, Loren H; Cravatt, Benjamin F","year":2012,"journal":"Chemistry & biology, 19(5), 579-88","doi":"10.1016/j.chembiol.2012.03.009","pmid":"22542104","tags":["neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The existing MAGL inhibitor JZL184, while useful for research, had low-level cross-reactivity with FAAH and peripheral carboxylesterases, which complicated interpretation of some experiments. The researchers developed a new class of O-hexafluoroisopropyl (HFIP) carbamate compounds.\n\nThese new inhibitors blocked MAGL in vitro and in vivo with excellent potency and greatly improved selectivity. Crucially, they showed no detectable cross-reactivity with FAAH, the enzyme that degrades the other major endocannabinoid anandamide.\n\nThis selectivity mattered because it allowed researchers to study the effects of elevating 2-AG specifically, without simultaneously affecting anandamide levels.","whyItMatters":"Better research tools lead to better science. By cleanly separating MAGL from FAAH inhibition, these compounds allowed researchers to ask more precise questions about the distinct roles of 2-AG and anandamide in the endocannabinoid system.","specificNumbers":"HFIP carbamates showed excellent potency and no detectable FAAH cross-reactivity, compared to JZL184 which had low-level cross-reactivity with FAAH and carboxylesterases.","methodology":"Medicinal chemistry study designing and synthesizing HFIP carbamate compounds. Tested selectivity against MAGL, FAAH, and other serine hydrolases using activity-based protein profiling. Validated in vivo activity in mice.","limitations":"Tool compound development study. These compounds were designed for research, not clinical use. In vivo validation was limited to mice. Long-term safety and pharmacokinetic profiles were not fully characterized."},{"rthcId":"RTHC-00549","title":"The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting cannabinoid receptors.","authors":"Chicca, A; Marazzi, J; Gertsch, J","year":2012,"journal":"British journal of pharmacology, 167(8), 1596-608","doi":"10.1111/j.1476-5381.2012.02059.x","pmid":"22646533","tags":["pain","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Previous research claimed the natural triterpenes alpha- and beta-amyrin bound directly to CB1 receptors at subnanomolar concentrations and relieved pain through cannabinoid receptors. This study challenged that finding.\n\nUsing validated binding assays, the researchers found no binding of either amyrin to human CB1 or CB2 receptors (Ki values greater than 10 micromolar, compared to the previously claimed 133 picomolar). Instead, beta-amyrin potently inhibited the breakdown of 2-AG (an endocannabinoid) without affecting anandamide breakdown.\n\nBeta-amyrin only weakly inhibited purified MAGL but more potently inhibited 2-AG breakdown in cell and brain homogenates, suggesting it targeted multiple alpha,beta-hydrolases involved in 2-AG metabolism.","whyItMatters":"This study corrected the scientific record while uncovering a potentially more interesting mechanism: a natural compound that relieves pain by indirectly boosting endocannabinoids rather than directly activating cannabinoid receptors. This could avoid psychoactive side effects.","specificNumbers":"No CB receptor binding (Ki > 10 micromolar vs previously claimed 133 pM). Beta-amyrin potently inhibited 2-AG hydrolysis. Weak inhibition of purified MAGL but potent inhibition in tissue homogenates.","methodology":"In vitro pharmacology study using validated CB receptor binding assays (hCB1 and hCB2 transfected CHO-K1 cells), endocannabinoid transport assays, and enzyme activity measurements with both purified enzymes and cell/tissue homogenates.","limitations":"In vitro study only. The discrepancy with previous binding data was unexplained. The mechanism of 2-AG protection in tissue homogenates (beyond MAGL) was not fully characterized. No in vivo validation was included."},{"rthcId":"RTHC-00550","title":"Abnormal striatal circuitry and intensified novelty seeking among adolescents who abuse methamphetamine and cannabis.","authors":"Churchwell, John C; Carey, Paul D; Ferrett, Helen L; Stein, Dan J; Yurgelun-Todd, Deborah A","year":2012,"journal":"Developmental neuroscience, 34(4), 310-7","doi":"10.1159/000337724","pmid":"22986770","tags":["youth","neuroscience","dopamine","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared brain scans from three groups of adolescents: healthy controls (10), methamphetamine users (9), and combined methamphetamine plus cannabis users (8). The combined Meth+cannabis group showed increased regional striatal volume and intensified novelty seeking compared to controls.\n\nThe degree of methamphetamine exposure correlated positively with both striatal volume and novelty seeking in both drug-using groups. The striatum is a brain region central to reward processing and motivation.\n\nThe findings supported theories that the striatum plays a key role in adolescent substance abuse vulnerability, and that drug use during adolescence may further modify this brain region while it is still developing.","whyItMatters":"The striatum undergoes significant remodeling during adolescence. If substance use during this period enlarges or alters striatal structure, it could create a feedback loop where drug use increases reward sensitivity, which in turn increases drug-seeking behavior.","specificNumbers":"Controls: n=10. Meth only: n=9. Meth+cannabis: n=8. Meth exposure positively correlated with striatal volume and novelty seeking in both drug-using groups.","methodology":"Cross-sectional neuroimaging study using 3T MRI. Three groups of adolescents: controls (n=10), methamphetamine users (n=9), methamphetamine+cannabis users (n=8). Structural brain imaging analyzed for regional striatal morphology. Novelty seeking assessed with Cloninger's Tridimensional Character Inventory.","limitations":"Very small sample sizes. Cross-sectional design cannot establish causation or temporal sequence. Cannot separate methamphetamine effects from cannabis effects in the co-use group. No longitudinal follow-up. Demographic differences between groups could confound results."},{"rthcId":"RTHC-00551","title":"Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial.","authors":"Corey-Bloom, Jody; Wolfson, Tanya; Gamst, Anthony; Jin, Shelia; Marcotte, Thomas D; Bentley, Heather; Gouaux, Ben","year":2012,"journal":"CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 184(10), 1143-50","doi":"10.1503/cmaj.110837","pmid":"22586334","tags":["medical-cannabis","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Thirty MS patients with treatment-resistant spasticity completed a placebo-controlled crossover trial. Each participant smoked cannabis or identical placebo cigarettes once daily for three days, with an 11-day washout between periods.\n\nSmoked cannabis reduced spasticity scores (modified Ashworth scale) by 2.74 points more than placebo (p<0.0001), a highly significant result. Pain scores on a visual analogue scale also improved by 5.28 points more than placebo (p=0.008).\n\nHowever, cognitive performance on the Paced Auditory Serial Addition Test decreased by 8.67 points more with cannabis than placebo (p=0.003). Walking speed did not significantly differ. No serious adverse events occurred.\n\nThe authors concluded smoked cannabis was superior to placebo but recommended future studies examine whether different doses could provide benefits with less cognitive impact.","whyItMatters":"This was one of very few randomized trials of smoked cannabis (rather than oral or spray formulations) for MS spasticity. The strong effect on spasticity and pain, combined with the cognitive tradeoff, gave clinicians concrete data for shared decision-making.","specificNumbers":"30 completers out of 37 randomized. Spasticity reduction: 2.74 points better than placebo (p<0.0001). Pain reduction: 5.28 points better (p=0.008). Cognitive decline: 8.67 points worse (p=0.003). Timed walk: no significant difference (p=0.2).","methodology":"Placebo-controlled, crossover trial. 37 randomized, 30 completed. Cannabis or identical placebo cigarettes smoked once daily for 3 days, with 11-day washout. Primary outcome: modified Ashworth scale. Secondary: VAS pain, timed walk, PASAT cognitive test.","limitations":"Small sample size (30 completers). Very short treatment period (3 days). The crossover design with 11-day washout may not have been long enough to eliminate carry-over effects. Blinding of smoked cannabis is inherently difficult despite identical-looking cigarettes."},{"rthcId":"RTHC-00552","title":"Approach-bias predicts development of cannabis problem severity in heavy cannabis users: results from a prospective FMRI study.","authors":"Cousijn, Janna; Goudriaan, Anna E; Ridderinkhof, K Richard; van den Brink, Wim; Veltman, Dick J; Wiers, Reinout W","year":2012,"journal":"PloS one, 7(9), e42394","doi":"10.1371/journal.pone.0042394","pmid":"22957019","tags":["addiction","neuroscience","cognition"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Thirty-three heavy cannabis users and 36 controls completed an fMRI task measuring automatic approach and avoidance tendencies toward cannabis-related images. Overall approach-bias activations did not differ between users and controls.\n\nHowever, within the heavy user group, lifetime cannabis use correlated with stronger approach-bias activation in fronto-limbic areas. More importantly, activation in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) during the task independently predicted cannabis problem severity six months later, beyond what craving alone could predict.\n\nUsers with higher DLPFC/ACC activity during cannabis approach trials but lower activity during avoidance trials showed decreasing problems over time, suggesting better cognitive control over automatic drug-seeking tendencies.","whyItMatters":"Identifying brain-based predictors of who will develop worsening cannabis problems could guide early intervention. The DLPFC and ACC are involved in cognitive control, suggesting that the ability to regulate automatic drug-seeking impulses is a key protective factor.","specificNumbers":"33 heavy users, 36 controls. DLPFC and ACC activation predicted 6-month problem severity. Prediction was independent of subjective craving measures.","methodology":"Prospective fMRI study comparing 33 heavy cannabis users with 36 matched controls. Neural approach-bias was measured with a Stimulus Response Compatibility task. Cannabis use and problem severity assessed at baseline and 6-month follow-up.","limitations":"Moderate sample size. Six-month follow-up is relatively short. The approach-bias task measures automatic tendencies in a lab setting, which may not perfectly reflect real-world behavior. Self-reported problem severity may not capture all relevant outcomes."},{"rthcId":"RTHC-00553","title":"State of the art treatments for cannabis dependence.","authors":"Danovitch, Itai; Gorelick, David A","year":2012,"journal":"The Psychiatric clinics of North America, 35(2), 309-26","doi":"10.1016/j.psc.2012.03.003","pmid":"22640758","tags":["addiction","quitting","youth","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review painted a sobering but nuanced picture of cannabis dependence treatment. Long-term abstinence rates in clinical trials were below 20%, and most people who could benefit from treatment never received it.\n\nThe most effective approaches combined motivational enhancement therapy with cognitive-behavioral coping skills and contingency management (incentive-based programs). Among adolescents, engaging families and community stakeholders added substantial value.\n\nA meta-analysis found that treatments for cannabis dependence actually had larger effect sizes than treatments for other substance use disorders, suggesting the treatments work, just not well enough. No pharmacological treatment had been firmly established, though several were under development.\n\nThe review highlighted that about 9% of cannabis users develop dependence, but given how many people use cannabis, the absolute number needing help exceeds treatment system capacity.","whyItMatters":"This review captured the gap between treatment demand and treatment efficacy for cannabis dependence. It identified the best available approaches while acknowledging their limitations, and pointed to innovations (phone/computer-based interventions, primary care integration) that could expand access.","specificNumbers":"Long-term abstinence: <20% in clinical trials. Cannabis dependence rate: ~9% of users. Treatment effect sizes for cannabis were larger than for other substance use disorders.","methodology":"Comprehensive narrative review of psychosocial interventions, pharmacological treatments, and delivery innovations for cannabis dependence. Covered adolescent and adult populations, including those with co-occurring disorders.","limitations":"Narrative review without systematic search methodology. Focused primarily on English-language literature. The 20% abstinence figure came from controlled trials, which may not represent real-world outcomes. Long-term follow-up data was limited."},{"rthcId":"RTHC-00554","title":"Therapeutic use of cannabis.","authors":"de Vries, Kay; Green, Anita J","year":2012,"journal":"Nursing times, 108(9), 12-5","doi":null,"pmid":"22479766","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined the dilemmas nurses face when patients with terminal or life-limiting illnesses use cannabis therapeutically in their homes. Evidence suggested cannabis may improve quality of life for these patients, driving increased use despite illegality.\n\nNurses providing home care encountered situations where patients used illegally obtained cannabis, creating professional tensions between patient advocacy, legal obligations, and evidence-based care. The review explored the legal, political, and ethical dimensions of this situation.\n\nThe authors noted that the gap between emerging therapeutic evidence and legal restrictions placed healthcare providers in an untenable position, particularly in community settings where they witnessed patient cannabis use directly.","whyItMatters":"This highlighted a real-world gap between drug policy and clinical practice that front-line healthcare workers navigated daily. The ethical tensions were particularly acute for patients with terminal illness who had limited time and treatment options.","specificNumbers":"Literature reviewed from 1996 onward. Focus population: people with life-limiting or terminal illnesses.","methodology":"Literature review of databases from 1996 onward, supplemented with internet material. Focused on the intersection of therapeutic cannabis use and nursing practice for patients with life-limiting illnesses.","limitations":"Brief review in a nursing journal. Limited scope and depth. Did not quantify how many nurses encountered this situation or how they handled it. UK-focused legal and ethical framework may not apply universally."},{"rthcId":"RTHC-00555","title":"Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ⁹-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour.","authors":"Deiana, Serena; Watanabe, Akihito; Yamasaki, Yuki; Amada, Naoki; Arthur, Marlene; Fleming, Shona; Woodcock, Hilary; Dorward, Patricia; Pigliacampo, Barbara; Close, Steve; Platt, Bettina; Riedel, Gernot","year":2012,"journal":"Psychopharmacology, 219(3), 859-73","doi":"10.1007/s00213-011-2415-0","pmid":"21796370","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers mapped the pharmacokinetic profiles of four phytocannabinoids (CBD, CBDV, THCV, CBG) after single-dose administration in rats and mice by both oral and injection routes. All four compounds readily crossed the blood-brain barrier.\n\nAbsorption varied significantly by route and species. In mice, injection consistently produced higher plasma and brain concentrations. In rats, oral administration actually yielded higher brain concentrations for CBD and CBDV, but injection was better for THCV and CBG.\n\nCBD at 120 mg/kg reduced obsessive-compulsive behavior (marble burying) in mice, with the behavioral effect timing matching its pharmacokinetic profile. This provided direct evidence linking CBD brain levels to a specific behavioral outcome.","whyItMatters":"Knowing how these compounds reach the brain and how long they stay there is essential for designing effective studies and, eventually, medications. The finding that oral CBD reached higher brain levels in rats than injection was counterintuitive and practically important.","specificNumbers":"CBD: 120 mg/kg. CBDV: 60 mg/kg. THCV: 30 mg/kg. CBG: 120 mg/kg. All crossed blood-brain barrier. CBD reduced marble burying on a pharmacokinetic-consistent time course.","methodology":"Pharmacokinetic study with single-dose administration of CBD, CBDV, THCV, and CBG to rats and mice via oral and intraperitoneal routes. Plasma and brain concentrations measured over time. CBD was also tested in the marble burying test for obsessive-compulsive behavior.","limitations":"Animal study; human pharmacokinetics may differ substantially. Single-dose design does not capture effects of repeated dosing. The vehicle (solutol vs cremophor) affected brain penetration, meaning formulation matters. Only one behavioral test was used for CBD."},{"rthcId":"RTHC-00556","title":"Resting state abnormalities in psychosis compared to acute cannabinoids and opioids challenges: a systematic review of functional imaging studies.","authors":"Denier, Niklaus; Walter, Marc; Bendfeldt, Kerstin; Lang, Undine; Borgwardt, Stefan","year":2012,"journal":"Current pharmaceutical design, 18(32), 5081-92","doi":null,"pmid":"22716140","tags":["psychosis","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This systematic review compared resting-state brain activity in three conditions: first-episode psychosis (FEP), acute cannabinoid effects, and acute opioid effects, using data from 22 neuroimaging studies.\n\nResults within each condition group were highly conflicting, with different studies showing different patterns. However, when comparing across conditions, some convergence emerged: both positive symptoms of psychosis and depersonalization experiences after cannabis both appeared to increase anterior cingulate cortex activity.\n\nThe anterior cingulate is a key node in the default mode network, involved in self-referential processing and internal monitoring. Its shared activation in psychosis and cannabis states suggested a common neural substrate for the altered self-experience characteristic of both states.","whyItMatters":"Identifying shared brain activity patterns between cannabis effects and psychosis provides a neurobiological explanation for why cannabis can trigger psychotic symptoms in vulnerable individuals. The anterior cingulate connection points to disrupted self-monitoring as a common mechanism.","specificNumbers":"22 studies reviewed. 279 FEP subjects/controls. 315 cannabinoid study participants. 113 opioid study participants. Anterior cingulate activation: shared between FEP positive symptoms and cannabis depersonalization.","methodology":"Systematic review of 22 studies using SPECT, PET, perfusion-weighted imaging, ASL, and resting-state fMRI. Compared baseline brain activity patterns across three conditions: first-episode psychosis, acute cannabinoid effects, and acute opioid effects.","limitations":"High inconsistency within condition groups limits confidence in cross-condition comparisons. Different imaging techniques and analysis methods across studies. Sample sizes were small in many included studies. Opioid comparison provided limited additional insight."},{"rthcId":"RTHC-00557","title":"Borderline personality traits and substance use: genetic factors underlie the association with smoking and ever use of cannabis, but not with high alcohol consumption.","authors":"Distel, Marijn A; Trull, Tim J; de Moor, Marleen M H; Vink, Jacqueline M; Geels, Lot M; van Beek, Jenny H D A; Bartels, Meike; Willemsen, Gonneke; Thiery, Evert; Derom, Catherine A; Neale, Michael C; Boomsma, Dorret I","year":2012,"journal":"Journal of personality disorders, 26(6), 867-79","doi":"10.1521/pedi.2012.26.6.867","pmid":"23281672","tags":["genetics","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers studied 5,638 Dutch and Belgian twins aged 21-50 from 3,567 families. Significant associations were found between borderline personality traits (BPT) and high alcohol consumption (r=0.192), regular smoking (r=0.299), and ever using cannabis (r=0.254).\n\nBivariate genetic analyses revealed different etiologies for each association. The correlations between BPT and both regular smoking and cannabis use were explained by common genetic factors, meaning the same genes that increase borderline traits also increase the likelihood of using these substances.\n\nFor heavy alcohol consumption, the story was different: the association with BPT was explained by unique environmental factors rather than shared genetics. This meant that the alcohol-BPT connection arose from life experiences that influence both traits, not from an underlying genetic vulnerability.","whyItMatters":"Understanding whether substance use in borderline personality is genetically driven or environmentally driven changes the treatment approach. Genetic overlap suggests shared neurobiology; environmental overlap suggests addressing life circumstances and coping strategies.","specificNumbers":"5,638 twins, 3,567 families. BPT-alcohol correlation: r=0.192 (environmental). BPT-smoking: r=0.299 (genetic). BPT-cannabis: r=0.254 (genetic).","methodology":"Twin study with 5,638 participants from 3,567 families. Bivariate genetic modeling decomposed the associations between borderline personality traits and substance use into genetic versus environmental components.","limitations":"Twin studies assume equal environments for identical and fraternal twins, which may not perfectly hold. Self-reported substance use and personality traits. \"Ever use of cannabis\" is a crude measure that does not capture frequency or problems. Dutch/Belgian population may not generalize."},{"rthcId":"RTHC-00558","title":"Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects.","authors":"Eichler, Martin; Spinedi, Luca; Unfer-Grauwiler, Sandra; Bodmer, Michael; Surber, Christian; Luedi, Markus; Drewe, Juergen","year":2012,"journal":"Planta medica, 78(7), 686-91","doi":"10.1055/s-0031-1298334","pmid":"22411724","tags":["cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Nine healthy male volunteers received heated cannabis extract, unheated cannabis extract, or synthetic THC (dronabinol) in a crossover study. The pharmacokinetic profiles were strikingly different.\n\nThe heated extract showed a lower THC blood level (AUC 2.84 pmol*h/mL) than the unheated extract (6.59 pmol*h/mL), which was itself slightly higher than dronabinol (4.58 pmol*h/mL). However, the heated extract produced higher total metabolite levels (THC + 11-OH-THC + THC-COOH + CBN combined).\n\nCBD blood levels were almost 2-fold higher from the unheated than heated extract. Since CBD can modulate THC's psychoactive effects, this suggested unheated extracts with higher CBD:THC ratios may produce better tolerability.","whyItMatters":"Traditional cannabis use often involved unheated preparations (tinctures, edibles with minimal heating). This study showed the heating process changes not just THC conversion from THCA but the entire metabolic profile, potentially affecting both efficacy and tolerability.","specificNumbers":"9 volunteers. THC AUC: heated 2.84, unheated 6.59, dronabinol 4.58 pmol*h/mL. CBD AUC: almost 2-fold higher in unheated. Higher total metabolites in heated extract.","methodology":"Double-blind, randomized, single-center, three-period crossover study in 9 healthy male volunteers. Compared heated cannabis extract, unheated cannabis extract (both with CBD:THC ratio >1), and synthetic THC. Blood samples measured cannabinoid and metabolite levels over 24 hours.","limitations":"Very small sample (9 volunteers). Pharmacokinetics were highly variable between individuals. Single-dose study. Clinical significance of the metabolic differences was not assessed. Only male volunteers."},{"rthcId":"RTHC-00559","title":"A preliminary examination of how serotonergic polymorphisms influence brain response following an adolescent cannabis intervention.","authors":"Feldstein Ewing, Sarah W; Mead, Hilary K; Yezhuvath, Uma; Dewitt, Sam; Hutchison, Kent E; Filbey, Francesca M","year":2012,"journal":"Psychiatry research, 204(2-3), 112-6","doi":"10.1016/j.pscychresns.2012.10.011","pmid":"23217578","tags":["genetics","youth","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"This preliminary study examined whether genetic variations in the serotonin system moderated brain responses to psychosocial treatment for adolescent cannabis use disorders. Two serotonin gene polymorphisms were tested: a receptor variant (rs6311) and a transporter variant (rs2020936).\n\nThe original hypotheses were not supported. However, the rs6311 C allele was significantly associated with brain activation in the medial frontal gyrus and precuneus after treatment, suggesting this serotonin receptor variant plays a role in how adolescent brains respond to cannabis treatment.\n\nThese regions are involved in self-reflection and internal processing, suggesting the genetic variant may influence treatment-related changes in self-awareness and motivation.","whyItMatters":"If genetic variants predict treatment response, future cannabis treatment could be personalized based on individual biology. The serotonin system connection also explains why anxiety and depression commonly co-occur with cannabis use disorders.","specificNumbers":"Two polymorphisms tested: rs6311 (serotonin receptor) and rs2020936 (transporter). rs6311 C allele associated with activation in medial frontal gyrus and precuneus.","methodology":"fMRI study of adolescents with cannabis use disorders following psychosocial treatment. Participants were genotyped for serotonin receptor (rs6311) and transporter (rs2020936) polymorphisms. Brain activation patterns were compared across genotypes.","limitations":"Preliminary study with small sample size. Original hypotheses were not supported. Single gene variant findings require replication. Could not determine whether the brain differences predicted actual treatment outcomes."},{"rthcId":"RTHC-00560","title":"The socioeconomic impact of drug-related crimes in Chile.","authors":"Fernández, Matías","year":2012,"journal":"The International journal on drug policy, 23(6), 465-72","doi":"10.1016/j.drugpo.2012.03.007","pmid":"22608568","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers estimated the socioeconomic impact of drug-related crime in Chile using Goldstein's tripartite model (psychopharmacological, economic-compulsive, and systemic violence). The total cost in 2006 was approximately $268 million USD.\n\nDirect drug law enforcement accounted for 36% of costs, while the remaining 64% came from crimes partially linked to drug use and trafficking. Police bore 32% of enforcement costs, penitentiaries 25%, and productivity losses from incarceration represented 29%.\n\nStrikingly, cocaine base paste (CBP) accounted for 53% of costs despite relatively low prevalence, while cannabis accounted for only 18% despite being the most commonly used drug. This disproportionality led the authors to recommend differentiating drug enforcement policies based on actual social and individual harm caused by each substance.","whyItMatters":"This analysis challenged the allocation of drug enforcement resources by showing cannabis, despite its higher prevalence, was associated with far less crime-related cost than cocaine products. Policy implications were clear: drug enforcement should be proportional to harm.","specificNumbers":"Total cost: $268 million USD (2006). Cannabis: 18%. Cocaine hydrochloride: 29%. Cocaine base paste: 53%. Police: 32%. Penitentiaries: 25%. Productivity losses: 29%.","methodology":"Socioeconomic impact analysis applying Goldstein's tripartite model. Quantified drug-crime connections and estimated costs across law enforcement, judiciary, penitentiary, and productivity losses for cannabis, cocaine hydrochloride, and cocaine base paste.","limitations":"Single-country study (Chile, 2006). The model relied on estimates and assumptions about drug-crime connections. Currency and cost figures may not translate to other contexts. Did not account for health costs or family impacts."},{"rthcId":"RTHC-00561","title":"JWH-018 and JWH-073: Δ⁹-tetrahydrocannabinol-like discriminative stimulus effects in monkeys.","authors":"Ginsburg, Brett C; Schulze, David R; Hruba, Lenka; McMahon, Lance R","year":2012,"journal":"The Journal of pharmacology and experimental therapeutics, 340(1), 37-45","doi":"10.1124/jpet.111.187757","pmid":"21965552","tags":["synthetic-cannabinoids","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested JWH-018 and JWH-073 (common synthetic cannabinoids in \"Spice\" and \"K2\" products) in monkeys trained to discriminate THC from placebo. Both synthetics fully substituted for THC, confirming they produce the same subjective effects through CB1 receptors.\n\nJWH-018 was about 3 times more potent than THC (ED50: 0.013 vs 0.044 mg/kg). JWH-073 was roughly equipotent. Critically, the duration of action was much shorter: JWH-018 lasted about 2 hours and JWH-073 about 1 hour, compared to THC's 4 hours.\n\nBoth synthetics also attenuated THC withdrawal in dependent monkeys, confirming pharmacological interchangeability. The shorter duration could promote more frequent dosing, increasing the number of drug-reward pairings and potentially accelerating dependence.","whyItMatters":"This study explained why synthetic cannabinoids may be more addictive than natural cannabis: they produce the same high but wear off faster, encouraging more frequent use. More frequent dosing strengthens the habit loop.","specificNumbers":"JWH-018 ED50: 0.013 mg/kg (3x more potent than THC). JWH-073 ED50: 0.058 mg/kg. Duration: JWH-018 ~2 hrs, JWH-073 ~1 hr, THC ~4 hrs. All reversed by CB1 antagonist rimonabant.","methodology":"Drug discrimination study in rhesus monkeys (n=4) trained to discriminate THC. Additionally tested in monkeys (n=3) trained to discriminate rimonabant (withdrawal) during chronic THC treatment. Dose-response curves, antagonism studies, and duration assessments were conducted.","limitations":"Small number of monkeys (3-4). Drug discrimination measures subjective effects, not all aspects of abuse liability. Only two synthetic cannabinoids were tested from hundreds that exist. Laboratory setting does not capture real-world use patterns."},{"rthcId":"RTHC-00562","title":"Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia.","authors":"Gleason, K A; Birnbaum, S G; Shukla, A; Ghose, S","year":2012,"journal":"Translational psychiatry, 2(11), e199","doi":"10.1038/tp.2012.122","pmid":"23188199","tags":["psychosis","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice received the CB1 agonist WIN55,212-2 during adolescence (postnatal days 30-35) or early adulthood (days 63-70) and were tested after postnatal day 120. Only adolescent exposure produced lasting behavioral changes.\n\nAdolescent-treated mice showed deficits in prepulse inhibition (a measure of sensorimotor gating commonly disrupted in schizophrenia) and fear conditioning (hippocampal-dependent learning). The hippocampus of these mice showed significantly reduced mGluR5 (a receptor involved in fear conditioning and endocannabinoid signaling).\n\nEndocannabinoid metabolism enzymes were also altered: increased MAGL and FAAH levels suggested faster endocannabinoid breakdown, meaning reduced endocannabinoid tone in the hippocampus. Adult-treated mice showed none of these lasting changes.","whyItMatters":"This study provided a causal mechanism linking adolescent cannabis exposure to schizophrenia-relevant brain changes. The selectivity for adolescent but not adult exposure supported the epidemiological finding that earlier cannabis use carries higher psychosis risk.","specificNumbers":"Adolescent treatment: PND 30-35. Adult treatment: PND 63-70. Testing after PND 120. Adolescent treatment reduced mGluR5 and increased MGL and FAAH in hippocampus. Adult treatment produced no lasting changes.","methodology":"Mice received WIN55,212-2 during adolescence (PND 30-35) or early adulthood (PND 63-70). Behavioral testing after PND 120 included prepulse inhibition and fear conditioning. Hippocampal molecular markers (mGluR5, DGL, MGL, FAAH) were quantified.","limitations":"Mouse model using synthetic cannabinoid, not THC. Very brief exposure window (5 days). The schizophrenia-like phenotype was limited to two behavioral measures. Human adolescence is much longer and more complex than mouse adolescence."},{"rthcId":"RTHC-00563","title":"CB1 - cannabinoid receptor antagonist effects on cortisol in cannabis-dependent men.","authors":"Goodwin, Robert S; Baumann, Michael H; Gorelick, David A; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; Schroeder, Jennifer R; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A","year":2012,"journal":"The American journal of drug and alcohol abuse, 38(1), 114-9","doi":"10.3109/00952990.2011.600398","pmid":"21797816","tags":["neuroscience","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Fourteen daily cannabis smokers received escalating THC doses (60-120 mg/day) for 8 days to standardize tolerance, then received rimonabant (20 or 40 mg) or placebo alongside the last THC dose. The study was terminated early when rimonabant was withdrawn from development.\n\nTen participants completed: five received 20 mg rimonabant, three received 40 mg, and two received placebo. Rimonabant blood concentration positively correlated with cortisol increases (r=0.53, p<0.01). Four of eight rimonabant recipients had cortisol levels at 11:30 AM that exceeded their 8:00 AM levels, the opposite of normal diurnal decline.\n\nDespite the cortisol trend, the 20-40 mg doses did not significantly precipitate frank cannabis withdrawal, consistent with the doses being below the threshold for full antagonism in tolerant individuals.","whyItMatters":"This was rare human evidence that CB1 receptors modulate the hypothalamic-pituitary-adrenal (HPA) stress axis during chronic cannabis exposure. The cortisol-rimonabant correlation supported the role of endocannabinoids in human stress regulation.","specificNumbers":"14 enrolled, 10 completed. Rimonabant-cortisol correlation: r=0.53, p<0.01. 4/8 rimonabant recipients showed reversed diurnal cortisol pattern. Study terminated early due to rimonabant withdrawal from development.","methodology":"Controlled study with 14 daily cannabis smokers. Standardized THC tolerance over 8 days (60-120 mg/day). Double-blind placebo or rimonabant (20 or 40 mg) with last THC dose. Plasma cortisol, cannabinoid, and rimonabant concentrations measured at 4 timepoints.","limitations":"Very small sample (10 completers). Study terminated early. Rimonabant doses may have been too low for full antagonism. No formal withdrawal assessment. Observational cortisol measurements without structured provocation."},{"rthcId":"RTHC-00564","title":"Medical marijuana: clearing away the smoke.","authors":"Grant, Igor; Atkinson, J Hampton; Gouaux, Ben; Wilsey, Barth","year":2012,"journal":"The open neurology journal, 6, 18-25","doi":"10.2174/1874205X01206010018","pmid":"22629287","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review summarized the growing clinical trial evidence for medical cannabis, focusing on recent trials of smoked and vaporized marijuana as well as botanical extracts. The strongest evidence supported cannabinoids for neuropathic pain management and MS spasticity.\n\nThe authors noted that the understanding of THC and cannabinoid mechanisms had advanced significantly, providing a scientific basis for therapeutic use. They presented a clinical algorithm for physicians to determine whether cannabis might be appropriate for individual patients, weighing benefits against risks.\n\nThe review positioned medical cannabis as a legitimate therapeutic option in jurisdictions where it was permitted, while acknowledging that, like all medications, it required careful benefit-risk assessment.","whyItMatters":"By providing a practical prescribing algorithm, this review moved the conversation from \"should cannabis be medical?\" to \"how should physicians use it?\" This was a significant shift toward treating cannabis as a medicine requiring clinical judgment.","specificNumbers":"Strongest evidence: neuropathic pain and MS spasticity. Clinical algorithm provided for physician decision-making.","methodology":"Narrative review of recent clinical trials with smoked/vaporized marijuana and cannabis extracts. Developed a clinical decision algorithm for physician guidance.","limitations":"Narrative review without systematic methodology. The clinical algorithm, while practical, was not validated in clinical practice. Evidence was still emerging and limited for most indications beyond pain and spasticity."},{"rthcId":"RTHC-00565","title":"The therapeutic potential of cannabis and cannabinoids.","authors":"Grotenhermen, Franjo; Müller-Vahl, Kirsten","year":2012,"journal":"Deutsches Arzteblatt international, 109(29-30), 495-501","doi":null,"pmid":"23008748","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review cataloged the therapeutic evidence for cannabinoids, noting that over 100 controlled clinical trials had been conducted since 1975. These trials led to three approved cannabis-based medicines: dronabinol, nabilone, and a 1:1 THC:CBD extract (Sativex).\n\nIn Germany, the cannabis extract was approved in 2011 for moderate-to-severe MS spasticity. It was commonly used off-label for anorexia, nausea, and neuropathic pain. Patients could also apply for government permission to buy medicinal cannabis flowers for supervised self-treatment.\n\nThe most common side effects (tiredness and dizziness) affected more than 10% of patients, but tolerance to these effects nearly always developed within a short time. Withdrawal symptoms were \"hardly ever a problem in the therapeutic setting.\"","whyItMatters":"By counting over 100 controlled trials, this review countered the claim that cannabis lacked scientific evidence. The regulatory framework in Germany, including patient access to medicinal flowers, represented one of the most developed systems at the time.","specificNumbers":"Over 100 controlled clinical trials since 1975. Three approved medicines: dronabinol, nabilone, THC:CBD extract. Side effects >10%: tiredness, dizziness. Tolerance to side effects developed quickly. Withdrawal rarely problematic in clinical use.","methodology":"Selective literature review of controlled clinical trials and regulatory approvals for cannabis-based medicines. Published in a German medical journal with a European regulatory perspective.","limitations":"Selective rather than systematic review. German/European focus. \"Over 100 trials\" includes trials of varying quality and for different conditions. Some conditions had much more evidence than others."},{"rthcId":"RTHC-00566","title":"\"Spice\" and \"K2\" herbal highs: a case series and systematic review of the clinical effects and biopsychosocial implications of synthetic cannabinoid use in humans.","authors":"Gunderson, Erik W; Haughey, Heather M; Ait-Daoud, Nassima; Joshi, Amruta S; Hart, Carl L","year":2012,"journal":"The American journal on addictions, 21(4), 320-6","doi":"10.1111/j.1521-0391.2012.00240.x","pmid":"22691010","tags":["synthetic-cannabinoids","psychosis","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The researchers conducted a systematic review of published reports on clinical effects of synthetic cannabinoids (SCs) in humans. Most reports highlighted potential toxicity, particularly acute anxiety and psychosis episodes.\n\nThe three documented cases were notable: experienced marijuana users with confirmed cannabis dependence and physical withdrawal began using SC products (\"Spice/K2\") regularly. They reported effects similar to marijuana and found them well tolerated. All three reported that SC products effectively alleviated their cannabis withdrawal symptoms.\n\nThe biopsychosocial factors behind SC initiation included drug testing avoidance (SCs were not detected on standard tests), legal status, curiosity, and self-medication of withdrawal. These factors helped explain the rapid adoption of SCs among cannabis-dependent populations.","whyItMatters":"The finding that SC products could relieve cannabis withdrawal confirmed their pharmacological overlap with THC. But the reports of acute anxiety and psychosis, combined with unknown long-term effects and rapidly changing formulations, raised serious public health concerns.","specificNumbers":"Three documented cases of cannabis-dependent users switching to SCs. All reported cannabis withdrawal relief. Most published reports highlighted anxiety and psychosis as adverse effects. SCs not detected on standard drug tests at the time.","methodology":"Systematic review of published reports on synthetic cannabinoid clinical effects, plus detailed documentation of three case studies of cannabis-dependent individuals who regularly used SC products.","limitations":"Case series (3 cases) is very limited evidence. Systematic review found mostly case reports and anecdotal data. SC products varied enormously in composition and potency. The rapidly evolving SC landscape meant findings quickly became outdated."},{"rthcId":"RTHC-00567","title":"Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD.","authors":"Han, Jing; Kesner, Philip; Metna-Laurent, Mathilde; Duan, Tingting; Xu, Lin; Georges, Francois; Koehl, Muriel; Abrous, Djoher Nora; Mendizabal-Zubiaga, Juan; Grandes, Pedro; Liu, Qingsong; Bai, Guang; Wang, Wei; Xiong, Lize; Ren, Wei; Marsicano, Giovanni; Zhang, Xia","year":2012,"journal":"Cell, 148(5), 1039-50","doi":"10.1016/j.cell.2012.01.037","pmid":"22385967","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"This study overturned a fundamental assumption about how cannabis impairs memory. Using conditional knockout mice lacking CB1 receptors in specific cell types, researchers found that deleting CB1 from astrocytes (brain support cells) completely abolished cannabinoid-induced working memory impairment and hippocampal synaptic depression (LTD).\n\nCritically, deleting CB1 receptors from glutamatergic (excitatory) or GABAergic (inhibitory) neurons did not prevent the memory impairment. This meant the cognitive effects of cannabis are mediated through its action on brain support cells, not through the neurons themselves.\n\nThe mechanism involved astroglial CB1 activation triggering glutamate release, which activated NMDA receptors on neurons and caused internalization of AMPA receptors, leading to synaptic depression in hippocampal circuits essential for working memory.","whyItMatters":"This was published in Cell, one of the top scientific journals, because it fundamentally changed understanding of how cannabis affects the brain. If memory impairment works through astrocytes, not neurons, then treatments targeting astrocyte CB1 receptors could potentially block cognitive side effects while preserving other cannabinoid benefits.","specificNumbers":"Working memory impairment: fully abolished in astroglial CB1 knockouts. Preserved in neuronal CB1 knockouts (both glutamatergic and GABAergic). Hippocampal LTD: also astrocyte-dependent.","methodology":"Study in conditional mutant mice lacking CB1 receptors in specific cell types: astroglial cells, glutamatergic neurons, or GABAergic neurons. Behavioral testing used spatial working memory tasks. In vivo electrophysiology measured hippocampal LTD. NMDA and AMPA receptor pharmacology confirmed the mechanism.","limitations":"Mouse study. Conditional knockouts are powerful but may have developmental compensation. Only spatial working memory was tested. The degree to which human astroglial CB1 receptors function identically to mouse is uncertain."},{"rthcId":"RTHC-00568","title":"Functional connectivity in brain networks underlying cognitive control in chronic cannabis users.","authors":"Harding, Ian H; Solowij, Nadia; Harrison, Ben J; Takagi, Michael; Lorenzetti, Valentina; Lubman, Dan I; Seal, Marc L; Pantelis, Christos; Yücel, Murat","year":2012,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 37(8), 1923-33","doi":"10.1038/npp.2012.39","pmid":"22534625","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Twenty-one current cannabis users with over 10 years of near-daily use were compared to 21 matched controls during a cognitive control task (Multi-Source Interference Task). There were no differences in behavioral performance or the magnitude of task-related brain activations between groups.\n\nHowever, functional connectivity analysis revealed a critical difference: cannabis users showed greater connectivity between the prefrontal cortex and occipitoparietal cortex as cognitive demands increased. The magnitude of this increased connectivity was associated with earlier age of cannabis onset and greater lifetime exposure.\n\nThe researchers interpreted this as compensatory: cannabis users' brains recruited additional neural resources to maintain normal performance. Their prefrontal control regions had to work harder to coordinate attention and perception.","whyItMatters":"The finding of normal performance but abnormal connectivity pattern challenges the simple narrative that cannabis harms cognition. Instead, it suggested the brain can compensate, at least for some tasks, but this compensation requires more neural resources, which may have limits.","specificNumbers":"21 cannabis users (>10 years daily), 21 controls. No behavioral performance differences. Greater prefrontal-occipitoparietal connectivity in users. Connectivity magnitude associated with earlier onset and greater lifetime use.","methodology":"Cross-sectional fMRI study comparing 21 daily cannabis users (>10 years) with 21 matched controls. Multi-Source Interference Task measured cognitive control. Psychophysiological interaction analysis assessed functional connectivity between brain regions.","limitations":"Cross-sectional design cannot determine whether connectivity differences predate cannabis use. Self-selected sample of long-term users who continued using, excluding those who quit due to problems. The cognitive task may not have been demanding enough to reveal performance deficits."},{"rthcId":"RTHC-00569","title":"Withdrawal from THC during adolescence: sex differences in locomotor activity and anxiety.","authors":"Harte-Hargrove, Lauren C; Dow-Edwards, Diana L","year":2012,"journal":"Behavioural brain research, 231(1), 48-59","doi":"10.1016/j.bbr.2012.02.048","pmid":"22421367","tags":["withdrawal","sex-differences","youth","anxiety"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Male and female rats received THC (2, 7.5, or 15 mg/kg) or vehicle during mid-adolescence (postnatal days 35-41). THC caused dose-dependent locomotor depression during administration in both sexes.\n\nDuring withdrawal, locomotor depression initially resolved but then re-emerged by the end of the abstinence period, with this rebound effect significantly greater in females than males. Regarding anxiety, high-dose THC increased anxiety-like behaviors while low-dose decreased them during administration, with females more sensitive to the anxiogenic (anxiety-increasing) effects.\n\nDuring abstinence, females again showed greater sensitivity to the anxiogenic effects of THC. The study also documented sensitization to THC's locomotor-depressing effects at moderate doses and subsequent tolerance development at the highest dose.","whyItMatters":"Sex differences in cannabis withdrawal have been understudied despite evidence that women may experience different withdrawal profiles than men. This animal study provided a biological basis for those differences during the vulnerable adolescent period.","specificNumbers":"Three THC doses: 2, 7.5, 15 mg/kg. Treatment window: PND 35-41 (mid-adolescence). Females showed greater locomotor depression and anxiety during withdrawal than males. Low dose decreased anxiety; high dose increased it.","methodology":"Male and female Sprague Dawley rats received THC (2, 7.5, or 15 mg/kg) or vehicle from PND 35-41. Locomotor activity and anxiety-related behaviors measured during drug administration and abstinence. Three dose levels allowed dose-response analysis by sex.","limitations":"Rat model; rat adolescence differs from human. Short treatment window (7 days). Behavioral measures of anxiety in rodents are proxies, not direct measures of the human experience. Only one strain tested."},{"rthcId":"RTHC-00570","title":"Cigarette smoking and its relationship to mood disorder symptoms and co-occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder.","authors":"Heffner, Jaimee L; DelBello, Melissa P; Anthenelli, Robert M; Fleck, David E; Adler, Caleb M; Strakowski, Stephen M","year":2012,"journal":"Bipolar disorders, 14(1), 99-108","doi":"10.1111/j.1399-5618.2012.00985.x","pmid":"22329477","tags":["addiction","mental-health","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 161 adolescents and adults with bipolar I disorder after their first hospitalization for a manic or mixed episode, for up to 8 years. In the first 12 months, bipolar symptom course did not differ by smoking status in either age group.\n\nHowever, among adolescents, cigarette smoking was significantly associated with developing new-onset cannabis or alcohol use disorders in the year following hospitalization. These were almost entirely new disorders, not preexisting conditions.\n\nImportantly, neither adolescents nor adults who were abstinent from smoking for at least two months experienced significant increases in depressive or manic symptoms. This countered the concern that quitting smoking would worsen bipolar disorder.","whyItMatters":"Clinicians often hesitate to address smoking in bipolar patients due to fear of mood worsening. This study showed smoking cessation did not worsen bipolar symptoms, while continuing to smoke predicted new substance use disorders in vulnerable teens.","specificNumbers":"80 adolescents, 81 adults. Median follow-up: 122 weeks. Smoking predicted new-onset cannabis and alcohol disorders in adolescents. 2+ months of smoking abstinence did not increase depressive or manic symptoms.","methodology":"Naturalistic, observational prospective study. 161 participants (80 adolescents, 81 adults) with bipolar I disorder followed after first hospitalization. Median follow-up: 122 weeks. Smoking status, substance use disorders, and mood symptoms assessed over time.","limitations":"Observational study cannot prove smoking caused the new substance disorders. Confounding factors (impulsivity, sensation-seeking) may explain both smoking and substance use development. Relatively small sample sizes for subgroup analyses."},{"rthcId":"RTHC-00571","title":"Seizure exacerbation in two patients with focal epilepsy following marijuana cessation.","authors":"Hegde, Manu; Santos-Sanchez, Carlos; Hess, Christopher P; Kabir, Arif A; Garcia, Paul A","year":2012,"journal":"Epilepsy & behavior : E&B, 25(4), 563-6","doi":"10.1016/j.yebeh.2012.09.024","pmid":"23159379","tags":["epilepsy","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Two patients with focal epilepsy had well-controlled seizures through regular outpatient marijuana use in addition to their anticonvulsant medications. When admitted to an epilepsy monitoring unit where they stopped marijuana, both developed dramatic increases in seizure frequency documented by video-EEG telemetry.\n\nImportantly, these seizure increases occurred without any other provocative procedures: no medication changes, no sleep deprivation, no other typical seizure triggers. The temporal correlation between marijuana cessation and seizure increase was compelling.\n\nThe authors discussed potential anticonvulsant mechanisms of cannabis, noting that both CB1 receptor activation and CBD have shown anticonvulsant properties in animal models.","whyItMatters":"While anecdotal, these cases were rigorously documented with continuous EEG monitoring. They provided some of the most concrete clinical evidence that cannabis may have genuine anticonvulsant properties in humans, motivating the formal clinical trials of CBD for epilepsy that followed.","specificNumbers":"Two patients with focal epilepsy. Both nearly seizure-free on marijuana. Dramatic seizure increase documented by video-EEG upon marijuana cessation. No other provocative factors.","methodology":"Case report of two patients with focal epilepsy. Seizure frequency documented by continuous video-EEG monitoring during admission to epilepsy monitoring unit where marijuana use was discontinued. No other medications were changed or provocative procedures used.","limitations":"Only two cases. Cannot prove marijuana was anticonvulsant versus that cessation was proconvulsant (rebound effect). Patients were using whole-plant cannabis, making it impossible to identify which component was responsible. No controlled comparison."},{"rthcId":"RTHC-00572","title":"Alcohol and marijuana use in the context of tobacco dependence treatment: impact on outcome and mediation of effect.","authors":"Hendricks, Peter S; Delucchi, Kevin L; Humfleet, Gary L; Hall, Sharon M","year":2012,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 14(8), 942-51","doi":"10.1093/ntr/ntr312","pmid":"22259148","tags":["addiction","drug-interactions","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from 739 adult cigarette smokers across three randomized cessation trials. Alcohol use after a quit attempt increased positive-reinforcement urges to smoke (the desire to smoke for pleasure), and these urges partially explained why drinkers were less likely to stay quit.\n\nMarijuana use, however, was not associated with tobacco abstinence outcomes at any timepoint (weeks 12, 24, 36, or 52). This suggested that modifying marijuana use might not be critical to successful cigarette cessation.\n\nPretreatment alcohol use also predicted worse outcomes, but through a different mechanism than the positive-reinforcement urge pathway, indicating multiple routes by which alcohol undermines quit attempts.","whyItMatters":"Clinicians often advise patients to stop all substance use when quitting cigarettes. This study suggested marijuana use does not need to be addressed for tobacco cessation to succeed, while alcohol use is a clear risk factor that does need attention.","specificNumbers":"739 participants across 3 trials. Follow-up: weeks 12, 24, 36, 52. Marijuana use: no association with abstinence at any timepoint. Alcohol after quitting: increased positive-reinforcement urge, which mediated reduced abstinence.","methodology":"Secondary analysis of 739 participants from 3 randomized smoking cessation clinical trials. Alcohol and marijuana use assessed pre-treatment and post-cessation. Biochemically verified 7-day point-prevalence smoking abstinence at weeks 12, 24, 36, and 52. Mediation analysis tested urge pathways.","limitations":"Secondary analysis of existing trial data. Marijuana use was likely underreported. The sample may have had low rates of heavy marijuana use. Self-reported marijuana use without biochemical verification."},{"rthcId":"RTHC-00573","title":"Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers","authors":"Hirvonen, Jussi; Goodwin, Robert S.; Li, Chuan-Tung; et al.","year":2012,"journal":"Molecular Psychiatry, 17(6), 642-649","doi":"10.1038/mp.2011.82","pmid":"21747398","tags":["neuroscience","addiction","withdrawal","tolerance"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Positron emission tomography showed lower availability of CB1 receptors in cortical regions among chronic daily cannabis smokers compared with non-using controls. The reduction tracked with years of cannabis use. After roughly four weeks of continuous, verified abstinence on a secure research unit, CB1 receptor measures rose to levels similar to controls, suggesting the change was reversible over about a month in this sample.","whyItMatters":"Tolerance to cannabis is widely discussed but hard to measure in living human brains. This study provided direct human imaging evidence that frequent cannabis exposure is associated with fewer available CB1 receptors in cortex, a pattern that shifted back toward typical levels after about a month without use. It grounded decades of preclinical findings in a human sample using a clinical imaging tool.","specificNumbers":"- Abstinence duration for receptor measures to normalize: about 4 weeks, roughly one month of no use under supervision\n- Regional pattern: downregulation was selective to cortical areas, with other regions less affected\n- Exposure link: greater receptor reduction was associated with more years of cannabis smoking\n- Design: baseline PET in chronic daily smokers and controls, repeat PET in smokers after monitored abstinence","methodology":"Researchers used positron emission tomography with a CB1-selective radioligand to compare receptor availability between chronic daily cannabis smokers and healthy controls. Participants who used cannabis underwent a second scan after approximately four weeks of abstinence maintained on a secure inpatient unit. Regional analyses focused on cortex versus other brain areas, and associations with years of cannabis use were tested. This was an observational imaging study with repeated measures in users, not a randomized trial.","limitations":"Sample size and demographics were not detailed in the abstract, which limits generalizability. The imaging signal reflects receptor availability, which can be influenced by both receptor number and competition from endogenous cannabinoids; PET cannot cleanly separate those factors. Only daily heavy smokers were studied, so patterns in occasional or intermittent users are unknown. Product potency, THC to CBD ratios, and timing of last use before the baseline scan were not reported. The study linked receptor measures to years of use but did not examine cognition, mood, withdrawal severity, or clinical outcomes, so functional implications remain unclear."},{"rthcId":"RTHC-00574","title":"Apparent inverse relationship between cannabinoid agonist efficacy and tolerance/cross-tolerance produced by Δ⁹-tetrahydrocannabinol treatment in rhesus monkeys.","authors":"Hruba, Lenka; Ginsburg, Brett C; McMahon, Lance R","year":2012,"journal":"The Journal of pharmacology and experimental therapeutics, 342(3), 843-9","doi":"10.1124/jpet.112.196444","pmid":"22718500","tags":["synthetic-cannabinoids","tolerance","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rhesus monkeys trained to discriminate THC were given daily THC (1 mg/kg) for 3 or 14 days. After 3 days, tolerance developed to THC (3-fold sensitivity loss) but not to higher-efficacy agonists CP-55,940, JWH-018, or JWH-073.\n\nAfter 14 days, tolerance extended to all compounds but was inversely related to agonist efficacy: THC sensitivity decreased 9.2-fold, while CP-55,940 decreased only 3.6-fold, JWH-018 decreased 4.3-fold, and JWH-073 decreased 5.6-fold.\n\nThis inverse relationship between agonist efficacy and tolerance development followed predictions from receptor theory: low-efficacy agonists (like THC) need more receptors to produce their effect, so receptor downregulation has a greater impact on them.","whyItMatters":"This explained why synthetic cannabinoid users may escalate doses differently than cannabis users. If synthetics resist tolerance, users might not need to increase doses as much, but the higher baseline potency plus sustained efficacy could increase dependence liability.","specificNumbers":"14-day tolerance: THC 9.2-fold, CP-55,940 3.6-fold, JWH-018 4.3-fold, JWH-073 5.6-fold. 3-day tolerance: THC 3-fold, others no change.","methodology":"Drug discrimination in rhesus monkeys (n=4) discriminating THC (0.1 mg/kg i.v.). Dose-response curves for THC, CP-55,940, JWH-018, and JWH-073 measured before and after 3 and 14 days of daily THC treatment (1 mg/kg s.c.).","limitations":"Small number of monkeys (4). Cross-tolerance rather than direct tolerance was measured for the synthetics. Only discriminative stimulus effects were assessed; other behavioral effects may show different tolerance patterns."},{"rthcId":"RTHC-00575","title":"Altered cerebral blood flow and neurocognitive correlates in adolescent cannabis users.","authors":"Jacobus, Joanna; Goldenberg, Diane; Wierenga, Christina E; Tolentino, Neil J; Liu, Thomas T; Tapert, Susan F","year":2012,"journal":"Psychopharmacology, 222(4), 675-84","doi":"10.1007/s00213-012-2674-4","pmid":"22395430","tags":["youth","neuroscience","cognition"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Twenty-three heavy adolescent marijuana users (200+ lifetime use days) and 23 matched controls underwent brain perfusion scans at baseline and after 4 weeks of monitored abstinence (confirmed by urine testing). At baseline, users showed reduced blood flow in the left temporal cortex, insula, medial frontal gyrus, and supramarginal gyrus, with increased flow in the right precuneus.\n\nAfter 4 weeks of abstinence, all between-group differences disappeared. No brain regions showed significant differences between former users and controls at follow-up.\n\nThis was the first study to examine cerebral blood flow in adolescent marijuana users, and its finding of full normalization after a month of abstinence suggested the neurovascular alterations were related to acute or subacute drug effects rather than permanent structural changes.","whyItMatters":"The reversibility of brain blood flow changes after just one month of abstinence is reassuring for adolescent cannabis users and their families. It suggested that at least some of the brain changes associated with heavy adolescent use are not permanent.","specificNumbers":"23 users (200+ lifetime use days), 23 controls. Reduced blood flow in 4 cortical regions at baseline. Increased flow in right precuneus. All differences resolved after 4 weeks abstinence.","methodology":"Prospective study with baseline and 4-week follow-up arterial spin labeling (ASL) MRI scans. 23 heavy adolescent marijuana users and 23 matched controls. Abstinence confirmed by sequential urine toxicology over 4 weeks.","limitations":"Four weeks may not be long enough for full normalization of all brain effects. Blood flow is only one measure of brain health. The study could not determine at what point during the 4 weeks normalization occurred. Relatively small sample."},{"rthcId":"RTHC-00576","title":"The prevalence of cannabis-involved driving in California.","authors":"Johnson, Mark B; Kelley-Baker, Tara; Voas, Robert B; Lacey, John H","year":2012,"journal":"Drug and alcohol dependence, 123(1-3), 105-9","doi":"10.1016/j.drugalcdep.2011.10.023","pmid":"22101027","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers collected anonymous oral fluid samples and breath tests from over 900 weekend nighttime drivers across six California jurisdictions. Overall, 14.4% tested positive for illegal drugs, with 8.5% positive for THC specifically.\n\nTHC-positive rates varied enormously by location: from 4.3% in Fresno to 18.3% in Eureka (a cannabis-producing region). Compared to 2007 National Roadside Survey data, THC-positive rates had increased, while rates for other illegal drugs had not.\n\nDrivers with medical cannabis permits were significantly more likely to test positive for THC, suggesting medical cannabis legislation contributed to increased cannabis-involved driving.","whyItMatters":"Nearly 1 in 10 weekend nighttime drivers testing positive for THC represented a significant road safety concern. The geographic variation and increase over time pointed to the influence of cannabis policies on driving behavior.","specificNumbers":"900+ drivers sampled. 14.4% positive for illegal drugs. 8.5% positive for THC. Range: 4.3% (Fresno) to 18.3% (Eureka). Medical cannabis permit holders: significantly more likely THC-positive. THC rates increased from 2007 to 2010.","methodology":"Cross-sectional roadside survey. Anonymous oral fluid and breath samples from 900+ weekend nighttime drivers across six California jurisdictions. Compared to 2007 National Roadside Survey data collected with comparable methods.","limitations":"THC-positive oral fluid does not necessarily indicate impairment at the time of testing. Weekend nighttime drivers may not represent all driving. Anonymous design prevented following up on driving outcomes. No crash data were linked."},{"rthcId":"RTHC-00577","title":"Antagonism of cannabinoid 1 receptors reverses the anxiety-like behavior induced by central injections of corticotropin-releasing factor and cocaine withdrawal.","authors":"Kupferschmidt, D A; Newman, A E; Boonstra, R; Erb, S","year":2012,"journal":"Neuroscience, 204, 125-33","doi":"10.1016/j.neuroscience.2011.07.022","pmid":"21784132","tags":["anxiety","addiction","neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether blocking CB1 receptors could reduce anxiety caused by two different triggers: direct brain injection of corticotropin-releasing factor (CRF, the brain's primary stress peptide) and withdrawal from 14 days of cocaine.\n\nAM251 reversed anxiety from both CRF and cocaine withdrawal in a dose-dependent manner when injected directly into the brain. At its highest dose alone (without CRF or cocaine), AM251 actually increased anxiety, showing dual effects depending on context.\n\nImportantly, AM251 increased plasma corticosterone (the rat stress hormone) regardless of CRF treatment or cocaine history, suggesting the anxiolytic effect worked through brain mechanisms independent of the hormonal stress axis (HPA).","whyItMatters":"The finding that CB1 blockade can both cause and relieve anxiety depending on dose and context resolved an apparent contradiction in the literature. It also identified endocannabinoid signaling as a mediator of stress peptide effects, independent of the hormonal stress response.","specificNumbers":"AM251 200 micrograms alone: anxiogenic. AM251 10-100 micrograms: reversed CRF-induced and cocaine withdrawal anxiety dose-dependently. Corticosterone elevated by AM251 regardless of other treatments.","methodology":"Two experiments in male rats using elevated plus maze for anxiety measurement. Experiment 1: AM251 (0, 10, 100, 200 micrograms, i.c.v.) before CRF (0.5 micrograms, i.c.v.). Experiment 2: 14 days cocaine (20 mg/kg), then 48-hour withdrawal with AM251 pretreatment. Plasma corticosterone measured after behavioral testing.","limitations":"Central (brain) administration of AM251 does not reflect oral drug delivery. Rat anxiety measures are behavioral proxies. Only male rats tested. The high dose anxiogenic effect limits therapeutic window."},{"rthcId":"RTHC-00578","title":"Impact of lowering confirmatory test cutoff value in pre-enlistment urine cannabinoids screening: about five years' experience in the French Gendarmerie.","authors":"Lecompte, Yannick; Perrin, Martine; Salle, Sophie; Roussel, Olivier","year":2012,"journal":"Journal of analytical toxicology, 36(8), 569-74","doi":"10.1093/jat/bks067","pmid":"22933660","tags":["workplace"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Researchers reviewed 986 confirmation analyses of positive cannabis screening tests from French Gendarmerie pre-enlistment examinations over 5 years (2005-2009). Standard guidelines set the confirmatory cutoff for THC-COOH at 15 ng/mL.\n\nWhen the cutoff was lowered to 5 ng/mL, confirmed positive results increased by 25.2%. The positive predictive value of the initial screening test rose from 63.9% to 80.0%, meaning fewer false alarms needed expensive confirmation testing.\n\nOnly one true-positive applicant appealed, and their THC-COOH level was confirmed to be incompatible with passive cannabis smoke exposure. The lower cutoff increased diagnostic sensitivity without altering specificity (no false positives were created).","whyItMatters":"Drug testing cutoffs are policy decisions with real consequences. This study showed that the standard 15 ng/mL cutoff was missing a quarter of cannabis users, and lowering it improved detection without creating false positives.","specificNumbers":"986 confirmation analyses over 5 years. Lowering cutoff from 15 to 5 ng/mL: 25.2% more confirmed positives. Positive predictive value: 63.9% to 80.0%. Only 1 appeal among all true positives.","methodology":"Retrospective review of 986 GC-MS confirmation analyses from pre-enlistment cannabis urine screening in the French Gendarmerie (2005-2009). Compared results at standard (15 ng/mL) and lowered (5 ng/mL) THC-COOH cutoffs.","limitations":"French military population may not represent other testing contexts. Only pre-enlistment screening, not workplace or clinical. The lower cutoff may be appropriate for zero-tolerance settings but overly strict for others. Cultural and legal context differs from other countries."},{"rthcId":"RTHC-00579","title":"The effect of cannabis use and cognitive reserve on age at onset and psychosis outcomes in first-episode schizophrenia.","authors":"Leeson, Verity C; Harrison, Isobel; Ron, Maria A; Barnes, Thomas R E; Joyce, Eileen M","year":2012,"journal":"Schizophrenia bulletin, 38(4), 873-80","doi":"10.1093/schbul/sbq153","pmid":"21389110","tags":["psychosis","cognition","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Ninety-nine first-episode schizophrenia patients were divided into lifetime cannabis users and never-users. Cannabis users developed psychosis at a younger age, with a strong linear relationship between age of first cannabis use and age of psychosis onset, including prodromal symptoms.\n\nParadoxically, cannabis users showed better cognitive function at psychosis onset, but this was explained by their higher premorbid IQ, not by a protective effect of cannabis. Social functioning was also better in users.\n\nRemarkably, three-quarters of cannabis users quit spontaneously over the follow-up period. Those who started cannabis later in life quit sooner, and earlier cessation was linked to fewer positive psychotic symptoms and fewer hospital days.","whyItMatters":"This study resolved an apparent paradox: cannabis users had earlier psychosis (bad prognosis indicator) but better cognition (good indicator). The explanation was that cannabis brought forward psychosis in people who were otherwise cognitively healthier, meaning early onset was caused by cannabis rather than reflecting intrinsically worse illness.","specificNumbers":"99 patients, 15-month follow-up. Strong linear relationship between age of first cannabis use and psychosis onset. 75% of cannabis users quit spontaneously. Later cannabis initiation predicted earlier cessation and fewer symptoms.","methodology":"Prospective cohort study of 99 first-episode schizophrenia patients without other substance abuse. Compared lifetime cannabis users to never-users on premorbid function, cognition, clinical outcomes, and cannabis use trajectory over 15 months.","limitations":"Excluded patients with other substance abuse, limiting generalizability. Cannabis use was self-reported. The linear relationship between cannabis onset and psychosis onset does not prove causation (though the dose-response pattern strengthens the case). 15-month follow-up is relatively short."},{"rthcId":"RTHC-00580","title":"Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity.","authors":"Leussink, Verena Isabell; Husseini, Leila; Warnke, Clemens; Broussalis, Erasmia; Hartung, Hans-Peter; Kieseier, Bernd C","year":2012,"journal":"Therapeutic advances in neurological disorders, 5(5), 255-66","doi":"10.1177/1756285612453972","pmid":"22973422","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered the biological rationale and clinical evidence for cannabinoids in MS spasticity. Anecdotal evidence of cannabis benefits for spasticity was confirmed by randomized, double-blind, placebo-controlled studies.\n\nSativex (1:1 THC:CBD oromucosal spray) received approval for MS-related spasticity in various countries based on these trials. The review contextualized this within the broader understanding of cannabinoid biology, including the endocannabinoid system's role in regulating neurotransmission and muscle tone.\n\nThe authors positioned Sativex as a valuable addition to the existing spasticity treatment armamentarium, particularly for patients not adequately controlled by conventional medications.","whyItMatters":"This review provided the scientific justification for using cannabinoids in MS at a time when approvals were being sought in multiple countries. The combination of biological rationale and clinical evidence strengthened the case.","specificNumbers":"Sativex approved in multiple countries for MS spasticity. 1:1 THC:CBD ratio. Confirmed by randomized, placebo-controlled trials.","methodology":"Narrative review of cannabinoid receptor biology, endocannabinoid system physiology, and clinical trial evidence for cannabinoids in MS spasticity.","limitations":"Narrative review without systematic methodology. Focused primarily on Sativex rather than other cannabinoid formulations. Treatment effect sizes were modest on average."},{"rthcId":"RTHC-00581","title":"Differences in the endocannabinoid system of sperm from fertile and infertile men.","authors":"Lewis, Sheena E M; Rapino, Cinzia; Di Tommaso, Monia; Pucci, Mariangela; Battista, Natalia; Paro, Rita; Simon, Luke; Lutton, Deborah; Maccarrone, Mauro","year":2012,"journal":"PloS one, 7(10), e47704","doi":"10.1371/journal.pone.0047704","pmid":"23082196","tags":["neuroscience","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared the endocannabinoid system in sperm from fertile and infertile men. Infertile men had markedly reduced levels of both anandamide (AEA) and 2-AG in their seminal plasma. The ratio of degradation to synthesis enzymes was increased in infertile sperm, meaning endocannabinoids were being broken down faster relative to production.\n\nVanilloid receptor (TRPV1) binding was detectable in fertile sperm but completely undetectable in infertile sperm, while CB1 and CB2 receptor levels did not differ between groups. Since TRPV1 is involved in capacitation and the acrosome reaction (key steps in fertilization), its absence in infertile sperm pointed to a specific functional defect.\n\nThe authors suggested these endocannabinoid system alterations could serve as biomarkers for male infertility and as targets for new treatments.","whyItMatters":"Male infertility affects many couples, and the endocannabinoid system's role was previously unappreciated. This study identified specific molecular targets that could lead to new diagnostic tests and treatments for male reproductive problems.","specificNumbers":"Reduced AEA and 2-AG in infertile seminal plasma. Increased degradation:biosynthesis enzyme ratios. TRPV1 binding: detectable in fertile, undetectable in infertile sperm. CB1 and CB2: no difference.","methodology":"Cross-sectional comparison of sperm from fertile and infertile men. Measured endocannabinoid content (LC-ESI-MS), enzyme mRNA and protein expression (qRT-PCR, Western Blot, ELISA), enzyme activity, and receptor binding (CB1, CB2, TRPV1).","limitations":"Cross-sectional design cannot determine whether endocannabinoid changes cause or result from infertility. Did not control for cannabis use by study participants. Sample sizes were not specified in the abstract. The functional significance of the TRPV1 finding requires validation."},{"rthcId":"RTHC-00582","title":"An fMRI Study of Neuronal Activation in Schizophrenia Patients with and without Previous Cannabis Use.","authors":"Løberg, Else-Marie; Nygård, Merethe; Berle, Jan Øystein; Johnsen, Erik; Kroken, Rune A; Jørgensen, Hugo A; Hugdahl, Kenneth","year":2012,"journal":"Frontiers in psychiatry, 3, 94","doi":"10.3389/fpsyt.2012.00094","pmid":"23115554","tags":["psychosis","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Twenty-six schizophrenia patients were divided into previous cannabis users and never-users and compared during an auditory attention task (dichotic listening) using fMRI. During the cognitive task, previous cannabis users showed remaining brain activations in effort-mode regions that were not seen in the no-cannabis group.\n\nConversely, during rest periods (task-absent condition), the no-cannabis group showed remaining activation in default-mode regions not seen in the cannabis group. This meant cannabis-using patients were better at \"switching on\" during tasks and \"switching off\" during rest.\n\nThe authors interpreted this as cannabis-using schizophrenia patients having lower neurocognitive vulnerability, consistent with previous behavioral studies showing better cognitive performance in cannabis-using patients.","whyItMatters":"The finding that cannabis-using schizophrenia patients showed more normal brain activation patterns supported the hypothesis that they represent a distinct subgroup with lower inherent cognitive vulnerability who may have been pushed into psychosis by cannabis rather than by severe underlying neurodevelopmental problems.","specificNumbers":"26 schizophrenia patients. Cannabis users: better task-related activation, less default-mode activation at rest. No-cannabis group: less task activation, more default-mode activation at rest.","methodology":"Cross-sectional fMRI study of 26 schizophrenia patients (DSM-IV and ICD-10 criteria) grouped by cannabis use history. Auditory dichotic listening task with instructions to focus attention on right or left ear. Brain activation compared during task-present and task-absent conditions.","limitations":"Small sample (26 patients). Cross-sectional design cannot determine whether cognitive differences predate or result from cannabis use. Previous cannabis use was self-reported. No healthy control group for comparison. Cannot rule out other substance use effects."},{"rthcId":"RTHC-00583","title":"Cost effectiveness of oromucosal cannabis-based medicine (Sativex®) for spasticity in multiple sclerosis.","authors":"Lu, Lanting; Pearce, Hilary; Roome, Chris; Shearer, James; Lang, Iain A; Stein, Ken","year":2012,"journal":"PharmacoEconomics, 30(12), 1157-71","doi":"10.2165/11598470-000000000-00000","pmid":"23072659","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Using a Markov model to project costs and quality-of-life benefits over 5 years, researchers estimated that adding Sativex to standard spasticity treatment cost an additional 7,600 pounds and gained 0.15 QALYs per patient. This yielded an incremental cost-effectiveness ratio (ICER) of 49,300 pounds per QALY.\n\nAt the UK's standard willingness-to-pay threshold of 30,000 pounds per QALY, Sativex was unlikely to be considered cost-effective. The results were most sensitive to Sativex price, daily dose, and the difference in quality of life between responders and non-responders.\n\nThe authors acknowledged this was \"unfortunate\" since Sativex appeared to benefit some patients, but the cost-per-benefit ratio did not meet standard economic thresholds.","whyItMatters":"This analysis revealed the tension between clinical efficacy and economic viability. A treatment can work and still not be funded if the cost per unit of benefit exceeds what healthcare systems are willing to pay.","specificNumbers":"Incremental cost: 7,600 pounds per patient over 5 years. QALY gain: 0.15 per patient. ICER: 49,300 pounds per QALY. UK WTP threshold: 30,000 pounds. Sativex unlikely cost-effective at current pricing.","methodology":"Cost-effectiveness analysis using a Markov model. Compared Sativex plus oral anti-spasticity medicines versus current standard treatment over 5 years. Primary outcome: ICER in cost per QALY. Sensitivity analyses explored uncertainty. UK healthcare perspective with 2009 cost data.","limitations":"Modeling depends on assumptions about treatment duration, response rates, and quality-of-life estimates. Five-year time horizon may not capture all relevant costs and benefits. UK cost structure may not apply to other countries."},{"rthcId":"RTHC-00584","title":"Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain.","authors":"Lucas, Philippe","year":2012,"journal":"Journal of psychoactive drugs, 44(2), 125-33","doi":null,"pmid":"22880540","tags":["medical-cannabis","pain","addiction","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compiled evidence from preclinical and clinical sources on using cannabis as an adjunct to or substitute for opiates in chronic pain. When used together, cannabinoids and opiates produced greater cumulative pain relief than either alone, allowing patients to use lower opiate doses and experience fewer opiate side effects.\n\nCannabioids could prevent the development of opiate tolerance and withdrawal, and could even restore opiate effectiveness after tolerance had developed (\"rekindling\" opiate analgesia). Novel research suggested cannabis might also help treat problematic substance use more broadly.\n\nThe review noted that community-based medical cannabis dispensaries had been successful at providing patients with safe cannabis access and might be reducing problematic opiate use in their communities.","whyItMatters":"As the opioid epidemic was emerging, this review highlighted cannabis as a potential harm-reduction strategy. If cannabis could reduce opiate doses and prevent tolerance, it might reduce the cascade from prescription opiates to dependence and overdose.","specificNumbers":"Cannabinoids enhanced opiate analgesia. Prevented opiate tolerance and withdrawal. Could rekindle opiate effectiveness after tolerance. Community dispensaries associated with reduced opiate use.","methodology":"Narrative review of preclinical studies, clinical evidence, and community-level observations on cannabis-opiate interactions for chronic pain. Covered both pharmacological synergies and public health implications.","limitations":"Narrative review with advocacy perspective. Much evidence was preclinical. Clinical data on cannabis-opiate substitution was limited. Community dispensary observations were ecological, not controlled studies. Did not address cannabis-specific risks."},{"rthcId":"RTHC-00585","title":"An Australian twin study of cannabis and other illicit drug use and misuse, and other psychopathology.","authors":"Lynskey, Michael T; Agrawal, Arpana; Henders, Anjali; Nelson, Elliot C; Madden, Pamela A F; Martin, Nicholas G","year":2012,"journal":"Twin research and human genetics : the official journal of the International Society for Twin Studies, 15(5), 631-41","doi":"10.1017/thg.2012.41","pmid":"22874079","tags":["genetics","addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers interviewed 3,824 young adult twins born 1972-1979 about cannabis and other drug use. Cannabis use was remarkably common: 75.2% of males and 64.7% of females reported some lifetime use, while 24.5% of males and 11.8% of females met criteria for cannabis abuse or dependence.\n\nGenetic analysis revealed consistently high heritability across cannabis phenotypes: early opportunity to use (72%), early onset use by age 16 (80%), using 11+ times lifetime (76%), and DSM abuse/dependence (72%). These were among the highest heritability estimates for any substance use phenotype.\n\nEarly age of cannabis onset was strongly associated with subsequent use of other illicit drugs and drug abuse/dependence, with some evidence that this was mediated by increased exposure to and opportunity to use other drugs.","whyItMatters":"The consistently high heritability (72-80%) across cannabis use stages meant that genetic factors strongly influence not just whether someone tries cannabis but also whether they develop problems with it. This has implications for prevention (targeting genetically vulnerable individuals) and destigmatization (addiction as biological vulnerability rather than moral failing).","specificNumbers":"3,824 twins, 3,567 families. Male cannabis use: 75.2%. Female: 64.7%. Male abuse/dependence: 24.5%. Female: 11.8%. Heritability: 72-80% across phenotypes.","methodology":"Twin study with 3,824 young adult twins and siblings from 3,567 families. Structured interviews assessed cannabis use stages, other drug use, and psychiatric conditions. Bivariate genetic modeling estimated heritability of cannabis phenotypes.","limitations":"Australian twin sample may not generalize to other populations. Self-reported drug use. Twin studies assume equal environments for identical and fraternal twins. High prevalence of cannabis use in this cohort (born 1970s) may affect generalizability to other eras."},{"rthcId":"RTHC-00586","title":"Cannabinoids disrupt hippocampal sharp wave-ripples via inhibition of glutamate release.","authors":"Maier, Nikolaus; Morris, Genela; Schuchmann, Sebastian; Korotkova, Tatiana; Ponomarenko, Alexey; Böhm, Claudia; Wozny, Christian; Schmitz, Dietmar","year":2012,"journal":"Hippocampus, 22(6), 1350-62","doi":"10.1002/hipo.20971","pmid":"21853502","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Using both in vivo and in vitro recordings in mice, researchers demonstrated that activating CB1 receptors suppressed sharp wave-ripples (SWRs) in the hippocampus. SWRs are brief, high-frequency oscillations that occur during rest and sleep and are considered essential for consolidating new memories.\n\nThe mechanism was selective: cannabinoids reduced the excitatory (glutamatergic) component of SWR-associated activity without affecting the inhibitory (GABAergic) component. This imbalance between excitation and inhibition disrupted the coordinated neuronal firing needed for memory replay.\n\nAdenosine, another presynaptic modulator of glutamate release, mimicked and blocked (occluded) the cannabinoid effect, confirming that inhibition of glutamate release at specific synapses was the key mechanism.","whyItMatters":"This study identified the specific brain mechanism by which cannabis impairs memory: not by preventing learning itself, but by disrupting the replay and consolidation process that turns short-term memories into long-term ones. This explains why cannabis users can learn things but may not retain them.","specificNumbers":"CB1 activation suppressed SWRs both in vivo and in vitro. Selective reduction of excitatory (inward) but not inhibitory (outward) charge transfer during SWRs. Adenosine mimicked and occluded the cannabinoid effect.","methodology":"Combined in vivo and in vitro hippocampal recordings in mice. Field recordings captured sharp wave-ripples. Whole-cell voltage-clamp recordings measured excitatory and inhibitory synaptic currents during SWRs. Pharmacological tools confirmed CB1-mediated glutamate release inhibition.","limitations":"Mouse study. In vitro slice recordings capture simplified network dynamics. The link between SWR suppression and actual memory impairment was inferred rather than directly tested. Acute cannabinoid effects may differ from chronic."},{"rthcId":"RTHC-00587","title":"Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers.","authors":"Martin-Santos, R; Crippa, J A; Batalla, A; Bhattacharyya, S; Atakan, Z; Borgwardt, S; Allen, P; Seal, M; Langohr, K; Farré, M; Zuardi, A W; McGuire, P K","year":2012,"journal":"Current pharmaceutical design, 18(32), 4966-79","doi":null,"pmid":"22716148","tags":["cbd","psychosis","anxiety"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Sixteen healthy male volunteers received oral THC (10 mg), CBD (600 mg), or placebo in a double-blind crossover design with one-month intervals between sessions. Measurements were taken before and at 1, 2, and 3 hours post-administration.\n\nTHC produced significant anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication, and increased heart rate compared to both placebo and CBD (p<0.01 for most measures).\n\nCBD produced no significant differences from placebo on any symptomatic or physiological variable measured. The 600 mg dose was safe and well tolerated.\n\nThis was one of the cleanest head-to-head comparisons of THC and CBD effects in the same individuals, confirming their fundamentally different pharmacological profiles.","whyItMatters":"This study provided clear evidence that CBD does not produce the psychoactive effects associated with cannabis. By testing both compounds in the same volunteers, it eliminated the possibility that differences between compounds were due to different study populations.","specificNumbers":"16 healthy males. THC 10 mg: significant anxiety, psychotic symptoms, sedation, intoxication, heart rate increase (p<0.01). CBD 600 mg: no differences from placebo on any measure.","methodology":"Randomized, double-blind, crossover, placebo-controlled trial. 16 healthy males. Three sessions at one-month intervals. Oral THC 10 mg, CBD 600 mg, or placebo. Physiological measures and symptom ratings at baseline and 1, 2, 3 hours post-dose. AUC and peak change analyses.","limitations":"Only male volunteers. Single-dose design. CBD at 600 mg is much higher than typical consumer doses but showed no effects, making it unlikely lower doses would. Oral administration has different pharmacokinetics than other routes."},{"rthcId":"RTHC-00588","title":"Cannabis use stages as predictors of subsequent initiation with other illicit drugs among French adolescents: use of a multi-state model.","authors":"Mayet, Aurélie; Legleye, Stéphane; Falissard, Bruno; Chau, Nearkasen","year":2012,"journal":"Addictive behaviors, 37(2), 160-6","doi":"10.1016/j.addbeh.2011.09.012","pmid":"21983294","tags":["youth","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Using a retrospective cohort of 29,393 French teenagers, researchers modeled all possible pathways from initial abstinence through cannabis initiation, daily cannabis use, and other illicit drug (OID) initiation using a Markov multi-state model.\n\nThe risk of initiating other illicit drugs was 21 times higher among cannabis experimenters and 124 times higher among daily cannabis users compared to non-users, after adjusting for tobacco and alcohol use. Tobacco and alcohol use also increased the risk of progressing to cannabis use.\n\nThe authors suggested OID experimentation could be a consequence of opportunity: once someone uses the most accessible illicit drug (cannabis), they gain access to social networks and markets where other drugs are available.","whyItMatters":"The 124-fold increase for daily users was striking and provided quantitative support for stage-based drug use progression. The opportunity-based explanation (access to drug networks) offered a more nuanced view than simple pharmacological gateway theories.","specificNumbers":"29,393 teenagers. Cannabis experimenters: 21x higher OID risk. Daily cannabis users: 124x higher OID risk. Tobacco initiation HR=1.2, daily tobacco HR=2.6, drunkenness HR=2.8 for cannabis progression.","methodology":"Retrospective cohort of 29,393 French teenagers. Markov multi-state model modeled all pathways from abstinence through cannabis stages to other drug initiation. Adjusted for tobacco and alcohol use as transition modifiers.","limitations":"Retrospective self-report data. French teenager population may not generalize globally. The 124-fold increase, while large, may partly reflect selection effects (people who use cannabis daily are different from non-users in many ways). Cannot prove causation despite the multi-state modeling approach."},{"rthcId":"RTHC-00589","title":"Characterizing smoking topography of cannabis in heavy users.","authors":"McClure, Erin A; Stitzer, Maxine L; Vandrey, Ryan","year":2012,"journal":"Psychopharmacology, 220(2), 309-18","doi":"10.1007/s00213-011-2480-4","pmid":"21922170","tags":["addiction","withdrawal","sleep"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Twenty heavy cannabis users had their smoking behavior objectively measured during periods of ad libitum use in an inpatient study. Users smoked with the greatest intensity (volume, duration) on initial puffs, with a steady decline on subsequent puffs, suggesting they front-loaded their dose.\n\nObjective smoking characteristics were significantly correlated with the severity of withdrawal during subsequent abstinence, particularly sleep quality and architecture, and craving. This dose-response relationship suggested higher cannabis intake caused worse withdrawal.\n\nSmoked topography measures correlated with self-reported cannabis use, validating self-report, but topography was more sensitive than self-report in predicting cannabis-related outcomes, suggesting objective measurement captures something self-report misses.","whyItMatters":"Understanding how people actually smoke cannabis, and that the manner of smoking predicts withdrawal, has clinical implications. If initial puff intensity predicts withdrawal severity, it could serve as a clinical indicator of dependence risk.","specificNumbers":"20 heavy cannabis users. Puff intensity declined over the course of a session. Smoking characteristics correlated with withdrawal severity and sleep disruption. Topography measures were more predictive than self-report.","methodology":"Inpatient study with 20 heavy cannabis users alternating between ad libitum cannabis use and abstinence. Smoking topography measured objectively (puff volume, duration, interval). Withdrawal, craving, sleep, and cognitive measures collected during abstinence.","limitations":"Small sample (20 participants). Inpatient setting may not reflect natural smoking behavior. Only smoking was studied, not other consumption methods. The relationship between topography and withdrawal was correlational."},{"rthcId":"RTHC-00590","title":"Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress.","authors":"Mecha, M; Torrao, A S; Mestre, L; Carrillo-Salinas, F J; Mechoulam, R; Guaza, C","year":2012,"journal":"Cell death & disease, 3(6), e331","doi":"10.1038/cddis.2012.71","pmid":"22739983","tags":["cbd","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether CBD could protect oligodendrocyte progenitor cells (OPCs), the cells that produce myelin in the brain, from immune-mediated damage relevant to multiple sclerosis. CBD at 1 micromolar concentration protected OPCs from oxidative stress and from apoptosis (programmed cell death) triggered by inflammatory signals.\n\nThe protective mechanism involved reducing endoplasmic reticulum (ER) stress, specifically by decreasing phosphorylation of key ER stress pathway initiators (PKR and eIF2alpha). CBD also reduced pro-death signals (CHOP, Bax, caspase 12) and increased anti-death signals (Bcl-2).\n\nImportantly, the protection did not work through any of the usual cannabinoid receptors (CB1, CB2, TRPV1, or PPAR-gamma), suggesting a novel mechanism of action.","whyItMatters":"Oligodendrocyte loss and demyelination are hallmarks of MS. If CBD can protect these cells from immune-mediated damage through a receptor-independent mechanism, it could complement existing MS treatments that target the immune system by directly protecting the brain cells at risk.","specificNumbers":"CBD protective at 1 micromolar. Protection independent of CB1, CB2, TRPV1, PPAR-gamma receptors. Reduced phosphorylation of PKR and eIF2alpha. Decreased CHOP, Bax, caspase 12. Increased Bcl-2.","methodology":"In vitro study using oligodendrocyte progenitor cell cultures. CBD tested against oxidative stress (ROS), LPS/IFN-gamma-induced apoptosis, and tunicamycin-induced ER stress. Receptor antagonists tested to identify mechanism. ER stress pathway markers measured by Western blot.","limitations":"In vitro cell culture study. OPC responses in culture may differ from their behavior in the intact brain. Single CBD concentration tested. The mechanism by which CBD reduces ER stress without known receptor involvement remains unclear."},{"rthcId":"RTHC-00591","title":"Persistent cannabis users show neuropsychological decline from childhood to midlife","authors":"Meier, Madeline H.; Caspi, Avshalom; Ambler, Antony; Harrington, HonaLee; Houts, Renate; Keefe, Richard S.E.; McDonald, Kay; Ward, Aimee; Poulton, Richie; Moffitt, Terrie E.","year":2012,"journal":"Proceedings of the National Academy of Sciences (PNAS), 109(40), E2657-E2664","doi":"10.1073/pnas.1206820109","pmid":"22927402","tags":["cognition","youth","neuroscience","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"People who used cannabis persistently across early adulthood showed declines across multiple neuropsychological domains by age 38 compared to their own pre-use performance at age 13. The pattern held after accounting for years of education and was echoed by informants, who reported more everyday cognitive problems in persistent users. Decline was concentrated among those who began in adolescence, and greater persistence of use was linked to larger declines. Stopping use in adulthood did not fully restore cognitive performance among adolescent-onset users, according to the study’s analyses.","whyItMatters":"Adolescents have been reporting lower perceived risk from regular cannabis use, and initiation has been occurring earlier for some. A long-running cohort with cognitive testing before and after the typical window of initiation offers a rare view of how persistent use tracks with midlife cognitive function without relying on adult-only snapshots.","specificNumbers":"- Sample: 1,037 individuals followed from birth to age 38 in New Zealand\n- Neuropsychological testing: completed at ages 13 and 38, spanning roughly 25 years\n- Cannabis assessments: 5 interview waves at ages 18, 21, 26, 32, and 38\n- Pattern: more persistent use associated with greater cognitive decline","methodology":"This was a prospective cohort analysis within the Dunedin Multidisciplinary Health and Development Study, which has followed 1,037 individuals born in 1972–1973 in New Zealand. Cannabis use was assessed in confidential interviews at ages 18, 21, 26, 32, and 38. Neuropsychological testing was conducted twice: once at age 13, before typical initiation of cannabis, and again at age 38, after years in which persistent use patterns could emerge. The investigators examined change from pre-use to midlife, evaluated persistence and age of onset, and adjusted for years of education. Informant reports of everyday cognitive problems were collected to complement test scores.","limitations":"Observational — cannot prove causation. Cannabis exposure was self-reported with no biological verification or potency data. Products in the 1980s-2000s were much lower potency than modern cannabis. Residual confounding from socioeconomic status, mental health, and other substance use is possible despite statistical controls. The cohort is from a single city in New Zealand, limiting generalizability. The Jackson et al. twin study challenge — showing no within-pair cognitive differences — significantly weakened the causal interpretation."},{"rthcId":"RTHC-00592","title":"The natural history of self-harm from adolescence to young adulthood: a population-based cohort study.","authors":"Moran, Paul; Coffey, Carolyn; Romaniuk, Helena; Olsson, Craig; Borschmann, Rohan; Carlin, John B; Patton, George C","year":2012,"journal":"Lancet (London, England), 379(9812), 236-43","doi":"10.1016/S0140-6736(11)61141-0","pmid":"22100201","tags":["youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"A population-based cohort of 1,943 Australian adolescents was followed from age 15.9 to 29 with seven waves of assessment. Self-harm was reported by 8% during adolescence, with higher rates in girls (10%) than boys (6%).\n\nDuring adolescence, incident self-harm was independently associated with depression and anxiety symptoms (HR 3.7), cannabis use (HR 2.4), high-risk alcohol use (HR 2.1), antisocial behavior (HR 1.9), and cigarette smoking (HR 1.8). Cannabis use remained a significant predictor after adjusting for all other risk factors.\n\nMost self-harming behavior resolved spontaneously during the transition to adulthood. Adolescent depression and anxiety was the strongest predictor of continuing self-harm into young adulthood (HR 5.9).","whyItMatters":"Cannabis was identified as an independent risk factor for self-harm, separate from depression, anxiety, and other substance use. This has implications for suicide prevention: addressing cannabis use in at-risk adolescents may be an underappreciated component of self-harm prevention.","specificNumbers":"1,943 adolescents, 7 waves, mean ages 15.9-29.0. Self-harm prevalence: 8% in adolescence. Cannabis HR: 2.4 (95% CI 1.4-4.4). Depression/anxiety: HR 3.7. Alcohol: HR 2.1. Most self-harm resolved spontaneously.","methodology":"Population-based stratified random sample of 1,943 adolescents from 44 schools in Victoria, Australia. Seven waves of questionnaires and telephone interviews from mean age 15.9 to 29.0 years (1992-2008). Cox regression for risk factor identification.","limitations":"Self-reported cannabis use and self-harm. Association does not prove causation. Confounding by personality traits, trauma, or other unmeasured factors is possible. Australian sample may not generalize globally."},{"rthcId":"RTHC-00593","title":"Pericyazine in the treatment of cannabis dependence in general practice: a naturalistic pilot trial.","authors":"Morley, Kirsten C; Haber, Paul S; Morgan, Madeleine L; Samara, Fares","year":2012,"journal":"Substance abuse and rehabilitation, 3, 43-7","doi":"10.2147/SAR.S30052","pmid":"24474865","tags":["addiction","quitting"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Twenty-one patients with cannabis dependence received pericyazine, a low-potency antipsychotic with sedative properties and low abuse potential, for 4 weeks in a community clinic setting. The dosing was flexible, up to 20 mg daily (8 tablets of 2.5 mg).\n\nSignificant reductions were observed in cannabis use, depression, anxiety, and insomnia severity across the treatment period. Pericyazine appeared to be well tolerated and easily administered in community clinics.\n\nHowever, without a placebo control group, the authors could not conclude that the medication itself caused the improvements. Placebo effects, natural recovery, and the supportive clinical setting could all have contributed.","whyItMatters":"With no approved medications for cannabis dependence, any preliminary positive signal deserves attention. Pericyazine's sedative properties could address cannabis withdrawal symptoms (insomnia, anxiety) while its low abuse liability made it safe for addiction populations.","specificNumbers":"21 patients. 4-week treatment. Up to 20 mg/day pericyazine. Significant reductions in cannabis use, depression, anxiety, insomnia. Well tolerated.","methodology":"Naturalistic open-label case series. 21 patients enrolled for 4-week pericyazine treatment (up to 20 mg/day). Weekly medical review. Cannabis use, depression, anxiety, and insomnia measured with validated tools at baseline and follow-up. ECG and blood monitoring for safety.","limitations":"Open-label without placebo control. Very small sample. Only 4-week treatment period. Cannot attribute improvements to the medication. High likelihood of placebo effect and regression to the mean."},{"rthcId":"RTHC-00594","title":"Cannabis use and schizotypy: the role of social anxiety and other negative affective states.","authors":"Najolia, Gina M; Buckner, Julia D; Cohen, Alex S","year":2012,"journal":"Psychiatry research, 200(2-3), 660-8","doi":"10.1016/j.psychres.2012.07.042","pmid":"22920791","tags":["psychosis","anxiety","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers studied over 650 college undergraduates, comparing those with elevated schizotypy traits to controls. Among cannabis users, social anxiety stood out as a consistent moderator: people with both schizotypy traits and higher social anxiety used cannabis more frequently and experienced more cannabis-related problems.\n\nThis pattern held across positive, negative, and disorganized schizotypy subtypes. Depression and trait anxiety also played a role, but their effects varied depending on the schizotypy subtype. Social anxiety was the most consistent predictor across all groups.","whyItMatters":"This study highlights social anxiety as a potential treatment target for cannabis-related problems in people with schizotypy traits. Rather than treating cannabis use in isolation, addressing the underlying social anxiety might reduce both the motivation to use and the harms that follow.","specificNumbers":"220 participants with schizotypy traits vs. 436 controls. Among cannabis users: 88 with schizotypy, 83 controls. Social anxiety moderated the schizotypy-cannabis relationship across all three schizotypy subgroups.","methodology":"The study used a cross-sectional design with 220 participants meeting schizotypy criteria and 436 controls, all college undergraduates. Schizotypy was measured with the SPQ-BR, social anxiety with the SIAS, and depression and trait anxiety with the BSI. Among those groups, 88 schizotypy participants and 83 controls were cannabis users whose frequency and problems were analyzed.","limitations":"The cross-sectional design means the study cannot determine whether social anxiety causes increased cannabis use or vice versa. The sample was limited to college undergraduates, who may not represent the broader population of people with schizotypy traits. Self-report measures are subject to recall and reporting biases."},{"rthcId":"RTHC-00595","title":"Cannabinoid hyperemesis syndrome: a case series and review of previous reports.","authors":"Nicolson, Stephen E; Denysenko, Lex; Mulcare, J Loretta; Vito, Jose P; Chabon, Brenda","year":2012,"journal":"Psychosomatics, 53(3), 212-9","doi":"10.1016/j.psym.2012.01.003","pmid":"22480624","tags":["appetite","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The authors described four patients who experienced recurring cycles of intense nausea and vomiting that were linked to long-term, heavy cannabis use. All four patients engaged in compulsive hot water bathing, which temporarily relieved their symptoms.\n\nPrevious cases from the medical literature were reviewed alongside these four, confirming a consistent pattern: chronic cannabis use, cyclical vomiting episodes, and relief from hot showers or baths. Symptoms resolved when patients stopped using cannabis.","whyItMatters":"Cannabinoid hyperemesis syndrome is frequently misdiagnosed because cannabis is typically associated with reducing nausea, not causing it. This paradox means patients often undergo extensive and expensive diagnostic workups before the actual cause is identified.","specificNumbers":"4 new cases described. All patients were chronic cannabis users. All exhibited compulsive hot water bathing. Symptoms resolved with cannabis cessation in each case.","methodology":"This was a case series describing four patients seen at a single institution, combined with a literature review of previously published CHS reports. The authors analyzed the clinical presentations, proposed pathophysiological mechanisms, and discussed diagnostic challenges.","limitations":"Case series provide descriptive evidence but cannot establish how common CHS is or identify which cannabis users are most at risk. The small number of cases limits generalizability. The pathophysiology remains hypothetical."},{"rthcId":"RTHC-00596","title":"O-hydroxyacetamide carbamates as a highly potent and selective class of endocannabinoid hydrolase inhibitors.","authors":"Niphakis, Micah J; Johnson, Douglas S; Ballard, T Eric; Stiff, Cory; Cravatt, Benjamin F","year":2012,"journal":"ACS chemical neuroscience, 3(5), 418-26","doi":"10.1021/cn200089j","pmid":"22860211","tags":["neuroscience","cbd","pain","anxiety","depression"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The researchers investigated O-hydroxyacetamide carbamate compounds and found they could be tuned to selectively inhibit FAAH (the enzyme that breaks down anandamide) or to simultaneously inhibit both FAAH and MAGL (which breaks down 2-AG). One compound, SA-57, showed remarkable selectivity in living animals.\n\nAt doses suitable for behavioral studies (0.125 to 12.5 mg/kg), these compounds raised brain levels of natural endocannabinoids without the broad psychoactive effects of directly activating cannabinoid receptors.","whyItMatters":"Direct cannabinoid receptor activation (like THC) produces a wide range of psychoactive effects. By instead boosting the body's own endocannabinoids through enzyme inhibition, these compounds could potentially provide pain relief, reduce anxiety, and improve mood without the full psychotropic profile.","specificNumbers":"Dose range tested: 0.125 to 12.5 mg/kg. SA-57 targeted only FAAH, MAGL, and one additional enzyme (ABHD6) out of the entire brain proteome.","methodology":"The study used competitive and click chemistry activity-based protein profiling to assess compound selectivity in mouse brains. Researchers tested multiple doses across the range to determine in vivo activity and selectivity profiles for FAAH and MAGL inhibition.","limitations":"This was a preclinical chemistry and pharmacology study conducted in rodents. Whether these compounds translate to safe, effective human therapeutics remains unknown. Long-term effects of sustained endocannabinoid elevation were not assessed."},{"rthcId":"RTHC-00597","title":"Two Sides of the Same Coin: Cannabis Dependence and Mental Health Problems in Help-Seeking Adolescent and Young Adult Outpatients.","authors":"Norberg, Melissa M; Battisti, Robert A; Copeland, Jan; Hermens, Daniel F; Hickie, Ian B","year":2012,"journal":"International journal of mental health and addiction, 10(6), 818-828","doi":null,"pmid":"23243411","tags":["addiction","mental-health","anxiety","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 36 young people seeking help for both cannabis dependence and mental health issues, the psychiatric picture was complex. Most had at least two Axis I disorders on top of their cannabis dependence. Anxiety disorders dominated, particularly PTSD, social phobia, and generalized anxiety disorder.\n\nParticipants reported moderate dependence severity, significant functional impairment, and numerous cannabis-related problems. While males and females used similar total amounts per month, females used cannabis more frequently.","whyItMatters":"Treatment programs that address cannabis use alone may miss the multiple co-occurring psychiatric conditions that young people bring to treatment. Effective intervention likely requires integrated approaches that address anxiety, trauma, and other conditions simultaneously.","specificNumbers":"36 participants aged 14-29. Most had 2+ Axis I disorders beyond cannabis dependence. PTSD, social phobia, and GAD were the most common anxiety diagnoses. Females used cannabis more frequently than males despite similar monthly quantities.","methodology":"The study used structured clinical interviews (SCID for DSM-IV-TR) to diagnose psychiatric conditions in 36 help-seeking young people aged 14 to 29. Cannabis use patterns were measured with a modified Timeline Followback interview and self-report questionnaires.","limitations":"The small sample of 36 participants limits generalizability. All participants were treatment-seeking, which means they may represent more severe cases than the general population of cannabis-dependent young people. The cross-sectional design cannot clarify whether psychiatric conditions preceded or followed cannabis dependence."},{"rthcId":"RTHC-00598","title":"Screening and managing cannabis use: comparing GP's and nurses' knowledge, beliefs, and behavior.","authors":"Norberg, Melissa M; Gates, Peter; Dillon, Paul; Kavanagh, David J; Manocha, Ramesh; Copeland, Jan","year":2012,"journal":"Substance abuse treatment, prevention, and policy, 7, 31","doi":"10.1186/1747-597X-7-31","pmid":"22827931","tags":["harm-reduction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 503 GPs and 161 nurses about their cannabis-related knowledge, beliefs, and clinical behaviors. GPs were more likely to have screened patients for cannabis use and provided related services, but they also reported more barriers: time constraints, lack of interest, and feeling that other issues took priority.\n\nNurses reported less knowledge, fewer skills, and less confidence that cannabis screening fell within their professional role. However, perceived screening skills predicted actual screening behavior for both professions, suggesting that training could increase service delivery.","whyItMatters":"Cannabis-related problems represent a significant unmet treatment need. Most people who need help for cannabis issues visit their GP or interact with nurses, making primary care a logical intervention point. But if clinicians feel unprepared or unconvinced of their role, opportunities for early intervention are missed.","specificNumbers":"503 GPs and 161 nurses surveyed. GPs were more likely to screen for cannabis use. Perceived screening skills predicted actual screening and referral to AOD services. Knowing a regular cannabis user increased referral likelihood.","methodology":"Cross-sectional survey distributed at Healthed conference seminars focused on women's and children's health in Australia. Differences between GPs and nurses were analyzed with chi-square tests and t-tests. Logistic regression identified predictors of cannabis-related service provision.","limitations":"The survey was distributed at conferences focused on women's and children's health, so attendees may not represent the broader GP and nursing workforce. Self-reported behaviors may not accurately reflect actual clinical practice. The study was conducted in Australia, which may limit applicability elsewhere."},{"rthcId":"RTHC-00599","title":"A brain on cannabinoids: the role of dopamine release in reward seeking.","authors":"Oleson, Erik B; Cheer, Joseph F","year":2012,"journal":"Cold Spring Harbor perspectives in medicine, 2(8)","doi":"10.1101/cshperspect.a012229","pmid":"22908200","tags":["dopamine","addiction","withdrawal","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"In animal models, cannabinoids activate the mesolimbic dopamine system, the same reward circuit engaged by other drugs of abuse. Dopamine release rises with drug exposure and with cues that predict drug availability. During withdrawal, dopamine signaling drops, consistent with negative affect and reduced motivation seen in withdrawal syndromes.\n\nPharmacologically disrupting endocannabinoid signaling reduces drug-evoked dopamine increases and lowers dopamine responses to reward-predictive cues. This places cannabinoid receptors, especially CB1, as key modulators of how strongly rewards and their signals trigger dopamine release.\n\nThe review argues that cannabis is not an exception in dopamine circuitry terms. At the level of mesolimbic signaling in animals, it aligns with other addictive drugs.","whyItMatters":"Reward, craving, and withdrawal map onto dopamine dynamics in animals. Placing cannabinoids within that framework clarifies why conditioned cues can be powerful and why withdrawal can feel flat or aversive. It also highlights the endocannabinoid system as a lever that can tune dopamine responses, a concept that has guided experimental treatment strategies for disorders of motivation.","specificNumbers":"- Direction of effect in animals: dopamine goes up with cannabinoid exposure and reward-predictive cues, down during withdrawal\n- Mechanistic handle: blocking CB1 or endocannabinoid signaling reduces drug- and cue-evoked dopamine release\n- Scope: evidence base is primarily preclinical, with limited and mixed human neuroimaging findings relative to potent stimulants","methodology":"Narrative review focused largely on preclinical work. The authors synthesize findings from animal studies using electrophysiology and electrochemistry to track mesolimbic dopamine, plus pharmacology that manipulates cannabinoid receptors and endogenous cannabinoids. Limited human data are referenced but the core evidence is animal-based. No quantitative pooling, study selection criteria, or risk-of-bias procedures are described in the abstract.","limitations":"This is a narrative review centered on animal studies, without a systematic search or bias assessment. Effects and mechanisms are synthesized qualitatively, not quantified across studies. Species, strain, and dosing differences can shape dopamine readouts. Human data on cannabis-induced dopamine release are limited and mixed, and the review’s therapeutic angle contrasts with later clinical experience showing psychiatric adverse events with CB1 antagonists. The abstract provides no dose, potency, or timeline details for cannabis or dronabinol exposures."},{"rthcId":"RTHC-00600","title":"Clinical efficacy and effectiveness of Sativex, a combined cannabinoid medicine, in multiple sclerosis-related spasticity.","authors":"Oreja-Guevara, Celia","year":2012,"journal":"Expert review of neurotherapeutics, 12(4 Suppl), 3-8","doi":"10.1586/ern.12.11","pmid":"22509985","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined accumulating clinical evidence for Sativex, an oromucosal spray containing equal parts THC and cannabidiol. Results from randomized controlled trials showed that patients with MS-related spasticity experienced reductions in symptom severity after using Sativex.\n\nBeyond symptom scores, patients reported improved ability to perform daily activities. Both patients and their caregivers perceived meaningful improvements in functional status. The review noted that MS-related spasticity is one of the most disabling symptoms and that existing monotherapies often fail to provide adequate control.","whyItMatters":"Spasticity affects a large proportion of MS patients and significantly reduces quality of life. The review highlighted that many patients require multiple medications and still achieve poor symptom control, making the positive results with Sativex particularly relevant for this underserved population.","specificNumbers":"Sativex is a 1:1 mixture of THC and CBD. A Spanish survey found that multidrug therapy and low control rates were common in MS spasticity management. RCT results showed reduction in spasticity severity and improved daily functioning.","methodology":"Narrative review of clinical trial data and a Spanish survey on current MS spasticity treatment practices. The review synthesized evidence from randomized controlled trials of Sativex in MS-related spasticity.","limitations":"This is a narrative review rather than a systematic review, so the selection of studies may reflect author judgment rather than comprehensive literature searching. Long-term efficacy and safety data were limited at the time of publication."},{"rthcId":"RTHC-00601","title":"Genetic etiology of the common liability to drug dependence: evidence of common and specific mechanisms for DSM-IV dependence symptoms.","authors":"Palmer, Rohan H C; Button, Tanya M; Rhee, Soo H; Corley, Robin P; Young, Susan E; Stallings, Michael C; Hopfer, Christian J; Hewitt, John K","year":2012,"journal":"Drug and alcohol dependence, 123 Suppl 1, S24-32","doi":"10.1016/j.drugalcdep.2011.12.015","pmid":"22243758","tags":["addiction","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using data from 2,484 twins, researchers found that dependence symptoms for alcohol, tobacco, and cannabis loaded onto a single underlying trait, suggesting a common vulnerability. Additive genetic factors explained more than 60% of this shared liability.\n\nHowever, a larger proportion of variation in each individual substance's dependence symptoms came from substance-specific genetic and environmental factors. This means that while there is a general genetic predisposition to drug dependence, each substance also has its own distinct biological and environmental influences.","whyItMatters":"Understanding that a common genetic factor underlies much of the overlap between substance dependence helps explain why people who develop problems with one substance are at elevated risk for problems with others. It also suggests that treatments targeting shared vulnerability pathways could potentially address multiple substance use disorders simultaneously.","specificNumbers":"2,484 twin registrants studied. Additive genetic factors explained 60%+ of the common liability. Both common and substance-specific genetic factors contributed to dependence symptoms. Gender differences in magnitude of genetic/environmental influences were accounted for.","methodology":"The study used univariate and multivariate twin modeling on data from the Center for Antisocial Drug Dependence. DSM-IV dependence symptoms were assessed with the Composite International Diagnostic Interview-Substance Abuse Module. Analyses were limited to twins who reported lifetime use of each substance.","limitations":"Twin studies estimate heritability but cannot identify specific genes. The sample was drawn from a study focused on antisocial behavior, which may not represent the general population. Analyses were limited to those who had used each substance, which may introduce selection bias."},{"rthcId":"RTHC-00602","title":"Combined effects of THC and caffeine on working memory in rats.","authors":"Panlilio, Leigh V; Ferré, Sergi; Yasar, Sevil; Thorndike, Eric B; Schindler, Charles W; Goldberg, Steven R","year":2012,"journal":"British journal of pharmacology, 165(8), 2529-38","doi":"10.1111/j.1476-5381.2011.01554.x","pmid":"21699509","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested THC and caffeine combinations in rats performing a working memory task. THC alone impaired memory only at the higher dose (3 mg/kg). Caffeine alone did not impair memory at any dose tested, though it initially disrupted rehearsal-like behavior before tolerance developed.\n\nThe surprising finding: when a dose of THC too low to impair memory on its own (1 mg/kg) was combined with caffeine (10 mg/kg), significant memory impairment occurred. Caffeine did not counteract THC's effects but actually made them worse.","whyItMatters":"Cannabis and caffeine are two of the most widely used psychoactive substances in the world, and many people consume both. The finding that caffeine can amplify THC's memory-impairing effects, rather than counteract them, challenges the common assumption that coffee might help offset cannabis-related cognitive effects.","specificNumbers":"THC at 3 mg/kg impaired memory. THC at 1 mg/kg alone had no effect. Caffeine at 10 mg/kg alone had no memory effect. Combined 1 mg/kg THC + 10 mg/kg caffeine produced significant memory impairment.","methodology":"Rats were tested using a delayed non-matching-to-position procedure, a standard working memory paradigm. They received THC (0, 1, 3 mg/kg) combined with caffeine (0, 1, 3, 10 mg/kg), a selective A1 receptor antagonist (CPT), or a selective A2A receptor antagonist (SCH58261). Behavior during delay periods was recorded as a measure of memory rehearsal.","limitations":"This was an animal study with doses that may not directly translate to human consumption patterns. The memory task, while well-validated, tests a specific type of working memory that may not capture all aspects of cognition. Rat physiology differs from human physiology in ways that could affect drug interactions."},{"rthcId":"RTHC-00603","title":"A review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence and future directions for research.","authors":"Pava, Matthew J; Woodward, John J","year":2012,"journal":"Alcohol (Fayetteville, N.Y.), 46(3), 185-204","doi":"10.1016/j.alcohol.2012.01.002","pmid":"22459871","tags":["addiction","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review compiled 50 years of research on the relationship between the endocannabinoid system and alcohol. Key findings included that CB1 receptors contribute to alcohol's rewarding and reinforcing properties, and that chronic alcohol consumption changes endocannabinoid transmitter levels and CB1 receptor expression in brain areas associated with addiction.\n\nIn vitro and ex vivo studies confirmed that both acute and chronic alcohol exposure produces meaningful alterations in endocannabinoid system function. The review mapped these changes across different stages of alcohol dependence.","whyItMatters":"Understanding how the endocannabinoid system interacts with alcohol could lead to new treatment approaches for alcohol dependence. If CB1 receptors help drive alcohol's rewarding effects, then targeting these receptors could potentially reduce alcohol cravings and consumption.","specificNumbers":"Review covers 50+ years of research. CB1 receptor was discovered in the late 1980s. Chronic alcohol use alters both endocannabinoid levels and CB1 expression in addiction pathways.","methodology":"Comprehensive narrative review spanning from early studies comparing behavioral effects of cannabinoids and alcohol, through the discovery of the endocannabinoid system in the 1990s, to recent pharmacological and genetic studies manipulating specific system components.","limitations":"As a narrative review, the selection of studies may not be comprehensive. Much of the evidence comes from preclinical models that may not fully translate to human alcohol dependence. The field was still relatively young at the time of publication."},{"rthcId":"RTHC-00604","title":"Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.","authors":"Pertwee, Roger G","year":2012,"journal":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367(1607), 3353-63","doi":"10.1098/rstb.2011.0381","pmid":"23108552","tags":["medical-cannabis","neuroscience","pain","epilepsy","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Three cannabinoid medicines were already in clinical use at the time: Cesamet (nabilone), Marinol (dronabinol), and Sativex (THC with CBD). The review identified numerous additional therapeutic targets including pain, epilepsy, anxiety, depression, neurodegenerative diseases, stroke, cancer, and cardiovascular disorders.\n\nFive strategies were proposed to improve the benefit-to-risk ratio: targeting cannabinoid receptors outside the blood-brain barrier, targeting receptors in specific tissues, targeting upregulated receptors (which increase in disease states), selectively activating CB2 receptors (which are less psychoactive), and using adjunctive multi-targeting approaches.","whyItMatters":"The main barrier to broader cannabinoid medicine use is the psychoactive side effect profile. This review laid out concrete strategies for separating the therapeutic effects from the unwanted psychoactive effects, providing a roadmap for next-generation cannabinoid therapeutics.","specificNumbers":"3 approved cannabinoid medicines reviewed. 5 strategies for improving benefit-to-risk ratio. Potential targets include 15+ disease categories ranging from pain to cancer to cardiovascular disorders.","methodology":"Narrative review of preclinical and clinical evidence for cannabinoid receptor agonists, covering approved medicines, potential therapeutic targets, and pharmacological strategies for improving efficacy and tolerability.","limitations":"Many of the proposed therapeutic targets were supported primarily by preclinical data at the time. The strategies are conceptual frameworks that still need to be validated through clinical trials. The review did not address regulatory or manufacturing challenges."},{"rthcId":"RTHC-00605","title":"Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis.","authors":"Podda, Giulio; Constantinescu, Cris S","year":2012,"journal":"Expert opinion on biological therapy, 12(11), 1517-31","doi":"10.1517/14712598.2012.721765","pmid":"22954177","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review analyzed clinical trials of nabiximols for three MS symptoms: spasticity, neuropathic pain, and bladder dysfunction. Trials demonstrated clinical efficacy across all three symptom categories. Nabiximols was licensed in the UK in 2010 and approved in other European countries and Canada.\n\nThe European Federation of Neurological Societies recommended cannabis-based medicines as second or third-line treatment for central neuropathic pain. The review also examined psychological effects associated with cannabinoid use in large RCTs and long-term follow-up studies.","whyItMatters":"MS patients often struggle with spasticity, pain, and bladder problems that respond poorly to existing treatments. This review provided a comprehensive picture of nabiximols as a treatment option for all three, helping clinicians understand where it fits in the treatment hierarchy.","specificNumbers":"Nabiximols is a 1:1 THC/CBD extract. Licensed in UK in 2010. Recommended as 2nd or 3rd-line treatment for central neuropathic pain by the European Federation of Neurological Societies.","methodology":"Narrative review of clinical trials and regulatory decisions regarding nabiximols (Sativex) for MS symptoms. Focused on randomized controlled trials for spasticity, pain, and bladder dysfunction, plus long-term follow-up and safety data.","limitations":"Long-term safety data were still sparse at the time of publication. MS is a progressive disease, so questions remained about whether nabiximols maintains efficacy as the disease advances. The natural history of MS makes long-term efficacy evaluation challenging."},{"rthcId":"RTHC-00606","title":"Potential control of multiple sclerosis by cannabis and the endocannabinoid system.","authors":"Pryce, Gareth; Baker, David","year":2012,"journal":"CNS & neurological disorders drug targets, 11(5), 624-41","doi":null,"pmid":"22583441","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined two distinct roles for cannabinoids in MS. First, the established symptom-relief function: cannabis reduces limb spasticity by modulating excessive neuronal signaling, which led to cannabis-based medicines being approved for pain and spasticity in MS.\n\nSecond, and more novel, experimental studies revealed that cannabinoids may have neuroprotective effects that could slow disease progression and delay the onset of symptoms like spasticity. This dual potential, treating both symptoms and underlying disease, represented a significant shift in thinking about cannabinoids in MS.","whyItMatters":"Most MS treatments address either symptoms or disease progression, but rarely both. If cannabinoids can do both simultaneously, they could represent a uniquely valuable class of MS therapeutics. The neuroprotective potential is particularly important because progressive nerve damage is what drives long-term disability in MS.","specificNumbers":"Cannabis-based medicines were approved for pain and spasticity in MS at the time of publication. Experimental evidence for neuroprotection came from multiple animal models of MS.","methodology":"Review of preclinical data from animal models of MS, clinical evidence from human studies, and analysis of the endocannabinoid system biology relevant to MS. Covered both symptom management and neuroprotection research.","limitations":"The neuroprotective evidence came primarily from animal models, which do not perfectly replicate human MS. Translating neuroprotective effects from preclinical models to clinical benefit has historically proven very difficult in neurology. Long-term clinical data were lacking."},{"rthcId":"RTHC-00607","title":"Cannabinoid receptor 1 signaling in embryo neurodevelopment.","authors":"Psychoyos, Delphine; Vinod, K Yaragudri; Cao, Jin; Xie, Shan; Hyson, Richard L; Wlodarczyk, Bogdan; He, Weimin; Cooper, Thomas B; Hungund, Basalingappa L; Finnell, Richard H","year":2012,"journal":"Birth defects research. Part B, Developmental and reproductive toxicology, 95(2), 137-50","doi":"10.1002/bdrb.20348","pmid":"22311661","tags":["pregnancy","neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using chick and mouse embryo models, researchers demonstrated that all major components of the endocannabinoid system are present during very early embryonic development, before neurogenesis (the formation of nerve cells) begins. This included CB1 receptors, the endocannabinoids anandamide and 2-AG, and the enzymes responsible for their production and breakdown.\n\nThe finding suggests the endocannabinoid system plays a role in fundamental embryonic development processes that precede brain formation, and that exposure to THC during this early window could disrupt these processes.","whyItMatters":"In utero THC exposure has been associated with increased risk of neurodevelopmental problems in offspring. This study provides a biological mechanism: if the endocannabinoid system is active even before brain development begins, cannabis exposure during the earliest stages of pregnancy could interfere with fundamental developmental processes.","specificNumbers":"CB1 receptors, anandamide (AEA), 2-AG, and five metabolic enzymes (NAPE-PLD, DAGL-alpha, DAGL-beta, MAGL, FAAH) were all detected in pre-neurogenesis embryos in both chick and mouse models.","methodology":"The study used biochemical techniques including analysis of receptor levels, endocannabinoid concentrations, and enzyme presence in chick and mouse embryo models at developmental stages before and during neurogenesis.","limitations":"The study used animal models (chick and mouse), which may not perfectly mirror human embryonic development. Detecting the presence of endocannabinoid system components does not prove they are functionally critical at this stage. The study did not test the effects of THC exposure at these early timepoints."},{"rthcId":"RTHC-00608","title":"Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'","authors":"Raichlen, David A.; Foster, Adam D.; Gerdeman, Gregory L.; Seillier, Alexandre; Giuffrida, Andrea","year":2012,"journal":"Journal of Experimental Biology, 215(8), 1331-1336","doi":"10.1242/jeb.063677","pmid":"22442371","tags":["exercise","neuroscience","cognition"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Circulating endocannabinoid levels rose after high-intensity endurance running in humans and in dogs. The same individuals did not show a significant rise during low-intensity walking.\n\nFerrets, a non-cursorial species, showed no significant endocannabinoid change at either exercise intensity. The pattern supports the idea that an endocannabinoid response tracks with endurance-style locomotion in species adapted for running. The study did not measure mood or euphoria, so it cannot show that endocannabinoids caused a subjective runner's high.","whyItMatters":"For decades, the runner's high was attributed mainly to endorphins. By 2012, evidence had begun pointing to the endocannabinoid system. Showing that high-intensity running in humans coincides with a blood endocannabinoid surge, and that a similar surge appears in a cursorial mammal but not a non-cursorial one, adds a comparative biology angle. It suggests a physiological signature that may help explain why endurance exercise persists in some species, while avoiding claims about cause.","specificNumbers":"- Species included: 3 total. Humans, dogs (cursorial), ferrets (non-cursorial)\n- High-intensity running: increased circulating endocannabinoids in 2 of 3 species (humans and dogs)\n- Low-intensity walking: no significant increase in any of the 3 species\n- Non-cursorial species result: 0 of 1 (ferrets) showed an endocannabinoid increase at any intensity","methodology":"Researchers measured blood endocannabinoids before and after treadmill exercise in three species: humans, dogs (cursorial), and ferrets (non-cursorial). Each species completed low-intensity walking and higher-intensity running sessions, and pre-post blood levels were compared within species. The abstract does not report sample sizes or which endocannabinoids were assayed. This was a short, acute, within-session comparison without randomization or blinding, and no subjective mood or pain ratings were collected.","limitations":"Sample sizes, participant characteristics, and exact analytes are not reported in the abstract. Only circulating endocannabinoids were measured, not brain levels or receptor activity. No mood, pain, or reward ratings were collected, so any link to the runner's high is inferred. Acute, single-session design without randomization or blinding. Treadmill running and blood draws can induce stress that may alter endocannabinoid levels. Species differed in familiarity with treadmills and in natural locomotor patterns, which could confound intensity matching across groups."},{"rthcId":"RTHC-00609","title":"Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor.","authors":"Ribeiro, Alison; Ferraz-de-Paula, Viviane; Pinheiro, Milena L; Vitoretti, Luana B; Mariano-Souza, Domenica P; Quinteiro-Filho, Wanderley M; Akamine, Adriana T; Almeida, Vinícius I; Quevedo, João; Dal-Pizzol, Felipe; Hallak, Jaime E; Zuardi, Antônio W; Crippa, José A; Palermo-Neto, João","year":2012,"journal":"European journal of pharmacology, 678(1-3), 78-85","doi":"10.1016/j.ejphar.2011.12.043","pmid":"22265864","tags":["cbd","inflammation","respiratory"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers induced acute lung injury in mice using LPS (a bacterial toxin) and administered a single 20 mg/kg dose of CBD beforehand. CBD decreased neutrophil migration into the lungs, reduced protein leakage (indicating less tissue damage), lowered the enzyme myeloperoxidase (a marker of neutrophil activity), and reduced pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2).\n\nThese anti-inflammatory effects persisted at 1, 2, and 4 days after injury. Critically, when researchers blocked the adenosine A2A receptor with a selective antagonist, all of CBD's anti-inflammatory effects were abolished, confirming this receptor as the mechanism.","whyItMatters":"Acute lung injury is a serious inflammatory condition with no established pharmacological treatment beyond supportive care. This study identified CBD as a potent anti-inflammatory agent in this context and pinpointed the specific receptor mechanism, which could guide development of targeted treatments.","specificNumbers":"Single dose of 20 mg/kg CBD. Anti-inflammatory effects measured at days 1, 2, and 4 post-injury. CBD reduced neutrophils, albumin, myeloperoxidase, TNF, IL-6, MCP-1, and MIP-2. All effects abolished by adenosine A2A receptor antagonist.","methodology":"Mouse model of acute lung injury induced by LPS. CBD (20 mg/kg) was administered before injury. Outcomes measured included leukocyte migration, albumin concentration in bronchoalveolar lavage fluid, myeloperoxidase activity, and cytokine/chemokine levels. The adenosine A2A receptor antagonist ZM241385 was used to test the mechanism.","limitations":"This was a mouse study, and the LPS model of acute lung injury does not perfectly replicate the human condition. CBD was given before injury (pre-treatment), which differs from the clinical scenario where treatment begins after injury occurs. Dosing may not translate directly to human applications."},{"rthcId":"RTHC-00610","title":"Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus.","authors":"Rock, E M; Bolognini, D; Limebeer, C L; Cascio, M G; Anavi-Goffer, S; Fletcher, P J; Mechoulam, R; Pertwee, R G; Parker, L A","year":2012,"journal":"British journal of pharmacology, 165(8), 2620-34","doi":"10.1111/j.1476-5381.2011.01621.x","pmid":"21827451","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers demonstrated that CBD's anti-nausea and anti-vomiting effects depend on serotonin 5-HT1A receptors in a specific brain region called the dorsal raphe nucleus (DRN). When 5-HT1A receptor antagonists were administered either systemically or directly into the DRN, CBD's effects were completely blocked.\n\nCBD injected directly into the DRN suppressed nausea-like behavior, and this was reversed by a systemic 5-HT1A antagonist. In vitro studies confirmed that CBD enhanced the ability of 5-HT1A agonists to activate their receptors in brainstem tissue. Low doses of CBD and a 5-HT1A agonist worked synergistically when combined.","whyItMatters":"Nausea and vomiting are common side effects of chemotherapy and other treatments. Understanding exactly how CBD reduces these symptoms, through serotonin receptors in a specific brain region, could help develop more targeted anti-nausea medications and explain why CBD helps some patients with treatment-resistant nausea.","specificNumbers":"CBD suppressed vomiting induced by 3 different triggers (nicotine, lithium chloride, cisplatin at 20 mg/kg). CBD showed a bell-shaped dose-response curve in vitro. Synergistic anti-nausea effects were observed when CBD was combined with the 5-HT1A agonist 8-OH-DPAT.","methodology":"Multiple approaches: vomiting studies in shrews (Suncus murinus) using nicotine, lithium chloride, and cisplatin as triggers; nausea studies in rats using conditioned gaping; microinjection into the DRN; in vitro receptor binding studies with brainstem membranes. 5-HT1A antagonists (WAY100135, WAY100635) were used to test the mechanism.","limitations":"The study used animal models (shrews and rats), and anti-nausea effects in animals may not directly predict human response. The bell-shaped dose-response curve suggests dosing would need careful optimization. Conditioned gaping in rats is a validated but indirect measure of nausea."},{"rthcId":"RTHC-00611","title":"Alterations of theory of mind network activation in chronic cannabis users.","authors":"Roser, Patrik; Lissek, Silke; Tegenthoff, Martin; Nicolas, Volkmar; Juckel, Georg; Brüne, Martin","year":2012,"journal":"Schizophrenia research, 139(1-3), 19-26","doi":"10.1016/j.schres.2012.05.020","pmid":"22695256","tags":["cognition","psychosis","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Fifteen chronic cannabis users and 14 controls underwent brain imaging while performing a theory of mind task (interpreting cartoon stories that required understanding characters' intentions). Cannabis users showed less activation in the left parahippocampal gyrus, right precuneus, and right cuneus, but greater activation in the left cuneus and right anterior cingulate gyrus.\n\nThese activation patterns resembled those previously documented in populations at risk for developing psychosis, suggesting that cannabis use affects social cognitive processing in ways that parallel other psychosis risk factors.","whyItMatters":"Theory of mind, the ability to understand what others are thinking and feeling, is a core social cognitive skill that is impaired in schizophrenia. Finding that chronic cannabis users show similar brain activation abnormalities suggests cannabis may affect the neural circuits underlying social cognition.","specificNumbers":"15 cannabis users vs. 14 controls. Altered activation found in 5 brain regions: reduced in left parahippocampal gyrus, right precuneus, right cuneus; increased in left cuneus and right anterior cingulate gyrus.","methodology":"Functional brain imaging (fMRI) during performance of a cartoon story task requiring theory of mind. Fifteen chronic cannabis users were compared to 14 healthy controls. Brain activation patterns were analyzed for between-group differences.","limitations":"The sample was small (15 users, 14 controls), limiting statistical power. The cross-sectional design cannot determine whether cannabis use caused the brain changes or whether pre-existing differences led people to use cannabis. Other substances used by participants could have contributed to the findings."},{"rthcId":"RTHC-00612","title":"Psychopathologic differences between cannabis-induced psychoses and recent-onset primary psychoses with abuse of cannabis.","authors":"Rubio, Gabriel; Marín-Lozano, Jesús; Ferre, Francisco; Martínez-Gras, Isabel; Rodriguez-Jimenez, Roberto; Sanz, Javier; Jimenez-Arriero, Miguel Angel; Carrasco, José Luis; Lora, David; Jurado, Rosa; López-Trabada, José Ramón; Palomo, Tomás","year":2012,"journal":"Comprehensive psychiatry, 53(8), 1063-70","doi":"10.1016/j.comppsych.2012.04.013","pmid":"22682680","tags":["psychosis","depression","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 181 patients with psychotic symptoms and cannabis use, 50 were diagnosed with cannabis-induced psychotic disorder (CIPD) and 104 with primary psychotic disorders. Using statistical modeling, researchers identified that depression and \"misattribution\" scores together classified patients with 96.78% accuracy.\n\nInterpersonal sensitivity, depressive symptoms, phobic anxiety, and insight-related measures were the most useful clinical variables for distinguishing between the two conditions. Patients with cannabis-induced psychosis showed a more \"neurotic\" symptom profile compared to those with primary psychotic disorders.","whyItMatters":"Distinguishing cannabis-induced psychosis from primary psychotic disorders that happen to co-occur with cannabis use has direct treatment implications. Cannabis-induced psychosis may resolve with abstinence, while primary psychotic disorders typically require ongoing antipsychotic treatment. Accurate diagnosis prevents both under- and over-treatment.","specificNumbers":"181 patients studied: 50 with cannabis-induced psychosis, 104 with primary psychotic disorders. Depression + misattribution model achieved 96.78% classification accuracy (95% CI: 94.43-99.13%).","methodology":"Cross-sectional study of 181 patients with psychotic symptoms and cannabis use admitted to psychiatry units at three university hospitals. Diagnoses were made using structured clinical interviews. The Symptom Checklist-90-R and SUMD were used for psychopathological assessment. ROC curve analysis identified the most discriminating variables.","limitations":"The cross-sectional design captures a snapshot at hospital admission; some patients initially diagnosed with cannabis-induced psychosis may later develop primary psychotic disorders. The sample came from three university hospitals, which may see more severe cases. The high classification accuracy may not replicate in other settings."},{"rthcId":"RTHC-00613","title":"Cannabinoids: novel medicines for the treatment of Huntington's disease.","authors":"Sagredo, Onintza; Pazos, M Ruth; Valdeolivas, Sara; Fernandez-Ruiz, Javier","year":2012,"journal":"Recent patents on CNS drug discovery, 7(1), 41-8","doi":null,"pmid":"22280340","tags":["medical-cannabis","neuroscience","cbd","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review examined the potential of cannabinoids to treat Huntington's disease (HD), a genetic neurodegenerative condition affecting primarily the striatum and cortex. While cannabinoids were initially studied for their ability to suppress the involuntary movements (chorea) characteristic of HD, the more promising avenue was disease modification.\n\nPreclinical studies using various HD models showed that cannabinoid agonists, including the phytocannabinoids in Sativex (THC and CBD), had anti-inflammatory, neuroprotective, and neuroregenerative properties. The authors reported being close to initiating a clinical trial of Sativex as a disease-modifying agent in HD patients.","whyItMatters":"Huntington's disease has no disease-modifying treatment. Current therapies only manage symptoms. If cannabinoids can slow the neurodegeneration that drives HD progression, it would represent a major therapeutic advance for a condition that currently has no way to alter its devastating course.","specificNumbers":"HD is caused by excess CAG repeats in the huntingtin gene. Sativex contains a 1:1 THC/CBD ratio. Three cannabinoid medicines were already approved for other conditions. Multiple experimental HD models were used to demonstrate neuroprotective effects.","methodology":"Review of preclinical evidence from various experimental models of Huntington's disease, including assessment of different cannabinoid agonist types. Also reviewed approved cannabinoid medicines (Cesamet, Marinol, Sativex) and their potential applicability to HD.","limitations":"All disease-modifying evidence came from animal and cell models. The history of neurodegenerative disease research is filled with treatments that showed preclinical promise but failed in human trials. The planned Sativex trial had not yet begun at the time of publication."},{"rthcId":"RTHC-00614","title":"Cannabinoids and muscular pain. Effectiveness of the local administration in rat.","authors":"Sánchez Robles, E Ma; Bagües Arias, A; Martín Fontelles, Ma I","year":2012,"journal":"European journal of pain (London, England), 16(8), 1116-27","doi":null,"pmid":"22354705","tags":["pain","medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested cannabinoid agonists in two muscle pain models (masseter jaw muscle and gastrocnemius calf muscle) induced by hypertonic saline injection. In the masseter model, both systemic (intraperitoneal) and local (intramuscular) administration of CB1 and CB2 agonists reduced pain behavior.\n\nIn the gastrocnemius model, local intramuscular administration was more effective than systemic administration. Selective antagonists confirmed that both CB1 and CB2 receptors contributed to the pain-reducing effects, establishing that the analgesia was genuinely mediated through cannabinoid receptors.","whyItMatters":"Musculoskeletal pain is extremely common and often difficult to control. Current treatments have significant limitations. The finding that cannabinoids can be injected directly into the affected muscle, avoiding systemic side effects including psychoactive effects, opens a potential new treatment approach.","specificNumbers":"Three agonists tested: WIN 55,212-2 (non-selective), ACEA (CB1-selective), JWH 015 (CB2-selective). Two antagonists for verification: AM 251 (CB1), AM 630 (CB2). Two pain models: masseter and gastrocnemius. Local injection was superior to systemic in the gastrocnemius model.","methodology":"Rat models using hypertonic saline injection to induce pain in masseter and gastrocnemius muscles. Tested non-selective agonist WIN 55,212-2, selective CB1 agonist ACEA, and selective CB2 agonist JWH 015. Verified specificity with selective antagonists AM 251 (CB1) and AM 630 (CB2).","limitations":"This was an animal study using acute pain models that may not represent chronic musculoskeletal pain conditions in humans. The doses and administration routes may not translate directly to clinical use. Long-term effects of local cannabinoid injection were not assessed."},{"rthcId":"RTHC-00615","title":"A snapshot of workplace drug testing in Italy.","authors":"Santoro, Paolo Emilio; De Nardis, Isabella; Fronterrè, Pietrangelo; Felli, Marialinda; Martello, Simona; Bergamaschi, Antonio; Chiarotti, Marcello","year":2012,"journal":"Drug testing and analysis, 4(2), 66-70","doi":"10.1002/dta.417","pmid":"22362571","tags":["workplace"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Under Italian workplace safety law, workers in hazardous jobs must undergo mandatory drug testing. Researchers collected 551 urine samples from workers across 42 Italian companies. Only 16 samples (2.9%) screened positive on immunoassay, and just 4 (0.7%) were confirmed positive by LC-MS/MS.\n\nThe confirmed positives included cocaine (2 samples), cannabis (1 sample), and both cocaine and cannabis (1 sample). The authors noted that Italian law requires workers to be informed the day before testing, which likely contributed to the unexpectedly low positive rate.","whyItMatters":"The study highlights a fundamental tension in workplace drug testing: policies requiring advance notice may defeat the purpose of testing by allowing workers to abstain temporarily. For safety-sensitive positions, this raises questions about whether the testing program effectively identifies workers who may be impaired on the job.","specificNumbers":"551 samples from 42 companies. 16 screened positive (2.9%). 4 confirmed positive (0.7%). Confirmed substances: cocaine (2), cannabis (1), cocaine + cannabis (1). Workers notified one day before testing.","methodology":"Cross-sectional study collecting urine samples from workers in safety-sensitive positions across 42 companies from September 2009 to February 2011. Screening by immunoassay with confirmatory testing by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Samples tested for cannabis, opiates, amphetamines, methamphetamines, cocaine, methadone, and MDMA.","limitations":"The study cannot determine whether the low positive rate reflects genuinely low drug use or successful abstinence before known tests. The sample may not represent all Italian industries. The testing protocol only captures recent use, missing those who abstained in advance."},{"rthcId":"RTHC-00616","title":"Investigating the interaction between schizotypy, divergent thinking and cannabis use.","authors":"Schafer, Gráinne; Feilding, Amanda; Morgan, Celia J A; Agathangelou, Maria; Freeman, Tom P; Valerie Curran, H","year":2012,"journal":"Consciousness and cognition, 21(1), 292-8","doi":"10.1016/j.concog.2011.11.009","pmid":"22230356","tags":["cognition","psychosis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers tested 160 cannabis users on two separate days: once sober and once intoxicated. Participants were divided into high and low trait creativity groups. When intoxicated, those with low baseline creativity showed significant improvement in verbal fluency, a key measure of divergent thinking, reaching levels comparable to the high-creativity group.\n\nCannabis also increased psychosis-like symptoms (state schizotypy) in both groups, and the high-creativity group had significantly higher trait schizotypy overall. However, the creativity boost and the psychosis-like symptoms did not appear to be directly linked to each other.","whyItMatters":"The stereotype that cannabis enhances creativity has persisted for decades. This study provides nuanced evidence: cannabis may help less creative individuals generate more ideas, but it does not appear to boost creativity in those who are already highly creative. The simultaneous increase in psychosis-like symptoms adds an important caveat.","specificNumbers":"160 cannabis users tested. Low creatives (n=47) showed increased verbal fluency when intoxicated. High creatives (n=43) had higher trait schizotypy. Cannabis increased state psychosis-like symptoms in both groups.","methodology":"Within-subjects design testing 160 cannabis users on separate sober and intoxicated days. Participants smoked cannabis naturalistically (their own supply). State and trait measures of schizotypy and creativity were administered. Quartile splits compared those lowest (n=47) and highest (n=43) in trait creativity.","limitations":"Verbal fluency is only one component of creativity. Participants used their own cannabis with no standardized dosing. The naturalistic setting introduced variability in strain, potency, and consumption method. The study measured acute effects only and cannot address chronic impacts on creativity."},{"rthcId":"RTHC-00617","title":"Impact of an 18-month, NHS-based, treatment exposure for heroin dependence: results from the London Area Treat 2000 Study.","authors":"Schifano, Fabrizio; Martinotti, Giovanni; Cunniff, Anna; Reissner, Volker; Scherbaum, Norbert; Ghodse, Hamid","year":2012,"journal":"The American journal on addictions, 21(3), 268-73","doi":"10.1111/j.1521-0391.2012.00226.x","pmid":"22494230","tags":["addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 100 heroin-dependent people in London over 18 months of NHS treatment. Heroin use days in the prior month dropped significantly, as did cocaine, benzodiazepine, and polydrug use. Injecting behavior decreased, employment increased, money spent on drugs fell, criminal activity declined, and suicidal ideation decreased.\n\nHowever, cannabis and alcohol use remained stubbornly unchanged throughout the 18-month period. This is concerning because these substances can undermine recovery and contribute to their own health problems.","whyItMatters":"While the overall treatment results are encouraging, the persistence of cannabis and alcohol use raises a red flag. Treatment programs focused on heroin may inadvertently allow other substance use to continue or even increase, potentially compromising long-term recovery.","specificNumbers":"100 participants followed for 18 months. Significant reductions in heroin (p<.001), cocaine (p<.05), benzodiazepines (p<.001), and polydrug use (p<.001). No significant change in cannabis or alcohol use. Suicidal ideation decreased (p<.05).","methodology":"Longitudinal prospective cohort study with repeated measures at baseline (T0), 9 months (T1), and 18 months (T2). The CIDI was used for psychiatric evaluation, EuropASI for drug abuse assessment, WHO-DAS II for disability, and UCLA-SSI for social support. 100 heroin users were recruited.","limitations":"The sample of 100 participants is modest. There was no control group to determine whether improvements were due to treatment versus natural recovery. Attrition over 18 months may have biased results if those doing worst dropped out. The study was conducted in London and may not generalize to other healthcare systems."},{"rthcId":"RTHC-00618","title":"Differential effects of single versus repeated alcohol withdrawal on the expression of endocannabinoid system-related genes in the rat amygdala.","authors":"Serrano, Antonia; Rivera, Patricia; Pavon, Francisco J; Decara, Juan; Suárez, Juan; Rodriguez de Fonseca, Fernando; Parsons, Loren H","year":2012,"journal":"Alcoholism, clinical and experimental research, 36(6), 984-94","doi":"10.1111/j.1530-0277.2011.01686.x","pmid":"22141465","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers compared the effects of continuous versus intermittent alcohol exposure on endocannabinoid system genes in the rat amygdala. Both exposure patterns reduced expression of FAAH and MAGL (enzymes that break down endocannabinoids) and cannabinoid receptor genes (CB1, CB2, GPR55) during withdrawal.\n\nCritically, the intermittent exposure group, which experienced repeated withdrawal cycles, showed more pronounced changes in MAGL and receptor expression than the continuous exposure group. Changes were generally worse at 24 hours of withdrawal compared to 6 hours. The enzymes involved in making 2-AG were not affected.","whyItMatters":"The amygdala controls fear, anxiety, and emotional responses. Dysregulated endocannabinoid signaling in this region during alcohol withdrawal could explain the intense anxiety and emotional disturbance that characterize withdrawal. The finding that repeated withdrawal worsens these changes supports the clinical observation that each withdrawal episode becomes harder.","specificNumbers":"Continuous group: 15 days of ethanol. Intermittent group: 5 d/wk for 3 weeks. Withdrawal assessed at 6 and 24 hours. Reductions found in FAAH, MAGL, CB1, CB2, and GPR55 mRNA. No changes in DAGL-alpha/beta (2-AG synthesis enzymes).","methodology":"Rats were maintained on either continuous (15 days) or intermittent (5 days/week for 3 weeks) 10% ethanol liquid diet. Controls received isocaloric ethanol-free diet. Amygdala tissue was harvested at 6 or 24 hours after ethanol withdrawal. Quantitative RT-PCR measured mRNA expression for endocannabinoid system components.","limitations":"Animal study results may not directly translate to human alcohol withdrawal. Gene expression (mRNA) does not always predict actual protein levels or functional activity. The study examined two specific timepoints and may have missed important dynamics at other withdrawal stages."},{"rthcId":"RTHC-00619","title":"Cannabinoid hyperemesis: A case series of 98 patients","authors":"Simonetto, Douglas A.; Oxentenko, Amy S.; Herman, Mark L.; Szostek, Jason H.","year":2012,"journal":"Mayo Clinic Proceedings, 87(2), 114-119","doi":"10.1016/j.mayocp.2011.10.005","pmid":"22305024","tags":["youth","addiction","quitting"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Across 98 patients under age 50 with recurrent vomiting and prior cannabis exposure, the pattern was consistent. Among those with duration data, over two-thirds reported using cannabis for more than two years before symptoms began. Among those with frequency data, nearly all used more than once per week. Abdominal pain was reported by 86 percent of the cohort.\n\nHot water exposure stood out. Of 57 patients with bathing behavior recorded, 91 percent said hot showers or baths relieved symptoms. That odd but recurring detail helped crystallize a clinical picture that had been emerging in scattered case reports.\n\nFollow-up was sparse. Only 10 patients had outcome data after the initial visit. Of those 10, seven reported stopping cannabis and six of those seven reported complete resolution of symptoms. With such a small and selective subset, that association should be interpreted cautiously.\n\nBased on these descriptive data, the authors proposed major and supportive diagnostic criteria for cannabinoid hyperemesis, aiming to standardize how it is identified.","whyItMatters":"By 2012, clinicians were seeing patients with cyclic vomiting, abdominal pain, and a peculiar report that hot showers gave relief. Individual case reports were accumulating, but a larger, structured series had been missing. This study gathered nearly 100 such patients into one dataset, described the shared features, and outlined criteria that many clinicians began using to recognize cannabinoid hyperemesis in practice.","specificNumbers":"- Cohort yield: 98 of 1,571 screened records (6 percent) met case definition\n- Age: all patients were younger than 50 years\n- Long-term exposure: 25 of 37 with duration data used cannabis more than 2 years before symptom onset (68 percent)\n- Frequent use: 71 of 75 with frequency data used more than once weekly (95 percent)","methodology":"Retrospective case series from a single academic center. Electronic medical records from January 1, 2005 to June 15, 2010 were screened. Inclusion required recurrent vomiting without another identified cause and cannabis use preceding symptom onset. Of 1,571 records initially identified, 98 patients met inclusion criteria. Symptom features, cannabis exposure history, and bathing behavior were abstracted when documented. Follow-up information was available for only 10 patients. No control group and no standardized toxicology confirmation were reported in the abstract.","limitations":"Single-center retrospective design with no control group. Case identification relied on chart documentation and clinician judgment, which introduces selection and misclassification risk. Key exposure variables were missing for many patients, including exact duration, dose, product type, and potency. Hot bathing behavior was only documented for a subset. Only 10 percent had follow-up data, and cessation was self-reported without objective verification. The series included only patients under 50, limiting generalizability to older adults."},{"rthcId":"RTHC-00620","title":"Endocannabinoids in nervous system health and disease: the big picture in a nutshell.","authors":"Skaper, Stephen D; Di Marzo, Vincenzo","year":2012,"journal":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367(1607), 3193-200","doi":"10.1098/rstb.2012.0313","pmid":"23108539","tags":["neuroscience","pain","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review provided a broad overview of the endocannabinoid system (ECS), describing how its two main signaling molecules, anandamide and 2-AG, regulate brain function through cannabinoid receptors. The ECS was characterized as fundamentally involved in stress recovery and homeostatic balance.\n\nKey functions included neuroprotection (defending neurons from damage), pain modulation, motor activity regulation, neurogenesis (birth of new neurons), synaptic plasticity (the basis of learning and memory), and immune/inflammatory control. The review served as an introduction to a themed journal issue exploring these functions in depth.","whyItMatters":"Understanding the endocannabinoid system's breadth of influence helps explain both why cannabis has such diverse effects and why the system represents such a promising therapeutic target. Nearly every major brain function has some endocannabinoid involvement.","specificNumbers":"THC was first isolated in 1964. At least 70 phytocannabinoid compounds identified in cannabis. Two primary endocannabinoids: anandamide and 2-AG. The ECS is involved in at least 7 major brain functions.","methodology":"Editorial overview introducing a themed journal issue on cannabinoids in biology and medicine. Synthesized the state of knowledge across multiple research domains related to the endocannabinoid system.","limitations":"As an overview editorial, it did not provide detailed critical analysis of individual claims. The therapeutic applications discussed were at varying stages of evidence, from well-established to highly speculative."},{"rthcId":"RTHC-00621","title":"Negative attributions towards people with substance use disorders in South Africa: variation across substances and by gender.","authors":"Sorsdahl, Katherine; Stein, Dan J; Myers, Bronwyn","year":2012,"journal":"BMC psychiatry, 12, 101","doi":"10.1186/1471-244X-12-101","pmid":"22871303","tags":["mental-health","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers presented 868 people with vignettes describing substance use involving alcohol, cannabis, methamphetamine, or heroin. Respondents held equally negative views across substances, with one notable exception: cannabis users were rated as significantly less dangerous than alcohol users.\n\nGender influenced responses: people were more likely to offer help to women who used alcohol but more likely to suggest forced treatment for men. Respondents who scored higher on their own substance use measures held more negative attitudes toward substance users. Black African respondents were more likely to offer help.","whyItMatters":"Stigma is a major barrier to seeking treatment for substance use disorders. Understanding how stigma varies by substance type, user gender, and cultural context helps design more effective anti-stigma campaigns and treatment outreach.","specificNumbers":"868 respondents surveyed. 8 vignettes across 4 substances and 2 genders. Cannabis rated significantly less dangerous than alcohol. People with higher own substance use scores held more negative attitudes toward other users.","methodology":"Street-intercept convenience sample of 868 South African adults. Each respondent received one of 8 vignettes varying by substance (alcohol, cannabis, methamphetamine, heroin) and protagonist gender. Attitudes were measured using standardized attribution scales. The ASSIST measured respondents' own substance use.","limitations":"Convenience sampling via street intercept is not representative of the broader South African population. Vignette-based responses may not predict actual behavior toward substance users. The study was conducted in one country with a specific cultural context around substance use."},{"rthcId":"RTHC-00622","title":"Association of herbal cannabis use with negative psychosocial parameters in patients with fibromyalgia.","authors":"Ste-Marie, Peter A; Fitzcharles, Mary-Ann; Gamsa, Ann; Ware, Mark A; Shir, Yoram","year":2012,"journal":"Arthritis care & research, 64(8), 1202-8","doi":"10.1002/acr.21732","pmid":"22730275","tags":["pain","medical-cannabis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 457 patients referred to a tertiary pain center with a fibromyalgia diagnosis. Thirteen percent used cannabinoids, with 80% of those using herbal cannabis (marijuana) and 24% using prescription cannabinoids.\n\nHerbal cannabis use was associated with current unstable mental illness (36% vs. 23%), opioid drug-seeking behavior (17% vs. 4%), and male sex (26% of men vs. 7% of women used cannabis). There was a trend toward cannabis users being unemployed and receiving disability payments. When the analysis was restricted to patients with validated FM diagnoses, the statistical significance was lost but the trends remained.","whyItMatters":"While many pain patients advocate for cannabis as treatment, this study raises questions about whether self-medication with herbal cannabis in fibromyalgia is genuinely therapeutic or whether it reflects other vulnerabilities. The associations with mental illness and drug-seeking behavior suggest some patients may be using cannabis for reasons beyond pain relief.","specificNumbers":"457 patients surveyed. 13% used cannabinoids. 80% of users chose herbal cannabis. Unstable mental illness: 36% of cannabis users vs. 23% of non-users (p=0.002). Opioid drug-seeking: 17% vs. 4% (p=0.002). Male sex: 26% vs. 7% (p=0.0002). One-third of all male patients used cannabinoids.","methodology":"Cross-sectional study of 457 patients referred with FM diagnosis to a tertiary care pain center. FM diagnosis was validated in 302 patients. Associations between cannabinoid use and psychosocial variables were examined. Self-reported prevalence of cannabinoid use was documented.","limitations":"Cross-sectional design cannot determine whether mental health problems and drug-seeking behavior caused cannabis use or resulted from it. Tertiary care patients represent the most complex cases and may not reflect the broader FM population. The validated FM subgroup was too small to maintain statistical significance."},{"rthcId":"RTHC-00623","title":"Examining the effects of former cannabis use on cerebellum-dependent eyeblink conditioning in humans.","authors":"Steinmetz, Adam B; Edwards, Chad R; Vollmer, Jennifer M; Erickson, Molly A; O'Donnell, Brian F; Hetrick, William P; Skosnik, Patrick D","year":2012,"journal":"Psychopharmacology, 221(1), 133-41","doi":"10.1007/s00213-011-2556-1","pmid":"22134474","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared three groups of 10 participants each on an eyeblink conditioning task that depends on the cerebellum. Current cannabis users showed significant impairments in both learning the association (CS-US pairing) and timing their conditioned responses.\n\nFormer cannabis users showed normal learning of the association, suggesting recovery. However, they still exhibited significantly shorter response latencies, meaning their timing was off. This indicates that while the ability to form associations recovers after quitting, the cerebellum's timing functions may sustain lasting changes.","whyItMatters":"The cerebellum is critical for precise motor timing, coordination, and certain types of learning. This study suggests that heavy cannabis use can cause lasting changes to cerebellar function that persist even after stopping use, although the overall learning capacity does recover.","specificNumbers":"10 participants per group. Current users showed impaired acquisition and timing. Former users showed normal acquisition but impaired (shorter) CR latencies. Unconditioned response amplitudes were normal in all groups, ruling out motor or sensory explanations.","methodology":"Cross-sectional comparison of former cannabis users (n=10), current cannabis users (n=10), and cannabis-naive controls (n=10). All were free of DSM-IV Axis I or II disorders. A standard delay eyeblink conditioning procedure was used with paired tone and airpuff stimuli.","limitations":"Very small sample sizes (10 per group) severely limit statistical power and generalizability. The cross-sectional design means pre-existing differences could explain the findings. Duration of abstinence in former users varied and may have influenced results. The task tests only one cerebellar function."},{"rthcId":"RTHC-00624","title":"Early substance use initiation and suicide ideation and attempts among students in France and the United States.","authors":"Swahn, Monica H; Bossarte, Robert M; Choquet, Marie; Hassler, Christine; Falissard, Bruno; Chau, Nearkasen","year":2012,"journal":"International journal of public health, 57(1), 95-105","doi":"10.1007/s00038-011-0255-7","pmid":"21523616","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from over 28,000 students across France and the United States. In France, early cannabis use initiation was associated with a 2.9-fold increased odds of suicide attempt after controlling for confounders. Early alcohol initiation (1.5-fold) and early smoking (1.9-fold) were also associated with suicide attempts in France.\n\nIn the United States, only early smoking was significantly associated with suicide attempts (1.5-fold). The different patterns between countries suggest that cultural and social factors modify how early substance use relates to suicidal behavior.","whyItMatters":"Early substance use and suicidal behavior are both critical public health concerns for young people. Understanding which substances carry the strongest associations with suicidality, and how these patterns differ across cultures, can inform targeted prevention strategies.","specificNumbers":"13,187 French students and 15,136 US students analyzed. Early cannabis use in France: OR=2.90 (95% CI 2.20-3.83) for suicide attempt. Early smoking in France: OR=1.92. Early alcohol in France: OR=1.52. Early smoking in US: OR=1.53. Sex differences were noted.","methodology":"Cross-sectional logistic regression using the 2003 ESPAD survey in France (n=13,187) and the 2003 YRBS in the United States (n=15,136). Early initiation was defined for alcohol, cigarettes, and cannabis. Suicide ideation and attempts were assessed. Analyses controlled for potential confounders including demographics and other risk factors.","limitations":"Cross-sectional design cannot establish whether early substance use causes suicidal behavior or whether both share common risk factors. Different survey instruments in the two countries limit direct comparison. Self-reported data on sensitive topics may be affected by underreporting."},{"rthcId":"RTHC-00625","title":"Does the \"gateway\" sequence increase prediction of cannabis use disorder development beyond deviant socialization? Implications for prevention practice and policy.","authors":"Tarter, Ralph E; Kirisci, Levent; Mezzich, Ada; Ridenour, Ty; Fishbein, Diana; Horner, Michelle; Reynolds, Maureen; Kirillova, Galina; Vanyukov, Michael","year":2012,"journal":"Drug and alcohol dependence, 123 Suppl 1, S72-8","doi":"10.1016/j.drugalcdep.2012.01.015","pmid":"22365896","tags":["addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed sons of fathers with and without substance use disorders from ages 10-12 through age 22. They tested whether the \"gateway\" hypothesis, that using legal drugs before cannabis matters, predicted cannabis use disorder development.\n\nThe key finding: non-normative socialization (association with deviant peers) mediated the link between childhood risk and later cannabis use disorder. Whether someone used legal drugs before or after trying cannabis did not improve prediction of who would develop problems. The order of drug use initiation was not a meaningful factor.","whyItMatters":"The \"gateway drug\" theory has been a cornerstone of anti-drug policy for decades, arguing that cannabis use leads to harder drugs partly because legal substances came first. This study directly challenges that framework, suggesting that who you spend time with matters more than what you tried first.","specificNumbers":"Tracked from age 10-12 to 22. Path analysis showed peer deviance mediated the childhood risk to cannabis disorder pathway. Adding the gateway sequence to the model did not improve prediction.","methodology":"Longitudinal prospective study tracking boys from age 10-12 to 22 years. Participants were sons of fathers with or without illicit drug SUDs. Path analysis was used to model relationships among transmissible risk, peer deviance (socialization), order of drug initiation, and cannabis use disorder development.","limitations":"The sample included only males, limiting generalizability to females. Participants were selected based on paternal substance use history, which may not represent the general population. The gateway concept was tested in a specific way (prediction of cannabis disorder) and may have relevance for other outcomes not tested here."},{"rthcId":"RTHC-00626","title":"Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability.","authors":"Tomasiewicz, Hilarie C; Jacobs, Michelle M; Wilkinson, Matthew B; Wilson, Steven P; Nestler, Eric J; Hurd, Yasmin L","year":2012,"journal":"Biological psychiatry, 72(10), 803-10","doi":"10.1016/j.biopsych.2012.04.026","pmid":"22683090","tags":["addiction","youth","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers demonstrated a direct causal chain linking adolescent THC exposure to adult heroin vulnerability. THC exposure during adolescence increased expression of the proenkephalin (Penk) gene in the nucleus accumbens shell, a brain region central to reward and motivation.\n\nWhen researchers selectively reduced Penk expression in THC-exposed rats, heroin self-administration decreased. Conversely, overexpressing Penk in THC-naive rats increased heroin self-administration. The mechanism involved epigenetic changes: THC reduced a specific histone modification (H3K9 methylation) that normally silences the Penk gene during development.","whyItMatters":"This is one of the first studies to establish a complete mechanistic chain from adolescent cannabis exposure through specific gene regulation changes to increased vulnerability to opioid self-administration. The epigenetic mechanism suggests THC does not just temporarily alter brain chemistry but changes how genes are regulated long-term.","specificNumbers":"THC reduced H3K9 methylation at the Penk gene. Penk knockdown reduced heroin self-administration in THC-exposed rats. Penk overexpression increased heroin self-administration in THC-naive rats. Changes occurred specifically in the nucleus accumbens shell.","methodology":"Viral-mediated gene manipulation (knockdown and overexpression) of Penk in the nucleus accumbens shell, combined with heroin self-administration behavioral testing. Chromatin immunoprecipitation analyzed histone modifications at five sites flanking the Penk gene. Adolescent rats received THC exposure during a developmental window.","limitations":"This was an animal study with THC doses and administration routes that differ from human cannabis use. Rats were given pure THC, not whole cannabis. The specific developmental timing in rats may not directly map onto human adolescence. The nucleus accumbens shell was studied in isolation from the broader reward circuit."},{"rthcId":"RTHC-00627","title":"Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington's disease: role of CB1 and CB2 receptors.","authors":"Valdeolivas, Sara; Satta, Valentina; Pertwee, Roger G; Fernández-Ruiz, Javier; Sagredo, Onintza","year":2012,"journal":"ACS chemical neuroscience, 3(5), 400-6","doi":"10.1021/cn200114w","pmid":"22860209","tags":["medical-cannabis","neuroscience","cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested a 1:1 combination of THC-rich and CBD-rich botanical extracts (mimicking Sativex) in rats with striatal lesions created by the toxin malonate, which models the inflammatory component of Huntington's disease.\n\nThe phytocannabinoid combination reduced edema measured by MRI, reversed the loss of healthy neurons and the increase in degenerating cells, attenuated reactive microglia and astrogliosis (markers of brain inflammation), and reduced inducible nitric oxide synthase and IGF-1 expression. Using selective receptor antagonists, the researchers confirmed that both CB1 and CB2 receptors were required for these protective effects.","whyItMatters":"Huntington's disease has no treatment that slows neurodegeneration. This study demonstrated neuroprotective effects of a cannabis-based medicine already approved for other conditions, using multiple objective measures of brain cell health and inflammation.","specificNumbers":"Sativex-like combination: 1:1 THC/CBD botanical extracts. Reduced edema (NMR imaging), reversed neuron loss (Nissl staining), reduced degenerating cells (FluoroJade-B), attenuated microglia (Iba-1) and astrogliosis (GFAP). Both CB1 and CB2 receptors required.","methodology":"Rat model of HD using unilateral striatal lesions with malonate (a mitochondrial complex II inhibitor). The Sativex-like combination was administered and compared to vehicle. Multiple histological and biochemical markers were assessed. CB1 antagonist SR141716 and CB2 antagonist AM630 were used to determine receptor involvement.","limitations":"The malonate model replicates some but not all features of human HD. The acute toxin-induced lesion differs from the progressive genetic neurodegeneration of actual HD. Doses and timing may not translate to human treatment. The combination of botanical extracts contains trace amounts of other cannabinoids that could contribute to effects."},{"rthcId":"RTHC-00628","title":"Evidence-based pharmacological treatment of substance use disorders and pathological gambling.","authors":"van den Brink, Wim","year":2012,"journal":"Current drug abuse reviews, 5(1), 3-31","doi":null,"pmid":"22126708","tags":["addiction","harm-reduction"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review evaluated the evidence base for pharmacological treatments across multiple substance use disorders. First-line medications were available for smoking cessation (nicotine replacement, bupropion, varenicline), alcohol dependence (naltrexone, acamprosate, disulfiram), opioid dependence (methadone, buprenorphine), and pathological gambling (opioid antagonists).\n\nFor cannabis and cocaine dependence, no pharmacological treatments had demonstrated sufficient evidence for approval, though multiple compounds were being tested. The review also discussed strategies to improve existing treatments: combining medications, adding psychotherapy, and better matching patients to treatments.","whyItMatters":"This review highlighted a significant treatment gap: while effective medications exist for nicotine, alcohol, and opioid dependence, cannabis and cocaine dependence lacked approved pharmacological options, leaving clinicians relying primarily on behavioral interventions for these conditions.","specificNumbers":"Effective medications identified for 4 of 6 conditions reviewed. Cannabis and cocaine dependence had no approved pharmacological treatments. Multiple compounds were in testing for both. Strategies to improve existing treatments included polypharmacy and psychotherapy combination.","methodology":"Systematic review of evidence primarily from randomized controlled trials and meta-analyses. Covered first and second-line pharmacological treatments for nicotine, alcohol, opioid, cocaine, and cannabis dependence plus pathological gambling.","limitations":"Reviews of pharmacological treatments may not fully capture the role of behavioral interventions, which are often the primary treatment for cannabis dependence. The landscape of available treatments changes as new trials are completed. The review focused on first and second-line treatments, potentially overlooking emerging options."},{"rthcId":"RTHC-00629","title":"The CB(1) receptor antagonist, AM281, improves recognition loss induced by naloxone in morphine withdrawal mice.","authors":"Vaseghi, Golnaz; Rabbani, Mohammed; Hajhashemi, Valiollah","year":2012,"journal":"Basic & clinical pharmacology & toxicology, 111(3), 161-5","doi":"10.1111/j.1742-7843.2012.00881.x","pmid":"22429707","tags":["neuroscience","cognition","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice made dependent on morphine showed significant memory impairment during naloxone-precipitated withdrawal, measured by an object recognition task. The cannabinoid receptor antagonist AM281 improved these memory deficits.\n\nChronic administration of AM281 at 2.5 mg/kg was more effective than a single acute dose at 5 mg/kg. The recognition index improved from -3.1% (essentially no memory) in withdrawal animals to 36.0% with chronic AM281 treatment. Giving AM281 alongside morphine during the dependence period was more protective than administering it only during withdrawal.","whyItMatters":"Cognitive impairment during opioid withdrawal is a significant clinical problem that can impair decision-making and participation in treatment. Identifying the endocannabinoid system as a contributor opens a potential therapeutic avenue for managing withdrawal-related cognitive deficits.","specificNumbers":"Chronic AM281 (2.5 mg/kg): recognition index improved from -3.1% to 36.0%. Acute AM281 (5 mg/kg): improved from -1.5% to 18.5%. Concurrent AM281 + morphine administration was more effective than acute AM281 during withdrawal alone.","methodology":"Male mice were made morphine-dependent with escalating doses (30-90 mg/kg) over 3 days. Withdrawal was precipitated with naloxone. Object recognition testing measured memory by comparing exploration of novel versus familiar objects. AM281 was administered either chronically or acutely.","limitations":"This was a mouse study with a specific withdrawal model that may not fully replicate human opioid withdrawal. The object recognition task tests only one type of memory. AM281 is a research tool, not an approved medication. The small sample and specific paradigm limit generalizability."},{"rthcId":"RTHC-00630","title":"Delay- and dose-dependent effects of Δ⁹-tetrahydrocannabinol administration on spatial and object working memory tasks in adolescent rhesus monkeys.","authors":"Verrico, Christopher D; Liu, Shijing; Bitler, Elizabeth J; Gu, Hong; Sampson, Allan R; Bradberry, Charles W; Lewis, David A","year":2012,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 37(6), 1357-66","doi":"10.1038/npp.2011.321","pmid":"22218091","tags":["cognition","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent rhesus monkeys received a range of THC doses (30-240 mcg/kg) intravenously while performing spatial and object working memory tasks. Spatial working memory accuracy decreased with higher doses and longer delay periods, showing a clear dose-response relationship.\n\nIn contrast, object working memory was not significantly affected by any THC dose. The spatial memory deficits were not due to motor or motivational impairments, as performance on control measures remained normal. This selective vulnerability suggests that different types of working memory mature at different rates, and the less mature function (spatial WM) is more susceptible to THC.","whyItMatters":"Adolescent cannabis use is common and increasing. This primate study, which more closely models human brain development than rodent studies, shows that immature cognitive functions are selectively vulnerable to THC. Spatial working memory, which matures later than object working memory, was specifically impaired.","specificNumbers":"Doses tested: 30-240 mcg/kg IV. Spatial WM: dose- and delay-dependent impairment. Object WM: no impairment at any dose. Motor and motivational measures: unaffected.","methodology":"Adolescent rhesus monkeys performed standardized spatial and object working memory tasks after receiving intravenous THC at doses of 0, 30, 60, 120, or 240 mcg/kg. Performance was measured as accuracy at different delay intervals. Control measures assessed motor and motivational function.","limitations":"Intravenous THC administration differs from typical human cannabis use (smoked or ingested). Pure THC was used rather than whole cannabis. The acute dosing protocol does not model chronic adolescent cannabis use. Small sample sizes are typical of primate studies but limit statistical power."},{"rthcId":"RTHC-00631","title":"No association of candidate genes with cannabis use in a large sample of Australian twin families.","authors":"Verweij, Karin J H; Zietsch, Brendan P; Liu, Jimmy Z; Medland, Sarah E; Lynskey, Michael T; Madden, Pamela A F; Agrawal, Arpana; Montgomery, Grant W; Heath, Andrew C; Martin, Nicholas G","year":2012,"journal":"Addiction biology, 17(3), 687-90","doi":"10.1111/j.1369-1600.2011.00320.x","pmid":"21507154","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used a large Australian twin family sample to test whether 10 genes previously reported to be associated with cannabis use actually replicated. Using a gene-based association test (which is more powerful than single-variant tests), none of the candidate genes reached even the most lenient significance threshold (p<0.05).\n\nThe authors concluded that the failure to replicate likely reflects limited understanding of cannabis neurobiology, potential publication bias in earlier studies, and the likelihood of false-positive findings in the original reports.","whyItMatters":"While cannabis use is clearly heritable (twin studies show this consistently), identifying the specific genes involved has proven extremely difficult. This large non-replication study serves as a cautionary example about the reliability of candidate gene findings in psychiatric genetics.","specificNumbers":"7,452 participants. 10 candidate genes tested. None reached p<0.05. This is consistent with the broader \"replication crisis\" in candidate gene studies for behavioral traits.","methodology":"Gene-based association testing in 7,452 participants from an Australian twin family sample. Tested 10 candidate genes previously reported as associated with lifetime frequency of cannabis use. The gene-based approach aggregates signal across all variants within each gene, providing more power than single-SNP tests.","limitations":"The study tested lifetime frequency of cannabis use, not cannabis dependence, which may have different genetic architecture. The Australian sample may differ genetically from the populations in which the original associations were found. Gene-based tests, while more powerful for some signals, may miss specific variants."},{"rthcId":"RTHC-00632","title":"Detection of drugs of abuse in simultaneously collected oral fluid, urine and blood from Norwegian drug drivers.","authors":"Vindenes, V; Lund, H M E; Andresen, W; Gjerde, H; Ikdahl, S E; Christophersen, A S; Øiestad, E L","year":2012,"journal":"Forensic science international, 219(1-3), 165-71","doi":"10.1016/j.forsciint.2012.01.001","pmid":"22284072","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers collected blood, urine, and oral fluid simultaneously from 100 suspected drug drivers in Norway. All drug groups detected in blood were also found in oral fluid. For cannabis, THC was detected in oral fluid and THC-COOH in urine. In 34 of 46 cannabis-positive cases, both oral fluid and urine confirmed use.\n\nOral fluid had advantages over urine: faster collection, less intrusive, and for opiates, the interpretation was actually more conclusive (heroin markers were more frequently detected). Cannabis was confirmed in only urine in 11 cases and only oral fluid in 1 case, suggesting urine has a longer detection window for cannabis.","whyItMatters":"Roadside drug testing is critical for traffic safety. Oral fluid collection is faster and less intrusive than urine, potentially improving law enforcement efficiency. The finding that it detects all relevant drug groups makes it a viable alternative for driving-under-the-influence cases.","specificNumbers":"100 drivers tested. Cannabis confirmed in 46 total cases: 34 positive in both oral fluid and urine, 11 in urine only, 1 in oral fluid only. Cocaine and heroin markers (6-MAM) were more frequently detected in oral fluid than urine.","methodology":"Cross-sectional study of 100 drivers suspected of drug-impaired driving in Norway. Blood, urine, and oral fluid collected simultaneously. Oral fluid and blood screened by LC-MS/MS. Urine screened by immunoassay with chromatographic confirmation. 25 commonly abused drugs and metabolites were included.","limitations":"The study included only 100 subjects, all pre-selected as suspected drug drivers. The oral fluid method included only 25 substances, potentially missing others. The longer detection window of urine for cannabis means oral fluid testing may miss some recent users. Cut-off values affect detection rates."},{"rthcId":"RTHC-00633","title":"Decline in genetic influence on the co-occurrence of alcohol, marijuana, and nicotine dependence symptoms from age 14 to 29.","authors":"Vrieze, Scott I; Hicks, Brian M; Iacono, William G; McGue, Matt","year":2012,"journal":"The American journal of psychiatry, 169(10), 1073-81","doi":null,"pmid":"22983309","tags":["addiction","genetics","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers followed twins from age 11 through 29, measuring nicotine, alcohol, and marijuana dependence symptoms at six timepoints. During adolescence (ages 14-17), the co-occurrence of symptoms across all three substances was strongly driven by a common genetic factor. This means that adolescent substance problems tend to be generalized rather than substance-specific.\n\nAs participants aged into their 20s, the influence of this shared genetic factor declined substantially. By age 24-29, substance dependence symptoms were increasingly driven by substance-specific factors, particularly nonshared environmental influences. Substance use became more specialized and less governed by a general vulnerability.","whyItMatters":"This study explains why adolescent substance use tends to be general (teens who use one substance often use others) while adult substance use becomes more specialized. The shift from shared genetic risk to specific environmental influences has direct implications for when and how to intervene.","specificNumbers":"3,762 twins assessed at 6 timepoints (ages 11-29). Substance symptoms peaked around age 20 and declined by age 29. Shared genetic influence was highest at ages 14-17 and declined from 17 to 24. Environmental influences increased with age.","methodology":"Community-representative twin sample (N=3,762) assessed at ages 11, 14, 17, 20, 24, and 29. Nicotine, alcohol, and marijuana abuse/dependence symptom counts were modeled using a single common factor at each age. Changes in factor loadings and genetic/environmental contributions were tested across timepoints.","limitations":"The community-representative sample may underrepresent individuals with severe substance use disorders who are difficult to retain in long-term studies. Symptom counts may not capture the full clinical picture of dependence. The twin modeling approach makes assumptions about equal environments for identical and fraternal twins."},{"rthcId":"RTHC-00634","title":"Evaluation of the safety and tolerability profile of Sativex: is it reassuring enough?","authors":"Wade, Derick","year":2012,"journal":"Expert review of neurotherapeutics, 12(4 Suppl), 9-14","doi":"10.1586/ern.12.12","pmid":"22509986","tags":["medical-cannabis","addiction","tolerance"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The reviewer evaluated published data on Sativex safety across several concern areas. Adverse effects occurred relatively frequently but were usually mild to moderate and rarely required stopping the medication. No dose escalation was observed in clinical trials or practice after the initial titration period.\n\nWhen patients stopped using Sativex, symptoms often returned (confirming therapeutic effect), but no evidence of physiological or psychological dependence was observed. Sudden cessation was generally safe. Benefits observed initially were maintained during long-term treatment, arguing against tolerance development.","whyItMatters":"One of the biggest concerns about any cannabis-based medicine is the potential for dependence and abuse. This review addressed those concerns directly, finding that Sativex in the MS spasticity context did not produce the dependence patterns associated with recreational cannabis use.","specificNumbers":"Initial pilot study from 2004. Long-term treatment maintained benefits. No dose escalation after initial titration. Adverse effects usually mild to moderate. No evidence of physiological or psychological dependence upon withdrawal.","methodology":"Narrative review of published clinical trial data, long-term follow-up studies, and clinical practice experience from the Oxford Centre for Enablement. Evaluated tolerability, psychoactivity, withdrawal effects, tolerance, and abuse potential.","limitations":"The review came primarily from one research center's experience, which may not represent all clinical settings. Patients in clinical trials are monitored more closely than typical patients. The MS patient population may not be representative of how the drug would behave in other populations."},{"rthcId":"RTHC-00635","title":"Cannabinoid receptor 1-expressing neurons in the nucleus accumbens.","authors":"Winters, Bradley D; Krüger, Juliane M; Huang, Xiaojie; Gallaher, Zachary R; Ishikawa, Masago; Czaja, Krzysztof; Krueger, James M; Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan","year":2012,"journal":"Proceedings of the National Academy of Sciences of the United States of America, 109(40), E2717-25","doi":"10.1073/pnas.1206303109","pmid":"23012412","tags":["neuroscience","addiction","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using genetically modified mice with fluorescent tagging of CB1-expressing neurons, researchers made several discoveries about these cells in the nucleus accumbens (NAc). All CB1-expressing neurons were fast-spiking interneurons (FSIs), a specific type of inhibitory neuron. These FSIs were electrically coupled to each other, forming a network that could synchronize neural activity.\n\nCritically, after cocaine withdrawal, these CB1-expressing FSIs became hyperexcitable, meaning they fired more readily. Since FSIs inhibit the main output neurons (medium spiny neurons) of the NAc, increased FSI activity would reduce NAc output, potentially contributing to the low motivation and anhedonia characteristic of drug withdrawal.","whyItMatters":"The nucleus accumbens is the brain's key reward center. Understanding that cannabinoid-receptor neurons in this area are specifically fast-spiking interneurons that can shut down reward circuit output provides a new understanding of how the endocannabinoid system regulates motivation, reward, and the withdrawal state.","specificNumbers":"CB1-expressing NAc neurons were exclusively FSIs. FSIs were electrically coupled to each other. FSIs provided feed-forward inhibition of MSNs. FSI excitability increased after cocaine withdrawal.","methodology":"Generated a knock-in mouse line expressing td-Tomato fluorescent protein in CB1-positive neurons. Used electrophysiology to characterize cell types, electrical coupling, and synaptic connections. Measured changes in membrane excitability following cocaine exposure and withdrawal.","limitations":"The study was conducted in mice using cocaine, not cannabis, as the drug of abuse. Results from genetically modified mouse lines may not perfectly reflect natural neuron function. The in vitro electrophysiology may not fully capture in vivo dynamics. The specific relevance to cannabis use was not directly tested."},{"rthcId":"RTHC-00636","title":"Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.","authors":"Wiskerke, Joost; Irimia, Cristina; Cravatt, Benjamin F; De Vries, Taco J; Schoffelmeer, Anton N M; Pattij, Tommy; Parsons, Loren H","year":2012,"journal":"ACS chemical neuroscience, 3(5), 407-17","doi":"10.1021/cn300036b","pmid":"22860210","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using microdialysis to measure endocannabinoid levels in the nucleus accumbens of living animals, researchers characterized six commonly used research compounds. FAAH inhibitors (URB597, PF-3845) selectively increased anandamide during neural activity without affecting 2-AG. The MAGL inhibitor URB602 increased 2-AG without affecting anandamide.\n\nA key finding was a species difference: JZL184, a widely used MAGL inhibitor, effectively boosted 2-AG in mice but not in rats. The dual FAAH/MAGL inhibitor JZL195 increased both endocannabinoids in both species. These species differences have important implications for interpreting prior research.","whyItMatters":"Understanding exactly how research tools affect endocannabinoid levels in living brains is critical for interpreting cannabinoid research and developing medicines. The species difference for JZL184 means that findings from mouse studies using this compound may not directly apply to rats or humans.","specificNumbers":"6 compounds tested. PF-3845 and URB597 selectively increased anandamide. URB602 selectively increased 2-AG. JZL184 worked in mice but not rats. JZL195 increased both in both species. AM404 modestly increased 2-AG. UCM707 had no effect on either.","methodology":"In vivo microdialysis in the nucleus accumbens of rats and mice. Potassium-induced depolarization was used to stimulate endocannabinoid release. Six compounds were tested: AM404 and UCM707 (transport inhibitors), URB597 and PF-3845 (FAAH inhibitors), URB602 (MAGL inhibitor), JZL184 (MAGL inhibitor), and JZL195 (dual FAAH/MAGL inhibitor).","limitations":"Microdialysis measures extracellular levels, which may not perfectly reflect synaptic concentrations. The nucleus accumbens was the only brain region studied; effects may differ in other areas. The compounds were tested under stimulated conditions, which may not reflect baseline endocannabinoid regulation."},{"rthcId":"RTHC-00637","title":"Spinal administration of the monoacylglycerol lipase inhibitor JZL184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat.","authors":"Woodhams, S G; Wong, A; Barrett, D A; Bennett, A J; Chapman, V; Alexander, S P H","year":2012,"journal":"British journal of pharmacology, 167(8), 1609-19","doi":"10.1111/j.1476-5381.2012.02179.x","pmid":"22924700","tags":["pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers applied JZL184, an inhibitor of the enzyme that breaks down the endocannabinoid 2-AG, directly to the spinal cord of anesthetized rats. This dose-dependently inhibited pain-processing neurons (wide dynamic range neurons) in response to mechanical stimulation. A single spinal dose completely abolished the expansion of receptive fields caused by inflammation, a key marker of central sensitization.\n\nParadoxically, despite strong functional effects, JZL184 did not measurably increase 2-AG levels in spinal cord tissue when measured in vivo, though it robustly inhibited the enzyme in vitro. The researchers suggested this discrepancy reflects highly localized sites of action.","whyItMatters":"Central sensitization, where the spinal cord amplifies pain signals, is a key driver of chronic pain conditions. This study showed that boosting endocannabinoid signaling at the spinal level could powerfully counteract this process, suggesting a precise therapeutic target for chronic pain.","specificNumbers":"JZL184 dose-dependently inhibited WDR neuron responses. A single dose abolished inflammation-induced receptive field expansion. Effects were partially CB1 receptor-dependent. No measurable change in bulk 2-AG levels despite strong functional effects.","methodology":"In vivo spinal electrophysiology in anesthetized rats measuring wide dynamic range neuron responses to mechanical stimulation. JZL184 administered spinally with and without hindpaw inflammation. CB1 receptor involvement tested with antagonist AM251. Spinal cord 2-AG levels and enzyme activity measured.","limitations":"Animal study using anesthetized rats, which may not reflect conscious pain processing. The discrepancy between in vivo and in vitro results raises questions about the mechanism. The rat version of MAGL may be less sensitive to JZL184 than the mouse version, complicating cross-species comparisons."},{"rthcId":"RTHC-00638","title":"Assessment of blinding to treatment allocation in studies of a cannabis-based medicine (Sativex®) in people with multiple sclerosis: a new approach.","authors":"Wright, Stephen; Duncombe, Paul; Altman, Douglas G","year":2012,"journal":"Trials, 13, 189","doi":"10.1186/1745-6215-13-189","pmid":"23046749","tags":["medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"The researchers addressed a critical concern about cannabis medicine trials: could patients tell whether they received the active drug based on side effects or prior cannabis experience, thereby biasing self-reported outcomes? Analyzing 666 patients across three Phase III placebo-controlled studies, they found no significant relationship between Sativex's effect on spasticity and either prior cannabis use or the occurrence of typical cannabis-related adverse events.\n\nThere was also no significant relationship between prior cannabis use and adverse event incidence, or between prior cannabis use and Sativex dosing. The results indicate that the blinding was maintained and the treatment differences were genuine.","whyItMatters":"Maintaining blinding in cannabis trials is uniquely challenging because patients may recognize the drug's psychoactive effects. This study provided evidence that Sativex trials successfully maintained blinding, strengthening confidence in the reported efficacy results.","specificNumbers":"666 patients across 3 Phase III trials. No significant relationship between treatment effect and prior cannabis use. No significant relationship between treatment effect and typical adverse events. No significant relationship between prior cannabis use and dose.","methodology":"Post-hoc analysis of 666 patients from three Phase III placebo-controlled RCTs of Sativex for MS spasticity. General linear modeling tested whether prior cannabis experience or typical adverse events predicted treatment effects on patient-reported spasticity outcomes.","limitations":"Statistical analysis can demonstrate lack of association but cannot prove that no individual patient became unblinded. The approach assumes that unblinding would manifest as measurable relationships between specific factors and outcomes. Some degree of unblinding below the detection threshold of the analysis may have occurred."},{"rthcId":"RTHC-00639","title":"The impact of cannabis use on cognitive functioning in patients with schizophrenia: a meta-analysis of existing findings and new data in a first-episode sample.","authors":"Yücel, Murat; Bora, Emre; Lubman, Dan I; Solowij, Nadia; Brewer, Warrick J; Cotton, Sue M; Conus, Philippe; Takagi, Michael J; Fornito, Alex; Wood, Stephen J; McGorry, Patrick D; Pantelis, Christos","year":2012,"journal":"Schizophrenia bulletin, 38(2), 316-30","doi":"10.1093/schbul/sbq079","pmid":"20660494","tags":["psychosis","cognition"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"In a surprising finding that contradicts common assumptions, the meta-analysis of 572 patients found that those with a history of cannabis use had superior neuropsychological functioning compared to non-using schizophrenia patients. This was primarily driven by studies including patients with lifetime (rather than current) cannabis history.\n\nA second study of 85 first-episode psychosis (FEP) patients confirmed the pattern: cannabis-using FEP patients showed only selective cognitive impairments while non-users showed generalized deficits. Cannabis users performed better on visual memory, working memory, and executive functioning. Patients who started cannabis earlier had even less cognitive impairment.","whyItMatters":"This counterintuitive finding has an important implication: cannabis-using patients who develop psychosis may represent a \"cognitively less impaired\" subgroup who needed an environmental trigger (cannabis) to develop psychosis. Non-using patients may have developed psychosis due to greater underlying cognitive vulnerability, without needing an external trigger.","specificNumbers":"Meta-analysis: 10 studies, 572 patients. FEP study: 59 cannabis users vs. 26 non-users vs. 43 controls. Cannabis users outperformed non-users on visual memory, working memory, and executive functioning. Earlier cannabis onset associated with less cognitive impairment.","methodology":"Two-part study. Study I: Meta-analysis of 10 studies comprising 572 patients with established schizophrenia. Study II: Neuropsychological testing of 85 first-episode psychosis patients (59 cannabis users, 26 non-users) and 43 healthy controls.","limitations":"The meta-analysis included mostly cross-sectional studies. Better cognition in cannabis users could reflect selection bias (more cognitively intact people are more likely to access and use cannabis). Lifetime cannabis history includes people who stopped years ago. The sample sizes, while reasonable for a meta-analysis, are modest."},{"rthcId":"RTHC-00640","title":"Multiple sclerosis and extract of cannabis: results of the MUSEC trial.","authors":"Zajicek, John Peter; Hobart, Jeremy C; Slade, Anita; Barnes, David; Mattison, Paul G","year":2012,"journal":"Journal of neurology, neurosurgery, and psychiatry, 83(11), 1125-32","doi":"10.1136/jnnp-2012-302468","pmid":"22791906","tags":["medical-cannabis","pain","sleep"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"The MUSEC trial randomized 279 MS patients across 22 UK centers to oral cannabis extract or placebo. After 12 weeks, the rate of relief from muscle stiffness was nearly double in the cannabis extract group compared to placebo (29.4% vs. 15.7%). The treatment effect appeared by week 4 and was maintained through week 12.\n\nSimilar improvements were seen for body pain, muscle spasms, and sleep quality. Multiple MS-specific patient-reported outcome measures corroborated these findings. Adverse events were consistent with known cannabinoid side effects, and no new safety concerns emerged.","whyItMatters":"MS-related spasticity significantly impairs quality of life and is often inadequately managed with existing medications. This large, well-designed trial provided strong evidence that oral cannabis extract offers meaningful symptom relief beyond what patients experience with placebo.","specificNumbers":"279 patients, 22 UK centers. Stiffness relief at 12 weeks: 29.4% CE vs. 15.7% placebo (OR 2.26; 95% CI 1.24-4.13; p=0.004). Dose range: 5-25 mg THC daily. Benefits also seen for pain, spasms, and sleep. Trial registration: NCT00552604.","methodology":"Double-blind, placebo-controlled, Phase III RCT at 22 UK centers. 144 patients received cannabis extract, 135 received placebo. Two-week dose titration from 5 mg to maximum 25 mg THC daily, followed by 10-week maintenance. Primary outcome: category rating scale for patient-reported muscle stiffness change from baseline.","limitations":"Patient-reported outcomes are subjective and may be influenced by expectations. Despite blinding, some patients may have recognized cannabinoid effects. The 12-week duration does not address long-term efficacy. The one-sided p-value threshold is less conservative than two-sided testing."},{"rthcId":"RTHC-00641","title":"Cannabidiol in humans-the quest for therapeutic targets.","authors":"Zhornitsky, Simon; Potvin, Stéphane","year":2012,"journal":"Pharmaceuticals (Basel, Switzerland), 5(5), 529-52","doi":"10.3390/ph5050529","pmid":"24281562","tags":["cbd","psychosis","anxiety","pain","epilepsy","sleep"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The review identified 34 studies: 16 in healthy subjects and 18 in clinical populations covering MS, schizophrenia, bipolar mania, social anxiety, pain, cancer, Huntington's disease, insomnia, and epilepsy.\n\nKey findings included: high inhaled/IV doses of CBD were needed to block THC effects. Oral/oromucosal CBD sometimes prolonged or intensified THC effects (contradicting the common belief that CBD always counteracts THC). Preliminary clinical evidence supported CBD for social anxiety disorder, insomnia, and epilepsy at doses of 150-600 mg/day, but mental sedation was a concern.","whyItMatters":"This was one of the first comprehensive systematic reviews of CBD's effects in humans, providing a reality check on both the hype and skepticism surrounding CBD. The finding that CBD can sometimes enhance rather than counteract THC is particularly important for patients using combination products.","specificNumbers":"34 studies reviewed (16 experimental, 18 clinical). Clinical conditions: MS (6), schizophrenia/bipolar (4), social anxiety (2), pain (2), cancer anorexia (1), Huntington's (1), insomnia (1), epilepsy (1). Therapeutic dose range: 150-600 mg/day oral.","methodology":"Systematic review searching PubMed and EMBASE for \"cannabidiol.\" Included randomized and crossover studies in healthy controls and clinical patients. Both CBD monotherapy and CBD+THC combination studies were included. 34 studies met inclusion criteria.","limitations":"Many of the included studies had small sample sizes. The clinical studies covered diverse conditions with different designs, making synthesis difficult. The review captured a relatively early stage of CBD clinical research when few large trials had been conducted."},{"rthcId":"RTHC-00642","title":"Distress, coping, and drug law enforcement in a series of patients using medical cannabis.","authors":"Aggarwal, Sunil Kumar; Carter, Gregory; Sullivan, Mark; Morrill, Richard; Zumbrunnen, Craig; Mayer, Jonathan","year":2013,"journal":"The Journal of nervous and mental disease, 201(4), 292-303","doi":"10.1097/NMD.0b013e318288d333","pmid":"23538974","tags":["medical-cannabis","mental-health","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Thirty-seven medical cannabis patients at a Washington state dispensary completed surveys about health behaviors, psychological distress, stress related to marijuana criminality, and law enforcement experiences. Their median psychological distress, measured by the Behavioral Symptom Inventory, was nearly 2.5 times higher than the general population but one-third lower than psychiatric outpatients.\n\nSeventy-six percent reported previous exposure to a total of 119 separate drug law enforcement tactics. Participants reported moderate stress related to marijuana's criminal status and used a wide range of coping methods. The study also noted that standard substance use disorder assessments were confounded by the legal ambiguity of medical cannabis.","whyItMatters":"Medical cannabis patients occupy a uniquely stressful position between receiving medical recommendation for a substance that remains federally illegal. This study documented the psychological toll of that conflicting legal status, including direct encounters with law enforcement.","specificNumbers":"37 subjects enrolled. Psychological distress 2.5x general population, one-third less than psychiatric outpatients. 76% reported drug law enforcement exposure. 119 total law enforcement tactics reported across participants.","methodology":"Dispensary-based survey of medical cannabis patients in Washington state. Measures included the BSI for psychological distress, custom measures for marijuana criminality stress, law enforcement exposure, and coping behaviors. Modified substance use assessment instruments were used.","limitations":"Very small sample size (37 participants) from a single dispensary. Convenience sampling limits generalizability. The elevated psychological distress could reflect the conditions for which patients sought medical cannabis rather than the stress of legal ambiguity. No control group."},{"rthcId":"RTHC-00643","title":"Functional imaging of implicit marijuana associations during performance on an Implicit Association Test (IAT).","authors":"Ames, Susan L; Grenard, Jerry L; Stacy, Alan W; Xiao, Lin; He, Qinghua; Wong, Savio W; Xue, Gui; Wiers, Reinout W; Bechara, Antoine","year":2013,"journal":"Behavioural brain research, 256, 494-502","doi":"10.1016/j.bbr.2013.09.013","pmid":"24029699","tags":["addiction","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Thirteen heavy cannabis users and 15 non-using controls (ages 18-25) completed a marijuana Implicit Association Test during fMRI. When processing positive cannabis associations (compatible trials), users showed greater bilateral activity in the dorsal striatum (caudate and putamen), brain regions associated with habit-based processing.\n\nIn contrast, non-users showed greater activity in the right inferior frontal gyrus during incompatible trials, which require more deliberate cognitive control. This pattern supports a dual-process model: cannabis use is driven by automatic habit processes in the striatum, while resistance to use involves prefrontal cortex-mediated deliberate control.","whyItMatters":"This study provides neurobiological evidence that cannabis use becomes increasingly driven by automatic, habit-based brain processes rather than deliberate decision-making. Understanding this shift from conscious choice to habit has implications for why quitting is difficult and how treatment might be designed.","specificNumbers":"13 heavy users vs. 15 controls. Users showed bilateral striatal activation (caudate, putamen, hippocampus) during compatible trials. Non-users showed prefrontal activation during incompatible trials. Users showed no significant activation during incompatible trials.","methodology":"Cross-sectional fMRI study comparing 13 heavy marijuana users and 15 non-using controls (ages 18-25) during performance of a marijuana Implicit Association Test. Group-by-condition interactions were analyzed for brain activation differences.","limitations":"Very small sample sizes limit statistical power and generalizability. Cross-sectional design cannot determine whether the brain differences preceded cannabis use or resulted from it. The IAT measures implicit associations, which may not directly translate to real-world use decisions. Only heavy users were compared to non-users, missing moderate use patterns."},{"rthcId":"RTHC-00644","title":"Pregabalin and topiramate regulate behavioural and brain gene transcription changes induced by spontaneous cannabinoid withdrawal in mice.","authors":"Aracil-Fernández, Auxiliadora; Almela, Pilar; Manzanares, Jorge","year":2013,"journal":"Addiction biology, 18(2), 252-62","doi":"10.1111/j.1369-1600.2011.00406.x","pmid":"22017514","tags":["withdrawal","anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice made tolerant to the synthetic cannabinoid CP-55,940 showed increased motor activity, rearing, and anxiety-like behavior on days 1 and 3 after cessation. Both pregabalin (40 mg/kg twice daily) and topiramate (50 mg/kg twice daily) blocked the motor signs and significantly reduced anxiety.\n\nAt the molecular level, cannabinoid withdrawal decreased tyrosine hydroxylase expression in the reward center and mu-opioid receptor expression in the nucleus accumbens, while increasing CB1 receptor expression. Both drugs reversed the tyrosine hydroxylase and CB1 changes but did not affect the opioid receptor changes.","whyItMatters":"Cannabis withdrawal, while not life-threatening, includes anxiety, irritability, and sleep disturbance that often drive relapse. Identifying existing medications that can manage these symptoms could improve quit success rates. Both pregabalin and topiramate are already approved for other conditions.","specificNumbers":"CP-55,940: 0.5 mg/kg twice daily for 7 days. Pregabalin: 40 mg/kg twice daily. Topiramate: 50 mg/kg twice daily. Both blocked motor signs and reduced anxiety on days 1 and 3. Both reversed TH decrease and CB1 increase in brain. Neither affected mu-opioid receptor changes.","methodology":"Mice received CP-55,940 (0.5 mg/kg twice daily for 7 days) to induce tolerance. Spontaneous withdrawal was assessed on days 1 and 3 by measuring motor activity, somatic signs, and anxiety-like behavior. Pregabalin or topiramate was administered during days 1-3. Gene expression was measured by qRT-PCR in VTA and nucleus accumbens.","limitations":"Animal study using a synthetic cannabinoid (CP-55,940) rather than THC, which may produce different withdrawal profiles. Mouse doses do not directly translate to human doses. Spontaneous withdrawal from 7 days of treatment may not model the withdrawal experienced by chronic human users. The anxiety measures are behavioral proxies, not direct measures of subjective experience."},{"rthcId":"RTHC-00645","title":"Discontinuous college enrollment: associations with substance use and mental health.","authors":"Arria, Amelia M; Caldeira, Kimberly M; Vincent, Kathryn B; Winick, Emily R; Baron, Rebecca A; O'Grady, Kevin E","year":2013,"journal":"Psychiatric services (Washington, D.C.), 64(2), 165-72","doi":"10.1176/appi.ps.201200106","pmid":"23474608","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 1,145 college students for four years. Depression symptoms at college entry predicted early enrollment gaps (first two years), while cannabis use predicted later gaps (years 3-4). Receiving a depression diagnosis during college was associated with both early and late discontinuity.\n\nImportantly, pre-college psychiatric diagnoses did not predict enrollment interruptions once background characteristics were controlled. This suggests that active substance use and mental health problems during college, not pre-existing conditions, drive enrollment disruption.","whyItMatters":"College dropout has long-term consequences for earnings, health, and life satisfaction. Understanding that cannabis use specifically predicts later enrollment gaps (not early ones) helps universities target interventions at the right time and for the right risk factors.","specificNumbers":"1,145 students followed for 4 years. Depression (BDI) predicted early but not late discontinuity. Cannabis and alcohol predicted late but not early discontinuity. Depression diagnosis during college predicted both. Pre-college diagnoses: not significant after controlling for background.","methodology":"Longitudinal study of 1,145 students at a large public university, interviewed annually for four years starting at college entry in 2004. Enrollment data from university records. Measures included BDI, BAI, childhood conduct problems, cannabis use, illicit drug use, and alcohol consumption. Multinomial logistic regression controlled for background characteristics.","limitations":"Single university study may not generalize to other institutions. Self-reported substance use may underestimate actual use. \"Discontinuous enrollment\" includes both voluntary and involuntary interruptions for various reasons. Cannabis use was measured at baseline and may have changed over the study period."},{"rthcId":"RTHC-00646","title":"Dispelling the myth of \"smart drugs\": cannabis and alcohol use problems predict nonmedical use of prescription stimulants for studying.","authors":"Arria, Amelia M; Wilcox, Holly C; Caldeira, Kimberly M; Vincent, Kathryn B; Garnier-Dykstra, Laura M; O'Grady, Kevin E","year":2013,"journal":"Addictive behaviors, 38(3), 1643-50","doi":"10.1016/j.addbeh.2012.10.002","pmid":"23254212","tags":["addiction","youth","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 984 college students over four annual waves. Over a third (38%) reported using prescription stimulants for studying by year 4. The key finding challenged the \"smart drug\" narrative: stimulant use for studying was not driven by students seeking an academic edge, but was associated with a trajectory of escalating substance use, increased class-skipping, and declining GPA.\n\nCanabis use disorder predicted increases in skipping class, which was associated with declining GPA, which in turn was associated with stimulant use for studying. Alcohol use disorder showed the same pattern.","whyItMatters":"The \"study drug\" phenomenon is often portrayed as ambitious students seeking a cognitive edge. This study reveals a darker picture: stimulant use for studying is associated with a decline driven by substance use problems. Rather than being a study aid, it may be a marker of students in academic trouble.","specificNumbers":"984 students, 4 annual waves. 38% used prescription stimulants for studying by year 4. Cannabis use disorder predicted increased class-skipping, which predicted declining GPA. The trajectory from substance problems to academic decline to stimulant use was confirmed for both cannabis and alcohol.","methodology":"Longitudinal prospective study of 984 students in the College Life Study at a large public US university. Four annual data waves. Measured DSM-IV cannabis and alcohol use disorders, class attendance, GPA (from university records), and nonmedical prescription stimulant use. Growth curve modeling estimated trajectory associations.","limitations":"Single university; findings may differ at other institutions. Self-reported stimulant use and class attendance are subject to bias. The study cannot prove the causal direction between cannabis use and academic decline. Students who dropped out were lost to follow-up."},{"rthcId":"RTHC-00647","title":"Cannabis affects people differently: inter-subject variation in the psychotogenic effects of Δ9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers.","authors":"Atakan, Z; Bhattacharyya, S; Allen, P; Martín-Santos, R; Crippa, J A; Borgwardt, S J; Fusar-Poli, P; Seal, M; Sallis, H; Stahl, D; Zuardi, A W; Rubia, K; McGuire, P","year":2013,"journal":"Psychological medicine, 43(6), 1255-67","doi":"10.1017/S0033291712001924","pmid":"23020923","tags":["psychosis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a double-blind, placebo-controlled study, 21 healthy men with minimal cannabis experience received 10 mg oral THC or placebo. About half (n=11) developed transient psychotic symptoms while the remainder (n=10) did not. The group experiencing psychotic symptoms made more inhibition errors and showed different brain activation in the left parahippocampal gyrus, bilateral middle temporal gyri, and right cerebellum.\n\nRemarkably, THC had opposite effects on brain activation in the two groups in these regions. The psychosis-prone group also showed less activation in temporal and cerebellar regions independent of THC, suggesting pre-existing neural differences.","whyItMatters":"This was the first demonstration that individual differences in sensitivity to THC's psychosis-inducing effects have a measurable neural basis. The finding that about half of participants experienced psychotic symptoms while the other half did not, with corresponding brain differences, helps explain why cannabis affects people so differently.","specificNumbers":"21 healthy men. 10 mg oral THC. 11 developed transient psychosis, 10 did not. Differential activation in parahippocampal gyrus, middle temporal gyri, and cerebellum. THC had opposite directional effects on brain activation in the two groups.","methodology":"Double-blind, placebo-controlled, pseudorandomized design. 21 healthy men with minimal cannabis experience received 10 mg oral THC or placebo. fMRI recorded during a go/no-go inhibition task. Participants split into transiently psychotic (n=11) and non-psychotic (n=10) groups based on PANSS positive scores after THC.","limitations":"Small sample size (21 subjects). Only men were studied. The post-hoc split into groups based on symptom response means the groups were not randomly assigned. Minimal cannabis experience may not reflect how regular users respond. A single dose does not model chronic exposure."},{"rthcId":"RTHC-00648","title":"The impact of perceived sleep quality and sleep efficiency/duration on cannabis use during a self-guided quit attempt.","authors":"Babson, Kimberly A; Boden, Matthew Tyler; Bonn-Miller, Marcel O","year":2013,"journal":"Addictive behaviors, 38(11), 2707-13","doi":"10.1016/j.addbeh.2013.06.012","pmid":"23906725","tags":["sleep","quitting","ptsd"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Researchers followed 102 cannabis-dependent military veterans for 6 months after a self-guided quit attempt. Veterans with poor perceived sleep quality (measured by the Pittsburgh Sleep Quality Index) showed significantly less reduction in cannabis use compared to those with good sleep quality.\n\nImportantly, it was the subjective perception of poor sleep, not objective sleep efficiency or duration, that predicted quit outcomes. The effect remained significant after adjusting for age, PTSD symptoms, alcohol, tobacco, opioid use, and cannabis withdrawal severity.","whyItMatters":"Sleep problems are one of the most commonly reported cannabis withdrawal symptoms and a frequent reason for relapse. This study identifies perceived sleep quality as a specific, modifiable target that could improve quit outcomes if addressed therapeutically.","specificNumbers":"102 veterans followed for 6 months. Poor perceived sleep quality predicted less cannabis reduction. Sleep efficiency/duration was unrelated to outcomes. Effect held after controlling for PTSD, alcohol, tobacco, opioids, and withdrawal severity.","methodology":"Cohort design following 102 cannabis-dependent, primarily male military veterans for 6 months after a self-guided cannabis quit attempt. Sleep quality measured by PSQI. Cannabis use measured by Timeline Followback. Generalized linear mixed modeling with Poisson distribution tested associations.","limitations":"Primarily male veteran sample limits generalizability to women and non-veterans. Self-report measures for both sleep quality and cannabis use. Self-guided quit attempts may not represent structured treatment outcomes. The subjective nature of the key predictor (perceived sleep quality) may overlap with general distress."},{"rthcId":"RTHC-00649","title":"Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving.","authors":"Battistella, Giovanni; Fornari, Eleonora; Thomas, Aurélien; Mall, Jean-Frédéric; Chtioui, Haithem; Appenzeller, Monique; Annoni, Jean-Marie; Favrat, Bernard; Maeder, Philippe; Giroud, Christian","year":2013,"journal":"PloS one, 8(1), e52545","doi":"10.1371/journal.pone.0052545","pmid":"23300977","tags":["driving","cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Thirty-one male occasional cannabis smokers underwent fMRI while performing a visuo-motor tracking task after smoking cannabis or placebo. Cannabis decreased brain activity in regions critical for detecting important information (anterior insula, thalamus, striatum) and for executive control (dorsolateral prefrontal cortex, superior parietal cortex).\n\nSimultaneously, cannabis increased activity in self-referential regions (rostral anterior cingulate, ventromedial prefrontal cortex), suggesting users became more focused on internal experience and less on the driving task. These brain changes correlated with subjective feelings of confusion rather than with blood THC levels.","whyItMatters":"This study showed that cannabis impairs driving-related brain function even when blood THC levels are low, challenging policies that set specific THC thresholds for impairment. The brain imaging data revealed the specific neural mechanisms by which cannabis degrades driving ability.","specificNumbers":"31 male occasional smokers. Cannabis decreased psychomotor skills. Decreased BOLD response in saliency detection and executive control networks. Increased BOLD response in self-referential networks. Effects correlated with confusion, not blood THC level.","methodology":"Placebo-controlled study of 31 male occasional cannabis smokers. Joint THC percentage and inhaled dose matched real-life conditions. fMRI paradigm: visuo-motor tracking task with active tracking, passive viewing, and rest. Blood THC and metabolite concentrations measured. Psychomotor skills assessed.","limitations":"Only male occasional smokers were studied; regular users with tolerance may respond differently. The fMRI tracking task is a proxy for driving, not actual driving. The study examined acute effects of a single smoking session. Sample size of 31 is moderate for fMRI."},{"rthcId":"RTHC-00650","title":"Development of an integrative cessation program for co-smokers of cigarettes and cannabis: demand analysis, program description, and acceptability.","authors":"Becker, Julia; Hungerbuehler, Ines; Berg, Oliver; Szamrovicz, Maciej; Haubensack, Andreas; Kormann, Adrian; Schaub, Michael P","year":2013,"journal":"Substance abuse treatment, prevention, and policy, 8, 33","doi":"10.1186/1747-597X-8-33","pmid":"24025478","tags":["quitting","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Through expert interviews, focus groups with former smokers, and an online survey, researchers confirmed strong demand for an integrated cessation program targeting both tobacco and cannabis. Current programs typically address only one substance.\n\nThe resulting six-session group program incorporated motivational interviewing, cognitive behavioral therapy, and self-control training. Both participants and instructors evaluated the program positively, particularly valuing the group discussions and modules on managing cravings, withdrawal, and high-risk situations during simultaneous cessation.","whyItMatters":"Tobacco and cannabis use are strongly interrelated, with many users co-smoking (mixing tobacco and cannabis or using both regularly). Addressing only one substance while ignoring the other can undermine cessation efforts. This was the first program designed to tackle both simultaneously.","specificNumbers":"Six course sessions developed. Combined motivational interviewing, CBT, and self-control training. Expert interviews, focus groups, and online survey conducted in preliminary phase. Both participants and instructors evaluated the program positively.","methodology":"Multi-phase development: preliminary study (expert interviews, user focus groups, online survey) to assess demand and content preferences; interdisciplinary expert team program development; acceptability evaluation by participants and instructors. Trial registered: ISRCTN15248397.","limitations":"This was a development and acceptability study, not an efficacy trial. Positive acceptability does not guarantee the program will actually help people quit. The study did not include a control group or measure cessation rates. The experts and focus group participants who guided development may not represent all co-users."},{"rthcId":"RTHC-00651","title":"Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers.","authors":"Bedi, Gillinder; Cooper, Ziva D; Haney, Margaret","year":2013,"journal":"Addiction biology, 18(5), 872-81","doi":"10.1111/j.1369-1600.2011.00427.x","pmid":"22260337","tags":["addiction","tolerance","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Fourteen regular marijuana smokers completed a within-subjects comparison of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg), and placebo across seven sessions. Both drugs increased ratings of feeling good, strong effects, and being \"high.\" Nabilone had a slower onset but more sustained effects, and its effects were more dose-related than dronabinol's.\n\nNabilone at 6-8 mg modestly reduced psychomotor speed, but overall was well tolerated. Heart rate increased dose-dependently with nabilone. The more predictable dose-response relationship and better bioavailability suggest nabilone may be more suitable than dronabinol as an agonist replacement therapy for cannabis dependence.","whyItMatters":"Dronabinol (oral THC) has been tested for cannabis dependence but failed to prevent relapse, possibly due to poor bioavailability. Nabilone's better bioavailability and more predictable dose-response could make it a superior agonist therapy, similar to how methadone or buprenorphine work for opioid dependence.","specificNumbers":"14 participants smoking 6.6 days/week. Nabilone tested at 2, 4, 6, 8 mg. Dronabinol at 10, 20 mg. Both increased positive mood ratings. Nabilone: slower onset, more dose-related. Nabilone 6-8 mg: modest psychomotor slowing. Dose-dependent heart rate increase with nabilone.","methodology":"Outpatient, within-subjects, double-blind, randomized protocol. 14 participants (4 female, 10 male) smoking marijuana 6.6 days/week. Seven sessions comparing nabilone (4 doses), dronabinol (2 doses), and placebo. Time-dependent subjective, cognitive, and cardiovascular effects measured.","limitations":"Small sample of 14 participants. All were current regular users, not treatment-seeking. Acute effects of single doses do not predict outcomes of sustained treatment. Outpatient setting means compliance and environmental factors were not controlled. The study assessed subjective effects but not actual cannabis reduction."},{"rthcId":"RTHC-00652","title":"Chemical probes of endocannabinoid metabolism.","authors":"Blankman, Jacqueline L; Cravatt, Benjamin F","year":2013,"journal":"Pharmacological reviews, 65(2), 849-71","doi":"10.1124/pr.112.006387","pmid":"23512546","tags":["neuroscience","pain","anxiety","addiction"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review described the development and application of chemical tools that selectively block the enzymes degrading each major endocannabinoid. FAAH inhibitors (boosting anandamide) and MAGL inhibitors (boosting 2-AG) have revealed that these two pathways serve different functions.\n\nIn pain models, both FAAH and MAGL inhibitors showed efficacy but through different mechanisms. In anxiety models, FAAH inhibition was anxiolytic while MAGL inhibition sometimes produced opposite effects. In addiction models, the two pathways had distinct roles in reward and withdrawal. The review emphasized that these differences have crucial implications for which pathway to target therapeutically.","whyItMatters":"Simply saying \"boost endocannabinoids\" is too imprecise. Anandamide and 2-AG have overlapping but distinct roles. This review mapped those differences, guiding the development of more targeted therapies that boost the right endocannabinoid for the right condition.","specificNumbers":"Two primary endocannabinoids: anandamide (FAAH substrate) and 2-AG (MAGL substrate). Two primary degrading enzymes: FAAH and MAGL. Applications tested: pain, anxiety/depression, addiction. Different and sometimes opposite effects from boosting each pathway.","methodology":"Comprehensive narrative review covering the pharmacological development of FAAH and MAGL inhibitors, their use in preclinical behavioral models, and the emerging understanding of differential anandamide vs. 2-AG function.","limitations":"Most evidence came from rodent studies. Species differences in enzyme pharmacology (particularly for MAGL inhibitors) complicate translation to humans. Long-term effects of sustained endocannabinoid elevation remain poorly understood. Clinical trial data for these inhibitors was limited at publication."},{"rthcId":"RTHC-00653","title":"Posttraumatic stress disorder and cannabis use characteristics among military veterans with cannabis dependence.","authors":"Boden, Matthew Tyler; Babson, Kimberly A; Vujanovic, Anka A; Short, Nicole A; Bonn-Miller, Marcel O","year":2013,"journal":"The American journal on addictions, 22(3), 277-84","doi":"10.1111/j.1521-0391.2012.12018.x","pmid":"23617872","tags":["ptsd","quitting","withdrawal","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 94 cannabis-dependent military veterans preparing for a quit attempt, those with PTSD reported significantly more coping-motivated cannabis use, more severe withdrawal symptoms, and stronger cravings related to compulsivity, emotionality, and anticipation.\n\nThe links between PTSD and coping motives and between PTSD and craving remained significant even after controlling for concurrent cannabis, alcohol, and tobacco use, and co-occurring mood, anxiety, and substance use diagnoses. PTSD symptom severity was positively associated with all cannabis use characteristics measured.","whyItMatters":"PTSD and cannabis use disorder frequently co-occur in veterans. This study identifies a specific mechanism, coping-motivated use, that creates a feedback loop: PTSD symptoms drive cannabis use for emotional relief, which prevents natural PTSD processing, which maintains PTSD symptoms, which drives more cannabis use.","specificNumbers":"94 cannabis-dependent veterans. PTSD associated with: increased coping motives, more severe withdrawal, stronger craving (compulsivity, emotionality, anticipation). Findings robust after controlling for alcohol, tobacco, mood, anxiety, and substance use diagnoses.","methodology":"Cross-sectional study of 94 cannabis-dependent military veterans immediately prior to a cannabis quit attempt. Measures of PTSD diagnosis, symptom severity, coping motives, use problems, withdrawal, and craving were administered. Analyses conducted with and without adjusting for other substance use and co-occurring diagnoses.","limitations":"Cross-sectional design cannot establish causal direction between PTSD and cannabis use characteristics. The veteran sample may not generalize to civilian populations. All measures were self-reported. The study captured a single timepoint immediately before a quit attempt, which may not represent typical use patterns."},{"rthcId":"RTHC-00654","title":"The effects of cannabis use expectancies on self-initiated cannabis cessation.","authors":"Boden, Matthew Tyler; McKay, James R; Long, W Robert; Bonn-Miller, Marcel O","year":2013,"journal":"Addiction (Abingdon, England), 108(9), 1649-57","doi":"10.1111/add.12233","pmid":"23627879","tags":["quitting","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"One hundred cannabis-dependent military veterans were followed during a self-initiated 4-week quit attempt. Positive cannabis expectancies (believing cannabis produces desirable effects) predicted multiple outcomes: higher baseline use, lapsing during the attempt, relapsing fully, and the overall trajectory of use during cessation.\n\nNegative expectancies (believing cannabis has bad effects) played a limited role, predicting only initial lapse but not sustained use or relapse. Results held after adjusting for demographics, motivation to quit, mental health diagnoses, and alcohol and tobacco use.","whyItMatters":"Understanding what predicts quit failure helps design better interventions. If positive expectancies, specific beliefs about cannabis benefits, drive continued use, then therapeutically challenging these beliefs could improve outcomes. Simply knowing cannabis is harmful (negative expectancies) was not enough to prevent relapse.","specificNumbers":"100 veterans followed 4 weeks. Positive expectancies predicted: baseline use (p=0.01), lapse (p=0.03), relapse (p=0.04), use trajectory (p=0.03). Negative expectancies predicted only lapse (p=0.01). Results robust after covariate adjustment.","methodology":"Cohort design following 100 cannabis-dependent military veterans for 4 weeks after a self-initiated quit attempt. Cannabis use expectancies measured at baseline with the Marijuana Effects Expectancy Questionnaire. Cannabis use tracked with Timeline Followback at baseline and during cessation. Analyses adjusted for multiple covariates.","limitations":"Self-guided quit attempts may not represent structured treatment settings. Military veterans may not be representative of all cannabis users. Four-week follow-up is relatively short. Expectancies were measured at baseline and may change during the quit attempt. Self-report measures for both expectancies and use."},{"rthcId":"RTHC-00655","title":"The pharmacologic and clinical effects of medical cannabis.","authors":"Borgelt, Laura M; Franson, Kari L; Nussbaum, Abraham M; Wang, George S","year":2013,"journal":"Pharmacotherapy, 33(2), 195-209","doi":"10.1002/phar.1187","pmid":"23386598","tags":["medical-cannabis","pain","psychosis","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review covered three types of cannabinoid medicines available in North America: dronabinol (Schedule III), nabilone (Schedule II), and medical cannabis (Schedule I). Pain and muscle spasms were the most common reasons for medical cannabis recommendations and had the most supporting evidence.\n\nStudies showed significant improvement in various pain types and muscle spasticity. Adverse effects were typically not serious, with dizziness being the most common. Key safety concerns included increased schizophrenia risk with adolescent use, memory and cognitive impairments, accidental pediatric ingestion, and lack of standardized safety packaging.","whyItMatters":"This review provided clinicians with a practical overview of the medical cannabis landscape at a time when state medical cannabis programs were expanding rapidly but clinical guidance was lacking. It balanced evidence of benefit with clearly articulated safety concerns.","specificNumbers":"Three cannabinoid medicines reviewed. Dronabinol: Schedule III. Nabilone: Schedule II. Medical cannabis: Schedule I. Most common uses: pain and muscle spasms. Most common adverse effect: dizziness. Key risk: adolescent use and schizophrenia.","methodology":"Narrative review of the pharmacology, dosage formulations, therapeutic benefits and risks, and safety concerns of medical cannabis products. Covered dronabinol, nabilone, nabiximols, and herbal medical cannabis.","limitations":"Narrative rather than systematic review. The evidence base was unevenly distributed across conditions. The comparison between pharmaceutical cannabinoids and herbal medical cannabis was complicated by different regulatory standards. Rapidly evolving legal landscape may have made some observations outdated quickly."},{"rthcId":"RTHC-00656","title":"Cannabis abuse is associated with better emotional memory in schizophrenia: a functional magnetic resonance imaging study.","authors":"Bourque, Josiane; Mendrek, Adrianna; Durand, Myriam; Lakis, Nadia; Lipp, Olivier; Stip, Emmanuel; Lalonde, Pierre; Grignon, Sylvain; Potvin, Stéphane","year":2013,"journal":"Psychiatry research, 214(1), 24-32","doi":"10.1016/j.pscychresns.2013.05.012","pmid":"23906663","tags":["psychosis","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared emotional memory and brain activation in three groups: 14 schizophrenia patients with cannabis abuse (dual-diagnosis, DD), 14 non-using schizophrenia patients (SCZ), and 21 healthy controls (HC). Non-using schizophrenia patients showed prominent impairment in recognizing both positive and negative emotional images, while cannabis-using patients showed smaller differences from healthy controls.\n\nBrain imaging revealed that non-using patients activated different brain regions (temporal, parietal, limbic, occipital) while cannabis-using patients showed activation patterns more similar to controls, particularly preserving frontal and limbic region activity.","whyItMatters":"Emotional memory is critical for social functioning and quality of life. The finding that cannabis-using patients have relatively preserved emotional memory and prefrontal function may help explain why some patients use cannabis, potentially to maintain emotional and cognitive abilities that are otherwise impaired by their illness.","specificNumbers":"14 DD patients, 14 SCZ patients, 21 healthy controls. Non-users showed prominent impairment for both positive and negative emotional recognition. Cannabis users showed smaller differences from controls. Cannabis users preserved frontal and limbic activation patterns.","methodology":"Cross-sectional fMRI study comparing three groups during an emotional memory recognition task with positive and negative pictures. 14 dual-diagnosis patients, 14 non-using schizophrenia patients, 21 healthy controls.","limitations":"Small sample sizes (14 per patient group) limit generalizability. Cross-sectional design cannot determine whether better function preceded cannabis use or resulted from it. Cannabis abuse has other negative consequences (poor compliance, relapse) that this study did not address. The groups may differ on unmeasured variables."},{"rthcId":"RTHC-00657","title":"Induction of endocannabinoid levels in juvenile rat brain following developmental chlorpyrifos exposure.","authors":"Carr, Russell L; Adams, Ashley L; Kepler, Darin R; Ward, Antonio B; Ross, Matthew K","year":2013,"journal":"Toxicological sciences : an official journal of the Society of Toxicology, 135(1), 193-201","doi":"10.1093/toxsci/kft126","pmid":"23761300","tags":["neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers exposed 10-day-old rat pups to the pesticide chlorpyrifos (CPF) daily for 7 days at three dose levels. All doses inhibited both FAAH and MAGL, the enzymes responsible for breaking down the endocannabinoids anandamide and 2-AG, and elevated both endocannabinoid levels in the brain.\n\nAt the lowest dose, FAAH inhibition (52%) was actually greater than cholinesterase inhibition (24%), the traditional toxicity marker. This level of FAAH inhibition was sufficient to produce a persistent pattern of elevated anandamide that did not return to normal within the measurement window. The authors suggested this could alter the development of neural circuits.","whyItMatters":"Chlorpyrifos is one of the most widely used pesticides worldwide. If it disrupts the endocannabinoid system in developing brains at low doses, this could have implications for neurodevelopment in children exposed to pesticide residues in food or the environment.","specificNumbers":"Doses: 1, 2.5, 5 mg/kg daily for 7 days in rat pups. At lowest dose: FAAH inhibition peaked at 52%, cholinesterase at 24%. Peak effects at 12 hours for most measures. Anandamide elevation persisted beyond 48 hours at the lowest dose.","methodology":"Juvenile rat pups (postnatal day 10) received oral CPF at 1, 2.5, or 5 mg/kg daily for 7 days. Forebrains were collected at 4, 12, 24, and 48 hours after the last dose. Enzyme activities and endocannabinoid levels were measured at each timepoint.","limitations":"Animal study using direct oral pesticide exposure, which may differ from typical human environmental exposures. The developmental timeline in rats does not perfectly map to human brain development. Functional consequences of elevated endocannabinoid levels were not directly tested."},{"rthcId":"RTHC-00658","title":"Cannabis cue-induced brain activation correlates with drug craving in limbic and visual salience regions: preliminary results.","authors":"Charboneau, Evonne J; Dietrich, Mary S; Park, Sohee; Cao, Aize; Watkins, Tristan J; Blackford, Jennifer U; Benningfield, Margaret M; Martin, Peter R; Buchowski, Maciej S; Cowan, Ronald L","year":2013,"journal":"Psychiatry research, 214(2), 122-31","doi":"10.1016/j.pscychresns.2013.06.005","pmid":"24035535","tags":["addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Sixteen cannabis-dependent adults viewed cannabis-related images during fMRI scanning. Cannabis cue exposure significantly increased craving scores. The cues activated multiple brain regions including the inferior orbital frontal cortex, posterior cingulate, parahippocampal gyrus, hippocampus, amygdala, superior temporal pole, and visual cortex.\n\nCraving scores correlated with brain activation in limbic (amygdala, hippocampus), paralimbic (superior temporal pole), and visual regions during the first fMRI run only. Subsequent runs showed no significant brain-craving correlations, suggesting habituation to the cues occurred.","whyItMatters":"Understanding the neural basis of cannabis craving could identify targets for treatment. The habituation pattern (brain-craving correlation only during first exposure) suggests that cue-exposure therapy might work differently for cannabis than expected, and that initial cue encounters are the most neurologically potent.","specificNumbers":"16 cannabis-dependent volunteers. Craving increased significantly with cue exposure. Brain-craving correlation present in first run only. Key regions: amygdala, hippocampus, superior temporal pole, occipital cortex.","methodology":"Cross-sectional fMRI study of 16 cannabis-dependent adult volunteers. Three cannabis cue-exposure fMRI runs were conducted. Marijuana Craving Questionnaire administered before and after each run. Brain activation was analyzed for correlations with craving scores.","limitations":"Very small sample (16 participants) limits statistical power and generalizability. The habituation effect could reflect scanner fatigue rather than true cue habituation. Visual cues may not capture all aspects of real-world cannabis triggers. No comparison group was included."},{"rthcId":"RTHC-00659","title":"Motivations to quit cannabis use in an adult non-treatment sample: are they related to relapse?","authors":"Chauchard, Emeline; Levin, Kenneth H; Copersino, Marc L; Heishman, Stephen J; Gorelick, David A","year":2013,"journal":"Addictive behaviors, 38(9), 2422-7","doi":"10.1016/j.addbeh.2013.04.002","pmid":"23685328","tags":["quitting","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 385 non-treatment-seeking cannabis users who had made serious self-guided quit attempts. Six motivational factors emerged: self-image/self-control, health concerns, interpersonal relationships, legal concerns, social acceptability, and self-efficacy.\n\nAt interview, 339 had relapsed. Self-image, health, relationship, and social acceptability motivations were associated with being abstinent. Legal concerns (hazard ratio 0.88) and social acceptability concerns (HR 0.83) were associated with slower relapse. Women were more motivated by self-image, health, and social acceptability than men. Older individuals were more motivated by health concerns.","whyItMatters":"Most cannabis users who quit do so without formal treatment. Understanding what motivates successful self-guided quitting helps design prevention messages and interventions. The finding that internal motivations (self-image) and external pressures (legal, social) both matter suggests multi-pronged approaches may be most effective.","specificNumbers":"385 participants, 339 had relapsed at interview. 6 motivational factors identified. Legal concerns: HR 0.88 for relapse. Social acceptability: HR 0.83. Women more motivated by self-image, health, social acceptability. Older users more motivated by health.","methodology":"Convenience sample of 385 non-treatment-seeking adult cannabis smokers (58% male, ages 16-64). All had made a self-defined \"serious\" quit attempt without formal treatment. The 176-item Marijuana Quit Questionnaire assessed motivations. Exploratory factor analysis identified motivational factors. Cox regression and GLM evaluated predictors of relapse.","limitations":"Convenience sample with retrospective recall of quit attempts. The high relapse rate (88%) limits conclusions about successful quitting. Motivations were measured at interview, which may differ from motivations at the time of the quit attempt. Self-defined \"serious\" quit attempts may vary widely in actual commitment."},{"rthcId":"RTHC-00660","title":"Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling.","authors":"Chen, Rongqing; Zhang, Jian; Fan, Ni; Teng, Zhao-Qian; Wu, Yan; Yang, Hongwei; Tang, Ya-Ping; Sun, Hao; Song, Yunping; Chen, Chu","year":2013,"journal":"Cell, 155(5), 1154-1165","doi":"10.1016/j.cell.2013.10.042","pmid":"24267894","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Published in the journal Cell, this study identified COX-2 (cyclooxygenase-2) as the key mediator of THC's memory-impairing effects. Repeated THC exposure induced COX-2 through CB1 receptor activation, which then caused glutamate receptor downregulation, dendritic spine density changes, and impaired synaptic plasticity in the hippocampus.\n\nBlocking COX-2 either pharmacologically or genetically eliminated all of THC's cognitive side effects: working memory impairment, fear memory disruption, and synaptic plasticity deficits. Crucially, in an Alzheimer's disease mouse model, THC's beneficial effects on reducing amyloid plaques and neurodegeneration were fully retained even with COX-2 inhibition.","whyItMatters":"This is a landmark finding because it identifies a way to separate THC's unwanted cognitive side effects from its medical benefits. If COX-2 inhibitors (common anti-inflammatory drugs like ibuprofen) can block THC's memory impairment while preserving its therapeutic effects, it could dramatically expand the medical applicability of cannabis.","specificNumbers":"Published in Cell (top-tier journal). COX-2 induction mediated via CB1 receptor G-protein beta-gamma subunits. COX-2 inhibition blocked: glutamate receptor downregulation, dendritic spine changes, LTP impairment, working memory deficits, fear memory deficits. Alzheimer's benefits of THC fully preserved with COX-2 inhibition.","methodology":"Comprehensive study using pharmacological COX-2 inhibitors and genetic COX-2 knockout mice. Assessed synaptic plasticity (LTP), dendritic spine density, glutamate receptor expression, working memory (Morris water maze), and fear conditioning. Also tested in an Alzheimer's disease mouse model.","limitations":"Animal study with repeated high-dose THC administration that may not reflect human cannabis use patterns. COX-2 inhibitors have their own side effect profile (cardiovascular risk, GI issues). The Alzheimer's model does not perfectly replicate human disease. Whether the finding translates to human cannabis use is unknown."},{"rthcId":"RTHC-00661","title":"Targeting the cannabinoid system for pain relief?","authors":"Chiou, Lih-Chu; Hu, Sherry Shu-Jung; Ho, Yu-Cheng","year":2013,"journal":"Acta anaesthesiologica Taiwanica : official journal of the Taiwan Society of Anesthesiologists, 51(4), 161-70","doi":"10.1016/j.aat.2013.10.004","pmid":"24529672","tags":["pain","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review covered multiple cannabinoid pain-relief strategies: exogenous cannabinoids (THC acting mainly through CB1), CB2-selective agonists (which avoid psychoactive effects), and endocannabinoid enzyme inhibitors (FAAH and MAGL inhibitors). It also described a newly discovered analgesic mechanism in the periaqueductal gray (PAG), a midbrain region that initiates descending pain inhibition.\n\nIn the PAG, receptor activation triggers a chain of enzymatic reactions producing 2-AG, which then inhibits GABAergic (inhibitory) neurons, effectively removing the brake on pain-suppressing pathways. Multiple neurotransmitter systems, including glutamate, acetylcholine, and orexin, can initiate this chain. Notably, acetaminophen's metabolite AM404 also works through this pathway.","whyItMatters":"Understanding the multiple pathways through which cannabinoids control pain reveals several distinct therapeutic opportunities. CB2-selective agonists could provide pain relief without cognitive or psychoactive effects. FAAH/MAGL inhibitors could boost natural pain-suppressing endocannabinoids. The PAG mechanism explains how the brain naturally uses endocannabinoids in stress-induced pain suppression.","specificNumbers":"CB1 receptors mediate central analgesic effects. CB2-selective agonists lack CNS side effects. Multiple receptor systems (mGluR5, M1/M3, OX1) activate the PAG 2-AG pathway. Acetaminophen's metabolite AM404 also activates this pathway.","methodology":"Narrative review covering exogenous cannabinoid pharmacology, endocannabinoid biosynthesis and degradation, CB1/CB2 receptor mechanisms, and a detailed analysis of the 2-AG-mediated disinhibition mechanism in the periaqueductal gray.","limitations":"Much of the PAG mechanism research was from the authors' own lab and awaited independent replication. The clinical relevance of the midbrain circuit had not been demonstrated in humans. The review was selective rather than systematic."},{"rthcId":"RTHC-00662","title":"Post traumatic stress disorder and resilience in veterans who served in the South African border war.","authors":"Connell, M A; Omole, O; Subramaney, U; Olorunju, S","year":2013,"journal":"African journal of psychiatry, 16(6)","doi":"10.4314/ajpsy.v16i6.55","pmid":"24173633","tags":["ptsd","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 54 responding veterans who served in the South African border war (1975-1988), 33% met criteria for PTSD. Despite this high rate, 94% showed normal to above-normal levels of resilience on the Connor Davidson Resilience Scale. PTSD was significantly associated with combat exposure.\n\nAmong substance use variables examined, only current cannabis use was significantly linked to PTSD (p=0.044). Alcohol and other substance use did not show significant associations. The resilience scores showed no association with PTSD severity, suggesting these may be independent dimensions.","whyItMatters":"This was one of the first studies examining PTSD in South African border war veterans, a conflict whose psychological impact has received little attention. The specific link between cannabis use and PTSD, rather than alcohol or other substances, aligns with research from other militaries suggesting cannabis may be used specifically to cope with PTSD symptoms.","specificNumbers":"54 respondents from 109 reachable veterans. 33% PTSD prevalence. 94% showed normal or above-normal resilience. Cannabis use significantly linked to PTSD (p=.044). Combat exposure significantly linked to PTSD (p=.012).","methodology":"Cross-sectional study using anonymous internet-based questionnaire. From 1,527 former high school students (1975-1988), 109 were reachable and 54 responded (49.5% response rate). IES-R assessed PTSD, CD-RISC measured resilience. Chi-square and regression analysis used.","limitations":"Very small sample (54 respondents) from a hard-to-reach population. Low response rate (49.5%) introduces selection bias. Internet-based recruitment may exclude veterans without internet access. Cross-sectional design cannot determine whether cannabis use preceded or followed PTSD."},{"rthcId":"RTHC-00663","title":"A human laboratory study investigating the effects of quetiapine on marijuana withdrawal and relapse in daily marijuana smokers.","authors":"Cooper, Ziva D; Foltin, Richard W; Hart, Carl L; Vosburg, Suzanne K; Comer, Sandra D; Haney, Margaret","year":2013,"journal":"Addiction biology, 18(6), 993-1002","doi":"10.1111/j.1369-1600.2012.00461.x","pmid":"22741619","tags":["withdrawal","addiction","sleep"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a double-blind, within-subjects study, 14 heavy cannabis smokers (averaging 10 joints/day) completed two 15-day medication phases (quetiapine 200 mg/day vs. placebo). During withdrawal (3 days without cannabis), quetiapine improved sleep quality, increased caloric intake, and reduced weight loss compared to placebo.\n\nHowever, during the relapse phase (4 days with cannabis available), quetiapine increased marijuana craving and self-administration. This paradoxical pattern, helping with withdrawal symptoms but worsening relapse, led the authors to conclude quetiapine does not show promise as a cannabis dependence treatment.","whyItMatters":"Cannabis withdrawal management is an unmet clinical need. While quetiapine's ability to address sleep, appetite, and weight loss is valuable, the increased craving and self-administration during the relapse phase represents a potentially dangerous trade-off that outweighs these benefits.","specificNumbers":"14 participants smoking 10 joints/day. Quetiapine 200 mg/day vs. placebo. Withdrawal phase: improved sleep quality, increased caloric intake, decreased weight loss. Relapse phase: increased craving, increased marijuana self-administration.","methodology":"Double-blind, counterbalanced, within-subjects laboratory study. 14 volunteers (10 male, 4 female) smoking 10 marijuana cigarettes/day. Each medication phase: 15 days total, last 8 inpatient. Day 1: active marijuana. Days 2-4: inactive marijuana (withdrawal). Days 5-8: active marijuana available (relapse). Subjective, sleep, caloric, and behavioral measures collected.","limitations":"Very small sample (14 participants). Non-treatment-seeking volunteers may differ from people trying to quit. The inpatient laboratory setting does not replicate real-world quit conditions. Only one dose (200 mg/day) was tested. The within-subjects design means each participant experienced both conditions."},{"rthcId":"RTHC-00664","title":"Changes in cannabis use among young people: impact on mental health.","authors":"Copeland, Jan; Rooke, Sally; Swift, Wendy","year":2013,"journal":"Current opinion in psychiatry, 26(4), 325-9","doi":"10.1097/YCO.0b013e328361eae5","pmid":"23689549","tags":["youth","mental-health","psychosis","anxiety","depression"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined current trends in youth cannabis use and their mental health implications. While overall cannabis use rates showed mixed trends globally, the THC content of available cannabis had shifted toward higher levels, potentially increasing psychotogenic and memory-impairing effects.\n\nAfter controlling for multiple confounders, longitudinal research showed cannabis use predicted anxiety disorders, depression, suicidal ideation, certain personality disorders, and interpersonal violence. These associations were stronger in adolescents than adults, and earlier initiation age increased risk further. Cannabis use disorder was most prevalent among youth.","whyItMatters":"This review consolidated evidence that the adolescent brain is particularly vulnerable to cannabis-related mental health consequences. The combination of increasing THC potency and adolescent neurological sensitivity creates a concerning situation for youth public health.","specificNumbers":"Cannabis use disorder most prevalent among youth. Longitudinal evidence after controlling confounders: cannabis predicts anxiety, depression, suicidality, personality disorders, violence. Associations stronger in adolescents vs. adults. Earlier initiation = greater risk.","methodology":"Narrative review of recent epidemiological data on cannabis use trends and longitudinal research on cannabis-mental health associations in young people. Focused on studies controlling for confounders.","limitations":"Narrative review may not capture all relevant studies. The causal direction between cannabis use and mental health remains debated. Confounding factors are difficult to fully control in observational studies. The review acknowledged that cannabis strains have changed alongside shifting potency profiles."},{"rthcId":"RTHC-00665","title":"Palmitoylethanolamide: from endogenous cannabimimetic substance to innovative medicine for the treatment of cannabis dependence.","authors":"Coppola, M; Mondola, R","year":2013,"journal":"Medical hypotheses, 81(4), 619-22","doi":"10.1016/j.mehy.2013.07.016","pmid":"23896215","tags":["addiction","neuroscience","withdrawal"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The authors proposed that PEA, a fatty acid amide with pharmacological similarities to THC, could serve as a treatment for cannabis dependence. PEA can activate cannabinoid receptors directly and indirectly, and also acts on TRPV1 receptors.\n\nThe hypothesis was that PEA could reduce cannabis cravings, treat withdrawal symptoms, decrease cannabis consumption, and prevent cannabis-induced neurotoxicity and neuropsychiatric disorders. The rationale was based on PEA's known anti-inflammatory, neuroprotective, and analgesic properties, combined with its endocannabinoid-like pharmacology.","whyItMatters":"No approved medications exist for cannabis dependence. PEA is an endogenous compound already available as a supplement with a good safety profile. If the hypothesis proves correct, it could provide a readily available treatment for cannabis withdrawal and dependence.","specificNumbers":"PEA is a fatty acid amide. Shares pharmacological properties with THC. Acts at cannabinoid receptors and TRPV1 receptors. Proposed for: anti-craving, withdrawal treatment, consumption reduction, neuroprotection.","methodology":"Hypothesis paper proposing PEA as a cannabis dependence treatment based on pharmacological similarities to THC and known biological properties. No original experimental data presented.","limitations":"This is a hypothesis paper with no experimental evidence for the proposed uses. The pharmacological similarities between PEA and THC are partial. The proposed anti-craving and anti-withdrawal effects are speculative. Clinical trials would be needed to test any of these claims."},{"rthcId":"RTHC-00666","title":"Sex differences in cannabinoid pharmacology: A reflection of differences in the endocannabinoid system?","authors":"Craft, Rebecca M.; Marusich, Julie A.; Wiley, Jenny L.","year":2013,"journal":"Life Sciences, 92(8-9), 476-481","doi":"10.1016/j.lfs.2012.06.009","pmid":"22728714","tags":["sex-differences","addiction","withdrawal","youth"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Across studies, sex differences showed up in both species but with uneven strength. In human research, women were reported to have higher rates of cannabis abuse and dependence, more severe withdrawal, and higher relapse risk compared with men. Lab tasks in people suggested women were more affected by cannabinoids, sometimes showing enhanced performance and sometimes worse performance depending on the task.\n\nIn rodents, the pattern was clearer. Females were more sensitive to cannabinoid effects on pain-related tests, motor activity, and the reinforcing properties of cannabinoids. Studies of exposure during adolescence in both humans and rodents linked female adolescents to greater adverse effects than males.\n\nThe review highlights gonadal hormones as a likely source of these differences. Estradiol was identified as the main candidate influencing adult responses, through both activational effects across the cycle and possible organizational effects earlier in life. Sex-linked differences in the endocannabinoid system have been documented in rodents. Comparable evidence in humans had not been firmly established at the time of publication.","whyItMatters":"Sex can shape how drugs are experienced and how problems develop. By pulling together human data with mechanistic animal work, this review flags that women and men may not respond to cannabinoids the same way, and that hormonal context could matter. That has consequences for study design, interpretation of lab findings, and how dependence and withdrawal are evaluated across sexes.","specificNumbers":"- Study type: narrative review spanning human observations and rodent experiments, no pooled statistics\n- Proposed mechanism: estradiol highlighted as a key hormonal driver of sex differences (largely from animal data)\n- Adolescence: both human and rodent studies linked female adolescents to greater adverse effects than males\n- Endocannabinoid system: sex differences documented in rodents; not firmly established in humans","methodology":"Narrative review of human and animal studies on sex differences in cannabinoid pharmacology, dependence, withdrawal, relapse, and task performance. The authors synthesize patterns across heterogeneous methods: epidemiologic observations, human laboratory tasks, and rodent experiments probing nociception, motor activity, reinforcement, and hormonal mechanisms. No systematic search strategy or pooled effect sizes were reported.","limitations":"This is a narrative review without a prespecified search strategy or quality ratings. Many human findings come from cross-sectional or laboratory task studies that do not establish causation and often do not control for menstrual phase, contraceptive use, or product potency. Mechanistic conclusions rest heavily on rodent data, which may not translate to humans. The paper predates today’s product diversity and higher-potency markets, and it does not quantify effect sizes."},{"rthcId":"RTHC-00667","title":"The association between phencyclidine use and partner violence: an initial examination.","authors":"Crane, Cory A; Easton, Caroline J; Devine, Susan","year":2013,"journal":"Journal of addictive diseases, 32(2), 150-7","doi":"10.1080/10550887.2013.797279","pmid":"23815422","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared 109 PCP users, 81 cannabis users, and 97 polysubstance (alcohol and cannabis) users from substance abuse evaluations. PCP users were more likely than both comparison groups to have received inpatient referrals, have significant legal histories, and have perpetrated both general violence and intimate partner violence in the past year.\n\nThe finding that PCP users were more violent than even polysubstance users (who used both alcohol and cannabis) suggests that PCP has a specific association with violence beyond what can be attributed to general substance use.","whyItMatters":"Cannabis is often discussed alongside more dangerous drugs, but this study provides context showing that the violence profile of cannabis users is significantly lower than PCP users. The cannabis-only group served as a comparison baseline, helping distinguish substance-specific effects.","specificNumbers":"109 PCP users vs. 81 cannabis users vs. 97 polysubstance users. PCP users had higher rates of: inpatient referrals, legal history, past-year general violence, past-year intimate partner violence. All comparisons significant relative to both other groups.","methodology":"Cross-sectional comparison of substance abuse evaluations from 109 PCP-addicted, 81 cannabis-abusing, and 97 polysubstance (alcohol and cannabis)-abusing offenders. Compared rates of inpatient referral, legal history, general violence, and intimate partner violence.","limitations":"Cross-sectional design cannot prove PCP use causes violence. All participants were offenders undergoing substance abuse evaluation, not a general population sample. Selection into PCP use may involve pre-existing traits that also predict violence. The groups may differ on unmeasured variables."},{"rthcId":"RTHC-00668","title":"Critical appraisal of the potential use of cannabinoids in cancer management.","authors":"Cridge, Belinda J; Rosengren, Rhonda J","year":2013,"journal":"Cancer management and research, 5, 301-13","doi":"10.2147/CMAR.S36105","pmid":"24039449","tags":["cancer","neuroscience","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review analyzed the anticancer evidence for endocannabinoids, phytocannabinoids, and synthetic cannabinoids across multiple cancer types including glioma, breast, prostate, liver, and lung cancer. Both in vitro (cell line) and in vivo (animal) studies showed cannabinoids could inhibit tumor growth through multiple mechanisms.\n\nKey pathways included the ERK signaling pathway and ceramide/lipid signaling. An emerging area was the interplay between autophagy (cellular self-digestion) and apoptosis (programmed cell death) in cannabinoid-induced cancer cell killing. However, results remained contradictory, with some studies showing cannabinoids promoting rather than inhibiting tumor growth under certain conditions.","whyItMatters":"Cancer patients increasingly use cannabis alongside conventional treatment. Understanding whether cannabinoids genuinely have anticancer properties, and under what conditions they might help versus harm, is critical for informed decision-making and future drug development.","specificNumbers":"Studies covered: glioma, breast, prostate, endothelial, liver, lung cancer. Key pathways: ERK signaling, ceramide signaling. Types of cannabinoids: endo-, phyto-, synthetic. Both pro- and anti-tumor effects documented depending on conditions.","methodology":"Critical narrative review of preclinical cannabinoid anticancer research. Covered endo-, phyto-, and synthetic cannabinoids across multiple cancer types. Analyzed mechanisms of action including cell signaling pathways, autophagy, and apoptosis.","limitations":"Most evidence was preclinical (cell lines and animal models). In vitro results often do not translate to in vivo efficacy. Contradictory findings across studies remained unresolved. The doses used in laboratory studies may not be achievable in the human body. Very few human clinical studies existed at the time."},{"rthcId":"RTHC-00669","title":"Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report.","authors":"Crippa, J A S; Hallak, J E C; Machado-de-Sousa, J P; Queiroz, R H C; Bergamaschi, M; Chagas, M H N; Zuardi, A W","year":2013,"journal":"Journal of clinical pharmacy and therapeutics, 38(2), 162-4","doi":"10.1111/jcpt.12018","pmid":"23095052","tags":["cbd","withdrawal","quitting"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 19-year-old heavy cannabis user experiencing withdrawal syndrome (increased anxiety, insomnia, loss of appetite, irritability, restlessness) was treated with cannabidiol (CBD) for 10 days. Daily symptom assessments showed the absence of significant withdrawal symptoms, anxiety symptoms, and dissociative symptoms throughout the treatment.\n\nThe rationale for CBD was that cannabis withdrawal results from desensitization of CB1 receptors by THC. CBD interacts with the endocannabinoid system differently from THC and does not produce psychoactive effects, making it a logical candidate for managing the transition off cannabis.","whyItMatters":"Cannabis withdrawal can be severe enough to prevent successful quitting. There are no approved medications for cannabis withdrawal. This case report suggests CBD, a non-psychoactive component of cannabis itself, could manage withdrawal symptoms, providing a basis for larger clinical trials.","specificNumbers":"1 patient, 19 years old, female. CBD treatment for 10 days. Absence of significant withdrawal, anxiety, and dissociative symptoms throughout.","methodology":"Single case report of a 19-year-old woman with cannabis withdrawal syndrome. CBD administered for 10 days with daily symptom assessments for withdrawal, anxiety, and dissociative symptoms.","limitations":"This is a single case report with no control condition. Withdrawal symptoms may have resolved naturally. No dose information was provided in the abstract. The case cannot establish whether CBD directly prevented withdrawal or whether other factors contributed. Case reports are the lowest level of clinical evidence."},{"rthcId":"RTHC-00670","title":"Neural mechanisms of risky decision-making and reward response in adolescent onset cannabis use disorder.","authors":"De Bellis, Michael D; Wang, Lihong; Bergman, Sara R; Yaxley, Richard H; Hooper, Stephen R; Huettel, Scott A","year":2013,"journal":"Drug and alcohol dependence, 133(1), 134-45","doi":"10.1016/j.drugalcdep.2013.05.020","pmid":"23773952","tags":["youth","addiction","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Three groups of male adolescents were compared during a decision-making fMRI task: 15 with cannabis use disorder in remission, 23 controls with other psychiatric conditions, and 18 healthy controls. Abstinent cannabis users showed hyperactivation in parietal/visual regions during risky decisions involving uncertainty, and hypoactivation in the orbitofrontal cortex to rewarded outcomes.\n\nBoth control groups differed significantly from the cannabis group (but not from each other) in both decision-making and reward processing. The number of different drug classes tried correlated negatively with orbitofrontal reward response, and cannabis use duration correlated negatively with orbitofrontal response to non-reward.","whyItMatters":"The persistence of abnormal brain activation patterns after remission from cannabis use disorder suggests that either cannabis caused lasting brain changes or these patterns represent pre-existing vulnerabilities. Either interpretation has implications for understanding adolescent addiction and predicting relapse risk.","specificNumbers":"15 CUD remission, 23 psychiatric controls, 18 healthy controls. CUD group: hyperactivation in parietal/occipital during risky decisions. Hypoactivation in OFC to reward. Number of drug classes negatively correlated with OFC reward response. CUD duration negatively correlated with OFC no-reward response.","methodology":"Cross-sectional fMRI study comparing three groups of male adolescents during the Decision-Reward Uncertainty Task. CUD group in full remission (n=15), psychiatric controls (n=23), healthy controls (n=18). Post-hoc ROI analyses examined correlations between brain activation and substance use variables.","limitations":"Small sample sizes, especially the CUD group (15). Cross-sectional design cannot determine whether brain differences preceded or resulted from cannabis use. Only males were studied. The CUD group was in remission, which means some recovery may have already occurred. Other substance exposure could have contributed."},{"rthcId":"RTHC-00671","title":"Exercise-induced acute coronary syndrome in a 24-year-old man with massive cannabis consumption.","authors":"Deharo, Pierre; Massoure, Pierre-Laurent; Fourcade, Laurent","year":2013,"journal":"Acta cardiologica, 68(4), 425-8","doi":null,"pmid":"24187771","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 24-year-old male soccer player presented with an acute coronary syndrome (heart attack) during exercise. He had no traditional cardiovascular risk factors (no diabetes, high blood pressure, high cholesterol, smoking tobacco, or family history), but had a history of massive cannabis addiction.\n\nCoronary angiography revealed complete occlusion of the proximal right coronary artery, and intravascular ultrasound showed atherosclerotic plaque disruption. Treatment involved thromboaspiration (removing the blood clot) and antithrombotic medications, which were successful without requiring stenting.","whyItMatters":"Heart attacks in 24-year-olds without traditional risk factors are extremely rare. The presence of atherosclerotic plaque and its disruption in a young, otherwise healthy athlete with heavy cannabis use adds to the evidence that cannabis may have cardiovascular toxicity, particularly when combined with physical exertion.","specificNumbers":"24 years old. No traditional cardiovascular risk factors. Complete occlusion of proximal right coronary artery. Atherosclerotic plaque disruption on intravascular ultrasound. Successful treatment without stenting.","methodology":"Single case report of a 24-year-old male presenting with exercise-induced acute coronary syndrome. Diagnostic workup included coronary angiography, intravascular ultrasound, and assessment of cardiovascular risk factors.","limitations":"Case reports cannot establish causation. Other unmeasured factors could have contributed. The definition of \"massive cannabis addiction\" is not quantified in the abstract. Exercise itself can trigger coronary events in people with undetected plaque. This is a single case."},{"rthcId":"RTHC-00672","title":"Analysis of tolerance and behavioral/physical dependence during chronic CB1 agonist treatment: effects of CB1 agonists, antagonists, and noncannabinoid drugs.","authors":"Desai, Rajeev I; Thakur, Ganesh A; Vemuri, V Kiran; Bajaj, Shama; Makriyannis, Alexandros; Bergman, Jack","year":2013,"journal":"The Journal of pharmacology and experimental therapeutics, 344(2), 319-28","doi":"10.1124/jpet.112.198374","pmid":"23197773","tags":["tolerance","addiction","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Squirrel monkeys chronically treated with the potent CB1 agonist AM411 developed enormous tolerance to cannabinoid agonists, with up to 250-fold rightward shifts in potency. At the same time, they became much more sensitive to CB1 antagonists (100-fold leftward shift for SR141716A), providing evidence of physical dependence.\n\nCritically, cross-tolerance developed with methamphetamine (4.8-fold) and the dopamine D2 agonist NPA (10-fold), but not with other dopamine or opioid drugs. The differences in tolerance magnitude among cannabinoid agonists may reflect differences in their pharmacological efficacy (how strongly they activate the receptor).","whyItMatters":"The cross-tolerance between the cannabinoid and dopamine systems provides strong evidence that these systems interact functionally. This has implications for understanding why cannabis users may have blunted responses to natural rewards and why stimulant effects may be altered in cannabis users.","specificNumbers":"Tolerance: >250-fold for AM411, methanandamide. >45-fold for AM4054, WIN55,212.2, THC. Antagonist sensitivity: >100-fold for SR141716A, >20-fold for AM4113. Cross-tolerance: 4.8-fold for methamphetamine, 10-fold for NPA. No change for other DA drugs, morphine, or naltrexone.","methodology":"Behavioral pharmacology study in squirrel monkeys using a fixed-ratio schedule of shock avoidance. Chronic treatment with AM411 (1.0 mg/kg/day, intramuscular). Dose-response curves for CB1 agonists, antagonists, dopamine-related drugs (methamphetamine, SKF82958, SCH23390, NPA, haloperidol), and opioid drugs (morphine, naltrexone) compared before and during chronic treatment.","limitations":"Primate behavioral pharmacology with small sample sizes typical of the field. The doses and chronic treatment regimen may not reflect human cannabis use. The behavioral measure (shock avoidance) is a specific assay that may not capture all aspects of drug effects. Only one chronic treatment dose was tested."},{"rthcId":"RTHC-00673","title":"The effect of tobacco and marijuana use on dental health status in Nevada adolescents: a trend analysis.","authors":"Ditmyer, Marcia; Demopoulos, Christina; McClain, Mildred; Dounis, Georgia; Mobley, Connie","year":2013,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 52(5), 641-8","doi":"10.1016/j.jadohealth.2012.11.002","pmid":"23352726","tags":["youth","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers screened 66,941 adolescents (ages 13-18) across Nevada middle and high schools from 2002 to 2010. Marijuana use rates were significantly higher than the national average (12.0% vs. 3.3%). Both tobacco and marijuana use were associated with significantly higher prevalence and severity of dental caries across all demographic variables and across all 8 years.\n\nMarijuana had the largest negative effect on dental health, exceeding even tobacco's impact. These associations held after controlling for gender, race/ethnicity, location, and secondhand smoke exposure.","whyItMatters":"Dental health is often overlooked in discussions of cannabis harm. This large study demonstrates that marijuana use has a substantial negative impact on adolescent dental health that exceeds tobacco, a substance with well-established oral health consequences. This finding adds to the harm profile for adolescent cannabis use.","specificNumbers":"66,941 adolescent dental screenings. 8 years of data (2002-2010). Nevada marijuana use: 12.0% vs. 3.3% national average. Marijuana had the largest negative effect on dental caries. Both substances associated with higher prevalence and severity across all subgroups.","methodology":"Retrospective cohort study using an ongoing statewide school-based dental health screening initiative across 8 years (2002-2010). 66,941 dental screenings. Self-reported tobacco and marijuana use. Caries prevalence and severity measured by dental professionals. Effect sizes reported.","limitations":"Self-reported substance use may be underreported in a school setting. The study cannot establish that marijuana directly caused worse dental health versus confounders like diet, oral hygiene habits, or access to dental care. Cross-sectional within each year, though trend data spans 8 years."},{"rthcId":"RTHC-00674","title":"Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment.","authors":"Englund, Amir; Morrison, Paul D; Nottage, Judith; Hague, Dominic; Kane, Fergus; Bonaccorso, Stefania; Stone, James M; Reichenberg, Avi; Brenneisen, Rudolf; Holt, David; Feilding, Amanda; Walker, Lucy; Murray, Robin M; Kapur, Shitij","year":2013,"journal":"Journal of psychopharmacology (Oxford, England), 27(1), 19-27","doi":"10.1177/0269881112460109","pmid":"23042808","tags":["cbd","psychosis","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In a between-subjects, double-blind design, 48 healthy participants received either 600 mg oral CBD (n=22) or placebo (n=26) before intravenous THC (1.5 mg). CBD pretreatment produced two key protective effects.\n\nFirst, clinically significant psychotic symptoms (3+ point increase on PANSS positive scale) were significantly less likely in the CBD group (OR=0.22), and paranoia scores were significantly lower. Second, verbal learning memory (HVLT-R) declined by 10.6% in the placebo group but only 0.4% in the CBD group, essentially eliminating THC's memory-impairing effect.","whyItMatters":"This study provides experimental evidence for the epidemiological observation that high-THC/low-CBD cannabis products are more harmful than balanced-ratio products. It also suggests CBD could serve as a protective agent against THC's negative psychiatric effects, with implications for medical cannabis formulation.","specificNumbers":"48 participants. CBD 600 mg oral, 210 min before THC 1.5 mg IV. Clinically significant psychosis: OR=0.22 in CBD group (p<0.05). Paranoia: significantly lower in CBD group (p<0.05). Memory decline: -10.6% (placebo) vs. -0.4% (CBD) (p<0.05).","methodology":"Between-subjects, double-blind, placebo-controlled RCT. 48 healthy participants (22 CBD, 26 placebo). CBD 600 mg oral administered 210 minutes before IV THC 1.5 mg. Outcomes: PANSS positive scores, State Social Paranoia Scale, Hopkins Verbal Learning Task-Revised.","limitations":"The between-subjects design means individual differences may have contributed. A single high IV THC dose is not equivalent to chronic cannabis smoking. The oral CBD was given 3.5 hours before IV THC, which may not reflect typical cannabis use where both cannabinoids are consumed simultaneously. The sample was healthy volunteers without psychosis risk factors."},{"rthcId":"RTHC-00675","title":"Clinical features associated with trait-impulsiveness in euthymic bipolar disorder patients.","authors":"Etain, B; Mathieu, F; Liquet, S; Raust, A; Cochet, B; Richard, J R; Gard, S; Zanouy, L; Kahn, J P; Cohen, R F; Bougerol, T; Henry, C; Leboyer, M; Bellivier, F","year":2013,"journal":"Journal of affective disorders, 144(3), 240-7","doi":"10.1016/j.jad.2012.07.005","pmid":"22901401","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared impulsivity scores between 385 stable (euthymic) bipolar patients and 185 healthy controls. Bipolar patients scored significantly higher on all impulsivity measures (motor, attentional, non-planning) than controls.\n\nHigher impulsivity was associated with alcohol misuse (p=0.005), cannabis misuse (p<0.0001), rapid cycling (p=0.006), and mixed episodes (p=0.002), with additive effects when multiple factors were present. Contrary to expectations, impulsivity was not associated with suicide attempts. Cannabis misuse showed the strongest individual association with impulsivity.","whyItMatters":"Understanding that impulsivity in bipolar disorder links specifically to substance misuse and a more severe illness course (rather than to suicide) helps clinicians know what to watch for. Highly impulsive bipolar patients may benefit most from substance use screening and prevention.","specificNumbers":"385 bipolar patients, 185 controls. All impulsivity subscores significantly higher in patients (p<0.0001). Cannabis misuse: p<0.0001 with impulsivity. Alcohol misuse: p=0.005. Rapid cycling: p=0.006. Mixed episodes: p=0.002. No association with suicide attempts.","methodology":"Cross-sectional comparison of BIS-10 impulsivity scores between 385 euthymic bipolar patients and 185 healthy controls. Associations between impulsivity and clinical features (suicide attempts, substance misuse, rapid cycling, mixed episodes) were examined.","limitations":"Cross-sectional design cannot establish whether impulsivity drives substance misuse or vice versa. Only one measure of impulsivity was used (BIS-10). Patients were euthymic at assessment, so impulsivity levels during mood episodes may differ. No cognitive assessment of impulsivity was performed."},{"rthcId":"RTHC-00676","title":"Diminished error-related brain activity as a promising endophenotype for substance-use disorders: evidence from high-risk offspring.","authors":"Euser, Anja S; Evans, Brittany E; Greaves-Lord, Kirstin; Huizink, Anja C; Franken, Ingmar H A","year":2013,"journal":"Addiction biology, 18(6), 970-84","doi":"10.1111/adb.12002","pmid":"23145495","tags":["youth","addiction","neuroscience","genetics"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared error-processing brain activity (ERN) between 28 high-risk adolescents (children of parents with substance use disorders) and 40 normal-risk controls during a flanker task. High-risk offspring showed smaller ERN amplitudes, reflecting impaired early error processing and suboptimal performance monitoring.\n\nCritically, this reduced error-processing was found even in high-risk offspring who had never used cannabis, suggesting it represents an inherited vulnerability rather than a drug-induced deficit. High-risk adolescents also had more internalizing symptoms and more frequent cannabis use, and cannabis use independently influenced the ERN.","whyItMatters":"If diminished error-processing is present before substance use begins, it could serve as a biomarker for identifying at-risk youth before they develop problems. This could enable targeted prevention for children of parents with addiction.","specificNumbers":"28 high-risk vs. 40 normal-risk adolescents. Smaller ERN amplitudes in high-risk group. Effect present in cannabis-naive high-risk offspring. Risk group predicted ERN above and beyond confounding variables. High-risk group: more internalizing symptoms, more cannabis use.","methodology":"Cross-sectional ERP study comparing high-risk (n=28, parents with SUD) and normal-risk (n=40) adolescents during an Eriksen Flanker Task. ERN amplitudes measured in response to errors. Cannabis use history and internalizing symptoms assessed. Analyses controlled for confounders.","limitations":"Relatively small sample sizes. Cross-sectional design limits causal conclusions despite the cannabis-naive subgroup analysis. The flanker task measures a specific type of error processing that may not capture all aspects of performance monitoring. Other genetic or environmental factors may contribute to the ERN differences."},{"rthcId":"RTHC-00677","title":"Integrating brain and behavior: evaluating adolescents' response to a cannabis intervention.","authors":"Feldstein Ewing, Sarah W; McEachern, Amber D; Yezhuvath, Uma; Bryan, Angela D; Hutchison, Kent E; Filbey, Francesca M","year":2013,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 27(2), 510-25","doi":"10.1037/a0029767","pmid":"22925010","tags":["youth","addiction","neuroscience","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Forty-three adolescent cannabis users (mean age 16) underwent motivational interviewing before brain scanning. During fMRI, they heard their own \"change talk\" (statements favoring quitting) and \"counterchange talk\" (statements favoring continued use) while viewing cannabis and control images.\n\nGreater brain activation during change talk (vs. counterchange talk) was found in self-referential processing areas (medial frontal gyrus, insula), but only during cannabis cues, not control cues. This specific activation pattern, change talk combined with cannabis cues in introspection regions (posterior cingulate, precuneus), predicted better outcomes at one-month follow-up: less frequent cannabis use, fewer problems, and lower dependence scores.","whyItMatters":"This study bridges neuroscience and clinical intervention by showing that motivational interviewing produces measurable brain changes that predict real-world outcomes. It validates the therapeutic mechanism of motivational interviewing at the neural level and suggests brain imaging could potentially identify which patients will respond to treatment.","specificNumbers":"43 adolescents, mean age 16. 83.7% male. Greater medial frontal gyrus and insula activation during change talk + cannabis cues. Posterior cingulate and precuneus activation during change talk predicted 1-month outcomes: less use, fewer problems, lower dependence.","methodology":"Longitudinal study with 43 adolescent cannabis users (83.7% male, 53.5% Hispanic, mean age 16). Motivational interviewing followed by fMRI cannabis cue-exposure paradigm using participants' own statements. One-month follow-up assessed cannabis use frequency, problems, and dependence.","limitations":"Relatively small sample of primarily male Hispanic adolescents. Only one-month follow-up. The fMRI paradigm uses the participant's own statements, which vary in content and emotional salience. The correlation between brain activation and outcomes does not prove causation. No control intervention group."},{"rthcId":"RTHC-00678","title":"Prevalence and key covariates of non-medical prescription opioid use among the general secondary student and adult populations in Ontario, Canada.","authors":"Fischer, Benedikt; Ialomiteanu, Anca; Boak, Angela; Adlaf, Edward; Rehm, Jürgen; Mann, Robert E","year":2013,"journal":"Drug and alcohol review, 32(3), 276-87","doi":"10.1111/dar.12025","pmid":"23305232","tags":["addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Two representative surveys in Ontario examined non-medical prescription opioid use (NMPOU): 4,023 adults and 3,266 secondary school students. NMPOU prevalence was notably high, especially among students (15.5%) compared to adults (5.9%).\n\nMultivariate analyses revealed different predictors by sex and age group. For male students, other drug use was the strongest independent predictor. For female students, rural residence, subjective social status, other drug use, and suicidal ideation were all independently associated. Among male adults, marital status and cannabis use were independent predictors. Among female adults, binge drinking was the key factor.","whyItMatters":"The finding that NMPOU was three times higher in students than adults signals that adolescence is a particularly high-risk period for prescription opioid misuse. The association between cannabis use and opioid misuse in adults raises questions about polysubstance use patterns.","specificNumbers":"Students: 15.5% past-year NMPOU. Adults: 5.9% past-year NMPOU. Independent predictors varied by sex. Cannabis use independently associated with NMPOU in male adults. Suicidal ideation associated in female students.","methodology":"Two population surveys: the Centre for Addiction and Mental Health Monitor (CM), a random-digit-dialing telephone survey of 4,023 adults (2010-2011 cycles), and the Ontario Student Drug Use and Health Survey (OSDUHS), a school-based questionnaire of 3,266 students in grades 7-12 (2011). Logistic regression identified independent predictors.","limitations":"Cross-sectional design cannot establish causal direction between cannabis use and opioid misuse. Self-reported data may underestimate true prevalence. The telephone-based adult survey may miss certain populations. Ontario-specific findings may not generalize to other regions."},{"rthcId":"RTHC-00679","title":"Marijuana poisoning.","authors":"Fitzgerald, Kevin T; Bronstein, Alvin C; Newquist, Kristin L","year":2013,"journal":"Topics in companion animal medicine, 28(1), 8-12","doi":"10.1053/j.tcam.2013.03.004","pmid":"23796481","tags":["harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review documented the clinical picture of marijuana poisoning in companion animals, primarily dogs. Common signs included depression, hypersalivation, dilated pupils, hypermetria, vomiting, urinary incontinence, tremors, hypothermia, and bradycardia. Higher doses could cause nystagmus, agitation, rapid breathing, tachycardia, ataxia, and seizures.\n\nWhile the minimum lethal oral dose for dogs is over 3 g/kg of THC (giving it a high safety margin), deaths had occurred from ingestion of food products containing concentrated medical-grade THC butter. Treatment was primarily supportive, with no specific antidote. The use of intralipid therapy to bind THC was emerging as a treatment strategy.","whyItMatters":"As cannabis becomes more accessible and concentrated products become more common, the risk to pets increases. Dogs are particularly vulnerable because they commonly ingest their owners' marijuana supply. The emergence of concentrated THC edibles creates a risk category that did not previously exist.","specificNumbers":"Minimum lethal oral dose: >3 g/kg THC. Clinical onset: within 60 minutes of oral ingestion. 15% of THC excreted in urine, rest via feces. Two cannabinoid receptors: CB1 (CNS) and CB2 (peripheral). Deaths reported from concentrated THC butter products.","methodology":"Narrative review of veterinary marijuana toxicology literature covering pharmacology, clinical presentation, diagnosis, and treatment. Included discussion of CB1 and CB2 receptor distribution in dogs, THC metabolism, and diagnostic testing limitations.","limitations":"Mostly based on case reports and clinical experience rather than controlled studies. Human urine drug tests for cannabinoids are unreliable in dogs. The lethal dose data comes from limited historical studies. Treatment recommendations were largely empirical."},{"rthcId":"RTHC-00680","title":"Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors.","authors":"Gaffal, E; Cron, M; Glodde, N; Tüting, T","year":2013,"journal":"Allergy, 68(8), 994-1000","doi":"10.1111/all.12183","pmid":"23889474","tags":["inflammation","cbd"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers applied THC topically to mice with allergic contact dermatitis (ear swelling model). THC effectively reduced ear swelling and immune cell infiltration not only in normal mice but also in mice genetically lacking both CB1 and CB2 cannabinoid receptors.\n\nThe mechanism involved three steps: THC inhibited IFN-gamma production by T cells, decreased production of chemokines CCL2, CCL8, and CXCL10 by skin cells (keratinocytes), and thereby limited recruitment of myeloid immune cells. All these effects occurred independently of CB1/CB2 receptors, suggesting THC acts on the skin immune system through alternative molecular targets.","whyItMatters":"Most cannabinoid therapeutic strategies focus on CB1 and CB2 receptors. This study reveals that THC's anti-inflammatory effects on skin work through entirely different pathways, opening new therapeutic avenues for inflammatory skin diseases that do not rely on traditional cannabinoid receptor mechanisms.","specificNumbers":"Anti-inflammatory effect in both wild-type and CB1/CB2 knockout mice. THC inhibited: IFN-gamma from T cells, CCL2 and IFN-gamma-induced CCL8 and CXCL10 from keratinocytes. Reduced myeloid immune cell infiltration. All effects CB1/CB2-independent.","methodology":"In vivo: DNFB-mediated allergic contact dermatitis in wild-type and CB1/CB2 receptor-deficient mice with topical THC. Immunohistochemistry for immune cell infiltration. In vitro: THC effects on T cell cytokine production, keratinocyte chemokine production, and myeloid cell recruitment assays.","limitations":"Mouse model of contact dermatitis may not perfectly replicate human inflammatory skin conditions. The specific molecular targets through which THC acts (since CB1/CB2 are excluded) were not identified. Topical application pharmacokinetics differ between mouse and human skin."},{"rthcId":"RTHC-00681","title":"Attention problems in childhood and adult substance use.","authors":"Galéra, Cédric; Pingault, Jean-Baptiste; Fombonne, Eric; Michel, Grégory; Lagarde, Emmanuel; Bouvard, Manuel-Pierre; Melchior, Maria","year":2013,"journal":"The Journal of pediatrics, 163(6), 1677-1683.e1","doi":"10.1016/j.jpeds.2013.07.008","pmid":"23972646","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 1,103 French youth from 1991 to 2009. Children with high levels of attention problems had higher rates of all four adult substance outcomes measured: regular tobacco smoking, alcohol problems, problematic cannabis use, and lifetime cocaine use.\n\nHowever, after adjusting for other childhood behavioral problems, early substance use, school difficulties, and family adversity, childhood attention problems only independently predicted regular tobacco smoking and lifetime cocaine use. The association with cannabis and alcohol problems was explained by confounding factors. Early cannabis exposure emerged as the strongest risk factor for all four substance use outcomes.","whyItMatters":"This study disentangled a complex web of childhood risk factors. While attention problems appear to predict substance use at first glance, most of that association is explained by co-occurring factors. Only the tobacco and cocaine links survived comprehensive adjustment, suggesting distinct pathways.","specificNumbers":"1,103 youth followed 18 years (1991-2009). High childhood attention problems associated with all 4 substance outcomes unadjusted. After full adjustment: only tobacco and cocaine remained significant. Early cannabis exposure: strongest predictor of all outcomes.","methodology":"Community-based longitudinal cohort of 1,103 French youth followed from 1991 to 2009 (18 years). Exposures measured at baseline: childhood behavioral problems (parent report), early substance use, school difficulties, family adversity. Outcomes at follow-up: tobacco, alcohol, cannabis, cocaine use (youth self-report).","limitations":"French cohort may not generalize to other populations. Childhood behavioral problems were parent-reported rather than clinically assessed. Early substance use was measured retrospectively. Attrition over 18 years could introduce selection bias. The \"early cannabis exposure\" finding does not prove causation."},{"rthcId":"RTHC-00682","title":"Predictors of marijuana relapse in the human laboratory: robust impact of tobacco cigarette smoking status.","authors":"Haney, Margaret; Bedi, Gillinder; Cooper, Ziva D; Glass, Andrew; Vosburg, Suzanne K; Comer, Sandra D; Foltin, Richard W","year":2013,"journal":"Biological psychiatry, 73(3), 242-8","doi":"10.1016/j.biopsych.2012.07.028","pmid":"22939992","tags":["addiction","quitting"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Study 1 combined data from five inpatient laboratory studies (51 daily marijuana smokers averaging 10 joints/day). When active marijuana became available, 49% relapsed on day one. Cigarette smokers (75%) were dramatically more likely to relapse than non-cigarette smokers, with an odds ratio of 19.\n\nStudy 2 isolated tobacco's direct effects by testing 15 marijuana-and-tobacco dual users under two conditions: smoking tobacco as usual versus after 5+ days of tobacco cessation. High relapse rates occurred regardless of tobacco condition (>87%). Tobacco cessation did not directly affect marijuana relapse, suggesting that being a tobacco smoker is a marker of relapse vulnerability rather than tobacco directly driving marijuana relapse.","whyItMatters":"This finding has major clinical implications. Marijuana treatment programs should assess tobacco smoking status as a key predictor of relapse. The 19-fold increased odds of relapse represent one of the strongest predictors identified in marijuana treatment research.","specificNumbers":"51 participants in Study 1. 49% relapsed on day 1. Cigarette smokers: 75% relapse. Non-smokers: much lower (OR=19 for smokers). Study 2: 15 dual users. >87% relapsed regardless of tobacco condition.","methodology":"Study 1: Combined analysis of 5 inpatient studies. 51 daily marijuana smokers (10 joints/day). Day 1: active marijuana. Days 2-4: no marijuana (withdrawal). Days 5-8: active marijuana available (relapse). Study 2: Within-subjects comparison in 15 dual users: smoking as usual vs. tobacco-quit condition.","limitations":"Laboratory relapse model may not perfectly reflect real-world relapse. Non-treatment-seeking participants differ from treatment seekers. Study 2 was small (15 participants). The high base rate of relapse (49% day 1) reflects the laboratory setting. The odds ratio of 19 may be inflated by the small non-smoker comparison group."},{"rthcId":"RTHC-00683","title":"Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse.","authors":"Haney, Margaret; Cooper, Ziva D; Bedi, Gillinder; Vosburg, Suzanne K; Comer, Sandra D; Foltin, Richard W","year":2013,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 38(8), 1557-65","doi":"10.1038/npp.2013.54","pmid":"23443718","tags":["withdrawal","quitting","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Eleven daily marijuana smokers (averaging 8.3 joints/day) completed a within-subjects study testing three nabilone doses (0, 6, 8 mg/day). Each phase included a withdrawal period (3 days without marijuana) and a relapse period (4 days with active marijuana available).\n\nBoth nabilone doses (6 and 8 mg/day) significantly reduced marijuana relapse and reversed withdrawal-related irritability, sleep disruption, and food intake changes. Neither dose increased ratings of capsule \"liking\" or desire to take capsules, suggesting low abuse potential. The 8 mg dose modestly worsened psychomotor performance. Notably, nabilone achieved these effects with once-daily dosing, making it practical for clinical use.","whyItMatters":"Dronabinol (oral THC) reduces withdrawal symptoms but does not reduce marijuana self-administration. Nabilone did both, making it a more promising medication candidate. Its better bioavailability and clearer dose-linearity compared to dronabinol may explain its superior efficacy.","specificNumbers":"11 participants, 8.3 joints/day. Nabilone 6 and 8 mg/day both effective. Reduced: relapse, irritability, sleep disruption, food intake changes (p<0.05). No increased capsule liking. 8 mg: modest psychomotor impairment. Once-daily dosing sufficient.","methodology":"Within-subjects, double-blind, placebo-controlled inpatient study. 11 participants (8 men, 3 women) using 8.3 joints/day. Three 8-day phases with different nabilone doses (0, 6, 8 mg/day, counterbalanced). Days 2-4: placebo marijuana (withdrawal). Days 5-8: active marijuana available (relapse).","limitations":"Very small sample (11 participants). Non-treatment-seeking volunteers may differ from treatment seekers. Inpatient laboratory setting does not replicate real-world conditions. Only two active doses tested. Short treatment duration (7 days) does not address long-term outcomes."},{"rthcId":"RTHC-00684","title":"Synthetic cannabinoid intoxication: a case series and review.","authors":"Harris, Carson R; Brown, Ashley","year":2013,"journal":"The Journal of emergency medicine, 44(2), 360-6","doi":"10.1016/j.jemermed.2012.07.061","pmid":"22989695","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Six patients presented to an emergency department over three months after using Spice products. All but one had tachycardia (elevated heart rate). Two patients were admitted after reporting seizures, and two experienced hallucinations. The average observation time was 2.8 hours, and no patients with seizures had recurrent episodes.\n\nThe case series highlighted that synthetic cannabinoids are chemically distinct from natural cannabis and produce different, often more severe clinical effects. The legal status of these compounds was still being determined, creating challenges for both healthcare providers and law enforcement.","whyItMatters":"Synthetic cannabinoids were marketed as a legal alternative to marijuana but carry significantly greater health risks. This case series provided early clinical documentation that these products cause effects not typically seen with natural cannabis, including seizures and significant tachycardia.","specificNumbers":"6 cases over 3 months. 5 of 6 had tachycardia. 2 admitted for seizures. 2 had hallucinations. Average ED observation: 2.8 hours. No recurrent seizures.","methodology":"Retrospective case series reviewing emergency department presentations over a 3-month period where patients reported Spice drug use as chief complaint. Clinical data, symptoms, treatments, and outcomes documented.","limitations":"Case series of only 6 patients cannot characterize the full spectrum of effects. Self-reported drug use may be inaccurate. The specific synthetic cannabinoid compounds were likely not identified. No analytical confirmation of the substances used. The 3-month window and single facility limit generalizability."},{"rthcId":"RTHC-00685","title":"Use of micronutrients attenuates cannabis and nicotine abuse as evidenced from a reversal design: a case study.","authors":"Harrison, Rachel; Rucklidge, Julia J; Blampied, Neville","year":2013,"journal":"Journal of psychoactive drugs, 45(2), 168-78","doi":null,"pmid":"23909004","tags":["quitting","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"As part of a broader study of micronutrients for psychiatric symptoms (ADHD, depression, anxiety), researchers observed that a participant spontaneously reduced cannabis and cigarette use while taking vitamin and mineral supplements. Using a reversal design (off-on-off-on-off), they documented on-off control of both psychiatric symptoms and substance use across multiple cycles.\n\nWhen micronutrients were consumed, cannabis and cigarette use decreased. When withdrawn, use resumed. This pattern repeated across cycles, despite substance use not being a treatment target. The researchers proposed that micronutrients may assist cessation by improving mood regulation and reducing anxiety, or by directly affecting brain reward circuitry through neurotransmitter precursors and cofactors.","whyItMatters":"The reversal design provides stronger evidence than a typical case report because the on-off pattern was replicated multiple times. While still a single case, the repeated association between micronutrient use and reduced substance use across multiple cycles suggests a real effect.","specificNumbers":"Single participant. Reversal design: 5 phases (off-on-off-on-off). Cannabis and cigarette use decreased during micronutrient phases and increased during withdrawal phases. Pattern consistent across cycles.","methodology":"Single-case reversal (ABAB) design. Participant took broad-spectrum micronutrients (vitamins and minerals) in an off-on-off-on-off pattern. Psychiatric symptoms and substance use assessed throughout. Substance cessation was not a treatment goal.","limitations":"Single case cannot establish generalizability. No placebo control for supplement effects. The participant knew when they were taking supplements, introducing expectancy effects. Substance use changes could reflect other fluctuating life factors. The specific mechanisms are speculative."},{"rthcId":"RTHC-00686","title":"Prevalence and correlates of heavy smoking and nicotine dependence in adolescents with bipolar and cannabis use disorders.","authors":"Heffner, Jaimee L; Anthenelli, Robert M; Adler, Caleb M; Strakowski, Stephen M; Beavers, Jennifer; DelBello, Melissa P","year":2013,"journal":"Psychiatry research, 210(3), 857-62","doi":"10.1016/j.psychres.2013.04.010","pmid":"23684537","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Eighty adolescents (ages 13-22) with both bipolar I disorder and cannabis abuse or dependence were assessed for tobacco use. Among those who had ever tried a cigarette, 49% were heavy smokers (10+ cigarettes/day) and 70% met lifetime criteria for nicotine dependence.\n\nHeavy smoking was associated with a more severe clinical profile: older age, heavier marijuana use with greater compulsive craving, lifetime diagnoses of ADHD and conduct disorder, illicit drug use disorders, and poorer overall functioning. Nicotine dependence was related to White race, higher current mania severity, and poorer functioning. Cannabis and tobacco use appeared deeply entangled in this population.","whyItMatters":"Adolescents with bipolar disorder and cannabis problems face a triple burden when tobacco is added. The finding that heavy smoking marks a more severe psychiatric profile suggests tobacco may be both a consequence of and contributor to psychiatric severity in this population.","specificNumbers":"80 adolescents with bipolar I + cannabis disorder. 49% were heavy smokers (10+/day). 70% met lifetime nicotine dependence criteria. Heavy smoking associated with: heavier marijuana use, ADHD, conduct disorder, other drug disorders, poorer functioning.","methodology":"Cross-sectional analysis of baseline data from a clinical trial involving 80 adolescents aged 13-22 with co-occurring bipolar I disorder and cannabis abuse or dependence. Diagnostic and symptom severity measures assessed. Heavy smoking defined as 10+ cigarettes/day.","limitations":"Cross-sectional design cannot establish causal relationships. The sample was drawn from a clinical trial, representing treatment-seeking individuals who may be more severe than the general bipolar population. The 13-22 age range spans adolescence and early adulthood, which may differ clinically."},{"rthcId":"RTHC-00687","title":"A comprehensive examination of delay discounting in a clinical sample of Cannabis-dependent military veterans making a self-guided quit attempt.","authors":"Heinz, Adrienne J; Peters, Erica N; Boden, Matthew T; Bonn-Miller, Marcel O","year":2013,"journal":"Experimental and clinical psychopharmacology, 21(1), 55-65","doi":"10.1037/a0031192","pmid":"23379614","tags":["addiction","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Seventy-two cannabis-dependent US veterans (95% male) interested in quitting completed a delay discounting task before making self-guided quit attempts and were followed for 6 months. Higher delay discounting (preferring smaller immediate rewards over larger delayed ones) correlated with greater compulsive craving for cannabis, younger age of first cannabis use, earlier start of regular smoking, and having previously sought professional help to quit.\n\nHowever, delay discounting did not predict any cessation outcomes, either in the first week after quitting or during the 6-month follow-up. This contrasts with findings for tobacco, alcohol, and opioids, where delay discounting does predict cessation outcomes.","whyItMatters":"The finding that impulsivity relates to how cannabis dependence develops (earlier onset, more craving) but not to whether quitting succeeds suggests that cannabis cessation may depend on different factors than cessation from other substances. Treatment approaches may need to target different mechanisms than those used for tobacco or alcohol.","specificNumbers":"72 veterans, 95% male. Higher DD correlated with: compulsive craving (rho=0.29), younger first use (r=-0.32), earlier regular use (r=-0.25), prior professional help (rho=0.27). DD did not predict: 1-week outcomes, 6-month abstinence, time to relapse.","methodology":"Prospective cohort study of 72 cannabis-dependent veterans (95% male) making self-guided quit attempts. Computerized delay discounting task at baseline. Follow-up at 1 week and monthly for 6 months. Cessation outcomes included point-prevalence abstinence, continuous abstinence, and time to relapse.","limitations":"Almost exclusively male veteran sample limits generalizability. Self-guided quit attempts may differ from formal treatment. Only one measure of impulsivity was used. The 6-month follow-up may be insufficient to detect long-term effects. Sample size may be underpowered for some analyses."},{"rthcId":"RTHC-00688","title":"Haloperidol for treatment of cannabinoid hyperemesis syndrome.","authors":"Hickey, Jami L; Witsil, Joanne C; Mycyk, Mark B","year":2013,"journal":"The American journal of emergency medicine, 31(6), 1003.e5-6","doi":"10.1016/j.ajem.2013.02.021","pmid":"23583118","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with cannabinoid hyperemesis syndrome (CHS), characterized by cyclical vomiting in the setting of chronic cannabis use, was treated with haloperidol in the emergency department. The condition had been unresponsive to conventional antiemetic medications.\n\nPatients with CHS typically report that only compulsive bathing and hot showers provide relief, and the condition frequently requires hospital admission due to intractable vomiting. In this case, haloperidol produced significant improvement, suggesting a potential pharmacological treatment option for a condition with very limited treatment options.","whyItMatters":"CHS is increasingly recognized as cannabis use grows, and current treatment options are limited. If haloperidol consistently works, it could transform ER management of CHS from prolonged observation and admission to rapid treatment and discharge.","specificNumbers":"1 patient with CHS. Unresponsive to conventional antiemetics. Significant improvement with haloperidol. CHS characterized by cyclical vomiting in chronic cannabis users.","methodology":"Single case report of CHS treated with haloperidol in an emergency department setting.","limitations":"Single case report provides the lowest level of clinical evidence. Spontaneous resolution cannot be excluded. The dose and timing of haloperidol were not detailed in the abstract. No comparison to other treatments. Long-term outcome was not reported."},{"rthcId":"RTHC-00689","title":"The cannabinoid CB2 receptor is necessary for nicotine-conditioned place preference, but not other behavioral effects of nicotine in mice.","authors":"Ignatowska-Jankowska, Bogna M; Muldoon, Pretal P; Lichtman, Aron H; Damaj, M Imad","year":2013,"journal":"Psychopharmacology, 229(4), 591-601","doi":"10.1007/s00213-013-3117-6","pmid":"23652588","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using both pharmacological (drug) and genetic (knockout mice) approaches, researchers found that CB2 receptors are essential for nicotine's rewarding effects. Nicotine-induced conditioned place preference was completely blocked by the CB2 antagonist SR144528 and was absent in CB2 knockout mice.\n\nConversely, the CB2 agonist O-1966, when combined with a sub-threshold nicotine dose, produced place preference. Interestingly, for cocaine the pattern was opposite: the CB2 agonist blocked cocaine reward, while CB2 knockout mice showed normal cocaine reward. CB2 receptors played no role in nicotine withdrawal symptoms or acute somatic effects like hypothermia and pain reduction.","whyItMatters":"This study revealed that CB2 receptors, previously thought to be mainly peripheral immune receptors, play a critical role in nicotine reward. The opposing roles in nicotine versus cocaine reward suggest sophisticated and substance-specific cannabinoid modulation of addiction.","specificNumbers":"Nicotine CPP blocked by SR144528 (3 mg/kg). Absent in CB2 knockout mice. CB2 agonist O-1966 (1-20 mg/kg) + subthreshold nicotine = CPP. O-1966 (20 mg/kg) blocked cocaine CPP. CB2 knockout: normal cocaine CPP, normal nicotine withdrawal.","methodology":"Conditioned place preference paradigm in wild-type mice with CB2 antagonist/agonist, and in CB2 knockout mice. Nicotine withdrawal precipitated with mecamylamine in nicotine-dependent mice. Acute nicotine effects (hypothermia, hypoalgesia) tested in CB2 knockout mice.","limitations":"Mouse conditioned place preference may not fully model human addiction. Genetic knockout creates lifelong absence, which may cause compensatory changes. Only one pharmacological antagonist and agonist were tested. The mechanism by which CB2 mediates nicotine reward was not identified."},{"rthcId":"RTHC-00690","title":"An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics.","authors":"Johnson, Jeremy R; Lossignol, Dominique; Burnell-Nugent, Mary; Fallon, Marie T","year":2013,"journal":"Journal of pain and symptom management, 46(2), 207-18","doi":"10.1016/j.jpainsymman.2012.07.014","pmid":"23141881","tags":["pain","medical-cannabis","cancer"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Forty-three patients with advanced cancer and pain inadequately managed by strong opioids entered an open-label extension study of THC/CBD spray (nabiximols/Sativex). Thirty-nine used THC/CBD spray and 4 used THC-only spray, self-titrating to symptom relief.\n\nPain severity and worst pain scores improved from baseline at each visit. Quality of life measures showed improvements in insomnia, pain, and fatigue domains. Critically, patients did not seek to increase their dose over time, nor did they increase their other pain medications, suggesting no development of tolerance. No new safety concerns emerged beyond those identified in the parent trial.","whyItMatters":"One of the biggest concerns about cannabinoid pain medications is tolerance development. This study provides evidence that THC/CBD spray maintains effectiveness for cancer pain over extended use without dose escalation, which would make it a practical long-term adjunct to opioid therapy.","specificNumbers":"43 patients entered (39 THC/CBD, 4 THC-only). Pain severity decreased at each visit. Worst pain decreased at each visit. Quality of life improved: insomnia, pain, fatigue domains. No dose escalation. No increase in other pain medications.","methodology":"Open-label, multicenter extension study following a three-arm RCT. 43 patients with cancer pain refractory to strong opioids. Self-titrated dosing. Brief Pain Inventory-Short Form and EORTC Quality of Life Questionnaire-C30 measured at regular visits.","limitations":"Open-label design with no placebo comparison in the extension phase. Small sample (43 patients). Selection bias: only patients who completed the parent trial and chose to continue were included. Advanced cancer patients have complex and changing pain patterns. No formal analysis of time-to-tolerance."},{"rthcId":"RTHC-00691","title":"Repeated low-dose administration of the monoacylglycerol lipase inhibitor JZL184 retains cannabinoid receptor type 1-mediated antinociceptive and gastroprotective effects.","authors":"Kinsey, Steven G; Wise, Laura E; Ramesh, Divya; Abdullah, Rehab; Selley, Dana E; Cravatt, Benjamin F; Lichtman, Aron H","year":2013,"journal":"The Journal of pharmacology and experimental therapeutics, 345(3), 492-501","doi":"10.1124/jpet.112.201426","pmid":"23412396","tags":["neuroscience","pain","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"The MAGL inhibitor JZL184 blocks the enzyme that breaks down the endocannabinoid 2-AG, boosting natural cannabinoid signaling. When given at high doses (16+ mg/kg daily for 6 days), it caused CB1 receptor downregulation, desensitization, antinociceptive tolerance, cross-tolerance to THC, and cannabinoid dependence.\n\nHowever, at low doses (8 mg/kg or less), JZL184 maintained its pain-relieving effects in a neuropathic pain model and stomach-protective effects against NSAID damage, with no CB1 receptor downregulation, no tolerance, no cross-tolerance to THC, and no dependence. This demonstrates that partial MAGL inhibition can provide therapeutic benefits without the drawbacks of full inhibition.","whyItMatters":"This study solved a key problem in endocannabinoid drug development. Full MAGL inhibition produces tolerance just like chronic THC, but partial inhibition maintains the benefits. This provides a roadmap for developing MAGL inhibitors as medicines: keep the dose low enough for partial inhibition.","specificNumbers":"High dose (16+ mg/kg): CB1 downregulation, desensitization, tolerance, cross-tolerance to THC, dependence. Low dose (8 mg/kg or less): no downregulation, no desensitization, maintained pain relief, maintained gastroprotection, no THC cross-tolerance, no dependence.","methodology":"Mouse studies using repeated daily JZL184 at multiple doses. CB1 receptor density measured by [3H]SR141716A binding. CB1 function measured by CP55,940-stimulated GTPgammaS binding. Behavioral assessments: neuropathic pain (chronic constriction injury), gastroprotection (NSAID-induced hemorrhage), THC cross-tolerance, rimonabant-precipitated withdrawal.","limitations":"Mouse studies may not translate to humans. Only one MAGL inhibitor was tested. The neuropathic pain model and gastroprotection model are specific paradigms. The 6-day treatment period is relatively short. Whether partial MAGL inhibition maintains efficacy over months or years is unknown."},{"rthcId":"RTHC-00692","title":"An investigation into \"two hit\" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice.","authors":"Klug, Maren; van den Buuse, Maarten","year":2013,"journal":"Frontiers in behavioral neuroscience, 7, 149","doi":"10.3389/fnbeh.2013.00149","pmid":"24155701","tags":["neuroscience","psychosis","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested a \"two-hit\" model for schizophrenia vulnerability: BDNF deficiency (genetic hit) combined with chronic young-adult cannabinoid exposure (environmental hit). BDNF heterozygous mice had lower baseline prepulse inhibition (PPI, a measure of sensory gating relevant to schizophrenia) and increased startle responses.\n\nChronic cannabinoid treatment during weeks 6-8 of life did not affect memory (Y-maze or novel object recognition) in any group. However, male BDNF-deficient mice that received chronic cannabinoid treatment showed marked PPI increases when given acute cannabinoid, while no other group showed this effect. This correlated with increased CB1 receptor density specifically in the nucleus accumbens.","whyItMatters":"This study models how genetic vulnerability (reduced neurotrophic support) and environmental exposure (adolescent cannabis use) might interact to alter brain function in ways relevant to schizophrenia. The sex-specific effect (males only) aligns with the higher incidence of schizophrenia in males.","specificNumbers":"BDNF HET: lower baseline PPI, higher startle. Male two-hit mice (BDNF HET + chronic CP): marked PPI increase with acute CP. CB1 receptor binding increased in nucleus accumbens of male two-hit mice only. No memory effects in any group.","methodology":"BDNF heterozygous and wild-type mice treated with CP55,940 during weeks 6-8 of life. After 2-week delay: Y-maze, novel object recognition, PPI with acute CP55,940 challenge. CB1 receptor binding autoradiography in nucleus accumbens and caudate.","limitations":"The PPI increase with acute cannabinoid is difficult to interpret, as PPI deficits (not increases) are the typical schizophrenia-relevant measure. The CP55,940 dose and regimen may not model human cannabis use. BDNF heterozygous mice are an imperfect model of schizophrenia vulnerability. Only one brain region showed receptor changes."},{"rthcId":"RTHC-00693","title":"Cannabinoids decrease the th17 inflammatory autoimmune phenotype.","authors":"Kozela, Ewa; Juknat, Ana; Kaushansky, Nathali; Rimmerman, Neta; Ben-Nun, Avraham; Vogel, Zvi","year":2013,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 8(5), 1265-76","doi":"10.1007/s11481-013-9493-1","pmid":"23892791","tags":["inflammation","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers studied immune cells that cause experimental autoimmune encephalitis (a model of multiple sclerosis) in mice. When these pathogenic T cells were reactivated, they produced large amounts of IL-17, a cytokine that drives autoimmune inflammation.\n\nBoth THC and CBD dose-dependently suppressed IL-17 production and secretion at concentrations of 0.1-5 micromolar. They also reduced IL-6, a key factor in Th17 cell development. CBD additionally increased IL-10, an anti-inflammatory cytokine. Neither cannabinoid affected TNF-alpha or IFN-gamma levels, showing specificity. The effects did not involve CB1, CB2, PPAR-gamma, 5-HT1A, or TRPV1 receptors, indicating a novel mechanism.","whyItMatters":"Th17 cells are major drivers of autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and psoriasis. A treatment that specifically suppresses the Th17 response while boosting anti-inflammatory IL-10 would be highly valuable, and cannabinoids appear to do exactly this.","specificNumbers":"THC and CBD: dose-dependent suppression at 0.1-5 micromolar. Suppressed: IL-17, IL-6. No effect on: TNF-alpha, IFN-gamma. CBD additionally increased IL-10. Receptor-independent: not through CB1, CB2, PPAR-gamma, 5-HT1A, or TRPV1.","methodology":"In vitro study using MOG35-55-specific encephalitogenic T cells reactivated with spleen-derived antigen presenting cells. THC and CBD tested at 0.1-5 micromolar. Cytokine measurements: IL-17, IL-6, IL-10, TNF-alpha, IFN-gamma. Receptor involvement assessed with selective antagonists.","limitations":"In vitro study with immune cells in a dish, not in living organisms. The concentrations used may not be achievable in the human body. The receptor-independent mechanism was identified by exclusion (blocking known receptors), but the actual target was not identified. Results from autoimmune encephalitis T cells may not generalize to all autoimmune conditions."},{"rthcId":"RTHC-00694","title":"A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.","authors":"Langford, R M; Mares, J; Novotna, A; Vachova, M; Novakova, I; Notcutt, W; Ratcliffe, S","year":2013,"journal":"Journal of neurology, 260(4), 984-97","doi":"10.1007/s00415-012-6739-4","pmid":"23180178","tags":["pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This study had two phases. In Phase A, 339 MS patients with neuropathic pain were randomized to THC/CBD spray or placebo for 14 weeks. The primary endpoint (30% pain reduction responder rate) was not met: 50% responded on THC/CBD versus 45% on placebo (p=0.234). However, a pre-planned interim analysis at week 10 showed a significant difference favoring THC/CBD (p=0.046).\n\nIn Phase B, 58 responders were re-randomized to continue THC/CBD spray or switch to placebo for 4 weeks. The results were clear: 57% of placebo patients lost treatment benefit versus only 24% on THC/CBD spray (p=0.04). Pain scores and sleep quality also significantly favored continued treatment.","whyItMatters":"While the primary Phase A endpoint was not met, the Phase B withdrawal design clearly demonstrated that THC/CBD spray maintains pain control. The high placebo response rate in Phase A (45%) likely obscured a real treatment effect, a common problem in pain trials.","specificNumbers":"Phase A: 339 patients (167 THC/CBD, 172 placebo). 50% vs 45% responders (p=0.234). Week 10 interim: significant (p=0.046). Phase B: 58 patients. Treatment failure: 57% placebo vs 24% THC/CBD (p=0.04). Pain difference: -0.79 points (p=0.028). Sleep quality: +0.99 points (p=0.015).","methodology":"Phase III, double-blind, placebo-controlled, two-phase study. Phase A: parallel-group, 339 patients, 14-week THC/CBD spray vs. placebo. Phase B: randomized withdrawal in 58 responders, 4 weeks. Primary Phase A endpoint: 30% responder rate at week 14. Primary Phase B endpoint: time to treatment failure.","limitations":"Phase A did not meet its primary endpoint, limiting regulatory conclusions. Phase B had a small sample (58 patients). The 4-week withdrawal phase was short. The high placebo response complicates interpretation. Not all Phase A participants entered Phase B, introducing selection bias."},{"rthcId":"RTHC-00695","title":"Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration?","authors":"Lee, Dayong; Karschner, Erin L; Milman, Garry; Barnes, Allan J; Goodwin, Robert S; Huestis, Marilyn A","year":2013,"journal":"Drug and alcohol dependence, 130(1-3), 68-76","doi":"10.1016/j.drugalcdep.2012.10.011","pmid":"23146820","tags":["medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Fourteen participants received oral THC (5 and 15 mg), low-dose Sativex, high-dose Sativex, and placebo in random order. After oral THC, oral fluid THC concentrations actually decreased over time (reflecting clearance of residual THC from prior smoked cannabis), with no measurable CBD or CBN.\n\nAfter Sativex spray, THC, CBD, and CBN all increased dramatically, peaking within 15-60 minutes. The CBD/THC ratio was 0.82-1.34, reflecting Sativex's composition. THCCOOH/THC ratios within 4.5 hours post-Sativex were consistently below 1.6 pg/ng, always lower than after oral THC or placebo. These distinct patterns could identify Sativex compliance and distinguish it from smoked cannabis.","whyItMatters":"As medical cannabinoids become more common, the ability to monitor medication compliance and detect unauthorized cannabis use becomes important. This study established that oral fluid testing can distinguish between different cannabinoid products based on their unique metabolite patterns.","specificNumbers":"14 participants. After Sativex: CBD/THC ratio 0.82-1.34. CBN/THC ratio 0.04-0.06. THCCOOH/THC <1.6 pg/ng within 4.5 hours. After oral THC: THC decreased over time, no CBD or CBN detected.","methodology":"Randomized, placebo-controlled crossover study. 14 participants received 5 mg oral THC, 15 mg oral THC, low-dose Sativex (5.4 mg THC + 5.0 mg CBD), high-dose Sativex (16.2 mg THC + 15.0 mg CBD), and placebo. Oral fluid collected for 10.5 hours. Analyzed for THC, CBD, CBN, THCCOOH.","limitations":"Small sample (14 participants). Oral fluid collection variability could affect results. The study participants had prior cannabis exposure, complicating baseline measurements. Real-world testing scenarios involve more variables than a controlled laboratory setting. The time window for detection varies."},{"rthcId":"RTHC-00696","title":"Oral fluid/plasma cannabinoid ratios following controlled oral THC and smoked cannabis administration.","authors":"Lee, Dayong; Vandrey, Ryan; Milman, Garry; Bergamaschi, Mateus; Mendu, Damodara R; Murray, Jeannie A; Barnes, Allan J; Huestis, Marilyn A","year":2013,"journal":"Analytical and bioanalytical chemistry, 405(23), 7269-79","doi":"10.1007/s00216-013-7159-8","pmid":"23831756","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Eleven chronic cannabis smokers lived on a closed research unit for 51 days, receiving different daily oral THC doses (0, 30, 60, 120 mg/day) with smoked cannabis challenges. Oral fluid THC levels were extremely variable, with ratios to plasma ranging from 0.04 to 348.5, largely driven by oral cavity contamination after smoking.\n\nWithin an hour of smoking, oral fluid THC was massively elevated relative to plasma (median 6.1-fold, up to 348-fold). By 13-17 hours, ratios decreased to 2.1 (range 0.2-20.7). In contrast, the THCCOOH (metabolite) to THC ratio was much more consistent (median 0.3-2.5 ng/microgram), making it a more reliable marker for interpreting oral fluid results.","whyItMatters":"Oral fluid is increasingly used for roadside impairment testing and workplace drug screening. This study reveals a fundamental challenge: oral fluid THC levels after smoking are dominated by oral cavity contamination, not systemic drug levels, making raw THC concentrations poor indicators of impairment.","specificNumbers":"11 smokers, 51 days inpatient. OF/P THC ratio: median 6.1 (range 0.2-348.5) within 1 hour of smoking. Decreased to median 2.1 (0.2-20.7) by 13-17 hours. After smoked challenge: median 1.4-5.5 at 0.25 hours, decreasing to 0.12-0.17 by 10.5 hours. THCCOOH/THC: median 0.3-2.5, much more stable.","methodology":"Controlled inpatient study. 11 chronic cannabis smokers, 51-day residential stay. Four 5-day oral THC sessions (0, 30, 60, 120 mg/day) each followed by a 5-puff smoked cannabis challenge, separated by 9-day ad libitum smoking periods. Oral fluid and plasma collected and analyzed for THC, metabolites.","limitations":"Small sample of chronic heavy smokers who may not represent occasional users. The controlled inpatient environment does not replicate real-world testing conditions. Only one cannabis potency level was tested for the smoked challenges. The very high variability makes individual-level prediction difficult."},{"rthcId":"RTHC-00697","title":"Amygdala activity contributes to the dissociative effect of cannabis on pain perception.","authors":"Lee, Michael C; Ploner, Markus; Wiech, Katja; Bingel, Ulrike; Wanigasekera, Vishvarani; Brooks, Jonathan; Menon, David K; Tracey, Irene","year":2013,"journal":"Pain, 154(1), 124-134","doi":"10.1016/j.pain.2012.09.017","pmid":"23273106","tags":["pain","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Healthy volunteers received either THC or placebo before a capsaicin-induced pain and hyperalgesia model with fMRI brain imaging. On average, THC reduced the reported unpleasantness of pain but not its intensity, a dissociative effect.\n\nThe specific analgesic effect on hyperalgesia was accompanied by reduced activity in the anterior mid-cingulate cortex. The reduction in pain unpleasantness correlated with right amygdala activity. THC also reduced functional connectivity between the amygdala and primary sensorimotor areas during ongoing pain. This disconnection between emotional and sensory pain processing was directly correlated with the magnitude of THC's dissociative effect on pain.","whyItMatters":"This study provides the first neuroimaging evidence explaining why cannabis users often describe their pain as \"still there but not bothering me.\" THC does not reduce the sensory signal of pain but rather changes how the brain emotionally processes that signal, through the amygdala.","specificNumbers":"THC reduced pain unpleasantness but not intensity. Hyperalgesia reduced with decreased anterior mid-cingulate activity. Right amygdala activity correlated with unpleasantness reduction. Reduced amygdala-sensorimotor connectivity correlated with dissociative effect magnitude.","methodology":"Randomized, double-blind, placebo-controlled fMRI study. Healthy volunteers received THC or placebo. Capsaicin applied to forearm to induce ongoing pain and hyperalgesia. Pain intensity and unpleasantness rated separately. fMRI captured brain activation patterns and functional connectivity.","limitations":"Healthy volunteers without chronic pain may process pain differently than chronic pain patients. Single-dose, acute study does not address chronic use. The capsaicin model produces a specific type of pain that may not represent all pain conditions. Individual variability in amygdala response was notable."},{"rthcId":"RTHC-00698","title":"Cannabis use and cannabis use disorders among individuals with mental illness","authors":"Lev-Ran, Shaul; Le Foll, Bernard; McKenzie, Kwame; George, Tony P.; Rehm, Jurgen","year":2013,"journal":"Comprehensive Psychiatry, 54(6), 589-598","doi":null,"pmid":"23375264","tags":["mental-health","addiction","cognition"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"People reporting a 12-month mental illness had much higher rates of cannabis involvement than those without. Weekly use was 4.4% versus 0.6%, less-than-weekly use was 5.4% versus 1.1%, and cannabis use disorders were 4.0% versus 0.4%. After adjusting for demographics and other substance use disorders, the odds of any cannabis use were 2.5 times higher and the odds of a cannabis use disorder were 3.2 times higher among people with a past-year mental illness.\n\nUse and disorder were not evenly distributed across diagnoses. Associations were strongest for bipolar disorder, other substance use disorders, and certain personality disorders, including antisocial, dependent, and histrionic personality disorder.\n\nAlthough only a subset of adults reported mental illness in the past year, they represented 72% of all cannabis users in the survey and were estimated to account for 83% of the cannabis consumed, based on self-reported frequency and typical daily dose.","whyItMatters":"Public health debates often treat cannabis use as broadly distributed across the population. This analysis suggests that, at least in 2001 to 2002, use and cannabis use disorders clustered among people with recent mental illness, with implications for how researchers characterize risk and where services are typically directed.","specificNumbers":"- Sample: 43,070 U.S. adults, 2001 to 2002 nationally representative survey\n- Weekly cannabis use: 4.4% with past-year mental illness vs 0.6% without (P<0.0001)\n- Less-than-weekly use: 5.4% vs 1.1% (P<0.0001)\n- Cannabis use disorder: 4.0% vs 0.4% (P<0.0001)","methodology":"Researchers analyzed 43,070 U.S. adults from the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative household survey. Psychiatric diagnoses were assessed with the Alcohol Use Disorders and Associated Disabilities Interview Schedule-IV, covering DSM-IV Axis I and II conditions over the past 12 months. Outcomes included cannabis use frequency (at least weekly, or less than weekly) and DSM-IV cannabis use disorders. Logistic models adjusted for sociodemographic factors and other substance use disorders. The team also estimated the share of total cannabis consumption attributable to people with and without mental illness using self-reported frequency and daily dose.","limitations":"Cross-sectional design cannot establish which came first, mental illness or cannabis involvement. Diagnoses relied on a structured interview (AUDADIS-IV), which can misclassify some Axis I and II conditions. Cannabis measures came from self-reported frequency and typical daily dose, with no verification of product potency, THC-to-CBD ratios, or mode of use. The consumption estimate (83%) depends on self-report–based calculations rather than direct measurement. Data were collected in 2001 to 2002, before major shifts in legalization, product potency, and market dynamics, which may limit relevance to current patterns. Residual confounding is possible despite adjustment for demographics and other substance use disorders."},{"rthcId":"RTHC-00699","title":"The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS.","authors":"Lutge, Elizabeth E; Gray, Andy; Siegfried, Nandi","year":2013,"journal":"The Cochrane database of systematic reviews, 2013(4), CD005175","doi":"10.1002/14651858.CD005175.pub3","pmid":"23633327","tags":["medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Seven randomized controlled trials were identified, all of short duration (21-84 days) with small sample sizes. Only three studies had adequate randomization and allocation concealment. The strongest finding came from a single pre-HAART study (n=139, only 88 evaluable) showing dronabinol patients were twice as likely to gain 2+ kg (RR 2.09), but the confidence interval crossed unity (95% CI 0.72-6.06), meaning the result was not statistically significant.\n\nBlinding was a major challenge because cannabis's psychoactive effects are quickly recognizable, particularly to experienced users. Outcomes measured varied widely across studies: weight, body fat, appetite, caloric intake, nausea, performance, and mood. The review concluded that long-term data on sustained effects and safety in patients on effective antiretroviral therapy was lacking.","whyItMatters":"This review highlighted a disconnect between regulatory approval and evidence quality. Dronabinol was approved for AIDS-associated anorexia, and several jurisdictions allowed medical marijuana for HIV/AIDS, yet the Cochrane review found the supporting evidence was limited, short-term, and methodologically weak.","specificNumbers":"7 RCTs included. Duration: 21-84 days. Largest study: n=139 (88 evaluable). Dronabinol weight gain: RR 2.09 (95% CI 0.72-6.06, not significant). Only 3 studies had adequate randomization.","methodology":"Cochrane systematic review searching CENTRAL, MEDLINE, and EMBASE through July 2012. Included RCTs and quasi-randomized studies of any cannabis intervention in adults with HIV/AIDS compared to placebo or active treatment. Two independent reviewers extracted data.","limitations":"All included studies were short-term and small. The review was conducted before modern antiretroviral therapy was universal, and the needs of HIV/AIDS patients have changed significantly. Cannabis blinding remains an inherent challenge. No meta-analysis was possible due to outcome heterogeneity."},{"rthcId":"RTHC-00700","title":"Marijuana use is associated with inattention in men and sleep quality in women with Attention-Deficit/Hyperactivity Disorder: a preliminary study.","authors":"Ly, Christine; Gehricke, Jean-G","year":2013,"journal":"Psychiatry research, 210(3), 1310-2","doi":"10.1016/j.psychres.2013.08.003","pmid":"23993465","tags":["cognition","sleep","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Fifty-six men and 20 women with ADHD (ages 18-45) were assessed for marijuana use, ADHD symptoms, and sleep quality. Moderate to strong correlations emerged between marijuana use and inattentive symptoms in men, and between marijuana use and decreased sleep quality in women.\n\nThe authors suggested that men and women with ADHD may use marijuana for different reasons. Men may use it in ways that worsen attention, while women's use patterns may particularly disrupt sleep architecture.","whyItMatters":"ADHD and cannabis use frequently co-occur, and this study suggests the consequences may differ by sex. Understanding these sex-specific patterns could help clinicians tailor advice and treatment for ADHD patients who use cannabis.","specificNumbers":"56 men, 20 women with ADHD. Ages 18-45. Moderate-strong correlation: marijuana use and inattention (men). Moderate-strong correlation: marijuana use and poor sleep quality (women).","methodology":"Cross-sectional study of 56 men and 20 women with ADHD, ages 18-45. Assessment of Hyperactivity and Attention for ADHD symptoms, drug use survey for marijuana use, Pittsburgh Sleep Quality Index for sleep. Correlational analyses.","limitations":"Very small sample, especially women (n=20). Cross-sectional design cannot determine causation. People with worse ADHD symptoms may use more marijuana, rather than marijuana worsening symptoms. No control group without ADHD. Self-reported marijuana use."},{"rthcId":"RTHC-00701","title":"Cannabis abuse and brain morphology in schizophrenia: a review of the available evidence.","authors":"Malchow, Berend; Hasan, Alkomiet; Fusar-Poli, Paolo; Schmitt, Andrea; Falkai, Peter; Wobrock, Thomas","year":2013,"journal":"European archives of psychiatry and clinical neuroscience, 263(1), 3-13","doi":"10.1007/s00406-012-0346-3","pmid":"22907121","tags":["psychosis","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The review examined MRI studies comparing schizophrenia patients with and without cannabis abuse, as well as high-risk individuals. While some evidence suggested chronic cannabis abuse could alter brain morphology in patients who continued using cannabis, results were inconsistent across studies.\n\nCritically, there was no convincing evidence that cannabis-related brain changes preceded schizophrenia onset when examining first-episode patients. Some weak evidence suggested cannabis might affect brain structures in high-risk subjects (those at elevated risk for psychosis), but these findings required replication.","whyItMatters":"Whether cannabis structurally changes the brain in ways that contribute to schizophrenia is a central question in the cannabis-psychosis debate. The finding that structural changes were not convincingly present before onset suggests cannabis may not cause the brain changes seen in schizophrenia, though it may modify them after illness onset.","specificNumbers":"Systematic review of structural MRI studies. Inconclusive results across studies. No convincing evidence of pre-onset structural changes in first-episode patients. Weak evidence for high-risk subject brain effects needing replication.","methodology":"Systematic review of structural MRI studies comparing high-risk and schizophrenia patients with and without cannabis abuse. Focused on brain morphological differences attributable to cannabis use in the context of psychosis.","limitations":"Most included studies were cross-sectional, limiting causal inference. Cannabis use was typically self-reported and varied widely in amount and duration. Different brain regions and measurement methods across studies made comparison difficult. Publication bias may have influenced available literature."},{"rthcId":"RTHC-00702","title":"Peripheral and spinal activation of cannabinoid receptors by joint mobilization alleviates postoperative pain in mice.","authors":"Martins, D F; Mazzardo-Martins, L; Cidral-Filho, F J; Gadotti, V M; Santos, A R S","year":2013,"journal":"Neuroscience, 255, 110-21","doi":"10.1016/j.neuroscience.2013.09.055","pmid":"24120553","tags":["pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Mice underwent plantar incision surgery and received ankle joint mobilization 24 hours later. The mobilization reduced mechanical hypersensitivity, and this effect was mediated by cannabinoid receptors. CB1 receptor involvement was confirmed at the spinal (intrathecal) and systemic (intraperitoneal) levels but not at the peripheral (intraplantar) level. CB2 receptors operated peripherally and systemically but not spinally.\n\nWhen mice were pretreated with either URB937 (FAAH inhibitor) or JZL184 (MAGL inhibitor), the pain-relieving effect of joint mobilization lasted significantly longer. This demonstrated that physical therapy activates the endocannabinoid system, and boosting endocannabinoid levels pharmacologically extends the therapeutic benefit.","whyItMatters":"This study provides a mechanistic explanation for why physical therapy reduces pain: it activates the endocannabinoid system. The finding that endocannabinoid-boosting drugs extend this effect opens the door to combining physical therapy with pharmacological endocannabinoid enhancement for better post-surgical pain management.","specificNumbers":"Joint mobilization: 9 minutes. CB1 involvement: spinal and systemic. CB2 involvement: peripheral and systemic. FAAH inhibitor URB937: 0.01-1 mg/kg extended mobilization effect. MAGL inhibitor JZL184: 0.016-16 mg/kg extended mobilization effect.","methodology":"Mouse plantar incision model. Ankle joint mobilization (9 minutes) 24 hours post-surgery. CB1 antagonist AM281 and CB2 antagonist AM630 administered by three routes (systemic, spinal, peripheral). FAAH inhibitor URB937 and MAGL inhibitor JZL184 tested as adjuncts to mobilization.","limitations":"Mouse model of surgical pain may not translate directly to human physical therapy. The ankle mobilization protocol is simplified compared to clinical physical therapy. Acute post-surgical pain is one specific pain type. The drug doses used may not be clinically feasible in humans."},{"rthcId":"RTHC-00703","title":"Cannabinoids and hallucinogens for headache.","authors":"McGeeney, Brian E","year":2013,"journal":"Headache, 53(3), 447-58","doi":"10.1111/head.12025","pmid":"23278122","tags":["pain","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review traced the historical use of cannabis for headache treatment, noting that it was a standard medicine for migraine before the 1937 prohibition. Cannabis was used both as an abortive (stopping a headache in progress) and prophylactic (preventing headaches) treatment.\n\nDespite prohibition, patients continue to use cannabis for headache, supported by the growing number of medical marijuana states. Cluster headache patients in particular have increasingly used both cannabis and hallucinogens (psilocybin, LSD) outside of medical recommendation, with considerable anecdotal success for aborting cluster periods and maintaining remission. However, no blinded studies on headache have been conducted for either drug class.","whyItMatters":"Migraine and cluster headache are severely debilitating conditions with limited treatment options. The historical prominence of cannabis as a headache treatment, combined with ongoing patient use and anecdotal success, makes the absence of controlled research a significant gap.","specificNumbers":"Schedule 1 classification since 1970. No blinded controlled studies on headache for either cannabinoids or hallucinogens. Cannabis was a standard migraine treatment before 1937.","methodology":"Narrative review of historical and contemporary use of cannabinoids and hallucinogens for headache disorders. Covered pre-prohibition medical literature, patient survey data, and mechanistic rationale.","limitations":"Narrative review without systematic methodology. Historical evidence is based on pre-modern medical standards. Anecdotal reports of efficacy cannot replace controlled trials. Patient self-medication introduces selection bias and placebo effects."},{"rthcId":"RTHC-00704","title":"The role of fatty acid amide hydrolase inhibition in nicotine reward and dependence.","authors":"Muldoon, Pretal P; Lichtman, Aron H; Parsons, Loren H; Damaj, M Imad","year":2013,"journal":"Life sciences, 92(8-9), 458-62","doi":"10.1016/j.lfs.2012.05.015","pmid":"22705310","tags":["neuroscience","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review described a puzzling finding: when FAAH, the enzyme that degrades anandamide, is inhibited or genetically deleted, the effects on nicotine dependence differ dramatically between species. In mice, FAAH disruption enhanced nicotine reward (conditioned place preference) and worsened withdrawal. In rats, FAAH inhibition blocked nicotine reward and had no effect on withdrawal.\n\nThe review proposed that this species difference may be due to FAAH's non-cannabinoid substrates. FAAH also degrades OEA and PEA, which act on TRPV1 and PPAR-alpha receptors rather than cannabinoid receptors. The balance between cannabinoid and non-cannabinoid effects of FAAH inhibition may differ between species.","whyItMatters":"Species differences in drug responses are a critical challenge for translating animal research to humans. If FAAH inhibition has opposite effects in mice and rats, knowing which species better predicts human responses is essential before developing FAAH inhibitors as smoking cessation aids.","specificNumbers":"FAAH substrates: anandamide (CB1/CB2), OEA (PPAR-alpha), PEA (PPAR-alpha, TRPV1). In mice: FAAH inhibition/knockout enhanced nicotine CPP and withdrawal. In rats: FAAH inhibition blocked nicotine CPP, no withdrawal effect.","methodology":"Mini-review covering pharmacological and genetic studies of FAAH inhibition in nicotine conditioned place preference and withdrawal models in both mice and rats. Discussed cannabinoid and non-cannabinoid receptor systems involved.","limitations":"Review of a limited number of studies. The species difference mechanism was proposed but not proven. It remains unknown whether human responses to FAAH inhibition more closely resemble mice or rats. Different FAAH inhibitors and experimental protocols across studies complicate comparison."},{"rthcId":"RTHC-00705","title":"Treatment of Tourette syndrome with cannabinoids.","authors":"Müller-Vahl, Kirsten R","year":2013,"journal":"Behavioural neurology, 27(1), 119-24","doi":"10.3233/BEN-120276","pmid":"23187140","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined the evidence for cannabinoid treatment of Tourette syndrome (TS). Two controlled trials investigated THC for TS and both found significant tic reduction compared to placebo on both self-rating and examiner-rating scales, without significant adverse effects.\n\nThe available data on THC's effect on obsessive-compulsive symptoms (which commonly co-occur with TS) were inconsistent. A Cochrane review concluded that definitive conclusions could not be drawn due to the lack of larger, longer trials. Despite this formal appraisal, many experts recommend THC for treatment-resistant adult TS patients, reflecting a gap between the formal evidence bar and clinical judgment.","whyItMatters":"Tourette syndrome can be severely debilitating, and existing treatments have significant side effects. The consistent finding of tic reduction across two controlled trials, combined with a good safety profile, positions THC as a viable option for treatment-resistant patients.","specificNumbers":"2 controlled trials of THC for TS. Both showed significant tic reduction vs. placebo. Self-rating and examiner-rating scales both improved. No significant adverse effects. Expert recommendation for treatment-resistant adults.","methodology":"Narrative review covering anecdotal reports, two controlled trials, and expert recommendations for cannabinoid use in Tourette syndrome. Also discussed the broader context of approved cannabinoid medications.","limitations":"Only two controlled trials exist, both small. The Cochrane review found the evidence insufficient for definitive conclusions. Long-term safety data are lacking. The trials were conducted by similar research groups. Optimal dosing, formulation, and treatment duration remain unclear."},{"rthcId":"RTHC-00706","title":"Metabolic effects of chronic cannabis smoking.","authors":"Muniyappa, Ranganath; Sable, Sara; Ouwerkerk, Ronald; Mari, Andrea; Gharib, Ahmed M; Walter, Mary; Courville, Amber; Hall, Gail; Chen, Kong Y; Volkow, Nora D; Kunos, George; Huestis, Marilyn A; Skarulis, Monica C","year":2013,"journal":"Diabetes care, 36(8), 2415-22","doi":"10.2337/dc12-2303","pmid":"23530011","tags":["cardiovascular","appetite"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Thirty chronic cannabis smokers (median 9.5 years use, 6 joints/day) were compared to 30 matched controls. Cannabis smokers had higher carbohydrate intake and more visceral abdominal fat (18% vs. 12%, p=0.004) but no difference in total body fat or liver fat content.\n\nHDL cholesterol was lower in smokers (49 vs. 55 mg/dL, p=0.02). Fat cells showed insulin resistance, with higher adipocyte insulin resistance index and less free fatty acid suppression during glucose testing. However, whole-body insulin sensitivity, pancreatic beta-cell function, incretin hormones, and glucose tolerance were all normal. This suggests cannabis selectively affects fat tissue metabolism without disrupting overall glucose control.","whyItMatters":"This study helps resolve the paradox of cannabis and metabolism. While epidemiological studies associate cannabis use with lower obesity and diabetes rates, this controlled comparison found some metabolic harms (visceral fat, HDL, fat cell insulin resistance). The preserved glucose tolerance despite these changes suggests a complex metabolic picture.","specificNumbers":"30 smokers vs. 30 controls, matched. Median use: 9.5 years, 6 joints/day. Visceral fat: 18% vs. 12% (p=0.004). HDL: 49 vs. 55 mg/dL (p=0.02). Fat cell insulin resistance: increased (p<0.05). Glucose, liver fat, beta-cell function: no difference.","methodology":"Cross-sectional, case-control study. 30 cannabis smokers matched to 30 controls by age, sex, ethnicity, and BMI. MRI quantified abdominal fat depots. Proton magnetic resonance spectroscopy measured liver fat. Oral glucose tolerance tests assessed insulin sensitivity and beta-cell function.","limitations":"Cross-sectional design cannot establish causation. Heavy cannabis smokers may differ from controls in unmeasured lifestyle factors (diet quality, physical activity patterns). Self-reported cannabis use. Relatively small sample. The higher carbohydrate intake in smokers may partially explain metabolic differences."},{"rthcId":"RTHC-00707","title":"The synthetic cannabinoid withdrawal syndrome.","authors":"Nacca, Nicholas; Vatti, Deepak; Sullivan, Ross; Sud, Payal; Su, Mark; Marraffa, Jeanna","year":2013,"journal":"Journal of addiction medicine, 7(4), 296-8","doi":"10.1097/ADM.0b013e31828e1881","pmid":"23609214","tags":["synthetic-cannabinoids","withdrawal"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Two patients presented with withdrawal symptoms from prolonged use of synthetic cannabinoids. The withdrawal syndrome was primarily characterized by anxiety and tachycardia without neurological findings or electrolyte disturbances.\n\nThe withdrawal was described as more severe than typical delta-9-THC withdrawal, which features anxiety, muscle aches, chills, and appetite loss. Notably, natural THC did not improve the synthetic cannabinoid withdrawal symptoms, possibly because synthetic products contain multiple heterogeneous compounds, including amphetamine-like substances, or because synthetic cannabinoids have much higher receptor potency than natural THC.","whyItMatters":"The finding that natural THC did not improve synthetic cannabinoid withdrawal is clinically important. It means the agonist replacement strategy (using natural THC to treat synthetic cannabinoid withdrawal, analogous to methadone for heroin) may not work, likely because synthetic cannabinoids are far more potent or act differently than natural THC.","specificNumbers":"2 patients with synthetic cannabinoid withdrawal. Primary symptoms: anxiety and tachycardia. No neurological findings or electrolyte disturbances. Natural THC did not help. Treatment: benzodiazepines (first line), quetiapine (possible adjunct).","methodology":"Case report of two patients with withdrawal symptoms presumed to be from synthetic cannabinoid use. Clinical presentation and management documented.","limitations":"Only 2 cases reported. The specific synthetic cannabinoids used were likely not identified analytically. Self-reported drug use histories. The products may have contained non-cannabinoid adulterants. No standardized assessment of withdrawal severity."},{"rthcId":"RTHC-00708","title":"Cannabis induces a clinical response in patients with Crohn's disease: a prospective placebo-controlled study.","authors":"Naftali, Timna; Bar-Lev Schleider, Lihi; Dotan, Iris; Lansky, Ephraim Philip; Sklerovsky Benjaminov, Fabiana; Konikoff, Fred Meir","year":2013,"journal":"Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 11(10), 1276-1280.e1","doi":"10.1016/j.cgh.2013.04.034","pmid":"23648372","tags":["medical-cannabis","inflammation"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Twenty-one patients with active Crohn's disease (CDAI >200) who had failed steroids, immunomodulators, and anti-TNF agents were randomized to cannabis cigarettes (115 mg THC twice daily) or placebo cigarettes (cannabis with THC extracted). After 8 weeks, 10 of 11 cannabis patients (90%) achieved clinical response (CDAI drop >100 points) versus 4 of 10 on placebo (40%, p=0.028).\n\nThe primary endpoint of complete remission (CDAI <150) was not met, with 5 of 11 (45%) achieving remission on cannabis versus 1 of 10 (10%) on placebo (p=0.43). Three patients in the cannabis group were weaned from corticosteroid dependency. Patients reported improved appetite and sleep with no significant side effects.","whyItMatters":"This was the first placebo-controlled trial of cannabis for Crohn's disease. The patients had failed all available treatments, making any clinical benefit significant. The 90% clinical response rate, combined with steroid weaning and symptom improvement, suggests cannabis may have genuine therapeutic value for inflammatory bowel disease.","specificNumbers":"21 patients, CDAI >200. Treatment failures: steroids, immunomodulators, anti-TNF. Cannabis: 115 mg THC twice daily for 8 weeks. Clinical response: 90% cannabis vs. 40% placebo (p=0.028). Complete remission: 45% vs. 10% (NS). 3 patients weaned from steroids.","methodology":"Prospective, randomized, placebo-controlled trial. 21 patients with treatment-resistant Crohn's disease (CDAI >200 despite steroids, immunomodulators, anti-TNF). Cannabis cigarettes containing 115 mg THC vs. THC-extracted placebo, twice daily for 8 weeks. Follow-up for 2 additional weeks.","limitations":"Very small sample (21 patients). The primary endpoint (remission) was not met. Blinding may have been compromised due to psychoactive effects. The short duration (8 weeks) does not address long-term outcomes. Smoking as the delivery route is not ideal for long-term use. Benefits may have been partly symptomatic rather than anti-inflammatory."},{"rthcId":"RTHC-00709","title":"Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine.","authors":"Navarrete, Francisco; Rodríguez-Arias, Marta; Martín-García, Elena; Navarro, Daniela; García-Gutiérrez, María S; Aguilar, María A; Aracil-Fernández, Auxiliadora; Berbel, Pere; Miñarro, José; Maldonado, Rafael; Manzanares, Jorge","year":2013,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 38(12), 2515-24","doi":"10.1038/npp.2013.157","pmid":"23817165","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CB2 knockout mice showed three key deficits in nicotine responses: they did not develop conditioned place preference (reward), they self-administered significantly less nicotine (reinforcement), and they showed no somatic withdrawal signs after chronic nicotine exposure. The CB2 antagonist AM630 also blocked nicotine reward and reduced self-administration in normal mice.\n\nMolecularly, CB2 knockout mice had lower expression of tyrosine hydroxylase and nicotinic receptor subunits (alpha3, alpha4) in the ventral tegmental area, a key reward region. Confocal microscopy revealed that CB2 receptors were physically located alongside nicotinic receptors in both the nucleus accumbens and VTA, providing an anatomical basis for their functional interaction.","whyItMatters":"This comprehensive study demonstrates that CB2 receptors are involved in every aspect of nicotine dependence: reward, reinforcement, and withdrawal. The physical colocalization of CB2 and nicotinic receptors in reward circuits provides a concrete mechanism for developing CB2-targeted smoking cessation treatments.","specificNumbers":"CB2 KO mice: no nicotine CPP, reduced self-administration, no withdrawal signs. AM630 (3 mg/kg) blocked CPP, (1-3 mg/kg) reduced self-administration. CB2 KO: lower TH, alpha3, alpha4 mRNA in VTA. CB2r colocalized with alpha3 and alpha4 nAChRs in NAc and VTA.","methodology":"CB2 knockout mice and wild-type littermates. Nicotine CPP and IV self-administration. CB2 antagonist AM630 in wild-type mice. Gene expression (TH, alpha3, alpha4 nAChR) in VTA by qPCR. CB2/nAChR colocalization by confocal microscopy. Mecamylamine-precipitated withdrawal in chronic nicotine-exposed mice.","limitations":"Genetic knockout creates lifelong CB2 absence, potentially causing compensatory changes. Lower VTA gene expression in knockouts could reflect developmental effects rather than acute CB2 function. Self-administration and CPP are behavioral models that may not fully capture human addiction. Only one CB2 antagonist was tested."},{"rthcId":"RTHC-00710","title":"Brief emergency department interventions for youth who use alcohol and other drugs: a systematic review.","authors":"Newton, Amanda S; Dong, Kathryn; Mabood, Neelam; Ata, Nicole; Ali, Samina; Gokiert, Rebecca; Vandermeer, Ben; Tjosvold, Lisa; Hartling, Lisa; Wild, T Cameron","year":2013,"journal":"Pediatric emergency care, 29(5), 673-84","doi":"10.1097/PEC.0b013e31828ed325","pmid":"23640153","tags":["youth","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Nine randomized controlled trials of emergency department-based brief interventions (BIs) for youth ages 21 and under were reviewed. Five trials had high risk of bias, 2 had unclear risk, and only 2 had low risk. Universal and targeted BIs did not significantly reduce alcohol use compared to standard care.\n\nSome specific findings were promising: in one trial (high risk of bias), peer-delivered motivational interviewing for cannabis increased abstinence and reduced physical altercations. In two trials (unclear risk of bias), MI reduced drinking and driving and alcohol-related injuries. Computer-based MI in one low-risk trial reduced alcohol-related consequences at 6 months. However, variation in outcome measurement and poor study quality prevented firm conclusions.","whyItMatters":"Emergency departments are a logical setting for substance use intervention, as youth may be presenting during or after harmful use. If brief interventions work, they could reach a large at-risk population at a teachable moment. The inconclusive evidence means more research is needed before recommending routine implementation.","specificNumbers":"9 RCTs included. 2 low risk, 2 unclear risk, 5 high risk of bias. Most comparisons showed no significant differences. Peer MI for cannabis: increased abstinence, reduced altercations (1 trial, high risk). Computer MI: reduced alcohol consequences at 6 months (1 trial, low risk).","methodology":"Systematic review searching 14 databases, trial registry, conference proceedings, and references. Included RCTs of youth 21 and under. Two independent reviewers selected studies and assessed quality. Qualitative synthesis (no meta-analysis due to heterogeneity).","limitations":"Most trials had high risk of bias. Outcome measures varied widely across studies, preventing meta-analysis. Small number of trials overall. Most focused on alcohol rather than other drugs. Youth in EDs may differ from general substance-using youth populations."},{"rthcId":"RTHC-00711","title":"A questionnaire survey of patients and carers of patients prescribed Sativex as an unlicensed medicine.","authors":"Notcutt, William G","year":2013,"journal":"Primary health care research & development, 14(2), 192-9","doi":"10.1017/S1463423612000333","pmid":"22784399","tags":["medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"One hundred twenty-four patients who had received repeat Sativex prescriptions completed a questionnaire survey (57% response rate). Most patients had multiple sclerosis, using Sativex primarily for spasticity and pain. The majority of both patients and their caregivers reported improvements across a range of daily functional activities.\n\nNotably, patients reported reduced use of concomitant anti-spasticity medications and reduced use of other healthcare resources after starting Sativex. Caregiver responses corroborated patient reports. The findings complemented RCT evidence by providing a real-world effectiveness perspective.","whyItMatters":"Clinical trial results do not always translate to real-world effectiveness. This survey provides evidence that Sativex produces patient-perceived benefits in daily life, reduces polypharmacy (fewer other medications needed), and reduces healthcare utilization, supporting its practical value beyond trial settings.","specificNumbers":"124 questionnaires returned (57% response rate). Most patients had MS. Primary indications: spasticity and pain. Majority reported improved daily function. Reduced anti-spasticity medication use. Reduced healthcare resource use.","methodology":"Questionnaire survey with mostly multiple-choice questions and some free-text. Distributed through UK prescribers to patients who had received repeat Sativex prescriptions within the previous 16 weeks. Developed in consultation with a patient organization. No control group. 57% response rate (124 returned).","limitations":"No control group. Only patients with repeat prescriptions were surveyed, creating selection bias (those who stopped would not be included). Self-reported outcomes are subject to bias. 43% non-response may reflect dissatisfied patients. UK-specific prescribing patterns may not generalize."},{"rthcId":"RTHC-00712","title":"Stability and change of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis DSM-IV dependence symptoms.","authors":"Palmer, R H C; Young, S E; Corley, R P; Hopfer, C J; Stallings, M C; Hewitt, J K","year":2013,"journal":"Behavior genetics, 43(5), 374-85","doi":"10.1007/s10519-013-9599-5","pmid":"23760788","tags":["genetics","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers studied 2,361 adolescents across two assessment waves to examine the stability of genetic and environmental influences on substance dependence liability. A common genetic factor influenced susceptibility to all three substances (alcohol, tobacco, cannabis) simultaneously, and this factor was perfectly stable across time (genetic correlation = 1.00).\n\nThe heritability of the shared dependence liability increased from 43% in the first assessment to 63% in the second, suggesting that genetic influences become more important as adolescents mature. There were limited gender differences in the magnitude of these effects. The consistency of the genetic factor across time indicates that the same genes continue to operate throughout development.","whyItMatters":"This study demonstrates that alcohol, tobacco, and cannabis dependence share a common genetic architecture. Rather than separate genetic risks for each substance, there appears to be a general \"addiction vulnerability\" gene set that becomes increasingly influential through adolescence.","specificNumbers":"2,361 adolescents. Heritability of common liability: 43% at wave 1, 63% at wave 2. Genetic correlation across time: 1.00 (0.55-1.00). Limited gender differences. Common genetic factor explained all genetic variance at both assessments.","methodology":"Longitudinal twin study of 2,361 adolescents. DSM-IV symptom counts obtained via structured diagnostic interview. Sex-limited longitudinal common pathway models examined genetic (A), shared environmental (C), and non-shared environmental (E) contributions. Two waves of assessment.","limitations":"Symptom counts rather than diagnoses were used. Twin samples may not represent the general population. The common pathway model assumes a single genetic liability, which may oversimplify. Cannabis and tobacco dependence were assessed differently than alcohol. Two timepoints limit the assessment of developmental trajectories."},{"rthcId":"RTHC-00713","title":"Inequalities in Croatian pupils' risk behaviors associated to socioeconomic environment at school and area level: a multilevel approach.","authors":"Pavic Simetin, Ivana; Kern, Josipa; Kuzman, Marina; Pförtner, Timo-Kolja","year":2013,"journal":"Social science & medicine (1982), 98, 154-61","doi":"10.1016/j.socscimed.2013.09.021","pmid":"24331894","tags":["youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Multilevel analysis of 1,601 Croatian secondary school students (age 15) from the WHO Health Behavior in School-aged Children study examined how individual, school, and area socioeconomic status related to risk behaviors. Individual SES explained the majority of differences across all risk behaviors.\n\nFor cannabis use specifically, school heterogeneity (vs. homogeneity) and medium school-level SES (vs. low) were associated with higher probability. Medium area-level SES was also associated with higher cannabis use compared to low area-level SES. Counter-intuitively, lower individual, school, and area SES played a protective role against most risk behaviors.","whyItMatters":"This study challenges the assumption that drug use is primarily a problem of disadvantaged communities. For cannabis specifically, medium-SES environments had higher use, suggesting that prevention programs need to target middle-class schools and neighborhoods as well.","specificNumbers":"1,601 pupils aged 15. Low individual SES: protective for tobacco, drunkenness. Medium school SES and school heterogeneity: higher cannabis use. Medium area SES: higher cannabis use and fighting. Gymnasium (advanced school) attendance: protective against fighting.","methodology":"Multilevel logistic regression analysis of WHO HBSC data from Croatia (2006). 1,601 pupils aged 15 in secondary schools. Three levels: individual, school, area. Risk behaviors: tobacco, drunkenness, cannabis, early sexual initiation, fighting. Census data for area-level SES.","limitations":"Croatian-specific findings may not generalize to other countries. Cross-sectional design cannot establish causation. Self-reported risk behaviors subject to social desirability bias. Only one age group (15-year-olds) studied. The WHO HBSC data are from 2006, and patterns may have changed."},{"rthcId":"RTHC-00714","title":"The medicalisation of revolt: a sociological analysis of medical cannabis users.","authors":"Pedersen, Willy; Sandberg, Sveinung","year":2013,"journal":"Sociology of health & illness, 35(1), 17-32","doi":"10.1111/j.1467-9566.2012.01476.x","pmid":"22827932","tags":["medical-cannabis","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"One hundred Norwegian cannabis users, none with legal access to medical cannabis, were interviewed about their medical motives. Cannabis was used for conditions like multiple sclerosis, ADHD, and rheumatism, as well as for quality-of-life purposes like sleep, relaxation, and wellbeing. The boundaries between medical and recreational use were consistently blurred.\n\nUsers employed several strategies to gain social acceptance: downplaying psychoactive effects like intoxication and euphoria, using the language of medicine and pharmacological research, and contrasting cannabis favorably with prescription medications' abuse potential. The medical cannabis movement had little success in Norway, partly because medical professionals could not accept that users might be more knowledgeable than experts about their own conditions.","whyItMatters":"This study examines a universal dynamic in cannabis policy: the tension between genuine medical use, self-medication, and recreational use dressed in medical language. Understanding these dynamics is crucial for designing cannabis policies that support legitimate medical needs without enabling misuse of medical frameworks.","specificNumbers":"100 Norwegian cannabis users interviewed. No legal medical cannabis access in Norway. Uses reported: MS, ADHD, rheumatism, sleep, relaxation, wellbeing. Strategies: downplaying high, using medical language, comparing favorably to prescription drugs.","methodology":"Qualitative study of 100 Norwegian cannabis users. In-depth interviews exploring medical motives and strategies for social acceptance. Sociological analysis of the medicalisation of cannabis use.","limitations":"Norwegian-specific context with no legal medical cannabis, which may produce different dynamics than jurisdictions with medical access. Self-selected sample of users willing to discuss their use. Qualitative methodology does not quantify how common these patterns are. The researcher's analytical framework may influence interpretation."},{"rthcId":"RTHC-00715","title":"Prospective study of QTc changes among former opiate addicts since admission to methadone maintenance treatment: benzodiazepine risk.","authors":"Peles, Einat; Linzy, Shirley; Kreek, Mary Jeanne; Adelson, Miriam","year":2013,"journal":"Journal of addiction medicine, 7(6), 428-34","doi":"10.1097/ADM.0b013e3182a8a4f2","pmid":"24145160","tags":["drug-interactions"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Four hundred twenty-one opiate addicts newly admitted to methadone maintenance were followed prospectively for 4.5 years. QTc intervals were measured at baseline and again at a steady methadone dose. QTc prolonged significantly from 424.5 ms at baseline to 438.6 ms at steady dose, but this prolongation was not affected by methadone dose level or treatment duration beyond 2 years.\n\nThe critical finding was that patients whose urine tested positive for benzodiazepine during steady-dose treatment had significantly greater QTc prolongation (p=0.003). Two patients who were benzodiazepine abusers died from undefined causes. Cannabis use was included as a variable but was not associated with additional QTc risk.","whyItMatters":"QTc prolongation can lead to fatal cardiac arrhythmias. This study identifies benzodiazepine co-use as a specific risk factor that clinicians should monitor in methadone patients. The finding that cannabis did not add QTc risk provides reassurance for methadone patients who also use cannabis.","specificNumbers":"421 patients. QTc: 424.5 ms baseline to 438.6 ms at steady dose (significant). Benzodiazepine positive: significantly greater QTc prolongation (p=0.003). Cannabis positive: no additional QTc effect. 2 benzodiazepine-abusing patients died (undefined causes).","methodology":"Prospective cohort study of 421 newly admitted methadone patients at 2 clinics. 4.5-year follow-up. Baseline ECG within 28 days of admission. Follow-up ECG at steady methadone dose with negative or positive urine toxicology. QTc intervals compared across conditions.","limitations":"Urine testing provides only a snapshot of substance use. Cannabis and benzodiazepine categories were combined in some analyses. The \"undefined\" deaths in benzodiazepine users cannot be definitively attributed to QTc prolongation. Not all patients had follow-up ECGs. Methadone dose was not randomized."},{"rthcId":"RTHC-00716","title":"The impact of marijuana use on glucose, insulin, and insulin resistance among US adults.","authors":"Penner, Elizabeth A; Buettner, Hannah; Mittleman, Murray A","year":2013,"journal":"The American journal of medicine, 126(7), 583-9","doi":"10.1016/j.amjmed.2013.03.002","pmid":"23684393","tags":["appetite","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using NHANES data from 2005-2010, researchers compared metabolic markers between 579 current marijuana users, 1,975 past users, and never-users. After adjusting for age, sex, race, alcohol use, tobacco use, income, physical activity, and BMI, current marijuana use was associated with 16% lower fasting insulin (95% CI: -26% to -6%) and 17% lower HOMA-IR (95% CI: -27% to -6%), an established measure of insulin resistance.\n\nCurrent users also had significantly smaller waist circumferences. Past users showed intermediate values between current and never-users. No significant dose-response relationship was found among current users.","whyItMatters":"Lower insulin resistance is associated with lower risk of diabetes, cardiovascular disease, and metabolic syndrome. If the association with cannabis is causal, it could explain the epidemiological observation of lower diabetes prevalence among cannabis users and have implications for metabolic disease treatment.","specificNumbers":"4,657 adults. 579 current users, 1,975 past users. Current use: -16% fasting insulin (CI: -26, -6). -17% HOMA-IR (CI: -27, -6). Smaller waist circumference (significant). No dose-response among current users.","methodology":"Cross-sectional analysis of NHANES 2005-2010 data. 4,657 adults. Self-reported marijuana use in a private room. Fasting blood samples after 9-hour fast. Multiple linear regression adjusting for demographics, lifestyle factors, and BMI.","limitations":"Cross-sectional design cannot establish causation. Cannabis users may differ from non-users in unmeasured ways (diet, lifestyle) that affect insulin. Self-reported cannabis use may be inaccurate. The lack of dose-response is difficult to explain if the effect is real. Adjustment for BMI may be over-adjustment if cannabis affects BMI."},{"rthcId":"RTHC-00717","title":"The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance.","authors":"Pesta, Dominik H; Angadi, Siddhartha S; Burtscher, Martin; Roberts, Christian K","year":2013,"journal":"Nutrition & metabolism, 10(1), 71","doi":"10.1186/1743-7075-10-71","pmid":"24330705","tags":["exercise"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review compared four commonly used drugs' effects on exercise performance. Caffeine had strong evidence as an ergogenic (performance-enhancing) aid. Nicotine had preliminary ergogenic evidence. Alcohol and THC were generally ergolytic (performance-impairing) but could theoretically enhance performance under specific circumstances.\n\nTHC was on the WADA prohibited list, yet the evidence suggested it impairs most performance measures: reduced reaction time, impaired motor coordination, decreased strength, and altered cardiovascular response to exercise. The theoretical ergogenic circumstances were limited to potential anti-anxiety effects that might benefit sports requiring calmness, and its role in recovery through pain and inflammation reduction.","whyItMatters":"The discrepancy between THC's prohibition by WADA and its actual performance-impairing effects raises questions about the rationale for its prohibition. If THC is ergolytic, athletes who use it are disadvantaging themselves, challenging the fairness-based argument for prohibition.","specificNumbers":"Caffeine: ergogenic (strong evidence). Nicotine: potentially ergogenic (preliminary). THC: generally ergolytic, on WADA prohibited list. Alcohol: generally ergolytic. THC impairs: reaction time, motor coordination, strength, cardiovascular response.","methodology":"Narrative review evaluating ergogenic and ergolytic evidence for caffeine, nicotine, ethanol, and THC. Examined mechanisms of action, physiological effects, and impact on recreational and elite sports performance.","limitations":"Narrative review may not capture all relevant studies. THC effects vary by dose, timing, tolerance, and individual sensitivity. Most exercise-THC studies were conducted in non-athletes. The specific circumstances where THC might be ergogenic are theoretical rather than demonstrated. Chronic versus acute use may have different effects."},{"rthcId":"RTHC-00718","title":"Childhood trajectories of inattention, hyperactivity and oppositional behaviors and prediction of substance abuse/dependence: a 15-year longitudinal population-based study.","authors":"Pingault, J-B; Côté, S M; Galéra, C; Genolini, C; Falissard, B; Vitaro, F; Tremblay, R E","year":2013,"journal":"Molecular psychiatry, 18(7), 806-12","doi":"10.1038/mp.2012.87","pmid":"22733124","tags":["youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers tracked behavioral trajectories of 1,803 children from age 6 to 12 using yearly parent and teacher reports, then assessed substance dependence at age 21. At age 21, prevalence was: nicotine 30.7%, alcohol 13.4%, cannabis 9.1%, cocaine 2.0%.\n\nOpposition was the most pervasive predictor: it predicted cannabis dependence (OR=2.33), cocaine dependence (OR=2.97), and marginally predicted alcohol abuse (OR=1.38). Inattention independently predicted nicotine dependence (OR=2.25) but not other substances after controlling for opposition. Hyperactivity did not independently predict any substance outcome. These findings suggest the well-known ADHD-substance use link is largely driven by co-occurring oppositional behavior, not attention or hyperactivity symptoms per se.","whyItMatters":"This study fundamentally reframes the ADHD-substance use relationship. Rather than attention problems driving addiction risk, it is the oppositional/defiant behavior that frequently accompanies ADHD. This has direct implications for prevention: targeting oppositional behavior in childhood may be more effective than targeting inattention.","specificNumbers":"1,803 children, ages 6-12, followed to 21. Age 21 prevalence: nicotine 30.7%, alcohol 13.4%, cannabis 9.1%, cocaine 2.0%. Opposition predicted: cannabis (OR=2.33), cocaine (OR=2.97). Inattention predicted: nicotine only (OR=2.25). Hyperactivity: no independent predictions.","methodology":"Population-based longitudinal study. 1,803 participants (814 males). Behavioral assessments yearly from age 6-12 (mother and teacher reports). Substance abuse/dependence assessed at age 21 by structured interview. Trajectory modeling of behavioral problems. Multivariate prediction controlling for all behavioral dimensions.","limitations":"Behavioral assessments relied on parent and teacher reports, not clinical diagnoses. Age 21 assessment is relatively early for lifetime substance outcomes. French Canadian population may not generalize. Opposition is often comorbid with conduct disorder, making it difficult to separate their contributions. Cannabis and cocaine dependence prevalence was relatively low, limiting statistical power."},{"rthcId":"RTHC-00719","title":"Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.","authors":"Porter, Brenda E; Jacobson, Catherine","year":2013,"journal":"Epilepsy & behavior : E&B, 29(3), 574-7","doi":"10.1016/j.yebeh.2013.08.037","pmid":"24237632","tags":["epilepsy","cbd","youth","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Nineteen parents of children with treatment-resistant epilepsy (13 with Dravet syndrome, 4 with Doose syndrome, 1 Lennox-Gastaut, 1 idiopathic) were surveyed via a Facebook support group. These children had tried an average of 12 antiepileptic drugs before turning to CBD-enriched cannabis.\n\nSixteen of 19 parents (84%) reported reduced seizure frequency: 2 (11%) reported complete seizure freedom, 8 (42%) reported greater than 80% reduction, and 6 (32%) reported 25-60% reduction. Parents also reported improved alertness, better mood, and improved sleep. Side effects were limited to drowsiness and fatigue.","whyItMatters":"This was one of the earliest surveys documenting what parents of children with severe epilepsy were already doing: turning to CBD-enriched cannabis after exhausting conventional treatments. It provided the first structured data supporting what would later be confirmed in clinical trials leading to FDA approval of Epidiolex.","specificNumbers":"19 children. Average of 12 AEDs tried previously. 84% reported seizure reduction. 11% seizure-free. 42% reported >80% reduction. 32% reported 25-60% reduction. Side effects: drowsiness, fatigue.","methodology":"Online survey of parents belonging to a Facebook group for CBD-enriched cannabis use in pediatric epilepsy. 19 responses met inclusion criteria (epilepsy diagnosis + current CBD-enriched cannabis use). Parent-reported seizure frequency and side effects.","limitations":"Parent-reported outcomes without medical verification. Facebook recruitment introduces severe selection bias (parents who perceived benefit were more likely to participate). No control group. No standardized CBD preparation (variable products, doses). Very small sample."},{"rthcId":"RTHC-00720","title":"Advances in the management of multiple sclerosis spasticity: experiences from recent studies and everyday clinical practice.","authors":"Pozzilli, Carlo","year":2013,"journal":"Expert review of neurotherapeutics, 13(12 Suppl), 49-54","doi":"10.1586/14737175.2013.865877","pmid":"24289844","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review summarized the clinical evidence for Sativex in MS spasticity. Up to 80% of MS patients experience spasticity during their disease course, and about one-third have moderate or severe symptoms despite oral anti-spasticity drugs. Sativex was recently approved in EU countries for treatment-resistant MS spasticity.\n\nIn clinical trials, Sativex provided initial relief within 4 weeks in about half of treatment-resistant patients. Among these initial responders, three-quarters achieved clinically significant improvement (30%+ reduction). In real-world practice, the mean daily dose was about 5 sprays, over 80% reported no adverse events, and follow-up studies showed continued benefit for at least 1 year without dose increases.","whyItMatters":"The \"trial and respond\" approach (4-week initial trial, continue only in responders) is clinically practical and maximizes benefit-to-risk ratio. The absence of dose escalation over a year addresses the key tolerance concern. Sativex fills a genuine gap for the one-third of MS patients with inadequately treated spasticity.","specificNumbers":"80% of MS patients experience spasticity. ~33% have moderate-severe despite treatment. Initial response in ~50% within 4 weeks. 30%+ improvement in 75% of responders. Mean daily dose: ~5 sprays. >80% no AEs. Benefit maintained 1+ year without dose increase.","methodology":"Expert review of clinical trial data, real-world practice data, and safety registry data for Sativex in MS spasticity. Covered the 4-week trial period approach for identifying responders.","limitations":"Expert review perspective rather than systematic review. Real-world data may reflect selection bias (patients who benefit continue, others stop). The 4-week trial period may miss slow responders. Long-term data beyond 1 year was limited at the time."},{"rthcId":"RTHC-00721","title":"Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors.","authors":"Pryce, G; Cabranes, A; Fernández-Ruiz, J; Bisogno, T; Di Marzo, V; Long, J Z; Cravatt, B F; Giovannoni, G; Baker, D","year":2013,"journal":"Multiple sclerosis (Houndmills, Basingstoke, England), 19(14), 1896-904","doi":"10.1177/1352458513485982","pmid":"23625705","tags":["neuroscience","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Mice with experimental autoimmune encephalomyelitis (EAE, a model of MS) developed spasticity that was treated with three different FAAH inhibitors (CAY100400, CAY100402, URB597). All reduced limb stiffness as measured by strain gauge. The anti-spastic effect was sustained with repeated dosing.\n\nCritically, the therapeutic effect was absent in FAAH-deficient mice, definitively proving that the drugs work specifically through FAAH inhibition rather than off-target effects. The MAGL inhibitor JZL184 also controlled spasticity. Importantly, anti-spastic effects occurred at doses that did not produce overt cannabinoid-like behavioral effects (sedation, catalepsy, hypothermia).","whyItMatters":"Cannabis extracts treat MS spasticity (Sativex is approved) but have dose-limiting side effects. FAAH inhibitors achieve the same anti-spastic effect by boosting the body's own endocannabinoids, avoiding the psychoactive side effects. This study provided definitive proof-of-concept for a new class of anti-spasticity drugs.","specificNumbers":"3 FAAH inhibitors tested: all reduced spasticity. Effect sustained with repeated dosing. Effect absent in FAAH-deficient mice (definitive target validation). MAGL inhibitor JZL184 also effective. No overt cannabimimetic side effects at therapeutic doses.","methodology":"EAE model in Biozzi ABH mice (wild-type and FAAH-deficient). Limb stiffness measured by strain gauge. Three FAAH inhibitors and one MAGL inhibitor tested. FAAH-deficient mice used to confirm target specificity. Repeated dosing to assess sustained efficacy.","limitations":"Mouse EAE model does not perfectly replicate human MS spasticity. The FAAH inhibitors tested have not been clinically developed for MS. Long-term effects and safety profiles are unknown. The transition from animal models to human MS is historically challenging."},{"rthcId":"RTHC-00722","title":"Marijuana and tobacco co-use in young adults: patterns and thoughts about use.","authors":"Ramo, Danielle E; Delucchi, Kevin L; Hall, Sharon M; Liu, Howard; Prochaska, Judith J","year":2013,"journal":"Journal of studies on alcohol and drugs, 74(2), 301-10","doi":null,"pmid":"23384378","tags":["youth","addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"An online survey of young adult tobacco users (ages 18-25) found that over half (53%) had also used marijuana in the past 30 days. Marijuana co-users were younger, had higher income, were more likely to be male and multiethnic, and were more commonly nondaily smokers compared to tobacco-only users.\n\nDays of marijuana use in the past month was associated with multiple measures of tobacco use intensity. However, among all the tobacco-related cognitions assessed (outcome expectations, desire, self-efficacy, difficulty, pros/cons, stage of change), only one significant association emerged: co-users had 25% lower odds of planning to quit tobacco permanently (OR=0.75, 95% CI: 0.58-0.98).","whyItMatters":"Marijuana and tobacco co-use is extremely common among young adults. The finding that co-users are less likely to plan quitting tobacco is clinically important: tobacco cessation interventions for young adults should assess and address marijuana use as a potential barrier to quit motivation.","specificNumbers":"53% of young adult tobacco users also used marijuana in past 30 days. Co-users: younger, higher income, more male, more nondaily smokers. OR=0.75 for planning to quit tobacco permanently. Other tobacco cognitions: no significant differences.","methodology":"Cross-sectional online survey. Participants ages 18-25 reporting past-month tobacco use. Assessed tobacco use patterns, marijuana use, tobacco-related cognitions and quit plans. Multivariable analysis.","limitations":"Online convenience sample may not represent all young adult smokers. Cross-sectional design cannot determine whether marijuana use causes lower quit intentions. Self-reported substance use. The single significant finding among many comparisons could be a chance result."},{"rthcId":"RTHC-00723","title":"Cannabis use and brain structural alterations of the cingulate cortex in early psychosis.","authors":"Rapp, Charlotte; Walter, Anna; Studerus, Erich; Bugra, Hilal; Tamagni, Corinne; Röthlisberger, Michel; Borgwardt, Stefan; Aston, Jacqueline; Riecher-Rössler, Anita","year":2013,"journal":"Psychiatry research, 214(2), 102-8","doi":"10.1016/j.pscychresns.2013.06.006","pmid":"24054726","tags":["psychosis","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers performed MRI brain scans on 23 first-episode psychosis (FEP) and 37 at-risk mental state (ARMS) patients, manually tracing the cingulate cortex. After controlling for age, gender, alcohol, brain volume, and antipsychotic medication, current cannabis use was negatively associated with cingulate volume.\n\nSpecifically, the posterior cingulate was reduced bilaterally in cannabis users regardless of diagnostic group. The left anterior cingulate was also reduced. These effects were independent of diagnosis, meaning cannabis appeared to affect this brain region similarly in both at-risk and first-episode patients. The cingulate cortex is rich in CB1 cannabinoid receptors, providing a biological explanation for the finding.","whyItMatters":"The cingulate cortex is one of the key brain regions implicated in schizophrenia. Finding that cannabis use is associated with reduced volume in this region across both at-risk and first-episode groups suggests cannabis may compound the brain changes associated with psychosis vulnerability.","specificNumbers":"23 FEP + 37 ARMS patients. Posterior cingulate: reduced bilaterally in cannabis users. Left anterior cingulate: reduced in cannabis users. Effects independent of diagnostic group and all covariates.","methodology":"Cross-sectional MRI study. 23 FEP and 37 ARMS subjects. Manual tracing of anterior and posterior cingulate cortex bilaterally. Cannabis use assessed with Basel Interview for Psychosis. Repeated measures ANCOVA controlling for covariates.","limitations":"Cross-sectional design cannot determine whether cannabis caused volume reduction or vice versa. Small sample sizes within each group. Manual tracing is reliable but operator-dependent. No healthy control comparison. Cannabis use was self-reported."},{"rthcId":"RTHC-00724","title":"Longitudinal associations of cannabis and illicit drug use with depression, suicidal ideation and suicidal attempts among Nova Scotia high school students.","authors":"Rasic, Daniel; Weerasinghe, Swarna; Asbridge, Mark; Langille, Donald B","year":2013,"journal":"Drug and alcohol dependence, 129(1-2), 49-53","doi":"10.1016/j.drugalcdep.2012.09.009","pmid":"23041136","tags":["youth","depression","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Nine hundred seventy-six students surveyed in grade 10 and again in grade 12 were assessed for cannabis, illicit drug use, depression, suicidal ideation, and suicide attempts. Illicit drug use (drugs other than cannabis), with or without cannabis co-use, was significantly associated with depression, suicidal ideation, and suicide attempts.\n\nHeavy cannabis use alone (without other illicit drugs) predicted depression but not suicidal ideation or attempts. This distinction suggests that cannabis has a specific relationship with depressive symptoms, while the broader suicidality risk is driven more by general illicit drug involvement.","whyItMatters":"The differentiation between cannabis-specific and general illicit drug effects is clinically important. Cannabis alone appears to increase depression risk but not suicide risk, while polysubstance use involving illicit drugs is a stronger marker for suicidality. This helps clinicians calibrate their concern based on substance use patterns.","specificNumbers":"976 students, grades 10 to 12, 2-year follow-up. Illicit drug use: significant for depression, suicidal ideation, suicide attempts. Heavy cannabis use alone: significant for depression only. Not significant for suicidal ideation or attempts.","methodology":"Longitudinal study of 976 students in 4 Nova Scotia high schools. Assessed in grade 10 (2000-2001) and grade 12 (2002-2003). Generalized estimating equations modeled depression, suicidal ideation, and suicide attempts among drug users and non-users.","limitations":"Relatively short follow-up (2 years). Self-reported substance use and mental health outcomes. \"Heavy cannabis use\" was defined by the study but details are not in the abstract. The sample was from a specific region that may not generalize. Confounding factors may explain the cannabis-depression link."},{"rthcId":"RTHC-00725","title":"Marijuana use patterns among patients with inflammatory bowel disease.","authors":"Ravikoff Allegretti, Jessica; Courtwright, Andrew; Lucci, Matthew; Korzenik, Joshua R; Levine, Jonathan","year":2013,"journal":"Inflammatory bowel diseases, 19(13), 2809-14","doi":"10.1097/01.MIB.0000435851.94391.37","pmid":"24185313","tags":["medical-cannabis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"A survey of 292 IBD patients at an academic medical center (94% response rate) found that 12.3% were active marijuana users, 39.0% were past users, and 48.6% had never used. Among current and past users, 16.4% used marijuana specifically for disease symptoms, with the majority rating it \"very helpful\" for abdominal pain, nausea, and diarrhea.\n\nChronic abdominal pain was the strongest predictor of both current use (OR=3.5) and medicinal use (OR=4.7). Younger age also predicted both use patterns. Notably, half of never-users expressed interest in using marijuana for abdominal pain if it were legally available.","whyItMatters":"The high response rate (94%) and the finding that patients with the most pain are most likely to use marijuana suggests genuine symptom-driven demand rather than recreational use with medical justification. The 50% interest among never-users indicates substantial unmet need for pain management in IBD.","specificNumbers":"292 patients, 94% response rate. 12.3% current users. 39% past users. 16.4% used for disease symptoms. Chronic pain: OR=3.5 for current use, OR=4.7 for medicinal use. 50% of never-users interested if legal.","methodology":"Prospective cohort survey at an academic medical center. 292 IBD patients (94% response rate). Self-reported marijuana use patterns, perceived benefits, and predictors of use. Multivariate logistic regression for predictors.","limitations":"Single academic medical center. Self-reported use and benefits. Cross-sectional design. Patients who found marijuana unhelpful may have stopped and not reported use. The survey did not distinguish between smoking, edibles, or other forms. No objective outcome measures."},{"rthcId":"RTHC-00726","title":"Immunomodulatory and therapeutic effects of Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients.","authors":"Rezapour-Firouzi, Soheila; Arefhosseini, Seyed Rafie; Mehdi, Farhoudi; Mehrangiz, Ebrahimi-Mamaghani; Baradaran, Behzad; Sadeghihokmabad, Elyar; Mostafaei, Somaiyeh; Fazljou, Seyed Mohammad Bagher; Torbati, Mohammad-ali; Sanaie, Sarvin; Zamani, Fatemeh","year":2013,"journal":"Complementary therapies in medicine, 21(5), 473-80","doi":"10.1016/j.ctim.2013.06.006","pmid":"24050582","tags":["inflammation","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"One hundred relapsing-remitting MS patients were randomized to three groups: Group A received hemp seed + evening primrose oils with a \"hot-nature\" dietary intervention, Group B received olive oil, and Group C received the oils without the diet. After 6 months (65 completed), Groups A and C showed significant improvements in disability scores (EDSS) and relapse rates. Immunological markers also improved: IL-17 and IFN-gamma (pro-inflammatory) decreased while IL-4 (anti-inflammatory) increased in Groups A and C.\n\nGroup B (olive oil only) showed only borderline improvement in relapse rate and worsening of immunological parameters.","whyItMatters":"Hemp seed oil is rich in omega-3 and omega-6 fatty acids but contains minimal cannabinoids. This study suggests that hemp-derived nutritional components, rather than psychoactive cannabinoids, may have therapeutic value in MS through immune modulation.","specificNumbers":"100 patients randomized, 65 completed. Groups A and C: significant improvement in EDSS and relapse rate. IL-17 and IFN-gamma decreased. IL-4 increased. Group B (olive oil): borderline relapse improvement, worsening immune markers.","methodology":"Double-blind, randomized trial. 100 RRMS patients (EDSS<6). Three groups over 6 months. Outcomes: Mizadj assessment, EDSS, relapse rate, IL-4, IFN-gamma, IL-17.","limitations":"High dropout rate (35%). The \"hot-nature diet\" is based on traditional medicine and may confound the oil supplementation effect. Small sample per group. The dietary intervention was not blinded. Six months is relatively short for MS outcomes. EDSS changes in this range may be difficult to detect."},{"rthcId":"RTHC-00727","title":"An exploratory study of cannabis withdrawal among Indigenous Australian prison inmates: study protocol.","authors":"Rogerson, Bernadette; Copeland, Jan; Buttner, Petra; Bohanna, India; Cadet-James, Yvonne; Sarnyai, Zoltan; Clough, Alan R","year":2013,"journal":"BMJ open, 3(5)","doi":"10.1136/bmjopen-2013-002951","pmid":"23793690","tags":["withdrawal","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study protocol addressed a critical gap: cannabis withdrawal has never been examined in Indigenous populations despite exceptionally high community cannabis use rates. When incarcerated, Indigenous Australians face abrupt enforced cannabis cessation, which can lead to irritability, anger, threatening behavior, violence, sleep disturbances, and self-harm.\n\nThe protocol planned to recruit 60 male and 60 female Indigenous prisoners (ages 18-40) at high risk of cannabis dependence upon entry to custody. A pictorial representation of the Cannabis Withdrawal Scale would be tested for reliability and validity. Salivary cortisol would be measured as a biomarker for withdrawal onset and severity.","whyItMatters":"Cannabis withdrawal in custodial settings is a safety issue: irritability and anger from withdrawal can escalate to violence and self-harm. Indigenous Australians are disproportionately incarcerated and have high cannabis dependence rates, making culturally appropriate assessment and management tools essential.","specificNumbers":"Planned sample: 60 male + 60 female Indigenous prisoners. Ages 18-40. Pictorial withdrawal scale for cross-cultural validity. Salivary cortisol as biomarker.","methodology":"Study protocol for prospective observational study. 120 Indigenous prisoners (60 male, 60 female). Pictorial Cannabis Withdrawal Scale. Salivary cortisol markers. Generalized estimating equations for changes over time. Qualitative assessment of culturally acceptable interventions.","limitations":"This is a study protocol, not a results paper. The challenges of research in custodial settings (consent, access, trust) are substantial. The pictorial withdrawal scale had not yet been validated. Salivary cortisol is influenced by many factors beyond cannabis withdrawal."},{"rthcId":"RTHC-00728","title":"Marijuana craving trajectories in an adolescent marijuana cessation pharmacotherapy trial.","authors":"Roten, Amanda T; Baker, Nathaniel L; Gray, Kevin M","year":2013,"journal":"Addictive behaviors, 38(3), 1788-91","doi":"10.1016/j.addbeh.2012.11.003","pmid":"23261493","tags":["youth","quitting","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Eighty-nine adolescents were randomized to N-acetylcysteine (NAC, 1200 mg twice daily) or placebo in an 8-week marijuana cessation trial. All received contingency management and counseling. Marijuana craving, measured by the short-form Marijuana Craving Questionnaire, decreased significantly over time in both groups with no between-group difference.\n\nHowever, NAC participants submitted significantly more negative urine cannabinoid tests than placebo participants (a finding from the parent trial). This dissociation, more abstinence without less craving, suggests NAC's cessation-promoting effect works through mechanisms other than craving reduction, possibly through glutamate modulation affecting habit and compulsive drug-seeking rather than the subjective desire to use.","whyItMatters":"Understanding how cessation medications work matters for treatment optimization. If NAC reduces use without reducing craving, it may work by interrupting automatic, habitual drug-seeking behavior rather than by reducing the conscious desire to use. This mechanistic insight could inform combination treatment approaches.","specificNumbers":"89 adolescents. NAC 1200 mg twice daily for 8 weeks. Craving decreased similarly in both groups (no between-group difference). NAC group: significantly more negative urine tests. Mechanism: not craving reduction.","methodology":"Secondary analysis of an 8-week, double-blind, placebo-controlled trial. 89 adolescents (NAC n=45, placebo n=44). All received contingency management and cessation counseling. Marijuana Craving Questionnaire-Short Form measured at multiple timepoints.","limitations":"Secondary analysis of a small trial. The craving measure may not capture all aspects of desire to use. Contingency management (paid for negative urine tests) could have influenced both craving and use independently. The mechanism is inferred, not directly tested."},{"rthcId":"RTHC-00729","title":"Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.","authors":"Sarris, Jerome; McIntyre, Erica; Camfield, David A","year":2013,"journal":"CNS drugs, 27(4), 301-19","doi":"10.1007/s40263-013-0059-9","pmid":"23653088","tags":["anxiety","cbd","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The review examined 1,525 papers and identified 53 plants with anxiolytic evidence, of which 21 had human clinical trials. Among those with the strongest evidence for chronic anxiety treatment were kava, chamomile, ginkgo, skullcap, milk thistle, passionflower, ashwagandha, and several others.\n\nCannabidiol-enriched (low-THC) cannabis was discussed among psychotropic plant-based treatments with emerging anxiolytic evidence. The review noted that CBD reduces anxiety without the psychoactive effects of THC and showed promise in social anxiety disorder. However, the evidence was still considered emerging compared to more established herbal anxiolytics.","whyItMatters":"Placing CBD in the context of other plant-based anxiolytics provides perspective. While CBD has received enormous popular attention, it is one of many plant medicines with anxiety evidence, and several herbs have stronger clinical trial support. This context helps patients make informed choices.","specificNumbers":"1,525 papers reviewed. 53 plants with anxiolytic evidence. 21 with clinical trials. Chronic efficacy: kava, chamomile, ginkgo, skullcap, milk thistle, passionflower, ashwagandha, others. Emerging: CBD-enriched cannabis, psilocybin, ayahuasca.","methodology":"Comprehensive narrative review searching MEDLINE, CINAHL, Scopus, and Cochrane Library through October 2012. Included studies using whole plant extracts. Part 2 of a two-part review covering plants with both preclinical and clinical evidence.","limitations":"Narrative review with subjective evidence grading. Many included studies had methodological issues (small samples, brief interventions). Clinical trial quality varied enormously across plants. The CBD evidence was still emerging at the time. Standardization of plant preparations is a persistent challenge."},{"rthcId":"RTHC-00730","title":"Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal.","authors":"Scavone, J L; Sterling, R C; Van Bockstaele, E J","year":2013,"journal":"Neuroscience, 248, 637-54","doi":"10.1016/j.neuroscience.2013.04.034","pmid":"23624062","tags":["pain","neuroscience","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review detailed how cannabinoid and opioid receptors interact at the molecular level, particularly in the locus coeruleus-norepinephrine (LC-NE) system, a key circuit in the negative effects of opiate addiction. Both receptor types are present in the LC, and their activation produces overlapping effects on norepinephrine release.\n\nAnimal studies showed that endocannabinoid manipulation could modify opiate withdrawal severity. Clinical observations suggested that marijuana use among opiate addicts may serve as self-medication for withdrawal symptoms. The review proposed that targeting the endocannabinoid system could provide novel interventions for managing opiate dependence and withdrawal.","whyItMatters":"With the opioid epidemic causing hundreds of thousands of deaths, new approaches to managing opiate dependence are urgently needed. The extensive interaction between cannabinoid and opioid systems suggests that cannabinoid-based interventions could complement existing treatments.","specificNumbers":"Locus coeruleus contains both CB1 and opioid receptors. Both systems modulate norepinephrine release. Endocannabinoid manipulation modified opiate withdrawal in animal models.","methodology":"Narrative review covering molecular interactions between cannabinoid and opioid receptors, animal studies of cannabinoid effects on opiate withdrawal, and clinical observations of marijuana use in opiate-dependent populations.","limitations":"Much of the evidence was preclinical. The clinical observations were not from controlled trials. The complexity of cannabinoid-opioid interactions means effects may differ depending on the specific cannabinoid, opioid, dose, and timing. Self-medication with marijuana introduces its own risks."},{"rthcId":"RTHC-00731","title":"Impact of cannabis use during stabilization on methadone maintenance treatment.","authors":"Scavone, Jillian L; Sterling, Robert C; Weinstein, Stephen P; Van Bockstaele, Elisabeth J","year":2013,"journal":"The American journal on addictions, 22(4), 344-51","doi":"10.1111/j.1521-0391.2013.12044.x","pmid":"23795873","tags":["drug-interactions","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"A retrospective chart analysis of 91 methadone maintenance patients examined cannabis use patterns during treatment. Cannabis use was high during methadone induction (the initial dose-stabilization period) and dropped significantly after stable dosing was achieved. History of cannabis use predicted cannabis use during treatment.\n\nCritically, cannabis use during MMT did not negatively impact the methadone induction process (dose stabilization, treatment compliance, opiate abstinence). Pilot data suggested that patients who used cannabis during stabilization actually had lower objective ratings of opiate withdrawal symptoms.","whyItMatters":"Many methadone clinics penalize or discharge patients for cannabis use, based on the assumption it impairs treatment. This study suggests the opposite: cannabis use during methadone stabilization was not harmful and may have reduced withdrawal symptoms. This has implications for treatment policies.","specificNumbers":"91 patients. Cannabis use: high during induction, dropped after stabilization. No negative impact on: dose stabilization, compliance, opiate abstinence. Pilot data: lower opiate withdrawal ratings in cannabis users during stabilization.","methodology":"Retrospective chart analysis of 91 outpatient MMT records. Cannabis use patterns before and during treatment. Association with opiate abstinence, methadone dose stabilization, and treatment compliance. Objective withdrawal ratings.","limitations":"Retrospective chart review with inherent limitations. Small sample (91 patients). The withdrawal finding was described as \"pilot data\" requiring confirmation. Cannabis use was objective (urine testing) but patterns were inferred from testing schedules. Selection bias: patients who stayed in treatment long enough for analysis."},{"rthcId":"RTHC-00732","title":"Chronic co-administration of the cannabinoid receptor agonist WIN55,212-2 during puberty or adulthood reverses 3,4 methylenedioxymetamphetamine (MDMA)-induced deficits in recognition memory but not in effort-based decision making.","authors":"Schulz, Sybille; Becker, Thorsten; Nagel, Ulrich; von Ameln-Mayerhofer, Andreas; Koch, Michael","year":2013,"journal":"Pharmacology, biochemistry, and behavior, 106, 91-100","doi":"10.1016/j.pbb.2013.03.011","pmid":"23541493","tags":["neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats received MDMA, the cannabinoid agonist WIN55,212-2, both, or vehicle for 25 days during either puberty (PD40-65) or adulthood (PD80-105). Ten days after treatment, MDMA alone impaired working memory in the novel object recognition test. Co-administration of the cannabinoid with MDMA reversed this memory deficit in both age groups.\n\nHowever, in an effort-based T-maze task (choosing between easy low-reward and difficult high-reward options), adult MDMA-treated rats showed impaired decision making that the cannabinoid did not reverse. These selective effects suggest the cannabinoid-MDMA interaction differentially affects hippocampal (memory) and corticolimbic (decision-making) circuits.","whyItMatters":"MDMA and cannabis are frequently combined by young adults. This study shows the interaction is complex: the cannabinoid protected against some MDMA-induced cognitive damage (memory) but not others (decision-making). This has implications for understanding the long-term effects of polysubstance use.","specificNumbers":"MDMA 7.5 mg/kg + WIN 1.2 mg/kg for 25 days. WIN reversed MDMA memory deficits in both pubertal and adult rats. WIN did not reverse MDMA decision-making deficits in adults. Acute MDMA decreased high-reward choices (cost-aversive behavior).","methodology":"Rat study with 4 treatment groups (vehicle, MDMA 7.5 mg/kg, WIN 1.2 mg/kg, MDMA+WIN) across 2 age windows (pubertal PD40-65, adult PD80-105). Behavioral testing 10 days after treatment ended: novel object recognition and effort-based T-maze. Acute drug challenge during T-maze testing.","limitations":"Rat model with specific doses that may not reflect human co-use patterns. Only one cannabinoid agonist and dose tested. The 10-day washout period is relatively short. Behavioral tasks measure specific cognitive domains and may not capture the full picture. Only male rats were studied."},{"rthcId":"RTHC-00733","title":"Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis.","authors":"Serpell, Michael G; Notcutt, William; Collin, Christine","year":2013,"journal":"Journal of neurology, 260(1), 285-95","doi":"10.1007/s00415-012-6634-z","pmid":"22878432","tags":["medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"One hundred forty-six MS patients entered an open-label follow-up of Sativex for spasticity. Mean treatment duration was 334 days, with an average of 7.3 sprays per day. Fifty-two patients (36%) withdrew in the first year, with 14% due to adverse events and 9% due to lack of efficacy.\n\nCommon treatment-related adverse events were dizziness (24.7%) and fatigue (12.3%), mostly mild to moderate. Serious adverse events occurred in only 5 patients (3.4%), with 2 psychiatric events in one patient. No psychoses, psychiatric trends, or withdrawal symptoms were observed upon abrupt cessation. Spasticity did not deteriorate over time, and patients reported continued benefit. No evidence of tolerance developing was found.","whyItMatters":"This study addresses three major concerns about long-term cannabinoid use: tolerance, psychosis risk, and dependence. All three were absent over nearly a year of treatment. For clinicians considering Sativex for their MS patients, these safety data are reassuring.","specificNumbers":"146 patients entered. Mean exposure: 334 days. Mean dose: 7.3 sprays/day. 36% withdrew (14% AEs, 9% lack efficacy). Common AEs: dizziness 24.7%, fatigue 12.3%. Serious AEs: 3.4%. No psychosis, no tolerance, no withdrawal on cessation.","methodology":"Open-label safety follow-up trial. 146 MS patients entering from a prior 6-week RCT. Self-titrated Sativex dosing. Primary outcome: safety and tolerability (AE incidence and severity). Secondary outcomes: tolerance development and dosing profile. NRS spasticity scale for efficacy.","limitations":"Open-label design with no placebo comparison. Only patients who chose to continue from the parent trial were included, introducing selection bias. The 36% withdrawal rate means the long-term data represents completers only. Psychiatric events in one patient (2 events) may be underrepresented."},{"rthcId":"RTHC-00734","title":"Cigarette smoking and quit attempts among injection drug users in Tijuana, Mexico.","authors":"Shin, Sanghyuk S; Moreno, Patricia Gonzalez; Rao, Smriti; Garfein, Richard S; Novotny, Thomas E; Strathdee, Steffanie A","year":2013,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 15(12), 2060-8","doi":"10.1093/ntr/ntt099","pmid":"23873979","tags":["addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Six hundred seventy injection drug users in Tijuana, Mexico were interviewed, with 89.7% being current cigarette smokers. Among smokers, 31.6% contemplated quitting in the next 6 months, 22% had previously quit for a year or more, and 20.6% had made a recent quit attempt.\n\nIn multivariable analysis, recent tobacco quit attempts were positively associated with higher income, smoking marijuana (PR=1.38), and smoking heroin (PR=1.85), and negatively associated with number of daily cigarettes. The positive association between marijuana smoking and tobacco quit attempts was unexpected and counterintuitive.","whyItMatters":"The finding that marijuana users made more tobacco quit attempts, not fewer, challenges the assumption that polysubstance use uniformly reduces cessation motivation. This could reflect marijuana smokers being more health-conscious or more aware of smoking harms, warranting further investigation.","specificNumbers":"670 IDUs. 89.7% current smokers. 31.6% contemplated quitting. 20.6% recent quit attempt. Marijuana smoking: PR=1.38 for quit attempts. Heroin smoking: PR=1.85. Higher income: PR=2.30.","methodology":"Cross-sectional study of 670 IDUs recruited through community outreach in Tijuana, Mexico. In-person interviews. Multivariable Poisson regression for prevalence ratios of tobacco quit attempts.","limitations":"Tijuana IDU population may not generalize to other populations. Cross-sectional design limits causal inference. The marijuana-quit attempt association has multiple possible explanations. Self-reported quit attempts may not reflect genuine attempts. The study could not assess quit success, only attempts."},{"rthcId":"RTHC-00735","title":"Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis.","authors":"Sisay, Sofia; Pryce, Gareth; Jackson, Samuel J; Tanner, Carolyn; Ross, Ruth A; Michael, Gregory J; Selwood, David L; Giovannoni, Gavin; Baker, David","year":2013,"journal":"PloS one, 8(10), e76907","doi":"10.1371/journal.pone.0076907","pmid":"24130809","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CB2 receptor knockout mice on a C57BL/6 background developed more severe EAE (MS model), consistent with prior reports. However, when the same CB2 knockout was bred into the Biozzi ABH background, the immune-enhancing effect of CB2 deletion was completely lost. Similarly, CB1 receptor and TRPV1 knockouts on the ABH background showed no disease alteration.\n\nGPR55 knockout mice showed less severe disease on the C57BL/6 background (especially females) but only marginal effects on the ABH background. The authors concluded that non-psychoactive doses of medicinal cannabis have marginal influence on the MS immune response, with THC immunosuppression occurring only at sedative doses through CB1 rather than CB2 receptors.","whyItMatters":"This study is a cautionary tale for cannabinoid research. Many conclusions about cannabinoid receptor roles in immunity come from one mouse strain. The finding that genetic background completely changes the outcome challenges the reliability of these conclusions and their translation to genetically diverse human populations.","specificNumbers":"CB2 KO on C57BL/6: augmented EAE. CB2 KO on ABH: no effect. CB1 KO on ABH: no effect. TRPV1 KO on ABH: no effect. GPR55 KO on C57BL/6: reduced EAE (females). GPR55 KO on ABH: marginal effect.","methodology":"EAE induction in multiple knockout mouse strains on two genetic backgrounds (C57BL/6 and Biozzi ABH). Gene knockouts: CB2 (two distinct knockouts), CB1, TRPV1, GPR55. Disease incidence and severity measured. Pharmacological THC challenge in both backgrounds.","limitations":"Mouse EAE is an imperfect model of human MS. The ABH background may be more resistant to genetic perturbation generally. The knockout approach creates lifelong absence rather than acute modulation. Only EAE disease scores were used, not detailed immunological characterization on both backgrounds."},{"rthcId":"RTHC-00736","title":"Prevalence and sociodemographic associations of common mental disorders in a nationally representative sample of the general population of Greece.","authors":"Skapinakis, Petros; Bellos, Stefanos; Koupidis, Sotirios; Grammatikopoulos, Ilias; Theodorakis, Pavlos N; Mavreas, Venetsanos","year":2013,"journal":"BMC psychiatry, 13, 163","doi":"10.1186/1471-244X-13-163","pmid":"23734578","tags":["mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"A survey of 4,894 Greeks found 14% had clinically significant psychiatric morbidity (17% females, 11% males). Most common disorders were generalized anxiety (4.1%), depression (2.9%), phobias (2.8%), mixed anxiety-depression (2.7%), panic (1.9%), and OCD (1.7%).\n\nSubstance use rates: harmful alcohol use 12.7%, regular smoking 39.6%, past-month cannabis use 2.1%. Psychiatric morbidity was associated with female gender, divorced/widowed status, low education, and unemployment. All substance use was more common in men. Mental disorders were often comorbid, undertreated, and associated with lower quality of life.","whyItMatters":"This was the first study to assess the full range of common mental disorders in a representative Greek sample, providing baseline data during the period leading into Greece's severe economic crisis. The combination of high psychiatric morbidity and undertreatment highlights a public health gap.","specificNumbers":"4,894 participants. 14% psychiatric morbidity (F: 17%, M: 11%). GAD 4.1%, depression 2.9%, phobias 2.8%, mixed 2.7%. Cannabis use 2.1%. Smoking 39.6%. Harmful alcohol 12.7%. Associated: female gender, divorced, low education, unemployment.","methodology":"Cross-sectional nationally representative survey. 4,894 individuals in private households (2009-2010). Revised Clinical Interview Schedule (CIS-R) for mental disorders. AUDIT for alcohol. Self-report for smoking and cannabis.","limitations":"Cross-sectional design captures a single timepoint. The CIS-R measures symptoms in the past week, which may not reflect chronic conditions. Cannabis and drug use may be underreported. The survey was conducted as economic crisis was beginning, potentially affecting results. Household sampling misses homeless and institutionalized populations."},{"rthcId":"RTHC-00737","title":"A preliminary study of functional brain activation among marijuana users during performance of a virtual water maze task.","authors":"Sneider, Jennifer Tropp; Gruber, Staci A; Rogowska, Jadwiga; Silveri, Marisa M; Yurgelun-Todd, Deborah A","year":2013,"journal":"Journal of addiction, 2013, 461029","doi":null,"pmid":"23951549","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Ten chronic marijuana users and 18 non-using controls performed a virtual version of the Morris water maze (a classic spatial memory test) during fMRI scanning. While both groups learned the task similarly, marijuana users showed a specific deficit in memory retrieval (finding a hidden platform using spatial memory).\n\nAt the brain level, non-users showed greater activation in the right parahippocampal gyrus and cingulate gyrus during memory retrieval compared to motor control conditions. Marijuana users showed reduced activation in these regions, suggesting they were not efficiently engaging the hippocampal memory circuits needed for spatial memory retrieval.","whyItMatters":"The hippocampus has the highest density of CB1 cannabinoid receptors in the brain, making it theoretically the most vulnerable region to chronic cannabis effects. This study provides direct fMRI evidence that chronic use is associated with reduced hippocampal-related activation during the type of memory that depends on this region.","specificNumbers":"10 MJ users vs. 18 controls. Task learning: no group difference. Memory retrieval: MJ users impaired. fMRI: reduced right parahippocampal and cingulate activation in MJ users. 3.0 Tesla scanner.","methodology":"Cross-sectional fMRI study. 10 chronic marijuana users vs. 18 non-using controls. Virtual water maze task with retrieval (hidden platform) and motor control (visible platform) conditions. BOLD fMRI at 3.0 Tesla. Contrast analysis: retrieval minus motor control.","limitations":"Very small sample (10 MJ users). Cross-sectional design cannot determine causation. No information on abstinence duration before scanning. Visuospatial memory is one specific domain and may not generalize. The control group was larger, creating unequal groups."},{"rthcId":"RTHC-00738","title":"Young adults at risk for stimulant dependence show reward dysfunction during reinforcement-based decision making.","authors":"Stewart, Jennifer L; Flagan, Taru M; May, April C; Reske, Martina; Simmons, Alan N; Paulus, Martin P","year":2013,"journal":"Biological psychiatry, 73(3), 235-41","doi":"10.1016/j.biopsych.2012.08.018","pmid":"23021534","tags":["addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"One hundred sixty-one occasional stimulant users and 48 controls performed a decision-making task during fMRI. Stimulant users showed greater anterior insula, inferior frontal gyrus, and dorsal striatum activation during late trials (when contingencies were already learned), suggesting they needed more brain resources to execute familiar decisions.\n\nFollow-up analyses revealed that this inefficiency was driven by the subgroup with high cannabis co-use. Occasional stimulant users with high cannabis use showed significantly greater activation than controls, while those with low cannabis use did not differ from controls. Cocaine users also showed greater inefficiency than prescription stimulant users.","whyItMatters":"This study suggests that cannabis and cocaine have additive negative effects on brain efficiency during decision-making. The inefficiency appeared during execution of already-learned contingencies, not during learning itself, suggesting the drugs affect the deployment of learned strategies rather than learning capacity.","specificNumbers":"161 stimulant users, 48 controls. Greater activation in anterior insula, IFG, dorsal striatum during late trials. High cannabis subgroup: significantly greater activation than controls. Low cannabis subgroup: no difference from controls. Cocaine users > prescription stimulant users.","methodology":"Cross-sectional fMRI study. 161 occasional stimulant users and 48 controls. Paper-Scissors-Rock task with changing win probabilities. BOLD fMRI during early (learning) and late (execution) trials. Subgroup analyses by cannabis use level and stimulant preference.","limitations":"Cross-sectional design cannot determine causation or temporal ordering. \"Occasional\" stimulant use is a heterogeneous category. Cannabis use was a post-hoc subgroup variable. The task measures a specific type of decision-making. Greater brain activation does not always mean inefficiency; it could reflect compensatory effort."},{"rthcId":"RTHC-00739","title":"A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.","authors":"Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W","year":2013,"journal":"European journal of clinical pharmacology, 69(5), 1135-47","doi":"10.1007/s00228-012-1441-0","pmid":"23179176","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In this Phase I pharmacokinetic trial, healthy male volunteers received a THC/CBD oral spray at three dose levels (2, 4, or 8 sprays) either as single doses or daily for nine days. Both THC and CBD were rapidly absorbed after spraying.\n\nPeak blood concentrations stayed below 12 ng/mL across all dose levels, well below the levels typically reported in people who smoke or inhale cannabis. THC showed greater bioavailability than CBD at every dose tested.\n\nImportantly, there was no evidence of accumulation with repeated daily dosing for any of the compounds measured. Variability between individuals ranged from moderate to high for all pharmacokinetic measures. The spray was well tolerated, with no serious adverse events reported.","whyItMatters":"Understanding how quickly cannabinoids are absorbed and whether they accumulate with repeated use is essential for medical formulation development. The finding that peak blood levels stayed far below those from smoking suggests oral spray delivery may carry a lower risk of the acute psychoactive effects associated with high-peak THC exposure.","specificNumbers":"Peak THC blood concentrations stayed below 12 ng/mL across all dose levels. Three dose tiers were tested: 2 sprays (5.4 mg THC, 5.0 mg CBD), 4 sprays (10.8 mg THC, 10.0 mg CBD), and 8 sprays (21.6 mg THC, 20.0 mg CBD). Nine consecutive days of dosing showed no accumulation.","methodology":"This was a Phase I, within-subject crossover study in healthy male volunteers. Participants received single or multiple doses of THC/CBD oromucosal spray (containing 2.7 mg THC and 2.5 mg CBD per spray) after overnight fasting. Plasma samples were analyzed using gas chromatography-mass spectrometry for THC, CBD, and the THC metabolite 11-hydroxy-THC.","limitations":"The study included only healthy male participants, so results may not generalize to females or people with medical conditions. Fasting conditions may not reflect real-world use. The controlled clinical setting differs from typical patient use patterns."},{"rthcId":"RTHC-00740","title":"Cannabinoid hyperemesis syndrome.","authors":"Sun, Shusen; Zimmermann, Anthony E","year":2013,"journal":"Hospital pharmacy, 48(8), 650-5","doi":"10.1310/hpj4808-650","pmid":"24421535","tags":["addiction","appetite"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review described cannabinoid hyperemesis syndrome (CHS), a condition associated with long-term cannabis use characterized by cycles of severe nausea and vomiting without another identifiable cause. A distinctive feature of CHS is that patients develop compulsive hot water bathing behavior, which temporarily relieves symptoms.\n\nPatients with CHS frequently visit emergency departments for relief but are often subjected to extensive diagnostic workups before receiving a correct diagnosis. The authors concluded that CHS is likely underrecognized and underdiagnosed, particularly in emergency settings.","whyItMatters":"As cannabis use has become more common, clinicians have increasingly recognized CHS as a distinct clinical entity. Awareness of this condition can help prevent unnecessary and invasive diagnostic procedures in patients whose symptoms have a straightforward explanation.","specificNumbers":"No large-scale prevalence data were reported. The review synthesized findings from published case reports and small case series available through 2013.","methodology":"The authors conducted a literature review using PubMed to identify published reports and case series describing cannabinoid hyperemesis syndrome, its clinical features, and management approaches.","limitations":"This was a narrative review based primarily on case reports and small series, not controlled studies. The exact prevalence of CHS remained unknown at the time of publication. The mechanisms behind compulsive hot bathing behavior were not well understood."},{"rthcId":"RTHC-00741","title":"Analysis of cannabis seizures in NSW, Australia: cannabis potency and cannabinoid profile.","authors":"Swift, Wendy; Wong, Alex; Li, Kong M; Arnold, Jonathon C; McGregor, Iain S","year":2013,"journal":"PloS one, 8(7), e70052","doi":"10.1371/journal.pone.0070052","pmid":"23894589","tags":["potency","cbd","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed 206 cannabis samples confiscated from recreational users under the New South Wales Cannabis Cautioning scheme, along with 26 samples from known indoor or outdoor cultivation sites. The street-level samples averaged 14.88% THC content but only 0.14% CBD.\n\nThe near-absence of CBD is notable because CBD is thought to moderate some of the adverse psychological effects of THC. Very low levels of other cannabinoids were also detected, including minimal cannabichromene, cannabinol, and tetrahydrocannabivarin (all below 0.1%).\n\nSamples from known indoor and outdoor cultivation sites showed no significant differences in THC content from each other.","whyItMatters":"Australia has one of the highest per capita rates of cannabis use globally, yet this was the first systematic analysis of the cannabinoid profile of cannabis available to Australian users. The findings confirmed that the high-THC, low-CBD trend seen in North American and European markets extends to Australia.","specificNumbers":"Mean THC content was 14.88%. Mean CBD content was 0.14%. Cannabigerol averaged 1.18%. Other cannabinoids (CBC, CBN, THC-V) were all below 0.1%. A total of 232 samples were analyzed (206 street-level, 26 from cultivation sites).","methodology":"Researchers used high-performance liquid chromatography (HPLC) to measure nine cannabinoids in 232 cannabis samples seized by New South Wales police. Street-level samples came from users holding 15 grams or less. Known provenance samples came from larger cultivation operations.","limitations":"Samples were limited to New South Wales and may not represent cannabis across all of Australia. Only samples confiscated by police were included, which may not reflect the full range of products available. The study measured cannabinoid content but did not assess health outcomes."},{"rthcId":"RTHC-00742","title":"Impact of ADHD and cannabis use on executive functioning in young adults.","authors":"Tamm, Leanne; Epstein, Jeffery N; Lisdahl, Krista M; Molina, Brooke; Tapert, Susan; Hinshaw, Stephen P; Arnold, L Eugene; Velanova, Katerina; Abikoff, Howard; Swanson, James M","year":2013,"journal":"Drug and alcohol dependence, 133(2), 607-14","doi":"10.1016/j.drugalcdep.2013.08.001","pmid":"23992650","tags":["cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared cognitive performance in young adults (average age 24) across four groups: those with childhood ADHD who used cannabis, those with ADHD who did not, non-ADHD cannabis users, and non-ADHD non-users. After controlling for IQ, socioeconomic status, alcohol use, and smoking, the ADHD groups performed worse than comparison groups on verbal memory, processing speed, decision-making, working memory, and response inhibition.\n\nNo significant effects of adult cannabis use emerged on any cognitive measure. There were also no significant interactions between ADHD and cannabis use, meaning cannabis did not worsen cognitive deficits beyond what ADHD alone produced.\n\nHowever, exploratory analyses suggested that individuals who began regular cannabis use before age 16 may have poorer executive functioning than those who started later.","whyItMatters":"This study challenges the assumption that cannabis use in adulthood necessarily adds to the cognitive impairments associated with ADHD. The finding that age of cannabis initiation may matter more than current use aligns with broader research on adolescent brain vulnerability.","specificNumbers":"The study included 128 young adults (mean age 24.2 years). The ADHD group showed deficits across six cognitive domains compared to comparison participants. 27 individuals began regular cannabis use before age 16, and 32 began at age 16 or later.","methodology":"This cross-sectional study compared 87 young adults with childhood ADHD diagnoses (42 cannabis users, 45 non-users) to 41 local comparison participants (20 cannabis users, 21 non-users) on a battery of neuropsychological tests. Cannabis use was defined as past-year monthly or more frequent use. Covariates included age, gender, IQ, socioeconomic status, and past-year alcohol and tobacco use.","limitations":"The cross-sectional design cannot determine causation. The cannabis-using groups were relatively small, particularly for the exploratory age-of-onset analysis. Only past-year use was measured, not lifetime cumulative exposure. The study could not fully account for all potential confounds."},{"rthcId":"RTHC-00743","title":"Novel adamantyl cannabinoids as CB1 receptor probes.","authors":"Thakur, Ganesh A; Bajaj, Shama; Paronis, Carol; Peng, Yan; Bowman, Anna L; Barak, Lawrence S; Caron, Marc G; Parrish, Demon; Deschamps, Jeffrey R; Makriyannis, Alexandros","year":2013,"journal":"Journal of medicinal chemistry, 56(10), 3904-21","doi":"10.1021/jm4000775","pmid":"23621789","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Scientists synthesized a series of novel cannabinoid compounds built on an adamantyl (diamond-shaped carbon cage) framework attached to the structure of natural THC. Among these, compound AM4054 showed high affinity for the CB1 receptor and acted as a full agonist, while compound AM4089 showed partial agonist activity with selectivity for CB1 over CB2.\n\nIn rat models measuring hypothermia and pain response, the in vivo effects matched the in vitro binding profiles. The adamantyl-substituted compounds showed improved pharmacological profiles compared to the traditionally used dimethylheptyl analogs.","whyItMatters":"Selective receptor probes are critical tools for understanding how the endocannabinoid system functions. These compounds help researchers study CB1 receptor signaling with greater precision than natural cannabinoids, which bind to multiple targets.","specificNumbers":"Two lead compounds emerged: AM4054 (full CB1 agonist with high affinity) and AM4089 (partial agonist with moderate CB1/CB2 selectivity). In vivo results in rat models were consistent with in vitro binding data.","methodology":"Researchers designed and synthesized a series of tricyclic cannabinoid analogues with modifications at the C-3 and 9-NAH (northern aliphatic hydroxyl) positions. Compounds were tested for receptor binding affinity (CB1 and CB2), functional activity using cAMP assays, and in vivo effects in rat models of hypothermia and analgesia.","limitations":"These are laboratory-synthesized research compounds, not medications. In vivo testing was limited to rat models of hypothermia and analgesia. Long-term safety, human pharmacokinetics, and therapeutic potential were not assessed."},{"rthcId":"RTHC-00744","title":"Reduction of dependence to cannabinoids by GLT-1 activating property of the beta-lactam antibiotic.","authors":"Ulugol, Ahmet","year":2013,"journal":"Medical hypotheses, 80(3), 247-8","doi":"10.1016/j.mehy.2012.11.040","pmid":"23253111","tags":["addiction","withdrawal","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This paper presented a hypothesis rather than experimental results. The author noted that GLT-1 glutamate transporters play a key role in regulating brain glutamate signaling, and that beta-lactam antibiotics (like penicillin-family drugs) have been shown to stimulate GLT-1 expression.\n\nPrevious research had demonstrated that beta-lactam antibiotics reduced tolerance and dependence to opioids, and reduced tolerance to cannabinoids. Since opioids and cannabinoids share many pharmacological properties, the author hypothesized that beta-lactam antibiotics might also reduce the development of dependence to cannabinoids through their GLT-1 activating effect.","whyItMatters":"Cannabis dependence currently has no approved pharmacological treatments. If the glutamate system plays a role in cannabinoid dependence, existing antibiotics might offer an unexpected avenue for treatment research.","specificNumbers":"No original experimental data were reported. The hypothesis was based on known pharmacological parallels between opioid and cannabinoid systems.","methodology":"This was a medical hypothesis paper that synthesized existing literature on GLT-1 transporters, beta-lactam antibiotics, and cannabinoid/opioid pharmacology to propose a novel therapeutic direction. No original experiments were conducted.","limitations":"This was purely a hypothesis with no experimental testing. The parallels between opioid and cannabinoid systems, while real, do not guarantee that interventions effective for one will work for the other. Long-term antibiotic use carries its own risks, including antibiotic resistance."},{"rthcId":"RTHC-00745","title":"Cannabis use as an indicator of risk for mental health problems in adolescents: a population-based study at secondary schools.","authors":"van Gastel, W A; Tempelaar, W; Bun, C; Schubart, C D; Kahn, R S; Plevier, C; Boks, M P M","year":2013,"journal":"Psychological medicine, 43(9), 1849-56","doi":"10.1017/S0033291712002723","pmid":"23200103","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a survey of 10,324 secondary school students aged 11 to 16, past-month cannabis use was associated with a 4.5-fold increase in the odds of clinically relevant mental health problems as measured by the Strengths and Difficulties Questionnaire. However, when researchers adjusted for a comprehensive list of other risk factors, cannabis was no longer significantly associated with poor mental health.\n\nThe risk factors that explained the association included low educational track, alcohol use, cigarette smoking, hard drug use, frequent truancy, unfavorable school evaluation, feeling unsafe at school, victimization, frequent illness-related absence, having a mentally ill parent, parental abuse, financial problems, and distress from adverse events. Many of these factors were also independently associated with cannabis use itself.","whyItMatters":"This study reframes cannabis use in adolescence not as a direct cause of mental health problems but as an indicator or marker that a young person may be experiencing multiple risk factors simultaneously. This distinction matters for how schools and public health systems approach prevention.","specificNumbers":"Among 10,324 students (ages 11-16), past-month cannabis use had an unadjusted odds ratio of 4.46 (95% CI: 3.46-5.76) for clinically relevant SDQ scores. After adjusting for all other risk factors, the association was no longer statistically significant.","methodology":"Cross-sectional survey of 10,324 students aged 11-16 participating in a Public Health Service School Survey in the Netherlands. Students reported on demographics, substance use, school factors, and stressful life events and completed the Strengths and Difficulties Questionnaire. Logistic regression models examined the cannabis-mental health association before and after adjusting for other risk factors.","limitations":"Cross-sectional design cannot determine temporal ordering or causation. Self-reported data may be subject to underreporting, especially for substance use. The study was conducted in the Netherlands, where cannabis policies differ from many other countries. A trend-level association remained after full adjustment, suggesting cannabis may still play some role."},{"rthcId":"RTHC-00746","title":"Cannabis use and suicidal ideation.","authors":"van Ours, Jan C; Williams, Jenny; Fergusson, David; Horwood, L John","year":2013,"journal":"Journal of health economics, 32(3), 524-37","doi":"10.1016/j.jhealeco.2013.02.002","pmid":"23518573","tags":["mental-health","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Using data from a 30-year birth cohort study, researchers examined the directional relationship between cannabis use and suicidal ideation. They found that intensive cannabis use, defined as several times per week or more, was associated with a higher rate of transitioning into suicidal ideation among males.\n\nImportantly, the analysis tested the reverse direction as well: whether suicidal ideation led to cannabis use. No evidence supported this pathway for either males or females. The one-directional nature of the finding strengthens the case for a meaningful link between heavy cannabis use and suicidal thinking in males, though the study did not establish direct causation.","whyItMatters":"Suicide is the second leading cause of death among youth aged 10 to 24 globally. Understanding modifiable risk factors is critical. The directional finding that heavy cannabis use preceded suicidal ideation, rather than the reverse, contributes important evidence to the public health picture.","specificNumbers":"The study followed a birth cohort for 30 years. Intensive cannabis use (several times per week or more) was associated with increased suicidal ideation in males. No reverse-direction effect was found for either sex.","methodology":"This was a longitudinal analysis based on the Christchurch Health and Development Study, a 30-year follow-up of a birth cohort in New Zealand. Researchers used hazard rate models to examine both whether cannabis use predicted transitions into suicidal ideation and whether suicidal ideation predicted transitions into cannabis use.","limitations":"The association was observed only in males, limiting generalizability. Even with longitudinal data and directional modeling, uncontrolled confounders could explain the relationship. The study defined \"intensive\" use broadly and did not assess cannabis potency or specific cannabinoid exposure."},{"rthcId":"RTHC-00747","title":"Effects of cannabis use on event related potentials in subjects at ultra high risk for psychosis and healthy controls.","authors":"van Tricht, Mirjam J; Harmsen, Emma C; Koelman, Johannes H T M; Bour, Lo J; van Amelsvoort, Thérèse A; Linszen, Don H; de Haan, Lieuwe; Nieman, Dorien H","year":2013,"journal":"International journal of psychophysiology : official journal of the International Organization of Psychophysiology, 88(2), 149-56","doi":"10.1016/j.ijpsycho.2013.03.012","pmid":"23541998","tags":["psychosis","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers measured brain wave responses (event-related potentials, or ERPs) in 48 ultra-high-risk (UHR) subjects and 50 healthy controls, split into cannabis users and non-users within each group. Healthy cannabis users and UHR subjects both showed smaller P300 amplitudes compared to non-using healthy controls.\n\nHealthy cannabis users also showed delayed P300 and N200 latencies, suggesting slower information processing speed associated with cannabis use. However, within the UHR group, cannabis users and non-users did not differ on any ERP measure.\n\nAssociations between brain wave abnormalities and clinical symptoms were found, particularly between N100 latencies and P300 amplitudes and the severity of positive symptoms and general psychopathology.","whyItMatters":"The P300 brain wave reflects attention and information processing capacity. Finding similar reductions in both healthy cannabis users and UHR subjects raises questions about whether cannabis produces information processing changes that resemble those seen in early psychosis-related states.","specificNumbers":"48 UHR subjects (19 cannabis users) and 50 healthy controls (21 cannabis users) were studied. Both UHR subjects and healthy cannabis users showed reduced P300 amplitudes compared to non-using controls.","methodology":"Cross-sectional study comparing ERP components (N100, N200, P200, P300) across four groups: UHR cannabis users (n=19), UHR non-users (n=29), healthy control cannabis users (n=21), and healthy control non-users (n=29). Standard oddball paradigm was used to elicit ERPs.","limitations":"Small sample sizes, particularly in the cannabis-using subgroups. Cross-sectional design cannot determine whether cannabis caused the ERP changes or whether pre-existing differences led to cannabis use. Cannabis use was not standardized for frequency, quantity, or potency."},{"rthcId":"RTHC-00748","title":"Single doses of THC and cocaine decrease proficiency of impulse control in heavy cannabis users.","authors":"van Wel, J H P; Kuypers, K P C; Theunissen, E L; Toennes, S W; Spronk, D B; Verkes, R J; Ramaekers, J G","year":2013,"journal":"British journal of pharmacology, 170(7), 1410-20","doi":"10.1111/bph.12425","pmid":"24106872","tags":["cognition","addiction","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a study of 61 heavy cannabis users with cocaine use history, single doses of THC impaired both psychomotor function and impulse control accuracy. Cocaine had a different pattern: it improved psychomotor speed but still increased errors on impulse control tasks.\n\nBoth substances reduced the proficiency of impulse control, meaning participants made more errors even when they felt faster. The psychomotor impairments from THC appeared smaller in magnitude compared to those previously reported in occasional cannabis users, consistent with tolerance development.\n\nThe finding that both drugs decreased impulse control proficiency suggests that acute intoxication with either substance may increase the risk of impulsive decision-making, including the decision to use more drugs.","whyItMatters":"Cannabis and cocaine are among the most commonly used drugs in Europe, and they are frequently used together. Understanding how each substance independently affects impulse control in the same population of heavy users provides insight into patterns of continued use and potential relapse risk.","specificNumbers":"61 heavy cannabis users participated. THC dose was weight-based. Cocaine dose was 300 mg. THC impaired psychomotor function and increased impulse errors. Cocaine improved psychomotor speed but also increased impulse errors.","methodology":"Double-blind, placebo-controlled, three-way crossover study. Sixty-one heavy cannabis users with cocaine use history received single doses of cannabis (THC based on body weight), cocaine HCl (300 mg), and placebo in randomized order. Participants completed tests of impulse control and psychomotor function after each condition.","limitations":"The study included only heavy cannabis users with cocaine experience, so results may not apply to occasional users or cannabis-only users. Single-dose administration may not reflect real-world polydrug use patterns. The crossover design assumed no carryover effects between conditions."},{"rthcId":"RTHC-00749","title":"The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users.","authors":"Vandrey, Ryan; Stitzer, Maxine L; Mintzer, Miriam Z; Huestis, Marilyn A; Murray, Jeannie A; Lee, Dayong","year":2013,"journal":"Drug and alcohol dependence, 128(1-2), 64-70","doi":"10.1016/j.drugalcdep.2012.08.001","pmid":"22921474","tags":["withdrawal","medical-cannabis","tolerance","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Thirteen daily cannabis smokers completed a within-subject crossover study receiving 0, 30, 60, and 120 mg dronabinol per day for five consecutive days each. Dronabinol dose-dependently reduced cannabis withdrawal symptoms, with higher doses providing greater relief.\n\nThe medication produced few adverse side effects and did not cause significant cognitive impairment at any dose tested, including the highest 120 mg dose. On the fifth day of each dosing period, participants smoked cannabis. Dronabinol did not alter the subjective effects of smoked cannabis, though the 60 and 120 mg doses reduced the heart rate increase normally caused by smoking.\n\nThe finding that dronabinol did not block the subjective effects of smoked cannabis distinguishes it from substitution therapies like methadone, which reduce the rewarding effects of the target drug.","whyItMatters":"Cannabis use disorder currently has no FDA-approved pharmacotherapy. Demonstrating that oral THC can suppress withdrawal symptoms safely at doses up to 120 mg/day supports continued development of agonist replacement strategies similar to those used for opioid and nicotine dependence.","specificNumbers":"13 daily cannabis users tested. Four dose levels: 0, 30, 60, 120 mg/day. Five-day dosing periods separated by nine-day washouts. Withdrawal was dose-dependently suppressed. No significant cognitive impairment at any dose.","methodology":"Within-subject crossover study with 13 daily cannabis smokers. Each participant received all four dose levels (0, 30, 60, 120 mg/day) for five consecutive days in counterbalanced order, separated by nine-day washout periods of ad libitum cannabis use. Withdrawal symptoms, craving, sleep quality, vital signs, and cognitive performance were assessed.","limitations":"Very small sample of 13 participants. Five-day dosing periods may not reflect the longer durations needed clinically. The nine-day ad libitum cannabis use between conditions complicates interpretation. Real-world treatment involves more variables than this controlled setting."},{"rthcId":"RTHC-00750","title":"A genetic perspective on the proposed inclusion of cannabis withdrawal in DSM-5.","authors":"Verweij, K J H; Agrawal, A; Nat, N O; Creemers, H E; Huizink, A C; Martin, N G; Lynskey, M T","year":2013,"journal":"Psychological medicine, 43(8), 1713-22","doi":"10.1017/S0033291712002735","pmid":"23194657","tags":["withdrawal","genetics","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"In a study of 2,276 Australian twins who had used cannabis at least once, 11.9% met criteria for DSM-5 cannabis withdrawal. About 50% of the variation in withdrawal symptoms was attributable to additive genetic factors, with the remaining variation due to non-shared environmental influences (unique experiences not shared between twins).\n\nThe most striking finding was that 99% of the genetic influences on cannabis withdrawal overlapped with genetic influences on abuse and dependence. This means the same genes that increase vulnerability to developing abuse or dependence also drive vulnerability to withdrawal symptoms.","whyItMatters":"This study provided genetic evidence supporting the inclusion of cannabis withdrawal as a diagnostic criterion in DSM-5. Finding that withdrawal shares nearly all its genetic basis with abuse/dependence suggests these are not separate phenomena but expressions of a common underlying genetic vulnerability.","specificNumbers":"2,276 lifetime cannabis-using twins. 11.9% met DSM-5 withdrawal criteria. Heritability of withdrawal was approximately 50%. Genetic overlap between withdrawal and abuse/dependence was 99%.","methodology":"Classical twin study using 2,276 lifetime cannabis-using adult Australian twins. Cannabis withdrawal was defined according to proposed DSM-5 criterion B. Cannabis abuse/dependence was defined using DSM-IV criteria. Univariate and bivariate twin models estimated genetic, shared environmental, and non-shared environmental contributions to withdrawal and its overlap with abuse/dependence.","limitations":"Twin studies estimate heritability at the population level and cannot identify specific genes. The sample was limited to Australian twins, who may not represent other populations. Self-reported withdrawal symptoms may be affected by recall bias. The 11.9% prevalence may underestimate withdrawal given the broad range of cannabis use experience in the sample."},{"rthcId":"RTHC-00751","title":"The genetic aetiology of cannabis use initiation: a meta-analysis of genome-wide association studies and a SNP-based heritability estimation.","authors":"Verweij, Karin J H; Vinkhuyzen, Anna A E; Benyamin, Beben; Lynskey, Michael T; Quaye, Lydia; Agrawal, Arpana; Gordon, Scott D; Montgomery, Grant W; Madden, Pamela A F; Heath, Andrew C; Spector, Timothy D; Martin, Nicholas G; Medland, Sarah E","year":2013,"journal":"Addiction biology, 18(5), 846-50","doi":"10.1111/j.1369-1600.2012.00478.x","pmid":"22823124","tags":["genetics"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Researchers conducted a meta-analysis of two genome-wide association studies (GWAS) involving more than 10,000 individuals to identify genetic variants associated with initiating cannabis use. No genetic variant reached genome-wide significance, and gene-based association testing also revealed no significant effects.\n\nUsing SNP-based heritability estimation, researchers calculated that only about 6% of the variation in cannabis initiation was attributable to common genetic variants. This is notable because twin studies have estimated the overall heritability of cannabis initiation at around 40%, suggesting that much of the genetic influence comes from rare variants, gene-gene interactions, or other sources not captured by common SNP arrays.","whyItMatters":"This null result is informative. It demonstrates that cannabis initiation is not driven by any single common genetic variant of large effect. The gap between the 6% SNP-heritability and 40% twin heritability suggests that the genetics of cannabis use initiation are highly complex and distributed across many genes.","specificNumbers":"Over 10,000 individuals were included. No variants reached genome-wide significance. SNP-based heritability was approximately 6%, compared to twin study estimates of about 40% for overall heritability of cannabis initiation.","methodology":"Meta-analysis of two genome-wide association studies with over 10,000 individuals. Standard GWAS methodology was used to test associations between common genetic variants and cannabis use initiation. Gene-based testing aggregated SNP effects within genes. SNP-based heritability was estimated using genomic-relatedness-based restricted maximum likelihood (GREML).","limitations":"Sample size, while large for its time, may have been insufficient to detect variants of very small effect. Only common genetic variants were tested. Cannabis use initiation is a complex phenotype influenced by many non-genetic factors. The study focused on initiation, not progression to regular use or dependence."},{"rthcId":"RTHC-00752","title":"Cannabis derivatives therapy for a seronegative stiff-person syndrome: a case report.","authors":"Vicente-Valor, M I; Garcia-Llopis, P; Mejia Andujar, L; Antonino de la Camara, G; García del Busto, N; Lopez Tinoco, M J; Quintana Vergara, B; Peiro Vilaplana, C; Dominguez Moran, J A; Sánchez Alcaraz, A","year":2013,"journal":"Journal of clinical pharmacy and therapeutics, 38(1), 71-3","doi":"10.1111/j.1365-2710.2012.01365.x","pmid":"22726074","tags":["medical-cannabis","cbd"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 40-year-old man with seronegative stiff-person syndrome (SPS), a rare disorder causing progressive muscle rigidity and painful spasms, had not responded adequately to standard treatments. After starting THC/CBD oromucosal spray (Sativex), he showed improvement across all eight dimensions of the SF-36 quality of life questionnaire at the 14-month follow-up.\n\nSPS is diagnosed based on clinical features and continuous motor unit activity on electrophysiology testing. This patient tested negative for glutamic acid decarboxylase (GAD) antibodies in both blood and cerebrospinal fluid, classifying him as seronegative.","whyItMatters":"Stiff-person syndrome is rare and difficult to treat. When standard therapies fail, clinicians have limited options. This case report documented a potential role for cannabinoid-based therapy in managing SPS symptoms, though it represents only a single patient experience.","specificNumbers":"One patient, age 40, with six years of symptoms. Treatment duration was 14 months. Improvement was documented across all eight SF-36 quality of life dimensions.","methodology":"Single case report describing a 40-year-old male with a six-year history of progressive muscle stiffness and intermittent spasms. After multiple unsuccessful standard treatments, THC/CBD oromucosal spray was introduced. Quality of life was assessed using the SF-36 questionnaire at baseline and after 14 months of treatment.","limitations":"This is a single case report with no control comparison. Placebo effects, natural disease fluctuation, and concurrent treatments could all contribute to the observed improvement. SF-36 is a subjective quality of life measure. The findings cannot be generalized without controlled trials."},{"rthcId":"RTHC-00753","title":"Has the intake of THC by cannabis users changed over the last decade? Evidence of increased exposure by analysis of blood THC concentrations in impaired drivers.","authors":"Vindenes, Vigdis; Strand, Dag Helge; Kristoffersen, Lena; Boix, Fernando; Mørland, Jørg","year":2013,"journal":"Forensic science international, 226(1-3), 197-201","doi":"10.1016/j.forsciint.2013.01.017","pmid":"23415163","tags":["driving","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers analyzed THC blood concentrations from 1,747 drivers apprehended in Norway on suspicion of driving under the influence of cannabis between 2000 and 2010. Mean THC concentrations increased from 4.0 ng/mL in 2000 to 6.6 ng/mL in 2010, a 58% increase over the decade.\n\nFor comparison, mean blood alcohol concentrations in impaired drivers increased only 3% over the same period, and amphetamine concentrations increased 16%. The disproportionate rise in THC levels suggested that cannabis users were being exposed to more THC, likely due to increasing potency of available cannabis products.\n\nThe increase in blood THC concentrations was partially paralleled by an increase in the percentage of drivers judged as lightly impaired by examining physicians.","whyItMatters":"While cannabis potency has been documented to increase in many countries, this study was among the first to demonstrate that increased product potency translated into higher human exposure. Blood concentrations directly reflect what the body is actually absorbing, not just what the product contains.","specificNumbers":"Mean THC blood concentration: 4.0 ng/mL (2000) to 6.6 ng/mL (2010), a 58% increase. Comparison: ethanol increased 3%, amphetamines increased 16%. Sample: 1,747 THC-only cases, 38,796 ethanol-only cases, 2,493 amphetamine-only cases.","methodology":"Retrospective analysis of blood samples from drivers apprehended for suspected impaired driving in Norway between 2000 and 2010. Cases involving only THC (n=1,747) were compared to cases involving only ethanol (n=38,796) or amphetamines (n=2,493) to provide context for the THC trend.","limitations":"The sample consisted of drivers suspected of impairment, not a representative population of cannabis users. Users of higher-potency cannabis might be more likely to be apprehended. The study could not control for whether users adjusted their consumption in response to higher potency (e.g., smoking less). Norwegian cannabis markets may not reflect global trends."},{"rthcId":"RTHC-00754","title":"Increased expression of cannabinoid receptor 1 in the nucleus accumbens core in a rat model with morphine withdrawal.","authors":"Yuan, Wei-Xin; Heng, Li-Jun; Ma, Jie; Wang, Xing-Qin; Qu, Li-Juan; Duan, Li; Kang, Jun-Jun; Chen, Liang-Wei; Gao, Guo-Dong","year":2013,"journal":"Brain research, 1531, 102-12","doi":"10.1016/j.brainres.2013.07.047","pmid":"23911834","tags":["neuroscience","addiction","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers examined CB1 cannabinoid receptor expression in the nucleus accumbens core (a key brain reward region) of rats during acute (1 day), latent (3 days), and chronic (3 weeks) morphine withdrawal. CB1 receptor expression was significantly increased at all three time points compared to controls.\n\nElectron microscopy revealed that CB1 receptors were primarily located on presynaptic terminals forming inhibitory (symmetrical) synapses. Both the number of CB1-positive terminals and the density of receptor particles at these terminals increased during withdrawal.\n\nWhen researchers injected the CB1 receptor blocker rimonabant directly into the nucleus accumbens, it reduced conditioned place preference (a measure of drug-seeking behavior) during morphine withdrawal.","whyItMatters":"Relapse is one of the biggest challenges in addiction treatment. This study identified the endocannabinoid system in the nucleus accumbens as persistently altered during opioid withdrawal, suggesting it may contribute to the drug-seeking behavior that underlies relapse.","specificNumbers":"CB1 receptor expression was elevated at 1 day, 3 days, and 3 weeks of morphine withdrawal. Increased receptor density was observed at inhibitory presynaptic terminals. Rimonabant infusion into the nucleus accumbens reduced conditioned place preference.","methodology":"Rats were exposed to morphine to establish conditioned place preference, then underwent withdrawal for 1 day, 3 days, or 3 weeks. CB1 receptor expression in the nucleus accumbens core was assessed using immunofluorescence microscopy and immunoelectron microscopy. The functional role of CB1 receptors was tested by infusing the antagonist rimonabant into the nucleus accumbens during withdrawal.","limitations":"This was an animal study in rats, and findings may not directly translate to humans. Morphine withdrawal was studied, not cannabis withdrawal. The forced morphine exposure paradigm differs from human patterns of drug use. Only one brain region was examined."},{"rthcId":"RTHC-00755","title":"Delta-9-tetrahydrocannabinol + cannabidiol. A reasonable option for some patients with multiple sclerosis.","authors":"","year":2014,"journal":"Prescrire international, 23(150), 145-8","doi":null,"pmid":"25121144","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review evaluated clinical trial evidence for a THC/CBD oromucosal spray in MS-related spasticity. Three placebo-controlled trials (about 300 patients total) individually failed to show clear anti-spastic efficacy, but combined analyses showed response rates of approximately 35% with the spray versus 25% with placebo.\n\nIn a larger trial of 572 patients, the 241 patients who responded after a 4-week trial period were randomized to continue the spray or switch to placebo. After 12 weeks, 75% of those continuing the spray maintained their response, compared to 51% switched to placebo.\n\nThe reviewers estimated that in practice, about 10% of patients whose standard anti-spastic medications are unsatisfactory would specifically benefit from the cannabis extract spray. Key adverse effects included neuropsychiatric symptoms that resolved when treatment stopped, with abuse potential becoming tangible at 16 or more sprays per day.","whyItMatters":"Conventional anti-spasticity medications have limited effectiveness for many MS patients. This independent review provided a realistic assessment of what cannabinoid spray therapy offers: meaningful benefit for a modest subset of patients, rather than a broadly effective treatment.","specificNumbers":"Response rates: approximately 35% with spray vs. 25% with placebo (combined analysis). In the enrichment trial, 75% of initial responders maintained response after 12 weeks vs. 51% on placebo. Estimated real-world benefit: about 10% of patients with inadequate standard treatment. Abuse risk increases from 16+ sprays per day.","methodology":"Independent review evaluating published double-blind, placebo-controlled trials of THC/CBD oromucosal spray for MS-related spasticity. The review synthesized data from three initial trials (approximately 300 patients) and one larger enrichment trial (572 patients).","limitations":"Individual trials failed to show significant efficacy on their own. The enrichment trial design (selecting responders before randomization) tends to exaggerate effect sizes. The estimated 10% real-world benefit rate means 90% of eligible patients would not be meaningfully helped. Drug interactions via P-glycoprotein inhibition add complexity."},{"rthcId":"RTHC-00756","title":"Brain regional cannabinoid CB(1) receptor signalling and alternative enzymatic pathways for 2-arachidonoylglycerol generation in brain sections of diacylglycerol lipase deficient mice.","authors":"Aaltonen, Niina; Riera Ribas, Casandra; Lehtonen, Marko; Savinainen, Juha R; Laitinen, Jarmo T","year":2014,"journal":"European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 51, 87-95","doi":"10.1016/j.ejps.2013.08.035","pmid":"24012970","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers studied brain tissue from mice genetically engineered to lack DAGLa or DAGLb, the two main enzymes thought to produce the endocannabinoid 2-AG. Despite deletion of these primary production pathways, CB1 receptor signaling (measured by G-protein activation) remained largely unchanged across brain regions.\n\nWhen researchers blocked 2-AG breakdown (allowing produced 2-AG to accumulate), sufficient 2-AG was generated through alternative enzymatic pathways to activate CB1 receptors throughout the brain. Mass spectrometry confirmed that this pool of 2-AG was produced by pathways distinct from either DAGLa or DAGLb.","whyItMatters":"The endocannabinoid system is more complex than previously thought. The existence of backup pathways for 2-AG production means that blocking a single enzyme may not be sufficient to fully suppress endocannabinoid signaling, which has implications for drug development targeting this system.","specificNumbers":"Brain regional CB1 receptor activity was largely unaltered in both DAGLa-knockout and DAGLb-knockout mice. Alternative pathways produced sufficient 2-AG to activate CB1 receptors throughout the brain when 2-AG breakdown was blocked.","methodology":"Functional autoradiography was used to measure CB1 receptor G-protein activity across brain regions in DAGLa-knockout, DAGLb-knockout, and wild-type mice. Following pharmacological blockade of 2-AG hydrolysis, 2-AG levels were measured using liquid chromatography tandem mass spectrometry (LC/MS/MS).","limitations":"Brain cryosection experiments may not fully reflect in vivo conditions. Genetic knockout animals may develop compensatory changes during development. The alternative 2-AG pathways were identified pharmacologically but not fully characterized enzymatically."},{"rthcId":"RTHC-00757","title":"Chronic exposure to WIN55,212-2 affects more potently spatial learning and memory in adolescents than in adult rats via a negative action on dorsal hippocampal neurogenesis.","authors":"Abboussi, Oualid; Tazi, Abdelouahhab; Paizanis, Eleni; El Ganouni, Soumaya","year":2014,"journal":"Pharmacology, biochemistry, and behavior, 120, 95-102","doi":"10.1016/j.pbb.2014.02.014","pmid":"24582851","tags":["youth","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers administered the synthetic cannabinoid WIN55,212-2 to adolescent rats (starting at postnatal day 27-30) and adult rats (starting at postnatal day 54-57) for 20 consecutive days, followed by a 20-day drug-free washout period. After washout, adolescent-treated rats showed significant deficits in spatial learning and memory in the Morris water maze test, while adult-treated rats did not.\n\nThe cognitive deficits in adolescent rats correlated with decreased numbers of newly generated neurons in the dorsal hippocampus, a brain region critical for spatial memory. Both age groups showed increased thigmotaxis (wall-hugging behavior in the maze) early in training, but only the adolescent group showed persistent learning and memory problems.","whyItMatters":"This study provided mechanistic evidence for why the adolescent brain may be particularly vulnerable to cannabis. By showing that reduced hippocampal neurogenesis correlated with cognitive deficits only in adolescent-exposed animals, it linked brain development disruption to functional outcomes.","specificNumbers":"Twenty days of daily cannabinoid exposure followed by 20-day washout. Adolescent exposure started at postnatal day 27-30. Adult exposure started at postnatal day 54-57. Dose: 1 mg/kg WIN55,212-2 daily. Spatial memory deficits appeared only in the adolescent group.","methodology":"Adolescent and adult Wistar rats received daily injections of WIN55,212-2 (1 mg/kg) or vehicle for 20 days, followed by a 20-day washout. Cognitive function was assessed using the Morris water maze and two-way active avoidance tests. Hippocampal neurogenesis was quantified using doublecortin immunostaining.","limitations":"WIN55,212-2 is a synthetic cannabinoid that differs from THC in potency and receptor selectivity. The dose and administration route (daily injection) do not mirror typical human cannabis use. Rat adolescence and human adolescence are not directly equivalent. Only spatial memory and one measure of neurogenesis were assessed."},{"rthcId":"RTHC-00758","title":"Initial reactions to tobacco and cannabis smoking: a twin study.","authors":"Agrawal, Arpana; Madden, Pamela A F; Bucholz, Kathleen K; Heath, Andrew C; Lynskey, Michael T","year":2014,"journal":"Addiction (Abingdon, England), 109(4), 663-71","doi":"10.1111/add.12449","pmid":"24325652","tags":["genetics","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"In a study of female twins, researchers examined how initial reactions to tobacco and cannabis (the first time each was used) related to later development of DSM-IV diagnoses. Positive and negative reaction factors emerged for both substances.\n\nInitial reactions to tobacco predicted the onset of both nicotine dependence and cannabis abuse/dependence, suggesting that first tobacco experiences may serve as a broader indicator of substance vulnerability. Initial reactions to cannabis, however, were associated only with cannabis-specific diagnoses.\n\nGenetic factors accounted for 27-35% of the variation in initial reactions to both substances. The overlap between reaction factors was partly attributable to shared genetic influences and partly to shared individual-specific environmental factors.","whyItMatters":"Understanding why some people progress from first use to dependence while others do not is central to addiction research. This study showed that measurable differences in how individuals respond to their very first drug experience are partially genetically influenced and predictive of later clinical outcomes.","specificNumbers":"2,393 twins with tobacco use history and 1,445 with cannabis use history were analyzed. Heritability of initial reaction factors: 27-35%. Genetic correlations between positive and negative reaction factors across substances ranged from 0.18 to 0.58.","methodology":"Factor analysis and Cox proportional hazards modeling in a population-based sample of Caucasian female twins aged 18-32 years. Tobacco analyses included 2,393 individuals with lifetime tobacco use; cannabis analyses included 1,445 with lifetime cannabis use. Classical twin modeling estimated genetic and environmental contributions to initial reactions and their covariation.","limitations":"The sample included only Caucasian female twins, limiting generalizability to males and other populations. Retrospective recall of initial reactions may be influenced by subsequent use patterns. The study could not determine which specific genetic variants underlie the heritable component."},{"rthcId":"RTHC-00759","title":"COX-2-derived endocannabinoid metabolites as novel inflammatory mediators.","authors":"Alhouayek, Mireille; Muccioli, Giulio G","year":2014,"journal":"Trends in pharmacological sciences, 35(6), 284-92","doi":"10.1016/j.tips.2014.03.001","pmid":"24684963","tags":["inflammation","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review explored a lesser-known function of COX-2, an enzyme best known for producing prostaglandins during inflammation. COX-2 also metabolizes the two main endocannabinoids, anandamide (AEA) and 2-AG. Rather than simply inactivating these endocannabinoids, COX-2 converts them into prostaglandin analogs: PG-glycerol esters from 2-AG and prostamides from AEA.\n\nThese COX-2-derived endocannabinoid metabolites are distinct from classical prostaglandins and appear to have their own biological effects, particularly in inflammation. The review synthesized emerging in vivo evidence about the roles of these novel lipid mediators.","whyItMatters":"NSAIDs and other COX-2 inhibitors are among the most widely used medications. Understanding that COX-2 generates bioactive metabolites from endocannabinoids adds complexity to how we understand both anti-inflammatory drug effects and endocannabinoid system function.","specificNumbers":"Two endocannabinoids (AEA and 2-AG) are metabolized by COX-2 into two classes of products (prostamides and PG-glycerol esters). The biological significance of these metabolites was still being characterized at the time of publication.","methodology":"Narrative review of published literature on COX-2 metabolism of endocannabinoids, the generation of prostaglandin-glycerol esters and prostamides, and their biological effects in inflammatory processes.","limitations":"The biological effects of these COX-2-derived endocannabinoid metabolites were not fully characterized at the time of publication. Much of the evidence came from in vitro and animal studies. The clinical relevance for human inflammation remained to be established."},{"rthcId":"RTHC-00760","title":"Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial.","authors":"Allsop, David J; Copeland, Jan; Lintzeris, Nicholas; Dunlop, Adrian J; Montebello, Mark; Sadler, Craig; Rivas, Gonzalo R; Holland, Rohan M; Muhleisen, Peter; Norberg, Melissa M; Booth, Jessica; McGregor, Iain S","year":2014,"journal":"JAMA psychiatry, 71(3), 281-91","doi":"10.1001/jamapsychiatry.2013.3947","pmid":"24430917","tags":["withdrawal","medical-cannabis","quitting","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In a double-blind clinical trial, 51 cannabis-dependent treatment seekers received either nabiximols (up to 86.4 mg THC and 80 mg CBD daily) or placebo during a 9-day inpatient admission, followed by 28 days of outpatient follow-up. Nabiximols significantly reduced overall withdrawal severity, with notable effects on irritability, depression, and cravings.\n\nPatients receiving nabiximols stayed in treatment significantly longer during the medication phase, with a number needed to treat of 2.84 for successful treatment retention. Importantly, participants could not distinguish between nabiximols and placebo, and those on nabiximols did not report feeling intoxicated.\n\nHowever, after medication ended, both groups showed similar reductions in cannabis use at follow-up. Nabiximols provided no advantage over placebo for long-term cannabis use, cannabis-related problems, or dependence severity.","whyItMatters":"No medications are approved for cannabis dependence or withdrawal. This trial, published in JAMA Psychiatry, demonstrated that agonist replacement with nabiximols can manage the acute withdrawal period effectively. The finding that withdrawal relief did not translate to better long-term outcomes echoes patterns seen with other substance use disorders.","specificNumbers":"51 participants randomized. Maximum daily dose: 86.4 mg THC + 80 mg CBD. Nabiximols significantly reduced withdrawal severity (P = .01). Treatment retention hazard ratio: 3.66 (95% CI: 1.18-11.37). Number needed to treat: 2.84. No significant differences in adverse events between groups.","methodology":"Two-site, double-blind, randomized clinical trial with inpatient and outpatient phases. 51 cannabis-dependent adults received a 6-day nabiximols or placebo regimen with standardized psychosocial interventions during a 9-day admission, followed by 28-day outpatient follow-up. Primary outcomes included withdrawal severity (Cannabis Withdrawal Scale), treatment retention, and adverse events.","limitations":"Small sample size of 51 participants limits statistical power. The 6-day medication course may have been too short. Inpatient setting does not reflect typical outpatient treatment conditions. Long-term outcomes were based on self-report."},{"rthcId":"RTHC-00761","title":"Relationship between seminal plasma levels of anandamide congeners palmitoylethanolamide and oleoylethanolamide and semen quality.","authors":"Amoako, Akwasi Atakora; Marczylo, Timothy Hywel; Elson, Janine; Taylor, Anthony Henry; Willets, Jonathon M; Konje, Justin Chi","year":2014,"journal":"Fertility and sterility, 102(5), 1260-7","doi":"10.1016/j.fertnstert.2014.07.767","pmid":"25212838","tags":["neuroscience","sex-differences"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers measured levels of two endocannabinoid-related molecules, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in seminal plasma from 90 men attending an infertility clinic. Men with poor sperm motility (asthenozoospermia) and those with multiple sperm quality problems (oligoasthenoteratozoospermia) had significantly lower PEA and OEA concentrations compared to men with normal semen parameters.\n\nWhen PEA and OEA were added to normal sperm samples in the lab, they rapidly and significantly improved sperm motility and maintained viability without affecting mitochondrial activity.\n\nThe authors noted that plant cannabinoids like THC and CBD could compete with these endocannabinoid-related molecules, potentially disrupting the finely tuned system that supports normal sperm function.","whyItMatters":"The endocannabinoid system plays regulatory roles throughout the reproductive system. This study identified specific endocannabinoid-related molecules as potentially important for maintaining normal sperm function, with implications for understanding how cannabis use might affect male fertility.","specificNumbers":"90 men were studied. PEA and OEA levels were significantly lower in men with asthenozoospermia and oligoasthenoteratozoospermia. Both PEA and OEA rapidly improved sperm motility in vitro.","methodology":"PEA and OEA were extracted from seminal plasma of 90 men attending an infertility clinic and quantified using ultra-high-performance liquid chromatography-tandem mass spectrometry. Sperm from men with normal parameters were exposed to PEA or OEA in vitro to assess effects on motility, viability, and mitochondrial activity.","limitations":"Observational design cannot establish whether low PEA/OEA caused poor sperm quality or resulted from the same underlying condition. The study did not directly test cannabis exposure. In vitro effects on sperm may not reflect in vivo conditions. The infertility clinic sample may not represent the general population."},{"rthcId":"RTHC-00762","title":"Cannabis use and first manic episode.","authors":"Bally, Nathalie; Zullino, Daniele; Aubry, Jean-Michel","year":2014,"journal":"Journal of affective disorders, 165, 103-8","doi":"10.1016/j.jad.2014.04.038","pmid":"24882185","tags":["mental-health","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the relationship between cannabis use and the onset of mania in bipolar disorder. Across the studies reviewed, lifetime cannabis use among bipolar patients was approximately 70%, with about 30% meeting criteria for cannabis abuse or dependence.\n\nCannabis use was associated with younger age at onset of first manic episode and with more frequent depressive and manic episodes, though the evidence was somewhat inconsistent. Cannabis consumption was also related to poorer overall outcomes and an increased risk of rapid cycling or mixed episodes.\n\nAn unexpected finding emerged regarding cognition: neurocognitive functioning appeared to be better in bipolar patients who used cannabis compared to those who did not, though this may reflect a selection effect where higher-functioning individuals are more likely to access and use cannabis.","whyItMatters":"Bipolar disorder affects approximately 1-2% of the population, and cannabis is the most commonly used drug among bipolar patients. Understanding whether cannabis triggers or accelerates manic episodes has direct implications for clinical management of bipolar disorder.","specificNumbers":"Approximately 70% lifetime cannabis use in bipolar patients. About 30% comorbid cannabis abuse or dependence. Cannabis use was associated with earlier first mania onset and more frequent mood episodes.","methodology":"Literature review searching Medline and PsychInfo databases for articles published between 1972 and December 2013 using keywords related to first manic episode, onset of mania, bipolar disorder, and cannabis.","limitations":"Definitions of cannabis use and dependence varied across studies. No controlled studies directly tested whether cannabis causes mania. The temporal relationship between cannabis use and first manic episode was often unclear. Selection biases in clinical samples may affect prevalence estimates."},{"rthcId":"RTHC-00763","title":"Is the clinical use of cannabis by oncology patients advisable?","authors":"Bar-Sela, Gil; Avisar, Adva; Batash, Ron; Schaffer, Moshe","year":2014,"journal":"Current medicinal chemistry, 21(17), 1923-30","doi":null,"pmid":"24606496","tags":["medical-cannabis","cancer","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review assessed the evidence for cannabis use by oncology patients. The authors found that clinical cannabis use in cancer patients had been rising significantly in several countries, driven primarily by public demand rather than scientific evidence.\n\nThe clinical evidence for symptom management was described as partial: cannabis showed some benefit for cancer-related pain, nausea and vomiting, and appetite loss, but the evidence was not considered robust. Recent data from THC/CBD combination studies provided the first clinical indication of cancer-related pain relief.\n\nLaboratory studies demonstrated anti-cancer effects of cannabis components, but no clinical research had been conducted to test these effects in human cancer patients. The authors noted that the difficulty of performing research on non-medicinal botanical products had limited proper study of cannabis extract despite strong public interest.","whyItMatters":"Cancer patients frequently turn to cannabis for symptom management, often based on anecdotal evidence or media reports. This review provided oncologists and pharmacists with an evidence-based assessment of what was actually supported by clinical data versus what remained speculative.","specificNumbers":"No specific trial statistics were reported. The review referenced recent THC/CBD combination data as the first clinical pain relief evidence. Anti-cancer effects were limited to laboratory findings with no clinical studies.","methodology":"Narrative review of published literature on cannabis chemistry, potential anti-cancer effects, and clinical evidence for symptom management in oncology patients.","limitations":"Narrative review without systematic methodology. The evidence landscape was rapidly changing at the time of publication. Cannabis chemistry complexity and product variability make standardized research challenging. Smoking as a delivery route carries its own cancer risk concerns."},{"rthcId":"RTHC-00764","title":"From counselor skill to decreased marijuana use: does change talk matter?","authors":"Barnett, Elizabeth; Moyers, Theresa B; Sussman, Steve; Smith, Caitlin; Rohrbach, Louise A; Sun, Ping; Spruijt-Metz, Donna","year":2014,"journal":"Journal of substance abuse treatment, 46(4), 498-505","doi":"10.1016/j.jsat.2013.11.004","pmid":"24462244","tags":["quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers analyzed 170 audio-recorded motivational interviewing (MI) sessions with alternative high school students. Using structural equation modeling, they found that the percentage of \"change talk\" (client language expressing desire, ability, reason, or commitment to change) mediated the relationship between counselor skill and marijuana use outcomes.\n\nSpecifically, when counselors demonstrated higher MI quality, students produced more change talk, which in turn predicted reduced marijuana use. This mediation pattern held for three of four MI quality indicators tested. Counselor reflections of change talk also showed a direct effect on marijuana outcomes.\n\nThe findings supported the theoretical model that change talk is an active ingredient in motivational interviewing, not just a byproduct of the therapeutic relationship.","whyItMatters":"Motivational interviewing is one of the most widely used approaches for addressing substance use, but the mechanisms through which it works have been debated. This study provided empirical support for the specific role of change talk, helping clinicians understand which conversational techniques actually drive outcomes.","specificNumbers":"170 MI sessions were analyzed. Change talk mediated 3 of 4 relationships between MI quality indicators and marijuana outcomes. Counselor reflections of change talk showed a direct main effect on outcomes.","methodology":"Data came from an MI booster intervention delivered to alternative high school students after a classroom-based drug abuse prevention program. 170 audio-recorded sessions were coded using the Motivational Interviewing Skill Code 2.5. Structural equation modeling tested whether change talk mediated the counselor skill to marijuana outcome pathway.","limitations":"The sample was from alternative high schools, which serve students at higher risk for substance use and may not represent typical adolescents. The study examined marijuana use specifically and may not generalize to other substances. Observational coding of sessions involves subjective judgment."},{"rthcId":"RTHC-00765","title":"Peer associations for substance use and exercise in a college student social network.","authors":"Barnett, Nancy P; Ott, Miles Q; Rogers, Michelle L; Loxley, Michelle; Linkletter, Crystal; Clark, Melissa A","year":2014,"journal":"Health psychology : official journal of the Division of Health Psychology, American Psychological Association, 33(10), 1134-42","doi":"10.1037/a0034687","pmid":"24364375","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers mapped the social network of 129 college students living in one residence hall and examined whether peers' substance use and exercise behaviors were associated with individual behavior. Students nominated an average of 4.1 hall members as important to them, with 53.9% of connections being reciprocal.\n\nSix distinct social clusters emerged within the hall, and these clusters differed significantly on substance use and exercise behaviors. After controlling for demographics, peer alcohol consumption and peer marijuana use were both significantly associated with individual substance use. However, peers' exercise levels showed no association with individual exercise.\n\nThe asymmetry between substance use and exercise as socially influenced behaviors suggests that peer-based interventions may be more effective for targeting substance use than physical activity.","whyItMatters":"Understanding that marijuana use clusters within peer networks helps explain how use spreads among college students and suggests that peer-based prevention programs could be effective targets for intervention.","specificNumbers":"129 students, 6 social clusters identified. Average of 4.1 nominated peers. 53.9% reciprocal ties. Peer marijuana and alcohol use were significantly associated with individual use. Peer exercise was not associated with individual exercise.","methodology":"Cross-sectional social network study of 129 undergraduates (51.9% female) in one residence hall. Web-based survey assessed substance use, exercise, and social connections. Community detection cluster analysis identified peer groupings. Network autocorrelation modeling examined associations between peer and participant behaviors.","limitations":"Cross-sectional design cannot determine whether peers influenced each other or whether similar individuals selected each other as friends (selection vs. influence). Limited to one residence hall at one university. Small sample size. Self-reported substance use may be subject to bias."},{"rthcId":"RTHC-00766","title":"Review article: the endocannabinoid system in liver disease, a potential therapeutic target.","authors":"Basu, P P; Aloysius, M M; Shah, N J; Brown, R S","year":2014,"journal":"Alimentary pharmacology & therapeutics, 39(8), 790-801","doi":"10.1111/apt.12673","pmid":"24612021","tags":["neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review documented the endocannabinoid system's extensive involvement in liver disease. CB1 and CB2 receptors, endocannabinoids, and their metabolic enzymes are all present in the liver and play roles in multiple conditions including non-alcoholic fatty liver disease, alcoholic liver disease, hepatic encephalopathy, and autoimmune hepatitis.\n\nThe system also influences related conditions such as altered liver blood flow, cirrhotic cardiomyopathy, metabolic syndrome, and ischemia/reperfusion injury. One drug targeting the endocannabinoid system (rimonabant, a CB1 blocker) had shown therapeutic success for liver disease but was withdrawn from the market due to serious neurological and psychiatric side effects.\n\nThe authors noted optimism about newer therapeutics that target peripheral endocannabinoid receptors without crossing the blood-brain barrier, potentially avoiding the central nervous system side effects that derailed earlier approaches.","whyItMatters":"Liver disease is a major global health burden, and current treatments are limited for many conditions. The endocannabinoid system offers multiple potential drug targets, but the challenge of avoiding central nervous system side effects has been a significant barrier to drug development.","specificNumbers":"The review covered multiple liver conditions. Rimonabant, the first marketed CB1 blocker, was withdrawn due to adverse psychiatric events. Novel peripherally restricted compounds were in preclinical development.","methodology":"Review of original articles and reviews summarizing preclinical and clinical research on the endocannabinoid system in liver disease pathophysiology and therapeutic targeting.","limitations":"Much of the evidence was preclinical. The peripheral-only drug strategy was still in early development at the time of publication. The complexity of the endocannabinoid system in liver pathophysiology makes predicting drug effects challenging."},{"rthcId":"RTHC-00767","title":"Effectiveness of different Web-based interventions to prepare co-smokers of cigarettes and cannabis for double cessation: a three-arm randomized controlled trial.","authors":"Becker, Julia; Haug, Severin; Sullivan, Robin; Schaub, Michael Patrick","year":2014,"journal":"Journal of medical Internet research, 16(12), e273","doi":"10.2196/jmir.3246","pmid":"25486674","tags":["quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a three-arm randomized trial of 325 tobacco-and-cannabis co-smokers, all three web-based interventions (personalized feedback, motivational interviewing-based, and psychoeducation control) produced a significant short-term increase in readiness to quit both substances simultaneously. However, no differences emerged between the three approaches, and the readiness increase did not persist at the 8-week follow-up.\n\nNone of the interventions produced significant changes in actual tobacco or cannabis use frequency at any time point. The finding that even simple psychoeducation produced the same short-term motivational effect as more sophisticated personalized techniques suggests that brief engagement with the topic itself, rather than any specific intervention technique, drove the initial readiness boost.","whyItMatters":"Tobacco and cannabis co-use is common, and quitting one often leads to increased use of the other. Finding effective ways to motivate simultaneous cessation is important, though this study showed that brief web-based tools alone were insufficient to change behavior.","specificNumbers":"2,467 assessed, 325 randomized. Short-term readiness increase: B = 0.33 (95% CI: 0.10-0.56, P = .006). No significant effect at 8-week follow-up (P = .69). No differences between intervention types. No changes in use frequency.","methodology":"Three-arm randomized trial comparing: (1) personalized normative feedback based on dependence/use assessment, (2) motivational interviewing-based web intervention, and (3) psychoeducational information only (active control). 325 co-smokers were randomized from 2,467 screened website visitors. Readiness to quit was measured before, immediately after, and 8 weeks post-intervention.","limitations":"High attrition from screening to randomization (325 of 2,467). The interventions were brief and fully automated. The 8-week follow-up may have been too short to detect delayed behavior change. Self-selected online participants may not represent all co-smokers."},{"rthcId":"RTHC-00768","title":"Response inhibition and elevated parietal-cerebellar correlations in chronic adolescent cannabis users.","authors":"Behan, B; Connolly, C G; Datwani, S; Doucet, M; Ivanovic, J; Morioka, R; Stone, A; Watts, R; Smyth, B; Garavan, H","year":2014,"journal":"Neuropharmacology, 84, 131-7","doi":"10.1016/j.neuropharm.2013.05.027","pmid":"23791961","tags":["youth","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Adolescent heavy cannabis users and matched non-using controls completed a Go/No-Go task (requiring them to inhibit a habitual response) during brain imaging. Cannabis users made more errors on the task, indicating poorer impulse control.\n\nSurprisingly, when researchers looked at which brain regions activated during the task, there were no differences between groups. Instead, the difference appeared in how brain regions communicated with each other: cannabis users showed heightened correlation patterns between bilateral inferior parietal lobules and the left cerebellum.\n\nThis abnormal connectivity pattern was replicated using resting-state brain imaging data (when participants were not performing any task) and was positively correlated with self-reported recent cannabis use. The findings suggest the problem was not in the activation of individual brain regions but in the wiring between them.","whyItMatters":"Most brain imaging studies of cannabis focus on which regions activate more or less. This study shifted focus to how regions connect, revealing that the problem in adolescent cannabis users may be in the communication between brain areas rather than the function of any single area.","specificNumbers":"Cannabis users showed impaired Go/No-Go performance. Heightened correlation between bilateral inferior parietal lobules and left cerebellum was found during both task and rest. The connectivity pattern correlated with recent cannabis use.","methodology":"Cross-sectional study comparing adolescent heavy cannabis users to age-matched non-using controls using a Go/No-Go paradigm during fMRI. Both task-related activation and functional connectivity were analyzed. Resting-state fMRI was also collected to assess intrinsic connectivity patterns.","limitations":"Cross-sectional design cannot determine whether cannabis caused the connectivity changes or whether pre-existing brain differences led to cannabis use. Sample size was not reported in the abstract. The study used a synthetic measure of recent use rather than controlled dosing."},{"rthcId":"RTHC-00769","title":"Barriers to access for Canadians who use cannabis for therapeutic purposes.","authors":"Belle-Isle, Lynne; Walsh, Zach; Callaway, Robert; Lucas, Philippe; Capler, Rielle; Kay, Robert; Holtzman, Susan","year":2014,"journal":"The International journal on drug policy, 25(4), 691-9","doi":"10.1016/j.drugpo.2014.02.009","pmid":"24947993","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 628 current therapeutic cannabis users in Canada, only 7% accessed cannabis exclusively from authorized (legal) sources. The vast majority relied on unauthorized sources despite the existence of a federal access program.\n\nKey barriers included difficulty finding a physician willing to support a program application, high costs of authorized cannabis, and complexity of the application process. Access varied by medical condition and overall health status.\n\nThe presence of medical cannabis dispensaries (which were not part of the regulatory regime at the time) was positively associated with access, suggesting these unofficial distribution points were filling a gap left by the formal program. Fewer than 5% of estimated therapeutic cannabis users in Canada were enrolled in the federal program.","whyItMatters":"When a regulated therapeutic cannabis program exists but only reaches 5% of estimated users, the regulatory framework is failing to serve patients. Understanding the specific barriers to access can inform policy improvements and reduce the harms of unregulated supply.","specificNumbers":"628 therapeutic users surveyed. Only 7% accessed exclusively from authorized sources. Fewer than 5% of estimated therapeutic users were enrolled in the federal program. Dispensary presence was positively associated with access.","methodology":"Cross-sectional survey of 628 current therapeutic cannabis users in Canada. A health services analytical framework examined barriers across five dimensions: accommodation, accessibility, availability, affordability, and acceptability.","limitations":"Self-selected survey sample may not represent all therapeutic users. Self-reported data on sources and use patterns. The study captured a specific point in Canadian policy that has since changed significantly with full legalization."},{"rthcId":"RTHC-00770","title":"Medical marijuana in neurology.","authors":"Benbadis, Selim R; Sanchez-Ramos, Juan; Bozorg, Ali; Giarratano, Melissa; Kalidas, Kavita; Katzin, Lara; Robertson, Derrick; Vu, Tuan; Smith, Amanda; Zesiewicz, Theresa","year":2014,"journal":"Expert review of neurotherapeutics, 14(12), 1453-65","doi":"10.1586/14737175.2014.985209","pmid":"25427150","tags":["medical-cannabis","cbd","pain","epilepsy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This expert review assessed the evidence for cannabinoids in neurological diseases. High-quality clinical trial evidence supported the safety and efficacy of cannabinoids for four indications: spasticity in multiple sclerosis, pain not responding to opioids, glaucoma, and nausea/vomiting.\n\nLower-level clinical evidence indicated potential usefulness for dystonia, tics, tremors, epilepsy, migraine, and weight loss, though more research was needed. The review distinguished between THC (psychoactive) and CBD (neuroprotective in preclinical studies without psychoactive effects).\n\nCommon adverse effects included weakness, mood changes, and dizziness. Cardiovascular side effects and potential pulmonary effects from chronic smoking were noted. Fatalities were described as rare even with recreational use. Psychological dependence was a concern, but physical dependence was less well documented.","whyItMatters":"Neurological patients represent a significant proportion of medical cannabis users. This review from neurologists provided a clinical framework for understanding which conditions had adequate evidence and which remained speculative.","specificNumbers":"Four indications had high-quality clinical evidence. Six additional conditions had lower-level evidence. CBD was highlighted as neuroprotective without psychoactive effects. Fatalities were rare even in recreational use.","methodology":"Expert review of published clinical trials, preclinical studies, and safety data on cannabinoids for neurological indications.","limitations":"The evidence base was limited by small sample sizes in many studies. Safety data were incomplete, especially for long-term use. The wide variety of cannabis preparations and routes of administration made comparing studies difficult."},{"rthcId":"RTHC-00771","title":"Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control.","authors":"Bhattacharyya, S; Iyegbe, C; Atakan, Z; Martin-Santos, R; Crippa, J A; Xu, X; Williams, S; Brammer, M; Rubia, K; Prata, D; Collier, D A; McGuire, P K","year":2014,"journal":"Psychological medicine, 44(15), 3315-28","doi":"10.1017/S0033291714000920","pmid":"25065544","tags":["genetics","cognition","dopamine","driving"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In a double-blind study, healthy occasional cannabis users received either THC or placebo and performed a response inhibition task during brain imaging. Carriers of the A allele of the AKT1 rs1130233 gene variant showed significantly increased errors after THC (P = 0.008), while G allele homozygotes showed no impairment.\n\nBrain imaging revealed that A allele carriers showed reduced activation in the left inferior frontal gyrus (a region critical for motor control) after THC, while G homozygotes showed modest enhancement. There was a direct correlation between the behavioral impairment and the brain activation change in this region.\n\nThe AKT1 gene influences dopamine signaling, and the inferior frontal cortex is rich in dopaminergic innervation, providing a mechanistic pathway linking genetics to THC-induced behavioral impairment.","whyItMatters":"People respond very differently to cannabis, and understanding why has been a persistent question. This study identified a specific genetic mechanism: a variant in a dopamine-related gene that determines whether THC impairs the brain region responsible for stopping inappropriate actions.","specificNumbers":"A allele carriers showed significantly increased inhibition errors (P = 0.008). G homozygotes showed no impairment. Behavioral-brain activation correlation: r = -0.327 (P = 0.045). AKT1 genotype modulated THC effects specifically in the inferior frontal gyrus.","methodology":"Double-blind, repeated-measures design in healthy occasional cannabis users. Participants received acute oral THC or placebo and performed a Go/No-Go response inhibition task during functional MRI. Participants were genotyped for the AKT1 rs1130233 single nucleotide polymorphism.","limitations":"The sample consisted of healthy occasional users and may not represent heavy or dependent users. The authors noted these results require independent replication. Oral THC administration differs from smoking in pharmacokinetics. Only one genetic variant was tested."},{"rthcId":"RTHC-00772","title":"Childhood and current ADHD symptom dimensions are associated with more severe cannabis outcomes in college students.","authors":"Bidwell, L C; Henry, E A; Willcutt, E G; Kinnear, M K; Ito, T A","year":2014,"journal":"Drug and alcohol dependence, 135, 88-94","doi":"10.1016/j.drugalcdep.2013.11.013","pmid":"24332802","tags":["cognition","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a study of 376 college undergraduates, researchers examined how specific ADHD symptom dimensions related to cannabis outcomes. Current and childhood inattention (IN) symptoms were independently associated with more severe cannabis use, craving, and problem use in young adulthood, even after controlling for comorbid psychopathology.\n\nChildhood hyperactivity-impulsivity (HI) symptoms were associated with earlier initiation of cannabis use but not with current severity. A key interaction emerged: current inattention symptoms moderated the relationship between cannabis use level and problems, such that higher inattention strengthened the link between use and negative outcomes.\n\nThis means that among students who use similar amounts of cannabis, those with more inattention symptoms experienced worse consequences.","whyItMatters":"ADHD is common among college students and is associated with higher rates of cannabis use. This study clarified that it is specifically the inattention dimension, not hyperactivity, that amplifies cannabis-related problems, which has implications for identifying at-risk students.","specificNumbers":"376 undergraduates studied. Current and childhood IN associated with worse cannabis outcomes (P < .01). Childhood HI associated with earlier initiation (P < .01). IN moderated use-to-problems relationship (P < .01).","methodology":"Cross-sectional assessment of 376 male and female undergraduates measuring cannabis variables, current and childhood ADHD symptoms, and comorbid internalizing and externalizing psychopathology. Statistical models controlled for symptoms of comorbid conditions to isolate ADHD-specific contributions.","limitations":"Cross-sectional design in a non-clinical college sample. ADHD symptoms were assessed dimensionally (not diagnostic categories) via self-report. The study cannot determine whether inattention causes worse cannabis outcomes or whether a third factor drives both."},{"rthcId":"RTHC-00773","title":"The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study.","authors":"Bloomfield, Michael A P; Morgan, Celia J A; Kapur, Shitij; Curran, H Valerie; Howes, Oliver D","year":2014,"journal":"Psychopharmacology, 231(11), 2251-9","doi":"10.1007/s00213-014-3523-4","pmid":"24696078","tags":["dopamine","cognition","neuroscience","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Every participant scored above the clinical cutoff for apathy on the Apathy Evaluation Scale. Within this small group, people with lower dopamine synthesis capacity in the striatum reported more apathy. The association was strongest in the associative striatum, a region involved in planning and goal-directed behavior (rho = -0.69, p = 0.006). The whole striatum also showed an inverse link (rho = -0.64, p = 0.015). Limbic and sensorimotor subdivisions did not show significant associations. Apathy scores were not significantly related to current cannabis consumption or age of first use in this sample.","whyItMatters":"Apathy and reduced drive are common complaints among regular users. The study links apathy severity to a dopamine synthesis marker in brain circuits tied to goal-directed behavior. It does not establish cause, but it maps a specific biological measure to a self-reported motivational state in living humans using a well-validated imaging tool.","specificNumbers":"- Sample: 14 regular cannabis users assessed once with [18F]-DOPA PET and an apathy questionnaire\n- Apathy scores: median 59.5 on the AES-S (IQR 7.5), well above the clinical cutoff of 34, meaning pronounced apathy in this group\n- Dopamine–apathy link, whole striatum: rho = -0.64, p = 0.015, lower dopamine synthesis associated with higher apathy\n- Dopamine–apathy link, associative striatum: rho = -0.69, p = 0.006, strongest association observed","methodology":"This was a cross-sectional imaging study of 14 regular cannabis users. Dopamine synthesis capacity was measured using [18F]-DOPA PET and summarized as K i(cer), an index of how readily the brain synthesizes dopamine using a cerebellar reference. Subjective apathy was measured with the self-rated Apathy Evaluation Scale. Researchers examined Spearman correlations between apathy scores and K i(cer) for the whole striatum and its functional subdivisions: associative, limbic, and sensorimotor. There was no non-user control group and no experimental manipulation.","limitations":"Very small sample size (n = 14) limits precision and generalizability. Cross-sectional design cannot determine directionality. No non-user control group, so it is unclear how these values compare to people who do not use cannabis. Apathy was self-rated, which can be influenced by mood and context. Cannabis product types, THC or CBD content, and timing of last use were not reported in the abstract. Null findings in limbic and sensorimotor regions could reflect true specificity or low statistical power."},{"rthcId":"RTHC-00774","title":"Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification: cannabis withdrawal syndrome and its correlation with delta-9-tetrahydrocannabinol and -metabolites in serum.","authors":"Bonnet, U; Specka, M; Stratmann, U; Ochwadt, R; Scherbaum, N","year":2014,"journal":"Drug and alcohol dependence, 143, 189-97","doi":"10.1016/j.drugalcdep.2014.07.027","pmid":"25127704","tags":["withdrawal","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Thirty-nine chronic cannabis-dependent patients were monitored during inpatient detoxification. Withdrawal symptoms peaked on day 4, with an average severity score of 10.4 out of 39 points, and declined to 2.9 points by day 16. The most dominant symptoms were craving, restlessness, nervousness, and sleeplessness. Clinical severity peaked at 5 out of 7 on a global impression scale (\"markedly ill\").\n\nWomen experienced significantly stronger withdrawal than men. On admission, THC and metabolite levels negatively correlated with withdrawal severity (higher levels meant less withdrawal, consistent with the pharmacological model). After admission, no correlation existed between blood levels and symptom severity.\n\nRemarkably, 28.2% of patients still had THC blood levels above 1 ng/mL after 16 days of confirmed abstinence (range: 1.3 to 6.4 ng/mL), reflecting THC's storage in body fat and slow release.","whyItMatters":"This study provided a detailed clinical timeline of cannabis withdrawal under controlled conditions. The finding that THC persists in blood for over two weeks has implications for drug testing, driving assessments, and understanding why some withdrawal symptoms may be prolonged.","specificNumbers":"39 patients. Withdrawal peaked day 4 (10.4/39 points), declined to 2.9/39 by day 16. CGI-S peaked at 5/7. 28.2% still had THC above 1 ng/mL at day 16. Women had significantly stronger withdrawal than men.","methodology":"Prospective observational study of 39 treatment-seeking cannabis dependents (ICD-10) in inpatient detoxification. Assessments at admission and abstinence days 2, 4, 8, and 16 using the Marijuana Withdrawal Checklist (MWC) and Clinical Global Impression-Severity scale. Serum THC, THC-OH, and THC-COOH were measured simultaneously.","limitations":"Relatively small sample of 39 patients. All were treatment-seeking, which may select for more severe dependence. Some patients received medications for withdrawal symptoms, though this did not affect the THC-withdrawal correlation. The study did not assess body composition, which affects THC storage and release."},{"rthcId":"RTHC-00775","title":"Acute and non-acute effects of cannabis on human memory function: a critical review of neuroimaging studies.","authors":"Bossong, Matthijs G; Jager, Gerry; Bhattacharyya, Sagnik; Allen, Paul","year":2014,"journal":"Current pharmaceutical design, 20(13), 2114-25","doi":null,"pmid":"23829369","tags":["cognition","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized neuroimaging studies examining both acute THC effects and long-term effects of cannabis use on learning and memory in adults and adolescents. A consistent pattern emerged across studies: cannabis use was associated with increased activity in memory-related brain areas and higher levels of deactivation in other regions.\n\nThis pattern has two possible interpretations. It could reflect \"neurophysiological inefficiency,\" where the brain must recruit more resources to achieve the same level of performance. Alternatively, it could represent a change in cognitive strategy that allows users to maintain task performance despite underlying processing changes.\n\nThe review noted that interpretation was significantly complicated by large differences between study populations in terms of frequency of cannabis use, age of onset, and duration of abstinence before testing.","whyItMatters":"Traditional neuropsychological testing sometimes shows minimal performance differences between cannabis users and non-users. Brain imaging reveals what happens beneath the surface: users may achieve similar scores but at a greater neural cost, which could have implications for long-term cognitive reserves.","specificNumbers":"The review encompassed multiple neuroimaging studies. Cannabis users consistently showed increased activation in memory-related areas. The exact pattern varied depending on cannabis use frequency, age of onset, and abstinence duration.","methodology":"Critical review of published neuroimaging studies (fMRI and related techniques) examining acute and non-acute effects of cannabis on human learning and memory function in both adult and adolescent populations.","limitations":"Large methodological differences between studies made direct comparisons difficult. Key variables including use frequency, age of onset, and abstinence duration varied widely. The review could not determine whether brain activation changes were caused by cannabis or preceded use. The dichotomy between \"inefficiency\" and \"strategy change\" was not resolved."},{"rthcId":"RTHC-00776","title":"Cannabis depenalisation, drug consumption and crime - evidence from the 2004 cannabis declassification in the UK.","authors":"Braakmann, Nils; Jones, Simon","year":2014,"journal":"Social science & medicine (1982), 115, 29-37","doi":"10.1016/j.socscimed.2014.06.003","pmid":"24937326","tags":["legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers exploited the 2004 UK declassification of cannabis (from Class B to Class C) as a natural experiment to test whether reduced penalties led to increases in drug use or crime. Using individual-level panel data from England and Wales (2003-2006), they compared outcomes across age groups that were differently affected by the penalty changes due to thresholds in British criminal law.\n\nThe difference-in-differences analysis found essentially no increases in cannabis consumption, use of other drugs, crime, or other forms of risky behavior following declassification. The null findings were consistent across multiple outcome measures.","whyItMatters":"A central concern about cannabis policy reform is that reducing penalties will increase use and associated harms. This study provided empirical evidence from a national-level policy change that declassification did not produce the feared increases.","specificNumbers":"Data covered 2003-2006 in England and Wales. No significant increases were found in cannabis use, other drug use, crime, or risky behavior following the 2004 declassification.","methodology":"Quasi-experimental study using individual-level longitudinal panel data from the Offending, Crime and Justice Survey (2003-2006). Difference-in-differences design exploited the fact that the 2004 cannabis declassification changed expected punishments differently across age groups due to legal thresholds.","limitations":"The UK declassification was a relatively modest policy change (reclassification, not full legalization). The three-year follow-up may not capture longer-term effects. The specific age-based threshold approach relies on assumptions about how different groups perceived the policy change. UK findings may not generalize to other legal and cultural contexts."},{"rthcId":"RTHC-00777","title":"Developmental trajectories of marijuana use from adolescence to adulthood: relationship with using weapons including guns.","authors":"Brook, Judith S; Lee, Jung Yeon; Finch, Stephen J; Brook, David W","year":2014,"journal":"Aggressive behavior, 40(3), 229-37","doi":"10.1002/ab.21520","pmid":"24338741","tags":["youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In a longitudinal study of 838 inner-city African American and Puerto Rican participants, researchers identified distinct trajectories of marijuana use from adolescence to adulthood and examined their association with violent behavior. Compared to the no/low use trajectory, the increasing marijuana use trajectory was associated with 3.37 times the odds of engaging in violence involving weapons (shooting or hitting someone).\n\nThe moderate use trajectory (AOR = 1.98) and even the \"quitter\" trajectory (AOR = 1.70) were also associated with increased odds of weapon-related violence compared to no/low use. The analyses controlled for other predictors of violent behavior.","whyItMatters":"Understanding the association between marijuana use patterns and violent behavior has implications for both public health prevention and criminal justice approaches. The finding that even \"quitter\" trajectories showed elevated violence risk suggests that exposure history matters beyond current use.","specificNumbers":"838 participants. Increasing use trajectory: AOR = 3.37 (P < .001). Moderate use trajectory: AOR = 1.98 (P < .01). Quitter trajectory: AOR = 1.70 (P < .05). All compared to no/low use.","methodology":"Longitudinal study following 838 inner-city African American and Puerto Rican participants. Growth mixture modeling identified marijuana use trajectories from adolescence to adulthood. Logistic regression examined associations between trajectory group membership and weapon-related violence.","limitations":"Observational design cannot establish causation. The specific inner-city, minority population limits generalizability. Weapon violence is rare and affected by many contextual factors. Self-reported marijuana use and violence may be subject to reporting bias. Confounders related to socioeconomic conditions and neighborhood exposure were not fully captured."},{"rthcId":"RTHC-00778","title":"Marijuana use and brain immune mechanisms.","authors":"Cabral, Guy A; Jamerson, Melissa","year":2014,"journal":"International review of neurobiology, 118, 199-230","doi":"10.1016/B978-0-12-801284-0.00008-7","pmid":"25175866","tags":["neuroscience","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined how cannabinoids affect immune function within the central nervous system. THC was found to exhibit immunosuppressive activity, particularly by inhibiting the migratory capability of microglia (the brain's resident immune cells) toward sites of microbial invasion.\n\nCBD also modulated immune function but appeared to work through different mechanisms than THC. The non-psychoactive nature of CBD made it a candidate for conditions involving neuroinflammation, though an unresolved question remained about whether its immunomodulatory effects could increase susceptibility to brain infections.\n\nThe review also highlighted evidence that cannabinoid exposure during early development could have long-term effects on the neuroimmune system, potentially altering fundamental immune responses to microbes in adulthood.","whyItMatters":"The brain has its own immune system, and understanding how cannabis compounds affect it is important for both medical cannabis development (especially for neuroinflammatory conditions) and for assessing potential risks of cannabis use on brain infection susceptibility.","specificNumbers":"No specific quantitative data were reported. The review synthesized findings from multiple preclinical studies on cannabinoid immune effects.","methodology":"Review of published literature on the effects of phytocannabinoids (THC and CBD) on immune-competent cells within the central nervous system, focusing on microglia, infection susceptibility, and developmental effects.","limitations":"Most evidence came from in vitro and animal studies. The clinical relevance of cannabinoid-induced neuroimmune changes in humans remained to be established. Dose, route, and duration of exposure likely matter but were not systematically addressed."},{"rthcId":"RTHC-00779","title":"Marijuana and alcohol use and attempted smoking cessation in adolescent boys and girls.","authors":"Camenga, Deepa R; Kong, Grace; Bagot, Kara; Hoff, Rani A; Potenza, Marc N; Krishnan-Sarin, Suchitra","year":2014,"journal":"Substance abuse, 35(4), 381-6","doi":"10.1080/08897077.2014.958207","pmid":"25174418","tags":["youth","quitting","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 804 adolescent cigarette smokers, researchers examined whether marijuana and alcohol use frequency predicted having ever attempted to quit smoking. Higher-frequency marijuana use (more than 6 times in the past 30 days) was associated with 44% lower odds of having made a cigarette quit attempt.\n\nA significant gender interaction emerged: the association was driven primarily by boys (59% lower odds, AOR = 0.41) rather than girls (29% lower odds, not statistically significant, AOR = 0.71). Frequent binge drinking (more than 5 days in the past month) was also associated with 51% lower odds of a quit attempt.\n\nThe findings suggest that adolescents with heavier substance use patterns may face additional barriers to initiating smoking cessation.","whyItMatters":"Adolescent smoking cessation is a public health priority. If frequent marijuana use reduces the likelihood of even attempting to quit cigarettes, it identifies a subgroup that may need additional support. The gender difference suggests that intervention approaches may need to be tailored.","specificNumbers":"804 adolescent smokers. Higher-frequency marijuana use: AOR = 0.56 (95% CI: 0.36-0.86). Boys specifically: AOR = 0.41 (95% CI: 0.22-0.77). Frequent binge drinking: AOR = 0.49 (95% CI: 0.29-0.83). Gender interaction P = .03.","methodology":"Cross-sectional analysis of survey data from high-school-aged adolescents. Current cigarette smokers (n=804) were classified by quit attempt history. Logistic regression models examined associations between marijuana/alcohol use frequency and history of cigarette quit attempts, testing for gender interactions.","limitations":"Cross-sectional design cannot establish causation. Self-reported quit attempts may not accurately reflect actual cessation behavior. The study defined quit attempts broadly (\"ever tried to stop smoking\"). Higher-frequency substance users may simply have less interest in health behavior changes overall."},{"rthcId":"RTHC-00780","title":"Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition.","authors":"Carr, Russell L; Graves, Casey A; Mangum, Lee C; Nail, Carole A; Ross, Matthew K","year":2014,"journal":"Neurotoxicology, 43, 82-89","doi":"10.1016/j.neuro.2013.12.009","pmid":"24373905","tags":["neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers exposed juvenile rat pups (10 days old) to low-level chlorpyrifos (CPF), a widely used pesticide, for seven days. At a dose of 0.5 mg/kg, the pesticide significantly inhibited FAAH, the enzyme that breaks down the endocannabinoid anandamide (AEA), leading to anandamide accumulation in the brain.\n\nImportantly, this occurred at a dose that did not inhibit brain cholinesterase (ChE), the traditionally recognized target of organophosphate pesticide toxicity. The finding suggests that the endocannabinoid system may be a more sensitive target of developmental pesticide exposure than the cholinergic system.","whyItMatters":"The endocannabinoid system plays critical roles in brain development. If common environmental pesticide exposure can disrupt this system at doses considered \"safe\" for the cholinergic system, it raises questions about current safety thresholds for developmental neurotoxicity.","specificNumbers":"Dose: 0.5 mg/kg CPF daily for 7 days. FAAH was significantly inhibited at 12 hours. AEA levels significantly increased. No significant change in brain ChE, MAGL, or 2-AG levels.","methodology":"Ten-day-old rat pups received daily oral doses of 0.5 mg/kg chlorpyrifos or corn oil vehicle for 7 days. Brain enzyme activities (ChE, MAGL, FAAH) and endocannabinoid levels (AEA, 2-AG) were measured at 4 and 12 hours after the final dose.","limitations":"Animal study with forced dosing that may not reflect typical human pesticide exposure levels. Only one dose level was tested. The functional consequences of anandamide accumulation on brain development were not assessed. Species differences between rats and humans limit direct translation."},{"rthcId":"RTHC-00781","title":"Is recent cannabis use associated with acute coronary syndromes? An illustrative case series.","authors":"Casier, Isabelle; Vanduynhoven, Philippe; Haine, Steven; Vrints, Chris; Jorens, Philippe G","year":2014,"journal":"Acta cardiologica, 69(2), 131-6","doi":null,"pmid":"24783463","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Researchers reported three cases where recent or chronic cannabis use preceded cardiac arrest requiring CPR. Each case involved a different cardiovascular mechanism:\n\nThe first patient presented with asystole and was found to have diffuse coronary vasospasm after acute cannabis use. The second, a young patient without known cardiovascular risk factors, had an acute heart attack with occlusion of two coronary arteries during chronic cannabis use. The third presented with ventricular fibrillation from a coronary artery occlusion.\n\nAll three patients had recent cannabis use confirmed by history and toxicological screening showed no other substance use besides cannabis.","whyItMatters":"The cardiovascular risks of cannabis are often underappreciated. These cases demonstrated that cannabis-associated cardiac events can occur through multiple mechanisms and can affect young people without any pre-existing cardiovascular risk factors.","specificNumbers":"Three patients. Three distinct cardiovascular mechanisms: coronary vasospasm, dual coronary artery occlusion, and ventricular fibrillation. All required CPR with restoration of spontaneous circulation.","methodology":"Case series of three patients who experienced cardiac arrest requiring CPR, each with confirmed recent cannabis use and negative toxicological screening for other substances. Clinical details including coronary angiography findings were reported.","limitations":"Case reports cannot prove causation. Three cases is a very small number. Other undetected factors may have contributed. The frequency of these events among all cannabis users is unknown and likely very low."},{"rthcId":"RTHC-00782","title":"Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications.","authors":"Castaneto, Marisol S; Gorelick, David A; Desrosiers, Nathalie A; Hartman, Rebecca L; Pirard, Sandrine; Huestis, Marilyn A","year":2014,"journal":"Drug and alcohol dependence, 144, 12-41","doi":"10.1016/j.drugalcdep.2014.08.005","pmid":"25220897","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This comprehensive review documented the rapid proliferation of synthetic cannabinoids (SC) as designer drugs since the early 2000s. Key findings included that most SC detected in herbal products (sold as \"Spice\" or \"K2\") have greater binding affinity to CB1 receptors than THC, and pharmacological effects 2 to 100 times more potent.\n\nAdverse effects reported in humans included nausea, vomiting, shortness of breath, hypertension, tachycardia, chest pain, acute kidney failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Long-term effects remained unknown.\n\nThe cat-and-mouse dynamic between clandestine laboratories and regulators was a central theme: as specific SC were classified as controlled substances, manufacturers modified their structures to create novel compounds that were neither legally controlled nor detectable by standard drug tests.","whyItMatters":"Synthetic cannabinoids represent a fundamentally different risk profile from plant cannabis. Understanding that these compounds are not simply \"fake weed\" but pharmacologically distinct and far more potent agents is critical for emergency medicine, public health, and harm reduction.","specificNumbers":"SC potency: 2-100 times greater than THC in vitro and in animal models. SC became popular as \"legal highs\" in the early 2000s. Adverse effects included psychosis, acute kidney failure, and cardiac events. Many SC escape standard cannabinoid screening tests.","methodology":"Systematic electronic literature search covering SC epidemiology, pharmacology, clinical effects, and regulatory status. The review synthesized preclinical, clinical, and forensic toxicology data.","limitations":"The rapidly evolving nature of the SC market means any review is immediately dated. Clinical data on individual compounds was often limited to case reports. Long-term effects of SC use were entirely unknown at the time of publication."},{"rthcId":"RTHC-00783","title":"Case of cannabinoid hyperemesis syndrome with long-term follow-up.","authors":"Cha, Jae Myung; Kozarek, Richard A; Lin, Otto S","year":2014,"journal":"World journal of clinical cases, 2(12), 930-3","doi":"10.12998/wjcc.v2.i12.930","pmid":"25516874","tags":["appetite","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 44-year-old man with a long history of marijuana addiction had suffered from chronic abdominal pain and attacks of uncontrollable vomiting for 16 years. He developed a compulsion to take up to 15 scalding hot showers per day to relieve his symptoms. All previous treatments had failed.\n\nAbstinence from marijuana led to rapid and complete resolution of all symptoms, including the compulsive hot showering behavior. The patient was followed for nine years after achieving abstinence, with no recurrence of symptoms.\n\nThis represented the longest published follow-up of cannabinoid hyperemesis syndrome, demonstrating that the prognosis is excellent when abstinence is maintained.","whyItMatters":"This case provided the first long-term follow-up data showing that CHS is fully and permanently reversible with sustained cannabis abstinence. The nine-year remission confirms that the condition is not self-perpetuating once the trigger is removed.","specificNumbers":"16 years of symptoms. Up to 15 hot showers per day. Complete resolution upon marijuana abstinence. Nine years of follow-up with no recurrence.","methodology":"Single case report with nine years of follow-up documenting the clinical course, treatment history, and long-term outcome of cannabinoid hyperemesis syndrome.","limitations":"Single case report. The mechanism by which abstinence resolves CHS is not fully understood. Not all CHS patients may achieve this outcome. Publication bias favors positive outcomes."},{"rthcId":"RTHC-00784","title":"Cannabis use and suicidal ideations in high-school students.","authors":"Chabrol, Henri; Melioli, Tiffany; Goutaudier, Nelly","year":2014,"journal":"Addictive behaviors, 39(12), 1766-8","doi":"10.1016/j.addbeh.2014.06.008","pmid":"25123343","tags":["mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 972 high school students on cannabis use, suicidal ideation, depressive symptoms, social anxiety, and personality traits. While cannabis use appeared associated with suicidal ideation in unadjusted analyses, this association was no longer significant after controlling for borderline and psychopathic personality traits.\n\nThe authors noted that previous studies showing inconsistent results regarding cannabis and suicidality may have been affected by failing to control for these specific personality traits, which are independently linked to both cannabis use and suicidal thinking.","whyItMatters":"This study highlights the importance of confounding in cannabis research. When personality traits that drive both cannabis use and suicidal thinking are properly accounted for, the apparent direct link between cannabis and suicidality diminished. This distinction matters for clinical assessment and prevention.","specificNumbers":"972 high school students. Cannabis use was not a significant independent predictor of suicidal ideation after adjusting for borderline and psychopathic personality traits, in either the total sample or the subsample of cannabis users.","methodology":"Cross-sectional survey of 972 high school students using validated questionnaires for cannabis use, suicidal ideation, depressive symptoms, social anxiety, and borderline and psychopathic personality traits. Regression analyses tested whether cannabis independently predicted suicidal ideation after adjustment for confounders.","limitations":"Cross-sectional design cannot establish temporal or causal relationships. Self-reported data on sensitive topics. Only one measure of suicidal ideation was used. The study controlled for borderline and psychopathic traits but may have missed other relevant confounders."},{"rthcId":"RTHC-00785","title":"Resting state functional magnetic resonance imaging reveals distinct brain activity in heavy cannabis users - a multi-voxel pattern analysis.","authors":"Cheng, H; Skosnik, P D; Pruce, B J; Brumbaugh, M S; Vollmer, J M; Fridberg, D J; O'Donnell, B F; Hetrick, W P; Newman, S D","year":2014,"journal":"Journal of psychopharmacology (Oxford, England), 28(11), 1030-40","doi":"10.1177/0269881114550354","pmid":"25237118","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used an advanced multi-voxel pattern analysis technique to identify brain differences in heavy male cannabis users compared to controls during resting-state fMRI (no task being performed). The analysis found distinct activity clusters in multiple brain regions including the middle frontal gyrus, precentral gyrus, superior frontal gyrus, posterior cingulate cortex, and cerebellum.\n\nBased on the functional connectivity patterns between these regions, the algorithm classified cannabis users from controls with 84-88% overall accuracy. The classification accuracy correlated with scores on impulsiveness measures, particularly attention and motor impulsivity subscales.","whyItMatters":"This study demonstrated that heavy cannabis use is associated with widespread, detectable changes in brain connectivity that persist even at rest. The high classification accuracy suggests these changes represent a reliable neural signature of heavy use.","specificNumbers":"84-88% classification accuracy distinguishing cannabis users from controls. Distinct clusters found in prefrontal, cingulate, and cerebellar regions. High correlations between classification accuracy and impulsiveness scores.","methodology":"Two-level multi-voxel pattern analysis of resting-state fMRI data from male heavy cannabis users and controls. First-level analysis identified distinct voxel clusters; second-level analysis examined functional connectivity between clusters. Classification accuracy was tested and correlated with behavioral impulsivity measures.","limitations":"Only male participants were included. Cross-sectional design cannot determine whether brain differences preceded or followed cannabis use. The resting-state approach, while ecologically valid, does not assess specific cognitive functions. Sample sizes in pattern analysis studies can affect generalizability."},{"rthcId":"RTHC-00786","title":"Cannabis withdrawal syndrome: An important diagnostic consideration in adolescents presenting with disordered eating.","authors":"Chesney, Tyler; Matsos, Laura; Couturier, Jennifer; Johnson, Natasha","year":2014,"journal":"The International journal of eating disorders, 47(2), 219-23","doi":"10.1002/eat.22229","pmid":"24281745","tags":["withdrawal","youth","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Three adolescents presented to an eating disorders program with gastrointestinal symptoms, food avoidance, and weight loss. None met criteria for an actual eating disorder. Instead, all three fulfilled DSM-5 criteria for cannabis withdrawal syndrome.\n\nThe cases demonstrated that cannabis withdrawal can produce symptoms that closely mimic eating disorders, particularly appetite loss, nausea, and associated weight loss. The authors emphasized that CWS is an important and under-recognized consideration when adolescents present with disordered eating patterns.","whyItMatters":"Misdiagnosis of cannabis withdrawal as an eating disorder can lead to unnecessary and potentially harmful treatments. As cannabis use among adolescents is common, clinicians evaluating teens with appetite loss and weight loss need to screen for recent changes in cannabis use.","specificNumbers":"Three adolescents. All met DSM-5 criteria for cannabis withdrawal syndrome. None met criteria for an eating disorder.","methodology":"Case series of three adolescents presenting to an eating disorders program. Clinical assessment revealed heavy cannabis use history and symptoms consistent with DSM-5 cannabis withdrawal syndrome rather than eating disorders.","limitations":"Three cases from a single program. The overlap between CWS and eating disorder symptoms may not always be this clear-cut. Some patients may have both conditions. The cases highlight a diagnostic consideration rather than establishing prevalence."},{"rthcId":"RTHC-00787","title":"The case for assessing cannabidiol in epilepsy.","authors":"Cilio, Maria Roberta; Thiele, Elizabeth A; Devinsky, Orrin","year":2014,"journal":"Epilepsia, 55(6), 787-90","doi":"10.1111/epi.12635","pmid":"24854434","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This editorial-style review from leading epilepsy researchers argued that pure CBD had accumulated sufficient preclinical evidence to justify systematic clinical investigation for treatment-resistant epilepsy. Basic research had demonstrated strong anticonvulsant effects in acute animal models, though data from chronic models was limited.\n\nCBD appeared to be well tolerated in available human data, and importantly, it lacked the psychotropic effects of THC that limit tolerability. Previous human epilepsy studies had been small and methodologically limited, with inconclusive results. Recent anecdotal reports of high-CBD medical marijuana showed promise but lacked controlled conditions.\n\nThe authors called for systematic safety, pharmacokinetic, and drug interaction studies as a foundation for double-blind, placebo-controlled efficacy trials, particularly targeting Dravet and Lennox-Gastaut syndromes.","whyItMatters":"This paper, authored by researchers who would go on to lead the pivotal CBD epilepsy trials, laid the intellectual groundwork for the clinical development program that ultimately led to FDA approval of Epidiolex in 2018.","specificNumbers":"No specific trial data were reported. The review cited strong preclinical anticonvulsant evidence and limited but promising human data. Target populations identified: Dravet syndrome and Lennox-Gastaut syndrome.","methodology":"Expert review and commentary on the state of evidence for CBD in epilepsy, including preclinical data, available human evidence, and proposed clinical trial strategy.","limitations":"The anticonvulsant mechanisms of CBD were not fully understood. Human evidence was limited to small, methodologically weak studies and anecdotal reports. Drug interactions between CBD and existing antiepileptic medications were unknown."},{"rthcId":"RTHC-00788","title":"Sleep and substance use disorders: an update.","authors":"Conroy, Deirdre A; Arnedt, J Todd","year":2014,"journal":"Current psychiatry reports, 16(10), 487","doi":"10.1007/s11920-014-0487-3","pmid":"25135784","tags":["sleep","withdrawal","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the bidirectional relationship between sleep disorders and substance use. For cannabis specifically, research had progressed beyond subjective reports to demonstrate that marijuana withdrawal produces measurable changes on objective sleep measures including polysomnography and actigraphy.\n\nThe review highlighted an interactive effect: substance use disrupts sleep through direct effects on neurotransmitter systems regulating the sleep-wake cycle, while poor sleep during withdrawal increases relapse vulnerability. Treatment studies had focused primarily on alcohol use disorders, with therapies for insomnia in cannabis disorders identified as a significant gap.","whyItMatters":"Sleep disturbance is one of the most frequently reported symptoms of cannabis withdrawal and one of the longest-lasting. Understanding it as both a consequence and a risk factor for continued use has implications for treatment design.","specificNumbers":"No specific statistics were reported. The review identified cannabis withdrawal sleep research as a growing field and insomnia treatment for cannabis disorders as a gap.","methodology":"Narrative review of recent research findings on sleep disturbance in substance use disorders, with emphasis on alcohol and cannabis. Covered neurobiological mechanisms, clinical findings, and treatment approaches.","limitations":"Narrative review without systematic methodology. Treatment evidence was largely limited to alcohol disorders. The specific mechanisms by which cannabis withdrawal disrupts sleep were not fully characterized."},{"rthcId":"RTHC-00789","title":"Investigation of sex-dependent effects of cannabis in daily cannabis smokers","authors":"Cooper, Ziva D.; Haney, Margaret","year":2014,"journal":"Drug and Alcohol Dependence, 136, 85-91","doi":"10.1016/j.drugalcdep.2013.12.013","pmid":"24440051","tags":["sex-differences","addiction","cognition","potency"],"studyType":"secondary-analysis","evidenceStrength":"preliminary","keyFinding":"Women gave higher \"Good\" (p<=0.05) and \"Take Again\" (p<=0.05) ratings than men under active cannabis conditions in a pooled analysis of four double-blind studies, despite no sex differences in intoxication ratings (\"High,\" \"Stimulated\") or cardiovascular response. This selective enhancement of abuse-related — but not intoxication — effects in women provides a potential mechanistic explanation for the telescoping effect in cannabis use disorder.","whyItMatters":"Epidemiological data consistently show that women progress from first cannabis use to cannabis use disorder faster than men — the telescoping effect. This study provides the first controlled human laboratory evidence for a potential mechanism: women experience stronger reinforcing effects from the same dose of cannabis. This has direct implications for sex-specific approaches to prevention, treatment, and clinical trial design.","specificNumbers":"- Sample: 70 daily cannabis smokers, 35 women and 35 men, matched for current use\n- THC potency tested: 3.27 to 5.50% in active cannabis; 0% in inactive placebo\n- Active cannabis vs placebo: stronger abuse-related and intoxication ratings (p≤0.0001)\n- Sex difference under active cannabis: higher 'Good' and 'Take Again' ratings in women (p≤0.05)","methodology":"Pooled secondary analysis of four double-blind, within-subject laboratory studies conducted at the New York State Psychiatric Institute. Seventy daily cannabis smokers (35 women, 35 men) were matched on current usage. Each participant completed 5–10 outpatient sessions over 2–8 weeks. Active cannabis (NIDA-supplied, 3.27–5.50% THC, ~800mg cigarettes) was compared to inactive placebo (0% THC) using a standardized smoking procedure (5-second inhalation, 10-second breath-hold, 40-second intervals). Subjective effects were assessed via VAS at 6 timepoints (15–195 minutes post-smoking). Cardiovascular monitoring at 7 timepoints.","limitations":"Small sample (n=70) with limited statistical power for interaction effects. THC potency (3.27–5.50%) far below modern market products (15–30%+ THC). Pooled four studies with potentially different procedures. Did not control for menstrual cycle phase, hormonal contraception, or body composition — all known modulators of cannabinoid pharmacokinetics. Measured acute subjective response, not actual progression to cannabis use disorder. The link from enhanced \"Good\" ratings to increased CUD risk remains a plausible hypothesis, not a demonstrated causal pathway."},{"rthcId":"RTHC-00790","title":"ADHD symptoms, autistic traits, and substance use and misuse in adult Australian twins.","authors":"De Alwis, Duneesha; Agrawal, Arpana; Reiersen, Angela M; Constantino, John N; Henders, Anjali; Martin, Nicholas G; Lynskey, Michael T","year":2014,"journal":"Journal of studies on alcohol and drugs, 75(2), 211-21","doi":null,"pmid":"24650814","tags":["cognition","addiction","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"In a study of 3,080 young adult Australian twins, researchers examined how ADHD symptoms and autistic traits independently related to substance use. Greater ADHD symptoms and higher autistic traits scores were each associated with elevated rates of regular smoking, cannabis use, and nicotine, alcohol, and cannabis use disorders, even after controlling for conduct disorder.\n\nA paradoxical pattern emerged for autistic traits and alcohol: individuals with higher autistic traits were less likely to report drinking to intoxication (possibly due to social factors, since drinking is often a social activity), but when they did drink, they were at elevated risk for developing alcohol dependence.\n\nThe findings suggest that both ADHD and autistic traits represent independent vulnerability factors for substance use disorders, operating through different mechanisms.","whyItMatters":"ADHD and autism spectrum traits frequently co-occur, and each independently increases substance use vulnerability. Understanding these separate pathways helps identify at-risk individuals and tailor prevention approaches.","specificNumbers":"3,080 twins (mean age 31.9 years). Both ADHD symptoms and autistic traits independently associated with cannabis use disorders. Autistic traits associated with less alcohol use but more alcohol dependence once use began.","methodology":"Cross-sectional analysis of interview and questionnaire data from 3,080 young adult Australian twins (mean age 31.9 years). DSM-IV substance use disorders were assessed. Logistic regression controlled for conduct disorder, sex, age, and zygosity.","limitations":"Twin sample may not represent the general population. Self-report measures of autistic traits and ADHD symptoms are dimensional and not equivalent to clinical diagnoses. Cross-sectional design cannot establish causation."},{"rthcId":"RTHC-00791","title":"Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.","authors":"Devinsky, Orrin; Cilio, Maria Roberta; Cross, Helen; Fernandez-Ruiz, Javier; French, Jacqueline; Hill, Charlotte; Katz, Russell; Di Marzo, Vincenzo; Jutras-Aswad, Didier; Notcutt, William George; Martinez-Orgado, Jose; Robson, Philip J; Rohrback, Brian G; Thiele, Elizabeth; Whalley, Benjamin; Friedman, Daniel","year":2014,"journal":"Epilepsia, 55(6), 791-802","doi":"10.1111/epi.12631","pmid":"24854329","tags":["cbd","epilepsy","medical-cannabis","psychosis","anxiety","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This landmark review by leading researchers summarized the evidence for CBD across multiple neuropsychiatric conditions. Key findings by indication:\n\nEpilepsy: CBD was anticonvulsant in most animal models. Human evidence was limited to small, uncontrolled studies and anecdotal reports. The antiepileptic mechanisms were not fully understood but involved multiple receptor and channel targets. Trials targeting Dravet and Lennox-Gastaut syndromes were being planned.\n\nAnxiety and psychosis: Preclinical and early clinical evidence supported anxiolytic and antipsychotic properties. CBD appeared well tolerated without the psychoactive effects of THC.\n\nAddiction: Early evidence suggested CBD might reduce drug-seeking behavior through effects on multiple neurotransmitter systems.\n\nAcross all conditions, the review concluded that well-powered, double-blind, randomized controlled trials were needed.","whyItMatters":"This review, published in the leading epilepsy journal by an author team that included key figures in subsequent CBD clinical development, established the scientific framework that guided the clinical trial program leading to FDA approval of Epidiolex.","specificNumbers":"Multiple receptor targets identified for CBD anticonvulsant effects. CBD appeared well tolerated in available human data. No well-powered RCTs existed for any CBD indication at the time of publication.","methodology":"Expert review summarizing presentations from a scientific conference where invited participants reviewed CBD physiology, mechanisms of action, pharmacology, animal model data, and human studies.","limitations":"Available human evidence was small-scale and methodologically limited. CBD mechanisms of action were not fully characterized. Drug interactions with antiepileptic medications were unknown. Long-term safety data were lacking."},{"rthcId":"RTHC-00792","title":"Executive attention impairment in adolescents with schizophrenia who have used cannabis.","authors":"Epstein, Katherine A; Kumra, Sanjiv","year":2014,"journal":"Schizophrenia research, 157(1-3), 48-54","doi":"10.1016/j.schres.2014.04.035","pmid":"24875171","tags":["psychosis","cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared attention performance across four groups of adolescents: early-onset schizophrenia with cannabis use disorder (EOS+CUD, n=18), schizophrenia only (EOS, n=34), cannabis use disorder only (CUD, n=29), and healthy controls (n=53). A significant interaction emerged: in the executive attention network, adolescents with both schizophrenia and cannabis use disorder performed worse than those with schizophrenia alone.\n\nHowever, adolescents with cannabis use disorder alone showed no difference from healthy controls. This selective effect suggests that cannabis has a moderating impact on attention specifically in the context of schizophrenia.\n\nThe attention deficit was associated with smaller surface area in the right caudal anterior cingulate cortex, suggesting an anatomical substrate for the cognitive impairment.","whyItMatters":"Cannabis use is common among people with schizophrenia, and understanding whether it worsens the cognitive deficits of the illness has direct clinical implications. The selective interaction found here suggests cannabis may specifically compound schizophrenia-related cognitive problems.","specificNumbers":"134 adolescents across four groups. Significant EOS x CUD interaction in executive attention. Attention deficit correlated with smaller right caudal anterior cingulate cortex surface area in the EOS+CUD group.","methodology":"Four-group comparison using the Attention Network Test during fMRI in 134 adolescents. 2x2 design crossing EOS status with CUD status. Brain surface area in the anterior cingulate cortex was measured and correlated with attention performance.","limitations":"Cross-sectional design. Relatively small group sizes, especially the EOS+CUD group (n=18). Cannot determine whether cannabis caused the attention deficit or whether more severely affected patients were more likely to use cannabis. The results are described as preliminary."},{"rthcId":"RTHC-00793","title":"Factors affecting noncompliance with buprenorphine maintenance treatment.","authors":"Fareed, Ayman; Eilender, Pamela; Ketchen, Bethany; Buchanan-Cummings, Ann Marie; Scheinberg, Kelly; Crampton, Kelli; Nash, Abigail; Shongo-Hiango, Hilaire; Drexler, Karen","year":2014,"journal":"Journal of addiction medicine, 8(5), 345-50","doi":"10.1097/ADM.0000000000000057","pmid":"25072677","tags":["addiction","drug-interactions"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"In a review of 69 veteran patients receiving buprenorphine maintenance for opioid use disorder, researchers found that positive urine drug screens for marijuana and benzodiazepines, along with being a cigarette smoker, were significantly associated with noncompliance (inaccurate pill counts).\n\nPsychiatric comorbidity was also independently associated with noncompliance. However, despite noncompliance with pill counts, patients were generally still taking their prescribed buprenorphine (confirmed by positive urine tests) and had high rates of negative screens for opioids and cocaine.","whyItMatters":"Identifying risk factors for treatment noncompliance helps clinicians provide more targeted support. Cannabis use during buprenorphine treatment may indicate broader patterns of difficulty with treatment adherence.","specificNumbers":"69 patients analyzed from 209 total. Cannabis, benzodiazepines, and smoking were significant predictors (F = 3.08, P = .03). Psychiatric comorbidity was independently significant (F = 4.88, P = .03).","methodology":"Retrospective chart review of 69 patients (from 209 total) in a VA Medical Center buprenorphine maintenance program (2006-2013). Multiple linear regression identified predictors of noncompliance defined by inaccurate pill count callbacks.","limitations":"Very small sample of 69 patients from a single VA center. Retrospective design with chart review limitations. Only 69 of 209 patients had pill count callbacks, introducing selection bias. Noncompliance was defined narrowly by pill count accuracy."},{"rthcId":"RTHC-00794","title":"Advances in the management of MS spasticity: recent observational studies.","authors":"Fernández, Oscar","year":2014,"journal":"European neurology, 72 Suppl 1, 12-4","doi":"10.1159/000367618","pmid":"25278118","tags":["medical-cannabis","cbd","driving"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This review compiled observational data from post-marketing registries and real-world studies of THC/CBD oromucosal spray (Sativex) for MS spasticity. The proportion of patients achieving clinically relevant improvement (30% or more reduction in spasticity) at 3 months was 41%, comparable to the 36% seen in the pivotal clinical trial.\n\nNotably, average daily doses in real practice were approximately 25% lower than those used in clinical trials, suggesting patients found effective doses below what was tested. There was no evidence of abuse, misuse, or other adverse events of special interest with this cannabis-based medicine. A specific study on driving ability found no impairment.","whyItMatters":"Clinical trials show what a drug can do under ideal conditions; real-world studies show what happens in daily practice. This data confirmed that the clinical trial results translated to real patients, with effectiveness maintained and no emerging safety concerns.","specificNumbers":"41% clinically relevant response at 3 months (vs. 36% in pivotal trial). Average daily doses approximately 25% lower than in clinical trials. No evidence of abuse, misuse, or driving impairment.","methodology":"Review of post-marketing safety registries from the UK and Germany, a safety study from Spain, and two German observational studies including one on driving ability.","limitations":"Observational studies are inherently less rigorous than RCTs. Selection bias may affect which patients continue treatment. Post-marketing registries may underreport adverse events. The driving study details were not fully described."},{"rthcId":"RTHC-00795","title":"Advances in the management of multiple sclerosis spasticity: recent clinical trials.","authors":"Fernández, Oscar","year":2014,"journal":"European neurology, 72 Suppl 1, 9-11","doi":"10.1159/000367616","pmid":"25278117","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review summarized the phase III clinical trial program for THC/CBD oromucosal spray in MS spasticity. A meaningful proportion of patients with treatment-resistant spasticity achieved clinically relevant improvement with active treatment versus placebo.\n\nA 4-week initial trial of therapy proved useful for identifying which patients would respond. After 50 weeks of treatment in a post-approval study, approximately two-thirds of patients, physicians, and caregivers reported improvement in spasticity. Importantly, the post-approval study showed no statistically significant effect on cognition or mood compared to placebo.\n\nThe spray was well tolerated, with no evidence of effects typically associated with recreational cannabis use. Responders experienced relief not only from spasticity but also from associated symptoms including spasms, urinary dysfunction, and sleep disturbances.","whyItMatters":"These trial results established the clinical evidence base for regulatory approval of THC/CBD spray in multiple countries. The finding that cognition and mood were unaffected after nearly a year of use addressed key safety concerns about long-term cannabis-based medicine use.","specificNumbers":"Approximately one-third of treatment-resistant patients responded. Two-thirds reported improvement at 50 weeks. No significant effect on cognition or mood. Associated symptom relief included spasms, urinary dysfunction, and sleep.","methodology":"Review of pivotal phase III clinical trials and a post-approval clinical trial for THC/CBD oromucosal spray in MS spasticity.","limitations":"The enriched design, while clinically practical, can overestimate effect sizes. Response rates of one-third mean two-thirds do not benefit. The specific responder characteristics were not well defined."},{"rthcId":"RTHC-00796","title":"The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward.","authors":"Flores, África; Maldonado, Rafael; Berrendero, Fernando","year":2014,"journal":"Biological psychiatry, 75(6), 499-507","doi":"10.1016/j.biopsych.2013.06.012","pmid":"23896204","tags":["addiction","dopamine","neuroscience","synthetic-cannabinoids"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Two complementary approaches pointed to the same result. Systemic dosing with SB334867, an orexin-1 receptor (Hcrtr-1) antagonist, reduced how often mice self-administered WIN55,212-2, a synthetic cannabinoid, and lowered the maximum effort they would expend for an infusion under a progressive ratio schedule. Mice genetically lacking Hcrtr-1 showed a similar reduction in reinforcing and motivational measures, reinforcing the pharmacology result.\n\nActivation mapping aligned with behavior. Contingent, but not noncontingent, self-administration of WIN55,212-2 increased the fraction of lateral hypothalamic hypocretin neurons expressing FosB/ΔFosB, a marker of repeated neuronal activation linked to motivation. Finally, the dopamine signal that typically follows Δ9-THC in the nucleus accumbens did not appear in Hcrtr-1 knockout mice during microdialysis testing. Together, the data position Hcrtr-1 as a node in the cannabinoid reward pathway in mice.","whyItMatters":"There were no accepted medications for cannabis dependence when this study was published. The hypocretin/orexin system had been tied to reward and stress across several drug classes. This work placed orexin-1 in the cannabinoid reinforcement circuit in mice, identifying a preclinical target that could inform future translational research while underscoring the need to test whether the same circuitry matters outside this model.","specificNumbers":"- Self-administration: reduced when mice received the orexin-1 antagonist SB334867 compared to vehicle\n- Motivation: lower breakpoints under a progressive ratio schedule after Hcrtr-1 blockade, indicating less willingness to work for the drug\n- Hypocretin neuron activation: increased FosB/ΔFosB in lateral hypothalamic hypocretin cells during contingent, not noncontingent, WIN55,212-2 intake\n- Accumbens dopamine: THC-evoked extracellular dopamine rise was absent in Hcrtr-1 knockout mice","methodology":"Researchers trained mice to self-administer the cannabinoid agonist WIN55,212-2 through an intravenous catheter, a standard operant model of drug reinforcement. They tested the effects of blocking hypocretin/orexin-1 with SB334867 and used Hcrtr-1 knockout mice to probe the same pathway genetically. Motivation was measured under progressive ratio schedules, where the required number of lever presses increases after each dose. To control for non-specific motor or learning effects, separate mice were trained to work for water. Neuronal activation in hypocretin neurons of the lateral hypothalamus was assessed with double-label immunofluorescence for FosB/ΔFosB and hypocretin-1. Lastly, in vivo microdialysis measured extracellular dopamine in the nucleus accumbens after acute THC. The abstract does not report sample sizes or drug doses. Mice were male per MeSH terms.","limitations":"This is an animal study using a synthetic cannabinoid (WIN55,212-2) delivered intravenously, a route and compound that do not mirror typical human cannabis exposure. Only males were used per MeSH terms. The abstract reports no sample sizes or antagonist doses. SB334867 can show off-target effects at certain concentrations. Developmental compensation in Hcrtr-1 knockout mice could contribute to the phenotype. The operant control with water suggests general performance was intact, but sedation or arousal changes were not detailed. THC was only used for the dopamine microdialysis readout, not for self-administration."},{"rthcId":"RTHC-00797","title":"The effects of cannabinoid administration on sleep: a systematic review of human studies","authors":"Gates, Peter J.; Albertella, Lucy; Copeland, Jan","year":2014,"journal":"Sleep Medicine Reviews, 18(6), 477-487","doi":"10.1016/j.smrv.2014.02.005","pmid":"24726015","tags":["sleep"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 39 human studies that administered a cannabinoid and measured sleep quantitatively, results did not converge. Some trials reported shorter time to fall asleep or longer total sleep time. Others found no change or detected worse sleep quality, fragmented sleep, or next-day sedation. Objective measures and self-reports often disagreed, and effects varied by product type, dose, timing, and whether use was acute or repeated.\n\nThe most consistent result was inconsistency. Heterogeneous designs, small samples, and weak blinding produced a patchwork of findings that the reviewers judged insufficient for a clear conclusion about cannabinoids helping or harming sleep on average.","whyItMatters":"Cannabis is widely used as a self-managed sleep aid. This review asked what controlled human studies actually measured when cannabinoids were given and sleep was quantified. In 2014, it set a baseline for how uncertain the evidence was, at a time when policy and consumer adoption were moving faster than the science.","specificNumbers":"- 39 human studies: all involved cannabinoid administration with quantitative sleep outcomes\n- 8 databases searched: broad literature sweep to identify eligible studies\n- Publication year: 2014 synthesis, summarizing decades of small and heterogeneous trials","methodology":"Reviewers searched eight databases for human studies that directly administered a cannabinoid and included at least one quantitative sleep-related outcome. They excluded reviews, opinion pieces, letters, very small case series (fewer than seven participants), published abstracts, posters, and non-English papers. Thirty-nine publications met criteria. The majority had methodological issues, including small samples, variable dosing and formulations, inconsistent outcome measures, limited or compromised blinding, and a mix of objective tools and self-reports that made comparisons difficult.","limitations":"The review synthesized mostly small, heterogeneous studies with variable dosing, formulations, and timing. Many lacked rigorous blinding or standardized sleep outcomes. The exclusion of non-English reports and very small case series may have missed data. The abstract does not indicate a meta-analysis, so results appear qualitative. Funding sources and conflicts of interest were not reported in the abstract, leaving potential bias unclear."},{"rthcId":"RTHC-00798","title":"Cannabinoids: new promising agents in the treatment of neurological diseases.","authors":"Giacoppo, Sabrina; Mandolino, Giuseppe; Galuppo, Maria; Bramanti, Placido; Mazzon, Emanuela","year":2014,"journal":"Molecules (Basel, Switzerland), 19(11), 18781-816","doi":"10.3390/molecules191118781","pmid":"25407719","tags":["medical-cannabis","neuroscience","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review evaluated the state of cannabinoid research for neurological diseases. Established clinical uses at the time included glaucoma treatment, chemotherapy-related nausea and vomiting, appetite stimulation in HIV-related wasting, and MS symptom management.\n\nResearch efforts were increasingly focused on targeting cannabinoid receptor activity in the central nervous system for neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's, ALS), as well as psychiatric and non-psychiatric neurological conditions. The review emphasized that overcoming psychotropic side effects remained the central challenge for expanding clinical use of cannabinoids.\n\nCBD, which lacks psychotropic effects, was highlighted as having particular promise due to its neuroprotective and anti-inflammatory properties without the psychoactive limitations of THC.","whyItMatters":"This review captured a moment when cannabinoid neurology was transitioning from established uses (nausea, appetite, spasticity) toward potential applications in neurodegenerative diseases, reflecting growing understanding of the endocannabinoid system's role in brain health.","specificNumbers":"Four established clinical indications were reviewed: glaucoma, chemotherapy nausea, HIV-related wasting, and MS spasticity. Multiple neurodegenerative conditions were under experimental investigation.","methodology":"Review of published experimental and clinical studies on cannabinoid use in neurological diseases, including both preclinical animal models and available human data.","limitations":"Much of the neurodegeneration evidence was preclinical. Clinical trials for most neurological conditions were small or absent. The challenge of separating therapeutic from psychotropic effects had not been fully solved for THC-based approaches."},{"rthcId":"RTHC-00799","title":"Short-term mediating factors of a school-based intervention to prevent youth substance use in Europe.","authors":"Giannotta, Fabrizia; Vigna-Taglianti, Federica; Rosaria Galanti, Maria; Scatigna, Maria; Faggiano, Fabrizio","year":2014,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 54(5), 565-73","doi":"10.1016/j.jadohealth.2013.10.009","pmid":"24332392","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a randomized trial across 143 schools in seven European countries (7,079 students), the Unplugged social influence-based prevention program was compared to usual health education. The program successfully changed several intermediate factors: participants endorsed less positive attitudes toward drugs, held fewer positive beliefs about substances, perceived less peer substance use, gained knowledge, and improved refusal skills for tobacco.\n\nThese changes appeared to mediate the program's effects on actual substance use, with decreased positive attitudes, increased refusal skills, and corrected norms about peer tobacco and cannabis use acting as mediating pathways. However, the mediating effects were generally weak and some were only marginally significant.","whyItMatters":"Understanding how prevention programs work (not just whether they work) guides program improvement. Knowing that attitude change and norm correction are active mechanisms, even if weak, helps developers focus on strengthening these specific components.","specificNumbers":"143 schools in 7 European countries. 7,079 students. Program effects were mediated through attitudes, refusal skills, and normative perceptions. Mediating effects were generally weak with some only marginally significant.","methodology":"Cluster-randomized trial in 143 schools across seven European countries with 7,079 pupils. Multilevel multiple mediation models examined whether changes in knowledge, attitudes, norms, and refusal skills mediated effects on tobacco, alcohol, and cannabis use at 3 months post-intervention.","limitations":"Only 3-month follow-up was assessed. Weak mediation effects suggest other unmeasured factors may be more important. Cross-country variation was not fully explored. Self-reported substance use may be biased."},{"rthcId":"RTHC-00800","title":"Is Project Towards No Drug Abuse (Project TND) an evidence-based drug and violence prevention program? A review and reappraisal of the evaluation studies.","authors":"Gorman, Dennis M","year":2014,"journal":"The journal of primary prevention, 35(4), 217-32","doi":"10.1007/s10935-014-0348-1","pmid":"24753017","tags":["youth","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This critical review examined all published evaluations of Project Towards No Drug Abuse (Project TND), a school-based prevention program. Across seven evaluation studies, very few main effects were found for cigarette, alcohol, and marijuana use.\n\nWhile studies reported main effects for \"hard drug\" use, the reviewer identified numerous threats to validity that may explain these findings, including analytical choices that could inflate results. Similarly, isolated subgroup effects found in early evaluations (such as effects on alcohol use among baseline nonusers) were not replicated in later studies, suggesting they may have resulted from multiple comparisons.\n\nThe reviewer concluded there was little evidence to support the assertion that Project TND is an effective drug or violence prevention program.","whyItMatters":"Project TND was classified as evidence-based by several registries and widely disseminated. This critical review raised important questions about the evidence threshold used to label prevention programs as effective and the consequences of widespread implementation of programs with limited evidence.","specificNumbers":"Seven evaluations reviewed. Very few main effects found for cigarettes, alcohol, or marijuana. Reported hard drug effects had \"numerous threats to validity.\" Early subgroup effects were not replicated in later studies.","methodology":"Critical review of publications from all seven evaluation studies of Project TND, examining main effects on drug use, subgroup analyses, and violence-related outcomes with attention to methodological rigor and replication.","limitations":"This is one reviewer's critical assessment and may be subject to its own interpretive biases. Not all researchers may agree with the severity of the methodological concerns raised. The review did not conduct a new analysis of the original data."},{"rthcId":"RTHC-00801","title":"Investigating correlates of synthetic marijuana and Salvia use in light and intermittent smokers and college students in a predominantly Hispanic sample.","authors":"Gutierrez, Kevin M; Cooper, Theodore V","year":2014,"journal":"Experimental and clinical psychopharmacology, 22(6), 524-9","doi":"10.1037/a0038014","pmid":"25285845","tags":["synthetic-cannabinoids","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Across two studies at a U.S./Mexico border university and health clinic, researchers found that 9-10% of participants had ever used synthetic cannabinoids or Salvia divinorum. Being male and using multiple tobacco products were associated with use in the clinic sample.\n\nAmong college students, past 30-day marijuana use and past 30-day ecstasy use were the strongest predictors of lifetime synthetic cannabinoid and Salvia use. Current marijuana use emerged as a particularly consistent predictor across both studies.","whyItMatters":"This was among the first studies to examine synthetic cannabinoid use in a predominantly Hispanic population. The strong link to current marijuana use suggests these novel substances may be used as supplements to rather than replacements for cannabis.","specificNumbers":"Study 1: 10% lifetime use of synthetic cannabinoids or Salvia (n=185). Study 2: 9% lifetime, 5% past-year, 3% past 30-day synthetic cannabinoid use (n=675). Past 30-day marijuana and ecstasy use were significant predictors.","methodology":"Two cross-sectional studies: Study 1 included 185 participants (83% Hispanic) from a clinic and university on the U.S./Mexico border; Study 2 included 675 participants (89.1% Hispanic) from the same university. Logistic regression identified correlates of synthetic cannabinoid and Salvia use.","limitations":"Cross-sectional convenience samples from a single border community. Predominantly Hispanic sample may not generalize to other populations. Self-reported data. Small prevalence means limited statistical power for some analyses."},{"rthcId":"RTHC-00802","title":"Detection of new psychoactive substance use among emergency room patients: results from the Swedish STRIDA project.","authors":"Helander, Anders; Bäckberg, Matilda; Hultén, Peter; Al-Saffar, Yasir; Beck, Olof","year":2014,"journal":"Forensic science international, 243, 23-9","doi":"10.1016/j.forsciint.2014.02.022","pmid":"24726531","tags":["synthetic-cannabinoids","youth","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The STRIDA project monitored new psychoactive substance (NPS) use among patients presenting to Swedish emergency departments and intensive care units. Of 189 initial samples submitted for analysis, 83% tested positive for at least one drug. Beyond classical substances (ethanol, cannabis, amphetamines), more than 50 different NPS were detected.\n\nThe NPS spectrum included synthetic cannabinoid receptor agonists (\"Spice\"), piperazines, substituted phenethylamines, synthetic cathinones, hallucinogenic tryptamines, piperidines, opioid-related substances, ketamine analogs, and GABA analogs. Users were predominantly young (median age 20, range 13-63) and male (79%).\n\nAbout half of cases involved multiple drug intoxications, making it difficult to attribute specific clinical symptoms to individual substances.","whyItMatters":"This project demonstrated the scale and diversity of the NPS problem in a high-income country. The detection of over 50 different substances in emergency patients shows that the challenge extends far beyond synthetic cannabinoids to a broad spectrum of novel compounds.","specificNumbers":"189 samples, 83% positive for at least one drug. Over 50 different NPS detected. Predominantly young males (median age 20, 79% male). About half were multiple drug intoxications. Age range: 13-63 years.","methodology":"Prospective monitoring project collecting urine and blood samples from drug intoxication cases at emergency departments across Sweden. Multi-component LC-MS/MS analysis identified a wide range of NPS. Clinical severity was graded using the Poisoning Severity Score.","limitations":"Emergency department presentations represent the most severe outcomes and do not capture the full spectrum of NPS use. Multiple drug intoxications complicated attribution of effects to individual substances. The project captured a snapshot that would have changed rapidly as new substances emerged."},{"rthcId":"RTHC-00803","title":"Expectancies for smoking cessation among drug-involved smokers: implications for clinical practice.","authors":"Hendricks, Peter S; Peters, Erica N; Thorne, Christopher B; Delucchi, Kevin L; Hall, Sharon M","year":2014,"journal":"Journal of substance abuse treatment, 46(3), 320-4","doi":"10.1016/j.jsat.2013.10.011","pmid":"24314605","tags":["quitting","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 507 non-treatment-seeking adult smokers, those who used marijuana and other drugs reported greater expectancies that quitting smoking would lead to adverse outcomes, such as worsening their drug use or causing other negative consequences. These adverse outcome expectancies statistically mediated the relationship between drug involvement and reduced motivation to quit smoking.\n\nThe pattern held across multiple substances: binge drinking, marijuana, cocaine, stimulants, opiates, and sedatives were all associated with greater adverse outcome expectancies, which in turn predicted lower desire to quit and lower likelihood of endorsing a goal of complete smoking abstinence.","whyItMatters":"Tobacco kills more people than any other substance. If drug-involved smokers avoid quit attempts because they believe quitting will destabilize their drug use, addressing these beliefs directly in clinical settings could improve smoking cessation rates in this high-risk population.","specificNumbers":"507 smokers studied. Adverse outcome expectancies mediated the relationship between drug involvement and quit motivation across all six substance categories tested.","methodology":"Cross-sectional survey of 507 non-treatment-seeking adult smokers from the community. Participants reported drug involvement, smoking abstinence expectancies (via the Smoking Abstinence Questionnaire), and motivation to quit. Mediation analyses tested whether adverse outcome expectancies explained the link between drug use and lower quit motivation.","limitations":"Cross-sectional design cannot establish causation. Self-selected community sample. Expectancies about quitting may not accurately predict actual outcomes. The study did not test whether correcting these beliefs changed behavior."},{"rthcId":"RTHC-00804","title":"Cannabis-associated myocardial infarction in a young man with normal coronary arteries.","authors":"Hodcroft, Christopher J; Rossiter, Melissa C; Buch, Ashesh N","year":2014,"journal":"The Journal of emergency medicine, 47(3), 277-81","doi":"10.1016/j.jemermed.2013.11.077","pmid":"24996293","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A previously healthy 21-year-old man who regularly smoked cannabis presented with an ST-elevation myocardial infarction (the most serious type of heart attack) during sports activity. Coronary angiography revealed a large thrombus (blood clot) in the left anterior descending coronary artery.\n\nThe unique contribution of this case was the use of intravascular ultrasound to definitively exclude atherosclerotic plaque rupture as the cause. The arteries were completely normal, ruling out the most common mechanism of heart attack in older patients. The only cardiovascular risk factors were cannabis and cigarette smoking.\n\nThis was described as the first report where atherosclerotic plaque rupture was excluded with high confidence using intravascular imaging in a cannabis-associated heart attack.","whyItMatters":"By ruling out atherosclerosis, this case pointed to alternative mechanisms by which cannabis might trigger heart attacks, such as vasospasm, direct prothrombotic effects, or endothelial dysfunction. Understanding the mechanism is critical for assessing who is at risk.","specificNumbers":"One patient, age 21. ST-elevation MI during sports. Large thrombus in left anterior descending artery. Intravascular ultrasound: no atherosclerosis at thrombus site.","methodology":"Single case report with coronary angiography and intravascular ultrasound imaging to characterize the coronary pathology and definitively exclude atherosclerosis.","limitations":"Single case report. The patient also smoked cigarettes, which is an independent cardiovascular risk factor. Cannot definitively prove cannabis caused the event. Case reports cannot establish incidence rates."},{"rthcId":"RTHC-00805","title":"Cannabinoid hyperemesis syndrome: a case report and review of pathophysiology.","authors":"Iacopetti, Corina L; Packer, Clifford D","year":2014,"journal":"Clinical medicine & research, 12(1-2), 65-7","doi":"10.3121/cmr.2013.1179","pmid":"24667219","tags":["appetite","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with a long history of nausea and vomiting had previously undergone extensive diagnostic workup and received a diagnosis of cyclic vomiting syndrome. Upon closer evaluation, the patient was found to have characteristic features of cannabinoid hyperemesis syndrome (CHS), including the classic association with chronic cannabis use and compulsive hot bathing behavior.\n\nThe case highlighted how CHS can be misdiagnosed as cyclic vomiting syndrome, leading to unnecessary and expensive diagnostic investigations. The review portion discussed potential mechanisms for CHS pathogenesis.","whyItMatters":"The antiemetic (anti-nausea) properties of cannabis are well known, making the paradoxical development of severe vomiting counterintuitive. This case reinforced the importance of considering CHS in the differential diagnosis and asking about cannabis use in patients with unexplained cyclic vomiting.","specificNumbers":"Cannabis lifetime use prevalence estimated at 42-46% in the U.S. One patient rediagnosed from cyclic vomiting syndrome to CHS.","methodology":"Single case report of a patient with prior diagnosis of cyclic vomiting syndrome who was rediagnosed with CHS, accompanied by a review of published literature on CHS pathophysiology.","limitations":"Single case report. CHS pathophysiology remained incompletely understood. The distinction between CHS and cyclic vomiting syndrome may not always be clear-cut."},{"rthcId":"RTHC-00806","title":"In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects.","authors":"Ignatowska-Jankowska, B M; Ghosh, S; Crowe, M S; Kinsey, S G; Niphakis, M J; Abdullah, R A; Tao, Q; O' Neal, S T; Walentiny, D M; Wiley, J L; Cravatt, B F; Lichtman, A H","year":2014,"journal":"British journal of pharmacology, 171(6), 1392-407","doi":"10.1111/bph.12298","pmid":"23848221","tags":["pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested KML29, a highly selective inhibitor of the enzyme MAGL (which breaks down the endocannabinoid 2-AG), in mouse models of pain. KML29 completely reversed inflammatory pain and partially reversed nerve injury pain. It also completely prevented stomach bleeding caused by the anti-inflammatory drug diclofenac.\n\nCritically, KML29 did not produce the classic cannabis-like side effects (catalepsy, hypothermia, reduced movement) that limit the use of THC and full cannabinoid receptor agonists. However, repeated high-dose treatment led to tolerance, accompanied by CB1 receptor desensitization.\n\nThe compound increased brain 2-AG levels while reducing arachidonic acid levels, without affecting anandamide levels, confirming its selective action on the 2-AG pathway.","whyItMatters":"Pain management is one of the most promising applications of the endocannabinoid system. Showing that 2-AG elevation via MAGL inhibition can produce pain relief without the psychoactive side effects of THC represents a potential path toward cannabinoid-based painkillers that do not impair daily function.","specificNumbers":"KML29 completely reversed carrageenan-induced mechanical allodynia. Partially reversed sciatic nerve injury allodynia. Completely prevented diclofenac gastric hemorrhages. No catalepsy, hypothermia, or hypomotility observed.","methodology":"In vivo testing in mice using carrageenan-induced inflammatory pain, sciatic nerve injury neuropathic pain, and diclofenac-induced gastric hemorrhage models. Cannabis-like side effects were assessed through locomotor activity, body temperature, catalepsy, and drug discrimination tests.","limitations":"Mouse studies do not directly predict human outcomes. Tolerance developed with repeated high-dose administration, which could limit long-term clinical use. Only acute and short-term dosing protocols were tested."},{"rthcId":"RTHC-00807","title":"The moderating effects of sex and age on the association between traumatic brain injury and harmful psychological correlates among adolescents.","authors":"Ilie, Gabriela; Adlaf, Edward M; Mann, Robert E; Boak, Angela; Hamilton, Hayley; Asbridge, Mark; Colantonio, Angela; Turner, Nigel E; Rehm, Jürgen; Cusimano, Michael D","year":2014,"journal":"PloS one, 9(9), e108167","doi":"10.1371/journal.pone.0108167","pmid":"25268238","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a population-based survey of 9,288 Ontario students in grades 7-12, lifetime traumatic brain injury (TBI) was reported by 23.1% of males and 17.1% of females. TBI was associated with cannabis use, cannabis dependence, drug use problems, cigarette smoking, psychological distress, suicidal ideation, bullying, and poor academic performance.\n\nSex moderated the relationship between TBI and cigarette smoking. Sex and age together moderated TBI's relationship with daily smoking, alcohol use, and physical injuries. Late adolescent males with TBI showed elevated daily smoking and injuries, while their female counterparts showed elevated past-year drinking.","whyItMatters":"TBI is common in adolescents and is a known risk factor for substance use. Understanding that the TBI-substance use relationship differs by sex and age helps target prevention and intervention efforts more precisely.","specificNumbers":"9,288 students. TBI prevalence: 23.1% males, 17.1% females. Cannabis use, cannabis dependence, and drug use problems were all associated with TBI history. Sex moderated TBI-smoking; sex and age moderated TBI-alcohol and TBI-injury relationships.","methodology":"Population-based cross-sectional survey of 9,288 Ontario 7th-12th graders (62% response rate). TBI was defined as a head blow resulting in at least 5 minutes of unconsciousness or overnight hospitalization. Thirteen behavioral and psychological correlates were examined with moderation analyses for sex and age.","limitations":"Cross-sectional design cannot determine whether TBI preceded or followed substance use. Self-reported TBI may be subject to recall bias. The 62% response rate raises questions about non-response bias, though preliminary analyses found no evidence of bias in TBI reporting."},{"rthcId":"RTHC-00808","title":"Physical activity and cannabis cessation.","authors":"Irons, Jessica G; Babson, Kimberly A; Bergeria, Cecilia L; Bonn-Miller, Marcel O","year":2014,"journal":"The American journal on addictions, 23(5), 485-92","doi":"10.1111/j.1521-0391.2014.12135.x","pmid":"24629045","tags":["exercise","quitting","withdrawal"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"In a study of 84 cannabis-dependent military veterans attempting self-guided cessation, those who reported low physical activity levels were significantly more likely to use cannabis during the first week after quitting compared to those with moderate or high activity levels. The difference was most pronounced during the first four days of the cessation period.\n\nIndividuals with low physical activity also reported greater mean cannabis use during those initial four days. No baseline differences existed between the low and moderate/high activity groups on other relevant variables.","whyItMatters":"Physical activity activates many of the same physiological systems as cannabis, including endocannabinoid signaling, stress response, and mood regulation. If exercise can serve as a partial substitute for cannabis effects during the critical early cessation period, it could be a simple, accessible intervention.","specificNumbers":"84 cannabis-dependent veterans. Low physical activity was associated with significantly more cannabis use during the first 4 days and first 7 days post-quit. No baseline differences between activity groups.","methodology":"Two-time-point prospective study of 84 cannabis-dependent veterans (3 female) who responded to study advertisements seeking individuals interested in a self-guided quit attempt. Physical activity levels and cannabis use were assessed by self-report at baseline and at one week post-quit.","limitations":"Small sample (84 participants, almost all male veterans). Self-reported physical activity and cannabis use. Observational design cannot confirm that exercise prevented relapse. Self-guided cessation may not represent clinical treatment populations."},{"rthcId":"RTHC-00809","title":"The subjective psychoactive effects of oral dronabinol studied in a randomized, controlled crossover clinical trial for pain.","authors":"Issa, Mohammed A; Narang, Sanjeet; Jamison, Robert N; Michna, Edward; Edwards, Robert R; Penetar, David M; Wasan, Ajay D","year":2014,"journal":"The Clinical journal of pain, 30(6), 472-8","doi":"10.1097/AJP.0000000000000022","pmid":"24281276","tags":["pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a randomized controlled trial with 30 chronic non-cancer pain patients on opioids, single doses of dronabinol (10 mg and 20 mg) produced significantly elevated scores on four of five psychoactivity subscales compared to placebo. Peak psychoactive effects at 2 hours after oral dosing were comparable to peak effects at 30 minutes after smoking marijuana.\n\nThe 10 mg dose produced effects similar to a low-strength (1.99% THC) marijuana cigarette, while 20 mg matched a high-strength (3.51% THC) cigarette. Importantly, daily morphine use, total pain relief, age, sex, and baseline pain level did not significantly affect the psychoactive profile.","whyItMatters":"As cannabinoid medications are prescribed more widely for pain, understanding their psychoactive profile is essential. These data show that oral dronabinol produces meaningful psychoactive effects that must be weighed against its analgesic benefits.","specificNumbers":"30 pain patients. 10 mg and 20 mg dronabinol elevated 4/5 ARCI subscales vs. placebo (P < 0.05). Peak effects at 2 hours comparable to smoked marijuana peak at 30 minutes (P = 0.80). Comparison: 10 mg matched low-strength, 20 mg matched high-strength marijuana.","methodology":"Randomized controlled trial with single doses of placebo, 10 mg, or 20 mg dronabinol in 30 chronic pain patients taking opioids and not using marijuana. Psychoactive effects measured hourly for 8 hours using the Addiction Research Center Inventory (ARCI). A comparison sample of 20 pain-free individuals who smoked marijuana provided reference values.","limitations":"Small sample of 30 patients. Single-dose design may not reflect chronic dosing. Comparison to smoked marijuana was made using a separate group of pain-free individuals, not within-subject. The marijuana comparison cigarettes (1.99% and 3.51% THC) are much weaker than modern cannabis."},{"rthcId":"RTHC-00810","title":"Cannabis, the pregnant woman and her child: weeding out the myths.","authors":"Jaques, S C; Kingsbury, A; Henshcke, P; Chomchai, C; Clews, S; Falconer, J; Abdel-Latif, M E; Feller, J M; Oei, J L","year":2014,"journal":"Journal of perinatology : official journal of the California Perinatal Association, 34(6), 417-24","doi":"10.1038/jp.2013.180","pmid":"24457255","tags":["pregnancy","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review summarized knowledge about cannabis use in pregnancy, including pharmacology, placental transfer, and developmental effects. Key findings included that cannabis compounds cross the placenta and enter breast milk, exposing the developing fetus and nursing infant to psychoactive substances.\n\nThe evidence suggested adverse effects on neurodevelopment, particularly during critical brain growth periods in fetal development and adolescent maturation. Reported effects included impacts on neuropsychiatric, behavioral, and executive functioning that could influence future adult productivity.\n\nHowever, the authors noted that reported rates of cannabis use in pregnancy are likely significantly underestimated, and much of the available literature had focused on other drugs (opioids, stimulants), leaving cannabis effects less well characterized.","whyItMatters":"Cannabis is one of the most widely used drugs among women of childbearing age, and use during pregnancy appears to be increasing. The limited but concerning evidence of developmental effects highlights the need for more research and clearer clinical guidance.","specificNumbers":"No specific prevalence statistics were reported, but the review noted that rates of prenatal cannabis exposure are likely significantly underestimated.","methodology":"Review of published articles, governmental guidelines, and data on cannabis use patterns in pregnant women, pharmacology of psychoactive compounds, placental and fetal transfer, and effects on pregnancy, the newborn, and child development.","limitations":"Limited quality data on cannabis use specifically during pregnancy. Difficulty separating cannabis effects from tobacco, alcohol, and socioeconomic confounders. Very limited data on cannabis effects during breastfeeding. Most studies focused on THC rather than whole-plant exposure."},{"rthcId":"RTHC-00811","title":"Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting.","authors":"Johnston, Jennifer; Lintzeris, Nicholas; Allsop, David J; Suraev, Anastasia; Booth, Jessica; Carson, Dean S; Helliwell, David; Winstock, Adam; McGregor, Iain S","year":2014,"journal":"Psychopharmacology, 231(24), 4623-36","doi":"10.1007/s00213-014-3611-5","pmid":"24880749","tags":["withdrawal","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a double-blind RCT, 38 cannabis-dependent adults were randomized to lithium (500 mg twice daily) or placebo for 8 days of inpatient withdrawal. Lithium did not significantly affect total withdrawal severity scores compared to placebo.\n\nHowever, lithium did significantly reduce three individual symptoms: loss of appetite, stomach aches, and nightmares/strange dreams. No significant differences were found in treatment retention or adverse events between groups.\n\nContrary to the preclinical hypothesis, lithium did not increase plasma oxytocin levels, the proposed mechanism by which it might reduce withdrawal. Both groups showed reduced cannabis use and improved outcomes at 30 and 90-day follow-up.","whyItMatters":"Negative trials are informative. Despite a compelling rationale from animal studies showing lithium reduces cannabinoid withdrawal through oxytocin release, the human trial did not confirm the overall benefit. This illustrates the gap between preclinical promise and clinical reality.","specificNumbers":"38 participants. Lithium 500 mg twice daily vs. placebo for 8 days. No significant difference in total withdrawal scores. Significant improvement in appetite loss, stomach aches, and nightmares. No increase in plasma oxytocin. Both groups improved at 30 and 90-day follow-up.","methodology":"Double-blind, placebo-controlled randomized trial. 38 treatment-seeking cannabis-dependent adults were randomized to lithium 500 mg or placebo twice daily during an 8-day inpatient admission. Withdrawal severity, cannabinoid levels, and oxytocin levels were measured. Follow-up at 14, 30, and 90 days post-discharge.","limitations":"Small sample of 38 participants. The 8-day treatment period was relatively short. Only one dose level was tested. The proposed oxytocin mechanism was not supported. The inpatient setting may differ from outpatient reality."},{"rthcId":"RTHC-00812","title":"Marijuana and lung diseases.","authors":"Joshi, Manish; Joshi, Anita; Bartter, Thaddeus","year":2014,"journal":"Current opinion in pulmonary medicine, 20(2), 173-9","doi":"10.1097/MCP.0000000000000026","pmid":"24384575","tags":["respiratory"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the respiratory effects of inhaling marijuana smoke. Smoking marijuana was consistently associated with chronic bronchitis symptoms (cough, phlegm, wheeze) and large airway inflammation. However, occasional marijuana use with low cumulative exposure did not appear to be a risk factor for chronic obstructive pulmonary disease (COPD).\n\nHeavy marijuana use alone may lead to airflow obstruction. The evidence for lung cancer was mixed: immunohistopathologic and epidemiologic data suggested biological plausibility, but it had been difficult to conclusively link marijuana smoking to cancer development.","whyItMatters":"As marijuana use increases and medicinal use expands, understanding respiratory risk is essential for both users and prescribers. The distinction between occasional and heavy use in terms of lung risk is clinically important.","specificNumbers":"No specific risk statistics were reported. The review distinguished between occasional/low cumulative use (not a COPD risk) and heavy regular use (may cause airflow obstruction).","methodology":"Review of recent studies examining the impact of inhaling marijuana smoke on the respiratory system.","limitations":"Difficulty separating marijuana and tobacco effects in epidemiological studies. No standard definition of \"heavy\" vs. \"occasional\" use. The cancer question may require decades of large-cohort follow-up to resolve definitively."},{"rthcId":"RTHC-00813","title":"Cannabis use: signal of increasing risk of serious cardiovascular disorders.","authors":"Jouanjus, Emilie; Lapeyre-Mestre, Maryse; Micallef, Joelle","year":2014,"journal":"Journal of the American Heart Association, 3(2), e000638","doi":"10.1161/JAHA.113.000638","pmid":"24760961","tags":["cardiovascular"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"From the French Addictovigilance Network database (2006-2010), researchers identified 35 serious cardiovascular complications among 1,979 total cannabis-related reports (1.8%). The patients were mostly men (85.7%) with an average age of 34.3 years.\n\nThe cardiovascular events included 22 cardiac complications (20 were acute coronary syndromes), 10 peripheral complications (arteriopathies and Buerger-like diseases affecting the limbs), and 3 cerebral complications. Nine of the 35 cases resulted in death, a mortality rate of 25.6%.\n\nThe authors noted that these events were likely underreported and emphasized that the public perception of cannabis as harmless was contradicted by these severe outcomes in young adults.","whyItMatters":"A 25.6% death rate among reported cardiovascular events is striking, even accounting for reporting bias toward severe cases. The occurrence of heart attacks, arterial disease, and stroke-like events in young adults challenges assumptions about cannabis safety.","specificNumbers":"35 cardiovascular events out of 1,979 cannabis reports (1.8%). 22 cardiac events (20 acute coronary syndromes). 10 peripheral vascular events. 3 cerebral events. 9 deaths (25.6% mortality). Average age: 34.3 years. 85.7% male.","methodology":"Analysis of spontaneous reports of cardiovascular complications related to cannabis collected by the French Addictovigilance Network from 2006 to 2010. All serious cardiovascular events were identified, described clinically, and followed to outcome.","limitations":"Spontaneous reporting systems capture only a fraction of actual events (underreporting). Reporting bias favors severe cases, inflating the apparent death rate. Cannabis use was determined by patient report, and other substances may have been involved. The study could not calculate population-level risk rates."},{"rthcId":"RTHC-00814","title":"Sadness, suicide, and drug misuse in Arkansas: results from the Youth Risk Behavior Survey 2011.","authors":"Kaley, Sean; Mancino, Michael J; Messias, Erick","year":2014,"journal":"The Journal of the Arkansas Medical Society, 110(9), 185-6","doi":null,"pmid":"24719998","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Using the 2011 Arkansas Youth Risk Behavior Survey, researchers examined drug use prevalence and associations with suicidality among high school students. Three types of substance misuse were reported by more than 10% of students: cannabis (33.3% ever use), inhalants (18.7% ever use), and prescription drugs without a prescription (13.2% ever use).\n\nAll three substances were associated with suicide outcomes, but the strength of association varied: prescription drug abuse had the strongest link, followed by inhalant abuse, then cannabis. This ordering suggests that while cannabis use is the most prevalent, it may carry less suicide-specific risk than other common substances.","whyItMatters":"Understanding which substances carry the strongest suicide risk associations helps prioritize prevention and screening efforts. While cannabis was the most commonly used substance, prescription drug abuse showed the strongest link to suicidality.","specificNumbers":"Cannabis: 33.3% ever use. Inhalants: 18.7% ever use. Prescription drugs: 13.2% ever use. Association strength with suicidality: prescription drugs > inhalants > cannabis.","methodology":"Cross-sectional analysis of the 2011 Arkansas Youth Risk Behavior Survey examining associations between three types of substance misuse and suicide outcomes (sadness, planning, attempts).","limitations":"Cross-sectional design from a single state. Brief abstract with limited methodological detail. Self-reported data. Cannot establish causation between substance use and suicidality."},{"rthcId":"RTHC-00815","title":"Youth risk behavior surveillance--United States, 2013.","authors":"Kann, Laura; Kinchen, Steve; Shanklin, Shari L; Flint, Katherine H; Kawkins, Joseph; Harris, William A; Lowry, Richard; Olsen, Emily O'Malley; McManus, Tim; Chyen, David; Whittle, Lisa; Taylor, Eboni; Demissie, Zewditu; Brener, Nancy; Thornton, Jemekia; Moore, John; Zaza, Stephanie","year":2014,"journal":"MMWR supplements, 63(4), 1-168","doi":null,"pmid":"24918634","tags":["youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"The 2013 Youth Risk Behavior Surveillance System, covering 104 health-risk behaviors among US high school students, found that 23.4% had used marijuana during the 30 days before the survey. Other key substance use findings: 34.9% had drunk alcohol and 15.7% had smoked cigarettes in the past 30 days.\n\nLong-term trend analysis showed that while many risky behaviors had decreased since monitoring began (physical fighting, cigarette use, sexual activity), marijuana lifetime use prevalence had not changed. The survey also found that 8.0% had attempted suicide in the past year and 19.6% had been bullied at school.\n\nData were available at national, state, and large urban school district levels, providing a comprehensive picture of youth health behavior.","whyItMatters":"The YRBSS is the gold standard for monitoring youth health behaviors in the United States. The finding that marijuana use prevalence has remained stable while cigarette use declined suggests different factors drive each behavior and that cigarette prevention strategies have not transferred to marijuana.","specificNumbers":"23.4% past 30-day marijuana use. 34.9% past 30-day alcohol use. 15.7% past 30-day cigarette smoking. 8.0% attempted suicide. 46.8% ever had sexual intercourse. 14.8% cyberbullied. Data from 42 states, 21 urban districts.","methodology":"National school-based Youth Risk Behavior Survey administered in 2013 across the United States, with additional state-level surveys (42 states) and large urban school district surveys (21 districts). Representative sampling of students in grades 9-12.","limitations":"Self-reported data collected in school settings. Students absent on survey day and out-of-school youth are missed. Social desirability bias may affect responses on sensitive topics. Response rates varied across jurisdictions."},{"rthcId":"RTHC-00816","title":"Cannabis abstinence during treatment and one-year follow-up: relationship to neural activity in men.","authors":"Kober, Hedy; DeVito, Elise E; DeLeone, Cameron M; Carroll, Kathleen M; Potenza, Marc N","year":2014,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 39(10), 2288-98","doi":"10.1038/npp.2014.82","pmid":"24705568","tags":["cognition","quitting","neuroscience"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Twenty cannabis-dependent men completed an fMRI cognitive control task before starting a 12-week treatment trial. Compared to 20 healthy controls, the cannabis-dependent group showed diminished brain activity during the Stroop task in regions critical for cognitive control and reward processing, including the dorsolateral prefrontal cortex and ventral striatum.\n\nWithin the cannabis group, greater pre-treatment activity in the dorsal anterior cingulate cortex (a cognitive control region) predicted less cannabis use during the 12-week treatment. Greater pre-treatment activity in the ventral striatum (a reward region) predicted less cannabis use during the subsequent one-year follow-up.\n\nThese findings suggest that the brain's capacity for cognitive control before treatment influences treatment outcomes.","whyItMatters":"If brain imaging can predict who will respond to treatment, it could help personalize treatment approaches. The finding also suggests that treatments enhancing cognitive control might improve cannabis outcomes.","specificNumbers":"20 cannabis-dependent and 20 healthy comparison participants. 12-week treatment followed by 1-year follow-up (n=18). Dorsal anterior cingulate activity predicted treatment response. Ventral striatum activity predicted long-term outcomes.","methodology":"Prospective study combining pre-treatment fMRI (Stroop color-word task) with outcomes from a 12-week randomized trial of cognitive behavioral therapy and/or contingency management, followed by one-year post-treatment assessment. 20 cannabis-dependent males and 20 healthy controls.","limitations":"Very small sample (20 per group, 18 at follow-up). Only male participants. Pre-treatment brain activity is correlational and may not be causal. The cannabis group may have had pre-existing brain differences unrelated to cannabis use."},{"rthcId":"RTHC-00817","title":"Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders [RETIRED]: report of the Guideline Development Subcommittee of the American Academy of Neurology.","authors":"Koppel, Barbara S; Brust, John C M; Fife, Terry; Bronstein, Jeff; Youssof, Sarah; Gronseth, Gary; Gloss, David","year":2014,"journal":"Neurology, 82(17), 1556-63","doi":"10.1212/WNL.0000000000000363","pmid":"24778283","tags":["medical-cannabis","cbd","pain","epilepsy"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This systematic review by the American Academy of Neurology evaluated 34 studies (8 Class I) on medical marijuana for neurological conditions. Key findings by indication:\n\nMS Spasticity: Oral cannabis extract was effective; nabiximols and THC were probably effective for patient-reported measures. MS Central Pain: Oral cannabis extract was effective; THC and nabiximols were probably effective. MS Urinary dysfunction: Nabiximols probably effective for reducing bladder voids; THC and oral extract probably ineffective. MS Tremor: THC, oral extract, and nabiximols were probably or possibly ineffective.\n\nFor Parkinson's dyskinesias: oral extract was probably ineffective. For Huntington's, Tourette syndrome, cervical dystonia, and epilepsy: oral cannabinoids were of unknown efficacy. The risk of serious psychopathological adverse effects was nearly 1%.","whyItMatters":"This was the first official systematic review and practice guideline from a major US medical society on medical marijuana. It provided the most authoritative evidence assessment available at the time and influenced clinical practice and policy.","specificNumbers":"34 studies reviewed, 8 Class I. Oral cannabis extract: effective for MS spasticity and central pain. Nabiximols: probably effective for spasticity, pain, bladder voids. Serious psychopathological adverse events: nearly 1%.","methodology":"Systematic review of medical marijuana studies from 1948 to November 2013, graded according to AAN classification for therapeutic evidence. 34 studies met inclusion criteria, 8 were rated Class I (highest quality).","limitations":"The evidence base was limited for most conditions beyond MS. Comparative effectiveness vs. other therapies was unknown. The \"unknown efficacy\" rating did not mean ineffective, just unstudied. The review has since been retired, potentially reflecting evolved evidence."},{"rthcId":"RTHC-00818","title":"Nabilone therapy for cannabis withdrawal presenting as protracted nausea and vomiting.","authors":"Lam, Philip W; Frost, David W","year":2014,"journal":"BMJ case reports, 2014","doi":"10.1136/bcr-2014-205287","pmid":"25246463","tags":["withdrawal","appetite","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 20-year-old woman developed protracted nausea and vomiting after abruptly stopping chronic cannabis use. This presentation was notable because nausea and vomiting are not included in the DSM-5 diagnostic criteria for cannabis withdrawal syndrome and represent an uncommon symptom pattern.\n\nThe patient was successfully treated with nabilone, a synthetic cannabinoid approved for chemotherapy-related nausea. This approach is consistent with growing evidence supporting agonist replacement therapy for cannabis withdrawal, similar to nicotine replacement for smoking cessation.","whyItMatters":"This case expanded the recognized symptom profile of cannabis withdrawal to include protracted nausea and vomiting, a presentation that could be confused with cannabinoid hyperemesis syndrome (which occurs during active use, not withdrawal). The distinction has opposite treatment implications.","specificNumbers":"One patient, age 20. Protracted nausea and vomiting secondary to cannabis withdrawal. Successfully treated with nabilone.","methodology":"Single case report documenting a 20-year-old woman with cannabis withdrawal presenting as protracted nausea and vomiting, treated with nabilone.","limitations":"Single case report. The protracted nausea presentation may be rare. Long-term outcomes were not reported. Cannot generalize to all withdrawal patients."},{"rthcId":"RTHC-00819","title":"Current knowledge on cannabinoids in oral fluid.","authors":"Lee, Dayong; Huestis, Marilyn A","year":2014,"journal":"Drug testing and analysis, 6(1-2), 88-111","doi":"10.1002/dta.1514","pmid":"23983217","tags":["driving"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review evaluated the science of oral fluid (saliva) testing for cannabinoids. Key findings included that THC concentrations in oral fluid can exceed 1,000 micrograms per liter shortly after smoking, while minor cannabinoids are detected at 10-fold lower and metabolites at 1,000-fold lower concentrations.\n\nEach cannabinoid has a distinct elimination profile and detection window influenced by administration route, dose, and drug use history. The review emphasized that appropriate interpretation of oral fluid test results requires comprehensive understanding of these variables, and that each drug testing program should establish its own cut-off criteria, collection procedures, and storage conditions.\n\nPassive environmental exposure, oral cavity metabolism, and individual physiological differences all affect results, complicating interpretation.","whyItMatters":"Oral fluid testing is increasingly used for roadside drug testing and workplace screening. Understanding the science behind these tests is essential for establishing fair cut-off values and interpreting results accurately.","specificNumbers":"THC in oral fluid: can exceed 1,000 micrograms/L after smoking. Minor cannabinoids: 10-fold lower. Metabolites: 1,000-fold lower. Detection windows vary by cannabinoid, route, dose, and use history.","methodology":"Review of published research on oral fluid cannabinoid testing, including pharmacokinetic properties, detection windows, correlation with blood and urine, onsite screening technologies, confirmatory methods, drug stability, and environmental exposure effects.","limitations":"The review highlighted significant gaps in understanding, including effects of passive exposure, chronic vs. acute use interpretation, and oral cavity metabolism. No consensus existed on optimal cut-off concentrations."},{"rthcId":"RTHC-00820","title":"Cannabis withdrawal in chronic, frequent cannabis smokers during sustained abstinence within a closed residential environment.","authors":"Lee, Dayong; Schroeder, Jennifer R; Karschner, Erin L; Goodwin, Robert S; Hirvonen, Jussi; Gorelick, David A; Huestis, Marilyn A","year":2014,"journal":"The American journal on addictions, 23(3), 234-42","doi":"10.1111/j.1521-0391.2014.12088.x","pmid":"24724880","tags":["withdrawal","sleep","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Twenty-nine chronic, frequent cannabis smokers were monitored during sustained abstinence on a closed research unit. Most withdrawal symptoms, including irritability and anxiety, were greatest during days 0-3 and decreased afterward. Cannabis craving also significantly decreased over time, and appetite began normalizing by day 4.\n\nHowever, two sleep-related symptoms moved in the opposite direction: strange dreams and difficulty getting to sleep increased over time rather than improving. This pattern suggests intrinsic sleep problems in chronic cannabis users that emerge as the sedating effects of cannabis wear off.\n\nSymptoms present on admission (likely residual drug effects) were positively correlated with plasma cannabinoid concentrations on day 0 but not afterward, confirming that initial symptoms reflected drug offset rather than withdrawal.","whyItMatters":"The dissociation between general withdrawal symptoms (improving) and sleep symptoms (worsening) has important clinical implications. Sleep disturbance that gets worse rather than better may drive relapse and may require specific treatment.","specificNumbers":"29 participants on admission, 66% remaining at 2 weeks, 34% at 4 weeks. Most symptoms peaked days 0-3. Strange dreams and insomnia increased over time. Appetite began normalizing day 4.","methodology":"Prospective observational study of 29 non-treatment-seeking chronic cannabis smokers on a closed research unit. Daily computer-administered assessments of psychological, sensory, and physical symptoms. Concurrent plasma and oral fluid cannabinoid measurements. Two-thirds remained after 2 weeks, one-third after 4 weeks.","limitations":"High attrition (only 34% remained at 4 weeks). Non-treatment-seeking participants may differ from those motivated to quit. The closed unit environment differs from real-world conditions. No control group of non-users for comparison."},{"rthcId":"RTHC-00821","title":"Treatment models for targeting tobacco use during treatment for cannabis use disorder: case series.","authors":"Lee, Dustin C; Budney, Alan J; Brunette, Mary F; Hughes, John R; Etter, Jean-Francois; Stanger, Catherine","year":2014,"journal":"Addictive behaviors, 39(8), 1224-30","doi":"10.1016/j.addbeh.2014.04.010","pmid":"24813547","tags":["quitting","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Approximately 50% of individuals seeking cannabis treatment also smoke tobacco, and tobacco use predicts worse cannabis treatment outcomes. This pilot study tested whether simultaneously addressing tobacco use would undermine cannabis treatment.\n\nSix participants received a 12-week program combining motivational enhancement, cognitive behavioral therapy, and contingency management for cannabis, plus an optional tobacco intervention with nicotine replacement therapy. All six completed the cannabis treatment, and five achieved cannabis abstinence.\n\nAll participants engaged with the tobacco intervention (completing at least one module), and half initiated nicotine replacement therapy. However, actual tobacco quit attempts were fewer than expected, and cessation outcomes were poor. The key finding was that adding tobacco treatment did not negatively impact cannabis outcomes.","whyItMatters":"Clinicians have long worried that addressing multiple substances simultaneously would overwhelm patients and worsen outcomes for both. This pilot provided initial evidence that dual targeting is safe and does not compromise cannabis treatment success.","specificNumbers":"Six participants. All completed cannabis treatment. Five achieved cannabis abstinence. All completed at least one tobacco module (mean 2.5). Three initiated nicotine replacement therapy. Tobacco quit attempts lower than expected.","methodology":"Case series of the first six participants in a pilot dual-substance treatment program. The 12-week program combined computer-assisted motivational and cognitive behavioral therapies with contingency management for cannabis, plus optional tobacco intervention.","limitations":"Only six participants with no control group. Pilot/feasibility design. Tobacco cessation outcomes were poor. Self-selected participants interested in both treatments may not represent typical cannabis treatment seekers."},{"rthcId":"RTHC-00822","title":"Examining potential school contextual influences on gambling among high school youth.","authors":"Lee, Grace P; Martins, Silvia S; Pas, Elise T; Bradshaw, Catherine P","year":2014,"journal":"The American journal on addictions, 23(5), 510-7","doi":"10.1111/j.1521-0391.2014.12142.x","pmid":"25065420","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a study of 25,456 students across 58 Maryland high schools, one-third reported lifetime gambling and 10% experienced gambling problems (31% of gamblers). Being male and using alcohol, marijuana, and non-medical prescription drugs were each associated with approximately twice the odds of gambling.\n\nAmong those who gambled, being male, African American, and using cigarettes, marijuana, and prescription drugs were associated with higher odds of gambling problems specifically. School-level factors (suspension rates, demographics) showed minimal associations with gambling.\n\nThe co-occurrence of substance use and gambling among adolescents suggests these behaviors share common risk factors and may benefit from integrated prevention approaches.","whyItMatters":"Gambling and substance use often cluster together in adolescents, yet prevention programs typically target them separately. Understanding their co-occurrence at the student and school level can inform more efficient prevention strategies.","specificNumbers":"25,456 students in 58 schools. 33% lifetime gambling. 10% gambling problems. Marijuana use: approximately 2x odds of gambling. Alcohol: approximately 2x odds. School-level factors showed minimal effects.","methodology":"Multilevel analysis of data from 25,456 students in 58 high schools participating in the Maryland Safe and Supportive Schools Initiative. Youth-reported demographics, gambling, and substance use were examined using weighted multilevel models.","limitations":"Cross-sectional design. Self-reported gambling and substance use. Cannot determine whether substance use leads to gambling or vice versa. Maryland-specific findings may not generalize."},{"rthcId":"RTHC-00823","title":"The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies","authors":"Lev-Ran, Shaul; Roerecke, Michael; Le Foll, Bernard; George, Tony P.; McKenzie, Kwame; Rehm, Jurgen","year":2014,"journal":"Psychological Medicine, 44(4), 797-810","doi":"10.1017/S0033291724003143","pmid":"39936870","tags":["depression","mental-health","youth"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"When researchers combined results from 22 longitudinal studies that adjusted for baseline depression, cannabis users had higher odds of later depression than non‑users. The pooled odds ratio was 1.29, which translates to roughly 29 percent higher odds on average. Most included samples were adolescents and many were based in the United States. Risk of bias was rated medium overall, with the biggest concern being how cannabis exposure was measured. Funnel plot and Egger testing did not flag publication bias. The signal is consistent across cohorts but modest in size and based on observational data.","whyItMatters":"Debates about cannabis and mental health often cite cross-sectional snapshots that cannot separate cause from correlation. This project aggregated only longitudinal studies that accounted for baseline depression, offering a clearer look at whether cannabis use is followed by higher odds of later depression in real-world cohorts during a period of shifting laws and rising potency.","specificNumbers":"- Pooled association: OR 1.29 (95% CI 1.13 to 1.46). About 29 percent higher odds of later depression among cannabis users\n- Studies pooled: 22 longitudinal cohorts, most with participants under 18 at baseline\n- Geography: 11 studies conducted in the United States\n- Bias rating: medium overall, driven largely by weak exposure measurement","methodology":"Systematic review and meta-analysis of longitudinal human studies that measured cannabis use, controlled for depression at baseline, and assessed later depression outcomes. The team screened 1,599 titles across databases and included 22 studies in the meta-analysis. Random effects models were used, along with multilevel meta-regression to explore moderators. Eleven studies were from the United States and most participants were under 18 at enrollment. Risk of bias was assessed and rated medium overall, with exposure measurement as a key weakness. Publication bias was evaluated using a funnel plot and Egger's Sandwich test, which did not suggest bias.","limitations":"Observational evidence only. Even with baseline adjustment, unmeasured confounding can explain part of the signal. Cannabis exposure was inconsistently measured, often as any use versus none, with little information on frequency, potency, product type, route, or duration. Most participants were adolescents, which narrows generalizability to older adults. Heterogeneity in how depression was assessed across cohorts can affect comparability. Funding sources and conflicts were not reported in the abstract. There is a timeline inconsistency in the provided materials, which cite a 2014 publication but describe a search window extending to March 2023; if this reflects an updated analysis that retained the original author list and title, the pooled estimate may differ from the 2014-only dataset."},{"rthcId":"RTHC-00824","title":"Attenuation of anticipatory nausea in a rat model of contextually elicited conditioned gaping by enhancement of the endocannabinoid system.","authors":"Limebeer, Cheryl L; Abdullah, Rehab A; Rock, Erin M; Imhof, Elizabeth; Wang, Kai; Lichtman, Aron H; Parker, Linda A","year":2014,"journal":"Psychopharmacology, 231(3), 603-12","doi":"10.1007/s00213-013-3282-7","pmid":"24043345","tags":["neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats that received JZL195, a dual inhibitor of the enzymes FAAH and MAGL, showed significantly less anticipatory nausea behavior (contextually elicited gaping) compared to untreated animals. The effect was mediated through CB1 receptors, as blocking CB1 with an antagonist reversed the anti-nausea effect.\n\nWhen JZL195 was combined with anandamide or 2-AG (the body's own cannabinoid molecules), the suppression of nausea was amplified beyond what JZL195 achieved alone. Anandamide on its own also reduced nausea behavior, but 2-AG alone did not.\n\nBrain analysis showed that JZL195 elevated levels of anandamide and related fatty acid molecules. The primary mechanism appeared to be FAAH inhibition, though MAGL inhibition also contributed.","whyItMatters":"Anticipatory nausea is a significant problem for chemotherapy patients and others who develop conditioned nausea responses. Current anti-nausea medications are largely ineffective against anticipatory nausea. This research suggests that enhancing the body's existing endocannabinoid system, rather than directly activating cannabinoid receptors with external compounds, could offer a targeted approach to this specific type of nausea.","specificNumbers":"JZL195 was administered at 10 mg/kg. AEA was given at 5.0 mg/kg and 2-AG at 1.25 mg/kg. The anti-nausea effect was CB1-mediated (reversed by SR141716) but not CB2-mediated (not reversed by AM630).","methodology":"Researchers used a rat model of anticipatory nausea in which animals were conditioned to associate a specific context with lithium chloride-induced illness. After four conditioning sessions, rats received various drug combinations before being placed back in the illness-paired context. Gaping behavior (an established measure of nausea in rats) was recorded. CB1 and CB2 receptor antagonists were used to determine which receptor pathway mediated the effects. Brain tissue was analyzed for endocannabinoid levels.","limitations":"This was an animal study using rats, and gaping behavior is a proxy measure for nausea that may not fully translate to the human experience. The drug doses and combinations used may not be directly applicable to human pharmacology. JZL195 is a research compound not available for clinical use."},{"rthcId":"RTHC-00825","title":"Subtypes of attention deficit-hyperactivity disorder (ADHD) and cannabis use","authors":"Loflin, Mallory; Earleywine, Mitch; De Leo, Joseph; Hobkirk, Andrea","year":2014,"journal":"Substance Use & Misuse, 49(4), 427-434","doi":null,"pmid":"24093525","tags":["cognition","youth","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among daily cannabis users, a higher proportion met symptom criteria for ADHD subtypes that include hyperactive‑impulsive symptoms compared with the inattentive subtype. Among nondaily users, the proportions meeting symptom criteria did not differ by subtype. The abstract does not report exact percentages or effect sizes, so the size of the difference is unclear.","whyItMatters":"ADHD is heterogeneous. Some people present primarily with inattention, others with hyperactivity and impulsivity, or both. Understanding how symptom profiles track with cannabis use patterns helps clarify who in real‑world samples tends to use daily and what motives or vulnerabilities might be involved. This study links daily use with hyperactive‑impulsive symptom profiles among users, which fits one version of the self‑medication hypothesis but can also reflect other explanations.","specificNumbers":"- Sample: 2,811 current cannabis users from a 2012 U.S. national survey\n- Comparison: daily users versus nondaily users\n- Outcome: daily users were more likely to meet criteria for hyperactive‑impulsive or combined ADHD subtypes than inattentive; nondaily users showed no subtype difference\n- Statistics: logistic regression and chi‑square; the abstract provides no odds ratios, confidence intervals, or p‑values","methodology":"Researchers analyzed data from a 2012 national U.S. survey of 2,811 current cannabis users. Participants reported ADHD symptoms experienced when not using cannabis. The team compared ADHD subtypes across daily versus nondaily users using logistic regression and chi‑square tests. This was cross‑sectional, based on self‑report, and limited to current users with no non‑user comparison group.","limitations":"Cross‑sectional survey data cannot establish directionality. ADHD status was inferred from self‑reported symptoms when not using cannabis rather than confirmed clinical diagnoses. The sample included only current cannabis users, so results do not generalize to non‑users or the general population. The abstract reports no effect sizes or exact proportions, which limits interpretation. Potential confounders such as age, sex, comorbidities, other substance use, and medication status are not detailed. Product type, THC or CBD content, and dose were not reported. Funding and conflicts of interest were not stated in the abstract."},{"rthcId":"RTHC-00826","title":"The case for medical marijuana in epilepsy.","authors":"Maa, Edward; Figi, Paige","year":2014,"journal":"Epilepsia, 55(6), 783-6","doi":"10.1111/epi.12610","pmid":"24854149","tags":["epilepsy","cbd","medical-cannabis","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Charlotte, a child with SCN1A-confirmed Dravet syndrome, experienced a dramatic reduction in seizure frequency after beginning adjunctive therapy with Charlotte's Web, a high-CBD/low-THC cannabis strain. Her seizures decreased from nearly 50 convulsive episodes per day to 2-3 nocturnal convulsions per month.\n\nThis improvement persisted for 20 months at the time of publication. During this period, Charlotte was successfully weaned from her other antiepileptic medications. The extract was slowly titrated over weeks and given alongside her existing drug regimen before the other medications were tapered.\n\nThe authors also argue that whole-plant cannabis extracts may have advantages over isolated pharmaceutical-grade CBD, citing potential synergistic effects among the plant's multiple compounds.","whyItMatters":"This case became one of the most publicly visible examples of medical cannabis for pediatric epilepsy after being featured on CNN. It helped catalyze a wave of families seeking cannabis-based treatments for treatment-resistant epilepsy and contributed to legislative changes in multiple states. It also raised important questions about whole-plant extracts versus isolated compounds.","specificNumbers":"Seizures dropped from ~50 convulsive seizures/day to 2-3 nocturnal convulsions/month. The improvement persisted for 20+ months. Charlotte was weaned from all other antiepileptic drugs during treatment.","methodology":"This is a single case report and review article. The clinical data comes from the documented treatment of one patient. The authors supplemented the case with a review of preclinical and clinical literature on cannabinoids in epilepsy, including historical context dating back to the 19th century.","limitations":"This is a single case report, which represents the lowest tier of clinical evidence. There was no blinding, no control group, and no way to rule out natural disease fluctuation, placebo effects, or other confounding factors. The dosing protocol was not standardized, and the results from one patient cannot be generalized."},{"rthcId":"RTHC-00827","title":"The effect of clozapine and risperidone on attentional bias in patients with schizophrenia and a cannabis use disorder: An fMRI study.","authors":"Machielsen, Marise Wj; Veltman, Dick J; van den Brink, Wim; de Haan, Lieuwe","year":2014,"journal":"Journal of psychopharmacology (Oxford, England), 28(7), 633-42","doi":"10.1177/0269881114527357","pmid":"24646809","tags":["psychosis","addiction","neuroscience","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a randomized trial of 36 patients with schizophrenia and cannabis use disorder, those treated with clozapine showed larger reductions in subjective craving and decreased activation of the insula during a cannabis-word Stroop task compared to those on risperidone. The insula is a brain region involved in craving and interoceptive awareness.\n\nDecreases in subjective craving were significantly associated with decreases in insula activation during the cannabis-related task, suggesting a shared neural mechanism. Risperidone-treated patients showed greater decreases in anterior cingulate cortex activation during a classical (non-cannabis) Stroop task.\n\nNineteen healthy controls were also included for baseline comparison of brain activity patterns.","whyItMatters":"Cannabis use disorder is highly prevalent among people with schizophrenia and worsens outcomes. This study provides neuroimaging evidence for why clozapine may be a better antipsychotic choice for this specific population, showing that it targets the brain's craving circuitry more effectively than risperidone.","specificNumbers":"36 patients with schizophrenia and 19 healthy controls participated. Measurements were taken at baseline and after 4 weeks of treatment. Clozapine reduced both craving and insula activation during cannabis-related cognitive tasks.","methodology":"Patients with schizophrenia and cannabis use disorder were randomized to receive either clozapine or risperidone. At baseline and after 4 weeks of medication, researchers measured brain activity using fMRI during two tasks: a classical Stroop task (measuring general cognitive control) and a cannabis word Stroop task (measuring attentional bias toward cannabis-related cues). Subjective craving was also assessed at both time points.","limitations":"The sample size was relatively small (36 patients total across two treatment groups). The study lasted only 4 weeks, so longer-term effects on craving and cannabis use were not assessed. The study did not measure actual cannabis consumption outcomes. Clozapine has significant side effects including required blood monitoring, which limits its first-line use."},{"rthcId":"RTHC-00828","title":"Effectiveness of the 'Healthy School and Drugs' prevention programme on adolescents' substance use: a randomized clustered trial.","authors":"Malmberg, Monique; Kleinjan, Marloes; Overbeek, Geertjan; Vermulst, Ad; Monshouwer, Karin; Lammers, Jeroen; Vollebergh, Wilma A M; Engels, Rutger C M E","year":2014,"journal":"Addiction (Abingdon, England), 109(6), 1031-40","doi":"10.1111/add.12526","pmid":"24612164","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Across all measures and both intervention conditions (e-learning and integral), the Healthy School and Drugs program showed no statistically significant effects on preventing new cases of alcohol, tobacco, or marijuana use at 32 months follow-up.\n\nThe program was tested in two formats: an e-learning version (digital lessons only) and an integral version (digital lessons plus school policy and parental involvement). Neither version outperformed the control condition for any substance.\n\nSpecifically, lifetime marijuana prevalence showed no differences between either intervention condition and controls (e-learning: B = 0.070, P = 0.732; integral: B = 0.186, P = 0.214). Similar null findings were observed across all alcohol and tobacco measures.","whyItMatters":"This study is a reminder that well-intentioned prevention programs do not always work. The null result raises questions about whether the specific program content, delivery method, or implementation quality was insufficient, or whether school-based prevention programs in general face fundamental challenges in changing adolescent substance use behavior.","specificNumbers":"3,784 students across 23 schools. Follow-up at 32 months. No significant effects on lifetime or 1-month prevalence of alcohol, tobacco, or marijuana use in either intervention condition.","methodology":"This was a randomized clustered trial involving 3,784 students aged 11-15 across 23 Dutch secondary schools. Schools were randomly assigned to one of three conditions: e-learning intervention, integral intervention (e-learning plus school policy and parent components), or control. Students completed digital questionnaires before the intervention and at 32-month follow-up. The primary outcomes were new incidences of substance use.","limitations":"The study measured incidence (new use) rather than changes in frequency among existing users. The 32-month follow-up may have missed shorter-term effects that faded. Implementation quality across schools was not closely monitored, and the authors note the program may have been implemented inadequately at some sites."},{"rthcId":"RTHC-00829","title":"Factors associated with substance use in adolescents with eating disorders.","authors":"Mann, Andrea P; Accurso, Erin C; Stiles-Shields, Colleen; Capra, Lauren; Labuschagne, Zandre; Karnik, Niranjan S; Le Grange, Daniel","year":2014,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 55(2), 182-7","doi":"10.1016/j.jadohealth.2014.01.015","pmid":"24656448","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Lifetime substance use prevalence varied substantially by eating disorder diagnosis: 48.7% among adolescents with bulimia nervosa, 28.6% in eating disorder not otherwise specified, and 24.6% in anorexia nervosa. Regular substance use (monthly, daily, or binge patterns) or a substance use disorder was present in 27.9% of all patients.\n\nIn the final statistical models, older age was the only factor that consistently predicted regular substance use across all substances. Older age and non-white race were associated with greater alcohol and cannabis use specifically.\n\nWhile binge-purge frequency and bulimia nervosa diagnosis were associated with substance use in initial analyses, these associations did not hold up once demographic factors like age, gender, and race were accounted for.","whyItMatters":"Co-occurring substance use and eating disorders in adolescents complicates treatment and worsens outcomes for both conditions. Understanding which subgroups are at highest risk helps clinicians screen more effectively and tailor interventions.","specificNumbers":"290 adolescents studied. Lifetime substance use: 48.7% in bulimia nervosa, 28.6% in ED-NOS, 24.6% in anorexia nervosa. Regular substance use or disorder: 27.9% overall.","methodology":"This cross-sectional study examined 290 adolescents aged 12-18 who presented for initial eating disorder evaluation at the University of Chicago Medicine between 2001 and 2012. Researchers assessed substance use patterns across alcohol, cannabis, tobacco, and other substances, along with DSM-5 eating disorder diagnosis, diagnostic scores, and demographic characteristics. Multinomial logistic regression tested associations between these factors.","limitations":"This was a cross-sectional study at a single treatment center, so it cannot establish whether eating disorders lead to substance use or vice versa. Self-reported substance use may be underestimated, especially in a clinical setting. The sample came from one university medical center and may not represent the broader population of teens with eating disorders."},{"rthcId":"RTHC-00830","title":"Evaluation of sex differences in cannabinoid dependence.","authors":"Marusich, Julie A; Lefever, Timothy W; Antonazzo, Kateland R; Craft, Rebecca M; Wiley, Jenny L","year":2014,"journal":"Drug and alcohol dependence, 137, 20-8","doi":"10.1016/j.drugalcdep.2014.01.019","pmid":"24582909","tags":["sex-differences","withdrawal","tolerance","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"After 6.5 days of twice-daily THC administration (30 mg/kg), rats challenged with the CB1 antagonist rimonabant displayed a pronounced withdrawal syndrome spanning multiple domains. Somatic signs included paw tremors, head twitches, and retropulsion. Cognitive disruptions included lack of locomotor habituation and impaired prepulse inhibition. Affective changes included increased startle reactivity.\n\nWith the exception of increased retropulsion (backward walking) in female rats, sex differences were minimal. Both sexes showed comparable withdrawal severity across most measures.\n\nDuring chronic THC dosing, both male and female rats experienced weight loss, and females showed disrupted estrous cycling. Spontaneous withdrawal (without rimonabant) produced only minimal overt signs, consistent with the pattern seen in human cannabis withdrawal.","whyItMatters":"This was the first study to systematically examine THC dependence in both male and female adult rats. The finding that withdrawal extends beyond somatic signs into cognitive and affective domains mirrors what humans report and suggests animal models may be more useful for studying cannabis withdrawal than previously thought.","specificNumbers":"THC dose: 30 mg/kg twice daily for 6.5 days. Withdrawal was precipitated with rimonabant. Female rats showed more retropulsion than males. Both sexes showed disrupted prepulse inhibition and increased startle reactivity.","methodology":"Adult male and female Sprague-Dawley rats received either 30 mg/kg THC or vehicle twice daily for 6.5 days. On day 7, rats were challenged with either vehicle or the CB1 antagonist rimonabant to precipitate withdrawal. Researchers assessed somatic signs (paw tremors, head twitches, retropulsion), cognitive measures (locomotor habituation, prepulse inhibition), and affective measures (startle reactivity).","limitations":"This was an animal study, and rat withdrawal patterns may not fully translate to human experience. Withdrawal was precipitated by a CB1 antagonist rather than occurring spontaneously, which may produce a more intense and acute withdrawal profile than natural cessation. The THC doses used were high relative to typical human consumption."},{"rthcId":"RTHC-00831","title":"Proximal and time-varying effects of cigarette, alcohol, marijuana and other hard drug use on adolescent dating aggression.","authors":"McNaughton Reyes, H Luz; Foshee, Vangie A; Bauer, Daniel J; Ennett, Susan T","year":2014,"journal":"Journal of adolescence, 37(3), 281-9","doi":"10.1016/j.adolescence.2014.02.002","pmid":"24636688","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using data tracking students from 8th through 12th grade, researchers found distinct patterns by substance type and sex. Marijuana use had a proximal (between-person) effect on dating aggression for girls, meaning girls who used marijuana were more likely to engage in dating aggression overall. Hard drug use showed a similar proximal effect for boys.\n\nAlcohol showed time-varying (within-person) effects for both sexes, meaning that at specific time points when an individual's alcohol use increased, their dating aggression also increased. Hard drug use also had time-varying effects for boys.\n\nCigarette use was not independently associated with dating aggression after controlling for other substances and risk factors.","whyItMatters":"Understanding which substances are associated with dating violence, and how those associations differ by sex, can help prevention programs target the right behaviors. The distinction between who is more likely to be aggressive (proximal effects) and when aggression peaks (time-varying effects) has practical implications for intervention timing.","specificNumbers":"Data spanned grades 8 through 12. Marijuana showed proximal effects on dating aggression for girls. Alcohol showed time-varying effects for both sexes. Hard drug use showed both proximal and time-varying effects for boys.","methodology":"Researchers used hierarchical growth modeling to analyze data from adolescents across grades 8 through 12. The analysis simultaneously examined proximal effects (whether substance-using adolescents were generally more aggressive) and time-varying effects (whether increases in substance use at specific time points coincided with increases in aggression). Demographic covariates and shared risk factors were controlled.","limitations":"The study relied on self-reported measures of both substance use and dating aggression. The analysis cannot establish causation; substance use and dating aggression may share common underlying risk factors. The specific mechanisms linking substances to aggression (pharmacological effects, social contexts, or shared impulsivity) were not distinguished."},{"rthcId":"RTHC-00832","title":"Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.","authors":"McPartland, John M; Guy, Geoffrey W; Di Marzo, Vincenzo","year":2014,"journal":"PloS one, 9(3), e89566","doi":"10.1371/journal.pone.0089566","pmid":"24622769","tags":["neuroscience","medical-cannabis","exercise","pain","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The review identified multiple categories of clinical interventions that enhance the endocannabinoid system. Pharmaceutical approaches included analgesics (acetaminophen, NSAIDs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants.\n\nComplementary and alternative medicine approaches that upregulated the system included massage and manipulation, acupuncture, dietary supplements, and herbal medicines.\n\nLifestyle factors also modulated the endocannabinoid system: diet, weight control, exercise, and psychoactive substance use (alcohol, tobacco, coffee, and cannabis). The authors connect these findings to the concept of \"endocannabinoid deficiency syndrome,\" which has been proposed as a factor in migraine, fibromyalgia, irritable bowel syndrome, and certain psychological disorders.","whyItMatters":"The endocannabinoid system is involved in pain, mood, sleep, appetite, and immune function. Understanding how to naturally support this system could offer therapeutic approaches for conditions where endocannabinoid tone may be deficient, potentially reducing reliance on external cannabinoids.","specificNumbers":"184 in vitro studies, 102 animal studies, and 36 human studies were included. The review identified upregulation mechanisms across cannabinoid receptors CB1 and CB2, ligand synthesis (anandamide and 2-AG), and degradation enzyme inhibition.","methodology":"The researchers searched PubMed for clinical trials, observational studies, and preclinical research on interventions that enhance the endocannabinoid system. Data synthesis was qualitative. After applying exclusion criteria, they included 184 in vitro studies, 102 in vivo animal studies, and 36 human studies.","limitations":"Most of the evidence came from preclinical studies (in vitro and animal). Only 36 human studies were included, many with small sample sizes. The clinical significance of measured endocannabinoid changes is often unclear. Qualitative synthesis means effect sizes across studies were not formally compared."},{"rthcId":"RTHC-00833","title":"Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence.","authors":"Milman, Garry; Bergamaschi, Mateus M; Lee, Dayong; Mendu, Damodara R; Barnes, Allan J; Vandrey, Ryan; Huestis, Marilyn A","year":2014,"journal":"Therapeutic drug monitoring, 36(2), 218-24","doi":"10.1097/FTD.0b013e3182a5c446","pmid":"24067260","tags":["medical-cannabis","withdrawal","addiction","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"During placebo dosing periods, blood THC and its metabolites consistently decreased, supporting the withdrawal symptoms observed. During active dronabinol dosing, all cannabinoid blood levels increased in a dose-dependent fashion. At the 120 mg/day dose, the metabolite THCCOOH increased significantly, and at 60 mg/day, the metabolite 11-OH-THC increased significantly.\n\nAfter a smoked cannabis challenge (5.9% THC cigarette), peak blood concentrations occurred within 15 minutes. However, the spike from smoking was only distinguishable from oral THC blood levels for about one hour, making it impractical to detect cannabis relapse during dronabinol treatment.\n\nThe ratio of THCCOOH to THC was higher after overnight dronabinol abstinence but could not reliably distinguish oral dosing from smoked cannabis.","whyItMatters":"Understanding the pharmacokinetics of oral THC during substitution therapy is essential for developing cannabis dependence treatments. The finding that relapse to smoked cannabis is nearly undetectable during dronabinol therapy has implications for clinical monitoring in treatment settings.","specificNumbers":"11 participants. Dronabinol doses: 0, 30, 60, 120 mg/day. Challenge cigarette: 5.9% THC. THC peak within 15 minutes of smoking. Smoked cannabis distinguishable from oral THC for approximately 1 hour only.","methodology":"Eleven daily cannabis smokers participated in a within-subject design with four 5-day medication sessions receiving 0, 30, 60, or 120 mg/day oral THC (dronabinol). Sessions were separated by 9 days of ad libitum cannabis smoking. On day 5 of each session, participants smoked one 5.9% THC cigarette. Blood samples were collected and analyzed for THC, 11-OH-THC, and THCCOOH using two-dimensional gas chromatography mass spectrometry.","limitations":"Only 11 participants were included. All were chronic, daily cannabis smokers, so results may not generalize to lighter users. The cannabis challenge used a relatively low-potency cigarette (5.9% THC). The study examined pharmacokinetics only, not clinical outcomes like sustained abstinence."},{"rthcId":"RTHC-00834","title":"Predicting creativity: the role of psychometric schizotypy and cannabis use in divergent thinking.","authors":"Minor, Kyle S; Firmin, Ruth L; Bonfils, Kelsey A; Chun, Charlotte A; Buckner, Julia D; Cohen, Alex S","year":2014,"journal":"Psychiatry research, 220(1-2), 205-10","doi":"10.1016/j.psychres.2014.08.044","pmid":"25219611","tags":["cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Divergent thinking (a measure of creativity) was greater in the positive schizotypy group compared to negative schizotypy and non-schizotypy groups, with small to medium effect sizes. Positive schizotypy significantly predicted divergent thinking across all groups.\n\nCannabis use and divergent thinking were associated in the non-schizotypy group, but not in either schizotypy group. When both positive schizotypy and cannabis use were entered as predictors simultaneously, positive schizotypy remained significant while cannabis use did not.\n\nThe pattern suggested a ceiling effect: cannabis use was only associated with increased creativity among people who were already low in creative thinking. For those with high baseline creativity (characteristic of positive schizotypy), cannabis use added nothing.","whyItMatters":"The popular belief that cannabis enhances creativity has influenced both recreational use and artistic culture. This study suggests the association is largely an artifact: people with certain personality traits (positive schizotypy) tend to both use cannabis and be more creative, but the cannabis itself may not be driving the creativity.","specificNumbers":"Positive schizotypy group: n=66. Negative schizotypy: n=22. Non-schizotypy: n=60. Positive schizotypy predicted creativity. Cannabis use did not predict creativity when schizotypy was controlled.","methodology":"Researchers compared three groups: positive schizotypy (n=66), negative schizotypy (n=22), and non-schizotypy (n=60). Divergent thinking was assessed using established creativity measures. Cannabis use was self-reported. Schizotypy was measured using psychometric instruments. Statistical analyses examined whether the relationship between cannabis and creativity was confounded by schizotypy.","limitations":"This was a cross-sectional study that cannot establish causation. The sample was relatively small, especially the negative schizotypy group. Divergent thinking is only one aspect of creativity. Cannabis use was self-reported and not experimentally manipulated, so dose, frequency, and acute versus chronic effects were not distinguished."},{"rthcId":"RTHC-00835","title":"The detection of THC, CBD and CBN in the oral fluid of Sativex® patients using two on-site screening tests and LC-MS/MS.","authors":"Molnar, Anna; Fu, Shanlin; Lewis, John; Allsop, David J; Copeland, Jan","year":2014,"journal":"Forensic science international, 238, 113-9","doi":"10.1016/j.forsciint.2014.03.004","pmid":"24699310","tags":["medical-cannabis","cbd","driving"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"After Sativex dosing, oral fluid contained very high concentrations of both THC and CBD. The primary Australian roadside screening test (DrugWipe II Twin) often gave false negative results even when THC concentrations were high. However, the secondary confirmation test (Cozart DDS) correctly identified THC in all Sativex-treated patients.\n\nTHC and CBD concentrations were extremely elevated shortly after dosing (over 5,356 ng/mL THC and over 3,826 ng/mL CBD) and remained detectable (over 67.6 ng/mL) two hours after administration. The average THC/CBD ratio across positive samples was 1.10, reflecting the 1:1 composition of Sativex.\n\nWhile the THC/CBD ratio could theoretically distinguish Sativex use from recreational cannabis (which would have much higher THC relative to CBD), this distinction would not work if a patient used both Sativex and non-medicinal cannabis.","whyItMatters":"As medicinal cannabis products become more widely prescribed, patients face the real-world problem of testing positive on roadside drug tests. This study demonstrates that legitimate Sativex users will likely test positive for THC in oral fluid tests, raising legal and practical concerns for patients who drive.","specificNumbers":"Low dose: 5.4 mg THC. High dose: 21.6 mg THC. Peak oral fluid THC: >5,356 ng/mL. Peak CBD: >3,826 ng/mL. THC/CBD ratio: 1.10 (RSD 19.9%). Detectable for 2+ hours. DrugWipe often gave false negatives; Cozart correctly identified all positive cases.","methodology":"This was a double-blind, placebo-controlled pilot study. Patients received either Sativex or placebo at two dose levels: low (5.4 mg THC) and high (21.6 mg THC). Oral fluid was tested before dosing and at intervals up to 2 hours after dosing using two roadside screening devices and confirmatory LC-MS/MS analysis.","limitations":"This was a small pilot study. Oral fluid concentrations immediately after oromucosal spray application may be artificially elevated due to direct oral contamination rather than systemic absorption. The 2-hour monitoring period may not have captured the full detection window. Only two screening devices were tested."},{"rthcId":"RTHC-00836","title":"The efficacy of an opportunistic cognitive behavioral intervention package (OCB) on substance use and comorbid suicide risk: a multisite randomized controlled trial.","authors":"Morley, Kirsten C; Sitharthan, Gomathi; Haber, Paul S; Tucker, Peter; Sitharthan, Thiagarajan","year":2014,"journal":"Journal of consulting and clinical psychology, 82(1), 130-40","doi":"10.1037/a0035310","pmid":"24364795","tags":["addiction","mental-health","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Over 6 months, there were no completed suicides and only 2 suicide attempts among 185 participants, which is a positive outcome regardless of treatment group. Suicide ideation, alcohol consumption, and cannabis use all decreased over time in both groups.\n\nHowever, there were no significant differences between the CBT intervention group and the treatment-as-usual group on any primary or secondary outcome. The specialized 8-session program plus group therapy did not outperform standard care in reducing suicidal ideation, substance use, depression, anxiety, or self-efficacy.\n\nNotably, cannabis use at baseline was one of the factors that predicted persistent suicide ideation at 6-month follow-up, along with higher psychiatric symptom severity.","whyItMatters":"People with substance use disorders who also experience suicidal behavior are at high risk. This study tested whether a tailored intervention could improve outcomes, and the null result is informative: it suggests that simply adding structured CBT sessions may not be sufficient for this complex population, and different approaches may be needed.","specificNumbers":"185 participants. 8-session intervention plus group therapy vs. TAU. 6-month follow-up. No completed suicides. 2 suicide attempts. No significant Treatment x Time interactions on any measure.","methodology":"This multi-site randomized controlled trial enrolled 185 outpatients who presented with both suicide risk and concurrent substance use. Participants were randomized to either an opportunistic cognitive behavioral intervention package (OCB; 8 individual sessions plus group therapy) or treatment as usual (TAU) over 6 months. Primary outcomes included suicidal behavior, suicide ideation, and substance use levels. Secondary outcomes included depression, anxiety, and self-efficacy.","limitations":"The control condition (treatment as usual) was not standardized and may have included effective therapeutic components. The study was powered to detect moderate effect sizes and may have missed smaller but meaningful differences. Low rates of suicide attempts made it difficult to detect differences in this outcome. Six months may be insufficient follow-up for this population."},{"rthcId":"RTHC-00837","title":"Cannabis for inflammatory bowel disease.","authors":"Naftali, Timna; Mechulam, Raphael; Lev, Lihi Bar; Konikoff, Fred M","year":2014,"journal":"Digestive diseases (Basel, Switzerland), 32(4), 468-74","doi":"10.1159/000358155","pmid":"24969296","tags":["medical-cannabis","inflammation","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The authors report on their own clinical research program alongside a broader literature review. In an observational study of 30 Crohn's disease patients, medical cannabis was associated with improved disease activity and reduced use of other medications.\n\nIn a subsequent placebo-controlled trial of 21 chronic Crohn's patients, 10 of 11 subjects receiving cannabis showed a decrease in Crohn's Disease Activity Index (CDAI) greater than 100 points, compared to 4 of 10 on placebo. Complete remission was achieved in 5 of 11 cannabis patients versus 1 of 10 placebo patients.\n\nHowever, in a separate study, low-dose cannabidiol alone did not improve Crohn's disease activity. The review also covers preclinical evidence that the endocannabinoid system is involved in major immune events and that cannabinoids reduce histologic inflammation in mouse models of colitis.","whyItMatters":"Inflammatory bowel diseases like Crohn's are chronic, often debilitating conditions with limited treatment options. This review consolidates early evidence suggesting cannabis may reduce symptoms and disease activity, while also highlighting that low-dose CBD alone was insufficient and that much more research is needed.","specificNumbers":"Observational study: 30 patients. Placebo-controlled trial: 21 patients, 10/11 on cannabis showed CDAI decrease >100 vs. 4/10 on placebo. Complete remission: 5/11 cannabis vs. 1/10 placebo. Low-dose CBD study: no effect on disease activity.","methodology":"This is a narrative review combining the authors' own clinical trial results with a broader literature survey. It covers preclinical studies in murine colitis models, observational clinical data, and controlled trial results. The authors also discuss the historical use of cannabis for gastrointestinal conditions.","limitations":"The clinical trials described were very small (21-30 patients). The placebo-controlled trial did not achieve statistical significance for remission. Symptom improvement may not correlate with objective mucosal healing. The review is narrative rather than systematic, and the authors are reviewing their own work."},{"rthcId":"RTHC-00838","title":"Psychiatric and substance-use comorbidities associated with lifetime crack cocaine use in young adults in the general population.","authors":"Narvaez, Joana C M; Jansen, Karen; Pinheiro, Ricardo T; Kapczinski, Flávio; Silva, Ricardo A; Pechansky, Flávio; Magalhães, Pedro V","year":2014,"journal":"Comprehensive psychiatry, 55(6), 1369-76","doi":"10.1016/j.comppsych.2014.04.021","pmid":"24933652","tags":["addiction","mental-health","depression","ptsd"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 1,560 young adults aged 18-24 in the general population, 2.5% reported lifetime crack cocaine use. In the final regression model, crack cocaine use was independently associated with higher total psychiatric symptom scores, post-traumatic stress disorder, antisocial personality disorder, and suicide risk.\n\nSubstance use associations were broad: crack cocaine use was linked to tobacco, alcohol, cannabis, cocaine, amphetamine, and inhalant use and dependence. Cannabis use was among the substances most commonly co-occurring with crack cocaine use.\n\nThe study was population-based rather than drawn from treatment settings, which provides a less biased picture of the psychiatric profile associated with crack cocaine use in the community.","whyItMatters":"Understanding the psychiatric and substance use profile of young people who use crack cocaine helps inform targeted interventions. The association with PTSD and suicide risk suggests that trauma-informed approaches may be particularly important for this population.","specificNumbers":"1,560 participants aged 18-24. Lifetime crack cocaine use prevalence: 2.5%. Associated conditions: PTSD, antisocial personality disorder, suicide risk. Associated substances: tobacco, alcohol, cannabis, cocaine, amphetamine, inhalants.","methodology":"This was a cross-sectional population-based study in Pelotas, Brazil, involving 1,560 participants aged 18-24. Lifetime substance use was assessed using the ASSIST inventory. Psychiatric conditions were assessed using the Mini-International Neuropsychiatric Interview (MINI), and common mental disorder symptoms were evaluated with the Self-Reported Questionnaire (SRQ).","limitations":"This was a cross-sectional study, so the direction of associations cannot be determined. Crack cocaine use may precede, follow, or co-occur with psychiatric conditions. Self-reported substance use may be underreported. The study was conducted in one Brazilian city and may not generalize to other settings."},{"rthcId":"RTHC-00839","title":"Pharmacological activation of CB1 receptor modulates long term potentiation by interfering with protein synthesis.","authors":"Navakkode, Sheeja; Korte, Martin","year":2014,"journal":"Neuropharmacology, 79, 525-33","doi":"10.1016/j.neuropharm.2013.11.018","pmid":"24412673","tags":["neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Pre-treating rat hippocampal brain slices with the CB1 receptor agonist WIN55,212-2 significantly impaired long-term potentiation (LTP), a cellular mechanism believed to underlie learning and memory. The mechanism was unexpected: CB1 activation increased rather than decreased protein synthesis.\n\nThis excess protein production disrupted the normal balance needed for LTP. Synapses that were primed with WIN55 and then received strong stimulation actually produced a form of late-LTP in pathways that would normally show only early-LTP, confirming that WIN55 triggered abnormal synthesis of plasticity-related proteins.\n\nAdditionally, CB1 receptor activation inhibited acetylcholine release through both muscarinic and nicotinic receptor pathways. This cholinergic disruption contributed to the overall synaptic deficits observed.","whyItMatters":"Cognitive impairment is one of the most well-documented effects of cannabis use. This study reveals a specific molecular mechanism: rather than simply blocking synaptic signaling, CB1 activation disrupts the precise balance of protein synthesis required for memory formation. This paradoxical overproduction of proteins may explain why cannabinoids impair rather than enhance learning.","specificNumbers":"WIN55 was used as the CB1 agonist. LTP was measured in CA1 apical dendrites. Both protein synthesis disruption and cholinergic inhibition contributed to the synaptic deficits.","methodology":"Researchers used rat hippocampal brain slices to study synaptic plasticity. Slices were pre-treated with WIN55,212-2 (a CB1 agonist) before receiving electrical stimulation protocols designed to induce LTP. Protein synthesis inhibitors and receptor antagonists were used to dissect the molecular mechanisms. Recordings were made from the apical dendrites of CA1 pyramidal neurons.","limitations":"This was an in vitro study using brain slices, which removes the complexity of intact brain circuits. The synthetic cannabinoid WIN55 may not perfectly replicate the effects of THC or endocannabinoids. Results from rat hippocampal tissue may not fully translate to human brain physiology."},{"rthcId":"RTHC-00840","title":"Performance, egg quality, and blood plasma chemistry of laying hens fed hempseed and hempseed oil.","authors":"Neijat, M; Gakhar, N; Neufeld, J; House, J D","year":2014,"journal":"Poultry science, 93(11), 2827-40","doi":"10.3382/ps.2014-03936","pmid":"25239534","tags":["cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Forty-eight laying hens fed hemp-containing diets for 12 weeks showed no significant differences from control-fed hens in feed intake, rate of lay, egg weight, body weight gain, or egg quality. Blood metabolites including proteins, glucose, uric acid, cholesterol, and electrolytes were unaffected.\n\nLiver enzyme levels (gamma-glutamyl transferase and aspartate aminotransferase) were actually lowest in hens fed moderate levels of hempseed (10% and 20%) and low hempseed oil (4.5%), suggesting a possible protective effect on liver health at moderate inclusion levels compared to higher levels or the control diet.\n\nAll diets were formulated to contain similar levels of crude fat (11%), energy (2,800 kcal/kg), and crude protein (17%), ensuring that differences were attributable to the hemp products rather than macronutrient imbalances.","whyItMatters":"Hemp products are a potential sustainable feed ingredient for poultry, offering omega fatty acids and protein. This study provides safety data supporting the use of hempseed and hempseed oil in laying hen diets without negative impacts on production or animal health.","specificNumbers":"48 hens, 6 diet groups, 12-week study. Hempseed: 10%, 20%, 30%. Hempseed oil: 4.5%, 9.0%. No effects on performance or egg quality. Lower liver enzymes at 10-20% hempseed and 4.5% hempseed oil.","methodology":"Forty-eight Lohmann LSL-Classic white-egg laying hens (19 weeks old) were individually caged and fed one of six diets for 12 weeks: hempseed at 10%, 20%, or 30%; hempseed oil at 4.5% or 9.0%; or a corn oil-based control. Performance, egg quality, and blood biochemistry were measured using repeated measures analysis.","limitations":"The sample size was small (8 hens per diet group). The study lasted only 12 weeks, so longer-term effects were not assessed. The protective liver enzyme finding was observational and the mechanism was not investigated. Results from one breed of laying hen may not generalize to all poultry."},{"rthcId":"RTHC-00841","title":"Universal Internet-based prevention for alcohol and cannabis use reduces truancy, psychological distress and moral disengagement: a cluster randomised controlled trial.","authors":"Newton, Nicola C; Andrews, Gavin; Champion, Katrina E; Teesson, Maree","year":2014,"journal":"Preventive medicine, 65, 109-15","doi":"10.1016/j.ypmed.2014.05.003","pmid":"24823906","tags":["youth","harm-reduction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Students who received the Internet-based Climate Schools: Alcohol and Cannabis course showed significant reductions in three key risk factors compared to controls. Truancy (skipping school), psychological distress, and moral disengagement (rationalizing harmful behavior) were all reduced at follow-up assessments conducted up to 12 months after the intervention.\n\nThe program had previously been shown to reduce alcohol and cannabis use. This analysis demonstrated that the same program produced broader benefits beyond substance use outcomes, addressing risk factors that are themselves associated with substance use and other problem behaviors.\n\nThe intervention consisted of two sets of six online lessons delivered approximately six months apart, making it a relatively low-intensity intervention for the breadth of outcomes affected.","whyItMatters":"Truancy, psychological distress, and moral disengagement are all risk factors for substance use and other problem behaviors. A single, scalable online program that addresses these upstream factors alongside substance use itself offers an efficient approach to adolescent prevention.","specificNumbers":"764 students, 10 schools. Intervention: 12 online lessons delivered in two modules 6 months apart. Significant reductions in truancy, psychological distress, and moral disengagement up to 12 months post-intervention.","methodology":"A cluster randomized controlled trial was conducted across 10 secondary schools in Sydney, Australia (2007-2008). 764 students (mean age 13.1 years) from 5 schools received the Climate Schools program while 5 schools served as controls receiving standard health classes. Assessments occurred at baseline, immediately post-intervention, and at 6 and 12 months following the intervention.","limitations":"The study was conducted in Australian schools and the program's content may not transfer directly to other cultural contexts. The control condition (usual health classes) varied across schools. Only self-reported outcomes were measured. The 12-month follow-up may not capture whether effects persist into later adolescence."},{"rthcId":"RTHC-00842","title":"A pilot study of an online universal school-based intervention to prevent alcohol and cannabis use in the UK.","authors":"Newton, Nicola C; Conrod, Patricia J; Rodriguez, Daniel M; Teesson, Maree","year":2014,"journal":"BMJ open, 4(5), e004750","doi":"10.1136/bmjopen-2013-004750","pmid":"24840248","tags":["youth","harm-reduction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"The Climate Schools program, originally developed and validated in Australia, was piloted in two UK secondary schools with Year 9 students (approximately 13-14 years old). Evaluations from both students and teachers were overwhelmingly positive.\n\nAmong students, 85% said the information on alcohol and cannabis was easy to understand, 84% said it was easy to learn, and 80% found the online cartoon format enjoyable. Among teachers, 100% said students could recall the information taught, 82% said the computer component was easy to implement, 100% said the teacher's manual was easy to use, and 82% said they would use the program again and recommend it to others.\n\nThe study focused on feasibility and acceptability rather than effectiveness outcomes, establishing whether the Australian-developed program could work in a UK context before conducting a full evaluation trial.","whyItMatters":"Evidence-based prevention programs developed in one country often fail when implemented in different cultural contexts. This pilot demonstrated that the Climate Schools program was acceptable and implementable in UK schools, an essential step before committing resources to a full effectiveness trial.","specificNumbers":"11 teachers and 222 students from 2 schools. Student evaluations: 85% found content easy to understand, 84% easy to learn, 80% enjoyed the format. Teacher evaluations: 100% said students recalled information, 82% found it easy to implement, 82% would use it again.","methodology":"This was a feasibility pilot study involving 11 teachers and 222 students from two secondary schools in southeast London. Teachers implemented the Climate Schools program (two modules of six lessons each, delivered approximately 6 months apart) over the school year. Post-program evaluations were collected from both students and teachers.","limitations":"This was a feasibility study with no control group and no measurement of actual substance use outcomes. Only two schools in southeast London participated, limiting generalizability. Evaluations may be subject to social desirability bias. The study did not assess whether the program would be effective in reducing substance use in a UK population."},{"rthcId":"RTHC-00843","title":"Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice.","authors":"Nicolussi, Simon; Viveros-Paredes, Juan Manuel; Gachet, María Salomé; Rau, Mark; Flores-Soto, Mario Eduardo; Blunder, Martina; Gertsch, Jürg","year":2014,"journal":"Pharmacological research, 80, 52-65","doi":"10.1016/j.phrs.2013.12.010","pmid":"24412246","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers identified guineensine from Piper nigrum (black pepper) as a potent inhibitor of anandamide (AEA) cellular uptake, with an EC50 of 290 nanomolar. Guineensine also inhibited 2-AG uptake. Importantly, it did not directly interact with cannabinoid receptors, FAAH, MAGL, or the fatty acid binding protein FABP5, meaning it works through a distinct mechanism from known endocannabinoid modulators.\n\nIn mice, guineensine produced the classic tetrad of cannabinoid effects: catalepsy (immobility), hypothermia (reduced body temperature), reduced locomotion, and analgesia (pain reduction). The catalepsy and analgesia were blocked by the CB1 receptor antagonist rimonabant, confirming these effects were mediated through the endocannabinoid system.\n\nStructure-activity analysis showed that the length of the carbon chain connecting the two functional groups of guineensine was important for its activity.","whyItMatters":"Guineensine represents a new class of endocannabinoid modulator with a mechanism distinct from FAAH or MAGL inhibition. Its identification in black pepper adds to the list of dietary compounds that interact with the endocannabinoid system and could serve as a scaffold for developing new drugs that enhance endocannabinoid tone without directly activating cannabinoid receptors.","specificNumbers":"EC50 for AEA uptake inhibition: 290 nM. Guineensine did not inhibit FAAH, MAGL, or serine hydrolases. Did not bind CB1, CB2, or FABP5. Produced catalepsy, hypothermia, reduced locomotion, and analgesia in mice.","methodology":"High-content screening identified guineensine from black pepper. Its effects on endocannabinoid uptake were tested in cell lines. Activity-based protein profiling confirmed it did not inhibit serine hydrolases. In vivo effects were assessed in BALB/c mice using the cannabinoid tetrad (catalepsy, body temperature, locomotion, tail-flick analgesia). The CB1 antagonist rimonabant was used to confirm endocannabinoid system involvement.","limitations":"This was a preclinical study using cell lines and mice. The concentrations of guineensine achievable through dietary black pepper consumption are likely far below those needed for pharmacological effects. The molecular target through which guineensine blocks endocannabinoid uptake was not identified."},{"rthcId":"RTHC-00844","title":"Mid-ventricular variant takotsubo cardiomyopathy associated with Cannabinoid Hyperemesis Syndrome: a case report.","authors":"Nogi, Masayuki; Fergusson, David; Chiaco, John Michael Chua","year":2014,"journal":"Hawai'i journal of medicine & public health : a journal of Asia Pacific Medicine & Public Health, 73(4), 115-8","doi":null,"pmid":"24765560","tags":["cardiovascular","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 32-year-old woman presented with severe epigastric pain, nausea, and vomiting after resuming marijuana use following a period of abstinence. Her EKG showed dynamic T-wave changes with modest cardiac biomarker elevation. Imaging revealed the mid-ventricular variant of takotsubo cardiomyopathy with normal coronary arteries.\n\nHer history was consistent with cannabinoid hyperemesis syndrome (CHS): previous episodes of cyclic vomiting relieved by compulsive hot water bathing, with symptoms resolving after marijuana cessation and recurring upon resumption of use.\n\nThis was only the second reported case associating takotsubo cardiomyopathy with CHS. The mechanism is not clearly defined, though the authors note that endocannabinoid receptors are expressed in heart muscle tissue, which could represent a pathway for cardiac involvement.","whyItMatters":"Cannabinoid hyperemesis syndrome is increasingly recognized as cannabis use becomes more prevalent. This case suggests that severe CHS episodes may carry cardiac risk through stress cardiomyopathy, adding to the known complications of the condition and highlighting the importance of recognizing CHS early.","specificNumbers":"Patient age: 32 years. EKG showed dynamic T-wave changes. Cardiac biomarkers were modestly elevated. Coronary arteries were normal on angiography. This was the second reported case of takotsubo cardiomyopathy with CHS.","methodology":"This is a single case report with a literature review. The patient was evaluated with EKG, echocardiography, ventriculography, and cardiac angiography. The diagnosis of takotsubo cardiomyopathy was based on characteristic wall motion abnormalities with normal coronary arteries. CHS was diagnosed based on the clinical pattern of cyclic vomiting with marijuana use.","limitations":"This is a single case report and cannot establish a causal relationship between CHS and takotsubo cardiomyopathy. The cardiac event may have been coincidental. The mechanism linking the two conditions is speculative. Case reports represent the lowest tier of clinical evidence."},{"rthcId":"RTHC-00845","title":"Childhood ADHD and addictive behaviours in adolescence: a canadian sample.","authors":"Ostojic, Dragana; Charach, Alice; Henderson, Joanna; McAuley, Tara; Crosbie, Jennifer","year":2014,"journal":"Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent, 23(2), 128-35","doi":null,"pmid":"24872828","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 142 adolescents diagnosed with ADHD before age 12, substance use rates were comparable to or lower than two large Canadian population samples. Cannabis use was reported by 14.2% of the ADHD sample, compared to 16.5% in the National Longitudinal Survey (ages 10-15) and 26.0% in the Ontario Student Drug Use Survey (ages 12-18).\n\nAlcohol use showed a similar pattern: 27.1% in the ADHD sample versus 28.6% and 58.6% in the two comparison groups. Cigarette use was also lower in the ADHD group (17.8%) compared to both population samples.\n\nTwo areas did warrant further attention: a possible increased risk for substance use among females with ADHD, and a non-significant trend toward higher gambling rates (7.9% vs. 4.3% in the provincial average).","whyItMatters":"ADHD has long been considered a risk factor for substance use disorders, but this study suggests the relationship may not be straightforward. In early adolescence, ADHD diagnosis alone may not increase the likelihood of substance use onset, challenging assumptions that could lead to unnecessary stigmatization of youth with ADHD.","specificNumbers":"ADHD sample (n=142): cannabis 14.2%, alcohol 27.1%, cigarettes 17.8%. NLSCY comparison: cannabis 16.5%, alcohol 28.6%, cigarettes 28.3%. OSDUHS comparison: cannabis 26.0%, alcohol 58.6%, cigarettes 21.9%. Gambling trend: ADHD 7.9% vs. provincial 4.3% (not significant).","methodology":"Researchers surveyed 142 adolescents (mean age 14.1 years) who had been diagnosed with ADHD before age 12 at a clinical center. Their substance use rates were compared to two large cross-sectional population studies: the Canadian National Longitudinal Survey of Children and Youth Ontario subsample (N=1,317) and the Ontario Student Drug Use and Health Survey (N=9,288).","limitations":"The ADHD sample was drawn from a clinic population, meaning these youth were receiving care and may not represent all adolescents with ADHD. The comparison groups came from different surveys with different methodologies and age ranges. The cross-sectional design cannot track whether ADHD youth develop higher substance use rates later in adolescence or adulthood."},{"rthcId":"RTHC-00846","title":"Marijuana: respiratory tract effects.","authors":"Owen, Kelly P; Sutter, Mark E; Albertson, Timothy E","year":2014,"journal":"Clinical reviews in allergy & immunology, 46(1), 65-81","doi":"10.1007/s12016-013-8374-y","pmid":"23715638","tags":["respiratory","cancer","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review found that marijuana smoke produces respiratory symptoms similar to tobacco: increased cough, sputum production, hyperinflation, and upper lobe emphysematous changes. However, at the time of publication, the evidence did not support a link between marijuana smoking and the development of COPD.\n\nThe cancer evidence was mixed. Some studies suggested marijuana smoke increases risk for head and neck squamous cell carcinoma, lung cancer, prostate cancer, and cervical cancer, while others found protective effects against malignancy. The carcinogenic effects remained unclear.\n\nMarijuana smoke was shown to inhibit immune function, which has dual implications: it could impair defense against infection but also suggests therapeutic potential for autoimmune conditions. The authors noted that as legalization expands and alternative consumption methods (edibles, beverages) become common, most existing research on smoked marijuana may not apply to these newer products.","whyItMatters":"As marijuana legalization expands, understanding its respiratory effects is critical for public health guidance. The distinction between marijuana and tobacco in terms of COPD risk, and the unclear cancer evidence, complicates the messaging around marijuana smoking and health.","specificNumbers":"Marijuana is the most commonly used drug of abuse in the US. The review covers effects on cough, sputum, hyperinflation, emphysema, COPD, multiple cancer types, and immune function.","methodology":"This is a narrative review examining the respiratory tract effects of marijuana. The authors synthesized evidence from epidemiological studies, physiological research, and clinical observations covering pulmonary function, cancer risk, and immune effects.","limitations":"This is a narrative review, not a systematic review, so study selection may be incomplete or biased. Most research examined whole marijuana smoke rather than THC or CBD specifically. Many studies had small sample sizes or inadequate controls for tobacco co-use. The research was conducted before widespread legalization changed use patterns."},{"rthcId":"RTHC-00847","title":"Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum.","authors":"Palomino, Ana; Pavón, Francisco-Javier; Blanco-Calvo, Eduardo; Serrano, Antonia; Arrabal, Sergio; Rivera, Patricia; Alén, Francisco; Vargas, Antonio; Bilbao, Ainhoa; Rubio, Leticia; Rodríguez de Fonseca, Fernando; Suárez, Juan","year":2014,"journal":"Frontiers in integrative neuroscience, 8, 22","doi":"10.3389/fnint.2014.00022","pmid":"24634647","tags":["neuroscience","addiction","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Acute cocaine exposure decreased DAGLa expression in the cerebellum, suggesting reduced production of the endocannabinoid 2-AG. It also decreased gene expression of tyrosine hydroxylase, glutaminase, a metabotropic glutamate receptor, and all ionotropic glutamate receptor subunits analyzed.\n\nRepeated cocaine exposure, which led to conditioned locomotion and sensitization, produced a different pattern: an increased NAPE-PLD/FAAH ratio (suggesting enhanced anandamide production) and a decreased DAGLb/MAGL ratio (suggesting reduced 2-AG). Repeated exposure also increased glutaminase expression but normalized glutamate receptor levels.\n\nThese findings indicate that the cerebellum, traditionally viewed as a motor coordination center, undergoes significant neurochemical changes during cocaine exposure that may contribute to the addiction process.","whyItMatters":"The cerebellum is increasingly recognized as playing a role in addiction beyond its traditional motor functions. This study maps out how cocaine reshapes two key signaling systems in this brain region, providing molecular targets that could help explain the cerebellum's contribution to addictive behaviors.","specificNumbers":"Acute cocaine: decreased DAGLa, TH, KGA, mGluR3, and all ionotropic receptor subunits. Repeated cocaine: increased NAPE-PLD/FAAH ratio, decreased DAGLb/MAGL ratio, increased LGA expression, normalized glutamate receptors.","methodology":"Mice received either acute or repeated cocaine injections. After treatment, cerebellar tissue was analyzed for gene and protein expression of endocannabinoid system components (CB1 receptors, synthesizing enzymes DAGLa/b and NAPE-PLD, degrading enzymes MAGL and FAAH) and glutamate system components (glutaminase isoforms, metabotropic and ionotropic receptors). Tyrosine hydroxylase expression was also measured.","limitations":"This was a mouse study, and cerebellar neurochemistry may differ in humans. Gene and protein expression changes do not necessarily translate to functional changes. The cocaine doses and schedules used may not reflect human exposure patterns. The study did not assess whether the cerebellar changes are necessary for addiction-related behaviors."},{"rthcId":"RTHC-00848","title":"Effects of cannabis on cognition in patients with MS: a psychometric and MRI study.","authors":"Pavisian, Bennis; MacIntosh, Bradley J; Szilagyi, Greg; Staines, Richard W; O'Connor, Paul; Feinstein, Anthony","year":2014,"journal":"Neurology, 82(21), 1879-87","doi":"10.1212/WNL.0000000000000446","pmid":"24789863","tags":["cognition","medical-cannabis","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Compared to matched MS patients who did not use cannabis, cannabis-using MS patients performed significantly worse on two cognitive measures: the more demanding version of the Paced Auditory Serial Addition Test (processing speed) and the 10/36 Spatial Recall Test (visual memory).\n\nOn fMRI during a working memory task, cannabis users showed more diffuse cerebral activation across all difficulty levels and made more errors on the most demanding task. During the hardest condition, cannabis users showed increased activation in parietal and anterior cingulate regions involved in working memory, suggesting they needed to recruit more brain resources to attempt the same tasks.\n\nNo group differences were found in resting-state brain networks or structural MRI measures (lesion volumes, brain tissue volumes, or white matter integrity), meaning the functional differences were not explained by greater structural brain damage in cannabis users.","whyItMatters":"MS already compromises cognitive function through brain inflammation and damage. This study suggests cannabis use may compound these cognitive problems by further disrupting the brain's compensatory mechanisms. For MS patients considering cannabis for symptom management, these cognitive trade-offs are important to understand.","specificNumbers":"20 cannabis users and 19 non-users with MS. Cannabis users performed worse on PASAT 2-second (p<0.02) and 10/36 Spatial Recall (p<0.03). More errors on 2-Back task (p<0.006). Increased parietal (p<0.007) and anterior cingulate (p<0.001) activation during demanding working memory tasks.","methodology":"Twenty MS patients who smoked cannabis and 19 non-using MS patients, matched on demographic and neurological variables, underwent fMRI during a working memory task (N-Back), resting-state fMRI, and structural MRI (including diffusion tensor imaging). A comprehensive neuropsychological battery assessed verbal memory, visual memory, processing speed, and attention.","limitations":"This was a cross-sectional study, so it cannot determine whether cannabis caused the cognitive differences or whether individuals with more cognitive difficulties were more likely to use cannabis. The cannabis users were assessed in an unintoxicated state, but chronic effects may differ from acute effects. The sample size was small (20 users, 19 non-users)."},{"rthcId":"RTHC-00849","title":"An examination of the validity of the standardized field sobriety test in detecting drug impairment using data from the Drug Evaluation and Classification program.","authors":"Porath-Waller, Amy J; Beirness, Douglas J","year":2014,"journal":"Traffic injury prevention, 15(2), 125-31","doi":"10.1080/15389588.2013.800638","pmid":"24345013","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"All drug categories, including cannabis, were significantly associated with impaired performance on standardized field sobriety tests. On the One Leg Stand test, users of all drug classes were significantly more likely to sway while balancing and use their arms for balance compared to drug-free individuals.\n\nCannabis users showed distinct patterns of impairment across the three test components. CNS depressant users showed the most impairment on the Horizontal Gaze Nystagmus test (lack of smooth pursuit and nystagmus at maximum deviation). On the Walk and Turn test, depressant, stimulant, and narcotic users had more difficulty maintaining balance during instructions.\n\nInterestingly, drug-impaired individuals were significantly less likely to hop during the One Leg Stand test, suggesting they compensated by keeping their foot down rather than attempting more complex balance maneuvers.","whyItMatters":"As cannabis-impaired driving becomes a growing concern with legalization, law enforcement needs validated tools for detecting impairment. This study provides evidence that standard field sobriety tests, originally developed for alcohol, can also detect cannabis-related impairment, though the patterns differ from alcohol impairment.","specificNumbers":"2,142 DEC evaluations analyzed. Drug categories: CNS stimulants, CNS depressants, narcotic analgesics, cannabis, and drug-free. All categories showed significant impairment on at least one SFST component.","methodology":"Researchers analyzed data from 2,142 completed Drug Evaluation and Classification (DEC) evaluations. These evaluations are conducted by specially trained Drug Recognition Experts on suspected drug-impaired drivers. Performance on the three SFST components (Horizontal Gaze Nystagmus, One Leg Stand, Walk and Turn) was compared across users of CNS stimulants, CNS depressants, narcotic analgesics, cannabis, and drug-free cases using multinomial logistic regression.","limitations":"The data came from DEC evaluations of individuals already suspected of impairment, introducing selection bias. The study could not assess sensitivity (how many impaired drivers pass the tests) or specificity in naturalistic settings. Cannabis was often used alongside other substances, making it difficult to isolate its specific effects. The study did not correlate SFST performance with THC blood levels."},{"rthcId":"RTHC-00850","title":"A review of the cultivation and processing of cannabis (Cannabis sativa L.) for production of prescription medicines in the UK.","authors":"Potter, David J","year":2014,"journal":"Drug testing and analysis, 6(1-2), 31-8","doi":"10.1002/dta.1531","pmid":"24115748","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis is an extremely inhomogeneous raw material, with cannabinoid ratios affected by genetics, growing conditions, storage conditions, maturity at harvest, and processing methods. GW Pharmaceuticals had to develop comprehensive quality control systems across all these variables to produce Sativex, the first cannabis-based medicine approved in the UK.\n\nThe company developed specific cannabis chemotypes (chemical varieties) to produce consistent THC and CBD ratios. The botanical considerations are particularly challenging because cannabinoid content varies across different parts of the plant, changes with maturity, and is affected by environmental conditions during growth.\n\nSativex was approved for treating spasticity due to multiple sclerosis and contains both THC and CBD along with other plant constituents. The pharmaceutical standardization process described represents a significant departure from the variability inherent in recreational or even most medical cannabis products.","whyItMatters":"The gap between recreational/medical cannabis products and pharmaceutical-grade cannabis medicines is enormous in terms of consistency and quality control. Understanding the challenges of standardizing cannabis helps explain why pharmaceutical development is difficult and why product-to-product variability remains a concern in the broader cannabis market.","specificNumbers":"Sativex contains both THC and CBD. It was the first cannabis-based medicine approved in the UK for MS spasticity. Cannabis contains over 100 cannabinoids whose ratios must be controlled.","methodology":"This is a descriptive review authored by a GW Pharmaceuticals researcher, detailing the company's approach to cultivating and processing cannabis for pharmaceutical use. It covers botanical considerations, genetic selection, growing protocols, harvesting, and quality control processes.","limitations":"This review is written by a GW Pharmaceuticals employee and describes the company's proprietary methods. It is inherently promotional and does not compare their approach to alternative manufacturing methods. The focus is on process rather than clinical efficacy."},{"rthcId":"RTHC-00851","title":"Functional connectivity alterations in brain networks relevant to self-awareness in chronic cannabis users.","authors":"Pujol, Jesus; Blanco-Hinojo, Laura; Batalla, Albert; López-Solà, Marina; Harrison, Ben J; Soriano-Mas, Carles; Crippa, Jose A; Fagundo, Ana B; Deus, Joan; de la Torre, Rafael; Nogué, Santiago; Farré, Magí; Torrens, Marta; Martín-Santos, Rocío","year":2014,"journal":"Journal of psychiatric research, 51, 68-78","doi":"10.1016/j.jpsychires.2013.12.008","pmid":"24411594","tags":["neuroscience","cognition","anxiety","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Compared to 29 controls, 28 heavy cannabis users showed increased functional connectivity within the core of the Default Mode Network and Insula Network, and enhanced anticorrelation between these two networks. These networks are central to self-awareness, internal thought, and emotional processing.\n\nThe connectivity changes were associated with behavioral measures in two directions: they correlated with reduced anxiety scores but also with impaired memory performance. The alterations were related to the amount of cannabis used.\n\nCritically, the brain connectivity changes partially persisted after one month of controlled abstinence, suggesting some effects of chronic cannabis use on self-awareness networks are not immediately reversible.","whyItMatters":"This study provides a neurobiological framework for understanding why people use cannabis recreationally: it alters the brain networks that generate self-awareness and process emotions, potentially reducing negative affect. However, the same changes appear to interfere with memory encoding, revealing a neural mechanism for the trade-off between emotional relief and cognitive cost.","specificNumbers":"28 heavy cannabis users and 29 controls. Two fMRI scans for cannabis users: during active use and after 1 month abstinence. Changes were dose-dependent and partially persisted after abstinence.","methodology":"Functional connectivity was assessed using resting-state fMRI in 28 heavy cannabis users and 29 control subjects. Cannabis users were scanned twice: during active use (in an unintoxicated state) and after one month of controlled abstinence. Behavioral measures included anxiety ratings and memory performance tests.","limitations":"The sample size was modest (28 users, 29 controls). The cross-sectional component cannot determine whether brain differences predated cannabis use. One month of abstinence may not be long enough to fully assess reversibility. Cannabis users may have differed from controls on unmeasured variables."},{"rthcId":"RTHC-00852","title":"Effects of hemp (Cannabis sativa L.) seed oil press-cake and decaffeinated green tea leaves (Camellia sinensis) on functional characteristics of gluten-free crackers.","authors":"Radočaj, Olga; Dimić, Etelka; Tsao, Rong","year":2014,"journal":"Journal of food science, 79(3), C318-25","doi":"10.1111/1750-3841.12370","pmid":"24527987","tags":["cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"All crackers containing hemp flour showed substantially better nutritional profiles compared to brown rice flour controls. Fiber content increased by 39% to 249%, carbohydrate content decreased by 8.4% to 42.3%, and protein levels were elevated.\n\nThe optimized formulation (20% hemp flour with 4g decaffeinated green tea leaves) provided: 14.1g protein per 100g, 8.4g fiber per 100g, and 3.2g omega-3 fatty acids per 100g. Adding green tea leaves further improved antioxidant properties.\n\nAll crackers, even those without green tea, showed antioxidant properties. The hemp-enriched crackers maintained acceptable sensory qualities, with an overall score of 8.9 in the optimized formulation.","whyItMatters":"The gluten-free market continues to grow, but many gluten-free products are nutritionally inferior to their wheat-based counterparts, particularly in fiber and protein. Hempseed press-cake, a by-product of oil production, offers a way to substantially improve the nutritional quality of gluten-free baked goods.","specificNumbers":"Optimized formulation: 20% hemp flour, 4g green tea leaves. Results: protein 14.1g/100g, fiber 8.4g/100g, omega-3 3.2g/100g, antioxidant activity 30.3 umol TE/g, overall score 8.9. Fiber increase: 39-249% over control.","methodology":"A mixture simplex centroid experimental design with two components was used. Researchers varied the proportions of hempseed oil press-cake and decaffeinated green tea leaves added to a brown rice flour base. Nutritional composition, antioxidant activity (DPPH assay), fatty acid profiles, mineral content, and sensory evaluation were assessed across all formulations.","limitations":"This was a laboratory formulation study, not a clinical trial measuring health outcomes. Consumer acceptance was based on limited sensory evaluation, not market testing. The optimal formulation may need adjustment for commercial production. Long-term storage stability was not assessed."},{"rthcId":"RTHC-00853","title":"Young adults who smoke cigarettes and marijuana: analysis of thoughts and behaviors.","authors":"Ramo, Danielle E; Delucchi, Kevin L; Liu, Howard; Hall, Sharon M; Prochaska, Judith J","year":2014,"journal":"Addictive behaviors, 39(1), 77-84","doi":"10.1016/j.addbeh.2013.08.035","pmid":"24090626","tags":["addiction","quitting","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 1,987 young adult cigarette smokers surveyed, nearly half (972) also reported past-month marijuana use. Among these dual users, frequency of use, temptation to use, measures of dependence, decisional balance (pros and cons), and past-year quit attempts were all significantly correlated between cigarettes and marijuana.\n\nHowever, motivation to quit was not correlated across substances. Participants reported greater desire and more advanced stages of change for quitting cigarettes compared to marijuana. They were more likely to endorse a cigarette abstinence goal. Paradoxically, they had lower confidence in their ability to quit and stay quit from cigarettes compared to marijuana.\n\nThis pattern suggests young adults view cigarettes as more problematic and are more open to quitting tobacco, even though they expect it to be harder.","whyItMatters":"The high rate of co-use among young adults means treatment programs need to consider both substances. The finding that motivation differs across substances suggests intervention approaches may need to be tailored: young adults may be more receptive to tobacco cessation messaging while viewing marijuana use as less problematic.","specificNumbers":"972 of 1,987 young adult smokers (49%) also used marijuana. 68% male, 71% Caucasian, mean age 20.4. Use frequency, dependence, and quit attempts were correlated across substances (all p<0.05). Motivation to quit was not correlated.","methodology":"Young adults aged 18-25 who had smoked at least one cigarette in the past 30 days completed an anonymous online survey. Of 1,987 respondents, 972 reported both past-month cigarette and marijuana use. Measures included frequency and severity of use, temptations, dependence, decisional balance, stage of change, quit attempts, and abstinence expectations for each substance.","limitations":"This was a cross-sectional online survey, subject to self-selection bias. The sample skewed male and Caucasian. Self-reported substance use may be inaccurate. The survey recruited cigarette smokers, so it cannot generalize to all young adult marijuana users. Causal relationships between cigarette and marijuana use patterns cannot be determined."},{"rthcId":"RTHC-00854","title":"THC:CBD spray and MS spasticity symptoms: data from latest studies.","authors":"Rekand, Tiina","year":2014,"journal":"European neurology, 71 Suppl 1, 4-9","doi":"10.1159/000357742","pmid":"24457846","tags":["medical-cannabis","cbd","pain","cognition","driving"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"A randomized, placebo-controlled long-term trial demonstrated that THC:CBD spray (Sativex) was not associated with cognitive decline, depression, or significant mood changes after 12 months of treatment. This addressed a key concern about long-term cannabinoid therapy.\n\nA prospective observational pilot study of 33 patients (ages 33-68) found that Sativex did not adversely influence standard driving ability in patients with moderate to severe MS spasticity.\n\nPatient registry data from the UK, Germany, and Spain reinforced the efficacy and safety observed in Phase III trials. Notably, patients in real-world practice used lower average doses than those in clinical studies (5-6.4 vs. >8 sprays/day), and effectiveness was maintained. In the German/UK registry, 45% of patients had been treated for over 2 years with no additional safety concerns identified.","whyItMatters":"Long-term safety data is essential for medicines used to treat chronic conditions like MS spasticity. The absence of cognitive decline after 12 months and the lack of driving impairment are reassuring findings for patients and prescribers concerned about chronic cannabinoid use.","specificNumbers":"Over 1,000 additional patients studied. No cognitive decline at 12 months. Driving not impaired in 33-patient pilot. Real-world dosing: 5-6.4 sprays/day (vs. >8 in trials). 45% of registry patients treated for >2 years.","methodology":"This is a review of multiple new data sources available in 2013: a randomized placebo-controlled long-term follow-up trial, a prospective observational driving study, and patient registries from the UK, Germany, and Spain. Together, these sources covered approximately 1,000 additional patients beyond the original Phase III trials.","limitations":"The driving study was a small pilot (n=33). Registry data is observational and subject to selection bias (patients who continue medication may be those who tolerate it well). The cognitive study assessed specific standardized measures and may not capture all aspects of cognitive function. The review was published in a supplement likely supported by the manufacturer."},{"rthcId":"RTHC-00855","title":"Marijuana use and maternal experiences of severe nausea during pregnancy in Hawai'i.","authors":"Roberson, Emily K; Patrick, Walter K; Hurwitz, Eric L","year":2014,"journal":"Hawai'i journal of medicine & public health : a journal of Asia Pacific Medicine & Public Health, 73(9), 283-7","doi":null,"pmid":"25285255","tags":["pregnancy","appetite"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 4,735 recently pregnant women in Hawaii, 6.0% reported marijuana use in the month before pregnancy and 2.6% reported use during pregnancy. Approximately 21.2% reported severe nausea during pregnancy.\n\nWomen who experienced severe nausea were significantly more likely to report marijuana use during pregnancy compared to those without severe nausea (3.7% vs. 2.3%; prevalence ratio 1.63, 95% CI: 1.08-2.44).\n\nThe study could not determine the direction of this relationship: women may have used marijuana to treat severe nausea, or marijuana use may have contributed to the nausea (as in cannabinoid hyperemesis syndrome), or both could have been driven by other factors.","whyItMatters":"Marijuana has been proposed as a treatment for severe pregnancy nausea (hyperemesis gravidarum), but this creates a clinical dilemma: cannabis use during pregnancy carries potential risks to fetal development. Understanding the relationship between marijuana use and pregnancy nausea is essential for clinical guidance.","specificNumbers":"4,735 respondents. Marijuana use: 6.0% in month before pregnancy, 2.6% during pregnancy. Severe nausea: 21.2%. Women with severe nausea were 63% more likely to use marijuana during pregnancy (PR=1.63, 95% CI: 1.08-2.44).","methodology":"This cross-sectional study used Hawaii Pregnancy Risk Assessment Monitoring System (PRAMS) data from 4,735 respondents, weighted to represent all pregnancies resulting in live births in Hawaii between 2009 and 2011. Self-reported marijuana use (before and during pregnancy) and severe nausea were assessed. Prevalence ratios and 95% confidence intervals were computed.","limitations":"This was a cross-sectional study, so temporal relationships cannot be determined. Self-reported marijuana use during pregnancy is likely underreported due to social desirability and legal concerns. The study could not distinguish between marijuana use for nausea relief versus recreational use that happened to coincide with nausea. Severity of nausea was self-reported."},{"rthcId":"RTHC-00856","title":"Endocannabinoid signaling in hypothalamic-pituitary-adrenocortical axis recovery following stress: effects of indirect agonists and comparison of male and female mice.","authors":"Roberts, Christopher J; Stuhr, Kara L; Hutz, Michael J; Raff, Hershel; Hillard, Cecilia J","year":2014,"journal":"Pharmacology, biochemistry, and behavior, 117, 17-24","doi":"10.1016/j.pbb.2013.11.026","pmid":"24316201","tags":["neuroscience","sex-differences","anxiety"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"After restraint stress, mice lacking CB1 receptors or treated with a CB1 antagonist showed prolonged elevation of corticosterone (the stress hormone), confirming endocannabinoid signaling helps the stress response return to baseline.\n\nThe MAGL inhibitor JZL184 (which increases 2-AG levels) accelerated corticosterone recovery in both male and female mice, though the timing differed: at stress offset in males and at 30 minutes recovery in females. The FAAH inhibitor URB597 (which increases anandamide) had no effect on corticosterone in either sex.\n\nFemale CB1 receptor knockout mice showed compensatory mechanisms not seen in males: they had greater serum corticosterone binding capacity, and their stress hormone levels were normal at 30 minutes (unlike males) but elevated at 90 minutes. This suggests females undergo compensatory adaptations when CB1 signaling is absent from birth.","whyItMatters":"The endocannabinoid system plays a critical role in turning off the stress response. This study identifies 2-AG, rather than anandamide, as the primary endocannabinoid involved and reveals important sex differences in how this system regulates stress hormones. These findings are relevant to understanding stress-related disorders and potential endocannabinoid-based treatments.","specificNumbers":"JZL184 reduced corticosterone at stress offset in males and at 30 min in females. URB597 had no effect in either sex. Male CB1 knockout mice had elevated corticosterone at 30 min. Female knockouts showed elevation at 90 min but not 30 min.","methodology":"Male and female wild-type and CB1 receptor knockout mice were subjected to restraint stress. Blood samples were collected at multiple time points during recovery. Some mice were pre-treated with rimonabant (CB1 antagonist), JZL184 (MAGL inhibitor), or URB597 (FAAH inhibitor). Corticosterone levels were measured by immunoassay. Serum binding capacity was assessed in knockout mice.","limitations":"This was a mouse study using pharmacological and genetic tools. The restraint stress model may not fully represent human stress experiences. Drug doses and timing were specific to the experimental protocol. Sex differences observed in knockout mice may reflect developmental compensation rather than acute sex-dependent mechanisms."},{"rthcId":"RTHC-00857","title":"Cannabinoids and schizophrenia: therapeutic prospects.","authors":"Robson, P J; Guy, G W; Di Marzo, V","year":2014,"journal":"Current pharmaceutical design, 20(13), 2194-204","doi":null,"pmid":"23829368","tags":["psychosis","cbd","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Standard antipsychotic drugs fail to adequately control symptoms in approximately one-third of schizophrenia patients. The review presents evidence that certain non-intoxicating phytocannabinoids, particularly CBD, have emerged as potential antipsychotic agents in both preclinical and clinical models.\n\nUnlike current antipsychotics that work by blocking dopamine D2 receptors, CBD's mechanism of action appears to be different, making synergistic combinations with existing medications theoretically possible. The endocannabinoid system is involved in emotion regulation, reward processing, sleep, stress response, and metabolic function, all of which are disrupted in schizophrenia.\n\nThe review also highlights that schizophrenia is associated with metabolic abnormalities, chronic inflammation, and HPA axis dysregulation. CBD has established anti-inflammatory and immunomodulatory effects that could potentially address these associated features beyond just psychotic symptoms.","whyItMatters":"Treatment-resistant schizophrenia remains a major clinical challenge. If CBD can augment existing antipsychotics through a non-dopaminergic mechanism while also addressing the metabolic and inflammatory components of the disease, it could represent a fundamentally new therapeutic approach.","specificNumbers":"Approximately one-third of schizophrenia patients do not achieve adequate symptom control with standard antipsychotics. The review covers THC (pro-psychotic) versus CBD (potentially antipsychotic) effects.","methodology":"This is a narrative review synthesizing preclinical and clinical data on cannabinoids in schizophrenia. It covers the role of the endocannabinoid system in mental health, the metabolic and inflammatory components of schizophrenia, and preliminary data on CBD as an antipsychotic agent.","limitations":"Clinical evidence for CBD as an antipsychotic was preliminary at the time of publication. The proposed combination therapy (CBD plus CB1 neutral antagonist plus standard antipsychotic) had not been tested in clinical trials. The review is primarily theoretical, building on preclinical data and limited clinical observations."},{"rthcId":"RTHC-00858","title":"Therapeutic potential of cannabinoid medicines.","authors":"Robson, P J","year":2014,"journal":"Drug testing and analysis, 6(1-2), 24-30","doi":"10.1002/dta.1529","pmid":"24006213","tags":["medical-cannabis","cbd","pain","epilepsy","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review covers the endocannabinoid system's role in immune response, appetite, cognition, emotion, perception, motor coordination, body temperature, sleep, and bone metabolism. THC and CBD have contrasting pharmacological profiles: THC activates cannabinoid receptors producing both therapeutic and intoxicating effects, while CBD modulates the system without intoxication.\n\nThe strongest clinical evidence existed for MS spasticity (Sativex), chronic neuropathic pain, and chemotherapy-induced nausea and vomiting. Emerging areas of research included epilepsy, psychosis, addiction, and metabolic disorders.\n\nThe review also considers the risks of drugs that inhibit the endocannabinoid system (like the withdrawn weight-loss drug rimonabant, which caused serious psychiatric side effects), demonstrating that both enhancing and suppressing this system carries therapeutic potential and risk.","whyItMatters":"This review provides a comprehensive overview of the state of cannabinoid medicine as of 2014, capturing a critical inflection point when cannabis-based medicines were transitioning from fringe therapies to regulated pharmaceuticals. It frames the therapeutic landscape that would continue to develop over the following decade.","specificNumbers":"Indications reviewed: MS spasticity, neuropathic pain, nausea/vomiting, appetite/weight (cancer/AIDS), psychosis, epilepsy, addiction, metabolic disorders. Key contrast: THC (intoxicating, receptor agonist) vs. CBD (non-intoxicating, modulatory).","methodology":"This is a narrative review of clinical research on cannabinoid medicines. It covers the pharmacology of THC and CBD, the endocannabinoid system, and clinical evidence across multiple indications. The review was published alongside related papers on cannabis cultivation and pharmaceutical development.","limitations":"This is a narrative review that predates many of the definitive clinical trials in cannabinoid medicine. The evidence base was still developing for most indications. The review was published in a journal focused on drug testing, and the selection of evidence may not be comprehensive."},{"rthcId":"RTHC-00859","title":"Neuroinflammation as a possible link between cannabinoids and addiction.","authors":"Rodrigues, Livia C M; Gobira, Pedro H; de Oliveira, Antonio Carlos; Pelição, Renan; Teixeira, Antonio Lucio; Moreira, Fabricio A; Campos, Alline Cristina","year":2014,"journal":"Acta neuropsychiatrica, 26(6), 334-46","doi":"10.1017/neu.2014.24","pmid":"25455257","tags":["neuroscience","addiction","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review synthesized evidence from 165 articles showing that substance dependence is accompanied by both changes in endocannabinoid signaling and activation of neuroinflammatory processes. Specifically, disruption of cannabinoid signaling during addiction appears to lead to microglial activation (the brain's immune cells becoming active) and increased production of inflammatory cytokines.\n\nEndocannabinoids normally act as immunomodulators by inhibiting cytokine production and microglial activation. When addiction disrupts this system, the resulting loss of anti-inflammatory endocannabinoid tone may contribute to the neuroinflammation observed in chronic substance users.\n\nThe review proposes that cannabinoids could potentially treat addiction in part through their anti-inflammatory and neuroprotective properties, though this remains theoretical.","whyItMatters":"If neuroinflammation is a meaningful component of addiction pathology, then anti-inflammatory interventions could represent a new therapeutic approach. The endocannabinoid system sits at the intersection of inflammation and reward processing, making it a uniquely positioned therapeutic target.","specificNumbers":"165 articles reviewed. Evidence covered: microglial activation, cytokine changes, endocannabinoid signaling disruption, and interactions between these systems during drug addiction.","methodology":"An evidence-based review of the literature was conducted, searching PubMed and BioMedCentral databases up to April 2014 with no date restrictions using the terms addiction, cannabinoids, and inflammation. 165 eligible articles were included.","limitations":"The evidence is largely correlational and preclinical. It remains uncertain whether endocannabinoid changes and neuroinflammation are causally or coincidentally associated with addiction. Human data is limited. The theoretical framework connecting these systems has not been validated through clinical intervention studies."},{"rthcId":"RTHC-00860","title":"Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado.","authors":"Salomonsen-Sautel, Stacy; Min, Sung-Joon; Sakai, Joseph T; Thurstone, Christian; Hopfer, Christian","year":2014,"journal":"Drug and alcohol dependence, 140, 137-44","doi":"10.1016/j.drugalcdep.2014.04.008","pmid":"24831752","tags":["driving","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using federal crash data from 1994 to 2011, researchers found a significant positive trend in the proportion of drivers in fatal crashes who tested positive for marijuana in Colorado after mid-2009, when commercial medical marijuana became widely available. The change in trend was statistically significant (change = 2.16, p<0.0001).\n\nIn contrast, 34 states without medical marijuana laws showed no significant changes in marijuana-positive fatal crash drivers during the same period. Neither Colorado nor the comparison states showed significant changes in alcohol-impaired fatal crash proportions.\n\nThe study defined the pre-commercial period as 1994 to June 2009 and the post-commercial period as July 2009 to 2011, using 36 six-month intervals.","whyItMatters":"This was among the first studies to examine the impact of marijuana commercialization on traffic safety using federal crash data. The finding of increased marijuana-positive fatal crashes after dispensary expansion raised important public health and policy concerns about marijuana legalization and driving safety.","specificNumbers":"Data: 36 six-month intervals (1994-2011). Change in trend after mid-2009: 2.16 (SE 0.45, p<0.0001) for marijuana-positive drivers in Colorado. No significant change in 34 comparison states. No significant change in alcohol-impaired proportions in either group.","methodology":"Researchers analyzed data from the Fatality Analysis Reporting System (FARS) across 36 six-month intervals from 1994 to 2011. They compared temporal changes in the proportions of drivers in fatal crashes who were marijuana-positive and alcohol-impaired in Colorado versus 34 non-medical marijuana states. Statistical analysis used interrupted time series methods to detect changes in trends.","limitations":"Testing positive for marijuana does not equal impairment at the time of the crash. THC metabolites can be detected days or weeks after use. Testing protocols varied across jurisdictions and over time. Not all fatally injured drivers were tested for marijuana, and testing rates may have increased after commercialization (detection bias). The study could not determine whether marijuana was a causal factor in the crashes."},{"rthcId":"RTHC-00861","title":"Proximal and distal social influence on alcohol consumption and marijuana use among middle school adolescents.","authors":"Salvy, Sarah-Jeanne; Pedersen, Eric R; Miles, Jeremy N V; Tucker, Joan S; D'Amico, Elizabeth J","year":2014,"journal":"Drug and alcohol dependence, 144, 93-101","doi":"10.1016/j.drugalcdep.2014.08.012","pmid":"25195080","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"All three sources of social influence, perceived peer norms, best friend use, and being around users, predicted both alcohol and marijuana consumption across the middle school years. However, their relative importance shifted with age.\n\nFor younger adolescents, perceived norms (beliefs about how many peers use substances) were strong predictors of use. As students progressed through middle school, the influence of perceived norms declined while the influence of actually being around peers who use substances increased.\n\nThere was also an interaction effect: when adolescents spent more time around peers who drink, the predictive value of perceived norms on alcohol consumption decreased further. For marijuana, best friend use and direct exposure maintained stable influence over time while perceived norms became less important.","whyItMatters":"Understanding how social influence on substance use evolves across adolescence has direct implications for prevention program design. Programs targeting younger teens should focus on correcting norm misperceptions, while programs for older teens should emphasize refusal skills and strategies for navigating social situations involving substance use.","specificNumbers":"11,667 adolescents from 16 schools, 5 time points (2008-2011). All three social influence sources predicted alcohol and marijuana use. Perceived norms became less influential with age while direct peer exposure became more influential.","methodology":"The study followed 11,667 adolescents (50% female, >65% Hispanic) in 6th, 7th, and 8th grades from 16 middle schools across three Southern California school districts. Participants were assessed at 5 time points from 2008 to 2011. The analysis examined three sources of social influence on alcohol and marijuana use: perceived peer norms, best friend use, and presence of substance-using peers.","limitations":"The sample was predominantly Hispanic from Southern California, which may limit generalizability. Self-reported substance use may be inaccurate. The study examined marijuana and alcohol but did not assess other substances. The observational design cannot establish whether peer influence causes substance use or whether substance-using teens select peers who also use."},{"rthcId":"RTHC-00862","title":"The dual FAAH/MAGL inhibitor JZL195 has enhanced effects on endocannabinoid transmission and motor behavior in rats as compared to those of the MAGL inhibitor JZL184.","authors":"Seillier, Alexandre; Dominguez Aguilar, David; Giuffrida, Andrea","year":2014,"journal":"Pharmacology, biochemistry, and behavior, 124, 153-9","doi":"10.1016/j.pbb.2014.05.022","pmid":"24911644","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"JZL184, a selective MAGL inhibitor, was able to elevate brain 2-AG levels in rats, contrary to some previous reports suggesting it was ineffective in this species. However, the motor suppression caused by JZL184 was found to operate through a CB1-independent mechanism.\n\nThe dual FAAH/MAGL inhibitor JZL195 produced enhanced effects compared to JZL184 alone, simultaneously elevating both anandamide (via FAAH inhibition) and 2-AG (via MAGL inhibition) in the brain. Its behavioral effects, including motor suppression, were more robust than JZL184.\n\nThe finding that JZL184's behavioral effects in rats were CB1-independent is notable, as its effects in mice are CB1-dependent, highlighting important species differences in endocannabinoid pharmacology.","whyItMatters":"Understanding species differences in endocannabinoid pharmacology is critical for translating preclinical findings to humans. The rat is generally considered more predictive of human drug responses than the mouse, so clarifying how endocannabinoid-targeting drugs work in rats is essential for drug development.","specificNumbers":"JZL184 elevated 2-AG in rat brain but its motor effects were CB1-independent. JZL195 elevated both anandamide and 2-AG and produced enhanced behavioral effects. Species differences noted between rat and mouse responses.","methodology":"Researchers compared the neurochemical and behavioral effects of JZL184 (MAGL inhibitor) and JZL195 (dual FAAH/MAGL inhibitor) in rats. Brain endocannabinoid levels were measured after systemic drug administration. Behavioral assessments focused on motor activity. CB1 receptor involvement was tested using antagonist pre-treatment.","limitations":"This was an animal study with limited behavioral measures (primarily motor activity). The CB1-independent mechanism of JZL184 in rats was not fully characterized. The doses used may not be directly relevant to human pharmacology. The study focused on acute administration and did not assess chronic effects."},{"rthcId":"RTHC-00863","title":"A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment.","authors":"Serpell, M; Ratcliffe, S; Hovorka, J; Schofield, M; Taylor, L; Lauder, H; Ehler, E","year":2014,"journal":"European journal of pain (London, England), 18(7), 999-1012","doi":"10.1002/j.1532-2149.2013.00445.x","pmid":"24420962","tags":["pain","medical-cannabis","cbd","sleep"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"At the 30% pain reduction threshold (considered clinically meaningful), significantly more patients on THC/CBD spray achieved this target compared to placebo (p=0.034). The mean pain score reduction was numerically larger in the THC/CBD group but did not reach statistical significance on the continuous measure.\n\nSecondary outcomes provided additional support: sleep quality improved significantly in the THC/CBD group (p=0.0072), and patients rated their overall condition as significantly more improved on the Subject Global Impression of Change (p=0.023).\n\nImportantly, these patients had peripheral neuropathic pain with allodynia (pain from normally non-painful touch) and were already on analgesic therapy, making them a treatment-resistant population where any additional benefit is clinically relevant.","whyItMatters":"Peripheral neuropathic pain with allodynia is notoriously difficult to treat. Current medications provide inadequate relief for many patients. This trial demonstrates that THC/CBD spray can provide meaningful additional pain relief in a subset of otherwise treatment-resistant patients.","specificNumbers":"303 screened, 246 randomized (128 THC/CBD, 118 placebo). 30% responder rate: significant (p=0.034, 95% CI: 1.05-3.70). Sleep quality: significant (p=0.0072). SGIC: significant (p=0.023). Mean pain score change: not significant.","methodology":"This 15-week randomized, double-blind, placebo-controlled parallel group study enrolled 303 patients with peripheral neuropathic pain and allodynia. 128 received THC/CBD spray and 118 received placebo as add-on therapy to their current analgesic regimen. Co-primary endpoints were the 30% responder rate and mean change in pain scores on a 0-10 numerical rating scale.","limitations":"The mean pain score change was not statistically significant, with only the responder analysis reaching significance. This suggests the benefit is concentrated in a subgroup rather than uniform across all patients. The 15-week duration may not capture long-term effects. The relatively high placebo response rate reduced the apparent treatment effect."},{"rthcId":"RTHC-00864","title":"Cannabis use by individuals with multiple sclerosis: effects on specific immune parameters.","authors":"Sexton, Michelle; Cudaback, Eiron; Abdullah, Rehab A; Finnell, John; Mischley, Laurie K; Rozga, Mary; Lichtman, Aron H; Stella, Nephi","year":2014,"journal":"Inflammopharmacology, 22(5), 295-303","doi":"10.1007/s10787-014-0214-z","pmid":"25135301","tags":["medical-cannabis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Monocyte migration (a measure of immune cell movement) was similarly inhibited by phytocannabinoids in samples from both MS patients and healthy controls, suggesting cannabis affects this immune parameter equally regardless of MS status.\n\nPlasma levels of two inflammatory markers, CCL2 and IL-17, were reduced in chronic cannabis users compared to non-users across both groups. Since IL-17 is particularly important in MS pathology, this reduction could have therapeutic implications.\n\nAnandamide (AEA) levels were significantly elevated in MS patients compared to controls, regardless of cannabis use. No significant differences were found in other endocannabinoids or signaling lipids. This elevation of anandamide may represent a compensatory response to the inflammatory disease process.","whyItMatters":"MS is an autoimmune disease where the immune system attacks the nervous system. If cannabis affects immune parameters similarly in MS patients and healthy people, this simplifies the interpretation of cannabis effects in MS. The reduction in IL-17, a key driver of MS pathology, is particularly noteworthy.","specificNumbers":"CCL2 and IL-17 reduced in cannabis users in both groups. AEA elevated in MS patients vs. controls regardless of cannabis use. Monocyte migration similarly inhibited by phytocannabinoids in both groups.","methodology":"Subjects with MS and healthy controls were enrolled and matched for age and BMI. Each provided a single blood draw. Researchers measured monocyte migration, plasma endocannabinoid levels, and cytokine levels. Cannabis use status was self-reported. Monocytes were tested for response to a set ratio of phytocannabinoids in vitro.","limitations":"This was a cross-sectional study with a single blood draw, so it cannot assess whether the immune changes are clinically meaningful or sustained. The sample sizes were small. Cannabis use was self-reported and not standardized. The study measured a limited set of immune parameters and cannot characterize the full immunological impact."},{"rthcId":"RTHC-00865","title":"Clinical endocannabinoid deficiency (CECD) revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?","authors":"Smith, Steele Clarke; Wagner, Mark S","year":2014,"journal":"Neuro endocrinology letters, 35(3), 198-201","doi":null,"pmid":"24977967","tags":["medical-cannabis","pain","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review revisits Ethan Russo's 2004 hypothesis that migraine, fibromyalgia, irritable bowel syndrome, and related conditions may share a common underlying cause: deficient endocannabinoid system function. Ten years later, the authors report that subsequent research has supported this concept.\n\nEvidence accumulated since the original proposal showed that cannabinoids can block spinal, peripheral, and gastrointestinal pain mechanisms relevant to these conditions. The list of conditions potentially linked to endocannabinoid deficiency has expanded beyond the original three.\n\nThe authors conclude that clinical experience is bearing out the theoretical framework, and call for more clinical trials to demonstrate the usefulness of medical cannabis for these conditions.","whyItMatters":"If endocannabinoid deficiency is a real clinical entity underlying multiple treatment-resistant conditions, it would provide a unifying explanation for why cannabis helps some patients with migraine, fibromyalgia, and IBS when other treatments have failed.","specificNumbers":"Review covers the decade from 2004-2014. Conditions discussed: migraine, fibromyalgia, irritable bowel syndrome, and a \"growing list\" of other medical conditions.","methodology":"This is a narrative review updating the clinical endocannabinoid deficiency concept proposed in 2004. The authors searched the National Library of Medicine database and other sources for literature published in the decade since the original hypothesis.","limitations":"This is a brief narrative review with apparent advocacy tone. The evidence cited is largely indirect, and no clinical trials specifically tested the endocannabinoid deficiency hypothesis. The review does not critically evaluate contradictory evidence. Measuring clinical endocannabinoid levels remains technically challenging."},{"rthcId":"RTHC-00866","title":"Factors associated with the development of self-harm amongst a socio-economically deprived cohort of adolescents in Santiago, Chile.","authors":"Spears, Melissa; Montgomery, Alan A; Gunnell, David; Araya, Ricardo","year":2014,"journal":"Social psychiatry and psychiatric epidemiology, 49(4), 629-37","doi":"10.1007/s00127-013-0767-y","pmid":"24097260","tags":["youth","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"In a cohort of 2,042 adolescents from socioeconomically deprived areas of Santiago, Chile, the lifetime prevalence of self-harm was 23%. Among those with no self-harm at baseline, 14% developed new self-harm episodes within six months.\n\nIn multivariable analyses controlling for other risk factors, cannabis misuse was independently associated with the onset of self-harm, alongside depressive symptoms, suicidal thoughts, and poor problem-solving skills.\n\nThe prevalence and incidence of self-harm differed substantially by gender, reflecting patterns seen in Western countries where self-harm is more common among females during adolescence.","whyItMatters":"Most research on adolescent self-harm has been conducted in Western, high-income countries. This study provides evidence from a low-income Latin American context, confirming that cannabis misuse is a risk factor for self-harm even in a different cultural and socioeconomic setting.","specificNumbers":"2,042 adolescents, median age 14. Lifetime self-harm prevalence: 23%. 6-month incidence of new self-harm: 14%. Risk factors: depressive symptoms, suicidal thoughts, poor problem-solving, cannabis misuse.","methodology":"This was a prospective cohort study nested within a cluster randomized controlled trial. 2,042 adolescents (median age 14) from deprived areas of Santiago, Chile were followed for 6 months. Self-harm was assessed at baseline and follow-up. Risk factors examined included depressive symptoms, suicidal thoughts, problem-solving skills, substance use, and demographic variables.","limitations":"The study cannot determine whether cannabis misuse causes self-harm or whether both are driven by shared underlying factors. Cannabis misuse was self-reported. The 6-month follow-up period may not capture the full trajectory of self-harm behavior. The sample is specific to low-income areas of Santiago and may not generalize broadly."},{"rthcId":"RTHC-00867","title":"Delta-9-tetrahydrocannabinol disrupts hippocampal neuroplasticity and neurogenesis in trained, but not untrained adolescent Sprague-Dawley rats.","authors":"Steel, Ryan W J; Miller, John H; Sim, Dalice A; Day, Darren J","year":2014,"journal":"Brain research, 1548, 12-9","doi":"10.1016/j.brainres.2013.12.034","pmid":"24398456","tags":["youth","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"When adolescent rats were trained on a spatial learning task while receiving daily THC (6 mg/kg), two key findings emerged. First, training normally increased neuroplasticity markers (PSD95, synapsin-I, synapsin-III) in control animals, but this training-induced increase did not occur in THC-treated animals.\n\nSecond, THC-treated animals that were training showed reduced levels of immature neuronal markers (DCX, PSA-NCAM), but this reduction was not caused by decreased cell division or cell survival. Instead, THC appeared to specifically impair the maturation of new neurons during the learning process.\n\nCritically, none of these effects were seen in untrained THC-treated animals. THC only disrupted brain plasticity in the context of active learning, suggesting it specifically interferes with training-induced adaptive responses rather than causing global neural damage.","whyItMatters":"This study reveals that THC's cognitive effects may be more specific than previously thought. Rather than broadly damaging the brain, THC appears to selectively interfere with the learning-dependent changes in brain structure that normally support memory formation. This has implications for understanding why cannabis affects academic performance in adolescents.","specificNumbers":"THC dose: 6 mg/kg daily, IP. Age: P28-P42 (adolescent). Training increased neuroplasticity markers in controls but not THC-treated rats. THC reduced immature neuron markers only in trained animals. Proliferation (Ki67) and survival (BrdU) were unaffected.","methodology":"Both untrained and trained adolescent Sprague-Dawley rats (P28-P42) received daily THC (6 mg/kg, IP) or vehicle for 15 days. Trained animals performed a spatial learning task. At the mid-training point, hippocampal tissue was analyzed for neuroplasticity markers (CB1R, PSD95, synapsin-I, synapsin-III) and neurogenesis markers (Ki67, DCX, PSA-NCAM, BrdU labeling).","limitations":"This was an animal study using a specific THC dose regimen that may not reflect human use patterns. The mid-training time point provides a snapshot but not the full trajectory of effects. The spatial task used may not capture all forms of learning. Rats were given pure THC, not whole-plant cannabis."},{"rthcId":"RTHC-00868","title":"Cannabis use and first-episode psychosis: relationship with manic and psychotic symptoms, and with age at presentation.","authors":"Stone, J M; Fisher, H L; Major, B; Chisholm, B; Woolley, J; Lawrence, J; Rahaman, N; Joyce, J; Hinton, M; Johnson, S; Young, A H","year":2014,"journal":"Psychological medicine, 44(3), 499-506","doi":"10.1017/S0033291713000883","pmid":"23701858","tags":["psychosis","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In 502 patients with first-episode psychosis tracked across London-based Early Intervention teams, cannabis use level was associated with younger age at presentation to services and with manic symptoms and conceptual disorganization, but not with delusions, hallucinations, negative symptoms, or daily functioning.\n\nThe most striking finding was in the longitudinal data: cannabis users who reduced or stopped their use following initial contact with psychiatric services showed the greatest improvement in symptoms at one year, compared to both continued users and non-users. Continued cannabis users remained more symptomatic than non-users at follow-up.\n\nThis pattern suggests cannabis use actively worsens the course of psychosis and that reducing use leads to better outcomes.","whyItMatters":"This is one of the larger naturalistic studies showing that cannabis reduction after first-episode psychosis is associated with better outcomes. The finding that reducers improved more than non-users suggests cannabis was actively suppressing their recovery, and its removal allowed greater therapeutic gains.","specificNumbers":"502 first-episode psychosis patients. 7 London Early Intervention teams. Cannabis use associated with younger presentation and manic symptoms. Greatest symptom improvement at 1 year in those who reduced/stopped cannabis use.","methodology":"Clinical data on 502 patients with first-episode psychosis were collected from seven London-based Early Intervention in psychosis teams using the MiData audit database. Patients were assessed at entry and after one year using the PANSS (Positive and Negative Syndrome Scale), Young Mania Rating Scale, and Global Assessment of Functioning. Cannabis and other drug use in the preceding 6 months was recorded at both time points.","limitations":"This was a naturalistic observational study, not a randomized trial. Patients who reduced cannabis may have differed from continued users in motivation, disease severity, or other factors. Cannabis use was self-reported. The specific products, potency, and frequency of use were not detailed."},{"rthcId":"RTHC-00869","title":"Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn's disease.","authors":"Storr, Martin; Devlin, Shane; Kaplan, Gilaad G; Panaccione, Remo; Andrews, Christopher N","year":2014,"journal":"Inflammatory bowel diseases, 20(3), 472-80","doi":"10.1097/01.MIB.0000440982.79036.d6","pmid":"24407485","tags":["medical-cannabis","inflammation","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 313 IBD patients surveyed, 17.6% had used cannabis specifically to treat their IBD symptoms, primarily through inhalation (96.4%). These patients reported notable subjective improvements: 83.9% said cannabis improved abdominal pain, 76.8% reported improved cramping, 48.2% noted improved joint pain, and 28.6% reported improved diarrhea.\n\nHowever, the key finding was in outcomes: cannabis use for more than 6 months for IBD symptoms was a strong independent predictor of requiring surgery in Crohn's disease patients (OR = 5.03, 95% CI: 1.45-17.46), even after controlling for demographics, tobacco smoking, time since diagnosis, and biologic medication use.\n\nCannabis use was not a predictor of IBD-related hospitalization in the previous year.","whyItMatters":"This study highlights a critical disconnect between subjective symptom relief and objective disease outcomes. Cannabis may effectively reduce pain and cramping while the underlying disease continues to progress, potentially leading patients to delay or avoid treatments that could prevent the need for surgery.","specificNumbers":"313 IBD patients. 17.6% used cannabis for IBD. Symptom improvement: pain 83.9%, cramping 76.8%, joint pain 48.2%, diarrhea 28.6%. Cannabis >6 months: OR 5.03 for surgery in Crohn's (95% CI: 1.45-17.46).","methodology":"This was a cross-sectional study of 313 consecutive IBD patients seen at the University of Calgary from July 2008 to March 2009. Patients completed a structured anonymous questionnaire covering cannabis use patterns, motivations, and perceived effects. Logistic regression identified predictors of poor outcomes (surgery, hospitalization).","limitations":"This was a cross-sectional study with self-reported data. The association between cannabis use and surgery could reflect confounding by disease severity: patients with more severe disease may be more likely to both use cannabis for symptom relief and eventually require surgery. Cannabis use patterns were not standardized. The sample was from a single center."},{"rthcId":"RTHC-00870","title":"Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.","authors":"Stout, Stephen M; Cimino, Nina M","year":2014,"journal":"Drug metabolism reviews, 46(1), 86-95","doi":"10.3109/03602532.2013.849268","pmid":"24160757","tags":["drug-interactions","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The review identified the specific cytochrome P-450 (CYP-450) enzymes responsible for metabolizing major cannabinoids. THC is primarily metabolized by CYP2C9 and CYP3A4. CBD is metabolized by CYP2C19 and CYP3A4. CBN uses CYP2C9 and CYP3A4. Synthetic cannabinoids JWH-018 and AM2201 use CYP1A2 and CYP2C9.\n\nClinical pharmacogenetic data confirmed CYP2C9 as important for THC metabolism, and a drug interaction study with ketoconazole (a CYP3A4 inhibitor) confirmed CYP3A4's role for both THC and CBD. However, a study with omeprazole suggested CYP2C19 may play a less significant role in CBD metabolism than in vitro data predicted.\n\nOverall, studies of THC, CBD, and CBN inhibition and induction of major CYP-450 enzymes suggested a low risk of clinically significant drug interactions with most use, though the authors noted that specific human data were lacking. Smoked cannabis appeared to induce CYP1A2, which metabolizes theophylline.","whyItMatters":"As cannabis use becomes more common alongside prescription medications, understanding drug interaction potential is essential for patient safety. This review provides the pharmacokinetic foundation for predicting which drug combinations could be problematic.","specificNumbers":"THC: CYP2C9, CYP3A4. CBD: CYP2C19, CYP3A4. CBN: CYP2C9, CYP3A4. JWH-018: CYP1A2, CYP2C9. AM2201: CYP1A2, CYP2C9. Overall drug interaction risk rated as low for most clinical use.","methodology":"This was a systematic review of published data on cannabinoid drug metabolism, including in vitro studies of enzyme substrates, inhibitors, and inducers, pharmacogenetic studies, and clinical pharmacokinetic interaction studies. The review covered both natural cannabinoids (THC, CBD, CBN) and synthetic cannabinoids (JWH-018, AM2201).","limitations":"Most data came from in vitro studies, which may not fully predict in vivo interactions. The low interaction risk assessment was based on limited human data. Cannabinoid doses used in in vitro studies may not reflect clinical concentrations. The review predated the widespread use of high-dose CBD products, which may pose greater interaction risks."},{"rthcId":"RTHC-00871","title":"Immune system: a possible nexus between cannabinoids and psychosis.","authors":"Suárez-Pinilla, Paula; López-Gil, José; Crespo-Facorro, Benedicto","year":2014,"journal":"Brain, behavior, and immunity, 40, 269-82","doi":"10.1016/j.bbi.2014.01.018","pmid":"24509089","tags":["psychosis","inflammation","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The review identified a clear dichotomy: endocannabinoids (produced naturally in the body) generally enhanced immune responses, while exogenous cannabinoids (from cannabis) had immunosuppressant effects. Both types shifted the immune response from Th1 (pro-inflammatory, antiviral) to Th2 (anti-inflammatory, allergic) patterns.\n\nBoth endogenous and synthetic cannabinoids modulated microglial function and neurotransmitter secretion. The peripheral immune effects of cannabinoids were predictable and consistent, but their effects in the central nervous system remained less clear.\n\nThe authors hypothesize that exposure to external cannabinoids during adolescence could trigger immunological dysfunctions that create latent vulnerability to psychosis, providing a biological mechanism linking cannabis use to psychotic disorders.","whyItMatters":"The link between cannabis use and psychosis is well-established epidemiologically, but the biological mechanism has been unclear. This review proposes that the immune system could be the missing link, offering a testable hypothesis for how cannabis exposure, particularly during adolescence, increases psychosis risk.","specificNumbers":"122 articles reviewed from 446 references. Key finding: exogenous cannabinoids are immunosuppressant while endocannabinoids enhance immune response. Both shift immune balance from Th1 to Th2.","methodology":"A comprehensive search of PubMed/MEDLINE, EMBASE, and ISI Web of Knowledge was conducted using combinations of terms related to immune function, cannabinoids, and endocannabinoid receptors. 122 articles were identified from 446 references. Studies were included if they reported quantitative or qualitative relationships between cannabinoid ligands, their receptors, and the immune system in vitro or in mammals including humans.","limitations":"The hypothesis linking cannabis immune effects to psychosis is largely theoretical. Most evidence comes from in vitro and animal studies. The causal chain from cannabis use to immune disruption to psychosis vulnerability has not been demonstrated in prospective human studies. The review acknowledges significant uncertainty about central nervous system immune effects."},{"rthcId":"RTHC-00872","title":"Prevalence of marijuana use at college entry and risk factors for initiation during freshman year.","authors":"Suerken, Cynthia K; Reboussin, Beth A; Sutfin, Erin L; Wagoner, Kimberly G; Spangler, John; Wolfson, Mark","year":2014,"journal":"Addictive behaviors, 39(1), 302-7","doi":null,"pmid":"24455784","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Nearly 30% of students arriving at college reported lifetime marijuana use. Among those who had never used before college, 8.5% initiated during freshman year.\n\nPredictors of having used marijuana before college included: having $100+ monthly spending money, rarely or never attending church, current cigarette/alcohol/hookah use, lifetime use of other illicit drugs, and higher sensation-seeking tendencies.\n\nPredictors of initiating marijuana during freshman year were different: Hispanic ethnicity, living on campus, and current cigarette and alcohol use. The shift from pre-college to freshman-year predictors suggests the college environment itself creates new risk factors, particularly residential living.","whyItMatters":"College represents a major transition period for substance use. Understanding that nearly one in ten previously non-using students starts marijuana during freshman year, and that living on campus is a key risk factor, has implications for campus-based prevention programming.","specificNumbers":"3,146 students from 11 colleges. 30% had used marijuana before college. 8.5% initiated during freshman year. Risk factors for initiation: Hispanic ethnicity, campus residence, cigarette use, alcohol use.","methodology":"Researchers used data from the first two semesters of a longitudinal study involving 3,146 students from 11 colleges in North Carolina and Virginia. Random-effects logistic regression models identified predictors of lifetime marijuana use at college entry and initiation during freshman year.","limitations":"The sample was from North Carolina and Virginia colleges and may not represent all college populations. Self-reported substance use may be inaccurate. The study did not measure frequency or quantity of marijuana use after initiation. The two-semester follow-up captures only the beginning of the college experience."},{"rthcId":"RTHC-00873","title":"Commentary--Project Towards No Drug Abuse: an evidence-based drug abuse prevention program.","authors":"Sussman, Steve; Valente, Thomas W; Rohrbach, Louise A; Dent, Clyde W; Sun, Ping","year":2014,"journal":"The journal of primary prevention, 35(4), 233-7","doi":"10.1007/s10935-014-0353-4","pmid":"24788544","tags":["youth","harm-reduction","addiction"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Project TND (Towards No Drug Abuse) was evaluated across seven group-randomized controlled trials. In all seven trials, a significant effect was found on hard drug use. The program also showed effects on alcohol use in four trials, and on cigarette and marijuana use in two trials (with a possible third trial showing marijuana effects).\n\nEarlier trials also found effects on violence-related behavior, though this outcome was not assessed in later trials. The consistency of hard drug use effects across seven independent replications is noteworthy for a school-based prevention program.\n\nThe authors note that the effects within each trial were statistically significant, with no more than a 10% chance of being obtained by chance alone (two-tailed testing).","whyItMatters":"Most school-based prevention programs have limited evidence of effectiveness, and few have been replicated in multiple independent trials. The consistent hard drug use reduction across seven trials provides unusually strong evidence that this particular program works.","specificNumbers":"7 group-randomized controlled trials. Effects on hard drug use: 7/7 trials. Effects on alcohol: 4/7 trials. Effects on cigarettes: 2/7 trials. Effects on marijuana: 2-3/7 trials.","methodology":"This is a commentary reviewing the accumulated evidence from seven group-randomized controlled trials of Project TND. The review examines the consistency of effects across replications for different substance use outcomes.","limitations":"The commentary format does not provide detailed methodology or effect sizes from each trial. The program effects on marijuana and cigarettes were inconsistent across trials. The author is the program developer, creating potential bias. Violence-related outcomes were not assessed in later trials, so the durability of those effects is unknown."},{"rthcId":"RTHC-00874","title":"Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis.","authors":"Syed, Yahiya Y; McKeage, Kate; Scott, Lesley J","year":2014,"journal":"Drugs, 74(5), 563-78","doi":"10.1007/s40265-014-0197-5","pmid":"24671907","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"strong","keyFinding":"In the largest multinational clinical trial using the approved treatment protocol, Sativex significantly reduced spasticity severity compared to placebo after 12 weeks in patients who had demonstrated initial response during a 4-week trial period. A significantly greater proportion of Sativex-treated patients achieved a 30% or greater reduction in spasticity (considered clinically relevant).\n\nThe approved protocol includes an important initial trial of therapy: only patients who demonstrate clinically significant improvement during the first 4 weeks continue treatment. This enrichment design ensures the drug is used in patients most likely to benefit.\n\nReal-world effectiveness data from the MOVE 2 study confirmed clinical trial findings. Side effects (primarily dizziness and fatigue) were most common in the first 4 weeks and typically resolved even with continued treatment.","whyItMatters":"This review provides the most complete picture available of Sativex as a treatment for MS spasticity, covering everything from its mechanism of action to its real-world effectiveness. The enrichment design (initial trial period) is a model for how cannabinoid medicines can be used to identify and treat responsive patients.","specificNumbers":"THC:CBD ratio approximately 1:1. Approved as add-on therapy for moderate to severe MS spasticity. Initial trial period: 4 weeks. Pivotal trial: 12 weeks double-blind. Significant 30% responder rate. Most common side effects: dizziness, fatigue (resolving within days).","methodology":"This is a comprehensive drug review covering the pharmacology, clinical efficacy, and tolerability of Sativex (THC/CBD oromucosal spray). It synthesizes data from Phase III clinical trials, the MOVE 2 real-world study, and pharmacological characterization.","limitations":"The enrichment design (4-week trial period) means efficacy data applies only to responders, not all MS spasticity patients. Long-term efficacy and safety data beyond clinical trial durations were limited. The review was published in a pharmaceutical journal and follows a standard drug review format that may not critically evaluate all limitations."},{"rthcId":"RTHC-00875","title":"Cannabis, cannabidiol, and epilepsy--from receptors to clinical response.","authors":"Szaflarski, Jerzy P; Bebin, E Martina","year":2014,"journal":"Epilepsy & behavior : E&B, 41, 277-82","doi":"10.1016/j.yebeh.2014.08.135","pmid":"25282526","tags":["epilepsy","cbd","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review covers three key areas. First, recreational cannabis use is widespread among adults with epilepsy, and medicinal use is growing with changing legal environments. High-CBD/low-THC products have become more available.\n\nSecond, while THC acts primarily through CB1 receptors, CBD's mechanism of action is less clear and likely involves multiple pharmacological targets (polypharmacological). There is anecdotal evidence of efficacy and discussion of a potential \"entourage effect\" between CBD and THC.\n\nThird, the endocannabinoid system plays a clear role in seizure generation, maintenance, and control in animal models. While cannabis has documented negative effects on the developing and mature brain, these effects appear relatively mild in most cases. The authors call for well-designed studies on both short- and long-term efficacy and safety of CBD products for seizures.","whyItMatters":"This review was published at a critical juncture when families were already using CBD products for epilepsy (following Charlotte's Web publicity) but before any controlled clinical trials had been completed. It frames the scientific questions that needed to be answered before CBD could be considered a legitimate epilepsy treatment.","specificNumbers":"THC acts via CB1 receptors. CBD has polypharmacological action. Endocannabinoid system shown to regulate seizures in animal models. Brain effects of cannabis described as \"relatively mild in most cases.\"","methodology":"This is a narrative review covering cannabinoid pharmacology, endocannabinoid system involvement in epilepsy, preclinical and anecdotal clinical evidence for CBD in seizure control, and known adverse effects of cannabis on the brain.","limitations":"The review was written before controlled clinical trial data became available. Much of the evidence was preclinical or anecdotal. The characterization of cannabis brain effects as \"relatively mild\" may understate risks for certain populations. The review does not provide quantitative analysis of efficacy data."},{"rthcId":"RTHC-00876","title":"Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation.","authors":"Szutorisz, Henrietta; DiNieri, Jennifer A; Sweet, Eric; Egervari, Gabor; Michaelides, Michael; Carter, Jenna M; Ren, Yanhua; Miller, Michael L; Blitzer, Robert D; Hurd, Yasmin L","year":2014,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 39(6), 1315-23","doi":"10.1038/npp.2013.352","pmid":"24385132","tags":["youth","addiction","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adult offspring of rats exposed to THC during adolescence displayed multiple abnormalities despite having no direct THC exposure. They worked harder to obtain heroin in self-administration tests (increased \"break point\"), showed enhanced stereotyped behaviors during heroin withdrawal, and had altered gene expression in the striatum affecting cannabinoid, dopamine, and glutamate receptor systems.\n\nSpecifically, the offspring showed decreased mRNA and protein expression and reduced NMDA receptor binding in the dorsal striatum. Electrophysiological recordings confirmed altered synaptic plasticity at excitatory synapses in the striatal circuits that mediate compulsive and goal-directed behaviors.\n\nThese transgenerational effects suggest that parental THC exposure can alter germline (egg or sperm) epigenetic programming in ways that affect the brain reward circuitry of subsequent generations.","whyItMatters":"This is one of the first studies to demonstrate that cannabis exposure in one generation can affect addiction vulnerability in the next generation through germline epigenetic changes. If these findings translate to humans, they suggest that adolescent cannabis use could have consequences extending beyond the individual user.","specificNumbers":"F1 offspring (never exposed to THC) showed: increased break point for heroin self-administration, enhanced stereotyped behaviors during withdrawal, decreased NMDA receptor binding in dorsal striatum, altered mRNA for cannabinoid/dopamine/glutamate receptors.","methodology":"Adolescent rats were exposed to THC, and their unexposed adult offspring (F1 generation) were tested for heroin self-administration behavior and withdrawal responses. Striatal brain tissue was analyzed for mRNA expression, protein levels, receptor binding, and electrophysiological properties of synaptic plasticity.","limitations":"This was a rat study, and transgenerational epigenetic effects may differ substantially between rodents and humans. The THC doses and exposure patterns used may not reflect human use. The study examined only one generation of offspring. The specific epigenetic mechanisms (DNA methylation, histone modification) were not fully characterized."},{"rthcId":"RTHC-00877","title":"Synthetic Cannabinoids: Pharmacology, Behavioral Effects, and Abuse Potential.","authors":"Tai, Sherrica; Fantegrossi, William E","year":2014,"journal":"Current addiction reports, 1(2), 129-136","doi":null,"pmid":"26413452","tags":["synthetic-cannabinoids","addiction","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review highlights a critical pharmacological difference between natural THC and synthetic cannabinoids: THC is a relatively weak partial agonist at CB1 receptors, while the majority of synthetic cannabinoids are full agonists with higher binding affinity. This distinction means synthetic cannabinoids can produce much stronger activation of cannabinoid receptors.\n\nAnimal studies using the cannabinoid tetrad (catalepsy, hypothermia, reduced locomotion, analgesia) and drug discrimination showed that synthetic cannabinoid effects were generally comparable to THC. However, in vitro assays consistently confirmed the higher efficacy of synthetic cannabinoids.\n\nSynthetic cannabinoids are popular partly because they avoid detection in standard drug screens and, at least initially, circumvent legal restrictions. Their structural diversity makes regulation and detection a moving target.","whyItMatters":"Synthetic cannabinoids are responsible for a disproportionate share of cannabinoid-related adverse events, including hospitalizations and deaths. Understanding that they are pharmacologically distinct from and more potent than THC is essential for public health messaging, clinical management, and regulatory response.","specificNumbers":"THC: weak CB1 partial agonist. Most synthetic cannabinoids: full CB1 agonists with higher affinity and efficacy. Standard drug screens do not detect most synthetic cannabinoids.","methodology":"This is a narrative review covering the pharmacology, behavioral effects, and abuse potential of synthetic cannabinoids. It synthesizes in vitro receptor binding data, in vivo animal behavioral studies, and clinical case reports.","limitations":"The rapidly evolving landscape of synthetic cannabinoids means the review may not cover all compounds in circulation. In vivo behavioral studies did not fully differentiate between partial and full agonist effects. Human clinical data was largely limited to case reports of adverse events. The pharmacology of many individual synthetic cannabinoids remains poorly characterized."},{"rthcId":"RTHC-00878","title":"St8sia2 deficiency plus juvenile cannabis exposure in mice synergistically affect higher cognition in adulthood.","authors":"Tantra, Martesa; Kröcher, Tim; Papiol, Sergi; Winkler, Daniela; Röckle, Iris; Jatho, Jasmin; Burkhardt, Hannelore; Ronnenberg, Anja; Gerardy-Schahn, Rita; Ehrenreich, Hannelore; Hildebrandt, Herbert","year":2014,"journal":"Behavioural brain research, 275, 166-75","doi":"10.1016/j.bbr.2014.08.062","pmid":"25200516","tags":["youth","cognition","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Juvenile THC treatment (7 mg/kg every other day for 3 weeks) had no appreciable effect on cognition in normal (wildtype) mice. However, mice lacking the St8sia2 gene (which encodes an enzyme important for neural cell adhesion molecule function) showed a synergistic negative effect on learning and memory.\n\nCritically, these cognitive deficits became apparent only months after the last THC dose, demonstrating a delayed onset effect. The delayed damage was accompanied by molecular changes: reduced polysialic acid-free NCAM-180 in the hippocampus and increased polysialic acid in a specific region of the dentate gyrus.\n\nThe St8sia2 gene variants have been associated with mental illness in humans, suggesting this gene-environment interaction model could be relevant to understanding why some people are more vulnerable to cannabis-related cognitive problems.","whyItMatters":"This study provides a concrete example of a gene-environment interaction in cannabis vulnerability. It shows that genetic background determines whether juvenile cannabis exposure causes lasting cognitive harm, helping explain why some adolescent cannabis users develop cognitive problems while others do not.","specificNumbers":"THC: 7 mg/kg every other day for 3 weeks. Cognitive effects emerged months after last THC. St8sia2 knockout mice showed synergistic damage with THC. Wildtype mice showed no cognitive effects from THC alone.","methodology":"Male St8sia2 knockout mice and wildtype controls received chronic THC (7 mg/kg every other day for 3 weeks) during the juvenile period. Cognitive testing was performed months after the last THC administration. Hippocampal tissue was analyzed for NCAM polysialylation patterns.","limitations":"This was a mouse study using a complete gene knockout, which is more extreme than the genetic variations seen in humans. The THC dose and schedule may not reflect human use patterns. The specific genetic variant (St8sia2) may account for only a small portion of human genetic vulnerability to cannabis effects."},{"rthcId":"RTHC-00879","title":"Alcohol and marijuana use patterns associated with unsafe driving among U.S. high school seniors: high use frequency, concurrent use, and simultaneous use.","authors":"Terry-McElrath, Yvonne M; O'Malley, Patrick M; Johnston, Lloyd D","year":2014,"journal":"Journal of studies on alcohol and drugs, 75(3), 378-89","doi":null,"pmid":"24766749","tags":["driving","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analysis of 72,053 high school seniors surveyed from 1976 to 2011 found that higher substance use frequency, particularly alcohol use frequency, was significantly associated with unsafe driving (tickets, warnings, or accidents).\n\nSimultaneous use (using alcohol and marijuana at the same time) was associated with the highest rates of unsafe driving, followed by concurrent use (using both substances but at different times), followed by alcohol use alone. Individuals who reported simultaneous use \"most or every time\" they used marijuana had the highest likelihood of reporting unsafe driving after either substance.\n\nThe risk gradient was clear: same-time combined use > different-time combined use > single substance use, suggesting the pharmacological interaction between alcohol and marijuana compounds impairment.","whyItMatters":"The distinction between simultaneous and concurrent use is rarely examined but appears to be important for driving risk. Prevention messaging that addresses the specific danger of combining alcohol and marijuana at the same time could help reduce teen driving fatalities.","specificNumbers":"72,053 students surveyed (1976-2011). Risk hierarchy: simultaneous use > concurrent use > alcohol alone > marijuana alone. Simultaneous users had highest rates of driving-related tickets, warnings, and accidents.","methodology":"Analyses used data from 72,053 students collected through Monitoring the Future annual surveys of nationally representative cross-sectional samples of U.S. 12th-grade students from 1976 to 2011. Two aspects of substance use were examined: frequency and simultaneous versus concurrent versus single-substance use status. Unsafe driving measures included tickets/warnings and accidents.","limitations":"All data was self-reported, including both substance use and driving outcomes. The cross-sectional design cannot establish causation. The study does not measure actual impairment, only self-reported unsafe driving events. Cannabis potency has changed dramatically over the study period (1976-2011), which could affect the relationship."},{"rthcId":"RTHC-00880","title":"Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know.","authors":"Thomas, Grace; Kloner, Robert A; Rezkalla, Shereif","year":2014,"journal":"The American journal of cardiology, 113(1), 187-90","doi":"10.1016/j.amjcard.2013.09.042","pmid":"24176069","tags":["cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review documents temporal associations between marijuana use and several serious cardiovascular events: myocardial infarction (heart attack), sudden cardiac death, cardiomyopathy, stroke, transient ischemic attack, and cannabis arteritis (inflammation of blood vessels).\n\nMarijuana is known to cause tachycardia (rapid heart rate), which could trigger cardiovascular events in vulnerable individuals. It also causes peripheral vasodilation, which can affect blood pressure and cardiac workload.\n\nThe authors emphasize that approximately 200 million people use marijuana worldwide, and as decriminalization and legalization expand, cardiologists should expect to encounter these potential complications more frequently. However, they note that the evidence is primarily based on case reports and temporal associations rather than controlled studies.","whyItMatters":"With expanding marijuana legalization, cardiologists need to be aware of potential cardiovascular risks, particularly for patients with pre-existing heart conditions. The review serves as a clinical alert for a risk that may increase in prevalence as marijuana use becomes more widespread.","specificNumbers":"Approximately 200 million marijuana users worldwide. Documented associations: myocardial infarction, sudden cardiac death, cardiomyopathy, stroke, TIA, cannabis arteritis.","methodology":"This is a brief narrative review focused on cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation. The authors reviewed case reports, case series, and available epidemiological data linking marijuana use to adverse cardiovascular events.","limitations":"The evidence is primarily from case reports and temporal associations, which cannot prove causation. The incidence of cardiovascular events attributable to marijuana is unknown. Many reported cases involved young people where other risk factors may have been present. Dose-response relationships have not been established."},{"rthcId":"RTHC-00881","title":"Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volunteers.","authors":"Tudge, Luke; Williams, Clare; Cowen, Philip J; McCabe, Ciara","year":2014,"journal":"The international journal of neuropsychopharmacology, 18(6)","doi":"10.1093/ijnp/pyu094","pmid":"25542687","tags":["neuroscience","appetite","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty healthy volunteers received either 10mg THCV or placebo in a double-blind crossover design. While subjective ratings of pleasantness, intensity, and wanting for food stimuli did not differ between conditions, brain imaging revealed significant differences.\n\nTHCV increased neural responses to chocolate-related stimuli (rewarding) in the midbrain, anterior cingulate cortex, caudate, and putamen. It also increased responses to aversive food stimuli (moldy strawberries/unpleasant taste) in the amygdala, insula, mid-orbitofrontal cortex, caudate, and putamen.\n\nThis pattern differs from rimonabant (a CB1 inverse agonist withdrawn for causing depression), which diminished reward responses and increased aversion. THCV's profile of enhancing both reward and aversion responses suggests it could reduce overeating without the depressive side effects that plagued rimonabant.","whyItMatters":"Rimonabant, the first CB1 antagonist for obesity, was withdrawn due to psychiatric side effects including depression and suicidality. THCV is a neutral CB1 antagonist (not an inverse agonist like rimonabant) and shows a different neural profile that might reduce appetite without causing depression, offering a potentially safer approach to cannabinoid-based obesity treatment.","specificNumbers":"20 volunteers, single 10mg dose, double-blind crossover. THCV increased reward responses in midbrain, ACC, caudate, putamen. Increased aversion responses in amygdala, insula, OFC, caudate, putamen. No subjective rating differences.","methodology":"Within-subject, double-blind, placebo-controlled design with 20 healthy volunteers. Each participant received 10mg THCV and placebo on separate occasions in randomized order. fMRI measured neural responses to rewarding stimuli (sight/flavor of chocolate) and aversive stimuli (picture of moldy strawberries/unpleasant strawberry taste).","limitations":"Only a single dose was tested in 20 healthy volunteers. The study measured neural responses, not actual eating behavior or weight loss. Long-term effects are unknown. The lack of subjective rating differences, despite brain activation changes, raises questions about the functional significance of the findings."},{"rthcId":"RTHC-00882","title":"A Gut Gone to Pot: A Case of Cannabinoid Hyperemesis Syndrome due to K2, a Synthetic Cannabinoid.","authors":"Ukaigwe, Anene; Karmacharya, Paras; Donato, Anthony","year":2014,"journal":"Case reports in emergency medicine, 2014, 167098","doi":"10.1155/2014/167098","pmid":"24872901","tags":["synthetic-cannabinoids","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 38-year-old man with a 10-year history of cannabis use and 1-year history of K2 (synthetic cannabinoid) use presented with episodic nausea, vomiting of clear fluids, and epigastric discomfort for one week. His symptoms were relieved only by hot showers, a hallmark of cannabinoid hyperemesis syndrome.\n\nExtensive workup including laboratory tests, imaging, and endoscopy was unrevealing. The diagnosis of CHS was ultimately made based on clinical criteria. The case highlights two important issues: synthetic cannabinoids can cause CHS just like natural cannabis, and conventional urine drug screens do not detect synthetic cannabinoids, leading to potentially expensive and unnecessary workups.\n\nThe authors note that CHS diagnosis can take up to 9 years, suggesting widespread underrecognition of this condition.","whyItMatters":"This case extends the recognition of CHS beyond natural cannabis to synthetic cannabinoids, which are increasingly prevalent. Since K2/Spice is not detected on standard urine drug screens, clinicians need to consider CHS even when drug tests are negative, especially in patients with cyclic vomiting relieved by hot showers.","specificNumbers":"Patient age: 38. Cannabis history: 10 years. K2 history: 1 year. Symptom duration: 1 week. Diagnostic delay for CHS: up to 9 years in the literature.","methodology":"This is a single case report with a review of relevant literature. The patient was evaluated with standard clinical workup. Diagnosis was based on proposed diagnostic criteria for CHS.","limitations":"This is a single case report and cannot establish prevalence or risk factors. The patient used both natural cannabis and K2, making it difficult to attribute CHS specifically to the synthetic cannabinoid. The specific K2 product and its active compound were not identified."},{"rthcId":"RTHC-00883","title":"The endocannabinoid system as a potential therapeutic target for pain modulation.","authors":"Ulugöl, Ahmet","year":2014,"journal":"Balkan medical journal, 31(2), 115-20","doi":"10.5152/balkanmedj.2014.13103","pmid":"25207181","tags":["pain","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review outlines the shift in cannabinoid pain research from directly activating cannabinoid receptors to enhancing the body's own endocannabinoid system. The most promising approach involves inhibiting the enzymes FAAH and MAGL that break down anandamide and 2-AG, respectively, thereby elevating endocannabinoid levels at sites of pain.\n\nA key advantage of this approach is that it enhances endocannabinoid signaling locally (where endocannabinoids are being produced in response to pain) rather than activating cannabinoid receptors throughout the brain, potentially reducing psychoactive side effects.\n\nThe review also highlights multi-target analgesia compounds that combine endocannabinoid enzyme inhibition with other pain-relevant mechanisms, potentially offering synergistic pain relief.","whyItMatters":"Current pain management options are inadequate for many patients, and opioid-based approaches carry significant risks. Endocannabinoid-based therapies could offer a new class of analgesics that work through the body's own pain-modulating system without the addiction potential of opioids or the psychoactive effects of THC.","specificNumbers":"Key targets: FAAH (degrades anandamide), MAGL (degrades 2-AG). Focus on multi-target compounds combining endocannabinoid modulation with other analgesic mechanisms.","methodology":"This is a narrative review covering the biosynthesis, transport, and metabolism of endocannabinoids, along with pharmacological approaches and potential therapeutic applications for pain management.","limitations":"Much of the evidence reviewed was preclinical. FAAH inhibitor clinical development faced setbacks (including a fatal clinical trial incident in 2016). The translation from preclinical promise to clinical success remains challenging. Individual variability in endocannabinoid system function may limit the approach."},{"rthcId":"RTHC-00884","title":"Catechol-O-methyltransferase gene methylation and substance use in adolescents: the TRAILS study.","authors":"van der Knaap, L J; Schaefer, J M; Franken, I H A; Verhulst, F C; van Oort, F V A; Riese, H","year":2014,"journal":"Genes, brain, and behavior, 13(7), 618-25","doi":"10.1111/gbb.12147","pmid":"24902721","tags":["genetics","dopamine","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In 463 adolescents (mean age 16), methylation of the membrane-bound COMT (MB-COMT) promoter was associated with non-daily smoking (OR=1.82, p=0.03), but not with daily smoking or alcohol use.\n\nA gene-epigenetic interaction was found for cannabis use: adolescents with the Met/Met genotype (associated with higher dopamine levels) and high MB-COMT promoter methylation were less likely to be high-frequency cannabis users compared to those with Val/Val or Val/Met genotypes. This suggests that the combination of high dopamine availability (Met/Met) and additional epigenetic reduction of COMT expression may be protective against frequent cannabis use.\n\nSoluble COMT (S-COMT) promoter methylation was not associated with any substance use measure.","whyItMatters":"This study bridges genetics and epigenetics in adolescent substance use, showing that it is not just which gene variants you carry but how those genes are regulated (through methylation) that influences substance use risk. This more nuanced view of genetic risk could eventually inform personalized prevention.","specificNumbers":"463 adolescents, mean age 16. MB-COMT methylation associated with non-daily smoking (OR=1.82, p=0.03). Met/Met genotype + high methylation: protective against high-frequency cannabis use. S-COMT methylation: no associations.","methodology":"In 463 adolescents from the TRAILS longitudinal study (mean age 16, 50.8% girls), substance use (cigarettes, alcohol, cannabis) was assessed by self-report questionnaires. From blood samples, COMT Val108/158Met genotype and methylation rates of both membrane-bound and soluble COMT promoters were measured. Logistic regression tested associations between methylation, genotype, and substance use.","limitations":"This was a cross-sectional analysis that cannot determine whether methylation changes preceded or resulted from substance use. Blood methylation may not reflect brain methylation patterns. The sample size was moderate, and the cannabis finding involved a subgroup analysis. The TRAILS study is Dutch, and findings may not generalize across populations."},{"rthcId":"RTHC-00885","title":"Association between stillbirth and illicit drug use and smoking during pregnancy.","authors":"Varner, Michael W; Silver, Robert M; Rowland Hogue, Carol J; Willinger, Marian; Parker, Corette B; Thorsten, Vanessa R; Goldenberg, Robert L; Saade, George R; Dudley, Donald J; Coustan, Donald; Stoll, Barbara; Bukowski, Radek; Koch, Matthew A; Conway, Deborah; Pinar, Halit; Reddy, Uma M","year":2014,"journal":"Obstetrics and gynecology, 123(1), 113-125","doi":"10.1097/AOG.0000000000000052","pmid":"24463671","tags":["pregnancy"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"Among 663 stillbirth deliveries and 1,932 live birth controls, a positive umbilical cord test for any illicit drug was associated with stillbirth (OR 1.94). Cannabis was the most commonly detected drug, and its positive cord test was associated with 2.34 times the odds of stillbirth (95% CI: 1.13-4.81), though this effect was partially confounded by smoking.\n\nBoth self-reported smoking and objective cotinine levels showed a dose-response relationship with stillbirth risk. Even apparent passive smoke exposure (positive cotinine but no reported smoking history) was associated with doubled stillbirth odds (OR 2.06, 95% CI: 1.24-3.41).\n\nCannabis use, smoking, illicit drug use, and secondhand smoke exposure, either separately or in combination, were all associated with increased stillbirth risk.","whyItMatters":"This is among the largest and most rigorously designed studies examining cannabis and stillbirth risk. The use of objective cord testing (rather than relying solely on self-report) strengthens the findings. As cannabis legalization expands, the relevance of these findings may increase.","specificNumbers":"663 stillbirths and 1,932 live births. Cannabis cord test: OR 2.34 (95% CI: 1.13-4.81). Any illicit drug: OR 1.94. Passive smoke: OR 2.06. Smoking showed dose-response relationship.","methodology":"The Stillbirth Collaborative Research Network conducted a case-control study from March 2006 to September 2008, covering over 90% of deliveries in five geographically diverse U.S. regions. Umbilical cord homogenate was tested for illicit drugs and maternal serum was analyzed for cotinine (a smoking biomarker). Objective biological measures supplemented self-reported data.","limitations":"The cannabis association was partially confounded by smoking, making it difficult to isolate the independent effect of cannabis. Not all cases had cord homogenate available (63% of stillbirths, 54% of controls). A positive cord test indicates exposure but does not quantify the amount or timing of use. The study cannot determine if cannabis was causally related to stillbirth or a marker for other risk factors."},{"rthcId":"RTHC-00886","title":"An Internet survey of marijuana and hot shower use in adults with cyclic vomiting syndrome (CVS).","authors":"Venkatesan, Thangam; Sengupta, Jyotirmoy; Lodhi, Atena; Schroeder, Abigail; Adams, Kathleen; Hogan, Walter J; Wang, Yanzhi; Andrews, Christopher; Storr, Martin","year":2014,"journal":"Experimental brain research, 232(8), 2563-70","doi":"10.1007/s00221-014-3967-0","pmid":"24792504","tags":["appetite","addiction","anxiety"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 437 CVS patients who completed questions about marijuana use, 81% reported use and only 19% had never used. 54% used marijuana for health reasons and 43% for recreational purposes. Users reported improvements in nausea, appetite, general well-being, stress levels, and vomiting.\n\nMarijuana users were more likely to be male and have an associated anxiety disorder. Hot shower/bath use for symptom relief was reported by 67% of all patients, and this was significantly associated with marijuana use (OR 2.54, 95% CI: 1.50-4.31, p=0.0006).\n\nImportantly, hot showers were not exclusive to marijuana users (they were also used by non-users), challenging the assumption that compulsive bathing is pathognomonic (uniquely diagnostic) of cannabinoid hyperemesis syndrome.","whyItMatters":"The overlap between cyclic vomiting syndrome and cannabinoid hyperemesis syndrome is a significant diagnostic challenge. This study shows that marijuana use is extremely common in CVS patients and that hot showers are used by both marijuana users and non-users, complicating the clinical distinction between these two conditions.","specificNumbers":"514 respondents, 437 completed marijuana questions. 81% used marijuana. 54% for health. 43% recreational. 67% used hot showers. Hot shower-marijuana association: OR 2.54 (p=0.0006).","methodology":"An anonymous internet-based survey was completed by 514 adults (18+) diagnosed with CVS by a healthcare provider. The survey assessed marijuana use patterns, motivations, perceived effects, and hot shower use. Mean age was 34 years, 63% female, 92% Caucasian, 82% from the USA.","limitations":"Internet-based surveys are subject to self-selection bias. Patients may not have received accurate diagnoses. The survey could not distinguish between CVS patients who use marijuana for symptom relief and CHS patients who have been misdiagnosed with CVS. The predominantly Caucasian, female, U.S. sample may not be representative."},{"rthcId":"RTHC-00887","title":"Repeated Δ9-tetrahydrocannabinol exposure in adolescent monkeys: persistent effects selective for spatial working memory.","authors":"Verrico, Christopher D; Gu, Hong; Peterson, Melanie L; Sampson, Allan R; Lewis, David A","year":2014,"journal":"The American journal of psychiatry, 171(4), 416-25","doi":"10.1176/appi.ajp.2013.13030335","pmid":"24577206","tags":["youth","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Seven pairs of adolescent male rhesus monkeys, matched for baseline cognitive ability, received either THC or vehicle intravenously 5 days/week for 6 months. THC-exposed monkeys showed a blunted trajectory of accuracy improvements on spatial working memory in a delay-dependent manner, meaning they failed to improve as much as controls over time on this task.\n\nCritically, object working memory (a task that matures earlier developmentally) was not affected. This selectivity suggests that THC's persistent effects are most evident when exposure coincides with the developmental stage during which the underlying neural circuits are actively maturing.\n\nNeither tolerance nor sensitization to THC's acute effects on working memory developed over the 6-month exposure period, assessed by comparing acute effects at the beginning and end of the study.","whyItMatters":"This is one of the most directly translatable studies on adolescent cannabis exposure and cognition. Nonhuman primates have brain development timelines and cognitive architectures much closer to humans than rodents. The finding that THC selectively impairs the cognitive domain still maturing during exposure provides a mechanistic explanation for epidemiological observations in human adolescents.","specificNumbers":"7 pairs of adolescent monkeys. 6 months of THC exposure. Spatial working memory: impaired in a delay-dependent manner. Object working memory: unaffected. No tolerance or sensitization over 6 months.","methodology":"Seven pairs of male adolescent rhesus monkeys were matched for baseline cognitive performance. One from each pair received THC intravenously 5 days/week for 6 months; the other received vehicle. Performance on spatial and object working memory tasks was assessed 23 or 71 hours after drug administration throughout the study. Acute THC effects were measured at the beginning and end of the 6-month period.","limitations":"The sample size was small (7 pairs). Intravenous THC administration differs from typical human cannabis use routes. Only male monkeys were studied. The study assessed performance during ongoing exposure; longer-term follow-up after cessation would clarify persistence. The specific neural mechanisms were not investigated."},{"rthcId":"RTHC-00888","title":"\"Unplugged,\" a European school-based program for substance use prevention among adolescents: overview of results from the EU-Dap trial.","authors":"Vigna-Taglianti, Federica D; Galanti, Maria Rosaria; Burkhart, Gregor; Caria, Maria Paola; Vadrucci, Serena; Faggiano, Fabrizio","year":2014,"journal":"New directions for youth development, 2014(141), 67-82, 11-2","doi":"10.1002/yd.20087","pmid":"24753279","tags":["youth","harm-reduction","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"The \"Unplugged\" program was evaluated in a randomized trial involving 7,079 students across seven European countries. The 12-session interactive curriculum, taught by teachers, was effective in reducing cigarette smoking, episodes of drunkenness, and cannabis use in the short term.\n\nHowever, the short-term effects were largely confined to boys, with age and self-esteem as possible explanations for the gender difference. At 15-month follow-up, beneficial effects persisted for drunkenness, alcohol-related problems, and cannabis use.\n\nEffects were stronger among students in schools with average low socioeconomic status, suggesting the program may be most beneficial for higher-risk populations.","whyItMatters":"Cross-national effectiveness is a high bar for prevention programs. That \"Unplugged\" showed effects across seven European countries with different cultures and drug policies strengthens confidence in its generalizability. The persistent effects on cannabis use at 15 months are particularly notable.","specificNumbers":"7,079 students across 7 European countries. 12 one-hour sessions. Short-term effects on smoking, drunkenness, and cannabis (boys only). 15-month effects on drunkenness, alcohol problems, and cannabis. Stronger effects in lower-SES schools.","methodology":"This was a randomized controlled trial involving 7,079 students from seven European countries. Schools were randomized to receive either the \"Unplugged\" program (12 one-hour interactive sessions) or usual education. Follow-up assessments were conducted at short-term and 15-month intervals.","limitations":"The gender specificity of short-term effects is concerning and not fully explained. The program was teacher-delivered, introducing variability in implementation quality. Different European countries may have had varying levels of program fidelity. The 15-month follow-up may not capture longer-term outcomes."},{"rthcId":"RTHC-00889","title":"Attention deficit hyperactivity disorder, other mental health problems, substance use, and driving: examination of a population-based, representative canadian sample.","authors":"Vingilis, Evelyn; Mann, Robert E; Erickson, Patricia; Toplak, Maggie; Kolla, Nathan J; Seeley, Jane; Jain, Umesh","year":2014,"journal":"Traffic injury prevention, 15 Suppl 1, S1-9","doi":"10.1080/15389588.2014.926341","pmid":"25307372","tags":["driving","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 3,485 licensed drivers surveyed, 3.22% screened positive for ADHD symptoms. Those screening positive were younger, reported more distress, antisocial behavior, anti-anxiety and antidepressant medication use, substance use, and social problems compared to those screening negative.\n\nHowever, there were no statistically significant differences between ADHD-positive and ADHD-negative groups on any driving outcome: driving after 2+ drinks, driving within an hour of cannabis use, street racing, or collision involvement in the past year.\n\nWhen a regression model controlled for age, sex, and kilometers driven, ADHD screening status was not associated with collision risk. Cannabis use ever approached but did not reach statistical significance as a collision predictor.","whyItMatters":"This is the first population-based study in Ontario to examine ADHD screening and driving outcomes in a representative adult sample. The null finding for driving risks is reassuring but should be interpreted cautiously given the limitations of self-report screening versus clinical diagnosis.","specificNumbers":"4,014 adults sampled, 3,485 licensed drivers. 3.22% screened positive for ADHD. No significant differences in driving after drinking, driving after cannabis, street racing, or collisions. Cannabis use approached significance for collision risk.","methodology":"Data came from the CAMH Ontario Monitor, a repeated cross-sectional telephone survey. 4,014 Ontario adults were sampled over 2 years. ADHD was assessed using the Adult ADHD Self-Report Scale (ASRS-V1.1). Multiple psychiatric, substance use, and driving measures were collected.","limitations":"ADHD was assessed by self-report screener, not clinical diagnosis. The ADHD-positive sample was small (3.22% of 4,014). Self-reported driving outcomes may underestimate risky behaviors. The telephone survey format excludes people without landlines. These results should be interpreted as preliminary."},{"rthcId":"RTHC-00890","title":"A universal harm-minimisation approach to preventing psychostimulant and cannabis use in adolescents: a cluster randomised controlled trial.","authors":"Vogl, Laura Elise; Newton, Nicola Clare; Champion, Katrina Elizabeth; Teesson, Maree","year":2014,"journal":"Substance abuse treatment, prevention, and policy, 9, 24","doi":"10.1186/1747-597X-9-24","pmid":"24943829","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 1,734 Year 10 students (mean age 15.4) across 21 Australian schools, the computer-based Climate Schools program increased knowledge of cannabis and psychostimulants and decreased pro-drug attitudes compared to usual drug education.\n\nThe program subdued ecstasy uptake and plateaued use frequency in the short term, though no effects on meth/amphetamine use were found. Students' intentions to use meth/amphetamine and ecstasy in the future decreased, but these effects did not last over time.\n\nA notable sex-specific finding emerged: females who received the program used cannabis significantly less frequently than female controls. Both teachers and students reported enjoying the program and finding it feasible to implement.","whyItMatters":"This study extends the Climate Schools model (previously validated for alcohol) to cannabis and psychostimulants. The computer-based delivery ensures consistent implementation quality and is scalable across school systems.","specificNumbers":"1,734 students from 21 schools. Mean age 15.4. Increased knowledge and decreased pro-drug attitudes. Reduced ecstasy uptake. Reduced cannabis frequency in females. Decreased future use intentions for meth/amphetamine and ecstasy (not sustained).","methodology":"A cluster randomized controlled trial with 1,734 Year 10 students from 21 Australian secondary schools. Schools were randomized to receive either six computer-based Climate Schools lessons or usual health classes. Outcomes were assessed at pre-test, post-test, and follow-up.","limitations":"Cannabis use effects were limited to females. Effects on future use intentions did not persist over time. The study was conducted in Australian schools and may not generalize to other contexts. The follow-up period was not long enough to assess lasting behavioral change."},{"rthcId":"RTHC-00891","title":"A rare case of cannabis hyperemesis syndrome relieved by hot water bathing.","authors":"Warner, Ben; Cairns, Stuart; Stone, Andy","year":2014,"journal":"Clinical medicine (London, England), 14(1), 86-7","doi":"10.7861/clinmedicine.14-1-86","pmid":"24532755","tags":["cardiovascular","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The case presents a typical CHS presentation: a chronic cannabis user with cyclical vomiting that was relieved by compulsive hot bathing. The authors emphasize that CHS is underrecognized in emergency department settings, leading to delayed diagnosis, unnecessary testing, and repeated presentations.\n\nEarly recognition of CHS can lead to simpler and more effective treatment: cannabis cessation. The authors advocate for increased awareness among emergency physicians to reduce the diagnostic delay and healthcare costs associated with this condition.","whyItMatters":"CHS is increasingly common as cannabis use rises with legalization. Emergency departments frequently encounter patients with cyclical vomiting, and recognizing CHS early can prevent unnecessary invasive testing and costly hospital admissions.","specificNumbers":"Single case report. CHS characterized by cyclical vomiting in a chronic cannabis user, relieved by hot baths, treated by cannabis cessation.","methodology":"This is a single case report with clinical description of the presentation, workup, and diagnosis of CHS.","limitations":"This is a single case report with minimal clinical detail. It does not add new scientific knowledge about CHS mechanisms or treatment beyond reinforcing existing understanding."},{"rthcId":"RTHC-00892","title":"Treatment of cannabis dependence using escitalopram in combination with cognitive-behavior therapy: a double-blind placebo-controlled study.","authors":"Weinstein, A M; Miller, H; Bluvstein, I; Rapoport, E; Schreiber, S; Bar-Hamburger, R; Bloch, M","year":2014,"journal":"The American journal of drug and alcohol abuse, 40(1), 16-22","doi":"10.3109/00952990.2013.819362","pmid":"24359507","tags":["addiction","quitting","depression","anxiety"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Cannabis-dependent users received 9 weeks of weekly CBT and motivational enhancement therapy along with either escitalopram (10 mg/day) or placebo. The dropout rate was high at 50%. Among the 52 patients in the intention-to-treat analysis, only 10 (19%) remained abstinent at 9 weeks.\n\nEscitalopram provided no advantage over placebo for cannabis abstinence rates, anxiety scores, or depression scores during withdrawal and abstinence. The authors note that the low overall abstinence rate and high dropout limited their ability to fully assess anxiety and depression outcomes.\n\nDespite the null result, the authors caution against concluding that SSRIs are definitively ineffective for cannabis withdrawal, given the study's limitations.","whyItMatters":"Cannabis dependence treatment remains challenging, and many cannabis users have co-occurring mood symptoms. This study tested whether addressing potential underlying depression and anxiety with an SSRI would improve quit outcomes. The null result informs treatment planning but does not close the door on pharmacological support.","specificNumbers":"52 participants. 9-week treatment. 50% dropout rate. 19% abstinent at 9 weeks. No difference between escitalopram and placebo on any outcome.","methodology":"This was a double-blind, placebo-controlled trial. 52 cannabis-dependent individuals were randomized to receive escitalopram (10 mg/day) or placebo for 9 weeks alongside weekly CBT and motivational enhancement therapy. Urine samples monitored THC levels, and questionnaires assessed anxiety and depression.","limitations":"The high dropout rate (50%) severely limited statistical power. Only 19% achieved abstinence, meaning anxiety and depression measures were assessed in mostly active users. The sample size was small. Escitalopram dosing (10 mg/day) may have been insufficient for some patients."},{"rthcId":"RTHC-00893","title":"Neural responses to subliminally presented cannabis and other emotionally evocative cues in cannabis-dependent individuals.","authors":"Wetherill, Reagan R; Childress, Anna Rose; Jagannathan, Kanchana; Bender, Julian; Young, Kimberly A; Suh, Jesse J; O'Brien, Charles P; Franklin, Teresa R","year":2014,"journal":"Psychopharmacology, 231(7), 1397-407","doi":"10.1007/s00213-013-3342-z","pmid":"24186078","tags":["addiction","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty treatment-seeking cannabis-dependent individuals were shown cannabis, sexual, and aversive images for only 33 milliseconds (too fast for conscious perception) using a backward-masking technique during fMRI. Despite not consciously seeing the images, participants showed increased brain activity in reward regions (left anterior insula, ventral striatum/amygdala) in response to cannabis cues.\n\nThis subliminal cannabis cue activation correlated with real-world behavior: activity in the bilateral insula and anterior cingulate cortex was positively associated with baseline cannabis craving, and activity in the medial orbitofrontal cortex correlated with years of cannabis use.\n\nThe neural response pattern to subliminal cannabis cues was similar to the response to subliminal sexual cues, supporting the theory that drug and natural rewards share common neural pathways.","whyItMatters":"This study demonstrates that the brains of cannabis-dependent people respond to drug-related cues even without conscious awareness. This has profound implications for understanding relapse: environmental triggers may activate craving circuitry before a person is even aware of the trigger.","specificNumbers":"20 cannabis-dependent participants. Images shown for 33 ms (subliminal). Reward region activation correlated with craving. OFC activation correlated with years of use.","methodology":"Twenty treatment-seeking cannabis-dependent adults (12 males) underwent event-related fMRI. Cannabis, sexual, and aversive images were presented for 33 milliseconds in a backward-masking paradigm (immediately followed by a neutral image to prevent conscious processing). Drug use history and craving were assessed before imaging.","limitations":"The sample was small (20 participants) and exclusively treatment-seeking, limiting generalizability. Backward masking does not guarantee complete absence of conscious processing. The cross-sectional design cannot determine whether subliminal reactivity predicts actual relapse. Only cannabis-dependent individuals were studied; comparison to recreational users would be informative."},{"rthcId":"RTHC-00894","title":"Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents.","authors":"Wiley, Jenny L; Walentiny, D Matthew; Wright, M Jerry; Beardsley, Patrick M; Burston, James J; Poklis, Justin L; Lichtman, Aron H; Vann, Robert E","year":2014,"journal":"European journal of pharmacology, 737, 97-105","doi":"10.1016/j.ejphar.2014.05.013","pmid":"24858366","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice and rats trained to discriminate THC from vehicle were tested with various endocannabinoid-enhancing strategies. Directly administering anandamide or 2-AG did not substitute for THC, even when combined with enzyme inhibitors. However, the FAAH inhibitor PF3845 enhanced anandamide's ability to produce THC-like effects in mice, and the MAGL inhibitor JZL184 increased THC-like responding on its own.\n\nIn rats, neither FAAH inhibition (URB597) nor MAGL inhibition (JZL184) alone produced significant THC-like effects. But combining both inhibitors approached full substitution for THC, suggesting that simultaneous elevation of both anandamide and 2-AG is necessary to replicate THC's subjective effects.\n\nSpecies differences were notable: what worked in mice did not always work in rats, highlighting the importance of species selection in preclinical cannabinoid research.","whyItMatters":"Understanding which endocannabinoids contribute to THC's subjective effects helps explain why cannabis produces the specific psychoactive experience it does. The finding that both endocannabinoids are needed to replicate THC's effects reveals the complexity of the endocannabinoid system.","specificNumbers":"THC discrimination doses: 5.6 mg/kg (mice), 3 mg/kg (rats). FAAH inhibitor PF3845 enhanced anandamide substitution. MAGL inhibitor JZL184 increased THC-like responding. Combined FAAH+MAGL inhibition approached full substitution in rats.","methodology":"Mice and rats were trained in a drug discrimination paradigm to distinguish THC from vehicle. Various combinations of exogenous endocannabinoids and enzyme inhibitors (FAAH and MAGL) were tested for their ability to substitute for THC. Brain endocannabinoid levels were measured after some treatments.","limitations":"Drug discrimination studies measure whether animals perceive a drug as \"THC-like\" but cannot directly measure subjective experience. Species differences between mice and rats complicate interpretation. The doses and routes of administration may not translate to human use."},{"rthcId":"RTHC-00895","title":"CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats.","authors":"Wills, Kiri L; Vemuri, Kiran; Kalmar, Alana; Lee, Alan; Limebeer, Cheryl L; Makriyannis, Alexandros; Parker, Linda A","year":2014,"journal":"Psychopharmacology, 231(22), 4291-300","doi":"10.1007/s00213-014-3575-5","pmid":"24770676","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using a conditioned place aversion paradigm (where rats learn to avoid a location associated with withdrawal), researchers found that CB1 receptor antagonism interfered with the emotional distress of morphine withdrawal. The neutral CB1 antagonists AM4113 and AM6527, as well as the inverse agonist/antagonist AM251 at higher doses, prevented rats from developing aversion to the withdrawal-paired location.\n\nIn contrast, FAAH inhibitors (URB597 and PF-3845), which boost anandamide levels, did not reduce withdrawal aversion. This suggests that reducing rather than enhancing endocannabinoid signaling is beneficial for this aspect of withdrawal.\n\nWhile the antagonists prevented the initial formation of withdrawal aversion, they did not prevent reinstatement (return) of previously established aversion, suggesting they may work best as preventive rather than therapeutic interventions.","whyItMatters":"The emotional/motivational aspects of opioid withdrawal (anxiety, dysphoria, distress) are major drivers of relapse. If CB1 antagonism can reduce these aversive emotional states, it could be a valuable addition to opioid withdrawal management strategies.","specificNumbers":"AM251 effective at 2.5 mg/kg but not 1 mg/kg. AM4113 and AM6527 (neutral antagonists) effective. URB597 and PF-3845 (FAAH inhibitors) not effective. Antagonists did not prevent reinstatement of previously established aversion.","methodology":"Rats received a high dose of morphine followed by naloxone-precipitated withdrawal paired with a specific floor texture in a one-trial conditioned place aversion paradigm. Various CB1 receptor modulators were administered before conditioning to test their effects on withdrawal aversion. Reinstatement testing evaluated whether antagonists could reverse previously established aversive memories.","limitations":"This was an animal study using a specific withdrawal paradigm. Precipitated withdrawal (using naloxone) produces a more acute syndrome than spontaneous withdrawal. The failure to prevent reinstatement limits therapeutic applicability. The distinction between neutral antagonists and inverse agonists may matter clinically but was not fully explored."},{"rthcId":"RTHC-00896","title":"Complementary and alternative medical therapies in multiple sclerosis--the American Academy of Neurology guidelines: a commentary.","authors":"Yadav, Vijayshree; Narayanaswami, Pushpa","year":2014,"journal":"Clinical therapeutics, 36(12), 1972-1978","doi":"10.1016/j.clinthera.2014.10.011","pmid":"25467189","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The AAN's comprehensive evidence-based guidelines issued Level A recommendations (strongest) that oral cannabis extract is effective short-term for spasticity-related symptoms and pain (excluding central neuropathic pain), and that ginkgo biloba is ineffective for cognitive improvement in MS.\n\nLevel B recommendations (probable) included: THC is probably effective for spasticity symptoms and pain but probably ineffective for objective spasticity or tremor. Sativex (nabiximols) is probably effective for spasticity symptoms, pain, and urinary frequency but probably ineffective for objective spasticity and bladder incontinence.\n\nThe guidelines emphasized significant concern about CNS-related adverse effects and noted that in the U.S., a lack of standardized, FDA-regulated preparations limits the practical application of these findings.","whyItMatters":"This represents the first major neurology professional organization to give its highest evidence grade (Level A) to a cannabis-based treatment. The distinction between subjective symptom improvement and objective measurement improvement is clinically important and well-articulated.","specificNumbers":"Level A: oral cannabis extract for spasticity symptoms and pain. Level B: THC for spasticity symptoms/pain; Sativex for spasticity symptoms/pain/urinary frequency; magnetic therapy for fatigue. Level B (ineffective): all cannabinoids for objective spasticity; fish oil for relapses/disability.","methodology":"This is a commentary on the AAN evidence-based practice guidelines published in March 2014. The guideline panel reviewed and classified articles according to the AAN therapeutic scheme, with recommendations linked to evidence strength.","limitations":"The commentary notes that U.S. availability of standardized cannabis preparations is limited. The guidelines cover evidence through September 2013 and may not reflect more recent data. The distinction between subjective and objective outcomes complicates implementation."},{"rthcId":"RTHC-00897","title":"Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology.","authors":"Yadav, Vijayshree; Bever, Christopher; Bowen, James; Bowling, Allen; Weinstock-Guttman, Bianca; Cameron, Michelle; Bourdette, Dennis; Gronseth, Gary S; Narayanaswami, Pushpa","year":2014,"journal":"Neurology, 82(12), 1083-92","doi":"10.1212/WNL.0000000000000250","pmid":"24663230","tags":["medical-cannabis","pain","cbd"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This is the full guideline publication (not the commentary). Key recommendations:\n\nLevel A (established): Clinicians might offer oral cannabis extract for spasticity symptoms and pain (excluding central neuropathic pain).\n\nLevel B (probable): THC for spasticity symptoms and pain; Sativex for spasticity symptoms, pain, and urinary frequency. These agents are probably ineffective for objective spasticity (short-term) and tremor. Sativex probably ineffective for objective spasticity and urinary incontinence.\n\nLevel C (possible): Cannabis agents possibly effective long-term for spasticity and pain.\n\nThe guidelines emphasize that cannabinoids may cause adverse effects and that clinicians should exercise caution regarding standardized versus non-standardized preparations and overall quality control.","whyItMatters":"This is the definitive AAN guideline on complementary and alternative medicine in MS, setting the standard of care for cannabis-based treatments in neurology practice. Its systematic methodology and graded recommendations provide clear clinical guidance.","specificNumbers":"Literature searched: 1970-September 2013. Level A: oral cannabis extract for spasticity symptoms/pain. Level B: THC and Sativex for symptoms/pain; ineffective for objective measures. Safety/efficacy of CAM interaction with MS disease-modifying therapies: unknown.","methodology":"Systematic literature review from 1970 to September 2013, with articles classified according to AAN evidence standards. Recommendations were graded based on evidence strength (Level A through Level C). The guideline development subcommittee included experts in MS, neurology, and evidence-based medicine.","limitations":"The literature search ended in September 2013 and does not include subsequent studies. U.S. access to standardized cannabis preparations remains limited. The guidelines acknowledge unknown interactions between cannabis and MS disease-modifying therapies. The distinction between subjective and objective outcomes creates clinical ambiguity."},{"rthcId":"RTHC-00898","title":"Cannabinoid receptor 2 agonist attenuates pain related behavior in rats with chronic alcohol/high fat diet induced pancreatitis.","authors":"Zhang, Liping; Kline, Robert H; McNearney, Terry A; Johnson, Michael P; Westlund, Karin N","year":2014,"journal":"Molecular pain, 10, 66","doi":"10.1186/1744-8069-10-66","pmid":"25403433","tags":["pain","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats with chronic pancreatitis induced by an alcohol/high-fat diet developed visceral pain behaviors by week 3 that persisted as long as the diet continued. Treatment with the CB2 agonist LY3038404 HCl (10 mg/kg orally, twice daily for 9 days) significantly improved three measures of pain: increased paw withdrawal thresholds, prolonged abdominal withdrawal latencies, and decreased responses to heat stimuli.\n\nBeyond pain relief, the drug had a tissue-protective effect. Untreated pancreatitis rats showed extensive pancreatic damage including cellular atrophy, fat deposition, and fibrosis. Treated rats had significantly less tissue damage and fibrosis.\n\nImportantly, the drug did not affect open field exploratory behavior or dark/light box preferences, indicating no effects on higher brain function or mood, a key advantage of CB2-targeted drugs over CB1-targeting compounds.","whyItMatters":"Chronic pancreatitis pain is notoriously difficult to treat, often requiring opioids with significant side effects. A CB2 agonist that reduces both pain and tissue damage without brain effects could offer a fundamentally different approach to managing this condition.","specificNumbers":"LY3038404 HCl: 10 mg/kg orally, twice daily for 9 days. Pain improvement after 3 days of dosing. No effects on brain function (open field, dark/light box). Pancreatic tissue significantly protected from damage and fibrosis.","methodology":"Rats were fed an alcohol/high-fat diet to induce chronic pancreatitis over 5 weeks. Pain was assessed using paw withdrawal thresholds, abdominal withdrawal latencies, and hotplate responses. After pancreatitis was established, rats received LY3038404 HCl or vehicle for 9 days. Pancreatic tissue was analyzed histologically. Brain function was assessed with open field and dark/light box tests.","limitations":"This was a rat model that may not fully replicate human chronic pancreatitis. The treatment period was only 9 days, so long-term effects are unknown. The alcohol/high-fat diet model represents one etiology of pancreatitis and may not apply to all causes. The drug is a research compound not available for clinical use."},{"rthcId":"RTHC-00899","title":"Committee Opinion No. 637: Marijuana Use During Pregnancy and Lactation.","authors":"","year":2015,"journal":"Obstetrics and gynecology, 126(1), 234-8","doi":"10.1097/01.AOG.0000467192.89321.a6","pmid":"26241291","tags":["pregnancy"],"studyType":"review","evidenceStrength":"strong","keyFinding":"ACOG issued a formal committee opinion stating that women who are pregnant or contemplating pregnancy should be encouraged to discontinue marijuana use. Self-reported marijuana use during pregnancy ranges from 2-5% in most studies, and this could increase with expanding legalization.\n\nKey recommendations included: obstetricians should not prescribe or suggest marijuana for medicinal purposes during preconception, pregnancy, or lactation. Women using medical marijuana should be encouraged to switch to alternative therapies with better pregnancy-specific safety data.\n\nThe opinion cited concerns about impaired neurodevelopment and the adverse effects of smoking as the primary reasons for the recommendation. Insufficient data existed to evaluate marijuana effects on infants during lactation, so use during breastfeeding was also discouraged.","whyItMatters":"This is the official position of the leading U.S. professional organization for obstetricians on marijuana use during pregnancy. It provides clear guidance for clinicians counseling pregnant patients, particularly as legalization makes marijuana more accessible.","specificNumbers":"Self-reported marijuana use during pregnancy: 2-5% in most studies. Cannabis is the most commonly used illicit drug during pregnancy.","methodology":"This is an ACOG Committee Opinion, which represents expert consensus based on available evidence. Committee opinions are produced by panels of specialists who review the relevant literature and provide clinical guidance.","limitations":"Committee opinions represent expert consensus rather than systematic evidence review. The evidence on marijuana and pregnancy outcomes is incomplete, with most studies limited by confounding factors (polysubstance use, socioeconomic differences). The opinion does not provide detailed analysis of the quality of underlying evidence."},{"rthcId":"RTHC-00900","title":"Cannabis in cancer care.","authors":"Abrams, D I; Guzman, M","year":2015,"journal":"Clinical pharmacology and therapeutics, 97(6), 575-86","doi":"10.1002/cpt.108","pmid":"25777363","tags":["cancer","medical-cannabis","pain","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review covers established and emerging roles of cannabis in cancer care. Established indications include chemotherapy-induced nausea and vomiting (dronabinol is FDA-approved for this) and anorexia associated with AIDS wasting syndrome.\n\nFor cancer-related pain, cannabinoids may be beneficial and possibly synergistic with opioid analgesics, potentially allowing lower opioid doses. Research on cannabinoids for HIV-related peripheral neuropathy suggests they may help with cancer-related neuropathic pain as well.\n\nThe review also discusses preclinical evidence that cannabinoids may have direct antitumor effects through activation of CB1 and CB2 receptors. However, clinical evidence for antitumor activity is limited. The main limitations of medical cannabinoid use are psychoactive effects and limited bioavailability.","whyItMatters":"Cancer patients increasingly use cannabis for symptom management, but the evidence base varies greatly by indication. This review provides a structured overview of what is established versus speculative, helping patients and clinicians make informed decisions.","specificNumbers":"FDA-approved: dronabinol for chemotherapy nausea and AIDS wasting. Cannabis interacts with CB1 (CNS) and CB2 (immune) receptors. Potential opioid-sparing effects for cancer pain. Preclinical antitumor activity noted.","methodology":"This is a narrative review covering the pharmacology of cannabinoids in cancer care, including their interaction with the endocannabinoid system, established clinical indications, emerging clinical applications, and preclinical antitumor data.","limitations":"Antitumor effects are based on preclinical data only and should not influence treatment decisions. The review does not provide systematic quality assessment of included studies. Cannabinoid bioavailability issues complicate clinical dosing. Psychoactive effects limit dose escalation."},{"rthcId":"RTHC-00901","title":"A cannabinoid receptor agonist N-arachidonoyl dopamine inhibits adipocyte differentiation in human mesenchymal stem cells.","authors":"Ahn, Seyeon; Yi, Sodam; Seo, Won Jong; Lee, Myeong Jung; Song, Young Keun; Baek, Seung Yong; Yu, Jinha; Hong, Soo Hyun; Lee, Jinyoung; Shin, Dong Wook; Jeong, Lak Shin; Noh, Minsoo","year":2015,"journal":"Biomolecules & therapeutics, 23(3), 218-24","doi":"10.4062/biomolther.2014.137","pmid":"25995819","tags":["neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Three endocannabinoids were tested for their effects on fat cell (adipocyte) development from human bone marrow stem cells. Anandamide (AEA) promoted adipocyte differentiation, while NADA inhibited it. 2-AG had no significant effect at non-toxic concentrations.\n\nThe difference between AEA and NADA was traced to their effects on PPARg, a nuclear receptor critical for fat cell formation. AEA directly activated PPARg, promoting fat storage. NADA did not affect PPARg but inhibited adipogenesis through CB1 receptor activation, an effect blocked by the CB1 antagonist rimonabant.\n\nInterestingly, rimonabant itself promoted fat cell formation when given alone, suggesting that baseline CB1 receptor activity normally suppresses adipocyte differentiation in these stem cells. This finding provides a molecular explanation for some metabolic effects of cannabinoid system modulation.","whyItMatters":"Understanding how different endocannabinoids regulate fat cell formation could lead to new approaches for treating obesity and metabolic disorders. The finding that CB1 activation suppresses rather than promotes fat cell development adds nuance to the complex relationship between the cannabinoid system and metabolism.","specificNumbers":"AEA promoted adipogenesis via PPARg activation. NADA inhibited adipogenesis via CB1. 2-AG had no effect at non-toxic doses. Rimonabant (CB1 inverse agonist) promoted adipogenesis, suggesting constitutive CB1 activity suppresses fat cell formation.","methodology":"Human bone marrow mesenchymal stem cells (hBM-MSCs) were induced to differentiate into adipocytes in the presence of three endocannabinoids: AEA, NADA, and 2-AG. PPARg transactivation assays determined direct receptor activation. CB1 and TRPV1 antagonists were used to identify the receptor pathways involved.","limitations":"This was an in vitro study using cultured human stem cells, which may not fully reflect in vivo fat tissue development. The concentrations used may not be physiologically relevant. The study did not assess whether these effects translate to changes in body fat in animals or humans."},{"rthcId":"RTHC-00902","title":"Cannabinoid hyperemesis syndrome: a cause of refractory nausea and vomiting in pregnancy.","authors":"Alaniz, Veronica I; Liss, Jill; Metz, Torri D; Stickrath, Elaine","year":2015,"journal":"Obstetrics and gynecology, 125(6), 1484-1486","doi":"10.1097/AOG.0000000000000595","pmid":"25774930","tags":["pregnancy","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 28-year-old pregnant woman was repeatedly admitted for episodic nausea, vomiting, and abdominal pain, experiencing complications including Mallory-Weiss esophageal tears and dehydration. Hospital staff noted she was showering compulsively during her admissions.\n\nAfter extensive workup revealed no other cause, she was diagnosed with cannabinoid hyperemesis syndrome. The treatment was simply abstinence from marijuana use.\n\nThe case illustrates that CHS and hyperemesis gravidarum share nearly identical presentations, making CHS likely underdiagnosed in pregnant women. The compulsive bathing behavior is a key distinguishing feature that should prompt clinicians to ask about cannabis use.","whyItMatters":"As cannabis use during pregnancy ranges from 2-5%, CHS may be misdiagnosed as hyperemesis gravidarum more often than recognized. Correct diagnosis avoids unnecessary testing and invasive procedures while directing the patient to the effective treatment: cannabis cessation.","specificNumbers":"Patient age: 28. Multiple hospitalizations. Complications: Mallory-Weiss tears, dehydration. Key diagnostic clue: compulsive showering during hospitalization.","methodology":"Single case report describing a pregnant woman with multiple admissions for intractable nausea and vomiting, eventually diagnosed with CHS after an extensive negative workup.","limitations":"Single case report. Cannot establish prevalence of CHS misdiagnosed as hyperemesis gravidarum. The interaction between pregnancy physiology and CHS is not well understood."},{"rthcId":"RTHC-00903","title":"Cannabinoid replacement therapy (CRT): Nabiximols (Sativex) as a novel treatment for cannabis withdrawal.","authors":"Allsop, D J; Lintzeris, N; Copeland, J; Dunlop, A; McGregor, I S","year":2015,"journal":"Clinical pharmacology and therapeutics, 97(6), 571-4","doi":"10.1002/cpt.109","pmid":"25777582","tags":["addiction","withdrawal","medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review outlines a novel approach to treating cannabis dependence using nabiximols (Sativex), a buccal spray containing THC and CBD. The rationale is analogous to opioid substitution therapy: providing a controlled, pharmaceutical-grade cannabinoid formulation to manage withdrawal and craving while patients engage in behavioral treatment.\n\nThe advantages of nabiximols over smoked cannabis include: controlled dosing, pharmaceutical-grade standardization, slower onset (reducing abuse potential), inclusion of CBD (which may modulate THC effects and has anxiolytic properties), and a delivery method that avoids the harms of smoking.\n\nRecent research findings relevant to clinical practice are reviewed, though the approach remains investigational.","whyItMatters":"Cannabis dependence treatment currently has no FDA-approved medications. Cannabinoid replacement therapy represents a paradigm shift that applies lessons learned from opioid substitution therapy to cannabis treatment, potentially offering a new evidence-based approach.","specificNumbers":"Nabiximols contains THC and CBD in approximately 1:1 ratio. Delivered as buccal spray. Approach modeled on opioid substitution therapy (methadone, buprenorphine).","methodology":"This is a narrative review outlining the rationale and evidence for using nabiximols as a cannabinoid replacement therapy. It reviews the pharmacological basis for the approach and recent relevant research.","limitations":"Clinical trial evidence for this approach was limited at the time of publication. The regulatory pathway for using a cannabinoid to treat cannabinoid dependence is complex. Long-term outcomes, optimal treatment duration, and appropriate patient selection criteria are unknown."},{"rthcId":"RTHC-00904","title":"Cannabinoid Hyperemesis Syndrome During Pregnancy: A Case Report.","authors":"Andrews, Karinna H; Bracero, Luis A","year":2015,"journal":"The Journal of reproductive medicine, 60(9-10), 430-2","doi":null,"pmid":"26592070","tags":["pregnancy","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report documents a pregnant woman with chronic marijuana use who presented with severe nausea, vomiting, and compulsive bathing, meeting criteria for cannabinoid hyperemesis syndrome. The presentation was initially evaluated as hyperemesis gravidarum due to the shared symptoms.\n\nThe authors emphasize that with marijuana legalization increasing, CHS incidence among pregnant women may rise. Recognition of CHS in this population is important because it avoids extensive unnecessary workups, reduces healthcare costs, and directs treatment toward the effective intervention: marijuana cessation.\n\nThe case illustrates the value of obtaining a complete substance use history, including marijuana, in all pregnant patients presenting with severe nausea and vomiting.","whyItMatters":"This is another case demonstrating the diagnostic overlap between CHS and hyperemesis gravidarum. As marijuana becomes more socially acceptable, healthcare providers need to routinely screen for cannabis use in pregnant patients with severe nausea.","specificNumbers":"Single case report. Chronic marijuana use history. Nausea, vomiting, compulsive bathing during pregnancy. Diagnosis: CHS.","methodology":"Single case report with clinical description and literature review of CHS in pregnancy.","limitations":"Single case report. Limited clinical detail in the abstract. Cannot establish how common CHS misdiagnosis is in pregnancy."},{"rthcId":"RTHC-00905","title":"Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?","authors":"Arjmand, Shokouh; Vaziri, Zohreh; Behzadi, Mina; Abbassian, Hassan; Stephens, Gary J; Shabani, Mohammad","year":2015,"journal":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 12(4), 778-87","doi":"10.1007/s13311-015-0367-5","pmid":"26152606","tags":["neuroscience","medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the potential of cannabinoid-based compounds to treat tremor associated with Parkinson's disease, multiple sclerosis, Huntington's disease, and forms of ataxia. The basal ganglia and cerebellum, brain regions central to motor control, contain high densities of cannabinoid receptors.\n\nAnecdotal reports from cannabis users have suggested symptom improvement, prompting formal research. However, controlled studies have produced mixed results. Some preclinical work shows cannabinoids modulating motor circuits through shared molecular pathways across these diseases.\n\nThe authors concluded that while the biological rationale is promising, clinical evidence has not yet demonstrated reliable tremor reduction. They called for expanded preclinical studies with different cannabinoid compounds, followed by controlled clinical trials.","whyItMatters":"Tremor is one of the most disabling symptoms of movement disorders and current treatments often provide incomplete relief. If cannabinoids could be shown to reduce tremor through their action on motor control circuits, they could fill a significant gap in treatment options for millions of patients worldwide.","specificNumbers":"Cannabinoid CB1 receptors are found at high density in the basal ganglia and cerebellum. The review covered tremor across 4 major motor disorder categories. Results across existing studies were described as inconclusive.","methodology":"The researchers conducted a narrative review of published literature on cannabinoid effects in tremor-related motor disorders. They examined preclinical and clinical studies across Parkinson's disease, multiple sclerosis, Huntington's disease, and cerebellar ataxia, focusing on shared molecular mechanisms.","limitations":"This is a narrative review, not a systematic review or meta-analysis, so study selection may not be comprehensive. Many of the studies reviewed were preclinical or uncontrolled. The authors noted that clinical trial data is largely absent for most tremor indications."},{"rthcId":"RTHC-00906","title":"Not in Education, Employment, or Training status among young Swiss men. Longitudinal associations with mental health and substance use.","authors":"Baggio, Stéphanie; Iglesias, Katia; Deline, Stéphane; Studer, Joseph; Henchoz, Yves; Mohler-Kuo, Meichun; Gmel, Gerhard","year":2015,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 56(2), 238-43","doi":"10.1016/j.jadohealth.2014.09.006","pmid":"25620308","tags":["youth","mental-health","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This study tracked 4,758 young Swiss men in their early 20s to understand what leads to becoming \"NEET\" (Not in Education, Employment, or Training). At baseline, 6.1% were NEET; at follow-up, 7.4% were NEET, but only 1.4% were NEET at both time points, suggesting it was usually temporary.\n\nThe longitudinal analysis found that cannabis use, daily smoking, and depressive symptoms at baseline predicted later NEET status. But being NEET did not predict later increases in substance use or mental health problems. The causal direction appeared to go one way: substance use and mental health led to disengagement, not the reverse.\n\nNEET youth differed from their peers only on substance use and depression, not on personality traits.","whyItMatters":"Understanding whether substance use drives disengagement from work and school, or whether disengagement drives substance use, has direct implications for where to target prevention efforts. These findings suggest intervening on cannabis use and mental health before young people drop out of productive roles.","specificNumbers":"4,758 young Swiss men studied. 6.1% NEET at baseline, 7.4% at follow-up. Only 1.4% NEET at both time points. Cannabis use, daily smoking, and depression all predicted later NEET status.","methodology":"Part of the Cohort Study on Substance Use Risk Factors, this study used a repeated-measures design with baseline and follow-up assessments. Researchers used cross-lagged panel models to test bidirectional relationships between NEET status, mental health, and substance use in 4,758 young Swiss men in their early 20s.","limitations":"The sample included only young men from Switzerland, limiting generalizability to women and other cultural contexts. Self-reported substance use may undercount actual use. The NEET definition does not distinguish between voluntary and involuntary disengagement."},{"rthcId":"RTHC-00907","title":"Cannabinoid hyperemesis syndrome: a guide for the practising clinician.","authors":"Bajgoric, Sanjin; Samra, Kiran; Chandrapalan, Subashini; Gautam, Nishant","year":2015,"journal":"BMJ case reports, 2015","doi":"10.1136/bcr-2015-210246","pmid":"26698198","tags":["addiction","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The authors presented a case of a young man who developed cannabinoid hyperemesis syndrome (CHS), characterized by cyclic episodes of severe nausea, vomiting, and abdominal pain. The patient found relief through compulsive hot water bathing, a hallmark feature of the condition.\n\nThe literature review accompanying the case outlined the three phases of CHS: a prodromal phase with morning nausea, a hyperemetic phase with intense vomiting, and a recovery phase after cannabis cessation. The condition is linked specifically to chronic, long-term cannabis use.\n\nThe authors emphasized that CHS is often misdiagnosed because cannabis is widely known as an antiemetic, leading clinicians to overlook it as a cause of vomiting. Cessation of cannabis use was identified as the definitive treatment.","whyItMatters":"CHS is frequently misdiagnosed, leading to expensive and unnecessary medical workups. Recognizing the pattern of cyclic vomiting plus hot bathing relief plus chronic cannabis use can save patients from prolonged suffering and unnecessary emergency department visits.","specificNumbers":"One case presented. Cannabis is described as the most widely used illicit drug worldwide. The three clinical phases (prodromal, hyperemetic, recovery) were characterized.","methodology":"Case report of a single patient with CHS, combined with a narrative review of existing literature on the condition's pathogenesis, clinical features, and management approaches.","limitations":"Single case report with limited generalizability. The pathogenesis of CHS was not fully explained at the time of publication. The literature review was narrative rather than systematic."},{"rthcId":"RTHC-00908","title":"Examination of the role of the combination of alcohol and cannabis in South Australian road crashes.","authors":"Baldock, M R J; Lindsay, V L","year":2015,"journal":"Traffic injury prevention, 16(5), 443-9","doi":"10.1080/15389588.2014.969804","pmid":"25287700","tags":["driving","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed hospital and forensic data from 1,074 crash-involved drivers and motorcyclists admitted to hospitals in South Australia over three years. About 1 in 5 had blood alcohol above the legal limit of 0.05. Routine drug testing found about 1 in 10 tested positive for drugs, with cannabis being the most common.\n\nA key finding was the overlap: more than a third of cannabis-positive cases also involved alcohol, and when alcohol was present alongside cannabis, blood alcohol levels tended to be very high (above 0.15 g/100 mL). The coroners' reports from fatal crashes showed similar patterns.\n\nThe authors concluded that while drug driving is a genuine problem, alcohol remains the primary substance driving road trauma, and roadside drug testing should not come at the expense of random breath testing programs.","whyItMatters":"Understanding the relative contribution of different substances to road crashes helps allocate enforcement and prevention resources effectively. The frequent co-occurrence of cannabis and high-level alcohol use suggests that polydrug impairment, not cannabis alone, may be the more relevant safety concern.","specificNumbers":"1,074 crash participants studied over 3 years. 1 in 5 had BAC above 0.05. 1 in 10 tested positive for drugs. Over half of drug-positive cases involved cannabis. More than a third of cannabis cases also involved alcohol. BAC in combined cases typically exceeded 0.15 g/100 mL.","methodology":"Cross-sectional study linking hospital admission data, police crash reports, and forensic blood test results for 1,074 crash participants over three years. A supplementary sample of 135 coroners' reports from fatal crashes was also analyzed.","limitations":"Cross-sectional design cannot establish whether cannabis directly contributed to crashes. THC detection in blood does not necessarily indicate impairment at the time of the crash. The study was limited to South Australia."},{"rthcId":"RTHC-00909","title":"Adolescent cannabis exposure interacts with mutant DISC1 to produce impaired adult emotional memory.","authors":"Ballinger, Michael D; Saito, Atsushi; Abazyan, Bagrat; Taniguchi, Yu; Huang, Ching-Hsun; Ito, Koki; Zhu, Xiaolei; Segal, Hadar; Jaaro-Peled, Hanna; Sawa, Akira; Mackie, Ken; Pletnikov, Mikhail V; Kamiya, Atsushi","year":2015,"journal":"Neurobiology of disease, 82, 176-184","doi":"10.1016/j.nbd.2015.06.006","pmid":"26093170","tags":["youth","cognition","psychosis","genetics","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers studied mice carrying a mutation in the DISC1 gene (disrupted in schizophrenia 1) to test whether adolescent THC exposure interacts with genetic vulnerability to worsen adult brain function. Mice with the DN-DISC1 mutation already showed mild memory deficits, but chronic adolescent THC treatment significantly worsened fear-associated memory in adulthood.\n\nAt the molecular level, cannabinoid CB1 receptor expression was reduced in the prefrontal cortex, hippocampus, and amygdala by either the gene mutation or THC exposure independently. When combined, THC and the mutation produced a synergistic reduction in neural activity during fear memory retrieval in these brain regions.\n\nThe results demonstrated a gene-environment interaction: the genetic risk factor made the brain more vulnerable to adolescent cannabis exposure, producing deficits that persisted into adulthood.","whyItMatters":"This study provides mechanistic evidence for the gene-environment interaction hypothesis in psychiatric illness. It suggests that adolescents carrying certain genetic variants may be disproportionately vulnerable to lasting cognitive effects from cannabis, which has implications for understanding differential risk.","specificNumbers":"CB1 receptor expression was reduced in 3 key brain regions (prefrontal cortex, hippocampus, amygdala). Synergistic reduction in c-Fos expression was observed during cue-dependent fear memory retrieval in DN-DISC1 mice with adolescent THC exposure.","methodology":"Controlled animal study using transgenic mice expressing dominant-negative mutant DISC1. Adolescent mice received chronic THC treatment, then underwent fear conditioning and memory testing in adulthood. Brain tissue was analyzed for CB1 receptor expression and c-Fos activation patterns.","limitations":"Animal model results do not directly translate to humans. The DISC1 mutation is one of many genetic factors linked to schizophrenia risk. THC was administered in isolation, without the other cannabinoids present in whole cannabis. Dosing patterns may not reflect human use."},{"rthcId":"RTHC-00910","title":"Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It's Been ….","authors":"Baron, Eric P","year":2015,"journal":"Headache, 55(6), 885-916","doi":"10.1111/head.12570","pmid":"26015168","tags":["medical-cannabis","pain","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This extensive review traced the history of medicinal cannabis from ancient use through its prominence in 19th-century medicine, when it was widely prescribed for headache, to its prohibition driven by political rather than scientific factors. The author documented how cannabinoids interact with endocannabinoid, serotonergic, and opioid pathways relevant to migraine and other headache disorders.\n\nThe literature search found supportive but limited evidence for cannabis in several headache types, including migraine and cluster headache. Most evidence came from case reports, anecdotal accounts, and laboratory research rather than controlled trials.\n\nThe review identified over 100 pharmacological compounds in cannabis, noting that the majority remain poorly understood. The author argued that modulating the endocannabinoid system through various receptor targets could provide the foundation for new medication classes.","whyItMatters":"Migraine affects hundreds of millions of people globally, and existing treatments are often inadequate. If cannabinoid-based approaches could be validated through clinical trials, they could offer new options. But this review makes clear that the evidence base remains largely anecdotal.","specificNumbers":"Almost half of US states had legalized medicinal cannabis at time of publication. Cannabis contains over 100 pharmacological compounds. The review covered headache, chronic pain, and multiple other state-approved conditions.","methodology":"Comprehensive narrative review covering the history of medicinal cannabis, endocannabinoid system pharmacology, clinical evidence across state-approved conditions, and detailed analysis of headache and migraine literature. Sources were drawn from PsycINFO, MEDLINE, and Google Scholar.","limitations":"Narrative review format means study selection was not systematic. Most headache-specific evidence was anecdotal or preclinical. The review was published when clinical trial activity was still limited by federal restrictions on cannabis research."},{"rthcId":"RTHC-00911","title":"The impact of cannabis use on clinical outcomes in recent onset psychosis.","authors":"Barrowclough, Christine; Gregg, Lynsey; Lobban, Fiona; Bucci, Sandra; Emsley, Richard","year":2015,"journal":"Schizophrenia bulletin, 41(2), 382-90","doi":"10.1093/schbul/sbu095","pmid":"25011381","tags":["psychosis","mental-health","anxiety","depression"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This study followed 110 people with early psychosis who also had cannabis abuse or dependence, measuring their substance use and symptoms at four time points over 18 months. Contrary to what many expected, cannabis dose was not associated with positive psychotic symptoms, negative symptoms, relapse, or hospital admissions.\n\nHowever, greater cannabis use was linked to higher subsequent depression and anxiety. When participants reduced their cannabis use, their anxiety scores dropped and their daily functioning improved. The relationship between cannabis reduction and depression was present but did not reach the threshold for statistical change.\n\nThe findings suggest that cannabis in early psychosis may be more relevant to mood and functioning than to psychotic symptoms themselves.","whyItMatters":"Early psychosis is a critical window for intervention. If cannabis reduction improves anxiety and functioning without necessarily affecting psychotic symptoms, treatment programs can set more nuanced and achievable goals rather than framing cannabis cessation solely as psychosis prevention.","specificNumbers":"110 participants studied over 18 months with assessments at 4 time points. Cannabis dose was associated with subsequent higher depression and anxiety. Reductions in cannabis use were significantly associated with reduced anxiety and improved functioning.","methodology":"Prospective study with repeated measures at baseline, 4.5, 9, and 18 months in 110 participants with early psychosis and comorbid cannabis abuse or dependence. Random intercept models estimated effects of cannabis dose on subsequent clinical outcomes, with substance use measured before psychopathology at each time point.","limitations":"The sample of 110 participants is relatively small. All participants had comorbid cannabis problems, which may not reflect the broader early psychosis population. Self-reported cannabis use may not be fully accurate. The study cannot establish causation."},{"rthcId":"RTHC-00912","title":"Feasibility of a group cessation program for co-smokers of cannabis and tobacco.","authors":"Becker, Julia; Haug, Severin; Kraemer, Thomas; Schaub, Michael P","year":2015,"journal":"Drug and alcohol review, 34(4), 418-26","doi":"10.1111/dar.12244","pmid":"25676414","tags":["quitting","harm-reduction","addiction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested a group cessation program for people who used both cannabis weekly and tobacco daily. The program ran five to six sessions using motivational interviewing, cognitive-behavioral therapy, and self-control training. Of 77 participants, 62.3% completed treatment.\n\nAt the end of treatment, 41.5% reported abstinence from cigarettes, cannabis, or both. At 6-month follow-up, 23.4% maintained abstinence from at least one substance. Individual rates at follow-up were 10.4% for cigarettes and 19.5% for cannabis. Dual abstinence validated by biochemical testing was achieved by 5.2% at follow-up.\n\nParticipants also showed improvements in depression, anxiety, drinking problems, cannabis use disorder symptoms, and nicotine dependence over the study period. Only three participants discontinued due to severe side effects.","whyItMatters":"Cannabis and tobacco are frequently used together, but most cessation programs target only one substance. This study demonstrated that addressing both simultaneously is feasible, with acceptable retention rates and mental health improvements, supporting the case for larger controlled trials.","specificNumbers":"77 participants enrolled. Target sample recruited within 9 months. 62.3% treatment retention. 41.5% abstinent from at least one substance post-treatment. 23.4% abstinent at 6-month follow-up. 5.2% achieved validated dual abstinence at follow-up.","methodology":"Open-label feasibility study using a repeated-measures design with pre-treatment, post-treatment, and 6-month follow-up assessments. The intervention included 5-6 group sessions based on motivational interviewing, CBT, and self-control training for 77 adults who smoked cannabis weekly and tobacco daily.","limitations":"No control group, so improvements cannot be attributed specifically to the intervention. Self-reported abstinence was only partially validated biochemically. The sample was self-selected, which likely overestimates treatment effects compared to the general population."},{"rthcId":"RTHC-00913","title":"An fMRI-Based Neural Signature of Decisions to Smoke Cannabis.","authors":"Bedi, Gillinder; Lindquist, Martin A; Haney, Margaret","year":2015,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 40(12), 2657-65","doi":"10.1038/npp.2015.135","pmid":"25962875","tags":["addiction","neuroscience","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Researchers combined brain imaging with a real-world-like purchasing task where daily cannabis smokers made repeated decisions to buy or decline puffs of cannabis at various prices. One randomly selected decision was actually carried out: if they had chosen to buy, they paid and smoked in the lab.\n\nUsing machine learning, a classifier achieved 100% accuracy distinguishing brain patterns during purchase decisions from decline decisions at the individual level. Key brain regions contributing to this neural signature included the dorsal striatum, insula, posterior parietal regions, anterior and posterior cingulate, and dorsolateral prefrontal cortex.\n\nPurchasing behavior followed expected patterns: participants bought more puffs at lower prices and of active cannabis compared to placebo. The findings provide a brain-based framework for understanding drug-related decision making.","whyItMatters":"Understanding the neural basis of decisions to use drugs could enable measurement of how treatments change decision-making processes in the brain, potentially improving addiction treatment development and evaluation.","specificNumbers":"21 daily cannabis smokers participated. 17 purchased cannabis and were included in fMRI analysis. Machine learning classifier achieved 100% accuracy at the individual level. 6 brain regions reliably contributed to the decision signature.","methodology":"Functional MRI study with a within-subject choice task. Twenty-one daily cannabis smokers made repeated decisions to purchase or decline 1-12 cannabis puffs at prices from $0.25 to $5. One decision was randomly implemented. Machine learning with leave-one-subject-out cross-validation identified discriminating neural patterns in 17 participants who purchased cannabis.","limitations":"Very small sample (17 in fMRI analysis). Participants were non-treatment-seeking daily users, so results may not generalize to those trying to quit. The laboratory environment may not fully capture real-world decision contexts. 100% accuracy in a small sample may reflect overfitting."},{"rthcId":"RTHC-00914","title":"The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer's disease.","authors":"Bedse, Gaurav; Romano, Adele; Lavecchia, Angelo M; Cassano, Tommaso; Gaetani, Silvana","year":2015,"journal":"Journal of Alzheimer's disease : JAD, 43(4), 1115-36","doi":"10.3233/JAD-141635","pmid":"25147120","tags":["neuroscience","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the role of endocannabinoid signaling in Alzheimer's disease (AD) pathology. The endocannabinoid system was found to interact with multiple mechanisms involved in AD progression, including amyloid-beta aggregation, tau phosphorylation, neuroinflammation, and oxidative stress.\n\nBoth endogenous cannabinoids and plant-derived cannabinoids appeared capable of modulating these disease processes through CB1 and CB2 receptor activation. CB2 receptors, concentrated on immune cells in the brain, were particularly relevant to the neuroinflammatory component of AD.\n\nThe authors argued that because AD involves multiple dysregulated pathways simultaneously, the endocannabinoid system's ability to influence several of these pathways at once makes it a more attractive therapeutic target than single-pathway approaches.","whyItMatters":"Current Alzheimer's treatments have limited effectiveness partly because they typically target only one disease mechanism. The endocannabinoid system's involvement in multiple AD pathways suggests a therapeutic approach that could address the disease's complexity more comprehensively.","specificNumbers":"AD is described as the most common form of progressive neurodegenerative disease. Two main cannabinoid receptors (CB1 and CB2) are implicated. Multiple pathways modulated: amyloid-beta, tau, inflammation, oxidative stress.","methodology":"Narrative review synthesizing preclinical and clinical literature on the role of endocannabinoid signaling in Alzheimer's disease pathogenesis and potential therapeutic applications.","limitations":"Much of the evidence is preclinical. The complexity of the endocannabinoid system means that therapeutic manipulation could produce unwanted effects. The review is narrative rather than systematic. Human clinical data on cannabinoids for AD was minimal at the time."},{"rthcId":"RTHC-00915","title":"Cannabinoid Hyperemesis Syndrome: A Case Report and Literature Review.","authors":"Beech, Robert A; Sterrett, David R; Babiuk, James; Fung, Henry","year":2015,"journal":"Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons, 73(10), 1907-10","doi":"10.1016/j.joms.2015.03.059","pmid":"25896565","tags":["addiction","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 42-year-old woman was admitted to the hospital with a jaw fracture. Her lab work revealed dangerously low potassium and metabolic alkalosis caused by weeks of chronic vomiting, multiple times daily. The vomiting was attributed to cannabinoid hyperemesis syndrome (CHS).\n\nThe CHS had to be addressed before her jaw surgery could proceed. Treatment involved fluid resuscitation, antiemetic medications, and marijuana cessation. Once her electrolytes normalized and vomiting stopped, she was able to undergo surgical repair of her mandibular fracture.\n\nThe authors emphasized that the dental and surgical communities should be aware of CHS, especially as cannabis legalization expands. They noted the paradox that while cannabis is known for its antiemetic properties, it can produce the opposite effect in some chronic users.","whyItMatters":"CHS can create medical complications that interfere with other treatments. This case illustrates how chronic vomiting from CHS caused electrolyte imbalances severe enough to delay necessary surgery, highlighting the condition's broader medical impact.","specificNumbers":"One patient, age 42. Severe hypokalemia and metabolic alkalosis from weeks of daily vomiting. Treatment required fluid resuscitation before surgical repair could proceed.","methodology":"Single case report documenting CHS presentation in a surgical patient, with discussion of clinical implications for the dental community.","limitations":"Single case report with no ability to generalize. The patient had comorbid conditions (hypertension, myasthenia gravis) that may have complicated the picture."},{"rthcId":"RTHC-00916","title":"Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders.","authors":"Belendiuk, Katherine A; Baldini, Lisa L; Bonn-Miller, Marcel O","year":2015,"journal":"Addiction science & clinical practice, 10, 10","doi":"10.1186/s13722-015-0032-7","pmid":"25896576","tags":["medical-cannabis","pain","ptsd","epilepsy","cancer"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the scientific evidence for cannabis treatment across the conditions most commonly approved by state medical marijuana programs. They identified 13 conditions shared by at least 80% of medical marijuana states: Alzheimer's disease, ALS, cachexia, cancer, Crohn's disease, epilepsy, glaucoma, hepatitis C, HIV/AIDS, MS/spasticity, severe pain, severe nausea, and PTSD.\n\nFor the majority of these conditions, the reviewers found insufficient evidence to support recommending medical marijuana. The strongest evidence existed for chronic pain and muscle spasticity. For other conditions, the available data consisted largely of anecdotal reports, small uncontrolled studies, or preclinical research.\n\nThe authors stressed the need for rigorous research comparing smoked marijuana to existing treatments, examining safety, tolerability, and efficacy across different formulations.","whyItMatters":"State medical marijuana programs approve conditions based on political and social factors as much as scientific evidence. This review highlights the gap between what is legally approved and what is scientifically supported, emphasizing the need for more research.","specificNumbers":"13 conditions reviewed across state medical marijuana programs. Shared by at least 80% of medical marijuana states. PTSD was the only psychological condition approved. Insufficient evidence found for the majority of conditions.","methodology":"Narrative review using literature searches in PsycINFO, MEDLINE, and Google Scholar. Included studies relevant to the 13 most commonly state-approved conditions for medical marijuana, plus PTSD as the sole approved psychological condition.","limitations":"Narrative review methodology means study selection was not exhaustive. Publication date (2015) means newer evidence was not included. The review focused on smoked marijuana and may have underrepresented pharmaceutical cannabinoid research."},{"rthcId":"RTHC-00917","title":"Butane Hash Oil Burns Associated with Marijuana Liberalization in Colorado.","authors":"Bell, Cameron; Slim, Jessica; Flaten, Hanna K; Lindberg, Gordon; Arek, Wiktor; Monte, Andrew A","year":2015,"journal":"Journal of medical toxicology : official journal of the American College of Medical Toxicology, 11(4), 422-5","doi":"10.1007/s13181-015-0501-0","pmid":"26289652","tags":["harm-reduction","legalization","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers documented all hydrocarbon burns related to butane hash oil (BHO) extraction admitted to a Colorado burn center from 2008 through 2014. Zero cases presented before medical marijuana liberalization. During the medical liberalization period (2009-2013), 19 cases were admitted. After recreational legalization in 2014, 12 cases were admitted in just 8 months.\n\nThe typical patient was a young white male (median age 26). Burns were often severe: median burn size was 10% of total body surface area, median hospital stay was 10 days, 21% required intubation for airway protection, and 19 patients needed skin grafting.\n\nBHO, which can contain up to 90% THC, is manufactured by passing highly volatile butane through cannabis plant material. The process creates explosion risk in enclosed spaces.","whyItMatters":"This study documented an unintended public health consequence of marijuana liberalization: increased burn injuries from amateur production of concentrated cannabis products. It highlights the need for safety regulations and public education as cannabis markets evolve.","specificNumbers":"29 total BHO burn cases. Zero before liberalization, 19 during medical era, 12 in 2014 alone. 89.7% male, 72.4% Caucasian. Median age 26. Median 10% TBSA burns. Median 10-day hospitalization. 21% intubated. 19 required skin grafts. BHO contains up to 90% THC.","methodology":"Cross-sectional study using the National Burn Repository to capture all hydrocarbon burns at a Colorado burn center from January 2008 through August 2014. Medical records were reviewed for cases specifically associated with BHO extraction.","limitations":"Single burn center in one state limits generalizability. The study cannot determine whether these injuries would have occurred without liberalization or represent new behavior. Some BHO-related burns may have been treated at other facilities."},{"rthcId":"RTHC-00918","title":"Opposite control of frontocortical 2-arachidonoylglycerol turnover rate by cannabinoid type-1 receptors located on glutamatergic neurons and on astrocytes.","authors":"Belluomo, Ilaria; Matias, Isabelle; Pernègre, Camille; Marsicano, Giovanni; Chaouloff, Francis","year":2015,"journal":"Journal of neurochemistry, 133(1), 26-37","doi":"10.1111/jnc.13044","pmid":"25626460","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used genetically modified mice lacking CB1 receptors on specific cell types to understand how different cells regulate the endocannabinoid 2-AG. When CB1 receptors were absent from glutamate neurons, 2-AG turnover in the frontal cortex decreased. When CB1 receptors were absent from astrocytes (support cells), 2-AG turnover increased.\n\nDespite these opposite effects on 2-AG production and degradation rates, baseline 2-AG levels remained constant across all genotypes. This was because the body compensated: changes in synthesis rates were matched by proportional changes in degradation rates.\n\nThis cell-type-specific regulation was primarily observed in the frontal cortex, with some effects in the hippocampus. The striatum showed minimal genotype effects.","whyItMatters":"Understanding that different cell types regulate endocannabinoids in opposite directions has implications for developing targeted cannabis-based therapies. It explains why simply measuring endocannabinoid levels at a single time point may miss important dynamic changes.","specificNumbers":"Three genotypes of conditional knockout mice tested. Three brain regions examined. 2-AG accumulation rates decreased in frontal cortex of glutamate neuron knockouts and increased in frontal cortex and hippocampus of astrocyte knockouts.","methodology":"Controlled animal study using three lines of conditional knockout mice, each lacking CB1 receptors from one cell type: forebrain GABAergic neurons, cortical glutamatergic neurons, or astrocytes. Mice were treated with JZL195, a dual enzyme inhibitor, and endocannabinoid levels were measured in frontal cortex, hippocampus, and striatum.","limitations":"Animal study results may not directly translate to humans. The conditional knockout approach completely removes receptors from a cell type rather than modulating them, which is more extreme than natural variation. JZL195 blocks both FAAH and MAGL simultaneously."},{"rthcId":"RTHC-00919","title":"Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo.","authors":"Bernal-Chico, Ana; Canedo, Manuel; Manterola, Andrea; Victoria Sánchez-Gómez, María; Pérez-Samartín, Alberto; Rodríguez-Puertas, Rafael; Matute, Carlos; Mato, Susana","year":2015,"journal":"Glia, 63(1), 163-76","doi":"10.1002/glia.22742","pmid":"25130621","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested JZL184, a drug that blocks the enzyme MAGL (which breaks down the endocannabinoid 2-AG), in cell cultures and two different mouse models of multiple sclerosis-like disease. In cultured oligodendrocytes (the cells that produce myelin), MAGL blockade protected against excitotoxic cell death through CB1 receptor activation.\n\nThe protection involved reduced calcium overload, preserved mitochondrial function, and decreased reactive oxygen species. In the chronic autoimmune model (EAE), JZL184 treatment decreased disease severity, prevented demyelination, and reduced inflammation. In the cuprizone model (which causes demyelination without immune involvement), JZL184 preserved myelin and suppressed microglial activation.\n\nThe endocannabinoid 2-AG itself, applied directly, also protected oligodendrocytes, suggesting the therapeutic benefit comes from boosting the body's own cannabinoid signaling.","whyItMatters":"Multiple sclerosis involves progressive loss of myelin, and current treatments primarily target the immune system. This study shows the endocannabinoid system can directly protect the myelin-producing cells themselves, suggesting a complementary therapeutic approach.","specificNumbers":"MAGL inhibitor JZL184 reduced disease severity in EAE model. Myelin was preserved in both EAE and cuprizone models. Protection depended on CB1 receptor activation. FAAH inhibition (URB597) showed no effect.","methodology":"Combined in vitro and in vivo study. Cell culture experiments tested MAGL and FAAH inhibitors on oligodendrocyte survival under excitotoxic conditions. Two mouse MS models were used: chronic EAE (immune-mediated) and cuprizone (toxin-induced demyelination). JZL184 was administered therapeutically after disease onset.","limitations":"Animal model results do not guarantee human efficacy. JZL184 affects 2-AG levels throughout the body, which could produce unwanted effects. The MS models do not fully replicate human disease complexity. Long-term safety of MAGL inhibition was not assessed."},{"rthcId":"RTHC-00920","title":"Use and effects of cannabinoids in military veterans with posttraumatic stress disorder.","authors":"Betthauser, Kevin; Pilz, Jeffrey; Vollmer, Laura E","year":2015,"journal":"American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 72(15), 1279-84","doi":"10.2146/ajhp140523","pmid":"26195653","tags":["ptsd","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Researchers reviewed 11 articles on cannabis use by military veterans who met diagnostic criteria for PTSD. Cross-sectional studies found that veterans with more severe PTSD symptoms reported greater motivation to use cannabis for coping, particularly those with difficulty regulating emotions or tolerating stress.\n\nFour small studies suggested cannabinoid use was associated with improvements in overall PTSD symptoms or specific symptoms like insomnia and nightmares. The pharmacologic rationale was documented: cannabinoids activate endogenous receptors involved in pleasure and memory processes, which overlap with the three core PTSD symptom clusters (re-experiencing, avoidance/numbing, and hyperarousal).\n\nHowever, the authors emphasized that the evidence base consisted entirely of small, mostly uncontrolled studies, and large well-designed trials were needed before cannabis could be recommended as a treatment approach.","whyItMatters":"Veterans with PTSD represent one of the largest populations using cannabis therapeutically, yet the evidence supporting this use remains preliminary. Understanding their experiences and outcomes is essential for developing evidence-based treatment guidelines.","specificNumbers":"11 articles reviewed. Four small studies suggested symptom improvements. Three core PTSD symptom clusters identified as potentially modulated by cannabinoids. Veterans with more severe PTSD showed greater cannabis use motivation.","methodology":"Literature review of 11 articles identified through structured search, examining cannabis and cannabinoid use by military veterans meeting standard PTSD diagnostic criteria.","limitations":"Only 11 articles met inclusion criteria, and most were small and uncontrolled. The review could not determine whether cannabis use improves PTSD outcomes or whether veterans with certain symptom profiles are simply more likely to self-medicate. Publication bias may favor positive results."},{"rthcId":"RTHC-00921","title":"Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis.","authors":"Bhattacharyya, Sagnik; Atakan, Z; Martin-Santos, R; Crippa, J A; Kambeitz, J; Malhi, S; Giampietro, V; Williams, S; Brammer, M; Rubia, K; Collier, D A; McGuire, P K","year":2015,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 25(1), 26-37","doi":"10.1016/j.euroneuro.2014.11.018","pmid":"25532865","tags":["psychosis","cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers gave 36 healthy men with minimal cannabis exposure either 10mg of oral THC or placebo in a double-blind crossover design, then scanned their brains during a task requiring them to withhold automatic responses (Go/No-Go task).\n\nTHC increased inhibition errors and reduced inhibition efficiency compared to placebo. It also reduced activation in the left inferior frontal gyrus, a brain region critical for stopping unwanted actions. The severity of transient psychotic symptoms induced by THC directly correlated with more frequent inhibition errors and lower inhibition efficiency.\n\nThe left inferior frontal activation was inversely correlated with both error frequency and psychotic symptom severity, suggesting that THC's disruption of this brain region may be a mechanism linking cannabis to transient psychotic experiences.","whyItMatters":"This study provides experimental evidence that THC disrupts the brain's ability to suppress unwanted responses, and that this specific cognitive impairment is directly related to the psychotic symptoms that THC can temporarily induce. This mechanistic link helps explain why cannabis use is associated with psychosis risk.","specificNumbers":"36 healthy men studied in crossover design. 10mg oral THC vs. placebo. THC increased inhibition errors and reduced inhibition efficiency. Left inferior frontal activation was reduced by THC. Psychotic symptom severity correlated with error frequency.","methodology":"Randomized, placebo-controlled, double-blind, within-subject crossover design. 36 healthy right-handed men with minimal cannabis exposure received 10mg oral delta-9-THC or placebo on separate sessions. Brain activation was measured with fMRI during a Go/No-Go response inhibition task.","limitations":"The study used healthy men with minimal cannabis exposure, so results may not generalize to regular users who may develop tolerance. Oral THC administration differs from smoked cannabis. 10mg is a specific dose and effects may vary at other doses. The crossover design means order effects are possible."},{"rthcId":"RTHC-00922","title":"Cannabinoid modulation of functional connectivity within regions processing attentional salience.","authors":"Bhattacharyya, Sagnik; Falkenberg, Irina; Martin-Santos, Rocio; Atakan, Zerrin; Crippa, Jose A; Giampietro, Vincent; Brammer, Mick; McGuire, Philip","year":2015,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 40(6), 1343-52","doi":"10.1038/npp.2014.258","pmid":"25249057","tags":["psychosis","neuroscience","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers administered THC, CBD, or placebo to healthy occasional cannabis users and scanned their brains during a task involving processing novel and salient stimuli. THC and CBD produced opposite effects on functional connectivity between brain regions central to attention and salience processing.\n\nTHC reduced connectivity between the dorsal striatum and prefrontal cortex, and this reduction was related to poorer task performance. CBD enhanced this same connection. Conversely, THC increased connectivity between the hippocampus and prefrontal cortex, while CBD reduced it.\n\nThese opposite effects on brain network communication occurred in regions involved in determining what is relevant and worth attending to, a process called salience attribution. Disrupted salience processing is a leading theory for how psychotic symptoms arise.","whyItMatters":"The finding that THC and CBD have opposite effects on brain connectivity in salience-processing regions provides a neural basis for why THC can induce psychotic-like experiences while CBD may protect against them. This has implications for understanding how different cannabis strains or ratios affect the brain.","specificNumbers":"Three conditions compared: THC, CBD, placebo. Three key brain regions analyzed: dorsal striatum, prefrontal cortex, hippocampus. THC and CBD showed opposite effects on fronto-striatal and mediotemporal-prefrontal connectivity.","methodology":"Randomized, placebo-controlled study in healthy occasional cannabis users. Participants received oral THC, CBD, or placebo and underwent fMRI during an oddball salience processing task. Seed cluster-based functional connectivity analysis examined correlations between salience-processing brain regions.","limitations":"The sample included only occasional cannabis users, so results may differ in regular or heavy users. Single-dose design does not capture effects of chronic use. The study used oral administration, which differs from smoked or vaped cannabis in onset and metabolism."},{"rthcId":"RTHC-00923","title":"The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone.","authors":"Bisaga, Adam; Sullivan, Maria A; Glass, Andrew; Mishlen, Kaitlyn; Pavlicova, Martina; Haney, Margaret; Raby, Wilfrid N; Levin, Frances R; Carpenter, Kenneth M; Mariani, John J; Nunes, Edward V","year":2015,"journal":"Drug and alcohol dependence, 154, 38-45","doi":"10.1016/j.drugalcdep.2015.05.013","pmid":"26187456","tags":["addiction","drug-interactions","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Sixty opioid-dependent participants were randomized to receive dronabinol (30mg/day) or placebo during inpatient detoxification and transition to extended-release naltrexone. Dronabinol significantly reduced the severity of opioid withdrawal symptoms during the inpatient phase.\n\nHowever, successful induction onto naltrexone (66% dronabinol vs. 55% placebo) and 8-week treatment completion rates (35% in both groups) were not significantly different. A post hoc finding revealed that 32% of participants who smoked marijuana during the outpatient phase, regardless of their assigned group, had lower insomnia and anxiety and were more likely to complete the full 8-week trial.\n\nThe study suggests dronabinol has a role in acute withdrawal management but may not be sufficient to improve longer-term treatment retention.","whyItMatters":"Opioid withdrawal is a major barrier to starting and maintaining treatment. Finding medications that ease this transition could save lives. While dronabinol helped with acute withdrawal, the treatment retention challenge remains unsolved.","specificNumbers":"60 participants (40 dronabinol, 20 placebo). Dronabinol reduced withdrawal severity (p=0.006). Naltrexone induction: 66% dronabinol vs. 55% placebo (not significant). 8-week completion: 35% in both groups. 32% who smoked marijuana outpatient were more likely to complete treatment.","methodology":"Randomized, double-blind, placebo-controlled trial. 40 participants received dronabinol 30mg/day and 20 received placebo during inpatient detoxification and naltrexone induction. All received extended-release naltrexone injections. Dronabinol or placebo continued for 5 weeks outpatient.","limitations":"Unequal group sizes (2:1 randomization). The post hoc marijuana use finding was not pre-planned and should be interpreted cautiously. Sample size may have been insufficient to detect moderate differences in retention. Outpatient marijuana use was self-selected, introducing selection bias."},{"rthcId":"RTHC-00924","title":"Cannabidiol as a potential treatment for anxiety disorders","authors":"Blessing, Esther M.; Steenkamp, Maria M.; Manzanares, Jorge; Marmar, Charles R.","year":2015,"journal":"Neurotherapeutics, 12(4), 825-836","doi":null,"pmid":"26341731","tags":["cbd","anxiety","mental-health"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Across animal models, CBD showed consistent anxiolytic-like effects spanning generalized anxiety, panic, social anxiety, obsessive-compulsive disorder, and post-traumatic stress. That is the strongest part of the evidence base, but it is preclinical.\n\nHuman data pointed in the same direction, with CBD associated with lower anxiety in acute experimental settings. Most of these were single-dose studies, often in tasks designed to provoke anxiety, and only a few included people with diagnosed anxiety disorders. Evidence on repeated or chronic dosing, real-world functioning, and sustained symptom change was largely missing at the time of publication.","whyItMatters":"By 2015, public interest in CBD for anxiety outpaced clinical evidence. This review pulled the scattered studies into one place and clarified a gap: encouraging acute signals with very limited data on sustained use in people with diagnosed anxiety disorders.","specificNumbers":"- Publication year: 2015, narrative review of preclinical, human experimental, clinical, and epidemiological studies\n- Anxiety conditions covered: 5 named disorders (GAD, panic disorder, social anxiety disorder, OCD, PTSD)\n- Human evidence: largely acute, single-dose studies in anxiety-provoking tasks; few trials in clinical populations\n- Chronic dosing: very limited investigation of multi-week or maintenance use","methodology":"The authors reviewed preclinical experiments, human laboratory studies, early clinical reports, and epidemiological findings on CBD and anxiety. It reads as a narrative synthesis rather than a formal systematic review. Study designs, doses, and populations varied widely, and the abstract does not report a risk-of-bias assessment or meta-analysis. The strongest human data involved acute dosing in experimental paradigms, not long-term treatment trials.","limitations":"Narrative review without reported risk-of-bias grading or quantitative synthesis. Heavy reliance on preclinical work and acute human experiments. Few studies in patients with diagnosed anxiety disorders. Minimal data on repeated or chronic dosing, dose-response, or functional outcomes. Funding and conflicts not reported in the abstract."},{"rthcId":"RTHC-00925","title":"The impact of posttraumatic stress disorder on cannabis quit success.","authors":"Bonn-Miller, Marcel O; Moos, Rudolf H; Boden, Matthew Tyler; Long, W Robert; Kimerling, Rachel; Trafton, Jodie A","year":2015,"journal":"The American journal of drug and alcohol abuse, 41(4), 339-44","doi":"10.3109/00952990.2015.1043209","pmid":"26043369","tags":["ptsd","quitting","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 104 cannabis-dependent veterans through a self-guided quit attempt, assessing them weekly for the first month and then monthly through 6 months. Veterans with PTSD used more cannabis at baseline and showed a slower initial decline in use following their quit attempt.\n\nHowever, PTSD diagnosis was not associated with the time to first lapse (any use after quitting) or the time to full relapse (return to regular use). The slower reduction pattern occurred even after accounting for alcohol and tobacco use, as well as co-occurring mood and anxiety disorders.\n\nThe findings suggest that PTSD does not necessarily make quitting cannabis harder in terms of relapse timing, but it does affect the trajectory of reduction, meaning veterans with PTSD may need more intensive early support.","whyItMatters":"Understanding how PTSD affects cannabis cessation patterns helps tailor treatment approaches. The finding that PTSD slows early reduction without accelerating relapse suggests a window for targeted intervention during the first weeks of a quit attempt.","specificNumbers":"104 veterans studied. Mean age 50.9 years. PTSD was associated with higher baseline cannabis use and slower initial decline. PTSD was not associated with time to first lapse or relapse. Results held after controlling for alcohol, tobacco, mood, and anxiety disorders.","methodology":"Prospective cohort study of 104 predominantly male, cannabis-dependent US veterans (mean age 50.9). Assessments occurred before a self-guided quit attempt, weekly for 4 weeks, and monthly through 6 months. Analyses controlled for alcohol and tobacco use and co-occurring psychiatric diagnoses.","limitations":"Self-guided quit attempt without structured treatment may not reflect outcomes with professional support. Predominantly male veteran sample limits generalizability. Cannabis use was self-reported. The relatively older sample (mean age 51) may not reflect younger veteran populations."},{"rthcId":"RTHC-00926","title":"Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification (Part II): Psychiatric complaints and their relation to delta-9-tetrahydrocannabinol and its metabolites in serum.","authors":"Bonnet, Udo; Borda, Thorsten; Scherbaum, Norbert; Specka, Michael","year":2015,"journal":"Drug and alcohol dependence, 155, 302-6","doi":"10.1016/j.drugalcdep.2015.08.003","pmid":"26298553","tags":["withdrawal","mental-health","cognition"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Thirty-five chronic cannabis-dependent individuals were monitored during inpatient detoxification using both clinician-rated and self-reported psychiatric scales. At admission, nearly 90% showed no or only mild depression, anxiety, or manic symptoms on clinician-rated scales. However, about 60% described strong psychiatric distress in self-reports.\n\nAll patients improved significantly within 16 days. Effect sizes ranged from 0.7 to 1.4 (Cohen's d), indicating medium to large improvements across all measures. THC blood levels at admission were associated with cognitive impairment and motor retardation but not with mood or anxiety symptoms.\n\nThe discrepancy between clinician observations and self-reports was attributed to withdrawal syndrome effects and executive dysfunction, which may alter patients' ability to accurately assess their own mental state.","whyItMatters":"This study provides a timeline for psychiatric improvement during supervised cannabis withdrawal. The 16-day improvement window and the discrepancy between how patients feel versus how they appear to clinicians are both clinically useful for managing expectations during detox.","specificNumbers":"35 patients studied. 90% showed mild or no clinician-rated psychiatric symptoms at admission. 60% self-reported strong psychiatric burden. Effect sizes 0.7-1.4 (Cohen's d) for improvement over 16 days. THC levels predicted cognitive impairment and motor retardation.","methodology":"Prospective observational study of 35 treatment-seeking chronic cannabis-dependent patients (ICD-10 criteria) without active comorbid psychiatric conditions. Assessed at admission and on abstinence days 8 and 16 using HAMD, HAMA, YMRS, BPRS, and SCL-90-R. Serum THC and metabolites measured simultaneously.","limitations":"Small sample of 35 patients. No control group. Patients were treatment-seeking and free of active comorbid conditions, which limits generalizability. Sixteen days may not capture the full duration of withdrawal symptoms."},{"rthcId":"RTHC-00927","title":"Psychological, social and familial factors associated with tobacco cessation among young adults.","authors":"Bowes, Lucy; Chollet, Aude; Fombonne, Eric; Melchior, Maria","year":2015,"journal":"European addiction research, 21(3), 153-159","doi":"10.1159/000367691","pmid":"25832118","tags":["quitting","youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 678 regular smokers from a French cohort study (mean age 28.9) who had smoked for an average of 10.5 years. About 60% had attempted to quit at least once. Using Cox regression models, the study identified factors associated with successful tobacco cessation of at least 12 months.\n\nCannabis use in the preceding year was negatively associated with quitting tobacco, as were recent financial difficulties. Living with a partner increased the likelihood of successful cessation. For women specifically, pregnancy or recent childbirth was associated with quitting.\n\nPersonality traits and adolescent factors played less of a role than current substance use and social circumstances in predicting tobacco cessation success.","whyItMatters":"Cannabis and tobacco are often used together, and this study shows that cannabis use actively interferes with tobacco cessation. Treatment programs that address both substances simultaneously may be more effective than targeting tobacco alone.","specificNumbers":"678 regular smokers studied. Mean age 28.9 years. Average smoking duration 10.5 years. 59.5% had attempted to quit at least once. Cannabis use and financial difficulties both negatively predicted cessation.","methodology":"Longitudinal analysis from the TEMPO cohort study linked with the GAZEL parental cohort in France. Cox proportional hazards models estimated hazard ratios for tobacco cessation of at least 12 months among 678 regular smokers, examining psychological, social, and familial predictors.","limitations":"French cohort may not generalize to other countries. Self-reported cannabis use and cessation. The study could not determine the mechanism by which cannabis interferes with tobacco cessation (social, pharmacological, or behavioral)."},{"rthcId":"RTHC-00928","title":"Dissecting the cannabinergic control of behavior: The where matters.","authors":"Busquets-Garcia, Arnau; Desprez, Tifany; Metna-Laurent, Mathilde; Bellocchio, Luigi; Marsicano, Giovanni; Soria-Gomez, Edgar","year":2015,"journal":"BioEssays : news and reviews in molecular, cellular and developmental biology, 37(11), 1215-25","doi":"10.1002/bies.201500046","pmid":"26260530","tags":["neuroscience","cognition","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how the location of CB1 receptors across different brain cell types and subcellular compartments determines the specific behavioral effects of cannabinoids. CB1 receptors are widely distributed across the brain on glutamatergic neurons, GABAergic neurons, astrocytes, and even on mitochondria within cells.\n\nThe same receptor produces different molecular and cellular effects depending on which cell type expresses it. For example, CB1 receptors on glutamatergic neurons and GABAergic neurons mediate different aspects of memory and feeding. CB1 receptors on astrocytes contribute to memory through distinct mechanisms. Even CB1 receptors on mitochondria within cells influence energy metabolism differently.\n\nThe authors argued that understanding these site-specific actions is essential for developing targeted cannabinoid-based medicines that produce desired effects without unwanted ones.","whyItMatters":"The location-dependent effects of CB1 receptors explain why cannabis produces such a wide range of effects simultaneously. This knowledge could enable development of cannabinoid medicines that target specific cell types to treat conditions like appetite disorders or memory problems without broad side effects.","specificNumbers":"CB1 receptors identified on at least 4 cell types (glutamatergic neurons, GABAergic neurons, astrocytes, mitochondria). Effects analyzed in two behavioral domains: memory and feeding.","methodology":"Narrative review synthesizing research on cell-type-specific and subcellular-compartment-specific functions of CB1 receptors, with a focus on memory and feeding behavior.","limitations":"Much of the evidence comes from genetic knockout mice, which completely remove receptors from cell types rather than modulating them. Human confirmation of cell-type-specific effects is limited."},{"rthcId":"RTHC-00929","title":"Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function.","authors":"Cabral, Guy A; Rogers, Thomas J; Lichtman, Aron H","year":2015,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 10(2), 193-203","doi":"10.1007/s11481-015-9615-z","pmid":"26054900","tags":["inflammation","neuroscience","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how cannabinoid signaling interacts with the brain's immune system. The traditional view of the brain as immune-privileged was described as oversimplified. Resident immune cells and cross-talk with peripheral immune cells are essential for normal brain function, but prolonged neuroinflammation characterizes diseases like multiple sclerosis, Alzheimer's, and ALS.\n\nPhytocannabinoids (from cannabis), synthetic cannabinoids, and endocannabinoids all demonstrated immunoregulatory and anti-inflammatory properties in brain tissue through cannabinoid receptor activation. These effects were seen in microglia (the brain's primary immune cells), astrocytes, and other brain immune-related cells.\n\nThe review highlighted both CB1 and CB2 receptor-mediated pathways as potential therapeutic targets, with CB2 receptors being particularly relevant because they are upregulated during neuroinflammation without producing the psychoactive effects associated with CB1 activation.","whyItMatters":"Neuroinflammation is a shared feature of many devastating brain diseases. If cannabinoid-based approaches can modulate brain immune responses without causing psychoactive effects (via CB2 targeting), they could complement existing treatments for conditions with limited therapeutic options.","specificNumbers":"Three neuroinflammatory diseases discussed: MS, Alzheimer's, ALS. Two cannabinoid receptors analyzed: CB1 and CB2. Multiple immune cell types covered: microglia, astrocytes, dendritic cells.","methodology":"Narrative review of literature on cannabinoid modulation of brain immune responses, covering phytocannabinoids, synthetic cannabinoids, and endocannabinoids across multiple neuroinflammatory disease models.","limitations":"Narrative review with mostly preclinical evidence. Clinical data on cannabinoid immunotherapy for neurological diseases was limited. The complexity of brain immune responses means in vitro findings may not translate to clinical settings."},{"rthcId":"RTHC-00930","title":"Strain dependence of adolescent Cannabis influence on heroin reward and mesolimbic dopamine transmission in adult Lewis and Fischer 344 rats.","authors":"Cadoni, Cristina; Simola, Nicola; Espa, Elena; Fenu, Sandro; Di Chiara, Gaetano","year":2015,"journal":"Addiction biology, 20(1), 132-42","doi":"10.1111/adb.12085","pmid":"23957273","tags":["neuroscience","addiction","dopamine","genetics","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested the \"gateway hypothesis\" by exposing adolescent rats of two genetically distinct strains (Lewis and Fischer 344) to THC and measuring heroin-related behaviors in adulthood. The strains responded very differently.\n\nIn Lewis rats (naturally more addiction-prone), adolescent THC did not increase heroin reward itself but potentiated the ability of a heroin dose to reinstate drug-seeking after extinction. In Fischer 344 rats (naturally more resilient), adolescent THC increased heroin reward and made it resistant to extinction.\n\nAt the brain level, adolescent THC amplified heroin's dopamine-releasing effects in the nucleus accumbens of both strains, but in different subregions. THC also affected emotional function only in Lewis rats. The findings suggest that genetic background determines whether and how adolescent cannabis exposure influences later opioid vulnerability.","whyItMatters":"The gateway hypothesis is one of the most debated topics in drug policy. This study provides mechanistic evidence that the answer is not universal but depends on genetic background, which helps explain why some adolescent cannabis users go on to use harder drugs and most do not.","specificNumbers":"Two rat strains compared. Lewis rats showed potentiated heroin reinstatement after adolescent THC. Fischer 344 rats showed increased heroin reward and resistance to extinction. Dopamine effects observed in nucleus accumbens shell and core.","methodology":"Controlled animal study using Lewis and Fischer 344 rat strains. Adolescent rats received THC, then adult responses were measured using conditioned place preference (heroin reward), microdialysis (dopamine release), and behavioral tests for cognition and anxiety.","limitations":"Rat genetic strains do not directly map to human genetic variation. THC was administered in isolation without other cannabinoids. The forced administration paradigm does not capture voluntary use patterns. Results may not translate across species."},{"rthcId":"RTHC-00931","title":"Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria.","authors":"Campos, A C; Brant, F; Miranda, A S; Machado, F S; Teixeira, A L","year":2015,"journal":"Neuroscience, 289, 166-80","doi":"10.1016/j.neuroscience.2014.12.051","pmid":"25595981","tags":["cbd","neuroscience","inflammation","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers infected mice with a malaria parasite that causes cerebral malaria and treated them with CBD (30mg/kg/day). CBD-treated mice showed improved survival and were protected from the memory deficits and anxiety that normally accompany the disease.\n\nAt the peak of disease (day 5), infected mice showed increased inflammatory cytokines (TNF-alpha and IL-6) in the hippocampus and prefrontal cortex. CBD treatment reduced these inflammatory markers and increased BDNF (brain-derived neurotrophic factor) in the hippocampus, a protein essential for learning and memory.\n\nThe memory protection persisted even after the parasites were cleared with antimalarial drugs, suggesting CBD prevented lasting brain damage rather than just temporarily masking symptoms. The findings point to CBD's anti-inflammatory and neuroprotective properties as the mechanisms.","whyItMatters":"Cerebral malaria kills hundreds of thousands annually, and survivors often suffer permanent neurological damage. If CBD can prevent brain damage as an adjunct to antimalarial treatment, it could improve outcomes for survivors in resource-limited settings.","specificNumbers":"CBD dose: 30mg/kg/day for 3 or 7 days. Assessed at day 5 post-infection (peak disease) and after parasite clearance. TNF-alpha and IL-6 reduced by CBD in hippocampus and prefrontal cortex. BDNF increased in hippocampus.","methodology":"Controlled animal study using a mouse model of cerebral malaria. Female mice were infected with Plasmodium berghei ANKA and treated with CBD, antimalarial artesunate, or combinations. Memory and anxiety were assessed using Novel Object Recognition, Morris Water Maze, Open Field, and Elevated Plus Maze tests. Brain cytokines and neurotrophins were measured.","limitations":"Mouse model of cerebral malaria does not perfectly replicate human disease. CBD doses used may not translate directly to human dosing. The study was relatively small and used a single CBD dose level. Human clinical trials in malaria have not been conducted."},{"rthcId":"RTHC-00932","title":"Impaired learning from errors in cannabis users: Dorsal anterior cingulate cortex and hippocampus hypoactivity.","authors":"Carey, Susan E; Nestor, Liam; Jones, Jennifer; Garavan, Hugh; Hester, Robert","year":2015,"journal":"Drug and alcohol dependence, 155, 175-82","doi":"10.1016/j.drugalcdep.2015.07.671","pmid":"26249266","tags":["cognition","addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Fifteen chronic cannabis users and 15 controls completed a paired-associate learning task during brain scanning. The task allowed researchers to track when participants successfully learned from their mistakes versus repeating the same errors.\n\nCannabis users corrected fewer errors overall and showed reduced activation in two key brain regions during error processing: the dorsal anterior cingulate cortex (dACC, which monitors for mistakes) and the left hippocampus (which re-encodes correct information after an error). In controls, the dACC showed significantly different activation between corrected and repeated errors, indicating the brain was distinguishing between productive and unproductive error processing. Cannabis users did not show this distinction.\n\nThe findings suggest that chronic cannabis use impairs the brain's ability to detect mistakes and use that feedback to improve performance.","whyItMatters":"Learning from mistakes is fundamental to adapting behavior. This impairment in error-based learning could contribute to the difficulty cannabis-dependent individuals have in changing their behavior, including reducing or stopping use despite negative consequences.","specificNumbers":"15 cannabis users vs. 15 controls. Lower error-correction rate in cannabis users. Reduced dACC and left hippocampal activation during error processing. Control group showed significant distinction between corrected and repeated errors; cannabis group did not.","methodology":"Cross-sectional fMRI study comparing 15 chronic cannabis users (mean age 22.4) with 15 matched controls (mean age 23.3) on a paired-associate learning task that tracked error correction during brain scanning.","limitations":"Very small sample (15 per group) limits statistical power and generalizability. Cross-sectional design cannot determine whether cannabis caused the impairments or whether pre-existing differences predisposed both cannabis use and poorer error learning. Only 4 females included."},{"rthcId":"RTHC-00933","title":"[18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users.","authors":"Ceccarini, Jenny; Kuepper, Rebecca; Kemels, Dieter; van Os, Jim; Henquet, Cécile; Van Laere, Koen","year":2015,"journal":"Addiction biology, 20(2), 357-67","doi":"10.1111/adb.12116","pmid":"24373053","tags":["addiction","neuroscience","tolerance"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used a specialized PET imaging technique with the radioligand [18F]MK-9470 to measure CB1 receptor availability in 10 chronic cannabis users within the first week after their last use. Compared to 10 age-matched controls, cannabis users showed an overall 11.7% global decrease in CB1 receptor availability.\n\nThe reductions were most pronounced in specific brain regions: temporal lobe (-12.7%), anterior cingulate cortex (-12.6%), posterior cingulate cortex (-13.5%), and nucleus accumbens (-11.2%). Both regional analysis and whole-brain voxel-based analysis confirmed this pattern.\n\nThese changes represent neuroadaptive responses to chronic cannabinoid exposure and are thought to underlie the development of tolerance (needing more cannabis for the same effect) and dependence. This was the first human study to use this particular high-affinity PET ligand for measuring CB1 changes in cannabis users.","whyItMatters":"This study provides direct human brain evidence for CB1 receptor downregulation in cannabis users, confirming in humans what was previously only known from animal studies. Understanding how the brain adapts to chronic cannabis may help predict treatment outcomes and develop targeted interventions.","specificNumbers":"10 cannabis users vs. 10 controls. Global CB1 decrease: -11.7%. Temporal lobe: -12.7%. Anterior cingulate: -12.6%. Posterior cingulate: -13.5%. Nucleus accumbens: -11.2%.","methodology":"Cross-sectional PET imaging study comparing 10 chronic cannabis users (mean age 26.0) with 10 age-matched healthy controls (mean age 23.0). Cannabis users were scanned within the first week after last consumption. Parametric images of CB1 receptor availability were analyzed using both volume-of-interest and voxel-based statistical approaches.","limitations":"Very small sample (10 per group). Cross-sectional design. Cannabis users were scanned within the first week of abstinence, so acute withdrawal effects could influence findings. No information on whether receptor levels normalize with sustained abstinence."},{"rthcId":"RTHC-00934","title":"Interaction between the endocannabinoid and serotonergic system in the exhibition of head twitch response in four mouse strains.","authors":"Ceci, Chiara; Proietti Onori, Martina; Macrì, Simone; Laviola, Giovanni","year":2015,"journal":"Neurotoxicity research, 27(3), 275-83","doi":"10.1007/s12640-014-9510-z","pmid":"25516122","tags":["neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers investigated whether URB597, a drug that boosts the body's own cannabinoid levels by blocking the enzyme that breaks them down, could reduce tic-like behaviors in mice. Head twitches were pharmacologically induced using a serotonin receptor agonist (DOI) to model tic disorders.\n\nURB597 significantly reduced tic-like head twitches across all four mouse strains tested (ABH, C57BL/6N, SJL/J, CD-1), demonstrating that the effect was robust across different genetic backgrounds. The drug caused only mild sedation in one strain and was otherwise well tolerated.\n\nThe rationale for this approach was that direct THC use has problematic side effects for tic treatment, while indirectly boosting endocannabinoids through enzyme inhibition might provide therapeutic benefit with fewer side effects.","whyItMatters":"Over 10% of school-age children experience transient tic disorders, and Tourette syndrome affects about 1%. Current treatments have significant side effects. Boosting endocannabinoids rather than using THC directly could offer a better-tolerated approach.","specificNumbers":"Four mouse strains tested. URB597 reduced tic-like behavior in all strains. Mild sedation observed in only one strain (C57BL/6N). Over 10% of children experience transient tics; 1% have Tourette syndrome.","methodology":"Controlled animal study testing URB597 (FAAH inhibitor) against DOI-induced head twitch responses in four mouse strains chosen to represent diverse genetic backgrounds. Behavioral observations quantified head twitches before and after treatment.","limitations":"Mouse head twitches induced by a drug are a model of tics but do not replicate the full complexity of human tic disorders or Tourette syndrome. URB597 has not been tested in human tic patients. The four strains may still not capture human genetic diversity."},{"rthcId":"RTHC-00935","title":"Do consumers substitute opium for hashish? An economic analysis of simultaneous cannabinoid and opiate consumption in a legal regime.","authors":"Chandra, Siddharth; Chandra, Madhur","year":2015,"journal":"Drug and alcohol dependence, 156, 170-175","doi":"10.1016/j.drugalcdep.2015.09.015","pmid":"26455552","tags":["legalization","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers analyzed a unique historical dataset from the Punjab province of British India (1907-1918), where both opium and cannabis were legal and taxed. Using econometric models, they found that opium and hashish (charas) functioned as economic substitutes: when hashish prices increased, opium consumption rose.\n\nThe cross-price elasticity was 0.14, meaning a 10% increase in hashish price led to approximately a 1.4% increase in opium consumption. Opium consumption also showed properties of addiction, with past consumption predicting future consumption (habit persistence coefficient of 0.47-0.49).\n\nInterestingly, opium and bhang (cannabis leaf, a milder preparation) were not substitutes, suggesting that the substitution relationship was specific to more potent preparations. Opium demand was slightly responsive to its own price but relatively inelastic, consistent with addictive substances.","whyItMatters":"The substitution between cannabis and opioids has major implications for drug policy. If restricting access to one substance pushes users toward a more dangerous alternative, prohibition policies could backfire. This historical natural experiment provides rare evidence from a legal dual-use regime.","specificNumbers":"Data from 1907-1918 (n=252). Cross-price elasticity: 0.14 (hashish-opium substitution). Habit persistence: 0.47-0.49. Own-price elasticity: -0.34 to -0.35. Wage income elasticity: 0.15.","methodology":"Econometric analysis using generalized method of moments (GMM) dynamic panel data models. Analyzed 252 observations from Punjab province, British India (1907-1918), examining opium consumption as a function of its own price, prices of two cannabis forms (bhang and charas), and wage income.","limitations":"Data is over 100 years old from a specific cultural and economic context. The potency and forms of cannabis and opium available then differ from modern substances. Price data may not capture black market dynamics. The findings may not generalize to contemporary settings."},{"rthcId":"RTHC-00936","title":"Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses.","authors":"Chiurchiù, Valerio; Leuti, Alessandro; Maccarrone, Mauro","year":2015,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 10(2), 268-80","doi":"10.1007/s11481-015-9584-2","pmid":"25601726","tags":["inflammation","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how cannabinoid signaling regulates the brain's immune responses, challenging the outdated view that the brain is immunologically isolated. The brain maintains active immune surveillance through resident cells (microglia) and communication with peripheral immune cells.\n\nWhen neuroinflammation becomes chronic, as in MS, Alzheimer's, and ALS, it causes progressive damage. Cannabinoids, whether from cannabis, synthetically produced, or naturally occurring in the body, demonstrated immunoregulatory properties in brain tissue. They modulated microglial activation, cytokine production, and immune cell migration through CB1 and CB2 receptor pathways.\n\nThe review emphasized that cannabinoid-based interventions could help manage neuroinflammatory disorders by dampening harmful immune responses while potentially preserving protective immunity.","whyItMatters":"Neuroinflammation contributes to disease progression in several of the most devastating brain disorders. Identifying cannabinoid-based approaches to regulate brain immunity could lead to new treatments for conditions with limited current options.","specificNumbers":"Three major neuroinflammatory diseases reviewed: MS, Alzheimer's, ALS. Two primary cannabinoid receptors involved: CB1 and CB2. Multiple immune cell types modulated by cannabinoids.","methodology":"Narrative review of literature on cannabinoid signaling and brain immune function, covering phytocannabinoids, synthetic cannabinoids, and endocannabinoids across MS, Alzheimer's, and ALS models.","limitations":"Predominantly preclinical evidence. The complexity of neuroimmune interactions means simplified models may not capture clinical reality. Cannabinoid effects on immunity are dose-dependent and context-dependent."},{"rthcId":"RTHC-00937","title":"Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol.","authors":"Cluny, Nina L; Keenan, Catherine M; Reimer, Raylene A; Le Foll, Bernard; Sharkey, Keith A","year":2015,"journal":"PloS one, 10(12), e0144270","doi":"10.1371/journal.pone.0144270","pmid":"26633823","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers gave daily THC to both diet-induced obese (DIO) and lean mice for 4 weeks. In obese mice, THC reduced weight gain, fat accumulation, and food intake. Lean mice were unaffected on all measures.\n\nA key finding was the gut microbiota connection: the high-fat diet changed the composition of gut bacteria in obese mice, and chronic THC administration prevented these obesity-related microbial changes. The gut microbiota alterations could potentially contribute to THC's anti-obesity effects.\n\nImportantly, THC did not reduce weight through sedation or altered gut transit time, as neither locomotor activity nor whole gut transit differed between THC and vehicle groups in either lean or obese mice. This addressed the common assumption that any weight effects might simply reflect reduced activity.","whyItMatters":"The paradox that cannabis acutely increases appetite (\"munchies\") yet regular users have lower obesity rates has puzzled researchers. This study provides a potential mechanism: chronic THC exposure may reshape gut bacteria and reduce caloric intake in a weight-dependent manner.","specificNumbers":"THC doses: 2mg/kg (3 weeks) then 4mg/kg (1 week). DIO mice showed reduced weight gain, fat gain, and food intake. Lean mice showed no changes. Gut microbiota changes in obesity were prevented by THC. No differences in locomotor activity or gut transit.","methodology":"Controlled animal study with DIO and lean adult male mice treated daily with vehicle or THC (2mg/kg for 3 weeks, then 4mg/kg for 1 additional week). Body weight, fat mass, energy intake, locomotor activity, gut transit, and gut microbiota were measured longitudinally.","limitations":"Animal study with forced THC administration at specific doses. Gut microbiota findings are correlational and do not prove causation. The 4-week duration may not capture longer-term effects. Results may not translate to humans using cannabis in typical patterns."},{"rthcId":"RTHC-00938","title":"Web-based treatment for substance use disorders: differential effects by primary substance.","authors":"Cochran, Gerald; Stitzer, Maxine; Campbell, Aimee N C; Hu, Mei-Chen; Vandrey, Ryan; Nunes, Edward V","year":2015,"journal":"Addictive behaviors, 45, 191-4","doi":"10.1016/j.addbeh.2015.02.002","pmid":"25697725","tags":["quitting","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This secondary analysis of a large multi-site trial (497 participants) examined whether a web-based behavioral treatment worked differently depending on the primary substance of abuse. Participants entering outpatient counseling were randomly assigned to receive treatment-as-usual with or without TES substituted for about 2 hours of usual counseling.\n\nPrimary stimulant users receiving TES were 3.59 times more likely to be abstinent in the final four weeks compared to those without TES. Cannabis users showed a similar magnitude of benefit (2.64 times more likely) and alcohol users as well (3.15 times), but neither reached statistical significance due to smaller subgroup sizes.\n\nPrimary opioid users showed no benefit from TES and trended toward worse outcomes (odds ratio 0.35). The findings suggest web-based behavioral treatments are most effective for stimulant, cannabis, and alcohol use disorders but may need different approaches for opioid dependence.","whyItMatters":"Web-based treatments can dramatically expand access to addiction care, particularly in underserved areas. Knowing which substance use disorders respond best helps clinicians match treatments to patients and avoid offering ineffective interventions.","specificNumbers":"497 participants across 4 substance groups. Stimulant users: AOR 3.59 (significant). Alcohol: AOR 3.15 (trending). Cannabis: AOR 2.64 (trending). Opioid: AOR 0.35 (no benefit). Cannabis users were 22.9% of the sample.","methodology":"Secondary analysis of a randomized multi-site effectiveness trial (NCT01104805). 497 participants entering outpatient counseling were categorized by primary substance: cannabis (22.9%), stimulants (34.4%), opioids (21.7%), alcohol (20.9%). TES replaced approximately 2 hours of usual counseling. Abstinence in final 4 weeks was the primary outcome.","limitations":"Secondary analysis with subgroup sizes that limited statistical power for cannabis and alcohol groups. Cannabis users were 22.9% of the sample (n=114). The study could not determine why opioid users did not benefit. Treatment-as-usual varied across sites."},{"rthcId":"RTHC-00939","title":"Nonsmoker Exposure to Secondhand Cannabis Smoke. III. Oral Fluid and Blood Drug Concentrations and Corresponding Subjective Effects.","authors":"Cone, Edward J; Bigelow, George E; Herrmann, Evan S; Mitchell, John M; LoDico, Charles; Flegel, Ronald; Vandrey, Ryan","year":2015,"journal":"Journal of analytical toxicology, 39(7), 497-509","doi":"10.1093/jat/bkv070","pmid":"26139312","tags":["harm-reduction","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Six non-smokers sat alternately with six cannabis smokers in a sealed chamber for one hour across three sessions. In the first session, smokers used 5.3% THC cannabis; in sessions 2 and 3, they used 11.3% THC cannabis (session 3 had ventilation).\n\nNon-smokers tested positive for THC in oral fluid and blood for up to 3 hours after exposure. The amounts of THC absorbed by non-smokers were proportionally less than active smokers but still measurable. Subjective effects (feeling high, sedated) correlated with the degree of exposure and cannabis potency.\n\nThe results indicated that extreme secondhand cannabis smoke exposure in an enclosed, unventilated space can produce effects that mimic, though to a lesser extent, active cannabis smoking. Ventilation substantially reduced exposure levels.","whyItMatters":"As cannabis potency increases, concerns about secondhand exposure grow. This study demonstrates that passive exposure in enclosed spaces can produce detectable THC levels and subjective effects, which has implications for workplace testing, childcare settings, and non-smoker rights.","specificNumbers":"6 smokers, 6 non-smokers. Cannabis potency: 5.3% and 11.3% THC. 1-hour exposure sessions. Positive blood and oral fluid tests for up to 3 hours post-exposure. Ventilation substantially reduced exposure. Subjective effects correlated with potency.","methodology":"Controlled exposure study with 6 cannabis smokers and 6 non-smokers in a sealed chamber. Three sessions varied cannabis potency (5.3% and 11.3% THC) and ventilation conditions. Oral fluid (ELISA and LC-MS/MS) and blood (LC-MS/MS) were analyzed at multiple time points. Subjective effects were rated before and after each session.","limitations":"Extreme exposure conditions (sealed chamber, no ventilation) do not represent typical real-world scenarios. Small sample (6 non-smokers). Only two potency levels tested. Short-term exposure effects studied; long-term consequences of repeated passive exposure are unknown."},{"rthcId":"RTHC-00940","title":"Non-smoker exposure to secondhand cannabis smoke. I. Urine screening and confirmation results.","authors":"Cone, Edward J; Bigelow, George E; Herrmann, Evan S; Mitchell, John M; LoDico, Charles; Flegel, Ronald; Vandrey, Ryan","year":2015,"journal":"Journal of analytical toxicology, 39(1), 1-12","doi":"10.1093/jat/bku116","pmid":"25326203","tags":["harm-reduction","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Six non-smokers were exposed to secondhand cannabis smoke in a sealed chamber with six smokers for one hour across three sessions. Urine specimens collected over 34 hours were tested at four immunoassay cutoff levels and confirmed by GC-MS.\n\nAt the standard federal workplace cutoff of 50 ng/mL, only a single positive occurred. No positives occurred at 75 or 100 ng/mL. However, multiple positives occurred at the lower 20 ng/mL cutoff, which some testing programs use. GC-MS confirmation showed maximum THCCOOH concentrations in non-smokers ranging from 1.3 to 57.5 ng/mL.\n\nHigher cannabis potency increased exposure levels, but room ventilation substantially reduced them. The authors concluded that positive tests from secondhand exposure are likely rare, limited to hours immediately after exposure, and occur only when exposure is obvious to the person involved.","whyItMatters":"The question of whether secondhand cannabis exposure can cause a failed drug test is important for workplace fairness. This study shows it is technically possible under extreme conditions at lower cutoffs, but practically unlikely at standard testing thresholds.","specificNumbers":"6 non-smokers, 6 smokers. Three sessions. At 100 ng/mL cutoff: 0 positives. At 75 ng/mL: 0 positives. At 50 ng/mL: 1 positive. At 20 ng/mL: multiple positives. THCCOOH by GC-MS: 1.3-57.5 ng/mL range in non-smokers. Ventilation substantially reduced levels.","methodology":"Controlled exposure study with 6 non-smokers and 6 smokers in a sealed chamber. Three sessions: 5.3% THC (no ventilation), 11.3% THC (no ventilation), 11.3% THC (with ventilation). Urine collected 0-34 hours post-exposure, analyzed by four immunoassays (cutoffs: 20, 50, 75, 100 ng/mL) and GC-MS (LOQ 0.75 ng/mL).","limitations":"Extreme exposure conditions (sealed chamber, 1 hour) do not reflect typical scenarios. Small sample size. Only two potency levels tested. Results may differ with different cannabis consumption methods (vaping, edibles produce no smoke)."},{"rthcId":"RTHC-00941","title":"Neuropsychological sex differences associated with age of initiated use among young adult cannabis users.","authors":"Crane, Natania A; Schuster, Randi Melissa; Mermelstein, Robin J; Gonzalez, Raul","year":2015,"journal":"Journal of clinical and experimental neuropsychology, 37(4), 389-401","doi":"10.1080/13803395.2015.1020770","pmid":"25832823","tags":["cognition","youth","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers examined 44 male and 25 female young adult cannabis users to determine whether the age of first cannabis use affected cognitive function differently by sex. After controlling for total lifetime cannabis use, earlier initiation was associated with poorer episodic memory, particularly immediate recall, in females but not males.\n\nSurprisingly, earlier initiation was associated with better decision-making overall, but exploratory analysis revealed this was driven by ADHD symptoms in females, suggesting a confound rather than a cannabis benefit. Earlier female initiators also had lower IQ, less education, and lower maternal education levels.\n\nFor males, earlier initiation was primarily associated with more lifetime cannabis use but not with neuropsychological differences after controlling for total exposure. The findings suggest males and females may have different risk profiles for cannabis-related cognitive effects.","whyItMatters":"Most cannabis research does not separate results by sex, potentially masking important differences. If females are more vulnerable to memory effects from early cannabis use, sex-specific prevention messaging and clinical guidance may be needed.","specificNumbers":"44 males and 25 females studied. Earlier female initiators showed poorer immediate recall. Earlier initiation linked to lower IQ, less education in females. Earlier initiation linked to more lifetime use in males.","methodology":"Cross-sectional neuropsychological study of 44 male and 25 female young adult cannabis users. Multiple cognitive domains were assessed after controlling for lifetime cannabis use. Sex-stratified analyses examined relationships between age of initiation and cognitive performance.","limitations":"Small sample, especially for females (n=25). Cross-sectional design cannot establish causation. Earlier initiation was associated with multiple confounds (lower IQ, less education) that could explain cognitive differences. ADHD symptoms as a confound complicate decision-making findings."},{"rthcId":"RTHC-00942","title":"Gateway to curiosity: Medical marijuana ads and intention and use during middle school.","authors":"D'Amico, Elizabeth J; Miles, Jeremy N V; Tucker, Joan S","year":2015,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 29(3), 613-9","doi":"10.1037/adb0000094","pmid":"26030167","tags":["youth","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 8,214 sixth-to-eighth graders in 16 Southern California middle schools in 2010 and 2011, assessing their exposure to medical marijuana advertising and their marijuana use and intentions. Cross-lagged regression analysis revealed a reciprocal relationship.\n\nGreater initial exposure to medical marijuana ads was significantly associated with higher probability of marijuana use and stronger intentions to use one year later. In the reverse direction, students who already used marijuana or had stronger intentions to use reported greater advertising exposure a year later, suggesting they were more attuned to noticing these ads.\n\nThe findings parallel what has been documented with alcohol and tobacco advertising: exposure to product marketing increases youth interest and use, creating a reinforcing cycle.","whyItMatters":"As more states legalize cannabis, advertising becomes more prevalent. This study provides early evidence that medical marijuana ads influence adolescent attitudes and behavior, similar to findings for alcohol and tobacco, supporting the case for advertising regulations.","specificNumbers":"8,214 students surveyed across 16 middle schools. 50% male, 52% Hispanic, mean age 13. Greater ad exposure predicted higher use and stronger intentions 1 year later. The relationship was bidirectional.","methodology":"Longitudinal survey of 8,214 students (50% male, 52% Hispanic, mean age 13) across 16 middle schools in Southern California. Assessed in 2010 and 2011. Cross-lagged regressions examined bidirectional relationships between advertising exposure, marijuana intentions, and marijuana use.","limitations":"Southern California sample during an early period of medical marijuana may not generalize to other regions or current recreational markets. Self-reported advertising exposure and marijuana use. Other factors could explain both increased ad exposure and increased use."},{"rthcId":"RTHC-00943","title":"The relationship between cannabis involvement and suicidal thoughts and behaviors.","authors":"Delforterie, M J; Lynskey, M T; Huizink, A C; Creemers, H E; Grant, J D; Few, L R; Glowinski, A L; Statham, D J; Trull, T J; Bucholz, K K; Madden, P A F; Martin, N G; Heath, A C; Agrawal, A","year":2015,"journal":"Drug and alcohol dependence, 150, 98-104","doi":"10.1016/j.drugalcdep.2015.02.019","pmid":"25772435","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from 9,583 individuals (58.5% female, aged 27-40) from the Australian Twin Registry, examining relationships between cannabis use levels and suicidal thoughts and behaviors. Cannabis involvement was categorized into four levels: no use, use only, 1-2 disorder symptoms, and 3+ symptoms.\n\nAll levels of cannabis involvement were associated with suicidal ideation (odds ratios 1.28-2.00), and these associations persisted after controlling for other psychiatric disorders and substance use. Cannabis involvement was also associated with unplanned (but not planned) suicide attempts.\n\nTwin analyses revealed that shared genetic factors (correlation 0.45) and environmental factors (correlation 0.21) contributed to the overlap between cannabis involvement and suicidal ideation, suggesting the association is partly explained by common underlying vulnerabilities rather than a direct causal link.","whyItMatters":"Understanding the association between cannabis use and suicidality is important for clinical screening. The finding that shared genetic and environmental factors partially explain the link helps clinicians understand that cannabis use may be a marker of underlying vulnerability rather than a direct cause.","specificNumbers":"9,583 individuals (58.5% female). All cannabis involvement levels associated with suicidal ideation (ORs 1.28-2.00). Genetic correlation: 0.45. Environmental correlation: 0.21. Cannabis associated with unplanned but not planned attempts.","methodology":"Cross-sectional analysis of 9,583 twins from the Australian Twin Registry, aged 27-40. The Semi-Structured Assessment of the Genetics of Alcoholism (SSAGA) assessed cannabis involvement at four levels. Multinomial logistic regression and twin genetic analyses examined associations with suicidal ideation and attempts.","limitations":"Cross-sectional design cannot determine temporal direction. Australian twin sample may not generalize to other populations. Self-reported data. The association is modest and substantially attenuated when controlling for confounders. Cannot distinguish effects of cannabis from correlated risk factors."},{"rthcId":"RTHC-00944","title":"Cost-Effectiveness of School-Based Prevention of Cannabis Use.","authors":"Deogan, Charlotte; Zarabi, Natalie; Stenström, Nils; Högberg, Pi; Skärstrand, Eva; Manrique-Garcia, Edison; Neovius, Kristian; Månsdotter, Anna","year":2015,"journal":"Applied health economics and health policy, 13(5), 525-42","doi":"10.1007/s40258-015-0175-4","pmid":"25972235","tags":["youth","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers used a Markov model to evaluate the cost-effectiveness of Project ALERT, a school-based substance prevention program, compared to standard drug education. The model tracked students through states of single use, regular use, daily use, and progression to other drugs, accounting for complications like psychosis, depression, and traffic accidents.\n\nBased on US effectiveness data, the program was cost-saving (returning $1.10 for every $1 spent). After adjusting for the Swedish context, it was cost-effective at 22,384 euros per quality-adjusted life-year (QALY), well below the willingness-to-pay threshold of 50,000 euros.\n\nWhen targeted specifically to at-risk boys (those not in education or work), the program became cost-saving after 9 years (returning $3.20 for every $1 spent after 20 years). This demonstrated that targeted prevention in high-risk groups provides substantially better economic returns.","whyItMatters":"Governments need economic evidence to justify prevention spending. This study demonstrates that school-based cannabis prevention programs are not just effective but economically rational investments, especially when targeted to high-risk populations.","specificNumbers":"Cost-saving at 1:1.1 ratio based on US data. Cost-effective at 22,384 euros/QALY in Swedish context. Targeted to at-risk boys: cost-saving after 9 years, 1:3.2 ratio at 20 years. Willingness-to-pay threshold: 50,000 euros/QALY.","methodology":"Cost-effectiveness analysis from the societal perspective using a Markov model. Based on Project ALERT effectiveness data, modeling progression through cannabis use states and complications. Follow-up periods from 1 year to lifetime. Costs inflated to 2013 levels with 3% discounting.","limitations":"Economic modeling relies on assumptions about state transitions and complication rates. US effectiveness data was adjusted for Sweden, introducing uncertainty. Long-term projections over 20+ years involve substantial modeling assumptions. The effectiveness of Project ALERT specifically has been debated."},{"rthcId":"RTHC-00945","title":"Cannabinoid Hyperemesis Syndrome in a 17-Year-Old Adolescent.","authors":"Desjardins, Noémie; Jamoulle, Olivier; Taddeo, Danielle; Stheneur, Chantal","year":2015,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 57(5), 565-7","doi":"10.1016/j.jadohealth.2015.07.019","pmid":"26372366","tags":["addiction","appetite","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 17-year-old visited the emergency department five times over one year with uncontrolled nausea, profuse vomiting, and weight loss. The diagnosis of cannabinoid hyperemesis syndrome (CHS) was not considered until after extensive and unnecessary medical workups.\n\nThe patient's symptoms improved with repetitive hot showering and resolved when cannabis use was stopped, both hallmark features of CHS. The authors noted that while cannabis use among Canadian youth was declining, it remained twice as prevalent as among adults, making adolescent CHS an underrecognized concern.\n\nThe case report emphasized that CHS should be included in the differential diagnosis for any case of cyclic vomiting, regardless of the patient's age. The condition is underdiagnosed in adults and even more so in adolescents, where clinicians may be less likely to inquire about substance use.","whyItMatters":"Five emergency visits before diagnosis means significant suffering, unnecessary testing, and healthcare costs. Increased awareness of CHS in adolescent patients could dramatically reduce time to diagnosis and improve care.","specificNumbers":"One patient, age 17. Five emergency department visits over one year. Canadian youth cannabis use was declining since 2008 but remained twice the adult rate.","methodology":"Single case report of a 17-year-old with cannabinoid hyperemesis syndrome, including review of clinical presentation, diagnostic considerations, and treatment approaches for CHS in the adolescent population.","limitations":"Single case report cannot establish prevalence or risk factors. Canadian healthcare context may differ from other systems. The case does not provide information about what level of use triggers CHS in adolescents."},{"rthcId":"RTHC-00946","title":"Smoked cannabis' psychomotor and neurocognitive effects in occasional and frequent smokers.","authors":"Desrosiers, Nathalie A; Ramaekers, Johannes G; Chauchard, Emeline; Gorelick, David A; Huestis, Marilyn A","year":2015,"journal":"Journal of analytical toxicology, 39(4), 251-61","doi":"10.1093/jat/bkv012","pmid":"25745105","tags":["driving","cognition","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Fourteen frequent cannabis smokers (4+ times per week) and 11 occasional smokers (less than twice per week) smoked a single 6.8% THC cigarette in a controlled setting. Performance was tested on tracking, divided attention, working memory, and risk-taking tasks at multiple time points.\n\nOccasional smokers showed significantly more difficulty on the critical tracking task 1.5 hours after smoking. Divided attention was also more impaired in occasional users, with group differences in tracking error, hit rate, false alarms, and reaction time. However, working memory and risk-taking showed no group differences.\n\nThe findings suggest that frequent cannabis users develop some tolerance to the psychomotor-impairing effects of THC, which has direct implications for interpreting impairment in driving-under-the-influence cases.","whyItMatters":"Driving impairment laws often treat all cannabis users the same. This study shows that the same dose produces very different levels of impairment depending on use frequency, which complicates the development of fair impairment thresholds.","specificNumbers":"14 frequent smokers (4+/week) and 11 occasional smokers (<2/week). One 6.8% THC cigarette. Occasional smokers significantly more impaired at 1.5 hours. No group differences on working memory or risk-taking tasks.","methodology":"Controlled laboratory study where 14 frequent and 11 occasional cannabis smokers entered a secure research unit approximately 19 hours before smoking one 6.8% THC cigarette. Performance was assessed at -1.75, 1.5, 3.5, 5.5, and 22.5 hours post-smoking using critical tracking, divided attention, n-back, and Balloon Analog Risk tasks.","limitations":"Relatively small sample sizes. Single dose of moderate-potency cannabis. Laboratory tasks may not fully capture real-world driving complexity. 19 hours of abstinence before the session may not reflect typical use patterns for frequent users."},{"rthcId":"RTHC-00947","title":"Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.","authors":"Di Marzo, Vincenzo; Centonze, Diego","year":2015,"journal":"CNS neuroscience & therapeutics, 21(3), 215-21","doi":"10.1111/cns.12358","pmid":"25475413","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the placebo response in enriched clinical trials of THC/CBD oromucosal spray (Sativex) for MS spasticity. In enriched designs, patients who respond during an initial open-label phase are randomized to continue treatment or switch to placebo.\n\nThe authors identified that placebo-allocated patients maintained some improvement after randomization, likely due to carryover effects from the enrichment phase and the pharmacological properties of cannabinoids (slow clearance). The overall therapeutic gain of THC/CBD spray over placebo was estimated at about 1.27 points on a 0-10 spasticity scale, representing a 20.1% improvement from baseline.\n\nThe review cautioned that enriched design studies for cannabinoid medications require careful interpretation, as the design itself can underestimate true treatment effects by inflating placebo responses.","whyItMatters":"Understanding how clinical trial design affects results is essential for accurate drug evaluation. If cannabinoid trials systematically underestimate treatment effects due to enriched designs and carryover, real clinical benefits may be larger than reported.","specificNumbers":"Overall therapeutic gain: ~1.27 points on 0-10 NRS. Improvement: ~20.1% from baseline NRS score. 16-week assessment period after enrichment. Enriched design inflated placebo responses.","methodology":"Review of enriched design clinical trial data for THC/CBD oromucosal spray in MS spasticity. Analyzed placebo effects during enrichment and post-randomization phases, examining carryover effects and other factors maintaining efficacy in placebo-allocated patients.","limitations":"Focus on a single medication (THC/CBD spray) and one condition (MS spasticity). The estimated therapeutic gain is an aggregate that may not apply to all patients. The review discusses potential biases but cannot fully quantify them."},{"rthcId":"RTHC-00948","title":"Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility.","authors":"du Plessis, Stefan S; Agarwal, Ashok; Syriac, Arun","year":2015,"journal":"Journal of assisted reproduction and genetics, 32(11), 1575-88","doi":"10.1007/s10815-015-0553-8","pmid":"26277482","tags":["pregnancy","sex-differences"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compiled evidence on how cannabis affects male reproductive function through the endocannabinoid system (ECS). The ECS is deeply involved in regulating the hypothalamus-pituitary-gonadal axis, sperm production, and sperm function.\n\nCannabinoid receptors (CB1 and CB2) are present throughout the male reproductive tract, including in the testes, epididymis, prostate, and on sperm cells themselves. Cannabis-derived cannabinoids can disrupt these systems by mimicking endocannabinoids.\n\nStudies reviewed showed that cannabis use was associated with reduced testosterone levels, impaired spermatogenesis, decreased sperm motility, premature acrosome reaction (which prevents fertilization), and disrupted capacitation (the process sperm undergo to become fertilization-capable). The review noted that marijuana has the highest consumption rate of illicit drugs in the US, with popularity increasing especially among men of reproductive age.","whyItMatters":"Male factor infertility is increasing, and cannabis use is rising among reproductive-age men. If cannabis contributes to fertility problems through documented endocannabinoid disruption, this is relevant information for couples trying to conceive.","specificNumbers":"Cannabinoid receptors found in testes, epididymis, prostate, and on sperm. Multiple reproductive functions affected: testosterone, spermatogenesis, motility, capacitation, acrosome reaction.","methodology":"Narrative review of in vivo and in vitro studies examining the effects of marijuana and cannabinoids on male reproductive hormones, spermatogenesis, and sperm function, with detailed coverage of the endocannabinoid system in male reproduction.","limitations":"Much evidence comes from animal studies or in vitro experiments. Human studies have been small and often poorly controlled for confounders. The review is narrative rather than systematic. Dose-response relationships are not well established."},{"rthcId":"RTHC-00949","title":"The combined effects of alcohol and cannabis on driving: Impact on crash risk.","authors":"Dubois, Sacha; Mullen, Nadia; Weaver, Bruce; Bédard, Michel","year":2015,"journal":"Forensic science international, 248, 94-100","doi":"10.1016/j.forsciint.2014.12.018","pmid":"25612879","tags":["driving","harm-reduction"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Researchers examined drivers aged 20+ involved in fatal crashes in the United States from 1991 to 2008 who had been tested for both alcohol and cannabis. Using a case-control design where \"cases\" were drivers with unsafe driving actions (UDAs) and \"controls\" had none, they estimated impairment risk.\n\nThe prevalence of combined THC and alcohol in fatal crash drivers increased approximately five-fold over the study period, from below 2% in 1991 to above 10% in 2008. THC alone was associated with a 16% increased odds of an UDA. Each 0.01 BAC unit increased UDA odds by 9-11%.\n\nWhen both substances were present, the odds of an UDA increased by an additional 8-10% per 0.01 BAC unit beyond either substance alone. The combined effect was greater than additive, indicating a synergistic interaction between alcohol and cannabis on driving impairment.","whyItMatters":"As cannabis legalization expands, many drivers may use both alcohol and cannabis before driving. Understanding that the combination is more dangerous than either substance alone is critical for public safety messaging and enforcement priorities.","specificNumbers":"Combined THC+alcohol prevalence in fatal crashes: <2% (1991) to >10% (2008). THC alone: 16% increased odds of UDA. Each 0.01 BAC: 9-11% increase. Combined: additional 8-10% per 0.01 BAC beyond individual risks.","methodology":"Case-control study using the Fatality Analysis Reporting System (FARS) for US fatal crashes 1991-2008. Cases were drivers with at least one unsafe driving action recorded; controls had none. Logistic regression estimated adjusted odds ratios for UDAs associated with alcohol alone, THC alone, and both combined.","limitations":"FARS data only captures fatal crashes, which may not represent all impaired driving. THC detection indicates recent use but not necessarily impairment at crash time. The case-control design using UDAs as the outcome may misclassify some cases. Confounders like other drug use may be present."},{"rthcId":"RTHC-00950","title":"PTSD and Cannabis-Related Coping Among Recent Veterans in New York City.","authors":"Elliott, Luther; Golub, Andrew; Bennett, Alexander; Guarino, Honoria","year":2015,"journal":"Contemporary drug problems, 42(1), 60-76","doi":"10.1177/0091450915570309","pmid":"28638168","tags":["ptsd","medical-cannabis","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Researchers conducted interviews and focus groups with veterans of Iraq and Afghanistan about their cannabis use for PTSD coping. Veterans consistently compared cannabis more favorably than alcohol or prescription medications, describing it as more effective for symptom management with fewer complications and side effects.\n\nSome veterans described cannabis as enabling an \"approach-based\" coping strategy, helping them engage in introspection and directly confront traumatic memories. Others recognized that their cannabis use represented avoidant coping, using it to numb or escape rather than address trauma.\n\nA nuanced group of veterans described motivations that did not fit neatly into approach or avoidance categories. They used cannabis primarily for symptom alleviation (sleep, anxiety, hyperarousal) without a specific intent to either confront or avoid their trauma. The authors suggested that coping theory may need more nuanced categories to capture how veterans actually use cannabis.","whyItMatters":"Veterans' own perspectives on cannabis for PTSD are often missing from clinical and policy discussions. Their comparisons to alcohol and prescriptions, and their nuanced descriptions of how cannabis fits into coping strategies, provide important context for treatment development.","specificNumbers":"Qualitative study with veterans of Iraq and Afghanistan conflicts. Three coping patterns identified: approach-based, avoidance-based, and symptom-alleviation-focused. Cannabis consistently compared favorably to alcohol and pharmaceuticals.","methodology":"Qualitative study using semi-structured interviews and focus groups with veterans of recent Iraq and Afghanistan conflicts in New York City. Thematic analysis examined cannabis use patterns, motivations, and comparisons with other substances.","limitations":"Qualitative study with a self-selected sample from one city. Veterans willing to discuss cannabis use may differ from those who are not. No outcome data to determine whether cannabis coping was actually beneficial or harmful in the long term."},{"rthcId":"RTHC-00951","title":"No evidence for reduction of opioid-withdrawal symptoms by cannabis smoking during a methadone dose taper.","authors":"Epstein, David H; Preston, Kenzie L","year":2015,"journal":"The American journal on addictions, 24(4), 323-8","doi":"10.1111/ajad.12183","pmid":"25846329","tags":["withdrawal","drug-interactions","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from 116 outpatient heroin and cocaine users undergoing a 10-week methadone taper, of whom 46 also used cannabis. Opioid withdrawal symptom scores did not differ overall between cannabis users and non-users.\n\nA temporal analysis found a slight, non-significant suggestion that higher withdrawal symptoms preceded cannabis use (suggesting self-medication attempts), but cannabis use in one week did not predict lower withdrawal symptoms the following week. Both findings were robust across 17 different sensitivity analyses controlling for potential confounders.\n\nThe authors concluded that these findings move the evidence for smoked cannabis as a reducer of opioid withdrawal symptoms from \"inconclusive\" closer to negative, at least in the context of a methadone taper. They noted this finding does not preclude other potential uses of cannabinoids in addiction treatment.","whyItMatters":"Claims that cannabis helps with opioid withdrawal are common among patients and some advocates. This study provides controlled evidence that in a clinical setting, cannabis did not demonstrably reduce withdrawal symptoms, which is important for setting realistic treatment expectations.","specificNumbers":"116 patients in methadone taper. 46 were cannabis users. No significant difference in withdrawal scores between users and non-users. Temporal analysis effect sizes near zero (r = .01 for cannabis reducing withdrawal). Controlled for 17 confounders.","methodology":"Secondary analysis of a clinical trial with 116 outpatient heroin and cocaine users who completed a 10-week methadone taper. Weekly urine screens for cannabinoids and biweekly withdrawal assessments were analyzed using lagged temporal analyses. Sensitivity analyses controlled for 17 potential confounders.","limitations":"Secondary analysis not designed to test this specific hypothesis. Cannabis use was self-directed, not controlled. The methadone taper context may not generalize to other opioid withdrawal settings. Only 46 cannabis users in the analytic sample. Urine screening may not capture all cannabis use patterns."},{"rthcId":"RTHC-00952","title":"Internalizing and externalizing psychopathology as predictors of cannabis use disorder onset during adolescence and early adulthood.","authors":"Farmer, Richard F; Seeley, John R; Kosty, Derek B; Gau, Jeff M; Duncan, Susan C; Lynskey, Michael T; Lewinsohn, Peter M","year":2015,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 29(3), 541-51","doi":"10.1037/adb0000059","pmid":"25799438","tags":["addiction","mental-health","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 816 participants through four diagnostic assessments between ages 16 and 30 to determine which psychiatric problems preceded the development of cannabis use disorders (CUDs). Using time-to-event analyses, they found that externalizing psychopathology from the developmental period just before CUD onset was a robust predictor.\n\nInternalizing disorders (depression, anxiety) did not predict CUD onset in either unadjusted or adjusted analyses. This finding held even after controlling for other psychiatric comorbidities.\n\nHowever, a large proportion of individuals who developed CUDs had no prior externalizing or internalizing psychopathology at all, indicating that psychiatric history is an incomplete predictor. The results suggest externalizing disorders are a useful risk marker but not the whole story.","whyItMatters":"Identifying who is at risk for developing cannabis use disorders can guide prevention efforts. The finding that externalizing behaviors (but not anxiety or depression) predict CUD onset suggests that prevention programs should focus on youth with behavioral problems rather than those with mood disorders.","specificNumbers":"816 participants, ages 16-30. 4 assessment points. Externalizing disorders from proximal periods predicted CUD onset. Internalizing disorders were non-predictive. Many CUD cases had no prior psychiatric history.","methodology":"Prospective longitudinal study with 816 participants completing 4 diagnostic assessments between ages 16 and 30. Current and past cannabis use disorders and full psychiatric disorder histories were assessed. Time-to-event analyses (unadjusted and adjusted) evaluated externalizing and internalizing psychopathology as CUD predictors.","limitations":"Limited to one cohort from Oregon. Four assessment points may miss disorders occurring between assessments. \"Externalizing psychopathology\" encompasses multiple disorders that may carry different risks. The finding that many CUD cases had no prior psychopathology limits predictive utility."},{"rthcId":"RTHC-00953","title":"What to make of cannabis and cognition in MS: In search of clarity amidst the haze.","authors":"Feinstein, Anthony; Banwell, Emma; Pavisian, Bennis","year":2015,"journal":"Multiple sclerosis (Houndmills, Basingstoke, England), 21(14), 1755-60","doi":"10.1177/1352458515607652","pmid":"26453678","tags":["cognition","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined the sparse literature on cannabis effects on cognition in people with multiple sclerosis. About 20% of MS patients use cannabis for symptom relief or as a lifestyle choice. Since MS itself impairs cognition in many patients, the question of whether cannabis adds to that impairment is clinically important.\n\nThe limited evidence available suggested that smoked cannabis may further compromise information processing speed and memory in MS patients. Brain imaging (fMRI) showed more inefficient cerebral activation patterns during cognitive tasks in MS patients who use cannabis compared to those who do not.\n\nFindings for pharmaceutical cannabis preparations (capsules or spray) were mixed and inconclusive. The authors emphasized that the evidence was preliminary due to methodological limitations and the small number of studies.","whyItMatters":"MS patients face a difficult trade-off: cannabis may help with spasticity and pain but could worsen cognitive function. Without clear data, patients and clinicians are making decisions in the dark. This review highlights the urgent need for dedicated research.","specificNumbers":"About 20% of MS patients use cannabis. Smoked cannabis associated with slower processing speed and poorer memory. fMRI showed less efficient brain activation patterns. Pharmaceutical cannabis findings were equivocal.","methodology":"Narrative review of existing literature on cannabis effects on cognition in MS patients, including both smoked cannabis and pharmaceutical preparations. Coverage included behavioral cognitive testing and fMRI brain imaging studies.","limitations":"Very few studies available for review. Methodological limitations in existing research (small samples, cross-sectional designs, confounders). Cannot determine whether observed cognitive differences are caused by cannabis or reflect pre-existing differences between users and non-users."},{"rthcId":"RTHC-00954","title":"13-year-old girl with recurrent, episodic, persistent vomiting: out of the pot and into the fire.","authors":"Felton, Diana; Zitomersky, Naamah; Manzi, Shannon; Lightdale, Jenifer R","year":2015,"journal":"Pediatrics, 135(4), e1060-3","doi":"10.1542/peds.2014-2116","pmid":"25733759","tags":["youth","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 13-year-old with recurrent episodic vomiting was being screened for cannabis use because clinicians increasingly consider cannabinoid hyperemesis syndrome (CHS) in patients with cyclic vomiting. After receiving intravenous pantoprazole (a proton pump inhibitor) for her GI symptoms, her urine cannabinoid screen came back positive.\n\nThis was determined to be a false positive caused by the medication. The pantoprazole package insert references this potential interference, but the phenomenon had not been documented in the published medical literature. The interaction is particularly problematic because patients with cyclic vomiting are both likely to receive PPIs and likely to be screened for cannabis.\n\nThe case highlights the importance of confirming positive immunoassay results with more specific testing methods before attributing vomiting to cannabis use.","whyItMatters":"As CHS awareness grows, more vomiting patients are being screened for cannabis. If a common medication can cause false-positive results, patients could be wrongly diagnosed with CHS, leading to inappropriate treatment recommendations and potentially ignoring the true cause of their symptoms.","specificNumbers":"One patient, age 13. False positive caused by intravenous pantoprazole (a PPI). The interference is documented in the pantoprazole package insert but not in published medical literature prior to this case.","methodology":"Single case report describing a false-positive cannabinoid urine screen in a pediatric patient with cyclic vomiting syndrome who received intravenous pantoprazole, with discussion of the clinical implications.","limitations":"Single case report. The mechanism of the false positive is not fully explained. It is unclear whether oral pantoprazole or other PPIs cause the same interference. Prevalence of this false-positive result is unknown."},{"rthcId":"RTHC-00955","title":"Psychosocial sequelae of cannabis use and implications for policy: findings from the Christchurch Health and Development Study.","authors":"Fergusson, David M; Boden, Joseph M; Horwood, L John","year":2015,"journal":"Social psychiatry and psychiatric epidemiology, 50(9), 1317-26","doi":"10.1007/s00127-015-1070-x","pmid":"26006253","tags":["youth","cognition","psychosis","addiction","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"The Christchurch Health and Development Study tracked 1,265 New Zealanders from birth to age 35, providing one of the most comprehensive longitudinal datasets on cannabis outcomes. Findings showed that individuals who used cannabis regularly or began using at earlier ages were at increased risk for multiple adverse outcomes.\n\nThese included lower levels of educational attainment, greater welfare dependence and unemployment, progression to other illicit drugs, and psychotic symptomatology. The associations were observed after adjusting for confounding factors.\n\nHowever, the authors made an important qualification: a substantial proportion of regular adult cannabis users did not experience harmful consequences. The study concluded that cannabis policy needs further development to regulate a substance that is widely used and increasingly legal.","whyItMatters":"Birth cohort studies following people for decades provide the strongest observational evidence for long-term cannabis outcomes. This study's finding that risk is real but not universal for regular users directly informs the policy challenge of regulating cannabis in a proportionate way.","specificNumbers":"1,265 participants followed from birth to age 35. Regular users showed increased risk for: lower education, welfare dependence, unemployment, other illicit drug use, psychotic symptoms. A substantial proportion of regular users experienced no harmful outcomes.","methodology":"Birth cohort study of 1,265 children born in Christchurch, New Zealand in 1977, followed from birth to age 35 with multiple assessment waves. Comprehensive data on cannabis use patterns, educational outcomes, employment, other drug use, and psychiatric symptoms were analyzed using methods that adjusted for confounders.","limitations":"Single cohort from one New Zealand city. Born in 1977, so their cannabis use occurred with lower-potency products than available today. Observational design, even with confounder adjustment, cannot fully establish causation. Attrition over 35 years may bias results."},{"rthcId":"RTHC-00956","title":"Clinical perspectives on medical marijuana (cannabis) for neurologic disorders.","authors":"Fife, Terry D; Moawad, Heidi; Moschonas, Constantine; Shepard, Katie; Hammond, Nancy","year":2015,"journal":"Neurology. Clinical practice, 5(4), 344-351","doi":null,"pmid":"26336632","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This commentary examined the clinical implications of the American Academy of Neurology's systematic review of cannabinoids for neurological disorders. Several cannabinoid preparations showed effectiveness or probable effectiveness for spasticity, central pain, and painful spasms in multiple sclerosis.\n\nThe authors noted that the review supports insurance coverage for prescription cannabinoids dronabinol and nabilone for MS indications, and many insurers already covered these medications for other approved uses. However, the review was unlikely to change coverage for herbal marijuana because it remains illegal under federal law.\n\nFor other neurological conditions, the available evidence was insufficient to support clinical recommendations. The commentary highlighted the gap between the scientific evidence for pharmaceutical cannabinoids and the accessibility issues created by marijuana's federal scheduling.","whyItMatters":"The disconnect between available pharmaceutical cannabinoids (covered by insurance) and herbal cannabis (not covered, federally illegal) creates inequity in patient access. This commentary helps clinicians understand what they can practically prescribe and what insurance will cover.","specificNumbers":"Cannabinoids showed effectiveness or probable effectiveness for 3 MS indications: spasticity, central pain, painful spasms. Insurance coverage supported for dronabinol and nabilone. Quality evidence lacking for other neurological conditions.","methodology":"Clinical perspectives commentary on the AAN evidence-based systematic review of randomized controlled trials of cannabis and cannabinoids in neurological disorders, with analysis of insurance and coverage implications.","limitations":"Commentary based on a single systematic review. Coverage policies vary by insurer and jurisdiction. The distinction between pharmaceutical and herbal cannabis may oversimplify the therapeutic landscape. Published before many states expanded medical programs."},{"rthcId":"RTHC-00957","title":"Cannabinoid Hyperemesis Syndrome: A Paradoxical Cannabis Effect.","authors":"Figueroa-Rivera, Ivonne Marie; Estremera-Marcial, Rodolfo; Sierra-Mercado, Marielly; Gutiérrez-Núñez, José; Toro, Doris H","year":2015,"journal":"Case reports in gastrointestinal medicine, 2015, 405238","doi":"10.1155/2015/405238","pmid":"26266060","tags":["addiction","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 29-year-old man presented with recurrent episodes of intractable vomiting that followed the classical triad of cannabinoid hyperemesis syndrome: cyclic vomiting, chronic marijuana use, and compulsive hot bathing. The diagnosis was made after other causes were excluded.\n\nThe authors emphasized that despite marijuana's well-established antiemetic properties, a paradoxical hyperemetic effect occurs in some chronic users. CHS remained underrecognized at the time of publication, leading to delayed diagnosis and unnecessary medical investigations.\n\nThe case reinforced that CHS should be considered plausible in any patient presenting with recurrent intractable vomiting and a strong history of cannabis use, even though it remains a diagnosis of exclusion.","whyItMatters":"Each CHS case report adds to the medical literature, helping establish diagnostic patterns and raising awareness among clinicians who may not yet be familiar with the condition.","specificNumbers":"One patient, age 29. Classical triad present: cyclic vomiting, chronic marijuana use, compulsive bathing. Diagnosis of exclusion.","methodology":"Single case report of a 29-year-old male with cannabinoid hyperemesis syndrome, with review of the paradoxical relationship between cannabis's antiemetic and hyperemetic effects.","limitations":"Single case report. Diagnosis of exclusion means other conditions must be ruled out first. No information on the specific quantity or duration of cannabis use that preceded the syndrome."},{"rthcId":"RTHC-00958","title":"Combined effects of marijuana and nicotine on memory performance and hippocampal volume.","authors":"Filbey, Francesca M; McQueeny, Tim; Kadamangudi, Shrinath; Bice, Collette; Ketcherside, Ariel","year":2015,"journal":"Behavioural brain research, 293, 46-53","doi":"10.1016/j.bbr.2015.07.029","pmid":"26187691","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared hippocampal brain volumes and memory performance across four groups: marijuana-only users (n=36), nicotine-only users (n=19), combined marijuana+nicotine users (n=19), and non-using controls (n=16).\n\nMarijuana and combined marijuana+nicotine groups had smaller total hippocampal volumes compared to nicotine-only and control groups. No significant group differences were found in immediate or delayed story recall performance.\n\nThe most intriguing finding was a brain-behavior interaction: in controls, larger hippocampal volume correlated with better memory as expected. But in combined marijuana+nicotine users, this relationship was inverted: smaller hippocampal volume was associated with better memory scores. This unique inversion suggests abnormal brain-behavior relationships in combined users that may reflect compensatory neural reorganization.","whyItMatters":"The inverted brain-behavior relationship in combined marijuana+nicotine users suggests that the brain may reorganize memory processes when both substances are used together. Understanding this interaction is important because combined use is extremely common.","specificNumbers":"4 groups: MJ-only (n=36), Nic-only (n=19), MJ+Nic (n=19), controls (n=16). MJ and MJ+Nic groups had smaller hippocampal volumes. No memory performance differences between groups. Inverted volume-memory relationship in MJ+Nic group.","methodology":"Cross-sectional study comparing hippocampal volumes (MRI) and memory performance (WMS-III logical memory) across four groups drawn from two larger studies. Total bilateral hippocampal volumes were compared controlling for total brain size and recent alcohol use.","limitations":"Small sample sizes, especially for nicotine-only (19) and controls (16). Cross-sectional design cannot determine causation or temporal direction. Groups were drawn from two separate studies, introducing potential batch effects. The inverted relationship may be a statistical artifact in a small sample."},{"rthcId":"RTHC-00959","title":"Independent Evaluation of Middle School-Based Drug Prevention Curricula: A Systematic Review.","authors":"Flynn, Anna B; Falco, Mathea; Hocini, Sophia","year":2015,"journal":"JAMA pediatrics, 169(11), 1046-52","doi":"10.1001/jamapediatrics.2015.1736","pmid":"26367105","tags":["youth","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Researchers conducted a systematic review specifically targeting independently evaluated randomized controlled trials of middle school drug prevention curricula. The distinction of \"independent\" evaluation was critical because developer-conducted evaluations tend to overestimate effectiveness.\n\nFrom 5,071 publications, only 13 articles met initial criteria, yielding 6 RCTs of 4 distinct programs. Among these, 42 single-drug outcome measures were reported. Only 3 of the 42 measures showed statistically significant differences between intervention and control groups. One program, Lions-Quest Skills for Adolescence, showed significant positive effects at final follow-up.\n\nThe authors concluded there is a striking lack of independent evidence supporting widely used programs, and new approaches to school-based prevention may be necessary.","whyItMatters":"Schools spend significant resources on drug prevention programs that may not work. When independent evaluators (not the program developers) test these programs, the evidence of effectiveness largely disappears, raising questions about how prevention dollars are spent.","specificNumbers":"5,071 publications reviewed. 13 articles met criteria. 6 RCTs of 4 programs identified. 42 single-drug outcome measures. Only 3 showed significant effects. 1 program (Lions-Quest) showed positive final follow-up results.","methodology":"Systematic review searching PsycInfo, ERIC, Science Citation Index, Social Science Citation Index, CINAHL, MEDLINE, EMBASE, and Cochrane databases from January 1984 to March 2015. Included only independently evaluated RCTs of universal, middle school-based drug prevention curricula available for US dissemination.","limitations":"The strict inclusion criteria (independent evaluation, RCT, middle school, US-available) may have excluded effective programs tested in other contexts. Some excluded programs may have positive evidence from non-independent evaluators. The small number of qualifying studies limits conclusions."},{"rthcId":"RTHC-00960","title":"How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.","authors":"Freeman, Daniel; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Antley, Angus; Slater, Mel; Godlewska, Beata; Cornish, Robert; Williams, Jonathan; Di Simplicio, Martina; Igoumenou, Artemis; Brenneisen, Rudolf; Tunbridge, Elizabeth M; Harrison, Paul J; Harmer, Catherine J; Cowen, Philip; Morrison, Paul D","year":2015,"journal":"Schizophrenia bulletin, 41(2), 391-9","doi":"10.1093/schbul/sbu098","pmid":"25031222","tags":["psychosis","anxiety","cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"This was the largest study of intravenous THC, randomizing 121 individuals with existing paranoid ideation to receive THC, placebo, or THC with prior cognitive awareness training. Paranoia was measured through a real social situation, virtual reality simulation, self-report, and interviewer assessment.\n\nTHC significantly increased paranoia, and the mediating mechanism was identified: THC increased negative affect (anxiety, worry, depression, negative self-thoughts) and anomalous experiences (unusual perceptions, altered sense of meaning). These two factors fully accounted for the increase in paranoia. Changes in working memory did not contribute to paranoia.\n\nMaking participants aware of THC's effects beforehand did not significantly reduce paranoid responses, suggesting that cognitive preparation alone is insufficient to prevent cannabis-induced paranoia in vulnerable individuals.","whyItMatters":"This study definitively demonstrated that THC causes paranoia in vulnerable individuals and identified the mechanism: it works through negative emotions and unusual perceptual experiences, not through cognitive impairment. This understanding could inform both prevention strategies and therapeutic approaches.","specificNumbers":"121 participants randomized to 3 groups. THC significantly increased paranoia, negative affect, and anomalous experiences. Negative affect and anomalous experiences fully mediated the THC-paranoia relationship. Working memory changes did not contribute. Cognitive awareness training had little impact.","methodology":"Randomized, placebo-controlled, between-groups study. 121 individuals with pre-existing paranoid ideation received placebo, intravenous THC, or THC with cognitive awareness training. Paranoia assessed via real social situation, immersive virtual reality, self-report, and interviewer measures. Mediation analysis tested causal pathways.","limitations":"Intravenous THC administration does not replicate typical cannabis use. Only individuals with pre-existing paranoid ideation were studied, so results may not apply to those without this vulnerability. Single-dose design. The between-groups design (rather than within-subject) may introduce individual variability."},{"rthcId":"RTHC-00961","title":"Gender differences in socio-demographic, clinical characteristics and psychiatric diagnosis in/of suicide attempters in a Mexican population.","authors":"Fresán, Ana; González-Castro, Thelma Beatriz; Peralta-Jiménez, Yesenia; Juárez-Rojop, Isela; Pool-García, Sherezada; Velázquez-Sánchez, Martha Patricia; López-Narváez, Lilia; Tovilla-Zárate, Carlos Alfonso","year":2015,"journal":"Acta neuropsychiatrica, 27(3), 182-8","doi":"10.1017/neu.2015.6","pmid":"25686910","tags":["mental-health","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers documented 140 suicide attempts at a Mexican hospital over two years. Women comprised 63.6% and men 36.4% of attempters. Significant gender differences emerged in risk profiles.\n\nMale attempters were significantly more likely to use cannabis, alcohol, and tobacco. They were predominantly diagnosed with substance-related disorders. Female attempters were more likely to be married and working as homemakers, and were predominantly diagnosed with stress-related disorders.\n\nThe findings suggest that suicide prevention strategies need to be gender-specific: focusing on substance use (including cannabis) for males and on stress-related contexts for females in this population.","whyItMatters":"Understanding gender-specific patterns in suicide attempts helps tailor prevention strategies. The strong association between cannabis and alcohol use in male attempters suggests substance use interventions could be an important suicide prevention tool for men.","specificNumbers":"140 suicide attempts. 63.6% female, 36.4% male. Males more likely to use cannabis (p<0.001), alcohol (p<0.001), and tobacco. Males: substance-related diagnoses. Females: stress-related diagnoses.","methodology":"Cross-sectional study of 140 suicide attempts documented at the General Hospital of Comalcalco, Tabasco, Mexico, between September 2010 and September 2012. DSM-IV diagnoses were established. The Suicide Intent Scale was applied. Gender comparisons used chi-square tests.","limitations":"Single hospital in one Mexican state. Small sample size (140). Cross-sectional design cannot determine causal direction. DSM-IV diagnostic criteria may not capture cultural nuances. Cannabis use rates in this population may differ from other countries."},{"rthcId":"RTHC-00962","title":"Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice.","authors":"Gamage, Thomas F; Ignatowska-Jankowska, Bogna M; Muldoon, Pretal P; Cravatt, Benjamin F; Damaj, M Imad; Lichtman, Aron H","year":2015,"journal":"Drug and alcohol dependence, 146, 7-16","doi":"10.1016/j.drugalcdep.2014.11.015","pmid":"25479915","tags":["withdrawal","drug-interactions","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether cannabinoid compounds could reduce different aspects of morphine withdrawal in mice. They examined both physical signs (jumping) and emotional aspects (conditioned place avoidance, where mice learn to avoid a location associated with withdrawal).\n\nTHC, the MAGL inhibitor JZL184, and the dual FAAH/MAGL inhibitor SA-57 all significantly reduced the percentage of mice that jumped during withdrawal. However, none of these compounds blocked the development of conditioned place avoidance, meaning mice still learned to avoid the withdrawal-associated environment.\n\nThe FAAH inhibitor PF-3845 (which boosts anandamide but not 2-AG) did not reduce either physical or emotional withdrawal. Importantly, none of the endocannabinoid-boosting drugs produced a place preference or aversion on their own, suggesting low abuse potential.","whyItMatters":"Separating physical and emotional aspects of withdrawal reveals that cannabinoids may help with some but not all dimensions of opioid withdrawal. This has implications for whether cannabinoid-based treatments could meaningfully improve the opioid withdrawal experience.","specificNumbers":"THC, JZL184, and SA-57 reduced jumping but not place avoidance. PF-3845 reduced neither. None produced place preference in non-dependent mice. Morphine pretreatment prevented both physical and emotional withdrawal. Clonidine blocked only emotional withdrawal.","methodology":"Controlled animal study using morphine-pelleted mice with naloxone-precipitated withdrawal. THC, JZL184 (MAGL inhibitor), PF-3845 (FAAH inhibitor), and SA-57 (dual inhibitor) were tested against conditioned place avoidance (emotional withdrawal) and jumping behavior (physical withdrawal). Non-dependent mice were tested for place preference/aversion.","limitations":"Mouse model may not fully capture human withdrawal experience. Precipitated withdrawal (using naloxone) is more abrupt than natural withdrawal. Drug doses were specific and may not represent optimal therapeutic ranges. The conditioned place avoidance paradigm measures one specific aspect of emotional response."},{"rthcId":"RTHC-00963","title":"Role of the endogenous cannabinoid system in nicotine addiction: novel insights.","authors":"Gamaleddin, Islam Hany; Trigo, Jose M; Gueye, Aliou B; Zvonok, Alexander; Makriyannis, Alexandros; Goldberg, Steven R; Le Foll, Bernard","year":2015,"journal":"Frontiers in psychiatry, 6, 41","doi":"10.3389/fpsyt.2015.00041","pmid":"25859226","tags":["addiction","neuroscience","quitting"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compiled evidence for the endocannabinoid system's involvement in nicotine addiction. The CB1 receptor inverse agonist rimonabant reduced nicotine-taking and nicotine-seeking in animal studies and improved smoking quit rates in randomized clinical trials.\n\nHowever, rimonabant was removed from the market due to increased psychiatric side effects (depression, suicidality) in humans. This withdrawal prompted research into alternative ways to modulate the endocannabinoid system for smoking cessation.\n\nThe review highlighted newer approaches targeting FAAH (the enzyme that breaks down anandamide), MAGL (the enzyme that breaks down 2-AG), and other endocannabinoid system components. These approaches might modulate nicotine addiction pathways without the psychiatric risks associated with directly blocking CB1 receptors.","whyItMatters":"Smoking remains a leading cause of preventable death, and existing cessation medications have limited effectiveness. If endocannabinoid system modulation can help people quit smoking without the psychiatric risks of rimonabant, it could save many lives.","specificNumbers":"Rimonabant improved quit rates in clinical trials. Removed from market due to psychiatric side effects. Multiple alternative endocannabinoid targets identified: FAAH, MAGL, and other components.","methodology":"Narrative review of preclinical and clinical evidence for the endocannabinoid system's role in nicotine addiction, covering CB1 receptor antagonism, enzyme inhibition, and other modulatory approaches.","limitations":"Narrative review without systematic methodology. Many alternative approaches are still preclinical. The transition from animal models to human clinical applications has proven difficult for endocannabinoid-based treatments."},{"rthcId":"RTHC-00964","title":"A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis.","authors":"Giacoppo, Sabrina; Galuppo, Maria; Pollastro, Federica; Grassi, Gianpaolo; Bramanti, Placido; Mazzon, Emanuela","year":2015,"journal":"Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences, 23, 48","doi":"10.1186/s40199-015-0131-8","pmid":"26489494","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested a topical 1% CBD cream formulation in mice with experimental autoimmune encephalomyelitis (EAE), the standard animal model for multiple sclerosis. When applied daily after disease onset, the CBD cream produced striking results.\n\nClinical disease scores dropped from a mean of 5.0 in untreated EAE mice to 1.5 in CBD-treated mice. The cream recovered hind limb paralysis and reduced the histological hallmarks of MS: lymphocyte infiltration and demyelination in spinal cord tissue.\n\nAt the molecular level, CBD cream reduced inflammatory immune cell markers (CD4 and CD8 T cells in the spleen), pro-inflammatory cytokines, markers of oxidative injury (nitrotyrosine, iNOS), and markers of programmed cell death (cleaved caspase 3). The effects were described as \"surprisingly\" robust for a topical application.","whyItMatters":"Topical application is appealing because it avoids many systemic side effects. If CBD cream can reduce neuroinflammation when applied to the skin, it could offer MS patients a simple, well-tolerated add-on treatment to current therapies.","specificNumbers":"Clinical score: 5.0 (EAE) vs. 1.5 (EAE + CBD cream). CD4 T cells: ~10.69% positive staining. CD8 T cells: ~35.96% positive staining (both in EAE). Reduced: pro-inflammatory cytokines, p-selectin, GFAP, oxidative markers, apoptosis markers.","methodology":"Controlled animal study using C57BL/6 mice with MOG-induced EAE. Daily topical 1% CBD cream (CBD dissolved in propylene glycol and basic O/A cream) applied after symptom onset. Multiple experimental groups including naive, EAE, EAE+CBD cream, and vehicle controls. Assessed by daily clinical scoring, histological evaluation, immunohistochemistry, and western blotting at day 28.","limitations":"Mouse model of MS does not fully replicate human disease. The mechanism by which topical application reaches the central nervous system is not explained. Single CBD concentration tested. No comparison to oral CBD administration. Results have not been replicated in humans."},{"rthcId":"RTHC-00965","title":"Cannabis use and mania symptoms: a systematic review and meta-analysis.","authors":"Gibbs, Melanie; Winsper, Catherine; Marwaha, Steven; Gilbert, Eleanor; Broome, Matthew; Singh, Swaran P","year":2015,"journal":"Journal of affective disorders, 171, 39-47","doi":"10.1016/j.jad.2014.09.016","pmid":"25285897","tags":["psychosis","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Researchers conducted a systematic review following PRISMA guidelines, searching five databases for prospective studies on cannabis use and mania. Six articles met inclusion criteria, covering 2,391 individuals who had experienced manic symptoms with a mean follow-up of 3.9 years.\n\nStudies supported an association between cannabis use and worsened manic symptoms in people with existing bipolar disorder diagnoses. A meta-analysis of two studies found cannabis use was associated with approximately 3 times the risk (OR 2.97, 95% CI: 1.80-4.90) of developing new-onset manic symptoms.\n\nThe authors noted their conclusions were preliminary due to the small number of studies and variable quality, but the direction and magnitude of the association was consistent across analyses.","whyItMatters":"While cannabis-psychosis links are well-studied, the cannabis-mania relationship receives less attention. A nearly 3-fold risk increase for new manic symptoms is clinically significant and relevant for both prevention messaging and management of people with or at risk for bipolar disorder.","specificNumbers":"6 studies, 2,391 individuals with mania. Mean follow-up: 3.9 years. Meta-analysis OR: 2.97 (95% CI: 1.80-4.90) for new-onset manic symptoms. Cannabis worsened mania in those with existing bipolar disorder.","methodology":"Systematic review following PRISMA guidelines, searching PsychINFO, Cochrane, Scopus, Embase, and MEDLINE for prospective studies. Six studies met criteria (2,391 individuals, mean follow-up 3.9 years). Meta-analysis of two studies estimated the odds ratio for new-onset manic symptoms.","limitations":"Only 6 studies met criteria, and only 2 were included in the meta-analysis. Variable study quality. The small evidence base makes conclusions preliminary. Confounders may not be fully addressed across all studies."},{"rthcId":"RTHC-00966","title":"Alcohol, cigarette, and illegal substance consumption among medical students: a cross-sectional survey.","authors":"Gignon, M; Havet, E; Ammirati, C; Traullé, S; Manaouil, C; Balcaen, T; Loas, G; Dubois, G; Ganry, O","year":2015,"journal":"Workplace health & safety, 63(2), 54-63","doi":"10.1177/2165079915570917","pmid":"25881656","tags":["youth","mental-health","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"A survey of 255 randomly selected French medical students found substantial rates of substance use. AUDIT scores indicated 11% were at risk for alcohol addiction and 21% were high-risk drinkers. Strong tobacco dependence affected 12%. The CAST screening tool showed 5% of cannabis users needed healthcare services.\n\nThe most striking finding was academic performance: cannabis users failed their medical school examinations at a rate of 89% compared to 39% for non-users. One quarter of participants had used other illegal drugs beyond cannabis, and 10% had considered suicide in the past 12 months.\n\nThe authors called for preventive measures, screening, and healthcare services for psychoactive substance consumption among medical students.","whyItMatters":"Medical students face unique stressors and will become the clinicians treating substance use disorders. High rates of substance use and the dramatic association between cannabis use and exam failure in this population highlight the need for support programs within medical education.","specificNumbers":"255 medical students surveyed. 11% at risk for alcohol addiction. 21% high-risk alcohol users. 12% strong tobacco dependence. 5% of cannabis users needed healthcare. Cannabis users: 89% exam failure rate vs. 39% non-users. 10% considered suicide in past year.","methodology":"Cross-sectional survey of 255 randomly selected second-to-sixth year French medical students from a pool of 1,021. Self-administered questionnaires assessed substance use with validated instruments: AUDIT (alcohol), Fagerstrom (tobacco), and CAST (cannabis).","limitations":"Cross-sectional design cannot determine whether cannabis caused exam failure or whether struggling students turned to cannabis. French medical education system may not generalize. Self-reported data. Selection bias is possible despite random sampling."},{"rthcId":"RTHC-00967","title":"Cannabis and Exercise Science: A Commentary on Existing Studies and Suggestions for Future Directions.","authors":"Gillman, Arielle S; Hutchison, Kent E; Bryan, Angela D","year":2015,"journal":"Sports medicine (Auckland, N.Z.), 45(10), 1357-63","doi":"10.1007/s40279-015-0362-3","pmid":"26178329","tags":["exercise","cognition"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This commentary highlighted a major gap in the scientific literature: the relationship between recreational cannabis use and exercise is essentially unexamined. Two opposing popular narratives exist: one claims cannabis decreases motivation, including motivation to exercise, while the other holds that cannabis enhances athletic activity (cannabis is even banned by the World Anti-Doping Agency).\n\nThe authors found limited scientific evidence to support either perspective. Given that cannabis policies are changing rapidly and recreational use is becoming more accepted, they argued that understanding how cannabis affects exercise performance, motivation, and recovery is increasingly important.\n\nThe commentary outlined research directions including the effects of cannabis on exercise motivation, acute performance, pain perception during exercise, and recovery processes.","whyItMatters":"Exercise is one of the most important health behaviors, and cannabis use is increasing. If cannabis significantly affects exercise motivation, performance, or recovery, this has public health implications that current evidence cannot address.","specificNumbers":"Cannabis is banned by the World Anti-Doping Agency. Limited scientific evidence found for either motivational impairment or performance enhancement claims.","methodology":"Commentary reviewing existing literature on cannabis and exercise science, identifying gaps, and proposing future research directions.","limitations":"This is a commentary, not a systematic review. The authors identified a gap rather than providing new data. The lack of existing research means even the research directions proposed are speculative."},{"rthcId":"RTHC-00968","title":"Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol.","authors":"Gomes, Felipe V; Llorente, Ricardo; Del Bel, Elaine A; Viveros, Maria-Paz; López-Gallardo, Meritxell; Guimarães, Francisco S","year":2015,"journal":"Schizophrenia research, 164(1-3), 155-63","doi":"10.1016/j.schres.2015.01.015","pmid":"25680767","tags":["cbd","psychosis","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used an animal model of schizophrenia based on blocking NMDA receptors (which mimics the glutamate dysfunction seen in schizophrenia) and tested whether CBD could reverse the resulting behavioral and brain changes.\n\nChronic MK-801 treatment impaired social interaction and novel object recognition in mice, modeling the negative symptoms and cognitive deficits of schizophrenia. It also increased reactive astrocytes in the prefrontal cortex and activated microglia (inflammatory brain cells) in the prefrontal cortex and hippocampus.\n\nRepeated CBD treatment (30 and 60 mg/kg) reversed both the behavioral impairments and the inflammatory glial changes. CBD's effects were comparable to those of clozapine, an established antipsychotic. The findings suggest CBD's antipsychotic-like effects may work through its anti-inflammatory and neuroprotective properties.","whyItMatters":"Current antipsychotics have significant side effects and poorly treat negative symptoms and cognitive deficits. If CBD can address these through anti-inflammatory mechanisms, it could offer a complementary or alternative approach with a better side effect profile.","specificNumbers":"CBD tested at 30 and 60 mg/kg. 5 brain regions examined. GFAP-positive astrocytes increased in mPFC by MK-801. Reactive microglia increased in mPFC and dorsal hippocampus. Both behavioral and glial changes reversed by CBD and clozapine. No neuron loss observed.","methodology":"Controlled animal study using chronic MK-801 (NMDA antagonist) administration for 28 days to model schizophrenia. CBD (30 and 60 mg/kg) and clozapine were given as repeated treatments. Social interaction and novel object recognition tests assessed behavior. Immunohistochemistry measured NeuN, Iba-1, and GFAP expression across 5 brain regions.","limitations":"Mouse model does not fully replicate human schizophrenia. NMDA antagonist models capture some but not all aspects of the disorder. CBD doses may not translate directly to human dosing. Long-term effects and safety of repeated CBD in this context are not established."},{"rthcId":"RTHC-00969","title":"The influence of cannabinoids on learning and memory processes of the dorsal striatum.","authors":"Goodman, Jarid; Packard, Mark G","year":2015,"journal":"Neurobiology of learning and memory, 125, 1-14","doi":"10.1016/j.nlm.2015.06.008","pmid":"26092091","tags":["cognition","neuroscience","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how cannabinoids affect the dorsal striatum, a brain region that controls habit formation and stimulus-response (S-R) learning. The evidence revealed a paradoxical pattern depending on duration of exposure.\n\nAcute administration of cannabinoid agonists or antagonists impaired habit memory in animal studies. However, chronic cannabinoid exposure and THC tolerance enhanced habit formation. Human studies of cannabis users also suggested enhanced S-R/habit memory.\n\nThe authors proposed that this pattern has dual clinical significance: the acute impairing effect on habit memory could be therapeutically useful for disorders involving dysfunctional habits (like PTSD or drug addiction relapse), while the enhancing effect of chronic use suggests a novel mechanism for marijuana addiction involving the habit memory system.","whyItMatters":"Understanding that chronic cannabis use strengthens habit circuitry provides a new framework for understanding cannabis addiction. It also suggests that acute cannabinoid administration might help break unwanted habitual behaviors in conditions like PTSD and addiction.","specificNumbers":"Acute disruption of endocannabinoid system impaired habit memory. Chronic exposure enhanced habit formation. CB1 receptors mediate striatal short-term and long-term depression. THC tolerance enhanced habit formation in mice.","methodology":"Narrative review synthesizing animal studies (rat maze tasks, mouse CB1 receptor knockdowns), human behavioral studies, and molecular research on cannabinoid-mediated synaptic plasticity in the dorsal striatum.","limitations":"The review is narrative and synthesizes across different species, tasks, and cannabinoid compounds. The acute-impairs/chronic-enhances pattern is a tentative conclusion. Human data on habit memory in cannabis users is limited."},{"rthcId":"RTHC-00970","title":"Cannabis use among juvenile detainees: typology, frequency and association.","authors":"Grigorenko, Elena L; Edwards, Laurel; Chapman, John","year":2015,"journal":"Criminal behaviour and mental health : CBMH, 25(1), 54-65","doi":"10.1002/cbm.1913","pmid":"24839230","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers examined a random 20% sample of all juveniles in Connecticut's state detention facilities. Lifetime marijuana use was 54% and daily use was 16%, both substantially higher than general population rates for this age group.\n\nDaily cannabis users demonstrated a more negative mental health profile compared to other detainees. However, they did not differ from the rest of the sample on criminal justice indicators such as total number of detentions, number of charges, or types of charges.\n\nThe findings suggest that among court-involved youth, cannabis use functions more as an indicator of mental health problems than as an independent driver of criminal behavior.","whyItMatters":"Understanding cannabis use patterns among detained youth helps target interventions. If cannabis use signals mental health problems rather than criminal trajectory, treatment approaches should focus on underlying mental health rather than punishing drug use.","specificNumbers":"371 detained juveniles, ages 10-16. Lifetime cannabis use: 54%. Daily use: 16%. Daily users had worse mental health profiles. No significant differences in criminal justice indicators between daily users and others.","methodology":"Cross-sectional study of records from a random 20% sample of all juveniles in Connecticut state detention facilities (n=371, ages 10-16). Data included self-reported cannabis use, mental health indicators, lifetime psychiatric diagnoses, and criminal justice indicators.","limitations":"Single state (Connecticut) detention system. Self-reported substance use may be underreported in a detention setting. Cross-sectional design. Records review lacks the depth of direct clinical assessment."},{"rthcId":"RTHC-00971","title":"Phenomenological subtypes of mania and their relationships with substance use disorders.","authors":"Güclü, Oya; Şenormancı, Ömer; Aydın, Erkan; Erkıran, Murat; Köktürk, Firuzan","year":2015,"journal":"Journal of affective disorders, 174, 569-73","doi":"10.1016/j.jad.2014.11.016","pmid":"25560193","tags":["psychosis","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers studied 96 inpatients hospitalized for bipolar manic episodes and identified two clusters of symptoms using factor and cluster analysis. Cluster 1 featured primarily elevated psychomotor activity (classic mania), while Cluster 2 was characterized by dysphoria (negative mood) and psychotic symptoms.\n\nSubstance use disorders differed significantly between clusters. In Cluster 1 (psychomotor elevation), 39% had alcohol use disorders alone. In Cluster 2 (dysphoric-psychotic), 31.6% had both alcohol and cannabis use disorders. Cluster 2 patients also had more suicide attempts: 47.4% had one attempt and 21.1% had two or more.\n\nThe authors suggested that patients with pure mania may self-medicate with alcohol's sedative effects, while the cannabis-psychosis association in dysphoric patients may reflect a causal relationship between cannabis and psychotic features.","whyItMatters":"Not all manic episodes are the same, and different presentations may have different relationships with substance use. Understanding that dysphoric-psychotic mania is specifically associated with cannabis use (and higher suicide risk) can guide more targeted clinical assessments.","specificNumbers":"96 bipolar manic inpatients. Cluster 1 (psychomotor): 39% alcohol use disorder. Cluster 2 (dysphoric-psychotic): 31.6% combined alcohol and cannabis disorders. Cluster 2: 47.4% one suicide attempt, 21.1% two or more attempts.","methodology":"Cross-sectional study of 96 inpatients hospitalized for bipolar manic episodes. Factor analysis of YMRS, MADRS, and SAPS items generated three factors. Hierarchical cluster analysis identified two patient subtypes. MAST assessed alcohol disorders. Substance use disorders and clinical variables were compared between clusters.","limitations":"Cross-sectional design at a single hospital. Cannot determine whether cannabis caused the psychotic features or whether psychosis-prone patients are more likely to use cannabis. Small sample for subgroup analysis. Turkish population may not generalize."},{"rthcId":"RTHC-00972","title":"Identifying classes of conjoint alcohol and marijuana use in entering freshmen.","authors":"Haas, Amie L; Wickham, Robert; Macia, Kathryn; Shields, Micah; Macher, Rayna; Schulte, Tilman","year":2015,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 29(3), 620-6","doi":"10.1037/adb0000089","pmid":"26168228","tags":["youth","addiction","driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used latent profile analysis to identify four distinct groups among 772 incoming college freshmen based on their alcohol and marijuana use patterns. The groups were: light drinking/no marijuana (40%), moderate drinking/no marijuana (25%), moderate drinking/marijuana (22%), and heavy drinking/marijuana (14%).\n\nThe most informative comparison was between the two moderate drinking groups. Those who also used marijuana were more likely to drink more than intended, drink to get drunk, and experienced more problems including higher rates of blackouts, physical injuries, and DUI, compared to moderate drinkers who did not use marijuana.\n\nThese differences occurred despite similar alcohol consumption levels, suggesting that marijuana use adds independent risk beyond what alcohol alone produces.","whyItMatters":"College prevention programs often focus on alcohol alone, but this study shows that combined marijuana-alcohol use creates additional risk. Students who use both substances experience more severe consequences even at the same drinking level, highlighting the need for polysubstance-focused interventions.","specificNumbers":"772 freshmen. 4 groups: light/no MJ (40%), moderate/no MJ (25%), moderate/MJ (22%), heavy/MJ (14%). Moderate drinkers+MJ had more: blackouts, injuries, DUI, drinking to get drunk vs. moderate drinkers without MJ.","methodology":"Latent profile analysis of 772 entering college freshmen (53% male, 60% White, mean age 18). Four groups identified based on alcohol and marijuana use patterns. Pairwise contrasts examined cross-class differences in demographics, drinking behaviors, and consequences.","limitations":"Cross-sectional data from a single university at one time point. Self-reported substance use and consequences. The study cannot determine whether marijuana directly causes additional problems or whether the same risk-taking tendencies drive both marijuana use and worse outcomes."},{"rthcId":"RTHC-00973","title":"Medical marijuana: review of the science and implications for developmental-behavioral pediatric practice.","authors":"Hadland, Scott E; Knight, John R; Harris, Sion K","year":2015,"journal":"Journal of developmental and behavioral pediatrics : JDBP, 36(2), 115-23","doi":"10.1097/DBP.0000000000000129","pmid":"25650954","tags":["medical-cannabis","youth","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review for developmental-behavioral pediatricians examined three domains: cannabis use epidemiology among youth, neurocognitive effects in adolescents, and proposed medical uses in pediatric conditions.\n\nRegular cannabis use among adolescents was associated with well-recognized neurocognitive changes, with the developing brain being particularly susceptible due to the endocannabinoid system's role in normal neurodevelopment. The review highlighted attention, memory, and executive function as domains most consistently affected.\n\nFor proposed medical uses in conditions like ADHD and autism spectrum disorder, the evidence was described as a \"dearth.\" The authors identified a significant gap between parent interest in medical cannabis for children and the available scientific evidence to guide clinical decisions.","whyItMatters":"Pediatricians are increasingly fielding questions from parents about medical cannabis for their children. This review provides a framework for evidence-based responses that acknowledge both the limited therapeutic evidence and the documented neurodevelopmental risks.","specificNumbers":"Conditions reviewed: ADHD, autism spectrum disorder, and other developmental-behavioral diagnoses. Evidence for pediatric medical uses described as a \"dearth.\" Neurocognitive risks well-documented for adolescent users.","methodology":"Narrative review examining epidemiology of cannabis use among children and adolescents, neurocognitive effects of regular cannabis use on developing brains, and proposed therapeutic uses of cannabis in developmental and behavioral conditions.","limitations":"Narrative review rather than systematic review. Published in 2015, so newer evidence is not included. Focuses on US context. Does not separately address CBD-only products, which have different risk profiles."},{"rthcId":"RTHC-00974","title":"HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid.","authors":"Haj, Christeene G; Sumariwalla, Percy F; Hanuš, Lumír; Kogan, Natalya M; Yektin, Zhana; Mechoulam, Raphael; Feldmann, Mark; Gallily, Ruth","year":2015,"journal":"The Journal of pharmacology and experimental therapeutics, 355(1), 66-75","doi":"10.1124/jpet.115.226100","pmid":"26272937","tags":["cbd","inflammation","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers synthesized HU-444, a novel derivative of CBD designed to be structurally incapable of converting to THC in acidic conditions (a potential concern with natural CBD). The compound showed strong anti-inflammatory properties both in cell cultures and in living animals.\n\nIn laboratory tests, HU-444 reduced reactive oxygen species production and inhibited TNF-alpha (a key inflammatory molecule) production by macrophages. In mice, it suppressed TNF-alpha production, reduced liver damage from inflammation, and lowered the severity of collagen-induced arthritis (a standard rheumatoid arthritis model).\n\nImportantly, HU-444 did not produce THC-like behavioral effects in mice, confirming its non-psychoactive profile. The researchers proposed it as a potential novel drug for rheumatoid arthritis and other inflammatory diseases.","whyItMatters":"CBD has demonstrated anti-inflammatory potential, but its possible conversion to THC in acidic environments raised concerns. HU-444 eliminates this issue while retaining anti-inflammatory activity, potentially offering a cleaner pharmaceutical candidate for inflammatory diseases.","specificNumbers":"HU-444 structurally cannot cyclize to THC. Reduced TNF-alpha production in vitro. Ameliorated liver damage in vivo. Lowered collagen-induced arthritis severity. No THC-like behavioral effects.","methodology":"Chemical synthesis and pharmacological evaluation. In vitro: reactive oxygen intermediates and TNF-alpha production in macrophages. In vivo: TNF-alpha suppression, liver damage model, and mouse collagen-induced arthritis model. Behavioral testing confirmed absence of THC-like effects.","limitations":"Preclinical study only, with no human data. Mouse arthritis models do not perfectly replicate human rheumatoid arthritis. The optimal dosing, long-term safety, and pharmacokinetics of HU-444 have not been established. Comparison to existing arthritis treatments was not made."},{"rthcId":"RTHC-00975","title":"Prevalence of marijuana use disorders in the United States between 2001-2002 and 2012-2013","authors":"Hasin, Deborah S.; Saha, Tulshi D.; Kerridge, Bradley T.; Goldstein, Rishe B.; Chou, S. Patricia; Zhang, Haitao; et al.","year":2015,"journal":"JAMA Psychiatry, 72(12), 1235-1242","doi":"10.1001/jamapsychiatry.2015.1858","pmid":"26502112","tags":["addiction","mental-health","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Past-year cannabis use rose from 4.1% of adults in 2001-2002 to 9.5% in 2012-2013. Past-year cannabis use disorder also increased, from 1.5% to 2.9% of adults. Among people who used cannabis in the past year, the proportion meeting DSM-IV criteria for abuse or dependence declined from 35.6% to 30.6%. In plain terms, more adults used cannabis and more adults had a disorder overall. But an average individual user in 2012-2013 was less likely to meet disorder criteria than an average user in 2001-2002. Increases in both use and disorder were detected across most demographic groups.","whyItMatters":"As laws and social acceptance shifted in the 2000s and early 2010s, this study provided a clear national snapshot of two linked trends: many more adults reporting cannabis use, and a larger number of adults meeting criteria for a use disorder. It also showed that the likelihood of disorder among users went down, pointing to population expansion as the main driver of the higher disorder count.","specificNumbers":"- Past-year use: 4.1% in 2001-2002 vs 9.5% in 2012-2013. Roughly 1 in 25 adults then, about 1 in 10 later (P<.05).\n- Past-year cannabis use disorder (DSM-IV): 1.5% vs 2.9%. About 1 in 67 adults then, about 1 in 34 later (P<.05).\n- Disorder among past-year users: 35.6% vs 30.6%. About 1 in 3 users met criteria in 2012-2013.\n- Samples: 43,093 adults in 2001-2002 and 36,309 in 2012-2013, both nationally representative.","methodology":"This study analyzed two nationally representative, face-to-face household surveys of U.S. adults: NESARC in 2001-2002 (N=43,093) and NESARC-III in 2012-2013 (N=36,309). Past-year cannabis use and DSM-IV cannabis use disorder (abuse or dependence) were assessed in both waves to enable comparison. Estimates were weighted to represent the U.S. adult population. The design is repeated cross-sectional, so it tracks population changes over time but does not follow the same individuals.","limitations":"Repeated cross-sections track populations, not individuals, so they cannot identify causes. Both surveys relied on self-report in face-to-face interviews, which can be affected by willingness to disclose that may have changed with shifting attitudes and laws. Although DSM-IV criteria were applied in both waves to aid comparability, differences in survey context and participation could influence estimates. Findings apply to adults only, not adolescents. The study period ends in 2013, before the more recent expansion of legal markets and product types."},{"rthcId":"RTHC-00976","title":"Concomitant cannabis abuse/dependence in patients treated with opioids for non-cancer pain.","authors":"Hefner, Kathryn; Sofuoglu, Mehmet; Rosenheck, Robert","year":2015,"journal":"The American journal on addictions, 24(6), 538-45","doi":"10.1111/ajad.12260","pmid":"26246069","tags":["pain","addiction","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined cannabis use disorder (CUD) rates among 1,316,464 VHA patients with non-cancer pain who received opioid medications. Using logistic regression controlling for confounders, they found that greater numbers of opioid prescription fills were associated with greater likelihood of having a CUD diagnosis.\n\nThe relationship held across prescription fill categories (0, 1-2, 3-10, 11-19, 20+), though it was somewhat reduced for those receiving the most prescriptions (20+) after controlling for confounders like other substance use disorders and psychotropic medications.\n\nThe authors concluded that cannabis and opioids appear to function as complements (associated with increased use of both) rather than substitutes (where more of one means less of the other), warranting increased clinical attention to cannabis use in patients receiving opioid prescriptions.","whyItMatters":"The substitution hypothesis (that cannabis could replace opioids and reduce the overdose epidemic) is a major policy argument. This study provides contrary evidence: in practice, cannabis and opioid use appear to go together rather than substitute for each other.","specificNumbers":"1,316,464 VHA patients analyzed. More opioid fills associated with more CUD. Relationship held across fill categories: 0, 1-2, 3-10, 11-19, 20+. Slightly attenuated at 20+ fills after adjustment.","methodology":"Cross-sectional analysis of 1,316,464 VHA patients with non-cancer pain diagnoses receiving opioid medications in fiscal year 2012. Bivariate and logistic regression analyses examined the relationship between number of opioid prescription fills and CUD diagnosis.","limitations":"Cross-sectional design cannot determine temporal direction. VHA patient population (predominantly male, older, with high comorbidity) may not generalize. CUD diagnosis may be underreported. Cannot determine whether patients used cannabis to manage pain or for other reasons."},{"rthcId":"RTHC-00977","title":"Critical Role of Mast Cells and Peroxisome Proliferator-Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo.","authors":"Hegde, Venkatesh L; Singh, Udai P; Nagarkatti, Prakash S; Nagarkatti, Mitzi","year":2015,"journal":"Journal of immunology (Baltimore, Md. : 1950), 194(11), 5211-22","doi":"10.4049/jimmunol.1401844","pmid":"25917103","tags":["cbd","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers discovered that CBD administration in mice triggered a robust immune response: the mobilization of myeloid-derived suppressor cells (MDSCs) in the abdominal cavity. These MDSCs expressed functional arginase 1 and potently suppressed T cell proliferation.\n\nThe mechanism involved mast cells and the PPAR-gamma receptor (peroxisome proliferator-activated receptor gamma). CBD was shown to enhance PPAR-gamma transcriptional activity, and blocking this receptor completely prevented MDSC induction. Mast cell-deficient mice showed markedly reduced MDSC responses.\n\nCBD-induced MDSCs were functional: when transferred to other mice, they suppressed LPS-induced acute inflammatory responses. The findings reveal a previously unknown pathway through which CBD modulates the immune system.","whyItMatters":"Understanding the specific immune pathways through which CBD works is essential for developing CBD-based therapies. This study identified a concrete molecular pathway (PPAR-gamma in mast cells leading to G-CSF and MDSC mobilization) that could be targeted more precisely.","specificNumbers":"CBD induced CD11b+Gr-1+ MDSCs in peritoneum. Both granulocytic and monocytic MDSC subtypes induced. Monocytic MDSCs showed higher suppressive function. MDSC induction markedly reduced in mast cell-deficient mice. PPAR-gamma antagonist completely blocked MDSC induction.","methodology":"Controlled animal study using wild-type and mast cell-deficient (Kit-mutant) mice. CBD was administered and MDSC induction was measured by flow cytometry. Functional suppression was tested via T cell proliferation assays and adoptive transfer experiments. PPAR-gamma involvement was confirmed using reporter assays and selective antagonists.","limitations":"Animal study using naive (healthy) mice. The immune-suppressive effects in healthy animals may not directly translate to therapeutic contexts. Long-term consequences of MDSC mobilization are unknown and could include impaired anti-tumor immunity. Doses may not translate to human use."},{"rthcId":"RTHC-00978","title":"Cannabinoid hyperemesis syndrome.","authors":"Heise, Lynn","year":2015,"journal":"Advanced emergency nursing journal, 37(2), 95-101","doi":"10.1097/TME.0000000000000062","pmid":"25929220","tags":["addiction","appetite"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review for emergency nursing practitioners outlined the key features of CHS. Standard antiemetic treatments are ineffective, and narcotics given for abdominal pain may cause worsening rebound pain. The only reliably effective treatment is abstinence from marijuana.\n\nThe review referenced a 2004 Australian study that identified 19 chronic marijuana users presenting to an emergency department with recurrent vomiting and abdominal pain as the foundational description of the syndrome. The author predicted that marijuana legalization would increase the number of long-term users and consequently the number of CHS cases.\n\nThe review emphasized that advanced practice nurses need to include CHS in their differential diagnosis for patients presenting with recurrent nausea, vomiting, and abdominal pain.","whyItMatters":"Emergency nurses are often the first clinicians to evaluate patients with CHS. Recognition of the syndrome can prevent unnecessary testing, inappropriate treatment (which may worsen symptoms), and repeated emergency visits.","specificNumbers":"Referenced 2004 study identified 19 chronic users with CHS. Standard antiemetics described as ineffective. Narcotics may cause rebound pain. Abstinence identified as the best treatment.","methodology":"Narrative review and clinical guide for advanced practice nurses working in emergency settings, covering recognition, differential diagnosis, and management of CHS.","limitations":"Narrative review for clinical practice rather than systematic research review. Based on limited published literature available at the time. Does not address the mechanism of CHS or predict individual risk."},{"rthcId":"RTHC-00979","title":"Brain activation to negative stimuli mediates a relationship between adolescent marijuana use and later emotional functioning.","authors":"Heitzeg, Mary M; Cope, Lora M; Martz, Meghan E; Hardee, Jillian E; Zucker, Robert A","year":2015,"journal":"Developmental cognitive neuroscience, 16, 71-83","doi":"10.1016/j.dcn.2015.09.003","pmid":"26403581","tags":["youth","mental-health","neuroscience","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tracked 40 participants from the Michigan Longitudinal Study, comparing 20 heavy marijuana users with 20 minimal-use controls. Emotional functioning was measured at three time points (ages ~13, ~20, ~23) and brain imaging was conducted at age ~20.\n\nIn controls, negative emotionality decreased and resilience increased across the three time points, a normal developmental trajectory. Heavy marijuana users did not show this improvement. Brain imaging revealed that heavy users had less activation to negative emotional words in temporal, prefrontal, and occipital cortices, insula, and amygdala.\n\nMediation analysis showed that dorsolateral prefrontal cortex activation to negative words mediated the association between marijuana group and later negative emotionality. Cuneus/lingual gyrus activation mediated the association with later resilience. This provides evidence for specific brain mechanisms linking adolescent cannabis use to emotional development.","whyItMatters":"This study provides both behavioral and brain-based evidence that heavy adolescent cannabis use interferes with normal emotional development. The mediation analysis identifies specific brain regions whose altered function explains why heavy users develop worse emotional outcomes.","specificNumbers":"40 participants (20 heavy users, 20 controls). 3 emotional assessments (ages ~13, ~20, ~23). Brain imaging at age ~20. DLPFC activation mediated negative emotionality. Cuneus/lingual gyrus mediated resilience. Controls showed improving trajectories; heavy users did not.","methodology":"Longitudinal study of 40 participants from the Michigan Longitudinal Study. Emotional functioning assessed at mean ages 13.4, 19.6, and 23.1. fMRI during an emotion-arousal word task at mean age 20.2. Mediation analysis tested whether brain activation patterns explained the relationship between marijuana use and emotional outcomes.","limitations":"Small sample (20 per group). Observational design cannot definitively prove cannabis caused the differences. Participants came from families with substance use histories, limiting generalizability. Multiple comparisons increase false positive risk."},{"rthcId":"RTHC-00980","title":"Polydrug use and its relationship with the familiar and social context amongst young college students.","authors":"Hernández-Serrano, Olga; Font-Mayolas, Sílvia; Gras, Maria Eugènia","year":2015,"journal":"Adicciones, 27(3), 205-13","doi":null,"pmid":"26437314","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 480 Spanish health and sports science undergraduates about their substance use and that of their closest reference persons (parents, siblings, best friend, and partner). Nearly half (46%) reported using two or more substances.\n\nThe most common polydrug pattern included cannabis plus alcohol and/or tobacco (50.7% of polydrug users). A smaller group used cannabis plus alcohol, tobacco, and at least one other illegal drug (16.7%). The simplest pattern was alcohol plus tobacco only (29.4%).\n\nThe strongest finding was the social correlation: the more a person's close reference persons used multiple substances, the more likely the participant was to be a polydrug user. This held across parents, siblings, best friends, and partners.","whyItMatters":"Prevention programs often focus on individual decision-making, but this study highlights the powerful influence of social environment. Polydrug use patterns mirror those of close family and friends, suggesting that family and peer-focused interventions may be more effective.","specificNumbers":"480 students surveyed. 46% reported polydrug use. Pattern A (alcohol+tobacco): 29.4%. Pattern B (cannabis+alcohol/tobacco): 50.7%. Pattern C (cannabis+alcohol+tobacco+other illegal): 16.7%. Strong correlation between participant and reference person polydrug use.","methodology":"Cross-sectional survey of 480 Spanish undergraduates (43.7% female, ages 18-36) studying health and sports science. Self-report questionnaire assessed substance use of participants and their closest reference persons. Polydrug patterns classified using European Observatory categories.","limitations":"Cross-sectional design cannot determine causal direction. Spanish health/sports science students may not represent all college students. Self-reported data about others' substance use may be inaccurate. Social environment correlations could reflect shared genetics or neighborhood effects."},{"rthcId":"RTHC-00981","title":"Non-smoker exposure to secondhand cannabis smoke II: Effect of room ventilation on the physiological, subjective, and behavioral/cognitive effects.","authors":"Herrmann, Evan S; Cone, Edward J; Mitchell, John M; Bigelow, George E; LoDico, Charles; Flegel, Ron; Vandrey, Ryan","year":2015,"journal":"Drug and alcohol dependence, 151, 194-202","doi":"10.1016/j.drugalcdep.2015.03.019","pmid":"25957157","tags":["harm-reduction","potency","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Non-cannabis-using individuals were exposed to secondhand smoke from six people smoking 11.3% THC cannabis in a sealed chamber for one hour under two conditions: unventilated and ventilated (11 air exchanges per hour).\n\nUnventilated exposure produced detectable THC in blood and urine, minor heart rate increases, mild-to-moderate self-reported sedation, and impaired performance on a cognitive task (digit symbol substitution). One urine specimen tested positive at 50 ng/mL and several at 20 ng/mL.\n\nWith ventilation, blood cannabinoid levels were much lower, and there were no sedative effects, no cognitive impairment, and no positive urine screens at any cutoff. The results demonstrate that ventilation is an extremely effective countermeasure against secondhand cannabis exposure.","whyItMatters":"This study provides concrete guidance: adequate ventilation virtually eliminates the physiological, cognitive, and drug-testing effects of secondhand cannabis smoke. This has practical implications for workplace policies, residential settings, and public spaces.","specificNumbers":"Cannabis: 11.3% THC. 1-hour exposure. Unventilated: positive drug tests (20 and 50 ng/mL), sedation, DSST impairment. Ventilated (11 exchanges/hour): no positive screens, no sedation, no cognitive impairment.","methodology":"Controlled exposure study with non-cannabis-using participants exposed to secondhand smoke in a chamber with experimentally manipulated ventilation. Unventilated vs. 11 air exchanges/hour. Physiological, subjective (VAS), and cognitive (DSST) measures compared to baseline.","limitations":"Only one ventilation rate tested. Extreme exposure conditions (sealed chamber, 6 smokers, 1 hour). Indoor ventilation rates in homes and workplaces vary widely. Does not address outdoor exposure or vaporizer emissions."},{"rthcId":"RTHC-00982","title":"Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users.","authors":"Hindocha, Chandni; Freeman, Tom P; Schafer, Grainne; Gardener, Chelsea; Das, Ravi K; Morgan, Celia J A; Curran, H Valerie","year":2015,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 25(3), 325-34","doi":"10.1016/j.euroneuro.2014.11.014","pmid":"25534187","tags":["cbd","cognition","psychosis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Forty-eight cannabis users received THC (8mg), CBD (16mg), THC+CBD (8mg+16mg), and placebo by inhalation in a four-way crossover design. They then completed an emotional facial affect recognition task with faces showing fear, anger, happiness, sadness, surprise, and disgust at varying intensities.\n\nCBD improved emotional face recognition at 60% intensity (moderate difficulty). THC impaired recognition of ambiguous faces at 40% intensity. When THC and CBD were combined, the impairment was eliminated, with performance similar to placebo.\n\nBoth THC alone and THC+CBD equally increased feelings of being \"stoned,\" but CBD did not influence this subjective feeling. Frequency of cannabis use and schizotypy scores did not modify the effects. This was the first human study directly comparing different cannabinoids on emotional processing.","whyItMatters":"Recognizing emotions in others is fundamental to social functioning. THC's impairment of this ability may contribute to social difficulties in cannabis users, while CBD's protective effect suggests that cannabis products with higher CBD ratios could be less socially impairing.","specificNumbers":"48 participants. 4 conditions (crossover). THC 8mg impaired recognition at 40% intensity. CBD 16mg improved recognition at 60% intensity. THC+CBD combination: no impairment. Both THC and THC+CBD increased feeling \"stoned\" equally.","methodology":"Randomized, double-blind, placebo-controlled, 4-way crossover design. 48 volunteers (selected for high and low cannabis use frequency and schizotypy) received inhaled THC (8mg), CBD (16mg), THC+CBD (8mg+16mg), and placebo. Emotional facial affect recognition task with 6 emotions at 20-100% intensity.","limitations":"Participants were cannabis users, so results may not generalize to non-users. Inhaled delivery of precise doses is difficult to standardize. The doses used may not reflect typical use. Single-session design does not address chronic effects."},{"rthcId":"RTHC-00983","title":"A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain.","authors":"Hoggart, B; Ratcliffe, S; Ehler, E; Simpson, K H; Hovorka, J; Lejčko, J; Taylor, L; Lauder, H; Serpell, M","year":2015,"journal":"Journal of neurology, 262(1), 27-40","doi":"10.1007/s00415-014-7502-9","pmid":"25270679","tags":["medical-cannabis","pain","cbd"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This open-label extension study followed 380 patients with peripheral neuropathic pain (from diabetes or allodynia) who had participated in two prior randomized controlled trials of THC/CBD oromucosal spray. Patients received the spray for an additional 38 weeks alongside their current pain medications.\n\nPain scores on a 0-10 scale decreased from a mean of 6.9 at the original baseline to 4.2 at the end of the extension. At least half of patients reported a clinically meaningful 30% improvement at all time points, with the proportion continuing to increase up to 9 months. Improvements were also seen in sleep quality, neuropathic pain subscales, patient global impression of change, and quality of life.\n\nCritically, patients did not seek to increase their dose over time, suggesting tolerance did not develop. The spray was well tolerated with no new safety concerns from long-term use.","whyItMatters":"Long-term pain management data for cannabinoids is scarce. This study demonstrates that THC/CBD spray can maintain effectiveness for nearly a year without dose escalation, addressing concerns about tolerance that limit the long-term utility of many pain medications.","specificNumbers":"380 patients entered; 234 completed (62%). Pain NRS: 6.9 baseline to 4.2 at end. At least 50% had 30% improvement at all time points. 38 weeks of follow-up. No dose escalation observed.","methodology":"Open-label, 38-week extension study of 380 patients from two parent randomized controlled trials. Patients had peripheral neuropathic pain from diabetes or allodynia. Primary outcome: 0-10 pain NRS. Secondary outcomes: sleep, neuropathic pain subscales, global impression, quality of life. Safety and dosing patterns tracked throughout.","limitations":"Open-label design means no placebo comparison for the extension phase. Patients who entered the extension were selected from prior RCTs (likely biased toward those who responded). 38% dropout rate may bias results toward better outcomes. Neuropathic pain from diabetes and allodynia may not represent all neuropathic pain types."},{"rthcId":"RTHC-00984","title":"A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts.","authors":"Hojnik, Marko; Dobovišek, Luka; Knez, Željko; Ferk, Polonca","year":2015,"journal":"Biomedical reports, 3(4), 554-558","doi":null,"pmid":"26171165","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested how estrogen (17-beta-estradiol) and cannabinoid CB2 receptor compounds interact in primary human osteoblasts (bone-forming cells). When a CB2 antagonist/inverse agonist (AM630) was combined with moderate estrogen (10 nM), it produced the same proliferation boost as a 10-fold higher estrogen dose (100 nM) alone.\n\nConversely, combining estrogen with a CB2 agonist (AM1241) decreased osteoblast proliferation compared to estrogen alone. This suggests that blocking CB2 receptors enhances estrogen's bone-building effects while activating them reduces it.\n\nThis was the first demonstration of a synergistic interaction between estrogen and CB2 receptor modulation in human osteoblasts, suggesting potential implications for treating or preventing bone diseases like osteoporosis.","whyItMatters":"Osteoporosis, particularly in postmenopausal women with declining estrogen, is a major health burden. If CB2 receptor modulation can amplify estrogen's bone-protective effects, it could lead to combination therapies that use lower estrogen doses with fewer side effects.","specificNumbers":"CB2 antagonist + estrogen 10 nM = estrogen 100 nM alone (10x amplification). CB2 agonist + estrogen reduced proliferation. Effects observed at both 24 and 48 hours.","methodology":"In vitro study using primary human osteoblasts in 5th passage. Cells exposed to different concentrations of estrogen, CB2 agonist (AM1241), and CB2 antagonist (AM630), alone and in combinations. Proliferation measured by WST-8 assay at 24 and 48 hours. Alkaline phosphatase activity confirmed osteoblast differentiation.","limitations":"In vitro study using isolated osteoblasts, which does not capture the complexity of bone remodeling in a living organism. Single concentrations of CB2 compounds tested. No in vivo confirmation. The molecular pathway of the synergy was not identified."},{"rthcId":"RTHC-00985","title":"The complex etiology of schizophrenia - general state of the art.","authors":"Hosák, Ladislav; Hosakova, Jirina","year":2015,"journal":"Neuro endocrinology letters, 36(7), 631-7","doi":null,"pmid":"26859583","tags":["psychosis","genetics"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized the complex, multi-factorial etiology of schizophrenia. While genetic factors are important (identified through genome-wide association studies and copy number variation analysis), environmental factors play crucial roles through gene-environment interactions.\n\nCannabis use and psychosocial stress were identified as the two most important environmental risk factors. Both may affect schizophrenia risk through potentiation of vulnerable brain pathways, and epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) serve as the molecular link between environmental exposures and gene expression changes.\n\nThe review emphasized that many research challenges remain, including the need for larger study samples, quantitative assessment of environmental exposures, and evaluation of multiple interacting genetic and environmental variables simultaneously.","whyItMatters":"Understanding where cannabis fits in the complex web of schizophrenia causation helps contextualize risk appropriately. Cannabis is not the sole cause but is among the most important modifiable risk factors, particularly for genetically vulnerable individuals.","specificNumbers":"Cannabis and psychosocial stress identified as the two most important environmental factors. Multiple genetic mechanisms reviewed: GWAS, CNVs, endophenotypes. Epigenetic mechanisms: DNA methylation, histone modifications, non-coding RNAs.","methodology":"Narrative review presenting a global view of schizophrenia causes and their interconnectivity, covering genetics, gene-environment interactions, epigenetics, and environmental risk factors.","limitations":"Narrative review reflecting the state of knowledge in 2015. The field is rapidly evolving. Many gene-environment interactions remain to be characterized. Quantifying environmental exposure (including cannabis use patterns) remains methodologically challenging."},{"rthcId":"RTHC-00986","title":"Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.","authors":"Hussain, Shaun A; Zhou, Raymond; Jacobson, Catherine; Weng, Julius; Cheng, Emily; Lay, Johnson; Hung, Phoebe; Lerner, Jason T; Sankar, Raman","year":2015,"journal":"Epilepsy & behavior : E&B, 47, 138-41","doi":"10.1016/j.yebeh.2015.04.009","pmid":"25935511","tags":["cbd","epilepsy","youth","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 117 parents who had given CBD-enriched cannabis preparations to their children for epilepsy. Among them, 53 had children with infantile spasms (IS) or Lennox-Gastaut syndrome (LGS), two of the most treatment-resistant forms of childhood epilepsy.\n\n85% of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. The median child had failed 8 previous antiseizure medication trials before starting CBD, with a median latency of 5 years from epilepsy onset to CBD initiation. Median CBD exposure was 6.8 months at 4.3 mg/kg/day.\n\nReported side effects were less common during CBD treatment than with prior medications, with the exception of increased appetite (30%). Additional benefits included improvements in sleep (53%), alertness (71%), and mood (63%).\n\nThe authors explicitly cautioned that the study is \"extraordinarily vulnerable to participation bias\" and does not represent compelling evidence of efficacy or safety.","whyItMatters":"While these results must be interpreted very cautiously due to severe methodological limitations, the degree of treatment resistance (median 8 failed medications) and the perceived benefits reported by parents highlight the urgent need for controlled clinical trials of CBD for IS and LGS.","specificNumbers":"117 parents surveyed, 53 with IS/LGS. 85% reported seizure reduction. 14% reported seizure freedom. Median 8 failed medications before CBD. Median CBD dose: 4.3 mg/kg/day. Median duration: 6.8 months. Improved sleep (53%), alertness (71%), mood (63%).","methodology":"Online survey of parents who administered CBD-enriched cannabis preparations to children with epilepsy. Recruited specifically parents of children with IS and LGS. Assessed perceived efficacy, dosage, tolerability, and additional effects. No blinding, no control group, no seizure verification.","limitations":"No blinding, no control group, no objective seizure measurement. Extraordinarily vulnerable to participation bias (parents who believed CBD helped were more likely to respond). Self-selected sample. Products varied in composition and quality. The authors themselves warned against over-interpreting."},{"rthcId":"RTHC-00987","title":"Lifetime influences for cannabis cessation in male incarcerated indigenous australians.","authors":"Jacups, Susan; Rogerson, Bernadette","year":2015,"journal":"Journal of psychoactive drugs, 47(2), 117-24","doi":"10.1080/02791072.2015.1014949","pmid":"25950591","tags":["quitting","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers interviewed 101 male Indigenous Australian inmates about their cannabis use and what motivated them to quit. Current users averaged 12.3 cones per day and were more likely to have had juvenile legal problems and lower school achievement.\n\nThe most powerful motivators for quitting were incarceration and family responsibilities. Employment responsibilities and negative self-image, which are common motivators in non-Indigenous populations, were rarely cited.\n\nThe findings suggest that cessation programs for Indigenous communities may work better when built around kinship responsibilities and social cohesion rather than emphasizing individual harm.","whyItMatters":"Most cannabis cessation research comes from urban, non-Indigenous populations where life events like marriage and employment drive quitting. This study reveals that culturally specific motivators exist, and programs designed for one population may not translate to another.","specificNumbers":"101 participants; mean consumption of 12.3 cones/day; current users had significantly more juvenile legal problems and younger school departure (p < 0.05)","methodology":"Cross-sectional study of 101 consenting male Indigenous Australian inmates. Researchers used the Marijuana Problems Inventory and both quantitative and qualitative questions about demographics, criminal history, drug use, and cessation influences.","limitations":"The sample was entirely male and incarcerated, limiting generalizability. Self-reported data may be subject to recall bias. The study did not track actual cessation outcomes, only reported motivators."},{"rthcId":"RTHC-00988","title":"The effects of marijuana exposure on expiratory airflow. A study of adults who participated in the U.S. National Health and Nutrition Examination Study.","authors":"Kempker, Jordan A; Honig, Eric G; Martin, Greg S","year":2015,"journal":"Annals of the American Thoracic Society, 12(2), 135-41","doi":"10.1513/AnnalsATS.201407-333OC","pmid":"25521349","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed lung function data from over 100,000 U.S. adults in the NHANES survey. Among those who had used marijuana, each additional day of use in the prior month was associated with increased forced vital capacity (FVC) but a decreased FEV1/FVC ratio.\n\nUp to 20 joint-years of cumulative use showed no association with obstructive lung disease. Above 20 joint-years, there was a twofold increased odds of having a low FEV1/FVC ratio, but this was driven by FVC increasing rather than FEV1 decreasing.\n\nThis pattern differs from tobacco-related lung disease, where FEV1 drops disproportionately.","whyItMatters":"This is one of the largest population-based studies examining marijuana and lung function. The finding that heavy use changes lung volumes in a pattern distinct from tobacco-related obstruction challenges assumptions about how cannabis smoke damages airways.","specificNumbers":"59.1% had used marijuana at least once; 12.2% used in past month; >20 joint-years: OR 2.1 (95% CI 1.1-3.9) for FEV1/FVC <70%; FVC increased 0.13% per additional use day (p = 0.0001)","methodology":"Cross-sectional analysis of U.S. adults from NHANES 2007-2010 cycles. Lung function was measured by standardized spirometry. Cannabis and tobacco exposure were assessed through survey questions. Multivariable regressions adjusted for tobacco use and other confounders.","limitations":"Cross-sectional design cannot establish causation. Self-reported marijuana use may be underestimated. The study could not account for varying potency or methods of consumption. Joint-year calculations rely on self-report accuracy."},{"rthcId":"RTHC-00989","title":"A population-based Swedish Twin and Sibling Study of cannabis, stimulant and sedative abuse in men.","authors":"Kendler, Kenneth S; Ohlsson, Henrik; Maes, Hermine H; Sundquist, Kristina; Lichtenstein, Paul; Sundquist, Jan","year":2015,"journal":"Drug and alcohol dependence, 149, 49-54","doi":"10.1016/j.drugalcdep.2015.01.016","pmid":"25660314","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed registry data from nearly 80,000 Swedish male twin and sibling pairs to understand whether genetic risk for drug abuse is substance-specific or shared across drug types.\n\nThe total heritability for cannabis, stimulant, and sedative abuse ranged from 64-70%. Of that genetic risk, 75-90% was non-specific, meaning the same genetic factors influenced vulnerability to all three substance types.\n\nAll shared environmental effects (18-20% of variance) were also non-specific. This suggests that genetic variation at the specific brain sites where each drug acts plays a surprisingly minor role in who develops substance abuse problems.","whyItMatters":"This confirms with objective data what interview-based studies suggested: the genetic architecture of drug abuse is mostly about general vulnerability rather than specific attraction to particular substances. This has implications for both prevention and treatment approaches.","specificNumbers":"Total heritability: 64-70% across substance types; 75-90% of genetic risk was non-specific; shared environment accounted for 18-20% of variance; 76,457 sibling pairs and 2,939 twin pairs analyzed","methodology":"Population-based study using Swedish national registries. Included 1,720 monozygotic twin pairs, 1,219 dizygotic twin pairs, and 76,457 near-age full sibling pairs. Substance abuse was identified through objective registry records rather than self-report. Structural equation modeling compared common pathway and independent pathway models.","limitations":"Male-only sample limits generalizability to women. Registry-based ascertainment may miss less severe cases. The study examined abuse rather than use, so findings may not apply to casual or recreational patterns."},{"rthcId":"RTHC-00990","title":"Cyclic vomiting presentations following marijuana liberalization in Colorado.","authors":"Kim, Howard S; Anderson, John D; Saghafi, Omeed; Heard, Kennon J; Monte, Andrew A","year":2015,"journal":"Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 22(6), 694-9","doi":"10.1111/acem.12655","pmid":"25903855","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared emergency department visits for cyclic vomiting before and after Colorado's 2009 medical marijuana liberalization. The prevalence nearly doubled, rising from 41 per 113,262 visits to 87 per 125,095 visits.\n\nPatients presenting with cyclic vomiting after liberalization were 3.6 times more likely to have documented marijuana use compared to those before liberalization.\n\nThe researchers could not determine whether the increase was due to more marijuana use, more honest reporting of use, or both.","whyItMatters":"This was an early population-level study linking marijuana policy changes to measurable shifts in emergency department presentations, contributing to growing recognition of cannabinoid hyperemesis syndrome as a clinical entity.","specificNumbers":"Prevalence ratio: 1.92 (95% CI 1.33-2.79); OR for marijuana use documentation: 3.59 (95% CI 1.44-9.00); 36 patients across 128 visits; 2,574 total visits reviewed","methodology":"Cross-sectional study reviewing 2,574 emergency department visits at a Colorado hospital. Identified 36 patients with cyclic vomiting across 128 visits using ICD-9 codes and Rome III diagnostic criteria. Compared prevalence and marijuana use documentation before and after 2009 liberalization.","limitations":"Single hospital study. Cannot distinguish between actual increases in cannabinoid hyperemesis and increased recognition or reporting. Cross-sectional design cannot prove causation. Small number of cyclic vomiting cases (36 patients)."},{"rthcId":"RTHC-00991","title":"Impact of Cannabis Use on Long-Term Remission in Bipolar I and Schizoaffective Disorder.","authors":"Kim, Sung-Wan; Dodd, Seetal; Berk, Lesley; Kulkarni, Jayashri; de Castella, Anthony; Fitzgerald, Paul B; Kim, Jae-Min; Yoon, Jin-Sang; Berk, Michael","year":2015,"journal":"Psychiatry investigation, 12(3), 349-55","doi":"10.4306/pi.2015.12.3.349","pmid":"26207128","tags":["mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 234 patients with bipolar I disorder or schizoaffective disorder for 24 months. About 11% were regular cannabis users (three or more times per week).\n\nCannabis use was significantly associated with lower likelihood of achieving remission. The pattern differed by sex: in women, cannabis was linked to lower depression remission, while in men, it was linked to lower mania remission.\n\nThe lowest remission rates were in patients who used both cannabis and tobacco, followed by tobacco-only users, with non-smokers having the best outcomes.","whyItMatters":"This study provides longitudinal evidence that cannabis use complicates bipolar disorder treatment, and reveals that the impact may differ between men and women and interact with tobacco use.","specificNumbers":"234 participants analyzed; 25 (10.7%) regular cannabis users; 24-month follow-up; combined cannabis and tobacco group had the lowest remission rates; sex-specific effects on depression (women) versus mania (men)","methodology":"Prospective observational study following 239 patients with bipolar I or schizoaffective disorder (bipolar type) over 24 months. Regular cannabis use defined as three or more times per week. Outcomes measured using the Hamilton Depression Rating Scale and Young Mania Rating Scale at evaluations throughout the follow-up period.","limitations":"Observational design cannot prove cannabis caused worse outcomes. Regular cannabis users may differ from non-users in ways not fully captured. Small number of cannabis users (n=25) limits statistical power. Dose and potency were not measured."},{"rthcId":"RTHC-00992","title":"The therapeutic potential of cannabinoids for movement disorders.","authors":"Kluger, Benzi; Triolo, Piera; Jones, Wallace; Jankovic, Joseph","year":2015,"journal":"Movement disorders : official journal of the Movement Disorder Society, 30(3), 313-27","doi":"10.1002/mds.26142","pmid":"25649017","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review examined basic science, animal, and clinical evidence for cannabinoids across multiple movement disorders. The endocannabinoid system modulates motor circuits, particularly within the basal ganglia.\n\nAnimal studies showed variable symptomatic benefits but more consistent neuroprotective effects in Parkinson's and Huntington's disease models. Clinical evidence suggested possible benefit for tics (as in Tourette syndrome) but probably no benefit for tremor in multiple sclerosis or for dyskinesias and motor symptoms in Parkinson's.\n\nData were insufficient to draw conclusions about dystonia, ataxia, or Huntington's, and no data existed for myoclonus or restless leg syndrome.","whyItMatters":"Despite widespread claims about cannabis helping with various neurological conditions, this review found that the evidence is much more limited than public perception suggests. The gap between promising animal data and disappointing clinical results highlights the complexity of translating cannabinoid research.","specificNumbers":"Over 60 neuroactive chemicals identified in cannabis; clinical evidence reviewed for Parkinson's, Huntington's, Tourette syndrome, multiple sclerosis tremor, dystonia, ataxia, and restless leg syndrome","methodology":"Narrative review of published basic science, preclinical, and clinical studies on cannabinoids and movement disorders. Covered over 60 neuroactive chemicals in cannabis and their interactions with the endocannabinoid system.","limitations":"Narrative review without systematic methodology. Many of the clinical studies reviewed were small or poorly controlled. Cannabis pharmacology is complex (60+ compounds), making it difficult to attribute effects to specific cannabinoids."},{"rthcId":"RTHC-00993","title":"An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults.","authors":"Kollins, Scott H; Schoenfelder, Erin N; English, Joseph S; Holdaway, Alex; Van Voorhees, Elizabeth; O'Brien, Benjamin R; Dew, Rachel; Chrisman, Allan K","year":2015,"journal":"Journal of substance abuse treatment, 48(1), 96-103","doi":"10.1016/j.jsat.2014.07.014","pmid":"25175495","tags":["drug-interactions","cognition","cardiovascular"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In a double-blind crossover experiment, 16 healthy adults received all combinations of placebo or 10mg THC with 0mg, 10mg, or 40mg methylphenidate (MPH) across six sessions.\n\nThe two drugs showed additive effects on heart rate: peak heart rate climbed from 89 beats per minute with THC alone to 96 with low-dose MPH added and 102 with high-dose MPH. Significant interactions appeared on subjective measures of \"Feel Drug,\" \"Good Effects,\" and \"Take Drug Again.\"\n\nTHC increased commission errors on attention tasks, while MPH reduced reaction time variability. On a working memory task, MPH decreased reaction times but THC partially reversed those gains.","whyItMatters":"Young adults commonly combine marijuana with illicit stimulant use. This is one of the first controlled studies examining what happens physiologically and cognitively when these substances interact, revealing potentially concerning cardiovascular effects.","specificNumbers":"16 participants; 6 sessions each; peak HR with 10mg THC + 40mg MPH: 102 bpm vs. 89 bpm with THC alone; significant THC x MPH interactions on three subjective measures","methodology":"Randomized, double-blind, crossover design with 16 healthy adults. Six sessions tested all combinations of THC (0 or 10mg oral) and MPH (0, 10, or 40mg oral). Sessions separated by at least 48 hours. Measured vital signs, subjective drug effects, continuous performance test, and n-back working memory task.","limitations":"Very small sample (n=16). Participants were healthy adults without ADHD, so findings may not apply to those with the condition. Used low-moderate doses that may not reflect real-world use patterns. Single oral THC dose does not replicate smoking."},{"rthcId":"RTHC-00994","title":"Dose-dependent effects of cannabis on the neural correlates of error monitoring in frequent cannabis users.","authors":"Kowal, Mikael A; van Steenbergen, Henk; Colzato, Lorenza S; Hazekamp, Arno; van der Wee, Nic J A; Manai, Meriem; Durieux, Jeffrey; Hommel, Bernhard","year":2015,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 25(11), 1943-53","doi":"10.1016/j.euroneuro.2015.08.001","pmid":"26298832","tags":["cognition","neuroscience","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Researchers used EEG to measure two brain signals related to error monitoring in frequent cannabis users: the error-related negativity (ERN), which reflects automatic error detection, and the error positivity (Pe), which reflects conscious error awareness.\n\nParticipants who received a high dose (22mg THC) showed significantly reduced ERN compared to placebo, meaning their brains were less effective at automatically detecting mistakes. Both high and low doses (5.5mg THC) reduced the Pe signal, suggesting that even modest cannabis doses impair conscious recognition of errors.\n\nThese effects occurred in people who already used cannabis at least four times per week, indicating that regular use does not fully protect against acute impairment of error monitoring.","whyItMatters":"Error monitoring is essential for recognizing and correcting mistakes in real time. Impairment of this process could affect driving, work performance, and decision-making, even in people who use cannabis regularly and may believe they have developed tolerance.","specificNumbers":"55 frequent cannabis users; 3 groups (placebo n=19, low dose n=18, high dose n=18); high dose significantly reduced ERN; both doses significantly reduced Pe vs. placebo","methodology":"Randomized, double-blind, between-groups design. Frequent cannabis users (minimum 4 times/week for 2+ years) were assigned to receive placebo (n=19), low-dose 5.5mg THC (n=18), or high-dose 22mg THC (n=18) via vaporizer. Error monitoring was measured using EEG during a Flanker task.","limitations":"Between-groups design means individual differences could influence results. Relatively small groups (18-19 per condition). Only examined frequent users, so results may not generalize to occasional users. Acute effects may not reflect chronic patterns."},{"rthcId":"RTHC-00995","title":"Cannabis and creativity: highly potent cannabis impairs divergent thinking in regular cannabis users.","authors":"Kowal, Mikael A; Hazekamp, Arno; Colzato, Lorenza S; van Steenbergen, Henk; van der Wee, Nic J A; Durieux, Jeffrey; Manai, Meriem; Hommel, Bernhard","year":2015,"journal":"Psychopharmacology, 232(6), 1123-34","doi":"10.1007/s00213-014-3749-1","pmid":"25288512","tags":["cognition","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether cannabis enhances creativity by giving regular users either placebo, low-dose (5.5mg THC), or high-dose (22mg THC) vaporized cannabis, then measuring their performance on creativity tasks.\n\nParticipants who received the high dose performed significantly worse on the Alternate Uses Task, a measure of divergent thinking (the ability to generate multiple creative solutions). Neither dose affected convergent thinking as measured by the Remote Associates Task.\n\nLow-dose cannabis had no impact on either creativity measure, challenging the common belief that a small amount of cannabis boosts creative output.","whyItMatters":"Many cannabis users report feeling more creative when high. This study suggests that the subjective experience of enhanced creativity does not match actual creative performance, and that high-potency products may actively impair the type of thinking most associated with creativity.","specificNumbers":"54 regular cannabis users in 3 groups of 18; high-dose group showed significantly worse divergent thinking; no significant effects of either dose on convergent thinking","methodology":"Randomized, double-blind, between-groups design with 54 regular cannabis users. Three groups received placebo (n=18), low-dose 5.5mg THC (n=18), or high-dose 22mg THC (n=18) via vaporizer. Creativity measured with the Alternate Uses Task (divergent thinking) and Remote Associates Task (convergent thinking).","limitations":"Small sample (18 per group). Between-groups design introduces individual variability. Only two creativity measures used. Lab-based creativity tasks may not capture real-world creative processes. Only tested regular users."},{"rthcId":"RTHC-00996","title":"Medical marijuana for cancer.","authors":"Kramer, Joan L","year":2015,"journal":"CA: a cancer journal for clinicians, 65(2), 109-22","doi":"10.3322/caac.21260","pmid":"25503438","tags":["medical-cannabis","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This clinical review examined evidence for three cannabinoid pharmaceuticals: dronabinol (synthetic THC), nabilone (THC analog), and nabiximols (THC/CBD spray), along with smoked marijuana.\n\nDronabinol had the most established evidence base, with FDA approval for chemotherapy nausea and AIDS-related anorexia. Nabilone was also well-studied for chemotherapy nausea. Nabiximols, available only through U.S. clinical trials at the time, was used in Canada and the UK for multiple sclerosis spasticity and pain.\n\nFor cancer-specific applications, evidence centered on nausea management, appetite stimulation, and pain relief, though the pain data was more limited. The review also documented adverse effects including dizziness, euphoria, sedation, and cognitive impairment.","whyItMatters":"This review from a leading oncology journal provided clinicians with an evidence-based perspective on cannabinoid use in cancer care, cutting through both the hype and stigma to identify where data actually supported benefit.","specificNumbers":"Three FDA-related cannabinoid drugs reviewed; dronabinol FDA-approved for two indications; nabiximols available in U.S. only through clinical trials","methodology":"Narrative review of published clinical literature on medical marijuana and cannabinoid pharmaceuticals, with emphasis on oncology-relevant indications. Published in a major oncology journal (CA: A Cancer Journal for Clinicians).","limitations":"Narrative review without systematic search methodology. Many reviewed studies predated modern cannabis products and potencies. Did not compare cannabinoids head-to-head with newer anti-nausea medications."},{"rthcId":"RTHC-00997","title":"A safer alternative: Cannabis substitution as harm reduction.","authors":"Lau, Nicholas; Sales, Paloma; Averill, Sheigla; Murphy, Fiona; Sato, Sye-Ok; Murphy, Sheigla","year":2015,"journal":"Drug and alcohol review, 34(6), 654-9","doi":"10.1111/dar.12275","pmid":"25919477","tags":["harm-reduction","addiction","pain"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Researchers conducted in-depth life history interviews with Baby Boomer (born 1946-1964) marijuana users in the San Francisco Bay Area to understand their harm reduction beliefs and substitution practices.\n\nParticipants described consciously choosing cannabis over alcohol, illicit drugs, and prescription medications. Their substitution decisions were based on three factors: perception of fewer adverse side effects, belief in lower addiction potential, and greater effectiveness at relieving symptoms like chronic pain.\n\nThe concept of substitution was defined as a deliberate choice to use one substance instead of or alongside another, based on perceived safety, addiction risk, symptom relief, access, and social acceptance.","whyItMatters":"This study frames cannabis substitution within harm reduction, a public health approach that recognizes abstinence is not always realistic or desired. For older adults managing chronic conditions, intentional substance substitution may represent a practical risk-reduction strategy.","specificNumbers":"Participants were Baby Boomers (born 1946-1964); primary cannabis users with lifetime experience with other substances; San Francisco Bay Area sample","methodology":"Qualitative study using semi-structured in-depth life history interviews with Baby Boomer cannabis users in the San Francisco Bay Area. Audio-recorded interviews were analyzed thematically alongside a questionnaire and health survey.","limitations":"Qualitative design reflects perceptions rather than measured outcomes. San Francisco Bay Area sample may not represent other regions. Self-selected participants who are primary cannabis users may have positive bias. No objective comparison of safety profiles."},{"rthcId":"RTHC-00998","title":"Outcomes from a computer-assisted intervention simultaneously targeting cannabis and tobacco use.","authors":"Lee, Dustin C; Budney, Alan J; Brunette, Mary F; Hughes, John R; Etter, Jean-Francois; Stanger, Catherine","year":2015,"journal":"Drug and alcohol dependence, 155, 134-40","doi":"10.1016/j.drugalcdep.2015.08.001","pmid":"26307942","tags":["quitting","addiction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Researchers enrolled 32 people who met criteria for cannabis use disorder and also smoked tobacco daily in a 12-week program that simultaneously treated both addictions. The cannabis component used computer-assisted behavioral treatment, while the tobacco component added tailored counseling and nicotine replacement therapy.\n\nParticipants achieved an average of 3.6 consecutive weeks of cannabis abstinence, comparable to a historical control group that received cannabis treatment only (3.1 weeks). Over half (56%) initiated tobacco quit attempts, and 28% achieved at least two consecutive weeks of tobacco abstinence.\n\nTobacco use (cigarettes per day) decreased more in the combined treatment group than in controls, though formal tobacco abstinence rates were not statistically different.","whyItMatters":"Cannabis and tobacco use frequently co-occur, and tobacco use predicts worse cannabis treatment outcomes. This study demonstrated that adding tobacco treatment does not undermine cannabis cessation efforts, addressing a common concern among clinicians.","specificNumbers":"32 participants; 12-week treatment; 3.6 weeks mean cannabis abstinence (vs. 3.1 in controls); 78% completed at least one tobacco module; 44% started NRT; 56% attempted tobacco quit; 28% achieved 2+ weeks tobacco abstinence","methodology":"Pilot study of 32 participants with cannabis use disorder and daily tobacco use. Received 12-week computer-assisted behavioral treatment for both substances, including nicotine replacement therapy for tobacco. Cannabis outcomes compared to a historical control group that received cannabis treatment alone.","limitations":"Small sample without randomization. Comparison to historical controls introduces potential confounding. 12-week follow-up is short. No long-term outcome data. Selection bias in participants willing to address both substances."},{"rthcId":"RTHC-00999","title":"Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release.","authors":"Lee, Sang-Hun; Ledri, Marco; Tóth, Blanka; Marchionni, Ivan; Henstridge, Christopher M; Dudok, Barna; Kenesei, Kata; Barna, László; Szabó, Szilárd I; Renkecz, Tibor; Oberoi, Michelle; Watanabe, Masahiko; Limoli, Charles L; Horvai, George; Soltesz, Ivan; Katona, István","year":2015,"journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience, 35(27), 10039-57","doi":"10.1523/JNEUROSCI.4112-14.2015","pmid":"26157003","tags":["neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using advanced electrophysiology and imaging in mouse hippocampus, researchers discovered that CB1 receptors at inhibitory synapses are constitutively active, meaning they continuously suppress GABA release even without being activated by endocannabinoids.\n\nThe endocannabinoid 2-AG is continuously produced and further suppresses GABA release, but its effect is tightly controlled by the presynaptic enzyme MGL. Surprisingly, anandamide acts through TRPV1 receptors to oppose 2-AG signaling, creating a push-pull regulatory mechanism.\n\nThese effects were specific to perisomatic (cell body-targeting) synapses and did not occur at dendritic synapses, revealing synapse-specific endocannabinoid regulation.","whyItMatters":"This study reveals that the endocannabinoid system does not simply turn inhibition on or off but uses multiple interacting molecular mechanisms to precisely calibrate how much GABA different synapses release. This complexity has implications for understanding how cannabis disrupts these finely tuned circuits.","specificNumbers":"CB1 inverse agonist AM251 increased transmission; neutral antagonist NESS0327 did not; JZL184 (MGL inhibitor) increased 2-AG and decreased GABA transmission; PF3845 (FAAH inhibitor) elevated anandamide but did not change synaptic activity directly","methodology":"Combined paired whole-cell patch-clamp recordings, liquid chromatography/tandem mass spectrometry for endocannabinoid measurement, super-resolution microscopy (STORM), and immunogold electron microscopy in mouse hippocampus.","limitations":"Animal study using mouse hippocampal slices. In vitro conditions may not fully replicate in vivo dynamics. Translation to human brain function requires caution. Focused on one brain region."},{"rthcId":"RTHC-01000","title":"Prevalence and Correlates of Social Smoking in Young Adults: Comparisons of Behavioral and Self-Identified Definitions.","authors":"Lisha, Nadra E; Delucchi, Kevin L; Ling, Pamela M; Ramo, Danielle E","year":2015,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 17(9), 1076-84","doi":"10.1093/ntr/ntu242","pmid":"25385876","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 1,811 young adult smokers (ages 18-25) recruited through Facebook to understand social smoking patterns. They found three distinct groups based on self-identification and behavior.\n\nThe largest group (46%) called themselves social smokers but actually smoked outside of social contexts too (\"self-identified only\"). True behavioral social smokers who only smoked in social settings made up 27%, and non-social smokers accounted for the remaining 27%.\n\nBoth social smoker groups were more likely to be male, use marijuana, and be marijuana-dependent compared to non-social smokers. True behavioral social smokers smoked less, were less addicted to cigarettes, and had higher desire to quit.","whyItMatters":"The disconnect between self-identified and actual social smoking suggests many young adults underestimate their smoking patterns. The strong association with marijuana use in social smoker groups points to overlapping substance use cultures among young adults.","specificNumbers":"1,811 participants; 46% self-identified only social smokers; 27% behavioral social smokers; 27% non-social smokers; social smoker groups more likely to be male, use marijuana, and have marijuana dependence","methodology":"Cross-sectional online survey of 1,811 young adults (18-25) who smoked at least one cigarette in the past 30 days, recruited through Facebook ads. Three social smoking categorization items determined group membership.","limitations":"Facebook recruitment introduces selection bias. Self-reported data on both smoking and marijuana use. Cross-sectional design cannot establish causal relationships. The \"social smoker\" classification relied on only three items."},{"rthcId":"RTHC-01001","title":"The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in rats.","authors":"Liu, Jing; Pope, Carey","year":2015,"journal":"Neurotoxicology, 46, 12-8","doi":"10.1016/j.neuro.2014.11.001","pmid":"25447325","tags":["neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether blocking the endocannabinoid system would worsen poisoning from two organophosphorus pesticides (paraoxon and chlorpyrifos oxon) in rats.\n\nThe CB1 antagonist AM251, given 30 minutes after pesticide exposure, significantly increased involuntary movements at lower pesticide doses. With higher doses of paraoxon, AM251 increased lethality.\n\nChlorpyrifos oxon was more potent at inhibiting the enzymes that break down endocannabinoids (FAAH and MAGL), meaning it simultaneously blocks acetylcholinesterase (causing poisoning) and boosts endocannabinoid levels (providing some natural protection). Blocking CB1 receptors removed this protective mechanism.","whyItMatters":"This study reveals that the endocannabinoid system functions as a natural protective mechanism during pesticide poisoning. Understanding this could inform treatment strategies for organophosphorus exposure, which affects agricultural workers and remains a chemical weapons concern.","specificNumbers":"AM251 increased toxicity signs at lower doses of both pesticides; AM251 increased lethality with higher paraoxon dose; chlorpyrifos oxon was 8-fold more potent at inhibiting FAAH and 19-fold more potent at inhibiting MAGL than paraoxon","methodology":"Rat study comparing two organophosphorus compounds at two doses each, with and without the CB1 antagonist AM251. Measured toxicity signs over 4 hours, lethality, and enzyme inhibition (AChE, FAAH, MAGL) in hippocampal tissue.","limitations":"Animal study with limited sample sizes. Used a single dose of AM251. The protective role of endocannabinoids may differ between acute and chronic exposure. Translation to human pesticide poisoning treatment requires further study."},{"rthcId":"RTHC-01002","title":"Cannabinoid hyperemesis syndrome: Marijuana is both antiemetic and proemetic.","authors":"Lu, Marvin Louis Roy Y; Agito, Markus D","year":2015,"journal":"Cleveland Clinic journal of medicine, 82(7), 429-34","doi":"10.3949/ccjm.82a.14023","pmid":"26185942","tags":["medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This clinical review described cannabinoid hyperemesis syndrome (CHS), a paradoxical condition where chronic marijuana use causes recurrent severe nausea and vomiting despite cannabis being known as an antiemetic.\n\nThe syndrome typically presents with cyclic episodes of vomiting, often accompanied by compulsive hot bathing (which temporarily relieves symptoms). Patients frequently undergo expensive and unnecessary investigations before the diagnosis is recognized.\n\nThe only proven treatment is complete cessation of marijuana use. The review emphasized that recognizing CHS can prevent unnecessary medical and surgical interventions in patients presenting with recurrent vomiting of unknown cause.","whyItMatters":"CHS is increasingly recognized as cannabis use becomes more widespread. Many patients cycle through multiple emergency department visits and undergo extensive testing before the diagnosis is made, creating significant healthcare costs and patient suffering.","specificNumbers":"Review summarized case report literature; typical presentation involves chronic marijuana use, cyclic vomiting episodes, and relief from hot bathing; only treatment is cannabis cessation","methodology":"Clinical review article examining published case reports and literature on the pathophysiology, presentation, diagnosis, and management of cannabinoid hyperemesis syndrome.","limitations":"Based primarily on case reports and clinical observations. The pathophysiology remains incompletely understood. Prevalence among chronic cannabis users is unknown."},{"rthcId":"RTHC-01003","title":"Endocannabinoid signaling at the periphery: 50 years after THC.","authors":"Maccarrone, Mauro; Bab, Itai; Bíró, Tamás; Cabral, Guy A; Dey, Sudhansu K; Di Marzo, Vincenzo; Konje, Justin C; Kunos, George; Mechoulam, Raphael; Pacher, Pal; Sharkey, Keith A; Zimmer, Andreas","year":2015,"journal":"Trends in pharmacological sciences, 36(5), 277-96","doi":"10.1016/j.tips.2015.02.008","pmid":"25796370","tags":["neuroscience","inflammation","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Written by many of the scientists who discovered key components of the endocannabinoid system, this comprehensive review examined how endocannabinoids function throughout the body beyond the brain.\n\nThe endocannabinoid system was found to control fundamental biological processes including cell survival, death, and differentiation across nearly every organ system. Specific roles were mapped in reproduction (embryo implantation, pregnancy maintenance), bone metabolism (bone density regulation), skin (barrier function, hair growth, sebum production), immune function (inflammation modulation), and gastrointestinal health (motility, secretion, inflammation).\n\nThe review established consensus that the peripheral endocannabinoid system is among the most widespread signaling systems in the human body.","whyItMatters":"This authoritative review, written by the founders of the field, established that the endocannabinoid system is not primarily a \"brain thing\" but a body-wide regulatory network. This understanding is fundamental to evaluating how cannabis use affects overall health.","specificNumbers":"THC isolated in 1964; anandamide discovered 1992; 2-AG discovered 1995; 12 co-authors including field pioneers; coverage spans reproductive, skeletal, dermatological, immunological, and gastrointestinal systems","methodology":"Collaborative review authored by 12 leading endocannabinoid researchers, including Raphael Mechoulam (who first isolated THC in 1964). Synthesized decades of basic science and clinical research on peripheral endocannabinoid function.","limitations":"As a narrative review by field leaders, it may emphasize the importance of the endocannabinoid system. Some findings are from animal models with uncertain human translation. The therapeutic potential discussed remains largely unrealized."},{"rthcId":"RTHC-01004","title":"Synthetic cannabinoid withdrawal: a new demand on detoxification services.","authors":"Macfarlane, Vicki; Christie, Grant","year":2015,"journal":"Drug and alcohol review, 34(2), 147-53","doi":"10.1111/dar.12225","pmid":"25588420","tags":["synthetic-cannabinoids","withdrawal","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Researchers reviewed records from Auckland detoxification services over 12 months and found 47 people presenting for help with synthetic cannabinoid withdrawal. Twenty required inpatient admission for medical management.\n\nThe most common withdrawal symptoms were agitation, irritability, anxiety, and mood swings. Symptoms were managed with diazepam and quetiapine. Notably, most patients did not have significant co-occurring substance dependence beyond nicotine.\n\nSynthetic cannabinoid withdrawal patients became the third largest group admitted to inpatient detox, behind only alcohol and methamphetamine, representing a new and substantial demand on treatment services.","whyItMatters":"This study documented an emerging clinical reality: synthetic cannabinoids can produce significant physical dependence and withdrawal that requires medical intervention, challenging assumptions that cannabinoid products do not cause serious withdrawal syndromes.","specificNumbers":"47 presentations in 12 months; 20 admitted as inpatients; third largest group in detox services; most common symptoms: agitation, irritability, anxiety, mood swings; treated with diazepam and quetiapine","methodology":"Retrospective audit of electronic and paper records from Auckland detoxification services between May 2013 and May 2014. Collected demographics, substance use patterns, withdrawal symptoms, and treatment data.","limitations":"Single-center retrospective audit. No standardized withdrawal assessment tools used. Cannot determine the true prevalence of synthetic cannabinoid dependence in the community. New Zealand's synthetic cannabinoid market may differ from other countries."},{"rthcId":"RTHC-01005","title":"Cannabis, tobacco smoking, and lung function: a cross-sectional observational study in a general practice population.","authors":"Macleod, John; Robertson, Roy; Copeland, Lorraine; McKenzie, James; Elton, Rob; Reid, Peter","year":2015,"journal":"The British journal of general practice : the journal of the Royal College of General Practitioners, 65(631), e89-95","doi":"10.3399/bjgp15X683521","pmid":"25624312","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers recruited 500 people from a Scottish general practice: some smoked only tobacco, others smoked both tobacco and cannabis (predominantly resin mixed with tobacco). Both groups had impaired lung function and respiratory symptoms, but those who also smoked cannabis reported more symptoms.\n\nAfter adjusting for tobacco exposure, each additional joint-year of cannabis was associated with a 0.3% increase in COPD prevalence. Cannabis smokers had higher total tobacco exposure when accounting for tobacco smoked in joints.\n\nCannabis and tobacco smokers were younger on average (37 vs. 45 years) but already showing additional respiratory effects beyond what their tobacco use alone would predict.","whyItMatters":"Most cannabis respiratory research comes from populations where cannabis is smoked pure. In the UK and Europe, mixing cannabis resin with tobacco is the dominant method, and this study specifically examined that pattern.","specificNumbers":"500 participants; mean age 45 (tobacco only) vs. 37 (cannabis + tobacco); 0.3% increase in COPD prevalence per joint-year (95% CI 0.0-0.5); median tobacco exposure 25 pack-years (tobacco only) vs. 22.5 including cannabis tobacco (combined group)","methodology":"Cross-sectional study in a Scottish general practice with 12,500 patients. 500 participants (242 males) completed respiratory questionnaires (NHANES and MRC) and standardized spirometry. Cannabis exposure measured in joint-years alongside tobacco pack-years.","limitations":"Cross-sectional design limits causal inference. Predominantly resin cannabis, which may differ from herbal cannabis in smoke composition. Single general practice population. Self-reported cannabis use may be underestimated."},{"rthcId":"RTHC-01006","title":"Cannabis hyperemesis syndrome: A case report review of treatment.","authors":"Mahmad, Abdul I; Jehangir, Waqas; Littlefield, Jay M; John, Sujith; Yousif, Abdalla","year":2015,"journal":"Toxicology reports, 2, 889-890","doi":"10.1016/j.toxrep.2015.05.015","pmid":"28962425","tags":["medical-cannabis","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 32-year-old man with no significant medical history arrived at the emergency department with five days of nausea, vomiting, and diffuse abdominal pain. He reported that hot showers alleviated his symptoms.\n\nHis vital signs and lab work were normal except for a positive urine THC screen. He was diagnosed with cannabinoid hyperemesis syndrome based on his 19-year history of daily cannabis use and the classic symptom pattern.\n\nTreatment with lorazepam and access to hot showers improved his nausea, and he was discharged the next day in stable condition.","whyItMatters":"This case adds to the growing body of reports documenting cannabinoid hyperemesis syndrome and highlights the importance of taking a thorough substance use history in patients with unexplained cyclic vomiting, potentially avoiding expensive and unnecessary diagnostic workups.","specificNumbers":"32-year-old male; 19 years of daily cannabis use; 5 days of symptoms; normal CBC and CMP; positive THC screen; discharged next day","methodology":"Single case report describing clinical presentation, workup, and management of one patient with cannabinoid hyperemesis syndrome.","limitations":"Single case report provides the lowest level of clinical evidence. No follow-up data on whether the patient ceased cannabis use or had recurrent episodes."},{"rthcId":"RTHC-01007","title":"Can cannabis use be prevented by targeting personality risk in schools? Twenty-four-month outcome of the adventure trial on cannabis use: a cluster-randomized controlled trial.","authors":"Mahu, Ioan T; Doucet, Christine; O'Leary-Barrett, Maeve; Conrod, Patricia J","year":2015,"journal":"Addiction (Abingdon, England), 110(10), 1625-33","doi":"10.1111/add.12991","pmid":"26011508","tags":["youth","mental-health","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers randomized 21 London secondary schools to receive either personality-targeted interventions or standard programming. The interventions were delivered by trained teachers to 1,038 high-risk ninth graders (average age 13.7) who had been identified as having one of four personality risk profiles: anxiety sensitivity, hopelessness, impulsivity, or sensation-seeking.\n\nAt 6 months, the intervention group had significantly lower cannabis use rates (OR = 0.67). Reductions in frequency of use persisted at 12 and 18 months.\n\nThe strongest finding came from subgroup analysis: the sensation-seeking intervention reduced cannabis initiation by 75% among sensation-seekers (OR = 0.25), suggesting this personality type is especially responsive to targeted prevention.","whyItMatters":"Most school drug prevention programs take a one-size-fits-all approach. This study showed that matching interventions to specific personality risk profiles, particularly sensation-seeking, can produce stronger prevention effects than generic programs.","specificNumbers":"1,038 high-risk students; 21 schools; OR 0.67 for cannabis use at 6 months; OR 0.25 for cannabis initiation among sensation-seekers; 24-month follow-up","methodology":"Cluster-randomized controlled trial across 21 secondary schools in London (12 intervention, 9 control). Personality risk measured with the Substance Use Risk Profile Scale. Cannabis use assessed every 6 months for 2 years using the Reckless Behaviour Questionnaire. Both logistic regression and two-part latent growth models were used.","limitations":"The overall intervention effects were not fully supported by all statistical models. Effects were strongest in sensation-seekers but weaker or non-significant for other personality profiles. London-specific sample. Teacher-delivered programs may vary in fidelity."},{"rthcId":"RTHC-01008","title":"The role of cannabinoids in regulation of nausea and vomiting, and visceral pain.","authors":"Malik, Zubair; Baik, Daniel; Schey, Ron","year":2015,"journal":"Current gastroenterology reports, 17(2), 429","doi":"10.1007/s11894-015-0429-1","pmid":"25715910","tags":["medical-cannabis","neuroscience","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review mapped cannabinoid receptors (CB1, CB2, and potentially GPR55) throughout the gastrointestinal tract and examined their roles in food intake, nausea, gastric secretion, motility, visceral sensation, inflammation, and cell proliferation.\n\nThe strongest evidence supported cannabinoid involvement in regulating nausea and vomiting, where the endocannabinoid system has provided new mechanistic insights. For visceral pain, animal models consistently showed that cannabinoids reduced sensitivity, but clinical data in IBS patients was scarce and did not support benefit.\n\nEmerging drug targets, particularly FAAH and MAGL inhibitors, showed promise in animal studies but lacked human validation. The review highlighted that compounds acting on these targets could avoid the psychoactive side effects of direct cannabinoid receptor agonists.","whyItMatters":"The GI tract contains a dense network of cannabinoid receptors, making it a logical therapeutic target. But this review revealed a gap between promising preclinical findings and disappointing clinical results, particularly for pain conditions.","specificNumbers":"Three cannabinoid receptor types identified in the GI tract (CB1, CB2, GPR55); FAAH and MAGL inhibitors identified as novel drug targets; IBS clinical data described as scarce and not supportive","methodology":"Narrative review of basic science and clinical literature on cannabinoid receptors and endocannabinoid signaling in the gastrointestinal tract.","limitations":"Narrative review without systematic methodology. Clinical data for GI applications was limited at the time. Animal model results may not translate to humans. Did not address cannabinoid hyperemesis syndrome in detail."},{"rthcId":"RTHC-01009","title":"Comparative effects of pulmonary and parenteral Δ⁹-tetrahydrocannabinol exposure on extinction of opiate-induced conditioned aversion in rats.","authors":"Manwell, Laurie A; Mallet, Paul E","year":2015,"journal":"Psychopharmacology, 232(9), 1655-65","doi":"10.1007/s00213-014-3798-5","pmid":"25395060","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether THC could help rats extinguish conditioned place aversion, a learned avoidance behavior triggered by memories of opiate withdrawal. They compared vaporized and injected THC at multiple doses.\n\nVaporized THC at 5mg and 10mg facilitated extinction of the aversive memory, meaning rats more quickly stopped avoiding the location they associated with withdrawal. However, the lowest vaporized dose (1mg) did not help.\n\nInjected THC showed the opposite pattern: the middle dose (1.0 mg/kg) prolonged the aversive memory fourfold compared to vehicle, while the lowest and highest injected doses had no effect. This suggests both dose and route of administration critically determine whether THC helps or hinders extinction of withdrawal-related memories.","whyItMatters":"Aversive memories associated with drug withdrawal drive relapse by creating powerful avoidance and craving. If THC can facilitate extinction of these memories, it could have therapeutic applications in addiction treatment, but the route and dose matter enormously.","specificNumbers":"Vaporized 5mg and 10mg THC facilitated extinction; 1mg did not; injected 1.0 mg/kg prolonged aversion fourfold; 20-28 extinction trials per group","methodology":"Rats were conditioned to associate a floor cue with naloxone-precipitated morphine withdrawal. During 20-28 extinction trials, they received either vaporized THC (1, 5, or 10mg) or injected THC (0.5, 1.0, or 1.5 mg/kg) before each trial.","limitations":"Animal study that may not translate directly to human addiction. The conditioned place aversion model is a simplified version of human withdrawal memories. Dose equivalency between routes is approximate."},{"rthcId":"RTHC-01010","title":"The impact of gonadal hormones on cannabinoid dependence.","authors":"Marusich, Julie A; Craft, Rebecca M; Lefever, Timothy W; Wiley, Jenny L","year":2015,"journal":"Experimental and clinical psychopharmacology, 23(4), 206-16","doi":"10.1037/pha0000027","pmid":"26237318","tags":["sex-differences","addiction","withdrawal","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers removed the gonads of male and female rats and selectively replaced hormones to isolate their effects on THC dependence. After twice-daily THC dosing for nearly a week, withdrawal was triggered with a CB1 antagonist.\n\nFemales with intact ovaries developed greater tolerance to THC-induced hypothermia than males. When hormones were replaced in gonadectomized animals, progesterone increased tolerance to THC's locomotor effects, while estradiol and progesterone together increased withdrawal-related chewing.\n\nIn males, testosterone replacement decreased withdrawal-related licking behavior, suggesting a protective effect. Overall, estradiol appeared to play a broader role than testosterone in modulating THC's behavioral effects.","whyItMatters":"Women report greater cannabis withdrawal symptoms than men, and this study provides a biological mechanism: female sex hormones (estrogen and progesterone) appear to promote THC dependence development, while testosterone may protect against it.","specificNumbers":"30 mg/kg THC twice daily for 6.5 days; sham females showed greater tolerance than sham males; progesterone increased tolerance to locomotor suppression; testosterone decreased withdrawal-related licking","methodology":"Adult rats were gonadectomized or sham-operated, with hormone replacement in half of gonadectomized animals. THC (30 mg/kg) or vehicle was given twice daily for 6.5 days. Withdrawal was precipitated with rimonabant on day 7. Measured somatic signs, startle amplitude, and temperature.","limitations":"Rat study using supraphysiological THC doses. Gonadectomy and hormone replacement create an artificial hormonal environment. Human hormonal interactions are more complex. Limited behavioral measures of withdrawal."},{"rthcId":"RTHC-01011","title":"Cortical thinness and volume differences associated with marijuana abuse in emerging adults.","authors":"Mashhoon, Y; Sava, S; Sneider, J T; Nickerson, L D; Silveri, M M","year":2015,"journal":"Drug and alcohol dependence, 155, 275-83","doi":"10.1016/j.drugalcdep.2015.06.016","pmid":"26249265","tags":["cognition","neuroscience","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared brain structure in 15 cannabis users and 15 non-users (average age ~22) using high-resolution MRI. The groups were matched on age, education, and alcohol use.\n\nWhole-brain analysis found cannabis users had significantly thinner cortex in the right fusiform gyrus, a region involved in visual processing and face recognition. The expected differences in prefrontal and limbic regions were not found.\n\nMore notably, cannabis users had significantly smaller thalamic volume bilaterally. Smaller thalamus size correlated with greater non-planning impulsivity and overall impulsivity scores, suggesting a link between cannabis-associated structural changes and impulsive behavior.","whyItMatters":"The thalamus acts as a relay station for sensory and cognitive information. Finding that cannabis use is associated with smaller thalamic volume and greater impulsivity suggests a potential mechanism linking cannabis to cognitive and behavioral changes in young adults.","specificNumbers":"15 users vs. 15 non-users; right thalamus p=0.05, left thalamus p=0.01; smaller thalamus associated with non-planning impulsivity (p<0.01) and overall impulsivity (p=0.04); right fusiform gyrus significantly thinner (p<0.05)","methodology":"Cross-sectional study comparing 15 marijuana users and 15 matched non-users. High-resolution structural MRI at 3 Tesla. Cortical thickness and volumetric analyses performed using FreeSurfer. A priori regions of interest included orbitofrontal cortex, cingulate cortex, amygdala, hippocampus, and thalamus.","limitations":"Very small sample (15 per group). Cross-sectional design cannot determine whether brain differences preceded or resulted from cannabis use. Predominantly male sample (only 2 females per group). Could not fully control for all potential confounders."},{"rthcId":"RTHC-01012","title":"Cold acclimation induces distinctive changes in the chromatin state and transcript levels of COR genes in Cannabis sativa varieties with contrasting cold acclimation capacities.","authors":"Mayer, Boris F; Ali-Benali, Mohamed Ali; Demone, Jordan; Bertrand, Annick; Charron, Jean-Benoit","year":2015,"journal":"Physiologia plantarum, 155(3), 281-95","doi":"10.1111/ppl.12318","pmid":"25534661","tags":["genetics"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers tested nine Cannabis sativa varieties for their ability to survive freezing after a cold acclimation period. The varieties fell into three groups based on cold tolerance, with substantial differences in survival.\n\nCold-hardy varieties accumulated higher levels of cold-regulated (COR) gene transcripts and maintained higher sugar levels throughout cold exposure. They also showed specific epigenetic modifications, including changes in histone acetylation, histone methylation, and DNA methylation at COR gene loci.\n\nWhen plants were returned to warm conditions (deacclimation), the hardy varieties showed increased DNA methylation at COR genes, suggesting an epigenetic memory mechanism that may help the plant manage repeated cold exposure.","whyItMatters":"As cannabis cultivation expands to colder climates, understanding the genetic and epigenetic basis of cold tolerance could guide breeding programs for more resilient varieties. This is fundamental plant biology research with agricultural applications.","specificNumbers":"9 Cannabis sativa varieties tested; 3 cold tolerance groups identified; epigenetic marks measured: H3K9ac, H3K27me3, methylcytosine; sugar accumulation and COR gene expression tracked","methodology":"Comparative study of nine Cannabis sativa varieties subjected to cold acclimation treatment. Measured freezing survival in whole-plant tests, soluble sugar accumulation, COR gene transcript levels, and epigenetic marks (H3K9ac, H3K27me3, DNA methylation) at specific loci.","limitations":"Controlled laboratory conditions may not perfectly replicate field conditions. The specific varieties studied may not represent the full genetic diversity of Cannabis sativa. Epigenetic mechanisms identified may not be the only factors determining cold tolerance."},{"rthcId":"RTHC-01013","title":"Variations in Cannabis Use Level and Correlates in Opiate-Users on Methadone Maintenance Treatment: A French Prospective Study.","authors":"Mayet, Aurélie; Lions, Caroline; Roux, Perrine; Mora, Marion; Maradan, Gwenaelle; Morel, Alain; Michel, Laurent; Marimoutou, Catherine; Carrieri, Maria Patrizia","year":2015,"journal":"Journal of substance abuse treatment, 58, 100-5","doi":"10.1016/j.jsat.2015.06.015","pmid":"26260134","tags":["addiction","drug-interactions"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 188 opioid-dependent individuals starting methadone maintenance treatment for 12 months, tracking cannabis use at enrollment, 3, 6, and 12 months.\n\nCannabis use levels showed no significant variation throughout treatment. The factors associated with cannabis use were the same before and after starting methadone, suggesting that treatment itself did not change cannabis use patterns.\n\nOngoing opioid use was associated with both non-daily cannabis use (OR = 3.11) and daily cannabis use (OR = 2.58). The number of health problems reported was specifically associated with daily cannabis use (OR = 1.12 per additional problem), supporting a self-medication hypothesis.","whyItMatters":"A common concern is that methadone treatment might drive patients to use cannabis as a substitute or coping mechanism. This study found no evidence for that, instead suggesting cannabis use reflects broader substance use vulnerability and health-related self-medication.","specificNumbers":"188 participants; 12-month follow-up; no significant variation in cannabis use (p=0.85); opioid use OR=3.11 (non-daily) and 2.58 (daily cannabis use); health problems OR=1.12 per problem for daily use","methodology":"Prospective cohort study following 188 opioid-dependent individuals initiating methadone maintenance for 12 months. Cannabis use measured at baseline and months 3, 6, and 12. Analyzed using mixed multinomial logistic regression to account for repeated measures.","limitations":"Observational design cannot prove causation. Self-reported cannabis use may be underestimated. Twelve-month follow-up may be too short to capture longer-term patterns. French healthcare context may not generalize globally."},{"rthcId":"RTHC-01014","title":"The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids.","authors":"McAllister, Sean D; Soroceanu, Liliana; Desprez, Pierre-Yves","year":2015,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 10(2), 255-67","doi":"10.1007/s11481-015-9608-y","pmid":"25916739","tags":["cbd","cancer","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how non-psychoactive cannabinoids, particularly CBD, affect cancer cells through mechanisms that do not require activation of CB1 or CB2 cannabinoid receptors.\n\nIn animal models, CBD inhibited the progression of glioblastoma, breast, lung, prostate, and colon cancers. The mechanisms included triggering autophagy (cellular self-digestion) and apoptosis (programmed cell death), inhibiting tumor cell invasion and metastasis, reducing blood vessel formation that feeds tumors, and limiting the stem-like potential of cancer cells.\n\nParticularly notable was CBD's ability to enhance the activity of first-line chemotherapy agents commonly used in cancer treatment, suggesting potential as a combination therapy.","whyItMatters":"Non-psychoactive cannabinoids offer potential antitumor activity without the high associated with THC. The ability to enhance standard chemotherapy is particularly promising, as it could improve treatment outcomes without adding psychoactive side effects.","specificNumbers":"Cancer types with CBD efficacy in animal models: glioblastoma, breast, lung, prostate, colon; mechanisms: autophagy, apoptosis, anti-invasion, anti-metastasis, anti-angiogenesis, cancer stem cell inhibition","methodology":"Review of preclinical literature examining non-psychoactive cannabinoids (primarily CBD) in cancer models. Focused on mechanisms including autophagy, apoptosis, invasion, metastasis, angiogenesis, and cancer stem cell inhibition.","limitations":"All evidence is from cell culture and animal models. No human clinical trial data for CBD as an antitumor agent. Doses used in preclinical studies may not be achievable in humans. The translation gap between animal cancer models and human cancer is well-documented."},{"rthcId":"RTHC-01015","title":"Relationship between plasma concentrations of the l-enantiomer of methadone and response to methadone maintenance treatment.","authors":"Meini, Milo; Moncini, Marco; Daini, Laura; Giarratana, Tania; Scaramelli, Daniela; Chericoni, Silvio; Stefanelli, Fabio; Rucci, Paola","year":2015,"journal":"European journal of pharmacology, 760, 1-6","doi":"10.1016/j.ejphar.2015.03.081","pmid":"25891369","tags":["drug-interactions","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers measured blood levels of the active form of methadone (l-methadone) in 94 opioid-dependent patients on maintenance treatment. They found that above 200 ng/ml, no patients reported heroin use, and above 250 ng/ml, craving was absent.\n\nA key secondary finding was that cannabis users had significantly lower plasma l-methadone concentrations compared to non-users, even after adjusting for methadone dosage. This suggests a pharmacokinetic interaction where cannabis may accelerate methadone metabolism.\n\nOther protective factors against heroin use included older age, stable employment, and being married.","whyItMatters":"If cannabis use lowers methadone blood levels, it could reduce methadone treatment effectiveness and contribute to continued opioid use. This has practical implications for dosing decisions in patients who also use cannabis.","specificNumbers":"94 patients; above 200 ng/ml l-methadone: no heroin use; above 250 ng/ml: no craving; 54.2% achieved 100-250 ng/ml at doses of 60+ mg/day; cannabis users had significantly lower l-methadone levels (p<0.05)","methodology":"Cross-sectional study of 94 consecutively recruited patients in methadone maintenance. Blood was drawn for l-methadone concentration, and urine analyses over the prior three weeks determined treatment response. Cannabis use was documented alongside demographic and dosing data.","limitations":"Cross-sectional design cannot establish causation. Small sample. Cannabis use was self-reported. The mechanism for lower methadone levels was not determined. Could reflect differences in metabolism, adherence, or other unmeasured factors."},{"rthcId":"RTHC-01016","title":"ENP11, a potential CB1R antagonist, induces anorexia in rats.","authors":"Méndez-Díaz, Mónica; Amancio-Belmont, Octavio; Hernández-Vázquez, Eduardo; Ruiz-Contreras, Alejandra E; Hernández-Luis, Francisco; Prospéro-García, Oscar","year":2015,"journal":"Pharmacology, biochemistry, and behavior, 135, 177-81","doi":"10.1016/j.pbb.2015.06.007","pmid":"26072692","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers synthesized ENP11, a chemical analog of rimonabant (the CB1 receptor blocker that was withdrawn from the market due to psychiatric side effects), and tested it in rats at three doses.\n\nENP11 reduced food intake during the first hour after administration. At 1.0 mg/kg, it successfully blocked the overeating caused by anandamide (an endocannabinoid). It also blocked anandamide-induced hypothermia, confirming it acts at CB1 receptors.\n\nImportantly, none of the tested doses affected pain perception or motor control, side effects that have been concerns with CB1-blocking compounds.","whyItMatters":"Rimonabant showed that blocking CB1 receptors could powerfully reduce appetite, but psychiatric side effects led to its withdrawal. Finding compounds that retain the appetite-suppressing effects without the broader side effects is an active goal in obesity pharmacology.","specificNumbers":"Three doses tested: 0.5, 1.0, 3.0 mg/kg; 1.0 mg/kg blocked anandamide-induced overeating and hypothermia; no effects on pain or motor control at any dose","methodology":"Rat study testing three doses of ENP11 (0.5, 1.0, 3.0 mg/kg) on food intake, pain perception, core temperature, and motor control. Also tested whether ENP11 could block anandamide-induced effects.","limitations":"Early-stage animal study. Acute effects only (no chronic dosing). Psychiatric side effects (the main concern with rimonabant) cannot be assessed in rat behavioral tests. Human translation is uncertain."},{"rthcId":"RTHC-01017","title":"Marijuana use in pregnancy and lactation: a review of the evidence.","authors":"Metz, Torri D; Stickrath, Elaine H","year":2015,"journal":"American journal of obstetrics and gynecology, 213(6), 761-78","doi":"10.1016/j.ajog.2015.05.025","pmid":"25986032","tags":["pregnancy","youth","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the evidence on marijuana use during pregnancy and lactation, noting that 3-30% of pregnant women use marijuana depending on the population studied.\n\nTHC freely crosses the placenta and is found in breast milk. The review identified several potential adverse outcomes: fetal growth restriction, possible associations with stillbirth and preterm birth, and emerging evidence of neurological effects including hyperactivity, poor cognitive function, and changes in dopamine receptors in exposed children.\n\nHowever, the evidence was far from uniform. Most studies were confounded by concurrent tobacco and other drug use, sociodemographic factors, lack of trimester-specific exposure data, and reliance on self-report without biological verification.","whyItMatters":"As marijuana legalization expands, more women may use it during pregnancy, potentially unaware of risks. This review highlighted both the potential harms and the significant gaps in evidence that make definitive risk counseling difficult.","specificNumbers":"Prevalence of use: 3-30% across populations; THC crosses placenta and enters breast milk; associated outcomes: fetal growth restriction, possible stillbirth, preterm birth, hyperactivity, cognitive effects","methodology":"Narrative review of published literature on marijuana use in pregnancy and lactation, with emphasis on perinatal outcomes and fetal neurodevelopment. Published in a leading obstetrics journal.","limitations":"Most existing studies have significant confounding from tobacco and other substance co-use. Self-reported marijuana use is unreliable. Lack of dose quantification by trimester. Difficulty isolating marijuana effects from sociodemographic risk factors."},{"rthcId":"RTHC-01018","title":"School and work status, drug-free workplace protections, and prescription drug misuse among Americans ages 15-25.","authors":"Miller, Ted; Novak, Scott P; Galvin, Deborah M; Spicer, Rebecca S; Cluff, Laurie; Kasat, Sandeep","year":2015,"journal":"Journal of studies on alcohol and drugs, 76(2), 195-203","doi":null,"pmid":"25785794","tags":["workplace","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from over 20,000 young adults in national surveys to examine how school status, employment, and workplace drug policies relate to prescription drug misuse.\n\nBeing a student was protective against prescription misuse. Among those ages 18-25, working consistently added further protection. Both awareness of a drug-free workplace policy (OR = 0.85) and access to Employee Assistance Programs (OR = 0.85) were independently associated with lower prescription drug misuse.\n\nAll four workplace program aspects were also significantly associated with lower marijuana use. However, none were associated with problem drinking, suggesting these programs specifically affect illicit drug behavior rather than all substance use.","whyItMatters":"The finding that workplace drug policies reduce marijuana and prescription drug misuse but not alcohol problems suggests these programs work through deterrence and culture change specific to illicit drug use, not through general behavior modification.","specificNumbers":"20,457 participants; EAP access OR=0.85 for prescription misuse; drug-free workplace awareness OR=0.85; all four program aspects significantly associated with lower marijuana use; none associated with problem drinking","methodology":"Secondary analysis of weighted data from the 2004-2008 National Surveys on Drug Use and Health. Included 20,457 young adults ages 15-25. Multivariate logistic regressions controlled for sex, race, community size, age group, and substance use history.","limitations":"Cross-sectional design cannot establish causation. People who choose workplaces with drug policies may differ from those who do not. Self-reported drug use and policy awareness. Data from 2004-2008 predates marijuana legalization in most states."},{"rthcId":"RTHC-01019","title":"Cannabis use in children with individualized risk profiles: Predicting the effect of universal prevention intervention.","authors":"Miovský, Michal; Vonkova, Hana; Čablová, Lenka; Gabrhelík, Roman","year":2015,"journal":"Addictive behaviors, 50, 110-6","doi":"10.1016/j.addbeh.2015.06.013","pmid":"26126178","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers used a randomized controlled prevention trial with 1,874 sixth-graders (average age 11.8) to predict how a universal prevention program would affect individual children based on their specific risk profiles.\n\nUsing eight risk and protective factors, they calculated personalized probabilities of cannabis use for each child with and without the intervention. Low-risk children had predicted probabilities of 4.3% with intervention versus 6.5% without. Moderate-risk children: 10.9% versus 15.3%. High-risk children: 25.5% versus 32.6%.\n\nSchool grades, thoughts of hurting oneself, and rule-breaking behavior were the three factors that most strongly distinguished high-risk from low-risk children.","whyItMatters":"This study demonstrates that universal prevention programs can be effective across all risk levels, but their impact varies substantially by individual risk profile. This personalized approach could help target resources more efficiently.","specificNumbers":"1,874 students; 33-month follow-up; low-risk: 4.3% vs. 6.5%; moderate-risk: 10.9% vs. 15.3%; high-risk: 25.5% vs. 32.6%; significant differences in all risk groups","methodology":"School-based randomized controlled trial over 33 months with 1,874 sixth-graders. Two-level random intercept logistic model for panel data. Eight risk/protective factors used to create individualized risk profiles and predict intervention effects.","limitations":"Predicted probabilities are model estimates, not observed outcomes. The eight risk factors may not capture all relevant predictors. Czech Republic sample may not generalize to other cultural contexts. Long-term effects beyond 33 months unknown."},{"rthcId":"RTHC-01020","title":"Marijuana and tobacco use and co-use among African Americans: results from the 2013, National Survey on Drug Use and Health.","authors":"Montgomery, LaTrice","year":2015,"journal":"Addictive behaviors, 51, 18-23","doi":"10.1016/j.addbeh.2015.06.046","pmid":"26186376","tags":["addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers examined 2,024 African American past-month marijuana and tobacco users from the 2013 National Survey on Drug Use and Health. Three groups emerged: 18.5% used marijuana only, 53.8% used tobacco only, and 27.7% used both.\n\nCompared to marijuana-only users, co-users were more likely to be marijuana dependent and reported more days of marijuana use per month. Compared to tobacco-only users, co-users were less likely to be nicotine dependent but started smoking cigarettes, cigars, and marijuana at younger ages.\n\nCo-users also reported more cigar use, suggesting a pattern of broader tobacco product experimentation alongside cannabis use.","whyItMatters":"African Americans face disproportionate health burdens from both tobacco and marijuana use. Understanding the co-use pattern is essential for designing prevention and treatment programs that address both substances simultaneously.","specificNumbers":"2,024 participants; 18.5% marijuana only; 53.8% tobacco only; 27.7% co-users; co-users more likely marijuana dependent; co-users started all substances at younger ages; less nicotine dependent than tobacco-only users","methodology":"Secondary analysis of 2,024 African Americans reporting past-30-day marijuana or tobacco use in the 2013 National Survey on Drug Use and Health. Compared three groups on dependence markers, frequency of use, and age of initiation.","limitations":"Cross-sectional design cannot determine causal relationships between co-use and dependence. Self-reported use data. National survey may not capture regional variation. Did not assess blunt use (marijuana wrapped in tobacco), which is common in this population."},{"rthcId":"RTHC-01021","title":"Prescription stimulant use is associated with earlier onset of psychosis.","authors":"Moran, Lauren V; Masters, Grace A; Pingali, Samira; Cohen, Bruce M; Liebson, Elizabeth; Rajarethinam, R P; Ongur, Dost","year":2015,"journal":"Journal of psychiatric research, 71, 41-7","doi":"10.1016/j.jpsychires.2015.09.012","pmid":"26522870","tags":["psychosis","drug-interactions","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 205 patients recruited from an inpatient psychiatric unit, 40% reported using prescription stimulants (mostly for ADHD) before the onset of psychosis.\n\nThose exposed to stimulants developed psychosis at an average age of 20.5 years compared to 24.6 years for unexposed patients. This 4-year difference remained significant after controlling for gender, IQ, education, cannabis use disorder, other drug abuse, and family history of psychosis.\n\nThere was a significant interaction with gender: stimulant exposure had a greater effect on age of onset in women, while the effect in men did not reach statistical significance.","whyItMatters":"ADHD is commonly diagnosed before psychosis onset, and stimulant medications are first-line treatment. If stimulants accelerate psychosis onset in vulnerable individuals, this has major implications for how ADHD is managed in people with psychosis risk factors.","specificNumbers":"205 patients; 40% had prior stimulant exposure; age of onset: 20.5 vs. 24.6 years (p<0.001); effect remained significant after controlling for cannabis and family history; stronger effect in females","methodology":"Cross-sectional study of 205 inpatients with psychotic disorders. Compared age of psychosis onset between those with and without prior prescription stimulant exposure. Multivariable analysis controlled for gender, IQ, education, cannabis use disorder, other substance abuse, and family history.","limitations":"Cross-sectional design cannot prove stimulants caused earlier onset. Retrospective self-report of stimulant use. People with earlier psychosis onset may have had more severe childhood symptoms leading to more stimulant prescribing. Dose and duration of stimulant use not captured."},{"rthcId":"RTHC-01022","title":"Medicinal cannabis.","authors":"Murnion, Bridin","year":2015,"journal":"Australian prescriber, 38(6), 212-5","doi":null,"pmid":"26843715","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the clinical evidence for medicinal cannabis and its derivatives in Australia's regulatory context. Possible clinical indications included spasticity and pain in multiple sclerosis, chemotherapy-induced nausea, cancer pain, and HIV neuropathy.\n\nHowever, the review emphasized that evidence was limited, often reflected subjective rather than objective outcomes, and was not conclusive for any indication. At the time, nabiximols (Sativex) was the only cannabinoid on Australia's therapeutic goods register, and cannabidiol was being considered for scheduling.\n\nThe review stressed that introducing cannabinoids therapeutically should be supported by regulatory and educational frameworks that minimize risks to patients and the community.","whyItMatters":"This review captured a pivotal moment in Australian medical cannabis policy, when legislative frameworks were being developed. It provided clinicians with a balanced evidence summary while acknowledging the gap between public enthusiasm and clinical proof.","specificNumbers":"One cannabinoid product on Australian register (nabiximols); CBD recommended for Schedule 4; Regulator of Medicinal Cannabis Bill 2014 under consideration","methodology":"Narrative review published in Australian Prescriber, examining clinical evidence for medicinal cannabis and the regulatory landscape in Australia as of 2015.","limitations":"Brief overview rather than systematic review. Focused on the Australian regulatory context. Evidence quality for most indications was described as limited and not conclusive."},{"rthcId":"RTHC-01023","title":"A non-classical cannabinoid syndrome.","authors":"Muschart, X; Flament, J","year":2015,"journal":"Acta clinica Belgica, 70(4), 299-300","doi":"10.1179/2295333714Y.0000000116","pmid":"25567676","tags":["medical-cannabis","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report described a patient with cannabinoid hyperemesis syndrome who presented with atypical features. Unlike the classic presentation where hot water relieves symptoms, this patient found relief from cold temperatures.\n\nThe patient also developed bradycardia (slow heart rate), which is not part of the classical CHS description. The authors emphasized that non-classical forms of CHS exist and that clinicians should maintain a broad differential when evaluating chronic cannabis users with cyclic vomiting.","whyItMatters":"Expanding the recognized presentation of CHS beyond the classic triad (cyclic vomiting, chronic cannabis use, hot water relief) could prevent missed diagnoses when patients present with non-classical features.","specificNumbers":"Single case; atypical features: bradycardia, cold-water relief (vs. typical hot-water relief)","methodology":"Single case report documenting an atypical presentation of cannabinoid hyperemesis syndrome with bradycardia and cold-temperature relief.","limitations":"Single case report represents the lowest level of clinical evidence. Cannot determine how common non-classical presentations are. Bradycardia could have had other causes."},{"rthcId":"RTHC-01024","title":"Alcohol Versus Cannabinoids: A Review of Their Opposite Neuro-Immunomodulatory Effects and Future Therapeutic Potentials.","authors":"Nair, Madhavan P; Figueroa, Gloria; Casteleiro, Gianna; Muñoz, Karla; Agudelo, Marisela","year":2015,"journal":"Journal of alcoholism and drug dependence, 3(1)","doi":null,"pmid":"26478902","tags":["inflammation","neuroscience","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compared the immunomodulatory effects of alcohol and cannabinoids, finding that they produce largely opposite effects on the immune system.\n\nAlcohol promotes inflammation by increasing pro-inflammatory cytokines and disrupting immune cell function, contributing to organ damage in chronic drinkers. Cannabinoids, by contrast, generally suppress inflammatory responses through CB1 and CB2 receptor activation.\n\nThe review presented cytokine data from human dendritic cells showing divergent effects of alcohol and cannabinoids on cytokine production. The endocannabinoid system was identified as a potential therapeutic target for treating alcohol-induced inflammation, with novel strategies including cannabinoid receptor modulation for alcohol dependence treatment.","whyItMatters":"Understanding that alcohol and cannabinoids have opposite immune effects opens the possibility that cannabinoid-based therapies could counteract alcohol-induced immune damage. This has implications for both addiction treatment and management of alcohol-related organ disease.","specificNumbers":"Cytokine data from human dendritic cells; compared CB1 and CB2 receptor effects; reviewed in vitro, in vivo, and clinical evidence for therapeutic applications","methodology":"Narrative review of published literature on neuro-immunomodulatory effects of alcohol and cannabinoids. Included original cytokine array data from human monocyte-derived dendritic cells comparing alcohol and cannabinoid effects.","limitations":"Narrative review with potential for selective citation. Cytokine data from cell cultures may not reflect whole-body immune responses. The therapeutic potential of cannabinoids for alcohol dependence remains largely theoretical."},{"rthcId":"RTHC-01025","title":"Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.","authors":"Nass, Sara R; Long, Jonathan Z; Schlosburg, Joel E; Cravatt, Benjamin F; Lichtman, Aron H; Kinsey, Steven G","year":2015,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 10(2), 364-70","doi":"10.1007/s11481-015-9593-1","pmid":"25715681","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested how two endocannabinoid-degrading enzymes, MAGL (which breaks down 2-AG) and FAAH (which breaks down anandamide), contribute to body temperature regulation under stress.\n\nInhibiting MAGL with JZL184 made hypothermia worse in mice challenged with either a bacterial endotoxin (LPS) or cold (4 degrees Celsius) environment. These effects were blocked by a CB1 antagonist but not a CB2 antagonist, confirming a CB1-mediated mechanism.\n\nIn contrast, inhibiting FAAH with PF-3845, which raises anandamide levels, had no effect on either type of hypothermia. Neither MAGL nor FAAH inhibition affected normal body temperature, showing these enzymes specifically matter during temperature challenges.","whyItMatters":"This study reveals that the two main endocannabinoid pathways (2-AG and anandamide) play fundamentally different roles in temperature regulation. Since THC activates the same receptors as 2-AG, this helps explain why cannabis use can affect body temperature.","specificNumbers":"LPS caused hypothermia lasting 12+ hours; cold (4 degrees Celsius) caused mild hypothermia resolving within 30 minutes; JZL184 worsened both; PF-3845 had no effect on either; effects blocked by rimonabant (CB1) but not SR144528 (CB2)","methodology":"Mouse study using MAGL inhibitor (JZL184) and FAAH inhibitor (PF-3845) followed by either LPS injection (2 mg/kg) or cold environment (4 degrees Celsius) challenge. Core body temperature measured over 12 hours. CB1 and CB2 antagonists used to identify receptor mechanisms.","limitations":"Mouse study with potential species differences. Used pharmacological inhibitors rather than genetic knockouts for the primary experiments. Acute challenges may not reflect chronic conditions."},{"rthcId":"RTHC-01026","title":"Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice.","authors":"Nozaki, Chihiro; Markert, Astrid; Zimmer, Andreas","year":2015,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 25(8), 1388-96","doi":"10.1016/j.euroneuro.2015.04.001","pmid":"25910421","tags":["pain","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used a nitroglycerin-induced migraine model in mice to test whether the endocannabinoid system could be targeted for migraine treatment. Mice genetically lacking FAAH, the enzyme that degrades anandamide, showed complete abolition of both mechanical allodynia (pain from gentle touch) and trigeminal neuron activation.\n\nTwo structurally different FAAH inhibitors (URB597 and PF3945) dose-dependently blocked the same pain responses in normal mice. The CB1 antagonist rimonabant completely reversed these protective effects, confirming the mechanism works through CB1 receptors.\n\nMice lacking CB1 or CB2 receptors, or the 2-AG-degrading enzyme MAGL, did not show the same protection, pinpointing FAAH and the anandamide/CB1 pathway as the critical target.","whyItMatters":"Migraine is a major cause of disability, and current treatments have significant limitations. Identifying FAAH inhibition as a potential migraine target opens a new therapeutic avenue that leverages the body's own pain-control system without the psychoactive effects of THC.","specificNumbers":"Complete abolition of allodynia in FAAH knockout mice; both URB597 and PF3945 dose-dependently blocked pain; effects completely reversed by rimonabant; MAGL knockout showed no protection","methodology":"Used genetic knockout mice (FAAH, MAGL, CB1, CB2) and two FAAH inhibitors (URB597 and PF3945) in a nitroglycerin-induced migraine model. Measured mechanical allodynia and trigeminal nucleus neuron activation. Verified receptor mechanisms with antagonist studies.","limitations":"Mouse migraine model may not fully replicate human migraine. FAAH inhibitors have had setbacks in clinical development (safety concerns in a different context). Acute pain model may not reflect chronic or episodic migraine patterns."},{"rthcId":"RTHC-01027","title":"An economic analysis of different cannabis decriminalization scenarios.","authors":"Ogrodnik, Marysia; Kopp, Pierre; Bongaerts, Xavier; Tecco, Juan M","year":2015,"journal":"Psychiatria Danubina, 27 Suppl 1, S309-14","doi":null,"pmid":"26417786","tags":["legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This economic review compared cannabis policy models from around the world, from full prohibition to consumption tolerance (Netherlands) to legalized markets (Uruguay, U.S. states).\n\nThe central finding was that repressive cannabis policies are costly and have limited impact on prevalence. Countries with strict enforcement do not have lower cannabis use rates than those with tolerant laws.\n\nLegalizing consumption significantly reduces enforcement costs. Full legalization of supply and consumption reduces costs further while creating employment and generating tax revenue. The review argued that legalization would not cause a sudden consumption spike, provided the government sets taxes to keep the product at its current street price.\n\nThe key risks identified were earlier initiation age and increased consumption if prices drop too low.","whyItMatters":"This analysis reframes the cannabis policy debate from a moral question to an economic one: which approach minimizes total social costs while achieving public health goals? The data suggest prohibition is the most expensive option with uncertain benefits.","specificNumbers":"Models compared: prohibition, decriminalization, consumption tolerance (Netherlands), full legalization (U.S. states, Uruguay); key variable: price regulation to prevent consumption increases","methodology":"Economic review of international literature on cannabis legislative models. Analyzed policy scenarios using fundamental market economy concepts, comparing costs and benefits of each approach.","limitations":"Economic modeling relies on assumptions about consumer behavior. International comparisons may not account for cultural differences. Long-term effects of legalization were not fully available at the time of publication."},{"rthcId":"RTHC-01028","title":"JWH-018 impairs sensorimotor functions in mice.","authors":"Ossato, A; Vigolo, A; Trapella, C; Seri, C; Rimondo, C; Serpelloni, G; Marti, M","year":2015,"journal":"Neuroscience, 300, 174-88","doi":"10.1016/j.neuroscience.2015.05.021","pmid":"25987201","tags":["synthetic-cannabinoids","driving","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers compared the synthetic cannabinoid JWH-018 (found in \"Spice\" and \"herbal blends\") with THC across a battery of sensorimotor tests in mice.\n\nJWH-018 impaired sensorimotor responses (visual, auditory, tactile) at extremely low doses (0.01-0.1 mg/kg), reduced spontaneous movement at intermediate doses, and caused convulsions, myoclonia, and hyperreflexia at high doses (6 mg/kg).\n\nTHC at the same doses also reduced some sensorimotor responses but did not inhibit spontaneous locomotion and did not cause any neurological alterations like convulsions. All effects of JWH-018 were blocked by a CB1 receptor antagonist, confirming they work through the same receptor system but with dramatically different intensity.","whyItMatters":"This study demonstrated that synthetic cannabinoids are not just \"stronger weed\" but produce qualitatively different and more dangerous effects, including sensory impairment at very low doses and seizures at high doses. This has direct implications for driving and workplace safety.","specificNumbers":"JWH-018 impaired sensorimotor function at 0.01-0.1 mg/kg; caused convulsions at 6 mg/kg; THC at same doses did not impair locomotion or cause neurological effects; all JWH-018 effects blocked by AM251","methodology":"Mouse study comparing JWH-018 and THC at doses from 0.01 to 6 mg/kg. Used a battery of behavioral tests for sensorimotor function (visual, auditory, tactile responses), video-tracking for locomotion, and observation for neurological effects. CB1 antagonist AM251 was used to confirm receptor mechanisms.","limitations":"Mouse study with potential species differences in drug sensitivity. Acute dosing only. The numerous synthetic cannabinoids on the market may have different potency and effect profiles than JWH-018 specifically."},{"rthcId":"RTHC-01029","title":"Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review.","authors":"Ostadhadi, Sattar; Rahmatollahi, Mahdieh; Dehpour, Ahmad-Reza; Rahimian, Reza","year":2015,"journal":"Phytotherapy research : PTR, 29(3), 332-8","doi":"10.1002/ptr.5265","pmid":"25504799","tags":["medical-cannabis","cancer","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This exploratory review examined evidence for cannabinoids addressing a wider range of chemotherapy side effects than just nausea and vomiting.\n\nBeyond the established use for chemotherapy-induced nausea, the review identified emerging evidence for cannabinoids in: appetite stimulation for cancer cachexia, protection against chemotherapy-induced bone loss (through CB2 receptor activation), reduction of kidney toxicity (nephroprotection), reduction of heart damage (cardioprotection), pain management, mood improvement, and relief from insomnia.\n\nThe review also noted that cannabinoids showed direct antitumoral effects in some preclinical models, suggesting they might simultaneously fight cancer while mitigating treatment side effects.","whyItMatters":"Chemotherapy side effects significantly affect quality of life and treatment adherence. If cannabinoids can address multiple side effects simultaneously while potentially having antitumor activity, they could serve as valuable adjuncts to cancer treatment.","specificNumbers":"Applications reviewed: anti-nausea, appetite stimulation, bone protection, nephroprotection, cardioprotection, pain relief, mood improvement, insomnia relief, antitumoral effects","methodology":"Exploratory review of preclinical and clinical literature on cannabinoid effects relevant to chemotherapy side effect management.","limitations":"Exploratory review covering a wide range of indications with varying evidence quality. Most evidence for newer applications was preclinical. Clinical data for bone, kidney, and heart protection from cannabinoids was minimal."},{"rthcId":"RTHC-01030","title":"Allowing cigarette or marijuana smoking in the home and car: prevalence and correlates in a young adult sample.","authors":"Padilla, Mabel; Berg, Carla J; Schauer, Gillian L; Lang, Delia L; Kegler, Michelle C","year":2015,"journal":"Health education research, 30(1), 179-91","doi":"10.1093/her/cyu051","pmid":"25214515","tags":["youth","harm-reduction","respiratory"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 2,002 students at two southeastern U.S. universities about allowing smoking in personal spaces. More students permitted marijuana (17%) than cigarettes (14.5%) in their homes, though more allowed cigarettes in cars (35.9%) than marijuana (27.3%).\n\nThe factors predicting each policy differed. Allowing cigarettes in the home was linked to younger age, minority status, living off campus, personal marijuana use, and parental tobacco use. Allowing marijuana in the home was linked to older age, not having children, living off campus, positive marijuana perceptions, and personal, parental, and friend marijuana use.\n\nPersonal marijuana use predicted allowing cigarettes in the home, and personal cigarette use predicted allowing marijuana in cars, showing how the two substances' secondhand smoke policies are interlinked.","whyItMatters":"Secondhand marijuana smoke exposure in personal settings is an understudied health concern. This study revealed that young adults are more permissive of marijuana than cigarette smoke in their homes, potentially exposing cohabitants to harmful combustion products.","specificNumbers":"2,002 respondents; 14.5% allowed cigarettes in home; 17.0% allowed marijuana in home; 35.9% allowed cigarettes in cars; 27.3% allowed marijuana in cars","methodology":"Cross-sectional online survey of 2,002 respondents at two southeastern U.S. universities in 2013. Multivariate logistic regression identified correlates of allowing cigarette versus marijuana smoking in homes and cars.","limitations":"Southeastern U.S. university sample may not generalize. Self-reported policies may not reflect actual behavior. Cross-sectional design. Did not measure actual secondhand exposure levels."},{"rthcId":"RTHC-01031","title":"Effect of Non-psychotropic Plant-derived Cannabinoids on Bladder Contractility: Focus on Cannabigerol.","authors":"Pagano, Ester; Montanaro, Vittorino; Di Girolamo, Antonio; Pistone, Antonio; Altieri, Vincenzo; Zjawiony, Jordan K; Izzo, Angelo A; Capasso, Raffaele","year":2015,"journal":"Natural product communications, 10(6), 1009-12","doi":null,"pmid":"26197538","tags":["cbd","medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested five non-psychoactive cannabinoids (CBD, CBG, CBDV, THCV, and CBC) on mouse bladder muscle contractions. Four of the five reduced contractions triggered by acetylcholine, with the rank order of effectiveness being CBG = THCV > CBD > CBDV. CBC had no effect.\n\nNone of the effective compounds affected contractions triggered by electrical stimulation, suggesting they work by blocking the chemical signal (acetylcholine) rather than the nerve-muscle connection directly.\n\nCBG's effect was not blocked by CB1 or CB2 receptor antagonists, indicating it works through a different mechanism than the traditional cannabinoid receptor pathway. Critically, CBG also reduced acetylcholine-induced contractions in human bladder tissue.","whyItMatters":"Overactive bladder affects millions of people, and current treatments have significant side effects. A non-psychoactive cannabinoid that reduces bladder contractions through a novel mechanism could offer a new treatment avenue without the cognitive effects of THC.","specificNumbers":"Five cannabinoids tested: CBD, CBG, CBDV, THCV, CBC; efficacy rank: CBG=THCV>CBD>CBDV; CBC had no effect; CBG effect not blocked by CB1 or CB2 antagonists; CBG active in human bladder tissue","methodology":"In vitro study testing five phytocannabinoids at concentrations from 10^-8 to 10^-4 M on mouse bladder contractility. CBG was further tested with CB1 and CB2 antagonists and on human bladder tissue.","limitations":"In vitro tissue study does not account for whole-body pharmacokinetics. Mouse and human tissue responses may differ in vivo. The mechanism of CBG action was not fully identified. Clinical trials in patients with bladder conditions were not conducted."},{"rthcId":"RTHC-01032","title":"Examining the role of common genetic variants on alcohol, tobacco, cannabis and illicit drug dependence: genetics of vulnerability to drug dependence.","authors":"Palmer, Rohan H C; Brick, Leslie; Nugent, Nicole R; Bidwell, L Cinnamon; McGeary, John E; Knopik, Valerie S; Keller, Matthew C","year":2015,"journal":"Addiction (Abingdon, England), 110(3), 530-7","doi":"10.1111/add.12815","pmid":"25424661","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed genetic data from 2,596 individuals in the Study of Addiction: Genetics and Environment to estimate how much common genetic variation contributes to drug dependence vulnerability.\n\nCommon single nucleotide polymorphisms (SNPs) explained 25-36% of the variance across three measures of drug problems. Drug dependence diagnoses and dependence vulnerability (ratio of symptoms to substances used) showed the largest genetic effects at 36% and 33% respectively.\n\nCritically, the genetic effects were almost entirely shared across the three measures, with genetic correlations ranging from 0.92 to 0.97. This means the same genetic variants that contribute to cannabis dependence also contribute to alcohol, tobacco, and cocaine dependence.","whyItMatters":"This study addresses the \"missing heritability\" problem in addiction genetics. While individual genes have tiny effects, the aggregate contribution of common genetic variants is substantial, explaining up to a third of vulnerability to drug dependence.","specificNumbers":"2,596 participants; SNP heritability: DD = 0.36, DV = 0.33, PU = 0.25; genetic correlations: 0.92-0.97 across measures; substances: alcohol, tobacco, cannabis, cocaine, other illicit drugs","methodology":"Genome-wide complex trait analysis (GCTA) of 2,596 unrelated individuals. Three phenotypic measures: diagnostic drug dependence factor score, problem use factor score, and dependence vulnerability ratio. Univariate and bivariate analyses estimated SNP-based heritability and genetic covariance.","limitations":"Selected sample from an addiction study may not represent the general population. GCTA provides aggregate estimates, not individual gene identification. Common SNPs only capture part of genetic variation. Environmental factors not fully accounted for."},{"rthcId":"RTHC-01033","title":"Cannabinoid abuse and addiction: Clinical and preclinical findings.","authors":"Panlilio, L V; Goldberg, S R; Justinova, Z","year":2015,"journal":"Clinical pharmacology and therapeutics, 97(6), 616-27","doi":"10.1002/cpt.118","pmid":"25788435","tags":["addiction","neuroscience","withdrawal"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized research on the mechanisms of cannabinoid abuse, withdrawal, and relapse from both human and animal studies.\n\nThe review described how cannabinoids produce rewarding effects through CB1 receptor activation in the brain's reward circuitry, how tolerance develops through receptor downregulation, and how withdrawal symptoms emerge when chronic stimulation stops. Cannabis withdrawal includes irritability, anxiety, sleep disturbance, and decreased appetite.\n\nSeveral potential pharmacotherapy targets were identified: FAAH inhibitors (which boost endocannabinoid levels), allosteric modulators of CB1 receptors, and medications targeting overlapping neurotransmitter systems. However, no approved treatments existed at the time of publication.","whyItMatters":"Cannabis use disorder affects millions of people worldwide, yet there are no FDA-approved medications for treatment. Understanding the neurobiology of cannabis addiction is essential for developing targeted treatments.","specificNumbers":"No approved medications for cannabis use disorder; potential targets reviewed: FAAH inhibitors, allosteric CB1 modulators, GABAergic agents, and others","methodology":"Comprehensive review of preclinical and clinical research on cannabinoid abuse, covering reward mechanisms, adverse effects, withdrawal, relapse, and potential pharmacotherapies.","limitations":"Many promising pharmacological targets had only preclinical support at the time. Animal models of cannabis reward and relapse may not fully capture human addiction. The review acknowledged that most candidate medications face significant development hurdles."},{"rthcId":"RTHC-01034","title":"Clinical correlates of first episode early onset psychosis in KwaZulu-Natal, South Africa.","authors":"Paruk, Saeeda; Jhazbhay, Khadija; Singh, Keshika; Sartorius, Benn; Burns, Jonathan K","year":2015,"journal":"Journal of child and adolescent mental health, 27(2), 103-11","doi":"10.2989/17280583.2015.1080710","pmid":"26357916","tags":["psychosis","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers assessed 45 adolescents (mean age 15.9) with first-episode psychosis in KwaZulu-Natal, South Africa. Cannabis use was strikingly prevalent: 56% reported lifetime use, and 96% of cannabis users were male.\n\nThe mean duration of untreated psychosis was 27.2 weeks (nearly 7 months), with younger children experiencing longer delays. The prodromal period (early warning signs before full psychosis) was poorly recognized by 49% of patients and caregivers.\n\nMale patients had slightly later onset (15.7 vs. 15.3 years) but dramatically higher cannabis use, suggesting that environmental factors like cannabis use may play different roles in psychosis onset for males versus females.","whyItMatters":"This study from a low-to-middle income country highlights that cannabis-psychosis associations observed in Western research also appear in African settings, and that delays in treatment are substantial, potentially worsening outcomes.","specificNumbers":"45 adolescents; mean age 15.9; 69% male; 56% lifetime cannabis use; 96% of cannabis users were male; mean DUP 27.2 weeks; negative correlation between DUP and age of onset (p<0.05)","methodology":"Cross-sectional assessment of 45 adolescents with first-episode psychosis using clinical interview, PANSS rating scale, SOS score, WHO ASSIST questionnaire, and urine cannabis testing.","limitations":"Small sample (45 patients). Single site in South Africa. Cross-sectional design cannot determine whether cannabis contributed to psychosis onset. Self-reported substance use may be unreliable. No comparison group of adolescents without psychosis."},{"rthcId":"RTHC-01035","title":"Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.","authors":"Patil, K R; Goyal, S N; Sharma, C; Patil, C R; Ojha, S","year":2015,"journal":"Current medicinal chemistry, 22(30), 3472-501","doi":null,"pmid":"26179998","tags":["cancer","cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how plant-derived cannabinoids (phytocannabinoids) from both cannabis and non-cannabis plants interact with the endocannabinoid system to fight cancer.\n\nThe review focused on strategies to avoid psychoactive effects: targeting CB2 receptors (found primarily on immune cells rather than in the brain), inhibiting endocannabinoid-degrading enzymes (FAAH and MAGL), and using non-psychoactive cannabinoids. CB2-selective compounds and enzyme inhibitors showed antitumor activity in preclinical models without the cognitive effects of THC.\n\nPhytocannabinoids from non-cannabis plants were also identified as promising candidates, including compounds that bind cannabinoid receptors and modulate endocannabinoid levels.","whyItMatters":"The main barrier to cannabinoid-based cancer treatment is psychoactive side effects from CB1 activation. This review mapped alternative strategies that could deliver antitumor effects without the high, potentially making cannabinoid cancer treatments clinically viable.","specificNumbers":"Targets reviewed: CB1, CB2 receptors, FAAH enzyme, MAGL enzyme; non-cannabis plant sources of phytocannabinoids identified; preclinical efficacy across multiple cancer types","methodology":"Comprehensive review of preclinical literature on phytocannabinoids as cancer therapeutics, focusing on mechanism of action through the endocannabinoid system, with emphasis on non-psychoactive strategies.","limitations":"All evidence preclinical. Non-cannabis phytocannabinoids are less well-characterized than cannabis-derived compounds. The translation gap between preclinical antitumor effects and clinical cancer treatment remains substantial."},{"rthcId":"RTHC-01036","title":"Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation.","authors":"Patsenker, Eleonora; Sachse, Philip; Chicca, Andrea; Gachet, María Salomé; Schneider, Vreni; Mattsson, Johan; Lanz, Christian; Worni, Mathias; de Gottardi, Andrea; Semmo, Mariam; Hampe, Jochen; Schafmayer, Clemens; Brenneisen, Rudolf; Gertsch, Jürg; Stickel, Felix; Semmo, Nasser","year":2015,"journal":"International journal of molecular sciences, 16(4), 7057-76","doi":"10.3390/ijms16047057","pmid":"25826533","tags":["inflammation","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers measured endocannabinoid levels in hepatitis C patients and found both anandamide and 2-AG were elevated in plasma compared to healthy controls. However, liver tissue levels and degrading enzyme activity were unchanged.\n\nIn immune cells, endocannabinoids suppressed the production of key antiviral and inflammatory cytokines (IFN-gamma, TNF-alpha, IL-2). The suppressive effect of anandamide on IL-2 was stronger in cells from hepatitis C patients than healthy controls.\n\nIn liver cells, 2-AG induced expression of inflammatory markers (IL-6, IL-17A, IL-32, COX-2) and enhanced activation of hepatic stellate cells (which produce scar tissue). This suggests endocannabinoids may simultaneously weaken the immune response to the virus while promoting liver fibrosis.","whyItMatters":"Cannabis use has been associated with faster fibrosis progression in hepatitis C patients. This study provides a mechanism: elevated endocannabinoids (which cannabis use would further increase) suppress antiviral immunity and promote liver scarring.","specificNumbers":"AEA and 2-AG elevated in HCV patient plasma; hepatic FAAH and MAGL activity unchanged; endocannabinoids suppressed IFN-gamma, TNF-alpha, IL-2; 2-AG induced IL-6, IL-17A, IL-32, COX-2 in hepatocytes","methodology":"Translational study measuring endocannabinoid levels by mass spectrometry in plasma and liver tissue of HCV patients. Enzyme activity assays, gene expression analysis, and co-culture experiments with immune and liver cells.","limitations":"Observational study with in vitro functional experiments. Sample sizes not specified in the abstract. In vitro cell responses may not fully reflect in vivo liver biology. The hepatitis C treatment landscape has changed dramatically."},{"rthcId":"RTHC-01037","title":"Descriptive epidemiology of major depressive disorder in Canada in 2012.","authors":"Patten, Scott B; Williams, Jeanne V A; Lavorato, Dina H; Wang, Jian Li; McDonald, Keltie; Bulloch, Andrew G M","year":2015,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 60(1), 23-30","doi":null,"pmid":"25886546","tags":["depression","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This national epidemiological survey assessed major depressive disorder in 25,113 Canadians using diagnostic interviews. The past-year prevalence of major depression was 3.9%.\n\nAmong those with depression, substance use was notable: 4.8% had alcohol abuse, 4.5% had alcohol dependence, 2.5% had cannabis abuse, and 2.9% had cannabis dependence. Generalized anxiety disorder co-occurred in nearly 25%.\n\nTreatment seeking had improved compared to earlier Canadian surveys (63.1% sought treatment), but antidepressant use remained stable at 33.1%. A concerning 37.5% of those accessing treatment perceived stigma from others about their condition. Suicide attempts were reported by 6.6%.","whyItMatters":"This study quantifies the overlap between depression and cannabis use disorders in a national population, while also showing that depression remains significantly undertreated and stigmatized despite being common.","specificNumbers":"25,113 respondents; past-year MDD prevalence 3.9%; cannabis abuse 2.5% and dependence 2.9% among those with MDD; 63.1% sought treatment; 33.1% on antidepressants; 6.6% attempted suicide; 37.5% perceived stigma","methodology":"National population-based survey (Canadian Community Health Survey - Mental Health, 2012) of 25,113 respondents using an adaptation of the WHO Composite International Diagnostic Interview. Complex survey design methods were used for prevalence estimates.","limitations":"Cross-sectional survey cannot determine causal direction between depression and cannabis use. Self-reported diagnoses and treatment. Household survey may miss homeless or institutionalized populations with higher depression rates."},{"rthcId":"RTHC-01038","title":"Endocannabinoids and Their Pharmacological Actions.","authors":"Pertwee, Roger G","year":2015,"journal":"Handbook of experimental pharmacology, 231, 1-37","doi":"10.1007/978-3-319-20825-1_1","pmid":"26408156","tags":["neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This comprehensive review catalogued 13 endogenous compounds that likely function as endocannabinoids based on being detected in mammalian tissue and binding to cannabinoid receptors.\n\nBeyond the well-known anandamide and 2-AG, the review identified 11 additional endocannabinoids including noladin ether, virodhamine, oleamide, and docosahexaenoylethanolamide. Eight of these were found to activate CB1 and sometimes CB2 receptors.\n\nRemarkably, the review also identified endogenous CB1 antagonists (sphingosine, haemopressin) and allosteric modulators. These include negative allosteric modulators (pepcan-12 and pregnenolone) and positive allosteric modulators (lipoxin A4), revealing that the body has built-in mechanisms to both amplify and dampen cannabinoid signaling.","whyItMatters":"The discovery that the endocannabinoid system has its own natural brakes (antagonists) and volume controls (allosteric modulators) transforms understanding of how the system maintains balance. This complexity has major implications for drug development.","specificNumbers":"13 probable orthosteric endocannabinoids identified; 8 activate CB1 receptors; 1 CB1 antagonist (sphingosine); 1 CB1 antagonist/inverse agonist (haemopressin); 3 allosteric modulators identified","methodology":"Comprehensive pharmacological review cataloguing all identified endocannabinoid compounds, their receptor binding properties, and functional effects based on in vitro evidence. Published in the Handbook of Experimental Pharmacology.","limitations":"Based on in vitro evidence; in vivo relevance of some compounds is uncertain. Some putative endocannabinoids may be present at concentrations too low to be physiologically significant. Receptor binding does not always predict functional activity in living systems."},{"rthcId":"RTHC-01039","title":"Minireview: From the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation.","authors":"Picone, Robert P; Kendall, Debra A","year":2015,"journal":"Molecular endocrinology (Baltimore, Md.), 29(6), 801-13","doi":"10.1210/me.2015-1062","pmid":"25866875","tags":["neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This minireview examined therapeutic opportunities from modulating CB1 and CB2 receptors across several disease areas.\n\nFor CB1: the receptor protects against excitotoxic brain damage, and CB1 modulation could limit addiction liability. CB1 also influences insulin release, insulin resistance, and feeding behavior, connecting it to diabetes and obesity.\n\nFor CB2: the receptor's presence on immune cells makes it relevant to ALS (where inflammatory cell activation drives motor neuron death), HIV-related neuroinflammation, and postmenopausal osteoporosis (where CB2 modulation affects bone remodeling).\n\nThe review emphasized that achieving receptor selectivity is essential for safe therapeutics, as CB1 activation causes psychoactive effects while CB2 modulation generally does not.","whyItMatters":"This review mapped out the most promising clinical applications for cannabinoid receptor modulation, showing that CB1 and CB2 offer complementary therapeutic opportunities across very different disease areas.","specificNumbers":"Disease areas: excitotoxicity (CB1), addiction (CB1), diabetes/obesity (CB1), ALS (CB2), HIV neuroinflammation (CB2), osteoporosis (CB2)","methodology":"Minireview synthesizing preclinical and clinical evidence on CB1 and CB2 receptor roles in specific disease states: excitotoxicity, addiction, metabolic disorders, ALS, HIV neuropathology, and osteoporosis.","limitations":"Minireview covering broad territory with limited depth per topic. Many therapeutic applications remained in preclinical stages. The failure of rimonabant (CB1 antagonist for obesity) illustrated the difficulty of translating cannabinoid research to safe drugs."},{"rthcId":"RTHC-01040","title":"Global patterns of domestic cannabis cultivation: sample characteristics and patterns of growing across eleven countries.","authors":"Potter, Gary R; Barratt, Monica J; Malm, Aili; Bouchard, Martin; Blok, Thomas; Christensen, Anne-Sofie; Decorte, Tom; Frank, Vibeke Asmussen; Hakkarainen, Pekka; Klein, Axel; Lenton, Simon; Perälä, Jussi; Werse, Bernd; Wouters, Marije","year":2015,"journal":"The International journal on drug policy, 26(3), 226-37","doi":"10.1016/j.drugpo.2014.12.007","pmid":"25582281","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The Global Cannabis Cultivation Research Consortium surveyed 6,530 predominantly small-scale cannabis growers from 11 countries about their demographics, methods, motivations, and criminal justice contacts.\n\nThe findings were remarkably consistent across countries: most growers came from \"normal\" rather than \"deviant\" backgrounds. The clear majority were motivated by reasons other than profit, primarily personal use and self-sufficiency.\n\nMinimal involvement in drug dealing or other criminal activities was reported. Some cross-country differences existed, suggesting that local political, geographical, and cultural factors influence how cultivators operate, but the core profile of the personal-use grower was consistent globally.","whyItMatters":"Drug policy often treats cannabis cultivation as organized crime. This survey showed that most small-scale growers are ordinary people growing for personal use, with profiles very different from commercial drug dealers. This distinction is relevant for proportionate enforcement and legalization design.","specificNumbers":"6,530 respondents; 11 countries; majority motivated by personal use; minimal involvement in drug dealing; consistent demographic profiles across countries","methodology":"Online survey of 6,530 cannabis cultivators from 11 countries conducted by the Global Cannabis Cultivation Research Consortium. Descriptive statistics highlighted similarities and differences across national samples.","limitations":"Online recruitment creates selection bias (more tech-savvy, English-speaking growers over-represented). Self-reported data may understate criminal involvement. Different recruitment strategies across countries complicate cross-national comparisons. Non-probability sample."},{"rthcId":"RTHC-01041","title":"Synthesis and biological evaluation of (3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.","authors":"Presley, Chaela S; Mustafa, Suni M; Abidi, Ammaar H; Moore, Bob M","year":2015,"journal":"Bioorganic & medicinal chemistry, 23(17), 5390-401","doi":"10.1016/j.bmc.2015.07.057","pmid":"26275680","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers designed and synthesized a series of compounds based on a 2,6-dihydroxy-biphenyl scaffold that selectively target the CB2 cannabinoid receptor as inverse agonists, without functional activity at CB1.\n\nKey structure-activity findings: an aromatic C ring was required for inverse agonist activity, with substitution at the 4-position being optimal. The resorcinol (dihydroxy) group was essential for CB2 selectivity and inverse agonist efficacy.\n\nTwo compounds (41 and 45) were identified as noncompetitive antagonists at CB2, meaning they block the receptor through a different mechanism than competitive antagonists. Although CB2 agonists have received more attention, CB2 inverse agonists are also emerging as having anti-inflammatory activity.","whyItMatters":"Developing CB2-selective drugs is a major goal in cannabinoid pharmacology because CB2 modulation could treat inflammation and immune conditions without the psychoactive effects of CB1 activation. These inverse agonists represent a new tool in that effort.","specificNumbers":"Compounds tested: series of dichloro-dihydroxy-biphenyl analogs; compounds 41 and 45 identified as noncompetitive CB2 antagonists; no functional CB1 activity","methodology":"Medicinal chemistry study synthesizing a series of dichloro-dihydroxy-biphenyl-aryl/alkyl-methanone analogs. Evaluated CB1 and CB2 binding affinity, potency, and efficacy. Antagonist studies performed against the cannabinoid agonist CP 55,940.","limitations":"Early-stage medicinal chemistry with in vitro testing only. Anti-inflammatory activity was inferred from the literature rather than directly demonstrated. No in vivo testing. Drug-like properties (bioavailability, toxicity) were not assessed."},{"rthcId":"RTHC-01042","title":"Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy.","authors":"Press, Craig A; Knupp, Kelly G; Chapman, Kevin E","year":2015,"journal":"Epilepsy & behavior : E&B, 45, 49-52","doi":"10.1016/j.yebeh.2015.02.043","pmid":"25845492","tags":["epilepsy","cbd","youth"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Researchers reviewed records of 75 children and adolescents treated with oral cannabis extracts (OCEs) at a single epilepsy center. Parents reported any improvement in 57% and a greater than 50% seizure reduction in 33%.\n\nResponse rates varied dramatically by epilepsy syndrome: Lennox-Gastaut syndrome (LGS) had an 88.9% responder rate, Dravet syndrome 23%, and Doose syndrome 0%.\n\nFamilies who had moved to Colorado specifically for OCE treatment reported higher response rates (47%) than families already living there (22%). Additional reported benefits included improved behavior (33%), language (10%), and motor skills (10%).\n\nHowever, 44% experienced adverse events including increased seizures (13%), somnolence (12%), and rare serious events including developmental regression, status epilepticus requiring intubation, and one death.","whyItMatters":"This study provided early clinical data on cannabis extracts for pediatric epilepsy, revealing both promise and significant concerns. The disconnect between parent-reported improvement and unchanged EEGs highlighted the need for controlled trials with objective measures.","specificNumbers":"75 patients; 57% any improvement; 33% >50% seizure reduction; LGS 88.9% response; Dravet 23%; Doose 0%; 44% adverse events; 13% increased seizures; relocated families 47% vs. local 22% response","methodology":"Retrospective chart review of children and adolescents given oral cannabis extracts for epilepsy at a single tertiary epilepsy center. Parent-reported outcomes. EEG data available for 8 responders showed no improvement.","limitations":"Retrospective, unblinded, parent-reported outcomes. No placebo control (expecting benefit could inflate response rates). Families who relocated to Colorado may have different reporting biases. Product composition varied. EEG data showed no improvement in responders."},{"rthcId":"RTHC-01043","title":"Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.","authors":"Pryce, Gareth; Baker, David","year":2015,"journal":"Handbook of experimental pharmacology, 231, 213-31","doi":"10.1007/978-3-319-20825-1_7","pmid":"26408162","tags":["medical-cannabis","neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the role of the endocannabinoid system in multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), two neurodegenerative conditions sharing the symptom of spasticity.\n\nAnecdotal reports of cannabis relieving MS symptoms were confirmed by animal models and clinical trials, leading to the approval of medicinal cannabis (nabiximols) for MS spasticity. Beyond symptom relief, experimental studies showed cannabinoids had neuroprotective effects in animal models of both MS and ALS.\n\nThe neuroprotective potential was particularly notable: cannabinoids appeared to slow neurodegeneration rather than just masking symptoms. This suggested the endocannabinoid system could be a target for disease-modifying therapies, not just symptom control.","whyItMatters":"While cannabis-based medicines are approved for MS symptom management, the possibility that they could also slow disease progression would represent a fundamental shift from palliative to disease-modifying therapy.","specificNumbers":"Nabiximols approved for MS spasticity; neuroprotective effects demonstrated in animal models of MS and ALS; endocannabinoid system components identified as potential disease-modifying targets","methodology":"Review of published preclinical and clinical evidence on the endocannabinoid system in MS and ALS, published in the Handbook of Experimental Pharmacology.","limitations":"Neuroprotective effects were primarily from animal models. Human clinical evidence for disease modification was limited. MS and ALS have different pathologies, and cannabinoid effects may differ between them."},{"rthcId":"RTHC-01044","title":"Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.","authors":"Pryce, Gareth; Riddall, Dieter R; Selwood, David L; Giovannoni, Gavin; Baker, David","year":2015,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 10(2), 281-92","doi":"10.1007/s11481-014-9575-8","pmid":"25537576","tags":["medical-cannabis","neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested cannabis-derived cannabinoids in a mouse model of relapsing-remitting multiple sclerosis (experimental autoimmune encephalomyelitis in ABH mice).\n\nSynthetic CBD slowed the accumulation of disability that occurs during the \"inflammatory penumbra\" (damage spreading from initial immune attack sites), possibly through blockade of voltage-gated sodium channels rather than through cannabinoid receptors.\n\nNon-sedating doses of THC did not suppress the immune attacks (relapses) themselves but dose-dependently slowed the accumulation of disability between attacks. In a human clinical trial, a planned subgroup analysis of less-disabled MS patients who progressed more rapidly showed significant slowing of progression with oral THC versus placebo.","whyItMatters":"This study provided both animal and preliminary human evidence that cannabinoids may protect nerve cells during MS. The distinction between suppressing immune attacks (which THC did not do) and slowing disability accumulation (which it did) is critical for understanding how cannabinoids might help.","specificNumbers":"Synthetic CBD slowed disability in relapsing EAE; non-sedating THC doses slowed progression dose-dependently; phase III subgroup: significant slowing of progression with oral THC in less-disabled, rapidly-progressing patients","methodology":"Mouse studies using experimental autoimmune encephalomyelitis (EAE) model with synthetic CBD and THC. Also reported results from a subgroup analysis of a 3-year phase III clinical trial of oral THC in progressive MS.","limitations":"Mouse model does not fully replicate human MS. The human clinical trial subgroup analysis was planned but not the primary outcome. CBD mechanism (sodium channel blockade) was suggested but not confirmed. THC doses that protect without sedation may be difficult to achieve clinically."},{"rthcId":"RTHC-01045","title":"A review of co-morbid tobacco and cannabis use disorders: possible mechanisms to explain high rates of co-use.","authors":"Rabin, Rachel Allison; George, Tony Peter","year":2015,"journal":"The American journal on addictions, 24(2), 105-116","doi":"10.1111/ajad.12186","pmid":"25662704","tags":["addiction","harm-reduction","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined why tobacco and cannabis are so frequently used together and why co-use complicates treatment of both substances.\n\nThe evidence showed bidirectional effects: tobacco use increases the likelihood of becoming cannabis dependent, and cannabis use promotes transition to heavier tobacco use. Tobacco smoking also threatens cannabis cessation, with cigarette smokers showing increased and accelerated relapse rates when trying to quit cannabis.\n\nThe review identified multiple mechanisms for co-use: synergistic neurobiological effects (both affect the endocannabinoid and nicotinic acetylcholine systems), compensatory effects (one substance modifying the effects of the other), shared route of administration (smoking), and both addiction vulnerability and gateway hypotheses operating in both directions.","whyItMatters":"Most addiction treatment programs address one substance at a time, but the strong bidirectional relationship between tobacco and cannabis suggests that simultaneous treatment may be more effective. Quitting one while continuing the other may undermine both efforts.","specificNumbers":"Tobacco promotes cannabis dependence; cannabis promotes heavier tobacco use; cigarette smokers have accelerated cannabis relapse rates; both gateway and addiction vulnerability hypotheses supported","methodology":"Narrative review of published studies examining co-morbid tobacco and cannabis use, focusing on neurobiological mechanisms, addiction theories, and treatment implications.","limitations":"Narrative review that may not capture all relevant literature. Mechanisms proposed are largely theoretical. Few intervention studies had directly tested simultaneous cessation at the time of publication."},{"rthcId":"RTHC-01046","title":"Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa.","authors":"Radwan, Mohamed M; ElSohly, Mahmoud A; El-Alfy, Abir T; Ahmed, Safwat A; Slade, Desmond; Husni, Afeef S; Manly, Susan P; Wilson, Lisa; Seale, Suzanne; Cutler, Stephen J; Ross, Samir A","year":2015,"journal":"Journal of natural products, 78(6), 1271-6","doi":"10.1021/acs.jnatprod.5b00065","pmid":"26000707","tags":["neuroscience","potency"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers isolated and characterized seven new naturally occurring cannabinoids from high-potency Cannabis sativa, all of which were hydroxylated (oxygen-containing) variants of known cannabinoids.\n\nWhen tested for binding to cannabinoid receptors, compound 3 (10-alpha-hydroxy-delta-8-THC) showed the highest affinity for CB1 receptors and produced the most potent cannabimimetic effects in mice (reduced movement, lowered body temperature, reduced pain sensitivity, and catalepsy). Compound 4 showed partial cannabimimetic actions, while compound 2 only produced reduced movement.\n\nThe discovery that high-potency cannabis contains novel psychoactive compounds beyond THC expands understanding of what users are actually consuming and what contributes to the effects of modern cannabis products.","whyItMatters":"High-potency cannabis is not simply \"more THC.\" This study revealed that it contains novel cannabinoids with their own receptor binding profiles and behavioral effects, complicating assumptions about what users are exposed to.","specificNumbers":"7 new cannabinoids isolated; 1 known compound (cannabiripsol) also studied; compound 3 had highest CB1 affinity and most potent behavioral effects; 10 compounds tested total","methodology":"Natural products chemistry study isolating cannabinoids from high-potency Cannabis sativa using chromatography. Structures determined by NMR, GC-MS, and high-resolution mass spectrometry. Binding affinity measured at CB1 and CB2 receptors. Behavioral effects tested in mice using the tetrad assay.","limitations":"Structural characterization and receptor binding are preliminary steps. In vivo testing was limited to a standard mouse behavioral battery. The concentrations of these new compounds in typical cannabis products were not quantified. Only one cannabis variety was studied."},{"rthcId":"RTHC-01047","title":"Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB2 receptor antagonists.","authors":"Ragusa, Giulio; Gómez-Cañas, María; Morales, Paula; Hurst, Dow P; Deligia, Francesco; Pazos, Ruth; Pinna, Gerard A; Fernández-Ruiz, Javier; Goya, Pilar; Reggio, Patricia H; Jagerovic, Nadine; García-Arencibia, Moisés; Murineddu, Gabriele","year":2015,"journal":"European journal of medicinal chemistry, 101, 651-67","doi":"10.1016/j.ejmech.2015.06.057","pmid":"26209834","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers modified the structure of the known CB2 antagonist SR144528, replacing its pyrazole ring with a pyrrole ring and varying other structural elements. Two compounds (6 and 10) showed high affinity for CB2 receptors in the low nanomolar range with selectivity over CB1.\n\nBoth compounds functioned as antagonists/inverse agonists at CB2, meaning they reduce the receptor's baseline activity. Computational docking studies revealed how these compounds fit into the CB2 binding pocket, and volume mapping identified the structural constraints that determine binding.\n\nThis work expanded the toolkit of CB2-selective compounds that could eventually be developed into anti-inflammatory medications without psychoactive effects.","whyItMatters":"CB2-selective drugs could treat inflammation and immune conditions without the psychoactive effects of CB1 activation. Each new structural class of CB2 ligands expands the options for drug development and helps map the receptor's binding site.","specificNumbers":"Two lead compounds (6 and 10) with Ki in low nM range at CB2; both CB2 antagonists/inverse agonists; no significant CB1 activity","methodology":"Medicinal chemistry study involving synthesis of pyrrole-based analogs of SR144528. Binding affinity measured at CB1 and CB2. Functional activity assessed by GTPgammaS binding and an in vitro CB2 bioassay. Computational modeling using Van der Waals volume maps and Glide docking.","limitations":"Early medicinal chemistry with in vitro data only. No in vivo testing. Drug-like properties (absorption, metabolism, toxicity) were not evaluated. The transition from binding studies to therapeutic applications is a long process."},{"rthcId":"RTHC-01048","title":"Natural Recovery From Cannabis Use in People With Psychosis: A Qualitative Study.","authors":"Rebgetz, Shane; Hides, Leanne; Kavanagh, David J; Choudhary, Anand","year":2015,"journal":"Journal of dual diagnosis, 11(3-4), 179-83","doi":"10.1080/15504263.2015.1100472","pmid":"26458187","tags":["psychosis","quitting"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Researchers interviewed 10 young adults (mean age 23) with early psychosis who had quit cannabis without formal treatment, averaging nearly 8 months of abstinence. Most had started cannabis at age 13.7 and progressed to daily use by age 17.\n\nThree main themes emerged for sustaining cessation: recognizing the negative impact of cannabis across multiple life domains (not just psychosis), having social support specifically for quitting, and using a combination of coping strategies rather than relying on a single approach.\n\nResisting peer pressure was commonly mentioned as critical. Participants who maintained abstinence had actively restructured their social environments to reduce exposure to cannabis-using peers.","whyItMatters":"Most research focuses on formal treatment programs, but many people quit cannabis on their own. Understanding natural recovery in people with psychosis can inform treatment design by identifying what actually helps people maintain change.","specificNumbers":"10 participants (6 men, 4 women); mean age 23; cannabis onset age 13.7; daily use by age 17; mean abstinence 7.9 months","methodology":"Qualitative study using semi-structured interviews with 10 people with early psychosis and lifetime cannabis misuse who had been abstinent for at least one month. Interpretative phenomenological analysis identified themes.","limitations":"Very small qualitative sample. Self-selected participants who successfully quit may not represent those who struggle. Only captured one month minimum of abstinence. No long-term follow-up to confirm sustained cessation."},{"rthcId":"RTHC-01049","title":"Influences of behavior and academic problems at school entry on marijuana use transitions during adolescence in an African-American sample.","authors":"Reboussin, Beth A; Ialongo, Nicholas S; Green, Kerry M","year":2015,"journal":"Addictive behaviors, 41, 51-7","doi":"10.1016/j.addbeh.2014.09.030","pmid":"25305658","tags":["youth","cognition","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tracked 458 low-income, urban African American children from first grade through early high school to see how early academic and behavior problems related to later marijuana use.\n\nTwo behavior problem classes emerged at school entry: externalizing (acting out) and attention/concentration difficulties. Academic problems co-occurred with both but were more strongly linked to attention/concentration issues.\n\nChildren with attention/concentration problems were more likely to transition from no marijuana involvement to actual use and problems starting in seventh grade. Children with externalizing behavior were more likely to transition from no involvement to having an opportunity to use during the high school transition.\n\nThis suggests that different behavior profiles lead to marijuana involvement through different pathways.","whyItMatters":"This study showed that risk for marijuana involvement begins before children even encounter the drug. Early academic and behavioral screening could identify children who need targeted prevention during critical transition periods.","specificNumbers":"458 participants; two behavior problem classes at school entry; attention/concentration problems predicted use and problems by 7th grade; externalizing behavior predicted opportunity exposure in high school transition","methodology":"Longitudinal study of 458 low-income, urban African American children using latent class and latent transition analyses. Behavior and academic problems assessed in first grade. Marijuana use transitions tracked from middle school through early high school.","limitations":"Single urban community in one geographic area. Low-income African American sample may not generalize to other populations. Self-reported marijuana use in adolescents may be unreliable. Attrition over the lengthy follow-up period."},{"rthcId":"RTHC-01050","title":"Troubled adolescents: substance abuse and mental disorder in young offenders.","authors":"Ribas-Siñol, Maria; Del Prado-Sanchez, Noemi; Claramunt-Mendoza, Jaume; Civit-Ramirez, Monica; Canalias-Perez, Oriol; Ochoa, Susana","year":2015,"journal":"Actas espanolas de psiquiatria, 43(6), 197-204","doi":null,"pmid":"26631302","tags":["youth","psychosis","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers studied 144 youth seen in a Therapeutic Juvenile Justice Unit in Spain. Drug use was extremely prevalent at 78.5%, with about half using only one substance.\n\nMental health diagnoses were common: 65.3% had an Axis I disorder (22.2% psychotic spectrum, 18.1% ADHD), and 42.4% had a personality disorder (16% antisocial, 6.9% borderline).\n\nSubstance preferences varied by diagnosis: psychotic teenagers tended to use cannabis, while ADHD patients gravitated toward both cannabis and cocaine. Significant associations were found between nationality and inhalant use, socioeconomic level and sedative/alcohol use, and parental death and alcohol use.","whyItMatters":"The extremely high rate of co-occurring substance use and mental illness in juvenile offenders suggests that the criminal justice system is often dealing with untreated psychiatric and addiction problems rather than purely criminal behavior.","specificNumbers":"144 youths; 78.5% drug users; 51.4% used only one substance; 65.3% Axis I disorder; 42.4% personality disorder; 22.2% psychotic spectrum; 18.1% ADHD; 16% antisocial personality","methodology":"Descriptive cross-sectional study of 144 youths assessed at a Therapeutic Juvenile Justice Unit in Barcelona, Spain. Assessed psychiatric diagnoses, substance use, and demographic/criminal characteristics.","limitations":"Single clinical unit in Spain. Descriptive study without control group. Small sample for subgroup analyses. Cultural and legal context may not translate to other countries. Selection bias toward more severe cases referred to a therapeutic unit."},{"rthcId":"RTHC-01051","title":"Peripherally Restricted Cannabinoids for the Treatment of Pain.","authors":"Romero-Sandoval, E Alfonso; Asbill, Scott; Paige, Candler A; Byrd-Glover, Kiara","year":2015,"journal":"Pharmacotherapy, 35(10), 917-25","doi":"10.1002/phar.1642","pmid":"26497478","tags":["pain","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined strategies to use cannabinoids for pain treatment while avoiding central nervous system effects. Cannabinoid receptors (CB1 and CB2) are abundant on peripheral pain-sensing nerves, and activating them locally can reduce pain signaling.\n\nSeveral approaches were discussed: using cannabinoid compounds that cannot cross the blood-brain barrier, developing CB2-selective agonists (since CB2 is less prevalent in the brain), and local delivery of cannabinoids directly to painful tissues.\n\nThe review noted that peripheral cannabinoid approaches could be particularly beneficial for conditions with prominent peripheral mechanisms, such as diabetic neuropathy and chemotherapy-induced neuropathy, where peripheral nerve damage drives pain.","whyItMatters":"The main barriers to cannabinoid pain medication are psychoactive effects and dependence potential. If cannabinoids can be restricted to peripheral nerves, these barriers could be eliminated while retaining pain-relieving activity.","specificNumbers":"23 states had legalized medical marijuana at the time; conditions highlighted: diabetic neuropathy, chemotherapy-induced neuropathy; strategies: blood-brain barrier exclusion, CB2 selectivity, local delivery","methodology":"Narrative review of scientific evidence for peripheral cannabinoid system targeting, examining available literature on strategies to achieve pain relief without CNS effects.","limitations":"Most peripheral cannabinoid approaches were in preclinical stages. Blood-brain barrier exclusion is difficult to achieve perfectly. Some pain conditions involve central sensitization that peripheral approaches alone may not address."},{"rthcId":"RTHC-01052","title":"Multiple sclerosis, cannabis, and cognition: A structural MRI study.","authors":"Romero, Kristoffer; Pavisian, Bennis; Staines, William R; Feinstein, Anthony","year":2015,"journal":"NeuroImage. Clinical, 8, 140-7","doi":"10.1016/j.nicl.2015.04.006","pmid":"26106538","tags":["cognition","neuroscience","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared 20 MS patients who smoked cannabis for symptom relief with 19 matched MS patients who did not. Both groups received cognitive testing and structural MRI brain scans.\n\nBoth groups showed correlations between reduced brain volume and cognitive impairment, but the cannabis group had more extensive deficits. Gray matter volume loss in the thalamus, basal ganglia, medial temporal, and medial prefrontal regions, plus white matter loss in the fornix, correlated with cognitive problems.\n\nCritically, the same amount of brain volume reduction was associated with more widespread cognitive impairment in cannabis users than non-users, suggesting cannabis amplifies the cognitive impact of MS-related brain damage.","whyItMatters":"Many MS patients use cannabis for symptom relief, but this study suggests it may worsen the cognitive decline that is already a major burden of the disease. The finding that cannabis amplifies the cognitive impact of brain atrophy is particularly concerning.","specificNumbers":"20 cannabis-using vs. 19 non-using MS patients; gray matter analysis: 33% variance, p<0.0001; white matter analysis: 17% variance, p<0.05; affected regions: thalamus, basal ganglia, medial temporal, prefrontal, fornix","methodology":"Cross-sectional study comparing 20 cannabis-using and 19 non-using MS patients matched on demographics. Structural MRI with Partial Least Squares multivariate analysis of brain-behavior associations. Cognitive assessment with the Brief Repeatable Neuropsychological Battery.","limitations":"Small sample sizes. Cross-sectional design cannot determine causation. Cannabis users may have had more severe MS leading to both more cannabis use and more cognitive decline. Did not control for cannabis dose or frequency."},{"rthcId":"RTHC-01053","title":"Inhaled medicinal cannabis and the immunocompromised patient.","authors":"Ruchlemer, Rosa; Amit-Kohn, Michal; Raveh, David; Hanuš, Lumír","year":2015,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 23(3), 819-22","doi":"10.1007/s00520-014-2429-3","pmid":"25216851","tags":["medical-cannabis","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers addressed a practical safety concern: medical cannabis carries bacteria and fungi on its leaves and flowers that could cause life-threatening infections in immunocompromised patients (such as those undergoing chemotherapy).\n\nThey cultured cannabis herb to identify contaminants, tested three sterilization methods, and measured how much cannabinoid activity was lost in each process. The goal was to find the optimal balance between eliminating microbial risk and preserving therapeutic potency.\n\nThe study demonstrated that systematic sterilization could eliminate the risk of opportunistic lung infections, particularly from inhaled mold spores, while maintaining clinically useful cannabinoid levels.","whyItMatters":"Cancer patients and others with compromised immune systems are among those most likely to benefit from medical cannabis for pain, nausea, and appetite. Without sterilization, inhaled cannabis could introduce deadly fungal infections.","specificNumbers":"Three sterilization methods compared; cannabinoid activity loss measured for each; primary risk: mold-related opportunistic lung infections; patient populations at risk: cancer patients, transplant recipients, HIV/AIDS patients","methodology":"Laboratory study culturing cannabis herb for microbial contamination, testing three sterilization methods, and measuring cannabinoid compound activity loss after each treatment.","limitations":"Small-scale laboratory study. Did not test the sterilization methods in a clinical setting. Specific cannabinoid compounds measured were limited. May not address all contaminants (pesticides, heavy metals)."},{"rthcId":"RTHC-01054","title":"Cannabinoid hyperemesis syndrome: an important differential diagnosis of persistent unexplained vomiting.","authors":"Ruffle, James K; Bajgoric, Sanjin; Samra, Kiran; Chandrapalan, Subashini; Aziz, Qasim; Farmer, Adam D","year":2015,"journal":"European journal of gastroenterology & hepatology, 27(12), 1403-8","doi":"10.1097/MEG.0000000000000489","pmid":"26445382","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Researchers identified 10 cases of cannabinoid hyperemesis syndrome (CHS) at gastroenterology clinics over two years. All had been previously misdiagnosed with various conditions.\n\nPatients experienced symptoms for a mean of 19.3 months before correct diagnosis. The median duration of cannabis use before symptoms began was 42 months. Eight of 10 patients (80%) had the classic compulsive hot water bathing behavior.\n\nDuring follow-up, three patients who returned to regular cannabis use experienced symptom recurrence, while those who maintained abstinence remained symptom-free. The authors emphasized that CHS is frequently missed because clinicians do not routinely ask about cannabis use in vomiting patients.","whyItMatters":"Nearly 20 months of unnecessary suffering and likely expensive diagnostic testing could be avoided by simply asking vomiting patients about cannabis use. CHS remains widely underdiagnosed despite increasing cannabis use.","specificNumbers":"10 cases; 5 men; mean age 27; symptom duration before diagnosis: 19.3 months; median cannabis use: 42 months; 80% had compulsive hot bathing; 3 relapsed with resumed cannabis use","methodology":"Retrospective cohort study of patients attending tertiary neurogastroenterology and secondary gastroenterology clinics from 2013-2015. Chart review of 10 identified CHS cases.","limitations":"Small retrospective case series from two clinics. Cannot establish prevalence. Patients seen at gastroenterology referral centers may represent more severe or diagnostic cases."},{"rthcId":"RTHC-01055","title":"The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers.","authors":"Rzepa, Ewelina; Tudge, Luke; McCabe, Ciara","year":2015,"journal":"The international journal of neuropsychopharmacology, 19(2)","doi":"10.1093/ijnp/pyv092","pmid":"26362774","tags":["neuroscience","appetite"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Researchers gave 20 healthy volunteers a single 10mg oral dose of THCV or placebo in a randomized crossover design, then scanned their brains with resting-state fMRI.\n\nTHCV produced no subjective effects (no feeling of being high), as expected for a CB1 neutral antagonist. However, it significantly altered brain network connectivity: reducing connections between the amygdala and the default mode network while increasing connections between the amygdala and the dorsal anterior cingulate cortex (part of the executive control network).\n\nUnder placebo, amygdala-precuneus connectivity correlated positively with body mass index. This correlation disappeared under THCV, suggesting the drug may normalize an obesity-related brain connectivity pattern.","whyItMatters":"The CB1 inverse agonist rimonabant was effective for obesity but caused depression. THCV is a neutral antagonist, meaning it blocks the receptor without the inverse agonist activity that may cause psychiatric side effects. This study suggests THCV affects brain networks relevant to obesity without mood changes.","specificNumbers":"20 volunteers; 10mg oral THCV; no subjective effects; reduced default mode network connectivity; increased cognitive control network connectivity; BMI correlation with amygdala-precuneus connectivity eliminated under THCV","methodology":"Randomized, within-subject, double-blind, placebo-controlled study. 20 healthy volunteers received 10mg oral THCV or placebo. Resting-state fMRI with seed-based connectivity analyses. Regions of interest: amygdala, insula, orbitofrontal cortex, dorsal medial prefrontal cortex.","limitations":"Very small sample (n=20). Single dose only. Healthy volunteers, not obese individuals. No measurement of food intake or weight. Resting-state connectivity changes do not prove clinical efficacy."},{"rthcId":"RTHC-01056","title":"Stimulants and Cannabis Use Among a Marginalized Population in British Columbia, Canada: Role of Trauma and Incarceration.","authors":"Saddichha, Sahoo; Werker, Gregory R; Schuetz, Christian; Krausz, Michael R","year":2015,"journal":"International journal of offender therapy and comparative criminology, 59(13), 1487-98","doi":"10.1177/0306624X14541661","pmid":"25028364","tags":["mental-health","addiction","psychosis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared cannabis and stimulant use patterns among a homeless population in British Columbia, finding distinct profiles for each substance.\n\nCannabis users had notably higher rates of lifetime psychotic disorders (32%). Among incarcerated cannabis users, there was greater childhood emotional neglect, and one in two had lifetime depressive disorders. Stimulant users were more likely to be female (43%), use multiple substances (average 3.2), and engage in survival sex (14%).\n\nChildhood physical abuse and Caucasian ethnicity were associated with greater crack cocaine use. The findings suggest a developmental cascade where childhood abuse leads to depression and psychopathology, increasing cannabis dependence risk and potentially contributing to psychosis development.","whyItMatters":"Understanding different trauma and mental health profiles associated with different substances can inform targeted interventions for homeless populations, rather than treating all substance use the same way.","specificNumbers":"32% of cannabis users had lifetime psychotic disorders; stimulant users: 43% female, 3.2 average substances, 14% survival sex; 50% of incarcerated cannabis users had depressive disorders; childhood emotional neglect linked to cannabis use","methodology":"Cross-sectional analysis from the BC Health of the Homeless Study, conducted in three British Columbia cities. Used the Maudsley Addiction Profile, Childhood Trauma Questionnaire, and MINI Plus psychiatric interview.","limitations":"Cross-sectional design cannot determine causal directions. Homeless populations have unique characteristics limiting generalizability. Self-reported trauma and substance use. Cannot separate pre-existing psychiatric vulnerability from substance effects."},{"rthcId":"RTHC-01057","title":"\"Disease modifying nutricals\" for multiple sclerosis.","authors":"Schmitz, Katja; Barthelmes, Julia; Stolz, Leonie; Beyer, Susanne; Diehl, Olaf; Tegeder, Irmgard","year":2015,"journal":"Pharmacology & therapeutics, 148, 85-113","doi":"10.1016/j.pharmthera.2014.11.015","pmid":"25435020","tags":["medical-cannabis","inflammation","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This extensive review examined nutritional and natural compounds as potential disease-modifying agents for multiple sclerosis. Among many compounds reviewed (vitamin D, fatty acids, probiotics, green tea, curcumin), cannabis constituents stood out for their dual role.\n\nCannabis compounds and \"endocannabinoid-enhancing\" nutraceuticals like FAAH inhibitors could provide both symptom relief (spasticity, pain) and disease modification through anti-inflammatory, immune-modifying, and antioxidant mechanisms. Many also inhibit pro-inflammatory NF-kB signaling and stabilize the blood-brain barrier.\n\nThe review concluded that while nutraceuticals alone would not solve MS therapeutic challenges, they could support pharmacological interventions or reveal novel drug structures.","whyItMatters":"MS patients increasingly seek complementary approaches. This review provides an evidence-based assessment of which natural compounds, including cannabis-derived ones, have biological plausibility for disease modification rather than just symptom relief.","specificNumbers":"Compounds reviewed: vitamin D, fatty acids, probiotics, cannabis constituents, green tea (EGCG), curcumin, sulforaphane, FAAH inhibitors; mechanisms: NF-kB inhibition, TLR modulation, blood-brain barrier stabilization","methodology":"Comprehensive review of nutritional and natural compounds with potential disease-modifying activity in MS, including evidence from experimental autoimmune encephalomyelitis models and clinical studies.","limitations":"Review covers many compounds with widely varying evidence levels. Most evidence from animal models. Nutraceutical dosing, bioavailability, and quality control are poorly standardized. Interactions with MS medications not well studied."},{"rthcId":"RTHC-01058","title":"Endocannabinoid regulation in human endometrium across the menstrual cycle.","authors":"Scotchie, Jessica G; Savaris, Ricardo F; Martin, Caitlin E; Young, Steven L","year":2015,"journal":"Reproductive sciences (Thousand Oaks, Calif.), 22(1), 113-23","doi":"10.1177/1933719114533730","pmid":"24819878","tags":["pregnancy","neuroscience","sex-differences"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers mapped endocannabinoid system components in the uterine lining of 49 regularly cycling women. They measured both synthetic enzymes (that produce endocannabinoids) and degrading enzymes (that break them down) across the menstrual cycle.\n\nDuring the secretory phase (when implantation occurs), the synthetic enzyme NAPE-PLD increased in multiple cell types, while degrading enzymes FAAH and MAGL also increased in glandular tissue. The net effect of simultaneously increasing both production and degradation suggests a tightly controlled endocannabinoid environment during implantation.\n\nCOX-2, which oxidizes endocannabinoids, showed maximum expression during the proliferative phase and peaked in luminal cells during early secretory phase.","whyItMatters":"The endocannabinoid system appears to play a critical role in preparing the uterine lining for embryo implantation. Cannabis use during the implantation window could disrupt this precisely timed system, with implications for fertility.","specificNumbers":"49 women; NAPE-PLD increased in luminal (p=0.001), stromal (p=0.007), glandular (p=0.04) cells during secretory phase; FAAH increased in glandular (p=0.009) and luminal (p=0.01) cells; COX-2 peaked in proliferative phase (p=0.002)","methodology":"Observational study of endometrial biopsies from 49 regularly cycling women. Protein localization by immunohistochemistry and mRNA expression by real-time RT-PCR across menstrual cycle phases.","limitations":"Measured enzyme expression rather than actual endocannabinoid levels. Did not study women using cannabis. Cross-sectional cycle phase comparisons rather than within-subject longitudinal tracking. The functional impact of these expression changes on implantation was not tested."},{"rthcId":"RTHC-01059","title":"Psychotic experiences are linked to cannabis use in adolescents in the community because of common underlying environmental risk factors.","authors":"Shakoor, Sania; Zavos, Helena M S; McGuire, Philip; Cardno, Alastair G; Freeman, Daniel; Ronald, Angelica","year":2015,"journal":"Psychiatry research, 227(2-3), 144-51","doi":"10.1016/j.psychres.2015.03.041","pmid":"25912376","tags":["psychosis","genetics","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used data from 4,830 twin pairs (aged 16) to determine whether the cannabis-psychosis association is driven by genetics, shared environment, or unique environment.\n\nCannabis use was modestly heritable (37%) with strong shared environmental influence (55%). Psychotic experiences had variable heritability (27-54%) depending on the specific symptom type.\n\nThe key finding: environmental influences explained virtually all of the covariation between cannabis use and paranoia, cognitive disorganization, and negative symptoms (69-100% from shared environment). Only the relationship between cannabis and hallucinations showed some familial (possibly genetic) influence.\n\nCannabis use explained only 2-5% of the total variance in psychotic experiences, suggesting the effect, while real, is modest.","whyItMatters":"If cannabis and psychotic experiences co-occur primarily because of shared environments (rather than shared genes), this suggests that modifying environmental factors (neighborhood, peer groups, family context) could reduce both cannabis use and psychotic risk simultaneously.","specificNumbers":"4,830 twin pairs; cannabis heritability 37%; shared environment 55%; cannabis explains 2-5% of variance in psychotic experiences; 69-100% of covariation due to shared environment","methodology":"Twin study of 4,830 16-year-old pairs using structural equation modeling. Self-reported and parent-reported psychotic experiences. Self-reported cannabis use. Multivariate liability threshold models estimated genetic and environmental contributions to covariation.","limitations":"Cross-sectional design in 16-year-olds. Twin modeling assumptions may not perfectly hold. Self-reported cannabis use at 16 may underestimate true use. Cannot identify which specific environmental factors drive the association."},{"rthcId":"RTHC-01060","title":"Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.","authors":"Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk","year":2015,"journal":"Journal of molecular neuroscience : MN, 56(4), 926-931","doi":"10.1007/s12031-015-0545-2","pmid":"25820672","tags":["neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested how five different cannabinoids affect the energy-producing machinery (electron transport chain) inside brain cell mitochondria.\n\nAll five compounds, whether receptor agonists (THC, anandamide, WIN55,212-2), an antagonist (AM251), or CBD, inhibited complexes II/III and IV of the mitochondrial respiratory chain at micromolar concentrations. This common effect occurred regardless of whether the compound activated or blocked cannabinoid receptors, indicating a non-receptor mechanism.\n\nAnandamide uniquely stimulated complex I activity, which may explain some of the distinct physiological effects of this endocannabinoid compared to plant-derived or synthetic cannabinoids. THC and AM251 also decreased citrate synthase activity.","whyItMatters":"Mitochondria produce the energy cells need to function. The finding that cannabinoids directly impair mitochondrial energy production, independent of receptor activation, reveals a fundamental cellular mechanism that could explain some cognitive and neural effects of cannabis.","specificNumbers":"Five cannabinoids tested: THC, anandamide, WIN55,212-2, AM251, CBD; all inhibited complexes II/III and IV; anandamide stimulated complex I; THC and AM251 decreased citrate synthase","methodology":"In vitro study measuring individual mitochondrial respiratory chain complex (I, II/III, IV) and citrate synthase activities in crude mitochondrial fractions from pig brain after exposure to five cannabinoids.","limitations":"In vitro study using isolated mitochondria. Concentrations used (micromolar) may not reflect brain concentrations during typical cannabis use. Pig brain tissue may not perfectly represent human mitochondria. Acute exposure only."},{"rthcId":"RTHC-01061","title":"Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy.","authors":"Smith, Lesley A; Azariah, Fredric; Lavender, Verna T C; Stoner, Nicola S; Bettiol, Silvana","year":2015,"journal":"The Cochrane database of systematic reviews, 2015(11), CD009464","doi":"10.1002/14651858.CD009464.pub2","pmid":"26561338","tags":["medical-cannabis","cancer"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This Cochrane systematic review analyzed 23 randomized controlled trials of cannabis-based medications for chemotherapy-induced nausea and vomiting, all conducted between 1975 and 1991.\n\nCompared to placebo, cannabinoids significantly increased complete absence of vomiting (RR 5.7) and complete absence of nausea and vomiting (RR 2.9). Patients preferred cannabinoids over placebo (RR 4.8).\n\nCompared to the older anti-emetic prochlorperazine, cannabinoids were not significantly different for nausea or vomiting control, but caused more dizziness (RR 2.4), euphoria (RR 18), feeling high (RR 6.2), and sedation (RR 1.4). Despite more side effects, patients preferred cannabinoids over prochlorperazine (RR 3.3).\n\nNo trials compared cannabinoids with modern anti-emetics like ondansetron.","whyItMatters":"This is the most rigorous review of cannabinoids for chemotherapy nausea, but it highlights a major limitation: all trials used old chemotherapy and anti-emetic regimens. How cannabinoids compare to modern treatments remains unknown.","specificNumbers":"23 RCTs; vs. placebo: RR 5.7 for no vomiting, RR 2.9 for no nausea/vomiting; vs. prochlorperazine: similar efficacy but RR 2.4 for dizziness, RR 18 for euphoria, RR 6.2 for feeling high; patient preference: RR 3.3 vs. prochlorperazine","methodology":"Cochrane systematic review and meta-analysis of 23 RCTs. Searched CENTRAL, MEDLINE, EMBASE, PsycINFO, and LILACS through January 2015. Random effects meta-analysis with risk ratios.","limitations":"All trials from 1975-1991. No comparison with ondansetron or other modern anti-emetics. Most trials at risk of bias. Low to moderate quality evidence. Do not reflect current chemotherapy regimens."},{"rthcId":"RTHC-01062","title":"Cannabis-related episodic memory deficits and hippocampal morphological differences in healthy individuals and schizophrenia subjects.","authors":"Smith, Matthew J; Cobia, Derin J; Reilly, James L; Gilman, Jodi M; Roberts, Andrea G; Alpert, Kathryn I; Wang, Lei; Breiter, Hans C; Csernansky, John G","year":2015,"journal":"Hippocampus, 25(9), 1042-51","doi":"10.1002/hipo.22427","pmid":"25760303","tags":["cognition","neuroscience","psychosis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared hippocampal shape in four groups: healthy controls (n=44), healthy controls with past cannabis use disorder (n=10), schizophrenia without substance history (n=28), and schizophrenia with past cannabis use disorder (n=15).\n\nBoth cannabis-using groups showed distinct hippocampal shape differences from their respective non-using counterparts, but the patterns differed. In healthy cannabis users, shape changes correlated with poorer episodic memory performance. In schizophrenia cannabis users, shape changes correlated with longer duration of cannabis use and shorter duration of remission.\n\nThis suggests cannabis-related hippocampal changes have different functional consequences depending on whether someone has schizophrenia.","whyItMatters":"The hippocampus is central to memory formation and is affected by both cannabis and schizophrenia. Finding that cannabis-related hippocampal changes differ between healthy and schizophrenia populations suggests the underlying neurobiology differs.","specificNumbers":"44 healthy controls; 10 healthy with past CUD; 28 schizophrenia without substance use; 15 schizophrenia with past CUD; distinct hippocampal shape patterns in each cannabis-using group","methodology":"Cross-sectional MRI study with four demographically matched groups. Large-deformation, high-dimensional brain mapping produced surface-based hippocampal representations. Correlated morphological differences with episodic memory and cannabis use history.","limitations":"Small groups (especially n=10 for healthy cannabis users). Past, not current, cannabis use studied. Cross-sectional design cannot determine whether hippocampal differences preceded or followed cannabis use. Shape changes do not reveal cellular mechanisms."},{"rthcId":"RTHC-01063","title":"Cannabis use in early adolescence: Evidence of amygdala hypersensitivity to signals of threat.","authors":"Spechler, Philip A; Orr, Catherine A; Chaarani, Bader; Kan, Kees-Jan; Mackey, Scott; Morton, Aaron; Snowe, Mitchell P; Hudson, Kelsey E; Althoff, Robert R; Higgins, Stephen T; Cattrell, Anna; Flor, Herta; Nees, Frauke; Banaschewski, Tobias; Bokde, Arun L W; Whelan, Robert; Büchel, Christian; Bromberg, Uli; Conrod, Patricia; Frouin, Vincent; Papadopoulos, Dimitri; Gallinat, Jurgen; Heinz, Andreas; Walter, Henrik; Ittermann, Bernd; Gowland, Penny; Paus, Tomáš; Poustka, Luise; Martinot, Jean-Luc; Artiges, Eric; Smolka, Michael N; Schumann, Gunter; Garavan, Hugh","year":2015,"journal":"Developmental cognitive neuroscience, 16, 63-70","doi":"10.1016/j.dcn.2015.08.007","pmid":"26347227","tags":["youth","neuroscience","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used fMRI to compare 70 fourteen-year-olds with cannabis use history to 70 carefully matched never-using controls while they watched short videos of angry and neutral faces.\n\nCannabis users showed significantly greater bilateral amygdala reactivity to angry faces compared to neutral faces. This heightened threat response was not seen in abstinent peers. In contrast, cortical regions that normally help regulate threat responses (right temporal-parietal junction, bilateral dorsolateral prefrontal cortex) failed to distinguish between angry and neutral faces in cannabis users, but did so in controls.\n\nThe results held even after excluding subjects with any psychiatric symptoms, suggesting the neural differences were specifically related to cannabis exposure, not pre-existing mental health conditions.","whyItMatters":"The amygdala has a high density of cannabinoid receptors, making it particularly sensitive to cannabis exposure. Heightened threat sensitivity during adolescence could increase vulnerability to anxiety and mood disorders later in life.","specificNumbers":"70 users vs. 70 controls; age 14; greater bilateral amygdala reactivity to angry faces in users; no cortical discrimination between angry/neutral in users; results unchanged after excluding psychiatric symptoms","methodology":"Cross-sectional fMRI study from the IMAGEN consortium. 70 cannabis-using and 70 matched control 14-year-olds. Groups matched on IQ, socioeconomic status, alcohol, and cigarette use. Affective face processing task with angry and neutral face videos.","limitations":"Cross-sectional design cannot determine whether neural differences preceded or resulted from cannabis use. Any cannabis use was included (no dose-response analysis). Despite careful matching, unmeasured confounders may exist."},{"rthcId":"RTHC-01064","title":"Marijuana for Glaucoma: A Recipe for Disaster or Treatment?","authors":"Sun, Xiaoshen; Xu, Chaoying S; Chadha, Nisha; Chen, Allshine; Liu, Ji","year":2015,"journal":"The Yale journal of biology and medicine, 88(3), 265-9","doi":null,"pmid":"26339209","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined whether marijuana or cannabinoid-based drugs could treat glaucoma. While marijuana does lower intraocular pressure (IOP), the effect only lasts 3-4 hours, meaning patients would need to use it 6-8 times daily to maintain pressure reduction.\n\nSuch frequent use would produce significant adverse effects including cognitive impairment, psychomotor slowing, and potential progression toward cannabis use disorder with withdrawal symptoms upon cessation.\n\nThe review concluded that the deleterious effects of marijuana outweigh the benefits of its IOP-lowering capacity in most glaucoma patients. Only under extremely rare circumstances might a few categories of patients be candidates. The authors called for research into focused cannabinoid delivery directly to the eye.","whyItMatters":"Glaucoma is one of the most commonly cited reasons for medical marijuana use, but this review demonstrates that the pharmacokinetics make it impractical as a glaucoma treatment and highlights the need for targeted eye-specific delivery.","specificNumbers":"IOP-lowering effect lasts 3-4 hours; would require 6-8 daily doses; adverse effects include cognitive impairment, psychomotor effects, CUD risk, and withdrawal symptoms","methodology":"Narrative review of published evidence on marijuana and cannabinoids for glaucoma treatment, examining efficacy, duration of action, and adverse effects.","limitations":"Narrative review. Did not systematically assess all available evidence. Focused primarily on smoked and oral marijuana rather than novel delivery methods. The \"extremely rare\" candidates for marijuana-based glaucoma treatment were not well defined."},{"rthcId":"RTHC-01065","title":"Lipopolysaccharide suppresses carboxylesterase 2g activity and 2-arachidonoylglycerol hydrolysis: A possible mechanism to regulate inflammation.","authors":"Szafran, Brittany; Borazjani, Abdolsamad; Lee, Jung Hwa; Ross, Matthew K; Kaplan, Barbara L F","year":2015,"journal":"Prostaglandins & other lipid mediators, 121(Pt B), 199-206","doi":"10.1016/j.prostaglandins.2015.09.005","pmid":"26403860","tags":["inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers hypothesized that inflammation would reduce the activity of enzymes that break down endocannabinoids, thereby boosting anti-inflammatory endocannabinoid levels. They injected mice with the bacterial toxin LPS and measured enzyme activities in brain, liver, and spleen.\n\nBrain and liver enzymes were largely unchanged, but spleen (a key immune organ) showed a modest decrease in carboxylesterase activity and reduced 2-AG hydrolysis at 6 hours post-LPS. This was confirmed in isolated spleen cells treated with LPS.\n\nProteomic analysis identified carboxylesterase 2g (Ces2g) as the enzyme specifically reduced by inflammation. By decreasing 2-AG breakdown in the spleen, the body may be boosting endocannabinoid signaling through CB2 receptors as a self-limiting mechanism on inflammation.","whyItMatters":"This study reveals a natural feedback mechanism: inflammation itself triggers the body to reduce endocannabinoid breakdown, potentially as a self-limiting control. This has implications for understanding why cannabis and endocannabinoids modulate immune responses.","specificNumbers":"LPS injection caused decreased Ces activity in spleen; decreased 2-AG hydrolysis at 6 hours; brain and liver enzymes unchanged; Ces2g identified as the specific enzyme suppressed","methodology":"Mouse study using LPS injection to induce inflammation. Activity-based protein profiling (ABPP) of serine hydrolases in brain, liver, and spleen at 6 and 24 hours. 2-AG hydrolase activity assays. ABPP-MudPIT proteomic analysis. Ex vivo splenocyte confirmation.","limitations":"Mouse study with acute LPS model that may not reflect chronic inflammation. The decrease in Ces activity was described as \"modest.\" The functional significance of Ces2g-mediated 2-AG hydrolysis relative to MAGL is unclear."},{"rthcId":"RTHC-01066","title":"Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist.","authors":"Tai, Sherrica; Nikas, Spyros P; Shukla, Vidyanand G; Vemuri, Kiran; Makriyannis, Alexandros; Järbe, Torbjörn U C","year":2015,"journal":"Psychopharmacology, 232(15), 2751-61","doi":"10.1007/s00213-015-3907-0","pmid":"25772338","tags":["withdrawal","neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers developed a mouse model of cannabinoid dependence using the potent, long-acting cannabinoid AM2389 and compared withdrawal precipitated by three different antagonists.\n\nBoth rimonabant (inverse agonist) and AM4113 (neutral antagonist) precipitated withdrawal signs, while AM6545 (a peripherally restricted antagonist that does not enter the brain) did not. This demonstrated two key points: withdrawal is centrally mediated (brain-based), and the inverse agonist properties of rimonabant are not responsible for withdrawal.\n\nWithdrawal was caused by rapid competition for CB1 receptor binding, meaning the antagonist quickly displaces the agonist from the receptor. This was confirmed when reinstating AM2389 or THC reversed withdrawal symptoms.","whyItMatters":"Understanding that cannabinoid withdrawal is caused by receptor competition rather than inverse agonism has implications for developing cannabis addiction treatments. Neutral antagonists may be therapeutically useful without the additional risks of inverse agonists.","specificNumbers":"AM2389 more potent and longer-acting than THC; both rimonabant and AM4113 precipitated withdrawal; AM6545 (peripheral only) did not; withdrawal reversed by AM2389 or THC reinstatement","methodology":"Mouse study using AM2389 for dependence induction. Acute characterization with tetrad tests. Tolerance measured after repeated dosing. Withdrawal precipitated by three antagonists with different pharmacological properties. Reversal tested with AM2389 and THC.","limitations":"Mouse model may not fully replicate human cannabinoid dependence. Used a very potent synthetic cannabinoid (AM2389) rather than THC for dependence induction. The psychiatric side effects of rimonabant may involve mechanisms beyond withdrawal precipitation."},{"rthcId":"RTHC-01067","title":"Interactions between ethanol and the endocannabinoid system at GABAergic synapses on basolateral amygdala principal neurons.","authors":"Talani, Giuseppe; Lovinger, David M","year":2015,"journal":"Alcohol (Fayetteville, N.Y.), 49(8), 781-94","doi":"10.1016/j.alcohol.2015.08.006","pmid":"26603632","tags":["neuroscience","addiction","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers examined how alcohol and the endocannabinoid system interact at inhibitory synapses in the basolateral amygdala (BLA), a brain region involved in processing emotional responses and drug dependence.\n\nAlcohol at intoxication-relevant concentrations increased the frequency of inhibitory signals, suggesting it acts directly on nerve terminals to boost GABA release. Activating CB1 cannabinoid receptors suppressed this signaling and blocked alcohol's boosting effect.\n\nSurprisingly, blocking CB1 receptors also prevented alcohol from enhancing inhibitory transmission. Meanwhile, alcohol blocked two forms of endocannabinoid-mediated suppression of inhibitory signaling. The findings point to a two-way antagonism: each system interferes with the other.","whyItMatters":"The amygdala plays a central role in emotional learning, anxiety, and addiction. Understanding how alcohol and cannabinoids interact in this region could help explain why co-use of these substances produces complex behavioral effects and may inform future research on treating alcohol use disorders.","specificNumbers":"Ethanol increased spontaneous inhibitory current frequency in both young and adult animals. CB1 activation inhibited GABAergic transmission and prevented ethanol potentiation. Ethanol blocked depolarization-induced suppression of inhibition (DSI), a well-established endocannabinoid-mediated effect.","methodology":"The study used electrophysiology recordings from brain slices of young and adult rats to measure inhibitory postsynaptic currents in BLA neurons. Researchers applied ethanol, CB1 agonists, CB1 antagonists, and various pharmacological tools to dissect the interaction between alcohol and endocannabinoid signaling at GABAergic synapses.","limitations":"This was an in-vitro study using rat brain slices, which does not capture the full complexity of intact brain circuits or human neurobiology. The concentrations of ethanol used were chosen to model intoxication, but may not perfectly replicate real-world exposure patterns."},{"rthcId":"RTHC-01068","title":"How beneficial is vaping cannabis to respiratory health compared to smoking?","authors":"Tashkin, Donald P","year":2015,"journal":"Addiction (Abingdon, England), 110(11), 1706-7","doi":"10.1111/add.13075","pmid":"26471152","tags":["respiratory","harm-reduction","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This commentary examined whether vaporizing cannabis provides meaningful respiratory health advantages over smoking it. The author noted that while vaping does reduce exposure to toxic particulates found in cannabis smoke, the clinical benefit to lung health is likely smaller than the advantage of switching from tobacco cigarettes to e-cigarettes.\n\nThe reasoning: smoked tobacco causes substantially more lung damage than smoked cannabis, so the room for improvement by switching to a vaporized form is comparatively greater for tobacco users than for cannabis users.","whyItMatters":"Many cannabis users choose vaping specifically to protect their lungs. This perspective suggests the respiratory benefit, while real, may be more modest than commonly assumed, particularly when compared to the well-documented benefits of switching from smoked tobacco to e-cigarettes.","specificNumbers":"No new quantitative data were presented. The commentary synthesized existing knowledge about comparative harms of smoked cannabis versus smoked tobacco.","methodology":"This was a published commentary in the journal Addiction by a pulmonary medicine researcher with expertise in cannabis and lung health. It drew on existing evidence about cannabis smoke toxicology and comparative respiratory harms.","limitations":"This was a brief commentary, not a systematic review or original study. It did not present new data and relied on the author's interpretation of existing evidence. Long-term comparative data on vaping versus smoking cannabis remain limited."},{"rthcId":"RTHC-01069","title":"Prevalence of Marijuana-Related Traffic on Twitter, 2012-2013: A Content Analysis.","authors":"Thompson, Leah; Rivara, Frederick P; Whitehill, Jennifer M","year":2015,"journal":"Cyberpsychology, behavior and social networking, 18(6), 311-9","doi":"10.1089/cyber.2014.0620","pmid":"26075917","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers analyzed a random sample of marijuana-related tweets from two periods: six months before and six months after the November 2012 U.S. election that legalized recreational cannabis in Colorado and Washington.\n\nAmong adolescent users, 65.6% of original tweets reflected a positive attitude toward marijuana, and 42.9% indicated personal use. Of tweets that mentioned parents, 36% suggested parental support for the adolescent's marijuana use.\n\nBetween the pre- and post-election periods, tweets about personal marijuana use increased, as did positive perceptions about the drug.","whyItMatters":"Social media discussions can normalize substance use among young people. The finding that positive marijuana content increased after legalization raises questions about how policy changes shape public discourse and potentially influence adolescent attitudes toward cannabis.","specificNumbers":"71,901 total tweets collected. 36,969 original tweets analyzed. 1,928 tweets from self-identified adolescents. 65.6% of adolescent tweets showed positive attitudes toward marijuana. 42.9% indicated personal use. 36% of parent-mentioning tweets suggested parental approval.","methodology":"The study collected a 1% random sample of all tweets matching marijuana-related search terms during two three-week windows (before and after the 2012 election). After excluding non-relevant and foreign-language tweets, 36,969 original tweets were analyzed using a structured codebook. Self-reported age was extracted from tweet metadata when available.","limitations":"The study relied on self-reported age, which is unreliable on Twitter. Only a 1% sample of tweets was captured. Content analysis cannot determine actual marijuana use behavior. The study cannot establish whether the increase in positive tweets caused changes in attitudes or behavior."},{"rthcId":"RTHC-01070","title":"Balanced modulation of striatal activation from D2 /D3 receptors in caudate and ventral striatum: Disruption in cannabis abusers.","authors":"Tomasi, Dardo; Wang, Gene-Jack; Volkow, Nora D","year":2015,"journal":"Human brain mapping, 36(8), 3154-66","doi":"10.1002/hbm.22834","pmid":"26058801","tags":["dopamine","neuroscience","cognition","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers used both fMRI and PET imaging to examine how dopamine D2/D3 receptors in two parts of the striatum modulate brain activity during a reaction-time task.\n\nIn healthy controls, dopamine receptors in the caudate (dorsal striatum) and ventral striatum showed a balanced push-pull pattern: caudate receptors inhibited ventral striatum activity while ventral striatum receptors facilitated it. This balance appeared linked to timely motor responses.\n\nIn cannabis users, this balanced modulation was absent. The disruption suggests that heavy cannabis use may alter the coordination between dorsal and ventral striatal circuits involved in reward processing and action timing.","whyItMatters":"The balance between dorsal and ventral striatal signaling is thought to be important for controlling impulsive behavior and timing actions appropriately. Disruption of this balance in cannabis users could help explain cognitive and motivational changes associated with heavy use.","specificNumbers":"14 healthy controls and 18 cannabis users were compared. The balanced D2/D3 receptor modulation between caudate and ventral striatum seen in controls was not statistically significant in cannabis users.","methodology":"The study combined fMRI during a sensorimotor reaction time task with PET scanning using [11C]raclopride to measure dopamine D2/D3 receptor availability. Participants included 14 healthy controls and 18 cannabis users (described as \"cannabis abusers\").","limitations":"The small sample size (32 total participants) limits statistical power. The cross-sectional design cannot determine whether the dopamine receptor disruption existed before cannabis use began or developed as a consequence. The study used the term \"cannabis abusers\" without detailing specific use patterns."},{"rthcId":"RTHC-01071","title":"Roadside drug testing: comparison of two legal approaches in Belgium.","authors":"Van der Linden, T; Wille, S M R; Ramírez-Fernandez, M; Verstraete, A G; Samyn, N","year":2015,"journal":"Forensic science international, 249, 148-55","doi":"10.1016/j.forsciint.2015.01.034","pmid":"25700110","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Belgium changed its roadside drug testing protocol in 2010, moving from urine-based screening to oral fluid-based screening. Researchers compared the results from both periods across roughly 8,000 drivers tested.\n\nUnder the old urine system, 88% of cannabis-positive screens were confirmed by blood testing. Under the new oral fluid system, 66% of cannabis-positive screens were confirmed. However, the overall false positive rate (drivers who screened positive but had no confirmed drugs above legal limits in blood) dropped from 17% to 8%.\n\nThe newer oral fluid approach also shifted how police identified potential impairment, moving from requiring visible signs of impairment to looking for signs of recent drug use.","whyItMatters":"Accurate roadside drug testing is essential for road safety policy. This real-world comparison shows that switching to oral fluid testing reduced false positives, meaning fewer sober drivers were subjected to unnecessary blood draws while still identifying impaired drivers.","specificNumbers":"About 4,100 urine and 3,900 oral fluid datasets analyzed. Cannabis confirmation rates: 88% (urine) vs. 66% (oral fluid). Cocaine: 21% vs. 30%. Amphetamines: 20% vs. 28%. Overall false positive rate dropped from 17% to 8%.","methodology":"The study analyzed approximately 4,100 urine screening datasets (April 2008 to September 2010) and 3,900 oral fluid screening datasets (October 2010 to March 2013). All positive screens were confirmed against plasma drug concentrations using established legal cutoff values.","limitations":"The two periods used different screening criteria (signs of impairment versus signs of recent use), which makes direct comparison complex. Different testing matrices detect different windows of use. The legal cutoff values also changed between periods, which could affect confirmation rates independently of the screening method."},{"rthcId":"RTHC-01072","title":"Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice.","authors":"von Rüden, E L; Bogdanovic, R M; Wotjak, C T; Potschka, H","year":2015,"journal":"Neurobiology of disease, 77, 238-45","doi":"10.1016/j.nbd.2015.03.016","pmid":"25796567","tags":["epilepsy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether increasing levels of the brain's own cannabinoid 2-AG, by blocking the enzyme MAGL that normally breaks it down, could slow epilepsy development in mice.\n\nUsing JZL184, a MAGL inhibitor, they found it significantly delayed the progression from mild to generalized seizures in the kindling model of temporal lobe epilepsy. Seizure duration and afterdischarge duration were both reduced during the kindling process.\n\nHowever, once mice were fully kindled (seizures fully established), JZL184 had only modest effects. The anti-seizure effects disappeared in mice genetically engineered to lack CB1 receptors in forebrain neurons, confirming the drug worked through the cannabinoid system.","whyItMatters":"Most epilepsy drugs manage existing seizures but do not prevent epilepsy from developing. This study suggests that boosting endocannabinoid signaling could potentially slow or prevent epilepsy development, which would represent a fundamentally different treatment approach.","specificNumbers":"JZL184 at 8 mg/kg significantly delayed generalized seizure development (p=0.0066). Seizure duration was reduced (p<0.0001). Afterdischarge duration decreased (p<0.001). Effects were absent in CB1 receptor knockout mice.","methodology":"Mice received JZL184 (8 mg/kg) or vehicle before kindling stimulations. Researchers tracked seizure severity scores, seizure duration, and afterdischarge duration. Conditional CB1 receptor knockout mice were used to confirm mechanism. The kindling model progressively induces seizures through repeated electrical stimulation.","limitations":"The kindling model is one of several epilepsy models and may not fully represent human epilepsy. Results from mice do not directly translate to humans. The drug showed limited benefit once seizures were already established, and long-term effects were not studied."},{"rthcId":"RTHC-01073","title":"Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.","authors":"Walentiny, D Matthew; Vann, Robert E; Wiley, Jenny L","year":2015,"journal":"Neuropharmacology, 93, 237-42","doi":"10.1016/j.neuropharm.2015.02.004","pmid":"25698527","tags":["neuroscience","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers compared mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for breaking down anandamide, with normal mice in a drug discrimination test using THC.\n\nBoth groups learned to discriminate THC at similar rates and showed similar THC dose-response curves. However, anandamide fully substituted for THC only in FAAH knockout mice, not in normal mice. A metabolically stable anandamide analog worked in both groups but was more potent in knockouts.\n\nThe MAGL inhibitor JZL184, which boosts 2-AG levels, produced near-full THC-like effects in normal mice and full substitution in FAAH knockouts. Combined FAAH and MAGL inhibition produced similar effects in both groups.","whyItMatters":"Understanding how the endocannabinoid system's own signaling molecules produce THC-like effects informs research on both cannabis pharmacology and potential therapeutic approaches that target endocannabinoid metabolism rather than directly activating cannabinoid receptors.","specificNumbers":"THC training dose: 5.6 mg/kg. Anandamide fully substituted for THC in FAAH knockouts but not wildtypes. JZL184 produced near-full substitution in wildtypes and full substitution in knockouts. Brain anandamide was elevated in FAAH knockouts. JZL184 increased 2-AG levels equally in both genotypes.","methodology":"FAAH knockout and wildtype mice were trained to discriminate THC (5.6 mg/kg) from vehicle in a two-lever operant task. Various cannabinoid compounds were tested for substitution. Brain endocannabinoid levels were quantified. The CB1 antagonist rimonabant was used to confirm receptor involvement.","limitations":"Drug discrimination in mice does not directly translate to human subjective experiences. Genetically engineered mice may have developmental compensations that differ from pharmacological enzyme inhibition. The study examined acute effects and may not reflect chronic exposure patterns."},{"rthcId":"RTHC-01074","title":"Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure.","authors":"Watson, Corey T; Szutorisz, Henrietta; Garg, Paras; Martin, Qammarah; Landry, Joseph A; Sharp, Andrew J; Hurd, Yasmin L","year":2015,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 40(13), 2993-3005","doi":"10.1038/npp.2015.155","pmid":"26044905","tags":["genetics","youth","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers examined whether THC exposure during adolescence could produce epigenetic changes that pass to the next generation. They exposed adolescent rats to THC, then studied the brains of their adult offspring who were never exposed to the drug.\n\nUsing genome-wide DNA methylation profiling, they identified 1,027 differentially methylated regions (DMRs) in the nucleus accumbens, a brain region central to reward processing. These changes were found primarily in introns, exons, and intergenic regions rather than gene promoters.\n\nAmong the affected genes, researchers found a network involved in glutamatergic synapse regulation. These genes also showed altered mRNA expression, suggesting the methylation changes had functional consequences for brain signaling.","whyItMatters":"If adolescent drug exposure can alter gene regulation in offspring who were never themselves exposed, it adds a new dimension to understanding drug-related vulnerability across generations. The nucleus accumbens is critical for motivation and reward, making changes there particularly relevant to addiction risk.","specificNumbers":"1,027 differentially methylated regions identified. 16 animals per group. DMRs were predominantly in introns, exons, and intergenic intervals, with significant depletion in gene promoters. A network of glutamatergic synapse genes showed both altered methylation and changed mRNA expression.","methodology":"Adolescent Long-Evans rats were exposed to THC. Their unexposed F1 offspring (16 with parental THC exposure, 16 without) were studied as adults. Enhanced Reduced Representation Bisulfite Sequencing was used to profile DNA methylation across the genome in nucleus accumbens tissue. Gene expression was measured via mRNA analysis.","limitations":"This was an animal study, and epigenetic findings in rats do not directly translate to humans. The THC doses and exposure patterns may differ from typical human adolescent use. The study examined one brain region and one generation of offspring. Whether these epigenetic changes affect actual behavior in offspring was not fully characterized."},{"rthcId":"RTHC-01075","title":"Analysis of Cannabinoids and Their Metabolites in Human Urine.","authors":"Wei, Binnian; Wang, Lanqing; Blount, Benjamin C","year":2015,"journal":"Analytical chemistry, 87(20), 10183-7","doi":"10.1021/acs.analchem.5b02603","pmid":"26411292","tags":["harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers developed and validated a new method for detecting cannabinoids in urine using ultra-high performance liquid chromatography with tandem mass spectrometry. The method could detect THC, CBD, CBN, and two major THC metabolites.\n\nThe detection limits ranged from 0.002 to 0.008 nanograms per milliliter for unconjugated forms and 0.005 to 0.017 ng/mL for total measurements. These limits were approximately 10 to 100 times more sensitive than previously reported methods.\n\nThe same method could also handle high concentrations found in active users (up to 800 ng/mL), eliminating the need for separate tests for different exposure levels.","whyItMatters":"The ability to detect trace cannabinoid exposure is important for research on secondhand marijuana smoke exposure, workplace and legal testing contexts, and understanding passive exposure risks. A single method that handles both trace and high-level detection streamlines large-scale research.","specificNumbers":"Detection limits: 0.002-0.008 ng/mL (unconjugated), 0.005-0.017 ng/mL (total). These were 10-100x more sensitive than existing methods. High-concentration range: 12.5-800 ng/mL. Run time: 6 minutes. Accuracy: <10% bias. Precision: <10% imprecision.","methodology":"The method used positive electrospray ionization mode for ultra-sensitive detection and simultaneously monitored negative mode for high-concentration samples. Validation showed accuracy within 10% bias and precision within 10% imprecision, with a 6-minute run time. An automated liquid-handling system was used for sample preparation.","limitations":"The study validated the analytical method but did not conduct a large-scale population study. Detecting trace cannabinoids in urine does not indicate impairment. The clinical significance of trace-level exposure from secondhand smoke remains unclear."},{"rthcId":"RTHC-01076","title":"Patterns of cannabis use in patients with Inflammatory Bowel Disease: A population based analysis.","authors":"Weiss, Alexandra; Friedenberg, Frank","year":2015,"journal":"Drug and alcohol dependence, 156, 84-89","doi":"10.1016/j.drugalcdep.2015.08.035","pmid":"26422462","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using data from the NHANES national health survey, researchers compared cannabis use patterns between people with inflammatory bowel disease (IBD) and matched controls.\n\nPeople with IBD were more likely to have ever used cannabis (67.3% vs. 60.0%) and started at a younger average age (15.7 years vs. 19.6 years). When they did use, IBD patients tended to use heavier amounts per session: 64.9% reported three or more joints per day compared to 80.5% of non-IBD subjects using two or fewer.\n\nHowever, IBD patients were less likely to have used cannabis consistently every month for a year. In regression analysis, having IBD, being male, and being over 40 predicted cannabis use.","whyItMatters":"Cannabis use among IBD patients is common but poorly understood. These population-level data suggest that IBD patients may use cannabis differently than the general population, potentially as symptom management, and that older males with IBD are the most likely users.","specificNumbers":"Weighted populations: ~2.08 million IBD subjects, ~2.01 million controls. Ever used cannabis: 67.3% (IBD) vs. 60.0% (controls). Age of first use: 15.7 years (IBD) vs. 19.6 years (controls). 20% of IBD patients had a history of drug or alcohol use disorder.","methodology":"Cases were identified from the NHANES database (2009-2010) as having ulcerative colitis or Crohn's disease. They were matched with controls using propensity score matching based on age, gender, and sample weighting. After weighting, approximately 2 million subjects per group were represented.","limitations":"NHANES relies on self-reported data, which may undercount cannabis use. The cross-sectional design cannot determine whether IBD drives cannabis use or whether cannabis use affects IBD. The 2009-2010 data predate widespread legalization. The study could not assess whether cannabis use improved or worsened IBD outcomes."},{"rthcId":"RTHC-01077","title":"Cannabinoids for medical use: A systematic review and meta-analysis","authors":"Whiting, Penny F.; Wolff, Robert F.; Deshpande, Sohan; Di Nisio, Marcello; Duffy, Steven; Hernandez, Adrian V.; et al.","year":2015,"journal":"JAMA, 313(24), 2456-2473","doi":null,"pmid":"26103030","tags":["medical-cannabis","pain","harm-reduction","appetite"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Across 79 RCTs, cannabinoids were linked to better symptom outcomes than placebo for several indications, but effects were often small and not consistently statistically significant across trials. The clearest pooled benefit was for complete chemotherapy-related nausea and vomiting response (47% vs 20%, OR 3.82), while chronic pain and spasticity showed smaller average improvements on common rating scales. Cannabinoids were also associated with a higher risk of short-term adverse events, including serious adverse events.","whyItMatters":"In 2015, medical cannabis policy and prescribing debates were moving faster than the clinical trial evidence for specific conditions and outcomes. This review tried to answer a basic but disputed question: for which indications do cannabinoids outperform placebo in RCTs, and what harms show up in the same trials. It also set a quality benchmark by applying the Cochrane risk of bias tool and showing how much of the evidence base depended on trials that did not meet low-bias standards.","specificNumbers":"• Chemotherapy nausea and vomiting: 47% complete response with cannabinoids vs 20% with placebo (OR (odds ratio) 3.82, 95% CI: 1.55-9.42; 3 trials). This is a large relative difference, but it comes from only 3 trials so precision is limited.\n• Pain responder outcome: 37% with cannabinoids vs 31% with placebo (OR 1.41, 95% CI: 0.99-2.00; 8 trials). This is a modest effect, and the CI includes values near no difference.\n• Pain intensity on a 0-10 scale: WMD (weighted mean difference) -0.46 (95% CI: -0.80 to -0.11; 6 trials). A change under 1 point on a 10-point scale is small and many people would not notice it.\n• Spasticity (Ashworth scale): WMD -0.36 (95% CI: -0.69 to -0.05; 7 trials). This is a small average change, even though the CI excludes zero.","methodology":"This was a systematic review and random-effects meta-analysis, meaning the authors searched broadly for RCTs and then statistically combined results when studies measured similar outcomes. They searched 28 databases from inception to April 2015 and included RCTs of cannabinoids for a defined list of conditions, including chemotherapy nausea and vomiting, HIV/AIDS appetite and weight outcomes, chronic pain, and multiple sclerosis-related spasticity. Two reviewers independently handled each stage, and trial quality was rated with the Cochrane risk of bias tool. The biggest weakness was study quality: only 4 of 79 trials were judged at low risk of bias, which limits how confidently pooled effects can be interpreted.","limitations":"Only 4 of the 79 included trials were rated low risk of bias, so many pooled estimates rest on trials with design or reporting problems. Several key pooled findings came from a small number of trials for that outcome (for example, 3 trials for chemotherapy nausea and vomiting), which makes the summary estimates less stable. Countries, ages, and sex distribution were not reported in the abstract, making it hard to know how well the pooled sample matches specific real-world patient groups."},{"rthcId":"RTHC-01078","title":"Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.","authors":"Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H","year":2015,"journal":"The Journal of pharmacology and experimental therapeutics, 352(2), 195-207","doi":"10.1124/jpet.114.218677","pmid":"25398241","tags":["dopamine","neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested how THC and drugs that increase natural brain cannabinoids affected the brain's reward system in mice using intracranial self-stimulation (ICSS), where animals press a lever to electrically stimulate the medial forebrain bundle.\n\nTHC and JZL184 (a MAGL inhibitor that boosts 2-AG) both reduced operant responding for brain stimulation, food, and spontaneous movement. The FAAH inhibitor PF-3845 (which boosts anandamide) had little effect.\n\nThe dual FAAH-MAGL inhibitor SA-57, which boosts both anandamide and 2-AG, produced ICSS depression similar in magnitude to THC. All effects were blocked by the CB1 receptor antagonist rimonabant but not by a CB2 antagonist.","whyItMatters":"The finding that THC and 2-AG boosting reduce brain reward signaling, rather than enhance it, helps explain why THC's reinforcing effects have been difficult to detect in rodent models. It also clarifies that the two main endocannabinoids (anandamide and 2-AG) have different effects on reward circuits.","specificNumbers":"THC and JZL184 attenuated ICSS, food responding, and locomotion. PF-3845 had minimal effects. SA-57 depression was similar in magnitude to THC. JZL184 elevated brain 2-AG. SA-57 elevated both anandamide and 2-AG. CB1 antagonist rimonabant blocked all effects.","methodology":"Male mice underwent intracranial self-stimulation testing, operant responding for food, and locomotor activity measurements. THC, JZL184, PF-3845, and SA-57 were tested at multiple doses. Brain endocannabinoid levels were quantified. CB1 and CB2 antagonists were used to determine receptor involvement.","limitations":"ICSS is one model of reward but does not capture all aspects of drug reinforcement. Mice were tested acutely, and chronic effects may differ. The doses used may not reflect typical human cannabis exposure patterns. Rodent reward neurobiology does not perfectly map to human experience."},{"rthcId":"RTHC-01079","title":"Diagnosing and treating cannabinoid hyperemesis.","authors":"Wilson, Olivia; Lutton, Stuart; Doherty, Kelly","year":2015,"journal":"Emergency nurse : the journal of the RCN Accident and Emergency Nursing Association, 23(8), 22-5","doi":"10.7748/en.23.8.22.s25","pmid":"26638755","tags":["withdrawal","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This article reviewed cannabinoid hyperemesis syndrome (CHS), a condition first described in 2004 that causes severe, recurring nausea and vomiting in people who regularly use cannabis.\n\nKey features of CHS include cyclical episodes of intense nausea and vomiting, temporary relief from hot water bathing (a distinctive hallmark), failure to respond to conventional antiemetic medications, and complete resolution when cannabis use stops.\n\nThe article noted that CHS is underrecognized in emergency settings, partly because the association between cannabis use and vomiting seems paradoxical, given that cannabis is often used to treat nausea.","whyItMatters":"CHS can lead to repeated emergency department visits and unnecessary diagnostic testing when clinicians are unaware of the condition. Recognition by emergency nurses can lead to faster diagnosis, appropriate treatment, and patient education about the need to stop cannabis use.","specificNumbers":"No specific prevalence data were presented. The article focused on clinical presentation, diagnostic criteria, and management strategies.","methodology":"This was a clinical review article published in a nursing journal that examined the existing literature on cannabinoid hyperemesis syndrome and included a case study illustrating patient management.","limitations":"This was a brief clinical review, not a systematic review or original research. The pathophysiology of CHS remains poorly understood. The article was written for a nursing audience and provides a clinical overview rather than in-depth mechanistic analysis."},{"rthcId":"RTHC-01080","title":"Profiles of medicinal cannabis patients attending compassion centers in rhode island.","authors":"Zaller, Nickolas; Topletz, Ariel; Frater, Susan; Yates, Gail; Lally, Michelle","year":2015,"journal":"Journal of psychoactive drugs, 47(1), 18-23","doi":"10.1080/02791072.2014.999901","pmid":"25715068","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 200 patients at two medical cannabis dispensaries in Rhode Island to understand who uses dispensaries and why.\n\nThe typical patient was male (73%), white (80%), college-educated (68%), and had health insurance (89%). Chronic pain management was the most common reason for medical cannabis use.\n\nPatients were more likely to report significant pain interference if they were older or used cannabis as a substitute for prescription medications. Those with higher incomes reported less pain interference. About 20% had a history of drug or alcohol use disorder. Most participants said medical cannabis improved their pain symptoms and expressed interest in alternatives to opioid-based treatment.","whyItMatters":"Understanding who uses medical cannabis dispensaries and why helps shape policy and clinical practice. The finding that many patients use cannabis as an alternative to prescription pain medications, combined with the fact that most report symptom improvement, is relevant to ongoing debates about cannabis as an opioid alternative.","specificNumbers":"200 participants surveyed. 73% male. 80% white. 68% college-educated. 89% had health insurance. 20% had a history of substance use disorder. Patients using cannabis as a prescription substitute were 2.47x more likely to report significant pain interference.","methodology":"Two hundred participants were recruited from two Compassion Centers in Rhode Island and completed a survey including the Brief Pain Inventory to assess pain interference. Multivariable logistic regression was used to identify predictors of significant pain interference.","limitations":"The sample of 200 patients from two dispensaries in one state may not represent medical cannabis patients nationally. Self-reported data may be subject to bias. The cross-sectional design cannot determine whether cannabis actually improved outcomes compared to other treatments."},{"rthcId":"RTHC-01081","title":"Cannabis and bipolar disorder: does quitting cannabis use during manic/mixed episode improve clinical/functional outcomes?","authors":"Zorrilla, I; Aguado, J; Haro, J M; Barbeito, S; López Zurbano, S; Ortiz, A; López, P; Gonzalez-Pinto, A","year":2015,"journal":"Acta psychiatrica Scandinavica, 131(2), 100-10","doi":"10.1111/acps.12366","pmid":"25430820","tags":["mental-health","quitting","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 1,922 adults with bipolar disorder over two years, dividing them into three groups based on cannabis use during a manic or mixed episode: current users (6.9%), previous users who quit during the episode (4.6%), and never-users (88.5%).\n\nPatients who stopped using cannabis during their manic episode showed clinical and functional outcomes statistically similar to those who never used cannabis. In contrast, patients who continued using cannabis had significantly lower rates of recovery and remission, higher rates of recurrence, greater work impairment, and were less likely to be living with a partner.","whyItMatters":"For people with bipolar disorder who use cannabis, this study provides evidence that quitting during a manic episode may lead to outcomes comparable to those who never used. It also reinforces that continued cannabis use during bipolar episodes is associated with measurably worse clinical trajectories.","specificNumbers":"1,922 patients analyzed. 6.9% current users, 4.6% previous users, 88.5% never users. Current users had lower recovery (p=0.004), lower remission (p=0.014), higher recurrence (p=0.014), and greater work impairment (p=0.016) compared to never users.","methodology":"Data came from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM), a 2-year prospective observational study across multiple European sites. Cannabis use was assessed between the 12-week and 24-month visits. Outcomes were analyzed using regression models controlling for confounding variables.","limitations":"This was an observational study, so the association between cannabis cessation and better outcomes could reflect other differences between the groups. Patients who quit may have had less severe illness or better treatment adherence overall. Self-reported cannabis use may be inaccurate. The relatively small proportion of cannabis users limits statistical power."},{"rthcId":"RTHC-01082","title":"Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring.","authors":"Zumbrun, Elizabeth E; Sido, Jessica M; Nagarkatti, Prakash S; Nagarkatti, Mitzi","year":2015,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 10(2), 245-54","doi":"10.1007/s11481-015-9586-0","pmid":"25618446","tags":["pregnancy","genetics","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined evidence from animal studies on how prenatal exposure to cannabinoids affects the developing immune system and whether those effects persist into adulthood or pass to future generations.\n\nAnimal models showed that in-utero cannabinoid exposure resulted in significant T cell dysfunction and weakened immune responses to viral antigens in offspring. The immunosuppressive effects appeared to be mediated through epigenetic mechanisms, including changes in microRNA expression, DNA methylation patterns, and histone modifications.\n\nThe authors argued that these epigenetic changes could have significant long-term immunological consequences and potentially transgenerational effects, though human data remain limited due to confounding factors like co-existing substance use.","whyItMatters":"Cannabis use during pregnancy is not uncommon and may increase as legalization expands. If prenatal exposure produces lasting immune changes through epigenetic mechanisms, this could have implications for offspring health that extend well beyond the prenatal period.","specificNumbers":"No specific prevalence data were presented. The review synthesized qualitative findings across multiple animal studies showing T cell dysfunction, reduced viral immune responses, and altered epigenetic markers in offspring.","methodology":"This was a narrative review synthesizing findings from animal studies on prenatal cannabinoid exposure and immune function, with a focus on epigenetic mechanisms including DNA methylation, histone modification, and microRNA regulation.","limitations":"The review relied primarily on animal data, which may not directly translate to human immune function. Human studies are confounded by co-existing drug use, nutrition, and environmental factors. The specific cannabinoid doses and exposure windows in animal studies may not reflect typical human patterns. Epigenetic findings in animals require cautious interpretation for human relevance."},{"rthcId":"RTHC-01083","title":"Medical use of cannabis products: Lessons to be learned from Israel and Canada.","authors":"Ablin, J; Ste-Marie, P A; Schäfer, M; Häuser, W; Fitzcharles, M-A","year":2016,"journal":"Schmerz (Berlin, Germany), 30(1), 3-13","doi":"10.1007/s00482-015-0083-4","pmid":"26767992","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review, written by physicians from Israel, Canada, and Germany, compared how Israel and Canada handle medical cannabis to inform Germany's policy development.\n\nIn Israel, the plant-based extract nabiximols could be prescribed for spasticity and cancer pain, while raw marijuana was permitted under strict government regulation for specific conditions including chronic neuropathic pain, cancer pain, IBD, and PTSD, but only after conventional treatments failed. Only designated physicians could prescribe it, and costs were not reimbursed by insurers.\n\nCanada allowed synthetic and plant-based cannabinoids for neuropathic and cancer pain, HIV-related anorexia, and chemotherapy nausea, with insurance coverage. Medical marijuana authorization required a healthcare practitioner and could be used for any condition, though costs were not covered. Both countries maintained multiple contraindications.","whyItMatters":"As more countries develop medical cannabis programs, learning from existing systems can help avoid pitfalls and adopt best practices. This comparison highlights different approaches to balancing patient access, quality control, professional oversight, and cost management.","specificNumbers":"Israel: specific conditions only, government-licensed growers, no insurance reimbursement for marijuana. Canada: synthetic cannabinoids covered by insurance, marijuana authorized by practitioners for any condition, costs not covered, licensed producers as sole supply source.","methodology":"This was a review article authored by physicians with expertise in medical cannabis policy from Israel, Canada, and Germany. It described the regulatory frameworks, approved indications, prescription processes, and insurance coverage in each jurisdiction.","limitations":"The review described regulatory frameworks as of 2016, which have since changed in all three countries. It focused on the policy and regulatory perspective rather than clinical outcomes. The authors' recommendation against patient cultivation may reflect specific jurisdictional concerns rather than universal best practices."},{"rthcId":"RTHC-01084","title":"Integrating cannabis into clinical cancer care.","authors":"Abrams, D I","year":2016,"journal":"Current oncology (Toronto, Ont.), 23(2), S8-S14","doi":"10.3747/co.23.3099","pmid":"27022315","tags":["cancer","medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the role of cannabis in cancer care across multiple domains. For symptom management, the evidence supported cannabis use for chemotherapy-induced nausea and vomiting, appetite stimulation, pain management (potentially synergistic with opioids), and peripheral neuropathy relief.\n\nInhaled cannabis was found to be more effective than placebo for peripheral neuropathy, and a pharmacokinetic study showed that vaporized cannabis did not significantly alter plasma opioid levels in patients on stable opioid therapy, suggesting safe co-administration with possible synergistic pain relief.\n\nBeyond symptoms, the review noted a growing body of preclinical research showing anti-tumor effects of cannabinoids through mechanisms involving apoptosis, anti-angiogenesis, and metastasis inhibition. However, no clinical trials had been conducted to confirm these effects in humans.","whyItMatters":"Cancer patients often use cannabis, with or without medical guidance. This review provides oncologists and patients with an evidence-based framework for understanding where cannabis might fit into cancer care, from well-supported symptom management to speculative anti-tumor potential.","specificNumbers":"Vaporized cannabis did not produce clinically significant changes in plasma opioid levels. Multiple preclinical studies showed anti-tumor effects through apoptosis, anti-angiogenesis, and metastasis inhibition. No clinical trials on direct anti-cancer effects had been completed at the time of publication.","methodology":"This was a clinical review article published in a medical oncology journal, synthesizing evidence from clinical trials, pharmacokinetic studies, preclinical research, and anecdotal reports about cannabis use in cancer care.","limitations":"The review acknowledged a lack of clinical trials for direct anti-cancer effects. Anecdotal reports of remarkable responses do not constitute clinical evidence. The symptom management evidence, while more robust, still has gaps regarding optimal dosing, formulations, and patient selection."},{"rthcId":"RTHC-01085","title":"Cannabinoid CB1 receptor inhibition blunts adolescent-typical increased binge alcohol and sucrose consumption in male C57BL/6J mice.","authors":"Agoglia, Abigail E; Holstein, Sarah E; Eastman, Vallari R; Hodge, Clyde W","year":2016,"journal":"Pharmacology, biochemistry, and behavior, 143, 11-7","doi":"10.1016/j.pbb.2016.01.009","pmid":"26800788","tags":["youth","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers gave adolescent and adult mice access to alcohol or sucrose in a binge-drinking paradigm. Adolescent mice consumed more of both substances compared to adults, consistent with what is observed in human adolescents.\n\nPre-treatment with AM-251, a CB1 receptor antagonist, dose-dependently reduced adolescent alcohol consumption down to adult levels without affecting adult intake. The same pattern appeared with sucrose: the drug reduced adolescent but not adult consumption.\n\nThe reductions were not explained by changes in locomotor activity or anxiety-like behavior, suggesting a specific effect on reward-driven consumption rather than general behavioral suppression.","whyItMatters":"Adolescent binge drinking is a major public health concern associated with long-term health consequences. This study identifies the endocannabinoid system, specifically CB1 receptor activity, as a potential mechanism driving increased binge consumption during adolescence compared to adulthood.","specificNumbers":"AM-251 at 1, 3, and 10 mg/kg dose-dependently reduced adolescent alcohol consumption. AM-251 at 3 mg/kg reduced adolescent sucrose consumption. Neither dose altered adult consumption of either substance. No changes in locomotor activity or thigmotaxis were observed.","methodology":"Adolescent and adult male C57BL/6J mice underwent a binge-drinking paradigm with access to 20% alcohol or 1% sucrose for 4 hours every other day. AM-251 was tested at 0, 1, 3, and 10 mg/kg in a Latin square design. Open-field locomotor activity and thigmotaxis (wall-hugging, an anxiety measure) were also assessed.","limitations":"This was a mouse study, and the CB1 antagonist AM-251 has known side effects in humans (rimonabant, a similar drug, was withdrawn from the market due to psychiatric side effects). Only male mice were tested. The binge-drinking paradigm, while validated, is a simplified model of human binge drinking."},{"rthcId":"RTHC-01086","title":"Therapeutic Use of Cannabis in Inflammatory Bowel Disease.","authors":"Ahmed, Waseem; Katz, Seymour","year":2016,"journal":"Gastroenterology & hepatology, 12(11), 668-679","doi":null,"pmid":"28035196","tags":["medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the evidence for cannabis as a treatment for inflammatory bowel disease (IBD), covering endocannabinoid system science, animal models, epidemiological data, and human studies.\n\nAnimal research showed that modulating the endocannabinoid system had therapeutic effects in mouse colitis models. Epidemiological data suggested cannabis use is common among IBD patients, with many reporting symptom improvement.\n\nHowever, human therapy studies had not yet demonstrated objective anti-inflammatory effects. The available evidence suggested cannabis may provide symptomatic relief (pain, appetite, nausea) without addressing the underlying intestinal inflammation. The review called for large, placebo-controlled trials using objective measures like inflammatory markers, biopsies, and endoscopy.","whyItMatters":"Many IBD patients use cannabis, and some report significant symptom relief. This review clarifies an important distinction: symptomatic improvement does not necessarily mean the underlying disease is being treated. Without evidence of anti-inflammatory effects, cannabis may mask symptoms while inflammation continues.","specificNumbers":"No specific trial results were presented. The review synthesized findings across preclinical models (showing endocannabinoid system involvement in IBD pathogenesis), surveys (showing high cannabis use among IBD patients), and limited clinical data.","methodology":"This was a comprehensive review article in a gastroenterology journal, examining preclinical evidence, epidemiological surveys, and the limited clinical trial data on cannabis and IBD. The review also addressed safety considerations and research gaps.","limitations":"The review highlighted the absence of large, double-blind, randomized controlled trials. Existing human data relied on subjective symptom reports rather than objective inflammatory measures. The review could not determine optimal dosing, formulation, or route of administration for potential therapeutic use."},{"rthcId":"RTHC-01087","title":"The effect of O-1602, an atypical cannabinoid, on morphine-induced conditioned place preference and physical dependence.","authors":"Alavi, Mohaddeseh Sadat; Hosseinzadeh, Hossein; Shamsizadeh, Ali; Roohbakhsh, Ali","year":2016,"journal":"Pharmacological reports : PR, 68(3), 592-7","doi":"10.1016/j.pharep.2015.12.009","pmid":"26971034","tags":["neuroscience","pain","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether O-1602, a compound that activates the GPR55 receptor (sometimes called a third cannabinoid receptor), could affect morphine reward and dependence in mice.\n\nIn a conditioned place preference test, O-1602 at lower doses (0.2 and 1 mg/kg) reduced the acquisition of morphine reward, meaning mice spent less time in the chamber associated with morphine. At all three doses tested, O-1602 also reduced the expression of established morphine preference.\n\nFor physical dependence, O-1602 at the highest dose (5 mg/kg) significantly reduced withdrawal symptoms including jumping and diarrhea when naloxone-precipitated withdrawal was triggered after repeated morphine administration. The highest dose also increased locomotor activity on its own.","whyItMatters":"Opioid dependence remains a major health challenge. Finding that a GPR55 agonist can reduce both the rewarding effects and physical dependence aspects of morphine opens a potential new avenue for addressing opioid use disorder through a cannabinoid-related receptor that is distinct from CB1 and CB2.","specificNumbers":"O-1602 at 0.2 and 1 mg/kg reduced acquisition of morphine CPP. All three doses (0.2, 1, 5 mg/kg) reduced expression of morphine CPP. O-1602 at 5 mg/kg reduced jumping and diarrhea during naloxone-precipitated morphine withdrawal. The 5 mg/kg dose increased locomotor activity.","methodology":"Male mice were tested in a biased conditioned place preference model using morphine (40 mg/kg). O-1602 was tested at 0.2, 1, and 5 mg/kg for effects on acquisition and expression of morphine preference. For physical dependence, mice received escalating morphine doses over three days, and withdrawal was triggered with naloxone. Locomotor activity was recorded throughout.","limitations":"This was a mouse study with a relatively simple behavioral paradigm. The highest effective dose (5 mg/kg) also increased locomotor activity, which could confound interpretation. GPR55 pharmacology is not fully characterized, and O-1602 may have off-target effects. Translation to human opioid dependence treatment would require extensive further research."},{"rthcId":"RTHC-01088","title":"The Changing Drug Culture: Emerging Drugs of Abuse and Legal Highs.","authors":"Albertson, Timothy E; Chenoweth, James A; Colby, Daniel K; Sutter, Mark E","year":2016,"journal":"FP essentials, 441, 18-24","doi":null,"pmid":"26881769","tags":["synthetic-cannabinoids","youth","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review for family practitioners cataloged the expanding landscape of synthetic recreational drugs. Synthetic cannabinoids, sold as \"K2\" or \"Spice,\" are sprayed onto herbal preparations and marketed as not for human consumption to avoid regulation.\n\nBecause the chemical compounds change frequently and are not included in routine drug screening, their use often goes undetected. The unpredictable concentrations of active ingredients make toxicity common. Adverse effects of synthetic cannabinoids include psychosis, among other serious reactions.\n\nThe review also covered synthetic cathinones (\"bath salts\"), MDMA variants, and new hallucinogens, noting that adolescents and young adults are the primary users of these substances.","whyItMatters":"Synthetic cannabinoids present unique clinical challenges because they are more potent and unpredictable than natural cannabis, they evade standard drug tests, and their chemical composition constantly shifts. Clinicians who are unaware of these substances may miss the diagnosis.","specificNumbers":"No specific prevalence data were presented. The review noted a \"large increase\" in synthetic drug use and identified adolescents and young adults as the primary user population.","methodology":"This was a clinical review published in a family practice education journal, summarizing the pharmacology, toxicology, and clinical presentation of emerging synthetic drugs for practicing clinicians.","limitations":"This was a clinical overview rather than a systematic review. It did not provide detailed epidemiological data or head-to-head comparisons of harm profiles. The rapidly changing nature of synthetic drugs means specific compounds discussed may no longer be prevalent."},{"rthcId":"RTHC-01089","title":"Substance use is a risk factor for violent behavior in male patients with bipolar disorder.","authors":"Alnıak, İzgi; Erkıran, Murat; Mutlu, Elif","year":2016,"journal":"Journal of affective disorders, 193, 89-93","doi":"10.1016/j.jad.2015.12.059","pmid":"26771949","tags":["mental-health","addiction","synthetic-cannabinoids"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers evaluated 100 male inpatients with bipolar disorder type I during mood episodes to identify factors associated with violent behavior (defined as physical aggression against others).\n\nCurrent substance use, rather than lifetime history of substance use disorder, was the key predictor: it was associated with a threefold increase in violence risk. The lifetime rate of substance use disorder in this population was 59%, and 39% were currently using substances.\n\nCannabis and alcohol were the most commonly used substances in both lifetime and current use groups, followed by synthetic cannabinoids. Patients who used any substance were more likely to have criminal records and prior incarceration. A previous history of violent behavior was another significant risk factor.","whyItMatters":"Understanding that current substance use, not just lifetime history, drives violence risk in bipolar disorder has practical implications for clinical management. It suggests that addressing active substance use could reduce violent behavior in this population.","specificNumbers":"100 male inpatients studied. 59% had lifetime substance use disorder. 39% had current substance use. Current use associated with 3x increased violence risk. Cannabis and alcohol were the most commonly used substances.","methodology":"One hundred male inpatients diagnosed with bipolar disorder type I were assessed during a current mood episode using validated scales including the Young Mania Rating Scale, Hamilton Depression Rating Scale, Barratt Impulsivity Scale, and Overt Aggression Scale. Logistic regression was used to predict violent behavior.","limitations":"The sample was limited to male inpatients, so findings may not apply to female patients or outpatients. Self-reported substance use may be inaccurate. Synthetic cannabinoid use relied on patient and family reports due to lack of laboratory detection. The cross-sectional design cannot establish causation."},{"rthcId":"RTHC-01090","title":"Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood.","authors":"Alteba, Shirley; Korem, Nachshon; Akirav, Irit","year":2016,"journal":"Learning & memory (Cold Spring Harbor, N.Y.), 23(7), 349-58","doi":"10.1101/lm.041608.116","pmid":"27317195","tags":["neuroscience","anxiety","cognition","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether cannabinoid treatment during late adolescence could reverse the long-term cognitive damage caused by early life stress in rats.\n\nMale and female rats were stressed during their first two weeks of life, then treated with the cannabinoid agonist WIN55,212-2 for two weeks during late adolescence. In adulthood, untreated stressed rats showed impaired short-term memory across multiple tasks. Males were additionally impaired in object recognition.\n\nCannabinoid treatment during adolescence prevented all of these stress-induced memory impairments and reduced anxiety levels. The treatment also normalized stress-induced changes in glucocorticoid receptors and CB1 receptors in the brain, though the specific receptor changes differed between males and females.","whyItMatters":"Early life stress is a major risk factor for mental health problems. This study suggests the endocannabinoid system may be a target for reversing stress-related cognitive damage, and that there may be a window during late adolescence when intervention is particularly effective.","specificNumbers":"Stress during postnatal days 7-14. Cannabinoid treatment during days 45-60 (equivalent to ages 18-25 in humans). Testing at day 90. Both sexes showed impaired spatial and social recognition memory. Males additionally showed impaired object recognition. WIN treatment prevented all impairments.","methodology":"Male and female rats were exposed to early stress (postnatal days 7-14), injected with WIN55,212-2 (1.2 mg/kg) for two weeks during late adolescence (days 45-60), and tested in adulthood (day 90) for working memory (spatial location, social recognition, novel object recognition), anxiety, and receptor expression in the hippocampus, prefrontal cortex, and amygdala.","limitations":"This was an animal study, and the cannabinoid used (WIN55,212-2) is a synthetic full agonist that is much more potent than THC. The stress model (maternal separation) is one of several and may not capture all forms of early adversity. The timing window and dosing may not translate directly to humans."},{"rthcId":"RTHC-01091","title":"Weeding Out the Truth: Adolescents and Cannabis.","authors":"Ammerman, Seth; Tau, Gregory","year":2016,"journal":"Journal of addiction medicine, 10(2), 75-82","doi":"10.1097/ADM.0000000000000199","pmid":"26985645","tags":["youth","cognition","addiction","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review addressed the growing tension between expanding cannabis legalization and concerns about adolescent use. As of late 2015, 23 states and DC had legalized medical cannabis, and 4 states plus DC had legalized recreational use for adults.\n\nThe review examined a range of issues relevant to the adolescent cannabis debate, including the changing potency and forms of cannabis products, the distinction between medical and recreational use frameworks, and the clinical evidence regarding effects on the developing brain.","whyItMatters":"As cannabis legalization continues to expand, clinicians who work with adolescents need up-to-date information about both risks and policy context. This review provided a framework for navigating these conversations.","specificNumbers":"As of November 2015: 23 states and DC had legalized medical cannabis. 4 states and DC had legalized recreational use for adults 21 and older.","methodology":"This was a clinical review article published in the Journal of Addiction Medicine, synthesizing current evidence on adolescent cannabis use across multiple domains.","limitations":"The abstract provided limited detail about specific findings. As a review, it synthesized existing evidence rather than presenting new data. The rapid pace of policy change means the legal framework described was quickly outdated."},{"rthcId":"RTHC-01092","title":"Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products.","authors":"Anderson, Gail D; Chan, Lingtak-Neander","year":2016,"journal":"Clinical pharmacokinetics, 55(11), 1353-1368","doi":null,"pmid":"27106177","tags":["drug-interactions","medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This pharmacokinetics review examined how tobacco smoking, cannabis use, and smoking cessation products interact with medications metabolized by liver enzymes.\n\nBoth marijuana and tobacco smoke induce the CYP1A2 enzyme through the same pathway (aromatic hydrocarbon receptor), and the effect is additive when both are smoked. When someone stops smoking, CYP1A2 activity drops quickly, potentially causing toxicity from medications that were previously metabolized at a faster rate.\n\nFor cannabis specifically, CYP3A4 appears to be the primary enzyme metabolizing both THC and CBD, meaning drugs that induce or inhibit CYP3A4 can significantly alter cannabinoid levels. Limited data also suggest CBD may inhibit CYP2C19, which could affect a range of medications metabolized by that enzyme.","whyItMatters":"As cannabis use increases, understanding how it interacts with prescription medications becomes critical for patient safety. The CYP1A2 induction from smoking cannabis could alter levels of drugs like clozapine, theophylline, and caffeine, while CBD's potential CYP2C19 inhibition could affect drugs like clopidogrel and certain antidepressants.","specificNumbers":"Both cannabis and tobacco smoking induce CYP1A2 (additive effect). CYP3A4 is the primary metabolic pathway for THC and CBD. CBD may significantly inhibit CYP2C19. Nicotine metabolism by CYP2A6 is induced by estrogen, resulting in lower nicotine levels in females, especially those on oral contraceptives.","methodology":"This was a comprehensive review of pharmacokinetic data on drug interactions involving tobacco smoke, cannabis, and smoking cessation products, published in a clinical pharmacokinetics journal.","limitations":"The review noted limited data on many cannabis-drug interactions, particularly for smoked cannabis versus pharmaceutical cannabinoid products. Most interaction data come from in-vitro studies or pharmaceutical cannabinoid preparations rather than whole-plant cannabis. Clinical studies are needed to determine real-world significance of many theoretical interactions."},{"rthcId":"RTHC-01093","title":"Cannabis and neuropsychiatry, 1: benefits and risks.","authors":"Andrade, Chittaranjan","year":2016,"journal":"The Journal of clinical psychiatry, 77(5), e551-4","doi":"10.4088/JCP.16f10841","pmid":"27249079","tags":["mental-health","addiction","cognition","driving"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review summarized the evidence on both benefits and risks of cannabis and cannabinoids. On the benefit side, a recent meta-analysis found cannabinoids were associated with modest benefits for chemotherapy-related nausea, small and inconsistent benefits for pain and spasticity, and inconclusive benefits for appetite, tics, mood, and sleep.\n\nOn the risk side, randomized controlled trials showed cannabinoids increase the risk of adverse events, serious adverse events, and dropout due to adverse events. Cannabis impairs cognition and is associated with increased traffic accident risk including fatal crashes. Long-term use may lead to dependence, respiratory problems, psychosis, and possibly cancer.\n\nThe review also noted concerns about use during pregnancy (potentially compromising fetal growth) and adolescence (potentially affecting neurodevelopment and social adjustment), and cautioned that older research findings may not apply to current high-potency strains.","whyItMatters":"This review provides a balanced assessment at a time when public perception often skews toward viewing cannabis as either completely benign or as a cure-all. The modest therapeutic benefits need to be weighed against documented risks, particularly for vulnerable populations.","specificNumbers":"No new quantitative data presented. The review cited meta-analytic evidence of modest benefits for nausea, small/inconsistent benefits for pain and spasticity, and increased odds of adverse events, traffic accidents, dependence, and psychosis.","methodology":"This was a clinical review published in the Journal of Clinical Psychiatry, synthesizing evidence from meta-analyses, randomized controlled trials, and observational studies on both the therapeutic benefits and health risks of cannabis.","limitations":"This was a narrative review that selectively summarized existing evidence. It did not conduct a systematic search or meta-analysis. The balance of benefit-to-risk reporting reflects the author's perspective. Cannabis research has continued to evolve since publication."},{"rthcId":"RTHC-01094","title":"Estrogen Receptor Beta and 2-arachidonoylglycerol Mediate the Suppressive Effects of Estradiol on Frequency of Postsynaptic Currents in Gonadotropin-Releasing Hormone Neurons of Metestrous Mice: An Acute Slice Electrophysiological Study.","authors":"Bálint, Flóra; Liposits, Zsolt; Farkas, Imre","year":2016,"journal":"Frontiers in cellular neuroscience, 10, 77","doi":"10.3389/fncel.2016.00077","pmid":"27065803","tags":["neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers investigated how estrogen controls GnRH neurons, the brain cells that regulate the reproductive hormone axis. Using mouse brain slices, they found that a low physiological concentration of estradiol reduced the frequency of spontaneous postsynaptic currents in GnRH neurons by about 50%.\n\nThis suppressive effect required the estrogen receptor beta (ERbeta), not ERalpha or the membrane estrogen receptor GPR30. Critically, the effect also required the endocannabinoid system: blocking CB1 receptors or blocking endocannabinoid synthesis inside the cell both eliminated estradiol's suppressive action.\n\nThe findings indicate that estrogen receptor beta and 2-AG/CB1 signaling are coupled and work together to mediate the negative feedback of estrogen on reproductive hormone neurons.","whyItMatters":"This study reveals a previously unrecognized connection between estrogen signaling and the endocannabinoid system in reproductive brain function. This link could help explain how cannabis use might affect reproductive hormones and fertility.","specificNumbers":"Estradiol at 10 picomolar reduced spontaneous postsynaptic current frequency by 49.62%. This effect was abolished by the estrogen receptor blocker Faslodex, the CB1 inverse agonist AM251, and the endocannabinoid synthesis blocker THL.","methodology":"Whole-cell patch clamp recordings were performed on GnRH neurons in acute brain slices from GnRH-GFP transgenic mice in the metestrous phase. Various receptor agonists, antagonists, and enzyme inhibitors were applied to dissect the signaling pathway. Tetrodotoxin was used to confirm direct effects on GnRH cells.","limitations":"This was an in-vitro study using mouse brain slices, which does not capture the full complexity of in-vivo reproductive regulation. The experiments used the metestrous phase only, and the interaction may differ across the estrous cycle. Translation to human reproductive physiology requires caution."},{"rthcId":"RTHC-01095","title":"Attitudes to cannabis and patterns of use among Canadians with multiple sclerosis.","authors":"Banwell, Emma; Pavisian, Bennis; Lee, Liesly; Feinstein, Anthony","year":2016,"journal":"Multiple sclerosis and related disorders, 10, 123-126","doi":"10.1016/j.msard.2016.09.008","pmid":"27919478","tags":["medical-cannabis","pain","sleep","anxiety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 225 people with multiple sclerosis (MS) attending neurology and neuropsychiatry clinics in Canada about their cannabis use and attitudes.\n\nOverall attitudes were favorable: 54.3% approved of cannabis and 43.7% endorsed full legalization, while another 43.7% supported legalization for medical use only. About 19.5% reported current use, and 56.1% had used cannabis at some point.\n\nThe most common reasons for current use were sleep (86%), pain (75%), anxiety (73%), and spasticity (68%). Patients attending the neuropsychiatry clinic were significantly more likely to use cannabis for depression and pain management. If cannabis were legal, 50.2% said they would use it, suggesting potential use could more than double.","whyItMatters":"With Canada having some of the highest MS rates globally, understanding cannabis use patterns in this population helps inform clinical practice and policy. The high participation rate (91.8%) and the distinction between neurology and neuropsychiatry clinic patients add nuance to the findings.","specificNumbers":"225 participants (91.8% response rate). 54.3% approved of cannabis. 19.5% current users. 56.1% lifetime use. 50.2% would use if legal. Symptom targets: sleep (86%), pain (75%), anxiety (73%), spasticity (68%).","methodology":"A consecutive sample of 246 MS patients was approached at neurology (n=118) and neuropsychiatry (n=107) clinics. Of those, 225 (91.8%) agreed to complete a questionnaire covering demographics, disease variables, and cannabis-related questions.","limitations":"Self-reported data may be subject to social desirability bias. The sample came from two clinics in one area and may not represent all Canadian MS patients. The study assessed reasons for use but not whether cannabis actually improved those symptoms."},{"rthcId":"RTHC-01096","title":"Mitigation of Marijuana-Related Legal Harms to Youth in California.","authors":"Banys, Peter","year":2016,"journal":"Journal of psychoactive drugs, 48(1), 11-20","doi":"10.1080/02791072.2015.1126770","pmid":"26891110","tags":["youth","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This policy review examined the consequences of criminalizing youth cannabis possession in California, arguing that the punishment often exceeds the harm of the drug.\n\nThe review cataloged eight categories of harm from the criminal justice approach to juveniles: arrest records, incarceration subculture exposure, zero-tolerance school expulsions, federal student loan ineligibility, employment screening problems, racial disparities in arrests, financial costs, and immigration complications.\n\nWhile California had reduced possession of under one ounce to an infraction in 2011, juvenile marijuana arrests still outnumbered arrests for harder drugs. The review recommended stable tax funding for school assistance programs, eliminating zero-tolerance policies in favor of retention programs, and reserving probation for larger quantities and repeat offenders.","whyItMatters":"The review highlighted a fundamental policy question that extends beyond California: whether the societal response to adolescent cannabis use creates more damage than the substance itself. The documented collateral consequences of juvenile arrests affect education, employment, housing, and immigration status.","specificNumbers":"After California's 2011 law change, possession under 1 oz. became an infraction. Juvenile marijuana arrests still exceeded arrests for harder drugs. Eight categories of harm from criminalization were documented.","methodology":"This was a policy review and analysis published in the Journal of Psychoactive Drugs, examining the legal landscape and consequences of juvenile marijuana enforcement in California.","limitations":"This was a policy analysis focused on California and may not fully apply to other jurisdictions. It advocated a particular policy position rather than presenting neutral analysis. The review did not quantify the harms of adolescent cannabis use for comparison with harms of criminalization."},{"rthcId":"RTHC-01097","title":"Synthetic cannabinoid JWH-018 and its halogenated derivatives JWH-018-Cl and JWH-018-Br impair Novel Object Recognition in mice: Behavioral, electrophysiological and neurochemical evidence.","authors":"Barbieri, M; Ossato, A; Canazza, I; Trapella, C; Borelli, A C; Beggiato, S; Rimondo, C; Serpelloni, G; Ferraro, L; Marti, M","year":2016,"journal":"Neuropharmacology, 109, 254-269","doi":"10.1016/j.neuropharm.2016.06.027","pmid":"27346209","tags":["synthetic-cannabinoids","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers compared the cognitive effects of three synthetic cannabinoids (JWH-018, JWH-018-Cl, and JWH-018-Br) with THC in mice using a novel object recognition test.\n\nAll three synthetic compounds dose-dependently impaired both short-term (2-hour) and long-term (24-hour) memory retention, and they were more potent than THC at producing these deficits.\n\nIn hippocampal brain slice experiments, the synthetic compounds also disrupted electrically evoked synaptic transmission, long-term potentiation (LTP, a cellular mechanism of memory), and the release of both glutamate and GABA. All behavioral and cellular effects were blocked by the CB1 receptor antagonist AM251, confirming the involvement of cannabinoid receptors.","whyItMatters":"Synthetic cannabinoids are sold as \"Spice\" or \"herbal blends\" and are often perceived as legal alternatives to cannabis. This study demonstrates that they produce more potent cognitive impairment than THC, supporting clinical observations of greater neurotoxicity with synthetic cannabinoid use.","specificNumbers":"JWH-018 and its halogenated derivatives impaired both 2-hour and 24-hour memory retention more potently than THC. All compounds negatively affected synaptic transmission, LTP, and glutamate/GABA release in hippocampal slices. All effects were blocked by CB1 antagonist AM251.","methodology":"Mice were tested in the novel object recognition task at 2 and 24 hours after training to assess short- and long-term memory. In parallel, hippocampal brain slices were used for electrophysiology (synaptic transmission and LTP) and neurochemistry (amino acid release). The CB1 antagonist AM251 was used to confirm receptor involvement.","limitations":"This was an animal study using acute dosing. Chronic effects were not examined. The doses used may not precisely reflect human exposure from smoking synthetic cannabinoid products. Mouse cognition and hippocampal function do not perfectly model human memory processes."},{"rthcId":"RTHC-01098","title":"Prioritizing Alcohol Prevention: Establishing Alcohol as the Gateway Drug and Linking Age of First Drink With Illicit Drug Use.","authors":"Barry, Adam E; King, Jessica; Sears, Cynthia; Harville, Cedric; Bondoc, Irina; Joseph, Kessy","year":2016,"journal":"The Journal of school health, 86(1), 31-8","doi":"10.1111/josh.12351","pmid":"26645418","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined data from 2,835 US 12th graders to determine which substance adolescents use first and how the age of first use relates to later drug involvement.\n\nAlcohol was the most commonly used substance, and the majority of polysubstance users consumed alcohol before trying tobacco or marijuana. This challenges the popular \"gateway drug\" narrative that typically focuses on marijuana.\n\nStudents who started drinking in 6th grade reported significantly more lifetime illicit substance use and more frequent illicit substance use than those who began in 9th grade or later. The effect sizes for these differences were large (eta squared = 0.30 and 0.28).","whyItMatters":"The finding that alcohol, not marijuana, is the most common entry point to substance use has implications for prevention priorities. It suggests that school-based prevention programs targeting alcohol use, potentially starting as early as third grade, could have a greater impact on reducing later illicit drug use.","specificNumbers":"2,835 12th graders sampled. Alcohol was the most common first substance. 6th-grade alcohol initiators: mean 1.9 illicit substances (SD 1.7) and mean frequency of 6.0 (SD 6.5). 9th-grade-or-later initiators had significantly lower use. Effect sizes: eta squared = 0.30 and 0.28 (large).","methodology":"The study analyzed data from a nationally representative sample of 2,835 US 12th graders. Researchers examined the sequence of substance initiation (alcohol, tobacco, marijuana) and used statistical analysis to compare illicit drug use outcomes based on age of first alcohol use.","limitations":"The cross-sectional design captures associations at one time point rather than following students over time. Self-reported substance use may be inaccurate. The study cannot determine whether early alcohol use causes later illicit drug use or whether both reflect common underlying risk factors."},{"rthcId":"RTHC-01099","title":"Prenatal, perinatal, and adolescent exposure to marijuana: Relationships with aggressive behavior.","authors":"Barthelemy, Olivier J; Richardson, Mark A; Cabral, Howard J; Frank, Deborah A","year":2016,"journal":"Neurotoxicology and teratology, 58, 60-77","doi":"10.1016/j.ntt.2016.06.009","pmid":"27345271","tags":["pregnancy","youth","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the evidence linking marijuana exposure at three developmental periods (prenatal, perinatal, and adolescent) to aggressive behavior.\n\nFor prenatal exposure, the evidence provided minimal support for a direct relationship with aggressive behavior in childhood. For adolescent use, acute intoxication showed at best a marginal association with aggression, while the association between chronic use and aggression was heavily influenced by demographic variables rather than direct pharmacological effects.\n\nCannabis withdrawal can include anger and irritability, but the evidence suggests these effects are not large or specific to cannabis compared to withdrawal from other substances.","whyItMatters":"Concerns about cannabis and violence or aggression frequently arise in public discourse. This review provides a more nuanced picture: the association is weak and largely explained by confounding factors, which is important for evidence-based policy and clinical discussions.","specificNumbers":"No new quantitative data were presented. The review synthesized existing literature across prenatal, perinatal, and adolescent exposure periods.","methodology":"This was a comprehensive review examining animal research, human prenatal exposure studies, and adolescent use studies. The review identified potential psychosocial and psychopharmacological mechanisms as well as relevant confounding factors.","limitations":"As a narrative review, the selection and emphasis of studies may reflect the authors' perspective. The review noted that confounding factors make it inherently difficult to isolate the effect of cannabis from co-occurring risk factors. The literature on prenatal exposure and long-term behavioral outcomes remains limited."},{"rthcId":"RTHC-01100","title":"Gender Dysphoria and Social Anxiety: An Exploratory Study in Spain.","authors":"Bergero-Miguel, Trinidad; García-Encinas, María A; Villena-Jimena, Amelia; Pérez-Costillas, Lucía; Sánchez-Álvarez, Nicolás; de Diego-Otero, Yolanda; Guzman-Parra, Jose","year":2016,"journal":"The journal of sexual medicine, 13(8), 1270-8","doi":"10.1016/j.jsxm.2016.05.009","pmid":"27319274","tags":["mental-health","anxiety"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers studied social anxiety among 210 individuals attending a public gender identity unit in Spain. The prevalence of social anxiety disorder was 31.4%, substantially higher than general population estimates.\n\nIn multivariable analysis, the strongest predictors of social anxiety disorder were depression score and current cannabis use, which was associated with nearly 4-fold increased odds of social anxiety (OR = 3.873). Other associated factors included younger age, hospitalization of parents during childhood, and nationality.\n\nSocial anxiety was also significantly associated with lifetime suicidal ideation, non-suicidal self-injury, perceived school violence during childhood, and unemployment.","whyItMatters":"The high rate of social anxiety in this population highlights an underrecognized mental health burden. The strong association with cannabis use raises questions about whether individuals with gender dysphoria and social anxiety may use cannabis as self-medication, or whether cannabis use exacerbates social anxiety in this vulnerable group.","specificNumbers":"210 participants (48% trans female, 52% trans male). 31.4% had social anxiety disorder. Cannabis use: OR = 3.873 for social anxiety. Depression: OR = 1.083 per BDI point. Lifetime suicidal ideation: RR = 1.902.","methodology":"A cross-sectional study of 210 individuals (48% trans female, 52% trans male) attending a public gender identity unit in Spain. Social anxiety was diagnosed using the Mini-International Neuropsychiatric Interview. Multiple validated instruments assessed depression, violence exposure, and social support.","limitations":"The cross-sectional design cannot determine whether cannabis use contributes to social anxiety or whether socially anxious individuals are more likely to use cannabis. The sample came from a single clinic in Spain and may not represent all individuals with gender dysphoria. The study assessed current cannabis use without measuring frequency or amount."},{"rthcId":"RTHC-01101","title":"A systematic review of passive exposure to cannabis.","authors":"Berthet, Aurélie; De Cesare, Mariangela; Favrat, Bernard; Sporkert, Frank; Augsburger, Marc; Thomas, Aurélien; Giroud, Christian","year":2016,"journal":"Forensic science international, 269, 97-112","doi":"10.1016/j.forsciint.2016.11.017","pmid":"27883985","tags":["harm-reduction","driving"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This systematic review identified biomarkers that can distinguish passive cannabis smoke exposure from active use across multiple biological matrices.\n\nIn everyday conditions, urinary THC-COOH levels from passive exposure should fall below standard positivity thresholds, especially when normalized to creatinine levels. In blood, passive exposure produces very low THC and THC-COOH concentrations compared to active use.\n\nIn hair, oral fluid, and sweat, the absence of THC-COOH is a key indicator. Its presence in hair suggests regular consumption; in oral fluid or sweat, it indicates recent use. However, under extreme exposure conditions (heavily smoky, unventilated environments), positive tests can occur even from passive exposure across all matrices.\n\nThe authors recommended that people who must demonstrate cannabis abstinence should avoid heavily smoky, unventilated environments.","whyItMatters":"Distinguishing passive from active cannabis exposure has important legal, occupational, and forensic implications. A false positive from secondhand smoke could have consequences for employment, custody disputes, driving enforcement, and drug treatment compliance monitoring.","specificNumbers":"958 papers identified, 21 selected for review. THC-COOH in urine should be below positivity thresholds after passive exposure (especially creatinine-normalized). Blood THC and THC-COOH concentrations from passive exposure are very low. THC-COOH absence in hair, oral fluid, and sweat indicates no active use.","methodology":"A systematic review was conducted, identifying 958 papers on passive cannabis exposure and selecting 21 for detailed analysis. Studies examined biomarkers in urine, blood, oral fluid, hair, and sebum following controlled passive exposure conditions.","limitations":"The review acknowledged that extreme passive exposure conditions can produce positive results. Real-world passive exposure varies widely based on ventilation, proximity, duration, and cannabis potency. The studies reviewed used controlled laboratory conditions that may not perfectly represent real-world scenarios."},{"rthcId":"RTHC-01102","title":"Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline.","authors":"Bhandari, Sanjay; Venkatesan, Thangam","year":2016,"journal":"Current treatment options in gastroenterology, 14(4), 495-506","doi":null,"pmid":"27757817","tags":["withdrawal","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined treatment options for cyclic vomiting syndrome (CVS), a disorder of episodic severe nausea and vomiting, and addressed the complicated relationship between CVS and cannabis.\n\nThe recognition that chronic cannabis use is associated with cyclic vomiting led to the proposed diagnosis of \"cannabinoid hyperemesis syndrome\" (CHS), which presents identically to CVS. The standard recommendation is cannabis abstinence, though the review noted there is \"scant evidence\" that marijuana use is actually causative.\n\nThe review explored the possibility that the endocannabinoid system may be involved in CVS pathophysiology regardless of cannabis use, and that therapeutic agents targeting this system could transform patient care. It also discussed prophylactic and abortive treatments and general management strategies.","whyItMatters":"CVS is often misdiagnosed, leading to years of unnecessary testing and treatment delays. The overlap with cannabinoid hyperemesis syndrome creates diagnostic confusion, and the review suggests the relationship may be more nuanced than simply \"cannabis causes vomiting.\"","specificNumbers":"No specific trial results were presented. The review noted CVS was initially thought to only affect children but is increasingly recognized in adults, and that there is an absence of randomized controlled trials for CVS treatment.","methodology":"This was a clinical review examining published literature and expert consensus on CVS treatment. Due to the absence of randomized controlled trials for CVS, recommendations were based on available evidence and clinical experience.","limitations":"No randomized controlled trials exist for CVS treatment, so all recommendations are based on lower-quality evidence. The distinction between CVS and CHS remains debated. The review presented one perspective on the cannabis-vomiting relationship that is not universally accepted."},{"rthcId":"RTHC-01103","title":"Metabolism of endocannabinoids.","authors":"Biernacki, Michał; Skrzydlewska, Elżbieta","year":2016,"journal":"Postepy higieny i medycyny doswiadczalnej (Online), 70(0), 830-43","doi":null,"pmid":"27516570","tags":["neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review provided a detailed account of how the body produces and breaks down its two main endocannabinoids: anandamide (AEA) and 2-arachidonoylglycerol (2-AG).\n\nBoth are synthesized from phospholipids in cell membranes. Anandamide is formed from N-arachidonoyl phosphatidylethanolamine through multiple enzymatic pathways. 2-AG is produced primarily through DAGL-mediated hydrolysis of phosphatidylinositol.\n\nThe primary role of endocannabinoids is activating cannabinoid receptors, with 2-AG having stronger affinity than anandamide. Unbound endocannabinoids are degraded: anandamide mainly by FAAH, 2-AG mainly by MAGL. Beyond hydrolysis, both can be oxidized by cyclooxygenase-2, lipoxygenases, and cytochrome P450 enzymes, producing metabolites that also have biological significance.","whyItMatters":"Understanding how the body makes and breaks down its own cannabinoids is fundamental to understanding both the effects of external cannabinoids (like THC) and the development of drugs that target the endocannabinoid system for therapeutic purposes.","specificNumbers":"Two main endocannabinoids: anandamide and 2-AG. Both are primarily CB1 agonists, with weaker CB2 and TRPV1 activity. 2-AG has stronger receptor affinity. Primary degradation enzymes: FAAH (anandamide) and MAGL (2-AG). Additional oxidative metabolism by COX-2, lipoxygenases, and cytochrome P450.","methodology":"This was a comprehensive review of endocannabinoid biochemistry published in a Polish journal of hygiene and experimental medicine, synthesizing the current understanding of endocannabinoid synthesis, receptor interactions, and degradation pathways.","limitations":"This was a review of known biochemistry rather than new research. The complexity of endocannabinoid metabolism means many details and regulatory mechanisms remain to be fully characterized. The biological significance of oxidative endocannabinoid metabolites is still being explored."},{"rthcId":"RTHC-01104","title":"Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats.","authors":"Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka; Toczek, Marek; Bielawska, Katarzyna; Skrzydlewska, Elżbieta","year":2016,"journal":"Toxicology and applied pharmacology, 301, 31-41","doi":"10.1016/j.taap.2016.04.006","pmid":"27086176","tags":["neuroscience","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether URB597, a FAAH inhibitor that increases anandamide levels, could help or harm liver health in rats with salt-induced hypertension.\n\nHypertension itself already elevated endocannabinoid levels (anandamide, 2-AG, and NADA) and CB1 receptors while increasing oxidative stress and decreasing antioxidant capacity in the liver.\n\nAdding URB597 further increased anandamide, NADA, and CB1 receptor levels. Rather than being protective, this additional endocannabinoid elevation decreased vitamin E and C levels, reduced antioxidant enzyme activities, lowered the protective transcription factor Nrf2, and increased oxidative damage to lipids, DNA, and proteins. The one positive effect was reduced inflammatory response.","whyItMatters":"FAAH inhibitors are being explored as potential therapeutics for various conditions. This study reveals an important caution: boosting endocannabinoid levels in the liver of hypertensive animals worsened oxidative stress despite reducing inflammation, highlighting the complexity of the endocannabinoid system in disease states.","specificNumbers":"Hypertension increased AEA, 2-AG, NADA, and CB1 levels. URB597 further increased AEA, NADA, and CB1. URB597 decreased vitamin E, vitamin C, glutathione peroxidase, glutathione reductase, and Nrf2 expression. Oxidative modifications to lipids, DNA, and proteins were increased. Inflammatory response was reduced.","methodology":"DOCA-salt hypertensive rats received chronic URB597 treatment. Liver tissue was analyzed for endocannabinoid levels, receptor expression, enzyme activities, antioxidant markers, oxidative modifications of lipids/DNA/proteins, transcription factor expression, and inflammatory markers.","limitations":"This was an animal study using a specific model of hypertension (DOCA-salt), which may not represent all forms of hypertension. Only liver tissue was examined. Chronic dosing protocols in rats may not reflect potential human therapeutic regimens. The study assessed biochemical markers rather than functional liver outcomes."},{"rthcId":"RTHC-01105","title":"The Use of Medical Marijuana in Cancer.","authors":"Birdsall, Shauna M; Birdsall, Timothy C; Tims, Lucas A","year":2016,"journal":"Current oncology reports, 18(7), 40","doi":"10.1007/s11912-016-0530-0","pmid":"27215434","tags":["cancer","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review addressed the state of evidence for medical marijuana in cancer care, identifying both the potential and the significant knowledge gaps.\n\nOn the benefit side, cannabis may help with cancer-related symptoms including nausea, pain, appetite loss, and possibly neuropathy. Preclinical data suggest potential anticancer effects, but no clinical trials had confirmed these in humans.\n\nOn the practical side, the review noted a disconnect: medical marijuana was legal in 24 states plus DC but remained federally illegal, creating challenges for research, prescribing, and quality control. Evidence-based dosing and administration guidance were described as lacking, and the quality of available cannabis products was inconsistent.","whyItMatters":"Cancer patients are among the most common medical cannabis users, yet many oncologists feel unprepared to discuss cannabis due to limited evidence. This review highlighted the need for clinical trials and standardized dosing to bridge the gap between patient demand and evidence-based medicine.","specificNumbers":"Medical marijuana legal in 24 states plus DC at time of publication. Federal Schedule I classification persisted. Evidence-based dosing information was described as lacking.","methodology":"This was a clinical review published in Current Oncology Reports, examining published research on cannabis in cancer care, including symptom management studies, preclinical anticancer research, legal considerations, and ongoing clinical trials.","limitations":"This was a narrative review that acknowledged the insufficient evidence on many topics it covered. The legal landscape described has since changed. The review could not provide definitive guidance on efficacy due to the limited trial data available."},{"rthcId":"RTHC-01106","title":"Cannabis Use and Risk of Psychiatric Disorders: Prospective Evidence From a US National Longitudinal Study.","authors":"Blanco, Carlos; Hasin, Deborah S; Wall, Melanie M; Flórez-Salamanca, Ludwing; Hoertel, Nicolas; Wang, Shuai; Kerridge, Bradley T; Olfson, Mark","year":2016,"journal":"JAMA psychiatry, 73(4), 388-95","doi":"10.1001/jamapsychiatry.2015.3229","pmid":"26886046","tags":["mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers followed a nationally representative sample of over 34,000 US adults over three years to examine whether cannabis use predicted the development of psychiatric disorders.\n\nAfter adjusting for a comprehensive set of confounders (demographics, family history, childhood adversity, prior psychiatric disorders, and more), cannabis use was strongly associated with subsequent substance use disorders: 6.2x for any substance use disorder, 9.5x for cannabis use disorder, 2.7x for alcohol use disorder, 2.6x for other drug use disorder, and 1.7x for nicotine dependence.\n\nHowever, cannabis use was not significantly associated with developing any mood disorder (OR 1.1) or any anxiety disorder (OR 0.9). These patterns held across multiple analytical approaches including propensity score matching.","whyItMatters":"This is one of the largest prospective studies to examine cannabis and psychiatric risk, and its pattern of results is notable: strong associations with substance use disorders but not with mood or anxiety disorders. This nuances the debate about cannabis and mental health by distinguishing which psychiatric outcomes are and are not associated with use.","specificNumbers":"34,653 respondents. 1,279 reported cannabis use at wave 1. Odds ratios for subsequent disorders: any substance use disorder 6.2, cannabis use disorder 9.5, alcohol use disorder 2.7, other drug use disorder 2.6, nicotine dependence 1.7. Any mood disorder 1.1 (not significant). Any anxiety disorder 0.9 (not significant).","methodology":"Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), with interviews at wave 1 (2001-2002) and wave 2 (2004-2005). The analysis included 34,653 respondents. Psychiatric disorders were assessed with structured diagnostic interviews. Multiple regression and propensity score matching were used, controlling for demographics, family history, childhood adversity, self-esteem, social deviance, recent trauma, and prior psychiatric conditions.","limitations":"Despite the large sample and prospective design, the study cannot prove causation. People who use cannabis may differ from non-users in ways not captured by the confounders measured. The three-year follow-up may be too short to detect slower-developing conditions. Cannabis potency and use patterns have changed since 2001-2005."},{"rthcId":"RTHC-01107","title":"Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain.","authors":"Boehnke, Kevin F; Litinas, Evangelos; Clauw, Daniel J","year":2016,"journal":"The journal of pain, 17(6), 739-44","doi":"10.1016/j.jpain.2016.03.002","pmid":"27001005","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 244 medical cannabis patients with chronic pain at a Michigan dispensary about how starting cannabis changed their medication patterns and quality of life.\n\nAmong participants, medical cannabis use was associated with a 64% decrease in opioid use (based on 118 patients who had previously used opioids). Patients also reported a decreased number of medications overall, fewer medication side effects, and a 45% improvement in quality of life.\n\nThe findings suggest that many chronic pain patients are substituting medical cannabis for opioids and other medications, and perceive the benefit and side effect profile of cannabis as superior.","whyItMatters":"In the context of the opioid crisis, any intervention that helps chronic pain patients reduce opioid use while maintaining or improving quality of life is significant. This study provides patient-level data supporting what population-level studies (linking medical cannabis laws to reduced opioid overdoses) have suggested.","specificNumbers":"244 patients surveyed. 64% decrease in opioid use (n=118 opioid users). 45% improvement in quality of life. Decreased number of total medications. Fewer medication side effects reported.","methodology":"An online cross-sectional retrospective survey of 244 medical cannabis patients with chronic pain who patronized a Michigan dispensary between November 2013 and February 2015. Participants self-reported changes in opioid use, medication use, quality of life, and side effects before and after starting cannabis.","limitations":"This was a self-reported retrospective survey with no control group or objective verification of medication changes. Dispensary patients who chose to respond may not represent all medical cannabis users. Selection bias is likely: patients who found cannabis helpful were probably more likely to continue visiting the dispensary and to participate. The survey design cannot determine whether cannabis actually caused the opioid reduction."},{"rthcId":"RTHC-01108","title":"Delta-9-tetrahydrocannabinol and cannabidiol: Separating the chemicals from the \"weed,\" a pharmacodynamic discussion.","authors":"Boggs, Douglas Lee; Peckham, Alyssa; Boggs, Angela A; Ranganathan, Mohini","year":2016,"journal":"The mental health clinician, 6(6), 277-284","doi":"10.9740/mhc.2016.11.277","pmid":"29955482","tags":["cbd","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the pharmacodynamic interplay between THC and CBD, the two most studied of the 70+ phytocannabinoids in cannabis.\n\nTHC directly activates CB1 and CB2 cannabinoid receptors, producing its well-known psychoactive effects. CBD, by contrast, has very low affinity for these receptors and works through other mechanisms. Evidence suggests CBD can decrease some of the psychomimetic (psychosis-like) effects of THC.\n\nThis opposing relationship between THC and CBD led to the development of Nabiximols (Sativex), a pharmaceutical spray containing a roughly 1:1 ratio of THC to CBD, approved for moderate to severe spasticity in multiple sclerosis.","whyItMatters":"Understanding that THC and CBD have opposing effects helps explain why different cannabis strains and products produce different experiences. It also has practical implications for medical cannabis formulation and for understanding why high-THC, low-CBD products may carry greater risk.","specificNumbers":"Cannabis contains more than 70 phytocannabinoids. THC and CBD are the two most studied. Nabiximols contains a roughly 1:1 THC:CBD ratio.","methodology":"This was a pharmacodynamic review published in The Mental Health Clinician, examining the evidence for how THC and CBD interact at the receptor and cellular level.","limitations":"The abstract provided limited mechanistic detail. The evidence for CBD reducing THC's effects comes from specific experimental paradigms and may not apply uniformly to all of THC's actions. The optimal ratio of THC to CBD for therapeutic purposes remains unclear."},{"rthcId":"RTHC-01109","title":"Cannabis and its effects on driving skills.","authors":"Bondallaz, Percy; Favrat, Bernard; Chtioui, Haïthem; Fornari, Eleonora; Maeder, Philippe; Giroud, Christian","year":2016,"journal":"Forensic science international, 268, 92-102","doi":"10.1016/j.forsciint.2016.09.007","pmid":"27701009","tags":["driving","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized evidence from laboratory, simulator, on-road, and brain imaging studies to assess how cannabis affects driving performance.\n\nCannabis impaired actual driving by increasing lane weaving and the mean distance to the vehicle ahead. Specific cognitive functions and psychomotor abilities showed acute and long-term dose-dependent impairments that extended beyond several weeks after stopping use.\n\nCombined use of alcohol and cannabis produced greater odds of driving errors than either substance alone. Blood sampling was identified as the most effective method for evaluating driver impairment, and blood tests could also identify chronic use suggesting long-term unfitness to drive. Some inconsistencies between studies were attributed to differences in cannabis use history, route of administration, dose, and study design.","whyItMatters":"As cannabis legalization expands, understanding its effects on driving becomes a public safety priority. This review consolidates evidence showing that cannabis impairs driving performance through multiple mechanisms, and that the effects can persist well beyond the period of acute intoxication.","specificNumbers":"Cannabis increased lane weaving and mean headway distance in on-road studies. Cognitive impairments extended beyond several weeks after cessation. Combined alcohol-cannabis use increased error rates beyond either substance alone.","methodology":"This was a comprehensive review examining laboratory studies, driving simulator studies, on-road driving studies, and structural and functional brain imaging research on cannabis and driving performance.","limitations":"Discrepancies between studies were noted, partly due to differences in participant cannabis use history, tolerance development, and study methodology. The correlation between blood THC levels and actual impairment remains poorly understood. Most studies used controlled laboratory or simulator settings rather than real-world driving."},{"rthcId":"RTHC-01110","title":"An Overlooked Victim of Cannabis: Losing Several Years of Well-being and Inches of Jejunum on the Way to Unravel Her Hyperemesis Enigma.","authors":"Bonnet, Udo","year":2016,"journal":"Clinical neuropharmacology, 39(1), 53-4","doi":"10.1097/WNF.0000000000000118","pmid":"26757305","tags":["withdrawal","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report described a patient with severe cannabinoid hyperemesis syndrome (CHS) that was notable for two reasons.\n\nFirst, the patient's symptoms worsened when she received dronabinol (a synthetic isomer of THC), providing what the authors called \"first direct clinical evidence\" that THC plays a key role in CHS pathogenesis. This strengthens the case that THC, rather than other cannabis compounds, drives the condition.\n\nSecond, the patient experienced an extended diagnostic odyssey with multiple hospital stays and extensive workups before she herself discovered the correct diagnosis via internet research. This pattern of delayed diagnosis is common in CHS because clinicians typically associate cannabis with anti-nausea effects, not vomiting. The patient became symptom-free during 12 months of confirmed cannabis abstinence.","whyItMatters":"The worsening of symptoms with prescription THC is a particularly telling observation, as it isolates THC from the many other compounds in cannabis. This case also highlights the ongoing problem of CHS being misdiagnosed or unrecognized, leading to unnecessary medical interventions.","specificNumbers":"12 months of controlled abstinence with complete symptom resolution. Multiple hospital stays with extensive workups before correct diagnosis.","methodology":"This was a single case report published in a clinical neuropharmacology journal, describing the clinical course, diagnostic challenges, and treatment outcome.","limitations":"Single case reports cannot establish causality or generalize to all CHS patients. The patient may have had unique characteristics that made her particularly susceptible. The mechanism by which THC causes emesis paradoxically remains incompletely understood."},{"rthcId":"RTHC-01111","title":"A literature review and meta-analyses of cannabis use and suicidality.","authors":"Borges, Guilherme; Bagge, Courtney L; Orozco, Ricardo","year":2016,"journal":"Journal of affective disorders, 195, 63-74","doi":"10.1016/j.jad.2016.02.007","pmid":"26872332","tags":["mental-health","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"This review and meta-analysis examined the relationship between cannabis use and suicidality across three outcomes: suicide death, suicidal ideation, and suicide attempt.\n\nFor chronic cannabis use, the pooled odds ratios from meta-analyses were: suicide death (2.56, based on 4 studies), suicidal ideation with any use (1.43, from 6 studies) and heavy use (2.53, from 5 studies), and suicide attempt with any use (2.23, from 6 studies) and heavy use (3.20, from 6 studies).\n\nFor acute cannabis use, the evidence was mostly limited to toxicology reports finding cannabis in approximately 9.5% of suicide decedents, with higher detection rates among those who died by non-overdose methods. The authors concluded that chronic cannabis use can predict suicidality, but noted inconsistent measurement of cannabis exposure and sometimes inadequate control for known risk factors.","whyItMatters":"These findings quantify the association between cannabis use and suicide risk across multiple outcomes. The dose-response pattern (heavier use associated with greater risk) adds plausibility to the association, though the authors cautioned about confounding.","specificNumbers":"Suicide death: OR 2.56 (4 studies). Suicidal ideation (any use): OR 1.43 (6 studies). Suicidal ideation (heavy use): OR 2.53 (5 studies). Suicide attempt (any use): OR 2.23 (6 studies). Suicide attempt (heavy use): OR 3.20 (6 studies). Acute cannabis detection in suicides: 9.5%.","methodology":"Systematic search of Medline, PsychInfo, Google Scholar, and public databases for the period 1990-2015. Random effects meta-analyses were conducted separately for any cannabis use versus heavy cannabis use and for each suicidality outcome.","limitations":"The authors acknowledged lack of homogeneity in how cannabis exposure was measured across studies, and in some cases insufficient control for known suicide risk factors (depression, other substance use, childhood adversity). The number of studies for some outcomes was small (4 for suicide death). Observational data cannot prove cannabis causes suicidality."},{"rthcId":"RTHC-01112","title":"Cannabinoid hyperemesis syndrome masquerading as an eating disorder.","authors":"Brewerton, Timothy D; Anderson, Odette","year":2016,"journal":"The International journal of eating disorders, 49(8), 826-9","doi":"10.1002/eat.22515","pmid":"26842268","tags":["withdrawal","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report highlighted a diagnostic overlap between cannabinoid hyperemesis syndrome (CHS) and eating disorders. A 22-year-old woman with a documented history of anorexia nervosa (binge-purge type), major depression, and OCD presented with episodic vomiting that was initially attributed to her eating disorder.\n\nThe correct diagnosis of CHS was complicated by three factors: her genuine history of an eating disorder made clinicians attribute the vomiting to purging behavior; she initially denied cannabis use; and the episodic nature of CHS can mimic cyclic vomiting patterns seen in eating disorders.\n\nCollateral history from family and a positive drug screen ultimately confirmed the CHS diagnosis.","whyItMatters":"As both cannabis use and eating disorder awareness increase, clinicians may encounter patients where these conditions overlap or mimic each other. Missing a CHS diagnosis in an eating disorder patient could lead to inappropriate treatment, while missing an eating disorder in a CHS patient could delay needed care.","specificNumbers":"Patient age: 22. Diagnoses: anorexia nervosa (binge-purge type), major depressive disorder, OCD, migraine, and CHS.","methodology":"This was a clinical case report published in the International Journal of Eating Disorders, describing the diagnostic process, clinical presentation, and implications for eating disorder clinicians.","limitations":"Single case reports cannot establish diagnostic guidelines or generalize to all patients. The coexistence of anorexia nervosa and CHS in this case may be uncommon. The case does not clarify whether CHS and eating disorder behaviors can mutually reinforce each other."},{"rthcId":"RTHC-01113","title":"Use of cannabis during pregnancy and birth outcomes in an Aboriginal birth cohort: a cross-sectional, population-based study.","authors":"Brown, Stephanie J; Mensah, Fiona K; Ah Kit, Jackie; Stuart-Butler, Deanna; Glover, Karen; Leane, Cathy; Weetra, Donna; Gartland, Deirdre; Newbury, Jonathan; Yelland, Jane","year":2016,"journal":"BMJ open, 6(2), e010286","doi":"10.1136/bmjopen-2015-010286","pmid":"26908527","tags":["pregnancy","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 344 Aboriginal women giving birth in South Australia to assess whether cannabis use during pregnancy was associated with adverse birth outcomes.\n\nOne in five women (20.5%) used cannabis during pregnancy, and 52% smoked cigarettes. Compared to mothers who used neither cannabis nor cigarettes, mothers who used cannabis had babies that were on average 565 grams lighter, were 6.5 times more likely to have low birth weight, and 3.8 times more likely to be small for gestational age.\n\nAfter adjusting for education, social characteristics, and exposure to stressful life events, the odds of low birth weight remained elevated at 3.9 times higher for cannabis-using mothers. The persistence of this association after controlling for social determinants suggests a biological effect of cannabis on fetal growth.","whyItMatters":"Indigenous communities already experience rates of stillbirth, preterm birth, and low birth weight two to three times higher than other populations. The finding that cannabis use is independently associated with reduced birth weight even after accounting for social factors highlights an additional, potentially modifiable risk factor.","specificNumbers":"344 women surveyed. 20.5% used cannabis during pregnancy. 52% smoked cigarettes. Cannabis users' babies were 565g lighter on average. Unadjusted OR for low birth weight: 6.5. Adjusted OR: 3.9. OR for small for gestational age: 3.8.","methodology":"Cross-sectional, population-based survey of women giving birth to Aboriginal babies in South Australia from July 2011 to June 2013. Data included cannabis use, cigarette smoking, stressful events, social health issues, and birth outcomes (weight and gestational age). Sample of 344 women representative of the broader population.","limitations":"Self-reported cannabis use may undercount actual use. The cross-sectional design limits causal inference. Cannabis and cigarette use overlapped substantially, making it difficult to fully separate their effects. The sample represented one geographic region and may not generalize to all Aboriginal communities."},{"rthcId":"RTHC-01114","title":"Behavioral Characterization of the Effects of Cannabis Smoke and Anandamide in Rats.","authors":"Bruijnzeel, Adriaan W; Qi, Xiaoli; Guzhva, Lidia V; Wall, Shannon; Deng, Jie V; Gold, Mark S; Febo, Marcelo; Setlow, Barry","year":2016,"journal":"PloS one, 11(4), e0153327","doi":"10.1371/journal.pone.0153327","pmid":"27065006","tags":["neuroscience","addiction","withdrawal"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers exposed rats to actual cannabis smoke (not just THC) to study behavioral effects, including whether it produces dependence.\n\nCannabis smoke caused a biphasic effect on locomotor activity: a brief increase followed by a prolonged decrease in movement and rearing behavior. The CB1 receptor antagonist rimonabant increased activity and prevented the smoke-induced decrease in rearing, confirming CB1 receptor involvement.\n\nIn a larger open field and elevated plus maze, smoke-exposed rats showed increased activity and spent more time in the center zone, suggesting reduced anxiety. Importantly, chronic cannabis smoke exposure produced physical dependence: rimonabant-precipitated withdrawal produced more somatic signs in smoke-exposed rats than air-control rats.\n\nSerum THC levels after smoke exposure (225 ng/mL) were similar to levels found in humans after smoking cannabis.","whyItMatters":"Most cannabis research uses purified THC rather than actual cannabis smoke, which contains many other compounds. This study used smoke exposure that produced clinically relevant blood THC levels, making it more translatable. The demonstration of physical dependence from smoke exposure adds to evidence that cannabis can produce physiological dependence.","specificNumbers":"Serum THC: 225 ng/mL after smoke exposure (similar to human levels). Cannabis smoke produced biphasic locomotor effects. Rimonabant precipitated more withdrawal signs in smoke-exposed rats. CBD and other cannabinoids were present in the smoke alongside THC.","methodology":"Cannabis cigarettes containing 5.7% THC were burned in a smoking machine. Rats were tested in small and large open fields and the elevated plus maze. CB1 antagonist rimonabant was used to probe receptor involvement and precipitate withdrawal. Anandamide effects were also tested. Serum THC was measured.","limitations":"Rats were exposed passively to smoke, which differs from voluntary human smoking. The cannabis cigarettes contained a specific THC concentration (5.7%) that may differ from current commercially available cannabis. Behavioral effects in rats do not directly translate to human subjective experience. The dependence model used precipitated withdrawal, which may overestimate the severity of spontaneous withdrawal."},{"rthcId":"RTHC-01115","title":"Effects of Marijuana Use on Brain Structure and Function: Neuroimaging Findings from a Neurodevelopmental Perspective.","authors":"Brumback, T; Castro, N; Jacobus, J; Tapert, S","year":2016,"journal":"International review of neurobiology, 129, 33-65","doi":"10.1016/bs.irn.2016.06.004","pmid":"27503447","tags":["youth","cognition","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined neuroimaging evidence on how marijuana affects brain structure and function, with a focus on developmental timing.\n\nA wide range of research has documented neurocognitive deficits associated with marijuana use, particularly when use begins during childhood or adolescence. Neuroimaging studies have begun to reveal potential mechanisms, showing alterations in both brain structure (volume, white matter integrity) and brain function (activation patterns during cognitive tasks).\n\nThe review used a neurodevelopmental framework to contextualize these findings, noting that the adolescent brain is particularly vulnerable because key processes like myelination and synaptic pruning are still ongoing during this period.","whyItMatters":"Understanding the brain mechanisms behind cannabis-related cognitive deficits is important for both clinical practice and public health messaging. The neurodevelopmental framework highlights why adolescent exposure is of particular concern.","specificNumbers":"The review noted marijuana is the third most popular recreational drug in America (behind tobacco and alcohol) with rising prevalence rates. Specific neuroimaging findings varied across studies.","methodology":"This was a review chapter examining recent neuroimaging data (structural MRI, functional MRI, diffusion tensor imaging) on brain changes associated with marijuana use, organized within a neurodevelopmental framework.","limitations":"Most neuroimaging studies are cross-sectional, meaning they cannot determine whether observed brain differences existed before cannabis use began. Differences in study populations, cannabis use patterns, and neuroimaging methods make direct comparisons difficult. The review noted the need for longitudinal studies that follow individuals from before cannabis initiation."},{"rthcId":"RTHC-01116","title":"Unusual side effect of cannabis use: acute abdomen due to duodenal perforation.","authors":"Buyukbese Sarsu, Sevgi","year":2016,"journal":"International journal of emergency medicine, 9(1), 18","doi":"10.1186/s12245-016-0114-7","pmid":"27387191","tags":["synthetic-cannabinoids","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report described a 16-year-old male who presented to the emergency department with abdominal distension, pain, and bilious vomiting. He had been regularly using synthetic cannabinoids (\"bonsai\") for 3 years.\n\nImaging revealed free air under the diaphragm, indicating perforation. Emergency surgery (laparotomy) found a perforation in the first part of the duodenum. Surgical repair with an omental patch (Graham patch) was successful, and the patient recovered without complications.\n\nThe authors attributed the peptic ulcer disease and perforation to the chronic effects of synthetic cannabinoids on gastric secretion and gastric emptying, noting that this is a rarely recognized complication.","whyItMatters":"Gastrointestinal perforation is a life-threatening complication that is not typically associated with substance use in adolescents. This case highlights that chronic synthetic cannabinoid use can produce serious gastrointestinal complications beyond the better-known CHS.","specificNumbers":"Patient age: 16. Duration of synthetic cannabinoid use: 3 years. Perforation location: first part of duodenum. Repair: Graham patch. Outcome: uncomplicated recovery.","methodology":"Single case report with clinical description, imaging findings, surgical intervention, and postoperative follow-up.","limitations":"A single case report cannot establish a causal relationship between synthetic cannabinoid use and duodenal perforation. The patient may have had other risk factors for peptic ulcer disease. The specific synthetic cannabinoid compounds used were not identified."},{"rthcId":"RTHC-01117","title":"Attention deficit hyperactivity disorder and drug addiction rehabilitation patients.","authors":"Camargo, Carlos Henrique Ferreira; Dornelles, Tarcísio Fanha; Barszcz, Karin; Martins, Eduardo Antunes","year":2016,"journal":"Arquivos de neuro-psiquiatria, 74(12), 1003-1007","doi":"10.1590/0004-282X20160163","pmid":"27991999","tags":["addiction","cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers evaluated 80 adult patients in therapeutic communities (drug rehabilitation) for ADHD and substance use patterns.\n\nWhile the overall prevalence of drug use did not differ between ADHD and non-ADHD patients, important pattern differences emerged. ADHD patients were admitted to rehabilitation at younger ages (p=0.004) and first used cocaine at younger ages (p=0.033).\n\nAmong ADHD patients specifically, there was a significant negative correlation between age of first cannabis use and subsequent severity of both cannabis use (p=0.017) and cocaine use (p=0.033). In other words, the earlier ADHD patients started using cannabis, the more severe their later use of both cannabis and cocaine became.","whyItMatters":"ADHD is common among people seeking substance use treatment, and this study suggests it may be associated with different addiction trajectories. The finding that earlier cannabis use in ADHD patients predicted more severe cocaine and cannabis use could inform targeted prevention strategies.","specificNumbers":"80 patients studied. ADHD patients had younger admission age (p=0.004) and earlier cocaine initiation (p=0.033). In ADHD patients: earlier cannabis use correlated with more severe cannabis use (p=0.017) and cocaine use (p=0.033).","methodology":"Cross-sectional study of 80 adult patients in therapeutic communities. ADHD presence and severity were assessed through validated questionnaires, alongside substance use history and patterns.","limitations":"The small sample size (80 patients) limits statistical power. The cross-sectional design cannot determine whether ADHD causes earlier substance use or whether other factors are involved. Patients in therapeutic communities represent the most severe end of substance use disorders and may not represent all ADHD individuals who use substances."},{"rthcId":"RTHC-01118","title":"Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on \"tetrad\", sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies.","authors":"Canazza, Isabella; Ossato, Andrea; Trapella, Claudio; Fantinati, Anna; De Luca, Maria Antonietta; Margiani, Giulia; Vincenzi, Fabrizio; Rimondo, Claudia; Di Rosa, Fabiana; Gregori, Adolfo; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; Marti, Matteo","year":2016,"journal":"Psychopharmacology, 233(21-22), 3685-3709","doi":null,"pmid":"27527584","tags":["synthetic-cannabinoids","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers conducted the first comprehensive pharmacological characterization of AKB48 and its fluorinated derivative 5F-AKB48, two synthetic cannabinoids sold as \"Spice\" products.\n\nBoth compounds showed nanomolar affinity for CB1 and CB2 receptors in binding experiments. In mice, they produced the classic cannabinoid \"tetrad\" effects (hypothermia, pain insensitivity, catalepsy, reduced movement) plus additional concerning effects: impaired visual, acoustic, and tactile senses; seizures; myoclonia (involuntary muscle jerks); hyperreflexia; and promoted aggression.\n\nBrain microdialysis showed both compounds stimulated dopamine release in the nucleus accumbens, a key reward center. All behavioral and neurochemical effects were blocked by the CB1 antagonist AM251. The fluorinated derivative (5F-AKB48) was generally more potent, suggesting that adding a fluorine atom increases the drug's effectiveness.","whyItMatters":"These findings explain why synthetic cannabinoid users report more severe and dangerous effects than cannabis users. The seizures, aggression, and sensory impairment produced by these compounds go well beyond what THC typically causes, and the fluorinated variant's increased potency shows how chemical modifications can amplify danger.","specificNumbers":"Nanomolar affinity for CB1 and CB2 receptors. Both compounds increased dopamine in nucleus accumbens. Fluorinated 5F-AKB48 showed greater potency than AKB48. All effects blocked by CB1 antagonist AM251.","methodology":"In vitro receptor binding on mouse and human CB1/CB2 receptors. In vivo studies in male CD-1 mice included tetrad testing, sensorimotor assessment, neurological evaluation, brain microdialysis for dopamine measurement, and comparison with THC and JWH-018.","limitations":"This was an animal study in mice. The doses used may not precisely reflect human exposure from synthetic cannabinoid products. Some effects (seizures, aggression) may not translate directly to human use patterns. Only acute effects were studied."},{"rthcId":"RTHC-01119","title":"Characterization of edible marijuana product exposures reported to United States poison centers.","authors":"Cao, Dazhe; Srisuma, Sahaphume; Bronstein, Alvin C; Hoyte, Christopher O","year":2016,"journal":"Clinical toxicology (Philadelphia, Pa.), 54(9), 840-846","doi":null,"pmid":"27418198","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed edible marijuana exposure calls reported to US poison centers from 2013 through 2015.\n\nOf 430 calls, 91% occurred in states with decriminalized medical or recreational marijuana. Colorado (166 calls) and Washington (96 calls) had the most. The number of calls increased every year of the study.\n\nChildren under 5 were the most common age group affected (109 calls, 25%), followed by teens aged 13-19 (78 calls). The most frequent effects were drowsiness (43%), rapid heart rate (31%), agitation (14%), and confusion (14%). Young children were more likely to experience drowsiness, uncoordinated movement, and red eyes.\n\nThree patients (ages 4, 10, and 57) required intubation for respiratory support. No deaths were reported. Most cases were either managed at home (23%) or treated and released from the emergency department (50%).","whyItMatters":"Edible marijuana products can be indistinguishable from regular food items, making accidental ingestion by children a significant risk. The delayed onset of edible effects (compared to smoking) can also lead adults to consume additional doses, resulting in overdose.","specificNumbers":"430 calls total. Colorado: 166, Washington: 96. Children under 5: 109 calls (25%). Ages 13-19: 78 calls. 91% from decriminalized states. 3 patients intubated. 12 admitted to critical care (3%). No deaths.","methodology":"Analysis of single-substance human exposure calls coded to marijuana edibles (brownies, candies, cookies, beverages, other foods) reported to the National Poison Data System from January 2013 to December 2015.","limitations":"Poison center data capture only cases that are called in and may undercount actual exposures. The increasing calls could partly reflect greater awareness of poison center reporting codes for edibles rather than purely increasing exposures. The study could not determine the exact THC dose consumed in most cases."},{"rthcId":"RTHC-01120","title":"The Relationships of Parental Alcohol Versus Tobacco and Marijuana Use With Early Adolescent Onset of Alcohol Use.","authors":"Capaldi, Deborah M; Tiberio, Stacey S; Kerr, David C R; Pears, Katherine C","year":2016,"journal":"Journal of studies on alcohol and drugs, 77(1), 95-103","doi":null,"pmid":"26751359","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers studied 146 children of 93 parents to determine whether parental tobacco and marijuana use predicted children's age of first alcohol use, beyond the known effects of parental alcohol use.\n\nMothers' alcohol use was significantly associated with children's earlier alcohol onset, while fathers' alcohol use alone was not. Children's age at onset was also predicted by mothers' tobacco use and by the interaction of fathers' marijuana and alcohol use together.\n\nThese effects held after controlling for parental education, child gender, and children's antisocial behavior. The authors highlighted that maternal substance use has received less research attention as a risk factor for children's substance use compared to paternal use.","whyItMatters":"Understanding which parental factors predict early alcohol use in children can improve prevention efforts. The finding that mothers' substance use plays a larger role than previously recognized suggests that prevention programs targeting maternal substance use could help delay children's drinking onset.","specificNumbers":"146 children of 93 parents (90 fathers, 85 mothers). Mothers' but not fathers' alcohol use predicted children's alcohol onset. Mothers' tobacco use independently predicted earlier onset. Fathers' marijuana use interacted with alcohol use to predict earlier onset.","methodology":"Longitudinal study following children of participants in the Oregon Youth Study, a long-running study of risk factors for delinquency. The sample included 146 children of 93 parents (90 fathers, 85 mothers). Parent substance use and child alcohol onset were assessed prospectively.","limitations":"The sample size was relatively small (146 children). The Oregon Youth Study participants may not represent all families. Only alcohol onset was studied, not cannabis or other substance initiation. The mechanisms by which parental substance use influences children (modeling, availability, genetics, prenatal exposure) were not disentangled."},{"rthcId":"RTHC-01121","title":"Associations between Polygenic Risk for Psychiatric Disorders and Substance Involvement.","authors":"Carey, Caitlin E; Agrawal, Arpana; Bucholz, Kathleen K; Hartz, Sarah M; Lynskey, Michael T; Nelson, Elliot C; Bierut, Laura J; Bogdan, Ryan","year":2016,"journal":"Frontiers in genetics, 7, 149","doi":"10.3389/fgene.2016.00149","pmid":"27574527","tags":["genetics","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers tested whether genetic risk for five psychiatric disorders (ADHD, autism, bipolar disorder, depression, and schizophrenia) predicted involvement with five substances (alcohol, cannabis, cocaine, nicotine, and opioids) in 2,573 European-American participants.\n\nA combined cross-disorder psychiatric risk score significantly predicted general substance involvement, explaining about 1.1% of variance. When broken down by specific disorders and substances, the strongest associations were:\n\n- Schizophrenia genetic risk linked to non-problem cannabis use, severe cannabis dependence, and severe cocaine dependence\n- Depression genetic risk linked to non-problem cannabis use and severe cocaine dependence\n\nThese associations survived correction for multiple testing, suggesting shared genetic architecture between psychiatric disorders and substance involvement.","whyItMatters":"This study provides genetic evidence for the commonly observed clinical co-occurrence of psychiatric disorders and substance use. The finding that schizophrenia genetic risk is associated with cannabis involvement has implications for understanding the cannabis-psychosis relationship.","specificNumbers":"2,573 participants. Cross-disorder psychiatric risk explained 1.10% of variance in substance involvement (p<0.001). Schizophrenia risk: associated with cannabis use, severe cannabis dependence, and severe cocaine dependence. Depression risk: associated with cannabis use and severe cocaine dependence.","methodology":"Polygenic risk scores were calculated from Psychiatric Genomics Consortium data for each of five disorders. These were tested against substance involvement measures ranging from ever-use to severe dependence in 2,573 participants from the Study of Addiction: Genetics and Environment.","limitations":"The study was limited to non-Hispanic European-American participants and may not generalize to other populations. Polygenic risk scores explain only a small fraction of total risk. The cross-sectional design cannot determine temporal relationships. Environmental factors likely account for far more variance than genetic factors alone."},{"rthcId":"RTHC-01122","title":"Longitudinal associations of friend-based social support and PTSD symptomatology during a cannabis cessation attempt.","authors":"Carter, Sarah P; DiMauro, Jennifer; Renshaw, Keith D; Curby, Timothy W; Babson, Kimberly A; Bonn-Miller, Marcel O","year":2016,"journal":"Journal of anxiety disorders, 38, 62-7","doi":"10.1016/j.janxdis.2016.01.008","pmid":"26836369","tags":["ptsd","quitting","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Researchers studied 116 veterans with cannabis dependence and PTSD symptoms who were attempting to quit cannabis use, tracking the relationship between PTSD and friend-based social support over 6 months.\n\nUsing a cross-lagged model, they found that earlier PTSD symptoms predicted later decreases in friend support, but the reverse was not significant. When the sample was split by relapse status, this negative effect of PTSD on future support was present only among veterans who relapsed in the first month after their quit attempt.\n\nThe findings suggest that substance use relapse may amplify the erosion of social support that PTSD can cause, creating a vicious cycle for those trying to quit.","whyItMatters":"Social support is important for both PTSD recovery and substance use cessation. This study identifies a pathway through which PTSD symptoms undermine the social resources that could help veterans maintain abstinence, with relapse further accelerating the loss of support.","specificNumbers":"116 veterans studied over 6 months. PTSD symptoms significantly predicted declining friend support. This effect was present only in those who relapsed in the first month.","methodology":"A longitudinal study following 116 veterans with cannabis dependence who initiated quit attempts. PTSD symptoms and friend-based social support were measured over 6 months. A cross-lagged autoregressive model was used to test bidirectional associations. Multigroup analysis compared those who relapsed within the first month to those who did not.","limitations":"The relatively small sample (116 veterans) limited the multigroup analysis. Only friend-based (not family) support was measured. All participants were veterans, limiting generalizability. The study cannot determine whether cannabis relapse caused the loss of social support or whether declining support occurred for other reasons in the relapse group."},{"rthcId":"RTHC-01123","title":"Weeding Out the Truth: Adolescents and Cannabis: Case and Discussion.","authors":"Caspersen, Shannon; Tau, Gregory Z; Ammerman, Seth","year":2016,"journal":"Journal of addiction medicine, 10(2), 83-8","doi":"10.1097/ADM.0000000000000195","pmid":"26985646","tags":["youth","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This clinical case conference presented a real adolescent patient with marijuana use disorder to expert clinicians. The experts shared their diagnostic reasoning, assessment approach, and treatment recommendations in response to the case details.\n\nThe format allowed different clinical perspectives to be presented and discussed, illustrating how experienced clinicians approach adolescent marijuana use disorders in practice.","whyItMatters":"Clinical case conferences bridge the gap between research evidence and real-world practice. They show how guidelines and evidence are applied to individual patients and highlight areas of clinical uncertainty.","specificNumbers":"No specific quantitative data were presented. The article focused on clinical reasoning rather than research findings.","methodology":"Clinical case conference format: a real patient case was presented to expert clinicians who provided their reasoning and recommendations, followed by a summary of the clinical discussion.","limitations":"Case conferences reflect expert opinion on a single case and do not constitute clinical trial evidence. The recommendations may not apply to all adolescent patients with marijuana use disorder."},{"rthcId":"RTHC-01124","title":"Prevention of Youthful Marijuana Use.","authors":"Cermak, Timmen L; Banys, Peter","year":2016,"journal":"Journal of psychoactive drugs, 48(1), 21-3","doi":"10.1080/02791072.2015.1117689","pmid":"26891015","tags":["youth","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This policy review critiqued traditional approaches to youth drug prevention as overly simplistic, relying on exaggerated risk messaging and one-size-fits-all abstinence approaches that are not grounded in science.\n\nThe authors recommended the Institute of Medicine's 1994 continuum of care model, which divides prevention into three tiers: universal prevention (broad population-level programs), selective prevention (targeting high-risk subgroups), and indicated prevention (for individuals already showing risk behaviors).\n\nThey highlighted Student Assistance Programs (SAPs) in high schools and community coalitions as practical examples of how this tiered model can be implemented. They also advocated for stable marijuana tax funding to support these programs.","whyItMatters":"Drug prevention programs have consumed significant resources with limited success. Tailoring prevention intensity to individual risk levels, rather than delivering the same message to everyone, is a more evidence-informed approach that could improve outcomes.","specificNumbers":"The Institute of Medicine model was developed in 1994. Three tiers: universal, selective, indicated. No specific outcome data were presented in this review.","methodology":"Policy review published in the Journal of Psychoactive Drugs, examining the evidence base for different prevention approaches and recommending a framework for implementation.","limitations":"This was a policy opinion piece rather than a systematic evaluation of prevention program effectiveness. It did not present outcome data comparing tiered versus non-tiered prevention approaches. Implementation challenges and costs of the recommended model were not fully addressed."},{"rthcId":"RTHC-01125","title":"A cross-validation trial of an Internet-based prevention program for alcohol and cannabis: Preliminary results from a cluster randomised controlled trial.","authors":"Champion, Katrina E; Newton, Nicola C; Stapinski, Lexine; Slade, Tim; Barrett, Emma L; Teesson, Maree","year":2016,"journal":"The Australian and New Zealand journal of psychiatry, 50(1), 64-73","doi":"10.1177/0004867415577435","pmid":"25801662","tags":["youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers conducted a cluster randomized controlled trial of the Climate Schools: Alcohol and Cannabis course, an internet-based prevention program, among 1,103 students (average age 13.25) from 13 Australian schools.\n\nImmediately after the intervention, students in the program showed significantly greater alcohol knowledge (effect size d=0.67) and cannabis knowledge (d=0.72) compared to controls. They were also less likely to have consumed any alcohol in the past 6 months (OR=0.69) and less likely to intend to use alcohol in the future (OR=0.62).\n\nHowever, there were no significant effects on binge drinking, cannabis use, or intentions to use cannabis. This cross-validation trial replicated the knowledge gains from the original trial but showed mixed behavioral results.","whyItMatters":"Internet-based prevention programs are scalable and can reach large numbers of students. This trial confirmed that the program effectively increases knowledge, but the disconnect between knowledge gains and behavioral change for cannabis highlights the challenge of translating education into prevention.","specificNumbers":"1,103 students from 13 schools. Age: mean 13.25 years. Alcohol knowledge: d=0.67. Cannabis knowledge: d=0.72. Reduced any alcohol use: OR=0.69. Reduced alcohol intentions: OR=0.62. No effects on binge drinking, cannabis use, or cannabis intentions.","methodology":"Cluster randomized controlled trial with 6 intervention schools and 7 control schools. Students (N=1,103, mean age 13.25) completed surveys at baseline and immediately post-intervention. Mixed-effects regressions were used to account for school-level clustering.","limitations":"Only immediate post-intervention effects were assessed; longer-term follow-up is needed. The program was tested in Australia and may not generalize to other countries. The lack of effect on cannabis behavior may reflect the younger age of participants (many had not yet initiated cannabis use). School-level clustering limits effective sample size."},{"rthcId":"RTHC-01126","title":"Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases.","authors":"Chicca, Andrea; Arena, Chiara; Manera, Clementina","year":2016,"journal":"Recent patents on CNS drug discovery, 10(2), 122-141","doi":null,"pmid":"27630088","tags":["neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined strategies for modulating the endocannabinoid system that go beyond directly activating CB1 and CB2 receptors, which has produced limited therapeutic success due to CB1-mediated side effects.\n\nAlternative approaches include inhibitors of the enzymes that break down endocannabinoids (FAAH for anandamide, MAGL for 2-AG, ABHD6, and ABHD12), as well as COX-2 inhibitors, diacylglycerol lipase inhibitors, and blockers of the endocannabinoid membrane transporter.\n\nThe review also discussed polypharmacological approaches that combine mild inhibition of multiple targets simultaneously. These indirect strategies aim to boost endocannabinoid levels at sites where they are naturally produced, providing more targeted effects than flooding all receptors with a direct agonist like THC.","whyItMatters":"Direct cannabinoid receptor activation (as THC does) produces significant side effects. These alternative approaches could potentially deliver therapeutic benefits for conditions like pain, anxiety, and neurological diseases with improved safety profiles.","specificNumbers":"Multiple enzyme targets reviewed: FAAH, MAGL, ABHD6, ABHD12, COX-2, diacylglycerol lipases, endocannabinoid transporter. Approaches span 10-15 years of development.","methodology":"Comprehensive review of patent literature, clinical trial registries, and published scientific literature on compounds targeting various elements of the endocannabinoid system beyond direct receptor activation.","limitations":"Many of the compounds reviewed were in early development stages. A FAAH inhibitor clinical trial by Bial resulted in serious adverse events in 2016 (though this was not discussed in this review). Translation from promising preclinical compounds to safe, effective drugs has proven challenging."},{"rthcId":"RTHC-01127","title":"Use of Cannabinoids for Spasticity and Pain Management in MS.","authors":"Chohan, Hardeep; Greenfield, Ariele L; Yadav, Vijayshree; Graves, Jennifer","year":2016,"journal":"Current treatment options in neurology, 18(1), 1","doi":"10.1007/s11940-015-0385-y","pmid":"26705757","tags":["medical-cannabis","pain","cognition"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review synthesized evidence from randomized trials on cannabinoid use for two of the most troubling MS symptoms: spasticity and pain.\n\nSeveral randomized trials provided Class 1 and 2 evidence (the highest levels) supporting cannabinoid products for these indications. However, the optimal ratio of THC to CBD and the ideal dosing were not yet established.\n\nThe review raised an important cautionary note: the safety and long-term cognitive effects of cannabinoid products in people with MS have not been evaluated. Since short-term memory and processing speed are already significantly impaired in many MS patients, the potential for cannabinoids to worsen cognitive function is a particular concern in this population.","whyItMatters":"MS spasticity and pain significantly affect quality of life and are often inadequately managed by existing treatments. Having Class 1-2 evidence supporting cannabinoids is notable, but the cognitive concern is especially important because MS patients cannot afford additional cognitive burden.","specificNumbers":"Class 1 and 2 evidence from multiple randomized trials. Optimal THC:CBD ratio and doses not yet determined. Short-term memory and processing speed already impaired in many MS patients.","methodology":"Clinical review of randomized controlled trials examining cannabinoid products for spasticity and pain in MS, published in Current Treatment Options in Neurology.","limitations":"The review noted that optimal dosing and formulation remain undefined. Long-term safety data in MS patients are lacking. The cognitive concern, while theoretically important, has not been systematically studied in cannabis-using MS patients."},{"rthcId":"RTHC-01128","title":"Relationship between marijuana and other illicit drug use and depression/suicidal thoughts among late middle-aged and older adults.","authors":"Choi, Namkee G; DiNitto, Diana M; Marti, C Nathan; Choi, Bryan Y","year":2016,"journal":"International psychogeriatrics, 28(4), 577-89","doi":"10.1017/S1041610215001738","pmid":"26542746","tags":["seniors","depression","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from nearly 30,000 Americans aged 50 and older to examine the relationship between marijuana use and depression and suicidal thoughts in this understudied population.\n\nAbout 6% of adults over 50 reported past-year illicit drug use. Compared to non-users, marijuana-only users had 1.54 times higher odds of a major depressive episode. Those using both marijuana and other drugs had 2.12 times higher odds, while those using other drugs only had 2.75 times higher odds.\n\nHowever, among people who used any illicit drug, there was no significant difference in depression or suicidal thoughts between marijuana-only users and other drug users. Among marijuana users, frequency of use correlated with suicidal thoughts only in those who already had major depression.","whyItMatters":"As the population ages and cannabis use among older adults increases, understanding the mental health associations in this age group becomes important. This is one of relatively few studies to focus specifically on marijuana and mental health in adults over 50.","specificNumbers":"29,634 individuals aged 50+. Nearly 6% reported past-year illicit drug use. Marijuana-only vs. non-users: OR 1.54 for depression. Other drugs only: OR 2.75. Both: OR 2.12. Suicidal thoughts among marijuana+other drug users: OR 2.44.","methodology":"Analysis of the 2008-2012 National Survey on Drug Use and Health (NSDUH), a nationally representative US survey. The sample included 29,634 individuals aged 50+. Logistic regression was used to test associations between drug use and mental health outcomes.","limitations":"Cross-sectional design cannot determine whether marijuana use contributes to depression or whether depressed older adults are more likely to use marijuana. Self-reported drug use may be underreported. The study could not distinguish between medical and recreational cannabis use."},{"rthcId":"RTHC-01129","title":"BSAFER: A Web-based intervention for drug use and intimate partner violence demonstrates feasibility and acceptability among women in the emergency department.","authors":"Choo, Esther K; Zlotnick, Caron; Strong, David R; Squires, Daniel D; Tapé, Chantal; Mello, Michael J","year":2016,"journal":"Substance abuse, 37(3), 441-449","doi":null,"pmid":"26714233","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01130","title":"Cannabinoid hyperemesis syndrome. A report of six new cases and a summary of previous reports.","authors":"Contreras Narváez, Carla; Mola Gilbert, Montserrat; Batlle de Santiago, Enric; Bigas Farreres, Jordi; Giné Serven, Eloy; Cañete Crespillo, Josep","year":2016,"journal":"Adicciones, 28(2), 90-8","doi":"10.20882/adicciones.776","pmid":"26990261","tags":["withdrawal"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A Spanish hospital reported six cases of cannabinoid hyperemesis syndrome (CHS) diagnosed between 2012 and 2014, accompanied by a summary of the 83 cases published worldwide through June 2014.\n\nThe average time from onset of acute CHS episodes to correct diagnosis was 6.1 years at this hospital, compared to an average of 3.1 years in previously published cases. This extended diagnostic delay demonstrates that healthcare professionals continue to be unaware of this condition.\n\nAll cases showed the hallmark features: cyclical vomiting unresponsive to standard antiemetics, relief from hot water bathing, and resolution with cannabis abstinence.","whyItMatters":"The persistent diagnostic delay of over 6 years means patients undergo years of unnecessary testing, hospital visits, and suffering before the correct diagnosis is made. Greater clinical awareness could dramatically improve outcomes.","specificNumbers":"6 new cases. Average diagnostic delay: 6.1 years (vs. 3.1 years in prior literature). 83 total cases published worldwide by June 2014, 4 previously from Spain.","methodology":"Case series of six patients diagnosed with CHS at Mataro Hospital in Spain, with comparison to the 83 previously published cases worldwide through June 2014.","limitations":"Small case series from a single hospital. The diagnostic delay may reflect local factors rather than universal patterns. The total number of published CHS cases (83 by 2014) likely represents a small fraction of actual cases."},{"rthcId":"RTHC-01131","title":"Adverse Effects of Synthetic Cannabinoids: Management of Acute Toxicity and Withdrawal.","authors":"Cooper, Ziva D","year":2016,"journal":"Current psychiatry reports, 18(5), 52","doi":"10.1007/s11920-016-0694-1","pmid":"27074934","tags":["synthetic-cannabinoids","withdrawal","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review addressed both acute toxicity and the less-discussed problem of dependence and withdrawal from synthetic cannabinoids (SCs).\n\nWhile case reports and media coverage focus on severe acute toxicity, the review highlighted that daily SC use resulting in dependence and withdrawal is a significant and often overlooked concern. Data collected from cannabis smokers in New York City over 3.5 years (2012-2015) confirmed a subset of people who use SCs daily.\n\nThere is no established evidence-based treatment for SC withdrawal. Some symptom relief has been reported with benzodiazepines and the atypical antipsychotic quetiapine, but controlled studies are lacking. The review called urgently for empirical studies on SC acute effects, withdrawal characterization, and treatment strategies.","whyItMatters":"As synthetic cannabinoids continue to circulate, clinicians need guidance on managing not just acute crises but also the dependence and withdrawal that develop with regular use. The current lack of evidence-based treatment protocols leaves clinicians without clear direction.","specificNumbers":"3.5 years of survey data (2012-2015) from the NYC metropolitan area. Benzodiazepines and quetiapine showed some withdrawal symptom relief. No controlled treatment studies existed at the time.","methodology":"Literature review combined with original survey data on SC use demographics, frequency, and adverse effects from the New York City metropolitan area (2012-2015).","limitations":"The review acknowledged a lack of controlled studies on SC effects and treatment. Survey data from NYC may not represent other regions. The rapidly changing SC market means findings about specific compounds may become outdated quickly."},{"rthcId":"RTHC-01132","title":"The endocannabinoid system: A novel player in human placentation.","authors":"Costa, M A","year":2016,"journal":"Reproductive toxicology (Elmsford, N.Y.), 61, 58-67","doi":"10.1016/j.reprotox.2016.03.002","pmid":"26965993","tags":["pregnancy","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how the endocannabinoid system participates in normal human placenta development and how cannabis use may disrupt this process.\n\nThe endocannabinoid system is expressed in human placentas and plays roles in trophoblast cell proliferation, apoptosis (programmed cell death), differentiation, and function. Abnormal expression of this system has been associated with infertility and miscarriages.\n\nTHC, which activates the same cannabinoid receptors as endogenous endocannabinoids, can interfere with these tightly regulated processes. The review argued that this provides a biological mechanism for the clinical observation that cannabis use during pregnancy is associated with fetal growth restriction.","whyItMatters":"Understanding the biological mechanisms by which cannabis affects pregnancy outcomes is important for both clinical advice and research priorities. This review moves beyond epidemiological associations to provide mechanistic explanations for fetal growth restriction.","specificNumbers":"No specific quantitative data presented. The review synthesized findings on cannabinoid receptor expression in placental tissue and the effects of eCBs and THC on trophoblast cell behavior.","methodology":"Review article examining published literature on endocannabinoid system expression and function in normal and pathological human placentas, and the effects of THC and endocannabinoids on trophoblast biology.","limitations":"Much of the evidence comes from in vitro studies of placental cells rather than whole-organism research. The concentrations of cannabinoids used in cell studies may not reflect actual placental exposure during cannabis use. Individual variability in placental cannabinoid receptor expression is not well characterized."},{"rthcId":"RTHC-01133","title":"Understanding Patients' Process to Use Medical Marijuana: A Southern New Jersey Community Engagement Project.","authors":"Crowell, Tara L","year":2016,"journal":"Journal of patient experience, 3(3), 81-87","doi":"10.1177/2374373516667002","pmid":"28725842","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 240 new patients at a New Jersey medical cannabis dispensary (Compassion Care Foundation) about their experience navigating the qualification process.\n\nThe most common qualifying conditions were intractable skeletal spasticity, chronic and severe pain, multiple sclerosis, and inflammatory bowel disease. About half of patients were first prompted to seek medical marijuana by their physicians, while the other half cited written information, friends, family, media, or the internet.\n\nOnce patients began the qualification process, it took an average of nearly 6 months to receive their first treatment. Despite this lengthy process, patient satisfaction improved as they progressed through the steps. Patients reported moderately high pain levels prior to treatment.","whyItMatters":"A 6-month wait to access an approved medical treatment highlights significant barriers in the medical cannabis qualification process. Understanding these barriers and patient experiences can inform policy improvements to reduce unnecessary delays.","specificNumbers":"240 patients surveyed. Average ~6 months from starting the process to first treatment. ~50% physician-referred. Top conditions: spasticity, chronic pain, MS, IBD. Moderately high pain levels reported prior to treatment.","methodology":"Cross-sectional survey of 240 new patients at a New Jersey medical cannabis dispensary, a community engagement project between Compassion Care Foundation and Stockton University. The survey assessed diagnosis, referral sources, process satisfaction, timeline, and pain levels.","limitations":"Single dispensary in one state. Patients who completed the process and visited the dispensary represent those who persisted through barriers; those who gave up are not captured. Self-reported data may be subject to recall bias. No outcome data on whether cannabis treatment was effective."},{"rthcId":"RTHC-01134","title":"Rapid changes in cannabinoid 1 receptor availability in cannabis-dependent male subjects after abstinence from cannabis","authors":"D'Souza, Deepak Cyril; Cortes-Briones, Jose A.; Ranganathan, Mohini; Thurnauer, Halle; Creatura, Gina; Surti, Toral; Planeta, Beata; Neumeister, Alexander; et al.","year":2016,"journal":"Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 1(1), 60-67","doi":"10.1016/j.bpsc.2015.09.008","pmid":"29560896","tags":["withdrawal","addiction","neuroscience","tolerance"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"At baseline, cannabis-dependent men had lower CB1 receptor availability across most brain regions compared with matched non‑users. The average difference was about 15 percent lower, which is a large gap for a brain receptor measure. After two days without cannabis, that group difference was no longer detectable, and it remained absent at 28 days.\n\nWithdrawal tracked with the imaging signal. Lower CB1 receptor availability after two days of abstinence was associated with more severe withdrawal symptoms.\n\nPut simply, frequent use was linked to reduced CB1 receptor availability, and that signal appeared to rebound quickly once use stopped.","whyItMatters":"Many people assume receptor changes from heavy cannabis use linger for weeks. This study reports a different timeline in men with dependence: a measurable CB1 signal was lower at baseline but aligned with controls within two days of abstinence. That has implications for how imaging studies are timed, how withdrawal is interpreted in relation to the endocannabinoid system, and how quickly the brain’s cannabinoid signaling appears to adapt when use stops.","specificNumbers":"- Sample: 11 cannabis-dependent men and 19 healthy male controls\n- Baseline CB1 availability: about 15% lower in dependent users compared with controls (a sizable gap for PET receptor measures; Cohen's d −1.11 indicates a large effect size)\n- Timing: group differences were not evident after 2 days of monitored abstinence, and still absent at 28 days\n- Controls rescanned: 4 of 19 controls had a 28‑day follow‑up scan","methodology":"Researchers used high-resolution PET imaging with the reversible tracer [11C]OMAR to index CB1 receptor availability via volume of distribution (V_T). Participants were 11 cannabis-dependent male subjects and 19 matched healthy controls. Cannabis-dependent participants were scanned at three points: baseline while neither intoxicated nor in acute withdrawal, then after two days and 28 days of monitored abstinence. Controls were scanned once at baseline, and a subset of four returned at 28 days. Analyses compared groups and examined correlations between receptor availability and withdrawal after two days.","limitations":"Only 11 cannabis-dependent participants and all were male, which limits generalizability. The control group’s 28‑day follow‑up included only four people, so longer‑term stability in controls is uncertain. PET V_T reflects more than receptor density alone and can be influenced by factors like tracer kinetics, so it is a proxy for availability rather than a direct receptor count. Product potency, route, frequency, tobacco use, and timing of last use prior to baseline were not detailed in the abstract, which could affect receptor measures and withdrawal. The study did not assess functional outcomes such as cognition or daily functioning alongside imaging."},{"rthcId":"RTHC-01135","title":"Rapid Changes in CB1 Receptor Availability in Cannabis Dependent Males after Abstinence from Cannabis.","authors":"D'Souza, Deepak Cyril; Cortes-Briones, Jose A; Ranganathan, Mohini; Thurnauer, Halle; Creatura, Gina; Surti, Toral; Planeta, Beata; Neumeister, Alexander; Pittman, Brian; Normandin, Marc; Kapinos, Michael; Ropchan, Jim; Huang, Yiyun; Carson, Richard E; Skosnik, Patrick D","year":2016,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 1(1), 60-67","doi":"10.1016/j.bpsc.2015.09.008","pmid":"26858993","tags":["tolerance","addiction","neuroscience"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Using high-resolution PET imaging, researchers measured CB1 receptor availability in 11 cannabis-dependent males and 19 matched healthy controls.\n\nAt baseline (while using cannabis), dependent subjects showed 15% lower CB1 receptor availability across nearly all brain regions compared to controls, a large effect (Cohen's d = -1.11). This confirmed that chronic cannabis use downregulates CB1 receptors.\n\nThe surprising finding was the speed of recovery: after just 2 days of monitored abstinence, the group differences in CB1 receptor availability were no longer evident. This normalization persisted at 28 days. There was also a strong negative correlation between CB1 availability and withdrawal symptoms at day 2, suggesting that receptor recovery relates to the experience of withdrawal.","whyItMatters":"This study provides direct evidence that cannabis-related brain changes reverse rapidly with abstinence. The finding that CB1 receptors normalize in just 2 days challenges assumptions about persistent brain changes from chronic cannabis use and has implications for treatment and recovery.","specificNumbers":"15% lower CB1 availability in cannabis users at baseline (Cohen's d = -1.11). Differences no longer significant after 2 days of abstinence. Remained normalized at 28 days. Negative correlation between CB1 recovery and withdrawal symptoms.","methodology":"Cannabis-dependent males (n=11) were scanned with [11C]OMAR PET at baseline, 2 days, and 28 days of monitored abstinence. Healthy controls (n=19) were scanned at baseline, with a subset (n=4) rescanned at 28 days. High Resolution Research Tomography (HRRT) was used for optimal image quality.","limitations":"Small sample size (11 cannabis users). Only males were studied. The study measured receptor availability, not function. Whether rapid receptor normalization translates to full functional recovery is not clear. The correlation with withdrawal symptoms is preliminary."},{"rthcId":"RTHC-01136","title":"Cannabinoids for Symptom Management and Cancer Therapy: The Evidence.","authors":"Davis, Mellar P","year":2016,"journal":"Journal of the National Comprehensive Cancer Network : JNCCN, 14(7), 915-22","doi":null,"pmid":"27407130","tags":["cancer","medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review from the National Comprehensive Cancer Network examined cannabinoids across multiple cancer-related applications.\n\nFor pain, multiple studies (mostly moderate to low quality) showed that THC and THC/CBD combinations modestly reduce cancer pain. For chemotherapy-induced nausea, dronabinol and nabilone were better than some older antiemetics but have largely been superseded by newer drugs (neurokinin-1 receptor antagonists and olanzapine). Both cannabinoids are recommended for breakthrough nausea among other options.\n\nDronabinol was ineffective for cancer-related appetite loss but did improve taste disturbances (dysgeusia). Preclinically, multiple cancers express cannabinoid receptors (correlated with tumor grade), and both cannabinoid agonists and paradoxically antagonists showed antitumor activity through apoptosis, anti-angiogenesis, and metastasis inhibition.\n\nThe review warned that smoked cannabis may contain Aspergillus fungus, posing infection risk to immunocompromised cancer patients.","whyItMatters":"This review from a major cancer network provides a balanced, evidence-graded assessment of where cannabinoids fit in cancer care, distinguishing between supported uses (antiemetic, modest pain relief) and unproven claims (direct anticancer effects).","specificNumbers":"THC/CBD modestly reduces cancer pain (moderate-low quality studies). Dronabinol ineffective for anorexia but improves dysgeusia. Cannabinoid receptors expressed in proportion to tumor grade. Both agonists and antagonists show preclinical antitumor activity.","methodology":"Comprehensive clinical review published in the Journal of the National Comprehensive Cancer Network, examining evidence across pain, nausea, appetite, and potential anticancer effects.","limitations":"Most pain studies were moderate to low quality. Few randomized trials used smoked or vaporized cannabis in cancer patients. Preclinical anticancer findings have not been confirmed in human trials. The Aspergillus contamination risk applies specifically to smoked cannabis."},{"rthcId":"RTHC-01137","title":"Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135.","authors":"De Luca, Maria Antonietta; Castelli, M Paola; Loi, Barbara; Porcu, Alessandra; Martorelli, Mariella; Miliano, Cristina; Kellett, Kathryn; Davidson, Colin; Stair, Jacqueline L; Schifano, Fabrizio; Di Chiara, Gaetano","year":2016,"journal":"Neuropharmacology, 105, 630-638","doi":"10.1016/j.neuropharm.2015.11.017","pmid":"26686391","tags":["synthetic-cannabinoids","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers characterized four third-generation synthetic cannabinoids (BB-22, 5F-PB-22, 5F-AKB-48, STS-135) and compared them to the earlier compound JWH-018.\n\nBB-22 and 5F-PB-22 had CB1 receptor binding affinities 30 and 26 times higher than JWH-018 respectively, with higher potency and efficacy as CB1 agonists. All four compounds stimulated dopamine release specifically in the nucleus accumbens shell (the brain's reward center) but not in other nearby regions.\n\nThe dopamine-stimulating effect was completely blocked by the CB1 antagonist AM251 and showed a bell-shaped dose-response curve. The compounds did not activate G-proteins in CB1 knockout mice, confirming CB1 receptor specificity.","whyItMatters":"The escalating potency of successive synthetic cannabinoid generations helps explain the increasing severity of clinical toxicity reports. Compounds 30 times more potent than earlier versions pose correspondingly greater risks of overdose and adverse effects.","specificNumbers":"BB-22 Ki: 0.11 nM (vs. JWH-018: 3.38 nM). 5F-PB-22 Ki: 0.13 nM. BB-22 Emax: 217% (vs. JWH-018: 163%). All four stimulated nucleus accumbens shell dopamine release at doses consistent with their CB1 affinity.","methodology":"In vitro receptor binding and GTPgammaS assays on rat and mouse CB1/CB2 receptors. In vivo brain microdialysis in freely moving mice measuring dopamine release in nucleus accumbens shell, core, and medial prefrontal cortex. CB1 knockout mice used for specificity.","limitations":"In vitro binding does not perfectly predict in vivo effects. Mouse dopamine studies may not directly translate to human reward processing. Only acute effects were studied. The specific compounds may have been replaced by even newer variants in the illicit market."},{"rthcId":"RTHC-01138","title":"Components of the cannabinoid system in the dorsal periaqueductal gray are related to resting heart rate.","authors":"Dean, Caron; Hillard, Cecilia J; Seagard, Jeanne L; Hopp, Francis A; Hogan, Quinn H","year":2016,"journal":"American journal of physiology. Regulatory, integrative and comparative physiology, 311(2), R254-62","doi":"10.1152/ajpregu.00154.2016","pmid":"27280429","tags":["cardiovascular","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers examined whether natural animal-to-animal variation in endocannabinoid signaling in the dorsal periaqueductal gray (dPAG), a brainstem region involved in autonomic control, correlated with baseline heart rate.\n\nHigher resting heart rate was associated with increased anandamide content and decreased FAAH enzyme activity in this brain region. FAAH and MAGL gene expression levels were negatively correlated with heart rate. When anandamide was directly injected into the dPAG of anesthetized rats, heart rate increased.\n\nAutonomic tone and heart rate (but not blood pressure) correlated with FAAH gene expression levels, suggesting that the endocannabinoid system in this specific brain region helps regulate baseline cardiovascular function.","whyItMatters":"This study identifies a specific brain region where endocannabinoid signaling influences cardiovascular function. Understanding how the endocannabinoid system regulates heart rate has implications for understanding both the cardiovascular effects of cannabis and potential therapeutic targets.","specificNumbers":"Higher anandamide content in dPAG correlated with higher heart rate. Lower FAAH activity correlated with higher heart rate. FAAH and MAGL transcript levels negatively correlated with heart rate. Exogenous anandamide in dPAG increased heart rate.","methodology":"Blood pressure was recorded telemetrically in rats. Heart rate variability was analyzed. Endocannabinoid content, enzyme activities, and gene transcript levels were measured in the dPAG. Exogenous anandamide was injected into the dPAG of anesthetized rats to test causality.","limitations":"This was an animal study using rats, and the findings may not directly translate to human cardiovascular regulation. Only the dPAG was examined; other brain regions also regulate heart rate. The correlational design (except for the injection experiment) cannot establish that endocannabinoids cause heart rate differences."},{"rthcId":"RTHC-01139","title":"Cannabis for Refractory Psoriasis-High Hopes for a Novel Treatment and a Literature Review.","authors":"Derakhshan, Nima; Kazemi, Mahboubeh","year":2016,"journal":"Current clinical pharmacology, 11(2), 146-7","doi":null,"pmid":"27164964","tags":["medical-cannabis","inflammation","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This brief review proposed a theoretical basis for using cannabinoids to treat psoriasis, a common skin disorder characterized by excessive skin cell proliferation.\n\nThe authors noted that psoriasis involves an interaction between the immune system and the nervous system through the cholinergic anti-inflammatory pathway. The endocannabinoid system intersects with both of these systems, suggesting cannabinoids could potentially modulate the inflammatory process driving psoriasis.\n\nThe review was largely theoretical, positioning cannabinoids as a \"potential addition to antipsoriatic armamentarium\" based on known anti-inflammatory and immunomodulatory properties.","whyItMatters":"Psoriasis affects millions of people and current treatments have significant limitations. While this review is theoretical, it identified a biologically plausible pathway through which cannabinoids might help, providing a rationale for future research.","specificNumbers":"No clinical data were presented. The review was based on theoretical pharmacological reasoning.","methodology":"Brief literature review published in Current Clinical Pharmacology, proposing a theoretical rationale for cannabinoid use in psoriasis based on known pharmacological pathways.","limitations":"This was a brief, theoretical review with no clinical data. The proposed mechanism is plausible but unproven. No dosing, formulation, or route of administration was suggested. The review did not address potential adverse effects of cannabinoid use in psoriasis patients."},{"rthcId":"RTHC-01140","title":"Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.","authors":"Devinsky, Orrin; Marsh, Eric; Friedman, Daniel; Thiele, Elizabeth; Laux, Linda; Sullivan, Joseph; Miller, Ian; Flamini, Robert; Wilfong, Angus; Filloux, Francis; Wong, Matthew; Tilton, Nicole; Bruno, Patricia; Bluvstein, Judith; Hedlund, Julie; Kamens, Rebecca; Maclean, Jane; Nangia, Srishti; Singhal, Nilika Shah; Wilson, Carey A; Patel, Anup; Cilio, Maria Roberta","year":2016,"journal":"The Lancet. Neurology, 15(3), 270-8","doi":"10.1016/S1474-4422(15)00379-8","pmid":"26724101","tags":["epilepsy","cbd","medical-cannabis","youth"],"studyType":"pilot-study","evidenceStrength":"moderate","keyFinding":"This landmark open-label trial enrolled 214 patients (aged 1-30 years) with severe, treatment-resistant epilepsy across 11 US epilepsy centers. Patients received oral CBD at 2-5 mg/kg per day, titrated up to 25-50 mg/kg per day, added to their existing anti-epileptic drugs.\n\nAmong the 137 patients included in the efficacy analysis, the median monthly motor seizure frequency dropped from 30.0 at baseline to 15.8 over 12 weeks, representing a median reduction of 36.5%. Patients with Dravet syndrome (20%) and Lennox-Gastaut syndrome (19%) were included.\n\nAdverse events occurred in 79% of patients (most commonly somnolence, decreased appetite, and diarrhea), but only 3% discontinued treatment due to adverse events. Serious adverse events occurred in 30% of patients. One death (sudden unexpected death in epilepsy) was considered unrelated to CBD.","whyItMatters":"This study was pivotal in building the evidence base that ultimately led to FDA approval of Epidiolex (pharmaceutical CBD) for certain epilepsy syndromes. It provided the first large-scale clinical data on CBD for epilepsy and demonstrated both efficacy and a manageable safety profile in a severely affected population.","specificNumbers":"214 enrolled, 162 in safety analysis, 137 in efficacy analysis. Median baseline seizures: 30/month. Median at 12 weeks: 15.8/month. Median reduction: 36.5%. Adverse events: 79%. Serious adverse events: 30%. Discontinuation from AEs: 3%. Status epilepticus in 6%. One death (unrelated).","methodology":"Open-label interventional trial across 11 US epilepsy centers as part of an expanded access program. Patients aged 1-30 with severe childhood-onset treatment-resistant epilepsy on stable anti-epileptic drug regimens received add-on CBD. The primary endpoint was median percentage change in motor seizure frequency at 12 weeks.","limitations":"Open-label design without a placebo control means the placebo effect and regression to the mean cannot be excluded. Patients and clinicians knew they were receiving CBD, which could influence reporting. The patient population was heterogeneous. The 12-week timeframe is relatively short for a chronic condition."},{"rthcId":"RTHC-01141","title":"Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway.","authors":"Dhopeshwarkar, Amey; Mackie, Ken","year":2016,"journal":"The Journal of pharmacology and experimental therapeutics, 358(2), 342-51","doi":"10.1124/jpet.116.232561","pmid":"27194477","tags":["neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers screened a wide range of CB2 cannabinoid receptor ligands across two signaling pathways: a canonical pathway (inhibition of adenylyl cyclase/G-protein) and a noncanonical pathway (arrestin recruitment).\n\nThe results revealed extreme functional selectivity. Classic cannabinoid ligands strongly activated the G-protein pathway but completely failed to recruit arrestins. Most aminoalkylindoles had moderate effects on both pathways. Endocannabinoids were G-protein biased with no arrestin recruitment. One compound (UR144) was arrestin-biased with no significant cyclase inhibition.\n\nEven compounds classified as \"antagonists\" showed unexpected behavior: AM630 and JTE907 were inverse agonists in the cyclase assay but low-efficacy agonists in the arrestin pathway.","whyItMatters":"CB2 receptors are promising therapeutic targets (they mediate anti-inflammatory effects without psychoactive effects), but this study shows that the same drug can behave as an agonist in one pathway and have no effect in another. This means conclusions about CB2 function based on one assay may be misleading.","specificNumbers":"CP55940 was most potent at both pathways. JWH133 was most efficacious at cyclase. Classic cannabinoids showed zero arrestin recruitment. UR144 was arrestin-biased. Endocannabinoids were G-protein biased.","methodology":"In vitro pharmacological screening of diverse CB2 receptor ligands in two assay systems: adenylyl cyclase inhibition (G-protein pathway) and beta-arrestin recruitment (noncanonical pathway). Multiple structural classes of compounds were tested.","limitations":"All experiments were in vitro and may not perfectly predict in vivo pharmacology. The study used a single cell expression system, and results may differ in cells with different receptor expression levels or signaling environments. The therapeutic implications of pathway bias at CB2 are still theoretical."},{"rthcId":"RTHC-01142","title":"Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis.","authors":"Di Giacomo, Daniele; De Domenico, Emanuela; Sette, Claudio; Geremia, Raffaele; Grimaldi, Paola","year":2016,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 30(4), 1453-63","doi":"10.1096/fj.15-279034","pmid":"26671998","tags":["sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers discovered that the CB2 cannabinoid receptor is involved in the normal process of sperm cell development (spermatogenesis) in mice.\n\nActivating CB2 with a specific agonist (JWH133) mimicked the effects of retinoic acid on gene expression in spermatogonia (sperm precursor cells), upregulating genes needed for meiosis (c-Kit, Stra8, Prdm9) through epigenetic modifications to histone markers.\n\nWhen young mice were given prolonged JWH133 treatment, they showed accelerated onset of spermatogenesis. Conversely, blocking CB2 with an antagonist delayed sperm cell maturation. Both over- and under-stimulation of CB2 disrupted the normal temporal progression of the spermatogenic cycle.\n\nThe findings suggest that proper CB2 signaling is important for maintaining the correct timing of sperm development, and cannabis use could potentially deregulate this process.","whyItMatters":"This is the first study to show that CB2 receptor signaling can regulate spermatogenesis through epigenetic mechanisms similar to retinoic acid. Since cannabis activates cannabinoid receptors, this provides a mechanism by which cannabis use could affect male fertility.","specificNumbers":"JWH133 treatment upregulated H3K4me3 and downregulated H3K9me2 at meiotic gene promoters. Prolonged JWH133 accelerated spermatogenesis onset in immature mice. CB2 antagonist delayed germ cell differentiation.","methodology":"In vitro: spermatogonia were treated with JWH133 (CB2 agonist) or retinoic acid, and epigenetic modifications and gene expression were measured. In vivo: immature mice received prolonged JWH133 or CB2 antagonist treatment, and spermatogenic progression was assessed.","limitations":"This was a mouse study, and the specific timing and regulation of spermatogenesis differs between mice and humans. The CB2 agonist used (JWH133) is more selective than THC, which activates both CB1 and CB2. Whether THC from cannabis produces the same effects through CB2 was not directly tested."},{"rthcId":"RTHC-01143","title":"The involvement of prescribed drugs in road trauma.","authors":"Drummer, Olaf H; Yap, Suwan","year":2016,"journal":"Forensic science international, 265, 17-21","doi":"10.1016/j.forsciint.2015.12.050","pmid":"26826848","tags":["driving"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Researchers reviewed coroner files and toxicology records of 2,638 fatally injured drivers in Victoria, Australia over 14 years (2000-2013), representing over 97% of all driver fatalities in the study period.\n\nDrugs were found in 34.4% of fatalities. Each driver was assessed for crash responsibility using a validated method. Cannabis (THC >2 ng/mL in blood) and amphetamines were associated with significantly elevated crash risk compared to drug-free drivers.\n\nIn contrast, prescription medications alone (opioids, benzodiazepines, antidepressants including SSRIs) did not show significantly elevated crash risk, though benzodiazepines showed a trend. Sedating antihistamines were detected in 1.1% of fatalities.","whyItMatters":"This large dataset provides important context for the drugged driving debate. While cannabis and amphetamines elevated crash risk, commonly prescribed medications that many people worry about (opioids, benzodiazepines, antidepressants) did not show statistically significant increases in crash responsibility when used alone.","specificNumbers":"2,638 driver fatalities (>97% of all). Drugs found in 34.4%. Alcohol (>=0.05) in 24.8%. Medicinal drugs in 21.2%. Antidepressants: 7.9%. Benzodiazepines: 7.0%. Opioids: 6.6%. Cannabis (THC >2 ng/mL) and amphetamines showed elevated crash risk.","methodology":"Retrospective analysis of coroner files and toxicology records for all driver fatalities in Victoria, Australia (2000-2013). Crash responsibility was assessed using a validated published method. Drug detection used sensitive analytical limits comparable to those for illicit drugs.","limitations":"This analysis cannot determine impairment at the time of the crash, only the presence of drugs in blood. Tolerance effects (regular prescription users may be less impaired than the blood levels suggest) may explain the null finding for prescription drugs. The THC cutoff of 2 ng/mL may not perfectly separate impaired from non-impaired drivers."},{"rthcId":"RTHC-01144","title":"Changes in cannabis potency over the last 2 decades (1995-2014): Analysis of current data in the United States","authors":"ElSohly, Mahmoud A.; Mehmedic, Zlatko; Foster, Susan; Gon, Chandrani; Chandra, Suman; Church, James C.","year":2016,"journal":"Biological Psychiatry, 79(7), 613-619","doi":"10.1016/j.biopsych.2016.01.004","pmid":"26903403","tags":["potency","youth","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers analyzed 38,681 cannabis samples seized by the DEA over twenty years. The trend was steady and one-directional: THC concentrations climbed from roughly 4% in 1995 to roughly 12% in 2014. That alone would matter, but the CBD side of the equation shifted even more dramatically. CBD content fell from about 0.28% to below 0.15%, pushing the THC-to-CBD ratio from 14:1 to approximately 80:1.\n\nThe composition of what was being seized changed too. Traditional marijuana samples declined while sinsemilla — the seedless, higher-potency form — rose. The market was selecting for stronger product with less of the compound some researchers believe moderates THC's effects.","whyItMatters":"When someone talks about smoking weed \"like they did in the '90s,\" the chemistry says otherwise. The plant material circulating in 2014 was a fundamentally different product than what was available in 1995 — roughly three times the THC and half the CBD. Most research on cannabis health effects was conducted when potency was far lower than what users encounter today, which means older safety data may not translate directly to modern products.\n\nThe disappearing CBD is arguably as important as the rising THC. Some evidence suggests CBD may buffer certain THC effects, including anxiety and psychosis risk. A market that selects almost exclusively for THC potency is, in effect, removing a potential safety margin.","specificNumbers":"• THC concentration: ~4% (1995) → ~12% (2014)\n• CBD concentration: ~0.28% (2001) → <0.15% (2014)\n• THC:CBD ratio: 14:1 (1995) → ~80:1 (2014)\n• Total samples analyzed: 38,681 over 20 years","methodology":"The Potency Monitoring Program at the University of Mississippi, funded by NIDA, received and analyzed cannabis samples confiscated by the DEA nationwide. Each sample was tested using a validated gas chromatography method (GC/FID) for THC, CBD, and other cannabinoid concentrations. The dataset spans January 1995 through December 2014.","limitations":"The data comes exclusively from DEA seizures, which may not represent what consumers actually purchased and used. Seizure patterns shifted over time as enforcement priorities changed. The study cannot determine whether the potency increase translated to higher THC intake per session, since users may have adjusted their consumption. Post-2014 data, including legal market products, is not captured here."},{"rthcId":"RTHC-01145","title":"Prevalence and correlates of a lifetime cannabis use disorder among pregnant former tobacco smokers.","authors":"Emery, Rebecca L; Gregory, Melissa P; Grace, Jennifer L; Levine, Michele D","year":2016,"journal":"Addictive behaviors, 54, 52-8","doi":"10.1016/j.addbeh.2015.12.008","pmid":"26717552","tags":["pregnancy","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers studied 273 pregnant women who had quit smoking tobacco as a result of pregnancy to understand how common cannabis use disorder was in this population and what predicted it.\n\nOverall, 14% met criteria for a lifetime cannabis use disorder. The strongest predictor by far was having a history of multiple psychiatric disorders, which was associated with 36.4 times higher odds. A lifetime alcohol use disorder also increased the odds (3.5x).\n\nAdditional predictors included more frequent prior attempts to quit tobacco and lower confidence about managing weight after quitting smoking. The findings suggest that women with co-occurring cannabis and tobacco dependence may need specialized treatment during pregnancy.","whyItMatters":"Cannabis use during pregnancy is common, and women who struggle with tobacco may also struggle with cannabis. The extremely strong association with multiple psychiatric disorders (OR=36.4) suggests that mental health screening is essential for identifying pregnant women at risk for cannabis use disorder.","specificNumbers":"273 pregnant women. 14% met lifetime cannabis use disorder criteria. History of multiple psychiatric disorders: OR 36.44. Lifetime alcohol use disorder: OR 3.54. More quit attempts: OR 1.12. Lower weight management self-efficacy: OR 0.78.","methodology":"Cross-sectional analysis of 273 pregnant former tobacco smokers enrolled in a randomized controlled trial for postpartum tobacco relapse prevention. Participants completed semi-structured psychiatric interviews and self-report measures during their third trimester.","limitations":"The sample was limited to pregnant women who had successfully quit tobacco, which may not represent all pregnant cannabis users. Lifetime (not current) cannabis use disorder was assessed. The very wide confidence interval on the psychiatric disorder odds ratio (5.03-264.27) reflects the small sample. Self-selected trial participants may differ from the general population."},{"rthcId":"RTHC-01146","title":"Byssinosis and COPD rates among factory workers manufacturing hemp and jute.","authors":"Er, Mukremin; Emri, Salih A; Demir, Ahmet U; Thorne, Peter S; Karakoca, Yalcin; Bilir, Nazmi; Baris, Izzettin Y","year":2016,"journal":"International journal of occupational medicine and environmental health, 29(1), 55-68","doi":"10.13075/ijomeh.1896.00512","pmid":"26489943","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01147","title":"Adult attention-deficit/hyperactivity disorder and its association with substance use and substance use disorders in young men.","authors":"Estévez, N; Dey, M; Eich-Höchli, D; Foster, S; Gmel, G; Mohler-Kuo, M","year":2016,"journal":"Epidemiology and psychiatric sciences, 25(3), 255-66","doi":"10.1017/S2045796015000360","pmid":"25989844","tags":["addiction","cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Researchers examined the relationship between ADHD and substance use in 5,677 Swiss men (average age 20) from a representative cohort study.\n\nMen with ADHD were more likely to have used nicotine, cannabis, and other illicit drugs (but not alcohol) at some point. ADHD was positively associated with earlier initiation of alcohol, nicotine, and cannabis, with riskier use patterns for these substances, and with alcohol use disorders and nicotine and cannabis dependence.\n\nImportantly, antisocial personality disorder (ASPD) was also strongly associated with these patterns. After adjusting for ASPD, the ADHD associations were reduced but remained significant, suggesting that ADHD has an independent contribution to substance use risk beyond its overlap with antisocial behavior.","whyItMatters":"This large, representative study clarifies that ADHD independently contributes to substance use risk in young men, even after accounting for the substantial overlap with antisocial personality. This has implications for targeted prevention in ADHD populations.","specificNumbers":"5,677 Swiss men (mean age 20). ADHD associated with lifetime nicotine, cannabis, and illicit drug use (but not alcohol). ADHD associated with earlier initiation of alcohol, nicotine, and cannabis. Associations reduced but remained significant after ASPD adjustment.","methodology":"Cross-sectional analysis from the Cohort Study on Substance Use Risk Factors (C-SURF), a representative sample of 5,677 Swiss men (mean age 20). ADHD was assessed with the Adult ADHD Self-Report Screener. Substance use was assessed for alcohol, nicotine, cannabis, and other drugs, controlling for demographics, depression, and ASPD.","limitations":"Only male participants were included. ADHD was assessed by self-report screener rather than clinical diagnosis. The cross-sectional design cannot determine whether ADHD causes earlier or riskier substance use. Swiss military recruitment-based sampling may not represent all young men."},{"rthcId":"RTHC-01148","title":"Cannabinoid receptor 1 (CNR1) gene variant moderates neural index of cognitive disruption during nicotine withdrawal.","authors":"Evans, D E; Sutton, S K; Jentink, K G; Lin, H-Y; Park, J Y; Drobes, D J","year":2016,"journal":"Genes, brain, and behavior, 15(7), 621-6","doi":"10.1111/gbb.12311","pmid":"27453054","tags":["genetics","neuroscience","quitting"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether genetic variation in the cannabinoid receptor 1 gene (CNR1) affected how much nicotine withdrawal disrupted cognitive function, as measured by resting brainwave (EEG) patterns.\n\nSeventy-three Caucasian smokers (15+ cigarettes/day) completed two lab sessions: one after smoking nicotine cigarettes and one after smoking placebo cigarettes following overnight deprivation. Three CNR1 gene variants were tested.\n\nOne variant (rs806379) significantly moderated the effect of nicotine deprivation on slow-wave EEG activity (a marker of cognitive disruption). Smokers homozygous for the major allele showed greater nicotine withdrawal-related cognitive disruption, suggesting they might benefit most from cannabinoid receptor-targeted smoking cessation medications.","whyItMatters":"This study suggests the endocannabinoid system influences vulnerability to nicotine withdrawal, and that genetic variation in cannabinoid receptors could predict who struggles most with quitting smoking. This could eventually support personalized smoking cessation treatment.","specificNumbers":"73 smokers (15+ cigarettes/day). CNR1 variant rs806379 moderated withdrawal EEG effects (p=0.004). Homozygous major allele carriers showed greater cognitive disruption during withdrawal.","methodology":"Within-subject crossover design. 73 Caucasian non-Hispanic smokers visited the lab twice following overnight nicotine deprivation. Either nicotine or placebo cigarettes were smoked before resting EEG was recorded across 17 electrodes. Three CNR1 polymorphisms were tested as moderators.","limitations":"Small sample size (73 participants). Only Caucasian non-Hispanic smokers were included. EEG changes are a proxy for cognitive disruption and may not perfectly predict real-world quit outcomes. The specific functional effect of the rs806379 variant is not fully characterized."},{"rthcId":"RTHC-01149","title":"Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways.","authors":"Farkas, Imre; Vastagh, Csaba; Farkas, Erzsébet; Bálint, Flóra; Skrapits, Katalin; Hrabovszky, Erik; Fekete, Csaba; Liposits, Zsolt","year":2016,"journal":"Frontiers in cellular neuroscience, 10, 214","doi":"10.3389/fncel.2016.00214","pmid":"27672360","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01150","title":"Trends and correlates of substance use disorders among probationers and parolees in the United States 2002-2014.","authors":"Fearn, Noelle E; Vaughn, Michael G; Nelson, Erik J; Salas-Wright, Christopher P; DeLisi, Matt; Qian, Zhengmin","year":2016,"journal":"Drug and alcohol dependence, 167, 128-39","doi":"10.1016/j.drugalcdep.2016.08.003","pmid":"27515722","tags":["addiction","legalization","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using national survey data from 2002 to 2014, researchers found that people on probation or parole had dramatically higher rates of substance use disorders across every category compared to the general population.\n\nMarijuana abuse and dependence were significantly elevated in this group, though alcohol-related disorders were still two to six times more common than marijuana-related ones. These elevated rates remained remarkably stable over the entire 12-year study period, showing no signs of improvement despite evolving drug policies.\n\nKey risk factors for substance disorders in this population included being younger, male, having lower education, lower income, higher risk-taking tendencies, and involvement in crime or violence.","whyItMatters":"This research highlights a persistent gap in how the criminal justice system addresses substance use. Despite decades of awareness, substance use disorder rates among supervised populations have barely changed, suggesting that current approaches to treatment within the justice system are falling short.","specificNumbers":"Probationers and parolees had substance use disorder rates four to nine times higher than unsupervised peers. Alcohol abuse and dependence rates were two to six times higher than marijuana rates within the supervised population. Trends remained stable from 2002 to 2014.","methodology":"The researchers analyzed data from the National Survey on Drug Use and Health (NSDUH), a large nationally representative survey. They used logistic regression to examine eight distinct substance use disorder outcomes among probationers and parolees, controlling for demographic and behavioral variables.","limitations":"The NSDUH relies on self-reported data, which may undercount substance use in a population that has strong incentives to minimize reporting. The cross-sectional design cannot determine whether criminal justice involvement precedes or follows substance use disorders."},{"rthcId":"RTHC-01151","title":"The association between cannabis use and anxiety disorders: Results from a population-based representative sample.","authors":"Feingold, Daniel; Weiser, Mark; Rehm, Jürgen; Lev-Ran, Shaul","year":2016,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 26(3), 493-505","doi":"10.1016/j.euroneuro.2015.12.037","pmid":"26775742","tags":["anxiety","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"This study followed thousands of Americans over three years to test whether cannabis use leads to anxiety disorders or vice versa. The results were largely negative on both fronts.\n\nCannabis use did not increase the risk of developing generalized anxiety, social anxiety, panic disorder, or specific phobias. Similarly, having an anxiety disorder at baseline did not predict future cannabis use or cannabis use disorders.\n\nOne notable exception emerged: people with panic disorder at baseline were significantly more likely to start using cannabis during the follow-up period, suggesting possible self-medication. And heavy cannabis use showed a trend toward increased social anxiety risk, though this did not hold up in the final adjusted analysis.","whyItMatters":"The relationship between cannabis and anxiety is one of the most debated topics in cannabis research. This study provides some of the strongest prospective evidence to date suggesting that for most people, cannabis use does not trigger anxiety disorders. The panic disorder finding adds nuance, suggesting some people may turn to cannabis to manage panic symptoms.","specificNumbers":"Cannabis use was not associated with any anxiety disorder incidence (AOR = 1.12). Heavy use showed a trend toward social anxiety (AOR = 1.98) but was not significant in the final model. People with baseline panic disorder were 2.2 times more likely to initiate cannabis use (AOR = 2.2, 95% CI 1.15-4.18).","methodology":"Data came from waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a large nationally representative prospective study. The researchers controlled for baseline anxiety disorders and used adjusted odds ratios to examine bidirectional associations between cannabis use and anxiety outcomes over three years.","limitations":"The 3-year follow-up period may be too short to capture long-term effects. Cannabis use was self-reported and may have been underreported. The study could not account for specific cannabis products, doses, or THC/CBD ratios, all of which may influence anxiety outcomes differently."},{"rthcId":"RTHC-01152","title":"THC:CBD in Daily Practice: Available Data from UK, Germany and Spain.","authors":"Fernández, Óscar","year":2016,"journal":"European neurology, 75 Suppl 1, 1-3","doi":"10.1159/000444234","pmid":"26901342","tags":["medical-cannabis","cbd"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Since Sativex became available in European countries in 2010 for treatment-resistant multiple sclerosis spasticity, real-world data has been collected through registry and observational studies across multiple countries.\n\nThe most recent analysis of registry data from over 900 patients in the UK, Germany, and Switzerland showed long-term continuation rates of 68% at one year, with an average dose of 5.4 sprays per day. No new safety concerns emerged, and adverse events of special interest for a cannabis-based medicine were limited.\n\nA separate prospective study in Spain involving 207 patients from 13 specialized MS centers produced closely matching results: 64.7% continuation rate at one year, average dose of 6.6 sprays per day, and a similar safety profile with no evidence of addiction, abuse, or misuse.","whyItMatters":"Clinical trials show a drug works under controlled conditions. Real-world evidence shows whether it works in everyday medical practice, where patients have more complex health situations and less supervision. The consistency of these results across four countries strengthens the case that Sativex is both effective and well-tolerated for MS spasticity.","specificNumbers":"Registry data (UK/Germany/Switzerland): 68% one-year continuation rate, mean dose 5.4 sprays/day, 900+ patients. Spain study: 64.7% one-year continuation rate, mean dose 6.6 sprays/day, 207 patients from 13 centers. No evidence of addiction, abuse, or misuse in either dataset.","methodology":"Two data sources were examined: a retrospective registry study collecting safety data from patients in the UK, Germany, and Switzerland (900+ patients), and a prospective safety study from 13 specialized MS centers in Spain (207 patients). Both tracked continuation rates, dosing, and adverse events.","limitations":"Observational studies lack the control of randomized trials and cannot account for all confounding factors. Patients who continued treatment may differ systematically from those who stopped. The studies focused on MS spasticity and cannot be generalized to other conditions."},{"rthcId":"RTHC-01153","title":"Cannabis Involvement and Nonsuicidal Self-Injury: A Discordant Twin Approach.","authors":"Few, Lauren R; Grant, Julia D; Nelson, Elliot C; Trull, Timothy J; Grucza, Richard A; Bucholz, Kathleen K; Verweij, Karin J H; Martin, Nicholas G; Statham, Dixie J; Madden, Pamela A F; Heath, Andrew C; Lynskey, Michael T; Agrawal, Arpana","year":2016,"journal":"Journal of studies on alcohol and drugs, 77(6), 873-880","doi":null,"pmid":"27797688","tags":["mental-health","youth","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers studied nearly 10,000 Australian twins to untangle whether cannabis use leads to nonsuicidal self-injury (NSSI) or whether both behaviors stem from shared genetic and environmental factors.\n\nLifetime cannabis use was associated with a 2.84 times higher odds of self-injury. However, when the researchers compared identical twins where one used cannabis and the other did not, this association disappeared. This means the link between lifetime cannabis use and self-injury is likely explained by shared genes and family environment rather than cannabis itself.\n\nBut the story changed for early cannabis use (before age 17). Even in identical twin pairs discordant for early use, the twin who started cannabis early had 3.2 times higher odds of self-injury. This suggests that starting cannabis use in adolescence carries a person-specific risk for self-harm that goes beyond shared genetics.","whyItMatters":"This is one of the most methodologically rigorous studies examining cannabis and self-harm because the twin design can separate genetic predisposition from potential causal effects. The finding that early-onset cannabis use carries independent risk even after controlling for genetics has direct implications for prevention efforts targeting adolescent cannabis use.","specificNumbers":"Lifetime cannabis use: OR = 2.84 (95% CI 2.23-3.61). Early cannabis use: OR = 2.15 (95% CI 1.75-2.65). In discordant identical twins, early cannabis use: OR = 3.20 (95% CI 1.17-8.73). Sample: 9,583 twins plus 3,787 replication sample.","methodology":"The study used data from 9,583 adult twins in the Australian Twin Registry. Researchers compared monozygotic (identical) twins discordant for cannabis use, which controls for shared genetics and family environment. Results were replicated in an independent sample of 3,787 female twins with temporal ordering of onset.","limitations":"The discordant twin sample for early cannabis use was small, which limits the precision of the effect estimate. Self-injury and cannabis use were both self-reported. The study cannot identify the specific mechanisms by which early cannabis use might increase self-harm risk."},{"rthcId":"RTHC-01154","title":"Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials.","authors":"Fitzcharles, M-A; Baerwald, C; Ablin, J; Häuser, W","year":2016,"journal":"Schmerz (Berlin, Germany), 30(1), 47-61","doi":"10.1007/s00482-015-0084-3","pmid":"26767993","tags":["pain","medical-cannabis","inflammation"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The researchers systematically searched for randomized controlled trials of cannabinoid products in fibromyalgia, osteoarthritis, chronic spinal pain, and rheumatoid arthritis. They found remarkably little evidence.\n\nOnly four short trials qualified: two in fibromyalgia (71 patients total, using nabilone), one in spinal pain (30 patients, nabilone), and one in rheumatoid arthritis (58 patients, THC/CBD). No trials in osteoarthritis met inclusion criteria.\n\nThe results were inconsistent. Some trials showed benefits for pain or sleep, but the evidence was not uniform across studies. Cannabinoids were generally well-tolerated and safe during the study periods, though troublesome side effects occurred.","whyItMatters":"Chronic pain from rheumatic diseases affects millions of people, and current treatments are often inadequate. This review reveals a striking gap between patient interest in cannabinoids and the available scientific evidence. As of 2015, the evidence base consisted of fewer than 200 patients across just four trials.","specificNumbers":"Four RCTs identified: 71 fibromyalgia patients, 30 spinal pain patients, 58 rheumatoid arthritis patients. Zero osteoarthritis RCTs. All trials were 2-5 weeks long. Three of four had high risk of bias. Pain refractory to conventional treatment was required in three studies.","methodology":"Systematic search through April 2015 across CENTRAL, PubMed, cannabis-med.org, and clinicaltrials.gov. Included randomized controlled trials of at least 2 weeks duration with at least 10 patients per arm. Study quality was assessed using the Cochrane Risk of Bias Tool. Three of four studies had high risk of bias.","limitations":"The tiny number of included trials severely limits the conclusions. All studies were very short (2-5 weeks), used different cannabinoid products and conditions, and three had high risk of bias. No herbal cannabis trials were identified."},{"rthcId":"RTHC-01155","title":"Efficacy, Tolerability, and Safety of Cannabinoid Treatments in the Rheumatic Diseases: A Systematic Review of Randomized Controlled Trials.","authors":"Fitzcharles, Mary-Ann; Ste-Marie, Peter A; Häuser, Winfried; Clauw, Daniel J; Jamal, Shahin; Karsh, Jacob; Landry, Tara; Leclercq, Sharon; Mcdougall, Jason J; Shir, Yoram; Shojania, Kam; Walsh, Zach","year":2016,"journal":"Arthritis care & research, 68(5), 681-8","doi":"10.1002/acr.22727","pmid":"26548380","tags":["pain","medical-cannabis","inflammation"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This review identified the same thin evidence base for cannabinoids in rheumatic diseases: four short studies totaling only 203 patients across rheumatoid arthritis, fibromyalgia, and osteoarthritis.\n\nCannabinoids had a statistically significant effect on pain in two of the studies and on sleep in two studies. Quality of life improved in one study. However, the osteoarthritis trial was terminated early because the treatment was not working.\n\nThe side effect profile was notable. Dizziness, cognitive problems, drowsiness, and nausea were reported by nearly half of patients. No serious adverse events occurred during the short study durations.","whyItMatters":"This review from a different research group confirms the same conclusion as RTHC-01154: the evidence base for cannabinoids in rheumatic pain is extremely thin. The additional detail on side effects (affecting nearly half of patients) and the failed osteoarthritis trial provide important counterweights to the narrative that cannabinoids are universally helpful for pain.","specificNumbers":"203 total patients across four studies. Pain significant in 2/4 studies. Sleep significant in 2/4 studies. Quality of life improved in 1/4. OA trial terminated for futility. Dizziness, cognitive problems, drowsiness, and nausea in nearly 50% of patients. All three completed studies had high risk of bias.","methodology":"Systematic search of Medline, Embase, and CENTRAL databases. Included randomized controlled trials comparing cannabinoids (phyto- and synthetic) with any control for rheumatic disease pain. Assessed efficacy (pain, sleep, quality of life), tolerability (dropout rates), and safety (serious adverse events). All three completed studies had high risk of bias.","limitations":"Extremely small combined sample size (203 patients). Short study durations. High risk of bias in all completed studies. No studies of herbal cannabis. Heterogeneous conditions and products limit comparison."},{"rthcId":"RTHC-01156","title":"Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development.","authors":"Ford, Benjamin M; Franks, Lirit N; Radominska-Pandya, Anna; Prather, Paul L","year":2016,"journal":"PloS one, 11(12), e0167240","doi":"10.1371/journal.pone.0167240","pmid":"27936172","tags":["neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Tamoxifen is primarily known as a breast cancer drug, but this study revealed that its chemical structure interacts with cannabinoid receptors in ways that could be therapeutically useful.\n\nThe researchers tested tamoxifen's two mirror-image forms (isomers) and their metabolic breakdown products at both CB1 and CB2 cannabinoid receptors. They found that different forms showed different receptor preferences. One metabolite (Z-4OHT) had notably higher affinity for both receptor types, while another (endoxifen) was relatively CB1-selective.\n\nAll tested forms acted as inverse agonists at both CB1 and CB2 receptors, meaning they reduce the baseline activity of these receptors. One form (Z-tamoxifen) was more potent than a well-known reference compound (AM630) at CB2 receptors.","whyItMatters":"This research opens a new avenue for cannabinoid drug development. Rather than starting from scratch, medicinal chemists could use tamoxifen's chemical scaffold as a starting point to design drugs that precisely target cannabinoid receptors, potentially avoiding the psychoactive effects of THC while harnessing therapeutic benefits.","specificNumbers":"Z-4OHT showed higher affinity for both CB1 and CB2 receptors compared to E-isomers. Endoxifen isomers were relatively CB1-selective. Z-tamoxifen exceeded the efficacy of the full inverse agonist AM630 at CB2 receptors. Z-tamoxifen and Z-endoxifen showed insurmountable antagonism at CB1 and CB2 receptors respectively.","methodology":"Laboratory study using cell-based assays to measure binding affinity, G-protein activation, and effects on adenylyl cyclase signaling at human CB1 and CB2 cannabinoid receptors. Different isomers and metabolites of tamoxifen were systematically compared.","limitations":"All experiments were conducted in cell cultures, not in living organisms. The concentrations needed for cannabinoid receptor effects may differ from those achieved during normal tamoxifen therapy. The therapeutic relevance of these interactions remains to be tested in animal models."},{"rthcId":"RTHC-01157","title":"Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity.","authors":"Franks, Lirit N; Ford, Benjamin M; Prather, Paul L","year":2016,"journal":"Frontiers in pharmacology, 7, 503","doi":"10.3389/fphar.2016.00503","pmid":"28066250","tags":["neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Building on the discovery that tamoxifen interacts with cannabinoid receptors, researchers screened 14 drugs from five structurally distinct classes of SERMs to find compounds with even better cannabinoid receptor properties.\n\nFour of five SERM classes bound to cannabinoid receptors. Among the standout findings: ospemifene selectively bound to CB1 receptors, bazedoxifene selectively bound to CB2 receptors, while nafoxidine and raloxifene bound to both non-selectively. All four acted as inverse agonists, reducing baseline receptor activity.\n\nThese newer SERMs showed improved pharmacological characteristics compared to tamoxifen, including better receptor affinity and selectivity. The variety of selectivity profiles across different chemical scaffolds gives drug developers multiple options for targeting specific cannabinoid receptor subtypes.","whyItMatters":"The ability to selectively target CB1 or CB2 receptors is a major goal in cannabinoid drug development. CB2-selective compounds could potentially treat inflammation and pain without psychoactive effects. This study shows that multiple existing drug scaffolds can achieve this selectivity, expanding the toolkit for medicinal chemists.","specificNumbers":"Fourteen SERMs from five classes screened. Four of five classes bound to cannabinoid receptors. Inverse agonist IC50 values ranged from nanomolar to low micromolar. Ospemifene was CB1-selective, bazedoxifene was CB2-selective.","methodology":"Radioligand binding assays screened 14 SERMs at human CB1 and CB2 receptors. The four most promising compounds underwent full characterization including G-protein activation assays, intracellular cAMP measurements in intact cells, and antagonism studies using concentration-effect curves.","limitations":"All data are from cell-based assays. Whether these SERM-derived compounds could be developed into practical cannabinoid drugs remains unknown. The concentrations needed for cannabinoid effects may be higher than typical therapeutic doses for their estrogen-related uses."},{"rthcId":"RTHC-01158","title":"Pregabalin for the Treatment of Drug and Alcohol Withdrawal Symptoms: A Comprehensive Review.","authors":"Freynhagen, Rainer; Backonja, Miroslav; Schug, Stephan; Lyndon, Gavin; Parsons, Bruce; Watt, Stephen; Behar, Regina","year":2016,"journal":"CNS drugs, 30(12), 1191-1200","doi":null,"pmid":"27848217","tags":["withdrawal","drug-interactions","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined evidence for using pregabalin, a nerve pain medication, to treat physical dependence and withdrawal symptoms across multiple substance categories including cannabinoids.\n\nThe available evidence was limited, with few randomized controlled studies. However, the findings that did exist were promising across several substance types, suggesting pregabalin may help manage the anxiety, sleep disturbance, and other discomfort associated with withdrawal.\n\nThe authors noted an important caveat: pregabalin itself carries potential for misuse or abuse, particularly in people with a history of substance use disorders. This creates a paradox where the population most likely to benefit may also be most vulnerable to developing problems with the treatment itself.","whyItMatters":"Cannabis withdrawal is increasingly recognized as a clinically meaningful syndrome that can derail quit attempts. Currently, there are no FDA-approved medications specifically for cannabis withdrawal. If pregabalin proves effective, it could fill an important treatment gap.","specificNumbers":"The review covered withdrawal from five substance categories: opioids, benzodiazepines, nicotine, cannabinoids, and alcohol. Randomized controlled data were described as sparse across all categories.","methodology":"Literature search of MEDLINE and Cochrane Library databases through December 2015. Search terms combined dependence or withdrawal with pregabalin. Cross-referencing of cited works and personal archives. Article selection based on expert opinion of the authors.","limitations":"Randomized controlled data were sparse. The review included studies selected based on expert opinion rather than systematic criteria, introducing potential selection bias. The risk of pregabalin misuse in substance-dependent populations limits its practical application."},{"rthcId":"RTHC-01159","title":"CB1 allosteric modulator Org27569 is an antagonist/inverse agonist of ERK1/2 signaling.","authors":"Gamage, Thomas F; Anderson, Johnathon C; Abood, Mary E","year":2016,"journal":"Cannabis and cannabinoid research, 1(1), 272-280","doi":"10.1089/can.2016.0028","pmid":"28660254","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Allosteric modulators bind to a different site on a receptor than the primary binding site, offering a way to fine-tune receptor activity rather than simply turning it on or off. Org27569 is the most-studied allosteric modulator of the CB1 cannabinoid receptor.\n\nThis study resolved conflicting reports about how Org27569 affects ERK signaling, a key pathway through which cannabinoid receptors influence cell behavior. The researchers found that Org27569 fully blocked ERK activation triggered by the synthetic cannabinoid CP55,940 but could not completely block ERK activation by THC or 2-AG (the body's own cannabinoid).\n\nOrg27569 also reduced baseline ERK activity below normal levels, an effect mediated specifically through CB1 receptors and their associated G-proteins. This is the first demonstration of ERK inverse agonism by Org27569.","whyItMatters":"Allosteric modulators represent a frontier in cannabinoid drug development because they could theoretically dial cannabinoid receptor activity up or down without the all-or-nothing effects of current drugs. Understanding exactly how Org27569 affects signaling pathways is essential for developing this approach into practical therapies.","specificNumbers":"CP55,940 (1 uM) produced significant receptor internalization at 20, 40, 60, and 120 minutes. Org27569 (10 uM) fully prevented this internalization. Org27569 reduced basal ERK phosphorylation in CB1-expressing cells but not untransfected cells. Effects were observed in both nuclear and cytosolic cell fractions.","methodology":"Cell-based experiments using HEK293 cells expressing human CB1 receptors. Researchers measured G-protein activation, ERK phosphorylation, receptor internalization via confocal imaging, and subcellular fractionation to determine where in the cell ERK changes occurred. Pertussis toxin was used to confirm the role of Gi/o proteins.","limitations":"All experiments were in cell cultures overexpressing CB1 receptors, which may not reflect receptor behavior in living brains. The concentrations used may not be achievable in vivo. The clinical relevance of ERK inverse agonism at CB1 receptors remains to be determined."},{"rthcId":"RTHC-01160","title":"Case Report of Intractable Vomiting and Abdominal Pain Related to Heavy Daily Cannabis Use.","authors":"Gammeter, William Bryce; Duke, Kyle A; Soundy, Timothy J","year":2016,"journal":"South Dakota medicine : the journal of the South Dakota State Medical Association, No, 60-63","doi":null,"pmid":"28817852","tags":["addiction","potency"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"An anxious, dehydrated teenager arrived at the emergency department with uncontrollable vomiting, weight loss, and abdominal pain. He reported that bathing and drinking large amounts of water were the only things that helped. He initially admitted only to social marijuana use.\n\nMultiple medications failed to control his symptoms, including benzodiazepines, antipsychotics, and anti-nausea drugs. After extensive medical testing found no other cause, the patient was referred to psychiatric care. Only under more detailed questioning did the full picture emerge: prior chemical dependency treatment, drug-related legal charges, and heavy daily use including dabbing, THC candy, and smoking several grams per day.\n\nThe authors warn that with the rise of high-potency products like concentrates and edibles, cannabinoid hyperemesis syndrome is likely to appear more frequently, in younger patients, and with shorter use histories than historically expected.","whyItMatters":"This case illustrates two important trends: the diagnostic challenge cannabinoid hyperemesis syndrome poses (especially when patients underreport use), and the emerging concern that today's high-potency products may accelerate the condition's onset. Historically, CHS required over a year of heavy daily use. Products like dabs may compress that timeline.","specificNumbers":"Patient used multiple high-potency products daily including dabs, THC candy, and several grams of smoked cannabis. Multiple medication classes (benzodiazepines, antipsychotics, antiemetics) failed to control symptoms. Historical CHS typically required over one year of heavy daily use.","methodology":"Case report of a single adolescent patient presenting to an emergency department. Clinical course, diagnostic workup, and treatment attempts are described. The diagnosis of cannabinoid hyperemesis syndrome was made after extensive testing ruled out other causes.","limitations":"Single case report with limited generalizability. The exact duration and quantity of the patient's cannabis use could not be precisely documented. The mechanisms by which high-potency products might accelerate CHS remain speculative."},{"rthcId":"RTHC-01161","title":"Cannabis withdrawal and sleep: A systematic review of human studies.","authors":"Gates, Peter; Albertella, Lucy; Copeland, Jan","year":2016,"journal":"Substance abuse, 37(1), 255-69","doi":"10.1080/08897077.2015.1023484","pmid":"25893849","tags":["withdrawal","sleep"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Sleep problems during cannabis withdrawal are among the most commonly reported symptoms and a major reason people relapse. This systematic review pulled together 36 human studies to clarify what happens to sleep when heavy users stop.\n\nThe review confirmed that sleep disruption is a consistent feature of cannabis withdrawal across studies. However, the specific details of how sleep is affected remained unclear due to methodological differences between studies.\n\nThe wide variety of measurement approaches, from self-report questionnaires to polysomnography, and differences in participant characteristics, cannabis use patterns, and withdrawal timelines made it difficult to draw precise conclusions about which aspects of sleep architecture are most affected.","whyItMatters":"Sleep disruption is one of the most distressing aspects of cannabis withdrawal and one of the strongest predictors of relapse. Understanding exactly how cannabis withdrawal affects sleep is essential for developing targeted treatments that could help people successfully stop or reduce their use.","specificNumbers":"Thirty-six publications met inclusion criteria from a search across eight databases. Sleep disruption was a consistent finding across studies, though specific aspects varied.","methodology":"Systematic literature search across eight electronic databases using cannabinoid and sleep-related search terms. Included human studies that involved cannabinoid administration and at least one quantitative sleep measure. Excluded reviews, opinion pieces, case studies with fewer than 8 participants, and non-English articles. Thirty-six publications met criteria.","limitations":"Methodological inconsistencies across the 36 included studies prevented definitive conclusions about specific sleep parameters. Studies varied in how they measured sleep, defined withdrawal, and characterized participants' cannabis use."},{"rthcId":"RTHC-01162","title":"Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.","authors":"Gerak, L R; France, C P","year":2016,"journal":"The Journal of pharmacology and experimental therapeutics, 357(2), 357-66","doi":"10.1124/jpet.115.231381","pmid":"26937020","tags":["pain","tolerance","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Combining opioids with cannabinoids is proposed as a way to enhance pain relief while potentially reducing opioid doses. This study tested what happens with prolonged combined treatment in monkeys.\n\nBefore treatment, morphine and THC both effectively eliminated pain responses. However, during twice-daily combined treatment, tolerance developed faster and more extensively than with morphine alone. Pain-relieving doses needed to increase 3 to 10 times above pre-treatment levels.\n\nThe key finding was about withdrawal. When treatment stopped, monkeys showed increased heart rate and observable withdrawal signs, but these were generally similar whether they had received morphine alone or morphine plus THC. So while THC enhanced morphine's pain-relieving effects and accelerated tolerance, it did not worsen the physical dependence picture.","whyItMatters":"The opioid epidemic has driven interest in combining opioids with cannabinoids to reduce opioid doses. This study provides mixed news: while the combination enhances acute pain relief, it also accelerates tolerance, which could undermine the dose-reduction strategy. The reassuring finding is that THC does not appear to worsen opioid dependence.","specificNumbers":"Tolerance produced 3 to 10-fold rightward shifts in pain relief dose-response curves. Greater shifts occurred with the morphine/THC combination than morphine alone. Withdrawal signs (heart rate increase, behavioral signs) were generally similar between treatment groups.","methodology":"Four rhesus monkeys received twice-daily injections of morphine (3.2 mg/kg) alone or combined with THC (1 mg/kg). Pain relief was measured using warm water tail withdrawal latency. Researchers tracked antinociceptive effects before, during, and after treatment, and monitored withdrawal signs when treatment was discontinued.","limitations":"Small sample size of four monkeys. Animal pain models may not translate directly to human chronic pain. The study used specific doses that may not reflect clinical ratios. The THC dose used was relatively high."},{"rthcId":"RTHC-01163","title":"Dorsal hippocampal NMDA receptors mediate the interactive effects of arachidonylcyclopropylamide and MDMA/ecstasy on memory retrieval in rats.","authors":"Ghaderi, Marzieh; Rezayof, Ameneh; Vousooghi, Nasim; Zarrindast, Mohammad-Reza","year":2016,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 66, 41-47","doi":"10.1016/j.pnpbp.2015.11.008","pmid":"26612394","tags":["cognition","neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both cannabinoids and MDMA (ecstasy) can impair memory individually, but this study found something unexpected: when given together, MDMA actually reversed the memory problems caused by a synthetic cannabinoid.\n\nThe researchers injected the synthetic cannabinoid ACPA directly into the hippocampus of rats, which impaired their ability to remember a passive avoidance task. When MDMA was also injected into the same brain region, it rescued this memory deficit at higher doses.\n\nThis reversal effect depended on NMDA receptors, which are critical for memory formation. Blocking NMDA receptors with the drug D-AP5 prevented MDMA from rescuing the cannabinoid-induced memory impairment. The authors suggest this interaction may help explain why some people combine cannabis and ecstasy.","whyItMatters":"This study provides insight into the brain mechanisms underlying polydrug use involving cannabis and MDMA. Understanding how these substances interact at the neural level could inform both harm reduction strategies and the development of treatments for cognitive effects of substance use.","specificNumbers":"ACPA at doses of 0.5-4 ng/rat impaired memory retrieval. MDMA at 0.5-1 ug/rat dose-dependently impaired memory alone but reversed ACPA-induced impairment at higher doses. D-AP5 at 1-2 ug/rat blocked MDMA's reversal effect.","methodology":"Adult male Wistar rats received direct microinjections into the CA1 region of the hippocampus through surgically implanted cannulas. Memory was tested using a step-through passive avoidance task. The NMDA receptor antagonist D-AP5 was used to test the role of glutamate signaling in the interaction.","limitations":"Direct brain injection does not reflect how people actually use these drugs. The synthetic cannabinoid ACPA may have different effects than THC. Rat memory tasks have limited applicability to human cognitive experiences. Doses and routes of administration are not clinically relevant."},{"rthcId":"RTHC-01164","title":"Variable activation in striatal subregions across components of a social influence task in young adult cannabis users.","authors":"Gilman, Jodi M; Lee, Sang; Kuster, John K; Lee, Myung Joo; Kim, Byoung Woo; van der Kouwe, Andre; Blood, Anne J; Breiter, Hans C","year":2016,"journal":"Brain and behavior, 6(5), e00459","doi":"10.1002/brb3.459","pmid":"27257518","tags":["cognition","neuroscience","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Twenty young adult cannabis users and 20 non-users completed a decision-making task while undergoing brain scans. The task measured how viewing other people's choices affected their own decisions.\n\nCannabis users showed activation in the middle striatum (caudate) when applying social information to their choices, an activation pattern not seen in controls. When cannabis users followed the group's choices rather than going against them, they showed greater activation in the nucleus accumbens, a key reward region. This reward-region activation correlated with the amount of drug use reported.\n\nDuring the feedback phase of the task, both groups showed nucleus accumbens activation, but cannabis users additionally showed dorsal caudate activation that controls did not.","whyItMatters":"Social influence is one of the strongest predictors of drug use initiation and maintenance, yet the brain mechanisms underlying social influence in drug users are poorly understood. This study suggests that cannabis users may find following peer influence more rewarding, which could reinforce continued use in social contexts.","specificNumbers":"Twenty cannabis users vs. 20 controls, ages 18-25. Nucleus accumbens activation during group-congruent choices correlated with amount of drug use. Cannabis users but not controls showed caudate activation when processing social information and during feedback.","methodology":"Cross-sectional fMRI study comparing 20 marijuana-using young adults (ages 18-25) with 20 age-matched controls. Participants completed a decision-making task where they could follow or go against group influence while undergoing functional MRI. A priori analyses focused on the nucleus accumbens, with additional analyses across the striatum.","limitations":"Cross-sectional design cannot determine whether brain differences preceded cannabis use or resulted from it. Small sample size limits statistical power. Unknown whether peers in the task were perceived as relevant by participants. Cannabis use was self-reported."},{"rthcId":"RTHC-01165","title":"Neural mechanisms of sensitivity to peer information in young adult cannabis users.","authors":"Gilman, Jodi M; Schuster, Randi M; Curran, Max T; Calderon, Vanessa; van der Kouwe, Andre; Evins, A Eden","year":2016,"journal":"Cognitive, affective & behavioral neuroscience, 16(4), 646-61","doi":"10.3758/s13415-016-0421-8","pmid":"27068178","tags":["cognition","neuroscience","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This companion study to RTHC-01164 used a slightly different social influence paradigm with 20 cannabis-using young adults and 23 controls. Participants made perceptual choices after seeing what their peers chose.\n\nBehaviorally, cannabis users and controls followed or opposed the group at similar rates. But cannabis users showed significantly longer reaction times when deciding to go against the group, suggesting they had to exert more cognitive effort to resist conformity.\n\nThe brain imaging revealed that cannabis users had significantly greater caudate activation when presented with peer information compared to controls. Across both groups, caudate activation correlated with self-reported susceptibility to influence. The longer reaction times when opposing the group were associated with greater frontal brain activation.","whyItMatters":"This study complements the findings of RTHC-01164 by showing that cannabis users are not simply more conformist, but rather that processing social information appears to require more neural resources for them. The reaction time data suggests that going against peers is cognitively more effortful for cannabis users, even when they ultimately make independent choices.","specificNumbers":"Twenty cannabis users vs. 23 controls. No behavioral difference in conformity rates, but cannabis users had slower reaction times when opposing group choices. Greater caudate activation to peer information in cannabis users. Caudate activation correlated with self-reported susceptibility to influence across groups.","methodology":"Cross-sectional fMRI study comparing 20 marijuana-using young adults with 23 controls. Participants viewed photographs of peers and their choices in a perceptual decision task during functional MRI scanning. Reaction times and brain activation were analyzed in relation to social conformity and resistance.","limitations":"Cross-sectional design cannot establish causality. The small sample size limits statistical power. Peers were unknown to participants, which may reduce the ecological validity of the social influence manipulation. Self-reported cannabis use."},{"rthcId":"RTHC-01166","title":"Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.","authors":"Gomis-González, Maria; Busquets-Garcia, Arnau; Matute, Carlos; Maldonado, Rafael; Mato, Susana; Ozaita, Andrés","year":2016,"journal":"Genes, 7(9)","doi":"10.3390/genes7090056","pmid":"27589806","tags":["neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Fragile X syndrome is the most common genetic cause of intellectual disability. Previous research from this group showed that blocking CB1 cannabinoid receptors with rimonabant corrected multiple features of the disease in mice. However, rimonabant was pulled from the market as an obesity drug due to psychiatric side effects at the doses used for weight loss.\n\nThis study asked whether much lower doses could still work. The answer was yes. Doses of rimonabant as low as 0.01 mg/kg normalized the memory deficit in Fragile X mice, and 0.1 mg/kg corrected abnormal brain signaling (mGluR-dependent long-term depression). These doses are 30 to 300 times lower than those needed for weight loss and presumably for causing side effects.\n\nAdditionally, a \"neutral\" CB1 antagonist called NESS0327, which blocks the receptor without the inverse agonist activity linked to side effects, also prevented memory deficits in Fragile X mice.","whyItMatters":"Fragile X syndrome has no approved pharmacological treatment. This study suggests that the endocannabinoid system is a viable therapeutic target and that the dose needed for treating cognitive deficits is far below the dose that caused problems in the obesity trials. This could potentially rehabilitate CB1 receptor targeting as a treatment strategy.","specificNumbers":"Rimonabant 0.01 mg/kg normalized cognition (30-300x below weight-loss doses). Rimonabant 0.1 mg/kg normalized mGluR-LTD brain signaling. Weight-loss doses in rodents: 3-10 mg/kg. NESS0327 (neutral antagonist) also effective for cognitive rescue.","methodology":"Electrophysiological recordings measured mGluR-dependent long-term depression in brain slices from Fragile X knockout mice treated with low-dose rimonabant. Behavioral testing used the novel object recognition task to assess cognitive function. NESS0327 was tested as an alternative neutral antagonist.","limitations":"Mouse models of Fragile X syndrome do not fully replicate the human condition. The effective doses were for acute administration; long-term safety at low doses has not been established. Human pharmacokinetics may differ from mice. The neutral antagonist NESS0327 has limited preclinical data."},{"rthcId":"RTHC-01167","title":"A cost-effectiveness model for the use of a cannabis-derived oromucosal spray for the treatment of spasticity in multiple sclerosis.","authors":"Gras, Adrien; Broughton, Julie","year":2016,"journal":"Expert review of pharmacoeconomics & outcomes research, 16(6), 771-779","doi":null,"pmid":"26750641","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using a 30-year Markov model, researchers compared the costs and health outcomes of adding the THC:CBD spray Sativex to standard care versus standard care alone for moderate-to-severe MS spasticity in Wales.\n\nThe incremental cost was estimated at 3,836 British pounds per patient over 30 years, with an incremental cost-effectiveness ratio of 10,891 pounds per quality-adjusted life year. This is well below the 20,000-30,000 pounds threshold typically used in the UK to determine cost-effectiveness.\n\nWhen the costs of home caregivers were factored in, the picture flipped dramatically. By reducing spasticity severity, Sativex reduced the need for intensive home care, generating estimated savings of 33,609 pounds per patient. In other words, the treatment more than paid for itself through reduced carer costs.","whyItMatters":"Health technology assessments determine whether treatments become available on public health systems. This analysis provides an economic justification for prescribing Sativex that goes beyond clinical effectiveness, showing it may actually save healthcare systems money when the full cost picture is considered.","specificNumbers":"Incremental cost: 3,836 pounds per patient over 30 years. ICER: 10,891 pounds per QALY. With carer costs included: savings of 33,609 pounds per patient (ICER: -95,423 pounds per QALY, meaning dominant). Hospital admission costs had the greatest impact on the base case.","methodology":"Markov model comparing THC:CBD plus standard care versus standard care alone over 30 years. Model parameters were drawn from clinical trials and real-world data. Sensitivity analysis examined the impact of hospital admission costs and carer costs on the results.","limitations":"Health economic models rely on assumptions about disease progression, treatment continuation, and costs that may not hold over 30 years. The model was specific to Wales and may not generalize to other healthcare systems. Carer cost estimates involve significant uncertainty."},{"rthcId":"RTHC-01168","title":"Cannabinoid hyperemesis syndrome and the onset of a manic episode.","authors":"Gregoire, Phillip; Tau, Michael; Robertson, David","year":2016,"journal":"BMJ case reports, 2016","doi":"10.1136/bcr-2016-215129","pmid":"27122104","tags":["mental-health","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report describes a patient with bipolar disorder who developed cannabinoid hyperemesis syndrome (CHS), the vomiting condition seen in heavy cannabis users. The resulting three weeks of persistent vomiting likely prevented adequate absorption of their mood stabilizer medication, lowering serum levels and precipitating a manic episode.\n\nThe case illustrates an underappreciated risk of CHS: for patients on oral psychiatric medications, prolonged vomiting can disrupt medication absorption and trigger the very psychiatric conditions those medications are designed to prevent.\n\nThe patient's CHS resolved with cessation of cannabis use, consistent with the established treatment for this condition.","whyItMatters":"This case highlights an important and overlooked interaction between heavy cannabis use and psychiatric treatment. CHS is not just a gastrointestinal problem. For the many patients who use cannabis while taking psychiatric medications, CHS-induced vomiting can create a dangerous secondary psychiatric crisis.","specificNumbers":"Three weeks of vomiting preceded the manic episode. CHS symptoms were characterized by cyclic nausea and vomiting with relief from hot bathing. Mood stabilizer serum levels were lowered by poor oral absorption during the vomiting period.","methodology":"Single case report of a patient presenting with both cannabinoid hyperemesis syndrome and bipolar mania. The temporal relationship between CHS-induced vomiting, medication levels, and mania onset was analyzed.","limitations":"Single case report cannot establish causality. Other factors may have contributed to the manic episode. The specific mood stabilizer levels before and during CHS were not reported in detail."},{"rthcId":"RTHC-01169","title":"Polytobacco, marijuana, and alcohol use patterns in college students: A latent class analysis.","authors":"Haardörfer, Regine; Berg, Carla J; Lewis, Michael; Payne, Jackelyn; Pillai, Drishti; McDonald, Bennett; Windle, Michael","year":2016,"journal":"Addictive behaviors, 59, 58-64","doi":"10.1016/j.addbeh.2016.03.034","pmid":"27074202","tags":["addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used latent class analysis to identify distinct patterns of substance use among 3,418 college students across seven US campuses. Five groups emerged.\n\nAbstainers made up 26.1%, alcohol-only users were the largest group at 38.9%, heavy polytobacco users comprised 7.3%, light polytobacco users 17.3%, and a distinctive group of little cigar/cigarillo, hookah, and marijuana co-users accounted for 10.4%.\n\nThe little cigar/hookah/marijuana cluster was the most stable over time, with 77.3% of members showing the same pattern across both 30-day and 4-month timeframes. This suggests this is a deeply entrenched use pattern, not just experimentation.\n\nRelative to abstainers, heavy polytobacco users perceived tobacco and marijuana as less harmful. Alcohol-only users perceived tobacco and marijuana use as less socially acceptable but were more likely to have friends using marijuana.","whyItMatters":"Substance use among college students is rarely limited to one product. Understanding the specific clusters of co-use helps prevention programs target the right combinations and the risk factors associated with each pattern. The stability of the marijuana/cigar/hookah cluster is particularly important for intervention design.","specificNumbers":"Five classes: Abstainers (26.1%), Alcohol only (38.9%), Heavy polytobacco (7.3%), Light polytobacco (17.3%), LCC/hookah/marijuana co-users (10.4%). The LCC/hookah/marijuana cluster was the most stable (77.3% consistent across timeframes). Sample: 3,418 students, ages 18-25, seven US campuses.","methodology":"Baseline data from a multiwave longitudinal study of 3,418 students aged 18-25 from seven US college campuses. Latent class analysis identified use patterns across tobacco products, marijuana, and alcohol. Multivariable logistic regression examined correlates of class membership.","limitations":"Cross-sectional baseline data cannot capture how use patterns evolve over time. Self-reported use may be underreported. Seven campuses may not represent all college environments. The study cannot determine whether the clustering reflects shared social contexts, pharmacological interactions, or both."},{"rthcId":"RTHC-01170","title":"Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis.","authors":"Haney, Margaret; Malcolm, Robert J; Babalonis, Shanna; Nuzzo, Paul A; Cooper, Ziva D; Bedi, Gillinder; Gray, Kevin M; McRae-Clark, Aimee; Lofwall, Michelle R; Sparenborg, Steven; Walsh, Sharon L","year":2016,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(8), 1974-82","doi":"10.1038/npp.2015.367","pmid":"26708108","tags":["cbd","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Some studies have suggested that CBD can counteract certain effects of THC, leading to widespread claims that CBD-rich products might reduce the downsides of cannabis use. This randomized, double-blind study tested that idea rigorously.\n\nThirty-one healthy cannabis smokers completed eight sessions where they received oral CBD (0, 200, 400, or 800 mg) 90 minutes before smoking either active or inactive cannabis. CBD alone produced no significant psychoactive or cardiovascular effects.\n\nThe key finding: CBD at any dose did not reduce the high, the positive subjective effects, the self-administration of cannabis, or the heart rate increase caused by smoked cannabis. Participants were just as likely to choose active cannabis over placebo cannabis regardless of CBD pretreatment.","whyItMatters":"This study directly challenges the popular notion that CBD counteracts THC. The failure of even very high CBD doses (800 mg) to blunt any measured effect of smoked cannabis suggests that adding CBD to cannabis products may not meaningfully reduce intoxication or the desire to use more.","specificNumbers":"31 participants (17 male, 14 female). CBD doses: 0, 200, 400, 800 mg oral. Cannabis: 5.30-5.80% THC. Eight sessions per participant. No significant effect of CBD on any outcome at any dose.","methodology":"Multi-site, randomized, double-blind, within-subject laboratory study. Thirty-one non-treatment-seeking cannabis smokers completed eight outpatient sessions testing four CBD doses against two cannabis conditions. A subset of 8 participants had plasma CBD levels measured after the 800 mg dose.","limitations":"The cannabis used (5.3-5.8% THC) was lower potency than much of what is available today. CBD was given orally while cannabis was smoked, creating different pharmacokinetic profiles. Participants were regular users who may have different responses than occasional users."},{"rthcId":"RTHC-01171","title":"Drug Recognition Expert (DRE) examination characteristics of cannabis impairment.","authors":"Hartman, Rebecca L; Richman, Jack E; Hayes, Charles E; Huestis, Marilyn A","year":2016,"journal":"Accident; analysis and prevention, 92, 219-29","doi":"10.1016/j.aap.2016.04.012","pmid":"27107471","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Law enforcement uses the Drug Evaluation and Classification Program (DECP) to assess suspected drug-impaired drivers, but the reliability of specific tests for detecting cannabis impairment has been uncertain. This study compared 302 toxicologically confirmed cannabis-impaired drivers against 302 non-impaired controls.\n\nThe finger-to-nose test stood out as the single best predictor, with sensitivity, specificity, positive predictive value, and negative predictive value all above 87% when using 3 or more misses as the criterion. Eyelid tremors during the Modified Romberg Balance test also performed well (all metrics above 86%).\n\nCombining at least 2 of 4 indicators (finger-to-nose misses, eyelid tremors, one-leg-stand clues, walk-and-turn clues) produced the strongest results, with all diagnostic characteristics above 96.7%.\n\nNotably, the commonly debated 5 ug/L blood THC cutoff showed limited relevance. There were no significant differences in impairment indicators between drivers above and below this threshold.","whyItMatters":"Unlike alcohol, there is no agreed-upon standard for cannabis impairment testing. This study provides the strongest evidence to date for which specific roadside tests reliably identify cannabis impairment, and it challenges the usefulness of blood THC concentration cutoffs.","specificNumbers":"Finger-to-nose test (3+ misses): all diagnostic metrics 87.1%+. Eyelid tremors: all metrics 86.1%+. Combined 2-of-4 criteria: all metrics 96.7%+. 302 confirmed cases vs. 302 controls. 5 ug/L THC cutoff showed no significant diagnostic value.","methodology":"Retrospective analysis of 302 toxicologically confirmed cannabis-only DECP cases (blood THC 1+ ug/L) compared to 302 normative non-impaired controls. Evaluated pulse, blood pressure, pupil size, and performance on four psychophysical tests.","limitations":"Cases were selected where Drug Recognition Experts successfully identified cannabis, potentially excluding cases where cannabis impairment was missed. The comparison to normative data rather than a matched control group introduces potential confounds. Polydrug cases were excluded."},{"rthcId":"RTHC-01172","title":"Prevalence and Correlates of DSM-5 Cannabis Use Disorder, 2012-2013: Findings from the National Epidemiologic Survey on Alcohol and Related Conditions-III.","authors":"Hasin, Deborah S; Kerridge, Bradley T; Saha, Tulshi D; Huang, Boji; Pickering, Roger; Smith, Sharon M; Jung, Jeesun; Zhang, Haitao; Grant, Bridget F","year":2016,"journal":"The American journal of psychiatry, 173(6), 588-99","doi":"10.1176/appi.ajp.2015.15070907","pmid":"26940807","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"This study provided the first nationally representative prevalence data for cannabis use disorder using the updated DSM-5 criteria. Among 36,309 US adults interviewed in 2012-2013, 2.5% met criteria for a past-year cannabis use disorder and 6.3% for a lifetime diagnosis.\n\nThose with cannabis use disorder used marijuana frequently, averaging 225 days per year for past-year cases. The disorder was strongly associated with other substance use disorders, mood disorders, anxiety, and personality disorders, with these associations strengthening as severity increased.\n\nPerhaps the most striking finding was the treatment gap: only 13.2% of those with a lifetime cannabis use disorder ever participated in treatment or 12-step programs.","whyItMatters":"This was the first major study to establish DSM-5 cannabis use disorder prevalence in the US population. The high comorbidity rates, association with disability, and massive treatment gap paint a picture of a condition that affects millions but is largely unaddressed by the healthcare system.","specificNumbers":"12-month prevalence: 2.5%. Lifetime prevalence: 6.3%. Mean use: 225 days/year (12-month cases), 274 days/year (lifetime cases). Young adults 18-24 had 7.2x higher odds than those 45+. Only 13.2% with lifetime diagnosis ever received treatment. 36,309 participants.","methodology":"Data from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III), a nationally representative face-to-face survey of 36,309 adults 18+ conducted in 2012-2013. Psychiatric disorders were assessed using structured clinical interviews (AUDADIS-5). DSM-5 criteria were applied.","limitations":"Cross-sectional data cannot determine whether cannabis use disorder causes psychiatric comorbidities or vice versa. Data were collected in 2012-2013, before many state legalization initiatives. Self-reported data may undercount cannabis use disorders."},{"rthcId":"RTHC-01173","title":"Training and Practices of Cannabis Dispensary Staff.","authors":"Haug, Nancy A; Kieschnick, Dustin; Sottile, James E; Babson, Kimberly A; Vandrey, Ryan; Bonn-Miller, Marcel O","year":2016,"journal":"Cannabis and cannabinoid research, 1(1), 244-251","doi":"10.1089/can.2016.0024","pmid":"28861496","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"As cannabis dispensaries have proliferated, patients increasingly rely on dispensary staff for guidance on which products to use for specific conditions. This study surveyed 55 dispensary employees about their training, knowledge, and recommendation practices.\n\nAlmost all staff (94%) reported providing specific cannabis advice to patients. However, only 55% had any formal training for their position, and just 20% had medical or scientific training.\n\nStaff recommendations followed some patterns: Indica strains were recommended for anxiety, pain, insomnia, nightmares, and Tourette syndrome. A 1:1 THC:CBD ratio was most commonly recommended for anxiety, Crohn's disease, hepatitis C, and PTSD. High CBD was recommended for arthritis, Alzheimer's, epilepsy, and muscle spasms.\n\nWhile many recommendations aligned with available evidence, some were inconsistent with it or could potentially worsen certain conditions.","whyItMatters":"Dispensary staff are functioning as de facto healthcare providers for many cannabis patients, yet most lack medical training. The gap between the advice-giving role and the training level raises important questions about patient safety and the quality of cannabis-based care.","specificNumbers":"55 dispensary staff surveyed. 94% give specific cannabis advice. 55% had some formal training. 20% had medical/scientific training. Indica most commonly recommended for anxiety, pain, insomnia. 1:1 THC:CBD most recommended for PTSD and Crohn's.","methodology":"Online survey of 55 medical and non-medical dispensary staff recruited via email and social media. Assessed demographics, dispensary features, formal training, and specific cannabis recommendation practices for various patient conditions.","limitations":"Very small sample (55 staff) recruited through convenience methods, limiting generalizability. Self-reported practices may not reflect actual behavior. The survey could not assess the accuracy of individual recommendations or patient outcomes."},{"rthcId":"RTHC-01174","title":"Influence of Previous Failed Antispasticity Therapy on the Efficacy and Tolerability of THC:CBD Oromucosal Spray for Multiple Sclerosis Spasticity.","authors":"Haupts, Michael; Vila, Carlos; Jonas, Anna; Witte, Kerstin; Álvarez-Ossorio, Lourdes","year":2016,"journal":"European neurology, 75(5-6), 236-43","doi":"10.1159/000445943","pmid":"27160412","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"A key question for any treatment is whether it works in difficult-to-treat patients. This post hoc analysis examined whether the THC:CBD spray Sativex helped MS spasticity patients who had already failed standard treatments.\n\nAmong 241 patients, researchers identified two groups: those who had failed at least one course of baclofen or tizanidine (162 patients), and those who had failed both (57 patients). In both groups, Sativex significantly outperformed placebo.\n\nThe treatment achieved both minimal clinically important improvement (18%+ spasticity reduction) and clinically important improvement (30%+ reduction) more often than placebo, regardless of pretreatment history. Sleep quality and walking ability also improved. Tolerability was unaffected by the number of prior treatment failures.","whyItMatters":"Treatment-resistant patients are the population most in need of alternative therapies. This analysis demonstrates that Sativex's effectiveness is not limited to \"easy\" cases and that patients who have exhausted conventional options can still benefit.","specificNumbers":"241 intent-to-treat patients. Group 1 (1+ failed therapy): 162 patients. Group 2 (2+ failed therapies): 57 patients. Significant improvement on MCID (18%+ improvement) and CID (30%+ improvement) versus placebo in all groups. Sleep quality and walking speed also improved.","methodology":"Post hoc analysis of an enriched-design randomized controlled trial of THC:CBD spray versus placebo. Patients were stratified by history of failed baclofen and/or tizanidine therapy. Outcomes included spasticity NRS score, sleep quality, and timed 10-meter walk.","limitations":"Post hoc analysis is exploratory and hypothesis-generating rather than confirmatory. The subgroups were defined after the trial completed, which increases the risk of finding spurious results. Sample sizes, particularly for the dual-failure group, were small."},{"rthcId":"RTHC-01175","title":"Roles for the endocannabinoid system in ethanol-motivated behavior.","authors":"Henderson-Redmond, Angela N; Guindon, Josée; Morgan, Daniel J","year":2016,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 65, 330-9","doi":"10.1016/j.pnpbp.2015.06.011","pmid":"26123153","tags":["addiction","neuroscience","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized evidence showing that the endocannabinoid system plays a central role in alcohol-motivated behavior. Chronic alcohol exposure increases endocannabinoid levels, which in turn downregulates CB1 receptors and uncouples them from their downstream signaling pathways.\n\nIn rodent studies, blocking CB1 receptors with rimonabant or genetically deleting them reduced voluntary alcohol drinking, alcohol-triggered dopamine release in the reward center (nucleus accumbens), self-administration of alcohol, and reinstatement/relapse behavior.\n\nPET brain imaging in human alcoholic patients confirmed similar CB1 receptor downregulation across multiple brain regions, suggesting the animal findings translate to humans.\n\nHowever, rimonabant's psychiatric side effects limit its clinical use. The review highlights two promising alternatives: negative allosteric modulators of CB1 and inhibitors of endocannabinoid breakdown enzymes.","whyItMatters":"Alcohol use disorder is a massive health problem with limited treatment options. The endocannabinoid system represents a validated therapeutic target, and understanding how it drives alcohol-seeking behavior could lead to new medications, particularly if the psychiatric side effects of direct CB1 blockade can be avoided.","specificNumbers":"Chronic alcohol exposure increases endocannabinoid levels in cell culture and rodent models. PET imaging confirms CB1 downregulation in multiple brain regions of human alcoholics. Rimonabant and CB1 genetic deletion reduce alcohol drinking, self-administration, and relapse in rodents.","methodology":"Narrative review synthesizing preclinical rodent studies, genetic knockout experiments, in vitro cell culture work, and human PET imaging studies examining the relationship between the endocannabinoid system and alcohol-motivated behavior.","limitations":"Most evidence comes from animal models that may not fully replicate human alcohol use disorder. Rimonabant's clinical failure limits the direct translatability. The newer approaches (allosteric modulators, enzyme inhibitors) remain in early development."},{"rthcId":"RTHC-01176","title":"Cannabinoid Hyperemesis Syndrome: A Case Report of Cyclic Severe Hyperemesis and Abdominal Pain with Long-Term Cannabis Use.","authors":"Hermes-Laufer, Julia; Del Puppo, Lola; Inan, Ihsan; Troillet, François-Xavier; Kherad, Omar","year":2016,"journal":"Case reports in gastrointestinal medicine, 2016, 2815901","doi":null,"pmid":"27980870","tags":["addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A young man with a history of heavy long-term cannabis use repeatedly showed up in the emergency room with severe cyclic nausea and vomiting that was only relieved by hot showers. Standard anti-nausea treatments were ineffective.\n\nThe diagnosis of cannabinoid hyperemesis syndrome was not made until his third ER visit. The authors emphasize that the syndrome, first described in 2004, remains poorly known among emergency medicine providers, leading to unnecessary and expensive diagnostic testing and delayed diagnosis.\n\nThe only effective long-term treatment was complete cessation of cannabis use. The authors note that standard anti-nausea medications targeting serotonin (5-HT3) or dopamine (D2) receptors do not work for this condition.","whyItMatters":"This case illustrates the real-world cost of underrecognizing CHS. Three ER visits with extensive workups represent significant healthcare spending and patient suffering that could have been avoided with earlier diagnosis. As cannabis use increases, CHS awareness among healthcare providers becomes more important.","specificNumbers":"Three ER visits before diagnosis. 26-year-old male with long-term heavy cannabis use. Standard antiemetics ineffective. Hot showers provided symptom relief. Complete cannabis cessation resolved the condition.","methodology":"Case report of a single patient with three emergency department presentations. Clinical course, failed treatments, and eventual diagnosis are described.","limitations":"Single case report. No quantification of cannabis use amounts or duration. No follow-up data on whether the patient successfully maintained abstinence."},{"rthcId":"RTHC-01177","title":"Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users.","authors":"Herrmann, Evan S; Cooper, Ziva D; Bedi, Gillinder; Ramesh, Divya; Reed, Stephanie C; Comer, Sandra D; Foltin, Richard W; Haney, Margaret","year":2016,"journal":"Psychopharmacology, 233(13), 2469-78","doi":"10.1007/s00213-016-4298-6","pmid":"27085870","tags":["withdrawal","sleep","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Eleven daily cannabis users completed three 8-day inpatient stays testing different medication conditions during monitored cannabis withdrawal.\n\nBoth zolpidem alone and zolpidem plus nabilone improved sleep during withdrawal. However, only the combination reduced withdrawal-related mood disruption and changes in food intake.\n\nThe most significant finding was about relapse: when active cannabis was made available on days 5-8, participants given the zolpidem-nabilone combination self-administered less cannabis than those on placebo. Zolpidem alone did not reduce cannabis self-administration.\n\nThe combination did produce small increases in some abuse-related subjective ratings, a potential concern. Neither medication condition affected cognitive performance.","whyItMatters":"There are no approved medications for cannabis use disorder. This study provides evidence that a combination pharmacotherapy targeting both sleep (zolpidem) and cannabinoid withdrawal (nabilone) may be more effective than targeting sleep alone, and suggests nabilone could reduce relapse.","specificNumbers":"11 daily cannabis users. 8-day inpatient phases. Nabilone 3 mg twice daily + zolpidem 12.5 mg at bedtime. Combination reduced cannabis self-administration vs. placebo. Both medication conditions improved sleep. Only combination improved mood and food intake.","methodology":"Placebo-controlled, within-subject, counter-balanced inpatient study. Eleven non-treatment-seeking daily cannabis users completed three 8-day phases testing placebo, zolpidem alone (12.5 mg at bedtime), and zolpidem (12.5 mg) plus nabilone (3 mg twice daily). Cannabis withdrawal was assessed on days 3-4 and relapse on days 5-8.","limitations":"Very small sample of 11 non-treatment-seeking users. The inpatient lab setting does not replicate real-world conditions. The slight abuse-related subjective effects of the combination warrant monitoring. Short study duration."},{"rthcId":"RTHC-01178","title":"A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.","authors":"Hjorth, Stephan; Karlsson, Cecilia; Jucaite, Aurelija; Varnäs, Katarina; Wählby Hamrén, Ulrika; Johnström, Peter; Gulyás, Balázs; Donohue, Sean R; Pike, Victor W; Halldin, Christer; Farde, Lars","year":2016,"journal":"Neuropharmacology, 101, 519-30","doi":"10.1016/j.neuropharm.2015.03.002","pmid":"25791528","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"As part of efforts to develop safer anti-obesity drugs targeting the CB1 receptor, researchers used PET brain imaging in six non-human primates to measure how much of the CB1 receptor population different drugs actually occupied at therapeutic-equivalent doses.\n\nThe surprise finding was that rimonabant and taranabant, both proven effective for weight loss in humans, only needed to occupy about 20-30% of CB1 receptors to produce their therapeutic effects. This is much lower than the typical 60-80% occupancy needed for most drugs targeting G-protein coupled receptors.\n\nThree novel CB1 antagonists developed by AstraZeneca showed similar binding characteristics. The researchers also noted that \"neutral\" CB1 antagonists (which block the receptor without reducing its baseline activity) might achieve therapeutic benefit with fewer psychiatric side effects than inverse agonists like rimonabant.","whyItMatters":"Understanding that only 20-30% receptor occupancy is needed for therapeutic effects opens the possibility of using much lower doses of CB1 antagonists, potentially staying below the threshold for psychiatric side effects while maintaining efficacy. This finding could guide clinical dose optimization for future CB1-targeting drugs.","specificNumbers":"42 PET measurements in 6 primates. 5 CB1 antagonists tested. Clinical efficacy doses produced only 20-30% CB1 receptor occupancy. Typical GPCR antagonists require 60-80% occupancy. Three novel AstraZeneca compounds showed binding affinity similar to rimonabant and taranabant.","methodology":"Forty-two PET measurements in six non-human primates using the CB1-specific radioligand [11C]SD5024. Five CB1 receptor antagonists were compared for receptor occupancy relative to dose and plasma exposure. Occupancy at clinically effective doses was estimated.","limitations":"Non-human primate pharmacokinetics may differ from humans. The 20-30% occupancy estimate is an approximation based on cross-species dose translation. No direct measurement of psychiatric side effects at different occupancy levels was performed."},{"rthcId":"RTHC-01179","title":"Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery.","authors":"Hu, Jianping; Feng, Zhiwei; Ma, Shifan; Zhang, Yu; Tong, Qin; Alqarni, Mohammed Hamed; Gou, Xiaojun; Xie, Xiang-Qun","year":2016,"journal":"Journal of chemical information and modeling, 56(6), 1152-63","doi":"10.1021/acs.jcim.5b00739","pmid":"27186994","tags":["neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Without an experimental crystal structure of the CB2 cannabinoid receptor, researchers have struggled to design drugs that precisely target it. This study built detailed computer models of CB2 in both its active (agonist-bound with G-protein) and inactive (inverse agonist-bound) states.\n\n100-nanosecond molecular dynamics simulations revealed the structural transformations CB2 undergoes during activation, including the breaking of a key \"ionic lock\" and outward/inward movements of transmembrane domains. The simulations identified specific amino acid residues critical for binding agonists versus inverse agonists.\n\nUsing these models for virtual drug screening, the researchers identified 10 candidate compounds. Two exhibited novel chemical structures and biological activity, serving as new chemical probes for studying CB2. Importantly, the inactive CB2 model produced hits that behaved as inverse agonists or neutral antagonists, while hits from the active model also showed antagonist properties.","whyItMatters":"CB2 receptors are promising drug targets for pain, inflammation, osteoporosis, and cancer treatment without the psychoactive effects associated with CB1 activation. Understanding the structural differences between active and inactive CB2 states accelerates rational drug design for these conditions.","specificNumbers":"100 ns molecular dynamics simulations for each state. Key residues identified: W258 in TM6, V164-L169 in TM4 for agonist binding; S180-F183 in ECL2 for inverse agonist binding. 10 virtual screening hits, 2 with novel scaffolds confirmed as biologically active.","methodology":"Homology modeling constructed CB2 structures based on related receptor templates. Two 100-nanosecond molecular dynamics simulations compared active and inactive states. Binding energy decomposition identified critical residues. Pharmacophore modeling and virtual screening identified candidate compounds from chemical databases.","limitations":"Homology models are approximations based on related but not identical receptor structures. Virtual screening hit rates are typically low, and the two confirmed compounds require extensive optimization before clinical relevance. In vitro activity does not guarantee in vivo efficacy."},{"rthcId":"RTHC-01180","title":"Involvement of TRPV1 in the Olfactory Bulb in Rimonabant-Induced Olfactory Discrimination Deficit.","authors":"Hu, Sherry Shu-Jung","year":2016,"journal":"The Chinese journal of physiology, 59(1), 21-32","doi":"10.4077/CJP.2016.BAE366","pmid":"26875559","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rimonabant is best known as a CB1 cannabinoid receptor blocker, but it also interacts with other receptors. This study investigated its effects on smell, a function increasingly linked to the endocannabinoid system.\n\nCB1 knockout mice showed impaired olfactory discrimination, confirming a role for CB1 in smell. But these mice also showed broader deficits in exploration, making interpretation difficult.\n\nWhen rimonabant was given to normal mice, either systemically or directly into the olfactory bulb, it impaired olfactory discrimination. The surprise: this impairment was reversed by blocking TRPV1 receptors (using capsazepine), not by activating CB1 receptors. This means rimonabant's effect on smell works through TRPV1, not CB1.\n\nInterestingly, only repeated (not single) doses of rimonabant impaired smell, and neither rimonabant nor the TRPV1 blocker affected general locomotion or exploration.","whyItMatters":"This study reveals that a drug's effects can be mediated by receptors other than its primary target. For rimonabant specifically, TRPV1-mediated olfactory effects could have contributed to the altered eating behavior seen in clinical use, since smell and taste are closely linked to appetite.","specificNumbers":"CB1 knockout mice showed impaired olfactory discrimination. Short-term (but not acute) rimonabant impaired smell in wild-type mice. TRPV1 antagonist capsazepine reversed the olfactory deficit. Neither drug affected locomotion or general exploration in wild-type mice.","methodology":"Mouse study using CB1 knockout mice and pharmacological approaches. Olfactory discrimination was tested using a habituation-dishabituation paradigm. Rimonabant and the TRPV1 antagonist capsazepine were administered systemically and directly into the olfactory bulb. Locomotion and exploratory behavior were also measured.","limitations":"Mouse olfactory systems differ from humans. The TRPV1-mediated mechanism needs confirmation in other species. The study used a specific olfactory discrimination task that may not capture all aspects of olfactory function. CB1 knockout mice had broader behavioral deficits complicating interpretation."},{"rthcId":"RTHC-01181","title":"The Role of Medicinal Cannabis in Clinical Therapy: Pharmacists' Perspectives.","authors":"Isaac, Sami; Saini, Bandana; Chaar, Betty B","year":2016,"journal":"PloS one, 11(5), e0155113","doi":"10.1371/journal.pone.0155113","pmid":"27171490","tags":["medical-cannabis","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"As Australia prepared to legalize medical cannabis, this study captured the views of 34 practicing pharmacists who would be responsible for dispensing it.\n\nThe majority supported national legalization of a standardized cannabis product and believed community pharmacies were the most suitable supply setting due to patient accessibility. Pharmacists identified themselves as essential gatekeepers who could ensure safe, informed access.\n\nHowever, several barriers emerged. Stigma around cannabis remained a concern, both from pharmacists themselves and from other healthcare providers. Safety questions about dosing, drug interactions, and side effects needed addressing. Most importantly, pharmacists highlighted a significant knowledge gap, noting they would need evidence-based training to confidently counsel patients.\n\nThe pharmacists also raised ethical and professional issues, including how to handle patient requests for conditions without strong evidence, and how to manage the transition from illicit to pharmaceutical supply.","whyItMatters":"Pharmacists are the final link between patients and their medications. Their perspectives on barriers, training needs, and practical implementation challenges are essential for successful medical cannabis programs. These findings directly informed Australian policy development.","specificNumbers":"34 registered pharmacists interviewed. Majority supported legalization and pharmacy-based supply. Key themes: stigma, legislation, safety, and collaboration. Community pharmacy identified as most suitable setting.","methodology":"Semi-structured interviews with 34 registered pharmacists across Australia. Interviews were audio-recorded, transcribed verbatim, and analyzed thematically using NVivo software.","limitations":"Small qualitative sample from one country. Pharmacists who agreed to participate may have been more favorable toward medical cannabis than the broader profession. Views were captured before implementation, so some concerns may not have materialized in practice."},{"rthcId":"RTHC-01182","title":"A Network Approach to Environmental Impact in Psychotic Disorder: Brief Theoretical Framework.","authors":"Isvoranu, Adela-Maria; Borsboom, Denny; van Os, Jim; Guloksuz, Sinan","year":2016,"journal":"Schizophrenia bulletin, 42(4), 870-3","doi":"10.1093/schbul/sbw049","pmid":"27179124","tags":["psychosis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This study applied network analysis, a novel mathematical framework, to understand how environmental risk factors relate to psychotic symptoms. Rather than treating psychosis as a single entity, network analysis maps the specific connections between individual symptoms and risk factors.\n\nThe researchers examined three environmental risk factors (cannabis use, developmental trauma, and urban environment) and their relationships with various symptom dimensions and psychosis expression in general population data.\n\nCannabis use emerged as the most connected environmental factor, with specific pathways linking it to psychosis symptoms. These pathways often ran through other psychiatric symptoms (anxiety, depression, hostility), suggesting that cannabis may contribute to psychosis not through a single direct mechanism but through a web of interconnected symptom changes.\n\nPeople exposed to environmental risk factors had more strongly interconnected symptom networks, suggesting that environmental exposure reduces the resilience of the overall mental health system.","whyItMatters":"Traditional research treats psychosis as a binary outcome (you have it or you don't). Network analysis reveals the specific symptom pathways through which risk factors like cannabis use may contribute to psychotic experiences, opening new possibilities for targeted prevention.","specificNumbers":"Three environmental risk factors examined. Seven psychopathology dimensions measured. Cannabis use had the most connections to symptoms of any environmental factor. Symptom networks were more strongly connected in environmentally exposed individuals.","methodology":"Network analysis using general population data. Three environmental risk factors and dimensional measures of psychopathology (anxiety, depression, interpersonal sensitivity, OCD, phobic anxiety, somatizations, hostility) were modeled as nodes in a network alongside psychosis expression. Edge weights represent the strength of connections between nodes.","limitations":"Cross-sectional data cannot establish temporal ordering. Network analysis identifies statistical associations, not necessarily causal pathways. General population data may not generalize to clinical populations. Cannabis use was broadly defined."},{"rthcId":"RTHC-01183","title":"Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study.","authors":"Jadoon, Khalid A; Ratcliffe, Stuart H; Barrett, David A; Thomas, E Louise; Stott, Colin; Bell, Jimmy D; O'Sullivan, Saoirse E; Tan, Garry D","year":2016,"journal":"Diabetes care, 39(10), 1777-86","doi":"10.2337/dc16-0650","pmid":"27573936","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This was the first randomized controlled trial testing cannabinoids specifically for glycemic control in type 2 diabetes. Sixty-two patients with non-insulin-treated diabetes were randomized to five groups: CBD alone, THCV alone, low-ratio CBD:THCV, high-ratio CBD:THCV, or placebo for 13 weeks.\n\nTHCV was the clear standout. Compared to placebo, it significantly decreased fasting blood sugar, improved pancreatic beta-cell function, increased the beneficial hormone adiponectin, and improved apolipoprotein A levels. However, it did not affect HDL cholesterol (the primary endpoint).\n\nCBD showed more modest effects, decreasing the inflammatory marker resistin and increasing the gut hormone GIP compared to baseline, but these changes were not significant compared to placebo.\n\nSurprisingly, the combination treatments (CBD plus THCV) had no significant impact on any endpoint, suggesting the compounds may interfere with each other.","whyItMatters":"THCV is a minor cannabinoid found in small amounts in some cannabis varieties. This trial provides the first human evidence that it has genuine metabolic effects in diabetes patients. If confirmed in larger trials, THCV could represent an entirely new class of diabetes medication derived from cannabis.","specificNumbers":"THCV decreased fasting glucose by 1.2 mmol/L vs. placebo (p<0.05). Beta-cell function improved by 44.51 points (p<0.01). Adiponectin increased (p<0.01). CBD decreased resistin by 898 pg/ml (p<0.05 vs. baseline). 62 patients, 13-week treatment. Both compounds were well-tolerated.","methodology":"Randomized, double-blind, placebo-controlled, parallel-group pilot study. Sixty-two subjects with non-insulin-treated type 2 diabetes across five treatment arms for 13 weeks. CBD was dosed at 100 mg twice daily and THCV at 5 mg twice daily. Primary endpoint: HDL cholesterol change. Extensive secondary and tertiary metabolic endpoints.","limitations":"Small pilot study (62 patients across 5 arms means very small per-group sizes). The primary endpoint (HDL) was not met. Thirteen weeks may be too short to see full metabolic effects. THCV is available in very limited quantities, which would constrain clinical development."},{"rthcId":"RTHC-01184","title":"A high efficacy cannabinergic ligand (AM4054) used as a discriminative stimulus: Generalization to other adamantyl analogs and Δ(9)-THC in rats.","authors":"Järbe, Torbjörn U C; LeMay, Brian J; Thakur, Ganesh A; Makriyannis, Alexandros","year":2016,"journal":"Pharmacology, biochemistry, and behavior, 148, 46-52","doi":"10.1016/j.pbb.2016.06.001","pmid":"27264437","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers trained rats to discriminate between the effects of the synthetic cannabinoid AM4054 and a vehicle (no drug). They then tested whether the rats would generalize this recognition to three structural analogs and to THC.\n\nAll tested compounds produced the same discriminative response as AM4054, confirming they all produce similar subjective effects through the CB1 receptor. The potency order was AM4054 being the most potent (matching or exceeding AM4083), followed by AM4050, then AM4089, with THC being the least potent.\n\nThe CB1 antagonist rimonabant blocked AM4054's discriminative effects, confirming CB1 receptor mediation. AM4089 was notably less potent than expected based on its binding affinity, which the authors attribute to it being a partial rather than full agonist at CB1.","whyItMatters":"Drug discrimination is a key tool for understanding how synthetic cannabinoids compare to THC in terms of their psychoactive effects. This study helps characterize a family of high-potency cannabinoids and identifies structural features that influence potency, which is relevant to both drug development and understanding synthetic cannabinoid abuse.","specificNumbers":"AM4054 training dose: 0.1 mg/kg. Potency order: AM4054 >= AM4083 >= AM4050 > AM4089 > THC. AM4089 was less potent than expected (partial agonist). Rimonabant blocked AM4054 effects (CB1-mediated). 9-beta-formyl group identified as key potency-enhancing feature.","methodology":"Drug discrimination study in rats trained to distinguish AM4054 (0.1 mg/kg) from vehicle. Generalization (substitution) testing with three analogs and THC. Antagonism testing with rimonabant. The paradigm measures whether a drug produces subjective effects similar to the training drug.","limitations":"Drug discrimination in rats measures subjective-like effects but cannot directly measure human psychoactive experience. The specific compounds tested are research tools, not drugs of abuse or therapeutic agents. Small number of animals (typical for this methodology)."},{"rthcId":"RTHC-01185","title":"[INCREMENT]9-Tetrahydrocannabinol discriminative stimulus effects of AM2201 and related aminoalkylindole analogs in rats.","authors":"Järbe, Torbjörn U C; Gifford, Roger S; Zvonok, Alexander; Makriyannis, Alexandros","year":2016,"journal":"Behavioural pharmacology, 27(2-3 Spec Issue), 211-4","doi":"10.1097/FBP.0000000000000196","pmid":"26397760","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AM2201 is a synthetic cannabinoid that has been found in \"Spice\" products sold as legal cannabis alternatives. Using rats trained to recognize THC's effects, researchers compared AM2201 and structural analogs to natural THC.\n\nAM2201 was 14 times more potent than THC in producing the same discriminative effects. Other analogs tested were 2.5 to 4 times more potent than THC. All compounds generalized fully to THC, meaning they produced equivalent subjective-like effects.\n\nRimonabant blocked AM2201's effects, confirming they are entirely CB1 receptor-dependent. Time-course data revealed that AM2201 likely peaks very rapidly with a functional half-life of only about 60 minutes, much shorter than THC's duration. This rapid onset and short duration could contribute to compulsive redosing.","whyItMatters":"The 14-fold potency difference between AM2201 and THC helps explain the more severe adverse effects reported with Spice products. The short half-life (about 60 minutes) means users may experience rapid cycles of intoxication and withdrawal, potentially driving compulsive redosing and increasing toxicity risk.","specificNumbers":"AM2201 was 14x more potent than THC. Other analogs: 2.5-4x more potent. AM2201 functional half-life: approximately 60 minutes. Rimonabant confirmed CB1-mediated effects. Full generalization to THC across all compounds.","methodology":"Drug discrimination in rats trained to recognize THC (3 mg/kg). AM2201 and analogs were tested for generalization (substitution). Rimonabant was used for antagonism studies. Time-course testing measured the onset and duration of AM2201's effects.","limitations":"Rat pharmacology may not directly translate to human experience. The study used pure compounds, while Spice products contain unknown mixtures and concentrations. Drug discrimination cannot assess the full toxicity profile of these compounds."},{"rthcId":"RTHC-01186","title":"Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains.","authors":"Jennings, Elaine M; Okine, Bright N; Olango, Weredeselam M; Roche, Michelle; Finn, David P","year":2016,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 64, 181-9","doi":"10.1016/j.pnpbp.2015.05.008","pmid":"25988529","tags":["pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic stress can make pain worse, but this study showed that genetic background dramatically changes this relationship. Two rat strains with different stress vulnerabilities showed opposite outcomes after 10 days of swim stress.\n\nNormal Sprague-Dawley rats developed enhanced pain sensitivity after repeated stress, as expected. But stress-vulnerable Wistar Kyoto rats actually showed reduced pain sensitivity after the same stress protocol.\n\nThe endocannabinoid system changes matched these behavioral differences. Stressed normal rats showed increased MAGL (an enzyme that breaks down endocannabinoids) in the spinal cord and decreased anandamide in the amygdala. These changes were absent in the stress-vulnerable strain. Additional strain differences in CB1 receptor expression and 2-AG levels were found in both the spinal cord and amygdala.","whyItMatters":"This study demonstrates that the interaction between stress and pain is not universal but depends on genetic background. The endocannabinoid system sits at this intersection, and understanding how it mediates different stress-pain outcomes in different genetic contexts could lead to more personalized approaches to pain treatment.","specificNumbers":"10 days of forced swim stress. SD rats: enhanced pain (late phase formalin response). WKY rats: reduced pain. SD rats showed increased MAGL mRNA in ipsilateral spinal cord and decreased anandamide in contralateral amygdala. These changes absent in WKY rats.","methodology":"Sprague-Dawley (stress-normal) and Wistar Kyoto (stress-vulnerable) rats were subjected to 10 days of forced swim stress. Inflammatory pain was assessed using the formalin test. Endocannabinoid levels, receptor expression, and enzyme levels were measured in the dorsal spinal cord and amygdala using RT-PCR and mass spectrometry.","limitations":"WKY rats are an inbred strain that may not directly model human genetic variation. The forced swim stress protocol is specific and may not generalize to other stress types. The formalin test measures acute inflammatory pain, which may differ from chronic pain conditions."},{"rthcId":"RTHC-01187","title":"Successful Treatment of Suspected Cannabinoid Hyperemesis Syndrome Using Haloperidol in the Outpatient Setting.","authors":"Jones, Jennifer L; Abernathy, Karen E","year":2016,"journal":"Case reports in psychiatry, 2016, 3614053","doi":"10.1155/2016/3614053","pmid":"27597918","tags":["addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Cannabinoid hyperemesis syndrome (CHS) is notoriously resistant to standard anti-nausea medications, and the only reliable long-term treatment is stopping cannabis. But many patients are reluctant to quit.\n\nThis case describes a patient with severe, treatment-resistant CHS who achieved complete resolution of nausea and vomiting with haloperidol, an older antipsychotic medication. Notably, this success occurred in the outpatient setting rather than the hospital.\n\nThe authors believe this is the first reported case of successful outpatient CHS treatment, suggesting that haloperidol could provide relief for patients who refuse to stop cannabis or who need symptom management while working toward cessation.","whyItMatters":"The current treatment paradigm for CHS essentially offers patients only one option: stop using cannabis. For patients who are unable or unwilling to quit immediately, having a pharmacological bridge like haloperidol could prevent repeated ER visits and reduce suffering during the transition to abstinence.","specificNumbers":"Complete resolution of nausea and vomiting with haloperidol. First reported outpatient treatment success. Standard antiemetics (serotonin and dopamine receptor antagonists) had failed.","methodology":"Single case report describing outpatient treatment of refractory CHS with haloperidol. The patient had failed standard antiemetic therapies.","limitations":"Single case report. No dosing details provided in the abstract. Haloperidol has its own side effect profile including sedation and movement disorders. Long-term use for CHS is not evaluated."},{"rthcId":"RTHC-01188","title":"Endocannabinoid regulation of β-cell functions: implications for glycaemic control and diabetes.","authors":"Jourdan, T; Godlewski, G; Kunos, G","year":2016,"journal":"Diabetes, obesity & metabolism, 18(6), 549-57","doi":"10.1111/dom.12646","pmid":"26880114","tags":["neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Pancreatic beta-cells, which produce insulin, contain all components of the endocannabinoid system. This review examined how endocannabinoids influence beta-cell function and what this means for diabetes.\n\nIn obesity and type 2 diabetes, endocannabinoid/CB1 receptor system activity increases. This increased activity affects multiple aspects of beta-cell function: basal and glucose-stimulated insulin secretion, beta-cell proliferation (growth of new insulin-producing cells), and beta-cell survival.\n\nBlocking CB1 receptors with both brain-penetrating and peripherally restricted antagonists improved glycemic control in animal models. The effectiveness of peripherally restricted CB1 antagonists (which do not enter the brain) is particularly significant because it demonstrates that the metabolic benefits do not require the brain-mediated effects that caused psychiatric side effects with rimonabant.","whyItMatters":"Type 2 diabetes is driven by progressive beta-cell failure. If the endocannabinoid system contributes to this failure, targeting it peripherally (avoiding brain effects) could represent a new treatment approach that addresses root causes rather than just managing symptoms.","specificNumbers":"Endocannabinoid/CB1 system activity is increased in obesity and type 2 diabetes. CB1 blockade improves glycemic control. Peripherally restricted CB1 antagonists are effective, demonstrating peripheral mechanisms are sufficient.","methodology":"Brief review surveying available literature on endocannabinoid modulation of pancreatic beta-cell function, with attention to autocrine and paracrine mechanisms and implications for glycemic control.","limitations":"Much of the evidence comes from animal models. The relative contribution of peripheral versus central CB1 mechanisms to metabolic improvement is still being determined. Human clinical data with peripherally restricted antagonists is limited."},{"rthcId":"RTHC-01189","title":"Cross-sectional data on alcohol and marijuana use and sexual behavior among male and female secondary school students in New Providence, The Bahamas.","authors":"Kaljee, Linda; Wang, Bo; Deveaux, Lynette; Lunn, Sonja; Rolle, Glenda; Villar, Maria Elena; Stanton, Bonita","year":2016,"journal":"International journal of adolescent medicine and health, 28(2), 133-40","doi":"10.1515/ijamh-2014-0079","pmid":"25781669","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This study examined substance use and sexual behavior among over 2,500 secondary school students in Nassau, The Bahamas. Nearly half of both boys (46.5%) and girls (44.8%) reported alcohol consumption. Marijuana use was much less common overall but showed a stark gender difference: 7.3% of males versus only 1.7% of females reported use in the past 6 months.\n\nSexual experience also showed a gender gap, with 43% of males and 16% of females reporting vaginal sex. After controlling for age and gender, both alcohol and marijuana use were independently associated with increased likelihood of engaging in sexual behavior in the past 6 months.\n\nThe authors emphasize that this represents a global correlation rather than evidence that substance use causes sexual behavior, and call for longitudinal research to understand the temporal relationship.","whyItMatters":"In island nations where HIV and sexually transmitted infections remain significant health concerns, understanding the relationship between substance use and sexual risk behavior helps inform prevention programs. The finding that marijuana use is independently associated with sexual behavior supports integrating substance use education into sexual health programs.","specificNumbers":"2,572 students (56% female). Mean age 14.2 years. Alcohol use: 46.5% males, 44.8% females. Marijuana use: 7.3% males, 1.7% females. Ever had vaginal sex: 43% males, 16% females. Being older, male, and using alcohol or marijuana all independently predicted recent sexual behavior.","methodology":"Cross-sectional baseline survey from a longitudinal randomized controlled evaluation of a school-based HIV prevention program. 2,572 government secondary school students in New Providence, The Bahamas. Mean age 14.2 years. Logistic regression analysis controlling for age and gender.","limitations":"Cross-sectional design cannot determine whether substance use leads to sexual behavior, vice versa, or both reflect shared risk factors. Self-reported data from school-based surveys may undercount sensitive behaviors. Only government school students were included."},{"rthcId":"RTHC-01190","title":"Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates.","authors":"Kangas, Brian D; Leonard, Michael Z; Shukla, Vidyanand G; Alapafuja, Shakiru O; Nikas, Spyros P; Makriyannis, Alexandros; Bergman, Jack","year":2016,"journal":"The Journal of pharmacology and experimental therapeutics, 357(1), 125-33","doi":"10.1124/jpet.115.228189","pmid":"26826191","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using touchscreen cognitive tests in squirrel monkeys, researchers compared THC with anandamide (the brain's own cannabinoid) and drugs that boost anandamide levels.\n\nTHC produced clear, dose-related impairments across multiple cognitive domains. The order of vulnerability was: discriminative capability was most sensitive, followed by learning, cognitive flexibility, and then short-term memory.\n\nAnandamide alone and the FAAH inhibitor URB597 (which raises natural anandamide levels) had no effect on any cognitive test. Even when anandamide was stabilized by FAAH inhibition to prevent its rapid breakdown, cognitive effects were minimal, limited to some short-term memory disruption in some subjects at high doses.\n\nAll drugs left motivation unaffected, suggesting the cognitive impairments from THC are not simply due to reduced willingness to perform.","whyItMatters":"This study suggests that therapeutics based on boosting the body's own endocannabinoid system (via FAAH inhibition) might provide medicinal benefits without the cognitive side effects of THC. This is a critical distinction for developing cannabinoid-based medicines.","specificNumbers":"THC impaired all four cognitive domains dose-dependently. Anandamide alone: no effects. URB597 alone: no effects. Anandamide + URB597: minimal effects, limited to short-term memory in some subjects. Motivation was unaffected by all drugs.","methodology":"Battery of five touchscreen cognitive tests in squirrel monkeys: learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Multiple cannabinoid drugs tested with rimonabant antagonism to confirm CB1 mediation.","limitations":"Small number of subjects typical for primate studies. Squirrel monkey cognition may not directly translate to humans. Anandamide was given exogenously rather than generated endogenously. The specific FAAH inhibitor URB597 has since been shown to have limitations in clinical translation."},{"rthcId":"RTHC-01191","title":"Youth Risk Behavior Surveillance - United States, 2015.","authors":"Kann, Laura; McManus, Tim; Harris, William A; Shanklin, Shari L; Flint, Katherine H; Hawkins, Joseph; Queen, Barbara; Lowry, Richard; Olsen, Emily O'Malley; Chyen, David; Whittle, Lisa; Thornton, Jemekia; Lim, Connie; Yamakawa, Yoshimi; Brener, Nancy; Zaza, Stephanie","year":2016,"journal":"Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002), 65(6), 1-174","doi":"10.15585/mmwr.ss6506a1","pmid":"27280474","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"The Youth Risk Behavior Surveillance System is the CDC's primary tool for monitoring health risk behaviors among US high school students. The 2015 survey covered 118 health behaviors across students in grades 9-12 nationwide and in 37 states and 19 large urban school districts.\n\nMarijuana use stood out as stubbornly persistent. While many other risk behaviors had decreased since tracking began (including cigarette use, alcohol use, and sexual activity), the prevalence of \"ever having used marijuana\" had not significantly changed over time.\n\nIn the 30 days before the survey, 21.7% of students had used marijuana, compared to 32.8% who had drunk alcohol and 10.8% who had smoked cigarettes. The gap between marijuana and cigarette use continued to narrow, reflecting declining cigarette use rather than increasing marijuana use.","whyItMatters":"This is the gold-standard dataset for understanding adolescent risk behaviors in the United States. The persistence of marijuana use rates while other substance use declines raises questions about whether prevention approaches for cannabis need to differ from those that have successfully reduced cigarette and alcohol use among teens.","specificNumbers":"21.7% used marijuana in past 30 days. 32.8% drank alcohol. 10.8% smoked cigarettes. 41.2% had ever had sexual intercourse. Marijuana use prevalence had not significantly changed over the tracking period. Most other risk behaviors had decreased.","methodology":"National school-based survey conducted by the CDC using a three-stage cluster sample design to produce nationally representative estimates. The 2015 survey included results from 37 state surveys and 19 large urban school district surveys. Standard statistical methods were used to assess trends over time.","limitations":"School-based surveys miss students who are absent, dropped out, or homeschooled. Self-reported data in school settings may be affected by social desirability. The survey captures prevalence but not frequency, quantity, or potency of use."},{"rthcId":"RTHC-01192","title":"Endocannabinoid System: A Multi-Facet Therapeutic Target.","authors":"Kaur, Rimplejeet; Ambwani, Sneha R; Singh, Surjit","year":2016,"journal":"Current clinical pharmacology, 11(2), 110-7","doi":null,"pmid":"27086601","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review provides a panoramic view of the endocannabinoid system as a therapeutic target, covering its role across a remarkable range of conditions: nausea, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disease, cancer, obesity, metabolic syndrome, Parkinson's, Huntington's, Alzheimer's, and Tourette's syndrome.\n\nApproved drugs at the time included nabilone and dronabinol (for chemotherapy-induced nausea) and Sativex (for MS spasticity). Epidiolex was under investigation for childhood seizures.\n\nThe review also addressed major setbacks: rimonabant's psychiatric side effects leading to its withdrawal, and the serious adverse events in a clinical trial of a FAAH inhibitor that raised safety concerns for the entire class.\n\nThe authors identified key challenges: developing tissue-selective cannabinoid drugs, creating peripherally restricted compounds that avoid brain effects, and designing appropriate dosage forms.","whyItMatters":"This review provides a snapshot of the cannabinoid therapeutics landscape at a pivotal moment, when both promise and peril were evident. Understanding both the successes and failures helps contextualize the ongoing effort to develop safe, effective cannabinoid medicines.","specificNumbers":"Approved drugs: nabilone, dronabinol (nausea), Sativex (MS spasticity). Under investigation: Epidiolex (seizures). Failed: rimonabant (obesity, psychiatric side effects), FAAH inhibitor (serious adverse events in trial). Dozens of potential therapeutic applications identified.","methodology":"Comprehensive narrative review of the endocannabinoid system's therapeutic applications, covering approved drugs, drugs in development, and failed candidates across multiple disease areas.","limitations":"Narrative review without systematic methodology. The breadth of coverage necessarily limits depth in any one area. Rapidly evolving field means some information was already outdated at publication."},{"rthcId":"RTHC-01193","title":"Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset of schizophrenia and related psychotic disorders.","authors":"Kelley, Mary E; Wan, Claire Ramsay; Broussard, Beth; Crisafio, Anthony; Cristofaro, Sarah; Johnson, Stephanie; Reed, Thomas A; Amar, Patrick; Kaslow, Nadine J; Walker, Elaine F; Compton, Michael T","year":2016,"journal":"Schizophrenia research, 171(1-3), 62-7","doi":"10.1016/j.schres.2016.01.015","pmid":"26785806","tags":["psychosis","addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This study examined 247 people experiencing their first episode of psychosis to determine whether marijuana use in the preceding years was temporally linked to psychosis onset.\n\nEscalation of marijuana use in the 5 years before psychosis onset was highly predictive. Going from no use to daily use during this period increased the hazard of psychosis onset by 3.6 times. Daily use at any point approximately doubled the rate of onset (HR = 2.2), even after controlling for alcohol and tobacco use.\n\nCumulative marijuana exposure was independently associated with an increased rate of psychosis onset, regardless of gender or family history. Importantly, the strength of the association was similar before and after the onset of prodromal symptoms, suggesting that escalating use is not simply a response to early psychotic experiences.\n\nThe study also found that early adult use (not just adolescent use) was associated with faster onset, challenging the focus exclusively on teen use.","whyItMatters":"This study provides some of the clearest temporal evidence linking marijuana escalation to psychosis onset. By demonstrating that the association exists both before and after prodromal symptom onset, and is independent of other substance use, it strengthens the case for a contributory role of marijuana in psychosis.","specificNumbers":"Escalation from no use to daily use: HR = 3.6 (p<0.0005). Daily use: HR = 2.2 (p<0.0005). Cumulative exposure associated with onset (p = 0.007). Independent of gender, family history, and concurrent alcohol/tobacco use. 247 first-episode patients from 6 psychiatric units.","methodology":"Enrolled 247 first-episode psychosis patients from six psychiatric units. Collected detailed lifetime marijuana, alcohol, and tobacco use histories and ages at onset of prodrome and psychosis in 210 patients. Cox regression (survival analysis) quantified hazard ratios for premorbid use variables.","limitations":"Retrospective recall of substance use history may be inaccurate, especially during prodromal periods when cognitive function is declining. No control group of cannabis users who did not develop psychosis. Cannot definitively establish causation. Cannabis potency was not measured."},{"rthcId":"RTHC-01194","title":"Correlates of Amount Spent on Marijuana Buds During a Discrete Purchase at Medical Marijuana Dispensaries: Results from a Pilot Study.","authors":"Kepple, Nancy Jo; Mulholland, Elycia; Freisthler, Bridget; Schaper, Elizabeth","year":2016,"journal":"Journal of psychoactive drugs, 48(1), 50-5","doi":"10.1080/02791072.2015.1116719","pmid":"26757234","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This pilot study surveyed 132 medical marijuana patients as they exited four dispensaries in Long Beach, California. The average amount spent on marijuana buds in a single transaction was $40.82, ranging from $10 to $255.\n\nAge and medical condition predicted spending differences. For every 10-year increase in age, patients spent approximately 10% more per visit. Patients with recommendations for anxiety, sleeping problems, or other nonspecified conditions spent significantly more per transaction than those treating chronic pain.\n\nThese purchasing patterns may reflect differences in product preferences, consumption rates, or the relative difficulty of managing different conditions with cannabis.","whyItMatters":"Understanding purchasing behavior helps characterize how patients actually use dispensaries and allocate personal resources to cannabis treatment. This data is relevant for policy makers, researchers studying patient-level economics, and dispensary operators.","specificNumbers":"Average spending: $40.82 per visit. Range: $10-$255. 132 patients across 4 dispensaries. 10-year age increase associated with 10% higher spending. Anxiety/sleep patients spent more than chronic pain patients.","methodology":"Exit survey of 132 medical marijuana patients (33 per dispensary) at four purposively sampled dispensary locations in Long Beach, California, in 2012. Multivariate regression analyzed spending in relation to demographics, medical conditions, and location.","limitations":"Very small pilot sample from one city. Exit surveys capture only one purchase and may not reflect typical behavior. Only marijuana buds were measured, excluding concentrates, edibles, and other products. 2012 data predates significant market evolution."},{"rthcId":"RTHC-01195","title":"Are Alcohol Anti-relapsing and Alcohol Withdrawal Drugs Useful in Cannabinoid Users?","authors":"Kleczkowska, Patrycja; Smaga, Irena; Filip, Małgorzata; Bujalska-Zadrozny, Magdalena","year":2016,"journal":"Neurotoxicity research, 30(4), 698-714","doi":null,"pmid":"27484692","tags":["withdrawal","drug-interactions","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis is frequently used alongside alcohol, and many people who use cannabis also take medications for alcohol use disorder (AUD) or alcohol withdrawal. This review examined the interactions between cannabinoids and three common alcohol treatment medications.\n\nDisulfiram, acamprosate, and naltrexone each interact with the endocannabinoid system in different ways. Some preclinical evidence suggests these medications may have effects relevant to cannabis use as well, either through direct pharmacological interactions or through shared neural pathways.\n\nThe review also highlighted the complexity of co-occurring cannabis and alcohol use, where medications intended for one substance may inadvertently affect the other. Understanding these interactions is important for clinicians managing patients with both conditions.","whyItMatters":"With no approved medications for cannabis use disorder, repurposing existing alcohol treatment drugs could provide a shortcut to treatment options. Understanding how these drugs interact with the endocannabinoid system is a necessary first step.","specificNumbers":"Three alcohol treatment medications reviewed: disulfiram, acamprosate, naltrexone. Each has distinct interactions with the endocannabinoid system.","methodology":"Narrative review summarizing preclinical and clinical evidence on interactions between cannabinoids and medications used for alcohol use disorder and alcohol withdrawal syndrome.","limitations":"Limited clinical evidence for cannabinoid-specific effects of alcohol medications. Most evidence is preclinical. The review covers a broad topic area with limited depth in specific interactions."},{"rthcId":"RTHC-01196","title":"The Impact of Enrolment in Methadone Maintenance Therapy on Initiation of Heavy Drinking among People Who Use Heroin.","authors":"Klimas, Jan; Wood, Evan; Nguyen, Paul; Dong, Huiru; Milloy, Michael John; Kerr, Thomas; Hayashi, Kanna","year":2016,"journal":"European addiction research, 22(4), 210-4","doi":"10.1159/000444513","pmid":"27045681","tags":["addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"There has been concern that people entering methadone maintenance therapy (MMT) for heroin addiction might substitute alcohol for heroin. This study followed 357 heroin users in Vancouver for up to 9 years to test this hypothesis.\n\nMethadone treatment did not predict heavy drinking initiation. In fact, those enrolled in MMT at some point had lower heavy drinking rates than those who never enrolled (4.6 vs. 16.2 per 100 person-years).\n\nThe surprise finding was about cannabis. Cannabis use was independently associated with a 2.06-fold increased risk of initiating heavy drinking, making it the strongest substance-use predictor in the model. Younger age was the only other significant predictor.","whyItMatters":"This study provides two important findings: methadone treatment does not drive heroin users toward heavy drinking (a concern that could discourage treatment), and cannabis use is a surprisingly strong predictor of heavy drinking in this population. The cannabis finding suggests potential cross-substance vulnerability.","specificNumbers":"357 heroin users followed. 208 (58%) enrolled in MMT during follow-up. 115 (32%) initiated heavy drinking. Incidence: 7.8 per 100 person-years overall. MMT enrolled: 4.6 vs. not enrolled: 16.2 per 100 person-years. Cannabis use: adjusted HR = 2.06 (95% CI 1.32-3.19). Younger age: adjusted HR = 0.74 per 10 years.","methodology":"Prospective community-based cohort study of people who inject drugs in Vancouver, Canada, from December 2005 to May 2014. Extended Cox regression analysis examined the effect of methadone enrollment on heavy drinking onset, controlling for demographic and substance-use characteristics.","limitations":"Observational study cannot establish causation. Cannabis use might be a marker for broader substance use vulnerability rather than a direct cause of heavy drinking. Self-reported substance use data. Vancouver's unique drug policy context may limit generalizability."},{"rthcId":"RTHC-01197","title":"Medical cannabis - the Canadian perspective.","authors":"Ko, Gordon D; Bober, Sara L; Mindra, Sean; Moreau, Jason M","year":2016,"journal":"Journal of pain research, 9, 735-744","doi":null,"pmid":"27757048","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review addressed the rapidly evolving Canadian medical cannabis landscape from both clinical and practical perspectives. Several randomized controlled trials demonstrated a significant, dose-dependent relationship between THC and neuropathic pain relief.\n\nHowever, significant barriers existed on both sides. From the patient perspective: cost (not covered by insurance), addiction concerns, social stigma, and lack of understanding about safe administration. From the physician perspective: questions about credibility, concern about criminality, gaps in clinical evidence, worry about patient addiction, and restrictive policies from medical governing bodies.\n\nThe review included case studies demonstrating medical marijuana use for neuropathic low-back pain, fibromyalgia, and multiple sclerosis. While preclinical data supported potential benefits for osteoarthritis, rheumatoid arthritis, fibromyalgia, and cancer pain, larger clinical trials were needed.","whyItMatters":"Canada was among the first countries to establish a comprehensive medical cannabis framework. The barriers identified in this review are universal challenges that any jurisdiction must address when implementing medical cannabis programs.","specificNumbers":"Multiple RCTs showed dose-dependent neuropathic pain relief with THC. Key barriers identified on both patient and physician sides. Case studies covered neuropathic low-back pain, fibromyalgia, and MS pain. Preclinical support for OA, RA, fibromyalgia, and cancer pain applications.","methodology":"Narrative review of clinical evidence and practical considerations for medical cannabis in the Canadian healthcare system, including case studies of patients with neuropathic pain conditions.","limitations":"Narrative review without systematic methodology. Case studies provide anecdotal rather than statistical evidence. Canadian-specific regulatory context may limit generalizability. Published before significant changes in Canadian cannabis law (2018 legalization)."},{"rthcId":"RTHC-01198","title":"Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease.","authors":"Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki","year":2016,"journal":"Neural plasticity, 2016, 8373020","doi":"10.1155/2016/8373020","pmid":"26881135","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The connection between cannabis and eye health goes back to the early 1970s when smoking cannabis was found to lower intraocular pressure (IOP). But this review argues that lowering IOP alone is not sufficient to prevent vision loss in diseases like glaucoma.\n\nGlaucoma and diabetic retinopathy are increasingly understood as neurodegenerative diseases characterized by ischemia-induced excitotoxicity and loss of retinal neurons. The review presents evidence that cannabinoids, both endogenous and synthetic, have neuroprotective properties that could directly protect retinal cells from death.\n\nThis neuroprotective potential goes beyond IOP reduction and suggests cannabinoids could address the underlying neurodegeneration that drives vision loss, potentially representing a new therapeutic strategy for retinal diseases.","whyItMatters":"Glaucoma is the second leading cause of blindness worldwide. If cannabinoids can protect retinal neurons beyond simply lowering eye pressure, they could complement existing treatments and potentially prevent vision loss that current therapies cannot address.","specificNumbers":"Cannabis has been known to lower IOP since the 1970s. Glaucoma is the second leading cause of blindness globally. Both CB1 and CB2 receptors are present in retinal tissue.","methodology":"Narrative review of preclinical evidence on the neuroprotective and therapeutic potential of endogenous and synthetic cannabinoids in retinal disease, including glaucoma and diabetic retinopathy.","limitations":"Most neuroprotection evidence is preclinical. The review does not quantify the degree of neuroprotection or compare it to existing treatments. Systemic cannabinoid delivery for eye disease raises questions about side effects versus local benefit."},{"rthcId":"RTHC-01199","title":"Adult attention deficit hyperactivity disorder symptom profiles and concurrent problems with alcohol and cannabis: sex differences in a representative, population survey.","authors":"Kolla, Nathan J; van der Maas, Mark; Toplak, Maggie E; Erickson, Patricia G; Mann, Robert E; Seeley, Jane; Vingilis, Evelyn","year":2016,"journal":"BMC psychiatry, 16, 50","doi":"10.1186/s12888-016-0746-4","pmid":"26920911","tags":["mental-health","addiction","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"ADHD and substance misuse frequently co-occur, but this study asked whether specific ADHD symptom profiles (hyperactivity, inattention, impulsivity) predicted substance problems differently in men versus women.\n\nAfter controlling for age, education, and other psychiatric symptoms, the patterns were strikingly sex-specific:\n\nIn men: hyperactive symptoms were linked to problematic alcohol use, and both hyperactive and impulsive symptoms were linked to problematic cannabis use.\n\nIn women: inattentive symptoms were the predictor for both problematic alcohol and cannabis use, while hyperactivity and impulsivity were not significant.\n\nAcross all models, externalizing behavior (conduct problems, antisocial behavior) was the strongest overall predictor, and younger age was consistently associated with higher risk.","whyItMatters":"These sex-specific patterns suggest that ADHD-related substance use risk operates through different mechanisms in men and women. This has implications for screening and prevention: inattentive women with ADHD may be at risk for substance problems that clinicians might miss if they focus only on the hyperactive/impulsive presentations more common in men.","specificNumbers":"5,080 respondents. Hyperactivity predicted problematic alcohol use in both sexes and cannabis in men. Impulsivity predicted cannabis problems in men only. Inattention predicted both alcohol and cannabis problems in women only. Externalizing behavior was the strongest predictor across all models.","methodology":"Cross-sectional telephone survey of 5,080 adults aged 18+ in Ontario, Canada, from 2011-2013. ADHD symptoms were measured using the Adult ADHD Self-Report Screener (ASRS-V1.1) plus additional items. Substance problems were assessed with AUDIT (alcohol) and ASSIST (cannabis). Logistic regression stratified by sex.","limitations":"Cross-sectional design cannot determine temporal ordering. Self-reported ADHD symptoms rather than clinical diagnosis. Telephone survey may have response bias. Canadian-specific sample may not generalize globally."},{"rthcId":"RTHC-01200","title":"Effective treatment of spasticity using dronabinol in pediatric palliative care.","authors":"Kuhlen, Michaela; Hoell, Jessica I; Gagnon, Gabriele; Balzer, Stefan; Oommen, Prasad T; Borkhardt, Arndt; Janßen, Gisela","year":2016,"journal":"European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 20(6), 898-903","doi":"10.1016/j.ejpn.2016.07.021","pmid":"27506815","tags":["medical-cannabis","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Sixteen children, adolescents, and young adults (ages 1.3-26.6 years) with complex neurological conditions received dronabinol for severe spasticity that had not responded to other treatments. This was provided by a specialized pediatric palliative care team in a home-care setting.\n\nThe results were promising: 12 of 16 patients (75%) experienced abolished or markedly improved spasticity. Two patients showed uncertain effects, and two did not benefit.\n\nTreatment was sustained for extended periods, with a median duration of 181 days (range 23-1,429 days). Effective doses varied widely from 0.08 to 1.0 mg/kg/day, with a median of 0.33 mg/kg/day.\n\nWhen administered using a gradual dose escalation approach, side effects were rare and mild, consisting of only vomiting and restlessness (one patient each). No serious or lasting side effects occurred, even in very young children or over extended treatment periods.","whyItMatters":"Children with severe neurological conditions often develop treatment-resistant spasticity that significantly impairs quality of life. This study provides some of the first evidence that synthetic THC can be safely and effectively used in pediatric palliative care for this purpose, with some children as young as 15 months.","specificNumbers":"16 patients, ages 1.3-26.6 years. 12/16 (75%) showed abolished or marked improvement. Median treatment: 181 days (up to 1,429 days). Effective dose: 0.08-1.0 mg/kg/day (median 0.33). Side effects: 2 patients (vomiting and restlessness). No serious adverse events.","methodology":"Open, uncontrolled, retrospective study of 16 patients treated with dronabinol (2.5% THC oil solution) between December 2010 and April 2015 by a pediatric palliative care team. Therapeutic efficacy and side effects were closely monitored.","limitations":"Open, uncontrolled, retrospective design with no comparison group. Small sample size. Heterogeneous patient population and neurological conditions. Placebo effects cannot be excluded. No standardized spasticity scales were described."},{"rthcId":"RTHC-01201","title":"Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s).","authors":"Kulkarni, Pushkar M; Kulkarni, Abhijit R; Korde, Anisha; Tichkule, Ritesh B; Laprairie, Robert B; Denovan-Wright, Eileen M; Zhou, Han; Janero, David R; Zvonok, Nikolai; Makriyannis, Alexandros; Cascio, Maria G; Pertwee, Roger G; Thakur, Ganesh A","year":2016,"journal":"Journal of medicinal chemistry, 59(1), 44-60","doi":"10.1021/acs.jmedchem.5b01303","pmid":"26529344","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CB1 receptor has a primary (orthosteric) binding site where THC and most cannabinoid drugs bind, and a secondary (allosteric) site where modulators can fine-tune receptor activity. But the exact location and structure of this allosteric site has been unknown.\n\nThis study created the first chemical tools to map this site. Researchers designed covalent probes, compounds that permanently attach to specific amino acids, based on two known allosteric modulators (Org27569 and PSNCBAM-1).\n\nThe lead compound, GAT100, emerged as a highly potent negative allosteric modulator that, unlike its parent compounds, did not exhibit inverse agonism (reducing baseline receptor activity). It also enhanced binding of orthosteric agonists. These properties make GAT100 a valuable research tool for understanding allosteric modulation and a potential starting point for drug development.","whyItMatters":"Mapping the CB1 allosteric site is essential for designing next-generation cannabinoid drugs that could modulate the receptor with more precision and fewer side effects than current drugs. GAT100 is the key that could unlock this understanding.","specificNumbers":"GAT100 identified as lead compound from a focused library. Most potent negative allosteric modulator in GTPgammaS and beta-arrestin assays. Reduced inverse agonism compared to Org27569. Positive allosteric modulation of CP55,940 binding.","methodology":"Medicinal chemistry study involving rational design, synthesis, and pharmacological characterization of covalent CB1 allosteric ligands. Compounds were tested in radioligand binding, GTPgammaS functional assays, and beta-arrestin recruitment assays.","limitations":"In vitro study with no in vivo validation. Covalent probes permanently modify the receptor, which limits their therapeutic potential but makes them valuable research tools. The allosteric site structure remains to be fully characterized."},{"rthcId":"RTHC-01202","title":"Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction.","authors":"Kutlu, Munir Gunes; Gould, Thomas J","year":2016,"journal":"Learning & memory (Cold Spring Harbor, N.Y.), 23(10), 515-33","doi":"10.1101/lm.042192.116","pmid":"27634143","tags":["cognition","neuroscience","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how drugs of abuse, including cannabis, interact with the hippocampus, a brain region critical for learning and memory, to contribute to addiction.\n\nThe relationship between cannabis and hippocampal function follows a two-phase pattern. During initial use, cannabis may enhance certain aspects of hippocampal function, potentially strengthening the formation of drug-context associations. These associations are the memories that connect the rewarding experience of drug use with the places, people, and situations where it occurred.\n\nDuring withdrawal, the pattern reverses. Cannabis withdrawal leads to hippocampus-dependent learning and memory deficits. According to the self-medication hypothesis, the discomfort of these cognitive deficits may drive relapse as users attempt to restore normal cognitive function by resuming use.\n\nThis dual pattern creates a cycle: enhanced learning during use builds stronger drug-context memories, while impaired learning during withdrawal provides motivation to return to use.","whyItMatters":"Understanding how the hippocampus contributes to addiction provides targets for intervention. If drug-context associations drive use and cognitive deficits drive relapse, treatments that weaken these associations or support cognition during withdrawal could help people quit.","specificNumbers":"Six drug classes reviewed: cocaine, amphetamine, nicotine, alcohol, opiates, and cannabis. Cannabis withdrawal uniquely impairs hippocampal learning. Initial exposure may enhance hippocampal function for drug-context association formation.","methodology":"Comprehensive narrative review of preclinical and clinical evidence on the effects of cocaine, amphetamine, nicotine, alcohol, opiates, and cannabis on hippocampal plasticity and hippocampus-dependent learning and memory.","limitations":"Much of the evidence comes from animal models. The review covers a broad topic area with necessarily limited depth for each substance. Human hippocampal function during cannabis withdrawal is less well characterized than animal models suggest."},{"rthcId":"RTHC-01203","title":"\"Those edibles hit hard\": Exploration of Twitter data on cannabis edibles in the U.S.","authors":"Lamy, Francois R; Daniulaityte, Raminta; Sheth, Amit; Nahhas, Ramzi W; Martins, Silvia S; Boyer, Edward W; Carlson, Robert G","year":2016,"journal":"Drug and alcohol dependence, 164, 64-70","doi":"10.1016/j.drugalcdep.2016.04.029","pmid":"27185160","tags":["legalization","potency"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers collected over 100,000 tweets mentioning cannabis edibles between May and July 2015. About 27% contained geographic data allowing state-level analysis.\n\nStates that allowed recreational and/or medical cannabis had significantly higher rates of edibles-related tweeting compared to states where cannabis remained fully illegal. This suggests that legal access drives both use and public conversation.\n\nOverall, cannabis edibles were positively perceived among Twitter users. However, the negative tweets were particularly informative: they described the unreliability of edible effects, variability in intensity, and difficulty predicting duration. These concerns align with the clinical reports of edible-related emergency department visits that emerged after legalization.\n\nThe authors propose Twitter analysis as an epidemiological monitoring tool for emerging drug use patterns and trends.","whyItMatters":"As edibles become more popular, understanding public attitudes and experiences is important for harm reduction. The positive framing of edibles on social media may encourage naive users, while the negative experiences described (unpredictable effects, excessive intensity) align with known clinical risks.","specificNumbers":"100,182 tweets collected. 26,975 (26.9%) had state-level geolocation. Significantly more edibles discussion in legal states. Generally positive sentiment overall. Negative tweets focused on unpredictable effects and intensity.","methodology":"Twitter data collected via API between May 1 and July 31, 2015, filtered through the eDrugTrends/Twitris platform. A random sample of geolocated tweets was manually coded for sentiment. State-level proportions were adjusted for total Twitter users per state. Permutation testing assessed differences by cannabis legislation status.","limitations":"Twitter users are not representative of the general population (younger, more urban, more tech-savvy). Tweets are brief and may not accurately represent complex experiences. Manual coding of a random sample may miss important patterns. Cannot verify actual edible use from tweets."},{"rthcId":"RTHC-01204","title":"Mapping Cannabinoid 1 Receptor Allosteric Site(s): Critical Molecular Determinant and Signaling Profile of GAT100, a Novel, Potent, and Irreversibly Binding Probe.","authors":"Laprairie, Robert B; Kulkarni, Abhijit R; Kulkarni, Pushkar M; Hurst, Dow P; Lynch, Diane; Reggio, Patricia H; Janero, David R; Pertwee, Roger G; Stevenson, Lesley A; Kelly, Melanie E M; Denovan-Wright, Eileen M; Thakur, Ganesh A","year":2016,"journal":"ACS chemical neuroscience, 7(6), 776-98","doi":"10.1021/acschemneuro.6b00041","pmid":"27046127","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Building on the initial discovery of GAT100 (RTHC-01201), this study comprehensively characterized its effects across an array of downstream signaling pathways.\n\nGAT100 functioned as a negative allosteric modulator of the orthosteric agonist CP55,940 and the endocannabinoids 2-AG and anandamide across multiple readouts: beta-arrestin1 recruitment, PLCbeta3 and ERK1/2 phosphorylation, cAMP accumulation, and CB1 receptor internalization.\n\nCritically, GAT100 was more potent and effective than both Org27569 and PSNCBAM-1 (the two most-studied CB1 allosteric modulators) in every assay tested. It also lacked the inverse agonism associated with those earlier compounds, a significant advantage for drug development.\n\nComputational docking studies identified C7.38(382) as a key structural feature of GAT100's binding to the allosteric site, providing critical information for designing next-generation allosteric drugs.","whyItMatters":"This comprehensive profiling establishes GAT100 as the gold-standard tool for studying CB1 allosteric modulation and provides the detailed signaling data needed to guide drug design. The identification of the key binding residue is a breakthrough for rational drug development.","specificNumbers":"GAT100 tested across 5+ signaling pathways. More potent and efficacious than Org27569 and PSNCBAM-1 in all assays. No inverse agonism. C7.38(382) identified as critical binding residue. Active in both overexpression and endogenous CB1 expression systems.","methodology":"Multi-assay functional profiling in HEK293A cells overexpressing CB1R and in Neuro2a and STHdhQ7/Q7 cells endogenously expressing CB1R. Assessed beta-arrestin1 recruitment, PLCbeta3 phosphorylation, ERK1/2 phosphorylation, cAMP accumulation, and receptor internalization. Computational docking studies identified key binding residues.","limitations":"All data are from cell-based systems. In vivo validation is needed. The covalent nature of GAT100 limits its therapeutic potential but enhances its value as a research tool. Endogenous expression systems used different cell types that may not fully reflect neuronal CB1 biology."},{"rthcId":"RTHC-01205","title":"Acute and chronic effects of cannabinoids on effort-related decision-making and reward learning: an evaluation of the cannabis 'amotivational' hypotheses.","authors":"Lawn, Will; Freeman, Tom P; Pope, Rebecca A; Joye, Alyssa; Harvey, Lisa; Hindocha, Chandni; Mokrysz, Claire; Moss, Abigail; Wall, Matthew B; Bloomfield, Michael Ap; Das, Ravi K; Morgan, Celia Ja; Nutt, David J; Curran, H Valerie","year":2016,"journal":"Psychopharmacology, 233(19-20), 3537-52","doi":"10.1007/s00213-016-4383-x","pmid":"27585792","tags":["cognition","addiction","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The \"amotivational syndrome\" associated with cannabis is one of the most debated topics in cannabis research. This study used two complementary designs to test it rigorously.\n\nStudy 1 gave 17 participants vaporized cannabis with THC only, THC plus CBD, or placebo on separate occasions. THC without CBD reduced the likelihood of choosing high-effort tasks for rewards, providing the first well-controlled evidence that THC acutely causes amotivation. Adding CBD influenced how THC affected sensitivity to expected reward value.\n\nStudy 2 compared 20 cannabis-dependent individuals with 20 non-dependent controls on the same effort task plus a reward learning task, all while sober. Cannabis-dependent individuals showed normal motivation on the effort task, challenging the chronic amotivation stereotype. However, they showed impaired reward learning, meaning they were less able to learn from positive feedback.\n\nThe takeaway: THC causes temporary amotivation that resolves when the drug wears off, while long-term cannabis dependence affects how people learn from rewards rather than reducing motivation itself.","whyItMatters":"This is the first well-powered, fully controlled study to objectively demonstrate the acute amotivational effects of THC. At the same time, it challenges the notion that chronic cannabis use permanently reduces motivation, showing instead that the issue is in reward learning rather than effort willingness.","specificNumbers":"Study 1: 17 participants, 8 mg THC reduced high-effort choices (p = 0.042). CBD influenced expected value sensitivity (p = 0.006). Study 2: 20 dependent vs. 20 controls. No difference in effort motivation. Dependent group showed weaker response bias on reward learning task (p = 0.007).","methodology":"Study 1: Randomized, double-blind, within-subject design. 17 participants received three vaporized treatments (8 mg THC, 8 mg THC + 10 mg CBD, placebo) on separate occasions. Study 2: Between-subjects comparison of 20 cannabis-dependent vs. 20 drug-using controls on effort and reward learning tasks while sober.","limitations":"Study 1 had a small sample. Study 2 could not control for depression and other confounders that might affect reward learning. Cannabis-dependent participants may have had residual THC affecting performance. The control group used other drugs."},{"rthcId":"RTHC-01206","title":"Broad impact of deleting endogenous cannabinoid hydrolyzing enzymes and the CB1 cannabinoid receptor on the endogenous cannabinoid-related lipidome in eight regions of the mouse brain.","authors":"Leishman, Emma; Cornett, Ben; Spork, Karl; Straiker, Alex; Mackie, Ken; Bradshaw, Heather B","year":2016,"journal":"Pharmacological research, 110, 159-172","doi":"10.1016/j.phrs.2016.04.020","pmid":"27109320","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system is often thought of in terms of two molecules (anandamide and 2-AG) and two receptors (CB1 and CB2). This study revealed it is far more interconnected with broader lipid signaling networks than previously appreciated.\n\nUsing mice with deleted FAAH, MAGL, or CB1 receptors, researchers measured over 70 lipids across eight brain regions. The findings were striking:\n\nDeleting MAGL (which breaks down 2-AG) massively increased 2-AG levels while significantly reducing arachidonic acid and the inflammatory prostaglandin PGE2 throughout the brain. Deleting FAAH (which breaks down anandamide) increased anandamide but did not affect arachidonic acid or PGE2, suggesting FAAH-derived arachidonic acid does not contribute to steady-state inflammatory lipid levels.\n\nDeleting CB1 receptors left anandamide and 2-AG unchanged but increased PGE2 in most brain areas, suggesting the receptor itself normally limits inflammatory signaling.","whyItMatters":"This study fundamentally expands our understanding of what the endocannabinoid system does. Rather than being an isolated signaling system, it is deeply embedded in broader lipid networks that control inflammation, neurotransmission, and cell function. This has major implications for predicting the effects of drugs that target endocannabinoid enzymes.","specificNumbers":"Over 70 lipids measured per sample. 8 brain regions analyzed. MAGL deletion: 2-AG up, AA and PGE2 down throughout brain. FAAH deletion: AEA up, no change in AA or PGE2. CB1 deletion: AEA and 2-AG unchanged, PGE2 up in most regions.","methodology":"Targeted lipidomics in FAAH knockout, MAGL knockout, and CB1 knockout mice compared to wild-type controls. Over 70 lipids measured per sample using HPLC/MS/MS across eight brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, midbrain, striatum, thalamus).","limitations":"Knockout models represent complete gene deletion, which is more extreme than pharmacological inhibition. Steady-state lipid levels may not reflect dynamic changes during actual signaling. Mouse brain lipid metabolism may differ from humans. Regional variation was observed but not always explained."},{"rthcId":"RTHC-01207","title":"Practical Aspects of Discussing Marijuana in a New Era.","authors":"Lenoue, Sean R; Wongngamnit, Narin; Thurstone, Christian","year":2016,"journal":"Journal of psychiatric practice, 22(6), 471-477","doi":null,"pmid":"27824781","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"As medical and recreational marijuana laws evolve, clinicians face a challenging communication environment. Patients may overestimate marijuana's benefits based on media coverage, while providers may lack current knowledge about evidence-based indications and risks.\n\nThe article offers practical guidance for clinicians: maintaining motivational interviewing skills (rather than lecturing or confronting patients about use), providing evidence-based informed consent that honestly addresses both potential benefits and known risks, and recognizing that the provider-patient relationship is the foundation for productive conversations about marijuana.\n\nThe authors emphasize that misconceptions exist on both sides. Some patients believe marijuana is harmless and helps everything, while some providers dismiss all potential medical applications. Neither position reflects the evidence.","whyItMatters":"The gap between patient expectations and clinical evidence creates a communication challenge that directly affects care quality. Clinicians who can discuss marijuana openly and knowledgeably build trust and improve outcomes, while those who avoid the topic or dismiss it lose opportunities to guide patients toward safer practices.","specificNumbers":"No specific quantitative data. The article addresses the qualitative challenge of clinical communication about a rapidly evolving topic.","methodology":"Clinical guidance article reviewing communication strategies, evidence-based approaches, and practical considerations for provider-patient conversations about marijuana.","limitations":"Guidance article without systematic evidence review. Recommendations are based on clinical experience and available evidence rather than tested interventions. The rapidly changing policy landscape may make some guidance outdated quickly."},{"rthcId":"RTHC-01208","title":"Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial.","authors":"Levin, Frances R; Mariani, John J; Pavlicova, Martina; Brooks, Daniel; Glass, Andrew; Mahony, Amy; Nunes, Edward V; Bisaga, Adam; Dakwar, Elias; Carpenter, Kenneth M; Sullivan, Maria A; Choi, Jean C","year":2016,"journal":"Drug and alcohol dependence, 159, 53-60","doi":"10.1016/j.drugalcdep.2015.11.025","pmid":"26711160","tags":["addiction","withdrawal"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"With no approved medications for cannabis use disorder, researchers tested a combination approach: dronabinol (synthetic THC, to ease withdrawal by providing cannabinoid receptor stimulation) plus lofexidine (an alpha-2 agonist, to reduce noradrenergic symptoms of withdrawal).\n\nOne hundred fifty-six cannabis-dependent adults were enrolled, with 122 randomized after a placebo lead-in week. Participants received either dronabinol 20 mg three times daily plus lofexidine 0.6 mg three times daily, or matching placebos, for 8 weeks with a 2-week taper and 1-week monitoring.\n\nThe result was clearly negative. The proportion achieving 3 weeks of abstinence during the maintenance phase was virtually identical: 27.9% for the medication group versus 29.5% for placebo. Both groups showed reduction in cannabis use over time, suggesting the behavioral therapy component (weekly motivational enhancement and relapse prevention) was driving improvement, not the medications.","whyItMatters":"This well-designed negative result is important because it eliminates a promising pharmacotherapy approach and redirects research efforts. The fact that both groups improved equally underscores the value of behavioral interventions for cannabis use disorder even in the absence of effective medication.","specificNumbers":"156 enrolled, 122 randomized. 3-week abstinence: 27.9% medication vs. 29.5% placebo. Dronabinol 20 mg TID + lofexidine 0.6 mg TID for 8 weeks. Both groups showed reduction in use over time. Weekly behavioral therapy provided to all.","methodology":"Randomized, double-blind, placebo-controlled, 11-week trial. 156 enrolled, 122 randomized after 1-week placebo lead-in. Dronabinol 20 mg TID plus lofexidine 0.6 mg TID versus matched placebo. All participants received weekly motivational enhancement and relapse prevention therapy. Primary outcome: 3 weeks abstinence during maintenance phase.","limitations":"The dronabinol dose may not have been high enough to fully replace the cannabinoid stimulation from heavy cannabis use. Lofexidine targets only the noradrenergic component of withdrawal. The placebo lead-in may have selected for participants less likely to respond to medication."},{"rthcId":"RTHC-01209","title":"Central administrations of hemopressin and related peptides inhibit gastrointestinal motility in mice.","authors":"Li, X-H; Lin, M-L; Wang, Z-L; Wang, P; Tang, H-H; Lin, Y-Y; Li, N; Fang, Q; Wang, R","year":2016,"journal":"Neurogastroenterology and motility, 28(6), 891-9","doi":"10.1111/nmo.12789","pmid":"26991932","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Hemopressin was identified as an endogenous peptide that acts on CB1 cannabinoid receptors. This study tested whether hemopressin and two related peptides (VD-Hpalpha and VD-Hpbeta) affect gastrointestinal motility when delivered directly to the brain.\n\nAll three peptides slowed gut movement across multiple measures: upper GI transit, colonic bead expulsion, and whole gut transit. These effects were blocked by the CB1 antagonist AM251 but not by the CB2 antagonist AM630, confirming they work through CB1 receptors.\n\nThe key finding for drug development was that these peptides were less potent at slowing the gut than the classical cannabinoid agonist WIN55,212-2. This lower potency on GI function could be therapeutically advantageous: cannabinoid peptides might provide pain relief at doses that do not significantly slow the gut, avoiding a common side effect of cannabinoid drugs.","whyItMatters":"Cannabinoid-based pain relievers often cause constipation and slowed digestion. If endogenous cannabinoid peptides can provide pain relief at doses below those that significantly affect the gut, they could offer a better therapeutic window than classical cannabinoids.","specificNumbers":"All three peptides slowed GI transit via CB1 receptors. Lower potency than WIN55,212-2 on all GI measures. Hpalpha and VD-Hpbeta inhibited whole gut transit at high doses. VD-Hpalpha did not affect whole gut transit. AM251 (CB1 blocker) reversed effects. AM630 (CB2 blocker) did not.","methodology":"Mouse study using intracerebroventricular (i.c.v.) administration of hemopressin, VD-Hpalpha, VD-Hpbeta, and WIN55,212-2. GI motility measured via upper GI transit (charcoal meal), colonic bead expulsion, and whole gut transit (Evans blue dye). CB1 and CB2 receptor involvement tested with selective antagonists.","limitations":"Intracerebroventricular administration does not reflect practical drug delivery. Mouse GI physiology differs from humans. The lower potency could also mean lower analgesic efficacy, which was not tested in this study. Peptide stability and blood-brain barrier penetration pose challenges for drug development."},{"rthcId":"RTHC-01210","title":"Presentations due to acute toxicity of psychoactive substances in an urban emergency department in Switzerland: a case series.","authors":"Liakoni, Evangelia; Dolder, Patrick C; Rentsch, Katharina M; Liechti, Matthias E","year":2016,"journal":"BMC pharmacology & toxicology, 17(1), 25","doi":"10.1186/s40360-016-0068-7","pmid":"27228985","tags":["addiction","synthetic-cannabinoids"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Over one year at a Swiss university hospital, researchers systematically tracked every emergency department visit related to recreational drug toxicity. Of 50,624 total ER visits, 210 (0.4%) were directly drug-related.\n\nCannabis was the most commonly detected substance at 33%, followed by cocaine at 27% and opioids at 19%. The typical patient was male (73%) with a mean age of 33 years.\n\nThe most frequent symptoms across all drug presentations were tachycardia (28%), anxiety (23%), nausea/vomiting (18%), and agitation (17%). Severe complications included two deaths, two heart attacks, 13 seizure cases, and 6 psychosis cases. Most patients (76%) were discharged home, while 10% required intensive care.\n\nNotably, despite widespread concern about novel psychoactive substances (NPS), only 2 of 210 cases involved NPS, suggesting classic drugs remain far more clinically significant.","whyItMatters":"This study provides a reality check on drug-related emergency presentations. While NPS receive enormous media attention, cannabis and cocaine remain responsible for the vast majority of acute drug toxicity cases in clinical practice.","specificNumbers":"210 drug-related cases out of 50,624 ER visits (0.4%). Cannabis: 33% of analytically confirmed cases. Cocaine: 27%. Opioids: 19%. Mean age: 33 years. 73% male. 76% discharged home. 10% ICU admission. Only 2 NPS cases.","methodology":"Prospective case series of all emergency department presentations at the University Hospital of Basel, Switzerland, from October 2014 to September 2015 with acute toxicity from recreational drug use. Analytical confirmation using immunoassays and LC-MS/MS capable of detecting novel psychoactive substances.","limitations":"Single center in one Swiss city. Self-reported drug use may be inaccurate. Not all patients received analytical confirmation. Cannabis detection may overrepresent its role in toxicity due to its long detection window. Polysubstance use was common."},{"rthcId":"RTHC-01211","title":"Personnel training and patient education in medical marijuana dispensaries in Oregon.","authors":"Linares, Roberto; Choi-Nurvitadhi, Jo; Cooper, Svetlana; Ham, YoungYoon; Ishmael, Jane E; Zweber, Ann","year":2016,"journal":"Journal of the American Pharmacists Association : JAPhA, 56(3), 270-273.e2","doi":"10.1016/j.japh.2015.12.015","pmid":"27079137","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"As Oregon dispensaries multiplied, researchers surveyed their staff about training and patient education practices. Of 141 surveys sent, 47 were initiated.\n\nThe most common training sources were on-the-job experience and the internet, rather than formal medical or pharmacological education. When recommending specific strains to patients, staff relied primarily on patients' stated preferences and symptoms, combined with their own personal experiences with the products.\n\nMost staff did advise patients about precautions and expected effects. However, they were least likely to discuss drug interactions or recommend that patients consult a pharmacist or prescriber, the areas where formal medical knowledge is most critical for safety.","whyItMatters":"This study reveals a knowledge gap with patient safety implications. Dispensary staff are providing medical guidance based on personal experience and internet research rather than clinical training, and they are least comfortable in exactly the areas (drug interactions) where errors could be most dangerous.","specificNumbers":"47 of 141 surveys initiated. Most common training: on-the-job and internet. Staff used patient preferences, symptoms, and personal experience for recommendations. Majority advised on precautions and effects. Least likely to advise on drug interactions or refer to pharmacists.","methodology":"Statewide cross-sectional email survey of Oregon Medical Marijuana Dispensary personnel. 47 of 141 surveys initiated. Questions covered training sources, knowledge bases, and advising practices.","limitations":"Low response rate (47 of 141) may introduce response bias. Self-reported practices may not reflect actual behavior. Small sample from one state. The survey could not assess the accuracy or safety of specific recommendations."},{"rthcId":"RTHC-01212","title":"CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction.","authors":"Lipina, Christopher; Vaanholt, Lobke M; Davidova, Anastasija; Mitchell, Sharon E; Storey-Gordon, Emma; Hambly, Catherine; Irving, Andrew J; Speakman, John R; Hundal, Harinder S","year":2016,"journal":"Aging cell, 15(2), 325-35","doi":"10.1111/acel.12438","pmid":"26757949","tags":["neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Aging is associated with metabolic decline, and this study found that the endocannabinoid system may be a key driver. In aged mice (17 months), CB1 receptor mRNA was elevated in skeletal muscle and liver compared to young mice (4 months), coinciding with reduced insulin sensitivity.\n\nTwo weeks of rimonabant treatment produced dramatic metabolic improvements in aged mice: improved glucose tolerance, enhanced insulin sensitivity in skeletal muscle and liver, reduced fat tissue inflammation, and decreased lipogenic gene expression. Strikingly, the same treatment had no significant metabolic effects in young mice, suggesting the benefits are specific to the overactivated endocannabinoid state of aging.\n\nRimonabant transiently reduced food intake in both age groups, but the effect was more profound in aged animals, coinciding with significant fat mass loss.","whyItMatters":"Aging-related insulin resistance and metabolic dysfunction affect hundreds of millions of people. This study provides a mechanistic explanation (CB1 receptor overactivation with age) and demonstrates that targeting this mechanism specifically improves metabolic function in aging, potentially opening a new therapeutic avenue.","specificNumbers":"Aged mice: 17 months. Young mice: 4 months. 14 days of rimonabant treatment. CB1 mRNA elevated in aged muscle and liver. Improved glucose tolerance, insulin sensitivity in muscle/liver/adipose in aged mice only. Reduced adipose inflammation and lipogenic gene expression.","methodology":"Young (4-month) and aged (17-month) male C57BL/6 mice received daily rimonabant or vehicle for 14 days. Outcomes included food intake, body composition, glucose tolerance, insulin sensitivity (muscle, liver, adipose tissue), inflammatory markers, and gene expression.","limitations":"Mouse aging may not directly model human metabolic aging. Rimonabant was withdrawn from human use due to psychiatric effects. The 14-day treatment period is short. Only male mice were studied. The mechanism connecting CB1 upregulation to aging was not fully elucidated."},{"rthcId":"RTHC-01213","title":"The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults.","authors":"Lisdahl, Krista M; Tamm, Leanne; Epstein, Jeffery N; Jernigan, Terry; Molina, Brooke S G; Hinshaw, Stephen P; Swanson, James M; Newman, Erik; Kelly, Clare; Bjork, James M","year":2016,"journal":"Drug and alcohol dependence, 161, 135-46","doi":"10.1016/j.drugalcdep.2016.01.032","pmid":"26897585","tags":["youth","cognition","neuroscience","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared brain structure in young adults with and without childhood ADHD who did or did not use cannabis regularly. After controlling for age, gender, brain size, nicotine, and binge drinking, cannabis use was associated with decreased cortical thickness in several brain regions.\n\nSpecifically, cannabis users (regardless of ADHD status) had thinner cortex in the right superior frontal sulcus, anterior cingulate, isthmus of the cingulate gyrus, and left superior frontal and precentral regions. These areas are rich in cannabinoid receptors and involved in cognitive control.\n\nInterestingly, ADHD diagnosis alone did not predict brain structure, but persistent ADHD (symptoms continuing into adulthood) was associated with thinner cortex in regions controlling movement and inhibition. For cannabis users with ADHD specifically, earlier onset of regular cannabis use predicted a different pattern of cortical changes.","whyItMatters":"ADHD is a major risk factor for cannabis use, and many young people with ADHD use cannabis. This study shows that cannabis affects brain structure in regions important for the very cognitive functions (attention, inhibition) that are already compromised in ADHD, suggesting a potential compounding effect.","specificNumbers":"Four groups: ADHD+cannabis (n=37), ADHD-only (n=44), cannabis-only (n=18), controls (n=21). Cannabis users: decreased cortical thickness in 5 frontal/cingulate regions. Persistent ADHD: decreased left precentral/postcentral thickness. All effects controlled for nicotine and binge drinking.","methodology":"Cross-sectional MRI study comparing four groups: ADHD with cannabis use (n=37), ADHD without use (n=44), non-ADHD cannabis users (n=18), and non-ADHD non-users (n=21). Multiple regression and MANCOVA controlled for age, gender, total brain volume, nicotine, and binge drinking.","limitations":"Cross-sectional design cannot determine causality. Groups were unequal in size. Cannabis use was self-reported. Could not control for all potential confounders (e.g., socioeconomic status, other substance use). Earlier cannabis onset in ADHD may reflect ADHD severity rather than a cannabis-specific effect."},{"rthcId":"RTHC-01214","title":"International trends in spice use: Prevalence, motivation for use, relationship to other substances, and perception of use and safety for synthetic cannabinoids.","authors":"Loeffler, George; Delaney, Eileen; Hann, Michael","year":2016,"journal":"Brain research bulletin, 126(Pt 1), 8-28","doi":"10.1016/j.brainresbull.2016.04.013","pmid":"27108542","tags":["synthetic-cannabinoids","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review compiled data from nationally and regionally representative surveys worldwide to characterize synthetic cannabinoid (Spice) use patterns.\n\nLifetime prevalence in the general population ranged from 0.2% to 4%. Use peaked in the late teens and early twenties and declined with age. Users were predominantly male. Limited longitudinal data suggested use was declining from its peak.\n\nMost Spice users reported trying the substance only a small number of times, and sustained regular use was uncommon. The most frequently cited motivation was curiosity. Spice users almost universally reported extensive histories of using other substances, suggesting they are a subset of broader polysubstance users rather than a distinct population.\n\nInterestingly, people consistently overestimated how common Spice use was among their peers, with perceived use rates significantly exceeding actual use.","whyItMatters":"This review provides much-needed context to the synthetic cannabinoid concern. While individual cases can be severe, population-level data shows use is generally uncommon, experimental, and transient. The finding that people overestimate peer use suggests media coverage may be amplifying perceived prevalence beyond reality.","specificNumbers":"Lifetime prevalence: 0.2-4% in general population. Peak use: late teens/early twenties. Most users: male, tried only a few times. Primary motivation: curiosity. Users overestimate peer use. Most Spice users have extensive other substance use histories.","methodology":"Literature review of national and international organizations and peer-reviewed publications reporting synthetic cannabinoid use in non-clinical populations. Focused on nationally and regionally representative surveys to establish population-level prevalence.","limitations":"Survey data may undercount Spice use. Rapid evolution of synthetic cannabinoid products makes it difficult to track specific compounds. Some surveys grouped synthetic cannabinoids with other substances. Longitudinal data was limited."},{"rthcId":"RTHC-01215","title":"Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans.","authors":"Lofwall, Michelle R; Babalonis, Shanna; Nuzzo, Paul A; Elayi, Samy Claude; Walsh, Sharon L","year":2016,"journal":"Drug and alcohol dependence, 164, 143-150","doi":"10.1016/j.drugalcdep.2016.05.002","pmid":"27234658","tags":["pain","drug-interactions","withdrawal"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The cannabinoid system shares neural circuitry with the opioid system, making it a rational target for treating opioid dependence. This proof-of-concept study tested whether dronabinol (synthetic THC) could suppress opioid withdrawal.\n\nTwelve opioid-dependent adults maintained on oxycodone underwent controlled withdrawal sessions, receiving single test doses of dronabinol (5, 10, 20, or 30 mg), oxycodone (30 or 60 mg), or placebo.\n\nLower dronabinol doses (5-10 mg) had minimal effects. Higher doses (20-30 mg) showed modest withdrawal suppression signals, but these were accompanied by dose-related increases in feeling high, sedation, feeling of heart racing, and actual tachycardia. Participants did not like dronabinol more than placebo and identified it as marijuana. Some cognitive impairment occurred at higher doses.\n\nThe authors concluded that while CB1 activation is a reasonable withdrawal treatment strategy, dronabinol's narrow therapeutic window and cardiovascular effects make it a poor candidate.","whyItMatters":"The opioid epidemic demands new treatment approaches. While this study finds dronabinol itself is not the answer, it establishes proof-of-concept that CB1 receptor activation can reduce opioid withdrawal, pointing to the need for cannabinoid drugs with better therapeutic windows.","specificNumbers":"12 opioid-dependent adults. Dronabinol doses: 5, 10, 20, 30 mg (reduced from planned 40 mg). 5-10 mg: similar to placebo. 20-30 mg: modest withdrawal suppression with tachycardia, sedation, and feeling high. Oxycodone produced expected withdrawal suppression.","methodology":"5-week inpatient, double-blind, randomized, placebo-controlled study. 12 opioid-dependent adults maintained on oxycodone 30 mg QID. Oxycodone was withheld for 21 hours to produce measurable withdrawal. Single test doses were administered in 7 experimental sessions. Observer and participant ratings assessed withdrawal suppression, agonist effects, and cognition.","limitations":"Very small sample (12 participants). Single-dose design may underestimate effects of repeated dosing. Only oxycodone dependence was studied. The highest planned dose (40 mg) had to be reduced to 30 mg due to adverse effects. Short withdrawal challenge may not reflect sustained withdrawal."},{"rthcId":"RTHC-01216","title":"Adolescent Cannabis Use: What is the Evidence for Functional Brain Alteration?","authors":"Lorenzetti, Valentina; Alonso-Lana, Silvia; Youssef, George J; Verdejo-Garcia, Antonio; Suo, Chao; Cousijn, Janna; Takagi, Michael; Yücel, Murat; Solowij, Nadia","year":2016,"journal":"Current pharmaceutical design, 22(42), 6353-6365","doi":"10.2174/1381612822666160805155922","pmid":"27514709","tags":["youth","cognition","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Adolescence is a critical period for brain development, particularly in regions with high cannabinoid receptor density. This systematic review identified 13 functional neuroimaging studies of adolescent cannabis users (ages 13-18) performing cognitive tasks.\n\nA consistent pattern emerged: adolescent cannabis users showed altered brain function, particularly in the frontal-parietal network that mediates cognitive control, working memory, and inhibition. However, their actual task performance was typically intact.\n\nThis dissociation between altered brain activity and preserved behavioral performance suggests a compensatory mechanism: adolescent brains may recruit additional neural resources to maintain normal performance despite cannabis-related disruption. Heavier cannabis use was associated with more pronounced brain function abnormalities in most studies.\n\nImportantly, few studies controlled for confounders like tobacco, alcohol, psychiatric symptoms, or family history, limiting conclusions about whether cannabis itself drives these changes.","whyItMatters":"The finding that adolescent brains can compensate for cannabis effects to maintain normal performance is concerning rather than reassuring. Compensatory mechanisms may mask developing problems and could eventually fail with continued or increased use, potentially leading to sudden cognitive decline.","specificNumbers":"13 fMRI studies reviewed. Ages 13-18 years. Most consistent finding: altered frontal-parietal network activity. Behavioral performance generally intact. Heavier use linked to greater alterations. Few studies controlled for tobacco, alcohol, or psychiatric confounders.","methodology":"Systematic review of fMRI studies in adolescent cannabis users (ages 13-18) performing working memory, inhibition, and reward processing tasks. Literature search identified 13 qualifying studies.","limitations":"Only 13 studies met criteria, limiting conclusions. Few controlled for important confounders. Cross-sectional designs cannot establish causation. Different studies used different tasks and analysis methods. \"Adolescent\" was defined broadly (13-18), spanning significant developmental stages."},{"rthcId":"RTHC-01217","title":"Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes.","authors":"Lu, Dai; Dopart, Rachel; Kendall, Debra A","year":2016,"journal":"Cell stress & chaperones, 21(1), 1-7","doi":"10.1007/s12192-015-0653-5","pmid":"26498013","tags":["neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system's overactivation in visceral obesity drives metabolic dysfunction through CB1 receptors. Rimonabant's clinical success in reducing weight and metabolic risk factors proved that CB1 blockade works, but its psychiatric side effects ended its use.\n\nThis review examines two promising alternatives. Peripherally restricted CB1 inverse agonists cannot cross the blood-brain barrier, so they target CB1 receptors only in metabolically active tissues (fat, liver, muscle) without affecting the brain. Preclinical studies show these compounds provide similar metabolic benefits without psychiatric effects.\n\nNeutral CB1 antagonists block the receptor without reducing its baseline signaling (unlike inverse agonists). This property may further reduce the risk of mood-related side effects.\n\nAdditionally, CB1 blockade may reduce endoplasmic reticulum and mitochondrial stress, which are contributors to obesity-induced insulin resistance, adding another mechanism for metabolic benefit.","whyItMatters":"Obesity and type 2 diabetes are among the largest global health challenges. CB1 blockade has proven metabolic efficacy, and this review provides a roadmap for how to achieve those benefits safely. The peripheral restriction strategy could rehabilitate an entire drug class.","specificNumbers":"Rimonabant reduced food intake, abdominal fat, fasting glucose, and cardiometabolic risk factors in humans. Peripherally restricted CB1 inverse agonists showed similar effects in preclinical models without psychiatric side effects. Neutral antagonists also effective in animal models.","methodology":"Narrative review of preclinical evidence for peripherally restricted CB1 inverse agonists and neutral CB1 antagonists in obesity and type 2 diabetes treatment.","limitations":"Most evidence is preclinical. No peripherally restricted or neutral CB1 antagonists have completed large-scale human trials. The assumption that peripheral restriction eliminates psychiatric effects needs clinical validation. Long-term safety data are lacking."},{"rthcId":"RTHC-01218","title":"An introduction to the endogenous cannabinoid system","authors":"Lu, Hui-Chen; Mackie, Ken","year":2016,"journal":"Biological Psychiatry, 79(7), 516-525","doi":null,"pmid":"26698193","tags":["neuroscience","psychosis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system (ECS) is one of the most widespread signaling networks in the brain. It operates through two primary endocannabinoids — 2-arachidonoyl glycerol (2-AG) and anandamide — that act as retrograde messengers, meaning they signal backward across synapses to regulate how much neurotransmitter gets released. CB1 receptors, the main targets, are among the most abundant receptors in the brain.\n\nDespite their structural similarities, 2-AG and anandamide are made and broken down by entirely different enzyme pathways, giving them distinct biological roles. THC from cannabis mimics these molecules, binding to the same receptors but without the precise timing and location control that endocannabinoids use. The review also examines how this system appears disrupted in schizophrenia, where altered endocannabinoid signaling may contribute to the condition.","whyItMatters":"You can't understand what cannabis does to the brain without understanding the system it acts on. This review lays out the machinery: the receptors, the molecules, the enzymes, and the feedback loops. When someone uses cannabis, THC doesn't create new effects from scratch — it takes over an existing system that normally regulates neural communication with precise timing. Cannabis essentially floods a signaling network designed for brief, targeted bursts.\n\nThe distinction between 2-AG and anandamide matters because it means the endocannabinoid system isn't one thing — it's at least two overlapping systems with different jobs. Drugs that target one pathway may have very different effects than drugs targeting the other.","specificNumbers":"• CB1 receptors are among the most abundant G protein-coupled receptors in the central nervous system\n• Two primary endocannabinoids: 2-AG and anandamide, with distinct synthesis/degradation pathways\n• The ECS modulates glutamate and GABA release through retrograde signaling","methodology":"Narrative review of preclinical and clinical literature on the endocannabinoid system, covering receptor pharmacology, synthesis and degradation pathways, synaptic plasticity mechanisms, and relevance to schizophrenia. Published in Biological Psychiatry as part of a themed issue on cannabinoids.","limitations":"As a narrative review, this paper summarizes existing knowledge rather than presenting new data. The schizophrenia connection, while biologically plausible, relies heavily on preclinical models that may not fully translate to human disease. The review was published in 2016 and the field has advanced since."},{"rthcId":"RTHC-01219","title":"Substituting cannabis for prescription drugs, alcohol and other substances among medical cannabis patients: The impact of contextual factors.","authors":"Lucas, Philippe; Walsh, Zach; Crosby, Kim; Callaway, Robert; Belle-Isle, Lynne; Kay, Robert; Capler, Rielle; Holtzman, Susan","year":2016,"journal":"Drug and alcohol review, 35(3), 326-33","doi":"10.1111/dar.12323","pmid":"26364922","tags":["medical-cannabis","harm-reduction","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This large survey of Canadian medical cannabis patients revealed remarkably high rates of substance substitution. Among 473 respondents, 87% reported substituting cannabis for at least one other substance category.\n\nThe most common substitution was for prescription drugs (80.3%), followed by alcohol (51.7%) and illicit substances (32.6%). Patients under 40 were more likely to substitute cannabis for all three categories.\n\nAn important finding was that patients who substituted cannabis for prescription drugs were more likely to report difficulty affording enough cannabis, suggesting that cost barriers may limit the substitution effect. The authors argue this points to a harm reduction role for medical cannabis.","whyItMatters":"The finding that 80% of medical cannabis patients reduce prescription drug use has enormous implications for the opioid crisis, polypharmacy management, and healthcare costs. If cannabis can safely replace even a fraction of prescription medications, the public health impact could be substantial.","specificNumbers":"473 medical cannabis patients surveyed. 87% substituted cannabis for at least one substance. 80.3% for prescription drugs. 51.7% for alcohol. 32.6% for illicit substances. Patients under 40 more likely to substitute across all categories. Cost barriers limited substitution.","methodology":"Cross-sectional survey (414 questions) of 473 Canadian medical cannabis patients, available online and in hard copy in 2011-2012. Assessed demographics, medical conditions, use patterns, substitution behavior, and access barriers.","limitations":"Self-selected sample of patients already committed to medical cannabis. No objective verification of reduced prescription drug use. Patients who substituted successfully may be more likely to respond. Cannot determine whether substitution led to better or worse health outcomes. Cross-sectional design."},{"rthcId":"RTHC-01220","title":"Hemopressin Peptides as Modulators of the Endocannabinoid System and their Potential Applications as Therapeutic Tools.","authors":"Macedonio, Giorgia; Stefanucci, Azzurra; Maccallini, Cristina; Mirzaie, Sako; Novellino, Ettore; Mollica, Adriano","year":2016,"journal":"Protein and peptide letters, 23(12), 1045-1051","doi":null,"pmid":"27748182","tags":["neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Hemopressin is a naturally occurring brain peptide derived from hemoglobin that acts as a negative allosteric modulator of CB1 cannabinoid receptors. This review examines the growing understanding of this peptide family and its therapeutic potential.\n\nHemopressin shows pain-relieving (antinociceptive), appetite-suppressing (hypophagic), and blood-pressure-lowering (hypotensive) effects. However, there is debate about whether hemopressin itself is the active endogenous molecule or a degradation product of a longer peptide, RVD-hemopressin, which may be more biologically active.\n\nRVD-hemopressin appears to bind to a similar site as rimonabant on the CB1 receptor and may also interact with opioid receptors. This dual-receptor activity opens possibilities for developing cannabinoid peptide drugs that simultaneously affect both pain systems.","whyItMatters":"The discovery of endogenous peptides that modulate cannabinoid receptors adds a new dimension to the endocannabinoid system. Unlike lipid endocannabinoids, peptides can be more easily modified by medicinal chemistry to create drugs with specific properties.","specificNumbers":"Hemopressin: nonapeptide from hemoglobin alpha-chain. RVD-hemopressin: longer, possibly more active precursor. Effects include antinociception, hypophagia, and hypotension. May share binding site with rimonabant. Possible cross-reactivity with opioid receptors.","methodology":"Narrative review of preclinical evidence on hemopressin, its peptide derivatives, and synthetic analogs, covering their pharmacology, physiological effects, and potential therapeutic applications.","limitations":"The endogenous status of hemopressin versus RVD-hemopressin is still debated. Most evidence is from animal studies. Peptide drugs face challenges with stability, bioavailability, and brain penetration. The precise binding mechanisms remain to be fully characterized."},{"rthcId":"RTHC-01221","title":"A user's guide to cannabinoid therapies in oncology.","authors":"Maida, V; Daeninck, P J","year":2016,"journal":"Current oncology (Toronto, Ont.), 23(6), 398-406","doi":"10.3747/co.23.3487","pmid":"28050136","tags":["medical-cannabis","cancer","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review provides a clinical roadmap for using cannabinoid therapies in cancer care. Patients with malignant disease have among the greatest unmet symptom management needs despite available treatments.\n\nCannabinoids offer a versatile toolkit. Pharmaceutical options include nabilone, dronabinol, and nabiximols (Sativex). Patients can also access dried botanical cannabis and edible oils. Treatment regimens can creatively combine these modalities.\n\nThe most established evidence supports cannabinoids for cancer-related pain, chemotherapy-induced nausea and vomiting, and anorexia/cachexia. A key advantage highlighted is cannabinoids' ability to address multiple symptoms simultaneously, potentially reducing the number of other medications needed (polypharmacy).\n\nThe authors argue that cannabinoid therapy could benefit cancer patients at all disease stages, from active treatment through palliative care, either as standalone treatment or as an adjunct to conventional therapies.","whyItMatters":"Cancer patients often take numerous medications for different symptoms. Cannabinoids' ability to simultaneously address pain, nausea, and appetite loss could simplify treatment regimens while improving quality of life, potentially also improving compliance with cancer-directed therapies like chemotherapy.","specificNumbers":"Three pharmaceutical cannabinoids reviewed: nabilone, dronabinol, nabiximols. Three primary evidence-based indications: pain, chemotherapy-induced nausea/vomiting, anorexia. Multiple formulation options: pharmaceuticals, dried botanical, edible oils.","methodology":"Clinical review and practical guide addressing available cannabinoid formulations, evidence-based indications, dosing considerations, and integration strategies for oncology practice.","limitations":"Much of the evidence for cannabinoids in cancer comes from small trials. The anti-tumor potential mentioned is mostly preclinical. Individual patient responses to cannabinoids vary widely. Drug interactions with cancer therapies need more study."},{"rthcId":"RTHC-01222","title":"The Cyclic AMP Assay Using Human Cannabinoid CB2 Receptor-Transfected Cells.","authors":"Marini, Pietro; Cascio, Maria Grazia; Pertwee, Roger G","year":2016,"journal":"Methods in molecular biology (Clifton, N.J.), 1412, 85-93","doi":"10.1007/978-1-4939-3539-0_9","pmid":"27245894","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01223","title":"A Systematic Review of the Respiratory Effects of Inhalational Marijuana.","authors":"Martinasek, Mary P; McGrogan, Jamie B; Maysonet, Alisha","year":2016,"journal":"Respiratory care, 61(11), 1543-1551","doi":null,"pmid":"27507173","tags":["respiratory"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This systematic review compiled 48 studies on the respiratory effects of smoking marijuana. The findings were organized by condition category.\n\nFor lung cancer, the evidence indicated risk from inhalational marijuana, though the relationship was complicated by concurrent tobacco use in many studies. For emphysema and COPD, an association with marijuana smoking was found, including cases of bullous emphysema and spontaneous pneumothorax.\n\nA wide range of respiratory symptoms were reported by marijuana smokers: wheezing, shortness of breath, altered pulmonary function tests, cough, phlegm production, and bronchodilation. The bronchodilation finding is notable as a potential short-term benefit that contrasts with long-term risks.","whyItMatters":"As marijuana use increases with legalization, understanding respiratory risks becomes more important. This review provides the most comprehensive compilation of evidence on smoked marijuana's effects on the lungs, helping users make informed decisions about consumption methods.","specificNumbers":"48 articles reviewed. Primary categories: lung cancer, bullous emphysema/COPD, and other respiratory symptoms. Symptoms reported: wheezing, shortness of breath, cough, phlegm, altered pulmonary function, bronchodilation, spontaneous pneumothorax.","methodology":"Systematic review using comparative methods between two researchers. Full-text articles were reviewed after abstract screening. Excluded: non-burning marijuana routes, animal studies, editorials, other systematic reviews, commentaries, non-English, and non-respiratory articles. 48 articles categorized by respiratory effects.","limitations":"Many studies could not fully separate marijuana effects from tobacco effects due to co-use. Study populations, methods, and definitions varied widely. The acute bronchodilation effect complicates interpretation. Some included studies were small or of lower quality."},{"rthcId":"RTHC-01224","title":"Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics.","authors":"May, Megan Brafford; Glode, Ashley E","year":2016,"journal":"Cancer management and research, 8, 49-55","doi":"10.2147/CMAR.S81425","pmid":"27274310","tags":["medical-cannabis","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Chemotherapy-induced nausea and vomiting (CINV) is one of patients' most feared side effects. While first-line treatments (corticosteroids, serotonin receptor antagonists, neurokinin antagonists) are effective for many patients, some continue to experience refractory nausea.\n\nThis review examined dronabinol's role in this treatment landscape. As a synthetic form of THC, dronabinol has been used for CINV since the 1980s. The review analyzed evidence for three use patterns: as monotherapy, combined with ondansetron (a serotonin antagonist), and combined with prochlorperazine (a dopamine antagonist).\n\nDronabinol showed lower efficacy than first-line agents and more adverse effects (drowsiness, dizziness, dysphoria). However, it provides a valuable option for patients who fail standard treatments, and combination with other antiemetics may improve its benefit-to-risk ratio.","whyItMatters":"Despite advances in antiemetic therapy, refractory CINV remains a significant problem. Having additional therapeutic options like dronabinol ensures that patients who fail first-line treatments have alternatives.","specificNumbers":"Dronabinol has been available for CINV since the 1980s. Lower efficacy than serotonin and neurokinin antagonists. More adverse effects than first-line agents. Evidence supports combination with ondansetron or prochlorperazine.","methodology":"Narrative review analyzing clinical evidence for dronabinol in CINV as monotherapy and in combination with ondansetron and prochlorperazine.","limitations":"Many studies of dronabinol for CINV are older and used methodology that would not meet current standards. Direct comparisons with newer first-line antiemetics are limited. Individual responses vary widely."},{"rthcId":"RTHC-01225","title":"Maintaining Drug-Free Workplaces Where Marijuana is Legal.","authors":"McGuire, Jo","year":2016,"journal":"Occupational health & safety (Waco, Tex.), 85(10), 72, 74","doi":null,"pmid":"30280864","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01226","title":"\"I Use Weed for My ADHD\": A Qualitative Analysis of Online Forum Discussions on Cannabis Use and ADHD.","authors":"Mitchell, John T; Sweitzer, Maggie M; Tunno, Angela M; Kollins, Scott H; McClernon, F Joseph","year":2016,"journal":"PloS one, 11(5), e0156614","doi":"10.1371/journal.pone.0156614","pmid":"27227537","tags":["mental-health","addiction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Despite ADHD being a risk factor for problematic cannabis use, there is growing online discourse portraying cannabis as a treatment for ADHD. This study is the first to systematically analyze these discussions.\n\nResearchers identified 268 online forum threads about cannabis and ADHD. A random 20% sample (55 threads, averaging 17.5 posts each) was coded by three raters. Among 401 coded posts:\n\n25% endorsed cannabis as therapeutic for ADHD, while only 8% described it as harmful. 5% said it was both therapeutic and harmful, and 2% said it had no effect. This pro-therapeutic pattern was consistent across years.\n\nImportantly, this positive framing of cannabis for ADHD did not extend to other conditions. Posts about mood disorders, other psychiatric conditions, and general daily life functioning did not show the same therapeutic bias, suggesting the ADHD-specific narrative is distinctive.\n\nSome posts claimed healthcare providers had sanctioned their cannabis use for ADHD, adding perceived legitimacy to the practice.","whyItMatters":"The internet increasingly shapes healthcare decisions. When patients or parents searching for ADHD information encounter overwhelmingly positive cannabis narratives online, this could influence self-medication decisions. Currently, there are no clinical recommendations or systematic research supporting cannabis for ADHD.","specificNumbers":"268 forum threads identified. 55 analyzed (mean 17.5 posts each). 401 posts coded. 25% said cannabis is therapeutic for ADHD. 8% said harmful. 5% said both. 2% said no effect. Cohen's kappa = 0.74 (good inter-rater reliability).","methodology":"Qualitative analysis of online forum discussions. 268 threads identified. 20% randomly selected (55 threads, 401 qualifying posts). Three raters coded content (Cohen's kappa = 0.74). Posts coded for therapeutic, harmful, both, or no effect endorsements.","limitations":"Online forum users are not representative of all people with ADHD. Posts may be influenced by cannabis-positive communities. Cannot verify ADHD diagnosis or actual cannabis effects. Coding captures stated opinions, not outcomes."},{"rthcId":"RTHC-01227","title":"Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males.","authors":"Mokrysz, C; Freeman, T P; Korkki, S; Griffiths, K; Curran, H V","year":2016,"journal":"Translational psychiatry, 6(11), e961","doi":"10.1038/tp.2016.225","pmid":"27898071","tags":["youth","cognition","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This groundbreaking study was the first to directly compare cannabis effects in adolescent (16-17) and adult (24-28) male users under controlled conditions.\n\nThe results defied simple assumptions about adolescent vulnerability. Compared to adults, adolescents reported feeling less stoned, had fewer psychotomimetic symptoms, less anxiety, and showed less memory impairment from cannabis. Their blood pressure and alertness were also less affected.\n\nBut alongside this apparent resilience, two concerning vulnerabilities emerged. First, cannabis impaired response inhibition (impulse control) in adolescents but not adults. Second, adolescents showed no satiety after cannabis: they wanted more regardless of whether they had received active or placebo cannabis, while adults felt satisfied after the active dose.\n\nThis combination of reduced subjective effects and lack of satiety could drive adolescents toward escalated use, as they may consume more to achieve the high adults get from less.","whyItMatters":"This is a landmark study. The contrasting profiles of adolescent resilience (blunted subjective and cognitive effects) and vulnerability (impaired inhibition and lack of satiety) provide a mechanistic explanation for why adolescent cannabis use tends to escalate: they feel the effects less, stop themselves less, and never feel they have had enough.","specificNumbers":"20 adolescents (16-17) vs. 20 adults (24-28), all male cannabis users. Adolescents: less stoned, fewer psychotomimetic symptoms, less memory impairment, less anxiety. BUT: impaired response inhibition, no satiety (wanted more cannabis regardless of active/placebo). Adults: opposite pattern on all measures.","methodology":"Placebo-controlled, double-blind, crossover design. 20 adolescent males (16-17 years) and 20 adult males (24-28 years), all current cannabis users. Vaporized active or placebo cannabis administered. Assessments: spatial working memory, episodic memory, response inhibition, blood pressure, heart rate, psychotomimetic symptoms, and subjective drug effects.","limitations":"Only male participants. All were current cannabis users, so findings may not apply to naive users. Moderate sample size. Single-session design may not capture effects of regular use. Cannabis was standardized but may not represent typical potency."},{"rthcId":"RTHC-01228","title":"Techniques and technologies for the bioanalysis of Sativex®, metabolites and related compounds.","authors":"Molnar, Anna; Fu, Shanlin","year":2016,"journal":"Bioanalysis, 8(8), 829-45","doi":"10.4155/bio-2015-0021","pmid":"27005853","tags":["driving","workplace","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"As medical cannabis products like Sativex become more widely prescribed, drug testing faces a growing challenge: how to distinguish legal medical use from illicit recreational use.\n\nThis review systematically examined methods for detecting THC and CBD across four biological matrices: blood, urine, oral fluid, and hair. Sativex contains approximately equal amounts of THC and CBD, producing a distinctive metabolic profile that could potentially be used to identify medical versus recreational cannabis use.\n\nThe review covers screening (immunoassays) and confirmatory testing (LC-MS/MS, GC-MS), discusses correlations between different sample types, and addresses current analytical pitfalls. Key challenges include the wide inter-individual variability in cannabinoid metabolism, the long detection windows for THC metabolites in urine, and the difficulty of establishing impairment from drug concentrations alone.","whyItMatters":"Patients prescribed Sativex should not face legal or employment consequences for using their medication. This review highlights the analytical challenges of protecting medical users while maintaining the integrity of drug testing programs.","specificNumbers":"Sativex contains THC and CBD in approximately 1:1 ratio. Four matrices reviewed: blood, urine, oral fluid, hair. Screening methods: immunoassays. Confirmation: LC-MS/MS and GC-MS.","methodology":"Narrative review of published research on bioanalytical methods for THC and CBD detection, with particular focus on Sativex use scenarios across workplace, roadside, and sports drug testing contexts.","limitations":"Technical review focused on analytical methods rather than policy solutions. Cannot fully resolve the medical vs. recreational use distinction. Inter-individual metabolic variation complicates interpretation. Rapidly evolving product landscape may outpace analytical methods."},{"rthcId":"RTHC-01229","title":"Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin.","authors":"Morano, Alessandra; Cifelli, Pierangelo; Nencini, Paolo; Antonilli, Letizia; Fattouch, Jinane; Ruffolo, Gabriele; Roseti, Cristina; Aronica, Eleonora; Limatola, Cristina; Di Bonaventura, Carlo; Palma, Eleonora; Giallonardo, Anna Teresa","year":2016,"journal":"Epilepsia open, 1(3-4), 145-151","doi":"10.1002/epi4.12015","pmid":"29588939","tags":["epilepsy","cbd","neuroscience"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with symptomatic partial epilepsy who had failed numerous medications and surgical treatments began self-medicating with cannabis. The clinical improvement was dramatic: seizure frequency decreased substantially and cognitive function recovered.\n\nBlood analysis revealed significant levels of cannabidivarin (CBDV), a relatively rare minor cannabinoid, alongside CBD and THC. The clinical improvement appeared to parallel high CBDV plasma concentrations.\n\nTo investigate CBDV's potential mechanism, the researchers performed electrophysiology experiments on human hippocampal tissue from four epilepsy surgery patients. They found that prolonged CBDV exposure reduced the \"rundown\" of GABA-A receptor currents, essentially helping inhibitory signaling maintain its strength over time. This finding was confirmed in tissue from a patient with Rasmussen encephalitis.\n\nThis suggests CBDV may combat seizures by enhancing the brain's inhibitory GABA system, a mechanism distinct from CBD's known actions.","whyItMatters":"While CBD (as Epidiolex) has gained attention for epilepsy, this study suggests another cannabinoid, CBDV, may also have anticonvulsant properties through a different mechanism. If confirmed, CBDV could expand the cannabinoid toolkit for treatment-resistant epilepsy.","specificNumbers":"One patient with drug-resistant partial epilepsy. Failed countless pharmacological and surgical treatments. Dramatic seizure reduction and cognitive improvement with cannabis. CBDV detected in blood. GABA-A receptor rundown reduced by CBDV exposure in tissue from 4 TLE patients and 1 RE patient.","methodology":"Case report with clinical monitoring (EEG, seizure diaries) and serial blood cannabinoid measurements. Complementary electrophysiology experiments using human epileptic hippocampal tissue transplanted into Xenopus oocytes to test CBDV effects on GABA-A receptor currents.","limitations":"Single case report cannot establish efficacy. The patient used whole-plant cannabis, so effects cannot be attributed solely to CBDV. The electrophysiology experiments used an artificial expression system. CBDV availability and dosing for clinical use are not established."},{"rthcId":"RTHC-01230","title":"Cannabis use in first episode psychosis: Meta-analysis of prevalence, and the time course of initiation and continued use.","authors":"Myles, Hannah; Myles, Nicholas; Large, Matthew","year":2016,"journal":"The Australian and New Zealand journal of psychiatry, 50(3), 208-19","doi":"10.1177/0004867415599846","pmid":"26286531","tags":["psychosis","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"This meta-analysis pooled data from 37 studies to characterize the epidemiology of cannabis use in first-episode psychosis.\n\nThree key findings emerged. First, the interval between starting regular cannabis use and psychosis onset averaged 6.3 years. This long delay is important for understanding the temporal relationship between cannabis and psychosis.\n\nSecond, approximately one-third (33.7%) of people experiencing first-episode psychosis were using cannabis at the time of onset. This is substantially higher than general population cannabis use rates.\n\nThird, cannabis use declined after psychosis treatment, with odds of continued use between 6 months and 10 years after onset being 0.56 (meaning about 44% reduction). This suggests that treatment engagement and psychosis experience lead many to reduce or stop cannabis use.","whyItMatters":"This meta-analysis provides the most precise estimates to date of the cannabis-psychosis timeline. The 6.3-year average between regular cannabis use onset and psychosis emergence defines a potential intervention window during which reducing cannabis use might prevent or delay psychosis onset.","specificNumbers":"37 samples included. Interval from regular cannabis to psychosis onset: 6.3 years (10 samples, SMD = 1.56). Cannabis use prevalence at first episode: 33.7% (35 samples, 95% CI 31-39%). Odds of continued use after treatment: 0.56 (19 samples, 95% CI 0.40-0.79).","methodology":"Meta-analysis of 37 observational studies identified through MEDLINE, EMBASE, PsycINFO, Web of Science, and CINAHL. Random-effects meta-analyses synthesized prevalence estimates, intervals between cannabis initiation and psychosis onset, and odds of continued cannabis use after treatment.","limitations":"Observational studies cannot prove causation. Heterogeneity across studies was noted. Recall bias in reporting cannabis use onset age. Different studies defined cannabis use differently. The meta-analysis cannot distinguish between causation and shared vulnerability."},{"rthcId":"RTHC-01231","title":"Cannabinoid receptor 2 expression modulates Gβ(1)γ(2) protein interaction with the activator of G protein signalling 2/dynein light chain protein Tctex-1.","authors":"Nagler, Marina; Palkowitsch, Lysann; Rading, Sebastian; Moepps, Barbara; Karsak, Meliha","year":2016,"journal":"Biochemical pharmacology, 99, 60-72","doi":"10.1016/j.bcp.2015.09.017","pmid":"26410677","tags":["neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers discovered that the CB2 cannabinoid receptor does not directly interact with a protein called Tctex-1, as previously suspected. Instead, CB2 competes with Tctex-1 for binding to another protein group called G-beta-gamma.\n\nWhen CB2 receptors were expressed in cells, they displaced Tctex-1 from its protein complex. The displaced Tctex-1 was then broken down by the cell's recycling machinery. This happened in a dose-dependent manner, meaning more CB2 receptors led to more Tctex-1 degradation.\n\nRemarkably, this effect did not require the CB2 receptor to be activated by any cannabinoid compound. Neither agonists nor inverse agonists changed the outcome. The mere presence of the receptor was sufficient to disrupt the protein complex.","whyItMatters":"This study reveals that cannabinoid receptors can influence cell behavior through pathways that have nothing to do with traditional receptor signaling. Because Tctex-1 controls cell proliferation by regulating the cell cycle, CB2's ability to trigger its degradation could have implications for understanding how the endocannabinoid system influences cell growth and potentially cancer.","specificNumbers":"CB2 receptor expression reduced Tctex-1 protein levels in a dose-dependent manner. Degradation occurred via both the proteasome and lysosomal pathways.","methodology":"The team used HEK293 cells (a common laboratory cell line) transfected with CB2 receptors. They employed co-immunoprecipitation experiments to track protein interactions and tested the effects of various cannabinoid ligands (JWH 133, 2-AG, AM 630) alongside protein degradation inhibitors (MG132, ammonium chloride/leupeptin, bafilomycin) to identify the breakdown pathway.","limitations":"This was an in vitro study using an artificial cell system with transfected receptors. The levels of CB2 expression in these experiments may not reflect physiological conditions. Whether this mechanism operates in actual human tissues remains to be determined."},{"rthcId":"RTHC-01232","title":"Go/No Go task performance predicts cortical thickness in the caudal inferior frontal gyrus in young adults with and without ADHD.","authors":"Newman, Erik; Jernigan, Terry L; Lisdahl, Krista M; Tamm, Leanne; Tapert, Susan F; Potkin, Steven G; Mathalon, Daniel; Molina, Brooke; Bjork, James; Castellanos, F Xavier; Swanson, James; Kuperman, Joshua M; Bartsch, Hauke; Chen, Chi-Hua; Dale, Anders M; Epstein, Jeffery N","year":2016,"journal":"Brain imaging and behavior, 10(3), 880-92","doi":"10.1007/s11682-015-9453-x","pmid":"26404018","tags":["cognition","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined the inferior frontal gyrus, a brain region central to stopping yourself from acting impulsively. They found two distinct patterns.\n\nFirst, people who performed worse on a stop-signal task (Go/No Go) actually had thicker cortex in this region, regardless of whether they had ADHD or used cannabis. This counterintuitive finding suggests that delayed brain maturation, not just less brain tissue, may underlie poor impulse control.\n\nSecond, independent of task performance, both persistent ADHD symptoms and more frequent cannabis use were associated with thinner cortex in the same region. These appeared to be separate effects operating through different neural mechanisms.","whyItMatters":"This is one of the few studies to disentangle the effects of ADHD and cannabis use on brain structure. The finding that both independently affect the same brain region but through distinct mechanisms suggests that cannabis use may compound existing structural differences in people with ADHD.","specificNumbers":"The sample included 114 young adults with and without childhood ADHD. Poorer Go/No Go performance correlated with thicker cortex, while persistent ADHD and cannabis use each correlated with thinner cortex in the same region.","methodology":"The study included 114 young adults, some with childhood ADHD diagnoses, who underwent MRI brain scanning and completed a Go/No Go impulse control task. Researchers used multiple linear regression to test associations between task performance, ADHD status, cannabis use frequency, and cortical thickness and surface area of the caudal inferior frontal gyrus.","limitations":"This was a cross-sectional study, so it cannot determine whether cannabis caused cortical thinning or whether people with thinner cortex were more likely to use cannabis. The sample was drawn from a longitudinal ADHD study, which may limit generalizability."},{"rthcId":"RTHC-01233","title":"Free and Glucuronide Whole Blood Cannabinoids' Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake.","authors":"Newmeyer, Matthew N; Swortwood, Madeleine J; Barnes, Allan J; Abulseoud, Osama A; Scheidweiler, Karl B; Huestis, Marilyn A","year":2016,"journal":"Clinical chemistry, 62(12), 1579-1592","doi":null,"pmid":"27899456","tags":["potency","driving"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Researchers gave the same dose of cannabis to both frequent and occasional users through three routes: smoking, vaporizing, and eating. They then tracked THC and its metabolites in blood for up to 72 hours.\n\nSmoking and vaporizing produced remarkably similar blood cannabinoid patterns. Edibles, however, produced significantly higher levels of the metabolites THCCOOH and THCCOOH-glucuronide.\n\nTwo minor cannabinoids, cannabigerol (CBG) and cannabinol (CBN), appeared in blood only after inhaling cannabis and disappeared quickly, making them potential markers of recent use. They were not detected at all after oral consumption.\n\nA combined cutoff of THC at or above 5 micrograms per liter plus a specific metabolite ratio produced detection windows under 8 hours for all consumption routes in frequent users.","whyItMatters":"Distinguishing recent cannabis use from past use is critical for DUI enforcement and workplace testing. Standard THC blood tests can show positive results for up to 30 days in frequent users, even when they are no longer impaired. This study provides evidence for biomarkers and cutoff combinations that narrow the detection window to hours rather than days.","specificNumbers":"CBG and CBN were detected after inhalation with short detection windows but not after oral dosing. A combined THC greater than or equal to 5 micrograms per liter plus THCCOOH/11-OH-THC ratio less than 20 produced detection windows under 8 hours for all routes in frequent smokers. No occasional smoker tested positive 1.5 hours after inhalation or 12 hours after oral use with this cutoff.","methodology":"This was a controlled, within-subject clinical trial. Participants received 50.6 mg of THC via smoking, vaporizing, or oral brownie across separate sessions. Blood was collected at multiple time points over 54 hours (occasional users) or 72 hours (frequent users). Researchers measured THC, its phase I and phase II metabolites, and minor cannabinoids using validated analytical methods.","limitations":"The study used a single THC dose (50.6 mg). Real-world consumption varies widely in dose and potency. The sample size was relatively small. The proposed cutoffs need validation in larger populations and real-world settings before adoption in legal or workplace contexts."},{"rthcId":"RTHC-01234","title":"Mixed-amphetamine salts increase abstinence from marijuana in patients with co-occurring attention-deficit/hyperactivity disorder and cocaine dependence.","authors":"Notzon, Daniel P; Mariani, John J; Pavlicova, Martina; Glass, Andrew; Mahony, Amy L; Brooks, Daniel J; Grabowski, John; Levin, Frances R","year":2016,"journal":"The American journal on addictions, 25(8), 666-672","doi":"10.1111/ajad.12467","pmid":"28051838","tags":["addiction","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a secondary analysis of a 14-week randomized controlled trial, researchers found that people with co-occurring ADHD and cocaine dependence who received mixed amphetamine salts (MAS-XR) had a significant decrease in the proportion of weeks where they used any marijuana, compared to placebo.\n\nHowever, among the weeks when participants did use marijuana, the proportion of days they used did not change. In other words, the medication helped more people have completely marijuana-free weeks, but when people did use, their pattern of use was similar to placebo.","whyItMatters":"ADHD, cocaine dependence, and cannabis use frequently co-occur. This finding suggests that effectively treating ADHD with stimulant medication may reduce cannabis use as a secondary benefit, possibly because some people use cannabis to self-medicate attention difficulties. If treating the underlying condition reduces substance use, it supports an integrated treatment approach.","specificNumbers":"57 participants total (37 MAS-XR, 20 placebo). Marijuana users were defined as those reporting use in the 30 days before the study. The MAS-XR group showed significantly more marijuana-free weeks over the 14-week trial.","methodology":"This was a secondary analysis of a 14-week randomized controlled trial. The original trial compared placebo, MAS-XR 60 mg, and MAS-XR 80 mg in people with co-occurring ADHD and cocaine dependence. For this analysis, both MAS-XR groups were combined (n=37) versus placebo (n=20). Marijuana use was tracked using timeline follow-back methods. Analysis used logistic mixed effects models.","limitations":"This was a secondary analysis, not the primary aim of the trial. The sample was small (57 participants). All participants also had cocaine dependence, limiting generalizability to people with ADHD and cannabis use without cocaine involvement. The study was not designed or powered to detect cannabis use outcomes."},{"rthcId":"RTHC-01235","title":"Cannabinoids for treatment of glaucoma.","authors":"Novack, Gary D","year":2016,"journal":"Current opinion in ophthalmology, 27(2), 146-50","doi":"10.1097/ICU.0000000000000242","pmid":"26840343","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the current state of cannabis for glaucoma treatment against a backdrop of increasing marijuana potency and legalization. The core pharmacology has not changed since the 1970s and 1980s: cannabis is an effective ocular hypotensive agent, meaning it reliably lowers pressure inside the eye.\n\nHowever, the same dose that lowers eye pressure also produces cardiovascular effects (including lowered blood pressure) and neurological effects. Lowered systemic blood pressure can reduce blood flow to the optic nerve, which could theoretically cancel out or even reverse the benefit of lower eye pressure.\n\nThe review noted that marijuana potency has increased dramatically, from about 2-3% THC in the 1970s to approximately 20% at the time of writing.","whyItMatters":"Glaucoma remains one of the most commonly cited reasons for medical marijuana use, despite the medical community's longstanding concerns about its practical limitations. This review clearly articulates the paradox: cannabis lowers eye pressure but may simultaneously reduce the blood flow needed to protect the optic nerve, potentially negating the benefit.","specificNumbers":"Marijuana potency increased from approximately 2-3% THC in the 1970s to approximately 20% by 2016. Many US states had passed laws allowing medicinal or recreational use by the time of publication.","methodology":"This was a narrative review published in Current Opinion in Ophthalmology, summarizing the current evidence on cannabis and glaucoma in the context of expanding legal access. The author reviewed existing pharmacological evidence and clinical considerations.","limitations":"This is a narrative review, not a systematic review. It reflects one author's interpretation of existing evidence. The review does not address newer cannabinoid formulations or delivery methods that might avoid systemic side effects, such as topical eye drops."},{"rthcId":"RTHC-01236","title":"Drug use among HIV+ adults aged 50 and older: findings from the GOLD II study.","authors":"Ompad, Danielle C; Giobazolia, Tatiana T; Barton, Staci C; Halkitis, Sophia N; Boone, Cheriko A; Halkitis, Perry N; Kapadia, Farzana; Urbina, Antonio","year":2016,"journal":"AIDS care, 28(11), 1373-7","doi":"10.1080/09540121.2016.1178704","pmid":"27145363","tags":["medical-cannabis","seniors","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In a sample of 95 HIV-positive patients aged 50 and older who were actively engaged in medical care, substance use was highly prevalent. Nearly half (48.4%) had used an illicit drug in the past 12 months, and 23.2% met criteria for drug dependence.\n\nMarijuana was the most commonly reported illicit drug at 32.6%, followed by cocaine and crack at 10.5% each. Most participants (81.1%) were at medium risk for an alcohol use disorder.\n\nAmong those who had used drugs in the past year, 37% had never been in any substance use treatment. Among those meeting dependence criteria, 27.3% had never participated in a 12-step program.","whyItMatters":"The population of people living with HIV aged 50 and older is growing due to effective antiretroviral therapy. High rates of substance use in this population intersect with complex medication regimens, age-related health conditions, and potential drug interactions. The finding that over a third of active drug users had never received treatment suggests a significant gap in integrated care.","specificNumbers":"95 participants. 48.4% used illicit drugs in the past year. 32.6% used marijuana. 23.2% met drug dependence criteria. 46.3% were current cigarette smokers. 37% of past-year drug users had never been in treatment.","methodology":"This was a cross-sectional study of 95 HIV-positive patients aged 50 and older recruited from two community health settings in New York City. Participants completed assessments of alcohol, tobacco, and illicit drug use, treatment history, and 12-step program participation.","limitations":"Small sample size (95 participants) from New York City limits generalizability. The study was cross-sectional and relied on self-reported drug use. Participants were all engaged in care, so those not in treatment may have different patterns. The study did not distinguish between medical and recreational cannabis use."},{"rthcId":"RTHC-01237","title":"Effect of JWH-250, JWH-073 and their interaction on \"tetrad\", sensorimotor, neurological and neurochemical responses in mice.","authors":"Ossato, Andrea; Canazza, Isabella; Trapella, Claudio; Vincenzi, Fabrizio; De Luca, Maria Antonietta; Rimondo, Claudia; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; Marti, Matteo","year":2016,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 67, 31-50","doi":"10.1016/j.pnpbp.2016.01.007","pmid":"26780169","tags":["synthetic-cannabinoids","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested JWH-250 and JWH-073, two synthetic cannabinoids frequently found together in \"herbal blend\" products, in mice. Both compounds individually caused hypothermia, increased pain threshold, caused catalepsy, reduced movement, impaired sensory responses (vision, hearing, touch), caused seizures, and promoted aggressiveness.\n\nBoth compounds also stimulated dopamine release in the brain's reward center (nucleus accumbens) in a dose-dependent manner. All effects were blocked by a CB1 receptor antagonist, confirming they work through the cannabinoid system.\n\nCritically, when researchers combined doses of each compound that were individually too low to produce effects, the combination still impaired visual responses, altered pain thresholds, and stimulated dopamine release. This suggests a synergistic or at minimum additive interaction.","whyItMatters":"Synthetic cannabinoid products (\"spice,\" \"K2\") typically contain mixtures of multiple synthetic cannabinoids. This study provides the first evidence that combining different synthetic cannabinoids can produce dangerous effects even at individually sub-threshold doses, which helps explain the unpredictable and often severe adverse reactions seen in emergency departments.","specificNumbers":"Both JWH-250 and JWH-073 had nanomolar affinity at CB1 and CB2 receptors. Sub-effective doses combined still impaired visual sensorimotor responses and stimulated mesolimbic dopamine transmission.","methodology":"The study used male CD-1 mice with in vitro receptor binding experiments and in vivo behavioral testing (tetrad test, sensorimotor assessments, neurological observations). Microdialysis in freely moving mice measured real-time dopamine release in the nucleus accumbens. The selective CB1 antagonist AM 251 was used to confirm receptor specificity.","limitations":"This was a mouse study. The doses, routes of administration, and drug combinations used may not reflect human exposure patterns. Only two specific synthetic cannabinoids were tested, while products on the market may contain many different compounds."},{"rthcId":"RTHC-01238","title":"Involvement of opioid system in antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251 after physical stress in mice.","authors":"Ostadhadi, Sattar; Haj-Mirzaian, Arya; Nikoui, Vahid; Kordjazy, Nastaran; Dehpour, Ahmad-Reza","year":2016,"journal":"Clinical and experimental pharmacology & physiology, 43(2), 203-12","doi":"10.1111/1440-1681.12518","pmid":"26609670","tags":["depression","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice subjected to foot-shock stress showed increased immobility in standard depression tests (forced swimming test and tail suspension test), modeling depressive behavior. The CB1 receptor inverse agonist AM-251 reversed this stress-induced depression-like behavior.\n\nThe key finding was that the opioid system appears to mediate this antidepressant effect. When researchers gave a low dose of the opioid blocker naltrexone alongside AM-251, the antidepressant effect was enhanced, meaning less AM-251 was needed. Conversely, a low dose of morphine blocked AM-251's antidepressant effect entirely.\n\nNone of the drug combinations affected general locomotor activity, confirming the effects were specific to depression-like behavior rather than general changes in movement.","whyItMatters":"This study reveals a previously unknown interaction between the cannabinoid and opioid systems in stress-related depression. The finding that blocking CB1 receptors produces antidepressant effects through opioid signaling suggests these two major neurotransmitter systems are more interconnected in mood regulation than previously recognized.","specificNumbers":"AM-251 at 0.5 mg/kg reversed stress-induced immobility. Co-administration with sub-effective naltrexone reduced the effective AM-251 dose to 0.1 mg/kg. Sub-effective morphine completely blocked AM-251's antidepressant effect at 0.5 mg/kg.","methodology":"Male mice were subjected to intermittent foot-shock stress for 30 minutes, then tested in the forced swimming test and tail suspension test. Researchers tested AM-251 alone and in combination with naltrexone (opioid antagonist) or morphine (opioid agonist). Locomotor activity was measured separately to rule out general motor effects.","limitations":"This was a mouse study using acute stress and acute drug treatment. Depression in humans is a chronic condition with complex causes that cannot be fully captured by rodent tests. AM-251 is a research tool compound, not a clinical drug. The results may not translate directly to human depression."},{"rthcId":"RTHC-01239","title":"Cannabinoid hyperemesis syndrome.","authors":"Parekh, Jai D; Wozniak, Susan E; Khan, Kamran; Dutta, Sudhir K","year":2016,"journal":"BMJ case reports, 2016","doi":"10.1136/bcr-2015-213620","pmid":"26791124","tags":["addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The authors presented a case of cannabinoid hyperemesis syndrome (CHS) encountered in an outpatient clinic and reviewed the existing literature. CHS is characterized by cyclical episodes of severe nausea and vomiting in chronic cannabis users, often accompanied by compulsive hot bathing, which patients discover temporarily relieves symptoms.\n\nThe condition is paradoxical because cannabis is well known for its anti-nausea properties, yet chronic use can trigger this severe vomiting syndrome. Understanding the diagnostic criteria and risk factors can prevent unnecessary and expensive investigations, as patients often undergo extensive workups including imaging and endoscopy before CHS is recognized.\n\nAbstaining from cannabis leads to symptom resolution in the majority of patients.","whyItMatters":"CHS is frequently misdiagnosed because clinicians may not connect vomiting with cannabis use, given cannabis's well-known anti-nausea properties. Patients often undergo expensive and invasive testing before the diagnosis is considered. Greater awareness can reduce healthcare costs and lead to faster symptom resolution.","specificNumbers":"The literature review covered patients over 18 years of age with CHS. Abstaining from cannabis resolved symptoms in the majority of patients.","methodology":"This was a case report from an outpatient clinic combined with a literature review using PubMed, limited to patients over 18 years of age with cannabinoid hyperemesis syndrome.","limitations":"Case reports provide the lowest level of evidence for clinical decision-making. The pathophysiology of CHS remains poorly understood, and the review does not quantify how common the condition is among chronic cannabis users."},{"rthcId":"RTHC-01240","title":"Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis-based pharmaceutical drugs.","authors":"Parmar, Jayesh R; Forrest, Benjamin D; Freeman, Robert A","year":2016,"journal":"Research in social & administrative pharmacy : RSAP, 12(4), 638-54","doi":"10.1016/j.sapharm.2015.09.002","pmid":"26443472","tags":["medical-cannabis","pain","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed 68 studies comparing the three FDA-approved cannabis-based medications (dronabinol, nabiximols, nabilone) with smoked and orally ingested marijuana. All share similar medical uses: neuropathic pain was the most common application across all forms.\n\nDronabinol (Marinol) was most used for weight gain, chemotherapy nausea, and neuropathic pain. Nabiximols (Sativex) was most used for multiple sclerosis spasticity and neuropathic pain. Nabilone (Cesamet) was most used for chemotherapy nausea and neuropathic pain.\n\nSmoked marijuana was most studied for neuropathic pain and glaucoma. Orally ingested marijuana was most studied for sleep improvement, pain reduction, and seizure control in multiple sclerosis.\n\nAll forms shared similar adverse effects, predominantly central nervous system effects, along with cardiovascular and respiratory effects. The review concluded there was insufficient high-quality evidence to support widespread medical marijuana use, with only moderate evidence supporting its use in pain and seizure management.","whyItMatters":"As medical marijuana programs expand, healthcare professionals increasingly face patient questions about cannabis for various conditions. This review provides a structured comparison of what the evidence supports for approved cannabis medications versus marijuana itself, giving clinicians a practical reference for counseling.","specificNumbers":"68 studies reviewed. Three FDA-approved cannabis medications compared with smoked and oral marijuana. CNS-related adverse effects were the most common category across all forms.","methodology":"The authors conducted a literature review using key search terms across cannabis medications and medical conditions. They reviewed 68 abstracts, analyzing and organizing them by medical use, efficacy, and adverse effects for each cannabis formulation.","limitations":"The review methodology was not systematic, and the search strategy was not exhaustive. The evidence landscape for medical marijuana has evolved significantly since 2016. The review focused on efficacy data available at the time and may not reflect current clinical practice."},{"rthcId":"RTHC-01241","title":"Endocannabinoid Signaling Regulates Sleep Stability.","authors":"Pava, Matthew J; Makriyannis, Alexandros; Lovinger, David M","year":2016,"journal":"PloS one, 11(3), e0152473","doi":"10.1371/journal.pone.0152473","pmid":"27031992","tags":["sleep","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Using multiple pharmacological tools, researchers mapped how the endocannabinoid system regulates sleep in mice. Increasing endocannabinoid levels (using JZL184 or AM3506) or directly activating CB1 receptors (using CP47,497) produced an initial increase in NREM sleep by making individual sleep bouts longer and more stable.\n\nHowever, both JZL184 and CP47,497 had a secondary effect that later reduced NREM sleep time and stability. Blocking CB1 receptors with AM281 fragmented NREM sleep and dramatically altered brainwave patterns, particularly reducing low-frequency power.\n\nImportantly, CB1 blockade did not prevent the rebound increase in NREM sleep after sleep deprivation. This means the endocannabinoid system helps maintain sleep quality and continuity but is not responsible for the homeostatic pressure that builds up when you stay awake too long.\n\nThe effects were also time-of-day dependent, with larger responses at certain times.","whyItMatters":"Cannabis users commonly report effects on sleep, both positive (falling asleep faster) and negative (disrupted sleep with withdrawal). This study provides a mechanistic explanation: the endocannabinoid system acts as a sleep stabilizer rather than a sleep driver. This distinction is crucial because it means cannabis may improve how well you stay asleep without addressing underlying sleep disorders.","specificNumbers":"JZL184 and CP47,497 increased NREM bout length initially. AM281 (CB1 blocker) fragmented NREM sleep. CB1 blockade did not reduce sleep rebound after total sleep deprivation. Drug effects depended on time of day of administration.","methodology":"The study used polysomnography (brain wave recording) in mice after systemic administration of various endocannabinoid system modulators. Researchers developed and validated an automated algorithm for unbiased scoring of sleep/wake states. They tested CB1 agonists, endocannabinoid degradation inhibitors, and a CB1 antagonist/inverse agonist, with some experiments including total sleep deprivation.","limitations":"This was a mouse study using pharmacological tools that may not precisely replicate the effects of cannabis use in humans. The automated sleep scoring algorithm, while validated, is novel and may not capture all nuances. Acute drug administration may not reflect chronic cannabis use patterns."},{"rthcId":"RTHC-01242","title":"Cannabis Hyperemesis Syndrome in the Emergency Department: How Can a Specialized Addiction Team Be Useful? A Pilot Study.","authors":"Pélissier, Fanny; Claudet, Isabelle; Gandia-Mailly, Peggy; Benyamina, Amine; Franchitto, Nicolas","year":2016,"journal":"The Journal of emergency medicine, 51(5), 544-551","doi":"10.1016/j.jemermed.2016.06.009","pmid":"27485997","tags":["addiction","harm-reduction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Over a seven-month period, a specialized addiction team in a French emergency department identified seven cases of cannabinoid hyperemesis syndrome (CHS) among cannabis users admitted for vomiting or abdominal pain.\n\nThe patients were young adults (mean age 24.7 years, mostly male). Five of seven reported compulsive hot bathing to relieve symptoms. All patients had negative biological workups, imaging, and endoscopy, indicating prior unnecessary testing.\n\nTHC blood levels were measured in four patients, with a mean concentration of 11.6 ng/mL. Treatment was symptomatic. Five of the seven patients began follow-up with the addiction team, suggesting the ED encounter created a pathway to ongoing care.","whyItMatters":"CHS remains under-diagnosed more than a decade after it was first described. This study demonstrates that embedding addiction specialists in emergency departments can improve early recognition, reduce unnecessary testing, and connect patients with ongoing treatment. The 71% follow-up rate (5 of 7 entering care) is notable for a population that often does not engage with addiction services.","specificNumbers":"7 patients identified over 7 months. Mean age 24.7 years. Mean THC blood level 11.6 ng/mL (4 patients tested). 5 of 7 (71%) compulsively used hot baths. 5 of 7 (71%) began addiction follow-up.","methodology":"This was a retrospective pilot study conducted at a French emergency department from June 2014 to January 2015. Cannabis users admitted for vomiting or abdominal pain were evaluated by a specialized addiction team and diagnosed with CHS. Medical records were then reviewed retrospectively.","limitations":"Very small sample size (7 patients). Retrospective design. Single center in France, which may not reflect practices elsewhere. The study cannot quantify how many CHS cases were missed during the same period. No control group to compare outcomes without addiction team involvement."},{"rthcId":"RTHC-01243","title":"Diagnostic Concordance between DSM-5 and ICD-10 Cannabis Use Disorders.","authors":"Proctor, Steven L; Williams, Daniel C; Kopak, Albert M; Voluse, Andrew C; Connolly, Kevin M; Hoffmann, Norman G","year":2016,"journal":"Addictive behaviors, 58, 117-22","doi":"10.1016/j.addbeh.2016.02.034","pmid":"26922159","tags":["addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared how the DSM-5 and ICD-10 diagnostic systems classify cannabis use disorders using data from 7,672 prison inmates. The two systems agreed well at the extremes: people with no DSM-5 diagnosis almost always had no ICD-10 diagnosis, and those with severe DSM-5 disorders almost always received an ICD-10 dependence diagnosis.\n\nThe disagreement emerged in the middle. Among those with a DSM-5 \"moderate\" cannabis use disorder, roughly half received an ICD-10 \"dependence\" diagnosis while the other half received the less severe \"harmful use\" label. This is clinically meaningful because the DSM-5 coding guidelines currently direct clinicians to assign ICD-10 dependence codes even for moderate diagnoses.","whyItMatters":"Since U.S. healthcare systems must use ICD-10 billing codes, the mapping between DSM-5 clinical diagnoses and ICD-10 codes has real-world consequences. When a moderate DSM-5 diagnosis gets coded as ICD-10 dependence, it may overstate the severity of the condition for billing, insurance, and clinical records purposes.","specificNumbers":"7,672 inmates assessed. Overall prevalence rates were comparable across systems. Concordance was high for no-diagnosis and severe categories. Approximately 50% of DSM-5 moderate cases mapped to ICD-10 dependence, and 50% to harmful use.","methodology":"Data came from routine clinical assessments of 6,871 male and 801 female inmates admitted to a state prison system between 2000 and 2003. DSM-5 and ICD-10 diagnostic determinations were made using algorithms corresponding to each system's criteria. Past 12-month prevalence rates were compared across systems.","limitations":"The sample consisted entirely of prison inmates, who may have higher rates and different patterns of substance use than the general population. The data were from 2000-2003, before the DSM-5 was published, so diagnostic criteria were applied retrospectively using algorithms. This limits the ecological validity of the findings."},{"rthcId":"RTHC-01244","title":"Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial.","authors":"Rabin, Rachel A; Ashare, Rebecca L; Schnoll, Robert A; Cinciripini, Paul M; Hawk, Larry W; Lerman, Caryn; Tyndale, Rachel F; George, Tony P","year":2016,"journal":"The American journal on addictions, 25(4), 291-6","doi":"10.1111/ajad.12382","pmid":"27187893","tags":["addiction","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 1,246 treatment-seeking tobacco smokers in a randomized trial, 220 were also current cannabis users. Participants received 12 weeks of either varenicline, nicotine patch, or placebo, all with behavioral counseling.\n\nAfter controlling for rate of nicotine metabolism, treatment arm, age, sex, alcohol use, and nicotine dependence level, cannabis users achieved biochemically verified 7-day abstinence from tobacco at the same rate as tobacco-only smokers.\n\nThis finding challenges the assumption that cannabis co-use undermines tobacco cessation efforts.","whyItMatters":"Many clinicians assume that cannabis use makes it harder to quit tobacco, which could lead to withholding treatment or adjusting expectations. This study suggests cannabis co-use is not a barrier to tobacco cessation success when appropriate treatment is provided.","specificNumbers":"1,246 tobacco smokers, 220 of whom were current cannabis users. Cannabis users had equal success rates for biochemically verified 7-day tobacco abstinence across all treatment arms.","methodology":"This was a secondary analysis of a large randomized controlled trial. 1,246 treatment-seeking tobacco smokers were randomly assigned to placebo, nicotine patch, or varenicline for 12 weeks with behavioral counseling. The primary outcome was biochemically verified 7-day point prevalence abstinence at end of treatment. Logistic regression controlled for multiple potential confounders.","limitations":"This was a secondary analysis, not the primary study aim. Cannabis use was defined as any use in the past 30 days, which includes a wide range of use patterns. The study did not examine whether cannabis use changed during or after the tobacco cessation attempt. Results reflect end-of-treatment outcomes, not long-term abstinence."},{"rthcId":"RTHC-01245","title":"Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes.","authors":"Ramaekers, J G; van Wel, J H; Spronk, D; Franke, B; Kenis, G; Toennes, S W; Kuypers, K P C; Theunissen, E L; Stiers, P; Verkes, R J","year":2016,"journal":"Brain imaging and behavior, 10(4), 1254-1263","doi":null,"pmid":"26667034","tags":["cognition","dopamine","genetics","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers gave 122 regular drug users acute doses of cannabis, cocaine, and placebo and measured cognitive impulsivity and brain connectivity. The effects of both drugs depended heavily on a specific genetic variant (DBH rs1611115) that controls how efficiently dopamine is converted to noradrenaline.\n\nIn participants with the low-activity variant (CT/TT genotype), both cannabis and cocaine increased cognitive impulsivity on a matching task and reduced functional connectivity between the nucleus accumbens (the brain's reward center) and multiple cortical regions. In participants with the high-activity variant (CC genotype), neither drug significantly affected impulsivity or connectivity.\n\nThe researchers propose that individuals with low-activity DBH genotypes experience a drug-induced hyperdopaminergic state that disrupts impulse control circuits, while those with high-activity genotypes have enough enzyme activity to buffer the dopamine surge.","whyItMatters":"This is one of the clearest demonstrations that genetics can determine whether a drug impairs cognitive function. The same dose of cannabis or cocaine had completely different effects depending on a single gene variant. This has implications for understanding why some people are more vulnerable to drug-related impairment and addiction.","specificNumbers":"122 drug users. Cannabis dose: 450 micrograms/kg THC. Cocaine dose: 300 mg. CT/TT genotype carriers showed increased impulsivity and reduced corticostriatal connectivity. CC genotype carriers showed no significant effects.","methodology":"This was a controlled within-subject study. 122 regular drug users received acute doses of cannabis (450 micrograms/kg THC), cocaine (300 mg), and placebo across sessions. Cognitive impulsivity was measured with the Matching Familiar Figures Test. Resting state fMRI was performed in a subset to measure functional connectivity. Participants were genotyped for DBH rs1611115.","limitations":"All participants were regular drug users, so results may not apply to occasional users or non-users. The study tested acute effects only; chronic effects may differ. The sample was genotyped after the study, so groups were not balanced by design. The fMRI subset was smaller than the full behavioral sample."},{"rthcId":"RTHC-01246","title":"Factors Affecting Drug Use During Incarceration: A Cross-Sectional Study of Opioid-Dependent Persons from India.","authors":"Rao, Ravindra; Mandal, Piyali; Gupta, Rishab; Ramshankar, Prashanth; Mishra, Ashwani; Ambekar, Atul; Jhanjee, Sonali; Dhawan, Anju","year":2016,"journal":"Journal of substance abuse treatment, 61, 13-7","doi":"10.1016/j.jsat.2015.08.009","pmid":"26470597","tags":["addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 101 opioid-dependent people attending drug treatment clinics who had contact with the criminal justice system. Most (85%) had been imprisoned at least once, and drug use continued during incarceration at high rates.\n\nBefore imprisonment, opioids were the most commonly used daily substance (68%), followed by cannabis (34%) and alcohol (22%). Inside prison, the pattern shifted: cannabis became the most common substance (35%), followed by opioids (19%). This shift likely reflects differences in drug availability within prisons.\n\nAfter release, 76% resumed substance use quickly, and 13% of opioid users experienced overdose soon after release, a well-documented period of heightened risk due to reduced tolerance.\n\nPrior cannabis use, injection drug use, and opioid use before imprisonment all predicted continued substance use while incarcerated.","whyItMatters":"This study documents that incarceration does not stop substance use and that drug availability within prisons shapes which substances people use. The shift from opioids to cannabis during imprisonment, and the high rate of opioid overdose after release, highlights the need for evidence-based drug treatment within the criminal justice system rather than relying on incarceration as a deterrent.","specificNumbers":"101 participants. 85% had been imprisoned. 65% used substances during imprisonment. Cannabis was most common in prison (35%), surpassing opioids (19%). 76% resumed use after release. 13% of opioid users experienced post-release overdose.","methodology":"Cross-sectional study using purposive sampling of 101 opioid-dependent individuals attending two community drug treatment clinics in India. A specifically designed assessment tool recorded criminal acts and substance use patterns before, during, and after their last imprisonment.","limitations":"This was a convenience sample from two clinics in India and may not represent all opioid-dependent incarcerated populations. Self-reported drug use during imprisonment may be underreported due to stigma and legal consequences. The cross-sectional design cannot establish causal relationships."},{"rthcId":"RTHC-01247","title":"ADHD and cannabis use in young adults examined using fMRI of a Go/NoGo task.","authors":"Rasmussen, Jerod; Casey, B J; van Erp, Theo G M; Tamm, Leanne; Epstein, Jeffery N; Buss, Claudia; Bjork, James M; Molina, Brooke S G; Velanova, Katerina; Mathalon, Daniel H; Somerville, Leah; Swanson, James M; Wigal, Tim; Arnold, L Eugene; Potkin, Steven G","year":2016,"journal":"Brain imaging and behavior, 10(3), 761-71","doi":"10.1007/s11682-015-9438-9","pmid":"26489976","tags":["youth","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared brain function during an impulse control task (Go/NoGo) across four groups: ADHD with and without cannabis use, and controls with and without cannabis use.\n\nParticipants with ADHD made significantly more errors on the task and showed less activation in frontal and parietal brain regions and frontal-striatal circuits, regardless of whether they used cannabis. Cannabis use alone did not significantly affect task performance or brain activation.\n\nHowever, an interaction emerged: control participants who used cannabis showed increased activation in the hippocampus and cerebellar vermis (areas rich in cannabinoid receptors) during successful impulse control. ADHD participants who used cannabis did not show this pattern. The researchers suggest controls may have recruited these regions as compensatory circuits, while ADHD participants could not.","whyItMatters":"This study helps disentangle the often-conflated effects of ADHD and cannabis on the brain. The finding that ADHD dominates the brain activation pattern regardless of cannabis use, while cannabis elicits compensatory activity only in non-ADHD brains, suggests that ADHD and cannabis use interact differently with impulse control circuitry than either condition alone would predict.","specificNumbers":"73 participants across 4 groups. ADHD participants made more commission errors. ADHD showed less frontoparietal/frontostriatal activation. Cannabis-using controls showed increased hippocampal and cerebellar activation. Cannabis-using ADHD participants did not show compensatory recruitment.","methodology":"Cross-sectional fMRI study comparing four groups: childhood ADHD with monthly cannabis use (n=25), childhood ADHD without cannabis use (n=25), local normative controls with cannabis use (n=11), and controls without cannabis use (n=12). Participants completed a Go/NoGo task during functional MRI scanning. Behavioral performance and brain activation patterns were analyzed for main effects and interactions.","limitations":"Small group sizes, particularly the control groups (11 and 12 participants). Cross-sectional design prevents causal conclusions. Cannabis use was defined as monthly or more, which includes a wide range of use patterns. The study focused on childhood ADHD, so results may not apply to adult-onset attention difficulties."},{"rthcId":"RTHC-01248","title":"Attentional dysfunction in abstinent long-term cannabis users with and without schizophrenia.","authors":"Rentzsch, Johannes; Stadtmann, Ada; Montag, Christiane; Kunte, Hagen; Plöckl, Doris; Hellweg, Rainer; Gallinat, Jürgen; Kronenberg, Golo; Jockers-Scherübl, Maria Christiane","year":2016,"journal":"European archives of psychiatry and clinical neuroscience, 266(5), 409-21","doi":"10.1007/s00406-015-0616-y","pmid":"26182894","tags":["cognition","psychosis","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers measured attention-related brainwave responses (P300) in four groups: schizophrenia patients with and without chronic cannabis use, and healthy controls with and without chronic cannabis use. All cannabis users had been abstinent for at least 28 days.\n\nAs expected, schizophrenia patients overall showed reduced P300 responses. But the cannabis effect was unexpected: chronic cannabis use was associated with reduced P300 responses in the healthy control group, but not in the schizophrenia group.\n\nIn healthy cannabis users, the P300 reduction correlated with both the amount and duration of cannabis use. In schizophrenia patients who used cannabis, no such correlation existed. The P300 differences between cannabis users and non-users in the healthy group were statistically significant, while the schizophrenia group showed no significant difference.","whyItMatters":"The finding that cannabis affects attention differently in people with and without schizophrenia has a provocative implication: it suggests the endocannabinoid system may already be altered in schizophrenia, making it less responsive to additional cannabinoid insult. This aligns with theories that endocannabinoid dysfunction is part of schizophrenia's underlying biology.","specificNumbers":"80 participants in 4 groups of 20. Mean cannabis use: 8.3 years (schizophrenia group), 9.1 years (controls). Minimum 28 days abstinent. Healthy cannabis users showed dose-dependent left-hemispheric P300 reduction (r = -0.50 for amount, r = -0.57 for duration).","methodology":"The study used auditory novelty and oddball P300 evoked potential paradigms in 80 participants divided into four groups of 20: schizophrenia with chronic cannabis use (abstinent 28+ days), schizophrenia without, healthy controls with chronic cannabis use (abstinent 28+ days), and healthy controls without. Mean duration of regular cannabis use was 8.3 years (schizophrenia group) and 9.1 years (control group).","limitations":"Cross-sectional design cannot establish causation. The 28-day abstinence requirement may not fully eliminate residual cannabis effects. The study included both first-episode and chronic schizophrenia patients, mixing different illness stages. The sample size (20 per group) limits statistical power."},{"rthcId":"RTHC-01249","title":"Effect of cannabis smoking on lung function and respiratory symptoms: a structured literature review.","authors":"Ribeiro, Luis Ig; Ind, Philip W","year":2016,"journal":"NPJ primary care respiratory medicine, 26, 16071","doi":"10.1038/npjpcrm.2016.71","pmid":"27763599","tags":["respiratory"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This structured literature review found a surprising divergence between cannabis and tobacco effects on lung function. Both cause symptoms of chronic bronchitis (cough, sputum production). However, while tobacco progressively reduces forced expiratory volume (FEV1) and forced vital capacity (FVC), recent large studies showed cannabis smoking was associated with increased FVC.\n\nThe mechanism behind this paradoxical finding is unclear, but the authors suggest acute bronchodilator effects of cannabis (opening airways) and anti-inflammatory properties may play a role.\n\nThe review also noted reports of bullous lung disease (enlarged air spaces in the lungs) associated with cannabis smoking, typically in younger patients than would be expected with tobacco-related emphysema. These findings come primarily from case reports and small series.","whyItMatters":"As cannabis use increases, understanding its respiratory effects is important for both individual health decisions and public health guidance. The finding that cannabis may not cause the same progressive lung function decline as tobacco challenges assumptions about inhaling any combusted plant material.","specificNumbers":"Cannabis smoking was associated with increased FVC in large population studies. Bullous lung disease has been reported in cannabis smokers at younger ages than typical for tobacco-related emphysema.","methodology":"Structured literature review examining published studies on the effects of cannabis smoking on lung function and respiratory symptoms. The review considered both large population-based studies and case reports, addressing the challenge of confounding from concurrent tobacco use.","limitations":"Long-term cannabis-only smoking studies are rare because most cannabis smokers also use tobacco. The review notes this confounding factor as a major limitation across the literature. Case reports of bullous lung disease cannot establish how common this condition is among cannabis smokers."},{"rthcId":"RTHC-01250","title":"Is the medical use of cannabis a therapeutic option for children?","authors":"Rieder, Michael J","year":2016,"journal":"Paediatrics & child health, 21(1), 31-4","doi":null,"pmid":"26941559","tags":["medical-cannabis","youth","epilepsy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This clinical review examined the evidence for medical cannabis use in children, prompted by case reports of children with refractory epilepsy responding to cannabis-based treatments. The author concluded that overall evidence is insufficient to support either the efficacy or safety of cannabis use for any indication in children.\n\nThe review emphasized several concerns: an increasing body of data suggests possible harm, particularly in conditions where the developing brain may be vulnerable. Smoking is explicitly rejected as an acceptable delivery method for children. The review also cautioned that therapeutic use in specific medical cases should not be used to justify recreational cannabis use by adolescents.\n\nDespite these concerns, the author acknowledged that exceptional cases exist where standard treatments have failed, and offered recommendations for therapeutic use in these circumstances: always under careful individual evaluation, within well-designed research studies, and with ongoing monitoring for both safety and efficacy.","whyItMatters":"Medical cannabis for children is among the most contentious topics in pediatric medicine. This review from a mainstream pediatric journal represents the medical establishment's cautious position: acknowledge that some children may benefit, particularly those with refractory epilepsy, but insist on rigorous evaluation and monitoring rather than broad access.","specificNumbers":"No specific numerical data were presented; the review synthesized existing evidence and provided clinical recommendations.","methodology":"This was a narrative clinical review published in Paediatrics & Child Health (a journal of the Canadian Paediatric Society), summarizing available evidence on cannabis use in pediatric populations and providing clinical recommendations.","limitations":"This is a narrative review reflecting one author's interpretation of available evidence, published before many subsequent clinical trials of pharmaceutical-grade CBD products in pediatric epilepsy. The review predates the FDA approval of Epidiolex (cannabidiol) for pediatric seizure disorders."},{"rthcId":"RTHC-01251","title":"Cannabinoid 2 (CB2) receptor agonism reduces lithium chloride-induced vomiting in Suncus murinus and nausea-induced conditioned gaping in rats.","authors":"Rock, Erin M; Boulet, Nathalie; Limebeer, Cheryl L; Mechoulam, Raphael; Parker, Linda A","year":2016,"journal":"European journal of pharmacology, 786, 94-99","doi":"10.1016/j.ejphar.2016.06.001","pmid":"27263826","tags":["neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested HU-308, a compound that selectively activates CB2 receptors (unlike THC, which primarily activates CB1 receptors in the brain), for anti-nausea and anti-vomiting effects.\n\nIn shrews (Suncus murinus, one of the few small animals that can vomit), HU-308 reduced lithium chloride-induced vomiting at doses of 2.5 and 5 mg/kg. In rats, the same compound suppressed conditioned gaping, a behavior that specifically models nausea rather than vomiting.\n\nBoth effects were blocked when animals were pre-treated with AM630, a selective CB2 receptor antagonist, confirming the effects were specifically mediated through CB2 receptors.\n\nThese are the first published findings demonstrating that a selective CB2 agonist can reduce nausea in animal models.","whyItMatters":"Cannabis-based anti-nausea treatments currently work through CB1 receptors, which also produce psychoactive effects like euphoria, impaired memory, and altered coordination. If CB2-targeted compounds can reduce nausea without these side effects, they could offer a cleaner therapeutic option for chemotherapy patients and others dealing with severe nausea.","specificNumbers":"HU-308 at 2.5 and 5 mg/kg reduced vomiting in shrews. HU-308 at 5 mg/kg suppressed conditioned gaping in rats. Both effects were blocked by the CB2 antagonist AM630.","methodology":"Two animal models were used. Lithium chloride-induced vomiting was measured in Suncus murinus (house musk shrews). Conditioned gaping, a validated model of nausea-related behavior, was measured in rats. The selective CB2 agonist HU-308 was tested at multiple doses, and the CB2 antagonist AM630 was used to confirm receptor specificity.","limitations":"HU-308 reduced but did not completely block vomiting or nausea-related behavior. These are animal models, and translation to human nausea is uncertain. The study did not compare CB2 agonist efficacy to existing anti-nausea treatments or CB1-based cannabinoids."},{"rthcId":"RTHC-01252","title":"The endocannabinoid system in the baboon (Papio spp.) as a complex framework for developmental pharmacology.","authors":"Rodriguez-Sanchez, Iram P; Guindon, Josee; Ruiz, Marco; Tejero, M Elizabeth; Hubbard, Gene; Martinez-de-Villarreal, Laura E; Barrera-Saldaña, Hugo A; Dick, Edward J; Comuzzie, Anthony G; Schlabritz-Loutsevitch, Natalia E","year":2016,"journal":"Neurotoxicology and teratology, 58, 23-30","doi":"10.1016/j.ntt.2016.06.006","pmid":"27327781","tags":["neuroscience","pregnancy"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers cloned and characterized the genes encoding key components of the endocannabinoid system in baboons and compared them to human versions. They found that while CB1 receptor genes were highly conserved between species, there were meaningful differences in other components.\n\nThe CB2 receptor gene showed a difference in the exact region containing the only known clinically relevant human polymorphism, suggesting this receptor may function differently in baboons than humans.\n\nThe enzyme DAGL-alpha, which helps produce the endocannabinoid 2-AG, showed differences near critical phosphorylation sites. These differences could affect how the enzyme is regulated.\n\nThe findings mean that studies testing cannabis effects in baboons and other non-human primates need to account for these species-specific differences, particularly in developmental toxicology studies relevant to cannabis use during pregnancy.","whyItMatters":"Non-human primates are used to study the developmental effects of cannabis, particularly for understanding risks during pregnancy. If their endocannabinoid systems differ from humans in functionally important ways, safety conclusions from these studies may not directly apply to human pregnancy.","specificNumbers":"CNR1 (CB1 receptor gene) was the best conserved between species. CB2 receptor showed a difference at the only known clinically relevant human polymorphism site. All DAGL-alpha differences were near phosphorylation sites in the hydroxylase domain.","methodology":"Researchers used PCR to amplify endocannabinoid system genes (CNR1, CNR2, FAAH, MAGL, DAGL-alpha) from baboon tissues. The sequences were cloned, verified, and compared to known human sequences including single nucleotide polymorphisms and haplotypes.","limitations":"This was a comparative genomics study focused on gene structure, not function. The actual functional consequences of the sequence differences have not been tested. The sample size of baboon tissues was not specified. The study characterized cDNA sequences but did not measure protein expression or receptor binding differences."},{"rthcId":"RTHC-01253","title":"Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.","authors":"Rohleder, Cathrin; Müller, Juliane K; Lange, Bettina; Leweke, F M","year":2016,"journal":"Frontiers in pharmacology, 7, 422","doi":null,"pmid":"27877130","tags":["cbd","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the evidence for cannabidiol (CBD) as a potential antipsychotic medication. While THC is associated with increased psychosis risk, CBD appears to have the opposite effect.\n\nIn animal studies, CBD showed antipsychotic properties in rodents and rhesus monkeys, though results varied depending on the behavioral test used, treatment duration, and experimental conditions.\n\nThe most striking finding came from a randomized, double-blind controlled clinical trial in which CBD produced antipsychotic effects comparable to amisulpride (a standard antipsychotic medication) in patients with acute schizophrenia. The crucial difference was side effects: while amisulpride caused the typical antipsychotic side effects (weight gain, metabolic changes, movement disorders), CBD's side effect profile was similar to placebo.\n\nThe clinical improvement from CBD was significantly associated with elevated levels of anandamide, an endocannabinoid, suggesting CBD may work by boosting the body's own cannabinoid system rather than through direct receptor binding.","whyItMatters":"Current antipsychotic medications all share a similar mechanism (dopamine receptor blockade) and come with significant side effects that lead many patients to stop taking them. CBD appears to work through an entirely different mechanism (endocannabinoid modulation) and demonstrated a dramatically better side effect profile, potentially offering the first mechanistically distinct antipsychotic in decades.","specificNumbers":"One RCT showed CBD was comparable to amisulpride for antipsychotic efficacy. CBD's side effect profile was similar to placebo. Clinical improvement correlated with elevated anandamide levels.","methodology":"Critical review of published literature including animal behavioral studies, individual case reports, and the first randomized double-blind controlled clinical trial of CBD for schizophrenia. The review examined both efficacy data and proposed mechanisms of action.","limitations":"Only one RCT existed at the time of this review. Animal study results were inconsistent across different experimental conditions. The mechanisms of CBD's antipsychotic action were not fully understood. The review was published before subsequent larger clinical trials could confirm or challenge the initial findings."},{"rthcId":"RTHC-01254","title":"Decision-Making Does not Moderate the Association between Cannabis Use and Body Mass Index among Adolescent Cannabis Users.","authors":"Ross, J Megan; Graziano, Paulo; Pacheco-Colón, Ileana; Coxe, Stefany; Gonzalez, Raul","year":2016,"journal":"Journal of the International Neuropsychological Society : JINS, 22(9), 944-949","doi":null,"pmid":"27079834","tags":["youth","appetite"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a sample of 238 adolescent cannabis users aged 14 to 18 (77% Hispanic), researchers found that greater lifetime cannabis use was associated with higher body mass index and a greater likelihood of being classified as overweight or obese.\n\nThe researchers hypothesized that decision-making abilities might moderate this relationship, since impulsive decision-making could lead to both more cannabis use and poorer dietary choices. However, decision-making performance did not interact with cannabis use to predict BMI, and was not independently associated with BMI either.\n\nThe association between cannabis use and higher BMI held even after controlling for depression, alcohol use, nicotine use, race, ethnicity, and IQ.","whyItMatters":"The relationship between cannabis and body weight is complex and contested. While some adult studies link cannabis use to lower BMI, this study found the opposite pattern in adolescents. This age-specific difference is important because adolescent weight trajectories have lifelong health implications.","specificNumbers":"238 adolescent cannabis users. More lifetime cannabis use was associated with higher BMI. The relationship was robust after controlling for depression, alcohol, nicotine, race/ethnicity, and IQ. Decision-making was not a moderator.","methodology":"Cross-sectional study of 238 adolescent cannabis users (ages 14-18, 56% male, 77% Hispanic) without significant developmental, neurological, or psychiatric disorders. Decision-making was measured using a validated behavioral task. BMI and weight classification were the outcome measures. Analysis controlled for multiple potential confounders.","limitations":"Cross-sectional design prevents determining causation. The sample was predominantly Hispanic, limiting generalizability. The study only included cannabis users, so it cannot compare users to non-users. Physical activity and detailed dietary data were not measured. The decision-making measure may not capture all relevant aspects of impulsivity."},{"rthcId":"RTHC-01255","title":"Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes.","authors":"Russo, Ethan B","year":2016,"journal":"Cannabis and cannabinoid research, 1(1), 154-165","doi":"10.1089/can.2016.0009","pmid":"28861491","tags":["medical-cannabis","pain","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Dr. Ethan Russo revisited his 2001 hypothesis that a deficiency in endocannabinoid tone could underlie several treatment-resistant pain syndromes. Since the original proposal, new evidence has strengthened the case.\n\nStatistically significant differences in cerebrospinal fluid anandamide levels have now been documented in migraine sufferers. Advanced brain imaging has demonstrated endocannabinoid system hypofunction in PTSD. Additional studies have shown that these conditions share features of hyperalgesia (heightened pain sensitivity) and central sensitization.\n\nThe theory proposes that all humans have a baseline endocannabinoid tone reflecting their levels of anandamide and 2-AG, the density of their cannabinoid receptors, and their enzyme activity. In some people, whether from genetic factors or acquired conditions, this tone drops below functional levels, producing pathological states.\n\nThe overlapping occurrence of migraine, fibromyalgia, and IBS in the same patients, their shared features of heightened pain sensitivity, and their common resistance to standard treatments all fit a shared underlying mechanism. Clinical data showing symptom improvement with cannabinoid treatment and lifestyle approaches that boost endocannabinoid tone further support the theory.","whyItMatters":"Millions of people suffer from migraine, fibromyalgia, and IBS, conditions that are often dismissed as psychosomatic and resist standard treatment. If an underlying endocannabinoid deficiency is the common thread, it validates these conditions as biological rather than psychological and opens a rational therapeutic pathway through endocannabinoid system modulation.","specificNumbers":"Statistically significant anandamide level differences documented in migraine patients' cerebrospinal fluid. Endocannabinoid system hypofunction confirmed via advanced imaging in PTSD.","methodology":"This was a comprehensive review updating the 2001 clinical endocannabinoid deficiency hypothesis with evidence published in the intervening 15 years. The author examined new data from cerebrospinal fluid studies, neuroimaging, genetic studies, and clinical trials relevant to the hypothesis.","limitations":"While the hypothesis has gained supporting evidence since 2001, it remains a theory. No definitive diagnostic test for endocannabinoid deficiency exists. The evidence is correlational: low endocannabinoid levels in these conditions does not prove the deficiency causes the condition. Large clinical trials testing this framework are still needed."},{"rthcId":"RTHC-01256","title":"Should we care about sativex-induced neurobehavioral effects? A 6-month follow-up study.","authors":"Russo, M; De Luca, R; Torrisi, M; Rifici, C; Sessa, E; Bramanti, P; Naro, A; Calabrò, R S","year":2016,"journal":"European review for medical and pharmacological sciences, 20(14), 3127-33","doi":null,"pmid":"27460745","tags":["medical-cannabis","cognition"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Forty cannabis-naive multiple sclerosis patients were assessed with comprehensive neuropsychological testing before starting Sativex treatment and again at 1 and 6 months. The study specifically targeted patients who had never used cannabis to isolate the drug's cognitive effects from pre-existing cannabis exposure.\n\nAfter 6 months of Sativex use, no significant neurobehavioral impairment was observed across the group. Only one patient out of 40 showed cognitive changes, confirming that significant side effects are uncommon but not impossible.\n\nThe authors recommended that MS patients should undergo extensive neuropsychological evaluation before starting Sativex, to enable detection of any rare but important individual adverse effects.","whyItMatters":"A major concern about cannabis-based medications is their potential to impair cognition, which is particularly relevant for MS patients who already face cognitive challenges from their disease. This study provides reassurance that Sativex, used as prescribed for spasticity, does not add significant cognitive burden.","specificNumbers":"40 cannabis-naive MS patients. No significant neurobehavioral impairment at 1 or 6 months. 1 out of 40 patients showed cognitive changes.","methodology":"Prospective cohort study of 40 cannabis-naive MS patients. All underwent clinical and neuropsychological assessment at baseline and after 1 and 6 months of Sativex treatment. Testing covered spasticity, associated symptoms, and the cognitive and psychiatric domains commonly impaired in MS.","limitations":"The sample was relatively small (40 patients). There was no placebo control group, so any cognitive changes from MS progression itself cannot be isolated from treatment effects. Six months may not be long enough to detect slow-onset cognitive effects. The single patient who showed changes demonstrates that individual variation exists."},{"rthcId":"RTHC-01257","title":"Efficacy evaluation of the school program Unplugged for drug use prevention among Brazilian adolescents.","authors":"Sanchez, Zila M; Sanudo, Adriana; Andreoni, Solange; Schneider, Daniela; Pereira, Ana Paula D; Faggiano, Fabrizio","year":2016,"journal":"BMC public health, 16(1), 1206","doi":null,"pmid":"27899107","tags":["youth","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers evaluated the Unplugged program, a European school-based drug prevention curriculum, adapted for Brazilian public middle schools. The program had no measurable effect on 11-12 year olds, but showed promising results for 13-15 year olds.\n\nAmong 13-15 year old marijuana users, 85.7% in the intervention group transitioned from use to non-use, compared to only 28.6% in the control group (OR = 17.5). Students who received the program maintained their pre-program drug use levels, while control group students showed significant increases in marijuana use and binge drinking over the same period.\n\nThe program consisted of 12 weekly classes focused on life skills, social influence resistance, and knowledge about drugs.","whyItMatters":"Most Brazilian schools lack structured drug prevention programs. This study demonstrates that a well-designed, culturally adapted program can reduce marijuana use among teens in the age group most likely to initiate use. The striking difference in transition rates (85.7% vs 28.6%) suggests meaningful impact.","specificNumbers":"2,185 students in 16 schools across 3 cities. 12 weekly program sessions. Among 13-15 year old marijuana users, 85.7% of intervention participants stopped using vs 28.6% of controls (OR = 17.5, p = 0.039).","methodology":"Non-randomized controlled trial conducted in 2013 with 2,185 students across 16 public schools in 3 Brazilian cities. The intervention group received 12 weekly Unplugged classes; the control group received no prevention programming. Multilevel analyses assessed changes in drug consumption over time and between groups.","limitations":"Non-randomized design introduces potential selection bias. The marijuana user subgroup was small, making the 85.7% vs 28.6% comparison less reliable despite statistical significance. Short follow-up period. The control schools had no prevention programming at all, which inflates the apparent effect size compared to an active control."},{"rthcId":"RTHC-01258","title":"Adolescent Δ(9)-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats.","authors":"Scherma, Maria; Dessì, Christian; Muntoni, Anna Lisa; Lecca, Salvatore; Satta, Valentina; Luchicchi, Antonio; Pistis, Marco; Panlilio, Leigh V; Fattore, Liana; Goldberg, Steven R; Fratta, Walter; Fadda, Paola","year":2016,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(5), 1416-26","doi":"10.1038/npp.2015.295","pmid":"26388146","tags":["youth","addiction","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Adolescent rats received increasing doses of THC for 11 consecutive days during the equivalent of human adolescence. When these rats reached adulthood, they showed enhanced acquisition of cannabinoid self-administration compared to controls who had received vehicle instead of THC.\n\nThe neurobiological explanation came from parallel experiments: THC-exposed rats showed a blunted dopamine response in their reward circuits. The cannabinoid agonist WIN55,212-2 was less effective at stimulating dopamine neuron firing in the ventral tegmental area and less effective at increasing dopamine release in the nucleus accumbens shell.\n\nThis creates a paradox that makes sense in the addiction context: the reward system becomes less responsive, so the animal needs more cannabinoid stimulation to achieve the same rewarding effect, driving increased self-administration.","whyItMatters":"This study provides a mechanistic explanation for why adolescent cannabis exposure might increase later addiction risk. The finding that early THC exposure dulls the reward system and simultaneously increases cannabinoid-seeking behavior mirrors what is seen in human addiction: tolerance to reward drives escalating use.","specificNumbers":"THC treatment spanned postnatal days 45-55 (rat adolescence). Doses were escalated over 11 days with twice-daily administration. THC-exposed rats showed enhanced acquisition of WIN55,212-2 self-administration in adulthood. Dopamine neuron firing and nucleus accumbens dopamine release were both reduced in THC-exposed animals.","methodology":"Male adolescent rats received escalating doses of THC (or vehicle) twice daily for 11 days during postnatal days 45-55. In adulthood, behavioral experiments measured intravenous self-administration of WIN55,212-2. Separate groups underwent electrophysiological recordings of dopamine neurons and microdialysis to measure dopamine release in the nucleus accumbens.","limitations":"This was a rat study using specific doses and a synthetic cannabinoid agonist for self-administration. The THC doses and exposure pattern may not reflect typical human adolescent use. Rats do not self-administer THC itself well, so a synthetic cannabinoid was used instead, which may not perfectly model human cannabis use."},{"rthcId":"RTHC-01259","title":"Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.","authors":"Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran; Makriyannis, Alexandros; Le Foll, Bernard; Bergman, Jack; Goldberg, Steven R; Justinova, Zuzana","year":2016,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(9), 2283-93","doi":"10.1038/npp.2016.27","pmid":"26888056","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers compared two types of CB1 receptor blockers in squirrel monkeys: rimonabant (an inverse agonist that was withdrawn from the market due to psychiatric side effects) and AM4113 (a newer neutral antagonist).\n\nBoth compounds reduced nicotine and THC self-administration and prevented relapse triggered by drug cues or priming doses. Neither compound affected cocaine or food-motivated behavior, demonstrating selectivity for cannabinoid and nicotine reward.\n\nHowever, both rimonabant and AM4113 did reduce cue-induced relapse for cocaine, suggesting endocannabinoid involvement in how drug-associated cues trigger craving across different drugs.\n\nThe key clinical implication is that neutral antagonists like AM4113 may provide the addiction-reducing benefits of rimonabant without the depression and anxiety side effects that led to rimonabant's withdrawal from the market.","whyItMatters":"Tobacco and cannabis are the two most commonly used addictive substances worldwide. A single medication that could reduce both addictions simultaneously would be enormously valuable. Rimonabant showed this potential but was too dangerous. Neutral antagonists may preserve the benefit while eliminating the psychiatric risk.","specificNumbers":"Both rimonabant and AM4113 reduced nicotine and THC self-administration. Neither affected cocaine or food reinforcement. Both reduced cue-induced reinstatement across all drug types. AM4113 is expected to have fewer psychiatric side effects than rimonabant.","methodology":"Squirrel monkey study using intravenous self-administration paradigms for nicotine, THC, and cocaine. Researchers measured maintenance of drug-taking behavior and reinstatement of drug-seeking after extinction (modeling relapse). Both rimonabant and AM4113 were tested against each drug and food reinforcement.","limitations":"Primate self-administration studies have good translational value but are not human clinical trials. AM4113 has not been tested in humans. The assumption that neutral antagonists will have fewer psychiatric side effects than inverse agonists has not been clinically confirmed. The sample size was small (typical for primate studies)."},{"rthcId":"RTHC-01260","title":"Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys.","authors":"Schindler, Charles W; Scherma, Maria; Redhi, Godfrey H; Vadivel, Subramanian K; Makriyannis, Alexandros; Goldberg, Steven R; Justinova, Zuzana","year":2016,"journal":"Psychopharmacology, 233(10), 1867-77","doi":"10.1007/s00213-016-4211-3","pmid":"26803499","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AM404 is an anandamide transport inhibitor that was being studied for its ability to reduce nicotine-seeking behavior. This study tested whether AM404 itself might be rewarding and found that it was.\n\nSquirrel monkeys readily self-administered AM404 intravenously, with the classic inverted U-shaped dose-response curve seen with drugs of abuse (peak responding at 10 micrograms/kg). AM404 also triggered reinstatement of drug-seeking behavior in monkeys previously trained to self-administer THC, anandamide, or cocaine.\n\nBoth effects were blocked by rimonabant (CB1 antagonist), confirming they were mediated through the endocannabinoid system. The FAAH inhibitor URB597 enhanced AM404's reinforcing effects, supporting a role for anandamide in driving self-administration.\n\nAnother anandamide transport inhibitor (VDM11) also maintained self-administration, suggesting this is a class effect rather than specific to AM404.","whyItMatters":"Endocannabinoid-boosting compounds are being explored as potential treatments for various conditions including addiction and pain. This study raises an important safety flag: compounds that increase brain endocannabinoid levels may themselves carry abuse potential, because the endocannabinoid system is part of the brain's reward circuitry.","specificNumbers":"AM404 self-administration peaked at 10 micrograms/kg/injection. AM404 reinstated drug-seeking previously reinforced by THC, anandamide, or cocaine. Both effects blocked by rimonabant (0.3 mg/kg). URB597 (0.3 mg/kg) potentiated AM404 reinforcing effects.","methodology":"Squirrel monkey intravenous self-administration study using fixed-ratio schedules. Monkeys with prior experience self-administering anandamide or cocaine were tested with AM404 substitution. Reinstatement experiments tested whether AM404 could trigger relapse to previously extinguished drug-seeking. Pharmacological antagonism with rimonabant confirmed mechanism. The FAAH inhibitor URB597 was used to test whether enhancing anandamide levels potentiated the effects.","limitations":"Primate self-administration does not necessarily predict human abuse patterns. The monkeys had prior experience with other drugs, which could sensitize them to reward from AM404. The clinical relevance depends on whether therapeutic doses in humans would reach reinforcing levels. AM404 also has some direct activity at other targets (TRPV1 receptors)."},{"rthcId":"RTHC-01261","title":"Adolescent social rejection alters pain processing in a CB1 receptor dependent manner.","authors":"Schneider, Peggy; Pätz, Monique; Spanagel, Rainer; Schneider, Miriam","year":2016,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 26(7), 1201-12","doi":"10.1016/j.euroneuro.2016.04.007","pmid":"27157075","tags":["pain","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers modeled adolescent social rejection by pairing adolescent Wistar rats with Fischer 344 rats, a strain known for being unresponsive to play solicitations. The Wistar adolescents showed clear signs of social distress: increased ultrasonic vocalizations at 50 kHz (associated with positive/seeking states) and increased play attacks, suggesting they were trying harder to engage their unresponsive partners.\n\nAfter these experiences, the socially rejected rats showed decreased pain sensitivity to thermal stimuli. A low dose of the CB1 receptor blocker SR141716 given before the social encounter prevented both the compensatory social behaviors and the subsequent pain changes.\n\nThis demonstrates that the endocannabinoid system mediates the link between social pain (rejection) and physical pain processing, providing a biological explanation for why social and physical pain overlap.","whyItMatters":"The overlap between social and physical pain is well documented in humans but poorly understood mechanistically. This study identifies the endocannabinoid system as a key mediator, suggesting that the same system activated by cannabis is involved in processing the pain of social rejection during the sensitive adolescent period.","specificNumbers":"Wistar rats paired with Fischer 344 partners showed increased 50 kHz ultrasonic vocalizations and increased play attacks. Social rejection reduced thermal pain sensitivity. Sub-threshold CB1 blockade prevented both social and pain-related effects.","methodology":"Female adolescent Wistar rats were paired with either same-strain partners (control) or Fischer 344 rats (social rejection model) for acute social interaction sessions. Behavioral analysis included play attacks, ultrasonic vocalizations, and pain sensitivity testing. The CB1 receptor antagonist SR141716 was administered at a sub-threshold dose before social encounters to test endocannabinoid involvement.","limitations":"This was a rodent study, and social dynamics in rats may not fully model human adolescent rejection. Only female rats were tested. The CB1 blocker was given before the social encounter, so it is unclear whether it would reverse already-established changes. The Fischer 344 pairing is a model of social rejection but not identical to human peer rejection."},{"rthcId":"RTHC-01262","title":"Cannabinoids: Medical implications.","authors":"Schrot, Richard J; Hubbard, John R","year":2016,"journal":"Annals of medicine, 48(3), 128-41","doi":"10.3109/07853890.2016.1145794","pmid":"26912385","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review covered the medical evidence for cannabinoid therapeutics across multiple conditions. Chronic cancer pain, neuropathic pain, and certain MS symptoms had the strongest evidence supporting cannabinoid efficacy. For these conditions, well-characterized cannabinoid medications have met FDA standards.\n\nThe review emphasized patient selection as critical: cannabinoid therapy is most appropriate when standard treatments have failed for a debilitating condition. Physicians certifying medical cannabis must inform patients about acute effects (impaired memory, coordination, and judgment), potential chronic effects (cannabis use disorder, cognitive impairment, chronic bronchitis), and social risks (workplace issues, driving impairment).\n\nThe review also noted that novel approaches to manipulating the endocannabinoid system are being explored to maximize benefits while minimizing harmful effects, moving beyond simply administering THC.","whyItMatters":"As medical cannabis programs expand, physicians need clear guidance on where the evidence supports use and how to counsel patients about risks. This review provides that framework, distinguishing between conditions with strong evidence and those with insufficient data.","specificNumbers":"Chronic cancer and neuropathic pain and certain MS symptoms had substantial evidence. Cannabis use disorder, cognitive impairment, and chronic bronchitis are documented chronic risks. Acute risks include impaired memory, coordination, judgment, and increased motor vehicle accident risk.","methodology":"Comprehensive narrative review published in Annals of Medicine, covering the history of medical cannabis, the endocannabinoid system, approved cannabinoid medications, medical conditions with evidence, adverse effects, and physician certification considerations.","limitations":"Narrative review format means the evidence selection and interpretation reflect the authors' perspective. The review predates several large clinical trials and regulatory changes. The rapid evolution of cannabis products (higher potency, new delivery methods) may not be fully captured."},{"rthcId":"RTHC-01263","title":"The association between cannabis use and suicidality among men and women: A population-based longitudinal study.","authors":"Shalit, Nadav; Shoval, Gal; Shlosberg, Dan; Feingold, Daniel; Lev-Ran, Shaul","year":2016,"journal":"Journal of affective disorders, 205, 216-224","doi":"10.1016/j.jad.2016.07.010","pmid":"27449554","tags":["mental-health","sex-differences","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Using data from over 30,000 participants followed over 3 years, researchers found strikingly different patterns between men and women in the cannabis-suicidality relationship.\n\nIn men, cannabis use predicted the development of new suicidal ideation. Any cannabis use nearly doubled the risk (AOR = 1.91), and daily use increased the risk more than 4-fold (AOR = 4.28). This association was not found in women.\n\nThe direction reversed for women: baseline suicidal ideation predicted the initiation of cannabis use (AOR = 2.34). Women who were already experiencing suicidal thoughts were more likely to start using cannabis, while this pattern was not found in men.\n\nNeither direction showed a significant association with actual suicide attempts in either sex.","whyItMatters":"This is one of the first studies to examine sex differences in the cannabis-suicidality relationship bidirectionally. The finding that the direction of the relationship is opposite in men and women has important clinical implications: in men, cannabis use may be a risk factor for developing suicidal thoughts, while in women, suicidal thoughts may drive cannabis use as a form of self-medication.","specificNumbers":"Men: any cannabis use AOR = 1.91 (1.02-3.56) for suicidality. Daily use AOR = 4.28 (1.32-13.82). Women: baseline suicidality AOR = 2.34 (1.42-3.87) for cannabis initiation. Over 30,000 participants followed for 3 years.","methodology":"Longitudinal population-based study using Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Bidirectional analyses were conducted separately by sex. Cannabis users (n=963) were compared with non-users (n=30,586), and suicidal individuals (n=1,805) were compared with non-suicidal individuals (n=25,729). Multivariate logistic regression controlled for multiple covariates.","limitations":"Suicidality was assessed only in individuals who reported depressed mood or anhedonia, potentially missing cases in non-depressed individuals. The wide confidence intervals for daily cannabis use in men (1.32-13.82) reflect relatively few daily users with suicidality outcomes. Observational data cannot prove causation even with longitudinal design. Self-reported cannabis use may be underreported."},{"rthcId":"RTHC-01264","title":"Hair analysis and its concordance with self-report for drug users presenting in emergency department.","authors":"Sharma, Gaurav; Oden, Neal; VanVeldhuisen, Paul C; Bogenschutz, Michael P","year":2016,"journal":"Drug and alcohol dependence, 167, 149-55","doi":"10.1016/j.drugalcdep.2016.08.007","pmid":"27522871","tags":["addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared hair analysis results with self-reported drug use (Timeline Follow Back) for four drug classes across 1,285 adult emergency department patients with moderate to severe drug problems.\n\nHair analysis and self-report showed high concordance for cannabis and street opioids but low to moderate concordance for cocaine and prescribed opioids. An important pattern emerged: people were significantly more accurate in reporting their primary drug of choice. Under-reporting of use given a positive hair test was always lower for the person's primary drug compared to secondary drugs.\n\nConversely, over-reporting of use given a negative hair test was higher for the drug of choice, suggesting some people reported using their preferred drug more than they actually did, or that hair analysis may not capture all patterns of use.","whyItMatters":"Clinical trials of addiction treatments rely on self-reported drug use, and there are longstanding concerns about accuracy. This study demonstrates that for cannabis specifically, self-report is quite reliable when compared to biological verification via hair analysis. This validates cannabis use data from clinical trials that relied on self-report.","specificNumbers":"1,285 participants from 6 US academic hospitals. High concordance for cannabis and street opioids. Low to moderate concordance for cocaine and prescribed opioids. Under-reporting was always lower for the participant's primary drug of choice.","methodology":"Secondary analysis of a National Drug Abuse Treatment Clinical Trials Network randomized trial (NCT01207791). 1,285 adult ED patients with moderate to severe drug problems were assessed at 3, 6, and 12 months. Both hair analysis and Timeline Follow Back self-reports covered the same 90-day periods.","limitations":"The sample consisted of people with moderate to severe drug problems presenting to emergency departments, which may not represent all drug users. Hair analysis itself has limitations: it may not detect very light use, results can be affected by hair treatments, and some populations may decline to provide hair samples. The 90-day recall window is long for self-report accuracy."},{"rthcId":"RTHC-01265","title":"Hookah Tobacco Smoking During the Transition to College: Prevalence of Other Substance Use and Predictors of Initiation.","authors":"Shepardson, Robyn L; Hustad, John T P","year":2016,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 18(5), 763-9","doi":"10.1093/ntr/ntv170","pmid":"26259986","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tracked 936 incoming college students from before the start of their freshman year through the first 30 days of college. Hookah use prevalence increased from 9% before college to 13.1% during the first month.\n\nAmong students who had never used hookah before college, 13.8% initiated hookah during the first 30 days. Only two substances predicted this initiation: alcohol (AOR = 1.11) and marijuana (AOR = 1.30). Other tobacco products, cigarettes, and illegal drugs did not independently predict hookah initiation.\n\nHookah users were more likely to use all other substances compared to non-users, and one-fifth of former hookah smokers resumed use during the first month of college.","whyItMatters":"The transition to college is a period of heightened vulnerability for substance use initiation. This study identifies pre-college marijuana and alcohol use as specific risk markers for hookah initiation, suggesting these students may benefit from targeted prevention during orientation periods.","specificNumbers":"936 students, 817 retained. Hookah prevalence: 9% pre-college to 13.1% first month. 13.8% of never-users initiated. Marijuana AOR = 1.30 (1.03-1.65). Alcohol AOR = 1.11 (1.05-1.17). 20% of former hookah users relapsed.","methodology":"Longitudinal study of 936 incoming students (50% female) at a single university. Participants reported past 30-day substance use before the start of the Fall 2011 semester and again 30 days later (n=817 retained). Substances assessed included hookah, cigarettes, other tobacco, alcohol, marijuana, and other illegal drugs. Adjusted logistic regression identified predictors of hookah initiation.","limitations":"Single university limits generalizability. Relatively short follow-up period (30 days). Self-reported substance use may be underreported. The study cannot determine whether marijuana use causally leads to hookah use or whether both reflect a common underlying propensity. The effect sizes were modest."},{"rthcId":"RTHC-01266","title":"Marijuana Use and Type 2 Diabetes Mellitus: a Review.","authors":"Sidney, Stephen","year":2016,"journal":"Current diabetes reports, 16(11), 117","doi":null,"pmid":"27747490","tags":["medical-cannabis","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the paradoxical relationship between cannabis use and diabetes. The endocannabinoid system is directly involved in fat tissue regulation and glucose/insulin metabolism, and blocking CB1 receptors (with rimonabant) reduced weight and improved metabolic markers. Logically, activating these receptors with cannabis should worsen metabolic health.\n\nYet the epidemiological evidence consistently showed the opposite. Across multiple studies, marijuana users had either the same or lower odds of diabetes compared to non-users. Similarly, despite the well-known appetite-stimulating effects of cannabis (\"the munchies\"), marijuana users generally had lower BMI and lower rates of obesity.\n\nThe review also covered the endocannabinoid system's role in adipose tissue, insulin sensitivity, metabolic syndrome, and prediabetes, noting that while the biology predicts one outcome, the population-level data show another.","whyItMatters":"With 29 million Americans having diabetes and cannabis use increasing due to legalization, understanding the metabolic effects of cannabis is a significant public health question. The consistent finding of lower or equal diabetes risk in cannabis users is one of the most counterintuitive results in cannabis epidemiology.","specificNumbers":"29 million Americans with diabetes (estimate at time of publication). Studies consistently found either lower or no difference in diabetes odds among cannabis users compared to non-users.","methodology":"Narrative review examining the human endocannabinoid system, the pharmacology of cannabinoids on adipose tissue and glucose metabolism, and epidemiological studies on the association between marijuana use and obesity, metabolic syndrome, prediabetes, and diabetes.","limitations":"Epidemiological studies cannot prove cannabis protects against diabetes. Cannabis users may differ from non-users in many ways (age, activity level, diet) that could explain the association. Observational data is subject to confounding and selection bias. The review was narrative rather than systematic."},{"rthcId":"RTHC-01267","title":"Marijuana-derived Δ-9-tetrahydrocannabinol suppresses Th1/Th17 cell-mediated delayed-type hypersensitivity through microRNA regulation.","authors":"Sido, Jessica M; Jackson, Austin R; Nagarkatti, Prakash S; Nagarkatti, Mitzi","year":2016,"journal":"Journal of molecular medicine (Berlin, Germany), 94(9), 1039-51","doi":"10.1007/s00109-016-1404-5","pmid":"27038180","tags":["inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers induced a delayed-type hypersensitivity response in mice (an overactive immune reaction driven by Th1 and Th17 inflammatory T cells) and then treated them with THC. The treatment reduced swelling and immune cell infiltration at the site of inflammation.\n\nTHC decreased lymphocyte activation and reduced the development of both Th1 and Th17 inflammatory cell types, including their signature transcription factors and cytokines.\n\nThe molecular mechanism involved microRNA (miR), small molecules that regulate gene expression. The immune response caused an overexpression of miR-21 (which promotes Th17 cells) and a decrease in miR-29b (which normally suppresses the inflammatory cytokine interferon-gamma). THC reversed both of these microRNA changes.\n\nWhen researchers directly manipulated these microRNAs in cells from immunized mice (inhibiting miR-21 or boosting miR-29b), they produced the same effects as THC treatment, confirming the mechanism.","whyItMatters":"This study identifies a precise molecular mechanism for THC's anti-inflammatory effects. Rather than just observing that THC reduces inflammation, it shows exactly how: by correcting the specific microRNA dysregulation that drives inflammatory T cell development. This level of mechanistic understanding could inform development of targeted anti-inflammatory therapies.","specificNumbers":"THC dose: 20 mg/kg. THC reversed miR-21 overexpression and miR-29b downregulation. miR-21 inhibition increased SMAD7 (anti-inflammatory). miR-29b mimicry decreased interferon-gamma expression.","methodology":"In vivo study using C57BL/6 mice with methylated BSA-induced delayed-type hypersensitivity. THC was administered at 20 mg/kg. Researchers measured swelling, immune cell infiltration, T cell activation, and Th1/Th17 lineage commitment. MicroRNA expression was quantified, and transfection experiments with miR-21 inhibitor and miR-29b mimic confirmed the mechanistic pathway.","limitations":"Animal study using a single dose of THC in a specific immune challenge model. The microRNA mechanism demonstrated may not apply to all types of inflammation. The 20 mg/kg dose is relatively high and may not reflect typical human exposure. Translation to human autoimmune conditions requires further research."},{"rthcId":"RTHC-01268","title":"Prenatal marijuana exposure impacts executive functioning into young adulthood: An fMRI study.","authors":"Smith, Andra M; Mioduszewski, Ola; Hatchard, Taylor; Byron-Alhassan, Aziza; Fall, Carley; Fried, Peter A","year":2016,"journal":"Neurotoxicology and teratology, 58, 53-59","doi":"10.1016/j.ntt.2016.05.010","pmid":"27263090","tags":["pregnancy","cognition","youth","neuroscience"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Thirty-one young adults (ages 18-22) from the Ottawa Prenatal Prospective Study, a long-running longitudinal study, underwent fMRI during four executive function tasks: visuospatial working memory, response inhibition, verbal working memory, and interference control.\n\nSixteen had been prenatally exposed to marijuana while 15 had not. Both groups performed the tasks equally well behaviorally, achieving similar accuracy and speed.\n\nHowever, brain blood flow patterns were significantly different. The prenatally exposed group consistently showed increased activity in left posterior brain regions across all four tasks. This pattern suggests the brain may be compensating, recruiting additional neural resources to achieve the same level of task performance.\n\nThe consistency of the left posterior activation increase across four different types of executive function tasks is notable, suggesting a broad rather than task-specific alteration.","whyItMatters":"This is one of the longest follow-up studies of prenatal marijuana exposure, showing that brain differences are detectable 18-22 years after exposure. While the prenatally exposed individuals performed tasks normally, the altered brain activation suggests they may be working harder to achieve the same results, which could have implications for cognitive reserve and performance under stress.","specificNumbers":"31 participants aged 18-22. 16 prenatally exposed, 15 controls. Equal task performance across all 4 executive function tasks. Consistently increased left posterior brain activation in exposed group across all tasks.","methodology":"Longitudinal cohort study from the Ottawa Prenatal Prospective Study (OPPS). 31 young adults (16 prenatally exposed, 15 controls) underwent fMRI during four executive function tasks. Prenatal marijuana exposure was documented during pregnancy through the OPPS protocols. Brain activation was compared between groups while controlling for behavioral performance.","limitations":"Small sample size (31 participants). The study cannot control for all postnatal environmental differences between groups. Cannabis-using mothers may have differed from non-using mothers in other ways that affected child development. The OPPS cohort used cannabis products from the 1990s, which were lower potency than current products."},{"rthcId":"RTHC-01269","title":"Acute effects of cocaine and cannabis on response inhibition in humans: an ERP investigation.","authors":"Spronk, Desirée B; De Bruijn, Ellen R A; van Wel, Janelle H P; Ramaekers, Johannes G; Verkes, Robbert J","year":2016,"journal":"Addiction biology, 21(6), 1186-1198","doi":"10.1111/adb.12274","pmid":"26037156","tags":["cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In a double-blind, placebo-controlled crossover study, 38 healthy drug-using volunteers received cocaine, cannabis, and placebo in separate sessions and performed a Go/NoGo impulse control task.\n\nCocaine improved performance: faster reaction times, better accuracy, and increased prefrontal NoGo-P3 brain activity (reflecting enhanced evaluative processing). Cannabis produced the opposite: slower reactions, worse accuracy, and decreased NoGo-P3 amplitude.\n\nCannabis also reduced the parietal P3 wave, suggesting broader attention disruption beyond just impulse control. Cocaine did not affect this component, indicating its effects were more specific to response control.\n\nNeither drug affected the N2 brain wave component, which reflects the earlier, pre-motor stage of response inhibition. This means both drugs acted on the evaluative stage (deciding whether the response was appropriate) rather than the initial detection stage.\n\nNeither trait impulsivity nor novelty seeking moderated any drug effects.","whyItMatters":"This is one of the few controlled studies directly comparing how two commonly used drugs affect the same cognitive process in the same individuals. The finding that they have precisely opposite effects on impulse control, and that these effects are reflected in measurable brain activity, provides a clear neural picture of how these substances modify cognitive function.","specificNumbers":"38 participants in a three-way crossover design. Cocaine: faster RTs, better accuracy, increased prefrontal NoGo-P3. Cannabis: slower RTs, worse accuracy, decreased prefrontal NoGo-P3 and parietal P3. Neither drug affected N2. Personality traits did not moderate effects.","methodology":"Double-blind, placebo-controlled, randomized three-way crossover design. 38 healthy drug-using volunteers completed a Go/NoGo task after receiving cocaine, cannabis, or placebo in separate sessions. Event-related potentials (ERPs) were recorded via EEG. Trait impulsivity and novelty seeking were measured as potential moderators.","limitations":"All participants were experienced drug users, so results may not generalize to drug-naive individuals. The study measured acute effects of single doses and does not address chronic use patterns. The crossover design controls for individual differences but cannot capture long-term neuroadaptations. Sample size was moderate."},{"rthcId":"RTHC-01270","title":"Alcohol use during a trial of N-acetylcysteine for adolescent marijuana cessation.","authors":"Squeglia, Lindsay M; Baker, Nathaniel L; McClure, Erin A; Tomko, Rachel L; Adisetiyo, Vitria; Gray, Kevin M","year":2016,"journal":"Addictive behaviors, 63, 172-7","doi":"10.1016/j.addbeh.2016.08.001","pmid":"27521979","tags":["youth","addiction","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a secondary analysis of a marijuana cessation trial for adolescents, researchers examined whether reducing marijuana use affected alcohol consumption. Among 116 marijuana-dependent adolescents aged 15-21, most (77 of 89 who returned for follow-up) also drank alcohol, averaging 1.3 binge drinking days per week.\n\nA key interaction emerged: in the NAC-treated group, less marijuana use (measured by urine testing) was associated with less alcohol use. This relationship was not found in the placebo group.\n\nImportantly, there was no evidence of compensatory drinking. The concern that teens who reduce marijuana might increase alcohol use was not supported. Instead, the opposite occurred in the NAC group: reducing one substance was associated with reducing the other.\n\nThis suggests NAC's glutamatergic mechanism may have broad effects on substance use rather than being specific to marijuana.","whyItMatters":"Adolescent substance use rarely involves just one substance. This finding suggests that an effective marijuana treatment may have beneficial spillover effects on alcohol use, at least when using NAC. It also addresses the common clinical concern that reducing one substance leads to increased use of another.","specificNumbers":"116 adolescents randomized. 77 of 89 who returned reported alcohol use. Average 1.3 binge drinking days per week. In NAC group, less marijuana use (via urine) was significantly associated with less alcohol use (p = 0.016). No such association in placebo group.","methodology":"Secondary analysis of an 8-week randomized, placebo-controlled trial. 116 marijuana-dependent adolescents (ages 15-21) received NAC 1200mg or placebo twice daily. Marijuana use was measured via urine cannabinoid levels. Alcohol use was assessed by self-report. Participants were not required to be alcohol users or interested in alcohol cessation.","limitations":"Secondary analysis, not the primary study aim. Alcohol use was not the target behavior. Self-reported alcohol use may be unreliable in adolescents. The sample was moderate in size. The correlation between reduced marijuana and reduced alcohol could reflect broader lifestyle changes rather than a direct NAC effect on alcohol."},{"rthcId":"RTHC-01271","title":"Anxiety, depression and risk of cannabis use: Examining the internalising pathway to use among Chilean adolescents.","authors":"Stapinski, Lexine A; Montgomery, Alan A; Araya, Ricardo","year":2016,"journal":"Drug and alcohol dependence, 166, 109-15","doi":"10.1016/j.drugalcdep.2016.06.032","pmid":"27427415","tags":["anxiety","youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers followed 2,508 ninth-graders from low-income schools in Santiago, Chile, for 18 months. Cannabis use was remarkably common: 40.3% reported using at least once during the study period.\n\nWhen examining which mental health symptoms predicted future cannabis use, depression, panic, and generalized anxiety all showed initial associations with greater cannabis use frequency. However, when all were tested simultaneously, only generalized anxiety symptoms remained independently significant.\n\nGeneralized anxiety increased the odds of using more frequently (OR = 1.23) and increased the risk of transitioning from non-user to user by 25% (OR = 1.25). Social anxiety and panic were not independently predictive once generalized anxiety was accounted for.","whyItMatters":"This study supports the self-medication hypothesis specifically for generalized anxiety in adolescents. Rather than depression or panic driving cannabis initiation, it appears that the chronic worry and tension characteristic of generalized anxiety most specifically predicts cannabis uptake, suggesting that teaching teens adaptive anxiety management could prevent cannabis initiation.","specificNumbers":"2,508 adolescents from 22 schools. 40.3% used cannabis at least once over 18 months. Generalized anxiety: OR = 1.23 for use frequency, OR = 1.25 for transitioning to use. Social anxiety and panic were not independently predictive.","methodology":"Longitudinal cohort study of 2,508 participants (45% female, mean age 14.5 years) from 22 low-income secondary schools in Santiago, Chile. Baseline mental health was assessed using the Beck Depression Inventory and the Revised Child Anxiety and Depression Scale. Cannabis use frequency was measured at baseline, 6 months, and 18 months. Adjusted analyses controlled for baseline cannabis use.","limitations":"Conducted in low-income schools in Santiago, Chile, which may limit generalizability. Self-reported cannabis use may be underestimated. The 18-month follow-up is relatively short. The study does not establish that anxiety caused cannabis use, only that it predicted it. Cultural factors may influence both anxiety expression and cannabis attitudes."},{"rthcId":"RTHC-01272","title":"Cannabinoid modulation of memory consolidation within the cerebellum.","authors":"Steinmetz, Adam B; Freeman, John H","year":2016,"journal":"Neurobiology of learning and memory, 136, 228-235","doi":"10.1016/j.nlm.2016.11.002","pmid":"27818269","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers injected cannabinoid compounds directly into the cerebellar cortex of rats at different time points relative to eyeblink conditioning, a form of motor learning that depends on the cerebellum.\n\nWhen given before training sessions, the cannabinoid agonist WIN55,212-2 and drugs that increase or decrease endocannabinoid levels all impaired learning. The rats had more difficulty acquiring the conditioned eyeblink response.\n\nBut when the same endocannabinoid-boosting drug (JZL-184) or cannabinoid agonist (WIN55,212-2) was given one hour after training, it actually enhanced memory consolidation. Conversely, blocking the endocannabinoid system after training impaired consolidation.\n\nThe effect was time-sensitive: manipulations given 3 or 6 hours after training had no effect, indicating a specific 1-3 hour post-training window during which endocannabinoids facilitate memory storage.","whyItMatters":"This study reveals that the endocannabinoid system plays a dual role in cerebellar memory: it interferes with the acquisition of new information but is actually needed for consolidating memories that have already been formed. This paradox helps explain conflicting findings about cannabis and memory.","specificNumbers":"WIN55,212-2 and endocannabinoid modulators impaired learning when given before training. JZL-184 and WIN55,212-2 enhanced consolidation when given 1 hour post-training. The CB1 inverse agonist SR141716A impaired consolidation at 1 hour. No effects at 3 or 6 hours post-training.","methodology":"Rats underwent eyeblink conditioning with infusions of cannabinoid compounds directly into the cerebellar cortex. Separate groups received cannabinoid agonists, endocannabinoid modulators, or antagonists either before training or 1, 3, or 6 hours after training. Learning was measured by the percentage of conditioned eyeblink responses over sessions.","limitations":"Eyeblink conditioning is a specific type of cerebellar-dependent motor learning that may not represent all types of memory. The study used direct brain infusions at precise doses, which differs from how cannabis affects the brain systemically. Rat cerebellar learning may not perfectly model human learning processes."},{"rthcId":"RTHC-01273","title":"Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex.","authors":"Sticht, Martin A; Limebeer, Cheryl L; Rafla, Benjamin R; Abdullah, Rehab A; Poklis, Justin L; Ho, Winnie; Niphakis, Micah J; Cravatt, Benjamin F; Sharkey, Keith A; Lichtman, Aron H; Parker, Linda A","year":2016,"journal":"Neuropharmacology, 102, 92-102","doi":"10.1016/j.neuropharm.2015.10.039","pmid":"26541329","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers identified the precise brain mechanism by which the endocannabinoid system suppresses nausea. During episodes of nausea, the brain region called the visceral insular cortex (VIC) showed selective increases in 2-AG, one of the two main endocannabinoids. Anandamide, the other main endocannabinoid, was not affected.\n\nBlocking the enzyme that breaks down 2-AG (MAGL) in the VIC reduced nausea-related behavior through CB1 receptors. Blocking the enzyme that breaks down anandamide (FAAH) had no effect on nausea.\n\nThe mechanism of action was revealed by measuring neural activation: MAGL inhibition reduced the number of activated neurons (Fos-positive cells) in the VIC during nausea, showing that 2-AG suppresses nausea by reducing neural activity in this brain region.","whyItMatters":"This study precisely identifies where and how the brain's natural anti-nausea system works. Understanding that 2-AG (not anandamide) in the visceral insular cortex is the key molecule could enable development of nausea treatments that are more targeted than whole-plant cannabis, potentially with fewer side effects.","specificNumbers":"2-AG was selectively elevated in the VIC during nausea episodes. MAGL inhibition increased 2-AG and reduced nausea via CB1 receptors. FAAH inhibition did not affect anandamide or nausea. MAGL inhibition reduced Fos immunoreactivity in the VIC.","methodology":"Rat study using conditioned gaping (a validated model of nausea behavior) induced by lithium chloride. Researchers performed local infusions of enzyme inhibitors into the visceral insular cortex, measured endocannabinoid levels during nausea using mass spectrometry, and quantified neural activation using c-Fos immunoreactivity. CB1 receptor involvement was confirmed with the antagonist AM251.","limitations":"Rat nausea models may not fully capture human nausea experience. Local brain infusions are precise but do not replicate how cannabis reaches the brain in real use. The study focused on one brain region, but nausea involves a network of brain areas. The results apply to acute, toxin-induced nausea and may not extend to all causes of nausea."},{"rthcId":"RTHC-01274","title":"The GOOD life: Study protocol for a social norms intervention to reduce alcohol and other drug use among Danish adolescents.","authors":"Stock, Christiane; Vallentin-Holbech, Lotte; Rasmussen, Birthe Marie","year":2016,"journal":"BMC public health, 15, 704","doi":"10.1186/s12889-016-3333-1","pmid":"27488390","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01275","title":"Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.","authors":"Stringer, S; Minică, C C; Verweij, K J H; Mbarek, H; Bernard, M; Derringer, J; van Eijk, K R; Isen, J D; Loukola, A; Maciejewski, D F; Mihailov, E; van der Most, P J; Sánchez-Mora, C; Roos, L; Sherva, R; Walters, R; Ware, J J; Abdellaoui, A; Bigdeli, T B; Branje, S J T; Brown, S A; Bruinenberg, M; Casas, M; Esko, T; Garcia-Martinez, I; Gordon, S D; Harris, J M; Hartman, C A; Henders, A K; Heath, A C; Hickie, I B; Hickman, M; Hopfer, C J; Hottenga, J J; Huizink, A C; Irons, D E; Kahn, R S; Korhonen, T; Kranzler, H R; Krauter, K; van Lier, P A C; Lubke, G H; Madden, P A F; Mägi, R; McGue, M K; Medland, S E; Meeus, W H J; Miller, M B; Montgomery, G W; Nivard, M G; Nolte, I M; Oldehinkel, A J; Pausova, Z; Qaiser, B; Quaye, L; Ramos-Quiroga, J A; Richarte, V; Rose, R J; Shin, J; Stallings, M C; Stiby, A I; Wall, T L; Wright, M J; Koot, H M; Paus, T; Hewitt, J K; Ribasés, M; Kaprio, J; Boks, M P; Snieder, H; Spector, T; Munafò, M R; Metspalu, A; Gelernter, J; Boomsma, D I; Iacono, W G; Martin, N G; Gillespie, N A; Derks, E M; Vink, J M","year":2016,"journal":"Translational psychiatry, 6(3), e769","doi":"10.1038/tp.2016.36","pmid":"27023175","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"The International Cannabis Consortium pooled genetic data from 13 cohorts totaling 32,330 participants. While no single genetic variant reached genome-wide significance on its own, gene-based analysis identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC, and KCNT2.\n\nNCAM1 had previously been linked to cigarette smoking and other substance use. CADM2 had been associated with body mass index, processing speed, and autism spectrum disorders, phenotypes also connected to cannabis use.\n\nAcross all common genetic variants combined, genetics explained 13-20% of the variation in lifetime cannabis use. The most striking finding was an exceptionally strong genetic correlation of 0.83 between lifetime cannabis use and lifetime cigarette smoking, meaning the genetic factors that predispose people to try cannabis are largely the same ones that predispose them to try cigarettes.","whyItMatters":"This study establishes that cannabis use has a substantial genetic component (13-20% from common variants alone, with twin studies showing 40-48% heritability). The 83% genetic correlation with cigarette smoking suggests that shared genetic pathways drive substance initiation broadly, rather than cannabis and tobacco having separate genetic architectures.","specificNumbers":"32,330 participants in primary analysis. 5,627 in replication. Four genes identified: NCAM1, CADM2, SCOC, KCNT2. SNP heritability: 13-20%. Genetic correlation with cigarette smoking: r = 0.83 (p = 1.85 x 10^-8).","methodology":"Meta-analysis of genome-wide association data from 13 cohorts (N=32,330) with four replication samples (N=5,627). Gene-based testing was performed using VEGAS. SNP-based heritability was estimated, and genetic correlations with cigarette use were calculated using LD score regression.","limitations":"No individual SNPs reached genome-wide significance, reflecting the polygenic nature of cannabis use. The study measured lifetime use (ever vs never), which lumps together experimental users and heavy chronic users. Different genetic factors may influence initiation versus progression to problematic use. Most participants were of European ancestry, limiting generalizability."},{"rthcId":"RTHC-01276","title":"Cannabinoids in Medical Practice.","authors":"Strouse, Thomas B","year":2016,"journal":"Cannabis and cannabinoid research, 1(1), 38-43","doi":"10.1089/can.2015.0010","pmid":"28861478","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This clinical review provided practical guidance for physicians navigating cannabinoid therapeutics. It distinguished between two FDA-approved cannabinoid products (with standardized dosing and safety data) and dispensary-purchased medical marijuana (unregulated, variable concentrations).\n\nThe strongest evidence supported cannabinoids for chemotherapy-related nausea and vomiting, poor appetite in advanced HIV, certain pain states, and MS-associated spasticity.\n\nThe review emphasized that recreational cannabis use has many known potential serious harms and urged physicians to proactively ask patients about cannabinoid use, regardless of the clinical context. Practical clinical suggestions were included for integrating cannabinoid conversations into routine care.","whyItMatters":"Many physicians lack training on cannabinoids and are unprepared for patient questions about medical marijuana. This concise review provides the essential clinical framework: where evidence supports use, what the known harms are, and how to approach the conversation with patients.","specificNumbers":"Two FDA-approved cannabinoid products at the time of publication. Four conditions with demonstrated efficacy: chemotherapy nausea/vomiting, HIV appetite loss, pain, MS spasticity.","methodology":"Narrative clinical review published in Cannabis and Cannabinoid Research, providing practical guidance for physicians based on existing evidence.","limitations":"Brief review format limits depth of evidence assessment. Published in 2016, before several subsequent regulatory changes and clinical trials. Does not address newer cannabinoid formulations or delivery methods."},{"rthcId":"RTHC-01277","title":"Epigenetic Effects of Cannabis Exposure.","authors":"Szutorisz, Henrietta; Hurd, Yasmin L","year":2016,"journal":"Biological psychiatry, 79(7), 586-94","doi":"10.1016/j.biopsych.2015.09.014","pmid":"26546076","tags":["genetics","neuroscience","pregnancy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the emerging field of cannabis epigenetics, where researchers study how cannabis exposure changes gene expression without altering the DNA sequence itself.\n\nAccumulating evidence from both human and animal studies showed that cannabinoids can modify epigenetic marks, including DNA methylation and histone modifications, in brain tissue and peripheral cells. These modifications can alter which genes are turned on or off, potentially explaining the persistent behavioral effects of cannabis that outlast the drug's presence in the body.\n\nPerhaps most provocatively, some animal studies suggested these epigenetic changes could be transmitted across generations. Parental cannabis exposure appeared to affect the epigenome of offspring, raising questions about intergenerational effects that go beyond the direct in-utero exposure that has been the traditional focus of concern.","whyItMatters":"If cannabis can change gene expression patterns that persist after the drug is gone and potentially pass to the next generation, it fundamentally changes how we think about cannabis safety. The effects may not be limited to the user or even the period of use, but could have biological consequences that extend across a lifetime and into the next generation.","specificNumbers":"The review covered human and animal studies showing aberrant epigenetic modifications in brain and peripheral tissues linked to cannabis exposure. Specific mechanistic details were sparse at the time of publication.","methodology":"Comprehensive review of published scientific literature examining epigenetic effects of cannabinoids, including studies in humans and animal models, covering DNA methylation, histone modifications, and chromatin remodeling.","limitations":"The field was in its early stages when this review was published. Mechanistic details were sparse, and many findings were correlational. Most epigenetic studies were in animal models with doses and exposure patterns that may not reflect human use. The intergenerational findings need much more replication."},{"rthcId":"RTHC-01278","title":"Efficacy, tolerability, and safety of cannabinoids for chemotherapy-induced nausea and vomiting--a systematic review of systematic reviews.","authors":"Tafelski, S; Häuser, W; Schäfer, M","year":2016,"journal":"Schmerz (Berlin, Germany), 30(1), 14-24","doi":"10.1007/s00482-015-0092-3","pmid":"26787227","tags":["medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This meta-review examined six systematic reviews of randomized controlled trials comparing cannabinoids (dronabinol, levonantradol, nabilone, and nabiximols) with placebo or conventional antiemetics for chemotherapy-induced nausea and vomiting (CINV).\n\nThe evidence showed moderate quality support for cannabinoid efficacy against both placebo and conventional antiemetics. However, there was equally moderate quality evidence that cannabinoids were less tolerated and less safe than both placebo and conventional antiemetics, with higher dropout rates due to adverse events.\n\nCritically, no studies compared cannabinoids with newer neurokinin-1 receptor antagonists, which are now standard in many CINV regimens. Only one RCT of whole plant extract was included.\n\nThe authors concluded that with safe and effective modern antiemetics available, cannabinoids should not be first- or second-line therapy for CINV. Some guidelines recommended them as third-line treatment for breakthrough nausea when standard treatments fail.","whyItMatters":"This review provides the clearest picture of where cannabinoids fit in CINV management: they work, but they are not as well tolerated as modern alternatives. This evidence-based positioning as third-line therapy helps clinicians make informed decisions rather than either dismissing cannabinoids entirely or promoting them as first-choice treatments.","specificNumbers":"Six systematic reviews analyzed. Cannabinoids studied: dronabinol, levonantradol, nabilone, nabiximols. Moderate quality evidence for efficacy against placebo and conventional antiemetics. Moderate quality evidence for worse tolerability and safety. One RCT of whole plant extract. No comparisons with neurokinin-1 antagonists.","methodology":"Systematic review of systematic reviews. Comprehensive search of MEDLINE, DARE, and Cochrane libraries through November 2015 for systematic reviews of RCTs comparing cannabinoids with placebo or conventional antiemetics for CINV. Methodological quality was assessed using AMSTAR.","limitations":"The systematic reviews included studied pharmaceutical cannabinoids, not herbal cannabis. Most original trials predated modern antiemetic regimens, so the comparators were older drugs. No comparisons with current standard-of-care antiemetics (neurokinin-1 antagonists). The review was published in German, potentially limiting its reach."},{"rthcId":"RTHC-01279","title":"Patterns of electronic cigarette use in current and ever users among college students in France: a cross-sectional study.","authors":"Tavolacci, Marie-Pierre; Vasiliu, Anca; Romo, Lucia; Kotbagi, Gayatri; Kern, Laurence; Ladner, Joël","year":2016,"journal":"BMJ open, 6(5), e011344","doi":"10.1136/bmjopen-2016-011344","pmid":"27235301","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a survey of 1,134 French college students, 23% had ever used e-cigarettes and 5.7% were current users. Three findings stand out.\n\nFirst, cannabis use was strongly associated with ever trying e-cigarettes (AOR = 2.44), alongside cigarette smoking (AOR = 3.97) and occasional binge drinking (AOR = 1.83).\n\nSecond, nearly half (45.8%) of those who had ever tried e-cigarettes had never smoked conventional cigarettes, challenging the assumption that e-cigarettes are primarily used by smokers trying to quit.\n\nThird, the profile of ever-users differed sharply from current users. Ever-users showed a pattern of sensation-seeking and experimentation with multiple substances. Current users were almost exclusively smokers using e-cigarettes as a cessation tool (AOR = 14.53 for current smoking).","whyItMatters":"The strong association between cannabis use and e-cigarette experimentation suggests these behaviors cluster together in a broader pattern of substance exploration. This has implications for prevention: programs targeting e-cigarette use may need to address cannabis and other substance use simultaneously.","specificNumbers":"1,134 students, mean age 20.8. E-cigarette ever use: 23%. Current use: 5.7%. Combined cigarette + e-cigarette use: 14.5%. 45.8% of e-cigarette experimenters never smoked. Cannabis use AOR for ever e-cigarette use: 2.44.","methodology":"Multi-center cross-sectional study conducted on two major campuses in France between October 2014 and February 2015. 1,134 students completed anonymous questionnaires about e-cigarette use, conventional smoking, alcohol, cannabis, sports, and eating disorders.","limitations":"Cross-sectional design cannot establish whether cannabis use led to e-cigarette experimentation or vice versa. French college students may have different substance use patterns than students in other countries. Self-reported data may underestimate substance use. The study predates the widespread adoption of pod-based e-cigarettes."},{"rthcId":"RTHC-01280","title":"Assessing Sample Bias among Venue-Based Respondents at Medical Marijuana Dispensaries.","authors":"Thomas, Crystal; Freisthler, Bridget","year":2016,"journal":"Journal of psychoactive drugs, 48(1), 56-62","doi":"10.1080/02791072.2015.1127450","pmid":"26882461","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Medical marijuana users are a \"hidden population\" that is difficult to access through traditional survey methods. Researchers from UCLA evaluated whether conducting surveys at dispensaries introduces systematic biases that would undermine the results.\n\nThey used a two-stage venue-based sampling approach and tested for two types of bias: selection bias (whether participating dispensaries differed systematically from non-participating ones) and respondent bias (whether patients who completed surveys differed from those who declined).\n\nBoth types of bias were generally absent. The dispensaries that participated were representative of dispensaries overall, and the patients who responded were representative of the broader patient population. This validation means that research findings from dispensary-based surveys can be used to inform policy and clinical practice with reasonable confidence.","whyItMatters":"Reliable data on medical cannabis patients is essential for evidence-based policy. This study validates a practical method for collecting that data, showing that dispensary-based research can produce findings that represent the broader population of medical cannabis users in a given area.","specificNumbers":"Selection bias was generally absent among participating dispensaries. Respondent bias was minimal among survey completers. Results were from the UCLA Medical Marijuana Study in Los Angeles.","methodology":"The study used the venue-based sampling procedures from the UCLA Medical Marijuana Study, employing a two-stage approach. Statistical analyses compared participating vs non-participating dispensaries and responding vs non-responding patrons on available characteristics.","limitations":"The study was conducted in Los Angeles, where dispensary culture and patient demographics may differ from other regions. Patients who obtain medical cannabis outside of dispensaries (home growing, online) are not captured. The methodology assumes dispensaries are the primary access point, which may not hold in all jurisdictions."},{"rthcId":"RTHC-01281","title":"Severe motor and vocal tics controlled with Sativex®.","authors":"Trainor, David; Evans, Lois; Bird, Rupert","year":2016,"journal":"Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists, 24(6), 541-544","doi":null,"pmid":"27558217","tags":["medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with treatment-resistant Tourette syndrome received Sativex (10.8 mg THC and 10 mg CBD daily, delivered as two oro-mucosal sprays twice daily) for four weeks.\n\nBoth subjective and objective measures showed marked improvement. The patient completed the Yale Global Tic Severity Scale, showing substantial self-reported improvement. More compellingly, video recordings made before and during treatment were rated by two assessors who were blind to the treatment stage, using a standardized rating scale. Both blinded assessors confirmed significant reductions in the frequency and severity of motor and vocal tics, with good inter-rater reliability.","whyItMatters":"Tourette syndrome has limited treatment options, and many patients do not respond adequately to available medications. This case adds to the growing evidence that cannabinoids may be effective for tic disorders, and the use of blinded objective assessment strengthens the finding beyond typical case reports.","specificNumbers":"10.8 mg THC and 10 mg CBD daily. Assessment at pre-treatment and weeks 1, 2, and 4. Both subjective and blinded objective measures showed marked improvement. Good inter-rater reliability between two blinded assessors.","methodology":"Single case report with assessment at pre-treatment and weeks 1, 2, and 4. Subjective assessment via Yale Global Tic Severity Scale. Objective assessment via blinded video rating using the Original Rush Videotape Rating Scale by two independent assessors.","limitations":"Single case report, the weakest level of clinical evidence. Placebo effects cannot be ruled out, even with blinded video assessment. Four weeks of follow-up is short. The patient's specific characteristics may not represent all Tourette syndrome patients."},{"rthcId":"RTHC-01282","title":"Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings.","authors":"Trigo, Jose M; Lagzdins, Dina; Rehm, Jürgen; Selby, Peter; Gamaleddin, Islam; Fischer, Benedikt; Barnes, Allan J; Huestis, Marilyn A; Le Foll, Bernard","year":2016,"journal":"Drug and alcohol dependence, 161, 298-306","doi":"10.1016/j.drugalcdep.2016.02.020","pmid":"26925704","tags":["addiction","withdrawal","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Nine cannabis-dependent community members underwent an 8-week trial alternating between smoking-as-usual periods and cannabis abstinence periods. During abstinence, they received either high fixed doses, self-titrated doses, or placebo of Sativex (up to 108 mg THC / 100 mg CBD daily).\n\nHigh fixed doses of Sativex were well tolerated and significantly reduced withdrawal symptoms compared to placebo, as measured by both the Cannabis Withdrawal Scale and Marijuana Withdrawal Checklist. However, Sativex did not significantly reduce craving.\n\nWhen participants self-titrated, they chose lower doses that showed limited efficacy compared to the high fixed doses. Participants also reported a significantly lower \"high\" from Sativex or placebo compared to their usual cannabis smoking, indicating Sativex did not simply replace the intoxication.","whyItMatters":"There is currently no approved pharmacological treatment for cannabis dependence. This study provides proof-of-concept that Sativex, at appropriately high doses, can manage withdrawal symptoms, which is often the primary barrier to successful cannabis cessation. The finding that self-titrated doses were insufficient is clinically important for treatment design.","specificNumbers":"9 participants. Doses up to 108 mg THC / 100 mg CBD daily. High fixed doses significantly reduced withdrawal. Self-titrated doses were lower and less effective. Craving was not significantly reduced. Participants reported less \"high\" from Sativex than usual cannabis.","methodology":"Proof-of-concept, double-blind, placebo-controlled trial using an ABACADAE design (four smoking-as-usual conditions alternating with four abstinence conditions). Nine cannabis-dependent subjects received randomized, counterbalanced doses of Sativex or placebo during abstinence periods. Withdrawal, craving, and subjective effects were measured with validated instruments. Compliance was verified by self-reports, vial weight, and toxicology.","limitations":"Very small sample size (9 participants). Proof-of-concept design does not establish efficacy. The alternating design with multiple conditions is complex. The dose of Sativex that worked was high and may raise concerns about simply substituting one cannabinoid product for another. Craving was not reduced, which could limit real-world effectiveness."},{"rthcId":"RTHC-01283","title":"Inhibition of monoacylglycerol lipase (MAGL) enhances cue-induced reinstatement of nicotine-seeking behavior in mice.","authors":"Trigo, Jose M; Le Foll, Bernard","year":2016,"journal":"Psychopharmacology, 233(10), 1815-22","doi":"10.1007/s00213-015-4117-5","pmid":"26490035","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether boosting 2-AG levels (by inhibiting its breakdown enzyme MAGL with JZL184) would affect nicotine-related behaviors in mice.\n\nMAGL inhibition had no effect on active nicotine self-administration, motivation for nicotine (progressive ratio), or food self-administration. However, the high dose (16 mg/kg) significantly enhanced cue-induced reinstatement of previously extinguished nicotine seeking. Importantly, JZL184 did not produce reinstatement on its own.\n\nThis pattern means that 2-AG does not seem to affect the ongoing rewarding effects of nicotine but amplifies the ability of nicotine-associated cues (sights, sounds, situations previously paired with smoking) to trigger relapse-like behavior.","whyItMatters":"Relapse triggered by environmental cues is one of the primary challenges in tobacco cessation. This study identifies the endocannabinoid 2-AG as a modulator of this cue-driven relapse process. If 2-AG amplifies cue reactivity, then blocking 2-AG production or action could potentially reduce cue-triggered cravings for tobacco.","specificNumbers":"JZL184 at 8 and 16 mg/kg did not affect nicotine self-administration or progressive-ratio breakpoints. JZL184 at 16 mg/kg significantly enhanced cue-induced reinstatement. No effect on food self-administration.","methodology":"Mouse study using intravenous nicotine self-administration under fixed-ratio and progressive-ratio schedules. JZL184 (0, 8, 16 mg/kg) was tested for effects on nicotine taking, motivation, and cue-induced reinstatement of extinguished nicotine seeking. Food self-administration was tested as a control for non-specific effects.","limitations":"Mouse study with limited sample size. Only one MAGL inhibitor was tested. The cue-induced reinstatement model, while validated, is an approximation of human relapse. The effect was seen only at the higher dose, raising questions about dose-response. JZL184 affects 2-AG globally, not in specific brain regions."},{"rthcId":"RTHC-01284","title":"THC:CBD Observational Study Data: Evolution of Resistant MS Spasticity and Associated Symptoms.","authors":"Trojano, Maria","year":2016,"journal":"European neurology, 75 Suppl 1, 4-8","doi":"10.1159/000444235","pmid":"26901343","tags":["medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The MOVE 2 Italy study tracked real-world outcomes of THC:CBD oromucosal spray (Sativex) for treatment-resistant MS spasticity across more than 30 Italian MS centers. After surpassing 300 enrolled patients, an interim analysis compared results with the German MOVE 2 study and the largest phase III randomized controlled trial.\n\nPatients showed meaningful improvements on both patient-reported and physician-rated spasticity scales over 3 months. Treatment discontinuations were limited, suggesting good tolerability.\n\nTwo key findings distinguished real-world from trial outcomes: patients achieved improvements at mean daily doses approximately one-third lower than those used in the pivotal RCT, and the proportion reporting adverse events was approximately one-third of the trial rate. THC:CBD spray was most commonly added to oral baclofen.","whyItMatters":"Real-world data often tells a different story than clinical trials. In this case, the story is more positive: patients achieved good results with lower doses and fewer side effects than expected from trial data. This suggests that the clinical trial setting may have led to higher dosing than necessary, and that in practice, lower doses are both effective and better tolerated.","specificNumbers":"Over 300 patients enrolled across 30+ Italian MS centers. Meaningful improvements on NRS and modified Ashworth scale over 3 months. Mean daily doses approximately one-third of RCT doses. Adverse event rate approximately one-third of RCT rate. Limited treatment discontinuations.","methodology":"Prospective observational study (MOVE 2 Italy) using web-based real-time data collection and patient diaries across more than 30 Italian MS centers. Outcomes included the patient-based 0-10 numerical rating scale for spasticity and physician-rated modified Ashworth scale. Interim analysis performed after 300 patient enrollment threshold.","limitations":"Observational design without a control group means improvements could reflect placebo effects or natural disease fluctuation. Interim analysis rather than final results. Selection bias may be present if centers or patients with better outcomes were more likely to be captured. No randomization or blinding."},{"rthcId":"RTHC-01285","title":"The association between cannabis use and motivation and intentions to quit tobacco within a sample of Australian socioeconomically disadvantaged smokers.","authors":"Twyman, Laura; Bonevski, Billie; Paul, Christine; Kay-Lambkin, Frances J; Bryant, Jamie; Oldmeadow, C; Palazzi, K; Guillaumier, A","year":2016,"journal":"Health education research, 31(6), 771-781","doi":null,"pmid":"27923866","tags":["addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In a survey of 369 current tobacco smokers receiving community services in New South Wales, Australia, 19% reported concurrent tobacco and cannabis use. Among those, 100% reported simultaneous use (using both during the same session).\n\nWeekly cannabis use was significantly associated with lower motivation to quit tobacco. However, cannabis use was not associated with intentions to quit in the next 30 days. This distinction suggests that cannabis users may have reduced general motivation for cessation but are not less likely to take concrete steps toward quitting when asked about near-term plans.","whyItMatters":"Socioeconomically disadvantaged smokers have higher smoking rates and face more barriers to quitting. Understanding that cannabis co-use may further reduce motivation (but not intention) is relevant for tailoring cessation interventions. The 100% rate of simultaneous use suggests the two substances are deeply intertwined in this population.","specificNumbers":"369 participants (77% consent rate). 19% (n=71) reported concurrent tobacco-cannabis use. 100% of concurrent users reported simultaneous use. Cannabis use associated with lower motivation but not lower 30-day quit intentions.","methodology":"Cross-sectional survey conducted in 2013-2014 with current tobacco smokers receiving aid from two community service organizations in New South Wales, Australia (77% consent rate). Weekly cannabis use in the past month, motivation to quit tobacco, and intentions to quit within 30 days were measured. Regression analyses examined associations.","limitations":"Cross-sectional design cannot determine whether cannabis use caused lower motivation or whether less motivated smokers were more likely to use cannabis. Small subgroup of cannabis users (n=71). Socioeconomically disadvantaged Australian sample may not generalize broadly. Self-reported cannabis use may be underreported."},{"rthcId":"RTHC-01286","title":"CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.","authors":"Tzadok, Michal; Uliel-Siboni, Shimrit; Linder, Ilan; Kramer, Uri; Epstein, Orna; Menascu, Shay; Nissenkorn, Andrea; Yosef, Omer Bar; Hyman, Eli; Granot, Dorit; Dor, Michael; Lerman-Sagie, Tali; Ben-Zeev, Bruria","year":2016,"journal":"Seizure, 35, 41-4","doi":"10.1016/j.seizure.2016.01.004","pmid":"26800377","tags":["epilepsy","cbd","youth","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers reported the experience of five Israeli pediatric epilepsy centers treating 74 children and adolescents (ages 1-18) with intractable epilepsy using CBD-enriched medical cannabis oil (20:1 CBD to THC ratio dissolved in olive oil).\n\nThese children had severe, treatment-resistant epilepsy: all had failed more than 7 antiepileptic drugs, and 66% had also failed a ketogenic diet, vagal nerve stimulator, or both. They were treated for an average of 6 months with CBD at doses ranging from 1 to 20 mg/kg/day.\n\nThe results were striking: 89% (66 of 74) reported seizure reduction. Of these, 18% had 75-100% reduction, 34% had 50-75% reduction, 12% had 25-50% reduction, and 26% had less than 25% reduction. Five patients (7%) reported seizure worsening.\n\nBeyond seizure control, improvements were observed in behavior, alertness, language, communication, motor skills, and sleep. Adverse effects included somnolence, fatigue, gastrointestinal issues, and irritability.","whyItMatters":"These children represented the most severe and treatment-resistant epilepsy cases. When more than 7 medications and even surgical/device interventions have failed, any seizure reduction is meaningful. The 89% response rate and the breadth of additional improvements are noteworthy for a population with almost no remaining treatment options.","specificNumbers":"74 patients aged 1-18. All failed 7+ antiepileptic drugs. 66% also failed ketogenic diet or VNS. CBD dose: 1-20 mg/kg/day. 89% had seizure reduction: 18% at 75-100%, 34% at 50-75%, 12% at 25-50%, 26% at <25%. 7% had seizure worsening. 5 patients withdrew due to side effects.","methodology":"Retrospective multicenter study across five Israeli pediatric epilepsy clinics. 74 patients aged 1-18 with intractable epilepsy (resistant to 7+ antiepileptic drugs) were treated with CBD-enriched cannabis oil (20:1 CBD:THC) at 1-20 mg/kg/day for at least 3 months (average 6 months). Seizure frequency was assessed by parental report during clinical visits.","limitations":"Retrospective design with seizure frequency assessed by parental report rather than objective measurement. No control group, so placebo effects cannot be excluded. The CBD:THC ratio was 20:1, so some effects could be from the small amount of THC. Different patients received different doses. Open-label treatment introduces expectation bias."},{"rthcId":"RTHC-01287","title":"E-cigarette use and subsequent cigarette and marijuana use among Hispanic young adults.","authors":"Unger, Jennifer B; Soto, Daniel W; Leventhal, Adam","year":2016,"journal":"Drug and alcohol dependence, 163, 261-4","doi":"10.1016/j.drugalcdep.2016.04.027","pmid":"27141841","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 1,332 Hispanic young adults in Los Angeles over one year. Among those who were not using marijuana in 2014, e-cigarette users were nearly twice as likely to be using marijuana by 2015 (24% vs 12%, OR = 1.97).\n\nThe effect was even stronger for cigarette smoking: among non-smokers, e-cigarette users were over 3 times more likely to become smokers (26% vs 7%, OR = 3.32).\n\nImportantly, among people who were already using marijuana or cigarettes, e-cigarette use was not associated with changes in use of either substance. E-cigarette use was also not associated with smoking cessation among current smokers.\n\nThis pattern suggests e-cigarettes may serve as a gateway to other substances for non-users but do not increase use among existing users or help smokers quit.","whyItMatters":"This is one of the first longitudinal studies to show that e-cigarette use predicts subsequent marijuana initiation, not just tobacco. The finding in a Hispanic young adult population is particularly important given disparities in substance use prevention and treatment access.","specificNumbers":"1,332 Hispanic young adults. Past-month prevalence in 2014: e-cigarettes 9%, cigarettes 21%, marijuana 23%. Among marijuana non-users, e-cigarette users had 1.97x odds of starting marijuana. Among non-smokers, e-cigarette users had 3.32x odds of starting cigarettes.","methodology":"Longitudinal survey study of 1,332 Hispanic young adults (59% female, mean age 22.7) in Los Angeles, California. Data collected in 2014 and 2015. Logistic regression examined whether e-cigarette use in 2014 predicted cigarette and marijuana use in 2015, controlling for age, sex, and other substance use.","limitations":"Observational design cannot prove e-cigarettes caused subsequent substance initiation. Unmeasured confounders (risk-taking personality, peer environment) could explain the association. The sample was entirely Hispanic young adults in Los Angeles, limiting generalizability. Two time points one year apart may miss important temporal patterns."},{"rthcId":"RTHC-01288","title":"Trajectories of perceived discrimination from adolescence to emerging adulthood and substance use among Hispanic youth in Los Angeles.","authors":"Unger, Jennifer B; Soto, Daniel W; Baezconde-Garbanati, Lourdes","year":2016,"journal":"Addictive behaviors, 53, 108-12","doi":"10.1016/j.addbeh.2015.10.009","pmid":"26477013","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers identified four distinct trajectories of perceived racial/ethnic discrimination among Hispanic youth from ages 14 to 23:\n\n1. Low and stable discrimination\n2. Increasing discrimination\n3. Initially high but decreasing discrimination\n4. High and stable discrimination\n\nCompared to the low-stable group, all three groups experiencing higher discrimination had elevated substance use. The increasing discrimination group had higher risk for alcohol, marijuana, and hard drug use. The high-stable group showed the same pattern. Even the group whose discrimination decreased over time still had higher risk for cigarette and alcohol use, suggesting that early exposure to discrimination may have lasting effects even when the experience improves.\n\nThe finding that different discrimination trajectories all led to elevated substance use suggests that experiencing discrimination at any point during adolescence or emerging adulthood is a risk factor.","whyItMatters":"This study establishes that the pattern of discrimination over time, not just its presence at any single point, matters for substance use outcomes. The finding that even decreasing discrimination still elevated some substance use risks suggests that the damage from early discrimination may not be fully reversible and that prevention needs to be proactive rather than reactive.","specificNumbers":"2,722 Hispanic students. Four discrimination trajectory groups identified. Increasing discrimination: higher risk of alcohol, marijuana, and hard drug use. High-stable discrimination: higher risk of alcohol, marijuana, and hard drug use. Decreasing discrimination: higher risk of cigarettes and alcohol.","methodology":"Longitudinal cohort study of 2,722 Hispanic students followed from 9th grade through emerging adulthood (approximately ages 14-23). Perceived discrimination was measured at multiple time points and growth mixture modeling identified four trajectory groups. Substance use outcomes (cigarettes, alcohol, marijuana, hard drugs) were compared across trajectory groups.","limitations":"All participants were Hispanic, so results may not generalize to other racial/ethnic groups. Self-reported discrimination and substance use are both subject to recall and reporting biases. The study cannot determine whether discrimination caused substance use or whether shared underlying factors drove both experiences."},{"rthcId":"RTHC-01289","title":"Prolonged activation of human islet cannabinoid receptors in vitro induces adaptation but not dysfunction.","authors":"Vilches-Flores, Alonso; Franklin, Zara; Hauge-Evans, Astrid C; Liu, Bo; Huang, Guo C; Choudhary, Pratik; Jones, Peter M; Persaud, Shanta J","year":2016,"journal":"BBA clinical, 5, 143-50","doi":"10.1016/j.bbacli.2016.03.009","pmid":"27114924","tags":["neuroscience","appetite"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers exposed human pancreatic islets (the cell clusters that produce insulin) to cannabinoid receptor agonists for up to 5 days and measured the effects on gene expression, hormone secretion, and cell survival.\n\nProlonged activation of both CB1 and CB2 receptors altered the expression of genes encoding endocannabinoid system components, showing the cells adapted to chronic stimulation. However, this adaptation did not translate into impaired function: insulin and glucagon secretion were not significantly affected at 5 days, and cell viability remained intact.\n\nInterestingly, CB2 activation with JWH015 temporarily enhanced insulin and glucagon content at 2 days but this effect normalized by 5 days, suggesting an adaptive response.\n\nThe study also characterized the endocannabinoid system in human islets, finding that the enzymes that make and break down endocannabinoids (NAPE-PLD, FAAH, MAGL) were much more abundant than the receptors themselves or the enzyme DAGLalpha.","whyItMatters":"The endocannabinoid system has been implicated in metabolic dysfunction, and CB1 blockers improved metabolic parameters in clinical trials (rimonabant). This study shows that the metabolic problems associated with endocannabinoid system overactivation in obesity and diabetes are probably not caused by direct damage to the insulin-producing cells.","specificNumbers":"Human islets exposed to CB1 and CB2 agonists for up to 5 days. No major effects on insulin or glucagon secretion at 5 days. JWH015 temporarily enhanced hormone content at 2 days. No significant impact on cell viability via caspase assays.","methodology":"Human pancreatic islets were maintained in culture for 2 and 5 days with or without CB1 (ACEA) or CB2 (JWH015) receptor agonists. Gene expression was measured by RT-PCR, hormone levels by radioimmunoassay, and cell viability by caspase activity assays and morphological assessment.","limitations":"In vitro study using isolated islets, which lack the systemic context of blood flow, nerve supply, and hormonal signals present in the body. The 5-day exposure may not capture longer-term effects. The agonist concentrations may not reflect physiological endocannabinoid levels. Human islets from organ donors may have been affected by the donor's health status."},{"rthcId":"RTHC-01290","title":"Cue-induced striatal activity in frequent cannabis users independently predicts cannabis problem severity three years later.","authors":"Vingerhoets, W A M; Koenders, L; van den Brink, W; Wiers, R W; Goudriaan, A E; van Amelsvoort, T; de Haan, L; Cousijn, J","year":2016,"journal":"Journal of psychopharmacology (Oxford, England), 30(2), 152-8","doi":"10.1177/0269881115620436","pmid":"26645206","tags":["addiction","neuroscience"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers scanned the brains of 31 treatment-naive frequent cannabis users while they viewed cannabis-related images and neutral images. Three years later, 23 of these participants were re-assessed.\n\nThe amount of brain activation in the left striatum (specifically the putamen) in response to cannabis cues at baseline significantly predicted problem severity at the 3-year follow-up, as measured by the Cannabis Use Disorder Identification Test. This prediction was independent of the amount of cannabis used, meaning it was not simply that heavier users had more problems.\n\nNone of the cue-induced brain activations predicted the amount of cannabis used at follow-up. This distinction is important: the brain response specifically predicted problems from use, not the quantity of use itself.\n\nAt follow-up, clinically dependent users showed higher baseline striatal activation (at trend level) compared to non-dependent users.","whyItMatters":"This study demonstrates that a brain scan can predict who will develop cannabis problems years before those problems fully manifest. If replicated, cue-reactivity fMRI could potentially serve as a biomarker for identifying high-risk cannabis users who might benefit from early intervention.","specificNumbers":"31 users at baseline, 23 at follow-up. Left striatum cue-reactivity significantly predicted Cannabis Use Disorder Identification Test scores at 3 years (p < 0.001). This prediction was independent of use quantity. Dependent users at follow-up showed higher baseline striatal activation (trend level).","methodology":"Prospective neuroimaging study. 31 treatment-naive frequent cannabis users completed a cue-reactivity fMRI task at baseline. 23 participants were reassessed 3 years later for cannabis use quantity and problem severity. Analyses focused on brain regions known to be important in cue reactivity: anterior cingulate cortex, orbitofrontal cortex, ventral tegmental area, amygdala, and striatum.","limitations":"Small sample size (23 at follow-up) means results should be considered preliminary. The striatal finding was in the dorsal (putamen) rather than ventral striatum, which is typically associated with cue reactivity. Some baseline-to-follow-up attrition occurred. A single brain scan may not capture the full picture of neural cue reactivity."},{"rthcId":"RTHC-01291","title":"Is attention deficit/hyperactivity disorder among men associated with initiation or escalation of substance use at 15-month follow-up? A longitudinal study involving young Swiss men.","authors":"Vogel, Tanja; Dom, Geert; van de Glind, Geurt; Studer, Joseph; Gmel, Gerhard; Strik, Werner; Moggi, Franz","year":2016,"journal":"Addiction (Abingdon, England), 111(10), 1867-78","doi":"10.1111/add.13422","pmid":"27061514","tags":["cognition","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"In a large cohort of 5,103 Swiss Army conscripts followed over 15 months, men screening positive for ADHD (4.2%) showed heavier baseline substance use and significantly higher rates of alcohol, tobacco, and cannabis use disorders compared to men without ADHD.\n\nHowever, the pattern over time was nuanced. While ADHD men used more of these substances, their use did not escalate over the follow-up period. The rates remained stable rather than increasing.\n\nWhere ADHD made the biggest difference was in initiating new substances. Men with ADHD were significantly more likely to start using amphetamines (OR = 3.81) and to begin non-medical use of ADHD medication (OR = 4.45). These associations were independent of conduct disorder in early adolescence, meaning ADHD itself, not just the behavioral problems that sometimes accompany it, was the risk factor.","whyItMatters":"This study disentangles ADHD from conduct disorder in predicting substance use trajectories. The finding that ADHD independently predicts initiation of new substances (not just continued use of existing ones) suggests that the novelty-seeking and impulsivity associated with ADHD drive the exploration of new drugs, which has important prevention implications.","specificNumbers":"5,103 participants. ADHD prevalence: 4.2% (n=215). ADHD associated with cannabis use disorder (chi-squared = 48.43, p < 0.001). Amphetamine initiation OR = 3.81 (2.20-6.60). ADHD medication misuse initiation OR = 4.45 (2.06-9.60). All associations independent of conduct disorder.","methodology":"Two-wave longitudinal cohort study of 5,103 male Swiss Army conscripts (mean age 20.0) from 21 cantons. ADHD was assessed using the Adult ADHD Self-Report Scale and conduct disorder using the MINI International Neuropsychiatric Interview Plus at baseline. Substance use was measured by questionnaire at baseline and 15-month follow-up.","limitations":"All-male military conscript sample limits generalizability to women and non-military populations. ADHD was assessed by self-report screening, not clinical diagnosis. The 15-month follow-up is relatively short. Swiss substance use patterns and drug availability may differ from other countries."},{"rthcId":"RTHC-01292","title":"Cannabinoids for fibromyalgia.","authors":"Walitt, Brian; Klose, Petra; Fitzcharles, Mary-Ann; Phillips, Tudor; Häuser, Winfried","year":2016,"journal":"The Cochrane database of systematic reviews, 7(7), CD011694","doi":"10.1002/14651858.CD011694.pub2","pmid":"27428009","tags":["medical-cannabis","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The Cochrane Collaboration, considered the gold standard for medical evidence review, found only two randomized controlled trials testing cannabinoids for fibromyalgia, with a combined total of just 72 participants. Both studies tested nabilone (a synthetic cannabinoid) at 1 mg/day.\n\nNo study reported the proportion of participants achieving meaningful pain relief (30% or 50% reduction) or significant improvement. All evidence was rated as very low quality due to indirectness, imprecision, and potential reporting bias.\n\nThird-tier (very low quality) evidence suggested nabilone might be slightly better than placebo for pain and quality of life, and slightly better than amitriptyline for sleep. But the differences were modest and the evidence was insufficient for any clinical recommendation.\n\nNo studies were found testing herbal cannabis, plant-based cannabinoids, or any synthetic cannabinoid other than nabilone for fibromyalgia.","whyItMatters":"Fibromyalgia patients are among the most common medical cannabis users, yet this Cochrane review reveals that the evidence supporting this use is almost nonexistent. Only 72 total patients have been studied in controlled trials, and the evidence quality is very low. This represents a massive gap between patient behavior and scientific evidence.","specificNumbers":"2 RCTs included. 72 total participants (studies of 32 and 40). Both tested nabilone 1 mg/day at bedtime. Study durations: 4 and 6 weeks. Very low quality evidence overall. No studies of herbal cannabis or other cannabinoids found.","methodology":"Cochrane systematic review searching CENTRAL, MEDLINE, and EMBASE through April 2016, plus clinical trial registries and author contact. Included RCTs of at least 4 weeks using any cannabis formulation for adults with fibromyalgia. Used three-tier evidence hierarchy and GRADE assessment.","limitations":"The review is limited by the scarcity of available trials rather than by its own methodology. Only two small studies existed. Both used nabilone specifically, which may not represent the effects of other cannabinoids or whole-plant cannabis. The short study durations (4-6 weeks) may not capture long-term effects."},{"rthcId":"RTHC-01293","title":"Evidence-based Treatment Options in Cannabis Dependency.","authors":"Walther, Lisa; Gantner, Andreas; Heinz, Andreas; Majić, Tomislav","year":2016,"journal":"Deutsches Arzteblatt international, 113(39), 653-659","doi":"10.3238/arztebl.2016.0653","pmid":"27776623","tags":["addiction","quitting","withdrawal"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This evidence-based review of treatment options for cannabis dependence found psychotherapy to be the most effective approach, with all psychotherapeutic interventions supported at evidence level Ia (the highest).\n\nCognitive behavioral therapy (CBT) combined with other techniques showed moderate to large effects (Cohen's d = 0.53-0.9) on cannabis consumption, psychosocial functioning, and dependence severity. Systemic multidimensional family therapy was beneficial for younger adolescents with high use and psychiatric comorbidities. Motivational interviewing was effective for patients regardless of initial desire for abstinence.\n\nFor pharmacotherapy, gabapentin showed a weak effect (d = 0.26) on consumption and abstinence. Cannabinoid receptor antagonists alleviated withdrawal symptoms. Critically, serotonergic antidepressants were found to potentially worsen withdrawal and increase relapse likelihood.\n\nAbstinence rates even with psychotherapy remained only moderate, highlighting the need for continued treatment development.","whyItMatters":"With cannabis use increasing globally and cannabis dependence now recognized as a clinical condition, practitioners need guidance on evidence-based treatments. This review provides a clear hierarchy: psychotherapy first, specific pharmacological adjuncts for withdrawal management, and a warning against using serotonergic antidepressants.","specificNumbers":"CBT: effect size d = 0.53-0.9 (evidence level Ia). Gabapentin: d = 0.26 (evidence level Ib). Cannabinoid receptor antagonists for withdrawal: d = 0.223 and 0.481 (evidence level Ib). Serotonergic antidepressants: may worsen withdrawal.","methodology":"Selective literature review of randomized controlled trials from PubMed and Cochrane databases, evaluating psychotherapeutic and pharmacological interventions for cannabis dependence. Evidence levels were assigned according to standard hierarchies.","limitations":"Selective rather than systematic review methodology. The evidence base for cannabis dependence treatment is smaller than for other substances. Many studies have small sample sizes and limited follow-up periods. The review was published in German, potentially limiting its reach."},{"rthcId":"RTHC-01294","title":"Unintentional Pediatric Exposures to Marijuana in Colorado, 2009-2015.","authors":"Wang, George Sam; Le Lait, Marie-Claire; Deakyne, Sara J; Bronstein, Alvin C; Bajaj, Lalit; Roosevelt, Genie","year":2016,"journal":"JAMA pediatrics, 170(9), e160971","doi":"10.1001/jamapediatrics.2016.0971","pmid":"27454910","tags":["youth","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Researchers examined unintentional marijuana exposures in children under 10 at Children's Hospital Colorado and the regional poison center from 2009 to 2015, spanning the periods before and after recreational marijuana legalization.\n\nThe rate of marijuana-related visits to the children's hospital nearly doubled, from 1.2 per 100,000 to 2.3 per 100,000 in the two years before versus after legalization. Annual poison center cases increased more than five-fold, from 9 in 2009 to 47 in 2015.\n\nColorado's increase (34% per year) outpaced the rest of the United States (19% per year), though both were increasing. The median age of affected children was about 2 years.\n\nEdible products were responsible for roughly half of all exposures. Child-resistant containers were absent in 9% of known scenarios, and poor supervision or storage was reported in 34%. Almost half of children's hospital patients in the two years after legalization were exposed to recreational (not medical) marijuana.","whyItMatters":"This is one of the most cited studies on the unintended pediatric consequences of marijuana legalization. It demonstrated that legalization led to more children accidentally ingesting marijuana, particularly edible products that can look like candy or treats. The findings influenced child-resistant packaging and dosage labeling regulations in multiple states.","specificNumbers":"81 children's hospital patients. 163 RPC cases. Median age: ~2 years. Hospital visit rate: 1.2 to 2.3 per 100,000 (p = 0.02). RPC cases: 9 (2009) to 47 (2015), 5-fold increase. Colorado increase: 34%/year vs US: 19%/year. Edibles: ~48-52% of exposures. Median hospital stay: 11 hours (26 hours if admitted).","methodology":"Retrospective cohort study of marijuana exposures in children 0-9 years at Children's Hospital Colorado (81 patients) and Colorado Regional Poison Center (163 cases) from January 2009 through December 2015. Rates were compared between the 2-year periods before and after recreational legalization. RPC trends were compared with the rest of the United States.","limitations":"Retrospective design relies on cases that were brought to medical attention. Less severe exposures may not have resulted in hospital visits or poison center calls. The study cannot definitively attribute all increases to legalization, as other factors (increased awareness, changing reporting practices) may contribute. The study covers only one state and one children's hospital."},{"rthcId":"RTHC-01295","title":"Decarboxylation Study of Acidic Cannabinoids: A Novel Approach Using Ultra-High-Performance Supercritical Fluid Chromatography/Photodiode Array-Mass Spectrometry.","authors":"Wang, Mei; Wang, Yan-Hong; Avula, Bharathi; Radwan, Mohamed M; Wanas, Amira S; van Antwerp, John; Parcher, Jon F; ElSohly, Mahmoud A; Khan, Ikhlas A","year":2016,"journal":"Cannabis and cannabinoid research, 1(1), 262-271","doi":"10.1089/can.2016.0020","pmid":"28861498","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01296","title":"One Minute of Marijuana Secondhand Smoke Exposure Substantially Impairs Vascular Endothelial Function.","authors":"Wang, Xiaoyin; Derakhshandeh, Ronak; Liu, Jiangtao; Narayan, Shilpa; Nabavizadeh, Pooneh; Le, Stephenie; Danforth, Olivia M; Pinnamaneni, Kranthi; Rodriguez, Hilda J; Luu, Emmy; Sievers, Richard E; Schick, Suzaynn F; Glantz, Stanton A; Springer, Matthew L","year":2016,"journal":"Journal of the American Heart Association, 5(8)","doi":"10.1161/JAHA.116.003858","pmid":"27464788","tags":["cardiovascular","respiratory"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers exposed rats to marijuana secondhand smoke at levels comparable to real-world tobacco secondhand smoke conditions and measured blood vessel function using femoral artery flow-mediated dilation (FMD), a standard measure of endothelial health.\n\nJust one minute of marijuana smoke exposure impaired FMD to a comparable extent as tobacco smoke. However, the recovery time was dramatically different: tobacco smoke impairment resolved relatively quickly, while marijuana smoke impairment persisted for at least 90 minutes.\n\nCritically, the impairment occurred even when the marijuana had no cannabinoids (THC, CBD removed) and when the rolling paper was removed (burning marijuana plant only). This means the vascular damage was caused by the combustion products themselves, not by any specific component of cannabis or rolling paper.\n\nEndothelium-independent vasodilation (tested with nitroglycerin) was not affected, confirming the damage was specific to the endothelial cells lining blood vessels.","whyItMatters":"As marijuana legalization expands, the assumption that marijuana secondhand smoke is harmless is increasingly relevant. This study demonstrates that marijuana smoke impairs blood vessel function through the same mechanism as tobacco smoke but with longer-lasting effects, challenging the notion that marijuana SHS is benign.","specificNumbers":"1 minute of marijuana SHS impaired FMD comparably to tobacco SHS. Marijuana SHS impairment lasted at least 90 minutes, longer than tobacco. Effect occurred without cannabinoids and without rolling paper. Endothelium-independent dilation was not affected.","methodology":"Rats had femoral artery FMD measured before and at multiple time points after exposure to marijuana secondhand smoke at concentrations matching real-world tobacco SHS conditions. Multiple conditions were tested: regular marijuana, cannabinoid-free marijuana, marijuana without rolling paper, tobacco, and chamber air (control). FMD and nitroglycerin-mediated dilation were used to distinguish endothelium-dependent from independent effects.","limitations":"This was a rat study, and the vascular response may differ in humans. The exposure was acute (one minute), and chronic effects were not studied. FMD is a marker of endothelial function, and the link between acute FMD impairment and long-term cardiovascular disease requires further investigation. The concentrations used matched tobacco SHS conditions but may not represent all marijuana smoke exposure scenarios."},{"rthcId":"RTHC-01297","title":"Urinary concentrations of PAH and VOC metabolites in marijuana users.","authors":"Wei, Binnian; Alwis, K Udeni; Li, Zheng; Wang, Lanqing; Valentin-Blasini, Liza; Sosnoff, Connie S; Xia, Yang; Conway, Kevin P; Blount, Benjamin C","year":2016,"journal":"Environment international, 88, 1-8","doi":"10.1016/j.envint.2015.12.003","pmid":"26690539","tags":["respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed urinary biomarkers of combustion by-products in participants from the National Health and Nutrition Examination Surveys (2005-2012), comparing self-reported recent marijuana users with non-users while carefully controlling for tobacco smoke exposure.\n\nExclusive marijuana users (no tobacco) had significantly elevated levels of multiple monohydroxy polycyclic aromatic hydrocarbons (OH-PAHs) compared to non-users. They also had significantly higher urinary thiocyanate and metabolites of acrylonitrile and acrylamide, all indicators of exposure to combustion toxicants.\n\nThese chemicals are concerning because PAHs include known carcinogens, and VOC metabolites indicate exposure to compounds linked to cancer, respiratory disease, and other health effects. The findings demonstrate that marijuana smoke, independent of tobacco, exposes users to many of the same toxic combustion by-products found in tobacco smoke.","whyItMatters":"While much attention focuses on the pharmacological effects of THC and CBD, the simple act of smoking any plant material produces toxic combustion by-products. This study provides biomarker evidence that marijuana smokers are exposed to many of the same carcinogens as tobacco smokers, supporting the rationale for non-combustion delivery methods.","specificNumbers":"NHANES data from 2005-2012. Multiple OH-PAH metabolites significantly elevated in marijuana users (p < 0.05). Urinary thiocyanate (p < 0.001), acrylonitrile metabolites (p < 0.001), and acrylamide metabolites (p < 0.001) all significantly higher in marijuana users vs non-users after controlling for tobacco.","methodology":"Cross-sectional analysis of NHANES data from 2005-2012. Urinary PAH and VOC metabolites were measured in adults aged 18 and older. Participants were categorized as exclusive recent marijuana users or non-users based on self-report. Multiple regression analyses adjusted for potential confounders including tobacco smoke exposure.","limitations":"Cross-sectional design provides a snapshot rather than exposure trends over time. Self-reported marijuana use may be underreported. The study identified exclusive marijuana users but cannot account for all potential confounders. Urinary metabolite levels indicate exposure but do not directly measure health outcomes. The study cannot determine dose-response relationships."},{"rthcId":"RTHC-01298","title":"Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment.","authors":"Wei, Don; Dinh, Drake; Lee, DaYeon; Li, Dandan; Anguren, Allison; Moreno-Sanz, Guillermo; Gall, Christine M; Piomelli, Daniele","year":2016,"journal":"Cannabis and cannabinoid research, 1(1), 81-89","doi":"10.1089/can.2015.0008","pmid":"28861483","tags":["neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers tested whether enhancing the endocannabinoid system could correct the core social impairment seen in autism spectrum disorder (ASD). They used URB597, a compound that increases anandamide levels by blocking the enzyme (FAAH) that breaks it down.\n\nThe results were striking: FAAH inhibition completely reversed social impairment in both the BTBR mouse model (a widely used autism model) and the fmr1 knockout mouse (a model of Fragile X Syndrome, the most common genetic cause of autism).\n\nThe social improvement was blocked by a CB1 receptor antagonist, confirming the mechanism operates through the endocannabinoid system. The effect was likely independent of anxiety changes, as FAAH inhibition did not alter BTBR mouse behavior in an anxiety test.\n\nThis builds on the researchers' earlier discovery that anandamide mediates the social reward effects of oxytocin, the \"social bonding\" hormone, through the endocannabinoid system.","whyItMatters":"Autism spectrum disorder currently has no pharmacological treatment for its core symptom: social impairment. The finding that endocannabinoid enhancement reversed social deficits in two different genetic models suggests a potentially broad therapeutic approach that addresses the core of ASD rather than peripheral symptoms.","specificNumbers":"URB597 completely reversed social impairment in both BTBR and fmr1-/- mice. CB1 receptor blockade prevented the prosocial effect. No change in anxiety behavior (elevated plus maze) in BTBR mice treated with URB597.","methodology":"Two mouse models of ASD were tested: BTBR mice and fmr1-/- mice (Fragile X model). Social behavior was assessed using the three-chambered social approach test, a standard paradigm measuring preference for social interaction. URB597 (FAAH inhibitor) was administered to increase anandamide levels. The CB1 receptor antagonist rimonabant was used to confirm receptor specificity. The elevated plus maze tested anxiety independently.","limitations":"Mouse models of autism, while useful, cannot fully capture the complexity of human ASD. The three-chambered test measures social approach, which is only one aspect of social behavior. FAAH inhibitors have not been tested for social behavior in humans with ASD. The study used acute drug administration, not chronic treatment."},{"rthcId":"RTHC-01299","title":"Chronic Δ(9)-Tetrahydrocannabinol Administration Reduces IgE(+)B Cells but Unlikely Enhances Pathogenic SIVmac251 Infection in Male Rhesus Macaques of Chinese Origin.","authors":"Wei, Qiang; Liu, Li; Cong, Zhe; Wu, Xiaoxian; Wang, Hui; Qin, Chuan; Molina, Patricia; Chen, Zhiwei","year":2016,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 11(3), 584-591","doi":"10.1007/s11481-016-9674-9","pmid":"27109234","tags":["inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Sixteen male Chinese-origin rhesus macaques were divided into four groups and treated with daily THC or placebo for 428 days. After one month of THC/placebo, half of each group was infected with a pathogenic strain of SIV (the primate equivalent of HIV).\n\nChronic THC did not increase viral loads: peak and steady-state plasma viral levels were comparable between THC-treated and placebo-treated infected animals. All infected macaques showed similar immune decline regardless of THC treatment, including drops in CD4/CD8 ratios and CD4+ T cell counts.\n\nTHC treatment significantly reduced the frequency of circulating IgE+ B cells, a finding with potential relevance to allergic and inflammatory conditions.\n\nDuring the study period, only one THC-treated infected animal died, compared to two deaths in the placebo-infected group. While the numbers are too small for statistical conclusions, the trend aligns with previous studies in Indian macaques showing THC did not worsen and may have reduced SIV-related mortality.","whyItMatters":"THC (as Marinol) is used as an appetite stimulant for AIDS patients, but whether THC affects HIV progression has been a concern. This study, using a primate model with a brain-tropic SIV strain causing neuroAIDS, provides reassurance that chronic THC does not worsen viral infection and may have modest immunomodulatory benefits.","specificNumbers":"16 macaques. 428 days of treatment. THC dose: 0.32 mg/kg IM twice daily. No significant differences in peak or steady-state viral loads. THC significantly reduced IgE+ B cell frequency. Deaths: 1/4 THC+SIV+ vs 2/4 placebo+SIV+.","methodology":"Controlled primate study. 16 male Chinese-origin rhesus macaques in 4 groups (THC+SIV+, THC+SIV-, placebo+SIV+, placebo-SIV-). THC administered intramuscularly at 0.32 mg/kg twice daily for 428 days. SIV challenge performed one month after starting THC/placebo. Viral loads, immune markers, and IgE+ B cells monitored throughout.","limitations":"Very small sample size (4 per group). The SIV strain used was a brain-tropic isolate from Chinese macaques, which may not represent all HIV subtypes. Chinese-origin macaques may respond differently to SIV than Indian-origin macaques used in previous studies. The THC dose and route (intramuscular) may not reflect human cannabis use patterns."},{"rthcId":"RTHC-01300","title":"Brain Imaging Studies on the Cognitive, Pharmacological and Neurobiological Effects of Cannabis in Humans: Evidence from Studies of Adult Users.","authors":"Weinstein, Aviv; Livny, Abigail; Weizman, Abraham","year":2016,"journal":"Current pharmaceutical design, 22(42), 6366-6379","doi":"10.2174/1381612822666160822151323","pmid":"27549374","tags":["cognition","neuroscience","psychosis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This comprehensive review synthesized 103 structural and functional brain imaging studies of cannabis users published between 2000 and 2016, providing the most complete picture to date of how cannabis affects the human brain.\n\nStructural findings: Regular cannabis use was associated with volumetric and tissue changes, particularly in the hippocampus (memory) and amygdala (emotion). Both gray matter and white matter alterations were documented.\n\nFunctional findings: Cannabis affected attention, memory, decision-making, emotional processing, and social cognition. Brain imaging showed that regular users recruited additional brain regions to compensate for impaired function, achieving similar performance through greater neural effort.\n\nDopamine findings: Pharmacological studies showed a modest increase in striatal dopamine after acute THC. However, chronic users showed reduced dopamine transporter occupancy and reduced dopamine synthesis, but not reduced dopamine receptor density. This pattern differs from other drugs of abuse.\n\nCBD vs THC: Studies confirmed that THC and CBD have opposing effects on emotion, cognition, and brain activation, with CBD protecting against THC's psychoactive effects.\n\nCB1 receptor imaging: PET studies showed downregulation of CB1 receptors in regular cannabis users.","whyItMatters":"This is one of the most comprehensive summaries of cannabis neuroimaging research. By integrating structural, functional, dopaminergic, and receptor imaging data, it provides a unified picture of how cannabis reshapes the brain. The compensatory recruitment finding is particularly important: normal task performance can mask underlying neural changes.","specificNumbers":"103 studies reviewed (structural and functional). Hippocampus and amygdala most consistently affected structurally. Chronic use: reduced dopamine transporter occupancy and synthesis. CB1 receptor downregulation confirmed by PET. CBD showed protective effects against THC.","methodology":"Systematic literature review of 103 eligible structural and functional brain imaging studies of recreational and regular cannabis users published January 2000 to January 2016. Studies included MRI, fMRI, PET, and pharmacological challenge studies.","limitations":"Most studies were cross-sectional, limiting causal conclusions. Study populations, methods, and definitions of \"regular use\" varied widely. Publication bias may favor studies finding differences. The review period ends in early 2016 and does not capture more recent neuroimaging advances."},{"rthcId":"RTHC-01301","title":"Abnormal medial prefrontal cortex activity in heavy cannabis users during conscious emotional evaluation.","authors":"Wesley, Michael J; Lile, Joshua A; Hanlon, Colleen A; Porrino, Linda J","year":2016,"journal":"Psychopharmacology, 233(6), 1035-44","doi":"10.1007/s00213-015-4180-y","pmid":"26690589","tags":["cognition","mental-health","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used fMRI to compare brain activity between 16 heavy cannabis users and 17 non-using controls as they evaluated emotional images from a standardized set (IAPS).\n\nBoth groups identified the same images as emotional and showed similar activation in visual, midbrain, and middle cingulate regions. But important differences emerged.\n\nControl participants showed amygdala and inferior frontal gyrus activation during emotional evaluation. Cannabis users did not. Cannabis users showed medial prefrontal cortex (mPFC) deactivation during emotional processing. Controls did not.\n\nDirect comparison confirmed that mPFC activity during both positive and negative emotional evaluation was significantly reduced in cannabis users. The researchers noted this pattern resembles what happens when people are under high cognitive load from non-emotional tasks, suggesting cannabis users may be expending more cognitive effort to process emotional information.","whyItMatters":"Previous research showed that cannabis users have diminished unconscious (subconscious) neural responses to emotional stimuli. This study extends the finding to conscious emotional evaluation, suggesting that the emotional processing deficit is pervasive rather than limited to automatic processing. This could affect relationships, empathy, and social functioning.","specificNumbers":"16 heavy cannabis users vs 17 controls. Both groups agreed on which stimuli were emotional. Controls showed amygdala and IFG activation; users did not. Users showed mPFC deactivation; controls did not. Between-group: significant mPFC hypoactivation in users for both positive and negative evaluation.","methodology":"Cross-sectional fMRI study. 16 heavy cannabis users and 17 non-using controls evaluated and categorized International Affective Picture System (IAPS) stimuli. Individual judgments were used to isolate brain activity during emotional versus neutral evaluation. Within-group and between-group analyses were performed.","limitations":"Small sample size (16 and 17). Cross-sectional design cannot determine whether cannabis caused the changes or whether pre-existing differences led to cannabis use. Users were not acutely intoxicated, but chronic residual effects cannot be separated from withdrawal. The study does not report the duration or amount of cannabis use in detail."},{"rthcId":"RTHC-01302","title":"Antimüllerian hormone in relation to tobacco and marijuana use and sources of indoor heating/cooking.","authors":"White, Alexandra J; Sandler, Dale P; D'Aloisio, Aimee A; Stanczyk, Frank; Whitworth, Kristina W; Baird, Donna D; Nichols, Hazel B","year":2016,"journal":"Fertility and sterility, 106(3), 723-30","doi":"10.1016/j.fertnstert.2016.05.015","pmid":"27240193","tags":["pregnancy","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined whether exposure to combustion products from tobacco, marijuana, and indoor heating sources affected antimullerian hormone (AMH) levels, a biomarker of ovarian reserve (the number of remaining eggs).\n\nHeavy tobacco smoking (20+ cigarettes/day) was associated with a 56.2% reduction in AMH levels compared to nonsmokers. Long-term environmental tobacco smoke exposure (10+ years) was associated with a 31.3% reduction. Indoor burning of wood or artificial fire logs was also associated with lower AMH.\n\nHowever, marijuana use was not associated with any change in AMH levels. Despite producing combustion by-products similar to tobacco, marijuana did not show the same toxic effect on ovarian reserve.","whyItMatters":"The finding that marijuana does not appear to affect ovarian reserve (unlike tobacco) is reassuring for women of reproductive age who use cannabis. It suggests that while both substances produce combustion by-products, their effects on reproductive biology differ, possibly due to different active compounds or exposure patterns.","specificNumbers":"913 premenopausal women. Heavy smoking (20+ cigs/day): -56.2% AMH. 10+ years ETS: -31.3% AMH. Wood burning 10+ times/year: -36.0% AMH. Fire logs 10+ times/year: -45.8% AMH. Marijuana: no significant association.","methodology":"Cross-sectional analysis of 913 premenopausal women (ages 35-54) from the Sister Study cohort (n=50,884). Serum AMH was measured by ultrasensitive ELISA. Exposure to tobacco, marijuana, and indoor heating/cooking sources was assessed by questionnaire.","limitations":"Cross-sectional design. Self-reported marijuana use may be underreported. The study could not assess frequency or amount of marijuana use in detail. AMH is one marker of ovarian reserve but does not represent all aspects of reproductive health. The study population (Sister Study) consists of women with sisters who had breast cancer, which may introduce selection bias."},{"rthcId":"RTHC-01303","title":"The inhibitory effect of combination treatment with leptin and cannabinoid CB1 receptor agonist on food intake and body weight gain is mediated by serotonin 1B and 2C receptors.","authors":"Wierucka-Rybak, M; Wolak, M; Juszczak, M; Drobnik, J; Bojanowska, E","year":2016,"journal":"Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 67(3), 457-63","doi":null,"pmid":"27512006","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Previous research showed that combining leptin (a satiety hormone) with AM 251 (a CB1 receptor blocker) reduced food intake and body weight more effectively than either compound alone. This study investigated whether the serotonin system mediates this effect.\n\nAs expected, combining leptin and AM 251 for 3 days significantly reduced food intake and body weight in rats, while neither compound alone had a significant effect at the doses used.\n\nBlocking either serotonin 5-HT1B receptors (with GR 127935) or 5-HT2C receptors (with SB 242084) completely abolished both the appetite-reducing and weight-loss effects of the leptin/AM 251 combination.\n\nThis reveals that the serotonin system is a necessary downstream mediator of the appetite-suppressing interaction between leptin and the endocannabinoid system.","whyItMatters":"Understanding how appetite-regulating systems interact is crucial for developing obesity treatments. The endocannabinoid system (targeted by the withdrawn drug rimonabant), leptin signaling (disrupted in obesity), and serotonin (targeted by several appetite medications) form an interconnected network. This study maps one of those connections.","specificNumbers":"Leptin 100 micrograms/kg + AM 251 1 mg/kg: significant reduction in food intake and body weight over 3 days. GR 127935 (3 mg/kg) or SB 242084 (0.5 mg/kg) completely abolished these effects. Neither leptin nor AM 251 alone at these doses significantly affected food intake.","methodology":"Male Wistar rats received simultaneous injections of leptin (100 micrograms/kg) and AM 251 (1 mg/kg) with or without serotonin receptor antagonists (GR 127935 for 5-HT1B, SB 242084 for 5-HT2C) for 3 days. Food intake and body weight were measured.","limitations":"Rat study that may not translate directly to human appetite regulation. Three days of treatment is short and does not address long-term effects or tolerance. The serotonin antagonists used block specific receptor subtypes, but the serotonin system is complex with many interacting receptors."},{"rthcId":"RTHC-01304","title":"The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model.","authors":"Wilkerson, Jenny L; Niphakis, Micah J; Grim, Travis W; Mustafa, Mohammed A; Abdullah, Rehab A; Poklis, Justin L; Dewey, William L; Akbarali, Hamid; Banks, Matthew L; Wise, Laura E; Cravatt, Benjamin F; Lichtman, Aron H","year":2016,"journal":"The Journal of pharmacology and experimental therapeutics, 357(1), 145-56","doi":"10.1124/jpet.115.229971","pmid":"26791602","tags":["pain","neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers combined morphine with MJN110, a selective MAGL inhibitor that boosts 2-AG levels, in a mouse model of neuropathic pain (chronic constriction injury).\n\nWhen used alone, both drugs reduced pain in a dose-dependent manner. When combined at low doses, the effect was synergistic (better than additive), meaning significantly lower doses of each drug produced full pain relief.\n\nThe combination produced pain relief through mu-opioid, CB1, and CB2 receptors simultaneously. Critically, the combination avoided three major side effects: it did not reduce gastric motility (no constipation), did not produce cannabis-like subjective effects (drug discrimination test), and when given repeatedly for 6 days, showed no evidence of tolerance development.\n\nThis is significant because opioid tolerance, constipation, and addiction are the primary clinical limitations of opioid pain treatment.","whyItMatters":"The opioid epidemic has highlighted the urgent need for alternative or opioid-sparing pain treatments. This study shows that boosting the body's natural endocannabinoid system can dramatically reduce the amount of morphine needed for pain relief while avoiding the most dangerous opioid side effects, including tolerance that drives dose escalation.","specificNumbers":"Morphine ED50: 2.4 mg/kg. MJN110 ED50: 0.43 mg/kg. Combination: synergistic (isobolographic analysis). 6 days of twice-daily combination dosing: no tolerance. No reduction in gastric motility. No cannabimimetic effects in drug discrimination. Required mu-opioid, CB1, and CB2 receptors.","methodology":"Mouse chronic constriction injury model of neuropathic pain. Dose-response curves generated for morphine and MJN110 separately. Isobolographic analysis determined synergistic, additive, or antagonistic interactions. Receptor involvement confirmed with selective antagonists for mu-opioid, CB1, and CB2 receptors. Side effect testing included gastric motility, drug discrimination (cannabimimetic effects), and 6-day repeated dosing for tolerance assessment.","limitations":"Mouse study that needs human translation. The 6-day tolerance assessment is short. The neuropathic pain model (CCI) may not represent all chronic pain conditions. MJN110 is a research tool, not an approved drug. The drug discrimination test for cannabimimetic effects may not capture all subjective experiences relevant to humans."},{"rthcId":"RTHC-01305","title":"Do police arrestees substitute legal highs for other drugs?","authors":"Wilkins, Chris; Parker, Karl; Prasad, Jitesh; Jawalkar, Sonie","year":2016,"journal":"The International journal on drug policy, 31, 74-9","doi":"10.1016/j.drugpo.2016.01.006","pmid":"26948501","tags":["synthetic-cannabinoids","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers interviewed 848 police detainees about their drug use, with a focus on whether legal highs (primarily synthetic cannabinoids) substituted for illegal drugs.\n\nAmong legal high users, 96% had used synthetic cannabinoids (SC), and 94% of those reporting substitution had substituted natural cannabis. Overall, 20% of SC+cannabis users reported reducing or stopping cannabis, while only 6% reported using more cannabis.\n\nHowever, the picture was complex. All SC users had higher baseline cannabis consumption regardless of substitution behavior. SC users who reported using more cannabis also used more methamphetamine and ecstasy, suggesting a polysubstance pattern rather than simple substitution.\n\nSC users were more likely to have recently been in drug treatment, suggesting this population may have been seeking alternatives to manage use.","whyItMatters":"The question of whether legal highs substitute for or complement illegal drug use has significant policy implications. A 20% reduction in cannabis use among SC users suggests modest substitution, but the finding that SC users consumed more cannabis overall complicates the harm reduction argument.","specificNumbers":"848 detainees. 96% of LH users used synthetic cannabinoids. 94% of substituters replaced cannabis. 54% never used SC. 34% used SC without changing cannabis. 9% used SC and reduced/stopped cannabis. 3% used SC and increased cannabis.","methodology":"Cross-sectional survey of 848 detainees at four central police stations in New Zealand. Detainees were interviewed about drug and legal high use and asked what impact legal high use had on their other drug use. Groups were compared on demographics and substance use levels.","limitations":"Police detainee population is not representative of all drug users. Self-reported substitution behavior may not be reliable. The cross-sectional design cannot establish causation. The \"legal\" status of synthetic cannabinoids was specific to New Zealand's regulatory context at the time."},{"rthcId":"RTHC-01306","title":"An exploratory study of the health harms and utilisation of health services of frequent legal high users under the interim regulated legal high market in central Auckland.","authors":"Wilkins, Chris; Prasad, Jitesh; Wong, K C; Rychert, Marta; Graydon-Guy, Thomas","year":2016,"journal":"The New Zealand medical journal, 129(1431), 51-8","doi":null,"pmid":"27005874","tags":["synthetic-cannabinoids","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers recruited 105 frequent legal high users from outside randomly selected licensed legal high stores in central Auckland during a period when synthetic cannabinoids were sold legally in New Zealand.\n\nEighty percent used synthetic cannabinoids (SC), and use was intensive: 47% of SC users consumed daily or more. A striking 58% of SC users were classified as dependent. Twenty-seven percent reported a lifetime history of mental illness.\n\nThe most commonly reported problems from SC use were insomnia (29%), nausea/vomiting (25%), short temper/agitation (21%), anxiety (21%), strange thoughts (16%), and heart palpitations (14%).\n\nDespite these problems, health service utilization was low: only 9% had seen a doctor about SC use, 3% called an ambulance, and 3% visited an emergency department. Most SC users also used other substances, including alcohol (80%), cannabis (59%), ecstasy (18%), and methamphetamine (15%).","whyItMatters":"This study captures a population using synthetic cannabinoids during a brief period of legal regulated sale. The 58% dependence rate is alarming and higher than typical cannabis dependence rates, supporting the argument that synthetic cannabinoids have greater addiction potential than natural cannabis.","specificNumbers":"105 participants. 80% used SC. 47% used SC daily+. 58% of SC users met dependence criteria. 27% had lifetime mental illness. 59% also used cannabis. Health service use: 9% GP, 3% ambulance, 3% ED, 3% hospitalization.","methodology":"Cross-sectional survey of frequent legal high users (monthly or more) recruited from outside 8 randomly selected licensed legal high stores in central Auckland, April-May 2014. 105 completed an online survey assessing use patterns, health problems, and healthcare utilization.","limitations":"Recruited outside legal high stores, which selects for frequent users and may overestimate dependence rates in the broader user population. Self-selected sample with potential bias. Small sample size. Cross-sectional design. The specific SC products available during this period may differ from products in other markets or time periods."},{"rthcId":"RTHC-01307","title":"Marijuana Legalization: Impact on Physicians and Public Health.","authors":"Wilkinson, Samuel T; Yarnell, Stephanie; Radhakrishnan, Rajiv; Ball, Samuel A; D'Souza, Deepak Cyril","year":2016,"journal":"Annual review of medicine, 67, 453-66","doi":"10.1146/annurev-med-050214-013454","pmid":"26515984","tags":["legalization","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This Annual Review of Medicine article assessed the public health landscape of marijuana legalization from a physician perspective.\n\nMedical evidence was limited to HIV/AIDS cachexia, chemotherapy nausea, neuropathic pain, and MS spasticity. Other therapeutic areas showed promise but lacked robust clinical evidence.\n\nRegarding legalization and use prevalence, the review noted that states with legal marijuana had higher use rates, but these higher rates generally existed before legalization, making it difficult to attribute increases to legalization itself.\n\nKey public health concerns included: acute impairment of driving (well documented), unintentional pediatric ingestion of edibles (increasing with legalization), the complex relationship between marijuana and opioid use (some evidence of substitution), and potential increases in dependence/addiction, psychosis, and pulmonary disorders.\n\nThe authors called for more research, noting the urgency given the rapidly shifting legal landscape.","whyItMatters":"As legalization accelerates, physicians face patient questions about cannabis with limited training and evolving evidence. This review provides a balanced framework for clinical decision-making and identifies the public health surveillance priorities that should accompany legalization.","specificNumbers":"Four conditions with established medical evidence: HIV cachexia, chemo nausea, neuropathic pain, MS spasticity. Higher use rates in legal states predated legalization. Public health concerns: driving, pediatric exposure, opioid interaction, addiction, psychosis, lung disease.","methodology":"Comprehensive narrative review published in the Annual Review of Medicine, covering medical evidence, legalization effects on prevalence, and emerging public health concerns.","limitations":"Narrative review format. Published in 2016, before several significant regulatory and research developments. The relationship between legalization and prevalence has become clearer since publication. Some public health concerns identified have been partially addressed by subsequent research."},{"rthcId":"RTHC-01308","title":"Effect of Pharmacological Modulation of the Endocannabinoid System on Opiate Withdrawal: A Review of the Preclinical Animal Literature.","authors":"Wills, Kiri L; Parker, Linda A","year":2016,"journal":"Frontiers in pharmacology, 7, 187","doi":"10.3389/fphar.2016.00187","pmid":"27445822","tags":["drug-interactions","neuroscience","withdrawal"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review synthesized animal research on how manipulating the endocannabinoid system affects opiate withdrawal. The key insight was a dissociation between somatic (physical) and affective (emotional) withdrawal.\n\nSomatic withdrawal symptoms (diarrhea, tremor, wet dog shakes) and affective withdrawal (aversion, anxiety, dysphoria) are mediated by different brain regions. The endocannabinoid system modulates both, but differently depending on where in the brain CB1 receptors are activated or blocked.\n\nCB1 agonists can alleviate some somatic withdrawal symptoms. CB1 antagonists can precipitate withdrawal in dependent animals. But the effects are brain region-specific: what helps in one area may not help in another.\n\nThe review also discussed how these findings relate to the conditioned place aversion paradigm, which measures the emotional/motivational aspects of withdrawal that are thought to drive continued drug use.","whyItMatters":"Opiate withdrawal is a major driver of continued opioid use and relapse. If the endocannabinoid system can modulate withdrawal, cannabis or cannabinoid-based treatments could potentially help people detox from opioids. But the brain region-specific effects mean that simple \"cannabis for withdrawal\" approaches may be too simplistic.","specificNumbers":"The review covered studies using CB1 agonists (WIN55,212-2, THC), CB1 antagonists (SR141716A/rimonabant), FAAH inhibitors, and endocannabinoid system modulators. Brain regions discussed include the basolateral amygdala, central amygdala, bed nucleus of the stria terminalis, ventral tegmental area, and periaqueductal gray.","methodology":"Review of preclinical animal literature examining the effects of pharmacological modulation of the endocannabinoid system on opiate withdrawal. Covered both acutely and chronically dependent animal models, somatic and affective withdrawal measures, and brain region-specific manipulations.","limitations":"Entirely based on animal studies. The pharmacological manipulations used (direct brain infusions, systemic CB1 agonists/antagonists) do not precisely replicate how humans use cannabis. Species differences in endocannabinoid systems may affect translation. The review focuses on acute withdrawal, not the long-term aspects of opioid recovery."},{"rthcId":"RTHC-01309","title":"Characteristics of Cannabis-Only and Other Drug Users Who Visit the Emergency Department.","authors":"Woodruff, Susan I; McCabe, Cameron T; Hohman, Melinda; Clapp, John D; Shillington, Audrey M; Eisenberg, Kimberly; Sise, C Beth; Castillo, Edward M; Chan, Theodore C; Sise, Michael J","year":2016,"journal":"Cannabis and cannabinoid research, 1(1), 149-153","doi":null,"pmid":"27689138","tags":["addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared three groups among 686 adult emergency department patients who reported drug use: daily cannabis-only users, non-daily cannabis-only users, and users of other drugs.\n\nThe three groups did not differ on most demographic factors or medical problem severity, but they differed significantly on substance-related outcomes. Users of drugs other than cannabis had the highest drug severity indicators, more psychiatric problems, and greater alcohol use severity.\n\nHowever, cannabis-only users were not without problems: 19-29% were identified as having problematic drug use. Daily cannabis-only users fared worse than non-daily users on drug severity and self-efficacy for avoiding drug use.\n\n45% of the entire drug-using ED sample was identified as having a drug use problem, highlighting the ED as an important screening venue.","whyItMatters":"Emergency departments are increasingly recognized as opportunities for substance use screening and intervention. This study helps clinicians match patients to appropriate care levels: cannabis-only users may benefit from brief interventions focusing on motivation and self-efficacy, while users of other drugs may need referral to specialty treatment.","specificNumbers":"686 drug-using ED patients. 45% identified as having a drug use problem. 19-29% of cannabis-only users had problematic use. Other drug users had higher severity scores. Daily cannabis users fared worse than non-daily users on drug severity and self-efficacy.","methodology":"Cross-sectional study of 686 adult patients at two emergency departments who reported drug use. Groups compared: daily cannabis-only users, non-daily cannabis-only users, and other drug users. Measures included Drug Abuse Screening Test, Addiction Severity Index, psychiatric status, and self-efficacy for drug avoidance.","limitations":"Cross-sectional ED sample may not represent all drug users. Self-reported drug use may be inaccurate in an ED setting. The study was conducted at only two EDs. Cannabis-only status is self-reported and may not be verified by drug testing."},{"rthcId":"RTHC-01310","title":"Damaging Effects of Cannabis Use on the Lungs.","authors":"Yayan, Josef; Rasche, Kurt","year":2016,"journal":"Advances in experimental medicine and biology, 952, 31-34","doi":null,"pmid":"27573646","tags":["respiratory","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the pulmonary effects of cannabis smoking. Cannabis smoke affects the lungs similarly to tobacco smoke, producing symptoms of increased cough, sputum production, and airway hyperinflation.\n\nWith increasing years of use, cannabis can cause serious lung diseases. It can weaken the immune system in the lungs, leading to pneumonia. Regular use has been linked to symptoms of chronic bronchitis, and heavy long-term use on its own may cause airway obstruction.\n\nBased on immunohistopathological and epidemiological evidence, the review concluded that cannabis poses a potential risk for lung cancer. However, the association was described as \"not decisive,\" meaning the evidence was suggestive but not conclusive. The difficulty in separating cannabis effects from tobacco effects (since many users smoke both) was noted as a major methodological challenge.","whyItMatters":"As cannabis use increases with legalization, understanding its respiratory effects independent of tobacco is important. This review provides a concise summary of the lung-related risks, which include bronchitis, immune suppression, airway obstruction, and a potential but unproven cancer risk.","specificNumbers":"The review synthesized evidence from immunohistopathological and epidemiological studies. Specific rates were not quantified, but associations were described for bronchitis, pneumonia, airway obstruction, and potential lung cancer risk.","methodology":"Narrative review examining immunohistopathological and epidemiological evidence on the respiratory effects of cannabis smoking, published as a chapter in Advances in Experimental Medicine and Biology.","limitations":"Brief review format limits depth. Does not systematically weigh conflicting evidence (some large studies found no cancer link). Cannot fully separate cannabis effects from tobacco effects. Does not address dose-response relationships or the effects of vaporization versus smoking."},{"rthcId":"RTHC-01311","title":"Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats.","authors":"Zamberletti, Erica; Gabaglio, Marina; Grilli, Massimo; Prini, Pamela; Catanese, Alberto; Pittaluga, Anna; Marchi, Mario; Rubino, Tiziana; Parolaro, Daniela","year":2016,"journal":"Pharmacological research, 111, 459-470","doi":"10.1016/j.phrs.2016.07.008","pmid":"27422357","tags":["youth","cognition","psychosis","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Male rats that received THC during adolescence showed lasting cognitive deficits and psychotic-like behaviors in adulthood, but no emotional disturbances. This contrasted with female rats from previous work by the same group, who developed emotional problems instead.\n\nAt the cellular level, THC-treated males had significantly increased expression of glutamate receptor subunits (GluN2B, GluA1, GluA2) and synaptic markers (synaptophysin, PSD95) in the hippocampus. Glutamate release from hippocampal nerve terminals was also elevated.\n\nThe hippocampus also showed persistent neuroinflammation, with increased TNF-alpha, iNOS, and COX-2 alongside reduced anti-inflammatory IL-10. Critically, none of these changes appeared in the prefrontal cortex, suggesting region-specific vulnerability.","whyItMatters":"This study adds to growing evidence that adolescent cannabis exposure can permanently reshape brain development, and that the effects differ by sex. The finding that males show hippocampal-centered damage while females show prefrontal-centered damage suggests the adolescent brain has region-specific windows of vulnerability to THC.","specificNumbers":"GluN2B, GluA1, and GluA2 receptor subunits were all significantly increased in hippocampal post-synaptic fractions. Synaptophysin and PSD95 markers were elevated. Pro-inflammatory markers TNF-alpha, iNOS, and COX-2 were increased while anti-inflammatory IL-10 was reduced. No alterations were found in the prefrontal cortex.","methodology":"Researchers treated adolescent male rats with escalating doses of THC twice daily from postnatal day 35 to 45 (roughly equivalent to human mid-adolescence). At adulthood, they ran behavioral tests for psychotic-like symptoms, emotional reactivity, and cognition. They then examined hippocampal and prefrontal cortex tissue for glutamate receptor expression, synaptic markers, neurotransmitter release, and inflammatory markers.","limitations":"This is an animal study using injected THC at controlled doses, which differs from how humans consume cannabis. The doses and timing may not directly translate to human adolescent use patterns. The study examined only one timepoint in adulthood, so it is unclear whether these changes persist lifelong or eventually resolve."},{"rthcId":"RTHC-01312","title":"Effects of the cannabinoid 1 receptor peptide ligands hemopressin, (m)RVD-hemopressin(α) and (m)VD-hemopressin(α) on memory in novel object and object location recognition tasks in normal young and Aβ1-42-treated mice.","authors":"Zhang, Rui-San; He, Zhen; Jin, Wei-Dong; Wang, Rui","year":2016,"journal":"Neurobiology of learning and memory, 134 Pt B, 264-74","doi":"10.1016/j.nlm.2016.07.030","pmid":"27481221","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Hemopressin (Hp), a natural peptide that blocks the CB1 cannabinoid receptor, improved memory formation and extended how long mice retained memories in object recognition tasks. Two CB1-activating peptides, RVD and VD, had the opposite effect in healthy mice, impairing memory.\n\nThe picture reversed in mice modeling Alzheimer's disease. In mice pre-treated with amyloid-beta to induce memory impairment, the CB1-activating peptides RVD and VD actually restored memory function. Hemopressin alone had no effect in these impaired mice.\n\nAll effects were confirmed to work through CB1 receptors, as they could be blocked by the CB1 antagonist AM251.","whyItMatters":"This research reveals that the endocannabinoid system contains its own set of peptide regulators with opposing effects on memory. The finding that CB1 activation impairs memory in healthy brains but restores it in diseased brains highlights how context determines whether cannabinoid signaling helps or hurts cognition.","specificNumbers":"Hemopressin improved both memory formation and retention in novel object recognition and object location recognition tasks. RVD and VD reversed memory impairment induced by amyloid-beta 1-42 injections given 14 days before testing. Effects were blocked by AM251 at 2 mg/kg.","methodology":"Researchers administered peptides directly into the brains (intracerebroventricular infusion) of mice before testing them on novel object recognition and object location recognition tasks. They tested healthy young mice and mice that had received amyloid-beta injections 14 days earlier to model Alzheimer's-like memory impairment. Various antagonists were used to confirm the receptor mechanisms.","limitations":"Peptides were delivered directly into the brain, a method not applicable to human treatment. The Alzheimer's model used (amyloid-beta injection) is simplified compared to actual disease progression. Mice were tested on relatively short timescales, leaving long-term effects unknown."},{"rthcId":"RTHC-01313","title":"Tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.","authors":"Zhu, Bin; Matthews, Jay M; Xia, Mingde; Black, Shawn; Chen, Cailin; Hou, Cuifen; Liang, Yin; Tang, Yuting; Macielag, Mark J","year":2016,"journal":"Bioorganic & medicinal chemistry letters, 26(22), 5597-5601","doi":"10.1016/j.bmcl.2016.09.026","pmid":"27671499","tags":["neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The research team developed a new class of compounds (tetrahydropyrazolo[4,3-c]pyridine derivatives) that potently block CB1 cannabinoid receptors but are restricted to the body's periphery. By adding polar chemical groups that increase the molecule's topological polar surface area, they reduced its ability to cross the blood-brain barrier.\n\nThis approach aims to retain the metabolic benefits of CB1 blockade (reduced appetite, improved metabolic markers) while avoiding the depression and anxiety that doomed rimonabant, the first CB1 blocker approved for obesity, which was pulled from the market due to psychiatric side effects.","whyItMatters":"The CB1 receptor remains one of the most promising drug targets for obesity, but the brain-penetrating version (rimonabant) was withdrawn due to psychiatric harm. This peripheral-only strategy represents a renewed attempt to harness the endocannabinoid system for metabolic disease without repeating past failures.","specificNumbers":"The compounds showed potent CB1 receptor inverse agonist activity with high peripheral selectivity, achieved by increasing the topological polar surface area of the molecules.","methodology":"Medicinal chemistry approach using structure-activity relationship analysis. Researchers systematically modified a molecular scaffold to increase polar surface area while maintaining potent CB1 inverse agonist activity. Compounds were tested for receptor binding affinity and brain penetration.","limitations":"This is early-stage drug design work reporting on compound properties rather than therapeutic outcomes. No clinical data on efficacy or safety in humans. Whether peripheral CB1 blockade alone provides sufficient metabolic benefit remains to be proven."},{"rthcId":"RTHC-01314","title":"Trends and Correlates of Cannabis-involved Emergency Department Visits: 2004 to 2011.","authors":"Zhu, He; Wu, Li-Tzy","year":2016,"journal":"Journal of addiction medicine, 10(6), 429-436","doi":null,"pmid":"27574753","tags":["harm-reduction","youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Between 2004 and 2011, cannabis-only ER visit rates increased from 51 to 73 per 100,000 people aged 12 and older, while cannabis-polydrug visit rates rose from 63 to 100 per 100,000. Both trends were statistically significant.\n\nAdolescents aged 12 to 17 showed the largest increase in cannabis-only ER visits, with a rate difference of 80 per 100,000. Non-Hispanic Black individuals had the most prevalent cannabis-related ER visits across racial and ethnic groups.\n\nAmong cannabis-involved visits, older patients were more likely to be hospitalized rather than treated and released, suggesting more severe outcomes with age.","whyItMatters":"This data captures a period of shifting cannabis attitudes and early legalization efforts in the US. The disproportionate increase among adolescents and racial disparities in ER presentations highlight populations that may need targeted public health attention as cannabis policy continues to evolve.","specificNumbers":"Cannabis-only ER visits: 51 to 73 per 100,000 (2004-2011, p=0.004). Cannabis-polydrug visits: 63 to 100 per 100,000 (p<0.001). Adolescents aged 12-17 had the largest rate increase (80 per 100,000 difference).","methodology":"Researchers analyzed data from the Drug Abuse Warning Network (DAWN), a national surveillance system tracking drug-related ER visits from 2004 to 2011. They examined trends in visit rates stratified by cannabis-only versus polydrug involvement, age, and race/ethnicity. Logistic regression was used to identify factors associated with hospitalization.","limitations":"DAWN data relies on ER reporting, which may vary across facilities. Cannabis \"involvement\" in an ER visit does not necessarily mean cannabis caused the visit. The data ends in 2011, before most state legalizations took effect. Self-reported substance use in ER settings may be unreliable."},{"rthcId":"RTHC-01315","title":"Association between cannabis use and treatment outcomes in patients receiving methadone maintenance treatment: a systematic review protocol.","authors":"Zielinski, Laura; Bhatt, Meha; Eisen, Rebecca B; Perera, Stefan; Bhatnagar, Neera; MacKillop, James; Steiner, Meir; McDermid Vaz, Stephanie; Thabane, Lehana; Samaan, Zainab","year":2016,"journal":"Systematic reviews, 5(1), 139","doi":"10.1186/s13643-016-0317-2","pmid":"27530914","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01316","title":"Predicting later problematic cannabis use from psychopathological symptoms during childhood and adolescence: Results of a 25-year longitudinal study.","authors":"Zohsel, Katrin; Baldus, Christiane; Schmidt, Martin H; Esser, Günter; Banaschewski, Tobias; Thomasius, Rainer; Laucht, Manfred","year":2016,"journal":"Drug and alcohol dependence, 163, 251-5","doi":"10.1016/j.drugalcdep.2016.04.012","pmid":"27114206","tags":["youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In a cohort followed from birth to age 25, childhood conduct and oppositional defiant behaviors (measured between ages 4.5 and 11) predicted problematic cannabis use in young adulthood. This held true even after controlling for co-occurring symptoms like attention problems, hyperactivity, and internalizing disorders.\n\nDuring adolescence (age 15), the picture shifted. Attention problems, rather than conduct issues, became the significant predictor of later problematic cannabis use when controlling for comorbidity.\n\nNeither hyperactivity/impulsivity nor internalizing disorders (anxiety, depression) independently predicted problematic cannabis use at either developmental stage.","whyItMatters":"This study suggests that the pathway to problematic cannabis use may begin years before any drug exposure. By identifying specific childhood behaviors that increase risk, it points toward early intervention opportunities, particularly for children with conduct problems and adolescents with attention difficulties.","specificNumbers":"Of 307 participants followed to age 25, 28 (9.1%) developed problematic cannabis use. Childhood conduct/oppositional behavior and adolescent attention problems were statistically significant predictors after controlling for comorbidities.","methodology":"Data came from the Mannheim Study of Children at Risk, an epidemiological cohort study following children from birth through adulthood. Researchers assessed psychopathology at ages 4.5 to 11 (childhood) and 15 (adolescence) using standardized measures, then evaluated cannabis use at age 25 through clinical interviews and self-report questionnaires. Of 307 participants, 28 (9.1%) met criteria for problematic cannabis use.","limitations":"The sample was relatively small (307 participants, 28 with problematic use), limiting statistical power. The study is observational, so it cannot confirm that behavior problems cause later cannabis use. Cultural and policy differences between Germany and other countries may affect generalizability."},{"rthcId":"RTHC-01317","title":"Accidental cannabis poisoning in the elderly.","authors":"Zupan Mežnar, Anja; Brvar, Miran; Kralj, Gregor; Kovačič, Dragan","year":2016,"journal":"Wiener klinische Wochenschrift, 128(Suppl 7), 548-552","doi":null,"pmid":"27900531","tags":["seniors","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"During a workshop on hemp's medicinal uses, attendees sampled various hemp food products. One participant brought cookies that actually contained marijuana rather than industrial hemp. About one hour after eating the cookies, people developed nausea, vomiting, dizziness, sleepiness, and difficulty walking.\n\nTwelve people went to the emergency department. Two required intensive care admission due to central nervous system depression. All patients were managed with supportive care and discharged without lasting health consequences.","whyItMatters":"As hemp food products become more popular, the potential for confusion between hemp and marijuana increases, particularly among older adults who may be less familiar with cannabis products. This case illustrates the real-world consequences of that confusion and the particular vulnerability of elderly populations to unexpected THC exposure.","specificNumbers":"12 people were treated in the ER. 2 were admitted to intensive care for CNS depression. Symptoms appeared approximately 1 hour after ingestion. All recovered without lasting effects.","methodology":"Clinical case report documenting the event, patient presentations, and outcomes. Patients were evaluated in the emergency department with standard clinical assessment.","limitations":"Single incident case report from one event. The exact THC content of the cookies was not reported. Individual patient details and dosing are limited. Cannot be generalized to predict outcomes of all accidental exposures."},{"rthcId":"RTHC-01318","title":"Cannabinoids, inflammation, and fibrosis.","authors":"Zurier, Robert B; Burstein, Sumner H","year":2016,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 30(11), 3682-3689","doi":null,"pmid":"27435265","tags":["inflammation","medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review surveyed anti-inflammatory actions across several cannabinoid categories. The phytocannabinoids THC, CBD, cannabichromene, and cannabinol all showed anti-inflammatory effects. Three approved synthetic preparations (nabilone, dronabinol, and Sativex) also demonstrated anti-inflammatory properties.\n\nThe most detailed discussion focused on ajulemic acid (AJA), a synthetic cannabinoid in phase 2 clinical trials that showed both anti-inflammatory and anti-fibrotic effects. The review proposed a mechanism involving PPAR-gamma activation and resolution of inflammation through specialized pro-resolving mediators.\n\nCritically, cannabinoids as a class appear to work through different mechanisms than NSAIDs and are generally free from NSAID-associated adverse effects like gastrointestinal bleeding and cardiovascular risk.","whyItMatters":"Chronic inflammation underlies many diseases but current anti-inflammatory drugs carry significant side effects. The finding that cannabinoids work through entirely different pathways than NSAIDs, with a generally better safety profile, opens a new therapeutic avenue. The progression of ajulemic acid into clinical trials represents the most advanced effort to translate cannabinoid anti-inflammatory science into medicine.","specificNumbers":"Ajulemic acid was in three phase 2 clinical trials at the time of publication. The review covered phytocannabinoids (THC, CBD, CBC, CBN), three synthetic preparations (nabilone, dronabinol, Sativex), and the endocannabinoid system.","methodology":"Narrative review surveying published research on the anti-inflammatory and anti-fibrotic effects of phytocannabinoids, endocannabinoids, synthetic cannabinoids, and related lipoamino acids. Focused particularly on mechanism of action and clinical development status.","limitations":"Narrative review without systematic methodology, so study selection may be incomplete. Much of the evidence comes from preclinical models. The clinical trial results for ajulemic acid were not yet available. The review was written by researchers involved in ajulemic acid development, representing a potential conflict of interest."},{"rthcId":"RTHC-01319","title":"Endocannabinoid system acts as a regulator of immune homeostasis in the gut.","authors":"Acharya, Nandini; Penukonda, Sasi; Shcheglova, Tatiana; Hagymasi, Adam T; Basu, Sreyashi; Srivastava, Pramod K","year":2017,"journal":"Proceedings of the National Academy of Sciences of the United States of America, 114(19), 5005-5010","doi":"10.1073/pnas.1612177114","pmid":"28439004","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid anandamide (AEA) and its receptor CB2 regulate immune tolerance in the gut and pancreas. Anandamide increased the number and suppressive function of regulatory CX3CR1-high macrophages in the gut, which expressed the highest levels of cannabinoid receptors among gut immune cells.\n\nCapsaicin, the compound that makes peppers hot, triggered the same pathway indirectly: it activated TRPV1 receptors, which caused local production of anandamide, which then acted through CB2. This also promoted differentiation of regulatory T cells (Tr1 cells) through an IL-27-dependent mechanism.\n\nIn a functional test, the immune tolerance created by this pathway could be transferred to other mice through CD4+ T cells. Oral administration of anandamide protected NOD mice (a model for type 1 diabetes) from developing the disease.","whyItMatters":"This study reveals a previously unknown conversation between the nervous system and immune system in the gut, mediated by endocannabinoids. The finding that this pathway can be activated by capsaicin (a dietary compound) to prevent autoimmune diabetes opens possibilities for both understanding and treating autoimmune conditions.","specificNumbers":"TRPV1 knockout and CB2 knockout mice had fewer CX3CR1-high regulatory macrophages in the gut. Oral anandamide administration protected NOD mice from developing type 1 diabetes. Immune tolerance was transferable via CD4+ T cells.","methodology":"The study used multiple mouse models including TRPV1 knockout and CB2 knockout mice, along with the NOD mouse model of type 1 diabetes. Researchers used flow cytometry, cell transfer experiments, and in vitro differentiation assays to map the signaling pathway from capsaicin/TRPV1 through anandamide/CB2 to immune regulatory cells.","limitations":"All findings are from mouse models and may not directly translate to human biology. The NOD mouse is an imperfect model of human type 1 diabetes. Oral anandamide dosing in mice differs significantly from what would be feasible in humans. The study does not address whether exogenous cannabinoids (like THC) would produce similar effects."},{"rthcId":"RTHC-01320","title":"Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins: a retrospective cohort study.","authors":"Agrawal, Arpana; Nelson, Elliot C; Bucholz, Kathleen K; Tillman, Rebecca; Grucza, Richard A; Statham, Dixie J; Madden, Pamela Af; Martin, Nicholas G; Heath, Andrew C; Lynskey, Michael T","year":2017,"journal":"The lancet. Psychiatry, 4(9), 706-714","doi":"10.1016/S2215-0366(17)30280-8","pmid":"28750823","tags":["depression","mental-health","addiction","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Among nearly 14,000 twins from the Australian Twin Registry, the identical twin who used cannabis frequently (100+ times) was significantly more likely to report major depressive disorder (odds ratio 1.98) and suicidal ideation (odds ratio 2.47) compared to their genetically identical co-twin who used less.\n\nThese associations persisted even after adjusting for early alcohol and nicotine use, early mood symptoms, conduct disorder, and childhood sexual abuse. Because identical twins share 100% of their genes and their early family environment, this design helps rule out the possibility that shared genetic or environmental factors explain the link.\n\nFor early cannabis use (regardless of frequency), the association with suicidal ideation was present in dizygotic twins, and the monozygotic estimate was consistent though not statistically significant on its own.","whyItMatters":"The twin design is one of the strongest tools available for separating the effects of a behavior from the genetic predisposition toward that behavior. The finding that frequent cannabis use is linked to depression and suicidal thoughts even within identical twin pairs suggests that the association cannot be fully explained by shared genetic liability.","specificNumbers":"Frequent cannabis users (100+ times) versus their identical twins: OR 1.98 (95% CI 1.11-3.53) for major depression, OR 2.47 (95% CI 1.19-5.10) for suicidal ideation. Sample: 13,986 twins across three study waves.","methodology":"Logistic regression analysis of retrospective data from same-sex twin pairs drawn from three waves of the Australian Twin Registry (1992-2009). Researchers identified monozygotic and dizygotic twin pairs discordant for cannabis use and compared their rates of depression, suicidal ideation, suicide plans, and suicide attempts. The combined sample included 13,986 twins (6,181 monozygotic and 7,805 dizygotic).","limitations":"Retrospective self-report data may be subject to recall bias. The study cannot determine directionality (whether cannabis led to depression or vice versa). Cannabis frequency was measured as a lifetime count, not continuous use. Cultural and policy contexts in Australia may differ from other countries. The confidence intervals for the monozygotic associations were wide."},{"rthcId":"RTHC-01321","title":"Reciprocal relationships between substance use and disorders and suicidal ideation and suicide attempts in the Collaborative Study of the Genetics of Alcoholism.","authors":"Agrawal, Arpana; Tillman, Rebecca; Grucza, Richard A; Nelson, Elliot C; McCutcheon, Vivia V; Few, Lauren; Conner, Kenneth R; Lynskey, Michael T; Dick, Danielle M; Edenberg, Howard J; Hesselbrock, Victor M; Kramer, John R; Kuperman, Samuel; Nurnberger, John I; Schuckit, Marc A; Porjesz, Bernice; Bucholz, Kathleen K","year":2017,"journal":"Journal of affective disorders, 213, 96-104","doi":"10.1016/j.jad.2016.12.060","pmid":"28213124","tags":["addiction","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"In a prospective cohort of over 3,200 participants, suicide attempts were associated with significantly increased odds of subsequently developing dependence on alcohol, nicotine, or cannabis (odds ratios 1.44 to 1.61). This held after adjusting for family history of alcohol problems, major depression, and other psychiatric disorders.\n\nSuicidal ideation showed a different pattern: it was associated with reduced odds (0.71 to 0.77) of initiating alcohol, nicotine, or cannabis use. In other words, people with suicidal thoughts were less likely to start using substances.\n\nThe reverse direction, whether early substance use predicted later suicidal behavior, showed limited evidence. Several sex and race differences emerged in the associations.","whyItMatters":"This study challenges the simple assumption that substance use leads to suicidal behavior. Instead, it found that the stronger directional pathway runs from suicide attempts to subsequent substance dependence, suggesting that substances may be used as coping mechanisms after suicidal crises rather than primarily causing them.","specificNumbers":"Suicide attempts associated with 1.44-1.61 odds of later alcohol, nicotine, and cannabis dependence. Suicidal ideation associated with 0.71-0.77 odds of initiating substance use. Sample: 3,277 participants from COGA.","methodology":"Prospective cohort data from the Collaborative Study of the Genetics of Alcoholism (COGA, N=3,277). Cross-sectional and discrete time survival analyses examined bidirectional associations between suicidal ideation/attempts and onset of substance use and dependence across alcohol, nicotine, and cannabis.","limitations":"The COGA sample was ascertained for family history of alcoholism, so it may not represent the general population. Not all participants were followed up, creating censored observations. Self-report of suicidal behavior and substance use may be subject to reporting bias. The study cannot establish causation."},{"rthcId":"RTHC-01322","title":"Adolescent Exposure to the Synthetic Cannabinoid WIN 55212-2 Modifies Cocaine Withdrawal Symptoms in Adult Mice.","authors":"Aguilar, María A; Ledesma, Juan Carlos; Rodríguez-Arias, Marta; Penalva, Carles; Manzanedo, Carmen; Miñarro, José; Arenas, M Carmen","year":2017,"journal":"International journal of molecular sciences, 18(6)","doi":"10.3390/ijms18061326","pmid":"28635664","tags":["youth","synthetic-cannabinoids","withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice pre-treated with the synthetic cannabinoid WIN 55212-2 during adolescence and then given chronic cocaine in adulthood showed a modified withdrawal profile compared to controls.\n\nAdolescent cannabinoid exposure prevented the anxiety increase normally seen during cocaine withdrawal. However, it produced greater depressive-like symptoms during cocaine cessation. The psychotic-like effects of WIN (measured by pre-pulse inhibition deficits) persisted into adulthood regardless of cocaine exposure, and memory impairment during cocaine withdrawal was not altered by prior cannabinoid treatment.\n\nThe results suggest that adolescent cannabinoid exposure does not simply worsen all cocaine withdrawal symptoms but selectively modifies the emotional dimensions of withdrawal.","whyItMatters":"Cannabis use in adolescence has been epidemiologically linked to later cocaine use, but the biological mechanisms are poorly understood. This study suggests that adolescent cannabinoid exposure creates lasting changes in how the brain responds to cocaine withdrawal, potentially altering the experience of quitting cocaine in ways that could affect relapse.","specificNumbers":"Adolescent WIN pre-treatment prevented cocaine withdrawal-induced anxiety (elevated plus maze) but increased depressive-like behavior (tail suspension test). Pre-pulse inhibition deficits from WIN persisted independently of cocaine exposure. Object recognition impairment during cocaine withdrawal was unaffected by prior WIN exposure.","methodology":"Juvenile mice received the CB1 agonist WIN 55212-2 during adolescence, then underwent chronic cocaine treatment in adulthood followed by withdrawal. Researchers tested four behavioral domains during withdrawal: pre-pulse inhibition (psychosis-like), object recognition (memory), elevated plus maze (anxiety), and tail suspension (depression-like).","limitations":"Used a synthetic cannabinoid (WIN 55212-2), which is more potent and selective than THC. The doses and administration route differ from human cannabis use. Mouse behavioral tests are approximations of human psychiatric symptoms. The study did not examine females."},{"rthcId":"RTHC-01323","title":"Marijuana Use and Self-reported Quality of Eyesight.","authors":"Akano, Obinna F","year":2017,"journal":"Optometry and vision science : official publication of the American Academy of Optometry, 94(5), 630-633","doi":"10.1097/OPX.0000000000001069","pmid":"28422803","tags":["harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Comparing 1,304 heavy marijuana users to 1,304 matched light or non-users from the National Longitudinal Survey of Youths, there was no statistically significant difference in self-reported quality of eyesight.\n\nWithin the heavy marijuana group, some demographic patterns emerged: males and high school graduates had decreased odds of reporting poor eyesight, while Black respondents had increased odds of reporting poor eyesight. However, the overall finding was a null result for the marijuana-eyesight association.","whyItMatters":"Despite known effects of cannabis on intraocular pressure and some aspects of visual processing, this large nationally representative study found no association between heavy use and self-perceived eyesight quality. This contributes to understanding the real-world functional impact of chronic cannabis use on vision.","specificNumbers":"No statistically significant difference in self-reported eyesight quality between 1,304 heavy marijuana users and 1,304 light/non-users. Sample drawn from 12,686 participants in NLSY79 (1979-2010).","methodology":"Cross-sectional analysis of the National Longitudinal Survey of Youths (NLSY79), a nationally representative sample of 12,686 people surveyed from 1979 to 2010. Researchers compared self-reported eyesight quality between 1,304 heavy marijuana users and 1,304 light/non-users using t-tests, multivariate logistic regression, and weighted analysis.","limitations":"Eyesight quality was self-reported, not clinically measured. Self-report may not detect subtle visual changes. The study could not assess specific visual functions like contrast sensitivity or color perception. Matching was based on use frequency, not duration or potency. The survey spanned decades during which cannabis potency increased significantly."},{"rthcId":"RTHC-01324","title":"The Revised Inventory of the Dimensions of Emerging Adulthood (IDEA-R) and Substance Use Among College Students.","authors":"Allem, Jon-Patrick; Sussman, Steve; Unger, Jennifer B","year":2017,"journal":"Evaluation & the health professions, 40(4), 401-408","doi":"10.1177/0163278716660742","pmid":"27468859","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among college students aged 18-25, those who endorsed the theme of \"experimentation/possibility\" as defining emerging adulthood were more likely to report both marijuana use and binge drinking. Conversely, those who saw emerging adulthood as a time of \"identity exploration\" were less likely to use marijuana.\n\nThe study used the Revised Inventory of the Dimensions of Emerging Adulthood (IDEA-R), a shorter version of a widely used scale measuring how young adults perceive their life stage. These subjective self-perceptions about what emerging adulthood means predicted substance use independently of demographic factors.","whyItMatters":"Understanding why some young adults use cannabis and others do not goes beyond availability and peer pressure. This study suggests that how young people conceptualize their life stage, whether as a time for trying new things or for figuring out who they are, shapes substance use decisions. This could inform prevention messaging.","specificNumbers":"Experimentation/possibility theme positively associated with marijuana use and binge drinking. Identity exploration theme negatively associated with marijuana use. Specific odds ratios were reported but the abstract focuses on direction of association.","methodology":"Cross-sectional survey of college students who completed the IDEA-R questionnaire and reported their substance use. Logistic regression models tested associations between transition-to-adulthood themes and both marijuana use and binge drinking, controlling for demographics.","limitations":"Cross-sectional design prevents determining whether attitudes cause substance use or substance use shapes attitudes. College students are not representative of all emerging adults. Self-report measures may be subject to social desirability bias. The study did not measure frequency or quantity of use."},{"rthcId":"RTHC-01325","title":"Perinatal maternal high-fat diet induces early obesity and sex-specific alterations of the endocannabinoid system in white and brown adipose tissue of weanling rat offspring.","authors":"Almeida, Mariana M; Dias-Rocha, Camilla P; Souza, André S; Muros, Mariana F; Mendonca, Leonardo S; Pazos-Moura, Carmen C; Trevenzoli, Isis H","year":2017,"journal":"The British journal of nutrition, 118(10), 788-803","doi":"10.1017/S0007114517002884","pmid":"29110748","tags":["pregnancy","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Maternal high-fat diet during pregnancy and nursing produced early obesity in rat pups, with enlarged white fat cells and increased lipid in brown fat tissue. The endocannabinoid system was altered in the offspring's fat tissue, but the pattern differed dramatically by sex.\n\nIn male pups, maternal high-fat diet decreased both CB1 and CB2 cannabinoid receptors in subcutaneous fat. In female pups, CB1 increased in visceral fat but decreased in subcutaneous fat. In brown fat tissue (which burns energy rather than storing it), CB1 increased in both sexes.\n\nEstrogen receptor expression was also differentially changed across fat depots in males and females, suggesting interconnected hormonal and endocannabinoid programming.","whyItMatters":"This study demonstrates that maternal nutrition can reprogram the endocannabinoid system in offspring before they ever encounter food choices of their own. The sex-specific patterns help explain why obesity risk and fat distribution differ between males and females, and point to the endocannabinoid system as a key mediator of this developmental programming.","specificNumbers":"Maternal diet: 9% fat (control) vs 29% fat (high-fat). CB1 and CB2 both decreased in male subcutaneous fat. CB1 increased in female visceral fat. CB1 increased in brown fat regardless of sex. Effects measured at weaning.","methodology":"Female rats received either standard diet (9% fat) or high-fat diet (29% fat) before mating, through pregnancy, and during lactation. Male and female pups were studied at weaning for fat cell size, lipid accumulation, cannabinoid receptor expression (CB1, CB2), metabolizing enzymes, and estrogen receptors across subcutaneous, visceral, and brown fat depots.","limitations":"Animal study using rats, whose fat biology differs from humans in important ways. The 29% fat diet, while considered high-fat for rats, produces different metabolic effects than human dietary patterns. Only one timepoint (weaning) was examined, so the persistence of these changes is unknown. Sample sizes were not specified in the abstract."},{"rthcId":"RTHC-01326","title":"Committee Opinion No. 722: Marijuana use during pregnancy and lactation","authors":"American College of Obstetricians and Gynecologists (Committee Opinion)","year":2017,"journal":"Obstetrics & Gynecology, 130(4), e205-e209","doi":"10.1097/AOG.0000000000002354","pmid":"28937574","tags":["pregnancy","cbd","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The American College of Obstetricians and Gynecologists issued a formal committee opinion stating that pregnant women should discontinue cannabis use, and that doctors should not prescribe or recommend it during pregnancy or lactation. Self-reported cannabis use during pregnancy ranged from 2% to 5% in most studies at the time, and ACOG anticipated that number would rise as more states legalized.\n\nThe opinion was based on concerns about impaired fetal neurodevelopment and the added risks of smoking as a delivery method. For women using cannabis medicinally, ACOG recommended switching to alternative treatments with better pregnancy-specific safety data. On breastfeeding, the position was more cautious than definitive: they acknowledged insufficient data to fully evaluate risks but discouraged use given the unknowns.","whyItMatters":"This wasn't a study finding new data. It was the most influential obstetrics organization in the country drawing a line based on what was known and, more importantly, what wasn't. The 2-5% self-reported use rate was likely an undercount given stigma around disclosure. With legalization expanding, ACOG was positioning ahead of what they expected to become a more common clinical question.\n\nThe distinction between \"we know this is harmful\" and \"we don't have enough data to say it's safe\" matters here. ACOG's recommendation was largely precautionary — the neurodevelopment concerns were real but not conclusively established in humans at the time.","specificNumbers":"• Self-reported cannabis use during pregnancy: 2–5% in most studies\n• Committee Opinion No. 722 — formal ACOG guidance\n• Recommendation: discontinue all cannabis use during pregnancy, preconception, and lactation","methodology":"Committee opinion from ACOG based on review of available clinical and preclinical evidence. Committee opinions represent expert consensus when rigorous evidence is limited — they carry institutional authority but are not systematic reviews or meta-analyses.","limitations":"Committee opinions are expert consensus documents, not systematic reviews. The evidence base ACOG drew from was limited, particularly for breastfeeding. The opinion didn't distinguish between different cannabis products, doses, or timing of use during pregnancy. Self-reported prevalence likely understates actual use."},{"rthcId":"RTHC-01327","title":"Developmentally Specific Associations Between CNR1 Genotype and Cannabis Use Across Emerging Adulthood.","authors":"Ashenhurst, James R; Harden, K Paige; Mallard, Travis T; Corbin, William R; Fromme, Kim","year":2017,"journal":"Journal of studies on alcohol and drugs, 78(5), 686-695","doi":null,"pmid":"28930056","tags":["genetics","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Using latent growth curve modeling across 10 waves of data from ages 18 to 24, one variant in the cannabinoid receptor gene CNR1 (rs806374) was significantly associated with cannabis use frequency. C carriers used cannabis more frequently at study onset (around age 18) compared to non-carriers.\n\nThis genetic effect was specific to the level of use, not its trajectory. The rate at which cannabis use changed over time (growth) did not differ by genotype. Peer drug use was a strong predictor of individual cannabis use that grew in effect size over time, but it did not moderate the genetic association.","whyItMatters":"This study pinpoints a developmental window (around age 18) when a specific genetic variant influences cannabis use frequency. The fact that the genetic effect was limited to initial level, not trajectory, suggests that genetic vulnerability to cannabis may operate primarily during the transition out of high school, after which environmental factors like peer influence become more important.","specificNumbers":"rs806374 C carriers showed significantly higher cannabis use frequency at baseline (age ~18). Effect was on level only, not growth. 8 SNPs tested, 1 significant after multiple comparison correction. Peer drug use effect grew over time but did not moderate the genetic association. Sample: 334 non-Hispanic White participants across 10 waves.","methodology":"Latent growth curve modeling of 10 longitudinal waves spanning ages 18.4 to 23.8 years in 334 non-Hispanic White participants. Eight independent SNPs in or near the CNR1 gene were tested for association with both level and growth of cannabis use. Peer drug use was included as a time-varying predictor and potential moderator. Corrections for multiple comparisons were applied.","limitations":"Small sample size (334 participants) limits statistical power. Restricted to non-Hispanic White individuals, so findings may not generalize to other populations. Only one of eight tested SNPs was significant, and the effect was modest. Self-reported cannabis use may be inaccurate."},{"rthcId":"RTHC-01328","title":"Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers.","authors":"Babalonis, Shanna; Haney, Margaret; Malcolm, Robert J; Lofwall, Michelle R; Votaw, Victoria R; Sparenborg, Steven; Walsh, Sharon L","year":2017,"journal":"Drug and alcohol dependence, 172, 9-13","doi":"10.1016/j.drugalcdep.2016.11.030","pmid":"28088032","tags":["cbd","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a randomized, placebo-controlled, double-blind study, 31 healthy frequent marijuana users received oral CBD at 0, 200, 400, and 800mg. Unlike smoked marijuana (5.3-5.8% THC), which reliably produced abuse-related subjective effects like feeling \"high,\" none of the CBD doses produced any signal for abuse liability.\n\nParticipants showed no difference from placebo on measures of drug liking, desire to take the drug again, or subjective \"high\" at any CBD dose tested. The results were consistent across the full dose range.","whyItMatters":"At the time of this study, CBD remained a Schedule I controlled substance in the US. This controlled human data demonstrating no abuse liability provided important evidence for regulatory decisions about CBD scheduling. The study addressed a significant gap, as no well-controlled abuse liability data had been available for CBD.","specificNumbers":"CBD doses: 200, 400, and 800mg oral. Active marijuana control: 5.3-5.8% THC smoked. 31 participants. 8 sessions per participant. Smoked marijuana produced significant abuse-related effects (p<0.05); CBD did not at any dose (p>0.05).","methodology":"Within-subject, randomized, placebo-controlled, double-blind, multi-site study. Participants received one dose combination per session across 8 once-weekly outpatient sessions (7.5 hours each). This was a secondary analysis specifically examining CBD's abuse liability profile, separate from the previously reported drug interaction findings.","limitations":"The study tested only oral CBD, not other routes like inhalation or sublingual. Participants were experienced marijuana users, who might respond differently than cannabis-naive individuals. The study measured acute effects in a clinical setting, not real-world use patterns. The dose ceiling of 800mg may not capture effects at higher doses."},{"rthcId":"RTHC-01329","title":"Cannabis, Cannabinoids, and Sleep: a Review of the Literature.","authors":"Babson, Kimberly A; Sottile, James; Morabito, Danielle","year":2017,"journal":"Current psychiatry reports, 19(4), 23","doi":"10.1007/s11920-017-0775-9","pmid":"28349316","tags":["sleep","cbd","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review pulled together what was known about cannabis and sleep through 2017, and the picture was split down the middle by compound. CBD showed preliminary promise for insomnia, REM sleep behavior disorder, and excessive daytime sleepiness. THC appeared to reduce sleep latency — the time it takes to fall asleep — but evidence suggested it could impair sleep quality with long-term use.\n\nSynthetic cannabinoids carved out their own niche. Nabilone showed potential for reducing PTSD-associated nightmares. Dronabinol showed short-term benefit for sleep apnea through its effects on serotonin-mediated breathing pauses. But across all of these findings, the authors repeatedly flagged the same problem: small studies, mixed results, and very little controlled research.","whyItMatters":"Sleep is one of the most common reasons people give for using cannabis, yet in 2017 the research base was remarkably thin. This review made that gap visible. The THC finding was particularly important to surface: something that helps you fall asleep faster but degrades sleep architecture over time is a trade-off most users probably aren't aware of.\n\nThe CBD findings, while preliminary, opened a research direction that has since attracted more attention. The distinction between \"helps you fall asleep\" and \"gives you good sleep\" is one that this review drew clearly.","specificNumbers":"• CBD: preliminary therapeutic potential for insomnia, REM behavior disorder, and daytime sleepiness\n• THC: may decrease sleep latency but impair long-term sleep quality\n• Nabilone: showed benefit for PTSD-related nightmares\n• Dronabinol: short-term benefit for sleep apnea","methodology":"Narrative literature review covering research on cannabis and sleep published through 2017. Examined findings across multiple sleep conditions: insomnia, obstructive sleep apnea, REM sleep behavior disorder, PTSD-related nightmares, and chronic pain-related sleep disturbance.","limitations":"Narrative review without systematic search methodology or quantitative synthesis. Most studies reviewed had small sample sizes. The review couldn't account for different cannabis strains, doses, or routes of administration. Published in 2017, so does not capture more recent research."},{"rthcId":"RTHC-01330","title":"Big conductance calcium-activated potassium channel openers control spasticity without sedation.","authors":"Baker, David; Pryce, Gareth; Visintin, Cristina; Sisay, Sofia; Bondarenko, Alexander I; Vanessa Ho, W S; Jackson, Samuel J; Williams, Thomas E; Al-Izki, Sarah; Sevastou, Ioanna; Okuyama, Masahiro; Graier, Wolfgang F; Stevenson, Lesley A; Tanner, Carolyn; Ross, Ruth; Pertwee, Roger G; Henstridge, Christopher M; Irving, Andrew J; Schulman, Jesse; Powell, Keith; Baker, Mark D; Giovannoni, Gavin; Selwood, David L","year":2017,"journal":"British journal of pharmacology, 174(16), 2662-2681","doi":"10.1111/bph.13889","pmid":"28677901","tags":["medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"VSN16R, designed as an analog of the endocannabinoid anandamide, controlled spasticity in a mouse model of multiple sclerosis (experimental encephalomyelitis) with a therapeutic window over 1,000-fold, meaning effective doses were far below those causing side effects.\n\nSurprisingly, VSN16R did not work through the known cannabinoid receptors (CB1, CB2, or GPR55). Instead, it activated the neuronal form of big conductance calcium-activated potassium (BKCa) channels. Opening these channels hyperpolarized neurons, reducing the excessive neural excitability that causes spasticity.\n\nThe compound was effective at plasma levels achievable and safe in humans, and it did not affect normal muscle tone, only reducing the excessive tone that defines spasticity.","whyItMatters":"Cannabis-based treatments for MS spasticity exist (Sativex) but cause sedation and intoxication through CB1 activation. This study identified a new target, the BKCa channel, discovered through cannabinoid-inspired drug design, that could control spasticity without these central nervous system side effects.","specificNumbers":"Therapeutic window: over 1,000-fold between effective and side effect-producing doses. VSN16R showed nanomolar activity in functional assays. Dose-dependent inhibition of spasticity in the EAE mouse model. No binding to CB1, CB2, or GPR55 receptors.","methodology":"Multi-method approach including chemical synthesis, receptor binding assays, electrophysiology, tissue-based functional assays, and in vivo testing in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS. Toxicological and safety studies were performed in both animals and humans.","limitations":"Preclinical study with limited human safety data at time of publication. The EAE mouse model does not fully replicate human MS spasticity. Whether the same BKCa-mediated effect translates to human neurons and spasticity remains to be confirmed in clinical trials. Long-term safety and efficacy data are not available."},{"rthcId":"RTHC-01331","title":"Medical Cannabis in Parkinson Disease: Real-Life Patients' Experience.","authors":"Balash, Yacov; Bar-Lev Schleider, Lihi; Korczyn, Amos D; Shabtai, Herzel; Knaani, Judith; Rosenberg, Alina; Baruch, Yehuda; Djaldetti, Ruth; Giladi, Nir; Gurevich, Tanya","year":2017,"journal":"Clinical neuropharmacology, 40(6), 268-272","doi":"10.1097/WNF.0000000000000246","pmid":"29059132","tags":["medical-cannabis","pain","sleep","depression"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Forty-seven Parkinson's patients (40 men, median Hoehn & Yahr stage III) who had used medical cannabis for at least 3 months reported their symptom changes via structured telephone interviews.\n\nThe largest effect sizes for improvement were: falls (r=0.89), pain relief (r=0.73), depression (r=0.64), tremor (r=0.64), muscle stiffness (r=0.62), and sleep (r=0.60). These are considered large effects by standard benchmarks.\n\nHowever, adverse effects were notable: 34.9% of smokers reported cough, and 17% each reported confusion and hallucinations. Five patients (10.6%) stopped treatment due to adverse effects. Most patients (80.9%) used cannabis by smoking, at a mean daily dose of 0.9g.","whyItMatters":"Parkinson's disease involves multiple disabling symptoms beyond the hallmark tremor, including pain, depression, sleep disturbance, and falls. The large effect sizes reported across multiple symptom domains suggest that medical cannabis may address the broader symptom burden of PD, though the uncontrolled design and potential for placebo effects limit the conclusions.","specificNumbers":"Effect sizes: falls r=0.89, pain r=0.73, depression r=0.64, tremor r=0.64, stiffness r=0.62, sleep r=0.60. Adverse effects: cough 34.9%, confusion 17%, hallucinations 17%. Treatment stopped: 10.6%. Mean daily dose: 0.9g. Mean treatment duration: 19.1 months.","methodology":"Retrospective survey using structured telephone interviews with standardized subjective global impression of change measures. Conducted across two centers. Patients had to have been using medical cannabis for at least 3 months and be non-demented. This was not a controlled trial; there was no placebo group.","limitations":"Uncontrolled retrospective survey with no placebo comparison. Self-reported improvements may reflect placebo effects, regression to the mean, or recall bias. The sample was predominantly male (85%). Most patients smoked cannabis, which has its own health risks. The cough rate highlights the unsuitability of smoking as a delivery method for patients with neurological disease."},{"rthcId":"RTHC-01332","title":"Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol.","authors":"Becker, Jérôme A J; Kieffer, Brigitte L; Le Merrer, Julie","year":2017,"journal":"Addiction biology, 22(5), 1205-1217","doi":"10.1111/adb.12405","pmid":"27126842","tags":["withdrawal","neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"After extended abstinence, mice that had been chronically treated with morphine, nicotine, THC, or alcohol all showed a common behavioral profile: reduced social recognition, increased motor stereotypies (repetitive behaviors), and increased anxiety. These shared behavioral changes were accompanied by corresponding patterns of neuronal activation (c-fos expression) in emotion and motivation brain circuits.\n\nCocaine-abstinent mice showed strikingly different, often opposite patterns at every level, including behavioral responses, neuronal activation, and gene expression. The researchers had previously identified a shared transcriptional signature in the extended amygdala for morphine, nicotine, THC, and alcohol abstinence, which cocaine abstinence did not share.\n\nThis supports a fundamental distinction between how the brain recovers from depressant-type substances versus psychostimulants.","whyItMatters":"Unified theories of addiction assume common mechanisms across all drugs, but this study reveals that protracted withdrawal divides neatly into two distinct categories. THC falls clearly into the same cluster as opiates, nicotine, and alcohol, sharing common withdrawal biology. This has practical implications for developing treatments that might address multiple substance withdrawals simultaneously.","specificNumbers":"Five substances tested: morphine, nicotine, THC, alcohol, cocaine. Four shared behavioral withdrawal features (all except cocaine). Gene expression and neuronal activation patterns in the extended amygdala were shared among morphine, nicotine, THC, and alcohol abstinent mice but divergent in cocaine-abstinent mice.","methodology":"Mice received chronic treatment with morphine, nicotine, THC, alcohol, or cocaine, then underwent protracted abstinence. Behavioral testing covered social recognition, motor stereotypies, and anxiety. Brain tissue was analyzed for c-fos expression patterns and gene expression in the extended amygdala.","limitations":"Animal study using forced chronic administration, which differs from human voluntary drug use patterns. Mice metabolize these substances differently than humans. The behavioral tests are approximations of human withdrawal symptoms. Only one abstinence timepoint was examined. The finding that cocaine differs may partly reflect the specific protocols used."},{"rthcId":"RTHC-01333","title":"Intra-accumbal blockade of endocannabinoid CB1 receptors impairs learning but not retention of conditioned relief.","authors":"Bergado Acosta, Jorge R; Schneider, Miriam; Fendt, Markus","year":2017,"journal":"Neurobiology of learning and memory, 144, 48-52","doi":"10.1016/j.nlm.2017.06.001","pmid":"28624517","tags":["neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"When the CB1 receptor blocker rimonabant was injected directly into the nucleus accumbens before conditioning, rats failed to learn relief associations. A cue paired with the offset of a mildly aversive stimulus normally produces relief learning, where the cue later reduces startle responses. CB1 blockade during learning eliminated this effect.\n\nHowever, when rimonabant was injected before a retention test (after learning had already occurred without drug treatment), relief memory was unaffected. This dissociation indicates that CB1 receptors in the nucleus accumbens are specifically required for the neural plasticity that forms relief memories, not for retrieving or expressing them.","whyItMatters":"Relief learning is a fundamental process: the brain learns that the end of something unpleasant is rewarding. This study shows that cannabinoid signaling in the nucleus accumbens is essential for forming these relief memories. This has implications for understanding how cannabis might affect emotional learning and why the endocannabinoid system is involved in processing relief and reward.","specificNumbers":"CB1 blockade before conditioning: relief learning was inhibited. CB1 blockade before retention test: no effect on previously learned relief. Drug used: SR141716A (rimonabant) injected directly into nucleus accumbens.","methodology":"Rats received direct injections of the CB1 antagonist/inverse agonist SR141716A (rimonabant) into the nucleus accumbens at different timepoints during a relief conditioning paradigm. Relief learning was measured by the attenuation of acoustic startle responses to a cue previously paired with relief from a mild foot shock.","limitations":"Animal study using direct brain injections, which is not applicable to human drug delivery. Only one brain region was tested. The study used a synthetic CB1 blocker rather than manipulating endocannabinoid levels directly. Relief learning in rats may not fully model human emotional processing."},{"rthcId":"RTHC-01334","title":"Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors.","authors":"Bhattacharyya, Sagnik; Egerton, Alice; Kim, Euitae; Rosso, Lula; Riano Barros, Daniela; Hammers, Alexander; Brammer, Michael; Turkheimer, Federico E; Howes, Oliver D; McGuire, Philip","year":2017,"journal":"Scientific reports, 7(1), 15025","doi":"10.1038/s41598-017-14203-4","pmid":"29101333","tags":["anxiety","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 14 healthy males studied with both fMRI and PET imaging, a 10mg oral dose of THC induced anxiety and changed how the right amygdala responded while processing fearful faces. Both of these effects, the subjective anxiety and the amygdala activation change, were positively correlated with the person's baseline CB1 receptor availability in the right amygdala.\n\nIn other words, men who had more CB1 receptors in their amygdala experienced more THC-induced anxiety. This provides the first direct evidence in humans linking individual variation in cannabinoid receptor density to vulnerability to cannabis-induced anxiety.","whyItMatters":"Cannabis-induced anxiety is one of the most common adverse effects of THC, but why some people experience it intensely while others do not has been unclear. This study identifies a biological marker, CB1 receptor density in the amygdala, that predicts individual vulnerability. This could eventually help predict who is likely to have negative anxiety responses to cannabis.","specificNumbers":"14 healthy males. 10mg oral THC vs placebo. CB1 availability in right amygdala positively correlated with both THC-induced anxiety and right amygdala activation during fear processing.","methodology":"Double-blind, placebo-controlled crossover design. 14 healthy males underwent fMRI on two occasions one month apart, after either 10mg oral THC or placebo, while performing a fear-processing task. CB1 receptor availability was independently measured using PET with the radioligand [11C]MePPEP.","limitations":"Very small sample (14 men only). No women were included. A single THC dose was tested. The correlational design cannot determine causation. PET imaging measures receptor availability, which reflects both receptor density and occupancy. The findings may not generalize to smoked or vaped cannabis."},{"rthcId":"RTHC-01335","title":"A selective review of medical cannabis in cancer pain management.","authors":"Blake, Alexia; Wan, Bo Angela; Malek, Leila; DeAngelis, Carlo; Diaz, Patrick; Lao, Nicholas; Chow, Edward; O'Hearn, Shannon","year":2017,"journal":"Annals of palliative medicine, 6(Suppl 2), S215-S222","doi":"10.21037/apm.2017.08.05","pmid":"28866904","tags":["pain","medical-cannabis","cancer","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review identified five clinical studies evaluating THC or CBD for cancer pain. THC oil capsules, THC:CBD oromucosal spray (nabiximols), and THC oromucosal sprays all showed some evidence of pain reduction in cancer patients.\n\nDoses ranged from 2.7 to 43.2 mg/day THC and 0 to 40 mg/day CBD. One study found significant pain relief at doses as low as 2.7-10.8 mg THC combined with 2.5-10.0 mg CBD. Higher THC doses correlated with increased pain relief in some but not all studies.\n\nReported side effects included drowsiness, low blood pressure, mental clouding, and nausea/vomiting.","whyItMatters":"Cancer pain is often inadequately managed with standard treatments, and patients who do not respond to opioids need alternatives. This review gathers the limited but growing clinical evidence that cannabis-based medicines may fill this gap, particularly for chronic and neuropathic cancer pain.","specificNumbers":"Five clinical studies reviewed (1975-2014). THC doses: 2.7-43.2 mg/day. CBD doses: 0-40 mg/day. Significant relief reported at doses as low as 2.7-10.8 mg THC + 2.5-10.0 mg CBD. Side effects: drowsiness, hypotension, mental clouding, nausea.","methodology":"Selective review of literature published on Medline between 1975 and 2017. The search identified five clinical studies evaluating THC or CBD for cancer pain, ranging from small pilot studies to double-blind placebo-controlled trials.","limitations":"Selective rather than systematic review, so study selection may be biased. Only five studies were included, most with small sample sizes. The studies span decades during which cannabis formulations and pain assessment methods changed substantially. Conflicting evidence on dose-response relationships."},{"rthcId":"RTHC-01336","title":"Attenuated frontal and sensory inputs to the basal ganglia in cannabis users.","authors":"Blanco-Hinojo, Laura; Pujol, Jesus; Harrison, Ben J; Macià, Dídac; Batalla, Albert; Nogué, Santiago; Torrens, Marta; Farré, Magí; Deus, Joan; Martín-Santos, Rocío","year":2017,"journal":"Addiction biology, 22(4), 1036-1047","doi":"10.1111/adb.12370","pmid":"26934839","tags":["cognition","neuroscience","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Resting-state brain imaging in 28 chronic cannabis users and 29 controls revealed two key connectivity changes. First, the positive connection between the striatum and the \"limbic\" frontal-basal ganglia circuit was weakened. Second, the normal negative correlation between the striatum and the fusiform gyrus (critical for recognizing visual features) was also attenuated.\n\nThese connectivity alterations correlated with lower arousal in response to emotional pictures, providing a functional link between the brain changes and the motivational apathy commonly associated with chronic cannabis use.\n\nAfter one month of abstinence, the connectivity changes showed a tendency to normalize, suggesting they represent reversible functional adaptations rather than permanent damage.","whyItMatters":"The \"amotivational syndrome\" associated with chronic cannabis use has been debated for decades. This study provides a neurobiological mechanism: cannabis weakens the inputs that the brain's motivation system receives from both internal (frontal lobe, planning) and external (visual processing, environmental) sources. The reversibility with abstinence is reassuring.","specificNumbers":"28 chronic cannabis users vs 29 controls. Two connectivity disruptions identified: striatum-frontal (limbic circuit) and striatum-fusiform gyrus. Lower arousal to affective pictures correlated with connectivity changes. Connectivity tended to normalize after 1 month abstinence.","methodology":"Resting-state functional MRI measured connectivity patterns in 28 chronic cannabis users and 29 controls. Behavioral tests included reaction time, verbal fluency, and responses to affective pictures. Assessments were repeated after one month of abstinence.","limitations":"Relatively small sample (28 users, 29 controls). Cross-sectional comparison cannot determine whether connectivity differences existed before cannabis use began. Only one month of abstinence was assessed. Cannabis use histories varied across participants. Resting-state fMRI has inherent methodological limitations."},{"rthcId":"RTHC-01337","title":"Cannabinoid hyperemesis and the cyclic vomiting syndrome in adults: recognition, diagnosis, acute and long-term treatment.","authors":"Blumentrath, Christian G; Dohrmann, Boris; Ewald, Nils","year":2017,"journal":"German medical science : GMS e-journal, 15, Doc06","doi":"10.3205/000247","pmid":"28400711","tags":["harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoid hyperemesis syndrome (CHS) and cyclic vomiting syndrome (CVS) share nearly identical presentations: recurrent episodes of severe nausea, vomiting, and abdominal pain. The review found that compulsive bathing behavior, previously thought to be unique to CHS, actually occurs in CVS patients as well.\n\nThe only reliable distinguishing criterion is therapeutic: complete and persistent resolution of all symptoms following cannabis cessation confirms CHS. Supportive criteria for CVS include psychiatric comorbidities (panic attacks, depression), history of migraines, and rapid gastric emptying.\n\nLong-term follow-up is essential but rarely conducted, making definitive differentiation difficult in practice. The authors developed a standard operating procedure for diagnosis and management applicable across healthcare settings.","whyItMatters":"Both CHS and CVS are poorly recognized by physicians, leading to delayed diagnosis and unnecessary testing. As cannabis use increases, CHS is becoming more common, but misdiagnosis as CVS (or vice versa) has treatment implications. The finding that hot bathing is not a reliable differentiator overturns a widely held clinical assumption.","specificNumbers":"The only reliable criterion: complete symptom resolution after cannabis cessation = CHS. Supportive CVS criteria: psychiatric comorbidities, migraine history, rapid gastric emptying. Both syndromes feature compulsive bathing behavior.","methodology":"Literature review using the LIVIVO search portal for life sciences. The review focused on identifying clinical features that distinguish CHS from CVS and developing a practical diagnostic and treatment approach.","limitations":"Literature review with inconsistent source data. Many published CHS and CVS cases lack long-term follow-up. The diagnostic criterion of symptom resolution after cannabis cessation requires sustained abstinence, which is difficult for many patients. The standard operating procedure was not validated in a clinical trial."},{"rthcId":"RTHC-01338","title":"The cannabis withdrawal syndrome: current insights.","authors":"Bonnet, Udo; Preuss, Ulrich W","year":2017,"journal":"Substance abuse and rehabilitation, 8, 9-37","doi":"10.2147/SAR.S109576","pmid":"28490916","tags":["withdrawal","addiction","sex-differences"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review synthesized evidence that regular cannabis use causes desensitization and downregulation of brain CB1 receptors, which begins reversing within the first 2 days of abstinence and normalizes within about 4 weeks. This receptor recovery timeline may define the neurobiological duration of the cannabis withdrawal syndrome.\n\nSeverity depends on the amount used before cessation, gender, genetic factors, and environmental influences. Women reported stronger withdrawal than men, including physical symptoms like nausea and stomach pain that are less prominent in males.\n\nFor treatment, gabapentin and THC analogs showed the most promise. Mirtazapine helped with withdrawal-related insomnia. Notably, venlafaxine worsened withdrawal symptoms, while other antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect.","whyItMatters":"Cannabis withdrawal is now recognized in the DSM-5, but many people and clinicians still doubt its existence. This review provides a thorough neurobiological framework showing why withdrawal occurs (receptor downregulation), how long it lasts (the 4-week CB1 recovery window), and what treatments help. The gender differences are particularly important for tailoring clinical approaches.","specificNumbers":"CB1 receptor recovery: begins within 2 days, normalizes within ~4 weeks of abstinence. Women report stronger symptoms. Promising treatments: gabapentin, THC analogs. Helpful for insomnia: mirtazapine. Harmful: venlafaxine. Ineffective: other antidepressants, atomoxetine, lithium, buspirone, divalproex.","methodology":"Comprehensive narrative review synthesizing animal and human evidence on cannabis withdrawal syndrome. Covers neurobiology (CB1 receptor changes), clinical presentation, gender differences, severity determinants, treatment approaches, and diagnostic criteria.","limitations":"Narrative review, not systematic, so coverage may be selective. The evidence base for pharmacological treatments is small. The 4-week CB1 recovery timeline may not account for longer-term synaptic changes. Individual variation in withdrawal severity is high, making generalizations difficult."},{"rthcId":"RTHC-01339","title":"Alcohol, cannabis and other drugs and subsequent suicide ideation and attempt among young Mexicans.","authors":"Borges, Guilherme; Benjet, Corina; Orozco, Ricardo; Medina-Mora, Maria-Elena; Menendez, David","year":2017,"journal":"Journal of psychiatric research, 91, 74-82","doi":"10.1016/j.jpsychires.2017.02.025","pmid":"28325681","tags":["youth","mental-health","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"In a prospective study following 1,071 young Mexicans from 2005 to 2013, cannabis use before age 15 was associated with nearly 4 times the risk of suicidal ideation (RR=3.97) and over 5 times the risk of suicide attempt (RR=5.23).\n\nEarly-onset cannabis use disorder among cannabis users tripled the risk of ideation (RR=3.30) and quadrupled the risk of attempt (RR=4.14). High-frequency cannabis use was associated with 4.6 times the risk of attempt, and recent cannabis use disorder with 4.7 times the risk.\n\nOther drugs showed some similar associations but generally to a lesser degree. For alcohol, only initiation before age 15 was linked to increased attempt risk (RR=1.79).","whyItMatters":"Suicide is a leading cause of death among young people in Mexico and globally. This prospective design, following the same individuals over eight years, strengthens the evidence that early and heavy cannabis use precedes suicidal behavior rather than simply co-occurring with it. The specificity of cannabis effects beyond other substances is notable.","specificNumbers":"Cannabis before age 15: ideation RR=3.97 (95% CI 1.43-11.03), attempt RR=5.23 (95% CI 1.17-23.32). Early-onset DUD: ideation RR=3.30, attempt RR=4.14. High-frequency use: attempt RR=4.60. Recent DUD: attempt RR=4.74. Alcohol before age 15: attempt RR=1.79.","methodology":"Prospective follow-up of the original Mexican Adolescent Mental Health Survey conducted in 2005, with follow-up in 2013 (n=1,071). Researchers estimated risk ratios for incident suicidal ideation and attempt based on earlier substance use patterns, adjusting for confounders.","limitations":"Relatively small follow-up sample (1,071 participants). Wide confidence intervals on some estimates reflect limited statistical power. Observational design cannot confirm causation. Self-reported substance use and suicidal behavior may be subject to reporting bias. The study cannot fully account for shared risk factors."},{"rthcId":"RTHC-01340","title":"20-year outcomes in adolescents who self-harm: a population-based cohort study.","authors":"Borschmann, Rohan; Becker, Denise; Coffey, Carolyn; Spry, Elizabeth; Moreno-Betancur, Margarita; Moran, Paul; Patton, George C","year":2017,"journal":"The Lancet. Child & adolescent health, 1(3), 195-202","doi":"10.1016/S2352-4642(17)30007-X","pmid":"30169168","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"In a population-based cohort of 1,671 Australians followed from adolescence to age 35, those who self-harmed during adolescence (8% of the cohort) had significantly worse outcomes across multiple domains: social disadvantage, mental health, and substance use.\n\nMost of these associations were explained by concurrent adolescent mental health disorders and substance use. However, weekly cannabis use at age 35 uniquely survived all adjustments (adjusted OR 2.27, 95% CI 1.09-4.69). Even after controlling for adolescent depression, anxiety, antisocial behavior, and substance use, adolescent self-harm still independently predicted heavy cannabis use two decades later.\n\nOther notable associations before full adjustment included daily smoking (OR 2.00), cannabis dependence (OR 2.67), and financial hardship (OR 1.88).","whyItMatters":"The finding that weekly cannabis use was the only outcome that remained independently associated with adolescent self-harm after exhaustive adjustment is striking. It suggests a specific pathway from self-harm to heavy cannabis use that operates independently of the mental health and behavioral problems typically blamed for both.","specificNumbers":"Sample: 1,671 analyzed (135 self-harmers, 1,536 controls). Weekly cannabis use at 35: OR 3.18 after mental health adjustment, OR 2.27 after full adjustment (95% CI 1.09-4.69). Cannabis dependence: OR 2.67 before adjustment. Daily smoking: OR 2.00. Self-harm prevalence: 8%.","methodology":"Prospective cohort study using the Victorian Adolescent Health Cohort Study (Australia). A stratified random sample of 1,943 adolescents from 44 schools was recruited starting in 1992 and followed through 2014. Self-harm was assessed across four adolescent waves (mean age 15.9). Outcomes at age 35 were analyzed using progressively adjusted logistic regression models.","limitations":"Self-harm was self-reported. Weekly cannabis use at age 35 was a relatively small outcome, and the confidence interval for the adjusted association was wide (1.09-4.69). The study cannot determine the mechanism linking self-harm to later cannabis use. Attrition over 20 years of follow-up may introduce bias."},{"rthcId":"RTHC-01341","title":"The Clinical Significance of Endocannabinoids in Endometriosis Pain Management.","authors":"Bouaziz, Jerome; Bar On, Alexandra; Seidman, Daniel S; Soriano, David","year":2017,"journal":"Cannabis and cannabinoid research, 2(1), 72-80","doi":"10.1089/can.2016.0035","pmid":"28861506","tags":["pain","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Endometriosis causes diffuse and poorly localized severe pain that is often inadequately managed by current medical, hormonal, and surgical approaches. The review described how endometriosis involves multiple overlapping pain mechanisms: inflammatory, neuropathic, and central sensitization.\n\nThe endocannabinoid system (ECS) intersects with several of these pain pathways. The review presented current data and theories about how modulating the ECS could target different aspects of endometriosis-associated pain, including the inflammatory component, nerve growth into endometrial lesions, and altered pain processing in the central nervous system.","whyItMatters":"Endometriosis affects roughly 10% of reproductive-age women and current pain management often fails. The endocannabinoid system represents a biologically plausible new target because it is involved in pain modulation, inflammation, and immune regulation, all of which are disrupted in endometriosis.","specificNumbers":"Endometriosis affects an estimated 10% of reproductive-age women. Current medical management has high recurrence rates. The review identified the ECS as relevant to inflammatory, neuropathic, and central sensitization pain mechanisms in endometriosis.","methodology":"Computerized literature search combining keywords \"endometriosis,\" \"endocannabinoid,\" \"cannabinoid receptor,\" \"THC,\" and \"pain mechanisms.\" The review synthesized findings on pain mechanisms in endometriosis and evidence for ECS involvement.","limitations":"This is a narrative review without systematic methodology. The evidence linking the ECS to endometriosis pain is largely theoretical and based on preclinical data. No clinical trials of cannabinoid treatments for endometriosis were included. The review does not address potential risks of cannabinoid use."},{"rthcId":"RTHC-01342","title":"The clinical implications of legalizing marijuana: Are physician and non-physician providers prepared?","authors":"Brooks, Elizabeth; Gundersen, Doris C; Flynn, Erin; Brooks-Russell, Ashley; Bull, Sheana","year":2017,"journal":"Addictive behaviors, 72, 1-7","doi":"10.1016/j.addbeh.2017.03.007","pmid":"28319813","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"A survey of 114 Colorado healthcare providers who care for children, adolescents, pregnant women, and breastfeeding women found that about half of those working with adolescents and pregnant/breastfeeding women assessed marijuana use at every or most visits. Only 23% of those working with children did so.\n\nProviders were generally knowledgeable about Colorado marijuana laws and cautious about supporting legalization. They perceived moderate to high health risks, particularly for certain populations. However, few felt completely knowledgeable about marijuana health risks, and many lacked confidence discussing specific effects.\n\nThe biggest knowledge gaps were around secondhand smoke exposure, underage use, safe storage of cannabis products, and the risks of edible overconsumption.","whyItMatters":"Legalization created a new clinical responsibility for providers, but this study shows that the medical education system had not kept up. Providers were screening for use but could not confidently discuss the specific risks, creating a gap between detection and effective counseling.","specificNumbers":"114 providers surveyed. ~50% assessed marijuana use at every/most visits with adolescents and pregnant women. 23% did so with children. Few felt completely knowledgeable about health risks. Key gaps: secondhand smoke, underage use, safe storage, edible overconsumption.","methodology":"Survey of 114 Colorado-based healthcare providers using Venue-Day-Time sampling methodology throughout the state. The sample included physicians, nurses, and medical assistants who care for vulnerable populations. The survey assessed knowledge of laws, risk perceptions, counseling practices, and training needs.","limitations":"Small sample (114 providers) from a single state. Venue-Day-Time sampling may not represent all Colorado providers. Self-reported knowledge and confidence may not reflect actual clinical competence. The survey captured a snapshot early in Colorado's legalization experience, when knowledge gaps would be expected to be largest."},{"rthcId":"RTHC-01343","title":"Marijuana and other substance use among male and female underage drinkers who drive after drinking and ride with those who drive after drinking.","authors":"Buckley, Lisa; Bonar, Erin E; Walton, Maureen A; Carter, Patrick M; Voloshyna, Diana; Ehrlich, Peter F; Cunningham, Rebecca M","year":2017,"journal":"Addictive behaviors, 71, 7-11","doi":"10.1016/j.addbeh.2017.02.016","pmid":"28231494","tags":["driving","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a sample of 2,150 underage drinkers (ages 16-20) from an emergency department, driving after drinking (DD) was reported by 22% of females and 28% of males. Riding with a driver who had been drinking (RWDD) was reported by 39% of females and 38% of males.\n\nMarijuana use was a strong predictor of both behaviors. For driving after drinking, marijuana use increased odds 2.3 times for females and 1.7 times for males. For riding with a drinking driver, marijuana increased odds 1.4 times for both sexes.\n\nPrescription drug misuse was also associated with driving after drinking for both sexes and with riding with drinking drivers for females.","whyItMatters":"This study reveals that marijuana use is independently associated with impaired driving decisions among underage drinkers, beyond the effects of alcohol itself. The combined risk of polysubstance use and impaired driving in adolescents represents a significant public safety concern.","specificNumbers":"Driving after drinking: 22% females, 28% males. Riding with drinking driver: 39% females, 38% males. Marijuana use increased DD odds: 2.3x (females), 1.7x (males). Marijuana increased RWDD odds: 1.4x (both sexes). Sample: 2,150 underage drinkers from 3,418 ED patients.","methodology":"Cross-sectional analysis from screening data for a randomized controlled trial. 16-20 year olds (N=3,418) were surveyed in an emergency department, with analysis restricted to 2,150 who reported past-year alcohol use (58% female). Logistic regression examined associations between substance use and risky driving behaviors.","limitations":"Cross-sectional design from an ED population, which may over-represent high-risk individuals. Self-reported behaviors may be subject to recall and social desirability bias. The study cannot determine whether marijuana use causes worse driving decisions or simply co-occurs with risk-taking personality traits. Past-year timeframe does not capture simultaneous use."},{"rthcId":"RTHC-01344","title":"Cannabis use and suicidal ideation: Test of the utility of the interpersonal-psychological theory of suicide.","authors":"Buckner, Julia D; Lemke, Austin W; Walukevich, Katherine A","year":2017,"journal":"Psychiatry research, 253, 256-259","doi":"10.1016/j.psychres.2017.04.001","pmid":"28395231","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 209 current cannabis-using college students, daily users (n=39) had more suicidal ideation than less frequent users (n=160). The direct link between daily use and suicidal ideation disappeared after accounting for two interpersonal factors: perceived burdensomeness (feeling like a burden to others) and thwarted belongingness (feeling disconnected from others).\n\nSpecifically, daily cannabis use predicted suicidal ideation indirectly through perceived burdensomeness, but only when thwarted belongingness was also high. Neither factor alone explained the association. This pattern is consistent with the Interpersonal-Psychological Theory of Suicide (IPTS), which posits that wanting to die requires both feeling burdensome and feeling disconnected.","whyItMatters":"This study moves beyond showing that cannabis use correlates with suicidality to identifying a psychological mechanism: interpersonal dysfunction. If daily cannabis use leads to feeling like a burden and feeling disconnected, and these feelings drive suicidal thinking, then interventions targeting social functioning in heavy cannabis users could reduce suicide risk.","specificNumbers":"209 cannabis-using undergraduates. 39 daily users vs 160 less frequent users. 76.1% female. The indirect effect of daily cannabis use on suicidal ideation through perceived burdensomeness was significant only at higher levels of thwarted belongingness.","methodology":"Cross-sectional moderated mediation analysis of 209 cannabis-using undergraduates (76.1% female). Daily users (n=39) were compared with less frequent users (n=160) on measures of suicidal ideation, perceived burdensomeness, and thwarted belongingness from the Interpersonal Needs Questionnaire.","limitations":"Cross-sectional design cannot establish temporal ordering. The sample was predominantly female college students, limiting generalizability. Daily users were a small group (n=39). Self-report measures of suicidal ideation may underrepresent true levels. The study cannot determine whether cannabis causes the interpersonal difficulties or vice versa."},{"rthcId":"RTHC-01345","title":"Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats.","authors":"Buntyn, Robert W; Alugubelly, Navatha; Hybart, Rachel L; Mohammed, Afzaal N; Nail, Carole A; Parker, Greta C; Ross, Matthew K; Carr, Russell L","year":2017,"journal":"International journal of toxicology, 36(5), 395-402","doi":"10.1177/1091581817725272","pmid":"28820005","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rat pups exposed to chlorpyrifos (CPF) from day 10 to 16 showed inhibition of fatty acid amide hydrolase (FAAH), the enzyme that breaks down anandamide, in the brain, spleen, and liver at all tested doses (0.5, 0.75, 1.0 mg/kg). MAGL, which breaks down 2-AG, was inhibited in brain and spleen only at the highest dose.\n\nIn the liver, total 2-AG breakdown was inhibited at all doses, but through non-MAGL enzymes, indicating that other lipase enzymes contribute to endocannabinoid metabolism peripherally. Cholinesterase (the traditional toxicity marker for organophosphates) was inhibited in spleen and liver at all doses but only in the brain at the highest dose.\n\nThis means endocannabinoid disruption in peripheral tissues occurs at CPF exposure levels below those that cause traditional neurotoxicity markers.","whyItMatters":"This study reveals that a widely used pesticide disrupts the endocannabinoid system in immune (spleen) and metabolic (liver) organs at exposure levels considered below the threshold for neurotoxicity. The endocannabinoid system regulates both immune function and lipid metabolism, so peripheral disruption could have health consequences not captured by traditional toxicity assessments.","specificNumbers":"FAAH inhibited in brain, spleen, and liver at all doses (0.5-1.0 mg/kg). MAGL inhibited in brain and spleen at 1.0 mg/kg only. Cholinesterase inhibited in peripheral tissues at all doses but in brain only at 1.0 mg/kg.","methodology":"Rat pups received oral exposure to 0.5, 0.75, or 1.0 mg/kg chlorpyrifos or a specific FAAH inhibitor (PF-04457845) daily from postnatal day 10 to 16. At 12 hours after the last dose, FAAH, MAGL, and cholinesterase activities were measured in brain, spleen, and liver tissue.","limitations":"Animal study with direct oral dosing that may not reflect typical human exposure routes or levels. Only one developmental timepoint was examined. The health consequences of peripheral endocannabinoid disruption were not assessed, only the enzyme inhibition itself. Rat physiology differs from human."},{"rthcId":"RTHC-01346","title":"Perspectives in the treatment for cannabinoid hyperemesis syndrome.","authors":"Burillo-Putze, Guillermo; Llorens, Pere","year":2017,"journal":"Adicciones, 29(2), 134-135","doi":"10.20882/adicciones.875","pmid":"28170059","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This brief communication discussed treatment options for cannabinoid hyperemesis syndrome (CHS), a condition characterized by severe cyclic vomiting in people who use cannabis heavily over long periods.\n\nThe authors highlighted two treatments that had shown promise: haloperidol, an antipsychotic medication, and topical capsaicin ointment applied to the abdomen. Traditional antiemetic medications often fail to control CHS symptoms, making alternative approaches clinically important.\n\nThe suggestion of capsaicin is notable because CHS patients characteristically find relief from hot showers and baths, and capsaicin activates the same TRPV1 heat receptors that hot water stimulates.","whyItMatters":"CHS is frequently misdiagnosed and resistant to standard antiemetic therapy, leading to repeated emergency department visits and extensive workups. Identifying effective treatments like haloperidol and capsaicin could reduce patient suffering and healthcare utilization for a condition that was only recently recognized.","specificNumbers":"Two treatments were highlighted: haloperidol (systemic) and capsaicin ointment (topical, applied to the abdomen).","methodology":"This was a published letter or short communication rather than a formal study. The authors reviewed emerging case reports and clinical observations regarding haloperidol and capsaicin as treatments for cannabinoid hyperemesis syndrome.","limitations":"This was a letter rather than a clinical trial. Evidence for both treatments was based on case reports and small series rather than randomized controlled data. Optimal dosing, treatment duration, and long-term effectiveness were not established."},{"rthcId":"RTHC-01347","title":"Neurocognitive Correlates in Driving Under the Influence of Cannabis.","authors":"Busardò, Francesco P; Pellegrini, Manuela; Klein, Julia; di Luca, Natale M","year":2017,"journal":"CNS & neurological disorders drug targets, 16(5), 534-540","doi":"10.2174/1871527316666170424115455","pmid":"28440193","tags":["driving","cognition"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review synthesized findings from 36 studies on cannabis and driving. Both experimental and epidemiological evidence converged on clear impairment. Cannabis affected critical-tracking tasks, increased lane weaving, decreased reaction time, and impaired divided attention.\n\nDriving under the influence of cannabis alone doubled or tripled crash risk. When cannabis was combined with alcohol, the odds ratio for driving-related injury jumped to 10.9, compared to 5.8 for cannabis alone in a case-crossover study.\n\nBrain imaging studies revealed both acute and chronic structural and functional changes in cognitive regions relevant to driving, including attention, executive function, and psychomotor control.","whyItMatters":"As cannabis use becomes more normalized, evidence-based information about driving impairment is critical. This review provides a comprehensive picture showing convergent evidence from multiple study types that cannabis meaningfully impairs driving, and that the combination with alcohol is particularly dangerous.","specificNumbers":"Cannabis alone: 2-3x crash risk. Cannabis + alcohol: OR 10.9 for driving-related injury vs 5.8 for cannabis alone. 36 studies reviewed across multiple databases. Impairments: critical tracking, lane weaving, reaction time, divided attention.","methodology":"Review of publications from PubMed, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE, and Google Scholar through January 2017. Selected 36 publications covering experimental studies (simulators, on-road tests), brain imaging, and epidemiological crash risk data.","limitations":"The review is not systematic (no PRISMA methodology). Included studies used varying THC doses, administration routes, and impairment assessments. Epidemiological studies face the challenge that THC remains detectable long after impairment has resolved. The 2-3x crash risk estimate is an aggregate that may vary by dose, tolerance, and individual factors."},{"rthcId":"RTHC-01348","title":"Hypophosphatemia in Users of Cannabis.","authors":"Cadman, Peter E","year":2017,"journal":"American journal of kidney diseases : the official journal of the National Kidney Foundation, 69(1), 152-155","doi":"10.1053/j.ajkd.2016.06.028","pmid":"27692442","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Between 2011 and 2014, six men treated for cannabinoid hyperemesis syndrome (CHS) at a VA Medical Center were found to have significant hypophosphatemia, with phosphate levels ranging from less than 1.0 to 1.3 mg/dL (normal: 2.5-4.5 mg/dL).\n\nIn three patients, phosphate levels normalized spontaneously within hours without supplementation, suggesting redistribution of phosphate between compartments rather than true depletion. Hyperventilation, observed in four of the six patients, may have contributed by shifting phosphate into cells.\n\nThis represents a previously unrecognized electrolyte complication of CHS that could have clinical consequences if severe or prolonged.","whyItMatters":"Severe hypophosphatemia can cause muscle weakness, respiratory failure, seizures, and cardiac dysfunction. Recognizing this as a feature of CHS is important for emergency medicine providers who may otherwise overlook phosphate testing in these patients or attribute symptoms to the hyperemesis itself.","specificNumbers":"6 male patients. Phosphate range: <1.0-1.3 mg/dL (normal 2.5-4.5). 3 patients normalized spontaneously within hours. Hyperventilation present in 4 of 6 patients. Study period: 2011-2014.","methodology":"Retrospective case series of six male patients treated for cannabinoid hyperemesis syndrome at the San Diego VA Medical Center between 2011 and 2014. Phosphate levels and clinical features were reviewed from medical records.","limitations":"Very small case series (6 patients, all male, all from a VA). The mechanism (hyperventilation-induced redistribution) is proposed but not definitively proven. Other causes of hypophosphatemia (vomiting, poor intake) may contribute. The cases may not represent the typical CHS population."},{"rthcId":"RTHC-01349","title":"Pharmaco-toxicological effects of the novel third-generation fluorinate synthetic cannabinoids, 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice. In vitro and in vivo studies.","authors":"Canazza, Isabella; Ossato, Andrea; Vincenzi, Fabrizio; Gregori, Adolfo; Di Rosa, Fabiana; Nigro, Federica; Rimessi, Alessandro; Pinton, Paolo; Varani, Katia; Borea, Pier Andrea; Marti, Matteo","year":2017,"journal":"Human psychopharmacology, 32(3)","doi":"10.1002/hup.2601","pmid":"28597570","tags":["synthetic-cannabinoids","harm-reduction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In vitro testing revealed that all three synthetic cannabinoids (5F-ADBINACA, AB-FUBINACA, STS-135) had nanomolar affinity for both mouse and human CB1 and CB2 receptors, making them far more potent than THC. They also induced neurotoxicity in cultured brain cells.\n\nIn mice, all three compounds produced a characteristic pattern: hypothermia, increased pain threshold, catalepsy, reduced movement, impaired sensory responses (visual, acoustic, tactile), seizures, myoclonus (involuntary muscle jerks), hyperreflexia, and promoted aggression.\n\nMost effects were fully blocked by the CB1 antagonist AM251, confirming CB1-mediated mechanisms. However, STS-135's visual sensory effects were only partially blocked, suggesting an additional CB1-independent mechanism for that compound.","whyItMatters":"These third-generation synthetic cannabinoids are sold as \"legal\" alternatives to cannabis but are orders of magnitude more potent. The seizure and aggression profile seen in this study matches clinical reports of severe reactions in human users. Understanding their pharmacology is essential for emergency medicine and toxicology.","specificNumbers":"All three compounds: nanomolar affinity at CB1 and CB2 receptors. Effects: hypothermia, analgesia, catalepsy, motor suppression, sensory impairment, seizures, myoclonus, hyperreflexia, aggression. All effects (except partial for STS-135 visual) blocked by AM251.","methodology":"Combined in vitro and in vivo study. In vitro: competition binding experiments for CB1/CB2 affinity and potency; neurotoxicity testing in mouse neuro-2a cells. In vivo: behavioral and neurological assessment in male CD-1 mice comparing the three synthetics with THC and JWH-018, with CB1 antagonist (AM251) challenge to confirm receptor mechanisms.","limitations":"Animal study using injected synthetic cannabinoids at controlled doses. Human users often smoke these compounds with unknown purity and dosing. The mouse model may not capture all human-relevant effects. Only male mice were tested. Long-term effects were not assessed."},{"rthcId":"RTHC-01350","title":"Decreased anxiety in juvenile rats following exposure to low levels of chlorpyrifos during development.","authors":"Carr, Russell L; Armstrong, Nathan H; Buchanan, Alenda T; Eells, Jeffrey B; Mohammed, Afzaal N; Ross, Matthew K; Nail, Carole A","year":2017,"journal":"Neurotoxicology, 59, 183-190","doi":"10.1016/j.neuro.2015.11.016","pmid":"26642910","tags":["neuroscience","anxiety","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rat pups exposed to chlorpyrifos (CPF) daily from postnatal day 10 to 16 at doses of 0.5, 0.75, and 1.0 mg/kg showed inhibition of FAAH (the enzyme that breaks down anandamide) at all doses, leading to elevated anandamide levels. At 0.75 and 1.0 mg/kg, 2-AG was also elevated.\n\nAt the two lower doses (0.5 and 0.75 mg/kg), FAAH was inhibited without any measurable cholinesterase inhibition in the brain, meaning the endocannabinoid disruption occurred below the threshold for traditional neurotoxicity.\n\nWhen tested at day 25 (about 9 days after the last exposure), all CPF-treated groups showed significantly decreased anxiety-like behavior, spending less time in a dark container before emerging into a brightly lit open field.","whyItMatters":"This study demonstrates that common pesticide exposure can alter anxiety behavior through the endocannabinoid system at doses considered \"safe\" by traditional neurotoxicity standards. It highlights that the endocannabinoid system may be a more sensitive target for environmental chemicals than the cholinergic system currently used to set safety limits.","specificNumbers":"All doses (0.5, 0.75, 1.0 mg/kg): FAAH inhibited, anandamide elevated, anxiety decreased. 0.5-0.75 mg/kg: no brain cholinesterase inhibition. 2-AG elevated at 0.75 and 1.0 mg/kg. Palmitoylethanolamide and oleoylethanolamide (other FAAH substrates) also elevated at all doses.","methodology":"Rat pups received daily oral doses of chlorpyrifos or corn oil vehicle from day 10 to 16. At 12 hours after the last dose, brain FAAH, MAGL, cholinesterase activity, and endocannabinoid levels were measured. On day 25, anxiety was assessed using an emergence test (latency to leave a dark container into a lit novel environment).","limitations":"Animal study with direct oral dosing that may not reflect environmental human exposure. The anxiety test measured one dimension of behavior at one timepoint. \"Decreased anxiety\" is not necessarily beneficial; it could reflect altered risk assessment. The study did not follow animals into adulthood to assess persistence."},{"rthcId":"RTHC-01351","title":"School collective occupation movements and substance use among adolescents: A school-level panel design.","authors":"Castillo-Carniglia, Alvaro; Kaufman, Jay S; Pizarro, Esteban; Marín, José D; Wintemute, Garen; Cerdá, Magdalena","year":2017,"journal":"Drug and alcohol dependence, 176, 21-27","doi":"10.1016/j.drugalcdep.2017.02.025","pmid":"28511034","tags":["legalization","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Marijuana use among Chilean adolescents doubled between 2009 and 2013, coinciding with a massive student movement in which hundreds of schools were occupied by students. However, after controlling for secular trends and school characteristics using a fixed-effects difference-in-difference model, there was no evidence that schools directly affected by strikes and occupations had different substance use outcomes.\n\nThe increase in marijuana use appeared to be part of broader social changes occurring among the school-age population rather than a consequence of the protest movement itself. Neither marijuana initiation, marijuana use, alcohol use, nor heavy use showed any causal link to school occupations.","whyItMatters":"Social movements and disruptions to normal routines are often blamed for increases in youth substance use. This study provides rigorous causal analysis showing that the dramatic 2011 Chilean school occupation movement, despite affecting large numbers of adolescents, was not responsible for the contemporaneous increase in marijuana use.","specificNumbers":"Marijuana use doubled from 2009 to 2013 among Chilean adolescents. No significant causal effect of school occupations on: marijuana initiation, marijuana use, alcohol use, or heavy use. Data spanned 2005-2015, grades 9-12.","methodology":"School-level aggregated panel design using five waves of the National Drug Surveys among Secondary Students (2005-2015) for students in grades 9-12. Fixed-effects difference-in-difference models compared schools that were occupied during 2011 with those that were not, before and after the movement.","limitations":"Ecological design using school-level aggregated data may miss individual-level variation. The movement was widespread, making it difficult to find true \"control\" schools. Other unmeasured factors may have changed simultaneously. The study cannot identify what did cause the marijuana increase if not the movement."},{"rthcId":"RTHC-01352","title":"Cannabis cultivation: Methodological issues for obtaining medical-grade product.","authors":"Chandra, Suman; Lata, Hemant; ElSohly, Mahmoud A; Walker, Larry A; Potter, David","year":2017,"journal":"Epilepsy & behavior : E&B, 70(Pt B), 302-312","doi":"10.1016/j.yebeh.2016.11.029","pmid":"28202406","tags":["medical-cannabis","cbd","epilepsy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review described the production practices of two institutions with extensive cannabis cultivation experience. GW Pharmaceuticals has developed a collection of cannabis chemotypes dominant in any one of eight different cannabinoids, with CBD and cannabidivarin (CBDV) chemotypes supporting epilepsy clinical trials.\n\nThe University of Mississippi, which holds the only federal license for cannabis research in the US, has established a germplasm bank of high-THC, high-CBD, and intermediate varieties. They developed an in vitro propagation protocol that produced cannabis clones with no detectable variations in morphology, physiology, biochemistry, or genetics compared to mother plants.\n\nBoth institutions covered breeding strategies, indoor and outdoor growing methods, harvesting protocols, and extraction techniques necessary for producing cannabis material that meets clinical trial standards.","whyItMatters":"Clinical research on cannabinoids requires standardized, consistent plant material. As CBD-based medicines advance through clinical trials (particularly for epilepsy), the ability to produce reliable chemotypes at scale becomes critical. This review documents the state of the art in medical-grade cannabis production.","specificNumbers":"GW Pharmaceuticals: 8 cannabinoid-dominant chemotypes, 2 (CBD, CBDV) supporting epilepsy trials. University of Mississippi: germplasm bank of high-THC, high-CBD, and intermediate varieties. In vitro clones showed no detectable genetic or biochemical variation from mother plants.","methodology":"Descriptive review of cultivation and production practices at GW Pharmaceuticals and the University of Mississippi. The review covered breeding, growing (indoor and outdoor), harvesting, and extraction methods used to produce research-grade cannabis.","limitations":"Descriptive review of two specific institutions; not generalizable to all cannabis production. Details on yield optimization and production efficiency were limited. The review did not address cost, scalability challenges, or quality control standards for international markets."},{"rthcId":"RTHC-01353","title":"Trends of Cannabis Use Disorder in the Inpatient: 2002 to 2011.","authors":"Charilaou, Paris; Agnihotri, Kanishk; Garcia, Pablo; Badheka, Apurva; Frenia, Douglas; Yegneswaran, Balaji","year":2017,"journal":"The American journal of medicine, 130(6), 678-687.e7","doi":"10.1016/j.amjmed.2016.12.035","pmid":"28161344","tags":["addiction","harm-reduction","mental-health","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among nearly 2.8 million hospital admissions with documented cannabis abuse/dependence (0.91% of all admissions), prevalence increased from 0.52% to 1.34% over the decade. The trend moved toward older and sicker patients with increasing rates of moderate to severe disability.\n\nThe most common primary diagnoses among cannabis-involved admissions were schizoaffective/mood disorders, followed by psychotic disorders and alcoholism. Inpatient mortality was 0.41%.\n\nTwo unexpected findings emerged: among non-tobacco smokers, cannabis users had a steeper increase in asthma prevalence than non-cannabis users. Among acute pancreatitis admissions, cannabis users actually had shorter hospital stays (-11%) and lower costs (-7%) than non-users.","whyItMatters":"The nearly tripling of cannabis-related inpatient diagnoses mirrors the outpatient trend but reveals that the inpatient population is shifting toward older, sicker patients. The psychiatric comorbidity pattern confirms that mental health, not physical health, drives most cannabis-related hospitalizations.","specificNumbers":"Total admissions with cannabis diagnosis: 2,833,567 (0.91% of all). Prevalence: 0.52% (2002) to 1.34% (2011). Mean age: 35.1 years, 62% male. Inpatient mortality: 0.41%. Mean stay: 6.23 days. Cannabis pancreatitis patients: -11% length of stay, -7% costs. Top diagnoses: schizoaffective/mood disorders, psychotic disorders, alcoholism.","methodology":"Analysis of the National Inpatient Sample (2002-2011), identifying cannabis abuse/dependence through ICD-9 codes 304.3* and 305.2*, excluding cases coded as \"in remission.\" National trend estimates and matched regression analyses were conducted.","limitations":"Administrative data (ICD-9 codes) may undercount cannabis diagnoses and cannot assess severity of use. Cannabis \"involvement\" does not mean cannabis caused the hospitalization. The study covers a period of changing social norms around cannabis, which may have affected diagnostic coding practices. Cannot distinguish between states with and without medical cannabis laws."},{"rthcId":"RTHC-01354","title":"Lung Disease Associated With Marijuana Use.","authors":"Chatkin, José Miguel; Zabert, Gustavo; Zabert, Ignacio; Chatkin, Gustavo; Jiménez-Ruiz, Carlos Andrés; de Granda-Orive, Jose Ignacio; Buljubasich, Daniel; Solano Reina, Segismundo; Figueiredo, Ana; Ravara, Sofia; Riesco Miranda, Juan Antonio; Gratziou, Christina","year":2017,"journal":"Archivos de bronconeumologia, 53(9), 510-515","doi":"10.1016/j.arbres.2017.03.019","pmid":"28483343","tags":["respiratory","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review established that marijuana smoke and tobacco smoke share many of the same combustion byproducts, including carcinogens and respiratory irritants. However, the two substances differ in psychoactive components and patterns of use (frequency, inhalation depth, breath-holding).\n\nCannabis smoke affects the respiratory tract, and the review compiled evidence on how marijuana inhalation impacts lung function. The authors emphasized that since inhalation is the most popular route of cannabis consumption, the respiratory effects deserve attention from pulmonary specialists.","whyItMatters":"With cannabis use prevalence estimated at 2.5-5% globally, a significant portion of the population regularly inhales combustion products. Pulmonologists need current evidence to counsel patients, but much of the existing guidance focuses on tobacco. This review bridges that gap.","specificNumbers":"Cannabis use prevalence: 2.5-5% globally. Cannabis is the second most commonly smoked substance after tobacco. Inhalation is the most popular route of consumption.","methodology":"Narrative review aimed at providing pulmonologists with updated scientific information on the respiratory effects of marijuana use. Focused on combustion products, exposure patterns, and clinical respiratory outcomes.","limitations":"Narrative review without systematic methodology. The abstract provides limited detail on specific findings. Cannabis use patterns vary widely, making generalizations about respiratory risk difficult. The review does not address non-combustion routes (vaporization, edibles)."},{"rthcId":"RTHC-01355","title":"Extract of Fructus Cannabis Ameliorates Learning and Memory Impairment Induced by D-Galactose in an Aging Rats Model.","authors":"Chen, Ning-Yuan; Liu, Cheng-Wu; Lin, Wei; Ding, Yi; Bian, Zhang-Ya; Huang, Ling; Huang, Hao; Yu, Kai-Hui; Chen, Si-Bang; Sun, Yu; Wei, Lei; Peng, Jun-Hua; Pan, Shang-Ling","year":2017,"journal":"Evidence-based complementary and alternative medicine : eCAM, 2017, 4757520","doi":"10.1155/2017/4757520","pmid":"29234402","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats given D-galactose to induce accelerated aging and memory impairment showed significant improvement when simultaneously treated with hemp seed extract (EFC). The extract improved behavioral performance in the Morris water maze, a standard test of spatial learning and memory.\n\nAt the cellular level, EFC increased superoxide dismutase (an antioxidant enzyme) while reducing malondialdehyde (a marker of oxidative damage) in the hippocampus. It also inhibited astrocyte activation (a sign of neuroinflammation), reduced phosphorylated tau, and suppressed presenilin 1 expression, both markers associated with Alzheimer's disease.\n\nAdditionally, EFC improved organ indices for the heart, liver, thymus, and spleen, suggesting broader health benefits beyond the brain.","whyItMatters":"Hemp seeds have been used in traditional Chinese medicine for centuries. This study provides a mechanistic basis for the cognitive-protective claims by showing effects on multiple aging-related pathways: oxidative stress, neuroinflammation, and Alzheimer's-related protein processing.","specificNumbers":"EFC doses: 200 and 400 mg/kg daily for 14 weeks. Increased superoxide dismutase, decreased malondialdehyde in hippocampus. Reduced phosphorylated tau and presenilin 1. Improved Morris water maze performance. Elevated organ indices for heart, liver, thymus, spleen.","methodology":"Rats received daily D-galactose injections (400 mg/kg) for 14 weeks to induce aging and memory impairment. Simultaneously, treatment groups received EFC at 200 or 400 mg/kg daily by oral gavage. Behavioral testing (Morris water maze), brain biochemistry (antioxidant markers, inflammatory markers, Alzheimer's-related proteins), and organ indices were assessed.","limitations":"Animal study using an artificial aging model (D-galactose injection), which differs from natural aging. The specific bioactive compounds in the hemp seed extract were not identified. Doses used may not translate to human consumption. The study was published in a complementary/alternative medicine journal."},{"rthcId":"RTHC-01356","title":"Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice.","authors":"Chen, Wei; Shui, Fengchun; Liu, Cheng; Zhou, Xinbo; Li, Wei; Zheng, Zhibing; Fu, Wei; Wang, Lili","year":2017,"journal":"Frontiers in pharmacology, 8, 707","doi":"10.3389/fphar.2017.00707","pmid":"29051736","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"TXX-522, designed based on rimonabant's core structure but engineered for minimal brain penetration, showed potent anti-obesity effects in high-fat diet mice. The compound had good CB1 receptor selectivity over CB2, strong binding affinity, and functional antagonist activity.\n\nIn vivo, TXX-522 showed minimal brain penetration and had no impact on food intake (confirming it stayed out of the brain's appetite centers). Despite not suppressing appetite, it produced significant weight loss and improved insulin resistance in obese mice, demonstrating that peripheral CB1 blockade alone can address metabolic dysfunction.\n\nDocking simulations showed TXX-522 binds CB1 in a manner similar to rimonabant, but its physicochemical properties prevent it from crossing the blood-brain barrier.","whyItMatters":"This represents continued progress toward solving the rimonabant problem: how to get the metabolic benefits of CB1 blockade without the psychiatric side effects. TXX-522 demonstrates that weight loss through peripheral CB1 blockade does not require appetite suppression, suggesting the metabolic improvements come from direct effects on fat tissue, liver, and other peripheral organs.","specificNumbers":"Good oral bioavailability. Minimal brain penetration confirmed in rats. No food intake reduction (confirming peripheral restriction). Significant weight loss and improved insulin resistance in diet-induced obese mice.","methodology":"Rational drug design based on rimonabant's structure. In vitro: receptor binding, CB1/CB2 selectivity, and functional assays. In vivo: brain/blood distribution studies in rats; anti-obesity efficacy, insulin sensitivity, and food intake measurements in high-fat diet-induced obese mice.","limitations":"Preclinical animal study; no human data. Mouse obesity models do not perfectly replicate human metabolic disease. Long-term safety and efficacy are unknown. The degree of brain penetration at higher doses or with chronic use was not reported."},{"rthcId":"RTHC-01357","title":"Cannabinoid CB1 receptor inverse agonist MJ08 stimulates glucose production via hepatic sympathetic innervation in rats.","authors":"Chen, Wei; Liu, Hongying; Guan, Hua; Xue, Nina; Wang, Lili","year":2017,"journal":"European journal of pharmacology, 814, 232-239","doi":"10.1016/j.ejphar.2017.08.030","pmid":"28844874","tags":["neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"MJ08, a CB1 receptor antagonist/inverse agonist more potent than rimonabant, was found to stimulate hepatic glucose production (HGP) in a dose-dependent manner in perfused rat livers. It also promoted expression of gluconeogenic genes.\n\nThe mechanism involved the liver's sympathetic nervous system. MJ08 triggered noradrenaline release from hepatic nerves and increased cAMP content in the liver. These effects were blocked by propranolol (a beta-blocker) and reserpine (which depletes noradrenaline), confirming the sympathetic pathway.\n\nImportantly, when tested on isolated hepatocytes (liver cells without nerve connections), only slight increases were seen, confirming that the main effect requires intact nerve connections to the liver.","whyItMatters":"This finding has direct implications for the development of peripheral CB1 blockers for obesity. Strong inverse agonist activity at liver CB1 receptors can raise blood sugar through sympathetic nerve activation, potentially worsening metabolic disease rather than treating it. This means CB1 weight-loss drugs must be carefully designed to avoid high inverse agonistic activity.","specificNumbers":"MJ08 showed superior inverse agonism compared to rimonabant. Dose-dependent increase in hepatic glucose production. Effects blocked by propranolol (beta-blocker), reserpine (sympathetic inhibitor), NF449 and H89 (cAMP pathway inhibitors), and WIN 55,212-2 (CB1 agonist).","methodology":"Perfused rat liver preparations to study glucose production. Primary cultured hepatocytes for comparison. Pharmacological blocking experiments using CB1 agonist, cAMP pathway inhibitors, beta-blocker, and sympathetic inhibitor to dissect the mechanism. Monoamine neurotransmitter and cAMP measurements.","limitations":"Animal study using perfused liver preparations, which may not fully replicate intact organism physiology. Only acute effects were studied. The relevance of this mechanism to human liver physiology is assumed but not confirmed. MJ08 is a research tool compound, not a drug candidate."},{"rthcId":"RTHC-01358","title":"Cannabinoid Poisoning by Hemp Seed Oil in a Child.","authors":"Chinello, Matteo; Scommegna, Salvatore; Shardlow, Alison; Mazzoli, Francesca; De Giovanni, Nadia; Fucci, Nadia; Borgiani, Paola; Ciccacci, Cinzia; Locasciulli, Anna; Calvani, Mauro","year":2017,"journal":"Pediatric emergency care, 33(5), 344-345","doi":"10.1097/PEC.0000000000000780","pmid":"27299295","tags":["youth","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A preschool child was prescribed hemp seed oil by a pediatrician to strengthen the immune system. After three weeks of daily ingestion, the child developed neurological symptoms. Urine testing detected the main metabolite of THC, and chemical analysis confirmed very low concentrations of THC in the hemp seed oil product.\n\nThe neurological symptoms resolved after intravenous hydration. After discharge, a possible mild withdrawal syndrome was reported, suggesting the child had developed some level of physiological dependence during the three-week exposure.\n\nThe authors noted this as the first reported case of cannabinoid poisoning from medically prescribed hemp seed oil in a preschool child.","whyItMatters":"Hemp seed oil is marketed as a health supplement and is sometimes recommended by healthcare providers. Even though it should contain only trace THC, this case shows that contaminated or poorly quality-controlled products can cause cannabinoid effects in small children, who are more sensitive due to lower body weight and immature metabolism.","specificNumbers":"Exposure: 3 weeks daily hemp seed oil. THC metabolites detected in urine. Very low THC concentration in the product. Symptoms: neurological (resolved with IV hydration). Possible mild withdrawal after cessation.","methodology":"Case report documenting the clinical presentation, treatment, and laboratory findings of a single pediatric patient. Urine toxicology and product analysis were performed.","limitations":"Single case report. The exact THC concentration in the oil was described as \"very low\" without precise quantification in the abstract. The child's symptoms could have other explanations. The reported withdrawal syndrome after discharge was not formally assessed."},{"rthcId":"RTHC-01359","title":"The effects of synthetic cannabinoids on executive function.","authors":"Cohen, K; Kapitány-Fövény, M; Mama, Y; Arieli, M; Rosca, P; Demetrovics, Z; Weinstein, A","year":2017,"journal":"Psychopharmacology, 234(7), 1121-1134","doi":"10.1007/s00213-017-4546-4","pmid":"28160034","tags":["synthetic-cannabinoids","cognition","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Across two study sites (Hungary and Israel), 38 synthetic cannabinoid users were compared with 43 recreational cannabis users and 41 non-users on computerized cognitive tests.\n\nSynthetic cannabinoid users performed significantly worse than both other groups on the n-back task (working memory accuracy), the Stroop task (response speed and accuracy, measuring inhibition), and a free-recall memory task (long-term memory). They also reported higher ratings of depression and anxiety.\n\nImportantly, recreational cannabis users did not show the same degree of impairment, suggesting that the cognitive deficits are specific to synthetic cannabinoids rather than cannabinoid exposure in general.","whyItMatters":"This is one of the first studies directly comparing cognitive function between synthetic cannabinoid users, natural cannabis users, and non-users. The finding that synthetic cannabinoid users are significantly more impaired than cannabis users provides evidence that these substances are genuinely more damaging to the brain, not just pharmacologically stronger.","specificNumbers":"38 synthetic cannabinoid users vs 43 cannabis users vs 41 non-users. Synthetic users: lower n-back accuracy, slower and less accurate Stroop performance, fewer words recalled. Higher depression and anxiety ratings. Two-country sample (Hungary, Israel).","methodology":"Cross-sectional comparison of three groups from two centers (Hungary and Israel). Cognitive testing included computerized n-back task (working memory), classical Stroop word-color task (inhibition), and free-recall memory task (long-term memory). Depression and anxiety were also assessed.","limitations":"Cross-sectional design cannot determine whether cognitive differences existed before drug use. Synthetic cannabinoid users may differ from cannabis users in polysubstance use, socioeconomic status, or other factors. The study did not control for specific synthetic cannabinoid products used. Small sample sizes limit statistical power."},{"rthcId":"RTHC-01360","title":"Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial.","authors":"Cooper, Ruth E; Williams, Emma; Seegobin, Seth; Tye, Charlotte; Kuntsi, Jonna; Asherson, Philip","year":2017,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 27(8), 795-808","doi":"10.1016/j.euroneuro.2017.05.005","pmid":"28576350","tags":["medical-cannabis","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In this pilot randomized, placebo-controlled trial, 30 adults with ADHD received either Sativex oromucosal spray (THC:CBD) or placebo. The primary outcome, cognitive performance and activity level measured by the QbTest, showed no significant difference, though active group scores were consistently better than placebo.\n\nSecondary outcomes were more encouraging: Sativex was associated with nominally significant improvement in hyperactivity/impulsivity (p=0.03) and a cognitive measure of inhibition (p=0.05). Trends toward improvement were seen for inattention (p=0.10) and emotional lability (p=0.11). Per-protocol effects (excluding dropouts) were stronger.\n\nHowever, results did not survive adjustment for multiple testing. One serious adverse event (muscular seizures/spasms) occurred in the active group.","whyItMatters":"Adults with ADHD frequently report self-medicating with cannabis, and some US psychiatrists prescribe it despite no prior controlled evidence. This is the first RCT to test cannabinoids for ADHD, and while not definitive, it provides preliminary experimental support for the self-medication theory by showing trends toward symptom improvement.","specificNumbers":"30 participants (15 active, 15 placebo). Hyperactivity/impulsivity: p=0.03. Cognitive inhibition: p=0.05. Inattention: p=0.10. Emotional lability: p=0.11. None significant after multiple testing correction. 1 serious adverse event (muscular seizures) in active group.","methodology":"Pilot randomized, double-blind, placebo-controlled trial (EMA-C trial). 30 adults with ADHD were randomized 1:1 to Sativex or placebo. Primary outcome: QbTest (computerized attention and activity measure). Secondary outcomes: ADHD symptom ratings and emotional lability. Recruitment: July 2014 to June 2015.","limitations":"Very small pilot study (n=30) underpowered to detect modest effects. Primary outcome was not significant. Secondary outcome significance did not survive multiple testing correction. One serious adverse event. Short duration. Does not address long-term efficacy or cognitive effects of sustained use."},{"rthcId":"RTHC-01361","title":"Alcohol or Drug Use and Trauma Recidivism.","authors":"Cordovilla-Guardia, Sergio; Vilar-López, Raquel; Lardelli-Claret, Pablo; Guerrero-López, Francisco; Fernández-Mondéjar, Enrique","year":2017,"journal":"Nursing research, 66(5), 399-404","doi":"10.1097/NNR.0000000000000231","pmid":"28858148","tags":["harm-reduction","driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 1,156 trauma patients (ages 16-70) hospitalized between 2011 and 2015, at least one substance was detected in 45.1%. Cannabis alone was found in 5.4% of patients. The consumption of any substance was associated with increased trauma recidivism (having a documented history of past trauma).\n\nThe adjusted odds ratio for multiple recidivism (more than one past trauma) was 3.17, and this association held regardless of age, gender, or the presence of previous psychiatric disorders. All substance groups (alcohol alone, cannabis alone, psychotropic medications, stimulants, and combinations) showed increased recidivism.","whyItMatters":"The finding that substance-positive trauma patients are significantly more likely to have prior traumas suggests a recurring cycle of substance use and injury. Screening for substance use in trauma settings could identify patients at high risk for future injuries and target them for intervention.","specificNumbers":"Substances detected in 45.1% of patients. Cannabis alone: 5.4%. Alcohol alone: 13.7%. Psychotropic medications: 12.5%. Multiple substances: 12.2%. Adjusted OR for multiple recidivism: 3.17 (95% CI 2.29-4.39).","methodology":"Cross-sectional analysis of 1,156 trauma patients admitted to a Spanish trauma hospital from November 2011 to March 2015. Substance presence was determined by laboratory testing (immunoassay for alcohol and 10 drug classes). Past trauma history was retrieved from the health information system covering records since 1999. Multinomial logistic regression estimated associations.","limitations":"Cross-sectional design cannot determine whether substance use causes trauma or whether trauma-prone individuals use more substances. Cannabis detection can reflect use days before the trauma event. Substance testing captures current intoxication, not chronic use patterns. Single-center study in Spain."},{"rthcId":"RTHC-01362","title":"Cannabis as a substitute for prescription drugs - a cross-sectional study.","authors":"Corroon, James M; Mischley, Laurie K; Sexton, Michelle","year":2017,"journal":"Journal of pain research, 10, 989-998","doi":"10.2147/JPR.S134330","pmid":"28496355","tags":["medical-cannabis","pain","anxiety","depression"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 2,774 cannabis users surveyed, 1,248 (46%) reported using cannabis as a substitute for prescription drugs. The most commonly replaced drug classes were opioids/narcotics (35.8%), anxiolytics/benzodiazepines (13.6%), and antidepressants (12.7%). A total of 2,473 substitutions were reported — approximately two medications per person who substituted. Medical cannabis users were 4.59 times more likely to substitute (95% CI 3.87-5.43). Female medical users showed the strongest signal at OR 6.09 (95% CI 4.65-7.80). State legal status had no significant effect on substitution behavior (47% vs 45%, p=0.58).","whyItMatters":"This study quantified a phenomenon that healthcare systems were largely ignoring: widespread, patient-driven substitution of cannabis for prescription medications. The finding that nearly half of cannabis users replace prescription drugs — particularly opioids during the peak of the opioid epidemic — has implications for harm reduction, clinical practice, and drug policy. The legal status finding is equally important: substitution happens regardless of the law, suggesting healthcare systems need to engage with this behavior rather than pretend it depends on policy.","specificNumbers":"2,774 cannabis users surveyed. 1,248 (46%) substituted. Substituted drugs: opioids 35.8%, benzodiazepines 13.6%, antidepressants 12.7%. 2,473 total substitutions (~2 per person). Medical users: 4.59x more likely to substitute. Pain/anxiety/depression: 1.66x more likely.","methodology":"Anonymous online 44-item questionnaire using REDCap, with PROMIS Global Health 10-item short form. Self-selected convenience sample of 2,774 cannabis users who had used at least once in the past 90 days. Recruited through social media, cannabis dispensary flyers in Washington State, Bastyr University website, public lectures, and online cannabis magazine. Data collected December 2013 to January 2016. Bastyr University IRB approved.","limitations":"Self-selected convenience sample recruited through cannabis-friendly channels, likely overrepresenting cannabis enthusiasts. Self-reported substitution with no clinical verification of medication changes or outcomes. Open-ended drug names created coding challenges. Some substituted drugs may have been OTC rather than prescription. PROMIS health scores show the sample was significantly less healthy than the general population. Timeline mismatch between data collection period (2013-2016) and legal status analysis date (2016). No information on whether substitution was medically supervised."},{"rthcId":"RTHC-01363","title":"Cannabis; Epidemiological, Neurobiological and Psychopathological Issues: An Update.","authors":"De Luca, Maria Antonietta; Di Chiara, Gaetano; Cadoni, Cristina; Lecca, Daniele; Orsolini, Laura; Papanti, Duccio; Corkery, John; Schifano, Fabrizio","year":2017,"journal":"CNS & neurological disorders drug targets, 16(5), 598-609","doi":"10.2174/1871527316666170413113246","pmid":"28412916","tags":["addiction","psychosis","youth","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review synthesized evidence across three domains. Epidemiologically, cannabis use typically starts between ages 15-24 and decreases with adult responsibilities. The highest prevalence is in North America, Australia, and Europe.\n\nNeurobiologically, cannabis shares some mechanism-of-action analogies with opiates. Clinical evidence supports concerns about the increased consumption among youth and the risk of psychotic disorder onset.\n\nThe review stated that cannabis intake during adolescence \"may facilitate the transition to the use and/or abuse of other psychotropic drugs, hence properly being considered a 'gateway drug.'\" The authors concluded that the social perception of low risk is at odds with biological and clinical evidence of cognitive impairment and mental health effects.","whyItMatters":"This review captures the tension between rising social acceptance and accumulating scientific evidence of harm, particularly for young users. The neurobiological parallels with opiates and the gateway drug discussion add important context to ongoing policy debates.","specificNumbers":"Cannabis use prevalence: varies by income, highest in North America, Australia, Europe. Typical initiation: ages 15-24. Use decreases with acquisition of adult responsibilities.","methodology":"Narrative review examining papers on epidemiological, neurobiological, and psychopathological aspects of cannabis use, searched through PubMed.","limitations":"Narrative review without systematic methodology. The gateway drug framing is contested in the research community. The review does not adequately distinguish between moderate and heavy use in its risk assessments. Published in a pharmacology journal, which may emphasize biological concerns over social context."},{"rthcId":"RTHC-01364","title":"School Protective Factors and Substance Use Among Lesbian, Gay, and Bisexual Adolescents in California Public Schools.","authors":"De Pedro, Kris Tunac; Esqueda, Monica Christina; Gilreath, Tamika D","year":2017,"journal":"LGBT health, 4(3), 210-216","doi":"10.1089/lgbt.2016.0132","pmid":"28498005","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analysis of California Healthy Kids Survey data (2013-2015) revealed that school protective factors were significantly associated with lower substance use among LGB youth. Higher school connectedness was associated with 22% decreased odds of inhalant use and 25% decreased odds of prescription pain medication use in the past 30 days.\n\nHigher levels of adult support in school were associated with 17% decreased odds of marijuana use on school property. These associations held even after controlling for school victimization, a well-established risk factor for substance use among LGB youth.\n\nThe findings suggest that positive school environments can buffer against substance use risk even in the presence of bullying and harassment.","whyItMatters":"LGB youth use substances at higher rates than heterosexual peers, often attributed to minority stress and victimization. This study shifts the focus from risk to protection, showing that school environments characterized by connection and supportive adults can reduce substance use even among this high-risk group.","specificNumbers":"School connectedness: 22% decreased odds of inhalant use (AOR 0.78), 25% decreased odds of prescription pain medication use (AOR 0.75). Adult support: 17% decreased odds of marijuana use on school property (AOR 0.83).","methodology":"Secondary analysis of the 2013-2015 California Healthy Kids Survey (CHKS). Examined associations between two school protective factors (school connectedness and adult support) and past 30-day and in-school use of cigarettes, alcohol, marijuana, inhalants, prescription pain medications, and other illegal drugs among LGB youth, controlling for school victimization.","limitations":"Cross-sectional design cannot establish causation. Self-reported substance use may be underreported. The survey does not capture the quality or type of adult support. LGB identification was self-reported and may not capture all sexual minority youth. California may differ from less supportive states."},{"rthcId":"RTHC-01365","title":"Second and Thirdhand Smoke Exposure, Attitudes and Protective Practices: Results from a Survey of Hispanic Residents in Multi-unit Housing.","authors":"Delgado-Rendon, Angelica; Cruz, Tess Boley; Soto, Daniel; Baezconde-Garbanati, Lourdes; Unger, Jennifer B","year":2017,"journal":"Journal of immigrant and minority health, 19(5), 1148-1155","doi":"10.1007/s10903-016-0540-x","pmid":"28074306","tags":["harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Although 97% of surveyed Hispanic tenants banned smoking inside their own apartments, 80% still reported tobacco secondhand smoke (SHS) infiltrating from other units within the past year. The problem of smoke migration between units affected the vast majority despite personal smoking bans.\n\n28% of respondents did not know that marijuana secondhand smoke (MSHS) exposure is also harmful to health. Interestingly, knowledge scores about smoke harm were higher among Spanish-speakers compared to English-dominant speakers.\n\n85% of respondents favored a complete ban on smoking in apartment buildings, indicating strong community support for policy solutions.","whyItMatters":"Multi-unit housing residents, disproportionately from minority and low-income communities, face involuntary exposure to both tobacco and marijuana smoke from neighboring units. As marijuana legalization expands, addressing marijuana secondhand smoke becomes an additional dimension of residential health protection.","specificNumbers":"402 Hispanic MUH tenants surveyed. 97% banned smoking in their homes. 80% reported SHS infiltration. 85% favored building-wide ban. 28% unaware marijuana smoke is harmful. Spanish-speakers had higher knowledge scores.","methodology":"Survey of 402 Hispanic tenants in randomly selected multi-unit housing units in eastern metro Los Angeles. Assessed characteristics, attitudes, knowledge, and behaviors related to secondhand smoke, thirdhand smoke, and marijuana smoke exposure.","limitations":"Single geographic area (eastern LA). Hispanic tenants may not represent all MUH populations. Self-reported smoke infiltration was not verified by air quality testing. The 28% knowledge gap about marijuana smoke could reflect genuine lack of information or uncertainty about evidence."},{"rthcId":"RTHC-01366","title":"Attenuation of Cocaine-Induced Conditioned Place Preference and Motor Activity via Cannabinoid CB2 Receptor Agonism and CB1 Receptor Antagonism in Rats.","authors":"Delis, Foteini; Polissidis, Alexia; Poulia, Nafsika; Justinova, Zuzana; Nomikos, George G; Goldberg, Steven R; Antoniou, Katerina","year":2017,"journal":"The international journal of neuropsychopharmacology, 20(3), 269-278","doi":"10.1093/ijnp/pyw102","pmid":"27994006","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CB1 antagonist rimonabant (3 mg/kg) decreased both the learning and expression of cocaine-induced place preference and reduced cocaine's stimulant effects on movement. The CB2 agonist JWH-133 (10 mg/kg) produced similar effects, also reducing cocaine place preference and abolishing cocaine-induced vertical activity.\n\nJWH-133's effects were specifically through CB2 receptors, as they were reversed by the CB2 antagonist AM630. The study found that CB1 and CB2 receptors appear to have opposite roles in regulating cocaine's effects: blocking CB1 or activating CB2 both reduced cocaine reward, suggesting these are complementary pharmacological strategies.\n\nImportantly, JWH-133 inhibited cocaine-related behaviors both during learning and during expression of already-learned associations, suggesting it could potentially help both prevention and treatment.","whyItMatters":"Cocaine addiction lacks effective pharmacological treatments. This study identifies two cannabinoid-based strategies, CB1 blockade and CB2 activation, that both reduce cocaine reward in animals. CB2 agonists are particularly interesting because they do not produce the psychiatric side effects associated with CB1 antagonists.","specificNumbers":"Rimonabant 3 mg/kg: reduced acquisition and expression of cocaine CPP, decreased motor activity. JWH-133 10 mg/kg: reduced acquisition and expression of cocaine CPP, abolished vertical activity. AM630 5 mg/kg: reversed JWH-133 effects (confirming CB2 mechanism). Cocaine dose: 20 mg/kg.","methodology":"Conditioned place preference (cocaine reward), conditioned motor activity, and open-field activity tests in rats. The CB1 antagonist rimonabant and CB2 agonist JWH-133 were administered at various time points to assess effects on acquisition and expression of cocaine conditioning. AM630 (CB2 antagonist) was used to confirm receptor specificity.","limitations":"Animal study using conditioned place preference, which models drug reward but not the full complexity of human addiction. Rimonabant was withdrawn from market due to psychiatric effects, limiting its clinical relevance. JWH-133 has not been tested in humans for cocaine addiction. The doses and timing may not translate directly to clinical use."},{"rthcId":"RTHC-01367","title":"Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding.","authors":"Deng, Hui; Kooijman, Sander; van den Nieuwendijk, Adrianus M C H; Ogasawara, Daisuke; van der Wel, Tom; van Dalen, Floris; Baggelaar, Marc P; Janssen, Freek J; van den Berg, Richard J B H N; den Dulk, Hans; Cravatt, Benjamin F; Overkleeft, Herman S; Rensen, Patrick C N; van der Stelt, Mario","year":2017,"journal":"Journal of medicinal chemistry, 60(1), 428-440","doi":"10.1021/acs.jmedchem.6b01482","pmid":"27992221","tags":["neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Through systematic medicinal chemistry, researchers created DH376 (compound 38), an inhibitor of diacylglycerol lipase (DAGL) with picomolar (trillionths of a molar) potency. DAGL is the enzyme responsible for producing 2-AG, the most abundant endocannabinoid that activates CB1 receptors.\n\nIn mice, DH376 temporarily reduced feeding after fasting, mimicking the effect of CB1 receptor inverse agonists. However, a negative control compound (DO53) that does not inhibit DAGL also affected feeding, suggesting these triazole urea compounds may influence energy balance through multiple molecular targets, not just DAGL inhibition.","whyItMatters":"Rather than blocking CB1 receptors directly (as rimonabant did), this approach targets the upstream enzyme that produces the endocannabinoid that activates CB1. However, the finding that non-DAGL-targeting compounds also affected feeding complicates the picture and suggests these chemical tools need further refinement.","specificNumbers":"DH376: picomolar DAGL inhibition. Temporarily reduced fasting-induced refeeding in mice. Negative control DO53 (non-DAGL inhibitor) also affected feeding, indicating off-target effects of the triazole urea scaffold.","methodology":"Structure-activity relationship studies with enantio- and diastereoselective synthesis of triazole urea compounds. In vitro: potency testing against DAGL and other serine hydrolases. In vivo: fasting-refeeding assay in mice comparing active DAGL inhibitors with a negative control compound.","limitations":"The negative control compound also affected feeding, undermining the conclusion that the feeding effects are DAGL-specific. These are tool compounds, not drug candidates. The triazole urea scaffold affects multiple serine hydrolases. Only acute feeding effects were tested."},{"rthcId":"RTHC-01368","title":"Validation of a Syndromic Case Definition for Detecting Emergency Department Visits Potentially Related to Marijuana.","authors":"DeYoung, Kathryn; Chen, Yushiuan; Beum, Robert; Askenazi, Michele; Zimmerman, Cali; Davidson, Arthur J","year":2017,"journal":"Public health reports (Washington, D.C. : 1974), 132(4), 471-479","doi":"10.1177/0033354917708987","pmid":"28586627","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers developed and validated a case definition for identifying marijuana-related ER visits using structured and free-text data from 15 Denver hospitals. The initial definition achieved 92.7% positive predictive value (PPV) in a validation period of 126,646 ER visits.\n\nAfter refinement, the final case definition achieved 95.7% PPV in a second validation period of 140,932 visits. The final definition contained just 6 keywords for marijuana or derivatives and 5 diagnosis codes for cannabis use, abuse, dependence, poisoning, and lung disease.\n\nThis tool enables near-real-time monitoring of marijuana-related ER visits, which is critical for tracking the public health impact of legalization.","whyItMatters":"As marijuana policies change rapidly, public health systems need reliable, efficient ways to monitor health impacts. This tool demonstrates that existing ER data systems can be leveraged for near-real-time marijuana surveillance with high accuracy, without requiring new data collection infrastructure.","specificNumbers":"Round 1: 524 matches from 126,646 visits, PPV 92.7%. Round 2: 698 matches from 140,932 visits, PPV 95.7%. Final definition: 6 keywords + 5 diagnosis codes. 15 Denver hospitals.","methodology":"Applied a syndromic case definition to BioSense 2.0 data from 15 Denver hospitals. Two rounds of validation with manual record review to determine true and false positives. Iterative refinement between rounds improved the PPV from 92.7% to 95.7%.","limitations":"Validated in one metropolitan area (Denver). The PPV measures accuracy of identified cases but does not capture sensitivity (cases missed). Free-text data quality varies across hospitals. The system identifies \"marijuana-related\" visits, not necessarily visits caused by marijuana."},{"rthcId":"RTHC-01369","title":"Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series.","authors":"Dezieck, Laurel; Hafez, Zachary; Conicella, Albert; Blohm, Eike; O'Connor, Mark J; Schwarz, Evan S; Mullins, Michael E","year":2017,"journal":"Clinical toxicology (Philadelphia, Pa.), 55(8), 908-913","doi":"10.1080/15563650.2017.1324166","pmid":"28494183","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Thirteen patients with daily cannabis use and symptoms consistent with cannabinoid hyperemesis syndrome (CHS) were treated with topical capsaicin cream at two academic medical center emergency departments. All 13 experienced symptom relief after capsaicin application.\n\nThe treatment was used after other approaches had failed. The proposed mechanism involves capsaicin binding to TRPV1 receptors with high specificity, overstimulating them to impair substance P signaling in the area postrema and nucleus tractus solitarius (brain regions that control vomiting). This may explain the antiemetic effect.","whyItMatters":"CHS is notoriously difficult to treat in the ER. Standard antiemetics often fail, and patients may receive unnecessary testing and prolonged stays. Topical capsaicin cream is inexpensive, widely available, and easy to apply. If these findings are confirmed in controlled trials, it could become a first-line ER treatment for CHS.","specificNumbers":"13 patients treated. All 13 experienced symptom relief. Treatment: topical capsaicin cream. Used at 2 academic medical centers. Mechanism: TRPV1 receptor overstimulation impairing substance P signaling.","methodology":"Retrospective case series. Electronic health records at two academic medical centers were queried to identify patients with documented daily cannabis use, CHS-consistent symptoms, and topical capsaicin treatment. Thirteen cases were identified.","limitations":"Retrospective, uncontrolled case series. No placebo comparison. 13 patients is a small number. Symptoms may have resolved spontaneously. The strength and application site of capsaicin cream varied. No standardized outcome measures."},{"rthcId":"RTHC-01370","title":"Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists.","authors":"Dhopeshwarkar, Amey; Murataeva, Natalia; Makriyannis, Alex; Straiker, Alex; Mackie, Ken","year":2017,"journal":"The Journal of pharmacology and experimental therapeutics, 360(2), 300-311","doi":"10.1124/jpet.116.236539","pmid":"27927913","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Two compounds (GW405833 and AM1710) that have been extensively used in research as selective CB2 receptor agonists were discovered to also antagonize CB1 receptor signaling. This makes them \"Janus\" ligands, named after the two-faced Roman god, as they simultaneously activate one receptor type while blocking the other.\n\nGW405833 was the more potent CB1 antagonist of the two, noncompetitively blocking multiple CB1 signaling pathways including adenylyl cyclase, ERK phosphorylation, and receptor internalization. Its interaction with CB1/arrestin signaling was complex: it initially potentiated arrestin recruitment at 20 minutes but shifted to antagonism after 1 hour.\n\nAM1710 behaved as a lower-potency competitive CB1 antagonist with some inverse agonist properties.","whyItMatters":"This is a critical methodological finding. Dozens of published studies have used GW405833 and AM1710 as \"selective CB2\" tools and attributed their effects solely to CB2 activation. The discovery of CB1 antagonism means those conclusions may need revision. Any experiment using these compounds must now account for their dual activity.","specificNumbers":"GW405833: noncompetitive CB1 antagonist across multiple signaling pathways. AM1710: low-potency competitive CB1 antagonist/inverse agonist. Time-dependent arrestin modulation by GW405833: potentiation at 20 min, antagonism at 1 hour.","methodology":"Autaptic hippocampal neurons (for endocannabinoid-mediated signaling), CB1-expressing HEK293 cells (for pathway-specific analysis), and multiple signaling readouts including adenylyl cyclase, ERK phosphorylation, PI(4,5)P2 signaling, receptor internalization, and arrestin recruitment.","limitations":"In vitro study using cell cultures and isolated neurons. The relevance of these findings to in vivo pharmacology depends on drug concentrations achieved in tissues. The complex, time-dependent signaling profiles make it difficult to predict net effects in whole organisms."},{"rthcId":"RTHC-01371","title":"Transient Cannabinoid Receptor 2 Blockade during Immunization Heightens Intensity and Breadth of Antigen-specific Antibody Responses in Young and Aged mice.","authors":"Dotsey, Emmanuel; Ushach, Irina; Pone, Egest; Nakajima, Rie; Jasinskas, Algis; Argueta, Donovan A; Dillon, Andrea; DiPatrizio, Nicholas; Davies, Huw; Zlotnik, Albert; Crompton, Peter D; Felgner, Philip L","year":2017,"journal":"Scientific reports, 7, 42584","doi":"10.1038/srep42584","pmid":"28209996","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The study first demonstrated that immune cells (macrophages and dendritic cells) produce the endocannabinoid 2-AG when activated by antigens, and that 2-AG levels increase in both blood and lymph nodes during vaccination. This endocannabinoid release appears to be a natural brake on immune activation.\n\nTransient administration of the CB2 antagonist AM630 (10 mg/kg) or inverse agonist JTE907 (3 mg/kg) during immunization heightened both the intensity and breadth of antigen-specific immune responses. This worked in both young and aged mice, with the improvement mediated by upregulation of immunomodulatory genes in secondary lymphoid tissues.\n\nThis represents the first demonstration that blocking endocannabinoid signaling during vaccination can serve as an immune adjuvant.","whyItMatters":"Vaccines are less effective in elderly people because of immune senescence. Finding that CB2 blockade boosts vaccine responses in aged mice opens a potential strategy for improving vaccination in the elderly. The discovery that the endocannabinoid system actively suppresses immune responses to vaccines is a fundamental new insight.","specificNumbers":"AM630 at 10 mg/kg and JTE907 at 3 mg/kg both enhanced vaccine responses. 2-AG levels were upregulated in serum and lymph nodes during vaccination. Enhanced responses seen in both young and aged mice.","methodology":"Mice received CB2 antagonist AM630 or inverse agonist JTE907 alongside vaccination. Immune responses were measured by antigen-specific antibody production (intensity and breadth). Endocannabinoid levels were measured in serum and lymph nodes. Gene expression analysis was performed on secondary lymphoid tissues.","limitations":"Mouse study that may not translate directly to human vaccination. Only transient CB2 blockade was tested, and chronic blockade could have different effects. The specific vaccine antigens used may not represent all vaccine types. Whether CB2 blockade would affect vaccine safety is unknown."},{"rthcId":"RTHC-01372","title":"Marijuana use in acute coronary syndromes.","authors":"Draz, Eman I; Oreby, Mervat M; Elsheikh, Eman A; Khedr, Lamia A; Atlam, Salwa A","year":2017,"journal":"The American journal of drug and alcohol abuse, 43(5), 576-582","doi":"10.1080/00952990.2016.1240800","pmid":"27820669","tags":["cardiovascular","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 138 young men (age 40 or under) admitted with acute heart attacks, 23 tested positive for cannabis only. Despite having no traditional cardiac risk factors besides tobacco smoking, cannabis-positive patients showed more severe cardiac presentations.\n\nST-elevation myocardial infarction (STEMI, the more severe type) was dominant in the cannabis group, while non-STEMI was more common in drug-free patients. Cannabis-positive patients had ischemic wall motion abnormalities (areas of the heart not moving properly) in 47.8% of cases versus 11.8% of drug-free patients.\n\nStrikingly, none of the cannabis-positive patients had normal coronary arteries, whereas 14.3% of drug-free patients did. Significant differences in echocardiography and angiography were observed.","whyItMatters":"Young people generally have very low rates of heart attack. Finding that cannabis-positive young men had more severe cardiac presentations despite fewer traditional risk factors suggests that cannabis may be an independent cardiac risk factor. The Egyptian context is important because cannabis use patterns differ from Western countries.","specificNumbers":"Cannabis-only patients (n=23): STEMI dominant, 47.8% wall motion abnormalities, 0% normal coronaries. Drug-free patients (n=34): NSTEMI dominant, 11.8% wall motion abnormalities, 14.3% normal coronaries. All patients: male, age 40 or younger.","methodology":"Cross-sectional study of 138 male patients aged 40 or younger with acute myocardial infarction admitted to a university hospital cardiac care unit in Egypt. Patients were divided by urine toxicology: cannabis-only (n=23), other substances (n=28), and negative (n=34). Cardiac evaluation included echocardiography and coronary angiography.","limitations":"Small sample from a single hospital in Egypt. Cross-sectional design cannot prove cannabis caused the heart attacks. Urine testing detects cannabis use within days, not necessarily acute intoxication at the time of the event. Tobacco smoking was common across groups and is itself a cardiac risk factor. The cannabis products used in Egypt may differ in composition from those elsewhere."},{"rthcId":"RTHC-01373","title":"Psychometric Properties of the Turkish Versions of the Cannabis Use Problems Identification Test (CUPIT) and the Adult Cannabis Problems Questionnaire (CPQ).","authors":"Evren, Cuneyt; Yilmaz Cengel, Hanife; Bozkurt, Muge; Evren, Bilge; Umut, Gokhan; Agachanli, Ruken","year":2017,"journal":"Journal of psychoactive drugs, 49(1), 83-89","doi":"10.1080/02791072.2016.1277047","pmid":"28195831","tags":["addiction","withdrawal","synthetic-cannabinoids"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"The CUPIT and CPQ questionnaires were validated in a Turkish clinical sample of 52 cannabis users and 45 synthetic cannabinoid users being treated for use disorders. Both instruments showed good internal consistency: CUPIT scored 0.89 and CPQ scored 0.87 (Cronbach's alpha).\n\nThe CUPIT and CPQ were strongly correlated with each other (r=0.76) and moderately correlated with the Cannabis Withdrawal Scale (r=0.63 and r=0.74 respectively), supporting convergent validity.\n\nPrincipal component analysis supported a two-factor structure for the CUPIT. The finding that both tools worked for synthetic cannabinoid users is particularly relevant given the high prevalence of synthetic cannabinoid use in Turkey.","whyItMatters":"Cannabis and synthetic cannabinoids are widely used in Turkey, and clinicians need validated screening and outcome tools in Turkish. Demonstrating that these instruments work for synthetic cannabinoid users is important because synthetic cannabinoid use disorder is common in Turkey and may present differently from natural cannabis use disorder.","specificNumbers":"CUPIT: alpha 0.89. CPQ: alpha 0.87. CUPIT-CPQ correlation: r=0.76. CUPIT-CWS correlation: r=0.63. CPQ-CWS correlation: r=0.74. Sample: 52 cannabis users, 45 synthetic cannabinoid users (all male outpatients).","methodology":"Psychometric validation study of Turkish translations of the CUPIT and CPQ in 97 male outpatients with cannabis (n=52) or synthetic cannabinoid (n=45) use disorder. Analyses included principal component analysis, internal consistency (Cronbach's alpha), and correlational validity against each other and the Cannabis Withdrawal Scale.","limitations":"Male-only sample limits generalizability. Relatively small sample size (97 total). Outpatient treatment-seeking population may differ from community samples. One CPQ subscale (CPQ-C) had low internal consistency (alpha 0.30). The study did not assess test-retest reliability."},{"rthcId":"RTHC-01374","title":"Cannabis and intractable chronic pain: an explorative retrospective analysis of Italian cohort of 614 patients.","authors":"Fanelli, Guido; De Carolis, Giuliano; Leonardi, Claudio; Longobardi, Adele; Sarli, Ennio; Allegri, Massimo; Schatman, Michael E","year":2017,"journal":"Journal of pain research, 10, 1217-1224","doi":"10.2147/JPR.S132814","pmid":"28579820","tags":["pain","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Following Italy's 2015 authorization of medical cannabis, researchers analyzed the first year of clinical use for chronic pain across six treatment centers. Only one center (Pisa) had extensive experience, treating 614 of 659 total patients.\n\nCannabis tea was the primary delivery method, and in nearly all cases, cannabis was used alongside existing pain treatments rather than as a replacement. Initial and follow-up cannabinoid concentrations varied considerably across patients.\n\nAt the first follow-up, 76.2% of patients continued treatment. Fewer than 15% discontinued due to side effects, and none of the side effects were severe.","whyItMatters":"This is the first large-scale snapshot of real-world cannabis use for chronic pain in Italy, providing data from a clinical setting rather than a controlled trial. The high continuation rate and low rate of severe side effects suggest acceptable tolerability in a diverse chronic pain population.","specificNumbers":"614 patients from Pisa center (of 659 total across six centers). 76.2% continued treatment at initial follow-up. <15% stopped due to side effects (none severe). Primary delivery: cannabis tea. Treatment period: December 2015-November 2016.","methodology":"Retrospective case series analyzing all chronic pain patients treated with oral or vaporized cannabis at six Italian centers from December 2015 to November 2016. Evaluated routes of administration, cannabis products used, dosing, effectiveness, and safety.","limitations":"Retrospective, uncontrolled case series with no placebo comparison. Continuation rate does not equal efficacy. Concentration variability limits reproducibility. Only one center contributed the vast majority of patients. Pain type heterogeneity makes it difficult to identify which conditions respond best. Short follow-up period."},{"rthcId":"RTHC-01375","title":"Efficacy and Tolerability of Phytomedicines in Multiple Sclerosis Patients: A Review.","authors":"Farzaei, Mohammad Hosein; Shahpiri, Zahra; Bahramsoltani, Roodabeh; Nia, Marjan Moghaddam; Najafi, Fariba; Rahimi, Roja","year":2017,"journal":"CNS drugs, 31(10), 867-889","doi":"10.1007/s40263-017-0466-4","pmid":"28948486","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Among ten medicinal plants with clinical evidence for MS symptom management, Cannabis sativa had the highest level of support. Its key bioactive compounds, THC and CBD, showed efficacy for spasticity, fatigue, urinary symptoms (incontinence, urgency, nocturia), memory performance, functional performance, and tremor.\n\nOther plants with positive evidence included ginkgo biloba, ginseng, green tea (epigallocatechin-3-gallate), and boswellia. All herbal medicines reviewed were mostly well tolerated with mild to moderate adverse effects.\n\nThe review covered clinical studies only, spanning publications from 1966 to February 2017.","whyItMatters":"By placing cannabis in the broader context of all medicinal plants studied for MS, this review provides perspective: cannabis is not just another herbal remedy for MS but the one with the most and strongest clinical evidence. This helps clinicians and patients make informed decisions about complementary therapies.","specificNumbers":"10 medicinal plants with clinical evidence for MS. Cannabis sativa: highest evidence level. Effective for: spasticity, fatigue, scotoma, incontinence, urgency, nocturia, memory, functional performance, tremor. Key compounds: THC, CBD.","methodology":"Systematic review of clinical studies from the Cochrane Library, PubMed, and Scopus (1966-2017). Only clinical studies evaluating medicinal plants for MS symptoms were included.","limitations":"The abstract does not detail the number or quality of cannabis studies included. \"Highest level of evidence\" is relative to other herbal medicines, which generally have limited clinical data. The review included all plant-based therapies, not just cannabis, so cannabis-specific analysis may be limited."},{"rthcId":"RTHC-01376","title":"Anorexigenic effects induced by RVD-hemopressin(α) administration.","authors":"Ferrante, Claudio; Recinella, Lucia; Leone, Sheila; Chiavaroli, Annalisa; Di Nisio, Chiara; Martinotti, Sara; Mollica, Adriano; Macedonio, Giorgia; Stefanucci, Azzurra; Dvorácskó, Szabolcs; Tömböly, Csaba; De Petrocellis, Luciano; Vacca, Michele; Brunetti, Luigi; Orlando, Giustino","year":2017,"journal":"Pharmacological reports : PR, 69(6), 1402-1407","doi":"10.1016/j.pharep.2017.05.015","pmid":"29145068","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Daily injections of RVD-hemopressin(alpha) (10 nmol) for 14 days reduced food intake in rats. However, body weight was unaffected despite the decreased eating. The researchers found that this paradox may be explained by decreased expression of UCP-1 (uncoupling protein 1) in brown adipose tissue, which would reduce thermogenic energy expenditure, offsetting the caloric deficit from eating less.\n\nAt the brain level, RVD-hemopressin(alpha) downregulated POMC gene expression and norepinephrine levels in the hypothalamus, providing a neuromodulatory mechanism for the appetite effects.","whyItMatters":"The brain produces its own peptides that modulate cannabinoid receptors. Understanding how these natural regulators affect appetite and metabolism could lead to more physiological approaches to treating obesity, working with the body's own cannabinoid control systems rather than against them.","specificNumbers":"RVD-hemopressin(alpha) 10 nmol daily for 14 days. Decreased food intake. No body weight change. Decreased UCP-1 in brown adipose tissue. Decreased POMC and norepinephrine in hypothalamus.","methodology":"Rats received 14 daily intraperitoneal injections of RVD-hemopressin(alpha) (10 nmol). Food intake and body weight were monitored. Brain tissue was analyzed for POMC gene expression and norepinephrine levels. Brown adipose tissue was assessed for UCP-1 gene expression.","limitations":"Animal study with direct peptide injection. The peptide likely does not cross the blood-brain barrier well, limiting its therapeutic potential. Only 14 days of treatment were assessed. The absence of weight loss despite reduced eating limits the translational value for obesity treatment."},{"rthcId":"RTHC-01377","title":"Cannabinoid Type 1 Receptor (CB1) Ligands with Therapeutic Potential for Withdrawal Syndrome in Chemical Dependents of Cannabis sativa.","authors":"Ferreira, Jaderson V; Chaves, Gisele A; Marino, Bianca L B; Sousa, Kessia P A; Souza, Lucilene R; Brito, Maiara F B; Teixeira, Hueldem R C; da Silva, Carlos H T P; Santos, Cleydson B R; Hage-Melim, Lorane I S","year":2017,"journal":"ChemMedChem, 12(16), 1408-1416","doi":"10.1002/cmdc.201700129","pmid":"28417566","tags":["withdrawal","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Researchers used computational chemistry tools to screen for potential drug candidates to treat cannabis withdrawal syndrome, focusing on compounds that could interact with the CB1 cannabinoid receptor. Among the candidates evaluated, stemphol (ZINC1730183, also known as 2-n-butyl-5-n-pentylbenzene-1,3-diol) showed favorable predictions both as a human CB1 ligand and for synthetic accessibility.\n\nThe approach was based on analyzing natural ligands of the CB1 receptor to identify structural features that could be replicated in drug candidates.","whyItMatters":"Cannabis withdrawal syndrome is recognized in the DSM-5 but has few effective pharmacological treatments. This computational approach represents an early step toward identifying new drug candidates that could target the CB1 receptor to manage withdrawal symptoms.","specificNumbers":"Lead compound: stemphol (ZINC1730183). Positive predictions for: CB1 receptor binding and synthetic accessibility.","methodology":"In silico (computational) drug design using molecular modeling, docking simulations, and ADMET (absorption, distribution, metabolism, excretion, toxicity) predictions. No experimental validation was performed.","limitations":"Purely computational study with no experimental validation. In silico predictions do not guarantee in vivo activity. The compound has not been tested for CB1 binding, pharmacological activity, or therapeutic efficacy. The gap between computational prediction and clinical drug is vast."},{"rthcId":"RTHC-01378","title":"The role of illicit drug use in sudden death in the young.","authors":"Fischbach, Peter","year":2017,"journal":"Cardiology in the young, 27(S1), S75-S79","doi":"10.1017/S1047951116002274","pmid":"28084963","tags":["cardiovascular","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review assessed the cardiac risks of major illicit drugs in young people. Cocaine's association with sudden death from myocardial ischemia is well established, amplified by concurrent smoking and alcohol. Amphetamines cause similar cardiovascular toxicity through autonomic stimulation and coronary vasospasm.\n\nFor marijuana, the review noted that it has \"long been thought to have very few adverse effects with the exception of long-term dependence.\" However, scattered reports document acute adverse events up to and including sudden death, apparently caused by myocardial infarction. The incidence ranges from rare for marijuana to \"not infrequent\" for cocaine.","whyItMatters":"As marijuana legalization expands, understanding its cardiac risk profile relative to other drugs is important. The review places marijuana cardiac events in context: far rarer than with cocaine or amphetamines, but not absent. Healthcare providers caring for sudden cardiac arrest survivors should consider drug use history.","specificNumbers":"Sudden death incidence: rare for marijuana, not infrequent for cocaine. Cocaine risk amplified by smoking and alcohol. Marijuana cardiac events appear to involve myocardial infarction.","methodology":"Narrative review of the cardiovascular toxicity and sudden death risk associated with cocaine, amphetamines, and marijuana in young people.","limitations":"Narrative review without systematic methodology. Marijuana cardiac events are described as \"scattered reports\" without quantification. The review does not address dose, potency, or route of administration. Attribution of cardiac death to marijuana is complicated by potential confounders."},{"rthcId":"RTHC-01379","title":"Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis.","authors":"Fitzpatrick, John-Mark K; Downer, Eric J","year":2017,"journal":"Neuropharmacology, 113(Pt B), 618-626","doi":"10.1016/j.neuropharm.2016.04.009","pmid":"27079840","tags":["medical-cannabis","inflammation","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Toll-like receptors (TLRs) are immune sensors that trigger inflammatory responses and play a pivotal role in the development of MS (as shown in animal models). The review presented evidence that cannabinoids modulate TLR signaling pathways both in the brain and in peripheral immune cells.\n\nSativex, a combination of plant cannabinoids approved for MS, has demonstrated efficacy for neuropathic pain and spasticity, but its precise cellular and molecular mechanisms have remained unclear. The review highlighted that cannabinoid-TLR interactions may partly explain how Sativex works, by dampening the innate immune responses that drive MS pathology.","whyItMatters":"Understanding how cannabis-based medicines work at the molecular level is essential for developing better treatments. The TLR connection suggests that cannabinoids may be addressing a fundamental driver of MS inflammation, not just masking symptoms, and could lead to more targeted therapies.","specificNumbers":"Sativex: plant-derived cannabinoid combination with clinical efficacy for MS pain and spasticity. TLR signaling: pivotal in EAE (animal MS model) development. Cannabinoid-TLR interplay: demonstrated both centrally and peripherally.","methodology":"Narrative review synthesizing evidence on TLR signaling in MS pathogenesis and its modulation by cannabinoids, both in the central nervous system and peripheral immune system.","limitations":"Narrative review based largely on preclinical and in vitro data. The specific mechanisms by which Sativex modulates TLR signaling in MS patients have not been confirmed in clinical studies. TLR biology is complex, and cannabinoid effects may vary by TLR type and cell context."},{"rthcId":"RTHC-01380","title":"Cannabinoid Hyperemesis Syndrome.","authors":"Fleming, J Eric; Lockwood, Sean","year":2017,"journal":"Federal practitioner : for the health care professionals of the VA, DoD, and PHS, 34(10), 33-36","doi":null,"pmid":"30766236","tags":["harm-reduction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review from a federal healthcare publication emphasized that cannabinoid hyperemesis syndrome (CHS) sits at the intersection of three converging trends: legislative efforts expanding cannabis access, increasing prevalence of cannabis use, and rising THC potency. These factors combine to make CHS a more commonly encountered but still frequently missed diagnosis.","whyItMatters":"CHS is often misdiagnosed or unrecognized, leading to repeated ER visits, unnecessary testing, and delayed treatment. Healthcare providers in federal settings (VA, military, public health) need awareness as cannabis use patterns evolve among their patient populations.","specificNumbers":"The review highlights three converging factors: legislative changes, increasing prevalence, and THC toxicity.","methodology":"Clinical review article published in a federal healthcare practitioner journal aimed at VA, DoD, and PHS healthcare professionals.","limitations":"Brief overview article with a very concise abstract. Limited detail on specific clinical recommendations or evidence base."},{"rthcId":"RTHC-01381","title":"Marijuana Use in Pregnancy: Concerns in an Evolving Era.","authors":"Foeller, Megan E; Lyell, Deirdre J","year":2017,"journal":"Journal of midwifery & women's health, 62(3), 363-367","doi":"10.1111/jmwh.12631","pmid":"28498631","tags":["pregnancy","youth","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Marijuana is the most commonly used illicit drug during pregnancy, and its use is increasing in the US. While much of the existing research has limitations (study design, confounding factors), a growing body of data suggests adverse outcomes from prenatal exposure.\n\nAssociations have been identified with decreased birth weight, increased spontaneous preterm birth, and impaired neurodevelopment among children and adults who were exposed in utero. Moderate concentrations of marijuana have also been detected in breast milk.\n\nMultiple professional societies have issued clear statements against marijuana use during pregnancy and lactation.","whyItMatters":"As marijuana becomes more available and socially accepted, pregnant women may perceive less risk from use. This review highlights that despite imperfect evidence, the signal for harm is consistent enough that professional medical organizations recommend against use during pregnancy and breastfeeding.","specificNumbers":"Marijuana: most commonly used illicit drug in pregnancy. Prevalence increasing in US. Associations: decreased birth weight, increased preterm birth, impaired neurodevelopment. THC detected in breast milk at moderate concentrations.","methodology":"Narrative review of existing research on marijuana use during pregnancy, covering birth outcomes, neurodevelopmental effects, and breast milk transmission.","limitations":"Existing research is limited by observational designs, confounding factors (tobacco, alcohol, socioeconomic status), and self-reported cannabis use. THC potency has increased substantially over time, so older studies may underestimate current risks. The review does not differentiate between occasional and heavy use."},{"rthcId":"RTHC-01382","title":"Pharmacological inhibition of cannabinoid receptor 1 stimulates gastric release of nesfatin-1 via the mTOR pathway.","authors":"Folgueira, Cintia; Barja-Fernandez, Silvia; Prado, Laura; Al-Massadi, Omar; Castelao, Cecilia; Pena-Leon, Veronica; Gonzalez-Saenz, Patricia; Baltar, Javier; Baamonde, Ivan; Leis, Rosaura; Dieguez, Carlos; Pagotto, Uberto; Casanueva, Felipe F; Tovar, Sulay A; Nogueiras, Ruben; Seoane, Luisa M","year":2017,"journal":"World journal of gastroenterology, 23(35), 6403-6411","doi":"10.3748/wjg.v23.i35.6403","pmid":"29085189","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"When rats were treated with the CB1 inverse agonist rimonabant, food intake decreased and gastric secretion of Nucb2/nesfatin-1 (a satiety peptide) increased. Circulating nesfatin-1 levels in the blood also rose.\n\nRimonabant activated the mTOR signaling pathway in the stomach, as shown by increased phosphorylated mTOR. When mTOR was blocked with rapamycin, rimonabant could no longer stimulate nesfatin-1 release, confirming that the mTOR/S6k pathway mediates this effect.\n\nThe same results were confirmed using a second CB1 antagonist (AM281), strengthening the conclusion that this is specifically a CB1-mediated mechanism.","whyItMatters":"This study reveals a specific mechanism by which the cannabinoid system in the stomach, not the brain, regulates appetite. The mTOR pathway connection is important because mTOR is a central cellular energy sensor. This peripheral circuit could be targeted to reduce appetite without affecting the brain.","specificNumbers":"Rimonabant increased gastric nesfatin-1 secretion and circulating levels. Rapamycin blocked rimonabant's effect on nesfatin-1 release. mTOR phosphorylation increased in gastric tissue after CB1 blockade. Confirmed with second CB1 antagonist AM281.","methodology":"Rats received rimonabant, rapamycin, rapamycin plus rimonabant, or vehicle. Gastric tissue was analyzed for Nucb2 mRNA, protein content, and mTOR pathway activation. Gastric secretomes (collected from tissue explants) and plasma were assayed for nesfatin-1 levels.","limitations":"Animal study using injected drugs. Rimonabant was withdrawn from human use due to psychiatric side effects. The gastric mTOR-nesfatin pathway may differ between rats and humans. Only acute effects were measured."},{"rthcId":"RTHC-01383","title":"Cannabis: An Overview of its Adverse Acute and Chronic Effects and its Implications.","authors":"Ford, Talitha C; Hayley, Amie C; Downey, Luke A; Parrott, Andrew C","year":2017,"journal":"Current drug abuse reviews, 10(1), 6-18","doi":"10.2174/1874473710666170712113042","pmid":"28707583","tags":["harm-reduction","addiction","cognition","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review surveyed evidence across multiple domains of cannabis harm. Acute and chronic use was associated with negative effects on mood states, psychiatric outcomes (including psychosis risk), neurocognition, driving ability, and general health.\n\nThe review noted that cannabis is \"highly addictive\" and that withdrawal effects can drive continued use. While CBD has demonstrated antioxidant, anticonvulsant, anti-inflammatory, and neuroprotective properties, high-potency recreational cannabis is characterized by high THC and low CBD, maximizing the harmful components.\n\nThe authors concluded that \"there is insufficient evidence to support the safety of cannabis and its subsequent legalisation for recreational use\" and that medical cannabis use \"should be done with care.\"","whyItMatters":"As cannabis legalization advances globally, this review provides a counterpoint by comprehensively cataloging documented harms. The distinction between high-THC recreational products and CBD-rich medical preparations is important for understanding why recreational and medical cannabis may have very different risk profiles.","specificNumbers":"Domains of harm: mood, psychiatric outcomes, neurocognition, driving, general health. High-potency cannabis: high THC, low CBD. CBD properties: antioxidant, anticonvulsant, anti-inflammatory, neuroprotective.","methodology":"Narrative review covering acute and chronic effects of cannabis on psychological, cognitive, psychiatric, and physical health outcomes.","limitations":"Narrative review that selectively presents evidence for harm. Does not systematically compare cannabis risks to those of legal substances like alcohol and tobacco. The claim that cannabis is \"highly addictive\" is debatable, as dependence rates are lower than for alcohol, tobacco, or opioids. The review does not adequately address dose-response relationships or differences between occasional and heavy use."},{"rthcId":"RTHC-01384","title":"Cannabis use by women during pregnancy does not influence infant DNA methylation of the dopamine receptor DRD4.","authors":"Fransquet, Peter D; Hutchinson, Delyse; Olsson, Craig A; Allsop, Steve; Elliott, Elizabeth J; Burns, Lucinda; Mattick, Richard; Saffery, Richard; Ryan, Joanne","year":2017,"journal":"The American journal of drug and alcohol abuse, 43(6), 671-677","doi":"10.1080/00952990.2017.1314488","pmid":"28448718","tags":["pregnancy","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 804 neonates whose mothers provided detailed trimester-by-trimester drug use information, 44 were exposed to maternal cannabis use during pregnancy. Testing 19 CpG sites in the DRD4 dopamine receptor gene promoter, cannabis exposure was associated with methylation at one site in multivariate models (p=0.047), but this would not survive correction for multiple testing.\n\nAt another CpG site, there was weak evidence that both cannabis and other drug use were independently associated with increased methylation, while tobacco showed a reverse association. However, none of the associations reached significance after multiple testing correction.\n\nThe overall conclusion was that there is no strong evidence of maternal cannabis affecting offspring DRD4 methylation.","whyItMatters":"This is the first study to directly examine whether prenatal cannabis exposure affects offspring DNA methylation at a specific dopamine receptor gene. The largely null result is notable because maternal tobacco smoking (which was also assessed) has well-documented effects on infant DNA methylation. Cannabis may affect the developing brain through mechanisms other than epigenetic modification of dopamine receptor genes.","specificNumbers":"804 neonates. 44 with cannabis-exposed mothers. 19 CpG sites tested. 1 nominally significant (p=0.047, would not survive multiple testing correction). Overall: no strong association.","methodology":"Mothers in the Triple B study provided detailed drug use information for each trimester. Buccal swabs were collected from neonates at 8 weeks (n=804). DRD4 promoter DNA methylation was measured using SEQUENOM MassARRAY. Multivariate models controlled for confounders.","limitations":"Only 44 cannabis-exposed infants, limiting statistical power. Only one gene (DRD4) was examined; cannabis could affect methylation at thousands of other sites. Buccal cell methylation may not reflect brain methylation. Cannabis use was self-reported. The 8-week timepoint may not capture transient methylation changes at birth."},{"rthcId":"RTHC-01385","title":"Conservative treatment of patients with thromboangiitis obliterans or cannabis-associated arteritis presenting with critical lower limb ischaemia.","authors":"Galyfos, George; Kerasidis, Stavros; Kastrisios, Georgios; Giannakakis, Sotirios; Sachmpazidis, Ioannis; Anastasiadou, Christiana; Geropapas, Georgios; Papapetrou, Anastasios; Papacharalampous, Gerasimos; Maltezos, Chrisostomos","year":2017,"journal":"VASA. Zeitschrift fur Gefasskrankheiten, 46(6), 471-475","doi":"10.1024/0301-1526/a000649","pmid":"28753096","tags":["cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Over six years, 23 patients (15 with thromboangiitis obliterans and 8 with cannabis-associated arteritis) presented with critical lower limb ischemia. None had risk factors other than smoking. All patients presented with rest pain, and 12 had ulcers or necrotic lesions.\n\nConservative treatment (28 days of intravenous iloprost plus bemiparin, followed by oral aspirin plus cilostazol) improved clinical symptoms and ankle-brachial index in all patients (from 0.46 to 0.54, p<0.05). During follow-up, only 3 patients required bypass surgery and 2 underwent major amputation.\n\nHowever, the smoking abstinence rate was very low at 13%, a critical concern since cessation is the most important factor in preventing disease progression.","whyItMatters":"Cannabis-associated arteritis (CAA) is an under-recognized vascular condition that can lead to limb loss in young people. This study shows that conservative treatment can avoid amputation in most patients, but the dismal 13% smoking cessation rate threatens long-term outcomes and highlights the addictive nature of cannabis and tobacco co-use.","specificNumbers":"23 patients (15 TAO, 8 CAA). Mean ABI: 0.46 at presentation, 0.54 after 28 days (p<0.05). 3 bypass surgeries, 2 major amputations during follow-up. Smoking abstinence: 13%. 12 patients with ulcers or necrotic lesions at presentation.","methodology":"Retrospective evaluation of patients with TAO or CAA presenting with critical limb ischemia between 2011 and 2016 at a single center. Patients requiring primary intervention were excluded. Outcomes included symptom recession, ABI improvement, lesion healing, amputation, revascularization, and abstinence rates.","limitations":"Small retrospective case series from a single center. No control group. TAO and CAA were analyzed together, though they may have different pathophysiology. Follow-up duration was not specified in the abstract. The low abstinence rate limits interpretation of long-term outcomes."},{"rthcId":"RTHC-01386","title":"Do Clinicians Ask Pregnant Women about Exposures to Tobacco and Cannabis Smoking, Second-Hand-Smoke and E-Cigarettes? An Australian National Cross-Sectional Survey.","authors":"Gould, Gillian S; Zeev, Yael Bar; Tywman, Laura; Oldmeadow, Christopher; Chiu, Simon; Clarke, Marilyn; Bonevski, Billie","year":2017,"journal":"International journal of environmental research and public health, 14(12)","doi":"10.3390/ijerph14121585","pmid":"29258185","tags":["pregnancy","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 378 Australian GPs and obstetricians, 95% asked pregnant patients about cigarette smoking at most visits. However, other exposures were assessed far less frequently: cannabis (58%), cannabis mixed with tobacco (38%), secondhand smoke (27%), e-cigarettes (13-14%), and chewing tobacco (10%).\n\nAboriginal health GPs were more likely to ask about cannabis compared to general obstetricians and GPs. The disparity suggests that healthcare providers focus heavily on cigarettes while underassessing other smoke and nicotine exposures that may also affect maternal and fetal health.","whyItMatters":"If clinicians rarely ask about cannabis, e-cigarettes, and secondhand smoke during pregnancy, they cannot counsel patients about these exposures or track their prevalence. This assessment gap represents a missed opportunity for preventive health, particularly as cannabis and e-cigarette use are increasing.","specificNumbers":"378 GPs and OBS surveyed. Asking rates: cigarettes 95%, cannabis 58%, cannabis+tobacco 38%, secondhand smoke 27%, e-cigarettes 13-14%, chewing tobacco 10%. Aboriginal health GPs asked about cannabis more often.","methodology":"Two cross-sectional surveys: one targeting GPs in Aboriginal and Torres Strait Islander health (NFATSIH) and another targeting GPs and obstetricians through RANZCOG. Surveys assessed frequency of asking about various smoke and nicotine exposures using Likert scales.","limitations":"Low response rate (6.2%). Australian healthcare context may not generalize to other countries. Self-reported screening practices may overestimate actual asking rates. The survey did not assess whether asking about cannabis changed clinical management."},{"rthcId":"RTHC-01387","title":"Role of cannabis in digestive disorders.","authors":"Goyal, Hemant; Singla, Umesh; Gupta, Urvashi; May, Elizabeth","year":2017,"journal":"European journal of gastroenterology & hepatology, 29(2), 135-143","doi":"10.1097/MEG.0000000000000779","pmid":"27792038","tags":["medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system performs protective activities throughout the gastrointestinal tract and modulates gut inflammation, motility, secretion, and pain perception. THC exerts biological functions on the GI tract through CB1 and CB2 receptors.\n\nThe review found promising evidence for cannabinoid therapy in several GI conditions: inflammatory bowel disease (especially Crohn's disease), irritable bowel syndrome, and secretion/motility-related disorders. Cannabis has also been used for GI symptoms including nausea and vomiting, anorexia, weight loss, and chronic abdominal pain.\n\nHowever, the review also covered cannabinoid hyperemesis syndrome and noted that while the current literature supports use for digestive disorders, the clinical efficacy remains unclear pending more rigorous trials.","whyItMatters":"GI disorders affect a large proportion of the population, and current treatments are often inadequate. The endocannabinoid system's broad involvement in gut function, from inflammation to motility to pain, suggests it could be a unified target for multiple GI conditions.","specificNumbers":"Conditions reviewed: IBD (especially Crohn's), IBS, motility disorders, nausea/vomiting, CHS, anorexia, chronic abdominal pain. Receptor targets: CB1 and CB2 in the GI tract.","methodology":"Narrative review of the role of cannabis and the endocannabinoid system in the gut, liver, and pancreas, covering both therapeutic potential and adverse effects (CHS).","limitations":"Narrative review without systematic methodology. The clinical evidence for most GI indications comes from small studies and case reports. The review acknowledges that clinical efficacy \"remains unclear.\" Does not address drug interactions or contraindications."},{"rthcId":"RTHC-01388","title":"Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome in Adolescents: A Case Series.","authors":"Graham, Jessica; Barberio, Michael; Wang, George Sam","year":2017,"journal":"Pediatrics, 140(6)","doi":"10.1542/peds.2016-3795","pmid":"29122973","tags":["youth","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Two adolescent patients presented to a pediatric emergency department with nausea, vomiting, and abdominal pain in the setting of chronic cannabis use. Standard antiemetic therapies failed to relieve their symptoms.\n\nBoth patients responded to topical capsaicin cream administration. The mechanism involves capsaicin's high-specificity binding to TRPV1 receptors, which impairs substance P signaling in brain regions that control vomiting (area postrema and nucleus tractus solitarius).\n\nThese are the first reported cases of capsaicin being used to treat CHS in pediatric patients. The treatment is cost-effective and has few serious side effects, making it an attractive alternative to haloperidol, which carries risks of dystonia, extrapyramidal reactions, and neuroleptic malignant syndrome.","whyItMatters":"CHS is increasingly recognized in adolescents but is often misdiagnosed. Standard treatments frequently fail, and alternatives like haloperidol carry significant risks in young patients. Capsaicin cream offers a safe, inexpensive option that the adult literature has shown to be effective, and this case series extends it to the pediatric population.","specificNumbers":"2 adolescent patients. Both had chronic cannabis use, nausea/vomiting/abdominal pain. Both failed standard antiemetics. Both responded to topical capsaicin. First pediatric cases reported.","methodology":"Case series of two adolescent patients with CHS symptoms refractory to standard antiemetic treatment, treated with topical capsaicin cream in a pediatric emergency department.","limitations":"Only two cases. No control group. Case reports cannot establish efficacy or determine optimal dosing. Self-resolving symptoms cannot be excluded. The long-term effectiveness and need for ongoing cannabis cessation were not assessed."},{"rthcId":"RTHC-01389","title":"Cannabis and Canada's children and youth.","authors":"Grant, Christina N; Bélanger, Richard E","year":2017,"journal":"Paediatrics & child health, 22(2), 98-102","doi":"10.1093/pch/pxx017","pmid":"29480902","tags":["youth","addiction","psychosis","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis is the most common illicit drug used by Canadian teenagers. The review found that adolescent cannabis use can cause functional and structural changes to the developing brain, leading to damage. Strong associations were documented with cannabis dependence and other substance use disorders, initiation and maintenance of tobacco smoking, depression, anxiety, psychosis, impaired neurological development, cognitive decline, and diminished school performance and lifetime achievement.\n\nThe review also noted that rates of acute medical care and hospitalization for younger children who accidentally ingest cannabis are increasing, adding a pediatric safety dimension.\n\nWith Canada debating cannabis regulation at the time of publication, the review emphasized that appropriate safeguards for children and youth are vital public health priorities.","whyItMatters":"This review from a national pediatric society represents the consensus medical view on adolescent cannabis risk. Published just before Canada legalized cannabis, it aimed to ensure that youth protection measures were incorporated into the regulatory framework.","specificNumbers":"Cannabis: most common illicit drug among Canadian teenagers. Associations: dependence, tobacco initiation, depression, anxiety, psychosis, cognitive decline, academic underperformance. Accidental pediatric ingestions: increasing.","methodology":"Clinical review from the Canadian Paediatric Society summarizing evidence on cannabis effects in children and adolescents, published in the context of Canada's upcoming legalization.","limitations":"Narrative review from a medical society, which may reflect a conservative perspective. Does not provide detailed risk quantification or distinguish between levels of use. May not adequately address potential benefits of reduced criminalization for youth. The review predates legalization outcomes that could validate or challenge its concerns."},{"rthcId":"RTHC-01390","title":"Apparent CB1 Receptor Rimonabant Affinity Estimates: Combination with THC and Synthetic Cannabinoids in the Mouse In Vivo Triad Model.","authors":"Grim, T W; Morales, A J; Thomas, B F; Wiley, J L; Endres, G W; Negus, S S; Lichtman, A H","year":2017,"journal":"The Journal of pharmacology and experimental therapeutics, 362(1), 210-218","doi":"10.1124/jpet.117.240192","pmid":"28442584","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Using pA2 and pKB analyses (quantitative pharmacological methods), researchers determined that the CB1 receptor antagonist rimonabant produced consistent rightward shifts in the dose-response curves of five synthetic cannabinoids (A-834,735D, WIN55,212-2, CP55,950, JWH-073, CP47,497) and THC.\n\nThe similarity of the rimonabant affinity estimates across all compounds indicates that CB1 receptors, and not other pharmacological targets, largely mediate the central effects of these synthetic cannabinoids (catalepsy, pain relief, and temperature reduction).\n\nThis is important because some researchers have speculated that the increased dangers of synthetic cannabinoids might be due to non-CB1 targets, but this quantitative analysis suggests their core pharmacological effects operate through the same receptor as THC.","whyItMatters":"Understanding whether synthetic cannabinoids work through CB1 or other targets has implications for both treatment and regulation. This study shows that their core effects are CB1-mediated, meaning their increased danger likely comes from higher potency and efficacy at CB1, not from activating different receptors.","specificNumbers":"5 synthetic cannabinoids tested: A-834,735D, WIN55,212-2, CP55,950, JWH-073, CP47,497. Plus THC. All showed similar pA2/pKB values with rimonabant, indicating CB1 mediation. Triad endpoints: catalepsy, antinociception, hypothermia.","methodology":"In vivo pharmacological analysis in mice using the cannabinoid triad (catalepsy, antinociception, hypothermia). The CB1 antagonist rimonabant was used to generate rightward shifts in dose-response curves for each compound. pA2 and pKB values were calculated to estimate apparent CB1 receptor affinity.","limitations":"Only tested three pharmacological endpoints (the classic triad). Synthetic cannabinoids may have non-CB1 effects on other systems (e.g., seizures, psychosis) not captured by this analysis. The analysis focuses on central effects; peripheral effects may involve other targets. Only five of the many synthetic cannabinoids in circulation were tested."},{"rthcId":"RTHC-01391","title":"Smoking status and its relationship to demographic and clinical characteristics in first episode psychosis.","authors":"Grossman, Michael; Bowie, Christopher R; Lepage, Martin; Malla, Ashok K; Joober, Ridha; Iyer, Srividya N","year":2017,"journal":"Journal of psychiatric research, 85, 83-90","doi":"10.1016/j.jpsychires.2016.10.022","pmid":"27863280","tags":["psychosis","addiction","cognition"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"In 140 patients entering specialized first-episode psychosis treatment, 53% smoked cigarettes: 47 were light/moderate smokers (1-19/day) and 27 were heavy smokers (20+/day). Smoking status was highly associated with cannabis use frequency.\n\nAfter adjusting for cannabis use, significant differences remained. Heavy smokers were older at program entry and had a later age of psychosis onset. Non-smokers had more education, better neurocognitive performance, and higher functioning than both smoking groups.\n\nThese findings suggest that cigarette smoking has independent effects on cognition and function in psychosis, beyond what can be attributed to co-occurring cannabis use.","whyItMatters":"Previous research on smoking and psychosis often failed to account for cannabis co-use, making it difficult to attribute effects to either substance. By statistically controlling for cannabis, this study shows that cigarette smoking carries its own independent associations with cognitive and functional outcomes in early psychosis.","specificNumbers":"140 FEP patients. 53% smoked cigarettes. 47 light/moderate (mean 9.8/day), 27 heavy (mean 26.4/day), 66 non-smokers. Heavy smokers: later psychosis onset. Non-smokers: more education, better cognition, higher functioning. Cannabis use: highly correlated with smoking status.","methodology":"Cross-sectional analysis of 140 patients entering specialized first-episode psychosis treatment. Divided into non-smokers (n=66), light/moderate smokers (n=47), and heavy smokers (n=27). Analyses adjusted for cannabis use frequency to isolate cigarette-specific associations.","limitations":"Cross-sectional design cannot determine causation. Self-reported substance use may be inaccurate. Cannabis use was controlled statistically but not experimentally. The sample may not represent all first-episode psychosis patients. Potential confounders (socioeconomic status, premorbid functioning) may not be fully captured."},{"rthcId":"RTHC-01392","title":"The Grass Might Be Greener: Medical Marijuana Patients Exhibit Altered Brain Activity and Improved Executive Function after 3 Months of Treatment.","authors":"Gruber, Staci A; Sagar, Kelly A; Dahlgren, Mary K; Gonenc, Atilla; Smith, Rosemary T; Lambros, Ashley M; Cabrera, Korine B; Lukas, Scott E","year":2017,"journal":"Frontiers in pharmacology, 8, 983","doi":"10.3389/fphar.2017.00983","pmid":"29387010","tags":["medical-cannabis","cognition"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Medical marijuana patients were assessed before starting treatment and after 3 months using fMRI while performing the Multi-Source Interference Test (MSIT). After treatment, patients showed improved task performance accompanied by changes in brain activation in the cingulate cortex and frontal regions.\n\nRemarkably, brain activation patterns after treatment appeared more similar to those of healthy controls from previous studies than at pre-treatment, suggesting potential normalization of brain function. This contrasts sharply with recreational cannabis research, which typically shows worsened performance and altered brain activation.\n\nPatients also reported improvements in clinical symptoms and health measures, and notable decreases in prescription medication use, particularly opioids and benzodiazepines.","whyItMatters":"This is one of the first studies to directly measure brain function changes in medical marijuana patients over time. The finding that medical use may improve rather than impair executive function directly challenges the assumption that all cannabis use degrades cognition. The opioid and benzodiazepine reduction adds practical clinical significance.","specificNumbers":"Improved MSIT performance after 3 months. Brain activation changes in cingulate cortex and frontal regions. Activation patterns moved toward healthy control norms. Notable decreases in opioid and benzodiazepine prescriptions.","methodology":"Longitudinal observational study of medical marijuana patients assessed before initiating treatment and after 3 months. fMRI during the MSIT captured brain activation changes. Clinical state, health measures, and prescription medication use were also tracked.","limitations":"Small pilot study without a control group. Improvement could reflect placebo effects, practice effects on repeated testing, or improvement in underlying conditions. The comparison to healthy controls is from previous studies, not matched. No randomization or blinding. Short follow-up period."},{"rthcId":"RTHC-01393","title":"Demographic trends among older cannabis users in the United States, 2006-13.","authors":"Han, Benjamin H; Sherman, Scott; Mauro, Pia M; Martins, Silvia S; Rotenberg, James; Palamar, Joseph J","year":2017,"journal":"Addiction (Abingdon, England), 112(3), 516-525","doi":"10.1111/add.13670","pmid":"27767235","tags":["seniors","addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analyzing data from 47,140 adults aged 50 and older in the National Survey on Drug Use and Health (2006-2013), researchers found significant increases in past-year cannabis use. Adults aged 50-64 showed a 57.8% relative increase, while those 65 and older showed a 250% relative increase.\n\nAmong older cannabis users, 6.9% met criteria for cannabis abuse or dependence. The majority perceived little risk: 85.3% saw no or slight risk from monthly use, and 79% saw no or slight risk from weekly use.\n\nOlder cannabis users were more likely to be younger (within the 50+ age range), male, non-Hispanic, free of multiple chronic conditions, and users of tobacco, alcohol, or other drugs.","whyItMatters":"The aging US population includes an unprecedented number of people who used cannabis in their youth. As social norms shift and medical cannabis becomes available, older adults are returning to or initiating cannabis use. Their low risk perception and the 250% increase among those 65+ represent an emerging public health phenomenon that healthcare systems are not yet equipped to address.","specificNumbers":"47,140 respondents aged 50+. Past-year use increase: 57.8% (ages 50-64), 250% (ages 65+). 6.9% met abuse/dependence criteria. Risk perception: 85.3% perceived no/slight risk from monthly use, 79% from weekly use.","methodology":"Secondary analysis of the National Survey on Drug Use and Health (NSDUH) from 2006 to 2013. Nationally representative probability sample of US households. Estimated trends, patterns, attitudes, and correlates of past-year cannabis use among adults aged 50+.","limitations":"Cross-sectional survey design. Self-reported cannabis use may be underreported due to stigma. Cannot distinguish medical from recreational use. Survey excludes institutionalized populations (nursing homes). Does not capture use changes after 2013."},{"rthcId":"RTHC-01394","title":"Cannabis and development of dual diagnoses: A literature review.","authors":"Hanna, Rebecca C; Perez, Jessica M; Ghose, Subroto","year":2017,"journal":"The American journal of drug and alcohol abuse, 43(4), 442-455","doi":"10.1080/00952990.2016.1213273","pmid":"27612527","tags":["psychosis","mental-health","depression","anxiety","youth","addiction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"This narrative review examined the relationship between cannabis use and psychiatric disorders across multiple categories. The strongest evidence linked cannabis use to psychosis and to subsequent use of other illicit substances.\n\nThe association between cannabis and bipolar disorder appeared in a few reports but remained less established. For depression and anxiety, the evidence was mixed, with some studies finding associations and others not.\n\nAge of cannabis use emerged as a critical factor. Adolescent-onset cannabis use showed the strongest associations with later psychiatric disorders, compared to adult-onset use. The reviewers noted that most studies struggled to account for confounding factors like withdrawal symptoms, other substance use, and childhood experiences.","whyItMatters":"As cannabis legalization expands, understanding the psychiatric risks associated with use becomes increasingly important. This review consolidates evidence showing that the relationship between cannabis and mental health is consistently adverse when associations exist, which has implications for clinical screening and public health messaging.","specificNumbers":"The review did not report pooled statistics but synthesized findings across multiple studies, concluding that \"substantial evidence\" supports cannabis-psychosis and cannabis-gateway associations, while depression and anxiety links remain \"mixed.\"","methodology":"The researchers conducted a narrative review using PubMed and PsychInfo databases, searching for literature on cannabis and psychiatric comorbidity using keywords related to cannabis, psychosis, schizophrenia, mood disorders, depression, mania, bipolar disorder, and anxiety.","limitations":"As a narrative rather than systematic review, this study did not use standardized methods for study selection or quality assessment. Many of the reviewed studies did not adequately control for confounding factors including other substance use, withdrawal effects, or pre-existing psychiatric conditions."},{"rthcId":"RTHC-01395","title":"Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?","authors":"Hasenoehrl, Carina; Storr, Martin; Schicho, Rudolf","year":2017,"journal":"Expert review of gastroenterology & hepatology, 11(4), 329-337","doi":"10.1080/17474124.2017.1292851","pmid":"28276820","tags":["medical-cannabis","inflammation","pain","cbd"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Fifty years after THC was identified, this expert review assessed the clinical translation of cannabinoids for inflammatory bowel diseases (IBD) including Crohn's disease and ulcerative colitis.\n\nSurveys and small clinical studies confirmed that IBD patients frequently use cannabis to manage diarrhea, abdominal pain, and appetite loss. Both plant-derived cannabinoids (THC and CBD) and synthetic versions (dronabinol, nabilone) showed potential for symptom relief in experimental models.\n\nHowever, the reviewers concluded there is still insufficient clinical evidence to prove efficacy, tolerability, and safety of cannabinoid-based medications for IBD patients, leaving clinicians without evidence-based guidelines for recommending these treatments.","whyItMatters":"IBD affects millions worldwide and many patients self-medicate with cannabis despite limited clinical evidence. This review identifies a significant gap between patient behavior and medical evidence, highlighting the urgent need for rigorous clinical trials.","specificNumbers":"Synthetic cannabinoids dronabinol and nabilone are already available by prescription. The review covers 50 years of cannabinoid research since THC's discovery.","methodology":"The researchers reviewed recent data on cannabis and cannabinoid effects in experimental IBD models and clinical trials with IBD patients using a PubMed database search. They also provided background on the endocannabinoid system and its relevance to gastrointestinal inflammation.","limitations":"This is a narrative expert commentary rather than a systematic review with formal quality assessment. Most evidence comes from preclinical models and small clinical studies, with very few randomized controlled trials available for analysis."},{"rthcId":"RTHC-01396","title":"Cannabis use patterns and motives: A comparison of younger, middle-aged, and older medical cannabis dispensary patients.","authors":"Haug, Nancy A; Padula, Claudia B; Sottile, James E; Vandrey, Ryan; Heinz, Adrienne J; Bonn-Miller, Marcel O","year":2017,"journal":"Addictive behaviors, 72, 14-20","doi":"10.1016/j.addbeh.2017.03.006","pmid":"28340421","tags":["medical-cannabis","addiction","youth","seniors","sleep","pain","cancer"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This dispensary-based study compared 217 medical cannabis patients across three age groups: younger (18-30), middle-aged (31-50), and older (51-72).\n\nAll age groups used cannabis at similar frequencies over the past month. However, younger users consumed larger quantities and showed higher rates of problematic cannabis use compared to middle-aged and older adults.\n\nThe relationship between age and problematic use was shaped by when someone started using regularly. Among younger users, earlier initiation of regular cannabis use predicted more problematic use. This pattern did not hold for older users.\n\nMiddle-aged adults were more likely to use cannabis for insomnia. Older adults were more likely to use it for chronic conditions like cancer, glaucoma, and HIV/AIDS. Younger users more often reported using cannabis when bored.","whyItMatters":"As medical cannabis access expands, understanding age-related patterns of use helps clinicians identify patients at higher risk for problematic use. The finding that younger patients use more and show more problems despite similar frequency suggests that medical cannabis programs may need age-specific monitoring.","specificNumbers":"217 participants across three age groups (18-30, 31-50, 51-72). All groups had similar monthly frequency of use, but younger users consumed greater quantities and had higher problematic use scores.","methodology":"Cross-sectional data were collected at a medical cannabis dispensary in San Francisco. The 217 participants were grouped by age and compared on cannabis use measures, motives, and medical conditions using ANOVAs, chi-square tests, and linear regression analyses.","limitations":"Cross-sectional design at a single San Francisco dispensary limits generalizability. Self-reported data may underestimate problematic use. The sample was not randomly selected and may not represent the broader medical cannabis population."},{"rthcId":"RTHC-01397","title":"Cannabinoids in Pain Management and Palliative Medicine.","authors":"Häuser, Winfried; Fitzcharles, Mary-Ann; Radbruch, Lukas; Petzke, Frank","year":2017,"journal":"Deutsches Arzteblatt international, 114(38), 627-634","doi":"10.3238/arztebl.2017.0627","pmid":"29017688","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This systematic review of systematic reviews examined the highest-quality evidence available on cannabinoids for pain management and palliative medicine.\n\nOf 750 publications identified, 11 systematic reviews met inclusion criteria. Three were high methodological quality and eight were moderate. The strongest finding was limited evidence supporting THC/CBD spray for neuropathic pain.\n\nFor cancer pain, rheumatic pain, gastrointestinal pain, and anorexia in cancer or AIDS, the evidence for any cannabinoid (dronabinol, nabilone, medical cannabis, or THC/CBD spray) was inadequate.\n\nThe reviewers highlighted a significant gap between public perception and scientific evidence: the public views cannabis-based medicines as effective and safe for pain, but the systematic evidence does not support this perception. Treatment with cannabis-based medicines was associated with central nervous system and psychiatric side effects.","whyItMatters":"This is one of the most rigorous assessments of cannabinoids for pain, reviewing reviews rather than individual studies. The clear gap it identifies between public perception and scientific evidence has direct implications for clinical practice and patient expectations.","specificNumbers":"750 publications identified; 11 systematic reviews met inclusion criteria (3 high quality, 8 moderate quality). 2 long-term observational studies with medical cannabis and 1 with THC/CBD spray were also analyzed.","methodology":"Systematic review of systematic reviews of RCTs and prospective observational studies, searching the Cochrane Database, Database of Abstracts of Reviews of Effects, and Medline from January 2009 to January 2017. Methodological quality was assessed using the AMSTAR instrument.","limitations":"The search period ended January 2017 and newer evidence may have emerged. The review focused on systematic reviews, meaning individual high-quality studies not yet included in a systematic review would be missed. The included reviews varied in their definitions of pain conditions and cannabinoid formulations."},{"rthcId":"RTHC-01398","title":"Enhanced anandamide signaling reduces flight behavior elicited by an approaching robo-beetle.","authors":"Heinz, Daniel E; Genewsky, Andreas; Wotjak, Carsten T","year":2017,"journal":"Neuropharmacology, 126, 233-241","doi":"10.1016/j.neuropharm.2017.09.010","pmid":"28890367","tags":["neuroscience","anxiety","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using a novel behavioral task that confronted mice with an erratically moving robo-beetle, researchers found that the two main endocannabinoids in the brain have opposite effects on fear and panic responses.\n\nBlocking the enzyme FAAH (which breaks down anandamide) with the drug URB597 reduced flight behavior and increased tolerance to the approaching beetle. This anti-panic effect was confirmed to work through CB1 receptors, as blocking those receptors eliminated the benefit.\n\nIn contrast, blocking MAGL (which breaks down 2-AG) with JZL184 actually increased flight behavior. This was unexpected given that both chemicals act through the same receptor system.\n\nHigh-anxiety mice strains (HAB and BALB/c) showed decreased tolerance and increased avoidance of the beetle compared to normal-anxiety mice, validating the task as a measure of innate fear responses.","whyItMatters":"This study reveals that the two main endocannabinoids have distinct and even opposing roles in panic-like responses. Understanding this distinction is critical for developing cannabinoid-based treatments for anxiety and panic disorders, as targeting anandamide specifically may be more therapeutic than broadly activating the endocannabinoid system.","specificNumbers":"URB597 at 0.3 mg/kg reduced flight behavior. JZL184 at 8 mg/kg increased flight behavior. Diazepam at 1 mg/kg increased tolerance but did not affect avoidance. CB1 antagonist SR141716A at 3 mg/kg blocked URB597 effects.","methodology":"Researchers developed the \"beetle mania task\" (BMT) to study innate fear responses in mice confronted with an erratically moving robo-beetle. They tested multiple mouse strains with varying anxiety levels and administered pharmacological agents targeting the endocannabinoid system (URB597 for FAAH inhibition, JZL184 for MAGL inhibition, diazepam for comparison).","limitations":"Animal study results may not translate directly to humans. The robo-beetle task is novel and has not been extensively validated across laboratories. Pharmacological doses may not reflect natural variation in endocannabinoid tone."},{"rthcId":"RTHC-01399","title":"Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation.","authors":"Helyes, Z; Kemény, Á; Csekő, K; Szőke, É; Elekes, K; Mester, M; Sándor, K; Perkecz, A; Kereskai, L; Márk, L; Bona, Á; Benkő, A; Pintér, E; Szolcsányi, J; Ledent, C; Sperlágh, B; Molnár, T F","year":2017,"journal":"American journal of physiology. Lung cellular and molecular physiology, 313(2), L267-L277","doi":"10.1152/ajplung.00354.2016","pmid":"28495855","tags":["respiratory","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study provided the first systematic, head-to-head comparison of marijuana and tobacco smoke effects on mouse lungs over four months of daily exposure.\n\nMarijuana inhalation triggered severe bronchial hyperreactivity within just one week. By one month, mice showed characteristic perivascular and peribronchial edema, atelectasis (collapsed lung tissue), apical emphysema, and neutrophil/macrophage infiltration. Damage progressively worsened, with destroyed bronchial mucosa, goblet cell hyperplasia, and severe emphysema by four months.\n\nIn comparison, tobacco smoke did not induce hyperresponsiveness until two months and caused inflammatory cell infiltration later with only mild emphysema.\n\nCritically, the lung damage from marijuana smoke was not mediated by the CB1 cannabinoid receptor. Mice genetically lacking CB1 receptors showed the same airway hyperresponsiveness and inflammation, indicating the damage comes from the smoke itself, not from cannabinoid signaling.","whyItMatters":"This is the first controlled animal study systematically comparing marijuana and tobacco smoke lung effects. The finding that marijuana caused earlier and more severe damage challenges assumptions that marijuana smoke is less harmful than tobacco. The CB1-independence of the damage means this is a combustion problem, not a cannabinoid problem.","specificNumbers":"Bronchial hyperreactivity appeared after 1 week with marijuana vs. 2 months with tobacco. Severe emphysema, atelectasis, and tissue destruction developed over 4 months of marijuana exposure. Tobacco caused only mild emphysema in the same timeframe.","methodology":"CD1 mice underwent four months of daily whole-body marijuana smoke exposure, with systematic assessment at weekly and monthly intervals. Measurements included unrestrained whole-body plethysmography (bronchial responsiveness), flow cytometry (bronchoalveolar lavage cell profiles), spectrophotometry (myeloperoxidase activity), ELISA (inflammatory cytokines), and histopathology. CB1 receptor knockout mice were used to test receptor involvement.","limitations":"Mouse lungs differ from human lungs in anatomy and immune response. The exposure protocol (daily whole-body exposure) may not reflect typical human smoking patterns. The study did not assess vaporized cannabis or distinguish between different smoking frequencies."},{"rthcId":"RTHC-01400","title":"Sex- and hormone-dependent alterations in alcohol withdrawal-induced anxiety and corticolimbic endocannabinoid signaling.","authors":"Henricks, Angela M; Berger, Anthony L; Lugo, Janelle M; Baxter-Potter, Lydia N; Bieniasz, Kennedy V; Petrie, Gavin; Sticht, Martin A; Hill, Matthew N; McLaughlin, Ryan J","year":2017,"journal":"Neuropharmacology, 124, 121-133","doi":"10.1016/j.neuropharm.2017.05.023","pmid":"28554848","tags":["neuroscience","sex-differences","anxiety","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study revealed striking sex differences in how the endocannabinoid system responds to alcohol withdrawal.\n\nMale rats exposed to chronic alcohol vapor showed increased anxiety-like behavior during withdrawal, along with reduced anandamide in the amygdala and reduced 2-AG in the prefrontal cortex. Widespread changes in endocannabinoid-related gene expression accompanied these neurochemical shifts.\n\nIntact female rats were largely protected from these effects. Neither anxiety nor endocannabinoid disruptions appeared during withdrawal in females.\n\nTo isolate the role of hormones, the researchers tested ovariectomized females with and without estradiol replacement. Removing ovaries made females respond more like males (reduced anandamide, gene expression changes). Estradiol replacement prevented the endocannabinoid content changes but did not restore full protection against withdrawal effects, suggesting other ovarian hormones (progesterone, others) also contribute.","whyItMatters":"This study helps explain why alcohol withdrawal symptoms differ between sexes and identifies the endocannabinoid system as a key mediator of these differences. Understanding this sex-specific biology could lead to more effective, sex-tailored treatments for alcohol dependence and withdrawal.","specificNumbers":"Six weeks of chronic intermittent alcohol vapor exposure. Male rats showed reduced AEA in the amygdala and reduced 2-AG in the prefrontal cortex during withdrawal. Intact females showed neither reduction.","methodology":"Intact male and female rats, plus ovariectomized females with or without estradiol replacement, underwent 6 weeks of chronic intermittent alcohol vapor exposure. Researchers measured anxiety-like behavior, endocannabinoid content (AEA and 2-AG), and endocannabinoid-related mRNA in the basolateral amygdala and ventromedial prefrontal cortex.","limitations":"Animal study using chronic alcohol vapor, which may not perfectly model human drinking patterns. The study examined acute withdrawal only and did not assess long-term outcomes. Hormonal manipulations were pharmacological rather than natural cycling."},{"rthcId":"RTHC-01401","title":"Immunoregulatory Role of Cannabinoids during Infectious Disease.","authors":"Hernández-Cervantes, Rosalía; Méndez-Díaz, Mónica; Prospéro-García, Óscar; Morales-Montor, Jorge","year":2017,"journal":"Neuroimmunomodulation, 24(4-5), 183-199","doi":"10.1159/000481824","pmid":"29151103","tags":["inflammation","medical-cannabis","cbd"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"This review examined the complex relationship between the endocannabinoid system, cannabis use, and infectious diseases caused by bacteria, viruses, parasites, and fungi.\n\nThe overall pattern is that recreational or medicinal cannabis use tends to increase susceptibility to infections because of its impact on immune modulation. Cannabis compounds can suppress certain immune responses that are important for fighting pathogens.\n\nHowever, the endocannabinoid system itself is involved in immune defense. Some evidence suggests endocannabinoid signaling participates in controlling and eliminating infectious agents including certain bacteria, viruses, and protozoa.\n\nCompounds isolated from Cannabis sativa have also shown direct antimicrobial properties in some laboratory settings. The reviewers noted that research on cannabis and fungal infections remains particularly sparse.","whyItMatters":"For medical cannabis patients, especially those with compromised immune systems, understanding how cannabinoids interact with infection defense is clinically relevant. The dual nature of the system, with endocannabinoids helping fight infections but exogenous cannabis potentially suppressing immunity, creates a nuanced risk-benefit picture.","specificNumbers":"The review covered infections across four pathogen categories: bacteria, viruses, parasites, and fungi, with fungi having the least available research.","methodology":"Narrative review of existing literature on the endocannabinoid system's role during infections, antimicrobial properties of Cannabis sativa compounds, and associations between marijuana use and infectious disease outcomes.","limitations":"Narrative review without systematic methodology. Many of the reviewed studies are preclinical or observational. The review does not distinguish between different cannabis preparations, doses, or routes of administration in terms of immune effects."},{"rthcId":"RTHC-01402","title":"Medical cannabis for the treatment of chronic pain and other disorders: misconceptions and facts.","authors":"Hill, Kevin P; Palastro, Matthew D","year":2017,"journal":"Polish archives of internal medicine, 127(11), 785-789","doi":"10.20452/pamw.4123","pmid":"29067992","tags":["medical-cannabis","pain"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"As cannabis policy changes accelerated worldwide, this review addressed the gap between patient expectations and clinical evidence for medical cannabis.\n\nThe authors found that the best current evidence supports medical cannabis for three specific conditions: chronic pain, neuropathic pain, and spasticity from multiple sclerosis. For other conditions, the evidence base was weaker or insufficient.\n\nThe review also cataloged potential acute and chronic effects of cannabis use that physicians must consider before recommending medical cannabis. These include cognitive effects, psychiatric risks, and dependence potential.\n\nThe authors emphasized that increasing patient requests for medical cannabis make it essential for physicians to become knowledgeable about the science and engage in open discussions about both potential benefits and risks.","whyItMatters":"This review directly addresses the clinical challenge physicians face: patients requesting medical cannabis based on broad claims while the evidence supports only a few specific conditions. It provides a framework for evidence-based conversations between doctors and patients.","specificNumbers":"Three conditions with the best current evidence: chronic pain, neuropathic pain, and MS-related spasticity.","methodology":"Narrative review of current evidence for cannabis and cannabinoids across multiple medical conditions, with assessment of acute and chronic risks of cannabis use.","limitations":"Brief narrative review without systematic search methodology or quality assessment. Published in a Polish medical journal, the perspective may emphasize European regulatory context. The rapidly evolving evidence base means some conclusions may have shifted since publication."},{"rthcId":"RTHC-01403","title":"Predicting Persistent, Limited, and Delayed Problematic Cannabis Use in Early Adulthood: Findings From a Longitudinal Study.","authors":"Hill, Sherika; Shanahan, Lilly; Costello, E Jane; Copeland, William","year":2017,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 56(11), 966-974.e4","doi":"10.1016/j.jaac.2017.08.012","pmid":"29096779","tags":["addiction","youth","mental-health","anxiety"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Following 1,229 people from childhood through age 30, this study identified four distinct patterns of problematic cannabis use (cannabis use disorder or daily use) in early adulthood.\n\nThe persistent pattern (6.7% of the sample) characterized people with problematic use in both late adolescence (19-21) and early adulthood (26-30). These individuals had more anxiety disorders across their development and more severe cannabis use disorder symptoms during late adolescence compared to those whose problems were limited to adolescence.\n\nThe limited pattern (13.3%) described people with problematic use only in late adolescence who then stopped. They had more childhood family instability and dysfunction as distinguishing risk factors.\n\nThe delayed pattern (3.7%) captured those who developed problems only in early adulthood (26-30). These individuals had more externalizing disorders, maltreatment, and peer bullying during childhood, suggesting that early adversity can fuel problematic cannabis use years later.\n\nNo significant differences were found by sex or race/ethnicity.","whyItMatters":"This is one of the longest-running studies to track cannabis use patterns from childhood through age 30. Identifying distinct risk profiles for different trajectories means prevention and intervention efforts could be tailored to specific risk factors rather than using one-size-fits-all approaches.","specificNumbers":"1,229 participants followed for 20 years. Persistent problematic use: 6.7%. Limited problematic use (adolescence only): 13.3%. Delayed problematic use (adulthood only): 3.7%. No sex or race/ethnicity differences.","methodology":"Prospective 20-year cohort study (Great Smoky Mountains Study, 1993-2015) with 1,229 participants representative of western North Carolina. Yearly assessments from ages 9-16, with follow-ups at 19, 21, 26, and 30. Multinomial logistic regression examined pairwise associations between use patterns and childhood/adolescent risk factors.","limitations":"Based on a single geographic region (western North Carolina), which may limit generalizability to urban or more diverse populations. Cannabis potency and availability changed significantly over the 20-year study period. Self-reported use may underestimate actual problematic patterns."},{"rthcId":"RTHC-01404","title":"Effectiveness of a pragmatic school-based universal resilience intervention in reducing tobacco, alcohol and illicit substance use in a population of adolescents: cluster-randomised controlled trial.","authors":"Hodder, Rebecca Kate; Freund, Megan; Bowman, Jenny; Wolfenden, Luke; Campbell, Elizabeth; Dray, Julia; Lecathelinais, Christophe; Oldmeadow, Christopher; Attia, John; Wiggers, John","year":2017,"journal":"BMJ open, 7(8), e016060","doi":"10.1136/bmjopen-2017-016060","pmid":"28821523","tags":["youth","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"This large cluster-randomized controlled trial tested whether building student resilience through school-based programs could reduce substance use among adolescents.\n\nTwenty intervention schools implemented resilience-building programs targeting individual protective factors (like problem-solving skills) and environmental factors (like caring relationships) for students in grades 7 through 10 over three years.\n\nAt follow-up, when students were 15-16 years old, there were no significant differences between intervention and control students on any substance use measure. Marijuana use rates were virtually identical (OR 1.12, p=0.57). The same null results applied to tobacco, alcohol, and other illicit substances.\n\nThe intervention also failed to increase individual or environmental protective factors, suggesting the program did not successfully build resilience at all, rather than building resilience that simply failed to reduce substance use.","whyItMatters":"This is one of the largest and most rigorous tests of whether school-based resilience programs prevent substance use. The null result across every outcome measured is significant because many school systems invest in similar resilience-building programs with the expectation of substance use prevention.","specificNumbers":"32 schools (20 intervention, 12 control). 2,105 students at follow-up. Marijuana use OR: 1.12 (95% CI 0.74-1.68, p=0.57). No significant effects on any primary or secondary outcome.","methodology":"Cluster-randomized controlled trial across 32 Australian secondary schools (20 intervention, 12 control). A cohort of grade 7 students was followed to grade 10 (ages 15-16). Intervention schools selected and implemented available resilience programs with implementation support. Online surveys measured substance use and protective factors at baseline and follow-up. 2,105 students provided follow-up data (69% of baseline).","limitations":"The pragmatic design allowed schools to choose their own resilience programs, which may have resulted in inconsistent implementation quality. The 31% attrition rate could introduce bias. Australian results may not generalize to other educational or cultural contexts."},{"rthcId":"RTHC-01405","title":"Cannabis and Pediatric Inflammatory Bowel Disease: Change Blossoms a Mile High.","authors":"Hoffenberg, Edward J; Newman, Heike; Collins, Colm; Tarbell, Sally; Leinwand, Kristina","year":2017,"journal":"Journal of pediatric gastroenterology and nutrition, 64(2), 265-271","doi":"10.1097/MPG.0000000000001393","pmid":"27579692","tags":["medical-cannabis","youth","inflammation"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Writing from Colorado, one of the first states to legalize recreational cannabis, pediatric gastroenterologists described the practical reality of caring for children and adolescents with IBD in an environment of increasing cannabis awareness and acceptance.\n\nThe review outlined the endocannabinoid system's role in gastrointestinal function, noting biological plausibility for both beneficial and harmful effects of cannabis in IBD. Cannabis could potentially reduce inflammation and symptoms, but could also impair developing brains and interact with other treatments.\n\nPublic perception of cannabis safety had outpaced the evidence, particularly for pediatric populations. The authors noted that federal legal barriers significantly hampered research efforts, making it difficult to generate the evidence needed to guide clinical decisions.\n\nThe review emphasized that pediatric gastroenterologists need to understand the cannabis landscape and be prepared to discuss it openly with patients and families, even without definitive evidence.","whyItMatters":"This is one of the few reviews addressing cannabis and IBD specifically in pediatric populations. Children and adolescents with IBD face a unique risk-benefit calculus: potential symptom relief versus developmental risks during critical brain maturation periods.","specificNumbers":"Colorado legalized medical cannabis in 2000 and recreational cannabis in 2012. The review does not report specific clinical outcome data.","methodology":"Narrative review describing the legalization landscape in Colorado, the endocannabinoid system's relevance to IBD, clinical experience with pediatric IBD patients, and research barriers created by federal cannabis scheduling.","limitations":"Primarily a perspective piece from a single institution in Colorado rather than a systematic evidence review. No original clinical data are presented. The pediatric-specific evidence for cannabis in IBD is extremely limited."},{"rthcId":"RTHC-01406","title":"Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with Δ9 -tetrahydrocannabinol.","authors":"Hoffman, Alexander F; Lycas, Matthew D; Kaczmarzyk, Jakub R; Spivak, Charles E; Baumann, Michael H; Lupica, Carl R","year":2017,"journal":"Addiction biology, 22(2), 390-399","doi":"10.1111/adb.12334","pmid":"26732435","tags":["synthetic-cannabinoids","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study directly compared three widely abused synthetic cannabinoids from \"Spice\" products with THC in their ability to disrupt brain communication in the mouse hippocampus, a region critical for memory and learning.\n\nJWH-018 was the most potent, inhibiting synaptic transmission with an EC50 of approximately 15 nM, roughly 47 times more potent than THC (EC50 approximately 700 nM). AM2201, a fluoropentyl derivative of JWH-018, was somewhat less potent (EC50 approximately 60 nM) but still about 12 times more potent than THC.\n\nThe newer synthetic cannabinoid XLR-11 showed potency similar to THC (EC50 approximately 900 nM).\n\nAll compounds worked through CB1 receptors, as confirmed by reversal with receptor antagonists and absence of effect in CB1 knockout mice. All compounds also significantly impaired long-term potentiation (LTP), the cellular mechanism underlying memory formation.","whyItMatters":"This study provides a mechanistic explanation for why \"Spice\" users experience more severe cognitive impairment and adverse effects than cannabis users. The dramatically higher potency of first-generation synthetic cannabinoids at disrupting hippocampal function translates directly to greater cognitive and behavioral disruption.","specificNumbers":"JWH-018 EC50: ~15 nM (47x more potent than THC). AM2201 EC50: ~60 nM (12x more potent). XLR-11 EC50: ~900 nM (similar to THC at ~700 nM). All compounds significantly impaired LTP.","methodology":"Electrophysiological recordings from mouse hippocampal brain slices measured excitatory postsynaptic currents during application of JWH-018, AM2201, XLR-11, and THC. CB1 receptor involvement was confirmed using selective antagonists (AM251, PIMSR1) and CB1 knockout mice. Long-term potentiation was measured to assess memory-related synaptic plasticity.","limitations":"In vitro brain slice recordings do not capture the full complexity of in vivo drug metabolism, blood-brain barrier penetration, or behavioral effects. The study tested acute exposure only and did not assess chronic exposure or withdrawal effects. Only three synthetic cannabinoids were tested among hundreds that have appeared on the market."},{"rthcId":"RTHC-01407","title":"Health effects of exposure to second- and third-hand marijuana smoke: a systematic review.","authors":"Holitzki, Hannah; Dowsett, Laura E; Spackman, Eldon; Noseworthy, Tom; Clement, Fiona","year":2017,"journal":"CMAJ open, 5(4), E814-E822","doi":"10.9778/cmajo.20170112","pmid":"29192095","tags":["respiratory","harm-reduction","legalization"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This systematic review examined 15 studies on the health effects of secondhand marijuana smoke exposure, finding three consistent outcomes.\n\nFirst, exposure to secondhand marijuana smoke produces detectable levels of cannabinoid metabolites (THC breakdown products) in the blood and urine of non-smokers. Second, non-smokers reported psychoactive effects after exposure. Third, eye irritation and discomfort were common complaints.\n\nThe strength of these effects was directly related to the THC content of the marijuana being smoked and was modulated by environmental factors: the amount of smoke produced, room ventilation, air volume, number of joints lit simultaneously, and number of smokers present.\n\nNo research was found on third-hand marijuana smoke (residue deposited on surfaces) or the long-term health effects of chronic secondhand exposure.","whyItMatters":"As marijuana legalization expands, secondhand smoke becomes a public health policy question analogous to tobacco. This review provides the evidence base for policies around where marijuana can be smoked, with implications for shared housing, public spaces, and workplace regulations.","specificNumbers":"1,701 abstracts screened; 60 full-text reviewed; 15 studies included. Studies ranged from good to poor quality. THC content and ventilation were the primary environmental mediators of exposure effects.","methodology":"Systematic review searching 6 databases from inception to October 2017. Abstract and full-text review were conducted in duplicate. Included studies were human, in vivo, or in vitro with more than one case, published in English or French, reporting original quantitative data. Study quality was assessed using the Downs and Black checklist. 15 studies met inclusion criteria from 1,701 abstracts.","limitations":"All included studies were rated good to poor quality. No evidence was found on long-term exposure effects or third-hand smoke. The 15 included studies used varied methodologies and exposure conditions, making direct comparison difficult."},{"rthcId":"RTHC-01408","title":"Reductions in cannabis use are associated with improvements in anxiety, depression, and sleep quality, but not quality of life.","authors":"Hser, Yih-Ing; Mooney, Larissa J; Huang, David; Zhu, Yuhui; Tomko, Rachel L; McClure, Erin; Chou, Chih-Ping; Gray, Kevin M","year":2017,"journal":"Journal of substance abuse treatment, 81, 53-58","doi":"10.1016/j.jsat.2017.07.012","pmid":"28847455","tags":["anxiety","depression","sleep","quitting","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This study tracked 302 adults with cannabis use disorder over 12 weeks of a medication trial, splitting them into those whose cannabis use decreased and those whose use increased.\n\nThe cannabis reduction group (152 people) showed statistically significant improvements in anxiety, depression, and sleep quality compared to the cannabis increase group (150 people), even after controlling for demographics, treatment condition, and concurrent tobacco and alcohol use.\n\nHowever, reductions in cannabis use did not translate into improved overall quality of life. This disconnect suggests that while reducing cannabis use alleviates specific psychiatric symptoms, broader life satisfaction may depend on other factors not addressed by cannabis reduction alone.\n\nThe findings held up after accounting for other substance use, meaning the improvements were specifically linked to changes in cannabis use rather than general behavioral changes.","whyItMatters":"This is one of the few studies to demonstrate a longitudinal relationship between changes in cannabis use and changes in mental health symptoms within the same individuals over time. The specificity of symptom improvement (anxiety, depression, sleep but not quality of life) provides nuanced evidence for clinical conversations about what reducing cannabis use can and cannot achieve.","specificNumbers":"302 adults over 12 weeks. Cannabis Use Reduction group: n=152. Cannabis Use Increase group: n=150. Significant improvements in anxiety (beta=-0.09, p<0.05), depression (beta=-0.11, p<0.01), and sleep quality (beta=-0.07, p<0.05). No change in quality of life.","methodology":"Secondary analysis of a 12-week cannabis use disorder medication trial with 302 adults (ages 18-50). Participants were classified into Cannabis Use Reduction (n=152) and Cannabis Use Increase (n=150) groups based on individual use trajectories. Latent growth curve models examined associations between use changes and changes in anxiety, depression, sleep quality, and quality of life, controlling for demographics and concurrent substance use.","limitations":"Secondary analysis of a treatment trial, so participants were already seeking to reduce use. The 12-week observation period may be too short to detect quality-of-life changes. Participants had cannabis use disorder, so findings may not apply to casual users. The direction of causality cannot be fully established."},{"rthcId":"RTHC-01409","title":"Repeated Acute Oral Exposure to Cannabis sativa Impaired Neurocognitive Behaviours and Cortico-hippocampal Architectonics in Wistar Rats.","authors":"Imam, A; Ajao, M S; Akinola, O B; Ajibola, M I; Ibrahim, A; Amin, A; Abdulmajeed, W I; Lawal, Z A; Ali-Oluwafuyi, A","year":2017,"journal":"Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria, 31(2), 153-159","doi":null,"pmid":"28262852","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats given oral cannabis extract (20 mg/kg) daily for seven consecutive days showed significant cognitive and neurological impairments compared to controls.\n\nIn the Open Field Test, cannabis-treated rats showed reduced rearing (exploratory behavior) and increased freezing, indicating decreased curiosity and increased anxiety-like behavior. In the Elevated Plus Maze, rearing was also reduced, further supporting anxiogenic effects.\n\nSpatial memory was impaired as measured by the Y-maze, with cannabis-treated rats showing reduced percentage alternation similar to rats given scopolamine, a drug known to impair memory.\n\nHistopathological examination revealed alterations in neuronal architecture in both the cerebral cortex and hippocampus, providing a structural basis for the observed cognitive deficits.","whyItMatters":"This study demonstrates that even relatively short-term oral cannabis exposure can produce measurable cognitive deficits and visible brain changes in a controlled animal model. The oral administration route is particularly relevant given the growing popularity of cannabis edibles.","specificNumbers":"18 rats across 3 groups. Cannabis dose: 20 mg/kg daily for 7 days. Cannabis-treated rats showed reduced rearing frequencies and impaired Y-maze alternation comparable to scopolamine-treated animals.","methodology":"Eighteen adult Wistar rats were randomly assigned to three groups: saline control, cannabis extract (20 mg/kg oral, 7 days), and scopolamine (1 mg/kg intraperitoneal, as a positive control for cognitive impairment). Behavioral assessments included the Open Field Test, Elevated Plus Maze, and Y-maze. Brains were subsequently examined histopathologically.","limitations":"Very small sample size (6 per group). Only a single dose was tested for a single duration. The cannabis extract composition and THC concentration were not specified in the abstract. Rat brain development differs from human brain development. Short observation period prevents assessment of whether effects reverse after discontinuation."},{"rthcId":"RTHC-01410","title":"Is haloperidol the wonder drug for cannabinoid hyperemesis syndrome?","authors":"Inayat, Faisal; Virk, Hafeez Ul Hassan; Ullah, Waqas; Hussain, Qulsoom","year":2017,"journal":"BMJ case reports, 2017","doi":"10.1136/bcr-2016-218239","pmid":"28052951","tags":["medical-cannabis","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report documented a patient with cannabinoid hyperemesis syndrome (CHS), a condition characterized by severe cyclic vomiting, nausea, and abdominal pain in people who use cannabis chronically.\n\nCHS is often unrecognized or misdiagnosed, leading to unnecessary medical workups and repeated hospitalizations. While long-term abstinence from cannabis is the definitive treatment, managing acute episodes has been challenging for clinicians.\n\nIn this case, haloperidol (an antipsychotic medication) successfully resolved the patient's symptoms when other conventional treatments had failed. The authors highlight haloperidol as a safe and effective acute treatment option for the unrelenting symptoms of CHS.","whyItMatters":"CHS is increasingly recognized as cannabis use has expanded, and emergency physicians need effective acute treatments. This case adds to growing evidence that haloperidol may be particularly effective for CHS, potentially because it blocks dopamine receptors involved in the vomiting pathway that traditional antiemetics do not adequately address.","specificNumbers":"Single patient case. The abstract does not specify the haloperidol dose used.","methodology":"Single case report documenting the clinical presentation, failed conventional treatments, and successful response to haloperidol in a patient with cannabinoid hyperemesis syndrome.","limitations":"Single case report provides the lowest level of clinical evidence. No control comparison or dosing protocol was established. The mechanism of action for haloperidol in CHS is not fully understood."},{"rthcId":"RTHC-01411","title":"Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis.","authors":"Iyer, Malliga R; Cinar, Resat; Katz, Alexis; Gao, Michael; Erdelyi, Katalin; Jourdan, Tony; Coffey, Nathan J; Pacher, Pal; Kunos, George","year":2017,"journal":"Journal of medicinal chemistry, 60(3), 1126-1141","doi":"10.1021/acs.jmedchem.6b01504","pmid":"28085283","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This medicinal chemistry study designed and synthesized a new class of compounds that combine two therapeutic mechanisms: blocking CB1 cannabinoid receptors and inhibiting inducible nitric oxide synthase (iNOS), both of which are implicated in liver fibrosis.\n\nThe key innovation was engineering these compounds to stay out of the brain, avoiding the psychiatric side effects (depression, anxiety, suicidality) that doomed the first-generation CB1 blocker rimonabant.\n\nA series of 3,4-diarylpyrazolinecarboximidamides were synthesized and tested. The lead compound (compound 7) demonstrated potent CB1 receptor binding, iNOS inhibition, and reduced food intake (via peripheral CB1 blockade). In animal models of liver fibrosis, it showed antifibrotic effects through the combined action of iNOS inhibition and CB1 receptor antagonism.","whyItMatters":"Liver fibrosis is a major global health burden with few effective treatments. This study demonstrates that the endocannabinoid system can be targeted therapeutically without the psychiatric risks that ended rimonabant's clinical use. The dual-mechanism approach could be more effective than targeting either pathway alone.","specificNumbers":"Lead compound 7 showed potent CB1 receptor binding affinity, iNOS inhibition, reduced food intake, and antifibrotic effects in animal models. The specific binding affinities are reported in the full text.","methodology":"Structure-activity relationship study involving synthesis and testing of a series of 3,4-diarylpyrazolinecarboximidamides. Compounds were evaluated in CB1 receptor binding assays, iNOS activity assays, food intake studies, and animal models of liver fibrosis. Brain penetrance was assessed to confirm peripheral restriction.","limitations":"Preclinical study with no human data. The long-term safety of chronic peripheral CB1 blockade combined with iNOS inhibition has not been established. Animal models of fibrosis may not fully predict human therapeutic outcomes. Only one lead compound was tested in vivo."},{"rthcId":"RTHC-01412","title":"Ligand-Assisted Protein Structure (LAPS): An Experimental Paradigm for Characterizing Cannabinoid-Receptor Ligand-Binding Domains.","authors":"Janero, David R; Korde, Anisha; Makriyannis, Alexandros","year":2017,"journal":"Methods in enzymology, 593, 217-235","doi":"10.1016/bs.mie.2017.06.022","pmid":"28750804","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01413","title":"Tripping with Synthetic Cannabinoids (\"Spice\"): Anecdotal and Experimental Observations in Animals and Man.","authors":"Järbe, Torbjörn U C; Raghav, Jimit Girish","year":2017,"journal":"Current topics in behavioral neurosciences, 32, 263-281","doi":"10.1007/7854_2016_16","pmid":"27753006","tags":["synthetic-cannabinoids","addiction","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review consolidated the scientific literature on \"Spice\" compounds, synthetic cannabinoids originally designed as research tools that became widely abused recreational drugs.\n\nIn behavioral assays comparing synthetic cannabinoids to THC, the synthetic compounds generally produced similar effects but often at greater potency or with additional toxicity. Studies documented abuse liability (animals will self-administer these compounds), rapid tolerance development, physical dependence, and withdrawal symptoms.\n\nThe review emphasized that these compounds were never intended for human consumption and that scientifically based information about their toxicity and long-term behavioral effects is extremely limited. Most safety data comes from emergency department reports and case series rather than controlled studies.\n\nMethodological challenges include the constant appearance of new compounds, variable composition of street products, and difficulties administering these compounds in controlled research settings.","whyItMatters":"Synthetic cannabinoids remain a significant public health threat, particularly among populations without access to regulated cannabis and those subject to drug testing. This review highlights how little is actually known about compounds that thousands of people have consumed.","specificNumbers":"The review covers multiple synthetic cannabinoid compounds but does not provide pooled statistics. It notes the \"fairly recent\" nature of recreational use and the nascent state of preclinical research.","methodology":"Literature review consolidating published behavioral studies of synthetic cannabinoids in both animals and humans, comparing effects to THC. Covers abuse liability, tolerance, dependence, withdrawal, and toxicity data.","limitations":"Much of the evidence comes from anecdotal reports and case series rather than controlled studies. The rapid turnover of compounds on the market means research is always behind the current products. Most preclinical studies focus on a small number of compounds that may not represent the full range of products available."},{"rthcId":"RTHC-01414","title":"The Increasing Use of Cannabis Among Older Americans: A Public Health Crisis or Viable Policy Alternative?","authors":"Kaskie, Brian; Ayyagari, Padmaja; Milavetz, Gary; Shane, Dan; Arora, Kanika","year":2017,"journal":"The Gerontologist, 57(6), 1166-1172","doi":"10.1093/geront/gnw166","pmid":"28077451","tags":["seniors","medical-cannabis","pain","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This essay examined the intersection of cannabis and aging in America, identifying multiple pathways through which older adults are increasingly using cannabis.\n\nSome older adults are responding to changing social and legal environments and using cannabis recreationally. Others are turning to cannabis for age-related health conditions, sometimes on a doctor's recommendation. Whether these recreational and medical pathways are separate or interconnected remains unclear.\n\nThe authors identified two particularly compelling policy arguments for cannabis among older adults. First, cannabis may serve as a substitute for prescription opioids and other commonly misused medications, potentially reducing harm. Second, cannabis has emerged as an option for the widespread undertreatment of pain at end of life.\n\nHowever, the authors emphasized that these policy alternatives require empirically driven, representative research before they can be responsibly implemented.","whyItMatters":"The aging population is the fastest-growing demographic of cannabis users, yet has received the least research attention. Understanding their motivations, patterns, and outcomes is essential as more states legalize cannabis and more older adults consider it for pain, sleep, and other age-related conditions.","specificNumbers":"The essay references the growing population of Americans aged 65+ but does not report original quantitative data.","methodology":"Essay reviewing trends in cannabis use among Americans aged 65+, applying the age-period-cohort paradigm to explain varied pathways to cannabis use. The authors considered both public health risks and policy alternatives.","limitations":"This is an essay/commentary rather than a systematic review or original research. It does not present new data and relies on existing literature that the authors acknowledge is insufficient for the older adult population."},{"rthcId":"RTHC-01415","title":"Medical cannabis: Another piece in the mosaic of autoimmunity?","authors":"Katz, D; Katz, I; Porat-Katz, B S; Shoenfeld, Y","year":2017,"journal":"Clinical pharmacology and therapeutics, 101(2), 230-238","doi":"10.1002/cpt.568","pmid":"27859024","tags":["medical-cannabis","inflammation","cbd","pain"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"This review examined cannabis and its active compounds as potential treatments for autoimmune diseases, conditions where the immune system mistakenly attacks the body's own tissues.\n\nThe evidence supports cannabinoids as immune-modulating agents that affect T-cells, B-cells, monocytes, and microglia cells. The overall effect is a reduction in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines, which is the opposite of what occurs in autoimmune diseases.\n\nClinical trials have already suggested effectiveness in three autoimmune conditions: multiple sclerosis (spasticity and pain), inflammatory bowel disease, and fibromyalgia. However, contradicting results and the lack of large-scale trials make these findings inconclusive.\n\nLaboratory and animal studies also show correlations between disease activity and cannabinoids in rheumatoid arthritis, type 1 diabetes, and systemic sclerosis, though these have not yet progressed to clinical trials.","whyItMatters":"Autoimmune diseases affect roughly 5-8% of the population and current treatments often carry significant side effects. If cannabinoids can modulate immune function with fewer side effects, they could complement or replace existing therapies for millions of patients.","specificNumbers":"Clinical trial evidence exists for three conditions: multiple sclerosis, inflammatory bowel disease, and fibromyalgia. Preclinical evidence exists for rheumatoid arthritis, type 1 diabetes, and systemic sclerosis.","methodology":"Narrative review of evidence on cannabinoids and autoimmunity, covering immune cell effects, clinical trials in MS/IBD/fibromyalgia, and preclinical data on rheumatoid arthritis, type 1 diabetes, and systemic sclerosis.","limitations":"Narrative review without systematic methodology. Clinical evidence remains limited to small trials with sometimes contradicting results. The leap from immune modulation in the lab to clinical benefit in patients is not always straightforward."},{"rthcId":"RTHC-01416","title":"Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults.","authors":"Kelly, Clare; Castellanos, F Xavier; Tomaselli, Olivia; Lisdahl, Krista; Tamm, Leanne; Jernigan, Terry; Newman, Erik; Epstein, Jeffery N; Molina, Brooke S G; Greenhill, Laurence L; Potkin, Steven G; Hinshaw, Stephen; Swanson, James M","year":2017,"journal":"NeuroImage. Clinical, 13, 188-200","doi":null,"pmid":"27995073","tags":["cognition","neuroscience","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This neuroimaging study examined 75 young adults (ages 21-25) followed since childhood as part of the landmark MTA study of ADHD, comparing brain functional connectivity across four groups: ADHD with cannabis use, ADHD without cannabis, non-ADHD with cannabis, and non-ADHD without cannabis.\n\nChildhood ADHD was associated with weakened connectivity in brain networks supporting executive function and motor control, consistent with known ADHD features.\n\nContrary to expectations, the effects of cannabis use were distinct from those of ADHD, affecting different brain networks. No interactions between ADHD diagnosis and cannabis use were observed, meaning cannabis did not appear to make ADHD-related brain changes worse.\n\nExploratory analyses linked the ADHD-related brain changes to poorer neurocognitive performance, while cannabis-related changes showed different behavioral correlates.","whyItMatters":"People with ADHD are at elevated risk for cannabis use, raising concerns that cannabis might compound ADHD-related brain differences. This study provides preliminary reassurance that the two effects are independent, though the small sample size means this finding needs replication.","specificNumbers":"75 participants: 23 ADHD + cannabis, 22 ADHD without cannabis, 15 comparison + cannabis, 15 comparison without cannabis. Followed since ages 7-9.9 from the MTA study.","methodology":"Resting-state fMRI study with a 2x2 design (ADHD vs. comparison x cannabis user vs. non-user) in 75 young adults from the MTA longitudinal study. Intrinsic functional connectivity was measured within 9 functional networks. Participants with ADHD had been followed since age 7-9.9 years.","limitations":"Small sample size (especially in comparison groups with only 15 each) limits statistical power. Cross-sectional brain imaging cannot determine causality or temporal ordering. Cannabis use was assessed at one time point without detailed history of use patterns. The study cannot rule out subtle interactions that would require larger samples to detect."},{"rthcId":"RTHC-01417","title":"Cannabis: Exercise performance and sport. A systematic review.","authors":"Kennedy, Michael C","year":2017,"journal":"Journal of science and medicine in sport, 20(9), 825-829","doi":"10.1016/j.jsams.2017.03.012","pmid":"28392338","tags":["exercise","cardiovascular","respiratory"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This systematic review searched for all published studies investigating THC's effects during formal exercise protocols, finding only 15 studies in the entire literature.\n\nNone of the 15 studies showed any improvement in aerobic exercise performance from THC. One positive finding was that cannabis inhibited exercise-induced asthma, suggesting possible bronchodilatory effects during physical activity.\n\nThe detrimental effects were more notable. Two studies found that marijuana triggered angina (chest pain) at lower workloads than normal in 100% of subjects tested, a significant cardiovascular safety concern. Strength was probably reduced. Some participants could not complete exercise protocols due to adverse reactions caused by cannabis.\n\nA finding relevant to drug testing: aerobic exercise caused only very small rises in blood THC concentrations (less than 1 ng/mL), suggesting that exercise-induced fat mobilization does not meaningfully release stored THC.","whyItMatters":"Despite cannabis being one of the most commonly detected substances in athlete drug testing, this review reveals remarkably little evidence that it enhances performance. The cardiovascular risks (angina at lower workloads) are particularly concerning for recreational exercisers who use cannabis.","specificNumbers":"Only 15 published studies exist on THC and exercise. Zero showed aerobic improvement. 100% of cardiac-vulnerable subjects experienced angina at lower workloads. Exercise caused THC blood rises of less than 1 ng/mL.","methodology":"Systematic review searching PubMed, Medline, and Embase for cannabis/THC in sport and exercise. Included studies with formal exercise protocols or rehabilitation/health screening programs. Excluded review articles, opinion pieces, and policy statements.","limitations":"Only 15 studies were found, reflecting the extremely limited research base. Many studies were older and used varying cannabis preparations, doses, and exercise protocols. The small number of studies prevents strong conclusions about specific exercise types or populations."},{"rthcId":"RTHC-01418","title":"Medical use of cannabis in Switzerland: analysis of approved exceptional licences.","authors":"Kilcher, Gablu; Zwahlen, Marcel; Ritter, Christopher; Fenner, Lukas; Egger, Matthias","year":2017,"journal":"Swiss medical weekly, 147, w14463","doi":"10.4414/smw.2017.14463","pmid":"28695562","tags":["medical-cannabis","pain","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This study analyzed all 1,193 patients approved for medical cannabis through Switzerland's exceptional licensing program in 2013 and 2014.\n\nThe program grew rapidly: 542 patients were treated in 2013 compared to 825 in 2014, a 52% increase. Over half (57%) of patients were women, and the average age was 57 years.\n\nChronic pain (49%) and spasticity (40%) were the two most common symptoms, aligning with the strongest evidence base for medical cannabis. Seventy-eight different diagnoses were recorded, with multiple sclerosis (22%), soft tissue disorders (10%), and back pain (8%) being the most frequent.\n\nNotably, 91% of patients paid for cannabis treatment out of pocket, indicating that insurance coverage had not caught up with medical practice. License extension rates increased from 26.4% in 2013 to 39.3% in 2014, suggesting growing satisfaction or perceived benefit among patients and their physicians.\n\nSubstantial regional variation existed in prescription rates, averaging 8 patients per 100,000 residents.","whyItMatters":"This is one of the few studies providing a comprehensive look at a national medical cannabis licensing program. The data on who receives cannabis, for what conditions, and at what cost provides a real-world picture of medical cannabis beyond clinical trials.","specificNumbers":"1,193 patients total. 542 in 2013, 825 in 2014 (52% increase). 57% women. Mean age 57 years. 49% chronic pain, 40% spasticity. 78 different diagnoses. 22% multiple sclerosis. 91% paid out of pocket. 8 per 100,000 residents average.","methodology":"Retrospective analysis of all requests for medical cannabinoid use approved by the Swiss Federal Office of Public Health in 2013 and 2014. Standardized data extraction captured demographics, diagnoses, indications, license duration, and payment source. Ethics approval from the Canton of Bern.","limitations":"Administrative data cannot capture treatment outcomes, side effects, or patient satisfaction. The exceptional licensing framework may underestimate actual medical cannabis use if patients obtained cannabis through other channels. No comparison to non-cannabis treatment outcomes was possible."},{"rthcId":"RTHC-01419","title":"Cannabis for Pain and Headaches: Primer.","authors":"Kim, Philip S; Fishman, Michael A","year":2017,"journal":"Current pain and headache reports, 21(4), 19","doi":"10.1007/s11916-017-0619-7","pmid":"28281107","tags":["pain","medical-cannabis","cbd"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"This primer reviewed the landscape of cannabis-based pain treatment for physicians, covering three main categories of active compounds.\n\nSynthetic cannabinoids like dronabinol and nabilone have already received FDA approval for chemotherapy-related nausea and HIV wasting, providing a regulatory pathway for cannabinoid medicines. Nabiximols (Sativex), a cannabis extract, is approved in Canada and the UK for spasticity and intractable pain.\n\nBeyond THC and CBD, phytocannabinoids have been identified as key compounds with analgesic and anti-inflammatory properties. The review also highlighted other cannabis compounds, including flavonoids and terpenes, that are being investigated for their individual effects and potential synergistic interactions (the \"entourage effect\").\n\nThe authors emphasized the endocannabinoid system as the biological foundation for these effects, noting that the identification of this intrinsic system has opened doors for further research into cannabis-based pain therapies.","whyItMatters":"This review serves as a practical primer for physicians who are increasingly asked about cannabis for pain. By organizing the evidence around specific compounds and approved medications, it provides a framework for evidence-based clinical conversations.","specificNumbers":"Dronabinol and nabilone are FDA-approved. Nabiximols is approved in Canada and the UK. Clinical trials for seizure disorders were ongoing at publication.","methodology":"Narrative review of medical literature on cannabis and cannabinoid pharmaceuticals, with emphasis on pain and headache conditions. Covers synthetic cannabinoids, phytocannabinoids, and other cannabis-derived compounds.","limitations":"Narrative review without systematic methodology or quality assessment. Does not present original data. The headache-specific evidence is particularly sparse. Published before major developments in CBD regulation."},{"rthcId":"RTHC-01420","title":"Cannabis use disorder and suicide attempts in Iraq/Afghanistan-era veterans.","authors":"Kimbrel, Nathan A; Newins, Amie R; Dedert, Eric A; Van Voorhees, Elizabeth E; Elbogen, Eric B; Naylor, Jennifer C; Ryan Wagner, H; Brancu, Mira; Beckham, Jean C; Calhoun, Patrick S","year":2017,"journal":"Journal of psychiatric research, 89, 1-5","doi":"10.1016/j.jpsychires.2017.01.002","pmid":"28129565","tags":["mental-health","addiction","ptsd"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This study examined the relationship between cannabis use disorder (CUD) and suicidal behavior in a large sample of 3,233 Iraq/Afghanistan-era veterans.\n\nVeterans with lifetime CUD had significantly higher odds of both current suicidal ideation (OR = 1.683) and lifetime suicide attempts (OR = 2.306). What makes this finding notable is that these associations persisted after statistically controlling for numerous other risk factors: sex, PTSD, depression, alcohol use disorder, non-cannabis drug use disorder, childhood sexual abuse history, and combat exposure.\n\nThe fact that CUD predicted suicide attempts independently of PTSD, depression, and other substance use disorders suggests it may represent a unique risk factor rather than simply a marker of other problems. This is particularly relevant for veteran populations, where suicide prevention is a critical priority.","whyItMatters":"Veteran suicide remains a national crisis. Identifying CUD as an independent risk factor for suicide attempts provides a specific, actionable screening target. Veterans with CUD may benefit from additional suicide risk assessment and prevention efforts.","specificNumbers":"3,233 veterans. CUD associated with suicidal ideation OR = 1.683 (p = 0.008). CUD associated with suicide attempts OR = 2.306 (p < 0.0001). Associations held after controlling for sex, PTSD, depression, alcohol use disorder, other drug use disorder, childhood sexual abuse, and combat exposure.","methodology":"Cross-sectional analysis of 3,233 Iraq/Afghanistan-era veterans using well-validated instruments to assess cannabis use disorder, suicidal ideation, suicide attempt history, and relevant covariates including PTSD, depression, alcohol use disorder, other drug use disorder, childhood sexual abuse, and combat exposure.","limitations":"Cross-sectional design cannot establish whether CUD contributes to suicide risk or whether underlying factors drive both CUD and suicidal behavior. Self-reported data may be affected by recall bias. The veteran population may not generalize to civilian populations."},{"rthcId":"RTHC-01421","title":"A dual inhibitor of FAAH and TRPV1 channels shows dose-dependent effect on depression-like behaviour in rats.","authors":"Kirkedal, Christian; Wegener, Gregers; Moreira, Fabricio; Joca, Sâmia Regiane Lourenco; Liebenberg, Nico","year":2017,"journal":"Acta neuropsychiatrica, 29(6), 324-329","doi":"10.1017/neu.2016.68","pmid":"27938441","tags":["depression","neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study tested the theory that anandamide produces a bell-shaped dose-response curve in depression because it activates two receptors with opposite effects: CB1 (antidepressant) and TRPV1 (pro-depressant).\n\nResearchers administered N-arachidonoyl-serotonin (AA-5HT), a dual inhibitor that both prevents anandamide breakdown (by blocking FAAH) and blocks TRPV1 activation, directly into the prefrontal cortex of rats at three doses.\n\nOnly the middle dose (0.250 nmol) produced significant antidepressant-like effects in the forced swim test. The low and high doses had no effect, demonstrating a dose-dependent response.\n\nThe antidepressant effect of the effective dose was partially blocked when co-administered with the CB1 receptor inverse agonist rimonabant, confirming that the benefit worked at least partly through CB1 receptor activation.","whyItMatters":"This study provides experimental support for the dual-receptor theory of anandamide in depression: CB1 activation helps while TRPV1 activation hurts. By simultaneously targeting both, AA-5HT may represent a more refined approach to cannabinoid-based antidepressant therapy than simply boosting anandamide alone.","specificNumbers":"Three doses tested: 0.125, 0.250, 0.500 nmol. Only 0.250 nmol showed significant antidepressant effect. Rimonabant (1.6 micrograms) partially attenuated the effect.","methodology":"Rats received direct injections of AA-5HT at three doses (0.125, 0.250, 0.500 nmol) into the medial prefrontal cortex. Behavior was assessed using the forced swim test. CB1 receptor involvement was confirmed by co-administering rimonabant (1.6 micrograms).","limitations":"The drug was injected directly into the brain, which is not a viable clinical administration route. The forced swim test is a screening tool that does not model all aspects of human depression. Only three doses were tested, and the optimal dose window may be narrow."},{"rthcId":"RTHC-01422","title":"Longitudinal study of hippocampal volumes in heavy cannabis users.","authors":"Koenders, L; Lorenzetti, V; de Haan, L; Suo, C; Vingerhoets, Wam; van den Brink, W; Wiers, R W; Meijer, C J; Machielsen, Mwj; Goudriaan, A E; Veltman, D J; Yücel, M; Cousijn, J","year":2017,"journal":"Journal of psychopharmacology (Oxford, England), 31(8), 1027-1034","doi":"10.1177/0269881117718380","pmid":"28741422","tags":["cognition","neuroscience","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This longitudinal study tracked hippocampal volumes in 20 heavy cannabis users and 23 matched controls over approximately 39 months using manual brain tracing, considered the gold standard for hippocampal measurement.\n\nAt baseline, there were no differences in hippocampal volume between heavy users and non-users. At follow-up, there were still no differences. Both groups showed hippocampal volume increases over time, following similar growth trajectories.\n\nNeither the dose of cannabis used nor the age at which cannabis use began affected hippocampal volumes. Cannabis users in this study began smoking around age 16 and used cannabis approximately five days per week.\n\nThe authors noted that their null finding contrasts with prior evidence of hippocampal alterations in older adult cannabis users, suggesting that young adult brains may be more resilient to cannabis effects at these use levels, or that cumulative exposure has not yet reached a threshold for detectable changes.","whyItMatters":"The hippocampus is central to memory and is rich in cannabinoid receptors, making it a primary concern for cannabis-related brain effects. This longitudinal null finding provides some reassurance for young adult heavy users, though the small sample and age range limit how broadly the finding can be applied.","specificNumbers":"20 heavy cannabis users, 23 controls. Mean age 21 (18-24). Follow-up after average 39 months (SD 2.4). Cannabis use: ~5 days/week, onset ~age 16. No significant volume differences at any time point.","methodology":"Longitudinal neuroimaging study with 20 heavy cannabis users (mean age 21, range 18-24) and 23 matched controls. MRI scans at baseline and follow-up (average 39 months apart). Hippocampal volumes measured using manual tracing on T1-weighted anatomical scans. Cannabis users averaged 5 days/week of use with onset around age 16.","limitations":"Small sample size limits statistical power to detect subtle effects. Manual tracing, while considered gold standard, may miss subfield-specific changes. The age range (18-24) captures only early adulthood. Cannabis users averaged 5 days/week, which, while heavy, may not represent the heaviest use patterns."},{"rthcId":"RTHC-01423","title":"Design and Synthesis of Cannabinoid 1 Receptor (CB1R) Allosteric Modulators: Drug Discovery Applications.","authors":"Kulkarni, Abhijit R; Garai, Sumanta; Janero, David R; Thakur, Ganesh A","year":2017,"journal":"Methods in enzymology, 593, 281-315","doi":"10.1016/bs.mie.2017.06.018","pmid":"28750808","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01424","title":"Inspired by Mary Jane? Mechanisms underlying enhanced creativity in cannabis users.","authors":"LaFrance, Emily M; Cuttler, Carrie","year":2017,"journal":"Consciousness and cognition, 56, 68-76","doi":"10.1016/j.concog.2017.10.009","pmid":"29065317","tags":["cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This study tested 412 sober cannabis users and 309 non-users on both self-reported and objective creativity measures to determine whether cannabis use is associated with enhanced creativity.\n\nAt first glance, the results supported the creative cannabis user stereotype. Sober cannabis users reported higher creativity and performed significantly better on a test of convergent thinking (the ability to find a single correct solution to a well-defined problem).\n\nHowever, when the researchers controlled for personality differences, specifically cannabis users' higher levels of openness to experience (a personality trait associated with curiosity, imagination, and appreciation for art and ideas), these creativity advantages disappeared entirely.\n\nThe finding suggests that cannabis users are not more creative because of cannabis. Rather, people with more open, creative personalities may be drawn to cannabis use. The creativity is an artifact of personality, not a product of the drug.","whyItMatters":"The \"creative stoner\" is one of the most persistent cannabis stereotypes. This study provides a clean test of that idea by measuring creativity while users were sober and statistically controlling for the personality trait that actually drives the association.","specificNumbers":"412 sober cannabis users vs. 309 non-users. Cannabis users scored higher on openness to experience, self-reported creativity, and convergent thinking. All creativity advantages disappeared when openness to experience was controlled.","methodology":"Cross-sectional study comparing 412 sober cannabis users and 309 non-users on measures of cannabis consumption, Big Five personality traits, self-reported creativity, and objective convergent thinking performance. Statistical analyses controlled for personality differences.","limitations":"Cross-sectional design cannot definitively establish the direction of causation (openness leading to cannabis use vs. cannabis use enhancing openness). The study tested convergent thinking but not divergent thinking (generating multiple novel ideas), which is another important creativity dimension. All testing was done while sober, so acute cannabis effects on creativity were not assessed."},{"rthcId":"RTHC-01425","title":"Assessment of tobacco, alcohol and cannabinoid metabolites in 645 meconium samples of newborns compared to maternal self-reports.","authors":"Lamy, Sandrine; Hennart, Benjamin; Houivet, Estelle; Dulaurent, Sylvain; Delavenne, Heloise; Benichou, Jacques; Allorge, Delphine; Marret, Stéphane; Thibaut, Florence","year":2017,"journal":"Journal of psychiatric research, 90, 86-93","doi":"10.1016/j.jpsychires.2017.02.012","pmid":"28237885","tags":["pregnancy","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This study compared what mothers reported about their substance use during pregnancy with what objective testing of their newborns' meconium (first stool) actually revealed.\n\nFor tobacco, meconium cotinine testing agreed well with maternal self-reports (Kappa = 0.79), and meconium testing actually predicted neonatal consequences of tobacco exposure better than self-reports alone.\n\nFor cannabis and alcohol, the story was different. Agreement between self-reports and meconium testing was low for both alcohol (Kappa = 0.13) and cannabis (Kappa = 0.30). Notably, the highest levels of alcohol metabolites in meconium were found in babies whose mothers denied drinking, suggesting significant underreporting of prenatal alcohol exposure.\n\nAmong 645 meconium samples collected from 724 mothers across all maternity units in Rouen, France, over two 5-week periods, polyconsumption (using multiple substances) was actually less common than expected based on meconium testing. An interesting finding in dizygotic twins showed that fetal exposure to substances can differ substantially even between twins sharing the same pregnancy.","whyItMatters":"Prenatal substance exposure has significant effects on neonatal health and child development. If mothers underreport cannabis and alcohol use during pregnancy, clinicians relying solely on self-reports will miss exposures. Meconium testing provides an objective alternative that captures third-trimester exposure.","specificNumbers":"724 mothers, 645 meconium samples. Tobacco agreement: Kappa = 0.79. Alcohol agreement: Kappa = 0.13. Cannabis agreement: Kappa = 0.30. Total cannabinoid-positive meconium samples were small in number.","methodology":"Cross-sectional study of 724 mothers and 645 meconium samples collected within 72 hours of delivery across all maternities in Rouen, Normandy. Maternal self-reports used the Addiction Severity Index (5th edition). Meconium was tested for cotinine (tobacco), ethyl-glucuronide (alcohol), and cannabinoid metabolites.","limitations":"The number of cannabis-positive and alcohol-positive meconium samples was small, limiting statistical precision for these substances. Meconium reflects only third-trimester exposure and may miss earlier pregnancy use. Cultural factors in France may affect reporting patterns differently than in other countries."},{"rthcId":"RTHC-01426","title":"Marijuana practices and patterns of use among young adult medical marijuana patients and non-patient marijuana users.","authors":"Lankenau, Stephen E; Fedorova, Ekaterina V; Reed, Megan; Schrager, Sheree M; Iverson, Ellen; Wong, Carolyn F","year":2017,"journal":"Drug and alcohol dependence, 170, 181-188","doi":"10.1016/j.drugalcdep.2016.10.025","pmid":"27987475","tags":["medical-cannabis","addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This study compared 210 young adult medical marijuana patients (MMP) with 156 non-patient marijuana users (NPU) aged 18-26 in Los Angeles.\n\nMedical patients used significantly more cannabis: an average of 76.4 days in the past 90 days compared to 59.2 days for non-patients. They also spent substantially more ($564.50 vs. $266.90 over 90 days).\n\nMedical patients were significantly more likely to vaporize their cannabis, both as concentrates and as flower, suggesting they were accessing and choosing non-combustible delivery methods more often than recreational users.\n\nAn interesting pattern emerged regarding other drugs: medical patients showed trends toward lower misuse of prescription drugs compared to non-patients, though this did not reach statistical significance.\n\nNotably, about 22.6% of both groups reported selling dispensary-obtained marijuana to someone else in the past 90 days, indicating diversion from the legal supply chain was common across both groups.","whyItMatters":"This study challenges simple narratives about medical versus recreational cannabis use. Medical patients used more cannabis but in potentially less harmful ways (more vaporizing, less prescription drug misuse). The diversion finding raises policy concerns about dispensary sales reaching non-patients.","specificNumbers":"210 medical patients, 156 non-patients. Mean days of use: 76.4 vs. 59.2 (p<0.001). Mean spending: $564.50 vs. $266.90 (p<0.001). Vaporization of concentrates: 1.5x more likely among MMP. 22.6% of both groups sold dispensary marijuana to others.","methodology":"Cross-sectional study of 366 young adults (18-26) sampled in Los Angeles in 2014-2015. Medical patients had current, verified recommendations. Self-reported marijuana and other drug use during the past 90 days were compared using unadjusted risk ratios and differences in means.","limitations":"Cross-sectional design in Los Angeles may not generalize to other markets. Self-reported data may be subject to social desirability bias. Medical marijuana recommendations in California at this time were relatively easy to obtain, blurring the line between medical and recreational users."},{"rthcId":"RTHC-01427","title":"Frequency of Cannabis Use Among Primary Care Patients in Washington State.","authors":"Lapham, Gwen T; Lee, Amy K; Caldeiro, Ryan M; McCarty, Dennis; Browne, Kendall C; Walker, Denise D; Kivlahan, Daniel R; Bradley, Katharine A","year":2017,"journal":"Journal of the American Board of Family Medicine : JABFM, 30(6), 795-805","doi":"10.3122/jabfm.2017.06.170062","pmid":"29180554","tags":["addiction","mental-health","depression","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This study analyzed cannabis use screening results from 22,095 primary care patients in Washington State, one of the first states to legalize recreational cannabis.\n\nOverall, 15.3% reported any past-year cannabis use and 3.1% reported daily use. These rates were substantially higher than national averages at the time.\n\nAge was the strongest predictor: 36% of patients aged 18-29 reported any cannabis use and 8.1% reported daily use. Among the youngest patients, behavioral health factors dramatically increased daily use rates. Young men aged 18-29 who also used tobacco had a 25.5% daily cannabis use rate, and those who screened positive for depression had a 31.7% daily use rate.\n\nThe study demonstrated the feasibility of routine cannabis screening in primary care, with 74% of eligible patients completing the screening question.","whyItMatters":"This is one of the first large-scale assessments of cannabis use among primary care patients in a legalized state. The high rates among young adults with behavioral health conditions highlight the need for integrated screening and intervention in primary care settings.","specificNumbers":"22,095 patients screened (74% completion). 15.3% any past-year use. 3.1% daily use. Ages 18-29: 36% any use, 8.1% daily. Young men with tobacco use: 25.5% daily cannabis use. Young patients with depression: 31.7% daily cannabis use.","methodology":"Observational cohort study of 29,857 adults visiting primary care clinics with annual behavioral health screening (March 2015 to February 2016). Cannabis use was assessed with a single-item frequency question. Depression, alcohol, and other drug use were also screened. Electronic health records provided tobacco use and behavioral health diagnoses.","limitations":"Single-item screening may miss nuances of use patterns. Patients seen in one health system in Washington State may not represent other populations. The study occurred shortly after recreational legalization, and patterns may have changed since. The 26% who did not complete screening may differ systematically from completers."},{"rthcId":"RTHC-01428","title":"Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor.","authors":"Laprairie, Robert B; Kulkarni, Pushkar M; Deschamps, Jeffrey R; Kelly, Melanie E M; Janero, David R; Cascio, Maria G; Stevenson, Lesley A; Pertwee, Roger G; Kenakin, Terrence P; Denovan-Wright, Eileen M; Thakur, Ganesh A","year":2017,"journal":"ACS chemical neuroscience, 8(6), 1188-1203","doi":"10.1021/acschemneuro.6b00310","pmid":"28103441","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01429","title":"GPR3 and GPR6, novel molecular targets for cannabidiol.","authors":"Laun, Alyssa S; Song, Zhao-Hui","year":2017,"journal":"Biochemical and biophysical research communications, 490(1), 17-21","doi":"10.1016/j.bbrc.2017.05.165","pmid":"28571738","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study identified two previously unknown molecular targets for CBD: GPR3 and GPR6, orphan receptors with no confirmed endogenous activators that are phylogenetically related to cannabinoid receptors.\n\nUsing a beta-arrestin2 recruitment assay, the researchers tested various endocannabinoids and phytocannabinoids against both receptors. Among all cannabinoids tested, CBD was the standout, significantly reducing beta-arrestin2 recruitment to both GPR3 and GPR6 in a concentration-dependent manner.\n\nThis means CBD acts as an inverse agonist at these receptors, reducing their constitutive (baseline) activity. CBD showed higher potency at GPR6 than GPR3.\n\nThe significance lies in what these receptors do: GPR3 has been implicated in Alzheimer's disease pathology, while GPR6 plays potential roles in Parkinson's disease. This discovery suggests that some of CBD's reported neuroprotective effects may work through these receptors rather than through the classical CB1 and CB2 cannabinoid receptors.","whyItMatters":"This is the first demonstration that GPR3 and GPR6 are molecular targets for CBD. If CBD's effects on these receptors translate to therapeutic benefit, it could provide a mechanistic basis for using CBD in neurodegenerative diseases, moving beyond anecdotal reports to targeted pharmacology.","specificNumbers":"CBD significantly reduced beta-arrestin2 recruitment at both receptors in a concentration-dependent manner, with higher potency at GPR6 than GPR3.","methodology":"In vitro study using beta-arrestin2 recruitment assays to test the activity of multiple endocannabinoids and phytocannabinoids at human GPR3 and GPR6 receptors. Concentration-response curves were generated for CBD at both receptors.","limitations":"In vitro study only, with no animal model or clinical validation. Inverse agonism at these receptors in a cell assay does not guarantee therapeutic benefit in the brain. The functional consequences of reducing GPR3/GPR6 signaling in living organisms remain to be determined."},{"rthcId":"RTHC-01430","title":"Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.","authors":"Lazzari, P; Serra, V; Marcello, S; Pira, M; Mastinu, A","year":2017,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 27(7), 667-678","doi":"10.1016/j.euroneuro.2017.03.010","pmid":"28377074","tags":["neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Weight gain is a major side effect of the antipsychotic olanzapine, and this study tested whether blocking CB1 cannabinoid receptors could counteract the metabolic problems without reducing the drug's psychiatric benefits.\n\nFemale rats treated with olanzapine for 15 days gained weight and developed alterations in blood markers related to energy balance and glucose metabolism. In the brain, olanzapine changed cannabinoid markers in the nucleus accumbens and shifted hunger-related signaling in the hypothalamus toward increased appetite.\n\nCo-treatment with either rimonabant (a CB1 inverse agonist) or the novel compound NESS06SM (a CB1 neutral antagonist) reversed these effects: food intake decreased, weight gain was reduced, blood parameters returned to normal, and liver and fat tissue enzymes were restored.\n\nCritically, neither CB1 antagonist interfered with olanzapine's positive behavioral effects, meaning the antipsychotic still worked as intended while its metabolic side effects were neutralized.","whyItMatters":"Antipsychotic-induced weight gain is a leading cause of treatment discontinuation and contributes to cardiovascular disease in psychiatric patients. Demonstrating that CB1 blockade can neutralize these side effects without reducing therapeutic efficacy opens a potential clinical pathway.","specificNumbers":"15-day olanzapine treatment. Novel CB1 neutral antagonist NESS06SM was compared to rimonabant. Both compounds decreased food intake, weight gain, and restored blood parameters and tissue enzymes.","methodology":"Female rats received 15-day treatment with olanzapine alone or in combination with CB1 receptor antagonists (rimonabant or NESS06SM). Outcomes included body weight, food intake, blood metabolic parameters, brain cannabinoid and hunger markers (nucleus accumbens, hypothalamus), behavioral effects, and liver/fat tissue enzyme expression.","limitations":"Animal study using female rats only, limiting generalizability across sexes. The 15-day treatment period is short relative to long-term antipsychotic use in humans. Rimonabant was withdrawn from human use due to psychiatric side effects, and the novel compound NESS06SM has not been tested in humans."},{"rthcId":"RTHC-01431","title":"Focus on cannabinoids and synthetic cannabinoids.","authors":"Le Boisselier, R; Alexandre, J; Lelong-Boulouard, V; Debruyne, D","year":2017,"journal":"Clinical pharmacology and therapeutics, 101(2), 220-229","doi":"10.1002/cpt.563","pmid":"27861784","tags":["synthetic-cannabinoids","neuroscience","cardiovascular","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review provided a state-of-the-art overview of both natural and synthetic cannabinoids, explaining why synthetic versions produce more extreme effects.\n\nThe key pharmacological difference: THC is a partial agonist at CB1 receptors (it activates them partially), while most synthetic cannabinoids are full agonists (they activate receptors to their maximum). Combined with higher receptor binding affinity, this explains why synthetic cannabinoid effects are more intense across the board, both desired effects and side effects.\n\nNeurological and cardiovascular complications are the most commonly reported adverse effects after synthetic cannabinoid poisoning. While most cases respond to conventional supportive care, severe outcomes including death occur in a minority of cases, predominantly with synthetic cannabinoids rather than natural cannabis.\n\nThe review also highlighted the endocannabinoid system's involvement in multiple neurotransmission pathways, explaining the broad range of both therapeutic and adverse effects of cannabinoid compounds.","whyItMatters":"Understanding the pharmacological basis for why synthetic cannabinoids are more dangerous than cannabis is essential for clinicians treating poisoning cases and for public health messaging targeting users who may assume synthetic products are similar to natural cannabis.","specificNumbers":"The review notes neurological and cardiovascular effects as the primary adverse outcomes, with severe cases mainly occurring with synthetic rather than natural cannabinoids.","methodology":"Review article synthesizing current knowledge on the pharmacology, effects, and risks of natural and synthetic cannabinoids, with emphasis on the receptor-level differences that explain their distinct clinical profiles.","limitations":"Narrative review without systematic search methodology. The rapidly evolving landscape of synthetic cannabinoids means any review is quickly outdated. Case severity data is largely drawn from case reports and poison center data rather than controlled studies."},{"rthcId":"RTHC-01432","title":"Human serum albumin: A modulator of cannabinoid drugs.","authors":"Leboffe, Loris; di Masi, Alessandra; Trezza, Viviana; Polticelli, Fabio; Ascenzi, Paolo","year":2017,"journal":"IUBMB life, 69(11), 834-840","doi":"10.1002/iub.1682","pmid":"28976704","tags":["neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study investigated whether human serum albumin (HSA), the most abundant protein in blood plasma, serves as a major transporter for cannabinoid drugs.\n\nUsing computational docking methods, the researchers found that HSA binds strongly to a wide range of cannabinoid compounds: indirect agonists (URB597, AM5206, JZL184, JZL195, AM404), direct agonists (WIN55,212-2, CP55,940), and the antagonist/inverse agonist SR141716 (rimonabant).\n\nBinding energies ranged from -5.4 to -10.9 kcal/mol. Given the high concentration of HSA in blood (~750 micromolar), the modeling suggests these complexes would form readily under physiological conditions.\n\nSince HSA already binds the natural endocannabinoid anandamide and THC, it appears to be a universal carrier for cannabinoid compounds. This has practical implications: the amount of HSA in a patient's blood could significantly affect how much \"free\" (active) cannabinoid drug is available to produce effects.","whyItMatters":"If HSA is a major determinant of cannabinoid drug levels in the blood, it could explain why cannabis and cannabinoid drugs affect people differently. Patients with lower albumin levels (liver disease, malnutrition, elderly) might experience stronger effects from the same dose, while those with higher albumin might need more.","specificNumbers":"Binding energies: -5.4 to -10.9 kcal/mol across 8 cannabinoid drugs. HSA blood concentration: ~750 micromolar. THC and anandamide are already known to bind HSA.","methodology":"In silico molecular docking study using computational methods to model the binding interactions between HSA and eight different cannabinoid drugs. Free energy calculations estimated binding strength. Results were contextualized against known HSA concentration in human blood.","limitations":"Computational (in silico) modeling only, without experimental confirmation of binding affinities or biological relevance. Docking scores do not always accurately predict real binding behavior. The study does not address whether HSA binding changes cannabinoid drug activity in living systems."},{"rthcId":"RTHC-01433","title":"Emotional disorders induced by Hemopressin and RVD-hemopressin(α) administration in rats.","authors":"Leone, Sheila; Recinella, Lucia; Chiavaroli, Annalisa; Martinotti, Sara; Ferrante, Claudio; Mollica, Adriano; Macedonio, Giorgia; Stefanucci, Azzurra; Dvorácskó, Szabolcs; Tömböly, Csaba; De Petrocellis, Luciano; Vacca, Michele; Brunetti, Luigi; Orlando, Giustino","year":2017,"journal":"Pharmacological reports : PR, 69(6), 1247-1253","doi":"10.1016/j.pharep.2017.06.010","pmid":"29128806","tags":["anxiety","depression","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study tested two naturally occurring peptides that modulate the endocannabinoid system and found they produce opposite emotional effects in rats.\n\nHemopressin, which blocks CB1 receptors (acting as an antagonist/inverse agonist), induced anxiogenic (anxiety-promoting) and depressive behavior when injected. At the neurochemical level, it decreased levels of norepinephrine, dopamine, and serotonin in the prefrontal cortex while increasing the enzymes that break these neurotransmitters down.\n\nRVD-hemopressin, a longer peptide that acts as a negative allosteric modulator of CB1, produced the opposite effects: it reduced anxiety, decreased depressive behavior, increased monoamine levels, and decreased the breakdown enzymes in the prefrontal cortex.\n\nBoth peptides are derived from the hemoglobin alpha chain, and their opposing effects suggest that the endocannabinoid system has multiple peptide-based regulatory mechanisms with distinct behavioral consequences.","whyItMatters":"This study reveals that the endocannabinoid system has peptide regulators with direct effects on mood-related brain chemistry. The opposing effects of these two peptides provide new targets for understanding and potentially treating anxiety and depression through the endocannabinoid system.","specificNumbers":"Both peptides dosed at 0.05 mg/kg intraperitoneally. Hemopressin decreased monoamines and increased MAO-B and COMT expression. RVD-hemopressin increased monoamines and decreased MAO-B and COMT expression in the prefrontal cortex.","methodology":"Rats received single intraperitoneal injections of hemopressin (0.05 mg/kg) or RVD-hemopressin (0.05 mg/kg). Behavior was assessed using the locomotor activity/open field test, light-dark exploration test, and forced swim test. Prefrontal cortex levels of norepinephrine, dopamine, and serotonin were measured by HPLC. Gene expression of MAO-B and COMT (neurotransmitter-degrading enzymes) was measured by RT-PCR.","limitations":"Single-dose, acute study in rats. The forced swim test and other behavioral measures are screening tools, not models of human depression. The peptides were injected peripherally, and their brain penetration and natural circulating levels are not well characterized."},{"rthcId":"RTHC-01434","title":"Evidence for the Risks and Consequences of Adolescent Cannabis Exposure.","authors":"Levine, Amir; Clemenza, Kelly; Rynn, Moira; Lieberman, Jeffrey","year":2017,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 56(3), 214-225","doi":"10.1016/j.jaac.2016.12.014","pmid":"28219487","tags":["youth","cognition","psychosis","addiction","mental-health"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This comprehensive review examined four neuropsychiatric outcomes most vulnerable to adolescent cannabis exposure: cognition, emotional functioning, psychosis risk, and addiction.\n\nThe clinical literature showed strong correlations between early, frequent, heavy adolescent cannabis use and poor cognitive and psychiatric outcomes in adulthood. However, the human studies could not conclusively prove that cannabis alone caused these deficits, because confounding factors were difficult to eliminate.\n\nThe animal literature filled this gap. Controlled experiments clearly showed that adolescent-onset cannabinoid exposure catalyzed molecular processes leading to persistent functional deficits in adulthood. Critically, these same deficits did not occur when exposure began in adulthood, providing strong evidence for a specific developmental vulnerability.\n\nThe animal findings modeled some of the adverse outcomes reported in human early-onset cannabis users, creating a convergence of evidence from both clinical and preclinical research pointing toward adolescence as a uniquely vulnerable period.","whyItMatters":"This review provides one of the most complete pictures of why adolescent cannabis exposure is qualitatively different from adult exposure. The convergence of human and animal evidence strengthens the case for age-specific prevention efforts and policy considerations.","specificNumbers":"The review synthesizes evidence across four outcome categories (cognition, emotional functioning, psychosis, addiction) from both human longitudinal studies and controlled animal experiments.","methodology":"Literature review searching PubMed, PsychInfo, and Google Scholar with no date restrictions, using terms combining adolescent/adult with cannabis/marijuana/THC/cannabinoid and terms related to deficits, impairment, development, and persistence.","limitations":"The human literature cannot fully control for confounders (pre-existing vulnerabilities, environmental factors, polysubstance use). Animal studies use standardized cannabinoid preparations that may not reflect the complexity of natural cannabis. The review does not quantify the dose or frequency threshold for harm."},{"rthcId":"RTHC-01435","title":"Differential expression of endocannabinoid system-related genes in the dorsal hippocampus following expression and reinstatement of morphine conditioned place preference in mice.","authors":"Li, Wei; Zhang, Cong-Li; Qiu, Zheng-Guo","year":2017,"journal":"Neuroscience letters, 643, 38-44","doi":"10.1016/j.neulet.2017.02.025","pmid":"28192193","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study examined how endocannabinoid-related genes in the hippocampus change across three phases of morphine addiction: initial reward, extinction, and relapse.\n\nDuring the expression of morphine reward (conditioned place preference), the hippocampus showed increased expression of FAAH and MAGL, the enzymes that break down the two main endocannabinoids (anandamide and 2-AG). At the same time, CB1 and CB2 receptor expression decreased. This pattern suggests active degradation of endocannabinoid signaling during morphine reward.\n\nDuring relapse (reinstatement of morphine preference), the pattern reversed: MAGL decreased while CB1 receptor expression increased. This opposite pattern suggests the endocannabinoid system reorganizes between initial drug reward and relapse.\n\nThe enzymes that create endocannabinoids (NAPEPLD and DAGL) did not change in any condition, meaning the shifts were driven by changes in degradation and receptor expression rather than production.","whyItMatters":"Understanding how the endocannabinoid system changes during different phases of opioid addiction could lead to phase-specific treatments. The finding that relapse involves different endocannabinoid changes than initial reward suggests that targeting the endocannabinoid system for relapse prevention would require a different approach than targeting initial drug effects.","specificNumbers":"During CPP expression: FAAH and MAGL mRNA increased, CB1R and CB2R decreased. During reinstatement: MAGL decreased, CB1R increased. Biosynthetic enzymes (NAPEPLD, DAGLa/b) unchanged across all conditions.","methodology":"Mice underwent morphine conditioned place preference (CPP) training, followed by extinction and reinstatement. Quantitative RT-PCR measured expression of endocannabinoid-related genes (CB1R, CB2R, FAAH, MAGL, NAPEPLD, DAGLa/b) in the dorsal hippocampus at each phase.","limitations":"Gene expression changes do not necessarily translate to protein level or functional changes. The study measured mRNA only, not endocannabinoid levels or receptor activity. Mouse conditioned place preference is a model of drug reward but does not capture all aspects of human addiction."},{"rthcId":"RTHC-01436","title":"Nucleus accumbens functional connectivity at age 20 is associated with trajectory of adolescent cannabis use and predicts psychosocial functioning in young adulthood.","authors":"Lichenstein, Sarah D; Musselman, Samuel; Shaw, Daniel S; Sitnick, Stephanie; Forbes, Erika E","year":2017,"journal":"Addiction (Abingdon, England), 112(11), 1961-1970","doi":"10.1111/add.13882","pmid":"28547854","tags":["youth","addiction","depression","neuroscience","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Following 158 young men from a longitudinal study that began in infancy, researchers identified three distinct trajectories of cannabis use from ages 14 to 19: stable high use, escalating use, and stable low use.\n\nThe trajectory of cannabis use significantly affected functional connectivity between the nucleus accumbens (the brain's reward center) and the medial prefrontal cortex. The escalating use group showed a pattern of negative connectivity between these regions, meaning the reward center and the decision-making center were working against each other rather than in coordination.\n\nThis disrupted brain connectivity pattern predicted real-world outcomes two years later at age 22: higher depressive symptoms, more anhedonia (inability to feel pleasure), and lower educational attainment.\n\nThe finding that it was the pattern of use across adolescence (escalating) rather than just amount that mattered suggests the trajectory of use during brain development may be as important as the total amount consumed.","whyItMatters":"This is one of the few studies to connect adolescent cannabis use trajectories, brain imaging, and real-world outcomes within the same individuals followed from childhood. The finding that escalating use specifically (not just any use) disrupts reward circuitry provides a more nuanced understanding of risk.","specificNumbers":"158 young men. Three trajectories: stable high, escalating, stable low. NAcc-mPFC connectivity effect: F=11.32, Z=4.04, p(FWE-corrected)<0.001. At age 22: negative connectivity correlated with depression (r=-0.17), anhedonia (r=-0.19), and lower education (t=-2.77).","methodology":"Longitudinal study from the Pitt Mother and Child Project, following male youth at high risk for psychopathology. 158 young men contributed fMRI data at age 20. Latent class growth analysis identified cannabis use trajectories from ages 14-19. Psychophysiological interaction analysis measured nucleus accumbens-prefrontal connectivity. Outcomes at age 22 included depression, anhedonia, and educational attainment.","limitations":"Male-only sample limits generalizability to women. High-risk sample (low-income families) may not represent all populations. Brain imaging at one time point cannot establish whether connectivity changes preceded cannabis use or resulted from it. Relatively small sample for trajectory analysis."},{"rthcId":"RTHC-01437","title":"The use of cannabis in supportive care and treatment of brain tumor.","authors":"Likar, Rudolf; Nahler, Gerhard","year":2017,"journal":"Neuro-oncology practice, 4(3), 151-160","doi":"10.1093/nop/npw027","pmid":"31385997","tags":["medical-cannabis","cancer","pain","cbd"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"This review examined the dual role of cannabinoids in brain tumor care: established palliative symptom management and emerging anti-tumor potential.\n\nFor palliative care, cannabinoids have documented roles in managing nausea, vomiting, pain, anxiety, and sleep disturbances in cancer patients. THC and nabilone also address anorexia and weight loss, while CBD has no appetite-stimulating effect but offers anxiolytic and antidepressant properties without psychoactive effects. Low-dose THC can improve mood.\n\nThe anti-tumor findings from animal glioma studies were striking. Relatively high doses of CBD and THC demonstrated significant tumor regression ranging from approximately 50% to 95%, with rare cases of complete tumor eradication. Adding radiation therapy (X-rays) or chemotherapy (temozolomide) enhanced the anti-tumor activity further. THC combined with CBD showed synergistic effects beyond either compound alone.\n\nThe authors concluded that while many questions remain about optimal treatment schedules, current evidence suggests cannabinoids could play an important role in brain tumor patient care.","whyItMatters":"Brain tumors, particularly gliomas, have among the worst prognoses of any cancer. Any treatment that could both improve quality of life through symptom management and potentially slow tumor growth represents a significant clinical opportunity.","specificNumbers":"Animal glioma studies showed 50-95% tumor volume regression with CBD and THC at high doses. Combination with temozolomide or radiation enhanced effects. THC+CBD showed synergistic anti-tumor activity.","methodology":"Narrative review of currently available cannabinoid preparations (dronabinol, CBD, nabiximols, nabilone), their palliative applications in brain tumor patients, and preclinical glioma studies examining anti-tumor effects.","limitations":"The impressive anti-tumor results are from animal studies with high cannabinoid doses that may not translate directly to human tumors. No large human clinical trials of cannabinoids as anti-tumor agents for brain tumors had been completed. Optimal dosing and treatment schedules for humans are unknown."},{"rthcId":"RTHC-01438","title":"The Endocannabinoid System and Anxiety.","authors":"Lisboa, S F; Gomes, F V; Terzian, A L B; Aguiar, D C; Moreira, F A; Resstel, L B M; Guimarães, F S","year":2017,"journal":"Vitamins and hormones, 103, 193-279","doi":"10.1016/bs.vh.2016.09.006","pmid":"28061971","tags":["anxiety","neuroscience","cbd"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This comprehensive chapter reviewed how the endocannabinoid system influences anxiety across both human anxiety disorders and animal models.\n\nThe system's effects on anxiety are remarkably complex. In specific brain areas including the prefrontal cortex, amygdala, bed nucleus of the stria terminalis, hippocampus, and periaqueductal gray, cannabinoid signaling can either increase or decrease anxiety depending on multiple factors.\n\nKey modulators include: which cannabinoid receptor is activated (CB1 vs. CB2 vs. TRPV1), which endocannabinoid is involved (anandamide vs. 2-AG), what the stress context is (acute vs. chronic stress), the dose administered, and which neurotransmitter systems are affected (GABA, glutamate, serotonin).\n\nThe review also covered how the endocannabinoid system interacts with the HPA (stress hormone) axis and the immune system to modulate anxiety, and discussed synaptic plasticity mechanisms through which chronic stress can remodel endocannabinoid signaling.","whyItMatters":"This review explains the fundamental paradox of cannabis and anxiety: why it can both relieve and worsen anxiety. By mapping the specific conditions under which endocannabinoid modulation produces anxiolytic versus anxiogenic effects, it provides the scientific foundation for developing targeted anxiety treatments.","specificNumbers":"Five brain regions reviewed in detail: medial prefrontal cortex, amygdaloid complex, bed nucleus of stria terminalis, hippocampus, and dorsal periaqueductal gray.","methodology":"Comprehensive review chapter covering recent advances in endocannabinoid-anxiety research in both humans and animal models, organized by brain region, receptor type, and mechanism.","limitations":"Much of the detailed mechanistic evidence comes from animal models. Translating region-specific and receptor-specific findings to human clinical applications remains challenging. The complexity of the system makes simple therapeutic predictions difficult."},{"rthcId":"RTHC-01439","title":"A Meta-analysis of the Effectiveness of Interactive Middle School Cannabis Prevention Programs.","authors":"Lize, Steven E; Iachini, Aidyn L; Tang, Weizhou; Tucker, Joshua; Seay, Kristen D; Clone, Stephanie; DeHart, Dana; Browne, Teri","year":2017,"journal":"Prevention science : the official journal of the Society for Prevention Research, 18(1), 50-60","doi":"10.1007/s11121-016-0723-7","pmid":"27785662","tags":["youth","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"This meta-analysis evaluated whether interactive (skill-building, participant-focused) drug prevention programs in middle schools reduced cannabis use among 12-14 year olds in North America.\n\nAcross 21 studies measuring cannabis use, the pooled effect size was small but statistically significant (d = -0.07, p < 0.01), favoring the prevention programs. This means interactive programs produced a modest reduction in cannabis use compared to control conditions.\n\nHowever, the programs did not significantly affect intention to use cannabis (3 studies) or refusal skills (3 studies), suggesting the behavioral change in cannabis use occurred through mechanisms other than changing attitudes or building refusal abilities.\n\nA key moderator finding was that teacher-delivered programs were significantly more effective (d = -0.08, p = 0.02) than programs delivered by other types of instructors. This suggests that the relationship between students and their regular teachers may enhance program effectiveness.","whyItMatters":"Schools invest substantial resources in drug prevention programs but the evidence for their effectiveness is often unclear. This meta-analysis provides quantitative evidence that interactive programs work, albeit modestly, and identifies teacher delivery as a key success factor.","specificNumbers":"30 studies, 23 independent samples. Cannabis use effect: d = -0.07 (p < 0.01). Intention to use: not significant (k=3). Refusal skills: not significant (k=3). Teacher-delivered programs: d = -0.08 (p = 0.02).","methodology":"Meta-analysis of 30 studies (23 independent samples) from January 1998 to March 2014. Included randomized and quasi-experimental evaluations of interactive school-based prevention programs for ages 12-14 in North American middle schools. Effect sizes (Cohen's d) calculated for cannabis use, intention to use, and refusal skills. Random effects models used.","limitations":"The effect size, while significant, is small. The small number of studies measuring intention to use and refusal skills limits conclusions about mechanisms. Publication bias could inflate the estimated effect. The review covers programs through 2014 and may not reflect newer approaches."},{"rthcId":"RTHC-01440","title":"Cannabinoid signaling in health and disease.","authors":"Lu, Yan; Anderson, Hope D","year":2017,"journal":"Canadian journal of physiology and pharmacology, 95(4), 311-327","doi":"10.1139/cjpp-2016-0346","pmid":"28263083","tags":["neuroscience","cardiovascular","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review provided a broad overview of the endocannabinoid system and its therapeutic potential, with particular attention to an emerging area: cardioprotection.\n\nThe endocannabinoid system is involved in a wide range of physiological processes, and several cannabinoids can be prescribed in Canada for conditions including nausea and pain. The review noted that beyond these established uses, an increasing number of reports suggest beneficial effects of endocannabinoid signaling for the cardiovascular system.\n\nHowever, the therapeutic potential of cannabinoids remains largely unrealized for two reasons. First, the mechanisms through which cannabinoids produce their effects are not fully understood. Second, pronounced psychoactive side effects have limited clinical development.\n\nThe review covered the basic components of the endocannabinoid system, known physiological roles, and the range of disease conditions in which cannabinoid receptor signaling has been implicated.","whyItMatters":"This review contextualizes the therapeutic potential of cannabinoids within the broader understanding of the endocannabinoid system, highlighting both the promise and the obstacles to clinical translation.","specificNumbers":"Several cannabinoids available by prescription in Canada for nausea and pain. The review covers multiple physiological systems but does not present original quantitative data.","methodology":"Review article providing an overview of the endocannabinoid system, its physiological roles, and conditions where cannabinoid signaling has therapeutic implications, with emphasis on cardioprotection.","limitations":"Broad overview that does not deeply analyze any single application. The cardioprotective evidence is described as emerging rather than established. Published from a Canadian perspective, regulatory context may differ in other countries."},{"rthcId":"RTHC-01441","title":"Medical cannabis access, use, and substitution for prescription opioids and other substances: A survey of authorized medical cannabis patients.","authors":"Lucas, Philippe; Walsh, Zach","year":2017,"journal":"The International journal on drug policy, 42, 30-35","doi":"10.1016/j.drugpo.2017.01.011","pmid":"28189912","tags":["medical-cannabis","pain","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This survey of 271 patients enrolled in Canada's medical cannabis program revealed widespread substitution of cannabis for other substances.\n\nThe headline finding: 63% of patients reported using cannabis as a substitute for prescription drugs. The most commonly substituted drug classes were pharmaceutical opioids (30%), benzodiazepines (16%), and antidepressants (12%). Patients also reported replacing alcohol (25%), tobacco (12%), and illicit drugs (3%).\n\nPain and mental health were the most prominent conditions for which patients found cannabis effective. The study was notable for being the first to match specific prescription drug substitution patterns to specific diagnostic categories.\n\nTwo policy-relevant findings emerged: 42% of authorized patients still purchased cannabis from illegal sources in addition to licensed producers, and over 55% were charged a fee to receive their medical recommendation, with nearly 25% paying $300 or more.","whyItMatters":"The opioid crisis makes any potential substitution effect of cannabis highly relevant. If medical cannabis patients are genuinely replacing opioids, benzodiazepines, and antidepressants, this has implications for prescribing patterns, public health policy, and insurance coverage.","specificNumbers":"271 respondents. 63% substituted cannabis for prescriptions. 30% replaced opioids. 16% replaced benzodiazepines. 12% replaced antidepressants. 25% replaced alcohol. 12% replaced tobacco. 42% still bought from illegal sources. 55% paid for medical recommendation.","methodology":"Online survey of 271 patients registered to purchase cannabis from Tilray, a federally authorized Licensed Producer under Canada's MMPR program. The 107-question survey covered demographics, patterns of use, and cannabis substitution effects.","limitations":"Self-reported data from a single licensed producer's patient base may not represent all medical cannabis users. Substitution is self-perceived and not verified by prescription records. The survey cannot determine whether patients achieved equivalent therapeutic outcomes with cannabis versus their previous medications."},{"rthcId":"RTHC-01442","title":"Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?","authors":"Maccarrone, Mauro; Maldonado, Rafael; Casas, Miguel; Henze, Thomas; Centonze, Diego","year":2017,"journal":"Expert review of clinical pharmacology, 10(4), 443-455","doi":"10.1080/17512433.2017.1292849","pmid":"28276775","tags":["medical-cannabis","pain","neuroscience","epilepsy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This expert review assessed the state of cannabinoid therapeutics roughly five years after THC/CBD oromucosal spray (Sativex) entered clinical practice for multiple sclerosis spasticity.\n\nFor MS spasticity, clinical trials confirmed the spray's efficacy and tolerability, establishing it as the most widely used prescription cannabinoid medicine internationally. The review noted that the complexity of the endocannabinoid system is becoming better understood, with new signaling mechanisms emerging.\n\nBeyond MS spasticity, the review cataloged active research into cannabinoids for various pain states, Alzheimer's disease, Parkinson's disease, Huntington's disease, and epilepsy. The authors emphasized that herbal cannabis contains many active ingredients, and individual cannabinoids have quite distinct biological activities requiring independent investigation.\n\nThe review called for continued characterization of individual cannabinoids in different diseases, noting that the therapeutic landscape is broader than any single cannabinoid product.","whyItMatters":"This review provides a practical checkpoint on cannabinoid medicine after real-world clinical experience. The confirmed efficacy of THC/CBD spray for MS spasticity validates the therapeutic approach, while the expanding research pipeline suggests many more applications may follow.","specificNumbers":"THC/CBD oromucosal spray: THC:CBD ratio of 1.08:1.00. Approximately five years of clinical use across numerous countries at time of publication. Active research in pain, Alzheimer's, Parkinson's, Huntington's, and epilepsy.","methodology":"Expert review of current data on the endocannabinoid system in relation to human diseases, focused on THC/CBD oromucosal spray as the primary clinical reference point and expanding to discuss potential future cannabinoid applications.","limitations":"Expert review rather than systematic analysis. The neurodegenerative disease applications are still investigational. The review focuses primarily on one product (Sativex) and may not fully represent the broader cannabinoid therapeutic landscape."},{"rthcId":"RTHC-01443","title":"System-specific activity in response to Δ9 -tetrahydrocannabinol: a functional magnetic resonance imaging study in awake male rats.","authors":"Madularu, Dan; Yee, Jason R; Kulkarni, Praveen; Ferris, Craig F","year":2017,"journal":"The European journal of neuroscience, 46(12), 2893-2900","doi":"10.1111/ejn.13754","pmid":"29057576","tags":["neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study produced the first functional MRI maps of THC effects in awake, drug-naive rats, avoiding the confounding effects of anesthesia used in most animal brain imaging studies.\n\nLow-dose THC produced more robust brain changes than high-dose THC, generating both increased and decreased BOLD (blood-oxygen-level dependent) signals. The strongest activations occurred in brain areas rich in CB1 cannabinoid receptors, the pain neural system, and the hippocampal system.\n\nThe low dose produced greater positive and negative BOLD signals compared to both vehicle (saline) and the high dose, which is consistent with the bell-shaped dose-response curve frequently observed with cannabinoids. The high dose may have produced receptor desensitization or different downstream signaling.\n\nThe resulting brain activation maps represent unique \"fingerprints\" of systemic THC administration that can be used for future comparisons between different doses, compounds, or administration routes.","whyItMatters":"Most previous brain imaging of cannabinoid effects used anesthetized animals, which fundamentally alters brain activity. By using awake rats, this study provides more translationally relevant data that can be compared to human cannabis brain imaging studies.","specificNumbers":"Two THC doses tested. Low dose produced greater BOLD signal changes than high dose. Activation concentrated in CB1-rich regions, pain circuits, and hippocampal networks.","methodology":"Functional MRI of awake male rats receiving intraperitoneal injections of low-dose THC, high-dose THC, or vehicle. BOLD signal changes were mapped across the brain to identify regions and neural systems responsive to THC.","limitations":"Rat brains differ from human brains in structure and receptor distribution. Intraperitoneal injection is not a typical human administration route. The study examined acute effects only. BOLD signal changes reflect blood flow, which is an indirect measure of neural activity."},{"rthcId":"RTHC-01444","title":"Effect of Marijuana Use on Thyroid Function and Autoimmunity.","authors":"Malhotra, Sonali; Heptulla, Rubina A; Homel, Peter; Motaghedi, Roja","year":2017,"journal":"Thyroid : official journal of the American Thyroid Association, 27(2), 167-173","doi":"10.1089/thy.2016.0197","pmid":"27799014","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007-2012, this study examined marijuana's effects on thyroid function in 5,280 adults aged 18-69.\n\nFifty-four percent of subjects reported lifetime cannabis use, with 15% having used recently (within 30 days). Recent marijuana users had a significantly lower frequency of elevated TSH (thyroid-stimulating hormone) and positive anti-thyroperoxidase antibodies (a marker of thyroid autoimmunity) compared to non-users and past users.\n\nAfter controlling for confounders, recent marijuana use remained an independent predictor of lower TSH levels (odds ratio 0.344 for TSH <5.6 microIU/mL, p = 0.04). However, the association with negative thyroid antibodies did not survive adjustment.\n\nImportantly, recent marijuana use was not associated with thyroid dysfunction, meaning marijuana users did not have abnormally overactive or underactive thyroids. The lower TSH levels stayed within normal range, suggesting a subtle modulatory effect rather than a disease-causing one.","whyItMatters":"With cannabis use becoming more prevalent, understanding its effects on organ systems beyond the brain is increasingly important. This large national study provides reassurance that marijuana use does not cause thyroid dysfunction while identifying a subtle hormonal signal that warrants monitoring.","specificNumbers":"5,280 adults. 54% lifetime use, 15% recent use. Recent users: OR 0.344 for TSH <5.6 (p = 0.04) after adjustment. No association with thyroid dysfunction or autoimmunity after adjustment.","methodology":"Cross-sectional analysis of NHANES data (2007-2012) including 5,280 adults ages 18-69 with marijuana use data and thyroid laboratory results. Subjects categorized as non-users, past users, and recent users. Univariate and multivariate logistic regression controlling for confounders.","limitations":"Cross-sectional design cannot establish causality. NHANES relies on self-reported marijuana use, which may underestimate true use. The study cannot distinguish between types, potency, or routes of cannabis use. TSH is a single snapshot that may not reflect chronic thyroid effects."},{"rthcId":"RTHC-01445","title":"Heavy cannabis use prior psychosis in schizophrenia: clinical, cognitive and neurological evidences for a new endophenotype?","authors":"Mallet, Jasmina; Ramoz, Nicolas; Le Strat, Yann; Gorwood, Philip; Dubertret, Caroline","year":2017,"journal":"European archives of psychiatry and clinical neuroscience, 267(7), 629-638","doi":"10.1007/s00406-017-0767-0","pmid":"28190094","tags":["psychosis","addiction","genetics","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This study compared 34 schizophrenia patients who reported heavy cannabis use before their first psychotic episode with 27 patients who did not.\n\nThe results were counterintuitive: heavy pre-psychosis cannabis users showed significantly fewer neurological soft signs (subtle neurological abnormalities considered markers of early neurodevelopmental impairment) and better cognitive functioning across multiple domains including reaction time, episodic memory, and visuoconstructive abilities.\n\nThese findings held after controlling for alcohol and tobacco use. Age and gender did not significantly differ between groups.\n\nThe authors interpreted this as evidence that heavy pre-psychosis cannabis use may define a distinct phenotype of schizophrenia. Rather than cannabis simply adding neurotoxic damage on top of existing vulnerability, the pattern suggests cannabis-associated psychosis may represent a different route to schizophrenia that involves less neurodevelopmental impairment but where cannabis provides the additional push toward illness.","whyItMatters":"This study challenges the simple narrative that cannabis damages the brain and causes psychosis. Instead, it suggests there may be at least two pathways to schizophrenia: one driven primarily by neurodevelopmental impairment and one where cannabis triggers psychosis in people with relatively intact neurodevelopment.","specificNumbers":"61 patients: 34 heavy pre-psychosis users, 27 non-heavy users. Heavy users showed significantly fewer neurological soft signs (p < 0.003) and better performance on reaction time (p = 0.03), episodic memory (p = 0.04), and visuoconstructive praxis (p = 0.03).","methodology":"Cross-sectional study of 61 schizophrenia patients (34 heavy pre-psychosis cannabis users, 27 non-heavy users) at a University Hospital and Medical Center. Assessment included the Diagnostic Interview for Genetic Studies, Neurological Evaluation Scale (neurological soft signs), PANSS (psychopathology), and a neurocognitive battery measuring attention, memory, and executive functions.","limitations":"Cross-sectional design cannot establish causality. Self-reported cannabis use before psychosis onset may be subject to recall bias. The sample size is relatively small. Patients with heavy cannabis use and better cognition may differ from non-users in unmeasured ways (intelligence, socioeconomic status)."},{"rthcId":"RTHC-01446","title":"Binding Site Characterization of AM1336, a Novel Covalent Inverse Agonist at Human Cannabinoid 2 Receptor, Using Mass Spectrometric Analysis.","authors":"Mallipeddi, Srikrishnan; Kreimer, Simion; Zvonok, Nikolai; Vemuri, Kiran; Karger, Barry L; Ivanov, Alexander R; Makriyannis, Alexandros","year":2017,"journal":"Journal of proteome research, 16(7), 2419-2428","doi":"10.1021/acs.jproteome.7b00023","pmid":"28374590","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01447","title":"Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets.","authors":"Mallipeddi, Srikrishnan; Janero, David R; Zvonok, Nikolai; Makriyannis, Alexandros","year":2017,"journal":"Biochemical pharmacology, 128, 1-11","doi":"10.1016/j.bcp.2016.11.014","pmid":"27890725","tags":["neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the concept of functional selectivity (biased agonism) at cannabinoid receptors, a phenomenon where different drugs binding to the same receptor can trigger different cellular responses.\n\nTraditionally, receptors were viewed as simple on/off switches. Functional selectivity reveals they are more like multi-channel dimmer switches: a drug can turn up one signaling pathway while leaving others unchanged or turning them down.\n\nChemically distinct classes of cannabinoid compounds show measurable signaling bias at CB1 and CB2 receptors, preferentially activating some pathways (like G-protein signaling) while not engaging others (like beta-arrestin recruitment). This selectivity appears to depend on both receptor structural features and ligand chemical properties.\n\nThe clinical significance is substantial: the adverse effects of conventional cannabinoid drugs (psychoactivity, tolerance, dependence) may be linked to specific signaling pathways. Designing drugs that avoid those pathways while activating therapeutic ones could produce safer cannabinoid medicines.","whyItMatters":"The clinical failure of several cannabinoid drugs (most notably rimonabant) was caused by engaging detrimental signaling pathways alongside therapeutic ones. Functional selectivity offers a solution: design drugs that activate only the beneficial pathways.","specificNumbers":"The review covers multiple signaling pathways including Gi/o protein coupling, beta-arrestin recruitment, MAPK/ERK, and intracellular calcium signaling at both CB1 and CB2 receptors.","methodology":"Review of known CB1 and CB2 signaling pathways, evidence for functional selectivity in response to endogenous and exogenous cannabinoid ligands, and structural features enabling pathway-selective receptor activation.","limitations":"Much functional selectivity data comes from in vitro cell-based assays that may not fully predict in vivo pharmacology. The relationship between specific signaling pathways and clinical outcomes is not yet fully mapped. Designing functionally selective drugs remains technically challenging."},{"rthcId":"RTHC-01448","title":"Adverse Structural and Functional Effects of Marijuana on the Brain: Evidence Reviewed.","authors":"Mandelbaum, David E; de la Monte, Suzanne M","year":2017,"journal":"Pediatric neurology, 66, 12-20","doi":"10.1016/j.pediatrneurol.2016.09.004","pmid":"27789118","tags":["cognition","neuroscience","psychosis","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This critical review focused specifically on evidence for structural and functional brain damage from cannabis, combined with neuropathological findings from a fatal case of cannabis-induced psychosis.\n\nThe literature review found strong evidence that chronic cannabis abuse causes cognitive impairment and brain damage, particularly to white matter (the brain's communication cables), where CB1 cannabinoid receptors are abundant.\n\nThe fatal case provided direct neuropathological evidence of white matter damage in a person who died from cannabis-induced psychosis, complementing the imaging-based evidence from living subjects.\n\nRegarding therapeutic claims, the review concluded that contrary to popular perception, there are few objective data supporting preferential use of cannabis over conventional therapy for neurological conditions such as multiple sclerosis, epilepsy, or schizophrenia. While cannabis may have symptom-management roles, claims that it restores brain structure and function lack evidence.","whyItMatters":"This review provides a counterpoint to the growing narrative that cannabis is broadly therapeutic for the brain. By combining literature review with direct pathological evidence, it makes a strong case for cannabis as neurotoxic to white matter, particularly with chronic use.","specificNumbers":"CB1 receptors are particularly abundant in white matter. The case report demonstrated neuropathological findings in a fatal cannabis-induced psychosis case.","methodology":"Critical review of evidence-based research on cannabis brain effects combined with a neuropathological case report of fatal cannabis-induced psychosis. The review assessed both therapeutic claims and harmful effects.","limitations":"A single case report cannot prove general causation. The review takes a critical stance that may emphasize harmful evidence over beneficial evidence. Some cannabis brain effects may be reversible with abstinence. The review does not quantify dose-response relationships."},{"rthcId":"RTHC-01449","title":"Cannabis use, COMT, BDNF and age at first-episode psychosis.","authors":"Mané, Anna; Bergé, Daniel; Penzol, Maria Jose; Parellada, Mara; Bioque, Miquel; Lobo, Antonio; González-Pinto, Ana; Corripio, Iluminada; Cabrera, Bibiana; Sánchez-Torres, Ana Maria; Saiz-Ruiz, Jerónimo; Bernardo, Miguel","year":2017,"journal":"Psychiatry research, 250, 38-43","doi":"10.1016/j.psychres.2017.01.045","pmid":"28142064","tags":["psychosis","genetics","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This study investigated whether cannabis use and two genes (COMT Val158Met and BDNF Val66Met) interact to influence when psychosis first appears.\n\nAmong 260 Caucasian first-episode psychosis patients, two factors independently predicted younger age at psychosis onset: early cannabis use and carrying the met-allele of the BDNF Val66Met polymorphism.\n\nThe BDNF finding is significant because BDNF (brain-derived neurotrophic factor) is critical for brain development and neural plasticity. The met variant reduces BDNF secretion, which could make the developing brain more vulnerable to environmental insults like cannabis.\n\nThe COMT gene variant, which has been extensively studied in relation to cannabis and psychosis, did not significantly predict age of onset in this sample.\n\nNotably, early cannabis use was significantly associated with male gender, consistent with the well-documented pattern of earlier and heavier cannabis use among males. This sex-specific pattern may contribute to the earlier psychosis onset often seen in men.","whyItMatters":"This study identifies a specific gene-environment interaction that influences when psychosis appears. If BDNF met-carriers are more vulnerable to cannabis-induced acceleration of psychosis, this could enable genetic risk stratification for cannabis use.","specificNumbers":"260 first-episode psychosis patients. Early cannabis use and BDNF met-allele independently predicted younger age at psychosis onset. Early cannabis use significantly associated with male gender. COMT was not significant.","methodology":"Cross-sectional study of 260 Caucasian first-episode psychosis patients. COMT Val158Met and BDNF Val66Met polymorphisms were genotyped. Early cannabis use, demographics, and age at psychosis onset were assessed. Logistic regression analyzed factors associated with early cannabis use and age at onset.","limitations":"Cross-sectional design cannot prove the BDNF variant and cannabis cause earlier psychosis rather than correlating with other factors. The study included only Caucasian patients, limiting ethnic generalizability. Cannabis potency and frequency were not detailed. The sample size may be underpowered for detecting gene-gene interactions."},{"rthcId":"RTHC-01450","title":"No significant effect of cannabis use on the count and percentage of circulating CD4 T-cells in HIV-HCV co-infected patients (ANRS CO13-HEPAVIH French cohort).","authors":"Marcellin, Fabienne; Lions, Caroline; Rosenthal, Eric; Roux, Perrine; Sogni, Philippe; Wittkop, Linda; Protopopescu, Camelia; Spire, Bruno; Salmon-Ceron, Dominique; Dabis, François; Carrieri, Maria Patrizia","year":2017,"journal":"Drug and alcohol review, 36(2), 227-238","doi":"10.1111/dar.12398","pmid":"27073179","tags":["medical-cannabis","inflammation"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This large longitudinal study examined whether cannabis use affects the most important immune marker in HIV management, the CD4 T-cell count, in patients co-infected with both HIV and hepatitis C.\n\nAmong 955 patients followed over multiple visits (2,386 total visits), cannabis use was remarkably common: 48% reported use in the preceding four weeks. Of cannabis users, 58% also smoked 10 or more tobacco cigarettes daily.\n\nAfter multiple statistical adjustments, cannabis use was not significantly associated with either CD4 T-cell count or CD4 T-cell percentage. Sensitivity analyses excluding tobacco users and heavy smokers confirmed the null finding.\n\nThis is clinically important because HIV-HCV co-infected patients often use cannabis for symptom management, and concerns about immunosuppression could theoretically limit its use in this already immunocompromised population.","whyItMatters":"HIV-HCV co-infected patients already face compromised immune function. If cannabis further reduced CD4 counts, it could accelerate disease progression. This study provides evidence-based reassurance that cannabis use does not measurably harm this critical immune parameter.","specificNumbers":"955 patients, 2,386 visits. 48% reported cannabis use. Cannabis use coefficient for CD4 count: 0.27 (95% CI -0.07 to 0.62, p=0.12). Cannabis use coefficient for CD4 percentage: -0.04 (95% CI -0.45 to 0.36, p=0.83).","methodology":"Longitudinal analysis of the ANRS CO13-HEPAVIH French cohort. Cannabis use assessed via annual self-administered questionnaires in 955 patients (2,386 visits). CD4 T-cell count and percentage analyzed using multivariate linear regression with generalized estimating equations. Sensitivity analyses excluded tobacco users.","limitations":"CD4 count and percentage are crude measures of immune function that do not capture cell functionality. Self-reported cannabis use may be inaccurate. The study did not assess cannabis dose, type, or administration route. All patients were on antiretroviral therapy, which itself maintains CD4 counts."},{"rthcId":"RTHC-01451","title":"A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity.","authors":"Marinelli, Lucio; Balestrino, Maurizio; Mori, Laura; Puce, Luca; Rosa, Gian Marco; Giorello, Laura; Currà, Antonio; Fattapposta, Francesco; Serrati, Carlo; Gandolfo, Carlo; Abbruzzese, Giovanni; Trompetto, Carlo","year":2017,"journal":"BMJ open, 7(9), e016843","doi":"10.1136/bmjopen-2017-016843","pmid":"28882919","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01452","title":"Trends of Youth Marijuana Treatment Admissions: Increasing Admissions Contrasted with Decreasing Drug Involvement.","authors":"Marzell, Miesha; Sahker, Ethan; Arndt, Stephan","year":2017,"journal":"Substance use & misuse, 52(13), 1778-1783","doi":"10.1080/10826084.2017.1311349","pmid":"28704115","tags":["youth","addiction","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This study examined national trends in youth marijuana treatment admissions from 1995 to 2012 using over 12 million treatment records.\n\nTwo divergent trends emerged: the number of youth admitted to substance abuse treatment for marijuana steadily increased, while the degree of drug involvement (severity of use) among those admitted dramatically dropped over nearly two decades.\n\nThe increasing admissions were largely youth in dependent living situations (living with parents), suggesting many were referred by parents, schools, or courts rather than seeking treatment voluntarily for severe problems.\n\nThe decreasing severity suggests that changing perceptions and policies around marijuana may have lowered the threshold for treatment referral. Youth who would not have been referred to treatment in earlier years were now entering the treatment system, even though their level of marijuana involvement was less severe.","whyItMatters":"This study reframes the narrative around increasing youth marijuana treatment admissions. Rather than indicating worsening marijuana problems among youth, the trend may reflect lower tolerance for marijuana use by schools, parents, and courts, resulting in treatment referrals for less severe use.","specificNumbers":"Over 12 million treatment admissions analyzed from 1995 to 2012. Increasing admissions of youth in dependent living (with parents). Dramatic decrease in drug involvement severity over 18 years.","methodology":"Analysis of first-time substance abuse treatment admissions among youth using the Treatment Episode Data Set-Admissions (TEDS-A) from SAMHSA (N = 12,025,787). Chi-squared analysis examined differences between admission years, and binomial logistic regression examined trends from 1995 to 2012.","limitations":"Administrative treatment data does not capture clinical outcomes. Changes in referral patterns, funding, and available treatment programs over 18 years confound interpretation. The study cannot determine whether early intervention for mild use prevents escalation."},{"rthcId":"RTHC-01453","title":"A brief report on Hispanic youth marijuana use: Trends in substance abuse treatment admissions in the United States.","authors":"Marzell, Miesha; Sahker, Ethan; Pro, George; Arndt, Stephan","year":2017,"journal":"Journal of ethnicity in substance abuse, 16(2), 155-164","doi":"10.1080/15332640.2015.1108256","pmid":"26822474","tags":["youth","addiction","legalization"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study tracked trends in Hispanic youth substance abuse treatment admissions for marijuana from 1995 to 2012 using national treatment data.\n\nHispanic youth marijuana admissions were associated with typical adolescent profiles: ages 15-17, in high school, and living in dependent situations (with parents or guardians).\n\nA notable finding was that female Hispanic youth admissions increased at greater rates than male admissions over the study period. This gender shift suggests changing patterns in how marijuana use among Hispanic girls is detected and referred to treatment.\n\nThe results pointed to decreasing tolerance of minor marijuana use by schools and community agencies as a driver of admissions, rather than increasing severity of marijuana problems. This mirrors the broader youth trend of more admissions but less severe drug involvement.","whyItMatters":"Hispanic youth are an underrepresented group in substance use research. The faster growth in female admissions highlights a potential gap in culturally specific prevention and treatment services for Hispanic girls.","specificNumbers":"Data from 1995 to 2012. Admissions associated with ages 15-17, high school enrollment, dependent living. Female admissions increased at greater rates than male.","methodology":"Analysis of national Treatment Episode Data Set-Admissions (TEDS-A) from SAMHSA examining Hispanic youth marijuana admissions from 1995 to 2012.","limitations":"Administrative data cannot capture cultural context, treatment outcomes, or whether treatment was appropriate for the severity level. Hispanic youth are a heterogeneous group encompassing many national origins and acculturation levels. Referral patterns may reflect institutional biases rather than actual use patterns."},{"rthcId":"RTHC-01454","title":"Differential effects of cannabinoid CB1 inverse agonists and antagonists on impulsivity in male Sprague Dawley rats: identification of a possibly clinically relevant vulnerability involving the serotonin 5HT1A receptor.","authors":"McLaughlin, Peter J; Jagielo-Miller, Julia E; Plyler, Emily S; Schutte, Kerry K; Vemuri, V Kiran; Makriyannis, Alexandros","year":2017,"journal":"Psychopharmacology, 234(6), 1029-1043","doi":"10.1007/s00213-017-4548-2","pmid":"28144708","tags":["neuroscience","mental-health","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 receptor inverse agonists like rimonabant showed promise as appetite suppressants but were withdrawn because they produced suicidal behavior in a small subpopulation during clinical trials. This study investigated why only some individuals were affected.\n\nThe researchers found that the CB1 inverse agonist AM 251 produced impulsivity in rats only when the serotonin 5HT1A receptor was simultaneously blocked. Without serotonin disruption, the CB1 blocker alone did not cause impulsive behavior.\n\nImportantly, a neutral CB1 antagonist (AM 6527, which blocks without inverse agonism) did not produce impulsivity even with serotonin disruption. A peripherally restricted CB1 antagonist (AM 6545, which does not enter the brain) also had no effect.\n\nThese findings suggest that the suicidal side effects of rimonabant may have occurred specifically in people who already had compromised serotonin signaling, and that neutral CB1 antagonists (rather than inverse agonists) may be safer alternatives.","whyItMatters":"Rimonabant's withdrawal was a major setback for cannabinoid-based obesity medicine. Understanding that the dangerous side effects required pre-existing serotonin vulnerability opens a path forward: either screening patients for serotonin risk or using neutral antagonists instead of inverse agonists.","specificNumbers":"AM 251 (inverse agonist) + WAY (5HT1A antagonist) produced impulsivity on both tasks. AM 6527 (neutral antagonist) + WAY showed mild effects on one task only. AM 6545 (peripheral) had no effects.","methodology":"Male Sprague Dawley rats were tested on two behavioral tasks measuring impulsivity (paced fixed consecutive number task and a novel variable consecutive number task) after receiving CB1 inverse agonist, antagonist, or peripherally restricted antagonist, with or without the serotonin 5HT1A antagonist WAY 100,635.","limitations":"Animal model of impulsivity may not fully capture human suicidal ideation. The serotonin blockade was pharmacologically induced rather than representing natural variation. Only male rats were tested."},{"rthcId":"RTHC-01455","title":"Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis.","authors":"Meng, Howard; Johnston, Bradley; Englesakis, Marina; Moulin, Dwight E; Bhatia, Anuj","year":2017,"journal":"Anesthesia and analgesia, 125(5), 1638-1652","doi":"10.1213/ANE.0000000000002110","pmid":"28537982","tags":["pain","medical-cannabis","cbd"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"This systematic review and meta-analysis addressed the conflicting recommendations from pain societies about cannabinoids for neuropathic pain.\n\nAcross 11 RCTs including 1,219 patients, selective cannabinoids (dronabinol, nabilone, nabiximols) produced a statistically significant reduction in pain scores compared to placebo or conventional treatment: -0.65 points on a 0-10 scale. While statistically significant, this was considered clinically small.\n\nBeyond pain scores, cannabinoid use was associated with improvements in quality of life and sleep, and no major adverse effects were reported. The evidence was graded as moderate quality with a weak recommendation using the GRADE approach.\n\nThe heterogeneity across studies was high (I-squared = 60%), reflecting variability in the etiology of neuropathic pain, types and doses of cannabinoids used, and study quality.","whyItMatters":"National and international pain societies have given contradictory recommendations about cannabinoids for neuropathic pain. This meta-analysis provides a quantitative answer: there is a real but small benefit, supporting cannabinoids as an option but not a first-line treatment.","specificNumbers":"11 RCTs, 1,219 patients (614 cannabinoid, 605 comparator). Pain reduction: -0.65 points on 0-10 NRS (95% CI -1.06 to -0.23, p=0.002). I-squared: 60%. GRADE: weak recommendation, moderate-quality evidence.","methodology":"Systematic review and meta-analysis of RCTs comparing selective cannabinoids (dronabinol, nabilone, nabiximols) with conventional treatments or placebo for chronic neuropathic pain. Searched MEDLINE, EMBASE, and other databases through March 2016. GRADE approach used for evidence certainty.","limitations":"High heterogeneity across studies. The effect size is small and may not be clinically meaningful for all patients. Studies varied in cannabinoid type, dose, and neuropathic pain etiology. The search ended March 2016 and newer trials are not included."},{"rthcId":"RTHC-01456","title":"Cannabis and alcohol use, and the developing brain.","authors":"Meruelo, A D; Castro, N; Cota, C I; Tapert, S F","year":2017,"journal":"Behavioural brain research, 325(Pt A), 44-50","doi":"10.1016/j.bbr.2017.02.025","pmid":"28223098","tags":["youth","cognition","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined how cannabis and alcohol affect the adolescent brain during a period when white and grey matter are still maturing and sex hormones are driving structural changes.\n\nNeuroimaging studies revealed differences in brain development between substance-using and non-using adolescents, including altered white matter myelination and grey matter volumes. The effects appeared related to the ongoing developmental processes that cannabis and alcohol disrupt.\n\nAn important distinction emerged: some associations between substance use and brain differences appeared to resolve after short-term abstinence, suggesting they may be temporary pharmacological effects. However, attentional deficits appeared to persist even after abstinence, suggesting more lasting impact on attention-related brain circuitry.\n\nThe review also noted sexually dimorphic features in brain development, suggesting that cannabis and alcohol may affect male and female adolescent brains differently.","whyItMatters":"Understanding which effects are temporary versus persistent helps prioritize prevention messages and guide clinical decisions. The finding that attentional deficits persist while other deficits may resolve suggests attention systems are particularly vulnerable during adolescent development.","specificNumbers":"The review synthesizes neuroimaging and neuropsychological data but does not report pooled statistics.","methodology":"Review of neuropsychological and neuroimaging studies examining the effects of cannabis and alcohol on adolescent brain development, including structural MRI, functional MRI, and neurocognitive assessment data.","limitations":"Review does not present systematic methodology or quality assessment. Most neuroimaging studies are cross-sectional, making it difficult to separate pre-existing differences from substance-caused changes. The combined review of cannabis and alcohol may obscure substance-specific effects."},{"rthcId":"RTHC-01457","title":"Development and initial validation of a marijuana cessation expectancies questionnaire.","authors":"Metrik, Jane; Farris, Samantha G; Aston, Elizabeth R; Kahler, Christopher W","year":2017,"journal":"Drug and alcohol dependence, 177, 163-170","doi":"10.1016/j.drugalcdep.2017.04.005","pmid":"28600928","tags":["quitting","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This study developed and validated the Marijuana Cessation Expectancies Questionnaire (MCEQ), the first tool specifically designed to measure what regular cannabis users expect to happen if they quit or reduce their use.\n\nSix distinct expectation factors emerged from the analysis of 151 regular marijuana users. Three were positive expectations: improved performance/motivation, fewer problems with authority, and better interpersonal functioning. Three were negative expectations: worsened mood states, less fun experiences, and changes in appetite/weight.\n\nThe MCEQ showed good internal consistency and strong concurrent validity with existing measures. Importantly, it predicted actual change behavior: users' cessation expectations were associated with whether they had previously attempted to quit, how much benefit they saw in reducing use, and how important they rated making a change.\n\nThe tool provides insights beyond traditional use expectancies (why people use) by capturing cessation expectancies (what they think will happen when they stop).","whyItMatters":"Understanding what people expect from quitting is clinically valuable because expectations influence behavior. If a user expects only negative outcomes from cessation, they are less likely to attempt it. This tool helps clinicians identify and address specific beliefs that may be barriers to change.","specificNumbers":"46 items, 6 factors, 61% variance explained. Internal consistency: alpha = 0.86 (full scale), 0.60-0.89 (subscales). 151 regular users averaging use on 64.7% of past 60 days.","methodology":"Two-phase development: content validity analysis from free responses of 94 participants to generate items, followed by administration of the 46-item questionnaire to 151 non-treatment-seeking regular marijuana users (average use on 64.7% of past 60 days). Exploratory factor analysis identified six factors accounting for 61% of variance.","limitations":"Non-treatment-seeking sample may not represent those most in need of cessation support. Cross-sectional validation does not confirm the tool predicts actual cessation outcomes over time. The sample was relatively young (mean age 21.4) and may not represent older users."},{"rthcId":"RTHC-01458","title":"The Influence of College Attendance on Risk for Marijuana Initiation in the United States: 1977 to 2015.","authors":"Miech, Richard A; Patrick, Megan E; O'Malley, Patrick M; Johnston, Lloyd D","year":2017,"journal":"American journal of public health, 107(6), 996-1002","doi":"10.2105/AJPH.2017.303745","pmid":"28426314","tags":["youth","addiction","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Using Monitoring the Future data tracking nationally representative cohorts from 1977 to 2015, this study examined college attendance as a risk factor for marijuana initiation among people who had never used marijuana by 12th grade.\n\nFor decades (1977-2012), college enrollment was associated with a modest 17-22% increased probability of starting marijuana use compared to non-college peers. But starting in 2013, this increased dramatically.\n\nBy 2013, the increased probability was 31%. By 2014, it was 41%. By 2015, college students who had never used marijuana by high school graduation were 51% more likely to start using than their non-college peers.\n\nThe year 2013 was identified as a watershed for increasing tolerance of marijuana use in the United States, coinciding with the implementation of recreational legalization in Colorado and Washington.","whyItMatters":"This reversal of the historical pattern, where college was only a modest risk factor, into a major risk factor for marijuana initiation signals a significant shift in the college environment. If this trend continues, colleges may need to develop new prevention and intervention programs.","specificNumbers":"Increased probability of past-year marijuana use for college vs. non-college: 17-22% average from 1977-2012. Then: 31% in 2013, 41% in 2014, 51% in 2015.","methodology":"Longitudinal panels from the Monitoring the Future study, following nationally representative 12th-grade samples from 1976 onward. Panel members aged 19-22 who had never used marijuana by 12th grade were analyzed for marijuana initiation. College enrollment status was assessed.","limitations":"The study cannot establish causation between legalization and increased college marijuana initiation. Other cultural factors (social media, changing attitudes) occurred simultaneously. The analysis focuses on initiation, not problematic use or outcomes. Data end in 2015 and patterns may have continued to evolve."},{"rthcId":"RTHC-01459","title":"Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia.","authors":"Mori, Marco Aurélio; Meyer, Erika; Soares, Ligia Mendes; Milani, Humberto; Guimarães, Francisco Silveira; de Oliveira, Rúbia Maria Weffort","year":2017,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 75, 94-105","doi":"10.1016/j.pnpbp.2016.11.005","pmid":"27889412","tags":["cbd","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study investigated CBD's effects on brain damage from blood flow restriction (ischemia) in mice, modeling what happens during a stroke.\n\nMice with induced brain ischemia developed long-lasting deficits: increased anxiety (day 9), memory impairment (days 12-18), and despair-like behavior (day 21). Short-term treatment with CBD at 10 mg/kg prevented all three types of impairment.\n\nCBD's neuroprotective effects operated through multiple mechanisms simultaneously. It reduced hippocampal neurodegeneration (preventing neuron death), decreased white matter injury, and suppressed the inflammatory glial cell response. CBD also increased hippocampal BDNF protein levels, a growth factor critical for brain repair.\n\nPerhaps most remarkably, CBD stimulated neurogenesis (birth of new brain cells) and promoted dendritic restructuring (regrowth of neuronal connections) in the hippocampus of ischemic animals, suggesting active brain repair rather than just damage prevention.","whyItMatters":"Stroke is a leading cause of disability worldwide with limited treatment options after the acute window. CBD's ability to both prevent damage and promote active brain repair through multiple mechanisms makes it an unusually promising candidate for post-stroke treatment.","specificNumbers":"CBD dose: 10 mg/kg. Behavioral deficits prevented: anxiety (day 9), memory impairment (days 12-18), despair behavior (day 21). CBD increased BDNF levels, stimulated neurogenesis, and promoted dendritic restructuring.","methodology":"Mice underwent bilateral common carotid artery occlusion (BCCAO) to model brain ischemia. CBD (10 mg/kg) was administered short-term. Multi-tiered behavioral testing over 21 days assessed anxiety, memory, and despair-like behavior. Histological analysis evaluated neurodegeneration, white matter injury, glial response, BDNF levels, neurogenesis, and dendritic structure.","limitations":"Mouse model of ischemia does not perfectly replicate human stroke. CBD was administered as treatment after the ischemic event but timing details may not translate to clinical practice. A single dose was tested. Long-term outcomes beyond 21 days were not assessed."},{"rthcId":"RTHC-01460","title":"The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.","authors":"Murillo-Rodriguez, Eric; Pastrana-Trejo, Jose Carlos; Salas-Crisóstomo, Mireille; de-la-Cruz, Miriel","year":2017,"journal":"CNS & neurological disorders drug targets, 16(4), 370-379","doi":"10.2174/1871527316666170223161908","pmid":"28240187","tags":["sleep","neuroscience","ptsd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review proposed a novel hypothesis: that the endocannabinoid system influences dream activity.\n\nThe reasoning builds on established evidence that the endocannabinoid system modulates multiple processes integral to dreaming: consciousness, learning and memory, attention, pain perception, emotions, and the sleep-wake cycle itself. Blocking CB1 receptors or inhibiting FAAH activity affects wakefulness, while blocking anandamide transport enhances sleep.\n\nPreliminary clinical evidence supports the hypothesis. Treatment with cannabinoids has been reported to decrease PTSD symptoms, including nightmares, suggesting direct modulation of dream content.\n\nThe review proposed a conceptual framework for understanding how the endocannabinoid system might influence the generation of dream experiences, integrating evidence from human and animal models on emotional states, sleep architecture, and consciousness.","whyItMatters":"If the endocannabinoid system modulates dream content, it could explain why cannabis users often report reduced dreaming and why PTSD patients sometimes find relief from nightmares with cannabinoids. Understanding this connection could lead to targeted treatments for trauma-related sleep disturbances.","specificNumbers":"The review cites preliminary PTSD studies showing cannabinoid-related nightmare reduction but does not report specific pooled statistics.","methodology":"Literature review of PubMed sources examining the endocannabinoid system's role in consciousness, emotions, sleep, and dream activity. Proposes a conceptual framework linking these functions.","limitations":"The dream modulation hypothesis is largely theoretical and has not been directly tested. The mechanisms linking endocannabinoid signaling to dream content remain speculative. PTSD nightmare reduction could work through anxiety reduction rather than direct dream modulation."},{"rthcId":"RTHC-01461","title":"Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation.","authors":"Murillo-Rodríguez, Eric; Di Marzo, Vincenzo; Machado, Sergio; Rocha, Nuno B; Veras, André B; Neto, Geraldo A M; Budde, Henning; Arias-Carrión, Oscar; Arankowsky-Sandoval, Gloria","year":2017,"journal":"Frontiers in molecular neuroscience, 10, 152","doi":"10.3389/fnmol.2017.00152","pmid":"28611585","tags":["sleep","neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study demonstrated that AA-5-HT, a dual FAAH inhibitor and TRPV1 blocker, is a potent sleep modulator in rats.\n\nWhen injected during the dark (active) period, AA-5-HT decreased wakefulness and increased both slow wave sleep and REM sleep in a dose-dependent manner. Interestingly, the same doses had no effect during the light (rest) period, when rats naturally sleep more.\n\nAA-5-HT also blocked the wake-promoting effects of two stimulants: CBD and modafinil. When rats were given CBD or modafinil during their normal sleep period, AA-5-HT prevented the resulting increase in wakefulness and allowed normal sleep to occur.\n\nIn sleep homeostasis experiments, CBD and modafinil prevented normal sleep rebound after total sleep deprivation. AA-5-HT blocked this effect, allowing proper sleep recovery. AA-5-HT also reduced wake-related neurotransmitters (dopamine, norepinephrine, epinephrine, serotonin) while increasing adenosine, a key sleep-promoting molecule.","whyItMatters":"This study identifies AA-5-HT as a sleep-promoting agent that works through the endocannabinoid system. Its ability to enhance sleep specifically during active periods (without over-sedating during rest) and to restore sleep homeostasis after deprivation suggests therapeutic potential for insomnia.","specificNumbers":"Three doses: 5, 10, 20 mg/kg. Effects seen only during dark period. AA-5-HT decreased dopamine, norepinephrine, epinephrine, serotonin and increased adenosine. Blocked wake-promoting effects of both CBD and modafinil.","methodology":"Rats received AA-5-HT (5, 10, or 20 mg/kg i.p.) during lights-on or lights-off periods. Sleep-wake states were recorded via EEG/EMG. Power spectral analysis assessed sleep quality. Neurotransmitter levels were measured. Interactions with CBD and modafinil were tested during both normal conditions and after total sleep deprivation.","limitations":"Animal study with intraperitoneal injection, not a clinically viable route. The interaction between AA-5-HT and CBD/modafinil is complex and may not translate directly to human pharmacology. Sleep architecture differs between rats and humans."},{"rthcId":"RTHC-01462","title":"Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn's Disease, a Randomized Controlled Trial.","authors":"Naftali, Timna; Mechulam, Refael; Marii, Amir; Gabay, Gila; Stein, Asaf; Bronshtain, Miriam; Laish, Ido; Benjaminov, Fabiana; Konikoff, Fred M","year":2017,"journal":"Digestive diseases and sciences, 62(6), 1615-1620","doi":"10.1007/s10620-017-4540-z","pmid":"28349233","tags":["cbd","inflammation","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This randomized, placebo-controlled trial tested oral CBD (10 mg twice daily) in 20 patients with moderately active Crohn's disease who had not responded to standard treatments.\n\nAfter 8 weeks of treatment, both the CBD and placebo groups showed similar improvements in disease activity (CDAI decreased from 337 to 220 in CBD group vs. 308 to 216 in placebo), with no statistically significant difference between them.\n\nCBD was safe: no side effects were observed, and liver function, kidney function, hemoglobin, and albumin all remained unchanged.\n\nThe authors acknowledged several possible explanations for the null result: CBD may genuinely not help Crohn's disease, or the dose may have been too low, the sample too small, or the lack of synergism with other cannabinoids (like THC) may have limited effectiveness.","whyItMatters":"This is one of the few randomized controlled trials testing CBD specifically (without THC) for inflammatory bowel disease. The null result at low dose is important because it tempers the enthusiasm generated by preclinical studies showing CBD's anti-inflammatory effects.","specificNumbers":"20 patients (19 completed). CDAI before: 337 vs. 308 (CBD vs. placebo). CDAI after 8 weeks: 220 vs. 216 (p = NS). CBD dose: 10 mg twice daily. No side effects.","methodology":"Randomized, placebo-controlled trial of 20 patients aged 18-75 with CDAI >200 (moderately active Crohn's). Oral CBD 10 mg or placebo twice daily for 8 weeks plus 2 weeks follow-up. Patients had failed standard treatments (steroids, thiopurines, TNF antagonists). ClinicalTrials.gov: NCT01037322.","limitations":"Very small sample (20 patients). Very low CBD dose (10 mg BID, far below doses used in epilepsy trials of 10-20 mg/kg/day). No THC component, which may be necessary for entourage effects. Short treatment duration."},{"rthcId":"RTHC-01463","title":"Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts.","authors":"Nallathambi, Rameshprabu; Mazuz, Moran; Ion, Aurel; Selvaraj, Gopinath; Weininger, Smadar; Fridlender, Marcelo; Nasser, Ahmad; Sagee, Oded; Kumari, Puja; Nemichenizer, Diana; Mendelovitz, Maayan; Firstein, Nave; Hanin, Orly; Konikoff, Fred; Kapulnik, Yoram; Naftali, Timna; Koltai, Hinanit","year":2017,"journal":"Cannabis and cannabinoid research, 2(1), 167-182","doi":"10.1089/can.2017.0027","pmid":"29082314","tags":["inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study systematically characterized which components of cannabis extracts produce anti-inflammatory effects in colon models relevant to inflammatory bowel disease.\n\nThe anti-inflammatory activity was traced to a specific fraction containing delta-9-tetrahydrocannabinolic acid (THCA), the raw precursor to THC found in unheated cannabis. THCA reduced interleukin-8 (a key inflammatory marker) in both colon cell lines and in tissue biopsies from IBD patients.\n\nThe effects were mediated at least partially through the GPR55 receptor, not the classical CB1 or CB2 cannabinoid receptors. A GPR55 antagonist significantly reduced the anti-inflammatory activity, while a CB2 antagonist affected cell proliferation rather than inflammation.\n\nCBD showed a different pattern: it had dose-dependent cytotoxic (cell-killing) activity, but its anti-inflammatory activity occurred only at low concentrations and in a bell-shaped manner (effective at low doses, ineffective at higher ones).\n\nThe authors concluded that for non-psychoactive IBD treatment, THCA should be preferred over CBD.","whyItMatters":"This study redirects the focus of cannabis-based IBD therapy from CBD (which showed limited anti-inflammatory activity) to THCA (which was highly effective). Since THCA is non-psychoactive (it has not been heated/decarboxylated into THC), it could provide anti-inflammatory benefits without the high.","specificNumbers":"THCA in fraction 7 was the primary anti-inflammatory component. GPR55 antagonist significantly reduced anti-inflammatory activity. CBD showed bell-shaped anti-inflammatory response (effective only at low concentrations). Results confirmed in IBD patient tissue biopsies.","methodology":"Cannabis flowers were extracted with ethanol and fractionated. Anti-inflammatory activity was tested on three epithelial cell lines and colon tissue biopsies from IBD patients. Chemical analysis used HPLC, mass spectrometry, and NMR. Gene expression of COX2 and MMP9 was measured by qRT-PCR. Receptor involvement was tested using specific antagonists.","limitations":"In vitro and ex vivo study; clinical effects in patients have not been tested. The extract fractionation process may not reflect whole-plant cannabis effects. THCA stability (it converts to THC with heat) creates formulation challenges for clinical use."},{"rthcId":"RTHC-01464","title":"Genetic and Environmental Contributions to the Association Between Cannabis Use and Psychotic-Like Experiences in Young Adult Twins.","authors":"Nesvåg, Ragnar; Reichborn-Kjennerud, Ted; Gillespie, Nathan A; Knudsen, Gun Peggy; Bramness, Jørgen G; Kendler, Kenneth S; Ystrom, Eivind","year":2017,"journal":"Schizophrenia bulletin, 43(3), 644-653","doi":"10.1093/schbul/sbw101","pmid":"27431873","tags":["psychosis","genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"This twin study of 2,793 young adults disentangled the genetic and environmental contributions to the cannabis-psychosis relationship.\n\nCannabis use disorder symptoms were strongly associated with psychotic-like experiences, with an incidence rate ratio of 6.3. Within twin pairs (controlling for shared genetics and family environment), the association remained significant at 3.5, confirming that factors beyond family background contribute.\n\nHeritability of cannabis use disorder symptoms was 88% in both men and women. Heritability of psychotic experiences was 77% in men and 43% in women, revealing a striking sex difference.\n\nThe genetic correlation between cannabis use disorder and psychotic experiences was 0.55, and the environmental correlation was 0.52, meaning both shared genes and shared environments contribute to the association.\n\nCritically, the model testing whether cannabis causes psychotic experiences fit the data significantly better than models proposing the reverse direction (psychosis leading to cannabis use) or reciprocal causation. This supports a directional effect from cannabis to psychosis.","whyItMatters":"Twin studies are among the most powerful methods for disentangling genetic and environmental influences. This study provides strong evidence for a causal direction from cannabis to psychosis, not the other way around, while also showing that shared genetics play a substantial role.","specificNumbers":"2,793 twins. Lifetime cannabis use: 10.4%. PLEs prevalence: 0.1-2.2%. CUD-PLE incidence rate ratio: 6.3 total, 3.5 within pairs. CUD heritability: 88%. PLE heritability: 77% (men), 43% (women). Genetic correlation: 0.55. Environmental correlation: 0.52.","methodology":"Population-based twin study of 2,793 young adults (63.5% female, mean age 28.2). Cannabis use disorder symptoms and psychotic-like experiences assessed via CIDI. Item Response Theory modeled latent risk. Co-twin control analysis assessed familial confounding. Biometric models estimated heritability, genetic/environmental correlations, and direction of causation.","limitations":"Cross-sectional assessment limits causal inference despite the direction-of-causation modeling. Self-reported cannabis use and psychotic experiences may be subject to bias. The predominantly female sample (63.5%) may affect generalizability. Psychotic-like experiences are subclinical and may not predict full psychotic disorders."},{"rthcId":"RTHC-01465","title":"Evaluation of divided attention psychophysical task performance and effects on pupil sizes following smoked, vaporized and oral cannabis administration.","authors":"Newmeyer, Matthew N; Swortwood, Madeleine J; Taylor, Megan E; Abulseoud, Osama A; Woodward, Thomas H; Huestis, Marilyn A","year":2017,"journal":"Journal of applied toxicology : JAT, 37(8), 922-932","doi":"10.1002/jat.3440","pmid":"28138971","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This controlled study compared impairment from smoked, vaporized, and oral cannabis on standard roadside sobriety tests used in driving under the influence evaluations.\n\nFor inhaled cannabis (smoked and vaporized), no significant impairment was detected because testing occurred 1.5 and 3.5 hours after dosing, by which time peak effects had subsided.\n\nOral cannabis (edibles) told a different story. Because edible THC is absorbed slowly, blood concentrations were still peaking during the 1.5-3.5 hour testing window. Occasional smokers who consumed oral cannabis had 6.4 times higher odds of showing two or more impairment clues on the one-leg stand and walk-and-turn tests compared to placebo.\n\nAmong all participants, oral cannabis caused significantly larger pupils under direct lighting at both 1.5 and 3.5 hours post-dose. Blood THC and its metabolite 11-hydroxy-THC both independently predicted impairment on these tests.\n\nFrequent cannabis users showed less impairment than occasional users, consistent with tolerance development.","whyItMatters":"As edible cannabis use increases, understanding its impairment timeline is critical for driving policy. Edibles produce peak impairment 1.5-3.5 hours after consumption, a delayed window that may catch users off guard if they drive thinking the effects have not yet started.","specificNumbers":"Oral cannabis: 6.4x higher odds of impairment in occasional users (95% CI 2.3-18.4). THC blood concentration OR for impairment: 1.3 per unit increase. 11-OH-THC OR: 1.5. Pupil dilation: 0.4-0.5 mm larger than placebo.","methodology":"Controlled study comparing frequent and occasional cannabis smokers after placebo, smoked, vaporized, and oral cannabis (6.9% THC, ~50.4 mg). Modified Romberg balance, one-leg stand, and walk-and-turn tests administered at 1.5 and 3.5 hours. Pupil sizes measured under direct lighting.","limitations":"Small sample size limits generalizability. Testing occurred at fixed time points that favored detecting oral but not inhaled impairment. The standardized field sobriety tests were designed for alcohol impairment and may not optimally detect cannabis effects. Only one dose was tested."},{"rthcId":"RTHC-01466","title":"Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor.","authors":"Nguyen, Thuy; Li, Jun-Xu; Thomas, Brian F; Wiley, Jenny L; Kenakin, Terry P; Zhang, Yanan","year":2017,"journal":"Medicinal research reviews, 37(3), 441-474","doi":"10.1002/med.21418","pmid":"27879006","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01467","title":"Evidence for the use of \"medical marijuana\" in psychiatric and neurologic disorders.","authors":"Noel, Christopher","year":2017,"journal":"The mental health clinician, 7(1), 29-38","doi":"10.9740/mhc.2017.01.029","pmid":"29955495","tags":["medical-cannabis","mental-health","pain","epilepsy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review took a deliberately narrow approach, examining only randomized clinical trials of phytocannabinoids (plant-derived cannabis) for psychiatric and neurologic conditions, excluding synthetic products like dronabinol and nabilone.\n\nThe search identified trials in dementia, multiple sclerosis, Parkinson's disease, Huntington's disease, schizophrenia, social anxiety disorder, depression, tobacco use disorder, and neuropathic pain.\n\nThe overall evidence base was thin. While some conditions showed promising signals, none had sufficient evidence for strong clinical recommendations. The variability between state medical marijuana laws in which conditions are approved for treatment further complicated the picture.\n\nThe authors emphasized that even for substances federally classified as illegal, clinicians must maintain evidence-based approaches and ensure patients have tried treatments with stronger evidence before turning to medical marijuana.","whyItMatters":"This review highlights a critical gap: state medical marijuana laws approve cannabis for conditions where RCT evidence of phytocannabinoid efficacy may be weak or absent. This disconnect between policy and evidence creates challenges for clinicians.","specificNumbers":"Conditions with identified RCTs: dementia, MS, Parkinson's, Huntington's, schizophrenia, social anxiety, depression, tobacco use disorder, neuropathic pain. State medical marijuana laws cover highly variable condition lists.","methodology":"PubMed search for randomized clinical trials of phytocannabinoids in human subjects for psychiatric and neurologic disorders. Excluded commercially available synthetics (dronabinol, nabilone, nabiximols) and synthetic cannabinoids.","limitations":"Excluding synthetic cannabinoids and nabiximols removes a substantial portion of the evidence base. RCTs of plant cannabis are rare partly because of regulatory barriers, so the lack of evidence does not necessarily mean lack of efficacy. The review predates several important CBD trials."},{"rthcId":"RTHC-01468","title":"Family Physicians' Perceived Prevalence, Safety, and Screening for Cigarettes, Marijuana, and Electronic-Nicotine Delivery Systems (ENDS) Use during Pregnancy.","authors":"Northrup, Thomas F; Klawans, Michelle R; Villarreal, Yolanda R; Abramovici, Adi; Suter, Melissa A; Mastrobattista, Joan M; Moreno, Carlos A; Aagaard, Kjersti M; Stotts, Angela L","year":2017,"journal":"Journal of the American Board of Family Medicine : JABFM, 30(6), 743-757","doi":"10.3122/jabfm.2017.06.170183","pmid":"29180549","tags":["pregnancy"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This survey of 417 US family physicians providing labor and delivery care revealed a gap between awareness and action regarding substance use during pregnancy.\n\nPhysicians estimated that roughly 6-25% of their pregnant patients used cigarettes (54% of doctors), marijuana (49%), and electronic cigarettes (24%). Most perceived all of these as unsafe during pregnancy: 99% for cigarettes, 92% for marijuana, 91% for electronic cigarettes.\n\nDespite this awareness, screening was inconsistent. While 85% consistently screened for cigarettes, only 63% consistently screened for marijuana, 48% for secondhand smoke exposure, 33% for electronic cigarettes, and 28% for synthetic marijuana. Only 18% screened consistently for all substances.\n\nA notable knowledge gap existed for synthetic marijuana (58% selected \"do not know\" for prevalence) and electronic cigarettes (27% \"do not know\"), suggesting physicians may not be aware of newer substance trends among pregnant women.","whyItMatters":"If nearly half of physicians believe a significant portion of pregnant patients use marijuana but only 63% screen for it, many exposed pregnancies go unidentified. This screening gap means missed opportunities for intervention and counseling.","specificNumbers":"417 obstetric providers. 92% perceived marijuana as unsafe in pregnancy. 63% consistently screened for marijuana use. 32% used laboratory testing for marijuana. 18% screened for all substances consistently.","methodology":"Web-based cross-sectional survey emailed to 3,750 US physicians in academic family medicine organizations. 1,248 responded (33.3%). Analysis focused on 417 who provided labor and delivery obstetric care. Questions assessed perceived prevalence, safety beliefs, and screening practices for multiple substances during pregnancy.","limitations":"Self-reported survey from academic family medicine settings may not represent community practices. 33.3% response rate may introduce response bias. Physician perceptions of prevalence may not reflect actual patient use rates."},{"rthcId":"RTHC-01469","title":"Systematic review: interventions for abdominal pain management in inflammatory bowel disease.","authors":"Norton, C; Czuber-Dochan, W; Artom, M; Sweeney, L; Hart, A","year":2017,"journal":"Alimentary pharmacology & therapeutics, 46(2), 115-125","doi":"10.1111/apt.14108","pmid":"28470846","tags":["pain","inflammation","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This systematic review searched for interventions specifically targeting abdominal pain in inflammatory bowel disease, finding a surprisingly sparse evidence base.\n\nOnly 15 papers met inclusion criteria. Among them, psychological interventions showed the most consistent results: four of six studies reported pain reduction with approaches including relaxation, cognitive behavioral therapy, and stress management. Both psychologist-led and self-directed stress management reduced pain compared to controls.\n\nCannabis evidence was limited but positive. One controlled trial reported reduced pain scores, and cannabis users self-reported pain relief. Two dietary interventions (avoiding sugary alcoholic drinks and using fermentable carbohydrates) also showed some effect.\n\nAntibiotics (for bacterial overgrowth) and transdermal nicotine patches reduced pain in specific subgroups. The authors emphasized that the overall evidence quality was predominantly small, uncontrolled studies.","whyItMatters":"Abdominal pain is one of the most disabling symptoms of IBD and persists even during remission, yet it has received remarkably little research attention. This review identifies a major gap and highlights promising directions.","specificNumbers":"15 papers included: 13 intervention studies, 2 cross-sectional surveys. 4 of 6 psychological studies showed pain reduction. 1 controlled cannabis trial reduced SF-36 and EQ-5D pain scores. Stress management symptom frequency reduction: -26.7 (psychologist-led), -11.3 (self-directed) vs. 17.2 (control).","methodology":"Systematic review of MEDLINE, EMBASE, PsycInfo, CINAHL, Scopus, and Cochrane Library through February 2016. Excluded disease-modifying interventions to focus specifically on pain management. Two researchers independently screened and extracted data.","limitations":"Predominantly small uncontrolled studies of moderate to low quality. Heterogeneous interventions prevent pooled analysis. Cannabis evidence limited to one controlled trial. The exclusion of disease-modifying treatments may miss indirect pain relief from inflammation control."},{"rthcId":"RTHC-01470","title":"Cannabinoids in treatment-resistant epilepsy: A review.","authors":"O'Connell, Brooke K; Gloss, David; Devinsky, Orrin","year":2017,"journal":"Epilepsy & behavior : E&B, 70(Pt B), 341-348","doi":"10.1016/j.yebeh.2016.11.012","pmid":"28188044","tags":["epilepsy","cbd","medical-cannabis","youth"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review traced the evolution of cannabis-based epilepsy treatment from millennia of traditional use to modern randomized controlled trials.\n\nThe strongest evidence centered on Epidiolex (purified CBD at 100 mg/mL). Open-label studies showed efficacy with an adequate safety profile in children and young adults with a spectrum of treatment-resistant epilepsies. Phase 3 RCTs then confirmed efficacy and safety specifically for Dravet syndrome and Lennox-Gastaut syndrome at doses of 10 and 20 mg/kg/day.\n\nThe review highlighted a critical distinction between pharmaceutical-grade CBD and artisanal preparations available from dispensaries. While Epidiolex has undergone rigorous clinical evaluation, the dispensary products vary widely in composition and have no validated safety or efficacy data.\n\nThe authors noted the importance of the placebo effect in cannabis epilepsy research, given intense media attention and strong parental beliefs in natural products. Drug interactions, particularly with clobazam, were identified as an important safety consideration.","whyItMatters":"Treatment-resistant epilepsy affects 30% of epilepsy patients and carries severe morbidity and mortality. Epidiolex represents the first plant-derived cannabinoid to undergo rigorous clinical trial evaluation, setting a precedent for the field.","specificNumbers":"30% of epilepsy patients are treatment-resistant. Epidiolex studied at 10 and 20 mg/kg/day. Phase 3 RCTs completed for Dravet syndrome and Lennox-Gastaut syndrome. 25 states plus DC had medical marijuana programs.","methodology":"Review of case reports, small series, surveys, open-label studies, and Phase 3 RCTs of cannabinoids for treatment-resistant epilepsy, with focus on CBD (Epidiolex) for Dravet and Lennox-Gastaut syndromes.","limitations":"The review captures a moment in time before FDA approval of Epidiolex (which came in 2018). Long-term safety data were still limited. The focus on Dravet and LGS may not apply to other epilepsy types. Drug interactions require ongoing study."},{"rthcId":"RTHC-01471","title":"Targeting Cannabinoid Signaling in the Immune System: \"High\"-ly Exciting Questions, Possibilities, and Challenges.","authors":"Oláh, Attila; Szekanecz, Zoltán; Bíró, Tamás","year":2017,"journal":"Frontiers in immunology, 8, 1487","doi":"10.3389/fimmu.2017.01487","pmid":"29176975","tags":["inflammation","medical-cannabis","cbd","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review summarized how the endocannabinoid system influences the immune system at multiple levels.\n\nCannabinoids affect nearly every type of immune cell: T-cells, B-cells, macrophages, dendritic cells, mast cells, and others. The general tendency is immunosuppressive, reducing inflammation and modulating immune responses. This makes cannabinoids potentially useful for inflammatory and autoimmune conditions like multiple sclerosis.\n\nHowever, the immunosuppressive effects also raise concerns. Dampened anti-pathogen immunity could increase infection susceptibility, and altered anti-tumor immunity could theoretically affect cancer surveillance.\n\nThe review examined both in vitro and in vivo evidence, noting that the effects are complex and context-dependent. Cannabinoid signaling can both promote and suppress different immune responses depending on the cell type, receptor, and physiological context.\n\nThe therapeutic potential extends to organ transplantation (preventing rejection) and inflammation-related diseases, but the dual nature of immunomodulation means careful targeting is needed.","whyItMatters":"Understanding how cannabinoids interact with the immune system is essential for both medical cannabis patients (who need to know the implications) and drug developers (who need to harness the beneficial effects while minimizing immune compromise).","specificNumbers":"The review covers both CB1 and CB2 receptors, endocannabinoids (AEA, 2-AG), and multiple phytocannabinoids across T-cells, B-cells, macrophages, dendritic cells, and other immune cell types.","methodology":"Review of recent findings on cannabinoid signaling in innate and adaptive immunity, covering in vitro experiments, animal models, and clinical observations. Summarized therapeutic potential and identified open questions and challenges.","limitations":"Comprehensive review but much evidence is from in vitro and animal studies. The complexity of the endocannabinoid-immune interaction makes simple predictions about clinical outcomes difficult. The review does not provide meta-analytic quantification of effects."},{"rthcId":"RTHC-01472","title":"The social exigencies of the gateway progression to the use of illicit drugs from adolescence into adulthood.","authors":"Otten, Roy; Mun, Chung Jung; Dishion, Thomas J","year":2017,"journal":"Addictive behaviors, 73, 144-150","doi":"10.1016/j.addbeh.2017.05.011","pmid":"28511099","tags":["addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This longitudinal study tracked 711 people without prior illicit drug use across three time points (ages 17, 22, and 27) to test whether friendships explain the \"gateway\" progression from cannabis to harder drugs.\n\nCannabis use at age 17 was positively associated with having friends who used illicit drugs at age 22. These drug-using friendships at 22 then predicted the participant's own onset of illicit drug use (cocaine, methamphetamine, or opiates) between ages 22 and 27.\n\nSeparately, progression of tobacco use from ages 17 to 22 also predicted onset of illicit drug use between 22 and 27, suggesting tobacco escalation is an independent pathway.\n\nThe findings support peer clustering theory: cannabis use shapes social networks toward drug-using peers, and those peer networks then provide access to and normalization of harder drugs. The gateway progression is not just pharmacological but fundamentally social.","whyItMatters":"This study provides a mechanistic explanation for the gateway pattern that focuses on social processes rather than pharmacology. If peer networks mediate the progression from cannabis to harder drugs, interventions targeting peer environments may be more effective than those targeting cannabis pharmacology alone.","specificNumbers":"711 participants tracked at ages 17, 22, and 27. Cannabis at 17 predicted drug-using friends at 22. Drug-using friends at 22 predicted illicit drug onset at 22-27. Cannabis at 22 predicted drug abuse/dependence at 28.","methodology":"Three waves of longitudinal data from a community sample of 711 male and female participants without illicit drug use history at baseline. Assessed tobacco, alcohol, cannabis use, onset and abuse/dependence of illicit drugs, and friends' reported drug use at ages 17, 22, and 27. Structural equation modeling tested the hypothesized mediational pathway.","limitations":"Self-reported data and perceived friends' drug use may be inaccurate. The study cannot rule out that common underlying factors (risk-seeking personality, adverse childhood experiences) drive both cannabis use and harder drug progression. The sample began without illicit drug use history, which may select for lower-risk individuals."},{"rthcId":"RTHC-01473","title":"Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice.","authors":"Owens, Robert A; Mustafa, Mohammed A; Ignatowska-Jankowska, Bogna M; Damaj, M Imad; Beardsley, Patrick M; Wiley, Jenny L; Niphakis, Micah J; Cravatt, Benjamin F; Lichtman, Aron H","year":2017,"journal":"Neuropharmacology, 125, 80-86","doi":"10.1016/j.neuropharm.2017.06.032","pmid":"28673548","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This study demonstrated that blocking MAGL, the enzyme that breaks down the endocannabinoid 2-AG, produces subjective effects in mice that are indistinguishable from those produced by THC-like drugs.\n\n12 of 13 mice successfully learned to discriminate the MAGL inhibitor MJN110 from vehicle, and the CB1 receptor antagonist rimonabant blocked this discriminative stimulus, confirming it works through CB1 receptors.\n\nThe synthetic cannabinoid CP55,940, another MAGL inhibitor (JZL184), and the dual FAAH/MAGL inhibitor SA-57 all fully substituted for MJN110, meaning they felt the same to the mice. However, the FAAH inhibitor PF-3845 (which boosts anandamide instead of 2-AG) did not substitute, showing that enhancing anandamide alone does not produce cannabis-like subjective effects.\n\nCombining FAAH inhibition with MAGL inhibition made the MAGL effect stronger (1.6x leftward shift), suggesting anandamide and 2-AG interact.\n\nThe findings suggest MAGL normally acts as a \"brake\" on 2-AG, keeping it below levels that would produce cannabis-like intoxication.","whyItMatters":"This study reveals that the brain's own endocannabinoid system is capable of producing cannabis-like intoxication if 2-AG accumulates beyond normal levels. Understanding this has implications for MAGL inhibitor drug development, which must consider abuse potential.","specificNumbers":"12 of 13 mice learned the discrimination. FAAH inhibitor caused 1.6x (95% CI 1.1-2.2) leftward shift of MAGL inhibitor dose-response. Rimonabant dose-dependently blocked the discriminative stimulus.","methodology":"Drug discrimination paradigm in C57BL/6J mice trained to distinguish MAGL inhibitor MJN110 from vehicle. Substitution tests with multiple compounds (CP55,940, SA-57, JZL184, PF-3845, ABHD6 inhibitor, COX-2 inhibitor, nicotine, diazepam). Rimonabant used to confirm CB1 mediation.","limitations":"Mouse drug discrimination may not perfectly predict human subjective experiences. The study used a single MAGL inhibitor for training. The ecological relevance of pharmacologically elevated 2-AG levels to natural endocannabinoid function is uncertain."},{"rthcId":"RTHC-01474","title":"Caffeine and Cannabis Effects on Vital Neurotransmitters and Enzymes in the Brain Tissue of Juvenile Experimental Rats.","authors":"Owolabi, J O; Olatunji, S Y; Olanrewaju, A J","year":2017,"journal":"Annals of neurosciences, 24(2), 65-73","doi":"10.1159/000475895","pmid":"28588361","tags":["neuroscience","dopamine","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Juvenile rats given cannabis, caffeine, or both for 21 days showed increased levels of GABA, glutamate, and dopamine across all treatment groups compared to controls.\n\nThe metabolic enzyme G-6-PDH was elevated in all treated animals, but the combination of low-dose cannabis plus low-dose caffeine produced the most significant increase. Caffeine alone generated more pronounced neurochemical changes than cannabis alone at the doses tested.\n\nThe cytochrome C oxidase results indicated altered energy metabolism in the brain tissue of all treated groups, suggesting both substances affected how developing brain cells process energy.","whyItMatters":"Adolescence is a critical period for brain development. Understanding how commonly consumed psychoactive substances affect neurotransmitter systems during this window could inform public health approaches to youth substance use. The finding that combining caffeine and cannabis amplified certain metabolic changes raises questions about how these frequently co-used substances interact in developing brains.","specificNumbers":"72 juvenile rats across 6 groups. Treatment lasted 21 days. Caffeine doses: 50 and 100 mg/kg. Cannabis doses: 200 and 500 mg/kg. GABA, glutamate, and dopamine were all elevated across treated groups. G-6-PDH was most significantly elevated in the combined low-dose group.","methodology":"Researchers divided 72 juvenile Wistar rats (approximately 40 days old) into six groups. Controls received nothing; other groups received high-dose caffeine (100 mg/kg), low-dose caffeine (50 mg/kg), high-dose cannabis (500 mg/kg), low-dose cannabis (200 mg/kg), or a combination of low-dose cannabis plus low-dose caffeine. All substances were given orally for 21 days. Brain tissue was then analyzed for neurotransmitter levels (GABA, glutamate, dopamine) and metabolic enzymes (cytochrome C oxidase, G-6-PDH).","limitations":"This was an animal study using oral gavage in rats, which does not perfectly replicate human patterns of consumption. The cannabis doses were high by human standards. The study measured tissue levels at a single time point (24 hours after last dose), so the trajectory of changes over time is unknown. Behavioral outcomes were not assessed, so the functional significance of the neurochemical changes remains unclear."},{"rthcId":"RTHC-01475","title":"Role of the endocannabinoid system in the control of mouse myometrium contractility during the menstrual cycle.","authors":"Pagano, Ester; Orlando, Pierangelo; Finizio, Stefania; Rossi, Antonietta; Buono, Lorena; Iannotti, Fabio Arturo; Piscitelli, Fabiana; Izzo, Angelo A; Di Marzo, Vincenzo; Borrelli, Francesca","year":2017,"journal":"Biochemical pharmacology, 124, 83-93","doi":"10.1016/j.bcp.2016.11.023","pmid":"27899300","tags":["neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Anandamide and 2-AG levels in mouse uterine tissue were significantly lower during the oestrus (fertile) phase compared to the dioestrus phase. The uterus only showed spontaneous contractions during dioestrus, and these contractions were driven by prostaglandins.\n\nActivating the CB1 receptor with the agonist ACEA reduced these spontaneous contractions, and CB2 activation with JWH133 had a smaller but similar effect. Neither agonist affected contractions triggered by external prostaglandins during the oestrus phase.\n\nBlocking the enzymes that break down endocannabinoids (FAAH and MAGL) also reduced spontaneous contractions, suggesting that the body's own endocannabinoids naturally help modulate uterine muscle activity.","whyItMatters":"This research reveals that the endocannabinoid system is actively involved in regulating uterine muscle contractions across the reproductive cycle. For cannabis users, this suggests that THC and other cannabinoids could potentially interfere with normal uterine function by disrupting these finely tuned endocannabinoid fluctuations.","specificNumbers":"Anandamide and 2-AG levels were significantly reduced during oestrus compared to dioestrus. CB1 agonist ACEA reduced spontaneous contractions. CB2 agonist JWH133 had a smaller but significant effect. FAAH inhibitor JNJ1661010 reduced contractions. MAGL inhibitor JZL184 had a lesser effect.","methodology":"Researchers measured endocannabinoid levels in mouse uterine tissue at different cycle stages using liquid chromatography-mass spectrometry. Gene and protein expression of cannabinoid receptors and metabolic enzymes were quantified. Uterine contractility was tested in vitro using isolated tissue strips, with pharmacological tools including CB1 and CB2 agonists, their antagonists, and inhibitors of endocannabinoid-degrading enzymes.","limitations":"This was a mouse study, and mouse reproductive cycles differ from human menstrual cycles. The in vitro contractility measurements used isolated tissue strips, which may not fully represent uterine behavior in a living organism. The study did not examine THC directly, instead using selective receptor agonists."},{"rthcId":"RTHC-01476","title":"Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination.","authors":"Palmieri, Beniamino; Laurino, Carmen; Vadalà, Maria","year":2017,"journal":"The Israel Medical Association journal : IMAJ, 19(2), 79-84","doi":null,"pmid":"28457055","tags":["cbd","medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Twelve females aged 12 to 24 with severe somatoform and dysautonomic symptoms following HPV vaccination received escalating doses of sublingual CBD-rich hemp oil over three months, starting at 25 mg/kg per day and increasing to a maximum of 150 mg/ml per day.\n\nOf the 12 participants, 8 completed the full treatment period. Two dropped out due to side effects and two stopped early because they saw no improvement. Among completers, quality of life scores improved significantly in physical functioning (p < 0.02), vitality (p < 0.03), and social role functioning (p < 0.02). Body pain also decreased significantly.\n\nThe improvements in emotional well-being did not reach statistical significance.","whyItMatters":"This is one of few studies examining CBD for dysautonomic syndrome, a condition characterized by dysfunction of the autonomic nervous system. While the results are encouraging for the patients who responded, the lack of a control group and the small sample size mean the findings should be interpreted cautiously.","specificNumbers":"12 participants enrolled. 4 dropped out (2 for adverse events, 2 for lack of improvement). Starting dose: 25 mg/kg/day. Maximum dose: 150 mg/ml/day. Treatment duration: 3 months. Physical component score improved (p < 0.02). Vitality improved (p < 0.03). Social functioning improved (p < 0.02).","methodology":"This was an open-label, retrospective, compassionate-use observational study with no control group. Patients received sublingual CBD-rich hemp oil with weekly dose escalation. Quality of life was measured using the SF-36 health survey questionnaire before and after the treatment period.","limitations":"No control group, no blinding, and only 12 participants. One-third of participants dropped out. The retrospective, compassionate-use design introduces significant bias. The improvements observed could reflect placebo effects, natural symptom fluctuation, or other factors. The specific relationship between HPV vaccination and the reported symptoms remains debated in the medical literature."},{"rthcId":"RTHC-01477","title":"The arguments for and against cannabinoids application in glaucomatous retinopathy.","authors":"Panahi, Yunes; Manayi, Azadeh; Nikan, Marjan; Vazirian, Mahdi","year":2017,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 86, 620-627","doi":"10.1016/j.biopha.2016.11.106","pmid":"28027538","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined evidence on cannabinoids for glaucoma from multiple angles. Exogenous cannabinoids do lower intraocular pressure (IOP), the main modifiable risk factor for glaucoma. Research has also identified a complete endocannabinoid system within the eye, including CB1 and CB2 receptors, that naturally helps regulate IOP.\n\nBeyond pressure reduction, cannabinoids showed neuroprotective properties that could help preserve retinal ganglion cells, the neurons that die in glaucoma. This dual mechanism (pressure lowering plus neuroprotection) makes cannabinoids theoretically attractive.\n\nHowever, the IOP-lowering effect of smoked or oral cannabis lasts only 3 to 4 hours, requiring frequent dosing. Systemic side effects including psychoactivity, cardiovascular changes, and reduced blood pressure (which may actually worsen glaucoma by reducing blood flow to the optic nerve) remain significant barriers. Topical eye drop formulations have been difficult to develop due to cannabinoids' poor water solubility.","whyItMatters":"Glaucoma is a leading cause of irreversible blindness worldwide. While cannabinoids can lower eye pressure, this review clarifies why they have not replaced conventional glaucoma treatments. The short duration of effect, delivery challenges, and the paradox that lowering blood pressure might harm the optic nerve all complicate the picture.","specificNumbers":"IOP-lowering effect lasts approximately 3-4 hours with systemic cannabinoid administration. Glaucoma affects the retinal ganglion cells. Both CB1 and CB2 receptors are present in ocular tissues.","methodology":"This was a narrative review of published literature covering the ocular endocannabinoid system, mechanisms of cannabinoid-induced IOP reduction, neuroprotective properties of cannabinoids, clinical survey data, bioavailability challenges, and adverse effects.","limitations":"This is a narrative review, not a systematic review or meta-analysis. The authors selected studies without a formal search protocol. Much of the evidence for neuroprotection comes from animal models. Clinical trial data on cannabinoids for glaucoma remains limited."},{"rthcId":"RTHC-01478","title":"Recreational stimulants, herbal, and spice cannabis: The core psychobiological processes that underlie their damaging effects.","authors":"Parrott, Andrew C; Hayley, Amie C; Downey, Luke A","year":2017,"journal":"Human psychopharmacology, 32(3)","doi":"10.1002/hup.2594","pmid":"28557129","tags":["addiction","mental-health","withdrawal","cognition","sleep"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review proposes that all recreational psychoactive drugs, including cannabis, cause harm through a shared core mechanism: acute mood gains followed by mood deficits on withdrawal, creating a cycle of psychobiological fluctuations.\n\nThese mood swings are surface indicators of deeper disruptions. The hypothalamic-pituitary-adrenal (HPA) axis gets repeatedly disturbed, cortisol secretion patterns become dysregulated, and homeostatic balance is thrown off. These disruptions manifest as increased stress, disturbed sleep, neurocognitive impairments, altered brain activity, and greater vulnerability to psychiatric conditions.\n\nThe same pattern was observed with novel synthetic cannabinoids (\"Spice\") and synthetic stimulants like mephedrone, suggesting this mechanism extends to newer drugs as well. The authors argue that psychobiological stability is best restored by quitting psychoactive drug use entirely.","whyItMatters":"Rather than treating each drug as having unique risks, this framework suggests a unified explanation for why regular use of any mood-altering substance tends to produce similar problems: stress, poor sleep, cognitive difficulties, and mental health vulnerability. For cannabis users, it challenges the perception that cannabis is fundamentally safer than stimulants in terms of chronic effects on well-being.","specificNumbers":"The review covered cannabis, MDMA, cocaine, mephedrone, and synthetic cannabinoids. All showed cyclical mood changes with acute gains followed by withdrawal deficits.","methodology":"This was a narrative review synthesizing empirical literature on recreational cannabinoids and stimulant drugs. The authors developed a theoretical framework explaining how different drug classes produce similar types of damage through shared psychobiological mechanisms.","limitations":"This is a theoretical review presenting a framework, not a systematic review testing a specific hypothesis. The comparison between cannabis and stimulants may oversimplify important pharmacological differences. The claim that quitting is the optimal path to restoration does not account for harm reduction approaches or the complex reasons people use substances."},{"rthcId":"RTHC-01479","title":"The clinical impact of a positive family history of psychosis or mental illness in psychotic and non-psychotic mentally ill adolescents.","authors":"Paruk, Saeeda; Jhazbhay, Khatija; Singh, Keshika; Sartorius, Benn; Burns, Jonathan K","year":2017,"journal":"Journal of child and adolescent mental health, 29(3), 219-229","doi":"10.2989/17280583.2017.1389741","pmid":"29092669","tags":["psychosis","youth","genetics"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Researchers compared 45 adolescents with first-episode early-onset psychosis (EOP) to 45 age- and gender-matched adolescents with non-psychotic mental illness. Family history of psychosis did not significantly differ between the two groups.\n\nHowever, among the psychotic adolescents, those with a positive family history of psychosis had significantly lower positive symptom scores on the PANSS (p = 0.009), meaning fewer hallucinations, delusions, and other positive symptoms at the time of first presentation. Family history was not associated with other clinical features.\n\nNotably, adolescents with non-psychotic mental illness were significantly more likely to have a family history of non-psychotic mental illness (47%) compared to the psychotic group (13%, p = 0.001).","whyItMatters":"The assumption that family history of psychosis predicts worse outcomes may not hold true at disease onset in adolescents. This finding could influence how clinicians interpret family history when evaluating young people with first psychotic episodes. The inclusion of cannabis screening adds context to understanding substance use patterns in this population.","specificNumbers":"45 psychotic adolescents vs. 45 matched controls. Family history of non-psychotic mental illness: 13% in EOP group vs. 47% in controls (p = 0.001). Positive family history of psychosis was associated with lower PANSS positive scores (p = 0.009).","methodology":"This was a case-control study at psychiatric services in South Africa. Forty-five adolescents with first-episode psychosis were matched with 45 controls who had non-psychotic mental illness. Assessments included the PANSS for symptom severity, the SOS inventory for symptom onset, and the WHO ASSIST screening tool for cannabis use.","limitations":"Small sample size (45 per group) limits statistical power. The study was conducted at a single site in South Africa, which may limit generalizability. Cannabis use data was collected but the abstract does not detail specific associations with outcomes. Cross-sectional design captures only the initial presentation, not long-term trajectory."},{"rthcId":"RTHC-01480","title":"Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson's disease.","authors":"Pasquarelli, Noemi; Porazik, Christoph; Bayer, Hanna; Buck, Eva; Schildknecht, Stefan; Weydt, Patrick; Witting, Anke; Ferger, Boris","year":2017,"journal":"Neurochemistry international, 110, 14-24","doi":"10.1016/j.neuint.2017.08.003","pmid":"28826718","tags":["neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested two strategies for boosting endocannabinoid levels in a chronic Parkinson's disease mouse model. The MAGL inhibitor KML29, which elevates 2-AG, significantly reduced striatal dopamine depletion caused by the neurotoxin MPTP. The FAAH inhibitor PF-3845, which elevates anandamide, did not.\n\nKML29 also increased expression of GDNF (glial cell line-derived neurotrophic factor), a protein that supports dopamine neuron survival. In contrast, PF-3845 had no effect on neurotrophic factor expression but did decrease CB2 receptor expression that had been elevated by the neurotoxin.\n\nFollow-up experiments in cultured microglia showed that 2-AG directly increased GDNF expression, suggesting that microglia (the brain's immune cells) may mediate the neuroprotective effects of MAGL inhibition.","whyItMatters":"Parkinson's disease involves the progressive loss of dopamine neurons, and current treatments manage symptoms without slowing disease progression. This study suggests that the two main endocannabinoids, 2-AG and anandamide, have fundamentally different neuroprotective potential, with 2-AG appearing to actively protect dopamine neurons through microglia-mediated growth factor release.","specificNumbers":"Both inhibitors dosed at 10 mg/kg. KML29 (MAGL inhibitor) significantly attenuated dopamine depletion. PF-3845 (FAAH inhibitor) did not. KML29 increased GDNF expression. 2-AG increased GDNF expression in cultured microglia. BDNF expression was not affected by either treatment.","methodology":"Mice received the neurotoxin MPTP/probenecid chronically to model Parkinson's disease. They were simultaneously treated with either the MAGL inhibitor KML29 (10 mg/kg) or the FAAH inhibitor PF-3845 (10 mg/kg). Striatal dopamine levels, endocannabinoid levels, and gene expression of neurotrophic factors and cannabinoid receptors were measured. Primary mouse microglia cultures were used for mechanistic follow-up.","limitations":"This was an animal study using a chemical model of Parkinson's disease (MPTP), which does not fully replicate the human disease. The MAGL inhibitor KML29 was given alongside the neurotoxin rather than after disease onset, so this was more prevention than treatment. Long-term effects and behavioral outcomes were not assessed."},{"rthcId":"RTHC-01481","title":"Medical Decision-Making Processes and Online Behaviors Among Cannabis Dispensary Staff.","authors":"Peiper, Nicholas C; Gourdet, Camille; Meinhofer, Angélica; Reiman, Amanda; Reggente, Nicco","year":2017,"journal":"Substance abuse : research and treatment, 11, 1178221817725515","doi":"10.1177/1178221817725515","pmid":"28855796","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 158 budtenders surveyed in California, 56% had received formal training. Trained budtenders were significantly more likely to have budtending as their primary job (74% vs. 53%), to have practiced more than five years (34% vs. 11%), and to receive sales commissions (57% vs. 16%).\n\nParadoxically, trained budtenders were significantly less likely to view medical decision-making as \"very important\" (47% vs. 68%) and less likely to describe their philosophy as patient-centered (77% vs. 89%). They also used more digital channels to communicate with patients, including email, text, mobile apps, video calls, and social media.\n\nThe finding that formal training was associated with less emphasis on patient-centered medical advice raises questions about what budtender training programs actually teach and whether they prioritize sales skills over patient care.","whyItMatters":"Dispensary budtenders are often the primary source of medical guidance for cannabis patients, yet their training, qualifications, and approach to patient care vary widely. This study reveals that formal training may not be producing the patient-centered outcomes one might expect, and the high rate of sales commissions among trained budtenders suggests potential conflicts of interest.","specificNumbers":"158 budtenders surveyed. 56% formally trained. Trained vs. untrained: primary job 74% vs. 53%, 5+ years experience 34% vs. 11%, sales commission 57% vs. 16%, medical decision-making \"very important\" 47% vs. 68%, patient-centered philosophy 77% vs. 89%.","methodology":"Cross-sectional internet survey administered between June and September 2016 to budtenders in the San Francisco Bay Area and Greater Los Angeles. A total of 158 budtenders completed the survey. Comparisons were made between formally trained and untrained budtenders on demographics, workplace characteristics, medical decision-making attitudes, and digital communication behaviors.","limitations":"Cross-sectional internet survey with a convenience sample from two California regions. Self-reported attitudes may not reflect actual behavior. The study was conducted before California's recreational legalization took effect (Proposition 64 passed November 2016), and the dispensary landscape has changed significantly since then. What counts as \"formal training\" was not standardized."},{"rthcId":"RTHC-01482","title":"Cannabis and Amphetamine Use Among Adolescents in Five Asian Countries.","authors":"Peltzer, Karl; Pengpid, Supa","year":2017,"journal":"Central Asian journal of global health, 6(1), 288","doi":"10.5195/cajgh.2017.288","pmid":"30881756","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 38,941 school-aged adolescents (mean age 15.4 years) in Iraq, Kuwait, Malaysia, Mongolia, and Vietnam, overall lifetime cannabis use was 0.9% and lifetime amphetamine use was 1.0%.\n\nCurrent cigarette smoking was the only variable significantly associated with cannabis use across all five countries. Male gender was associated with cannabis use in Kuwait and Mongolia. Parental smoking was associated with cannabis use in Kuwait and Iraq.\n\nFor amphetamine use, the predictors were different and more tied to mental health: suicidal ideation, school truancy, being a victim of physical assault, bullying victimization, and anxiety were significant predictors in various country combinations, with current cigarette use again significant everywhere.","whyItMatters":"While most cannabis research focuses on Western populations, this study provides data on adolescent use patterns in Asian countries where cannabis remains highly stigmatized and largely illegal. The consistent link between cigarette smoking and cannabis use across culturally diverse countries suggests this association is not culturally specific.","specificNumbers":"38,941 adolescents surveyed. Mean age 15.4 years. Lifetime cannabis use: 0.9%. Lifetime amphetamine use: 1.0%. Current cigarette smoking was associated with cannabis use in all five countries.","methodology":"Cross-sectional analysis using data from the Global School-Based Student Health Survey (GSHS), a WHO-supported standardized survey. Logistic regression was used to identify predictors of lifetime cannabis and amphetamine use across the five countries.","limitations":"Cross-sectional design cannot determine whether cigarette smoking leads to cannabis use or both share common risk factors. Self-report in school settings may underestimate true prevalence, especially in countries with harsh drug penalties. School-based surveys miss out-of-school youth who may have higher substance use rates. Data are from different years across the five countries."},{"rthcId":"RTHC-01483","title":"Concise review of the management of iatrogenic emesis using cannabinoids: emphasis on nabilone for chemotherapy-induced nausea and vomiting.","authors":"Pergolizzi, Joseph V; Taylor, Robert; LeQuang, Jo Ann; Zampogna, Gianpietro; Raffa, Robert B","year":2017,"journal":"Cancer chemotherapy and pharmacology, 79(3), 467-477","doi":"10.1007/s00280-017-3257-1","pmid":"28235999","tags":["medical-cannabis","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined nabilone's pharmacology and clinical trial evidence for treating chemotherapy-induced nausea and vomiting (CINV). Nabilone is a single-entity synthetic cannabinoid receptor agonist with a mechanism of action distinct from existing antiemetics like 5-HT3 antagonists, NK1 antagonists, and dopamine antagonists.\n\nExisting preventive therapies for CINV are often inadequate, particularly for delayed nausea and vomiting that occurs hours to days after chemotherapy. Nabilone's unique cannabinoid receptor-mediated mechanism makes it a valuable addition to the antiemetic toolkit, especially when standard agents fall short.\n\nThe authors note that cannabinoid antiemetics may have been underutilized historically due to the stigma and legal status of marijuana, despite nabilone being a single synthetic compound unrelated to botanical cannabis.","whyItMatters":"Chemotherapy-induced nausea remains one of the most feared side effects of cancer treatment and can cause patients to delay or refuse life-saving chemotherapy. Having additional effective antiemetics, particularly for delayed nausea that resists conventional treatments, directly affects cancer treatment outcomes and patient quality of life.","specificNumbers":"Marijuana contains nearly 500 components. Nabilone is a single-entity synthetic cannabinoid. CINV affects the majority of patients on certain chemotherapy regimens. Existing antiemetic classes include 5-HT3 antagonists, dopamine receptor antagonists, NK1 receptor antagonists, antimuscarinic anticholinergics, and antihistamines.","methodology":"Narrative review of nabilone's basic pharmacology, mechanism of action, and clinical trial data for prophylaxis and treatment of CINV.","limitations":"Narrative review without systematic search methodology. The clinical trial data reviewed was not assessed for risk of bias. Side effects including psychoactive effects (drowsiness, dizziness, euphoria, dysphoria) are present with nabilone, though the review emphasizes efficacy over adverse effects. Direct comparison data with newer antiemetics is limited."},{"rthcId":"RTHC-01484","title":"Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?","authors":"Perucca, Emilio","year":2017,"journal":"Journal of epilepsy research, 7(2), 61-76","doi":"10.14581/jer.17012","pmid":"29344464","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"After years of uncontrolled observations and anecdotal reports, three rigorous placebo-controlled trials of purified CBD (Epidiolex) provided the first class 1 evidence that CBD improves seizure control in specific epilepsy syndromes.\n\nIn Dravet syndrome, CBD reduced the frequency of convulsive seizures (tonic-clonic, tonic, clonic, and atonic) compared to placebo. In Lennox-Gastaut syndrome, CBD reduced the frequency of drop seizures.\n\nHowever, the review raises a critical complication: CBD markedly increases plasma levels of N-desmethylclobazam, the active metabolite of clobazam, a commonly co-prescribed anti-seizure medication. Many trial participants were taking clobazam, meaning some of the observed seizure reduction could be due to this drug interaction rather than a direct anti-seizure effect of CBD. The author argues that subgroup analyses of patients not taking clobazam are needed to resolve this question.","whyItMatters":"This review marks a turning point in the evidence base for CBD in epilepsy. For the first time, controlled trial evidence confirmed what families and clinicians had reported anecdotally for years. But the author's identification of the clobazam interaction as a potential confound is important: if a significant portion of the benefit comes from boosted clobazam levels, then CBD's direct anti-seizure effect may be smaller than the headline results suggest.","specificNumbers":"Three placebo-controlled trials completed. CBD reduced convulsive seizures in Dravet syndrome and drop seizures in Lennox-Gastaut syndrome vs. placebo. CBD significantly increased N-desmethylclobazam plasma levels in patients co-medicated with clobazam.","methodology":"Comprehensive narrative review covering the preclinical anticonvulsant profile of CBD, uncontrolled clinical observations with CBD-enriched extracts, and the three pivotal placebo-controlled adjunctive-therapy trials in Dravet syndrome and Lennox-Gastaut syndrome.","limitations":"The review is authored by a single expert and is not a formal systematic review. The clobazam interaction concern, while scientifically valid, has not been definitively resolved by the time of this review. The trials studied pharmaceutical-grade CBD, not over-the-counter CBD products, which vary widely in quality and composition."},{"rthcId":"RTHC-01485","title":"A patient with a curious case of cyclical vomiting.","authors":"Phillips, Hayden R; Smith, David A","year":2017,"journal":"JAAPA : official journal of the American Academy of Physician Assistants, 30(2), 1-3","doi":"10.1097/01.JAA.0000511789.29560.74","pmid":"28098679","tags":["appetite","withdrawal"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The case describes the clinical presentation of cannabinoid hyperemesis syndrome, a condition increasingly recognized in emergency departments as cannabis legalization expands. The hallmark features include severe cyclical nausea and vomiting, recurrent epigastric or periumbilical pain, and the characteristic finding that symptoms are only relieved by hot bathing or showering.\n\nThe syndrome occurs in habitual daily cannabis users and often leads to extensive and unnecessary medical testing before diagnosis, as the symptoms mimic many gastrointestinal conditions. Definitive resolution comes only with cessation of cannabis use.\n\nThe authors emphasize that with wider legalization and increasing availability, cannabis-related emergency department visits are rising, and healthcare providers need to recognize CHS early to avoid prolonged diagnostic workups.","whyItMatters":"CHS represents one of the clearest adverse effects of chronic heavy cannabis use. Its distinctive feature of hot water relief is nearly pathognomonic (uniquely characteristic of the condition), but many clinicians remain unaware of it, leading to repeated emergency visits, unnecessary imaging, endoscopies, and prolonged patient suffering before diagnosis.","specificNumbers":"Cannabis-related ED visits are increasing with legalization. CHS features three phases: prodromal (early morning nausea), hyperemetic (intense vomiting), and recovery (after cessation).","methodology":"Single case report with clinical description and literature context.","limitations":"Single case report cannot establish prevalence, risk factors, or mechanisms. The pathophysiology of CHS remains incompletely understood. Why only some chronic heavy users develop the syndrome while others do not is unclear."},{"rthcId":"RTHC-01486","title":"Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.","authors":"Philpott, Holly T; O'Brien, Melissa; McDougall, Jason J","year":2017,"journal":"Pain, 158(12), 2442-2451","doi":"10.1097/j.pain.0000000000001052","pmid":"28885454","tags":["cbd","pain","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested CBD's effects on osteoarthritis (OA) pain in rats using both therapeutic and preventive approaches. In end-stage OA (day 14 after disease induction), CBD dose-dependently decreased joint nerve firing rate, increased the pain threshold for paw withdrawal, and improved weight bearing on the affected limb (all p < 0.0001).\n\nWhen administered on day 1 to target the initial inflammatory phase, CBD reduced acute joint inflammation including blood flow changes and immune cell trafficking (p < 0.0001). Most strikingly, this early CBD treatment prevented the development of pain at later time points (p < 0.0001) and was neuroprotective, preserving nerve fiber myelination in the joint (p < 0.05).\n\nThe neuroprotective finding was notable: OA causes peripheral neuropathy (nerve damage) in affected joints, and CBD appeared to prevent this nerve degradation when given early enough.","whyItMatters":"Osteoarthritis is the most common joint disease worldwide, and its pain component involves both inflammation and nerve damage. Current analgesics manage symptoms but do not address nerve degeneration. CBD's dual action in this model, reducing pain while also protecting nerves, suggests a mechanism that goes beyond simple symptom relief.","specificNumbers":"CBD doses: 100-300 micrograms (local administration). Pain reduction in end-stage OA: p < 0.0001. Acute inflammation reduction on day 1: p < 0.0001. Prevention of later pain development: p < 0.0001. Neuroprotection: p < 0.05. Sample sizes: n = 6-8 per group.","methodology":"Osteoarthritis was induced in male Wistar rats by intra-articular injection of monoiodoacetate (MIA). Pain was assessed using in vivo electrophysiology (joint nerve firing), von Frey hair algesiometry (withdrawal threshold), and dynamic incapacitance (weight bearing). CBD was administered locally at doses of 100-300 micrograms. Inflammation was measured via blood flow and leukocyte trafficking. Nerve health was assessed by G-ratio analysis of myelination.","limitations":"Animal study using direct injection into the joint, which does not represent oral or topical CBD use in humans. The MIA model of OA causes rapid, chemically-induced joint damage that differs from the slow progression of human OA. Only male rats were studied. The CBD doses used were relatively high for local administration."},{"rthcId":"RTHC-01487","title":"Coronary vasospasm complicating cannabinoid hyperemesis syndrome.","authors":"Pierard, Sophie; Hantson, Philippe","year":2017,"journal":"Journal of cardiology cases, 15(4), 115-118","doi":"10.1016/j.jccase.2016.12.001","pmid":"30279755","tags":["cardiovascular","withdrawal"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 41-year-old man with a long history of cannabis smoking presented with recurrent episodes of epigastric and retrosternal (chest) pain. He had undergone multiple negative gastrointestinal investigations over time.\n\nDuring one hospitalization, ECG and echocardiographic changes were consistent with takotsubo cardiomyopathy (stress cardiomyopathy). Shortly after, he was readmitted with a ST-elevation myocardial infarction (STEMI) caused by coronary vasospasm, confirmed on cardiac catheterization.\n\nThe case raises the concern that cannabinoid hyperemesis syndrome (CHS), which typically presents with abdominal pain, may also involve cardiac complications. While a direct causal link between CHS and acute coronary syndrome has not been established, there is growing epidemiological evidence that cannabis smoking can trigger coronary vasospasm in young adults.","whyItMatters":"This case highlights that chest pain in CHS patients should not be automatically attributed to the gastrointestinal syndrome. Cannabis has independent cardiovascular effects including potential for coronary vasospasm, and CHS patients may be at particular risk because their recurrent presentations lead clinicians to attribute all symptoms to the known condition.","specificNumbers":"Patient age: 41. Takotsubo cardiomyopathy identified on echocardiography. STEMI caused by coronary vasospasm confirmed on catheterization.","methodology":"Single case report with clinical history, ECG findings, echocardiography, and cardiac catheterization results.","limitations":"Single case report cannot establish causation between cannabis use and the cardiac events. The patient's cardiovascular risk factors beyond cannabis use were not detailed in the abstract. Takotsubo cardiomyopathy and coronary vasospasm can occur without cannabis use."},{"rthcId":"RTHC-01488","title":"Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep.","authors":"Piper, Brian J; DeKeuster, Rebecca M; Beals, Monica L; Cobb, Catherine M; Burchman, Corey A; Perkinson, Leah; Lynn, Shayne T; Nichols, Stephanie D; Abess, Alexander T","year":2017,"journal":"Journal of psychopharmacology (Oxford, England), 31(5), 569-575","doi":"10.1177/0269881117699616","pmid":"28372506","tags":["medical-cannabis","pain","addiction","sleep","anxiety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,513 New England dispensary members surveyed, the rates of medication reduction after starting medical cannabis varied significantly by drug class. The highest reduction rates were for opioids (76.7%), followed by anti-anxiety medications (71.8%), migraine medications (66.7%), and sleep medications (65.2%).\n\nThe reduction in antidepressant use was notably lower at 37.6%, and alcohol reduction was 42.0%. The opioid, anti-anxiety, migraine, and sleep medication reductions were all statistically significantly greater than the reductions in antidepressants or alcohol (p < 0.0001).\n\nAn important social finding: patients' spouses, family members, and friends were more likely to know about their medical cannabis use than their primary care providers.","whyItMatters":"The opioid epidemic has driven intense interest in whether medical cannabis could serve as a substitute for prescription opioids. This study provides patient-reported data suggesting substantial medication substitution, particularly for opioids, anxiety medications, and sleep aids. However, the finding that doctors were often unaware of their patients' cannabis use highlights a gap in coordinated care.","specificNumbers":"1,513 dispensary members surveyed. Reduced opioid use: 76.7%. Reduced anti-anxiety meds: 71.8%. Reduced migraine meds: 66.7%. Reduced sleep meds: 65.2%. Reduced alcohol: 42.0%. Reduced antidepressants: 37.6%. All comparisons to antidepressant/alcohol reduction: p < 0.0001.","methodology":"Online cross-sectional survey of New England dispensary members (n = 1,513). Participants were asked about their medical history, conditions, cannabis experiences, and changes in use of other medications since starting medical cannabis.","limitations":"Self-reported, retrospective, cross-sectional design. No verification of actual medication changes through pharmacy records or physician confirmation. Selection bias: dispensary members who found cannabis helpful may be more likely to respond. No control group of patients who tried cannabis and found it unhelpful. \"Reduced use\" does not necessarily mean \"appropriate reduction\" since some patients may need their original medications."},{"rthcId":"RTHC-01489","title":"Chronic pain patients' perspectives of medical cannabis.","authors":"Piper, Brian J; Beals, Monica L; Abess, Alexander T; Nichols, Stephanie D; Martin, Maurice W; Cobb, Catherine M; DeKeuster, Rebecca M","year":2017,"journal":"Pain, 158(7), 1373-1379","doi":"10.1097/j.pain.0000000000000899","pmid":"28328576","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 984 dispensary members (two-thirds with chronic pain), the average self-rated effectiveness of medical cannabis was 74.6% on a scale from 0% (no relief) to 100% (complete relief). The average annual spending was $3,064.\n\nWhen asked what they liked most, the top themes were: health benefits (36% of responses, particularly pain relief and medication reduction), the product itself (14.2%, including knowing the exact strain), and non-health benefits (14.1%).\n\nWhen asked what they liked least, the top themes were: cost (28.4%), unwanted effects (21.7%, particularly lung-related concerns), social stigma (11.4%), and access difficulties (8.2%). The qualitative data revealed tension between patients who found cannabis highly effective but struggled with its cost, legal barriers, and the judgment of others.","whyItMatters":"Understanding patient perspectives, both positive and negative, is essential for improving medical cannabis programs. The finding that cost and stigma are major barriers, even among patients who find cannabis effective, points to systemic issues beyond pharmacology that affect treatment outcomes.","specificNumbers":"984 participants. Average effectiveness rating: 74.6%. Average annual spending: $3,064 (median $2,320, range $52-$52,140). 2,592 responses to \"like most.\" 1,678 responses to \"like least.\" Health benefits: 36% of positive responses. Cost: 28.4% of negative responses.","methodology":"Online cross-sectional survey of New England dispensary members (N = 984) with open-ended questions coded into themes and subthemes. Both quantitative ratings and qualitative responses were analyzed.","limitations":"Self-selected sample of dispensary members who were active enough to complete an online survey. Patients who stopped using cannabis or were dissatisfied would be underrepresented. Self-rated effectiveness is subjective and may not correspond to clinical measures. Regional data from New England may not generalize nationally."},{"rthcId":"RTHC-01490","title":"Perceived harms and benefits of tobacco, marijuana, and electronic vaporizers among young adults in Colorado: implications for health education and research.","authors":"Popova, Lucy; McDonald, Emily Anne; Sidhu, Sohrab; Barry, Rachel; Richers Maruyama, Tracey A; Sheon, Nicolas M; Ling, Pamela M","year":2017,"journal":"Addiction (Abingdon, England), 112(10), 1821-1829","doi":"10.1111/add.13854","pmid":"28449191","tags":["youth","harm-reduction","potency"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Through 32 in-depth interviews with young adults aged 18-26 in Denver who used tobacco, marijuana, or vaporizers, researchers identified five dimensions these users applied when evaluating harms and benefits.\n\nCombustion: smoking anything was considered more harmful than non-combustible forms (edibles, vaporizers). Potency: edibles and marijuana concentrates were seen as more potentially harmful due to overdose risk from getting too much THC. Chemicals: products with additives were considered more harmful than \"pure\" or \"natural\" plant products. Addiction: participants recognized physical nicotine addiction but described marijuana dependence as mainly psychological or lifestyle-related. Source of knowledge: personal experience, warning labels, media, retailer opinions, and medical advice all shaped perceptions.\n\nParticipants generally viewed marijuana as more \"natural\" and therefore safer than tobacco, a perception the authors suggest could be misleading given that marijuana smoke also contains harmful chemicals.","whyItMatters":"Understanding how young adults reason about substance risks is essential for designing effective health education. The finding that many users equate \"natural\" with \"safe\" suggests a gap in health messaging. The potency dimension is particularly relevant as concentrates and edibles become more prevalent in legal markets.","specificNumbers":"32 participants aged 18-26 in Denver, CO. Five dimensions of harm evaluation identified. Participants used tobacco, marijuana, and/or vaporizers.","methodology":"Semi-structured qualitative interviews with 32 young adults aged 18-26 in Denver, Colorado who used tobacco, marijuana, or vaporizers. Interviews covered perceived harms and benefits and personal experiences. Data were analyzed thematically.","limitations":"Small qualitative sample (32 participants) from a single city in the first legal recreational market. Findings reflect the specific cultural context of Denver in the early legalization period. Qualitative research identifies themes but cannot quantify how prevalent each belief is in the broader population."},{"rthcId":"RTHC-01491","title":"Impact of synthetic cannabinoids on the duration of opioid-related withdrawal and craving among patients of addiction clinics in Kazakhstan: A prospective case-control study.","authors":"Prilutskaya, Mariya; Bersani, Francesco Saverio; Corazza, Ornella; Molchanov, Sergey","year":2017,"journal":"Human psychopharmacology, 32(3)","doi":"10.1002/hup.2618","pmid":"28631421","tags":["synthetic-cannabinoids","addiction","withdrawal"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 193 patients with opioid use disorder undergoing detoxification in Kazakhstan, the 47 who also regularly used synthetic cannabinoids (SCs) experienced significantly longer withdrawal and craving symptoms compared to those who did not use SCs (p < 0.001).\n\nThe study identified a dose-response relationship: higher SC intake in the past 30 days (p = 0.045), more recent SC use (p = 0.033), longer total duration of SC use (p < 0.001), and higher SC doses (p < 0.001) were all independently associated with longer symptom duration.\n\nThis was the first prospective study to examine how synthetic cannabinoid use affects the course of opioid withdrawal, revealing that polysubstance use involving SCs creates a more difficult detoxification process.","whyItMatters":"Synthetic cannabinoids are increasingly used alongside opioids in many parts of the world. Understanding that SC use complicates opioid detoxification has practical implications for treatment planning: patients with concurrent SC use may need longer treatment stays and different management protocols.","specificNumbers":"193 total patients. 47 (24.4%) used synthetic cannabinoids. SC users had significantly longer withdrawal (p < 0.001) and craving (p < 0.001). Dose-response relationships confirmed for SC intake (p = 0.045), recency (p = 0.033), duration (p < 0.001), and dosage (p < 0.001).","methodology":"Prospective case-control study at addiction clinics in Kazakhstan. 193 patients with opioid use disorder underwent integrated detoxification. 47 were regular SC users. Opioid withdrawal was measured using the Clinical Opiate Withdrawal Scale and craving was assessed with a visual analogue scale at multiple time points.","limitations":"Conducted at addiction clinics in Kazakhstan, which may limit generalizability to other populations and treatment settings. The synthetic cannabinoids used were not chemically identified, and SC products vary widely in composition and potency. The study did not account for other substances of use beyond SCs and opioids."},{"rthcId":"RTHC-01492","title":"Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer.","authors":"Proto, Maria Chiara; Fiore, Donatella; Piscopo, Chiara; Franceschelli, Silvia; Bizzarro, Valentina; Laezza, Chiara; Lauro, Gianluigi; Feoli, Alessandra; Tosco, Alessandra; Bifulco, Giuseppe; Sbardella, Gianluca; Bifulco, Maurizio; Gazzerro, Patrizia","year":2017,"journal":"Scientific reports, 7(1), 11678","doi":"10.1038/s41598-017-11688-x","pmid":"28916833","tags":["cancer","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested rimonabant, a CB1 receptor inverse agonist, on two colon cancer cell lines carrying mutations associated with metastatic cancer that responds poorly to chemotherapy.\n\nRimonabant inhibited the Wnt/beta-catenin signaling pathway, one of the most important cancer-promoting pathways in colorectal cancer, and increased the phosphorylation (deactivation) of beta-catenin. In one cell line (HCT116), it also activated a non-canonical Wnt pathway through Wnt5A and CaMKII. Part of rimonabant's mechanism involved directly inhibiting the p300/KAT3B histone acetyltransferase, an enzyme that helps activate cancer-promoting genes.\n\nIn living mice with HCT116 tumor xenografts, rimonabant significantly reduced tumor growth and disrupted the nuclear localization of beta-catenin (the protein must be in the nucleus to drive cancer gene expression).","whyItMatters":"Colorectal cancer with activated Wnt/beta-catenin signaling (present in over 85% of cases) is particularly difficult to treat with existing chemotherapy. Rimonabant's ability to inhibit this pathway through a novel mechanism, cannabinoid receptor modulation combined with direct epigenetic enzyme inhibition, opens a new therapeutic angle.","specificNumbers":"Over 85% of colorectal cancers involve APC/Wnt/beta-catenin pathway activation. Two cell lines tested (HCT116, SW48). Rimonabant significantly reduced xenograft tumor growth in vivo. p300/KAT3B histone acetyltransferase was directly inhibited.","methodology":"In vitro experiments on HCT116 and SW48 colon cancer cell lines examined rimonabant's effects on the Wnt/beta-catenin pathway. Histone acetyltransferase activity assays tested direct enzyme inhibition. In vivo experiments used HCT116 xenografts in mice to assess tumor growth effects.","limitations":"Rimonabant was withdrawn from the European market in 2008 due to psychiatric side effects (depression, suicidal ideation) when used as an anti-obesity drug. Its use as a cancer therapy would require careful risk-benefit assessment. The cell lines and xenograft model may not fully represent human colon cancer biology. The study examined only two specific genetic profiles of colorectal cancer."},{"rthcId":"RTHC-01493","title":"Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-13, in mice.","authors":"Pryce, Gareth; Baker, David","year":2017,"journal":"British journal of pharmacology, 174(21), 3790-3794","doi":"10.1111/bph.13973","pmid":"28800377","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers induced cannabinoid intoxication in mice using the synthetic CB1 agonist CB-13, which caused significant hypothermia and visible sedation. Twenty minutes after CB-13 administration, the CB1 receptor antagonist/inverse agonist AM251 was given.\n\nAM251 rapidly reversed the hypothermic effects of CB-13, returning body temperature toward normal. There was also a subjective reversal of visible sedation. The key finding was that the antagonist worked therapeutically (after intoxication had already occurred), not just prophylactically (before exposure).\n\nThe authors argue that with the emergence of extremely potent synthetic cannabinoids (\"Spice,\" \"Black Mamba\") causing life-threatening intoxications and deaths, a single-dose cannabinoid receptor antagonist could serve as a life-saving antidote, analogous to naloxone for opioid overdose.","whyItMatters":"Synthetic cannabinoid overdoses have caused numerous hospitalizations and deaths, and currently there is no specific antidote. This proof-of-concept study demonstrates that a CB1 receptor antagonist can reverse at least some cannabinoid effects after they have already begun, supporting the development of an emergency antidote for clinical use.","specificNumbers":"AM251 administered 20 minutes after CB-13 intoxication. Hypothermic effect was rapidly reversed. CB1 receptor antagonists have been widely used in research with established safety profiles for single doses.","methodology":"Biozzi ABH mice received the synthetic CB1 agonist CB-13. Body temperature was monitored as a measure of cannabinoid intoxication. AM251 was administered 20 minutes after CB-13 to test therapeutic (post-intoxication) reversal. Sedation was assessed observationally.","limitations":"Mouse study using a single synthetic cannabinoid and a single antagonist. Many synthetic cannabinoids in recreational use may have off-target effects not mediated by CB1 receptors, which an antagonist would not reverse. AM251 is a research tool, not a clinical drug. The study measured hypothermia as a proxy for intoxication; more severe effects (seizures, psychosis, cardiovascular collapse) were not modeled."},{"rthcId":"RTHC-01494","title":"Effects of Extended Cannabis Abstinence on Cognitive Outcomes in Cannabis Dependent Patients with Schizophrenia vs Non-Psychiatric Controls.","authors":"Rabin, Rachel A; Barr, Mera S; Goodman, Michelle S; Herman, Yarissa; Zakzanis, Konstantine K; Kish, Stephen J; Kiang, Michael; Remington, Gary; George, Tony P","year":2017,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 42(11), 2259-2271","doi":"10.1038/npp.2017.85","pmid":"28443616","tags":["cognition","psychosis","quitting"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Nineteen cannabis-dependent patients with schizophrenia and 20 cannabis-dependent controls without psychiatric illness attempted 28 days of cannabis abstinence. Abstinence rates were similar between groups (42% of patients, 55% of controls).\n\nAmong the schizophrenia patients who achieved abstinence, verbal learning and memory (measured by the Hopkins Verbal Learning Test-Revised) improved significantly over the 28 days (p < 0.03), with a large effect size (d = 1.07). Controls who abstained showed a smaller improvement (d = 0.66).\n\nThe finding that schizophrenia patients showed greater cognitive recovery than controls suggests that cannabis may be disproportionately impairing cognitive function in people with schizophrenia, and that these effects are at least partially reversible with abstinence.","whyItMatters":"Cannabis use is extremely common among people with schizophrenia, and there has been debate about whether it helps or harms cognitive function in this population. This study provides prospective evidence that abstinence leads to measurable cognitive improvement, particularly in verbal memory, a domain critical for daily functioning and treatment engagement.","specificNumbers":"19 schizophrenia patients and 20 controls. 42% of patients achieved abstinence vs. 55% of controls (not significantly different, p = 0.53). Verbal memory improvement in schizophrenia abstainers: d = 1.07 (large effect). Controls: d = 0.66 (medium effect). Abstinence verified by urinalysis at day 28.","methodology":"Prospective 28-day cannabis abstinence study with cognitive testing at days 0, 14, and 28. Abstinence was incentivized through contingency reinforcement and verified by twice-weekly urinalysis (THC-COOH < 20 ng/ml at day 28). A comprehensive neuropsychological battery assessed multiple cognitive domains. Clinical symptoms were monitored weekly.","limitations":"Very small sample size (fewer than 10 abstainers per group after dropout). Only male participants. The contingency reinforcement paradigm may not translate to real-world clinical settings. Less than half of participants achieved the full 28 days of abstinence. The study could not determine whether longer abstinence would produce further improvement."},{"rthcId":"RTHC-01495","title":"New pyridazinone-4-carboxamides as new cannabinoid receptor type-2 inverse agonists: Synthesis, pharmacological data and molecular docking.","authors":"Ragusa, Giulio; Gómez-Cañas, María; Morales, Paula; Rodríguez-Cueto, Carmen; Pazos, María R; Asproni, Battistina; Cichero, Elena; Fossa, Paola; Pinna, Gerard A; Jagerovic, Nadine; Fernández-Ruiz, Javier; Murineddu, Gabriele","year":2017,"journal":"European journal of medicinal chemistry, 127, 398-412","doi":"10.1016/j.ejmech.2017.01.002","pmid":"28088085","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01496","title":"Drug-Herb Interactions in the Elderly Patient with IBD: a Growing Concern.","authors":"Rahman, Haider; Kim, Marina; Leung, Galen; Green, Jesse A; Katz, Seymour","year":2017,"journal":"Current treatment options in gastroenterology, 15(4), 618-636","doi":"10.1007/s11938-017-0154-y","pmid":"28918484","tags":["drug-interactions","inflammation","medical-cannabis","seniors"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Nearly half of patients with inflammatory bowel disease (IBD) have used complementary and alternative medicine at some point, and elderly IBD patients face particular risks because they often take multiple medications for comorbid conditions.\n\nThe review covers over 20 herbs commonly used by IBD patients, including cannabis, and details their potential interactions with standard IBD drugs like immunomodulators, biologics, and corticosteroids. Cannabis was included alongside turmeric, boswellia, wormwood, and others.\n\nFor older patients, the combination of polypharmacy, altered drug metabolism, and herbal supplement use creates a complex landscape of potential interactions that providers may not be asking about or even aware of.","whyItMatters":"Many IBD patients use herbal supplements without telling their doctors, and many doctors do not ask. In elderly patients who are already on multiple medications, adding cannabis or other herbs without awareness of potential interactions could lead to unexpected drug levels, side effects, or reduced treatment efficacy.","specificNumbers":"Nearly 50% of IBD patients have used complementary/alternative medicine. The elderly are the fastest-growing IBD demographic. Over 20 herbs reviewed for interaction potential.","methodology":"Narrative review covering common herbal supplements used by IBD patients, including background, suggested use, evidence in IBD, and potential drug-herb interactions with IBD medications, with focus on the elderly population.","limitations":"Narrative review without systematic search methodology. Cannabis was one of many herbs discussed, and the depth of cannabis-specific interaction data was limited. Much of the interaction evidence is theoretical or based on pharmacological principles rather than documented clinical cases."},{"rthcId":"RTHC-01497","title":"A novel peptide that improves metabolic parameters without adverse central nervous system effects.","authors":"Reckziegel, Patrícia; Festuccia, William T; Britto, Luiz R G; Jang, Karen L Lopes; Romão, Carolina M; Heimann, Joel C; Fogaça, Manoela V; Rodrigues, Naielly S; Silva, Nicole R; Guimarães, Francisco S; Eichler, Rosangela A S; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A; Heimann, Andrea S; Ferro, Emer S","year":2017,"journal":"Scientific reports, 7(1), 14781","doi":"10.1038/s41598-017-13690-9","pmid":"29093454","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01498","title":"Cannabis as a Substitute for Opioid-Based Pain Medication: Patient Self-Report.","authors":"Reiman, Amanda; Welty, Mark; Solomon, Perry","year":2017,"journal":"Cannabis and cannabinoid research, 2(1), 160-166","doi":"10.1089/can.2017.0012","pmid":"28861516","tags":["medical-cannabis","pain","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 2,897 medical cannabis patients surveyed, 34% reported using opioid-based pain medication in the past six months. The responses from these opioid users were striking:\n\n97% strongly agreed or agreed that they could decrease their opioid use when also using cannabis. 81% strongly agreed or agreed that cannabis alone was more effective at treating their condition than cannabis combined with opioids. Patients overwhelmingly reported that cannabis provided pain relief comparable to their other medications but without the unwanted side effects.\n\nSimilar patterns were reported by patients using cannabis alongside non-opioid pain medications, suggesting the substitution effect was not limited to opioids.","whyItMatters":"Prescription opioid overdoses are the leading cause of accidental death in the United States. Patient-reported data consistently suggests that many opioid users can reduce their consumption when they have access to medical cannabis. While self-report data has limitations, the near-unanimous agreement (97%) is notable and aligns with ecological data showing lower opioid overdose rates in medical cannabis states.","specificNumbers":"2,897 patients surveyed. 34% used opioids in past 6 months. 97% agreed cannabis allowed decreased opioid use. 81% agreed cannabis alone was more effective than cannabis with opioids.","methodology":"Cross-sectional survey of 2,897 medical cannabis patients. Survey collected data on concurrent medication use, perceived effectiveness, and substitution behaviors.","limitations":"Self-report survey without clinical verification of opioid reduction. Severe selection bias: patients who found cannabis effective enough to continue using it are overrepresented, while those who tried and abandoned cannabis are absent. No clinical outcomes data (pain scores, functional measures). Cross-sectional design cannot determine causation."},{"rthcId":"RTHC-01499","title":"Opposing Effects of Cannabis Use on Late Auditory Repetition Suppression in Schizophrenia Patients and Healthy Control Subjects.","authors":"Rentzsch, Johannes; Kronenberg, Golo; Stadtmann, Ada; Neuhaus, Andres; Montag, Christiane; Hellweg, Rainer; Jockers-Scherübl, Maria Christiane","year":2017,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 2(3), 263-271","doi":"10.1016/j.bpsc.2016.10.004","pmid":"29528297","tags":["psychosis","cognition","neuroscience"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Researchers measured how the brain filters repeated auditory signals in four groups: schizophrenia patients with and without cannabis use, and healthy controls with and without cannabis use. They focused on \"repetition suppression,\" where the brain normally dampens its response to a repeated sound.\n\nFor the P200 brain wave component, cannabis had opposite effects depending on diagnosis. In healthy controls, chronic cannabis use was associated with worse suppression (0.55 vs. 0.40, p < 0.02), meaning poorer signal filtering. In schizophrenia patients, cannabis use was associated with better suppression (0.36 vs. 0.54, p < 0.02), meaning improved signal filtering.\n\nAmong healthy controls, total lifetime cannabis consumption correlated with worse P200 suppression (r = 0.28, p < 0.007). Among schizophrenia patients, longer time since last cannabis use correlated with worse P200 suppression (r = 0.42, p < 0.002), suggesting the benefit faded with abstinence.","whyItMatters":"This study provides neurophysiological evidence for the paradox of cannabis use in schizophrenia: while cannabis is a risk factor for psychosis, many patients report subjective benefits. The opposing effects on P200 suppression suggest that the endocannabinoid system may be fundamentally altered in schizophrenia, meaning cannabis interacts with a different neurological landscape in these patients.","specificNumbers":"34 schizophrenia patients with cannabis, 33 without. 45 controls with cannabis, 61 without. Interaction between diagnosis and cannabis on P200 suppression: p < 0.001. Cannabis-using controls: suppression ratio 0.55. Non-using controls: 0.40. Cannabis-using schizophrenia: 0.36. Non-using schizophrenia: 0.54.","methodology":"Mixed-sample study with 34 schizophrenia patients and 45 healthy controls who were chronic heavy cannabis users, plus 33 schizophrenia patients and 61 healthy controls without cannabis use. Auditory event-related potentials were recorded using a paired-stimulus paradigm measuring P50, N100, and P200 repetition suppression.","limitations":"Cross-sectional design cannot determine causation. Cannabis users in both groups may differ from non-users in ways beyond cannabis exposure (other substance use, medication differences). P200 suppression is one of many possible measures of sensory processing, and its clinical relevance is debated. The study measured chronic heavy use and did not assess the effects of different doses or patterns of use."},{"rthcId":"RTHC-01500","title":"An Endocannabinoid Uptake Inhibitor from Black Pepper Exerts Pronounced Anti-Inflammatory Effects in Mice.","authors":"Reynoso-Moreno, Inés; Najar-Guerrero, Israel; Escareño, Noé; Flores-Soto, Mario Eduardo; Gertsch, Jürg; Viveros-Paredes, Juan Manuel","year":2017,"journal":"Journal of agricultural and food chemistry, 65(43), 9435-9442","doi":"10.1021/acs.jafc.7b02979","pmid":"28942644","tags":["inflammation","pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Guineensine, a dietary compound present in both black and long pepper, was previously shown to inhibit cellular endocannabinoid uptake, effectively boosting the body's own cannabinoid levels. Researchers tested whether this mechanism would translate to anti-inflammatory and pain-relieving effects in living animals.\n\nThe results were potent: guineensine inhibited inflammatory pain by 95.6% at 2.5 mg/kg, reduced edema (swelling) by 50.0% at 5 mg/kg, and produced acute pain relief of 66.1% at 5 mg/kg. It also suppressed inflammatory cytokine production during endotoxemia.\n\nThe pain relief and hypothermia caused by guineensine were blocked by the CB1 antagonist rimonabant, confirming involvement of the endocannabinoid system. However, guineensine also showed activity at dopamine transporters, serotonin 5HT2A receptors, and sigma receptors, revealing a broader pharmacological profile than previously appreciated.","whyItMatters":"The idea that a common dietary compound from black pepper could produce significant anti-inflammatory and analgesic effects through the endocannabinoid system is intriguing. It supports the concept that endocannabinoid tone, not just direct receptor activation by THC, plays an important role in pain and inflammation regulation.","specificNumbers":"Inflammatory pain inhibition: 95.6% at 2.5 mg/kg. Edema inhibition: 50.0% at 5 mg/kg. Acute analgesia: 66.1% at 5 mg/kg. Effects on pain and hypothermia blocked by CB1 antagonist rimonabant. Additional targets: dopamine transporter (DAT), 5HT2A, sigma receptors.","methodology":"Mouse models of acute and inflammatory pain and endotoxemia. Guineensine was injected intraperitoneally at various doses. CB1 receptor involvement was tested using the antagonist rimonabant. A screen of 45 CNS-related receptors, ion channels, and transporters was performed to identify additional targets.","limitations":"Animal study using intraperitoneal injection, not oral consumption. The doses needed for therapeutic effects may far exceed what dietary black pepper consumption provides. The polypharmacology (multiple receptor targets) makes it difficult to attribute effects solely to endocannabinoid mechanisms. No human studies exist for guineensine."},{"rthcId":"RTHC-01501","title":"Cannabinoid hyperemesis syndrome: A disorder of the HPA axis and sympathetic nervous system?","authors":"Richards, John R","year":2017,"journal":"Medical hypotheses, 103, 90-95","doi":"10.1016/j.mehy.2017.04.018","pmid":"28571820","tags":["withdrawal","appetite","cardiovascular"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This hypothesis paper proposes a neurobiological mechanism for cannabinoid hyperemesis syndrome (CHS) that explains both the vomiting and the characteristic relief from hot water bathing.\n\nThe author argues that chronic or excessive cannabis use leads to abnormal stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS). Over time, this overstimulation causes dysfunction of the endocannabinoid system, which normally plays a critical role in maintaining homeostasis (internal balance) of the autonomic nervous system after stress.\n\nWhen this regulatory system breaks down, the result is the cyclical pattern of CHS: intense nausea, vomiting, and abdominal pain that standard antiemetics cannot control. The hot water bathing provides relief potentially by restoring some degree of autonomic balance through cutaneous thermoreceptor activation. The framework also explains why benzodiazepines and antipsychotics (which dampen autonomic arousal) work better for CHS than traditional antiemetics.","whyItMatters":"CHS has been recognized clinically for over a decade but its pathophysiology remains poorly understood. A coherent mechanistic framework could guide treatment development beyond the current approach of symptom management. Understanding CHS as an autonomic disorder rather than a simple gastrointestinal problem reframes how clinicians should approach these patients.","specificNumbers":"Cannabis legalization, use, and potency have all increased worldwide over the past decade. Standard antiemetics frequently fail in CHS. Benzodiazepines and antipsychotics show better treatment success.","methodology":"Medical hypothesis paper reviewing existing literature on the endocannabinoid system, HPA axis, sympathetic nervous system, and clinical features of CHS to propose a unifying mechanistic explanation.","limitations":"This is a hypothesis paper, not an experimental study. The proposed mechanism has not been directly tested. The author draws on circumstantial evidence and physiological reasoning rather than new data. Alternative mechanisms (including direct effects on gut motility via CB1 receptors in the gastrointestinal tract) are not fully addressed."},{"rthcId":"RTHC-01502","title":"Pharmacologic Treatment of Cannabinoid Hyperemesis Syndrome: A Systematic Review.","authors":"Richards, John R; Gordon, Brent K; Danielson, Aaron R; Moulin, Aimee K","year":2017,"journal":"Pharmacotherapy, 37(6), 725-734","doi":"10.1002/phar.1931","pmid":"28370228","tags":["withdrawal","appetite","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The systematic review analyzed 63 eligible articles covering 205 CHS patients. The evidence quality was generally low: only 4 prospective studies (level 2), 3 retrospective studies (level 3), 12 case series (level 4), and 44 case reports (level 5).\n\nFor acute treatment, benzodiazepines (particularly lorazepam) were the most frequently cited effective medication, followed by haloperidol and topical capsaicin cream. Hot showers and baths were universally effective across all case-level studies.\n\nFor long-term management, tricyclic antidepressants showed the most promise in the limited prospective data. Standard antiemetics (ondansetron, promethazine, diphenhydramine) were mentioned but authors did not consistently endorse their efficacy.\n\nImportantly, conventional antiemetics that work well for other causes of vomiting were frequently associated with treatment failure in CHS, underscoring the unique pathophysiology of this condition.","whyItMatters":"CHS has become increasingly common with cannabis legalization, yet emergency physicians and clinicians have had little evidence-based guidance for treatment. This systematic review provides the most comprehensive summary of treatment options available, even though the evidence base remains limited to mostly case reports.","specificNumbers":"1,262 articles screened. 63 included. 205 human subjects total. 4 level-2 studies (64 subjects). 3 level-3 studies (43 subjects). 12 level-4 case series (54 subjects). 44 level-5 case reports (44 subjects). Hot showers: universally effective.","methodology":"Systematic review searching Medline, PsycINFO, DARE, OpenGrey, Google Scholar, and the Cochrane Library from inception to February 2017. Evidence was graded using Oxford Center for Evidence-Based Medicine guidelines. 1,262 articles were screened, 63 included.","limitations":"The vast majority of evidence comes from case reports and case series (level 4-5), the weakest forms of clinical evidence. No randomized controlled trials existed at the time of this review. Publication bias likely favors reporting of successful treatments. The heterogeneity of dosing, timing, and outcome measures across studies limits firm conclusions."},{"rthcId":"RTHC-01503","title":"Cannabis and crash responsibility while driving below the alcohol per se legal limit.","authors":"Romano, Eduardo; Voas, Robert B; Camp, Bayliss","year":2017,"journal":"Accident; analysis and prevention, 108, 37-43","doi":"10.1016/j.aap.2017.08.003","pmid":"28841409","tags":["driving"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Analyzing 4,294 drivers involved in fatal crashes in California from 1993-2009, researchers found that cannabis elevated crash responsibility even when alcohol was absent or minimal.\n\nAt zero blood alcohol concentration (BAC), cannabis-positive drivers had an odds ratio of 1.89 for crash responsibility compared to substance-negative drivers. At very low alcohol levels (0 < BAC < 0.05 g/dL, below any legal limit), the odds ratio jumped to 3.42.\n\nThe interaction between cannabis and even small amounts of alcohol appeared to amplify crash risk substantially. These findings suggest that focusing impaired driving enforcement only on high-BAC drivers misses a meaningful source of crash risk from cannabis-impaired driving.","whyItMatters":"As cannabis legalization spreads, understanding its independent contribution to crash risk becomes critical for traffic safety policy. This study addresses a specific gap: whether cannabis is dangerous for drivers who have consumed little or no alcohol, since previous research had mainly established the combined risk.","specificNumbers":"4,294 drivers in fatal crashes. Cannabis at zero BAC: OR = 1.89 for crash responsibility. Cannabis at 0 < BAC < 0.05: OR = 3.42. Data from California, 1993-2009.","methodology":"Retrospective analysis of fatal crashes merging California SWITRS and FARS databases from 1993-2009. Logistic regression modeled the contribution of alcohol and drugs to crash responsibility. Sample was restricted to 1993-2009 to account for changes in lab testing practices. 4,294 drivers were analyzed.","limitations":"Retrospective analysis of crash records with limited control for confounding variables. Drug testing in fatal crashes was not systematic or standardized across jurisdictions and time periods. Cannabis detection in blood or urine does not necessarily indicate acute impairment at the time of the crash, as THC metabolites can persist for days or weeks. The study could not determine dose or timing of cannabis use."},{"rthcId":"RTHC-01504","title":"Marijuana and the Risk of Fatal Car Crashes: What Can We Learn from FARS and NRS Data?","authors":"Romano, Eduardo; Torres-Saavedra, Pedro; Voas, Robert B; Lacey, John H","year":2017,"journal":"The journal of primary prevention, 38(3), 315-328","doi":"10.1007/s10935-017-0478-3","pmid":"28500615","tags":["driving"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The authors examined why two studies using similar databases and approaches produced opposite conclusions about marijuana's contribution to fatal crash risk. Li et al. (2013) found marijuana significantly increased crash risk, while Romano et al. (2014) found no significant increase after controlling for confounders.\n\nThe key source of divergence was limitations in the FARS (Fatality Analysis Reporting System) database. Drug testing of fatally injured drivers is not standardized across jurisdictions: different states test for different drugs at different rates, using different methods, and testing rates have changed dramatically over time. These inconsistencies mean that the pool of tested drivers is not representative of all drivers in fatal crashes.\n\nThe authors conclude that FARS should not be used to examine trends in drug use prevalence among crash-involved drivers or to obtain precise risk estimates. However, under certain conditions (data from jurisdictions that routinely test, with consistent procedures), it could provide relative risk comparisons.","whyItMatters":"Policy decisions about cannabis and driving are heavily influenced by epidemiological research. If the major databases used for this research produce contradictory results depending on analytic choices, policymakers need to understand these limitations. This paper serves as a critical methodological caution for all drugged driving research.","specificNumbers":"Two studies compared: Li et al. 2013 (found significant crash risk from marijuana) vs. Romano et al. 2014 (found no significant risk). Both used FARS and NRS databases. Testing rates and methods varied widely across jurisdictions and over time.","methodology":"Methodological comparison of two published case-control studies that used FARS and NRS databases. The authors identified specific analytic choices and database limitations that led to contradictory results.","limitations":"This is a methodological critique, not new empirical research. The authors do not provide definitive answers about whether marijuana increases crash risk, instead highlighting why existing studies disagree. Their own prior work (Romano et al. 2014) is one of the two studies being compared, creating potential bias."},{"rthcId":"RTHC-01505","title":"Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.","authors":"Rosenberg, Evan C; Patra, Pabitra H; Whalley, Benjamin J","year":2017,"journal":"Epilepsy & behavior : E&B, 70(Pt B), 319-327","doi":"10.1016/j.yebeh.2016.11.006","pmid":"28190698","tags":["epilepsy","cbd","neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review surveyed decades of preclinical research on plant cannabinoids in models of seizures, epilepsy, epileptogenesis (the development of epilepsy), and seizure-related neuroprotection.\n\nIn simple acute seizure models, activating CB1 receptors typically reduced seizures, and blocking them worsened seizures. However, in more complex models of chronic epilepsy, the picture became far more nuanced. Factors including the brain regions involved, the balance between excitatory and inhibitory circuits, receptor desensitization, whether the drug was a full or partial agonist, and the timing and duration of treatment all influenced whether endocannabinoid modulation was anti- or pro-epileptic.\n\nCBD and CBDV (cannabidavarin) stood out for their more consistent anti-seizure effects across models. Two Phase III clinical trials of CBD in Dravet syndrome and Lennox-Gastaut syndrome provided pivotal evidence of efficacy. However, the molecular mechanism of CBD's anti-seizure action remained poorly understood at the time of this review.","whyItMatters":"This review provides essential context for the CBD-epilepsy story: while CBD's clinical benefits are becoming established, the broader endocannabinoid system's role in epilepsy is far more complex than \"cannabinoids stop seizures.\" Understanding these complexities is important for developing next-generation treatments and for setting realistic expectations about cannabis-based epilepsy therapies.","specificNumbers":"Over 100 individual plant cannabinoids identified in cannabis. Two Phase III clinical trials of CBD completed (Dravet syndrome and Lennox-Gastaut syndrome). CBD and CBDV showed the most consistent anti-seizure effects in preclinical models.","methodology":"Comprehensive narrative review of the published literature on plant cannabinoid effects in preclinical models of seizures, epilepsy, epileptogenesis, and neuroprotection.","limitations":"Narrative review without systematic methodology. The complexity of the preclinical literature makes synthesis difficult, as results depend heavily on the specific model, species, drug, and protocol used. Many animal models of epilepsy do not perfectly replicate human epilepsy. The review's scope is broad, necessarily sacrificing depth in some areas."},{"rthcId":"RTHC-01506","title":"Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits.","authors":"Rossignoli, Matheus Teixeira; Lopes-Aguiar, Cleiton; Ruggiero, Rafael Naime; Do Val da Silva, Raquel Araujo; Bueno-Junior, Lezio Soares; Kandratavicius, Ludmyla; Peixoto-Santos, José Eduardo; Crippa, José Alexandre; Cecilio Hallak, Jaime Eduardo; Zuardi, Antonio Waldo; Szawka, Raphael Escorsim; Anselmo-Franci, Janete; Leite, João Pereira; Romcy-Pereira, Rodrigo Neves","year":2017,"journal":"Neuroscience, 350, 85-93","doi":"10.1016/j.neuroscience.2017.03.019","pmid":"28344069","tags":["cbd","cognition","neuroscience","ptsd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether CBD delivered directly to the prefrontal cortex could interfere with the consolidation of fear memories in rats. The timing proved critical.\n\nWhen CBD was infused immediately after contextual fear conditioning, it had no effect on memory. When infused 5 hours later, it significantly impaired fear memory consolidation. This selective time window aligns with research showing that the prefrontal cortex is recruited at specific intervals after memory formation, not continuously.\n\nThe 5-hour CBD treatment was associated with reduced dopamine turnover in the prefrontal cortex at the time of memory retrieval (5 days later). It also reduced expression of the immediate early genes c-fos and zif-268 in the hippocampus, prefrontal cortex, and thalamus, brain regions critical for fear memory networks.","whyItMatters":"Post-traumatic stress disorder (PTSD) involves the persistence of fear memories that resist normal extinction. Understanding that there are specific time windows after a traumatic event when memory consolidation can be disrupted has direct implications for treatment timing. CBD's ability to interfere with this process at a specific window suggests potential for preventing traumatic memory solidification.","specificNumbers":"Effective time window: 5 hours post-conditioning (not immediate). Memory tested 5 days after conditioning. Reduced dopamine turnover in PFC. Reduced c-fos and zif-268 expression in hippocampus, PFC, and thalamus.","methodology":"Bilateral infusion of CBD into the rat prefrontal cortex either immediately or 5 hours after contextual fear conditioning. Memory was tested 5 days later. Microdialysis measured extracellular neurotransmitter levels. Immunohistochemistry quantified expression of activity-dependent transcription factors (c-fos and zif-268) across brain regions.","limitations":"Animal study using direct brain injection, a route not feasible in humans. The fear conditioning paradigm is a simplified model of trauma. Whether systemic CBD (oral or inhaled) reaches the prefrontal cortex in sufficient concentrations to produce these effects is unknown. The 5-hour window was one of only two time points tested; the actual window could be wider or narrower."},{"rthcId":"RTHC-01507","title":"Simple and Fast Gas-chromatography Mass Spectrometry Assay to Assess Delta 9-Tetrahydrocannabinol and Cannabidiol in Dogs Treated with Medical Cannabis for Canine Epilepsy.","authors":"Rotolo, Maria C; Graziano, Silvia; Pellegrini, Manuela; Corlazzoli, Daniele; Antinori, Lucia; Porcarelli, Laura; Pichini, Simona","year":2017,"journal":"Current pharmaceutical biotechnology, 18(10), 821-827","doi":"10.2174/1389201018666171122115815","pmid":"29173160","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01508","title":"Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.","authors":"Russo, Ethan B; Marcu, Jahan","year":2017,"journal":"Advances in pharmacology (San Diego, Calif.), 80, 67-134","doi":"10.1016/bs.apha.2017.03.004","pmid":"28826544","tags":["medical-cannabis","cbd","pain","neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This major review, authored by leading cannabis researchers, argued that the pharmacology of cannabis cannot be reduced to THC and CBD alone. The review covered several key areas:\n\nTerpenoids (aromatic compounds like myrcene, limonene, pinene, linalool, and beta-caryophyllene) contribute pharmacological effects at concentrations found in cannabis, including anti-inflammatory, analgesic, anxiolytic, and anti-cancer properties. Their synergistic relationships with cannabinoids form the \"entourage effect.\"\n\nLesser-known cannabinoids including CBG, CBC, CBN, THCV, and CBDV each have distinct pharmacological profiles. CBD itself showed \"remarkably versatile pharmacology\" across pain, anxiety, psychosis, inflammation, and seizure disorders.\n\nOther plant parts yield unique compounds: friedelin from roots, canniprene from leaves, cannabisin from seed coats, and cannflavin A from sprouts, each with independent pharmacological interest.","whyItMatters":"This review reframes cannabis from a \"THC delivery system\" to a complex pharmacological plant with dozens of active compounds working in concert. Understanding these interactions is essential for developing better cannabis-based medicines and for explaining why different cannabis strains or preparations produce different effects despite similar THC/CBD ratios.","specificNumbers":"Over 100 individual phytocannabinoids identified. Cannabis golden age of pharmacology began in the 1960s with Mechoulam's isolation of CBD and THC. Review covers terpenoids, flavonoids, and compounds from roots, leaves, seed coats, and sprouts.","methodology":"Comprehensive narrative review covering the pharmacology of phytocannabinoids, terpenoids, flavonoids, and other cannabis-derived compounds. Authored by Ethan Russo and Jahan Marcu, prominent researchers in cannabis pharmacology.","limitations":"Narrative review that synthesizes a vast literature without systematic methodology. Some of the claimed synergies are based on theoretical pharmacological reasoning rather than rigorous clinical evidence. The authors are prominent advocates for whole-plant cannabis medicine, which may influence emphasis. Many of the lesser-known compounds have limited preclinical data."},{"rthcId":"RTHC-01509","title":"The role of Sativex in robotic rehabilitation in individuals with multiple sclerosis: Rationale, study design, and methodology.","authors":"Russo, Margherita; Dattola, Vincenzo; Logiudice, Anna Lisa; Ciurleo, Rosella; Sessa, Edoardo; De Luca, Rosaria; Bramanti, Placido; Bramanti, Alessia; Naro, Antonino; Calabrò, Rocco Salvatore","year":2017,"journal":"Medicine, 96(46), e8826","doi":"10.1097/MD.0000000000008826","pmid":"29145345","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01510","title":"CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.","authors":"Saravia, Rocio; Flores, África; Plaza-Zabala, Ainhoa; Busquets-Garcia, Arnau; Pastor, Antoni; de la Torre, Rafael; Di Marzo, Vincenzo; Marsicano, Giovanni; Ozaita, Andrés; Maldonado, Rafael; Berrendero, Fernando","year":2017,"journal":"Biological psychiatry, 81(7), 625-634","doi":"10.1016/j.biopsych.2016.07.007","pmid":"27737762","tags":["cognition","neuroscience","addiction","quitting"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers discovered that the cognitive deficits occurring during nicotine withdrawal are mediated by the endocannabinoid system, specifically through CB1 receptors on inhibitory (GABAergic) neurons.\n\nDuring nicotine withdrawal in mice, 2-AG levels (but not anandamide) increased. This 2-AG surge, acting through CB1 receptors on GABA neurons, caused memory impairment. Blocking CB1 receptors with rimonabant or genetically deleting CB1 receptors specifically from GABA neurons prevented the cognitive deficits.\n\nThe withdrawal also caused structural brain changes: mature dendritic spines on hippocampal CA1 neurons decreased at day 4 of withdrawal, and this decrease correlated with memory performance. These structural changes were normalized in mice lacking CB1 receptors on GABA neurons and by rimonabant treatment.","whyItMatters":"Cognitive difficulties during nicotine withdrawal are a major predictor of relapse in people trying to quit smoking. Identifying the endocannabinoid system as the mechanism driving these cognitive deficits opens a potential therapeutic target. If CB1 modulation could prevent withdrawal-related cognitive impairment, it might help smokers quit more successfully.","specificNumbers":"2-AG levels increased during nicotine withdrawal (anandamide unchanged). 2-AG synthesis inhibitor O7460 abolished cognitive deficits. CB1 antagonist rimonabant prevented memory impairment. Mature dendritic spines decreased at day 4 of withdrawal. Spine density correlated with memory performance.","methodology":"Nicotine withdrawal was precipitated by the nicotinic antagonist mecamylamine in mice. Multiple pharmacological (rimonabant, 2-AG synthesis inhibitor O7460, 2-AG degradation inhibitor JZL184) and genetic (conditional CB1 receptor knockout on GABA neurons) approaches were used. Memory was assessed behaviorally. Dendritic spine density was quantified on hippocampal neurons.","limitations":"Mouse model of precipitated withdrawal may not fully replicate the gradual withdrawal humans experience when quitting smoking. Rimonabant was withdrawn from the human market due to psychiatric side effects, limiting direct clinical translation. The study examined a specific type of memory; other cognitive domains were not assessed."},{"rthcId":"RTHC-01511","title":"Prevalence, correlates, and trends in tobacco use and cessation among current, former, and never adult marijuana users with a history of tobacco use, 2005-2014.","authors":"Schauer, Gillian L; King, Brian A; McAfee, Timothy A","year":2017,"journal":"Addictive behaviors, 73, 165-171","doi":"10.1016/j.addbeh.2017.04.023","pmid":"28525833","tags":["addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using nationally representative data from 2013-2014, the study examined tobacco use and cessation patterns among adults who had ever used tobacco, stratified by marijuana use status.\n\nCurrent marijuana users who had ever used tobacco showed dramatically different tobacco patterns: 69.1% were current tobacco users, only 9.1% had recently quit, and only 21.8% had achieved sustained cessation (quit for more than 12 months). In contrast, among never-marijuana users who had ever used tobacco, only 28.2% were current tobacco users and 65.5% had achieved sustained cessation.\n\nFormer marijuana users fell in between: 38.5% current tobacco use, 53.1% sustained cessation.\n\nOn a positive note, from 2005 to 2014, current tobacco use declined and sustained cessation increased among all marijuana use groups, suggesting that even among marijuana users, tobacco cessation progress was being made.","whyItMatters":"Approximately 70% of adult marijuana users also use tobacco, making co-use the norm rather than the exception. If marijuana use significantly interferes with tobacco cessation, this has major public health implications given that tobacco remains the leading preventable cause of death.","specificNumbers":"Current marijuana users: 69.1% current tobacco, 9.1% recent cessation, 21.8% sustained cessation. Former marijuana users: 38.5% current tobacco, 8.4% recent cessation, 53.1% sustained cessation. Never marijuana users: 28.2% current tobacco, 6.3% recent cessation, 65.5% sustained cessation. All groups showed improvement from 2005-2014.","methodology":"Cross-sectional analysis of the National Survey on Drug Use and Health (NSDUH), 2005-2014. Nationally representative household survey of U.S. civilians aged 18+. Weighted estimates and logistic regression analyses compared tobacco use patterns by marijuana use status.","limitations":"Cross-sectional design cannot determine whether marijuana use causes lower tobacco cessation rates or both are driven by shared risk factors. Self-report data may underestimate both marijuana and tobacco use. The study could not account for the mode of marijuana consumption (joint smoking versus edibles or vaporizing), which matters because joint smokers may maintain tobacco habits through the shared smoking behavior."},{"rthcId":"RTHC-01512","title":"Synthetic cannabinoids found in \"spice\" products alter body temperature and cardiovascular parameters in conscious male rats.","authors":"Schindler, Charles W; Gramling, Benjamin R; Justinova, Zuzana; Thorndike, Eric B; Baumann, Michael H","year":2017,"journal":"Drug and alcohol dependence, 179, 387-394","doi":"10.1016/j.drugalcdep.2017.07.029","pmid":"28846955","tags":["synthetic-cannabinoids","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers compared THC and four synthetic cannabinoids (CP55,940, JWH-018, AM2201, XLR-11) found in \"Spice\" products. All compounds produced dose-dependent hypothermia (temperature drops) that was blocked by the CB1 antagonist rimonabant, confirming cannabinoid receptor involvement.\n\nHowever, the synthetic cannabinoids also elevated blood pressure during the first hour, and this hypertensive effect was NOT blocked by either rimonabant or the neutral CB1 antagonist AM4113. Instead, the blood pressure increase was blocked by the ganglionic blocker hexamethonium and the alpha-1 adrenergic antagonist prazosin.\n\nThis revealed a dual mechanism: hypothermia was cannabinoid receptor-mediated, but the blood pressure elevation was driven by increased central sympathetic nervous system outflow, independent of cannabinoid receptors. This non-cannabinoid cardiovascular effect may explain why synthetic cannabinoid users experience cardiovascular emergencies that would not be expected from CB1 receptor activation alone.","whyItMatters":"Synthetic cannabinoid-related cardiovascular emergencies (heart attacks, strokes, hypertensive crises) are a growing clinical problem. This study reveals that these cardiovascular effects occur through a mechanism separate from the cannabinoid receptors, explaining why they may be more dangerous than natural cannabis and why CB1 antagonists alone may not reverse them.","specificNumbers":"Potency ranking for hypothermia: CP55,940 > AM2201 = JWH-018 > THC = XLR-11. Blood pressure elevation occurred in the first hour. Rimonabant blocked hypothermia but NOT blood pressure effects. Hexamethonium and prazosin blocked the blood pressure increase.","methodology":"Male rats received subcutaneous injections of THC or synthetic cannabinoids. Biotelemetry transmitters measured body temperature and blood pressure continuously for 3 hours. Antagonists were used to identify receptor mechanisms. Potency rankings were established across compounds.","limitations":"Animal study using subcutaneous injection, which differs from the typical human route of smoking/vaporizing. Only four synthetic cannabinoids were tested, while hundreds exist in the recreational market. Blood pressure and temperature are surrogate measures; direct cardiac effects were not assessed. Chronic exposure effects were not studied."},{"rthcId":"RTHC-01513","title":"Cannabis Withdrawal: A Review of Neurobiological Mechanisms and Sex Differences.","authors":"Schlienz, Nicolas J; Budney, Alan J; Lee, Dustin C; Vandrey, Ryan","year":2017,"journal":"Current addiction reports, 4(2), 75-81","doi":"10.1007/s40429-017-0143-1","pmid":"29057200","tags":["withdrawal","neuroscience","sex-differences","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review synthesized preclinical and clinical research on cannabis withdrawal, identifying several key findings.\n\nLong-term cannabis use downregulates CB1 receptors throughout the brain. This reduced receptor density directly correlates with withdrawal severity during early abstinence. Importantly, CB1 receptor density recovers with extended abstinence, providing a neurobiological basis for why withdrawal symptoms are time-limited.\n\nSex differences are emerging as an important factor. Females showed increased rate and severity of a subset of cannabis withdrawal symptoms compared to males. This parallels sex differences seen in withdrawal from other substances and may have implications for treatment approaches.\n\nThe review also noted that most clinical withdrawal studies have predominantly male samples, creating a significant knowledge gap about the female experience of cannabis withdrawal.","whyItMatters":"Cannabis withdrawal syndrome was only added to the DSM-5 in 2013, and awareness remains limited among both clinicians and the public. Understanding the neurobiological basis (CB1 downregulation) and the influence of sex on withdrawal severity can improve clinical support for people trying to quit cannabis.","specificNumbers":"CB1 receptor density decreases with chronic cannabis use. Reduced CB1 density correlates with increased withdrawal severity. CB1 receptor density recovers with extended abstinence. Females show increased rate and severity of some withdrawal symptoms.","methodology":"Narrative review of preclinical (animal) and clinical (human) research on the neurobiology of cannabis withdrawal, with specific attention to CB1 receptor dynamics, endocannabinoid system components, and sex differences.","limitations":"Many clinical studies are limited by small sample sizes and predominantly male participants. The review acknowledges that endocannabinoid enzymes, negative allosteric modulators, and other neurobiological systems that may influence withdrawal have been insufficiently studied. Preclinical findings may not directly translate to human withdrawal experiences."},{"rthcId":"RTHC-01514","title":"E-cigarette use and asthma in a multiethnic sample of adolescents.","authors":"Schweitzer, Rebecca J; Wills, Thomas A; Tam, Elizabeth; Pagano, Ian; Choi, Kelvin","year":2017,"journal":"Preventive medicine, 105, 226-231","doi":"10.1016/j.ypmed.2017.09.023","pmid":"28964850","tags":["respiratory","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a statewide survey of 6,089 high school students in Hawaii (mean age 15.8), current e-cigarette use was significantly associated with currently having asthma (adjusted OR = 1.48) and with previously having asthma (aOR = 1.22).\n\nNotably, after controlling for e-cigarette use and demographic factors, neither cigarette smoking nor marijuana use were significantly associated with asthma in the multivariate analysis. This suggests that e-cigarettes may have a stronger independent association with asthma than either combustible tobacco or marijuana in this adolescent population.\n\nRacial and ethnic disparities were also observed: Black, Native Hawaiian, other Pacific Islander, and Filipino students had higher rates of asthma compared to Asian American and Caucasian students.","whyItMatters":"E-cigarettes are frequently marketed as safer alternatives to smoking, including among adolescents. This study adds to growing evidence that e-cigarette aerosol may have significant respiratory health effects. The finding that marijuana was not independently associated with asthma after controlling for e-cigarette use provides context for understanding the relative respiratory risks of different inhalation methods.","specificNumbers":"6,089 students. 50% female. Mean age 15.8 years. 33 high schools. Current e-cigarette use and current asthma: aOR = 1.48 (CI 1.26-1.74). E-cigarette use and previous asthma: aOR = 1.22 (CI 1.07-1.40). Marijuana and cigarette smoking: nonsignificant in multivariate model.","methodology":"Cross-sectional survey administered in classrooms across 33 high schools statewide in Hawaii in 2015. Multinomial regression examined the association between e-cigarette use and asthma, controlling for cigarette smoking, marijuana use, and six demographic covariates.","limitations":"Cross-sectional design cannot determine causation: teens with asthma might be more likely to use e-cigarettes (reverse causation) rather than e-cigarettes causing asthma. Self-reported data on both substance use and asthma diagnosis. Hawaii's multiethnic population may not be representative of the broader U.S. The study could not distinguish between nicotine and cannabis vaporizers."},{"rthcId":"RTHC-01515","title":"Study on the prescribing patterns of antipsychotic medication in a rural England Community Mental Health Team.","authors":"Seshadri, Madhavan; Elsemary, Ahmed; Thalitaya, Madhusudan Deepak; Chikodzore, Lawrence; Nagalingam, Priya","year":2017,"journal":"Psychiatria Danubina, 29(Suppl 3), 524-529","doi":null,"pmid":"28953820","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01516","title":"Alternate policing strategies: Cost-effectiveness of cautioning for cannabis offences.","authors":"Shanahan, Marian; Hughes, Caitlin Elizabeth; McSweeney, Tim; Griffin, Beth Ann","year":2017,"journal":"The International journal on drug policy, 41, 140-147","doi":"10.1016/j.drugpo.2016.12.012","pmid":"28139329","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared two police responses to minor cannabis offenses in Australia: formal caution (with referral to education/treatment) versus traditional arrest and charge.\n\nAmong 544 matched offenders (195 arrested, 355 cautioned), there was no statistically significant difference in self-reported cannabis use days before and after the police intervention between the two groups. Both groups showed similar patterns of continued or changed use regardless of whether they were arrested or cautioned.\n\nHowever, costs were significantly different. The mean cost for arrest was $733 compared to $388 for caution, after matching on age, prior criminal conviction, cannabis consumption, employment status, criminal activity, and severity of dependence. Cautioning saved roughly half the cost per offender while producing equivalent outcomes.","whyItMatters":"This study provides economic evidence for cannabis diversion programs. If cautioning produces the same outcomes as arrest at half the cost, the policy argument for diversion becomes straightforward: it saves public resources without increasing cannabis use. This evidence is relevant to the global debate about decriminalization and alternatives to criminal penalties.","specificNumbers":"544 matched offenders. 195 arrested, 355 cautioned. Mean cost: arrest $733 (SD 151), caution $388 (SD 111). No significant difference in cannabis use pre- and post-intervention.","methodology":"Purpose-built nationwide online survey of detected cannabis offenders in Australia. Propensity score weighting and doubly robust regression addressed differences between groups. Cost data included policing, court, penalties, assessment, treatment, and educational sessions.","limitations":"Self-selected online survey of detected offenders, which may not represent all cannabis offenders. Self-reported cannabis use is subject to bias. The study could not account for deterrence effects on the broader population (people who were never detected). Cost estimates did not include long-term consequences of criminal records on employment and housing."},{"rthcId":"RTHC-01517","title":"Clinical Characteristics and Angiographic Findings of Acute Myocardial Infarction Associated With Marijuana Use: Consecutive Case Series.","authors":"Sharma, Navneet; Lee, Justin; Aponte, Carla Saladini; Marmur, Jonathan D; Lawson, William E; Mann, Noelle N; Salifu, Moro O; Youssef, Irini; McFarlane, Samy I","year":2017,"journal":"SciFed journal of cardiology, 2(1)","doi":null,"pmid":"30320313","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Over four years at an inner-city hospital, researchers identified 8 patients (10 total events) who had ST-elevation myocardial infarction (STEMI) associated with marijuana use. The mean age was 40.1 years, ranging from 26 to 59.\n\nThe demographic profile was striking: 9 of 10 cases were male, and 8 were Black, reflecting the patient population of the urban hospital. Most concerning, 3 of 10 cases (30%) had no known cardiovascular risk factors at all on admission, and 2 had only a single risk factor. This means half of the marijuana-associated heart attacks occurred in people who would not typically be considered at risk.\n\nAll patients had angiographic evidence of obstructive coronary artery disease, and peak troponin levels were high (mean 93.5 ng/ml), indicating substantial cardiac damage.","whyItMatters":"Heart attacks in young people with few risk factors demand explanation. This case series adds to growing evidence that marijuana use may be an independent cardiovascular risk factor, particularly concerning given that many users and clinicians do not consider cardiac risk when assessing cannabis use.","specificNumbers":"8 patients, 10 STEMI events. Mean age: 40.1 years (range 26-59). 9 male, 1 female. 30% had zero CVD risk factors. Peak troponin: mean 93.5 ng/ml. All had obstructive coronary disease on angiography.","methodology":"Retrospective chart review of patients presenting with STEMI and positive cannabis use at a single inner-city hospital coronary care unit from December 2013 to April 2017.","limitations":"Case series without a control group cannot establish causation. The temporal relationship between marijuana use and STEMI was not precisely characterized. Single inner-city hospital with a specific patient demographic. Selection bias: patients at this hospital may not represent all marijuana-associated cardiac events. Cannabis was self-reported and not necessarily verified by blood testing."},{"rthcId":"RTHC-01518","title":"Gender differences among treatment-seeking adults with cannabis use disorder: Clinical profiles of women and men enrolled in the achieving cannabis cessation-evaluating N-acetylcysteine treatment (ACCENT) study.","authors":"Sherman, Brian J; McRae-Clark, Aimee L; Baker, Nathaniel L; Sonne, Susan C; Killeen, Therese K; Cloud, Kasie; Gray, Kevin M","year":2017,"journal":"The American journal on addictions, 26(2), 136-144","doi":"10.1111/ajad.12503","pmid":"28152236","tags":["sex-differences","withdrawal","addiction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Comparing 86 women and 216 men entering a multi-site cannabis cessation trial, women presented with a more clinically complex picture despite using cannabis at similar rates and quantities.\n\nWomen reported significantly greater withdrawal intensity (p = 0.001) and negative impact of withdrawal (p = 0.001), driven primarily by physiological and mood symptoms. Women were more likely to have lifetime panic disorder (p = 0.038) and current agoraphobia (p = 0.022). They reported more days of poor physical health (p = 0.006) and more cannabis-related medical problems (p = 0.023).\n\nAmong those with chronic pain, women reported significantly higher pain scores than men (p = 0.006). Importantly, men and women did not differ on any baseline measures of cannabis use itself, meaning the clinical differences were not explained by women using more cannabis.","whyItMatters":"Women have fared worse than men in cannabis pharmacotherapy trials, and this study helps explain why: they enter treatment with more severe withdrawal, more psychiatric comorbidity, and more pain. This suggests that one-size-fits-all cannabis treatment approaches may disadvantage women, and that gender-specific treatment planning could improve outcomes.","specificNumbers":"86 women, 216 men. Women had greater withdrawal intensity (p = 0.001) and negative impact (p = 0.001). Lifetime panic disorder: women more likely (p = 0.038). Current agoraphobia: women more likely (p = 0.022). More days poor physical health (p = 0.006). Higher pain scores among those with chronic pain (p = 0.006). No differences in cannabis use measures.","methodology":"Baseline comparison of women (n = 86) and men (n = 216) entering the ACCENT study, a multi-site randomized controlled trial of N-acetylcysteine for cannabis cessation within the National Drug Abuse Treatment Clinical Trials Network.","limitations":"Treatment-seeking population may not represent all cannabis-dependent individuals. Women were underrepresented (28% of sample), limiting statistical power for some comparisons. Cross-sectional baseline data cannot determine whether the sex differences are causes or consequences of cannabis dependence. The study examined baseline profiles but did not report treatment outcomes by gender."},{"rthcId":"RTHC-01519","title":"Individual, peer, and family factor modification of neighborhood-level effects on adolescent alcohol, cigarette, e-cigarette, and marijuana use.","authors":"Shih, Regina A; Parast, Layla; Pedersen, Eric R; Troxel, Wendy M; Tucker, Joan S; Miles, Jeremy N V; Kraus, Lisa; D'Amico, Elizabeth J","year":2017,"journal":"Drug and alcohol dependence, 180, 76-85","doi":"10.1016/j.drugalcdep.2017.07.014","pmid":"28886395","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"The study followed 2,539 high school students and college freshmen originally recruited from Southern California middle schools. Perceptions of neighborhood disorganization, poor social cohesion, and visible alcohol/drug problems were all associated with higher odds of marijuana and other substance use one year later.\n\nHowever, two individual-level factors consistently buffered the negative neighborhood effects. Resistance self-efficacy (RSE), a teen's confidence in their ability to say no to substances, reduced the impact of living in a disorganized neighborhood. Similarly, having weaker affiliations with substance-using peers also protected against neighborhood risk.\n\nInterestingly, objective census tract-level disadvantage (poverty, unemployment) was not longitudinally associated with substance use, while subjective perceptions of neighborhood problems were. This suggests that how teens perceive their environment matters more than objective economic indicators.","whyItMatters":"Prevention programs often focus on either community-level or individual-level interventions. This study shows they work together: even in high-risk neighborhoods, teens with strong personal resistance skills and fewer substance-using friends were less likely to use marijuana. This supports multi-level prevention approaches.","specificNumbers":"2,539 adolescents. Perceptions of neighborhood disorganization, low social cohesion, and drug problems predicted ATOD use. Resistance self-efficacy and peer factors consistently buffered neighborhood effects. Census tract disadvantage was NOT predictive longitudinally.","methodology":"Longitudinal analysis of 2,539 Southern California adolescents. Multivariate logistic regressions with interaction terms tested whether parental monitoring, resistance self-efficacy, and peer substance use modified the relationship between neighborhood measures and substance use one year later.","limitations":"Self-reported substance use and neighborhood perceptions. Southern California sample may not generalize nationally. The \"buffering\" effects were measured as statistical interactions, which can be unstable in observational data. The study combined alcohol, tobacco, e-cigarettes, and marijuana into the analysis, making it difficult to isolate marijuana-specific effects."},{"rthcId":"RTHC-01520","title":"MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future.","authors":"Simon, Vincent; Cota, Daniela","year":2017,"journal":"European journal of endocrinology, 176(6), R309-R324","doi":"10.1530/EJE-16-1044","pmid":"28246151","tags":["neuroscience","appetite"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review charted the evolution of understanding about the endocannabinoid system (ECS) and metabolism. Early research focused on the brain: CB1 receptors in the hypothalamus and reward circuits drove food intake and energy balance. This led to rimonabant, a brain-penetrant CB1 antagonist that effectively treated obesity and metabolic disorders but was withdrawn in 2009 due to psychiatric side effects (depression, anxiety, suicidal ideation).\n\nHowever, research has since revealed extensive peripheral ECS involvement in metabolism. CB1 receptors in adipose tissue, liver, skeletal muscle, and pancreas regulate fat storage, insulin sensitivity, lipid metabolism, and glucose homeostasis independently of brain effects. Peripherally restricted CB1 antagonists that cannot cross the blood-brain barrier have shown effectiveness in reducing body weight, adiposity, insulin resistance, and dyslipidemia in obese animal models, without the psychiatric side effects.\n\nNew developments include the discovery of endogenous allosteric inhibitors of CB1, the crystal structure of human CB1, and evidence that CB2 receptors also participate in metabolic regulation.","whyItMatters":"The withdrawal of rimonabant was a major setback for cannabinoid-based metabolic therapy. This review shows that the science did not stop there: peripheral ECS modulation may achieve the metabolic benefits of rimonabant without the psychiatric risks. Understanding how the endocannabinoid system regulates metabolism also explains aspects of the \"munchies\" and why chronic cannabis users have paradoxically been associated with lower obesity rates in some studies.","specificNumbers":"Rimonabant was removed from the market in 2009. CB1 receptors are present in adipose tissue, liver, skeletal muscle, and pancreas. Peripherally restricted CB1 antagonists reduced body weight and metabolic markers in obese animals without CNS side effects.","methodology":"Comprehensive narrative review covering the history, current state, and future directions of endocannabinoid system involvement in metabolic regulation.","limitations":"Narrative review with potential for selective citation. Peripherally restricted CB1 antagonists have only been tested in animals at the time of this review. The complexity of the ECS makes predicting clinical outcomes from preclinical data particularly challenging. The full consequences of chronically blocking peripheral CB1 receptors are unknown."},{"rthcId":"RTHC-01521","title":"A review of Indian research on co-occurring cannabis use disorders& psychiatric disorders.","authors":"Singh, Shalini; Balhara, Yatan Pal Singh","year":2017,"journal":"The Indian journal of medical research, 146(2), 186-195","doi":"10.4103/ijmr.IJMR_791_15","pmid":"29265019","tags":["psychosis","mental-health","cognition"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The review identified 52 published Indian studies on co-occurring cannabis use disorders and psychiatric conditions. Studies on cannabis and psychosis (n = 16) primarily described acute psychotic episodes with predominant positive symptoms (hallucinations, delusions) following cannabis use.\n\nSix studies observed an overall increased prevalence of all psychiatric disorders among cannabis users, while 14 found high rates of substance use in people already diagnosed with psychiatric conditions. Seven studies examined cognitive effects of cannabis.\n\nA critical limitation across the Indian literature: all studies except one used exclusively male subjects, and only a single study described service delivery models for dual-diagnosis patients. Most research used cross-sectional designs with treatment-seeking populations, leaving fundamental questions about causation, neurobiology, and optimal management unanswered.","whyItMatters":"India has one of the world's oldest cultural relationships with cannabis (bhang, charas, ganja), and cannabis use is widespread. Understanding the Indian context, where patterns of use, preparations, and cultural attitudes differ from Western settings, adds important diversity to the global cannabis-mental health evidence base. The near-total exclusion of women from Indian cannabis research represents a major knowledge gap.","specificNumbers":"52 Indian studies included. 16 on cannabis and psychosis. 14 on substance use among psychiatric patients. 7 on cognitive effects. All but 1 study had all-male subjects. Only 1 study addressed service delivery for dual diagnosis.","methodology":"Systematic electronic search for published Indian literature on cannabis use disorders and co-occurring psychiatric conditions, conducted in May 2015. 52 English-language articles from India were included.","limitations":"Systematic review limited to Indian publications, which may not be indexed in all international databases. Most included studies were observational and cross-sectional. The review was conducted in 2015 and published in 2017, so more recent Indian research is not included. The almost exclusive focus on male subjects severely limits generalizability."},{"rthcId":"RTHC-01522","title":"The endocannabinoid system as a target for addiction treatment: Trials and tribulations.","authors":"Sloan, Matthew E; Gowin, Joshua L; Ramchandani, Vijay A; Hurd, Yasmin L; Le Foll, Bernard","year":2017,"journal":"Neuropharmacology, 124, 73-83","doi":"10.1016/j.neuropharm.2017.05.031","pmid":"28564576","tags":["addiction","withdrawal","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined randomized controlled trial evidence for cannabinoid-based medications across different addictions.\n\nFor cannabis use disorder: THC-containing medications like dronabinol and nabiximols (Sativex) effectively reduced withdrawal symptoms. This agonist substitution approach parallels how methadone is used for opioid dependence. Dronabinol may also help reduce opioid withdrawal symptoms.\n\nFor tobacco: The CB1 inverse agonist rimonabant showed promising smoking cessation effects in clinical trials, but its psychiatric side effects (depression, anxiety, suicidal ideation) led to removal from the market. It was never approved in the United States.\n\nFor alcohol: Very few trials had investigated cannabinoid medications for alcohol use disorder at the time of this review, representing a significant gap.\n\nThe review highlighted emerging approaches: FAAH inhibitors (which boost anandamide) and neutral CB1 antagonists (which lack the psychiatric side effects of inverse agonists like rimonabant) as promising future options.","whyItMatters":"Addiction treatment options remain limited, and the endocannabinoid system's involvement in reward and dependence makes it a logical therapeutic target. This review provides a practical summary of what works, what failed, and what is coming next in cannabinoid-based addiction treatment.","specificNumbers":"Dronabinol and nabiximols: effective for cannabis withdrawal (RCT evidence). Dronabinol: may reduce opioid withdrawal. Rimonabant: effective for smoking cessation but removed from market. Few RCTs for alcohol use disorder.","methodology":"Narrative review of randomized controlled trials evaluating cannabinergic medications for substance use disorders, including cannabis, opioid, tobacco, and alcohol use disorders.","limitations":"Narrative review without systematic search methodology. The evidence base for cannabinoid medications in addiction is still relatively small, with most RCTs having modest sample sizes. The review does not cover newer compounds that have entered clinical testing since publication."},{"rthcId":"RTHC-01523","title":"Variation in cannabis potency and prices in a newly legal market: evidence from 30 million cannabis sales in Washington state.","authors":"Smart, Rosanna; Caulkins, Jonathan P; Kilmer, Beau; Davenport, Steven; Midgette, Greg","year":2017,"journal":"Addiction (Abingdon, England), 112(12), 2167-2177","doi":"10.1111/add.13886","pmid":"28556310","tags":["potency","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Analyzing Washington State's cannabis traceability data from July 2014 to September 2016 (over 44 million purchases), the study revealed several market trends.\n\nTraditional cannabis flower still dominated at 66.6% of spending, but extracts for inhalation (concentrates) grew by 145.8% in market share, reaching 21.2% of sales. The average THC level for extracts was 68.7%, more than triple that of flower (20.6%).\n\nConsumers paid a premium for potency: for flower products, both THC (coefficient = 0.012) and CBD (coefficient = 0.017) were associated with statistically significant per-gram price increases. CBD commanded an even higher price premium than THC, despite CBD's much lower average concentrations in most products.\n\nQuantity discounts were small but significant (elasticity = -0.06), meaning bulk buyers saved modestly per gram.","whyItMatters":"This is one of the most comprehensive analyses of a legal cannabis market ever conducted, covering over 44 million transactions. It provides hard data on what consumers actually buy, what they pay, and how the market is evolving. The rapid growth of high-potency concentrates is particularly relevant for public health, as these products deliver THC at levels far exceeding traditional flower.","specificNumbers":"44,482,176 total purchases analyzed. 31,052,123 flower purchases after trimming outliers. Flower: 66.6% of spending, average THC 20.6%. Extracts: grew to 21.2% of spending, average THC 68.7%. THC premium: $0.012/gram per percentage point. CBD premium: $0.017/gram per percentage point. Quantity discount elasticity: -0.06.","methodology":"Secondary analysis of Washington State's mandatory cannabis traceability system data. Descriptive statistics assessed product trends and potency. Hedonic regressions estimated how THC, CBD, and purchase quantity influenced flower pricing across 31 million flower purchases.","limitations":"Washington State data may not represent other legal markets. The traceability system captures legal market transactions only; illegal market activity is not included. Product testing accuracy and consistency across labs is a known concern. The study period (2014-2016) covers the early years of legal sales, and the market has continued to evolve."},{"rthcId":"RTHC-01524","title":"Parent use of cannabis for intractable pediatric epilepsy: Everyday empiricism and the boundaries of scientific medicine.","authors":"Sobo, Elisa J","year":2017,"journal":"Social science & medicine (1982), 190, 190-198","doi":"10.1016/j.socscimed.2017.08.003","pmid":"28865255","tags":["epilepsy","medical-cannabis","cbd"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Twenty-five parents who used, had used, or sought to use cannabis for their children's epilepsy were interviewed about their evidentiary standards, research methods, and aims.\n\nContrary to stereotypes of alternative medicine users rejecting science, these parents generally described their work as experimentation. They saw their careful tracking of doses, seizure counts, and side effects as adhering to scientific practices, and they viewed their individual-patient data as contributing to the broader medical cannabis knowledge base.\n\nThe parents did not reject biomedicine. Instead, they were driven by biomedical dependency (their children required ongoing medical care), high caregiver burden (managing intractable seizures), and a deep desire for their children's biomedical \"demarginalization,\" meaning they wanted their children's cannabis use to be recognized and supported within the medical system rather than forced to exist outside it.\n\nThis collaborative stance toward medicine, combined with the practical demands of managing a child's uncontrolled seizures, produced a form of lay research that both challenged and reinforced the boundaries between expert and non-expert knowledge.","whyItMatters":"Parents of children with intractable epilepsy are often portrayed as either desperate science-deniers or brave pioneers. This study complicates both narratives: these parents are embedded in the medical system, want scientific legitimacy, and approach cannabis treatment with methodical rigor. Understanding their perspective can help clinicians engage more productively with families using cannabis for pediatric epilepsy.","specificNumbers":"25 parents in Southern California. All had children with intractable epilepsy. Parents described systematic dose tracking and seizure monitoring. None rejected biomedicine entirely.","methodology":"Qualitative interview study of 25 Southern California parents in 2016. Semi-structured interviews explored evidentiary standards, research practices, and attitudes toward biomedical science in the context of pediatric cannabis use for epilepsy.","limitations":"Small qualitative sample from one geographic area. Parents willing to be interviewed about cannabis use may be more articulate and confident than those who are not. The study focused on parents' self-descriptions of their methods, not on whether those methods actually produced reliable evidence. Selection bias toward parents who found cannabis helpful enough to continue."},{"rthcId":"RTHC-01525","title":"Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment-a Systematic Review.","authors":"Sorensen, Cecilia J; DeSanto, Kristen; Borgelt, Laura; Phillips, Kristina T; Monte, Andrew A","year":2017,"journal":"Journal of medical toxicology : official journal of the American College of Medical Toxicology, 13(1), 71-87","doi":"10.1007/s13181-016-0595-z","pmid":"28000146","tags":["withdrawal","appetite","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This extensive systematic review analyzed 2,178 articles, ultimately including 183 studies with cumulative case data. The diagnostic profile of CHS was characterized by 14 features, with the major ones being:\n\n100% had a history of regular cannabis use. 100% had cyclic nausea and vomiting. 96.8% had resolution of symptoms after stopping cannabis. 92.3% reported compulsive hot bathing with symptom relief. 97.4% used cannabis at least weekly. 85.1% had abdominal pain. 72.9% were male.\n\nThe pathophysiology remained unclear despite extensive review, with no single mechanism adequately explaining why only some chronic users develop CHS. For treatment, the evidence was strongest for cannabis cessation as the definitive cure. In the acute setting, supportive care with IV fluids, dopamine antagonists (like haloperidol), topical capsaicin cream, and avoidance of narcotic medications showed some benefit. Standard antiemetics were frequently ineffective.","whyItMatters":"This is the most comprehensive systematic review of CHS published to date, providing clinicians with the best available evidence for diagnosis and treatment. The high specificity of the diagnostic criteria (particularly the hot bathing behavior at 92.3%) gives clinicians a clear clinical picture to recognize.","specificNumbers":"2,178 articles screened. 183 included. 14 diagnostic characteristics identified. Regular cannabis use: 100%. Cyclic vomiting: 100%. Resolution with cessation: 96.8%. Hot bathing relief: 92.3%. Weekly+ use: 97.4%. Abdominal pain: 85.1%. Male predominance: 72.9%.","methodology":"Systematic review searching MEDLINE, Ovid MEDLINE, Embase, Web of Science, and the Cochrane Library from 2000 to September 2015. Articles were evaluated using GRADE criteria. Data from case reports and series were combined in a cumulative synthesis.","limitations":"Most included studies were case reports and case series (low-quality evidence by GRADE standards). Publication bias likely favors reporting of classic CHS presentations, potentially inflating the frequency of diagnostic features. The search ended in 2015, and CHS knowledge has continued to evolve. No randomized treatment trials existed at the time of review."},{"rthcId":"RTHC-01526","title":"Perspectives of Cannabinoid Type 2 Receptor (CB2R) Ligands in Neurodegenerative Disorders: Structure-Affinity Relationship (SAfiR) and Structure-Activity Relationship (SAR) Studies.","authors":"Spinelli, Francesco; Capparelli, Elena; Abate, Carmen; Colabufo, Nicola A; Contino, Marialessandra","year":2017,"journal":"Journal of medicinal chemistry, 60(24), 9913-9931","doi":"10.1021/acs.jmedchem.7b00155","pmid":"28608697","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01527","title":"Functional effects of cannabinoids during dopaminergic specification of human neural precursors derived from induced pluripotent stem cells.","authors":"Stanslowsky, Nancy; Jahn, Kirsten; Venneri, Anna; Naujock, Maximilian; Haase, Alexandra; Martin, Ulrich; Frieling, Helge; Wegner, Florian","year":2017,"journal":"Addiction biology, 22(5), 1329-1342","doi":"10.1111/adb.12394","pmid":"27027565","tags":["neuroscience","dopamine","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used human induced pluripotent stem cells (iPSCs) to grow neurons and studied how cannabinoids affected their development into dopamine-producing cells.\n\nAt high concentrations (10 micromolar), both the endogenous cannabinoid anandamide (AEA) and THC significantly decreased neuronal functionality, indicated by reduced ion currents and synaptic activity. This suggests neurotoxic effects at high exposure levels during neurogenesis.\n\nAt low concentration (1 micromolar), THC had no marked effect on neuronal or dopaminergic maturation. Interestingly, low-dose anandamide actually enhanced synaptic activity frequency, suggesting the endocannabinoid system normally supports neuronal development at physiological levels but becomes harmful at supraphysiological concentrations.\n\nDNA methylation in gene promotor regions important for neuronal function was not significantly affected, indicating the cannabinoid effects were not mediated through this epigenetic mechanism.","whyItMatters":"This study uses human-derived neurons rather than animal models to study THC's effects on brain development, making the findings more directly relevant to human biology. The concentration-dependent results suggest a threshold below which THC may have minimal developmental impact and above which significant disruption occurs.","specificNumbers":"Concentrations tested: 1 and 10 micromolar. 10 micromolar AEA and THC: significantly decreased neuronal functionality. 1 micromolar THC: no marked effects. 1 micromolar AEA: enhanced synaptic activity frequency. No significant DNA methylation changes at any concentration.","methodology":"Human cord blood-derived iPSCs were differentiated into neural precursor cells and then into mature neurons. Cultures were exposed to anandamide or THC at 1 or 10 micromolar during dopaminergic differentiation. Neuronal function was assessed by electrophysiology (ion currents and synaptic activity). DNA methylation was analyzed in relevant gene promotor regions.","limitations":"In vitro study: neurons in a dish do not fully replicate the complexity of brain development in a living organism. The concentrations used may not directly correspond to THC levels in the developing human brain after cannabis use. iPSC-derived neurons may not perfectly recapitulate native neuronal development. Only two concentrations were tested."},{"rthcId":"RTHC-01528","title":"Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: A literature review","authors":"Steenkamp, Maria M.; Blessing, Esther M.; Galatzer-Levy, Isaac R.; Hollahan, Lisa C.; Anderson, William T.","year":2017,"journal":"Depression and Anxiety, 34(3), 207-216","doi":null,"pmid":"28245077","tags":["ptsd","cbd","medical-cannabis","sleep","psychosis","depression","anxiety","addiction"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The biological case for cannabis helping PTSD was compelling. The endocannabinoid system is deeply involved in fear extinction, stress response, and emotional memory processing — exactly the mechanisms disrupted in PTSD. Animal studies showed cannabinoids could facilitate fear extinction and reduce anxiety-like behavior.\n\nBut the clinical evidence didn't match the biology. Treatment outcome studies of whole-plant cannabis for PTSD were limited and methodologically weak. The one area with real signal was nightmares: nabilone, a synthetic cannabinoid, showed benefit for PTSD-related nightmares and sleep disruption. Beyond that, the cupboard was nearly bare.\n\nMeanwhile, the potential harms were better documented than the benefits. Cannabis use was associated with worse outcomes in depression, anxiety, psychosis, and substance misuse — conditions that frequently co-occur with PTSD. The review found stronger evidence for marijuana's harmful effects on psychosis and substance misuse development than for its therapeutic effects on PTSD itself.","whyItMatters":"This review captured a tension that still exists: the biology says the endocannabinoid system should be a therapeutic target for PTSD, but giving people cannabis or THC is a blunt tool for a precise problem. The distinction between \"the endocannabinoid system is involved in PTSD\" and \"smoking weed treats PTSD\" is enormous, and this paper drew that line clearly.\n\nThe finding that evidence for harm was actually stronger than evidence for benefit was particularly important. Many veterans and trauma survivors were already self-medicating with cannabis based on the biological plausibility alone, without knowing the clinical evidence hadn't caught up.","specificNumbers":"• Nabilone: showed benefit specifically for PTSD-related nightmares and sleep\n• Cannabis associated with worse outcomes in comorbid conditions: depression, anxiety, psychosis, substance misuse\n• Stronger evidence for cannabis causing psychosis and substance misuse than for treating PTSD","methodology":"Systematic literature review examining preclinical and clinical evidence for cannabinoids in PTSD treatment. Covered animal models of fear conditioning, human endocannabinoid research, clinical treatment studies, and evidence of psychiatric harms. Published in Depression and Anxiety.","limitations":"Published in 2017, so does not capture more recent clinical trials. The review notes that existing treatment studies had significant methodological limitations. Cannot determine causation in the association between cannabis use and worse psychiatric outcomes in PTSD. Does not address different cannabis products, doses, or delivery methods."},{"rthcId":"RTHC-01529","title":"Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB1 and CB2 receptors.","authors":"Stern, Cristina A J; da Silva, Thiago R; Raymundi, Ana M; de Souza, Camila P; Hiroaki-Sato, Vinicius A; Kato, Luiza; Guimarães, Francisco S; Andreatini, Roberto; Takahashi, Reinaldo N; Bertoglio, Leandro J","year":2017,"journal":"Neuropharmacology, 125, 220-230","doi":"10.1016/j.neuropharm.2017.07.024","pmid":"28754373","tags":["cbd","ptsd","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers induced different intensities of fear memories in rats using varying shock levels, creating either specific fear (responding only to the original context) or generalized fear (responding fearfully to new, similar contexts).\n\nCBD (3-30 mg/kg) given immediately after fear acquisition disrupted consolidation of both types. For specific fear, it reduced conditioned freezing. For generalized fear, it reduced fear generalization, stress-related ultrasonic vocalizations (22 kHz calls), and resistance to extinction. CBD had no effect on short-term memory, and delayed treatment (not immediately after acquisition) was ineffective.\n\nMechanistically, both CB1 receptor blockade (AM251) and CB2 receptor blockade (AM630) prevented CBD's memory-disrupting effects, whether the antagonists were given systemically or directly into the dorsal hippocampus. The FAAH inhibitor URB597 (which boosts anandamide) replicated CBD's effects, suggesting CBD works indirectly through anandamide signaling.","whyItMatters":"Fear generalization, where fear extends beyond the original traumatic context to everyday situations, is a hallmark of PTSD. This study shows CBD can disrupt not just specific fear memories but also this pathological generalization process. The involvement of both CB1 and CB2 receptors in the hippocampus provides mechanistic targets for future therapeutic development.","specificNumbers":"CBD doses: 3-30 mg/kg. Effective only when given immediately after acquisition (not delayed). Both AM251 (CB1 antagonist) and AM630 (CB2 antagonist) blocked CBD effects. FAAH inhibitor URB597 replicated CBD effects. Dorsal hippocampus confirmed as the critical brain region.","methodology":"Contextual fear conditioning in rats with varying shock intensities. CBD or vehicle was given immediately or delayed after conditioning. Memory was tested 24 hours later. Pharmacological antagonists identified receptor involvement. Intra-hippocampal microinjections localized effects to the dorsal hippocampus.","limitations":"Animal study using injection routes not feasible in humans. The fear conditioning paradigm is a simplified model of trauma. CBD was effective only when given immediately after fear acquisition, which may not translate to treating established traumatic memories. The involvement of two receptor types complicates potential pharmaceutical development."},{"rthcId":"RTHC-01530","title":"Age of Onset, Current Use of Alcohol, Tobacco or Marijuana and Current Polysubstance Use Among Male and Female Mexican Students.","authors":"Strunin, Lee; Díaz-Martínez, Alejandro; Díaz-Martínez, L Rosa; Heeren, Timothy; Chen, Clara; Winter, Michael; Kuranz, Seth; Hernández-Ávila, Carlos A; Fernández-Varela, Héctor; Solís-Torres, Cuauhtémoc","year":2017,"journal":"Alcohol and alcoholism (Oxford, Oxfordshire), 52(5), 564-571","doi":"10.1093/alcalc/agx027","pmid":"28481972","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In this large cross-sectional survey of first-year university students in Mexico City, most students initiated alcohol at age 15, tobacco at 15-16, and marijuana at 16-17.\n\nEarlier initiation of alcohol and tobacco was associated with continued current use of those substances. Gender differences in alcohol and tobacco were small, but males were significantly more likely than females to use marijuana and to be polysubstance users.\n\nFamily substance use was associated with earlier onset across substances. Most importantly, there was a significant association between the earliest age of initiating any of the three substances and current polysubstance use, suggesting that early substance exposure, regardless of the specific substance, increases vulnerability to broader substance use patterns.","whyItMatters":"Mexico has unique cultural factors around substance use (legal drinking age, attitudes toward marijuana, family dynamics) that influence initiation patterns. This large study demonstrates that the age-of-onset principle, earlier use predicting more problematic use patterns, holds across cultural contexts.","specificNumbers":"22,224 students aged 17-20. Most common initiation ages: alcohol 15, tobacco 15-16, marijuana 16-17. Males significantly more likely to use marijuana and be polysubstance users. Family substance use predicted earlier onset. Earlier age of any substance initiation predicted polysubstance use.","methodology":"Cross-sectional survey of 22,224 first-year university students in Mexico City in 2012. Chi-square tests and logistic regression examined associations between gender, age of onset, order of onset, family substance use, and current polysubstance use.","limitations":"Cross-sectional design captures only one time point. University students are not representative of all Mexican young people. Self-report may underestimate substance use. The study cannot determine whether early onset causes polysubstance use or whether both share common risk factors."},{"rthcId":"RTHC-01531","title":"An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use.","authors":"Suraev, Anastasia S; Todd, Lisa; Bowen, Michael T; Allsop, David J; McGregor, Iain S; Ireland, Carol; Lintzeris, Nicholas","year":2017,"journal":"Epilepsy & behavior : E&B, 70(Pt B), 334-340","doi":"10.1016/j.yebeh.2017.02.005","pmid":"28238865","tags":["epilepsy","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Epilepsy Action Australia surveyed 976 people with epilepsy nationwide. Among adults with epilepsy, 15% were currently using or had used cannabis products for seizure treatment. Among parents/guardians of children with epilepsy, 13% reported using cannabis for their child.\n\nAmong those who had used cannabis products, 90% of adults and 71% of parents reported success in reducing seizure frequency. The main motivations were managing treatment-resistant epilepsy and seeking a more favorable side-effect profile compared to standard antiepileptic drugs.\n\nThe most significant predictor of cannabis use was the number of previously tried antiepileptic drugs. Each additional failed medication increased the likelihood of turning to cannabis, reflecting the desperation of treatment-resistant epilepsy. Over half of respondents (56% of adults, 62% of parents) expressed willingness to participate in clinical trials of cannabinoids.","whyItMatters":"This study quantifies what clinicians suspected: people with epilepsy turn to cannabis after conventional treatments fail, and most report benefit. The finding that the number of failed medications predicts cannabis use has practical implications: clinicians managing treatment-resistant epilepsy should proactively discuss cannabis with patients who have exhausted multiple options.","specificNumbers":"976 respondents. 15% of adults and 13% of parents had used cannabis. 90% of adults and 71% of parents reported seizure reduction. Number of prior antiepileptic drugs was the strongest predictor of cannabis use. 56% of adults and 62% of parents willing to join clinical trials.","methodology":"Australian nationwide online survey conducted through Epilepsy Action Australia's website and Facebook page. 976 responses met inclusion criteria. 39 questions assessed demographics, clinical factors, cannabis use experiences, and attitudes.","limitations":"Online survey promoted through an epilepsy advocacy organization, creating selection bias toward engaged patients. Self-reported seizure reduction was not verified by medical records or seizure diaries. Respondents who tried cannabis and found it unhelpful may be underrepresented. The cannabis products used were unregulated and uncharacterized."},{"rthcId":"RTHC-01532","title":"Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge.","authors":"Surkin, P N; Di Rosso, M E; Correa, F; Elverdin, J C; Genaro, A M; De Laurentiis, A; Fernández-Solari, J","year":2017,"journal":"Journal of neuroendocrinology, 29(8)","doi":"10.1111/jne.12499","pmid":"28665507","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"When the immune system is activated by infection, reproductive function shuts down. Researchers investigated whether the endocannabinoid system mediates this shutdown by blocking CB1 receptors in the brain during an immune challenge (LPS injection).\n\nLPS suppressed the entire reproductive hormone cascade: GnRH content in the hypothalamus decreased, followed by drops in LH and testosterone in plasma. It also decreased Kiss1 expression and prostaglandin E2 while increasing the inhibitory hormone GnIH (Rfrp3).\n\nBlocking CB1 receptors with AM251 prevented all of these reproductive disruptions, confirming that endocannabinoids mediate the immune-reproductive axis shutdown via hypothalamic CB1 receptors.\n\nParadoxically, CB1 blockade also enhanced the inflammatory response to LPS, particularly in the hypothalamus. This suggests a dual role: the endocannabinoid system both mediates the reproductive shutdown and simultaneously helps contain the inflammation that triggered it.","whyItMatters":"This study reveals a fundamental biological mechanism: during infection, the endocannabinoid system coordinates the suppression of reproductive function, an energy-conservation response that allows the body to focus resources on fighting infection. Understanding this mechanism has implications for fertility issues related to chronic inflammation and for understanding how cannabis use might affect reproductive function during illness.","specificNumbers":"LPS at 5 mg/kg induced immune activation. AM251 at 500 ng/5 microliters blocked CB1 in the brain. Measurements at 90 and 180 minutes. AM251 prevented LPS-induced decreases in GnRH, LH, testosterone, Kiss1, and PGE2. AM251 prevented LPS-induced increase in GnIH. AM251 enhanced inflammatory cytokines in the hypothalamus.","methodology":"Male adult rats received intracerebroventricular AM251 (CB1 antagonist) followed by intraperitoneal LPS (immune activator). Plasma hormones (LH, testosterone), hypothalamic neuropeptides (GnRH, kisspeptin, GnIH), inflammatory cytokines, and prostaglandin E2 were measured at 90 and 180 minutes post-LPS.","limitations":"Animal study using acute immune challenge (LPS injection), which is a simplified model of infection. Only male rats were studied. The intracerebroventricular route of AM251 administration is not clinically feasible. The study examined acute time points (90-180 minutes) and did not assess longer-term reproductive consequences."},{"rthcId":"RTHC-01533","title":"Pros and Cons of Medical Cannabis use by People with Chronic Brain Disorders.","authors":"Suryadevara, Uma; Bruijnzeel, Dawn M; Nuthi, Meena; Jagnarine, Darin A; Tandon, Rajiv; Bruijnzeel, Adriaan W","year":2017,"journal":"Current neuropharmacology, 15(6), 800-814","doi":"10.2174/1570159X14666161101095325","pmid":"27804883","tags":["medical-cannabis","psychosis","mental-health","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review examined evidence on cannabis use across six brain disorders, finding a mixed picture that varied dramatically by condition.\n\nNeurological disorders with some benefit: Cannabis reduced pain and spasticity in multiple sclerosis, decreased tremor, rigidity, and pain in Parkinson's disease, and improved quality of life in ALS by helping appetite, pain, and spasticity. In late-stage Alzheimer's, cannabis products improved food intake, sleep quality, and reduced agitation.\n\nPsychiatric disorders with clear risks: Cannabis use was more common among people with schizophrenia than healthy controls. It acted as a risk factor for developing schizophrenia, increased positive symptoms (hallucinations, delusions) in existing patients, though it may have diminished negative symptoms. Cannabis use worsened bipolar disorder with no evidence of benefit.\n\nAcross all conditions, the review noted that chronic cannabis use carries risks of cognitive impairment and dependence.","whyItMatters":"This review provides a condition-by-condition assessment that highlights how the risk-benefit calculation for cannabis varies dramatically depending on the diagnosis. For neurological conditions with pain and spasticity, there appears to be therapeutic value. For psychiatric conditions, particularly schizophrenia and bipolar disorder, the evidence points toward harm.","specificNumbers":"Six brain disorders reviewed: ALS, MS, AD, PD, bipolar disorder, schizophrenia. Cannabis use is more prevalent among people with schizophrenia than controls. Bipolar disorder: no evidence of benefit, evidence of worsening. MS: evidence of reduced pain and spasticity. PD: evidence of reduced tremor, rigidity, pain.","methodology":"Narrative review of published literature on cannabis use in ALS, MS, Alzheimer's disease, Parkinson's disease, bipolar disorder, and schizophrenia.","limitations":"Narrative review without systematic methodology. The evidence quality varies dramatically across conditions (stronger for MS, weaker for ALS and AD). Cannabis preparations and doses differed across studies. The review does not distinguish between THC-dominant and CBD-dominant products, which may have very different effects on psychiatric symptoms."},{"rthcId":"RTHC-01534","title":"Cannabinoid disposition in oral fluid after controlled smoked, vaporized, and oral cannabis administration.","authors":"Swortwood, Madeleine J; Newmeyer, Matthew N; Andersson, Maria; Abulseoud, Osama A; Scheidweiler, Karl B; Huestis, Marilyn A","year":2017,"journal":"Drug testing and analysis, 9(6), 905-915","doi":"10.1002/dta.2092","pmid":"27647820","tags":["driving","cbd"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"This controlled study compared oral fluid (saliva) pharmacokinetics after three routes of cannabis administration: smoking, vaporizing, and oral (brownie) consumption.\n\nPeak THC in saliva occurred during or immediately after consumption for all routes, driven by direct oral mucosa contamination from inhaled smoke/vapor or the brownie itself. Smoked and vaporized cannabis produced significantly higher peak THC concentrations than oral consumption in frequent smokers.\n\nFor occasional smokers, a key difference emerged: oral (edible) dosing produced more positive results for the metabolites 11-OH-THC and THCCOOH than inhaled routes, widening the detection window. This means edible users might test positive for metabolites longer than smokers.\n\nThe researchers also identified that THCV and CBG at very low cutoff levels (0.3 micrograms per liter) could serve as markers of recent cannabis use, as these minor cannabinoids clear from saliva relatively quickly.","whyItMatters":"Oral fluid testing is increasingly used for roadside cannabis detection and workplace testing. Understanding how different consumption methods affect what shows up in saliva, and for how long, is critical for interpreting test results fairly. The finding that edibles create different detection patterns than smoking has practical implications for both users and law enforcement.","specificNumbers":"Cannabis dose: 6.9% THC. Oral fluid collected up to 54-72 hours post-dose. Six cannabinoids measured: THC, 11-OH-THC, THCCOOH, THCV, CBD, CBG. Smoked/vaporized: higher peak THC. Oral: more metabolite-positive specimens. THCV and CBG at 0.3 micrograms/L: markers of recent use.","methodology":"Controlled dosing study with frequent and occasional cannabis smokers. Each participant completed four sessions: active brownie + placebo cigarette, placebo brownie + active cigarette, active vaporized dose, or placebo vaporized dose. Only one active dose (6.9% THC) per session. Oral fluid collected up to 54-72 hours post-dose. Six cannabinoids quantified by LC-MS/MS.","limitations":"Small study size (numbers not specified in abstract). Only one THC concentration tested (6.9%). The cannabis market now includes products with much higher THC levels. Oral fluid pharmacokinetics can vary significantly between individuals based on salivary flow, oral pH, and other factors. CBD-dominant products were not tested."},{"rthcId":"RTHC-01535","title":"Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway.","authors":"Todd, Stephanie M; Zhou, Cilla; Clarke, David J; Chohan, Tariq W; Bahceci, Dilara; Arnold, Jonathon C","year":2017,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 27(2), 132-145","doi":"10.1016/j.euroneuro.2016.12.004","pmid":"28043732","tags":["cbd","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers examined whether CBD modulates THC's effects during repeated co-administration over 15 days in mice. The behavioral results were mixed: CBD modestly inhibited THC-induced rebound locomotor hyperactivity and slightly reduced acute sensorimotor gating effects, but only at a 1:1 ratio. Increasing to 5:1 CBD:THC did not enhance these effects. CBD did not alter THC-induced anxiety or the development of tolerance.\n\nHowever, the molecular findings were more surprising. The combination of CBD and THC increased histone H3 acetylation (H3K9/14ac) in the ventral tegmental area (VTA) and ΔFosB expression in the nucleus accumbens, both markers associated with neuroadaptation in the reward pathway. These changes were not seen with either compound alone, suggesting their combination produces \"supradditive\" (greater than the sum of parts) molecular effects.\n\nImportantly, there was no evidence of CBD potentiating THC's behavioral effects, but the long-term molecular changes suggest the brain's reward circuitry responds differently to the combination than to either compound individually.","whyItMatters":"Medical cannabis products like Sativex use specific CBD:THC ratios, and many consumers choose \"balanced\" products. This study suggests that while CBD may offer some acute behavioral protection against THC effects, the long-term molecular consequences of combining the two may be more complex than assumed. The epigenetic changes in reward circuitry warrant further investigation.","specificNumbers":"15-day treatment period. CBD:THC ratios: 1:1 and 5:1. Modest behavioral effects at 1:1 only. Increased H3K9/14ac in VTA. Increased ΔFosB in nucleus accumbens. No CBD potentiation of THC behavior. No anxiety reduction from CBD co-administration.","methodology":"Mice received 15 days of treatment with THC alone, CBD alone, or CBD+THC at 1:1 or 5:1 ratios. Behavioral tests included locomotor activity, sensorimotor gating, anxiety, and pharmacological tolerance. Brain tissue was analyzed for histone acetylation and ΔFosB expression in the mesolimbic dopamine pathway.","limitations":"Mouse study that may not directly translate to humans. Only two CBD:THC ratios tested. The functional significance of the epigenetic changes (histone acetylation, ΔFosB) for behavior is not established by this study. The doses and treatment duration may not reflect typical human cannabis use patterns."},{"rthcId":"RTHC-01536","title":"Outcomes of a family-based HIV prevention intervention for substance using juvenile offenders.","authors":"Tolou-Shams, Marina; Dauria, Emily; Conrad, Selby M; Kemp, Kathleen; Johnson, Sarah; Brown, Larry K","year":2017,"journal":"Journal of substance abuse treatment, 77, 115-125","doi":"10.1016/j.jsat.2017.03.013","pmid":"28476263","tags":["youth","addiction","quitting"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Forty-seven caregiver-youth dyads in a juvenile drug court program were randomized to either a 5-session family-based intervention integrating substance use prevention with affect management strategies, or an adolescent-only psychoeducation control.\n\nAt 3 months, youth in the family-based intervention showed enhanced motivation to change their marijuana use, decreased marijuana use, and decreased risky sexual behavior compared to the control condition.\n\nThe intervention's emphasis on affect management (emotional regulation) strategies was based on the theory that emotion dysregulation underlies the co-occurrence of substance use, delinquency, and sexual risk-taking in justice-involved youth.","whyItMatters":"Approximately 80% of arrested youth are supervised in the community rather than detained. Justice-involved youth have higher rates of substance use, psychiatric problems, and risky behaviors than their peers. This pilot provides preliminary evidence that addressing marijuana use within a family context and teaching emotional regulation skills may be more effective than youth-only education.","specificNumbers":"47 caregiver-youth dyads. 5-session intervention. 3-month follow-up. Improvements in motivation to change marijuana use, decreased marijuana use, and decreased risky sexual behavior.","methodology":"Pilot randomized controlled trial with 47 caregiver-youth dyads in a juvenile drug court. Five-session family-based intervention versus time-matched adolescent-only psychoeducation. Data collected at baseline and 3 months post-intervention.","limitations":"Very small pilot sample (47 dyads). Short follow-up (3 months). No long-term outcome data. Justice-involved youth may not be representative of all adolescent marijuana users. The pilot design cannot definitively establish efficacy."},{"rthcId":"RTHC-01537","title":"Running Out of Options: Rhabdomyolysis Associated with Cannabis Hyperemesis Syndrome.","authors":"Trappey, Bernard E; Olson, Andrew P J","year":2017,"journal":"Journal of general internal medicine, 32(12), 1407-1409","doi":"10.1007/s11606-017-4111-1","pmid":"28664257","tags":["withdrawal","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 24-year-old daily marijuana user with a history of CHS discovered that running, like hot bathing, alleviated his nausea and vomiting symptoms. During an episode, he jogged continuously for 15 hours, which led to rhabdomyolysis, a dangerous condition where muscle tissue breaks down and releases proteins into the blood that can damage the kidneys.\n\nThis is the first reported case of exercise-alleviated CHS symptoms. The authors propose that exercise, like hot water bathing, works by redistributing blood flow away from the gut (the enteric circulation). This blood flow redistribution hypothesis could explain why both heat (which causes cutaneous vasodilation) and exercise (which redirects blood to muscles) provide symptomatic relief in CHS.","whyItMatters":"This case provides a novel data point for understanding CHS pathophysiology. The finding that exercise mimics hot water in relieving symptoms supports the theory that CHS is related to abnormal enteric blood flow regulation. It also highlights the desperation of CHS patients, who may engage in extreme behaviors to find relief from an illness that standard antiemetics cannot treat.","specificNumbers":"Patient age: 24. Duration of continuous running: 15 hours. Result: rhabdomyolysis. First reported case of exercise-relieved CHS.","methodology":"Single case report with clinical description and mechanistic hypothesis.","limitations":"Single case report. The blood flow redistribution hypothesis has not been directly tested. Rhabdomyolysis from 15 hours of running could occur independent of CHS. The case does not prove that exercise is a generally effective CHS treatment."},{"rthcId":"RTHC-01538","title":"Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients.","authors":"Treat, Lauren; Chapman, Kevin E; Colborn, Kathryn L; Knupp, Kelly G","year":2017,"journal":"Epilepsia, 58(1), 123-127","doi":"10.1111/epi.13617","pmid":"27859038","tags":["epilepsy","medical-cannabis","cbd","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"A retrospective review of 119 pediatric epilepsy patients using oral cannabis extracts (OCEs) revealed high rates of discontinuation. 71% stopped using their cannabis product during the study, with an average duration of use of 11.7 months.\n\nPerceived seizure benefit was the only factor significantly associated with longer use (p < 0.05). However, only about 13% of patients achieved greater than 50% seizure reduction. Adverse events were reported in 19% of patients, with somnolence (drowsiness) and paradoxical worsening of seizures being the most common.\n\nSurprisingly, families of children with Dravet syndrome (the condition that would later respond best to pharmaceutical CBD in clinical trials) terminated OCE use more quickly than families of children with other epilepsy syndromes.","whyItMatters":"This study provides a reality check for cannabis-for-epilepsy enthusiasm. While surveys of cannabis-using families report high satisfaction rates, this clinical chart review tells a different story: most families discontinued cannabis extracts, and the minority who continued did so because they perceived seizure benefit. The low rate of 50%+ seizure reduction contrasts with the more optimistic patient-reported data from surveys.","specificNumbers":"119 patients. 71% discontinued OCEs. Average use: 11.7 months (range 0.3-57 months). ~13% achieved >50% seizure reduction. 19% had adverse events. Somnolence and seizure worsening most common side effects. Dravet families discontinued faster.","methodology":"Retrospective chart review of children and adolescents who received oral cannabis extracts for epilepsy treatment. Duration of use served as a proxy measure for perceived benefit.","limitations":"Retrospective chart review relies on clinical documentation quality. The OCE products were unregulated and varied in composition and potency. Duration of use is an imperfect proxy for efficacy. Some families may have stopped for reasons other than lack of efficacy (cost, access, family decisions)."},{"rthcId":"RTHC-01539","title":"Patterns of marijuana and tobacco use associated with suboptimal self-rated health among US adult ever users of marijuana.","authors":"Tsai, James; Rolle, Italia V; Singh, Tushar; Boulet, Sheree L; McAfee, Timothy A; Grant, Althea M","year":2017,"journal":"Preventive medicine reports, 6, 251-257","doi":"10.1016/j.pmedr.2017.03.014","pmid":"28392993","tags":["addiction","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using nationally representative NHANES data (2009-2012) from 3,210 adults who had used marijuana at least once, researchers examined how patterns of marijuana and tobacco co-use related to self-rated health.\n\nAmong ever marijuana users, 24.7% were regular marijuana smokers who also currently used tobacco, 21.1% were regular marijuana smokers without tobacco, and 15.2% were non-regular marijuana smokers with tobacco.\n\nCompared to non-regular marijuana users without tobacco (the reference group), the adjusted prevalence ratios for reporting \"fair\" or \"poor\" health were: regular marijuana + tobacco: 1.98 (nearly double the odds), non-regular marijuana + tobacco: 1.82, and regular marijuana without tobacco: 1.34.\n\nTobacco use was the dominant driver of worse self-rated health, but regular marijuana use alone was also significantly associated with suboptimal health status.","whyItMatters":"This study separates the effects of marijuana and tobacco, which are commonly used together. The finding that regular marijuana use alone (without tobacco) was still associated with worse self-rated health challenges the narrative that marijuana is entirely benign. However, the effect was much smaller than tobacco's contribution.","specificNumbers":"3,210 NHANES respondents. Regular marijuana + tobacco: aPR 1.98 (CI 1.50-2.61). Non-regular marijuana + tobacco: aPR 1.82 (CI 1.40-2.37). Regular marijuana without tobacco: aPR 1.34 (CI 1.05-1.69). Tobacco verified by cotinine ≥3.08 ng/mL.","methodology":"Cross-sectional analysis of NHANES 2009-2012 data. Tobacco use verified by serum cotinine levels (not self-report). Regular marijuana use defined as at least once monthly for more than one year. Multivariable log-linear regression controlled for demographics and other covariates.","limitations":"Cross-sectional design cannot determine causation. Self-rated health is subjective and influenced by many factors. The association between regular marijuana use and poor self-rated health could reflect confounding by other health behaviors, socioeconomic factors, or the conditions that lead people to use marijuana. Regular use was defined as monthly for a year, which encompasses a wide range of consumption patterns."},{"rthcId":"RTHC-01540","title":"Cannabis Use in Palliative Oncology: A Review of the Evidence for Popular Indications.","authors":"Turgeman, Ilit; Bar-Sela, Gil","year":2017,"journal":"The Israel Medical Association journal : IMAJ, 19(2), 85-88","doi":null,"pmid":"28457056","tags":["medical-cannabis","cancer","pain","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review assessed cannabis and cannabinoid use across the spectrum of palliative care needs in cancer patients.\n\nThe best-established indications were chemotherapy-induced nausea and vomiting (CINV), where synthetic cannabinoids like nabilone and dronabinol have been approved for decades, and cancer-related pain, where cannabis showed benefit particularly for pain not adequately controlled by opioids alone.\n\nEmerging evidence supported use for anorexia/cachexia (cancer-related weight loss), insomnia, and anxiety, though clinical trial data for these indications was limited. Side effects appeared manageable and subsided after discontinuation.\n\nThe review also noted preclinical evidence of anti-cancer (anti-neoplastic) effects of cannabinoids across a wide range of cancer cell lines and some animal models, but emphasized that these effects have not been confirmed in human clinical trials.","whyItMatters":"Cancer patients often face multiple symptoms simultaneously: pain, nausea, poor appetite, insomnia, and anxiety. Cannabis's potential to address multiple symptoms with a single intervention is attractive for palliative care, where quality of life is the primary goal.","specificNumbers":"Approved cannabinoids for CINV include nabilone and dronabinol. Evidence supports pain, nausea, appetite, sleep, and anxiety indications. Anti-cancer effects demonstrated in preclinical studies only. Side effects manageable and reversible.","methodology":"Narrative review of published literature on cannabis and cannabinoid-based medicines in palliative oncology.","limitations":"Narrative review without systematic search methodology. Much of the evidence comes from studies of synthetic cannabinoids rather than whole-plant cannabis. The anti-cancer claims remain preclinical and should not be interpreted as suggesting cannabis treats cancer. The review does not distinguish between THC-dominant and CBD-dominant products."},{"rthcId":"RTHC-01541","title":"Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington's Disease.","authors":"Valdeolivas, Sara; Sagredo, Onintza; Delgado, Mercedes; Pozo, Miguel A; Fernández-Ruiz, Javier","year":2017,"journal":"International journal of molecular sciences, 18(4)","doi":"10.3390/ijms18040684","pmid":"28333097","tags":["medical-cannabis","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"R6/2 mice (a transgenic model of Huntington's disease) were treated daily with a Sativex-like phytocannabinoid combination (3 mg/kg each of CBD and THC) starting at 4 weeks of age, when motor symptoms typically begin.\n\nThe treatment did not improve rotarod performance (a measure of motor coordination that deteriorates from week 6 to 10 in these mice). However, it markedly attenuated clasping behavior, a measure of dystonia (involuntary muscle contractions).\n\nPET imaging at 10 weeks showed reduced metabolic activity in the basal ganglia of R6/2 mice, which was partially attenuated by the cannabinoid treatment. MRS analysis at 12 weeks revealed multiple metabolic abnormalities reflecting energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/NAA, and NAA/choline ratios) were completely reversed by the cannabinoid treatment.","whyItMatters":"Huntington's disease has no disease-modifying treatment. While this cannabinoid combination did not reverse the motor deficits, the improvement in dystonia and reversal of metabolic brain changes suggest partial neuroprotective effects that warrant further investigation.","specificNumbers":"Dose: 3 mg/kg each CBD + THC daily. Treatment started at 4 weeks. Clasping behavior: markedly attenuated. Rotarod: no improvement. Basal ganglia metabolism: partially preserved on PET. Taurine/creatine, taurine/NAA, NAA/choline ratios: completely reversed.","methodology":"R6/2 transgenic mice (Huntington's disease model) and wild-type controls received daily treatment with Sativex-like phytocannabinoid combination or vehicle from week 4. Assessment included behavioral testing, in vivo PET imaging, and ex vivo proton MRS spectroscopy of the striatum.","limitations":"Mouse model: R6/2 mice develop severe disease very rapidly (weeks), unlike human Huntington's which progresses over decades. Only one dose and ratio were tested. The motor coordination deficits (rotarod) did not improve, which is the most clinically relevant motor outcome. The metabolic improvements may not translate to functional clinical benefit."},{"rthcId":"RTHC-01542","title":"Deficits in striatal dopamine release in cannabis dependence.","authors":"van de Giessen, E; Weinstein, J J; Cassidy, C M; Haney, M; Dong, Z; Ghazzaoui, R; Ojeil, N; Kegeles, L S; Xu, X; Vadhan, N P; Volkow, N D; Slifstein, M; Abi-Dargham, A","year":2017,"journal":"Molecular psychiatry, 22(1), 68-75","doi":"10.1038/mp.2016.21","pmid":"27001613","tags":["dopamine","addiction","cognition"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"Eleven severely cannabis-dependent participants (free of all comorbidities, including nicotine use) and 12 healthy controls underwent PET brain scans before and after amphetamine challenge to measure dopamine release.\n\nCannabis-dependent participants had significantly lower dopamine release in the striatum (p = 0.002, effect size 1.48), including the associative striatum (ES = 1.39), sensorimotor striatum (ES = 1.41), and the pallidus (ES = 1.16). These are large effect sizes, indicating substantial dopamine system impairment.\n\nLower dopamine release in the associative striatum correlated with inattention and \"negative\" symptoms (flat affect, reduced motivation) in the cannabis-dependent group, and with poorer working memory and learning performance in both groups. The deficits persisted even after 5-7 days of standardized inpatient abstinence.","whyItMatters":"This is one of the most rigorous demonstrations that cannabis dependence is associated with dopaminergic deficits similar to those seen in other addictions. By excluding all comorbidities (including nicotine), the study isolated cannabis's specific contribution. The large effect sizes and the correlation with real-world cognitive and psychiatric symptoms make these findings clinically significant.","specificNumbers":"11 cannabis-dependent, 12 controls. Striatal dopamine release: p = 0.002, ES = 1.48. Associative striatum: p = 0.003, ES = 1.39. Sensorimotor striatum: p = 0.003, ES = 1.41. Pallidus: p = 0.012, ES = 1.16. Lower release correlated with inattention, negative symptoms, and cognitive deficits. 5-7 days abstinence before scans.","methodology":"PET imaging with [11C]-(+)-PHNO before and after oral amphetamine in 11 cannabis-dependent subjects (comorbidity-free, nicotine-free) and 12 healthy controls. Cannabis-dependent participants were inpatient for 5-7 days prior to scans. MRS glutamate measures were also obtained.","limitations":"Small sample size (11 per group). 5-7 days of abstinence may not be enough to determine whether deficits are permanent or reversible. The study selected severely dependent participants, so findings may not generalize to moderate or recreational users. Only male participants were included (based on abstract). The cross-sectional design cannot determine whether reduced dopamine release precedes or follows cannabis dependence."},{"rthcId":"RTHC-01543","title":"Pharmacokinetic Profile of Oral Cannabis in Humans: Blood and Oral Fluid Disposition and Relation to Pharmacodynamic Outcomes.","authors":"Vandrey, Ryan; Herrmann, Evan S; Mitchell, John M; Bigelow, George E; Flegel, Ronald; LoDico, Charles; Cone, Edward J","year":2017,"journal":"Journal of analytical toxicology, 41(2), 83-99","doi":"10.1093/jat/bkx012","pmid":"28158482","tags":["driving","potency"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Six healthy adults per dose received cannabis brownies containing 10, 25, or 50 mg THC, with specimens collected for 9 days.\n\nBlood THC concentrations were remarkably low: mean peak levels were only 1, 3.5, and 3.3 ng/mL for the three doses, far lower than levels seen after smoking. Oral fluid THC concentrations peaked immediately after eating (from residue in the mouth, not systemic absorption).\n\nSubjective drug effects and cognitive impairment were dose-dependent, peaked at 1.5-3 hours, and lasted 6-8 hours. Whole blood cannabinoid levels correlated significantly with subjective drug effects, but oral fluid levels did not reliably predict impairment.\n\nThe THC detection window in blood was 0-22 hours and in oral fluid was 1.9-22 hours. The 11-OH-THC metabolite had concentrations similar to THC itself, and the THCCOOH metabolite had higher concentrations and longer detection times.","whyItMatters":"Most cannabis pharmacokinetic research has studied smoking. As edibles grow in market share, understanding their unique profile is critical. The low blood THC levels from oral cannabis complicate drug testing: a person may be significantly impaired (effects lasting 6-8 hours) while having blood THC below per se legal limits designed for smoked cannabis.","specificNumbers":"Doses: 10, 25, 50 mg THC brownies. Peak blood THC: 1, 3.5, 3.3 ng/mL. Peak effects: 1.5-3 hours. Duration: 6-8 hours. Detection window (blood): 0-22 hours. Detection window (oral fluid): 1.9-22 hours. Blood levels correlated with subjective effects. Oral fluid levels did not predict impairment.","methodology":"Controlled pharmacokinetic study with 18 healthy adults (6 per dose). Cannabis brownies at 10, 25, or 50 mg THC. Blood and oral fluid specimens collected at baseline and for 9 days (6 days inpatient, 3 outpatient). Subjective effects, cardiovascular measures, and cognitive performance assessed for 8 hours.","limitations":"Small sample (6 per dose). Only one cannabis product tested (brownies). The 50 mg dose did not produce higher peak THC than the 25 mg dose, possibly due to variable absorption. Individual variation in oral absorption is well-known. The study used healthy adults without tolerance, who may respond differently than regular users."},{"rthcId":"RTHC-01544","title":"Pharmacological comparison of traditional and non-traditional cannabinoid receptor 1 blockers in rodent models in vivo.","authors":"Varga, Balázs; Kassai, Ferenc; Szabó, György; Kovács, Péter; Fischer, János; Gyertyán, István","year":2017,"journal":"Pharmacology, biochemistry, and behavior, 159, 24-35","doi":"10.1016/j.pbb.2017.06.012","pmid":"28666894","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers conducted the first direct comparison of classical and next-generation CB1 receptor blockers for anti-obesity potential and psychiatric side effects.\n\nAll five classical CB1 antagonists (rimonabant, taranabant, otenabant, ibipinabant, surinabant) effectively reduced body weight and food intake in obese rats in a body weight-dependent manner, with only slight effects on metabolic syndrome markers. However, all five also increased ultrasonic vocalizations (a measure of anxiety/distress in rats), confirming that the psychiatric side effects are a class effect, not specific to rimonabant.\n\nThe non-traditional alternatives fared poorly: the partial agonist O-1269 and the neutral antagonist LH-21 caused convulsive behavior at effective doses. The neutral antagonist VCHSR and the peripherally restricted inverse agonist JD-5037 showed no activity at the doses tested.","whyItMatters":"The withdrawal of rimonabant from the obesity market raised hopes that alternative CB1 blockers could achieve weight loss without psychiatric side effects. This study dashes those hopes for the specific compounds tested, showing that the alternatives either shared the problems or lacked efficacy. The endocannabinoid system remains a tantalizing but elusive target for obesity treatment.","specificNumbers":"5 classical CB1 blockers tested: rimonabant, taranabant, otenabant, ibipinabant, surinabant. 4 non-traditional alternatives: O-1269, VCHSR, LH-21, JD-5037. All classical blockers reduced weight but increased anxiety. O-1269 and LH-21: convulsions. VCHSR and JD-5037: no activity.","methodology":"In vivo screening cascade in rats: potency testing (CB1 agonist-induced hypothermia reversal, fasting-induced food intake), diet-induced obesity model with metabolic markers, and anxiety assessment via ultrasonic vocalization testing.","limitations":"Rat study that may not predict human responses. Only one dose or limited dose range was tested for some compounds. The non-traditional compounds may have performed better at different doses or with different formulations. Ultrasonic vocalizations as a measure of anxiety may not perfectly correspond to human psychiatric side effects."},{"rthcId":"RTHC-01545","title":"Psychosocial determinants of marijuana use among African American youth.","authors":"Vidourek, Rebecca A; King, Keith A; Montgomery, LaTrice","year":2017,"journal":"Journal of ethnicity in substance abuse, 16(1), 43-65","doi":"10.1080/15332640.2015.1084256","pmid":"26643414","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"A survey of 7,488 African American students from 133 metropolitan schools found that 18.5% reported past-year marijuana use, with males significantly more likely to use than females.\n\nRisk factors for marijuana use included getting in trouble at school and with police, and attending parties where alcohol and other drugs were present. Conversely, having multiple protective factors from parents, teachers, and school significantly reduced marijuana use.\n\nThe protective factors operated across multiple domains: parental monitoring and engagement, positive teacher relationships, and school connectedness all independently contributed to lower marijuana use. Having protective factors in multiple domains was more beneficial than protection from any single source.","whyItMatters":"African American youth face unique cultural and environmental pressures regarding substance use. This study identifies specific, actionable protective factors (parent involvement, teacher relationships, school connection) that reduce marijuana use in this population, providing targets for culturally informed prevention programs.","specificNumbers":"7,488 African American students. 133 schools. 18.5% past-year marijuana use. Males more likely than females. Risky behaviors (school trouble, police trouble, drug parties) were risk factors. Parent, teacher, and school protective factors reduced use.","methodology":"Cross-sectional survey using the PRIDE instrument (a nationally recognized substance use survey) administered to 7,488 African American middle and high school students from 133 metropolitan schools.","limitations":"Cross-sectional design cannot determine causation. Self-reported marijuana use may be underreported. The PRIDE survey captures school-attending youth, missing those who have dropped out. Metropolitan schools may not represent rural African American communities. The study did not examine marijuana potency, frequency, or consequences."},{"rthcId":"RTHC-01546","title":"Psychotic Symptoms in Attention-Deficit/Hyperactivity Disorder: An Analysis of the MTA Database.","authors":"Vitiello, Benedetto; Perez Algorta, Guillermo; Arnold, L Eugene; Howard, Andrea L; Stehli, Annamarie; Molina, Brooke S G","year":2017,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 56(4), 336-343","doi":"10.1016/j.jaac.2017.01.016","pmid":"28335878","tags":["psychosis","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers followed 509 MTA study participants (childhood ADHD) and 276 age-matched controls for 16 years, assessing psychotic symptoms through young adulthood.\n\nADHD did not increase the risk for psychotic symptoms. The rates were essentially identical: 5% of ADHD participants and 4% of controls screened positive for at least one psychotic symptom (p = 0.60). Clinician-confirmed psychotic symptoms were rare and similar between groups (1.1% vs. 0.7%, p = 0.72). Most psychotic symptoms were transient.\n\nHowever, across both groups, cannabis use emerged as a significant independent factor. Greater cannabis use was reported by those who screened positive for psychotic symptoms (p < 0.05) and those with clinician-confirmed psychotic symptoms (p < 0.01).\n\nThe findings support the recommendation that youth should not use cannabis, particularly given that ADHD youth already have higher rates of substance use.","whyItMatters":"Parents of children with ADHD have long worried about their children's vulnerability to serious mental illness. This 16-year study provides strong reassurance that ADHD itself does not increase psychosis risk. However, the cannabis-psychosis link adds urgency to addressing substance use in the ADHD population, where substance use rates are already elevated.","specificNumbers":"509 ADHD participants, 276 controls at year 16. Psychosis screening: 5% ADHD vs. 4% controls (p = 0.60). Clinician-confirmed: 1.1% vs. 0.7% (p = 0.72). Cannabis use: significantly higher in screen-positive (p < 0.05) and confirmed-positive (p < 0.01) groups.","methodology":"Longitudinal follow-up of the Multimodal Treatment Study of Children with ADHD (MTA), the largest and longest ADHD treatment study. Assessments at 6, 8, 10, 12, 14, and 16 years post-enrollment. Trained research assistants administered a psychosis screener; positive screens were evaluated by study clinicians. Original enrollment mean age: 8.5 years. Year 16 mean age: 25.1 years.","limitations":"The MTA sample was originally treatment-seeking and not population-representative. Psychotic symptoms were screened and confirmed at specific assessment points, potentially missing episodes between visits. The study cannot determine whether cannabis caused the psychotic symptoms or whether shared vulnerability led to both cannabis use and psychosis."},{"rthcId":"RTHC-01547","title":"Pediatric Concerns Due to Expanded Cannabis Use: Unintended Consequences of Legalization.","authors":"Wang, George Sam","year":2017,"journal":"Journal of medical toxicology : official journal of the American College of Medical Toxicology, 13(1), 99-105","doi":"10.1007/s13181-016-0552-x","pmid":"27139708","tags":["youth","legalization","pregnancy","cbd","epilepsy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review identified cannabis legalization's impact on children across four developmental stages.\n\nPrenatal: Cannabis remains one of the most commonly used substances during pregnancy, with increasing use as legalization normalizes cannabis. Concerns exist about effects on fetal brain development, though evidence is mixed.\n\nEarly childhood: Accidental ingestion of cannabis edibles by young children has increased substantially in legalization states. Edible products (gummies, cookies, brownies) are particularly attractive and accessible to children.\n\nAdolescence: Concerns about increased availability, normalization of use, and higher-potency products. Data on whether legalization increases adolescent use is mixed.\n\nMedical use: CBD shows promise for pediatric epilepsy, but the review emphasizes the need for rigorous clinical trials rather than reliance on unregulated products with variable composition and potency.","whyItMatters":"Cannabis legalization policies are primarily designed with adults in mind. This review systematically catalogs the pediatric consequences that are often overlooked in policy debates, from poison control calls about toddlers who ate cannabis edibles to questions about prenatal brain development.","specificNumbers":"Cannabis is one of the most commonly used substances in pregnancy. Accidental exposures in young children increased with legalization. CBD for pediatric epilepsy requires clinical trials for evidence.","methodology":"Narrative review of pediatric cannabis concerns across the developmental spectrum, from prenatal through adolescence, including medical use.","limitations":"Narrative review without systematic methodology. The evidence on many pediatric concerns is limited or mixed. The review was published before Epidiolex's FDA approval, so the CBD-epilepsy landscape has changed. Quantitative data on the magnitude of pediatric impacts is still developing."},{"rthcId":"RTHC-01548","title":"Marijuana and acute health care contacts in Colorado.","authors":"Wang, George Sam; Hall, Katelyn; Vigil, Daniel; Banerji, Shireen; Monte, Andrew; VanDyke, Mike","year":2017,"journal":"Preventive medicine, 104, 24-30","doi":"10.1016/j.ypmed.2017.03.022","pmid":"28365373","tags":["legalization","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Analyzing Colorado health data from 2000-2015, the study documented escalating marijuana-related healthcare contacts across three measures.\n\nHospitalizations with marijuana-related billing codes increased from 274 per 100,000 in 2000 to 593 per 100,000 in 2015, more than doubling over the period. The increase accelerated after both medical (2010) and recreational (2014) liberalization.\n\nAmong ER visits with marijuana-related codes, the prevalence of mental illness was five-fold higher (5.07) than ER visits without marijuana codes, suggesting a strong association between marijuana-related emergencies and psychiatric conditions.\n\nPoison control calls remained stable from 2000-2009, then significantly increased from 42 to 93 after medical marijuana policy liberalization in 2010. After recreational legalization in 2014, calls increased another 79.7% (from 123 to 221). Calls involving children under 17 also increased after 2014.","whyItMatters":"Colorado is the most-studied natural experiment in cannabis legalization. These data provide concrete evidence that legalization is associated with increased marijuana-related healthcare utilization. The five-fold higher rate of mental illness among marijuana ER visits is particularly important for understanding the psychiatric dimensions of cannabis use.","specificNumbers":"Hospitalizations: 274 to 593 per 100,000 (2000-2015). Mental illness prevalence in marijuana ER visits: 5.07x higher than non-marijuana visits. Poison control calls: 42 (2009) to 93 (2010, post-medical), then 123 to 221 (2013-2014, post-recreational, +79.7%). Under-17 calls also increased after 2014.","methodology":"Retrospective analysis using Colorado Hospital Association data (hospitalizations and ER visits with marijuana billing codes), and Regional Poison Center marijuana exposure calls, from 2000 to 2015.","limitations":"Billing code-based analysis may capture marijuana mentions that are incidental rather than causal. Increased coding and disclosure after legalization may inflate the apparent increase. The study cannot determine what proportion of increased healthcare contacts represents genuinely new problems versus better detection. No comparison state data was included."},{"rthcId":"RTHC-01549","title":"Synthetic Cathinone and Cannabinoid Designer Drugs Pose a Major Risk for Public Health.","authors":"Weinstein, Aviv M; Rosca, Paola; Fattore, Liana; London, Edythe D","year":2017,"journal":"Frontiers in psychiatry, 8, 156","doi":"10.3389/fpsyt.2017.00156","pmid":"28878698","tags":["synthetic-cannabinoids","psychosis","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review compared synthetic cannabinoids to natural cannabis across several dimensions. Synthetic cannabinoids have effects somewhat similar to natural cannabis but are substantially more potent and longer-lasting than THC, owing to their high affinity and full agonist activity at cannabinoid receptors (THC is only a partial agonist).\n\nThe psychiatric effects are more severe than natural cannabis: psychosis, mania, suicidal ideation, paranoid delusions, and dependence have all been linked to synthetic cannabinoid use. The potency difference means that doses in recreational products can produce effects that natural cannabis never would.\n\nA key public health challenge is the rapid development of novel compounds: as authorities ban specific synthetic cannabinoids, manufacturers modify the chemical structure to create legal alternatives. New screening techniques are constantly needed to detect evolving compounds.","whyItMatters":"Synthetic cannabinoids represent one of the most dangerous developments in the recreational drug landscape. Unlike natural cannabis, which has a relatively large margin of safety, synthetic cannabinoids can cause life-threatening toxicity, severe psychiatric emergencies, and death. Public education about the fundamental difference between these products and natural cannabis is critical.","specificNumbers":"Synthetic cannabinoids are full agonists at CB1 (THC is a partial agonist). Novel compounds are developed rapidly to evade regulation. Linked to psychosis, mania, suicidal ideation, and dependence.","methodology":"Narrative review of published literature on the prevalence, epidemiology, bio-behavioral effects, and detection of synthetic cathinones and synthetic cannabinoids.","limitations":"The review covers two distinct drug classes (synthetic cathinones and synthetic cannabinoids), making cannabis-specific conclusions less detailed. Much of the evidence comes from case reports and poison center data rather than controlled studies. The rapidly evolving nature of synthetic drugs means the specific compounds discussed may already be outdated."},{"rthcId":"RTHC-01550","title":"Street racing among the Ontario adult population: Prevalence and association with collision risk.","authors":"Wickens, Christine M; Smart, Reginald G; Vingilis, Evelyn; Ialomiteanu, Anca R; Stoduto, Gina; Mann, Robert E","year":2017,"journal":"Accident; analysis and prevention, 103, 85-91","doi":"10.1016/j.aap.2017.03.021","pmid":"28391091","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01551","title":"The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice.","authors":"Wilkerson, Jenny L; Ghosh, Sudeshna; Mustafa, Mohammed; Abdullah, Rehab A; Niphakis, Micah J; Cabrera, Roberto; Maldonado, Rafael L; Cravatt, Benjamin F; Lichtman, Aron H","year":2017,"journal":"Neuropharmacology, 114, 156-167","doi":"10.1016/j.neuropharm.2016.11.015","pmid":"27890602","tags":["pain","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"SA-57, which simultaneously boosts both endocannabinoids (anandamide via FAAH inhibition and 2-AG via MAGL inhibition), produced multiple therapeutically relevant effects in mice.\n\nFor pain: SA-57 reversed both neuropathic pain (nerve injury model) and inflammatory pain (carrageenan model). Its anti-pain effects required both CB1 and CB2 receptors, while its anti-swelling effects required only CB2.\n\nFor opioid enhancement: Low doses of SA-57 (which elevated anandamide but not 2-AG) significantly augmented morphine's pain-relieving effects without producing THC-like behavioral side effects. This \"opioid-sparing\" effect could allow lower opioid doses.\n\nFor addiction: SA-57 reduced heroin-reinforced nose-poking behavior and lowered the progressive ratio breakpoint (how hard mice would work) for heroin, suggesting it reduced heroin's rewarding properties.","whyItMatters":"This study addresses two major public health crises simultaneously: chronic pain and opioid addiction. A compound that enhances morphine's pain relief (allowing lower doses) while also reducing the desire for heroin could fundamentally change pain management. The endocannabinoid system is positioned at the intersection of pain and reward, making it a promising therapeutic target.","specificNumbers":"SA-57 was more potent at elevating anandamide than 2-AG. Low doses augmented morphine without cannabimimetic side effects. Anti-allodynic effects required CB1 and CB2 receptors. Anti-edematous effects required CB2 only. SA-57 reduced heroin nose-poking and progressive ratio breakpoint.","methodology":"Chronic constriction injury (CCI) model of neuropathic pain and carrageenan inflammatory pain model in mice. Receptor involvement tested with selective antagonists. Morphine combination experiments for opioid-sparing effects. Heroin self-administration paradigm for addiction-related outcomes.","limitations":"Mouse study with acute pain models that may not represent chronic human pain. SA-57 is a research tool compound, not a clinical drug. The heroin self-administration results, while striking, need replication and extension to other opioid paradigms. Long-term safety of dual FAAH-MAGL inhibition is unknown."},{"rthcId":"RTHC-01552","title":"CB₁ receptor antagonism in the bed nucleus of the stria terminalis interferes with affective opioid withdrawal in rats.","authors":"Wills, Kiri L; DeVuono, Marieka V; Limebeer, Cheryl L; Vemuri, Kiran; Makriyannis, Alexandros; Parker, Linda A","year":2017,"journal":"Behavioral neuroscience, 131(4), 304-11","doi":"10.1037/bne0000201","pmid":"28714716","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The bed nucleus of the stria terminalis (BNST) is part of the extended amygdala, a brain circuit involved in addiction, anxiety, and stress. Researchers investigated whether cannabinoid receptor modulation in this region could affect the aversive experience of opioid withdrawal.\n\nIn Experiment 1, infusing the CB1 antagonist AM251 directly into the BNST prevented naloxone-precipitated morphine withdrawal from producing conditioned place aversion (a measure of the unpleasant experience of withdrawal). This means blocking CB1 in the BNST eliminated the negative emotional component of opioid withdrawal.\n\nIn Experiment 2, infusing the MAGL inhibitor MJN110 (which boosts 2-AG) into the BNST did NOT prevent withdrawal aversion, unlike previous findings with MJN110 in other brain regions. This suggests different brain areas use different endocannabinoid mechanisms to process withdrawal distress.","whyItMatters":"The emotional distress of opioid withdrawal is a primary driver of relapse. Understanding exactly where and how the endocannabinoid system modulates withdrawal aversion could lead to targeted interventions that reduce the suffering of withdrawal without simply substituting one drug for another.","specificNumbers":"AM251 in BNST: prevented withdrawal-induced place aversion. MJN110 in BNST: did not prevent aversion (unlike in other brain regions). Previous work showed AM251 also worked in central amygdala and MJN110 worked in basolateral amygdala and insular cortex.","methodology":"Rats were made morphine-dependent, then withdrawal was precipitated with naloxone. Conditioned place aversion measured the aversive experience of withdrawal. CB1 antagonist (AM251) or MAGL inhibitor (MJN110) was microinjected directly into the BNST before conditioning trials.","limitations":"Animal study using precipitated withdrawal, which is more acute than natural withdrawal. The BNST microinjection approach is not feasible in humans. The study measured conditioned place aversion, not all aspects of withdrawal. The specific mechanism by which CB1 blockade in the BNST reduces withdrawal aversion is not fully explained."},{"rthcId":"RTHC-01553","title":"Detecting biomarkers of secondhand marijuana smoke in young children.","authors":"Wilson, Karen M; Torok, Michelle R; Wei, Binnian; Wang, Lanqing; Robinson, Michelle; Sosnoff, Connie S; Blount, Benjamin C","year":2017,"journal":"Pediatric research, 81(4), 589-592","doi":"10.1038/pr.2016.261","pmid":"27911435","tags":["youth","respiratory"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers tested urine from 43 young children (ages 1 month to 2 years) hospitalized with bronchiolitis in Colorado for marijuana metabolites using highly sensitive LC/MS/MS testing.\n\n16% of samples were positive for COOH-THC (the primary marijuana metabolite), with concentrations ranging from 0.03 to 1.5 ng/mL. Two subjects had levels above 1 ng/mL. The exposure was detected through secondhand marijuana smoke, not intentional administration.\n\nNon-white children had significantly more exposure than white children (44% vs. 9%, p < 0.05). Children with higher tobacco smoke exposure (cotinine > 2.0 ng/mL) were more likely to also be positive for marijuana metabolites (40% vs. 7%, p < 0.01), suggesting households with tobacco smoke are also more likely to expose children to marijuana smoke.","whyItMatters":"This is one of the first studies to objectively document secondhand marijuana smoke exposure in young children. The 16% positivity rate is concerning given that these children were already hospitalized with a respiratory illness. Whether secondhand marijuana smoke contributed to or worsened their bronchiolitis is unknown but raises important questions.","specificNumbers":"43 children tested. 16% positive for COOH-THC. Range: 0.03-1.5 ng/mL. 2 children had levels > 1 ng/mL. 77% male. 52% under 1 year. Non-white children: 44% vs. 9% exposed (p < 0.05). High tobacco exposure: 40% vs. 7% also marijuana-exposed (p < 0.01).","methodology":"Cross-sectional study of children aged 1 month to 2 years hospitalized with bronchiolitis in Colorado (2013-2015). Parent survey and urine analysis for cotinine (tobacco metabolite) and COOH-THC (marijuana metabolite) using LC/MS/MS with very low detection limits (0.015 ng/mL for COOH-THC).","limitations":"Very small sample (43 children). Single-site study in Colorado. Cannot determine whether the marijuana exposure contributed to the bronchiolitis. The detection of metabolites confirms exposure but cannot determine the magnitude, frequency, or route (could be from clothing or surfaces, not just smoke). No comparison to hospitalized children outside legalization states."},{"rthcId":"RTHC-01554","title":"Haloperidol, a Novel Treatment for Cannabinoid Hyperemesis Syndrome.","authors":"Witsil, Joanne C; Mycyk, Mark B","year":2017,"journal":"American journal of therapeutics, 24(1), e64-e67","doi":"10.1097/MJT.0000000000000157","pmid":"25393073","tags":["withdrawal","appetite","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Four patients with CHS who failed standard emergency department therapy (including conventional antiemetics) showed significant improvement after treatment with haloperidol, an antipsychotic that primarily blocks dopamine D2 receptors.\n\nThe authors propose a mechanistic explanation: CHS involves dysregulation of cannabinoid type 1 (CB1) receptors, and recent animal research has revealed complex interactions between dopamine and CB1 signaling. Haloperidol's success may relate to its ability to modulate these dopamine-cannabinoid interactions rather than through its traditional antiemetic mechanism.\n\nThe case series highlights a practical clinical point: CHS patients often undergo excessive laboratory and radiographic testing and require hospital admission because standard antiemetics fail. If haloperidol can quickly resolve symptoms in the emergency department, it could reduce unnecessary testing and admission.","whyItMatters":"CHS remains a diagnostic and therapeutic challenge in emergency departments. Standard antiemetics frequently fail, leading to prolonged ER stays, excessive workups, and hospital admissions. Haloperidol represents a potentially effective, widely available, and inexpensive treatment option.","specificNumbers":"4 patients. All failed standard ED antiemetics. All improved significantly with haloperidol. Complex dopamine-CB1 receptor interactions proposed as mechanism.","methodology":"Case series of 4 CHS patients treated with haloperidol in the emergency department after failure of standard antiemetic therapy.","limitations":"Only 4 cases without controls. Improvement could coincide with natural symptom resolution. Haloperidol has its own side effects (sedation, movement disorders, QT prolongation) that were not discussed. The proposed mechanism is speculative. The optimal haloperidol dose for CHS has not been established."},{"rthcId":"RTHC-01555","title":"Strokes are possible complications of cannabinoids use.","authors":"Wolff, Valérie; Jouanjus, Emilie","year":2017,"journal":"Epilepsy & behavior : E&B, 70(Pt B), 355-363","doi":"10.1016/j.yebeh.2017.01.031","pmid":"28237318","tags":["cardiovascular","synthetic-cannabinoids","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers compiled 98 cases from the medical literature where stroke occurred in the context of cannabinoid use. Of these, 85 followed natural cannabis use and 13 followed synthetic cannabinoid use. The average age was just 32 years old, and men were nearly four times more likely to be affected than women.\n\nThe vast majority of cases (85 of 98) involved ischemic strokes, where blood flow to the brain is blocked, rather than hemorrhagic strokes involving bleeding. Most patients (81%) were chronic cannabis users, and 18% had recently increased their consumption shortly before the stroke occurred.\n\nWhile 46% of patients recovered with no or few lasting effects, five people died following their strokes. A proposed mechanism in about 27% of cases was reversible cerebral vasoconstriction, where blood vessels in the brain suddenly narrow. The authors suggest some individuals may have a genetic predisposition that makes them more vulnerable to this vascular toxicity.","whyItMatters":"While cannabinoid-associated strokes appear to be rare compared to the large number of people who use cannabis worldwide, the fact that they disproportionately affect young adults is concerning. Young people typically have very low stroke risk, and any factor that increases it warrants attention. The review also highlights that these cases may be underreported because clinicians do not always ask about or test for cannabis use in stroke patients.","specificNumbers":"98 total cases identified in the literature. 85 involved natural cannabis, 13 involved synthetic cannabinoids. Mean age was 32.3 years. Male-to-female ratio was 3.7 to 1. Cannabis was smoked with tobacco in 66% of cases. 81% were chronic users. 46% had favorable outcomes. 5 patients died. Reversible cerebral vasoconstriction was identified in 27% of cases.","methodology":"This was a narrative review that compiled all published case reports and case series of cannabinoid-associated strokes from the medical literature. The authors analyzed patient demographics, type of cannabinoid used, type of stroke, clinical outcomes, and proposed mechanisms across all 98 reported cases.","limitations":"The review is limited to published case reports, which represent a selection bias toward unusual or severe cases. There is no denominator showing how many cannabis users did not experience strokes, making it impossible to calculate actual risk rates. Tobacco co-use in 66% of cases complicates attribution. The temporal correlation between cannabis use and stroke does not establish causation, as the authors themselves acknowledge."},{"rthcId":"RTHC-01556","title":"Medical Cannabinoids in Children and Adolescents: A Systematic Review.","authors":"Wong, Shane Shucheng; Wilens, Timothy E","year":2017,"journal":"Pediatrics, 140(5)","doi":"10.1542/peds.2017-1818","pmid":"29061872","tags":["medical-cannabis","youth","epilepsy"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Researchers systematically reviewed 2,743 citations from medical databases and identified 22 studies involving 795 children and adolescents who received cannabinoid treatments. The evidence was strongest for treating chemotherapy-induced nausea and vomiting, an area where cannabinoids have been studied longest in pediatric populations.\n\nEvidence for epilepsy treatment was described as increasing, reflecting a growing body of research. For other conditions including spasticity, neuropathic pain, PTSD, and Tourette syndrome, the evidence was considered insufficient to draw conclusions.\n\nThe quality of most studies was limited. The majority lacked control groups, had small sample sizes, and used varying cannabinoid formulations and doses. Only five of the 22 studies were randomized controlled trials. Long-term follow-up to identify potential adverse effects was largely absent.","whyItMatters":"As medical marijuana becomes legal in more jurisdictions, parents increasingly seek cannabinoid treatments for their children. This review provides a clear-eyed assessment of what the evidence actually supports, highlighting the gap between public enthusiasm and scientific documentation. The lack of long-term safety data in developing brains is a particular concern that warrants more research.","specificNumbers":"2,743 citations screened. 22 studies met inclusion criteria. 795 total participants across all studies. Only 5 were randomized controlled trials. Study types: 5 RCTs, 5 retrospective chart reviews, 5 case reports, 4 open-label trials, 2 parent surveys, 1 case series.","methodology":"Following PRISMA guidelines, researchers searched PubMed, Medline, and CINAHL databases through May 2017. They screened 2,743 citations, reviewed 103 full texts, and included 21 articles containing 22 studies. Study types included five RCTs, five retrospective chart reviews, five case reports, four open-label trials, two parent surveys, and one case series.","limitations":"The review was limited by the heterogeneity and small size of available studies. Different cannabinoid formulations, doses, and delivery methods across studies make direct comparisons difficult. Publication bias may overrepresent positive results. The search was conducted in 2017 and does not include more recent pediatric CBD studies."},{"rthcId":"RTHC-01557","title":"Cannabis sativa (Hemp) Seeds, Δ9-Tetrahydrocannabinol, and Potential Overdose.","authors":"Yang, Yi; Lewis, Melissa M; Bello, Angelica M; Wasilewski, Ewa; Clarke, Hance A; Kotra, Lakshmi P","year":2017,"journal":"Cannabis and cannabinoid research, 2(1), 274-281","doi":"10.1089/can.2017.0040","pmid":"29098190","tags":["potency","cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers tested three brands of consumer-grade hemp seeds using four different extraction methods to measure THC and CBD content. Across nearly all brands and methods, THC levels exceeded Canada's legal limit of 10 micrograms per gram.\n\nThe most efficient extraction method (Soxhlet extraction) revealed THC concentrations as high as 1,250% of the legal limit. If someone consumed the recommended 30 grams of hemp seeds per day, they could potentially ingest up to 3.8 milligrams of THC, a dose that could produce noticeable effects in sensitive individuals.\n\nTHC and CBD levels varied significantly even within the same brand, reflecting the inhomogeneous nature of hemp seeds. It remained unclear whether the high THC levels were due to seed contamination from contact with THC-rich plant parts, or some other factor.","whyItMatters":"Hemp seeds are widely marketed as a health food, and many consumers have no idea they could contain meaningful amounts of THC. For people who are drug tested, are sensitive to THC, or are giving hemp seeds to children, these findings raise practical safety questions about a product many consider completely benign.","specificNumbers":"Legal limit in Canada: 10 micrograms of THC per gram of hemp seeds. Maximum THC found: up to 1,250% of legal limit. Potential daily THC intake from 30g serving: up to 3.8 mg. Three brands tested with four extraction methods each.","methodology":"Three brands of consumer-grade hemp seeds were purchased and tested using four different extraction procedures: Soxhlet extraction, sonication, maceration, and reflux. Total THC and CBD were quantified for each brand using each method. The researchers compared results across methods to determine which most accurately captured total cannabinoid content.","limitations":"Only three brands were tested, which limits generalizability. The study used laboratory extraction methods that may not reflect how THC is absorbed during normal digestion. The actual bioavailability of THC from hemp seeds during eating could be lower than what extraction methods capture. No human subjects were involved to test actual effects."},{"rthcId":"RTHC-01558","title":"Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation.","authors":"Zgair, Atheer; Lee, Jong Bong; Wong, Jonathan C M; Taha, Dhiaa A; Aram, Jehan; Di Virgilio, Daisy; McArthur, Joshua W; Cheng, Yu-Kit; Hennig, Ivo M; Barrett, David A; Fischer, Peter M; Constantinescu, Cris S; Gershkovich, Pavel","year":2017,"journal":"Scientific reports, 7(1), 14542","doi":"10.1038/s41598-017-15026-z","pmid":"29109461","tags":["medical-cannabis","cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers discovered that co-administering cannabinoids with dietary lipids dramatically increased their transport through the intestinal lymphatic system in rats. CBD concentrations in lymph fluid were 250-fold higher than in blood plasma, while THC concentrations were 100-fold higher.\n\nThese lymphatic concentrations exceeded the threshold needed to produce immunomodulatory effects when tested on human lymphocytes. CBD showed stronger immunosuppressive effects than THC across the cell types tested.\n\nParticularly notable was the finding that immune cells from multiple sclerosis patients were more susceptible to the immunosuppressive effects of cannabinoids than cells from healthy volunteers or cancer patients. This suggests that taking cannabinoids with a high-fat meal could be therapeutically meaningful for autoimmune conditions, though the authors also caution that this lymphatic transport route requires careful consideration in immunocompromised patients.","whyItMatters":"Most people who take oral cannabis do so with food, often without knowing that fat content dramatically changes how cannabinoids are absorbed and distributed. This study reveals a previously underappreciated absorption pathway that could explain why edibles sometimes produce unpredictable effects and why cannabinoids might be particularly effective for certain immune conditions when taken with fatty meals.","specificNumbers":"CBD lymph concentrations: 250-fold higher than plasma. THC lymph concentrations: 100-fold higher than plasma. Lymphatic cannabinoid levels exceeded immunomodulatory thresholds in human cells. MS patient lymphocytes showed greater susceptibility to cannabinoid immunosuppression than healthy or cancer patient cells.","methodology":"This was a mixed study combining animal pharmacokinetics with human cell experiments. Rats received oral cannabinoids with lipids, and researchers measured cannabinoid concentrations in lymph fluid versus blood plasma. The immunomodulatory thresholds were then tested on human lymphocytes from MS patients, cancer patients, and healthy volunteers using the lymphatic concentrations observed in rats.","limitations":"Pharmacokinetic data came from rats, and lymphatic transport rates may differ in humans. The immunological experiments used cells in culture, not whole-body immune responses. The specific lipid formulations used may not reflect typical dietary fat intake. Human clinical trials would be needed to confirm that this lymphatic transport pathway produces meaningful therapeutic benefits."},{"rthcId":"RTHC-01559","title":"Association between cannabis use and methadone maintenance treatment outcomes: an investigation into sex differences.","authors":"Zielinski, Laura; Bhatt, Meha; Sanger, Nitika; Plater, Carolyn; Worster, Andrew; Varenbut, Michael; Daiter, Jeff; Pare, Guillaume; Marsh, David C; Desai, Dipika; MacKillop, James; Steiner, Meir; McDermid Vaz, Stephanie; Thabane, Lehana; Samaan, Zainab","year":2017,"journal":"Biology of sex differences, 8, 8","doi":"10.1186/s13293-017-0130-1","pmid":"28367308","tags":["addiction","sex-differences","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers studied 414 men and 363 women receiving methadone maintenance treatment for opioid use disorder across multiple clinics in Ontario, Canada. They found a striking sex difference in how cannabis use related to treatment outcomes.\n\nWomen who used cannabis during treatment were significantly more likely to also use illicit opioids compared to women who did not use cannabis. The association held after controlling for other variables, with cannabis-using women having 82% higher odds of illicit opioid use.\n\nIn men, no significant relationship between cannabis use and illicit opioid use was found. Notably, the heaviness of cannabis use (how much or how often) did not predict outcomes in either sex, suggesting it was any cannabis use, rather than the amount, that mattered for women.","whyItMatters":"Opioid use disorder treatment is a life-or-death matter, and identifying factors that predict relapse can help target interventions. The sex-specific nature of this finding suggests that treatment programs may need different approaches for men and women when it comes to addressing concurrent cannabis use. With cannabis legalization expanding, understanding these interactions becomes more urgent.","specificNumbers":"777 participants total: 414 men and 363 women. Women using cannabis had 82% higher odds of illicit opioid use (OR = 1.82, 95% CI 1.18-2.82, p = 0.007). No significant association in men. Heaviness of cannabis use was not associated with outcomes in either sex.","methodology":"This was a multicentre cross-sectional study recruiting participants from Canadian Addiction Treatment Centre sites in Ontario. Sex differences in the association between cannabis use and illicit opioid use were analyzed using multivariable logistic regression. A secondary analysis examined heaviness of cannabis use as a predictor.","limitations":"The cross-sectional design cannot determine whether cannabis use causes opioid relapse or whether both behaviors reflect a common underlying factor. Self-reported cannabis and opioid use may be underreported. The study did not account for the reasons behind cannabis use (recreational versus self-medication). Results from Canadian clinics may not generalize to other settings."},{"rthcId":"RTHC-01560","title":"Emotion regulation deficits in regular marijuana users.","authors":"Zimmermann, Kaeli; Walz, Christina; Derckx, Raissa T; Kendrick, Keith M; Weber, Bernd; Dore, Bruce; Ochsner, Kevin N; Hurlemann, René; Becker, Benjamin","year":2017,"journal":"Human brain mapping, 38(8), 4270-4279","doi":"10.1002/hbm.23671","pmid":"28560818","tags":["cognition","mental-health","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared 23 regular marijuana users to 20 non-using controls using brain imaging during an emotion regulation task. Participants viewed negative images and were asked to use cognitive reappraisal, essentially reframing the meaning of what they saw to reduce its emotional impact.\n\nCannabis users showed significantly worse emotion regulation success on the behavioral level. Their brain scans revealed increased activity in frontal motor regions during reappraisal attempts, which the researchers interpreted as an unsuccessful attempt to recruit additional neural resources to compensate for impaired regulation.\n\nCritically, cannabis users showed impaired ability to dampen amygdala activity during emotion regulation. This was accompanied by decreased functional connectivity between the amygdala and the dorsolateral prefrontal cortex, a connection considered essential for top-down emotional control. The amygdala essentially was not receiving the regulatory signals from higher brain regions as effectively.","whyItMatters":"Difficulty regulating negative emotions is a known risk factor for mental health problems and substance use disorders. If regular cannabis use impairs the brain circuits responsible for emotion regulation, this could create a feedback loop where cannabis is used to cope with negative emotions but simultaneously weakens the brain's own capacity to manage them.","specificNumbers":"23 regular marijuana users and 20 non-using controls. Cannabis users showed significantly worse behavioral emotion regulation (p < 0.05). Increased frontal network activity in users during reappraisal (p < 0.05, FWE corrected). Impaired amygdala downregulation with decreased amygdala-DLPFC connectivity (p < 0.05, FWE corrected).","methodology":"This was a cross-sectional fMRI study comparing 23 regular marijuana users to 20 demographically matched non-using controls. Participants completed a cognitive emotion regulation (reappraisal) paradigm during brain scanning. Both behavioral performance and neural activity patterns were measured and compared between groups.","limitations":"The cross-sectional design cannot determine whether cannabis caused the emotion regulation deficits or whether people with pre-existing deficits were more likely to use cannabis. The sample was small. The study did not assess specific cannabis use parameters like potency, strain, or frequency in detail. Only one type of emotion regulation strategy (reappraisal) was tested."},{"rthcId":"RTHC-01561","title":"Psychotic patients who used cannabis frequently before illness onset have higher genetic predisposition to schizophrenia than those who did not.","authors":"Aas, M; Melle, I; Bettella, F; Djurovic, S; Le Hellard, S; Bjella, T; Ringen, P A; Lagerberg, T V; Smeland, O B; Agartz, I; Andreassen, O A; Tesli, M","year":2018,"journal":"Psychological medicine, 48(1), 43-49","doi":"10.1017/S0033291717001209","pmid":"28967348","tags":["psychosis","genetics","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers assigned schizophrenia polygenic risk scores to 381 schizophrenia spectrum patients, 220 bipolar disorder spectrum patients, and 415 healthy controls. The polygenic risk score reflects how many common genetic variants associated with schizophrenia each person carries.\n\nPatients who had used cannabis weekly to daily before their first illness episode had the highest genetic risk scores for schizophrenia, regardless of whether they were diagnosed with schizophrenia or bipolar disorder. The difference was statistically significant.\n\nThe effect was strongest among those who began heavy cannabis use before age 18. These early-onset frequent users had the largest difference in genetic risk compared to patients who never or rarely used cannabis, with a moderate effect size of 0.42.","whyItMatters":"This finding helps untangle the complex relationship between cannabis and psychosis. Rather than cannabis simply \"causing\" psychosis, the data suggest that individuals with higher genetic loading for schizophrenia may be more likely to use cannabis heavily before becoming ill. This does not rule out cannabis as an additional environmental trigger, but it suggests the relationship involves both genetic vulnerability and cannabis exposure.","specificNumbers":"381 schizophrenia spectrum patients, 220 bipolar spectrum patients, 415 healthy controls. Weekly-to-daily cannabis users before illness had highest polygenic risk scores (p = 0.02, Cohen's d = 0.33). Early-onset frequent users (before age 18) versus non-users: p = 0.003, Cohen's d = 0.42. Reference sample for risk scores: 81,535 participants from PGC.","methodology":"This was an observational genetic study using polygenic risk scores calculated from the Psychiatric Genomics Consortium schizophrenia case-control study (N = 81,535). An independent sample of 381 schizophrenia spectrum cases, 220 bipolar spectrum cases, and 415 healthy controls was genotyped and scored. Cannabis use history before illness onset was collected and participants were grouped by frequency of use.","limitations":"The study cannot determine causality or direction of effect. It is possible that the same genes that increase schizophrenia risk also increase cannabis use propensity. Cannabis use history was based on retrospective self-report, which may be inaccurate. The study focused on common genetic variants and did not account for rare mutations or environmental factors beyond cannabis."},{"rthcId":"RTHC-01562","title":"Effect of Vaporized Cannabis on Exertional Breathlessness and Exercise Endurance in Advanced Chronic Obstructive Pulmonary Disease. A Randomized Controlled Trial.","authors":"Abdallah, Sara J; Smith, Benjamin M; Ware, Mark A; Moore, Michelle; Li, Pei Zhi; Bourbeau, Jean; Jensen, Dennis","year":2018,"journal":"Annals of the American Thoracic Society, 15(10), 1146-1158","doi":"10.1513/AnnalsATS.201803-198OC","pmid":"30049223","tags":["medical-cannabis","respiratory"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Despite decades-old studies showing that smoked cannabis can act as a bronchodilator in healthy people and those with asthma, this randomized controlled trial found no such benefit in people with advanced COPD.\n\nSixteen adults with severe COPD (average lung function at 36% of predicted normal) inhaled vaporized cannabis containing 18.2% THC or a control. Researchers then measured their breathlessness during cycling exercise, exercise endurance time, lung function at rest, and various cardiac and metabolic parameters.\n\nAcross every outcome measured, there was no clinically meaningful difference between the cannabis and control conditions. Breathlessness ratings during exercise were nearly identical (2.7 versus 2.6 Borg units). Exercise endurance times were similar (3.8 versus 4.2 minutes). Spirometry, impulse oscillometry, cognitive function, psychoactivity, and mood also showed no significant differences.","whyItMatters":"Some people with COPD use cannabis hoping it will help their breathing, partly based on old studies showing bronchodilatory effects in other populations. This rigorous trial found that those earlier findings do not translate to advanced COPD. The null result is itself important information, as it helps patients and clinicians make informed decisions.","specificNumbers":"16 participants with advanced COPD. Mean FEV1: 36% predicted. Cannabis dose: 35 mg at 18.2% THC. Breathlessness at isotime: 2.7 (cannabis) vs 2.6 (control) Borg units. Exercise endurance: 3.8 (cannabis) vs 4.2 (control) minutes. No significant differences in any measured outcome.","methodology":"This was a randomized controlled trial of 16 adults with advanced COPD (mean FEV1 36% predicted). Participants inhaled 35 mg of vaporized cannabis (18.2% THC, less than 0.99% CBD) or control. Outcomes included breathlessness during cardiopulmonary exercise testing, exercise endurance time, resting lung function (spirometry and impulse oscillometry), cognitive function, psychoactivity, and mood.","limitations":"The sample was very small at 16 participants. Only a single dose was tested, and chronic effects might differ. The cannabis used had very low CBD content, and CBD may have different respiratory effects. Only advanced COPD was studied, and results might differ in mild or moderate disease. The study design was acute rather than looking at longer-term outcomes."},{"rthcId":"RTHC-01563","title":"Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts.","authors":"Abidi, Ammaar H; Presley, Chaela S; Dabbous, Mustafa; Tipton, David A; Mustafa, Suni M; Moore, Bob M","year":2018,"journal":"Archives of oral biology, 87, 79-85","doi":"10.1016/j.archoralbio.2017.12.005","pmid":"29274621","tags":["inflammation","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tested three cannabinoid compounds on human periodontal ligament fibroblasts, the cells that anchor teeth to bone. When these cells were stimulated with bacterial toxins (P. gingivalis LPS), TNF-alpha, or IL-1-beta to mimic periodontal inflammation, all three cannabinoids effectively reduced the production of two key inflammatory markers: IL-6 and MCP-1.\n\nThe endocannabinoid anandamide (AEA), the CB2-selective agonist HU-308, and the CB2 inverse agonist SMM-189 all demonstrated anti-inflammatory activity. Interestingly, anandamide alone increased IL-6 production without inflammatory stimulation, but in the context of active inflammation, it was suppressive.\n\nThe effective concentrations were in the micromolar range, with HU-308 being the most potent (EC50 of 7.3 micromolar) and SMM-189 intermediate (EC50 of 13 micromolar).","whyItMatters":"About 65 million American adults have periodontitis, a chronic inflammatory condition that causes tooth loss. Current treatments have limitations, and new anti-inflammatory approaches are needed. The finding that cannabinoid receptor ligands, especially those targeting CB2 receptors, can reduce inflammation in the specific cells affected by gum disease opens a potential new avenue for periodontal treatment.","specificNumbers":"65 million US adults have periodontitis. EC50 values: anandamide 16 micromolar, SMM-189 13 micromolar, HU-308 7.3 micromolar. All three compounds reduced both IL-6 and MCP-1 production in stimulated cells. Anandamide alone increased IL-6 but not MCP-1.","methodology":"Primary human periodontal ligament fibroblasts were cultured and exposed to inflammatory stimuli (P. gingivalis LPS, TNF-alpha, IL-1-beta). Cannabinoid compounds at various concentrations were applied, and IL-6 and MCP-1 production were measured using Mesoscale Discovery immunoassay kits. Cytotoxicity was assessed to establish safe concentration ranges.","limitations":"This was an in vitro study using isolated cells, not whole tissues or living organisms. The concentrations effective in cell culture may not be achievable in the oral cavity. No animal models or human subjects were tested. The study did not assess whether the anti-inflammatory effects would translate to reduced tissue destruction or improved clinical outcomes."},{"rthcId":"RTHC-01564","title":"The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report.","authors":"Abrams, Donald I","year":2018,"journal":"European journal of internal medicine, 49, 7-11","doi":"10.1016/j.ejim.2018.01.003","pmid":"29325791","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The National Academies of Sciences, Engineering and Medicine conducted a comprehensive review of the health effects of cannabis, with a 16-member committee analyzing 10,000 recent abstracts across 11 health categories.\n\nFor therapeutic effects, the committee found conclusive or substantial evidence that cannabis or cannabinoids effectively treat three conditions: chronic pain in adults, chemotherapy-induced nausea and vomiting, and spasticity associated with multiple sclerosis.\n\nModerate evidence supported cannabis for improving secondary sleep disturbances. For many other conditions, including appetite improvement, Tourette syndrome, anxiety, PTSD, cancer, irritable bowel syndrome, epilepsy, and neurodegenerative disorders, the evidence was described as limited, insufficient, or absent.\n\nThe report specifically identified multiple barriers to cannabis research in the United States that may explain why more conditions have not been adequately studied, suggesting the gaps in evidence reflect regulatory obstacles rather than necessarily a lack of therapeutic potential.","whyItMatters":"This is one of the most authoritative reviews of cannabis therapeutics ever conducted, coming from the National Academies, the same body that advises the US government on science. Its conclusions carry significant weight in policy discussions and clinical decision-making. The identification of research barriers is equally important, as it acknowledges that absence of evidence does not equal evidence of absence.","specificNumbers":"16-member committee. 10,000 abstracts reviewed. 11 health endpoint categories examined. 3 conditions with conclusive or substantial evidence of benefit: chronic pain, chemotherapy-induced nausea, MS spasticity. 1 condition with moderate evidence: secondary sleep disturbances.","methodology":"The NASEM committee followed key features of a systematic review process, searching relevant databases and reviewing 10,000 recent abstracts. Priority was given to recently published systematic reviews and primary research addressing 11 health categories. Standardized language was used to categorize evidence strength: conclusive, substantial, moderate, limited, or insufficient.","limitations":"The review was constrained by the quality and quantity of available research, which the authors acknowledged was itself limited by regulatory barriers. The rapidly evolving landscape of cannabis products and formulations means some findings may not reflect current clinical practice. The committee could only assess published literature, which may not capture all clinical experience."},{"rthcId":"RTHC-01565","title":"Associations between adolescent cannabis use and brain structure in psychosis.","authors":"Abush, Hila; Ghose, Subroto; Van Enkevort, Erin A; Clementz, Brett A; Pearlson, Godfrey D; Sweeney, John A; Keshavan, Matcheri S; Tamminga, Carol A; Ivleva, Elena I","year":2018,"journal":"Psychiatry research. Neuroimaging, 276, 53-64","doi":"10.1016/j.pscychresns.2018.03.008","pmid":"29628270","tags":["psychosis","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined brain structure in 109 people with psychotic disorders, comparing those with and without a history of adolescent cannabis use. Both groups showed lower total and regional gray matter density compared to healthy controls, as expected in psychotic disorders.\n\nHowever, the group with adolescent cannabis use showed significantly less gray matter reduction than the non-using psychosis group. This was especially pronounced in schizophrenia patients, where non-users showed extensive gray matter loss in frontal, temporal, parietal, and subcortical regions, while users with adolescent cannabis history did not differ significantly from healthy controls in brain structure.\n\nThis suggests that psychosis with a history of adolescent cannabis use may represent a distinct subtype, potentially driven by different etiological factors. Those who develop psychosis through the cannabis pathway may not need as much underlying brain pathology to become ill.","whyItMatters":"This finding challenges the simple narrative that cannabis damages the brain and causes psychosis. Instead, it suggests that cannabis-associated psychosis may represent a different pathway to illness, one that requires less pre-existing brain pathology. People who develop psychosis through the cannabis route may have fundamentally different neurobiology than those who develop it without cannabis involvement.","specificNumbers":"109 psychotic patients analyzed. Both cannabis-using and non-using psychosis groups had lower gray matter density than controls. Cannabis-using psychosis group showed attenuated (less severe) gray matter reductions. Schizophrenia patients without cannabis history showed robust gray matter loss in fronto-temporal, parietal, and subcortical regions. Cannabis-using psychosis patients did not differ significantly from healthy controls in brain structure.","methodology":"This was a cross-sectional neuroimaging study using voxel-based morphometry to measure gray matter density in 109 people with psychotic disorders (schizophrenia and bipolar I) and healthy controls. Participants were stratified by history of adolescent cannabis use. Regional and total gray matter density estimates were compared across groups.","limitations":"The cross-sectional design cannot determine whether the brain structure differences existed before psychosis onset. Sample sizes within subgroups were relatively small. The study relied on self-reported cannabis use history. There may be other confounding factors that differ between cannabis-using and non-using psychosis patients. Gray matter density is only one measure of brain structure and function."},{"rthcId":"RTHC-01566","title":"Analysis of the Uptake, Metabolism, and Behavioral Effects of Cannabinoids on Zebrafish Larvae.","authors":"Achenbach, John C; Hill, Jessica; Hui, Joseph P M; Morash, Michael G; Berrue, Fabrice; Ellis, Lee D","year":2018,"journal":"Zebrafish, 15(4), 349-360","doi":"10.1089/zeb.2017.1541","pmid":"29634460","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers used zebrafish larvae as a high-throughput model to study how cannabinoids are absorbed, metabolized, and affect behavior. THC and CBD each produced distinct behavioral patterns, with different concentration-response profiles that correlated with their uptake kinetics.\n\nWhen THC and CBD were combined, both the behavioral responses and the uptake kinetics shifted compared to when either compound was tested alone. This suggests the two major cannabinoids interact in ways that affect how each is absorbed and processed, not just how they act on receptors.\n\nImportantly, the metabolites detected in zebrafish larvae, the breakdown products of THC and CBD, were similar to those found in mammalian systems. This validates zebrafish as a useful model for studying cannabinoid pharmacology and screening cannabis strains or products.","whyItMatters":"Testing individual cannabinoids and their combinations in mammals is slow and expensive. Zebrafish larvae offer a rapid screening model that, as this study demonstrates, metabolizes cannabinoids similarly to mammals. This could accelerate research on how different cannabis strains and cannabinoid ratios produce different effects.","specificNumbers":"THC and CBD showed distinct concentration-response behavioral profiles. Combined THC+CBD shifted both uptake kinetics and behavioral patterns compared to either alone. THC and CBD metabolites in zebrafish matched mammalian metabolites.","methodology":"Zebrafish larvae were exposed to various concentrations of THC, CBD, or combinations of both. Uptake kinetics were measured over time to track absorption rates. Behavioral pattern analysis was used to measure locomotor responses. Metabolites were identified and compared to known mammalian THC and CBD metabolites.","limitations":"Zebrafish are not mammals, and despite similar metabolites, the pharmacological responses may differ in important ways. The behavioral readout in larvae is limited to locomotion and does not capture complex behaviors or subjective states. The concentrations used may not reflect human exposure levels. This is a proof-of-concept study rather than a direct guide to human pharmacology."},{"rthcId":"RTHC-01567","title":"Medicinal cannabinoids in palliative care.","authors":"Agar, Meera","year":2018,"journal":"British journal of clinical pharmacology, 84(11), 2491-2494","doi":"10.1111/bcp.13671","pmid":"29923616","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The author examined the evidence base for using medicinal cannabinoids in people with palliative diagnoses, where treatments increasingly focus on symptom management earlier in the disease trajectory. Despite strong public support for cannabis availability in palliative care, the clinical evidence tells a more cautious story.\n\nFor key palliative symptoms like pain and nausea, clinical data has been inconclusive. The author specifically noted that data from chemotherapy-induced nausea and vomiting cannot be readily extrapolated to palliative care nausea, as the underlying mechanisms differ.\n\nThe review advocated for exploring medicinal cannabinoids within clinical trials to accelerate the evidence base. For patients with refractory symptoms where other treatments have failed, the author suggested that off-label prescribing should consider pharmacokinetic and pharmacodynamic interactions, drug-drug interactions, and include informed discussion with patients and regular review of whether the treatment is actually helping.","whyItMatters":"Palliative care patients have some of the most urgent needs for symptom relief, and many are interested in cannabis. This review provides a measured perspective that acknowledges the therapeutic potential while cautioning against assuming efficacy without adequate evidence. It bridges the gap between patient demand and clinical evidence.","specificNumbers":"No specific quantitative findings reported. The review assessed the quality of evidence across multiple symptom domains in palliative care.","methodology":"This was a narrative review and clinical commentary examining the current evidence for medicinal cannabinoids in palliative care populations, with attention to the endocannabinoid system as a therapeutic target and practical considerations for prescribing.","limitations":"This is a narrative review and clinical commentary rather than a systematic review. The author's opinions, while informed, reflect a single expert perspective. The palliative care population is heterogeneous, and general conclusions may not apply to specific patients or conditions."},{"rthcId":"RTHC-01568","title":"Adolescent Synthetic Cannabinoid Exposure Produces Enduring Changes in Dopamine Neuron Activity in a Rodent Model of Schizophrenia Susceptibility.","authors":"Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J","year":2018,"journal":"The international journal of neuropsychopharmacology, 21(4), 393-403","doi":"10.1093/ijnp/pyy003","pmid":"29329382","tags":["synthetic-cannabinoids","psychosis","dopamine","youth"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers used a novel rodent model where about 40% of rats carry genetic susceptibility to a schizophrenia-like phenotype. When these susceptible rats were exposed to a synthetic cannabinoid (WIN55,212-2) during adolescence, a significantly larger proportion developed the characteristic hyperdopaminergic state associated with schizophrenia after reaching adulthood.\n\nCritically, the same adolescent synthetic cannabinoid exposure had no observable effect on the non-susceptible rats. This mirrors the human epidemiological pattern where most adolescents who use cannabis do not develop psychosis, but those with genetic vulnerability are at elevated risk.\n\nThe acquired schizophrenia-like phenotype appeared to involve alterations in parvalbumin interneuron function within the hippocampus. Additionally, adolescent exposure to an endocannabinoid upregulator (URB597) also increased the proportion of susceptible rats developing elevated dopamine neuron activity, but without changing behavioral sensitivity to amphetamine, highlighting important differences between exogenous and endogenous cannabinoid signaling.","whyItMatters":"This study provides experimental evidence for the gene-environment interaction model of cannabis and psychosis. The finding that only genetically susceptible animals were affected by adolescent cannabinoid exposure explains why the vast majority of young cannabis users do not develop psychosis while a vulnerable minority does. It also identifies specific neural mechanisms that may mediate this risk.","specificNumbers":"Approximately 40% of F2 MAM rats naturally display schizophrenia-like phenotype. Synthetic cannabinoid dose: 0.2 mg/kg WIN55,212-2. Endocannabinoid upregulator dose: 0.3 mg/kg URB597. Adolescent synthetic cannabinoid exposure significantly increased proportion of susceptible rats developing hyperdopaminergic phenotype. Non-susceptible rats showed no changes.","methodology":"The F2 methylazoxymethanol acetate rat model was used, where approximately 40% of offspring display schizophrenia-like features. Adolescent rats received either WIN55,212-2 (synthetic cannabinoid, 0.2 mg/kg), URB597 (endocannabinoid upregulator, 0.3 mg/kg), or vehicle. Adult outcomes included dopamine neuron activity recordings and behavioral amphetamine sensitivity testing.","limitations":"Animal models cannot fully replicate human schizophrenia. The synthetic cannabinoid WIN55,212-2 is more potent and less nuanced than natural cannabis. The dosing regimen may not reflect typical human use patterns. Parvalbumin interneuron changes were suggested but not fully characterized. The model captures some but not all features of schizophrenia."},{"rthcId":"RTHC-01569","title":"Age of onset of cannabis use and decision making under uncertainty.","authors":"Alameda-Bailén, Jose Ramón; Salguero-Alcañiz, Pilar; Merchán-Clavellino, Ana; Paíno-Quesada, Susana","year":2018,"journal":"PeerJ, 6, e5201","doi":"10.7717/peerj.5201","pmid":"30002988","tags":["cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers compared decision-making ability across three groups: 72 participants divided into early-onset cannabis users (who started before 18), late-onset users (who started at 18 or later), and non-using controls. They used a computerized version of the Iowa Gambling Task, where participants choose from card decks with varying risk-reward profiles.\n\nEarly-onset consumers performed significantly worse than both late-onset users and controls. When researchers applied a computational model to understand the decision-making process, they found that early-onset users were more influenced by the raw magnitude of gains and losses rather than their probability, and their choices were more determined by short-term results without adequate aversion to losses.\n\nLate-onset users did not show the same decision-making deficits, performing similarly to non-users. This pattern suggests that the age at which cannabis use begins may be more important than cannabis use itself for long-term decision-making ability.","whyItMatters":"Decision-making is a fundamental executive function that affects everything from financial choices to risk behavior. If starting cannabis before the brain finishes developing (around age 25) specifically impairs this capacity, it provides a concrete reason for prevention efforts to focus on delaying the age of first use rather than simply preventing all use.","specificNumbers":"72 participants total: 19 women, 53 men. Three groups: early-onset users, late-onset users, non-users. Early-onset users showed significantly worse IGT performance. Computational modeling revealed early-onset users had less loss aversion and more recency bias in their decisions.","methodology":"This was a cross-sectional study of 72 participants (19 women, 53 men) divided into three groups via purposive sampling: early-onset cannabis consumers, late-onset consumers, and non-consumer controls. Decision-making was assessed using the \"Cartas\" program (computerized Iowa Gambling Task) in both direct and inverse versions. The Prospect Valence Learning computational model was applied to characterize decision-making along four dimensions: utility, loss aversion, recency, and consistency.","limitations":"The sample was small at 72 participants, and the cross-sectional design cannot determine whether pre-existing decision-making differences led to earlier cannabis use rather than the reverse. The study did not control for concurrent use of other substances. Purposive rather than random sampling limits generalizability."},{"rthcId":"RTHC-01570","title":"The future of type 1 cannabinoid receptor allosteric ligands.","authors":"Alaverdashvili, Mariam; Laprairie, Robert B","year":2018,"journal":"Drug metabolism reviews, 50(1), 14-25","doi":"10.1080/03602532.2018.1428341","pmid":"29355038","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01571","title":"PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: Evaluation of a novel oleic acid conjugate in preclinical rat models.","authors":"Alen, Francisco; Decara, Juan; Brunori, Gloria; You, Zhi-Bing; Bühler, Kora-Mareen; López-Moreno, Jose Antonio; Cippitelli, Andrea; Pavon, Francisco Javier; Suárez, Juan; Gardner, Eliot L; de la Torre, Rafael; Ciccocioppo, Roberto; Serrano, Antonia; Rodríguez de Fonseca, Fernando","year":2018,"journal":"Biochemical pharmacology, 157, 235-243","doi":"10.1016/j.bcp.2018.09.008","pmid":"30195735","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01572","title":"n-3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids.","authors":"Alharthi, Nahed; Christensen, Peter; Hourani, Wafa; Ortori, Catherine; Barrett, David A; Bennett, Andrew J; Chapman, Victoria; Alexander, Stephen P H","year":2018,"journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids, 1863(11), 1433-1440","doi":"10.1016/j.bbalip.2018.08.003","pmid":"30591150","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system produces a family of signaling molecules called N-acylethanolamines (NAEs), of which anandamide is the most famous. Researchers systematically tested the full range of NAEs at cannabinoid and TRPV1 receptors and made a significant discovery about how dietary fatty acids connect to the endocannabinoid system.\n\nNAEs derived from omega-6 fatty acids (including anandamide) activated both CB1 and CB2 receptors, making them full endocannabinoids. But NAEs derived from omega-3 fatty acids selectively activated CB2 receptors without activating CB1. Since CB2 receptors mediate anti-inflammatory effects without the psychoactive properties associated with CB1, this suggests a specific molecular pathway through which omega-3 fatty acids could produce anti-inflammatory benefits.\n\nThe researchers also found that commonly studied NAEs like PEA, SEA, and OEA are not endocannabinoids or endovanilloids at all. Their higher natural concentrations compared to polyunsaturated NAEs reflect slower breakdown rates rather than greater biological activity at cannabinoid receptors.","whyItMatters":"This study provides a molecular bridge between two major areas of health research: omega-3 fatty acids and the endocannabinoid system. If omega-3 derived endocannabinoids preferentially activate anti-inflammatory CB2 receptors, it could explain why diets high in omega-3 fatty acids are associated with reduced inflammation and why the omega-6 to omega-3 ratio in the diet matters for health.","specificNumbers":"Omega-6 derived NAEs activated both CB1 and CB2 receptors plus TRPV1 channels. Omega-3 derived NAEs activated CB2 receptors only (some also activated TRPV1 but not CB1). PEA, SEA, and OEA were confirmed as non-endocannabinoids despite high endogenous concentrations. Higher concentrations of PEA/SEA/OEA reflected slower FAAH hydrolysis rates.","methodology":"Researchers developed novel quantification assays to measure multiple NAEs in biological tissues and their rates of hydrolysis by fatty acid amide hydrolase (FAAH). The full range of NAEs was tested in rapid-response assays at CB1, CB2, and TRPV1 receptors to determine receptor selectivity profiles.","limitations":"Receptor activation was tested in cell-based assays, and the in vivo significance of the CB2 selectivity of omega-3 NAEs remains to be confirmed. The study did not directly test whether dietary omega-3 supplementation changes the NAE profile in tissues enough to produce measurable anti-inflammatory effects. Concentrations effective in assays may not reflect physiological levels."},{"rthcId":"RTHC-01573","title":"Medicinal Cannabis-Potential Drug Interactions.","authors":"Alsherbiny, Muhammad A; Li, Chun Guang","year":2018,"journal":"Medicines (Basel, Switzerland), 6(1)","doi":"10.3390/medicines6010003","pmid":"30583596","tags":["medical-cannabis","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the known and potential pharmacokinetic and pharmacodynamic interactions between cannabinoids and other medications. The review identified several key interaction pathways.\n\nCannabinoids are metabolized by cytochrome P450 enzymes (particularly CYP3A4, CYP2C9, and CYP2C19) and UDP-glucuronosyltransferases, the same enzyme systems that process many common medications. Both THC and CBD can inhibit or induce these enzymes, potentially raising or lowering blood levels of co-administered drugs.\n\nAdditionally, cannabinoids interact with membrane transporters including P-glycoprotein, breast cancer resistance proteins, and multidrug resistance proteins. These transporters affect how drugs are absorbed and distributed throughout the body.\n\nThe review noted that while cannabinoids are generally well tolerated, bidirectional interactions should be expected, meaning cannabinoids can change how other drugs work, and other drugs can change how cannabinoids work. This is particularly important for elderly patients, people with chronic diseases, and those with kidney or liver conditions.","whyItMatters":"As cannabis use expands legally and more patients combine it with prescription medications, understanding drug interactions becomes critical for safety. Many patients do not tell their doctors about cannabis use, and many doctors do not ask. This creates a blind spot where interactions could cause unexpected changes in drug efficacy or toxicity.","specificNumbers":"Key CYP enzymes involved: CYP3A4, CYP2C9, CYP2C19. Key transporters: P-glycoprotein, breast cancer resistance proteins, multidrug resistance proteins. Key metabolic pathways: cytochrome P450 system, UDP-glucuronosyltransferases. Populations at highest risk: elderly, chronic disease patients, liver/kidney impairment.","methodology":"This was a narrative review of published literature on cannabinoid pharmacokinetics, pharmacodynamics, and documented or potential drug interactions, with attention to the enzyme systems and transporters involved.","limitations":"Many potential interactions identified in this review are theoretical, based on shared enzyme pathways rather than documented clinical events. In vitro enzyme inhibition data may not translate directly to clinically meaningful interactions at typical cannabis doses. The review does not quantify the likelihood or severity of specific interactions."},{"rthcId":"RTHC-01574","title":"The Effects of Social Presence on Adherence-Focused Guidance in Problematic Cannabis Users: Protocol for the CANreduce 2.0 Randomized Controlled Trial.","authors":"Amann, Manuel; Haug, Severin; Wenger, Andreas; Baumgartner, Christian; Ebert, David D; Berger, Thomas; Stark, Lars; Walter, Marc; Schaub, Michael P","year":2018,"journal":"JMIR research protocols, 7(1), e30","doi":"10.2196/resprot.9484","pmid":"29386176","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01575","title":"Synthesis and pharmacological characterization of functionalized 6-piperazin-1-yl-purines as cannabinoid receptor 1 (CB1) inverse agonists.","authors":"Amato, George S; Manke, Amruta; Vasukuttan, Vineetha; Wiethe, Robert W; Snyder, Rodney W; Runyon, Scott P; Maitra, Rangan","year":2018,"journal":"Bioorganic & medicinal chemistry, 26(15), 4518-4531","doi":"10.1016/j.bmc.2018.07.043","pmid":"30077609","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01576","title":"Three-year retention in methadone opioid agonist treatment: A survival analysis of clients by dose, area deprivation, and availability of alcohol and cannabis outlets.","authors":"Amiri, Solmaz; Hirchak, Katherine; Lutz, Robert; McDonell, Michael G; McPherson, Sterling M; Roll, John M; Amram, Ofer","year":2018,"journal":"Drug and alcohol dependence, 193, 63-68","doi":"10.1016/j.drugalcdep.2018.08.024","pmid":"30340146","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01577","title":"The Social Context of Adolescent Co-Use of Cigarillos and Marijuana Blunts.","authors":"Antognoli, Elizabeth; Koopman Gonzalez, Sarah; Trapl, Erika; Cavallo, David; Lim, Rock; Lavanty, Brittany; Flocke, Susan","year":2018,"journal":"Substance use & misuse, 53(4), 654-661","doi":"10.1080/10826084.2017.1355388","pmid":"28933976","tags":["youth","respiratory"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Researchers conducted in-depth interviews with 30 adolescents aged 14 to 18 who smoked at least one cigarillo per week. Nearly all participants (83%) reported using cigarillos both as tobacco products and as wrappers for marijuana blunts.\n\nThree key social patterns emerged that drove the co-use of these products. First, group smoking and product sharing normalized the transition between cigarillo and blunt use. Second, many teens believed that cigarillos enhanced or extended the marijuana high. Third, cigarillos served as a substitute for blunts when marijuana was unavailable or when its use was being monitored by parents or authorities.\n\nThe participants averaged 13 cigarillos per week as a standalone tobacco product, indicating substantial tobacco use alongside their marijuana consumption. The findings suggest that marijuana use through blunts can serve as a gateway to tobacco addiction rather than the other way around.","whyItMatters":"The relationship between marijuana and tobacco use in adolescents is often discussed as tobacco leading to marijuana. This study reveals the reverse pathway: marijuana blunt smoking introduces and reinforces tobacco use through cigarillos. As marijuana becomes more accessible to young people, this tobacco-acquisition pathway could undermine tobacco prevention efforts.","specificNumbers":"30 adolescents interviewed, ages 14-18. All smoked cigarillos as tobacco products, averaging 13 per week. 25 of 30 (83%) also used cigarillos for marijuana blunts. Study conducted December 2015 to April 2016.","methodology":"This was a qualitative study using in-depth semi-structured interviews with 30 adolescents aged 14-18 recruited through purposive sampling. All reported smoking at least one cigarillo per week. Interviews captured smoking products, practices, preferences, beliefs, and experiences. Analysis followed a phenomenological approach to identify emergent themes.","limitations":"The sample was small (30 participants) and recruited through purposive sampling from a single geographic area, limiting generalizability. Self-reported data may be subject to social desirability bias. The qualitative design identifies patterns but cannot establish prevalence or causal relationships."},{"rthcId":"RTHC-01578","title":"Effects of the \"Circle of Life\" HIV-prevention program on marijuana use among American Indian middle school youths: a group randomized trial in a Northern Plains tribe.","authors":"Asdigian, Nancy L; Whitesell, Nancy Rumbaugh; Keane, Ellen M; Mousseau, Alicia C; Kaufman, Carol E","year":2018,"journal":"The American journal of drug and alcohol abuse, 44(1), 120-128","doi":"10.1080/00952990.2016.1265122","pmid":"28032813","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers evaluated a secondary benefit of the Circle of Life (COL) program, a culturally tailored HIV and STD prevention intervention delivered in all 13 middle schools on a rural Northern Plains reservation. While the program was designed primarily to delay sexual initiation, the study examined whether it also affected marijuana use.\n\nAcross 635 American Indian middle school students, the overall risk of initiating marijuana use was 17.3% lower in the COL intervention group compared to the control group. This is notable because the program was not specifically designed to target marijuana use.\n\nHowever, the intervention did not affect how frequently students used marijuana once they had started. Students who initiated marijuana use in both groups used it at similar rates. This suggests the program was effective at preventing uptake but not at reducing consumption among those who had already begun.","whyItMatters":"American Indian and Alaska Native communities face disproportionate substance use rates, and marijuana use often begins in early adolescence. Finding that a culturally tailored intervention not specifically targeting marijuana still reduced initiation by 17% suggests that comprehensive, culturally grounded prevention programs can have spillover benefits across multiple risk behaviors.","specificNumbers":"635 American Indian middle school students across 13 schools. 47% female. Risk of marijuana initiation was 17.3% lower in the intervention group. No significant effect on frequency of marijuana use among those who initiated. Study conducted 2006-2007.","methodology":"This was a secondary analysis of a school-based group randomized controlled trial conducted in 2006-2007 across all 13 middle schools on a rural Northern Plains reservation. The sample included 635 American Indian students (47% female). Discrete-time survival analysis assessed marijuana initiation risk, and latent growth curve modeling evaluated frequency of use over time.","limitations":"This was a secondary analysis, meaning the study was not specifically designed to test marijuana prevention effects. The sample was from a single reservation, limiting generalizability to other AI/AN communities or populations. Data were collected in 2006-2007 and may not reflect current patterns. Self-reported marijuana use may be underreported."},{"rthcId":"RTHC-01579","title":"Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology.","authors":"Atsmon, Jacob; Heffetz, Daphna; Deutsch, Lisa; Deutsch, Frederic; Sacks, Hagit","year":2018,"journal":"Clinical pharmacology in drug development, 7(7), 751-758","doi":"10.1002/cpdd.408","pmid":"29125702","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Researchers tested a new oral CBD formulation called PTL101, which embeds highly purified CBD in seamless gelatin matrix beadlets, against Sativex oromucosal spray as a reference product. In a randomized crossover study with healthy volunteers, the 10 mg PTL101 dose produced 1.7 times higher peak blood levels and 1.3 times higher overall CBD exposure compared to the spray.\n\nThe time to reach peak blood levels was similar for both formulations at 3 to 3.5 hours, though PTL101 showed about a 1-hour lag in initial absorption. When the dose was increased from 10 mg to 100 mg, the resulting blood levels increased approximately 15-fold, slightly more than proportional to the dose increase.\n\nBoth formulations were well tolerated with no notable safety concerns, establishing PTL101 as a potentially more efficient oral delivery system for CBD.","whyItMatters":"CBD bioavailability has been a persistent challenge in cannabinoid medicine. Oral CBD typically has low absorption, with much of the dose lost to first-pass metabolism. A formulation that delivers more CBD into the bloodstream from the same dose could improve therapeutic outcomes and reduce the amount of CBD patients need to take.","specificNumbers":"PTL101 10 mg vs Sativex: 1.7-fold higher Cmax, 1.3-fold higher AUC. Relative bioavailability of PTL101: 134% compared to Sativex. Tmax: 3-3.5 hours for both. 10-fold dose increase (10 to 100 mg) produced approximately 15-fold increase in Cmax and AUC. 1-hour absorption lag with PTL101.","methodology":"This was a randomized, crossover, single-dose pharmacokinetic study in healthy volunteers comparing PTL101 (gelatin matrix pellet CBD formulation) at 10 mg and 100 mg doses with Sativex oromucosal spray as a reference product. Blood samples were collected at multiple time points to measure CBD pharmacokinetic parameters including Cmax, AUC, and Tmax.","limitations":"This was a single-dose study in healthy volunteers, not patients with conditions that CBD is used to treat. The sample size was small. Long-term safety and repeated dosing were not assessed. The enhanced bioavailability needs to be confirmed to translate to improved clinical outcomes. Food effects were not evaluated."},{"rthcId":"RTHC-01580","title":"Dronabinol oral solution in the management of anorexia and weight loss in AIDS and cancer.","authors":"Badowski, Melissa E; Yanful, Paa Kwesi","year":2018,"journal":"Therapeutics and clinical risk management, 14, 643-651","doi":"10.2147/TCRM.S126849","pmid":"29670357","tags":["medical-cannabis","appetite","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the evidence for dronabinol, a synthetic form of THC, in treating anorexia and weight loss associated with HIV/AIDS and cancer. Dronabinol works by acting on cannabinoid receptors in the brain that control appetite and prevent vomiting.\n\nFor HIV/AIDS, dronabinol has been FDA-approved since 1985 in capsule form, with a newer oral solution approved in 2016. The oral solution provides an \"easy-to-swallow\" alternative that may improve adherence in patients who struggle with capsules.\n\nFor cancer-related anorexia and weight loss, there is no approved indication despite the condition being common and debilitating. The review noted a lack of standardized definitions and recent clinical data in both settings, making it difficult to quantify the true incidence of the problem and the treatment response. The pharmacokinetic considerations of the newer oral solution formulation were also characterized.","whyItMatters":"Appetite loss and wasting are devastating complications of HIV/AIDS and cancer that significantly reduce quality of life and survival. Dronabinol remains one of the few FDA-approved options specifically targeting appetite stimulation, and the newer oral solution formulation may improve access for patients with swallowing difficulties.","specificNumbers":"Dronabinol oral capsule FDA-approved in 1985. Oral solution approved in 2016. Available in two formulations: oral capsule and oral solution. Indicated for HIV/AIDS-related anorexia. No approved indication for cancer-related anorexia.","methodology":"This was a narrative review of available data on oral dronabinol formulations for the management of anorexia and weight loss in HIV/AIDS and cancer, including pharmacotherapeutic considerations of the newest oral solution formulation.","limitations":"This is a narrative review without systematic search methodology. The lack of standardized definitions for anorexia in these populations limits the ability to compare studies. Much of the clinical data for dronabinol is dated. The review focuses on dronabinol specifically and does not compare it to whole-plant cannabis products or other cannabinoid formulations."},{"rthcId":"RTHC-01581","title":"Does Cannabis Use Influence Opioid Outcomes and Quality of Life Among Buprenorphine Maintained Patients? A Cross-sectional, Comparative Study.","authors":"Bagra, Igam; Krishnan, Vijay; Rao, Ravindra; Agrawal, Alok","year":2018,"journal":"Journal of addiction medicine, 12(4), 315-320","doi":"10.1097/ADM.0000000000000406","pmid":"29543612","tags":["addiction","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers studied 100 randomly selected men who had been stable on buprenorphine maintenance for opioid use disorder for an average of 96 months. Compliance with buprenorphine was excellent across the group, with patients taking their medication on approximately 87 of every 90 days.\n\nThirty-five percent were currently using cannabis, and 77% had used it at some point in their lives. Current cannabis users were on significantly lower buprenorphine doses (7.9 mg vs 8.9 mg per day), yet showed no significant differences in opioid use, cravings, or withdrawal symptoms compared to non-users.\n\nEmployment rates, daily earnings, and quality of life scores across all domains were comparable between cannabis users and non-users. The findings suggest that concurrent cannabis use does not negatively impact the effectiveness of buprenorphine maintenance treatment for opioid use disorder.","whyItMatters":"Whether cannabis use undermines opioid treatment is a practical clinical question with real consequences. Some treatment programs prohibit cannabis use, potentially excluding patients who could benefit from opioid treatment. This study provides evidence that cannabis use may not warrant exclusion from buprenorphine treatment, especially given the lower buprenorphine doses among cannabis users.","specificNumbers":"100 male patients studied. Average buprenorphine treatment duration: 96 months. Compliance: 86.92 days out of 90. 35% currently using cannabis. 77% lifetime cannabis use. Cannabis users on lower buprenorphine doses: 7.9 mg vs 8.9 mg (p = 0.04). No significant differences in opioid use, cravings, withdrawals, employment, or quality of life.","methodology":"This was a cross-sectional study of 100 randomly selected adult male patients attending a community drug treatment clinic who had been stabilized on buprenorphine for more than 3 months. Measures included the WHO-ASSIST substance involvement screening tool and WHO Quality of Life-Brief assessment. Cannabis users and non-users were compared on buprenorphine dose, opioid outcomes, employment, and quality of life.","limitations":"The sample was exclusively male, limiting generalizability to women. The cross-sectional design cannot determine causation. Patients were long-term stable patients (average 96 months), who may differ from those early in treatment. Cannabis use was self-reported. The study was conducted at a single community clinic in India, and findings may not generalize to other treatment settings."},{"rthcId":"RTHC-01582","title":"Medical and non-medical marijuana use in depression: Longitudinal associations with suicidal ideation, everyday functioning, and psychiatry service utilization.","authors":"Bahorik, Amber L; Sterling, Stacy A; Campbell, Cynthia I; Weisner, Constance; Ramo, Danielle; Satre, Derek D","year":2018,"journal":"Journal of affective disorders, 241, 8-14","doi":"10.1016/j.jad.2018.05.065","pmid":"30086434","tags":["depression","mental-health","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 307 psychiatry outpatients with depression over 12 months, tracking marijuana use, mental health symptoms, and treatment engagement. At baseline, 40% used marijuana, with the majority (72%) reporting non-medical use.\n\nNon-medical marijuana users showed a troubling pattern across multiple dimensions. At baseline, they had higher suicidal ideation, worse mental health functioning, and fewer psychiatry visits compared to non-users. Over the 12-month follow-up, they improved less in depression symptoms and suicidal ideation than non-users.\n\nMedical marijuana users showed a different profile: worse mental and physical health functioning at baseline compared to non-users, but the longitudinal trajectory was not as clearly unfavorable as for non-medical users.\n\nParticularly concerning was the finding that non-medical marijuana users attended fewer psychiatry visits, suggesting that marijuana use may reduce treatment-seeking behavior in depressed patients, potentially compounding the problem.","whyItMatters":"Many people with depression use marijuana for relief, but this study suggests that non-medical use may actually impede recovery. The combination of worse symptom trajectories and fewer psychiatry visits creates a double risk: the condition may worsen while treatment engagement declines. This has practical implications for clinicians treating depression in marijuana-using patients.","specificNumbers":"307 outpatients with depression. 40% used marijuana at baseline. 71.7% of users reported non-medical use, 28.2% medical. Non-medical users: higher suicidal ideation (B = 1.08, p = .002), worse mental health (B = -3.79, p = .015), fewer psychiatry visits (B = -0.69, p = .009). Over time, non-medical users improved less in depression (B = 1.49, p = .026) and suicidal ideation (B = 1.08, p = .003).","methodology":"This was a longitudinal study of 307 psychiatry outpatients participating in a trial of drug/alcohol use treatment for depression. Past 30-day marijuana use (medical and non-medical), depression/anxiety symptoms, psychiatry visits, and functional health status were measured at baseline, 3, 6, and 12 months. Regression and growth curve models compared outcomes across medical users, non-medical users, and non-users.","limitations":"Participants were psychiatry outpatients, limiting generalizability to the broader depressed population. The observational design cannot determine whether marijuana caused worse outcomes or whether more severely depressed patients were more likely to use marijuana non-medically. Self-reported marijuana use and categorization as medical versus non-medical may be unreliable. The study did not control for dose, frequency, or THC/CBD content."},{"rthcId":"RTHC-01583","title":"Differences in demographic and clinical characteristics between cannabis users and non-drug users: A retrospective study of patients at first hospitalization due to psychotic symptoms.","authors":"Balan Moshe, Livia; Weizman, Abraham; Ben Dor, David H; Konas, Shai; Fischel, Zvi; Aizenberg, Dov; Gothelf, Doron; Valevski, Avi","year":2018,"journal":"Psychiatry research, 268, 454-459","doi":"10.1016/j.psychres.2018.07.037","pmid":"30130713","tags":["psychosis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers reviewed records of 318 patients at their first psychiatric hospitalization for psychotic symptoms, comparing 106 cannabis users (33%) to non-drug users. At first admission, the groups differed dramatically in diagnostic severity: only 20.3% of cannabis users received a severe mental illness diagnosis compared to 53.3% of non-users.\n\nHowever, this gap disappeared by the second hospitalization. Both groups showed conversion rates of 79-80% from non-severe to severe mental illness diagnoses between first and second admissions. Cannabis users had shorter initial hospitalizations, but their five-year rehospitalization rates were not significantly different from non-users.\n\nThe high conversion rate in cannabis users raises two possibilities: either severe mental illness was being under-diagnosed at first admission because clinicians attributed symptoms to cannabis use, or cannabis exposure was actively contributing to the development of more severe illness over time.","whyItMatters":"The finding that cannabis users are initially diagnosed less severely but later receive the same diagnoses has major clinical implications. If clinicians are attributing psychotic symptoms to cannabis use and assigning less severe diagnoses as a result, patients may receive inadequate treatment. Alternatively, if cannabis is driving illness progression, this supports early intervention.","specificNumbers":"318 patients total, 106 cannabis users (33.3%). Non-users: 53.3% severe mental illness at first admission. Cannabis users: 20.3% severe mental illness at first admission. Both groups: 79-80% conversion to severe mental illness by second admission. Cannabis users had shorter first hospitalization. 5-year rehospitalization rates were similar.","methodology":"This was a retrospective chart review cohort study at Geha Mental Health Center, Israel, covering admissions between August 2002 and December 2013. A total of 318 patients were included: 106 cannabis users and 212 non-drug users. Demographics, diagnoses, hospitalization duration, and rehospitalization rates were compared. Diagnostic stability between first and second admissions was assessed.","limitations":"Retrospective chart review depends on the quality of medical records. The study was conducted at a single center in Israel. Cannabis use was based on clinical documentation and may be inconsistently recorded. The study could not determine whether cannabis caused illness progression or whether initial diagnoses were simply inaccurate. Only two time points (first and second admission) were analyzed."},{"rthcId":"RTHC-01584","title":"Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling.","authors":"Balla, Andrea; Dong, Bin; Shilpa, Borehalli M; Vemuri, Kiran; Makriyannis, Alexandros; Pandey, Subhash C; Sershen, Henry; Suckow, Raymond F; Vinod, K Yaragudri","year":2018,"journal":"Neuropharmacology, 131, 200-208","doi":"10.1016/j.neuropharm.2017.10.040","pmid":"29109060","tags":["addiction","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Previous CB1 receptor blockers like rimonabant were effective against obesity and nicotine addiction but were withdrawn because they caused depression and suicidal ideation. Researchers tested AM4113, a \"neutral antagonist\" that blocks the CB1 receptor without producing the inverse agonist effects believed to cause psychiatric side effects.\n\nAM4113 suppressed binge-like alcohol consumption in mice using a drinking-in-the-dark model. Importantly, it did so without affecting body weight, general activity levels, or preference for sweet and bitter tastes, indicating the reduction was specific to alcohol rather than a general appetite or motivation suppression.\n\nThe compound also reduced alcohol-induced dopamine release in the nucleus accumbens, a brain region central to reward and addiction. This suggests the endocannabinoid system plays a direct role in regulating how alcohol activates the brain's reward circuitry, and that blocking this pathway can reduce binge drinking without the dangerous psychiatric side effects of earlier compounds.","whyItMatters":"Binge drinking causes enormous health and social harm, and effective treatments are limited. The endocannabinoid system represents a promising treatment target, but previous drugs targeting it were pulled due to psychiatric risks. This study suggests a way to retain the therapeutic benefits of CB1 blockade while potentially avoiding the dangerous side effects.","specificNumbers":"AM4113 had slower brain elimination than plasma elimination. Suppressed ethanol consumption and preference. No significant effects on body weight, ambulatory activity, saccharin/quinine preference, or ethanol metabolism. Reduced ethanol-induced dopamine release in nucleus accumbens.","methodology":"Researchers examined the pharmacokinetics of AM4113 in mice (brain and plasma distribution) and tested its effects on binge-like ethanol consumption using a two-bottle choice drinking-in-dark paradigm in C57BL/6J mice. Specificity was assessed by measuring effects on body weight, locomotor activity, taste preferences, and ethanol metabolism. Microdialysis measured dopamine release in the nucleus accumbens during ethanol consumption.","limitations":"This is an animal study, and results may not translate to human binge drinking. The psychiatric safety advantage of neutral antagonists over inverse agonists needs confirmation in human trials. The drinking-in-dark model captures some but not all aspects of human binge drinking. Long-term effects were not assessed."},{"rthcId":"RTHC-01585","title":"Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort.","authors":"Baron, Eric P; Lucas, Philippe; Eades, Joshua; Hogue, Olivia","year":2018,"journal":"The journal of headache and pain, 19(1), 37","doi":"10.1186/s10194-018-0862-2","pmid":"29797104","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 2,032 medical cannabis patients and found that pain syndromes accounted for 42% of cannabis use, with chronic pain being the most common reason. Among the 505 patients using cannabis for headaches, 88% screened positive for probable migraine using a validated questionnaire.\n\nHybrid cannabis strains were preferred across all pain subtypes. The most popular strain among headache and migraine patients was \"OG Shark,\" which is high in THC/THCA, low in CBD/CBDA, and contains the terpenes beta-caryophyllene and beta-myrcene, both known for anti-inflammatory and analgesic properties.\n\nPerhaps the most striking finding was the high rate of prescription medication substitution. Between 41% and 60% of pain patients reported replacing prescription drugs with cannabis. Opioids were the most commonly substituted medication across all groups, ranging from 40.5% to 72.8%. Among headache patients specifically, opioids (43.4%), antidepressants/anti-anxiety medications (39%), and NSAIDs (21%) were the most commonly replaced.","whyItMatters":"This is one of the largest studies to characterize how medical cannabis patients with specific pain conditions actually use cannabis, what strains they prefer, and what medications they replace. The high rate of opioid substitution is particularly relevant to the opioid crisis, suggesting that medical cannabis access may provide an alternative for some chronic pain patients.","specificNumbers":"2,032 patients surveyed. Pain syndromes: 42.4% of all use. Chronic pain: 29.4%. Arthritis: 9.3%. Headache: 3.7%. 88% of headache patients screened positive for probable migraine. 41.2-59.5% substituted prescriptions with cannabis. Opioid substitution: 40.5-72.8% across pain groups. Preferred headache strain: OG Shark (high THC, low CBD, beta-caryophyllene, beta-myrcene).","methodology":"This was a cross-sectional electronic survey of patients registered with a medical cannabis provider in Canada. The 2,032 respondents provided data on cannabis use patterns, preferred strains, consumption methods, and prescription medication substitution. Headache patients were screened for migraine probability using the validated ID Migraine questionnaire. Strain biochemical profiles were analyzed.","limitations":"Self-reported data from registered medical cannabis patients may not represent all cannabis users with pain. There was no verification of diagnoses beyond the ID Migraine screen. The substitution data reflects patient perception, not medically confirmed tapering. The study cannot determine whether cannabis was equally effective as the medications it replaced."},{"rthcId":"RTHC-01586","title":"Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science.","authors":"Baron, Eric P","year":2018,"journal":"Headache, 58(7), 1139-1186","doi":"10.1111/head.13345","pmid":"30152161","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review examined the medicinal properties of individual components in cannabis well beyond the usual focus on THC and CBD. The author catalogued the therapeutic potential of major and minor cannabinoids, primary and secondary terpenes, and flavonoids, explaining how these work synergistically to produce what is called the entourage effect.\n\nFor pain and migraine specifically, the review found accumulating evidence for therapeutic benefits, though most evidence comes from studies of general chronic pain rather than headache-specific trials. The review also identified supporting evidence that cannabis may assist in opioid detoxification and weaning, positioning it as a potential tool against the opioid epidemic.\n\nThe detailed profiling of individual compounds enables understanding of why different cannabis strains produce different effects. For example, the terpene beta-caryophyllene activates CB2 receptors and has anti-inflammatory properties, while myrcene has analgesic and sedative effects. Knowledge of these individual properties is necessary for developing strain-specific treatments targeted at specific conditions.","whyItMatters":"Most cannabis research and clinical discussion focuses narrowly on THC and CBD, but cannabis contains over 100 cannabinoids plus numerous terpenes and flavonoids. Understanding the individual and synergistic properties of these compounds is essential for developing standardized, condition-specific cannabis medicines rather than treating all cannabis as a single drug.","specificNumbers":"Cannabis contains over 100 cannabinoids, numerous terpenes, and various flavonoids. The review covered major cannabinoids (THC, CBD, CBG, CBN, CBC, THCV), primary terpenes (myrcene, limonene, linalool, alpha-pinene, beta-caryophyllene), secondary terpenes, and multiple flavonoids with individual medicinal property profiles.","methodology":"This was a comprehensive narrative review of the medical literature covering the use of cannabis and cannabinoids in pain, migraine, headache, and facial pain, combined with a detailed examination of the pharmacological properties of individual cannabinoids, terpenes, and flavonoids.","limitations":"Much of the evidence for individual compounds comes from preclinical or in vitro studies rather than human clinical trials. The entourage effect, while plausible, has limited direct clinical evidence. The review necessarily covers a vast amount of pharmacological data, and the depth of evidence varies widely across compounds."},{"rthcId":"RTHC-01587","title":"The Influence of DAT1, COMT, and BDNF Genetic Polymorphisms on Total and Subregional Hippocampal Volumes in Early Onset Heavy Cannabis Users.","authors":"Batalla, Albert; Lorenzetti, Valentina; Chye, Yann; Yücel, Murat; Soriano-Mas, Carles; Bhattacharyya, Sagnik; Torrens, Marta; Crippa, José A S; Martín-Santos, Rocío","year":2018,"journal":"Cannabis and cannabinoid research, 3(1), 1-10","doi":"10.1089/can.2017.0021","pmid":"29404409","tags":["cognition","genetics","dopamine","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers examined hippocampal brain structure in 59 young men aged 18-30, including 30 chronic cannabis users who started regular use before age 16 and 29 controls. They combined high-resolution brain imaging with genetic testing for three dopamine-related genes: COMT, DAT1, and BDNF.\n\nCannabis users showed emerging alterations in total hippocampal volume and in specific subregions (CA1, CA2/3, and CA4), with associations between the amount of cannabis use and the degree of volume changes.\n\nThe most novel finding was an interaction between cannabis use and the DAT1 dopamine transporter gene. Normally, different variants of DAT1 (associated with higher or lower dopamine availability) relate to hippocampal size in a predictable pattern. Cannabis exposure disrupted this normal gene-brain relationship, suggesting that cannabis interferes with how dopamine gene variants shape hippocampal development.","whyItMatters":"The hippocampus is critical for memory and learning, and its development during adolescence makes it potentially vulnerable to cannabis exposure. This study shows that the effects of cannabis on hippocampal structure are not uniform but depend on an individual's genetic makeup, particularly genes controlling dopamine signaling. This could help explain why some young cannabis users develop cognitive problems while others do not.","specificNumbers":"59 young men (30 cannabis users, 29 controls). Ages 18-30. Cannabis users started regular use before age 16. Altered subregions: CA1, CA2/3, CA4. Cannabis x DAT1 interaction significant for total hippocampal volume and fissure subregion. DAT1 variants: 9/9R (high dopamine) and 10/10R (low dopamine).","methodology":"This was a cross-sectional neuroimaging-genetics study of 59 male Caucasian young adults aged 18-30. Hippocampal volumes were manually traced and automatically segmented into subregions using high-resolution MRI. Participants were genotyped for COMT, DAT1, and BDNF polymorphisms. Cannabis users had begun regular use before age 16.","limitations":"The sample was small (59 participants) and restricted to male Caucasians, limiting generalizability. The cross-sectional design cannot determine whether hippocampal differences preceded or followed cannabis use. Cannabis use was measured retrospectively. Multiple genetic comparisons increase the risk of false-positive findings. Only three candidate genes were tested."},{"rthcId":"RTHC-01588","title":"Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.","authors":"Belbasis, L; Köhler, C A; Stefanis, N; Stubbs, B; van Os, J; Vieta, E; Seeman, M V; Arango, C; Carvalho, A F; Evangelou, E","year":2018,"journal":"Acta psychiatrica Scandinavica, 137(2), 88-97","doi":"10.1111/acps.12847","pmid":"29288491","tags":["psychosis","genetics"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Researchers conducted an umbrella review, a review of reviews, to systematically evaluate all published meta-analyses of non-genetic risk factors and biomarkers for schizophrenia spectrum disorders. They identified 98 associations across 41 eligible papers.\n\nOf these 98 associations, 62 showed nominally significant effects. However, when subjected to rigorous quality assessment including tests for publication bias, small-study effects, and excess significance bias, only five risk factors showed truly robust evidence: childhood adversities, cannabis use, history of obstetric complications, stressful events during adulthood, and serum folate level.\n\nThe vast majority of associations (72 of 98) exhibited large between-study heterogeneity, 13 showed evidence of small-study effects (suggesting publication bias), and 18 showed excess significance bias. This means that many commonly cited risk factors and biomarkers for schizophrenia may be less reliable than individual studies suggest.","whyItMatters":"With hundreds of studies claiming various risk factors for schizophrenia, it is difficult for clinicians, patients, and policymakers to know which ones truly matter. This umbrella review cuts through the noise and identifies the factors with the most reliable evidence. Cannabis being one of only five robust risk factors underscores its significance in psychosis research.","specificNumbers":"41 eligible papers reviewed containing 98 associations. 62 associations nominally significant. 72 had large between-study heterogeneity. 13 showed small-study effects. 18 showed excess significance bias. Only 5 factors met robust evidence criteria: childhood adversities, cannabis use, obstetric complications, adult stressful events, low serum folate.","methodology":"This was an umbrella review capturing all meta-analyses and Mendelian randomization studies examining non-genetic risk factors and schizophrenia spectrum disorders. For each meta-analysis, the researchers calculated summary effect sizes, confidence and prediction intervals, heterogeneity (I-squared), and tested for small-study effects and excess significance bias.","limitations":"The umbrella review is limited by the quality of the underlying meta-analyses. Some risk factors may have insufficient meta-analytic coverage rather than genuinely weak evidence. The review focused on non-genetic factors and did not integrate gene-environment interactions. The criteria for \"robust\" evidence may be conservative, potentially excluding legitimate associations."},{"rthcId":"RTHC-01589","title":"Point-of-sale marketing and context of marijuana retailers: Assessing reliability and generalizability of the marijuana retail surveillance tool.","authors":"Berg, Carla J; Henriksen, Lisa; Cavazos-Rehg, Patricia; Schauer, Gillian L; Freisthler, Bridget","year":2018,"journal":"Preventive medicine reports, 11, 37-41","doi":"10.1016/j.pmedr.2018.05.010","pmid":"29984136","tags":["legalization"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers field-tested a standardized surveillance tool at 25 randomly selected recreational marijuana retailers in Seattle to assess marketing practices and regulatory compliance. The tool examined three domains: neighborhood context, compliance and security, and marketing.\n\nMost retailers were located near restaurants (92%), grocery stores (68%), and liquor stores (52%). Two were within two blocks of schools and four near parks. Almost all (92%) had exterior age signage and verified age upon entry.\n\nMarketing practices were common: 96% had interior advertisements, most frequently for edibles. Price promotions were found in 68% of retailers, typically as loyalty programs or daily deals. Only one retailer displayed potential health warnings, while three posted health claims. Some retailers sold branded apparel, which is prohibited.\n\nThe tool showed high inter-rater reliability (Kappas 0.73-1.00), validating it for standardized surveillance of the emerging legal marijuana retail environment.","whyItMatters":"As recreational marijuana legalization expands, monitoring the retail environment is essential for understanding how marketing and store placement might influence use patterns. This tool provides a standardized way to track compliance with regulations and identify potential public health concerns, much as alcohol and tobacco retail environments are monitored.","specificNumbers":"25 retailers assessed. 92% near restaurants, 68% near grocery stores, 52% near liquor stores, 44% near bars. 2 within two blocks of schools. 92% had exterior age signage. 92% verified age. 96% had interior ads (76 total, average 3 per store). 68% had price promotions. Only 1 displayed health warnings. Inter-rater reliability: Kappa 0.73-1.00.","methodology":"Two trained observers independently assessed 25 randomly selected Seattle recreational marijuana retailers (20 recreational-only, 5 recreational/medical) using a standardized surveillance tool. The tool evaluated contextual features, compliance measures, and marketing practices. Inter-rater reliability was calculated using Cohen's Kappa.","limitations":"Only 25 retailers in a single city were assessed, limiting generalizability. Seattle was an early adopter of recreational marijuana and may not represent other markets. The tool captures observable features but cannot assess digital marketing, social media promotion, or customer-level outcomes. A single snapshot does not capture changes over time."},{"rthcId":"RTHC-01590","title":"A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in Cannabis.","authors":"Berman, Paula; Futoran, Kate; Lewitus, Gil M; Mukha, Dzmitry; Benami, Maya; Shlomi, Tomer; Meiri, David","year":2018,"journal":"Scientific reports, 8(1), 14280","doi":"10.1038/s41598-018-32651-4","pmid":"30250104","tags":["potency","epilepsy","cbd"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers developed a new analytical method to profile 94 individual phytocannabinoids across 10 different subclasses in 36 of the most commonly prescribed medical cannabis strains in Israel. This went far beyond the standard practice of measuring only THC and CBD.\n\nThe most clinically significant finding was their demonstration that equally high-CBD cannabis extracts (all 50% CBD by weight) produced different anticonvulsant effects. Despite having the same CBD concentration, some extracts were more effective than others, proving that the other cannabinoids, terpenes, and compounds in the extract mattered.\n\nThis challenges the current practice of characterizing medical cannabis primarily by THC and CBD content, showing that this two-compound description is insufficient to predict therapeutic outcomes. The 94 identified compounds create distinct \"fingerprints\" for each strain that better predict its effects.","whyItMatters":"Most patients, doctors, and regulators focus on THC and CBD percentages when selecting or evaluating medical cannabis. This study provides direct evidence that this approach is inadequate. Two products with identical CBD content can have very different therapeutic effects because of their other compounds. This has major implications for quality control, product labeling, and clinical expectations.","specificNumbers":"94 phytocannabinoids identified from 10 subclasses. 36 medical cannabis strains profiled. All tested extracts contained 50% CBD by weight. Different extracts produced different anticonvulsant effects despite equal CBD content.","methodology":"Researchers developed a new ESI-LC/MS/MS analytical method capable of identifying phytocannabinoids from 10 different subclasses. They profiled 36 commonly prescribed medical cannabis strains in Israel, identifying 94 individual phytocannabinoids. To demonstrate the practical importance of comprehensive profiling, they compared the anticonvulsant effects of several high-CBD extracts with equal CBD content (50% w/w) in preclinical models.","limitations":"The anticonvulsant comparison was a demonstration rather than a full clinical study. The analytical method identifies compounds present but does not establish which specific non-CBD compounds drove the differences in anticonvulsant effects. The 36 strains profiled represent Israeli medical cannabis and may not cover all strains available globally."},{"rthcId":"RTHC-01591","title":"Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of δ-9-THC.","authors":"Bhattacharyya, Sagnik; Sainsbury, Thomas; Allen, Paul; Nosarti, Chiara; Atakan, Zerrin; Giampietro, Vincent; Brammer, Michael; McGuire, P K","year":2018,"journal":"Psychological medicine, 48(16), 2748-2756","doi":"10.1017/S0033291718000387","pmid":"29502548","tags":["psychosis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers gave 36 healthy men either 10 mg oral THC or placebo in a randomized crossover design and measured both psychotic symptoms and brain activity during a verbal learning task using fMRI. They then divided participants into those who experienced transient psychotic symptoms after THC (14 men) and those who did not (22 men).\n\nThe key finding was visible before any THC was given. Under placebo conditions, the group that would later develop psychotic symptoms from THC already showed significantly greater engagement of the left hippocampus during verbal encoding compared to the non-sensitive group. This pre-existing difference in hippocampal activation was directly correlated with the severity of psychotic symptoms later induced by THC.\n\nImportantly, this pattern was specific to psychosis sensitivity. When the researchers created subgroups based on anxiety sensitivity to THC instead, no such hippocampal difference was found, suggesting this is a specific marker for psychotic vulnerability rather than general THC sensitivity.","whyItMatters":"Identifying who is at risk for psychotic reactions to cannabis before they happen is one of the most important unsolved problems in cannabis research. This study suggests that hippocampal activation during learning could serve as a biomarker, potentially allowing identification of vulnerable individuals before they experience adverse effects.","specificNumbers":"36 healthy males studied. 14 (39%) experienced transient psychotic symptoms from THC. 22 did not. Significantly greater left hippocampal activation under placebo in the sensitive group (p < 0.001). Correlation between hippocampal activation and symptom severity: Spearman's rho = 0.44, p = 0.008. Finding survived leave-one-out analysis.","methodology":"This was a pseudo-randomized, double-blind, repeated-measures, within-subject crossover study. Thirty-six healthy males received 10 mg oral THC and placebo on separate occasions. Psychopathological assessments and fMRI during a verbal learning task were performed under both conditions. Participants were classified into THC-psychosis-sensitive (n=14) and non-sensitive (n=22) groups.","limitations":"The sample included only healthy men, and findings may differ in women or in clinical populations. The classification into sensitive and non-sensitive groups was based on a single THC exposure. The study cannot determine whether the hippocampal difference is genetic, developmental, or environmental in origin. Sample sizes within subgroups were relatively small (14 and 22)."},{"rthcId":"RTHC-01592","title":"Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development.","authors":"Bialer, Meir; Johannessen, Svein I; Koepp, Matthias J; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve","year":2018,"journal":"Epilepsia, 59(10), 1842-1866","doi":"10.1111/epi.14555","pmid":"30368788","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This progress report from the Fourteenth Eilat Conference on New Antiepileptic Drugs documented a landmark regulatory event: on June 25, 2018, the FDA approved a standardized cannabidiol oral solution (Epidiolex) for treating seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older.\n\nThe report placed cannabidiol within the broader context of antiepileptic drug development, alongside other compounds in advanced clinical development including cannabidivarin, fenfluramine, ganaxolone, and several others. For cannabidiol specifically, the report noted promising efficacy and safety results from placebo-controlled randomized controlled trials.\n\nThe conference highlighted that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development, many with innovative mechanisms of action. The inclusion of two cannabinoid-derived compounds (cannabidiol and cannabidivarin) among these reflects the growing acceptance of the endocannabinoid system as a legitimate therapeutic target in epilepsy.","whyItMatters":"The FDA approval of Epidiolex was a watershed moment for cannabinoid medicine, representing the first plant-derived cannabinoid product to receive FDA approval for any condition. Its inclusion in a mainstream conference on antiepileptic drugs signals the integration of cannabinoid research into conventional pharmaceutical development.","specificNumbers":"FDA approval: June 25, 2018. Approved for: Lennox-Gastaut syndrome and Dravet syndrome. Age cutoff: patients 2 years and older. Conference attendance: 168 delegates from 28 countries. Other cannabinoid in pipeline: cannabidivarin.","methodology":"This was a conference progress report summarizing preclinical and clinical data presented at the Eilat XIV conference (Madrid, May 2018) for investigational antiepileptic compounds, attended by 168 delegates from 28 countries.","limitations":"This is a conference progress report rather than a systematic review. The data on individual compounds reflects presentations rather than peer-reviewed publications in all cases. The report covers a broad range of compounds with varying evidence levels."},{"rthcId":"RTHC-01593","title":"Evaluating the Long-Term Effectiveness of School-Based Depression, Anxiety, and Substance Use Prevention Into Young Adulthood: Protocol for the Climate School Combined Study.","authors":"Birrell, Louise; Newton, Nicola C; Slade, Tim; Chapman, Catherine; Mewton, Louise; McBride, Nyanda; Hides, Leanne; Chatterton, Mary Lou; Allsop, Steve; Healy, Annalise; Mather, Marius; Quinn, Catherine; Mihalopoulos, Cathrine; Teesson, Maree","year":2018,"journal":"JMIR research protocols, 7(11), e11372","doi":"10.2196/11372","pmid":"30401663","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01594","title":"Potential of Endocannabinoids to Control Bladder Pain.","authors":"Bjorling, Dale E; Wang, Zun-Yi","year":2018,"journal":"Frontiers in systems neuroscience, 12, 17","doi":"10.3389/fnsys.2018.00017","pmid":"29867382","tags":["pain","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Bladder-related pain is one of the most common forms of visceral pain, and opioids remain a primary treatment despite their well-known side effects. Researchers reviewed the potential of the endocannabinoid system as an alternative therapeutic target.\n\nAnimal experiments have shown that inhibiting the enzymes that break down the endocannabinoids anandamide (AEA) and 2-AG can prevent the development of both visceral and somatic pain. By blocking fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), endocannabinoid levels rise naturally, producing analgesic effects without the psychoactive properties of exogenous THC.\n\nHowever, several challenges limit clinical translation. Anandamide also activates TRPV1 pain channels, which could paradoxically increase pain at certain concentrations. Cyclooxygenase (COX) enzymes also metabolize endocannabinoids, complicating the pharmacology. Dual inhibitors targeting FAAH plus TRPV1, or FAAH plus COX, are being developed to address these challenges. Local application within the bladder could potentially deliver effects with fewer systemic side effects.","whyItMatters":"Bladder pain conditions like interstitial cystitis affect millions of people and are notoriously difficult to treat. The endocannabinoid system offers a mechanistically distinct approach from opioids, potentially providing pain relief without the addiction risk and side effects that make long-term opioid use problematic for chronic bladder conditions.","specificNumbers":"Two primary endocannabinoids reviewed: anandamide (AEA) and 2-AG. Two primary degrading enzymes: FAAH (degrades AEA) and MAGL (degrades 2-AG). Dual inhibitors under development: FAAH + TRPV1 blockers, FAAH + COX inhibitors. Local bladder application proposed but not yet explored.","methodology":"This was a narrative review of the endocannabinoid system as a therapeutic target for bladder pain, examining preclinical evidence for endocannabinoid-modulating approaches, pharmacological challenges, and emerging dual-inhibitor compounds.","limitations":"Most evidence comes from animal models, and clinical translation of FAAH and MAGL inhibitors has been disappointing in some cases. The complex pharmacology involving multiple enzymes and receptors makes drug development challenging. The review is focused on bladder pain specifically, and findings may not apply to other pain conditions. No human clinical data on endocannabinoid modulation for bladder pain were available."},{"rthcId":"RTHC-01595","title":"Appraising the \"entourage effect\": Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer.","authors":"Blasco-Benito, Sandra; Seijo-Vila, Marta; Caro-Villalobos, Miriam; Tundidor, Isabel; Andradas, Clara; García-Taboada, Elena; Wade, Jeff; Smith, Stewart; Guzmán, Manuel; Pérez-Gómez, Eduardo; Gordon, Mara; Sánchez, Cristina","year":2018,"journal":"Biochemical pharmacology, 157, 285-293","doi":"10.1016/j.bcp.2018.06.025","pmid":"29940172","tags":["cancer","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers directly compared pure THC against a standardized botanical drug preparation (BDP) containing the full spectrum of cannabis compounds in cell culture and animal models of three breast cancer subtypes: ER+/PR+, HER2+, and triple-negative.\n\nThe botanical preparation was consistently more potent than pure THC at producing antitumor responses across all three subtypes. Interestingly, this increased potency was not explained by the five most abundant terpenes in the preparation, suggesting other minor cannabinoids or compounds contributed to the effect.\n\nThe mechanisms also differed. Pure THC acted primarily by activating CB2 receptors and generating reactive oxygen species. The botanical preparation modulated different targets and mechanisms of action, suggesting the entourage effect involves not just enhanced potency but qualitatively different biological activity.\n\nWhen cannabinoids were combined with standard cancer treatments (tamoxifen, lapatinib, or cisplatin), the effects were additive in cell cultures, though in vivo combinations showed no interactions, either positive or negative.","whyItMatters":"This is one of the most rigorous preclinical comparisons of pure THC versus whole-plant cannabis in cancer models. The finding that the botanical preparation was more effective and worked through different mechanisms provides scientific support for using standardized whole-plant preparations rather than isolated THC in future cancer research.","specificNumbers":"Botanical preparation more potent than pure THC across all 3 breast cancer subtypes. Effect not driven by the 5 most abundant terpenes. Different mechanisms of action: pure THC via CB2/ROS, botanical via alternative targets. Additive effects with tamoxifen, lapatinib, cisplatin in vitro. No interaction (positive or negative) in vivo combinations.","methodology":"Researchers compared pure THC and a standardized botanical drug preparation in cell culture models and animal models of ER+/PR+, HER2+, and triple-negative breast cancer. Mechanistic studies examined CB2 receptor activation, reactive oxygen species, and alternative targets. Combination studies tested cannabinoids with tamoxifen, lapatinib, and cisplatin.","limitations":"This is preclinical research in cell cultures and animal models that may not translate to human breast cancer treatment. The specific compounds responsible for the enhanced effect of the botanical preparation were not identified. The in vivo combination studies showed no interaction with standard therapies, which could limit clinical utility. No human clinical data are available."},{"rthcId":"RTHC-01596","title":"Residual effects of cannabis use in adolescent and adult brains - A meta-analysis of fMRI studies.","authors":"Blest-Hopley, Grace; Giampietro, Vincent; Bhattacharyya, Sagnik","year":2018,"journal":"Neuroscience and biobehavioral reviews, 88, 26-41","doi":"10.1016/j.neubiorev.2018.03.008","pmid":"29535069","tags":["cognition","neuroscience","youth"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Researchers conducted separate meta-analyses of fMRI studies comparing brain function in adult and adolescent cannabis users to non-users during various cognitive tasks.\n\nIn adult cannabis users (530 users vs 580 controls across 13 studies), brain activation was increased in the superior and posterior temporal regions and inferior frontal gyrus, while decreased in the visual cortex, insula, and middle temporal gyrus. These changes may reflect compensatory neuroadaptive processes where the brain recruits additional regions to maintain cognitive performance.\n\nIn adolescent cannabis users (219 users vs 224 controls across 7 studies), the pattern was different: increased activation was found in the inferior parietal gyrus and putamen compared to controls. The distinct patterns between age groups suggest that cannabis affects developing and mature brains through different mechanisms.\n\nThe meta-analytic approach was important because individual fMRI studies of cannabis have produced inconsistent results, making it difficult to draw conclusions from any single study.","whyItMatters":"By pooling data across many studies, this meta-analysis resolves inconsistencies in individual brain imaging studies of cannabis effects. The finding that adults and adolescents show different patterns of altered brain function supports the argument that the developing brain responds differently to cannabis, with potentially different long-term consequences.","specificNumbers":"20 studies included: 13 adult, 7 adolescent. Adults: 530 cannabis users vs 580 controls. Adolescents: 219 cannabis users vs 224 controls. Adult changes: increased temporal/frontal activation, decreased visual/insular activation. Adolescent changes: increased parietal/putamen activation.","methodology":"Systematic literature search identified 20 manuscripts (13 adult, 7 adolescent studies) meeting inclusion criteria. Separate meta-analyses used coordinate-based methods to synthesize fMRI activation data across studies employing various cognitive tasks. Adult analyses: 530 cannabis users vs 580 controls. Adolescent analyses: 219 cannabis users vs 224 controls.","limitations":"The studies included used different cognitive tasks, which complicates interpretation of pooled results. The meta-analysis cannot determine whether brain changes preceded or followed cannabis use. Cross-sectional data cannot assess whether changes are reversible. The adolescent analysis had fewer studies and participants than the adult analysis."},{"rthcId":"RTHC-01597","title":"Meta-analysis of neurocognition in young psychosis patients with current cannabis use.","authors":"Bogaty, Sophia E R; Lee, Rico S C; Hickie, Ian B; Hermens, Daniel F","year":2018,"journal":"Journal of psychiatric research, 99, 22-32","doi":"10.1016/j.jpsychires.2018.01.010","pmid":"29407284","tags":["psychosis","cognition"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Previous research had suggested that psychosis patients with lifetime cannabis use appeared to have better cognitive function than non-using patients. This meta-analysis challenged that finding by focusing specifically on current cannabis users and younger patients.\n\nAcross 14 studies, young psychosis patients who were currently using cannabis performed worse than non-using patients on several cognitive measures: premorbid IQ, current IQ, verbal learning, verbal working memory, and motor inhibition. This contradicts the narrative of cannabis-using psychosis patients having superior cognition.\n\nOne exception was conceptual set-shifting, where cannabis-using patients actually outperformed non-users. This isolated advantage amidst broader deficits suggests different cognitive profiles in cannabis-using versus non-using psychosis patients.\n\nAge was a moderating factor, with older age predicting worse performance in processing speed, sustained attention, and verbal memory among cannabis users, but better performance in verbal learning and verbal fluency.","whyItMatters":"Understanding the cognitive effects of cannabis in psychosis is important for treatment planning and for understanding the biology of cannabis-associated psychosis. If cannabis-using patients have worse cognition, this challenges the idea that they represent a \"healthier\" subgroup and suggests cannabis may actively impair cognitive function on top of psychosis-related deficits.","specificNumbers":"308 studies identified, 14 met inclusion criteria. Cannabis-using patients performed worse on: premorbid IQ, current IQ, verbal learning, verbal working memory, motor inhibition. Cannabis users outperformed non-users on conceptual set-shifting. Increasing age predicted worse cognitive performance in several domains among cannabis users.","methodology":"Systematic search of 308 studies identified 14 comparing neurocognition between current cannabis users and non-users with psychotic disorders, with mean age between 15 and 45 years. Effect sizes were extracted from cognitive test performance and analyzed using random effects modeling with moderator analyses.","limitations":"The studies used varied cognitive assessments, making direct comparison imperfect. The age range (15-45) is broad. Current cannabis use was defined differently across studies. The meta-analysis cannot determine whether cannabis caused the cognitive deficits or whether patients with worse cognition were more likely to continue using. Sample sizes within individual studies varied."},{"rthcId":"RTHC-01598","title":"Maternal and paternal cannabis use during pregnancy and the risk of psychotic-like experiences in the offspring.","authors":"Bolhuis, Koen; Kushner, Steven A; Yalniz, Selda; Hillegers, Manon H J; Jaddoe, Vincent W V; Tiemeier, Henning; El Marroun, Hanan","year":2018,"journal":"Schizophrenia research, 202, 322-327","doi":"10.1016/j.schres.2018.06.067","pmid":"29983267","tags":["pregnancy","psychosis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 3,692 children from the Generation R birth cohort to examine whether parental cannabis use during pregnancy affected the risk of psychotic-like experiences at age 10. They used a clever study design: comparing maternal versus paternal cannabis use to disentangle direct prenatal exposure effects from shared genetic/familial factors.\n\nMaternal cannabis use during pregnancy was associated with a 38% increase in offspring psychotic-like experiences. But critically, paternal cannabis use during pregnancy showed a nearly identical association (44% increase), even though fathers do not directly expose the fetus.\n\nFurthermore, maternal cannabis use exclusively before pregnancy (but not during) showed similar associations to continued use during pregnancy, suggesting the timing of exposure mattered less than the fact that the parent used cannabis.\n\nThis pattern strongly suggests that shared genetic vulnerabilities or familial factors, rather than direct chemical exposure of the fetus to cannabis, largely explain the association between parental cannabis use and offspring psychotic-like experiences.","whyItMatters":"This study provides a more nuanced understanding of why children of cannabis-using parents may develop psychotic-like experiences. Rather than cannabis directly damaging the developing fetus, the finding that paternal use shows the same association points to shared genetics and family environment as the primary pathway. This has implications for how we counsel families and design prevention strategies.","specificNumbers":"3,692 participants from Generation R cohort. Maternal cannabis use: adjusted OR = 1.38 (95% CI 1.03-1.85). Paternal cannabis use: adjusted OR = 1.44 (95% CI 1.14-1.82). Pre-pregnancy-only maternal use showed comparable estimates to continued use during pregnancy. Offspring assessed at age 10.","methodology":"This prospective cohort study was embedded in the Generation R birth cohort (N = 3,692). Maternal cannabis exposure was verified using both self-reports and urine cannabis metabolite levels. Paternal cannabis use was reported by mothers. Offspring psychotic-like experiences were assessed at age 10. Adjusted odds ratios were calculated controlling for confounders.","limitations":"Psychotic-like experiences at age 10 are subclinical and may not develop into psychotic disorders. Paternal cannabis use was reported by mothers, which may be less accurate than direct reporting. The study cannot completely rule out indirect paternal effects (secondhand smoke exposure, parenting behavior). Self-reported cannabis use may underestimate actual use."},{"rthcId":"RTHC-01599","title":"Cannabis and cannabinoid drug development: evaluating botanical versus single molecule approaches.","authors":"Bonn-Miller, Marcel O; ElSohly, Mahmoud A; Loflin, Mallory J E; Chandra, Suman; Vandrey, Ryan","year":2018,"journal":"International review of psychiatry (Abingdon, England), 30(3), 277-284","doi":"10.1080/09540261.2018.1474730","pmid":"30179534","tags":["medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers outlined the two parallel approaches to cannabinoid drug development and their respective challenges. The botanical approach derives medications directly from the cannabis plant, offering the potential entourage effect but facing challenges with standardization, batch consistency, and regulatory complexity. The single-molecule approach synthesizes individual cannabinoids for pharmaceutical development, offering precise dosing and regulatory clarity but potentially missing synergistic effects.\n\nBoth approaches face unique complications from the expanding legalization of cannabis. Legalization creates a situation where patients can access unregulated cannabis products that compete with pharmaceutical development, potentially undermining the incentive to conduct expensive clinical trials.\n\nThe commentary also highlighted regulatory challenges, noting that the botanical approach must navigate agricultural regulation alongside pharmaceutical approval, while the single-molecule approach faces competition from the very plant compounds it seeks to purify. Public health considerations were discussed, including the need for quality control regardless of the regulatory pathway chosen.","whyItMatters":"The pathway through which cannabis medicines are developed has direct implications for patients. Whole-plant products may offer broader therapeutic effects through the entourage mechanism, but single-molecule drugs offer more precise dosing and better-studied safety profiles. Understanding this debate helps patients and clinicians make informed choices.","specificNumbers":"Two development pathways: botanical (plant-derived) and single molecule (synthesized). Two synthetic cannabinoid drugs FDA-approved at time of publication. Multiple state-level legalization programs creating competing access pathways.","methodology":"This was a commentary discussing the two major cannabinoid drug development strategies, their challenges, and the impact of legalization on pharmaceutical development.","limitations":"This is a commentary reflecting expert opinions rather than presenting new data. The discussion is framed within the US regulatory context and may not fully apply to other jurisdictions. The commentary was published before several significant regulatory developments."},{"rthcId":"RTHC-01600","title":"Therapeutic Benefit of Smoked Cannabis in Randomized Placebo-Controlled Studies.","authors":"Bowen, Lynneice L; McRae-Clark, Aimee L","year":2018,"journal":"Pharmacotherapy, 38(1), 80-85","doi":"10.1002/phar.2064","pmid":"29178487","tags":["medical-cannabis","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Despite 90% of marijuana users in 2014 using the smoked form, researchers could find only seven randomized placebo-controlled trials that specifically tested smoked cannabis for medical purposes.\n\nThe results were mixed. Cannabis did not outperform placebo for experimentally evoked pain or for improving the timed walk test. For glaucoma, smoked cannabis did reduce intraocular pressure, but the effect lasted less than four hours, making it impractical for this chronic condition.\n\nThe most consistent finding was that smoked marijuana, even at lower THC concentrations, increased total daily calorie intake and number of eating occasions. This appetite-stimulating effect was robust across studies.\n\nNeither of the studies examining quality of life as a secondary outcome found significant improvements with cannabis use.","whyItMatters":"The overwhelming majority of medical cannabis use involves smoking, yet the evidence base for this specific route of administration is remarkably thin. With only seven qualifying trials, policy decisions about medical marijuana are being made with very limited evidence for the way most patients actually use it.","specificNumbers":"90% of marijuana users in 2014 used smoked form. Only 7 RCTs met inclusion criteria. 28 states had legalized medical marijuana at time of publication. Cannabis did not beat placebo for pain or walking tests. Glaucoma pressure reduction lasted less than 4 hours. Consistent increase in daily calorie intake.","methodology":"A systematic literature search identified randomized controlled trials studying smoked cannabis for medical conditions. Only studies with smoked cannabis (excluding other administration methods), placebo controls, and disease-specific primary endpoints were included. Open-label studies were excluded. Seven studies met all criteria.","limitations":"The small number of qualifying trials limits the ability to draw broad conclusions. The strict inclusion criteria excluded studies using other delivery methods that might inform the effects of cannabis. Some conditions may benefit from smoked cannabis in ways not captured by the specific outcomes measured. The review was published early in the modern era of cannabis research."},{"rthcId":"RTHC-01601","title":"A Survey on the Medical Use of Cannabis in Europe: A Position Paper.","authors":"Bramness, Jørgen G; Dom, Geert; Gual, Antoni; Mann, Karl; Wurst, Friedrich Martin","year":2018,"journal":"European addiction research, 24(4), 201-205","doi":"10.1159/000492757","pmid":"30134238","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The European Federation of Addiction Societies surveyed its member organizations across 17 countries to assess the state of medical cannabis in Europe. The landscape differed markedly from the United States.\n\nThe cannabis extract nabiximol (Sativex), a mouth spray containing THC and CBD, was the most widely available cannabis-based medical product across Europe. Synthetic cannabinoids and standardized cannabis flower were far less prevalent. No European country allowed growing cannabis for personal medical use.\n\nCross-border transport of medical cannabis products was quite limited. Medical cannabis use was restricted to specific central medical conditions in most countries, though off-label prescribing was prevalent in some.\n\nThe European Federation of Addiction Societies issued a position statement stressing the need for further efficacy studies, warnings about dangers of increasing popularity, and calling for European-level regulations covering registration, medical indications, product standardization, and sales rules.","whyItMatters":"Understanding how medical cannabis is handled in Europe provides contrast to the US approach and highlights alternative regulatory models. The European emphasis on standardized pharmaceutical preparations (like Sativex) over whole-plant cannabis reflects a different risk-benefit calculation and regulatory philosophy.","specificNumbers":"28 responses from 17 European countries. 34 EUFAS member societies in 19 countries surveyed. Sativex most prevalent cannabis-based product. No country allows personal medical growing. Two FDA-approved synthetic cannabinoids mentioned. Off-label use prevalent in some countries.","methodology":"A web-based survey was sent to all 34 member societies of EUFAS in 19 European countries during summer 2017. Twenty-eight responses were received from 17 countries covering the availability, prescription patterns, and regulatory status of medical cannabis products.","limitations":"The survey relied on responses from addiction society representatives, who may not fully represent all medical specialties prescribing cannabis. Not all member societies responded. The survey captured a snapshot from 2017 and the landscape has evolved since. Some countries may have been underrepresented."},{"rthcId":"RTHC-01602","title":"Clinical Correlates of Cannabis Use Among Individuals With Attention Deficit Hyperactivity Disorder.","authors":"Brandt, Ariel; Rehm, Jürgen; Lev-Ran, Shaul","year":2018,"journal":"The Journal of nervous and mental disease, 206(9), 726-732","doi":"10.1097/NMD.0000000000000877","pmid":"30124577","tags":["cognition","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using data from the National Epidemiologic Survey on Alcohol and Related Conditions, researchers examined cannabis use patterns among adults with and without ADHD. The prevalence of cannabis use was more than three times higher in people with ADHD (14.3%) compared to those without (4.3%).\n\nAmong ADHD patients who used cannabis, those with the hyperactive subtype initiated use significantly earlier, at an average age of 13.8 years, compared to 16.3 years for the inattentive subtype. This 2.5-year gap in initiation age is clinically meaningful given the vulnerability of the developing brain during early adolescence.\n\nCannabis-using ADHD patients also had notably higher rates of psychiatric comorbidity. Having any psychiatric disorder was 2.8 times more likely, and lifetime personality disorders were 4 times more likely in ADHD patients who used cannabis compared to those who did not.","whyItMatters":"ADHD is one of the most common neurodevelopmental disorders, and understanding its relationship with cannabis use has practical implications. The finding that hyperactive individuals start using cannabis nearly 2.5 years earlier than inattentive types suggests that impulsivity and hyperactivity drive earlier substance use initiation, creating a larger window of developmental vulnerability.","specificNumbers":"Cannabis use prevalence: 14.3% with ADHD vs 4.3% without. Hyperactive subtype initiation age: 13.8 years. Inattentive subtype initiation age: 16.3 years (p = 0.0017). Any psychiatric disorder: AOR = 2.8 (95% CI 1.08-6.41). Lifetime personality disorder: AOR = 4.04 (95% CI 1.84-8.84).","methodology":"Data were from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (2004-2005). Psychiatric disorders were assessed using the AUDADIS structured interview. Multivariate logistic regression models adjusted for sociodemographics, psychiatric disorders, and substance use disorders.","limitations":"The cross-sectional design cannot determine whether ADHD drives cannabis use or whether both share common risk factors. The data are from 2004-2005 and may not reflect current patterns. Self-reported ADHD diagnosis and cannabis use may be subject to recall bias. The study cannot assess whether cannabis use represented self-medication for ADHD symptoms."},{"rthcId":"RTHC-01603","title":"Substance use and suicidal ideation and behaviour in low- and middle-income countries: a systematic review.","authors":"Breet, Elsie; Goldstone, Daniel; Bantjes, Jason","year":2018,"journal":"BMC public health, 18(1), 549","doi":"10.1186/s12889-018-5425-6","pmid":"29699529","tags":["mental-health","addiction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Researchers systematically reviewed 108 studies examining the relationship between substance use and suicidal ideation and behavior in low- and middle-income countries, where 75% of global suicides occur.\n\nThe association between substance use and suicidal behavior was remarkably consistent across all substances studied (alcohol, tobacco, cannabis, illicit drugs, prescription drug misuse), all dimensions of substance use (intoxication, use, and pathological use), and all dimensions of suicidal behavior (ideation, non-fatal attempts, and completed suicide).\n\nHowever, the review revealed significant gaps. Most research came from upper-middle-income countries, with only 22% from lower-middle-income and low-income countries. Research focused heavily on alcohol and tobacco while neglecting cannabis, opioids, sedatives, stimulants, and other substances. Most studies used cross-sectional designs, limiting causal conclusions.","whyItMatters":"Substance use is one of the most modifiable risk factors for suicide. In low- and middle-income countries where mental health resources are scarce, addressing substance use could be a practical suicide prevention strategy. The consistent association across all substance types, including cannabis, highlights the importance of integrated substance use and mental health approaches.","specificNumbers":"108 studies included. 75% of global suicides occur in LMICs. Only 22% of studies came from lower-middle-income and low-income countries. Positive association found across all substance types, all use dimensions, and all suicidal behavior dimensions. Most studies were cross-sectional.","methodology":"Systematic search of five databases identified English-language quantitative studies published between January 2006 and February 2016 examining associations between substance use and suicidal ideation and behavior in LMICs. Methodological quality was assessed using the SIGN checklist. 108 studies were included.","limitations":"Most studies were cross-sectional, preventing causal conclusions. Research was concentrated in upper-middle-income countries, limiting generalizability to the poorest nations. Cannabis-specific findings were limited by the small number of studies focusing on this substance. Cultural and methodological heterogeneity across 108 studies complicates synthesis."},{"rthcId":"RTHC-01604","title":"Attitudes, perceptions, and use of marijuana in youth with multiple sclerosis.","authors":"Brenton, J Nicholas; Schreiner, Teri; Karoscik, Krystle; Richter, Meg; Ferrante, Samantha; Waldman, Amy; Banwell, Brenda","year":2018,"journal":"Journal of neurology, 265(2), 417-423","doi":"10.1007/s00415-017-8715-5","pmid":"29273844","tags":["medical-cannabis","youth","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 52 consecutive pediatric-onset MS patients from three US centers about their marijuana use attitudes and habits. Nearly half (48%) reported using marijuana, with most beginning in mid-to-late adolescence.\n\nThe most common reasons for use were relaxation (72%), improvement of medical problems (64%), and stress reduction (52%). This high rate of perceived medical benefit is notable given the limited evidence for marijuana in MS-related symptoms in young patients.\n\nPerhaps most striking was the cognitive dissonance: 64% of marijuana users acknowledged that it negatively affected their memory and focus, yet continued to use it. Cost and access were not barriers to use, despite all respondents being under age 21.\n\nThis is particularly concerning because MS itself affects brain development and cognitive function in young patients, and marijuana exposure during adolescence could compound these effects.","whyItMatters":"Youth with MS face a unique double vulnerability: MS already impairs brain development, and adding marijuana exposure during adolescence could worsen cognitive outcomes. The finding that nearly half are using marijuana despite recognizing its memory effects suggests that current education and support are insufficient to address this risk.","specificNumbers":"52 pediatric-onset MS patients surveyed. 48% reported marijuana use. Most started in mid-to-late adolescence. Reasons: relaxation (72%), medical improvement (64%), stress reduction (52%). 64% of users perceived negative effects on memory and focus. All respondents under age 21.","methodology":"A structured questionnaire was administered to 52 consecutive pediatric-onset MS patients at three US pediatric MS centers. The survey captured attitudes toward marijuana, personal use habits, perceived benefits and harms, and access barriers.","limitations":"The sample was small (52 patients) and drawn from three specialty centers, limiting generalizability. The survey relied on self-report and may underestimate use. No cognitive testing was performed to verify the self-perceived memory effects. The study did not compare outcomes between users and non-users."},{"rthcId":"RTHC-01605","title":"Orosensory Detection of Dietary Fatty Acids Is Altered in CB₁R-/- Mice.","authors":"Brissard, Léa; Leemput, Julia; Hichami, Aziz; Passilly-Degrace, Patricia; Maquart, Guillaume; Demizieux, Laurent; Degrace, Pascal; Khan, Naim Akhtar","year":2018,"journal":"Nutrients, 10(10)","doi":"10.3390/nu10101347","pmid":"30241419","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers discovered that the CB1 cannabinoid receptor, the same receptor activated by THC, plays a previously unknown role in the tongue's ability to detect and prefer dietary fats.\n\nMice genetically engineered to lack CB1 receptors showed significantly lower preference for solutions containing rapeseed oil or the fatty acid linoleic acid compared to normal mice. Blocking CB1 receptors with rimonabant in normal mice produced the same reduction in fat preference.\n\nThe mechanism involved taste bud cells. While the fat-detecting receptors (CD36 and GPR120) were present at normal levels in CB1-deficient mice, the cells showed impaired calcium signaling in response to fatty acids. This means the cells could detect fat but could not properly translate that signal into a taste sensation.\n\nAdditionally, CB1-deficient mice had decreased levels of GLP-1, a hormone involved in satiety signaling, in their taste bud cells, suggesting the endocannabinoid system affects both fat taste perception and the hormonal response to dietary fat.","whyItMatters":"This study reveals a new mechanism through which the endocannabinoid system influences food intake: by modulating how the tongue perceives dietary fat. This helps explain why cannabis users often crave fatty foods (\"the munchies\") and why the CB1 blocker rimonabant reduced food intake in obesity trials. Understanding this taste-level mechanism could inform new approaches to managing obesity.","specificNumbers":"CB1R knockout mice showed low preference for rapeseed oil and linoleic acid. Rimonabant administration produced similar fat preference reduction. No difference in CD36 or GPR120 protein levels. Impaired calcium signaling in CB1R knockout taste bud cells. Decreased proglucagon, GLP-1R mRNA, and GLP-1 basal levels in CB1R knockout mice.","methodology":"Behavioral preference tests compared CB1R knockout mice and wild-type mice for fat-containing solutions. Rimonabant was used to pharmacologically block CB1R in normal mice. Taste bud cells were analyzed for protein expression (CD36, GPR120), calcium signaling responses to fatty acids, and GLP-1 mRNA and protein levels.","limitations":"This is an animal study using knockout mice, which may not directly translate to human taste perception. The CB1R knockout affects the entire body, not just taste buds, making it difficult to isolate tongue-specific effects. The study used pure fatty acid solutions rather than complex foods. Human taste bud physiology may differ from mice."},{"rthcId":"RTHC-01606","title":"Cannabinoids for epilepsy: What do we know and where do we go?","authors":"Brodie, Martin J; Ben-Menachem, Elinor","year":2018,"journal":"Epilepsia, 59(2), 291-296","doi":"10.1111/epi.13973","pmid":"29214639","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The authors reviewed the rapidly evolving field of cannabinoids for epilepsy, noting several important developments and remaining challenges.\n\nRecent randomized placebo-controlled trials confirmed CBD's efficacy in two severe childhood epilepsy syndromes: Dravet syndrome and Lennox-Gastaut syndrome. This represented a major advance from the earlier era of anecdotal reports.\n\nHowever, the review highlighted significant practical challenges. Cannabinoids appear to work through mechanisms other than the endogenous cannabinoid receptors CB1 and CB2, and the exact mechanism of antiseizure activity remains unclear. The pharmacokinetics are complex, with variable bioavailability making it difficult to develop consistent oral formulations.\n\nDrug interactions represent a major complication for everyday use, particularly since epilepsy patients typically take multiple antiseizure medications. The review noted that further placebo-controlled studies were underway testing cannabidivarin (CBDV) in adults with focal epilepsy, potentially expanding the range of epilepsy types that might respond to cannabinoid treatment.","whyItMatters":"As CBD-based epilepsy treatments move from clinical trials to clinical practice, understanding the practical challenges is crucial for patients and clinicians. The drug interaction profile is particularly important because poorly managed interactions could paradoxically worsen seizure control or cause toxicity from co-administered medications.","specificNumbers":"Randomized trials confirmed efficacy in Dravet and Lennox-Gastaut syndromes. Cannabidivarin trials underway for adult focal epilepsy. Two endogenous cannabinoid receptors (CB1, CB2) do not appear to mediate the antiseizure effect.","methodology":"This was a narrative review of the current state of cannabinoid research in epilepsy, covering mechanisms of action, pharmacokinetics, clinical trial evidence, drug interactions, and ongoing research.","limitations":"This is a brief narrative review rather than a systematic review. The evidence at the time was strongest for two severe childhood epilepsies, and generalizability to other epilepsy types was uncertain. Drug interaction data were still accumulating. Long-term safety data were limited."},{"rthcId":"RTHC-01607","title":"Toxicology of Marijuana, Synthetic Cannabinoids, and Cannabidiol in Dogs and Cats.","authors":"Brutlag, Ahna; Hommerding, Holly","year":2018,"journal":"The Veterinary clinics of North America. Small animal practice, 48(6), 1087-1102","doi":"10.1016/j.cvsm.2018.07.008","pmid":"30342565","tags":["medical-cannabis","cbd","synthetic-cannabinoids"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"As cannabis becomes more accessible through both medical and recreational legalization, pet exposures to cannabis products have increased significantly. This veterinary review documented the clinical picture across different product types.\n\nDogs are particularly vulnerable to THC toxicity because they have more CB1 receptors in the cerebellum than humans, making them more sensitive to effects on coordination and consciousness. Common signs of marijuana exposure in dogs include ataxia (uncoordinated movement), sedation, urinary incontinence, and sometimes agitation or hyperesthesia. While most cases resolve with supportive care, rare fatalities have been reported.\n\nThe rise of CBD products marketed specifically for pets adds complexity, as these products are largely unregulated and may contain more THC than labeled. Synthetic cannabinoid exposures, though less common, tend to produce more severe and unpredictable clinical signs.\n\nThe review emphasized that veterinarians need to be prepared to recognize and manage these exposures, and that owners may not always disclose cannabis use in the household.","whyItMatters":"As cannabis products proliferate in homes, pets are increasingly exposed, whether through edibles left accessible, secondhand smoke, or CBD products given intentionally. Understanding the clinical picture helps pet owners recognize when their animal needs veterinary attention and helps veterinarians provide appropriate treatment.","specificNumbers":"Dogs have more cerebellar CB1 receptors than humans. Exposure sources include recreational marijuana, medical products, CBD pet products, and synthetic cannabinoids. Common signs: ataxia, sedation, urinary incontinence. Most cases resolve with supportive care. Rare fatalities reported.","methodology":"This was a narrative review of cannabis toxicology in companion animals, covering the endocannabinoid system in dogs and cats, common cannabis products causing exposure, clinical signs, and treatment approaches.","limitations":"The review is narrative rather than systematic. Exact incidence rates of pet cannabis exposure are difficult to establish because owners may not report exposure or seek veterinary care. Most data come from case reports and poison control databases rather than systematic studies. Species-specific differences between dogs and cats are not fully characterized."},{"rthcId":"RTHC-01608","title":"Therapeutic Cannabis and Endocannabinoid Signaling System Modulator Use in Otolaryngology Patients.","authors":"Bryant, Lucas M; Daniels, Kelly E; Cognetti, David M; Tassone, Patrick; Luginbuhl, Adam J; Curry, Joseph M","year":2018,"journal":"Laryngoscope investigative otolaryngology, 3(3), 169-177","doi":"10.1002/lio2.154","pmid":"30062131","tags":["medical-cannabis","cancer","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the endocannabinoid signaling system in the context of ear, nose, and throat medicine. Cannabis is the most widely used illicit substance worldwide, and otolaryngologists encounter its effects and potential benefits across multiple conditions.\n\nThe review identified potential therapeutic roles in several domains. For pain management, cannabinoids showed promise for chronic head and neck pain. For inflammation, endocannabinoid system modulation could address various inflammatory conditions in the head and neck. Research has demonstrated potential antineoplastic benefits in oral, thyroid, and skin cancers.\n\nOn the risk side, the review documented adverse effects of cannabis use relevant to otolaryngology, including effects on the oral mucosa, throat irritation from smoking, and potential interactions with surgical anesthesia. Two synthetic cannabinoids (dronabinol and nabilone) were FDA-approved at the time of publication for chemotherapy-related nausea/vomiting, cachexia, and appetite loss.\n\nThe authors emphasized that with increasing use and changing legislation, otolaryngologists need to be aware of both the adverse manifestations and potential therapeutic benefits when discussing cannabis with patients.","whyItMatters":"Otolaryngologists see patients for conditions ranging from head/neck cancer to chronic pain to sleep disorders, many of which involve the endocannabinoid system. As more patients use or ask about cannabis, these specialists need to understand both the risks and potential benefits specific to their field.","specificNumbers":"Two FDA-approved synthetic cannabinoids at time of publication. Approved indications: chemotherapy-related nausea/vomiting, cachexia, appetite loss. Research showing potential anti-cancer effects in oral, thyroid, and skin cancers.","methodology":"This was a narrative review of the current literature on cannabis use, the endocannabinoid signaling system, and their relevance to otolaryngology practice, including regulatory status and clinical implications.","limitations":"This is a broad narrative review covering many topics at a general level. Much of the therapeutic evidence is preclinical. The review does not provide specific dosing or clinical guidance for using cannabinoids in otolaryngic conditions. The regulatory landscape has evolved since publication."},{"rthcId":"RTHC-01609","title":"Hippocampal Protein Kinase C Signaling Mediates the Short-Term Memory Impairment Induced by Delta9-Tetrahydrocannabinol.","authors":"Busquets-Garcia, Arnau; Gomis-González, Maria; Salgado-Mendialdúa, Victòria; Galera-López, Lorena; Puighermanal, Emma; Martín-García, Elena; Maldonado, Rafael; Ozaita, Andrés","year":2018,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(5), 1021-1031","doi":"10.1038/npp.2017.175","pmid":"28816239","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Using a novel object recognition test in mice, researchers dissected the molecular mechanisms behind THC's effects on memory and made a key discovery: short-term and long-term memory impairment from THC operate through entirely different molecular pathways.\n\nTHC impaired short-term memory specifically through activation of protein kinase C (PKC) in the hippocampus. When researchers blocked PKC either systemically or directly in the hippocampus before THC administration, the short-term memory impairment was completely prevented. However, the same PKC blockers did not protect against long-term memory impairment.\n\nConversely, blocking mTOR (mammalian target of rapamycin), a pathway previously known to mediate THC's long-term memory effects, did not prevent the short-term memory deficit.\n\nAt the molecular level, THC caused a transient increase in PKC phosphorylation in the hippocampus, which paralleled the timing of cognitive impairment. THC also enhanced phosphorylation of neurogranin, a postsynaptic protein involved in synaptic plasticity, in a PKC-dependent manner.","whyItMatters":"Understanding the specific molecular mechanism behind THC's memory-impairing effects opens the door to developing interventions that could prevent cognitive side effects while preserving therapeutic benefits. The discovery that short-term and long-term memory impairment use different pathways suggests that targeted approaches could potentially block one without affecting the other.","specificNumbers":"PKC inhibitors prevented THC-induced short-term memory impairment. mTOR inhibitors prevented long-term but not short-term memory impairment. Transient PKC phosphorylation increase observed in hippocampus after THC. PKC-dependent neurogranin phosphorylation enhanced by THC. PKC-theta identified as a potential mediating isoform.","methodology":"Mice were tested on a novel object recognition memory paradigm. THC was administered systemically, and PKC inhibitors or mTOR inhibitors were given either systemically or directly into the hippocampus via microinjection. Immunoblot analysis measured PKC phosphorylation, PKC isoform expression, and neurogranin phosphorylation in hippocampal tissue.","limitations":"This is a mouse study, and the specific PKC pathways may function differently in human hippocampal neurons. The novel object recognition task captures only one dimension of memory. PKC inhibitors used are research tools, not clinical drugs. The study used acute THC exposure and results may differ with chronic use."},{"rthcId":"RTHC-01610","title":"Biphasic effects of THC in memory and cognition.","authors":"Calabrese, Edward J; Rubio-Casillas, Alberto","year":2018,"journal":"European journal of clinical investigation, 48(5), e12920","doi":"10.1111/eci.12920","pmid":"29574698","tags":["cognition","potency"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The well-known cognitive impairment from THC — disrupted short-term memory, slower processing — turns out to be only half the story. Recent animal research showed that chronic low-dose THC administration to old mice actually improved neurological function, promoted hippocampal neurogenesis, and protected against inflammation-induced cognitive damage.\n\nThe authors argue this isn't contradictory — it's hormesis, a biological pattern where a substance produces opposite effects at low versus high doses. At the doses that impair young brains, THC overwhelms endocannabinoid signaling. But at very low doses in aging brains where the endocannabinoid system has naturally declined, THC may restore signaling to a functional range.\n\nThe review also highlights evidence that low-dose THC prevented neurodegenerative processes in animal models of Alzheimer's disease and restored memory in aging mice — findings that would seem impossible based only on the impairment literature.","whyItMatters":"This paper challenges the straightforward narrative that THC is bad for your brain. It's not saying THC is good for your brain either — it's saying the answer depends on dose, age, and baseline endocannabinoid function. That's a much more nuanced and scientifically accurate picture.\n\nThe hormesis framework is important because it explains why studies seem to contradict each other. A study showing THC impairs memory in college students and a study showing low-dose THC restores memory in elderly mice aren't actually contradictory — they're measuring different parts of the same dose-response curve in different biological contexts.","specificNumbers":"• Young animals: THC at standard doses disrupted short-term memory\n• Old animals: chronic low-dose THC improved neurological function\n• Low-dose THC promoted hippocampal neurogenesis in aging brains\n• Low-dose THC showed protective effects in Alzheimer's disease models","methodology":"Narrative review synthesizing preclinical studies on THC's dose-dependent and age-dependent effects on cognition, neurogenesis, and neuroprotection. Analyzes findings through the framework of hormesis (biphasic dose-response). Published in the European Journal of Clinical Investigation.","limitations":"All findings on beneficial cognitive effects come from animal models (primarily mice), not human studies. The doses that improved cognition in old mice are far lower than what recreational users typically consume. Hormesis is a framework, not a proven mechanism for THC specifically. The review does not address whether these effects would occur with smoked cannabis versus purified THC."},{"rthcId":"RTHC-01611","title":"Comprehensive quality evaluation of medical Cannabis sativa L. inflorescence and macerated oils based on HS-SPME coupled to GC-MS and LC-HRMS (q-exactive orbitrap®) approach.","authors":"Calvi, Lorenzo; Pentimalli, Daniela; Panseri, Sara; Giupponi, Luca; Gelmini, Fabrizio; Beretta, Giangiacomo; Vitali, Davide; Bruno, Massimo; Zilio, Emanuela; Pavlovic, Radmila; Giorgi, Annamaria","year":2018,"journal":"Journal of pharmaceutical and biomedical analysis, 150, 208-219","doi":"10.1016/j.jpba.2017.11.073","pmid":"29247961","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01612","title":"Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study.","authors":"Campbell, Gabrielle; Hall, Wayne D; Peacock, Amy; Lintzeris, Nicholas; Bruno, Raimondo; Larance, Briony; Nielsen, Suzanne; Cohen, Milton; Chan, Gary; Mattick, Richard P; Blyth, Fiona; Shanahan, Marian; Dobbins, Timothy; Farrell, Michael; Degenhardt, Louisa","year":2018,"journal":"The Lancet. Public health, 3(7), e341-e350","doi":"10.1016/S2468-2667(18)30110-5","pmid":"29976328","tags":["pain","medical-cannabis","addiction"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"This prospective national cohort followed 1,514 Australians with chronic non-cancer pain who were prescribed opioids over four years. Cannabis use was common and growing: by the four-year follow-up, 24% had used cannabis for pain and 60% expressed interest in using it.\n\nThe results challenged the narrative that cannabis helps chronic pain patients. Compared to non-users at four years, cannabis users had greater pain severity (both less frequent and daily users), greater pain interference with daily life, lower self-efficacy in managing pain, and higher anxiety scores.\n\nCritically, the study found no evidence that cannabis use reduced prescribed opioid use or increased rates of opioid discontinuation. The hoped-for \"opioid-sparing\" effect of cannabis was not observed in this real-world cohort.\n\nTemporal analyses confirmed there was no evidence that cannabis use preceded improvements in pain: the association between cannabis use and worse outcomes was consistent rather than reflecting a treatment response.","whyItMatters":"This is one of the largest and longest prospective studies of cannabis use in chronic pain patients on opioids. The findings directly counter the popular narrative that cannabis can replace opioids for chronic pain. While other study types have suggested opioid-sparing effects, this real-world longitudinal data found the opposite: cannabis users did worse across multiple outcomes.","specificNumbers":"1,514 participants. 4-year follow-up. 24% used cannabis for pain by year 4. Interest in cannabis grew from 33% (baseline) to 60% (year 4). Cannabis users had greater pain severity: RR 1.14 (less frequent) and 1.17 (daily use). Greater pain interference: RR 1.21 and 1.14. Higher anxiety: RR 1.07 and 1.10. No evidence of opioid reduction.","methodology":"The Pain and Opioids IN Treatment (POINT) study was a prospective national observational cohort. Participants were recruited through community pharmacies across Australia from 2012-2014 and followed with yearly interviews for 4 years. Logistic regression examined cross-sectional associations, and lagged mixed-effects models examined temporal relationships between cannabis use and outcomes.","limitations":"This is an observational study and cannot prove that cannabis caused worse outcomes. People who use cannabis for pain may have more severe or refractory pain to begin with, explaining the worse scores. The study did not control for cannabis type, potency, or route of administration. Australian cannabis access differs from other countries. Self-selection bias could not be eliminated."},{"rthcId":"RTHC-01613","title":"Sex Differences in Prevalence of Emergency Department Patient Substance Use.","authors":"Cannon, Robert D; Beauchamp, Gillian A; Roth, Paige; Stephens, Jennifer; Burmeister, David B; Richardson, David M; Balbi, Alanna M; Park, Tennessee D; Dusza, Stephen W; Greenberg, Marna Rayl","year":2018,"journal":"Clinical therapeutics, 40(2), 197-203","doi":"10.1016/j.clinthera.2017.12.013","pmid":"29336846","tags":["addiction","sex-differences"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers analyzed 10,511 emergency department visits across three Pennsylvania hospitals over 18 months where the final diagnosis involved substance use. Alcohol dominated at 54.3%, followed by opioids at 19.2%, and cannabis at 14.4%.\n\nThe overall population was predominantly male (65.6%) with a mean age of 43.6 years. However, sex-specific patterns emerged for different substances. Males with cannabis-related ED visits were older than females with cannabis visits, mirroring the alcohol pattern. For opioids, the relationship reversed: females were older (41.3 years) than males (38.9 years) at opioid-related visits.\n\nFemales tended to be younger overall and were more likely to be discharged after their ED visit (36.1% vs 32.3%), while males were more likely to be admitted.","whyItMatters":"Emergency departments are often the frontline for managing substance-related crises. Understanding that cannabis accounts for nearly 1 in 7 substance-related ED visits, and that patterns differ by sex and age, can inform resource allocation, screening protocols, and targeted intervention strategies.","specificNumbers":"10,511 substance-related ED visits. Mean age 43.6 years. 65.6% male. Alcohol: 54.3%. Opioids: 19.2%. Cannabis: 14.4%. Females younger overall (42.4 vs 44.3 years, p < 0.001). Females more likely discharged (36.1% vs 32.3%, p < 0.001). Males older for cannabis and alcohol visits; females older for opioid visits (41.3 vs 38.9 years, p < 0.001).","methodology":"Retrospective electronic data analysis of ED visits at 3 hospitals in northeastern Pennsylvania from January 2016 through July 2017. All visits with substance use diagnosis codes (F10-F19, excluding nicotine) were included. Data captured primary substance, sex, age, date, and disposition. Time series analysis assessed trends by sex.","limitations":"The study was limited to three hospitals in one region of Pennsylvania and may not represent national patterns. Only visits coded with substance use diagnoses were captured, potentially missing cases where substance use was not documented. The study could not distinguish between primary cannabis toxicity and cannabis as a secondary finding. Retrospective data abstraction depends on coding accuracy."},{"rthcId":"RTHC-01614","title":"Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss mice.","authors":"Carvalho, Renata K; Santos, Monaliza L; Souza, Maingredy R; Rocha, Thiago L; Guimarães, Francisco S; Anselmo-Franci, Janete A; Mazaro-Costa, Renata","year":2018,"journal":"Journal of applied toxicology : JAT, 38(9), 1215-1223","doi":"10.1002/jat.3631","pmid":"29766538","tags":["cbd","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers gave young male mice daily oral CBD at two doses (15 and 30 mg/kg) for 34 consecutive days, then allowed a 35-day recovery period before assessing reproductive parameters.\n\nThe higher CBD dose caused a 76% decrease in total circulating testosterone, though levels remained within the physiological normal range. Both doses significantly altered the stages of sperm development (spermatogenesis), increasing early stages while decreasing later stages. The number of Sertoli cells, which support sperm development, was reduced at the higher dose.\n\nIn both CBD groups, sperm counts in the epididymis were reduced by 38%, and the remaining sperm showed head abnormalities and cytoplasmic droplets on the flagellum, indicating impaired sperm maturation.\n\nThese changes were observed after the 35-day recovery period, meaning they persisted well after CBD exposure stopped. This raises questions about the reversibility of CBD's reproductive effects.","whyItMatters":"CBD is increasingly used chronically, including by young people and children with epilepsy. The finding that chronic exposure reduces testosterone, impairs sperm production, and causes morphological abnormalities raises important safety questions that have not been adequately addressed in human studies. The persistence of effects after a recovery period is particularly concerning.","specificNumbers":"CBD doses: 15 and 30 mg/kg daily for 34 days. 35-day recovery period before assessment. 76% decrease in testosterone at higher dose (remained within normal range: 240-1100 ng/dL). 38% reduction in epididymal sperm count in both CBD groups. Increased stages I-VI of spermatogenesis, decreased stages VII-VIII and XII. Decreased Sertoli cells at higher dose. Sperm head abnormalities and flagellum cytoplasmic droplets in both groups.","methodology":"Male Swiss mice at 21 days of age received oral CBD at 15 or 30 mg/kg daily for 34 consecutive days, with a control group receiving sunflower oil. After a 35-day recovery period, reproductive organs were weighed, testosterone measured, and spermatogenesis, sperm production, and sperm morphology were assessed through histomorphometry.","limitations":"This is a mouse study, and doses relative to body weight are much higher than typical human CBD use. The reproductive physiology of mice differs from humans in important ways. Only two doses were tested, and lower doses closer to human clinical use were not examined. The study assessed a single time point after recovery and could not determine if longer recovery would reverse the effects."},{"rthcId":"RTHC-01615","title":"Initiation of vaporizing cannabis: Individual and social network predictors in a longitudinal study of young adults.","authors":"Cassidy, Rachel N; Meisel, Matthew K; DiGuiseppi, Graham; Balestrieri, Sara; Barnett, Nancy P","year":2018,"journal":"Drug and alcohol dependence, 188, 334-340","doi":"10.1016/j.drugalcdep.2018.04.014","pmid":"29857317","tags":["youth","potency"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tracked 1,313 first-year college students using social network methods to understand the emerging trend of vaping cannabis. By the second survey, 9.4% had vaped cannabis in their lifetime but not recently, 7.5% were current vapers, and 5.9% initiated vaping cannabis between the two surveys.\n\nThe strongest predictor of initiating cannabis vaping was having peers in one's social network who also initiated cannabis vaping during the same period. Notably, simply having peers who used cannabis in any form or peers who used e-cigarettes was not sufficient. It was specifically peers who started vaping cannabis that predicted initiation.\n\nPrior experience with both cannabis (any form) and electronic nicotine delivery systems also predicted cannabis vaping initiation. This suggests that cannabis vaping represents a convergence of two existing behaviors, cannabis use and vaping, rather than an entirely new behavior.","whyItMatters":"Cannabis vaping has grown rapidly, particularly among young adults, and involves higher-potency THC concentrates. Understanding the specific peer influence pathway, that it is specifically cannabis-vaping peers who drive initiation, can inform targeted prevention strategies on college campuses.","specificNumbers":"1,313 first-year college students surveyed. 9.4% had vaped cannabis lifetime but not recently. 7.5% were current cannabis vapers. 5.9% initiated between surveys. Prior cannabis use, prior ENDS use, and peers who initiated cannabis vaping all predicted initiation. General cannabis-using or ENDS-using peers did not predict initiation.","methodology":"Longitudinal study of 1,313 first-year college students surveyed at two time points during their first year, using social network methods to map peer relationships and substance use. Surveys were available for two weeks beginning in the sixth week of each semester. Predictors of cannabis vaping initiation were analyzed.","limitations":"The study was conducted at a single university and may not represent all college populations. Self-reported cannabis vaping may be underreported. The social network methods capture nominated peers but may miss other influential relationships. The two-wave design cannot capture more nuanced temporal dynamics. Cannabis vaping products and prevalence have changed since the study."},{"rthcId":"RTHC-01616","title":"The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis-related spasticity.","authors":"Celius, Elisabeth G; Vila, Carlos","year":2018,"journal":"Brain and behavior, 8(5), e00962","doi":"10.1002/brb3.962","pmid":"29761015","tags":["medical-cannabis","driving","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed all available evidence on whether Sativex, a THC:CBD mouth spray prescribed for MS-related spasticity, affects driving ability. The evidence was reassuring.\n\nDriving studies and real-world registries showed no increase in motor vehicle accidents associated with Sativex use. Most patients actually reported improved driving ability after starting the medication, likely because reduced spasticity and potentially better cognitive function outweighed any mild impairment from the THC component.\n\nAn important pharmacological distinction was noted: blood THC levels from Sativex are significantly lower than levels associated with recreational herbal cannabis use. The controlled, metered-dose delivery of the spray produces more stable and modest THC exposure compared to smoking or consuming cannabis.\n\nHowever, the review cautioned that THC blood measurements after Sativex could exceed legal driving thresholds in some countries, recommending that patients carry a medical certificate and know their country's specific regulations.","whyItMatters":"For MS patients, losing the ability to drive can mean losing independence. Many patients fear that a THC-containing medication will prevent them from driving. This review provides evidence that at therapeutic doses, Sativex does not impair driving and may actually improve it by reducing the spasticity that was affecting driving performance.","specificNumbers":"No increase in motor vehicle accidents associated with Sativex use. Majority of patients reported improved driving ability. THC blood levels from Sativex significantly lower than recreational cannabis. Blood THC may still exceed legal thresholds in some countries.","methodology":"Systematic PubMed search from 2000 to 2017 for articles on THC:CBD oromucosal spray and driving performance, supplemented with relevant references and known articles. Evidence from driving studies and real-world patient registries was synthesized.","limitations":"The review relied on limited driving study data and real-world registries rather than large randomized trials specifically designed to assess driving. Patient self-report of improved driving may be biased. The legal implications of blood THC levels vary by jurisdiction and were not comprehensively mapped. Long-term effects on driving were not assessed."},{"rthcId":"RTHC-01617","title":"Cluster randomised controlled trial of an online intervention to prevent ecstasy and new psychoactive substance use among adolescents: final results and implications for implementation.","authors":"Champion, Katrina E; Newton, Nicola Clare; Stapinski, Lexine; Teesson, Maree","year":2018,"journal":"BMJ open, 8(11), e020433","doi":"10.1136/bmjopen-2017-020433","pmid":"30478103","tags":["synthetic-cannabinoids","youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers tested a web-based prevention program delivered through school health education classes to 1,126 Australian students across 11 schools. The Climate Schools: Ecstasy and Emerging Drugs module used cartoon storylines to deliver harm-minimization information about ecstasy and new psychoactive substances including synthetic cannabinoids.\n\nAt the 2-year follow-up, students in the control group were 3.56 times more likely to intend to use synthetic cannabis compared to those who received the intervention. This effect on intentions was the primary significant finding.\n\nKnowledge about ecstasy and new psychoactive substances was also significantly higher in the intervention group, but only among students who completed all four lessons. Students who received an incomplete dose (three or fewer lessons) showed no significant difference from controls, highlighting that the program needs to be delivered in full to be effective.","whyItMatters":"Synthetic cannabinoids pose unique dangers because of their unpredictable potency and adverse effects. Finding a scalable, web-based prevention program that reduces intentions to use these substances is valuable, especially given the challenges of keeping prevention content current as new synthetic drugs continuously emerge.","specificNumbers":"1,126 students from 11 schools. Mean age 14.9 years. Controls 3.56 times more likely to intend synthetic cannabis use (OR = 3.56, p = 0.01). Knowledge significantly higher only in full-dose group (ecstasy p = 0.001, NPS p = 0.04). No significant differences between incomplete dose and controls.","methodology":"Cluster randomized controlled trial with 1,126 students (mean age 14.9 years) from 11 Australian secondary schools. Five schools received the four-lesson internet-based intervention; six served as controls (health education as usual). Outcomes measured at baseline, post-test, 6, 12, and 24 months included intentions to use, knowledge, and lifetime use of ecstasy and NPS.","limitations":"The study measured intentions to use rather than actual use as the primary outcome. Students were not blinded to their assignment. Attrition over 2 years may have biased results. The program was tested in Australian schools and may not generalize to other cultural contexts. Self-reported outcomes are subject to response bias."},{"rthcId":"RTHC-01618","title":"Cannabis Withdrawal in Adults With Attention-Deficit/Hyperactivity Disorder.","authors":"Chauchard, Emeline; Hartwell, Karen J; McRae-Clark, Aimee L; Sherman, Brian J; Gorelick, David A","year":2018,"journal":"The primary care companion for CNS disorders, 20(1)","doi":"10.4088/PCC.17m02203","pmid":"29489073","tags":["withdrawal","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers studied 23 cannabis-dependent adults with ADHD who described their most serious quit attempt without formal treatment. Nearly all (96%) experienced at least one cannabis withdrawal symptom, and 30% met full DSM-5 diagnostic criteria for cannabis withdrawal syndrome.\n\nThe withdrawal experience was remarkably similar to what has been reported in cannabis-dependent adults without psychiatric comorbidity. This was somewhat surprising, given that ADHD involves dysregulation of attention and mood that might be expected to amplify withdrawal symptoms.\n\nThe most common motivation for quitting was financial, with 87% citing saving money as a reason. The most common strategy for maintaining abstinence was avoiding people who smoke marijuana (43%). These practical motivations and strategies differed from the clinical reasons typically assumed to drive quit attempts.\n\nThe finding that ADHD does not appear to worsen cannabis withdrawal contrasts with ADHD's known effect of amplifying tobacco withdrawal, suggesting different neurobiological mechanisms underlie withdrawal from these two substances.","whyItMatters":"ADHD patients have high rates of cannabis use and dependence. Understanding that their withdrawal experience is not unusually severe (contrary to what might be expected) can inform treatment planning. The practical nature of their quit motivations (money, social pressure) can help clinicians frame cessation conversations.","specificNumbers":"23 adults with ADHD and cannabis dependence. 82.6% male. Mean age 27.4 years. 96% reported at least 1 withdrawal symptom. 30% met DSM-5 cannabis withdrawal criteria. Most common quit motivation: saving money (87%). Most common abstinence strategy: avoiding marijuana-using peers (43%).","methodology":"Twenty-three adults with ADHD enrolled in a clinical trial of atomoxetine for cannabis dependence completed the Marijuana Quit Questionnaire about their most serious previous quit attempt made without formal treatment. Study conducted between November 2005 and June 2008.","limitations":"The sample was very small (23 participants) and predominantly male. Withdrawal was assessed retrospectively about a past quit attempt rather than prospectively. All participants were enrolled in a treatment trial, which may not represent the broader ADHD-cannabis population. The comparison to non-ADHD populations was indirect rather than within-study."},{"rthcId":"RTHC-01619","title":"Self-initiated use of topical cannabidiol oil for epidermolysis bullosa.","authors":"Chelliah, Malcolm P; Zinn, Zachary; Khuu, Phoung; Teng, Joyce M C","year":2018,"journal":"Pediatric dermatology, 35(4), e224-e227","doi":"10.1111/pde.13545","pmid":"29786144","tags":["cbd","medical-cannabis","pain"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Epidermolysis bullosa (EB) is a rare genetic blistering skin disorder that causes chronic wounds, pain, and limited mobility with few effective treatments. Three patients with EB independently began using topical CBD oil and were observed in this case series.\n\nAll three patients reported meaningful improvements: faster wound healing, less blistering, and significant pain reduction. The most dramatic case was a patient who was completely weaned off oral opioid analgesics after starting topical CBD. The other two patients also experienced meaningful pain relief.\n\nThe patients attributed the benefits to CBD's proposed anti-inflammatory and analgesic properties. The topical application allowed direct delivery to affected skin areas, potentially achieving therapeutic concentrations locally without significant systemic effects.","whyItMatters":"Epidermolysis bullosa has very limited treatment options, and patients live with chronic pain that often requires opioids. If topical CBD can reduce pain and improve wound healing in this population, it would represent a significant advance for a condition that affects quality of life severely from birth.","specificNumbers":"3 patients with epidermolysis bullosa. All 3 reported faster wound healing, less blistering, and pain improvement. 1 patient completely weaned off oral opioid analgesics.","methodology":"This was an observational case series of 3 patients with epidermolysis bullosa who self-initiated topical CBD oil use. Clinical observations of wound healing, blistering frequency, and pain levels were documented.","limitations":"Only 3 patients were observed, with no control group, blinding, or standardized outcome measures. Patients self-initiated CBD use, introducing potential placebo effects and reporting bias. The specific CBD products, concentrations, and application protocols were not standardized. The observational design cannot establish causation."},{"rthcId":"RTHC-01620","title":"The Endocannabinoid System across Postnatal Development in Transmembrane Domain Neuregulin 1 Mutant Mice.","authors":"Chesworth, Rose; Long, Leonora E; Weickert, Cynthia Shannon; Karl, Tim","year":2018,"journal":"Frontiers in psychiatry, 9, 11","doi":"10.3389/fpsyt.2018.00011","pmid":"29467679","tags":["psychosis","neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers tracked the development of the endocannabinoid system across eight time points from birth to adulthood in mice carrying a mutation in neuregulin 1 (Nrg1), a known schizophrenia risk gene. These mutant mice are known to have exaggerated responses to cannabis exposure.\n\nThe study mapped the developmental trajectory of four key endocannabinoid system components: CB1 receptors and three enzymes involved in producing and breaking down the endocannabinoid 2-AG. In normal mice, these markers showed dynamic developmental changes, with synthesis and breakdown enzymes peaking around postnatal days 21-35 before declining and stabilizing. Hippocampal CB1 receptor expression peaked at day 21 and then decreased.\n\nSurprisingly, despite the Nrg1 mutant mice's known heightened cannabis sensitivity, none of the endocannabinoid system markers differed between mutant and control mice at any developmental time point. This suggests that the increased cannabis vulnerability in these genetically at-risk mice is not due to differences in the endocannabinoid system itself, but rather to other neural mechanisms.","whyItMatters":"Understanding why some individuals are more sensitive to cannabis is crucial for identifying who is at risk for cannabis-related psychosis. This study narrows the search by ruling out developmental differences in the endocannabinoid system as the explanation, redirecting attention toward other neural pathways that may mediate this vulnerability.","specificNumbers":"8 developmental time points assessed: postnatal days 7, 10, 14, 21, 28, 35, 49, and 161. 4 endocannabinoid markers measured: CB1R, DAGLalpha, MGLL, ABHD6. No sex differences found in any marker. No Nrg1 genotype differences at any time point. Endocannabinoid markers peaked around PND 21-35.","methodology":"Male and female heterozygous Nrg1 transmembrane domain mutant mice and wild-type littermates were assessed at postnatal days 7, 10, 14, 21, 28, 35, 49, and 161. Quantitative PCR measured mRNA expression of CB1R, DAGLalpha, MGLL, and ABHD6 in the prelimbic cortex and hippocampus.","limitations":"Only mRNA expression was measured, not protein levels or functional receptor activity. The four markers studied represent only part of the endocannabinoid system. Other endocannabinoid components not measured may show genotype differences. The Nrg1 mutation is one of many schizophrenia risk genes, and findings may not generalize to other genetic risk factors."},{"rthcId":"RTHC-01621","title":"The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases.","authors":"Chiurchiù, Valerio; van der Stelt, Mario; Centonze, Diego; Maccarrone, Mauro","year":2018,"journal":"Progress in neurobiology, 160, 82-100","doi":"10.1016/j.pneurobio.2017.10.007","pmid":"29097192","tags":["medical-cannabis","inflammation","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This extensive review examined both clinical and preclinical evidence for cannabinoid-based interventions in MS. The authors distinguished between two therapeutic levels: symptom management and disease modification.\n\nFor symptom management, both preclinical and clinical data support cannabinoids for controlling spasticity and chronic pain in MS. These are the established therapeutic uses, with Sativex approved in many countries for MS spasticity.\n\nFor disease modification, only preclinical data were available, but they were encouraging. Cannabinoids and endocannabinoid modulators showed neuroprotective effects in animal models of MS, suggesting they could potentially slow disease progression by reducing neuroinflammation and protecting neurons from damage.\n\nThe review connected these findings to other neuroinflammatory diseases, noting that the mechanisms through which cannabinoids reduce inflammation and protect neurons in MS models are relevant to conditions like Parkinson's disease, Alzheimer's disease, and other neurodegenerative disorders.","whyItMatters":"Most MS treatments either manage symptoms or attempt to slow progression, but rarely do both. If cannabinoid-based approaches can address both levels, they could offer a unique therapeutic profile. The current clinical evidence supports symptom management, while the preclinical neuroprotection data point toward a potentially broader role.","specificNumbers":"Clinical evidence supports: spasticity and chronic pain management. Preclinical evidence supports: neuroprotection, reduced neuroinflammation, slowed disease progression. Sativex approved for MS spasticity in multiple countries. Connections drawn to Parkinson's, Alzheimer's, and other neurodegenerative diseases.","methodology":"Comprehensive narrative review of preclinical and clinical studies examining the endocannabinoid system as a therapeutic target in MS, with attention to both symptom control and neuroprotective/disease-modifying potential, and connections to other neuroinflammatory conditions.","limitations":"Disease modification evidence comes exclusively from animal models. Translating neuroprotective effects from preclinical models to human MS has historically been challenging. The review covers a vast amount of data at varying evidence levels. Specific dosing, formulation, and timing questions remain unanswered."},{"rthcId":"RTHC-01622","title":"Marijuana use among adults: Initiation, return to use, and continued use versus quitting over a one-year follow-up period.","authors":"Choi, Namkee G; DiNitto, Diana M; Marti, C Nathan","year":2018,"journal":"Drug and alcohol dependence, 182, 19-26","doi":"10.1016/j.drugalcdep.2017.10.006","pmid":"29120860","tags":["addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Using data from the Population Assessment of Tobacco and Health study, researchers tracked marijuana use transitions over one year in over 26,000 US adults.\n\nAmong people who had never used marijuana, 2.36% initiated use. Among those who had used in the past but not recently, 10.42% returned to use. And among current users, 72.54% continued using, while 27.46% stopped.\n\nThe 18-24 age group was most likely to initiate, resume, or continue use. Mental health problems predicted both initiation among never-users and return to use among former users, suggesting marijuana use may partly reflect self-medication.\n\nFor continued use versus quitting, three factors stood out: initiating marijuana before age 18, using weekly or more frequently (2.34 times higher odds of continuing), and reporting use-related problems (1.40 times higher odds of continuing). Marijuana initiation and return to use were also associated with starting other substances during the same period.","whyItMatters":"Understanding the patterns of marijuana use transitions helps target prevention and intervention efforts. The finding that early initiation, frequent use, and existing problems predict continued use identifies who is most likely to develop persistent patterns, while the link between mental health and initiation suggests a self-medication pathway that could be addressed clinically.","specificNumbers":"26,204 adults studied. Initiation among never-users: 2.36%. Return among former users: 10.42%. Continued use among current users: 72.54%. Ages 18-24 most likely to transition. Weekly+ use: AOR = 2.34 for continued use. Use problems: AOR = 1.40 for continued use. Initiation before age 18 predicted continuation.","methodology":"Two waves of the Population Assessment of Tobacco and Health (PATH) Study were analyzed (N = 26,204 adults aged 18+). Multivariable logistic regression examined associations between Wave 1 characteristics and Wave 2 marijuana use status across three transition types: never-to-initiation, former-to-return, and continued use versus quitting.","limitations":"The one-year follow-up may not capture longer-term use trajectories. Self-reported marijuana use may be underreported. The PATH study did not distinguish between medical and recreational use. The analysis cannot determine whether mental health problems cause marijuana initiation or whether both share common causes."},{"rthcId":"RTHC-01623","title":"Synthetic and Non-synthetic Cannabinoid Drugs and Their Adverse Effects-A Review From Public Health Prospective.","authors":"Cohen, Koby; Weinstein, Aviv M","year":2018,"journal":"Frontiers in public health, 6, 162","doi":"10.3389/fpubh.2018.00162","pmid":"29930934","tags":["synthetic-cannabinoids","psychosis","cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the epidemiology and health effects of synthetic cannabinoids compared to natural cannabis from a public health perspective. The differences were stark.\n\nSynthetic cannabinoid products contain mixtures of psychoactive compounds that bind to cannabinoid receptors with much higher potency than THC from natural cannabis. While they replicate the basic effects of cannabis, they induce substantially more severe adverse effects.\n\nAcute effects include respiratory difficulties, hypertension, tachycardia, chest pain, muscle twitches, acute kidney failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Chronic use has been associated with serious psychiatric conditions, medical complications, and even death.\n\nThe unpredictability is a key danger: unlike natural cannabis with relatively predictable THC content, synthetic products contain unknown concentrations of multiple active compounds, any of which could produce toxic effects. As regulations ban specific compounds, manufacturers modify the chemical structure slightly, creating new untested substances.","whyItMatters":"Synthetic cannabinoids remain widely available despite regulatory efforts, and users often underestimate the risk because they view them as a form of cannabis. This review makes clear that synthetic cannabinoids are a fundamentally different and more dangerous class of drugs that happen to target the same receptors.","specificNumbers":"Synthetic cannabinoids bind cannabinoid receptors with higher potency than THC. Adverse effects include: respiratory difficulties, hypertension, tachycardia, chest pain, acute renal failure, psychosis, suicidal ideation. Chronic use associated with death. Continuous chemical modification circumvents regulation.","methodology":"Narrative review of current literature on the epidemiology, acute effects, and chronic effects of synthetic and natural cannabinoid drugs, conducted from a public health perspective.","limitations":"This is a narrative review and does not systematically assess the quality of included studies. Adverse effect data come largely from case reports and poison control data rather than controlled studies. The rapidly evolving landscape of synthetic cannabinoids means any review quickly becomes outdated. Prevalence data are likely underestimates due to underreporting."},{"rthcId":"RTHC-01624","title":"Longitudinal assessment of the effect of cannabis use on hospital readmission rates in early psychosis: A 6-year follow-up in an inpatient cohort.","authors":"Colizzi, Marco; Burnett, Natoy; Costa, Rosalia; De Agostini, Mattia; Griffin, James; Bhattacharyya, Sagnik","year":2018,"journal":"Psychiatry research, 268, 381-387","doi":"10.1016/j.psychres.2018.08.005","pmid":"30121541","tags":["psychosis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 161 patients admitted to an early psychosis intervention unit for 6 years, tracking hospital readmissions and total time spent hospitalized. Cannabis use was extremely common, with 62.4% reporting lifetime use at admission.\n\nCannabis use significantly predicted both the number of subsequent hospital readmissions and the total length of stay over the following 6 years. This relationship remained significant even after adjusting for use of other substances, indicating that cannabis had an independent effect on psychosis outcomes.\n\nThe impact was not evenly distributed across demographics. Male patients who used cannabis had particularly longer hospital stays compared to females. Black patients who used cannabis also had longer stays compared to other ethnic groups. These demographic disparities within the cannabis-using psychosis population highlight additional vulnerability factors.\n\nThe average patient had 2.2 readmissions over 6 years, spending a total of 197 days in the hospital, representing an enormous burden on both patients and healthcare systems.","whyItMatters":"Hospital readmission is one of the most concrete and costly outcomes in psychosis care. This study demonstrates that cannabis use at the first psychosis admission has lasting consequences for the disease trajectory, predicting worse outcomes for years to come. The economic implications are substantial.","specificNumbers":"161 early psychosis patients. 62.4% had lifetime cannabis use. Average initial admission: 54.3 days. Over 6 years: 2.2 readmissions on average, 197.4 total hospital days. Cannabis predicted more readmissions and longer stays independent of other substance use. Male and Black patients most affected.","methodology":"Retrospective cohort study of 161 consecutive early psychosis inpatients. Cannabis use at admission and hospital readmission data (number of readmissions and total length of stay) over a 6-year follow-up were extracted from clinical records. Analyses adjusted for use of other substances.","limitations":"The retrospective design limits causal conclusions. Cannabis use was assessed at admission and may not reflect ongoing patterns. Readmission data does not capture outpatient functioning or community care. The study did not account for cannabis type, potency, or frequency. Racial disparities may reflect systemic healthcare factors rather than biological differences."},{"rthcId":"RTHC-01625","title":"Previous cannabis exposure modulates the acute effects of delta-9-tetrahydrocannabinol on attentional salience and fear processing.","authors":"Colizzi, Marco; McGuire, Philip; Giampietro, Vincent; Williams, Steve; Brammer, Mick; Bhattacharyya, Sagnik","year":2018,"journal":"Experimental and clinical psychopharmacology, 26(6), 582-598","doi":"10.1037/pha0000221","pmid":"30138003","tags":["tolerance","psychosis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Twenty-four healthy men participated in a double-blind THC challenge study, divided into 12 never-users (fewer than 5 lifetime joints) and 12 abstinent modest users (about 25 lifetime joints). Both groups received THC and placebo on separate occasions.\n\nThe never-users experienced significantly more THC-induced psychotic symptoms and behavioral impairment on attention tasks than the modest users. Under THC, never-users shifted to recruiting different brain areas to perform tasks, suggesting the drug fundamentally disrupted their normal brain processing patterns.\n\nModest cannabis users showed a different baseline pattern even under placebo: they processed attentional and emotional stimuli using different brain areas compared to never-users, suggesting lasting residual effects from their modest exposure history. However, when challenged with THC, their responses were more blunted and less disrupted.\n\nThe severity of psychotic symptoms and cognitive impairment from THC correlated with the degree of neurophysiological disruption, but only in never-users. Modest users showed an exposure-dependent tolerance that protected them from the worst acute effects.","whyItMatters":"This study provides neurobiological evidence for cannabis tolerance at remarkably low exposure levels. Even about 25 lifetime joints created measurable differences in how the brain responded to THC. This has implications for understanding why first-time or rare cannabis users may have more dramatic reactions, including psychotic symptoms.","specificNumbers":"24 healthy men: 12 non-users (<5 lifetime joints), 12 modest users (24.5 lifetime joints). THC-induced psychotic symptoms more pronounced in non-users (p < 0.04). Behavioral impairment greater in non-users. Non-users showed more neurophysiological disruption. Modest users showed residual brain function changes under placebo.","methodology":"Double-blind, randomized, placebo-controlled, repeated-measures, within-subject crossover study with fMRI. Twenty-four healthy men received THC challenge: 12 non-users (<5 lifetime joints) and 12 abstinent modest users (24.5 lifetime joints). Attentional salience and emotional processing were assessed behaviorally and neurophysiologically.","limitations":"The sample was small (24 participants) and exclusively male. The definition of \"modest\" use (about 25 joints) is arbitrary. The study cannot determine whether the blunted response in modest users represents true tolerance or selection bias (people less sensitive to THC may use more). Cross-sectional comparison of groups with different exposure histories limits causal inference."},{"rthcId":"RTHC-01626","title":"Modulation of acute effects of delta-9-tetrahydrocannabinol on psychotomimetic effects, cognition and brain function by previous cannabis exposure.","authors":"Colizzi, Marco; McGuire, Philip; Giampietro, Vincent; Williams, Steve; Brammer, Mick; Bhattacharyya, Sagnik","year":2018,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 28(7), 850-862","doi":"10.1016/j.euroneuro.2018.04.003","pmid":"29935939","tags":["tolerance","psychosis","cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Using the same 24-participant THC challenge design, this companion study focused on cognitive processing and psychotomimetic effects. Compared to never-users, abstinent modest cannabis users showed a complex profile of both residual effects and acquired tolerance.\n\nAt baseline (under placebo), modest users showed worse cognitive performance and stronger right-hemisphere brain activation during cognitive tasks. These residual effects persisted despite abstinence, suggesting lasting neural changes from even modest cannabis exposure.\n\nHowever, when both groups received THC, a reversal appeared. Acute THC produced greater psychotomimetic symptoms in never-users than in modest users. In never-users, the severity of THC-induced psychotic symptoms and cognitive impairment correlated directly with the degree of brain activity disruption, a relationship not seen in modest users.\n\nThe brain activity patterns revealed three distinct states: normal processing (never-users under placebo), acutely disrupted processing (never-users under THC), and an intermediate state seen in modest users that showed features of both adaptation and residual change.","whyItMatters":"This study reveals a paradox of modest cannabis use: it creates residual cognitive changes but also builds tolerance that buffers against the most dramatic acute effects of THC. This helps explain the clinical observation that cannabis-naive individuals are most at risk for acute psychotic reactions to cannabis.","specificNumbers":"24 healthy men. Modest users had worse cognitive performance under placebo (p < 0.047). Greater right-hemisphere activation in modest users during cognitive processing. Psychotomimetic symptoms greater in non-users under THC (p = 0.040). Brain activity pattern: intermediate state in modest users under THC.","methodology":"Double-blind, randomized, placebo-controlled, repeated-measures, within-subject crossover study with fMRI. Twenty-four healthy men: 12 non-users and 12 abstinent modest users. Cognitive processing, psychotomimetic symptoms, and brain activation patterns were measured under both THC and placebo conditions.","limitations":"Small sample of 24 male participants. The modest user group was defined by approximately 25 lifetime uses, an arbitrary threshold. Cannot separate true tolerance from pre-existing differences. Cross-sectional design limits causal conclusions. Only cognitive and psychotic symptom domains were assessed."},{"rthcId":"RTHC-01627","title":"Examination of Market Segmentation among Medical Marijuana Dispensaries.","authors":"Cooke, Alexis; Freisthler, Bridget; Mulholland, Elycia","year":2018,"journal":"Substance use & misuse, 53(9), 1463-1467","doi":"10.1080/10826084.2017.1413391","pmid":"29303392","tags":["legalization","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers applied niche-marketing theory to medical marijuana dispensaries, testing whether dispensaries attract different populations rather than simply serving local medical need. They surveyed 132 patients at four dispensaries in Long Beach, California.\n\nSignificant differences emerged between dispensaries in terms of patient race and medical conditions treated. Patients at different dispensaries had different demographic profiles, and these profiles did not match the demographics of the surrounding census tracts.\n\nPatients often traveled from outside the immediate area to reach their chosen dispensary, further suggesting that factors beyond simple proximity and medical need drove dispensary selection. This pattern is consistent with market segmentation, where dispensaries target specific customer types rather than serving the general medical population.\n\nThe findings raise questions about whether some dispensaries may be oriented toward recreational users seeking medical cards rather than genuinely targeting medical need.","whyItMatters":"As medical marijuana programs expand, understanding whether dispensaries serve genuine medical needs or function as de facto recreational outlets has policy implications. Evidence of market segmentation suggests that dispensary placement and regulation decisions should consider the actual customer base rather than assuming all dispensaries serve the same population.","specificNumbers":"132 patients surveyed at 4 dispensaries. Significant associations between dispensary and race (chi-squared = 31.219, p < 0.05). Significant associations between dispensary and medical condition (chi-squared = 22.123, p < 0.05). Patient demographics differed from surrounding community demographics at all 4 dispensaries.","methodology":"Exit surveys of 132 patients at four medical marijuana dispensaries in Long Beach, CA. Data collected included demographics, purchase information, medical condition, and home address. Patient demographics were compared across dispensaries and against census tract data for dispensary locations using chi-squared tests.","limitations":"Only 132 patients across 4 dispensaries in one city were studied. The small sample size limits generalizability. Exit survey methodology may not capture all customers. The study cannot definitively distinguish between medical need-driven and market-driven dispensary selection. Self-reported medical conditions were not verified."},{"rthcId":"RTHC-01628","title":"The effect of interactions between genetics and cannabis use on neurocognition. A review.","authors":"Cosker, E; Schwitzer, T; Ramoz, N; Ligier, F; Lalanne, L; Gorwood, P; Schwan, R; Laprévote, V","year":2018,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 82, 95-106","doi":"10.1016/j.pnpbp.2017.11.024","pmid":"29191570","tags":["cognition","genetics","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers systematically reviewed 13 studies examining how genetic variations influence the cognitive effects of cannabis use. The most consistent finding involved the COMT gene, which regulates dopamine breakdown in the prefrontal cortex.\n\nPeople with the Val variant of the COMT gene showed greater impairment in working memory, verbal and visual memory, and sustained attention during cannabis intoxication compared to those with the Met variant. The COMT gene also modulated sustained attention effects during regular cannabis use, not just acute intoxication.\n\nSeveral other genes showed potential modulatory effects: the CNR1 gene (encoding the CB1 receptor), the AKT1 gene (involved in dopamine signaling), the DBH gene (involved in norepinephrine synthesis), and the serotonin transporter gene (5-HTT/SLC6A4).\n\nThe review noted that most of these genes are also linked to schizophrenia risk, suggesting that the genetic factors determining how cannabis affects cognition may overlap with those determining vulnerability to cannabis-related psychosis.","whyItMatters":"Not everyone responds to cannabis the same way cognitively. Understanding the genetic basis of these differences could eventually enable personalized risk assessment, identifying individuals who are most vulnerable to cannabis-related cognitive impairment before they experience it.","specificNumbers":"13 studies included. Key gene: COMT Val allele associated with greater cognitive impairment during intoxication. Other modulatory genes identified: CNR1, AKT1, DBH, 5-HTT/SLC6A4. Cognitive domains affected: working memory, verbal memory, visual memory, sustained attention.","methodology":"Systematic search of PubMed, Web of Science, and ScienceDirect databases for studies measuring neurocognition and assessing genotypes in the context of cannabis use. Thirteen articles meeting inclusion criteria were reviewed.","limitations":"Only 13 studies were available, limiting the ability to draw firm conclusions. Most studies were small and used different cognitive assessments. Gene-gene interactions were not addressed. Environmental factors that interact with genetics were largely unexplored. Replication of findings across studies was limited."},{"rthcId":"RTHC-01629","title":"Efficacy of a Web-Based Tailored Intervention to Reduce Cannabis Use Among Young People Attending Adult Education Centers in Quebec.","authors":"Côté, José; Tessier, Sébastien; Gagnon, Hélène; April, Nicole; Rouleau, Geneviève; Chagnon, Miguel","year":2018,"journal":"Telemedicine journal and e-health : the official journal of the American Telemedicine Association, 24(11), 853-860","doi":"10.1089/tmj.2017.0144","pmid":"29466093","tags":["quitting","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers tested a theory-based, web-tailored intervention to reduce cannabis use among 588 young adults (ages 18-24) attending adult education centers in Quebec. Participants were randomly assigned to receive the intervention or serve as controls.\n\nAmong the 343 participants who had used cannabis in the past year, 10.8% in the experimental group reduced their use at follow-up compared to only 5.1% in the control group, a statistically significant difference.\n\nThe intervention also significantly increased intention to abstain from cannabis in the coming month. While the control group's intention remained stable, the experimental group showed a meaningful increase, suggesting the program successfully shifted attitudes and planned behavior.\n\nThe intervention was grounded in motivational interviewing and cognitive behavioral principles, with content tailored to each participant's risk profile, use patterns, and readiness to change.","whyItMatters":"Young adults who use cannabis frequently are often difficult to reach through traditional treatment programs. Web-based interventions can be delivered at scale, at low cost, and without the stigma associated with formal treatment. This study demonstrates that even a brief tailored online program can produce measurable reductions in cannabis use.","specificNumbers":"588 participants randomized (295 experimental, 293 control). 343 reported past-year cannabis use. Cannabis use reduction: 10.8% experimental vs 5.1% control (chi-squared = 9.89, p = 0.007). Intention to abstain: increased in experimental group (5.07 to 5.45), stable in controls (5.32 to 5.36; interaction p = 0.005).","methodology":"Randomized controlled trial with 588 young adults (18-24 years) from adult education centers in Quebec. Participants were randomly assigned to a web-based tailored intervention or control group. Cannabis use (primary outcome) and intention to abstain (secondary outcome) were assessed at baseline and post-intervention. Intention-to-treat analysis was used.","limitations":"The follow-up period was short, and it is unclear if reductions were sustained. The effect size was modest (about 6 percentage point difference). Self-reported cannabis use may be unreliable. The study was conducted in Quebec adult education centers, which may not represent all young adult populations. Attrition rates were not detailed."},{"rthcId":"RTHC-01630","title":"Parental Restriction of Movie Viewing Prospectively Predicts Adolescent Alcohol and Marijuana Initiation: Implications for Media Literacy Programs.","authors":"Cox, Melissa J; Gabrielli, Joy; Janssen, Tim; Jackson, Kristina M","year":2018,"journal":"Prevention science : the official journal of the Society for Prevention Research, 19(7), 914-926","doi":"10.1007/s11121-018-0891-8","pmid":"29717391","tags":["youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 1,023 adolescents to examine whether parental restrictions on movie viewing predicted subsequent substance use initiation. The results showed that restriction of R-rated movies specifically was protective against both alcohol and marijuana initiation at 1- and 2-year follow-ups.\n\nImportant nuances emerged within the R-rated restriction category. Adolescents allowed to watch R-rated movies with adult supervision were protected against substance use initiation. However, adolescents who watched R-rated movies despite parental restrictions were at heightened risk for alcohol initiation, suggesting that parental rule-breaking itself was a risk marker.\n\nChanges in parental movie restrictions over time were not predictive of substance use initiation over the subsequent year, suggesting that the initial level of restriction established the behavioral pattern.\n\nAll analyses controlled for important parental, personality, and behavioral factors that might confound the relationship, strengthening the argument that media restriction itself contributes to protection.","whyItMatters":"Youth are heavy consumers of media, and exposure to substance use in movies has been linked to real-world use. This study provides actionable evidence for parents: restricting R-rated movies, particularly when combined with supervised viewing of borderline content, appears to reduce the risk of adolescent substance use initiation.","specificNumbers":"1,023 adolescents studied with 1- and 2-year follow-up. R-rated movie restriction protective of both alcohol and marijuana initiation. Supervised R-rated viewing also protective. Watching R-rated movies despite restrictions heightened alcohol initiation risk. Changes in restrictions not predictive of subsequent-year outcomes.","methodology":"Longitudinal study of 1,023 adolescents with 1- and 2-year follow-up. Logistic regression assessed odds of alcohol and marijuana initiation across movie rating categories. Analyses controlled for parental, personality, and behavioral correlates of substance use.","limitations":"The observational design cannot prove causation. Parental movie restriction may be a marker of overall parenting quality rather than a direct cause of protection. Self-reported movie viewing and substance use may be inaccurate. The study predates the streaming era, and current media access patterns may produce different results."},{"rthcId":"RTHC-01631","title":"Longitudinal predictors of cigarette use among students from 24 Texas colleges.","authors":"Creamer, MeLisa R; Loukas, Alexandra; Clendennen, Stephanie; Mantey, Dale; Pasch, Keryn E; Marti, C Nathan; Perry, Cheryl L","year":2018,"journal":"Journal of American college health : J of ACH, 66(7), 617-624","doi":"10.1080/07448481.2018.1431907","pmid":"29419363","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01632","title":"Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age.","authors":"Crippa, José A; Guimarães, Francisco S; Campos, Alline C; Zuardi, Antonio W","year":2018,"journal":"Frontiers in immunology, 9, 2009","doi":"10.3389/fimmu.2018.02009","pmid":"30298064","tags":["cbd","medical-cannabis","anxiety","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Brazilian researchers who have been at the forefront of CBD research reviewed the translational evidence, from basic science to clinical application, for CBD across multiple neuropsychiatric conditions.\n\nThe most established properties of CBD include anxiolytic (anxiety-reducing), antipsychotic, and neuroprotective effects. These properties have been demonstrated in both preclinical models and human studies.\n\nBeyond these core effects, evidence was accumulating for CBD's potential in epilepsy (where it was approaching FDA approval), substance abuse and dependence, schizophrenia, social phobia, PTSD, depression, bipolar disorder, sleep disorders, and Parkinson's disease.\n\nThe review emphasized that CBD does not produce the typical subjective effects of marijuana, making it an attractive therapeutic candidate. Controlled clinical trials across these neuropsychiatric populations were underway at the time of publication, with results expected to support the translation of research findings to clinical practice.","whyItMatters":"CBD has emerged as one of the most promising therapeutic molecules from the cannabis plant, precisely because it lacks the psychoactive properties of THC. This review provides a comprehensive overview of the evidence base that has driven the rapid growth of CBD research and product development.","specificNumbers":"Established CBD properties: anxiolytic, antipsychotic, neuroprotective. Conditions with emerging evidence: epilepsy, substance abuse, schizophrenia, social phobia, PTSD, depression, bipolar disorder, sleep disorders, Parkinson's disease. Multiple controlled clinical trials underway.","methodology":"Non-systematic review of studies dealing with therapeutic applications of CBD, with particular emphasis on research performed by Brazilian investigators who have contributed significantly to the field.","limitations":"This is a non-systematic review with potential selection bias toward positive findings. Much of the evidence is preclinical. Clinical trial data were still forthcoming at the time of publication. The review does not critically assess the quality of individual studies. Dosing, formulation, and duration questions remain largely unanswered."},{"rthcId":"RTHC-01633","title":"Cannabis Use During the Perinatal Period in a State With Legalized Recreational and Medical Marijuana: The Association Between Maternal Characteristics, Breastfeeding Patterns, and Neonatal Outcomes.","authors":"Crume, Tessa L; Juhl, Ashley L; Brooks-Russell, Ashley; Hall, Katelyn E; Wymore, Erica; Borgelt, Laura M","year":2018,"journal":"The Journal of pediatrics, 197, 90-96","doi":"10.1016/j.jpeds.2018.02.005","pmid":"29605394","tags":["pregnancy","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from 3,207 Colorado women who completed the Pregnancy Risk Assessment Monitoring System survey with state-added cannabis questions. In a state where both medical and recreational marijuana were legal, 5.7% reported using cannabis at any point during pregnancy and 5% of breastfeeding women used it in the early postnatal period.\n\nPrenatal cannabis use was associated with a 50% increased likelihood of delivering a low birth weight baby, even after controlling for maternal age, race/ethnicity, education level, and tobacco use during pregnancy. This independent association was statistically significant.\n\nHowever, small for gestational age, preterm birth, and neonatal intensive care unit admission were not significantly associated with prenatal cannabis use after controlling for tobacco use. This suggests that while cannabis may affect fetal growth, it may not independently increase the risk of these other adverse outcomes.","whyItMatters":"Colorado was one of the first states to legalize recreational marijuana, making it a natural laboratory for studying the effects of legalization on perinatal cannabis use. The finding of a significant association with low birth weight in a population-based sample provides important evidence for prenatal counseling and screening.","specificNumbers":"3,207 Colorado women surveyed. Prenatal cannabis use: 5.7%. Postnatal use among breastfeeding mothers: 5.0%. Low birth weight: 50% increased likelihood with prenatal cannabis (OR 1.5, 95% CI 1.1-2.1, p = 0.02). No significant association with preterm birth, SGA, or NICU admission after controlling for tobacco.","methodology":"Cross-sectional analysis of 3,207 respondents from the 2014-2015 Colorado PRAMS survey with state-developed cannabis questions. Multiple logistic regression evaluated relationships between prenatal cannabis use and neonatal outcomes (low birth weight, small for gestational age, preterm birth, NICU admission), controlling for maternal demographics and tobacco use.","limitations":"Self-reported cannabis use likely underestimates true prevalence. The cross-sectional design limits causal conclusions. Cannabis use was measured dichotomously (any use during pregnancy) without capturing dose, frequency, or timing. The survey could not distinguish between different cannabis products or potencies. Residual confounding from unmeasured factors is possible."},{"rthcId":"RTHC-01634","title":"Adult Cellular Neuroadaptations Induced by Adolescent THC Exposure in Female Rats Are Rescued by Enhancing Anandamide Signaling.","authors":"Cuccurazzu, Bruna; Zamberletti, Erica; Nazzaro, Cristiano; Prini, Pamela; Trusel, Massimo; Grilli, Mariagrazia; Parolaro, Daniela; Tonini, Raffaella; Rubino, Tiziana","year":2018,"journal":"The international journal of neuropsychopharmacology, 21(11), 1014-1024","doi":"10.1093/ijnp/pyy057","pmid":"29982505","tags":["youth","depression","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Female rats exposed to THC during adolescence developed depressive-like behaviors and measurable brain changes in adulthood. Researchers tested whether boosting endocannabinoid levels by inhibiting the enzyme FAAH (which breaks down anandamide) could reverse these effects.\n\nThe FAAH inhibitor URB597 successfully rescued multiple brain changes caused by adolescent THC. In the prefrontal cortex, it restored deficits in endocannabinoid-mediated signaling and synaptic plasticity that had been disrupted by THC exposure. In the hippocampus, it recovered normal levels of neurogenesis (the birth of new neurons) in the dentate gyrus.\n\nCritically, the rescue of depressive-like behavior required functional CB1 receptors, confirming that the therapeutic effect operated through the endocannabinoid system. This suggests that adolescent THC exposure creates lasting deficits in endocannabinoid tone that can be corrected by boosting endocannabinoid levels in adulthood.","whyItMatters":"This study demonstrates that brain changes from adolescent cannabis exposure are not necessarily permanent and can potentially be reversed by pharmacological intervention in adulthood. The specific mechanism, restoring endocannabinoid tone, provides a therapeutic target for addressing the mood and cognitive consequences of adolescent cannabis use.","specificNumbers":"Adolescent THC caused: deficits in prefrontal endocannabinoid signaling, impaired synaptic plasticity, reduced hippocampal neurogenesis, depressive-like behavior. URB597 rescued: endocannabinoid signaling, synaptic plasticity, neurogenesis, depressive-like behavior. Rescue required CB1 receptor activity.","methodology":"Female rats received THC during adolescence. In adulthood, they received the FAAH inhibitor URB597 or vehicle. Biochemical, morphofunctional, and electrophysiological studies assessed endocannabinoid signaling and synaptic plasticity in the prefrontal cortex and neurogenesis in the hippocampal dentate gyrus.","limitations":"This is an animal study using female rats only, and results may not translate to humans. The THC exposure regimen may not reflect typical human adolescent use patterns. URB597 is a research tool, not a clinically available medication. The study assessed depressive-like behaviors, which are imperfect models of human depression. Long-term durability of the rescue was not assessed."},{"rthcId":"RTHC-01635","title":"Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: Reversal by cannabidiol.","authors":"da Silva, Vanessa Kappel; de Freitas, Betânia Souza; Dornelles, Victória Campos; Kist, Luiza Wilges; Bogo, Maurício Reis; Silva, Milena Carvalho; Streck, Emílio Luiz; Hallak, Jaime Eduardo; Zuardi, Antônio Waldo; Crippa, José Alexandre S; Schröder, Nadja","year":2018,"journal":"Brain research bulletin, 139, 1-8","doi":"10.1016/j.brainresbull.2018.01.014","pmid":"29374603","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Iron accumulation in the brain is recognized as a contributing factor in neurodegenerative diseases. Researchers used a rat model of brain iron overload, previously shown to cause severe memory deficits and oxidative stress, to test whether CBD could protect mitochondria.\n\nIron loading caused multiple forms of mitochondrial damage: deletions in mitochondrial DNA, decreased epigenetic regulation of mitochondrial DNA, reduced mitochondrial ferritin levels, and impaired succinate dehydrogenase activity (a key enzyme in cellular energy production).\n\nCBD treatment for 14 days in adulthood rescued several of these changes. It restored mitochondrial ferritin levels, recovered the epigenetic regulation of mitochondrial DNA, and normalized succinate dehydrogenase activity. These molecular-level rescues provide specific targets through which CBD may exert neuroprotective effects.\n\nThe findings support CBD as a potential disease-modifying agent rather than just a symptom manager in neurodegenerative diseases.","whyItMatters":"Neurodegenerative diseases like Parkinson's and Alzheimer's involve iron accumulation and mitochondrial dysfunction. Identifying specific molecular targets through which CBD protects mitochondria provides a mechanistic basis for developing CBD-based neuroprotective treatments, moving beyond the general claim of \"neuroprotection\" to specific biological pathways.","specificNumbers":"CBD treatment: 14 days in adulthood. Iron-induced changes rescued by CBD: mitochondrial ferritin levels, epigenetic modulation of mtDNA, succinate dehydrogenase activity. Iron-induced changes not fully rescued: mtDNA deletions (not reported as rescued).","methodology":"Rats received iron in the neonatal period to induce brain iron accumulation. In adulthood, they received CBD for 14 consecutive days. Mitochondrial DNA integrity, epigenetic modulation, mitochondrial ferritin levels, and succinate dehydrogenase activity were measured in brain tissue.","limitations":"This is an animal model of iron-induced neurodegeneration that may not fully replicate human neurodegenerative diseases. The iron loading was artificial, administered in the neonatal period. CBD dosing may not reflect clinically achievable brain concentrations in humans. Long-term effects and behavioral correlates were not assessed in this study."},{"rthcId":"RTHC-01636","title":"The perception of pre- and post-natal marijuana exposure on health outcomes: A content analysis of Twitter messages.","authors":"Dakkak, H; Brown, R; Twynstra, J; Charbonneau, K; Seabrook, J A","year":2018,"journal":"Journal of neonatal-perinatal medicine, 11(4), 409-415","doi":"10.3233/NPM-17133","pmid":"29843262","tags":["pregnancy","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers collected 550 tweets from Twitter's inception through April 2017 that discussed marijuana use during pregnancy or breastfeeding.\n\nThe majority of tweets (77.6%) had a neutral tone, suggesting widespread uncertainty about the health effects of cannabis exposure during pregnancy. The sources attached to tweets, however, were more likely to report negative health outcomes.\n\nThe most commonly reported risks of prenatal marijuana exposure were poor brain development (27.3%), inadequate nervous system development (23.6%), low birth weight (23.3%), poor behavioral outcomes (21.0%), and infant memory issues (19.3%).\n\nFor the breastfeeding period, the most frequently reported concern was the inverse association between marijuana use and the quality and quantity of breast milk.","whyItMatters":"Social media is increasingly where people get health information, especially on stigmatized topics they may not feel comfortable discussing with a doctor. Understanding what information is circulating on platforms like Twitter about cannabis and pregnancy reveals gaps in public health messaging.","specificNumbers":"550 tweets analyzed. 77.6% had neutral tone. Top prenatal concerns: brain development (27.3%), nervous system (23.6%), low birth weight (23.3%), behavior (21.0%), memory (19.3%).","methodology":"Content analysis of tweets collected from 2006 to April 2017 using search terms related to marijuana and pregnancy or infant health. All 550 captured tweets were coded for tone (positive, negative, neutral) and linked sources were examined for health outcome reporting.","limitations":"Twitter data captures public discourse, not health outcomes or actual use patterns. Tweets were collected through keyword searches which may have missed relevant discussions. The study could not determine whether tweet content influenced actual behavior. The analysis predates major changes in cannabis legalization and Twitter platform dynamics."},{"rthcId":"RTHC-01637","title":"Cannabinoids and glial cells: possible mechanism to understand schizophrenia.","authors":"de Almeida, Valéria; Martins-de-Souza, Daniel","year":2018,"journal":"European archives of psychiatry and clinical neuroscience, 268(7), 727-737","doi":"10.1007/s00406-018-0874-6","pmid":"29392440","tags":["psychosis","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"This review examined the intersection of two lines of research: glial cell dysfunction in schizophrenia and the endocannabinoid system's effects on glial cells.\n\nGlial cells, which include oligodendrocytes, microglia, and astrocytes, perform essential functions in the brain including myelination, metabolic support, and immune response. Impairments in these cells disrupt neuronal communication and homeostasis in ways implicated in schizophrenia.\n\nThe endocannabinoid system has been linked to schizophrenia pathophysiology through its modulation of dopaminergic and glutamatergic neurotransmission, both associated with positive, negative, and cognitive symptoms.\n\nCritically, glial cells express cannabinoid receptors and synthesize endocannabinoids. Cannabinoid drugs affect glial cell functions that are specifically disrupted in schizophrenia, suggesting these cells could be a pharmacological target for treatment.","whyItMatters":"Schizophrenia treatment has focused primarily on neurotransmitter systems. If glial cells represent an overlooked target, and cannabinoid drugs can modulate their function, this opens a potentially new therapeutic approach for a disorder that remains difficult to treat.","specificNumbers":"Three main glial cell types affected: oligodendrocytes, microglia, astrocytes. Endocannabinoid system modulates both dopaminergic and glutamatergic transmission implicated in schizophrenia.","methodology":"Narrative review synthesizing published research on glial cell changes in schizophrenia, endocannabinoid system involvement in the disorder, and the effects of cannabinoids on glial cell function.","limitations":"This is a narrative review synthesizing existing research rather than reporting new data. Much of the evidence connecting cannabinoids, glial cells, and schizophrenia comes from preclinical studies. The complexity of schizophrenia means that targeting one system may not translate to clinical benefit."},{"rthcId":"RTHC-01638","title":"The Psychiatric Consequences of Cannabinoids.","authors":"De Aquino, Joao P; Sherif, Mohamed; Radhakrishnan, Rajiv; Cahill, John D; Ranganathan, Mohini; D'Souza, Deepak C","year":2018,"journal":"Clinical therapeutics, 40(9), 1448-1456","doi":"10.1016/j.clinthera.2018.03.013","pmid":"29678279","tags":["mental-health","psychosis","anxiety","depression","withdrawal","addiction","cognition","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This overview examined the psychiatric effects of both plant-based and synthetic cannabinoids across different timeframes.\n\nAcutely, cannabinoids produce multiphasic, dose-dependent effects on anxiety, mood, and perception while impairing cognition and psychomotor function. In healthy individuals, these acute negative effects tend to be milder compared to people with pre-existing psychiatric conditions.\n\nWith chronic exposure, the probability of developing tolerance and dependence increases. A problematic pattern of use can lead to clinically significant impairment, and cessation in tolerant, dependent individuals produces a withdrawal syndrome.\n\nLong-term cannabis exposure has been linked to anxiety, psychotic, and mood disorders in the research literature. The authors noted that even with limitations in existing evidence, the plausibility of a causal relationship and the potential for long-term brain changes from regular exposure, especially in adolescents, warrant clinical attention.","whyItMatters":"With rising cannabis use rates and expanding legalization, clinicians and the public need a clear picture of the full spectrum of psychiatric effects, from single-use experiences through chronic exposure to withdrawal.","specificNumbers":"Effects are dose-dependent and multiphasic. Chronic use increases probability of tolerance, dependence, and withdrawal. Acute effects milder in healthy individuals vs. those with pre-existing psychiatric conditions.","methodology":"Commentary and overview synthesizing published literature on acute, chronic, and withdrawal-related psychiatric effects of plant-based and synthetic cannabinoids, with discussion of clinical implications.","limitations":"This is a commentary synthesizing existing literature rather than conducting new analysis. The authors acknowledge limitations in the existing evidence base. The review does not quantify absolute risk levels or differentiate effects by specific cannabinoid profiles, doses, or routes of administration."},{"rthcId":"RTHC-01639","title":"Psychosis and synthetic cannabinoids.","authors":"Deng, Huiqiong; Verrico, Christopher D; Kosten, Thomas R; Nielsen, David A","year":2018,"journal":"Psychiatry research, 268, 400-412","doi":"10.1016/j.psychres.2018.08.012","pmid":"30125871","tags":["synthetic-cannabinoids","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the clinical literature on psychotic symptoms following synthetic cannabinoid (SC) use.\n\nMultiple clinical reports documented induction of psychotic symptoms after consuming SC products, including both new-onset psychosis in people with no psychiatric history and psychotic relapses in those with prior episodes.\n\nThe review found that the relationship between SCs and psychosis is more complex than any single chemical component can explain. Unlike natural cannabis, SC products contain a constantly changing mix of potent full agonists at cannabinoid receptors, compared to THC which is a partial agonist.\n\nThe authors concluded that the psychotic effects of SCs may not be a simple extension of the typical effects of cannabis or natural cannabinoids, warranting distinct clinical consideration.","whyItMatters":"Synthetic cannabinoids are often misleadingly marketed as cannabis alternatives, but their pharmacology is fundamentally different and more dangerous. Understanding that SC-related psychosis operates through distinct mechanisms helps clinicians recognize and treat these cases appropriately.","specificNumbers":"SCs broadly impact psychological state (mood, suicidal thoughts, psychosis) and physiological functions (cardiovascular, gastrointestinal, urinary). Products have gained popularity as abused drugs over the past decade across many countries.","methodology":"Literature review of clinical reports, case studies, and pharmacological research on synthetic cannabinoid products and their association with psychotic symptoms, including analysis of chemical mechanisms.","limitations":"Much of the evidence comes from case reports and clinical observations rather than controlled studies. The constantly changing chemical composition of SC products makes it difficult to attribute effects to specific compounds. Confounding from polysubstance use is common in clinical reports."},{"rthcId":"RTHC-01640","title":"Rural and urban substance use differences: Effects of the transition to college.","authors":"Derefinko, Karen J; Bursac, Zoran; Mejia, Michael G; Milich, Richard; Lynam, Donald R","year":2018,"journal":"The American journal of drug and alcohol abuse, 44(2), 224-234","doi":"10.1080/00952990.2017.1341903","pmid":"28726520","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers tracked substance use among 431 college students from freshman through junior year, comparing rural and urban backgrounds.\n\nAs freshmen, rural students were less likely to use alcohol and marijuana than their urban counterparts. By junior year, rural students' rates had risen to match urban levels. This convergence suggests the college environment itself drives substance use increases regardless of background.\n\nTobacco showed a different pattern: no rural/urban differences overall, though rural minorities were more likely to use tobacco across all years.\n\nThe strongest predictor of future substance use across all years and all substances was perceived peer use. Students who believed their peers were using more alcohol, tobacco, or marijuana were significantly more likely to use that substance themselves in subsequent years.","whyItMatters":"The college transition represents a critical window for substance use escalation. Understanding that rural students catch up to urban peers suggests that campus culture and perceived norms may be more influential than pre-college background in shaping long-term use patterns.","specificNumbers":"431 students tracked (48% male). Rural students started with lower marijuana and alcohol use as freshmen. Rates converged by junior year. Perceived peer use was significant predictor across all substances and all years.","methodology":"Longitudinal cohort study of 431 undergraduate students (48% male) from a large public southeastern university. Self-reported substance use data collected yearly during freshman, sophomore, and junior years. Rural/urban background determined by hometown characteristics.","limitations":"Single university in the southeastern US may not generalize to other regions or institution types. Self-reported data is subject to recall and social desirability bias. Rural/urban classification was binary and may not capture the full spectrum of community types. Attrition over three years was not detailed."},{"rthcId":"RTHC-01641","title":"Primary Causes of Hospitalizations and Procedures, Predictors of In-hospital Mortality, and Trends in Cardiovascular and Cerebrovascular Events Among Recreational Marijuana Users: A Five-year Nationwide Inpatient Assessment in the United States.","authors":"Desai, Rupak; Shamim, Sofia; Patel, Krupa; Sadolikar, Ashish; Kaur, Vikram Preet; Bhivandkar, Siddhi; Patel, Smit; Savani, Sejal; Mansuri, Zeeshan; Mahuwala, Zabeen","year":2018,"journal":"Cureus, 10(8), e3195","doi":"10.7759/cureus.3195","pmid":"30402363","tags":["cardiovascular"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers analyzed the National Inpatient Sample, identifying over 2.3 million hospitalizations with a recorded history of recreational marijuana use from 2010 to 2014.\n\nThe most common psychiatric discharge diagnoses were mood disorders (20.6%), schizophrenia and other psychotic disorders (10.6%), and substance or alcohol-related disorders (10.4%). Suicide and intentional self-injury (3.6%) was the leading cause of emergency admission.\n\nAmong non-psychiatric diagnoses, the most common were diabetes with chronic complications (2.2%), acute myocardial infarction (1.2%), nonspecific chest pain (1.1%), and congestive heart failure (1%).\n\nThe top independent predictors of in-hospital mortality were coagulopathy (OR 5.94), acute myocardial infarction (OR 4.59), and pulmonary circulation disorder (OR 2.95). Major cardiovascular and cerebrovascular events showed increasing trends among users over the five-year period.","whyItMatters":"This is one of the largest analyses of hospitalization patterns among marijuana users. The finding that cardiovascular events are increasing among this population, and that cardiac events are strong predictors of in-hospital mortality, provides important safety signal data.","specificNumbers":"2,317,343 weighted hospitalizations analyzed. Top psychiatric: mood disorders 20.6%, schizophrenia 10.6%. Suicide/self-injury 3.6% of emergency admissions. AMI 1.2% of non-psychiatric diagnoses. Mortality predictors: coagulopathy OR 5.94, AMI OR 4.59, pulmonary circulation disorder OR 2.95.","methodology":"Retrospective analysis of the National Inpatient Sample (NIS) for 2010-2014, identifying hospitalizations with ICD-9 codes for recreational marijuana use. Descriptive statistics with discharge weights for national estimates. Multivariate regression for mortality predictors.","limitations":"The NIS captures associations, not causation. Marijuana use was identified by ICD-9 codes, which likely undercount actual users and may reflect documentation patterns rather than prevalence. The database cannot distinguish frequency, amount, or route of cannabis use. Confounders like tobacco use, obesity, and other substances were not fully separated from cannabis effects."},{"rthcId":"RTHC-01642","title":"Recommendations From Cannabis Dispensaries About First-Trimester Cannabis Use.","authors":"Dickson, Betsy; Mansfield, Chanel; Guiahi, Maryam; Allshouse, Amanda A; Borgelt, Laura M; Sheeder, Jeanelle; Silver, Robert M; Metz, Torri D","year":2018,"journal":"Obstetrics and gynecology, 131(6), 1031-1038","doi":"10.1097/AOG.0000000000002619","pmid":"29742676","tags":["pregnancy","medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers used a mystery caller approach to contact 400 randomly selected Colorado dispensaries. The caller stated she was 8 weeks pregnant and experiencing morning sickness.\n\n69% of dispensaries recommended cannabis products for first-trimester nausea. Medical dispensaries were most likely to recommend use (83.1%), compared to retail (60.4%) and dual-licensed (61.7%) dispensaries.\n\n65% of dispensaries based their recommendations on personal opinion rather than scientific evidence. 36% stated that cannabis use is safe during pregnancy.\n\n81.5% of dispensaries ultimately recommended discussing cannabis use with a healthcare provider, but only 31.8% made this recommendation without being prompted by the caller. The rest only suggested it when the caller specifically asked.","whyItMatters":"Cannabis dispensaries are a primary point of contact for people seeking cannabis products, including pregnant women. The finding that most dispensaries recommended cannabis for morning sickness based on personal opinion, with few proactively suggesting medical consultation, highlights a significant gap in prenatal safety communication.","specificNumbers":"400 dispensaries contacted. 69% recommended cannabis for morning sickness. Medical 83.1% vs. retail 60.4% vs. dual 61.7%. 65% based on personal opinion. 36% said cannabis is safe in pregnancy. Only 31.8% unprompted suggested talking to a provider.","methodology":"Statewide cross-sectional study using a mystery caller approach. 400 dispensaries randomly selected from the Colorado Department of Revenue Enforcement Division website. Recommendations compared by license type (medical, retail, both) and location (rural vs. urban).","limitations":"Single state (Colorado) study may not reflect dispensary practices in other states. The mystery caller method captures one interaction point and may not reflect advice given during in-person visits. The study cannot determine whether dispensary recommendations actually influence pregnant people's behavior. Published in 2018, and dispensary training requirements may have changed since."},{"rthcId":"RTHC-01643","title":"BET 1: Haloperidol in cannabinoid hyperemesis syndrome.","authors":"Dida, Joana; Walji, Noorin","year":2018,"journal":"Emergency medicine journal : EMJ, 35(11), 711-712","doi":"10.1136/emermed-2018-208170.1","pmid":"30337420","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01644","title":"Beneficial Effect of Alcohol Withdrawal on Gut Permeability and Microbial Translocation in Patients with Alcohol Use Disorder.","authors":"Donnadieu-Rigole, Hélène; Pansu, Nathalie; Mura, Thibault; Pelletier, Stéphanie; Alarcon, Régis; Gamon, Lucie; Perney, Pascal; Apparailly, Florence; Lavigne, Jean-Philippe; Dunyach-Remy, Catherine","year":2018,"journal":"Alcoholism, clinical and experimental research, 42(1), 32-40","doi":"10.1111/acer.13527","pmid":"29030980","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01645","title":"The Legalization of Medical/Recreational Marijuana: Implications for School Health Drug Education Programs.","authors":"Donnelly, Joseph; Young, Michael","year":2018,"journal":"The Journal of school health, 88(9), 693-698","doi":"10.1111/josh.12669","pmid":"30133781","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01646","title":"The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain.","authors":"Donvito, Giulia; Nass, Sara R; Wilkerson, Jenny L; Curry, Zachary A; Schurman, Lesley D; Kinsey, Steven G; Lichtman, Aron H","year":2018,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(1), 52-79","doi":"10.1038/npp.2017.204","pmid":"28857069","tags":["pain","neuroscience","medical-cannabis","inflammation","drug-interactions"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This comprehensive review examined the entire endocannabinoid system as a source of pain treatment targets, covering CB1 and CB2 receptors plus the enzymes that make and break down endocannabinoids (FAAH and MAGL).\n\nIn preclinical models, cannabinoid receptor agonists and inhibitors of endocannabinoid-regulating enzymes (FAAH and MAGL) produced reliable antinociceptive (pain-reducing) effects across multiple inflammatory and neuropathic pain models.\n\nA particularly notable finding: these compounds offered opioid-sparing effects, meaning they could reduce the amount of opioid medication needed for pain control.\n\nClinical studies showed that medicinal cannabis or cannabinoid-based medications relieve pain in cancer, multiple sclerosis, and fibromyalgia. However, clinical data had not yet demonstrated analgesic efficacy for FAAH or MAGL inhibitors in human trials.\n\nThe gap between strong preclinical results and limited clinical translation for enzyme inhibitors remained a key challenge in the field.","whyItMatters":"The opioid crisis has created urgent need for alternative pain medications. The endocannabinoid system represents a parallel pain-modulating pathway, and the finding that cannabinoid-based approaches can spare opioid use is particularly significant for patients with chronic pain conditions.","specificNumbers":"Key targets: CB1 and CB2 receptors, FAAH enzyme, MAGL enzyme. Clinical efficacy shown for: cancer pain, MS pain, fibromyalgia. Opioid-sparing effects demonstrated in preclinical models.","methodology":"Comprehensive review of preclinical and clinical evidence on endocannabinoid system targets for pain, covering CB1/CB2 receptor agonists, FAAH inhibitors, and MAGL inhibitors across inflammatory and neuropathic pain models.","limitations":"The gap between preclinical promise and clinical results for enzyme inhibitors is a significant concern. Cannabinoid receptor agonists carry side effect profiles including psychoactive effects. Long-term safety data for many of these approaches remains limited. Not all pain conditions were covered equally."},{"rthcId":"RTHC-01647","title":"Oral fluid testing for marijuana intoxication: enhancing objectivity for roadside DUI testing.","authors":"Doucette, Mitchell L; Frattaroli, Shannon; Vernick, Jon S","year":2018,"journal":"Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention, 24(1), 78-80","doi":"10.1136/injuryprev-2016-042264","pmid":"28572268","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01648","title":"Acute Marijuana Intoxication in Children.","authors":"Dowd, M Denise","year":2018,"journal":"Pediatric annals, 47(12), e474-e476","doi":"10.3928/19382359-20181119-02","pmid":"30543374","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01649","title":"Pre- and postnatal tobacco and cannabis exposure and child behavior problems: Bidirectional associations, joint effects, and sex differences.","authors":"Eiden, Rina D; Zhao, Junru; Casey, Meghan; Shisler, Shannon; Schuetze, Pamela; Colder, Craig R","year":2018,"journal":"Drug and alcohol dependence, 185, 82-92","doi":"10.1016/j.drugalcdep.2017.11.038","pmid":"29428324","tags":["pregnancy","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 247 low-income mothers and their children from pregnancy through age 3, tracking prenatal substance exposure and child behavior problems.\n\nPrenatal tobacco exposure showed stronger effects in girls: girls in the tobacco-exposed group had higher internalizing problems, anxiety/depression, and attention problems compared to other groups. The association between cigarettes per day during pregnancy and behavioral problems at age 3 was stronger for girls than boys.\n\nA particularly striking finding was a bidirectional relationship between maternal cannabis use and child behavior. Higher maternal cannabis use during the infant-toddler period predicted higher behavior problems at age 2. But the relationship went both ways: those behavior problems at age 2 then predicted higher maternal cannabis use a year later, suggesting a feedback loop.\n\nThe joint effects of tobacco and cannabis exposure did not consistently produce worse outcomes than tobacco alone.","whyItMatters":"The bidirectional finding is clinically important: not only does maternal substance use affect child behavior, but difficult child behavior may drive increased maternal substance use, creating a cycle that could escalate without intervention targeting both the parent and child.","specificNumbers":"247 mother-child pairs. Three groups: tobacco + cannabis (97), tobacco only (81), control (69). Assessments at each trimester and 5 postnatal timepoints through age 3. Girls showed stronger effects than boys for prenatal tobacco exposure.","methodology":"Longitudinal cohort study of 247 mothers and children (97 prenatal tobacco + cannabis, 81 tobacco only, 69 non-exposed). Assessed during each trimester and at 2, 9, 16 months, 2 years, and 3 years. Primarily young, unmarried, low-income, minority participants.","limitations":"Sample was primarily low-income, young, and minority, limiting generalizability. The three groups (tobacco+cannabis, tobacco only, control) could not fully separate individual substance effects. Cannabis use was self-reported. The sample size limited statistical power for detecting smaller effects and interaction terms."},{"rthcId":"RTHC-01650","title":"Factors associated with successful vs. unsuccessful smoking cessation: Data from a nationally representative study.","authors":"El-Khoury Lesueur, Fabienne; Bolze, Camille; Melchior, Maria","year":2018,"journal":"Addictive behaviors, 80, 110-115","doi":"10.1016/j.addbeh.2018.01.016","pmid":"29407680","tags":["quitting","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from a nationally representative French survey of 2,110 current or former smokers, comparing three groups: those who never quit or quit less than 6 months, unsuccessful quitters (relapsed after 6+ months), and successful quitters (abstinent 6+ months).\n\nBoth successful and unsuccessful quitting shared common predictors: no cannabis use, older age, and intermediate or high occupational grade.\n\nFactors that specifically distinguished successful quitters from unsuccessful ones were no e-cigarette use, no environmental tobacco smoke exposure, fear of health consequences, perceived harmfulness of smoking, high educational attainment, and good overall health.\n\nNotably, cannabis use was associated with both failed quit attempts and never quitting, suggesting it is a barrier to smoking cessation regardless of the quit trajectory.","whyItMatters":"Identifying what differentiates successful from unsuccessful quitters helps target interventions. The finding that cannabis use is a barrier to smoking cessation is particularly relevant as cannabis legalization expands and dual use becomes more common.","specificNumbers":"4,342 adults surveyed, 2,110 current/former smokers analyzed. Three-group comparison. No cannabis use associated with both successful and unsuccessful cessation vs. not quitting. E-cigarette use associated with unsuccessful rather than successful quitting.","methodology":"Cross-sectional analysis of the DePICT nationally representative telephone survey of 4,342 French adults aged 18-64. Among 2,110 current or former smokers, multinomial logistic regression compared predictors of no quit attempt, unsuccessful cessation, and successful cessation.","limitations":"Cross-sectional design cannot establish temporal relationships. Self-reported data subject to recall bias. French population may not generalize to other countries with different cannabis and tobacco use norms. E-cigarette technology and use patterns have evolved since data collection."},{"rthcId":"RTHC-01651","title":"Associations between childhood ADHD, gender, and adolescent alcohol and marijuana involvement: A causally informative design.","authors":"Elkins, Irene J; Saunders, Gretchen R B; Malone, Stephen M; Keyes, Margaret A; McGue, Matt; Iacono, William G","year":2018,"journal":"Drug and alcohol dependence, 184, 33-41","doi":"10.1016/j.drugalcdep.2017.11.011","pmid":"29402677","tags":["youth","addiction","cognition","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers studied 3,762 twins (64% identical) to determine whether childhood ADHD causally leads to adolescent substance use or whether shared genetic and environmental factors explain the link.\n\nChildren with more severe ADHD symptoms initiated alcohol and marijuana use earlier, escalated to frequent or heavy use faster, and developed more symptoms of substance use problems by age 17.\n\nFemales with more hyperactivity-impulsivity had higher alcohol consumption and progressed further toward daily marijuana use than males with similar symptoms.\n\nThe critical test: when identical twins who differed in ADHD severity were compared, the twin with more severe ADHD did not have significantly worse substance outcomes than their co-twin. This pattern suggests that shared genetics and family environment, rather than ADHD itself causing substance use, primarily explain the association.\n\nWhen other factors were controlled for, hyperactivity-impulsivity remained associated with both substances, and inattention remained specifically associated with marijuana but not alcohol.","whyItMatters":"This study uses a genetically informative design to address a fundamental question: does ADHD cause substance use problems, or do the same genes and environments that produce ADHD also increase substance use risk? The answer (mostly shared causes, not direct causation) has implications for prevention strategies.","specificNumbers":"3,762 twins studied (64% identical). ADHD predicted earlier initiation and faster escalation to frequent use by age 17. Females with hyperactivity-impulsivity showed higher alcohol and marijuana use than males. Twin difference analysis: non-significant, suggesting shared etiology.","methodology":"Three population-based twin samples (N=3,762, 64% monozygotic), including one oversampling females with ADHD. Childhood inattentive and hyperactive-impulsive symptoms predicted alcohol and marijuana outcomes by age 17. Twin difference analyses separated shared familial effects from within-pair (potentially causal) effects.","limitations":"ADHD symptoms were assessed retrospectively or by parent report, not clinical diagnosis. Substance use was assessed by age 17, which may miss later-developing patterns. The study focused on symptom dimensions rather than categorical ADHD diagnosis. Twin studies assume equal environments for identical and fraternal twins, which may not perfectly hold."},{"rthcId":"RTHC-01652","title":"Cannabis for pediatric epilepsy: protocol for a living systematic review.","authors":"Elliott, Jesse; DeJean, Deirdre; Clifford, Tammy; Coyle, Doug; Potter, Beth; Skidmore, Becky; Alexander, Christine; Repetski, Alexander E; McCoy, Bláthnaid; Wells, George A","year":2018,"journal":"Systematic reviews, 7(1), 95","doi":"10.1186/s13643-018-0761-2","pmid":"30021618","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01653","title":"Clinical and functional outcomes of cannabis use among individuals with anxiety disorders: A 3-year population-based longitudinal study.","authors":"Feingold, Daniel; Rehm, Jürgen; Factor, Hagai; Redler, Avigayil; Lev-Ran, Shaul","year":2018,"journal":"Depression and anxiety, 35(6), 490-501","doi":"10.1002/da.22735","pmid":"29486095","tags":["anxiety","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers analyzed data from 3,723 individuals with diagnosed anxiety disorders (social anxiety, panic disorder, generalized anxiety disorder, specific phobias) from the National Epidemiologic Survey on Alcohol and Related Conditions.\n\nIn unadjusted analysis, remission rates from anxiety disorders decreased with increasing levels of cannabis use, suggesting cannabis worsened outcomes.\n\nHowever, after adjusting for baseline confounders, the association between cannabis use and lower remission rates was no longer statistically significant. This means that pre-existing differences between cannabis users and non-users, not cannabis itself, likely explained the poorer outcomes.\n\nTwo specific exceptions emerged: individuals with cannabis use disorders were significantly more likely to report breaking up from a romantic relationship (OR 3.85) and repeatedly quitting school (OR 6.02) compared to non-users, even after adjustment.","whyItMatters":"This finding challenges the assumption that cannabis use worsens anxiety disorders. The disappearance of the association after controlling for baseline factors suggests that people who use cannabis already differ from non-users in ways that predict worse outcomes, independent of their cannabis use.","specificNumbers":"3,723 individuals with anxiety disorders. Unadjusted: lower remission with more cannabis use. Adjusted: no significant difference in remission. Cannabis use disorder linked to relationship breakup (OR 3.85) and quitting school (OR 6.02).","methodology":"Longitudinal analysis of Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Focused on 3,723 individuals with any anxiety disorder at Wave 1. Cannabis users and those with cannabis use disorders compared to non-users on remission, functioning, and quality of life at Wave 2 (approximately 3 years later), controlling for baseline confounders.","limitations":"Observational design cannot fully rule out residual confounding even after adjustment. Self-reported cannabis use and diagnostic assessments are subject to bias. The 3-year follow-up may be too short to detect longer-term effects. Cannabis use patterns (frequency, potency, cannabinoid profile) were not detailed."},{"rthcId":"RTHC-01654","title":"Medical Use of Cannabinoids.","authors":"Fraguas-Sánchez, Ana Isabel; Torres-Suárez, Ana Isabel","year":2018,"journal":"Drugs, 78(16), 1665-1703","doi":"10.1007/s40265-018-0996-1","pmid":"30374797","tags":["medical-cannabis","pain","epilepsy","cancer","neuroscience","cbd","inflammation","ptsd","appetite"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This extensive review covered the therapeutic landscape of cannabinoids across dozens of medical conditions.\n\nSix cannabinoid medications had already received regulatory approval: nabilone and dronabinol capsules for chemotherapy nausea and vomiting, dronabinol capsules and oral solution for anorexia, THC:CBD oromucosal spray (Sativex) for MS-related spasticity and cancer pain, and CBD oral solution (Epidiolex) for Dravet and Lennox-Gastaut epilepsy syndromes.\n\nBeyond approved uses, the review found evidence supporting potential applications in inflammatory and neuropathic pain, various cancer types (brain, breast, prostate), neurodegenerative diseases (Parkinson's, Huntington's, Alzheimer's), PTSD and anxiety disorders, irritable bowel syndrome, eye diseases, and substance abuse disorders (particularly alcohol and opioid).\n\nThe endocannabinoid system's involvement in energy balance, appetite, blood pressure, pain modulation, nausea, memory, learning, and immune response explains the breadth of potential therapeutic applications.","whyItMatters":"This review provides a single-source overview of where cannabinoid medicine stands across all major therapeutic areas. It distinguishes between approved uses with established evidence and emerging applications still under investigation, helping readers understand the full spectrum from proven to experimental.","specificNumbers":"Six approved cannabinoid medications. Conditions with evidence: pain (cancer, MS, fibromyalgia), epilepsy (Dravet, Lennox-Gastaut), chemotherapy nausea, anorexia, MS spasticity, cancer (brain, breast, prostate), neurodegeneration (Parkinson's, Huntington's, Alzheimer's), PTSD, anxiety, IBS, eye diseases, addiction (alcohol, opioid).","methodology":"Comprehensive narrative review of preclinical and clinical evidence on cannabinoid therapeutics, covering efficacy, safety, and tolerability data across multiple medical conditions. Includes review of approved medications and ongoing clinical trials.","limitations":"As a narrative review, this does not systematically assess evidence quality across all conditions. The breadth of coverage means individual conditions receive limited depth. Evidence strength varies dramatically across conditions, from approved medications to early preclinical work. Published in 2018, so recent clinical trial results are not included."},{"rthcId":"RTHC-01655","title":"The tamoxifen derivative ridaifen-B is a high affinity selective CB2 receptor inverse agonist exhibiting anti-inflammatory and anti-osteoclastogenic effects.","authors":"Franks, Lirit N; Ford, Benjamin M; Fujiwara, Toshifumi; Zhao, Haibo; Prather, Paul L","year":2018,"journal":"Toxicology and applied pharmacology, 353, 31-42","doi":"10.1016/j.taap.2018.06.009","pmid":"29906493","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01656","title":"Proof of active cannabis use comparing 11-hydroxy-∆9-tetrahydrocannabinol with 11-nor-9-carboxy-tetrahydrocannabinol concentrations.","authors":"Franz, Thomas; Skopp, Gisela; Schwarz, Gerlinde; Musshoff, Frank","year":2018,"journal":"Drug testing and analysis, 10(10), 1573-1578","doi":"10.1002/dta.2415","pmid":"29845743","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01657","title":"Cannabis Dampens the Effects of Music in Brain Regions Sensitive to Reward and Emotion.","authors":"Freeman, Tom P; Pope, Rebecca A; Wall, Matthew B; Bisby, James A; Luijten, Maartje; Hindocha, Chandni; Mokrysz, Claire; Lawn, Will; Moss, Abigail; Bloomfield, Michael A P; Morgan, Celia J A; Nutt, David J; Curran, H Valerie","year":2018,"journal":"The international journal of neuropsychopharmacology, 21(1), 21-32","doi":"10.1093/ijnp/pyx082","pmid":"29025134","tags":["neuroscience","dopamine","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers gave 16 cannabis users three different treatments across separate sessions: cannabis with CBD, cannabis without CBD, and placebo, then measured brain responses to music using fMRI.\n\nCannabis without CBD dampened the brain's response to music in several key regions: bilateral auditory cortex, right hippocampus, right amygdala, and right ventral striatum (a core reward region). Activity in the ventral striatum correlated with how much pleasure participants reported from music.\n\nCritically, cannabis with CBD did not differ from placebo on any brain imaging measures. CBD appeared to restore the functional connectivity between the ventral striatum and auditory cortex that THC-only cannabis disrupted.\n\nParadoxically, both types of cannabis increased participants' subjective ratings of wanting to listen to music and enhanced their sound perception, even though the brain's reward circuitry was less responsive.","whyItMatters":"This is one of the first studies to show that cannabis can dampen the brain's natural reward response to a pleasurable activity, which may help explain the motivational and anhedonia effects some users experience. The finding that CBD offsets this dampening adds to evidence that the CBD content of cannabis matters for its effects on reward processing.","specificNumbers":"16 cannabis users. Three sessions (cannabis+CBD, cannabis alone, placebo). Cannabis dampened response in auditory cortex (p=.005/.008), hippocampus (p=.025), amygdala (p=.025), ventral striatum (p=.033). CBD restored striatal-auditory connectivity (p=.003/.030).","methodology":"Double-blind, placebo-controlled crossover study. 16 cannabis users inhaled cannabis with CBD, cannabis without CBD, and placebo across 3 sessions. fMRI measured brain responses to music vs. scrambled sound controls. Regions of interest identified from a meta-analysis of music-evoked reward and emotion.","limitations":"Small sample size (16 participants) limits statistical power and generalizability. All participants were existing cannabis users, so results may not apply to naive users. The cannabis preparations used specific THC and CBD doses that may not reflect real-world products. Music preference was not individualized."},{"rthcId":"RTHC-01658","title":"Do characteristics of marijuana use correspond to overall health levels for medical marijuana patients?","authors":"Freisthler, Bridget; Cooke, Alexis","year":2018,"journal":"Journal of substance use, 23(3), 307-311","doi":"10.1080/14659891.2017.1394383","pmid":"30881220","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 312 medical marijuana patients recruited from 16 dispensaries across Los Angeles.\n\nPatients who smoked marijuana (vs. other consumption methods), had more medical conditions for which they received their recommendation, and used marijuana more times per day reported lower levels of general health.\n\nThe number of days using marijuana per month was associated with worse health over the past year.\n\nThe authors noted that medical marijuana use did not appear to improve overall health status based on these results, but emphasized that the cross-sectional design means the direction of causation is unknown. Sicker patients likely use marijuana more frequently and for more conditions, rather than marijuana use necessarily making them sicker.","whyItMatters":"As medical marijuana use becomes more widespread, understanding the relationship between use patterns and health outcomes matters. This study highlights the challenge of confounding by indication: sicker people use more medical marijuana, making it appear that marijuana is associated with worse health.","specificNumbers":"312 patients from 16 dispensaries. Smoking method, more medical conditions, and more daily uses all associated with lower general health. More days per month associated with worse past-year health change.","methodology":"Cross-sectional survey of 312 patients from 16 medical marijuana dispensaries in Los Angeles. Short intercept survey plus longer patient survey covering health, use behaviors, preferences, and demographics. Hierarchical linear modeling accounted for patients nested within dispensaries.","limitations":"Cross-sectional design cannot establish causation or direction of association. Self-reported health measures are subjective. LA dispensary patients may not represent medical marijuana users elsewhere. No control group of non-users with similar conditions. Specific medical conditions and their severity were not detailed."},{"rthcId":"RTHC-01659","title":"Cannabis for the Treatment of Epilepsy: an Update.","authors":"Gaston, Tyler E; Szaflarski, Jerzy P","year":2018,"journal":"Current neurology and neuroscience reports, 18(11), 73","doi":"10.1007/s11910-018-0882-y","pmid":"30194563","tags":["epilepsy","cbd","medical-cannabis","drug-interactions"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This review compiled all available evidence on cannabis-derived treatments for epilepsy, from artisanal products through FDA-approved purified CBD.\n\nWhile artisanal CBD products showed high rates of reported seizure improvement in surveys and retrospective studies, these lacked controlled dosing and rigorous design.\n\nThe stronger evidence came from open-label expanded access programs (EAPs) and randomized controlled trials of highly purified CBD (Epidiolex). The EAPs showed significant seizure frequency improvement across various treatment-resistant epilepsy types. The RCTs demonstrated significant seizure reduction compared to placebo specifically in Dravet syndrome and Lennox-Gastaut syndrome.\n\nImportant safety findings: the most common side effects were diarrhea and sedation, with sedation much more common in patients also taking clobazam. Liver enzyme elevations occurred, particularly in patients also taking valproate. CBD significantly increases levels of N-desmethylclobazam (clobazam's active metabolite) through CYP2C19 inhibition. Other possible interactions were identified with rufinamide, zonisamide, topiramate, and eslicarbazepine.","whyItMatters":"This review documents the journey from anecdotal reports to FDA approval for CBD in epilepsy, one of the most significant developments in cannabinoid medicine. The detailed drug interaction data is critical for clinicians managing patients on multiple anti-epileptic drugs.","specificNumbers":"RCTs showed significant seizure reduction vs. placebo in Dravet and Lennox-Gastaut syndromes. Most common side effects: diarrhea and sedation. CBD inhibits CYP2C19, increasing N-desmethylclobazam levels. Possible interactions with rufinamide, zonisamide, topiramate, eslicarbazepine.","methodology":"Comprehensive review of published evidence on CBD for epilepsy, including artisanal product surveys, open-label expanded access programs, randomized placebo-controlled trials, and pharmacokinetic interaction studies.","limitations":"Much of the artisanal product evidence comes from surveys and uncontrolled studies. The RCTs focused on two specific epilepsy syndromes and may not generalize to all epilepsy types. Long-term safety data was still accumulating at the time of publication. The review does not cover THC-containing preparations in detail."},{"rthcId":"RTHC-01660","title":"Δ9-Tetrahydrocannabinol-like discriminative stimulus effects of five novel synthetic cannabinoids in rats.","authors":"Gatch, Michael B; Forster, Michael J","year":2018,"journal":"Psychopharmacology, 235(3), 673-680","doi":"10.1007/s00213-017-4783-6","pmid":"29138877","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01661","title":"Gene variants and educational attainment in cannabis use: mediating role of DNA methylation.","authors":"Gerra, Maria Carla; Jayanthi, Subramaniam; Manfredini, Matteo; Walther, Donna; Schroeder, Jennifer; Phillips, Karran A; Cadet, Jean Lud; Donnini, Claudia","year":2018,"journal":"Translational psychiatry, 8(1), 23","doi":"10.1038/s41398-017-0087-1","pmid":"29353877","tags":["genetics","neuroscience","addiction"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Researchers compared genetic variants and DNA methylation patterns between 40 cannabis users and 96 control subjects.\n\nA variant in the CNR1 gene (which codes for the CB1 cannabinoid receptor) was significantly associated with cannabis use (p=0.01). A trend was also observed for a variant in the CNR2 gene (CB2 receptor, p=0.058).\n\nCannabis users showed significantly higher DNA methylation at two specific locations: exon 8 of the DRD2 gene (dopamine D2 receptor, p=0.034) and a CpG-rich region of the NCAM1 gene (neural cell adhesion molecule, p=0.0004). Higher methylation typically means reduced gene expression.\n\nHigher education level appeared to decrease the risk of cannabis use, and females were less likely to use cannabis than males.\n\nThe researchers noted that the altered methylation could be either a pre-existing marker that predisposes to cannabis use or a consequence of long-term cannabis exposure.","whyItMatters":"This study connects three levels of biology: genetic variants (DNA sequence), epigenetics (DNA methylation), and behavior (cannabis use). The finding that dopamine receptor gene methylation differs in cannabis users provides a potential biological mechanism for how cannabis use might alter brain reward circuitry.","specificNumbers":"40 cannabis users vs. 96 controls. CNR1 rs1049353 significantly associated (p=0.01). DRD2 exon 8 hypermethylated in users (p=0.034). NCAM1 CpG region hypermethylated (p=0.0004). Females less likely to use. Higher education protective.","methodology":"Case-control candidate gene association study with 40 cannabis users and 96 controls. Examined variants in ANKK1, NCAM1, CNR1, and CNR2 genes. DNA methylation analyzed using MeDIP-qPCR at candidate regions in dopaminergic and endocannabinoid pathway genes.","limitations":"Small sample size (40 users) limits statistical power and increases risk of false positives. Cross-sectional design cannot determine whether methylation differences preceded or followed cannabis use. Candidate gene approach examines only pre-selected genes, missing genome-wide effects. Confounders like tobacco and alcohol use were not fully detailed."},{"rthcId":"RTHC-01662","title":"Mortality risk in a sample of emergency department patients who use cocaine with alcohol and/or cannabis.","authors":"Gilmore, Devin; Zorland, Jennifer; Akin, Joanna; Johnson, J Aaron; Emshoff, James G; Kuperminc, Gabriel P","year":2018,"journal":"Substance abuse, 39(3), 266-270","doi":"10.1080/08897077.2017.1389799","pmid":"28991520","tags":["cardiovascular","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 1,669 patients from two urban emergency departments and tracked mortality over 36 months using the National Death Index.\n\nThe use of cocaine and cannabis, both individually and in combination, was associated with significantly higher mortality risk compared to other ED patients after controlling for demographics.\n\nThis mortality risk was present whether cocaine and cannabis were used separately or together, suggesting that both substances independently contribute to elevated risk in this population.\n\nThe authors noted that further research was needed to determine whether these results were stable across racial and ethnic groups.","whyItMatters":"Emergency department patients who use substances represent a high-risk population. Quantifying the mortality risk associated with specific substance use patterns helps prioritize intervention efforts and informs clinical decision-making during ED visits.","specificNumbers":"1,669 ED patients surveyed. 36-month follow-up (2009-2012). Cocaine and cannabis use, individually and combined, associated with significantly higher mortality. Used ASSIST screening tool for risk categorization.","methodology":"Prospective cohort of 1,669 patients from 2 urban EDs surveyed using the ASSIST screening tool. 36-month mortality data obtained from the National Death Index (2009-2012). Cox regression modeled mortality by drug risk groups, controlling for demographics.","limitations":"ED patients are not representative of the general population. Mortality associations do not establish causation; substance users may have other risk factors driving mortality. The study could not fully separate the effects of polysubstance use. Specific causes of death were not detailed. Relatively small sample for mortality outcomes."},{"rthcId":"RTHC-01663","title":"Evaluation of Dräger DrugTest 5000 in a Naturalistic Setting.","authors":"Gjerde, Hallvard; Clausen, Grethe Brennhovd; Andreassen, Espen; Furuhaugen, Håvard","year":2018,"journal":"Journal of analytical toxicology, 42(4), 248-254","doi":"10.1093/jat/bky003","pmid":"29409046","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01664","title":"Trends in Cannabis and Cigarette Use Among Parents With Children at Home: 2002 to 2015.","authors":"Goodwin, Renee D; Cheslack-Postava, Keely; Santoscoy, Samantha; Bakoyiannis, Nina; Hasin, Deborah S; Collins, Bradley N; Lepore, Stephen J; Wall, Melanie M","year":2018,"journal":"Pediatrics, 141(6)","doi":"10.1542/peds.2017-3506","pmid":"29759986","tags":["legalization","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers analyzed nationally representative data from the National Survey on Drug Use and Health to track cannabis and cigarette use trends among parents with children at home from 2002 to 2015.\n\nPast-month cannabis use among parents increased from 4.9% in 2002 to 6.8% in 2015, while cigarette smoking declined from 27.6% to 20.2%.\n\nThe increase in cannabis use was most pronounced among cigarette-smoking parents, rising from 11.0% to 17.4%. Among non-smoking parents, cannabis use also increased but remained lower (2.4% to 4.0%).\n\nCannabis use was nearly 4 times more common among cigarette smokers versus non-smokers (17.4% vs. 4.0%), and daily cannabis use showed a similar disparity (4.6% vs. 0.8%).\n\nThe overall percentage of parents using either cigarettes or cannabis or both decreased from 29.7% to 23.5%, as the decline in smoking outpaced the increase in cannabis use.","whyItMatters":"Children's exposure to secondhand smoke in the home has been a major public health focus. As cigarette smoking declines but cannabis use rises among parents, public health messaging about secondhand exposure needs to expand to include cannabis smoke.","specificNumbers":"Cannabis use among parents: 4.9% (2002) to 6.8% (2015). Among smoking parents: 11.0% to 17.4%. Among non-smoking parents: 2.4% to 4.0%. Cannabis 4x more common in smokers vs. non-smokers (OR 3.88). Combined cigarette/cannabis parent use: 29.7% to 23.5%.","methodology":"Analysis of the National Survey on Drug Use and Health, an annual nationally representative cross-sectional study. Logistic regression estimated associations between cigarette smoking and cannabis use among parents with children at home from 2002 to 2015.","limitations":"Self-reported data may underestimate substance use. Cross-sectional annual surveys cannot track individual parents over time. Cannabis use was measured as any past-month use, not specifically use in the home or around children. Legalization status was not directly analyzed as a predictor."},{"rthcId":"RTHC-01665","title":"Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?","authors":"Grill, Magdalena; Hasenoehrl, Carina; Storr, Martin; Schicho, Rudolf","year":2018,"journal":"Medical cannabis and cannabinoids, 1(1), 28-35","doi":"10.1159/000489036","pmid":"34676319","tags":["medical-cannabis","inflammation","cancer","pain"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Researchers reviewed the evidence on cannabinoids for inflammatory bowel disease (IBD) and colorectal cancer.\n\nFor IBD, in vitro and animal data showed cannabinoids reduce intestinal inflammation through multiple mechanisms. However, clinical evidence was limited to patient questionnaires and small pilot studies. No approved cannabinoid medications exist for IBD.\n\nFor colorectal cancer, only preclinical data were available showing anti-tumor effects of cannabinoids, with no clinical studies in humans.\n\nThe review noted that currently approved cannabinoid medications (THC, dronabinol, nabilone) are used for pain, spasticity, and chemotherapy-induced nausea, not for IBD or cancer treatment. Medical cannabis authorization remained limited to a small number of countries.","whyItMatters":"IBD and colorectal cancer are significant health burdens with limited treatment options. While the preclinical data on cannabinoids is encouraging, this review clearly delineates the gap between laboratory promise and clinical evidence, informing patients and clinicians about the current state of knowledge.","specificNumbers":"Currently approved cannabinoid medications: THC/dronabinol/nabilone for nausea, dronabinol for anorexia, THC:CBD spray for MS spasticity and cancer pain, CBD for epilepsy. None indicated for IBD. Zero clinical trials for cannabinoids in colorectal cancer.","methodology":"Narrative review of preclinical and clinical literature on cannabinoids in intestinal inflammation and gastrointestinal carcinogenesis.","limitations":"Narrative review without systematic methodology. Heavy reliance on preclinical data for both conditions. The small pilot studies in IBD have significant methodological limitations. Cannabis self-medication by IBD patients is not well captured in clinical studies."},{"rthcId":"RTHC-01666","title":"Probing the endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity.","authors":"Grimm, Oliver; Löffler, Martin; Kamping, Sandra; Hartmann, Aljoscha; Rohleder, Cathrin; Leweke, Markus; Flor, Herta","year":2018,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 28(7), 841-849","doi":"10.1016/j.euroneuro.2018.04.004","pmid":"29887287","tags":["cbd","neuroscience","psychosis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Researchers conducted a crossover pharmacological fMRI study giving 16 healthy male volunteers placebo, 10mg oral THC, and 600mg oral CBD in separate sessions, then measuring resting-state brain connectivity.\n\nCBD significantly increased connectivity between frontal cortex regions and the striatum compared to placebo. This fronto-striatal circuit is important for executive functioning, decision making, salience generation, and motivation.\n\nContrary to expectations, THC did not show significant effects compared to placebo, which the researchers attributed to likely insufficient THC concentration in the brain during scanning (the oral dose may not have peaked in time).\n\nThe fronto-striatal connectivity enhanced by CBD is of particular interest because disruptions in this circuit are observed in schizophrenia and other neuropsychiatric conditions, potentially providing a neural correlate for CBD's reported antipsychotic effects.","whyItMatters":"Understanding how CBD affects brain connectivity in healthy volunteers provides a foundation for understanding its therapeutic potential. The specific enhancement of fronto-striatal connectivity, a circuit disrupted in psychosis, offers a plausible neural mechanism for CBD's antipsychotic effects seen in clinical studies.","specificNumbers":"16 healthy males. Three sessions: placebo, 10mg THC, 600mg CBD. CBD increased fronto-striatal connectivity vs. placebo. THC showed no significant effects (likely timing issue). 3T MRI scanner used.","methodology":"Double-blind, placebo-controlled crossover study. 16 healthy male volunteers received placebo, 10mg oral THC, and 600mg oral CBD across 3 sessions. Resting-state fMRI measured seed-voxel connectivity from caudate and putamen striatal regions. Scanned in a 3T scanner.","limitations":"Small sample size (16 males only). THC findings inconclusive due to likely dosing/timing issues. Single-session design cannot capture chronic effects. Resting-state connectivity does not directly measure functional outcomes. Healthy volunteers may respond differently than patients with neuropsychiatric conditions."},{"rthcId":"RTHC-01667","title":"Cannabis, from plant to pill.","authors":"Grof, Christopher P L","year":2018,"journal":"British journal of clinical pharmacology, 84(11), 2463-2467","doi":"10.1111/bcp.13618","pmid":"29701252","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01668","title":"Cannabis decriminalization: A study of recent policy change in five U.S. states.","authors":"Grucza, Richard A; Vuolo, Mike; Krauss, Melissa J; Plunk, Andrew D; Agrawal, Arpana; Chaloupka, Frank J; Bierut, Laura J","year":2018,"journal":"The International journal on drug policy, 59, 67-75","doi":"10.1016/j.drugpo.2018.06.016","pmid":"30029073","tags":["legalization","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Researchers examined the effects of cannabis decriminalization in five states (Massachusetts 2008, Connecticut 2011, Rhode Island 2013, Vermont 2013, Maryland 2014) using federal crime statistics and Youth Risk Behavior Survey data.\n\nDecriminalization was associated with a 75% reduction in drug-related arrests for youth (95% CI: 44-89%), with similar magnitude reductions for adult arrests.\n\nCritically, decriminalization was not associated with any increase in past-30-day cannabis use prevalence among youth. The relative change was -0.2% (95% CI: -4.5% to 4.3%), effectively zero. This finding held both overall and in each individual decriminalization state.\n\nThe results suggest that decriminalization achieved its intended consequence (reducing arrest burden) without the commonly feared unintended consequence (increased youth use).","whyItMatters":"This study directly addresses the central concern about cannabis decriminalization: that reducing penalties will increase use, especially among young people. The finding that arrests dropped dramatically while youth use remained unchanged provides important evidence for policy debates.","specificNumbers":"75% reduction in youth drug arrests (95% CI: 44-89%). Past-30-day youth cannabis use change: -0.2% (95% CI: -4.5% to 4.3%). Five states analyzed: MA (2008), CT (2011), RI (2013), VT (2013), MD (2014). Study period: 2007-2015.","methodology":"Difference-in-difference regression framework comparing trends in the five decriminalization states against states with no major cannabis policy changes during the observation period (2007-2015). Arrest data from federal crime statistics; youth use data from state Youth Risk Behavior Surveys.","limitations":"The observation period may be too short to capture longer-term changes in use patterns. Youth Risk Behavior Survey data is self-reported and school-based (misses dropouts). The five states may not represent all decriminalization contexts. The difference-in-difference approach assumes parallel trends would have continued without policy change."},{"rthcId":"RTHC-01669","title":"THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders.","authors":"Guennewig, Boris; Bitar, Maina; Obiorah, Ifeanyi; Hanks, James; O'Brien, Elizabeth A; Kaczorowski, Dominik C; Hurd, Yasmin L; Roussos, Panos; Brennand, Kristen J; Barry, Guy","year":2018,"journal":"Translational psychiatry, 8(1), 89","doi":"10.1038/s41398-018-0137-3","pmid":"29691375","tags":["neuroscience","psychosis","cognition","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers exposed neurons derived from human induced pluripotent stem cells (hiPSCs) to THC and analyzed the effects on gene expression.\n\nBoth acute and chronic THC exposure dampened the neurons' transcriptional response when stimulated with potassium chloride (which mimics neuronal activation). Essentially, THC-treated neurons failed to activate their genes appropriately in response to stimulation.\n\nThe gene expression changes in THC-treated neurons showed significant alterations in synaptic, mitochondrial, and glutamate signaling pathways. This blunted response pattern resembled effects previously observed in neurons derived from schizophrenia patients.\n\nAdditionally, the THC-affected genes showed significant overlap with genes associated with autism and intellectual disability, suggesting shared molecular pathways across neuropsychiatric disorders that are exacerbated by THC.","whyItMatters":"This study uses human neurons (derived from stem cells) rather than animal models, providing more relevant data on how THC affects human neural gene expression. The overlap between THC-induced changes and schizophrenia-associated patterns provides a molecular basis for understanding the cannabis-psychosis link.","specificNumbers":"Both acute and chronic THC exposure tested. Significant alterations in synaptic, mitochondrial, and glutamate signaling genes. THC-affected genes overlapped with genes associated with schizophrenia, autism, and intellectual disability.","methodology":"In vitro study using human iPSC-derived neurons exposed to THC acutely and chronically. RNA transcriptomic analysis compared gene expression profiles between THC-treated and vehicle-control neurons after potassium chloride-induced depolarization.","limitations":"In vitro iPSC-derived neurons do not fully replicate the complexity of neurons in a living brain. THC concentrations used may not match physiological brain levels during actual cannabis use. The study cannot determine whether these gene expression changes are reversible. iPSC neurons may represent a developmental stage different from adult neurons."},{"rthcId":"RTHC-01670","title":"In Vitro Model of Neuroinflammation: Efficacy of Cannabigerol, a Non-Psychoactive Cannabinoid.","authors":"Gugliandolo, Agnese; Pollastro, Federica; Grassi, Gianpaolo; Bramanti, Placido; Mazzon, Emanuela","year":2018,"journal":"International journal of molecular sciences, 19(7)","doi":"10.3390/ijms19071992","pmid":"29986533","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01671","title":"The Prevalence of Cannabinoid Hyperemesis Syndrome Among Regular Marijuana Smokers in an Urban Public Hospital.","authors":"Habboushe, Joseph; Rubin, Ada; Liu, Haoming; Hoffman, Robert S","year":2018,"journal":"Basic & clinical pharmacology & toxicology, 122(6), 660-662","doi":"10.1111/bcpt.12962","pmid":"29327809","tags":["withdrawal","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed patients aged 18-49 at the oldest public hospital in the United States, screening for those who smoked marijuana at least 20 days per month.\n\nOf 2,127 patients approached, 155 met the criteria of smoking 20 or more days per month. Among these frequent users, 32.9% (95% CI: 25.5-40.3%) met criteria for a phenomenon consistent with cannabinoid hyperemesis syndrome (CHS).\n\nCHS classification was based on reporting nausea and vomiting combined with rating hot showers as 5 or more on a 10-point relief scale. Hot shower relief is considered a hallmark symptom of CHS that distinguishes it from other causes of cyclic vomiting.\n\nExtrapolating to the general population, the researchers estimated that approximately 2.75 million Americans (95% CI: 2.13-3.38 million) may suffer annually from a phenomenon similar to CHS.","whyItMatters":"CHS has been considered rare, but this is the first study attempting to estimate its prevalence among heavy users. A 33% rate among daily smokers, if confirmed, would make CHS far more common than previously assumed and an important consideration for cannabis users and clinicians.","specificNumbers":"2,127 patients approached, 155 met daily smoking criteria. 32.9% (95% CI: 25.5-40.3%) met CHS criteria. Estimated 2.75 million Americans annually (2.13-3.38 million). Used 20+ days/month as frequent use cutoff.","methodology":"Cross-sectional questionnaire administered to a convenience sample of ED patients aged 18-49 at an urban public hospital. Screened for marijuana use 20+ days/month. CHS defined by nausea/vomiting plus hot shower relief rating of 5+/10. National prevalence extrapolated from sample.","limitations":"Convenience sample from a single urban ED is not representative of all cannabis users. The CHS classification relied on a proxy measure (hot shower relief rating) rather than clinical diagnosis. Self-reported marijuana use frequency may be inaccurate. The national prevalence extrapolation from a single-site ED sample is speculative. The survey could not rule out other causes of nausea and vomiting."},{"rthcId":"RTHC-01672","title":"The Consumption of Cannabis by Fibromyalgia Patients in Israel.","authors":"Habib, George; Avisar, Irit","year":2018,"journal":"Pain research and treatment, 2018, 7829427","doi":"10.1155/2018/7829427","pmid":"30140459","tags":["pain","medical-cannabis","sleep","depression","anxiety"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 383 fibromyalgia patients through Israeli Facebook support groups.\n\nOf respondents, 84% reported consuming cannabis, but only 44% had a medical cannabis license. Among licensed users, 55% bought additional cannabis beyond their medical allowance on the black market.\n\nSelf-reported benefits were high: 94% reported pain relief, 93% improved sleep quality, 87% improvement in depression, and 62% improvement in anxiety.\n\nThe average monthly consumption was 31.4 grams, with 80% smoking pure cannabis or cannabis mixed with tobacco. Only 12% reported adverse effects, and just 8% reported feeling dependent on cannabis.\n\n64% of cannabis-consuming patients worked full or part-time, and 74% reported driving as usual while using cannabis.","whyItMatters":"The extremely high rates of self-reported benefit highlight the disconnect between patient experience and the limited clinical trial evidence for cannabis in fibromyalgia. The finding that most users are unlicensed and many supplement medical allowances with black market purchases reveals the gap between medical cannabis regulation and actual patient behavior.","specificNumbers":"383 respondents out of 2,705 group members (14%). 84% used cannabis, 44% licensed. Average 31.4g/month. Pain relief 94%, sleep improvement 93%, depression improvement 87%, anxiety improvement 62%. Adverse effects 12%. Dependence reported 8%. 55% of licensed bought on black market.","methodology":"Anonymous Internet-based questionnaire posted to three large fibromyalgia Facebook groups in Israel. 383 of 2,705 group members responded (14% response rate). Questions covered demographics, cannabis use patterns, subjective effects, adverse effects, dependence, driving, and employment.","limitations":"Self-selected online survey sample with 14% response rate creates significant selection bias. No control group. Self-reported benefits cannot be separated from placebo effects. Facebook group members may be more cannabis-positive than the broader fibromyalgia population. No objective measures of pain, sleep, or mood."},{"rthcId":"RTHC-01673","title":"Medical Cannabis for the Treatment of Fibromyalgia.","authors":"Habib, George; Artul, Suheil","year":2018,"journal":"Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases, 24(5), 255-258","doi":"10.1097/RHU.0000000000000702","pmid":"29461346","tags":["pain","medical-cannabis","sleep"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers collected data from registries at two Israeli hospitals on fibromyalgia patients treated with medical cannabis.\n\nOf 30 identified patients, 26 were included. All completed the Revised Fibromyalgia Impact Questionnaire for the period before and after starting medical cannabis treatment.\n\nEvery patient reported significant improvement on every parameter of the questionnaire after commencing medical cannabis. The mean dosage was 26 grams per month with an average treatment duration of 10.4 months.\n\nRemarkably, 13 patients (50%) stopped taking all other fibromyalgia medications after starting medical cannabis. Only 8 patients (30%) experienced adverse effects, described as very mild.","whyItMatters":"While small and uncontrolled, the finding that 50% of patients could stop all other medications is clinically notable. Fibromyalgia medications often carry significant side effect burdens, and if cannabis can serve as a replacement therapy for some patients, this warrants investigation in controlled trials.","specificNumbers":"26 patients (73% female, mean age 37.8). Mean dose 26g/month. Mean duration 10.4 months. 100% improvement on all questionnaire parameters. 50% stopped all other medications. 30% had mild adverse effects.","methodology":"Retrospective observational study of 26 fibromyalgia patients (73% female, mean age 37.8) from registries at two Israeli hospitals. Patients completed the Revised Fibromyalgia Impact Questionnaire for pre- and post-medical cannabis periods. Mean cannabis dose 26g/month, mean treatment duration 10.4 months.","limitations":"Very small sample (26 patients) with no control group. Retrospective questionnaire comparing recalled pre-treatment status to current status introduces recall bias. No blinding or placebo control. Hospital registry patients may not represent all fibromyalgia patients. The 100% improvement rate is unusual and may reflect selection or reporting biases."},{"rthcId":"RTHC-01674","title":"The Potential of Cannabidiol Treatment for Cannabis Users With Recent-Onset Psychosis.","authors":"Hahn, Britta","year":2018,"journal":"Schizophrenia bulletin, 44(1), 46-53","doi":"10.1093/schbul/sbx105","pmid":"29083450","tags":["cbd","psychosis","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review examined the potential of CBD as a treatment specifically for cannabis users with recent-onset psychosis, a population with currently poor outcomes and no specialized effective intervention.\n\nCannabis misuse is a major factor associated with poor outcomes after a first psychotic break and is especially common in individuals with recent-onset psychosis. Behavioral interventions aimed at reducing cannabis use have been unsuccessful in this population.\n\nThe review compiled evidence that CBD has a broad pharmacological profile including antipsychotic and anxiolytic effects, does not activate CB1 or CB2 receptors (unlike THC), and has at most subtle subjective effects.\n\nCritically, CBD attenuates THC's harmful effects both acutely and chronically, including psychotogenic, anxiogenic, and cognitive impairments. Modern cannabis strains have low CBD concentrations, which may contribute to their higher psychosis risk.\n\nThe authors proposed that CBD treatment could improve the disease trajectory for this specific population by both treating psychotic symptoms and mitigating the ongoing harm from THC if patients continue using cannabis.","whyItMatters":"People with early psychosis who use cannabis represent a treatment-resistant group: behavioral interventions to stop cannabis use have failed, and continued use worsens outcomes. CBD potentially addresses both the psychosis and the cannabis harm simultaneously, offering a novel therapeutic strategy.","specificNumbers":"Cannabis misuse is prevalent in schizophrenia and especially common in recent-onset psychosis. Modern cannabis strains have low CBD concentrations. CBD does not activate CB1 or CB2 receptors. Behavioral interventions for cannabis reduction have been unsuccessful in this population.","methodology":"Narrative review synthesizing evidence on CBD's pharmacological profile, antipsychotic properties, neuroprotective effects, and capacity to attenuate THC's adverse effects, with focus on clinical implications for recent-onset psychosis with comorbid cannabis use.","limitations":"The proposal is based on indirect evidence combining separate findings on CBD as antipsychotic and CBD as THC-attenuator. No clinical trials had directly tested CBD in cannabis-using psychosis patients at the time. CBD's antipsychotic evidence, while growing, was still limited. The optimal dosing and treatment duration were unknown."},{"rthcId":"RTHC-01675","title":"Opposing actions of CRF-R1 and CB1 receptors on VTA-GABAergic plasticity following chronic exposure to ethanol.","authors":"Harlan, Benjamin A; Becker, Howard C; Woodward, John J; Riegel, Arthur C","year":2018,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(10), 2064-2074","doi":"10.1038/s41386-018-0106-9","pmid":"29946104","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01676","title":"Cortical thickness, cortical surface area and subcortical volumes in schizophrenia and bipolar disorder patients with cannabis use.","authors":"Hartberg, Cecilie Bhandari; Lange, Elisabeth H; Lagerberg, Trine Vik; Haukvik, Unn K; Andreassen, Ole A; Melle, Ingrid; Agartz, Ingrid","year":2018,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 28(1), 37-47","doi":"10.1016/j.euroneuro.2017.11.019","pmid":"29254657","tags":["psychosis","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared brain scans of patients with schizophrenia or bipolar disorder who had used cannabis (132 patients) against those who had not (182 patients) and 277 healthy controls.\n\nAfter controlling for confounders including tobacco and alcohol use, cannabis-using patients showed reduced cortical thickness in the caudal middle frontal gyrus compared to non-user patients and healthy controls.\n\nHowever, when patients with co-occurring alcohol and other illicit drug use were excluded, these findings were no longer significant. This suggests the brain differences may have been driven by polysubstance use rather than cannabis alone.\n\nOne finding persisted: patients whose cannabis use started before their illness onset showed cortical thinning in the caudal middle frontal gyrus. This supports the idea that early cannabis exposure before psychiatric illness develops may have a specific effect on frontal cortex development.\n\nOverall, the authors concluded that cannabis use is associated with limited brain structural effects in both schizophrenia and bipolar disorder.","whyItMatters":"This study addresses the question of whether cannabis use worsens the brain changes already present in serious mental illness. The finding that effects are limited, and largely disappear when polysubstance use is controlled for, provides reassurance while highlighting the importance of early use timing.","specificNumbers":"314 patients (132 cannabis users, 182 non-users) plus 277 healthy controls. 11 preselected brain regions per hemisphere analyzed. Caudal middle frontal gyrus showed thinning with cannabis use. Effects non-significant after excluding polysubstance users. Pre-illness-onset use associated with persistent cortical thinning.","methodology":"MRI brain scans from 77 schizophrenia and 55 bipolar patients with cannabis history (lifetime use >10 times in one month or abuse/dependence), 97 schizophrenia and 85 bipolar patients without cannabis use, and 277 healthy controls. Cortical thickness, surface area, and subcortical volumes compared using hypothesis-driven and exploratory analyses.","limitations":"Cross-sectional design cannot determine temporal causation. Cannabis use history was retrospective and binary (user vs. non-user) without detailed dose-response data. The loss of significance after excluding polysubstance users may reflect reduced statistical power rather than absence of effect. Sample sizes within subgroups were relatively small."},{"rthcId":"RTHC-01677","title":"US Epidemiology of Cannabis Use and Associated Problems.","authors":"Hasin, Deborah S","year":2018,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(1), 195-212","doi":"10.1038/npp.2017.198","pmid":"28853439","tags":["addiction","legalization","youth","pregnancy","driving","withdrawal"],"studyType":"review","evidenceStrength":"strong","keyFinding":"This comprehensive review documented the shifting landscape of cannabis use in the United States.\n\nBoth adults and adolescents increasingly perceive cannabis as harmless. Meanwhile, the evidence showed national increases in cannabis potency, prenatal and unintentional childhood exposure, adult cannabis use, cannabis use disorders, cannabis-related emergency room visits, and fatal vehicle crashes involving cannabis.\n\nRegarding medical marijuana laws (MMLs): many studies indicated that MMLs did not increase adolescent cannabis use. However, MMLs appeared to increase cannabis potency, unintentional childhood exposures, adult cannabis use, and adult cannabis use disorders.\n\nAn intriguing ecological finding: MMLs appeared associated with substitution of cannabis for opioids, and possibly for psychiatric medications.\n\nThe review noted that some people can use cannabis without harm, but potential problems include prenatal exposure effects, decline in educational or occupational functioning after early adolescent use, impaired driving, cannabis use disorders, cannabis withdrawal, and psychiatric comorbidity.","whyItMatters":"This review by a leading epidemiologist provides a single-source overview of US cannabis trends during a period of rapid legal change. The finding that perception of harmlessness is increasing while measurable harms are also increasing highlights a growing disconnect between public attitudes and public health data.","specificNumbers":"29 states had medical marijuana laws, 8 had recreational marijuana laws at time of review. National increases documented in: cannabis potency, use, use disorders, ER visits, fatal vehicle crashes. MMLs did not increase adolescent use but did increase adult use and disorders.","methodology":"Comprehensive narrative review of US epidemiological data, published studies, and trend analyses on cannabis use patterns, associated problems, and the impact of medical and recreational marijuana laws.","limitations":"As a narrative review, it synthesizes selectively rather than systematically. Many of the trends documented are ecological associations that cannot prove causation. The landscape of cannabis laws changes rapidly, potentially outdating specific findings. Individual-level data on causation between MMLs and behavior change is limited."},{"rthcId":"RTHC-01678","title":"Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents - An observational, longitudinal study.","authors":"Hausman-Kedem, Moran; Menascu, Shay; Kramer, Uri","year":2018,"journal":"Brain & development, 40(7), 544-551","doi":"10.1016/j.braindev.2018.03.013","pmid":"29674131","tags":["epilepsy","cbd","medical-cannabis","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers followed 57 patients aged 1-20 years with epilepsy of various causes who were treated with CBD-enriched cannabis oil (CBD:THC ratio of 20:1) for at least 3 months, with a median follow-up of 18 months.\n\nOf 46 patients included in efficacy analysis, 26 (56%) achieved at least 50% reduction in mean monthly seizure frequency.\n\nResponse rates did not differ significantly by epilepsy type or cannabis strain used. However, younger age at treatment onset and higher CBD doses (>11 mg/kg/day) were associated with better response.\n\nThe average CBD dose was 11.4 mg/kg/day. Adverse reactions were reported in 46% of patients and were the main reason for treatment cessation.\n\nThe results are based on parental reports of seizure frequency, and the authors emphasized the need for randomized controlled trials to assess true efficacy.","whyItMatters":"This study provides real-world data on CBD-enriched cannabis for a broader range of pediatric epilepsy types than the FDA-approved indications (Dravet and Lennox-Gastaut syndromes). The high adverse reaction rate (46%) and the finding that it was the main reason for treatment cessation provide important safety data for clinicians and families.","specificNumbers":"57 patients, 46 in efficacy analysis. 56% achieved 50%+ seizure reduction. Average CBD dose 11.4 mg/kg/day. CBD:THC ratio 20:1. Median follow-up 18 months. Adverse reactions in 46%. Younger age and higher doses predicted better response.","methodology":"Observational, longitudinal study of 57 patients (age 1-20) with various epilepsy etiologies treated with CBD:THC 20:1 cannabis oil extract for at least 3 months. Median follow-up 18 months. 46 patients included in efficacy analysis. Response defined as 50% or greater reduction in monthly seizure frequency.","limitations":"Observational design without placebo control means response rates may include placebo effects. Seizure frequency based on parental report, not EEG monitoring. No randomization. Adverse event rate may reflect the specific product used. 11 patients were excluded from efficacy analysis, potentially biasing results."},{"rthcId":"RTHC-01679","title":"Cannabis Use in Individuals With Spinal Cord Injury or Moderate to Severe Traumatic Brain Injury in Colorado.","authors":"Hawley, Lenore A; Ketchum, Jessica M; Morey, Clare; Collins, Kathleen; Charlifue, Susan","year":2018,"journal":"Archives of physical medicine and rehabilitation, 99(8), 1584-1590","doi":"10.1016/j.apmr.2018.02.003","pmid":"29524396","tags":["pain","medical-cannabis","sleep","anxiety"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers surveyed 116 Colorado adults who had sustained spinal cord injury (SCI) or moderate to severe traumatic brain injury (TBI), combining focus group data with a telephone survey.\n\n70% reported cannabis use before their injury (67% SCI, 74% TBI) and 48% reported use after their injury (53% SCI, 45% TBI).\n\nReasons for use differed between groups. Among SCI respondents, the top reasons were reducing spasticity (70%), recreation (63%), and improving sleep (63%). Among TBI respondents, the top reasons were recreational (72%), reducing stress/anxiety (62%), and improving sleep (55%).\n\nOverall, the most common reasons across both groups were recreational (67%), reducing stress/anxiety (62.5%), and improving sleep (59%). Smoking was the most common method of use.","whyItMatters":"Cannabis use is highly prevalent in SCI and TBI populations, yet most rehabilitation clinicians have limited data on how these patients use cannabis and why. The finding that many continue using post-injury, particularly for symptom management, has implications for rehabilitation care planning and drug interaction awareness.","specificNumbers":"116 participants (SCI and TBI). Pre-injury use: 70% (67% SCI, 74% TBI). Post-injury use: 48% (53% SCI, 45% TBI). Top SCI reasons: spasticity 70%, recreation 63%, sleep 63%. Top TBI reasons: recreation 72%, stress/anxiety 62%, sleep 55%.","methodology":"Mixed-methods observational study. Focus groups identified key issues, which informed telephone survey development. 116 Colorado adults with SCI or moderate-to-severe TBI from Craig Hospital participated.","limitations":"Single-site (Colorado, where cannabis is legal) limits generalizability. Self-reported data subject to bias. Convenience sample from one rehabilitation hospital. No comparison to non-cannabis-using patients on outcomes. Small sample size limits subgroup analyses."},{"rthcId":"RTHC-01680","title":"Designed Cultural Adaptation and Delivery Quality in Rural Substance Use Prevention: an Effectiveness Trial for the Keepin' it REAL Curriculum.","authors":"Hecht, Michael L; Shin, YoungJu; Pettigrew, Jonathan; Miller-Day, Michelle; Krieger, Janice L","year":2018,"journal":"Prevention science : the official journal of the Society for Prevention Research, 19(8), 1008-1018","doi":"10.1007/s11121-018-0937-y","pmid":"30056616","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01681","title":"Predictors of heroin abstinence in opiate substitution therapy in heroin-only users and dual users of heroin and crack.","authors":"Heidebrecht, F; MacLeod, M B; Dawkins, L","year":2018,"journal":"Addictive behaviors, 77, 210-216","doi":"10.1016/j.addbeh.2017.10.013","pmid":"29065377","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01682","title":"New Challenges: Developing Gendered and Equitable Responses to Involuntary Exposures to Electronic Nicotine Delivery Systems (ENDS) and Cannabis Vaping.","authors":"Hemsing, Natalie; Greaves, Lorraine","year":2018,"journal":"International journal of environmental research and public health, 15(10)","doi":"10.3390/ijerph15102097","pmid":"30257435","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01683","title":"Recovery schools for improving behavioral and academic outcomes among students in recovery from substance use disorders: a systematic review.","authors":"Hennessy, Emily A; Tanner-Smith, Emily E; Finch, Andrew J; Sathe, Nila; Kugley, Shannon","year":2018,"journal":"Campbell systematic reviews, 14(1), 1-86","doi":"10.4073/csr.2018.9","pmid":"37131375","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01684","title":"Interferon-α-Mediated Activation of T Cells from Healthy and HIV-Infected Individuals Is Suppressed by Δ9-Tetrahydrocannabinol.","authors":"Henriquez, Joseph E; Rizzo, Michael D; Crawford, Robert B; Gulick, Peter; Kaminski, Norbert E","year":2018,"journal":"The Journal of pharmacology and experimental therapeutics, 367(1), 49-58","doi":"10.1124/jpet.118.250308","pmid":"30026298","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01685","title":"Acute side effects after consumption of the new synthetic cannabinoids AB-CHMINACA and MDMB-CHMICA.","authors":"Hermanns-Clausen, Maren; Müller, Dieter; Kithinji, Josephine; Angerer, Verena; Franz, Florian; Eyer, Florian; Neurath, Hartmud; Liebetrau, Gesine; Auwärter, Volker","year":2018,"journal":"Clinical toxicology (Philadelphia, Pa.), 56(6), 404-411","doi":"10.1080/15563650.2017.1393082","pmid":"29072524","tags":["synthetic-cannabinoids"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers prospectively studied 44 patients treated in emergency departments after using synthetic cannabinoids, with lab confirmation of AB-CHMINACA and/or MDMB-CHMICA in blood or urine.\n\nBased on the Poison Severity Score, poisoning severity was minor in 4 cases, moderate in 31 cases, and severe in 9 cases (20%).\n\nThe most common neuropsychiatric symptoms were CNS depression (61%), disorientation (45%), generalized seizures (27%), combativeness (18%), and extreme agitation (16%). Symptoms lasted 24 hours or longer in 34% of cases.\n\nThese rates were notably higher than those previously reported for earlier-generation synthetic cannabinoids (aminoalkylindole-type like JWH-018). The authors concluded that these \"third generation\" synthetic cannabinoids appear to be associated with more severe clinical toxicity.\n\nIn 19 of 44 cases, more than one synthetic cannabinoid was detected, complicating attribution of effects to specific compounds.","whyItMatters":"As synthetic cannabinoid chemistry evolves, each new generation appears to carry increased risk. The finding that third-generation compounds produce more seizures, more severe poisoning, and longer symptom duration than earlier generations is a critical public health warning.","specificNumbers":"44 patients (39 male, 5 female, ages 12-48). AB-CHMINACA detected in 20 serum samples, MDMB-CHMICA in 19. Severe poisoning: 20%. Seizures: 27%. Symptoms 24+ hours: 34%. CNS depression: 61%. Disorientation: 45%. Multiple SCs in 19 cases.","methodology":"Prospective observational study of patients in EDs after synthetic cannabinoid use. Clinical and lab data reported to poison control centre. Serum and/or urine analyzed by LC-MS/MS. 44 patients (39 male, 5 female, ages 12-48). Severity graded by Poison Severity Score.","limitations":"In 19 of 44 cases, multiple synthetic cannabinoids were present, making it difficult to attribute effects to specific compounds. Other psychoactive substances were found in 7 cases. Prospective design at select EDs may not capture all presentations. The sample size limits generalization about specific compounds."},{"rthcId":"RTHC-01686","title":"Cannabinoid hyperemesis syndrome presentation to the emergency department: A two-year multicentre retrospective chart review in a major urban area.","authors":"Hernandez, Jeremy M; Paty, Jared; Price, Ira M","year":2018,"journal":"CJEM, 20(4), 550-555","doi":"10.1017/cem.2017.381","pmid":"28835305","tags":["withdrawal","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers reviewed charts of all adults aged 18-55 presenting to two major urban tertiary care EDs and one urgent care centre with vomiting complaints over two years.\n\nOf 494 cases, 19.4% of charts specifically reported cannabis use. Among regular cannabis users (more than three times per week), 43% had repeat ED visits for similar complaints.\n\nThe resource utilization was substantial: 92% had bloodwork, 92% received IV fluids, 89% received antiemetics, 27% received opiates, 19% underwent imaging, 8% were admitted to hospital, and 8% were referred to gastroenterology.\n\nThe findings suggest that CHS may be frequently overlooked as a diagnosis, leading to unnecessary investigations and repeat visits. The authors noted a lack of screening for CHS in ED history-taking, particularly in quantifying cannabis use and eliciting the hallmark symptoms.","whyItMatters":"The high rate of repeat visits, unnecessary investigations, and opiate prescriptions in cannabis-using patients with vomiting suggests significant healthcare waste and potential patient harm from missed CHS diagnoses. Simple screening questions about cannabis use frequency could prevent expensive workups.","specificNumbers":"494 cases reviewed. 19.4% reported cannabis use. 43% of regular users had repeat visits. 92% bloodwork, 92% IV fluids, 89% antiemetics, 27% opiates, 19% imaging, 8% admitted, 8% GI referral. Inter-rater kappa=1.","methodology":"Retrospective chart review of adults aged 18-55 presenting with vomiting or discharged with vomiting/cyclical vomiting diagnosis at two urban tertiary care EDs and one urgent care centre over 2 years. Standardized abstraction with trained abstractors. Inter-rater reliability kappa=1.","limitations":"Retrospective chart review depends on documentation quality. Cannabis use may be under-documented in charts. Cannot confirm CHS diagnosis without hot shower relief assessment. Single urban centre may not represent all EDs. The 19.4% cannabis use rate likely underestimates true prevalence."},{"rthcId":"RTHC-01687","title":"Sweet flowers are slow, and weeds make haste: leveraging methodology from research on tobacco, alcohol, and opioid analgesics to make rapid and policy-relevant advances in cannabis science.","authors":"Herrmann, Evan S; Jarvis, Brantley P; Sparks, Alicia C; Cohn, Amy M; Koszowski, Bartosz; Rosenberry, Zachary R; Coleman-Cowger, Victoria H; Pickworth, Wallace B; Peters, Erica N","year":2018,"journal":"International review of psychiatry (Abingdon, England), 30(3), 238-250","doi":"10.1080/09540261.2018.1465400","pmid":"30179535","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01688","title":"Substance use and misuse among children and youth with mental illness : A pilot study.","authors":"Herz, V; Franzin, N; Huemer, J; Mairhofer, D; Philipp, J; Skala, K","year":2018,"journal":"Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater, 32(1), 18-25","doi":"10.1007/s40211-017-0231-4","pmid":"28639209","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers assessed substance use among 25 adolescents aged 12-17 admitted to an Austrian psychiatric inpatient unit.\n\nLifetime prevalence of any substance use was 76%, with regular use in 32%. Specific prevalences were alcohol (76%), nicotine (44%), and illicit drugs (36%, predominantly cannabis).\n\nOlder age predicted tobacco (p=0.023), drug (p=0.021), and cannabis use (p=0.015). Family dysfunction predicted regular substance use (p=0.035) and cannabis use specifically (p=0.02). History of trauma predicted regular use (p=0.047) and tobacco use (p=0.011).\n\nPeer substance use was the strongest social predictor: it significantly predicted any substance use (p<0.001) and regular use (p=0.026).\n\nSubstance-using adolescents showed more academic failure, school absenteeism, and behavioral problems. Critically, alcohol (p=0.02), drug (p=0.017), and regular substance use (p=0.007) were linked to suicidal ideation.","whyItMatters":"Adolescent psychiatric inpatients represent one of the highest-risk populations for substance use problems. The links between substance use, suicidal ideation, family dysfunction, and trauma in this group highlight the need for comprehensive screening and integrated treatment.","specificNumbers":"25 inpatients aged 12-17. Lifetime use 76%, regular use 32%. Alcohol 76%, nicotine 44%, illicit drugs 36%. Cannabis use predicted by age (p=0.015) and family dysfunction (p=0.02). Suicidal ideation linked to drug use (p=0.017) and regular use (p=0.007).","methodology":"Cross-sectional pilot study of 25 adolescents aged 12-17 on an Austrian child and adolescent psychiatry inpatient unit. Self-report measures of substance use and sociodemographics, CAGE and FTND screening, clinical data from medical records.","limitations":"Very small sample size (25 patients) severely limits statistical power and generalizability. Single inpatient unit in Austria may not reflect other settings or countries. Cross-sectional design cannot establish causation between substance use and psychiatric symptoms. Self-report data in an inpatient setting may be affected by social desirability."},{"rthcId":"RTHC-01689","title":"Systematic Review of the Costs and Benefits of Prescribed Cannabis-Based Medicines for the Management of Chronic Illness: Lessons from Multiple Sclerosis.","authors":"Herzog, Samuel; Shanahan, Marian; Grimison, Peter; Tran, Anh; Wong, Nicole; Lintzeris, Nicholas; Simes, John; Stockler, Martin; Morton, Rachael L","year":2018,"journal":"PharmacoEconomics, 36(1), 67-78","doi":"10.1007/s40273-017-0565-6","pmid":"28866778","tags":["medical-cannabis","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Researchers systematically reviewed the economic costs and benefits of prescribed cannabis-based medicines across all chronic illnesses.\n\nOf 2,514 records identified, only 10 studies met criteria, all focused on multiple sclerosis (MS). No economic evaluations existed for any other condition.\n\nFour of five industry-sponsored cost-utility analyses found nabiximols cost-effective for MS spasticity. Cost per quality-adjusted life-year (QALY) ranged from dominant (saving money) in Spain to £49,257 in the UK. However, nabiximols was not associated with statistically significant improvements in EQ-5D quality of life scores compared to standard care.\n\nThe disconnect between cost-effectiveness claims and lack of significant quality of life improvement raises questions about the robustness of these economic analyses.\n\nStudy quality was moderate overall, with limited inclusion of societal costs and limited discussion of potential bias.","whyItMatters":"As cannabis-based medicines are considered for insurance coverage and health system formularies, economic evidence is critical. The finding that most existing evidence is industry-sponsored and limited to one condition (MS) highlights the need for independent economic evaluations across the many conditions where cannabinoids are used.","specificNumbers":"2,514 records screened, 10 met criteria. All 10 for MS. Cost per QALY: £49,257 (UK), £10,891 (Wales), €11,214 (Germany), €4,968 (Italy), dominant (Spain). 4 of 5 industry-sponsored analyses found nabiximols cost-effective. EQ-5D improvements not statistically significant.","methodology":"Systematic review of eight medical and economic databases from inception to December 2016. MeSH headings and text words combined for economic evaluations and cannabis-based medicines. Quality assessed with relevant checklists. PROSPERO registered (CRD42014006370).","limitations":"All studies were for MS only, limiting applicability to other conditions. Most were industry-sponsored, introducing potential bias. The non-significant quality of life improvements raise questions about cost-effectiveness models. Only European health system perspectives were represented. Study quality was moderate."},{"rthcId":"RTHC-01690","title":"Genetic vulnerability to schizophrenia is associated with cannabis use patterns during adolescence.","authors":"Hiemstra, Marieke; Nelemans, Stefanie A; Branje, Susan; van Eijk, Kristel R; Hottenga, Jouke-Jan; Vinkers, Christiaan H; van Lier, Pol; Meeus, Wim; Boks, Marco P","year":2018,"journal":"Drug and alcohol dependence, 190, 143-150","doi":"10.1016/j.drugalcdep.2018.05.024","pmid":"30031300","tags":["genetics","psychosis","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers followed 372 adolescents from the RADAR-Y study, tracking substance use from ages 13-20 while measuring each participant's genetic vulnerability to schizophrenia using polygenic risk scores.\n\nHigh schizophrenia genetic vulnerability was specifically associated with a stronger increase in cannabis use during ages 16-20. This relationship was consistent across multiple polygenic risk score thresholds.\n\nNo clear relationship was found between schizophrenia genetic risk and smoking or alcohol use, making the association specific to cannabis.\n\nThis specificity is particularly noteworthy: if the association were simply about genetic predisposition to substance use in general, it should have appeared for alcohol and tobacco as well. The cannabis-specific finding supports the hypothesis that shared genetic factors specifically link schizophrenia vulnerability and cannabis use behavior.","whyItMatters":"This finding helps explain why cannabis use and schizophrenia co-occur: it may not be simply that cannabis causes psychosis, but that shared genetic factors make some individuals both more likely to use cannabis and more vulnerable to schizophrenia. This has profound implications for understanding causation in the cannabis-psychosis relationship.","specificNumbers":"372 adolescents followed ages 13-20. Higher schizophrenia PRS predicted stronger cannabis use increase ages 16-20 (multiple thresholds significant at p<0.001). No relationship with alcohol or smoking. Cannabis-specific association supports shared genetic architecture.","methodology":"Longitudinal cohort (RADAR-Y study, N=372). Piecewise latent growth curve modeling analyzed cannabis, smoking, and alcohol use trajectories from ages 13-20 (split at age 16). Polygenic risk scores for schizophrenia calculated at multiple p-value thresholds. Bonferroni-corrected significance at p<0.001.","limitations":"Moderate sample size (372) for genomic analyses. Dutch adolescent sample may not generalize to other populations. Polygenic risk scores explain only a small fraction of schizophrenia heritability. Cannabis use was self-reported. The study period (ages 13-20) may miss later-onset patterns."},{"rthcId":"RTHC-01691","title":"Circulating endocannabinoids: from whence do they come and where are they going?","authors":"Hillard, Cecilia J.","year":2018,"journal":"Neuropsychopharmacology, 43(1), 155-172","doi":"10.1038/npp.2017.130","pmid":"28653665","tags":["inflammation","pain","exercise","ptsd"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Endocannabinoids aren't just in the brain. They circulate in the bloodstream, and their levels shift in response to specific physiological states. This review mapped those patterns across multiple domains.\n\nEnergy balance was the most consistent finding: endocannabinoid signaling tracked with increased energy consumption and storage, supporting the system's role in appetite and metabolism. Physical exercise mobilized endocannabinoids — a finding that contributes to the \"runner's high\" hypothesis and may explain some of exercise's analgesic and mood-elevating effects.\n\n2-AG, one of the two main endocannabinoids, followed a strong circadian rhythm that became dysregulated when sleep was disrupted. Circulating levels also shifted with inflammation, chronic pain, and stress. In PTSD specifically, endocannabinoid concentrations were altered in ways that suggested the system's stress-recovery function was impaired.","whyItMatters":"This review connects cannabis science to broader biology. The endocannabinoid system isn't just relevant when someone uses cannabis — it's active in exercise, sleep, eating, stress recovery, and pain processing every day. Understanding these baseline patterns helps explain why cannabis affects so many different things: it's acting on a system that already touches nearly every major physiological process.\n\nThe exercise connection is particularly interesting. If runner's high partly comes from endocannabinoids, then exercise and cannabis may be acting on overlapping pathways — which could matter for both addiction treatment and mental health.","specificNumbers":"• 2-AG levels follow a significant circadian rhythm, disrupted by sleep loss\n• Exercise increases circulating endocannabinoid levels\n• Endocannabinoid concentrations altered in PTSD, chronic pain, and inflammation\n• Endocannabinoid signaling consistently associated with increased energy intake and storage","methodology":"Comprehensive review of human studies measuring circulating endocannabinoid concentrations (primarily 2-AG and anandamide) in relation to physiological states and clinical conditions. Published in Neuropsychopharmacology. Covers energy balance, exercise, sleep, stress, pain, and psychiatric conditions.","limitations":"Circulating endocannabinoid levels may not reflect brain levels or tissue-specific signaling. Many factors influence blood concentrations simultaneously, making it difficult to isolate individual contributions. The review synthesizes human observational data, which cannot establish causation. Methods for measuring endocannabinoids vary across studies."},{"rthcId":"RTHC-01692","title":"Medical Marijuana for Minors May Be Considered Child Abuse.","authors":"Hines, Larissa; Glick, Jill; Bilka, Kristin; Lantos, John D","year":2018,"journal":"Pediatrics, 142(4)","doi":"10.1542/peds.2017-4310","pmid":"30213842","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01693","title":"Overlap of heritable influences between cannabis use disorder, frequency of use and opportunity to use cannabis: trivariate twin modelling and implications for genetic design.","authors":"Hines, Lindsey A; Morley, Katherine I; Rijsdijk, Fruhling; Strang, John; Agrawal, Arpana; Nelson, Elliot C; Statham, Dixie; Martin, Nicholas G; Lynskey, Michael T","year":2018,"journal":"Psychological medicine, 48(16), 2786-2793","doi":"10.1017/S0033291718000478","pmid":"29530110","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Researchers used data from 3,303 Australian twins to decompose the genetic and environmental contributions to three stages of cannabis involvement: opportunity to use, frequency of use, and cannabis abuse/dependence.\n\nAll three stages were substantially heritable: opportunity (64%), frequency (74%), and abuse/dependence (78%). Shared environment played no significant role; the remaining variance was due to unique environmental factors.\n\nCritically, there was extensive genetic overlap between stages. Opportunity shared 45% of its genetic influences with frequency of use. And of the genetic influences on cannabis abuse/dependence, only 17% were unique from those acting on opportunity and frequency.\n\nThis means that 83% of the genetic risk for developing a cannabis use disorder is the same genetic risk that determines whether someone has the opportunity to try cannabis and how often they use it. The disorder-specific genetics (vulnerability to lose control once using) accounts for a relatively small proportion.","whyItMatters":"This finding has major implications for genetic research: studies searching for genes specific to cannabis addiction will mostly find genes that affect whether someone uses cannabis at all. This means genetic studies of cannabis use disorder must carefully account for exposure to avoid misidentifying general use genes as disorder genes.","specificNumbers":"Heritability: opportunity 64%, frequency 74%, abuse/dependence 78%. Shared environment ~0 for all. Opportunity shares 45% of genetic influences with frequency. Only 17% of genetic influences on abuse/dependence are unique from those acting on opportunity and frequency.","methodology":"Trivariate Cholesky decomposition in 3,303 Australian twins measuring age of onset of cannabis use opportunity, lifetime frequency of use, and lifetime DSM-IV cannabis abuse/dependence. Estimated additive genetic (A), shared environment (C), and unique environment (E) contributions and overlap.","limitations":"Australian twin sample may not generalize to other populations. DSM-IV criteria used (not DSM-5). Self-reported measures of opportunity, frequency, and diagnosis. Twin designs assume equal environments for identical and fraternal twins. The Cholesky decomposition assumes a specific causal ordering (opportunity -> frequency -> disorder)."},{"rthcId":"RTHC-01694","title":"Spicing it up - synthetic cannabinoid receptor agonists and psychosis - a systematic review.","authors":"Hobbs, Melissa; Kalk, Nicola J; Morrison, Paul D; Stone, James M","year":2018,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 28(12), 1289-1304","doi":"10.1016/j.euroneuro.2018.10.004","pmid":"30454908","tags":["synthetic-cannabinoids","psychosis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Researchers synthesized evidence from 2 toxicology reports, 4 case-control studies, 3 cross-sectional studies, and 15 case reports on synthetic cannabinoid receptor agonists (SCRAs) and psychosis.\n\nThe toxicology reports identified toxic psychosis and delirium (40%), agitation (10%), and hallucinations (4-7%) as main presenting features. The median age was 25 years and approximately 80% were male.\n\nCross-sectional studies found SCRA use present in 10-13% of patients presenting to acute psychiatric services, often as the cause of their presentation. Psychotic symptoms were present in 15% of patients attending emergency departments after SCRA use.\n\nCase-control studies reported that SCRA use was significantly associated with psychotic symptoms and that SCRA users had higher levels of positive psychotic symptoms than natural cannabis users.\n\nCase reports documented a wide range of positive and negative psychotic symptoms, self-harm, agitation, and aggressive behavior. Importantly, SCRA use could trigger psychosis in individuals with no past psychiatric history.","whyItMatters":"This systematic review provides the most comprehensive picture to date of the SCRA-psychosis relationship, demonstrating that synthetic cannabinoids carry greater psychosis risk than natural cannabis and affect a significant proportion of acute psychiatric presentations.","specificNumbers":"24 studies reviewed. SCRA use in 10-13% of acute psychiatric patients. 15% of ED SCRA patients had psychotic symptoms. 40% of toxicology cases had toxic psychosis/delirium. Median age 25, ~80% male. Higher positive symptoms than natural cannabis users.","methodology":"Systematic literature review identifying 24 studies (2 toxicology reports, 4 case-control, 3 cross-sectional, 15 case reports). Case report symptoms coded against PANSS items. Studies covered multiple countries and clinical settings.","limitations":"The evidence base is heavily weighted toward case reports, which have inherent selection and reporting biases. Many studies could not confirm SCRA identity through toxicological analysis. Polysubstance use was common. Long-term outcomes after SCRA-induced psychosis were rarely documented."},{"rthcId":"RTHC-01695","title":"Social Factors and Animal Models of Cannabis Use.","authors":"Hood, Lauren","year":2018,"journal":"International review of neurobiology, 140, 171-200","doi":"10.1016/bs.irn.2018.07.006","pmid":"30193704","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01696","title":"Adverse Effects of Cannabis on Male Reproduction.","authors":"Hsiao, Philip; Clavijo, Raul I","year":2018,"journal":"European urology focus, 4(3), 324-328","doi":"10.1016/j.euf.2018.08.006","pmid":"30146239","tags":["sex-differences"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the effects of cannabis on clinical markers of male fertility and the endocannabinoid system's role in reproductive function.\n\nThe endocannabinoid system plays important roles in sex hormone production, sperm production (spermatogenesis), and sperm function. Both CB1 and CB2 cannabinoid receptors are expressed in testicular tissue and on sperm cells.\n\nRegarding sex hormones (testosterone, LH, FSH), the evidence was contradictory. Some studies showed cannabis-associated decreases, others showed no effect, and some showed increases.\n\nHowever, the evidence was more consistent for sperm parameters: most studies associated cannabis use with lower sperm concentrations. This suggests a negative impact on male fertility potential, even if the hormonal mechanisms remain unclear.\n\nThe review was motivated by two converging trends: increasing cannabis use as regulations relax worldwide, and declining semen quality observed in developed countries, with couples increasingly delaying conception.","whyItMatters":"With cannabis use increasing and couples delaying conception, understanding cannabis effects on sperm is increasingly relevant. The consistent finding of lower sperm concentrations, despite contradictory hormone data, provides practical information for men of reproductive age.","specificNumbers":"CB1 and CB2 receptors expressed in testicular tissue and sperm. Most studies show lower sperm concentrations with cannabis use. Evidence on testosterone, LH, and FSH is contradictory across studies.","methodology":"Mini-review of published studies on cannabis effects on male reproductive hormones, sperm parameters, and the role of the endocannabinoid system in male reproductive function.","limitations":"Mini-review format covers breadth rather than depth. The contradictory hormone findings may reflect different study designs, cannabis types, doses, and populations. Most human studies are observational and cannot establish causation. Effects on assisted reproduction outcomes (IVF success) are not well studied."},{"rthcId":"RTHC-01697","title":"Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology.","authors":"Hudson, Roger; Rushlow, Walter; Laviolette, Steven R","year":2018,"journal":"Psychopharmacology, 235(2), 447-458","doi":"10.1007/s00213-017-4766-7","pmid":"29063964","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01698","title":"Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.","authors":"Ibarra-Lecue, Inés; Mollinedo-Gajate, Irene; Meana, J Javier; Callado, Luis F; Diez-Alarcia, Rebeca; Urigüen, Leyre","year":2018,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(10), 2028-2035","doi":"10.1038/s41386-018-0076-y","pmid":"29748632","tags":["psychosis","neuroscience","dopamine","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers exposed mice to chronic THC during an early developmental window and then examined serotonin 2A receptor (5-HT2AR) function in the frontal cortex.\n\nChronic THC shifted the receptor toward coupling with inhibitory G-proteins (Gαi1, Gαi3, Gαo, and Gαz) rather than the standard Gαq/11 pathway. This specific signaling pattern has been linked to psychotic symptoms in humans.\n\nTHC-treated mice also showed disrupted prepulse inhibition, a standard lab measure of sensory gating deficits seen in schizophrenia.\n\nCritically, the drug rapamycin (which blocks the Akt/mTOR pathway) prevented both the receptor signaling shift and the schizophrenia-like behavioral effects.\n\nThis is the first mechanistic explanation for how chronic cannabis exposure during early life could increase psychosis risk later on, pointing to a specific molecular pathway rather than a vague association.","whyItMatters":"Epidemiological data have long linked adolescent cannabis use to later psychosis risk, but the biological mechanism was unknown. This study identifies a specific molecular pathway (Akt/mTOR-driven changes in serotonin receptor signaling) that could explain the connection, which matters for understanding who might be most vulnerable.","specificNumbers":"THC induced supersensitive coupling of 5-HT2AR to four inhibitory G-proteins (Gαi1, Gαi3, Gαo, Gαz) without changing the canonical Gαq/11 pathway. Rapamycin fully blocked these signaling changes and the associated behavioral deficits.","methodology":"Mouse study using chronic THC administration during early development. Measured 5-HT2AR G-protein coupling using [35S]GTPγS binding assays. Behavioral testing included prepulse inhibition. Rapamycin was used to test whether blocking Akt/mTOR could prevent the observed changes.","limitations":"Mouse study, so direct translation to human adolescent cannabis use is uncertain. THC doses and exposure timing may not map cleanly onto human patterns. The study used pure THC without CBD, which may modulate these effects in whole-plant cannabis."},{"rthcId":"RTHC-01699","title":"Determination of Acid and Neutral Cannabinoids in Extracts of Different Strains of Cannabis sativa Using GC-FID.","authors":"Ibrahim, Elsayed A; Gul, Waseem; Gul, Shahbaz W; Stamper, Brandon J; Hadad, Ghada M; Abdel Salam, Randa A; Ibrahim, Amany K; Ahmed, Safwat A; Chandra, Suman; Lata, Hemant; Radwan, Mohamed M; ElSohly, Mahmoud A","year":2018,"journal":"Planta medica, 84(4), 250-259","doi":"10.1055/s-0043-124088","pmid":"29237190","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01700","title":"Pseudo-Wellens' syndrome secondary to concurrent cannabis and phencyclidine intoxication.","authors":"Inayat, Faisal; Riaz, Iqra; Ali, Nouman Safdar; Figueredo, Vincent M","year":2018,"journal":"BMJ case reports, 2018","doi":"10.1136/bcr-2018-225755","pmid":"29960973","tags":["cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient arrived with atypical left chest pain and dizziness that started 6 hours after smoking phencyclidine (PCP)-laced cannabis.\n\nThe ECG showed new deep biphasic T-wave inversions in anterolateral leads, a pattern characteristic of Wellens' syndrome, which typically indicates critical blockage of the left anterior descending artery and imminent heart attack risk.\n\nHowever, troponin levels were normal and coronary angiography revealed no coronary artery disease. The ECG changes resolved as the chest pain subsided, consistent with a drug-induced mimic rather than true coronary pathology.\n\nThe authors diagnosed pseudo-Wellens' syndrome caused by acute PCP and cannabis intoxication.","whyItMatters":"Emergency physicians encountering Wellens' syndrome ECG patterns need to consider drug intoxication as a cause, particularly in younger patients. Misdiagnosis could lead to unnecessary invasive cardiac procedures, while missing true Wellens' syndrome could be fatal.","specificNumbers":"Troponin T levels were normal. ECG showed sinus rhythm with new deep biphasic T-wave inversions in anterolateral leads. Coronary angiography showed no pathological processes. Symptoms and ECG changes resolved within 6 hours of onset.","methodology":"Single case report with ECG documentation, cardiac biomarker testing (troponin T), and coronary angiography to rule out true coronary artery disease.","limitations":"Single case report, so the findings cannot be generalized. The cannabis was laced with PCP, making it impossible to separate the cardiac effects of each substance. No follow-up data on whether the patient experienced recurrent episodes."},{"rthcId":"RTHC-01701","title":"Adolescent Brain Surface Area Pre- and Post-Cannabis and Alcohol Initiation.","authors":"Infante, M Alejandra; Courtney, Kelly E; Castro, Norma; Squeglia, Lindsay M; Jacobus, Joanna","year":2018,"journal":"Journal of studies on alcohol and drugs, 79(6), 835-843","doi":null,"pmid":"30573013","tags":["youth","neuroscience","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers obtained brain scans from 69 adolescents at baseline (ages 12-14, before any substance use) and again at follow-up (ages 17-21).\n\nParticipants were split into three groups: alcohol-only initiators, alcohol-plus-cannabis initiators, and minimal-use controls.\n\nAll groups showed surface area decreases over time (consistent with normal brain maturation), but the pattern differed by substance use.\n\nA significant group-by-time interaction appeared in three regions: bilateral medial orbitofrontal cortices and right insula. In these areas, the alcohol-only group showed more substantial surface area decreases than the alcohol-plus-cannabis group.\n\nThe right medial orbitofrontal cortex finding survived conservative vertex-wise analysis, with the alcohol-only group showing significantly greater surface area reduction compared to the combined alcohol-plus-cannabis group.","whyItMatters":"This is one of few studies with pre-substance-use baseline brain scans, which helps distinguish pre-existing brain differences from substance-induced changes. The unexpected finding that alcohol-only users showed greater surface area loss than cannabis-plus-alcohol users challenges assumptions about additive brain effects.","specificNumbers":"69 youth total (23 per group). Baseline ages 12-14, follow-up ages 17-21. Significant group-by-time interactions in bilateral medial orbitofrontal cortices and right insula. Right medial orbitofrontal cortex finding survived vertex-wise analysis at p < .001.","methodology":"Longitudinal neuroimaging study with baseline scans before substance use initiation and 6-year follow-up. Groups matched demographically. Used FreeSurfer parcellation of 34 cortical regions per hemisphere. Repeated measures ANCOVA for group comparisons with vertex-wise analysis for confirmation.","limitations":"Small sample size (23 per group) limits statistical power. Groups differed in substance use patterns beyond just the alcohol/cannabis distinction. Surface area is one metric of brain structure and may not capture functional changes. The alcohol-plus-cannabis group may have had different overall exposure levels."},{"rthcId":"RTHC-01702","title":"Heavy Episodic Drinking Trajectories Among Underage Young Adult Women: The Role of Feminine Norms.","authors":"Iwamoto, Derek Kenji; Corbin, William; Brady, Jennifer; Grivel, Margaux; Clinton, Lauren; Kaya, Aylin; Lejuez, Carl","year":2018,"journal":"Alcoholism, clinical and experimental research, 42(3), 551-560","doi":"10.1111/acer.13582","pmid":"29412467","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01703","title":"Synthesis of 13 C6 -labeled, dual-target inhibitor of cannabinoid-1 receptor (CB1 R) and inducible nitric oxide synthase (iNOS).","authors":"Iyer, Malliga R; Cinar, Resat; Coffey, Nathan J; Kunos, George","year":2018,"journal":"Journal of labelled compounds & radiopharmaceuticals","doi":"10.1002/jlcr.3639","pmid":"29790591","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01704","title":"Cannabis Use, Lung Cancer, and Related Issues.","authors":"Jett, James; Stone, Emily; Warren, Graham; Cummings, K Michael","year":2018,"journal":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 13(4), 480-487","doi":"10.1016/j.jtho.2017.12.013","pmid":"29374567","tags":["cancer","respiratory","medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the evidence on cannabis, lung cancer risk, and therapeutic applications in oncology.\n\nOn lung cancer risk: smoking cannabis has not been proven to be a risk factor for lung cancer development. However, the authors noted that existing studies are limited by small sample sizes, self-reporting errors, few heavy cannabis-only smokers in study populations, and confounding from concurrent tobacco use.\n\nOn therapeutic use: increasing evidence supports cannabis for managing chemotherapy-induced nausea and vomiting (CINV) and cancer-related pain. However, studies are limited by difficulties in standardizing doses and accurately measuring the biological activity of different cannabis compounds.\n\nThe authors called for controlled trials with standardized CBD and THC dosing to better establish both safety and therapeutic potential.","whyItMatters":"With cannabis use rising and cancer patients increasingly asking about it, this review from a major oncology journal provides a balanced assessment. The finding that cannabis smoking has not been proven to cause lung cancer is notable, though the authors are careful to emphasize the limitations of existing evidence rather than declaring it safe.","specificNumbers":"Millions of regular cannabis users worldwide were referenced. No specific risk ratios for lung cancer were established due to insufficient data quality.","methodology":"Narrative review of clinical and preclinical literature on cannabis, lung cancer, and cancer symptom management. Published in the Journal of Thoracic Oncology.","limitations":"Narrative review rather than systematic review or meta-analysis. Limited by the quality of underlying studies. The lung cancer safety question remains open rather than resolved."},{"rthcId":"RTHC-01705","title":"Validity of oral fluid test for Delta-9-tetrahydrocannabinol in drivers using the 2013 National Roadside Survey Data.","authors":"Jin, Huiyan; Williams, Sharifa Z; Chihuri, Stanford T; Li, Guohua; Chen, Qixuan","year":2018,"journal":"Injury epidemiology, 5(1), 3","doi":"10.1186/s40621-018-0134-2","pmid":"29457201","tags":["driving","potency","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared oral fluid and blood THC test results from 4,596 drivers stopped during the 2013 National Roadside Survey.\n\nOverall, 8.9% tested positive for THC in oral fluid and 9.4% in blood.\n\nUsing blood testing as the reference standard, oral fluid testing showed 79.4% sensitivity (correctly identifying positive cases) and 98.3% specificity (correctly identifying negative cases).\n\nHowever, oral fluid THC concentration was a poor predictor of actual blood THC levels. The log-transformed oral fluid concentration explained only 29% of the variation in blood THC concentration, meaning 71% of the variation was unexplained.\n\nA 10% increase in oral fluid THC concentration was associated with only a 2.4% increase in blood THC concentration.","whyItMatters":"Roadside drug testing for cannabis relies heavily on oral fluid because blood draws are impractical. This study confirms oral fluid works well for detecting whether someone has used cannabis but cannot reliably indicate how impaired they might be, which has major implications for traffic law enforcement.","specificNumbers":"4,596 drivers tested. 8.9% positive in oral fluid, 9.4% positive in blood. Sensitivity: 79.4% (95% CI: 75.2%-83.1%). Specificity: 98.3% (95% CI: 97.9%-98.7%). Oral fluid THC explained only 29% of blood THC variation. Each 10% oral fluid increase associated with 2.4% blood increase (95% CI: 2.1%-2.8%).","methodology":"Cross-sectional analysis of 4,596 drivers from the 2013 National Roadside Survey who provided both oral fluid and blood samples. Sensitivity/specificity analysis for detection, plus correlation and linear regression on log-transformed concentrations for quantitative comparison.","limitations":"Cross-sectional roadside data, so the timing of last cannabis use was unknown. Different oral fluid collection devices and blood sample handling could affect results. The study measured THC presence, not actual driving impairment."},{"rthcId":"RTHC-01706","title":"Chronic Δ9-THC in Rhesus Monkeys: Effects on Cognitive Performance and Dopamine D2/D3 Receptor Availability.","authors":"John, William S; Martin, Thomas J; Solingapuram Sai, Kiran Kumar; Nader, Susan H; Gage, H Donald; Mintz, Akiva; Nader, Michael A","year":2018,"journal":"The Journal of pharmacology and experimental therapeutics, 364(2), 300-310","doi":"10.1124/jpet.117.244194","pmid":"29203575","tags":["cognition","dopamine","neuroscience","tolerance"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Six adult male rhesus monkeys were tested on cognitive tasks using touchscreen tests (CANTAB) before and during 12 weeks of daily THC (1.0-2.0 mg/kg).\n\nAcute THC impaired cognitive performance in a task-specific manner and reduced food-motivated responding and body temperature.\n\nDuring chronic treatment, THC produced persistent residual impairment only to working memory, measured 22 hours after each dose. Other cognitive domains showed tolerance development.\n\nWorking memory recovered to baseline within two weeks of abstinence.\n\nPET imaging comparing four THC-treated monkeys to four drug-naive controls found no difference in dopamine D2/D3 receptor availability, suggesting the cognitive effects were not driven by changes in dopamine receptor density.\n\nThe authors suggested that interventions targeting working memory could improve treatment outcomes for cannabis use disorder.","whyItMatters":"This primate study provides a controlled look at how chronic THC affects cognition over time, something impossible to study as rigorously in humans. The finding that working memory was selectively vulnerable while other functions showed tolerance is clinically relevant for understanding cannabis use disorder.","specificNumbers":"6 monkeys, 12 weeks of daily THC (1.0-2.0 mg/kg s.c.). Working memory was the only domain with persistent residual impairment at 22 hours post-dose. Recovery occurred within 2 weeks of abstinence. No significant difference in D2/D3 receptor availability between 4 THC-treated and 4 control monkeys.","methodology":"Primate study with six rhesus monkeys. Acute THC dose-response testing followed by 12 weeks of daily chronic THC. Cognitive assessment via CANTAB touchscreen battery. Dopamine D2/D3 receptor availability measured by PET with [11C]-raclopride in a subgroup (4 THC-treated vs 4 controls).","limitations":"Very small sample size (6 monkeys, 4 per group for PET). Only male monkeys studied. THC doses may not map directly to human consumption patterns. D2/D3 receptors are one component of the dopamine system; other aspects (release, synthesis, D1 receptors) were not measured."},{"rthcId":"RTHC-01707","title":"Exploring the Ligand Efficacy of Cannabinoid Receptor 1 (CB1) using Molecular Dynamics Simulations.","authors":"Jung, Sang Won; Cho, Art E; Yu, Wookyung","year":2018,"journal":"Scientific reports, 8(1), 13787","doi":"10.1038/s41598-018-31749-z","pmid":"30213978","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01708","title":"The relation between gray matter volume and the use of alcohol, tobacco, cocaine and cannabis in male polysubstance users.","authors":"Kaag, A M; Schulte, M H J; Jansen, J M; van Wingen, G; Homberg, J; van den Brink, W; Wiers, R W; Schmaal, L; Goudriaan, A E; Reneman, L","year":2018,"journal":"Drug and alcohol dependence, 187, 186-194","doi":"10.1016/j.drugalcdep.2018.03.010","pmid":"29679913","tags":["neuroscience","cognition","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers measured gray matter volume in 169 men across six groups ranging from non-users to heavy polysubstance users (alcohol, tobacco, cocaine, and cannabis).\n\nThe number of substances used was negatively associated with volume in the dorsal and ventral medial prefrontal cortex (mPFC). More substances used correlated with less volume in these regions.\n\nWithout controlling for other substances, alcohol, tobacco, and cocaine all showed negative associations with dorsal mPFC volume. But after controlling for polysubstance use, these associations disappeared for the mPFC.\n\nSubstance-specific effects did emerge in other regions: tobacco was specifically associated with reduced thalamic volume, and cocaine with reduced ventrolateral PFC volume, even after accounting for other substance use.\n\nCannabis did not show independent effects on gray matter volume after controlling for other substance use.","whyItMatters":"Most brain imaging studies of cannabis users do not adequately control for polysubstance use. This study demonstrates that brain volume differences often attributed to individual substances may actually reflect cumulative polysubstance exposure, which changes how we interpret neuroimaging findings.","specificNumbers":"169 males: 15 non-users, 89 moderate drinkers, 27 drinkers + tobacco, 13 drinkers + tobacco + cocaine, 10 heavy drinkers + tobacco + cocaine, 15 heavy drinkers + tobacco + cannabis + cocaine. Dorsal and ventral mPFC volume negatively correlated with number of substances.","methodology":"Cross-sectional neuroimaging study of 169 males in six substance use groups. Voxel-based morphometry for gray matter volume. Regression analyses with and without controlling for co-occurring substance use.","limitations":"Cross-sectional design cannot establish causation. All-male sample limits generalizability. Cannabis users were only in the heaviest polysubstance group, making it hard to isolate cannabis-specific effects. No pre-substance-use baseline measurements."},{"rthcId":"RTHC-01709","title":"Cannabis use predicts risks of heart failure and cerebrovascular accidents: results from the National Inpatient Sample.","authors":"Kalla, Aditi; Krishnamoorthy, Parasuram M; Gopalakrishnan, Akshaya; Figueredo, Vincent M","year":2018,"journal":"Journal of cardiovascular medicine (Hagerstown, Md.), 19(9), 480-484","doi":"10.2459/JCM.0000000000000681","pmid":"29879084","tags":["cardiovascular","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers identified cannabis users aged 18-55 in the National Inpatient Sample 2009-2010 database and compared their cardiovascular outcomes to the general population.\n\nPrevalence of heart failure, stroke, coronary artery disease, sudden cardiac death, and hypertension were all significantly higher in cannabis users.\n\nAfter multivariate regression adjusting for age, sex, hypertension, diabetes, hyperlipidemia, coronary artery disease, tobacco use, and alcohol use, cannabis use remained an independent predictor of heart failure (OR 1.1, 95% CI 1.03-1.18) and stroke (OR 1.24, 95% CI 1.14-1.34).\n\nThe stroke association was notably stronger than the heart failure association.","whyItMatters":"As cannabis use becomes more widespread, understanding cardiovascular risks matters for public health. This large database study suggests cannabis may carry independent cardiovascular risk even in younger adults, a population typically considered low-risk for heart failure and stroke.","specificNumbers":"Cannabis use independently predicted heart failure (OR 1.1, 95% CI 1.03-1.18, p < 0.01) and stroke (OR 1.24, 95% CI 1.14-1.34, p < 0.001) after adjusting for age, sex, hypertension, diabetes, hyperlipidemia, coronary artery disease, tobacco, and alcohol use.","methodology":"Retrospective analysis of the National Inpatient Sample 2009-2010. Cannabis use identified by ICD-9 code 304.3 (cannabis dependence). Multivariate logistic regression adjusting for traditional cardiovascular risk factors.","limitations":"Retrospective database study relying on ICD-9 codes, which likely undercount cannabis use and only capture those with documented cannabis dependence. Cannot determine dose, frequency, or method of cannabis use. Cannot establish causation. Hospitalized patients may not represent all cannabis users."},{"rthcId":"RTHC-01710","title":"Cannabis and the Anxiety of Fragmentation-A Systems Approach for Finding an Anxiolytic Cannabis Chemotype.","authors":"Kamal, Brishna S; Kamal, Fatima; Lantela, Daniel E","year":2018,"journal":"Frontiers in neuroscience, 12, 730","doi":"10.3389/fnins.2018.00730","pmid":"30405331","tags":["anxiety","cbd","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Medical cannabis patients receiving organically grown cannabis from a single source rated cannabis as highly effective for anxiety (average 8.03 out of 10 on a Likert scale).\n\nPatients identified which strains they found most and least effective for anxiety. The top four and bottom four strains were then chemically analyzed by HPLC-MS/MS (for cannabinoids) and GC-MS (for terpenes).\n\nTHC and trans-nerolidol showed statistically significant correlations with increased anxiety relief.\n\nSix terpenes correlated with decreased anxiety relief: guaiol, eucalyptol, γ-terpinene, α-phellandrene, 3-carene, and sabinene hydrate.\n\nThe findings support the \"entourage effect\" hypothesis, suggesting that the therapeutic profile of cannabis for anxiety depends on the specific combination of cannabinoids and terpenes, not just THC or CBD levels alone.","whyItMatters":"Most cannabis-for-anxiety research focuses on THC and CBD. This study takes a systems approach, analyzing terpene profiles alongside cannabinoids to identify which chemical signatures are associated with anxiety relief. This could eventually help guide strain selection for patients.","specificNumbers":"Average anxiety relief rating: 8.03/10. THC and trans-nerolidol positively correlated with anxiolytic activity (statistically significant). Six terpenes negatively correlated: guaiol, eucalyptol, γ-terpinene, α-phellandrene, 3-carene, sabinene hydrate.","methodology":"Patient survey combined with chemical analysis. Medical cannabis patients rated strain effectiveness for anxiety. Top and bottom strains analyzed by HPLC-MS/MS (cannabinoids) and GC-MS (terpenes). Statistical correlations between chemical profiles and patient-reported effectiveness.","limitations":"Small number of strains analyzed (top 4 and bottom 4). Patient self-report is subjective and susceptible to expectation effects. Single-source cannabis limits generalizability. Correlational design cannot establish which compounds are causing the effects."},{"rthcId":"RTHC-01711","title":"Potential of an Interactive Drug Prevention Mobile Phone App (Once Upon a High): Questionnaire Study Among Students.","authors":"Kapitány-Fövény, Máté; Vagdalt, Eszter; Ruttkay, Zsófia; Urbán, Róbert; Richman, Mara J; Demetrovics, Zsolt","year":2018,"journal":"JMIR serious games, 6(4), e19","doi":"10.2196/games.9944","pmid":"30514697","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01712","title":"\"Where does the high road lead?\" Potential implications of cannabis legalization for pediatric injuries in Canada.","authors":"Karbakhsh, Mojgan; Smith, Jennifer; Pike, Ian","year":2018,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 109(5-6), 752-755","doi":"10.17269/s41997-018-0137-3","pmid":"30264194","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01713","title":"Cannabinoid Hyperemesis Syndrome and the Consulting Psychiatrist: A Case Study of Diagnosis and Treatment for an Emerging Disorder in Psychiatric Practice.","authors":"Kast, Kristopher A; Gershengoren, Liliya","year":2018,"journal":"Journal of psychiatric practice, 24(1), 51-55","doi":"10.1097/PRA.0000000000000279","pmid":"29320384","tags":["harm-reduction","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with cannabinoid hyperemesis syndrome was initially misdiagnosed, requiring psychiatric consultation for proper identification.\n\nCHS involves cyclic episodes of severe nausea and vomiting in chronic cannabis users, often with compulsive hot bathing for symptom relief. It resolves with cannabis cessation.\n\nThe patient was successfully treated with intravenous haloperidol, an antipsychotic not typically used for nausea but increasingly reported as effective for CHS.\n\nThe authors reviewed literature from emergency medicine, toxicology, and gastroenterology, including proposed diagnostic criteria and off-label treatment options for CHS, with emphasis on what consulting psychiatrists need to know about this condition.","whyItMatters":"CHS is increasingly common as cannabis use rises, but it is frequently misdiagnosed because many clinicians (including psychiatrists) are unfamiliar with it. Patients may undergo extensive and unnecessary gastrointestinal workups before the correct diagnosis is reached.","specificNumbers":"Treatment with intravenous haloperidol was effective. Specific dosing and timeline details were reported in the case.","methodology":"Single case report with literature review. Included proposed diagnostic criteria for CHS and review of treatment options across multiple medical specialties.","limitations":"Single case report. Haloperidol effectiveness for CHS is based on case reports and small series, not randomized trials. The mechanism by which haloperidol helps CHS is not fully understood."},{"rthcId":"RTHC-01714","title":"Short-Term Genetic Selection for Adolescent Locomotor Sensitivity to Delta9-Tetrahydrocannabinol (THC).","authors":"Kasten, Chelsea R; Zhang, Yanping; Mackie, Ken; Boehm, Stephen L","year":2018,"journal":"Behavior genetics, 48(3), 224-235","doi":"10.1007/s10519-018-9894-2","pmid":"29550900","tags":["genetics","neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers selectively bred mice for sensitivity or resistance to the locomotor effects of a single THC dose (10 mg/kg) during adolescence.\n\nTHC-locomotor sensitivity proved to be moderately heritable, with the strongest heritability estimates seen in females from the F2 to S3 generations.\n\nAn important correlated trait emerged: mice selected for THC-locomotor sensitivity also showed increased anxiety-like activity in the open field test, suggesting shared genetic factors between THC sensitivity and anxiety.\n\nThis is the first demonstration that adolescent THC-locomotor sensitivity can be influenced through selective breeding, establishing a genetic basis for individual differences in cannabis response.","whyItMatters":"Individual differences in cannabis response are well-documented but poorly understood. This study establishes a genetic foundation for these differences and reveals that genetic predisposition to THC sensitivity co-occurs with anxiety-related traits, which could help explain why some individuals are more vulnerable to negative cannabis effects.","specificNumbers":"THC dose: 10 mg/kg. Selection was moderately heritable. Greatest heritability estimates in females from F2 to S3 generations. THC-sensitive lines showed significantly increased anxiety-like behavior in open field.","methodology":"Short-term selective breeding (bidirectional selection) for adolescent locomotor response to acute THC (10 mg/kg i.p.) in the open field test. Heritability estimated across generations. Anxiety-like behavior assessed as a correlated trait.","limitations":"Mouse model may not fully translate to human genetics of cannabis response. Short-term selective breeding (few generations). Only locomotor sensitivity was selected for; other aspects of THC response (reward, cognition) were not directly assessed."},{"rthcId":"RTHC-01715","title":"Cannabinoids for the treatment of rheumatic diseases - where do we stand?","authors":"Katz-Talmor, Daphna; Katz, Itay; Porat-Katz, Bat-Sheva; Shoenfeld, Yehuda","year":2018,"journal":"Nature reviews. Rheumatology, 14(8), 488-498","doi":"10.1038/s41584-018-0025-5","pmid":"29884803","tags":["medical-cannabis","pain","inflammation","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the available evidence on cannabinoids for rheumatic diseases.\n\nPreliminary clinical trials have explored cannabis effects on rheumatoid arthritis, osteoarthritis, and fibromyalgia. Additional preclinical evidence links the cannabinoid system to systemic sclerosis and juvenile idiopathic arthritis.\n\nCannabinoids exert immunomodulatory effects on multiple immune cell types including T cells, B cells, and macrophages, which is theoretically relevant to autoimmune rheumatic conditions.\n\nPain is considered a prevalent indication for medicinal cannabis in countries where it is legal, and rheumatic disease pain is a common reason patients seek cannabis.\n\nHowever, the authors concluded that available evidence is not sufficient to support recommending cannabinoid treatment for rheumatic diseases, calling for more rigorous research.","whyItMatters":"Rheumatic disease patients are among the most common users of medical cannabis for pain, yet rheumatologists have limited evidence to guide them. This high-profile review from a top rheumatology journal summarizes what is and is not known.","specificNumbers":"Preliminary trials covered rheumatoid arthritis, osteoarthritis, and fibromyalgia. Immunomodulatory effects documented on T cells, B cells, and macrophages. Associations noted with systemic sclerosis and juvenile idiopathic arthritis.","methodology":"Narrative review published in Nature Reviews Rheumatology covering clinical trials, preclinical studies, and immunological research on cannabinoids in rheumatic disease contexts.","limitations":"Narrative review rather than systematic review. Available primary studies are small, few, and methodologically limited. The authors acknowledge that evidence is insufficient for clinical recommendations."},{"rthcId":"RTHC-01716","title":"Profiles of Patients Who Use Marijuana for Inflammatory Bowel Disease.","authors":"Kerlin, Ann Marie; Long, Millie; Kappelman, Michael; Martin, Christopher; Sandler, Robert S","year":2018,"journal":"Digestive diseases and sciences, 63(6), 1600-1604","doi":"10.1007/s10620-018-5040-5","pmid":"29594968","tags":["medical-cannabis","inflammation","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 2,357 inflammatory bowel disease patients living in states where marijuana was legal, with 1,666 (71%) completing the survey.\n\nOnly 214 patients (12.8%) had asked their doctor about marijuana use, and just 73 (4.4%) used prescription marijuana.\n\nAmong 234 patients living where both medical and recreational marijuana was legal, 49 (20.9%) reported using recreational marijuana specifically for IBD.\n\nMarijuana users reported high perceived benefits (80.7%). However, users also reported more depression, anxiety, pain interference, and lower social satisfaction than non-users.\n\nPatients on prescription marijuana had more active disease and greater use of steroids, narcotics, and the sleep aid zolpidem, suggesting marijuana use was concentrated among those with harder-to-treat disease.","whyItMatters":"This study reveals a common pattern in medical cannabis use: patients who use it tend to be sicker and more symptomatic, which complicates the interpretation of both perceived benefits and associated harms. The low rate of physician consultation (12.8%) suggests a disconnect between patient cannabis use and clinical care.","specificNumbers":"1,666 respondents (71% response rate). 12.8% asked their doctor about marijuana. 4.4% used prescription marijuana. 20.9% recreational use in dual-legal states. 80.7% of users reported benefits. Users had more depression, anxiety, pain interference, and lower social satisfaction.","methodology":"Cross-sectional internet-based survey through the CCFA Partners cohort. Surveyed IBD patients in states with legal marijuana access. Bivariate statistics and logistic regression to identify factors associated with marijuana use.","limitations":"Cross-sectional design cannot determine whether cannabis helped, hurt, or had no effect on symptoms. Self-selected internet cohort may not represent all IBD patients. Self-reported cannabis use and perceived benefits are subject to recall and desirability bias."},{"rthcId":"RTHC-01717","title":"Risks and Benefits of Marijuana Use: A National Survey of U.S. Adults.","authors":"Keyhani, Salomeh; Steigerwald, Stacey; Ishida, Julie; Vali, Marzieh; Cerdá, Magdalena; Hasin, Deborah; Dollinger, Camille; Yoo, Sodahm R; Cohen, Beth E","year":2018,"journal":"Annals of internal medicine, 169(5), 282-290","doi":"10.7326/M18-0810","pmid":"30039154","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Researchers surveyed a probability-based sample of 16,280 U.S. adults in 2017, with 9,003 responding (55.3% response rate).\n\nAbout 14.6% reported using marijuana in the past year.\n\nBelief in benefits was widespread: 81% cited at least one benefit. The most common: pain management (66%), treating diseases like epilepsy and MS (48%), and anxiety/stress/depression relief (47%).\n\nRisk awareness was also high: 91% identified at least one risk. Top risks cited: legal problems (51.8%), addiction (50%), and impaired memory (42%).\n\nSeveral beliefs diverged from established evidence: 29.2% agreed that smoking marijuana prevents health problems. About 18% believed secondhand marijuana smoke is safe for adults, and 7.6% believed it is safe for children. Only 7.3% considered marijuana use safe during pregnancy. About 22.4% believed marijuana is not at all addictive.\n\nThe authors concluded that Americans' views of marijuana are more favorable than existing evidence supports.","whyItMatters":"Public perception drives policy and personal health decisions. When a significant portion of the public believes marijuana prevents health problems or is not addictive, this creates a gap between perception and evidence that has real consequences for individual health choices and public health messaging.","specificNumbers":"9,003 respondents (55.3% response rate). 14.6% past-year use. 81% cited at least 1 benefit. 91% cited at least 1 risk. 66% cited pain management as a benefit. 29.2% believed smoking prevents health problems. 22.4% believed marijuana is not at all addictive. 7.3% considered use safe during pregnancy.","methodology":"Probability-based online survey of 16,280 U.S. adults in 2017 using the GfK KnowledgePanel. 55.3% response rate (n = 9,003). Funded by the National Heart, Lung, and Blood Institute.","limitations":"Online survey with 55.3% response rate, so non-responders may differ systematically. Self-reported marijuana use likely underestimates true prevalence. Survey wording may have influenced responses. Cross-sectional snapshot from 2017."},{"rthcId":"RTHC-01718","title":"Emergency Department Treatment of Cannabinoid Hyperemesis Syndrome: A Review.","authors":"Khattar, Neera; Routsolias, Joanne C","year":2018,"journal":"American journal of therapeutics, 25(3), e357-e361","doi":"10.1097/MJT.0000000000000655","pmid":"28953512","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01719","title":"Recurrent Nausea and Vomiting in a Pregnant Woman with Chronic Marijuana Use.","authors":"Kim, Hyunyoung G; Moon, Jeremiah; Dixon, Heather; Tullar, Paul","year":2018,"journal":"Case reports in obstetrics and gynecology, 2018, 9746062","doi":"10.1155/2018/9746062","pmid":"30305971","tags":["pregnancy","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 20-year-old pregnant woman was admitted multiple times for recurrent nausea and vomiting. She was initially assumed to have hyperemesis gravidarum, a common pregnancy complication.\n\nClinicians observed that she was taking frequent hot showers, a hallmark behavior of cannabinoid hyperemesis syndrome (CHS). Further history revealed chronic cannabis use.\n\nWith no other identifiable cause for her symptoms, she was diagnosed with CHS and managed with antiemetics and cannabis abstinence.\n\nThe case highlights how CHS can be masked by pregnancy because its symptoms closely resemble hyperemesis gravidarum, leading to delayed diagnosis and unnecessary workups.","whyItMatters":"Cannabis use during pregnancy is increasing, and CHS in pregnant women is likely underdiagnosed because nausea and vomiting are expected pregnancy symptoms. Misattributing CHS to hyperemesis gravidarum delays the key intervention (cannabis cessation) and exposes the fetus to continued cannabis.","specificNumbers":"Patient was 20 years old with multiple hospital admissions. Daily cannabis use preceded the onset of symptoms. Symptoms resolved with antiemetics and cannabis abstinence.","methodology":"Single case report of a 20-year-old pregnant woman with multiple hospital admissions. Diagnosis reached by exclusion of other causes and recognition of compulsive hot shower behavior.","limitations":"Single case report. No objective confirmation of CHS diagnosis beyond symptom resolution with cannabis cessation. The patient may have had concurrent hyperemesis gravidarum."},{"rthcId":"RTHC-01720","title":"The Impact of Cannabis Use Disorder on Suicidal and Nonsuicidal Self-Injury in Iraq/Afghanistan-Era Veterans with and without Mental Health Disorders.","authors":"Kimbrel, Nathan A; Meyer, Eric C; DeBeer, Bryann B; Gulliver, Suzy B; Morissette, Sandra B","year":2018,"journal":"Suicide & life-threatening behavior, 48(2), 140-148","doi":"10.1111/sltb.12345","pmid":"28295524","tags":["mental-health","addiction","ptsd"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined the association between cannabis use disorder (CUD) and self-injury among Iraq/Afghanistan-era veterans.\n\nAfter adjusting for sex, age, sexual orientation, combat exposure, traumatic life events, traumatic brain injury, PTSD, depression, alcohol use disorder, and non-cannabis drug use disorder, CUD remained significantly associated with both suicidal self-injury (OR 3.10, p = .045) and nonsuicidal self-injury (OR 5.12, p = .009).\n\nCUD was the only variable significantly associated with self-injury across all three statistical models (combined, suicidal, and nonsuicidal).\n\nThe findings are consistent with prior civilian research and suggest CUD may increase veterans' risk for self-injurious behavior.","whyItMatters":"Veteran suicide prevention is a major public health priority. The finding that cannabis use disorder was more consistently associated with self-injury than PTSD, depression, or alcohol use disorder challenges assumptions about which risk factors deserve the most clinical attention in this population.","specificNumbers":"CUD associated with suicidal self-injury: OR 3.10, p = .045. CUD associated with nonsuicidal self-injury: OR 5.12, p = .009. CUD was the only variable significant across all three regression models.","methodology":"Cross-sectional analysis of Iraq/Afghanistan-era veterans. Self-injury assessed as both suicidal and nonsuicidal. Logistic regression adjusting for multiple established risk factors for self-injury including combat exposure, PTSD, depression, TBI, and substance use disorders.","limitations":"Cross-sectional design cannot establish whether CUD causes self-injury or whether both reflect a shared underlying vulnerability. Self-reported measures of cannabis use and self-injury. The study assessed cannabis use disorder, not cannabis use in general, so findings may not apply to controlled cannabis use."},{"rthcId":"RTHC-01721","title":"Cannabinoid Hyperemesis Syndrome Masquerading as Uremia: An Educational Case Report.","authors":"Klassen, Judith; Wilson, Gail","year":2018,"journal":"Canadian journal of kidney health and disease, 5, 2054358118791146","doi":"10.1177/2054358118791146","pmid":"30159161","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 37-year-old man with bipolar disorder (treated with lithium) had progressive renal insufficiency from interstitial fibrosis. When he developed persistent severe nausea and vomiting, it was attributed to uremia (toxin buildup from kidney failure).\n\nDialysis was initiated but did not improve his symptoms. Multiple investigations found no other cause.\n\nThe patient had a history of daily marijuana use that predated the nausea and vomiting. When he stopped using marijuana, his symptoms resolved completely.\n\nHe elected to discontinue dialysis and was still alive 7 months later, confirming that the nausea was not uremia-driven.\n\nThe case illustrates how CHS can masquerade as uremic symptoms in patients with coexisting kidney disease, potentially leading to unnecessary dialysis.","whyItMatters":"Dialysis is a major medical intervention with significant impact on quality of life. This case shows that CHS can mimic uremic symptoms convincingly enough to trigger dialysis initiation. In patients with kidney disease who also use cannabis, CHS should be considered before attributing vomiting to uremia.","specificNumbers":"Patient was 37 years old. Daily marijuana use. Dialysis initiated but ineffective. Symptoms resolved with marijuana cessation. Patient alive and off dialysis 7 months later.","methodology":"Single case report with clinical follow-up. Diagnosis of CHS confirmed by symptom resolution with marijuana cessation and lack of improvement with dialysis.","limitations":"Single case report. The patient did have real kidney disease, so some component of his symptoms could have been uremic. The definitive test (symptom resolution with cessation) is retrospective."},{"rthcId":"RTHC-01722","title":"Attention deficit hyperactivity disorder and arrest history: Differential association of clinical characteristics by sex.","authors":"Kolla, Nathan J; van der Maas, Mark; Erickson, Patricia G; Mann, Robert E; Seeley, Jane; Vingilis, Evelyn","year":2018,"journal":"International journal of law and psychiatry, 58, 150-156","doi":"10.1016/j.ijlp.2018.04.006","pmid":"29853005","tags":["addiction","mental-health","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 5,196 Ontario adults to examine whether ADHD predicted arrest history after controlling for other criminogenic factors.\n\nIn the combined sample, conduct disorder symptoms, problematic alcohol use, and problematic cannabis use all predicted arrest history. ADHD did not.\n\nSex-specific analyses revealed important differences:\n- For men: conduct disorder symptoms, alcohol problems, cannabis problems, and general distress predicted arrests.\n- For women: only conduct disorder symptoms and problematic cannabis use predicted arrests.\n\nNotably, conduct disorder symptoms and cannabis misuse had stronger effects on arrest history for women than for men.\n\nADHD did not predict arrest history in any model, suggesting that earlier studies linking ADHD to criminality may have been confounded by co-occurring conduct disorder and substance use.","whyItMatters":"This challenges the commonly cited link between ADHD and criminality by showing it disappears when conduct disorder and substance use are properly controlled. The sex-specific finding that cannabis misuse was a stronger predictor of arrests for women than men adds nuance to understanding gendered pathways to criminal justice involvement.","specificNumbers":"5,196 adults surveyed. Cannabis misuse and conduct disorder were significant predictors of arrest in the combined sample. Both had stronger effects for women than men. ADHD was not significant in any of the three models.","methodology":"Telephone population survey of 5,196 Ontario adults. ADHD screened with ASRS-V1.1. Cannabis misuse assessed with ASSIST. Conduct disorder assessed with MINI. Three separate logistic regression analyses (combined, male, female).","limitations":"Cross-sectional self-report survey. Arrest history is self-reported and may be subject to recall or social desirability bias. Ontario-specific findings may not generalize to other jurisdictions. Cannabis \"misuse\" as defined by screening tools may capture a wide range of use patterns."},{"rthcId":"RTHC-01723","title":"Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes.","authors":"Kong, Tae Yeon; Kim, Ju-Hyun; Kim, Dong Kyun; Lee, Hye Suk","year":2018,"journal":"Archives of pharmacal research, 41(7), 691-710","doi":"10.1007/s12272-018-1055-x","pmid":"30039377","tags":["synthetic-cannabinoids","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the metabolism of 13 prevalent synthetic cannabinoids, mapping which cytochrome P450 (CYP) enzymes, UDP-glucuronosyltransferases (UGTs), and carboxylesterases are responsible for breaking them down.\n\nSynthetic cannabinoids are substrates of multiple drug-metabolizing enzymes, meaning these enzymes process and eliminate them from the body.\n\nCritically, synthetic cannabinoids also inhibit CYP and UGT enzymes. This means they can interfere with the metabolism of other drugs taken concurrently, potentially causing dangerous increases in blood levels of co-administered medications.\n\nThe review emphasized the urgency of understanding these interactions given the rise in synthetic cannabinoid poisonings and the likelihood that users are taking multiple substances simultaneously.","whyItMatters":"Synthetic cannabinoid users frequently use other drugs simultaneously, and emergency departments are seeing increasing poisoning cases. Understanding which enzymes process these substances and which other drugs might interact is essential for toxicology and emergency medicine.","specificNumbers":"13 synthetic cannabinoids reviewed. Multiple CYP enzymes, UGTs, and carboxylesterases identified as metabolizing enzymes. Inhibitory effects on CYP and UGT activities documented for predicting drug-drug interactions.","methodology":"Comprehensive review of published literature on metabolic pathways of 13 prevalent synthetic cannabinoids. Covered CYP enzyme characterization, UGT involvement, and inhibition studies.","limitations":"Review of existing literature, which is incomplete for many newer synthetic cannabinoids. In vitro enzyme studies may not perfectly predict in vivo drug interactions. The rapid emergence of new compounds means the review is inherently incomplete."},{"rthcId":"RTHC-01724","title":"Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation.","authors":"Krcevski-Skvarc, N; Wells, C; Häuser, W","year":2018,"journal":"European journal of pain (London, England), 22(3), 440-454","doi":"10.1002/ejp.1147","pmid":"29134767","tags":["medical-cannabis","legalization","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The European Pain Federation (EFIC) surveyed its national chapters on the status of cannabis-based medicines for chronic pain and palliative care.\n\n31 of 37 chapters responded, revealing large disparities:\n\nTHC/CBD oromucosal spray (Sativex) was approved for MS spasticity in 21 chapters. Plant-derived THC (dronabinol) was approved for palliative care in only 4 chapters. Synthetic THC (nabilone) was approved for chemo-related nausea in 4 chapters.\n\n8 chapters had exceptional access programs and 6 had expanded access for medical cannabis.\n\nOnly the German and Israeli pain societies recommended cannabis-based medicines as third-line therapy for chronic pain. Conversely, the German medical association and Finnish experts did not recommend prescribing medical cannabis, citing insufficient evidence.\n\nCost coverage by insurance or state systems varied enormously across countries.","whyItMatters":"Patients with identical conditions receive vastly different access to cannabis-based medicines depending on which European country they live in. This patchwork of policies creates inequity and reflects the tension between patient demand, political pressure, and evidence requirements.","specificNumbers":"31 of 37 EFIC chapters responded. THC/CBD spray approved in 21 chapters. Dronabinol approved in 4 chapters. Nabilone approved in 4 chapters. 8 chapters with exceptional access, 6 with expanded access programs.","methodology":"Survey of European Pain Federation national chapter representatives (31 of 37 responded). Assessed approval status, access programs, cost coverage, and professional society positions on cannabis-based medicines.","limitations":"Survey methodology with potential for incomplete or outdated responses. Rapidly evolving regulatory landscape means findings may not reflect current status. Did not assess actual prescribing rates or patient access beyond formal approval."},{"rthcId":"RTHC-01725","title":"Medical cannabis in the treatment of cancer pain and spastic conditions and options of drug delivery in clinical practice.","authors":"Landa, Leos; Jurica, Jan; Sliva, Jiri; Pechackova, Monika; Demlova, Regina","year":2018,"journal":"Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, 162(1), 18-25","doi":"10.5507/bp.2018.007","pmid":"29560966","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01726","title":"Cannabinoid Hyperemesis Syndrome: Public Health Implications and a Novel Model Treatment Guideline.","authors":"Lapoint, Jeff; Meyer, Seth; Yu, Charles K; Koenig, Kristi L; Lev, Roneet; Thihalolipavan, Sayone; Staats, Katherine; Kahn, Christopher A","year":2018,"journal":"The western journal of emergency medicine, 19(2), 380-386","doi":"10.5811/westjem.2017.11.36368","pmid":"29560069","tags":["harm-reduction","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The San Diego Emergency Medicine Oversight Commission, county health services, and Kaiser Permanente toxicology created an expert consensus guideline for CHS treatment.\n\nKey recommendations:\n- Treatment should focus on symptom relief and patient education about cannabis cessation.\n- Topical capsaicin (the active compound in chili peppers) is recommended as a first-line treatment. It is readily available and mimics the symptom relief patients seek from hot showers.\n- Antipsychotics (haloperidol and olanzapine) have been reported to provide complete symptom relief in limited case studies.\n- Conventional antiemetics including antihistamines, serotonin antagonists, dopamine antagonists, and benzodiazepines may have limited effectiveness.\n- Emergency physicians should avoid opioids if CHS diagnosis is certain.\n- Cannabis cessation is the only intervention that provides complete, lasting symptom relief.\n\nThe guideline was designed to reduce unnecessary opioid exposure, minimize healthcare resource use, and improve patient safety.","whyItMatters":"CHS patients often receive repeated ED visits with expensive workups, unnecessary procedures, and opioid prescriptions that do not address the underlying problem. A standardized treatment guideline can reduce costs, improve outcomes, and avoid contributing to opioid exposure.","specificNumbers":"Capsaicin recommended as first-line. Haloperidol and olanzapine reported to provide complete relief in limited studies. Conventional antiemetics described as having limited effectiveness.","methodology":"Expert consensus panel including emergency medicine oversight, public health, and medical toxicology. Literature review informing guideline development.","limitations":"Consensus-based guideline rather than evidence-based practice guideline. Underlying evidence is primarily case reports and case series. No randomized controlled trials of CHS treatments existed at the time of publication."},{"rthcId":"RTHC-01727","title":"Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis.","authors":"Lattanzi, Simona; Brigo, Francesco; Trinka, Eugen; Zaccara, Gaetano; Cagnetti, Claudia; Del Giovane, Cinzia; Silvestrini, Mauro","year":2018,"journal":"Drugs, 78(17), 1791-1804","doi":"10.1007/s40265-018-0992-5","pmid":"30390221","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Researchers pooled data from four randomized, placebo-controlled trials of oral CBD as add-on therapy in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) whose seizures were not controlled by existing medications.\n\nBoth CBD dose levels showed similar efficacy: the pooled difference in seizure frequency reduction was 19.5 percentage points (95% CI 8.1-31.0) for 10 mg/kg/day and 19.9 percentage points (95% CI 11.8-28.1) for 20 mg/kg/day compared to placebo.\n\nThe higher dose carried more risk: treatment withdrawal risk was 4.20 times higher for 20 mg/kg/day (95% CI 1.82-9.68) versus placebo but not significantly elevated for 10 mg/kg/day (RR 1.45, 95% CI 0.28-7.41).\n\nAdverse events occurred in 87.9% of CBD patients versus 72.2% on placebo (RR 1.22). The most common side effects were somnolence, decreased appetite, diarrhea, and elevated liver enzymes.\n\nAdverse event-related treatment discontinuation was significantly higher with CBD (8.9% vs 1.8%).","whyItMatters":"This meta-analysis provided key evidence supporting CBD as a treatment for severe childhood epilepsies. The finding that 10 mg/kg/day was similarly effective but safer than 20 mg/kg/day has practical implications for dosing, as it suggests the lower dose may offer a better benefit-risk balance.","specificNumbers":"550 patients across 4 trials. Seizure reduction vs placebo: ~20 percentage points for both doses. Adverse events: 87.9% CBD vs 72.2% placebo. Treatment withdrawal RR for 20 mg: 4.20 (p = .001). Treatment withdrawal RR for 10 mg: 1.45 (not significant). Somnolence, decreased appetite, diarrhea, and elevated aminotransferases were the main side effects.","methodology":"Systematic review and meta-analysis of four randomized, placebo-controlled, blinded trials. 550 patients with LGS or DS. Risk ratios calculated with 95% confidence intervals via inverse variance method.","limitations":"Only four trials available, all in LGS and DS specifically. Results may not generalize to other epilepsy types. All trials used pharmaceutical-grade CBD (Epidiolex), so findings do not apply to unregulated CBD products. Short trial durations limit understanding of long-term safety."},{"rthcId":"RTHC-01728","title":"Efficacy and Safety of Adjunctive Cannabidiol in Patients with Lennox-Gastaut Syndrome: A Systematic Review and Meta-Analysis.","authors":"Lattanzi, Simona; Brigo, Francesco; Cagnetti, Claudia; Trinka, Eugen; Silvestrini, Mauro","year":2018,"journal":"CNS drugs, 32(10), 905-916","doi":"10.1007/s40263-018-0558-9","pmid":"30132269","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01729","title":"Growing practices and the use of potentially harmful chemical additives among a sample of small-scale cannabis growers in three countries.","authors":"Lenton, Simon; Frank, Vibeke A; Barratt, Monica J; Potter, Gary R; Decorte, Tom","year":2018,"journal":"Drug and alcohol dependence, 192, 250-256","doi":"10.1016/j.drugalcdep.2018.07.040","pmid":"30292153","tags":["harm-reduction","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 1,722 current and recent small-scale recreational cannabis growers across three countries about their growing practices.\n\nOverall, 44% reported using any chemical fertilizers, supplements, or insecticides.\n\nLogistic regression found that hydroponic growing was the only significant predictor of chemical use. Other factors like country, experience level, or scale did not independently predict chemical use.\n\nA major concern was plant growth regulators (PGRs), which limit plant size and stimulate bud production. Many PGRs have been banned from food crops but are found unlisted in cannabis growing nutrients sold online and in hydroponic stores.\n\nThe researchers found that product labeling and uncertainty about constituents made it difficult for both growers and researchers to determine which products contained PGRs or other harmful chemicals.","whyItMatters":"As legal cannabis markets grow, consumer safety depends on understanding what chemicals end up in the final product. This study reveals that even small-scale growers commonly use chemicals, and the products available to them are poorly labeled, creating a hidden health risk for consumers.","specificNumbers":"1,722 growers surveyed across 3 countries. 44% used chemical fertilizers, supplements, or insecticides. Hydroponic growing was the sole significant predictor of chemical use.","methodology":"Web survey of 1,722 cannabis growers in Australia, Denmark, and the UK. Logistic regression to identify predictors of chemical use. Assessment of product labeling and constituent transparency.","limitations":"Self-selected web survey sample may not represent all cannabis growers. Self-reported chemical use may underestimate actual use. Product constituent analysis was limited by poor labeling. Three-country sample may not generalize globally."},{"rthcId":"RTHC-01730","title":"When and How to Treat Possible Cannabis Use Disorder.","authors":"Lévesque, Annie; Le Foll, Bernard","year":2018,"journal":"The Medical clinics of North America, 102(4), 667-681","doi":"10.1016/j.mcna.2018.02.009","pmid":"29933822","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01731","title":"Medical Cannabis for Pediatric Moderate to Severe Complex Motor Disorders.","authors":"Libzon, Stephanie; Schleider, Lihi Bar-Lev; Saban, Naama; Levit, Luda; Tamari, Yulia; Linder, Ilan; Lerman-Sagie, Tally; Blumkin, Lubov","year":2018,"journal":"Journal of child neurology, 33(9), 565-571","doi":"10.1177/0883073818773028","pmid":"29766748","tags":["medical-cannabis","cbd","youth","pain"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Twenty-five children aged 1-17 with complex motor disorders (combinations of spasticity, dystonia, and other movement abnormalities) were enrolled in a pilot study testing CBD-enriched cannabis oil.\n\nTwo formulations were compared: a 20:1 CBD:THC ratio (0.25% THC) and a 6:1 ratio (0.83% THC). Both were 5% CBD oil.\n\nAfter 5 months of treatment, significant improvement was observed in the total cohort for spasticity, dystonia, sleep difficulties, pain severity, and quality of life, regardless of which formulation patients received.\n\nAdverse effects were rare: 2 patients had worsening seizures, 2 had behavioral changes, and 1 had somnolence.\n\nThe study was approved by the institutional ethics committee.","whyItMatters":"Children with complex motor disorders have limited treatment options and significant suffering from spasticity and pain. This pilot study suggests CBD-enriched cannabis oil may help across multiple symptom domains simultaneously, which is unusual for a single intervention in this population.","specificNumbers":"25 patients, ages 1-17. Two formulations: 20:1 CBD:THC (0.25% THC) and 6:1 CBD:THC (0.83% THC). 5-month treatment period. Significant improvement in spasticity, dystonia, sleep, pain, and QOL. Adverse effects: seizure worsening (2), behavioral changes (2), somnolence (1).","methodology":"Open-label pilot study of 25 children with complex motor disorders. Two CBD-enriched oil formulations (20:1 and 6:1 CBD:THC) administered for 5 months. Outcomes assessed included spasticity, dystonia, sleep, pain, and quality of life.","limitations":"Open-label design without placebo control, so improvement could reflect placebo effect, natural fluctuation, or caregiver expectation. Small sample (25 patients). No blinding between the two CBD:THC ratios. Short duration for a chronic condition."},{"rthcId":"RTHC-01732","title":"Slowly Signaling G Protein-Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence.","authors":"Lin, Xiaoyan; Dhopeshwarkar, Amey S; Huibregtse, Megan; Mackie, Ken; Hohmann, Andrea G","year":2018,"journal":"Molecular pharmacology, 93(2), 49-62","doi":"10.1124/mol.117.109355","pmid":"29192123","tags":["pain","cbd","drug-interactions","tolerance"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers characterized LY2828360, a CB2 cannabinoid receptor agonist that had previously failed in a clinical trial for osteoarthritis due to lack of efficacy.\n\nIn vitro, LY2828360 was identified as a \"G protein-biased\" agonist: it activated G protein signaling but did not recruit arrestin, a pattern that may explain its sustained efficacy.\n\nIn mice with chemotherapy-induced neuropathic pain (from paclitaxel), LY2828360 at 3 mg/kg/day for 12 days suppressed pain without developing tolerance. The effect was absent in CB2 knockout mice, confirming it worked through CB2 receptors.\n\nWhen co-administered with morphine, LY2828360 prevented morphine tolerance from developing. LY2828360 also remained effective in mice that were already tolerant to morphine.\n\nThere was a trend toward reduced morphine dependence (fewer naloxone-precipitated withdrawal jumps) in mice receiving both drugs.","whyItMatters":"Opioid tolerance is a major clinical problem: patients need escalating doses for the same pain relief, increasing addiction and overdose risk. A drug that both treats neuropathic pain independently and prevents opioid tolerance could transform pain management, particularly for cancer patients on chemotherapy.","specificNumbers":"LY2828360 at 3 mg/kg/day for 12 days: sustained pain relief without tolerance. Co-administration with morphine (10 mg/kg/day): morphine tolerance blocked in wild-type but not CB2 knockout mice. Trend toward reduced withdrawal signs (p = 0.055).","methodology":"Mouse study using CB2 knockout and wild-type mice. Paclitaxel-induced neuropathic pain model. In vitro receptor characterization (cAMP, ERK1/2, arrestin recruitment, inositol phosphate, receptor internalization). 12-day chronic dosing paradigms.","limitations":"Mouse model of chemotherapy pain may not translate directly to human neuropathic pain. LY2828360 previously failed in a human osteoarthritis trial. The trend toward reduced morphine dependence did not reach statistical significance (p = 0.055). CB2 agonists can have immunosuppressive effects not assessed here."},{"rthcId":"RTHC-01733","title":"The effects of synthetic cannabinoids (SCs) on brain structure and function.","authors":"Livny, A; Cohen, K; Tik, N; Tsarfaty, G; Rosca, P; Weinstein, A","year":2018,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 28(9), 1047-1057","doi":"10.1016/j.euroneuro.2018.07.095","pmid":"30082140","tags":["synthetic-cannabinoids","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Fifteen chronic synthetic cannabinoid (SC) users and 15 healthy controls underwent MRI scans while performing cognitive tasks.\n\nSC users showed reduced total gray matter volume compared to controls, along with reduced volume in specific regions: middle frontal gyrus, frontal orbital gyrus, inferior frontal gyrus, insula, anterior cingulate cortex, and precuneus.\n\nOn a working memory task (N-back), SC users performed worse behaviorally and showed diminished brain activation in the precuneus, cuneus, lingual gyrus, hippocampus, and cerebellum.\n\nOn a response inhibition task (Go-No-Go), no group differences were found in either performance or brain activation.\n\nThis was the first study showing both overall and region-specific gray matter volume reductions in chronic SC users, and the first to demonstrate impaired neural mechanisms for working memory specifically.","whyItMatters":"Synthetic cannabinoids are far more potent than natural cannabis and their brain effects are poorly understood. This study provides the first neuroimaging evidence of structural and functional brain changes in chronic SC users, suggesting vulnerability of the frontal-parietal network that supports working memory.","specificNumbers":"15 SC users, 15 controls. Reduced gray matter in middle frontal gyrus, frontal orbital gyrus, inferior frontal gyrus, insula, anterior cingulate, and precuneus. Diminished activation during N-back in precuneus, cuneus, lingual gyrus, hippocampus, and cerebellum.","methodology":"Cross-sectional neuroimaging study. 15 SC users vs 15 controls. Structural MRI for gray matter volume. Functional MRI during N-back (working memory) and Go-No-Go (response inhibition) tasks.","limitations":"Very small sample (15 per group). Cross-sectional design cannot determine whether brain differences preceded or resulted from SC use. SC users likely used other substances as well. No data on specific SC compounds used, doses, or duration."},{"rthcId":"RTHC-01734","title":"Effect of chronic THC administration in the reproductive organs of male mice, spermatozoa and in vitro fertilization.","authors":"López-Cardona, A P; Ibarra-Lecue, I; Laguna-Barraza, R; Pérez-Cerezales, S; Urigüen, L; Agirregoitia, N; Gutiérrez-Adán, A; Agirregoitia, E","year":2018,"journal":"Biochemical pharmacology, 157, 294-303","doi":"10.1016/j.bcp.2018.07.045","pmid":"30077641","tags":["pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers gave male mice daily THC (10 mg/kg) for 30 days and compared reproductive outcomes to vehicle-treated controls.\n\nTHC treatment decreased cannabinoid receptor 1 (Cnr1) gene expression in the brain cortex but not in the testes.\n\nTesticular and epididymal weight showed no differences between groups. Histological analysis of the testes was normal in THC-treated mice.\n\nSperm motility and concentration were unaffected by chronic THC.\n\nDNA methylation analysis at three CpG regions of the Cnr1 gene showed no changes in either brain tissue or embryos generated by in vitro fertilization.\n\nIVF outcomes were no different when using sperm from THC-treated versus control mice.\n\nThe authors stated their findings contradict the belief that THC consumption has a negative effect on male reproductive processes.","whyItMatters":"Previous studies have linked chronic cannabis use to sperm abnormalities and decreased fertility. This controlled mouse study found no such effects, suggesting the relationship between THC and male fertility may be more nuanced than previously assumed.","specificNumbers":"10 mg/kg/day THC for 30 days. No significant differences in: testicular weight, epididymal weight, testicular histology, sperm motility, sperm concentration, DNA methylation at 3 CpG regions, or IVF embryo production. Cnr1 mRNA decreased in cortex but not testes.","methodology":"Mouse study with 30-day chronic THC treatment (10 mg/kg/day) versus vehicle. Assessed testicular weight, histology, sperm motility, sperm concentration, Cnr1 gene expression, DNA methylation (bisulfite sequencing), and IVF outcomes.","limitations":"Mouse model may not translate to human reproductive physiology. Single dose level (10 mg/kg) may not capture dose-response effects. 30-day exposure may be insufficient to detect long-term damage. IVF is an artificial system that may not reflect natural conception. Only three CpG regions assessed for methylation."},{"rthcId":"RTHC-01735","title":"Palatability and oral cavity tolerability of THC:CBD oromucosal spray and possible improvement measures in multiple sclerosis patients with resistant spasticity: a pilot study.","authors":"Lus, Giacomo; Cantello, Roberto; Danni, Maura Chiara; Rini, Agusto; Sarchielli, Paola; Tassinari, Tiziana; Signoriello, Elisabetta","year":2018,"journal":"Neurodegenerative disease management, 8(2), 105-113","doi":"10.2217/nmt-2017-0056","pmid":"29683408","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01736","title":"Denise Kandel's classic work on the gateway sequence of drug acquisition.","authors":"Lynskey, Michael T; Agrawal, Arpana","year":2018,"journal":"Addiction (Abingdon, England), 113(10), 1927-1932","doi":"10.1111/add.14190","pmid":"29575218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01737","title":"Fronto-striatal effective connectivity of working memory in adults with cannabis use disorder.","authors":"Ma, Liangsuo; Steinberg, Joel L; Bjork, James M; Keyser-Marcus, Lori; Vassileva, Jasmin; Zhu, Min; Ganapathy, Venkatesh; Wang, Qin; Boone, Edward L; Ferré, Sergi; Bickel, Warren K; Gerard Moeller, F","year":2018,"journal":"Psychiatry research. Neuroimaging, 278, 21-34","doi":"10.1016/j.pscychresns.2018.05.010","pmid":"29957349","tags":["cognition","neuroscience","addiction","dopamine"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared brain connectivity between 23 adults with cannabis use disorder and 23 demographically matched controls during a working memory (N-back) task.\n\nCompared to controls, CUD participants showed reduced modulatory connectivity from the right dorsolateral prefrontal cortex (R-DLPFC) to the left caudate during working memory.\n\nHowever, CUD participants showed increased connectivity in three other prefrontal-striatal pathways: left DLPFC to left caudate, right DLPFC to right caudate, and right ventrolateral PFC to left caudate.\n\nThe authors interpreted this as a compensatory pattern: the CUD brain may recruit additional prefrontal-striatal connections to maintain working memory performance when the primary pathway is impaired.","whyItMatters":"This study goes beyond simply showing \"more or less brain activation\" to examine how brain regions communicate during cognitive tasks. The compensatory connectivity pattern suggests the CUD brain works harder to achieve similar performance, which could have implications for cognitive fatigue and vulnerability under stress.","specificNumbers":"23 CUD subjects, 23 controls. Smaller modulatory change in R-DLPFC to L-caudate. Greater modulatory changes in L-DLPFC to L-caudate, R-DLPFC to R-caudate, and R-VLPFC to L-caudate pathways.","methodology":"Cross-sectional fMRI study. 23 CUD subjects and 23 controls matched on sociodemographic factors and substance use history. N-back working memory task with 2-back and 0-back conditions. Effective connectivity analysis of prefrontal-striatal pathways.","limitations":"Small sample size (23 per group). Cross-sectional design cannot determine whether connectivity changes preceded or resulted from cannabis use. Groups were matched on substance use history, but lifetime cannabis exposure may still differ in unmeasured ways."},{"rthcId":"RTHC-01738","title":"Distress intolerance moderation of neurophysiological markers of response inhibition after induced stress: Relations with cannabis use disorder.","authors":"Macatee, Richard J; Albanese, Brian J; Crane, Natania A; Okey, Sarah A; Cougle, Jesse R; Schmidt, Norman B","year":2018,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 32(8), 944-955","doi":"10.1037/adb0000418","pmid":"30407026","tags":["cognition","neuroscience","addiction","anxiety"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers tested whether high distress intolerance (difficulty tolerating negative emotions) would lead to stress-induced impairment of response inhibition in frequent cannabis users.\n\nCannabis users with high and low distress intolerance completed a Go/No-Go task during EEG recording before and after a laboratory stressor.\n\nContrary to the hypothesis, cannabis users with high distress intolerance showed enhanced conflict-monitoring neural activity (N2 amplitude) after stress rather than impairment. This enhancement was associated with faster reaction times and fewer past-month cannabis problems.\n\nEnhanced P3a amplitude (evaluative processing) was associated with increased cannabis problems regardless of stress, suggesting different neural processes contribute differently to cannabis use patterns.\n\nThe authors concluded that stress-enhanced conflict monitoring may be an adaptive neural response that protects against cannabis use disorder in at-risk individuals.","whyItMatters":"The finding that stress enhanced rather than impaired cognitive control in high-DI cannabis users challenges assumptions about the stress-addiction pathway. It suggests that some at-risk individuals may have adaptive neural responses that protect against escalating cannabis use.","specificNumbers":"Distress intolerance significantly moderated stressor effects on N2 (conflict monitoring) but not P3a (evaluative processing) amplitude. Enhanced N2 associated with faster reaction time and decreased past-month cannabis problems.","methodology":"Cross-sectional EEG study. Frequent cannabis users categorized by high/low distress intolerance. Go/No-Go task before and after laboratory stressor. N2 and P3a event-related potential components measured as markers of conflict monitoring and evaluation.","limitations":"Cross-sectional design. Laboratory stressor may not capture real-world stress. EEG measures neural electrical activity but cannot pinpoint exact brain regions. Frequent cannabis users as the entire sample limits comparison to non-users."},{"rthcId":"RTHC-01739","title":"Practical considerations in medical cannabis administration and dosing.","authors":"MacCallum, Caroline A; Russo, Ethan B","year":2018,"journal":"European journal of internal medicine, 49, 12-19","doi":"10.1016/j.ejim.2018.01.004","pmid":"29307505","tags":["medical-cannabis","cbd","drug-interactions","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The authors compiled practical clinical guidance for medical cannabis dosing and administration.\n\nKey recommendations:\n- Total daily THC should generally be limited to 30 mg/day or less to avoid psychoactive effects and tolerance development.\n- THC should preferably be combined with CBD, which can attenuate THC-associated anxiety and tachycardia.\n- CBD is less potent than THC and may require much higher doses for its anti-inflammatory and analgesic benefits.\n- Dose initiation should start at modest levels with slow titration over up to two weeks.\n- Administration methods covered include smoking, vaporization, and oral ingestion, each with different onset times and bioavailability profiles.\n\nThe review addressed cannabis-drug interactions, patient monitoring standards, and special populations including epilepsy, cancer, chronic pain, elderly patients, Parkinson's disease, pediatrics, concurrent opioid use, and driving.","whyItMatters":"Clinicians authorized to prescribe cannabis often lack practical guidance on how to dose it. This review fills that gap with specific, actionable recommendations rather than vague suggestions, helping physicians move from \"yes you can prescribe cannabis\" to \"here is how to do it safely.\"","specificNumbers":"THC limit: 30 mg/day or less. Titration period: up to 2 weeks. Covered administration methods: smoking, vaporization, oral. Special populations addressed: epilepsy, cancer, chronic pain, elderly, Parkinson's, pediatrics, opioid co-use, driving.","methodology":"Narrative review synthesizing pharmacological data, clinical trial findings, and expert recommendations on cannabis dosing, administration, and monitoring.","limitations":"Narrative review based on limited clinical trial data. Many recommendations reflect expert opinion rather than randomized trial evidence. Optimal doses likely vary significantly between patients and conditions."},{"rthcId":"RTHC-01740","title":"Comparing the effect of clozapine and risperidone on cue reactivity in male patients with schizophrenia and a cannabis use disorder: A randomized fMRI study.","authors":"Machielsen, Marise W J; Veltman, Dick J; van den Brink, Wim; de Haan, Lieuwe","year":2018,"journal":"Schizophrenia research, 194, 32-38","doi":"10.1016/j.schres.2017.03.030","pmid":"28351544","tags":["psychosis","addiction","dopamine","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Thirty-eight patients with schizophrenia (30 with cannabis use disorder, 8 without) and 20 healthy controls were included. Patients were randomized to clozapine or risperidone.\n\nAt baseline, patients with comorbid cannabis use disorder showed higher subjective craving and greater brain activation to cannabis-related images compared to those without CUD and healthy controls, across most regions of interest.\n\nAfter 4 weeks of treatment, clozapine-treated patients reported significantly greater reduction in craving (F=6.0, p=0.04) and showed a larger decrease in amygdala activation during cannabis-related images compared to risperidone-treated patients (T=3.94, p=0.006).\n\nSubjective craving correlated significantly with thalamus and insula activation during cannabis cue exposure.\n\nThe findings provide neurobiological evidence for clozapine's superiority in this dual-diagnosis population, likely through differential effects on dopamine signaling.","whyItMatters":"Cannabis use disorder in schizophrenia is extremely common and worsens outcomes. Clozapine is often recommended for this population but evidence for why has been limited. This study provides both subjective and neurobiological evidence that clozapine reduces cannabis craving more effectively than risperidone.","specificNumbers":"38 patients, 20 controls. Craving reduction: clozapine > risperidone (F=6.0, p=0.04). Amygdala activation decrease: clozapine > risperidone (T=3.94, pFWE=0.006). Craving correlated with thalamus and insula activation.","methodology":"Randomized fMRI study. 38 schizophrenia patients (30 with CUD, 8 without) and 20 healthy controls. Randomized to clozapine or risperidone. Brain response to cannabis-related, positive, and neutral images at baseline and 4 weeks. ROIs: amygdala, ventral striatum, insula, thalamus, orbitofrontal cortex, anterior cingulate.","limitations":"Small sample size (38 patients). Short treatment duration (4 weeks). Unequal group sizes for CUD status. Open-label medication assignment. Cannot determine whether craving reduction translates to actual cannabis use reduction long-term."},{"rthcId":"RTHC-01741","title":"Patient Counseling Guidelines for the Use of Cannabis for the Treatment of Chemotherapy-Induced Nausea/Vomiting and Chronic Pain.","authors":"Makary, Patrick; Parmar, Jayesh R; Mims, Natalie; Khanfar, Nile M; Freeman, Robert A","year":2018,"journal":"Journal of pain & palliative care pharmacotherapy, 32(4), 216-225","doi":"10.1080/15360288.2019.1598531","pmid":"31070496","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01742","title":"Oximes short-acting CB1 receptor agonists.","authors":"Malamas, Michael S; Raghav, Jimit Girish; Ma, Xiaoyu; Honrao, Chandrashekhar; Wood, JodiAnne T; Benchama, Othman; Zhou, Han; Mallipeddi, Srikrishnan; Makriyannis, Alexandros","year":2018,"journal":"Bioorganic & medicinal chemistry, 26(18), 4963-4970","doi":"10.1016/j.bmc.2018.08.003","pmid":"30122284","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01743","title":"Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview.","authors":"Mandolini, G M; Lazzaretti, M; Pigoni, A; Oldani, L; Delvecchio, G; Brambilla, P","year":2018,"journal":"Epidemiology and psychiatric sciences, 27(4), 327-335","doi":"10.1017/S2045796018000239","pmid":"29789034","tags":["cbd","psychosis","anxiety","addiction","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed all clinical studies investigating CBD as treatment for psychiatric symptoms and linked findings to pharmacological mechanisms.\n\nFor schizophrenia: CBD may exert antipsychotic effects primarily through facilitation of endocannabinoid signaling and CB1 receptor antagonism. Clinical data support this application.\n\nFor anxiety: CBD showed acute anxiolytic effects in patients with generalized social anxiety disorder through modification of cerebral blood flow in specific brain regions and serotonin 1A receptor agonism.\n\nFor addiction: CBD may reduce cannabis and tobacco withdrawal symptoms through modulation of endocannabinoid, serotonergic, and glutamatergic systems.\n\nFor cognition: Despite promising preclinical pro-cognitive effects, clinical studies in psychiatric disorders have not shown significant cognitive benefits.\n\nThe authors concluded that larger randomized controlled trials and biological measures are needed to confirm these effects.","whyItMatters":"Understanding not just whether CBD works but how it works for different psychiatric conditions is essential for developing targeted therapies. This review organizes the evidence by condition and mechanism, providing a framework for future research.","specificNumbers":"Antipsychotic effects linked to endocannabinoid facilitation and CB1 antagonism. Anxiolytic effects linked to serotonin 1A agonism and cerebral blood flow modification. Withdrawal reduction linked to endocannabinoid, serotonergic, and glutamatergic modulation.","methodology":"Critical review of clinical studies from PubMed database investigating CBD as treatment for psychiatric symptoms. Focused on linking clinical efficacy to pharmacological mechanisms of action.","limitations":"Current clinical studies are small and often lack adequate controls. The review is narrative rather than systematic. Different psychiatric conditions may require different CBD doses and formulations. The pro-cognitive effects that seem promising in animal studies have not translated to human psychiatric populations."},{"rthcId":"RTHC-01744","title":"A case of cannabinoid hyperemesis syndrome with Heliobacter pylori and preeclampsia during pregnancy.","authors":"Manning Meurer, Madeline; Chakrala, Kalyan; Gowda, Dinesh; Burns, Charles; Kelly, Randall; Schlabritz-Loutsevitch, Natalia","year":2018,"journal":"Substance abuse, 39(1), 9-13","doi":"10.1080/08897077.2017.1356790","pmid":"28723278","tags":["pregnancy","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 21-year-old first-time pregnant woman was diagnosed with hyperemesis gravidarum at 6 weeks and later developed preeclampsia at 35 weeks.\n\nA drug screen at 30 weeks was positive for cannabis, leading to a CHS diagnosis that had been masked by pregnancy-related nausea.\n\nAfter labor induction, the infant was born with a negative umbilical cord drug test and developed normally.\n\nPost-delivery endoscopy revealed moderate chronic gastritis with H. pylori infection confirmed by immunostaining.\n\nThis was the first case reporting the co-occurrence of chronic cannabis use, H. pylori colonization, and preeclampsia in pregnancy. The authors suggested a possible cannabinoid-related pathway linking pregnancy complications and bacterial colonization.","whyItMatters":"The overlap of CHS, H. pylori, and preeclampsia in a single patient raises the possibility that cannabinoid signaling could influence both gastrointestinal bacterial colonization and pregnancy-specific vascular complications. While speculative, this hypothesis deserves investigation given rising cannabis use during pregnancy.","specificNumbers":"Patient was 21 years old, primigravida. Hyperemesis gravidarum diagnosed at 6 weeks. Cannabis screen positive at 30 weeks. Preeclampsia at 35 weeks. Infant cord blood drug test negative.","methodology":"Single case report with post-delivery esophagogastroduodenoscopy and tissue biopsies. H. pylori confirmed by immunostaining.","limitations":"Single case report with no ability to establish causal relationships between the three conditions. H. pylori infection is common and may be coincidental. The preeclampsia may be unrelated to cannabis use. No mechanism proposed beyond speculation."},{"rthcId":"RTHC-01745","title":"Negative affectivity as a mechanism underlying perceived distress tolerance and cannabis use problems, barriers to cessation, and self-efficacy for quitting among urban cannabis users.","authors":"Manning, Kara; Paulus, Daniel J; Hogan, Julianna B D; Buckner, Julia D; Farris, Samantha G; Zvolensky, Michael J","year":2018,"journal":"Addictive behaviors, 78, 216-222","doi":"10.1016/j.addbeh.2017.11.041","pmid":"29216571","tags":["addiction","anxiety","mental-health","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers studied 203 urban adult daily cannabis users (29.2% female, mean age 37.7, 63% African American) to understand why low distress tolerance is linked to cannabis problems.\n\nNegative affectivity (the general tendency to experience negative emotions) significantly mediated the relationship between distress tolerance and multiple cannabis outcomes:\n- Cannabis use problems (b=-0.58, 95% CI [-1.14, -0.21])\n- Cannabis withdrawal (b=-0.65, 95% CI [-1.36, -0.21])\n- Self-efficacy for quitting (b=-0.83, 95% CI [-1.85, -0.22])\n- Perceived barriers to cessation (b=-0.71, 95% CI [-1.51, -0.24])\n\nIn other words, people who perceive they cannot tolerate distress tend to experience more negative emotions generally, which in turn drives cannabis problems, withdrawal severity, low confidence in quitting, and perception of more barriers to stopping.","whyItMatters":"Identifying negative affectivity as the mechanism linking distress intolerance to cannabis problems suggests a specific treatment target. Interventions that help daily users manage negative emotions could potentially reduce cannabis problems and improve quitting success.","specificNumbers":"203 daily cannabis users. 29.2% female, mean age 37.7, 63% African American. Significant indirect effects through negative affectivity on all four outcomes (all confidence intervals excluded zero).","methodology":"Cross-sectional study of 203 daily cannabis users. Self-report measures of distress tolerance, negative affectivity, cannabis use problems, withdrawal, quitting self-efficacy, and perceived cessation barriers. Mediation analysis to test indirect effects.","limitations":"Cross-sectional design cannot establish causal direction. Self-report measures of all variables. Sample limited to urban daily users, mostly African American, so generalizability is uncertain. Distress tolerance was measured as perceived capability, not actual behavioral tolerance."},{"rthcId":"RTHC-01746","title":"Heavy Cannabis Use Associated With Reduction in Activated and Inflammatory Immune Cell Frequencies in Antiretroviral Therapy-Treated Human Immunodeficiency Virus-Infected Individuals.","authors":"Manuzak, Jennifer A; Gott, Toni M; Kirkwood, Jay S; Coronado, Ernesto; Hensley-McBain, Tiffany; Miller, Charlene; Cheu, Ryan K; Collier, Ann C; Funderburg, Nicholas T; Martin, Jeffery N; Wu, Michael C; Isoherranen, Nina; Hunt, Peter W; Klatt, Nichole R","year":2018,"journal":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 66(12), 1872-1882","doi":"10.1093/cid/cix1116","pmid":"29471387","tags":["inflammation","medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers measured immune cell activation in 198 HIV-positive individuals on antiretroviral therapy, categorized by cannabis use level based on plasma THC metabolite concentration.\n\nHeavy cannabis users had significantly decreased frequencies of activated (HLA-DR+CD38+) CD4+ and CD8+ T cells compared to non-users.\n\nHeavy users also had decreased frequencies of intermediate and nonclassical monocyte subsets (inflammatory monocyte types).\n\nAdditionally, heavy cannabis users had reduced frequencies of antigen-presenting cells producing interleukin-23 and TNF-α, two pro-inflammatory cytokines.\n\nThe authors noted that while clinical implications are unclear, these findings suggest cannabis use is associated with a \"potentially beneficial reduction in systemic inflammation and immune activation\" in the context of treated HIV.","whyItMatters":"Chronic immune activation persists in HIV-positive patients even on effective antiretroviral therapy and drives many non-AIDS complications. If cannabis reduces this activation, it could have therapeutic implications for the large number of HIV-positive individuals who already use cannabis.","specificNumbers":"198 HIV-positive individuals on ART. Heavy cannabis users had decreased HLA-DR+CD38+ CD4+ and CD8+ T cells, decreased intermediate and nonclassical monocytes, and decreased IL-23 and TNF-α-producing antigen-presenting cells.","methodology":"Cross-sectional study of 198 HIV-infected, ART-treated individuals. Cannabis use categorized by plasma THC-COOH levels via mass spectrometry (heavy, medium, occasional, non-user). Immune cell phenotyping by flow cytometry.","limitations":"Cross-sectional design cannot determine causation. Heavy cannabis users may differ from non-users in ways not measured. Reduced immune activation could theoretically impair needed immune responses. Clinical outcomes (disease progression, infections) were not assessed."},{"rthcId":"RTHC-01747","title":"Subcortical Local Functional Hyperconnectivity in Cannabis Dependence.","authors":"Manza, Peter; Tomasi, Dardo; Volkow, Nora D","year":2018,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 3(3), 285-293","doi":"10.1016/j.bpsc.2017.11.004","pmid":"29486870","tags":["neuroscience","dopamine","psychosis","addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined resting-state brain connectivity in subcortical regions using data from 441 young adults in the Human Connectome Project.\n\nThirty cannabis-dependent subjects were compared to 30 controls matched on age, sex, education, BMI, anxiety, depression, and alcohol/tobacco use.\n\nCannabis-dependent individuals showed markedly increased local functional connectivity in several subcortical regions: ventral striatum (where the nucleus accumbens is located), midbrain (where dopamine-producing neurons reside), brainstem, and lateral thalamus.\n\nThese hyperconnectivity effects occurred without significant differences in subcortical brain volumes.\n\nThe effects were most pronounced in individuals who began cannabis use earliest in life and who reported high levels of negative emotionality.\n\nThe researchers interpreted these findings as reflecting changes in dopaminergic circuits implicated in both psychosis and habit formation/reward processing.","whyItMatters":"This study pinpoints changes in dopamine-related brain circuits that could explain both the reward/habit aspects of cannabis dependence and the increased psychosis risk associated with early-onset heavy use. The well-matched controls and large parent dataset strengthen the findings.","specificNumbers":"441 young adults total, 30 cannabis-dependent vs 30 matched controls. Increased local connectivity in ventral striatum, midbrain, brainstem, and lateral thalamus. Effects strongest with earlier onset and higher negative emotionality. No subcortical volume differences.","methodology":"Cross-sectional analysis of Human Connectome Project resting-state fMRI data. 30 cannabis-dependent subjects vs 30 matched controls from a pool of 441 young adults. Local functional connectivity density mapping of subcortical regions.","limitations":"Cross-sectional design from a single timepoint. Small dependent group (30) despite large parent dataset. Cannot determine whether hyperconnectivity preceded or resulted from cannabis use. Resting-state connectivity may not reflect task-related brain function."},{"rthcId":"RTHC-01748","title":"Attenuation of Listeria monocytogenes Virulence by Cannabis sativa L. Essential Oil.","authors":"Marini, Emanuela; Magi, Gloria; Ferretti, Gianna; Bacchetti, Tiziana; Giuliani, Angelica; Pugnaloni, Armanda; Rippo, Maria Rita; Facinelli, Bruna","year":2018,"journal":"Frontiers in cellular and infection microbiology, 8, 293","doi":"10.3389/fcimb.2018.00293","pmid":"30186775","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01749","title":"Review of the neurological benefits of phytocannabinoids.","authors":"Maroon, Joseph; Bost, Jeff","year":2018,"journal":"Surgical neurology international, 9, 91","doi":"10.4103/sni.sni_45_18","pmid":"29770251","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01750","title":"Rates of cannabis use in patients with cancer.","authors":"Martell, K; Fairchild, A; LeGerrier, B; Sinha, R; Baker, S; Liu, H; Ghose, A; Olivotto, I A; Kerba, M","year":2018,"journal":"Current oncology (Toronto, Ont.), 25(3), 219-225","doi":"10.3747/co.25.3983","pmid":"29962840","tags":["medical-cannabis","cancer","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers distributed surveys to 3,138 cancer patients across two comprehensive and two community cancer centers in a Canadian province, with 1,987 usable responses (63% response rate).\n\nLifetime cannabis use was reported by 43%, independent of age, sex, education level, or cancer type.\n\nCannabis was acquired primarily through friends (80%), with only 10% from regulated medical dispensaries.\n\nOf 356 patients (18%) who used cannabis in the past 6 months, 36% were new users who started after their cancer diagnosis.\n\nReasons for recent use included cancer-related pain (46%), nausea (34%), other cancer symptoms (31%), and non-cancer-related reasons (56%, which could overlap with other categories).\n\nMost users (81% of those with any use) had used dried leaves.","whyItMatters":"This is one of the most comprehensive assessments of cannabis use among cancer patients. The finding that 36% of recent users were new to cannabis after diagnosis shows that cancer itself is driving new cannabis uptake, while the low rate of dispensary use (10%) suggests most cancer patients are outside the regulated medical cannabis system.","specificNumbers":"1,987 respondents (63% response rate). 43% lifetime use. 18% used in past 6 months. 36% of recent users were new users. Sources: friends 80%, dispensaries 10%. Reasons: pain 46%, nausea 34%, other cancer symptoms 31%, non-cancer 56%. 81% used dried leaves.","methodology":"Anonymous survey distributed to cancer patients at four cancer centers across an entire Canadian provincial health jurisdiction. 3,138 distributed, 1,987 analyzed (63% response rate).","limitations":"Cross-sectional survey with 63% response rate. Self-reported data subject to recall and social desirability bias. Canadian provincial sample may not generalize to other jurisdictions. Survey did not assess cannabis dose, frequency, or specific products used."},{"rthcId":"RTHC-01751","title":"Passing on Pot: High School Seniors' Reasons for Not Using Marijuana as Predictors of Future Use.","authors":"Martz, Meghan E; Schulenberg, John E; Patrick, Megan E","year":2018,"journal":"Journal of studies on alcohol and drugs, 79(5), 761-769","doi":null,"pmid":"30422790","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01752","title":"Psychosocial and cessation-related differences between tobacco-marijuana co-users and single product users in a college student population.","authors":"Masters, Matthew N; Haardörfer, Regine; Windle, Michael; Berg, Carla","year":2018,"journal":"Addictive behaviors, 77, 21-27","doi":"10.1016/j.addbeh.2017.09.007","pmid":"28941933","tags":["addiction","quitting","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers studied 721 college students aged 18-25 who used cigarettes and/or marijuana: 238 cigarette-only, 331 marijuana-only, and 152 co-users.\n\nCo-users rated the importance of quitting higher for cigarettes than marijuana, but had lower confidence in their ability to quit cigarettes versus marijuana.\n\nCo-users were more likely to report readiness to quit cigarettes (vs. marijuana) and more likely to have made recent quit attempts for cigarettes (vs. marijuana).\n\nAmong single-product users: 41.18% of cigarette-only users reported recent quit attempts vs. 21.75% of marijuana-only users. Readiness to quit was 15.13% for cigarette-only and 23.26% for marijuana-only users.\n\nCorrelates of co-use (vs. single use) included attending public/technical colleges (vs. private), using little cigars/cigarillos, using e-cigarettes, and alcohol use.\n\nThe factors predicting readiness to quit and actual quit attempts differed for cigarettes versus marijuana, suggesting cessation programs need product-specific approaches.","whyItMatters":"The finding that co-users prioritize quitting cigarettes over marijuana has implications for cessation programs. Co-users may benefit from sequential approaches that leverage their motivation to quit tobacco while addressing marijuana use as a related but distinct behavior.","specificNumbers":"721 users: 238 cigarette-only, 331 marijuana-only, 152 co-users. Importance rated higher for quitting cigarettes vs marijuana (p<0.001). Confidence rated lower for quitting cigarettes vs marijuana (p<0.001). 41.18% of cigarette-only users had recent quit attempts vs 21.75% of marijuana-only users.","methodology":"Cross-sectional study of 721 college students aged 18-25 from seven Georgia campuses. Multinomial logistic regression for user group correlates. Binary logistic regression for cessation outcomes.","limitations":"Cross-sectional design from seven Georgia campuses. Self-reported substance use. College student sample limits generalizability to non-college young adults. Co-use defined broadly without dose-response data."},{"rthcId":"RTHC-01753","title":"Associations Between Early Onset of E-cigarette Use and Cigarette Smoking and Other Substance Use Among US Adolescents: A National Study.","authors":"McCabe, Sean Esteban; West, Brady T; McCabe, Vita V","year":2018,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 20(8), 923-930","doi":"10.1093/ntr/ntx231","pmid":"29986103","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01754","title":"Impaired Driving Associated with the Synthetic Cannabinoid 5f-Adb.","authors":"McCain, K R; Jones, J O; Chilbert, K T; Patton, A L; James, L P; Moran, J H","year":2018,"journal":"Journal of forensic science & criminology, 6(1)","doi":"10.15744/2348-9804.6.105","pmid":"30956998","tags":["synthetic-cannabinoids","driving","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Law enforcement witnessed erratic driving by a 45-year-old male in fall 2017. Roadside evaluation concluded the driver was intoxicated.\n\nComprehensive toxicology analysis found no alcohol, THC, or other drugs in the driver's blood.\n\nGas chromatography-mass spectrometry analysis of cigarettes found in the vehicle detected the synthetic cannabinoid 5F-ADB (also known as 5F-MDMB-PINACA).\n\nForensic LC-MS/MS testing detected the 5F-ADB metabolite 7 in the driver's blood at 26.37 ng/mL, with no other drugs present.\n\nThis represented one of the first cases conclusively demonstrating that synthetic cannabinoids (\"K2\" or \"Spice\") can significantly impair driving at relatively low concentrations.","whyItMatters":"Standard drug testing often misses synthetic cannabinoids because they are structurally different from THC. This case demonstrates that impaired drivers can test \"clean\" on routine screens while being significantly impaired by potent synthetic compounds, highlighting the need for expanded testing panels.","specificNumbers":"5F-ADB metabolite 7 detected at 26.37 ng/mL in blood. No other drugs detected. Driver was 45 years old.","methodology":"Case report with comprehensive toxicology. Cigarette analysis by GC-MS. Blood analysis by validated forensic LC-MS/MS. 5F-ADB metabolite 7 quantified at 26.37 ng/mL.","limitations":"Single case report. No established impairment threshold for 5F-ADB. No cognitive or psychomotor testing was performed to quantify the degree of impairment. The metabolite concentration may not correlate linearly with impairment."},{"rthcId":"RTHC-01755","title":"A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.","authors":"McCoy, Bláthnaid; Wang, Laura; Zak, Maria; Al-Mehmadi, Sameer; Kabir, Nadia; Alhadid, Kenda; McDonald, Kyla; Zhang, Grace; Sharma, Rohit; Whitney, Robyn; Sinopoli, Katia; Snead, O Carter","year":2018,"journal":"Annals of clinical and translational neurology, 5(9), 1077-1088","doi":"10.1002/acn3.621","pmid":"30250864","tags":["epilepsy","cbd","medical-cannabis","youth"],"studyType":"pilot-study","evidenceStrength":"moderate","keyFinding":"Twenty children with Dravet syndrome received add-on therapy with TIL-TC150, a cannabis oil containing 100 mg/mL CBD and 2 mg/mL THC.\n\nDoses ranged from 2-16 mg/kg/day of CBD (mean achieved: 13.3 mg/kg/day) and 0.04-0.32 mg/kg/day of THC (mean: 0.27 mg/kg/day).\n\nNineteen of 20 participants completed the 20-week intervention.\n\nResults showed a median motor seizure reduction of 70.6%, with 63% of patients achieving at least 50% seizure reduction.\n\nThere was a statistically significant improvement in quality of life and reduction in EEG spike activity.\n\nAdverse events during titration included somnolence, anorexia, and diarrhea. Liver enzyme and platelet abnormalities were observed in patients also taking valproic acid.\n\nThe study provided the first safety and dosing data for THC-containing cannabis preparations in Dravet syndrome, complementing the pure CBD (Epidiolex) trial data.","whyItMatters":"While pure CBD (Epidiolex) trials have established CBD for Dravet syndrome, this study adds evidence that a CBD-dominant oil containing small amounts of THC is also safe and effective, with a notably high 70.6% median seizure reduction that compares favorably to pure CBD trial results.","specificNumbers":"20 children, 19 completed 20 weeks. Mean CBD dose: 13.3 mg/kg/day (range 7-16). Mean THC dose: 0.27 mg/kg/day (range 0.14-0.32). Median motor seizure reduction: 70.6%. 50% responder rate: 63%. Significant QOL improvement and EEG spike reduction.","methodology":"Prospective open-label trial. 20 children with Dravet syndrome. TIL-TC150 (Tilray cannabis oil: 100 mg/mL CBD, 2 mg/mL THC) as add-on therapy for 20 weeks. Monitored for seizure frequency, EEG changes, quality of life, and adverse events.","limitations":"Open-label design without placebo control, so true drug effect is uncertain. Small sample of 20 patients. Adverse events overlapped with those of concomitant medications (particularly valproic acid). 20-week duration may not capture long-term tolerance or adverse effects."},{"rthcId":"RTHC-01756","title":"Impact of Fabp1 Gene Ablation on Uptake and Degradation of Endocannabinoids in Mouse Hepatocytes.","authors":"McIntosh, Avery L; Huang, Huan; Landrock, Danilo; Martin, Gregory G; Li, Shengrong; Kier, Ann B; Schroeder, Friedhelm","year":2018,"journal":"Lipids, 53(6), 561-580","doi":"10.1002/lipd.12071","pmid":"30203570","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01757","title":"Protecting the public from exposure to secondhand cannabis smoke and vapour following legalization.","authors":"McKee, Geoffrey; McClure, Shelley; Fyfe, Murray; Stanwick, Richard","year":2018,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 109(2), 223-226","doi":"10.17269/s41997-018-0054-5","pmid":"29981035","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01758","title":"Knowledge, Skills, and Attitudes Regarding the Use of Medical Cannabis in the Hospice Population: An Educational Intervention.","authors":"Mendoza, Kelly S; McPherson, Mary Lynn","year":2018,"journal":"The American journal of hospice & palliative care, 35(5), 759-766","doi":"10.1177/1049909117738246","pmid":"29121790","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01759","title":"Differential relationships of PTSD and childhood trauma with the course of substance use disorders.","authors":"Mergler, Michaela; Driessen, Martin; Havemann-Reinecke, Ursula; Wedekind, Dirk; Lüdecke, Christel; Ohlmeier, Martin; Chodzinski, Claudia; Teunißen, Sibylle; Weirich, Steffen; Kemper, Ulrich; Renner, Walter; Schäfer, Ingo","year":2018,"journal":"Journal of substance abuse treatment, 93, 57-63","doi":"10.1016/j.jsat.2018.07.010","pmid":"30126542","tags":["ptsd","addiction","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers divided 459 patients with substance use disorders into three groups: childhood trauma plus PTSD (CT-PTSD, n=95), childhood trauma without PTSD (CT-only, n=134), and no trauma (n=209).\n\nA graded pattern emerged across nearly all outcomes, with CT-PTSD worst, CT-only intermediate, and no-trauma best.\n\nBoth trauma groups reported significantly higher anxiety, depression, suicidal thoughts, and suicide attempts than the no-trauma group.\n\nThe CT-PTSD group had significantly younger age at first cannabis and alcohol use, more cannabis use in the past month, and more lifetime drug overdoses compared to the no-trauma group.\n\nThe authors concluded that both childhood trauma and PTSD independently contribute to substance use severity, and treatment programs should assess and address both domains rather than focusing on one alone.","whyItMatters":"Many addiction treatment programs screen for PTSD but not for childhood trauma in the absence of PTSD. This study shows that childhood trauma alone (without meeting PTSD criteria) is associated with worse outcomes, suggesting that trauma-informed treatment should be broader than just PTSD treatment.","specificNumbers":"459 patients: 95 CT-PTSD, 134 CT-only, 209 no trauma. CT-PTSD group had younger age at first cannabis and alcohol use, more past-month cannabis use, and more lifetime overdoses than no-trauma group. Graded association across all three groups.","methodology":"Cross-sectional study of 459 SUD patients. PTSD diagnosed via IDCL and PDS. Childhood trauma assessed with CTQ. Substance use and psychiatric symptoms assessed with EuropASI. Three-group comparison (CT-PTSD, CT-only, no trauma).","limitations":"Cross-sectional design cannot establish causal direction. Self-reported childhood trauma may be affected by current mental state. The CT-only group may include people with sub-threshold PTSD. Cannabis-specific effects are embedded within broader substance use patterns."},{"rthcId":"RTHC-01760","title":"Marijuana Use in Pregnancy and While Breastfeeding.","authors":"Metz, Torri D; Borgelt, Laura M","year":2018,"journal":"Obstetrics and gynecology, 132(5), 1198-1210","doi":"10.1097/AOG.0000000000002878","pmid":"30234728","tags":["pregnancy","harm-reduction","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Researchers reviewed the literature on marijuana use during pregnancy and breastfeeding, published in a major obstetrics journal.\n\nKey findings:\n- Marijuana crosses the placenta and is present in breast milk, directly exposing the fetus and nursing infant.\n- The endocannabinoid system plays important roles in implantation, placentation, and fetal neurologic development, making disruption biologically plausible.\n- Two recent systematic reviews and meta-analyses found associations between marijuana use and adverse perinatal outcomes, especially with heavy use.\n- Three longitudinal cohort studies demonstrated possible effects of prenatal exposure on long-term neurobehavioral outcomes in children.\n- Marijuana use may be associated with growth restriction, stillbirth, spontaneous preterm birth, and NICU admission.\n- Many women cited medical reasons for prenatal use: nausea/vomiting, anxiety, and chronic pain.\n\nLimitations acknowledged: most studies are retrospective, rely on self-report (which underestimates use), and many fail to adequately control for tobacco and sociodemographic confounders.\n\nDespite these limitations, the authors recommended women refrain from marijuana during pregnancy and lactation.","whyItMatters":"Cannabis use during pregnancy is increasing as legalization expands and perceived safety rises. This review from a leading obstetrics journal provides obstetricians with a comprehensive summary of the evidence and a clear recommendation to share with patients.","specificNumbers":"Prevalence of prenatal marijuana use is increasing. Marijuana crosses the placenta and passes into breast milk. Two meta-analyses found adverse perinatal associations. Three longitudinal cohorts found potential neurobehavioral effects. Associations noted with growth restriction, stillbirth, preterm birth, and NICU admission.","methodology":"Narrative review published in Obstetrics and Gynecology covering animal studies, human cohort studies, systematic reviews, and meta-analyses on marijuana in pregnancy and breastfeeding.","limitations":"Narrative review. Underlying studies have significant methodological limitations including self-report bias, confounding by tobacco and socioeconomic factors, and lack of dose-response data. Definitive randomized trials are unethical in pregnancy."},{"rthcId":"RTHC-01761","title":"Day-Level Associations Between Substance Use and HIV Risk Behavior Among a Diverse Sample of Transgender Women.","authors":"Millar, Brett M; English, Devin; Moody, Raymond L; Rendina, H Jonathon; Cain, Demetria; Antebi-Gruszka, Nadav; Carter, Joseph A; Parsons, Jeffrey T","year":2018,"journal":"Transgender health, 3(1), 210-219","doi":"10.1089/trgh.2018.0032","pmid":"30596148","tags":["harm-reduction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Researchers collected 60-day timeline follow-back data from 214 transgender women in New York City to examine day-level links between substance use and sexual risk behavior.\n\nAll three substance types studied (heavy drinking, marijuana, stimulants) were associated with greater odds of any sexual activity on days when used.\n\nCritically, only marijuana use was associated with increased odds of HIV transmission risk behavior (TRB) on days when sex occurred. This association was moderated by overall use frequency: the link between daily marijuana use and TRB was significant only among women with higher overall rates of marijuana use.\n\nHeavy drinking showed a different pattern, with stronger effects on sexual activity among those with higher overall drinking rates. Stimulant use effects were stronger among those with lower overall stimulant use rates.","whyItMatters":"Transgender women face disproportionately high HIV rates. This study identifies marijuana use as specifically linked to sexual risk behavior (not just sexual activity), distinguishing it from alcohol and stimulants. This has implications for targeted HIV prevention interventions.","specificNumbers":"214 transgender women. 60-day follow-back. All three substances linked to any sexual activity. Only marijuana linked to TRB on sex days. Marijuana-TRB link significant only among those with higher overall marijuana use rates.","methodology":"Intensive longitudinal design using 60-day timeline follow-back interviews. 214 transgender women in NYC. Multilevel models testing day-level substance use as predictor of any sex and TRB, adjusting for overall use levels.","limitations":"Observational design cannot prove marijuana causes risk behavior. NYC sample may not generalize. Timeline follow-back relies on retrospective recall. Specific sexual contexts and partner types were not fully characterized."},{"rthcId":"RTHC-01762","title":"Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure.","authors":"Miller, Sally; Daily, Laura; Leishman, Emma; Bradshaw, Heather; Straiker, Alex","year":2018,"journal":"Investigative ophthalmology & visual science, 59(15), 5904-5911","doi":"10.1167/iovs.18-24838","pmid":"30550613","tags":["cbd","medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Researchers tested topical THC and CBD on intraocular pressure (IOP) in mice.\n\nA single topical application of THC lowered IOP by approximately 28% for 8 hours in male mice. This effect was mediated by combined activation of two receptors: CB1 and GPR18.\n\nThe effect was sex-dependent: THC lowered IOP more in males than females. mRNA levels of both CB1 and GPR18 receptors were higher in male mouse eyes, potentially explaining the sex difference.\n\nCBD was not simply inactive as previously assumed. It had two opposing effects on eye pressure: one that could lower it and one that could raise it.\n\nMost importantly, CBD prevented THC from lowering IOP. This has significant implications for cannabis-based glaucoma treatments, as products containing both THC and CBD (which includes most whole-plant cannabis) may be less effective than THC alone.","whyItMatters":"Cannabis has been used for glaucoma for decades, but this study reveals that CBD may actually counteract THC's beneficial IOP-lowering effect. This means whole-plant cannabis or CBD-rich products could be counterproductive for glaucoma, and sex differences may affect treatment response.","specificNumbers":"THC lowered IOP by ~28% for 8 hours in male mice. Effect mediated by CB1 and GPR18 receptors. Stronger in males (higher CB1 and GPR18 mRNA in male eyes). CBD prevented THC from lowering IOP.","methodology":"Mouse study using tonometry to measure IOP after topical application of THC and CBD. mRNA expression analysis of cannabinoid receptors. Lipid analysis of CBD treatment effects. Tested in both male and female mice.","limitations":"Mouse study may not translate directly to human eyes. Topical application in mice differs from how humans typically use cannabis. The sex difference needs confirmation in humans. The mechanism by which CBD blocks THC's IOP effect is not fully characterized."},{"rthcId":"RTHC-01763","title":"Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure.","authors":"Miller, Sally; Kulkarni, Shashank; Ciesielski, Alex; Nikas, Spyros P; Mackie, Ken; Makriyannis, Alexandros; Straiker, Alex","year":2018,"journal":"Pharmaceuticals (Basel, Switzerland), 11(2)","doi":"10.3390/ph11020050","pmid":"29786643","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01764","title":"Acute myocardial infarction triggered by use of synthetic cannabis.","authors":"Mills, Brooke; Dishner, Emma; Velasco, Carlos E","year":2018,"journal":"Proceedings (Baylor University. Medical Center), 31(2), 200-202","doi":"10.1080/08998280.2017.1416243","pmid":"29706819","tags":["synthetic-cannabinoids","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A young woman presented to the hospital with an anterior ST elevation myocardial infarction (STEMI) shortly after using synthetic cannabis.\n\nST elevation myocardial infarction is a serious type of heart attack involving complete blockage of a coronary artery.\n\nThe temporal relationship between synthetic cannabis use and the cardiac event was notable, as the patient was young and otherwise not in a typical demographic for heart attacks.\n\nThe case report highlighted the cardiovascular risks of synthetic cannabinoids, which are far more potent than natural cannabis and can cause coronary vasospasm, arrhythmias, and direct cardiac toxicity.","whyItMatters":"Heart attacks in young women are rare, and when they occur shortly after synthetic cannabinoid use, the temporal association strongly suggests a causal link. Synthetic cannabinoids can cause severe coronary vasospasm even in people with no pre-existing heart disease.","specificNumbers":"Young female patient. Anterior STEMI. Temporal onset shortly after synthetic cannabis use.","methodology":"Single case report with clinical documentation of STEMI following synthetic cannabis use.","limitations":"Single case report. Limited clinical details available in the abstract. Cannot definitively prove the synthetic cannabis caused the MI versus being coincidental."},{"rthcId":"RTHC-01765","title":"Genome-wide association meta-analysis of age at first cannabis use.","authors":"Minică, Camelia C; Verweij, Karin J H; van der Most, Peter J; Mbarek, Hamdi; Bernard, Manon; van Eijk, Kristel R; Lind, Penelope A; Liu, Meng Zhen; Maciejewski, Dominique F; Palviainen, Teemu; Sánchez-Mora, Cristina; Sherva, Richard; Taylor, Michelle; Walters, Raymond K; Abdellaoui, Abdel; Bigdeli, Timothy B; Branje, Susan J T; Brown, Sandra A; Casas, Miguel; Corley, Robin P; Davey-Smith, George; Davies, Gareth E; Ehli, Erik A; Farrer, Lindsay; Fedko, Iryna O; Garcia-Martínez, Iris; Gordon, Scott D; Hartman, Catharina A; Heath, Andrew C; Hickie, Ian B; Hickman, Matthew; Hopfer, Christian J; Hottenga, Jouke Jan; Kahn, René S; Kaprio, Jaakko; Korhonen, Tellervo; Kranzler, Henry R; Krauter, Ken; van Lier, Pol A C; Madden, Pamela A F; Medland, Sarah E; Neale, Michael C; Meeus, Wim H J; Montgomery, Grant W; Nolte, Ilja M; Oldehinkel, Albertine J; Pausova, Zdenka; Ramos-Quiroga, Josep A; Richarte, Vanesa; Rose, Richard J; Shin, Jean; Stallings, Michael C; Wall, Tamara L; Ware, Jennifer J; Wright, Margaret J; Zhao, Hongyu; Koot, Hans M; Paus, Tomas; Hewitt, John K; Ribasés, Marta; Loukola, Anu; Boks, Marco P; Snieder, Harold; Munafò, Marcus R; Gelernter, Joel; Boomsma, Dorret I; Martin, Nicholas G; Gillespie, Nathan A; Vink, Jacqueline M; Derks, Eske M","year":2018,"journal":"Addiction (Abingdon, England), 113(11), 2073-2086","doi":"10.1111/add.14368","pmid":"30003630","tags":["genetics","youth","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Researchers conducted the largest genome-wide association study of age at first cannabis use to date.\n\nTwin analysis (8,055 twins from three cohorts) estimated heritability at 38% (95% CI 19-60%). Shared environment explained 39% and unique environment 22% of the variation.\n\nThe GWAS meta-analysis of 24,953 individuals identified five significant SNPs on chromosome 16 within the ATP2C2 gene (a calcium-transporting ATPase). The strongest association was at rs1574587 (p = 4.09 x 10^-9).\n\nAlthough these SNPs did not replicate in a smaller sample of 3,735 individuals, the ATP2C2 gene was also significant in gene-based analysis (p = 1.33 x 10^-6).\n\nATP2C2 has been previously associated with cocaine dependence, and a related gene (ATP2B2) in the same calcium signaling pathway has been linked to opioid dependence, suggesting a shared biological mechanism across substance use disorders.","whyItMatters":"Earlier cannabis initiation is consistently linked to worse outcomes including dependence and polysubstance use. Finding that timing of first use is substantially heritable (38%) and potentially linked to calcium signaling pathways opens new avenues for understanding and potentially predicting who is at greatest risk.","specificNumbers":"Heritability: 38% (95% CI 19-60%). Shared environment: 39%. Unique environment: 22%. 24,953 discovery sample, 3,735 replication. Top SNP: rs1574587 in ATP2C2 (p = 4.09 x 10^-9). Gene-based: ATP2C2 (p = 1.33 x 10^-6).","methodology":"Twin-based heritability analysis (8,055 twins). GWAS meta-analysis of 24,953 individuals from nine European, North American, and Australian cohorts. Replication sample of 3,735. Gene-based tests. SNP-based heritability estimation.","limitations":"Top genetic findings did not replicate in the smaller sample. SNP-based heritability was not significant, suggesting many small genetic effects rather than a few large ones. Only European-ancestry cohorts included. Age at first use is influenced by many environmental factors beyond genetics."},{"rthcId":"RTHC-01766","title":"How Substance Users With ADHD Perceive the Relationship Between Substance Use and Emotional Functioning.","authors":"Mitchell, John T; Weisner, Thomas S; Jensen, Peter S; Murray, Desiree W; Molina, Brooke S G; Arnold, L Eugene; Hechtman, Lily; Swanson, James M; Hinshaw, Stephen P; Victor, Elizabeth C; Kollins, Scott H; Wells, Karen C; Belendiuk, Katherine A; Blonde, Andrew; Nguyen, Celeste; Ambriz, Lizeth; Nguyen, Jenny L","year":2018,"journal":"Journal of attention disorders, 22(9_suppl), 49S-60S","doi":"10.1177/1087054716685842","pmid":"28166690","tags":["mental-health","addiction","cognition"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Researchers analyzed narrative comments from 92 persistent and desistent substance users from the MTA (Multimodal Treatment Study of ADHD) adult follow-up (ages 21.7-26.7).\n\nPersistent substance users generally perceived that substance use positively affects emotional states and that positive emotional effects outweigh negative ones. This perception did not differ between ADHD and non-ADHD groups.\n\nHowever, qualitative analysis revealed ADHD-specific perceptions: both ADHD and non-ADHD persistent users reported that cannabis enhanced positive mood, but ADHD persistent users additionally perceived cannabis as improving negative mood and ADHD symptoms specifically.\n\nThese self-medication perceptions may help explain why cannabis use is elevated among people with ADHD and why it persists despite potential negative consequences.","whyItMatters":"Understanding why people with ADHD are more likely to use cannabis persistently requires understanding their subjective experience. If they perceive cannabis as genuinely helping their ADHD symptoms and mood, simply telling them to stop may be ineffective without providing alternative symptom management.","specificNumbers":"92 total (67 persistent, 25 desistent substance users). 50 ADHD, 17 comparison group among persisters. No ADHD group differences in broad substance-mood perceptions. ADHD-specific perception: cannabis improves negative mood and ADHD symptoms.","methodology":"Mixed qualitative-quantitative analysis. 67 persistent and 25 desistent substance users from the MTA adult follow-up. 50 ADHD and 17 comparison group among persisters. Narrative coding of substance use-emotion perceptions.","limitations":"Small qualitative sample. Self-reported perceptions may not reflect actual therapeutic benefit. MTA participants have extensive treatment histories that may not generalize. Persistent users may be motivated to justify continued use."},{"rthcId":"RTHC-01767","title":"Improving police conceptual knowledge of Mexico's law on cannabis possession: Findings from an assessment of a police education program.","authors":"Mittal, Maria L; Artamonova, Irina; Baker, Pieter; Strathdee, Steffanie A; Cepeda, Javier; Bañuelos, Arnulfo; Morales, Mario; Arredondo, Jaime; Rocha-Jimenez, Teresita; Clairgue, Erika; Bustamante, Elaine; Patiño, Efrain; Gaines, Tommi; Beletsky, Leo","year":2018,"journal":"The American journal on addictions, 27(8), 608-611","doi":"10.1111/ajad.12827","pmid":"30516331","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01768","title":"Successful Treatment of Cannabinoid Hyperemesis Syndrome with Topical Capsaicin.","authors":"Moon, Andrew M; Buckley, Sarah A; Mark, Nicholas M","year":2018,"journal":"ACG case reports journal, 5, e3","doi":"10.14309/crj.2018.3","pmid":"29379817","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with cannabinoid hyperemesis syndrome experienced symptom improvement after topical capsaicin application.\n\nThe authors proposed a novel mechanistic model: chronic cannabis use decreases signaling through the transient receptor potential vanilloid subtype 1 (TRPV1) receptor, which alters gastric motility and triggers the nausea/vomiting cycle.\n\nThis model explains the previously puzzling observation that CHS patients compulsively seek hot baths: both hot water and capsaicin activate TRPV1 receptors, temporarily restoring the signaling that chronic cannabis has dampened.\n\nPrevious models focused solely on CB1 receptor derangement, but the TRPV1 model fills gaps in understanding, including why hot bathing provides relief and why the syndrome develops only in some chronic users (who may have different baseline TRPV1 sensitivity).","whyItMatters":"Understanding why capsaicin and hot water work for CHS is not just academic. If the TRPV1 mechanism is correct, it suggests new therapeutic targets and explains individual differences in CHS susceptibility. It also supports capsaicin as a rational (not just empirical) treatment.","specificNumbers":"Single patient improved with topical capsaicin. TRPV1 receptor is activated by marijuana, capsaicin, and heat. Chronic cannabis use proposed to decrease TRPV1 signaling.","methodology":"Single case report with a proposed mechanistic model linking TRPV1 receptor downregulation to CHS pathophysiology.","limitations":"Single case report. The TRPV1 mechanism is proposed but not proven. The model does not fully explain why only some chronic cannabis users develop CHS. No controlled comparison to other treatments."},{"rthcId":"RTHC-01769","title":"Social Media Posts by Recreational Marijuana Companies and Administrative Code Regulations in Washington State.","authors":"Moreno, Megan A; Gower, Aubrey D; Jenkins, Marina C; Scheck, Josh; Sohal, Jaymin; Kerr, Bradley; Young, Henry N; Cox, Elizabeth","year":2018,"journal":"JAMA network open, 1(7), e182242","doi":"10.1001/jamanetworkopen.2018.2242","pmid":"30646364","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01770","title":"Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function.","authors":"Morgan, Celia J A; Freeman, Tom P; Hindocha, Chandni; Schafer, Grainne; Gardner, Chelsea; Curran, H Valerie","year":2018,"journal":"Translational psychiatry, 8(1), 181","doi":"10.1038/s41398-018-0191-x","pmid":"30185793","tags":["psychosis","cbd","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Forty-eight cannabis users were selected based on schizotypal personality scores and use frequency, then received four vaporized conditions in crossover design: placebo, THC 8 mg, CBD 16 mg, and THC 8 mg + CBD 16 mg.\n\nTHC alone increased psychotic symptoms on the PSI, increased negative symptoms on the BPRS, and robustly impaired both episodic and working memory.\n\nCo-administration of CBD at a 2:1 ratio (16 mg CBD with 8 mg THC) did not attenuate any of these THC effects.\n\nCBD alone reduced PSI scores, but only in light cannabis users. Frequent users showed no benefit from CBD alone.\n\nThe authors noted that frequent cannabis users may show a blunted antipsychotic response to CBD, which is concerning given high rates of cannabis use disorders in schizophrenia patients.","whyItMatters":"The popular belief that CBD protects against THC's negative effects is not supported at this dose ratio when both are vaporized. This has direct implications for consumers who choose high-CBD products assuming they are \"safer\" and for the medical cannabis industry marketing CBD-containing products.","specificNumbers":"48 cannabis users. THC 8 mg, CBD 16 mg (2:1 ratio). THC increased PSI scores, BPRS negative symptoms, and impaired episodic and working memory. CBD did not attenuate any THC effect. CBD alone reduced PSI only in light users.","methodology":"Randomized, double-blind, crossover design. 48 cannabis users selected by schizotypal scores (low/high) and use frequency (light/heavy). Four vaporized conditions. Measures: BPRS, PSI, immediate and delayed prose recall, 1-back and 2-back tasks.","limitations":"Single-dose acute study may not reflect chronic use patterns. Only one CBD:THC ratio (2:1) tested. Vaporized route may produce different dynamics than oral administration. Selection of participants by schizotypal scores and use frequency creates a specific sample."},{"rthcId":"RTHC-01771","title":"Cannabis, a Significant Risk Factor for Violent Behavior in the Early Phase Psychosis. Two Patterns of Interaction of Factors Increase the Risk of Violent Behavior: Cannabis Use Disorder and Impulsivity; Cannabis Use Disorder, Lack of Insight and Treatment Adherence.","authors":"Moulin, Valerie; Baumann, Philipp; Gholamrezaee, Mehdi; Alameda, Luis; Palix, Julie; Gasser, Jacques; Conus, Philippe","year":2018,"journal":"Frontiers in psychiatry, 9, 294","doi":"10.3389/fpsyt.2018.00294","pmid":"30022956","tags":["psychosis","addiction","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers studied 265 early psychosis patients to understand how cannabis use disorder interacts with other risk factors for violent behavior.\n\nCannabis use disorder was independently associated with violent behavior during treatment.\n\nClassification and Regression Tree (CART) analysis revealed two distinct patient profiles with elevated violence rates:\n\n1. CUD + impulsivity: patients with both cannabis use disorder and high impulsivity had the highest rates of violent behavior.\n\n2. CUD + lack of insight + treatment non-adherence: patients with cannabis use disorder who also lacked awareness of their illness and did not follow treatment had elevated violence rates.\n\nImportantly, among patients with CUD, those who had good insight and treatment adherence had lower violence rates. This suggests that insight and treatment adherence can moderate the violence risk associated with cannabis use disorder in early psychosis.","whyItMatters":"Early psychosis patients are at elevated risk for both cannabis use and violent behavior. Identifying specific risk profiles (CUD + impulsivity, or CUD + poor insight + non-adherence) allows clinicians to target interventions more precisely rather than treating all early psychosis patients as equally at risk.","specificNumbers":"265 early psychosis patients. Two violence risk profiles identified via CART: (1) CUD + impulsivity, (2) CUD + lack of insight + non-adherence. Insight and treatment adherence moderated violence risk in CUD patients.","methodology":"Retrospective analysis of 265 early psychosis patients from the TIPP program in Lausanne. Logistic regression for risk factors. CART analysis to identify hierarchical combinations of risk factors for violent behavior during treatment.","limitations":"Retrospective design. Single treatment program in Lausanne. Violent behavior was assessed during treatment, not in the community. CART analysis is exploratory and the identified profiles need prospective validation."},{"rthcId":"RTHC-01772","title":"Cannabis-based medicines for chronic neuropathic pain in adults.","authors":"Mücke, Martin; Phillips, Tudor; Radbruch, Lukas; Petzke, Frank; Häuser, Winfried","year":2018,"journal":"The Cochrane database of systematic reviews, 3(3), CD012182","doi":"10.1002/14651858.CD012182.pub2","pmid":"29513392","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"The Cochrane Collaboration reviewed 16 randomized, double-blind controlled trials (1,750 patients, 2-26 weeks) of cannabis-based medicines for chronic neuropathic pain.\n\nFormulations included: THC/CBD oromucosal spray (10 studies), nabilone (2), inhaled herbal cannabis (2), and dronabinol (2).\n\nEfficacy was modest: 21% of cannabis patients achieved 50% or greater pain relief vs 17% with placebo (NNT 20, low-quality evidence). For 30% pain relief: 39% vs 33% (NNT 11, moderate-quality evidence).\n\nHarms were notable: 10% discontinued due to adverse events vs 5% on placebo (NNH 25). Nervous system adverse events occurred in 61% vs 29% (NNH 3). Psychiatric disorders occurred in 17% vs 5% (NNH 10).\n\nThe authors concluded that \"potential benefits might be outweighed by potential harms\" and noted that study populations excluded people with substance abuse history and significant comorbidities, limiting real-world applicability.","whyItMatters":"Cochrane reviews are considered the gold standard of evidence synthesis. This review's conclusion that harms may outweigh benefits for neuropathic pain is a significant counterpoint to the enthusiastic promotion of cannabis for chronic pain. The NNT of 20 for 50% pain relief is notably worse than many existing pain treatments.","specificNumbers":"16 trials, 1,750 patients. 50% pain relief: 21% vs 17%, NNT 20 (low quality). 30% pain relief: 39% vs 33%, NNT 11 (moderate quality). Adverse event withdrawal: NNH 25. Nervous system AEs: 61% vs 29%, NNH 3. Psychiatric AEs: 17% vs 5%, NNH 10.","methodology":"Cochrane systematic review and meta-analysis. 16 RCTs, 1,750 participants. Random-effects model. GRADE quality assessment. NNT and NNH calculations. Quality ranged from low to high across studies.","limitations":"Most studies used THC/CBD spray (Sativex), limiting generalizability to other cannabis products. Study populations excluded substance abuse and significant comorbidities. Short trial durations (2-26 weeks). No long-term safety data available."},{"rthcId":"RTHC-01773","title":"Cannabinoid exposure and altered DNA methylation in rat and human sperm.","authors":"Murphy, Susan K; Itchon-Ramos, Nilda; Visco, Zachary; Huang, Zhiqing; Grenier, Carole; Schrott, Rose; Acharya, Kelly; Boudreau, Marie-Helene; Price, Thomas M; Raburn, Douglas J; Corcoran, David L; Lucas, Joseph E; Mitchell, John T; McClernon, F Joseph; Cauley, Marty; Hall, Brandon J; Levin, Edward D; Kollins, Scott H","year":2018,"journal":"Epigenetics, 13(12), 1208-1221","doi":"10.1080/15592294.2018.1554521","pmid":"30521419","tags":["pregnancy","genetics","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers compared DNA methylation in sperm from human cannabis users versus non-users, and from THC-exposed versus unexposed rats.\n\nIn human sperm, cannabis users differed from non-users by at least 10% methylation at 3,979 CpG sites.\n\nPathway analysis identified Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched in THC-exposed rat sperm (p < 0.01), providing cross-species validation.\n\nTHC exposure levels in humans correlated significantly with methylation changes for 177 genes, suggesting a dose-response relationship.\n\nThere was substantial overlap between genes with altered methylation in rat sperm (this study) and genes previously reported as having altered methylation in the brains of rat offspring born to THC-exposed parents.\n\nCannabis use in humans was also associated with significantly lower sperm concentration.","whyItMatters":"This is among the first studies to show that cannabis use alters the epigenetic signature of sperm in ways that affect developmental pathways, with potential implications for offspring. The cross-species replication strengthens the finding, and the overlap with offspring brain methylation patterns raises intergenerational concerns.","specificNumbers":"3,979 CpG sites differed by ≥10% between cannabis users and non-users. Hippo Signaling and Cancer pathways enriched (Bonferroni p < 0.02 in humans, p < 0.01 in rats). 177 genes showed dose-response correlation with THC levels. Cannabis use associated with lower sperm concentration.","methodology":"Cross-sectional human comparison (cannabis users vs non-users) and controlled rat experiment (THC vs vehicle). DNA methylation by reduced representation bisulfite sequencing. Pathway analysis. Correlation of THC levels with methylation. Sperm concentration measurement.","limitations":"Human component is cross-sectional (cannabis users may differ in other ways). Small sample sizes in both human and rat studies. Methylation changes in sperm do not necessarily translate to functional changes in offspring. Reduced sperm concentration could have multiple causes."},{"rthcId":"RTHC-01774","title":"Endocannabinoid system in systemic lupus erythematosus: First evidence for a deranged 2-arachidonoylglycerol metabolism.","authors":"Navarini, Luca; Bisogno, Tiziana; Mozetic, Pamela; Piscitelli, Fabiana; Margiotta, Domenico Paolo Emanuele; Basta, Fabio; Afeltra, Antonella; Maccarrone, Mauro","year":2018,"journal":"The international journal of biochemistry & cell biology, 99, 161-168","doi":"10.1016/j.biocel.2018.04.010","pmid":"29655919","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01775","title":"Universal cannabis outcomes from the Climate and Preventure (CAP) study: a cluster randomised controlled trial.","authors":"Newton, Nicola C; Teesson, Maree; Mather, Marius; Champion, Katrina E; Barrett, Emma L; Stapinski, Lexine; Carragher, Natacha; Kelly, Erin; Conrod, Patricia J; Slade, Tim","year":2018,"journal":"Substance abuse treatment, prevention, and policy, 13(1), 34","doi":"10.1186/s13011-018-0171-4","pmid":"30253790","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Researchers randomized 26 Australian high schools (2,190 students, mean age 13.3) to four conditions: universal prevention (Climate), selective prevention for high-risk students (Preventure), combined (CAP), or health education as usual.\n\nBoth Climate and CAP groups showed significantly greater increases in cannabis-related knowledge compared to controls (p < 0.001), with higher knowledge maintained at 6, 12, and 24 months.\n\nThere was no significant difference between Climate and CAP groups, suggesting the combined approach did not add knowledge benefit beyond the universal program alone.\n\nNo significant differences were detected between intervention and control groups on cannabis use or cannabis-related harms. However, the prevalence of these outcomes was lower than anticipated, which may have limited statistical power.\n\nBayesian analyses were inconclusive: there was insufficient evidence to conclude either that the interventions had no effect or that they had a meaningfully large effect on cannabis use.","whyItMatters":"Increasing knowledge is an important first step in prevention, but knowledge alone does not always change behavior. This study shows that well-designed school programs can sustain cannabis knowledge gains for years, while the behavioral impact remains uncertain during early adolescence.","specificNumbers":"2,190 students from 26 schools. Knowledge significantly higher in Climate and CAP groups at 6, 12, and 24 months (p < 0.001). No significant differences in cannabis use or harms. Cannabis use prevalence lower than anticipated, limiting power.","methodology":"Cluster RCT. 26 Australian high schools, 2,190 students (mean age 13.3). Four conditions: Climate, Preventure, CAP, control. Assessments at baseline, 6, 12, 24, and 36 months. Multilevel mixed linear models. Bayesian sensitivity analyses.","limitations":"Underpowered for cannabis use outcomes due to lower-than-expected prevalence. 3-year follow-up may be insufficient to see behavioral effects in a population starting at age 13. Australian context may not generalize to other countries. No blinding of students or teachers to condition."},{"rthcId":"RTHC-01776","title":"Internet-Based Universal Prevention for Students and Parents to Prevent Alcohol and Cannabis Use Among Adolescents: Protocol for the Randomized Controlled Trial of Climate Schools Plus.","authors":"Newton, Nicola Clare; Chapman, Cath; Slade, Tim; Conroy, Chloe; Thornton, Louise; Champion, Katrina Elizabeth; Stapinski, Lexine; Koning, Ina; Teesson, Maree","year":2018,"journal":"JMIR research protocols, 7(8), e10849","doi":"10.2196/10849","pmid":"30120084","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01777","title":"The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews.","authors":"Nielsen, Suzanne; Germanos, Rada; Weier, Megan; Pollard, John; Degenhardt, Louisa; Hall, Wayne; Buckley, Nicholas; Farrell, Michael","year":2018,"journal":"Current neurology and neuroscience reports, 18(2), 8","doi":"10.1007/s11910-018-0814-x","pmid":"29442178","tags":["medical-cannabis","pain","cbd"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Researchers conducted a \"review of reviews\" to synthesize high-quality systematic reviews on cannabinoids for multiple sclerosis symptoms.\n\nEleven eligible systematic reviews were identified, providing data from 32 studies including 10 moderate-to-high quality RCTs.\n\nFive reviews concluded there was sufficient evidence that cannabinoids may be effective for MS-related pain and/or spasticity.\n\nFew reviews reported conclusions for other MS symptoms including disability/progression, bladder function, tremor/ataxia, or quality of life.\n\nThe authors noted that cannabinoid effects on pain and spasticity were \"modest\" rather than large, and identified a critical evidence gap: no studies compared cannabinoids to non-cannabinoid treatments, only to placebo.","whyItMatters":"This is the most comprehensive evidence synthesis on cannabinoids for MS, aggregating findings from 11 prior reviews. The consistent finding of modest benefit for pain and spasticity, combined with the absence of comparator studies, helps clinicians set realistic expectations with patients.","specificNumbers":"11 systematic reviews, 32 primary studies, 10 moderate-to-high quality RCTs. 5 reviews supported efficacy for pain and/or spasticity. No non-cannabinoid comparator studies exist.","methodology":"Systematic review of systematic reviews. Searched for high-quality reviews examining cannabinoids (nabiximols, nabilone, dronabinol, plant-based) for MS symptoms. 11 reviews included, covering 32 primary studies.","limitations":"Review of reviews inherits limitations of underlying reviews and primary studies. \"Modest\" effects are not precisely quantified across all reviews. Different reviews used different inclusion criteria and quality assessments."},{"rthcId":"RTHC-01778","title":"Medicinal Cannabis in Pregnancy - Panacea or Noxious Weed?","authors":"O'Connor, Mike","year":2018,"journal":"Journal of law and medicine, 25(3), 634-646","doi":null,"pmid":"29978658","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01779","title":"Using Facebook to Recruit Parents to Participate in a Family Program to Prevent Teen Drug Use.","authors":"Oesterle, Sabrina; Epstein, Marina; Haggerty, Kevin P; Moreno, Megan A","year":2018,"journal":"Prevention science : the official journal of the Society for Prevention Research, 19(4), 559-569","doi":"10.1007/s11121-017-0844-7","pmid":"29116552","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01780","title":"Effectiveness of Fresh Start: A Randomized Study of a School-Based Program to Retain a Negative Attitude Toward Substance Use in Secondary School Freshmen.","authors":"Onrust, Simone A; van der Heijden, Amy; Zschämisch, Anna L; Speetjens, Paula A M","year":2018,"journal":"Substance use & misuse, 53(6), 921-930","doi":"10.1080/10826084.2017.1385082","pmid":"29083249","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01781","title":"Cannabis consumption and psychosis or schizophrenia development.","authors":"Ortiz-Medina, María Bettina; Perea, Marta; Torales, Julio; Ventriglio, Antonio; Vitrani, Giovanna; Aguilar, Lourdes; Roncero, Carlos","year":2018,"journal":"The International journal of social psychiatry, 64(7), 690-704","doi":"10.1177/0020764018801690","pmid":"30442059","tags":["psychosis","youth","genetics"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Researchers reviewed 66 papers examining the relationship between cannabis use and psychosis in people without pre-existing schizophrenia.\n\nThe main conclusion: cannabis use doubles the risk of developing psychosis in vulnerable individuals.\n\nAdditional findings:\n- A dose-response relationship exists: heavier cannabis use is associated with greater psychosis risk.\n- Age of first use matters: earlier initiation is associated with higher risk.\n- Gene-environment interactions modulate the association, meaning genetic susceptibility influences how much cannabis increases individual psychosis risk.\n\nThe evidence was drawn from 23 cohort studies (which follow people over time) and 43 reviews, representing a substantial evidence base accumulated over decades of research.","whyItMatters":"The doubling of psychosis risk is one of the most consistently replicated findings in cannabis research. This review synthesizes decades of evidence and adds clarity about dose, age, and genetic factors that modify the risk, helping to identify who is most vulnerable.","specificNumbers":"66 papers reviewed (23 cohort, 43 reviews). Cannabis doubles psychosis risk in vulnerable people. Dose-response relationship documented. Age-of-first-use effect documented. Gene-environment interactions described.","methodology":"Systematic review of PubMed database through May 2018. Keywords \"cannabis\" and \"psychosis.\" 66 papers analyzed: 23 cohort studies, 43 reviews. Published in English and Spanish.","limitations":"Narrative rather than quantitative meta-analysis. \"Vulnerable people\" is broadly defined. Most underlying studies cannot fully separate correlation from causation. Publication bias may inflate the association."},{"rthcId":"RTHC-01782","title":"A Qualitative Investigation Comparing Psychosocial and Physical Sexual Experiences Related to Alcohol and Marijuana Use among Adults.","authors":"Palamar, Joseph J; Acosta, Patricia; Ompad, Danielle C; Friedman, Samuel R","year":2018,"journal":"Archives of sexual behavior, 47(3), 757-770","doi":"10.1007/s10508-016-0782-7","pmid":"27439599","tags":["harm-reduction","sex-differences"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Twenty-four adults who recently used marijuana before sex were interviewed about how alcohol and marijuana differently affected their sexual experiences.\n\nAlcohol effects: facilitated social connections and meeting sexual partners, but was more likely to lead to atypical partner choices (someone they would not normally choose) and feelings of regret after sex. Alcohol was associated with sexual dysfunction including erectile dysfunction.\n\nMarijuana effects: enhanced physical sensations of sex and body/sex organs, increased the perceived length and intensity of sex, and enhanced orgasm experiences. The illegality of marijuana reportedly facilitated intimate encounters through shared secret behavior.\n\nBoth substances had negative sexual effects, but the types differed.\n\nExperiences were mostly similar across genders, with some variation.\n\nParticipants generally described alcohol as a social/disinhibiting drug that could lead to poor sexual decisions, versus marijuana as a sensory enhancer that changed the quality of sexual experience.","whyItMatters":"Understanding how specific substances affect sexual decision-making and experiences is important for harm reduction and sexual health programming. The finding that alcohol and marijuana affect sexuality through different mechanisms suggests substance-specific prevention approaches may be needed.","specificNumbers":"24 adults, 50% female, all heterosexual. Alcohol: more partner regret, more social facilitation, more sexual dysfunction. Marijuana: enhanced sensations, longer/more intense sex, enhanced orgasm.","methodology":"Qualitative study using semi-structured interviews with 24 adults (50% female, all heterosexual, HIV-negative) who recently used marijuana before sex. Thematic analysis comparing psychosocial and physical sexual experiences.","limitations":"Small qualitative sample (24 participants). All heterosexual and HIV-negative, limiting generalizability. Self-reported experiences subject to recall bias. No dose-response data."},{"rthcId":"RTHC-01783","title":"Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.","authors":"Pamplona, Fabricio A; da Silva, Lorenzo Rolim; Coan, Ana Carolina","year":2018,"journal":"Frontiers in neurology, 9, 759","doi":"10.3389/fneur.2018.00759","pmid":"30258398","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Researchers pooled data from 11 observational studies involving 670 patients with treatment-resistant epilepsy to compare CBD-rich extracts to purified CBD products.\n\nOverall, 64% of patients (399/622) reported seizure improvement.\n\nCBD-rich extracts were associated with significantly better outcomes:\n- 71% improvement rate (318/447) vs 46% for purified CBD (81/175), p < 0.0001.\n- Lower average dose needed: 6.0 mg/kg/day vs 25.3 mg/kg/day.\n- Fewer mild adverse effects: 33% vs 76%, p < 0.0001.\n- Fewer severe adverse effects: 2.2% vs 12.6%, p < 0.0001 (note: rates of severe AEs with purified CBD corrected).\n\nThe authors attributed the difference to synergistic effects of CBD with other phytocompounds (the entourage effect), though they noted this needs confirmation in controlled trials.","whyItMatters":"This is the first systematic comparison of whole-plant CBD extracts versus purified CBD for epilepsy. If the entourage effect is real, it means the pharmaceutical approach of isolating single compounds may sacrifice efficacy. The 4-fold dose difference has practical implications for cost and side effects.","specificNumbers":"670 patients, 11 studies. CBD-rich extracts: 71% improvement, 6.0 mg/kg/day mean dose, 33% mild AEs. Purified CBD: 46% improvement, 25.3 mg/kg/day mean dose, 76% mild AEs. Both differences highly significant (p < 0.0001).","methodology":"Meta-analysis of 11 observational clinical studies. 670 patients with treatment-resistant epilepsy. Fischer test for categorical comparisons. Treatment duration 3-12 months (mean 6.2 months). Doses ranged 1-50 mg/kg/day.","limitations":"All observational studies, not randomized trials. Different formulations, doses, and patient populations across studies. Selection bias likely (patients choosing whole-plant may differ from those using purified). Retrospective data quality varies. The entourage effect is proposed but not directly tested."},{"rthcId":"RTHC-01784","title":"Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists.","authors":"Pandey, Pankaj; Roy, Kuldeep K; Liu, Haining; Ma, Guoyi; Pettaway, Sara; Alsharif, Walid F; Gadepalli, Rama S; Rimoldi, John M; McCurdy, Christopher R; Cutler, Stephen J; Doerksen, Robert J","year":2018,"journal":"Molecules (Basel, Switzerland), 23(10)","doi":"10.3390/molecules23102630","pmid":"30322136","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01785","title":"GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.","authors":"Pasman, Joëlle A; Verweij, Karin J H; Gerring, Zachary; Stringer, Sven; Sanchez-Roige, Sandra; Treur, Jorien L; Abdellaoui, Abdel; Nivard, Michel G; Baselmans, Bart M L; Ong, Jue-Sheng; Ip, Hill F; van der Zee, Matthijs D; Bartels, Meike; Day, Felix R; Fontanillas, Pierre; Elson, Sarah L; de Wit, Harriet; Davis, Lea K; MacKillop, James; Derringer, Jaime L; Branje, Susan J T; Hartman, Catharina A; Heath, Andrew C; van Lier, Pol A C; Madden, Pamela A F; Mägi, Reedik; Meeus, Wim; Montgomery, Grant W; Oldehinkel, A J; Pausova, Zdenka; Ramos-Quiroga, Josep A; Paus, Tomas; Ribases, Marta; Kaprio, Jaakko; Boks, Marco P M; Bell, Jordana T; Spector, Tim D; Gelernter, Joel; Boomsma, Dorret I; Martin, Nicholas G; MacGregor, Stuart; Perry, John R B; Palmer, Abraham A; Posthuma, Danielle; Munafò, Marcus R; Gillespie, Nathan A; Derks, Eske M; Vink, Jacqueline M","year":2018,"journal":"Nature neuroscience, 21(9), 1161-1170","doi":"10.1038/s41593-018-0206-1","pmid":"30150663","tags":["genetics","addiction","psychosis","mental-health"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"In the largest GWAS of lifetime cannabis use to date, researchers analyzed 184,765 individuals and identified eight genome-wide significant SNPs in six genomic regions.\n\nAll measured genetic variants combined explained 11% of the variance in cannabis use.\n\nGene-based tests revealed 35 significant genes in 16 regions. The strongest finding was CADM2, previously associated with substance use and risk-taking behavior.\n\nS-PrediXcan analyses showed 21 genes had different expression levels between cannabis users and non-users.\n\nSignificant genetic correlations were found with 14 of 25 tested traits, including smoking, alcohol use, schizophrenia, and risk-taking.\n\nMendelian randomization analysis provided evidence for a causal positive influence of schizophrenia risk on cannabis use. This means genetic liability for schizophrenia increases the probability of using cannabis, not just the reverse.","whyItMatters":"The Mendelian randomization finding is a game-changer for the cannabis-schizophrenia debate. While epidemiology has long shown that cannabis users have higher psychosis risk, this genetic analysis shows the arrow can also point the other direction: people genetically predisposed to schizophrenia are more likely to use cannabis, possibly as self-medication.","specificNumbers":"N = 184,765. 8 genome-wide significant SNPs in 6 regions. 35 significant genes via gene-based tests. 11% variance explained by all SNPs. 21 genes with differential expression. 14 significant genetic correlations with other traits. CADM2 was the strongest finding.","methodology":"Genome-wide association meta-analysis. N = 184,765. Gene-based tests (MAGMA). S-PrediXcan transcriptomic analyses. LD score regression for genetic correlations. Mendelian randomization for causal inference.","limitations":"European-ancestry cohorts only. Lifetime cannabis use is a binary measure that does not capture dose, frequency, or recency. Mendelian randomization assumptions may be violated. 11% variance explained means most genetic variance is still unaccounted for."},{"rthcId":"RTHC-01786","title":"Cannabis Use Disorder in Young Adults with Acute Myocardial Infarction: Trend Inpatient Study from 2010 to 2014 in the United States.","authors":"Patel, Rikinkumar S; Katta, Shailaja Reddy; Patel, Riddhi; Ravat, Virendrasinh; Gudipalli, Ravikumar; Patel, Viralkumar; Patel, Jenil","year":2018,"journal":"Cureus, 10(8), e3241","doi":"10.7759/cureus.3241","pmid":"30410847","tags":["cardiovascular","addiction","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers examined trends in acute myocardial infarction (AMI) among cannabis users using the National Inpatient Sample from 2010 to 2014.\n\nKey findings:\n- AMI admissions among cannabis users increased 32% over the study period (p = 0.001).\n- Mean age was 41 years and remained stable.\n- AMI was predominant in males (79.1%), with a 38.3% increase in prevalence among female cannabis users.\n- In-hospital mortality increased 60% (1.0% in 2010 to 1.6% in 2014).\n- Mean hospitalization costs averaged $65,879 per admission.\n- Mean length of stay showed a decreasing trend (p = 0.003) while costs increased (p = 0.024).\n- Moderate-to-severe morbidity was prevalent (p = 0.001).","whyItMatters":"The 32% increase in AMI admissions among cannabis users and 60% rise in mortality represent concerning trends. While this may partly reflect increased cannabis use and improved detection, it suggests a growing cardiovascular burden that warrants clinical attention.","specificNumbers":"32% increase in AMI admissions among cannabis users (p = 0.001). Mean age: 41 years. Male predominance: 79.1%. Female prevalence increase: 38.3%. In-hospital mortality: 1.0% (2010) to 1.6% (2014), 60% increase. Mean hospitalization cost: $65,879.","methodology":"Retrospective analysis of the Nationwide Inpatient Sample (NIS) 2010-2014. AMI as primary diagnosis (N = 379,843). Cannabis use disorder as secondary diagnosis. Trend analysis with Pearson chi-square and independent t-tests.","limitations":"Retrospective database study relying on ICD codes. Cannabis use disorder diagnosis likely undercounts actual cannabis use. Cannot determine causation or dose-response. Increasing trends may partly reflect increased cannabis use detection and documentation rather than true incidence changes."},{"rthcId":"RTHC-01787","title":"Is Cannabis Use Associated With the Worst Inpatient Outcomes in Attention Deficit Hyperactivity Disorder Adolescents?","authors":"Patel, Rikinkumar S; Patel, Priya; Shah, Kaushal; Kaur, Mandeep; Mansuri, Zeeshan; Makani, Ramkrishna","year":2018,"journal":"Cureus, 10(1), e2033","doi":"10.7759/cureus.2033","pmid":"29535906","tags":["youth","addiction","cognition","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers analyzed 11,232 ADHD adolescent hospital admissions from 2010-2014, of which 1.79% had comorbid cannabis use disorder.\n\nCUD prevalence was highest in ages 15-18 (73%) and in white adolescents (71%).\n\nADHD adolescents with CUD had significantly worse hospitalization outcomes:\n- 1.8 times higher odds of hospitalization costs exceeding the median ($12,247)\n- 2.1 times higher odds of inpatient stays exceeding 5 days\n- Higher rates of transfer to acute care hospitals and skilled nursing facilities\n\nParadoxically, CUD was associated with reduced utilization of treatments:\n- Psychotropic medication use reduced by 55% (aOR = 0.448)\n- Behavioral therapy use reduced by 59% (aOR = 0.412)\n\nCUD dramatically increased alcohol abuse risk: 17-fold higher odds (aOR = 17.141).","whyItMatters":"The finding that ADHD adolescents with CUD receive less psychiatric treatment despite having worse outcomes is a critical clinical gap. Whether this reflects treatment resistance, clinical avoidance, or system failures, it points to a population being underserved at a critical developmental stage.","specificNumbers":"11,232 ADHD hospitalizations, 1.79% with CUD. aOR for costs >$12,247: 1.835 (p=0.002). aOR for stay >5 days: 2.099 (p<0.001). aOR for alcohol abuse: 17.141 (p<0.001). Psychotropic med use reduced: aOR 0.448 (p=0.017). Behavioral therapy reduced: aOR 0.412 (p=0.048).","methodology":"Retrospective analysis of Nationwide Inpatient Sample (NIS) 2010-2014. ADHD as primary diagnosis, CUD as secondary. Binomial logistic regression for adjusted odds ratios.","limitations":"Retrospective database study with inherent coding limitations. Cannot determine why treatment utilization was lower. Small percentage with CUD (1.79%) may reflect under-detection. Cannot assess outpatient treatment or follow-up."},{"rthcId":"RTHC-01788","title":"Demographic and socioenvironmental predictors of premorbid marijuana use among patients with first-episode psychosis.","authors":"Pauselli, Luca; Birnbaum, Michael L; Vázquez Jaime, Beatriz Paulina; Paolini, Enrico; Kelley, Mary E; Broussard, Beth; Compton, Michael T","year":2018,"journal":"Schizophrenia research, 197, 544-549","doi":"10.1016/j.schres.2018.01.020","pmid":"29397281","tags":["psychosis","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers examined what predicted premorbid marijuana use patterns in 247 patients with first-episode psychosis.\n\nThree marijuana use variables were studied: age at initiation, escalation trajectory in the five years before psychosis onset, and cumulative dose.\n\nAge at initiation of cigarette smoking was the strongest predictor, linked to all three marijuana variables: earlier marijuana initiation, faster escalation to daily use, and higher cumulative dose.\n\nDuring childhood, poorer academic performance predicted earlier marijuana initiation, while poorer sociability was related to faster escalation and higher cumulative dose.\n\nExperiencing euphoric effects from marijuana was positively correlated with escalation and cumulative dose, but having negative experiences was unrelated.\n\nTraumatic childhood/adolescent experiences correlated with rapid escalation and amount used, but not with age of initiation.","whyItMatters":"Understanding what drives heavy premorbid marijuana use in people who later develop psychosis can identify early warning signs and prevention targets. The finding that cigarette smoking initiation was the strongest predictor suggests tobacco prevention could have downstream effects on cannabis-related psychosis risk.","specificNumbers":"247 first-episode psychosis patients. Cigarette smoking initiation age predicted all three marijuana variables. Poor academics predicted earlier initiation. Poor sociability predicted faster escalation. Trauma predicted faster escalation and higher dose. Euphoric effects predicted escalation and dose; negative effects did not.","methodology":"Cross-sectional analysis of 247 first-episode psychosis patients. Data on lifetime substance use, premorbid adjustment, trauma, perceived neighborhood social disorder, and cannabis use experiences. Bivariate and regression analyses.","limitations":"Cross-sectional design with retrospective recall of premorbid use in patients already experiencing psychosis. Recall may be affected by current illness. Only first-episode patients studied; patterns may differ for cannabis users who do not develop psychosis."},{"rthcId":"RTHC-01789","title":"Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer.","authors":"Pellati, Federica; Borgonetti, Vittoria; Brighenti, Virginia; Biagi, Marco; Benvenuti, Stefania; Corsi, Lorenzo","year":2018,"journal":"BioMed research international, 2018, 1691428","doi":"10.1155/2018/1691428","pmid":"30627539","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01790","title":"Prevalence and Sociodemographic Correlates of Adolescent Use and Polyuse of Combustible, Vaporized, and Edible Cannabis Products.","authors":"Peters, Erica N; Bae, Dayoung; Barrington-Trimis, Jessica L; Jarvis, Brantley P; Leventhal, Adam M","year":2018,"journal":"JAMA network open, 1(5), e182765","doi":"10.1001/jamanetworkopen.2018.2765","pmid":"30646180","tags":["youth","potency","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Researchers surveyed 3,177 tenth-grade students (mean age 16.1, 54% girls) from 10 Los Angeles high schools.\n\nEver-use prevalence: combustible (smoking) 31.3%, edible 21.3%, vaporized 10.5%. Past 30-day use: combustible 13.4%, edible 7.8%, vaporized 4.9%.\n\nAmong recent cannabis users, combustible was used most frequently (2.65 more days/month than edible, 1.75 more than vaporized).\n\nMost cannabis users (62%) used multiple administration methods. 8.2% of all students had tried all three methods.\n\nSociodemographic differences emerged:\n- Boys had higher vaporized use but similar rates of combustible and edible use.\n- Lower SES students had higher combustible and edible use but similar vaporized use.\n- The diverse sample was 48% Hispanic, 17% Asian, 16% white.","whyItMatters":"The high prevalence of edible cannabis use among adolescents (21%) is notable because edibles carry unique risks including delayed onset leading to overconsumption, difficulty dosing, and accidental ingestion. The finding that most users consume via multiple methods suggests prevention needs to address the full spectrum of cannabis products.","specificNumbers":"3,177 students, mean age 16.1. Ever use: 31.3% combustible, 21.3% edible, 10.5% vaporized. 30-day use: 13.4%, 7.8%, 4.9%. 61.7% of users used multiple methods. 8.2% used all three. Low SES: higher combustible and edible use.","methodology":"Cross-sectional survey of 3,177 tenth-grade students from 10 Los Angeles high schools. Part of the Happiness and Health Study prospective cohort. Self-reported ever use, past 30-day use, and frequency.","limitations":"Los Angeles-specific sample in a legalized state. Self-report may underestimate use. 2015 data precedes some changes in the cannabis market. Cross-sectional design cannot track progression across product types."},{"rthcId":"RTHC-01791","title":"Ability to monitor driving under the influence of marijuana among non-fatal motor-vehicle crashes: An evaluation of the Colorado electronic accident reporting system.","authors":"Peterson, Alexis B; Sauber-Schatz, Erin K; Mack, Karin A","year":2018,"journal":"Journal of safety research, 65, 161-167","doi":"10.1016/j.jsr.2018.03.006","pmid":"29776525","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01792","title":"Altered Brain Developmental Trajectories in Adolescents After Initiating Drinking.","authors":"Pfefferbaum, Adolf; Kwon, Dongjin; Brumback, Ty; Thompson, Wesley K; Cummins, Kevin; Tapert, Susan F; Brown, Sandra A; Colrain, Ian M; Baker, Fiona C; Prouty, Devin; De Bellis, Michael D; Clark, Duncan B; Nagel, Bonnie J; Chu, Weiwei; Park, Sang Hyun; Pohl, Kilian M; Sullivan, Edith V","year":2018,"journal":"The American journal of psychiatry, 175(4), 370-380","doi":"10.1176/appi.ajp.2017.17040469","pmid":"29084454","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01793","title":"Mother of Berries, ACDC, or Chocolope: Examination of the Strains Used by Medical Cannabis Patients in New England.","authors":"Piper, Brian J","year":2018,"journal":"Journal of psychoactive drugs, 50(2), 95-104","doi":"10.1080/02791072.2017.1390179","pmid":"29064777","tags":["medical-cannabis","sleep","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Researchers conducted two studies to understand cannabis strain preferences among medical patients.\n\nStudy I catalogued strains from the online database Leafly.com, finding 1,987 strains listed. Hybrids were significantly more likely than Cannabis indica strains to have gustatory (taste-related) names.\n\nStudy II surveyed 455 medical cannabis patients from New England about strain preferences.\n\nStrain preferences were highly state and dispensary-specific. For example, 21.5% of Maine patients preferred Mother of Berries (M.O.B.).\n\nMany respondents reported developing time-dependent patterns: sativa strains during the day (for energy/focus) and indica strains at night (for sleep).\n\nHybrid and indica strains were most common across dispensaries.\n\nThe authors called for longitudinal and controlled investigations to determine which strains are most effective for specific conditions.","whyItMatters":"The vast number of strains (1,987) with minimal standardization means patients are essentially navigating an unregulated product landscape. The finding that preferences are dispensary-specific rather than condition-specific suggests strain selection may be driven more by availability than by evidence.","specificNumbers":"1,987 strains catalogued. 455 patients surveyed. 21.5% of Maine patients preferred M.O.B. Many patients used sativa by day, indica by night.","methodology":"Study I: cataloguing of Leafly.com strain database. Study II: anonymous online survey of 455 medical cannabis patients in New England. Descriptive analysis of strain preferences by state and dispensary.","limitations":"Self-selected online survey. New England-specific sample. Strain names are not standardized across dispensaries. The indica/sativa classification has limited scientific basis. No objective measures of strain effects."},{"rthcId":"RTHC-01794","title":"Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury.","authors":"Piro, Justin R; Suidan, Georgette L; Quan, Jie; Pi, YeQing; O'Neill, Sharon M; Ilardi, Marissa; Pozdnyakov, Nikolay; Lanz, Thomas A; Xi, Hualin; Bell, Robert D; Samad, Tarek A","year":2018,"journal":"Journal of neuroinflammation, 15(1), 142","doi":"10.1186/s12974-018-1166-9","pmid":"29759062","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01795","title":"Iodine-Promoted Aromatization of p-Menthane-Type Phytocannabinoids.","authors":"Pollastro, Federica; Caprioglio, Diego; Marotta, Patrizia; Moriello, Aniello Schiano; De Petrocellis, Luciano; Taglialatela-Scafati, Orazio; Appendino, Giovanni","year":2018,"journal":"Journal of natural products, 81(3), 630-633","doi":"10.1021/acs.jnatprod.7b00946","pmid":"29240420","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01796","title":"Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.","authors":"Porcari, Giulia S; Fu, Cary; Doll, Emily D; Carter, Emma G; Carson, Robert P","year":2018,"journal":"Epilepsy & behavior : E&B, 80, 240-246","doi":"10.1016/j.yebeh.2018.01.026","pmid":"29429908","tags":["epilepsy","cbd","medical-cannabis","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Researchers reviewed records of 108 pediatric epilepsy patients using artisanal CBD oil preparations at a tertiary medical center.\n\n39% of patients achieved greater than 50% seizure reduction, with 10% becoming seizure-free.\n\nNo patients achieved CBD monotherapy, but AED weaning became possible in 22% of patients.\n\nPatients also taking clobazam had a slightly higher response rate (44% vs 33% without clobazam), but this difference was not statistically significant.\n\nSedation was the most common side effect, occurring in less than 4% of patients, all of whom were also taking clobazam.\n\nNotably, 14% of patients showed increased alertness and improved verbal interactions, a positive cognitive effect.\n\nBenefits were more marked in the CBD-alone group compared to CBD + clobazam, but this difference was also not statistically significant.","whyItMatters":"While pharmaceutical CBD (Epidiolex) data gets the most attention, most families using CBD for epilepsy are using artisanal preparations from dispensaries. This real-world data from a tertiary center shows that artisanal products can be effective, with response rates comparable to clobazam and with a favorable side effect profile.","specificNumbers":"108 patients. 39% achieved >50% seizure reduction. 10% seizure-free. AED weaning possible in 22%. Sedation in <4% (all on clobazam). 14% showed increased alertness/verbal interactions. Clobazam subgroup: 44% vs 33% response (not significant).","methodology":"Retrospective study of 108 pediatric epilepsy patients using artisanal CBD preparations. Medical record review. Subgroup comparison by clobazam use. Comparison of CBD responder rate to clobazam responder rate in overlapping cohort.","limitations":"Retrospective design. Artisanal products are not standardized (varying CBD content, purity, and other cannabinoid levels). No placebo control. Observer/caregiver bias in reporting seizure counts. Small numbers in subgroup analyses."},{"rthcId":"RTHC-01797","title":"Rimonabant, a potent CB1 cannabinoid receptor antagonist, is a Gαi/o protein inhibitor.","authors":"Porcu, Alessandra; Melis, Miriam; Turecek, Rostislav; Ullrich, Celine; Mocci, Ignazia; Bettler, Bernhard; Gessa, Gian Luigi; Castelli, M Paola","year":2018,"journal":"Neuropharmacology, 133, 107-120","doi":"10.1016/j.neuropharm.2018.01.024","pmid":"29407764","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01798","title":"Structure-Activity Relationship of Cannabis Derived Compounds for the Treatment of Neuronal Activity-Related Diseases.","authors":"Prandi, Cristina; Blangetti, Marco; Namdar, Dvora; Koltai, Hinanit","year":2018,"journal":"Molecules (Basel, Switzerland), 23(7)","doi":"10.3390/molecules23071526","pmid":"29941830","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01799","title":"Effects of Δ9-tetrahydrocannabinol on irinotecan-induced clinical effects in rats.","authors":"Prester, Ljerka; Mikolić, Anja; Jurič, Andreja; Fuchs, Nino; Neuberg, Marijana; Lucić Vrdoljak, Ana; Brčić Karačonji, Irena","year":2018,"journal":"Chemico-biological interactions, 294, 128-134","doi":"10.1016/j.cbi.2018.08.009","pmid":"30130528","tags":["cancer","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Co-administration of THC with irinotecan in rats caused greater leukopenia than irinotecan alone, but the expected rise in the liver enzyme AST seen with irinotecan alone did not occur in the combination group.","whyItMatters":"Many cancer patients use cannabis to manage chemotherapy side effects. This study suggests THC may have both helpful and harmful interactions with at least one chemo drug, highlighting the need to understand these interactions before combining treatments.","specificNumbers":"THC dose was 7 mg/kg orally. Irinotecan dose was 100 mg/kg. Urinary THC metabolite concentrations were higher in the irinotecan + THC group compared to THC-only, suggesting a pharmacokinetic interaction.","methodology":"Male rats received single-dose irinotecan alone or with repeated oral THC (1, 3, or 7 days). Blood and urine were analyzed for blood counts, liver enzymes, inflammatory markers, and THC metabolites.","limitations":"Animal study using a single chemo drug and relatively high doses. Results may not translate directly to humans. Only male rats were studied. Short follow-up period."},{"rthcId":"RTHC-01800","title":"Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex.","authors":"Prini, Pamela; Rusconi, Franceso; Zamberletti, Erica; Gabaglio, Marina; Penna, Federica; Fasano, Mauro; Battaglioli, Elena; Parolaro, Daniela; Rubino, Tiziana","year":2018,"journal":"Journal of psychiatry & neuroscience : JPN, 43(2), 87-101","doi":"10.1503/jpn.170082","pmid":"29481316","tags":["youth","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Adolescent THC exposure increased levels of the histone modification H3K9me3 and the enzyme Suv39H1 in the prefrontal cortex, altering expression of genes tied to synaptic plasticity. Pharmacologically blocking H3K9me3 during THC exposure prevented cognitive deficits.","whyItMatters":"This study identifies a specific molecular mechanism through which adolescent cannabis exposure may cause lasting cognitive harm - epigenetic changes that alter how genes are read. The fact that blocking these changes prevented cognitive deficits suggests potential therapeutic targets.","specificNumbers":"Changes were primarily in H3K9me3, a repressive histone mark. Suv39H1 (the enzyme responsible) was significantly increased after adolescent but not adult THC exposure.","methodology":"Female rats received THC during adolescence or adulthood. Researchers analyzed histone modifications, chromatin remodeling enzymes, and gene expression in the prefrontal cortex over time. A separate group received the epigenetic drug chaetocin alongside THC to test whether blocking chromatin changes prevented behavioral effects.","limitations":"Only female rats were studied. Gene expression analysis covered a limited subset of genes. Animal doses and exposure patterns may not reflect typical human use."},{"rthcId":"RTHC-01801","title":"Impact of substance use disorder on gray matter volume in schizophrenia.","authors":"Quinn, Margaret; McHugo, Maureen; Armstrong, Kristan; Woodward, Neil; Blackford, Jennifer; Heckers, Stephan","year":2018,"journal":"Psychiatry research. Neuroimaging, 280, 9-14","doi":"10.1016/j.pscychresns.2018.08.002","pmid":"30121336","tags":["psychosis","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using voxel-based morphometry, researchers found that schizophrenia patients had reduced gray matter in several brain regions regardless of substance use history. No additional gray matter differences were found between patients with and without cannabis/alcohol use histories.","whyItMatters":"A major concern in schizophrenia research is whether substance use confounds brain structure findings. This study suggests that cannabis and alcohol use do not significantly worsen the gray matter reductions already associated with schizophrenia.","specificNumbers":"158 schizophrenia patients total (92 with and 66 without substance use history) compared to 88 healthy controls. Gray matter reductions were found in bilateral precentral gyrus, right medial frontal cortex, right thalamus, bilateral amygdala, and bilateral cerebellum.","methodology":"VBM brain imaging compared 92 schizophrenia patients with substance use histories, 66 without substance use histories, and 88 healthy controls.","limitations":"Cross-sectional design limits causal conclusions. Substance use histories were clinically assessed rather than biologically verified. The study did not examine other brain measures like white matter or functional connectivity."},{"rthcId":"RTHC-01802","title":"A method to achieve extended cannabis abstinence in cannabis dependent patients with schizophrenia and non-psychiatric controls.","authors":"Rabin, Rachel A; Kozak, Karolina; Zakzanis, Konstantine K; Remington, Gary; Stefan, Cristiana; Budney, Alan J; George, Tony P","year":2018,"journal":"Schizophrenia research, 194, 47-54","doi":"10.1016/j.schres.2017.05.006","pmid":"28506704","tags":["psychosis","addiction","quitting"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"With contingency management incentives and twice-weekly urine monitoring, cannabis-dependent schizophrenia patients achieved abstinence rates statistically similar to controls (42.1% vs 55%, p=0.53). Both groups showed increased withdrawal symptoms during abstinence, confirming genuine cessation.","whyItMatters":"Cannabis use disorders are about 8 times more common in people with schizophrenia than in the general population. This study shows that structured abstinence programs can work for this population, and at rates not far from the general population.","specificNumbers":"42.1% (8/19) of patients achieved 28-day abstinence vs 55% (11/20) of controls (p=0.53). Quantitative THC-COOH metabolite levels below 20 ng/mL confirmed abstinence.","methodology":"19 cannabis-dependent schizophrenia patients and 20 non-psychiatric controls underwent 28 days of monitored abstinence with contingency management. Urine was tested twice weekly using qualitative and quantitative methods (GC-MS). Subjective withdrawal assessments were also used.","limitations":"Small sample size (39 total). Contingency management provides financial incentives that may not reflect real-world motivation. 28 days may not indicate long-term abstinence capacity."},{"rthcId":"RTHC-01803","title":"Synthesis, Pharmacological Evaluation, and Docking Studies of Novel Pyridazinone-Based Cannabinoid Receptor Type 2 Ligands.","authors":"Ragusa, Giulio; Bencivenni, Serena; Morales, Paula; Callaway, Tyra; Hurst, Dow P; Asproni, Battistina; Merighi, Stefania; Loriga, Giovanni; Pinna, Gerard A; Reggio, Patricia H; Gessi, Stefania; Murineddu, Gabriele","year":2018,"journal":"ChemMedChem, 13(11), 1102-1114","doi":"10.1002/cmdc.201800152","pmid":"29575721","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01804","title":"Alcohol and Drug Use, Pain and Psychiatric Symptoms among Adults Seeking Outpatient Psychiatric Treatment: Latent Class Patterns and Relationship to Health Status.","authors":"Ramo, Danielle E; Bahorik, Amber L; Delucchi, Kevin L; Campbell, Cynthia I; Satre, Derek D","year":2018,"journal":"Journal of psychoactive drugs, 50(1), 43-53","doi":"10.1080/02791072.2017.1401185","pmid":"29199899","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Four classes emerged: moderate symptoms with wide-range drug use (22%), moderate depression/panic only (38%), depression/anxiety with tobacco and cannabis (28%), and severe wide-range symptoms and substance use (12%). Cannabis use was notably prevalent across three of the four classes.","whyItMatters":"Understanding that psychiatric outpatients cluster into distinct profiles of co-occurring substance use and mental health symptoms can help clinicians provide more targeted, effective treatment rather than one-size-fits-all approaches.","specificNumbers":"Mean age 38, 69% White, 60% female. Class sizes: 22%, 37.8%, 28%, 12%. Cannabis use was elevated in classes 1, 3, and 4.","methodology":"405 patients presenting for intake at a psychiatry outpatient clinic completed computerized assessments of psychiatric problems, drinking, and drug use. Latent class analysis identified distinct symptom-substance use profiles.","limitations":"Cross-sectional design at a single clinic. Self-reported substance use. The sample was predominantly White and female. Cannot determine whether substance use preceded or followed psychiatric symptoms."},{"rthcId":"RTHC-01805","title":"Pharmacological inhibition of 2-arachidonoilglycerol hydrolysis enhances memory consolidation in rats through CB2 receptor activation and mTOR signaling modulation.","authors":"Ratano, Patrizia; Petrella, Carla; Forti, Fabrizio; Passeri, Pamela Petrocchi; Morena, Maria; Palmery, Maura; Trezza, Viviana; Severini, Cinzia; Campolongo, Patrizia","year":2018,"journal":"Neuropharmacology, 138, 210-218","doi":"10.1016/j.neuropharm.2018.05.030","pmid":"29842858","tags":["neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The MAGL inhibitor JZL184, which boosts 2-AG levels, enhanced memory consolidation when given right after training in a fear-based learning task. This effect was mediated specifically through CB2 receptors and involved suppression of the mTOR signaling pathway in the hippocampus.","whyItMatters":"Most endocannabinoid research on memory has focused on CB1 receptors. This study reveals that 2-AG and CB2 receptors play a fundamental role in how the brain consolidates memories of aversive experiences, opening a new research direction.","specificNumbers":"JZL184 enhanced memory consolidation. CB2 antagonist AM630 blocked the effect, while CB1 antagonist AM251 did not. 2-AG signaling prevented mTOR activation in the hippocampus via CB2.","methodology":"Rats were trained on an inhibitory avoidance task (a fear-based learning paradigm). JZL184 was administered immediately after training. CB1 and CB2 antagonists were used to determine which receptor mediated the memory effect. mTOR pathway components were measured in hippocampal tissue.","limitations":"Animal study with acute drug administration. The inhibitory avoidance task measures a specific type of memory. Results may not generalize to other memory types or to humans."},{"rthcId":"RTHC-01806","title":"Simultaneous quantification of cannabinoids tetrahydrocannabinol, cannabidiol and CB1 receptor antagonist in rat plasma: An application to characterize pharmacokinetics after passive cannabis smoke inhalation and co-administration of rimonabant.","authors":"Ravula, Abhigyan; Chandasana, Hardik; Setlow, Barry; Febo, Marcelo; Bruijnzeel, Adriaan W; Derendorf, Hartmut","year":2018,"journal":"Journal of pharmaceutical and biomedical analysis, 160, 119-125","doi":"10.1016/j.jpba.2018.07.004","pmid":"30077950","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01807","title":"Cannabis use is associated with lower rates of initiation of injection drug use among street-involved youth: A longitudinal analysis.","authors":"Reddon, Hudson; DeBeck, Kora; Socias, Maria Eugenia; Dong, Huiru; Wood, Evan; Montaner, Julio; Kerr, Thomas; Milloy, Michael-John","year":2018,"journal":"Drug and alcohol review, 37(3), 421-428","doi":"10.1111/dar.12667","pmid":"29430806","tags":["harm-reduction","addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In a multivariable analysis, daily or more frequent cannabis use was associated with slower rates of injection drug initiation (adjusted hazard ratio 0.66, 95% CI 0.45-0.98). Sub-analyses showed this association was specific to injection stimulants, not injection opioids.","whyItMatters":"The gateway drug theory suggests cannabis leads to harder drugs. This longitudinal study found the opposite - daily cannabis use was associated with slower progression to injection drug use among a high-risk population, challenging a cornerstone of prohibitionist drug policy.","specificNumbers":"481 youth followed over 10 years. 228 (47.4%) reported daily cannabis use. 103 (21.4%) initiated injection drug use. Adjusted hazard ratio for daily cannabis users: 0.66 (95% CI 0.45-0.98, p=0.038).","methodology":"Prospective cohort study following 481 street-involved youth aged 14-26 in Vancouver, Canada from 2005-2015. Extended Cox regression with time-updated covariates examined factors associated with injection drug initiation.","limitations":"Observational study cannot prove causation. Self-reported drug use. Specific to street-involved youth in Vancouver, which may not generalize. Potential for unmeasured confounders."},{"rthcId":"RTHC-01808","title":"Comorbid Cannabis and Tobacco Use Disorders in Hospitalized Patients with Psychotic-Spectrum Disorders.","authors":"Reeves, Lauren E; Gaudiano, Brandon A; Metrik, Jane; Guzman Holst, Carolina; Morena, Alexandra; Sydnor, Valerie J; Weinstock, Lauren M; Epstein-Lubow, Gary","year":2018,"journal":"Journal of dual diagnosis, 14(3), 171-180","doi":"10.1080/15504263.2018.1470359","pmid":"30265850","tags":["psychosis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Patients with both cannabis and tobacco use disorders (CUD + TUD) had significantly higher odds of also having alcohol and stimulant use disorders compared to patients with neither. Stimulant and polysubstance use disorder diagnoses were associated with tobacco use disorder. More prescribed psychotropic medications was linked to tobacco use disorder.","whyItMatters":"Tobacco and cannabis are the most commonly used substances among people with psychosis. Understanding how these use patterns cluster with other substance use and clinical characteristics can help clinicians screen more effectively and tailor treatment during hospitalization.","specificNumbers":"829 patients with psychotic-spectrum disorders. Four groups: cannabis use disorder only, tobacco use disorder only, both, and neither. Age and gender varied significantly across groups.","methodology":"Retrospective analysis of electronic medical records from 829 patients with psychotic-spectrum disorders admitted to a psychiatric hospital. Patients were categorized into four groups based on cannabis and/or tobacco use disorder. Multinomial logistic regression compared groups controlling for age and sex.","limitations":"Retrospective chart review at a single hospital. Diagnoses depended on clinical documentation quality. Cross-sectional snapshot during hospitalization. Age differences between groups may account for some findings."},{"rthcId":"RTHC-01809","title":"Marijuana and Cannabinoids in ESRD and Earlier Stages of CKD.","authors":"Rein, Joshua L; Wyatt, Christina M","year":2018,"journal":"American journal of kidney diseases : the official journal of the National Kidney Foundation, 71(2), 267-274","doi":"10.1053/j.ajkd.2017.06.020","pmid":"28811049","tags":["medical-cannabis","pain"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The review found emerging evidence supporting potential benefits of medical marijuana for four common symptoms in advanced CKD and dialysis patients: chronic pain, nausea/vomiting, anorexia/cachexia, and pruritus (itching). The endocannabinoid system appears to play a role in kidney function and disease.","whyItMatters":"Patients on dialysis often suffer from symptoms that are difficult to treat with conventional medications due to altered drug metabolism and increased side effect risk. Cannabinoids represent a potential alternative, especially as legal access expands.","specificNumbers":"29 US states had medical marijuana programs at time of publication. CKD/ESRD patients experience chronic pain, nausea, appetite loss, and itching at rates far exceeding the general population.","methodology":"Narrative review of available evidence on medical marijuana use for symptom management in chronic kidney disease and end-stage renal disease.","limitations":"Narrative review based on limited direct evidence in CKD/ESRD populations. Most cannabinoid research has been in other patient populations. No clinical trials specific to kidney disease patients were available."},{"rthcId":"RTHC-01810","title":"Effects of Adolescent THC Exposure on the Prefrontal GABAergic System: Implications for Schizophrenia-Related Psychopathology.","authors":"Renard, Justine; Rushlow, Walter J; Laviolette, Steven R","year":2018,"journal":"Frontiers in psychiatry, 9, 281","doi":"10.3389/fpsyt.2018.00281","pmid":"30013490","tags":["youth","psychosis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review synthesizes evidence that adolescent THC exposure targets schizophrenia-related molecular pathways in the prefrontal cortex and mesolimbic dopamine system. Specifically, THC-induced GABAergic hypofunction in the PFC may lead to dysregulated dopamine signaling - a core feature of schizophrenia.","whyItMatters":"Understanding the specific neural mechanisms linking adolescent cannabis use to psychosis risk could inform prevention strategies and potentially identify biomarkers for vulnerability.","specificNumbers":"The review covers effects in the prefrontal cortex (PFC), ventral tegmental area (VTA), and nucleus accumbens (NAc) - the three key brain regions implicated in schizophrenia.","methodology":"Review of preclinical studies examining how adolescent THC exposure affects GABAergic neurotransmission in the prefrontal cortex and its downstream effects on dopamine signaling.","limitations":"Based primarily on animal studies. The leap from rat prefrontal cortex findings to human schizophrenia involves significant assumptions. Doses used in animal studies may not reflect human exposure."},{"rthcId":"RTHC-01811","title":"Cannabinoids for Treatment of MS Symptoms: State of the Evidence.","authors":"Rice, Jessica; Cameron, Michelle","year":2018,"journal":"Current neurology and neuroscience reports, 18(8), 50","doi":"10.1007/s11910-018-0859-x","pmid":"29923025","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Nabiximols (Sativex), oral cannabis extract (OCE), and synthetic THC are probably effective for patient-reported spasticity and central pain in MS. However, OCE and synthetic THC did not reduce physician-measured spasticity scores. Cannabinoids were generally well-tolerated, though risks include psychosis in at-risk individuals and cardiovascular events.","whyItMatters":"MS patients frequently deal with spasticity and pain that are difficult to control with conventional medications. This review provides the strongest available evidence base for using cannabinoids as a treatment option for these symptoms.","specificNumbers":"Most study participants used 20-40 mg of THC daily in divided doses. Cannabinoids were the only complementary/alternative medicine intervention with strong evidence in MS. Adverse events were more common with cannabinoids but serious adverse events were rare.","methodology":"Review synthesizing findings from two recent high-quality systematic reviews of cannabinoid use in MS, with discussion of available formulations and dosing.","limitations":"Patient-reported spasticity improvements did not match physician-measured scores, raising questions about the nature of the benefit. Optimal dosing remains uncertain. Long-term safety data is limited."},{"rthcId":"RTHC-01812","title":"Cannabinoid Hyperemesis Syndrome: Pathophysiology and Treatment in the Emergency Department.","authors":"Richards, John R","year":2018,"journal":"The Journal of emergency medicine, 54(3), 354-363","doi":"10.1016/j.jemermed.2017.12.010","pmid":"29310960","tags":["harm-reduction","potency"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS may result from the endocannabinoid system being overwhelmed by chronic cannabis use, with acute episodes triggered by stress or fasting. Standard antiemetics often fail because CHS involves different pathways than typical nausea. Benzodiazepines and antipsychotics work through their sedating effects, while capsaicin activates TRPV1 receptors through an entirely different mechanism.","whyItMatters":"CHS is increasingly common as cannabis potency and use rise, and patients often make repeated ER visits because standard treatments do not work. Understanding why and which alternatives are effective can reduce suffering and healthcare costs.","specificNumbers":"CHS has become more prevalent with increasing cannabis potency and legalization. Treatment failure with standard antiemetics is common. Capsaicin, benzodiazepines, and antipsychotics represent the three main alternative treatment approaches.","methodology":"Review of CHS pathophysiology and published literature on pharmacologic treatment in the emergency department setting.","limitations":"Limited high-quality research despite increasing CHS prevalence. Most treatment evidence comes from case reports and case series rather than controlled trials. The exact mechanism of CHS remains incompletely understood."},{"rthcId":"RTHC-01813","title":"Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment.","authors":"Richards, John R; Lapoint, Jeff M; Burillo-Putze, Guillermo","year":2018,"journal":"Clinical toxicology (Philadelphia, Pa.), 56(1), 15-24","doi":"10.1080/15563650.2017.1349910","pmid":"28730896","tags":["harm-reduction","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Capsaicin and hot water both activate TRPV1 receptors, which share extensive cross-talk with the endocannabinoid system. TRPV1 activation triggers modulation of tachykinins, somatostatin, PACAP, CGRP, and histaminergic/cholinergic/serotonergic transmission - all of which have anti-emetic potential. The review identified 137 relevant articles detailing these mechanisms.","whyItMatters":"CHS patients often instinctively seek hot showers for relief, and capsaicin cream has emerged as a treatment option. Understanding why these work reveals fundamental connections between the endocannabinoid system and temperature-sensing pathways that could lead to better treatments.","specificNumbers":"2,417 articles screened, 137 included. About 20 published cases of capsaicin successfully treating CHS. TRPV1 responds to temperatures above 43 degrees C and pH below 6.","methodology":"Systematic literature search of PubMed, OpenGrey, and Google Scholar through April 2017, screening 2,417 articles for relevant thermoregulatory and anti-emetic mechanisms. 137 articles were included.","limitations":"Largely theoretical, connecting mechanisms from separate research areas. Most CHS treatment evidence is from case reports. The exact contribution of each proposed pathway remains unknown."},{"rthcId":"RTHC-01814","title":"Comparing medical and recreational cannabis use among employees: associations with health and work-related outcomes.","authors":"Rineer, Jennifer R; Duhart Clarke, Sarah; Cluff, Laurie A; Peiper, Nicholas C","year":2018,"journal":"International review of psychiatry (Abingdon, England), 30(3), 268-276","doi":"10.1080/09540261.2018.1465397","pmid":"30179533","tags":["workplace","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"While some differences in health and work outcomes were initially seen between medical, recreational, and mixed-use cannabis users, several disappeared after controlling for health-related factors. One persistent difference: medical and mixed-use cannabis users were more concentrated in construction and mining industries.","whyItMatters":"Nearly one in five US employees reports past-year cannabis use. As legalization expands, employers need to understand whether medical and recreational users differ in ways that are relevant to workplace policies and safety.","specificNumbers":"Nearly 1 in 5 US employees reported past-year cannabis use. Medical and mixed-use cannabis users were significantly overrepresented in construction and mining.","methodology":"Analysis of employed respondents from the National Survey on Drug Use and Health (NSDUH), comparing medical-only, recreational-only, and mixed-use cannabis users on workplace characteristics and health outcomes.","limitations":"Cross-sectional survey data. Self-reported cannabis use and medical status. NSDUH definitions of medical use may not match state-specific legal definitions. Cannot determine whether industry differences reflect job-related pain or other factors."},{"rthcId":"RTHC-01815","title":"HIV-infected cannabis users have lower circulating CD16+ monocytes and IFN-γ-inducible protein 10 levels compared with nonusing HIV patients.","authors":"Rizzo, Michael D; Crawford, Robert B; Henriquez, Joseph E; Aldhamen, Yasser A; Gulick, Peter; Amalfitano, Andrea; Kaminski, Norbert E","year":2018,"journal":"AIDS (London, England), 32(4), 419-429","doi":"10.1097/QAD.0000000000001704","pmid":"29194121","tags":["inflammation","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"HIV+ cannabis users had lower circulating CD16+ monocytes and plasma IP-10 (both implicated in HIV-associated neuroinflammation) compared to HIV+ non-users. In-vitro THC treatment impaired the transition of monocytes to the inflammatory CD16+ state and reduced IP-10 production, confirming a direct anti-inflammatory effect.","whyItMatters":"HIV-associated neuroinflammation, driven partly by activated monocytes, contributes to cognitive decline even in patients on antiretroviral therapy. If cannabis can reduce this inflammatory process, it could help protect against HIV-related brain damage.","specificNumbers":"HIV+ cannabis users had lower CD16+ monocytes and plasma IP-10. Monocytes from cannabis users were resistant to IFN-alpha-induced CD16 upregulation, while monocytes from non-users showed pronounced CD16 induction.","methodology":"Compared circulating CD16+ monocyte levels and plasma IP-10 between HIV+ cannabis users and non-users using flow cytometry. In-vitro experiments with THC on isolated blood cells confirmed direct effects on monocyte activation and IP-10 production.","limitations":"Observational comparison; cannabis users may differ from non-users in other ways. Cannabis users' exposure varied in dose and duration. In-vitro THC concentrations may not reflect physiological levels."},{"rthcId":"RTHC-01816","title":"Attention-deficit hyperactivity disorder and addictions (substance and behavioral): Prevalence and characteristics in a multicenter study in France.","authors":"Romo, Lucia; Ladner, Joel; Kotbagi, Gayatri; Morvan, Yannick; Saleh, Dalia; Tavolacci, Marie Pierre; Kern, Laurence","year":2018,"journal":"Journal of behavioral addictions, 7(3), 743-751","doi":"10.1556/2006.7.2018.58","pmid":"30010409","tags":["mental-health","addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Students with ADHD had significantly higher scores on substance use measures (alcohol, cannabis, tobacco) and behavioral addictions (gambling, compulsive buying, eating disorders, internet addiction) compared to non-ADHD students. ADHD students also repeated classes more often and rated their academic performance lower.","whyItMatters":"ADHD is a common but often undiagnosed condition in university students. Understanding that it is linked to elevated cannabis use and multiple other addictive behaviors can help universities target screening and support services more effectively.","specificNumbers":"1,517 students, mean age 20.6. ADHD prevalence: 5.6%. 42.2% of ADHD students had repeated a year vs 25.7% overall. Sex ratio M:F was 0.46.","methodology":"Cross-sectional survey of 1,517 university students at two French universities using validated screening tools for ADHD, substance use, and behavioral addictions.","limitations":"Cross-sectional design. ADHD was screened, not formally diagnosed. Two French universities may not be representative of all student populations. Self-reported substance use."},{"rthcId":"RTHC-01817","title":"Cannabis Therapeutics and the Future of Neurology.","authors":"Russo, Ethan B","year":2018,"journal":"Frontiers in integrative neuroscience, 12, 51","doi":"10.3389/fnint.2018.00051","pmid":"30405366","tags":["medical-cannabis","neuroscience","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review presents evidence supporting cannabis-based interventions for intractable epilepsy, brain tumors, Parkinson disease, Alzheimer disease, and traumatic brain injury/CTE. These conditions share some pathological processes that may respond to cannabinoid mechanisms including CB1, CB2, PPARgamma, and 5-HT1A receptor activity.","whyItMatters":"Neurology has largely been limited to symptomatic treatment of neurodegenerative diseases. This review argues that cannabis compounds may offer something more ambitious: the potential to slow, arrest, or even reverse pathological processes rather than just managing symptoms.","specificNumbers":"Five target conditions examined: intractable epilepsy, brain tumors, Parkinson disease, Alzheimer disease, and TBI/CTE. Multiple compounds considered: THC, CBD, THCA, CBDA, and terpenes like caryophyllene.","methodology":"Narrative review synthesizing basic science and clinical evidence for cannabinoid-based treatments across five neurological conditions, examining multiple cannabis compounds and their mechanisms of action.","limitations":"Narrative review by a prominent cannabis medicine advocate. Much of the evidence is preclinical or from small studies. The breadth of conditions covered limits depth of analysis for any single disease."},{"rthcId":"RTHC-01818","title":"Investigational cannabinoids in seizure disorders, what have we learned thus far?","authors":"Ružić Zečević, Dejana; Folić, Marko; Tantoush, Ziyad; Radovanović, Milan; Babić, Goran; Janković, Slobodan M","year":2018,"journal":"Expert opinion on investigational drugs, 27(6), 535-541","doi":"10.1080/13543784.2018.1482275","pmid":"29842819","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Preclinical studies confirmed anticonvulsant activity of CBD and CBDV across multiple epilepsy models. Clinical trials showed clear therapeutic benefit of CBD for treatment-resistant seizures in Dravet syndrome and drop seizures in Lennox-Gastaut syndrome, with good safety profiles.","whyItMatters":"About one-third of epilepsy patients are drug-resistant. CBD has become the first cannabis-derived compound approved for epilepsy, and several other cannabinoids in the research pipeline could expand treatment options.","specificNumbers":"Four cannabinoids investigated: CBD, CBDV, THCV, and THCA. CBD showed benefit specifically in Dravet syndrome and Lennox-Gastaut syndrome (LGS). Clinical trials for CBDV results were still pending at publication.","methodology":"Review of preclinical and clinical studies on investigational cannabinoids for epilepsy, searched across MEDLINE, SCOPUS, EBSCO, Google Scholar, and SCINDEX databases.","limitations":"Clinical evidence was strongest for CBD; other cannabinoids still lacked human trial data. The full therapeutic potential across epilepsy types remains unknown."},{"rthcId":"RTHC-01819","title":"Cannabinoids for Treatment of Dystonia in Huntington's Disease.","authors":"Saft, Carsten; von Hein, Sarah Maria; Lücke, Thomas; Thiels, Charlotte; Peball, Marina; Djamshidian, Atbin; Heim, Beatrice; Seppi, Klaus","year":2018,"journal":"Journal of Huntington's disease, 7(2), 167-173","doi":"10.3233/JHD-170283","pmid":"29562549","tags":["medical-cannabis","neuroscience"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"UHDRS motor scores improved from 70.9 to 60.6 (mean change 10.3 points, 95% CI 6.0-14.6, p=0.018). The dystonia subscore improved from 12.3 to 8.0 (mean change 4.3 points, 95% CI 2.3-6.3, p=0.018). Patients also showed improvements in gait, fine motor skills, weight gain, and behavior.","whyItMatters":"Treatment options for dystonia in Huntington's disease are extremely limited. This case series provides evidence that cannabinoids may fill a significant therapeutic gap for one of HD's most debilitating symptoms.","specificNumbers":"Motor score improved by 10.3 points (from 70.9 to 60.6). Dystonia subscore improved by 4.3 points (from 12.3 to 8.0). Both improvements were statistically significant (p=0.018).","methodology":"Case series of seven early-onset HD patients assessed with the Unified Huntington's Disease Rating Scale before and after starting cannabinoids, with no other medication changes during the observation period.","limitations":"Small case series without placebo control or blinding. All patients had early-onset HD, which may differ from typical adult-onset HD. No standardized cannabinoid formulation or dose across patients."},{"rthcId":"RTHC-01820","title":"Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells.","authors":"Saliba, Soraya Wilke; Jauch, Hannah; Gargouri, Brahim; Keil, Albrecht; Hurrle, Thomas; Volz, Nicole; Mohr, Florian; van der Stelt, Mario; Bräse, Stefan; Fiebich, Bernd L","year":2018,"journal":"Journal of neuroinflammation, 15(1), 322","doi":"10.1186/s12974-018-1362-7","pmid":"30453998","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01821","title":"Are cannabis-using and non-using patients different groups? Towards understanding the neurobiology of cannabis use in psychotic disorders.","authors":"Sami, Musa Basseer; Bhattacharyya, Sagnik","year":2018,"journal":"Journal of psychopharmacology (Oxford, England), 32(8), 825-849","doi":"10.1177/0269881118760662","pmid":"29591635","tags":["psychosis","neuroscience"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Cannabis use is associated with increased risk of developing psychotic disorders, increased hospitalization, longer hospital stays, and treatment failure. The systematic review of 70 studies (3,000+ patients) found evidence for distinct neurobiological patterns in cannabis-using versus non-using psychosis patients, though the biological underpinnings remain to be fully elucidated.","whyItMatters":"If cannabis-using psychosis patients truly represent a neurobiologically distinct subgroup, they may need different treatment approaches. Understanding these differences could lead to more personalized interventions.","specificNumbers":"70 studies reviewed, over 3,000 patients included. Evidence covers risk of developing psychosis, hospitalization patterns, and treatment response in cannabis-using versus non-using patients.","methodology":"Two-part approach: summary of longitudinal evidence on cannabis-psychosis associations, plus systematic review of 70 studies examining neurobiological and neurochemical mechanisms in over 3,000 patients with psychotic disorders or at increased risk.","limitations":"Many included studies were cross-sectional. Establishing causation from observational data is inherently limited. Heterogeneity in cannabis use patterns and psychosis definitions across studies."},{"rthcId":"RTHC-01822","title":"Presynaptic cannabinoid CB2 receptors modulate [3 H]-Glutamate release at subthalamo-nigral terminals of the rat.","authors":"Sánchez-Zavaleta, Rodolfo; Cortés, Hernán; Avalos-Fuentes, José Arturo; García, Ubaldo; Segovia Vila, José; Erlij, David; Florán, Benjamín","year":2018,"journal":"Synapse (New York, N.Y.), 72(11), e22061","doi":"10.1002/syn.22061","pmid":"30022523","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01823","title":"Association Between Socio-Demographic and Health Functioning Variables Among Patients with Opioid Use Disorder Introduced by Prescription: A Prospective Cohort Study.","authors":"Sanger, Nitika; Bhatt, Meha; Shams, Ieta; Shahid, Hamnah; Luo, Candice; Tam, Sabrina Lue; Samaan, M Constantine; de Souza, Russell; Thabane, Lehana; Samaan, Zainab","year":2018,"journal":"Pain physician, 21(6), E623-E632","doi":null,"pmid":"30508993","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01824","title":"Cannabidiol for Epilepsy: New Hope on the Horizon?","authors":"Sanmartin, Paul E; Detyniecki, Kamil","year":2018,"journal":"Clinical therapeutics, 40(9), 1438-1441","doi":"10.1016/j.clinthera.2018.07.020","pmid":"30150078","tags":["epilepsy","cbd"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Early anecdotal evidence for cannabis as an anticonvulsant was recently replaced by high-quality data from randomized controlled studies. This led to FDA approval of purified CBD for two highly refractory pediatric epilepsy syndromes. About one-third of epilepsy patients are drug-resistant, defined as failure despite adequate trials of at least two appropriate medications.","whyItMatters":"The FDA approval of CBD for epilepsy represents a landmark moment - the first cannabis-derived prescription drug approved in the United States. It validates decades of patient advocacy and demonstrates that rigorous clinical trials can be conducted with cannabis compounds.","specificNumbers":"Approximately 50 million people worldwide have epilepsy. About one-third (roughly 17 million) are drug-resistant. FDA approved purified CBD for Dravet and Lennox-Gastaut syndromes.","methodology":"Review of evidence from early anecdotal reports through modern randomized controlled trials supporting CBD as an anticonvulsant.","limitations":"Short review focused on the approval pathway. Does not deeply analyze trial data or long-term outcomes. Approval was limited to two specific syndromes."},{"rthcId":"RTHC-01825","title":"Pregabalin misuse in methadone maintenance treatment patients in Israel: Prevalence and risk factors.","authors":"Sason, Anat; Adelson, Miriam; Schreiber, Shaul; Peles, Einat","year":2018,"journal":"Drug and alcohol dependence, 189, 8-11","doi":"10.1016/j.drugalcdep.2018.04.025","pmid":"29857329","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01826","title":"Effects of cannabis use on body mass, fasting glucose and lipids during the first 12 months of treatment in schizophrenia spectrum disorders.","authors":"Scheffler, F; Kilian, S; Chiliza, B; Asmal, L; Phahladira, L; du Plessis, S; Kidd, M; Murray, R M; Di Forti, M; Seedat, S; Emsley, R","year":2018,"journal":"Schizophrenia research, 199, 90-95","doi":"10.1016/j.schres.2018.02.050","pmid":"29519756","tags":["psychosis","appetite","cardiovascular"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"There was a significant group-by-time interaction (p=0.002): cannabis-negative patients showed greater BMI increases over 12 months than cannabis-positive patients. Post hoc tests showed the cannabis-negative group had significant increases in fasting glucose, triglycerides, and decreased HDL cholesterol, while the cannabis-positive group showed no significant changes in these markers.","whyItMatters":"Antipsychotic-induced weight gain is a major side effect that contributes to cardiovascular disease and treatment non-adherence. Understanding why some patients gain less weight could lead to better metabolic management strategies.","specificNumbers":"109 patients total: 40 cannabis-positive, 69 cannabis-negative. Significant group-by-time interaction for BMI (p=0.002). More cannabis-negative patients had elevated waist circumference at endpoint (p=0.003).","methodology":"109 minimally treated first-episode patients with schizophrenia-spectrum disorders received standardized depot antipsychotic treatment over 12 months. 40 tested positive for cannabis at any point; 69 tested negative at all time points. Repeated measures compared BMI, fasting glucose, and lipids over time.","limitations":"Observational within a treatment study - cannot prove cannabis caused the weight difference. Cannabis users may have different lifestyle factors (diet, smoking). Urine testing only indicates recent use, not quantity or frequency."},{"rthcId":"RTHC-01827","title":"Medicinal cannabis (Bedrolite) substitution therapy in inpatients with a psychotic disorder and a comorbid cannabis use disorder: A case series.","authors":"Schipper, Regi; Dekker, Mathilde; de Haan, Lieuwe; van den Brink, Wim","year":2018,"journal":"Journal of psychopharmacology (Oxford, England), 32(3), 353-356","doi":"10.1177/0269881117735684","pmid":"29039260","tags":["psychosis","harm-reduction","cbd"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The low-THC medicinal cannabis variant Bedrolite was not effective in treating inpatients with psychotic disorders and comorbid cannabis use disorder. The harm reduction strategy of replacing high-THC street cannabis with low-THC medicinal cannabis did not achieve its goals.","whyItMatters":"With no proven treatments for cannabis use disorder in psychosis patients, harm reduction through cannabis substitution was a creative approach. Its failure here suggests that patients may be seeking the THC effects specifically, not just the cannabis experience.","specificNumbers":"Seven inpatients studied. Bedrolite contains relatively low THC and relatively high CBD compared to typical street cannabis.","methodology":"Case series of seven inpatients diagnosed with a psychotic disorder and treatment-resistant cannabis use disorder who received Bedrolite (low THC, relatively high CBD) as substitution therapy.","limitations":"Very small case series (n=7). Inpatient setting may not reflect real-world use. Only one medicinal cannabis product tested. No control group for comparison."},{"rthcId":"RTHC-01828","title":"The effect of high-dose dronabinol (oral THC) maintenance on cannabis self-administration.","authors":"Schlienz, Nicolas J; Lee, Dustin C; Stitzer, Maxine L; Vandrey, Ryan","year":2018,"journal":"Drug and alcohol dependence, 187, 254-260","doi":"10.1016/j.drugalcdep.2018.02.022","pmid":"29689485","tags":["addiction","tolerance","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Chronic dronabinol dosing significantly reduced cannabis self-administration compared to placebo maintenance. Both low-dose (120 mg/day) and high-dose (180-240 mg/day) dronabinol reduced use equally, with no additional benefit from the higher dose. Dronabinol also suppressed withdrawal symptoms.","whyItMatters":"There are currently no FDA-approved medications for cannabis use disorder. This study provides evidence that an agonist replacement approach (similar to methadone for opioids) could work for cannabis dependence.","specificNumbers":"13 daily cannabis users studied. Low-dose dronabinol: 120 mg/day (40 mg three times daily). High-dose: 180-240 mg/day (60-80 mg three times daily). 12-day maintenance periods per condition.","methodology":"Residential within-subjects crossover study with 13 non-treatment-seeking daily cannabis users. Participants received placebo, low-dose (120 mg/day), or high-dose (180-240 mg/day) dronabinol for 12 days each. Cannabis self-administration was measured under forced-choice and progressive ratio conditions.","limitations":"Small sample (n=13). Non-treatment-seeking participants may differ from those wanting to quit. Residential laboratory setting does not reflect real-world cannabis access. Short 12-day maintenance periods."},{"rthcId":"RTHC-01829","title":"Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial.","authors":"Schoedel, Kerri A; Szeto, Isabella; Setnik, Beatrice; Sellers, Edward M; Levy-Cooperman, Naama; Mills, Catherine; Etges, Tilden; Sommerville, Kenneth","year":2018,"journal":"Epilepsy & behavior : E&B, 88, 162-171","doi":"10.1016/j.yebeh.2018.07.027","pmid":"30286443","tags":["cbd","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Therapeutic CBD (750 mg) showed significantly low abuse potential. High doses (1500 mg, 4500 mg) had detectable subjective effects compared to placebo but were significantly lower than alprazolam and dronabinol on drug-liking, overall-liking, and take-drug-again measures (all P values 0.004 or less). CBD did not impair cognitive or psychomotor function at any dose.","whyItMatters":"This study was critical for CBD's regulatory pathway. By demonstrating low abuse potential in a population most sensitive to detecting drug effects, it supported the argument that CBD should not be heavily restricted, paving the way for more accessible medical use.","specificNumbers":"43 subjects dosed, 35 in pharmacodynamic analysis. CBD at 750 mg showed no significant drug-liking versus placebo. Even at 4500 mg (6x therapeutic dose), CBD drug-liking was significantly lower than both active controls.","methodology":"Single-dose, randomized, double-blind, double-dummy, placebo- and active-controlled crossover trial in 43 healthy recreational polydrug users. CBD (750, 1500, 4500 mg) was compared with alprazolam (2 mg), dronabinol (10 mg, 30 mg), and placebo.","limitations":"Single-dose study does not assess abuse potential of chronic use. Polydrug user population is specific. Very high doses (4500 mg) are unlikely to be used clinically. The oral solution formulation may differ from other CBD products."},{"rthcId":"RTHC-01830","title":"Cannabinoid-Based Therapies and Brain Development: Potential Harmful Effect of Early Modulation of the Endocannabinoid System.","authors":"Schonhofen, Patrícia; Bristot, Ivi Juliana; Crippa, José Alexandre; Hallak, Jaime Eduardo Cecílio; Zuardi, Antônio Waldo; Parsons, Richard B; Klamt, Fábio","year":2018,"journal":"CNS drugs, 32(8), 697-712","doi":"10.1007/s40263-018-0550-4","pmid":"30109642","tags":["cbd","youth","epilepsy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system regulates progenitor cell fate, neural differentiation, migration, and survival from early developmental stages. Exogenous cannabinoids including CBD can interact with this system. While CBD has proven therapeutic value for pediatric epilepsy, potential long-term neurodevelopmental effects of modulating the ECS during childhood remain largely unstudied.","whyItMatters":"Thousands of children are now taking CBD for epilepsy. This review raises an important cautionary point: the same system being modulated therapeutically also plays essential roles in brain development, and we do not yet know the long-term consequences.","specificNumbers":"CBD has both endocannabinoid (ECS-mediated) and non-endocannabinoid targets. ECS components are functional from early developmental stages. FDA approved purified CBD from Cannabis for pediatric epilepsy.","methodology":"Review of current knowledge on CBD-based therapies in pediatric patients, CBD mechanisms of action, and the role of the endocannabinoid system in neurodevelopment.","limitations":"Largely theoretical concerns based on the known biology of the ECS in development. No direct evidence of harm from CBD treatment in children. Extrapolating from basic science to clinical risk involves significant uncertainty."},{"rthcId":"RTHC-01831","title":"Cannabinoid hyperemesis syndrome: Review of the literature and of cases reported to the French addictovigilance network.","authors":"Schreck, Benoît; Wagneur, Nicolas; Caillet, Pascal; Gérardin, Marie; Cholet, Jennyfer; Spadari, Michel; Authier, Nicolas; Tournebize, Juliana; Gaillard, Marion; Serre, Anais; Carton, Louise; Pain, Stéphanie; Jolliet, Pascale; Victorri-Vigneau, Caroline","year":2018,"journal":"Drug and alcohol dependence, 182, 27-32","doi":"10.1016/j.drugalcdep.2017.09.038","pmid":"29132050","tags":["harm-reduction","potency"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CHS mainly affects young male subjects who have smoked cannabis daily for several years. Hot baths/showers provide the most effective symptom relief, while antiemetics and dopamine antagonists are generally ineffective. The 29 French cases displayed the same characteristics as the 113 cases identified in the international literature.","whyItMatters":"CHS is increasingly recognized worldwide. This study confirms the syndrome presents consistently across different countries and healthcare systems, supporting the existence of a well-defined clinical entity rather than a reporting artifact.","specificNumbers":"137 articles identified, 55 selected with 113 reported cases. 29 additional French cases analyzed. Young males who smoke daily for years are the typical profile.","methodology":"Systematic search of MEDLINE, PsycINFO, and Cochrane Library identified 55 articles with 113 reported cases. Additionally analyzed 29 cases reported to the French addictovigilance network.","limitations":"Case report-based analysis subject to reporting bias. Mild or atypical cases may be underdiagnosed. Pathophysiology remains unclear. No standardized diagnostic criteria at time of publication."},{"rthcId":"RTHC-01832","title":"Association of cannabis with cognitive functioning in adolescents and young adults: A systematic review and meta-analysis","authors":"Scott, J. Cobb; Slomiak, Samantha T.; Jones, Jason D.; Rosen, Adon F.G.; Moore, Tyler M.; Gur, Ruben C.","year":2018,"journal":"JAMA Psychiatry, 75(6), 585-595","doi":null,"pmid":"29710074","tags":["cognition","youth","withdrawal","addiction"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"This was the first quantitative synthesis of the cannabis-cognition literature in adolescents and young adults. The researchers pulled together 69 studies covering 2,152 cannabis users and 6,575 controls, all with a mean age of 26 or younger.\n\nThe headline finding was a small overall effect size for reduced cognitive functioning across 10 domains. Learning and memory showed the most consistent deficits. But the critical nuance came in the moderator analysis: studies that required at least 72 hours of abstinence before testing found no significant association between cannabis use and cognitive performance.\n\nThat 72-hour finding reframed the entire discussion. It suggested that much of the cognitive difference seen in cannabis users may reflect the acute and residual effects of recent use rather than lasting brain changes. The paper didn't rule out long-term effects — it just showed that the evidence for permanent cognitive damage was weaker than the cross-sectional studies alone suggested.","whyItMatters":"For years, the narrative was that cannabis damages young brains — period. This meta-analysis didn't refute that concern entirely, but it substantially complicated the story. The effect sizes were small, not the dramatic deficits often implied in public health messaging. And the abstinence finding suggested the brain recovers more than the scare campaigns implied.\n\nThis matters for policy, for parents, and for young people themselves. There's a difference between \"cannabis causes small, mostly reversible cognitive effects\" and \"cannabis permanently damages your brain.\" Both justify caution, but only one is what the data actually showed.","specificNumbers":"• 69 studies, 2,152 cannabis users, 6,575 comparison participants\n• Mean age across studies: 20.6 years (users), 20.8 years (controls)\n• Overall effect size: small (Cohen's d) for reduced cognitive function\n• After 72+ hours abstinence: no significant cognitive differences\n• Learning and memory: most consistently affected domain","methodology":"Systematic review and meta-analysis following MOOSE guidelines. Searched PubMed, PsycInfo, Academic Search Premier, Scopus, and reference lists through May 2017. Included 69 cross-sectional studies. Calculated effect sizes using multivariate mixed-effects models across 10 cognitive domains. Examined moderating variables including abstinence duration, age of onset, and frequency of use.","limitations":"Cross-sectional studies cannot establish causation — people with pre-existing cognitive differences may be more likely to use cannabis. The 72-hour abstinence finding doesn't rule out very subtle long-term effects that standard cognitive tests might miss. Most participants were male (68.4%). Studies varied widely in how they defined \"frequent use.\" Cannot assess effects of high-potency modern cannabis products specifically."},{"rthcId":"RTHC-01833","title":"Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake.","authors":"Serrano, Antonia; Pavon, Francisco J; Buczynski, Matthew W; Schlosburg, Joel; Natividad, Luis A; Polis, Ilham Y; Stouffer, David G; Zorrilla, Eric P; Roberto, Marisa; Cravatt, Benjamin F; Martin-Fardon, Rémi; Rodriguez de Fonseca, Fernando; Parsons, Loren H","year":2018,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(9), 1840-1850","doi":"10.1038/s41386-018-0055-3","pmid":"29748627","tags":["addiction","neuroscience","anxiety"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Alcohol dependence decreased baseline 2-AG levels and increased glutamate and GABA in the central amygdala. Acute withdrawal intensified these changes. Re-exposure to alcohol restored 2-AG and GABA levels. MAGL inhibitors (which boost 2-AG) reduced both anxiety-like behavior and excessive alcohol consumption in dependent animals.","whyItMatters":"This study reveals that the endocannabinoid system in the amygdala - a key brain region for emotional processing - becomes dysregulated in alcohol dependence. This provides a biological mechanism for why alcohol-dependent individuals experience anxiety during withdrawal and drink excessively.","specificNumbers":"Alcohol dependence decreased baseline 2-AG and increased glutamate and GABA. MAGL inhibitors MJN110 (10 and 20 mg/kg in rats) and JZL184 (1 and 3 mg/kg in mice) reduced anxiety and excessive drinking.","methodology":"Rats and mice were made alcohol-dependent through chronic intermittent exposure. In vivo microdialysis measured endocannabinoid and amino acid levels in the central amygdala. Pharmacological studies tested the effects of endocannabinoid-boosting drugs on anxiety and alcohol consumption.","limitations":"Animal study results may not translate directly to humans. The specific doses and administration routes are experimental. The central amygdala is one of many brain regions involved in addiction."},{"rthcId":"RTHC-01834","title":"Patterns in adolescent cannabis use predict the onset and symptom structure of schizophrenia-spectrum disorder.","authors":"Shahzade, C; Chun, J; DeLisi, L E; Manschreck, T C","year":2018,"journal":"Schizophrenia research, 197, 539-543","doi":"10.1016/j.schres.2018.01.008","pmid":"29402581","tags":["psychosis","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Factor analysis of cannabis use motives produced four groups (sedation, stimulation, social pressure, recreation). These motive factor scores significantly predicted schizophrenia-spectrum disorder risk and schizotypal symptom severity. The factors followed a hierarchical structure explaining their relative involvement in SSD risk.","whyItMatters":"If the reasons for starting cannabis use can predict psychosis risk, this offers a potential screening tool. Rather than simply asking \"do you use cannabis,\" clinicians could assess why someone uses to better identify who is at highest risk.","specificNumbers":"178 participants total: healthy controls with cannabis use and schizophrenia patients with cannabis use. Four motive factors identified: sedation, stimulation, social pressure, and recreation.","methodology":"178 participants in two samples: healthy controls with cannabis use and schizophrenia patients with cannabis use. Structured interviews with participants and family informants assessed diagnostic information, cannabis use motives, and clinical measures.","limitations":"Cross-sectional design limits causal conclusions. Retrospective recall of motives may be inaccurate. No assessment of cannabis potency, frequency, or duration. Relatively small sample for factor analysis."},{"rthcId":"RTHC-01835","title":"Cannabis hyperemesis syndrome.","authors":"Sharma, Umesh","year":2018,"journal":"BMJ case reports, 2018","doi":"10.1136/bcr-2018-226524","pmid":"30323105","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01836","title":"Cannabinoid-glutamate interactions and neural oscillations: implications for psychosis.","authors":"Sherif, Mohamed A; Cortes-Briones, Jose A; Ranganathan, Mohini; Skosnik, Patrick D","year":2018,"journal":"The European journal of neuroscience, 48(8), 2890-2902","doi":"10.1111/ejn.13800","pmid":"29247465","tags":["psychosis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CB1Rs and NMDARs have direct and indirect interactions in brain regions implicated in schizophrenia (hippocampus, frontal cortex, cerebellum). Both systems converge on GABA interneurons: CB1R agonists and NMDAR antagonists each reduce GABAergic neurotransmission, leading to unsynchronized pyramidal neuron activity and disrupted neural oscillations involved in information processing.","whyItMatters":"Schizophrenia research has developed separate cannabinoid and glutamate models of the disorder. This review argues these are not competing explanations but complementary mechanisms that converge on disrupted brain oscillations, potentially explaining why cannabis use increases psychosis risk.","specificNumbers":"Theta oscillations (4-7 Hz) and gamma oscillations (30-80 Hz) are the key frequencies discussed. Three brain regions examined: hippocampus, frontal cortex, and cerebellum.","methodology":"Review synthesizing literature on cannabinoid-glutamate interactions in the context of neural oscillations and schizophrenia, aiming to bridge the \"cannabis model\" and \"ketamine model\" of psychosis.","limitations":"Largely theoretical synthesis. Much evidence comes from acute drug administration studies rather than chronic exposure. The relationship between oscillatory disruptions and clinical symptoms is complex and not fully understood."},{"rthcId":"RTHC-01837","title":"Momentary factors during marijuana use as predictors of lapse during attempted abstinence in young adults.","authors":"Shrier, Lydia A; Sarda, Vishnudas; Jonestrask, Cassandra; Harris, Sion Kim","year":2018,"journal":"Addictive behaviors, 83, 167-174","doi":"10.1016/j.addbeh.2017.12.032","pmid":"29317146","tags":["quitting","youth","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Nearly 3 in 4 participants (73.5%) lapsed during attempted abstinence. The combination of negative effect expectancies, perceived family support, confidence to abstain, and situational permissibility during use was highly accurate in predicting who would lapse. Greater percent of days with use, easy accessibility, and situational permissibility were each associated with lapse.","whyItMatters":"Most young heavy cannabis users who try to quit relapse on their own. Understanding the real-time factors that predict relapse could enable personalized digital interventions that provide support at the moments when people are most vulnerable.","specificNumbers":"34 participants, ages 18-25, using 5+ days/week. 73.5% lapsed during attempted abstinence. Smartphone assessments captured affect, craving, accessibility, permissibility, and motivation multiple times daily.","methodology":"34 young adults aged 18-25 using marijuana 5+ days/week completed ecological momentary assessment (EMA) via smartphone multiple times daily for two weeks of regular use, then two weeks of attempted abstinence.","limitations":"Small sample (n=34). Self-selected participants willing to attempt abstinence and use monitoring technology. Two-week abstinence period is short. EMA compliance may vary."},{"rthcId":"RTHC-01838","title":"Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans.","authors":"Skosnik, Patrick D; Hajós, Mihály; Cortes-Briones, Jose A; Edwards, Chad R; Pittman, Brian P; Hoffmann, William E; Sewell, Andrew R; D'Souza, Deepak C; Ranganathan, Mohini","year":2018,"journal":"Neuropharmacology, 135, 412-423","doi":"10.1016/j.neuropharm.2018.03.036","pmid":"29604295","tags":["neuroscience","cognition","psychosis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Both THC and THC+CBD disrupted P50 sensory gating in humans and reduced evoked theta and gamma oscillations. In rats, the CB1R agonist CP-55940 disrupted gating in the hippocampus and entorhinal cortex, effects reversed by the CB1R antagonist AM-251. Theta oscillation reductions correlated with gating impairment in humans.","whyItMatters":"Sensory gating - the brain's ability to filter out redundant stimuli - is impaired in schizophrenia. This study shows THC disrupts the same process through CB1 receptors, providing a mechanistic link between cannabis use and psychosis-like symptoms.","specificNumbers":"15 human subjects, 4 conditions. THC disrupted P50 gating ratio significantly. THC-induced theta power reduction correlated with gating impairment (r = -0.629, p < 0.012). CBD did not block THC's effects.","methodology":"Translational study: 15 human subjects received IV THC, CBD, THC+CBD, or placebo in a crossover design with EEG recording. Separately, 6 rats received a CB1R agonist, CB1R agonist+antagonist, or vehicle with local field potential recording from hippocampus and entorhinal cortex.","limitations":"Small sample sizes (15 humans, 6 rats). Acute dosing only. The rat CB1R agonist (CP-55940) differs pharmacologically from THC. CBD may need different dosing to show protective effects."},{"rthcId":"RTHC-01839","title":"The current state and future perspectives of cannabinoids in cancer biology.","authors":"Śledziński, Paweł; Zeyland, Joanna; Słomski, Ryszard; Nowak, Agnieszka","year":2018,"journal":"Cancer medicine, 7(3), 765-775","doi":"10.1002/cam4.1312","pmid":"29473338","tags":["cancer","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids exhibit anticancer properties through multiple mechanisms: inhibiting cell proliferation, stimulating autophagy and apoptosis, and potentially inhibiting angiogenesis and metastasis. However, the review also discusses cases where cannabinoids stimulated cancer cell proliferation, and notes the complex role of the endocannabinoid system in cancer development.","whyItMatters":"While cannabinoids are currently approved only for palliative cancer care (pain and nausea), growing preclinical evidence suggests they may have direct anticancer properties. Understanding both the promise and complexity is essential for responsible research translation.","specificNumbers":"Multiple signaling pathways identified, including those controlling cell proliferation and survival. Both in vitro and in vivo evidence reviewed across multiple cancer types.","methodology":"Review of in vitro and in vivo preclinical evidence for cannabinoid anticancer activity, molecular mechanisms, and currently ongoing clinical trials.","limitations":"Most evidence is preclinical. In vitro conditions differ significantly from human tumors. Dosing in animal studies may not translate to humans. Limited clinical trial data available at time of review."},{"rthcId":"RTHC-01840","title":"Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol.","authors":"Smeriglio, Antonella; Giofrè, Salvatore V; Galati, Enza M; Monforte, Maria T; Cicero, Nicola; D'Angelo, Valeria; Grassi, Gianpaolo; Circosta, Clara","year":2018,"journal":"Fitoterapia, 127, 101-108","doi":"10.1016/j.fitote.2018.02.002","pmid":"29427593","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01841","title":"High-intensity cannabis use is associated with retention in opioid agonist treatment: a longitudinal analysis.","authors":"Socías, Maria Eugenia; Wood, Evan; Lake, Stephanie; Nolan, Seonaid; Fairbairn, Nadia; Hayashi, Kanna; Shulha, Hennady P; Liu, Seagle; Kerr, Thomas; Milloy, M-J","year":2018,"journal":"Addiction (Abingdon, England), 113(12), 2250-2258","doi":"10.1111/add.14398","pmid":"30238568","tags":["harm-reduction","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Daily cannabis use was positively associated with retention in OAT (adjusted OR 1.21, 95% CI 1.04-1.41). Compared to non-users, daily users had increased odds of retention (aOR 1.20, 95% CI 1.02-1.43), but less-than-daily users did not (aOR 1.00, 95% CI 0.87-1.14), suggesting a dose-response relationship.","whyItMatters":"Retention in opioid agonist treatment is the single strongest predictor of reduced opioid-related morbidity and mortality. If daily cannabis use supports treatment retention, it could be an important harm reduction consideration during the opioid crisis.","specificNumbers":"820 participants, 57.8% men, 32.2% HIV-positive. Median follow-up 81 months. Daily cannabis use: aOR 1.21 (95% CI 1.04-1.41) for treatment retention. Less-than-daily use showed no association.","methodology":"Longitudinal analysis of 820 participants from two community-recruited prospective cohorts of people who use illicit drugs in Vancouver, Canada. Followed for a median of 81 months with 6-month assessment periods.","limitations":"Observational study cannot prove causation. Self-reported cannabis use. Vancouver population may not generalize. Unmeasured confounders possible. Cannot determine why cannabis use might support retention."},{"rthcId":"RTHC-01842","title":"Effects of Legal Access to Cannabis on Scheduled II-V Drug Prescriptions.","authors":"Stith, Sarah S; Vigil, Jacob M; Adams, Ian Marshall; Reeve, Anthony P","year":2018,"journal":"Journal of the American Medical Directors Association, 19(1), 59-64.e1","doi":"10.1016/j.jamda.2017.07.017","pmid":"28899660","tags":["medical-cannabis","legalization","pain"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"28 of 83 MCP patients (34%) ceased all scheduled prescription medications by the end of the observation period, versus only 1 of 42 comparison patients (2%). MCP patients showed statistically significant monthly decreases in number of prescriptions, distinct drug classes, prescription fill dates, and prescribing providers.","whyItMatters":"Co-prescribing of controlled substances (Schedule II-V) is a major safety concern and healthcare burden. This study provides some of the first Prescription Monitoring Program data showing medical cannabis enrollment is associated with significant reductions in dangerous prescription drug use.","specificNumbers":"34% of MCP patients stopped all scheduled drugs vs 2% of comparisons. Significant monthly decreases in all 4 measures (counts of -0.02 to -0.04, P values <.001 to .017). Differences were significant by 10 months post-enrollment.","methodology":"Pragmatic historical cohort study comparing 83 chronic pain patients who enrolled in New Mexico's Medical Cannabis Program with 42 non-enrolled patients over 24 months using Prescription Monitoring Program data.","limitations":"Observational study with non-randomized groups. Comparison group was small (n=42). Cannot confirm patients actually used cannabis or that cannabis caused the prescription changes. New Mexico-specific results."},{"rthcId":"RTHC-01843","title":"Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies.","authors":"Stockings, Emily; Campbell, Gabrielle; Hall, Wayne D; Nielsen, Suzanne; Zagic, Dino; Rahman, Rakin; Murnion, Bridin; Farrell, Michael; Weier, Megan; Degenhardt, Louisa","year":2018,"journal":"Pain, 159(10), 1932-1954","doi":"10.1097/j.pain.0000000000001293","pmid":"29847469","tags":["pain","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"For 30% pain reduction: 29% on cannabinoids vs 25.9% on placebo (NNT=24). For 50% pain reduction: no significant difference. Overall pain intensity reduction was equivalent to just 3 mm on a 100 mm visual analogue scale. Adverse events were common: NNH was only 6 (81.2% vs 66.2%). No significant impacts on physical or emotional functioning.","whyItMatters":"This is one of the largest and most rigorous meta-analyses of cannabinoids for chronic pain. Its sobering conclusion challenges the widespread belief that cannabis is highly effective for pain, while noting that some patients do benefit.","specificNumbers":"104 studies, 9,958 participants. NNT for 30% pain reduction: 24 (CI 15-61). Pain intensity reduction: 3 mm on 100 mm scale. NNH for adverse events: 6 (CI 5-8). 48 studies on neuropathic pain, 7 on fibromyalgia.","methodology":"Systematic review and meta-analysis of 104 studies (47 RCTs, 57 observational) with 9,958 participants, searched across MEDLINE, Embase, PsycINFO, CENTRAL, and clinicaltrials.gov. IMMPACT guidelines followed.","limitations":"Heterogeneity across studies in cannabinoid type, dose, formulation, and pain condition. Most RCTs were relatively short-term. Publication bias possible. Average effects may mask meaningful responses in subgroups."},{"rthcId":"RTHC-01844","title":"Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence.","authors":"Stockings, Emily; Zagic, Dino; Campbell, Gabrielle; Weier, Megan; Hall, Wayne D; Nielsen, Suzanne; Herkes, Geoffrey K; Farrell, Michael; Degenhardt, Louisa","year":2018,"journal":"Journal of neurology, neurosurgery, and psychiatry, 89(7), 741-753","doi":"10.1136/jnnp-2017-317168","pmid":"29511052","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"CBD 20 mg/kg/day achieved 50%+ seizure reduction more than placebo (RR 1.74, NNT=8). CBD was more effective for complete seizure freedom (RR 6.17) and quality of life improvement (RR 1.73). However, it increased risk of adverse events (RR 1.24) and serious adverse events (RR 2.55). Observational studies showed 48.5% achieving 50%+ seizure reduction.","whyItMatters":"This systematic review provides the most comprehensive evidence base for CBD in epilepsy, quantifying both benefits and risks. The NNT of 8 for meaningful seizure reduction is clinically significant and compares favorably to many existing antiepileptic drugs.","specificNumbers":"36 studies, mean age 16.1 years. NNT for 50%+ seizure reduction: 8 (CI 6-17). Complete seizure freedom RR: 6.17. QoL improvement RR: 1.73. AE RR: 1.24. SAE RR: 2.55. In observational studies: 48.5% achieved 50%+ reduction, 8.5% seizure-free.","methodology":"Systematic review of 36 studies (6 RCTs, 30 observational) from Medline, Embase, and PsycINFO through October 2017. Mean participant age 16.1 years. Analyses in Stata 15.0.","limitations":"Most RCT evidence was from pediatric populations with rare, severe epilepsy syndromes (Dravet, Lennox-Gastaut). Limited data on other epilepsy types and adult populations. Observational studies may overestimate effectiveness."},{"rthcId":"RTHC-01845","title":"Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community.","authors":"Suraev, A; Lintzeris, N; Stuart, J; Kevin, R C; Blackburn, R; Richards, E; Arnold, J C; Ireland, C; Todd, L; Allsop, D J; McGregor, I S","year":2018,"journal":"Scientific reports, 8(1), 10154","doi":"10.1038/s41598-018-28127-0","pmid":"29977078","tags":["epilepsy","cbd","potency"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"There was high variability in cannabinoid content across extracts. Most samples contained low CBD concentrations despite parents believing they were using CBD-rich products. THC was present in nearly every sample. No clear chemical differences existed between extracts families rated as \"effective\" versus \"ineffective.\"","whyItMatters":"Many families are using illicit cannabis products for their children's epilepsy without knowing what's actually in them. This study reveals a dangerous knowledge gap: parents think they are giving CBD, but most products contain significant THC and unpredictable CBD levels.","specificNumbers":"65 families interviewed. 41 current/past cannabis extract users. THC present in nearly every sample. Most samples had low CBD. No chemical difference between \"effective\" and \"ineffective\" extracts.","methodology":"Semi-structured interviews with 65 Australian families (41 current/past users, 24 non-users of cannabis extracts) whose children had epilepsy. Chemical analysis of extracts for cannabinoid content, comparing \"effective\" vs \"ineffective\" samples.","limitations":"Convenience sample of families already engaged with cannabis use. Chemical analysis of samples was limited to cannabinoid content. \"Effective\" and \"ineffective\" ratings were subjective parent assessments."},{"rthcId":"RTHC-01846","title":"Control of myogenic tone and agonist induced contraction of intramural coronary resistance arterioles by cannabinoid type 1 receptors and endocannabinoids.","authors":"Szekeres, Mária; Nádasy, György L; Soltész-Katona, Eszter; Hunyady, László","year":2018,"journal":"Prostaglandins & other lipid mediators, 134, 77-83","doi":"10.1016/j.prostaglandins.2017.10.001","pmid":"29031792","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01847","title":"Examining effects of medical cannabis narratives on beliefs, attitudes, and intentions related to recreational cannabis: A web-based randomized experiment.","authors":"Sznitman, Sharon R; Lewis, Nehama","year":2018,"journal":"Drug and alcohol dependence, 185, 219-225","doi":"10.1016/j.drugalcdep.2017.11.028","pmid":"29471226","tags":["legalization","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Viewing patient narratives about successful medical cannabis use indirectly increased positive attitudes, beliefs, and intentions related to recreational cannabis use by first changing attitudes toward medical cannabis. When patients were presented as not responsible for their illness (external attribution), the effect on medical cannabis attitudes was stronger, which in turn further increased recreational cannabis positivity.","whyItMatters":"This study demonstrates a \"spillover effect\" where positive medical cannabis coverage in media influences attitudes toward recreational use. This has implications for both cannabis advocates and prevention programs.","specificNumbers":"396 Israeli participants randomly assigned across conditions. Narrative exposure indirectly increased recreational cannabis attitudes through changed medical cannabis attitudes. External attribution (patient not to blame) strengthened the effect.","methodology":"Randomized experiment with 396 Israeli participants assigned to view either a narrative (patient testimonial) or non-narrative video about medical cannabis. Videos were further manipulated by disease stigma and responsibility attribution.","limitations":"Israeli sample may not generalize to other cultural contexts. Single exposure to a video - real-world media exposure is cumulative. Measured attitudes and intentions, not actual behavior."},{"rthcId":"RTHC-01848","title":"High times for cannabis: Epigenetic imprint and its legacy on brain and behavior.","authors":"Szutorisz, Henrietta; Hurd, Yasmin L","year":2018,"journal":"Neuroscience and biobehavioral reviews, 85, 93-101","doi":"10.1016/j.neubiorev.2017.05.011","pmid":"28506926","tags":["neuroscience","youth","pregnancy","genetics"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoid exposure during critical developmental periods creates epigenetic changes (modifications to how genes are read) that persist long after exposure ends. Human and animal studies show these disruptions occur in both the brain and peripheral tissues. Most striking: some effects transmit to the next generation through germline (sperm/egg) modifications.","whyItMatters":"The concept that cannabis use could affect not just the user but potentially their future children through epigenetic inheritance adds an entirely new dimension to the risk assessment of cannabis use, particularly during reproductive years.","specificNumbers":"Cannabis is the most commonly used illicit substance worldwide. Exponential increase in cannabis studies over two decades. Epigenetic effects documented across lifespan and into subsequent generation.","methodology":"Review of human and animal studies examining epigenetic disruptions from prenatal, adolescent, and parental germline cannabis/cannabinoid exposure.","limitations":"Mechanistic investigations remain sparse. Most transgenerational evidence comes from animal studies. Human epigenetic studies face confounding factors. The clinical significance of observed epigenetic changes is not always clear."},{"rthcId":"RTHC-01849","title":"Assessment of rimonabant-like adverse effects of purported CB1R neutral antagonist / CB2R agonist aminoalkylindole derivatives in mice.","authors":"Tai, Sherrica; Vasiljevik, Tamara; Sherwood, Alexander M; Eddington, Sarah; Wilson, Catheryn D; Prisinzano, Thomas E; Fantegrossi, William E","year":2018,"journal":"Drug and alcohol dependence, 192, 285-293","doi":"10.1016/j.drugalcdep.2018.08.011","pmid":"30300803","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01850","title":"[18F]FMPEP-d2 PET imaging shows age- and genotype-dependent impairments in the availability of cannabinoid receptor 1 in a mouse model of Alzheimer's disease.","authors":"Takkinen, Jatta S; López-Picón, Francisco R; Kirjavainen, Anna K; Pihlaja, Rea; Snellman, Anniina; Ishizu, Tamiko; Löyttyniemi, Eliisa; Solin, Olof; Rinne, Juha O; Haaparanta-Solin, Merja","year":2018,"journal":"Neurobiology of aging, 69, 199-208","doi":"10.1016/j.neurobiolaging.2018.05.013","pmid":"29909177","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01851","title":"Examining Burnout, Depression, and Attitudes Regarding Drug Use Among Lebanese Medical Students During the 4 Years of Medical School.","authors":"Talih, Farid; Daher, Michel; Daou, Dayane; Ajaltouni, Jean","year":2018,"journal":"Academic psychiatry : the journal of the American Association of Directors of Psychiatric Residency Training and the Association for Academic Psychiatry, 42(2), 288-296","doi":"10.1007/s40596-017-0879-x","pmid":"29396837","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01852","title":"Risperidone versus other antipsychotics for people with severe mental illness and co-occurring substance misuse.","authors":"Temmingh, Henk S; Williams, Taryn; Siegfried, Nandi; Stein, Dan J","year":2018,"journal":"The Cochrane database of systematic reviews, 1(1), CD011057","doi":"10.1002/14651858.CD011057.pub2","pmid":"29355909","tags":["psychosis","addiction"],"studyType":"meta-analysis","evidenceStrength":"preliminary","keyFinding":"No clear differences between risperidone and clozapine, olanzapine, perphenazine, quetiapine, or ziprasidone on psychotic symptoms, substance use reduction, or study completion in dual diagnosis patients. One small trial (n=28) found clozapine was associated with lower cannabis craving than risperidone.","whyItMatters":"Up to 75% of people with serious mental illness have co-occurring substance use disorders. Clinicians need evidence to guide antipsychotic choice in this common scenario, but this review found the evidence base is insufficient to make recommendations.","specificNumbers":"8 RCTs, 1,073 participants. All evidence rated very low to low quality by GRADE criteria. Clozapine showed lower cannabis craving (MD 7.00, 95% CI 2.37-11.63) in one trial of 28 patients.","methodology":"Cochrane systematic review of 8 RCTs with 1,073 participants comparing risperidone to other antipsychotics in people with serious mental illness and co-occurring substance misuse. GRADE quality assessment applied.","limitations":"Very low to low quality evidence throughout. Most trials were small, secondary analyses of larger studies, or subgroup analyses. Heterogeneous study designs. Missing data on important outcomes like metabolic effects and quality of life."},{"rthcId":"RTHC-01853","title":"Adolescent cannabis use and brain systems supporting adult working memory encoding, maintenance, and retrieval.","authors":"Tervo-Clemmens, Brenden; Simmonds, Daniel; Calabro, Finnegan J; Day, Nancy L; Richardson, Gale A; Luna, Beatriz","year":2018,"journal":"NeuroImage, 169, 496-509","doi":"10.1016/j.neuroimage.2017.12.041","pmid":"29253654","tags":["youth","cognition","neuroscience"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Earlier cannabis age of onset was associated with longer reaction times and reduced posterior parietal cortex activation during encoding, which mediated the age-of-onset effect. However, age-of-onset associations did not differ between single-use and repeated-use groups. Greater total cannabis use was associated with increased DLPFC activation during maintenance. Surprisingly, cannabis users generally performed better than never-users.","whyItMatters":"This study provides a nuanced picture: while earlier cannabis onset affects brain activation patterns during memory encoding, the finding that even single use showed the same pattern as repeated use suggests these differences may reflect pre-existing risk factors rather than cannabis-caused damage.","specificNumbers":"75 adults at age 28 (60 with reported use, 15 no use). Earlier onset linked to slower RT and reduced PPC encoding activation. Greater total use linked to increased DLPFC maintenance activation. Cannabis users outperformed never-users on accuracy and speed.","methodology":"75 adults with longitudinal cannabis use assessments and prenatal drug exposure data completed a spatial working memory task during fMRI at age 28. All passed same-day drug screens. Fast event-related design separated encoding, maintenance, and retrieval phases.","limitations":"Small never-user group (n=15). Cannot fully separate cannabis effects from pre-existing risk factors. Prenatal drug exposure in many participants adds complexity. Cross-sectional brain imaging cannot establish causation."},{"rthcId":"RTHC-01854","title":"Early Cannabis Use and Neurocognitive Risk: A Prospective Functional Neuroimaging Study.","authors":"Tervo-Clemmens, Brenden; Simmonds, Daniel; Calabro, Finnegan J; Montez, David F; Lekht, Julia A; Day, Nancy L; Richardson, Gale A; Luna, Beatriz","year":2018,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 3(8), 713-725","doi":"10.1016/j.bpsc.2018.05.004","pmid":"30033100","tags":["youth","cognition","neuroscience"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"At age 12, before any cannabis use, teens who would initiate cannabis by 15 already showed activation differences in frontoparietal (increased) and visual association (decreased) regions, and poorer executive planning scores. At follow-up, a cannabis dose-response relationship was found in cuneus activation, but this was not associated with cognitive performance. Limited support for a direct cannabis exposure effect.","whyItMatters":"This is one of the strongest designs for disentangling cause and effect in cannabis neuroscience. By measuring brains before anyone used cannabis, researchers could show that many \"cannabis effects\" actually preceded cannabis use, fundamentally challenging the assumption that cannabis causes these brain differences.","specificNumbers":"85 participants, 22 initiated cannabis by age 15. Baseline (age 12) differences found in frontoparietal and visual association activation and Stockings of Cambridge executive planning scores before any cannabis use.","methodology":"85 participants completed working memory fMRI and cognitive assessments at age 12 (before cannabis use) and age 15. By follow-up, 22 had initiated cannabis. Baseline neurocognitive measures were compared between future initiators and non-initiators.","limitations":"Relatively small cannabis-initiating group (n=22). Only 3 years between baseline and follow-up. More prolonged exposure may be needed to observe true cannabis effects. Cannot fully rule out other substance use effects."},{"rthcId":"RTHC-01855","title":"Effects of repeated long-term psychosocial stress and acute cannabinoid exposure on mouse corticostriatal circuitries: Implications for neuropsychiatric disorders.","authors":"Tomas-Roig, Jordi; Piscitelli, Fabiana; Gil, Vanesa; Quintana, Ester; Ramió-Torrentà, Lluís L; Del Río, Jose Antonio; Moore, Timothy Patrick; Agbemenyah, Hope; Salinas, Gabriela; Pommerenke, Claudia; Lorenzen, Stephan; Beißbarth, Tim; Hoyer-Fender, Sigrid; Di Marzo, Vincenzo; Havemann-Reinecke, Ursula","year":2018,"journal":"CNS neuroscience & therapeutics, 24(6), 528-538","doi":"10.1111/cns.12810","pmid":"29388323","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01856","title":"Modulation of central endocannabinoid system results in gastric mucosal protection in the rat.","authors":"Tóth, V E; Fehér, Á; Németh, J; Gyertyán, I; Zádori, Z S; Gyires, K","year":2018,"journal":"Brain research bulletin, 139, 224-234","doi":"10.1016/j.brainresbull.2018.02.012","pmid":"29438780","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01857","title":"Alcohol and Cannabis Use and Sexual Risk Behaviors in the Malawi Defence Force.","authors":"Tran, Bonnie Robin; Davis, Anthony; Ito, Stanley I; Matchere, Faustin; Reader, Elizabeth; Nkhoma, Victor; Grillo, Michael; Banda, Alfred Chitsa","year":2018,"journal":"AIDS and behavior, 22(9), 2851-2860","doi":"10.1007/s10461-018-2167-5","pmid":"29869734","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01858","title":"Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice.","authors":"Trexler, Kristen R; Nass, Sara R; Crowe, Molly S; Gross, Joshua D; Jones, Margaret S; McKitrick, Austin W; Siderovski, David P; Kinsey, Steven G","year":2018,"journal":"Drug and alcohol dependence, 191, 14-24","doi":"10.1016/j.drugalcdep.2018.05.029","pmid":"30071445","tags":["withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC withdrawal (both precipitated and spontaneous) caused increased plasma corticosterone, suppressed marble burying (suggesting anxiety/anhedonia), increased struggling in the tail suspension test (despair-like behavior), and classic somatic withdrawal signs. The MAGL inhibitor JZL184 attenuated somatic withdrawal and spontaneous withdrawal behaviors, and THC itself reduced spontaneous withdrawal.","whyItMatters":"Human cannabis withdrawal involves mood changes, anxiety, and irritability - symptoms poorly captured by traditional animal models focused on physical signs. These new tests better model the symptoms that drive human relapse, enabling better preclinical testing of treatments.","specificNumbers":"THC doses: 1, 10, or 50 mg/kg for 6 days. Spontaneous withdrawal signs appeared at 24-48 hours. JZL184 attenuated somatic but not mood-related withdrawal signs.","methodology":"Mice received THC (1-50 mg/kg) or JWH-018 for 6 days. Withdrawal was either precipitated with rimonabant or assessed spontaneously after 24-48 hours of abstinence. Novel behavioral assays (marble burying, tail suspension) were used alongside classic somatic sign counts.","limitations":"Mouse models may not fully reflect human withdrawal experience. Novel behavioral assays need further validation. Only male C57BL/6J mice were studied. THC doses were relatively high."},{"rthcId":"RTHC-01859","title":"Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial.","authors":"Trigo, Jose M; Soliman, Alexandra; Quilty, Lena C; Fischer, Benedikt; Rehm, Jürgen; Selby, Peter; Barnes, Allan J; Huestis, Marilyn A; George, Tony P; Streiner, David L; Staios, Gregory; Le Foll, Bernard","year":2018,"journal":"PloS one, 13(1), e0190768","doi":"10.1371/journal.pone.0190768","pmid":"29385147","tags":["addiction","quitting","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Nabiximols was well-tolerated with no serious adverse events. Cannabis use was reduced in both groups (nabiximols 70.5% vs placebo 42.6%), though the difference was not statistically significant. Nabiximols reduced cannabis craving but did not significantly improve abstinence rates or withdrawal scores versus placebo. Participants could not distinguish nabiximols from placebo effects.","whyItMatters":"There are no approved medications for cannabis use disorder. This pilot trial demonstrates that nabiximols is safe and tolerable in cannabis-dependent patients, and both groups achieved substantial use reductions when combined with behavioral therapy.","specificNumbers":"40 participants. Nabiximols dose up to 113.4 mg THC/105 mg CBD daily for 12 weeks. Cannabis use reduction: 70.5% (nabiximols) vs 42.6% (placebo). Participants could not tell nabiximols from placebo.","methodology":"Double-blind, randomized clinical trial with 40 treatment-seeking cannabis-dependent participants. Self-titrated nabiximols (up to 113.4 mg THC/105 mg CBD daily) or placebo for 12 weeks, plus Motivational Enhancement Therapy and Cognitive Behavioral Therapy.","limitations":"Small sample (n=40). Underpowered to detect between-group differences. Both groups received effective behavioral therapy, potentially masking medication effects. Self-titration may have led to suboptimal dosing."},{"rthcId":"RTHC-01860","title":"Marijuana and Its Effects on Athletic Performance: A Systematic Review.","authors":"Trinh, Kien V; Diep, Dion; Robson, Hannah","year":2018,"journal":"Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine, 28(4), 350-357","doi":"10.1097/JSM.0000000000000471","pmid":"28767469","tags":["exercise","cognition"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Only three trials met inclusion criteria. Low-quality evidence suggested marijuana may increase bronchodilation but decrease physical work capacity. No significant effects on grip strength were found. The evidence for effects on heart rate, blood pressure, and exercise duration remained unclear due to study limitations.","whyItMatters":"Despite widespread cannabis use among athletes, the scientific evidence base for its effects on performance is remarkably thin. This review highlights a major knowledge gap in an area of significant practical importance.","specificNumbers":"Only 3 trials found. Two had high risk of bias, one had unclear risk. Low-quality evidence for both ergogenic (bronchodilation) and ergolytic (decreased work capacity) effects.","methodology":"Systematic review searching MEDLINE, EMBASE, CINAHL, PsycINFO, AMED, and SPORTDiscus through September 2016. Study quality assessed using Cochrane tools.","limitations":"Only three studies met inclusion criteria, all with significant limitations. No meta-analysis possible due to heterogeneity. Studies were older and used smoked marijuana, which may differ from modern products."},{"rthcId":"RTHC-01861","title":"Health risk behaviors among high school and university adolescent students.","authors":"Tsitsimpikou, Christina; Tsarouhas, Konstantinos; Vasilaki, Fotini; Papalexis, Petros; Dryllis, Georgios; Choursalas, Athanasios; Spandidos, Demetrios A; Tsatsakis, Aristides; Charvalos, Ekaterina; Bacopoulou, Flora","year":2018,"journal":"Experimental and therapeutic medicine, 16(4), 3433-3438","doi":"10.3892/etm.2018.6612","pmid":"30233692","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01862","title":"Bullying victimization and illicit drug use among students in Grades 7 to 12 in Manitoba, Canada: a cross-sectional analysis.","authors":"Turner, Sarah; Taillieu, Tamara; Fortier, Janique; Salmon, Samantha; Cheung, Kristene; Afifi, Tracie O","year":2018,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 109(2), 183-194","doi":"10.17269/s41997-018-0030-0","pmid":"29981027","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01863","title":"Cannabinoid pharmacology and therapy in gut disorders.","authors":"Uranga, J A; Vera, G; Abalo, R","year":2018,"journal":"Biochemical pharmacology, 157, 134-147","doi":"10.1016/j.bcp.2018.07.048","pmid":"30076849","tags":["medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The GI tract expresses endocannabinoids, their receptors, and metabolizing enzymes. This system participates in motor and sensory activity, nausea/emesis, epithelial barrier maintenance, and cellular homeostasis. Cannabinoid agents may normalize dysmotility and reduce pain in IBS, decrease inflammation in IBD, and play a role in regulating the cell niche in colorectal cancer.","whyItMatters":"Gastrointestinal disorders affect millions of people, and current treatments are often inadequate. The discovery that the GI tract has its own endocannabinoid system opens multiple new therapeutic avenues.","specificNumbers":"Covers four major GI conditions: IBS, IBD, colorectal cancer, and chemotherapy-induced GI side effects (nausea/vomiting, constipation, diarrhea).","methodology":"Review of recent findings on cannabinoid receptors, natural and synthetic ligands, and metabolizing enzymes in normal GI function and in IBS, IBD, colon cancer, and chemotherapy-induced GI side effects.","limitations":"Review covers a broad area with varying levels of evidence across conditions. Much evidence is preclinical. Clinical trial data for cannabinoids in GI disorders is still limited."},{"rthcId":"RTHC-01864","title":"A missed opportunity? Cannabis legalization and reparations in Canada.","authors":"Valleriani, Jenna; Lavalley, Jennifer; McNeil, Ryan","year":2018,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 109(5-6), 745-747","doi":"10.17269/s41997-018-0121-y","pmid":"30225575","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01865","title":"Acceptance of pharmaceutical cannabis substitution by cannabis using patients with schizophrenia.","authors":"van Amsterdam, Jan; Vervloet, Jojanneke; de Weert, Gerdien; Buwalda, Victor J A; Goudriaan, Anna E; van den Brink, Wim","year":2018,"journal":"Harm reduction journal, 15(1), 47","doi":"10.1186/s12954-018-0253-7","pmid":"30236118","tags":["psychosis","harm-reduction","potency"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Both substitute variants (low THC/no CBD and low THC/high CBD) were appreciated by patients. However, they preferred their usual high-potency cannabis. The low THC/high CBD variant was reported as too short-acting by 32% and not strong enough by 36%. The low THC variant was reported as not strong enough by 64%.","whyItMatters":"This study explores whether cannabis substitution (replacing high-potency with lower-risk products) is feasible in schizophrenia patients. While acceptance was positive, the preference for usual cannabis suggests substitution may work better as part of a gradual reduction strategy.","specificNumbers":"12 male patients. Three cannabis types: usual high-potency, low THC/no CBD, and low THC/high CBD. 64% found low THC variant not strong enough. 36% found low THC/high CBD not strong enough. 32% found low THC/high CBD effects too short.","methodology":"Crossover design with 12 male schizophrenia patients who daily smoked high-potency cannabis. Each patient smoked their usual cannabis on two occasions (unblinded) and each substitute variant on two occasions (blinded, randomized).","limitations":"Very small sample (n=12). All male. Short-term preference assessment does not indicate long-term compliance. Unblinded comparison to usual cannabis biases preference. No clinical outcome measures."},{"rthcId":"RTHC-01866","title":"The role of CA1 CB1 receptors on lithium-induced spatial memory impairment in rats.","authors":"Vaseghi, Salar; Babapour, Vahab; Nasehi, Mohammad; Zarrindast, Mohammad-Reza","year":2018,"journal":"EXCLI journal, 17, 916-934","doi":"10.17179/excli2018-1511","pmid":"30564071","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01867","title":"Sleep Disturbances, Psychosocial Difficulties, and Health Risk Behavior in 16,781 Dutch Adolescents.","authors":"Verkooijen, Sanne; de Vos, Nelleke; Bakker-Camu, Betty J W; Branje, Susan J T; Kahn, René S; Ophoff, Roel A; Plevier, Carolien M; Boks, Marco P M","year":2018,"journal":"Academic pediatrics, 18(6), 655-661","doi":"10.1016/j.acap.2018.03.003","pmid":"29530583","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01868","title":"Associations between marijuana use and tobacco cessation outcomes in young adults.","authors":"Vogel, Erin A; Rubinstein, Mark L; Prochaska, Judith J; Ramo, Danielle E","year":2018,"journal":"Journal of substance abuse treatment, 94, 69-73","doi":"10.1016/j.jsat.2018.08.010","pmid":"30243420","tags":["addiction","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Marijuana use was associated with lower likelihood of tobacco abstinence (OR 0.56, 95% CI 0.35-0.90) and lower likelihood of reducing smoking (OR 0.71, 95% CI 0.51-0.98) over 12 months. However, marijuana use was not related to motivation to quit, engagement in the cessation program, quit attempts, or stage of change.","whyItMatters":"Marijuana and tobacco co-use is common in young adults. This study reveals that while marijuana users are equally motivated to quit tobacco, they are less successful - suggesting marijuana use creates a specific barrier to tobacco cessation that current programs do not adequately address.","specificNumbers":"500 young adults, ages 18-25. Marijuana users: 44% less likely to abstain from tobacco (OR 0.56). 29% less likely to reduce smoking (OR 0.71). No difference in motivation, engagement, or quit attempts.","methodology":"500 young adult smokers (18-25) enrolled in a 3-month Facebook-based smoking cessation intervention. Marijuana use and smoking behaviors were assessed at baseline, 3, 6, and 12 months.","limitations":"Observational within a trial setting. Self-reported marijuana and tobacco use. Facebook-based intervention may not represent other cessation approaches. Cannot determine why marijuana use reduces cessation success."},{"rthcId":"RTHC-01869","title":"The use of cannabis in response to the opioid crisis: A review of the literature.","authors":"Vyas, Marianne Beare; LeBaron, Virginia T; Gilson, Aaron M","year":2018,"journal":"Nursing outlook, 66(1), 56-65","doi":"10.1016/j.outlook.2017.08.012","pmid":"28993073","tags":["medical-cannabis","pain","legalization"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The 10 included studies collectively suggest medical cannabis laws could be associated with decreased prescription opioid use, fewer POM-related hospitalizations, lower rates of opioid overdose, and reduced national healthcare expenditures related to opioid overdose and misuse. Four studies examined individual-level cannabis-for-opioid substitution; six examined state-level opioid outcomes.","whyItMatters":"The opioid crisis kills tens of thousands of Americans annually. This review presents converging evidence from multiple study designs that medical cannabis access may reduce opioid-related harms, suggesting cannabis policy could be one component of addressing the epidemic.","specificNumbers":"11,513 records identified, 10 met criteria. Four cross-sectional surveys on individual substitution. Six secondary analyses on state-level outcomes (overdose fatalities, hospitalizations, Medicare/Medicaid costs).","methodology":"Systematic literature review of Medline, PubMed, CINAHL, and Cochrane databases for peer-reviewed articles published 2010-2017. 11,513 records identified, 789 abstracts reviewed, 134 full-text screened, 10 met inclusion criteria.","limitations":"Sparse literature with notable limitations across studies. Ecological studies cannot prove individual-level causation. Cross-sectional surveys rely on self-report. Federal policy restrictions constrain cannabis research. Confounding by other state-level changes possible."},{"rthcId":"RTHC-01870","title":"Impact of Marijuana Legalization in Colorado on Adolescent Emergency and Urgent Care Visits.","authors":"Wang, George Sam; Davies, Sara Deakyne; Halmo, Laurie Seidel; Sass, Amy; Mistry, Rakesh D","year":2018,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 63(2), 239-241","doi":"10.1016/j.jadohealth.2017.12.010","pmid":"29609916","tags":["legalization","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Marijuana-related visits increased from 1.8 per 1,000 visits in 2009 to 4.9 per 1,000 in 2015 (p<.0001). Behavioral health evaluation was obtained for 67% of visits, and 71% of those received a psychiatric diagnosis. Ethanol was the most common co-ingestant (12%).","whyItMatters":"While national survey data suggested no increase in adolescent marijuana use after legalization, this hospital data reveals a different picture: more teens are presenting to emergency departments with marijuana-related problems, many with psychiatric issues.","specificNumbers":"4,202 marijuana-related visits from 2005-2015. Rate increased from 1.8 to 4.9 per 1,000 visits (2009-2015). 67% received behavioral health evaluation. 71% of those had a psychiatric diagnosis. 12% involved ethanol co-ingestion.","methodology":"Retrospective review of marijuana-related visits to a Colorado children's hospital from 2005-2015, identified by ICD codes and urine drug screens, for patients aged 13-20.","limitations":"Single hospital system. ICD coding may not capture all marijuana-related visits. Cannot determine causation with legalization. Increased diagnosis could reflect increased screening rather than true increase. Does not distinguish medical from recreational context."},{"rthcId":"RTHC-01871","title":"Cannabinoid receptor 2 as a novel target for promotion of renal cell carcinoma prognosis and progression.","authors":"Wang, Jianfeng; Xu, Yunze; Zhu, Liangsong; Zou, Yun; Kong, Wen; Dong, Baijun; Huang, Jiwei; Chen, Yonghui; Xue, Wei; Huang, Yiran; Zhang, Jin","year":2018,"journal":"Journal of cancer research and clinical oncology, 144(1), 39-52","doi":"10.1007/s00432-017-2527-y","pmid":"28993942","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01872","title":"Cannabis and the Health and Performance of the Elite Athlete.","authors":"Ware, Mark A; Jensen, Dennis; Barrette, Amy; Vernec, Alan; Derman, Wayne","year":2018,"journal":"Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine, 28(5), 480-484","doi":"10.1097/JSM.0000000000000650","pmid":"30153174","tags":["exercise","medical-cannabis","pain"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"There is no direct evidence of cannabis as a performance-enhancing drug. Evidence for serious health harms in athletes is limited but potential for abuse and mental health issues should be considered. Cannabis use is associated with certain high-risk sports. The potential role of cannabis in pain management and concussion-related symptom relief deserves further attention.","whyItMatters":"Cannabis is prohibited in competition by WADA despite no evidence of performance enhancement. As legalization expands, athletes and sports medicine providers need evidence-based guidance rather than policy-driven assumptions.","specificNumbers":"Cannabis use prevalence among elite athletes is not well-known. No evidence for performance enhancement. Limited evidence for both serious harms and benefits. Associated with high-risk sports.","methodology":"Non-systematic literature review of Medline and PubMed for articles on cannabis/marijuana and sports/athletic performance.","limitations":"Non-systematic review may miss relevant studies. Limited evidence base across all areas. Cannabis products vary enormously in composition. Athletic populations are understudied."},{"rthcId":"RTHC-01873","title":"Is cannabis a risk factor for suicide attempts in men and women with psychotic illness?","authors":"Waterreus, A; Di Prinzio, P; Badcock, J C; Martin-Iverson, M; Jablensky, A; Morgan, V A","year":2018,"journal":"Psychopharmacology, 235(8), 2275-2285","doi":"10.1007/s00213-018-4924-6","pmid":"29766209","tags":["psychosis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In unadjusted analyses, daily cannabis users of both sexes had significantly increased odds of suicide attempts. After adjusting for depression, loneliness, homelessness, and hallucinations, the association was no longer significant. Depression was the strongest predictor for both sexes. Post hoc analysis found daily cannabis use may increase risk in older men specifically.","whyItMatters":"While cannabis is often assumed to increase suicide risk in psychosis, this study shows the apparent association is largely explained by depression and social adversity. This redirects clinical attention to treating depression and addressing social factors rather than focusing solely on cannabis use.","specificNumbers":"1,790 participants total. 168 (9.4%) attempted suicide in the past year. Daily cannabis users had elevated risk in unadjusted analysis, but not after adjustment. Depression was the strongest predictor for both sexes.","methodology":"Analysis of data from 1,065 men and 725 women in the Australian national survey of psychosis. Separate models for each sex examined the impact of daily, casual, or no past-year cannabis use on past-year suicide attempts.","limitations":"Cross-sectional design cannot determine causation. Self-reported cannabis use and suicide attempts. Cannot fully separate the effects of cannabis from its correlates. Post hoc subgroup finding (older men) needs replication."},{"rthcId":"RTHC-01874","title":"A Systematic Review of the Efficacy of Cannabinoid Agonist Replacement Therapy for Cannabis Withdrawal Symptoms.","authors":"Werneck, Maira Aguiar; Kortas, Guilherme Trevizan; de Andrade, Arthur Guerra; Castaldelli-Maia, João Mauricio","year":2018,"journal":"CNS drugs, 32(12), 1113-1129","doi":"10.1007/s40263-018-0577-6","pmid":"30361897","tags":["withdrawal","addiction","quitting"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Dronabinol, nabilone, and nabiximols, used alone or in combination with other drugs, showed promise in reducing cannabis withdrawal symptoms. The effect appeared dose-dependent. These medications were considered safe with good tolerability and few adverse effects. About 30% of regular cannabis users experience withdrawal, rising to 50-95% among highly dependent/treatment-seeking users.","whyItMatters":"Cannabis withdrawal was only recognized as a formal diagnosis in 2013 (DSM-5). With high relapse rates often driven by withdrawal symptoms, having effective treatments could significantly improve outcomes for people trying to quit.","specificNumbers":"30% of regular cannabis users experience withdrawal. 50-95% of highly dependent users experience withdrawal. 10 trials included in review. Three medications studied: dronabinol, nabilone, nabiximols.","methodology":"Systematic review searching PubMed, Web of Science, and PsycINFO through September 2017. 243 studies screened, 10 met inclusion criteria. Quality assessed using Cochrane tool. PROSPERO-registered protocol.","limitations":"Only 10 studies available with methodological differences. No meta-analysis was performed. Most studies were small. Different cannabinoid medications make comparison difficult. Limited data on long-term outcomes."},{"rthcId":"RTHC-01875","title":"Understanding marijuana's effects on functional connectivity of the default mode network in patients with schizophrenia and co-occurring cannabis use disorder: A pilot investigation.","authors":"Whitfield-Gabrieli, Susan; Fischer, Adina S; Henricks, Angela M; Khokhar, Jibran Y; Roth, Robert M; Brunette, Mary F; Green, Alan I","year":2018,"journal":"Schizophrenia research, 194, 70-77","doi":"10.1016/j.schres.2017.07.029","pmid":"28823723","tags":["psychosis","neuroscience","cognition"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"At baseline, schizophrenia patients showed DMN hyperconnectivity (correlated with positive symptom severity) and reduced anticorrelation between the DMN and executive control network compared to controls. After cannabinoid administration, DMN hyperconnectivity was reduced and DMN-ECN anticorrelation increased. The magnitude of anticorrelation after cannabinoid administration correlated with working memory performance.","whyItMatters":"DMN hyperconnectivity is a consistent finding in schizophrenia and is linked to psychotic symptoms. The remarkable finding that cannabinoids normalized this aberrant connectivity suggests a potential mechanism by which some schizophrenia patients may derive benefit from cannabis use, despite its general risks.","specificNumbers":"12 patients, 12 controls. DMN hyperconnectivity at baseline correlated with positive symptom severity. After cannabinoid administration, DMN connectivity normalized toward control levels. Post-cannabinoid DMN-ECN anticorrelation correlated with working memory performance.","methodology":"Pilot study with 12 schizophrenia-CUD patients and 12 healthy controls. Resting-state fMRI at baseline and after patients smoked a 3.6% THC cannabis cigarette or ingested a 15 mg THC pill. Default mode network connectivity analyzed.","limitations":"Very small pilot (n=12 per group). No placebo control for the cannabinoid administration. Low THC dose (3.6% or 15 mg). Cannot determine whether this network normalization translates to clinical benefit. Acute effects may differ from chronic effects."},{"rthcId":"RTHC-01876","title":"Increased Use of Medical Marijuana: Skepticism vs. Evidence.","authors":"Wick, Jeannette Y","year":2018,"journal":"The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists, 33(12), 680-689","doi":"10.4140/TCP.n.2018.680.","pmid":"30545431","tags":["medical-cannabis","seniors"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Medical marijuana use is growing among long-term care residents. Facilities face unique challenges including federal illegality (affecting Medicare/Medicaid facilities), state-by-state regulatory variation, the difference between plant-derived and synthetic products, and the need for pharmacist guidance. Some facilities are developing accommodation policies despite the legal quagmire.","whyItMatters":"The growing population of older adults using medical cannabis creates unique challenges in institutional settings where federal funding, drug interactions, and cognitive effects must all be considered alongside state-level legalization.","specificNumbers":"30 states had approved medical marijuana at time of publication. Two FDA-approved synthetic cannabinoids (for chemotherapy nausea and AIDS appetite). Plant-derived products differ from synthetics in multiple ways.","methodology":"Review of the regulatory landscape, pharmacological considerations, and practical challenges of medical marijuana in long-term care and senior care pharmacy settings.","limitations":"Practical review rather than systematic analysis. Rapidly changing legal landscape means specific guidance becomes outdated quickly. Limited evidence specifically in elderly populations."},{"rthcId":"RTHC-01877","title":"Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids.","authors":"Wiley, Jenny L; Owens, R Allen; Lichtman, Aron H","year":2018,"journal":"Current topics in behavioral neurosciences, 39, 153-173","doi":"10.1007/7854_2016_24","pmid":"27278640","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01878","title":"An examination of the association between prenatal cocaine exposure and brain activation measures of arousal and attention in young adults: An fMRI study using the Attention Network Task.","authors":"Willford, Jennifer A; Singhabahu, Dil; Herat, Athula; Richardson, Gale A","year":2018,"journal":"Neurotoxicology and teratology, 69, 1-10","doi":"10.1016/j.ntt.2018.06.004","pmid":"29953942","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01879","title":"Points & Pearls: Cannabinoids: emerging evidence in use and abuse.","authors":"Williams, Mollie; Gupta, Nachi; Nusbaum, Jeffrey","year":2018,"journal":"Emergency medicine practice, 20(Suppl 8), 1-2","doi":null,"pmid":"30070813","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01880","title":"Cannabinoids: emerging evidence in use and abuse.","authors":"Williams, Molly V","year":2018,"journal":"Emergency medicine practice, 20(8), 1-20","doi":null,"pmid":"30020736","tags":["harm-reduction","synthetic-cannabinoids"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Emergency departments are seeing increasing cannabinoid-related presentations. Key management considerations include distinguishing natural from synthetic cannabinoid intoxication, recognizing CHS as a diagnosis of exclusion, and utilizing emerging treatments (haloperidol, topical capsaicin, hot water bathing) when standard antiemetics fail.","whyItMatters":"As cannabis legalization expands and synthetic cannabinoid products proliferate, emergency physicians need practical, evidence-based guidance for managing the increasing number of cannabinoid-related presentations.","specificNumbers":"Reviews both natural and synthetic cannabinoid presentations. Covers acute intoxication and chronic use complications. Discusses CHS treatments: hot water bathing, haloperidol, and topical capsaicin.","methodology":"Comprehensive review of cannabinoid pathophysiology, clinical presentations, and current evidence for emergency department management.","limitations":"Review covers a broad area with varying evidence quality. Some treatment recommendations are based on case reports. Rapidly evolving landscape may outdate some guidance."},{"rthcId":"RTHC-01881","title":"Marijuana and Tobacco Coexposure in Hospitalized Children.","authors":"Wilson, Karen M; Torok, Michelle R; Wei, Binnian; Wang, Lanqing; Lowary, Michelle; Blount, Benjamin C","year":2018,"journal":"Pediatrics, 142(6)","doi":"10.1542/peds.2018-0820","pmid":"30455340","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"46% of children had detectable COOH-THC (marijuana metabolite) and 11% had detectable THC itself. Of those with detectable THC, 6 of 9 were under 8 years old. Children with positive results were more likely to have parents who used daily, smoked (vs other forms), used in the home, and smoked in another room rather than outside.","whyItMatters":"This is among the first studies to biologically confirm secondhand marijuana smoke exposure in children. The finding that nearly half of tested children had detectable marijuana metabolites raises serious questions about passive exposure risks to developing children.","specificNumbers":"Median child age: 6 years. 46% had detectable COOH-THC. 11% had detectable THC. Of 9 with detectable THC, 6 were under 8. No differences by age, sex, race, or socioeconomic status.","methodology":"Cross-sectional study of children hospitalized in Colorado with parents in a smoking cessation study. Remaining urine samples were analyzed for cotinine and marijuana metabolites using LC-MS/MS.","limitations":"Children were selected from a tobacco smoking cessation study, so all parents were smokers - not representative of all parents. Colorado-specific sample. Cannot determine health effects from exposure. Cannot distinguish secondhand smoke from other exposure routes."},{"rthcId":"RTHC-01882","title":"CB1 cannabinoid receptor ligands augment the antidepressant-like activity of biometals (magnesium and zinc) in the behavioural tests.","authors":"Wośko, Sylwia; Serefko, Anna; Szopa, Aleksandra; Wlaź, Piotr; Wróbel, Andrzej; Wlaź, Aleksandra; Górska, Jolanta; Poleszak, Ewa","year":2018,"journal":"The Journal of pharmacy and pharmacology, 70(4), 566-575","doi":"10.1111/jphp.12880","pmid":"29380383","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01883","title":"Neuroimaging meta-analysis of cannabis use studies reveals convergent functional alterations in brain regions supporting cognitive control and reward processing.","authors":"Yanes, Julio A; Riedel, Michael C; Ray, Kimberly L; Kirkland, Anna E; Bird, Ryan T; Boeving, Emily R; Reid, Meredith A; Gonzalez, Raul; Robinson, Jennifer L; Laird, Angela R; Sutherland, Matthew T","year":2018,"journal":"Journal of psychopharmacology (Oxford, England), 32(3), 283-295","doi":"10.1177/0269881117744995","pmid":"29338547","tags":["cognition","neuroscience"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis users showed decreased activation in the anterior cingulate cortex (linked to cognitive control) and dorsolateral prefrontal cortex (linked to attention). Conversely, increased activation was observed in the striatum (linked to reward processing). These regions co-activated with broader networks, suggesting widespread functional consequences.","whyItMatters":"By aggregating across many individual studies, this meta-analysis identifies the most robust brain changes associated with cannabis use: impaired cognitive control and enhanced reward processing. This pattern is consistent with addiction neuroscience models.","specificNumbers":"Three key regions identified: decreased anterior cingulate cortex activation (cognitive control), decreased DLPFC activation (attention), increased striatum activation (reward). Each region was functionally decoded using large database.","methodology":"Activation likelihood estimation meta-analysis of neuroimaging studies comparing cannabis users to non-users. Ancillary analyses used a large neuroimaging repository to characterize co-activation networks and functionally decode affected regions.","limitations":"Cross-sectional neuroimaging studies cannot determine whether brain changes preceded or followed cannabis use. Heterogeneity in cannabis use patterns across studies. Meta-analytic approach may miss subtle or region-specific effects."},{"rthcId":"RTHC-01884","title":"Medical use of cannabis: Italian and European legislation.","authors":"Zaami, S; Di Luca, A; Di Luca, N M; Montanari Vergallo, G","year":2018,"journal":"European review for medical and pharmacological sciences, 22(4), 1161-1167","doi":"10.26355/eurrev_201802_14405","pmid":"29509270","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01885","title":"Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the Pentylenetetrazol induced tonic- clonic seizures.","authors":"Zareie, Parisa; Sadegh, Mehdi; Palizvan, Mohammad Reza; Moradi-Chameh, Homeira","year":2018,"journal":"Metabolic brain disease, 33(3), 939-948","doi":"10.1007/s11011-018-0195-5","pmid":"29504066","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01886","title":"Monoacylglycerol lipase inhibitor JZL184 prevents HIV-1 gp120-induced synapse loss by altering endocannabinoid signaling.","authors":"Zhang, Xinwen; Thayer, Stanley A","year":2018,"journal":"Neuropharmacology, 128, 269-281","doi":"10.1016/j.neuropharm.2017.10.023","pmid":"29061509","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01887","title":"CB1 cannabinoid receptor agonist mouse VD-hemopressin(α) produced supraspinal analgesic activity in the preclinical models of pain.","authors":"Zheng, Ting; Zhang, Run; Zhang, Ting; Zhang, Meng-Na; Xu, Biao; Song, Jing-Jing; Li, Ning; Tang, Hong-Hai; Wang, Pei; Wang, Rui; Fang, Quan","year":2018,"journal":"Brain research, 1680, 155-164","doi":"10.1016/j.brainres.2017.12.013","pmid":"29274880","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01888","title":"Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.","authors":"Zhou, Lili; Zhou, Shan; Yang, Peng; Tian, Yuan; Feng, Zhiwei; Xie, Xiang-Qun; Liu, Youhua","year":2018,"journal":"Kidney international, 94(4), 756-772","doi":"10.1016/j.kint.2018.05.023","pmid":"30093080","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01889","title":"Altered orbitofrontal activity and dorsal striatal connectivity during emotion processing in dependent marijuana users after 28 days of abstinence.","authors":"Zimmermann, Kaeli; Yao, Shuxia; Heinz, Marcel; Zhou, Feng; Dau, Wolfgang; Banger, Markus; Weber, Bernd; Hurlemann, René; Becker, Benjamin","year":2018,"journal":"Psychopharmacology, 235(3), 849-859","doi":"10.1007/s00213-017-4803-6","pmid":"29197984","tags":["addiction","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"After 28+ days of abstinence, dependent marijuana users showed increased medial orbitofrontal cortex (mOFC) activity during negative emotional stimuli, stronger mOFC-dorsal striatal and mOFC-amygdala coupling, and increased mOFC-dorsal striatal resting connectivity compared to controls. Processing of positive stimuli was unaffected.","whyItMatters":"If brain changes persist after a month of abstinence, they may represent either long-term consequences of use or pre-existing vulnerabilities. Either way, they could contribute to relapse by altering how former users process negative emotions.","specificNumbers":"19 marijuana users, 18 controls. 28+ days abstinent. Significant increases in mOFC activity and mOFC-striatal/amygdala coupling during negative emotions (p<0.022, FWE-corrected). Resting connectivity also altered (p<0.03, FWE-corrected).","methodology":"Task-based and resting state fMRI comparing 19 dependent marijuana users (28+ days abstinent) with 18 matched non-using controls. Emotion processing task with positive and negative stimuli.","limitations":"Cross-sectional design cannot determine if changes preceded use. Relatively small sample. 28 days may not be sufficient for full neural recovery. Cannot rule out effects of prior cannabis use on brain development."},{"rthcId":"RTHC-01890","title":"Enhancement of Endocannabinoid-dependent Depolarization-induced Suppression of Excitation in Glycinergic Neurons by Prolonged Exposure to High Doses of Salicylate.","authors":"Zugaib, João; Leão, Ricardo M","year":2018,"journal":"Neuroscience, 376, 72-79","doi":"10.1016/j.neuroscience.2018.02.016","pmid":"29462704","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01891","title":"Perceived barriers for cannabis cessation: Relations to cannabis use problems, withdrawal symptoms, and self-efficacy for quitting.","authors":"Zvolensky, Michael J; Paulus, Daniel J; Garey, Lorra; Manning, Kara; Hogan, Julianna B D; Buckner, Julia D; Rogers, Andrew H; Kathryn McHugh, R","year":2018,"journal":"Addictive behaviors, 76, 45-51","doi":"10.1016/j.addbeh.2017.07.011","pmid":"28753466","tags":["quitting","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Structural equation modeling showed perceived barriers for quitting were significantly associated with cannabis use problems (beta=0.50), greater withdrawal symptoms (beta=0.39), and lower self-efficacy for quitting (beta=-0.17). The racially diverse sample (63.4% Black/African American) strengthens generalizability.","whyItMatters":"Understanding perceived barriers to quitting cannabis can inform more effective cessation interventions. The strong relationship between barriers and both problems and withdrawal suggests that addressing perceived barriers could improve quit outcomes.","specificNumbers":"145 cannabis users. 63.4% Black/African American. Barriers-problems beta=0.50. Barriers-withdrawal beta=0.39. Barriers-self-efficacy beta=-0.17. All significant (p<0.001 to p=0.028).","methodology":"Community-recruited sample of 145 cannabis users completed measures of perceived cessation barriers, cannabis use problems, withdrawal symptoms, and self-efficacy. Structural equation modeling tested relationships.","limitations":"Cross-sectional design cannot determine causality. Perceived barriers may be consequences rather than causes of use problems. Community sample may differ from treatment-seeking populations. Self-report measures."},{"rthcId":"RTHC-01892","title":"Suicidal behavior among substance users: data from the Second Brazilian National Alcohol and Drug Survey (II BNADS).","authors":"Abdalla, Renata R; Miguel, André C; Brietzke, Elisa; Caetano, Raul; Laranjeira, Ronaldo; Madruga, Clarice S","year":2019,"journal":"Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999), 41(5), 437-440","doi":"10.1590/1516-4446-2018-0054","pmid":"30785535","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among cannabis users, 31.5% reported suicidal ideation and 16.5% reported suicide attempts, compared to 9.9% and 5.4% in the general sample. After adjusting for demographic characteristics, tobacco use, family history of suicide, and depression, cannabis use remained positively associated with both suicidal ideation and attempts.","whyItMatters":"The persistence of the cannabis-suicide association after adjusting for depression and other confounders suggests cannabis use may be an independent risk marker for suicidal behavior, warranting screening in cannabis-using populations.","specificNumbers":"4,607 participants. Cannabis users: 31.5% suicidal ideation (vs 9.9% overall), 16.5% suicide attempts (vs 5.4% overall). Associations remained significant after adjusting for depression, tobacco use, family history, and demographics.","methodology":"National probability sample survey (II BNADS) of 4,607 Brazilians aged 14+ using multistage cluster design. Self-reported substance use, suicidal ideation, and suicide attempts. Response rate 77%.","limitations":"Cross-sectional design cannot determine causation. Self-reported measures of both substance use and suicidality. Cannabis users may differ from non-users in unmeasured ways. Brazilian context may differ from other countries."},{"rthcId":"RTHC-01893","title":"Adolescent exposure to Δ9-tetrahydrocannabinol delays acquisition of paired-associates learning in adulthood.","authors":"Abela, Andrew R; Rahbarnia, Arya; Wood, Suzanne; Lê, Anh D; Fletcher, Paul J","year":2019,"journal":"Psychopharmacology, 236(6), 1875-1886","doi":"10.1007/s00213-019-5171-1","pmid":"30694374","tags":["youth","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"THC-exposed rats took longer to learn a paired-associates learning task in adulthood, particularly with visually identical stimuli. However, they caught up when trials used visually distinct stimuli. Sensorimotor gating (PPI) was also impaired but appeared to decrease over time (tested at 5 days, 4 months, and 6 months post-exposure).","whyItMatters":"This study demonstrates that adolescent THC exposure can impair adult cognitive function, but also offers a more nuanced picture than typically presented: the deficits appear to diminish over time, suggesting some degree of neural recovery.","specificNumbers":"THC doses escalated from 2.5 to 10 mg/kg over PND 35-45. Learning delays were significant for location-based but not visually distinct stimuli. PPI impairments decreased from 5 days to 6 months post-exposure.","methodology":"Adolescent rats (PND 35-45) received escalating THC doses (2.5, 5, then 10 mg/kg). After abstinence, adults were tested on a touchscreen paired-associates learning task. Prepulse inhibition was tested at three time points post-exposure.","limitations":"Animal study with doses that may not reflect human use patterns. Only male rats studied. Limited to two cognitive measures. Recovery could reflect compensation rather than true neural recovery."},{"rthcId":"RTHC-01894","title":"Should Oncologists Recommend Cannabis?","authors":"Abrams, Donald I","year":2019,"journal":"Current treatment options in oncology, 20(7), 59","doi":"10.1007/s11864-019-0659-9","pmid":"31161270","tags":["cancer","medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis analgesic effects are supported by the best clinical evidence. THC is already FDA-approved for chemotherapy nausea (since 1986) and AIDS wasting (since 1992). Significant preclinical anticancer activity exists but clinical evidence is absent. A single intervention addressing nausea, appetite, pain, mood, and sleep is a valuable addition to palliative care. Evidence for serious harms from cannabis inhalation is scant.","whyItMatters":"Cancer patients often take multiple medications for different symptoms. This review argues that cannabis could address several symptoms simultaneously, reducing polypharmacy and improving quality of life for patients with limited time.","specificNumbers":"THC approved for chemotherapy nausea since 1986, appetite stimulation since 1992. Pain relief has the strongest clinical evidence. Multiple symptom domains addressed by one intervention: nausea, appetite, pain, mood, sleep.","methodology":"Narrative review by an oncologist examining the evidence for cannabis in cancer care, covering pain, nausea, appetite, mood, sleep, and potential anticancer properties.","limitations":"Narrative review by a known cannabis medicine advocate. Anticancer evidence is preclinical only. Recommendations go beyond what some systematic reviews support. Risk tolerance may differ by patient population."},{"rthcId":"RTHC-01895","title":"Altered Swimming Behaviors in Zebrafish Larvae Lacking Cannabinoid Receptor 2.","authors":"Acevedo-Canabal, Agnes; Colón-Cruz, Luis; Rodriguez-Morales, Roberto; Varshney, Gaurav K; Burgess, Shawn; González-Sepúlveda, Lorena; Yudowski, Guillermo; Behra, Martine","year":2019,"journal":"Cannabis and cannabinoid research, 4(2), 88-101","doi":"10.1089/can.2018.0025","pmid":"31236475","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01896","title":"Implementing social justice in the transition from illicit to legal cannabis.","authors":"Adinoff, Bryon; Reiman, Amanda","year":2019,"journal":"The American journal of drug and alcohol abuse, 45(6), 673-688","doi":"10.1080/00952990.2019.1674862","pmid":"31634005","tags":["legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Progress in five social justice areas: expungement of prior convictions (some progress, especially misdemeanors), cannabis-related arrests in legal environments (decreased), industry diversity (very limited), equity program funding (very limited), and risk of legalization harming previously targeted populations (no evidence of increased harm).","whyItMatters":"Cannabis prohibition disproportionately targeted minority communities for decades. As legalization generates billions in revenue, this review asks whether the benefits are reaching the communities most harmed by the war on drugs - and finds the answer is largely no.","specificNumbers":"Five social justice domains assessed. Some progress in two (expungement, reduced arrests). Very limited progress in two (industry diversity, equity funding). No evidence of new harms in one.","methodology":"Iterative and focused review examining social justice outcomes of cannabis legalization across five domains.","limitations":"Focused review rather than systematic analysis. Rapidly changing policy landscape. Difficult to measure social justice outcomes quantitatively. Limited data collection on equity outcomes."},{"rthcId":"RTHC-01897","title":"Cannabis Use Disorder and Post-Deployment Suicide Attempts in Iraq/Afghanistan-Era Veterans.","authors":"Adkisson, Kelsie; Cunningham, Katherine C; Dedert, Eric A; Dennis, Michelle F; Calhoun, Patrick S; Elbogen, Eric B; Beckham, Jean C; Kimbrel, Nathan A","year":2019,"journal":"Archives of suicide research : official journal of the International Academy for Suicide Research, 23(4), 678-687","doi":"10.1080/13811118.2018.1488638","pmid":"29952737","tags":["mental-health","addiction","ptsd"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Lifetime cannabis dependence was significantly associated with post-deployment suicide attempts (AOR=7.963, p=.014) after controlling for pre-deployment suicide attempts, PTSD, depression, pain, non-cannabis substance use disorder, and gender. This is the first evidence that heavy cannabis use may be a unique risk factor for suicide in veterans.","whyItMatters":"Veteran suicide is a public health crisis. While some veterans use cannabis to self-medicate PTSD and pain, this study suggests cannabis dependence (not casual use) may independently increase suicide risk, complicating the risk-benefit calculation.","specificNumbers":"319 veterans studied. Cannabis dependence associated with AOR=7.963 for post-deployment suicide attempts (p=.014). Controlled for pre-deployment attempts, PTSD, depression, pain, other substance use, and gender.","methodology":"Retrospective analysis of 319 veterans deployed to Iraq or Afghanistan. Structured clinical interviews and self-report questionnaires assessed cannabis dependence, suicide attempts, PTSD, depression, pain, and other substance use.","limitations":"Retrospective design with recall bias. Relatively small sample. Cannot determine causation. Cannabis dependence may be a marker for severity of underlying conditions. Self-selected veteran sample may not be representative."},{"rthcId":"RTHC-01898","title":"Current state of evidence of cannabis utilization for treatment of autism spectrum disorders.","authors":"Agarwal, Rumi; Burke, Shanna L; Maddux, Marlaina","year":2019,"journal":"BMC psychiatry, 19(1), 328","doi":"10.1186/s12888-019-2259-4","pmid":"31664964","tags":["medical-cannabis","cbd","youth","mental-health"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Only five small studies have specifically examined cannabis use in autism spectrum disorders. Results were mixed and inconclusive for most conditions, with epilepsy being the sole exception showing clearer benefit.","whyItMatters":"Families of children with ASD are increasingly turning to cannabis despite a near-total absence of rigorous evidence. Three large clinical trials were underway at the time of this review, but conclusions remained far ahead of the data.","specificNumbers":"Only 5 small studies specifically examined cannabis in ASD. 3 large-scale clinical trials were in progress. Adverse outcomes reported included severe psychosis, increased agitation, somnolence, decreased appetite, and irritability.","methodology":"Literature review analyzing peer-reviewed studies on cannabis use in ASD populations, including systematic reviews, reports, and experimental studies.","limitations":"The review identified very few ASD-specific cannabis studies, so it relied heavily on extrapolating from research on shared symptoms like anxiety and sleep disorders. The wide range of cannabis compositions and dosages across studies limits generalizability."},{"rthcId":"RTHC-01899","title":"Transcriptomic and barrier responses of human airway epithelial cells exposed to cannabis smoke.","authors":"Aguiar, Jennifer A; Huff, Ryan D; Tse, Wayne; Stämpfli, Martin R; McConkey, Brendan J; Doxey, Andrew C; Hirota, Jeremy A","year":2019,"journal":"Physiological reports, 7(20), e14249","doi":"10.14814/phy2.14249","pmid":"31646766","tags":["respiratory","neuroscience","cancer"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Cannabis smoke induced gene expression profiles that overlapped significantly with tobacco smoke, including DNA replication stress, oxidative stress responses, impaired epithelial barrier function, suppressed antiviral pathways, and increased inflammatory mediator production.","whyItMatters":"As cannabis legalization expands, understanding the respiratory effects of smoked cannabis becomes a public health priority. This study provides some of the first controlled molecular evidence that cannabis smoke may not be as harmless to lungs as some users assume.","specificNumbers":"Cannabis smoke impaired epithelial barrier function, suppressed antiviral responses, and increased inflammatory mediators. Gene expression changes showed significant correlation with published tobacco smoke exposure datasets from human bronchial brushings.","methodology":"In vitro study exposing human airway epithelial cells (Calu-3 cell line) to cannabis smoke with tobacco smoke as a positive control. Functional and transcriptomic (gene expression) analyses were performed.","limitations":"This was an in vitro study using a single cell line, not human lungs. The exposure conditions may not perfectly replicate real-world smoking patterns. Long-term and dose-dependent effects cannot be assessed in this model."},{"rthcId":"RTHC-01900","title":"Combination of Cannabinoids, Δ9- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways.","authors":"Al-Ghezi, Zinah Zamil; Miranda, Kathryn; Nagarkatti, Mitzi; Nagarkatti, Prakash S","year":2019,"journal":"Frontiers in immunology, 10, 1921","doi":"10.3389/fimmu.2019.01921","pmid":"31497013","tags":["cbd","medical-cannabis","inflammation","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC+CBD combination (10 mg/kg each) attenuated experimental autoimmune encephalomyelitis in mice by reducing brain-infiltrating inflammatory T cells and pro-inflammatory molecules while increasing anti-inflammatory markers. Neither THC nor CBD alone achieved these effects. The combination also significantly altered microRNA expression in brain immune cells.","whyItMatters":"THC+CBD combinations are already approved for MS-related spasticity in many countries, but how they suppress neuroinflammation was poorly understood. This study identifies specific microRNA changes as a potential mechanism, opening new avenues for understanding why the combination works better than either compound alone.","specificNumbers":"THC+CBD decreased IL-17, IFN-gamma, TNF-alpha, IL-1beta, and IL-6 in the brain while increasing FoxP3, IL-4, IL-10, and TGF-beta. Seven miRNAs were downregulated (including miR-155-5p and miR-21a-5p) and two were upregulated. Effects required both CB1 and CB2 receptors.","methodology":"Mouse model of multiple sclerosis (EAE) treated with THC+CBD combination versus individual cannabinoids. Used CB1/CB2 knockout mice to confirm receptor dependence. Performed miRNA microarray analysis on brain-derived CD4+ T cells. Included transfection studies and Mir21 knockout mice.","limitations":"This is a mouse model that does not perfectly replicate human MS. The EAE model represents only certain aspects of MS pathology. Doses used in mice may not translate directly to human dosing. The miRNA findings are correlational within the treatment context."},{"rthcId":"RTHC-01901","title":"Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome.","authors":"Al-Ghezi, Zinah Zamil; Busbee, Philip Brandon; Alghetaa, Hasan; Nagarkatti, Prakash S; Nagarkatti, Mitzi","year":2019,"journal":"Brain, behavior, and immunity, 82, 25-35","doi":"10.1016/j.bbi.2019.07.028","pmid":"31356922","tags":["cbd","medical-cannabis","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC+CBD treatment reduced a mucin-degrading gut bacterium (Akkermansia muciniphila) that was elevated in EAE mice, lowered brain LPS levels, and increased beneficial short-chain fatty acids. Fecal transplants from treated mice to untreated mice confirmed that gut microbiome changes played a critical role in the therapeutic effect.","whyItMatters":"The gut-brain axis is increasingly recognized as a factor in neurological diseases. This study provides direct evidence that cannabinoids can reshape the gut microbiome in ways that reduce neuroinflammation, adding a new dimension to how cannabis-based medicines might work in MS.","specificNumbers":"THC+CBD significantly reduced Akkermansia muciniphila abundance. Brain LPS levels were elevated in EAE mice and reversed by treatment. Short-chain fatty acids (butyric, isovaleric, and valeric acids) were significantly higher in treated mice compared to disease controls.","methodology":"Mouse model of MS (EAE) treated with THC+CBD combination. Used 16S rRNA sequencing to analyze gut microbiome composition. Fecal material transfer experiments tested whether microbiome changes were causally involved. In silico metabolomics analyzed bacterial metabolic pathways.","limitations":"Mouse gut microbiome composition differs from humans. EAE is an imperfect model of human MS. The fecal transplant experiments confirm causality in mice but not in humans. Specific bacterial species involved may differ across species."},{"rthcId":"RTHC-01902","title":"Cannabinoid-deficient Benin republic hemp (Cannabis sativa L.) improves semen parameters by reducing prolactin and enhancing anti-oxidant status.","authors":"Alagbonsi, Abdullateef Isiaka; Olayaki, Luqman Aribidesi; Abdulrahim, Halimat Amin; Adetona, Thomson Sijuade; Akinyemi, Gbemileke Tobiloba","year":2019,"journal":"BMC complementary and alternative medicine, 19(1), 132","doi":"10.1186/s12906-019-2541-5","pmid":"31208410","tags":["medical-cannabis","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Benin Republic hemp extract, which contains no THC or cannabichromene and only trace cannabinol, increased sperm count, morphology, and viability in rats. The mechanism appeared to involve reduced prolactin levels and enhanced antioxidant status rather than cannabinoid receptor activity.","whyItMatters":"Cannabis is generally associated with reduced male fertility, but this study suggests the gonadotoxic effects may be driven by specific cannabinoids like THC rather than the plant itself. Hemp varieties lacking these compounds had the opposite effect on sperm.","specificNumbers":"Both doses (2 mg/kg and 10 mg/kg) of Benin hemp increased sperm count, morphology, and viability. The extract contained no cannabichromene or THC. The 10 mg/kg dose increased total antioxidant capacity and catalase activity.","methodology":"Randomized controlled animal study with 36 male Wistar rats in 6 groups receiving different doses of Benin hemp extract with or without bromocriptine (a prolactin inhibitor). Measured semen parameters, reproductive hormones, and antioxidant markers.","limitations":"Rat reproductive physiology differs from humans. The study used a single hemp variety, so results may not generalize to other cannabinoid-deficient products. Sperm motility was not improved despite other parameter gains."},{"rthcId":"RTHC-01903","title":"Cannabidiol improves vocal learning-dependent recovery from, and reduces magnitude of deficits following, damage to a cortical-like brain region in a songbird pre-clinical animal model.","authors":"Alalawi, Ali; Dodu, Julien C; Woolley-Roberts, Marie; Brodie, James; Di Marzo, Vincenzo; Soderstrom, Ken","year":2019,"journal":"Neuropharmacology, 158, 107716","doi":"10.1016/j.neuropharm.2019.107716","pmid":"31325430","tags":["cbd","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD at 10 and 100 mg/kg effectively reduced the time required to recover vocal phonology and syntax after brain microlesions in zebra finches. For phonology specifically, CBD also reduced the magnitude of the disruption itself. Recovery of learned song requires sensorimotor learning dependent on auditory feedback.","whyItMatters":"This is the first study to show CBD can improve recovery of a complex learned behavior after brain injury. Unlike simple motor tasks, birdsong requires the same kind of sensorimotor integration humans use for speech, making this a potentially relevant model for post-stroke vocal recovery.","specificNumbers":"~10% of HVC destroyed by microlesions. Song was typically impaired for ~7 days. CBD at 10 and 100 mg/kg accelerated recovery. 4 dose levels tested across 3 surgery conditions with n=5-6 per group. 20-day recording period.","methodology":"Controlled animal study using adult male zebra finches. Bilateral microlesions destroyed ~10% of HVC (a pre-vocal motor cortical-like brain region). Four CBD doses (0, 1, 10, 100 mg/kg) were tested across three surgery conditions (microlesion, no-microlesion, sham). Birds were recorded over 20 days.","limitations":"Zebra finch vocal learning, while analogous to human speech in some ways, is not identical. The microlesion model creates clean, targeted damage unlike typical human brain injuries. Sample sizes were small (n=5-6 per group)."},{"rthcId":"RTHC-01904","title":"Hair cannabinoid concentrations in emergency patients with cannabis hyperemesis syndrome.","authors":"Albert, Khala; Sivilotti, Marco L A; Gareri, Joey; Day, Andrew; Ruberto, Aaron J; Hookey, Lawrence C","year":2019,"journal":"CJEM, 21(4), 477-481","doi":"10.1017/cem.2018.479","pmid":"30806339","tags":["medical-cannabis","appetite","potency"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Hair cannabinoid concentrations were similar between cannabis hyperemesis patients (THC median 220 pg/mg), recreational user controls (150 pg/mg), and emergency department controls (270 pg/mg). The only significant difference was a 2.6-fold lower THC:CBN ratio in hyperemesis cases compared to recreational user controls.","whyItMatters":"Cannabis hyperemesis syndrome remains poorly understood. This study suggests it is not simply caused by consuming more cannabis than others. Individual susceptibility likely plays a role, similar to motion sickness or morning sickness.","specificNumbers":"Hair THC: cases 220 pg/mg (median), recreational controls 150 pg/mg, ED controls 270 pg/mg. THC:CBN ratio was 2.6-fold lower in cases (95% CI 1.3-5.7). Hair CBD was often unquantifiably low in all groups. 46 total subjects analyzed.","methodology":"Age- and sex-matched case-control study comparing hair cannabinoid concentrations (THC, CBN, CBD, THC-COOH) in 16 cannabis hyperemesis patients, 16 recreational user controls, and 14 emergency department controls. All subjects had positive urine THC.","limitations":"Small sample size (16 cases). Hair analysis reflects average exposure over months but cannot capture acute dosing patterns. The THC:CBN ratio finding needs replication. Specific cannabis products and consumption methods were not controlled."},{"rthcId":"RTHC-01905","title":"Efficacy of cannabinoids in paediatric epilepsy.","authors":"Ali, Shayma; Scheffer, Ingrid E; Sadleir, Lynette G","year":2019,"journal":"Developmental medicine and child neurology, 61(1), 13-18","doi":"10.1111/dmcn.14087","pmid":"30402932","tags":["cbd","epilepsy","youth","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"CBD produced a 38-41% median reduction in all seizures compared to 13-19% on placebo in three RCTs for Dravet and Lennox-Gastaut syndromes. Responder rates (50% seizure reduction) were 39-46% for CBD versus 14-27% for placebo. CBD was well tolerated, with sedation, diarrhea, and decreased appetite as the most common side effects.","whyItMatters":"This review confirmed that CBD has crossed the threshold from anecdotal remedy to evidence-based treatment for specific severe childhood epilepsies, with efficacy comparable to drugs that have been used for decades.","specificNumbers":"38-41% median reduction in all seizures (vs 13-19% placebo). 39-46% responder rate at 50% seizure reduction (vs 14-27% placebo). Common adverse effects: sedation, diarrhea, decreased appetite.","methodology":"Review of three randomized, placebo-controlled, double-blind clinical trials examining pharmaceutical-grade CBD in Dravet syndrome and Lennox-Gastaut syndrome, with additional context on CBD pharmacology and clinical considerations.","limitations":"The trials focused on only two epilepsy syndromes (Dravet and Lennox-Gastaut). CBD mechanism of action remains unknown. Sedation from CBD-benzodiazepine interaction complicates interpretation of some side effects."},{"rthcId":"RTHC-01906","title":"Review of the many faces of synthetic cannabinoid toxicities.","authors":"Alipour, Azita; Patel, Puja Baldev; Shabbir, Zaheera; Gabrielson, Stephen","year":2019,"journal":"The mental health clinician, 9(2), 93-99","doi":"10.9740/mhc.2019.03.093","pmid":"30842917","tags":["synthetic-cannabinoids","cardiovascular","psychosis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoids produced a wide range of severe toxicities including arrhythmias, myocardial infarction, sudden cardiac death, psychosis, suicidal ideation, seizures, acute tubular necrosis, and intracranial hemorrhage. An outbreak of coagulopathies linked to brodifacoum-contaminated products caused at least 4 deaths.","whyItMatters":"Synthetic cannabinoids are marketed as safe marijuana alternatives, but they are far more potent at cannabinoid receptors and produce unpredictable, sometimes fatal toxicities. Their constantly changing chemical compositions and absence from standard drug tests make them particularly dangerous.","specificNumbers":"At least 4 deaths from brodifacoum-contaminated synthetic cannabinoids. Toxicities affected cardiovascular, neurological, renal, and hematological systems. Products are not detected on routine drug screens.","methodology":"Literature review searching PubMed and SciFinder databases for reports on synthetic cannabinoid toxicities, limited to human studies in English.","limitations":"The review relied on published case reports and case series, which may overrepresent severe outcomes. The constantly changing composition of synthetic cannabinoids means findings may not apply to newer formulations."},{"rthcId":"RTHC-01907","title":"Persistence of use of prescribed cannabinoid medicines in Manitoba, Canada: a population-based cohort study.","authors":"Alkabbani, Wajd; Marrie, Ruth Ann; Bugden, Shawn; Alessi-Severini, Silvia; Bolton, James M; Daeninck, Paul; Leong, Christine","year":2019,"journal":"Addiction (Abingdon, England), 114(10), 1791-1799","doi":"10.1111/add.14719","pmid":"31240747","tags":["medical-cannabis","pain","addiction","seniors"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 5,452 new prescribed cannabinoid users, 18.1% continued use at 1 year. Median duration was 31 days. Nabilone had the longest median use (33 days) and nabiximols the shortest (20 days). Fibromyalgia, osteoarthritis, and substance use disorder were associated with longer use, while cancer was associated with much shorter use.","whyItMatters":"Real-world persistence data reveals that most prescribed cannabinoid patients stop relatively quickly. The reasons differ by condition: cancer patients may stop due to disease progression or death, while chronic pain patients may persist longer because their conditions are ongoing.","specificNumbers":"5,452 new users studied. 18.1% (95% CI 17.08-19.12) still using at 1 year. Median duration: 31 days (IQR 25-193). Nabilone median: 33 days. Nabiximols median: 20 days. Cancer patients had HR 2.73 for discontinuation (95% CI 2.02-3.67). Substance use disorder had HR 0.85 for discontinuation.","methodology":"Retrospective population-based cohort study using administrative health data from the Manitoba Population Research Data Repository. Included all new cannabinoid prescription users from April 2004 to April 2016, followed for 1 year.","limitations":"Administrative data cannot capture reasons for discontinuation (inefficacy, side effects, symptom resolution, or death). Cannabis obtained outside the medical system was not tracked. The study period predated Canadian recreational legalization."},{"rthcId":"RTHC-01908","title":"Interactive effects of PTSD and substance use on suicidal ideation and behavior in military personnel: Increased risk from marijuana use.","authors":"Allan, Nicholas P; Ashrafioun, Lisham; Kolnogorova, Kateryna; Raines, Amanda M; Hoge, Charles W; Stecker, Tracy","year":2019,"journal":"Depression and anxiety, 36(11), 1072-1079","doi":"10.1002/da.22954","pmid":"31475423","tags":["ptsd","mental-health","addiction","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"PTSD symptoms and marijuana use both independently predicted suicidal ideation and behavior at follow-up. Critically, their interaction was also significant: at high (but not low) levels of PTSD symptoms, more days using marijuana predicted increased PTSD symptoms over time and greater likelihood of suicidal behavior. This interactive effect was not found for alcohol or opioid use.","whyItMatters":"Medical marijuana has been proposed as a PTSD treatment, but this study found that among military personnel with elevated PTSD symptoms, marijuana use was associated with worse outcomes. The interaction pattern suggests marijuana may be particularly harmful for those with severe PTSD.","specificNumbers":"545 participants (mean age 31.9, 88.2% male). Follow-up at 1, 3, 6, and 12 months. Marijuana use predicted suicidal ideation likelihood at 1 month and suicidal behavior over the 11-month follow-up. The PTSD-marijuana interaction was significant for both worsening PTSD and suicidal behavior.","methodology":"Longitudinal cohort study of 545 current and former military personnel at risk for suicide but not in active mental health treatment. Self-report measures of PTSD, substance use, and suicidality were collected by telephone at baseline and 1, 3, 6, and 12 months.","limitations":"Observational design cannot establish causation. Self-report measures may underestimate substance use. Participants were not in active treatment, which may limit generalizability. Cannabis type, dose, and cannabinoid content were not assessed."},{"rthcId":"RTHC-01909","title":"Maternal high-fat diet impairs leptin signaling and up-regulates type-1 cannabinoid receptor with sex-specific epigenetic changes in the hypothalamus of newborn rats.","authors":"Almeida, Mariana M; Dias-Rocha, Camilla P; Reis-Gomes, Clara F; Wang, Haimei; Atella, Georgia C; Cordeiro, Aline; Pazos-Moura, Carmen C; Joss-Moore, Lisa; Trevenzoli, Isis H","year":2019,"journal":"Psychoneuroendocrinology, 103, 306-315","doi":"10.1016/j.psyneuen.2019.02.004","pmid":"30776574","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01910","title":"β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.","authors":"Aly, Esraa; Khajah, Maitham A; Masocha, Willias","year":2019,"journal":"Molecules (Basel, Switzerland), 25(1)","doi":"10.3390/molecules25010106","pmid":"31892132","tags":["pain","cbd","inflammation","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Beta-caryophyllene (BCP) prevented the development of mechanical allodynia when co-administered with the NRTI zalcitabine and attenuated established pain through CB2 receptor activation. A CB2 antagonist (AM 630) blocked the pain-relieving effect, while a CB1 antagonist (AM 251) did not, confirming the CB2-specific mechanism. BCP also reduced inflammatory cytokines in paw skin and brain.","whyItMatters":"HIV-associated neuropathic pain responds poorly to available drugs. While smoked cannabis has shown benefit in clinical trials, the psychoactive effects of CB1 activation limit its use. BCP offers a potential alternative that targets pain through CB2 without psychoactive side effects.","specificNumbers":"5 days of zalcitabine treatment induced mechanical allodynia. BCP reduced cytokine transcripts (IL-1beta, TNF-alpha, IFN-gamma) in both paw skin and brain. AM 630 (CB2 antagonist) blocked BCP effects. AM 251 (CB1 antagonist) did not.","methodology":"Controlled animal study using female BALB/c mice treated with zalcitabine (ddC) for 5 days to induce neuropathic pain. BCP, minocycline, or pentoxifylline were co-administered. CB1 and CB2 receptor antagonists were used to determine mechanism. Cytokine transcripts and Erk1/2 phosphorylation were measured.","limitations":"Mouse model of neuropathic pain may not fully represent the human condition. Only female mice were used. The NRTI tested (zalcitabine) is no longer commonly used in HIV treatment. Doses may not translate directly to humans."},{"rthcId":"RTHC-01911","title":"Cannabis, Cannabinoids, and the Endocannabinoid System-Is there Therapeutic Potential for Inflammatory Bowel Disease?","authors":"Ambrose, Tim; Simmons, Alison","year":2019,"journal":"Journal of Crohn's & colitis, 13(4), 525-535","doi":"10.1093/ecco-jcc/jjy185","pmid":"30418525","tags":["medical-cannabis","inflammation","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"In animal models, both exogenous cannabinoids and modulation of the endocannabinoid system consistently improved colitis. However, this did not translate to human IBD in the few clinical trials conducted. The largest study was limited by poor medication tolerance due to THC content. Cannabis use surveys show patients report symptom improvements, but controlled evidence is lacking.","whyItMatters":"IBD patients are already using cannabis for symptom relief based on anecdotal reports, but the disconnect between strong animal data and weak human trial results highlights a critical evidence gap. Understanding why preclinical promise has not translated to clinical benefit is essential.","specificNumbers":"The largest clinical trial was limited by poor THC tolerance. Cannabis use surveys show IBD patients commonly report improvements in pain, appetite, and diarrhea. Preclinical models using pharmacological receptor agonists, genetic knockouts, and enzyme inhibitors largely showed improvements.","methodology":"Narrative review synthesizing preclinical studies (chemical colitis models, genetic knockout models, enzyme inhibition studies), clinical surveys of cannabis use in IBD, and the limited clinical trial data available.","limitations":"Very few clinical trials have been conducted in human IBD. Animal colitis models (mainly chemical-induced) do not perfectly represent human Crohn's or ulcerative colitis. Survey data on cannabis use is subject to recall and reporting bias."},{"rthcId":"RTHC-01912","title":"Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.","authors":"Anderson, Lyndsey L; Absalom, Nathan L; Abelev, Sarah V; Low, Ivan K; Doohan, Peter T; Martin, Lewis J; Chebib, Mary; McGregor, Iain S; Arnold, Jonathon C","year":2019,"journal":"Epilepsia, 60(11), 2224-2234","doi":"10.1111/epi.16355","pmid":"31625159","tags":["cbd","epilepsy","drug-interactions","youth"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD potently inhibited liver enzymes (CYP3A4, CYP2C19) that metabolize clobazam and its metabolite, increasing plasma clobazam levels. However, a sub-anticonvulsant dose of CBD did not improve seizure outcomes despite raising clobazam levels, while an anticonvulsant dose did. This proves the interaction is not purely pharmacokinetic. CBD and clobazam together also enhanced inhibitory GABA receptor activation, revealing a novel pharmacodynamic mechanism.","whyItMatters":"Critics have suggested CBD's anti-seizure effect in clinical trials was just a side effect of boosting clobazam levels. This study refutes that claim by showing CBD has genuine anticonvulsant activity and a direct pharmacodynamic interaction with clobazam at GABA receptors.","specificNumbers":"CBD potently inhibited CYP3A4-mediated clobazam metabolism and CYP2C19-mediated N-desmethylclobazam metabolism. Sub-anticonvulsant CBD dose did NOT improve outcomes despite raising clobazam levels. Anticonvulsant CBD dose improved efficacy against both thermally-induced and spontaneous seizures.","methodology":"Multi-method preclinical study: in vitro enzyme inhibition assays, mouse pharmacokinetic studies, the Scn1a+/- Dravet syndrome mouse model for seizure testing (thermally induced and spontaneous seizures), and Xenopus oocyte GABA receptor electrophysiology.","limitations":"Mouse model of Dravet syndrome, while well-established, may not fully represent human disease. In vitro enzyme and receptor studies may not perfectly predict in vivo interactions. Specific dose translation to humans requires clinical confirmation."},{"rthcId":"RTHC-01913","title":"Neuropsychiatric Sequelae in Adolescents With Acute Synthetic Cannabinoid Toxicity.","authors":"Anderson, Sarah Ann R; Oprescu, Anna M; Calello, Diane; Monte, Andrew; Dayan, Peter S; Hurd, Yasmin L; Manini, Alex F","year":2019,"journal":"Pediatrics, 144(2)","doi":"10.1542/peds.2018-2690","pmid":"31285395","tags":["synthetic-cannabinoids","youth","psychosis","neuroscience"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoid-only exposure (n=107) was associated with 3.4x higher odds of coma/CNS depression (OR 3.42, 95% CI 1.51-7.75) and 3.9x higher odds of seizures (OR 3.89, 95% CI 1.39-10.94) compared to cannabis-only exposure (n=86). Interestingly, SC-only exposure was associated with lower odds of agitation (OR 0.18), while SC-polydrug exposure showed the opposite pattern.","whyItMatters":"This provides the first large multicenter comparison of neuropsychiatric outcomes between synthetic cannabinoid and traditional cannabis use specifically in adolescents, the age group most likely to use these products.","specificNumbers":"SC-only: OR 3.42 for coma/CNS depression, OR 3.89 for seizures, OR 0.18 for agitation. SC-polydrug: OR 3.11 for agitation, OR 4.8 for seizures. 107 SC-only cases, 86 cannabis-only cases, 38 SC-polydrug cases, 117 cannabis-polydrug cases.","methodology":"Retrospective analysis of the Toxicology Investigators Consortium Case Registry, a multicenter registry with data prospectively collected by medical toxicologists. Reviewed SC and cannabis exposures in adolescents from 2010-2018 across four exposure groups.","limitations":"Retrospective design with potential selection bias (only captures ED presentations). Specific synthetic cannabinoid compounds were generally unknown. Polydrug use complicates attribution. The registry may not capture milder cases."},{"rthcId":"RTHC-01914","title":"Impact of Medical Cannabis on Patient-Reported Symptoms for Patients With Cancer Enrolled in Minnesota's Medical Cannabis Program.","authors":"Anderson, Susan P; Zylla, Dylan M; McGriff, Deepa M; Arneson, Tom J","year":2019,"journal":"Journal of oncology practice, 15(4), e338-e345","doi":"10.1200/JOP.18.00562","pmid":"30860938","tags":["medical-cannabis","cancer","pain","sleep","anxiety","appetite"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Significant reductions were found across all 8 symptoms (anxiety, appetite loss, depression, sleep disturbance, fatigue, nausea, pain, and vomiting) within 4 months of starting medical cannabis. The proportion achieving 30% or greater symptom reduction ranged from 27% (fatigue) to 50% (vomiting). Adverse effects were reported by only 10.5% of patients.","whyItMatters":"Minnesota's program is unique in routinely collecting standardized symptom data, providing real-world evidence on medical cannabis outcomes in cancer patients at a scale that individual clinical trials rarely achieve.","specificNumbers":"All 8 symptoms showed significant reduction (all p < .001). 30% or greater symptom reduction: fatigue 27%, vomiting 50%. Adverse effects in 10.5% of patients. Symptom scores measured at each cannabis purchase over 4 months.","methodology":"Observational study using patient-reported symptom scores collected routinely by Minnesota's medical cannabis program. Patients rated 8 symptoms at their worst in the last 24 hours before each purchase. Baseline scores were compared with averages over the first 4 months.","limitations":"No control group or randomization. Symptom improvement could reflect placebo effect, disease progression, or concurrent treatments. Self-reported data before purchases may reflect selection bias (patients who benefit keep purchasing). Drop-out bias not addressed."},{"rthcId":"RTHC-01915","title":"A case report positive for synthetic cannabinoids: are cardiovascular effects related to their protracted use?","authors":"Anzillotti, Luca; Marezza, Francesca; Calò, Luca; Banchini, Antonio; Cecchi, Rossana","year":2019,"journal":"Legal medicine (Tokyo, Japan), 41, 101637","doi":"10.1016/j.legalmed.2019.101637","pmid":"31683096","tags":["synthetic-cannabinoids","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The report documents a cardiac tamponade case with toxicology positive for synthetic cannabinoids. The authors reviewed evidence that synthetic cannabinoids can affect the cardiovascular system through multiple mechanisms including hypotension, bradycardia, myocardial infarction, arrhythmias, and interference with platelet aggregation.","whyItMatters":"Cardiac tamponade is a life-threatening emergency that has not been widely associated with synthetic cannabinoid use. This case expands the known range of cardiovascular complications and highlights the importance of toxicology testing for novel psychoactive substances.","specificNumbers":"Toxicology was positive for synthetic cannabinoids. Known SC cardiovascular effects include: hypotension, bradycardia, myocardial infarction, atrial fibrillation, prolonged QTc, and Mobitz type II atrioventricular block.","methodology":"Single case report with toxicological analysis and literature review of synthetic cannabinoid cardiovascular effects.","limitations":"A single case report cannot establish causation. Other contributing factors to the cardiac tamponade may have been present. The specific synthetic cannabinoid compound was not identified."},{"rthcId":"RTHC-01916","title":"Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study.","authors":"Aran, Adi; Cassuto, Hanoch; Lubotzky, Asael; Wattad, Nadia; Hazan, Esther","year":2019,"journal":"Journal of autism and developmental disorders, 49(3), 1284-1288","doi":"10.1007/s10803-018-3808-2","pmid":"30382443","tags":["cbd","youth","mental-health","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Following CBD-rich cannabis treatment, behavioral outbreaks were \"much improved\" or \"very much improved\" in 61% of 60 children with ASD and severe behavioral problems, as rated by caregivers on the Clinical Global Impression of Change scale. Adverse events included sleep disturbances (14%), irritability (9%), and loss of appetite (9%). One girl using higher-THC cannabis had a transient psychotic episode.","whyItMatters":"This was one of the first studies to specifically examine CBD-based cannabis treatment in children with autism, providing preliminary evidence of feasibility and potential benefit for severe behavioral problems that are often resistant to standard treatments.","specificNumbers":"60 children studied. Mean age 11.8 (range 5.0-17.5). 77% low functioning. 83% boys. 61% showed much or very much improved behavioral outbreaks. Adverse events: sleep disturbances 14%, irritability 9%, loss of appetite 9%. 1 case of transient serious psychosis (higher THC product).","methodology":"Retrospective feasibility study assessing tolerability and efficacy of CBD-rich cannabis in 60 children with ASD and severe behavioral problems. Mean age 11.8 years, 77% low functioning, 83% boys. Efficacy measured using Caregiver Global Impression of Change scale.","limitations":"Retrospective design with no control group or blinding. Caregiver-reported outcomes are subjective. CBD-rich cannabis composition varied. The psychotic episode in the higher-THC case raises safety questions about THC content in this population. Small sample without long-term follow-up."},{"rthcId":"RTHC-01917","title":"The Endocannabinoid System as a Window Into Microglial Biology and Its Relationship to Autism.","authors":"Araujo, Daniel John; Tjoa, Karensa; Saijo, Kaoru","year":2019,"journal":"Frontiers in cellular neuroscience, 13, 424","doi":"10.3389/fncel.2019.00424","pmid":"31619967","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01918","title":"Bipolar disorder and the endocannabinoid system.","authors":"Arjmand, Shokouh; Behzadi, Mina; Kohlmeier, Kristi A; Mazhari, Shahrzad; Sabahi, Abdolreza; Shabani, Mohammad","year":2019,"journal":"Acta neuropsychiatrica, 31(4), 193-201","doi":"10.1017/neu.2019.21","pmid":"31159897","tags":["mental-health","depression","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system exerts neuromodulatory effects on neurotransmitter systems critical for emotion regulation. Limited clinical and molecular evidence suggests ECS dysfunction may contribute to bipolar disorder pathophysiology, with selective CB2 receptor agonists showing potential for mood stabilization.","whyItMatters":"Bipolar disorder remains inadequately treated in a significant subset of patients. If ECS manipulation can stabilize mood, it would open an entirely new class of treatment targets for a condition with limited pharmacological options.","specificNumbers":"No specific numerical outcomes reported. The review highlights that the ECS role in BD has been \"almost neglected\" in research despite available data suggesting mood regulation involvement.","methodology":"Perspective review synthesizing clinical, molecular, and anecdotal evidence on the relationship between the endocannabinoid system and bipolar disorder.","limitations":"The available data on ECS and bipolar disorder is very limited. The CB2 mood stabilization hypothesis is based on indirect evidence rather than clinical trials. Cannabis use in BD also carries risks including triggering manic episodes."},{"rthcId":"RTHC-01919","title":"Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition.","authors":"Arkell, Thomas R; Lintzeris, Nicholas; Kevin, Richard C; Ramaekers, Johannes G; Vandrey, Ryan; Irwin, Christopher; Haber, Paul S; McGregor, Iain S","year":2019,"journal":"Psychopharmacology, 236(9), 2713-2724","doi":"10.1007/s00213-019-05246-8","pmid":"31044290","tags":["driving","cbd","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Both THC-dominant and THC/CBD equivalent cannabis increased lane weaving during simulated driving. THC/CBD equivalent cannabis actually produced worse impairment on divided attention and auditory processing tasks than THC-dominant cannabis. Peak plasma THC concentrations were higher with THC/CBD cannabis, suggesting a pharmacokinetic interaction where CBD increases THC absorption.","whyItMatters":"Many consumers and regulators assume CBD mitigates THC impairment, which influences product labeling, driving policies, and consumer choices. This study challenges that assumption directly.","specificNumbers":"14 participants. 125 mg cannabis vaporized per session. 11% THC in both active conditions. THC/CBD cannabis produced worse performance on Divided Attention Task and Paced Auditory Serial Addition Task. Peak plasma THC was higher with THC/CBD cannabis. Subjective \"stoned\" ratings did not differ between active conditions.","methodology":"Randomized, double-blind, within-subjects crossover design with 14 healthy light cannabis users. Three conditions: THC-dominant (11% THC, <1% CBD), THC/CBD equivalent (11% THC, 11% CBD), or placebo. Simulated driving and cognitive testing at 20-60 min and 200-240 min post-vaporization.","limitations":"Small sample (n=14) of light cannabis users. Simulated driving may not perfectly represent real-world conditions. Only one CBD:THC ratio was tested. Acute dosing does not capture chronic use patterns."},{"rthcId":"RTHC-01920","title":"Detection of Δ9 THC in oral fluid following vaporized cannabis with varied cannabidiol (CBD) content: An evaluation of two point-of-collection testing devices.","authors":"Arkell, Thomas R; Kevin, Richard C; Stuart, Jordyn; Lintzeris, Nicholas; Haber, Paul S; Ramaekers, Johannes G; McGregor, Iain S","year":2019,"journal":"Drug testing and analysis, 11(10), 1486-1497","doi":"10.1002/dta.2687","pmid":"31442003","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01921","title":"Self-management strategies amongst Australian women with endometriosis: a national online survey.","authors":"Armour, Mike; Sinclair, Justin; Chalmers, K Jane; Smith, Caroline A","year":2019,"journal":"BMC complementary and alternative medicine, 19(1), 17","doi":"10.1186/s12906-019-2431-x","pmid":"30646891","tags":["pain","medical-cannabis","cbd","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Self-management was used by 76% of women with endometriosis. Cannabis received the highest self-rated effectiveness for pain reduction (7.6/10), followed by heat (6.52), dietary changes (6.39), and hemp/CBD oil (6.33). Physical interventions like yoga and exercise were rated less effective. Alcohol (53.8%) and exercise (34.2%) had the highest rates of adverse events.","whyItMatters":"Endometriosis affects roughly 10% of reproductive-age women and current medical treatments often provide inadequate pain relief. Understanding which self-management strategies patients find most effective can inform clinical conversations and research priorities.","specificNumbers":"484 respondents. 76% used self-management strategies. Cannabis effectiveness: 7.6/10. Heat: 6.52/10. CBD oil: 6.33/10. Dietary changes: 6.39/10. Most common strategies: heat (70%), rest (68%), meditation/breathing (47%). Adverse events: alcohol 53.8%, exercise 34.2%.","methodology":"Cross-sectional online survey distributed via social media through Australian endometriosis support groups. 484 valid responses from women aged 18-45 with confirmed endometriosis diagnosis. Collected between October-December 2017.","limitations":"Self-reported effectiveness is subjective and subject to recall bias. Recruitment through support groups may not represent all women with endometriosis. Cannabis use was not broken down by type, dose, or frequency. No control group."},{"rthcId":"RTHC-01922","title":"Synthetic Cannabinoid-Associated Multiple Organ Failure: Case Series and Literature Review.","authors":"Armstrong, Faith; McCurdy, Michael T; Heavner, Mojdeh S","year":2019,"journal":"Pharmacotherapy, 39(4), 508-513","doi":"10.1002/phar.2241","pmid":"30811628","tags":["synthetic-cannabinoids","cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All six patients had altered mental status and severe rhabdomyolysis (peak CK up to >320,000 U/L). Five of six had acute kidney injury, four required continuous dialysis. Five had fever, three had myocardial injury. Two needed emergency fasciotomies for compartment syndrome. Two developed fulminant liver failure, one requiring MARS therapy as bridge to successful transplant; the other patient without it died.","whyItMatters":"This case series documents the most severe end of the synthetic cannabinoid toxicity spectrum, including the first reported case requiring liver transplantation. It demonstrates that SC use can cause simultaneous failure of multiple organ systems.","specificNumbers":"6 patients. Peak CK: 4,000 to >320,000 U/L. Acute kidney injury: 5/6. Continuous dialysis: 4/6. Fever: 5/6. Seizures: 3/6. Troponin elevation: 3/6. Emergency fasciotomies: 2/6. Fulminant liver failure: 2/6. Deaths: 1/6.","methodology":"Multicenter descriptive case series of six patients admitted to intensive care units at three Maryland hospitals between March-July 2016 with known synthetic cannabinoid use and multiple organ failure.","limitations":"Small case series from a single geographic region and time period. Specific synthetic cannabinoid compounds were not identified. Pre-existing conditions or co-ingestants may have contributed. Cannot determine incidence of severe outcomes among all SC users."},{"rthcId":"RTHC-01923","title":"Association of smoked cannabis with treatment resistance in schizophrenia.","authors":"Arsalan, Arsalan; Iqbal, Zafar; Tariq, Muhammad; Ayonrinde, Oyedeji; Vincent, John B; Ayub, Muhammad","year":2019,"journal":"Psychiatry research, 278, 242-247","doi":"10.1016/j.psychres.2019.06.023","pmid":"31229838","tags":["psychosis","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The treatment resistance rate was over 60% in this cohort. Ongoing cannabis use was significantly associated with treatment resistance after controlling for treatment adherence. The study excluded cases where non-adherence could explain treatment failure, strengthening the cannabis-treatment resistance link.","whyItMatters":"Treatment-resistant schizophrenia is one of the most challenging conditions in psychiatry. If cannabis use contributes to treatment resistance, it identifies a modifiable factor that could improve outcomes for a substantial number of patients.","specificNumbers":"230 patients studied. Over 90% male. Treatment resistance rate: >60%. Cannabis use was associated with treatment resistance. Only adherent patients were included to rule out non-compliance as a confound.","methodology":"Cross-sectional study of 230 schizophrenia patients at a psychiatric hospital in Khyber Pakhtunkhwa, Pakistan. Clinical evaluation using PANSS and CGI scales. Treatment resistance defined as failure to respond to two adequate antipsychotic trials. Adherent patients only.","limitations":"Cross-sectional design cannot establish causation. Self-reported cannabis use may be underreported. The heavily male cohort limits generalizability. Specific cannabis types, doses, and duration of use were not detailed. High treatment resistance rate may reflect referral bias at a tertiary hospital."},{"rthcId":"RTHC-01924","title":"The Potential of Cannabinoid-Based Treatments in Tourette Syndrome.","authors":"Artukoglu, Bekir B; Bloch, Michael H","year":2019,"journal":"CNS drugs, 33(5), 417-430","doi":"10.1007/s40263-019-00627-1","pmid":"30977108","tags":["medical-cannabis","mental-health","neuroscience"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"There is a strong biological rationale for cannabinoid effects on tics, and many patients report improvement with cannabis. However, only two small randomized, placebo-controlled trials of THC have been published, and these merely suggested possible benefits. Trials of other cannabinoid agents are ongoing. The authors recommend restricting clinical use to adults given developmental risks.","whyItMatters":"Tourette syndrome has limited pharmacological options, and many patients report cannabis helps their tics. But the evidence base consists of just two small trials, creating a gap between patient experience and clinical guidance.","specificNumbers":"Only 2 small randomized controlled trials published (both testing THC). Multiple anecdotal case reports and series describe tic improvement. Additional trials of cannabinoid system agents are ongoing.","methodology":"Comprehensive literature search of PubMed for randomized controlled trials and clinical trials of cannabis-derived medications in Tourette syndrome. Extracted population, intervention, safety, and outcome data.","limitations":"Extremely limited trial data. Only THC has been tested in RCTs, not CBD or other cannabinoids. Safety profile is largely unknown in this population. Developmental effects of cannabinoids in children with Tourette syndrome are a concern."},{"rthcId":"RTHC-01925","title":"Delayed Intracerebral Hemorrhage after Synthetic Cannabis (Bonsai) Abuse; Case Report and Literature Review.","authors":"Aydin, Gülçin; Bakar, Bülent","year":2019,"journal":"Bulletin of emergency and trauma, 7(3), 330-334","doi":"10.29252/beat-0703019","pmid":"31392236","tags":["synthetic-cannabinoids","cardiovascular","respiratory"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient initially presented with dyspnea, hemoptysis, and agitation after synthetic cannabinoid (\"Bonsai\") use. Initial brain CT was normal, but the patient developed delayed intracerebral hemorrhage in two locations (left frontal and right posterior parietal) during hospitalization. The delayed onset suggests SC-induced vascular damage or coagulopathy rather than direct acute injury.","whyItMatters":"The delayed onset of brain hemorrhage after an initially normal CT scan is a critical clinical warning. Patients who appear to improve after synthetic cannabinoid exposure may still be at risk for life-threatening intracranial complications.","specificNumbers":"25-year-old male. Initial CT normal. Diffuse alveolar hemorrhage on thoracic CT. Patient regained consciousness on day 2, then lost consciousness again. Hemorrhage found in left frontal and right posterior parietal regions. Recovery took 3 weeks after second intubation.","methodology":"Single case report with serial CT imaging documenting the progression from initial normal brain imaging to delayed bilateral intracerebral hemorrhage following synthetic cannabinoid use.","limitations":"Single case report. Specific synthetic cannabinoid compound not identified. Other contributing factors (e.g., pre-existing vascular abnormalities) could not be fully excluded. The temporal relationship suggests but does not prove causation."},{"rthcId":"RTHC-01926","title":"Epidemiology, Clinical Characteristics, and Associations for Rome IV Functional Nausea and Vomiting Disorders in Adults.","authors":"Aziz, Imran; Palsson, Olafur S; Whitehead, William E; Sperber, Ami D; Simrén, Magnus; Törnblom, Hans","year":2019,"journal":"Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 17(5), 878-886","doi":"10.1016/j.cgh.2018.05.020","pmid":"29857155","tags":["medical-cannabis","appetite"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"FNVDs affected 2.2% of the population. CVS prevalence was higher in the US (2%) than Canada (0.7%) or UK (1%). All 7 cases meeting cannabinoid hyperemesis criteria were in the US. Hot water bathing to relieve vomiting was significantly more common in CVS (44%) than CNVS (19%) and was independent of cannabis use but augmented by it.","whyItMatters":"This is one of the first population-level estimates of cannabinoid hyperemesis syndrome prevalence using standardized diagnostic criteria. The finding that hot bathing behavior occurs in all functional vomiting disorders, not just cannabinoid hyperemesis, challenges assumptions about diagnosis.","specificNumbers":"5,931 adults surveyed. 2.2% (n=131) met FNVD criteria. US prevalence: 3%. CVS: US 2%, Canada 0.7%, UK 1%. 7 cannabinoid hyperemesis cases, all in US. Hot bathing: CVS 44% vs CNVS 19% (p=.03). Cannabis augmented hot bathing behavior.","methodology":"Internet cross-sectional health survey of 5,931 adults across the US, Canada, and UK in 2015. Quota-based sampling for demographic balance. Rome IV diagnostic criteria for functional nausea and vomiting disorders.","limitations":"Internet survey with self-reported symptoms. Cannabis use patterns were not detailed. The 7 cannabinoid hyperemesis cases are too few for meaningful subgroup analysis. Cultural differences in cannabis access may explain geographic variation."},{"rthcId":"RTHC-01927","title":"Use of Cannabis to Relieve Pain and Promote Sleep by Customers at an Adult Use Dispensary.","authors":"Bachhuber, Marcus; Arnsten, Julia H; Wurm, Gwen","year":2019,"journal":"Journal of psychoactive drugs, 51(5), 400-404","doi":"10.1080/02791072.2019.1626953","pmid":"31264536","tags":["pain","sleep","medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"65% of adult-use customers used cannabis for pain relief, and 74% used it for sleep. Among those using cannabis for pain, 80% found it very or extremely helpful. 82% of those on OTC pain medications and 88% of those on opioids reported reducing or stopping those medications. For sleep, 84% found cannabis helpful, and 87% on OTC and 83% on prescription sleep aids reported reducing or stopping.","whyItMatters":"This study reveals that \"recreational\" dispensary customers are frequently using cannabis for symptom management, particularly pain and sleep. The reported medication substitution, especially reducing opioid use, has significant public health implications.","specificNumbers":"1,000 respondents. Pain use: 65%. Sleep use: 74%. Pain effectiveness (very/extremely helpful): 80%. Reduced/stopped OTC pain meds: 82%. Reduced/stopped opioids: 88%. Sleep effectiveness: 84%. Reduced/stopped OTC sleep aids: 87%. Reduced/stopped Rx sleep aids: 83%.","methodology":"Survey conducted at two retail cannabis stores in Colorado between August-October 2016. 1,000 adult-use only customer respondents (medical certification holders excluded). Electronic survey provided by store staff.","limitations":"Self-reported data from dispensary customers who chose to participate, likely biasing toward positive experiences. No verification of medication changes or clinical outcomes. Cross-sectional design cannot confirm causation. Colorado population may not generalize."},{"rthcId":"RTHC-01928","title":"Closing the Yield Gap for Cannabis: A Meta-Analysis of Factors Determining Cannabis Yield.","authors":"Backer, Rachel; Schwinghamer, Timothy; Rosenbaum, Phillip; McCarty, Vincent; Eichhorn Bilodeau, Samuel; Lyu, Dongmei; Ahmed, Md Bulbul; Robinson, George; Lefsrud, Mark; Wilkins, Olivia; Smith, Donald L","year":2019,"journal":"Frontiers in plant science, 10, 495","doi":"10.3389/fpls.2019.00495","pmid":"31068957","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01929","title":"End User-Informed Mobile Health Intervention Development for Adolescent Cannabis Use Disorder: Qualitative Study.","authors":"Bagot, Kara; Hodgdon, Elizabeth; Sidhu, Natasha; Patrick, Kevin; Kelly, Mikaela; Lu, Yang; Bath, Eraka","year":2019,"journal":"JMIR mHealth and uHealth, 7(10), e13691","doi":"10.2196/13691","pmid":"31588909","tags":["youth","addiction","quitting"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Five themes emerged from focus groups with 37 cannabis-using teens: (1) rewards mimicking social media engagement plus prosocial activity rewards for progressive use reduction, (2) ability to self-monitor progress, (3) peer social support within the app, (4) privacy through discrete logo/name and usernames, (5) individualized frequency and content of notifications.","whyItMatters":"Current cannabis use interventions for adolescents have modest effects and high relapse rates. Understanding what teens actually want in a cessation tool could improve engagement and retention, which are the biggest barriers to treatment effectiveness.","specificNumbers":"37 participants across 6 focus groups. Age range: 14-17. 5 key themes identified. Participants valued social media-style rewards, progress tracking, peer support, privacy, and customizable reminders.","methodology":"Qualitative study using six semistructured focus groups with 37 adolescents aged 14-17 who used cannabis, recruited from San Diego County high schools. Iterative coding with structural and pattern coding.","limitations":"Small sample from a single geographic area. Focus groups may not capture the views of more isolated or heavily using teens. Preferences expressed in focus groups may not predict actual app engagement. No testing of a prototype."},{"rthcId":"RTHC-01930","title":"Synthetic cannabinoid-associated coagulopathy secondary to long-acting anticoagulant rodenticides: Observational case series and management recommendations.","authors":"Bahouth, Mona N; Kraus, Peggy; Dane, Kathryn; Plazas Montana, Manuela; Tsao, William; Tabaac, Burton; Jasem, Jagar; Schmidlin, Holly; Einstein, Evan; Streiff, Michael B; Shanbhag, Satish","year":2019,"journal":"Medicine, 98(36), e17015","doi":"10.1097/MD.0000000000017015","pmid":"31490385","tags":["synthetic-cannabinoids","harm-reduction","cardiovascular"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Hematuria was the most common bleeding symptom. 75% had INR >9.6 at presentation (normal is ~1.0). 92% of those tested were positive for brodifacoum. 75% achieved INR below 2 within 24 hours of treatment. One patient (6%) died. Median hospital stay was 4 days. Average pharmacological treatment cost was $5,300.","whyItMatters":"The brodifacoum contamination outbreak demonstrated that synthetic cannabinoid dangers extend beyond the drugs themselves to their unregulated manufacturing. This series provides a practical management algorithm for a toxicity pattern emergency physicians may encounter again.","specificNumbers":"16 patients. INR >9.6: 75%. Brodifacoum positive: 12/13 tested (92%). INR <2 within 24 hours: 75%. Death: 1/16 (6%). Median hospital stay: 4 days (IQR 3-6). Average treatment cost: $5,300 (range $2,241-$8,086).","methodology":"Observational case series of 16 patients with suspected exposure to LAAR-contaminated synthetic cannabinoids and associated bleeding, treated within the Johns Hopkins Health System. Management included IV/oral vitamin K, blood products, and laboratory monitoring.","limitations":"Single health system cohort. Long-term outcomes after discharge not reported. Brodifacoum has a very long half-life, so patients may need prolonged vitamin K treatment beyond the study period. Specific SC compounds not identified."},{"rthcId":"RTHC-01931","title":"Planning Capacity for Mental Health and Addiction Services in the Emergency Department: A Discrete-Event Simulation Approach.","authors":"Baia Medeiros, Deyvison T; Hahn-Goldberg, Shoshana; Aleman, Dionne M; O'Connor, Erin","year":2019,"journal":"Journal of healthcare engineering, 2019, 8973515","doi":"10.1155/2019/8973515","pmid":"31281618","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01932","title":"Dark Classics in Chemical Neuroscience: Δ9-Tetrahydrocannabinol.","authors":"Banister, Samuel D; Arnold, Jonathon C; Connor, Mark; Glass, Michelle; McGregor, Iain S","year":2019,"journal":"ACS chemical neuroscience, 10(5), 2160-2175","doi":"10.1021/acschemneuro.8b00651","pmid":"30689342","tags":["neuroscience","addiction","medical-cannabis","pain","psychosis","cognition"],"studyType":"review","evidenceStrength":"strong","keyFinding":"THC primarily acts as a partial agonist at CB1 receptors, producing its distinctive intoxication. It is approved for chronic pain, chemotherapy-induced nausea/vomiting, and MS spasticity, and is being investigated for anorexia nervosa, dementia agitation, and Tourette syndrome. Robust debates continue around its capacity to produce psychosis, cognitive impairment, and its addictive and gateway potential.","whyItMatters":"With an estimated 192 million cannabis users globally, understanding THC at the molecular, clinical, and societal level is essential. This review serves as a definitive reference point for the science and controversies surrounding the world's most widely used illicit psychoactive compound.","specificNumbers":"192 million estimated cannabis users globally. THC available as Marinol, Sativex, and Namisol. Approved indications: chronic pain, chemotherapy nausea/vomiting, MS spasticity. Under investigation: anorexia nervosa, dementia agitation, Tourette syndrome.","methodology":"Comprehensive narrative review covering THC chemistry, pharmacology, therapeutic uses, history, and societal context as part of the \"Dark Classics in Chemical Neuroscience\" series.","limitations":"As a narrative review, this does not provide systematic evidence synthesis or meta-analysis. The breadth of topics covered means individual areas receive less depth than dedicated reviews."},{"rthcId":"RTHC-01933","title":"Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy.","authors":"Bar-Lev Schleider, Lihi; Mechoulam, Raphael; Saban, Naama; Meiri, Gal; Novack, Victor","year":2019,"journal":"Scientific reports, 9(1), 200","doi":"10.1038/s41598-018-37570-y","pmid":"30655581","tags":["medical-cannabis","cbd","youth","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"After six months of treatment with cannabis oil (30% CBD, 1.5% THC), 82.4% of 188 ASD patients were still in active treatment. Of 93 patients assessed: 30.1% reported significant improvement, 53.7% moderate improvement, 6.4% slight improvement, and only 8.6% had no change. The most common side effect was restlessness (6.6%). No patients reported worsening.","whyItMatters":"This is one of the largest prospective studies of medical cannabis for autism, with 6-month follow-up data. The high continuation rate (82.4%) and broad improvement (83.8% of assessed patients) suggest the treatment is both tolerable and perceived as beneficial.","specificNumbers":"188 ASD patients. 82.4% (155) still in active treatment at 6 months. 93 patients assessed: significant improvement 30.1%, moderate 53.7%, slight 6.4%, no change 8.6%. Side effects in 25.2%: restlessness 6.6% most common. Cannabis oil: 30% CBD, 1.5% THC.","methodology":"Prospective observational study analyzing data collected as part of a treatment program for 188 ASD patients receiving medical cannabis between 2015-2017 in Israel. Treatment primarily used cannabis oil with 30% CBD and 1.5% THC. Outcomes assessed via structured questionnaires at 6 months.","limitations":"No control group or blinding. Caregiver-reported outcomes are subjective. The 17.6% who discontinued and the additional patients not assessed at 6 months may have had different outcomes. Selection bias: patients who seek cannabis treatment may be predisposed to report benefit."},{"rthcId":"RTHC-01934","title":"Endocannabinoid System and Alcohol Abuse Disorders.","authors":"Basavarajappa, Balapal S","year":2019,"journal":"Advances in experimental medicine and biology, 1162, 89-127","doi":"10.1007/978-3-030-21737-2_6","pmid":"31332736","tags":["addiction","neuroscience","dopamine","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Alcohol alters endocannabinoid levels and CB1 receptor expression in brain addiction circuits. CB1 receptors significantly contribute to the motivational and reinforcing properties of alcohol. The ECS also plays a role in fetal alcohol spectrum disorders (FASD), with both acute and chronic alcohol exposure producing relevant alterations in ECS function during development.","whyItMatters":"Understanding how alcohol hijacks the endocannabinoid system could lead to new treatments for alcohol addiction and prevention strategies for fetal alcohol disorders. CB1 receptor-targeted therapies represent a potential but largely unexplored approach to alcohol use disorders.","specificNumbers":"CB1 receptors are present in both inhibitory and excitatory neurons at presynaptic terminals. CB2 receptors are found in microglia, astrocytes, and neuronal subpopulations. Chronic alcohol consumption alters eCB transmitters and CB1R expression in addiction-related brain nuclei.","methodology":"Comprehensive literature review covering preclinical and clinical studies on the endocannabinoid system role in alcohol use disorders and fetal alcohol spectrum disorders.","limitations":"Much of the evidence comes from animal models. Translation of preclinical ECS findings to human alcohol use disorders remains limited. The complexity of ECS signaling makes it difficult to predict therapeutic outcomes from mechanistic studies alone."},{"rthcId":"RTHC-01935","title":"Distinct functions of endogenous cannabinoid system in alcohol abuse disorders.","authors":"Basavarajappa, Balapal S; Joshi, Vikram; Shivakumar, Madhu; Subbanna, Shivakumar","year":2019,"journal":"British journal of pharmacology, 176(17), 3085-3109","doi":"10.1111/bph.14780","pmid":"31265740","tags":["addiction","neuroscience","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The ECS plays a major role in the motivation to abuse alcohol, with chronic alcohol consumption modulating endocannabinoids and CB1 receptor expression in brain addiction circuits. Separately, the ECS has a distinct function in the development of fetal alcohol spectrum disorders, suggesting these are mechanistically separable processes.","whyItMatters":"By distinguishing the ECS roles in alcohol addiction versus fetal alcohol effects, this review clarifies that different therapeutic strategies may be needed for each condition rather than a one-size-fits-all approach to ECS manipulation.","specificNumbers":"CB1 receptors are present in inhibitory and excitatory presynaptic terminals. CB2 receptors found in neuronal subpopulations, microglia, and astrocytes at both pre- and postsynaptic terminals. Chronic alcohol modulates eCBs and CB1R expression in addiction circuits.","methodology":"Comprehensive review assessing recent literature on the function of the endocannabinoid system in alcohol abuse disorders, covering both adult addiction pathways and developmental effects.","limitations":"Primarily based on preclinical data. The distinction between \"distinct functions\" may be more nuanced than presented. Clinical applications of ECS-targeted therapies for alcohol disorders remain theoretical."},{"rthcId":"RTHC-01936","title":"The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review.","authors":"Batalla, Albert; Janssen, Hella; Gangadin, Shiral S; Bossong, Matthijs G","year":2019,"journal":"Journal of clinical medicine, 8(7)","doi":"10.3390/jcm8071058","pmid":"31330972","tags":["cbd","psychosis","addiction","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"CBD as monotherapy or adjunct to antipsychotics improved symptoms in schizophrenia patients, with particularly promising effects in early-stage illness. For substance use disorders, CBD+THC mixtures showed positive effects on short-term cannabis withdrawal and craving. Blood anandamide levels emerged as a potential biomarker for CBD treatment response in psychosis.","whyItMatters":"CBD is unique among cannabinoids in potentially treating both psychosis and addiction, two conditions that frequently co-occur and are notoriously difficult to manage together. Identifying who benefits most could make CBD treatment more targeted and effective.","specificNumbers":"CBD improved psychosis symptoms in clinical studies, with stronger effects in early illness stages. CBD+THC reduced short-term cannabis withdrawal and craving. Anandamide blood levels identified as potential biomarker. No studies found on comorbid schizophrenia and substance use.","methodology":"Systematic review of human clinical studies investigating CBD efficacy for schizophrenia, substance use disorders, and their comorbidity. Examined patient profiles most likely to benefit.","limitations":"Limited number of clinical studies available. Most psychosis studies were small. Substance use disorder evidence mainly comes from cannabis use disorder, not other substances. No studies addressed the comorbidity directly."},{"rthcId":"RTHC-01937","title":"Overview of \"home\" cultivation policies and the case for community-based cannabis supply.","authors":"Belackova, Vendula; Roubalova Stefunkova, Michaela; van de Ven, Katinka","year":2019,"journal":"The International journal on drug policy, 71, 36-46","doi":"10.1016/j.drugpo.2019.05.021","pmid":"31200326","tags":["legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"At least 27 jurisdictions have adopted non-prohibitive approaches to home cannabis cultivation, ranging from full legalization to de facto depenalization. Key policy limitations include possession thresholds for harvested product, rules about sharing, and disproportionate sanctions for violations. The authors argue home cultivation policies could be expanded into community-level supply models.","whyItMatters":"Home cultivation is often overlooked in cannabis policy debates that focus on commercial markets. But it represents an alternative supply model that could engage existing cannabis communities, reduce black market reliance, and give users more control over product quality.","specificNumbers":"27+ jurisdictions with non-prohibitive home cultivation. 12 jurisdictions fully legalized (including 3 US states with home-grow only). 8 jurisdictions decriminalized. Others depenalized through law or court rulings. Countries span from Uruguay to South Africa to Canada.","methodology":"Policy review of laws and regulations pertaining to home cannabis cultivation in states and countries that have legalized, decriminalized, or applied other non-prohibitive approaches.","limitations":"Policy review without empirical data on outcomes. The feasibility of community supply models is theoretical. Regulatory details change rapidly. Some jurisdictions listed may have since changed their policies."},{"rthcId":"RTHC-01938","title":"Quantitative biochemical screening for marijuana use and concordance with tobacco use in urban adolescents.","authors":"Benowitz, Neal; Nardone, Natalie; St Helen, Gideon; Addo, Newton; Jacob, Peyton; Liakoni, Evangelia; Jain, Shonul; Hooshfar, Shirin; Lynch, Kara","year":2019,"journal":"Drug and alcohol dependence, 205, 107583","doi":"10.1016/j.drugalcdep.2019.107583","pmid":"31600618","tags":["youth","addiction","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The standard immunoassay substantially underestimated THC exposure compared to high-sensitivity chromatographic testing. THC was detected in 25% of 686 adolescents. Prevalence increased with age and was higher among non-Hispanic Black participants. Active tobacco smokers had 80% prevalence of THC use (OR 13.2). Urine cotinine and THC metabolite levels were significantly correlated (r=0.60).","whyItMatters":"If standard drug tests underestimate adolescent marijuana use, prevalence data and clinical screening may be systematically inaccurate. The strong tobacco-marijuana concordance suggests screening for one substance should trigger screening for the other.","specificNumbers":"686 adolescents. THC detected in 25%. Cigarette smokers: 80% THC prevalence, OR 13.2 for predicting THC use. Cotinine-THC correlation: r=0.60. Standard immunoassay had high specificity but only moderate sensitivity.","methodology":"Cross-sectional study of 686 adolescents aged 12-21 seen at Zuckerberg San Francisco General Hospital (2012-2014). Urine tested using both standard immunoassay and high-sensitivity liquid chromatographic assays for nicotine and THC metabolites.","limitations":"Single urban hospital setting may not represent all adolescent populations. Cross-sectional design cannot determine directionality of the tobacco-marijuana relationship. Urine testing captures recent use but not patterns over time."},{"rthcId":"RTHC-01939","title":"Experimental Cannabinoid 2 Receptor Activation by Phyto-Derived and Synthetic Cannabinoid Ligands in LPS-Induced Interstitial Cystitis in Mice.","authors":"Berger, Geraint; Arora, Nipun; Burkovskiy, Ian; Xia, Yanfang; Chinnadurai, Anu; Westhofen, Robert; Hagn, Georg; Cox, Ashley; Kelly, Melanie; Zhou, Juan; Lehmann, Christian","year":2019,"journal":"Molecules (Basel, Switzerland), 24(23)","doi":"10.3390/molecules24234239","pmid":"31766439","tags":["cbd","pain","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both beta-caryophyllene (BCP) and the synthetic CB2 agonist HU308 significantly reduced leukocyte adhesion in bladder venules and improved capillary perfusion when instilled directly into the bladder. BCP was comparable to HU308 and superior to DMSO (the FDA-approved treatment). Oral BCP also reduced inflammation and mechanical pain.","whyItMatters":"Interstitial cystitis has limited treatment options and current therapies are often inadequate. BCP is a natural compound with GRAS (Generally Regarded as Safe) status found in common foods, making it a particularly accessible potential treatment candidate.","specificNumbers":"BCP significantly reduced leukocyte adhesion in bladder venules. BCP improved capillary perfusion. Effects comparable to synthetic CB2 agonist HU308. Superior to DMSO (FDA-approved treatment). Oral BCP also effective for inflammation and pain.","methodology":"Animal study using LPS-induced interstitial cystitis in mice. Intravital microscopy measured bladder inflammation. Behavioral testing assessed pain. Compared BCP, synthetic CB2 agonist HU308, and DMSO (standard treatment).","limitations":"Mouse model using LPS-induced cystitis may not fully represent the complex human condition. Single study without dose-response optimization. Translation from intravital microscopy endpoints to clinical outcomes is uncertain."},{"rthcId":"RTHC-01940","title":"Engaging Parents to Prevent Adolescent Substance Use: A Randomized Controlled Trial.","authors":"Bergman, Peter; Dudovitz, Rebecca N; Dosanjh, Kulwant K; Wong, Mitchell D","year":2019,"journal":"American journal of public health, 109(10), 1455-1461","doi":"10.2105/AJPH.2019.305240","pmid":"31415193","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"By the end of 8th grade, lifetime use of alcohol or marijuana was 18.2% in the control group versus 10.2% in the intervention group (p=.02). The intervention consisted only of sending parents weekly text messages, phone calls, or emails about missed assignments, grades, and behavior. Parenting self-efficacy and student grades were similar between groups.","whyItMatters":"This is a remarkably simple and cheap intervention that achieved meaningful substance use reduction without directly targeting substance use at all. By keeping parents informed about school performance, the intervention apparently enhanced natural parental monitoring.","specificNumbers":"318 students enrolled. Lifetime alcohol/marijuana use: 10.2% intervention vs 18.2% control (p=.02). 81% Latino. 50% household income <$15,000. Cost: $15/student/year, automatable to near-zero marginal cost.","methodology":"Randomized controlled trial in Los Angeles enrolling 318 7th graders and their parents in 2014, with follow-up through 2016. Half had household income under $15,000; 81% were Latino. Intervention: weekly parent communications about academic performance and behavior.","limitations":"Self-reported substance use may be underestimated. Predominantly Latino, low-income sample may not generalize. The mechanism is unclear since parenting self-efficacy and grades did not differ. Relatively short follow-up (grades 7-8)."},{"rthcId":"RTHC-01941","title":"Recent trends in cyclic vomiting syndrome-associated hospitalisations with liberalisation of cannabis use in the state of Colorado.","authors":"Bhandari, Sanjay; Jha, Pinky; Lisdahl, Krista M; Hillard, Cecilia J; Venkatesan, Thangam","year":2019,"journal":"Internal medicine journal, 49(5), 649-655","doi":"10.1111/imj.14164","pmid":"30426628","tags":["appetite","legalization","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"CVS hospitalizations increased 46% from 806 (2010) to 1,180 (2014). Cannabis use prevalence in CVS patients (13-17%) was dramatically higher than in non-CVS hospitalizations (1.7%). Cannabis use increased in both groups following recreational legalization in 2012.","whyItMatters":"This provides population-level evidence linking cannabis legalization to increased cyclic vomiting hospitalizations, a relationship with significant healthcare cost implications as more states legalize.","specificNumbers":"CVS hospitalizations up 46%: 806 (2010) to 1,180 (2014). Cannabis use in CVS: 13% (primary diagnosis) to 17% (all-listed). Non-CVS cannabis use: 1.7%. Cannabis use increased dramatically in both groups after 2012 legalization.","methodology":"Retrospective analysis of the Colorado State Inpatient Database covering all hospital admissions from 2010-2014. Five-year trends in CVS hospitalizations and cannabis use analyzed. Multivariate logistic regression for predictors of cannabis use in CVS.","limitations":"Observational study cannot prove causation between legalization and CVS increases. ICD coding for CVS may have changed over time (increased awareness = more diagnoses). Cannot distinguish cannabinoid hyperemesis from other CVS causes in administrative data."},{"rthcId":"RTHC-01942","title":"Pharmacological and Behavioral Effects of the Synthetic Cannabinoid AKB48 in Rats.","authors":"Bilel, Sabrine; Tirri, Micaela; Arfè, Raffaella; Stopponi, Serena; Soverchia, Laura; Ciccocioppo, Roberto; Frisoni, Paolo; Strano-Rossi, Sabina; Miliano, Cristina; De-Giorgio, Fabio; Serpelloni, Giovanni; Fantinati, Anna; De Luca, Maria Antonietta; Neri, Margherita; Marti, Matteo","year":2019,"journal":"Frontiers in neuroscience, 13, 1163","doi":"10.3389/fnins.2019.01163","pmid":"31736697","tags":["synthetic-cannabinoids","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AKB48 at low doses (0.25 mg/kg) preferentially stimulated dopamine release in the nucleus accumbens shell (reward center) and impaired visual reflexes at 0.3 mg/kg. Higher doses caused hypolocomotion, hypothermia, analgesia, catalepsy, and cardiorespiratory changes (bradycardia, mild bradypnea, SpO2 reduction). All effects were blocked by the CB1 antagonist AM251. Plasma AKB48 levels correlated linearly with dose and behavioral effects.","whyItMatters":"This is the first systematic study of AKB48 in vivo, providing a dose-response profile that explains both why users seek these drugs (low-dose dopamine stimulation) and what makes them dangerous (steep dose-response curve to dangerous effects).","specificNumbers":"Low dose (0.25 mg/kg): increased dopamine in nucleus accumbens shell. 0.3 mg/kg: impaired visual reflexes. 0.5 mg/kg: impaired place preference, hypolocomotion. 3 mg/kg: hypothermia, analgesia, catalepsy, bradycardia, SpO2 reduction. All effects CB1-mediated.","methodology":"Comprehensive pharmacological characterization in male rats: microdialysis for dopamine measurement, behavioral testing (locomotion, sensorimotor reflexes, startle/PPI, conditioned place preference), and simultaneous plasma pharmacokinetics at multiple doses.","limitations":"Rat pharmacology may not directly translate to humans. Only male rats tested. AKB48 formulations available to users may differ from the pure compound tested. Street products often contain unknown mixtures of synthetic cannabinoids."},{"rthcId":"RTHC-01943","title":"Cannabinoid therapy in epilepsy.","authors":"Billakota, Santoshi; Devinsky, Orrin; Marsh, Eric","year":2019,"journal":"Current opinion in neurology, 32(2), 220-226","doi":"10.1097/WCO.0000000000000660","pmid":"30676535","tags":["cbd","epilepsy","medical-cannabis","youth"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Epidiolex (>99% CBD, <0.10% THC) received FDA approval for Dravet and Lennox-Gastaut syndromes and EMA approval for Lennox-Gastaut syndrome, based on Phase III RCTs and open-label trials demonstrating efficacy and safety. CBD mechanism of action remains unknown and does not appear to work through cannabinoid receptors.","whyItMatters":"Epidiolex approval represents a watershed moment: the first time a cannabis-derived compound passed the full regulatory approval process. It validates the therapeutic potential of cannabinoids while setting a standard for evidence-based cannabis medicine.","specificNumbers":"Epidiolex: >99% CBD, <0.10% THC. FDA approved for Dravet and Lennox-Gastaut syndromes. EMA approved for Lennox-Gastaut syndrome. Based on Phase III RCTs and open-label trial data.","methodology":"Review of the history, pharmacology, and clinical trial data supporting CBD approval for epilepsy, including Phase III RCTs and prospective open-label trials.","limitations":"Approval is limited to two rare epilepsy syndromes. CBD mechanism of action is still unknown. The review does not address effectiveness of non-pharmaceutical cannabis products for epilepsy. Long-term safety data is still accumulating."},{"rthcId":"RTHC-01944","title":"Gene-environment interaction between an endocannabinoid system genetic polymorphism and cannabis use in first episode of psychosis.","authors":"Bioque, Miquel; Mas, Sergi; Costanzo, Maria Cristina; Cabrera, Bibiana; Lobo, Antonio; González-Pinto, Ana; Rodriguez-Toscano, Elisa; Corripio, Iluminada; Vieta, Eduard; Baeza, Immaculada; Ibáñez, Ángela; Fraile, Miguel Gutiérrez; Cuesta, Manuel J; Mezquida, Gisela; Lafuente, Amalia; Bernardo, Miguel","year":2019,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29(6), 786-794","doi":"10.1016/j.euroneuro.2019.04.005","pmid":"31076188","tags":["psychosis","genetics","youth"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"The FAAH rs2295633 genetic polymorphism interacted with cannabis use to dramatically increase psychosis risk. Cannabis users homozygous for the T allele had OR 10.69 for first-episode psychosis compared to cannabis users without this genotype. The effect was absent in non-cannabis users, confirming a true gene-environment interaction. TT carriers with cannabis use were also more likely to need high-potency antipsychotics.","whyItMatters":"This identifies a specific genetic vulnerability that could explain why some cannabis users develop psychosis while most do not. If replicated, it could enable genetic screening to identify individuals at highest risk from cannabis use.","specificNumbers":"321 FEP patients, 241 healthy controls. FAAH rs2295633 TT genotype + cannabis use: OR 10.69 for FEP. 15 ECS-related SNPs tested. TT carriers with cannabis use more often required high-potency antipsychotics.","methodology":"Case-control study of 321 first-episode psychosis patients and 241 matched healthy controls in Spain. Examined gene-environment interactions between 15 endocannabinoid system SNPs and cannabis use history.","limitations":"This is a single study requiring replication in independent samples. The specific FAAH variant has not been widely studied. The mechanism linking this polymorphism to psychosis risk is not established. Self-reported cannabis use history may be inaccurate."},{"rthcId":"RTHC-01945","title":"Factor structure of the Cannabis Experiences Questionnaire in a first-episode psychosis sample.","authors":"Birnbaum, Michael L; Cleary, Sean D; Ramsay Wan, Claire; Pauselli, Luca; Compton, Michael T","year":2019,"journal":"Early intervention in psychiatry, 13(3), 495-501","doi":"10.1111/eip.12509","pmid":"29052952","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01946","title":"Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis.","authors":"Black, Nicola; Stockings, Emily; Campbell, Gabrielle; Tran, Lucy T; Zagic, Dino; Hall, Wayne D; Farrell, Michael; Degenhardt, Louisa","year":2019,"journal":"The lancet. Psychiatry, 6(12), 995-1010","doi":"10.1016/S2215-0366(19)30401-8","pmid":"31672337","tags":["medical-cannabis","cbd","mental-health","depression","anxiety","ptsd","psychosis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Pharmaceutical THC (with or without CBD) produced only a very small improvement in anxiety among patients with other medical conditions (SMD -0.25). THC worsened negative symptoms of psychosis. THC did not significantly improve any other mental health outcome. THC nearly doubled adverse events (OR 1.99) and nearly tripled withdrawals due to adverse events (OR 2.78). Very few RCTs examined CBD or medicinal cannabis specifically.","whyItMatters":"This is the most comprehensive meta-analysis of cannabinoids for mental disorders published in a top-tier psychiatric journal. Its sobering conclusions challenge the widespread assumption that cannabis-based medicines are broadly effective for mental health conditions.","specificNumbers":"83 studies total (40 RCTs, n=3,067). Anxiety improvement: SMD -0.25 (very low quality). Psychosis negative symptoms worsened: SMD 0.36. Adverse events: OR 1.99. Withdrawals from adverse events: OR 2.78. Depression: 42 studies (23 RCTs, n=2,551). Anxiety: 31 studies (17 RCTs, n=605).","methodology":"Systematic review and meta-analysis searching MEDLINE, Embase, PsycINFO, and Cochrane databases (1980-2018). Included RCTs and observational studies of any medicinal cannabinoid in adults for depression, anxiety, ADHD, Tourette syndrome, PTSD, or psychosis. GRADE quality assessment applied.","limitations":"Most included RCTs examined THC-based pharmaceuticals, not CBD or whole-plant cannabis. Many conditions had very few RCTs (Tourette: 2 RCTs n=36; PTSD: 1 RCT n=10; ADHD: 1 RCT n=30). The evidence was rated very low to low quality by GRADE criteria."},{"rthcId":"RTHC-01947","title":"Threat Responsiveness as a Function of Cannabis and Alcohol Use Disorder Severity.","authors":"Blair, Robert James R; White, Stuart F; Tyler, Patrick M; Johnson, Kimberly; Lukoff, Jennie; Thornton, Laura C; Leiker, Emily K; Filbey, Francesca; Dobbertin, Matt; Blair, Karina S","year":2019,"journal":"Journal of child and adolescent psychopharmacology, 29(7), 526-534","doi":"10.1089/cap.2019.0004","pmid":"31170004","tags":["youth","addiction","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Increasing CUD symptomatology was associated with decreased responding to looming threat stimuli in regions including rostral frontal cortex, fusiform gyrus, and amygdala. This pattern was specific to cannabis use disorder; alcohol use disorder severity showed no relationship with threat responsiveness.","whyItMatters":"Dulled threat responsiveness could have real-world consequences for adolescent safety and decision-making. The finding that this effect is specific to cannabis and not alcohol suggests a unique neurotoxic impact of cannabis on the developing threat processing system.","specificNumbers":"87 adolescents scanned. 45 above clinical cutoffs for CUD or AUD. Decreased activation in amygdala, rostral frontal cortex, and fusiform gyrus with increasing CUD severity. No relationship with AUD severity.","methodology":"fMRI study of 87 adolescents (43 male) with varying CUD/AUD severity (45 above clinical cutoffs). Scanned during a looming threat task with threatening and neutral faces/animals that appeared to approach or recede.","limitations":"Cross-sectional design cannot determine whether CUD caused the brain changes or whether pre-existing differences predispose to CUD. Relatively small sample. CUD and AUD severity were correlated, though the study controlled for this. Cannabis is not the only factor affecting these brain regions in adolescence."},{"rthcId":"RTHC-01948","title":"Regular cannabis use is associated with altered activation of central executive and default mode networks even after prolonged abstinence in adolescent users: Results from a complementary meta-analysis.","authors":"Blest-Hopley, Grace; Giampietro, Vincent; Bhattacharyya, Sagnik","year":2019,"journal":"Neuroscience and biobehavioral reviews, 96, 45-55","doi":"10.1016/j.neubiorev.2018.10.026","pmid":"30395923","tags":["cognition","youth","neuroscience"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Adolescent cannabis users abstinent for over 25 days showed significantly greater activation in central executive and default mode network components compared to non-using controls. This finding is notable because evidence suggests cognitive performance deficits typically resolve within this timeframe, meaning brain function changes persist even after behavioral recovery.","whyItMatters":"The dissociation between recovered cognitive performance and persistent brain function changes is clinically important. It suggests the adolescent brain compensates for cannabis-related changes by recruiting additional neural resources, which may have long-term consequences.","specificNumbers":"20 studies included. 12 studied current users (361 vs 394 controls). 3 studied abstinent users (98 vs 106 controls). Abstinence threshold: >25 days (600 hours). Persistent alterations found in central executive and default mode networks.","methodology":"Meta-analysis of 20 fMRI studies: 12 examining current cannabis users (361 users vs 394 controls) and 3 examining abstinent cannabis users in 5 comparisons (98 abstinent users vs 106 controls).","limitations":"The studies of abstinent users were conducted in overlapping samples, limiting the independence of findings. Only 3 studies examined abstinent users. The meta-analysis could not control for pre-existing differences. The specific brain regions affected varied across studies."},{"rthcId":"RTHC-01949","title":"Cerebellar alterations in cannabis users: A systematic review.","authors":"Blithikioti, Chrysanthi; Miquel, Laia; Batalla, Albert; Rubio, Belen; Maffei, Giovanni; Herreros, Ivan; Gual, Antoni; Verschure, Paul; Balcells-Oliveró, Mercedes","year":2019,"journal":"Addiction biology, 24(6), 1121-1137","doi":"10.1111/adb.12714","pmid":"30811097","tags":["cognition","neuroscience","addiction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The three most consistent findings across 40 studies were: (1) increased cerebellar gray matter volume after chronic use, (2) altered cerebellar resting state activity after acute or chronic use, and (3) deficits in memory, decision-making, and associative learning (cerebellar-dependent tasks). Earlier age of onset and greater exposure were associated with more alterations.","whyItMatters":"The cerebellum is increasingly recognized as important for cognition, emotion, and learning, not just motor coordination. Its high density of CB1 receptors makes it a prime target for cannabis effects, yet it has been understudied compared to cortical regions.","specificNumbers":"40 studies included from 348 screened. High CB1 receptor density in cerebellum. 3 main findings: increased gray matter volume, altered resting activity, deficits in memory/decision-making/learning. Earlier onset and higher exposure = more alterations.","methodology":"Systematic review searching three databases for studies on cannabis effects on cerebellar structure, function, and cerebellar-dependent behavioral tasks. 348 records screened, 40 included in qualitative synthesis.","limitations":"Included studies had variable methods for assessing cannabis use. Tobacco was a confounding factor in many studies. The review could not determine causality. Increased cerebellar volume could be compensatory rather than pathological."},{"rthcId":"RTHC-01950","title":"Cannabinoid toxicity in pediatrics.","authors":"Blohm, Eike; Sell, Peter; Neavyn, Mark","year":2019,"journal":"Current opinion in pediatrics, 31(2), 256-261","doi":"10.1097/MOP.0000000000000739","pmid":"30694824","tags":["youth","harm-reduction","potency"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Young children hospitalized for cannabis toxicity are increasingly exposed to high-concentration products (edibles, resins, vaping fluid) containing extremely high cannabinoid levels, leading to sedation, respiratory depression, and other adverse effects. Chronic adolescent use is associated with neurocognitive changes and cannabinoid hyperemesis syndrome.","whyItMatters":"Legalization has made high-potency cannabis products more accessible in households with children. The mismatch between these products (designed for adult tolerance) and pediatric vulnerability creates a growing emergency medicine challenge.","specificNumbers":"Products involved include edibles, resins, and vaping fluid with extremely high cannabinoid concentrations. Acute toxicity in young children: sedation, respiratory depression. Chronic adolescent toxicity: neurocognitive changes, cannabinoid hyperemesis.","methodology":"Review of recent literature on THC pharmacokinetics, pharmacodynamics, developmental impacts, and presentations of acute and chronic cannabinoid toxicity in pediatric patients.","limitations":"Review-level evidence without pooled quantitative data. The specific incidence of pediatric exposures varies by state and over time. Not all product types are equally well-studied for pediatric effects."},{"rthcId":"RTHC-01951","title":"The neuropsychopharmacology of cannabis: A review of human imaging studies.","authors":"Bloomfield, Michael A P; Hindocha, Chandni; Green, Sebastian F; Wall, Matthew B; Lees, Rachel; Petrilli, Katherine; Costello, Harry; Ogunbiyi, M Olabisi; Bossong, Matthijs G; Freeman, Tom P","year":2019,"journal":"Pharmacology & therapeutics, 195, 132-161","doi":"10.1016/j.pharmthera.2018.10.006","pmid":"30347211","tags":["neuroscience","cognition","dopamine","psychosis","addiction","youth"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Cannabis and THC acutely affect executive, emotional, reward, and memory processing through direct CB1 effects and indirect effects on glutamate, GABA, and dopamine systems. CBD may partially offset some acute effects. Heavy chronic use, especially during adolescence, is associated with persistent alterations that increase risk for addiction and psychosis.","whyItMatters":"This is the most comprehensive neuroimaging review of cannabis effects available, synthesizing evidence across multiple brain systems and imaging modalities to create a unified picture of how cannabis affects the human brain.","specificNumbers":"THC acts as partial agonist at CB1 receptors. Indirect effects on glutamate, GABA, and dopamine systems. CBD found in some cannabis forms may offset certain acute effects. Adolescent exposure carries higher risk for lasting changes.","methodology":"Comprehensive state-of-the-art review synthesizing all available human neuroimaging research on acute and chronic cannabis effects, including PET, SPECT, and fMRI studies.","limitations":"Imaging studies have variable methods, sample sizes, and definitions of cannabis use. Most studies are cross-sectional, limiting causal conclusions. Many confounds (tobacco, alcohol, mental health) are difficult to control. Publication bias may affect the literature."},{"rthcId":"RTHC-01952","title":"Qualitative Analysis of Cannabis Use Among Older Adults in Colorado.","authors":"Bobitt, Julie; Qualls, Sara H; Schuchman, Melissa; Wickersham, Robert; Lum, Hillary D; Arora, Kanika; Milavetz, Gary; Kaskie, Brian","year":2019,"journal":"Drugs & aging, 36(7), 655-666","doi":"10.1007/s40266-019-00665-w","pmid":"30924098","tags":["seniors","medical-cannabis","pain","legalization"],"studyType":"qualitative","evidenceStrength":"moderate","keyFinding":"Five themes emerged from 17 focus groups: (1) older adults want more education and research about cannabis, (2) healthcare providers are not communicating about cannabis, (3) accessing medical cannabis is difficult, (4) medical cannabis users report positive outcomes, and (5) stigma continues to prevent open discussion. Both users and non-users participated.","whyItMatters":"Older adults are the fastest-growing cannabis user demographic, yet they face unique barriers including provider reluctance, stigma, and a healthcare system largely unprepared to guide their use. This study gives voice to their actual experiences and needs.","specificNumbers":"136 participants over age 60. 17 focus groups in 15 cities. 5 main themes identified from 16 codes. Both users and non-users of cannabis participated. Conducted in Colorado, where recreational cannabis has been legal since 2012.","methodology":"Qualitative study with 17 focus groups in 15 Colorado cities (June-November 2017). 136 participants over age 60 recruited from senior centers, health clinics, and dispensaries. Thematic analysis with NVivo software.","limitations":"Colorado residents in a legal state may not represent seniors in non-legal states. Focus group participants are self-selected. Qualitative findings cannot be quantified for prevalence. The stigma theme may suppress some viewpoints even in focus groups."},{"rthcId":"RTHC-01953","title":"Pills to Pot: Observational Analyses of Cannabis Substitution Among Medical Cannabis Users With Chronic Pain.","authors":"Boehnke, Kevin F; Scott, J Ryan; Litinas, Evangelos; Sisley, Suzanne; Williams, David A; Clauw, Daniel J","year":2019,"journal":"The journal of pain, 20(7), 830-841","doi":"10.1016/j.jpain.2019.01.010","pmid":"30690169","tags":["pain","medical-cannabis","harm-reduction","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"80% of 1,321 medical cannabis users with chronic pain reported substituting cannabis for traditional pain medications: 53% for opioids, 22% for benzodiazepines. Reasons cited were fewer side effects and better symptom management. Experienced users (1+ years) were more likely to take no concomitant pain medications (43% vs 30%) and report improved health (74% vs 67%).","whyItMatters":"Chronic pain is the most common reason for medical cannabis licenses. If cannabis consistently enables patients to reduce opioid and benzodiazepine use, it has direct implications for the opioid crisis and benzodiazepine dependency epidemic.","specificNumbers":"1,321 participants. 80% substituted cannabis for pain meds. 53% for opioids, 22% for benzodiazepines. Medical-only users: older (52 vs 47), less likely to drink (66% vs 79%), more likely to currently take opioids (21% vs 11%). Experienced users: no concomitant meds 43% vs 30%; improved health 74% vs 67%.","methodology":"Ongoing nationwide online survey of medical cannabis users with chronic pain. 1,321 participants (59% female, 54% aged 50+). Examined effects of cannabis on pain management, health, and medication use, stratified by recreational co-use and duration of cannabis experience.","limitations":"Self-reported data from medical cannabis users, biased toward those who found cannabis helpful. No clinical verification of medication changes. Cross-sectional design. No pain severity or functional outcome measures. Cannot determine whether substitution is medically appropriate."},{"rthcId":"RTHC-01954","title":"Cannabis Use Preferences and Decision-making Among a Cross-sectional Cohort of Medical Cannabis Patients with Chronic Pain.","authors":"Boehnke, Kevin F; Scott, J Ryan; Litinas, Evangelos; Sisley, Suzanne; Clauw, Daniel J; Goesling, Jenna; Williams, David A","year":2019,"journal":"The journal of pain, 20(11), 1362-1372","doi":"10.1016/j.jpain.2019.05.009","pmid":"31132510","tags":["pain","medical-cannabis","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"76.5% used cannabis daily, 93.4% used 2+ administration routes, and 72.5% used 3+ routes. Women, medical-only users, and novices were less likely to smoke or vaporize and preferred edibles, tinctures, and topicals with low THC:high CBD ratios. Only 2.6% selected products with medical professional input, while 54.9% relied on dispensary employee advice.","whyItMatters":"The wide variability in how chronic pain patients use cannabis makes standardized clinical guidance nearly impossible. The finding that only 2.6% get medical input in product selection highlights a massive gap in clinical engagement.","specificNumbers":"1,321 participants, 59% female. Daily use: 76.5%. 3+ routes: 72.5%. Medical professional input: 2.6%. Dispensary advice: 54.9%. Women preferred low THC:high CBD. Medical-only users preferred edibles, tinctures, topicals over smoking.","methodology":"Cross-sectional online survey of 1,321 medical cannabis users with chronic pain (59% female). Examined cannabinoid preferences, administration routes, and product selection, stratified by sex, use intentions (medical-only vs medical+recreational), and experience level.","limitations":"Self-selected online sample biased toward engaged cannabis users. No clinical outcomes linked to preferences. Product availability varies by state. Dispensary employee advice quality is unregulated and unstandardized."},{"rthcId":"RTHC-01955","title":"The neuropsychological profiles of young psychosis patients with and without current cannabis use.","authors":"Bogaty, Sophia E R; Crouse, Jacob J; Hickie, Ian B; Hermens, Daniel F","year":2019,"journal":"Cognitive neuropsychiatry, 24(1), 40-53","doi":"10.1080/13546805.2018.1562887","pmid":"30621505","tags":["psychosis","cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Healthy controls outperformed both patient groups across most cognitive measures, but no significant differences were found between cannabis-using (n=24) and cannabis-abstinent (n=79) psychosis patients on any cognitive measure, including premorbid intelligence, processing speed, flexibility, memory, attention, and visuospatial function.","whyItMatters":"Some research suggests former cannabis users with psychosis have better cognition than never-users, implying cannabis may precipitate psychosis in otherwise higher-functioning individuals. This study, conducted at illness onset rather than later, found no such difference.","specificNumbers":"24 cannabis-using and 79 cannabis-naive psychosis patients, aged 16-25. Both groups impaired vs healthy controls. No significant differences between groups on premorbid IQ, psychomotor speed, mental flexibility, verbal learning/memory, verbal fluency, sustained attention, or visuospatial learning.","methodology":"Cross-sectional comparison of 24 cannabis-using and 79 cannabis-naive psychosis patients aged 16-25, plus healthy controls. Comprehensive neurocognitive battery administered at or near illness onset.","limitations":"Small cannabis-using group (n=24). Cross-sectional design at a single timepoint. Cannabis use was current, not historical, so acute effects may mask underlying differences. Cannot determine whether cannabis caused or merely preceded psychosis."},{"rthcId":"RTHC-01956","title":"Cannabidiol (CBD) use in psychiatric disorders: A systematic review.","authors":"Bonaccorso, Stefania; Ricciardi, Angelo; Zangani, Caroline; Chiappini, Stefania; Schifano, Fabrizio","year":2019,"journal":"Neurotoxicology, 74, 282-298","doi":"10.1016/j.neuro.2019.08.002","pmid":"31412258","tags":["cbd","psychosis","anxiety","addiction","mental-health"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"From 1,301 screened papers, 27 met inclusion criteria (RCTs of CBD for psychiatric disorders). Limited evidence suggested potential therapeutic effects for substance use disorders, chronic psychosis, and anxiety. Evidence was insufficient for depression, PTSD, sleep, cognitive impairment, eating disorders, and other conditions.","whyItMatters":"With CBD products increasingly marketed for mental health conditions, this systematic review provides a reality check: while some conditions show promise, the clinical trial base is tiny relative to the scale of CBD use for psychiatric symptoms.","specificNumbers":"1,301 papers identified. 190 after abstract screening. 27 met inclusion criteria. Most promising: substance use disorders, chronic psychosis, anxiety. Insufficient evidence for depression, PTSD, sleep, cognition, eating disorders.","methodology":"Systematic review following PRISMA guidelines, searching for RCTs of CBD for psychiatric conditions including substance use, psychosis, anxiety, mood, cognitive, sleep, personality, eating, OCD, PTSD, and somatic disorders.","limitations":"Very few RCTs available. Heterogeneous CBD formulations and doses across studies. Most studies had small sample sizes. The systematic review could only assess what has been studied, leaving many conditions essentially unexamined."},{"rthcId":"RTHC-01957","title":"Terpenes in Cannabis sativa - From plant genome to humans.","authors":"Booth, Judith K; Bohlmann, Jörg","year":2019,"journal":"Plant science : an international journal of experimental plant biology, 284, 67-72","doi":"10.1016/j.plantsci.2019.03.022","pmid":"31084880","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01958","title":"Acute effects of ∆9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype.","authors":"Bossong, Matthijs G; van Hell, Hendrika H; Schubart, Chris D; van Saane, Wesley; Iseger, Tabitha A; Jager, Gerry; van Osch, Matthias J P; Jansma, J Martijn; Kahn, René S; Boks, Marco P; Ramsey, Nick F","year":2019,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29(6), 766-776","doi":"10.1016/j.euroneuro.2019.03.010","pmid":"30975584","tags":["neuroscience","cognition","genetics","dopamine"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"THC increased perfusion in bilateral insula, medial superior frontal cortex, and left orbital frontal gyrus. The orbital frontal area showed decreased connectivity with the precuneus. THC effects on left insula perfusion correlated with subjective changes in perception and relaxation. COMT genotype significantly modulated THC effects, with Val/Met heterozygotes showing increased executive network perfusion after THC while other genotypes did not.","whyItMatters":"This study identifies a specific gene (COMT) that influences individual vulnerability to acute THC effects, providing a biological basis for why cannabis affects people differently. The COMT gene is already known to influence prefrontal dopamine levels.","specificNumbers":"39 healthy volunteers. THC increased perfusion in bilateral insula, medial superior frontal cortex, left middle orbital frontal gyrus. Left insula perfusion correlated with subjective perception/relaxation changes. COMT Val/Met heterozygotes showed unique executive network response.","methodology":"Pharmacological MRI study with 39 healthy volunteers. Used Arterial Spin Labelling for perfusion and fMRI for resting state connectivity. Examined THC effects and their modulation by COMT Val158Met genotype.","limitations":"Sample size of 39 limits genetic subgroup analysis power. Single acute THC dose may not represent chronic use patterns. Only one genetic variant examined. Healthy volunteers may not represent clinical populations."},{"rthcId":"RTHC-01959","title":"Suicide ideation, planning, and attempts: the case of the Latinx LGB youth.","authors":"Boyas, Javier F; Villarreal-Otálora, Tatiana; Alvarez-Hernandez, Luis R; Fatehi, Mariam","year":2019,"journal":"Health promotion perspectives, 9(3), 198-206","doi":"10.15171/hpp.2019.28","pmid":"31508340","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was a significant independent predictor of suicidal ideation (OR 1.76), suicide planning (OR 2.46), and suicide attempts (OR 3.12) among Latinx LGB adolescents, even after controlling for bullying, sexual assault, and depression. The association strengthened across the suicidality continuum from ideation to attempt.","whyItMatters":"Latinx LGB youth face intersecting risk factors for suicidality. Cannabis use emerged as one of the strongest independent predictors, particularly for suicide attempts, suggesting it should be considered in suicide risk assessment for this population.","specificNumbers":"451 Latinx LGB youth. Suicidal ideation: 40%. Planning: 34%. Attempts: 21%. Cannabis use ORs: ideation 1.76, planning 2.46, attempts 3.12. Other predictors: bullying, sexual assault, depression.","methodology":"Cross-sectional analysis of 451 self-identified Latinx LGB participants from the 2017 National Youth Risk Behavioral Survey. Backward elimination logistic regression examined predictors at each level of suicidality.","limitations":"Cross-sectional design cannot establish causation. Self-reported data. Cannabis use frequency and amount not specified. Other substance use not fully controlled. The sample came from a school-based survey, excluding youth not in school."},{"rthcId":"RTHC-01960","title":"Altered motor development following late gestational alcohol and cannabinoid exposure in rats.","authors":"Breit, Kristen R; Zamudio, Brandonn; Thomas, Jennifer D","year":2019,"journal":"Neurotoxicology and teratology, 73, 31-41","doi":"10.1016/j.ntt.2019.03.005","pmid":"30943441","tags":["pregnancy","youth","cognition","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabinoid exposure (CP-55,940) during the brain growth spurt accelerated early motor development while alcohol delayed it. Combined exposure partially neutralized each other on some measures. However, cannabinoid exposure exacerbated alcohol-related impairment in motor coordination specifically in female rats. Both substances reduced body growth, with combined exposure worsening the effect.","whyItMatters":"With roughly half of pregnant cannabis users also drinking alcohol, understanding the combined effects is critical. The finding that cannabinoids specifically worsened alcohol-related motor problems in females suggests sex-specific vulnerability to dual exposure.","specificNumbers":"CP-55,940 doses: 0.1, 0.25, 0.4 mg/kg/day. Alcohol: 5.25 g/kg/day. Exposure: PD 4-9. Motor testing: PD 12-20 and PD 30-32. Cannabinoids accelerated early motor milestones. Combined exposure exacerbated alcohol motor impairment in females specifically.","methodology":"Two-experiment rat study. Experiment 1: neonatal rats exposed to cannabinoid receptor agonist CP-55,940 at three doses (PD 4-9). Experiment 2: combined cannabinoid and alcohol exposure. Motor development tested PD 12-20, motor coordination tested PD 30-32 (adolescence).","limitations":"Rat model using a synthetic cannabinoid agonist, not THC itself. Neonatal rat exposure corresponds to third-trimester human brain development. Doses may not translate directly to human use. Motor testing captures only one domain of potential harm."},{"rthcId":"RTHC-01961","title":"Pharmacological evidence of medicinal cannabis in oncology: a systematic review.","authors":"Brown, Danielle; Watson, Michael; Schloss, Janet","year":2019,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 27(9), 3195-3207","doi":"10.1007/s00520-019-04774-5","pmid":"31062109","tags":["medical-cannabis","cancer"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Of 18 selected articles (10 RCTs, 2 experimental, 2 retrospective cohort, 4 case studies), only 4 reported absorption data and only 1 drug interaction study was identified. There is almost no evidence on the pharmacokinetics of medicinal cannabis specifically in cancer patients.","whyItMatters":"Without absorption data, cannabis dosing in cancer patients is essentially guesswork. Cancer patients may metabolize cannabinoids differently due to their disease, other medications, and compromised organ function, making this gap particularly dangerous.","specificNumbers":"18 articles selected: 10 RCTs, 2 experimental, 2 retrospective cohort, 4 case studies. Only 4 reported absorption data. Only 1 drug interaction study found.","methodology":"Systematic literature review across six databases for studies reporting pharmacological data on medicinal cannabis in oncology.","limitations":"Systematic review can only identify what has been studied. The lack of pharmacokinetic data may partly reflect the difficulty of conducting such studies in cancer populations and the challenges of cannabinoid analytical methods."},{"rthcId":"RTHC-01962","title":"Health care experiences and birth outcomes: Results of an Aboriginal birth cohort.","authors":"Brown, Stephanie J; Gartland, Deirdre; Weetra, Donna; Leane, Cathy; Francis, Theresa; Mitchell, Amanda; Glover, Karen","year":2019,"journal":"Women and birth : journal of the Australian College of Midwives, 32(5), 404-411","doi":"10.1016/j.wombi.2019.05.015","pmid":"31202584","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01963","title":"Correlation of EEG biomarkers of cannabis with measured driving impairment.","authors":"Brown, Timothy; McConnell, Marissa; Rupp, Greg; Meghdadi, Amir; Richard, Christian; Schmitt, Rose; Gaffney, Gary; Milavetz, Gary; Berka, Chris","year":2019,"journal":"Traffic injury prevention, 20(sup2), S148-S151","doi":"10.1080/15389588.2019.1662256","pmid":"31674856","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01964","title":"Cannabis use as a risk factor for causing motor vehicle crashes: a prospective study.","authors":"Brubacher, Jeffrey R; Chan, Herbert; Erdelyi, Shannon; Macdonald, Scott; Asbridge, Mark; Mann, Robert E; Eppler, Jeffrey; Lund, Adam; MacPherson, Andrew; Martz, Walter; Schreiber, William E; Brant, Rollin; Purssell, Roy A","year":2019,"journal":"Addiction (Abingdon, England), 114(9), 1616-1626","doi":"10.1111/add.14663","pmid":"31106494","tags":["driving","harm-reduction","legalization"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"No increased crash risk in drivers with THC <2 or 2-5 ng/mL. At THC >=5 ng/mL, adjusted OR was 1.74 (95% CI 0.59-6.36, non-significant). By contrast, BAC >=0.08% showed OR 6.00 (95% CI 3.87-9.75, p<0.01). Other recreational drugs: OR 1.82. Sedating medications: OR 1.45.","whyItMatters":"This is one of the most rigorous studies comparing cannabis and alcohol driving risk using prospective data and objective blood levels. The findings suggest THC-based per se driving laws (particularly at low thresholds like 2 ng/mL) may be penalizing drivers who are not actually impaired.","specificNumbers":"3,005 injured drivers tested. THC detected in 8.3%. Alcohol in 14.4%. Other drugs in 8.9%. Sedating meds in 19.8%. THC <5 ng/mL: no increased risk. THC >=5 ng/mL: OR 1.74 (NS). BAC >=0.08%: OR 6.00 (p<0.01).","methodology":"Prospective responsibility analysis of injured drivers at British Columbia trauma centres. Blood from clinical samples tested for broad-spectrum toxicology. Police reports analyzed for crash responsibility. Adjusted for age, sex, and other impairing substances.","limitations":"Only non-fatally injured drivers included, which may underestimate risk for the most severe crashes. THC blood levels reflect timing of use but not consistent impairment levels across individuals. The 5+ ng/mL group was small, limiting statistical power."},{"rthcId":"RTHC-01965","title":"Effects in rats of adolescent exposure to cannabis smoke or THC on emotional behavior and cognitive function in adulthood.","authors":"Bruijnzeel, Adriaan W; Knight, Parker; Panunzio, Stefany; Xue, Song; Bruner, Matthew M; Wall, Shannon C; Pompilus, Marjory; Febo, Marcelo; Setlow, Barry","year":2019,"journal":"Psychopharmacology, 236(9), 2773-2784","doi":"10.1007/s00213-019-05255-7","pmid":"31044291","tags":["youth","cognition","depression","anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Despite testing both cannabis smoke and THC at multiple doses during the adolescent period (P29-49 or P35-45), adult rats showed no significant effects on anxiety (open field, elevated plus maze), depression (sucrose preference, forced swim), or cognition (novel object recognition) after abstinence until P70. Some subtle sex differences were slightly attenuated.","whyItMatters":"This null finding challenges the assumption that adolescent cannabis exposure directly causes lasting psychological harm. If the behavioral deficits seen in human studies are not reproduced in controlled animal experiments, non-cannabinoid factors (social environment, other substance use, pre-existing vulnerabilities) may drive the human associations.","specificNumbers":"Cannabis smoke: PD 29-49. THC ascending doses: PD 35-45. Adult testing: PD 70. No significant effects on open field, elevated plus maze, sucrose preference, forced swim, or novel object recognition. Some sex-dependent measures slightly attenuated.","methodology":"Two experiments in Long-Evans rats. Cannabis smoke exposure PD 29-49 or ascending THC doses PD 35-45. Adult behavioral testing at P70 for anxiety, depression, and cognition. Both sexes tested.","limitations":"Rat behavior may not fully model human psychiatric conditions. The abstinence period (to P70) may not be long enough. Cannabis smoke exposure methods may not replicate human consumption patterns. Only behavioral outcomes were measured, not neurochemical or structural changes."},{"rthcId":"RTHC-01966","title":"Endocannabinoid and Prostanoid Crosstalk in Pain.","authors":"Buisseret, Baptiste; Alhouayek, Mireille; Guillemot-Legris, Owein; Muccioli, Giulio G","year":2019,"journal":"Trends in molecular medicine, 25(10), 882-896","doi":"10.1016/j.molmed.2019.04.009","pmid":"31160168","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01967","title":"Implementation and Effectiveness of an Online Responsible Vendor Training Program for Recreational Marijuana Stores in Colorado, Oregon, and Washington State.","authors":"Buller, David B; Woodall, W Gill; Saltz, Robert; Grayson, Andrew; Buller, Mary Klein","year":2019,"journal":"Journal of public health management and practice : JPHMP, 25(3), 238-244","doi":"10.1097/PHH.0000000000000843","pmid":"30180110","tags":["legalization","harm-reduction","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 420 trained employees, ID checking ability improved significantly (pre: 3.91 to post: 4.58, p<.001), as did confidence to use inventory tracking (pre: 2.52 to post: 2.85, p<.001) and to spot intoxicated customers (pre: 2.79 to post: 2.94, p<.001). 78.4% found the training user-friendly, 68.8% were satisfied, and 91.1% would recommend it.","whyItMatters":"As recreational marijuana markets expand, responsible sales practices are critical for preventing underage access and intoxicated use. This study shows that approaches proven effective in the alcohol market can successfully transfer to cannabis retail.","specificNumbers":"225 stores enrolled. 420 employees trained (43.5% female, 88.4% under 40). ID checking improved from 3.91 to 4.58. Intoxication detection confidence: 2.79 to 2.94. 91.1% would recommend. 5 training modules.","methodology":"Randomized controlled trial of 225 state-licensed retail recreational marijuana stores across Colorado, Oregon, and Washington State. 125 stores received the online training. 420 employees completed 5 training modules between June 2017-February 2018.","limitations":"Self-reported improvements may not translate to actual behavior change. No measurement of whether trained stores actually prevented more underage or intoxicated sales. Short-term assessment without long-term follow-up. Voluntary participation may bias toward more motivated stores."},{"rthcId":"RTHC-01968","title":"Cannabis effects on brain structure, function, and cognition: considerations for medical uses of cannabis and its derivatives.","authors":"Burggren, Alison C; Shirazi, Anaheed; Ginder, Nathaniel; London, Edythe D","year":2019,"journal":"The American journal of drug and alcohol abuse, 45(6), 563-579","doi":"10.1080/00952990.2019.1634086","pmid":"31365275","tags":["neuroscience","cognition","youth","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Decades of research link recreational cannabis use to cognitive impairment across multiple domains, structural and functional brain differences associated with early and heavy use, and heightened risks during adolescence when brain development is ongoing. Yet some cannabinoid formulations are FDA-approved, including for pediatric applications.","whyItMatters":"The tension between recreational cannabis risks and medical cannabinoid benefits is a central policy challenge. This review explicitly addresses this paradox, arguing that understanding brain effects should inform both recreational regulation and medical prescribing.","specificNumbers":"Cannabis is the most widely used illicit substance worldwide. Legalization has substantially increased availability and use in the US. Brain development continues into early adulthood. Some cannabinoid formulations are FDA-approved for children.","methodology":"Review consolidating findings on cannabis effects on brain structure, function, and cognition, with emphasis on implications for age limits and guidelines for both recreational and medical use.","limitations":"Review-level evidence without meta-analytic pooling. Much of the underlying literature is cross-sectional and cannot establish causation. Recreational cannabis products differ substantially from pharmaceutical cannabinoids in composition and purity."},{"rthcId":"RTHC-01969","title":"Cocaine-Induced Reinstatement of Cocaine Seeking Provokes Changes in the Endocannabinoid and N-Acylethanolamine Levels in Rat Brain Structures.","authors":"Bystrowska, Beata; Frankowska, Małgorzata; Smaga, Irena; Niedzielska-Andres, Ewa; Pomierny-Chamioło, Lucyna; Filip, Małgorzata","year":2019,"journal":"Molecules (Basel, Switzerland), 24(6)","doi":"10.3390/molecules24061125","pmid":"30901889","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01970","title":"Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms.","authors":"Calpe-López, Claudia; García-Pardo, M Pilar; Aguilar, Maria A","year":2019,"journal":"Molecules (Basel, Switzerland), 24(14)","doi":"10.3390/molecules24142583","pmid":"31315244","tags":["cbd","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD reversed cocaine-induced toxicity and seizures, blocked amphetamine behavioral sensitization, reduced cocaine and methamphetamine self-administration, promoted extinction of drug-place associations, and prevented stress- and drug-induced reinstatement. Observational human studies suggest CBD may reduce crack-cocaine withdrawal, craving, impulsivity, and paranoia.","whyItMatters":"There are currently no approved medications for cocaine or methamphetamine addiction. If CBD can reduce relapse and craving through the multiple mechanisms identified, it could fill a critical gap in addiction treatment.","specificNumbers":"CBD prevented cocaine seizures and toxicity. Reduced self-administration of cocaine and METH. Enhanced extinction and impaired reconsolidation of cocaine conditioned place preference. Prevented priming-induced reinstatement of METH seeking. Observational data: reduced craving, impulsivity, paranoia.","methodology":"Review of preclinical and limited human research on CBD effects on cocaine and methamphetamine use disorders, plus analysis of potential mechanisms including neuroadaptation prevention, drug memory erasure, cognitive restoration, and mental health comorbidity treatment.","limitations":"Most evidence is preclinical. Observational human data is preliminary. CBD doses used in animal studies may not translate to humans. The specific mechanisms remain hypothetical. No completed randomized controlled trials in humans."},{"rthcId":"RTHC-01971","title":"Adolescent female school dropouts who use drugs and engage in risky sex: effects of a brief pilot intervention in Cape Town, South Africa.","authors":"Carney, Tara; Browne, Felicia A; Myers, Bronwyn; Kline, Tracy L; Howard, Brittni; Wechsberg, Wendee M","year":2019,"journal":"AIDS care, 31(1), 77-84","doi":"10.1080/09540121.2018.1500008","pmid":"30021470","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01972","title":"Cannabis use and suicide attempts among 86,254 adolescents aged 12-15 years from 21 low- and middle-income countries.","authors":"Carvalho, Andre F; Stubbs, Brendon; Vancampfort, Davy; Kloiber, Stefan; Maes, Michael; Firth, Joseph; Kurdyak, Paul A; Stein, Dan J; Rehm, Jürgen; Koyanagi, Ai","year":2019,"journal":"European psychiatry : the journal of the Association of European Psychiatrists, 56, 8-13","doi":"10.1016/j.eurpsy.2018.10.006","pmid":"30447436","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Past 30-day cannabis use was significantly associated with suicide attempts (OR 2.03, 95% CI 1.42-2.91) after multivariable adjustment. Lifetime cannabis use showed an even stronger association (OR 2.30, 95% CI 1.74-3.04). These associations held across 21 countries with widely varying cannabis prevalence rates.","whyItMatters":"This is one of the largest studies examining the cannabis-suicide association, and the first to systematically assess it across multiple low- and middle-income countries. The consistency of the finding across vastly different cultural contexts strengthens the case for a real association.","specificNumbers":"86,254 adolescents from 21 countries. Mean age 13.7. Past 30-day cannabis: 2.8% (range 0.5% Laos to 37.6% Samoa). Lifetime cannabis: 3.9%. Suicide attempts past year: 10.5%. Adjusted OR: 2.03 (30-day) and 2.30 (lifetime).","methodology":"Cross-sectional analysis of the Global School-based Student Health Survey data from 86,254 adolescents (mean age 13.7) in 21 low- and middle-income countries. Multivariable logistic regression adjusted for potential confounders.","limitations":"Cross-sectional design cannot establish causation. Self-reported measures in school settings. Students not in school were excluded. Cultural differences in reporting both cannabis use and suicidality may affect comparisons. Specific confounders like mental health treatment availability could not be assessed."},{"rthcId":"RTHC-01973","title":"What Every Pediatric Gynecologist Should Know About Marijuana Use in Adolescents.","authors":"Chadi, Nicholas; Levy, Sharon","year":2019,"journal":"Journal of pediatric and adolescent gynecology, 32(4), 349-353","doi":"10.1016/j.jpag.2019.03.004","pmid":"30923025","tags":["youth","pregnancy","sex-differences","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Despite limited research specifically on gynecological conditions, the many risks of adolescent marijuana use include negative effects on developing brains, adverse reproductive outcomes (menstrual irregularities, pregnancy complications), risky sexual behavior, and mental health problems. These risks likely outweigh potential benefits for adolescents.","whyItMatters":"Pediatric gynecologists are uniquely positioned to screen for and counsel about marijuana use in teenage girls, yet most have limited training on this topic. With legalization expanding, the information gap between patients and providers is growing.","specificNumbers":"No specific quantitative data highlighted. Review covers brain development effects, reproductive outcomes, sexual health risks, and mental health associations. Notes that adolescent marijuana use shows no sign of decreasing.","methodology":"Narrative review of current literature on marijuana risks and potential benefits during adolescence, with focus on reproductive, sexual health, and mental health outcomes relevant to pediatric gynecology.","limitations":"Limited research specifically addresses marijuana effects on gynecological conditions. Much of the evidence is extrapolated from general adolescent cannabis research. The review does not include meta-analytic data."},{"rthcId":"RTHC-01974","title":"Disseminated Intravascular Coagulopathy Secondary to Unintentional Brodifacoum Poisoning via Synthetic Marijuana.","authors":"Chan, Abigail; Adashek, Michael; Kang, Julian; Medina, Adriana","year":2019,"journal":"Journal of hematology, 8(1), 40-43","doi":"10.14740/jh486","pmid":"32300441","tags":["synthetic-cannabinoids","cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient developed severe coagulopathy and cardiac arrest after synthetic cannabinoid use contaminated with brodifacoum. The case illustrates the life-threatening potential of contaminated synthetic cannabinoid products and the difficulty of detection through standard drug screening.","whyItMatters":"This case adds to the mounting evidence of a synthetic cannabinoid contamination crisis. Unlike previous reports focusing on bleeding, this case involved both DIC and cardiac arrest, demonstrating the extreme end of the toxicity spectrum.","specificNumbers":"Severe coagulopathy documented. Cardiac arrest occurred. Brodifacoum identified as the contaminant. Standard drug screening unable to detect synthetic cannabinoids.","methodology":"Single case report documenting the clinical presentation, workup, and management of DIC and cardiac arrest secondary to brodifacoum-contaminated synthetic cannabinoid use.","limitations":"Single case report. Cannot determine how common this specific presentation is. The mechanism by which brodifacoum contaminates synthetic cannabinoid products remains unclear."},{"rthcId":"RTHC-01975","title":"Longitudinal patterns of amphetamine use from adolescence to adulthood: A latent class analysis of a 20-year prospective study of Australians.","authors":"Chan, Gary C K; Butterworth, Peter; Becker, Denise; Degenhardt, Louisa; Stockings, Emily; Hall, Wayne; Patton, George","year":2019,"journal":"Drug and alcohol dependence, 194, 121-127","doi":"10.1016/j.drugalcdep.2018.08.042","pmid":"30419406","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01976","title":"New trends in cannabis potency in USA and Europe during the last decade (2008-2017).","authors":"Chandra, Suman; Radwan, Mohamed M; Majumdar, Chandrani G; Church, James C; Freeman, Tom P; ElSohly, Mahmoud A","year":2019,"journal":"European archives of psychiatry and clinical neuroscience, 269(1), 5-15","doi":"10.1007/s00406-019-00983-5","pmid":"30671616","tags":["potency","legalization","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Picking up where ElSohly's earlier analysis left off, this study tracked another decade of cannabis potency data from the University of Mississippi's monitoring program. The trends not only continued — they accelerated. Average THC concentration nearly doubled from 8.9% in 2008 to 17.1% in 2017. The THC-to-CBD ratio, already high, climbed from 23:1 to 104:1.\n\nBut the bigger story was concentrates. Hash oil samples (now called cannabis concentrates) went from 0.5% of seized samples to 4.7%, and their average THC concentration skyrocketed from 6.7% to 55.7%. The seizure data also revealed a structural shift: fewer samples overall were being seized as states legalized, but what was seized was dramatically more potent.\n\nEuropean data from the Netherlands, UK, France, and Italy showed parallel trends — this wasn't a U.S.-only phenomenon.","whyItMatters":"This is the sequel to the 1995–2014 potency study (RTHC-00039), and the trajectory only steepened. The average joint in 2017 carried roughly twice the THC of one from 2008 and four times what was available in the mid-1990s. Meanwhile, concentrates — barely a factor a decade earlier — emerged as a distinct product category testing above 55% THC.\n\nThe vanishing CBD is the quiet part of this story. A THC:CBD ratio of 104:1 means modern cannabis has essentially zero CBD relative to THC. If CBD does moderate THC's psychiatric effects (as some research suggests), the market has systematically eliminated that buffer.","specificNumbers":"• Average THC: 8.9% (2008) → 17.1% (2017)\n• THC:CBD ratio: 23:1 (2008) → 104:1 (2017)\n• Concentrate THC: 6.7% (2008) → 55.7% (2017)\n• Concentrate share of seizures: 0.5% (2008) → 4.7% (2017)\n• Total samples analyzed: 18,108","methodology":"Analysis of 18,108 cannabis samples seized by the DEA and analyzed at the University of Mississippi's Potency Monitoring Program using validated GC/FID methods. Covers January 2008 through December 2017. Also reviews potency monitoring data from European programs for cross-national comparison.","limitations":"Limited to DEA-seized samples, which increasingly underrepresent the market as legalization reduces the illicit supply. Fewer samples were available in later years. Cannot determine whether users adjust consumption to compensate for higher potency. European data came from different monitoring programs with varying methodologies."},{"rthcId":"RTHC-01977","title":"Cannabis-Associated Asthma and Allergies.","authors":"Chatkin, J M; Zani-Silva, L; Ferreira, I; Zamel, N","year":2019,"journal":"Clinical reviews in allergy & immunology, 56(2), 196-206","doi":"10.1007/s12016-017-8644-1","pmid":"28921405","tags":["respiratory","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Multiple studies associate marijuana use with increased asthma symptoms and other allergic disease manifestations, as well as increased frequency of medical visits. Cannabis can cause allergic reactions through direct sensitization. The review emphasizes that cannabis is an underrecognized precipitating factor for acute asthma and allergic attacks.","whyItMatters":"As cannabis use normalizes, clinicians may not think to ask about it when evaluating asthma exacerbations or allergic reactions. Cannabis may be an unrecognized trigger in patients with poorly controlled asthma or unexplained allergic symptoms.","specificNumbers":"Cannabis inhalation is the most common form of use. Pulmonary complications may be the most common form of drug-induced pulmonary disease worldwide. Multiple studies documented increased asthma symptoms and medical visits.","methodology":"Narrative review of English, Spanish, and Portuguese literature from 1970-2017 on the relationship between cannabis use and asthma/allergic diseases.","limitations":"Narrative review without systematic methodology or meta-analysis. Much of the evidence is observational. Long-term effects in allergic asthma patients are not well studied. The review cannot distinguish between smoked cannabis effects and inherent allergenicity."},{"rthcId":"RTHC-01978","title":"Heavy Cannabis Use Associated with Wernicke's Encephalopathy.","authors":"Chaudhari, Amit; Li, Zi Ying; Long, Alan; Afshinnik, Arash","year":2019,"journal":"Cureus, 11(7), e5109","doi":"10.7759/cureus.5109","pmid":"31523540","tags":["addiction","cognition","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient presented with seizures secondary to cannabis hyperemesis-induced vomiting and hyponatremia. Brain MRI showed bilateral thalamic hyperintensities characteristic of Wernicke's encephalopathy. IV thiamine led to gradual improvement. The patient had no significant alcohol history (1-2 beers/week 20 years prior).","whyItMatters":"Wernicke's encephalopathy is traditionally associated with alcoholism. This case demonstrates that cannabis hyperemesis syndrome can cause sufficient malnutrition to produce this serious brain condition, a complication clinicians may not anticipate.","specificNumbers":"41-year-old male. Status epilepticus at presentation. Bilateral thalamic hyperintensities on T2 FLAIR MRI. No significant alcohol history. Memory deficits and confabulations after stabilization. 2 months into rehabilitation at time of report.","methodology":"Single case report with brain MRI documentation. Comprehensive negative workup for other causes (infectious, autoimmune). Clinical response to thiamine treatment supported the diagnosis.","limitations":"Single case report. Remote alcohol history (though minimal) could theoretically have contributed. Cannabis hyperemesis syndrome leading to Wernicke's is presumably rare. Long-term cognitive outcome not reported."},{"rthcId":"RTHC-01979","title":"Cannabis and Neuropsychiatric Disorders: An Updated Review.","authors":"Chayasirisobhon, Sirichai","year":2019,"journal":"Acta neurologica Taiwanica, 28(2), 27-39","doi":null,"pmid":"31867704","tags":["cbd","medical-cannabis","pain","psychosis","epilepsy","anxiety"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD has demonstrated therapeutic benefit across multiple neuropsychiatric conditions including autism spectrum disorder, anxiety, psychosis, neuropathic pain, cancer pain, migraine, MS, Alzheimer disease, Parkinson disease, Huntington disease, hypoxic-ischemic injury, and epilepsy. CBD is generally well tolerated with low abuse potential. THC limitations may restrict some clinical applications.","whyItMatters":"The breadth of conditions where CBD shows promise, combined with its favorable safety profile, makes it one of the most versatile therapeutic candidates currently being investigated across neurology and psychiatry.","specificNumbers":"CBD shows benefit across 12+ neuropsychiatric conditions listed. Most common adverse events: diarrhea and somnolence. Low abuse potential demonstrated. Over 100 naturally occurring cannabinoid chemicals in cannabis.","methodology":"Updated narrative review of CBD and cannabinoid therapeutic potential, with emphasis on the distinction between psychotropic THC and non-psychotropic CBD effects across neuropsychiatric conditions.","limitations":"Narrative review format without systematic methodology. Many of the cited benefits are based on preliminary evidence. The review covers conditions at very different evidence levels without always distinguishing them."},{"rthcId":"RTHC-01980","title":"Cannabidiol: A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes.","authors":"Chen, Jeffrey W; Borgelt, Laura M; Blackmer, Allison B","year":2019,"journal":"The Annals of pharmacotherapy, 53(6), 603-611","doi":"10.1177/1060028018822124","pmid":"30616356","tags":["cbd","epilepsy","youth","drug-interactions"],"studyType":"review","evidenceStrength":"strong","keyFinding":"In the GWPCARE trial series, CBD reduced key seizure frequencies by 17-23% compared to placebo as adjunctive therapy in patients 2+ years old. Common adverse effects: somnolence, diarrhea, elevated liver enzymes. Important drug interactions with clobazam, valproates, and CYP2C19/3A4 inhibitors/inducers. This is the first cannabis-derived FDA-approved medication.","whyItMatters":"This clinical pharmacy-focused review provides the practical dosing, monitoring, and interaction information clinicians need to safely prescribe CBD for epilepsy, going beyond efficacy to address real-world implementation.","specificNumbers":"Seizure reduction: 17-23% over placebo. Approved for patients 2+ years old. Key interactions: clobazam, valproates, CYP2C19 and CYP3A4 modulators. Adverse effects: somnolence, diarrhea, hepatic transaminase elevations.","methodology":"Review of EMBASE and MEDLINE (1946-October 2018) plus product labeling and ClinicalTrials.gov for efficacy, safety, pharmacology, and pharmacokinetics of Epidiolex in Dravet and Lennox-Gastaut syndromes.","limitations":"Approved for only two epilepsy syndromes. Long-term safety data still accumulating. Drug interactions complicate use in patients on multiple anti-epileptic drugs. Mechanism of action remains hypothesized, not confirmed."},{"rthcId":"RTHC-01981","title":"Cannabis-related emergencies in children and teens.","authors":"Chen, Yih-Chieh; Klig, Jean E","year":2019,"journal":"Current opinion in pediatrics, 31(3), 291-296","doi":"10.1097/MOP.0000000000000752","pmid":"31090567","tags":["youth","harm-reduction","psychosis","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis-related pediatric ED visits are rising with changing legislation. Presentations range from GI, psychiatric, and cardiorespiratory effects to trauma from impaired psychomotor function. Young children may present with hyperkinesis or coma from accidental ingestion. Chronic complications include cannabinoid hyperemesis syndrome, depression, psychosis, and cognitive impairment.","whyItMatters":"As cannabis becomes more available, emergency clinicians need to recognize the full spectrum of cannabis presentations in children and adolescents, from acute ingestion to chronic use complications.","specificNumbers":"ED presentations span gastrointestinal, psychiatric, cardiorespiratory, and trauma categories. Young children: hyperkinesis and coma. Teens: acute intoxication, hyperemesis, depression, injuries. Cannabis-related pediatric ED visits increasing.","methodology":"Review of current literature on the spectrum of cannabis-related emergency department presentations in pediatric populations.","limitations":"Review without meta-analytic pooling. Exact incidence rates are difficult to determine. Clinical presentation overlap with other conditions may lead to under-recognition."},{"rthcId":"RTHC-01982","title":"Increasing Depression and Substance Use Among Former Smokers in the United States, 2002-2016.","authors":"Cheslack-Postava, Keely; Wall, Melanie M; Weinberger, Andrea H; Goodwin, Renee D","year":2019,"journal":"American journal of preventive medicine, 57(4), 429-437","doi":"10.1016/j.amepre.2019.05.014","pmid":"31443956","tags":["addiction","depression","mental-health","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Among former smokers, past-year marijuana use rose from 5.35% to 10.09% (2002-2016), depression increased from 4.88% to 6.04% (2005-2016), and binge alcohol use rose from 17.22% to 22.33% (2002-2016). All trends were statistically significant. Alcohol abuse/dependence did not change.","whyItMatters":"Former smokers now outnumber current smokers in the US. Rising marijuana use, depression, and binge drinking in this population threaten sustained cigarette abstinence, potentially undermining decades of tobacco control progress.","specificNumbers":"Marijuana use: 5.35% to 10.09% (OR per year 1.08). Depression: 4.88% to 6.04% (OR 1.01). Binge drinking: 17.22% to 22.33% (OR 1.03). All p<0.05. Nationally representative data.","methodology":"Analysis of the National Survey on Drug Use and Health (NSDUH), a nationally representative annual cross-sectional survey. Adults 18+ who smoked 100+ lifetime cigarettes but no past-year cigarettes. 2002-2016 data.","limitations":"Cross-sectional surveys cannot track individuals over time. Self-reported data. Cannot determine whether marijuana use preceded or followed smoking cessation. Cannabis product types and potency not assessed."},{"rthcId":"RTHC-01983","title":"The Mediating Effect of Social Controls on Marijuana Use Among Adolescent Bullies, Victims, and Bully-Victims: A Comparison of Various Approaches to Mediation.","authors":"Cho, Sujung; Norman, Lauren","year":2019,"journal":"Substance use & misuse, 54(5), 796-810","doi":"10.1080/10826084.2018.1543326","pmid":"30596307","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Adolescent bullies and bully-victims had higher marijuana use rates than victims or uninvolved youth. Parental attachment and prosocial peer attachment significantly decreased marijuana use likelihood for bullies and bully-victims, partially mediating the bullying-marijuana relationship. Pure victimization alone was not significantly related to marijuana use.","whyItMatters":"This identifies modifiable protective factors (family and peer relationships) that could be targeted in prevention programs for the specific youth most at risk: those who bully others or experience both sides of bullying.","specificNumbers":"12,642 adolescents. Bullies and bully-victims had significantly higher marijuana use. Parental attachment and prosocial peer attachment both significantly reduced marijuana use. Social controls partially mediated the bullying-marijuana link.","methodology":"Cross-sectional analysis of 12,642 adolescents from the Health Behavior in School-Aged Children survey. Multiple mediation approaches tested the role of social control measures between bullying status and marijuana use.","limitations":"Cross-sectional design. Self-reported bullying and substance use. Cannot determine temporal order. Social desirability bias may affect reporting of both bullying and marijuana use."},{"rthcId":"RTHC-01984","title":"Driving Under the Influence of Cannabis: A Framework for Future Policy.","authors":"Chow, Robert M; Marascalchi, Bryan; Abrams, Winfred B; Peiris, Nathalie A; Odonkor, Charles A; Cohen, Steven P","year":2019,"journal":"Anesthesia and analgesia, 128(6), 1300-1308","doi":"10.1213/ANE.0000000000003575","pmid":"31094805","tags":["driving","legalization","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Marijuana use is associated with significant cognitive and psychomotor effects. Blood THC levels do not correlate well with impairment level, unlike blood alcohol. Acute infrequent cannabis use typically causes impairment, but this is not consistently the case for chronic heavy users. Cannabis driving laws vary widely across states.","whyItMatters":"As more states legalize, cannabis driving enforcement needs a scientific foundation. This review highlights the fundamental problem: unlike alcohol, there is no reliable biomarker-impairment relationship for cannabis.","specificNumbers":"28 epidemiological studies, 16 acute cognitive studies, 8 chronic studies reviewed. Cannabis is a commonly found substance in DUI cases. Blood THC does not correlate with impairment. Chronic heavy users may not show consistent impairment.","methodology":"MEDLINE search reviewing 28 epidemiological studies, 16 acute cognitive/psychomotor studies, 8 chronic studies, and relevant state and federal laws.","limitations":"Review-level evidence. Studies vary in methodology, cannabis potency, and impairment measures. The distinction between acute/infrequent and chronic/heavy use adds complexity. State laws continue to change rapidly."},{"rthcId":"RTHC-01985","title":"Alcohol and Cannabis Consumption Does Not Diminish Cure Rates in a Real-World Cohort of Chronic Hepatitis C Virus Infected Patients on Opioid Substitution Therapy-Data From the German Hepatitis C-Registry (DHC-R).","authors":"Christensen, Stefan; Buggisch, Peter; Mauss, Stefan; Böker, Klaus Hw; Müller, Tobias; Klinker, Hartwig; Zimmermann, Tim; Serfert, Yvonne; Weber, Bernd; Reimer, Jens; Wedemeyer, Heiner","year":2019,"journal":"Substance abuse : research and treatment, 13, 1178221819835847","doi":"10.1177/1178221819835847","pmid":"30944519","tags":["medical-cannabis","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use did not significantly influence SVR rates in either intention-to-treat or per-protocol analysis, regardless of opioid substitution therapy status. High alcohol consumption slightly reduced ITT cure rates (due to more lost-to-follow-up), but per-protocol rates were similar. OST patients had higher LTFU rates but similar per-protocol cure rates.","whyItMatters":"Concerns about cannabis and alcohol use in hepatitis C patients on opioid substitution have led some clinicians to defer or deny treatment. This study shows these concerns are unfounded for cure rates.","specificNumbers":"739 OST patients, 7,008 non-OST. Non-OST/no drug use SVR: 91-92% (ITT). OST SVR: 83-86% (ITT). Difference mainly due to LTFU (11-12% vs 2-3%). Cannabis use: no significant effect on SVR in any analysis.","methodology":"Analysis of the German Hepatitis C Registry (DHC-R), a national multicenter prospective real-world registry. 739 OST patients and 7,008 non-OST patients treated with direct-acting antivirals.","limitations":"Self-reported substance use may be underestimated. Cannabis type and quantity not specified. LTFU after end of treatment could mask some treatment failures. German healthcare context may not generalize to all settings."},{"rthcId":"RTHC-01986","title":"Prevalence of Involuntary Environmental Cannabis and Tobacco Smoke Exposure in Multi-Unit Housing.","authors":"Chu, Alanna K; Kaufman, Pamela; Chaiton, Michael","year":2019,"journal":"International journal of environmental research and public health, 16(18)","doi":"10.3390/ijerph16183332","pmid":"31509994","tags":["harm-reduction","legalization","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among multi-unit housing residents in Ontario, 7.5% reported environmental cannabis smoke (ECS) exposure and 6.6% reported environmental tobacco smoke (ETS) exposure from neighboring units. ECS exposure was associated with being single, lower household income, and past-year cannabis use. Cannabis smoke exposure prevalence was comparable to tobacco smoke.","whyItMatters":"As cannabis legalization expands, involuntary exposure to cannabis smoke in multi-unit housing is an emerging public health concern. This is the first study to measure its prevalence alongside tobacco smoke exposure.","specificNumbers":"Environmental cannabis smoke: 7.5% (95% CI 5.4-10.4%). Environmental tobacco smoke: 6.6% (95% CI 4.5-9.5%). Exposed individuals more likely to be single, have lower income, and have used cannabis.","methodology":"Population random-digit-dial survey from the 2017 Centre for Addiction and Mental Health Monitor for Ontario, Canada. Self-reported cannabis and tobacco smoke entering the home from neighboring units at least once in the past 6 months.","limitations":"Self-reported exposure with potential recall bias. Ontario-specific, pre-full Canadian legalization (October 2018). Cannot distinguish between smoke from the building interior versus exterior. No objective measurement of smoke levels."},{"rthcId":"RTHC-01987","title":"Alteration to hippocampal volume and shape confined to cannabis dependence: a multi-site study.","authors":"Chye, Yann; Lorenzetti, Valentina; Suo, Chao; Batalla, Albert; Cousijn, Janna; Goudriaan, Anna E; Jenkinson, Mark; Martin-Santos, Rocio; Whittle, Sarah; Yücel, Murat; Solowij, Nadia","year":2019,"journal":"Addiction biology, 24(4), 822-834","doi":"10.1111/adb.12652","pmid":"30022573","tags":["neuroscience","addiction","cognition"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis users as a whole (n=140) did not differ from controls (n=121) in hippocampal volume or shape. However, dependent users (n=70) had significantly smaller right and left hippocampi compared to both controls (n=106) and non-dependent users (n=50), regardless of cannabis dosage. Shape analysis revealed localized deflations in the superior-medial body of the hippocampus.","whyItMatters":"This study resolves a longstanding debate by showing that hippocampal changes are specific to dependence, not cannabis use per se. The finding held after controlling for dose, suggesting dependence involves neurobiological changes beyond the direct pharmacological effects of cannabis.","specificNumbers":"121 controls, 140 cannabis users (70 dependent, 50 non-dependent). Dependent users: significantly smaller bilateral hippocampi. Non-dependent users: no difference from controls. Shape changes: superior-medial body deflation. Results held in 41:41:41 matched subsample.","methodology":"Multi-site study aggregating MRI data from four research sites. Three comparison levels: users vs controls; dependent vs non-dependent vs controls; matched subsample controlling for onset age and dosage. Volumetric and vertex-level shape analysis.","limitations":"Cross-sectional design cannot determine if smaller hippocampi preceded or followed dependence. Multi-site aggregation introduces variability. Cannabis dependence diagnosis varied across sites. Other substance use and mental health comorbidities may contribute."},{"rthcId":"RTHC-01988","title":"Positive and Negative Effects of Cannabis and Cannabinoids on Health.","authors":"Cohen, Koby; Weizman, Abraham; Weinstein, Aviv","year":2019,"journal":"Clinical pharmacology and therapeutics, 105(5), 1139-1147","doi":"10.1002/cpt.1381","pmid":"30703255","tags":["medical-cannabis","harm-reduction","psychosis","cardiovascular","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Repeated cannabis use is associated with respiratory and cardiovascular disorders, cognitive alterations, psychosis, schizophrenia, and mood disorders. However, causal relationships are largely missing. Simultaneously, cannabinoid-based drugs show promising therapeutic potential for neurological and psychiatric disorders. Both the popularity and the evidence gaps are growing.","whyItMatters":"Cannabis policy often operates in the space between demonstrated associations and unproven causation. This review honestly addresses both sides, providing a framework for conversations about cannabis that acknowledge uncertainty rather than treating the science as settled.","specificNumbers":"Cannabis is the most popular illicit drug in the Western world. Associated harms include respiratory, cardiovascular, cognitive, and psychiatric effects. Causal relationships are not established for most. Therapeutic potential spans neurological and psychiatric conditions.","methodology":"Contemporary narrative review covering adverse effects, safety, and therapeutic potential of cannabis and cannabinoid-based drugs.","limitations":"Narrative review without systematic methodology. The balance between harms and benefits varies by condition, dose, and population. \"Causal relations missing\" does not mean no causation exists."},{"rthcId":"RTHC-01989","title":"Modulatory effects of cannabinoids on brain neurotransmission.","authors":"Cohen, Koby; Weizman, Abraham; Weinstein, Aviv","year":2019,"journal":"The European journal of neuroscience, 50(3), 2322-2345","doi":"10.1111/ejn.14407","pmid":"30882962","tags":["neuroscience","dopamine","psychosis","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CB1 and CB2 receptors interact with six major neurotransmitter systems: dopamine, serotonin, noradrenaline, GABA, glutamate, and opioids. Acute and chronic cannabis exposure produces distinct pharmacological alterations across these systems. The neuromodulatory role of the endocannabinoid system explains why cannabis affects such a wide range of mental health domains.","whyItMatters":"Understanding how cannabinoids interact with established neurotransmitter systems is essential for predicting both therapeutic effects and risks. The breadth of these interactions explains why cannabis has such diverse and sometimes contradictory effects.","specificNumbers":"6 major neurotransmitter systems modulated: dopamine, serotonin, noradrenaline, GABA, glutamate, opioids. Both CB1 and CB2 receptors involved. Acute and chronic effects differ.","methodology":"Review summarizing preclinical and clinical data on cannabinoid receptor interactions with major central neurotransmitter systems, covering both acute and chronic exposure effects.","limitations":"Much of the evidence is preclinical. Translating neurotransmitter-level findings to clinical outcomes is complex. The review covers breadth at the expense of depth for individual neurotransmitter interactions."},{"rthcId":"RTHC-01990","title":"Cortical Thickness and Subcortical Volumes in Adolescent Synthetic Cannabinoid Users with or Without ADHD: a Preliminary Study.","authors":"Çolak, Çiğdem; Çelik, Zehra Çakmak; Zorlu, Nabi; Kitiı, Ömer; Yüncü, Zeki","year":2019,"journal":"Noro psikiyatri arsivi, 56(3), 167-172","doi":"10.29399/npa.23495","pmid":"31523140","tags":["synthetic-cannabinoids","youth","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"SC users with and without ADHD had reduced cortical thickness in left caudal middle frontal and left superior frontal areas compared to controls. SC users with ADHD also showed reduced thickness in right precentral and postcentral gyri. SC users without ADHD had increased right nucleus accumbens volume, which was not seen in SC+ADHD users.","whyItMatters":"ADHD is overrepresented among adolescent substance users. This study shows that comorbid ADHD and synthetic cannabinoid use produce a different pattern of brain changes than either condition alone, suggesting additive or interactive effects.","specificNumbers":"28 SC users (15 without ADHD, 13 with ADHD), 13 controls. Reduced cortical thickness: left caudal middle frontal and superior frontal (both SC groups). Additional right precentral/postcentral thinning (ADHD group only). Increased right nucleus accumbens (SC without ADHD only).","methodology":"Structural MRI comparing 28 SC users (15 without ADHD, 13 with ADHD combined type) and 13 controls. Examined cortical thickness, surface area, and subcortical volumes.","limitations":"Very small sample sizes limit generalizability. Cross-sectional design. Specific SC compounds unknown. Cannot determine whether brain changes preceded or followed SC use. No matching for other substance use."},{"rthcId":"RTHC-01991","title":"Synergistic action of CB1 and 5-HT2B receptors in preventing pilocarpine-induced status epilepticus in rats.","authors":"Colangeli, Roberto; Di Maio, Roberto; Pierucci, Massimo; Deidda, Gabriele; Casarrubea, Maurizio; Di Giovanni, Giuseppe","year":2019,"journal":"Neurobiology of disease, 125, 135-145","doi":"10.1016/j.nbd.2019.01.026","pmid":"30716469","tags":["epilepsy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"WIN55,212-2 (CB1 agonist at 2 mg/kg) and RO60-0175 (5-HT2B/2C agonist at 3 mg/kg) were ineffective alone against EEG seizures but combined they reduced seizure incidence, severity, and increased latency to seizure onset. The effect was blocked by CB1 and 5-HT2B antagonists but not by 5-HT2C or 5-HT2A antagonists, pinpointing the specific receptor interaction.","whyItMatters":"This reveals a new synergistic anti-seizure mechanism that could enable lower doses of cannabinoid drugs by combining them with serotonin-targeting agents, potentially reducing side effects while maintaining efficacy.","specificNumbers":"WIN 2 mg/kg + RO 3 mg/kg: reduced EEG seizure incidence and severity. Neither effective alone at these doses. Effect blocked by AM251 (CB1 antagonist) and RS127445 (5-HT2B antagonist). Not blocked by 5-HT2C or 5-HT2A antagonists.","methodology":"Video-EEG recording in rats treated with pilocarpine to induce status epilepticus. Tested cannabinoid (WIN) and serotonin (RO) agonists alone and combined, with selective receptor antagonists to identify the mechanism.","limitations":"Rat model of status epilepticus may not represent all human epilepsy types. Synthetic cannabinoid used, not CBD or THC. Single dose combinations tested. Translation to clinical use requires human safety and efficacy data."},{"rthcId":"RTHC-01992","title":"Descriptive Psychopathology of the Acute Effects of Intravenous Delta-9-Tetrahydrocannabinol Administration in Humans.","authors":"Colizzi, Marco; Weltens, Nathalie; McGuire, Philip; Van Oudenhove, Lukas; Bhattacharyya, Sagnik","year":2019,"journal":"Brain sciences, 9(4)","doi":"10.3390/brainsci9040093","pmid":"31027219","tags":["psychosis","sex-differences","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In the 20 minutes after THC, 94% experienced at least mild symptoms (19% moderate-severe). 31% still had mild symptoms at 2.5 hours. After placebo, 62% had no symptoms at all. Acute physical reactions were 2.5x more frequent with THC (31% vs 12% placebo). Women had more negative symptoms (56-89%) than men (0-29%), and all acute physical reactions occurred exclusively in women.","whyItMatters":"This controlled study demonstrates that even a very low dose of THC produces near-universal psychotomimetic effects in cannabis-naive individuals, and reveals striking sex differences that have implications for both recreational use and medical dosing.","specificNumbers":"16 participants, 7 male. 1.19 mg IV THC. 94% experienced symptoms. 19% moderate-severe. 31% still symptomatic at 2.5 hours. Physical reactions: THC 31% vs placebo 12%. Women: 56-89% negative symptoms vs men 0-29%. Physical reactions: exclusively female.","methodology":"Double-blind, randomized, placebo-controlled crossover study of IV THC (1.19 mg/2 mL) in 16 healthy participants (7 male) with modest previous cannabis exposure.","limitations":"Very small sample (16 participants, 9 female, 7 male). IV administration does not replicate typical use. Single dose study. Participants had modest prior cannabis experience. Cross-over design may introduce order effects."},{"rthcId":"RTHC-01993","title":"What cancer patients actually know regarding medical cannabis? A cross-sectional survey with a critical analysis of the current attitudes.","authors":"Cortellini, Alessio; Porzio, Giampiero; Cofini, Vincenza; Necozione, Stefano; Giusti, Raffaele; Marchetti, Paolo; Aloe Spiriti, Maria A; Costanzi, Andrea; Peris, Flaminia; Ravoni, Giulio; Spinelli, Giuseppe; Ficorella, Corrado; Verna, Lucilla","year":2019,"journal":"Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 25(6), 1439-1444","doi":"10.1177/1078155219843161","pmid":"31042135","tags":["medical-cannabis","cancer","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"81% of patients had heard about medical cannabis, but only 2% from healthcare professionals. 34% had considered using cannabis for their own health problems, especially pain (55%). Patients with higher education were more likely to know about cannabis and medical cannabis. Metastatic patients were less informed than those on adjuvant treatment.","whyItMatters":"Medical cannabis has been legally available in Italy since 1998, yet only 2% of cancer patients learn about it from their healthcare team. This communication failure leaves patients to rely on potentially unreliable information sources.","specificNumbers":"232 patients. 81% heard of medical cannabis. 2% from healthcare professionals. 34% considered using it. Pain most common reason (55%). 18% believed cannabis could worsen symptoms. Higher education: OR 3.52 for cannabis knowledge, OR 3.21 for medical cannabis knowledge.","methodology":"Cross-sectional knowledge survey of 232 cancer patients at two Italian outpatient cancer centers and a home care service, February-April 2018.","limitations":"Italian healthcare context may differ from other countries. Self-report survey. Patients at cancer centers may not represent all cancer patients. Only captured awareness and attitudes, not actual use patterns."},{"rthcId":"RTHC-01994","title":"Cannabis acute use impacts symptoms and functionality in a cohort of antipsychotic naïve First Episode of Psychosis individuals.","authors":"Coutinho, Luccas S; Honorato, Hianna; Higuchi, Cinthia H; Cavalcante, Daniel A; Belangeiro, Sintia; Noto, Mariane; Bressan, Rodrigo A; Cordeiro, Quirino; Noto, Cristiano; Gadelha, Ary","year":2019,"journal":"Schizophrenia research. Cognition, 16, 12-16","doi":"10.1016/j.scog.2018.10.002","pmid":"30581766","tags":["psychosis","addiction","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Acute cannabis users had higher excitement symptoms and worse functioning at baseline. However, at 10-week follow-up, they showed higher response rates for excitement and positive symptoms than non-users. More days of recent cannabis use predicted worse functionality at baseline but not at follow-up, suggesting the acute cannabis effects resolved with treatment.","whyItMatters":"Studying antipsychotic-naive patients eliminates a major confound in psychosis research. The finding that cannabis-related symptoms resolve well with treatment suggests they may represent a pharmacologically modifiable component of the psychotic presentation.","specificNumbers":"175 patients at baseline, 99 at follow-up. All antipsychotic-naive. Acute cannabis users: higher excitement symptoms, worse baseline functioning. Better 10-week response for excitement and positive symptoms. Cannabis effects on functioning resolved by follow-up.","methodology":"Prospective cohort study in Sao Paulo, Brazil. 175 antipsychotic-naive first-episode psychosis patients assessed at baseline, 99 reassessed at 10-week follow-up. Cannabis exposure variables: acute use, lifetime use, age at first use.","limitations":"Significant attrition (175 to 99 at follow-up). Self-reported cannabis use. Short 10-week follow-up. Brazilian population may not generalize. Cannot determine whether the better response reflects a different illness subtype or resolution of acute cannabis effects."},{"rthcId":"RTHC-01995","title":"Exploring associations between early substance use and longitudinal socio-occupational functioning in young people engaged in a mental health service.","authors":"Crouse, Jacob J; Chitty, Kate M; Iorfino, Frank; White, Django; Nichles, Alissa; Zmicerevska, Natalia; Guastella, Adam J; Moustafa, Ahmed A; Hermens, Daniel F; Scott, Elizabeth M; Hickie, Ian B","year":2019,"journal":"PloS one, 14(1), e0210877","doi":"10.1371/journal.pone.0210877","pmid":"30653581","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-01996","title":"Deficient Functioning of Frontostriatal Circuits During the Resolution of Cognitive Conflict in Cannabis-Using Youth.","authors":"Cyr, Marilyn; Tau, Gregory Z; Fontaine, Martine; Levin, Frances R; Marsh, Rachel","year":2019,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 58(7), 702-711","doi":"10.1016/j.jaac.2018.09.436","pmid":"30768406","tags":["youth","addiction","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis-using youth (n=28) showed decreased conflict-related activation in ventromedial prefrontal cortex, striatum, pallidum, and thalamus compared to healthy controls (n=32) during a Simon task. Frontostriatal connectivity did not differ between groups. Findings are consistent with adult cannabis studies and suggest these circuit disturbances appear early.","whyItMatters":"Self-regulatory control deficits are thought to both contribute to and result from addiction. This study shows frontostriatal circuit changes appear early in the course of cannabis use, not just after years of chronic use.","specificNumbers":"28 cannabis-using youth, 32 controls. Decreased activation in vmPFC, striatum, pallidum, thalamus during conflict. Connectivity was similar between groups. Findings consistent with adult literature.","methodology":"fMRI study of 28 cannabis-using youth and 32 age-matched healthy controls during a Simon conflict task. General linear modeling compared brain activation patterns. Psychophysiologic interaction analyses examined frontostriatal connectivity.","limitations":"Cross-sectional design cannot determine causality. Cannabis use history varied. Other substance use and psychiatric comorbidities may contribute. Small sample. Cannot distinguish pre-existing traits from cannabis effects."},{"rthcId":"RTHC-01997","title":"Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder.","authors":"Dale, Tristan; Downs, Jenny; Olson, Heather; Bergin, Ann Marie; Smith, Stephanie; Leonard, Helen","year":2019,"journal":"Epilepsy research, 151, 31-39","doi":"10.1016/j.eplepsyres.2019.02.001","pmid":"30771550","tags":["cbd","epilepsy","youth","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Evidence supports cannabinoids for refractory epilepsies similar to CDD (Dravet, Lennox-Gastaut syndromes). Specific evidence for CDD includes multiple anecdotal reports and an open-label trial showing CBD was associated with significant seizure reduction. This provides the first comprehensive overview of cannabis potential for CDD.","whyItMatters":"CDD is an extremely debilitating genetic disorder with early-onset seizures that rarely respond to existing treatments. Parents are already seeking cannabis products, and this review provides the first organized assessment of the evidence specifically for this condition.","specificNumbers":"CBD proven effective in Dravet and Lennox-Gastaut (Phase III RCTs). CDD-specific: multiple anecdotal reports plus open-label trial showing significant seizure reduction with CBD.","methodology":"Comprehensive review covering cannabis history, mechanism of action, efficacy and safety in epilepsy, and specific evidence for CDKL5 Deficiency Disorder. Includes burden of disease analysis.","limitations":"CDD-specific evidence is limited to anecdotal reports and one open-label trial. The syndrome is too rare for large RCTs. Extrapolation from Dravet and Lennox-Gastaut may not be fully valid. Mechanism of CBD action in CDD is unknown."},{"rthcId":"RTHC-01998","title":"Caring for people with multiple sclerosis who use cannabis for symptom control.","authors":"Daly, Laura; Gibson, Caroline E; Dewing, Jan","year":2019,"journal":"British journal of community nursing, 24(6), 257","doi":"10.12968/bjcn.2019.24.6.265","pmid":"31166770","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"A large proportion of people with MS use cannabis to self-manage symptoms or believe in its potential benefits. Qualitative research exploring their experiences is severely lacking worldwide and absent in UK nursing literature. Patients may not feel safe discussing cannabis use with health professionals, fearing judgment. This creates barriers to person-centered care relationships.","whyItMatters":"Community nurses are frontline caregivers who encounter MS patients using cannabis in their homes. Without open communication about cannabis use, nurses cannot provide safe, informed care or identify potential drug interactions or adverse effects.","specificNumbers":"Large proportion of MS patients use or believe in cannabis benefits. Qualitative research on their experiences is lacking worldwide. Completely absent in UK nursing literature.","methodology":"Literature review of qualitative and quantitative research on MS patients who use cannabis, with focus on UK community nursing context.","limitations":"Brief review focused on UK nursing context. Does not include systematic search methodology. Limited qualitative evidence available to synthesize. Cannabis legal status varies significantly across jurisdictions."},{"rthcId":"RTHC-01999","title":"Δ9-THC and related cannabinoids suppress substance P- induced neurokinin NK1-receptor-mediated vomiting via activation of cannabinoid CB1 receptor.","authors":"Darmani, Nissar A; Belkacemi, Louiza; Zhong, Weixia","year":2019,"journal":"European journal of pharmacology, 865, 172806","doi":"10.1016/j.ejphar.2019.172806","pmid":"31738934","tags":["neuroscience","appetite","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Delta-9-THC, WIN55,212-2, and CP55,940 all dose-dependently suppressed vomiting triggered by substance P and the selective NK1 receptor agonist GR73632 in least shrews. The antiemetic effect was blocked by the CB1 antagonist SR141716A.","whyItMatters":"Chemotherapy-induced nausea involves both serotonin and substance P pathways. This study shows THC can block the substance P pathway specifically, helping explain why cannabinoids work against nausea that conventional anti-serotonin drugs miss.","specificNumbers":"THC suppressed SP-evoked vomiting dose-dependently via both i.p. and s.c. routes. The CB1 antagonist SR141716A fully blocked THC's antiemetic effect. The NK1 antagonist netupitant suppressed vomiting caused by high-dose SR141716A.","methodology":"Researchers administered varying doses of three cannabinoid receptor agonists to least shrews before inducing vomiting with substance P or GR73632. They tested whether a CB1 antagonist could reverse the antiemetic effects.","limitations":"Conducted in least shrews, not humans. The doses used may not translate directly to human pharmacology. Only acute vomiting was studied, not delayed or anticipatory nausea."},{"rthcId":"RTHC-02000","title":"Cannabidiol as a potential treatment for psychosis.","authors":"Davies, Cathy; Bhattacharyya, Sagnik","year":2019,"journal":"Therapeutic advances in psychopharmacology, 9, 2045125319881916","doi":"10.1177/2045125319881916","pmid":"31741731","tags":["cbd","psychosis","neuroscience","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD shows potential as a novel antipsychotic with a unique non-dopamine-D2 mechanism of action. Clinical evidence suggests possible benefits for positive, negative, and cognitive symptoms of psychosis, with a favorable safety and tolerability profile.","whyItMatters":"Current antipsychotics all work by blocking dopamine D2 receptors, causing significant side effects. A substantial number of patients don't respond adequately. CBD represents a fundamentally different pharmacological approach that could help treatment-resistant patients.","specificNumbers":"Psychotic disorders like schizophrenia contribute substantially to the global burden of disease. D2 antagonists have been the mainstay since the 1950s, but a significant proportion of patients don't achieve adequate remission.","methodology":"Narrative review synthesizing preclinical studies, human experimental and neuroimaging research, and clinical trials evaluating CBD's antipsychotic effects, safety, tolerability, and potential mechanisms.","limitations":"This is a narrative review, not a systematic review or meta-analysis. The clinical evidence base for CBD as an antipsychotic is still limited, with few large-scale randomized controlled trials completed."},{"rthcId":"RTHC-02001","title":"Adverse Consequences of Co-Occurring Opioid Use Disorder and Cannabis Use Disorder Compared to Opioid Use Disorder Only.","authors":"De Aquino, Joao P; Sofuoglu, Mehmet; Stefanovics, Elina; Rosenheck, Robert","year":2019,"journal":"The American journal of drug and alcohol abuse, 45(5), 527-537","doi":"10.1080/00952990.2019.1607363","pmid":"31112429","tags":["addiction","harm-reduction","pain","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Veterans with co-occurring OUD and CUD received fewer opioid prescriptions (mean 3.79 vs 4.8) compared to the OUD-only group, but had a higher likelihood of inpatient psychiatric admission (RR = 1.95) and homelessness (RR = 1.52).","whyItMatters":"The idea that cannabis might substitute for opioids has gained attention, but this study shows the relationship is complicated. While cannabis co-use was associated with fewer opioid prescriptions, it didn't translate to better overall outcomes.","specificNumbers":"234,181 veterans studied (94% male). Co-occurring OUD+CUD group: 8.6% of sample. Mean opioid prescriptions: 3.79 (OUD+CUD) vs 4.8 (OUD only). Psychiatric admission risk ratio: 1.95. Homelessness risk ratio: 1.52. No significant difference in ED visits.","methodology":"Retrospective analysis of 234,181 veterans with drug use disorder diagnoses from the National Veterans Health Administration, comparing outcomes across four groups: co-occurring OUD+CUD, OUD only, CUD only, and other drug use disorders using logistic and linear regression models.","limitations":"Retrospective design cannot establish causation. The veteran population is predominantly male, limiting generalizability. Cannabis use disorder is clinically different from controlled medical cannabis use. Self-reported SC use relied on honesty."},{"rthcId":"RTHC-02002","title":"Therapeutic Prospects of Cannabidiol for Alcohol Use Disorder and Alcohol-Related Damages on the Liver and the Brain.","authors":"De Ternay, Julia; Naassila, Mickaël; Nourredine, Mikail; Louvet, Alexandre; Bailly, François; Sescousse, Guillaume; Maurage, Pierre; Cottencin, Olivier; Carrieri, Patrizia Maria; Rolland, Benjamin","year":2019,"journal":"Frontiers in pharmacology, 10, 627","doi":"10.3389/fphar.2019.00627","pmid":"31214036","tags":["cbd","addiction","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"In animal models, CBD reduced overall alcohol drinking by decreasing ethanol intake, motivation for ethanol, relapse, anxiety, and impulsivity. CBD also reduced alcohol-related liver steatosis and fibrosis, and prevented alcohol-related neuronal loss.","whyItMatters":"Alcohol use disorder affects millions globally with limited treatment options. If CBD can simultaneously reduce drinking behavior and protect organs already damaged by alcohol, it could represent a dual-purpose intervention unlike anything currently available.","specificNumbers":"16 million adults in the US suffer from alcohol use disorders. CBD reduced alcohol-related liver damage by reducing lipid accumulation, stimulating autophagy, modulating inflammation, and reducing oxidative stress.","methodology":"Narrative review of experimental studies examining CBD's effects on alcohol drinking behavior, alcohol-related liver toxicity (steatosis, fibrosis), and alcohol-related brain damage in animal models.","limitations":"All evidence comes from animal models. No human clinical trials for CBD in alcohol use disorder were reviewed. Doses and routes of administration in animal studies may not translate to humans. Narrative review methodology is less rigorous than systematic review."},{"rthcId":"RTHC-02003","title":"Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats.","authors":"Deabold, Kelly A; Schwark, Wayne S; Wolf, Lisa; Wakshlag, Joseph J","year":2019,"journal":"Animals : an open access journal from MDPI, 9(10)","doi":"10.3390/ani9100832","pmid":"31635105","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02004","title":"Cannabinoid hyperemesis syndrome: a review of the literature.","authors":"Deceuninck, Eleonore; Jacques, Denis","year":2019,"journal":"Psychiatria Danubina, 31(Suppl 3), 390-394","doi":null,"pmid":"31488758","tags":["appetite","medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS manifests as incoercible cyclical vomiting, diffuse abdominal pain, and compulsive hot showering in chronic cannabis users. Patients typically experience years of diagnostic delay, repeated emergency visits, and unnecessary invasive examinations before correct diagnosis.","whyItMatters":"As cannabis use increases, more people may develop CHS without being correctly diagnosed. Physicians unfamiliar with the condition subject patients to years of expensive, invasive testing when the clinical presentation is actually distinctive and recognizable.","specificNumbers":"Literature spans 2004-2019. Diagnostic delay is typically several years. Patients make frequent emergency department visits before correct diagnosis.","methodology":"Literature review of scientific articles published between 2004 and 2019 from Cochrane, Medline, PubMed, and PsycInfo databases using keywords \"hyperemesis,\" \"cannabis,\" and \"cannabinoid.\"","limitations":"This is a narrative literature review, not a systematic review with defined quality assessment. Prevalence data for CHS are limited. The pathophysiology of CHS, including why hot showers provide relief, remains poorly understood."},{"rthcId":"RTHC-02005","title":"Exploring the Diagnosis and Profile of Cannabis Allergy.","authors":"Decuyper, Ine Ilona; Van Gasse, Athina Ludovica; Faber, Margaretha A; Elst, Jessy; Mertens, Christel; Rihs, Hans-Peter; Hagendorens, Margo M; Sabato, Vito; Lapeere, Hilde; Bridts, Chris H; De Clerck, Luc S; Ebo, Didier Gaston","year":2019,"journal":"The journal of allergy and clinical immunology. In practice, 7(3), 983-989.e5","doi":"10.1016/j.jaip.2018.09.017","pmid":"30273677","tags":["harm-reduction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Can s 3-based diagnostic tests showed the best combination of predictive values (80% positive, 60% negative) for confirming cannabis allergy. Can s 3-positive patients had significantly more cofactor-mediated reactions and cross-reactive sensitizations to other plant lipid transfer proteins.","whyItMatters":"Cannabis allergy is an emerging concern as legalization increases exposure. Standardized diagnostic tests don't exist yet, and many clinicians are unaware the condition exists. This study identifies the most reliable testing approaches.","specificNumbers":"120 cannabis allergy patients studied. 72% of those with likely anaphylaxis were Can s 3 sensitized. Can s 3-based tests: 80% positive predictive value, 60% negative predictive value. sIgE hemp: 82% sensitivity but only 32% specificity. 72% of anaphylaxis patients also had systemic reactions to plant-derived foods.","methodology":"Clinical study of 120 patients with cannabis allergy, stratified by symptom severity, compared against 62 healthy and 189 atopic controls. Five diagnostic tests were evaluated: sIgE hemp, sIgE and basophil activation test with recombinant Can s 3, BAT with crude cannabis extract, and skin prick test with nCan s 3-rich extract.","limitations":"Not all cannabis allergy patients are Can s 3 positive, suggesting other allergens play a role. The study lacked standardized cannabis allergen preparations. Cross-reactivity patterns may vary by population and geographic region."},{"rthcId":"RTHC-02006","title":"Genome-wide association study implicates CHRNA2 in cannabis use disorder.","authors":"Demontis, Ditte; Rajagopal, Veera Manikandan; Thorgeirsson, Thorgeir E; Als, Thomas D; Grove, Jakob; Leppälä, Kalle; Gudbjartsson, Daniel F; Pallesen, Jonatan; Hjorthøj, Carsten; Reginsson, Gunnar W; Tyrfingsson, Thorarinn; Runarsdottir, Valgerdur; Qvist, Per; Christensen, Jane Hvarregaard; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Huckins, Laura M; Stahl, Eli A; Timmermann, Allan; Agerbo, Esben; Hougaard, David M; Werge, Thomas; Mors, Ole; Mortensen, Preben Bo; Nordentoft, Merete; Daly, Mark J; Stefansson, Hreinn; Stefansson, Kari; Nyegaard, Mette; Børglum, Anders D","year":2019,"journal":"Nature neuroscience, 22(7), 1066-1074","doi":"10.1038/s41593-019-0416-1","pmid":"31209380","tags":["addiction","genetics","cognition"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"A variant (rs56372821) near the CHRNA2 gene reached genome-wide significance for cannabis use disorder risk (P = 9.31 x 10^-12) and replicated independently (P = 3.27 x 10^-3). Higher genetic loading for cognitive performance variants was associated with decreased CUD risk.","whyItMatters":"This is the first robustly replicated genetic variant for cannabis use disorder. Understanding the biological pathways involved could lead to targeted prevention or treatment strategies, and the cholinergic connection links cannabis addiction biology to nicotine pathways.","specificNumbers":"Discovery: 2,387 cases, 48,985 controls. Replication: 5,501 cases, 301,041 controls. Lead variant P-value: 9.31 x 10^-12. Twin heritability estimates for CUD: 51-70%. Cannabis is the most frequently used illicit substance worldwide; ~1 in 10 users become dependent.","methodology":"Genome-wide association study of 2,387 CUD cases and 48,985 controls, with replication in 5,501 cases and 301,041 controls. Gene expression analysis and polygenic scoring for cognitive traits were also performed.","limitations":"GWAS identifies associations, not mechanisms. The identified variant explains only a small fraction of CUD heritability. European-ancestry populations were overrepresented, limiting generalizability. Environmental factors interacting with genetic risk were not captured."},{"rthcId":"RTHC-02007","title":"Formation of HETE-EAs and dihydroxy derivatives in mouse kidney tissue and analysis by high-performance liquid chromatography tandem mass spectrometry.","authors":"Dempsey, Sara K; Gesseck, Ashley M; Ahmad, Ashfaq; Daneva, Zdravka; Ritter, Joseph K; Poklis, Justin L","year":2019,"journal":"Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1126-1127, 121748","doi":"10.1016/j.jchromb.2019.121748","pmid":"31437772","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02008","title":"Hospital Stay in Synthetic Cannabinoid Users With Bipolar Disorder, Schizophrenia, or Other Psychotic Disorders Compared With Cannabis Users.","authors":"Deng, Huiqiong; Desai, Pratikkumar V; Mohite, Satyajit; Okusaga, Olaoluwa O; Zhang, Xiang Yang; Nielsen, David A; Kosten, Thomas R","year":2019,"journal":"Journal of studies on alcohol and drugs, 80(2), 230-235","doi":null,"pmid":"31014468","tags":["synthetic-cannabinoids","psychosis","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users had significantly shorter hospital stays (8.02 days) and lower antipsychotic doses than the no-drug group (10.19 days). Synthetic cannabinoid users (8.29 days) did not differ significantly from either group on length of stay or medication doses.","whyItMatters":"Synthetic cannabinoids are often assumed to cause more severe psychiatric episodes than natural cannabis. This study found that's not reflected in hospital stay duration or medication needs, challenging assumptions about relative acute psychiatric impact.","specificNumbers":"Hospital stay: SC group 8.29 days, cannabis group 8.02 days, no-drug group 10.19 days (p < .001). Antipsychotic doses (chlorpromazine equivalents): SC 254.64 mg, cannabis 219.16 mg, no-drug 294.79 mg (p = .002). SC group: n=77, cannabis: n=248, no-drug: n=1,336.","methodology":"Retrospective medical records review of 1,661 psychiatric inpatients with bipolar disorder, schizophrenia, or other psychotic disorders, comparing synthetic cannabinoid users (n=77), cannabis users (n=248), and non-drug users (n=1,336) on hospital stay length and antipsychotic doses at discharge.","limitations":"Small synthetic cannabinoid group (n=77) limits statistical power. SC use was self-reported without urine confirmation. Retrospective design. Single-site study. Doesn't capture readmission rates or long-term outcomes. Multiple SC compounds were likely involved but not differentiated."},{"rthcId":"RTHC-02009","title":"In-hospital outcomes of inflammatory bowel disease in cannabis users: a nationwide propensity-matched analysis in the United States.","authors":"Desai, Rupak; Patel, Upenkumar; Goyal, Hemant; Rimu, Afrina Hossain; Zalavadia, Dipen; Bansal, Pardeep; Shah, Nihar","year":2019,"journal":"Annals of translational medicine, 7(12), 252","doi":"10.21037/atm.2019.04.63","pmid":"31355219","tags":["inflammation","medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"In Crohn's disease, cannabis users had lower rates of colorectal cancer (0.3% vs 1.2%), parenteral nutrition need, and anemia, but higher rates of fistulizing disease and lower GI hemorrhage. Both CD and UC cannabis users had shorter hospital stays (4.2 vs 5.0 days for CD; 4.3 vs 5.7 days for UC) and lower charges.","whyItMatters":"Cannabis has known anti-inflammatory properties, and IBD patients increasingly use it for symptom management. This large national analysis provides real-world data on how cannabis use correlates with hospitalization outcomes in this population.","specificNumbers":"Crohn's: 6,002 propensity-matched patients. Colorectal cancer: 0.3% vs 1.2% (cannabis vs non). Hospital stay: 4.2 vs 5.0 days. Charges: $28,956 vs $35,180. UC: 1,481 matched patients. Hospital stay: 4.3 vs 5.7 days. Charges lower with cannabis use (p < .001).","methodology":"Propensity-matched analysis of the Nationwide Inpatient Sample (2010-2014) comparing cannabis-using vs non-using hospitalizations for Crohn's disease (6,002 matched) and ulcerative colitis (1,481 matched) using ICD-9 codes.","limitations":"Observational propensity-matched study cannot establish causation. ICD-9 codes for cannabis use likely underestimate prevalence. No data on cannabis type, dose, frequency, or route of administration. Recreational use codes may miss medical users."},{"rthcId":"RTHC-02010","title":"The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study","authors":"Di Forti, Marta; Quattrone, Diego; Freeman, Tom P.; Tripoli, Giada; Gayer-Anderson, Charlotte; Quigley, Harriet; et al.","year":2019,"journal":"The Lancet Psychiatry, 6(5), 427-436","doi":null,"pmid":"30902669","tags":["psychosis","cognition","potency"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"This multicentre study across 11 sites in Europe and Brazil compared 901 people experiencing first-episode psychosis with 1,237 population controls. The pattern was consistent: daily cannabis use was associated with 3.2 times higher odds of psychotic disorder compared to never-users. For daily users of high-potency cannabis (THC above 10%), the odds jumped to nearly 5 times higher.\n\nBut the most striking finding was geographic. In cities where high-potency cannabis dominated the market — London and Amsterdam — the population attributable fractions were highest. The researchers estimated that if high-potency cannabis were no longer available, 30% of new psychosis cases in London and 50% in Amsterdam could theoretically be prevented. In cities where lower-potency products were more common, the estimated impact was much smaller.\n\nThis didn't prove causation, but it showed something beyond individual risk: cannabis potency at the market level appeared to shape psychosis incidence at the population level.","whyItMatters":"Previous studies linked cannabis to psychosis risk at the individual level. This study scaled that question up to entire cities and found that the local cannabis market — specifically how potent the available product was — appeared to influence how many people developed psychotic disorders. That's a different kind of finding. It suggests that potency regulation at the policy level could be a public health lever.\n\nThe London and Amsterdam numbers were particularly striking because those cities had the highest-potency cannabis markets AND the highest psychosis incidence in the study. The correlation was ecological, not proof, but the consistency across sites made it harder to dismiss.","specificNumbers":"• Daily cannabis use: 3.2x higher odds of psychotic disorder vs never-use\n• Daily high-potency use (10%+ THC): ~5x higher odds\n• London: 30% of new psychosis cases attributable to high-potency cannabis (estimated)\n• Amsterdam: 50% attributable (estimated)\n• 901 first-episode psychosis cases, 1,237 controls across 11 sites","methodology":"Multicentre case-control study (EU-GEI project) across 11 sites in 6 European countries and Brazil. Recruited patients aged 18-64 presenting with first-episode psychosis and population-representative controls. Used adjusted logistic regression models. Cannabis potency was classified using national and Europe-wide data on expected THC concentrations: low potency (<10% THC) vs high potency (10%+ THC). Calculated population attributable fractions assuming causality.","limitations":"Case-control design cannot prove causation. People predisposed to psychosis may be drawn to cannabis use (reverse causation). Self-reported cannabis use is unreliable, and potency was estimated from market data rather than measured in what participants actually consumed. Population attributable fractions assume a causal relationship that hasn't been proven. Cultural and diagnostic differences across 11 sites may affect comparability."},{"rthcId":"RTHC-02011","title":"New Synthetic Cannabinoids Metabolism and Strategies to Best Identify Optimal Marker Metabolites.","authors":"Diao, Xingxing; Huestis, Marilyn A","year":2019,"journal":"Frontiers in chemistry, 7, 109","doi":"10.3389/fchem.2019.00109","pmid":"30886845","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02012","title":"CANNABINOID CONUNDRUM:: A STUDY OF MARIJUANA AND HEMP LEGALITY IN THE UNITED STATES.","authors":"Dickson, Kennedy; Janasie, Catherine; Willett, Kristine L","year":2019,"journal":"Arizona journal of environmental law & policy, 10(20), 132-150","doi":null,"pmid":"34007734","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02013","title":"Discovery of Orexant and Anorexant Agents with Indazole Scaffold Endowed with Peripheral Antiedema Activity.","authors":"Dimmito, Marilisa P; Stefanucci, Azzurra; Pieretti, Stefano; Minosi, Paola; Dvorácskó, Szabolcs; Tömböly, Csaba; Zengin, Gokhan; Mollica, Adriano","year":2019,"journal":"Biomolecules, 9(9)","doi":"10.3390/biom9090492","pmid":"31527522","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02014","title":"Are oral fluid testing devices effective for the roadside detection of recent cannabis use? A systematic review.","authors":"Dobri, S C D; Moslehi, A H; Davies, T C","year":2019,"journal":"Public health, 171, 57-65","doi":"10.1016/j.puhe.2019.03.006","pmid":"31102828","tags":["driving","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Nine oral fluid testing devices were evaluated, and none met the minimum 80% benchmark for sensitivity, specificity, and accuracy set by the ROSITA, ROSITA-2, and DRUID projects. Devices detecting lower THC concentrations performed better than those with higher cutoffs.","whyItMatters":"As more jurisdictions legalize cannabis and need to enforce impaired driving laws, reliable roadside detection is critical. This review shows the technology isn't there yet, creating a gap between legal frameworks and enforcement capability.","specificNumbers":"15 studies reviewed. 9 devices evaluated. Target benchmark: 80% for sensitivity, specificity, and accuracy. None of the devices met all three criteria. Lower THC detection thresholds correlated with better performance.","methodology":"Systematic review searching eight databases (PubMed, Web of Science, MEDLINE, Engineering Village, Embase, Compendex, CINAHL, Scopus) for studies evaluating on-site oral fluid drug screening devices for cannabis detection. Fifteen articles were selected for review.","limitations":"Lack of standardized test protocols across studies made comparison difficult. Confirmation analyses varied between blood and oral fluid. Many subjects had used multiple drugs. Device technology may have improved since the studies reviewed."},{"rthcId":"RTHC-02015","title":"The epigenetic modulation of alcohol/ethanol and cannabis exposure/co-exposure during different stages.","authors":"Dobs, Yasminah Elsaadany; Ali, Mohamed Medhat","year":2019,"journal":"Open biology, 9(1), 180115","doi":"10.1098/rsob.180115","pmid":"30958117","tags":["genetics","neuroscience","youth","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Both alcohol and cannabis independently modulate the epigenome through chromatin modification and remodeling, affecting gene activation and silencing. Co-exposure may have compounding effects that differ across developmental stages, contributing to addiction, behavioral abnormalities, and neurodegeneration.","whyItMatters":"Most substance research studies alcohol and cannabis separately, but many people use both. Understanding how they interact at the molecular level through epigenetic changes could reveal why co-use carries different risks than either substance alone.","specificNumbers":"97.5 million Americans over 12 have used cannabis for non-medical use. 1 in 10 cannabis users develop dependence. 16% of US substance abuse admissions are cannabis-related (second to alcohol). 16 million adults have alcohol use disorders.","methodology":"Narrative review covering epigenetic mechanisms (DNA methylation, histone modification, chromatin remodeling) affected by cannabis and alcohol exposure, examining evidence across prenatal, adolescent, and adult stages.","limitations":"This is a narrative review with inherent selection bias. Much of the evidence comes from animal studies. The epigenetic overlap between alcohol and cannabis is largely theoretical at this stage. Individual genetic variation in epigenetic susceptibility was not addressed."},{"rthcId":"RTHC-02016","title":"Cannabinoid exposure during pregnancy and its impact on immune function.","authors":"Dong, Catherine; Chen, Jingwen; Harrington, Amy; Vinod, K Yaragudri; Hegde, Muralidhar L; Hegde, Venkatesh L","year":2019,"journal":"Cellular and molecular life sciences : CMLS, 76(4), 729-743","doi":"10.1007/s00018-018-2955-0","pmid":"30374520","tags":["pregnancy","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids mediate robust immunomodulation by altering cytokine levels, causing apoptosis of lymphoid cells, and inducing suppressor cells. Maternal exposure during pregnancy could lead to dysregulation of both innate and adaptive immune systems in the developing fetus, with emerging evidence for epigenetic mechanisms causing long-lasting impact.","whyItMatters":"Cannabis use during pregnancy is increasing, yet the immunological consequences for the developing fetus are poorly understood. This review highlights that cannabinoids don't just cross the placenta but may fundamentally alter how the fetal immune system develops.","specificNumbers":"Cannabinoids mediate effects through G-protein coupled CB1 and CB2 receptors. They alter cytokine levels, induce apoptosis of lymphoid cells, and generate immune suppressor cells. Epigenetic mechanisms may cause effects lasting beyond the exposure period.","methodology":"Review of research on cannabinoid effects on the immune system, focusing on CB1 and CB2 receptor-mediated immunomodulation and its implications for fetal and offspring immune development following in utero exposure.","limitations":"Much of the evidence comes from animal models and in vitro studies. Human data on fetal immune effects of cannabinoid exposure are limited. The specific doses and timing that pose risk during pregnancy are not established."},{"rthcId":"RTHC-02017","title":"Using recreational cannabis to treat insomnia: Evidence from over-the-counter sleep aid sales in Colorado.","authors":"Doremus, Jacqueline M; Stith, Sarah S; Vigil, Jacob M","year":2019,"journal":"Complementary therapies in medicine, 47, 102207","doi":"10.1016/j.ctim.2019.102207","pmid":"31779999","tags":["sleep","legalization","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Sleep aid market shares were growing before recreational cannabis availability, but the trend reversed with dispensary entry (-0.33 percentage points from a mean growth of 0.14). The decline increased with more dispensaries and higher county-level cannabis sales, and was driven by diphenhydramine and doxylamine products rather than herbal or melatonin supplements.","whyItMatters":"Sleep disturbances are not a qualifying condition under any US medical cannabis law, yet this data shows people are already substituting cannabis for OTC sleep aids at scale. This gap between actual use and regulatory recognition has implications for both policy and clinical research.","specificNumbers":"236% decrease in sleep aid market share growth trend after dispensary entry. -0.33 percentage point shift (95% CI: -0.43 to -0.24, p < 0.01) from mean growth of 0.14. Effect size increased with dispensary count and sales volume. Driven by diphenhydramine/doxylamine products, not melatonin.","methodology":"Multivariable panel regression using UPC-level grocery store scanner data comparing monthly sleep aid market shares against dispensary access (existence, sales, count) across Colorado counties between December 2013 and December 2014.","limitations":"Ecological study design cannot confirm individual-level substitution. Only covers one year of data in one state. Scanner data from grocery stores may not capture all OTC sleep aid purchases. Cannot determine whether cannabis is equally or more effective than OTC sleep aids."},{"rthcId":"RTHC-02018","title":"Cannabis as a cause of death: A review.","authors":"Drummer, Olaf H; Gerostamoulos, Dimitri; Woodford, Noel W","year":2019,"journal":"Forensic science international, 298, 298-306","doi":"10.1016/j.forsciint.2019.03.007","pmid":"30925348","tags":["cardiovascular","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"At least 35 people presented with significant cardiovascular emergencies after recently smoking cannabis, and at least 13 deaths from cardiovascular mechanisms have been reported. Multiple cases of stroke and vascular arteritis (sometimes requiring limb amputation) have also been documented.","whyItMatters":"Cannabis is widely perceived as physically safe, but these documented cardiovascular deaths and emergencies challenge that assumption. The true incidence is likely higher than reported, given that cannabis is rarely considered as a contributing factor in sudden death investigations.","specificNumbers":"At least 35 cardiovascular emergency presentations reported. At least 13 deaths from cardiovascular mechanisms documented. Multiple cases of stroke and vascular arteritis with limb amputation. These figures are described as likely underestimates.","methodology":"Review of published case reports of hospital admissions for cardiovascular events associated with cannabis use, epidemiological studies, and case reports of sudden death attributed to cannabis, spanning the forensic and clinical literature.","limitations":"Based on case reports, which are the weakest form of evidence for establishing causation. Positive THC levels after death don't prove causation. Many cases involved cofactors like tobacco or other substances. Prevalence-based risk estimation is not possible from case reports alone."},{"rthcId":"RTHC-02019","title":"Ethical Implications for Providers Regarding Cannabis Use in Children With Autism Spectrum Disorders.","authors":"Duvall, Susanne W; Lindly, Olivia; Zuckerman, Katharine; Msall, Michael E; Weddle, Melissa","year":2019,"journal":"Pediatrics, 143(2)","doi":"10.1542/peds.2018-0558","pmid":"30610100","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02020","title":"Change in alcohol and other drug use during five years of continuous opioid substitution treatment.","authors":"Eastwood, Brian; Strang, John; Marsden, John","year":2019,"journal":"Drug and alcohol dependence, 194, 438-446","doi":"10.1016/j.drugalcdep.2018.11.008","pmid":"30502545","tags":["addiction","harm-reduction","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Continued high-level heroin use during OST predicted continued high-level crack cocaine use (RRR 58.7), continued high-level alcohol use (RRR 1.2), and increasing unspecified drug use (RRR 1.7), but was associated with less high-and-increasing cannabis use (RRR 0.5).","whyItMatters":"Understanding how different substance use patterns cluster during long-term opioid treatment helps clinicians identify which patients need additional support. The finding that cannabis use did not escalate alongside heroin non-response adds nuance to polysubstance use assumptions.","specificNumbers":"7,717 patients followed for 5 years. Continued high heroin use predicted crack (RRR 58.7), alcohol (RRR 1.2), but less cannabis escalation (RRR 0.5). Increasing crack use reduced odds of successful treatment completion (AOR 0.2-0.5).","methodology":"Prospective observational cohort of 7,717 adults continuously enrolled in opioid substitution treatment with methadone or buprenorphine from 2008/09 to 2013/14 in England. Multi-level latent class growth analysis identified substance use trajectories across 11 six-monthly clinical reviews.","limitations":"Observational design cannot determine causation. Cannabis and other drug use were clinician-assessed, not biochemically verified at every timepoint. English treatment population may not generalize to other healthcare systems."},{"rthcId":"RTHC-02021","title":"Marijuana use and driving in Washington State: Risk perceptions and behaviors before and after implementation of retail sales.","authors":"Eichelberger, Angela H","year":2019,"journal":"Traffic injury prevention, 20(1), 23-29","doi":"10.1080/15389588.2018.1530769","pmid":"30822133","tags":["driving","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"THC-positive daytime drivers increased from 8% before retail sales to 23% six months after. Nighttime THC prevalence was unchanged (19-20%). Drivers who perceived marijuana as very likely to impair driving had 40% lower odds of testing THC-positive. Self-reported use did not predict changes.","whyItMatters":"This is one of the first studies to combine roadside biological testing with survey data around a legalization event. The disconnect between self-reported use and test results suggests surveys alone underestimate actual cannabis-impaired driving prevalence.","specificNumbers":"2,355 drivers surveyed across 3 waves. Daytime THC-positive: 8% pre-retail to 23% post-retail. Nighttime THC-positive: 19% to 20% (unchanged). Perceived impairment risk reduced THC-positive odds by 40%. Perceived arrest risk had no effect.","methodology":"Three-wave roadside survey of 2,355 drivers in Washington State (June 2014, November-December 2014, June 2015) with marijuana questionnaires and biological specimens (oral fluid, blood for THC, breath for alcohol).","limitations":"THC-positive status does not necessarily indicate impairment at the time of driving. One year of follow-up may not capture long-term trends. Washington State results may not generalize to other states with different markets and demographics."},{"rthcId":"RTHC-02022","title":"Prediction and Experimental Confirmation of Novel Peripheral Cannabinoid-1 Receptor Antagonists.","authors":"El-Atawneh, Shayma; Hirsch, Shira; Hadar, Rivka; Tam, Joseph; Goldblum, Amiram","year":2019,"journal":"Journal of chemical information and modeling, 59(9), 3996-4006","doi":"10.1021/acs.jcim.9b00577","pmid":"31433190","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02023","title":"Cannabis-based products for pediatric epilepsy: A systematic review.","authors":"Elliott, Jesse; DeJean, Deirdre; Clifford, Tammy; Coyle, Doug; Potter, Beth K; Skidmore, Becky; Alexander, Christine; Repetski, Alexander E; Shukla, Vijay; McCoy, Bláthnaid; Wells, George A","year":2019,"journal":"Epilepsia, 60(1), 6-19","doi":"10.1111/epi.14608","pmid":"30515765","tags":["epilepsy","cbd","youth","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"CBD reduced median monthly seizure frequency by 19.8% vs placebo (95% CI: -27.0% to -12.6%) and increased the proportion achieving 50%+ seizure reduction (RR = 1.76). However, seizure freedom was not significantly different. Diarrhea was significantly more common with CBD (RR = 2.25).","whyItMatters":"This provides the most rigorous assessment of CBD for pediatric epilepsy at the time of publication. The moderate-certainty evidence supports its use for drug-resistant cases, while clearly noting that results apply specifically to pharmaceutical-grade CBD, not all cannabis products.","specificNumbers":"4 RCTs + 19 non-randomized studies. Seizure frequency reduction: -19.8% (95% CI: -27.0% to -12.6%). 50%+ seizure reduction: RR 1.76 (95% CI: 1.07-2.88). Diarrhea: RR 2.25 (95% CI: 1.38-3.68). No significant difference in seizure freedom, quality of life, or sleep.","methodology":"Living systematic review with meta-analysis of 4 RCTs and 19 non-randomized studies. Searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature. Risk of bias assessed per study; GRADE used for quality of evidence per outcome.","limitations":"All non-randomized studies were at high risk of bias. Evidence is primarily limited to pharmaceutical-grade CBD. Quality of life and sleep outcomes showed no significant improvement. Short follow-up periods in most studies."},{"rthcId":"RTHC-02024","title":"Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings.","authors":"Elsaid, Sonja; Kloiber, Stefan; Le Foll, Bernard","year":2019,"journal":"Progress in molecular biology and translational science, 167, 25-75","doi":"10.1016/bs.pmbts.2019.06.005","pmid":"31601406","tags":["cbd","mental-health","psychosis","epilepsy","addiction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"CBD is safe, well-tolerated, and efficacious for several seizure disorders. It shows anxiolytic effects in social anxiety disorder and antipsychotic effects in schizophrenia. Parkinson's patients reported improved sleep and quality of life. No human studies existed for Alzheimer's or unipolar depression at the time of review.","whyItMatters":"This review maps the landscape of CBD research across neuropsychiatric conditions, clearly distinguishing where clinical evidence exists (epilepsy) from where only preclinical data supports therapeutic potential (depression, Alzheimer's).","specificNumbers":"CBD demonstrated anti-epileptic, anti-oxidant, anti-inflammatory, antipsychotic, anxiolytic, and antidepressant properties in preclinical studies. Clinical efficacy confirmed for seizure disorders. CBD treatment alone was insufficient for Huntington's disease choreic movements.","methodology":"Narrative review summarizing selected preclinical and clinical studies examining CBD effects across neuropsychiatric disorders including epilepsy, psychosis, anxiety, Parkinson's, Huntington's, addiction, Alzheimer's, and depression.","limitations":"Narrative review with inherent selection bias in study inclusion. Many conditions discussed have only preclinical evidence. Sample sizes in existing clinical trials are generally small. Long-term safety data are limited."},{"rthcId":"RTHC-02025","title":"Adult attention-deficit/hyperactivity disorder, risky substance use and substance use disorders: a follow-up study among young men.","authors":"Estévez-Lamorte, Natalia; Foster, Simon; Eich-Höchli, Dominique; Moggi, Franz; Gmel, Gerhard; Mohler-Kuo, Meichun","year":2019,"journal":"European archives of psychiatry and clinical neuroscience, 269(6), 667-679","doi":"10.1007/s00406-018-0958-3","pmid":"30483874","tags":["addiction","youth","cognition","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"ADHD predicted persistent risky alcohol and nicotine use and was positively linked to alcohol use disorder but negatively linked to cannabis use disorder at follow-up. For all substance use disorders, ADHD was associated with both persistence and maturing out, with early alcohol initiation distinguishing between these trajectories for AUD.","whyItMatters":"The counterintuitive finding that ADHD was associated with maturing out of risky cannabis use, while predicting persistent alcohol and nicotine problems, suggests that substance-specific prevention strategies are needed rather than blanket approaches.","specificNumbers":"4,975 Swiss men, mean age 20. ADHD predicted persistent risky alcohol use, persistent risky nicotine use, and maturing out of risky cannabis use. ADHD was positively linked to AUD but negatively to CUD at 15-month follow-up.","methodology":"Prospective cohort of 4,975 Swiss men (mean age 20) from the Cohort Study on Substance Use Risk Factors, with baseline and 15-month follow-up assessments of ADHD, risky substance use, and substance use disorders, adjusted for sociodemographics and comorbidity.","limitations":"Male-only sample limits generalizability to women. Relatively short 15-month follow-up. Swiss military conscript population may not represent broader populations. Self-reported substance use and ADHD assessment."},{"rthcId":"RTHC-02026","title":"Gastrointestinal Adverse Events of Cannabinoid 1 Receptor Inverse Agonists suggest their Potential Use in Irritable Bowel Syndrome with Constipation: A Systematic Review and Meta-Analysis.","authors":"Fabisiak, Adam; Włodarczyk, Marcin; Fabisiak, Natalia; Storr, Martin; Fichna, Jakub","year":2019,"journal":"Journal of gastrointestinal and liver diseases : JGLD, 28(4), 473-481","doi":"10.15403/jgld-265","pmid":"31826058","tags":["inflammation","medical-cannabis","pain"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Rimonabant 20mg produced significantly more GI adverse events than placebo (OR 2.05) and overall adverse events (OR 1.35). Taranabant showed similar patterns (GI AEs OR 1.75, overall OR 1.36). Both drugs also caused significantly more psychiatric adverse events.","whyItMatters":"IBS with constipation has limited treatment options. This creative approach of repurposing a known side effect (diarrhea from CB1 blockers) into a therapeutic benefit illustrates how understanding the endocannabinoid system's role in gut function could yield new treatments.","specificNumbers":"18 trials analyzed. Rimonabant 20mg: GI AEs OR 2.05 (CI: 1.65-2.55, p<0.001), psychiatric AEs OR 1.79 (CI: 1.46-2.21). Taranabant 0.5-8mg: GI AEs OR 1.75 (CI: 1.29-2.37), psychiatric AEs OR 1.82 (CI: 1.54-2.16).","methodology":"Systematic review and meta-analysis of 18 clinical trials published through May 2018 reporting at least one month of treatment with rimonabant or taranabant, analyzing gastrointestinal adverse events using odds ratios.","limitations":"The trials analyzed were designed for obesity/metabolic conditions, not IBS. GI adverse events were secondary outcomes, not primary endpoints. Psychiatric side effects (which led to rimonabant's withdrawal) remain a barrier. No IBS-specific trials have been conducted."},{"rthcId":"RTHC-02027","title":"Comprehensive investigation on synthetic cannabinoids: Metabolic behavior and potency testing, using 5F-APP-PICA and AMB-FUBINACA as model compounds.","authors":"Fabregat-Safont, David; Mardal, Marie; Noble, Carolina; Cannaert, Annelies; Stove, Christophe P; Sancho, Juan V; Linnet, Kristian; Hernández, Félix; Ibáñez, María","year":2019,"journal":"Drug testing and analysis, 11(9), 1358-1368","doi":"10.1002/dta.2659","pmid":"31192526","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02028","title":"Sex, THC, and hormones: Effects on density and sensitivity of CB1 cannabinoid receptors in rats.","authors":"Farquhar, Charlotte E; Breivogel, Christopher S; Gamage, Thomas F; Gay, Elaine A; Thomas, Brian F; Craft, Rebecca M; Wiley, Jenny L","year":2019,"journal":"Drug and alcohol dependence, 194, 20-27","doi":"10.1016/j.drugalcdep.2018.09.018","pmid":"30391834","tags":["sex-differences","tolerance","addiction","cognition"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers gave male and female rats twice-daily THC injections for a week and then measured CB1 receptor density and function across four brain regions: cerebellum, hippocampus, prefrontal cortex, and striatum. Before THC treatment, sex differences in CB1 receptors were minimal — one exception was higher receptor activation in female hippocampi.\n\nAfter repeated THC, both sexes showed pronounced receptor desensitization (reduced function) and downregulation (fewer receptors). But the magnitude of change was consistently greater in females across all brain regions. When researchers removed ovaries or testes and replaced hormones selectively, estradiol emerged as a contributing factor — it influenced how strongly the brain's cannabinoid receptors responded to chronic THC exposure.\n\nThe results suggest that biological sex shapes how the brain adapts to repeated cannabis exposure at the receptor level, potentially explaining why men and women sometimes respond differently to cannabis.","whyItMatters":"Most cannabis research has historically been conducted on male subjects — animal and human. This study directly compared male and female brains under identical THC exposure and found the female brain adapted more dramatically. If these receptor-level differences translate to humans, they could explain clinical observations that women develop cannabis tolerance differently, may be more sensitive to certain effects, and potentially face different addiction trajectories.\n\nThe estradiol finding adds another layer: hormonal fluctuations across the menstrual cycle could theoretically change how cannabis affects a woman's brain from week to week.","specificNumbers":"• THC dose: 30 mg/kg twice daily for 1 week\n• Brain regions tested: cerebellum, hippocampus, prefrontal cortex, striatum\n• Females showed greater CB1 desensitization and downregulation in all regions\n• Baseline sex differences were minimal (except hippocampal activation)","methodology":"Adult Sprague-Dawley rats underwent gonadectomy or sham surgery. Half of gonadectomized females received estradiol replacement; half of males received testosterone. All groups received either vehicle or 30 mg/kg THC twice daily for one week. Brain tissue was collected and analyzed using CP55,940-stimulated [35S]GTPγS binding (receptor function) and [3H]SR141716A saturation binding (receptor density).","limitations":"Rat brains are not human brains. The THC dose (30 mg/kg twice daily) was high relative to typical human consumption. One week of dosing may not reflect chronic human use patterns. The study measured receptor changes but not behavioral outcomes, so the functional significance of these differences in real-world terms is unclear."},{"rthcId":"RTHC-02029","title":"Illicit drug use and prescription drug misuse among young adult medical cannabis patients and non-patient users in Los Angeles.","authors":"Fedorova, Ekaterina V; Schrager, Sheree M; Robinson, Lucy F; Cepeda, Alice; Wong, Carolyn F; Iverson, Ellen; Lankenau, Stephen E","year":2019,"journal":"Drug and alcohol dependence, 198, 21-27","doi":"10.1016/j.drugalcdep.2019.01.026","pmid":"30861391","tags":["medical-cannabis","youth","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Self-reported medical cannabis use was associated with 50% lower odds of illicit drug use (AOR 0.5). Use of cannabis concentrates increased odds of illicit drug use 2.8x, and edible use doubled the odds of prescription drug misuse. Using cannabis alone (vs. socially) halved prescription misuse odds.","whyItMatters":"This distinguishes between different cannabis use patterns rather than treating all use as equivalent. The finding that cannabis form (concentrates, edibles) matters more than frequency challenges the gateway drug framing that focuses on amount of use.","specificNumbers":"210 medical cannabis patients, 156 non-patient users, aged 18-26. Medical use: AOR 0.5 for illicit drugs. Concentrate use: AOR 2.8 for illicit drugs. Edible use: AOR 2.0 for prescription misuse. Solitary use: AOR 0.5 for prescription misuse. White race: AOR 3.0 for illicit drugs.","methodology":"Baseline survey of 210 medical cannabis patients and 156 non-patient cannabis users aged 18-26 in Los Angeles (2014-15), using logistic regression to examine associations between cannabis practices and other drug use.","limitations":"Cross-sectional design cannot determine directionality. Small sample from one city. Self-reported medical use may reflect rationalization rather than genuine medical motivation. Baseline data only from a longitudinal study."},{"rthcId":"RTHC-02030","title":"Coming off cannabis: a cognitive and magnetic resonance imaging study in patients with multiple sclerosis.","authors":"Feinstein, Anthony; Meza, Cecilia; Stefan, Cristiana; Staines, Richard W","year":2019,"journal":"Brain : a journal of neurology, 142(9), 2800-2812","doi":"10.1093/brain/awz213","pmid":"31363742","tags":["cognition","medical-cannabis","quitting"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"After 28 days of abstinence, the withdrawal group performed significantly better on every cognitive measure (P < 0.0001 for all) compared to the continuation group. fMRI showed the abstinent group completed more trials correctly with faster reaction times and significantly increased brain activation in frontal, caudate, and cerebellar regions.","whyItMatters":"This is one of the few controlled studies directly measuring what happens when chronic cannabis users stop. The dramatic improvements across every cognitive domain after just 28 days suggest that cannabis-related cognitive deficits in MS patients are largely reversible.","specificNumbers":"40 MS patients, frequent long-term cannabis users. Withdrawal group improved on every cognitive index (P < 0.0001). fMRI: more correct trials (P < 0.012), faster reaction time (P < 0.002). Increased bilateral inferior frontal gyri, caudate, and cerebellar activation (P < 0.001). THC was the predominant cannabinoid consumed.","methodology":"Controlled study of 40 MS patients who used cannabis at least 4 days/week for years. Patients were divided into cannabis continuation and withdrawal groups with assessments at baseline and day 28 including neuropsychological battery, structural MRI, functional MRI, and urine testing for compliance.","limitations":"Small sample size (40 patients). Non-randomized group assignment (odd-even selection). Only 28 days of abstinence studied. One patient in withdrawal group failed abstinence. Cannot separate acute withdrawal effects from genuine cognitive recovery."},{"rthcId":"RTHC-02031","title":"The synthetic cannabinoid JWH-018 modulates Saccharomyces cerevisiae energetic metabolism.","authors":"Ferreira, Carla; Couceiro, Joana; Família, Carlos; Jardim, Carolina; Antas, Pedro; Santos, Cláudia N; Outeiro, Tiago F; Tenreiro, Sandra; Quintas, Alexandre","year":2019,"journal":"FEMS yeast research, 19(5)","doi":"10.1093/femsyr/foz042","pmid":"31329229","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02032","title":"Association of Prenatal Cannabis Exposure With Psychosis Proneness Among Children in the Adolescent Brain Cognitive Development (ABCD) Study.","authors":"Fine, Jeremy D; Moreau, Allison L; Karcher, Nicole R; Agrawal, Arpana; Rogers, Cynthia E; Barch, Deanna M; Bogdan, Ryan","year":2019,"journal":"JAMA psychiatry, 76(7), 762-764","doi":"10.1001/jamapsychiatry.2019.0076","pmid":"30916716","tags":["pregnancy","psychosis","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Maternal cannabis use during pregnancy, particularly after the mother knew she was pregnant, was associated with higher psychosis proneness scores in their children, based on data from the large-scale Adolescent Brain Cognitive Development study.","whyItMatters":"The ABCD study is the largest long-term study of brain development in the US, making these findings particularly important. An association between prenatal cannabis exposure and psychosis proneness could have significant public health implications as cannabis use during pregnancy increases.","specificNumbers":"Data drawn from the ABCD study cohort. Association found between prenatal cannabis exposure and psychosis proneness. Stronger signal when maternal use continued after knowledge of pregnancy.","methodology":"Cohort analysis using data from the ongoing ABCD study, a landmark US longitudinal study tracking brain development in thousands of children. Compared psychosis proneness scores between children exposed and unexposed to prenatal cannabis.","limitations":"Published as a brief research letter with limited methodological detail. Prenatal cannabis exposure was maternally reported, which may be subject to recall and social desirability bias. Association does not prove causation. Confounding factors like other substance use and socioeconomic factors may contribute."},{"rthcId":"RTHC-02033","title":"Do Toxic Synthetic Cannabinoid Receptor Agonists Have Signature in Vitro Activity Profiles? A Case Study of AMB-FUBINACA.","authors":"Finlay, David B; Manning, Jamie J; Ibsen, Mikkel Søes; Macdonald, Christa E; Patel, Monica; Javitch, Jonathan A; Banister, Samuel D; Glass, Michelle","year":2019,"journal":"ACS chemical neuroscience, 10(10), 4350-4360","doi":"10.1021/acschemneuro.9b00429","pmid":"31513380","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02034","title":"Did marijuana legalization in Washington State reduce racial disparities in adult marijuana arrests?","authors":"Firth, Caislin L; Maher, Julie E; Dilley, Julia A; Darnell, Adam; Lovrich, Nicholas P","year":2019,"journal":"Substance use & misuse, 54(9), 1582-1587","doi":"10.1080/10826084.2019.1593007","pmid":"31096823","tags":["legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among adults 21+, marijuana arrest rates dropped dramatically after legalization of possession and stayed low after retail market opening. African American arrest rates fell in absolute terms, but relative disparities grew from 2.5x to 5x higher than White rates. Among 18-20 year olds, rates dropped less dramatically and relative disparities were unchanged.","whyItMatters":"Reducing racial disparities in marijuana enforcement was an explicit justification for legalization. While absolute numbers of arrests decreased for everyone, the relative targeting of African Americans actually intensified, challenging whether legalization achieves its equity goals.","specificNumbers":"Adult 21+ arrest rates dropped dramatically after December 2012 legalization. Relative disparity: African American rates were 2.5x White rates before legalization, rising to 5x after retail market opened. Among 18-20 year olds: arrest rates decreased but relative disparities remained unchanged.","methodology":"Analysis of 2012-2015 National Incident Based Reporting System data for Washington State, using negative binomial regression models to examine monthly marijuana arrest rates by race, adjusted for age and sex, comparing periods before and after legalization and retail market opening.","limitations":"Only covers 2012-2015 (three years post-legalization). Washington State patterns may not generalize. NIBRS data capture arrests, not all police encounters. The growing relative disparity may partly reflect White arrest rates dropping faster rather than African American rates being maintained."},{"rthcId":"RTHC-02035","title":"Tobacco and cannabis use in college students are predicted by sex-dimorphic interactions between MAOA genotype and child abuse.","authors":"Fite, Paula J; Brown, Shaquanna; Hossain, Waheeda; Manzardo, Ann; Butler, Merlin G; Bortolato, Marco","year":2019,"journal":"CNS neuroscience & therapeutics, 25(1), 101-111","doi":"10.1111/cns.13002","pmid":"29952131","tags":["genetics","youth","addiction","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In female students, high-activity MAOA alleles combined with physical and emotional abuse predicted lifetime tobacco and cannabis use. In males, low-activity MAOA alleles combined with physical abuse predicted tobacco use but not cannabis use.","whyItMatters":"The MAOA gene has been called the \"warrior gene\" for its link to aggression when combined with childhood adversity. This study shows the same gene-environment interaction predicts substance use, but with sex-opposite patterns, highlighting why substance use prevention may need to be personalized.","specificNumbers":"500 college students. In females: high-activity MAOA + physical/emotional abuse predicted cannabis and tobacco use. In males: low-activity MAOA + physical abuse predicted tobacco use only. Ages 18-25.","methodology":"Cross-sectional study of 500 college students (ages 18-25) from a large Midwestern university. Participants were surveyed for child maltreatment history and lifetime substance use, with saliva samples genotyped for the MAOA upstream variable number tandem repeat polymorphism.","limitations":"Cross-sectional design cannot establish causation. Self-reported substance use and maltreatment history. Predominantly university sample limits generalizability. MAOA genotyping captures one variant; other genetic factors were not examined."},{"rthcId":"RTHC-02036","title":"Position Statement: A Pragmatic Approach for Medical Cannabis and Patients with Rheumatic Diseases.","authors":"Fitzcharles, Mary-Ann; Niaki, Omid Zahedi; Hauser, Winfried; Hazlewood, Glen","year":2019,"journal":"The Journal of rheumatology, 46(5), 532-538","doi":"10.3899/jrheum.181120","pmid":"30647183","tags":["medical-cannabis","pain","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"No clinical trials of medical cannabis in rheumatology patients existed at the time of review. Evidence is insufficient for benefit in fibromyalgia, osteoarthritis, rheumatoid arthritis, and back pain, but there is evidence of a high risk of harm. Short-term psychomotor effects are expected; long-term risks are unknown.","whyItMatters":"With cannabis legalized in Canada, rheumatology patients are increasingly using it for pain and inflammation. This position statement addresses a practical reality: patients are using cannabis regardless of evidence gaps, so clinicians need guidance on harm reduction.","specificNumbers":"Zero clinical trials of medical cannabis in rheumatology patients. Evidence insufficient for fibromyalgia, osteoarthritis, rheumatoid arthritis, and back pain. High risk of harm documented. Short-term psychomotor risks anticipated.","methodology":"Literature review by the Canadian Rheumatology Association Therapeutics Committee, assessing available evidence on medical cannabis for rheumatic conditions and developing a pragmatic position statement approved by the CRA board.","limitations":"Position statement rather than systematic review. Based on absence of evidence rather than evidence of absence. Extrapolates from non-rheumatology cannabis research. Does not differentiate between cannabis products, doses, or routes."},{"rthcId":"RTHC-02037","title":"Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression.","authors":"Fitzgibbon, Marie; Kerr, Daniel M; Henry, Rebecca J; Finn, David P; Roche, Michelle","year":2019,"journal":"Brain, behavior, and immunity, 82, 372-381","doi":"10.1016/j.bbi.2019.09.006","pmid":"31505257","tags":["pain","depression","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Repeated IFN-alpha treatment increased formalin-evoked pain behavior in mice. Endocannabinoid levels (2-AG and AEA) rose in pain-processing brain regions (PAG and RVM) after formalin in IFN-alpha-treated mice. Local administration of endocannabinoid-boosting drugs (PF3845 and MJN110) reduced the heightened pain response in depressed but not control mice.","whyItMatters":"Depression and chronic pain frequently co-occur, and this study reveals the endocannabinoid system as a mechanistic link. The finding that boosting endocannabinoids specifically helped the heightened pain in depression suggests targeted therapeutic potential for this common comorbidity.","specificNumbers":"IFN-alpha increased formalin-evoked pain without affecting hot plate responses. 2-AG levels increased in PAG and RVM; AEA increased in RVM. PF3845 (AEA booster) and MJN110 (2-AG booster) at 1 microgram/10 microliters reduced hyperalgesia only in IFN-alpha-treated mice.","methodology":"Male C57/Bl6 mice received repeated IFN-alpha (8000 IU/g/day) to induce depressive-like behavior confirmed by forced swim and sucrose preference tests. Pain responses were measured via hot plate and formalin tests, with endocannabinoid levels measured in brain and peripheral tissues by LC-MS/MS.","limitations":"Mouse model with pharmacologically induced depression (IFN-alpha), which may not fully represent human depression. Only male mice used. Only inflammatory pain was studied, not other pain types. Peripheral drug administration only."},{"rthcId":"RTHC-02038","title":"Effects of CBD-Enriched Cannabis sativa Extract on Autism Spectrum Disorder Symptoms: An Observational Study of 18 Participants Undergoing Compassionate Use.","authors":"Fleury-Teixeira, Paulo; Caixeta, Fabio Viegas; Ramires da Silva, Leandro Cruz; Brasil-Neto, Joaquim Pereira; Malcher-Lopes, Renato","year":2019,"journal":"Frontiers in neurology, 10, 1145","doi":"10.3389/fneur.2019.01145","pmid":"31736860","tags":["cbd","medical-cannabis","youth","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Of 15 patients who adhered to treatment, 14 showed improvement in at least one of eight symptom categories. Nine of 10 non-epileptic patients improved 30%+ in at least one category. The strongest improvements were in seizures, ADHD, sleep disorders, and communication/social interaction deficits. Nine of 10 patients on other medications were able to reduce or withdraw them while maintaining improvements.","whyItMatters":"Autism spectrum disorder has limited pharmacological treatment options, and many existing medications have significant side effects. This is among the first published reports of CBD-rich extract specifically for autism symptoms in non-epileptic patients.","specificNumbers":"18 patients enrolled, 15 completed (3 discontinued for adverse effects). 14/15 improved in at least one category. 9/10 non-epileptic patients improved 30%+ in at least one area. 4/10 non-epileptic patients improved 30%+ in four or more categories. 9/10 on other medications reduced or withdrew them. CBD:THC ratio 75:1.","methodology":"Observational cohort of 18 autistic patients (10 non-epileptic, 5 epileptic, 3 discontinued) treated with compassionate-use standardized CBD-enriched cannabis extract (75:1 CBD:THC ratio) for 6-9 months, evaluating eight symptom categories.","limitations":"Very small sample (18 patients). No control group or blinding. Observational design subject to placebo effect and reporting bias. Non-standardized outcome measures. Three patients discontinued due to adverse effects, representing 17% attrition."},{"rthcId":"RTHC-02039","title":"Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy.","authors":"Franco, Valentina; Perucca, Emilio","year":2019,"journal":"Drugs, 79(13), 1435-1454","doi":"10.1007/s40265-019-01171-4","pmid":"31372958","tags":["epilepsy","cbd","medical-cannabis","drug-interactions"],"studyType":"review","evidenceStrength":"strong","keyFinding":"CBD at 10 and 20 mg/kg/day was superior to placebo in reducing drop seizures (LGS) and convulsive seizures (DS) across four RCTs. Oral bioavailability is low but increases fourfold with high-fat meals. About half of trial participants were on clobazam, and CBD increases its active metabolite norclobazam, potentially contributing to both efficacy and adverse effects.","whyItMatters":"Epidiolex was a landmark FDA approval for a cannabis-derived medicine. This review unpacks the complexity behind the headlines, particularly the clobazam interaction that complicates understanding whether CBD's benefits come from its own effects or from boosting another drug.","specificNumbers":"FDA-approved for Dravet and Lennox-Gastaut syndromes (2018). Doses: 10 and 20 mg/kg/day in two divided doses. Bioavailability increases 4x with high-fat meals. ~50% of trial participants on clobazam. Mechanism may involve GPR55 antagonism, TRPV1 desensitization, adenosine reuptake inhibition.","methodology":"Comprehensive review of CBD pharmacology including mechanism of action, pharmacokinetics, clinical trial results from four randomized controlled trials, drug interactions, and adverse event profiles for epilepsy treatment.","limitations":"The exact antiseizure mechanism remains unclear. Most clinical evidence comes from patients on multiple medications, making it hard to isolate CBD's direct contribution. Variable pharmacokinetics (especially food effects) make consistent dosing challenging."},{"rthcId":"RTHC-02040","title":"Increasing potency and price of cannabis in Europe, 2006-16.","authors":"Freeman, Tom P; Groshkova, Teodora; Cunningham, Andrew; Sedefov, Roumen; Griffiths, Paul; Lynskey, Michael T","year":2019,"journal":"Addiction (Abingdon, England), 114(6), 1015-1023","doi":"10.1111/add.14525","pmid":"30597667","tags":["potency","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using data from 28 EU member states plus Norway and Turkey, researchers tracked three variables for both cannabis resin and herbal cannabis: potency (% THC), price (euros per gram), and value (milligrams of THC per euro).\n\nCannabis resin showed the most dramatic changes. Potency more than doubled from 8.14% THC in 2006 to 17.22% in 2016. Price also rose, from 8.21 to 12.27 euros per gram, but not fast enough to offset the potency increase — so the value (THC per euro) climbed from 11.0 to 16.4 mg per euro. Users were getting more THC for their money.\n\nThe timing was notable: resin potency and value were relatively flat from 2006 to 2011, then increased sharply from 2011 to 2016. Herbal cannabis potency also increased but more modestly. The net result: European cannabis markets delivered progressively more THC at progressively better value over the decade.","whyItMatters":"Price matters for public health. When a drug becomes more potent AND cheaper per unit of active ingredient, consumption patterns change. This study showed that European cannabis markets followed the same trajectory as alcohol markets in prior decades — products got stronger while the cost of intoxication dropped. That combination historically increases population-level harm.\n\nThe 2011 inflection point in resin potency suggests something changed in production or supply chains around that time. The researchers didn't identify the cause, but the acceleration coincided with innovations in cannabis resin production techniques.","specificNumbers":"• Resin potency: 8.14% THC (2006) → 17.22% (2016)\n• Resin price: €8.21/g (2006) → €12.27/g (2016)\n• Resin value: 11.0 mg THC/€ (2006) → 16.4 mg THC/€ (2016)\n• Herbal cannabis potency also increased, but more modestly\n• Data from 30 countries over 11 years","methodology":"Repeated cross-sectional study using data collected by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) from 28 EU member states, Norway, and Turkey. Price adjusted for inflation using Harmonised Indices of Consumer Prices. Mixed-effects linear regression with random intercepts and slopes to account for variation across countries.","limitations":"Data quality varied across 30 countries with different collection methods. Potency measurements came from seized samples and may not represent retail purchases. Cannot determine whether consumers adjusted their intake in response to potency changes. Does not cover legal market products, which emerged in some countries during this period."},{"rthcId":"RTHC-02041","title":"Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders.","authors":"Friedman, Daniel; French, Jacqueline A; Maccarrone, Mauro","year":2019,"journal":"The Lancet. Neurology, 18(5), 504-512","doi":"10.1016/S1474-4422(19)30032-8","pmid":"30910443","tags":["epilepsy","medical-cannabis","pain","neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Randomized controlled trials provide evidence of CBD's anti-seizure effects for Lennox-Gastaut and Dravet syndromes. Cannabis-based treatments for MS pain and spasticity are approved in some countries. However, small clinical trials found no effects for Huntington's disease, ADHD, or dementia.","whyItMatters":"Published in a top-tier neurology journal, this review provides a reality check on cannabinoid therapeutics. While epilepsy and MS have genuine evidence, the enthusiasm around cannabis for neurological conditions generally outpaces the science.","specificNumbers":"CBD approved for Lennox-Gastaut and Dravet syndromes based on RCTs. Cannabis-based treatments for MS pain and spasticity approved in some countries. No effect found in small trials for Huntington's disease, ADHD, and dementia.","methodology":"Narrative review published in The Lancet Neurology examining the evidence for cannabinoids across neurological disorders including epilepsy, multiple sclerosis, pain, and neurodegenerative diseases, focusing on randomized controlled trial data.","limitations":"Narrative review format. Negative findings for conditions like ADHD and dementia may reflect underpowered studies rather than true absence of effect. Mechanisms of cannabinoid action remain incompletely understood."},{"rthcId":"RTHC-02042","title":"Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders.","authors":"Galaj, Ewa; Xi, Zheng-Xiong","year":2019,"journal":"CNS drugs, 33(10), 1001-1030","doi":"10.1007/s40263-019-00664-w","pmid":"31549358","tags":["addiction","medical-cannabis","cbd","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Neutral CB1R antagonists (AM4113), CB2R agonists (JWH133, Xie2-64), and phytocannabinoids (CBD, beta-caryophyllene, THCV) show therapeutic potential for SUDs in animals. Clinical trials of dronabinol, nabilone, and the FAAH inhibitor PF-04457845 show promising results for cannabis and opioid withdrawal.","whyItMatters":"Substance use disorders affect millions with limited treatment options. The endocannabinoid system is deeply involved in reward pathways, making cannabinoid-based drugs logical therapeutic candidates. The field has recovered from the rimonabant setback with more targeted strategies.","specificNumbers":"Rimonabant withdrawn from clinical trials worldwide in 2008 due to depression and suicidality. Multiple new strategies now under investigation: peripheral CB1R antagonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, FAAH inhibitors, MAGL inhibitors, FABP inhibitors.","methodology":"Comprehensive review of endocannabinoid system biology, cannabis reward and aversion mechanisms, and cannabinoid-based medication development for substance use disorders, covering preclinical and clinical trial data.","limitations":"Most evidence from animal models. Clinical trial data limited to a few compounds. Long-term safety of newer approaches unknown. Translation from animal addiction models to human substance use disorders is historically unreliable."},{"rthcId":"RTHC-02043","title":"Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons (Papio spp.).","authors":"Gandhi, Kushal; Montoya-Uribe, Vanessa; Martinez, Stacy; David, Samuel; Jain, Bobby; Shim, Grace; Li, Cun; Jenkins, Susan; Nathanielsz, Peter; Schlabritz-Loutsevitch, Natalia","year":2019,"journal":"Physiological reports, 7(6), e14024","doi":"10.14814/phy2.14024","pmid":"30912236","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02044","title":"The Mental Health of Young Canadians Who Are Not Working or in School.","authors":"Gariépy, Geneviève; Iyer, Srividya","year":2019,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 64(5), 338-344","doi":"10.1177/0706743718815899","pmid":"30595044","tags":["youth","mental-health","depression","anxiety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Being NEET was associated with depression (OR 1.67), generalized anxiety disorder (OR 2.65), and other drug use disorder (OR 3.22), but was not associated with cannabis use disorder (OR 0.97) or alcohol use disorder (OR 1.03).","whyItMatters":"The assumption that cannabis use drives youth out of productive activity is not supported here. Mental health disorders, not cannabis or alcohol, were the conditions most strongly associated with youth disengagement from school and work.","specificNumbers":"5,622 Canadian youth, ages 15-29. ~10% were NEET. Cannabis use disorder OR: 0.97 (95% CI: 0.47-2.00). Depression OR: 1.67. Generalized anxiety OR: 2.65. Other drug use disorder OR: 3.22. Alcohol use disorder OR: 1.03.","methodology":"Cross-sectional analysis of 5,622 youth aged 15-29 from the 2012 Canadian Community Health Survey-Mental Health, using structured interviews for past-year mental and substance disorders with logistic regression adjusted for sociodemographic, health, and geographic variables.","limitations":"Cross-sectional design cannot establish causation or directionality. Cannabis use disorder may be underreported. \"Other drug use disorder\" category is broad. Single timepoint from 2012 before Canadian legalization."},{"rthcId":"RTHC-02045","title":"Genetic and environmental risk factors in the non-medical use of over-the-counter or prescribed analgesics, and their relationship to major classes of licit and illicit substance use and misuse in a population-based sample of young adult twins.","authors":"Gillespie, Nathan A; Bates, Timothy C; Hickie, Ian B; Medland, Sarah E; Verhulst, Brad; Kirkpatrick, Robert M; Kendler, Kenneth S; Martin, Nicholas G; Benotsch, Eric G","year":2019,"journal":"Addiction (Abingdon, England), 114(12), 2229-2240","doi":"10.1111/add.14750","pmid":"31313399","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"NMUA heritability was 46%. Genetic correlations were moderate with cannabis use (rg=0.41), nicotine use (rg=0.45), and nicotine dependence (rg=0.34), but weak with cannabis use disorder (rg=0.15) and alcohol use disorder (rg=0.07). This suggests the genetics of trying substances overlaps, but the genetics of developing disorders is largely distinct.","whyItMatters":"The distinction between genetics of substance use versus substance use disorder is crucial. The same genes that increase likelihood of trying substances don't necessarily increase the risk of becoming dependent, suggesting different biological mechanisms for initiation versus addiction.","specificNumbers":"2,007 twins, 66% female, mean age 25.9. NMUA lifetime prevalence: 19.4%. Heritability: 46% (95% CI: 0.29-0.57). Genetic correlations: cannabis use rg=0.41, nicotine use rg=0.45, nicotine dependence rg=0.34, cannabis use disorder rg=0.15, alcohol use disorder rg=0.07.","methodology":"Biometrical genetic analysis of 2,007 young adult twins (66% female, mean age 25.9) from the Brisbane Longitudinal Twin Study, using structural equation univariate and multivariate modeling to estimate heritability and genetic correlations between NMUA and other substance outcomes.","limitations":"Australian twin sample may not generalize globally. Self-reported substance use. Predominantly female sample (66%). Cross-sectional retrospective assessment. NMUA category combines non-opioid and opioid analgesics."},{"rthcId":"RTHC-02046","title":"Strengths and limitations of two cannabis-impaired driving detection methods: a review of the literature.","authors":"Ginsburg, Brett C","year":2019,"journal":"The American journal of drug and alcohol abuse, 45(6), 610-622","doi":"10.1080/00952990.2019.1655568","pmid":"31498702","tags":["driving","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Unlike alcohol, THC blood concentrations poorly correspond to amount consumed, crash risk, or degree of impairment. Standard field sobriety tests have not been developed or validated for cannabis, and cannabis impairment is difficult to distinguish from effects of aging or certain medications.","whyItMatters":"Cannabis use doubles automobile crash risk, yet neither of the two standard approaches for detecting impaired driving works reliably for cannabis. This leaves both cannabis users and law enforcement without clear guidance on driving fitness after use.","specificNumbers":"Cannabis associated with approximately 2-fold increase in crash risk. Per se THC limits poorly predict impairment. No validated field sobriety test for cannabis. Cannabis impairment difficult to distinguish from aging or medication effects.","methodology":"Perspective review examining the strengths and limitations of two cannabis-impaired driving detection approaches: per se blood/breath concentration tests and functional field sobriety tests, compared against their established use for alcohol detection.","limitations":"Perspective piece rather than systematic review. The 2-fold crash risk estimate varies across studies. Individual tolerance differences make any per se limit inherently imprecise. Technology may improve faster than this review anticipated."},{"rthcId":"RTHC-02047","title":"What is medicinal cannabis?","authors":"Glass, Michelle; Ashton, John C","year":2019,"journal":"The New Zealand medical journal, 132(1494), 49-56","doi":null,"pmid":"31048824","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis comes in diverse forms with various active ingredients, contrasting with legal and pharmaceutical definitions of medicines. The authors argue that the definition of what constitutes a medicine should not be changed to accommodate cannabis, and that cannabis products should meet the same standards as other medicines.","whyItMatters":"The term \"medicinal cannabis\" is used loosely to describe everything from FDA-approved pharmaceuticals to unregulated plant products. Without clear standards, patients, prescribers, and regulators cannot make informed decisions about quality, dosing, and evidence.","specificNumbers":"Cannabis contains multiple active ingredients in varying concentrations across products. Quality control, prescriber practice, and clinical evidence assessment all affected by this variability.","methodology":"Expert commentary examining what \"medicinal cannabis\" means from pharmaceutical and regulatory perspectives, published during New Zealand's cannabis reform debate.","limitations":"Expert opinion piece from two authors. Does not include systematic evidence review. New Zealand-specific regulatory context may not apply elsewhere. Does not address patient access barriers that strict standards might create."},{"rthcId":"RTHC-02048","title":"Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood: A Systematic Review and Meta-analysis.","authors":"Gobbi, Gabriella; Atkin, Tobias; Zytynski, Tomasz; Wang, Shouao; Askari, Sorayya; Boruff, Jill; Ware, Mark; Marmorstein, Naomi; Cipriani, Andrea; Dendukuri, Nandini; Mayo, Nancy","year":2019,"journal":"JAMA psychiatry, 76(4), 426-434","doi":"10.1001/jamapsychiatry.2018.4500","pmid":"30758486","tags":["youth","depression","anxiety","mental-health"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Adolescent cannabis use was associated with depression in young adulthood (OR 1.37, 95% CI: 1.16-1.62), suicidal ideation (OR 1.50, 95% CI: 1.11-2.03), and suicide attempt (OR 3.46, 95% CI: 1.53-7.84). The association with anxiety was not statistically significant (OR 1.18, 95% CI: 0.84-1.67).","whyItMatters":"Published in JAMA Psychiatry, this is one of the most rigorous analyses of the adolescent cannabis-depression link. The elevated suicide attempt risk is particularly concerning given the high prevalence of adolescent cannabis use worldwide.","specificNumbers":"23,317 individuals across 11 studies. Depression OR: 1.37 (I2=0%). Suicidal ideation OR: 1.50 (I2=0%). Suicide attempt OR: 3.46 (I2=61.3%). Anxiety OR: 1.18 (not significant). All adjusted for baseline depression/anxiety/suicidality.","methodology":"Systematic review and meta-analysis searching five databases (Medline, Embase, CINAHL, PsycInfo, Proquest) for longitudinal and prospective studies of cannabis use in adolescents under 18 with depression outcomes in young adults 18-32. Eleven studies comprising 23,317 individuals were included. Random-effects meta-analysis with quality assessment.","limitations":"Observational studies cannot prove causation. Residual confounding possible despite adjustment for baseline mental health. Suicide attempt association had high heterogeneity (I2=61.3%). Dose-response relationships not fully characterized across all studies."},{"rthcId":"RTHC-02049","title":"Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis.","authors":"Godlewski, Grzegorz; Cinar, Resat; Coffey, Nathan J; Liu, Jie; Jourdan, Tony; Mukhopadhyay, Bani; Chedester, Lee; Liu, Ziyi; Osei-Hyiaman, Douglas; Iyer, Malliga R; Park, Joshua K; Smith, Roy G; Iwakura, Hiroshi; Kunos, George","year":2019,"journal":"Cell metabolism, 29(6), 1320-1333.e8","doi":"10.1016/j.cmet.2019.04.012","pmid":"31105045","tags":["addiction","neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The peripheral CB1R inverse agonist JD5037 reduced ethanol drinking in wild-type mice but not in mice lacking CB1R, ghrelin, or the ghrelin receptor. JD5037 inhibited formation of active ghrelin without affecting its inactive precursor. Blocking gastric vagal afferents eliminated the effect.","whyItMatters":"Previous CB1 receptor blockers (like rimonabant) failed because they acted in the brain and caused psychiatric side effects. This study shows a peripheral-only CB1 blocker can reduce alcohol drinking through a gut-brain pathway, potentially avoiding brain-related side effects entirely.","specificNumbers":"JD5037 reduced ethanol drinking in wild-type but not CB1R-/-, ghrelin-/-, or GHS-R1A-/- mice. The drug reduced octanoyl-ghrelin (active form) without affecting desacyl-ghrelin (inactive precursor). Effect eliminated by blocking gastric vagal afferents.","methodology":"Pharmacological study in multiple mouse strains (wild-type and knockout models lacking CB1R, ghrelin peptide, or GHS-R1A) testing the peripheral CB1R inverse agonist JD5037 on ethanol drinking, with mechanistic investigation of ghrelin production in stomach cells and vagal nerve signaling.","limitations":"Mouse model; alcohol drinking behavior in mice may not fully represent human alcoholism. JD5037 has not been tested in humans for this purpose. The relative contribution of this peripheral pathway versus central mechanisms in human alcohol seeking is unknown."},{"rthcId":"RTHC-02050","title":"The impact of plain packaging and health warnings on consumer appeal of cannabis products.","authors":"Goodman, Samantha; Leos-Toro, Cesar; Hammond, David","year":2019,"journal":"Drug and alcohol dependence, 205, 107633","doi":"10.1016/j.drugalcdep.2019.107633","pmid":"31678837","tags":["legalization","youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Full branding was more appealing and more youth-oriented than plain packaging (p<0.001). Health warnings reduced appeal (p<0.001). Edible gummies were more appealing and more youth-oriented than pre-rolled joints or cannabis oil (p<0.001). Gummies were rated significantly more appealing by 16-35 year olds than older adults.","whyItMatters":"Canada implemented plain packaging and health warnings for cannabis upon legalization. This provides the first large-scale experimental evidence that these tobacco-style regulations work for cannabis too, especially for reducing youth appeal.","specificNumbers":"27,045 participants across US and Canada. Full branding > brand logo > plain packaging in appeal (p<0.001). Health warnings reduced appeal (p<0.001). Edible gummies most appealing and most youth-oriented (p<0.001). 16-18 and 19-35 year olds rated gummies more appealing than older adults (p<0.02).","methodology":"Randomized experimental task within the International Cannabis Policy Study. 27,045 participants (Canada n=9,987, legal US states n=7,376, illegal US states n=9,682) aged 16-65 were randomly assigned to view one of 18 cannabis product images in a 3x2x3 factorial design (branding x warnings x product type).","limitations":"Online experimental setting may not fully predict real-world purchasing behavior. Participants viewed images, not physical products. Short-term appeal measurement may not predict long-term consumer behavior. US states with legal cannabis may have different cultural attitudes."},{"rthcId":"RTHC-02051","title":"Age-related differences in the impact of cannabis use on the brain and cognition: a systematic review.","authors":"Gorey, Claire; Kuhns, Lauren; Smaragdi, Eleni; Kroon, Emese; Cousijn, Janna","year":2019,"journal":"European archives of psychiatry and clinical neuroscience, 269(1), 37-58","doi":"10.1007/s00406-019-00981-7","pmid":"30680487","tags":["youth","cognition","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"General executive functioning appears more impaired in adolescent frequent cannabis users compared to adult users. Age effects may be most prominent among very heavy and dependent users. Craving and inhibitory control may not decrease as much post-intoxication in adolescents. Adolescent vulnerability to reduced learning may not persist after sustained abstinence.","whyItMatters":"The adolescent brain is still developing, theoretically making it more vulnerable to cannabis effects. This review directly addresses that hypothesis with studies that actually compared age groups, rather than just studying adolescents alone.","specificNumbers":"Four hypotheses generated: (1) executive function more impaired in adolescent users, (2) age effects strongest in heavy/dependent users, (3) craving/inhibition persist longer post-intoxication in adolescents, (4) learning deficits may recover with abstinence in adolescents.","methodology":"Systematic review of human and animal studies that formally tested whether age (adolescent vs adult) moderates the relationship between cannabis exposure and cognitive outcomes.","limitations":"Relatively few studies directly compared age groups. Heterogeneous study designs and outcome measures. Animal studies may not translate to humans. The review generated hypotheses rather than definitive conclusions."},{"rthcId":"RTHC-02052","title":"Employment and Marijuana Use Among Washington State Adolescents Before and After Legalization of Retail Marijuana.","authors":"Graves, Janessa M; Whitehill, Jennifer M; Miller, Mary E; Brooks-Russell, Ashley; Richardson, Susan M; Dilley, Julia A","year":2019,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 65(1), 39-45","doi":"10.1016/j.jadohealth.2018.12.027","pmid":"30879883","tags":["youth","legalization","workplace"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Between 2010 and 2016, marijuana use decreased among 8th and 10th graders regardless of work status. Among 12th graders, working youth showed significantly increased use relative to non-workers (AOR 1.34, 95% CI: 1.22-1.48). Youth in formal work settings (retail, service) were more likely to use than those in informal settings (babysitting).","whyItMatters":"Working 12th graders represent teens with the most independence, disposable income, and exposure to adult environments where cannabis may be more accessible. This group may need targeted prevention as legalization creates new access pathways.","specificNumbers":"76,000+ students surveyed annually. Use decreased among working and non-working 8th/10th graders (2010-2016). Working 12th graders: AOR 1.34 (95% CI: 1.22-1.48) increase relative to non-working peers. Stronger associations with more work hours.","methodology":"Difference-in-differences analysis using 2010 and 2016 data from Washington's Healthy Youth Survey (76,000+ youth annually), comparing marijuana use by work status and hours among 8th, 10th, and 12th graders in public schools before and after legalization.","limitations":"Cross-sectional surveys at two time points cannot establish causation. Self-reported marijuana use. Cannot distinguish between legalization effects and secular trends. Work setting categories are broad."},{"rthcId":"RTHC-02053","title":"Synthetic cannabinoid use disorder: an update for general psychiatrists.","authors":"Grigg, Jasmin; Manning, Victoria; Arunogiri, Shalini; Lubman, Dan I","year":2019,"journal":"Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists, 27(3), 279-283","doi":"10.1177/1039856218822749","pmid":"30663326","tags":["synthetic-cannabinoids","addiction","psychosis","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoid use is associated with more rapid development of dependence than cannabis, increased psychiatric risks, complex withdrawal syndromes, and serious physical adverse effects including seizures, cardiotoxicity, and death, suggesting a need for more intensive clinical management.","whyItMatters":"Synthetic cannabinoids are often perceived as legal or safer alternatives to cannabis, but the clinical reality is much more dangerous. Psychiatrists encountering these patients need to know that standard cannabis management protocols are insufficient.","specificNumbers":"Compared to cannabis: more rapid dependence development, increased psychiatric risks, complex withdrawal with seizures, cardiotoxicity, and deaths. Management requires more intensive approaches than for natural cannabis.","methodology":"Literature review searching MEDLINE and Embase for articles of all methodological designs published through June 2018, focusing on physical and psychiatric adverse effects of chronic synthetic cannabinoid use and clinical management strategies.","limitations":"Literature review rather than systematic review. Synthetic cannabinoids are a diverse group of chemicals; findings may not apply equally to all compounds. Many reports are case-based. Long-term outcome data are limited."},{"rthcId":"RTHC-02054","title":"Determining the Roles that Club Drugs, Marijuana, and Heavy Drinking Play in PrEP Medication Adherence Among Gay and Bisexual Men: Implications for Treatment and Research.","authors":"Grov, Christian; Rendina, H Jonathon; John, Steven A; Parsons, Jeffrey T","year":2019,"journal":"AIDS and behavior, 23(5), 1277-1286","doi":"10.1007/s10461-018-2309-9","pmid":"30306433","tags":["harm-reduction","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"No event-level effect of marijuana use or heavy drinking on PrEP adherence was found. Club drug use increased odds of missing PrEP by 55% same-day and 60% next-day. Missing one dose increased odds of missing the next day by eightfold. Club drug users averaged 1.6 missed doses in 30 days.","whyItMatters":"Concerns that cannabis might interfere with medication adherence are not supported here. For HIV prevention specifically, cannabis use does not appear to compromise the effectiveness of daily PrEP, while club drugs do present a genuine risk.","specificNumbers":"104 participants, 9,532 days of data, 10 weeks. Club drugs: 55% increased odds same-day, 60% next-day (carryover effect). Missing one dose: 8x odds of missing the next day. Marijuana: no significant effect. Heavy drinking: no significant effect.","methodology":"Retrospective 30-day timeline follow-back interviews plus prospective semi-weekly diaries for 10 weeks with 104 PrEP-using gay and bisexual men (half club drug users), generating 9,532 person-days of data.","limitations":"Small sample (n=104). Self-reported substance use and PrEP adherence. All participants were from one city. Club drug use was the primary research focus, with marijuana as a secondary analysis."},{"rthcId":"RTHC-02055","title":"Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens.","authors":"Gu, Zhen; Singh, Shilpa; Niyogi, Rajarshi G; Lamont, Gwyneth J; Wang, Huizhi; Lamont, Richard J; Scott, David A","year":2019,"journal":"Frontiers in immunology, 10, 2288","doi":"10.3389/fimmu.2019.02288","pmid":"31681262","tags":["inflammation","cbd","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"All three major phytocannabinoids (CBD, CBN, THC) at physiological doses suppressed pro-inflammatory cytokine release (IL-12, IL-6, IL-8, TNF) and enhanced anti-inflammatory IL-10 in response to three oral pathogens. The effect operated through a common CB2/PI3K axis. In mice, CBD suppressed P. gingivalis-induced immune markers in wild-type but not CB2 knockout mice.","whyItMatters":"Cannabis use is an established risk factor for periodontitis, but the mechanism was unknown. This study identifies a specific pathway: cannabinoids suppress the immune system's ability to fight the bacteria that cause gum disease, potentially allowing unchecked bacterial damage.","specificNumbers":"Physiological dose: 1.0 mcg/ml. Higher doses (5+ mcg/ml) killed immune cells and inhibited some bacterial growth. CBD, CBN, and THC all suppressed IL-12 p40, IL-6, IL-8, TNF while enhancing IL-10. CB2/PI3K pathway confirmed. T. denticola was resistant to all cannabinoid doses tested.","methodology":"In vitro study exposing human innate immune cells and gingival keratinocytes to three oral pathogens with and without phytocannabinoids at physiological doses (1.0 mcg/ml). Pathway investigated through pharmaceutical inhibition and gene silencing. In vivo verification using wild-type and CB2 knockout mice.","limitations":"In vitro study with in vivo mouse confirmation, not human in vivo data. Physiological relevance of the doses used may vary based on consumption method. Only three oral pathogens studied. Long-term periodontal outcomes not measured."},{"rthcId":"RTHC-02056","title":"Illegal cannabis use is common among Danes with multiple sclerosis.","authors":"Gustavsen, S; Søndergaard, H B; Andresen, S R; Magyari, M; Sørensen, P S; Sellebjerg, F; Oturai, A B","year":2019,"journal":"Multiple sclerosis and related disorders, 33, 5-12","doi":"10.1016/j.msard.2019.05.008","pmid":"31129415","tags":["medical-cannabis","pain","sleep","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"49% had tried cannabis, 21% were current users, and only 21% of current users had prescribed cannabis. Recreational/illegal use was reported by 17%. Primary use reasons: pain relief (61%), spasticity (52%), sleep disturbances (46%). Most common adverse effects: drowsiness (30%), feeling subdued (23%), dizziness (13%). 44% of non-users would consider cannabis if legalized.","whyItMatters":"This is the most comprehensive MS cannabis use survey published. The gap between patient demand (49% have tried, 44% of non-users would consider) and prescription access (only 21% of users have prescriptions) reveals a massive unmet need being filled by illegal channels.","specificNumbers":"3,606 surveyed, 2,009 valid responses (62% response). 49% ever used cannabis. 21% current users. Only 21% of current users had prescriptions. Pain: 61%. Spasticity: 52%. Sleep: 46%. Adverse effects mild: drowsiness 30%, subdued feeling 23%, dizziness 13%.","methodology":"Anonymous questionnaire sent to all 3,606 patients at the Danish Multiple Sclerosis Center (62% response rate, 2,009 valid responses), covering sociodemographic factors, clinical characteristics, and cannabis use patterns.","limitations":"Self-reported efficacy without objective measures or placebo comparison. 38% non-response rate may introduce bias. Danish regulatory environment specific. Survey cannot establish whether cannabis is genuinely effective or reflects placebo/expectancy effects."},{"rthcId":"RTHC-02057","title":"Early Somatosensory Processing Over Time in Individuals at Risk to Develop Psychosis.","authors":"Hagenmuller, Florence; Heekeren, Karsten; Roser, Patrik; Haker, Helene; Theodoridou, Anastasia; Walitza, Susanne; Rössler, Wulf; Kawohl, Wolfram","year":2019,"journal":"Frontiers in psychiatry, 10, 47","doi":"10.3389/fpsyt.2019.00047","pmid":"30890966","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02058","title":"Activation of ATP-sensitive K-channel promotes the anticonvulsant properties of cannabinoid receptor agonist through mitochondrial ATP level reduction.","authors":"Haj-Mirzaian, Arvin; Ramezanzadeh, Kiana; Afshari, Khashayar; Mousapour, Pouria; Abbasi, Nooshin; Haj-Mirzaian, Arya; Nikbakhsh, Rajan; Haddadi, Nazgol-Sadat; Dehpour, Ahmad Reza","year":2019,"journal":"Epilepsy & behavior : E&B, 93, 1-6","doi":"10.1016/j.yebeh.2019.01.025","pmid":"30776677","tags":["epilepsy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"WIN 55,212-2 at 10 mg/kg significantly increased clonic seizure threshold via CB1 (blocked by AM-251) but not CB2 (AM-630 had no effect). The potassium channel blocker glibenclamide reversed the anticonvulsant effect. The potassium channel opener cromakalim enhanced the effect of a subeffective WIN dose. CB1 agonism decreased hippocampal ATP levels.","whyItMatters":"Understanding the precise mechanism of cannabinoid anticonvulsant effects is crucial for developing better epilepsy drugs. This study adds a new piece: the CB1-ATP-potassium channel pathway provides a specific molecular target that could be independently optimized.","specificNumbers":"WIN 55,212-2 at 10 mg/kg increased seizure threshold (p<0.001). Effect blocked by CB1 antagonist AM-251 (p<0.001) but not CB2 antagonist AM-630. Glibenclamide (1 mg/kg) reversed the effect (p<0.001). Cromakalim (10 mcg/kg) + subeffective WIN dose (3 mg/kg) = significant anticonvulsant effect.","methodology":"Male NMRI mice treated with combinations of cannabinoid receptor agonist/antagonists and potassium channel openers/blockers, with clonic seizure threshold as the primary outcome and hippocampal ATP measurement to clarify the mechanism.","limitations":"Mouse model using pharmacologically induced seizures, not a chronic epilepsy model. WIN 55,212-2 is a synthetic cannabinoid, not THC or CBD. Single acute dose study. ATP measurement at one brain region only."},{"rthcId":"RTHC-02059","title":"Cannabis, a potential treatment option in pediatric IBD? Still a long way to go.","authors":"Halbmeijer, Nienke; Groeneweg, Michael; De Ridder, Lissy","year":2019,"journal":"Expert review of clinical pharmacology, 12(4), 355-361","doi":"10.1080/17512433.2019.1582330","pmid":"30767696","tags":["inflammation","cbd","youth","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis may relieve IBD symptoms and improve quality of life in individual patients. The endocannabinoid system plays a role in gastrointestinal tract function with potential anti-inflammatory effects. However, no adequate pediatric evidence exists to recommend cannabis or cannabinoids for IBD in children.","whyItMatters":"Pediatric IBD is rising, and parents are increasingly asking about cannabis options. This review provides clinicians with a framework for discussing why cannabis cannot yet be recommended for children with IBD despite adult-oriented enthusiasm.","specificNumbers":"Rising incidence of pediatric IBD onset. Current treatment relies on immunomodulatory therapy. Cannabis and purified ingredients show potential anti-inflammatory effects. No adequate pediatric safety or efficacy data exist.","methodology":"Narrative review of recent literature on cannabis use in IBD with a focus on pediatric patients, including background on the endocannabinoid system in the gastrointestinal tract and discussion of various cannabis forms and purified ingredients.","limitations":"Narrative review without systematic methodology. Limited primary research on cannabis in pediatric IBD. Draws mostly from adult data and extrapolation. Does not quantify the strength of anti-inflammatory effects."},{"rthcId":"RTHC-02060","title":"Public health implications of legalising the production and sale of cannabis for medicinal and recreational use.","authors":"Hall, Wayne; Stjepanović, Daniel; Caulkins, Jonathan; Lynskey, Michael; Leung, Janni; Campbell, Gabrielle; Degenhardt, Louisa","year":2019,"journal":"Lancet (London, England), 394(10208), 1580-1590","doi":"10.1016/S0140-6736(19)31789-1","pmid":"31657733","tags":["legalization","harm-reduction","youth","driving"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Cannabis legalisation has been associated with increased use in some populations and possible increases in road crashes. Medicinal cannabis regulations may have increased recreational use. The review warns that profit-driven commercial cannabis industries may resist effective regulation, as seen with alcohol and tobacco.","whyItMatters":"Published in one of the world's top medical journals, this is the most authoritative overview of legalization's public health implications. Its warning about commercial cannabis following the alcohol/tobacco playbook is particularly relevant for countries still deciding on legalization models.","specificNumbers":"Cannabis is the most commonly used illicit drug globally. Legalization associated with increased use in some populations. Road crash concerns documented. Alcohol and tobacco policy examples used to project long-term cannabis industry effects.","methodology":"Comprehensive review published in The Lancet assessing public health impacts of cannabis legalization in the Americas, covering use patterns, health effects, medicinal evidence, regulatory approaches, effects on use and harms, and policy recommendations.","limitations":"Most legalization data comes from US states and Canada with relatively short follow-up periods. Long-term effects are projected from alcohol/tobacco analogies, which may not perfectly predict cannabis industry behavior. Policy recommendations may not apply to all regulatory contexts."},{"rthcId":"RTHC-02061","title":"Sex Differences in the Association Between Cannabis Use and Suicidal Ideation and Attempts, Depression, and Psychological Distress Among Canadians.","authors":"Halladay, Jillian E; Boyle, Michael H; Munn, Catharine; Jack, Susan M; Georgiades, Katholiki","year":2019,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 64(5), 345-350","doi":"10.1177/0706743718804542","pmid":"30260680","tags":["mental-health","depression","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Significant sex differences were found for cannabis use and suicidal thoughts/attempts and psychological distress, but not for major depressive episodes. Occasional female users (1-4x/month) had higher distress than male counterparts. Regular female users (>1x/week) had higher distress and more suicidal thoughts and attempts than regular male users.","whyItMatters":"Most cannabis research does not examine sex differences, yet this study shows the mental health associations differ significantly between men and women. This has direct implications for how cannabis risks are communicated and how clinicians screen for problems.","specificNumbers":"43,466 Canadians surveyed. Occasional use (1-4x/month): women had higher psychological distress than men. Regular use (>1x/week): women had higher distress AND more suicidal thoughts/attempts. No sex difference for major depressive episodes.","methodology":"Analysis of 2002 and 2012 Canadian Community Health Survey-Mental Health data (n=43,466), a nationally representative sample of Canadians aged 15+, using linear and binary logistic regressions with weighting and bootstrapping.","limitations":"Cross-sectional design cannot determine whether cannabis causes worse mental health in women or whether women with worse mental health are more likely to use cannabis. Self-reported measures. Combining 2002 and 2012 data spans a period of changing cannabis attitudes."},{"rthcId":"RTHC-02062","title":"Cannabis and Psychosis: Are We any Closer to Understanding the Relationship?","authors":"Hamilton, Ian; Monaghan, Mark","year":2019,"journal":"Current psychiatry reports, 21(7), 48","doi":"10.1007/s11920-019-1044-x","pmid":"31161275","tags":["psychosis","mental-health","genetics"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The evidence for cannabis as a direct cause of schizophrenia has not been established. Biological and genetic research has dominated at the expense of social and cultural factors. Research has been overly reliant on male participants from Western countries, limiting generalizability.","whyItMatters":"The cannabis-psychosis question is one of the most contentious in cannabis science. This review highlights that after decades of research, the fundamental question of causation remains open, and the research field has significant blind spots.","specificNumbers":"Three hypotheses examined: (1) cannabis triggers schizophrenia, (2) schizophrenia drives cannabis use (self-medication), (3) common factors account for both. Biological and genetic research dominates. Social/cultural factors underexplored.","methodology":"Narrative review updating the literature on the cannabis-schizophrenia relationship, examining the three dominant hypotheses and identifying gaps in the research base.","limitations":"Narrative review without systematic methodology. Does not quantify the strength of evidence for each hypothesis. The scope is limited to schizophrenia specifically, not broader psychotic experiences."},{"rthcId":"RTHC-02063","title":"A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice.","authors":"Han, Ji Hye; Shin, Hanho; Park, Ju-Young; Rho, Jun Gi; Son, Dong Hwee; Kim, Ki Woo; Seong, Je Kyung; Yoon, Sung-Hwa; Kim, Wook","year":2019,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33(3), 4314-4326","doi":"10.1096/fj.201801152RR","pmid":"30566396","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02064","title":"The annual cannabis holiday and fatal traffic crashes.","authors":"Harper, Sam; Palayew, Adam","year":2019,"journal":"Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention, 25(5), 433-437","doi":"10.1136/injuryprev-2018-043068","pmid":"30696698","tags":["driving","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Between 1992 and 2016, April 20th showed a non-significant 12% increase in fatal crash involvement relative to control days one week apart (IRR 1.12, 95% CI: 0.97-1.28), but no increase when compared to broader control periods or all other days (IRR 0.98, 95% CI: 0.88-1.10).","whyItMatters":"A prior widely-cited study claimed 4/20 increased fatal crashes by 12%. This more thorough analysis shows that finding depends entirely on which control days are chosen, and the effect disappears with broader comparisons.","specificNumbers":"IRR vs 1-week controls: 1.12 (95% CI: 0.97-1.28, not significant). IRR vs 1-2 week controls: 1.05 (95% CI: 0.92-1.28). IRR vs all other days: 0.98 (95% CI: 0.88-1.10). Data spans 1975-2016.","methodology":"Analysis of Fatal Analysis Reporting System data from 1975-2016, comparing drivers involved in fatal crashes on April 20th (16:20-23:59) against multiple control periods including one week, two weeks, and all other days of the year.","limitations":"Cannot distinguish cannabis-specific effects from general holiday or celebration effects. Cannabis use on 4/20 is not measured directly. The analysis assumes fatal crash involvement reflects impairment risk, which depends on many factors."},{"rthcId":"RTHC-02065","title":"Role of the endocannabinoid system in the dorsal hippocampus in the cardiovascular changes and delayed anxiety-like effect induced by acute restraint stress in rats.","authors":"Hartmann, Alice; Fassini, Aline; Scopinho, América; Correa, Fernando Ma; Guimarães, Francisco S; Lisboa, Sabrina F; Resstel, Leonardo Bm","year":2019,"journal":"Journal of psychopharmacology (Oxford, England), 33(5), 606-614","doi":"10.1177/0269881119827799","pmid":"30789299","tags":["anxiety","neuroscience","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The FAAH inhibitor URB597 injected into the dorsal hippocampus prevented stress-induced cardiovascular responses (heart rate increase, blood pressure rise, temperature drop) and delayed anxiety. The CB1 antagonist AM251 exacerbated cardiovascular stress responses and blocked URB597's protective effects.","whyItMatters":"This reveals the hippocampal endocannabinoid system as a dual regulator of both the physical and psychological responses to stress. A single molecular target in one brain region controls both the immediate cardiovascular reaction and the delayed anxiety that follows.","specificNumbers":"AM251 (CB1 antagonist) at 10-300 pmol exacerbated stress cardiovascular responses. URB597 (FAAH inhibitor) at 10 pmol prevented both cardiovascular and 24-hour delayed anxiety responses. AM251 pretreatment blocked URB597's effects.","methodology":"In vivo pharmacology in rats using intra-hippocampal injections of CB1 antagonist AM251 and FAAH inhibitor URB597 before acute restraint stress. Cardiovascular parameters measured during stress; elevated plus maze for anxiety assessed 24 hours post-stress.","limitations":"Acute stress model in rats with direct brain injection. Does not model chronic stress exposure. Only male rats used. Human hippocampal endocannabinoid function may differ. Drug delivery route is not clinically practical."},{"rthcId":"RTHC-02066","title":"Cyclic vomiting syndrome: Pathophysiology, comorbidities, and future research directions.","authors":"Hasler, William L; Levinthal, David J; Tarbell, Sally E; Adams, Kathleen A; Li, B U K; Issenman, Robert M; Sarosiek, Irene; Jaradeh, Safwan S; Sharaf, Ravi N; Sultan, Shahnaz; Venkatesan, Thangam","year":2019,"journal":"Neurogastroenterology and motility, 31 Suppl 2(Suppl 2), e13607","doi":"10.1111/nmo.13607","pmid":"31241816","tags":["appetite","medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CVS is characterized by severe episodic emesis with no randomized controlled trials to guide treatment. CHS is an increasingly recognized CVS-like condition associated with chronic cannabis use. Associations with migraine, mitochondrial disorders, autonomic dysfunction, and psychiatric conditions provide pathophysiologic clues.","whyItMatters":"CVS and CHS are frequently confused, with different treatment implications. Understanding their shared and distinct features helps clinicians distinguish between them and choose appropriate management. CHS resolves with cannabis cessation; CVS requires different approaches.","specificNumbers":"No placebo-controlled randomized trials for CVS exist. Associated conditions: migraine, mitochondrial disorders, autonomic dysfunction, psychiatric comorbidities. A multicenter registry is proposed as the foundation for future research.","methodology":"Expert review of CVS pathophysiology, comorbidities, and future research directions, proposing a multicenter registry approach to advance understanding and treatment development.","limitations":"Review article without systematic methodology. CVS lacks standardized diagnostic criteria and outcome measures. The overlap between CVS and CHS is not fully characterized. Treatment recommendations based on limited clinical data."},{"rthcId":"RTHC-02067","title":"Developmental pathways of adolescent cannabis use: Risk factors, outcomes and sex-specific differences.","authors":"Hawes, Samuel W; Trucco, Elisa M; Duperrouzel, Jacqueline C; Coxe, Stefany; Gonzalez, Raul","year":2019,"journal":"Substance use & misuse, 54(2), 271-281","doi":"10.1080/10826084.2018.1517177","pmid":"30395775","tags":["youth","mental-health","sex-differences","depression"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Three cannabis use trajectories were identified: low (74%), chronic (12%), and escalating (14%). Boys were more likely to show escalating and chronic patterns. Conduct disorder symptoms showed the most robust bidirectional association with cannabis use trajectories, both predicting and being predicted by them.","whyItMatters":"Most at-risk youth didn't develop problematic cannabis patterns, challenging assumptions about inevitability. The conduct disorder connection suggests behavioral problems and cannabis use fuel each other, creating a cycle that interventions could target.","specificNumbers":"401 youth, 90% Hispanic, 46% female. Low trajectory: 74%. Chronic: 12%. Escalating: 14%. Boys more likely in chronic and escalating groups. Conduct disorder most strongly and bidirectionally associated with cannabis trajectories.","methodology":"Trajectory-based modeling in 401 predominantly Hispanic (90%) at-risk youth (46% female) tracked from ages 14-18, controlling for baseline substance use and demographics, with psychopathology measured as both predictor and outcome.","limitations":"Predominantly Hispanic sample from one region limits generalizability. Four-year follow-up from ages 14-18 may miss later trajectory changes. Self-reported substance use. At-risk sample may not represent general population."},{"rthcId":"RTHC-02068","title":"Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats.","authors":"He, Xiang-Hu; Jordan, Chloe J; Vemuri, Kiran; Bi, Guo-Hua; Zhan, Jia; Gardner, Eliot L; Makriyannis, Alexandros; Wang, Yan-Lin; Xi, Zheng-Xiong","year":2019,"journal":"Acta pharmacologica Sinica, 40(3), 365-373","doi":"10.1038/s41401-018-0059-x","pmid":"29967454","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AM4113 dose-dependently inhibited heroin self-administration but not cocaine or methamphetamine self-administration. Unlike rimonabant, AM4113 did not increase brain stimulation reward thresholds (a measure of depression/aversion). Rimonabant reduced heroin and methamphetamine self-administration but also produced aversive-like effects.","whyItMatters":"Rimonabant showed promise for addiction but was pulled due to depression and suicidality. The neutral antagonist AM4113 retains the anti-addictive effects for heroin while avoiding the mood-lowering properties, representing a potential breakthrough for opioid addiction treatment.","specificNumbers":"AM4113 (3 and 10 mg/kg) reduced heroin but not cocaine or methamphetamine self-administration. SR141716A (3 and 10 mg/kg) reduced heroin and methamphetamine self-administration. AM4113 had no effect on brain stimulation reward; SR141716A increased thresholds (indicating aversive effects).","methodology":"Rats were trained to self-administer heroin, cocaine, or methamphetamine and then treated with AM4113 or rimonabant. Brain stimulation reward thresholds were measured as an index of mood/aversion effects.","limitations":"Rat model of self-administration may not fully predict human treatment response. AM4113 has not been tested in humans. Only acute effects studied. The specific selectivity for heroin over cocaine/methamphetamine requires mechanistic explanation."},{"rthcId":"RTHC-02069","title":"Cannabidiol (CBD) for Treatment of Neurofibromatosis-related Pain and Concomitant Mood Disorder: A Case Report.","authors":"Hegazy, Omar; Platnick, Howard","year":2019,"journal":"Cureus, 11(12), e6312","doi":"10.7759/cureus.6312","pmid":"31938604","tags":["cbd","pain","depression","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"CBD was used to manage chronic pain from neurofibromas and associated mood disorder (depression and anxiety) in a patient with neurofibromatosis type 1, leveraging its reported anti-inflammatory, analgesic, mood-stabilizing, and anxiolytic properties.","whyItMatters":"Neurofibromatosis causes chronic pain that is difficult to treat with conventional medications, and the psychological burden is significant. This case adds to the growing interest in CBD for complex pain conditions with comorbid mood disorders.","specificNumbers":"NF1 is a common genetic disorder. Pain sources include plexiform and subcutaneous neurofibromas, musculoskeletal symptoms, and headaches. CBD used for both pain and mood symptoms.","methodology":"Single patient case report describing CBD use for NF1-related pain and mood disorder, with narrative review of CBD's pharmacological properties.","limitations":"Single case report, the weakest level of clinical evidence. No control comparison. Subjective outcome assessment. Cannot generalize to other NF1 patients. No standardized dosing protocol described."},{"rthcId":"RTHC-02070","title":"Cannabis: An ancient friend or foe? What works and doesn't work.","authors":"Henschke, Philip","year":2019,"journal":"Seminars in fetal & neonatal medicine, 24(2), 149-154","doi":"10.1016/j.siny.2019.02.001","pmid":"30827870","tags":["pregnancy","youth","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system is critical for brain development across fetal, infant, and adolescent stages. Exogenous cannabinoids can cause supra-physiological stimulation that disrupts normal central nervous system development. Cannabis is common among pregnant women, and the long-term effects of in utero exposure are increasingly documented.","whyItMatters":"Published in a fetal and neonatal medicine journal, this targets the clinicians most likely to encounter pregnant cannabis users. As medicinal cannabis expands, more pregnant women may consider it for morning sickness or other symptoms without understanding developmental risks.","specificNumbers":"Cannabis is the most frequently used recreational drug in Western societies. Use is common among pregnant women. The endocannabinoid system undergoes critical developmental changes throughout fetal, infant, and adolescent periods.","methodology":"Review of historical cannabis use, the endocannabinoid system's role in brain development, evidence on in utero cannabis exposure effects, and implications of medicinal cannabis products during pregnancy.","limitations":"Narrative review without systematic methodology. Much evidence on in utero effects comes from observational studies with confounding factors. Long-term developmental outcomes are difficult to attribute solely to cannabis exposure."},{"rthcId":"RTHC-02071","title":"Drivers who tested positive for cannabis in oral fluid: a longitudinal analysis of administrative data for Spain between 2011 and 2016.","authors":"Herrera-Gómez, Francisco; García-Mingo, Mercedes; Colás, Mónica; González-Luque, Juan Carlos; Alvarez, F Javier","year":2019,"journal":"BMJ open, 9(8), e026648","doi":"10.1136/bmjopen-2018-026648","pmid":"31455697","tags":["driving","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Of 65,244 confirmed drug-positive tests (2011-2016), 51,869 (79.5%) were THC-positive. In 50.8% of THC-positive tests, cocaine and amphetamines were also detected. Polysubstance use predominated at lower THC levels (58.6% of those under 25 ng/mL). Mean age was 29.6 years; men accounted for 96.3% of THC-positive drivers.","whyItMatters":"The massive scale of this dataset (nearly 180,000 tests) reveals that cannabis-positive driving rarely occurs in isolation. Half of THC-positive drivers also had cocaine or amphetamines, complicating attribution of impairment risk to cannabis alone.","specificNumbers":"179,645 roadside tests. 65,244 drug-positive. 51,869 THC-positive (79.5%). 50.8% of THC-positive also had cocaine/amphetamines. THC-only decreased with age (OR 0.948). Polysubstance increased with age (OR 1.021). Men: 96.3% of THC-positive. Men had higher THC concentrations (OR 1.394).","methodology":"Analysis of national administrative data from Spain's roadside drug testing program, 179,645 oral fluid tests between 2011 and 2016, with confirmation analysis for driving-impairing substances.","limitations":"Administrative testing data, not a random sample of all drivers. Only drug-positive tests analyzed, not the full 179,645. Spanish driving culture and drug use patterns may not generalize. Cannot determine impairment level from substance detection alone."},{"rthcId":"RTHC-02072","title":"Varenicline and nabilone in tobacco and cannabis co-users: effects on tobacco abstinence, withdrawal and a laboratory model of cannabis relapse.","authors":"Herrmann, Evan S; Cooper, Ziva D; Bedi, Gillinder; Ramesh, Divya; Reed, Stephanie Collins; Comer, Sandra D; Foltin, Richard W; Haney, Margaret","year":2019,"journal":"Addiction biology, 24(4), 765-776","doi":"10.1111/adb.12664","pmid":"30378231","tags":["addiction","quitting","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Varenicline doubled cotinine-verified tobacco abstinence (46% vs 24%) and reduced mood disturbance and cigarette craving. Nabilone attenuated cannabis withdrawal in both groups but did not affect cannabis relapse. Age of first cigarette and cigarette craving were independent predictors of cannabis relapse.","whyItMatters":"Tobacco and cannabis are frequently co-used, and tobacco use worsens cannabis cessation outcomes. This study is among the first to test medications specifically for this co-use pattern, finding that addressing tobacco (varenicline) may be key to improving cannabis outcomes.","specificNumbers":"Tobacco abstinence: 46% varenicline vs 24% placebo. Nabilone attenuated cannabis withdrawal but not relapse. Age of first cigarette and cigarette craving predicted cannabis relapse outcomes independently.","methodology":"Two-phase study: 15-day outpatient phase with randomized active or placebo varenicline plus tobacco abstinence instruction, followed by 16-day inpatient phase with crossover nabilone/placebo and cannabis exposure, withdrawal, and relapse paradigms. Non-treatment-seeking tobacco-cannabis co-users.","limitations":"Small sample of non-treatment-seeking participants. Laboratory relapse model may not reflect real-world conditions. Short duration. Nabilone dosing may not have been optimized for relapse prevention."},{"rthcId":"RTHC-02073","title":"How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.","authors":"Hoch, Eva; Niemann, Dominik; von Keller, Rupert; Schneider, Miriam; Friemel, Chris M; Preuss, Ulrich W; Hasan, Alkomiet; Pogarell, Oliver","year":2019,"journal":"European archives of psychiatry and clinical neuroscience, 269(1), 87-105","doi":"10.1007/s00406-019-00984-4","pmid":"30706168","tags":["medical-cannabis","mental-health","psychosis","ptsd","addiction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 14 RCTs (1,629 participants) covering dementia, cannabis/opioid dependence, psychosis, social anxiety, PTSD, anorexia nervosa, ADHD, and Tourette's disorder, cannabis-based medicines as adjuncts were associated with symptom improvements but not remission. Severe adverse effects were rare.","whyItMatters":"This provides a reality check on cannabis for mental health. Improvements were seen, but no condition achieved remission, and sample sizes remain small. The gap between popular enthusiasm for cannabis as a mental health treatment and the evidence base is clear.","specificNumbers":"14 RCTs, 1,629 participants. Diagnoses: dementia, cannabis/opioid dependence, psychosis/schizophrenia, social anxiety, PTSD, anorexia nervosa, ADHD, Tourette's. Improvements in several symptoms. No remission achieved. Severe adverse effects in single cases only.","methodology":"Review of systematic reviews and RCTs searching five databases (2006-August 2018). Four systematic reviews (of 11 RCTs) and 14 RCTs with 1,629 participants were included. Narrative synthesis due to heterogeneous outcomes. Risk of bias and SIGN checklists applied.","limitations":"Too heterogeneous for meta-analysis. Small trial sizes across all conditions. Many different THC/CBD formulations and doses used. Adjunctive use only (added to existing treatment), not standalone. Short follow-up periods in most trials."},{"rthcId":"RTHC-02074","title":"Cannabis Oil Use by Adolescents and Young Adults With Inflammatory Bowel Disease.","authors":"Hoffenberg, Edward J; McWilliams, Shannon; Mikulich-Gilbertson, Susan; Murphy, Brittany; Hoffenberg, Analice; Hopfer, Christian J","year":2019,"journal":"Journal of pediatric gastroenterology and nutrition, 68(3), 348-352","doi":"10.1097/MPG.0000000000002189","pmid":"30801394","tags":["inflammation","cbd","youth","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"15 cannabis oil users and 67 non-users had similar clinical characteristics and pain/appetite scores. 60% of CO users had used in the past 30 days (average 22 times). Most common perceived effects: improved sleep, reduced nausea, increased appetite. Only 6 of 15 used exclusively oil; most also used other cannabis products.","whyItMatters":"Young IBD patients are self-medicating with cannabis oil despite limited evidence, using various CBD:THC ratios and strengths. This reality demands open clinician-patient dialogue rather than dismissal of patient-initiated treatment.","specificNumbers":"15 CO users, 67 non-users, ages 13-23. 60% used in past 30 days. Average use: 22 times/month; 4 used daily. Various CBD:THC ratios reported. Top perceived benefits: sleep, nausea, appetite. Only 6/15 used oil exclusively.","methodology":"Descriptive study of IBD patients aged 13-23 at Children's Hospital Colorado (2015-2017) using chart abstraction, self-report, and serum cannabinoid levels to compare cannabis oil users with non-users.","limitations":"Very small sample (15 users). Single-center study. No objective outcome measures for perceived benefits. Self-selected users may be biased toward positive reporting. Diverse CBD:THC ratios prevent dose-response analysis."},{"rthcId":"RTHC-02075","title":"Use of Guanfacine for Cannabis Use Disorder and Related Symptomology.","authors":"Holst, Manuela; Mathai, David S; Patel, Marguerite M; Rodgman, Christopher; Keller, Jake; Hussain, Mariyah Z; De La Garza, Richard; Kosten, Thomas R; Verrico, Christopher D","year":2019,"journal":"The American journal on addictions, 28(6), 455-464","doi":"10.1111/ajad.12959","pmid":"31483544","tags":["addiction","quitting","withdrawal"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Guanfacine (3 mg/day) showed no significant effects on cannabis withdrawal, craving, or sleep compared to placebo. Trends were observed for increased positive mood symptoms and decreased craving-associated compulsivity. The authors note their subjects had early onset and severe cannabis use, potentially increasing treatment resistance.","whyItMatters":"No medications are FDA-approved for cannabis use disorder. Even negative results from pilot studies contribute to the field by ruling out approaches and identifying potential signals worth pursuing in larger trials.","specificNumbers":"7 participants. Guanfacine 3 mg/day vs placebo, 8 days each. No significant effects on withdrawal, craving, or sleep. Trends for positive mood improvement and decreased compulsive craving. Early onset, long-duration cannabis use in subjects.","methodology":"Within-subjects crossover pilot study with 7 non-treatment-seeking volunteers meeting DSM-IV criteria for cannabis use disorder. Two 8-day inpatient periods (guanfacine 3 mg/day vs placebo) following standardized abstinence onset (30 mg synthetic THC on day 1).","limitations":"Very small sample (n=7). Non-treatment-seeking participants. Short 8-day treatment period. Within-subjects design may have carryover effects. Subjects had severe cannabis use histories that may increase treatment resistance."},{"rthcId":"RTHC-02076","title":"Cannabis Hyperemesis Syndrome in Palliative Care: A Case Study and Narrative Review.","authors":"Howard, Ileana","year":2019,"journal":"Journal of palliative medicine, 22(10), 1227-1231","doi":"10.1089/jpm.2018.0531","pmid":"31084461","tags":["harm-reduction","medical-cannabis","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"In a palliative care patient with advanced ALS, cannabis hyperemesis presented atypically without the classic hot bath behavior (due to physical disability). Symptoms may have improved with dose reduction rather than complete abstinence. Primary symptom management (pain, spasticity, nausea, anxiety) must be balanced against CHS risk.","whyItMatters":"Most CHS guidance assumes patients can simply stop cannabis. In palliative care, where cannabis may be managing critical symptoms like pain and spasticity in terminal illness, the risk-benefit calculation is different, and dose reduction may be a more realistic option.","specificNumbers":"Patient with advanced ALS. CHS diagnosed. Classic hot bath behavior absent due to disability. Dose reduction (rather than complete cessation) may have been sufficient. Primary symptoms managed with cannabis: pain, spasticity, nausea, anxiety.","methodology":"Single case report with narrative synthesis of CHS literature, focusing on unique considerations for palliative care patients.","limitations":"Single case report. The finding that dose reduction may suffice is based on one patient and cannot be generalized. Atypical presentation makes diagnosis challenging. No comparative data on dose reduction vs cessation strategies."},{"rthcId":"RTHC-02077","title":"Medical Marijuana Policy Reform Reaches Florida: A Scoping Review.","authors":"Howell, Khadesia; Washington, Alexandria; Williams, Paula M; Mathis, Arlesia L; Luque, John S","year":2019,"journal":"Florida public health review, 16, 128-136","doi":null,"pmid":"31891164","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02078","title":"Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus through Bidirectional Control of ERK1-2 Phosphorylation.","authors":"Hudson, Roger; Renard, Justine; Norris, Christopher; Rushlow, Walter J; Laviolette, Steven R","year":2019,"journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(44), 8762-8777","doi":"10.1523/JNEUROSCI.0708-19.2019","pmid":"31570536","tags":["cbd","psychosis","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Intra-hippocampal THC increased VTA dopamine neuron firing and bursting, decreased GABA frequency, and amplified oscillatory activity via ERK1-2 phosphorylation. THC also potentiated emotional salience in behavioral tests. CBD co-administration reversed all changes by downregulating pERK1-2, and pharmacological reactivation of pERK1-2 blocked CBD's protective effects.","whyItMatters":"This identifies the first specific molecular mechanism by which CBD counteracts THC's psychosis-like effects: ERK1-2 phosphorylation in the hippocampus. This could explain why high-THC/low-CBD strains are associated with greater psychosis risk and inform both strain recommendations and drug development.","specificNumbers":"THC increased VTA DA frequency and bursting, decreased GABA frequency, amplified beta/gamma/epsilon oscillations. All effects reversed by CBD co-administration. Mechanism: THC upregulates pERK1-2; CBD downregulates it. Pharmacological ERK reactivation blocked CBD's protective effect.","methodology":"In vivo electrophysiology in male Sprague Dawley rats with intra-hippocampal drug delivery. Measured VTA dopamine and GABA neuron activity, oscillatory magnitudes, and pERK1-2 levels. Behavioral tests included morphine place preference and fear conditioning assays.","limitations":"Rat model with direct hippocampal injection, not oral or inhaled cannabinoid administration. Acute effects only. Male rats only. The translation from this specific mechanism to human psychosis risk is assumed but not demonstrated."},{"rthcId":"RTHC-02079","title":"Medical Cannabis for Adult Attention Deficit Hyperactivity Disorder: Sociological Patient Case Report of Cannabinoid Therapeutics in Finland.","authors":"Hupli, Aleksi Mikael Markunpoika","year":2019,"journal":"Medical cannabis and cannabinoids, 1(2), 112-118","doi":"10.1159/000495307","pmid":"34676327","tags":["medical-cannabis","cognition","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"After experiencing adverse effects from methylphenidate and alternative medications, the patient was prescribed Bedrocan (THC-dominant) for ADHD symptom relief and Bediol (THC+CBD) to moderate the THC effects and improve sleep. Over 5 years, the THC-dominant product helped with frustration tolerance, anger outbursts, boredom, and concentration.","whyItMatters":"ADHD treatment in adults relies heavily on stimulant medications that many patients cannot tolerate. This detailed case adds to limited evidence that some ADHD patients may benefit from cannabinoid therapeutics, particularly for emotional regulation symptoms.","specificNumbers":"Patient diagnosed with ADHD at age 33. Initial treatment: Ritalin 10mg twice daily. Adverse effects led to alternatives. Medical cannabis prescribed 2010: Bedrocan (THC-dominant) and Bediol (THC+CBD). 5-year treatment period. Symptoms improved: frustration tolerance, anger, boredom, concentration.","methodology":"Detailed single-patient case report with sociological framing, describing a patient's journey from methylphenidate to medical cannabis for adult ADHD, prescribed through Germany and confirmed by Finnish neurologist. Includes brief literature review of cannabis for ADHD.","limitations":"Single case report, the weakest evidence level. Patient self-reported outcomes without objective measures. No placebo comparison. The patient sought cannabinoid treatment actively, suggesting potential bias. Regulatory and cultural context (Finland) may affect generalizability."},{"rthcId":"RTHC-02080","title":"Enhanced tolerance of industrial hemp (Cannabis sativa L.) plants on abandoned mine land soil leads to overexpression of cannabinoids.","authors":"Husain, Rabab; Weeden, Hannah; Bogush, Daniel; Deguchi, Michihito; Soliman, Mario; Potlakayala, Shobha; Katam, Ramesh; Goldman, Stephen; Rudrabhatla, Sairam","year":2019,"journal":"PloS one, 14(8), e0221570","doi":"10.1371/journal.pone.0221570","pmid":"31465423","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02081","title":"Cannabis and Health Research: Rapid Progress Requires Innovative Research Designs.","authors":"Hutchison, Kent E; Bidwell, L Cinnamon; Ellingson, Jarrod M; Bryan, Angela D","year":2019,"journal":"Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research, 22(11), 1289-1294","doi":"10.1016/j.jval.2019.05.005","pmid":"31708066","tags":["medical-cannabis","legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"63% of the US population has access to medicinal cannabis markets offering increasingly diverse and potent products. The scientific literature does not adequately inform public policy, medical decision making, or harm reduction approaches. Key barriers include federal scheduling, DEA licensing, and limited approved research cannabis.","whyItMatters":"Millions of people are using cannabis products with minimal scientific guidance. The regulatory barriers that prevent proper research create an information vacuum filled by marketing claims and anecdotes, which is harmful to both users and non-users.","specificNumbers":"63% of US population with medicinal cannabis access. Increasingly diverse and potent products available. Research barriers include federal Schedule I status, DEA licensing requirements, and NIDA-supplied cannabis that doesn't match commercial products.","methodology":"Review examining the state of cannabis research for commonly treated conditions, barriers to research progress, and proposed innovative research designs to address knowledge gaps.","limitations":"Focuses on US regulatory context, though similar barriers exist in other countries. Proposed innovative designs have not been fully validated. Does not provide a timeline for when the knowledge gap might close."},{"rthcId":"RTHC-02082","title":"Whole blood transcriptome analysis in ewes fed with hemp seed supplemented diet.","authors":"Iannaccone, Marco; Ianni, Andrea; Contaldi, Felice; Esposito, Salvatore; Martino, Camillo; Bennato, Francesca; De Angelis, Elisabetta; Grotta, Lisa; Pomilio, Francesco; Giansante, Daniele; Martino, Giuseppe","year":2019,"journal":"Scientific reports, 9(1), 16192","doi":"10.1038/s41598-019-52712-6","pmid":"31700124","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02083","title":"Cannabinoid CB1 and CB2 Receptor-Mediated Arrestin Translocation: Species, Subtype, and Agonist-Dependence.","authors":"Ibsen, Mikkel Søes; Finlay, David B; Patel, Monica; Javitch, Jonathan A; Glass, Michelle; Grimsey, Natasha Lillia","year":2019,"journal":"Frontiers in pharmacology, 10, 350","doi":"10.3389/fphar.2019.00350","pmid":"31024316","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02084","title":"Cannabis and multiple sclerosis.","authors":"Ingram, Gillian; Pearson, Owen R","year":2019,"journal":"Practical neurology, 19(4), 310-315","doi":"10.1136/practneurol-2018-002137","pmid":"31201234","tags":["medical-cannabis","pain","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"About half of MS patients report previous or current medicinal cannabis use. Despite governments worldwide relaxing regulations, questions remain about how clinicians should prescribe or recommend products. Access to pharmaceutical-grade cannabis remains highly restricted even where legal.","whyItMatters":"MS patients are already using cannabis in large numbers. Neurologists need practical guidance that acknowledges this reality while navigating the gap between patient demand and available evidence.","specificNumbers":"Approximately 50% of MS patients report medicinal cannabis use. Many governments relaxing regulations worldwide. Pharmaceutical-grade product access remains highly restricted.","methodology":"Clinical review for practicing adult neurologists, summarizing what is known about cannabis use in multiple sclerosis and the practical challenges of integrating cannabis into MS care.","limitations":"Clinical review rather than systematic review. General overview without detailed efficacy analysis. Prescribing guidance remains vague by necessity due to limited evidence."},{"rthcId":"RTHC-02085","title":"Paternal activation of CB2 cannabinoid receptor impairs placental and embryonic growth via an epigenetic mechanism.","authors":"Innocenzi, Elisa; De Domenico, Emanuela; Ciccarone, Fabio; Zampieri, Michele; Rossi, Gabriele; Cicconi, Rosella; Bernardini, Roberta; Mattei, Maurizio; Grimaldi, Paola","year":2019,"journal":"Scientific reports, 9(1), 17034","doi":"10.1038/s41598-019-53579-3","pmid":"31745152","tags":["pregnancy","genetics","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"JWH-133 (CB2 agonist) exposure in male mice decreased sperm count, impaired placental development, and reduced offspring growth. These effects were associated with altered DNA methylation and hydroxymethylation at imprinted genes in sperm, with the changes conserved in placenta, demonstrating epigenetic transmission from father to offspring.","whyItMatters":"This is the first demonstration that CB2 receptor activation in male germ cells can cause epigenetic changes transmitted to the next generation through sperm. It shifts the cannabis-pregnancy conversation from maternal-only to include paternal exposure risks.","specificNumbers":"JWH-133 (selective CB2 agonist) reduced sperm count. Altered DNA methylation/hydroxymethylation at imprinted genes in sperm. Changes conserved in placenta. Reduced offspring growth. Impaired placental development.","methodology":"Male mice exposed to JWH-133 (selective CB2 agonist), then assessed for sperm quality, offspring growth, and placental development. Epigenetic analysis of DNA methylation/hydroxymethylation at imprinted genes in sperm and placental tissue.","limitations":"Mouse model using a synthetic CB2-selective agonist, not cannabis or THC. The specific compound (JWH-133) may not replicate the effects of recreational cannabinoids which primarily target CB1. Epigenetic changes at imprinted genes may be species-specific."},{"rthcId":"RTHC-02086","title":"Effects of the synthetic cannabinoid 5F-AMB on anxiety and recognition memory in mice.","authors":"Ito, Shiho; Deyama, Satoshi; Domoto, Masaki; Zhang, Tong; Sasase, Hitoki; Fukao, Akari; Esaki, Hirohito; Hinoi, Eiichi; Kaneko, Shuji; Kaneda, Katsuyuki","year":2019,"journal":"Psychopharmacology, 236(7), 2235-2242","doi":"10.1007/s00213-019-05222-2","pmid":"30868181","tags":["synthetic-cannabinoids","anxiety","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Central 5F-AMB produced anxiolytic effects and impaired recognition memory acquisition via CB1 receptors (blocked by AM251). Systemic 5F-AMB severely reduced locomotor activity. Direct prefrontal cortex infusion impaired memory but did not reduce anxiety, suggesting different brain regions mediate each effect.","whyItMatters":"Synthetic cannabinoids like 5F-AMB are increasingly found in illegal products, yet their specific effects on brain function are largely unknown. This study maps which brain functions they affect and through which mechanisms.","specificNumbers":"5F-AMB 0.3 mg/kg IP dramatically decreased locomotor activity (partially reversed by AM251 3 mg/kg). ICV 5F-AMB 10 nmol: anxiolytic + memory impairment (both blocked by AM251). Intra-mPFC 5F-AMB: impaired memory only, not anxiety.","methodology":"Behavioral pharmacology in C57BL/6J mice using intraperitoneal, intracerebroventricular, and intra-prefrontal cortex administration of 5F-AMB with the CB1 antagonist AM251. Assessed via open field test (anxiety, locomotion) and novel object recognition test (memory).","limitations":"Mouse model with direct brain injection for mechanistic studies. Single synthetic cannabinoid studied. Acute effects only. The severe locomotor effect of systemic administration complicates interpretation of other behavioral measures."},{"rthcId":"RTHC-02087","title":"Effects of chronic cannabinoid exposure during adolescence on reward preference and mPFC activation in adulthood.","authors":"Jacobs-Brichford, Eliza; Manson, Kirk F; Roitman, Jamie D","year":2019,"journal":"Physiology & behavior, 199, 395-404","doi":"10.1016/j.physbeh.2018.12.006","pmid":"30529340","tags":["youth","cognition","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adult rats that received WIN 55,212-2 during adolescence (postnatal days 30-60) showed subtle changes in choice behavior and significantly reduced mPFC neural activity during lever presses and reward delivery in a probabilistic reward task, suggesting impaired excitatory-inhibitory balance from adolescent exposure.","whyItMatters":"This provides direct neural evidence that adolescent cannabinoid exposure disrupts the prefrontal cortex's reward processing into adulthood, a mechanism that could underlie real-world difficulties with decision-making, motivation, and substance use vulnerability.","specificNumbers":"WIN 55,212-2 administered postnatal days 30-60. Adult task performance showed subtle choice pattern changes. mPFC activity reduced at both lever press (choice time) and reward delivery in WIN-treated animals compared to controls.","methodology":"Male and female rats received daily WIN 55,212-2 or vehicle from postnatal day 30-60. In adulthood, animals performed a probabilistic reward choice task while mPFC neural activity was recorded electrophysiologically.","limitations":"Used a synthetic cannabinoid (WIN 55,212-2), not THC or cannabis. Choice behavior effects were subtle. Only mPFC examined; other reward-related regions may also be affected. Rats received daily injections, which differs from typical human consumption patterns."},{"rthcId":"RTHC-02088","title":"A systematic review of phytocannabinoid exposure on the endocannabinoid system: Implications for psychosis.","authors":"Jacobson, Maya R; Watts, Jeremy J; Boileau, Isabelle; Tong, Junchao; Mizrahi, Romina","year":2019,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29(3), 330-348","doi":"10.1016/j.euroneuro.2018.12.014","pmid":"30635160","tags":["psychosis","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The most established finding is CB1 receptor downregulation after chronic and recent cannabis exposure. This pattern may mirror endocannabinoid system changes observed in psychosis. However, it remains uncertain whether CB1 downregulation also occurs in cannabis users who have schizophrenia.","whyItMatters":"If cannabis causes endocannabinoid system changes that resemble those seen in psychosis, this provides a biological mechanism linking cannabis use to psychotic disorders. Understanding this overlap could inform both prevention and treatment.","specificNumbers":"CB1 receptor downregulation is the most consistently reported change after chronic cannabis use. The pattern overlaps with endocannabinoid alterations observed in psychosis. Uncertainty remains for cannabis users with schizophrenia.","methodology":"Systematic review of studies examining the effects of exogenous cannabinoids on the endocannabinoid system in humans with and without psychotic disorders.","limitations":"Limited number of human studies examining endocannabinoid system changes after cannabis use. Unclear whether CB1 changes are cause or effect in psychosis. Different imaging and measurement methods across studies complicate comparison."},{"rthcId":"RTHC-02089","title":"Cannabis and the developing brain: What does the evidence say?","authors":"Jacobus, Joanna; Courtney, Kelly E; Hodgdon, Elizabeth A; Baca, Rachel","year":2019,"journal":"Birth defects research, 111(17), 1302-1307","doi":"10.1002/bdr2.1572","pmid":"31385460","tags":["youth","neuroscience","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Across two prospective studies (3 and 6 years), recency, frequency, and age of onset of cannabis use were the key variables predicting poorer neural health outcomes. There is also evidence that preexisting differences in brain architecture may contribute to vulnerability and outcome differences.","whyItMatters":"Prospective studies that follow teens over time are far more informative than cross-sectional snapshots. These findings suggest the brain impact of teen cannabis use is not fixed but varies by modifiable use patterns, offering prevention leverage.","specificNumbers":"Two prospective studies: 3-year and 6-year average follow-up. Key predictors: recency of use, frequency of use, age of onset. Preexisting brain architecture differences also contribute to outcomes.","methodology":"Summary of findings from two prospective investigations using structural neuroimaging and neurocognitive assessment in adolescent cannabis users, with average follow-ups of 3 and 6 years.","limitations":"Summary of two lab's prospective studies, not a systematic review. Structural imaging captures anatomy, not function. Larger studies (like ABCD) are still underway and will provide more definitive answers."},{"rthcId":"RTHC-02090","title":"Cannabidiol attenuates mechanical allodynia in streptozotocin-induced diabetic rats via serotonergic system activation through 5-HT1A receptors.","authors":"Jesus, Carlos Henrique Alves; Redivo, Daiany Darlly Bello; Gasparin, Aléxia Thamara; Sotomaior, Bruna Bittencourt; de Carvalho, Milene Cristina; Genaro, Karina; Zuardi, Antonio Waldo; Hallak, Jaime Eduardo Cecílio; Crippa, José Alexandre; Zanoveli, Janaina Menezes; da Cunha, Joice Maria","year":2019,"journal":"Brain research, 1715, 156-164","doi":"10.1016/j.brainres.2019.03.014","pmid":"30898678","tags":["cbd","pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Acute CBD (0.3 and 3 mg/kg) reduced mechanical allodynia in diabetic rats. The effect was blocked by the 5-HT1A antagonist WAY 100135 but not by CB1 (AM251) or CB2 (AM630) antagonists. Sub-chronic CBD (14 days) produced sustained pain relief and restored depleted spinal cord serotonin levels.","whyItMatters":"Diabetic neuropathic pain affects most diabetic patients and responds poorly to current treatments. This study shows CBD works through an unexpected mechanism (serotonin, not cannabinoid receptors) and actually corrects the underlying serotonin deficit, not just masking pain.","specificNumbers":"CBD 0.3 and 3 mg/kg effective acutely. Effect blocked by 5-HT1A antagonist (WAY 100135 3 mcg/rat intrathecal). Not blocked by CB1 (AM251) or CB2 (AM630) antagonists. 14-day treatment sustained relief. Diabetic rats had lower spinal serotonin; CBD 0.3 mg/kg restored it.","methodology":"Streptozotocin-induced diabetic rats treated with acute or sub-chronic (14-day) CBD at multiple doses. Mechanical pain threshold assessed with electronic Von Frey. Pharmacological antagonism used to identify the mechanism. Spinal cord serotonin levels measured.","limitations":"Rat model of chemically induced diabetes. Intraperitoneal injection, not oral. The serotonergic mechanism found here may not be the only or primary mechanism in other pain types. No human data for CBD in diabetic neuropathy."},{"rthcId":"RTHC-02091","title":"Enzymatic analysis of glucuronidation of synthetic cannabinoid 1-naphthyl 1-(4-fluorobenzyl)-1H-indole-3-carboxylate (FDU-PB-22).","authors":"Jones, Sabrina; Yarbrough, Azure L; Shoeib, Amal; Bush, John M; Fantegrossi, William E; Prather, Paul L; Radominska-Pandya, Anna; Fujiwara, Ryoichi","year":2019,"journal":"Xenobiotica; the fate of foreign compounds in biological systems, 49(12), 1388-1395","doi":"10.1080/00498254.2019.1580403","pmid":"30739533","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02092","title":"Factors Associated with Poly Drug Use in Adolescents.","authors":"Jongenelis, Michelle; Pettigrew, Simone; Lawrence, David; Rikkers, Wavne","year":2019,"journal":"Prevention science : the official journal of the Society for Prevention Research, 20(5), 695-704","doi":"10.1007/s11121-019-00993-8","pmid":"30707340","tags":["youth","addiction","depression","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"20.3% had used at least one substance in the past 30 days, 6.7% used two, and 3.3% used all three. The most common combination was alcohol+tobacco, followed by alcohol+cannabis. Conduct problems, depression, and school environment accounted for the most variance in poly drug use.","whyItMatters":"Prevention programs often target substances individually, but a third of substance-using teens used multiple substances. Targeting the underlying drivers, particularly depression and conduct problems, could be more efficient than substance-specific approaches.","specificNumbers":"1,661 adolescents, ages 15-17. 20.3% used 1+ substance. 6.7% used 2. 3.3% used all 3. Most common combination: alcohol+tobacco, then alcohol+cannabis. Top predictors: conduct problems, depression, school environment.","methodology":"Survey of 1,661 Australian adolescents aged 15-17 (50.9% male) assessing past 30-day use of alcohol, tobacco, and cannabis, with psychological, environmental, and demographic factors analyzed using weighted multilevel logistic regression.","limitations":"Cross-sectional design cannot determine causation. Australian adolescent population may differ from other countries. Self-reported substance use. Past-30-day window may miss less frequent users."},{"rthcId":"RTHC-02093","title":"Adolescent Δ9-Tetrahydrocannabinol Exposure and Astrocyte-Specific Genetic Vulnerability Converge on Nuclear Factor-κB-Cyclooxygenase-2 Signaling to Impair Memory in Adulthood.","authors":"Jouroukhin, Yan; Zhu, Xiaolei; Shevelkin, Alexey V; Hasegawa, Yuto; Abazyan, Bagrat; Saito, Atsushi; Pevsner, Jonathan; Kamiya, Atsushi; Pletnikov, Mikhail V","year":2019,"journal":"Biological psychiatry, 85(11), 891-903","doi":"10.1016/j.biopsych.2018.07.024","pmid":"30219209","tags":["youth","psychosis","genetics","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Astrocyte-specific expression of DN-DISC1 combined with adolescent THC synergistically impaired recognition memory in adult mice. The mechanism involved NF-kB-COX-2 inflammatory pathway activation in astrocytes and decreased parvalbumin-positive inhibitory connections in the hippocampus. A COX-2 inhibitor (NS398) prevented the cognitive deficits.","whyItMatters":"This answers a critical question: why do some adolescent cannabis users develop lasting cognitive problems while others don't? Genetic vulnerability in astrocytes, not neurons, determined whether THC caused lasting harm, and the inflammatory mechanism is potentially treatable.","specificNumbers":"DN-DISC1 in astrocytes + adolescent THC: synergistic memory impairment. Mechanism: NF-kB-COX-2 pathway activation in astrocytes. Decreased parvalbumin-positive boutons around hippocampal CA3 pyramidal neurons. COX-2 inhibitor NS398 prevented cognitive deficits.","methodology":"Transgenic mice with inducible dominant-negative DISC1 expression selectively in astrocytes were treated with THC during adolescence. Adult recognition memory was tested. Molecular pathways examined included NF-kB-COX-2 signaling and hippocampal parvalbumin interneuron connectivity.","limitations":"Transgenic mouse model with artificial DISC1 disruption. Single memory test (recognition memory). The DISC1 gene's role in human schizophrenia risk is debated. COX-2 inhibition has its own side effects that limit clinical translation."},{"rthcId":"RTHC-02094","title":"Synthetic Strategies for (-)-Cannabidiol and Its Structural Analogs.","authors":"Jung, Byunghyuck; Lee, Jungkyu K; Kim, Jungnam; Kang, Eunhye K; Han, Sang Yeong; Lee, Hee-Yoon; Choi, Insung S","year":2019,"journal":"Chemistry, an Asian journal, 14(21), 3749-3762","doi":"10.1002/asia.201901179","pmid":"31529613","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02095","title":"Investigating a novel fMRI cannabis cue reactivity task in youth.","authors":"Karoly, Hollis C; Schacht, Joseph P; Meredith, Lindsay R; Jacobus, Joanna; Tapert, Susan F; Gray, Kevin M; Squeglia, Lindsay M","year":2019,"journal":"Addictive behaviors, 89, 20-28","doi":"10.1016/j.addbeh.2018.09.015","pmid":"30243035","tags":["youth","addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis-using youth showed greater whole-brain activation to cannabis cues compared to non-cannabis cues in brain regions underlying incentive salience, reward, and visual attention. Cannabis images were rated as more rewarding than matched non-cannabis images. No differences were found for active versus passive cue contrasts.","whyItMatters":"This is the first US adolescent fMRI study of cannabis cue reactivity. Heightened reward-region activation to cannabis images may reflect the neural basis for cue-triggered craving and relapse, offering a potential biomarker and intervention target.","specificNumbers":"41 youth, ages 17-21, 46.3% female. Cannabis cues rated more rewarding than non-cannabis cues. Greater activation in reward, incentive salience, and visual attention regions. No active vs passive cue differences.","methodology":"fMRI study of 41 non-treatment-seeking cannabis-using youth (ages 17-21, 46.3% female) viewing visual cannabis and matched non-cannabis cues during scanning, with self-report and biological substance use measures.","limitations":"No control group of non-cannabis-using youth. Small sample. Cross-sectional design cannot determine whether heightened reactivity causes continued use or results from it. Non-treatment-seeking sample."},{"rthcId":"RTHC-02096","title":"Preliminary evidence that computerized approach avoidance training is not associated with changes in fMRI cannabis cue reactivity in non-treatment-seeking adolescent cannabis users.","authors":"Karoly, Hollis C; Schacht, Joseph P; Jacobus, Joanna; Meredith, Lindsay R; Taylor, Charles T; Tapert, Susan F; Gray, Kevin M; Squeglia, Lindsay M","year":2019,"journal":"Drug and alcohol dependence, 200, 145-152","doi":"10.1016/j.drugalcdep.2019.04.007","pmid":"31132681","tags":["youth","addiction","neuroscience","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CAAT training shifted approach bias toward avoidance while sham training increased approach bias (trend p=0.055). However, no significant neural changes emerged on fMRI between CAAT and sham groups. Small-to-medium effect sizes were observed for decreased amygdala (d=0.36) and medial prefrontal (d=0.48) activation to cannabis cues in the CAAT group.","whyItMatters":"Computer-based interventions are attractive because they're scalable and cheap. While this particular approach reduced cannabis use behaviorally, the brain mechanism appears not to involve changes in cue reactivity, meaning the intervention may work through other neural pathways.","specificNumbers":"37 youth completed all sessions with usable imaging. CAAT: n=19, sham: n=18. Approach bias shift: trend p=0.055. No significant fMRI changes. Effect sizes: amygdala d=0.36, mPFC d=0.48 (small-to-medium, non-significant).","methodology":"Sub-study of a larger RCT: 37 cannabis-using youth (ages 17-21) completed pre and post fMRI scans around 6 sessions of CAAT (n=19) or sham training (n=18), with cannabis cue reactivity task.","limitations":"Very small neuroimaging subsample (n=37). The larger trial showed behavioral effects; the subsample may have been underpowered to detect neural changes. Only examined cue reactivity; other neural measures might show changes. Non-treatment-seeking sample."},{"rthcId":"RTHC-02097","title":"ST elevation myocardial infarction following a cannabis smoking binge.","authors":"Katranas, Sotirios; Ziakas, Antonios; Didagelos, Matthaios","year":2019,"journal":"Cardiology in the young, 29(6), 847-848","doi":"10.1017/S1047951119001008","pmid":"31199218","tags":["cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 26-year-old male with no prior cardiac history presented with ST-elevation myocardial infarction and subsequent heart failure after heavy cannabis smoking. The case adds to the literature on acute MI following cannabis use and discusses possible pathophysiologic mechanisms.","whyItMatters":"Heart attacks in 26-year-olds are extremely rare. When they occur after cannabis use, the potential cardiovascular mechanisms (coronary vasospasm, increased oxygen demand, platelet activation) deserve attention, especially as cannabis use increases among young people.","specificNumbers":"Patient: 26-year-old male. Diagnosis: ST-elevation myocardial infarction with heart failure. Trigger: cannabis smoking binge.","methodology":"Single case report with literature review of acute myocardial infarction following cannabis smoking and potential pathophysiologic mechanisms.","limitations":"Single case report cannot prove causation. Other cardiovascular risk factors may have been present. Cannabis binge dosing may not represent typical use patterns. Temporal association does not equal causation."},{"rthcId":"RTHC-02098","title":"Effects of cannabinoid modulation on hypothalamic nesfatin-1 and insulin resistance.","authors":"Kaya, Oktay; Yilmaz, Makbule Elif; Bayram, Sinasi; Gunduz, Ozgur; Kizilay, Gulnur; Ozturk, Levent","year":2019,"journal":"The Chinese journal of physiology, 62(5), 182-187","doi":"10.4103/CJP.CJP_50_19","pmid":"31670281","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"WIN 55,212-2 reduced brain nesfatin-1 immunoreactivity in sleep-deprived mice, an effect prevented by either CB1 or CB2 antagonists. Serum nesfatin-1 levels were unchanged. Insulin resistance was higher in the CB2 antagonist and WIN+CB2 antagonist groups, suggesting CB2 involvement in glucose metabolism.","whyItMatters":"This reveals a new connection between cannabinoid receptors and appetite-regulating signals in the brain. The finding that CB2 receptors affect insulin resistance independently adds to evidence that cannabinoids influence metabolism through multiple pathways.","specificNumbers":"60 mice, 72-hour sleep deprivation. WIN reduced brain nesfatin-1 positive cell count. Both CB1 and CB2 antagonists prevented the nesfatin-1 reduction. Serum nesfatin-1 unchanged across groups. Insulin resistance higher in CB2-related groups.","methodology":"Sixty mice subjected to 72-hour REM sleep deprivation and treated with WIN 55,212-2 (cannabinoid agonist), AM251 (CB1 antagonist), SR144528 (CB2 antagonist), or combinations. Blood glucose, insulin, and nesfatin-1 measured; brain nesfatin-1 assessed by immunohistochemistry.","limitations":"Sleep deprivation model adds a confound. Acute drug administration only. Only male mice. The relationship between central nesfatin-1 reduction and actual eating behavior was not tested."},{"rthcId":"RTHC-02099","title":"Engaging Youth (Adolescents and Young Adults) to Change Frequent Marijuana Use: Motivational Enhancement Therapy (MET) in Primary Care.","authors":"Kells, Meredith; Burke, Pamela J; Parker, Sarah; Jonestrask, Cassandra; Shrier, Lydia A","year":2019,"journal":"Journal of pediatric nursing, 49, 24-30","doi":"10.1016/j.pedn.2019.08.011","pmid":"31473464","tags":["youth","quitting","mental-health"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Most youth reported their main reason for cannabis use was emotional coping. Negative feelings were a top-3 trigger. Distraction was the most common alternative strategy. Education/career was the most common one-year goal. Over half identified family as a very important value. Top pros of using less: achieving goals, self-improvement, saving money.","whyItMatters":"This shows that frequent young cannabis users are not apathetic. They have goals, values, and ambivalence about their use. Meeting them with motivational therapy in primary care can elicit this information and create leverage for change.","specificNumbers":"56 completed session 1, 46 completed session 2. Main reason: emotional coping. Top trigger: negative feelings. Alternative: distraction. 1-year goals: education/career. Most important value: family (>50%). Contemplation group: relationships were both pro and con of change.","methodology":"Content analysis of two Motivational Enhancement Therapy (MET) sessions with 56 primary care patients aged 15-24 using cannabis 3+ times/week, comparing youth in pre-contemplation versus contemplation stages of change.","limitations":"Pilot study without a control group measuring outcomes. Small sample. Self-reported information in a therapeutic context may be subject to social desirability. Brief 2-session intervention."},{"rthcId":"RTHC-02100","title":"Use of gas chromatography-mass spectrometry for definitive diagnosis of synthetic cannabinoid toxicity in a dog.","authors":"Kelmer, Efrat; Shimshoni, Jakob A; Merbl, Yael; Kolski, Ofer; Klainbart, Sigal","year":2019,"journal":"Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001), 29(5), 573-577","doi":"10.1111/vec.12872","pmid":"31342645","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02101","title":"Marijuana use among patients with epilepsy at a tertiary care center.","authors":"Kerr, Alysse; Walston, Victoria; Wong, Victoria S S; Kellogg, Marissa; Ernst, Lia","year":2019,"journal":"Epilepsy & behavior : E&B, 97, 144-148","doi":"10.1016/j.yebeh.2019.05.037","pmid":"31252269","tags":["epilepsy","medical-cannabis","cbd","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"87.2% used cannabis to treat epilepsy. 82% agreed it improved seizure control. Most common strains: high-CBD (30.8%) or multiple types (30.8%). Methods: smoking (66.7%), edibles (48.7%), concentrates (43.6%). Only 2/39 knew their dose. Fewer women used primarily THC (10% vs 47% of men).","whyItMatters":"Even as pharmaceutical CBD (Epidiolex) gained FDA approval, epilepsy patients were already self-treating with dispensary products. The near-universal inability to state doses highlights a fundamental safety gap between pharmaceutical and dispensary cannabis.","specificNumbers":"39 cannabis-using epilepsy patients. 87.2% used for seizures. 82% agreed it helped. Only 2/39 knew their dose. High-CBD: 30.8%. Multiple types: 30.8%. Smoking: 66.7%. Edibles: 48.7%. Women vs men using THC-dominant: 10% vs 47%.","methodology":"Nine-item survey of patients seen in an epilepsy clinic over 9 months at a tertiary care center in Oregon, where recreational cannabis was legalized in 2015.","limitations":"Small convenience sample from one clinic. Self-reported seizure improvement without objective seizure diary data. Survey design limits depth of response. Oregon-specific population."},{"rthcId":"RTHC-02102","title":"CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist.","authors":"Kevin, Richard C; Anderson, Lyndsey; McGregor, Iain S; Boyd, Rochelle; Manning, Jamie J; Glass, Michelle; Connor, Mark; Banister, Samuel D","year":2019,"journal":"Frontiers in pharmacology, 10, 595","doi":"10.3389/fphar.2019.00595","pmid":"31191320","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CUMYL-4CN-BINACA acted as a potent CB1 receptor agonist and produced seizures at a lower dose than any previously tested synthetic cannabinoid. A CB1 antagonist blocked the seizure activity, while a CB2 antagonist had no effect.","whyItMatters":"Synthetic cannabinoids keep getting more potent. Understanding which compounds cause seizures and at what doses helps explain why emergency room visits linked to these drugs continue to rise.","specificNumbers":"CB1 receptor binding affinity Ki = 2.6 nM; functional potency EC50 = 0.58 nM; seizures observed at 0.3 mg/kg (lowest dose reported for any SCRA).","methodology":"Researchers tested the compound in mice, measuring hypothermic and pro-convulsant effects, and used receptor antagonists to determine which cannabinoid receptors mediated the effects.","limitations":"Mouse study only. Human responses to this compound may differ. The study did not examine chronic exposure or dose-response across a wide range."},{"rthcId":"RTHC-02103","title":"In-silico designing and characterization of binding modes of two novel inhibitors for CB1 receptor against obesity by classical 3D-QSAR approach.","authors":"Khan, Naveed; Halim, Sobia Ahsan; Khan, Waqasuddin; Zafar, Syed Kashif; Ul-Haq, Zaheer","year":2019,"journal":"Journal of molecular graphics & modelling, 89, 199-214","doi":"10.1016/j.jmgm.2019.03.016","pmid":"30908997","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02104","title":"Perspectives on cannabis as a substitute for opioid analgesics.","authors":"Khan, Sara P; Pickens, Thomas A; Berlau, Daniel J","year":2019,"journal":"Pain management, 9(2), 191-203","doi":"10.2217/pmt-2018-0051","pmid":"30681029","tags":["pain","medical-cannabis","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The review found evidence from preclinical, clinical, and epidemiological studies suggesting cannabis can complement or partially substitute for opioids in pain management, with some studies showing reduced opioid prescriptions in states with medical cannabis laws.","whyItMatters":"The opioid crisis has driven urgent interest in alternatives. If cannabis can safely reduce opioid dependence for pain patients, it could save lives, but clinicians need clear evidence to guide recommendations.","specificNumbers":"The review references ecological studies showing states with medical cannabis laws had 24.8% lower mean opioid overdose mortality rates compared to states without such laws.","methodology":"Narrative review examining preclinical data, clinical studies, and population-level research on cannabis-opioid interactions for pain management.","limitations":"Narrative review without systematic methodology. Many of the underlying studies are observational or ecological, making causal claims difficult. Cannabis preparation, dosing, and route of administration vary widely across studies."},{"rthcId":"RTHC-02105","title":"Resolution of Cannabinoid Hyperemesis Syndrome with Benzodiazepines: A Case Series.","authors":"Kheifets, Mark; Karniel, Eli; Landa, Daniel; Vons, Shelly Abigail; Meridor, Katya; Charach, Gideon","year":2019,"journal":"The Israel Medical Association journal : IMAJ, 21(6), 404-407","doi":null,"pmid":"31280510","tags":["appetite","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All four patients presented with cyclical nausea, vomiting, and abdominal pain in the context of chronic cannabis use. Standard antiemetics and proton pump inhibitors failed, but benzodiazepines resolved symptoms in each case.","whyItMatters":"CHS is often misdiagnosed, leading to expensive workups and prolonged suffering. Recognizing the syndrome early and knowing that benzodiazepines may help could shorten hospital stays and reduce unnecessary testing.","specificNumbers":"Four patients, all with documented chronic cannabis use, all failed conventional antiemetic therapy, all responded to benzodiazepines.","methodology":"Case series of four patients admitted to an internal medicine department, all diagnosed with CHS after excluding other gastrointestinal and neurological causes.","limitations":"Very small case series (n=4) with no control group. The mechanism by which benzodiazepines help CHS is proposed but not proven. Results may not generalize to all CHS patients."},{"rthcId":"RTHC-02106","title":"Is there a role for cannabidiol in psychiatry?","authors":"Khoury, Julia Machado; Neves, Maila de Castro Lourenço das; Roque, Marco Antônio Valente; Queiroz, Daniela Alves de Brito; Corrêa de Freitas, André Augusto; de Fátima, Ângelo; Moreira, Fabrício A; Garcia, Frederico Duarte","year":2019,"journal":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 20(2), 101-116","doi":"10.1080/15622975.2017.1285049","pmid":"28112021","tags":["cbd","psychosis","anxiety","addiction","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Evidence levels varied: B-level for cannabis withdrawal, C2 for cannabis addiction, C1 for positive symptoms in schizophrenia and anxiety in social anxiety disorder. No evidence was found for depression or bipolar disorder. Side effects were generally mild (sedation, dizziness).","whyItMatters":"CBD is widely marketed for psychiatric conditions despite limited clinical evidence. This review provides a structured assessment of what the science actually supports.","specificNumbers":"692 records screened, 13 studies included (6 case reports, 7 trials), 201 total subjects. Evidence graded B for cannabis withdrawal, C1 for schizophrenia positive symptoms and social anxiety, C2 for cannabis addiction.","methodology":"Systematic review searching PubMed, Scielo, and ClinicalTrials.gov, classifying evidence according to WFSBP task force standards. Included 6 case reports and 7 trials covering 201 subjects.","limitations":"Most included studies were small and did not reach statistical significance. Only 201 total subjects across all studies. No evidence found for depression or bipolar disorder. Publication bias possible."},{"rthcId":"RTHC-02107","title":"Cannabinoids Reduce Inflammation but Inhibit Lymphocyte Recovery in Murine Models of Bone Marrow Transplantation.","authors":"Khuja, Iman; Yekhtin, Zhanna; Or, Reuven; Almogi-Hazan, Osnat","year":2019,"journal":"International journal of molecular sciences, 20(3)","doi":"10.3390/ijms20030668","pmid":"30720730","tags":["cbd","inflammation","cancer"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In an allogeneic transplant model, THC-high and CBD-high cannabis extracts reduced GVHD severity and improved survival better than pure cannabinoids. However, both THC and CBD inhibited lymphocyte reconstitution in syngeneic models, with CB2 receptor involvement confirmed.","whyItMatters":"Bone marrow transplant patients often use cannabis for symptom relief. This study reveals a tradeoff: cannabinoids may reduce harmful inflammation (GVHD) but could also slow the immune recovery that transplant patients desperately need.","specificNumbers":"Cannabis extracts (THC-high and CBD-high) significantly improved survival in the allogeneic model compared to pure THC or CBD alone.","methodology":"Researchers compared THC, CBD, and cannabis extracts in vitro lymphocyte assays and in two mouse bone marrow transplant models (syngeneic and allogeneic), measuring immune reconstitution, GVHD severity, and survival.","limitations":"Mouse models only. Dosing regimens may not translate to human transplant patients. The study did not test different timing strategies that might preserve anti-GVHD benefits while minimizing immune suppression."},{"rthcId":"RTHC-02108","title":"Hemisphere-dependent endocannabinoid system activity in prefrontal cortex and hippocampus of the Flinders Sensitive Line rodent model of depression.","authors":"Kirkedal, C; Elfving, B; Müller, H K; Moreira, F A; Bindila, L; Lutz, B; Wegener, G; Liebenberg, N","year":2019,"journal":"Neurochemistry international, 125, 7-15","doi":"10.1016/j.neuint.2019.01.023","pmid":"30716357","tags":["depression","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"2-AG was lower in the left hippocampus and left prefrontal cortex of depression-prone FSL rats compared to controls. AEA was higher in the right hippocampus. CB1 receptor and FAAH protein levels were decreased in the left hippocampus, while mRNA for multiple eCB components was decreased in the right prefrontal cortex.","whyItMatters":"If depression involves hemisphere-specific endocannabinoid deficits, treatments targeting the eCB system might need to account for lateralized brain function, a nuance most current approaches overlook.","specificNumbers":"2-AG was significantly lower in left hippocampus and left prefrontal cortex of FSL rats. AEA was elevated in right hippocampus. Plasma AEA was increased and 2-AG decreased in FSL rats.","methodology":"Compared endocannabinoid levels (LC/MRM), receptor expression (qPCR), and protein levels (Western blot) in left and right prefrontal cortex and hippocampus of Flinders Sensitive Line (depression model) vs. Flinders Resistant Line rats.","limitations":"Animal model using inbred rat strains, which may not fully represent human depression. Small sample sizes typical of such studies. Hemisphere-specific findings need replication."},{"rthcId":"RTHC-02109","title":"Cannabidiol-from Plant to Human Body: A Promising Bioactive Molecule with Multi-Target Effects in Cancer.","authors":"Kis, Brigitta; Ifrim, Feng Chen; Buda, Valentina; Avram, Stefana; Pavel, Ioana Zinuca; Antal, Diana; Paunescu, Virgil; Dehelean, Cristina Adriana; Ardelean, Florina; Diaconeasa, Zorita; Soica, Codruta; Danciu, Corina","year":2019,"journal":"International journal of molecular sciences, 20(23)","doi":"10.3390/ijms20235905","pmid":"31775230","tags":["cbd","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review documents CBD's effects against cancer through multiple mechanisms: inhibiting cell proliferation, promoting cancer cell death, blocking invasion and angiogenesis, and modulating inflammation and immune responses. These effects have been observed in breast, lung, colon, prostate, glioblastoma, and other cancer types.","whyItMatters":"Cancer patients frequently ask about CBD. This review consolidates the mechanistic evidence showing CBD acts through multiple pathways, while also noting the significant gap between laboratory findings and clinical proof.","specificNumbers":"Over 100 phytocannabinoids have been detected in Cannabis sativa. CBD showed effects across at least six distinct anti-cancer mechanisms (anti-proliferative, pro-apoptotic, cytotoxic, anti-invasive, anti-angiogenic, and immunomodulatory).","methodology":"Comprehensive review of in vitro cell studies, in vivo animal models, and available clinical data on CBD's anticancer properties, covering mechanisms of action and pharmacological profile.","limitations":"Most evidence comes from cell cultures and animal models. Clinical data is scarce. Doses used in laboratory studies may not be achievable in humans. CBD's bioavailability challenges are acknowledged but not resolved."},{"rthcId":"RTHC-02110","title":"Opportunities for cannabis in supportive care in cancer.","authors":"Kleckner, Amber S; Kleckner, Ian R; Kamen, Charles S; Tejani, Mohamedtaki A; Janelsins, Michelle C; Morrow, Gary R; Peppone, Luke J","year":2019,"journal":"Therapeutic advances in medical oncology, 11, 1758835919866362","doi":"10.1177/1758835919866362","pmid":"31413731","tags":["medical-cannabis","cancer","pain","appetite"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The review found reasonable evidence to consider cannabis for nausea/vomiting, appetite loss, and pain as supplemental treatment. Promising but insufficient evidence exists for chemotherapy-induced peripheral neuropathy, GI distress, and sleep disorders. Evidence for cognitive impairment, anxiety, depression, and fatigue remains scant.","whyItMatters":"Cancer patients are among the highest-use populations for medical cannabis, yet oncologists often lack guidance on what cannabis can and cannot do for their patients' symptoms.","specificNumbers":"The review assessed cannabis evidence across at least nine symptom categories in cancer patients, finding reasonable evidence for three (nausea/vomiting, appetite loss, pain) and promising evidence for three more (neuropathy, GI distress, sleep).","methodology":"Literature review across cancer, HIV, multiple sclerosis, IBD, PTSD, and other fields to inform cannabis use in cancer supportive and palliative care.","limitations":"Narrative review without systematic search methodology. Draws on evidence from non-cancer populations which may not directly translate. Cannabis preparation and dosing varied widely across included studies."},{"rthcId":"RTHC-02111","title":"A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb® Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects.","authors":"Knaub, Katharina; Sartorius, Tina; Dharsono, Tanita; Wacker, Roland; Wilhelm, Manfred; Schön, Christiane","year":2019,"journal":"Molecules (Basel, Switzerland), 24(16)","doi":"10.3390/molecules24162967","pmid":"31426272","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The SEDDS-CBD formulation produced a 4.4-fold higher peak concentration (Cmax), 2.85-fold higher 8-hour exposure (AUC0-8h), and reached peak levels in 1 hour versus 3 hours for standard MCT oil. The formulation also reduced gender-based absorption differences.","whyItMatters":"CBD's poor and unpredictable oral absorption is a major barrier to consistent therapeutic effects. A delivery system that dramatically improves bioavailability could make CBD dosing more reliable and effective.","specificNumbers":"25 mg CBD dose; Cmax 4.4-fold higher; AUC0-8h 2.85-fold higher; AUC0-24h 1.70-fold higher; Tmax 1.0 hour vs. 3.0 hours; 16 subjects in crossover design.","methodology":"Randomized, double-blind, crossover study in 16 healthy volunteers under fasting conditions, comparing SEDDS-CBD against the same hemp extract in MCT oil, both standardized to 25 mg CBD.","limitations":"Small sample (16 subjects). Tested only a single 25 mg dose under fasting conditions. Long-term use not assessed. The formulation technology is proprietary (VESIsorb), limiting independent replication."},{"rthcId":"RTHC-02112","title":"Effect of Computer-Based Substance Use Screening and Brief Behavioral Counseling vs Usual Care for Youths in Pediatric Primary Care: A Pilot Randomized Clinical Trial.","authors":"Knight, John R; Sherritt, Lon; Gibson, Erin Bray; Levinson, Jordan A; Grubb, Laura K; Samuels, Ronald C; Silva, Thomas; Vernacchio, Louis; Wornham, Wendy; Harris, Sion Kim","year":2019,"journal":"JAMA network open, 2(6), e196258","doi":"10.1001/jamanetworkopen.2019.6258","pmid":"31225897","tags":["youth","quitting","driving"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"At-risk youth receiving the computer-based screening and brief intervention (CSBI) showed significantly reduced cannabis use (HR 0.62) and reduced riding with impaired drivers (RR 0.58) compared to usual care over 12 months. Alcohol use and heavy drinking trended lower but did not reach statistical significance.","whyItMatters":"Annual pediatric checkups are a missed opportunity for substance use screening. A system that works within existing visit structure and meaningfully reduces cannabis use and dangerous driving behavior could be implemented widely.","specificNumbers":"869 screened; 211 at-risk at baseline; HR for cannabis use 0.62 (95% CI 0.41-0.94); RR for riding with impaired driver 0.58 (95% CI 0.37-0.91); 82.4% received cannabis counseling in CSBI group.","methodology":"Pilot randomized clinical trial with 965 youth ages 12-18 across 5 pediatric practices and 54 practitioners, with 12-month follow-up using Timeline Followback assessment. CSBI group (n=628) received computer screening plus practitioner counseling.","limitations":"Pilot study with unequal randomization (628 vs 243). Self-reported outcomes. No significant prevention effect among youth without baseline use. Effect on heavy drinking did not reach significance."},{"rthcId":"RTHC-02113","title":"Cannabinoid hyperemesis syndrome.","authors":"Knowlton, Mary C","year":2019,"journal":"Nursing, 49(10), 42-45","doi":"10.1097/01.NURSE.0000577992.82047.67","pmid":"31568081","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02114","title":"Prospective evaluation of oral cannabis extracts in children with epilepsy.","authors":"Knupp, Kelly G; Rice, John D; Helmkamp, Laura J; Galinkin, Jeffrey; Sempio, Cristina; Jost, Klawitter; Chapman, Kevin E","year":2019,"journal":"Seizure, 72, 23-27","doi":"10.1016/j.seizure.2019.09.007","pmid":"31550641","tags":["epilepsy","cbd","youth","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The 24% responder rate (50%+ seizure reduction) matched placebo rates from formal clinical trials. Three children (14%) stopped the extract early due to perceived worsening of seizures. CBD blood levels showed no significant association with response.","whyItMatters":"Many families turn to artisanal cannabis products for their children's epilepsy. This prospective study suggests these products may perform no better than placebo, possibly due to lower CBD doses than those used in pharmaceutical trials.","specificNumbers":"32 enrolled, 21 analyzed; median age 10.3 years; median seizure frequency 2.7/day at baseline; 5/21 (24%) responded; median high CBD dose 0.9 mg/kg/day (vs. 10-20 mg/kg/day in pharmaceutical trials); 3/21 (14%) withdrew due to perceived seizure increase.","methodology":"Prospective observational study enrolling 32 children; 21 completed the protocol with 4-week baseline and 12-week treatment periods. Seizure frequency, CBD, and THC-COOH blood levels assessed every 4 weeks.","limitations":"Small sample (21), no control group, observational design. CBD doses used were much lower than in RCTs of pharmaceutical-grade products. Product variability among artisanal preparations likely."},{"rthcId":"RTHC-02115","title":"Canadian dog owners' use and perceptions of cannabis products.","authors":"Kogan, Lori R; Hellyer, Peter W; Silcox, Sarah; Schoenfeld-Tacher, Regina","year":2019,"journal":"The Canadian veterinary journal = La revue veterinaire canadienne, 60(7), 749-755","doi":null,"pmid":"31281193","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02116","title":"Exposure to cannabinoids can lead to persistent cognitive and psychiatric disorders.","authors":"Krebs, Marie-Odile; Kebir, Oussama; Jay, Therese M","year":2019,"journal":"European journal of pain (London, England), 23(7), 1225-1233","doi":"10.1002/ejp.1377","pmid":"30793421","tags":["psychosis","cognition","youth","neuroscience"],"studyType":"narrative-review","evidenceStrength":"strong","keyFinding":"Cannabis use is associated with dose-dependent cognitive deficits and a 2-fold or greater increase in psychosis risk. THC produces transient psychotic symptoms in healthy humans that CBD can attenuate. Adolescent exposure in rodents causes structural brain changes and impaired synaptic plasticity in fronto-limbic systems that persist into adulthood.","whyItMatters":"With cannabis legalization expanding, understanding who is most vulnerable to lasting harm is critical. This review marshals evidence from multiple research approaches pointing to adolescence as a particularly risky period.","specificNumbers":"Cannabis use associated with approximately 2-fold increased risk of psychosis. Effects are modulated by dose, duration, age of first use, and genetic factors including shared genetic predisposition with schizophrenia.","methodology":"Narrative review integrating epidemiological studies, experimental human studies with THC/CBD, and rodent adolescent exposure models, examining the endocannabinoid system's role in brain maturation.","limitations":"Narrative review without systematic methodology. Causality is difficult to establish from epidemiological data alone. Genetic confounders (shared predisposition to both cannabis use and psychosis) complicate interpretation."},{"rthcId":"RTHC-02117","title":"Long-term monitoring of drug consumption patterns in a large-sized European city using wastewater-based epidemiology: Comparison of two sampling schemes for the assessment of multiannual trends.","authors":"Krizman-Matasic, Ivona; Senta, Ivan; Kostanjevecki, Petra; Ahel, Marijan; Terzic, Senka","year":2019,"journal":"The Science of the total environment, 647, 474-485","doi":"10.1016/j.scitotenv.2018.07.441","pmid":"30086499","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02118","title":"Effects of Fatty Acid Amide Hydrolase Inhibitors Acute Administration on the Positive and Cognitive Symptoms of Schizophrenia in Mice.","authors":"Kruk-Slomka, Marta; Banaszkiewicz, Izabela; Slomka, Tomasz; Biala, Grazyna","year":2019,"journal":"Molecular neurobiology, 56(11), 7251-7266","doi":"10.1007/s12035-019-1596-0","pmid":"31004320","tags":["psychosis","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"URB 597 (FAAH inhibitor) at 0.3 mg/kg attenuated MK-801-induced memory impairment, but at 1 mg/kg it worsened it. JZL 184 (MAGL inhibitor) at 20-40 mg/kg intensified memory impairment and at 1 mg/kg potentiated hyperlocomotion caused by MK-801.","whyItMatters":"The endocannabinoid system is a potential therapeutic target for schizophrenia, but this study shows the relationship is not straightforward. Dose matters enormously, with low and high doses producing opposite effects.","specificNumbers":"URB 597 at 0.3 mg/kg improved memory; at 1 mg/kg it worsened memory. JZL 184 at 20-40 mg/kg worsened memory. JZL 184 at 1 mg/kg increased hyperlocomotion induced by MK-801 at both 0.3 and 0.6 mg/kg.","methodology":"Mice received MK-801 (NMDA antagonist) to model schizophrenia symptoms, then FAAH inhibitor URB 597 or MAGL inhibitor JZL 184 at various doses. Locomotor activity and passive avoidance memory were measured.","limitations":"Mouse model using pharmacological induction of schizophrenia-like symptoms, which may not fully represent human schizophrenia. Only acute (single dose) administration tested. No chronic exposure data."},{"rthcId":"RTHC-02119","title":"Cannabimimetic plants: are they new cannabinoidergic modulators?","authors":"Kumar, Amit; Premoli, Marika; Aria, Francesca; Bonini, Sara Anna; Maccarinelli, Giuseppina; Gianoncelli, Alessandra; Memo, Maurizio; Mastinu, Andrea","year":2019,"journal":"Planta, 249(6), 1681-1694","doi":"10.1007/s00425-019-03138-x","pmid":"30877436","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02120","title":"Cannabinoid Attenuation of Intestinal Inflammation in Chronic SIV-Infected Rhesus Macaques Involves T Cell Modulation and Differential Expression of Micro-RNAs and Pro-inflammatory Genes.","authors":"Kumar, Vinay; Torben, Workineh; Mansfield, Joshua; Alvarez, Xavier; Vande Stouwe, Curtis; Li, Jian; Byrareddy, Siddappa N; Didier, Peter J; Pahar, Bapi; Molina, Patricia E; Mohan, Mahesh","year":2019,"journal":"Frontiers in immunology, 10, 914","doi":"10.3389/fimmu.2019.00914","pmid":"31114576","tags":["inflammation","medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"THC-treated SIV-infected macaques showed downregulated pro-inflammatory microRNAs and genes, higher expression of tight junction proteins (occludin, claudin-3), reduced T cell activation, increased anti-inflammatory macrophages, and complete prevention of lymph node fibrosis seen in all vehicle-treated animals.","whyItMatters":"HIV-associated gut inflammation drives disease progression and is difficult to treat even with antiretroviral therapy. THC's ability to reduce intestinal inflammation and prevent the irreversible lymph node fibrosis that characterizes chronic HIV infection represents a potentially significant therapeutic avenue.","specificNumbers":"THC prevented lymph node fibrosis in all 8 treated animals (0/8 fibrosis) vs. all 9 vehicle-treated animals showing fibrosis (9/9). MMP8 (tissue-degrading enzyme) was significantly downregulated via miR-204 targeting.","methodology":"Chronically SIV-infected rhesus macaques received either THC (n=8) or vehicle (n=9). Researchers profiled miRNA and mRNA expression in colon tissue, assessed gut barrier proteins, measured T cell activation by flow cytometry, and examined lymph node fibrosis.","limitations":"Primate model, not human clinical data. Sample sizes were small (8-9 per group). Long-term effects of chronic THC use in immunocompromised individuals need human study. THC dosing may not match typical human use patterns."},{"rthcId":"RTHC-02121","title":"The Impact of Perioperative Cannabis Use: A Narrative Scoping Review.","authors":"Ladha, Karim S; Manoo, Varuna; Virji, Ali-Faizan; Hanlon, John G; Mclaren-Blades, Alexander; Goel, Akash; Wijeysundera, Duminda N; Kotra, Lakshmi P; Ibarra, Carlos; Englesakis, Marina; Clarke, Hance","year":2019,"journal":"Cannabis and cannabinoid research, 4(4), 219-230","doi":"10.1089/can.2019.0054","pmid":"31872058","tags":["medical-cannabis","pain"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"The review identified several perioperative concerns for cannabis users: potential increased anesthetic requirements, altered post-operative pain processing, cannabis withdrawal syndrome risk, and cardiovascular effects. However, the number of available studies is small and study designs are markedly heterogeneous.","whyItMatters":"With increasing cannabis use, anesthesiologists and surgeons encounter cannabis users regularly but have little evidence-based guidance. Understanding the perioperative implications is essential for patient safety.","specificNumbers":"The review does not provide pooled statistics due to the heterogeneity of available studies, instead presenting a qualitative synthesis organized by perioperative phase and organ system.","methodology":"Narrative scoping review examining published studies on cannabis use in the perioperative period, supplemented by literature on cannabis physiology outside the surgical context.","limitations":"Scoping review limited by small number of available studies with heterogeneous designs. Many recommendations are extrapolated from non-surgical cannabis physiology studies. No meta-analysis possible."},{"rthcId":"RTHC-02122","title":"Guidelines for public health and safety metrics to evaluate the potential harms and benefits of cannabis regulation in Canada.","authors":"Lake, Stephanie; Kerr, Thomas; Werb, Dan; Haines-Saah, Rebecca; Fischer, Benedikt; Thomas, Gerald; Walsh, Zach; Ware, Mark A; Wood, Evan; Milloy, M-J","year":2019,"journal":"Drug and alcohol review, 38(6), 606-621","doi":"10.1111/dar.12971","pmid":"31577059","tags":["legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Twenty-eight indicators were identified under five themes: public safety, cannabis use trends, other substance use trends, cardiovascular/respiratory health, and mental health/cognition. Early data from US jurisdictions showed little consensus on harms but emerging evidence for benefits like reduced opioid use.","whyItMatters":"Canada's legalization is a natural experiment. Without agreed-upon metrics to track outcomes, it would be impossible to know whether the policy is working or where adjustments are needed.","specificNumbers":"28 indicators identified across 5 broad themes. Preliminary data from legalized US jurisdictions referenced for each indicator where available.","methodology":"Systematic search of five scientific databases to compile cannabis-related public health and safety indicators, supplemented with preliminary evidence from US states and Canadian provinces that had already legalized.","limitations":"Framework is proposed rather than validated. Preliminary evidence from other jurisdictions may not translate to Canada. Many indicators lack reliable baseline data."},{"rthcId":"RTHC-02123","title":"Frequency of cannabis and illicit opioid use among people who use drugs and report chronic pain: A longitudinal analysis.","authors":"Lake, Stephanie; Walsh, Zach; Kerr, Thomas; Cooper, Ziva D; Buxton, Jane; Wood, Evan; Ware, Mark A; Milloy, M J","year":2019,"journal":"PLoS medicine, 16(11), e1002967","doi":"10.1371/journal.pmed.1002967","pmid":"31743343","tags":["pain","harm-reduction","addiction","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"After adjusting for demographics, substance use, and health factors, daily cannabis use was associated with significantly lower odds of daily illicit opioid use (adjusted OR 0.50, 95% CI 0.34-0.74, p < 0.001). The most common therapeutic reasons for cannabis use were pain (36%), sleep (35%), stress (31%), and nausea (30%).","whyItMatters":"This is rare individual-level longitudinal data supporting the population-level finding that cannabis access may reduce opioid use. Most prior evidence was ecological (state-level), making individual associations difficult to establish.","specificNumbers":"1,152 participants; 40% reported daily illicit opioid use; 36% reported daily cannabis use; adjusted OR 0.50 (95% CI 0.34-0.74); median age 49.3 years; 36.8% women.","methodology":"Longitudinal analysis of 1,152 people who use drugs with chronic pain from two prospective Vancouver cohorts (June 2014-December 2017), using generalized linear mixed-effects models with 6-month follow-up periods.","limitations":"Self-reported substance use and pain. Population is people who already use drugs, not representative of all chronic pain patients. No data on cannabis preparations, dosages, or administration methods. Observational design cannot prove causation."},{"rthcId":"RTHC-02124","title":"Piperidine and piperazine inhibitors of fatty acid amide hydrolase targeting excitotoxic pathology.","authors":"Lamani, Manjunath; Malamas, Michael S; Farah, Shrouq I; Shukla, Vidyanand G; Almeida, Michael F; Weerts, Catherine M; Anderson, Joseph; Wood, JodiAnne T; Farizatto, Karen L G; Bahr, Ben A; Makriyannis, Alexandros","year":2019,"journal":"Bioorganic & medicinal chemistry, 27(23), 115096","doi":"10.1016/j.bmc.2019.115096","pmid":"31629610","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02125","title":"Cannabidiol as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome.","authors":"Lattanzi, S; Trinka, E; Russo, E; Striano, P; Citraro, R; Silvestrini, M; Brigo, F","year":2019,"journal":"Drugs of today (Barcelona, Spain : 1998), 55(3), 177-196","doi":"10.1358/dot.2019.55.3.2909248","pmid":"30938373","tags":["epilepsy","cbd","youth"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review critically examined CBD's pharmacology and recent clinical trial data showing its efficacy and safety as add-on treatment for LGS and DS, two severe childhood epilepsy syndromes where existing treatments fail to control seizures in most cases.","whyItMatters":"Up to one-third of epilepsy patients are treatment-resistant. LGS and DS are among the most severe forms, and CBD represents the first genuinely new mechanism of action for these patients in years.","specificNumbers":"Epilepsy affects approximately 70 million people worldwide. Up to one-third are resistant to existing anticonvulsant therapy.","methodology":"Critical review of CBD pharmacology and the most recent clinical studies evaluating efficacy and safety as adjunctive treatment for LGS and DS seizures.","limitations":"Review summarizes existing clinical trial data rather than presenting new findings. Long-term outcomes and optimal dosing strategies are still being established."},{"rthcId":"RTHC-02126","title":"Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results.","authors":"Laux, Linda C; Bebin, E Martina; Checketts, Daniel; Chez, Michael; Flamini, Robert; Marsh, Eric D; Miller, Ian; Nichol, Kathryn; Park, Yong; Segal, Eric; Seltzer, Laurie; Szaflarski, Jerzy P; Thiele, Elizabeth A; Weinstock, Arie","year":2019,"journal":"Epilepsy research, 154, 13-20","doi":"10.1016/j.eplepsyres.2019.03.015","pmid":"31022635","tags":["epilepsy","cbd","youth","medical-cannabis"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"At 12 weeks, CBD reduced median monthly major motor seizures by 50% and total seizures by 44%. These reductions remained consistent through 96 weeks. At 12 weeks, 53% of patients had 50%+ reduction in major motor seizures and 6% were seizure-free.","whyItMatters":"Clinical trials show efficacy under controlled conditions, but expanded access programs reveal how treatments perform in real-world clinical practice. These results confirm that CBD's seizure-reducing benefits persist long-term.","specificNumbers":"607 total patients (152 with LGS/DS); median 3 concomitant AEDs; median treatment duration 78.3 weeks; 50% reduction in major motor seizures at 12 weeks; 53% achieved 50%+ reduction; 6% seizure-free; 28% withdrew (20% for lack of efficacy); somnolence 30%, diarrhea 24%.","methodology":"Expanded access program (closely reflecting clinical practice) at 25 US sites. 152 patients with LGS or DS received pharmaceutical CBD (Epidiolex) at 2-10 mg/kg/day, titrated up to 25-50 mg/kg/day. Interim analysis through 96 weeks of treatment.","limitations":"No control group (expanded access design). 28% withdrawal rate, with 20% leaving due to lack of efficacy, which could bias long-term results toward responders. Patients were on multiple concomitant medications."},{"rthcId":"RTHC-02127","title":"Treatment of Seizures Associated with Lennox-Gastaut and Dravet Syndromes: A Focus on Cannabidiol Oral Solution.","authors":"Lazaridis, Dovena; Eraikhuemen, Nathaniel; Williams, Kia; Lovince, Judith","year":2019,"journal":"P & T : a peer-reviewed journal for formulary management, 44(5), 255-266","doi":null,"pmid":"31080333","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02128","title":"Δ9-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation.","authors":"Lecca, Salvatore; Luchicchi, Antonio; Scherma, Maria; Fadda, Paola; Muntoni, Anna Lisa; Pistis, Marco","year":2019,"journal":"Frontiers in behavioral neuroscience, 13, 202","doi":"10.3389/fnbeh.2019.00202","pmid":"31551729","tags":["youth","psychosis","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats exposed to maternal immune activation (MIA) had fewer active dopamine neurons, lower firing rates, and altered activity patterns. Adolescent THC exposure (PND 45-55) attenuated several of these MIA-induced dopamine deficits rather than worsening them as predicted by the two-hit model.","whyItMatters":"The two-hit hypothesis predicts that prenatal infection plus adolescent cannabis use should compound psychosis risk. This study challenges that simple additive model, suggesting the interaction between prenatal vulnerability and adolescent cannabis is more complex than assumed.","specificNumbers":"THC administered at 2 mg/kg/day from postnatal day 45-55. Dopamine neuron recordings performed at PND 70-90. MIA offspring showed reduced number and firing rate of VTA dopamine cells.","methodology":"Pregnant rats received poly(I:C) to activate the immune system. Male offspring received THC or vehicle during adolescence (PND 45-55). In adulthood (PND 70-90), VTA dopamine neuron activity was recorded, and responses to nicotine and cocaine were tested.","limitations":"Male rats only. Single THC dose and duration tested. The two-hit model is a simplification of human schizophrenia. Results may not extend to chronic or higher-dose cannabis exposure."},{"rthcId":"RTHC-02129","title":"Injection opioid use as a predictor of treatment outcomes among methadone-maintained opioid-dependent patients.","authors":"Ledgerwood, David M; Lister, Jamey J; LaLiberte, Benjamin; Lundahl, Leslie H; Greenwald, Mark K","year":2019,"journal":"Addictive behaviors, 90, 191-195","doi":"10.1016/j.addbeh.2018.10.046","pmid":"30412910","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02130","title":"The utility of droperidol in the treatment of cannabinoid hyperemesis syndrome.","authors":"Lee, Carl; Greene, Shaun L; Wong, Anselm","year":2019,"journal":"Clinical toxicology (Philadelphia, Pa.), 57(9), 773-777","doi":"10.1080/15563650.2018.1564324","pmid":"30729854","tags":["appetite","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Droperidol-treated CHS patients had significantly shorter hospital stays (6.7 vs. 13.9 hours, p=.014), needed fewer antiemetic doses overall, and used half as much ondansetron and metoclopramide as the non-droperidol group.","whyItMatters":"CHS is increasingly common and standard antiemetics are largely ineffective. Droperidol offers a potential targeted treatment that could significantly reduce ER resource use and patient suffering.","specificNumbers":"689 records screened, 76 met CHS criteria; droperidol group: median stay 6.7 hours, median 137 min to discharge after last dose; no droperidol: median stay 13.9 hours, 185 min to discharge; most common droperidol dose 0.625 mg IV.","methodology":"Retrospective review of 689 electronic medical records from a single tertiary hospital (2006-2016), identifying 76 presentations meeting CHS diagnostic criteria. Compared 37 droperidol-treated vs. 39 non-droperidol presentations.","limitations":"Retrospective, single-center study. No randomization. Droperidol group selection may have been influenced by clinician experience or patient severity. Relatively small sample (76 presentations)."},{"rthcId":"RTHC-02131","title":"Sequential and simultaneous treatment approaches to cannabis use disorder and tobacco use.","authors":"Lee, Dustin C; Walker, Denise D; Hughes, John R; Brunette, Mary F; Scherer, Emily; Stanger, Catherine; Etter, Jean-Francois; Auty, Samantha; Budney, Alan J","year":2019,"journal":"Journal of substance abuse treatment, 98, 39-46","doi":"10.1016/j.jsat.2018.12.005","pmid":"30665602","tags":["quitting","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"No significant differences in cannabis outcomes between simultaneous and sequential tobacco treatment during weeks 1-12. Most simultaneous participants engaged with the tobacco intervention (62% initiated counseling, 50% made quit attempts). However, only 30% of sequential participants continued to the delayed tobacco phase, highlighting the risk of deferring treatment.","whyItMatters":"Tobacco use is common among people seeking cannabis treatment and predicts worse cannabis outcomes. Clinicians often hesitate to address both substances simultaneously, but this study suggests that concern may be unfounded.","specificNumbers":"67 adults enrolled; SIM: 62% initiated tobacco counseling, 50% made quit attempts, 41% used NRT; SEQ: 39% made quit attempts spontaneously before tobacco phase began; only 30% of SEQ continued to weeks 13-24.","methodology":"Proof-of-concept RCT with 67 adults receiving simultaneous (SIM) or sequential (SEQ) tobacco cessation during outpatient cannabis use disorder treatment. SIM received tobacco intervention weeks 1-12; SEQ received it weeks 13-24. Both included web-based counseling plus nicotine replacement therapy.","limitations":"Small sample (67), proof-of-concept design. High attrition in the sequential arm compromised comparison. Tobacco cessation outcomes were poor in both groups. Single-site study."},{"rthcId":"RTHC-02132","title":"Divergent Response to Cannabinoid Receptor Stimulation in High and Low Stress-Induced Analgesia Mouse Lines Is Associated with Differential G-Protein Activation.","authors":"Lesniak, Anna; Chmielewska, Diana; Poznanski, Piotr; Bujalska-Zadrozny, Magdalena; Strzemecka, Joanna; Sacharczuk, Mariusz","year":2019,"journal":"Neuroscience, 404, 246-258","doi":"10.1016/j.neuroscience.2019.02.015","pmid":"30794845","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02133","title":"Adverse outcome pathway of developmental neurotoxicity resulting from prenatal exposures to cannabis contaminated with organophosphate pesticide residues.","authors":"Leung, Maxwell C K; Silva, Marilyn H; Palumbo, Amanda J; Lohstroh, Peter N; Koshlukova, Svetlana E; DuTeaux, Shelley B","year":2019,"journal":"Reproductive toxicology (Elmsford, N.Y.), 85, 12-18","doi":"10.1016/j.reprotox.2019.01.004","pmid":"30668982","tags":["pregnancy","youth","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The proposed adverse outcome pathway shows that cannabinoids and chlorpyrifos share molecular targets affecting neurodevelopment. Both disrupt endocannabinoid signaling and acetylcholinesterase activity, potentially compounding effects on neuronal migration, synaptogenesis, and brain maturation when exposure occurs simultaneously.","whyItMatters":"Cannabis products can contain pesticide residues, and pregnant women may be unknowingly exposed to both. The emerging legal cannabis market still lacks consistent pesticide testing and standards in many jurisdictions.","specificNumbers":"Several US states are moving toward pesticide regulation in cannabis, but standards vary widely. Chlorpyrifos was selected as a model pesticide due to its documented developmental neurotoxicity.","methodology":"Theoretical construction of an adverse outcome pathway (AOP) by curating existing literature on the molecular, cellular, and tissue-level events linking prenatal cannabinoid-pesticide co-exposure to developmental neurotoxicity.","limitations":"Entirely theoretical. The proposed adverse outcome pathway has not been experimentally validated as a whole. Real-world pesticide contamination levels on cannabis products are not well characterized."},{"rthcId":"RTHC-02134","title":"Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring.","authors":"Levin, Edward D; Hawkey, Andrew B; Hall, Brandon J; Cauley, Marty; Slade, Susan; Yazdani, Elisa; Kenou, Bruny; White, Hannah; Wells, Corinne; Rezvani, Amir H; Murphy, Susan K","year":2019,"journal":"Neurotoxicology and teratology, 74, 106806","doi":"10.1016/j.ntt.2019.04.003","pmid":"31028824","tags":["pregnancy","genetics","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Paternal THC exposure (2 mg/kg/day for 12 days) did not affect litter size, sex ratio, birth weight, or survival, but caused significant, long-lasting impairment in attentional performance and increased habituation of locomotor activity in adult offspring.","whyItMatters":"Most research on cannabis and reproduction focuses on maternal exposure. This study demonstrates that paternal cannabis use before conception can also affect offspring through epigenetic changes in sperm, expanding the scope of reproductive risk.","specificNumbers":"2 mg/kg/day oral THC for 12 days (described as modest dose and brief period). Significant attention impairment detected in offspring during adulthood. No effects on clinical health markers at birth.","methodology":"Male rats received oral THC (2 mg/kg/day for 12 days) or vehicle before mating. Offspring were tested in adulthood for attention (operant task) and locomotor behavior. Previous work from the same group confirmed THC-associated changes in sperm DNA methylation.","limitations":"Rat model with single dose level and duration. Mechanism (epigenetic transmission) is inferred from companion methylation study but not directly proven in this behavioral study. Only male offspring behavioral data presented."},{"rthcId":"RTHC-02135","title":"E-cigarette Use, or Vaping, Practices and Characteristics Among Persons with Associated Lung Injury - Utah, April-October 2019.","authors":"Lewis, Nathaniel; McCaffrey, Keegan; Sage, Kylie; Cheng, Chia-Jung; Green, Jordan; Goldstein, Leah; Campbell, Hillary; Ferrell, Deanna; Malan, Nathan; LaCross, Nathan; Maldonado, Alejandra; Board, Amy; Hanchey, Arianna; Harris, Dixie; Callahan, Sean; Aberegg, Scott; Risk, Ilene; Willardson, Sarah; Carter, Amy; Nakashima, Allyn; Duncan, Janae; Burnett, Cindy; Atkinson-Dunn, Robyn; Dunn, Angela","year":2019,"journal":"MMWR. Morbidity and mortality weekly report, 68(42), 953-956","doi":"10.15585/mmwr.mm6842e1","pmid":"31647788","tags":["respiratory","harm-reduction","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"92% of interviewed patients reported using THC-containing products, 66% used nicotine products, and 60% used both. Most THC products came from informal sources (friends, illicit dealers). Testing of THC cartridges found vitamin E acetate in 17 of 20 (85%) samples. 89% of patients were hospitalized and 49% required breathing assistance.","whyItMatters":"This investigation was part of the evidence that ultimately linked EVALI to vitamin E acetate in illicit THC cartridges, a finding that changed both public health messaging and industry practices.","specificNumbers":"83 patients identified; 79 chart reviews; 53 interviews; 92% used THC products; 89% of tested cartridges contained vitamin E acetate; 89% hospitalized; 49% needed breathing assistance; THC products used 1-5x/day.","methodology":"Epidemiological investigation of 83 Utah EVALI patients. Medical chart abstractions completed for 79 patients, detailed interviews with 53, and product testing of 20 THC cartridges from 6 patients.","limitations":"Cross-sectional investigation with self-reported exposures. Product samples available from only 6 of 53 interviewed patients. Unable to determine definitive causal agent at time of publication."},{"rthcId":"RTHC-02136","title":"Cannabinoid CB2 Agonist AM1710 Differentially Suppresses Distinct Pathological Pain States and Attenuates Morphine Tolerance and Withdrawal.","authors":"Li, Ai-Ling; Lin, Xiaoyan; Dhopeshwarkar, Amey S; Thomaz, Ana Carla; Carey, Lawrence M; Liu, Yingpeng; Nikas, Spyros P; Makriyannis, Alexandros; Mackie, Ken; Hohmann, Andrea G","year":2019,"journal":"Molecular pharmacology, 95(2), 155-168","doi":"10.1124/mol.118.113233","pmid":"30504240","tags":["pain","neuroscience","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AM1710 produced sustained relief from paclitaxel-induced nerve pain without tolerance. Prior AM1710 treatment delayed morphine tolerance development and attenuated morphine physical dependence. However, AM1710 failed to reduce pain from inflammatory (CFA) or surgical nerve injury (PSNL) models, showing it is not a broad-spectrum pain treatment.","whyItMatters":"A pain treatment that works through CB2 receptors (not CB1) avoids the psychoactive effects of THC. The added benefit of delaying opioid tolerance could make it valuable as combination therapy.","specificNumbers":"AM1710 at 5 mg/kg/day for 12 days delayed morphine tolerance; 10 mg/kg was ineffective in CFA and PSNL models; the drug did not precipitate withdrawal in THC-tolerant mice, confirming it does not block CB1 receptors.","methodology":"In vitro signaling studies in HEK cells expressing CB2 receptors, plus in vivo testing in mice across three pain models (paclitaxel neuropathy, CFA inflammation, and partial sciatic nerve ligation), with additional morphine tolerance and dependence assessments.","limitations":"Mouse study only. The selective efficacy for chemo neuropathy but not other pain types limits clinical applicability. Signaling profile differences between human and mouse CB2 receptors noted but described as modest."},{"rthcId":"RTHC-02137","title":"Opposite effects of cannabinoid CB1 and CB2 receptors on antipsychotic clozapine-induced cardiotoxicity.","authors":"Li, Liliang; Dong, Xiaoru; Tu, Chunyan; Li, Xiaoqing; Peng, Zhao; Zhou, Yiling; Zhang, Dingang; Jiang, Jieqing; Burke, Allen; Zhao, Ziqin; Jin, Li; Jiang, Yan","year":2019,"journal":"British journal of pharmacology, 176(7), 890-905","doi":"10.1111/bph.14591","pmid":"30707759","tags":["cardiovascular","neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Clozapine decreased endocannabinoid levels and caused myocardial inflammation and fibrosis in mice. CB1 receptor antagonists (rimonabant, AM281) reduced heart damage, while CB2 receptor agonists (AM1241, JWH-133) also protected the heart. Combined treatment with both provided even greater protection.","whyItMatters":"Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but cardiotoxicity limits its use. Understanding how the endocannabinoid system mediates this damage could lead to cardioprotective co-treatments.","specificNumbers":"Clozapine decreased endocannabinoid levels in serum and cardiomyocytes. CB1 receptors decreased and relocated intracellularly; CB2 receptors increased and moved to cell surface. Combined CB1 antagonist + CB2 agonist provided additive cardioprotection.","methodology":"Mice received clozapine alone or with selective CB1 antagonists or CB2 agonists. Heart tissue was examined for inflammation, fibrosis, and receptor expression. Cultured cardiomyocytes were used to confirm direct cellular effects.","limitations":"Mouse study with clozapine doses that may not directly translate to human therapeutic levels. The study did not test whether cardioprotection interfered with clozapine's antipsychotic efficacy. No human data."},{"rthcId":"RTHC-02138","title":"Elevation of endocannabinoids in the brain by synthetic cannabinoid JWH-018: mechanism and effect on learning and memory.","authors":"Li, Ren-Shi; Fukumori, Ryo; Takeda, Tomoki; Song, Yingxia; Morimoto, Satoshi; Kikura-Hanajiri, Ruri; Yamaguchi, Taku; Watanabe, Kazuhito; Aritake, Kousuke; Tanaka, Yoshitaka; Yamada, Hideyuki; Yamamoto, Tsuneyuki; Ishii, Yuji","year":2019,"journal":"Scientific reports, 9(1), 9621","doi":"10.1038/s41598-019-45969-4","pmid":"31270353","tags":["synthetic-cannabinoids","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"JWH-018 elevated anandamide and 2-AG levels in the hippocampus by suppressing the enzymes that break them down (FAAH and MAGL). It simultaneously reduced BDNF, a key protein for synaptic plasticity. All effects were blocked by the CB1 antagonist AM251, confirming CB1-dependent mechanisms.","whyItMatters":"Synthetic cannabinoids are often far more potent than natural cannabis. Understanding how they impair memory at the molecular level helps explain their cognitive dangers and may inform treatment strategies.","specificNumbers":"JWH-018 significantly elevated both AEA and 2-AG levels. FAAH and MAGL activity were suppressed. BDNF levels decreased. All changes were reversed by CB1 antagonist AM251.","methodology":"Acute JWH-018 administration in rats with hippocampal metabolomic profiling. Endocannabinoid levels, degradation enzyme activity, and BDNF levels measured with and without CB1 antagonist co-administration.","limitations":"Acute single-dose study in rats. Chronic exposure effects not examined. Hippocampal metabolomics provides a snapshot, not a dynamic picture. JWH-018 is an older synthetic cannabinoid; newer variants may act differently."},{"rthcId":"RTHC-02139","title":"Dermatology-Related Uses of Medical Cannabis Promoted by Dispensaries in Canada, Europe, and the United States.","authors":"Lim, Megan; Kirchhof, Mark G","year":2019,"journal":"Journal of cutaneous medicine and surgery, 23(2), 178-184","doi":"10.1177/1203475418808761","pmid":"30380925","tags":["medical-cannabis","cbd"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Dispensary websites claimed cannabis treats acne, aging, dermatitis, psoriasis, lupus, epidermolysis bullosa, and even melanoma. Psoriasis, dermatitis, and chronic pain were the most commonly cited dermatologic indications. Most of these claims are not supported by clinical evidence.","whyItMatters":"Patients increasingly arrive at dermatology appointments having seen cannabis marketed for their conditions. Clinicians need to know what claims are being made so they can have informed conversations.","specificNumbers":"Dispensary claims covered at least 12 dermatologic conditions. US state-approved dermatologic indications include psoriasis, lupus, nail-patella syndrome, and severe pain. Health Canada lists psoriasis, dermatitis, and pruritus as potential uses.","methodology":"Survey of dispensary websites in Canada, the US, and Europe, tabulating dermatologic claims. Comparison with approved indications in the US (by state) and Health Canada's listed potential uses.","limitations":"Website survey captures a snapshot of marketing claims, which change over time. Did not assess whether patients actually use cannabis for these conditions or their outcomes."},{"rthcId":"RTHC-02140","title":"Reliability and Validity of the Newton Screen for Alcohol and Cannabis Misuse in a Pediatric Emergency Department Sample.","authors":"Linakis, James G; Bromberg, Julie R; Casper, T Charles; Chun, Thomas H; Mello, Michael J; Ingebretsen, Hailey; Spirito, Anthony","year":2019,"journal":"The Journal of pediatrics, 210, 154-160.e1","doi":"10.1016/j.jpeds.2019.02.038","pmid":"30967250","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"For cannabis use disorder, the Newton screen achieved baseline sensitivity of 93.1% and specificity of 93.5%. For alcohol use disorder, sensitivity was 78.3% with 93.0% specificity. Predictive validity at 1-3 year follow-up showed high specificity but lower sensitivity for both substances.","whyItMatters":"Emergency departments see adolescents who might not otherwise encounter substance use screening. A brief, validated tool that works in the chaotic ED environment could identify at-risk teens and connect them with early intervention.","specificNumbers":"4,898 adolescents across 16 EDs; cannabis screening sensitivity 93.1%, specificity 93.5%; alcohol screening sensitivity 78.3%, specificity 93.0%; predictive validity maintained high specificity at 1-3 year follow-up.","methodology":"Validation study within 16 pediatric emergency departments (PECARN network) enrolling 4,898 adolescents aged 12-17. Concurrent validity assessed against structured DSM-based interviews. Convergent validity tested against AUDIT. Predictive validity assessed at 1, 2, and 3 years.","limitations":"Higher sensitivity for cannabis than alcohol may reflect the tool's design or differences in adolescent substance use patterns. Predictive sensitivity was lower at follow-up, suggesting it may miss some who develop problems later. ED populations may differ from general adolescent populations."},{"rthcId":"RTHC-02141","title":"Tempering aversive/traumatic memories with cannabinoids: a review of evidence from animal and human studies.","authors":"Lisboa, Sabrina F; Vila-Verde, C; Rosa, J; Uliana, D L; Stern, C A J; Bertoglio, L J; Resstel, L B; Guimaraes, F S","year":2019,"journal":"Psychopharmacology, 236(1), 201-226","doi":"10.1007/s00213-018-5127-x","pmid":"30604182","tags":["ptsd","neuroscience","cbd","mental-health"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Direct or indirect CB1 receptor activation consistently facilitated extinction of aversive/traumatic memories across animal and human studies. Effect sizes were large (Cohen's d >= 1.0) in most cases. Key brain areas involved include the medial prefrontal cortex, amygdala, and hippocampus. Timing of administration (around memory formation or reminders) influenced outcomes.","whyItMatters":"PTSD is fundamentally a disorder of aversive memory that resists extinction. If cannabinoids reliably facilitate this extinction process, they could enhance exposure-based therapies that are the current gold standard for PTSD treatment.","specificNumbers":"Effect sizes were large (Cohen's d >= 1.0) in most studies. Effects observed in medial prefrontal cortex, amygdala, and hippocampus. Both CB1 activation and endocannabinoid augmentation were effective.","methodology":"Comprehensive review of animal and human studies on cannabinoid interventions for aversive memory extinction, with effect size calculations for each intervention.","limitations":"Most data comes from animal studies with relatively simple fear conditioning paradigms. Human PTSD involves more complex memory processing. Few clinical trials have tested cannabinoid augmentation of PTSD therapy."},{"rthcId":"RTHC-02142","title":"A cross-sectional examination of choice and behavior of veterans with access to free medicinal cannabis.","authors":"Loflin, Mallory J E; Babson, Kimberly; Sottile, James; Norman, Sonya B; Gruber, Staci; Bonn-Miller, Marcel O","year":2019,"journal":"The American journal of drug and alcohol abuse, 45(5), 506-513","doi":"10.1080/00952990.2019.1604722","pmid":"31135227","tags":["medical-cannabis","harm-reduction","addiction","ptsd"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"The majority of veterans reported using cannabis as a substitute for prescription medications, alcohol, tobacco, or illicit substances. However, they predominantly chose high-THC/low-CBD products and smoked them frequently (modal use >4x/day, 5-8 grams/week). Most used cannabis to self-treat multiple physical and mental health conditions.","whyItMatters":"As veteran access to cannabis expands, this study reveals a concerning pattern: while substitution away from opioids and alcohol may be beneficial, veterans are gravitating toward the highest-risk cannabis products without clinical guidance.","specificNumbers":"93 veterans surveyed; 84.9% male; modal use >4x/day; 5-8 grams/week typical; majority selected high THC/low CBD formulations; most used smoked route of administration.","methodology":"Cross-sectional self-report survey of 93 US military veterans (84.9% male) with access to free cannabis through a veterans' collective, assessing formulation choices, routes of administration, and substitution practices.","limitations":"Small, self-selected sample (93 veterans). Cross-sectional design cannot establish substitution as causal. No objective verification of substitution claims. Free access may not reflect typical use patterns."},{"rthcId":"RTHC-02143","title":"Human lung epithelial cells cultured in the presence of radon-emitting rock experience gene expression changes similar to those associated with tobacco smoke exposure.","authors":"Loiselle, Julie J; Knee, Jose M; Sutherland, Leslie C","year":2019,"journal":"Journal of environmental radioactivity, 196, 64-81","doi":"10.1016/j.jenvrad.2018.10.008","pmid":"30396064","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02144","title":"Ligand discrimination during virtual screening of the CB1 cannabinoid receptor crystal structures following cross-docking and microsecond molecular dynamics simulations.","authors":"Loo, Jason S E; Emtage, Abigail L; Murali, Lahari; Lee, Sze Siew; Kueh, Alvina L W; Alexander, Stephen P H","year":2019,"journal":"RSC advances, 9(28), 15949-15956","doi":"10.1039/c9ra01095e","pmid":"35521393","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02145","title":"Does regular cannabis use affect neuroanatomy? An updated systematic review and meta-analysis of structural neuroimaging studies.","authors":"Lorenzetti, Valentina; Chye, Yann; Silva, Pedro; Solowij, Nadia; Roberts, Carl A","year":2019,"journal":"European archives of psychiatry and clinical neuroscience, 269(1), 59-71","doi":"10.1007/s00406-019-00979-1","pmid":"30706169","tags":["cognition","neuroscience","youth"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Regular cannabis users had significantly smaller volumes of the hippocampus (SMD=0.14) and both medial (SMD=0.30) and lateral (SMD=0.19) orbitofrontal cortex compared to controls. These regions are densely innervated with cannabinoid receptors and involved in reward, learning, memory, and motivation.","whyItMatters":"This is the most comprehensive neuroimaging meta-analysis on cannabis to date, providing quantitative evidence that regular use is associated with structural brain differences in regions that underpin the cognitive deficits commonly reported.","specificNumbers":"30 studies included; 106 effect sizes across 17 meta-analyses; hippocampus SMD=0.14 (p=0.02, I2=74%); medial OFC SMD=0.30 (p=0.0001, I2=51%); lateral OFC SMD=0.19 (p=0.002, I2=26%). Volume differences not significantly associated with cannabis duration or dosage.","methodology":"Systematic review and meta-analysis of 30 structural MRI studies, conducting 17 separate meta-analyses (one per brain region) using standardized mean difference. Meta-regressions explored associations with cannabis duration and dosage.","limitations":"Cross-sectional studies cannot determine whether smaller volumes preceded or resulted from cannabis use. Significant heterogeneity in hippocampal results (I2=74%). No significant dose-response relationship found. Confounders like alcohol and tobacco use not fully controlled."},{"rthcId":"RTHC-02146","title":"Cannabis and mental illness: a review.","authors":"Lowe, Darby J E; Sasiadek, Julia D; Coles, Alexandria S; George, Tony P","year":2019,"journal":"European archives of psychiatry and clinical neuroscience, 269(1), 107-120","doi":"10.1007/s00406-018-0970-7","pmid":"30564886","tags":["mental-health","psychosis","anxiety","depression","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review found increasing documentation of potential harms from cannabis use in patients with psychotic and mood disorders, while data supporting beneficial effects in psychiatric populations remains limited. A reconciled addiction vulnerability and allostatic model was proposed to explain why mentally ill individuals are particularly susceptible to cannabis use disorders.","whyItMatters":"With cannabis legalization expanding, people with mental illness represent a particularly vulnerable population who may be attracted to cannabis for symptom relief while being at elevated risk for adverse effects.","specificNumbers":"The review covers effects across three major psychiatric disorder categories: psychotic disorders (schizophrenia), mood disorders, and anxiety disorders.","methodology":"Narrative review of cannabis effects across schizophrenia, mood disorders, and anxiety disorders, combined with a theoretical framework integrating addiction vulnerability and allostatic hypotheses.","limitations":"Narrative review without systematic methodology. The proposed theoretical framework for understanding co-morbid addiction has not been empirically tested. Evidence base varies in quality across disorder types."},{"rthcId":"RTHC-02147","title":"Cannabis hyperemesis syndrome: still under recognised after all these years.","authors":"Lua, Joanne; Olney, Lauren; Isles, Chris","year":2019,"journal":"The journal of the Royal College of Physicians of Edinburgh, 49(2), 132-134","doi":"10.4997/JRCPE.2019.210","pmid":"31188343","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02148","title":"Medical cannabis patterns of use and substitution for opioids & other pharmaceutical drugs, alcohol, tobacco, and illicit substances; results from a cross-sectional survey of authorized patients.","authors":"Lucas, Philippe; Baron, Eric P; Jikomes, Nick","year":2019,"journal":"Harm reduction journal, 16(1), 9","doi":"10.1186/s12954-019-0278-6","pmid":"30691503","tags":["medical-cannabis","harm-reduction","addiction","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"69.1% reported substituting cannabis for prescription drugs (35.3% of those for opioids), 44.5% for alcohol, 31.1% for tobacco, and 26.6% for illicit substances. Among the 610 mentions of specific opioid medications, patients reported total cessation in 59.3% of cases. Pain and mental health conditions accounted for 83.7% of respondents.","whyItMatters":"This is one of the largest and most detailed surveys of medical cannabis substitution patterns. The finding that nearly 60% of opioid substituters reported complete cessation adds significant individual-level data to the population-level evidence.","specificNumbers":"2,032 respondents; 62.6% male; mean age 40; 74.6% daily use; mean 1.5g/day; 69.1% substituted for Rx drugs; 35.3% of Rx substitution was opioids; 59.3% reported total opioid cessation; 44.5% substituted for alcohol; 31.1% for tobacco.","methodology":"A 239-question cross-sectional survey of 2,032 Canadian medical cannabis patients registered with a federally authorized licensed producer (January 2017).","limitations":"Self-reported data without medical record verification. Patients registered with licensed producers may not represent all medical cannabis users. Cross-sectional design cannot establish causal substitution. Selection bias likely (patients who benefit from cannabis are more likely to respond)."},{"rthcId":"RTHC-02149","title":"Correlation of Breath and Blood Δ9-Tetrahydrocannabinol Concentrations and Release Kinetics Following Controlled Administration of Smoked Cannabis.","authors":"Lynch, Kara L; Luo, Y Ruben; Hooshfar, Shirin; Yun, Cassandra","year":2019,"journal":"Clinical chemistry, 65(9), 1171-1179","doi":"10.1373/clinchem.2019.304501","pmid":"31296552","tags":["driving","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"THC breath concentrations peaked at 15 minutes post-smoking (median 17.8 pg/L) and declined to <5% of peak in all participants by 3 hours. Blood and breath THC decay kinetics were highly correlated within and across individuals, supporting breath as a physiologically meaningful measure of recent cannabis exposure.","whyItMatters":"Unlike blood THC, which can remain elevated for days in regular users, breath THC appears to track the impairment window more closely. This could provide law enforcement and workplace testing with a more functionally relevant measure.","specificNumbers":"20 volunteers; median peak breath THC 17.8 pg/L at 15 minutes; declined to <5% of peak by 3 hours in all participants; blood and breath kinetics highly correlated.","methodology":"Controlled study with 20 volunteers providing timed blood and breath samples before and after smoking cannabis. Cannabinoid concentrations measured by LC-MS/MS. Release kinetics and matrix correlations calculated.","limitations":"Small sample (20 volunteers). Controlled setting may not reflect real-world smoking patterns. THC was detectable at baseline in some participants, complicating interpretation. Does not establish a breath THC threshold correlated with impairment."},{"rthcId":"RTHC-02150","title":"Plant Growth-Promoting Rhizobacteria for Cannabis Production: Yield, Cannabinoid Profile and Disease Resistance.","authors":"Lyu, Dongmei; Backer, Rachel; Robinson, W George; Smith, Donald L","year":2019,"journal":"Frontiers in microbiology, 10, 1761","doi":"10.3389/fmicb.2019.01761","pmid":"31456755","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02151","title":"A Novel Standardized Cannabis sativa L. Extract and Its Constituent Cannabidiol Inhibit Human Polymorphonuclear Leukocyte Functions.","authors":"Mabou Tagne, Alex; Marino, Franca; Legnaro, Massimiliano; Luini, Alessandra; Pacchetti, Barbara; Cosentino, Marco","year":2019,"journal":"International journal of molecular sciences, 20(8)","doi":"10.3390/ijms20081833","pmid":"31013912","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both CM5 (5% CBD cannabis extract) and pure CBD inhibited polymorphonuclear leukocyte migration, ROS production, and TNF-alpha production. CM5 was more potent than CBD alone for cell migration and TNF-alpha inhibition, but less effective for ROS suppression, suggesting other cannabis components contribute to anti-inflammatory effects.","whyItMatters":"The finding that a whole cannabis extract outperformed pure CBD for certain immune functions adds to evidence for an entourage effect and has implications for whether patients should use isolates or full-spectrum products.","specificNumbers":"CM5 standardized to 5% CBD. Both CM5 and CBD inhibited three PMN functions. CM5 was more potent than CBD for cell migration and TNF-alpha; CBD was more effective for ROS reduction.","methodology":"In vitro study testing CM5 (standardized Cannabis sativa extract with 5% CBD) and pure CBD on human PMN functions: Boyden chamber migration assay, spectrofluorimetric ROS measurement, and TNF-alpha by RT-PCR and ELISA.","limitations":"In vitro only (cell cultures, not in living organisms). Single extract formulation tested. The specific non-CBD components contributing to enhanced extract potency were not identified."},{"rthcId":"RTHC-02152","title":"Demographic and clinical profiles of admitted psychiatric patients of the East London Mental Health Unit in the Eastern Cape, South Africa.","authors":"Madala-Witbooi, Nombulelo J; Adeniyi, Oladele Vincent","year":2019,"journal":"Medicine, 98(52), e18399","doi":"10.1097/MD.0000000000018399","pmid":"31876712","tags":["psychosis","mental-health","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Schizophrenia (31.6%) and cannabis-related psychiatric disorders (31.6%) were tied as the most common reasons for psychiatric hospitalization, followed by bipolar type-1 disorder (21.9%) and alcohol-related disorders (15.5%). Most patients were male, single, and admitted involuntarily.","whyItMatters":"In a resource-limited setting where psychiatric beds are scarce, cannabis-related disorders consuming nearly a third of inpatient capacity has major implications for mental health service planning.","specificNumbers":"186 patients with complete data; 58% male; 38% psychotic, 31% violent at admission; cannabis disorders 31.6% = schizophrenia 31.6% > bipolar 21.9% > alcohol 15.5%. Most (72.6%) were single; 45.7% had secondary education.","methodology":"Retrospective cross-sectional audit of 186 psychiatric in-patient medical records at the East London Mental Health Unit, Eastern Cape, South Africa (January-December 2016).","limitations":"Single-center study in one region of South Africa. Retrospective design relying on medical records. Cannot distinguish cannabis as cause versus co-occurring factor. Small sample (186)."},{"rthcId":"RTHC-02153","title":"Burden of Comorbidities in Hospitalizations for Cannabis Use-associated Intractable Vomiting during Post-legalization Period.","authors":"Madireddy, Sowmya; Patel, Rikinkumar S; Ravat, Virendrasinh; Ajibawo, Temitope; Lal, Anthony; Patel, Jenil; Patel, Riddhi; Goyal, Hemant","year":2019,"journal":"Cureus, 11(8), e5502","doi":"10.7759/cureus.5502","pmid":"31511820","tags":["appetite","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Hospitalizations for intractable vomiting with CUD showed a significant increasing trend from 2010-2014 (N=9,601 total). Anxiety disorders increased from 20.8% to 30.8% as a comorbidity, while depression decreased from 19.2% to 16.4%. Concomitant tobacco abuse/dependence was present in 41.2% of patients.","whyItMatters":"As cannabis use increases, so do its paradoxical gastrointestinal side effects. The rising hospitalization trend predated widespread legalization, suggesting the problem may have worsened further since this data was collected.","specificNumbers":"9,601 hospitalizations total (2010-2014); significant increasing trend; anxiety comorbidity rose from 20.8% to 30.8%; depression fell from 19.2% to 16.4%; tobacco co-use 41.2%.","methodology":"Retrospective cohort study using the Nationwide Inpatient Sample (2010-2014), identifying patients aged 16-50 with primary diagnosis of intractable vomiting and cannabis use disorder.","limitations":"Administrative database study relying on discharge codes. CHS may be underdiagnosed and coded inconsistently. Cannot determine cannabis potency, frequency, or product type from billing data."},{"rthcId":"RTHC-02154","title":"Comprehensive Determination of Unregulated Pesticide Residues in Oregon Cannabis Flower by Liquid Chromatography Paired with Triple Quadrupole Mass Spectrometry and Gas Chromatography Paired with Triple Quadrupole Mass Spectrometry.","authors":"Maguire, Wesley J; Call, Cameron W; Cerbu, Cornel; Jambor, Katie L; Benavides-Montes, Victor E","year":2019,"journal":"Journal of agricultural and food chemistry, 67(46), 12670-12674","doi":"10.1021/acs.jafc.9b01559","pmid":"31398037","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02155","title":"Cannabis Associated \"High\" Cardiovascular Morbidity and Mortality: Marijuana Smoke Like Tobacco Smoke? A Déjà Vu/Déjà Vécu Story?","authors":"Manolis, Theodora A; Manolis, Antonis A; Manolis, Antonis S","year":2019,"journal":"Mini reviews in medicinal chemistry, 19(11), 870-879","doi":"10.2174/1389557518666181114113947","pmid":"30426899","tags":["cardiovascular","respiratory","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Despite different active ingredients (THC vs nicotine), cannabis and tobacco smoke contain largely identical combustion chemicals. Cannabis-associated cardiovascular complications include acute coronary syndromes, potentially lethal arrhythmias, and ischemic strokes. Different smoking techniques (deeper inhalation, longer breath-holding) may cause longer chemical retention from cannabis.","whyItMatters":"The public health messaging that cannabis is \"natural\" and therefore safe may be masking cardiovascular risks that mirror those already well-established for tobacco, especially when smoked.","specificNumbers":"The review notes that cannabis smoke contains many of the same 4,000+ chemicals as tobacco smoke, with cardiovascular complications emerging at younger ages in cannabis users.","methodology":"Literature review of cannabis pharmacology, cardiovascular effects, comparison with tobacco effects, and special populations (adolescents, secondhand smoke, exercise).","limitations":"Narrative review without systematic methodology. Concomitant tobacco and cannabis use confounds many studies. Dose-response data are limited. Most cardiovascular case reports are anecdotal."},{"rthcId":"RTHC-02156","title":"Medical Marijuana in the Pediatric Population With Epilepsy-What You Should Know.","authors":"Markle, Michelle; Nativio, Donna G","year":2019,"journal":"Journal of pediatric health care : official publication of National Association of Pediatric Nurse Associates & Practitioners, 33(6), 626-632","doi":"10.1016/j.pedhc.2019.03.002","pmid":"31160106","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02157","title":"Newest evidence for tetrahydrocannabinol:cannabidiol oromucosal spray from randomized clinical trials.","authors":"Marková, Jolana","year":2019,"journal":"Neurodegenerative disease management, 9(2s), 9-13","doi":"10.2217/nmt-2018-0050","pmid":"30657024","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"strong","keyFinding":"A Phase IV trial found no effect of THC:CBD spray on cognition and mood after 50 weeks of treatment. The SAVANT study showed add-on THC:CBD spray was significantly more effective than readjusting standard antispasticity medication alone.","whyItMatters":"Post-marketing studies provide real-world evidence that is often lacking at initial drug approval. These studies address the two most common concerns about long-term cannabinoid medication: cognitive impairment and whether it outperforms existing treatments.","specificNumbers":"Phase IV study: 50 weeks of treatment with no cognitive or mood effects detected. SAVANT: THC:CBD spray was significantly superior to readjusted standard antispasticity therapy.","methodology":"Review of two post-approval randomized trials: a double-blind Phase IV cognitive safety study and the SAVANT trial comparing add-on THC:CBD spray vs. optimized standard treatment.","limitations":"Review summarizes two trials rather than conducting new analysis. Both trials used enrichment designs (pre-selecting responders). Long-term data beyond 50 weeks for cognitive effects not available."},{"rthcId":"RTHC-02158","title":"Sativex® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial.","authors":"Markovà, Jolana; Essner, Ute; Akmaz, Bülent; Marinelli, Marcella; Trompke, Christiane; Lentschat, Arnd; Vila, Carlos","year":2019,"journal":"The International journal of neuroscience, 129(2), 119-128","doi":"10.1080/00207454.2018.1481066","pmid":"29792372","tags":["medical-cannabis","cbd","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"77.4% of patients receiving add-on THC:CBD spray achieved clinically relevant (30%+) spasticity NRS improvement versus 32.1% on placebo (p<0.0001). THC:CBD spray also significantly improved pain (p=0.0013) and muscle tone on modified Ashworth scale (p=0.0007). Adverse events were mild to moderate.","whyItMatters":"This trial addressed a practical clinical question: when standard treatments are not working, should clinicians add Sativex or keep adjusting conventional medications? The results strongly favor adding Sativex.","specificNumbers":"191 entered Phase A; 106 randomized; 77.4% vs 32.1% responder rate (p<0.0001); pain NRS p=0.0013; modified Ashworth scale p=0.0007; adverse events mild/moderate.","methodology":"Two-phase enriched-design RCT. Phase A: 191 patients received open-label THC:CBD spray for 4 weeks to identify initial responders (20%+ NRS improvement). Phase B: 106 responders randomized to THC:CBD spray (n=53) or placebo (n=53) for 12 weeks, with underlying antispasticity medication optimization permitted in both groups.","limitations":"Enriched design (pre-selected responders in Phase A) inflates apparent efficacy in Phase B. Relatively small Phase B sample (53 per arm). 12-week randomized phase may not capture long-term differences."},{"rthcId":"RTHC-02159","title":"Unique versus shared associations between self-reported behavioral addictions and substance use disorders and mental health problems: A commonality analysis in a large sample of young Swiss men.","authors":"Marmet, Simon; Studer, Joseph; Wicki, Matthias; Bertholet, Nicolas; Khazaal, Yasser; Gmel, Gerhard","year":2019,"journal":"Journal of behavioral addictions, 8(4), 664-677","doi":"10.1556/2006.8.2019.70","pmid":"31891314","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02160","title":"Predictors of future suicide attempt among adolescents with suicidal thoughts or non-suicidal self-harm: a population-based birth cohort study.","authors":"Mars, Becky; Heron, Jon; Klonsky, E David; Moran, Paul; O'Connor, Rory C; Tilling, Kate; Wilkinson, Paul; Gunnell, David","year":2019,"journal":"The lancet. Psychiatry, 6(4), 327-337","doi":"10.1016/S2215-0366(19)30030-6","pmid":"30879972","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use at age 16 predicted first suicide attempt by 21 in both high-risk groups: OR 2.61 (95% CI 1.11-6.14) among those with suicidal thoughts and OR 2.14 (95% CI 1.04-4.41) among those with non-suicidal self-harm. Other key predictors included illicit drug use, sleep problems, and exposure to others' self-harm. Many commonly cited risk factors were NOT predictive.","whyItMatters":"Most adolescents with suicidal thoughts or self-harm will NOT attempt suicide. Identifying which few will is clinically crucial. This study shows cannabis use is one of the strongest markers, while many traditional risk factors failed to predict escalation.","specificNumbers":"12% of each high-risk group (38/310 with suicidal thoughts, 46/380 with self-harm) attempted suicide by age 21. Cannabis OR 2.61 (suicidal thoughts group), OR 2.14 (self-harm group). Self-harm OR 2.78, illicit drugs OR 2.47.","methodology":"Population-based birth cohort study (ALSPAC, UK) following 1,025 adolescents at elevated risk (456 with suicidal thoughts, 569 with self-harm at age 16) through age 21, using prospectively recorded risk factors and logistic regression.","limitations":"Observational design cannot establish causality. Cannabis use may be a marker for other risk factors or self-medication for distress rather than a causal factor. UK birth cohort may not generalize globally. Self-reported measures."},{"rthcId":"RTHC-02161","title":"Alcohol-induced conditioned place preference is modulated by CB2 cannabinoid receptors and modifies levels of endocannabinoids in the mesocorticolimbic system.","authors":"Martín-Sánchez, Ana; Warnault, Vincent; Montagud-Romero, Sandra; Pastor, Antoni; Mondragón, Neus; De La Torre, Rafael; Valverde, Olga","year":2019,"journal":"Pharmacology, biochemistry, and behavior, 183, 22-31","doi":"10.1016/j.pbb.2019.06.007","pmid":"31220547","tags":["addiction","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Alcohol-conditioned place preference was associated with decreased anandamide and other N-acylethanolamines in the medial prefrontal cortex and ventral midbrain. Blocking CB2 receptors during conditioning reduced alcohol reward. However, activating CB2 reduced both alcohol AND food reward, suggesting a non-specific effect on reward processing.","whyItMatters":"Understanding how the endocannabinoid system mediates alcohol reward could inform treatments for alcohol use disorder. CB2 receptors are of particular interest because they can be targeted without the psychoactive effects of CB1 manipulation.","specificNumbers":"Anandamide and other N-acylethanolamines were markedly decreased in medial prefrontal cortex and ventral midbrain of alcohol-conditioned mice. AM630 (CB2 antagonist) reduced alcohol CPP during acquisition.","methodology":"Conditioned place preference (CPP) paradigm in C57BL/6 mice with endocannabinoid level measurement in brain regions (LC-MS/MS). CB2 receptor agonist (JWH133) and antagonist (AM630) administered during acquisition phase.","limitations":"Mouse model of alcohol preference, not addiction. CB2 agonist reduced food reward too, raising selectivity concerns. Acute pharmacological manipulation may not predict chronic treatment effects."},{"rthcId":"RTHC-02162","title":"Perceptions of non-traditional tobacco products between asthmatic and non-asthmatic college students.","authors":"Martinasek, Mary P; White, Robin M; Wheldon, Christopher W; Gibson-Young, Linda","year":2019,"journal":"The Journal of asthma : official journal of the Association for the Care of Asthma, 56(5), 498-504","doi":"10.1080/02770903.2018.1471705","pmid":"29714513","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02163","title":"Prevalence and determinants of tobacco, e-cigarettes, and cannabis use among nursing students: A multicenter cross-sectional study.","authors":"Martínez, Cristina; Baena, Antoni; Castellano, Yolanda; Fu, Marcela; Margalef, Mercè; Tigova, Olena; Feliu, Ariadna; Laroussy, Kenza; Galimany, Jordi; Puig, Montse; Bueno, Albert; López, Antonio; Fernández, Esteve","year":2019,"journal":"Nurse education today, 74, 61-68","doi":"10.1016/j.nedt.2018.11.018","pmid":"30583124","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02164","title":"Syndromic Surveillance of Emergency Department Visits for Acute Adverse Effects of Marijuana, Tri-County Health Department, Colorado, 2016-2017.","authors":"Marx, Grace E; Chen, Yushiuan; Askenazi, Michele; Albanese, Bernadette A","year":2019,"journal":"Public health reports (Washington, D.C. : 1974), 134(2), 132-140","doi":"10.1177/0033354919826562","pmid":"30721641","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 44,942 total ER visits, 1% were flagged as potential marijuana cases; 188 of 422 reviewed records (45%) were confirmed acute adverse effects. 95% reported intentional use. Non-Colorado residents and edible users were significantly overrepresented among confirmed cases compared to non-cases.","whyItMatters":"Post-legalization monitoring requires validated surveillance tools. This study confirms that existing ER data systems can reliably track marijuana-related visits, enabling evidence-based policy responses.","specificNumbers":"44,942 total ER visits; 453 flagged (1%); 188 confirmed cases; 58% male; 95% intentional use; PPV ranged 36-64% by hospital; edible users and non-residents significantly overrepresented.","methodology":"Validation study comparing syndromic surveillance queries (ICD-10 codes and keywords) against physician-reviewed medical records at 3 Colorado hospitals during 2016-2017.","limitations":"Three hospitals in one Colorado county, not statewide. PPV varied substantially by hospital. Only captures ER presentations, missing less severe adverse effects managed at home or in urgent care."},{"rthcId":"RTHC-02165","title":"Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity.","authors":"Mason, Natasha L; Theunissen, Eef L; Hutten, Nadia R P W; Tse, Desmond H Y; Toennes, Stefan W; Stiers, Peter; Ramaekers, Johannes G","year":2019,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29(2), 247-256","doi":"10.1016/j.euroneuro.2018.12.003","pmid":"30553697","tags":["neuroscience","dopamine","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"THC increased striatal glutamate concentrations and reduced functional connectivity (FC) between the nucleus accumbens and cortical areas, indicating increased dopamine activity. Glutamate changes correlated strongly with FC alterations. FC changes correlated with subjective high and decreased attention task performance. Effects were dose-dependent, appearing when THC blood levels exceeded 2 ng/ml.","whyItMatters":"This is one of the first human studies to show the neurochemical cascade through which THC produces its subjective and cognitive effects: THC boosts glutamate, which enhances dopamine, which disconnects reward circuits from cortical control.","specificNumbers":"20 occasional users; 300 ug/kg THC dose; effects dose-dependent above 2 ng/ml blood THC; glutamate changes strongly correlated with connectivity loss; connectivity changes correlated with subjective high and attention deficits.","methodology":"Double-blind, placebo-controlled study in 20 occasional cannabis users receiving 300 ug/kg THC or placebo in two dose regimes (full and divided dose). Magnetic resonance spectroscopy measured glutamate, GABA, and dopamine proxies; fMRI measured functional connectivity.","limitations":"Small sample (20 participants). Occasional users may respond differently than chronic users. Two dose regimes with 10 participants each limits statistical power. Single-session acute dosing only."},{"rthcId":"RTHC-02166","title":"Synthetic cannabinoid use among college students.","authors":"Mathews, Eva M; Jeffries, Emily; Hsieh, Chenen; Jones, Glenn; Buckner, Julia D","year":2019,"journal":"Addictive behaviors, 93, 219-224","doi":"10.1016/j.addbeh.2019.02.009","pmid":"30772774","tags":["synthetic-cannabinoids","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"7.9% lifetime synthetic cannabinoid use; 16.7% of users considered or visited the ER. Natural cannabis users had OR 7.63 for trying synthetics. 92.2% of synthetic users also used natural cannabis. Common reasons for use: legality, avoiding drug tests, and availability, not enjoyment or perceived safety.","whyItMatters":"Students are not choosing synthetic cannabinoids because they want them. They are using them to avoid drug tests and legal consequences, a finding with direct implications for drug testing policies.","specificNumbers":"1,140 students; 7.9% (n=90) lifetime use; 15.6% regular users; 16.7% considered/went to ER; OR 7.63 for natural cannabis users; 92.2% of synthetic users also used natural cannabis.","methodology":"Online survey of 1,140 undergraduates assessing synthetic cannabinoid use prevalence, consequences, reasons for use, and associations with natural cannabis use.","limitations":"Self-report survey at a single university. Social desirability bias possible. Cross-sectional design cannot establish temporal ordering. Synthetic cannabinoid formulations vary widely."},{"rthcId":"RTHC-02167","title":"Tobacco and cannabis co-use: Drug substitution, quit interest, and cessation preferences.","authors":"McClure, Erin A; Tomko, Rachel L; Salazar, Claudia A; Akbar, Saima A; Squeglia, Lindsay M; Herrmann, Evan; Carpenter, Matthew J; Peters, Erica N","year":2019,"journal":"Experimental and clinical psychopharmacology, 27(3), 265-275","doi":"10.1037/pha0000244","pmid":"30556733","tags":["quitting","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"About 80% had tried to quit tobacco vs 40% for cannabis. Quit interest was 7.07/10 for tobacco vs 2.39/10 for cannabis. When attempting tobacco cessation, 50% perceived increased cannabis use. When attempting cannabis cessation, 62% perceived increased tobacco use. This bidirectional substitution pattern complicates treatment.","whyItMatters":"Co-use of cannabis and tobacco is common but rarely addressed in treatment. The finding that people substitute one for the other during quit attempts has critical implications for how cessation programs should be designed.","specificNumbers":"282 participants; 57% female; mean age 33.3; quit interest tobacco 7.07/10, cannabis 2.39/10; 80% tried quitting tobacco, 40% tried quitting cannabis; 50% increased cannabis during tobacco quit, 62% increased tobacco during cannabis quit.","methodology":"Two online survey samples (Amazon MTurk) combined (N=282), assessing quit interest, treatment preferences, and perceived drug substitution among adult cannabis-tobacco co-users across the US.","limitations":"Online convenience sample (MTurk) may not represent treatment-seeking populations. Self-reported perceived substitution, not objectively measured. Cross-sectional design."},{"rthcId":"RTHC-02168","title":"Efficacy of Capsaicin for the Treatment of Cannabinoid Hyperemesis Syndrome: A Systematic Review.","authors":"McConachie, Sean M; Caputo, Ryan A; Wilhelm, Sheila M; Kale-Pradhan, Pramodini B","year":2019,"journal":"The Annals of pharmacotherapy, 53(11), 1145-1152","doi":"10.1177/1060028019852601","pmid":"31104487","tags":["appetite","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Five full-text articles and 6 conference abstracts were included. Case reports and series (n=18 patients) found capsaicin effective for CHS. However, both retrospective cohort studies failed to find significant benefits for capsaicin on ER length of stay as primary outcome.","whyItMatters":"Capsaicin is recommended as first-line CHS treatment in some guidelines, but this review reveals the evidence behind that recommendation is essentially case reports. The two studies with better designs found no benefit.","specificNumbers":"241 articles screened; 11 included; 18 patients in case reports/series all showed benefit; 2 retrospective cohort studies found no significant improvement in ER length of stay.","methodology":"Systematic review searching MEDLINE, CINAHL, and EMBASE through March 2019. Included 5 full-text articles (3 case reports, 2 case series) and 6 conference abstracts (1 case report, 3 case series, 2 retrospective cohorts).","limitations":"All evidence is low methodological quality. Publication bias likely (positive case reports more likely published). No randomized trials exist. Capsaicin dosing and application varied across studies."},{"rthcId":"RTHC-02169","title":"Impaired driving: A case report. Pickup truck centerline crossover collision with medium-size bus on U.S. Highway 83, Concan, Texas, United States.","authors":"McKay, Mary Pat; Poland, Kristin; Karol, Donald; Marshall, Rafael; Kaminski, Ronald","year":2019,"journal":"Traffic injury prevention, 20(sup2), S165-S168","doi":"10.1080/15389588.2019.1661668","pmid":"31663778","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02170","title":"Legal and Regulatory Issues Governing Cannabis and Cannabis-Derived Products in the United States.","authors":"Mead, Alice","year":2019,"journal":"Frontiers in plant science, 10, 697","doi":"10.3389/fpls.2019.00697","pmid":"31263468","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02171","title":"Synergistic effects of marijuana abuse and HIV infection on neural activation during a cognitive interference task.","authors":"Meade, Christina S; Bell, Ryan P; Towe, Sheri L; Chen, Nan-Kuei; Hobkirk, Andrea L; Huettel, Scott A","year":2019,"journal":"Addiction biology, 24(6), 1235-1244","doi":"10.1111/adb.12678","pmid":"30239074","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The MJ+/HIV+ group showed the greatest activation increase in the left fronto-insular cortex during cognitive interference, beyond what either marijuana or HIV produced alone. This activation correlated with cumulative years of marijuana use. Marijuana independently affected bilateral parietal regions, while HIV affected the anterior cingulate cortex.","whyItMatters":"HIV-infected individuals use marijuana at higher rates than the general population. If the two conditions compound each other's neural effects, clinicians need to understand this interaction to manage cognitive health in this population.","specificNumbers":"93 adults (20 MJ+/HIV+, 19 MJ+/HIV-, 29 MJ-/HIV+, 25 MJ-/HIV-). MJ+/HIV+ group had largest activation in left fronto-insular cortex. Signal change correlated with years of regular marijuana use among MJ+ participants.","methodology":"Cross-sectional fMRI study of 93 adults in four groups (MJ+/HIV+, MJ+/HIV-, MJ-/HIV+, MJ-/HIV-) performing a counting Stroop task, analyzing main and interactive effects on neural activation.","limitations":"Cross-sectional design cannot determine causality or temporal ordering. Cannot separate effects of HIV medication from HIV itself. Cannabis use patterns self-reported. Relatively small subgroups."},{"rthcId":"RTHC-02172","title":"Cannabis Inhalation and Voice Disorders: A Systematic Review.","authors":"Meehan-Atrash, Jiries; Korzun, Tetiana; Ziegler, Aaron","year":2019,"journal":"JAMA otolaryngology-- head & neck surgery, 145(10), 956-964","doi":"10.1001/jamaoto.2019.1986","pmid":"31393535","tags":["respiratory"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The only laryngeal study found dark vocal folds in cannabis smokers. Six clinical studies showed association between cannabis inhalation and respiratory problems that improved with cessation or switching to vaporizing. Light cannabis smoking maintained lung function long-term, while heavy use was associated with negative changes.","whyItMatters":"Voice professionals, singers, and public speakers who use cannabis need to know about vocal fold risks. This is the first systematic review specifically addressing cannabis and voice disorders.","specificNumbers":"19 studies included (6 clinical, 13 basic science/animal). Only 1 study assessed laryngeal symptoms directly. Light use maintained lung function; heavy use showed negative changes. Switching to vaporizing reduced respiratory symptoms.","methodology":"Systematic review per PRISMA guidelines, searching PubMed, CINAHL, Scopus, and Cochrane (2007-2018). Identified 6 clinical science and 13 basic science/animal studies on inhaled cannabis and vocal/respiratory function.","limitations":"Very limited direct evidence on vocal effects (one study). Most evidence extrapolated from respiratory studies. Cannot separate cannabis combustion effects from cannabinoid effects. No controlled trials."},{"rthcId":"RTHC-02173","title":"Associations between adolescent cannabis use frequency and adult brain structure: A prospective study of boys followed to adulthood.","authors":"Meier, Madeline H; Schriber, Roberta A; Beardslee, Jordan; Hanson, Jamie; Pardini, Dustin","year":2019,"journal":"Drug and alcohol dependence, 202, 191-199","doi":"10.1016/j.drugalcdep.2019.05.012","pmid":"31357120","tags":["youth","neuroscience","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Four adolescent cannabis use trajectories were identified: non-users/infrequent, desisters, escalators, and chronic-frequent users. Despite these distinct patterns, no significant differences in adult brain structure were found in any of 14 subcortical or cortical regions of interest, including hippocampus, amygdala, nucleus accumbens, and multiple frontal cortical areas.","whyItMatters":"This is one of the few truly prospective studies tracking cannabis use from adolescence into adulthood with neuroimaging. The null finding challenges the assumption that adolescent cannabis use causes lasting structural brain damage.","specificNumbers":"~1,000 boys in full cohort; 181 underwent adult MRI at ages 30-36; 14 brain regions examined; 4 cannabis use trajectories; zero significant structural differences found.","methodology":"Pittsburgh Youth Study, a longitudinal study of ~1,000 boys. Cannabis use assessed annually ages 13-19. Structural MRI performed on 181 participants at ages 30-36. Latent class growth analysis identified four use trajectories.","limitations":"Male-only sample. Subset (181 of ~1,000) may not be fully representative. Cannabis potency was likely lower in the 1990s-2000s than today. Does not rule out functional brain changes without structural correlates."},{"rthcId":"RTHC-02174","title":"Gender differences of patients at-risk for psychosis regarding symptomatology, drug use, comorbidity and functioning - Results from the EU-GEI study.","authors":"Menghini-Müller, Stephanie; Studerus, Erich; Ittig, Sarah; Heitz, Ulrike; Egloff, Laura; Andreou, Christina; Valmaggia, Lucia R; Kempton, Matthew J; van der Gaag, Mark; de Haan, Lieuwe; Nelson, Barnaby; Barrantes-Vidal, Neus; Nordentoft, Merete; Ruhrmann, Stephan; Sachs, Gabriele; Rutten, Bart P; Os, Jim van; Riecher-Rössler, Anita; McGuire, Philip; Valmaggia, Lucia R; Kempton, Matthew J; Calem, Maria; Tognin, Stefania; Modinos, Gemma; de Haan, Lieuwe; van der Gaag, Mark; Velthorst, Eva; Kraan, Tamar C; van Dam, Daniella S; Burger, Nadine; Nelson, Barnaby; McGorry, Patrick; Amminger, G Paul; Pantelis, Christos; Politis, Athena; Goodall, Joanne; Riecher-Rössler, Anita; Borgwardt, Stefan; Rapp, Charlotte; Ittig, Sarah; Studerus, Erich; Smieskova, Renata; Bressan, Rodrigo; Gadelha, Ary; Brietzke, Elisa; Asevedo, Graccielle; Asevedo, Elson; Zugman, Andre; Barrantes-Vidal, Neus; Domínguez-Martínez, Tecelli; Racioppi, Anna; Cristóbal-Narváez, Paula; Kwapil, Thomas R; Monsonet, Manel; Kazes, Mathilde; Daban, Claire; Bourgin, Julie; Gay, Olivier; Mam-Lam-Fook, Célia; Krebs, Marie-Odile; Nordholm, Dorte; Randers, Lasse; Krakauer, Kristine; Glenthøj, Louise; Glenthøj, Birte; Nordentoft, Merete; Ruhrmann, Stephan; Gebhard, Dominika; Arnhold, Julia; Klosterkötter, Joachim; Sachs, Gabriele; Lasser, Iris; Winklbaur, Bernadette; Delespaul, Philippe A; Rutten, Bart P; van Os, Jim","year":2019,"journal":"European psychiatry : the journal of the Association of European Psychiatrists, 59, 52-59","doi":"10.1016/j.eurpsy.2019.04.007","pmid":"31075522","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02175","title":"Marijuana as a Substitute for Prescription Medications: A Qualitative Study.","authors":"Mercurio, Alana; Aston, Elizabeth R; Claborn, Kasey R; Waye, Katherine; Rosen, Rochelle K","year":2019,"journal":"Substance use & misuse, 54(11), 1894-1902","doi":"10.1080/10826084.2019.1618336","pmid":"31179810","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Three key themes emerged: (1) patients perceived cannabis as having fewer/better side effects and improving quality of life versus prescriptions, (2) patients used cannabis to supplement or replace other medications including opioids, and (3) stigma, travel restrictions, cost, and inability of providers to give dosing/strain guidance significantly limited use.","whyItMatters":"Patient perspectives reveal practical barriers that surveys miss. The inability of healthcare providers to give dosing guidance leaves patients to experiment on their own, potentially leading to suboptimal or unsafe use.","specificNumbers":"25 participants (Rhode Island medical cannabis cardholders); 3 major themes identified; patients specifically mentioned opioid substitution as a primary use case.","methodology":"Qualitative semi-structured interviews with 25 Rhode Island medical cannabis cardholders, with audio recording, verbatim transcription, and thematic coding.","limitations":"Small qualitative sample (25) from one state. Self-selected medical cannabis users may have more positive views. No clinical outcome verification. Rhode Island policies may not generalize."},{"rthcId":"RTHC-02176","title":"Early Sexual Trauma Exposure and Neural Response Inhibition in Adolescence and Young Adults: Trajectories of Frontal Theta Oscillations During a Go/No-Go Task.","authors":"Meyers, Jacquelyn; McCutcheon, Vivia V; Pandey, Ashwini K; Kamarajan, Chella; Subbie, Stacey; Chorlian, David; Salvatore, Jessica; Pandey, Gayathri; Almasy, Laura; Anokhin, Andrey; Bauer, Lance; Bender, Annah; Dick, Danielle M; Edenberg, Howard J; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Agrawal, Arpana; Bucholz, Kathleen; Porjesz, Bernice","year":2019,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 58(2), 242-255.e2","doi":"10.1016/j.jaac.2018.07.905","pmid":"30738551","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02177","title":"The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice.","authors":"Micale, Vincenzo; Drago, Filippo; Noerregaard, Pia K; Elling, Christian E; Wotjak, Carsten T","year":2019,"journal":"Frontiers in pharmacology, 10, 207","doi":"10.3389/fphar.2019.00207","pmid":"30949045","tags":["neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Oral TM38837 required 10x higher doses than rimonabant to produce comparable fear-promoting effects (100 mg/kg vs 10 mg/kg). When injected directly into the brain, TM38837 was still less potent at promoting fear. Previous studies showed equivalent weight-loss efficacy between the two drugs, suggesting a therapeutic window for TM38837.","whyItMatters":"Rimonabant was pulled from the market due to psychiatric side effects (anxiety, depression, suicidality). If a peripherally restricted CB1 blocker can reduce weight without penetrating the brain enough to cause these effects, it could resurrect an entire drug class.","specificNumbers":"TM38837 oral: only 100 mg/kg (but not 10 or 30 mg/kg) increased fear. Rimonabant oral: 10 mg/kg significantly increased fear. Intracerebral: TM38837 10-30 ug/mouse caused less fear response than rimonabant 1-10 ug/mouse.","methodology":"Fear conditioning paradigm in mice (C57BL/6N) comparing oral and intracerebral TM38837 vs rimonabant at multiple doses, measuring freezing behavior during tone re-exposure.","limitations":"Mouse study; human psychiatric side effects may not be predicted by mouse fear conditioning. The therapeutic window between metabolic efficacy and fear promotion has not been validated in humans. Long-term safety unknown."},{"rthcId":"RTHC-02178","title":"Marijuana use among adolescents is associated with deleterious alterations in mature BDNF.","authors":"Miguez, Maria Jose; Chan, Wenyaw; Espinoza, Luis; Tarter, Ralph; Perez, Caroline","year":2019,"journal":"AIMS public health, 6(1), 4-14","doi":"10.3934/publichealth.2019.1.4","pmid":"30931339","tags":["youth","neuroscience","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Pre-existing BDNF levels did not differ between groups, but marijuana use predicted subsequent BDNF alterations (p=0.001). Younger adolescents showed BDNF increases during early/moderate use. Older adolescents had steeper BDNF increases, especially when escalating use. The findings demonstrate BDNF changes were secondary to marijuana use, not pre-existing.","whyItMatters":"BDNF is essential for brain development and plasticity. This is the first study to show that BDNF changes followed marijuana initiation rather than preceding it, establishing a temporal relationship suggesting causation.","specificNumbers":"500 adolescents; 4 trajectory groups; pre-use BDNF similar across groups (p=0.4); marijuana use significant predictor of BDNF change (p=0.001); younger and older adolescents showed different BDNF response patterns.","methodology":"Single-site longitudinal cohort of 500 urban healthy adolescents with repeated plasma m-BDNF measurements. Multi-method marijuana use assessment. Group-based trajectory modeling identified four groups: naive (60%), starters (14%), chronic (20%), experimenters/quitters (6%). GLM regression controlled for confounders.","limitations":"Single-site study. Plasma BDNF may not directly reflect brain BDNF. 500 participants but small subgroups (starters 14%, quitters 6%). Cannot fully exclude all confounders. BDNF has many functions beyond brain development."},{"rthcId":"RTHC-02179","title":"Cannabis and the exocannabinoid and endocannabinoid systems. Their use and controversies.","authors":"Millán-Guerrero, Rebeca Olivia; Isais-Millán, Sara","year":2019,"journal":"Gaceta medica de Mexico, 155(5), 471-474","doi":"10.24875/GMM.M20000334","pmid":"32091020","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02180","title":"Cannabis y los sistemas exocannabinoide y endocannabinoide. Su uso y controversias.","authors":"Millán-Guerrero, Rebeca Olivia; Isais-Millán, Sara","year":2019,"journal":"Gaceta medica de Mexico, 155(5), 508-512","doi":"10.24875/GMM.19004881","pmid":"31695229","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02181","title":"A systematic review of cannabidiol dosing in clinical populations.","authors":"Millar, S A; Stone, N L; Bellman, Z D; Yates, A S; England, T J; O'Sullivan, S E","year":2019,"journal":"British journal of clinical pharmacology, 85(9), 1888-1900","doi":"10.1111/bcp.14038","pmid":"31222854","tags":["cbd","medical-cannabis","epilepsy"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"23 of 35 studies reported significant improvement in primary outcomes. Epilepsy was the most studied condition (11 studies, all positive) with average RCT dose of 15 mg/kg/day. Studies of diabetes, Crohn's, ocular hypertension, fatty liver, and chronic pain found no positive effects, but used lower doses (average 2.4 mg/kg/day). No study reported plasma CBD concentrations.","whyItMatters":"The absence of standardized CBD dosing guidance leaves patients and clinicians guessing. This review reveals that negative results may reflect underdosing rather than true inefficacy, especially for non-epilepsy conditions.","specificNumbers":"1,038 articles retrieved, 35 met inclusion criteria; 23 showed significant improvement; effective range <1 to 50 mg/kg/day; epilepsy average RCT dose ~15 mg/kg/day; conditions with negative results averaged 2.4 mg/kg/day; 0 studies reported plasma concentrations.","methodology":"Systematic review searching PubMed, EMBASE, and ClinicalTrials.gov, identifying 35 studies across 13 medical contexts involving CBD-only administration.","limitations":"Could not conduct meta-analysis due to heterogeneity. Small sample sizes in many included studies (range n=6-62 for negative RCTs). No plasma concentration data available in any study. Publication bias possible."},{"rthcId":"RTHC-02182","title":"Adolescent exposure to Δ9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons.","authors":"Miller, Michael L; Chadwick, Benjamin; Dickstein, Dara L; Purushothaman, Immanuel; Egervari, Gabor; Rahman, Tanni; Tessereau, Chloe; Hof, Patrick R; Roussos, Panos; Shen, Li; Baxter, Mark G; Hurd, Yasmin L","year":2019,"journal":"Molecular psychiatry, 24(4), 588-600","doi":"10.1038/s41380-018-0243-x","pmid":"30283037","tags":["youth","neuroscience","psychosis","genetics"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"THC exposure disrupted normal PFC development by inducing premature spine pruning and dendritic atrophy. There was minimal overlap between the transcriptomes of THC-treated and control rats, indicating fundamentally altered developmental trajectories. Dysregulated gene networks related to cell morphogenesis, dendritic development, and cytoskeleton organization were shared between THC-treated rats and schizophrenia patients.","whyItMatters":"This study provides a molecular mechanism linking adolescent cannabis use to psychiatric vulnerability: THC does not just damage neurons but fundamentally alters their developmental trajectory, pushing gene expression onto a path that resembles schizophrenia.","specificNumbers":"THC caused premature pruning in late adolescence and dendritic atrophy in early adulthood. Dysregulated co-expression networks were enriched for cytoskeletal and neurite development genes shared with schizophrenia patients.","methodology":"Rat model with adolescent THC exposure. Layer III pyramidal neurons analyzed using cell-type-specific high-resolution microscopy, laser capture microdissection, and next-generation RNA sequencing.","limitations":"Rat model with THC doses that may not match human exposure. Only layer III pyramidal neurons examined. Male rats only. Cannot confirm the same transcriptional changes occur in human adolescents."},{"rthcId":"RTHC-02183","title":"Treatment of Gilles de la Tourette Syndrome with Cannabis-Based Medicine: Results from a Retrospective Analysis and Online Survey.","authors":"Milosev, Leonie M; Psathakis, Nikolas; Szejko, Natalia; Jakubovski, Ewgeni; Müller-Vahl, Kirsten R","year":2019,"journal":"Cannabis and cannabinoid research, 4(4), 265-274","doi":"10.1089/can.2018.0050","pmid":"31872061","tags":["medical-cannabis","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"85% reported tic improvement (about 60% reduction), 55% improved comorbidities (especially OCD, ADHD, sleep), and 93% reported better quality of life. Of those who could compare, 66% preferred medicinal cannabis, 18% dronabinol, 11% nabiximols, 5% street cannabis. Adverse events occurred in 50% but were rated tolerable.","whyItMatters":"Tourette syndrome treatment options are limited and often have significant side effects. This is the largest dataset to date comparing different cannabis-based medicine formulations for tics, and patient preference for THC-rich strains suggests an entourage effect.","specificNumbers":"98 patients total; 85% reported tic improvement (~60% reduction); 55% improved comorbidities; 93% improved QoL; 50% had adverse events (tolerable); 66% preferred medicinal cannabis over dronabinol (18%) and nabiximols (11%).","methodology":"Two-part study: retrospective analysis of 98 adult GTS patients who used cannabis-based medicines at a specialty clinic, plus an online survey (n=40) for more detailed data on treatment preferences and experiences.","limitations":"Retrospective, open-label design with no control group. Subjective self-reported outcomes. Selection bias toward patients who continued treatment. Variable dosing across preparations."},{"rthcId":"RTHC-02184","title":"Measuring Disturbance of the Endocannabinoid System in Psychosis: A Systematic Review and Meta-analysis.","authors":"Minichino, Amedeo; Senior, Morwenna; Brondino, Natascia; Zhang, Sam H; Godwlewska, Beata R; Burnet, Philip W J; Cipriani, Andrea; Lennox, Belinda R","year":2019,"journal":"JAMA psychiatry, 76(9), 914-923","doi":"10.1001/jamapsychiatry.2019.0970","pmid":"31166595","tags":["psychosis","neuroscience"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"CSF anandamide was significantly elevated in schizophrenia (SMD 0.97, p<.001). Blood anandamide was also higher (SMD 0.55, p=.03). CB1 receptor expression on peripheral immune cells was increased (SMD 0.57, p<.001). Higher endocannabinoid tone was found early in illness, in antipsychotic-naive patients, and was inversely associated with symptom severity.","whyItMatters":"This JAMA Psychiatry meta-analysis establishes the endocannabinoid system as a measurable biomarker in psychosis. The pattern (elevated early, normalized by treatment, inversely related to symptoms) suggests it may be a compensatory protective mechanism.","specificNumbers":"CSF AEA: SMD 0.97 (95% CI 0.67-1.26, p<.001, I2=54.8%); blood AEA: SMD 0.55 (95% CI 0.05-1.04, p=.03, I2=89.6%); CB1R expression: SMD 0.57 (95% CI 0.31-0.84, p<.001, I2=0%).","methodology":"Systematic review and meta-analysis per PRISMA, searching Web of Science and PubMed. 18 studies included with 3 separate meta-analyses for CSF anandamide (5 studies, 226 patients, 385 controls), blood anandamide (9 studies, 344 patients, 411 controls), and CB1R expression (3 studies, 88 patients, 179 controls).","limitations":"Moderate to high heterogeneity, especially for blood anandamide (I2=89.6%). Not all studies controlled for cannabis use, a major confounder. Relatively small sample sizes for CB1R analysis."},{"rthcId":"RTHC-02185","title":"The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study.","authors":"Mitelpunkt, Alexis; Kramer, Uri; Hausman Kedem, Moran; Zilbershot Fink, Efrat; Orbach, Rotem; Chernuha, Veronika; Fattal-Valevski, Aviva; Deutsch, Lisa; Heffetz, Daphna; Sacks, Hagit","year":2019,"journal":"Epilepsy & behavior : E&B, 98(Pt A), 233-237","doi":"10.1016/j.yebeh.2019.07.007","pmid":"31394352","tags":["epilepsy","cbd","youth"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Median seizure count reduced by 81.9% from baseline. Monthly seizure frequency decreased by 73.4% (p<0.05). 56% of patients were responders (50%+ reduction), and 2 patients became seizure-free. 73% of caregivers reported improved condition; 82% reported reduced seizure severity. Treatment adherence was 96.3%.","whyItMatters":"CBD bioavailability is a major challenge. This gelatin bead formulation (PTL-101) addresses that issue, and the 82% seizure reduction and high adherence (96%) suggest the formulation matters for clinical outcomes.","specificNumbers":"16 enrolled, 11 completed; mean age 9.1 years; average dose 13.6 mg/kg/day; 81.9% median seizure reduction; 56% responders; 2 seizure-free; adherence 96.3%; AEs: insomnia 25%, somnolence 18.8%.","methodology":"Phase II, open-label, single-center study. 16 pediatric patients with TRE (history of 4+ failed AEDs). 4-week baseline, 2-week titration (up to 25 mg/kg or 450 mg), 10-week maintenance. Average maintenance dose 13.6 mg/kg/day.","limitations":"Open-label, no control group, single center, small sample (16). 5 patients dropped out. The 82% reduction may partly reflect regression to the mean or placebo effects without a control group."},{"rthcId":"RTHC-02186","title":"Drug-drug interactions between antiepileptics and cannabinoids.","authors":"Miziak, Barbara; Walczak, Aleksandra; Szponar, Jarosław; Pluta, Ryszard; Czuczwar, Stanisław J","year":2019,"journal":"Expert opinion on drug metabolism & toxicology, 15(5), 407-415","doi":"10.1080/17425255.2019.1605355","pmid":"30991855","tags":["epilepsy","cbd","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"In animal models, WIN 55,212-2 (CB1/CB2 agonist) potentiated anticonvulsant activity of various AEDs but caused profound neurotoxicity when combined with conventional AEDs. ACEA (selective CB1 agonist) enhanced phenobarbital and levetiracetam without adverse effects or pharmacokinetic interactions. Clinical CBD add-on therapy reduced seizure frequency with retention rates of 14-24% at 12 weeks to 1 year, reaching 35% at 2 years.","whyItMatters":"Most epilepsy patients on CBD are taking multiple other medications. Understanding which combinations are safe and effective is critical for clinical practice, especially as CBD use in epilepsy grows rapidly.","specificNumbers":"Clinical CBD retention rate: 14-24% (12 weeks to 1 year), 35% at 2 years. Most common AEs: diarrhea, somnolence, poor appetite. ACEA enhanced phenobarbital and levetiracetam without pharmacokinetic interactions in mice.","methodology":"Literature review of PubMed through December 2018, covering both experimental (animal model) and clinical data on AED-cannabinoid interactions.","limitations":"Animal interaction data may not translate directly to humans. Clinical retention rates reflect a mix of efficacy and tolerability. Limited pharmacokinetic interaction data in humans."},{"rthcId":"RTHC-02187","title":"Adherence to Consolidated Standards of Reporting Trials (CONSORT) Guidelines for Reporting Safety Outcomes in Trials of Cannabinoids for Chronic Pain: Protocol for a Systematic Review.","authors":"Mohiuddin, Mohammed M; Mizubuti, Glenio; Haroutounian, Simon; Smith, Shannon; Campbell, Fiona; Park, Rex; Gilron, Ian","year":2019,"journal":"JMIR research protocols, 8(1), e11637","doi":"10.2196/11637","pmid":"30688655","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02188","title":"Acute effect of vaporized Cannabis on sleep and electrocortical activity.","authors":"Mondino, Alejandra; Cavelli, Matías; González, Joaquín; Santana, Noelia; Castro-Zaballa, Santiago; Mechoso, Bùrix; Bracesco, Nelson; Fernandez, Santiago; Garcia-Carnelli, Carlos; Castro, María José; Umpierrez, Eleuterio; Murillo-Rodriguez, Eric; Torterolo, Pablo; Falconi, Atilio","year":2019,"journal":"Pharmacology, biochemistry, and behavior, 179, 113-123","doi":"10.1016/j.pbb.2019.02.012","pmid":"30822492","tags":["sleep","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"A single vaporized dose of Cannabis with THC 11.5% (and negligible other cannabinoids) was linked to a short-lived increase in NREM sleep (non-REM sleep, a deeper non-dream sleep stage), but only at the 200 mg dose and only during the first hour of the light phase. No sleep changes were reported during the dark (active) phase, or at lower doses (40 mg and 80 mg). At 200 mg, EEG (electroencephalography, a recording of brain electrical rhythms) changes included reduced high-frequency power during wake and REM sleep in the light phase, plus reduced sleep-spindle coherence during NREM sleep in the dark phase.","whyItMatters":"In 2019, vaporization was increasingly discussed in medical-cannabis settings as an inhalation route that can deliver THC quickly, but controlled sleep physiology data were limited. The study question was narrow and practical for basic sleep research: whether low plasma THC levels from vaporized, THC-dominant Cannabis shift sleep architecture and cortical rhythms measured by EEG. The work also separated light and dark phases, which matters in rats because sleep pressure and activity differ strongly across the circadian cycle.","specificNumbers":"• Cannabis chemotype: THC 11.5% with negligible other cannabinoids (a THC-dominant preparation, not a mixed-cannabinoid product). This limits conclusions to a specific composition.\n• Doses tested: 0 mg (control), 40 mg, 80 mg, and 200 mg of vaporized Cannabis (animal study, not tested in humans). Only the highest dose was linked to measurable sleep and EEG changes.\n• Recording window: 6 hours of polysomnography (animal study, not tested in humans). This captures acute effects but not longer-term sleep patterns.\n• THC plasma concentrations: up to 6.7 ng/mL at the 200 mg dose (animal study, not tested in humans). This is a low blood level in the study’s framing, but the abstract does not provide comparative benchmarks.","methodology":"This was an animal sleep physiology study testing the acute effects of vaporized, THC-dominant Cannabis on rat sleep. Rats were chronically prepared for polysomnography so the researchers could score wake, NREM sleep, and REM sleep from electrophysiology recordings. Each animal received vaporized Cannabis at 0 mg, 40 mg, 80 mg, or 200 mg immediately before a 6-hour recording session conducted in both the light and dark phases. For the highest dose, the team also ran quantitative EEG analyses (spectral power and coherence) to look at brain-rhythm changes across sleep states. A major weakness is that the abstract does not report N, randomization, or blinding procedures, which makes it hard to judge robustness and bias control.","limitations":"Sample size, randomization, and blinding were not described in the abstract, and the reported sleep effect was limited to the first hour of the light phase at the highest dose. This was tested in rats, not humans. Animal results frequently do not translate to human outcomes."},{"rthcId":"RTHC-02189","title":"Discovery of novel benzofuran-based compounds with neuroprotective and immunomodulatory properties for Alzheimer's disease treatment.","authors":"Montanari, Serena; Mahmoud, Ali Mokhtar; Pruccoli, Letizia; Rabbito, Alessandro; Naldi, Marina; Petralla, Sabrina; Moraleda, Ignacio; Bartolini, Manuela; Monti, Barbara; Iriepa, Isabel; Belluti, Federica; Gobbi, Silvia; Di Marzo, Vincenzo; Bisi, Alessandra; Tarozzi, Andrea; Ligresti, Alessia; Rampa, Angela","year":2019,"journal":"European journal of medicinal chemistry, 178, 243-258","doi":"10.1016/j.ejmech.2019.05.080","pmid":"31185414","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02190","title":"Acute Illness Associated With Cannabis Use, by Route of Exposure: An Observational Study.","authors":"Monte, Andrew A; Shelton, Shelby K; Mills, Eleanor; Saben, Jessica; Hopkinson, Andrew; Sonn, Brandon; Devivo, Michael; Chang, Tae; Fox, Jacob; Brevik, Cody; Williamson, Kayla; Abbott, Diana","year":2019,"journal":"Annals of internal medicine, 170(8), 531-537","doi":"10.7326/M18-2809","pmid":"30909297","tags":["harm-reduction","legalization","cardiovascular","psychosis"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Edible cannabis ER visits were disproportionate to sales (10.7% of visits vs 0.32% of THC sales). Compared to inhaled, edible visits had more psychiatric symptoms (18% vs 10.9%), intoxication (48% vs 28%), and cardiovascular symptoms (8% vs 3.1%). Inhaled cannabis visits more often involved cannabinoid hyperemesis (18% vs 8.4%).","whyItMatters":"This is the definitive study showing edibles are disproportionately represented in ER visits. The disconnect between sales volume and ER visits suggests that edibles pose unique risks, likely related to delayed onset and difficulty dosing.","specificNumbers":"9,973 cannabis-coded visits; 2,567 (25.7%) attributable to cannabis; 238 (9.3%) edible-related; edibles: 0.32% of THC sales but 10.7% of attributable visits; psychiatric 18% vs 10.9%; intoxication 48% vs 28%; cardiovascular 8% vs 3.1%.","methodology":"Chart review of 9,973 ER visits with cannabis ICD codes at a large urban Colorado hospital (2012-2016). 2,567 (25.7%) were at least partially attributable to cannabis. Compared clinical presentations by route of exposure.","limitations":"Single academic center in Colorado. Self-reported exposure data. Limited dose information available. Cannot determine whether edible users consumed more THC or were simply more sensitive to its effects."},{"rthcId":"RTHC-02191","title":"Factors Associated With Marijuana Use Among Treatment-seeking Adult Cigarette Smokers in the Criminal Justice Population.","authors":"Montgomery, LaTrice; Schiavon, Samantha; Cropsey, Karen","year":2019,"journal":"Journal of addiction medicine, 13(2), 147-152","doi":"10.1097/ADM.0000000000000466","pmid":"30394995","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02192","title":"Prevalence and Effects of Cigarette Smoking, Cannabis Consumption, and Co-use in Adults From 15 Countries With Congenital Heart Disease.","authors":"Moons, Philip; Luyckx, Koen; Kovacs, Adrienne H; Holbein, Christina E; Thomet, Corina; Budts, Werner; Enomoto, Junko; Sluman, Maayke A; Yang, Hsiao-Ling; Jackson, Jamie L; Khairy, Paul; Cook, Stephen C; Chidambarathanu, Shanthi; Alday, Luis; Eriksen, Katrine; Dellborg, Mikael; Berghammer, Malin; Johansson, Bengt; Mackie, Andrew S; Menahem, Samuel; Caruana, Maryanne; Veldtman, Gruschen; Soufi, Alexandra; Fernandes, Susan M; White, Kamila; Callus, Edward; Kutty, Shelby; Apers, Silke","year":2019,"journal":"The Canadian journal of cardiology, 35(12), 1842-1850","doi":"10.1016/j.cjca.2019.07.635","pmid":"31813510","tags":["cardiovascular","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis-only use had a negligible effect on physical functioning, mental health, and quality of life. Tobacco-only had a small negative effect. Co-use of both had the most detrimental effects, particularly a moderate negative impact on mental health. Large intercountry variation was observed.","whyItMatters":"Adults with congenital heart disease are a uniquely vulnerable population for substance use effects. Knowing that cannabis alone has negligible cardiovascular impact but co-use with tobacco is harmful can inform clinical counseling.","specificNumbers":"4,028 adults with CHD from 15 countries; men: 14% tobacco, 8% cannabis, 4% both; women: 11% tobacco, 4% cannabis, 1% both. Switzerland highest smoking (24% men); Canada highest cannabis (19% men).","methodology":"Cross-sectional APPROACH-IS study of 4,028 adults with CHD from 15 countries, using validated questionnaires with propensity-weighted doubly robust estimation to balance groups.","limitations":"Cross-sectional design. Self-reported substance use. Cannot assess acute cardiovascular events. Propensity weighting cannot fully eliminate confounding. Variable legal status of cannabis across 15 countries affects reporting."},{"rthcId":"RTHC-02193","title":"Antitumor Cannabinoid Chemotypes: Structural Insights.","authors":"Morales, Paula; Jagerovic, Nadine","year":2019,"journal":"Frontiers in pharmacology, 10, 621","doi":"10.3389/fphar.2019.00621","pmid":"31214034","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02194","title":"A Population-Based Analysis of the Relationship Between Substance Use and Adolescent Cognitive Development.","authors":"Morin, Jean-François G; Afzali, Mohammad H; Bourque, Josiane; Stewart, Sherry H; Séguin, Jean R; O'Leary-Barrett, Maeve; Conrod, Patricia J","year":2019,"journal":"The American journal of psychiatry, 176(2), 98-106","doi":"10.1176/appi.ajp.2018.18020202","pmid":"30278790","tags":["youth","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis showed lagged (neurotoxic) effects on inhibitory control and working memory, and concurrent effects on delayed memory recall and perceptual reasoning. These effects were independent of alcohol use. Alcohol showed vulnerability effects but no evidence of lasting (lagged) cognitive impact. Some evidence of developmental sensitivity was found for cannabis effects.","whyItMatters":"Published in the American Journal of Psychiatry, this study separates four theoretical models of how substances affect cognition and finds that cannabis uniquely shows the neurotoxicity pattern (lasting effects from prior use), while alcohol does not.","specificNumbers":"3,826 students from 31 schools; 4 annual assessments; 4 cognitive domains tested; cannabis showed significant lagged effects on inhibitory control and working memory; cannabis effects independent of alcohol effects.","methodology":"Population-based longitudinal study of 3,826 seventh-graders from 31 schools in Greater Montreal, assessed annually for 4 years on substance use and four cognitive domains using computerized testing. Multilevel regression models tested vulnerability, concurrent, and lagged effects.","limitations":"Self-reported substance use. Cannabis potency not assessed. Four-year follow-up may not capture long-term recovery. Greater Montreal population may not generalize globally. Computerized cognitive testing may miss real-world functional impairment."},{"rthcId":"RTHC-02195","title":"A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects.","authors":"Morrison, Gilmour; Crockett, Julie; Blakey, Graham; Sommerville, Kenneth","year":2019,"journal":"Clinical pharmacology in drug development, 8(8), 1009-1031","doi":"10.1002/cpdd.665","pmid":"30791225","tags":["cbd","epilepsy","drug-interactions"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"CBD increased N-desmethylclobazam (active clobazam metabolite) 3.4-fold for both Cmax and AUC. Stiripentol exposure increased modestly (Cmax 1.3-fold, AUC 1.6-fold). No clinically relevant effect on valproate. Clobazam increased 7-OH-CBD levels 1.5-1.7-fold. Stiripentol slightly decreased CBD metabolite levels. CBD was moderately well tolerated with all three AEDs.","whyItMatters":"These three AEDs are among the most commonly co-prescribed with CBD for Lennox-Gastaut and Dravet syndromes. Knowing that CBD triples the active clobazam metabolite is clinically actionable: clobazam doses may need reduction when adding CBD.","specificNumbers":"N-desmethylclobazam: Cmax and AUC 3.4-fold increase. Clobazam: 1.2-fold increase. Stiripentol: Cmax 1.3-fold, AUC 1.6-fold. Valproate: no relevant change. 7-OH-CBD with clobazam: Cmax 1.7-fold, AUC 1.5-fold.","methodology":"Phase 1, open-label, fixed-sequence drug-drug interaction study in healthy volunteers, examining bidirectional pharmacokinetic interactions between pharmaceutical CBD (Epidiolex) and clobazam, stiripentol, and valproate at steady state.","limitations":"Healthy volunteers, not epilepsy patients. Single-dose escalation design. Cannot assess whether interactions change with chronic dosing or in patients with hepatic impairment."},{"rthcId":"RTHC-02196","title":"Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting.","authors":"Mortimer, Toni Leigh; Mabin, Tom; Engelbrecht, Anna-Mart","year":2019,"journal":"Future oncology (London, England), 15(9), 1035-1049","doi":"10.2217/fon-2018-0530","pmid":"30720344","tags":["medical-cannabis","cancer","cbd","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids reduce CINV primarily by inhibiting serotonin release from enterochromaffin cells in the small intestine, disrupting the vomiting reflex. While THC is well-studied for this indication, CBD may offer comparable antiemetic effects without psychoactive properties, plus additional benefits for pain and appetite.","whyItMatters":"CINV remains one of the most debilitating chemotherapy side effects. CBD's potential as a non-psychoactive antiemetic could expand cannabinoid medicine to patients who cannot tolerate THC's cognitive effects.","specificNumbers":"The review covers multiple mechanisms of action including serotonin inhibition, along with secondary benefits for organ toxicity, pain, and appetite loss during chemotherapy.","methodology":"Narrative review of preclinical and clinical studies on cannabinoid use for CINV, with emphasis on CBD's mechanisms and its potential advantages over THC-based preparations.","limitations":"Much of the CBD-specific evidence for CINV is preclinical. Clinical trial data on CBD alone for nausea is limited. Optimal dosing and formulation for antiemetic CBD use have not been established."},{"rthcId":"RTHC-02197","title":"Memory deficits induced by chronic cannabinoid exposure are prevented by adenosine A2AR receptor antagonism.","authors":"Mouro, Francisco M; Köfalvi, Attila; André, Luís A; Baqi, Younis; Müller, Christa E; Ribeiro, Joaquim A; Sebastião, Ana M","year":2019,"journal":"Neuropharmacology, 155, 10-21","doi":"10.1016/j.neuropharm.2019.05.003","pmid":"31103616","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic istradefylline (3 mg/kg/28 days) reversed memory deficits (Novel Object Recognition Test) caused by chronic WIN 55,212-2 (1 mg/kg/28 days). In hippocampal slices, the A2A antagonist partially rescued cannabinoid-impaired long-term potentiation. Neither chronic treatment affected A2A or CB1 receptor binding in hippocampus or prefrontal cortex.","whyItMatters":"Patients on long-term cannabinoid therapies (e.g., for epilepsy, pain, spasticity) may experience cognitive side effects. If A2A antagonists can reverse these without affecting cannabinoid therapeutic efficacy, they could be valuable co-treatments.","specificNumbers":"Istradefylline 3 mg/kg/day for 28 days reversed memory deficits. WIN 55,212-2 300 nM impaired hippocampal LTP. SCH 58261 100 nM partially rescued LTP. No changes in A2A or CB1 receptor binding after chronic treatment.","methodology":"Chronic 28-day treatment in rats with behavioral memory testing (NORT), electrophysiological hippocampal recordings (LTP), and receptor binding assays for A2A and CB1 receptors in hippocampus and PFC.","limitations":"Rat model using a synthetic cannabinoid (WIN 55,212-2), not THC or CBD. LTP rescue was partial, not complete. Behavioral assessment limited to object recognition. 28-day treatment may not predict longer-term outcomes."},{"rthcId":"RTHC-02198","title":"Brain activation to cannabis- and alcohol-related words in alcohol use disorder.","authors":"Müller-Oehring, Eva M; Le Berre, Anne-Pascale; Serventi, Matthew; Kalon, Ember; Haas, Amie L; Padula, Claudia B; Schulte, Tilman","year":2019,"journal":"Psychiatry research. Neuroimaging, 294, 111005","doi":"10.1016/j.pscychresns.2019.111005","pmid":"31715379","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02199","title":"Single and combined effects of plant-derived and synthetic cannabinoids on cognition and cannabinoid-associated withdrawal signs in mice.","authors":"Myers, Alyssa M; Siegele, Patrick B; Foss, Jeffrey D; Tuma, Ronald F; Ward, Sara Jane","year":2019,"journal":"British journal of pharmacology, 176(10), 1552-1567","doi":"10.1111/bph.14147","pmid":"29338068","tags":["cbd","cognition","withdrawal","anxiety"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"THC caused significant motor and cognitive impairment in Barnes maze; adding CBD did not attenuate these effects. Chronic THC caused CB1-mediated withdrawal signs; adding CBD did not reduce withdrawal. CBD alone did not impair cognition, did not cause CB1-dependent withdrawal, and produced anxiolytic effects that persisted even when attempting to precipitate withdrawal.","whyItMatters":"The popular belief that CBD counteracts THC's negative effects was not supported in this comprehensive animal study. However, CBD's standalone safety profile (no cognitive impairment, no dependence, anxiolytic) supports its therapeutic use as a monotherapy.","specificNumbers":"THC caused significant Barnes maze impairment; CBD addition did not attenuate. Chronic THC withdrawal precipitated by SR141716; CBD addition did not reduce. CBD alone: no cognitive impairment, no CB1-dependent withdrawal, significant anxiolysis.","methodology":"Multiple dose combinations of THC, CBD, and WIN55212 tested in C57BL/6 mice. Cognition assessed via conditional discrimination and Barnes maze. Withdrawal precipitated with SR141716 (CB1 antagonist), WAY100635 (5-HT1A), capsazepine (TRPV1), and SCH58261 (A2A).","limitations":"Mouse model; CBD-THC interactions may differ in humans. Specific dose ratios tested may not reflect real-world cannabis use. CBD's anxiolytic mechanism (not CB1-mediated) warrants further exploration."},{"rthcId":"RTHC-02200","title":"Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications.","authors":"Nagappan, Arulkumar; Shin, Jooyeon; Jung, Myeong Ho","year":2019,"journal":"International journal of molecular sciences, 20(9)","doi":"10.3390/ijms20092109","pmid":"31035653","tags":["appetite","neuroscience","cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CB1 receptor activation in the liver promotes insulin resistance via increased energy intake/storage, impaired glucose and lipid metabolism, enhanced oxidative stress, and inflammatory responses. Peripheral CB1 blockade improved insulin sensitivity, glucose metabolism, reduced hepatic steatosis and body weight in obese mice. Central CB1 antagonists were suspended due to psychiatric adverse effects.","whyItMatters":"With the failure of rimonabant, the field needs alternative approaches. This review maps exactly how CB1 drives metabolic disease and points to peripheral-only CB1 blockade as a viable path forward.","specificNumbers":"Peripheral CB1 blockade improved insulin sensitivity, reduced hepatic steatosis and body weight in obese mice. Central CB1 antagonists caused psychiatric adverse effects leading to market withdrawal.","methodology":"Comprehensive review of CB1 receptor role in hepatic insulin resistance, covering molecular mechanisms, animal models, and therapeutic strategies including peripheral-only CB1 antagonists.","limitations":"Review draws heavily on animal data. Peripheral CB1 antagonists have not yet been validated in large human trials. The distinction between central and peripheral effects may not be absolute at therapeutic doses."},{"rthcId":"RTHC-02201","title":"Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity.","authors":"Namdar, Dvora; Voet, Hillary; Ajjampura, Vinayaka; Nadarajan, Stalin; Mayzlish-Gati, Einav; Mazuz, Moran; Shalev, Nurit; Koltai, Hinanit","year":2019,"journal":"Molecules (Basel, Switzerland), 24(17)","doi":"10.3390/molecules24173031","pmid":"31438532","tags":["cancer","medical-cannabis","potency"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Specific terpenoid groups were statistically associated with THC-rich or CBD-rich strains. Only terpenoids naturally co-occurring with a cannabinoid in the same strain enhanced its cytotoxic activity against breast and colon cancer cell lines. This effect was most potent when terpenoids were present in the natural ratios found in cannabis flower.","whyItMatters":"This provides some of the first scientific evidence for strain-specific entourage effects. It suggests that cannabis breeding has inadvertently selected for cannabinoid-terpenoid combinations that work together, and that mixing terpenoids randomly may not achieve the same synergy.","specificNumbers":"17 cannabis strains profiled. Terpenoid-cannabinoid correlations identified statistically. Natural ratio combinations were most effective for cytotoxicity on MDA-MB-231 and HCT-116 cell lines.","methodology":"Analytical profiling (HPLC, GC/MS) of secondary metabolites in 17 cannabis strains. Column separation of compounds. Cell viability assays on MDA-MB-231 (breast cancer) and HCT-116 (colon cancer) cell lines with various cannabinoid-terpenoid combinations.","limitations":"In vitro cell line study only. Anti-cancer activity in a dish does not predict clinical efficacy. The mechanism of terpenoid-cannabinoid synergy was not identified. Limited to two cancer cell lines."},{"rthcId":"RTHC-02202","title":"Substances as Self-Treatment for Cognitive Test Anxiety among Undergraduate Students.","authors":"Ne'Eman-Haviv, Vered; Bonny-Noach, Hagit","year":2019,"journal":"Journal of psychoactive drugs, 51(1), 78-84","doi":"10.1080/02791072.2018.1564090","pmid":"30657440","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02203","title":"EXTENDED ATTENUATION OF CORTICOSTRIATAL POWER AND COHERENCE AFTER ACUTE EXPOSURE TO VAPOURIZED Δ9 TETRAHYDROCANNABINOL IN RATS.","authors":"Nelong, Tapia Foute; Jenkins, Bryan W; Perreault, Melissa L; Khokhar, Jibran Y","year":2019,"journal":"The Canadian journal of addiction, 10(3), 60-66","doi":"10.1097/cxa.0000000000000063","pmid":"32944610","tags":["neuroscience","cognition","psychosis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Vaporized THC suppressed gamma power (>32-100 Hz) in the dorsal striatum, orbitofrontal cortex, and prefrontal cortex of rats, with most changes still present a week after a single exposure.","whyItMatters":"Gamma oscillations play a key role in cognition, and reduced gamma activity is a hallmark of schizophrenia. This study shows that even one session of vaporized THC can produce lasting changes in these brain rhythms.","specificNumbers":"Gamma suppression was observed in the >32-100 Hz range across the dorsal striatum, orbitofrontal cortex, and prefrontal cortex. Effects persisted at least 7 days after a single exposure.","methodology":"Rats were implanted with electrode arrays in three brain regions. They received vaporized THC or vehicle via a Volcano vaporizer in a crossover design with a one-week washout period, and local field potentials were recorded.","limitations":"This was a rat study, so direct translation to humans is uncertain. The sample size was not reported in the abstract, and only a single dose was tested."},{"rthcId":"RTHC-02204","title":"Overcoming the Psychiatric Side Effects of the Cannabinoid CB1 Receptor Antagonists: Current Approaches for Therapeutics Development.","authors":"Nguyen, Thuy; Thomas, Brian F; Zhang, Yanan","year":2019,"journal":"Current topics in medicinal chemistry, 19(16), 1418-1435","doi":"10.2174/1568026619666190708164841","pmid":"31284863","tags":["addiction","appetite","drug-interactions","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Rimonabant demonstrated effectiveness for treating obesity and smoking cessation but was withdrawn from the European market due to psychiatric side effects. Researchers are now pursuing neutral antagonists, peripherally restricted ligands, and allosteric modulators to avoid these risks.","whyItMatters":"The CB1 receptor remains one of the most promising drug targets for obesity and addiction, but the failure of rimonabant showed that blocking it in the brain carries serious mental health risks. New approaches could unlock the therapeutic potential without the danger.","specificNumbers":"Rimonabant was the first-in-class CB1R antagonist. It was withdrawn from the European market after reports of anxiety, depression, and suicidal ideation.","methodology":"Narrative review of two decades of research on CB1 receptor-targeted therapeutics, covering animal and human studies of various drug development strategies.","limitations":"This is a narrative review, not a systematic review. Some of the newer drug strategies discussed were still in preclinical stages at the time of writing."},{"rthcId":"RTHC-02205","title":"The Role of Mass Spectrometry in the Cannabis Industry.","authors":"Nie, Ben; Henion, Jack; Ryona, Imelda","year":2019,"journal":"Journal of the American Society for Mass Spectrometry, 30(5), 719-730","doi":"10.1007/s13361-019-02164-z","pmid":"30993637","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02206","title":"Cannabinoid Hyperemesis Syndrome: Reports of Fatal Cases.","authors":"Nourbakhsh, Mahra; Miller, Angela; Gofton, Jeff; Jones, Graham; Adeagbo, Bamidele","year":2019,"journal":"Journal of forensic sciences, 64(1), 270-274","doi":"10.1111/1556-4029.13819","pmid":"29768651","tags":["harm-reduction","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 27-year-old female, 27-year-old male, and 31-year-old male with histories of cyclical nausea, vomiting, chronic cannabis use, and negative workups all died. CHS was determined to be the cause of death in two cases and a contributing factor in the third.","whyItMatters":"CHS is often dismissed as uncomfortable but not dangerous. These cases demonstrate that in rare circumstances, CHS can be fatal, underscoring the importance of recognizing it early in emergency settings.","specificNumbers":"3 deaths reported. All decedents were ages 27-31. All had postmortem blood positive for THC. CHS was the attributed cause of death in 2 of 3 cases.","methodology":"Case report of three forensic cases, including clinical history, postmortem toxicology revealing THC in blood, and autopsy findings.","limitations":"Case reports cannot establish prevalence or risk factors. Only three cases were described, and the exact mechanism of death in CHS remains unclear."},{"rthcId":"RTHC-02207","title":"The Surprising Reach of FDA Regulation of Cannabis, Even After Descheduling.","authors":"O'Connor, Sean M; Lietzan, Erika","year":2019,"journal":"The American University law review, 68(3), 823-925","doi":null,"pmid":"30919712","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02208","title":"Parental Cannabis Use Is Associated with Cannabis Initiation and Use in Offspring.","authors":"O'Loughlin, Jennifer L; Dugas, Erika N; O'Loughlin, Erin K; Winickoff, Jonathan P; Montreuil, Annie; Wellman, Robert J; Sylvestre, Marie-Pierre; Hanusaik, Nancy","year":2019,"journal":"The Journal of pediatrics, 206, 142-147.e1","doi":"10.1016/j.jpeds.2018.10.057","pmid":"30454963","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Grade 6 students whose parents reported past-year cannabis use were 1.8 times more likely to initiate cannabis during high school. In young adults, having one cannabis-using parent roughly doubled the odds of use, and having two cannabis-using parents increased odds 7.1-fold.","whyItMatters":"With cannabis legalization expanding, more parents may be open about their use. These findings suggest parental cannabis use is an independent risk factor for offspring use, regardless of whether mothers or fathers are the users.","specificNumbers":"aOR for cannabis initiation with parental use: 1.8. aOR for adult offspring use with mother using: 2.8 (95% CI 1.4-5.8). Father using: 2.1 (95% CI 1.2-3.8). Two parents using: 7.1.","methodology":"Two longitudinal studies in Montreal: AdoQuest followed 1,048 parent-child pairs from grade 6 through high school; the Nicotine Dependence in Teens study tracked 584 participants and their parents into adulthood (mean age 24). Both used multivariable logistic regression.","limitations":"Observational design cannot prove causation. The studies were conducted in Montreal, which may not generalize to all populations. Parental use was self-reported and could be underestimated."},{"rthcId":"RTHC-02209","title":"The endocannabinoid system is affected by cholesterol dyshomeostasis: Insights from a murine model of Niemann Pick type C disease.","authors":"Oddi, Sergio; Caporali, Paola; Dragotto, Jessica; Totaro, Antonio; Maiolati, Marzia; Scipioni, Lucia; Angelucci, Clotilde Beatrice; Orsini, Cristina; Canterini, Sonia; Rapino, Cinzia; Maccarrone, Mauro; Fiorenza, Maria Teresa","year":2019,"journal":"Neurobiology of disease, 130, 104531","doi":"10.1016/j.nbd.2019.104531","pmid":"31302243","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02210","title":"Distinct effects of cocaine and cocaine + cannabis on neurocognitive functioning and abstinence: A six-month follow-up study.","authors":"Oliveira, Hercílio Pereira de; Gonçalves, Priscila Dib; Ometto, Mariella; Santos, Bernardo Dos; Malbergier, André; Amaral, Ricardo; Nicastri, Sergio; Andrade, Arthur Guerra de; Cunha, Paulo Jannuzzi","year":2019,"journal":"Drug and alcohol dependence, 205, 107642","doi":"10.1016/j.drugalcdep.2019.107642","pmid":"31683245","tags":["cognition","addiction","drug-interactions"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Both cocaine groups performed worse than controls on multiple cognitive measures. The cocaine + cannabis group performed worse than the cocaine-only group on processing speed, inhibitory control, and sustained attention, while the cocaine-only group did worse on mental flexibility. Cannabis use did not reduce cocaine relapse at 1, 3, or 6 months.","whyItMatters":"Some non-controlled studies have suggested smoked cannabis might help cocaine addiction. This study found the opposite: adding cannabis worsened cognitive outcomes without reducing relapse.","specificNumbers":"63 cocaine + cannabis users, 24 cocaine-only users, 36 controls. Follow-up at 1, 3, and 6 months. Cannabis did not decrease relapse rates at any time point.","methodology":"Compared 63 cocaine users with heavy cannabis use, 24 cocaine users with minimal cannabis use, and 36 controls. Neurocognitive testing occurred after two weeks of supervised detoxification, with relapse follow-up at 1, 3, and 6 months.","limitations":"The cocaine + cannabis group was larger than the cocaine-only group, which may affect statistical power. Cannabis use was defined by a lifetime threshold (50 uses), not current frequency. This was not a randomized trial."},{"rthcId":"RTHC-02211","title":"Impact of tobacco, alcohol and cannabis use on treatment outcomes among patients experiencing first episode psychosis: Data from the national RAISE-ETP study.","authors":"Oluwoye, Oladunni; Monroe-DeVita, Maria; Burduli, Ekaterina; Chwastiak, Lydia; McPherson, Sterling; McClellan, Jon M; McDonell, Michael G","year":2019,"journal":"Early intervention in psychiatry, 13(1), 142-146","doi":"10.1111/eip.12542","pmid":"29356438","tags":["psychosis","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"At baseline, 50% of first-episode psychosis patients smoked tobacco, 28% used alcohol, and 24% used cannabis. Over 24 months, tobacco smokers had higher illness severity, missed more antipsychotic pills, and had worse psychiatric symptoms. Cannabis users had higher illness severity and more positive symptoms.","whyItMatters":"Substance use is extremely common in people experiencing their first psychotic episode. This study shows each substance carries its own pattern of harm, with tobacco being the most broadly damaging to treatment outcomes.","specificNumbers":"404 participants. 50% (n=209) smoked tobacco, 28% (n=113) used alcohol, 24% (n=95) used cannabis. Cannabis users had higher illness severity (beta=0.18, p<.05) and more positive symptoms (beta=1.56, p<.05).","methodology":"Secondary analysis of 404 participants in the RAISE-ETP study, which tested coordinated specialty care for first-episode psychosis across community mental health agencies in the US. Used generalized estimating equations over 24 months.","limitations":"Observational design; substance use was self-reported at baseline only and may have changed during the study. Cannot determine whether substance use caused worse outcomes or if sicker patients were more likely to use."},{"rthcId":"RTHC-02212","title":"Use of medicinal cannabis and synthetic cannabinoids in post-traumatic stress disorder (PTSD): A systematic review","authors":"Orsolini, Laura; Chiappini, Stefania; Volpe, Umberto; De Berardis, Domenico; Latini, Roberto; Papanti, Gabriele Duccio; Corkery, John Martin","year":2019,"journal":"Medicina (Kaunas), 55(9), 525","doi":"10.3390/medicina55090525","pmid":"31450833","tags":["ptsd","medical-cannabis","synthetic-cannabinoids","anxiety","sleep"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This systematic review gathered everything published through May 2019 on cannabis and synthetic cannabinoids for PTSD. The interest was clearly growing: patients were increasingly turning to cannabis, and several U.S. states listed PTSD as a qualifying condition for medical marijuana.\n\nThe most consistent finding across studies was nabilone's effectiveness for PTSD-related nightmares and sleep disturbance. Several studies reported significant reductions in nightmare frequency and severity. For broader PTSD symptoms — hyperarousal, avoidance, re-experiencing — the results were more mixed. Some observational studies showed symptom improvement, but the methodological quality was generally low.\n\nThe reviewers found that most available evidence came from case reports, case series, and open-label studies rather than randomized controlled trials. The gap between patient demand and scientific evidence remained wide.","whyItMatters":"By 2019, cannabis for PTSD had become one of the most politically charged topics in medical marijuana debates. Veterans' groups advocated strongly for access. States were adding PTSD to qualifying conditions. But this review showed the evidence base hadn't kept pace with the policy. The strongest signal — nabilone for nightmares — was specific and replicable, but the broader claim that cannabis treats PTSD remained unsupported by rigorous evidence.\n\nThat doesn't mean cannabis doesn't help. It means the research hadn't been done properly enough to say either way with confidence.","specificNumbers":"• Nabilone: most consistent evidence, particularly for nightmare reduction\n• Most evidence from case reports, case series, and open-label studies\n• Searched through May 2019 across three databases\n• PTSD is a qualifying condition for medical cannabis in multiple U.S. states","methodology":"Systematic review following PRISMA guidelines. Searched PubMed, Cochrane Library, and Web of Science through May 2019. Included all study types reporting on cannabis or synthetic cannabinoids for PTSD treatment. Organized results by substance type (plant-based cannabis vs synthetic cannabinoids).","limitations":"Most included studies were low quality (case reports, case series, open-label designs). Publication bias likely favored positive results. Cannabis products varied widely across studies in type, dose, and route. Cannot distinguish between symptom improvement and general anxiolytic effects. Search was limited to three databases."},{"rthcId":"RTHC-02213","title":"Cannabidiol improves behavioural and neurochemical deficits in adult female offspring of the maternal immune activation (poly I:C) model of neurodevelopmental disorders.","authors":"Osborne, Ashleigh L; Solowij, Nadia; Babic, Ilijana; Lum, Jeremy S; Huang, Xu-Feng; Newell, Kelly A; Weston-Green, Katrina","year":2019,"journal":"Brain, behavior, and immunity, 81, 574-587","doi":"10.1016/j.bbi.2019.07.018","pmid":"31326506","tags":["cbd","psychosis","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Three weeks of CBD treatment (10 mg/kg) restored recognition memory and social interaction in female poly I:C offspring. CBD also normalized NMDA receptor binding in the prefrontal cortex and increased GABA-related markers in the hippocampus. However, CBD reduced social behavior in healthy control rats.","whyItMatters":"Most schizophrenia research uses male animals. This study specifically tested CBD in female offspring, addressing a significant gap given that sex differences exist in schizophrenia onset and treatment response.","specificNumbers":"CBD dose: 10 mg/kg daily for ~3 weeks. 16 pregnant rats total. CBD restored recognition memory and sociability in poly I:C offspring but reduced social interaction in control rats.","methodology":"Pregnant rats received poly I:C (immune activation) or saline on gestational day 15. Female offspring received CBD (10 mg/kg, i.p.) or vehicle for three weeks starting at postnatal day 56. Behavioral testing included novel object recognition, T-maze, and social interaction. Brain tissue was analyzed for endocannabinoid, glutamate, and GABA markers.","limitations":"Animal model; results may not translate to humans. Only one CBD dose was tested. The negative effects of CBD on control rats warrant further investigation."},{"rthcId":"RTHC-02214","title":"Associations between driving under the influence or riding with an impaired driver and future substance use among adolescents.","authors":"Osilla, Karen Chan; Seelam, Rachana; Parast, Layla; D'Amico, Elizabeth J","year":2019,"journal":"Traffic injury prevention, 20(6), 563-569","doi":"10.1080/15389588.2019.1615620","pmid":"31356125","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02215","title":"Urinary tetrahydrocannabinol is associated with poorer working memory performance and alterations in associated brain activity.","authors":"Owens, Max M; McNally, Shannon; Petker, Tashia; Amlung, Michael T; Balodis, Iris M; Sweet, Lawrence H; MacKillop, James","year":2019,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 44(3), 613-619","doi":"10.1038/s41386-018-0240-4","pmid":"30644440","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"A positive urine THC screen was associated with worse working memory and differential brain response during an N-back task. Decreased BOLD signal in task-positive regions and increased signal in task-negative regions mediated the THC-working memory relationship. Lifetime cannabis use, age of first use, and other history measures showed no association.","whyItMatters":"This large-sample study distinguishes between current and historical cannabis effects on cognition. The finding that only active THC presence (not lifetime history) predicted impairment suggests effects are short-term and residual rather than permanent.","specificNumbers":"N = 1,038 participants. THC+ status predicted worse working memory. Lifetime use, age of first use, and other historical measures showed no association with performance or brain activity.","methodology":"Cross-sectional analysis of 1,038 participants from the Human Connectome Project. Multiple cannabis involvement indicators were examined against behavioral performance and fMRI brain activity during a visual N-back working memory task.","limitations":"Cross-sectional design cannot determine causation. Urine THC reflects recent use but not exact timing or dose. The study did not distinguish between frequent and occasional recent users."},{"rthcId":"RTHC-02216","title":"Developing a phone-based measure of impairment after acute oral ∆9-tetrahydrocannabinol.","authors":"Pabon, Elisa; de Wit, Harriet","year":2019,"journal":"Journal of psychopharmacology (Oxford, England), 33(9), 1160-1169","doi":"10.1177/0269881119862533","pmid":"31407943","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Across two double-blind studies with oral THC (7.5 and 15 mg), standard computer tasks detected impairment in cognitive speed, reaction time, and working memory. However, most brief phone-based versions of the same tasks did not detect THC-induced impairment.","whyItMatters":"Unlike alcohol breathalyzers, there is no reliable quick test for cannabis impairment. This study shows how difficult it is to compress cognitive testing into a brief, phone-friendly format sensitive enough to detect THC effects.","specificNumbers":"Two studies, n=24 each. THC doses: 7.5 mg and 15 mg oral. Computer tasks detected impairment; most phone tasks did not.","methodology":"Two double-blind, within-subjects studies (n=24 each) with healthy non-daily cannabis users. Participants received oral THC capsules (0, 7.5, 15 mg) in three sessions. At peak drug effect, they completed both standard computer-based cognitive tasks and brief phone-based tasks measuring speed, reaction time, fine motor ability, working memory, and time perception.","limitations":"Small sample sizes (24 per study). Only oral THC was tested; smoked or vaped cannabis may produce different impairment patterns. The phone tasks were prototypes, not a fully developed app."},{"rthcId":"RTHC-02217","title":"Endogenous and synthetic cannabinoids induce the downregulation of cannabinoid CB1 receptor in retina.","authors":"Papadogkonaki, Sofia; Theodorakis, Κostas; Thermos, Kyriaki","year":2019,"journal":"Experimental eye research, 185, 107694","doi":"10.1016/j.exer.2019.107694","pmid":"31199905","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02218","title":"Cannabis use correlates with aggressive behavior and long-acting injectable antipsychotic treatment in Asian patients with schizophrenia.","authors":"Park, Seon-Cheol; Oh, Hong Seok; Tripathi, Adarsh; Kallivayalil, Roy Abraham; Avasthi, Ajit; Grover, Sandeep; Tanra, Andi Jayalangkara; Kanba, Shigenobu; Kato, Takahiro A; Inada, Toshiya; Chee, Kok Yoon; Chong, Mian-Yoon; Lin, Shih-Ku; Sim, Kang; Xiang, Yu-Tao; Tan, Chay Hoon; Javed, Afzal; Sartorius, Norman; Shinfuku, Naotaka; Park, Yong Chon","year":2019,"journal":"Nordic journal of psychiatry, 73(6), 323-330","doi":"10.1080/08039488.2019.1632381","pmid":"31240984","tags":["psychosis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"After adjusting for multiple variables, lifetime cannabis use in Asian schizophrenia patients was independently associated with aggressive behavior (aOR 1.58, 95% CI 1.01-2.49) and with long-acting injectable antipsychotic treatment (aOR 1.80, 95% CI 1.44-2.82).","whyItMatters":"Most cannabis-psychosis research comes from Western populations. This large multi-country Asian dataset provides evidence that the cannabis-aggression link in schizophrenia extends across cultural contexts.","specificNumbers":"132 cannabis users vs. 1,756 non-users. Aggressive behavior aOR: 1.58 (95% CI 1.01-2.49, p=.047). Long-acting injectable antipsychotic use aOR: 1.80 (95% CI 1.44-2.82, p=.001).","methodology":"Cross-sectional analysis of the REAP-AP consortium survey, which collected psychotropic prescription patterns from Asian schizophrenia patients. Compared 132 lifetime cannabis users with 1,756 non-users using binary logistic regression, adjusting for age, sex, region, income, duration of untreated psychosis, and comorbidity.","limitations":"Cross-sectional design cannot establish causation. Cannabis use was based on lifetime self-report. The cannabis-using group was much smaller than the non-using group. Cultural factors around cannabis use in Asia may limit generalizability."},{"rthcId":"RTHC-02219","title":"Emerging Role of Aprepitant in Cannabis Hyperemesis Syndrome.","authors":"Parvataneni, Swetha; Varela, Lionel; Vemuri-Reddy, Sireesha M; Maneval, Mandy L","year":2019,"journal":"Cureus, 11(6), e4825","doi":"10.7759/cureus.4825","pmid":"31403013","tags":["harm-reduction","medical-cannabis","drug-interactions"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with CHS who did not respond to common anti-emetics was successfully treated with aprepitant, an NK1 receptor antagonist typically used for chemotherapy-induced nausea.","whyItMatters":"CHS can be extremely difficult to treat, and standard anti-emetics often fail. This case suggests aprepitant may be a useful option when other treatments are ineffective.","specificNumbers":"1 patient described. Aprepitant succeeded after all other common anti-emetics failed.","methodology":"Single case report documenting clinical course and treatment response.","limitations":"Single case report; effectiveness in one patient does not guarantee it will work for others. No control comparison or dosing optimization was performed."},{"rthcId":"RTHC-02220","title":"Cannabis and Male Fertility: A Systematic Review.","authors":"Payne, Kelly S; Mazur, Daniel J; Hotaling, James M; Pastuszak, Alexander W","year":2019,"journal":"The Journal of urology, 202(4), 674-681","doi":"10.1097/JU.0000000000000248","pmid":"30916627","tags":["sex-differences","medical-cannabis","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabis was associated with reduced sperm count and concentration, abnormal morphology, reduced motility and viability, and inhibited capacitation and fertilizing capacity. Animal models showed testicular atrophy and reduced libido, but these have not been replicated in humans. Effects on testosterone were inconclusive.","whyItMatters":"Cannabis use is prominent among males of reproductive age, and many users may be unaware of potential fertility effects. This consolidation of evidence provides a clearer picture of what is and is not established.","specificNumbers":"Cannabis associated with reduced sperm count and concentration, abnormal morphology, reduced motility and viability. Luteinizing hormone levels were lowered. Follicle-stimulating hormone unchanged. Testosterone effects inconclusive.","methodology":"Systematic review of PubMed/MEDLINE literature examining cannabis effects on male fertility, covering human and animal studies.","limitations":"Many findings are from animal studies that have not been replicated in humans. Human studies varied in design and cannabis exposure measures. The review did not conduct a meta-analysis."},{"rthcId":"RTHC-02221","title":"Cannabis and Psychosis Through the Lens of DSM-5.","authors":"Pearson, Nathan T; Berry, James H","year":2019,"journal":"International journal of environmental research and public health, 16(21)","doi":"10.3390/ijerph16214149","pmid":"31661851","tags":["psychosis","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis intoxication can produce transient psychotic symptoms. When symptoms meet severity and duration thresholds, the diagnosis becomes cannabis-induced psychotic disorder, which in turn is heavily associated with future schizophrenia diagnoses. The review organizes diverse evidence into this clinical framework.","whyItMatters":"The cannabis-psychosis literature is overwhelming and fragmented. Organizing it by DSM-5 diagnoses helps clinicians understand where on the spectrum a given patient falls and what that might mean for prognosis.","specificNumbers":"Cannabis-induced psychotic disorder is \"heavily associated\" with future schizophrenia diagnoses. The exact conversion rates varied across cited studies.","methodology":"Narrative review examining experimental studies, epidemiological data, and case series, organized by DSM-5 diagnostic categories.","limitations":"Narrative review, not systematic. The DSM-5 framework, while useful, may oversimplify the heterogeneity of psychotic experiences related to cannabis."},{"rthcId":"RTHC-02222","title":"Cannabis and amphetamine use and socio-ecological (proximal and distal) factors among school-going adolescents in four countries in the Caribbean and four countries in South America.","authors":"Peltzer, Karl; Pengpid, Supa","year":2019,"journal":"International journal of adolescent medicine and health, 33(1)","doi":"10.1515/ijamh-2018-0030","pmid":"30973823","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02223","title":"Cannabinoids and Mental Health, Part 1: The Endocannabinoid System and Exogenous Cannabinoids.","authors":"Penn, Andrew","year":2019,"journal":"Journal of psychosocial nursing and mental health services, 57(9), 7-10","doi":"10.3928/02793695-20190813-01","pmid":"31461513","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02224","title":"Ventral hippocampal overexpression of Cannabinoid Receptor Interacting Protein 1 (CNRIP1) produces a schizophrenia-like phenotype in the rat.","authors":"Perez, Stephanie M; Donegan, Jennifer J; Boley, Angela M; Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J","year":2019,"journal":"Schizophrenia research, 206, 263-270","doi":"10.1016/j.schres.2018.11.006","pmid":"30522798","tags":["psychosis","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Viral-mediated overexpression of CNRIP1 in the ventral hippocampus caused impairments in latent inhibition and social interaction (behavioral correlates of schizophrenia) and increased dopamine neuron population activity in the ventral tegmental area, a putative marker of psychosis.","whyItMatters":"Previous studies found abnormal CNRIP1 DNA methylation in postmortem brains of people with schizophrenia. This study shows that simply overexpressing this cannabinoid-regulating protein is enough to produce schizophrenia-like changes in rats.","specificNumbers":"CNRIP1 overexpression impaired latent inhibition and social interaction. VTA dopamine neuron population activity was significantly increased.","methodology":"Sprague Dawley rats received viral-mediated CNRIP1 overexpression in the ventral hippocampus. They were tested for latent inhibition, social interaction, and VTA dopamine neuron activity via electrophysiology.","limitations":"Animal model; behavioral correlates in rats are imperfect proxies for human schizophrenia symptoms. Only one brain region (ventral hippocampus) was targeted."},{"rthcId":"RTHC-02225","title":"Cannabinoid Hyperemesis.","authors":"Pergolizzi, Joseph V; LeQuang, Jo Ann; Bisney, John F","year":2019,"journal":"Medical cannabis and cannabinoids, 1(2), 73-95","doi":"10.1159/000494992","pmid":"34676325","tags":["harm-reduction","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS presents as cyclical episodes of severe nausea and vomiting in long-term cannabis users, separated by asymptomatic periods. Unlike other cyclic vomiting syndromes, it responds to hot showers and topical capsaicin. Abstinence from cannabinoids causes resolution, sometimes within hours.","whyItMatters":"Many clinicians and cannabis users are unaware of CHS. Patients often undergo unnecessary tests and procedures before receiving a correct diagnosis. With increasing cannabis legalization, CHS is expected to become more common.","specificNumbers":"Symptoms may require hospitalization. Resolution can occur within hours to days of cannabis cessation.","methodology":"Narrative review of clinical literature on CHS, covering diagnosis, pathophysiology, symptom management, and clinical implications.","limitations":"Narrative review without systematic methodology. The exact mechanism of CHS remains unknown."},{"rthcId":"RTHC-02226","title":"Characteristics of a Multistate Outbreak of Lung Injury Associated with E-cigarette Use, or Vaping - United States, 2019.","authors":"Perrine, Cria G; Pickens, Cassandra M; Boehmer, Tegan K; King, Brian A; Jones, Christopher M; DeSisto, Carla L; Duca, Lindsey M; Lekiachvili, Akaki; Kenemer, Brandon; Shamout, Mays; Landen, Michael G; Lynfield, Ruth; Ghinai, Isaac; Heinzerling, Amy; Lewis, Nathaniel; Pray, Ian W; Tanz, Lauren J; Patel, Anita; Briss, Peter A","year":2019,"journal":"MMWR. Morbidity and mortality weekly report, 68(39), 860-864","doi":"10.15585/mmwr.mm6839e1","pmid":"31581168","tags":["respiratory","harm-reduction","youth"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"As of September 2019, 805 cases of vaping-associated lung injury were reported. Among 514 patients with substance data, 76.9% used THC-containing products, 56.8% used nicotine products, 36.0% used THC exclusively, and 16.0% used nicotine exclusively. The median patient age was 23, and 69% were male.","whyItMatters":"This was a landmark public health emergency that changed how regulators, clinicians, and consumers think about vaping safety. The strong association with THC products highlighted the risks of unregulated cannabis vaping cartridges.","specificNumbers":"805 cases across 46 states. 12 deaths in 10 states. Median age: 23 years. Range: 13-72 years. 69% male. 76.9% used THC products. 36% used THC exclusively.","methodology":"CDC-coordinated multistate surveillance investigation using case reports from 46 state health departments and one territory as of September 24, 2019.","limitations":"Data were collected early in the outbreak (September 2019) and the specific chemical cause had not yet been identified at time of publication. Substance use was self-reported. The investigation was ongoing."},{"rthcId":"RTHC-02227","title":"Schizophrenia is associated with increased risk of subsequent substance abuse diagnosis: A nation-wide population-based register study.","authors":"Petersen, Stine Mai; Toftdahl, Nanna Gilliam; Nordentoft, Merete; Hjorthøj, Carsten","year":2019,"journal":"Addiction (Abingdon, England), 114(12), 2217-2226","doi":"10.1111/add.14746","pmid":"31301685","tags":["psychosis","addiction"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Among 3.1 million individuals followed for over 100 million person-years, 14,007 developed schizophrenia, and 2,885 were subsequently diagnosed with substance abuse. Schizophrenia was associated with increased risk of cannabis abuse (aHR 2.48), alcohol abuse (aHR 1.94), stimulant abuse (aHR 1.77), and other substance abuse (aHR 1.36). The association persisted 10-15 years after schizophrenia diagnosis.","whyItMatters":"Most research focuses on whether cannabis causes psychosis. This study flips the question: it shows that schizophrenia itself is a strong risk factor for developing substance abuse, particularly cannabis abuse. This has implications for treatment and monitoring.","specificNumbers":"Cohort: 3,133,968 individuals. 103,212,328 person-years at risk. 14,007 developed schizophrenia. Overall substance abuse HR: 3.69 (95% CI 3.56-3.83). Cannabis-specific aHR: 2.48 (95% CI 2.34-2.64). Effect persisted 10-15 years (HR 2.50).","methodology":"Prospective cohort study using Danish national registers covering all individuals born 1955-1999, followed from 1968-2013. Cox regression adjusted for calendar year, gender, urbanicity, co-abuse, other psychiatric diagnoses, parental substance abuse and psychiatric history, and socioeconomic position.","limitations":"Observational register data; substance abuse diagnoses may undercount actual substance use. The one-year exclusion window (substance abuse diagnosed within a year of schizophrenia) was chosen to reduce reverse causation but is somewhat arbitrary."},{"rthcId":"RTHC-02228","title":"Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague-Dawley rats.","authors":"Petrie, Gavin N; Wills, Kiri L; Piscitelli, Fabiana; Smoum, Reem; Limebeer, Cheryl L; Rock, Erin M; Humphrey, Ashlyn E; Sheppard-Perkins, Madeleine; Lichtman, Aron H; Mechoulam, Raphael; Di Marzo, Vincenzo; Parker, Linda A","year":2019,"journal":"Psychopharmacology, 236(9), 2623-2633","doi":"10.1007/s00213-019-05237-9","pmid":"30993360","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02229","title":"Insights into the role of cannabis in the management of inflammatory bowel disease.","authors":"Picardo, Sherman; Kaplan, Gilaad G; Sharkey, Keith A; Seow, Cynthia H","year":2019,"journal":"Therapeutic advances in gastroenterology, 12, 1756284819870977","doi":"10.1177/1756284819870977","pmid":"31523278","tags":["medical-cannabis","inflammation","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"In animal models, cannabinoids improved intestinal inflammation through the endocannabinoid system. However, the few randomized controlled trials of cannabis or CBD in IBD patients failed to show efficacy for modifying inflammatory disease activity. Cannabis may still be effective for symptomatic management (pain, appetite, nausea).","whyItMatters":"Many IBD patients use cannabis for symptom relief, and cultural acceptance is growing. Clinicians need to understand the gap between promising animal data and disappointing human trial results.","specificNumbers":"Animal models showed improvement in experimental IBD. Few RCTs conducted; none demonstrated efficacy for inflammatory disease activity.","methodology":"Narrative review of preclinical and clinical data on cannabis and cannabinoids in IBD management.","limitations":"Narrative review. Very few RCTs exist to draw from. The distinction between symptomatic relief and disease modification is critical but hard to study."},{"rthcId":"RTHC-02230","title":"Pure delta-9-tetrahydrocannabinol and its combination with cannabidiol in treatment-resistant Tourette syndrome: A case report.","authors":"Pichler, Eva-Maria; Kawohl, Wolfram; Seifritz, Erich; Roser, Patrik","year":2019,"journal":"International journal of psychiatry in medicine, 54(2), 150-156","doi":"10.1177/0091217418791455","pmid":"30058466","tags":["medical-cannabis","cbd"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Standard antipsychotic treatments (risperidone, aripiprazole) and pure delta-9-THC had no significant effect on tics. When the patient received a daily combination of 10 mg THC and 20 mg CBD, there was a rapid and highly significant improvement on the Yale Global Tic Severity Scale.","whyItMatters":"This case suggests that the combination of THC and CBD may be more effective than either alone for Tourette syndrome, and that CBD may be the key therapeutic component.","specificNumbers":"Daily dose: 10 mg THC + 20 mg CBD. Outcome: rapid, highly significant improvement on the Yale Global Tic Severity Scale. Prior treatments (risperidone, aripiprazole, pure THC) all failed.","methodology":"Single case report of a female patient with treatment-resistant Tourette syndrome who sequentially tried multiple treatments.","limitations":"Single case report; results may not generalize. No blinding or placebo control. The sequential nature of treatments makes it hard to rule out time-related or placebo effects."},{"rthcId":"RTHC-02231","title":"Purified Cannabidiol for Treatment of Refractory Epilepsies in Pediatric Patients with Developmental and Epileptic Encephalopathy.","authors":"Pietrafusa, Nicola; Ferretti, Alessandro; Trivisano, Marina; de Palma, Luca; Calabrese, Costanza; Carfì Pavia, Giusy; Tondo, Ilaria; Cappelletti, Simona; Vigevano, Federico; Specchio, Nicola","year":2019,"journal":"Paediatric drugs, 21(4), 283-290","doi":"10.1007/s40272-019-00341-x","pmid":"31179531","tags":["cbd","epilepsy","youth"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Eleven of 29 patients (37.9%) achieved 50% or greater seizure reduction. One patient became seizure-free. No patients experienced worsening seizure frequency. Adverse effects were reported in 7 patients (24%), mostly somnolence, decreased appetite, and diarrhea, all mild and transient.","whyItMatters":"Pharmaceutical-grade CBD (Epidiolex) was approved in the US for Dravet and Lennox-Gastaut syndromes but was not available internationally. This study tested artisanal purified CBD in a broader range of severe epilepsies, showing potential benefit beyond the approved indications.","specificNumbers":"29 patients enrolled. 41.4% male. Mean age: 9.3 years (range 1.9-16.3). Mean CBD exposure: 11.2 months. 37.9% had 50%+ seizure reduction. 1 patient seizure-free. 62.1% had no benefit. 24.1% had mild adverse effects.","methodology":"Single-center, prospective, open-label study at Bambino Gesu Children's Hospital in Rome. Patients aged 1-18 with treatment-refractory developmental and epileptic encephalopathy received purified CBD oil (98-99% pure) at 2-25 mg/kg/day added to existing antiepileptic drugs for at least 6 months.","limitations":"Open-label study with no placebo group or blinding. Small sample size. Artisanal formulation, not pharmaceutical-grade. All patients were on concurrent antiepileptic drugs."},{"rthcId":"RTHC-02232","title":"Prenatal cannabinoid exposure and altered neurotransmission.","authors":"Pinky, Priyanka D; Bloemer, Jenna; Smith, Warren D; Moore, Timothy; Hong, Hao; Suppiramaniam, Vishnu; Reed, Miranda N","year":2019,"journal":"Neuropharmacology, 149, 181-194","doi":"10.1016/j.neuropharm.2019.02.018","pmid":"30771373","tags":["pregnancy","neuroscience","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Prenatal cannabinoid exposure alters multiple neurotransmitter systems including dopamine, serotonin, GABA, glutamate, and opioid systems. These changes are brain region-specific, develop at different time points, and differ between male and female offspring. Human studies show deficits in attention and executive function in exposed children.","whyItMatters":"Marijuana use during pregnancy is steadily increasing despite evidence of harm. Understanding exactly which brain systems are affected helps explain the behavioral deficits observed in exposed children and underscores the biological basis for concern.","specificNumbers":"Alterations documented across dopamine, serotonin, GABA, glutamate, and endogenous opioid systems. Changes were region-specific and sexually dimorphic.","methodology":"Narrative review summarizing observed neurotransmitter changes from animal and human studies of prenatal cannabinoid exposure, including both marijuana and synthetic cannabinoids.","limitations":"Much of the evidence comes from animal studies using specific cannabinoid compounds that may not perfectly replicate human marijuana use. Human studies are confounded by polydrug use and socioeconomic factors."},{"rthcId":"RTHC-02233","title":"Relationship Between Cannabis Use and Erectile Dysfunction: A Systematic Review and Meta-Analysis.","authors":"Pizzol, Damiano; Demurtas, Jacopo; Stubbs, Brendon; Soysal, Pinar; Mason, Corina; Isik, Ahmet Turan; Solmi, Marco; Smith, Lee; Veronese, Nicola","year":2019,"journal":"American journal of men's health, 13(6), 1557988319892464","doi":"10.1177/1557988319892464","pmid":"31795801","tags":["sex-differences","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Across 3,395 men (1,035 cannabis users, 2,360 controls), the overall ED prevalence was 69.1% in cannabis users versus 34.7% in controls. The odds ratio for ED in cannabis users was 3.83 (95% CI: 1.30-11.28, p=.02), though heterogeneity was high (I-squared = 90%).","whyItMatters":"Erectile dysfunction is rarely discussed in the context of cannabis use. This meta-analysis provides the first pooled estimate of this relationship, suggesting a significant association that may be relevant for the many young men who use cannabis.","specificNumbers":"5 studies, 3,395 men. ED prevalence: 69.1% in cannabis users vs. 34.7% in controls. OR = 3.83 (95% CI 1.30-11.28, p=.02). I-squared = 90%. Prediction interval: 0.35-7.26.","methodology":"Systematic review and meta-analysis of major databases through January 2019. Five case-control studies were included. Random-effects model was used to calculate pooled odds ratios.","limitations":"Only five case-control studies were available. Heterogeneity was very high (I-squared = 90%), and prediction intervals overlapped 1.00. All studies involved smoked cannabis; other consumption methods were not represented."},{"rthcId":"RTHC-02234","title":"Aplicaciones terapéuticas por acción de los cannabinoides.","authors":"Plancarte-Sánchez, Ricardo; Mansilla-Olivares, Armando; De Los Reyes-Pacheco, Víctor Alfonso; Meneses-González, Fernando","year":2019,"journal":"Gaceta medica de Mexico, 155(3), 307-318","doi":"10.24875/GMM.18004928","pmid":"31219471","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02235","title":"Cannabidiol as a suggested candidate for treatment of autism spectrum disorder.","authors":"Poleg, Shani; Golubchik, Pavel; Offen, Daniel; Weizman, Abraham","year":2019,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 89, 90-96","doi":"10.1016/j.pnpbp.2018.08.030","pmid":"30171992","tags":["cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"ASD has no effective treatment for core symptoms. CBD has been proposed based on its interactions with the endocannabinoid system, but the review found no convincing preclinical or clinical evidence of efficacy and safety in ASD patients at the time of writing.","whyItMatters":"Many parents of children with ASD are turning to CBD products. This review provides a reality check: while the theoretical basis is interesting, the actual evidence supporting CBD for ASD is extremely limited.","specificNumbers":"No convincing preclinical or clinical data showing efficacy or safety at the time of review.","methodology":"Narrative review of available preclinical and clinical data on medical cannabis and CBD for ASD patients.","limitations":"Narrative review with limited primary data to draw from. The field was in very early stages at time of publication."},{"rthcId":"RTHC-02236","title":"Selective Cannabinoid 2 Receptor Agonists as Potential Therapeutic Drugs for the Treatment of Endotoxin-Induced Uveitis.","authors":"Porter, Richard Frederick; Szczesniak, Anna-Maria; Toguri, James Thomas; Gebremeskel, Simon; Johnston, Brent; Lehmann, Christian; Fingerle, Jürgen; Rothenhäusler, Benno; Perret, Camille; Rogers-Evans, Mark; Kimbara, Atsushi; Nettekoven, Matthias; Guba, Wolfgang; Grether, Uwe; Ullmer, Christoph; Kelly, Melanie E M","year":2019,"journal":"Molecules (Basel, Switzerland), 24(18)","doi":"10.3390/molecules24183338","pmid":"31540271","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02237","title":"Indoor cannabis smoke and children's health.","authors":"Posis, Alexander; Bellettiere, John; Liles, Sandy; Alcaraz, John; Nguyen, Benjamin; Berardi, Vincent; Klepeis, Neil E; Hughes, Suzanne C; Wu, Tianying; Hovell, Melbourne F","year":2019,"journal":"Preventive medicine reports, 14, 100853","doi":"10.1016/j.pmedr.2019.100853","pmid":"30976488","tags":["youth","respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Homes with indoor cannabis smoking had higher air particle concentrations than those with cigarette smoking alone (3,131 vs. 3,095 particles/0.01ft3). Homes with both had the highest levels (6,006). Children in homes with indoor cannabis smoking had 1.83 times the odds of more adverse health outcomes compared to non-cannabis homes, though this was not statistically significant (95% CI 0.89-3.80, p=0.10).","whyItMatters":"Research on secondhand cannabis smoke exposure in children is scarce. While this study did not achieve statistical significance, the magnitude of the association suggests indoor cannabis smoking adds to the health burden on children already exposed to tobacco smoke.","specificNumbers":"192 families analyzed. 29 (15.1%) reported indoor cannabis smoking. Air particles: no indoor smoking 1,968, cannabis only 3,131, cigarettes only 3,095, both 6,006 particles/0.01ft3. Child health OR: 1.83 (95% CI 0.89-3.80, p=0.10).","methodology":"Cross-sectional study of 192 families in San Diego County with at least one cigarette smoker and one child under 14. Air particle monitors were placed in homes for 7 days. Child health outcomes (ED visits for respiratory issues, ear infections, bronchitis, asthma, eczema) were assessed.","limitations":"Not statistically significant. Small number of cannabis-smoking households (n=29). All homes already had tobacco smokers, making it hard to isolate cannabis effects. Self-reported cannabis use."},{"rthcId":"RTHC-02238","title":"Knowledge and practice of harm-reduction behaviours for alcohol and other illicit substance use in adolescents with type 1 diabetes.","authors":"Potter, Kathryn; Virtanen, Heidi; Luca, Paola; Pacaud, Danièle; Nettel-Aguirre, Alberto; Kaminsky, Laura; Ho, Josephine","year":2019,"journal":"Paediatrics & child health, 24(1), e51-e56","doi":"10.1093/pch/pxy075","pmid":"30833824","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02239","title":"Benefits and harms of medical cannabis: a scoping review of systematic reviews.","authors":"Pratt, Misty; Stevens, Adrienne; Thuku, Micere; Butler, Claire; Skidmore, Becky; Wieland, L Susan; Clemons, Mark; Kanji, Salmaan; Hutton, Brian","year":2019,"journal":"Systematic reviews, 8(1), 320","doi":"10.1186/s13643-019-1243-x","pmid":"31823819","tags":["medical-cannabis","pain"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Pain management was the most commonly studied condition. A small number of reviews found benefits for pain, but analysis quality varied widely. Adverse effects were reported in 83% of reviews comparing cannabis to placebo and 83% comparing to active drugs. Minor harms (drowsiness, dizziness) were common. Serious harms were reported in 36% of reviews. Only 1 of 72 reviews was rated high quality; 36 were moderate, 35 were low/critically low.","whyItMatters":"This is a review of reviews, providing a bird's-eye view of the entire medical cannabis evidence base. The finding that 71 of 72 reviews were not high quality is a damning assessment of the field's evidence standards.","specificNumbers":"1,975 citations screened. 72 systematic reviews included. 1/72 rated high quality. 36 moderate quality. 35 low/critically low quality. Adverse effects in 83% of reviews vs. placebo. Serious harms in 36% of those reviews.","methodology":"Scoping review of systematic reviews from multiple databases. Two reviewers selected and charted data from 72 included systematic reviews covering various medical conditions.","limitations":"Scoping review methodology provides a broad overview but does not synthesize quantitative results. The quality of included reviews varied dramatically. The review was limited to systematic reviews, potentially missing primary research."},{"rthcId":"RTHC-02240","title":"In vitro Phase I metabolism of indazole carboxamide synthetic cannabinoid MDMB-CHMINACA via human liver microsome incubation and high-resolution mass spectrometry.","authors":"Presley, Brandon C; Logan, Barry K; Jansen-Varnum, Susan A","year":2019,"journal":"Drug testing and analysis, 11(8), 1264-1276","doi":"10.1002/dta.2615","pmid":"31108568","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02241","title":"The effect of cannabidiol (CBD) on low-frequency activity and functional connectivity in the brain of adults with and without autism spectrum disorder (ASD).","authors":"Pretzsch, Charlotte M; Voinescu, Bogdan; Mendez, Maria A; Wichers, Robert; Ajram, Laura; Ivin, Glynis; Heasman, Martin; Williams, Steven; Murphy, Declan Gm; Daly, Eileen; McAlonan, Gráinne M","year":2019,"journal":"Journal of psychopharmacology (Oxford, England), 33(9), 1141-1148","doi":"10.1177/0269881119858306","pmid":"31237191","tags":["cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CBD significantly increased fractional amplitude of low-frequency fluctuations (fALFF) in the cerebellar vermis and right fusiform gyrus across all participants, but post-hoc analysis showed this was driven by the ASD group with no significant change in controls. In ASD participants only, CBD altered functional connectivity between the cerebellar vermis and subcortical/cortical targets.","whyItMatters":"This is one of the first studies to directly measure how CBD affects brain activity in people with ASD. The finding that CBD had a different effect in ASD versus controls suggests it may preferentially target neural circuits that are already atypical.","specificNumbers":"34 men (17 ASD, 17 controls). 600 mg CBD or placebo. CBD increased fALFF in cerebellar vermis and right fusiform gyrus (primarily in ASD). CBD altered vermal functional connectivity in ASD only.","methodology":"Double-blind, placebo-controlled, crossover design. 34 healthy men (17 with ASD, 17 neurotypical controls) received 600 mg oral CBD or placebo. Task-free fMRI was acquired to measure brain activity and functional connectivity.","limitations":"Small sample size. Single dose only. All male participants, limiting generalizability. The study measured brain activity changes, not behavioral outcomes."},{"rthcId":"RTHC-02242","title":"Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder.","authors":"Pretzsch, Charlotte Marie; Freyberg, Jan; Voinescu, Bogdan; Lythgoe, David; Horder, Jamie; Mendez, Maria Andreina; Wichers, Robert; Ajram, Laura; Ivin, Glynis; Heasman, Martin; Edden, Richard A E; Williams, Steven; Murphy, Declan G M; Daly, Eileen; McAlonan, Gráinne M","year":2019,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 44(8), 1398-1405","doi":"10.1038/s41386-019-0333-8","pmid":"30758329","tags":["cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Across groups, CBD increased subcortical glutamate (Glx) but decreased cortical Glx. For GABA, CBD increased levels in controls but decreased them in ASD participants, with a significant group difference in the dorsomedial prefrontal cortex. This suggests the excitation-inhibition balance responds differently to CBD in ASD.","whyItMatters":"Excitation-inhibition imbalance is a leading theory in ASD neuroscience. This study provides the first direct evidence that CBD modulates glutamate and GABA differently in autistic versus neurotypical brains.","specificNumbers":"34 men (17 ASD, 17 controls). 600 mg CBD. Subcortical Glx increased, cortical Glx decreased (both groups). GABA+ increased in controls, decreased in ASD. Group difference in DMPFC GABA+ was significant.","methodology":"Double-blind, placebo-controlled, crossover design. 34 men (17 ASD, 17 neurotypical) received 600 mg oral CBD or placebo. Magnetic resonance spectroscopy (MRS) measured glutamate (Glx) and GABA+ levels in basal ganglia and dorsomedial prefrontal cortex at peak plasma levels (2 hours post-dose).","limitations":"Small sample size (17 per group). Single dose. All male participants. MRS measures cannot distinguish between intracellular and extracellular neurotransmitter pools. No behavioral outcomes measured."},{"rthcId":"RTHC-02243","title":"The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications.","authors":"Qian, Yuli; Gurley, Bill J; Markowitz, John S","year":2019,"journal":"Journal of clinical psychopharmacology, 39(5), 462-471","doi":"10.1097/JCP.0000000000001089","pmid":"31433338","tags":["drug-interactions","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CYP2C9, CYP1A1/2, and CYP1B1 are likely inhibited by all three major cannabinoids (THC, CBD, CBN). CYP2D6, CYP2C19, CYP2B6, and CYP2J2 are inhibited by THC and CBD. CYP3A4/5/7 is potentially inhibited by CBD alone. Clinical evidence supports CBD inhibition of CYP2C19 and various cannabis products inhibiting CYP2C9.","whyItMatters":"As medical cannabis and CBD products proliferate, patients often take them alongside prescription medications. This review identifies specific enzyme pathways at risk, helping clinicians anticipate dangerous interactions.","specificNumbers":"THC, CBD, and CBN all inhibit CYP2C9, CYP1A1/2, CYP1B1. THC and CBD inhibit CYP2D6, CYP2C19, CYP2B6, CYP2J2. CBD inhibits CYP3A4/5/7, UGT1A9, and potentially CES1. Cannabis smoking induces CYP1A2.","methodology":"Systematic literature search of Google Scholar and PubMed through March 2019 for in vitro and clinical studies of cannabis drug interaction potential. In vitro inhibition parameters were compared to physiologically achievable cannabinoid concentrations.","limitations":"Many findings are based on in vitro data that may not reflect real-world clinical significance. Clinical drug interaction studies with cannabis are still limited. Most in vivo data involves smoked cannabis or CBD specifically."},{"rthcId":"RTHC-02244","title":"Cannabis and Turmeric as Complementary Treatments for IBD and Other Digestive Diseases.","authors":"Quezada, Sandra M; Cross, Raymond K","year":2019,"journal":"Current gastroenterology reports, 21(2), 2","doi":"10.1007/s11894-019-0670-0","pmid":"30635796","tags":["medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids modulate gut motility and visceral pain and have anti-inflammatory properties. Clinical trials suggest a therapeutic role in IBD, IBS, nausea/vomiting, and GI motility disorders. Turmeric shows promise as adjuvant IBD treatment. Neither has been compared to standard IBD therapy. Reports of serious adverse effects from synthetic cannabinoids highlight safety concerns.","whyItMatters":"Many IBD patients already use these complementary therapies. This review helps clinicians understand what the evidence actually supports versus what remains unproven.","specificNumbers":"Neither cannabis nor turmeric has been compared to standard IBD therapy. Synthetic cannabinoids have caused serious adverse effects.","methodology":"Narrative review of the most recent studies on cannabis and turmeric for IBD and other intestinal diseases.","limitations":"Narrative review. Limited clinical trial data for both cannabis and turmeric in IBD. No head-to-head comparisons with standard treatments."},{"rthcId":"RTHC-02245","title":"Review: brain neurobiology of gambling disorder based on rodent models.","authors":"Quintero Garzola, Gabriel C","year":2019,"journal":"Neuropsychiatric disease and treatment, 15, 1751-1770","doi":"10.2147/NDT.S192746","pmid":"31308669","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02246","title":"Phytotherapy as a Complementary Medicine for Multiple Sclerosis.","authors":"Rabiei, Zahra","year":2019,"journal":"Turkish journal of pharmaceutical sciences, 16(2), 246-251","doi":"10.4274/tjps.galenos.2018.90522","pmid":"32454721","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02247","title":"Marijuana use and major depressive disorder are additively associated with reduced verbal learning and altered cortical thickness.","authors":"Radoman, Milena; Hoeppner, Susanne S; Schuster, Randi M; Evins, A Eden; Gilman, Jodi M","year":2019,"journal":"Cognitive, affective & behavioral neuroscience, 19(4), 1047-1058","doi":"10.3758/s13415-019-00704-4","pmid":"30809764","tags":["cognition","depression","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"MDD and marijuana use had additive effects on memory recall and cortical thickness in the middle temporal gyrus. MDD alone (but not marijuana alone) was associated with poorer initial learning, fewer words recalled, more intrusion errors, and lower retention. The combination produced the worst outcomes.","whyItMatters":"Depression and marijuana use frequently co-occur in young adults. Finding that their effects are additive rather than redundant suggests that marijuana use among people with depression carries an extra cognitive cost.","specificNumbers":"141 participants ages 18-25. Additive effects on verbal recall and middle temporal gyrus thickness. MDD alone associated with poorer learning, fewer words recalled, more intrusion errors.","methodology":"Cross-sectional study of 141 young adults (ages 18-25) in four groups: marijuana only (n=46), MDD only (n=23), MDD + marijuana (n=24), and healthy controls (n=48). Participants completed the California Verbal Learning Test and a subset (n=82) underwent structural MRI.","limitations":"Cross-sectional design cannot determine causation. The MDD and MDD+MJ groups were smaller than the other groups. The MRI subsample was 82 of 141 participants."},{"rthcId":"RTHC-02248","title":"Association between cannabis laws and opioid prescriptions among privately insured adults in the US.","authors":"Raji, Mukaila A; Abara, N Ogechi; Salameh, Habeeb; Westra, Jordan R; Kuo, Yong-Fang","year":2019,"journal":"Preventive medicine, 125, 62-68","doi":"10.1016/j.ypmed.2019.05.012","pmid":"31125629","tags":["legalization","pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In states with medical cannabis laws, opioid prescription rates (>30-day and >90-day) were significantly lower for adults aged 18-54 (aORs ranging from 0.56 to 0.77). The association was not significant for ages 55-64. Recreational use and decriminalization laws showed no significant association with opioid prescriptions in any age group.","whyItMatters":"The opioid crisis has driven interest in whether cannabis access could reduce opioid dependence. This study provides evidence that medical cannabis laws specifically (not recreational or decriminalization) are associated with lower opioid prescribing in younger adults.","specificNumbers":"Medical cannabis states: >30-day opioid aOR = 0.56 (ages 18-25), 0.67 (26-35), 0.67 (36-45), 0.76 (46-54). All p < 0.0001. Not significant for ages 55-64. No association with recreational or decriminalization laws.","methodology":"Cross-sectional analysis of the 2016 Clinformatics Data Mart, a nationwide commercial insurance database. Multilevel multivariable analysis compared opioid prescribing patterns across states with different cannabis law stringencies, stratified by five age groups.","limitations":"Cross-sectional design; cannot establish causation. Only privately insured adults included. State-level confounders (pain management culture, prescribing policies) could explain differences. Cannabis use itself was not measured."},{"rthcId":"RTHC-02249","title":"Emergent Medical Illnesses Related to Cannabis Use.","authors":"Randall, Karen; Hayward, Kathleen","year":2019,"journal":"Missouri medicine, 116(3), 226-228","doi":null,"pmid":"31527946","tags":["harm-reduction","legalization","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Post-legalization ED presentations include cannabinoid hyperemesis, acute psychosis, cannabinoid catatonia syndrome, acute myo-pericarditis, pediatric ingestions, increases in fatal motor vehicle collisions, and hash-oil burn injuries. THC concentrations have risen dramatically (from 1-3 mg per joint in the 1990s to 18+ mg today). Some patients self-report using 2,000+ mg of THC daily.","whyItMatters":"Colorado was one of the first states to legalize recreational cannabis, making it a natural experiment. The ED data provides a real-world picture of health consequences that laboratory studies cannot capture.","specificNumbers":"1990s joints: 1-3 mg THC. Current Colorado joints: 18+ mg THC. Some patients self-report 2,000+ mg THC/day. In 2015, 2.6 million new cannabis users, 45% aged 12-17.","methodology":"Narrative review of cannabis-related health and safety effects observed in Colorado emergency departments over four years of legalization.","limitations":"Narrative review from one state. Does not include systematic data collection or comparison to pre-legalization rates. Some conditions (like CHS) may have been underdiagnosed previously."},{"rthcId":"RTHC-02250","title":"Highs and lows of cannabinoid-dopamine interactions: effects of genetic variability and pharmacological modulation of catechol-O-methyl transferase on the acute response to delta-9-tetrahydrocannabinol in humans.","authors":"Ranganathan, Mohini; De Aquino, Joao P; Cortes-Briones, Jose A; Radhakrishnan, Rajiv; Pittman, Brian; Bhakta, Savita; D'Souza, Deepak C","year":2019,"journal":"Psychopharmacology, 236(11), 3209-3219","doi":"10.1007/s00213-019-05273-5","pmid":"31187152","tags":["genetics","dopamine","cognition","psychosis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Val/Val individuals showed the greatest THC-induced working memory and attention deficits. COMT genotype did not influence THC's psychotomimetic or subjective effects. Tolcapone (a COMT inhibitor) reduced THC-induced working memory deficits but not psychotomimetic effects, suggesting dopaminergic signaling selectively mediates cognitive but not psychotic effects of THC.","whyItMatters":"This helps explain why some people experience significant cognitive impairment from cannabis while others do not. COMT genotype may be a useful predictor of vulnerability to THC's cognitive effects.","specificNumbers":"74 subjects in sub-study I. Val/Val most sensitive to THC-induced cognitive deficits. Tolcapone 200 mg reduced THC working memory impairment. Neither COMT genotype nor tolcapone affected psychotomimetic effects.","methodology":"Two sub-studies. Sub-study I: 74 healthy subjects genotyped for COMT Val/Met received IV THC (0.05 mg/kg) or placebo in a double-blind crossover. Sub-study II: Val/Val and Met/Met homozygous subjects received tolcapone 200 mg followed by IV THC or placebo on two additional days.","limitations":"IV THC administration does not replicate typical cannabis use. Sample size was moderate. Only one COMT polymorphism was studied. Tolcapone has limited clinical use due to liver toxicity concerns."},{"rthcId":"RTHC-02251","title":"Modulation of Endocannabinoid-Binding Receptors in Human Neuroblastoma Cells by Tunicamycin.","authors":"Rapino, Cinzia; Castellucci, Annalisa; Lizzi, Anna Rita; Sabatucci, Annalaura; Angelucci, Clotilde B; Tortolani, Daniel; Rossi, Gianna; D'Andrea, Gabriele; Maccarrone, Mauro","year":2019,"journal":"Molecules (Basel, Switzerland), 24(7)","doi":"10.3390/molecules24071432","pmid":"30979007","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02252","title":"The prefrontal cortical endocannabinoid system modulates fear-pain interactions in a subregion-specific manner.","authors":"Rea, Kieran; McGowan, Fiona; Corcoran, Louise; Roche, Michelle; Finn, David P","year":2019,"journal":"British journal of pharmacology, 176(10), 1492-1505","doi":"10.1111/bph.14376","pmid":"29847859","tags":["neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CB1 receptor antagonist AM251 attenuated fear-conditioned analgesia (FCA) when injected into the infralimbic or prelimbic cortex, but reduced freezing only in the infralimbic region. The FAAH inhibitor URB597 attenuated FCA and freezing in the infralimbic cortex but prolonged FCA in the prelimbic cortex. Neither drug had effects in the anterior cingulate cortex.","whyItMatters":"The endocannabinoid system is a drug target for both pain and anxiety. This study reveals that its role varies dramatically even within adjacent brain subregions, which has implications for precision medicine approaches.","specificNumbers":"Three prefrontal subregions tested: infralimbic, prelimbic, anterior cingulate cortex. AM251 and URB597 had distinct, subregion-specific effects on pain suppression and fear.","methodology":"Male rats received intra-prefrontal cortex microinjections of AM251 (CB1 antagonist), URB597 (FAAH inhibitor), or combination, then underwent formalin-evoked pain testing in a fear-conditioned arena previously paired with footshock.","limitations":"Rat study using microinjections that do not replicate systemic cannabis use. Only male rats were tested. The pharmacological tools used (AM251, URB597) affect endocannabinoids broadly, not just anandamide."},{"rthcId":"RTHC-02253","title":"Impacts of cannabinoid epigenetics on human development: reflections on Murphy et. al. 'cannabinoid exposure and altered DNA methylation in rat and human sperm' epigenetics 2018; 13: 1208-1221.","authors":"Reece, Albert Stuart; Hulse, Gary Kenneth","year":2019,"journal":"Epigenetics, 14(11), 1041-1056","doi":"10.1080/15592294.2019.1633868","pmid":"31293213","tags":["genetics","pregnancy","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Building on the Murphy et al. findings that cannabis exposure shifts DNA methylation in both rat and human sperm (with hypermethylation predominating), this review argues this provides a mechanism for transgenerational transmission of epigenomic instability. The authors link these epigenetic changes to diverse cannabis-related teratological effects including neurological, cardiovascular, immune, and cancer-related outcomes.","whyItMatters":"This suggests cannabis does not just affect the user but could alter the biological blueprint passed to children through sperm, potentially affecting multiple generations.","specificNumbers":"Substantial shifts in both hypo- and hypermethylation observed, with hypermethylation predominating. Linked to trends in jurisdictions including the USA, Hawaii, Colorado, Canada, France, and Australia.","methodology":"Commentary and extended review building on Murphy et al. (2018) findings of cannabis-induced DNA methylation changes in sperm, integrating epidemiological data from the US, Hawaii, Colorado, Canada, France, and Australia.","limitations":"Commentary building on one study. The link between sperm methylation changes and actual health outcomes in offspring is inferential, not proven. The epidemiological associations drawn are ecological and may reflect confounding."},{"rthcId":"RTHC-02254","title":"Medical marijuana. What can we learn from the experiences in Canada, Germany and Thailand?","authors":"Rehm, Jürgen; Elton-Marshall, Tara; Sornpaisarn, Bundit; Manthey, Jakob","year":2019,"journal":"The International journal on drug policy, 74, 47-51","doi":"10.1016/j.drugpo.2019.09.001","pmid":"31525639","tags":["legalization","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Two pressures drive medical marijuana expansion: patients self-medicating for conditions without evidence of cannabis effectiveness, and cannabis industry lobbying for lenient regulations. Canada (early adopter), Germany (late adopter), and Thailand (middle-income) all illustrate this pattern. Lenient regulations that only require a prescription without specifying indications are likely to increase demand.","whyItMatters":"Medical marijuana programs are often seen as harm reduction, but if regulations are too lenient, they can become de facto recreational legalization without appropriate safety oversight.","specificNumbers":"Three countries analyzed: Canada (early adopter), Germany (late adopter), Thailand (middle-income). Evidence lacking for many self-medication indications.","methodology":"Policy analysis comparing medical marijuana programs in three countries: Canada, Germany, and Thailand.","limitations":"Policy analysis with limited quantitative data. Focuses on three countries that may not represent all regulatory approaches. Industry influence is asserted but not quantified."},{"rthcId":"RTHC-02255","title":"Antipsychotic treatment failure in patients with psychosis and co-morbid cannabis use: A systematic review.","authors":"Reid, Sam; Bhattacharyya, Sagnik","year":2019,"journal":"Psychiatry research, 280, 112523","doi":"10.1016/j.psychres.2019.112523","pmid":"31450032","tags":["psychosis","drug-interactions"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Seven studies met inclusion criteria. Cannabis use was associated with increased odds of non-remission, prescription of more unique antipsychotic medications, cumulative clozapine prescription, and poor treatment trajectories. One study found lower past-year cannabis use in clozapine patients, and another found differences in chlorpromazine equivalent doses for olanzapine.","whyItMatters":"Treatment failure in psychosis often leads to escalation through multiple medications, eventually reaching clozapine. If cannabis is a modifiable factor contributing to this progression, early cessation could prevent unnecessary treatment intensification.","specificNumbers":"7 studies included. Cannabis associated with increased non-remission, more unique antipsychotic prescriptions, more clozapine prescriptions, and worse treatment trajectories.","methodology":"Systematic review of Ovid databases (Embase, MEDLINE, PsycINFO) for studies examining cannabis use and antipsychotic treatment failure in psychosis patients. Seven articles met eligibility.","limitations":"Only seven studies met criteria, highlighting the paucity of research. Heterogeneous study designs and variable definitions of cannabis use and treatment failure. No prospective studies specifically designed to test this question."},{"rthcId":"RTHC-02256","title":"Cannabis use and acute coronary syndrome.","authors":"Richards, John R; Bing, Mary L; Moulin, Aimee K; Elder, Joshua W; Rominski, Robert T; Summers, Phillip J; Laurin, Erik G","year":2019,"journal":"Clinical toxicology (Philadelphia, Pa.), 57(10), 831-841","doi":"10.1080/15563650.2019.1601735","pmid":"30964363","tags":["cardiovascular","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Five Level I systematic reviews, 14 Level II studies (83,961 subjects), and 14 Level III studies (457,495 subjects) were identified. All but five of these highlighted increased cardiovascular risk. In 51 case reports (62 subjects, average age 31), 60% showed ST-elevation, 35% had left anterior descending artery involvement, 34% had cardiomyopathy, and 23% died.","whyItMatters":"Cannabis is widely perceived as cardiovascularly benign, but this extensive review shows a consistent signal of increased heart attack risk, particularly in young adults who would not typically be at risk.","specificNumbers":"85 publications, 541,518 subjects. 5 Level I reviews, 14 Level II studies (83,961 subjects), 14 Level III studies (457,495 subjects). Case reports: avg age 31, 60% ST-elevation, 23% died. Only 10% female.","methodology":"Systematic review of PubMed, Google Scholar, and OpenGrey following PRISMA guidelines. Focused on smoked phytogenic cannabis and acute coronary syndrome. 85 publications covering 541,518 subjects were included.","limitations":"No Level I randomized controlled trials specifically address this association. Case reports are inherently biased toward severe outcomes. Most evidence involves smoked cannabis; other forms were excluded."},{"rthcId":"RTHC-02257","title":"Legalized Cannabis in Colorado Emergency Departments: A Cautionary Review of Negative Health and Safety Effects.","authors":"Roberts, Brad A","year":2019,"journal":"The western journal of emergency medicine, 20(4), 557-572","doi":"10.5811/westjem.2019.4.39935","pmid":"31316694","tags":["legalization","harm-reduction","psychosis","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The most concerning effects were psychosis, suicide, and other substance abuse. Cognitive impairments may not be reversible with abstinence. Additional concerns include fatal motor vehicle collisions, cardiovascular and pulmonary damage, pediatric exposures, contaminants (infectious agents, heavy metals, pesticides), and hash-oil burns. \"Budtenders\" provide medical advice without medical training.","whyItMatters":"Colorado is a real-world natural experiment in cannabis legalization. This review catalogs the negative health consequences that other states should anticipate and prepare for.","specificNumbers":"Multiple categories of harm documented. Cannabis research may benefit seizures, MS spasticity, chemo nausea, chronic pain, cardiovascular outcomes, and sleep disorders.","methodology":"Narrative review of health and safety effects observed in Colorado emergency departments since cannabis legalization.","limitations":"Narrative review from one state. No systematic data collection or pre/post comparison. May overrepresent emergency presentations relative to overall population experience."},{"rthcId":"RTHC-02258","title":"Urgent need for \"EBMM\" in pediatric oncology: Evidence based medical marijuana.","authors":"Rod Rassekh, S","year":2019,"journal":"Pediatric hematology and oncology, 36(5), 253-254","doi":"10.1080/08880018.2019.1651805","pmid":"31402734","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02259","title":"Healthy and Concentrated Cannabis Plants: How to Use Acronyms to Optimize Production.","authors":"Roggen, Markus","year":2019,"journal":"Journal of AOAC International, 102(2), 421-426","doi":"10.5740/jaoacint.18-0205","pmid":"30157992","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02260","title":"Association of CNR1 genotypes with changes in neurocognitive performance after eighteen-month treatment in patients with first-episode psychosis.","authors":"Rojnic Kuzman, Martina; Bosnjak Kuharic, Dina; Ganoci, Lana; Makaric, Porin; Kekin, Ivana; Rossini Gajsak, Linda; Prpic, Nikola; Bozina, Tamara; Bajic, Zarko; Bozina, Nada","year":2019,"journal":"European psychiatry : the journal of the Association of European Psychiatrists, 61, 88-96","doi":"10.1016/j.eurpsy.2019.07.004","pmid":"31398679","tags":["genetics","psychosis","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Carriers of the CNR1 rs7766029 CC genotype showed significantly greater improvement in verbal memory (Wechsler, Wechsler 30') and attention (Digit span F). The rs12720071 AG genotype was linked to improved executive function but lower language improvement. After full adjustment (age, sex, cannabis use, negative symptoms), the rs7766029 association with Wechsler 30' remained significant.","whyItMatters":"If cannabinoid receptor gene variants predict who will improve cognitively during psychosis treatment, this could help personalize treatment plans and identify patients who may need additional cognitive interventions.","specificNumbers":"159 patients enrolled, 121 genotyped. rs7766029 CC carriers showed greater Wechsler 30' improvement (significant at FDR <15% after full adjustment). rs7766029 also associated with stress perception changes.","methodology":"Longitudinal study of 159 first-episode psychosis patients from two Croatian hospitals (2014-2017). Neurocognitive testing at baseline and 18 months. CNR1 polymorphisms (rs7766029, rs12720071) genotyped in 121 patients. Associations adjusted for multiple covariates.","limitations":"Moderate sample size. FDR threshold of 15% is relatively liberal. Two sites in Croatia may not generalize to other populations. Cannabis use was controlled for but may interact with genotype in complex ways."},{"rthcId":"RTHC-02261","title":"The utility of delta 9-tetrahydrocannabinol (THC) measures obtained from oral fluid samples in traffic safety.","authors":"Romano, Eduardo; Moore, Christine; Kelley-Baker, Tara; Torres-Saavedra, Pedro A","year":2019,"journal":"Traffic injury prevention, 20(7), 667-672","doi":"10.1080/15389588.2019.1635690","pmid":"31356118","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using data from 7,517 drivers in the National Roadside Survey, oral fluid THC > 0 ng/mL was a good predictor of any blood THC. However, as blood and oral fluid concentrations increased above zero, sensitivity (true positive rate) decreased. Accuracy was also lower when drivers used cannabis concurrently with other drugs.","whyItMatters":"Law enforcement needs practical, non-invasive tools for detecting cannabis-impaired drivers. Oral fluid testing is less invasive than blood draws, but this study quantifies its limitations.","specificNumbers":"7,517 drivers with both oral fluid and blood results. Oral fluid THC > 0 was a good predictor of blood THC > 0. Sensitivity decreased at higher thresholds. Multi-drug users had lower prediction accuracy.","methodology":"Cross-sectional analysis of 7,517 drivers from the 2007 and 2013-2014 National Roadside Surveys who provided both oral fluid and blood samples. Hurdle model analysis examined predictive accuracy accounting for consumption decisions.","limitations":"Laboratory analysis, not point-of-care devices that police would actually use. Cross-sectional design at roadside surveys, not under controlled conditions. Oral fluid THC reflects recent use timing more than impairment level."},{"rthcId":"RTHC-02262","title":"Use of Alcohol and Cannabis Among Adults Driving Children in Washington State.","authors":"Romano, Eduardo; Kelley-Baker, Tara; Hoff, Staci; Eichelberger, Angela; Ramírez, Anthony","year":2019,"journal":"Journal of studies on alcohol and drugs, 80(2), 196-200","doi":null,"pmid":"31014464","tags":["driving","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Drivers with children were less likely to be alcohol positive (0.2% vs. 4.5%, p < .0001) but equally likely to be THC positive (14.1% vs. 17.7%, p = .29). Among drivers who perceived no impairment risk from cannabis, 40.6% of those with a child and 28.9% of those without tested positive for THC.","whyItMatters":"Adults appear to self-regulate alcohol use when driving with children but do not similarly reduce cannabis use, possibly because they perceive cannabis as less impairing or less risky.","specificNumbers":"2,056 drivers (1,238 male). Alcohol positive with child: 0.2%, without: 4.5%. THC positive with child: 14.1%, without: 17.7%. Among those perceiving no cannabis risk, 40.6% with a child tested THC positive.","methodology":"Cross-sectional analysis of 2,056 drivers from the Washington State Roadside Survey (2014-2015). Oral fluid, blood, and breath samples collected to measure cannabis and alcohol. Self-reported data assessed risk perceptions.","limitations":"Cross-sectional roadside survey; THC presence does not confirm impairment at the time of driving. Self-reported risk perceptions may not reflect actual behavior. Washington State may not generalize to other jurisdictions."},{"rthcId":"RTHC-02263","title":"Impact of Chronic Cannabis Use on Auditory Mismatch Negativity Generation in Schizophrenia Patients.","authors":"Roser, Patrik; Pichler, Eva-Maria; Habermeyer, Benedikt; Kawohl, Wolfram; Juckel, Georg","year":2019,"journal":"Pharmacopsychiatry, 52(3), 126-133","doi":"10.1055/a-0573-9866","pmid":"29506304","tags":["psychosis","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Schizophrenia patients without cannabis use showed reduced frontocentral MMN to duration deviants compared to healthy controls, as expected. However, schizophrenia patients with comorbid cannabis use showed greater MMN amplitudes than non-using patients, with no significant difference from healthy controls.","whyItMatters":"This counterintuitive finding suggests that schizophrenia patients who use cannabis may represent a cognitively less impaired subgroup, rather than cannabis protecting the brain. It challenges simple assumptions about cannabis always worsening cognition in psychosis.","specificNumbers":"20 schizophrenia patients without CUD, 21 with CUD, 20 healthy controls. Schizophrenia + CUD patients had greater MMN amplitudes than non-CUD patients at central electrodes.","methodology":"Cross-sectional EEG study comparing 20 schizophrenia patients without CUD, 21 with CUD, and 20 healthy controls. Auditory oddball paradigm measured MMN to frequency and duration deviants.","limitations":"Small cross-sectional study; cannot determine causation. The design cannot distinguish whether cannabis improved cognition or whether less impaired patients are more likely to use cannabis."},{"rthcId":"RTHC-02264","title":"Designer drugs – still a threat?","authors":"Rozenek, Emil Bartosz; Wilczyńska, Karolina; Górska, Monika; Waszkiewicz, Napoleon","year":2019,"journal":"Przeglad epidemiologiczny, 73(3), 337-347","doi":"10.32394/pe.73.23","pmid":"31766831","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02265","title":"A retrospective study of the role of long-acting injectable antipsychotics in preventing rehospitalization in early psychosis with cannabis use.","authors":"Rozin, Emily; Vanaharam, Vivek; D'Mello, Dale; Palazzolo, Scott; Adams, Cathy","year":2019,"journal":"Addictive behaviors reports, 10, 100221","doi":"10.1016/j.abrep.2019.100221","pmid":"31828200","tags":["psychosis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis users were significantly more dissatisfied with antipsychotic medication (Chi-square 9.67, p < .002) and more likely to be rehospitalized (Chi-square 4.40, p = .036). Patients on long-acting injectable antipsychotics were rehospitalized less frequently than those on oral formulations (Chi-square 4.61, p = .032).","whyItMatters":"Cannabis-using psychosis patients face a double challenge: they are less satisfied with medication and more likely to relapse. Long-acting injectables may help by removing the daily adherence decision.","specificNumbers":"24 cannabis users, 27 non-users. Cannabis users more dissatisfied (p < .002) and more rehospitalized (p = .036). Long-acting injectables associated with fewer rehospitalizations (p = .032).","methodology":"Retrospective study in an early psychosis program in mid-Michigan. Compared cannabis users (n=24) and non-users (n=27) on medication satisfaction and rehospitalization. Patient perceptions assessed using a single question from the NAVIGATE Patient Self-Rating Form.","limitations":"Small retrospective study. Single site. Medication satisfaction assessed with a single question. Cannot determine if cannabis caused dissatisfaction or if more dissatisfied patients were more likely to use cannabis."},{"rthcId":"RTHC-02266","title":"Neural and behavioral correlates of attentional bias to cannabis cues among adults with cannabis use disorders.","authors":"Ruglass, Lesia M; Shevorykin, Alina; Dambreville, Naomi; Melara, Robert D","year":2019,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 33(1), 69-80","doi":"10.1037/adb0000423","pmid":"30589308","tags":["addiction","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis users had more difficulty ignoring cannabis distractors (selective attention failure), committed more errors when cannabis cues were present, and showed an augmented and earlier N1 ERP component (125-200 ms post-stimulus) to cannabis cues, indicating an involuntary early perceptual bias toward cannabis-related stimuli.","whyItMatters":"Attentional bias toward drug cues is a known driver of craving and relapse. This study shows that cannabis cues capture attention at a very early, automatic level in the brain, suggesting the bias is involuntary and hard to control.","specificNumbers":"20 cannabis users, 20 controls. N1 component (125-200 ms) was earlier and larger in cannabis users for cannabis cues. More errors on cannabis-cue trials in users vs. controls.","methodology":"Pilot study comparing 20 individuals with cannabis use disorders (mean age 26.2) and 20 healthy controls (mean age 28). Participants completed a visual attention task with cannabis-related, positive, negative, and neutral images while behavioral responses and event-related potentials were recorded via EEG.","limitations":"Pilot study with small sample size. Cross-sectional design. Cannot determine if attentional bias causes or results from heavy cannabis use."},{"rthcId":"RTHC-02267","title":"Multiple endocannabinoid-mediated mechanisms in the regulation of energy homeostasis in brain and peripheral tissues.","authors":"Ruiz de Azua, Inigo; Lutz, Beat","year":2019,"journal":"Cellular and molecular life sciences : CMLS, 76(7), 1341-1363","doi":"10.1007/s00018-018-2994-6","pmid":"30599065","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02268","title":"Medical Marijuana Guidelines for Practice: Health Policy Implications.","authors":"Russell, Kathleen; Cahill, Maureen; Duderstadt, Karen G","year":2019,"journal":"Journal of pediatric health care : official publication of National Association of Pediatric Nurse Associates & Practitioners, 33(6), 722-726","doi":"10.1016/j.pedhc.2019.07.010","pmid":"31655786","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02269","title":"Denying renal transplantation to an adolescent medical cannabis user: An ethical case study.","authors":"Ryan, Jennie E; Noeder, Maia; Burke, Christine; Stubblefield, Samuel C; Sulieman, Salwa; Miller, Elissa G","year":2019,"journal":"Pediatric transplantation, 23(5), e13467","doi":"10.1111/petr.13467","pmid":"31124250","tags":["medical-cannabis","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 20-year-old woman recommended for renal transplant was originally denied active listing because of her medical cannabis use. The review found that many healthcare providers are uninformed or misinformed about the actual risks of cannabis in immunocompromised patients.","whyItMatters":"As medical cannabis becomes legal in more states, transplant teams will increasingly face this dilemma. Denying life-saving treatment based on a legal medical therapy raises serious ethical concerns.","specificNumbers":"Medical cannabis is legal in over half of US states. 1 patient initially denied transplant listing. Few professional organizations provide guidance on this issue.","methodology":"Ethical case study with literature review examining perceived versus actual risks of cannabis use in transplant patients and the ethics of denying transplants based on medical cannabis use.","limitations":"Single case report. The actual transplant outcomes for cannabis users versus non-users remain poorly studied. The ethics discussion, while important, is opinion-based."},{"rthcId":"RTHC-02270","title":"Brodifacoum does not modulate human cannabinoid receptor-mediated hyperpolarization of AtT20 cells or inhibition of adenylyl cyclase in HEK 293 cells.","authors":"Sachdev, Shivani; Boyd, Rochelle; Grimsey, Natasha L; Santiago, Marina; Connor, Mark","year":2019,"journal":"PeerJ, 7, e7733","doi":"10.7717/peerj.7733","pmid":"31579608","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02271","title":"Safety and Efficacy of Medical Cannabis in Fibromyalgia.","authors":"Sagy, Iftach; Bar-Lev Schleider, Lihi; Abu-Shakra, Mahmoud; Novack, Victor","year":2019,"journal":"Journal of clinical medicine, 8(6)","doi":"10.3390/jcm8060807","pmid":"31195754","tags":["medical-cannabis","pain"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Pain intensity decreased from median 9.0 to 5.0 (p < .001). Treatment response was achieved by 81.1% of patients. Age over 60 was associated with lower odds of response (OR 0.34). Prior cannabis experience predicted better outcomes (OR 2.46). Only 7.6% discontinued before six months. Most common adverse effects were mild: dizziness (7.9%), dry mouth (6.7%), GI symptoms (5.4%).","whyItMatters":"Fibromyalgia is notoriously difficult to treat. This is one of the larger prospective studies showing that medical cannabis can provide meaningful, sustained pain relief with an acceptable safety profile.","specificNumbers":"367 patients. 82% female. Mean age 52.9. Pain: 9.0 to 5.0 (p < .001). 81.1% treatment response. 7.6% discontinued early. Dizziness 7.9%, dry mouth 6.7%, GI symptoms 5.4%.","methodology":"Prospective observational study at a specialized medical cannabis clinic in Israel (2015-2017). 367 fibromyalgia patients followed for six months with questionnaire-based assessments. Response rate was 70.8%.","limitations":"Observational study with no placebo control or blinding. Self-selected patient population at a cannabis clinic. 29.2% did not respond to the six-month follow-up, introducing potential bias."},{"rthcId":"RTHC-02272","title":"Response of Medical Cannabis (Cannabis sativa L.) Genotypes to K Supply Under Long Photoperiod.","authors":"Saloner, Avia; Sacks, Mollie M; Bernstein, Nirit","year":2019,"journal":"Frontiers in plant science, 10, 1369","doi":"10.3389/fpls.2019.01369","pmid":"31803198","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02273","title":"Cannabidiol: A Review of Clinical Efficacy and Safety in Epilepsy.","authors":"Samanta, Debopam","year":2019,"journal":"Pediatric neurology, 96, 24-29","doi":"10.1016/j.pediatrneurol.2019.03.014","pmid":"31053391","tags":["cbd","epilepsy","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD modulates multiple endogenous systems for anticonvulsant effects. It has broad drug interactions with CYP3A4 and CYP2C19 substrates. Liver enzyme elevation occurs especially when co-administered with valproate. FDA-approved pharmaceutical-grade CBD is expensive and schedule V, while other CBD products remain schedule I and unregulated.","whyItMatters":"Many families are turning to CBD for epilepsy, but the practical reality is complicated by drug interactions, cost, regulatory inconsistency, and the risk of unregulated products.","specificNumbers":"FDA approved for Dravet and Lennox-Gastaut syndromes. Drug interactions with CYP3A4 and CYP2C19 substrates. Liver enzyme elevation with valproate co-administration. Pharmaceutical CBD reclassified as schedule V.","methodology":"Narrative review of CBD's clinical efficacy, mechanism of action, drug interactions, regulatory status, and practical challenges for epilepsy treatment.","limitations":"Narrative review. Does not include its own meta-analysis. The exact anticonvulsant mechanism remains unknown."},{"rthcId":"RTHC-02274","title":"The role of normative beliefs in the mediation of a school-based drug prevention program: A secondary analysis of the #Tamojunto cluster-randomized trial.","authors":"Sanchez, Zila M; Valente, Juliana Y; Fidalgo, Thiago M; Leal, Ana Paula; Medeiros, Pollyanna Fausta de Pimentel de; Cogo-Moreira, Hugo","year":2019,"journal":"PloS one, 14(1), e0208072","doi":"10.1371/journal.pone.0208072","pmid":"30615625","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02275","title":"Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.","authors":"Sands, Tristan T; Rahdari, Shahryar; Oldham, Michael S; Caminha Nunes, Eduardo; Tilton, Nicole; Cilio, Maria Roberta","year":2019,"journal":"CNS drugs, 33(1), 47-60","doi":"10.1007/s40263-018-0589-2","pmid":"30460546","tags":["cbd","epilepsy","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Seven of 26 children (26.9%) achieved sustained >50% seizure reduction, including 3 (11.5%) who became seizure-free. However, 80.8% had adverse events (appetite loss 38%, diarrhea 35%, weight loss 31%), 23.1% had serious adverse events (status epilepticus, catatonia, hypoalbuminemia), and 15 (57.7%) discontinued for lack of efficacy. Retention declined rapidly in the first 6 months.","whyItMatters":"This is one of the longest follow-up studies of CBD for childhood epilepsy. While the responders had dramatic results (including seizure freedom), the high adverse event and discontinuation rates give a realistic picture of long-term use.","specificNumbers":"26 children enrolled. Mean age 9.3 years. Mean CBD exposure 21 months. 26.9% sustained >50% seizure reduction. 11.5% seizure-free. 80.8% adverse events. 23.1% serious adverse events. 57.7% discontinued for lack of efficacy. 34.6% retained at 24 months.","methodology":"Open-label prospective study through expanded access programs (April 2013-December 2014). 26 children aged 1-17 with refractory epilepsy received CBD as add-on therapy at 5-25 mg/kg/day. Mean treatment duration was 21 months (range 4-53 months).","limitations":"Open-label study with no placebo group. Small sample size. Artisanal CBD formulation, not pharmaceutical-grade. All patients on concurrent antiepileptic drugs making it hard to isolate CBD effects."},{"rthcId":"RTHC-02276","title":"Effects of Cannabidiol on Diabetes Outcomes and Chronic Cerebral Hypoperfusion Comorbidities in Middle-Aged Rats.","authors":"Santiago, Amanda Nunes; Mori, Marco Aurélio; Guimarães, Francisco Silveira; Milani, Humberto; Weffort de Oliveira, Rúbia Maria","year":2019,"journal":"Neurotoxicity research, 35(2), 463-474","doi":"10.1007/s12640-018-9972-5","pmid":"30430393","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Diabetes worsened cognitive deficits from chronic cerebral hypoperfusion in middle-aged rats. CBD (10 mg/kg daily for 30 days) improved memory performance and reduced hippocampal levels of multiple inflammation markers (iNOS, Iba1, GFAP, arginase 1). CBD also attenuated the BDNF decrease caused by hypoperfusion. CBD did not affect neuroplasticity markers (GAP-43, synaptophysin) and caused weight loss.","whyItMatters":"Diabetes and aging together dramatically increase the risk of cognitive decline from reduced brain blood flow. Finding that CBD can protect against this combined insult suggests it targets the inflammatory pathway that worsens the damage.","specificNumbers":"CBD dose: 10 mg/kg daily for 30 days. Reduced iNOS, Iba1, GFAP, and arginase 1 in hippocampus. Preserved BDNF levels. Did not affect GAP-43 or synaptophysin. Caused weight loss.","methodology":"Middle-aged rats (14 months) were made diabetic with streptozotocin, subjected to chronic cerebral hypoperfusion surgery, then treated with CBD 10 mg/kg/day for 30 days. Memory, inflammation markers, and neuroplasticity markers were assessed.","limitations":"Animal study using a pharmacological diabetes model. Only one CBD dose tested. The weight loss effect of CBD needs further investigation. Results may not translate directly to humans."},{"rthcId":"RTHC-02277","title":"Concomitant THC and stress adolescent exposure induces impaired fear extinction and related neurobiological changes in adulthood.","authors":"Saravia, Rocio; Ten-Blanco, Marc; Julià-Hernández, Marina; Gagliano, Humberto; Andero, Raül; Armario, Antonio; Maldonado, Rafael; Berrendero, Fernando","year":2019,"journal":"Neuropharmacology, 144, 345-357","doi":"10.1016/j.neuropharm.2018.11.016","pmid":"30439419","tags":["youth","neuroscience","anxiety"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent mice given both THC and stress showed impaired cued fear extinction in adulthood, with decreased neuronal activity in the basolateral amygdala and infralimbic prefrontal cortex. These mice also had more immature dendritic spines in BLA pyramidal neurons and elevated corticosterone after fear conditioning. Crucially, neither THC nor stress alone produced these effects.","whyItMatters":"Many adolescents who use cannabis are also experiencing significant stress. This study shows these two factors interact to produce long-lasting anxiety-related brain changes that neither factor would cause alone.","specificNumbers":"THC + stress group showed impaired fear extinction. Decreased c-Fos in BLA and infralimbic cortex. Increased immature dendritic spines in BLA. Elevated corticosterone after fear conditioning. Neither THC nor stress alone produced these effects.","methodology":"Adolescent mice received THC treatment and/or stress exposure. In adulthood, they underwent cued fear conditioning and extinction testing. Brain tissue was analyzed for neuronal activity (c-Fos), structural plasticity (dendritic spines), and corticosterone levels.","limitations":"Mouse model; human translation uncertain. Only one THC dose regimen and one type of stress were tested. Fear extinction is a model for anxiety but does not fully replicate human anxiety disorders."},{"rthcId":"RTHC-02278","title":"Beneficial and deleterious effects of cannabinoids in the brain: the case of ultra-low dose THC.","authors":"Sarne, Yosef","year":2019,"journal":"The American journal of drug and alcohol abuse, 45(6), 551-562","doi":"10.1080/00952990.2019.1578366","pmid":"30864864","tags":["cognition","neuroscience"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review examined what happens when you give mice THC at doses so low they produce no detectable behavioral effects — 3 to 4 orders of magnitude below what it takes to get a mouse \"high.\" The results were striking: these ultra-low doses protected against various types of brain injury, including carbon monoxide toxicity, MDMA-induced damage, and age-related cognitive decline.\n\nThe proposed mechanism was preconditioning. Ultra-low THC appeared to activate mild cellular stress responses that made neurons more resilient to subsequent insults — similar to how small doses of a toxin can build tolerance. At conventional doses, THC overwhelmed these protective mechanisms and instead impaired cognitive function.\n\nThe author positioned this as a specific case of hormesis: the same compound producing opposite effects depending on the dose, with beneficial effects occurring far below the psychoactive threshold.","whyItMatters":"This challenges the assumption that the only interesting THC dose is one that gets you high. If ultra-low doses — too small to produce psychoactive effects — can protect brain cells, that opens a completely different medical application than anything in the current cannabis conversation. The protective effect against age-related cognitive decline is particularly interesting given aging population demographics.\n\nBut it's critical to note these are mouse studies at doses with no human equivalent established. The gap between \"protects mouse neurons\" and \"protects human cognition\" is enormous.","specificNumbers":"• Ultra-low dose: ~0.002 mg/kg (3-4 orders of magnitude below conventional)\n• Conventional experimental doses: 1-10 mg/kg\n• Protection demonstrated against: carbon monoxide toxicity, MDMA-induced damage, age-related cognitive decline\n• Ultra-low doses produced no detectable behavioral effects in mice","methodology":"Narrative review of preclinical studies from the author's research group and others, examining ultra-low dose THC (0.002 mg/kg, compared to standard experimental doses of 1-10 mg/kg) in mouse models of brain injury and cognitive decline.","limitations":"All evidence comes from mouse models. Ultra-low doses have not been tested in humans for neuroprotection. The author reviewed primarily their own group's research, limiting independence. The mechanism (preconditioning) is proposed but not definitively established. Clinical translation would require determining whether ultra-low doses even reach the brain in humans through standard routes."},{"rthcId":"RTHC-02279","title":"Cannabinoids in the treatment of rheumatic diseases: Pros and cons.","authors":"Sarzi-Puttini, Piercarlo; Ablin, Jacob; Trabelsi, Adva; Fitzcharles, Mary-Ann; Marotto, Daniela; Häuser, Winfried","year":2019,"journal":"Autoimmunity reviews, 18(12), 102409","doi":"10.1016/j.autrev.2019.102409","pmid":"31648042","tags":["medical-cannabis","pain","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids may help rheumatic diseases through anti-inflammatory/immunomodulatory activity and pain management. However, reviews are being published faster than trials, often reaching conflicting conclusions. The evidence for efficacy is limited and some data suggest potential harms. Safety concerns include driving risks, workplace safety, and pediatric intoxication.","whyItMatters":"Many rheumatology patients use or are curious about cannabis, especially for chronic pain. This review highlights that the enthusiasm has outpaced the evidence, and cannabis was often legalized without going through standard regulatory approval.","specificNumbers":"Systematic review publications outpacing RCTs. Reviews reach conflicting conclusions about efficacy and safety.","methodology":"Narrative review discussing advantages and limitations of cannabis for rheumatic conditions, including analysis of the imbalance between reviews and primary research.","limitations":"Narrative review. The fundamental problem it identifies (more reviews than trials) means any conclusions are built on a thin foundation."},{"rthcId":"RTHC-02280","title":"Medical cannabis and cannabinoids in rheumatology: where are we now?","authors":"Sarzi-Puttini, Piercarlo; Batticciotto, Alberto; Atzeni, Fabiola; Bazzichi, Laura; Di Franco, Manuela; Salaffi, Fausto; Marotto, Daniela; Ceribelli, Angela; Ablin, Jacob N; Hauser, Winfred","year":2019,"journal":"Expert review of clinical immunology, 15(10), 1019-1032","doi":"10.1080/1744666X.2019.1665997","pmid":"31512536","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02281","title":"Cannabis-based product use in a multiple sclerosis cohort.","authors":"Schabas, A J; Vukojevic, V; Taylor, C; Thu, Z; Badyal, A; Chan, J K; Devonshire, V; Traboulsee, A; Sayao, A L; Carruthers, R","year":2019,"journal":"Multiple sclerosis journal - experimental, translational and clinical, 5(3), 2055217319869360","doi":"10.1177/2055217319869360","pmid":"31598330","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 188 survey respondents, 19% used cannabis daily, 6% weekly, 4% monthly, 21% rarely, and 50% never. Among regular users (daily/weekly/monthly), oral (78%) and smoked/vaporized (76%) were the most common routes. From electronic medical records of 561 patients, 19% had documented cannabis use.","whyItMatters":"MS patients are among the most frequent cannabis users in the chronic disease population. Understanding usage patterns helps clinicians have informed conversations with patients about risks and benefits.","specificNumbers":"188 survey respondents. 19% (37) daily users. 6% (11) weekly. 4% (7) monthly. 21% (39) rarely. 50% (94) never. Among users: 78% oral, 76% smoked/vaporized, 25% topical, 9% mucosal.","methodology":"Two-part study: anonymous survey distributed to 600 MS patients at the University of British Columbia Hospital MS clinic (January-March 2018, 188 returned), plus retrospective EMR data extraction from 561 patients.","limitations":"Single-center study in Canada where cannabis is legal. Low survey response rate (31.3%). Anonymous survey may still underestimate use. EMR data depends on patients disclosing use to providers."},{"rthcId":"RTHC-02282","title":"Quantification of Eight Cannabinoids Including Cannabidiol in Human Urine Via Liquid Chromatography Tandem Mass Spectrometry.","authors":"Scheidweiler, Karl B; Barnes, Allan J","year":2019,"journal":"Methods in molecular biology (Clifton, N.J.), 1872, 11-22","doi":"10.1007/978-1-4939-8823-5_2","pmid":"30350275","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02283","title":"Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer's Disease.","authors":"Schubert, David; Kepchia, Devin; Liang, Zhibin; Dargusch, Richard; Goldberg, Joshua; Maher, Pamela","year":2019,"journal":"Molecular neurobiology, 56(11), 7719-7730","doi":"10.1007/s12035-019-1637-8","pmid":"31104297","tags":["neuroscience","medical-cannabis","cbd","seniors"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Nine of 11 cannabinoids protected cells in four distinct neurodegeneration assays (proteotoxicity, trophic loss, oxidative stress, energy loss). They removed intraneuronal amyloid-beta, reduced oxidative damage, and worked even in neurons lacking CB1 and CB2 receptors. THC and CBN showed synergistic neuroprotective effects when combined. Structure-activity analysis showed aromatic hydroxyls are necessary but not sufficient for neuroprotection.","whyItMatters":"Alzheimer's drug development has a 99%+ failure rate. This study shows cannabinoids protect neurons through multiple mechanisms simultaneously, which may be more effective than single-target approaches.","specificNumbers":"11 cannabinoids tested. 9 were neuroprotective across 4 assays. THC + CBN showed synergistic neuroprotection. Protection occurred even without CB1 and CB2 receptors.","methodology":"Pre-clinical drug screening platform testing 11 cannabinoids across four phenotypic neurodegeneration assays modeling aging-related brain toxicities. Pairwise combination testing for synergy. Structure-activity relationship analysis.","limitations":"Pre-clinical cell-based assays, not animal or human studies. The drug screening platform, while validated, may not fully predict in vivo outcomes. No cognitive or behavioral outcomes were measured."},{"rthcId":"RTHC-02284","title":"Cross-domain correlates of cannabis use disorder severity among young adults.","authors":"Schuster, Randi Melissa; Hareli, Maya; Moser, Amelia D; Lowman, Kelsey; Gilman, Jodi; Ulysse, Christine; Schoenfeld, David; Evins, A Eden","year":2019,"journal":"Addictive behaviors, 93, 212-218","doi":"10.1016/j.addbeh.2019.01.029","pmid":"30753972","tags":["addiction","youth","cognition","anxiety"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 71 candidate variables, five predicted CUD severity: more frequent cannabis use in the past 90 days, greater expectations that cannabis causes cognitive/behavioral impairment, greater self-reported metacognitive deficits, greater anxiety, and lower reaction time variability on sustained attention (though this last variable was less robust).","whyItMatters":"Rather than assuming what drives cannabis use disorder severity, this study let the data identify the strongest correlates. The finding that cognitive self-perception matters more than actual cognitive performance suggests that how users think about their impairment matters.","specificNumbers":"76 participants ages 18-25. 71 candidate variables examined. 27 significant univariately. 5 in final multivariable model: use frequency, cognitive impairment expectancy, metacognitive deficits, anxiety, reaction time variability.","methodology":"Data-driven, hypothesis-free analysis of 76 young adults (ages 18-25) who used cannabis at least weekly. Seventy-one candidate variables spanning demographics, mood, personality, substance use, and cognition were examined. Stepwise multivariable selection with internal validation.","limitations":"Small sample (n=76). Cross-sectional design. All participants were already weekly users, so results may not generalize to less frequent users. Hypothesis-free approach may miss theoretically important variables."},{"rthcId":"RTHC-02285","title":"Genetic tools weed out misconceptions of strain reliability in Cannabis sativa: implications for a budding industry.","authors":"Schwabe, Anna L; McGlaughlin, Mitchell E","year":2019,"journal":"Journal of cannabis research, 1(1), 3","doi":"10.1186/s42238-019-0001-1","pmid":"33526091","tags":["potency","legalization","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using 10 microsatellite markers, researchers found two genetic groups, but these did not correspond to sativa/indica/hybrid labels. Most strains had at least one genetic outlier, meaning the same strain name from different dispensaries could be genetically different. After removing outliers, many strains showed considerable stability.","whyItMatters":"Millions of consumers choose products based on sativa/indica labels, believing they predict effects. This study shows those labels have no genetic foundation, meaning consumers may be making decisions based on unreliable information.","specificNumbers":"30 strains tested from dispensaries in 3 states. 10 microsatellite markers used. 2 genetic groups found, but neither corresponded to sativa/indica/hybrid labels. Most strains had at least 1 genetic outlier.","methodology":"Developed 10 de-novo microsatellite markers from the Purple Kush genome. Tested 30 commercially available drug-type cannabis strains obtained from dispensaries in three US states.","limitations":"Limited to 30 strains. Microsatellite markers capture only part of genetic variation. Chemical profiles (cannabinoid and terpene content) were not measured and may be more relevant to effects than overall genetic identity."},{"rthcId":"RTHC-02286","title":"Identification and biochemical analyses of selective CB2 agonists.","authors":"Scott, Caitlin E; Tang, Yaliang; Alt, Andrew; Burford, Neil T; Gerritz, Samuel W; Ogawa, Lisa M; Zhang, Litao; Kendall, Debra A","year":2019,"journal":"European journal of pharmacology, 854, 1-8","doi":"10.1016/j.ejphar.2019.03.054","pmid":"30951717","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02287","title":"Therapeutic Effect of a Novel Fatty Acid Amide Hydrolase Inhibitor PF04457845 in the Repetitive Closed Head Injury Mouse Model.","authors":"Selvaraj, Prabhuanand; Wen, Jie; Tanaka, Mikiei; Zhang, Yumin","year":2019,"journal":"Journal of neurotrauma, 36(10), 1655-1669","doi":"10.1089/neu.2018.6226","pmid":"30526351","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02288","title":"Surface Detection of THC Attributable to Vaporizer Use in the Indoor Environment.","authors":"Sempio, Cristina; Lindley, Emily; Klawitter, Jost; Christians, Uwe; Bowler, Russell P; Adgate, John L; Allshouse, William; Awdziejczyk, Lauren; Fischer, Sarah; Bainbridge, Jacquelyn; Vandyke, Mike; Netsanet, Rahwa; Crume, Tessa; Kinney, Gregory L","year":2019,"journal":"Scientific reports, 9(1), 18587","doi":"10.1038/s41598-019-55151-5","pmid":"31819131","tags":["harm-reduction","respiratory"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"THC was detected on 6 of 15 surface samples collected from a room where cannabis was vaporized, at quantifiable levels of 348-4,882 ng/m2. All control samples from outside the study room were negative.","whyItMatters":"Third-hand tobacco smoke exposure (from surface residue) is a recognized health concern. This is the first study to show that cannabis vapor similarly deposits on surfaces, creating a potential exposure pathway for non-users in shared spaces.","specificNumbers":"6 of 15 surface samples positive for THC. Levels: 348-4,882 ng/m2. All negative controls were clean.","methodology":"Surface samples were collected using isopropanol-imbued non-woven wipes from hard surfaces and objects in a room where cannabis was vaporized. Samples were analyzed using LC-ESI-MS/MS with online extraction. Standardized three-pattern swabbing protocol was used.","limitations":"Single room study. Unknown how long THC persists on surfaces. Unknown whether surface-deposited THC is bioavailable through skin contact. Only THC was measured; other cannabinoids were not assessed."},{"rthcId":"RTHC-02289","title":"Stopping cannabis use benefits outcome in psychosis: findings from 10-year follow-up study in the PAFIP-cohort.","authors":"Setién-Suero, E; Neergaard, K; Ortiz-García de la Foz, V; Suárez-Pinilla, P; Martínez-García, O; Crespo-Facorro, B; Ayesa-Arriola, R","year":2019,"journal":"Acta psychiatrica Scandinavica, 140(4), 349-359","doi":"10.1111/acps.13081","pmid":"31381129","tags":["psychosis","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Persistent cannabis users had more severe symptoms (BPRS: p < .001; SAPS: p = .002) and poorer functioning (DAS: p = .048; GAF: p = .033) at 10 years compared to ex-users and never-users. Ex-users showed a similar pattern to never-users on all measures.","whyItMatters":"This is one of the longest follow-up studies to show that quitting cannabis after a first psychotic episode can essentially normalize outcomes. The message is clear: it is never too late to benefit from quitting.","specificNumbers":"209 FEP patients followed for 10 years. Persistent users: worse BPRS (p < .001), SAPS (p = .002), DAS (p = .048), GAF (p = .033). Ex-users indistinguishable from never-users.","methodology":"Longitudinal study of 209 first-episode psychosis patients from the PAFIP cohort, divided into persistent users, ex-users, and never-users. Clinical, functional, and cognitive outcomes assessed at baseline and 10-year follow-up.","limitations":"Observational design; self-selected quitters may differ from persistent users in ways not captured. Cannabis use assessed by self-report. Specific consumption patterns and potency were not detailed."},{"rthcId":"RTHC-02290","title":"A Survey of Cannabis Acute Effects and Withdrawal Symptoms: Differential Responses Across User Types and Age.","authors":"Sexton, Michelle; Cuttler, Carrie; Mischley, Laurie K","year":2019,"journal":"Journal of alternative and complementary medicine (New York, N.Y.), 25(3), 326-335","doi":"10.1089/acm.2018.0319","pmid":"30383388","tags":["withdrawal","harm-reduction","seniors"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Most common acute effects: improved sleep, calmness, desire to eat, creativity, dry mouth. Most common withdrawal: irritability, insomnia, anxiety. Medical users had fewer undesirable acute effects but more withdrawal symptoms. Adults 50+ had fewer undesirable effects overall. Only 17% believed cannabis is addictive.","whyItMatters":"The aging population accessing cannabis is growing faster than any other demographic. Understanding that older adults and medical users experience cannabis differently can improve clinical counseling and product recommendations.","specificNumbers":"2,905 respondents. Top acute effects: improved sleep, calm, appetite, creativity, dry mouth. Top withdrawal: irritability, insomnia, anxiety. 17% believed cannabis is addictive.","methodology":"Survey of 2,905 cannabis users analyzed with hierarchical logistic regression controlling for demographic and use characteristics. Compared medical vs. recreational users and age groups.","limitations":"Self-selected survey sample. Self-reported effects may be influenced by expectations. Medical vs. recreational categorization is self-defined and may overlap. Cross-sectional design."},{"rthcId":"RTHC-02291","title":"Trends and Related Factors of Cannabis-Associated Emergency Department Visits in the United States: 2006-2014.","authors":"Shen, Jay J; Shan, Guogen; Kim, Pearl C; Yoo, Ji Won; Dodge-Francis, Carolee; Lee, Yong-Jae","year":2019,"journal":"Journal of addiction medicine, 13(3), 193-200","doi":"10.1097/ADM.0000000000000479","pmid":"30418337","tags":["harm-reduction","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis-associated ED visits increased monotonically at 7% per year. Ages 12-17 had the highest risk, declining with age. Uninsured patients were over 40% more likely to visit the ED than privately insured. The South region had the highest utilization, but the West showed the fastest growth (15.4% to 26% over the study period).","whyItMatters":"Even before widespread legalization, cannabis ED visits were steadily rising. This provides a baseline for understanding how subsequent policy changes (legalization in many states after 2012) may have accelerated or moderated this trend.","specificNumbers":"265,128 cannabis-associated ED visits analyzed. 7% annual increase. Ages 12-17 highest risk. Uninsured 40%+ more likely to visit. West region grew from 15.4% to 26%.","methodology":"Pooled serial cross-sectional study using 2006-2014 National Emergency Department Sample data. Hierarchical multivariable analysis of 265,128 cannabis-associated ED visits among patients aged 12+.","limitations":"National Emergency Department Sample relies on coding accuracy. \"Cannabis-associated\" does not mean cannabis caused the visit. Could not distinguish primary from incidental cannabis involvement."},{"rthcId":"RTHC-02292","title":"The impacts of potency, warning messages, and price on preferences for Cannabis flower products.","authors":"Shi, Yuyan; Cao, Ying; Shang, Ce; Pacula, Rosalie Liccardo","year":2019,"journal":"The International journal on drug policy, 74, 1-10","doi":"10.1016/j.drugpo.2019.07.037","pmid":"31382201","tags":["legalization","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Both users and non-users preferred higher CBD and lower prices. Users also preferred higher THC. Graphic warning messages had mixed effects. Medical users were less responsive to THC than recreational or dual users, and prioritized CBD content (47% relative importance) over price. All other groups prioritized price (51-64%).","whyItMatters":"Understanding consumer preferences can inform product regulation. The finding that medical users care most about CBD while recreational users chase THC has implications for how products should be labeled and marketed.","specificNumbers":"2,400 participants from 6 states. 12 discrete choice scenarios each. Price most important for most groups (51-64%). CBD most important for medical users (47%). Medical users less responsive to THC.","methodology":"Cross-sectional online survey with discrete choice experiments. 2,400 adults aged 21+ from 6 US states with recreational legalization (1,200 users, 1,200 non-users). Each respondent evaluated 12 scenarios with varying THC, CBD, warning messages, and price. Nested logit regression analysis.","limitations":"Hypothetical choice experiment may not reflect real purchasing behavior. Online sample may not represent all cannabis consumers. Only flower products were studied; concentrates, edibles, and vapes were not included."},{"rthcId":"RTHC-02293","title":"Association between medical cannabis laws and opioid overdose mortality has reversed over time.","authors":"Shover, Chelsea L; Davis, Corey S; Gordon, Sanford C; Humphreys, Keith","year":2019,"journal":"Proceedings of the National Academy of Sciences of the United States of America, 116(26), 12624-12626","doi":"10.1073/pnas.1903434116","pmid":"31182592","tags":["legalization","pain"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Extending the Bachhuber et al. (2014) analysis from 2010 to 2017 using identical methods, the association between medical cannabis laws and opioid overdose mortality reversed from -21% to +23%. Neither recreational cannabis laws nor low-THC cannabis laws were associated with opioid mortality changes.","whyItMatters":"The original 2014 study was widely cited by the cannabis industry and advocates as evidence that medical cannabis reduces opioid deaths. This reversal demonstrates the danger of drawing causal conclusions from ecological correlations.","specificNumbers":"Original finding (1999-2010): -21% opioid mortality. Extended finding (1999-2017): +23% opioid mortality. Medical cannabis used by about 2.5% of US population. Neither recreational nor low-THC laws showed association.","methodology":"Replication and extension of Bachhuber et al. (2014) using the same state-level panel regression methods through 2017. Analyzed associations between medical cannabis law adoption and opioid analgesic overdose mortality rates.","limitations":"Ecological (state-level) analysis cannot capture individual-level substitution. The reversal itself does not prove medical cannabis increases opioid deaths. The authors interpret the association in both directions as likely spurious."},{"rthcId":"RTHC-02294","title":"Alcohol and marijuana use among young injured drivers in Arizona, 2008-2014.","authors":"Shults, Ruth A; Jones, Jefferson M; Komatsu, Kenneth K; Sauber-Schatz, Erin K","year":2019,"journal":"Traffic injury prevention, 20(1), 9-14","doi":"10.1080/15389588.2018.1527032","pmid":"30681899","tags":["driving","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of drivers with BAC results, 19% tested positive (82% of those at or above 0.08 g/dL). Of drivers with THC results, 30% tested positive. American Indians had the highest THC-positive rates (38%) and highest dual positive rates (28%). Substance-positive drivers were less likely to wear seat belts or helmets.","whyItMatters":"The high rate of THC positivity (30%) among injured young drivers, combined with reduced safety behavior, suggests cannabis-impaired driving is a substantial contributor to youth traffic injuries.","specificNumbers":"5,069 injured drivers. 19% BAC-positive (82% at 0.08+). 30% THC-positive. American Indians: 38% THC-positive, 28% dual positive. Annual injured drivers declined 41% over the study period.","methodology":"Retrospective analysis of 5,069 injured drivers aged 16-20 evaluated at Arizona level 1 trauma centers (2008-2014) using the Arizona State Trauma Registry. Descriptive analysis of BAC and THC test results by demographics and safety behaviors.","limitations":"Only injured drivers at level 1 trauma centers, not representative of all young drivers. Not all drivers were tested for both substances. THC presence indicates recent use but not necessarily impairment at time of crash."},{"rthcId":"RTHC-02295","title":"Synthetic Cannabinoids JWH-122 and THJ-2201 Disrupt Endocannabinoid-Regulated Mitochondrial Function and Activate Apoptotic Pathways as a Primary Mechanism of In Vitro Nephrotoxicity at In Vivo Relevant Concentrations.","authors":"Silva, João P; Araújo, Ana Margarida; de Pinho, Paula Guedes; Carmo, Helena; Carvalho, Félix","year":2019,"journal":"Toxicological sciences : an official journal of the Society of Toxicology, 169(2), 422-435","doi":"10.1093/toxsci/kfz050","pmid":"30796436","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02296","title":"Concerns of Patients With Cancer on Accessing Cannabis Products in a State With Restrictive Medical Marijuana Laws: A Survey Study.","authors":"Singh, Vinita; Zarrabi, Ali J; Curseen, Kimberly A; Sniecinski, Roman; Welsh, Justine W; McKenzie-Brown, Anne M; Baer, Wendy; Gillespie, Theresa W","year":2019,"journal":"Journal of oncology practice, 15(10), 531-538","doi":"10.1200/JOP.19.00184","pmid":"31442099","tags":["medical-cannabis","cancer","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 101 patients in Georgia's low-THC oil program, 76% had advanced cancer as their qualifying condition. Cannabis was rated extremely helpful for pain. Major concerns: ability to obtain THC (68%) and legality issues (64%). Several patients were using unapproved cannabis formulations. Physicians were the primary information source for 48%.","whyItMatters":"Georgia exemplifies the problem of restrictive medical cannabis laws: patients are legally authorized but have no in-state dispensaries or reliable access points, forcing them to navigate a confusing and potentially illegal landscape.","specificNumbers":"101 respondents. 56% male. 64% over age 50. 76% qualified for advanced cancer. 68% concerned about obtaining product. 64% concerned about legality. 48% got information from physicians. 38% used unapproved formulations.","methodology":"Survey of patients registered for medical marijuana (low-THC oil cards) in an ambulatory palliative care practice in Georgia.","limitations":"Single clinic, single state. Small sample. Self-reported outcomes. Georgia's laws are among the most restrictive and may not generalize to other medical cannabis states."},{"rthcId":"RTHC-02297","title":"Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies.","authors":"Sloan, Matthew E; Grant, Caroline W; Gowin, Joshua L; Ramchandani, Vijay A; Le Foll, Bernard","year":2019,"journal":"Acta pharmacologica Sinica, 40(3), 342-350","doi":"10.1038/s41401-018-0081-z","pmid":"30166624","tags":["neuroscience","psychosis","addiction","ptsd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabis users consistently had decreased CB1 receptor binding compared to controls, normalizing after short abstinence periods. Alcohol use disorder and schizophrenia showed inconsistent results (some studies finding increased, others decreased binding). Preliminary evidence of altered CB1 binding was also found in anorexia nervosa and PTSD.","whyItMatters":"This review consolidates brain imaging evidence that the endocannabinoid system is disrupted across a wide range of psychiatric disorders, not just cannabis-related conditions. This supports the endocannabinoid system as a transdiagnostic treatment target.","specificNumbers":"Five psychiatric disorders studied via PET: cannabis use disorder, alcohol use disorder, schizophrenia, PTSD, eating disorders. Cannabis users: consistent CB1 decrease. Alcohol/schizophrenia: inconsistent results.","methodology":"Comprehensive review of PET imaging studies comparing endocannabinoid signaling (primarily CB1 receptor binding) between psychiatric patients and healthy controls across five disorder categories.","limitations":"Most studies used CB1 radiotracers, limiting assessment of other endocannabinoid components. Small sample sizes in many PET studies. Inconsistent findings in some disorders make it hard to draw firm conclusions."},{"rthcId":"RTHC-02298","title":"Early evidence of the impact of cannabis legalization on cannabis use, cannabis use disorder, and the use of other substances: Findings from state policy evaluations.","authors":"Smart, Rosanna; Pacula, Rosalie Liccardo","year":2019,"journal":"The American journal of drug and alcohol abuse, 45(6), 644-663","doi":"10.1080/00952990.2019.1669626","pmid":"31603710","tags":["legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"MCLs increase adult but not adolescent cannabis use. Less regulated supply provisions may increase adult cannabis use disorders. Some evidence suggests MCLs reduce opioid-related harms. Effects on alcohol and tobacco are uncertain. RCLs show little impact on adolescent prevalence but may increase college student use. Effects of RCLs on other substance use are unknown.","whyItMatters":"As cannabis legalization spreads globally, understanding its effects on population-level substance use is critical for policy design. This review highlights the importance of law specifics, not just legalization status.","specificNumbers":"MCLs increase adult cannabis use but not adolescent use. MCLs may increase adult CUD when supply is less regulated. RCLs show little impact on adolescent prevalence. College student use may increase under RCLs.","methodology":"Narrative review of quasi-experimental studies examining how medical and recreational cannabis laws affect cannabis use and related substance use patterns.","limitations":"Narrative review. Many studies treat MCLs or RCLs as binary when they vary significantly in implementation. Long-term effects of RCLs are largely unknown as most are recently enacted."},{"rthcId":"RTHC-02299","title":"Cannabis Use for Medicinal Purposes among Canadian University Students.","authors":"Smith, Jacqueline M; Mader, Joel; Szeto, Andrew C H; Arria, Amelia M; Winters, Ken C; Wilkes, T Chris R","year":2019,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 64(5), 351-355","doi":"10.1177/0706743718818420","pmid":"30602305","tags":["medical-cannabis","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"52% had used cannabis at least once; 11% reported medicinal use. Among medicinal users, 85% also had recreational motives, 38% replaced traditional medication with cannabis, 78% used for at least one mental health condition, and 13.6% met CUD criteria. None of the reported ailments met Canadian prescribing guidelines or had strong evidence.","whyItMatters":"University students are self-medicating with cannabis for conditions lacking evidence of effectiveness, replacing evidence-based treatments, and developing use disorders. The line between medical and recreational use is blurry in this population.","specificNumbers":"2,212 respondents. 52% ever used cannabis. 11% medicinal use. 85% of medicinal users also used recreationally. 38% replaced medication. 78% used for mental health. 13.6% met CUD criteria.","methodology":"Cross-sectional web-based survey of a random sample of 4,000 Canadian university students (2,212 completed, 55.3% response rate, mean age 23.2 years).","limitations":"Single university in Canada. Self-reported medicinal status. Cross-sectional design. Response rate, while decent, may overrepresent cannabis-interested students."},{"rthcId":"RTHC-02300","title":"Cannabinoid hyperemesis syndrome: An unrecognized cause of nausea and vomiting.","authors":"Smith, Tiffany N; Walsh, Anne; Forest, Christopher P","year":2019,"journal":"JAAPA : official journal of the American Academy of Physician Assistants, 32(4), 1-5","doi":"10.1097/01.JAA.0000554231.86747.0a","pmid":"30913155","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02301","title":"A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects.","authors":"Solowij, Nadia; Broyd, Samantha; Greenwood, Lisa-Marie; van Hell, Hendrika; Martelozzo, Dave; Rueb, Kuna; Todd, Juanita; Liu, Zheng; Galettis, Peter; Martin, Jennifer; Murray, Robin; Jones, Alison; Michie, Patricia T; Croft, Rodney","year":2019,"journal":"European archives of psychiatry and clinical neuroscience, 269(1), 17-35","doi":"10.1007/s00406-019-00978-2","pmid":"30661105","tags":["potency","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"CBD alone (400 mg) showed some intoxicating properties vs. placebo. When combined with 8 mg THC, low CBD (4 mg) enhanced intoxication while high CBD (400 mg) reduced it. The enhancement by low-dose CBD was especially prominent in infrequent cannabis users and consistent across objective and subjective measures. Most effects were significant at p < .0001.","whyItMatters":"This fundamentally challenges the simple narrative that \"CBD counteracts THC.\" The dose matters enormously, and low-dose CBD (the ratio found in many commercial products) may actually make THC more intoxicating.","specificNumbers":"36 participants. 5 conditions. CBD alone (400 mg) was somewhat intoxicating. Low CBD (4 mg) + THC (8 mg) enhanced intoxication. High CBD (400 mg) + THC (8 mg) reduced intoxication. Effects significant at p < .0001.","methodology":"Randomized, placebo-controlled trial with 36 participants (31 male) completing 5 drug conditions one week apart: placebo, CBD alone (400 mg), THC alone (8 mg), THC + low CBD (4 mg), THC + high CBD (400 mg). Administered by vaporization.","limitations":"Relatively small sample (n=36). Predominantly male (31/36). Vaporization delivery may not generalize to other routes. Only two CBD doses tested, so the threshold for switching from enhancement to reduction is unknown."},{"rthcId":"RTHC-02302","title":"Individual factors influencing the duration of untreated psychosis.","authors":"Souaiby, Lama; Gauthier, Claire; Kazes, Mathilde; Mam-Lam-Fook, Célia; Daban, Claire; Plaze, Marion; Gaillard, Raphaël; Krebs, Marie-Odile","year":2019,"journal":"Early intervention in psychiatry, 13(4), 798-804","doi":"10.1111/eip.12562","pmid":"29575691","tags":["psychosis"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"No single sociodemographic or disease factor predicted duration of untreated psychosis (DUP) individually except education level. In multivariate analysis, age at inclusion, negative symptoms, and cannabis use history significantly predicted longer DUP.","whyItMatters":"Longer DUP is associated with worse long-term outcomes in psychosis. If cannabis use contributes to delayed treatment-seeking, this is a modifiable factor that early intervention programs should address.","specificNumbers":"33 patients studied. Cannabis use, age, and negative symptoms were significant predictors of DUP in multivariate analysis. No other individual factors were significant.","methodology":"Prospective study of 33 consecutive patients crossing the CAARMS psychosis threshold at a specialized early detection clinic in Paris. DUP and cannabis history assessed through comprehensive interviews of patients, parents, and practitioners.","limitations":"Very small sample (n=33). Single-center study in Paris. DUP measurement depends on accurate recall of symptom onset. Multivariate model with three predictors in 33 subjects has limited statistical power."},{"rthcId":"RTHC-02303","title":"Cannabinoid CB1 and CB2 receptor mechanisms underlie cannabis reward and aversion in rats.","authors":"Spiller, Krista J; Bi, Guo-Hua; He, Yi; Galaj, Ewa; Gardner, Eliot L; Xi, Zheng-Xiong","year":2019,"journal":"British journal of pharmacology, 176(9), 1268-1281","doi":"10.1111/bph.14625","pmid":"30767215","tags":["addiction","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using electrical brain stimulation in rats, researchers mapped out how THC affects the brain's reward system at different doses. The result was a clean biphasic pattern: low doses of THC mildly enhanced brain-stimulation reward, while higher doses inhibited it — meaning higher doses made the stimulation less rewarding, not more.\n\nThe mechanism split neatly by receptor type. When researchers blocked CB1 receptors, the low-dose reward enhancement disappeared. When they blocked CB2 receptors, the high-dose reward suppression disappeared. Selective CB1 agonists confirmed the reward effect; selective CB2 agonists confirmed the aversive effect.\n\nThis provides a biological explanation for why cannabis can feel pleasant at one dose and deeply unpleasant at another — and why inexperienced users who consume too much often have negative experiences rather than simply \"more\" of the positive experience.","whyItMatters":"This study provides a mechanistic explanation for something cannabis users know intuitively: there's a sweet spot, and going past it doesn't make things better. The finding that CB1 and CB2 receptors produce opposing effects on reward explains the biphasic dose-response that shows up across cannabis research — in cognition, anxiety, nausea, and now reward.\n\nIt also has implications for addiction science. If the rewarding effects are CB1-mediated and self-limiting because CB2 kicks in at higher doses, cannabis may have a built-in ceiling on its rewarding properties. This could partly explain why cannabis has a lower addiction liability than drugs that produce dose-dependent reward without an opposing mechanism.","specificNumbers":"• Low-dose THC: mild brain-stimulation reward enhancement (CB1-mediated)\n• High-dose THC: reward suppression (CB2-mediated)\n• CB1 antagonist (AM251) blocked the low-dose reward effect\n• CB2 antagonist (AM630) blocked the high-dose aversive effect","methodology":"Electrical intracranial self-stimulation (ICSS) paradigm in adult Sprague-Dawley rats. Tested two mixed CB1/CB2 agonists (THC and WIN55,212-2), then used selective receptor antagonists (AM251 for CB1, AM630 for CB2) to dissect receptor-specific contributions. Confirmed with selective CB1 and CB2 agonists.","limitations":"Rat brain reward circuitry is similar but not identical to human reward circuits. The ICSS paradigm measures brain stimulation reward, which is related to but not the same as the subjective experience of using cannabis. Doses were administered by injection, not inhalation. The CB2 receptor findings are relatively new and less established than CB1 pharmacology."},{"rthcId":"RTHC-02304","title":"Screening for Adolescent Alcohol Use in the Emergency Department: What Does It Tell Us About Cannabis, Tobacco, and Other Drug Use?","authors":"Spirito, Anthony; Bromberg, Julie R; Casper, T Charles; Chun, Thomas; Mello, Michael J; Mull, Colette C; Shenoi, Rohit P; Vance, Cheryl; Ahmad, Fahd; Bajaj, Lalit; Brown, Kathleen M; Chernick, Lauren S; Cohen, Daniel M; Fein, Joel; Horeczko, Timothy; Levas, Michael N; McAninch, B; Monuteaux, Michael C; Grupp-Phelan, Jackie; Powell, Elizabeth C; Rogers, Alexander; Suffoletto, Brian; Linakis, James G","year":2019,"journal":"Substance use & misuse, 54(6), 1007-1016","doi":"10.1080/10826084.2018.1558251","pmid":"30727811","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02305","title":"Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia.","authors":"Stark, Tibor; Ruda-Kucerova, Jana; Iannotti, Fabio Arturo; D'Addario, Claudio; Di Marco, Roberta; Pekarik, Vladimir; Drazanova, Eva; Piscitelli, Fabiana; Bari, Monica; Babinska, Zuzana; Giurdanella, Giovanni; Di Bartolomeo, Martina; Salomone, Salvatore; Sulcova, Alexandra; Maccarrone, Mauro; Wotjak, Carsten T; Starcuk, Zenon; Drago, Filippo; Mechoulam, Raphael; Di Marzo, Vincenzo; Micale, Vincenzo","year":2019,"journal":"Neuropharmacology, 146, 212-221","doi":"10.1016/j.neuropharm.2018.11.035","pmid":"30496751","tags":["cbd","psychosis","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Peripubertal CBD treatment (30 mg/kg/day from PND 19-39) reversed social interaction deficits and cognitive impairment in MAM rats. CBD also normalized increased CB1 receptor mRNA and protein expression (and reduced DNA methylation at the CB1 promoter) in the prefrontal cortex. A CB1 antagonist (AM251) partially replicated CBD's effects, but the antipsychotic haloperidol did not.","whyItMatters":"This suggests that early intervention with CBD during a critical developmental window could prevent schizophrenia-like symptoms from manifesting. The fact that haloperidol (a standard antipsychotic) failed where CBD succeeded highlights CBD's unique mechanism.","specificNumbers":"CBD 30 mg/kg/day from PND 19-39. Reversed social interaction and novel object recognition deficits. Normalized CB1 mRNA, protein expression, and DNA methylation in prefrontal cortex. Haloperidol did not produce these effects.","methodology":"MAM (methylazoxymethanol) model: pregnant rats received MAM at gestational day 17 to produce offspring with schizophrenia-like features. Offspring received CBD (30 mg/kg/day), AM251 (0.5 mg/kg/day), or haloperidol (0.6 mg/kg/day) during the peripubertal period (PND 19-39). Behavioral testing and molecular analysis conducted in adulthood.","limitations":"Animal model using a specific prenatal insult that may not replicate all aspects of human schizophrenia. Only one CBD dose tested. The peripubertal treatment window is specific and may not translate directly to human adolescence."},{"rthcId":"RTHC-02306","title":"Diverse TRPV1 responses to cannabinoids.","authors":"Starkus, J; Jansen, C; Shimoda, L M N; Stokes, A J; Small-Howard, A L; Turner, H","year":2019,"journal":"Channels (Austin, Tex.), 13(1), 172-191","doi":"10.1080/19336950.2019.1619436","pmid":"31096838","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02307","title":"Endocannabinoid regulation of homeostatic feeding and stress-induced alterations in food intake in male rats.","authors":"Sticht, Martin A; Lau, David J; Keenan, Catherine M; Cavin, Jean-Baptiste; Morena, Maria; Vemuri, Venkata Kiran; Makriyannis, Alexandros; Cravatt, Benjamin F; Sharkey, Keith A; Hill, Matthew N","year":2019,"journal":"British journal of pharmacology, 176(10), 1524-1540","doi":"10.1111/bph.14453","pmid":"30051485","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02308","title":"Cannabis and youth protection in Colorado's commercial adult-use market: A qualitative investigation.","authors":"Subritzky, Todd; Lenton, Simon; Pettigrew, Simone","year":2019,"journal":"The International journal on drug policy, 74, 116-126","doi":"10.1016/j.drugpo.2019.09.007","pmid":"31586774","tags":["legalization","youth","harm-reduction"],"studyType":"qualitative","evidenceStrength":"moderate","keyFinding":"Qualitative interviews with 32 key stakeholders and analysis of 13 government documents revealed five themes: advertising restrictions, education efforts, appropriation of funds for prevention, impact assessment challenges, and evolving messages in prevention campaigns. Stakeholders noted that while advertising restrictions existed pre-implementation, enforcement and funding for youth education were ongoing challenges.","whyItMatters":"As more jurisdictions legalize cannabis, Colorado serves as the longest-running case study for how youth protection measures play out in practice versus on paper.","specificNumbers":"13 government documents analyzed. 32 stakeholders interviewed. 5 themes identified. Pre-implementation phase covered November 2012 through December 2013. Interviews conducted in 2016 and 2017.","methodology":"Qualitative descriptive methodology using document analysis of 13 government documents from the pre-implementation phase (2012-2013) and 32 semi-structured interviews with regulators and stakeholders conducted in 2016-2017.","limitations":"Qualitative study with no quantitative outcome measures. Limited to one state. Stakeholder perspectives may not fully represent youth experiences."},{"rthcId":"RTHC-02309","title":"Feasibility and effects of galantamine on cognition in humans with cannabis use disorder.","authors":"Sugarman, Dawn E; De Aquino, Joao P; Poling, James; Sofuoglu, Mehmet","year":2019,"journal":"Pharmacology, biochemistry, and behavior, 181, 86-92","doi":"10.1016/j.pbb.2019.05.004","pmid":"31082417","tags":["addiction","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Both the galantamine and placebo groups showed modest improvements in response inhibition and attention over 10 days. Cannabis withdrawal and craving decreased over time in both groups. No significant treatment effect or treatment-by-time interaction was found for galantamine versus placebo.","whyItMatters":"As cannabis use and THC concentrations increase, finding ways to counteract cognitive effects becomes more relevant. This pilot establishes that galantamine is at least safe in this population.","specificNumbers":"30 participants (73.5% male, 26.5% female). 8 mg/day galantamine dose. 10-day treatment period. 3 cognitive assessments. 6 time points for self-reported measures.","methodology":"Randomized, double-blind, parallel-group trial with 30 participants with cannabis use disorder. Participants received either 8 mg/day galantamine or placebo for 10 days, with cognitive assessments at three time points.","limitations":"Very small sample size (30 participants). Short treatment duration (10 days). The 8 mg/day dose was the lowest therapeutic dose, and higher doses might produce different results. No acute cannabis intoxication was tested."},{"rthcId":"RTHC-02310","title":"Marijuana trajectories and associations with driving risk behaviors in Canadian youth.","authors":"Sukhawathanakul, Paweena; Thompson, Kara; Brubacher, Jeff; Leadbeater, Bonnie","year":2019,"journal":"Traffic injury prevention, 20(5), 472-477","doi":"10.1080/15389588.2019.1622097","pmid":"31194581","tags":["driving","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Chronic cannabis users and those with increasing use patterns were more likely to engage in risky impaired driving behaviors. Frequency of cannabis use independently predicted impaired driving risk after controlling for age, sex, socioeconomic status, other substance use, and simultaneous substance use. Youth using cannabis more than once a week were also more likely to drink heavily and use alcohol simultaneously.","whyItMatters":"With cannabis legalization expanding, understanding which usage patterns predict driving risk can help target prevention efforts toward the highest-risk groups.","specificNumbers":"10-year follow-up period (2003-2013). 6 biennial interviews. 5 user groups identified: chronic users, increasers, occasional users, decreasers, and abstainers. Cannabis use more than once a week associated with increased driving risk.","methodology":"Longitudinal Victoria Healthy Youth Survey following youth biennially over 6 occasions across 10 years (2003-2013), examining the association between marijuana use trajectories and impaired driving risks.","limitations":"Self-reported data. Single Canadian city (Victoria). Driving risk was self-reported, not measured through accident records or driving performance tests."},{"rthcId":"RTHC-02311","title":"The Role of Cannabis in the Management of Inflammatory Bowel Disease: A Review of Clinical, Scientific, and Regulatory Information.","authors":"Swaminath, Arun; Berlin, Eric P; Cheifetz, Adam; Hoffenberg, Ed; Kinnucan, Jami; Wingate, Laura; Buchanan, Sarah; Zmeter, Nada; Rubin, David T","year":2019,"journal":"Inflammatory bowel diseases, 25(3), 427-435","doi":"10.1093/ibd/izy319","pmid":"30358848","tags":["medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Preclinical data demonstrate cannabinoid anti-inflammatory, antidiarrheal, and pain-limiting properties. Human studies show benefits in symptom control and quality of life, but biomarker profiles and endoscopic healing have not improved, meaning the underlying disease process appears unaffected.","whyItMatters":"IBD patients frequently ask about cannabis, and many self-medicate. The disconnect between symptom relief and disease modification is critical information for making informed decisions.","specificNumbers":"No specific patient counts provided. Review covered preclinical animal models, human clinical studies, and safety data across the existing literature.","methodology":"White paper reviewing preclinical data, clinical studies, safety data, and the regulatory landscape for medical cannabis use in inflammatory bowel disease.","limitations":"Narrative review without systematic search methodology. Federal Schedule I classification limits the quality and quantity of available research."},{"rthcId":"RTHC-02312","title":"Vaporized Cannabis Is Effective and Well-Tolerated in an Adolescent with Tourette Syndrome.","authors":"Szejko, Natalia; Jakubovski, Ewgeni; Fremer, Carolin; Müller-Vahl, Kirsten R","year":2019,"journal":"Medical cannabis and cannabinoids, 2(1), 60-63","doi":"10.1159/000496355","pmid":"34676335","tags":["medical-cannabis","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"After initial vaporized cannabis (4.4 mg THC equivalent), the parents reported immediate and nearly complete tic remission. A regular combination of vaporized cannabis (up to 22 mg THC/day) plus oral THC drops (up to 12.5 mg/day) maintained marked tic reduction. During a clinic visit, significant improvement in tics, premonitory urges, and overall impairment was observed 30 minutes after vaporization.","whyItMatters":"Cannabis treatment in minors is controversial, and documented cases with clinical observation are rare. This case provides direct clinical measurement of effects in a pediatric patient.","specificNumbers":"Patient age: 12. Initial dose: 0.02 g vaporized cannabis (4.4 mg THC). Maintenance: up to 0.1 g/day vaporized (22 mg THC/day) plus 12.5 mg oral THC/day. Clinical observation: 0.15 g vaporized (33 mg THC) plus 7 mg oral THC taken 6 hours prior.","methodology":"Single case report of a 12-year-old boy. Parents (both physicians) initiated cannabis treatment independently. Clinical assessment conducted during a subsequent visit at a specialized Tourette clinic.","limitations":"Single case report with no control or blinding. Parents initiated treatment without specialist consultation. No long-term follow-up data. Self-ratings and parent ratings may be biased."},{"rthcId":"RTHC-02313","title":"The effects of marijuana smoking on lung function in older people.","authors":"Tan, Wan C; Bourbeau, Jean; Aaron, Shawn D; Hogg, James C; Maltais, François; Hernandez, Paul; Marciniuk, Darcy D; Chapman, Kenneth R; To, Teresa; FitzGerald, J Mark; Walker, Brandie L; Road, Jeremy; Zheng, Liyun; Zhou, Guohai; Yau, Trevor; Benedetti, Andrea; O'Donnell, Denis; Sin, Don D","year":2019,"journal":"The European respiratory journal, 54(6)","doi":"10.1183/13993003.00826-2019","pmid":"31537703","tags":["respiratory","seniors"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among heavy marijuana users, the risk of COPD was significantly increased (adjusted OR 2.45, 95% CI 1.55-3.88). Heavy marijuana smokers who also smoked tobacco experienced faster FEV1 decline of 29.5 mL/year compared to never-smokers, while heavy tobacco smokers alone declined 21.1 mL/year.","whyItMatters":"Most marijuana-lung studies focus on younger populations. This study specifically examines older adults, where cumulative exposure effects become more apparent and COPD risk is most relevant.","specificNumbers":"1,285 participants aged 40+. ~20% had been or were current marijuana smokers. 83% of marijuana smokers also smoked tobacco. Heavy use defined as >20 joint-years. COPD risk: adjusted OR 2.45 (95% CI 1.55-3.88). FEV1 decline: 29.5 mL/year for heavy dual smokers vs. 21.1 mL/year for heavy tobacco only.","methodology":"Longitudinal analysis of 1,285 males and females aged 40+ from the Canadian Cohort of Obstructive Lung Disease study, with spirometry performed before and after bronchodilator on multiple occasions. Mixed effects regression models adjusted for age, sex, and BMI.","limitations":"Self-reported marijuana use. 83% of marijuana smokers also used tobacco, making it difficult to isolate marijuana-specific effects. Observational design cannot establish causation."},{"rthcId":"RTHC-02314","title":"Pulmonary effects of inhaled cannabis smoke.","authors":"Tashkin, Donald P; Roth, Michael D","year":2019,"journal":"The American journal of drug and alcohol abuse, 45(6), 596-609","doi":"10.1080/00952990.2019.1627366","pmid":"31298945","tags":["respiratory"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis smoking topography (deeper inhalation, longer breath-holding) results in higher per-puff exposures to tar and gases compared to tobacco. Chronic cough, sputum, wheeze, and airway inflammation are similar between cannabis and tobacco smokers. Cannabis smoke has modest bronchodilator properties but of unclear clinical significance. Alveolar macrophages from cannabis smokers show deficits in cytokine production and antimicrobial activity not seen in tobacco smokers.","whyItMatters":"With cannabis use increasing, understanding the respiratory profile of smoked cannabis helps inform harm reduction choices, particularly for people who also smoke tobacco.","specificNumbers":"No specific pooled numbers. Review synthesized findings across the existing literature on cannabis smoking and respiratory health.","methodology":"Focused literature review examining respiratory symptoms, lung function, bronchial mucosa changes, alveolar macrophage function, COPD, lung cancer, and pulmonary infection risks.","limitations":"Relative paucity of well-controlled studies. Most research is confounded by concurrent tobacco use. Conflicting outcomes across studies prevent firm conclusions."},{"rthcId":"RTHC-02315","title":"Single center experience with medical cannabis in Gilles de la Tourette syndrome.","authors":"Thaler, Avner; Arad, Shira; Schleider, Lihi Bar-Lev; Knaani, Judith; Taichman, Tali; Giladi, Nir; Gurevich, Tanya","year":2019,"journal":"Parkinsonism & related disorders, 61, 211-213","doi":"10.1016/j.parkreldis.2018.10.004","pmid":"30292733","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The overall global impression of efficacy score was 3.85 out of 5. Thirty-eight of 42 patients reported some benefit, most commonly tic reduction, better sleep, and improved mood. Ten patients with more than one year of use chose to stop treatment for various reasons, including one case of psychosis.","whyItMatters":"Controlled trials of cannabis for Tourette syndrome are few and small. Real-world data from a clinical setting helps fill the evidence gap, even if it cannot establish efficacy the way a trial can.","specificNumbers":"42 patients surveyed (33 males). Mean age 34.5. Global efficacy score: 3.85/5. 38 patients reported benefit. 10 patients (with 1+ year use) stopped treatment. 1 patient developed psychosis.","methodology":"Cross-sectional phone interview survey of 42 Tourette syndrome patients (33 males, mean age 34.5) treated with medical cannabis at a single center. Efficacy rated on a 1-5 Likert scale.","limitations":"Single-center survey with no control group or blinding. Subjective self-report measures only. Selection bias likely (patients who found benefit may be more willing to participate). No standardized tic severity measurements."},{"rthcId":"RTHC-02316","title":"Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors.","authors":"Tham, Mylyne; Yilmaz, Orhan; Alaverdashvili, Mariam; Kelly, Melanie E M; Denovan-Wright, Eileen M; Laprairie, Robert B","year":2019,"journal":"British journal of pharmacology, 176(10), 1455-1469","doi":"10.1111/bph.14440","pmid":"29981240","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02317","title":"Neurocognition and Subjective Experience Following Acute Doses of the Synthetic Cannabinoid JWH-018: Responders Versus Nonresponders.","authors":"Theunissen, Eef L; Hutten, Nadia R P W; Mason, Natasha L; Toennes, Stefan W; Kuypers, Kim P C; Ramaekers, Johannes G","year":2019,"journal":"Cannabis and cannabinoid research, 4(1), 51-61","doi":"10.1089/can.2018.0047","pmid":"31363493","tags":["synthetic-cannabinoids","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"JWH-018 increased heart rate and impaired critical tracking and memory performance overall. Participants who experienced a subjective high (\"responders\") had significantly higher serum JWH-018 concentrations and showed additional impairments in reaction time plus increased confusion, amnesia, dissociation, derealization, and depersonalization. Lack of control over drug delivery may have contributed to the large variability in response.","whyItMatters":"Synthetic cannabinoids are often marketed as legal alternatives to cannabis but may carry distinct risks. This controlled study documents specific cognitive and psychological effects under laboratory conditions.","specificNumbers":"17 participants. Doses: 2-6.2 mg JWH-018. 12-hour monitoring. Responders had significantly higher serum concentrations. Impairments in critical tracking and memory across all participants.","methodology":"Placebo-controlled, crossover study with 17 healthy cannabis-experienced participants. Participants inhaled vaporized JWH-018 (2-6.2 mg) and were monitored for 12 hours with vital signs, cognitive tests, and subjective experience measures.","limitations":"Small sample size (17). Variability in drug delivery by vaporization. All participants had prior cannabis experience, so results may not generalize to naive users."},{"rthcId":"RTHC-02318","title":"Marijuana Use in Pregnancy: A Review.","authors":"Thompson, Rebecca; DeJong, Katherine; Lo, Jamie","year":2019,"journal":"Obstetrical & gynecological survey, 74(7), 415-428","doi":"10.1097/OGX.0000000000000685","pmid":"31343707","tags":["pregnancy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"THC readily crosses the placenta, and cannabinoid receptors have been identified in fetal brain and placenta. Available studies support some degree of developmental disruption, including increased risk of fetal growth restriction and adverse neurodevelopmental consequences. However, most research was done in the 1980s with lower-THC cannabis, relied on self-report, and was confounded by polysubstance use.","whyItMatters":"Cannabis is the most commonly used dependent substance in pregnancy, and THC concentrations have increased dramatically since the older studies were conducted, making updated research critical.","specificNumbers":"No specific pooled statistics. Review notes marijuana is the most commonly used dependent substance in pregnancy and that much research dates to the 1980s.","methodology":"Literature review of PubMed-indexed studies on cannabis, cannabinoids, and marijuana in relation to fetal outcomes, perinatal outcomes, pregnancy, and lactation.","limitations":"Most underlying studies are observational or retrospective with small samples. Self-reported use. Confounded by polysubstance abuse. Older studies used lower-THC cannabis."},{"rthcId":"RTHC-02319","title":"Emerging Public Health Law and Policy Issues Concerning State Medical Cannabis Programs.","authors":"Tilburg, William C; Hodge, James G; Gourdet, Camille","year":2019,"journal":"The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics, 47(2_suppl), 108-111","doi":"10.1177/1073110519857331","pmid":"31298127","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02320","title":"Stress and drug abuse-related disorders: The promising therapeutic value of neurosteroids focus on pregnenolone-progesterone-allopregnanolone pathway.","authors":"Tomaselli, Giovanni; Vallée, Monique","year":2019,"journal":"Frontiers in neuroendocrinology, 55, 100789","doi":"10.1016/j.yfrne.2019.100789","pmid":"31525393","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02321","title":"Exposure to tobacco smoke during the early postnatal period modifies receptors and enzymes of the endocannabinoid system in the brainstem and striatum in mice.","authors":"Torres, Larissa Helena; Balestrin, Natalia Trigo; Spelta, Lídia Emmanuela Wiazowski; Duro, Stephanie de Oliveira; Pistis, Marco; Marcourakis, Tania","year":2019,"journal":"Toxicology letters, 302, 35-41","doi":"10.1016/j.toxlet.2018.12.002","pmid":"30553937","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02322","title":"CB1 positive allosteric modulation attenuates Δ9-THC withdrawal and NSAID-induced gastric inflammation.","authors":"Trexler, K R; Eckard, M L; Kinsey, S G","year":2019,"journal":"Pharmacology, biochemistry, and behavior, 177, 27-33","doi":"10.1016/j.pbb.2018.12.009","pmid":"30597181","tags":["withdrawal","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"ZCZ011 (at 10 mg/kg and above) significantly reduced somatic withdrawal signs including head twitches and paw tremors in both precipitated and spontaneous THC withdrawal models. Importantly, ZCZ011 did not affect locomotor activity and did not produce conditioned place preference, suggesting it lacks the rewarding and sedating properties of direct CB1 agonists.","whyItMatters":"Cannabis withdrawal is increasingly recognized as a clinical problem. A drug that eases withdrawal without producing its own psychoactive effects or abuse potential could be a useful treatment tool.","specificNumbers":"THC dose: 10 mg/kg. ZCZ011 effective at 10 mg/kg and above. Rimonabant precipitating dose: 3 mg/kg. ZCZ011 also blocked NSAID-induced gastric ulcers when combined with 1 mg/kg JZL184.","methodology":"Mice were repeatedly administered THC (10 mg/kg) then withdrawal was either precipitated with rimonabant or allowed to occur spontaneously via THC abstinence. ZCZ011 was tested at multiple doses. Additional experiments tested ZCZ011 for anti-ulcer properties.","limitations":"Animal study only (mice). Effects may not translate to humans. THC withdrawal in mice presents differently than in humans. No cognitive outcomes measured."},{"rthcId":"RTHC-02323","title":"Oral Fluid and Drug Impairment: Pairing Toxicology with Drug Recognition Expert Observations.","authors":"Truver, Michael T; Palmquist, Kaitlyn B; Swortwood, Madeleine J","year":2019,"journal":"Journal of analytical toxicology, 43(8), 637-643","doi":"10.1093/jat/bkz075","pmid":"31504595","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02324","title":"A Mechanistic and Pathophysiological Approach for Stroke Associated with Drugs of Abuse.","authors":"Tsatsakis, Aristides; Docea, Anca Oana; Calina, Daniela; Tsarouhas, Konstantinos; Zamfira, Laura-Maria; Mitrut, Radu; Sharifi-Rad, Javad; Kovatsi, Leda; Siokas, Vasileios; Dardiotis, Efthimios; Drakoulis, Nikolaos; Lazopoulos, George; Tsitsimpikou, Christina; Mitsias, Panayiotis; Neagu, Monica","year":2019,"journal":"Journal of clinical medicine, 8(9)","doi":"10.3390/jcm8091295","pmid":"31450861","tags":["cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis-related stroke mechanisms include transient vasospasm that can cause ischemic stroke. Case reports of cannabis-induced stroke disproportionately involve young people. Synthetic cannabinoids can also cause vasospasm leading to ischemic stroke. Common stroke mechanisms across drugs of abuse include arrhythmias, cardioembolism, hypoxia, vascular toxicity, and effects on thrombotic mechanisms.","whyItMatters":"Stroke in young people is often unexplained, and drug use may be an underrecognized contributing factor. Understanding the specific mechanisms helps with both diagnosis and prevention.","specificNumbers":"No specific incidence rates provided. Review covered multiple drug classes and their associated stroke mechanisms.","methodology":"Narrative review examining mechanistic and pathophysiological pathways linking cocaine, amphetamines, heroin, morphine, cannabis, synthetic cannabinoids, and anabolic steroids to both ischemic and hemorrhagic stroke.","limitations":"Based largely on case reports and mechanistic data rather than large epidemiological studies. Cannot establish how common drug-related stroke actually is. Cannabis-specific evidence is limited."},{"rthcId":"RTHC-02325","title":"Cannabis for cancer - illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology.","authors":"Turgeman, Ilit; Bar-Sela, Gil","year":2019,"journal":"Expert opinion on investigational drugs, 28(3), 285-296","doi":"10.1080/13543784.2019.1561859","pmid":"30572744","tags":["cancer","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Sufficient evidence supports cannabis for palliative indications in oncology, including chemotherapy-induced nausea and vomiting, cancer-related pain, anorexia, insomnia, and anxiety. Preclinical data show potent antineoplastic (antitumor) activity through immunological and direct mechanisms. However, no clinical trials have confirmed antitumor effects in humans. Concepts like synergism with conventional treatments, dosing sequence, and molecular cross-talk remain largely unexplored.","whyItMatters":"Cancer patients are among the most common medical cannabis users, but there is a large gap between what preclinical research suggests about antitumor effects and what has been proven in humans.","specificNumbers":"No specific pooled statistics. Review covered both natural and synthetic cannabinoids across palliative and potential antitumor applications.","methodology":"Narrative review classifying cannabinoids by natural and synthetic subtypes, examining mechanisms of action, clinical evidence for palliative indications, and preclinical evidence for antitumor activity.","limitations":"Narrative review. No meta-analysis of palliative outcomes. Antitumor evidence is entirely preclinical. Regulatory barriers limit clinical trial design and conduct."},{"rthcId":"RTHC-02326","title":"Cannabichromene is a cannabinoid CB2 receptor agonist.","authors":"Udoh, Michael; Santiago, Marina; Devenish, Steven; McGregor, Iain S; Connor, Mark","year":2019,"journal":"British journal of pharmacology, 176(23), 4537-4547","doi":"10.1111/bph.14815","pmid":"31368508","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02327","title":"An Update of Current Cannabis-Based Pharmaceuticals in Pain Medicine.","authors":"Urits, Ivan; Borchart, Matthew; Hasegawa, Morgan; Kochanski, Justin; Orhurhu, Vwaire; Viswanath, Omar","year":2019,"journal":"Pain and therapy, 8(1), 41-51","doi":"10.1007/s40122-019-0114-4","pmid":"30721403","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Nabiximols, a specific cannabis extract, has demonstrated benefit for pain related to spasticity in multiple sclerosis, cancer pain, and chronic pain conditions. Epidiolex (CBD oral solution), approved in the US for epilepsy, may also offer pain relief. Investigational synthetic cannabinoids from companies like Cara Therapeutics and Zynerba Pharmaceuticals are targeting neuropathic pain and allodynia specifically.","whyItMatters":"The shift from smoked cannabis to pharmaceutical-grade cannabinoid products addresses the inconsistent delivery and dosing problems of smoking, potentially making cannabinoid therapy more precise and reliable.","specificNumbers":"No specific trial data pooled. Review covered nabiximols (available in Canada and Europe), Epidiolex (available in US), and investigational drugs from Cara Therapeutics and Zynerba Pharmaceuticals.","methodology":"Narrative review of currently available and developmental cannabis pharmaceutical derivatives for pain management.","limitations":"Narrative review without systematic methodology. Many of the drugs discussed were still investigational at time of publication."},{"rthcId":"RTHC-02328","title":"Driver-related risk factors of fatal road traffic crashes associated with alcohol or drug impairment.","authors":"Valen, Anja; Bogstrand, Stig Tore; Vindenes, Vigdis; Frost, Joachim; Larsson, Magnus; Holtan, Anders; Gjerde, Hallvard","year":2019,"journal":"Accident; analysis and prevention, 131, 191-199","doi":"10.1016/j.aap.2019.06.014","pmid":"31306833","tags":["driving"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"THC was found above impairment limits in 4% of fatally injured drivers. Unlike alcohol and stimulants (which were associated with speeding, no seatbelt, and no license), cannabis impairment was specifically associated only with not having a valid driver license. Drug/alcohol-impaired drivers were far more likely to speed (68% vs 32%), skip seatbelts (69% vs 30%), and lack valid licenses (26% vs 1%) compared to sober drivers.","whyItMatters":"Understanding which risky behaviors accompany which substances can help target enforcement and prevention efforts more effectively.","specificNumbers":"772 fatally injured drivers/riders (2005-2015). Alcohol: 20%. Medicinal drugs: 10%. Stimulants: 5%. Cannabis (THC): 4%. Impaired drivers vs sober: speeding 68% vs 32%, no seatbelt 69% vs 30%, no valid license 26% vs 1%.","methodology":"Retrospective analysis of Norwegian road traffic crash registries and forensic toxicology databases covering fatally injured car/van drivers and motorcycle riders from 2005-2015 (n=772). Multivariable logistic regression adjusted for substance groups, age, and sex.","limitations":"Norwegian data may not generalize to other countries. Only fatally injured drivers included, which may not represent all impaired driving. Post-mortem toxicology cannot determine exact impairment at time of crash."},{"rthcId":"RTHC-02329","title":"An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia.","authors":"van de Donk, Tine; Niesters, Marieke; Kowal, Mikael A; Olofsen, Erik; Dahan, Albert; van Velzen, Monique","year":2019,"journal":"Pain, 160(4), 860-869","doi":"10.1097/j.pain.0000000000001464","pmid":"30585986","tags":["pain","medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"None of the four treatments (high-THC, THC+CBD, high-CBD, placebo) had greater effect than placebo on spontaneous or electrical pain. However, THC-containing varieties significantly increased pressure pain threshold. More patients receiving THC+CBD (Bediol) showed 30% pain reduction compared to placebo (90% vs 55%). CBD inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, suggesting pharmacokinetic synergy but pharmacodynamic antagonism.","whyItMatters":"This is one of the few rigorous RCTs testing pharmaceutical-grade cannabis in fibromyalgia, a condition where many patients self-medicate with cannabis. The complex THC-CBD interaction findings challenge simple assumptions about cannabinoid combinations.","specificNumbers":"20 patients. Bedrocan: 22.4mg THC. Bediol: 13.4mg THC + 17.8mg CBD. Bedrolite: 18.4mg CBD. 90% vs 55% achieved 30% pain reduction (Bediol vs placebo, p=0.01). Pain scores correlated with drug high (ρ=-0.5, p<0.001).","methodology":"Randomized placebo-controlled 4-way crossover trial with 20 fibromyalgia patients. Four varieties tested: Bedrocan (22.4mg THC), Bediol (13.4mg THC + 17.8mg CBD), Bedrolite (18.4mg CBD), and placebo. Single vapor inhalation with 3-hour monitoring.","limitations":"Only 20 patients. Single inhalation rather than sustained treatment. Fibromyalgia-specific results may not apply to other pain conditions. Correlation between pain relief and feeling high raises questions about whether analgesic effects are truly separate from psychoactive effects."},{"rthcId":"RTHC-02330","title":"The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus.","authors":"Veilleux, Alain; Di Marzo, Vincenzo; Silvestri, Cristoforo","year":2019,"journal":"Current diabetes reports, 19(11), 117","doi":"10.1007/s11892-019-1248-9","pmid":"31686231","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02331","title":"Role of chronic cannabis use: Cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome.","authors":"Venkatesan, Thangam; Levinthal, David J; Li, B U K; Tarbell, Sally E; Adams, Kathleen A; Issenman, Robert M; Sarosiek, Irene; Jaradeh, Safwan S; Sharaf, Ravi N; Sultan, Shahnaz; Stave, Christopher D; Monte, Andrew A; Hasler, William L","year":2019,"journal":"Neurogastroenterology and motility, 31 Suppl 2(Suppl 2), e13606","doi":"10.1111/nmo.13606","pmid":"31241817","tags":["medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis is commonly used in cyclic vomiting syndrome (CVS) for its antiemetic properties, yet chronic use has also been linked to cannabinoid hyperemesis syndrome (CHS). \"Compulsive hot water bathing\" has been associated with CHS but is not diagnostic. Existing data are heterogeneous with limited follow-up, making it difficult to determine whether cannabis is causal, merely coincidental, or a trigger in people already predisposed to CVS. The authors propose revised diagnostic criteria for CHS.","whyItMatters":"Misdiagnosis in either direction has consequences: treating CVS patients as having CHS may deny them a helpful antiemetic, while missing CHS means the underlying cause persists.","specificNumbers":"First CHS description in 2004. Review analyzed all published case series and case reports against Rome IV criteria. No specific counts of cases meeting criteria provided.","methodology":"Narrative review analyzing published case series and case reports on CHS, evaluating how many meet Rome IV criteria, and proposing revised diagnostic criteria.","limitations":"Based primarily on case reports and case series. No large prospective studies exist. Diagnostic criteria for CHS remain debated."},{"rthcId":"RTHC-02332","title":"Hypothalamic endocannabinoid signalling modulates aversive responses related to panic attacks.","authors":"Viana, Thércia G; Bastos, Juliana R; Costa, Rayssa B; Hott, Sara C; Mansur, Frederico S; Coimbra, Cândido C; Resstel, Leonardo B; Aguiar, Daniele C; Moreira, Fabrício A","year":2019,"journal":"Neuropharmacology, 148, 284-290","doi":"10.1016/j.neuropharm.2019.01.022","pmid":"30677422","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02333","title":"Sex Differences in the Association Between School Experiences and Marijuana Use Among African American Adolescents.","authors":"Vidourek, Rebecca A; King, Keith A","year":2019,"journal":"Journal of community health, 44(3), 534-543","doi":"10.1007/s10900-019-00652-7","pmid":"30968261","tags":["youth","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"For females, the strongest risk factors were negative school feelings (OR 2.72), finding courses uninteresting (OR 2.70), and poor grades (OR 2.52). For males, the strongest risk factors were feeling school was unimportant for later life (OR 3.47), negative school feelings (OR 2.36), and poor grades (OR 2.73). Perceived peer marijuana use was dramatically more predictive for females (OR 8.29) than males (OR 3.42).","whyItMatters":"Prevention programs often take a one-size-fits-all approach, but these findings suggest that the pathways to marijuana use differ by sex, even within the same racial/ethnic group.","specificNumbers":"Females: negative feelings OR 2.72, uninteresting courses OR 2.70, poor grades OR 2.52, perceived peer use OR 8.29. Males: school unimportant OR 3.47, negative feelings OR 2.36, poor grades OR 2.73, perceived peer use OR 3.42.","methodology":"Secondary analysis of the 2012 National Survey on Drug Use and Health. Multivariable logistic regression examining past-month marijuana use among African American adolescents by school experiences and sex.","limitations":"Cross-sectional data cannot establish causation. Self-reported marijuana use. 2012 data may not reflect current trends. Focused on African American adolescents only."},{"rthcId":"RTHC-02334","title":"Knowledge, attitudes and behaviours on tobacco, alcohol and other drugs among Nigerian secondary school students: Differences by geopolitical zones.","authors":"Vigna-Taglianti, Federica; Alesina, Marta; Damjanović, Ljiljana; Mehanović, Emina; Akanidomo, Ibanga; Pwajok, Juliet; Prichard, Glen; van der Kreeft, Peer; Virk, Harsheth K","year":2019,"journal":"Drug and alcohol review, 38(6), 712-724","doi":"10.1111/dar.12974","pmid":"31452278","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02335","title":"Four-year health trajectories of children prenatally exposed to cocaine and/or cannabis. A retrospective, cohort study in La Pampa, Argentina.","authors":"Villarreal, Marina; Belmonte, Valeria; Abdala, Agustina; Olivares, Jorge L","year":2019,"journal":"Archivos argentinos de pediatria, 117(6), 360-367","doi":"10.5546/aap.2019.eng.360","pmid":"31758877","tags":["pregnancy"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Exposed children (n=29) had significantly fewer health checkups (p<0.0001), more emergency department visits (p=0.03), and more hospitalizations (p=0.007), primarily for respiratory conditions. They also had higher rates of chronic obstructive pulmonary disease, more changes of home, and more legal interventions. One exposed child and two parents had violent deaths; no deaths occurred in the unexposed group.","whyItMatters":"Most prenatal cannabis/cocaine exposure studies focus on birth outcomes. This study tracks children over four years, capturing ongoing health and social consequences.","specificNumbers":"29 exposed, 58 unexposed children. Fewer checkups (p<0.0001). More ER visits (p=0.03). More hospitalizations (p=0.007). 1 child death and 2 parent deaths in exposed group. 0 deaths in unexposed group.","methodology":"Retrospective cohort study with a double control group in La Pampa, Argentina. 29 exposed children detected through urine testing at birth and 58 unexposed children followed for 4 years (2009-2013).","limitations":"Very small sample (29 exposed). Most mothers were poly-drug users, so cannabis effects cannot be separated from cocaine. Retrospective design. Single hospital in Argentina. Social confounders are significant."},{"rthcId":"RTHC-02336","title":"Cannabidiol does not display drug abuse potential in mice behavior.","authors":"Viudez-Martínez, Adrián; García-Gutiérrez, María S; Medrano-Relinque, Juan; Navarrón, Carmen M; Navarrete, Francisco; Manzanares, Jorge","year":2019,"journal":"Acta pharmacologica Sinica, 40(3), 358-364","doi":"10.1038/s41401-018-0032-8","pmid":"30022153","tags":["cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (15, 30, and 60 mg/kg) failed to induce conditioned place preference (no rewarding effects). No withdrawal symptoms or motor changes appeared 12 hours after repeated dosing. CBD plasma was nearly undetectable at 12 hours. In an oral self-administration paradigm, mice showed equal motivation and consumption for CBD solution and plain water.","whyItMatters":"Concerns about CBD abuse potential have slowed research and clinical development. This comprehensive behavioral profile helps address those concerns at the preclinical level.","specificNumbers":"CPP tested at 15, 30, 60 mg/kg. Withdrawal assessed after 30 mg/kg twice daily for 6 days. Plasma measured at 2, 4, 8, 12, and 24 hours. Self-administration: 50 mg/kg oral CBD vs water.","methodology":"Multiple behavioral paradigms in C57BL/6J mice: conditioned place preference (CPP) at three doses, spontaneous withdrawal assessment after 6 days of treatment, locomotor activity testing, plasma concentration measurements, and an oral self-administration paradigm comparing CBD water to plain water.","limitations":"Animal study (mice); human abuse potential may differ. Specific doses and routes may not reflect human use patterns. Oral self-administration is less sensitive than intravenous paradigms."},{"rthcId":"RTHC-02337","title":"Aerobic Fitness Level Moderates the Association Between Cannabis Use and Executive Functioning and Psychomotor Speed Following Abstinence in Adolescents and Young Adults.","authors":"Wade, Natasha E; Wallace, Alexander L; Swartz, Ann M; Lisdahl, Krista M","year":2019,"journal":"Journal of the International Neuropsychological Society : JINS, 25(2), 134-145","doi":"10.1017/S1355617718000966","pmid":"30474579","tags":["exercise","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Increased cannabis use was associated with poorer working memory and psychomotor speed after 3 weeks of abstinence. Higher aerobic fitness (VO2 max) was associated with better visual memory, verbal fluency, and sequencing ability. The interaction between cannabis use and fitness predicted performance on psychomotor speed, visual memory, and sequencing, meaning fit cannabis users performed better than unfit cannabis users on these tasks.","whyItMatters":"If aerobic fitness can buffer against cognitive effects of cannabis use, exercise could be an accessible and inexpensive intervention for cannabis users concerned about cognitive health.","specificNumbers":"79 participants (37 cannabis users). Ages 16-26. 3 weeks monitored abstinence. VO2 max testing. Fitness moderated cannabis effects on psychomotor speed, visual memory, and sequencing ability.","methodology":"Cross-sectional study of 79 young adults (37 cannabis users) aged 16-26, balanced for aerobic fitness. After 3 weeks of monitored abstinence, participants completed neuropsychological testing and a maximal oxygen consumption test. Multiple regressions controlled for alcohol, nicotine, gender, and depression.","limitations":"Cross-sectional design cannot determine causation. Relatively small sample. Cannot determine whether fit users had less severe use patterns or other protective factors. Three weeks of abstinence may not reflect typical use conditions."},{"rthcId":"RTHC-02338","title":"Dissociable effects of cannabis with and without cannabidiol on the human brain's resting-state functional connectivity.","authors":"Wall, Matthew B; Pope, Rebecca; Freeman, Tom P; Kowalczyk, Oliwia S; Demetriou, Lysia; Mokrysz, Claire; Hindocha, Chandni; Lawn, Will; Bloomfield, Michael Ap; Freeman, Abigail M; Feilding, Amanda; Nutt, David; Curran, H Valerie","year":2019,"journal":"Journal of psychopharmacology (Oxford, England), 33(7), 822-830","doi":"10.1177/0269881119841568","pmid":"31013455","tags":["cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Both cannabis strains reduced functional connectivity in the default mode network (DMN) and salience network compared to placebo. Cannabis without CBD specifically disrupted the posterior cingulate cortex (PCC) in the DMN, and this disruption correlated with subjective feelings of being \"stoned\" and \"high.\" CBD-containing cannabis restored the salience network disruption caused by THC, potentially explaining CBD's therapeutic potential for psychosis and addiction.","whyItMatters":"This study identifies specific brain networks affected by THC and shows that CBD can partially counteract these effects, providing a neurobiological basis for why CBD-containing cannabis may be less harmful.","specificNumbers":"17 volunteers. 3 treatments. Cann-CBD: 8mg THC. Cann+CBD: 8mg THC + 10mg CBD. 3 brain networks examined (default mode, executive control, salience). PCC disruption correlated with feeling \"stoned.\"","methodology":"Within-subjects design with 17 healthy volunteers (experienced but not regular cannabis users) receiving three treatments: cannabis with THC only (8mg THC), cannabis with THC+CBD (8mg THC + 10mg CBD), and placebo. Resting-state fMRI examined three brain networks.","limitations":"Small sample (17). Single-dose design. Experienced users only. fMRI measures blood flow patterns as a proxy for brain activity. Cannabis strains differed in more than just CBD content."},{"rthcId":"RTHC-02339","title":"Effects of Cannabis Use and Subclinical ADHD Symptomology on Attention Based Tasks in Adolescents and Young Adults.","authors":"Wallace, Alexander L; Wade, Natasha E; Hatcher, Kelah F; Lisdahl, Krista M","year":2019,"journal":"Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists, 34(5), 700-705","doi":"10.1093/arclin/acy080","pmid":"30295694","tags":["cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users demonstrated significantly slower hit rate response on the Continuous Performance Test (CPT), an attention task. Subclinical ADHD symptoms (measured by parent report) did not independently predict any attention deficits and did not moderate the effects of cannabis use on attention.","whyItMatters":"The suggestion that attention problems in cannabis users might simply reflect underlying ADHD is common. This study challenges that narrative by showing the deficits persist after accounting for subclinical ADHD.","specificNumbers":"72 participants (34 cannabis users, 38 controls). Cannabis use significantly predicted slower CPT hit rate. ADHD symptoms did not predict any cognitive outcomes.","methodology":"Cross-sectional study of 72 participants (34 cannabis users, 38 controls) aged adolescents and young adults. Neuropsychological tasks of inhibition and attention were administered. ADHD symptoms assessed by parent report on the Child Behaviors Checklist.","limitations":"Small sample size. Cross-sectional design. ADHD symptoms were subclinical (participants with diagnosed ADHD were excluded). Parent-reported ADHD symptoms may underestimate actual symptoms in this age group."},{"rthcId":"RTHC-02340","title":"Exploring the components of an efficacious computer brief intervention for reducing marijuana use among adults in the emergency department.","authors":"Waller, Rebecca; Bonar, Erin E; Fernandez, Anne C; Walton, Maureen A; Chermack, Stephen T; Cunningham, Rebecca M; Blow, Frederic C","year":2019,"journal":"Journal of substance abuse treatment, 99, 67-72","doi":"10.1016/j.jsat.2019.01.014","pmid":"30797396","tags":["quitting","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The \"evoking-change\" domain (concerns about use and benefits of change) was significantly associated with reduced marijuana use at 6 months (B=-2.91, p<0.01). Within this domain, items about concerns regarding family and friends predicted the largest reduction: up to 5.5 fewer days of marijuana use per month (B=-5.49, p<0.01).","whyItMatters":"Computer-delivered interventions are scalable, low-cost, and can be delivered in busy settings like emergency departments. Knowing which components work allows for more efficient intervention design.","specificNumbers":"237 ED patients. 46% male. 54% African-American. Mean age 30.7. Evoking-change domain: B=-2.91, p<0.01. Family/friend concerns: up to 5.5 fewer days/month (B=-5.49, p<0.01). 6-month follow-up.","methodology":"Secondary analysis of 237 emergency department patients reporting recent drug use who received a computer-based brief intervention with a virtual health counselor. Five motivational interviewing domains were examined as predictors of past 30-day marijuana use at 6-month follow-up.","limitations":"Secondary analysis of a trial designed to test the overall intervention, not individual components. Self-reported marijuana use. Single urban ED. Component analysis may have limited statistical power."},{"rthcId":"RTHC-02341","title":"Brief report: Characterization of marijuana use in us college students by state marijuana legalization status as reported to an online survey.","authors":"Wang, George Sam; Haynes, Colleen; Besharat, Andrea; Lait, Marie-Claire Le; Green, Jody L; Dart, Richard C; Roosevelt, Genie","year":2019,"journal":"The American journal on addictions, 28(4), 266-269","doi":"10.1111/ajad.12870","pmid":"30901123","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Students in medical marijuana states were significantly more likely to use marijuana compared to non-legal states (p<0.001). Less than 30% of students across all states perceived marijuana use as a health risk. Smoking and edibles were the most common consumption methods. No differences in risk perception were found between legal and non-legal states.","whyItMatters":"With legalization expanding, understanding whether legal status affects use patterns and risk perception among college students informs prevention efforts on campuses.","specificNumbers":"7,105 students enrolled. <30% perceived marijuana as a health risk. Students in medical states used significantly more (p<0.001). Smoking and edibles were most common methods.","methodology":"Secondary analysis of the RADARS System College Survey Program, surveying students in university, technical, or online schools. Students were compared by state marijuana legalization status.","limitations":"Cross-sectional, self-reported data. Cannot determine causation. Survey methodology details limited. No distinction between recreational and medical use states. The study notes \"concentrated products\" but provides limited detail."},{"rthcId":"RTHC-02342","title":"Cannabinoid receptor-mediated modulation of inhibitory inputs to mitral cells in the main olfactory bulb.","authors":"Wang, Ze-Jun; Hu, Sherry Shu-Jung; Bradshaw, Heather B; Sun, Liqin; Mackie, Ken; Straiker, Alex; Heinbockel, Thomas","year":2019,"journal":"Journal of neurophysiology, 122(2), 749-759","doi":"10.1152/jn.00100.2018","pmid":"31215302","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02343","title":"The epigenetic legacy of illicit drugs: developmental exposures and late-life phenotypes.","authors":"Wanner, Nicole M; Colwell, Mathia L; Faulk, Christopher","year":2019,"journal":"Environmental epigenetics, 5(4), dvz022","doi":"10.1093/eep/dvz022","pmid":"31777665","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02344","title":"Exploring cannabis use by patients with multiple sclerosis in a state where cannabis is legal.","authors":"Weinkle, Laura; Domen, Christopher H; Shelton, Ian; Sillau, Stefan; Nair, Kavita; Alvarez, Enrique","year":2019,"journal":"Multiple sclerosis and related disorders, 27, 383-390","doi":"10.1016/j.msard.2018.11.022","pmid":"30502644","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"38% (n=96) of MS patients were current cannabis users. Users had higher disability than non-users (PDDS=2 vs 1, p=0.02). 57% classified their use as strictly medicinal. Most common targets were pain and insomnia/poor sleep. Users reported greater than 60% benefit/relief from cannabis. Over 90% of all respondents wanted more cannabis research for MS, and 74% would consider using cannabis.","whyItMatters":"MS has limited effective treatments for symptoms like pain and sleep disruption. This real-world snapshot from a legal state shows how many MS patients are using cannabis and how they rate its effectiveness.","specificNumbers":"38% current users (n=96). Users had higher disability (PDDS 2 vs 1, p=0.02). 57% strictly medicinal use. >60% reported benefit. 90%+ want more research. 74% would consider cannabis for MS.","methodology":"Cross-sectional survey of MS patients at a large academic MS clinic in Colorado (where cannabis is legal recreationally and medicinally). Assessed cannabis use patterns, MS history, disability (PDDS), quality of life (PROMIS-10), and cognition (Neuro-QoL).","limitations":"Cross-sectional survey from a single clinic in a legal state. Self-reported data and outcomes. Selection bias likely. Cannot determine whether cannabis caused improvement or whether users simply perceive benefit."},{"rthcId":"RTHC-02345","title":"Is There Less Opioid Abuse in States Where Marijuana Has Been Decriminalized, Either for Medicinal or Recreational Use? A Clin-IQ.","authors":"Wendelboe, Aaron M; Mathew, Richard; Chongsuwat, Tana; Rainwater, Elizabeth; Wendelboe, Mark A; Wickersham, Elizabeth; Chou, Ann F","year":2019,"journal":"Journal of patient-centered research and reviews, 6(4), 267-273","doi":"10.17294/2330-0698.1704","pmid":"31768406","tags":["legalization","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 10 studies meeting inclusion criteria (3 cross-sectional, 6 ecological, 1 retrospective cohort), 8 found associations between marijuana decriminalization policies and reduced prescription opioid use. One study was inconclusive, and the retrospective cohort study reported an increase in adverse opioid-related outcomes. The ecological designs use aggregate data and cannot establish that the same individuals used cannabis instead of opioids.","whyItMatters":"The opioid crisis has driven interest in cannabis as a potential substitute for opioid pain management. Understanding whether this population-level relationship holds is critical for policy decisions.","specificNumbers":"10 studies met inclusion criteria. 8 found association between marijuana policies and reduced opioid use. 1 inconclusive. 1 found increased adverse outcomes. Study types: 3 cross-sectional, 6 ecological, 1 retrospective cohort.","methodology":"Clinical inquiry (Clin-IQ) searching Ovid MEDLINE, MEDLINE In-Process, and Embase for population-based studies from January 2012 through December 2018 examining the relationship between marijuana decriminalization and opioid-related outcomes.","limitations":"Mostly ecological studies using aggregate data. Cannot determine individual substitution behavior. Confounded by other policy changes occurring simultaneously. Search limited to one database family."},{"rthcId":"RTHC-02346","title":"A Review of Human Studies Assessing Cannabidiol's (CBD) Therapeutic Actions and Potential.","authors":"White, C Michael","year":2019,"journal":"Journal of clinical pharmacology, 59(7), 923-934","doi":"10.1002/jcph.1387","pmid":"30730563","tags":["cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Refractory seizure control has strong evidence. Acute CBD before anxiety-provoking events and chronic CBD for schizophrenia are promising but not proven. For most other conditions CBD is marketed for, evidence is weak or very weak. CBD is not risk-free: adverse effects include somnolence and GI symptoms, drug interactions occur, liver function test elevations have been documented, and potential effects on suicidal ideation need further study.","whyItMatters":"CBD products are widely available and marketed for dozens of conditions, but the gap between marketing claims and actual evidence is substantial. This review helps separate what is proven from what is speculative.","specificNumbers":"No specific pooled statistics. Review covered FDA-approved Epidiolex and various non-FDA-approved CBD products. THC content threshold for legal CBD: <0.3%.","methodology":"Review of human clinical studies evaluating CBD across multiple conditions, with assessment of evidence quality for each indication.","limitations":"Narrative review. Evidence quality varies widely across conditions. Non-FDA-approved products have unknown quality, making it difficult to draw conclusions from studies using them."},{"rthcId":"RTHC-02347","title":"Incidence of Pediatric Cannabis Exposure Among Children and Teenagers Aged 0 to 19 Years Before and After Medical Marijuana Legalization in Massachusetts.","authors":"Whitehill, Jennifer M; Harrington, Calla; Lang, Cheryl J; Chary, Michael; Bhutta, Waqaas A; Burns, Michele M","year":2019,"journal":"JAMA network open, 2(8), e199456","doi":"10.1001/jamanetworkopen.2019.9456","pmid":"31418807","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Single-substance cannabis calls increased from 0.4 to 1.1 per 100,000 population after medical marijuana legalization (IRR 2.4, 95% CI 1.5-3.9), a 140% increase. Teens aged 15-19 accounted for 81.7% of all calls. Edible product exposures increased after legalization across most age groups. Over the 8-year period, 218 total cannabis exposure calls were received (98 single-substance, 120 polysubstance).","whyItMatters":"Despite childproof packaging and warning labels, pediatric exposures still increased, suggesting these measures alone are insufficient to protect children in legal cannabis markets.","specificNumbers":"218 total calls over 8 years (2009-2016). 140% increase in single-substance calls (IRR 2.4). 60.6% male. 81.7% aged 15-19. Single-substance calls: 29 before vs 69 after legalization.","methodology":"Cross-sectional comparison of pediatric cannabis exposure cases reported to the Regional Center for Poison Control and Prevention, comparing 4 years before and after medical marijuana legalization in Massachusetts (2009-2016).","limitations":"Poison control data likely undercount actual exposures. Cannot determine causation. Temporal association with legalization does not prove legalization caused the increase. No data on severity or outcomes."},{"rthcId":"RTHC-02348","title":"Exploring perceptions among people who drive after cannabis use: Collision risk, comparative optimism and normative influence.","authors":"Wickens, Christine M; Watson, Tara Marie; Mann, Robert E; Brands, Bruna","year":2019,"journal":"Drug and alcohol review, 38(4), 443-451","doi":"10.1111/dar.12923","pmid":"30896069","tags":["driving"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Many participants viewed driving under the influence of cannabis as less risky than driving under alcohol or other drugs. Comparative optimism bias was evident: participants perceived themselves as less likely than others to crash while stoned. Friends were seen as more accepting of cannabis-impaired driving than family. Opinions of fellow cannabis users were considered more credible than those of non-users (normative influence).","whyItMatters":"Understanding the psychological mechanisms behind cannabis-impaired driving decisions can improve the effectiveness of public health campaigns and road safety messaging.","specificNumbers":"20 participants interviewed from an impaired driving remedial program.","methodology":"Semi-structured interviews with 20 participants in a remedial program for impaired drivers. Thematic analysis with two independent coders, applying social cognition concepts.","limitations":"Small qualitative sample (20). Participants were already caught for impaired driving, so may not represent typical cannabis-impaired drivers. Self-report subject to social desirability bias."},{"rthcId":"RTHC-02349","title":"Tolerance and dependence to Δ9-tetrahydrocannabinol in rhesus monkeys: Activity assessments.","authors":"Wilkerson, Jenny L; Schulze, David R; McMahon, Lance R","year":2019,"journal":"PloS one, 14(3), e0209947","doi":"10.1371/journal.pone.0209947","pmid":"30861005","tags":["tolerance","withdrawal"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic THC (1 mg/kg every 12 hours) produced dependence: rimonabant-precipitated withdrawal caused up to 20-fold increase in home-cage activity. Intermittent THC (0.1 mg/kg every 3 days) did not produce dependence signs. Abrupt discontinuation of chronic THC caused immediate (within 24 hours) and progressive increases in activity. THC was somewhat more potent in reducing activity in the intermittent group, consistent with tolerance development in the chronic group.","whyItMatters":"Primate models are more translatable to humans than rodent models. This study establishes clear, measurable physical dependence in primates using a simple behavioral measure.","specificNumbers":"Chronic: 1 mg/kg every 12 hours. Intermittent: 0.1 mg/kg every 3 days. Rimonabant doses: 0.1-3.2 mg/kg. Up to 20-fold activity increase during precipitated withdrawal. Spontaneous withdrawal began within 24 hours.","methodology":"Two groups of rhesus monkeys: one receiving chronic THC (1 mg/kg every 12 hours) and one receiving intermittent THC (0.1 mg/kg every 3 days). Home-cage activity was measured continuously. Withdrawal was assessed via rimonabant challenge and abrupt discontinuation.","limitations":"Animal study (primates). Activity is only one measure of withdrawal. Dose and frequency may not directly correspond to human use patterns."},{"rthcId":"RTHC-02350","title":"Regular cannabis use, with and without tobacco co-use, is associated with respiratory disease.","authors":"Winhusen, Theresa; Theobald, Jeff; Kaelber, David C; Lewis, Daniel","year":2019,"journal":"Drug and alcohol dependence, 204, 107557","doi":"10.1016/j.drugalcdep.2019.107557","pmid":"31557578","tags":["respiratory"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Regular cannabis use was associated with increased risk of asthma (OR 1.32-1.50), COPD (OR 1.44-2.17), and pneumonia (OR 1.80-2.13) across all groups. Importantly, cannabis users without tobacco use disorder still showed elevated respiratory disease risk: asthma OR 1.32, COPD OR 2.17, pneumonia OR 2.13. Tobacco users had the highest overall prevalence regardless of cannabis status.","whyItMatters":"Most studies of cannabis and respiratory disease are confounded by concurrent tobacco use. This study specifically examined cannabis users without tobacco use disorder and still found elevated respiratory risk.","specificNumbers":"8,932 cannabis users total. 4,678 with tobacco use disorder. 4,254 without tobacco use disorder. Non-tobacco cannabis users: asthma OR 1.32, COPD OR 2.17, pneumonia OR 2.13.","methodology":"Retrospective analysis using IBM Watson Health Explorys electronic health records. 8,932 cannabis-using patients matched to controls using propensity score methods, controlling for demographics, zip code income, BMI, and tobacco status.","limitations":"Retrospective EHR data. Cannabis use identified by diagnosis codes and urine screens, which may miss occasional users or include former users. Cannot determine method of cannabis consumption. Residual confounding possible."},{"rthcId":"RTHC-02351","title":"Parental views on state cannabis laws and marijuana use for their medically vulnerable children.","authors":"Wisk, Lauren E; Levy, Sharon; Weitzman, Elissa R","year":2019,"journal":"Drug and alcohol dependence, 199, 59-67","doi":"10.1016/j.drugalcdep.2018.12.027","pmid":"30999251","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"While 89.9% said any marijuana use was risky for their child, 27.9% would approve if prescribed as medicine. Parents reporting decriminalization were more amenable to teen use, less concerned about impact on their child's condition, and more accepting of marijuana as medicine. Parents in legal medical or recreational states were more likely to report their child had tried or regularly used marijuana. Parents in recreational states were paradoxically less likely to agree marijuana has medical benefits for their child.","whyItMatters":"Parents of medically vulnerable children face unique decisions about cannabis. Understanding how legal environment shapes their risk perception can inform clinical guidance.","specificNumbers":"595 parents surveyed. 89.9% said use was risky. 27.9% would approve if prescribed. 11.1% reported decriminalization. 35.6% reported legal medical use. 5.7% reported legal recreational use.","methodology":"Nationally administered web-based survey of 595 parents of adolescents (ages 13-18) with type 1 diabetes, rheumatic disease, or ADHD. Multivariate ordinal logistic regression modeled effects of perceived state cannabis laws on parental views.","limitations":"Cross-sectional web survey. Parents self-reported their state's legal status (which may not be accurate). Selection bias from web-based recruitment. Three specific conditions may not represent all chronically ill teens."},{"rthcId":"RTHC-02352","title":"Seizures as a complication of recreational drug use: Analysis of the Euro-DEN Plus data-set.","authors":"Wolfe, Caitlin E; Wood, David M; Dines, Alison; Whatley, Benjamin P; Yates, Christopher; Heyerdahl, Fridtjof; Hovda, Knut Erik; Giraudon, Isabelle; Dargan, Paul I","year":2019,"journal":"Neurotoxicology, 73, 183-187","doi":"10.1016/j.neuro.2019.04.003","pmid":"30974132","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 23,947 ED presentations, 4.2% involved seizures. Synthetic cannabinoids were associated with 2.90 times higher seizure odds (95% CI 2.19-3.84), and fentanyl with 2.63 times (95% CI 1.20-5.80). Natural cannabis was associated with lower seizure incidence (OR 0.65, 95% CI 0.50-0.86). Patients with seizures had significantly higher rates of coma, cardiac arrest, intubation, ICU admission, and death.","whyItMatters":"Synthetic cannabinoids are often perceived as cannabis alternatives, but this large dataset shows they carry fundamentally different and more dangerous clinical profiles, particularly regarding seizure risk.","specificNumbers":"23,947 presentations (2014-2017). 1,013 (4.2%) with seizures. Synthetic cannabinoids: OR 2.90 (95% CI 2.19-3.84). Fentanyl: OR 2.63 (95% CI 1.20-5.80). Cannabis: OR 0.65 (95% CI 0.50-0.86). Heroin: OR 0.46.","methodology":"Retrospective analysis of the European Drug Emergencies Plus (Euro-DEN Plus) Network database covering ED presentations with acute recreational drug toxicity from January 2014 to December 2017 across multiple European centers.","limitations":"Observational data. Seizure occurrence may be underreported. Self-reported drug use may be inaccurate. Polysubstance use common. Cannot establish causation."},{"rthcId":"RTHC-02353","title":"Minimal Physiologically Based Pharmacokinetic Model of Intravenously and Orally Administered Delta-9-Tetrahydrocannabinol in Healthy Volunteers.","authors":"Wolowich, William R; Greif, Robert; Kleine-Brueggeney, Maren; Bernhard, Werner; Theiler, Lorenz","year":2019,"journal":"European journal of drug metabolism and pharmacokinetics, 44(5), 691-711","doi":"10.1007/s13318-019-00559-7","pmid":"31114948","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02354","title":"Acute Cannabis Toxicity.","authors":"Wong, Kei U; Baum, Carl R","year":2019,"journal":"Pediatric emergency care, 35(11), 799-804","doi":"10.1097/PEC.0000000000001970","pmid":"31688799","tags":["youth","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Unintentional cannabis ingestions in children can cause significant toxicity including encephalopathy, coma, and respiratory depression. ED visits and poison control calls for pediatric cannabis exposure are rising in states with liberalized cannabis laws. Cannabis-containing products (edibles) are a particular risk for young children.","whyItMatters":"Pediatric clinicians in legalized states need to recognize cannabis toxicity quickly, as the presentation (altered mental status, respiratory depression) can mimic more serious conditions.","specificNumbers":"No specific pooled statistics. Review synthesized trends in pediatric cannabis exposure data from multiple sources.","methodology":"Narrative review of pediatric acute cannabis toxicity, covering recognition, evaluation, management, and counseling approaches.","limitations":"Narrative review. Does not provide specific prevalence or incidence data. Focused on acute toxicity, not long-term effects."},{"rthcId":"RTHC-02355","title":"Insights into biased signaling at cannabinoid receptors: synthetic cannabinoid receptor agonists.","authors":"Wouters, Elise; Walraed, Jolien; Banister, Samuel D; Stove, Christophe P","year":2019,"journal":"Biochemical pharmacology, 169, 113623","doi":"10.1016/j.bcp.2019.08.025","pmid":"31472128","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02356","title":"Detection of In Utero Cannabis Exposure in Umbilical Cord Tissue by a Sensitive Liquid Chromatography-Tandem Mass Spectrometry Method.","authors":"Wu, Fang; Jensen, Triniti L; McMillin, Gwendolyn A","year":2019,"journal":"Methods in molecular biology (Clifton, N.J.), 1872, 211-222","doi":"10.1007/978-1-4939-8823-5_20","pmid":"30350293","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02357","title":"Δ8 -Tetrahydrocannabivarin has potent anti-nicotine effects in several rodent models of nicotine dependence.","authors":"Xi, Zheng-Xiong; Muldoon, Pretal; Wang, Xiao-Fei; Bi, Guo-Hua; Damaj, M Imad; Lichtman, Aron H; Pertwee, Roger G; Gardner, Eliot L","year":2019,"journal":"British journal of pharmacology, 176(24), 4773-4784","doi":"10.1111/bph.14844","pmid":"31454413","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Delta-8-THCV (which acts as a CB1 antagonist and CB2 agonist) significantly reduced nicotine self-administration in rats, blocked both cue-induced and nicotine-induced relapse to nicotine-seeking, attenuated nicotine-induced conditioned place preference, and reduced nicotine withdrawal symptoms including anxiety, somatic signs, and pain hypersensitivity in mice.","whyItMatters":"Nicotine addiction is among the hardest to treat. A cannabis-related compound that addresses multiple aspects of nicotine dependence (self-administration, relapse, and withdrawal) could represent a novel therapeutic approach.","specificNumbers":"Tested across 7 rodent models. Delta-8-THCV acts as CB1 antagonist and CB2 agonist. Significantly attenuated all measured nicotine dependence outcomes.","methodology":"Seven rodent models: nicotine self-administration, cue-triggered seeking after abstinence, nicotine-triggered reinstatement, conditioned place preference, withdrawal-induced anxiety, somatic withdrawal signs, and withdrawal-induced hyperalgesia.","limitations":"Rodent studies only. Effects may not translate to humans. Doses used may not be achievable or safe in humans. No human pharmacokinetic data for delta-8-THCV."},{"rthcId":"RTHC-02358","title":"Protein Changes in Response to Lead Stress of Lead-Tolerant and Lead-Sensitive Industrial Hemp Using SWATH Technology.","authors":"Xia, Cheng; Hong, Li; Yang, Yang; Yanping, Xu; Xing, Huang; Gang, Deng","year":2019,"journal":"Genes, 10(5)","doi":"10.3390/genes10050396","pmid":"31121980","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02359","title":"The effects of delta-9-tetrahydrocannabinol on Krüppel-like factor-4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat.","authors":"Yanar, Karolin; Coskun, Zeynep Mine; Beydogan, Alisa Bahar; Aydin, Seval; Bolkent, Sema","year":2019,"journal":"Journal of cellular biochemistry, 120(9), 16219-16228","doi":"10.1002/jcb.28903","pmid":"31081965","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02360","title":"Effect of adding medical cannabis to analgesic treatment in patients with low back pain related to fibromyalgia: an observational cross-over single centre study.","authors":"Yassin, Mustafa; Oron, Amir; Robinson, Dror","year":2019,"journal":"Clinical and experimental rheumatology, 37 Suppl 116(1), 13-20","doi":null,"pmid":"30418116","tags":["pain","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Standard analgesic therapy (oxycodone/naloxone + duloxetine) produced minor improvement over baseline. Adding medical cannabis allowed significantly higher improvement in all patient-reported outcomes (FIQR, VAS, ODI, SF-12) at 3 months, maintained at 6 months. Lumbar range of motion improved after 3 months of cannabis therapy and continued improving at 6 months.","whyItMatters":"Fibromyalgia with low back pain is difficult to treat, and standard medications often provide incomplete relief. This cross-over design allows within-patient comparison.","specificNumbers":"31 patients. Standard therapy: oxycodone/naloxone 5/2.5mg BID + duloxetine 30mg daily for 3 months. Cannabis therapy: minimum 6 months. Improvement in all PROs at 3 and 6 months of cannabis. ROM improved progressively.","methodology":"Observational cross-over study of 31 patients. After screening, patients received 3 months of standardized analgesic therapy (oxycodone/naloxone 5/2.5mg twice daily plus duloxetine 30mg daily), then could opt into medical cannabis therapy for a minimum of 6 months.","limitations":"Not randomized or blinded. Patients self-selected into cannabis arm (bias toward those expecting benefit). No placebo cannabis control. Small sample. Cannot separate cannabis effects from placebo or time effects."},{"rthcId":"RTHC-02361","title":"Characterization of mental health in cannabis dispensary users, using structured clinical interviews and standardized assessment instruments.","authors":"Yau, Jade C; Yu, Shu Min; Panenka, William J; Pearce, Hadley; Gicas, Kristina M; Procyshyn, Ric M; MacCallum, Caroline; Honer, William G; Barr, Alasdair M","year":2019,"journal":"BMC psychiatry, 19(1), 335","doi":"10.1186/s12888-019-2324-z","pmid":"31675939","tags":["mental-health","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using the MINI structured clinical interview, lifetime prevalence of mental illness was high. Current psychiatric disorder rates were low for mood disorders but high for anxiety disorders and substance abuse/dependence. Cannabis use patterns differed between psychiatric conditions. Many subjects endorsed psychological symptoms on standardized measures (stress, fatigue, sleep disturbance, depression, somatic symptoms, pain).","whyItMatters":"Most studies of dispensary users rely on self-report checklists. Using validated clinical instruments provides a more rigorous picture of mental health in this population.","specificNumbers":"100 medical cannabis users. Structured MINI interview administered to all. Multiple standardized questionnaires completed. High lifetime mental illness prevalence. Low current mood disorder rates. High anxiety and substance disorder rates.","methodology":"Cross-sectional study of 100 medical cannabis users recruited from a community dispensary. All completed the MINI structured clinical interview plus standardized questionnaires (Perceived Stress Scale-10, PROMIS Fatigue and Sleep scales, Beck Depression Inventory, PHQ-15, Brief Pain Inventory).","limitations":"Cross-sectional design. Single dispensary. No control group. Cannot determine causation. Selection bias (dispensary users who agreed to participate). Sample may not represent all medical cannabis users."},{"rthcId":"RTHC-02362","title":"Cannabidivarin completely rescues cognitive deficits and delays neurological and motor defects in male Mecp2 mutant mice.","authors":"Zamberletti, Erica; Gabaglio, Marina; Piscitelli, Fabiana; Brodie, James S; Woolley-Roberts, Marie; Barbiero, Isabella; Tramarin, Marco; Binelli, Giorgio; Landsberger, Nicoletta; Kilstrup-Nielsen, Charlotte; Rubino, Tiziana; Di Marzo, Vincenzo; Parolaro, Daniela","year":2019,"journal":"Journal of psychopharmacology (Oxford, England), 33(7), 894-907","doi":"10.1177/0269881119844184","pmid":"31084246","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02363","title":"Tetrahydrocannabinol: cannabidiol oromucosal spray for treating symptoms of multiple sclerosis spasticity: newest evidence.","authors":"Ziemssen, Tjalf","year":2019,"journal":"Neurodegenerative disease management, 9(2s), 1-2","doi":"10.2217/nmt-2018-0048","pmid":"30657019","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02364","title":"Emergency Department and Radiological Cost of Delayed Diagnosis of Cannabinoid Hyperemesis.","authors":"Zimmer, David I; McCauley, Ross; Konanki, Varun; Dynako, Joseph; Zackariya, Nuha; Shariff, Faadil; Miller, Joseph; Binz, Sophia; Walsh, Mark","year":2019,"journal":"Journal of addiction, 2019, 1307345","doi":"10.1155/2019/1307345","pmid":"30723570","tags":["harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Patients averaged 17.9 ED visits before cannabinoid hyperemesis was diagnosed. Total costs for combined ED visits and radiological evaluations averaged $76,920.92 per patient. The diagnosis can be made primarily through thorough history and physical examination, but requires clinician awareness of the syndrome.","whyItMatters":"Cannabinoid hyperemesis is becoming more common with increased cannabis use, and the enormous cost of delayed diagnosis represents both wasted healthcare resources and unnecessary patient suffering.","specificNumbers":"17 patients. 3 medical centers. 2010-2015. Average 17.9 ED visits before diagnosis. Average cost: $76,920.92 per patient.","methodology":"Retrospective observational study of 17 patients diagnosed with cannabinoid hyperemesis at three US medical centers (two academic, one community) from 2010 to 2015.","limitations":"Very small sample (17 patients). Three centers in one country. Costs may vary by region. Retrospective design. No standardized diagnostic criteria at the time."},{"rthcId":"RTHC-02365","title":"Cannabidiol improves metabolic dysfunction in middle-aged diabetic rats submitted to a chronic cerebral hypoperfusion.","authors":"Zorzenon, Maria Rosa Trentin; Santiago, Amanda Nunes; Mori, Marco Aurélio; Piovan, Silvano; Jansen, Cler Antônia; Perina Padilha, Maria Eduarda; Ciotta, Simone Rocha; Cezar de Freitas Mathias, Paulo; Guimarães, Francisco Silveira; Weffort de Oliveira, Rubia Maria; Milani, Paula Gimenez; Mareze-Costa, Cecília Edna","year":2019,"journal":"Chemico-biological interactions, 312, 108819","doi":"10.1016/j.cbi.2019.108819","pmid":"31499052","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02366","title":"Morphine improved stress-induced amnesia and anxiety through interacting with the ventral hippocampal endocannabinoid system in rats.","authors":"Abbasi-Habashi, Sima; Ghasemzadeh, Zahra; Rezayof, Ameneh","year":2020,"journal":"Brain research bulletin, 164, 407-414","doi":"10.1016/j.brainresbull.2020.09.002","pmid":"32937186","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02367","title":"Vaping-associated lung injury caused by inhalation of cannabis oil.","authors":"Abeles, Michael; Popofsky, Stephanie; Wen, Andy; Valsamis, Christina; Webb, Angela; Halaby, Claudia; Pirzada, Melodi","year":2020,"journal":"Pediatric pulmonology, 55(1), 226-228","doi":"10.1002/ppul.24579","pmid":"31746559","tags":["respiratory","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The case documented severe acute lung injury secondary to inhalation of cannabis oil via a vape pen. The short-term and long-term effects of cannabis oil inhalation are not well understood. The authors proposed a new term to describe lung injury related to vaping.","whyItMatters":"Vaping is increasingly popular among adolescents, with a growing proportion using devices to inhale cannabis oil. Documenting these cases helps establish the scope of the problem.","specificNumbers":"Single case report. Patient was an adolescent.","methodology":"Single case report of an adolescent with vaping-associated lung injury from cannabis oil.","limitations":"Single case report. Cannot establish incidence or prevalence. Specific contaminants (such as vitamin E acetate) may not have been fully characterized."},{"rthcId":"RTHC-02368","title":"The effects of fatty acid amide hydrolase and monoacylglycerol lipase inhibitor treatments on lipopolysaccharide-induced airway inflammation in mice.","authors":"Abohalaka, Reshed; Bozkurt, Turgut Emrah; Nemutlu, Emirhan; Onder, Sevgen Celik; Sahin-Erdemli, Inci","year":2020,"journal":"Pulmonary pharmacology & therapeutics, 62, 101920","doi":"10.1016/j.pupt.2020.101920","pmid":"32416152","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02369","title":"Marijuana Use: Early Recognition for a Cannabinoid Hyperemesis Syndrome.","authors":"Abrams, Tara; Gantioque, Raymund","year":2020,"journal":"Advanced emergency nursing journal, 42(1), 30-36","doi":"10.1097/TME.0000000000000283","pmid":"32000189","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02370","title":"Emerging Use of Epidiolex (Cannabidiol) in Epilepsy.","authors":"Abu-Sawwa, Renad; Scutt, Brielle; Park, Yong","year":2020,"journal":"The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 25(6), 485-499","doi":"10.5863/1551-6776-25.6.485","pmid":"32839652","tags":["epilepsy","cbd","drug-interactions"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Epidiolex was FDA-approved June 2018 for patients aged 2+ with Dravet or Lennox-Gastaut syndrome. Common side effects include somnolence, decreased appetite, and diarrhea. Significant drug interactions occur with clobazam (increased active metabolite levels) and valproate (hepatotoxicity risk). CBD is metabolized primarily by CYP3A4 and CYP2C19, creating numerous potential interactions with other antiepileptic drugs.","whyItMatters":"Patients with Dravet and Lennox-Gastaut syndromes have limited treatment options. Understanding both the benefits and the interaction risks of Epidiolex is essential for safe prescribing.","specificNumbers":"FDA approved June 25, 2018. Approved for ages 2+. Metabolized by CYP3A4 and CYP2C19. Significant interactions with clobazam and valproate.","methodology":"State-of-the-art review covering CBD history, pharmacology, toxicology, clinical evidence, side effects, and drug-drug interactions in epilepsy.","limitations":"Limited long-term efficacy and safety data. Drug interaction studies are ongoing. Review reflects knowledge at time of publication."},{"rthcId":"RTHC-02371","title":"Cannabis Vaping-Induced Acute Pulmonary Toxicity: Case Series and Review of Literature.","authors":"Adapa, Sreedhar; Gayam, Vijay; Konala, Venu Madhav; Annangi, Srinadh; Raju, Mina P; Bezwada, Vishnu; McMillan, Christine; Dalal, Hussain; Mandal, Amrendra; Naramala, Srikanth","year":2020,"journal":"Journal of investigative medicine high impact case reports, 8, 2324709620947267","doi":"10.1177/2324709620947267","pmid":"32755249","tags":["respiratory","harm-reduction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Literature review identified cases of acute respiratory failure from vaping cannabis oil. Common clinical features included respiratory failure requiring various modes of ventilation. The review summarized common laboratory abnormalities and the role of steroids in treatment. Different cannabis oil formulations and key ingredients were identified as potentially responsible for vaping-associated lung injury.","whyItMatters":"Acute respiratory failure from cannabis vaping can be life-threatening. Understanding the clinical presentation and responsible ingredients helps clinicians respond appropriately.","specificNumbers":"No specific pooled statistics provided. Review compiled clinical details across published cases.","methodology":"Case series with literature review analyzing published reports of acute respiratory failure from vaping cannabis oil, summarizing clinical details including age, length of stay, ventilation mode, and treatment.","limitations":"Based on published case reports which may not represent all cases. Specific causative agents were still being investigated at time of publication."},{"rthcId":"RTHC-02372","title":"Can Hemp Help? Low-THC Cannabis and Non-THC Cannabinoids for the Treatment of Cancer.","authors":"Afrin, Farjana; Chi, Mengna; Eamens, Andrew L; Duchatel, Ryan J; Douglas, Alicia M; Schneider, Jennifer; Gedye, Craig; Woldu, Ameha S; Dun, Matthew D","year":2020,"journal":"Cancers, 12(4)","doi":"10.3390/cancers12041033","pmid":"32340151","tags":["cancer","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"THC can inhibit cancer cell growth via CB1R and CB2R modulation, but clinical confirmation is lacking. Non-THC cannabinoids like CBD work through different mechanisms: non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and transcription factors that modulate oncogenic signaling and redox homeostasis. Cannabinoids also have anti-inflammatory properties relevant to peritumoural edema and the tumor immune microenvironment.","whyItMatters":"Low-THC cannabis and CBD products are widely available without the psychoactive effects of THC. Understanding their anti-cancer mechanisms could inform future treatment development without the barriers associated with THC.","specificNumbers":"No specific clinical data. Review covered preclinical evidence across multiple cancer types and cannabinoid compounds.","methodology":"Review documenting emerging mechanisms of anti-cancer actions of non-THC cannabinoids, covering preclinical evidence from cell and animal studies.","limitations":"Entirely preclinical evidence. No human clinical trials confirm anti-cancer effects. In vitro results often do not translate to clinical benefit. Doses used in lab studies may not be achievable in humans."},{"rthcId":"RTHC-02373","title":"The Synthetic Cannabinoids THJ-2201 and 5F-PB22 Enhance In Vitro CB1 Receptor-Mediated Neuronal Differentiation at Biologically Relevant Concentrations.","authors":"Alexandre, João; Malheiro, Rui; Dias da Silva, Diana; Carmo, Helena; Carvalho, Félix; Silva, João Pedro","year":2020,"journal":"International journal of molecular sciences, 21(17)","doi":"10.3390/ijms21176277","pmid":"32872617","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02374","title":"Phytoradiotherapy: An Integrative Approach to Cancer Treatment by Combining Radiotherapy With Phytomedicines.","authors":"Alfonzetti, Tyler; Yasmin-Karim, Sayeda; Ngwa, Wilfred; Avery, Stephen","year":2020,"journal":"Frontiers in oncology, 10, 624663","doi":"10.3389/fonc.2020.624663","pmid":"33628736","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02375","title":"Perspectives on formation of medical cannabis market in Ukraine based on holistic approach.","authors":"Aliekperova, Nataliia; Kosyachenko, Кostyantyn; Kaniura, Oleksandr","year":2020,"journal":"Journal of cannabis research, 2(1), 33","doi":"10.1186/s42238-020-00044-y","pmid":"33526139","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02376","title":"Cannabis use and stressful life events during the perinatal period: cross-sectional results from Pregnancy Risk Assessment Monitoring System (PRAMS) data, 2016.","authors":"Allen, Alicia M; Jung, Alesia M; Alexander, Adam C; Allen, Sharon S; Ward, Kenneth D; al'Absi, Mustafa","year":2020,"journal":"Addiction (Abingdon, England), 115(9), 1707-1716","doi":"10.1111/add.15003","pmid":"32032979","tags":["pregnancy"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"16.4% of respondents used cannabis pre-pregnancy, with 36.4% continuing during pregnancy. Among those who quit during pregnancy, 23.2% relapsed postpartum. Nine of 14 stressful life events were associated with pre-pregnancy use (e.g., partner/mother jailed: aOR 2.16). Four events predicted continued use during pregnancy (e.g., partner lost job: aOR 2.19). Postpartum relapse was linked to partner saying they did not want the pregnancy (aOR 2.86).","whyItMatters":"Understanding that stress drives perinatal cannabis use suggests that addressing stressors could be more effective than simply telling women to stop using cannabis during pregnancy.","specificNumbers":"6,061 women across 5 states. 16.4% pre-pregnancy use. 36.4% continued during pregnancy. 23.2% postpartum relapse. Partner jailed: aOR 2.16. Partner lost job: aOR 2.19. Partner did not want pregnancy: aOR 2.86 for postpartum relapse.","methodology":"Cross-sectional analysis of PRAMS 2016 data from five US states (Alaska, Colorado, Maine, Michigan, Washington). Logistic regression adjusted for demographics, geography, and cigarette smoking among 6,061 women who delivered a live infant.","limitations":"Cross-sectional design. Self-reported cannabis use (likely underreported). Five states may not represent the whole US. Cannot establish causation between stress and cannabis use."},{"rthcId":"RTHC-02377","title":"Advances in Neurobiology and Pharmacology of GPR12.","authors":"Allende, Gonzalo; Chávez-Reyes, Jesús; Guerrero-Alba, Raquel; Vázquez-León, Priscila; Marichal-Cancino, Bruno A","year":2020,"journal":"Frontiers in pharmacology, 11, 628","doi":"10.3389/fphar.2020.00628","pmid":"32457622","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02378","title":"Synthetic cannabinoids JWH-018, JWH-122, UR-144 and the phytocannabinoid THC activate apoptosis in placental cells.","authors":"Almada, Marta; Alves, Patrícia; Fonseca, Bruno M; Carvalho, Félix; Queirós, Cláudio R; Gaspar, Helena; Amaral, Cristina; Teixeira, Natércia A; Correia-da-Silva, Georgina","year":2020,"journal":"Toxicology letters, 319, 129-137","doi":"10.1016/j.toxlet.2019.11.004","pmid":"31730886","tags":["pregnancy","synthetic-cannabinoids"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"All four cannabinoids decreased cell viability without membrane damage (indicating apoptosis, not necrosis). Cell cycle arrest at G2/M phase was observed. JWH-018 and JWH-122 increased reactive oxygen species. THC, UR-144, and JWH-122 caused mitochondrial membrane potential loss. All compounds activated caspase-9 and caspase-3/-7 (apoptotic markers). The mechanisms varied: UR-144 acted through CB1 only, JWH-018 and THC through both CB1 and CB2, and JWH-122 was receptor-independent.","whyItMatters":"Placental trophoblast turnover relies on balanced proliferation and apoptosis. Cannabinoid-induced apoptosis could disrupt normal placental development, potentially explaining associations between cannabis use and adverse pregnancy outcomes.","specificNumbers":"Four cannabinoids tested. All induced caspase-9 and caspase-3/-7 activation. Synthetic cannabinoids affected cells at lower concentrations than THC. Three different receptor-mediated mechanisms identified.","methodology":"In vitro study using BeWo human placental cytotrophoblast cell line. Cells were exposed to synthetic cannabinoids (JWH-018, JWH-122, UR-144) and THC. Cell viability, cell cycle, ROS, mitochondrial function, and caspase activation were measured.","limitations":"In vitro study using a cell line, not intact placental tissue. Concentrations used may not reflect physiological levels. Cannot directly predict in vivo pregnancy outcomes."},{"rthcId":"RTHC-02379","title":"The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation.","authors":"Almogi-Hazan, Osnat; Khuja, Iman; Ritter, Sivan; Or, Reuven","year":2020,"journal":"Rambam Maimonides medical journal, 11(1)","doi":"10.5041/RMMJ.10391","pmid":"32017682","tags":["cancer","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Current cancer applications of cannabinoids are mainly palliative (pain and anti-emetic effects). Preclinical data on anti-proliferative properties remain inconsistent, with no conclusive animal model or clinical trial data. Critically, the immunomodulatory effects of cannabinoids may conflict with cancer immunotherapy and bone marrow transplant approaches, where robust immune function is essential.","whyItMatters":"As immunotherapy becomes a standard cancer treatment, the potential for cannabis to dampen the immune response it relies on is a clinically important but understudied concern.","specificNumbers":"No specific clinical outcome data. Review synthesized preclinical and clinical knowledge about cannabinoid immunomodulation in oncology.","methodology":"Review covering preclinical models, limited clinical data, and the specific concern about interactions between cannabinoid immunomodulation and cancer immunotherapy.","limitations":"Narrative review. Anti-tumor data are preclinical and inconsistent. Immunomodulatory interactions with immunotherapy are theoretical. No clinical trials address this interaction."},{"rthcId":"RTHC-02380","title":"The synthetic cannabinoids phenomenon: from structure to toxicological properties. A review.","authors":"Alves, Vera L; Gonçalves, João L; Aguiar, Joselin; Teixeira, Helena M; Câmara, José S","year":2020,"journal":"Critical reviews in toxicology, 50(5), 359-382","doi":"10.1080/10408444.2020.1762539","pmid":"32530350","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoids are the largest NPS class with 190 substances reported to the EU Early Warning System (2008-2018) and ~280 reported worldwide. Unlike THC (partial agonist), synthetic cannabinoids are full agonists at cannabinoid receptors, making them much more potent. Product composition varies in both substance type and amount. Some may have long half-lives, prolonging psychoactive effects. They have been associated with deaths and acute intoxications across Europe.","whyItMatters":"Synthetic cannabinoids are widely available, constantly evolving to evade regulation, and significantly more dangerous than natural cannabis. Understanding their properties is essential for harm reduction and clinical response.","specificNumbers":"190 substances notified to EU Early Warning System (2008-2018). ~280 reported worldwide to UNODC. Labeled \"not for human consumption\" to circumvent legislation. Sold as \"Spice,\" \"K2,\" and similar brands.","methodology":"Comprehensive review covering development history, abuse patterns, legal status, chemical classification, and pharmacological and toxicological properties of synthetic cannabinoids.","limitations":"Review cannot cover all emerging compounds. Toxicological data for many substances are incomplete. Legal status information rapidly becomes outdated."},{"rthcId":"RTHC-02381","title":"Exploring Stereochemical and Conformational Requirements at Cannabinoid Receptors for Synthetic Cannabinoids Related to SDB-006, 5F-SDB-006, CUMYL-PICA, and 5F-CUMYL-PICA.","authors":"Ametovski, Adam; Macdonald, Christa; Manning, Jamie J; Haneef, S A Syed; Santiago, Marina; Martin, Lewis; Sparkes, Eric; Reckers, Andrew; Gerona, Roy R; Connor, Mark; Glass, Michelle; Banister, Samuel D","year":2020,"journal":"ACS chemical neuroscience, 11(21), 3672-3682","doi":"10.1021/acschemneuro.0c00591","pmid":"33054155","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02382","title":"Young Adults With Higher Motives and Expectancies of Regular Cannabis Use Show Poorer Psychosocial Functioning.","authors":"Amiet, Danielle; Youssef, George J; Hagg, Lauryn J; Lorenzetti, Valentina; Parkes, Linden; Solowij, Nadia; Yücel, Murat","year":2020,"journal":"Frontiers in psychiatry, 11, 599365","doi":"10.3389/fpsyt.2020.599365","pmid":"33384630","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Two distinct user classes emerged: Low Motives/Expectancies (n=158) and High Motives/Expectancies (n=171). The High class reported higher symptoms of psychosis (positive and negative), depression, anxiety, and stress. They were more likely to meet cannabis use disorder criteria, had more nicotine dependence and other illicit drug use, and were more likely to get high before work and drive under the influence.","whyItMatters":"Not all regular cannabis users are alike. Identifying high-risk profiles based on motives and expectations could help target interventions to those most likely to experience problems.","specificNumbers":"329 weekly users. 2 classes: Low Motives (n=158) and High Motives (n=171). High class had more psychosis symptoms, depression, anxiety, stress, CUD criteria, nicotine dependence, and reckless behavior.","methodology":"Online survey of 329 weekly cannabis users via Amazon Mechanical Turk. Latent class analysis using motives and expectations to identify user profiles. Classes compared on mental health and behavioral outcomes.","limitations":"Amazon Mechanical Turk sample may not represent all cannabis users. Cross-sectional design cannot determine causation. Self-reported measures. Weekly use threshold may capture diverse use patterns."},{"rthcId":"RTHC-02383","title":"Spatial access to opioid treatment program and alcohol and cannabis outlets: analysis of missed doses of methadone during the first, second, and third 90 days of treatment.","authors":"Amiri, Solmaz; Lutz, Robert B; McDonell, Michael G; Roll, John M; Amram, Ofer","year":2020,"journal":"The American journal of drug and alcohol abuse, 46(1), 78-87","doi":"10.1080/00952990.2019.1620261","pmid":"31237791","tags":["addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Shorter distance from home to the opioid treatment program decreased missed methadone doses during the first 90 days. Shorter distance to the nearest cannabis retail outlet increased missed doses during the first and second 90 days. Shorter distance to the closest off-premise alcohol outlet increased missed doses during the third 90 days. The proximity effects shifted over time as patients progressed through treatment.","whyItMatters":"The location of cannabis retail outlets relative to addiction treatment centers may affect treatment outcomes, a finding relevant to zoning and licensing decisions for cannabis retailers.","specificNumbers":"752 clients at 3 months, 689 at 6 months, 584 at 9 months. 50% female. Cannabis outlet proximity increased missed doses in months 1-6. Alcohol outlet proximity increased missed doses in months 7-9.","methodology":"Retrospective analysis of 752, 689, and 584 clients retained in treatment for at least 3, 6, and 9 months respectively (50% female). Distance between home, OTP, and alcohol/cannabis outlets was measured. Generalized linear models were used.","limitations":"Single treatment program. Observational design cannot prove causation. Proximity does not necessarily mean exposure or use. Other neighborhood factors may confound the relationship."},{"rthcId":"RTHC-02384","title":"Self-reported Secondhand Marijuana Smoke (SHMS) Exposure in Two New York City (NYC) Subsidized Housing Settings, 2018: NYC Housing Authority and Lower-Income Private Sector Buildings.","authors":"Anastasiou, Elle; Chennareddy, Sumanth; Wyka, Katarzyna; Shelley, Donna; Thorpe, Lorna E","year":2020,"journal":"Journal of community health, 45(3), 635-639","doi":"10.1007/s10900-019-00783-x","pmid":"31807996","tags":["harm-reduction","respiratory"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"67% of residents reported smelling marijuana smoke in their home over the past year, compared to 60% for cigarette smoke. Smoking status and smelling secondhand tobacco smoke were both strong predictors of smelling secondhand marijuana smoke. Nearly two-thirds of residents perceived smoking marijuana and secondhand marijuana smoke as harmful to health.","whyItMatters":"As marijuana use increases, secondhand exposure in shared housing environments becomes a growing concern, particularly as smoke-free policies may not address marijuana smoke.","specificNumbers":"1,030 participants from 21 buildings. Response rates: 35% NYCHA, 32% Section 8. 67% smelled marijuana smoke. 60% smelled cigarette smoke. ~2/3 perceived secondhand marijuana smoke as harmful.","methodology":"Cross-sectional survey of residents in 21 subsidized housing buildings in NYC: 10 NYCHA buildings (n=559) and 11 Section 8 buildings (n=471). Surveys collected April-November 2018, prior to smoke-free housing policy implementation.","limitations":"Self-reported exposure (smelling smoke, not biomarker-verified). Low response rates (32-35%). NYC housing may not represent other settings. Cross-sectional design."},{"rthcId":"RTHC-02385","title":"Adverse effects of cannabinoids.","authors":"Anciones, Carla; Gil-Nagel, Antonio","year":2020,"journal":"Epileptic disorders : international epilepsy journal with videotape, 22(S1), 29-32","doi":"10.1684/epd.2019.1125","pmid":"31941644","tags":["cbd","epilepsy","drug-interactions"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Short-term CBD side effects are generally transitory, dose-dependent, and mild to moderate: somnolence, decreased appetite, and diarrhea. However, severe life-threatening reactions can occur, often related to uncontrolled combinations with valproate (hepatotoxicity risk) or clobazam (excessive sedation). These are widely used in Dravet and Lennox-Gastaut patients who are the target population for CBD.","whyItMatters":"The very patients most likely to benefit from CBD (those with severe epilepsy) are also taking the drugs most likely to cause dangerous interactions with CBD, making monitoring essential.","specificNumbers":"No specific incidence rates. Review noted dose-dependent effects and identified valproate and clobazam as primary interaction risks.","methodology":"Brief review summarizing available data on short-term adverse events from clinical trials that led to Epidiolex FDA approval.","limitations":"Brief review focused on short-term effects. Long-term safety data are lacking. Based primarily on clinical trial populations."},{"rthcId":"RTHC-02386","title":"Cigarette and Cannabis Smoking Effects on GPR15+ Helper T Cell Levels in Peripheral Blood: Relationships with Epigenetic Biomarkers.","authors":"Andersen, Allan M; Lei, Man-Kit; Beach, Steven R H; Philibert, Robert A; Sinha, Sushmita; Colgan, John D","year":2020,"journal":"Genes, 11(2)","doi":"10.3390/genes11020149","pmid":"32019074","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02387","title":"Global brain network dynamics predict therapeutic responsiveness to cannabidiol treatment for refractory epilepsy.","authors":"Anderson, David E; Madhavan, Deepak; Swaminathan, Arun","year":2020,"journal":"Brain communications, 2(2), fcaa140","doi":"10.1093/braincomms/fcaa140","pmid":"33376981","tags":["epilepsy","cbd","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Patients who achieved >70% seizure reduction (responders) showed increased network integration (higher global efficiency, lower degree) and increased segregation (higher modularity) in the beta frequency band compared to non-responders. Higher CBD doses were associated with increased network integration and segregation in delta, theta, and alpha bands.","whyItMatters":"Predicting which patients will respond to CBD before or early in treatment could save time, reduce unnecessary medication trials, and improve outcomes for children with severe epilepsy.","specificNumbers":"Responders defined as >70% seizure frequency reduction. Brain networks analyzed in 4 frequency bands (delta 1-3 Hz, theta 4-7 Hz, alpha 8-12 Hz, beta 13-30 Hz). Significant differences found exclusively in beta band.","methodology":"Observational study of refractory epilepsy patients (Lennox-Gastaut or Dravet syndrome) undergoing serial EEG before and during CBD treatment. Graph theoretical analysis of brain network dynamics extracted from phase coherence measurements.","limitations":"Small sample size (not specified). Observational design. Single-center study. Network measures are complex and may not be readily available in all clinical settings."},{"rthcId":"RTHC-02388","title":"Interactions between cannabidiol and Δ9 -tetrahydrocannabinol in modulating seizure susceptibility and survival in a mouse model of Dravet syndrome.","authors":"Anderson, Lyndsey L; Low, Ivan K; McGregor, Iain S; Arnold, Jonathon C","year":2020,"journal":"British journal of pharmacology, 177(18), 4261-4274","doi":"10.1111/bph.15181","pmid":"32608111","tags":["epilepsy","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (100 mg/kg) alone was anticonvulsant against heat-induced seizures. Low-dose THC (0.1 and 0.3 mg/kg) was also anticonvulsant, but higher doses were not. A sub-threshold dose of CBD (12 mg/kg) enhanced THC's anticonvulsant effect. However, when CBD and THC were given together chronically, spontaneous seizure severity and mortality increased, a surprising and concerning finding.","whyItMatters":"Many cannabis products marketed for epilepsy contain both THC and CBD. This study suggests that while acute low-dose combinations may help, chronic use of the combination could be harmful.","specificNumbers":"CBD anticonvulsant at 100 mg/kg. THC anticonvulsant at 0.1 and 0.3 mg/kg. Sub-threshold CBD (12 mg/kg) enhanced THC effect. Chronic co-administration increased seizure severity and mortality.","methodology":"Preclinical study using Scn1a+/- mice (Dravet syndrome model). Tested CBD and THC alone and combined on heat-induced seizures, spontaneous seizures, and premature mortality.","limitations":"Mouse model; results may not translate to humans. Doses used are relative to mouse physiology. Mechanisms of chronic harm were not fully elucidated."},{"rthcId":"RTHC-02389","title":"A Rapid Review of the Impact of Systems-Level Policies and Interventions on Population-Level Outcomes Related to the Opioid Epidemic, United States and Canada, 2014-2018.","authors":"Ansari, Bahareh; Tote, Katherine M; Rosenberg, Eli S; Martin, Erika G","year":2020,"journal":"Public health reports (Washington, D.C. : 1974), 135(1_suppl), 100S-127S","doi":"10.1177/0033354920922975","pmid":"32735190","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02390","title":"New insights in hemp chemical composition: a comprehensive polar lipidome characterization by combining solid phase enrichment, high-resolution mass spectrometry, and cheminformatics.","authors":"Antonelli, Michela; Benedetti, Barbara; Cannazza, Giuseppe; Cerrato, Andrea; Citti, Cinzia; Montone, Carmela Maria; Piovesana, Susy; Laganà, Aldo","year":2020,"journal":"Analytical and bioanalytical chemistry, 412(2), 413-423","doi":"10.1007/s00216-019-02247-6","pmid":"31760447","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02391","title":"In Vitro Phase I Metabolic Profiling of the Synthetic Cannabinoids AM-694, 5F-NNEI, FUB-APINACA, MFUBINAC, and AMB-FUBINACA.","authors":"Apirakkan, Orapan; Gavrilović, Ivana; Cowan, David A; Abbate, Vincenzo","year":2020,"journal":"Chemical research in toxicology, 33(7), 1653-1664","doi":"10.1021/acs.chemrestox.9b00466","pmid":"32301604","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02392","title":"Medical Cannabis in Children.","authors":"Aran, Adi; Cayam-Rand, Dalit","year":2020,"journal":"Rambam Maimonides medical journal, 11(1)","doi":"10.5041/RMMJ.10386","pmid":"32017680","tags":["medical-cannabis","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Robust evidence exists only for pure CBD treating specific refractory epilepsies (Dravet, Lennox-Gastaut). In practice, artisanal CBD-rich cannabis products are being used for various epilepsy types and autism-related irritability. Other pediatric conditions being considered include Tourette syndrome and spasticity. Recreational cannabis use in youth is associated with serious adverse events, so medical use decisions should be made with caution.","whyItMatters":"Pediatric medical cannabis use is growing rapidly, outpacing the evidence base. Parents need clear guidance about what is proven versus experimental.","specificNumbers":"No specific pooled statistics. Review covered FDA-approved CBD (Epidiolex) and artisanal CBD-rich products.","methodology":"Review summarizing current evidence for safety, tolerability, and efficacy of medical cannabis in children with epilepsy and autism spectrum disorder.","limitations":"Review, not primary research. Limited evidence for conditions beyond specific refractory epilepsies. Artisanal product quality is variable."},{"rthcId":"RTHC-02393","title":"Effect of Cannabidiol and Δ9-Tetrahydrocannabinol on Driving Performance: A Randomized Clinical Trial.","authors":"Arkell, Thomas R; Vinckenbosch, Frederick; Kevin, Richard C; Theunissen, Eef L; McGregor, Iain S; Ramaekers, Johannes G","year":2020,"journal":"JAMA, 324(21), 2177-2186","doi":"10.1001/jama.2020.21218","pmid":"33258890","tags":["driving","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"THC-dominant and THC/CBD-equivalent cannabis significantly increased lane weaving (SDLP +2.33cm and +2.81cm respectively) at 40-100 minutes after vaporization. By 240-300 minutes, no significant impairment remained in any condition. CBD-dominant cannabis did not significantly affect driving at either time point. For reference, a 0.05% BAC increases SDLP by 2.4cm.","whyItMatters":"This is one of the only studies using actual on-road driving tests (not simulators) to measure cannabis impairment, published in JAMA, providing high-quality evidence for driving policy.","specificNumbers":"26 participants (mean age 23.2, 16 women). 13.75mg THC and/or CBD doses. SDLP at 40-100 min: placebo 18.28cm, THC 20.59cm (+2.33), THC/CBD 21.09cm (+2.81), CBD 18.21cm (-0.07). At 240-300 min: no significant differences. 16 of 188 drives (8.5%) terminated for safety.","methodology":"Double-blind, within-participants, randomized clinical trial at Maastricht University with 26 healthy occasional cannabis users. Four conditions: THC-dominant (13.75mg), CBD-dominant (13.75mg), THC/CBD-equivalent (13.75mg each), and placebo. On-road 100km driving tests at 40 and 240 minutes post-consumption.","limitations":"Occasional users only (regular users may differ). Single dose tested. 8.5% of drives terminated for safety concerns. CBD-dominant effect size could not exclude clinically important impairment."},{"rthcId":"RTHC-02394","title":"Prescribing medicinal cannabis.","authors":"Arnold, Jonathon C; Nation, Tamara; McGregor, Iain S","year":2020,"journal":"Australian prescriber, 43(5), 152-159","doi":"10.18773/austprescr.2020.052","pmid":"33093741","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"More than 100 cannabis products are available in Australia, mostly oral preparations (oils) or capsules containing THC or CBD. By end of 2019, over 28,000 approvals had been issued involving 1,400+ doctors, mostly GPs. Over 70,000 approvals were projected for 2020. Most prescriptions are for chronic non-cancer pain, anxiety, cancer-related symptoms, epilepsy, and neurological disorders. Supply chain problems can delay dispensing.","whyItMatters":"Australia's system provides a model for regulated medical cannabis access that other countries may follow, with lessons about what works and what challenges remain.","specificNumbers":"Over 100 products available. 28,000+ approvals by end 2019. 1,400+ prescribing doctors. 70,000+ projected by end 2020. Most approvals for chronic non-cancer pain, anxiety, cancer symptoms, epilepsy.","methodology":"Clinical review of Australia's medical cannabis prescribing framework, covering access schemes, available products, evidence for indications, and practical prescribing considerations.","limitations":"Australian system may not apply to other regulatory contexts. Evidence supporting some common indications (e.g., chronic pain, anxiety) is limited. No outcome data on whether prescriptions are effective."},{"rthcId":"RTHC-02395","title":"Comparison between a morocco and a native-born population, in a sample of first episode psychosis.","authors":"Arranz, Sara; Camacho, Julia; Andrés, Claudia; Niubó, Inés; Sanchez Gistau, Vanessa","year":2020,"journal":"Revista de psiquiatria y salud mental, 13(2), 73-79","doi":"10.1016/j.rpsm.2019.03.004","pmid":"31109904","tags":["psychosis","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Moroccan patients (28.9% of sample) were more likely to be male, had fewer years of education, and lower functionality scores. They reported less cannabis use than native-born patients. After multivariate analysis, only lower functionality (OR 0.93) and lower education (OR 0.75) remained significantly associated with Moroccan origin. Clinical characteristics at entry and discharge did not differ between groups. Moroccan patients showed a better side effect profile from medication.","whyItMatters":"Immigration and ethnicity influence psychosis presentation and outcomes. Understanding these differences helps tailor treatment approaches for diverse populations.","specificNumbers":"83 patients. 28.9% Moroccan origin. Lower functionality: OR 0.93. Lower education: OR 0.75. Less cannabis use in Moroccan group.","methodology":"Cross-sectional study of 83 inpatients with first-episode psychosis. Functionality, symptomatology, cannabis use patterns, antipsychotic dosing, and side effects compared between Moroccan and Spanish-born patients.","limitations":"Small sample size. Single hospital. Cross-sectional design. Self-reported cannabis use may be affected by cultural stigma. No follow-up data."},{"rthcId":"RTHC-02396","title":"Epilepsy and cannabidiol: a guide to treatment.","authors":"Arzimanoglou, Alexis; Brandl, Ulrich; Cross, J Helen; Gil-Nagel, Antonio; Lagae, Lieven; Landmark, Cecilie Johannessen; Specchio, Nicola; Nabbout, Rima; Thiele, Elizabeth A; Gubbay, Oliver; The Cannabinoids International Experts Panel","year":2020,"journal":"Epileptic disorders : international epilepsy journal with videotape, 22(1), 1-14","doi":"10.1684/epd.2020.1141","pmid":"32096470","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02397","title":"Cannabidiol disrupts conditioned fear expression and cannabidiolic acid reduces trauma-induced anxiety-related behaviour in mice.","authors":"Assareh, Neda; Gururajan, Anand; Zhou, Cilla; Luo, Jia Lin; Kevin, Richard C; Arnold, Jonathon C","year":2020,"journal":"Behavioural pharmacology, 31(6), 591-596","doi":"10.1097/FBP.0000000000000565","pmid":"32483052","tags":["anxiety","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD disrupted cued fear memory expression (conditioned fear response) but did not affect generalized anxiety. CBDA normalized trauma-induced generalized anxiety-like behavior but did not affect conditioned fear. Neither compound affected contextual fear expression. The dissociable effects suggest different mechanisms and potential complementary therapeutic roles.","whyItMatters":"CBDA is the naturally occurring acidic precursor to CBD that appears more potent in some animal models. Understanding how it differs from CBD could lead to better targeted treatments for PTSD and anxiety disorders.","specificNumbers":"Not specified in abstract. CBD and CBDA tested at doses showing dissociable effects on fear versus anxiety.","methodology":"Mice underwent Pavlovian fear conditioning. 24 hours later, CBD or CBDA was administered before testing for fear expression and generalized anxiety-like behavior.","limitations":"Mouse study. Fear conditioning is only a partial model of human PTSD. Doses and routes may not translate. Short-term assessment only."},{"rthcId":"RTHC-02398","title":"Uses, Effects and Toxicity of Synthetic Cannabinoids from the Perspective of People with Lived Experiences.","authors":"Assi, Sulaf; Marshall, Danielle; Bersani, Francesco Saverio; Corazza, Ornella","year":2020,"journal":"Journal of psychoactive drugs, 52(3), 237-247","doi":"10.1080/02791072.2020.1723748","pmid":"32027228","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Content analysis of 1,660 posts from 50 threads (2004-2016) revealed significant information exchange about SC consumption characteristics, modalities of use, experienced effects, and toxicity. While growing attention has been given to SC chemical and pharmacological profiles, very little is known about subjective user experiences. Users shared detailed experiential data that could inform prevention and treatment approaches.","whyItMatters":"User-reported experiences provide real-world data that controlled studies cannot capture, including information about why people choose synthetic cannabinoids, how they use them, and what negative effects they experience.","specificNumbers":"1,660 posts analyzed. 50 threads. Time period: 2004-2016.","methodology":"Qualitative content analysis of online discussion forums. 1,660 posts from 50 threads posted between 2004 and 2016 were examined for characteristics of users, SC use patterns, and reported effects and toxicity.","limitations":"Online forum data cannot be verified. Users may not be representative of all SC users. No structured data collection. Self-report subject to bias and exaggeration."},{"rthcId":"RTHC-02399","title":"Cannabis Hyperemesis Syndrome: A Still Under-Recognized Syndrome.","authors":"Attout, Hassene; Amichi, Sofia; Josse, Françoise; Appavoupoule, Vincent; Randriajohany, Andry; Thirapathi, Yogananda","year":2020,"journal":"European journal of case reports in internal medicine, 7(5), 001588","doi":"10.12890/2020_001588","pmid":"32399447","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02400","title":"Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.","authors":"Auger, Nathalie; Paradis, Gilles; Low, Nancy; Ayoub, Aimina; He, Siyi; Potter, Brian J","year":2020,"journal":"BMC medicine, 18(1), 328","doi":"10.1186/s12916-020-01804-6","pmid":"33208143","tags":["cardiovascular","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Women with cannabis use disorders had 1.48 times the risk of cardiovascular hospitalization (95% CI 1.27-1.72). Cannabis with other substances had stronger association (HR 1.84) than cannabis alone (HR 1.30, borderline significant). Cannabis use disorder was strongly associated with hemorrhagic stroke even after adjusting for other substance use (HR 2.08, CI 1.07-4.05). Cardiovascular hospitalization incidence was 58.4 vs 33.6 per 10,000 person-years.","whyItMatters":"This is one of the largest and longest studies examining cannabis and cardiovascular risk in women, providing evidence that cannabis use disorder may have lasting cardiovascular consequences.","specificNumbers":"1,247,035 women. 18,998,986 person-years. Overall CVD: HR 1.48 (95% CI 1.27-1.72). Cannabis alone: HR 1.30. Cannabis + other substances: HR 1.84. Hemorrhagic stroke: HR 2.08 (95% CI 1.07-4.05).","methodology":"Longitudinal cohort of 1,247,035 pregnant women in Quebec, Canada (1989-2019). 18,998,986 person-years of follow-up. Cox regression adjusted for patient characteristics.","limitations":"Cannabis use disorder identified by diagnostic codes (may miss non-disordered use). Confounding by other substance use partially addressed but not eliminated. Healthy user bias possible."},{"rthcId":"RTHC-02401","title":"Cannabinoid CB1 Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice.","authors":"Avalos, Bryant; Argueta, Donovan A; Perez, Pedro A; Wiley, Mark; Wood, Courtney; DiPatrizio, Nicholas V","year":2020,"journal":"Nutrients, 12(9)","doi":"10.3390/nu12092874","pmid":"32962222","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02402","title":"Understanding sex differences in long-term outcomes after a first episode of psychosis.","authors":"Ayesa-Arriola, Rosa; de la Foz, Víctor Ortíz-García; Setién-Suero, Esther; Ramírez-Bonilla, María Luz; Suárez-Pinilla, Paula; Son, Jacqueline Mayoral-van; Vázquez-Bourgon, Javier; Juncal-Ruiz, María; Gómez-Revuelta, Marcos; Tordesillas-Gutiérrez, Diana; Crespo-Facorro, Benedicto","year":2020,"journal":"NPJ schizophrenia, 6(1), 33","doi":"10.1038/s41537-020-00120-5","pmid":"33219222","tags":["psychosis","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"At first contact, women were older at onset, had higher premorbid adjustment and IQ, were more often employed and living independently. During the first 3 years in specialized early intervention services (EIS), women had higher recovery rates (50% vs 30.8%) and responded better to lower antipsychotic doses. After 10 years (following discharge from EIS to community services), women only maintained an advantage in negative symptoms; recovery rates no longer differed significantly (46.7% vs 34.4%). Antipsychotic doses increased after EIS discharge. Cannabis use remained more common among men at all time points.","whyItMatters":"The narrowing of the sex gap after specialized care ends raises questions about whether longer-duration EIS programs could maintain women's early advantage.","specificNumbers":"209 patients (95 females, 114 males). 3-year recovery: 50% women vs 30.8% men. 10-year recovery: 46.7% women vs 34.4% men (not significant). Cannabis use more common in men at all time points. Antipsychotic doses increased after EIS discharge.","methodology":"Longitudinal cohort of 209 first-episode psychosis patients (95 females, 114 males) reassessed 8-16 years after initial contact with the PAFIP early intervention program in Spain.","limitations":"Single EIS program. Some attrition over 10 years. Observational design. Cannabis use differences may contribute to sex differences beyond biological factors."},{"rthcId":"RTHC-02403","title":"Topical Capsaicin for Treating Cannabinoid Hyperemesis Syndrome.","authors":"Aziz, Ansar; Waheed, Tayyab; Oladunjoye, Olubunmi; Oladunjoye, Adeolu; Hanif, Midhat; Latif, Fareena","year":2020,"journal":"Case reports in gastrointestinal medicine, 2020, 8868385","doi":"10.1155/2020/8868385","pmid":"33294233","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02404","title":"Therapeutic potential of opioid/cannabinoid combinations in humans: Review of the evidence.","authors":"Babalonis, Shanna; Walsh, Sharon L","year":2020,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 36, 206-216","doi":"10.1016/j.euroneuro.2020.03.002","pmid":"32273144","tags":["pain","drug-interactions"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Preclinical studies show cannabinoids enhance opioid analgesia and reduce required opioid doses in animals. However, controlled human studies and clinical trials have not demonstrated robust analgesic or opioid-sparing effects. Meta-analyses do not strongly support cannabinoids for chronic pain. There may be a modest signal for THC suppressing some opioid withdrawal symptoms, but not complete amelioration. Despite anecdotal and correlational reports, no strong data support cannabis reducing opioid overdose.","whyItMatters":"Public advocacy for cannabis as an opioid replacement is widespread, but the disconnect between preclinical promise and clinical reality could lead to harmful policy decisions if not clearly communicated.","specificNumbers":"No specific pooled statistics. Review synthesized preclinical, clinical trial, and meta-analytic evidence.","methodology":"Review of preclinical evidence, controlled human laboratory studies, clinical trials, and meta-analyses examining opioid/cannabinoid combinations for pain and opioid use disorder.","limitations":"Narrative review structure. Human studies may use different doses, formulations, and outcomes than optimal. Some animal-to-human translational failure may reflect methodological issues rather than true lack of effect."},{"rthcId":"RTHC-02405","title":"Roles of Cannabinoids in Melanoma: Evidence from In Vivo Studies.","authors":"Bachari, Ava; Piva, Terrence J; Salami, Seyed Alireza; Jamshidi, Negar; Mantri, Nitin","year":2020,"journal":"International journal of molecular sciences, 21(17)","doi":"10.3390/ijms21176040","pmid":"32839414","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02406","title":"Cannabis use during pregnancy and postpartum.","authors":"Badowski, Sophia; Smith, Graeme","year":2020,"journal":"Canadian family physician Medecin de famille canadien, 66(2), 98-103","doi":null,"pmid":"32060189","tags":["pregnancy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"In utero cannabis exposure has been associated with long-term neurodevelopmental outcomes that persist into young adulthood. Cannabis should not be used to treat nausea and vomiting in pregnancy. Chronic cannabis use might lead to cannabinoid hyperemesis syndrome. There is no known safe level of cannabis use during pregnancy or lactation.","whyItMatters":"Cannabis is the most commonly used illicit substance in pregnancy, and some women use it specifically for morning sickness, making clear clinical guidance essential.","specificNumbers":"No specific incidence or outcome data pooled.","methodology":"Literature review using Ovid MEDLINE searching pregnancy, cannabis, lactation, and cannabinoid hyperemesis terms.","limitations":"Narrative review. Underlying studies are mostly observational with confounders. No randomized data on pregnancy outcomes."},{"rthcId":"RTHC-02407","title":"Prevalence of cannabis withdrawal symptoms among people with regular or dependent use of cannabinoids: A systematic review and meta-analysis","authors":"Bahji, Anees; Stephenson, Callum; Tyo, Richard; Hawken, Emily R.; Seitz, Dallas P.","year":2020,"journal":"JAMA Network Open, 3(4), e202370","doi":null,"pmid":"32271390","tags":["withdrawal","addiction","quitting"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"This was the first meta-analysis to estimate how common cannabis withdrawal syndrome actually is. Pooling 23 studies with 27,461 participants who had regular or dependent cannabis use, the researchers found a prevalence of 47% — meaning roughly half of heavy users experienced clinically significant withdrawal when they stopped.\n\nThe withdrawal symptoms weren't subtle. The most commonly reported were irritability, nervousness or anxiety, sleep difficulty, decreased appetite, restlessness, depressed mood, and anger or aggression. These typically appeared within the first week of cessation and resolved within 2-4 weeks.\n\nSeveral factors predicted higher withdrawal rates. People with more severe cannabis use disorder, those using more frequently, and those with comorbid mental health conditions were more likely to experience withdrawal. The 47% figure also masked a wide range across studies — from under 20% in some samples to over 70% in others, reflecting differences in how withdrawal was measured and who was studied.","whyItMatters":"For years, cannabis withdrawal was dismissed or minimized — both in popular culture and in clinical settings. This meta-analysis put a hard number on it: 47%. That's not everyone, but it's not a small minority either. Roughly half of heavy users will experience a clinically recognizable withdrawal syndrome when they stop.\n\nThis matters for anyone trying to quit. Knowing that irritability, insomnia, and anxiety during the first two weeks are a documented medical phenomenon — not a personal weakness — changes how people approach cessation. It also strengthens the clinical case for cannabis use disorder as a real condition with measurable physiological features.","specificNumbers":"• Cannabis withdrawal prevalence: 47% (95% CI: 41-54%) among regular/dependent users\n• 23 studies, 27,461 participants\n• Most common symptoms: irritability, anxiety, sleep difficulty, decreased appetite, restlessness\n• Higher risk factors: more severe CUD, higher frequency of use, comorbid mental health conditions","methodology":"Systematic review and meta-analysis published in JAMA Network Open. Searched eight databases from inception through June 2019. Included studies using validated instruments to measure cannabis withdrawal syndrome in people with regular or dependent cannabinoid use. Used random-effects meta-analysis for prevalence estimates. Assessed heterogeneity and conducted subgroup analyses.","limitations":"High heterogeneity across studies (I² values) reflects differences in withdrawal definitions, assessment tools, and study populations. Most participants were from clinical or treatment-seeking samples, which may overestimate withdrawal prevalence in the general user population. Self-report measures are subject to recall and response bias. The meta-analysis could not determine which withdrawal symptoms were most functionally impairing."},{"rthcId":"RTHC-02408","title":"Illicit drugs are now more common than alcohol among South Australian crash-involved drivers and riders.","authors":"Baldock, Matthew; Lindsay, Tori","year":2020,"journal":"Traffic injury prevention, 21(1), 1-6","doi":"10.1080/15389588.2020.1712715","pmid":"31999482","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Over 15% of crash-involved drivers and motorcyclists tested positive for proscribed drugs (THC, methamphetamine, or MDMA), compared to about 11% of drivers and 5% of motorcyclists with illegal blood alcohol. THC was found in 6.3% of drivers and 9.4% of motorcyclists. Drug rates increased from 10.5% (2008-2010) to 15.2% (2014-2017) while illegal alcohol rates declined from 20.2% to 9.3%.","whyItMatters":"The shift from alcohol to drug impairment in crashes represents a changing landscape that requires updated enforcement strategies and public messaging.","specificNumbers":"Drivers: methamphetamine 9.7%, THC 6.3%. Motorcyclists: THC 9.4%, methamphetamine 6.2%. Drug-positive rate: 10.5% (2008-2010) to 15.2% (2014-2017). Illegal BAC: 20.2% to 9.3%.","methodology":"Analysis of mandatory blood test results from crash-involved road users over age 16 at the major trauma hospital in Adelaide, South Australia (2014-2017), compared to earlier data (2008-2010).","limitations":"Single trauma hospital. Only three drugs tested. Positive test does not confirm impairment at time of crash. Comparison to earlier data involves different methodology nuances."},{"rthcId":"RTHC-02409","title":"Pregnant Canadians' Perceptions About the Transmission of Cannabis in Pregnancy and While Breastfeeding and the Impact of Information From Health Care Providers on Discontinuation of Use.","authors":"Bartlett, Katelyn; Kaarid, Kaija; Gervais, Nicole; Vu, Nancy; Sharma, Sapna; Patel, Tejal; Shea, Alison K","year":2020,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 42(11), 1346-1350","doi":"10.1016/j.jogc.2020.04.015","pmid":"32739359","tags":["pregnancy"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"94.3% perceived cannabis is transmitted to the fetus and 91.2% to the infant via breastmilk. 99% said legalization did not influence their choice to use cannabis in pregnancy. 4.2% continued using during pregnancy. Surprisingly, women who continued using were more likely to have received cannabis information from a provider (52%) than those who quit (35%, p=0.035).","whyItMatters":"The finding that provider counseling was associated with continued use challenges assumptions about the effectiveness of current clinical messaging approaches.","specificNumbers":"478 women surveyed. 94.3% knew cannabis reaches fetus. 91.2% knew it reaches infant via breastmilk. 99% said legalization was not a factor. 4.2% continued use. Providers: 52% of users vs 35% of quitters received provider information (p=0.035).","methodology":"Anonymous survey of 478 pregnant women at obstetrical, midwifery, and family practice clinics in the greater Hamilton, Ontario area.","limitations":"Cross-sectional survey from one region. Self-reported data. Small number who continued use. Cannot determine direction of the counseling association."},{"rthcId":"RTHC-02410","title":"A Case of Toxicity from Cannabidiol Gummy Ingestion.","authors":"Bass, Jessica; Linz, David R","year":2020,"journal":"Cureus, 12(4), e7688","doi":"10.7759/cureus.7688","pmid":"32431968","tags":["cbd","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"After consuming 370mg of CBD gummies (from two packages, well above the 30mg serving size), the patient developed slurred speech, vomiting, respiratory depression (O2 sat 78-84%), sinus bradycardia (HR 47), and hypotension (BP 88/52). Comprehensive urine toxicology was negative. He required continuous stimulation to maintain a patent airway and recovered fully by the next morning.","whyItMatters":"CBD products sold at gas stations and convenience stores are unregulated, with unknown purity and potential contamination. This case shows serious adverse effects from a product the patient believed was safe.","specificNumbers":"370mg CBD consumed (two packages). Serving size listed as 30mg. O2 dropped to 78%. Heart rate dropped to 47. Blood pressure 88/52. Full recovery by next morning.","methodology":"Single case report of a 56-year-old male with no prior substance abuse or significant medical history.","limitations":"Single case report. Product contents were not independently verified. The toxicology was only for standard substances and may have missed novel adulterants."},{"rthcId":"RTHC-02411","title":"In Silico Identification of MYB and bHLH Families Reveals Candidate Transcription Factors for Secondary Metabolic Pathways in Cannabis sativa L.","authors":"Bassolino, Laura; Buti, Matteo; Fulvio, Flavia; Pennesi, Alessandro; Mandolino, Giuseppe; Milc, Justyna; Francia, Enrico; Paris, Roberta","year":2020,"journal":"Plants (Basel, Switzerland), 9(11)","doi":"10.3390/plants9111540","pmid":"33187168","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02412","title":"The Impact of Cannabidiol on Human Brain Function: A Systematic Review.","authors":"Batalla, Albert; Bos, Julian; Postma, Amber; Bossong, Matthijs G","year":2020,"journal":"Frontiers in pharmacology, 11, 618184","doi":"10.3389/fphar.2020.618184","pmid":"33551817","tags":["cbd","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"In healthy volunteers, CBD enhanced fronto-striatal resting state connectivity and had opposite effects to THC during emotional processing (fronto-temporal), verbal memory (fronto-striatal), response inhibition (fronto-limbic-striatal), and auditory/visual processing (temporo-occipital). In psychiatric populations, CBD showed intermediate brain activity between placebo and healthy controls during cognitive tasks. CBD modulated limbic activity in anxiety and metabolite levels in autism spectrum disorder.","whyItMatters":"Understanding how CBD changes brain function provides a biological basis for its therapeutic effects and helps explain why it may work for psychosis, anxiety, and other disorders.","specificNumbers":"194 studies identified, 17 met inclusion criteria. All examined acute CBD effects. Studies covered healthy volunteers and patients with psychosis risk, established psychosis, anxiety, and autism.","methodology":"Systematic review of 17 neuroimaging studies (from 194 identified) examining acute CBD effects on brain function in healthy volunteers and psychiatric patients. Published through May 2020.","limitations":"All studies examined acute (single-dose) effects. Small sample sizes across studies. Heterogeneous methods and populations. No long-term neuroimaging data."},{"rthcId":"RTHC-02413","title":"Cannabinoids in the Older Person: A Literature Review.","authors":"Beedham, William; Sbai, Magda; Allison, Isabel; Coary, Roisin; Shipway, David","year":2020,"journal":"Geriatrics (Basel, Switzerland), 5(1)","doi":"10.3390/geriatrics5010002","pmid":"31941020","tags":["seniors","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"From 35 relevant studies, cannabinoids demonstrate some efficacy for pain and chemotherapy-related nausea. Limited data suggest potential benefits for spasticity and anxiety. Risks in older patients appear moderate and comparable to other analgesic drug classes. However, research quality is weak, and few older patients have been specifically enrolled in cannabinoid studies.","whyItMatters":"Older adults are the fastest-growing group of medical cannabis users but are also more vulnerable to adverse effects like falls, cognitive impairment, and drug interactions.","specificNumbers":"35 studies identified. Evidence for pain and nausea. Limited data for spasticity and anxiety. Few older patients enrolled in existing studies.","methodology":"Narrative literature review searching CENTRAL, Medline, Embase, CINAHL, psycINFO, Cochrane, and Web of Science. 35 studies identified as relevant.","limitations":"Narrative review. Weak underlying research quality. Few studies specifically enrolled older adults. Extrapolation from younger populations may not be valid."},{"rthcId":"RTHC-02414","title":"Attitudes and Knowledge of Australian Gastroenterologists Around the Use of Medicinal Cannabis for Inflammatory Bowel Disease.","authors":"Benson, Melissa J; Abelev, Sarah V; Corte, Crispin J; Connor, Susan J; McGregor, Iain S","year":2020,"journal":"Crohn's & colitis 360, 2(2), otaa045","doi":"10.1093/crocol/otaa045","pmid":"36777304","tags":["medical-cannabis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"39% had patients using medical cannabis. Only 21% supported MC in IBD. Only 28% wanted to prescribe. Just 6% understood access pathways. Only 31% felt comfortable discussing MC with patients. 20% cited adverse effects as a barrier. Driving impairment (64%) and developing brain effects (56%) were top concerns. Yet most ranked MC as less hazardous than steroids, immunomodulators, and biologics. 53% supported patient participation in clinical trials.","whyItMatters":"The disconnect between patient use (39% of specialists had MC-using patients) and specialist support (21%) creates a gap in clinical guidance.","specificNumbers":"93 respondents (70 gastroenterologists, 23 trainees). 39% had MC-using patients. 21% supported MC in IBD. 28% wanted to prescribe. 6% understood access pathways. 31% comfortable discussing. 64% concerned about driving. 53% supported clinical trials.","methodology":"Anonymous 30-item survey of 70 Australian gastroenterologists and 23 trainees, collected April-August 2019.","limitations":"Small sample from one country. Self-selected respondents may not represent all gastroenterologists. Survey conducted before some evidence updates."},{"rthcId":"RTHC-02415","title":"Cannabis and cannabidiol (CBD) for the treatment of fibromyalgia.","authors":"Berger, Amnon A; Keefe, Joseph; Winnick, Ariel; Gilbert, Elasaf; Eskander, Jonathan P; Yazdi, Cyrus; Kaye, Alan D; Viswanath, Omar; Urits, Ivan","year":2020,"journal":"Best practice & research. Clinical anaesthesiology, 34(3), 617-631","doi":"10.1016/j.bpa.2020.08.010","pmid":"33004171","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Fibromyalgia affects up to 10% of the population. Only physical exercise has strong evidence as a treatment. Few randomized cannabis trials exist for fibromyalgia, and their objectivity has been questioned. However, many retrospective trials and patient surveys suggest significant pain alleviation, sleep improvement, and symptom relief. Cannabis use carries risks including psychiatric, cognitive, developmental effects, and addiction potential.","whyItMatters":"Fibromyalgia is prevalent and undertreated, with most medications providing insufficient relief. Cannabis is increasingly used by patients, but the evidence gap between self-report and controlled trials needs closing.","specificNumbers":"Prevalence up to 10%. Only physical exercise has strong treatment evidence. A handful of randomized trials exist for cannabis in fibromyalgia.","methodology":"Systematic review of evidence for cannabis and CBD in fibromyalgia treatment, including pathophysiology, diagnosis, current treatments, and cannabinoid evidence.","limitations":"Limited randomized trial data. Patient surveys subject to bias and placebo effects. Heterogeneous fibromyalgia populations make comparison difficult."},{"rthcId":"RTHC-02416","title":"The impact of naturalistic cannabis use on self-reported opioid withdrawal.","authors":"Bergeria, Cecilia L; Huhn, Andrew S; Dunn, Kelly E","year":2020,"journal":"Journal of substance abuse treatment, 113, 108005","doi":"10.1016/j.jsat.2020.108005","pmid":"32359667","tags":["withdrawal","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"62.5% (125/200) had used cannabis to treat opioid withdrawal. Cannabis most commonly improved anxiety, tremors, and trouble sleeping. Only 6% (12 participants) reported cannabis worsened withdrawal, specifically yawning, teary eyes, and runny nose. Across all symptoms, more participants reported improvement than worsening with cannabis. Women reported greater withdrawal relief than men.","whyItMatters":"Four US states had legalized medical cannabis for opioid use disorder treatment. Self-reported data on which withdrawal symptoms cannabis helps or worsens can guide clinical research priorities.","specificNumbers":"200 participants. 62.5% used cannabis for withdrawal. Improved: anxiety, tremors, sleep. Worsened in 6%: yawning, teary eyes, runny nose. Women reported greater relief.","methodology":"Online survey of 200 individuals recruited via Amazon Mechanical Turk with past-month opioid and cannabis use and opioid withdrawal experience. Participants rated symptom changes with and without cannabis.","limitations":"Self-report survey via MTurk. No verification of opioid use disorder or withdrawal. Retrospective recall. No control group. Cannabis dose and type unknown."},{"rthcId":"RTHC-02417","title":"Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop-seizure frequency.","authors":"Bergmann, Kirsten Riber; Broekhuizen, Karen; Groeneveld, Geert Jan","year":2020,"journal":"British journal of clinical pharmacology, 86(2), 380-385","doi":"10.1111/bcp.14158","pmid":"31657863","tags":["epilepsy","cbd","drug-interactions"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Simulations showed that the observed seizure reduction from CBD could be replicated by assuming: (1) patients on clobazam had a 2- to 7-fold increase in norclobazam (active metabolite) exposure, and (2) patients not on clobazam had seizure reduction and variability similar to placebo. This suggests CBD's apparent anti-seizure effect may be primarily a drug interaction rather than a direct pharmacological effect.","whyItMatters":"If CBD's benefit is primarily through boosting clobazam, simply increasing clobazam doses might achieve the same effect at lower cost, though with potentially more side effects.","specificNumbers":"CBD dose: 20 mg/kg/day. Norclobazam exposure increase: 2- to 7-fold. Simulated patients on 10 or 20 mg clobazam.","methodology":"Clinical trial simulations modeling the effect of 20 mg/kg/day CBD on drop-seizure frequency in Lennox-Gastaut syndrome, assuming known CBD-clobazam interaction parameters.","limitations":"Simulation study, not empirical trial. Assumptions may not fully reflect clinical reality. Does not account for all possible mechanisms of CBD action."},{"rthcId":"RTHC-02418","title":"Cannabinoidomics - An analytical approach to understand the effect of medical Cannabis treatment on the endocannabinoid metabolome.","authors":"Berman, Paula; Sulimani, Liron; Gelfand, Anat; Amsalem, Keren; Lewitus, Gil M; Meiri, David","year":2020,"journal":"Talanta, 219, 121336","doi":"10.1016/j.talanta.2020.121336","pmid":"32887067","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02419","title":"Endocannabinoid system alterations in Alzheimer's disease: A systematic review of human studies.","authors":"Berry, Alex J; Zubko, Olga; Reeves, Suzanne J; Howard, Robert J","year":2020,"journal":"Brain research, 1749, 147135","doi":"10.1016/j.brainres.2020.147135","pmid":"32980333","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02420","title":"Regulatory sampling of industrial hemp plant samples (Cannabis sativa L.) using UPLC-MS/MS method for detection and quantification of twelve cannabinoids.","authors":"Berthold, Erin C; Yang, Rui; Sharma, Abhisheak; Kamble, Shyam H; Kanumuri, Siva R; King, Tamara I; Popa, Raluca; Freeman, Joshua H; Brym, Zachary T; Avery, Bonnie A; McCurdy, Christopher R","year":2020,"journal":"Journal of cannabis research, 2(1), 42","doi":"10.1186/s42238-020-00050-0","pmid":"33526142","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02421","title":"Concomitant Substance Use Increases the Toxic Effect of synthetic cannabinoid (Bonsai): A Prospective Study.","authors":"Beydilli, İnan; Duyan, Murat; Yılmaz, Fevzi; Arslan, Engin Deniz; Korkmaz, İlhan; Akçimen, Mehmet; Keşaplı, Mustafa; İmak, Arefe; Çakır, Umut Cengiz; Kavalcı, Cemil; Ararat, Ertan; Ellidağ, Hamit","year":2020,"journal":"Acta bio-medica : Atenei Parmensis, 92(1), e2021006","doi":"10.23750/abm.v92i1.9989","pmid":"33682827","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"69.4% of patients had concomitant drug intake. Most common co-substances: THC (32.7%), alcohol (30.6%), cocaine (20.4%), opiates (18.4%), amphetamines (14.3%). The concomitant group had significantly lower Glasgow Coma Scores (p=0.003), longer symptom remission times, and higher hospitalization rates (p=0.020). No patients in the bonsai-only group required hospitalization. Median symptom remission time was 3 hours; median ED follow-up was 6 hours.","whyItMatters":"Most synthetic cannabinoid users also use other substances, and the combination significantly increases the severity of toxicity and healthcare utilization.","specificNumbers":"49 patients analyzed (91.8% male, mean age 26.7). 69.4% had concomitant drug use. GCS significantly lower in poly-drug group (p=0.003). No hospitalizations in bonsai-only group. Most common symptom: tachycardia (75.5%).","methodology":"Prospective study of 217 ED patients with reported bonsai intake. 49 with confirmed positive urinary metabolites were analyzed in two groups: bonsai-only and bonsai with concomitant substances.","limitations":"Small sample (49 patients). Single country (Turkey). Only patients with positive urinary metabolites included. Self-reported substance use history."},{"rthcId":"RTHC-02422","title":"Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats.","authors":"Bhatt, Dhyey; Hazari, Ali; Yamakawa, Glenn R; Salberg, Sabrina; Sgro, Marissa; Shultz, Sandy R; Mychasiuk, Richelle","year":2020,"journal":"Brain communications, 2(1), fcaa042","doi":"10.1093/braincomms/fcaa042","pmid":"32954298","tags":["neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC after repeated mild TBI was beneficial for 3 of 6 behavioral outcomes: reducing anxiety, reducing depressive-like behaviors, and improving short-term working memory deficits. THC also normalized gene expression changes in the hippocampus, nucleus accumbens, and prefrontal cortex. THC administered before injury had no notable benefits, suggesting timing is critical.","whyItMatters":"Adolescents have the highest concussion rates and are also frequent cannabis users. Understanding whether THC helps or hurts recovery from concussions is directly clinically relevant.","specificNumbers":"THC improved 3 of 6 behavioral outcomes when given post-injury. No benefit when given pre-injury. Beneficial gene expression changes in hippocampus, nucleus accumbens, and prefrontal cortex.","methodology":"Male and female adolescent Sprague-Dawley rats received THC or vehicle either before or after repeated mild brain injuries. Behavioral testing measured post-concussive symptoms. Brain regions were examined for mRNA expression of Bdnf, Cnr1, Comt, GR, Iba-1, and Vegf-2R.","limitations":"Animal study in rats. Adolescent rat physiology differs from human. Single THC dose protocol. Cannot directly inform human concussion management."},{"rthcId":"RTHC-02423","title":"Does cannabidiol have antiseizure activity independent of its interactions with clobazam? An appraisal of the evidence from randomized controlled trials.","authors":"Bialer, Meir; Perucca, Emilio","year":2020,"journal":"Epilepsia, 61(6), 1082-1089","doi":"10.1111/epi.16542","pmid":"32452568","tags":["epilepsy","cbd","drug-interactions"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"47-68% of CBD trial patients were taking clobazam, which shows complex interactions with CBD (3.4-5 fold norclobazam increase). Seizure improvement was greater when CBD was added to clobazam vs other medications. However, seizure control was also improved in patients not on clobazam, and was statistically significant for the 10 mg/kg/d dose in one LGS trial. Meta-analyses of pooled LGS and DS patients not on clobazam provided stronger evidence of independent CBD anti-seizure effects.","whyItMatters":"This addresses the critical question of whether CBD is truly anti-epileptic or merely boosting clobazam levels, concluding that both mechanisms contribute.","specificNumbers":"4 pivotal RCTs. 47-68% on clobazam. Norclobazam increase: 3.4-5 fold. Independent effect significant at 10 mg/kg/d in one LGS trial. Meta-analysis of non-clobazam patients showed significant benefit.","methodology":"Appraisal of four pivotal randomized placebo-controlled CBD trials (Dravet and Lennox-Gastaut syndromes), using subgroup analyses from the European Medicines Agency Public Assessment Report.","limitations":"Subgroup analyses were not pre-specified. Small numbers in non-clobazam subgroups. Meta-analysis of subgroups has inherent limitations."},{"rthcId":"RTHC-02424","title":"Phytocannabinoids: Useful Drugs for the Treatment of Obesity? Special Focus on Cannabidiol.","authors":"Bielawiec, Patrycja; Harasim-Symbor, Ewa; Chabowski, Adrian","year":2020,"journal":"Frontiers in endocrinology, 11, 114","doi":"10.3389/fendo.2020.00114","pmid":"32194509","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02425","title":"Novel halogenated synthetic cannabinoids impair sensorimotor functions in mice.","authors":"Bilel, Sabrine; Tirri, Micaela; Arfè, Raffaella; Ossato, Andrea; Trapella, Claudio; Serpelloni, Giovanni; Neri, Margherita; Fattore, Liana; Marti, Matteo","year":2020,"journal":"Neurotoxicology, 76, 17-32","doi":"10.1016/j.neuro.2019.10.002","pmid":"31610187","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02426","title":"Antinociceptive effects of treadmill exercise in a rat model of Parkinson's disease: The role of cannabinoid and opioid receptors.","authors":"Binda, K H; Real, C C; Ferreira, A F F; Britto, L R; Chacur, M","year":2020,"journal":"Brain research, 1727, 146521","doi":"10.1016/j.brainres.2019.146521","pmid":"31697924","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02427","title":"Developmental differences in the effects of CB1/2R agonist WIN55212-2 on extinction of learned fear.","authors":"Bisby, Madelyne A; Richardson, Rick; Baker, Kathryn D","year":2020,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 99, 109834","doi":"10.1016/j.pnpbp.2019.109834","pmid":"31830508","tags":["youth","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"WIN55212-2, a CB1/CB2 receptor agonist, improved fear extinction in adult rats but impaired extinction acquisition in both adolescent and juvenile rats. CB1 receptor protein expression decreased linearly from juvenile to adolescent to adult stages in the prefrontal cortex and amygdala.","whyItMatters":"The developing brain may respond to cannabinoid receptor activation differently than the adult brain, particularly for processes tied to emotional regulation and fear learning.","specificNumbers":"CB1 receptor protein showed a linear decrease across age in both medial prefrontal cortex and amygdala. Impaired extinction in adolescents was consistent across multiple drug doses.","methodology":"Rats at juvenile, adolescent, and adult developmental stages received WIN55212-2 or vehicle before extinction training following fear conditioning. CB1 receptor protein was quantified via Western blot in the medial prefrontal cortex and amygdala.","limitations":"Animal model; WIN55212-2 is a synthetic agonist that activates both CB1 and CB2 receptors, so effects may not directly translate to cannabis exposure in humans."},{"rthcId":"RTHC-02428","title":"Is the Adolescent Brain at Greater Vulnerability to the Effects of Cannabis? A Narrative Review of the Evidence.","authors":"Blest-Hopley, Grace; Colizzi, Marco; Giampietro, Vincent; Bhattacharyya, Sagnik","year":2020,"journal":"Frontiers in psychiatry, 11, 859","doi":"10.3389/fpsyt.2020.00859","pmid":"33005157","tags":["youth","cognition","neuroscience","mental-health"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Adolescent cannabis users show altered functional connectivity within established brain circuits, with largely increased functional activation compared to controls. The endocannabinoid system undergoes developmental changes during adolescence that may make it more susceptible to cannabis exposure.","whyItMatters":"Adolescence involves critical brain development, and understanding whether cannabis use during this window carries elevated risk compared to adult use has direct public health implications.","specificNumbers":"No specific effect sizes reported; the review synthesizes findings across multiple studies.","methodology":"Narrative review synthesizing human neuroimaging studies of adolescent cannabis users, cognitive performance data, and preclinical evidence on adolescent-specific vulnerability.","limitations":"Narrative review (not systematic); many underlying studies are cross-sectional, making it difficult to establish whether cannabis caused observed brain changes or whether pre-existing differences preceded use."},{"rthcId":"RTHC-02429","title":"A Systematic Review of Human Neuroimaging Evidence of Memory-Related Functional Alterations Associated with Cannabis Use Complemented with Preclinical and Human Evidence of Memory Performance Alterations.","authors":"Blest-Hopley, Grace; Giampietro, Vincent; Bhattacharyya, Sagnik","year":2020,"journal":"Brain sciences, 10(2)","doi":"10.3390/brainsci10020102","pmid":"32069958","tags":["cognition","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Twelve fMRI studies showed cannabis users had altered brain activation during memory tasks compared to non-users. Performance studies indicated cannabis users performed worse on verbal memory tasks. Longitudinal studies suggested cannabis may play a causal role in memory deficits.","whyItMatters":"Understanding the neural basis of cannabis-related memory changes helps clarify whether observed deficits reflect altered brain processing rather than just behavioral differences.","specificNumbers":"12 fMRI studies identified showing altered functional brain activation in cannabis users during memory tasks.","methodology":"Systematic review of fMRI studies examining brain function during memory tasks in cannabis users vs. non-users, supplemented with narrative reviews of behavioral performance and preclinical evidence.","limitations":"Limited number of fMRI studies available; heterogeneity in study designs, cannabis exposure measures, and memory tasks; preclinical evidence was not conclusive on memory deficits."},{"rthcId":"RTHC-02430","title":"The effects of acute cannabidiol on cerebral blood flow and its relationship to memory: An arterial spin labelling magnetic resonance imaging study.","authors":"Bloomfield, Michael A P; Green, Sebastian F; Hindocha, Chandni; Yamamori, Yumeya; Yim, Jocelyn Lok Ling; Jones, Augustus P M; Walker, Hannah R; Tokarczuk, Pawel; Statton, Ben; Howes, Oliver D; Curran, H Valerie; Freeman, Tom P","year":2020,"journal":"Journal of psychopharmacology (Oxford, England), 34(9), 981-989","doi":"10.1177/0269881120936419","pmid":"32762272","tags":["cbd","neuroscience","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CBD increased cerebral blood flow in the hippocampus by an average of 15 mL/100g/min compared to placebo (Cohen's d = 0.75, p = 0.004). Greater CBD-induced increases in orbitofrontal CBF correlated with faster reaction times on a working memory task (r = -0.73, p = 0.005).","whyItMatters":"The hippocampus is central to memory formation, and showing that CBD increases blood flow there suggests a potential mechanism for CBD's therapeutic effects in conditions involving memory dysfunction.","specificNumbers":"Hippocampal CBF increase: 15.00 mL/100g/min (95% CI: 5.78-24.21), Cohen's d = 0.75. Orbitofrontal CBF and 2-back reaction time correlation: r = -0.73, p = 0.005.","methodology":"Randomized, crossover, double-blind design with 15 healthy participants receiving 600mg oral CBD or placebo on separate days. Cerebral blood flow measured at rest using arterial spin labelling MRI 3 hours after ingestion. Memory assessed via digit span, n-back, and prose recall tasks.","limitations":"Very small sample (15 participants); single-dose design; no differences in actual memory task performance were detected; only healthy participants studied."},{"rthcId":"RTHC-02431","title":"Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI.","authors":"Blount, Benjamin C; Karwowski, Mateusz P; Shields, Peter G; Morel-Espinosa, Maria; Valentin-Blasini, Liza; Gardner, Michael; Braselton, Martha; Brosius, Christina R; Caron, Kevin T; Chambers, David; Corstvet, Joseph; Cowan, Elizabeth; De Jesús, Víctor R; Espinosa, Paul; Fernandez, Carolina; Holder, Cory; Kuklenyik, Zsuzsanna; Kusovschi, Jennifer D; Newman, Cody; Reis, Gregory B; Rees, Jon; Reese, Chris; Silva, Lalith; Seyler, Tiffany; Song, Min-Ae; Sosnoff, Connie; Spitzer, Carleen R; Tevis, Denise; Wang, Lanqing; Watson, Cliff; Wewers, Mark D; Xia, Baoyun; Heitkemper, Douglas T; Ghinai, Isaac; Layden, Jennifer; Briss, Peter; King, Brian A; Delaney, Lisa J; Jones, Christopher M; Baldwin, Grant T; Patel, Anita; Meaney-Delman, Dana; Rose, Dale; Krishnasamy, Vikram; Barr, John R; Thomas, Jerry; Pirkle, James L","year":2020,"journal":"The New England journal of medicine, 382(8), 697-705","doi":"10.1056/NEJMoa1916433","pmid":"31860793","tags":["respiratory","harm-reduction","potency"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"Vitamin E acetate was detected in bronchoalveolar lavage fluid from 48 of 51 EVALI patients (94%) across 16 states but was absent in all 99 healthy comparators. Among case patients with available data, 94% had detectable THC or its metabolites in lung fluid or reported vaping THC products in the 90 days before symptom onset.","whyItMatters":"This NEJM study provided the strongest direct evidence linking vitamin E acetate to the EVALI outbreak, helping public health authorities identify the cause and issue targeted warnings about illicit THC vaping products.","specificNumbers":"48 of 51 (94%) EVALI patients had vitamin E acetate in lung fluid. 47 of 50 (94%) had THC or metabolites in lung fluid or reported vaping THC. 30 of 47 (64%) also had nicotine or metabolites. Zero healthy comparators had vitamin E acetate.","methodology":"BAL fluids from 51 EVALI patients in 16 states and 99 healthy participants were analyzed using isotope dilution mass spectrometry for vitamin E acetate, plant oils, medium-chain triglyceride oil, coconut oil, petroleum distillates, and diluent terpenes.","limitations":"Convenience sample; no BAL fluid was available from all patients; cannot completely rule out other contributing toxicants; the study identifies association, not definitive causation."},{"rthcId":"RTHC-02432","title":"Cannabinoids and psychotic symptoms: A potential role for a genetic variant in the P2X purinoceptor 7 (P2RX7) gene.","authors":"Boks, Marco P; He, Yujie; Schubart, Chris D; Gastel, Willemijn van; Elkrief, Laurent; Huguet, Guillaume; Eijk, Kristel van; Vinkers, Christiaan H; Kahn, René S; Paus, Tomás; Conrod, Patricia; Hol, Elly M; de Witte, Lot D","year":2020,"journal":"Brain, behavior, and immunity, 88, 573-581","doi":"10.1016/j.bbi.2020.04.051","pmid":"32330591","tags":["psychosis","genetics","neuroscience"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"A SNP in the P2RX7 gene (rs7958311) was associated with increased psychotic-like experiences in regular cannabis users (p = 1.10 x 10^-7) and was replicated in the IMAGEN cohort (p = 0.020). In vitro, THC and CBD reduced the P2X7 receptor's immune response in a genotype-dependent manner.","whyItMatters":"This identifies a specific genetic pathway that may explain why some cannabis users develop psychotic symptoms while others do not, potentially opening doors for targeted prevention.","specificNumbers":"Discovery: rs7958311 association p = 1.10 x 10^-7 (N = 1,262). Replication: p = 0.020 (N = 1,217). P2X7 receptor immune response was reduced by THC and CBD in a genotype-dependent manner.","methodology":"Genome-wide environment-interaction study (GWEIS) in 1,262 individuals without psychiatric disorders, enriched for extremes of cannabis use and psychotic-like experiences. Replication in the IMAGEN cohort (n = 1,217). Functional validation through in vitro monocyte experiments.","limitations":"Discovery p-value did not reach genome-wide significance (5 x 10^-8); enriched sampling design may limit generalizability; in vitro immune findings may not fully reflect brain-level effects."},{"rthcId":"RTHC-02433","title":"Cannabis use, depression and suicidal ideation in adolescence: direction of associations in a population based cohort.","authors":"Bolanis, Despina; Orri, Massimiliano; Castellanos-Ryan, Natalie; Renaud, Johanne; Montreuil, Tina; Boivin, Michel; Vitaro, Frank; Tremblay, Richard E; Turecki, Gustavo; Côté, Sylvana M; Séguin, Jean R; Geoffroy, Marie-Claude","year":2020,"journal":"Journal of affective disorders, 274, 1076-1083","doi":"10.1016/j.jad.2020.05.136","pmid":"32663935","tags":["youth","depression","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Depression at age 15 predicted weekly cannabis use at age 17 (OR = 2.30, 95% CI: 1.19-4.43), even after adjusting for other substance use. Weekly cannabis use at 15 was initially associated with suicidal ideation at 17 (OR = 2.19, 95% CI: 1.04-4.58), but this association disappeared after controlling for other substance use.","whyItMatters":"This study helps untangle the direction of the cannabis-depression relationship, suggesting depression may drive cannabis use rather than the reverse, and that polysubstance use complicates simple causal narratives.","specificNumbers":"Weekly cannabis use: 7.0% at age 15, rising to 15.6% by age 20. Weekly users were 11-15 times more likely to continue using over time. Depression predicting cannabis: OR = 2.30. Cannabis-suicidal ideation link (before adjustment): OR = 2.19.","methodology":"Population-based cohort of 1,606 adolescents from Quebec followed from 1997, with cross-lagged analyses examining the direction of associations between cannabis use frequency, depressive symptoms, and suicidal ideation at ages 15, 17, and 20.","limitations":"Quantity of cannabis consumed was not measured; self-reported data; Quebec-specific population may limit generalizability; observational design cannot fully establish causation."},{"rthcId":"RTHC-02434","title":"In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?","authors":"Brancato, Anna; Castelli, Valentina; Lavanco, Gianluca; Marino, Rosa Anna Maria; Cannizzaro, Carla","year":2020,"journal":"Journal of psychopharmacology (Oxford, England), 34(6), 663-679","doi":"10.1177/0269881120916135","pmid":"32338122","tags":["pregnancy","youth","cognition","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In utero THC-exposed adolescent rats showed impaired aversive limbic memory (but intact neutral memory), decreased NPY-positive neurons in limbic regions, altered Homer protein expression, and increased alcohol consumption, relapse, and compulsive-like drinking behavior in operant chambers.","whyItMatters":"As cannabis use during pregnancy increases alongside legalization, understanding potential long-term effects on offspring brain development and vulnerability to addiction is a growing public health concern.","specificNumbers":"THC dose: 2 mg/kg subcutaneous to pregnant dams. Offspring showed decreased NPY-positive neurons and region-specific Homer protein changes. Increased alcohol drinking, relapse, and conflict behavior were observed in operant chamber testing.","methodology":"Pregnant rats received subcutaneous THC (2 mg/kg) during gestation. Adolescent male offspring were assessed in two cohorts: one for behavioral reactivity, memory, and neurobiological markers (NPY, Homer proteins); another for instrumental learning and alcohol self-administration through early adulthood.","limitations":"Animal model with subcutaneous THC administration, which differs from human cannabis use routes and patterns; only male offspring studied; single THC dose level."},{"rthcId":"RTHC-02435","title":"Comparison of the Neurotoxic and Seizure-Inducing Effects of Synthetic and Endogenous Cannabinoids with Δ9-Tetrahydrocannabinol.","authors":"Breivogel, Chris S; Wells, Jacob R; Jonas, Amreen; Mistry, Artik H; Gravley, Morgan L; Patel, Rajul M; Whithorn, Brianna E; Brenseke, Bonnie M","year":2020,"journal":"Cannabis and cannabinoid research, 5(1), 32-41","doi":"10.1089/can.2019.0003","pmid":"32322674","tags":["synthetic-cannabinoids","neuroscience","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"JWH-073 and AM-2201 produced significantly more convulsions than THC, HU-210, methanandamide, or CBD. Methanandamide caused no seizures but produced greater hypothermia than THC. Convulsions and hypothermia from several agonists were blocked by a CB1 antagonist but not a CB2 antagonist.","whyItMatters":"Synthetic cannabinoids found in street products have been linked to seizures and deaths in humans. This study provides controlled evidence that synthetics are genuinely more seizure-prone than THC.","specificNumbers":"JWH-073 and AM-2201 produced significantly more convulsions than THC. Methanandamide and CBD produced zero convulsions. Seizure-inducing effects were CB1-mediated (blocked by CB1 but not CB2 antagonist).","methodology":"Mice received intraperitoneal injections of THC (50 mg/kg), JWH-073 (30 mg/kg), AM-2201 (1 mg/kg), or other cannabinoids at various doses. Convulsions and body temperature changes were quantified. Chronic dosing with tolerance and withdrawal assessment was also performed.","limitations":"Mouse model; doses were matched for equivalent analgesic/hypothermic potency rather than recreational potency; limited number of synthetic compounds tested relative to the hundreds on the market."},{"rthcId":"RTHC-02436","title":"Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity.","authors":"Brizzi, Antonella; Aiello, Francesca; Boccella, Serena; Cascio, Maria Grazia; De Petrocellis, Luciano; Frosini, Maria; Gado, Francesca; Ligresti, Alessia; Luongo, Livio; Marini, Pietro; Mugnaini, Claudia; Pessina, Federica; Corelli, Federico; Maione, Sabatino; Manera, Clementina; Pertwee, Roger G; Di Marzo, Vincenzo","year":2020,"journal":"Bioorganic & medicinal chemistry, 28(11), 115513","doi":"10.1016/j.bmc.2020.115513","pmid":"32340793","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02437","title":"Evaluation of an Occupational Safety and Health Training for Cannabis Cultivation Workers.","authors":"Brown, Carol E; Shore, Erin; Van Dyke, Mike V; Scott, Joshua; Smith, Roberta","year":2020,"journal":"Annals of work exposures and health, 64(7), 765-769","doi":"10.1093/annweh/wxaa026","pmid":"32185387","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02438","title":"Potential Adverse Drug Events with Tetrahydrocannabinol (THC) Due to Drug-Drug Interactions.","authors":"Brown, Joshua D","year":2020,"journal":"Journal of clinical medicine, 9(4)","doi":"10.3390/jcm9040919","pmid":"32230864","tags":["drug-interactions","cbd","potency","genetics"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review mapped out the pharmacological interactions between THC and other medications, revealing a more complex picture than most cannabis users — or their doctors — appreciate. THC is primarily broken down by two liver enzymes: CYP3A4 and CYP2C9. Dozens of common medications either inhibit or induce these same enzymes, meaning they can increase or decrease THC's effects in unpredictable ways.\n\nThe genetics add another layer. CYP2C9 polymorphisms are highly prevalent — up to 35% of Caucasians carry variants that significantly increase THC bioavailability. These individuals effectively get more THC from the same dose, which matters both for effects and side effects.\n\nBeyond metabolism, THC has pharmacodynamic interactions: it can enhance sedation from CNS depressants, affect heart rate and blood pressure when combined with cardiovascular drugs, and potentially impact immune function. The review also noted that THC itself can inhibit or induce various drug-metabolizing enzymes, meaning cannabis use could alter the effectiveness of other medications a patient is taking.","whyItMatters":"Medical cannabis is increasingly prescribed to people who are already taking multiple medications — exactly the population where drug interactions matter most. The safety profile of cannabis has historically been extrapolated from recreational use by young, healthy people. This review showed that assumption breaks down for medically complex patients.\n\nThe CYP2C9 genetic finding is particularly significant. Over a third of Caucasian patients may metabolize THC differently than expected, leading to stronger or longer effects from the same dose. Pharmacogenomic testing before prescribing cannabis is not standard practice, but this paper suggests it probably should be.","specificNumbers":"• Primary THC metabolism: CYP3A4 and CYP2C9 enzymes\n• CYP2C9 polymorphism prevalence: up to 35% in Caucasians\n• Carriers get increased THC bioavailability from the same dose\n• Interaction categories: metabolic, CNS depression, cardiovascular, immunological","methodology":"Narrative review of published literature on THC pharmacokinetics, drug-metabolizing enzyme interactions, genetic polymorphisms affecting THC metabolism, and pharmacodynamic interactions with other medication classes.","limitations":"Many potential interactions are theoretical, based on known enzyme pathways rather than documented clinical cases. The clinical significance of most interactions hasn't been studied in controlled settings. THC metabolism research is largely based on oral or injected THC, which may not reflect smoked or vaporized cannabis pharmacokinetics. CBD was not the focus but also has significant enzyme interactions."},{"rthcId":"RTHC-02439","title":"EEG biomarkers acquired during a short, straight-line simulated drive to predict impairment from cannabis intoxication.","authors":"Brown, Timothy L; Richard, Christian; Meghdadi, Amir; Poole, Jared; Fink, Abigail; Stevanović Karić, Marija; McConnell, Marissa; Rupp, Greg; Schmitt, Rose; Gaffney, Gary G; Milavetz, Gary; Berka, Chris","year":2020,"journal":"Traffic injury prevention, 21(sup1), S130-S134","doi":"10.1080/15389588.2020.1814957","pmid":"32975441","tags":["driving","neuroscience","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Standard deviation of lane position (SDLP) was significantly worse and heart rate elevated during THC sessions compared to placebo. Theta frequency band (4-7 Hz) EEG power was significantly decreased under THC. Theta power was negatively correlated with SDLP impairment during THC but not placebo sessions.","whyItMatters":"No validated field test exists for cannabis driving impairment. If EEG biomarkers reliably correlate with impaired driving performance, they could form the basis for objective impairment testing.","specificNumbers":"10 subjects; 500mg cannabis at 6.7% THC; SDLP significantly worse under THC; theta power (4-7 Hz) significantly decreased; theta-SDLP correlation significant in dosed condition (no significant EEG-SDLP correlations in placebo condition).","methodology":"Randomized, crossover, double-blind study with 10 subjects receiving 500mg cannabis (6.7% THC) or placebo via vaporizer. EEG recorded during a 45-minute simulated drive including a 10-minute straight rural road segment. Driving metrics synchronized with EEG data.","limitations":"Very small sample (10 subjects); simulated driving rather than real-world conditions; single dose and route of administration; short straight-line driving may not capture all impairment-relevant behaviors."},{"rthcId":"RTHC-02440","title":"Cannabis-impaired driving and Canadian youth.","authors":"Brubacher, Jeff R; Chan, Herbert; Staples, John A","year":2020,"journal":"Paediatrics & child health, 25(Suppl 1), S21-S25","doi":"10.1093/pch/pxaa017","pmid":"32581627","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02441","title":"Pharmacology and legal status of cannabidiol.","authors":"Brunetti, Pietro; Lo Faro, Alfredo Fabrizio; Pirani, Filippo; Berretta, Paolo; Pacifici, Roberta; Pichini, Simona; Busardò, Francesco Paolo","year":2020,"journal":"Annali dell'Istituto superiore di sanita, 56(3), 285-291","doi":"10.4415/ANN_20_03_06","pmid":"32959794","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02442","title":"Sales to apparently alcohol-intoxicated customers and online responsible vendor training in recreational cannabis stores in a randomized trial.","authors":"Buller, David B; Woodall, W Gill; Saltz, Robert; Grayson, Andrew; Svendsen, Sierra; Cutter, Gary R","year":2020,"journal":"The International journal on drug policy, 83, 102860","doi":"10.1016/j.drugpo.2020.102860","pmid":"32707476","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02443","title":"Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.","authors":"Burgdorf, Caitlin E; Jing, Deqiang; Yang, Ruirong; Huang, Chienchun; Hill, Matthew N; Mackie, Ken; Milner, Teresa A; Pickel, Virginia M; Lee, Francis S; Rajadhyaksha, Anjali M","year":2020,"journal":"Science advances, 6(7), eaay1502","doi":"10.1126/sciadv.aay1502","pmid":"32095523","tags":["genetics","youth","addiction","sex-differences","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent female FAAHC/A mice (but not males) showed enhanced mesolimbic dopamine circuitry from VTA to nucleus accumbens, altered CB1 receptor levels at inhibitory and excitatory terminals in the VTA, and increased THC conditioned place preference that persisted into adulthood.","whyItMatters":"This identifies a specific genetic mechanism that could explain sex differences in cannabis vulnerability during adolescence, with relevance to a human gene variant already linked to substance use problems.","specificNumbers":"The FAAH polymorphism enhanced VTA-to-NAc dopamine circuitry and altered CB1R at both inhibitory and excitatory VTA terminals specifically in adolescent females. THC preference persisted into adulthood.","methodology":"Genetic knock-in mouse model (FAAHC/A) recapitulating a human FAAH polymorphism associated with problematic drug use. Researchers examined mesolimbic dopamine circuitry, CB1R levels, and THC conditioned place preference in adolescent and adult mice of both sexes.","limitations":"Mouse model; THC conditioned place preference is a proxy for reward, not direct addiction; the FAAH variant studied is one of many genetic factors that could influence cannabis vulnerability."},{"rthcId":"RTHC-02444","title":"Novel therapeutic and drug development strategies for tobacco use disorder: endocannabinoid modulation.","authors":"Butler, Kevin; Le Foll, Bernard","year":2020,"journal":"Expert opinion on drug discovery, 15(9), 1065-1080","doi":"10.1080/17460441.2020.1767581","pmid":"32425077","tags":["addiction","neuroscience","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CB1 receptor neutral antagonists and fatty acid amide hydrolase (FAAH) inhibitors demonstrated positive effects across multiple addiction-related factors including nicotine reinforcement, cue-induced reinstatement, and withdrawal. The CB1 inverse agonist rimonabant was effective for cessation but caused psychiatric side effects.","whyItMatters":"Tobacco use disorder remains a leading cause of preventable death, and existing treatments have high relapse rates. The endocannabinoid system offers novel targets that could complement current cessation strategies.","specificNumbers":"Rimonabant (CB1 inverse agonist) was effective for smoking cessation but withdrawn due to psychiatric adverse effects. CB1 neutral antagonists and FAAH inhibitors showed positive effects across several addiction-related endpoints.","methodology":"Expert review examining studies on endocannabinoid modulation (CB1 receptor, CB2 receptor, anandamide, and 2-AG pathways) across addiction-related factors: nicotine reinforcement, reinstatement of drug seeking, withdrawal severity, and executive function.","limitations":"Much of the evidence is from preclinical models; few human clinical trials exist for CB1 neutral antagonists or FAAH inhibitors in tobacco cessation specifically; the field is still at an early stage."},{"rthcId":"RTHC-02445","title":"Evidence of Slow Neural Processing, Developmental Differences and Sensitivity to Cannabis Effects in a Sample at Clinical High Risk for Psychosis From the NAPLS Consortium Assessed With the Human Startle Paradigm.","authors":"Cadenhead, Kristin S; Duncan, Erica; Addington, Jean; Bearden, Carrie; Cannon, Tyrone D; Cornblatt, Barbara A; Mathalon, Dan; McGlashan, Thomas H; Perkins, Diana O; Seidman, Larry J; Tsuang, Ming; Walker, Elaine F; Woods, Scott W; Bauchman, Peter; Belger, Ayse; Carrión, Ricardo E; Donkers, Franc; Johannesen, Jason; Light, Gregory; Niznikiewicz, Margaret; Nunag, Jason; Roach, Brian","year":2020,"journal":"Frontiers in psychiatry, 11, 833","doi":"10.3389/fpsyt.2020.00833","pmid":"33005152","tags":["psychosis","neuroscience","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"CHR participants who converted to psychosis had significantly slower startle latency than non-converters, driven by female participants. PPI showed a significant group-by-cannabis interaction: cannabis users in the CHR group had greater PPI than non-users, opposite to the pattern in healthy controls. PPI correlated significantly with age in CHR but not healthy participants.","whyItMatters":"Identifying biomarkers that predict who among at-risk individuals will develop psychosis could enable earlier intervention. The finding that cannabis alters sensory gating differently in this population suggests distinct neurobiological effects.","specificNumbers":"543 CHR participants, 218 healthy controls, ages 12-35. 58 CHR participants converted to psychosis at 1-year follow-up. Significant group-by-cannabis interaction on PPI. Slower startle latency predicted conversion, driven by females.","methodology":"Prospective study of 543 CHR and 218 normal comparison participants aged 12-35 from the NAPLS consortium. Startle reactivity, latency, and prepulse inhibition were measured at baseline, with psychotic conversion assessed at 1-year follow-up.","limitations":"Observational design; cannabis use was self-reported and not experimentally controlled; 1-year follow-up may miss later conversions; the sex-specific latency finding needs replication."},{"rthcId":"RTHC-02446","title":"The Void in Clinician Counseling of Cannabis Use.","authors":"Calcaterra, Susan L; Cunningham, Chinazo O; Hopfer, Christian J","year":2020,"journal":"Journal of general internal medicine, 35(6), 1875-1878","doi":"10.1007/s11606-019-05612-4","pmid":"31898125","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02447","title":"Cannabinoids for fibromyalgia pain: a critical review of recent studies (2015-2019).","authors":"Cameron, Erinn C; Hemingway, Samantha L","year":2020,"journal":"Journal of cannabis research, 2(1), 19","doi":"10.1186/s42238-020-00024-2","pmid":"33526114","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Five studies using six different cannabis treatments (including nabilone, dronabinol, Bedrocan, Bediol, CBD, and medical cannabis) showed generally favorable patient-reported outcomes for fibromyalgia pain. However, the review identified significant methodological limitations including issues with generalizability and validity.","whyItMatters":"Fibromyalgia affects 5-7% of the global population and responds poorly to traditional pain treatments. Cannabinoids represent a potential alternative, but the evidence base needs strengthening.","specificNumbers":"5 studies identified involving 827 participants, using 6 different cannabinoid treatments. Timeframe: 2015-2019.","methodology":"Systematic search following PRISMA guidelines of PubMed and Medline databases (2015-2019) for all study designs examining cannabis preparations for fibromyalgia, excluding prior systematic reviews and meta-analyses.","limitations":"Only 5 studies met inclusion criteria; significant methodological problems identified in included studies; heterogeneous treatments and outcomes make comparison difficult; the review itself is limited by the underlying evidence quality."},{"rthcId":"RTHC-02448","title":"Association between the use of Cannabis and elevated suicide risk in high school adolescents from Santa Marta, Colombia.","authors":"Campo-Arias, Adalberto; Suárez-Colorado, Yuly Paola; Caballero-Domínguez, Carmen Cecilia","year":2020,"journal":"Biomedica : revista del Instituto Nacional de Salud, 40(3), 569-577","doi":"10.7705/biomedica.4988","pmid":"33030835","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Lifetime cannabis use prevalence was 11.6% and high suicide risk was 13.3%. Cannabis use was associated with high suicide risk after adjustment (OR = 1.88, 95% CI: 1.23-2.88).","whyItMatters":"This provides data on cannabis-suicide associations in a Latin American adolescent population, where such research has been limited.","specificNumbers":"1,462 students; mean age 14.4 years; 60.3% female; 11.6% lifetime cannabis use; 13.3% high suicide risk; adjusted OR = 1.88 (95% CI: 1.23-2.88).","methodology":"Cross-sectional study with probabilistic sample of 1,462 high school students aged 13-17 in Santa Marta, Colombia. Suicide risk quantified using the CES-D suicide ideation scale, with scores above 8 categorized as high risk.","limitations":"Cross-sectional design prevents causal inference; single Colombian city may not generalize; self-reported measures; did not account for polysubstance use; lifetime cannabis use measure does not distinguish frequency or recency."},{"rthcId":"RTHC-02449","title":"Effectiveness of cannabidiol in a prospective cohort of children with drug-resistant epileptic encephalopathy in Argentina.","authors":"Caraballo, Roberto; Demirdjian, Graciela; Reyes, Gabriela; Huaman, Marina; Gutierrez, Robinson","year":2020,"journal":"Seizure, 80, 75-80","doi":"10.1016/j.seizure.2020.06.005","pmid":"32544657","tags":["epilepsy","cbd","medical-cannabis","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 49 children followed for 3-12 months, 80% responded to CBD add-on therapy. Seizure reduction of at least 25% occurred in 77.6%, at least 50% in 73.5%, and at least 75% in 49%. Mean monthly seizure frequency dropped from 959 to 381 (median decrease 66%, p < 0.001). The most common adverse effect was drowsiness (32%), often resolved by adjusting clobazam dose.","whyItMatters":"Children with drug-resistant epileptic encephalopathies have few treatment options. Real-world effectiveness data from diverse clinical settings supplements evidence from controlled trials.","specificNumbers":"49 children analyzed; mean age 10.5 years; median age at first seizure 7 months. 80% responders. 73.5% achieved 50%+ seizure reduction. 49% achieved 75%+ reduction. Median seizure frequency decrease: 66%. Drowsiness in 32%.","methodology":"Prospective cohort study at a single pediatric hospital in Buenos Aires, Argentina. 50 patients with drug-resistant epileptic encephalopathies enrolled between October 2018 and October 2019. CBD oil added to standard antiseizure medications. Mean follow-up: 8.5 months.","limitations":"Open-label, single-center, no control group; relatively small sample; interim analysis with variable follow-up periods; the drowsiness-clobazam interaction suggests some benefit may come from altered clobazam metabolism."},{"rthcId":"RTHC-02450","title":"Anytime is the Right Time: A Content Analysis of Marijuana Ads in Freely Distributed Print Media in Western Washington State, USA.","authors":"Carlini, Beatriz H; Harwick, Robin; Garrett, Sharon","year":2020,"journal":"Substance use & misuse, 55(5), 806-817","doi":"10.1080/10826084.2019.1703749","pmid":"31876238","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02451","title":"The Synthetic Cannabinoid URB447 Reduces Brain Injury and the Associated White Matter Demyelination after Hypoxia-Ischemia in Neonatal Rats.","authors":"Carloni, Silvia; Crinelli, Rita; Palma, Linda; Álvarez, Francisco J; Piomelli, Daniele; Duranti, Andrea; Balduini, Walter; Alonso-Alconada, Daniel","year":2020,"journal":"ACS chemical neuroscience, 11(9), 1291-1299","doi":"10.1021/acschemneuro.0c00047","pmid":"32271539","tags":["neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"URB447 strongly reduced brain injury when given before hypoxia-ischemia. When given 3 hours after injury (a clinically feasible window), it still reduced neurodegeneration, white matter damage, astrogliosis, and microglial activation. The CB1 antagonist SR141716A had a comparable protective effect, while the CB1 agonist WIN-55,212-2 reduced URB447's benefit.","whyItMatters":"Perinatal brain injury from oxygen deprivation affects roughly 1-3 per 1,000 live births and has limited treatment options. A 3-hour therapeutic window is clinically relevant for treating affected newborns.","specificNumbers":"URB447 reduced neurodegeneration and white matter damage when given 3 hours post-injury. CB1 agonist WIN-55,212-2 diminished URB447's protective effect, pointing to CB2 activation and CB1 blockade as the mechanism.","methodology":"Neonatal rat model of hypoxia-ischemia. URB447 (a CB1 antagonist/CB2 agonist) administered either before or 3 hours after injury. Effects compared with CB1 antagonist SR141716A and CB1 agonist WIN-55,212-2. Brain injury, white matter damage, and inflammatory markers assessed histologically.","limitations":"Animal model; neonatal rat brain development does not perfectly match human timing; single compound studied; long-term functional outcomes not assessed."},{"rthcId":"RTHC-02452","title":"Marijuana Use and Adherence to Smoking Cessation Treatment Among Callers to Tobacco Quitlines.","authors":"Carpenter, Kelly M; Torres, Alula J; Salmon, Erica E; Carlini, Beatriz H; Vickerman, Katrina A; Schauer, Gillian L; Bush, Terry","year":2020,"journal":"Preventing chronic disease, 17, E102","doi":"10.5888/pcd17.200110","pmid":"32915131","tags":["addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among quitline callers, 24% used marijuana in the past 30 days (28.9% Alaska, 25.0% Oregon, 16.7% DC). Current marijuana users were more likely to complete 3+ counseling calls but less likely to receive nicotine replacement therapy. Among users, 42.6% wanted to quit or reduce marijuana use.","whyItMatters":"Tobacco quitlines serve over 400,000 callers annually. Understanding co-use patterns could help tailor cessation services and identify opportunities to address multiple substance use simultaneously.","specificNumbers":"24% past 30-day marijuana use. Of marijuana users: 62.3% used 1-19 days, 9.0% used 20-29 days, 28.7% used all 30 days. 42.6% wanted to quit or reduce. Marijuana users were less likely to receive NRT (68.4% vs 74.1%) but more likely to complete 3+ calls.","methodology":"Observational study of 1,059 smokers aged 21+ who called quitlines in Oregon, Alaska, and Washington DC (September-December 2016). Demographics, tobacco/marijuana use, and quitline engagement data collected.","limitations":"Three states/jurisdictions only; self-reported data; no outcome data on whether co-use affected tobacco cessation success; observational design."},{"rthcId":"RTHC-02453","title":"Cannabis-related driving and passenger behaviours among high school students: a cross-sectional study using survey data.","authors":"Carpino, Melissa; Langille, Donald; Ilie, Gabriela; Asbridge, Mark","year":2020,"journal":"CMAJ open, 8(4), E754-E761","doi":"10.9778/cmajo.20200081","pmid":"33234582","tags":["driving","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Greater perceived risk of regular cannabis use was associated with reduced driving under the influence (DUIC) and riding with a cannabis-impaired driver (RWCD) in a dose-response pattern. Students perceiving great risk had adjusted RR of 0.06 (95% CI: 0.04-0.10) for DUIC and 0.09 (95% CI: 0.07-0.12) for RWCD, compared to those perceiving no risk.","whyItMatters":"With cannabis legalization, understanding what drives risky driving decisions in young people can inform public health messaging and prevention campaigns.","specificNumbers":"Survey response rate: 76.2% (52,103 of 68,415 students grades 7-12). 14,520 in grades 11-12 analyzed. Great perceived risk vs. no risk: adjusted RR 0.06 for DUIC, 0.09 for RWCD. Associations consistent across sexes and urban/rural settings.","methodology":"Cross-sectional analysis of 14,520 grade 11-12 students from the 2016-2017 Canadian Student Tobacco, Alcohol and Drugs Survey across 9 provinces. Multinomial logistic regression examined associations between perceived risk and cannabis-related driving behaviors.","limitations":"Cross-sectional design; self-reported behaviors and perceptions; New Brunswick and territories excluded; risk perception and behavior measured at same time point so direction cannot be determined."},{"rthcId":"RTHC-02454","title":"Do-It-Yourself medicine? The impact of light cannabis liberalization on prescription drugs.","authors":"Carrieri, Vincenzo; Madio, Leonardo; Principe, Francesco","year":2020,"journal":"Journal of health economics, 74, 102371","doi":"10.1016/j.jhealeco.2020.102371","pmid":"32920244","tags":["medical-cannabis","legalization","pain","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using the staggered rollout of light cannabis shops across Italian provinces, the study documented significant substitution effects between CBD products and five prescription drug categories: anxiolytics, sedatives, opioids, antidepressants, and antipsychotics.","whyItMatters":"This provides some of the strongest economic evidence that legal access to CBD products leads people to substitute away from prescription medications, with implications for drug policy and healthcare costs.","specificNumbers":"Significant substitution effects documented for five drug categories: anxiolytics, sedatives, opioids, antidepressants, and antipsychotics. The study used high-frequency data across all Italian provinces.","methodology":"Natural experiment exploiting Italy's unintended 2017 liberalization of CBD-based \"light cannabis.\" High-frequency prescription drug sales data analyzed using the staggered local availability of light cannabis across Italian provinces as a quasi-experimental design.","limitations":"Cannot identify individual-level substitution; ecological design using province-level data; cannot determine whether patients benefited from switching to CBD; unregulated CBD products may have variable quality."},{"rthcId":"RTHC-02455","title":"Cannabis and Canabidinoids on the Inflammatory Bowel Diseases: Going Beyond Misuse.","authors":"Carvalho, Antonelly Cassio Alves de; Souza, Gabriela Achete de; Marqui, Samylla Vaz de; Guiguer, Élen Landgraf; Araújo, Adriano Cressoni; Rubira, Claudio José; Goulart, Ricardo de Alvares; Flato, Uri Adrian Prync; Bueno, Patricia Cincotto Dos Santos; Buchaim, Rogério Leone; Barbalho, Sandra M","year":2020,"journal":"International journal of molecular sciences, 21(8)","doi":"10.3390/ijms21082940","pmid":"32331305","tags":["medical-cannabis","inflammation","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis use was associated with improvement in ulcerative colitis and Crohn's disease symptom scores and quality of life across reviewed studies. THC and CBD showed relevant anti-inflammatory and antioxidant properties. However, no standardization exists for plant variety, route of administration, or dosing.","whyItMatters":"IBD affects millions worldwide and current treatments often have significant side effects. Understanding whether cannabis compounds could complement existing therapies is clinically relevant.","specificNumbers":"No specific pooled effect sizes reported; the review synthesizes findings across multiple studies showing symptom score improvement.","methodology":"Literature review searching PubMed/Medline, PMC, EMBASE, and Cochrane databases for studies on cannabis effects in ulcerative colitis and Crohn's disease.","limitations":"No meta-analysis performed; wide heterogeneity in cannabis preparations studied; many studies have small samples; no standardized treatment protocols exist."},{"rthcId":"RTHC-02456","title":"Prenatal cannabinoid exposure alters the ovarian reserve in adult offspring of rats.","authors":"Castel, Pierre; Barbier, Magalie; Poumerol, Elodie; Mandon-Pépin, Béatrice; Tassistro, Virginie; Lepidi, Hubert; Pelissier-Alicot, Anne-Laure; Manzoni, Olivier J; Courbiere, Blandine","year":2020,"journal":"Archives of toxicology, 94(12), 4131-4141","doi":"10.1007/s00204-020-02877-1","pmid":"32833042","tags":["pregnancy","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Young adult rats (PND90) exposed prenatally to the CB1/CB2 agonist WIN55212 had decreased ovarian reserve, an effect reversed by prenatal CB1 receptor blockade with SR141716. Conversely, prenatal CB1 blockade alone resulted in higher ovarian reserve counts. Prenatal cannabinoid modulation also altered mRNA levels of endocannabinoid system enzymes and ovarian reserve regulation genes. No effect was seen at PND6.","whyItMatters":"Ovarian reserve is established during fetal life and determines reproductive lifespan. If prenatal cannabinoid exposure affects this process, it could have implications for the future fertility of daughters born to cannabis-using mothers.","specificNumbers":"WIN55212: 0.5 mg/kg; SR141716: 3 mg/kg; THC: 5 mg/kg. Ovarian reserve decrease appeared at PND90 but not PND6, indicating a delayed effect. CB1 blockade reversed the decrease.","methodology":"Four groups of pregnant rats received WIN55212 (0.5 mg/kg), SR141716 (3 mg/kg), THC (5 mg/kg), or vehicle. Ovarian reserve was histologically assessed in female offspring at postnatal days 6, 40, and 90. RT-PCR measured gene expression changes.","limitations":"Animal model with synthetic cannabinoid agonist rather than cannabis; doses and routes may not reflect human exposure patterns; ovarian reserve counts are a proxy for fertility, not a direct fertility measure."},{"rthcId":"RTHC-02457","title":"Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol.","authors":"Černe, Katarina","year":2020,"journal":"Arhiv za higijenu rada i toksikologiju, 71(1), 1-11","doi":"10.2478/aiht-2020-71-3301","pmid":"32597140","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02458","title":"A new software-assisted analytical workflow based on high-resolution mass spectrometry for the systematic study of phenolic compounds in complex matrices.","authors":"Cerrato, Andrea; Cannazza, Giuseppe; Capriotti, Anna Laura; Citti, Cinzia; La Barbera, Giorgia; Laganà, Aldo; Montone, Carmela Maria; Piovesana, Susy; Cavaliere, Chiara","year":2020,"journal":"Talanta, 209, 120573","doi":"10.1016/j.talanta.2019.120573","pmid":"31892002","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02459","title":"Acute eosinophilic pneumonia associated with non-cigarette smoking products: a systematic review.","authors":"Chaaban, Toufic","year":2020,"journal":"Advances in respiratory medicine, 88(2), 142-146","doi":"10.5603/ARM.2020.0088","pmid":"32383466","tags":["respiratory","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Twelve cases were identified: 5 from marijuana, 2 from waterpipe, 2 from e-cigarettes, 2 from heat-not-burn cigarettes, and 1 from synthetic cannabinoids. Median age was 20 years. A recent change in smoking habits was reported in 50% of cases. 42% required mechanical ventilation and 83% needed ICU care. All responded to corticosteroid therapy.","whyItMatters":"Acute eosinophilic pneumonia is a serious but treatable lung condition. Recognizing that multiple non-cigarette inhalation products can trigger it helps clinicians make faster diagnoses.","specificNumbers":"12 cases; median age 20; 75% male. 5 marijuana, 2 waterpipe, 2 e-cigarette, 2 heat-not-burn, 1 synthetic cannabinoid. 50% had recent change in smoking habits. 42% required mechanical ventilation. 83% treated in ICU. All responded to corticosteroids.","methodology":"Systematic review of PubMed searching for acute eosinophilic pneumonia cases associated with marijuana, waterpipe, e-cigarette, or heat-not-burn cigarette use. Cases identified using modified Philit criteria. Illicit drug use cases excluded.","limitations":"Only 12 cases identified; case reports and series are subject to publication bias; cannot establish incidence rates; the rarity of cases limits generalizability."},{"rthcId":"RTHC-02460","title":"Parental Optimism and Perceived Control over Children's Initiation of Tobacco, Cannabis, and Opioid Use.","authors":"Chadi, Nicholas; Winickoff, Jonathan P; Drouin, Olivier","year":2020,"journal":"International journal of environmental research and public health, 17(17)","doi":"10.3390/ijerph17176181","pmid":"32858864","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02461","title":"Cannabinoids and the endocannabinoid system in anxiety, depression, and dysregulation of emotion in humans.","authors":"Chadwick, Verity L; Rohleder, Cathrin; Koethe, Dagmar; Leweke, F Markus","year":2020,"journal":"Current opinion in psychiatry, 33(1), 20-42","doi":"10.1097/YCO.0000000000000562","pmid":"31714262","tags":["anxiety","depression","ptsd","cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Some evidence suggests cannabinoids, CBD, or CBD-enriched cannabis have anxiety-reducing properties. Depression may be worsened by cannabis use, though RCTs are lacking. New evidence indicates CBD or CBD-enriched cannabis for PTSD and emotion regulation can induce reduced responses to fear and stress. The endocannabinoid system appears to be a key player in anxiety and PTSD.","whyItMatters":"With increasing medicinal use and social tolerance of cannabis, understanding which psychiatric conditions might benefit or worsen from cannabinoid use is clinically urgent.","specificNumbers":"No pooled effect sizes; the review summarizes trends across recent publications.","methodology":"Review of evidence published in the 18 months prior to publication on cannabis and cannabinoids in relation to anxiety, depression (unipolar and bipolar), PTSD, and emotionally unstable personality disorders. Also covers endocannabinoids as potential biomarkers.","limitations":"Weak evidence overall; lack of well-designed RCTs for most conditions reviewed; heterogeneous cannabinoid preparations; most anxiety/PTSD findings are preliminary."},{"rthcId":"RTHC-02462","title":"Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.","authors":"Chaves, Carolina; Bittencourt, Paulo Cesar T; Pelegrini, Andreia","year":2020,"journal":"Pain medicine (Malden, Mass.), 21(10), 2212-2218","doi":"10.1093/pm/pnaa303","pmid":"33118602","tags":["pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"After 8 weeks, the cannabis group showed significant FIQ score improvement vs. placebo (p = 0.005) and vs. baseline (p < 0.001). Specific improvements were seen in \"feel good,\" \"pain,\" \"do work,\" and \"fatigue\" scores. The placebo group only improved on the \"depression\" score. No intolerable adverse effects occurred.","whyItMatters":"Fibromyalgia has limited effective treatments. This is one of the few RCTs testing THC-dominant cannabis oil specifically for fibromyalgia, showing significant improvement across multiple symptom domains.","specificNumbers":"17 women; 8-week trial; THC oil: 24.44 mg/mL THC, 0.51 mg/mL CBD. Starting dose: ~1.22 mg THC/day. FIQ score significantly improved in cannabis group vs. placebo (p = 0.005) and vs. baseline (p < 0.001).","methodology":"Double-blind, randomized, placebo-controlled trial. 17 women with fibromyalgia from a low-income neighborhood in Florianopolis, Brazil. THC-rich cannabis oil (24.44 mg/mL THC, 0.51 mg/mL CBD) starting at 1 drop/day with dose increases. Fibromyalgia Impact Questionnaire at baseline and 5 visits over 8 weeks.","limitations":"Very small sample (17 participants); 8-week duration; specific population (low-income Brazilian women) may limit generalizability; no long-term follow-up; low starting doses."},{"rthcId":"RTHC-02463","title":"What has been the impact of new drug treatments on epilepsy?","authors":"Chen, Zhibin; Brodie, Martin J; Kwan, Patrick","year":2020,"journal":"Current opinion in neurology, 33(2), 185-190","doi":"10.1097/WCO.0000000000000803","pmid":"32049739","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02464","title":"Setting the baseline: a description of cannabis poisonings at a Canadian pediatric hospital prior to the legalization of recreational cannabis.","authors":"Cheng, Phoebe; Zagaran, Atousa; Rajabali, Fahra; Turcotte, Kate; Babul, Shelina","year":2020,"journal":"Health promotion and chronic disease prevention in Canada : research, policy and practice, 40(5-6), 193-200","doi":"10.24095/hpcdp.40.5/6.08","pmid":"32529979","tags":["youth","harm-reduction","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Of 911 total poisonings, 114 (12.5%) were cannabis-related. Most were from intentional use by teens (median age 15), with 71.1% involving cannabis with other substances. Fewer than 10 were inadvertent ingestions by young children (median age 3), all at home from family-owned cannabis. Cannabis poisonings occurred more often on weekdays.","whyItMatters":"Establishing pre-legalization baselines allows future comparisons to determine whether recreational cannabis legalization changed the pattern of pediatric cannabis exposures.","specificNumbers":"114 cannabis-related of 911 total poisonings (12.5%). Intentional use: 28.9% cannabis only, 71.1% with co-ingestions. Median age for inadvertent ingestion: 3 years. Median age for intentional use: 15 years. Most consumed via inhalation with peers.","methodology":"Retrospective analysis of cannabis poisonings treated at BC Children's Hospital ED from 2016-2018, using the Canadian Hospitals Injury Reporting and Prevention Program database. Electronic health records reviewed for additional context.","limitations":"Single hospital; pre-legalization period only; relies on ED presentations which may undercount less severe cases; retrospective chart review."},{"rthcId":"RTHC-02465","title":"Sex Without Contraceptives in a Multicenter Study of Adolescent Emergency Department Patients.","authors":"Chernick, Lauren S; Chun, Thomas H; Richards, Rachel; Bromberg, Julie R; Ahmad, Fahd A; McAninch, Brett; Mull, Colette; Shenoi, Rohit; Suffoletto, Brian; Casper, Charlie; Linakis, James; Spirito, Anthony","year":2020,"journal":"Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 27(4), 283-290","doi":"10.1111/acem.13867","pmid":"31596987","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02466","title":"Cannabitwinol, a Dimeric Phytocannabinoid from Hemp, Cannabis sativa L., Is a Selective Thermo-TRP Modulator.","authors":"Chianese, Giuseppina; Lopatriello, Annalisa; Schiano-Moriello, Aniello; Caprioglio, Diego; Mattoteia, Daiana; Benetti, Emanuele; Ciceri, Daniele; Arnoldi, Lolita; De Combarieu, Eric; Vitale, Rosa M; Amodeo, Pietro; Appendino, Giovanni; De Petrocellis, Luciano; Taglialatela-Scafati, Orazio","year":2020,"journal":"Journal of natural products, 83(9), 2727-2736","doi":"10.1021/acs.jnatprod.0c00668","pmid":"32880179","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02467","title":"Mobile Assessment of Acute Effects of Marijuana on Cognitive Functioning in Young Adults: Observational Study.","authors":"Chung, Tammy; Bae, Sang Won; Mun, Eun-Young; Suffoletto, Brian; Nishiyama, Yuuki; Jang, Serim; Dey, Anind K","year":2020,"journal":"JMIR mHealth and uHealth, 8(3), e16240","doi":"10.2196/16240","pmid":"32154789","tags":["cognition","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Higher subjective marijuana ratings were associated with slower reaction times on all three mobile tasks (Flowers: B=2.29, p=.008; Stroop: B=2.74, p=.01; DSST: B=3.08, p=.03) and fewer correct responses on two of three tasks. Distraction moderated the association for some tasks.","whyItMatters":"Traditional lab studies of cannabis impairment may not capture real-world effects. Mobile assessment in natural environments provides ecologically valid data on how marijuana affects daily cognitive functioning.","specificNumbers":"60 participants; 2,703 data points; 451 (16.7%) marijuana use reports. Significant slowing on all 3 tasks. Significant accuracy decreases on 2 of 3 tasks. Effects described as \"slight\" decreases in cognitive functioning.","methodology":"Observational study of 60 young adults (aged 18-25) who used marijuana at least twice weekly. Mobile cognitive tasks (visuospatial working memory, attentional bias, processing speed) delivered 3 times daily plus self-initiated during marijuana use, for up to 30 days. 2,703 data points collected including 451 marijuana use reports.","limitations":"Small sample; self-reported marijuana ratings; no objective THC measurement; participants were regular users who may have developed tolerance; \"slight\" effects may not be clinically meaningful."},{"rthcId":"RTHC-02468","title":"Why do apprentices smoke much more than high school students? Understanding educational disparities in smoking with a Oaxaca-blinder decomposition analysis.","authors":"Chyderiotis, Sandra; Benmarhnia, Tarik; Spilka, Stanislas; Beck, François; Andler, Raphaël; Legleye, Stéphane; Menvielle, Gwenn","year":2020,"journal":"BMC public health, 20(1), 924","doi":"10.1186/s12889-020-09050-4","pmid":"32532252","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02469","title":"Cannabis Use in Adolescence: A Review of Neuroimaging Findings.","authors":"Chye, Yann; Christensen, Erynn; Yücel, Murat","year":2020,"journal":"Journal of dual diagnosis, 16(1), 83-105","doi":"10.1080/15504263.2019.1636171","pmid":"31311489","tags":["youth","cognition","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Adolescent cannabis users showed alterations mainly in frontal and parietal regions and associated brain activation related to inhibitory control, reward, and memory. However, adult studies examining onset age were more mixed, with many not finding age-of-onset effects on brain imaging metrics.","whyItMatters":"Determining whether adolescence is a uniquely vulnerable period for cannabis effects on the brain, or whether observed differences reflect general use factors, has major implications for policy and prevention.","specificNumbers":"43 studies on adolescent cannabis users; 20 studies on onset age effects in adults. Most consistent findings in frontal and parietal regions related to inhibitory control, reward, and memory.","methodology":"PubMed and Scopus searches for empirical neuroimaging studies examining brain effects in adolescent cannabis users and adult studies exploring age-of-onset effects. 43 adolescent user studies and 20 onset-age studies identified.","limitations":"Most underlying studies are cross-sectional; difficulty separating adolescent-specific effects from general cannabis use factors; varied definitions of \"adolescent\" across studies; limited control for confounders."},{"rthcId":"RTHC-02470","title":"Pitfalls in the analysis of phytocannabinoids in cannabis inflorescence.","authors":"Citti, Cinzia; Russo, Fabiana; Sgrò, Salvatore; Gallo, Alfonso; Zanotto, Antonio; Forni, Flavio; Vandelli, Maria Angela; Laganà, Aldo; Montone, Carmela Maria; Gigli, Giuseppe; Cannazza, Giuseppe","year":2020,"journal":"Analytical and bioanalytical chemistry, 412(17), 4009-4022","doi":"10.1007/s00216-020-02554-3","pmid":"32285185","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02471","title":"Is the Urine Cannabinoid Level Measured via a Commercial Point-of-Care Semiquantitative Immunoassay a Cannabis Withdrawal Syndrome Severity Predictor?","authors":"Claus, Benedikt Bernd; Specka, Michael; McAnally, Heath; Scherbaum, Norbert; Schifano, Fabrizio; Bonnet, Udo","year":2020,"journal":"Frontiers in psychiatry, 11, 598150","doi":"10.3389/fpsyt.2020.598150","pmid":"33343424","tags":["withdrawal","tolerance"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Urinary THC-COOH levels significantly correlated with Marijuana Withdrawal Checklist scores across the 24-day study (r = 0.248, p < 0.001). Day-to-day changes in THC-COOH also predicted withdrawal severity. MWC scores correlated strongly with Clinical Global Impression severity (r = 0.812). Females showed prolonged THC-COOH elimination and cannabis withdrawal.","whyItMatters":"A simple urine test that can predict withdrawal severity could help clinicians plan treatment duration and intensity for cannabis detoxification.","specificNumbers":"78 subjects; 24-day inpatient detox; 13 measurement days. THC-COOH and MWC correlation: r = 0.248. MWC and CGI-S correlation: r = 0.812. Females showed prolonged elimination and withdrawal.","methodology":"Observational study of 78 adult chronic cannabis-dependent subjects over 24-day inpatient detoxification with 13 serial measurement days. Point-of-care enzyme immunoassay measured urinary THC-COOH. Repeated measures correlation and multilevel linear models used.","limitations":"Moderate correlation means the test is informative but not highly precise; single-center study; POC immunoassay is less accurate than mass spectrometry; sex difference finding needs replication given small female subsample."},{"rthcId":"RTHC-02472","title":"Reality and Legality: Disentangling What Is Actual from What Is Tolerated in Comparisons of Hemp Extracts with Pure CBD.","authors":"Cogan, P S","year":2020,"journal":"Journal of dietary supplements, 17(5), 527-542","doi":"10.1080/19390211.2020.1790710","pmid":"32677489","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02473","title":"The 'entourage effect' or 'hodge-podge hashish': the questionable rebranding, marketing, and expectations of cannabis polypharmacy.","authors":"Cogan, Peter S","year":2020,"journal":"Expert review of clinical pharmacology, 13(8), 835-845","doi":"10.1080/17512433.2020.1721281","pmid":"32116073","tags":["medical-cannabis","potency"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The entourage effect concept, first proposed as a hypothesis in 1998, has been promoted as an established therapeutic principle despite lacking robust evidence. The review found that commonly cited phytochemicals have their own adverse effects, claims invoke ill-defined pharmacological activities, and the scientific literature has been overinterpreted to support marketing claims.","whyItMatters":"The entourage effect is widely used to market whole-plant cannabis products as superior to purified cannabinoids. Understanding whether this claim has scientific merit affects consumer choices and product regulation.","specificNumbers":"The entourage effect was first coined in 1998. The review examines multiple primary sources commonly cited as evidence and finds them insufficient to support the broad claims made.","methodology":"Critical analysis of the primary literature commonly cited as supporting the entourage effect, supplemented with PubMed and Google Scholar searches. Examines the original hypothesis, contributing phytochemicals, and their adverse effects.","limitations":"This is one perspective; some researchers and clinicians do report clinical differences between whole-plant and isolated cannabinoid preparations. The absence of proof is not proof of absence."},{"rthcId":"RTHC-02474","title":"Cannabinoids as an Emerging Therapy for Posttraumatic Stress Disorder and Substance Use Disorders.","authors":"Cohen, Jacob; Wei, Zelan; Phang, Jonathan; Laprairie, Robert B; Zhang, Yanbo","year":2020,"journal":"Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society, 37(1), 28-34","doi":"10.1097/WNP.0000000000000612","pmid":"31895187","tags":["ptsd","addiction","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis has received attention for potential to help PTSD patients, many of whom do not respond to current pharmacological treatments. PTSD commonly co-occurs with substance use disorder, complicating treatment. Preliminary legalization data indicate cannabis use may reduce use of more harmful drugs like opioids.","whyItMatters":"PTSD is a leading psychiatric disorder with limited effective pharmacotherapy, and its frequent co-occurrence with substance use disorder creates a challenging treatment landscape where new approaches are needed.","specificNumbers":"No specific effect sizes; the review summarizes preliminary evidence and identifies the need for rigorous clinical studies.","methodology":"Narrative review examining the evidence for cannabinoids in PTSD and substance use disorders, including observational data from legalization contexts.","limitations":"Primarily anecdotal and observational evidence; no completed large-scale RCTs of cannabis for PTSD at time of publication; self-medication with cannabis carries its own risks."},{"rthcId":"RTHC-02475","title":"Personality Traits and Psychotic Proneness Among Chronic Synthetic Cannabinoid Users.","authors":"Cohen, Koby; Rosenzweig, Shiri; Rosca, Paola; Pinhasov, Albert; Weizman, Abraham; Weinstein, Aviv","year":2020,"journal":"Frontiers in psychiatry, 11, 355","doi":"10.3389/fpsyt.2020.00355","pmid":"32477173","tags":["synthetic-cannabinoids","psychosis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"SC users scored higher than natural cannabis users and non-users on neuroticism and schizotypal symptoms (SPQ-B), but lower on agreeableness and extraversion. SC users also had lower conscientiousness than non-users. Higher openness and lower conscientiousness predicted schizotypy for both SC and natural cannabis users.","whyItMatters":"Synthetic cannabinoids are associated with more severe psychiatric outcomes than natural cannabis. Understanding personality profiles may help identify individuals at greater risk.","specificNumbers":"42 SC users, 39 natural cannabis users, 47 non-users. Mean age 26; 23 females, 105 males. SC users scored significantly higher on neuroticism and SPQ-B and lower on agreeableness and extraversion.","methodology":"Cross-sectional comparison of 42 chronic synthetic cannabinoid users, 39 natural cannabis users, and 47 non-using controls (mean age 26). Assessments included Big Five personality inventory, Schizotypal Personality Questionnaire-Brief, depression and anxiety scales.","limitations":"Cross-sectional design; cannot determine causation direction; participants excluded if they had mental disorder diagnoses, which may underestimate psychotic proneness; self-report measures."},{"rthcId":"RTHC-02476","title":"A lottery test of the effect of dispensaries on emergency room visits in Arizona.","authors":"Conyers, Gregory; Ayres, Ian","year":2020,"journal":"Health economics, 29(8), 854-864","doi":"10.1002/hec.4013","pmid":"32548868","tags":["legalization","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Zip codes winning a dispensary license saw cannabis-related ER visits increase approximately 45% relative to non-winning zip codes over four years. Weak evidence of increased opioid-related visits was also found. The lottery design provides unusually strong causal evidence for the effect of dispensary access.","whyItMatters":"The lottery design approximates a randomized experiment, providing stronger causal evidence than typical dispensary studies about the health effects of expanding medical marijuana access.","specificNumbers":"Approximately 45% increase in cannabis ER visits in winning zip codes vs. non-winning over 4 years. 36 winning vs. 48 losing zip codes across 69 contested areas. Likely underestimates due to spillover effects.","methodology":"Natural experiment using Arizona's August 2012 lottery for medical marijuana dispensary licenses. 36 winning zip codes compared to 48 losing zip codes using propensity score weighting. ER discharge data from 2010-2016 for cannabis, opioid, alcohol, and cocaine-related visits.","limitations":"ER discharge data may not capture all cannabis-related presentations; spillover between neighboring zip codes likely attenuates the measured effect; cannot distinguish between more use vs. more acute reactions; Arizona-specific context."},{"rthcId":"RTHC-02477","title":"Current Aspects of the Endocannabinoid System and Targeted THC and CBD Phytocannabinoids as Potential Therapeutics for Parkinson's and Alzheimer's Diseases: a Review.","authors":"Cooray, R; Gupta, V; Suphioglu, C","year":2020,"journal":"Molecular neurobiology, 57(11), 4878-4890","doi":"10.1007/s12035-020-02054-6","pmid":"32813239","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02478","title":"Attenuation of fear-conditioned analgesia in rats by monoacylglycerol lipase inhibition in the anterior cingulate cortex: Potential role for CB2 receptors.","authors":"Corcoran, Louise; Mattimoe, Darragh; Roche, Michelle; Finn, David P","year":2020,"journal":"British journal of pharmacology, 177(10), 2240-2255","doi":"10.1111/bph.14976","pmid":"31967664","tags":["pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"MGL inhibition (increasing 2-AG) in the ACC attenuated fear-conditioned analgesia. This effect was blocked by the CB2 antagonist AM630 but not the CB1 antagonist AM251. The CB2 antagonist alone reduced pain behavior in non-fear-conditioned rats. Both CB1 and CB2 receptor mRNA were confirmed in the ACC.","whyItMatters":"Understanding how the brain's own pain-suppression systems work through the endocannabinoid system could reveal new therapeutic targets for pain and fear-related disorders.","specificNumbers":"MJN110 increased 2-AG levels in ACC and attenuated FCA. AM630 (CB2 antagonist) blocked MJN110's effect. AM251 (CB1 antagonist) did not alter MJN110's effect. CB1 and CB2 mRNA confirmed in ACC.","methodology":"Male rats underwent fear conditioning (arena paired with footshock) followed by formalin-evoked pain testing. Microinjection of MGL inhibitor MJN110, CB2 antagonist AM630, or CB1 antagonist AM251 into the anterior cingulate cortex. 2-AG levels confirmed via mass spectrometry.","limitations":"Animal model; male rats only; fear-conditioned analgesia is one specific form of endogenous pain suppression; pharmacological specificity of tools used."},{"rthcId":"RTHC-02479","title":"Neurocognitive Correlates of Adolescent Cannabis Use: An Overview of Neural Activation Patterns in Task-Based Functional MRI Studies.","authors":"Coronado, Clarisa; Wade, Natasha E; Aguinaldo, Laika D; Mejia, Margie Hernandez; Jacobus, Joanna","year":2020,"journal":"Journal of pediatric neuropsychology, 6(1), 1-13","doi":"10.1007/s40817-020-00076-5","pmid":"33425663","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02480","title":"Labeling of Cannabidiol Products: A Public Health Perspective.","authors":"Corroon, Jamie; MacKay, Douglas; Dolphin, William","year":2020,"journal":"Cannabis and cannabinoid research, 5(4), 274-278","doi":"10.1089/can.2019.0101","pmid":"33381640","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02481","title":"Maternal cannabis use in pregnancy and child neurodevelopmental outcomes.","authors":"Corsi, Daniel J; Donelle, Jessy; Sucha, Ewa; Hawken, Steven; Hsu, Helen; El-Chaâr, Darine; Bisnaire, Lise; Fell, Deshayne; Wen, Shi Wu; Walker, Mark","year":2020,"journal":"Nature medicine, 26(10), 1536-1540","doi":"10.1038/s41591-020-1002-5","pmid":"32778828","tags":["pregnancy","youth","cognition"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Autism spectrum disorder incidence was 4.00 per 1,000 person-years among cannabis-exposed children vs. 2.42 among unexposed. The fully adjusted hazard ratio was 1.51 (95% CI: 1.17-1.96) in the matched cohort. Higher incidence of intellectual disability and learning disorders was also observed but was less statistically robust.","whyItMatters":"Published in Nature Medicine, this is one of the largest studies linking prenatal cannabis exposure to autism risk, providing data that informs public health guidance for pregnant women.","specificNumbers":"ASD incidence: 4.00 vs. 2.42 per 1,000 person-years. Adjusted HR: 1.51 (95% CI: 1.17-1.96). Ontario births 2007-2012.","methodology":"Population-based retrospective analysis of all live births in Ontario, Canada (April 2007 to March 2012). Pregnancy data linked to provincial health databases for neurodevelopmental outcomes. Matching techniques and Cox proportional hazards regression used to control for confounding.","limitations":"Retrospective design; cannabis use self-reported at prenatal visits (likely underreported); cannot account for all confounders (genetics, other substance use, social factors); the authors explicitly caution about residual confounding."},{"rthcId":"RTHC-02482","title":"Disrupting the endocannabinoid system in early adolescence negatively impacts sociability.","authors":"Cossio, Daniela; Stadler, Henry; Michas, Zoe; Johnston, Colin; Lopez, Hassan H","year":2020,"journal":"Pharmacology, biochemistry, and behavior, 188, 172832","doi":"10.1016/j.pbb.2019.172832","pmid":"31778723","tags":["youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both the CB1/CB2 agonist CP55,940 and the CB1 antagonist AM251, given daily from PND 25-39, reduced sociability in adolescent rats without affecting anxiety. Males showed greater sociability than females, and sociability was higher in adolescence than adulthood. The drug effects did not persist into adulthood (PND 66-70).","whyItMatters":"The finding that disrupting endocannabinoid signaling in either direction impairs social behavior suggests the system needs to be precisely tuned during adolescent development.","specificNumbers":"72 rats (36 male, 36 female). Both CP55,940 (0.4 mg/kg) and AM251 (0.5 mg/kg) reduced sociability at PND 40-44. No effect on anxiety. Effects did not persist to PND 66-70.","methodology":"36 male and 36 female Long Evans rats received daily injections of vehicle, CP55,940 (CB1/CB2 agonist), or AM251 (CB1 antagonist) from postnatal day 25-39. Sociability and anxiety tested at PND 40-44 and PND 66-70 using three-chambered apparatus and elevated plus maze.","limitations":"Animal model; synthetic cannabinoid agents used rather than cannabis; the transient nature of effects may not reflect chronic human cannabis exposure; sociability measures may not fully capture human social complexity."},{"rthcId":"RTHC-02483","title":"Cannabinoid hyperemesis syndrome: A case study and discussion.","authors":"Creedon, Eliza S; Maloy, Melony K; DelloStritto, Rita A","year":2020,"journal":"Journal of the American Association of Nurse Practitioners, 32(3), 269-276","doi":"10.1097/JXX.0000000000000215","pmid":"31274681","tags":["harm-reduction","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"CHS symptoms include cyclical nausea, vomiting, and abdominal pain in chronic cannabis users, often relieved by compulsive hot bathing. The condition is becoming more prevalent but frequently goes unrecognized. The pathophysiology remains largely unknown, and symptoms can be complicated by comorbidities.","whyItMatters":"CHS is likely underdiagnosed, leading to unnecessary and costly workups. Better recognition by emergency clinicians could improve patient outcomes and reduce healthcare costs.","specificNumbers":"CHS first described in literature in 2004. Review covers 10 years of published literature.","methodology":"Case study with patient interview and chart review, combined with a 10-year literature review to consolidate findings on clinical characteristics, pathogenesis, diagnostics, and treatment approaches.","limitations":"Single case study supplemented with narrative review; CHS pathophysiology remains poorly understood; no standardized diagnostic criteria or treatment protocols exist."},{"rthcId":"RTHC-02484","title":"Cannabinoids and the expanded endocannabinoid system in neurological disorders.","authors":"Cristino, Luigia; Bisogno, Tiziana; Di Marzo, Vincenzo","year":2020,"journal":"Nature reviews. Neurology, 16(1), 9-29","doi":"10.1038/s41582-019-0284-z","pmid":"31831863","tags":["neuroscience","medical-cannabis","epilepsy","pain"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Beyond the classical CB1/CB2 system, an expanded \"endocannabinoidome\" includes biochemically related mediators with their own receptors and enzymes. Clinical success has come from nabiximols (THC+CBD) for MS spasticity/pain and purified CBD for pediatric epilepsy. The endocannabinoidome is involved in multiple neurological diseases.","whyItMatters":"This review from a leading neurology journal provides the most comprehensive framework for understanding how cannabinoid-based therapeutics interact with a system far more complex than originally understood.","specificNumbers":"Two cannabinoid-based medicines approved: nabiximols (THC+CBD) for MS spasticity/pain, and purified CBD for Dravet and Lennox-Gastaut syndromes. The review covers Parkinson's, Alzheimer's, Huntington's, MS, ALS, TBI, stroke, epilepsy, and glioblastoma.","methodology":"Comprehensive review published in Nature Reviews Neurology covering the endocannabinoid system and endocannabinoidome, their involvement in neurological disorders, and current/potential therapeutic applications.","limitations":"Review of a broad field; many therapeutic applications remain preclinical; the complexity of the endocannabinoidome makes drug development challenging."},{"rthcId":"RTHC-02485","title":"Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson's disease.","authors":"Crivelaro do Nascimento, Glauce; Ferrari, Daniele Pereira; Guimaraes, Francisco Silveira; Del Bel, Elaine Aparecida; Bortolanza, Mariza; Ferreira-Junior, Nilson Carlos","year":2020,"journal":"Neuropharmacology, 163, 107808","doi":"10.1016/j.neuropharm.2019.107808","pmid":"31706993","tags":["cbd","pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The Parkinson's model (6-OHDA) decreased thermal and mechanical pain thresholds. Both acute and chronic CBD treatment reversed this hyperalgesia and allodynia. CBD's pain-relieving effect was potentiated by a FAAH inhibitor and TRPV1 antagonist, and blocked by CB1/CB2 inverse agonist, suggesting CBD increases endogenous anandamide levels.","whyItMatters":"Pain is a prevalent but undertreated non-motor symptom of Parkinson's disease. CBD could offer a targeted approach if its mechanisms in this context are understood.","specificNumbers":"6-OHDA model decreased both thermal and mechanical nociceptive thresholds. Acute and chronic CBD reversed both hyperalgesia and allodynia. FAAH inhibitor and TRPV1 antagonist potentiated CBD; CB1/CB2 inverse agonist blocked it.","methodology":"Mouse model of Parkinson's (6-hydroxydopamine lesion). CBD administered acutely or chronically. Co-administration studies with FAAH inhibitor, TRPV1 antagonist, and CB1/CB2 inverse agonist to elucidate mechanisms.","limitations":"Mouse model; 6-OHDA is a toxic model that does not fully recapitulate human Parkinson's; CBD doses used may not translate directly to human dosing; mechanism studies used pharmacological tools with potential off-target effects."},{"rthcId":"RTHC-02486","title":"A perspective on cannabinoids for treating epilepsy: Do they really change the landscape?","authors":"Cross, J Helen; Cock, Hannah","year":2020,"journal":"Neuropharmacology, 170, 107861","doi":"10.1016/j.neuropharm.2019.107861","pmid":"31770546","tags":["epilepsy","cbd","medical-cannabis","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Only purified CBD formulations have been rigorously evaluated in controlled trials, showing modest but significant improvements in motor seizures. Key adverse effects include diarrhea, somnolence, and reduced appetite, with up to 1 in 23 risk of serious adverse events. Significant drug interactions: valproate increases hepatotoxicity risk; clobazam interaction contributes to somnolence and potentially efficacy.","whyItMatters":"There is significant public enthusiasm for cannabis-based treatments for epilepsy that outpaces the actual evidence. This review helps calibrate expectations while acknowledging genuine therapeutic value.","specificNumbers":"Up to 1 in 23 risk of serious adverse events from CBD. Drug interactions with valproate (hepatotoxicity) and clobazam (somnolence, efficacy). Only purified CBD has been rigorously tested in controlled trials.","methodology":"Review summarizing current knowledge of cannabinoids for epilepsy, including controlled trial data for purified CBD, animal model evidence, drug interactions, and the gap between evidence and public perception.","limitations":"No comparative effectiveness studies between CBD and other antiseizure medications; unclear how much of CBD's benefit is from direct anticonvulsant effect vs. clobazam interaction; limited evidence for THC-containing products."},{"rthcId":"RTHC-02487","title":"Daily Cannabis Users with Sickle Cell Disease Show Fewer Admissions than Others with Similar Pain Complaints.","authors":"Curtis, Susanna A; Brandow, Amanda M; DeVeaux, Michelle; Zeltermam, Daniel; Devine, Lesley; Roberts, John D","year":2020,"journal":"Cannabis and cannabinoid research, 5(3), 255-262","doi":"10.1089/can.2019.0036","pmid":"32923662","tags":["pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Daily cannabis users with SCD had worse pain episode severity scores than others (56.7 vs. 48.8, p = 0.02) yet had 1.8 fewer annual admissions (p = 0.01) and 1.2 fewer annual ER visits (p = 0.01). Opioid dispensing was similar between groups after matching for age, gender, genotype, hydroxyurea use, and pain impact scores.","whyItMatters":"Sickle cell disease causes severe pain crises that drive frequent hospitalization. If cannabis use genuinely reduces healthcare utilization without increasing opioid needs, it could have significant clinical implications.","specificNumbers":"Daily users: pain severity 56.7 vs. 48.8 (p = 0.02). 1.8 fewer annual admissions (p = 0.01). 1.2 fewer annual ER visits (p = 0.01). Similar opioid amounts dispensed after matching.","methodology":"Cross-sectional study of adults with sickle cell disease comparing daily cannabis users with non-daily users. Validated patient-reported measures of pain and quality of life. Matched for age, gender, SCD genotype, hydroxyurea use, and pain impact scores.","limitations":"Cross-sectional design; cannot determine if cannabis caused the reduction in admissions; self-selection bias (patients who manage well at home may be more likely to choose cannabis); small sample implied by single-center design."},{"rthcId":"RTHC-02488","title":"Microstructure analysis of the effects of the cannabinoid agents HU-210 and rimonabant in rats licking for sucrose.","authors":"D'Aquila, Paolo S","year":2020,"journal":"European journal of pharmacology, 887, 173468","doi":"10.1016/j.ejphar.2020.173468","pmid":"32781169","tags":["appetite","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"HU-210 reduced licking by decreasing burst number and intra-burst lick rate (a motor competence index). These effects were antagonized by rimonabant (CB1 antagonist), confirming CB1 dependence. Rimonabant at 0.5 mg/kg decreased burst number late in sessions, resembling reward devaluation, suggesting it reduced \"liking.\"","whyItMatters":"Understanding how cannabinoids affect feeding behavior at the microstructural level helps separate reward effects from motor effects, which has implications for understanding both appetite regulation and cannabinoid side effects.","specificNumbers":"HU-210: 25, 50, 100 ug/kg. Rimonabant: 0.5, 1 mg/kg. HU-210 reduced both burst number and intra-burst lick rate. Rimonabant at 0.5 mg/kg reduced burst number late in session.","methodology":"Two experiments analyzing the microstructure of licking for 10% sucrose in 30-minute sessions. Experiment 1 tested rimonabant-HU-210 interactions; Experiment 2 tested a dose range of HU-210. Licking burst patterns analyzed for reward and motor components.","limitations":"Animal model using synthetic agonists; sucrose licking is a simplified model of feeding behavior; HU-210 is pharmacologically distinct from THC."},{"rthcId":"RTHC-02489","title":"Slow Titration of Cannabidiol Add-On in Drug-Resistant Epilepsies Can Improve Safety With Maintained Efficacy in an Open-Label Study.","authors":"D'Onofrio, Gianluca; Kuchenbuch, Mathieu; Hachon-Le Camus, Caroline; Desnous, Béatrice; Staath, Véronique; Napuri, Sylvia; Ville, Dorothée; Pedespan, Jean-Michel; Lépine, Anne; Cances, Claude; de Saint-Martin, Anne; Teng, Théo; Chemaly, Nicole; Milh, Mathieu; Villeneuve, Nathalie; Nabbout, Rima","year":2020,"journal":"Frontiers in neurology, 11, 829","doi":"10.3389/fneur.2020.00829","pmid":"32903409","tags":["epilepsy","cbd","medical-cannabis","drug-interactions","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"At 6 months, mean seizure frequency decreased 41% from baseline, and 37.8% had 50%+ seizure reduction. Adverse events occurred in 48.8%, mainly somnolence (21%), asthenia (16%), and behavioral changes (13%). Abnormal transaminases occurred in 11 patients receiving both valproate and clobazam. Concomitant clobazam did not increase efficacy rates.","whyItMatters":"Slow titration may allow clinicians to achieve similar seizure control with fewer side effects, improving the risk-benefit profile of CBD therapy for severe childhood epilepsy.","specificNumbers":"125 patients enrolled. Doses: 10 mg/kg/day at M1, 14 at M2, 15.5 at M6. 26 discontinued (19 for lack of efficacy). AEs in 48.8%. Somnolence 21%, asthenia 16%. 37.8% achieved 50%+ seizure reduction at M6. 1 SUDEP.","methodology":"Prospective, open-label, multicenter study in 7 French reference centers. 125 patients (62 LGS, 48 Dravet, 15 other) with slow CBD titration to 10 mg/kg/day over at least 1 month, then gradual increase to max 20 mg/kg/day. Assessed at months 1, 2, and 6.","limitations":"Open-label without control group; heterogeneous epilepsy types; variable follow-up; one SUDEP occurred (not necessarily related to CBD)."},{"rthcId":"RTHC-02490","title":"Characterizing psychosis-relevant phenomena and cognitive function in a unique population with isolated, chronic and very heavy cannabis exposure.","authors":"D'Souza, Deepak Cyril; Ganesh, Suhas; Cortes-Briones, Jose; Campbell, Michael H; Emmanuel, Maisha K","year":2020,"journal":"Psychological medicine, 50(14), 2452-2459","doi":"10.1017/S0033291719002721","pmid":"31615592","tags":["psychosis","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cases averaged 30,000+ lifetime cannabis exposures with no other substance use. They had significantly higher SPQ scores (24 vs. 13, p = 0.031) and lower composite cognitive scores (-0.23 vs. +0.28, p = 0.03) than controls. Moderate to large effect sizes were noted for attention, psychomotor speed, working memory, cognitive flexibility, visuospatial processing, and verbal memory. A subsample showed worse scores than their own non-using siblings.","whyItMatters":"This study addresses a major limitation in cannabis research: confounding from other substance use. By studying a population that exclusively uses cannabis, the findings are more directly attributable to cannabis itself.","specificNumbers":"15 cases, 12 controls. Mean SPQ: 24 vs. 13 (p = 0.031). Composite cognition: -0.23 vs. +0.28 (p = 0.03). Cases averaged 30,000+ lifetime cannabis exposures. Moderate to large effect sizes across cognitive domains.","methodology":"Cross-sectional study of 15 ultra-heavy cannabis users from a unique cultural group where cannabis use is central but all other substances (tobacco, alcohol) are forbidden. Compared with 12 matched controls from the same community. Schizotypal Personality Questionnaire and culture-neutral cognitive battery administered.","limitations":"Very small sample; cross-sectional design; the unique cultural context may limit generalizability; cannot determine whether pre-existing differences led to cannabis use patterns."},{"rthcId":"RTHC-02491","title":"Recreational cannabis use impairs driving performance in the absence of acute intoxication.","authors":"Dahlgren, M Kathryn; Sagar, Kelly A; Smith, Rosemary T; Lambros, Ashley M; Kuppe, Madeline K; Gruber, Staci A","year":2020,"journal":"Drug and alcohol dependence, 208, 107771","doi":"10.1016/j.drugalcdep.2019.107771","pmid":"31952821","tags":["driving","cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis users showed increased accidents, speed, lateral movement, and reduced rule-following compared to controls. When divided by onset age, all significant driving impairment was localized to early-onset users (before age 16). Late-onset users (16+) did not differ significantly from controls. Impulsivity significantly contributed to performance differences.","whyItMatters":"This suggests chronic cannabis use may impair driving ability even when users are not actively intoxicated, with age of first regular use being a critical factor.","specificNumbers":"Cannabis users had increased accidents, speed, lateral movement, and reduced rule-following. All impairment localized to early-onset (<16) group. Late-onset (16+) group did not differ from controls. Impulsivity was a significant covariate.","methodology":"Cross-sectional study comparing non-intoxicated heavy recreational cannabis users with healthy controls on a customized driving simulator. Users divided into early-onset (<16) and late-onset (16+) groups. Impulsivity assessed as a covariate.","limitations":"Cross-sectional design; simulated driving not identical to real driving; cannot determine if early-onset users had pre-existing differences that led to both earlier use and poorer driving; relatively small sample."},{"rthcId":"RTHC-02492","title":"Guanfacine extended-release for cannabis use disorder: a pilot feasibility trial.","authors":"Dakwar, Elias; Mahony, Amy; Choi, C Jean; Pavlicova, Martina; Brooks, Daniel; Mariani, John P; Levin, Frances R","year":2020,"journal":"The American journal of drug and alcohol abuse, 46(1), 44-48","doi":"10.1080/00952990.2019.1620259","pmid":"31339797","tags":["addiction","withdrawal"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Among 22 cannabis-dependent individuals, daily cannabis use in grams (p = .004), dollars spent (p < .001), and days of use (p = .007) significantly decreased over the 8-week study. Retention at week 8 was 41%. Three participants achieved 3+ weeks of total abstinence. No significant differences between two titration schedules.","whyItMatters":"No approved pharmacotherapy exists for cannabis use disorder. This pilot suggests guanfacine, an alpha-2 adrenergic agonist already approved for ADHD, warrants further study as a potential treatment.","specificNumbers":"22 participants; 41% retention at 8 weeks; significant reductions in grams (p = .004), dollars (p < .001), and days of use (p = .007); 3 participants achieved 3+ weeks abstinence.","methodology":"Eight-week open-label outpatient pilot trial of guanfacine extended-release (G-XR) in 22 cannabis-dependent adults. Two titration schedules tested (gradual to 4 mg or highest tolerated dose). Standard medication management provided.","limitations":"Open-label without placebo control; very small sample; 41% retention suggests tolerability challenges; natural reduction over time cannot be excluded."},{"rthcId":"RTHC-02493","title":"Do the effects of cannabis on the hippocampus and striatum increase risk for psychosis?","authors":"Daniju, Y; Bossong, M G; Brandt, K; Allen, P","year":2020,"journal":"Neuroscience and biobehavioral reviews, 112, 324-335","doi":"10.1016/j.neubiorev.2020.02.010","pmid":"32057817","tags":["psychosis","neuroscience","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Using the MAM rodent model as a framework, the review found clear evidence that cannabis/cannabinoids affect hippocampal and medial temporal lobe function and structure. However, evidence that cannabis increases striatal dopamine function was less robust. Limited evidence existed for cannabis effects on cortical and striatal glutamate levels.","whyItMatters":"The dopamine hypothesis is central to understanding psychosis. If cannabis-related psychosis operates through hippocampal dysfunction rather than direct dopamine effects, it could change therapeutic approaches.","specificNumbers":"No specific pooled statistics; the review synthesizes evidence across imaging and preclinical studies and finds the hippocampal evidence stronger than the striatal dopamine evidence.","methodology":"Review using the methylazoxymethanol acetate (MAM) rodent model of psychosis as a framework to examine cannabis effects on hippocampal-striatal-dopamine pathways. Examines neuroimaging and preclinical evidence.","limitations":"Relies on animal model as framework; limited human neuroimaging studies directly testing the proposed pathway; the MAM model may not perfectly recapitulate cannabis-related psychosis."},{"rthcId":"RTHC-02494","title":"Characteristics and circumstances of synthetic cannabinoid-related death.","authors":"Darke, Shane; Duflou, Johan; Farrell, Michael; Peacock, Amy; Lappin, Julia","year":2020,"journal":"Clinical toxicology (Philadelphia, Pa.), 58(5), 368-374","doi":"10.1080/15563650.2019.1647344","pmid":"31389266","tags":["synthetic-cannabinoids","cardiovascular","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Causes of death: accidental toxicity (38.2%), natural disease (20%), suicide (10.9%), accidental toxicity with CVD (9.1%), traumatic accident (10.9%). Cardiovascular findings included severe atherosclerosis (20%), myocardial fibrosis (18%), and cardiomegaly (12%). AB-CHMINACA was found in 38.2% of cases. Mean age was 37.2 years; 91.1% male.","whyItMatters":"The prominence of cardiovascular disease in relatively young decedents raises concerns about chronic cardiovascular toxicity from synthetic cannabinoids, beyond the acute toxicity risk.","specificNumbers":"55 deaths; mean age 37.2; 91.1% male. Accidental toxicity 38.2%. Severe atherosclerosis 20%. AB-CHMINACA 38.2%. Sudden collapse was most common presentation (25.5%). Co-substances: alcohol 34.5%, THC 23.6%.","methodology":"Retrospective study of all 55 cases in Australia's National Coronial Information System (2000-2017) where synthetic cannabinoid use contributed to death. Demographics, circumstances, toxicology, and organ pathology analyzed.","limitations":"Australian data may not reflect SC composition in other countries; retrospective coronial data; cardiovascular disease may reflect pre-existing conditions rather than SC-caused damage; selection bias toward most severe outcomes."},{"rthcId":"RTHC-02495","title":"Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats.","authors":"Datta, Udita; Kelley, Leslie K; Middleton, Jason W; Gilpin, Nicholas W","year":2020,"journal":"Psychopharmacology, 237(12), 3729-3739","doi":"10.1007/s00213-020-05650-5","pmid":"32857187","tags":["pain","drug-interactions","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Intra-PAG DAMGO (opioid agonist) dose-dependently reversed morphine-induced hyperalgesia. GAT211 (CB1 PAM) alone did not affect nociception. When co-administered, GAT211 antagonized DAMGO's pain-relieving effects in morphine-withdrawn rats. Electrophysiology showed GAT211 attenuated DAMGO-induced suppression of synaptic inhibition in vlPAG neurons.","whyItMatters":"Cannabinoid-opioid combinations are being explored for pain management. This finding that a CB1 positive allosteric modulator can antagonize opioid effects in certain contexts adds important complexity to this therapeutic strategy.","specificNumbers":"DAMGO dose-dependently reversed hyperalgesia. GAT211 alone had no effect on nociception. Co-administration: GAT211 antagonized DAMGO in morphine-withdrawn rats. Electrophysiology confirmed GAT211 blocked DAMGO's synaptic effects via CB1R.","methodology":"Rats chronically treated with morphine or saline received intra-PAG injections of DAMGO (opioid agonist), GAT211 (CB1 PAM), or both. Thermal nociception measured. Slice electrophysiology examined synaptic transmission in the ventrolateral PAG.","limitations":"Single brain region examined (PAG); morphine-withdrawn state may not represent all clinical contexts; GAT211 is one specific CB1 PAM and results may not generalize to others."},{"rthcId":"RTHC-02496","title":"Refinement of cg05575921 demethylation response in nascent smoking.","authors":"Dawes, Kelsey; Andersen, Allan; Papworth, Emma; Hundley, Brandon; Hutchens, Natasha; El Manawy, Heba; Becker, Ashley; Sampson, Luke; Philibert, Willem; Gibbons, Frederick X; Gerrard, Meg; Philibert, Robert","year":2020,"journal":"Clinical epigenetics, 12(1), 92","doi":"10.1186/s13148-020-00882-w","pmid":"32580755","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02497","title":"Diversity of molecular targets and signaling pathways for CBD.","authors":"de Almeida, Douglas L; Devi, Lakshmi A","year":2020,"journal":"Pharmacology research & perspectives, 8(6), e00682","doi":"10.1002/prp2.682","pmid":"33169541","tags":["cbd","neuroscience","pain","anxiety"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD's effects are mediated through multiple molecular mechanisms rather than a single target. Primary targets include the serotonin 5-HT1A receptor and TRPV1 channel. Additional targets include cannabinoid receptors (CB1, CB2), opioid receptors, and other GPCRs and ion channels. This multi-target profile explains CBD's broad spectrum of effects.","whyItMatters":"Understanding CBD's diverse targets explains why it shows effects across anxiety, pain, inflammation, and epilepsy, and helps guide development of more targeted therapeutics.","specificNumbers":"Two primary targets identified: serotonin 5-HT1A receptor and TRPV1 channel. Additional targets include CB1, CB2, opioid receptors, GPR55, and other GPCRs and ion channels.","methodology":"Review synthesizing in vitro and in vivo evidence, randomized clinical trial data, and real-world observations on CBD's molecular targets and signaling pathways.","limitations":"Many target interactions characterized in vitro at concentrations that may not be achieved clinically; the relative contribution of each target to therapeutic effects remains unclear."},{"rthcId":"RTHC-02498","title":"Impact of cannabis on non-medical opioid use and symptoms of posttraumatic stress disorder: a nationwide longitudinal VA study.","authors":"De Aquino, Joao P; Sofuoglu, Mehmet; Stefanovics, Elina A; Rosenheck, Robert A","year":2020,"journal":"The American journal of drug and alcohol abuse, 46(6), 812-822","doi":"10.1080/00952990.2020.1818248","pmid":"33035104","tags":["ptsd","addiction","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Of 1,413 veterans with current non-medical opioid use, 30.3% also used cannabis. At baseline, cannabis co-users had slightly fewer opioid use days (small effect, p < .05) and slightly less severe PTSD (d = 0.16, p = .003). At 4-month follow-up, there were no significant differences in substance use or PTSD symptoms between groups.","whyItMatters":"Multiple states have authorized cannabis for PTSD and as an opioid substitute. This large veteran study provides longitudinal evidence that challenges both of these policy rationales.","specificNumbers":"1,413 veterans with opioid use; 438 (30.3%) also used cannabis. Baseline: slightly fewer opioid days (small effect) and slightly less PTSD severity (d = 0.16) in cannabis users. Follow-up: no significant differences.","methodology":"Nationwide longitudinal VA study (1992-2011) of veterans in specialized intensive PTSD treatment. Veterans with opioid use 7+ days/month were compared: those with cannabis co-use vs. those without. Assessed at admission and 4 months post-discharge.","limitations":"Observational design; cannabis use was self-reported and not standardized; the population was in intensive PTSD treatment which may overshadow cannabis effects; historical data (1992-2011) may not reflect current cannabis products."},{"rthcId":"RTHC-02499","title":"In Silico Infrared Characterization of Synthetic Cannabinoids by Quantum Chemistry and Chemometrics.","authors":"de Castro, Jade Simões; Rodrigues, Caio Henrique Pinke; Bruni, Aline Thaís","year":2020,"journal":"Journal of chemical information and modeling, 60(4), 2100-2114","doi":"10.1021/acs.jcim.9b00871","pmid":"32118417","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02500","title":"Impaired semen quality in trans women: prevalence and determinants.","authors":"de Nie, I; Meißner, A; Kostelijk, E H; Soufan, A T; Voorn-de Warem, I A C; den Heijer, M; Huirne, J; van Mello, N M","year":2020,"journal":"Human reproduction (Oxford, England), 35(7), 1529-1536","doi":"10.1093/humrep/deaa133","pmid":"32613241","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02501","title":"Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure.","authors":"de Salas-Quiroga, Adán; García-Rincón, Daniel; Gómez-Domínguez, Daniel; Valero, Manuel; Simón-Sánchez, Samuel; Paraíso-Luna, Juan; Aguareles, José; Pujadas, Mitona; Muguruza, Carolina; Callado, Luis F; Lutz, Beat; Guzmán, Manuel; de la Prida, Liset Menéndez; Galve-Roperh, Ismael","year":2020,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 45(5), 877-886","doi":"10.1038/s41386-020-0621-3","pmid":"31982904","tags":["pregnancy","neuroscience","cognition","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adult male mice exposed to THC prenatally showed altered hippocampal oscillations, brain hyperexcitability, and spatial memory impairment. A striking interneuronopathy of CCK-containing interneurons in the hippocampus was restricted to male offspring. Using conditional CB1R knockout mice, the CCK-interneuron reduction required CB1R on GABAergic interneurons, indicating cell-autonomous THC action. Sharp-wave ripples (crucial for memory consolidation) were altered in males.","whyItMatters":"This provides a mechanistic explanation for how prenatal THC can cause long-lasting, sex-specific cognitive impairment through selective damage to a specific type of hippocampal interneuron.","specificNumbers":"CCK-containing interneuron reduction confined to male offspring. Sharp-wave ripple alterations in CA1 stratum pyramidale of males only. CB1R on GABAergic interneurons required for the effect.","methodology":"Prenatal THC exposure in mice. Adult offspring assessed with in vivo hippocampal electrophysiology, behavioral testing, and immunohistochemistry. Conditional CB1R knockout mice used to determine cell-autonomous mechanisms.","limitations":"Mouse model; THC dose and timing may not match human prenatal exposure; only spatial memory tested; the protective mechanism in females was not identified."},{"rthcId":"RTHC-02502","title":"The relationship between cannabis use and cognition in people diagnosed with first-episode psychosis.","authors":"de Vos, Chloé; Leopold, Karolina; Blanke, Elisabeth S; Siebert, Stefan; Baumgardt, Johanna; Burkhardt, Eva; Bechdolf, Andreas","year":2020,"journal":"Psychiatry research, 293, 113424","doi":"10.1016/j.psychres.2020.113424","pmid":"32862065","tags":["psychosis","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 89 FEP patients, 61 (68.5%) were lifetime cannabis users. Cannabis users had significantly more positive psychotic symptoms, while non-users displayed more negative symptoms. There were no differences between groups on tests of verbal memory, verbal fluency, or attention.","whyItMatters":"The concern that cannabis compounds cognitive deficits in psychosis has treatment implications. This finding of no additive cognitive effect is reassuring but must be interpreted carefully.","specificNumbers":"89 FEP patients; 61 (68.5%) lifetime cannabis users. Cannabis users: more positive symptoms. Non-users: more negative symptoms. No cognitive differences on any task.","methodology":"Cross-sectional study of 89 people diagnosed with first-episode psychosis. Cannabis use defined as 3+ times/week for 4+ weeks. Cognitive battery assessed verbal memory, verbal fluency, and attention. Controlled for recency of use and other illicit substance use.","limitations":"Cross-sectional; relatively small sample; lifetime use definition does not capture current exposure; limited cognitive battery (3 domains); cannot determine if pre-existing cognitive abilities differ."},{"rthcId":"RTHC-02503","title":"A Pilot Trial of Topical Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome.","authors":"Dean, Diana J; Sabagha, Noor; Rose, Kaitlin; Weiss, Alexander; France, John; Asmar, Timothy; Rammal, Jo-Ann; Beyer, Margaret; Bussa, Rebecca; Ross, Jacob; Chaudhry, Kaleem; Smoot, Thomas; Wilson, Kathleen; Miller, Joseph","year":2020,"journal":"Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 27(11), 1166-1172","doi":"10.1111/acem.14062","pmid":"32569429","tags":["harm-reduction","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"At 60 minutes, mean nausea severity was 3.2 cm (capsaicin) vs. 6.4 cm (placebo) on a 0-10 scale (difference = -3.2 cm, 95% CI: -0.9 to -5.4). Nausea reduction: 46% (capsaicin) vs. 25% (placebo). Complete nausea resolution: 29.4% (capsaicin) vs. 0% (placebo, RR = 3.4). At 30 minutes, the difference was not yet statistically significant.","whyItMatters":"CHS has no established treatment. Topical capsaicin is inexpensive, readily available, and this is the first RCT testing it for CHS, moving beyond case reports to controlled evidence.","specificNumbers":"30 patients (17 capsaicin, 13 placebo). At 60 min: 3.2 vs. 6.4 cm nausea (difference -3.2). 46% vs. 25% nausea reduction. Complete resolution: 29.4% vs. 0%. 1 patient discontinued for skin irritation.","methodology":"Double-blind, randomized, placebo-controlled pilot trial of 30 adults presenting with suspected CHS exacerbation. 0.1% capsaicin or placebo cream applied to anterior abdomen. Nausea assessed by visual analog scale at 30 and 60 minutes.","limitations":"Small pilot trial; not powered for definitive conclusions; suspected CHS diagnosis (no gold standard exists); 30-minute endpoint was not significant; one patient could not tolerate the cream."},{"rthcId":"RTHC-02504","title":"Metabolic Engineering Strategies of Industrial Hemp (Cannabis sativa L.): A Brief Review of the Advances and Challenges.","authors":"Deguchi, Michihito; Kane, Shriya; Potlakayala, Shobha; George, Hannah; Proano, Renata; Sheri, Vijay; Curtis, Wayne R; Rudrabhatla, Sairam","year":2020,"journal":"Frontiers in plant science, 11, 580621","doi":"10.3389/fpls.2020.580621","pmid":"33363552","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02505","title":"Establishment and optimization of a hemp (Cannabis sativa L.) agroinfiltration system for gene expression and silencing studies.","authors":"Deguchi, Michihito; Bogush, Daniel; Weeden, Hannah; Spuhler, Zachary; Potlakayala, Shobha; Kondo, Takumasa; Zhang, Zhanyuan J; Rudrabhatla, Sairam","year":2020,"journal":"Scientific reports, 10(1), 3504","doi":"10.1038/s41598-020-60323-9","pmid":"32103049","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02506","title":"The Italian panorama of cannabis light preparation: Determination of cannabinoids by LC-UV.","authors":"Dei Cas, Michele; Casagni, Eleonora; Saccardo, Anna; Arnoldi, Sebastiano; Young, Craig; Scotti, Stefano; Vieira de Manicor, Edgardo; Gambaro, Veniero; Roda, Gabriella","year":2020,"journal":"Forensic science international, 307, 110113","doi":"10.1016/j.forsciint.2019.110113","pmid":"31927249","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02507","title":"Hemp in Veterinary Medicine: From Feed to Drug.","authors":"Della Rocca, Giorgia; Di Salvo, Alessandra","year":2020,"journal":"Frontiers in veterinary science, 7, 387","doi":"10.3389/fvets.2020.00387","pmid":"32850997","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02508","title":"Brain Morphology of Cannabis Users With or Without Psychosis: A Pilot MRI Study.","authors":"Delvecchio, Giuseppe; Oldani, Lucio; Mandolini, Gian Mario; Pigoni, Alessandro; Ciappolino, Valentina; Schiena, Giandomenico; Lazzaretti, Matteo; Caletti, Elisabetta; Barbieri, Viviana; Cinnante, Claudia; Triulzi, Fabio; Brambilla, Paolo","year":2020,"journal":"Journal of visualized experiments : JoVE","doi":"10.3791/60881","pmid":"32894263","tags":["psychosis","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"CIP patients showed extensive grey matter decreases in right superior frontal gyrus, precentral, superior temporal gyrus, bilateral insula, right precuneus, right medial occipital gyrus, right fusiform gyrus, and left hippocampus compared to non-psychotic chronic cannabis users. Grey matter volumes negatively correlated with BPRS-Activity scores in CIP patients.","whyItMatters":"Understanding what distinguishes cannabis users who develop psychosis from those who do not could identify biomarkers for psychosis risk before symptoms emerge.","specificNumbers":"10 CIP patients vs. 12 non-psychotic cannabis users. Grey matter reductions found in 8+ brain regions. Negative correlation between BPRS-Activity and GM volumes in CIP group.","methodology":"Pilot study comparing 3T MRI brain scans of 10 cannabis-induced psychosis patients with 12 non-psychotic chronic cannabis users. Sociodemographic, clinical, and psychosocial variables correlated with brain measures.","limitations":"Very small pilot study; cross-sectional design cannot determine if brain changes preceded or followed psychosis onset; no healthy non-using control group; medication effects possible in CIP group."},{"rthcId":"RTHC-02509","title":"Monoacylglycerol lipase inhibitors: modulators for lipid metabolism in cancer malignancy, neurological and metabolic disorders.","authors":"Deng, Hui; Li, Weimin","year":2020,"journal":"Acta pharmaceutica Sinica. B, 10(4), 582-602","doi":"10.1016/j.apsb.2019.10.006","pmid":"32322464","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02510","title":"Evidence supporting the benefits of marijuana for Crohn's disease and ulcerative colitis is extremely limited: a meta-analysis of the literature.","authors":"Desmarais, Anna; Smiddy, Stephen; Reddy, Sneha; El-Dallal, Mohammed; Erlich, Jonathan; Feuerstein, Joseph D","year":2020,"journal":"Annals of gastroenterology, 33(5), 495-499","doi":"10.20524/aog.2020.0516","pmid":"32879596","tags":["medical-cannabis","inflammation"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"For UC (1 trial, 60 patients): no difference in remission (RR 1.02) or response (RR 0.99). Adverse events higher with marijuana (RR 1.28). For Crohn's (2 trials, 40 patients): no significant difference in remission (RR 0.72) or response (RR 0.15, borderline). GRADE quality: low to very low.","whyItMatters":"Despite widespread patient use of marijuana for IBD, this meta-analysis reveals that the controlled trial evidence base is almost nonexistent, with only 71 total patients across all eligible trials.","specificNumbers":"334 studies screened; 3 eligible (1 UC, 2 Crohn's). UC: 29 marijuana vs. 31 placebo. Crohn's: 21 marijuana vs. 19 placebo. No significant differences in remission or response. GRADE: low to very low.","methodology":"Meta-analysis following PRISMA guidelines. Systematic search of PubMed, Embase, and Web of Science (June 2019). Of 334 studies reviewed, only 3 RCTs met eligibility. GRADE methodology assessed evidence quality.","limitations":"Only 3 trials eligible; extremely small total sample (71 patients); heterogeneous cannabis preparations; GRADE quality low to very low; cannot rule out benefit that larger trials might detect."},{"rthcId":"RTHC-02511","title":"Cannabidiol efficacy independent of clobazam: Meta-analysis of four randomized controlled trials.","authors":"Devinsky, Orrin; Thiele, Elizabeth A; Wright, Stephen; Checketts, Daniel; Morrison, Gilmour; Dunayevich, Eduardo; Knappertz, Volker","year":2020,"journal":"Acta neurologica Scandinavica, 142(6), 531-540","doi":"10.1111/ane.13305","pmid":"32592183","tags":["epilepsy","cbd","drug-interactions"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"CBD vs. placebo seizure reduction: treatment ratio 0.59 (p < .0001) with clobazam, 0.85 (p = .0226) without clobazam. 50% responder rate odds ratio: 2.51 (p < .0001) with clobazam, 2.40 (p = .0020) without. Somnolence, rash, pneumonia, and aggression were more common with concomitant clobazam.","whyItMatters":"A persistent question has been whether CBD's seizure benefit depends on its interaction with clobazam rather than direct anticonvulsant effects. This meta-analysis demonstrates independent efficacy.","specificNumbers":"With clobazam: treatment ratio 0.59 (p < .0001), 50% responder OR 2.51. Without clobazam: treatment ratio 0.85 (p = .0226), 50% responder OR 2.40. AEs higher with clobazam for somnolence, rash, pneumonia, aggression.","methodology":"Stratified meta-analysis of 4 large RCTs (2 Lennox-Gastaut, 2 Dravet syndrome) evaluating CBD 10 and 20 mg/kg/day. Results stratified by clobazam use. Negative binomial regression and logistic regression used. Pharmacokinetic exposure-response analysis included.","limitations":"Post-hoc stratified analysis of existing trials, not prospective; the difference in treatment ratios with/without clobazam could reflect a synergistic effect; cannot fully exclude confounding by clobazam indication."},{"rthcId":"RTHC-02512","title":"Cannabinoid Hyperemesis Syndrome: A Review of Potential Mechanisms.","authors":"DeVuono, Marieka V; Parker, Linda A","year":2020,"journal":"Cannabis and cannabinoid research, 5(2), 132-144","doi":"10.1089/can.2019.0059","pmid":"32656345","tags":[],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Cannabinoid hyperemesis syndrome is one of the most counterintuitive conditions in medicine: cannabis, widely known for treating nausea, causing severe cyclical vomiting in heavy users. This review examined what was known about why.\n\nThe leading theories centered on the biphasic nature of cannabinoids. At low doses, cannabinoids are antiemetic through CB1 receptor activation in the brainstem. But chronic high-dose exposure appears to desensitize these receptors and shift the balance toward pro-emetic pathways. TRPV1 receptors — the same receptors that respond to capsaicin (hot pepper) — emerge as key players, which explains the characteristic symptom of CHS: patients find relief from hot showers and baths, which activate TRPV1 externally.\n\nThe review also highlighted that CHS shares features with cyclical vomiting syndrome and anticipatory nausea from chemotherapy, suggesting overlapping brain mechanisms. Standard antiemetics typically don't work for CHS. Anxiolytics, sedatives, hot showers, and ultimately cannabis cessation are the only consistently effective treatments.","whyItMatters":"CHS is underdiagnosed because most patients — and many doctors — don't connect vomiting with cannabis use. It's the opposite of what both parties expect cannabis to do. This review laid out the biology behind the paradox: the same receptor system that suppresses nausea at one dose can promote vomiting when chronically overstimulated.\n\nThe hot shower finding is medically important beyond CHS. It points to TRPV1 as a central player, which opens potential pharmacological targets. And the fact that standard antiemetics don't work means emergency departments need to recognize CHS specifically rather than treating it as generic vomiting.","specificNumbers":"• Only permanent cure: complete cannabis cessation\n• Hot showers/baths provide temporary relief (TRPV1 mechanism)\n• Standard antiemetics: ineffective for CHS\n• Effective treatments: anxiolytics, sedatives, hot water, cessation\n• Prevalence unknown due to underdiagnosis and symptom overlap","methodology":"Narrative review of clinical case literature, preclinical cannabinoid pharmacology, and proposed pathophysiological mechanisms for CHS. Published in Cannabis and Cannabinoid Research.","limitations":"CHS prevalence remains unknown due to underdiagnosis. Most evidence comes from case reports and case series rather than controlled studies. The proposed mechanisms (receptor desensitization, TRPV1) are plausible but not definitively proven. The review cannot explain why only some heavy users develop CHS while others don't."},{"rthcId":"RTHC-02513","title":"Nausea-Induced Conditioned Gaping Reactions in Rats Produced by High-Dose Synthetic Cannabinoid, JWH-018.","authors":"DeVuono, Marieka V; Hrelja, Kelly M; Petrie, Gavin N; Limebeer, Cheryl L; Rock, Erin M; Hill, Matthew N; Parker, Linda A","year":2020,"journal":"Cannabis and cannabinoid research, 5(4), 298-304","doi":"10.1089/can.2019.0103","pmid":"33381644","tags":["synthetic-cannabinoids","neuroscience","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"JWH-018 at 1 and 3 mg/kg produced conditioned gaping (nausea). The 3 mg/kg effect was reversed by rimonabant, confirming CB1 mediation. JWH-018 elevated serum corticosterone levels, indicating HPA axis activation. This parallels previous findings with high-dose THC.","whyItMatters":"JWH-018 has been found in \"Spice\" products linked to cannabinoid hyperemesis syndrome. This study provides mechanistic evidence that synthetic cannabinoids produce nausea through CB1-mediated stress response activation.","specificNumbers":"JWH-018 at 1 and 3 mg/kg induced conditioned gaping. Rimonabant reversed 3 mg/kg effect. Corticosterone elevated at 3 mg/kg vs. vehicle.","methodology":"Rats received 3 daily conditioning trials pairing saccharin with JWH-018 (0, 0.1, 1, 3 mg/kg). Rimonabant pretreatment tested for CB1 involvement. Serum corticosterone analyzed after 3 daily JWH-018 injections.","limitations":"Animal model; conditioned gaping is a proxy for nausea; JWH-018 doses may not match human recreational exposure; only one synthetic cannabinoid tested."},{"rthcId":"RTHC-02514","title":"Role of the stress response and the endocannabinoid system in Δ9-tetrahydrocannabinol (THC)-induced nausea.","authors":"DeVuono, Marieka V; La Caprara, Olivia; Sullivan, Megan T; Bath, Alexandra; Petrie, Gavin N; Limebeer, Cheryl L; Rock, Erin M; Hill, Matthew N; Parker, Linda A","year":2020,"journal":"Psychopharmacology, 237(7), 2187-2199","doi":"10.1007/s00213-020-05529-5","pmid":"32399633","tags":["neuroscience","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Antalarmin (CRH antagonist), MJN110 (2-AG elevator), URB597 (AEA elevator), propranolol, WAY-100635, and chlordiazepoxide all blocked THC-induced conditioned gaping. The standard anti-emetic ondansetron did not. THC at 10 mg/kg significantly elevated corticosterone compared to 0.5 mg/kg, showing dose-dependent HPA activation.","whyItMatters":"This explains why CHS patients do not respond to standard anti-nausea medications but find relief from hot showers and benzodiazepines: the nausea is driven by stress pathway activation, not the typical serotonin-mediated mechanism.","specificNumbers":"6 different stress-response inhibitors blocked THC nausea. Ondansetron at 0.1 and 0.01 mg/kg did not. THC 10 mg/kg produced significantly higher corticosterone than 0 or 0.5 mg/kg.","methodology":"Male rats in a conditioned gaping model of nausea. THC (10 mg/kg) paired with saccharin. Pre-treatments tested: CRH antagonist, endocannabinoid enhancers (MJN110, URB597), propranolol, WAY-100635, ondansetron, chlordiazepoxide. Corticosterone measured at different THC doses.","limitations":"Animal model; male rats only; conditioned gaping is a proxy for nausea; high-dose acute THC may not fully recapitulate chronic CHS in humans."},{"rthcId":"RTHC-02515","title":"Marijuana and the Pediatric Population.","authors":"Dharmapuri, Sadhana; Miller, Kathleen; Klein, Jonathan D","year":2020,"journal":"Pediatrics, 146(2)","doi":"10.1542/peds.2019-2629","pmid":"32661188","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02516","title":"Different Effects of Cannabis Abuse on Adolescent and Adult Brain.","authors":"Dhein, Stefan","year":2020,"journal":"Pharmacology, 105(11-12), 609-617","doi":"10.1159/000509377","pmid":"32629444","tags":["youth","neuroscience","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"THC activation of CB1 receptors diminishes neuronal growth factor production and affects signaling cascades involved in synapse formation. Since these processes are critical during puberty's neuronal conversion, THC affects adolescent brains differently. Adolescent cannabis users showed structural grey matter loss in certain regions. THC content in cannabis preparations has increased over 40 years.","whyItMatters":"As THC potency increases and adolescent use continues, understanding the molecular basis for why developing brains are more vulnerable has direct implications for prevention messaging.","specificNumbers":"THC potency has increased over 40 years. THC is a partial agonist at CB1 and CB2. Grey matter loss observed in adolescent users in specific brain regions.","methodology":"Narrative review synthesizing evidence on THC's molecular effects on neuronal development, structural brain imaging studies in adolescent users, and behavioral differences between adolescent and adult cannabis effects.","limitations":"Narrative review; many underlying studies are cross-sectional; difficult to separate THC effects from pre-existing vulnerabilities; increasing potency claims need regional context."},{"rthcId":"RTHC-02517","title":"The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders
.","authors":"Di Marzo, Vincenzo","year":2020,"journal":"Dialogues in clinical neuroscience, 22(3), 259-269","doi":"10.31887/DCNS.2020.22.3/vdimarzo","pmid":"33162769","tags":["neuroscience","cbd","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoidome extends beyond classical CB1/CB2 to include numerous lipid mediators, receptors, and enzymes involved in neuropsychiatric disorders. Non-euphoric plant cannabinoids like CBD have a wide therapeutic window because they hit multiple eCBome targets. The eCBome also connects to the microbiota-gut-brain axis, emerging as important for affective and cognitive functions.","whyItMatters":"This framework from a leading researcher explains why CBD may help diverse neuropsychiatric conditions and introduces the gut microbiome as a new frontier for understanding cannabinoid therapeutics.","specificNumbers":"No specific effect sizes; the review provides a conceptual framework connecting the eCBome, plant cannabinoids, and the gut-brain axis.","methodology":"Expert review by Vincenzo Di Marzo (a pioneer of endocannabinoid research) covering the eCBome concept, its role in neuropsychiatric disorders, the pharmacology of non-psychoactive cannabinoids, and the gut-brain connection.","limitations":"Conceptual review by a single author; many proposed connections are still theoretical; the gut-brain-eCBome axis in humans remains poorly characterized."},{"rthcId":"RTHC-02518","title":"Vaping-Associated Acute Respiratory Failure Due to Acute Lipoid Pneumonia.","authors":"Dicpinigaitis, Peter V; Trachuk, Polina; Fakier, Feizal; Teka, Mestawet; Suhrland, Mark J","year":2020,"journal":"Lung, 198(1), 31-33","doi":"10.1007/s00408-019-00277-6","pmid":"31583455","tags":["respiratory","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A healthy 28-year-old developed acute respiratory failure 2 weeks after using a street-purchased THC vape cartridge. BAL with oil red O staining confirmed acute exogenous lipoid pneumonia. Diffuse alveolar hemorrhage and eosinophilic pneumonia were excluded. IV corticosteroids led to survival and discharge.","whyItMatters":"This case contributed to the evolving recognition of EVALI during the 2019 outbreak, confirming that THC-containing vape oils can cause acute lipoid pneumonia requiring ICU-level care.","specificNumbers":"1 case: 28-year-old male; acute respiratory failure 2 weeks after starting street THC vape cartridge. Oil red O staining confirmed lipoid pneumonia. All 6 reported cases (including prior 5) survived with IV corticosteroids.","methodology":"Case report with diagnostic workup including bronchoscopy, BAL cytology with oil red O staining, and imaging. Reviewed alongside 5 previously reported cases.","limitations":"Single case report; cannot determine which specific component of the vape product caused the lung injury; no product testing performed."},{"rthcId":"RTHC-02519","title":"Neuronal nicotinic acetylcholine receptors mediate ∆9 -THC dependence: Mouse and human studies.","authors":"Donvito, Giulia; Muldoon, Pretal P; Jackson, Kia J; Ahmad, Urslan; Zaveri, Nur T; McIntosh, J Michael; Chen, Xiangning; Lichtman, Aron H; Damaj, M Imad","year":2020,"journal":"Addiction biology, 25(1), e12691","doi":"10.1111/adb.12691","pmid":"30378732","tags":["addiction","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Alpha3beta4 nAChR antagonist/partial agonist reduced THC withdrawal signs. Alpha5 and alpha6 nAChR knockout mice had decreased withdrawal. Beta2 and alpha7 knockouts showed no change. Human genetic association studies confirmed that variations in genes coding for alpha5, alpha3, beta4, and alpha6 nAChRs were associated with cannabis disorder phenotypes.","whyItMatters":"This identifies specific nicotinic receptor subtypes as potential medication targets for cannabis dependence, supported by converging evidence from animal pharmacology, knockout genetics, and human genomics.","specificNumbers":"AuIB (alpha3beta4 antagonist) and AT-1001 (alpha3beta4 partial agonist) dose-dependently attenuated THC withdrawal. Alpha5 and alpha6 KO mice: decreased withdrawal. Beta2, alpha7 KO: no change. Human genes: CHRNA5, CHRNA3, CHRNB4, CHRNA6 associated with cannabis disorder.","methodology":"Multi-approach study: pharmacological challenges in THC-dependent mice, knockout mouse models (alpha5, alpha6, beta2, alpha7 nAChRs), and human genetic association studies for cannabis disorder phenotypes.","limitations":"Animal withdrawal model uses rimonabant-precipitated withdrawal which may not fully match human spontaneous withdrawal; human genetic associations are correlational; specific mechanism of nicotinic-cannabinoid interaction not fully elucidated."},{"rthcId":"RTHC-02520","title":"Using the National Incident-Based Reporting System (NIBRS) to examine racial and ethnic disparities in cannabis incidents.","authors":"Doonan, Samantha M; Hamilton, Jessica R; Johnson, Julie K","year":2020,"journal":"The American journal of drug and alcohol abuse, 46(5), 513-519","doi":"10.1080/00952990.2020.1803894","pmid":"32897106","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02521","title":"Odds of culpability associated with use of impairing drugs in injured drivers in Victoria, Australia.","authors":"Drummer, Olaf H; Gerostamoulos, Dimitri; Di Rago, Matthew; Woodford, Noel W; Morris, Carla; Frederiksen, Tania; Jachno, Kim; Wolfe, Rory","year":2020,"journal":"Accident; analysis and prevention, 135, 105389","doi":"10.1016/j.aap.2019.105389","pmid":"31812899","tags":["driving","harm-reduction"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"THC-positive drivers had modestly increased culpability odds (OR 1.9, 95% CI: 1.2-3.1). Methamphetamine: OR 19 at all concentrations. Benzodiazepines: OR 3.2 (95% CI: 1.6-6.1). Antidepressants, antipsychotics, and opioids: no significant increase. Combinations of alcohol with THC or benzodiazepines, and THC with methamphetamine, showed large increases.","whyItMatters":"This large, well-designed culpability study puts THC's driving risk in context alongside other substances, showing it is real but modest compared to methamphetamine and alcohol, while drug combinations are particularly dangerous.","specificNumbers":"5,000 drivers; THC OR 1.9 (1.2-3.1); methamphetamine OR 19; benzodiazepines OR 3.2 (1.6-6.1); alcohol showed large dose-dependent increases. Drug combinations: substantially amplified risk.","methodology":"Culpability analysis of 5,000 injured drivers (1,000/year for 5 years) from Victoria, Australia, with comprehensive blood toxicology. Logistic regression with drug-free drivers as reference. Multivariable models adjusted for crash attributes.","limitations":"Australian drivers may differ from other populations; blood THC levels do not perfectly correlate with impairment timing; injured drivers are a selected sample; some substances may be underdetected."},{"rthcId":"RTHC-02522","title":"Discrimination of legal and illegal Cannabis spp. according to European legislation using near infrared spectroscopy and chemometrics.","authors":"Duchateau, Céline; Kauffmann, Jean-Michel; Canfyn, Michaël; Stévigny, Caroline; De Braekeleer, Kris; Deconinck, Eric","year":2020,"journal":"Drug testing and analysis, 12(9), 1309-1319","doi":"10.1002/dta.2865","pmid":"32453873","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02523","title":"Adolescent cannabinoid exposure interacts with other risk factors in schizophrenia: A review of the evidence from animal models.","authors":"Dunn, Ariel L; Michie, Patricia T; Hodgson, Deborah M; Harms, Lauren","year":2020,"journal":"Neuroscience and biobehavioral reviews, 116, 202-220","doi":"10.1016/j.neubiorev.2020.06.028","pmid":"32610181","tags":["psychosis","youth","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"When adolescent cannabinoid exposure was combined with early-life adversity in animal models, patterns of synergistic and protective effects emerged. Models incorporating maternal deprivation and maternal immune activation showed the most consistent synergistic effects with adolescent cannabinoid exposure. Sex-specific effects were commonly observed.","whyItMatters":"Schizophrenia results from multiple interacting risk factors. Understanding which combinations amplify risk most could guide targeted prevention for high-risk adolescents.","specificNumbers":"Multiple models reviewed. Most consistent synergistic effects: maternal deprivation + adolescent cannabinoids, and maternal immune activation + adolescent cannabinoids. Sex differences frequently observed.","methodology":"Review evaluating animal models that combine adolescent cannabinoid exposure with other schizophrenia risk factors (maternal deprivation, maternal immune activation, social isolation, genetic models). Behavioral, cognitive, and morphological outcomes assessed.","limitations":"Animal models use synthetic cannabinoids at standardized doses; human cannabis exposure is more variable; not all combinations of risk factors have been tested; sex differences need more systematic study."},{"rthcId":"RTHC-02524","title":"Precipitated Δ9-THC withdrawal reduces motivation for sucrose reinforcement in mice.","authors":"Eckard, M L; Trexler, K R; Kotson, B T; Anderson, K G; Kinsey, S G","year":2020,"journal":"Pharmacology, biochemistry, and behavior, 195, 172966","doi":"10.1016/j.pbb.2020.172966","pmid":"32526216","tags":["withdrawal","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Precipitated THC withdrawal (via rimonabant) caused large decreases in break point, overall response rate, and run rate on a progressive-ratio schedule in THC-treated but not vehicle-treated mice. Spontaneous withdrawal had no effect. The CB1 positive allosteric modulator ZCZ011 did not prevent the withdrawal-induced impairment.","whyItMatters":"Cannabis withdrawal involves subjective dysphoria (low mood, reduced motivation) that drives relapse. This model captures these subjective aspects better than traditional somatic withdrawal signs.","specificNumbers":"THC 10 mg/kg for 5-6 days. Precipitated (not spontaneous) withdrawal reduced break point, response rate, and run rate in THC-treated vs. vehicle-treated mice. ZCZ011 (10 mg/kg) did not prevent impairment.","methodology":"Male and female mice received THC (10 mg/kg) or vehicle for 5-6 days. Behavior measured on a progressive-ratio schedule of sucrose reinforcement. Withdrawal precipitated with rimonabant (2 mg/kg) or assessed spontaneously over 3 days.","limitations":"Rimonabant-precipitated withdrawal is more severe than typical human withdrawal; spontaneous withdrawal had no effect (suggesting the model may overestimate withdrawal impact); only one CB1 PAM tested."},{"rthcId":"RTHC-02525","title":"Cannabis use disorder among veterans: Comorbidity and mental health treatment utilization.","authors":"Ecker, Anthony H; Lang, Brent; Hogan, Julianna; Cucciare, Michael A; Lindsay, Jan","year":2020,"journal":"Journal of substance abuse treatment, 109, 46-49","doi":"10.1016/j.jsat.2019.11.003","pmid":"31856950","tags":["addiction","mental-health","ptsd"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of veterans with CUD (2010-2016), 79.1% had a comorbid mental health disorder and 76.8% had another substance use disorder. Veterans with CUD plus a mental health disorder used more individual psychotherapy than those with CUD alone. CUD was rarely an isolated diagnosis.","whyItMatters":"CUD among veterans is almost never a standalone condition. Effective treatment requires addressing co-occurring disorders, and integrated treatment models may be more appropriate than treating CUD in isolation.","specificNumbers":"79.1% comorbid mental health disorder; 76.8% comorbid substance use disorder. Veterans with CUD + mental health disorder used more individual psychotherapy than CUD alone.","methodology":"Retrospective analysis of national Veterans Health Administration administrative and clinical records from 2010-2016 examining comorbidity rates and mental health service utilization among veterans with CUD diagnoses.","limitations":"Administrative data may have coding biases; CUD diagnoses in the VA may be underreported due to stigma and federal prohibition; cannot determine temporal ordering of diagnoses."},{"rthcId":"RTHC-02526","title":"Medicinal and Recreational Marijuana: Review of the Literature and Recommendations for the Plastic Surgeon.","authors":"Edalatpour, Armin; Attaluri, Pradeep; Larson, Jeffrey D","year":2020,"journal":"Plastic and reconstructive surgery. Global open, 8(5), e2838","doi":"10.1097/GOX.0000000000002838","pmid":"33133899","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02527","title":"Sociopolitical Externalities Impacting Worker Health in Washington State's Cannabis Industry.","authors":"Ehrlich, Trecia; Simpson, Christopher; Busch Isaksen, Tania","year":2020,"journal":"Annals of work exposures and health, 64(7), 683-692","doi":"10.1093/annweh/wxz083","pmid":"31785200","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02528","title":"Combined neurotoxic effects of cannabis and nandrolone decanoate in adolescent male rats.","authors":"El-Shamarka, Marwa El-Sayed; Sayed, Rabab H; Assaf, Naglaa; Zeidan, Hala M; Hashish, Adel F","year":2020,"journal":"Neurotoxicology, 76, 114-125","doi":"10.1016/j.neuro.2019.11.001","pmid":"31704101","tags":["youth","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Combined cannabis + nandrolone caused learning/spatial memory deficits, hypo-locomotion, anxiety, and aggression. Severe damage to hippocampal and prefrontal cortex architecture with decreased BDNF. Combined treatment increased oxidative stress, inflammatory cytokines, and activated both intrinsic and extrinsic apoptotic pathways beyond either drug alone.","whyItMatters":"Nandrolone (an anabolic steroid) and cannabis are commonly co-used, particularly among young males. Understanding that the combination amplifies neurotoxicity has direct harm reduction implications.","specificNumbers":"Nandrolone 15 mg/kg + cannabis 20 mg/kg daily for 1 month. Combined treatment: increased MDA and NO, decreased glutathione, elevated TNF-alpha and IL-1-beta, upregulated caspases 3, 8, 9 and cytochrome c in hippocampus and PFC.","methodology":"Adolescent male rats received nandrolone (15 mg/kg) and/or cannabis extract (20 mg/kg) daily for 1 month. Assessed: Morris water maze, open field, elevated plus maze, defensive aggression test. Brain biochemistry: BDNF, oxidative stress markers, cytokines, caspases.","limitations":"Animal model with relatively high doses; cannabis extract composition may differ from human use; only male rats studied; 1-month treatment with immediate testing does not capture long-term or recovery effects."},{"rthcId":"RTHC-02529","title":"Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens.","authors":"Ellermann, Melissa; Pacheco, Alline R; Jimenez, Angel G; Russell, Regan M; Cuesta, Santiago; Kumar, Aman; Zhu, Wenhan; Vale, Gonçalo; Martin, Sarah A; Raj, Prithvi; McDonald, Jeffrey G; Winter, Sebastian E; Sperandio, Vanessa","year":2020,"journal":"Cell, 183(3), 650-665.e15","doi":"10.1016/j.cell.2020.09.022","pmid":"33031742","tags":["medical-cannabis","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice with elevated 2-AG levels were protected from enteric infection. The endocannabinoid directly blocked the bacterial receptor QseC, a signaling molecule that activates pathogen attack systems.","whyItMatters":"This is the first demonstration that endocannabinoids are directly sensed by bacteria and can modulate bacterial behavior, opening a new avenue for understanding how the endocannabinoid system influences gut health and infection resistance.","specificNumbers":"The study identified QseC, a histidine kinase encoded in the core Enterobacteriaceae genome, as the receptor through which 2-AG blocks type three secretion systems essential for infection.","methodology":"Researchers used mouse models with elevated 2-AG levels and exposed them to Enterobacteriaceae pathogens. They identified the bacterial receptor QseC as the target through which 2-AG inhibits virulence gene expression.","limitations":"This was an animal study using mouse models, and the relevance to human gut infections remains to be established. The study focused on Enterobacteriaceae pathogens specifically."},{"rthcId":"RTHC-02530","title":"Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.","authors":"Elliott, Jesse; DeJean, Deirdre; Potter, Beth K; Coyle, Doug; Clifford, Tammy; McCoy, Bláthnaid; Wells, George A","year":2020,"journal":"Epilepsy & behavior : E&B, 111, 107120","doi":"10.1016/j.yebeh.2020.107120","pmid":"32570201","tags":["medical-cannabis","epilepsy"],"studyType":"qualitative","evidenceStrength":"moderate","keyFinding":"Most parents encountered resistance from their child's neurologist when seeking medical cannabis authorization, forcing many to seek authorization through cannabis clinics instead of their existing care team.","whyItMatters":"Even in Canada, where medical cannabis is legal, families of children with drug-resistant epilepsy face systemic barriers that can compromise care quality and create financial hardship.","specificNumbers":"Participants reported spending up to $2,000 per month on medical cannabis. Most parents were unable to get reimbursement through public or private insurance programs.","methodology":"Qualitative study using semi-structured interviews with 19 parents of children with drug-resistant epilepsy in Canada. Data was analyzed using a patient-centered access to care framework across five dimensions: approachability, acceptability, availability, affordability, and appropriateness.","limitations":"Small qualitative sample of 19 parents, which may not represent all experiences. The study was conducted in a specific Canadian policy context."},{"rthcId":"RTHC-02531","title":"Cannabis-based products for pediatric epilepsy: An updated systematic review.","authors":"Elliott, Jesse; DeJean, Deirdre; Clifford, Tammy; Coyle, Doug; Potter, Beth K; Skidmore, Becky; Alexander, Christine; Repetski, Alexander E; Shukla, Vijay; McCoy, Bláthnaid; Wells, George A","year":2020,"journal":"Seizure, 75, 18-22","doi":"10.1016/j.seizure.2019.12.006","pmid":"31865133","tags":["medical-cannabis","epilepsy","cbd"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Data from both RCTs and non-randomized studies suggest cannabidiol reduces seizure frequency as adjunctive treatment, though RCTs showed no statistically significant difference for seizure freedom, quality of life, or sleep disruption compared to placebo.","whyItMatters":"This updated review adds 12 new studies since 2018 and provides the most comprehensive evidence summary for cannabidiol in pediatric epilepsy, confirming earlier findings of seizure frequency reduction.","specificNumbers":"35 studies analyzed (12 new since April 2018), including 4 RCTs. Seizure freedom RR: 6.77 (95% CI 0.36-128.38). Quality of life MD: 0.6 (95% CI -2.6 to 3.9).","methodology":"Updated systematic review searching for studies published through May 2019. Included RCTs and non-randomized studies of cannabis-based products in children with epilepsy. Four RCTs and 31 non-randomized studies were analyzed.","limitations":"Wide confidence intervals for seizure freedom reflect small sample sizes. Most studies used CBD as adjunctive treatment, making it difficult to isolate its independent effect. Increased GI adverse events are a concern."},{"rthcId":"RTHC-02532","title":"Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ1-42 peptide in rat hippocampal neurons.","authors":"Elmazoglu, Zubeyir; Rangel-López, Edgar; Medina-Campos, Omar Noel; Pedraza-Chaverri, José; Túnez, Isaac; Aschner, Michael; Santamaría, Abel; Karasu, Çimen","year":2020,"journal":"Neurochemistry international, 140, 104817","doi":"10.1016/j.neuint.2020.104817","pmid":"32781098","tags":["neuroscience","cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"All five cannabinoid agents preserved cell viability, stimulated mitochondrial membrane potential, and reduced oxidative damage and inflammation. URB597, which blocks the enzyme that breaks down endocannabinoids, was the most effective.","whyItMatters":"Hyperglycemia and amyloid beta are both implicated in Alzheimer's disease, and this study suggests the endocannabinoid system could be a therapeutic target for neuroprotection in conditions where both are present.","specificNumbers":"Five agents tested: AEA, 2-AG, CP 55-940, WIN 55,212-2, and URB597. Concentrations ranged from 1 nM to 1 μM. Treatment with 150 mM glucose followed by 500 nM amyloid beta 1-42.","methodology":"Cell culture study using primary rat hippocampal neurons exposed to a combined insult of high glucose (150 mM) plus amyloid beta 1-42 peptide (500 nM). Five cannabinoid agents were tested at concentrations from 1 nM to 1 μM.","limitations":"This is a cell culture study using rat neurons, not a whole-animal or human study. The combined insult model, while relevant, is an artificial simulation of Alzheimer's disease pathology."},{"rthcId":"RTHC-02533","title":"Moderating role of cannabis use between insight and depression in early psychosis.","authors":"Elowe, Julien; Golay, Philippe; Baumann, Philipp S; Solida-Tozzi, Alessandra; Conus, Philippe","year":2020,"journal":"Schizophrenia research, 215, 61-65","doi":"10.1016/j.schres.2019.11.030","pmid":"31780343","tags":["psychosis","depression","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"A three-way interaction between cannabis use, insight, and medication adherence predicted depression levels one year post-diagnosis. High insight was linked to higher depression only when combined with ongoing cannabis use.","whyItMatters":"Insight is generally considered beneficial in psychosis treatment, but this study reveals that continued cannabis use may convert that advantage into a risk factor for depression, identifying a specific subgroup needing targeted intervention.","specificNumbers":"214 first-episode psychosis patients followed for 36 months. Depression measured by MADRS scores at one year. Cannabis use assessed on a continuum.","methodology":"Prospective observational study of 214 first-episode psychosis patients enrolled in a specialized early psychosis program and followed for 36 months. Multivariate regression models examined the interaction between insight, cannabis use (on a continuum), and medication adherence on outcomes at one year.","limitations":"Observational design cannot establish causation. Cannabis use was self-reported on a continuum rather than objectively measured. The specific mechanisms linking cannabis, insight, and depression remain unclear."},{"rthcId":"RTHC-02534","title":"PnAn13, an antinociceptive synthetic peptide inspired in the Phoneutria nigriventer toxin PnTx4(6-1) (δ-Ctenitoxin-Pn1a).","authors":"Emerich, Bruna Luiza; Ferreira, Renata Cristina Mendes; Machado-de-Avila, Ricardo Andrez; Resende, Jarbas Magalhães; Duarte, Igor Dimitri G; de Lima, Maria Elena","year":2020,"journal":"Toxicon: X, 7, 100045","doi":"10.1016/j.toxcx.2020.100045","pmid":"32875290","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02535","title":"Predictors of psychosis breakthrough during 24 months of long-acting antipsychotic maintenance treatment in first episode schizophrenia.","authors":"Emsley, Robin; Asmal, Laila; Rubio, Jose M; Correll, Christoph U; Kane, John M","year":2020,"journal":"Schizophrenia research, 225, 55-62","doi":"10.1016/j.schres.2019.11.025","pmid":"31767510","tags":["psychosis","addiction","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"About 21% of patients developed breakthrough psychotic symptoms despite assured medication adherence via long-acting injections. Current cannabis use independently predicted breakthrough episodes, and post-breakthrough treatment response was poorer than the initial response.","whyItMatters":"By using long-acting injectable antipsychotics, this study removes non-adherence as a factor, showing that breakthrough psychosis occurs even with guaranteed medication delivery, and that cannabis use is a modifiable risk factor.","specificNumbers":"99 patients (mean age 24.1, 73.7% male). 21 of 99 (21.2%) developed breakthrough psychosis after a mean of 17.4 months. Mean follow-up was 20 months.","methodology":"Prospective cohort of 99 previously minimally treated first-episode schizophrenia-spectrum patients treated with long-acting injectable antipsychotics and followed for up to 24 months with regular assessments.","limitations":"Relatively small sample of 99 patients from a single site. The association between cannabis use and breakthrough psychosis is observational and does not prove causation."},{"rthcId":"RTHC-02536","title":"Autonomy, competence and relatedness and cannabis and alcohol use among youth in Canada: a cross-sectional analysis.","authors":"Enns, Aganeta; Orpana, Heather","year":2020,"journal":"Health promotion and chronic disease prevention in Canada : research, policy and practice, 40(5-6), 201-210","doi":"10.24095/hpcdp.40.5/6.09","pmid":"32529980","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Relatedness (feeling connected to others) and competence (feeling capable) were consistently associated with lower odds of 30-day and more frequent cannabis use, alcohol use, and binge drinking. Autonomy, however, was associated with higher odds of these behaviors.","whyItMatters":"This study provides evidence that positive mental health factors, not just risk factors, are associated with substance use patterns, supporting strengths-based prevention approaches.","specificNumbers":"All associations were significant except competence and more frequent cannabis use among boys, and autonomy and more frequent alcohol use among girls.","methodology":"Cross-sectional analysis of the 2014/2015 Canadian Student Tobacco, Alcohol and Drugs Survey (CSTADS). Grade 7-12 students completed the Children's Intrinsic Needs Satisfaction Scale (CINSS) measuring autonomy, competence, and relatedness. Associations with substance use were examined via logistic regression, stratified by sex.","limitations":"Cross-sectional design prevents causal conclusions. Self-reported substance use may be underreported. The autonomy finding may reflect measurement issues rather than a true protective-factor reversal."},{"rthcId":"RTHC-02537","title":"Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain.","authors":"Escudero-Lara, Alejandra; Argerich, Josep; Cabañero, David; Maldonado, Rafael","year":2020,"journal":"eLife, 9","doi":"10.7554/eLife.50356","pmid":"31931958","tags":["medical-cannabis","pain","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC alleviated mechanical pain hypersensitivity, reduced pain unpleasantness, restored memory deficits, and inhibited the growth of endometrial cysts. It also modified uterine innervation but did not affect anxiety-like behavior.","whyItMatters":"Endometriosis affects an estimated 10% of women of reproductive age and lacks adequate treatment. This study suggests THC may not only manage symptoms but could potentially modify the disease itself by inhibiting cyst growth.","specificNumbers":"THC dose: 2 mg/kg daily. The treatment alleviated mechanical hypersensitivity, restored cognitive function, and inhibited cyst development.","methodology":"Female mice underwent surgical induction of endometriosis, then received daily THC treatments (2 mg/kg). Researchers measured mechanical pain sensitivity, anxiety behavior, memory function, uterine innervation, and cyst development.","limitations":"Animal study using a surgically induced model that may not fully replicate human endometriosis. The dose and administration route may not translate directly to human use. THC did not address the anxiety component."},{"rthcId":"RTHC-02538","title":"The potential of cannabidiol in the COVID-19 pandemic.","authors":"Esposito, Giuseppe; Pesce, Marcella; Seguella, Luisa; Sanseverino, Walter; Lu, Jie; Corpetti, Chiara; Sarnelli, Giovanni","year":2020,"journal":"British journal of pharmacology, 177(21), 4967-4970","doi":"10.1111/bph.15157","pmid":"32519753","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02539","title":"Revisiting CB1 cannabinoid receptor detection and the exploration of its interacting partners.","authors":"Esteban, Pedro F; Garcia-Ovejero, Daniel; Paniagua-Torija, Beatriz; Moreno-Luna, Rafael; Arredondo, Luis F; Zimmer, Andreas; Arevalo-Martin, Angel; Molina-Holgado, Eduardo","year":2020,"journal":"Journal of neuroscience methods, 337, 108680","doi":"10.1016/j.jneumeth.2020.108680","pmid":"32145227","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02540","title":"Endocannabinoid Receptors in the CNS: Potential Drug Targets for the Prevention and Treatment of Neurologic and Psychiatric Disorders.","authors":"Estrada, José Antonio; Contreras, Irazú","year":2020,"journal":"Current neuropharmacology, 18(8), 769-787","doi":"10.2174/1570159X18666200217140255","pmid":"32065105","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02541","title":"Cannabis use: A co-existing condition in first-episode bipolar mania patients.","authors":"Etyemez, Semra; Currie, Terrence T; Hamilton, Jane E; Weaver, Michael F; Findley, J Chase; Soares, Jair; Selek, Salih","year":2020,"journal":"Journal of affective disorders, 263, 289-291","doi":"10.1016/j.jad.2019.11.097","pmid":"31818791","tags":["addiction","mental-health","psychosis"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Of 15 patients who received urine drug screening, 7 (47%) tested positive for cannabinoids, a rate substantially higher than the general population. Only two patients tested positive for other substances.","whyItMatters":"The high prevalence of cannabis use among first-episode mania patients adds to evidence linking cannabis use to the onset of bipolar disorder, though the direction of this association remains unclear.","specificNumbers":"20 patients identified from 15,969 records. 15 received UDS. 7 of 15 (47%) positive for cannabis. Mean age: 28.65 years. 50% female. Mean hospital stay: 7.15 days.","methodology":"Retrospective cohort study examining 15,969 inpatient psychiatric records from 2012-2013 at a single center to identify patients admitted with a first manic episode (single episode mania per ICD-9 criteria).","limitations":"Very small sample of 20 patients, making statistical analysis limited. Single center, retrospective design. Urine drug screening was not performed on all patients. The study cannot determine whether cannabis use preceded or followed mood symptoms."},{"rthcId":"RTHC-02542","title":"Cohort study of medical cannabis authorisation and healthcare utilisation in 2014-2017 in Ontario, Canada.","authors":"Eurich, Dean; Lee, Cerina; Zongo, Arsene; Minhas-Sandhu, Jasjett K; Hanlon, John G; Hyshka, Elaine; Dyck, Jason","year":2020,"journal":"Journal of epidemiology and community health, 74(3), 299-304","doi":"10.1136/jech-2019-212438","pmid":"31831619","tags":["medical-cannabis","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Medical cannabis patients had a short-term increase in physician visits and hospitalizations within the first month, but these differences were not statistically significant over the 6-month follow-up. Emergency department visits showed a slight but significant decrease.","whyItMatters":"This large real-world study provides reassurance that medical cannabis authorization does not lead to sustained increases in healthcare system burden and may even modestly reduce emergency department visits.","specificNumbers":"9,925 medical cannabis patients matched with 17,732 controls. Initial increase: 4,330 additional physician visits per 10,000 patients in the first month. ED visits decreased by 19 per 10,000 patients over follow-up (p=0.014).","methodology":"Matched cohort study comparing 9,925 medical cannabis patients (inhaled or oral) at specialized clinics with 17,732 non-authorized controls in Ontario (2014-2017). Interrupted time series and multivariate Poisson regression analyses were used.","limitations":"Six-month follow-up is relatively short. The study could not assess why patients used healthcare services or whether cannabis replaced other treatments. Selection bias is possible since patients who seek medical cannabis may differ from controls."},{"rthcId":"RTHC-02543","title":"Evaluation of Pesticides Found in Oregon Cannabis from 2016 to 2017.","authors":"Evoy, Richard; Kincl, Laurel","year":2020,"journal":"Annals of work exposures and health, 64(7), 770-774","doi":"10.1093/annweh/wxz075","pmid":"31621879","tags":["harm-reduction","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Both recreational and medicinal cannabis products contained high pesticide levels, with 50 different pesticides identified. Medical cannabis products had mean pesticide residue levels 3-12 times higher than recreational products. Nine pesticides found were classified as highly or extremely hazardous.","whyItMatters":"The finding that medical cannabis, used by patients with health conditions, contained significantly more pesticide contamination than recreational products highlights a regulatory gap that could put vulnerable consumers and cannabis workers at risk.","specificNumbers":"50 pesticides identified in cannabis products. Medical cannabis had 3-12 times higher mean residual pesticide levels than recreational. 9 of 50 pesticides were classified as WHO Class Ia (extremely hazardous) or Ib (highly hazardous).","methodology":"Analysis of Oregon state pesticide testing data for both recreational and medicinal cannabis products. The Oregon Department of Agriculture developed testing regulations and a list of approved pesticides following legalization in 2014.","limitations":"The study used state testing data, which may not capture all products on the market. Pesticide testing methods and detection limits evolved during the study period. The health effects of pesticide exposure via cannabis consumption are not well characterized."},{"rthcId":"RTHC-02544","title":"Role for endocannabinoids in early pregnancy: recent advances and the effects of cannabis use.","authors":"Ezechukwu, Henry C; Diya, Cornelius A; Shrestha, Nirajan; Hryciw, Deanne H","year":2020,"journal":"American journal of physiology. Endocrinology and metabolism, 319(3), E557-E561","doi":"10.1152/ajpendo.00210.2020","pmid":"32744098","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02545","title":"Use of legal and illegal substances in Malé (Republic of Maldives) assessed by wastewater analysis.","authors":"Fallati, Luca; Castiglioni, Sara; Galli, Paolo; Riva, Francesco; Gracia-Lor, Emma; González-Mariño, Iria; Rousis, Nikolaos I; Shifah, Mohamed; Messa, Maria Cristina; Strepparava, Maria Grazia; Vai, Marina; Zuccato, Ettore","year":2020,"journal":"The Science of the total environment, 698, 134207","doi":"10.1016/j.scitotenv.2019.134207","pmid":"31499350","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02546","title":"The seed of industrial hemp (Cannabis sativa L.): Nutritional Quality and Potential Functionality for Human Health and Nutrition.","authors":"Farinon, Barbara; Molinari, Romina; Costantini, Lara; Merendino, Nicolò","year":2020,"journal":"Nutrients, 12(7)","doi":"10.3390/nu12071935","pmid":"32610691","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02547","title":"Acute neuroradiological, behavioral, and physiological effects of nose-only exposure to vaporized cannabis in C57BL/6 mice.","authors":"Farra, Yasmeen M; Eden, Matthew J; Coleman, James R; Kulkarni, Praveen; Ferris, Craig F; Oakes, Jessica M; Bellini, Chiara","year":2020,"journal":"Inhalation toxicology, 32(5), 200-217","doi":"10.1080/08958378.2020.1767237","pmid":"32475185","tags":["neuroscience","cardiovascular","anxiety"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis inhalation decreased heart rate and blood pressure but promoted anxiety-like behavior in the open field test. Brain imaging (BOLD fMRI) showed cannabis increased sensory awareness while reducing behavioral arousal. Blood THC levels peaked at 136 ng/mL and increased linearly with dose.","whyItMatters":"This study establishes a controlled mouse model for cannabis inhalation that mimics human delivery, enabling future research on chronic cannabis use effects that would be difficult to study in humans.","specificNumbers":"Cannabis contained 10.3% THC, 0.05% CBD. Particle size: 243 nm (count median diameter). Peak blood THC: 136 ng/mL. THC levels increased linearly with aerosolized mass.","methodology":"Male adult C57BL/6 mice received nose-only exposure to vaporized cannabis (10.3% THC, 0.05% CBD). Researchers measured serum THC levels, blood pressure, heart rate, open-field behavior, and awake brain activity via BOLD fMRI.","limitations":"Animal study using a single acute exposure in male mice only. The nose-only delivery system, while controlled, may not perfectly replicate human smoking or vaping behavior. Only one cannabis formulation was tested."},{"rthcId":"RTHC-02548","title":"Adverse Experience Reports of Seizures in Youth and Young Adult Electronic Nicotine Delivery Systems Users.","authors":"Faulcon, Lisa M; Rudy, Susan; Limpert, Jean; Wang, Baoguang; Murphy, Iilun","year":2020,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 66(1), 15-17","doi":"10.1016/j.jadohealth.2019.10.002","pmid":"31866055","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02549","title":"Developmental trajectories of illicit drug use, prescription drug misuse and cannabis practices among young adult cannabis users in Los Angeles.","authors":"Fedorova, Ekaterina V; Schrager, Sheree M; Robinson, Lucy F; Roth, Alexis M; Wong, Carolyn F; Iverson, Ellen; Lankenau, Stephen E","year":2020,"journal":"Drug and alcohol review, 39(6), 743-752","doi":"10.1111/dar.13078","pmid":"32390280","tags":["addiction","youth","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Self-reported medical cannabis use was negatively associated with membership in high illicit drug use trajectories. However, use of concentrates and edibles was associated with high drug use trajectories for both illicit drugs and prescription misuse.","whyItMatters":"The study suggests that self-reported medical cannabis use may indicate a different relationship with substances than recreational use, while certain cannabis product types may signal broader patterns of drug use.","specificNumbers":"301 completers out of 366 enrolled. Two-trajectory solutions (high/low) for both illicit drug use and prescription misuse. Medical cannabis patient status, edibles use, and cannabis days all decreased by wave 4.","methodology":"Longitudinal study surveying 210 medical cannabis patients and 156 non-patient users in Los Angeles annually over four waves (2014-2018). Developmental trajectory modeling identified high/low groups for illicit drug use and prescription drug misuse.","limitations":"Self-reported data may undercount actual drug use. The sample was limited to Los Angeles and may not generalize. The association between product type and drug trajectories does not establish causation."},{"rthcId":"RTHC-02550","title":"The \"Entourage Effect\": Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders.","authors":"Ferber, Sari Goldstein; Namdar, Dvora; Hen-Shoval, Danielle; Eger, Gilad; Koltai, Hinanit; Shoval, Gal; Shbiro, Liat; Weller, Aron","year":2020,"journal":"Current neuropharmacology, 18(2), 87-96","doi":"10.2174/1570159X17666190903103923","pmid":"31481004","tags":["cbd","anxiety","depression","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system is involved in depression, anxiety, and bipolar disorders, and the review proposes that terpenes found in cannabis (such as those also in lavender oil) may enhance cannabinoid therapeutic effects through complementary receptor mechanisms.","whyItMatters":"If the entourage effect is real, it could mean that whole-plant cannabis preparations work differently than isolated cannabinoids, with implications for how cannabis-based medicines are formulated.","specificNumbers":"Standardized lavender essential oil has demonstrated clinical efficacy in anxiety disorders, providing a precedent for terpene-based therapeutics.","methodology":"Narrative review examining preclinical evidence for cannabinoid effects on mood and anxiety disorders, standardized essential oil studies, and the theoretical basis for terpene-cannabinoid synergy.","limitations":"The review relies heavily on preclinical data and theoretical mechanisms. Direct clinical evidence for terpene-cannabinoid synergy in mood disorders is essentially absent."},{"rthcId":"RTHC-02551","title":"Premorbid Adjustment and IQ in Patients With First-Episode Psychosis: A Multisite Case-Control Study of Their Relationship With Cannabis Use.","authors":"Ferraro, Laura; La Cascia, Caterina; Quattrone, Diego; Sideli, Lucia; Matranga, Domenica; Capuccio, Veronica; Tripoli, Giada; Gayer-Anderson, Charlotte; Morgan, Craig; Sami, Musa B; Sham, Pak; de Haan, Lieuwe; Velthorst, Eva; Jongsma, Hannah E; Kirkbride, James B; Rutten, Bart P F; Richards, Alexander L; Roldan, Laura; Arango, Celso; Bernardo, Miquel; Bobes, Julio; Sanjuan, Julio; Santos, Jose Luis; Arrojo, Manuel; Tarricone, Ilaria; Tortelli, Andrea; Szöke, Andrei; Del-Ben, Cristina Marta; Selten, Jean-Paul; Lynskey, Michael; Jones, Peter B; Van Os, Jim; La Barbera, Daniele; Murray, Robin M; Di Forti, Marta","year":2020,"journal":"Schizophrenia bulletin, 46(3), 517-529","doi":"10.1093/schbul/sbz077","pmid":"31361020","tags":["psychosis","cognition","mental-health"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"Psychosis patients who used cannabis occasionally or daily had better premorbid social adjustment than patients who never used. This difference was specific to patients and not seen in controls. IQ was 3 points higher in occasional users vs. never-users in both groups.","whyItMatters":"This challenges the idea that cannabis use alone explains cognitive differences between psychosis patients. Instead, it suggests that patients who were more socially functional before illness were more likely to encounter and use cannabis.","specificNumbers":"948 FEP patients, 1,313 controls, 6 countries. IQ was 3 points higher in occasional users vs. never-users (both groups). Daily users had worse academic adjustment than occasional or never-users (both groups).","methodology":"Multisite case-control study across 6 countries comparing IQ and premorbid adjustment (academic and social) by cannabis use frequency in 948 first-episode psychosis patients and 1,313 population controls.","limitations":"Cross-sectional assessment of premorbid functioning relies on retrospective reports. The study cannot determine the direction of causation between social functioning, cannabis use, and psychosis onset."},{"rthcId":"RTHC-02552","title":"Youth Exposure to Marijuana Advertising in Oregon's Legal Retail Marijuana Market.","authors":"Fiala, Steven C; Dilley, Julia A; Everson, Erik M; Firth, Caislin L; Maher, Julie E","year":2020,"journal":"Preventing chronic disease, 17, E110","doi":"10.5888/pcd17.190206","pmid":"32975510","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"About 72% of 8th graders and 78% of 11th graders reported marijuana advertising exposure. Odds were higher for girls, LGB youth, current marijuana users, 8th graders living with an adult who uses marijuana, and students in districts closer to retail stores.","whyItMatters":"Prior research on tobacco and alcohol shows that advertising exposure is linked to lower perceived risk and increased youth use, making widespread marijuana advertising exposure a potential public health concern.","specificNumbers":"14,852 8th graders and 11,895 11th graders surveyed. 72.2% of 8th graders and 78.1% of 11th graders reported past-month marijuana ad exposure. Most common sources: storefronts and online.","methodology":"Cross-sectional analysis of a 2017 school-based survey of Oregon 8th graders (N=14,852) and 11th graders (N=11,895). Logistic regression examined subgroup differences in reported advertising exposure.","limitations":"Self-reported advertising exposure may not accurately capture actual exposure. The study cannot establish a causal link between advertising exposure and marijuana use. Oregon-specific regulations may not generalize to other states."},{"rthcId":"RTHC-02553","title":"Current application of cannabidiol (CBD) in the management and treatment of neurological disorders.","authors":"Fiani, Brian; Sarhadi, Kasra John; Soula, Marisol; Zafar, Atif; Quadri, Syed A","year":2020,"journal":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 41(11), 3085-3098","doi":"10.1007/s10072-020-04514-2","pmid":"32556748","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02554","title":"Terpenoids From Cannabis Do Not Mediate an Entourage Effect by Acting at Cannabinoid Receptors.","authors":"Finlay, David B; Sircombe, Kathleen J; Nimick, Mhairi; Jones, Callum; Glass, Michelle","year":2020,"journal":"Frontiers in pharmacology, 11, 359","doi":"10.3389/fphar.2020.00359","pmid":"32269529","tags":["neuroscience","cbd"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"None of the five terpenes tested (myrcene, alpha-pinene, beta-pinene, beta-caryophyllene, and limonene) showed direct interactions with CB1 or CB2 receptors, either alone or in mixtures. They did not alter the binding of THC or CBD. A weak interaction of beta-caryophyllene with CB2 was the only possible exception.","whyItMatters":"This study provides direct evidence against one proposed mechanism for the entourage effect, specifically that terpenes enhance cannabinoid activity by interacting with cannabinoid receptors.","specificNumbers":"Five terpenes tested: myrcene, alpha-pinene, beta-pinene, beta-caryophyllene, and limonene. None altered [3H]-CP55,940 binding or the binding/function of THC, CBD, or 2-AG at CB1 or CB2.","methodology":"In vitro study using human CB1 and CB2 receptors expressed in HEK293 cells. Radioligand binding assays tested for orthosteric and allosteric interactions. Functional assays measured receptor activation.","limitations":"In vitro study that cannot capture the full complexity of in vivo pharmacology. Terpenes may interact with other receptor systems not tested. The concentrations used may not reflect those achieved through cannabis consumption."},{"rthcId":"RTHC-02555","title":"Cannabis and the Developing Adolescent Brain.","authors":"Fischer, Adina S; Tapert, Susan F; Lee Louie, Dexter; Schatzberg, Alan F; Singh, Manpreet K","year":2020,"journal":"Current treatment options in psychiatry, 7(2), 144-161","doi":"10.1007/s40501-020-00202-2","pmid":"32714742","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02556","title":"Cannabinoid hyperemesis syndrome in the pregnant patient: clinical case and literature review.","authors":"Flament, Julien; Scius, Nathan; Thonon, Henri","year":2020,"journal":"International journal of emergency medicine, 13(1), 52","doi":"10.1186/s12245-020-00311-y","pmid":"33115404","tags":["medical-cannabis","pregnancy"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The case illustrates that cannabinoid hyperemesis syndrome should be considered in the differential diagnosis of vomiting during pregnancy, particularly when hot baths provide relief and conventional causes are excluded.","whyItMatters":"Vomiting in pregnancy is common and typically attributed to morning sickness. CHS may be underdiagnosed in pregnant cannabis users because clinicians do not routinely ask about cannabis use in the prenatal setting.","specificNumbers":"Patient was 29 years old. Symptoms included uncontrolled vomiting with relief from hot baths. She continued pregnancy and delivered without complications after diagnosis.","methodology":"Clinical case report of a single pregnant patient presenting with uncontrolled vomiting secondary to chronic cannabis use, with literature review.","limitations":"Single case report with limited generalizability. The diagnosis was based on clinical presentation and exclusion of other causes rather than definitive testing."},{"rthcId":"RTHC-02557","title":"Cannabis and multiple sclerosis.","authors":"Fragoso, Yara Dadalti; Carra, Adriana; Macias, Miguel Angel","year":2020,"journal":"Expert review of neurotherapeutics, 20(8), 849-854","doi":"10.1080/14737175.2020.1776610","pmid":"32515670","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Evidence-based data from 33 studies with over 7,500 patients supports nabiximols for MS-related spasticity, pain, and urinary symptoms. However, the review found no scientific evidence supporting smoked marijuana for MS patients.","whyItMatters":"The review distinguishes between evidence-based cannabis medicine (nabiximols) and unregulated marijuana smoking, providing clinicians with clear guidance on what cannabis-related treatments have actual support.","specificNumbers":"33 studies reviewed, over 7,500 patients. 12 studies from the UK, 11 from Italy. Nabiximols treats spasticity, pain, and urinary symptoms.","methodology":"Expert review examining published clinical evidence on cannabis-derived treatments for MS, including 33 studies (12 from the UK, 11 from Italy) involving nabiximols.","limitations":"Expert review rather than systematic review or meta-analysis. Legislation, cost, and prescribing restrictions limit real-world access and experience with nabiximols in many countries."},{"rthcId":"RTHC-02558","title":"Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial.","authors":"Freeman, Tom P; Hindocha, Chandni; Baio, Gianluca; Shaban, Natacha D C; Thomas, Emily M; Astbury, Danica; Freeman, Abigail M; Lees, Rachel; Craft, Sam; Morrison, Paul D; Bloomfield, Michael A P; O'Ryan, Dominic; Kinghorn, Jane; Morgan, Celia J A; Mofeez, Ali; Curran, H Valerie","year":2020,"journal":"The lancet. Psychiatry, 7(10), 865-874","doi":"10.1016/S2215-0366(20)30290-X","pmid":"32735782","tags":["cbd","addiction","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"CBD 400mg reduced urinary THC metabolites by 94 ng/mL and increased abstinent days by 0.48 per week compared to placebo. CBD 800mg reduced metabolites by 72 ng/mL and increased abstinence by 0.27 days per week. CBD 200mg was eliminated as inefficacious at interim analysis.","whyItMatters":"No pharmacological treatment currently exists for cannabis use disorder. This trial provides the first clinical evidence that CBD could fill this gap, with the 400mg dose showing the strongest overall results.","specificNumbers":"82 participants enrolled. CBD 400mg: THC-COOH decreased by 94.21 ng/mL (95% CI -161.83 to -35.56), abstinence increased by 0.48 days/week. 94% completed treatment. No severe adverse events.","methodology":"Phase 2a double-blind, placebo-controlled, randomized adaptive Bayesian trial at University College London. 82 participants with cannabis use disorder were randomized to CBD 200mg, 400mg, 800mg, or placebo for 4 weeks. The 200mg dose was eliminated at interim analysis.","limitations":"Small sample size (82 total). Short treatment duration (4 weeks). Single site. The adaptive Bayesian design, while efficient, means the 200mg dose was tested in fewer participants."},{"rthcId":"RTHC-02559","title":"Is Recovery from Cannabis Dependence Possible? Factors that Help or Hinder Recovery in a National Sample of Canadians with a History of Cannabis Dependence.","authors":"Fuller-Thomson, Esme; Jayanthikumar, Janany; Redmond, Melissa L; Agbeyaka, Senyo","year":2020,"journal":"Advances in preventive medicine, 2020, 9618398","doi":"10.1155/2020/9618398","pmid":"32351740","tags":["addiction","quitting","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"72% were in remission from cannabis dependence, and 53% were free of major psychiatric disorders and substance dependence. However, only 43% achieved positive mental health (remission plus happiness/life satisfaction plus social well-being), significantly lower than the 74% rate in people without cannabis dependence history.","whyItMatters":"The finding that a majority achieve remission is encouraging, but the gap in positive mental health compared to the general population suggests that recovery from cannabis dependence requires more than just stopping use.","specificNumbers":"336 with cannabis dependence history out of 20,777 surveyed. 72% in remission. 53% free of psychiatric disorders and substance dependence. 43% achieved positive mental health vs. 74% in comparison group.","methodology":"Secondary analysis of Statistics Canada's 2012 Canadian Community Health Survey-Mental Health (n=20,777), identifying 336 individuals with lifetime cannabis dependence. WHO-CIDI measures assessed dependence, remission, and mental health.","limitations":"Cross-sectional design captures a snapshot rather than tracking recovery over time. Self-reported data may not capture all relevant factors. The 2012 data predates major legalization changes."},{"rthcId":"RTHC-02560","title":"Synthetic cannabinoids enhanced ethanol-induced motor impairments through reduction of central glutamate neurotransmission.","authors":"Funada, Masahiko; Takebayashi-Ohsawa, Mika; Tomiyama, Ken-Ich","year":2020,"journal":"Toxicology and applied pharmacology, 408, 115283","doi":"10.1016/j.taap.2020.115283","pmid":"33068620","tags":["synthetic-cannabinoids","driving","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Synthetic cannabinoids enhanced ethanol-induced motor impairment on a rotarod test. This effect was blocked by a CB1 receptor antagonist but not a CB2 antagonist. The combination reduced extracellular glutamate levels in the cerebellum more than alcohol alone.","whyItMatters":"Synthetic cannabinoids and alcohol are frequently used together, and this study identifies a specific brain mechanism (reduced cerebellar glutamate) that explains why the combination causes worse motor impairment than either substance alone.","specificNumbers":"Ethanol dose: 2 g/kg. Two synthetic cannabinoids tested: JWH-018 and AB-CHMINACA. Effects blocked by CB1 antagonist AM251 but not CB2 antagonist AM630.","methodology":"Mouse study testing motor coordination on an accelerating rotarod after administering ethanol (2 g/kg) alone or combined with JWH-018 or AB-CHMINACA. Microdialysis measured cerebellar glutamate levels. Microelectrode arrays assessed neuronal network activity in cerebellar cultures.","limitations":"Animal study using injected synthetic cannabinoids, which may not replicate human exposure patterns. Only two synthetic cannabinoids were tested among hundreds that exist. The specific glutamate mechanism may not fully explain real-world impairment."},{"rthcId":"RTHC-02561","title":"Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies.","authors":"Fusar-Poli, Laura; Cavone, Vito; Tinacci, Silvia; Concas, Ilaria; Petralia, Antonino; Signorelli, Maria Salvina; Díaz-Caneja, Covadonga M; Aguglia, Eugenio","year":2020,"journal":"Brain sciences, 10(9)","doi":"10.3390/brainsci10090572","pmid":"32825313","tags":["medical-cannabis","cbd","epilepsy"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabinoids improved some autism-associated symptoms including problem behaviors, sleep problems, and hyperactivity, with limited side effects. They also reduced medication burden and seizure frequency in patients with comorbid epilepsy. Evidence on core ASD symptoms (social communication, repetitive behaviors) remained scarce.","whyItMatters":"Autism spectrum disorder has limited treatment options, particularly for associated behavioral symptoms. These preliminary findings suggest cannabinoids could address comorbid symptoms and reduce polypharmacy.","specificNumbers":"10 published studies reviewed plus 4 ongoing trials identified. Most studies used CBD-dominant preparations. Side effects were primarily cardiac and metabolic, described as limited.","methodology":"Systematic review following PRISMA guidelines, searching Web of Knowledge, PsycINFO, and Embase. Ten studies (8 papers, 2 abstracts) were included, plus 4 ongoing trials from ClinicalTrials.gov.","limitations":"Most included studies were observational with small samples and no control groups. Heterogeneous study designs, cannabis preparations, and outcome measures make comparison difficult."},{"rthcId":"RTHC-02562","title":"Cannabinoid hyperemesis syndrome: definition, pathophysiology, clinical spectrum, insights into acute and long-term management.","authors":"Gajendran, Mahesh; Sifuentes, Joshua; Bashashati, Mohammad; McCallum, Richard","year":2020,"journal":"Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 68(8), 1309-1316","doi":"10.1136/jim-2020-001564","pmid":"33115959","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02563","title":"Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-like Behaviors in Experimental Animals.","authors":"Galaj, Ewa; Xi, Zheng-Xiong","year":2020,"journal":"International journal of molecular sciences, 22(1)","doi":"10.3390/ijms22010134","pmid":"33374481","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02564","title":"Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT1A and TRPV1 receptor mechanisms.","authors":"Galaj, Ewa; Bi, Guo-Hua; Yang, Hong-Ju; Xi, Zheng-Xiong","year":2020,"journal":"Neuropharmacology, 167, 107740","doi":"10.1016/j.neuropharm.2019.107740","pmid":"31437433","tags":["cbd","addiction","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (10-40 mg/kg) reduced cocaine self-administration, shifted the cocaine dose-response curve downward, and lowered break-points for cocaine seeking. CBD also attenuated cocaine-enhanced brain stimulation reward. These effects were blocked by CB2, 5-HT1A, and TRPV1 antagonists but not by CB1, GPR55, or opioid receptor antagonists.","whyItMatters":"No FDA-approved medication exists for cocaine use disorder. This study identifies specific receptor mechanisms through which CBD reduces cocaine reward, providing a roadmap for clinical development.","specificNumbers":"CBD doses: 10-40 mg/kg for self-administration, 3-20 mg/kg for brain stimulation reward. CBD blocked cocaine-induced dopamine increases in the nucleus accumbens. Effects mediated by CB2, 5-HT1A, and TRPV1, not CB1 or opioid receptors.","methodology":"Rat study using intravenous cocaine self-administration, progressive-ratio reinforcement schedules, intracranial brain-stimulation reward, and in vivo microdialysis to measure dopamine levels in the nucleus accumbens.","limitations":"Animal study results may not translate directly to humans. CBD was effective against lower cocaine doses but not high doses, suggesting it may not help the most severe cases. The specific receptor interactions need verification in humans."},{"rthcId":"RTHC-02565","title":"In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018.","authors":"Gamage, Thomas F; Barrus, Daniel G; Kevin, Richard C; Finlay, David B; Lefever, Timothy W; Patel, Purvi R; Grabenauer, Megan A; Glass, Michelle; McGregor, Iain S; Wiley, Jenny L; Thomas, Brian F","year":2020,"journal":"Pharmacology, biochemistry, and behavior, 193, 172918","doi":"10.1016/j.pbb.2020.172918","pmid":"32247816","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"EG-018 had high affinity for CB1 (21 nM) and CB2 (7 nM) but behaved as a weak partial agonist, unlike typical synthetic cannabinoids. When injected into the abdomen, it produced no effects, but intravenous administration caused reduced movement, catalepsy, and hypothermia, with only catalepsy being CB1-mediated.","whyItMatters":"EG-018 has been detected in illicit products and human samples, so understanding its pharmacology is important for toxicology and public health. Its unusual partial agonist profile distinguishes it from more dangerous full-agonist synthetic cannabinoids.","specificNumbers":"CB1 affinity: 21 nM. CB2 affinity: 7 nM. No effects via i.p. at 100 mg/kg. IV at 56 mg/kg produced hypomotility, catalepsy, hypothermia. Only catalepsy was blocked by rimonabant (CB1 antagonist).","methodology":"In vitro binding studies at human CB1 and CB2 receptors in HEK293 cells. In vivo testing in mice using the cannabinoid tetrad (hypomotility, catalepsy, hypothermia, analgesia) and THC drug discrimination via both intraperitoneal and intravenous administration.","limitations":"The lack of effect via intraperitoneal administration suggests pharmacokinetic issues (possibly rapid metabolism) that complicate interpretation. Only basic behavioral assays were used."},{"rthcId":"RTHC-02566","title":"Cannabidiol in sport: Ergogenic or else?","authors":"Gamelin, François-Xavier; Cuvelier, Gregory; Mendes, Antoine; Aucouturier, Julien; Berthoin, Serge; Di Marzo, Vincenzo; Heyman, Elsa","year":2020,"journal":"Pharmacological research, 156, 104764","doi":"10.1016/j.phrs.2020.104764","pmid":"32205233","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02567","title":"Psychosis-Relevant Effects of Intravenous Delta-9-Tetrahydrocannabinol: A Mega Analysis of Individual Participant-Data from Human Laboratory Studies.","authors":"Ganesh, Suhas; Cortes-Briones, Jose; Ranganathan, Mohini; Radhakrishnan, Rajiv; Skosnik, Patrick D; D'Souza, Deepak Cyril","year":2020,"journal":"The international journal of neuropsychopharmacology, 23(9), 559-570","doi":"10.1093/ijnp/pyaa031","pmid":"32385508","tags":["psychosis","neuroscience","tolerance"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"44.75% of THC infusions produced clinically meaningful positive psychosis symptoms. Conceptual disorganization, hallucinations, blunted affect, and poor attention were most frequently affected. Higher THC doses increased symptoms, while frequent prior cannabis use blunted them.","whyItMatters":"This is the most comprehensive analysis of THC-induced psychosis-like effects in controlled settings, confirming the dose-dependent relationship and demonstrating that tolerance from regular use partially protects against these effects.","specificNumbers":"400 IV THC infusions across 10 studies. 44.75% showed clinically meaningful positive symptom increases. Dose association: beta=11.13. Frequent cannabis use association: beta=-0.575. Strong correlation with perceptual alterations (rs=0.514).","methodology":"Individual participant-data mega-analysis of 10 double-blind, randomized, placebo-controlled crossover studies using intravenous THC infusions in healthy volunteers. The PANSS (Positive and Negative Syndrome Scale) measured psychotomimetic effects.","limitations":"Intravenous THC administration does not replicate real-world cannabis use (smoking, edibles). Participants were healthy volunteers, not people at high risk for psychosis. The controlled setting may moderate psychological responses."},{"rthcId":"RTHC-02568","title":"Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders.","authors":"García-Gutiérrez, María S; Navarrete, Francisco; Gasparyan, Ani; Austrich-Olivares, Amaya; Sala, Francisco; Manzanares, Jorge","year":2020,"journal":"Biomolecules, 10(11)","doi":"10.3390/biom10111575","pmid":"33228239","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02569","title":"Cannabidiol for the treatment of psychosis among patients with schizophrenia and other primary psychotic disorders: A systematic review with a risk of bias assessment.","authors":"Ghabrash, Maykel Farag; Coronado-Montoya, Stephanie; Aoun, John; Gagné, Andrée-Anne; Mansour, Flavi; Ouellet-Plamondon, Clairélaine; Trépanier, Annie; Jutras-Aswad, Didier","year":2020,"journal":"Psychiatry research, 286, 112890","doi":"10.1016/j.psychres.2020.112890","pmid":"32126328","tags":["cbd","psychosis","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CBD showed limited antipsychotic efficacy across studies, with no evidence supporting cognitive or functional benefits. However, CBD had a notably advantageous side effect profile compared to standard antipsychotics and was well tolerated across all studies.","whyItMatters":"Current antipsychotics often have significant side effects that reduce adherence. If CBD could serve as an adjunctive treatment with fewer side effects, it might improve tolerability even if its direct antipsychotic effects are modest.","specificNumbers":"8 eligible studies, 210 total participants. Observational studies had higher risk of bias than experimental studies.","methodology":"Systematic review searching CINAHL, EBM, EMBASE, MEDLINE, and PubMed from 1970 to 2019 for experimental and observational studies evaluating CBD's antipsychotic and cognitive properties in people with psychotic disorders.","limitations":"Small total sample across studies. Heterogeneous study designs, dosing, and participant criteria make comparison difficult. Risk of bias was higher in observational studies."},{"rthcId":"RTHC-02570","title":"Cannabinoid receptors and the proconvulsant effect of toxoplasmosis in mice.","authors":"Ghanbari, Mohammad-Mahdi; Joneidi, Marzieh; Kiani, Bahere; Babaie, Jalal; Sayyah, Mohammad","year":2020,"journal":"Microbial pathogenesis, 144, 104204","doi":"10.1016/j.micpath.2020.104204","pmid":"32315753","tags":["epilepsy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CB1 agonist ACEA, the endocannabinoid-boosting agent JZL184, and the CB2 antagonist AM630 all raised seizure thresholds in both healthy and Toxoplasma-infected mice. Conversely, CB1 antagonist AM251 and CB2 agonist HU308 lowered thresholds.","whyItMatters":"Toxoplasmosis affects roughly one-third of the global population and is a recognized risk factor for epilepsy. This study identifies the cannabinoid system as a potential therapeutic target for infection-related seizure vulnerability.","specificNumbers":"Infected mice had substantially lower seizure thresholds than uninfected mice. JZL184, ACEA, and AM630 each raised thresholds in a dose-dependent manner.","methodology":"Mice were infected with T. gondii cysts intraperitoneally. During acute and chronic infection, various cannabinoid receptor agonists and antagonists were administered intracerebroventricularly before measuring seizure threshold via pentylenetetrazole infusion.","limitations":"Animal study using direct brain injection of drugs, which does not reflect practical human drug delivery. The Toxoplasma model may not fully replicate infection-related epilepsy in humans."},{"rthcId":"RTHC-02571","title":"Safety and pharmacokinetics of medical cannabis preparation in a monocentric series of young patients with drug resistant epilepsy.","authors":"Gherzi, Marcella; Milano, Giulia; Fucile, Carmen; Calevo, Maria Grazia; Mancardi, Maria Margherita; Nobili, Lino; Astuni, Pietro; Marini, Valeria; Barco, Sebastiano; Cangemi, Giuliana; Manfredini, Luca; Mattioli, Francesca; De Grandis, Elisa","year":2020,"journal":"Complementary therapies in medicine, 51, 102402","doi":"10.1016/j.ctim.2020.102402","pmid":"32507423","tags":["medical-cannabis","epilepsy","cbd","youth"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"The cannabis preparation was generally well tolerated, with adverse events in 6 of 10 patients (mostly GI, sleep, or behavioral issues). Two patients discontinued. THC and CBD blood levels correlated with administered doses, supporting the feasibility of therapeutic drug monitoring.","whyItMatters":"This is one of the few studies examining a whole-plant cannabis preparation (rather than purified CBD) in pediatric epilepsy, providing pharmacokinetic data that could guide dosing in future studies.","specificNumbers":"10 patients enrolled. Cannabis FM2: 5.2-7.2% THC, 8.2-11.1% CBD (ratio 3:5). CBD doses: 1-4 mg/kg/day. 6/10 had adverse events. 2/10 discontinued. 64% retention at 6 months would apply if extrapolated.","methodology":"Prospective open trial enrolling 10 patients (ages 2.5-23.2) with drug-resistant epilepsy. Patients received a galenic decoction of Italian cannabis FM2 (THC:CBD ratio 3:5). CBD doses were titrated from 1 to 4 mg/kg/day. Safety and pharmacokinetics were monitored.","limitations":"Very small sample (10 patients), no control group, and open-label design. The galenic decoction preparation may vary between batches. Short follow-up."},{"rthcId":"RTHC-02572","title":"Cannabinoid use in psychotic patients impacts inflammatory levels and their association with psychosis severity.","authors":"Gibson, Claire L; Bassir Nia, Anahita; Spriggs, Sharron A; DeFrancisco, Daniel; Swift, Amy; Perkel, Charles; Zhong, Xiaobo; Mazumdar, Madhu; Fernandez, Nicolas; Patel, Manishkumar; Kim-Schulze, Seunghee; Hurd, Yasmin L","year":2020,"journal":"Psychiatry research, 293, 113380","doi":"10.1016/j.psychres.2020.113380","pmid":"32818918","tags":["psychosis","inflammation","synthetic-cannabinoids"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"While PANSS psychosis scores were similar between groups, cannabinoid-positive patients showed a negative correlation between IL-6 levels and psychosis severity, meaning higher inflammation was associated with lower symptom scores. Synthetic cannabinoid-positive patients were more likely to require emergency agitation medication.","whyItMatters":"The inverse relationship between IL-6 and psychosis severity in cannabinoid users suggests that cannabinoids may alter the typical inflammation-psychosis connection, potentially through immunomodulatory effects.","specificNumbers":"59 cannabinoid-positive vs. 60 cannabinoid-negative patients. IL-6 negatively correlated with PANSS total (p=0.040), positive (p=0.035), and negative (p=0.024) subscales in cannabinoid-positive group.","methodology":"Cross-sectional study comparing 59 acutely psychotic inpatients with positive cannabinoid toxicology (natural and/or synthetic) to 60 patients with negative cannabinoid toxicology. Inflammatory markers and PANSS scores were measured.","limitations":"Cross-sectional design cannot establish causation. The cannabinoid-positive group included both natural and synthetic users. IFN-gamma differences were not significant after adjusting for covariates."},{"rthcId":"RTHC-02573","title":"Post-Mortem Toxicology: A Systematic Review of Death Cases Involving Synthetic Cannabinoid Receptor Agonists.","authors":"Giorgetti, Arianna; Busardò, Francesco Paolo; Tittarelli, Roberta; Auwärter, Volker; Giorgetti, Raffaele","year":2020,"journal":"Frontiers in psychiatry, 11, 464","doi":"10.3389/fpsyt.2020.00464","pmid":"32523555","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"No reliable toxic or lethal concentration ranges have been established for synthetic cannabinoids. Even after comprehensive post-mortem examination, toxicology, and circumstantial analysis, the cause and manner of death remained unclear in some cases.","whyItMatters":"Synthetic cannabinoids are the largest group of new psychoactive substances in Europe, yet forensic pathologists and toxicologists still lack basic reference data for determining whether these substances caused a death.","specificNumbers":"380 studies identified, 34 included. 8 case series and 26 case reports analyzed. Toxicological results must be interpreted with caution due to the absence of established toxic ranges.","methodology":"Systematic literature search through January 2019 across multiple databases. Included death cases with toxicological confirmation of synthetic cannabinoids in blood or urine and at least an external examination. 34 manuscripts (8 case series, 26 case reports) were included.","limitations":"Limited to published case reports and series, which may not represent all deaths. Post-mortem redistribution can alter drug concentrations. Many cases involved polydrug use, complicating attribution."},{"rthcId":"RTHC-02574","title":"Adding medical cannabis to standard analgesic treatment for fibromyalgia: a prospective observational study.","authors":"Giorgi, Valeria; Bongiovanni, Sara; Atzeni, Fabiola; Marotto, Daniela; Salaffi, Fausto; Sarzi-Puttini, Piercarlo","year":2020,"journal":"Clinical and experimental rheumatology, 38 Suppl 123(1), 53-59","doi":null,"pmid":"32116208","tags":["medical-cannabis","pain","sleep"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Medical cannabis most consistently improved sleep quality (44% of patients) and overall fibromyalgia impact (33%). Half of patients showed moderate improvement in anxiety and depression. Nearly half reduced or stopped concomitant analgesic treatment. Lower BMI correlated with better outcomes.","whyItMatters":"Fibromyalgia is difficult to treat, and many patients have inadequate pain relief. The finding that medical cannabis allowed nearly half to reduce other medications suggests it may not just add benefit but could simplify treatment regimens.","specificNumbers":"102 patients enrolled. 64% retention at 6 months. 44% improved sleep (PSQI). 33% improved overall (FIQR). 50% moderate anxiety/depression improvement. 47% reduced or stopped other analgesics. BMI correlated with outcomes (p=0.017).","methodology":"Prospective observational study of 102 consecutive fibromyalgia patients with VAS pain scores of 4 or higher despite existing treatment. Patients received oil-diluted cannabis extracts (Bedrocan: 22% THC, <1% CBD; or Bediol: 6.3% THC, 8% CBD) for 6 months.","limitations":"No control group or blinding, so placebo effects cannot be ruled out. Self-selected patient population. Two different cannabis formulations were used, making it difficult to determine which is more effective."},{"rthcId":"RTHC-02575","title":"Cannabis Use and Internalizing/Externalizing Symptoms in Youth: A Canadian Population-Based Study.","authors":"Girgis, Joseph; Pringsheim, Tamara; Williams, Jeanne; Shafiq, Samreen; Patten, Scott","year":2020,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 67(1), 26-32","doi":"10.1016/j.jadohealth.2020.01.015","pmid":"32115324","tags":["youth","mental-health","anxiety","depression","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Frequent cannabis use was associated with elevated externalizing symptoms (OR 2.17 in males, 5.13 in females) and internalizing symptoms (OR 2.07 in males, 3.40 in females). These associations persisted after adjusting for binge drinking, smoking, and parenting factors.","whyItMatters":"The markedly stronger associations in females suggest that girls who use cannabis frequently may be particularly vulnerable to mental health effects, which has implications for targeted prevention.","specificNumbers":"Externalizing: OR 2.17 (1.80-2.62) males, 5.13 (4.24-6.21) females. Internalizing: OR 2.07 (1.74-2.47) males, 3.40 (2.73-4.24) females. Associations persisted after adjusting for confounders.","methodology":"Cross-sectional analysis of the 2014 Ontario Child Health Study using the Emotional and Behavioural Scales. Logistic regression estimated associations between cannabis use frequency and elevated symptoms, with replicate bootstrap weighting for design effects.","limitations":"Cross-sectional design cannot determine whether cannabis use preceded or followed the development of symptoms. Self-reported cannabis use may be underreported. The study cannot distinguish between different cannabis products or potencies."},{"rthcId":"RTHC-02576","title":"Epigenetics and the endocannabinoid system signaling: An intricate interplay modulating neurodevelopment.","authors":"Gomes, Telma Marisa; Dias da Silva, Diana; Carmo, Helena; Carvalho, Félix; Silva, João Pedro","year":2020,"journal":"Pharmacological research, 162, 105237","doi":"10.1016/j.phrs.2020.105237","pmid":"33053442","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02577","title":"Psychotic disorders hospitalizations associated with cannabis abuse or dependence: A nationwide big data analysis.","authors":"Gonçalves-Pinho, Manuel; Bragança, Miguel; Freitas, Alberto","year":2020,"journal":"International journal of methods in psychiatric research, 29(1), e1813","doi":"10.1002/mpr.1813","pmid":"31808250","tags":["psychosis","addiction","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-related psychotic disorder hospitalizations rose 29.4 times over 15 years. Among all psychosis hospitalizations, those with a cannabis diagnosis increased from 0.87% in 2000 to 10.60% in 2015. Patients were predominantly male (89.8%) with a mean age of about 31 years.","whyItMatters":"The dramatic increase occurred during a period of changing cannabis consumption patterns in Portugal, including higher potency products and more frequent use, suggesting a dose-response relationship at the population level.","specificNumbers":"Hospitalizations rose from 20 (2000) to 588 (2015). Total: 3,233 hospitalizations. Average cost: about 3,500 euros per episode. 89.8% male. Mean age: 30.66 years. Cannabis coding rose from 0.87% to 10.60% of all psychosis hospitalizations.","methodology":"Retrospective observational study analyzing all hospitalizations in Portuguese public hospitals from 2000 to 2015. Cases were identified by primary diagnosis of psychotic disorder/schizophrenia with secondary diagnosis of cannabis dependence or abuse (ICD-9 codes).","limitations":"Administrative data relies on coding accuracy, and increased awareness of cannabis-psychosis links may have led to more frequent secondary diagnosis coding over time. The study cannot establish causation between cannabis use and psychosis."},{"rthcId":"RTHC-02578","title":"Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant.","authors":"Gonçalves, Elaine C D; Baldasso, Gabriela M; Bicca, Maíra A; Paes, Rodrigo S; Capasso, Raffaele; Dutra, Rafael C","year":2020,"journal":"Molecules (Basel, Switzerland), 25(7)","doi":"10.3390/molecules25071567","pmid":"32235333","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02579","title":"Cannabis and Cannabinoids in the Treatment of Rheumatic Diseases.","authors":"Gonen, Tal; Amital, Howard","year":2020,"journal":"Rambam Maimonides medical journal, 11(1)","doi":"10.5041/RMMJ.10389","pmid":"32017684","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02580","title":"Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease.","authors":"Gotfried, Jonathan; Naftali, Timna; Schey, Ron","year":2020,"journal":"Gastroenterology, 159(1), 62-80","doi":"10.1053/j.gastro.2020.03.087","pmid":"32333910","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02581","title":"Safety Considerations in Cannabinoid-Based Medicine.","authors":"Gottschling, Sven; Ayonrinde, Oyedeji; Bhaskar, Arun; Blockman, Marc; D'Agnone, Oscar; Schecter, Danial; Suárez Rodríguez, Luis David; Yafai, Sherry; Cyr, Claude","year":2020,"journal":"International journal of general medicine, 13, 1317-1333","doi":"10.2147/IJGM.S275049","pmid":"33299341","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02582","title":"Update on the developmental consequences of cannabis use during pregnancy and lactation.","authors":"Grant, Kimberly S; Conover, Elizabeth; Chambers, Christina D","year":2020,"journal":"Birth defects research, 112(15), 1126-1138","doi":"10.1002/bdr2.1766","pmid":"32770666","tags":["pregnancy","youth","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Prenatal cannabis exposure was not associated with a unique pattern of birth defects or reductions in global IQ, but specific cognitive skills (attention and memory) were negatively affected. Long-term impacts included increased depressive symptoms, anxiety, and delinquency. Infant exposure through breast milk appeared relatively low.","whyItMatters":"Cannabis use during pregnancy is increasing as legalization spreads and perceived risk decreases. The evidence of specific cognitive and psychological effects, rather than gross birth defects, highlights subtle risks that may not be immediately apparent.","specificNumbers":"THC levels in cannabis products are increasing. Specific cognitive domains affected: attention and memory. Psychological outcomes: increased depression, anxiety, and delinquency. Infant exposure via breast milk described as relatively low compared to maternal exposure.","methodology":"Narrative review summarizing epidemiological studies on cannabis use during pregnancy and lactation, including data on congenital anomalies, fetal growth, cognitive development, and psychological outcomes.","limitations":"Most existing studies have limited ability to quantify actual THC exposure. Confounders (tobacco, alcohol, socioeconomic factors) are difficult to fully control. The review notes that weaknesses in past research make definitive conclusions challenging."},{"rthcId":"RTHC-02583","title":"International differences in patterns of cannabis use among adult cigarette smokers: Findings from the 2018 ITC Four Country Smoking and Vaping Survey.","authors":"Gravely, Shannon; Driezen, Pete; Smith, Danielle M; Borland, Ron; Lindblom, Eric N; Hammond, David; McNeill, Ann; Hyland, Andrew; Cummings, K Michael; Chan, Gary; Thompson, Mary E; Boudreau, Christian; Martin, Nadia; Ouimet, Janine; Loewen, Ruth; Quah, Anne C K; Goniewicz, Maciej L; Thrasher, James F; Fong, Geoffrey T","year":2020,"journal":"The International journal on drug policy, 79, 102754","doi":"10.1016/j.drugpo.2020.102754","pmid":"32305827","tags":["addiction","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Countries with more permissive cannabis regulations (Canada, US) had higher co-use rates and daily cannabis use among co-users. Co-users in England (90%) and Australia (86%) were far more likely to mix tobacco with cannabis than those in Canada (39%) or the US (22%).","whyItMatters":"The dramatic differences in co-use patterns between countries suggest that cannabis regulation shapes not just use rates but also how cannabis is consumed, with implications for both cannabis and tobacco policy.","specificNumbers":"Co-use rates: Canada 36.3%, US 29.1%, England 21.6%, Australia 21.4%. Daily cannabis use among co-users: US 40.2%, Canada 35.2%, England 26.3%, Australia 21.7%. Tobacco-cannabis mixing: England 90.4%, Australia 86.0%, Canada 38.5%, US 22.3%.","methodology":"Cross-sectional data from the 2018 International Tobacco Control 4-Country Vaping Survey. 10,035 adult cigarette smokers from Canada, US, Australia, and England were surveyed about cannabis use patterns and perceptions.","limitations":"Cross-sectional design at one time point. Only cigarette smokers were included, not the general population. Self-reported data. Different cultural and regulatory contexts make direct comparisons complex."},{"rthcId":"RTHC-02584","title":"Anticonvulsive Properties of Cannabidiol in a Model of Generalized Seizure Are Transient Receptor Potential Vanilloid 1 Dependent.","authors":"Gray, Royston A; Stott, Colin G; Jones, Nicholas A; Di Marzo, Vincenzo; Whalley, Benjamin J","year":2020,"journal":"Cannabis and cannabinoid research, 5(2), 145-149","doi":"10.1089/can.2019.0028","pmid":"32656346","tags":["cbd","epilepsy","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD at 50 and 100 mg/kg significantly raised seizure thresholds in wildtype mice but not in TRPV1 knockout mice. At the highest dose, CBD showed partial efficacy even in knockouts, suggesting TRPV1 is a primary but not sole mechanism.","whyItMatters":"Understanding how CBD prevents seizures is critical for optimizing its clinical use. This study identifies TRPV1 as a key mechanism, which could guide the development of more targeted anti-seizure treatments.","specificNumbers":"CBD tested at 50 and 100 mg/kg. Both doses raised threshold significantly in wildtype mice. Neither dose raised threshold in TRPV1 knockout mice, except partial effect at the highest dose.","methodology":"Maximal electroshock threshold model comparing CBD effects in TRPV1 knockout and wildtype mice. CBD and the positive control diazepam were administered at multiple doses, with seizure threshold measured by electroshock.","limitations":"Single seizure model (maximal electroshock threshold) may not represent all seizure types. Knockout mice develop compensatory mechanisms that could confound interpretation. The partial effect at high doses suggests other targets also contribute."},{"rthcId":"RTHC-02585","title":"The proposed mechanisms of action of CBD in epilepsy.","authors":"Gray, Royston A; Whalley, Benjamin J","year":2020,"journal":"Epileptic disorders : international epilepsy journal with videotape, 22(S1), 10-15","doi":"10.1684/epd.2020.1135","pmid":"32053110","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02586","title":"Sex and Gender Interactions on the Use and Impact of Recreational Cannabis.","authors":"Greaves, Lorraine; Hemsing, Natalie","year":2020,"journal":"International journal of environmental research and public health, 17(2)","doi":"10.3390/ijerph17020509","pmid":"31947505","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02587","title":"A Review of Cannabis and Interactions With Anticoagulant and Antiplatelet Agents.","authors":"Greger, Jessica; Bates, Vernice; Mechtler, Laszlo; Gengo, Fran","year":2020,"journal":"Journal of clinical pharmacology, 60(4), 432-438","doi":"10.1002/jcph.1557","pmid":"31724188","tags":["drug-interactions","medical-cannabis","cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis components can inhibit liver enzymes (CYP2C9, CYP2C19) and transporters involved in metabolizing blood thinners. Case reports showed cannabis inhibited warfarin metabolism, increasing INR and bleeding risk. CBD may reduce conversion of clopidogrel to its active form, potentially increasing stroke risk.","whyItMatters":"Patients using blood thinners for cardiac conditions, stroke prevention, or post-stent management are at high risk from drug interactions. With increasing medical and recreational cannabis use, clinicians need to be aware of these potential interactions.","specificNumbers":"665 articles screened, 6 relevant publications identified. THC inhibits CYP2C9 (warfarin metabolism). CBD inhibits CYP2C19 (clopidogrel activation). Case reports documented increased INR with cannabis-warfarin co-use.","methodology":"Review screening 665 articles from PubMed and EMBASE. Six relevant publications were identified: 4 case reports, 1 in vitro study, and 1 pharmacokinetic article.","limitations":"Very limited direct evidence (only 6 relevant publications). Most data comes from case reports and in vitro studies. Clinical significance of these interactions in real-world dosing is not well established."},{"rthcId":"RTHC-02588","title":"Exploring the Use of State Medical Cannabis Legislation as a Proxy for Medical Cannabis Use Among Patients Receiving Chemotherapy.","authors":"Gressler, Laura E; Baltz, Alan P; Costantino, Ryan C; Slejko, Julia F; Onukwugha, Eberechukwu","year":2020,"journal":"Current treatment options in oncology, 22(1), 1","doi":"10.1007/s11864-020-00803-2","pmid":"33215230","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02589","title":"Marijuana Use and Potential Implications of Marijuana Legalization.","authors":"Grigsby, Tamara M; Hoffmann, Laurel M; Moss, Michael J","year":2020,"journal":"Pediatrics in review, 41(2), 61-72","doi":"10.1542/pir.2018-0347","pmid":"32005683","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02590","title":"Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial.","authors":"Grimison, P; Mersiades, A; Kirby, A; Lintzeris, N; Morton, R; Haber, P; Olver, I; Walsh, A; McGregor, I; Cheung, Y; Tognela, A; Hahn, C; Briscoe, K; Aghmesheh, M; Fox, P; Abdi, E; Clarke, S; Della-Fiorentina, S; Shannon, J; Gedye, C; Begbie, S; Simes, J; Stockler, M","year":2020,"journal":"Annals of oncology : official journal of the European Society for Medical Oncology, 31(11), 1553-1560","doi":"10.1016/j.annonc.2020.07.020","pmid":"32801017","tags":["medical-cannabis","cbd","cancer"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Complete response improved from 14% with placebo to 25% with THC:CBD (RR 1.77, p=0.041). Similar improvements were seen for absence of emesis, use of rescue medications, and quality-of-life scores. However, 31% experienced moderate or severe cannabinoid-related side effects like sedation and dizziness.","whyItMatters":"This is one of the first rigorous trials of standardized oral THC:CBD for refractory chemotherapy nausea, a significant unmet need since many patients fail standard antiemetics.","specificNumbers":"81 randomized, 72 completed efficacy analysis. Complete response: 25% THC:CBD vs 14% placebo (RR 1.77, 90% CI 1.12-2.79). 31% had moderate-severe cannabinoid side effects. 83% preferred cannabis. Median age 55, 78% female.","methodology":"Phase II, multicentre, double-blind, placebo-controlled crossover trial. Patients who experienced CINV despite guideline-consistent antiemetics received self-titrated THC 2.5mg/CBD 2.5mg capsules (1-4 capsules, three times daily, days -1 to 5) or matching placebo across two chemotherapy cycles.","limitations":"Small phase II sample. Self-titrated dosing introduces variability. The 31% rate of moderate-severe side effects (sedation, dizziness, disorientation) is significant and may limit practical use."},{"rthcId":"RTHC-02591","title":"Contribution of Dopamine Transporter Gene Methylation Status to Cannabis Dependency.","authors":"Grzywacz, Anna; Barczak, Wojciech; Chmielowiec, Jolanta; Chmielowiec, Krzysztof; Suchanecka, Aleksandra; Trybek, Grzegorz; Masiak, Jolanta; Jagielski, Paweł; Grocholewicz, Katarzyna; Rubiś, Blazej","year":2020,"journal":"Brain sciences, 10(6)","doi":"10.3390/brainsci10060400","pmid":"32586035","tags":["genetics","addiction","dopamine"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"No overall difference in DAT1 gene promoter methylation was found between groups. However, individual CpG sites showed significant methylation differences, particularly at sites bound by transcription factors involved in nervous system development (SP1, p53, PAX5, GR).","whyItMatters":"The dopamine transporter is central to reward and addiction. Finding that specific methylation sites differ in cannabis-dependent individuals could help explain why some people are more vulnerable to cannabis dependence.","specificNumbers":"201 cannabis-dependent patients, 285 matched controls. Significant differences at individual CpG sites bound by SP1, p53, PAX5, and GR transcription factors.","methodology":"Case-control study comparing DNA methylation patterns in the DAT1 gene promoter between 201 cannabis-dependent patients and 285 age- and sex-matched healthy controls. DNA was extracted from peripheral blood, bisulfite-converted, and sequenced.","limitations":"Cross-sectional design cannot determine whether methylation differences preceded or resulted from cannabis dependence. Blood cell methylation may not perfectly reflect brain methylation. The clinical significance of the specific CpG site differences is unknown."},{"rthcId":"RTHC-02592","title":"Relationship between cannabis use frequency and major depressive disorder in adolescents: Findings from the National Survey on Drug Use and Health 2012-2017.","authors":"Gukasyan, Natalie; Strain, Eric C","year":2020,"journal":"Drug and alcohol dependence, 208, 107867","doi":"10.1016/j.drugalcdep.2020.107867","pmid":"31958677","tags":["youth","depression","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Adolescents with any cannabis use history had significantly higher rates of major depressive disorder and past-year suicide attempts. However, the association between use frequency and depression was counter to expectations: past-year users did not consistently show worse depression than those who used over a year ago.","whyItMatters":"The non-linear relationship between cannabis use frequency and depression challenges simple dose-response assumptions and suggests the cannabis-depression relationship is more complex than \"more use equals more depression.\"","specificNumbers":"14,873 cannabis users vs 73,079 never-users. Cannabis users had significantly higher rates of lifetime MDD, past-year MDD, MDD with severe impairment, and past-year suicide attempts (all p values significant).","methodology":"Analysis of the National Survey on Drug Use and Health (2012-2017). 14,873 adolescents with cannabis use history were compared to 73,079 never-users using weighted logistic regression controlling for demographics and other substance use.","limitations":"Cross-sectional design cannot establish whether cannabis use preceded depression or vice versa. Self-reported data in adolescents may be unreliable. The frequency-depression pattern requires replication and further investigation."},{"rthcId":"RTHC-02593","title":"Investigation of DNA damage, oxidative stress, and inflammation in synthetic cannabinoid users.","authors":"Guler, E M; Bektay, M Y; Akyildiz, A G; Sisman, B H; Izzettin, F V; Kocyigit, A","year":2020,"journal":"Human & experimental toxicology, 39(11), 1454-1462","doi":"10.1177/0960327120930057","pmid":"32508150","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoid users had significantly higher DNA damage, plasma oxidant status, myeloperoxidase activity, and inflammatory markers (IL-1-beta, IL-6, TNF-alpha). Antioxidant capacity (TAS) and thiol levels were significantly lower, indicating depleted antioxidant defenses.","whyItMatters":"While synthetic cannabinoid toxicity has been documented through case reports, this study provides systematic biomarker evidence that regular use causes measurable oxidative stress, DNA damage, and chronic inflammation.","specificNumbers":"40 synthetic cannabinoid users studied. Significantly higher: DNA damage, TOS, MPO, disulfide, IL-1-beta, IL-6, TNF-alpha. Significantly lower: TAS, total thiol, native thiol.","methodology":"Case-control study comparing 40 synthetic cannabinoid users to healthy controls in Turkey. Measurements included comet assay for DNA damage, total oxidant/antioxidant status, thiol-disulfide balance, myeloperoxidase activity, and cytokine levels from blood samples.","limitations":"Small sample size (40 users). Cross-sectional design cannot determine whether biomarker changes are reversible after cessation. The specific synthetic cannabinoids used were not identified. Lifestyle confounders may not be fully controlled."},{"rthcId":"RTHC-02594","title":"Predicting factors for non-suicidal self-injury in patients with schizophrenia spectrum disorders and the role of substance use.","authors":"Güney, Erengül; Alnıak, İzgi; Erkıran, Murat","year":2020,"journal":"Asian journal of psychiatry, 52, 102068","doi":"10.1016/j.ajp.2020.102068","pmid":"32371364","tags":["psychosis","addiction","mental-health","synthetic-cannabinoids"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Substance use disorder increased NSSI risk approximately 4-fold. The NSSI prevalence was 43.6%, with self-cutting as the most common method and affect regulation as the primary motivation. Cannabis and synthetic cannabinoids were the most commonly abused substances among patients with NSSI.","whyItMatters":"The finding that substance use, particularly cannabis and synthetic cannabinoids, is a modifiable risk factor for self-harm in schizophrenia patients has direct clinical implications for prevention and treatment.","specificNumbers":"165 patients. NSSI prevalence: 43.6%. Lifetime SUD rate: 38.2% overall, 55.6% in NSSI group. SUD associated with ~4-fold increase in NSSI risk. Most common substances in NSSI group: cannabis and synthetic cannabinoids.","methodology":"Cross-sectional study of 165 patients with schizophrenia spectrum disorders in remission. NSSI was assessed using the Inventory of Statements About Self-injury (ISAS). Lifetime substance use disorders were evaluated. Logistic regression identified predictors.","limitations":"Cross-sectional design cannot establish causation. The sample was limited to patients in remission, which may not represent those with active psychosis. The role of specific substances (cannabis vs. synthetic cannabinoids) was not disaggregated."},{"rthcId":"RTHC-02595","title":"Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors.","authors":"Haider, Achi; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M","year":2020,"journal":"Journal of medicinal chemistry, 63(18), 10287-10306","doi":"10.1021/acs.jmedchem.0c00778","pmid":"32787079","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02596","title":"The costs and benefits of cannabis control policies
.","authors":"Hall, Wayne","year":2020,"journal":"Dialogues in clinical neuroscience, 22(3), 281-287","doi":"10.31887/DCNS.2020.22.3/whall","pmid":"33162771","tags":["legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis policy entails unavoidable trade-offs: prohibition reduces use but creates criminal justice harms; depenalization reduces enforcement costs with minimal impact on use rates; medical legalization may increase adult use; and recreational legalization paired with commercialization is likely to increase use based on patterns from alcohol, tobacco, and gambling industries.","whyItMatters":"As more jurisdictions consider cannabis policy reform, understanding the evidence-based trade-offs of each approach helps policy makers make informed decisions rather than relying on ideology alone.","specificNumbers":"The review draws on experience from multiple jurisdictions with various policy approaches, comparing outcomes on use rates, criminal justice involvement, public health indicators, and economic effects.","methodology":"Narrative review examining evidence on the impacts of three forms of cannabis policy liberalization (depenalization, medical legalization, recreational legalization) using data from jurisdictions that have implemented each approach.","limitations":"Many cannabis policy changes are recent, making long-term outcome data scarce. Different jurisdictions implemented different regulatory details, making direct comparisons difficult. The review necessarily involves some speculation about future impacts."},{"rthcId":"RTHC-02597","title":"Cannabis Use as a Risk Factor for Depression, Anxiety, and Suicidality: Epidemiological Associations and Implications for Nurses.","authors":"Halladay, Jillian E; MacKillop, James; Munn, Catharine; Jack, Susan M; Georgiades, Katholiki","year":2020,"journal":"Journal of addictions nursing, 31(2), 92-101","doi":"10.1097/JAN.0000000000000334","pmid":"32487935","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02598","title":"Temporal Changes in the Cross-Sectional Associations between Cannabis Use, Suicidal Ideation, and Depression in a Nationally Representative Sample of Canadian Adults in 2012 Compared to 2002.","authors":"Halladay, Jillian E; Munn, Catharine; Boyle, Michael; Jack, Susan M; Georgiades, Katholiki","year":2020,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 65(2), 115-123","doi":"10.1177/0706743719854071","pmid":"31177831","tags":["depression","mental-health","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Monthly cannabis use was consistently associated with both suicidal ideation and major depressive episodes across both time points. Critically, these associations strengthened over the decade, with 2012 monthly users having significantly higher odds of both outcomes compared to 2002 monthly users.","whyItMatters":"The strengthening association over time could reflect changes in cannabis potency, use patterns, or population composition, and provides a pre-legalization baseline for monitoring mental health effects after Canada's 2018 recreational legalization.","specificNumbers":"43,466 Canadians surveyed. 2012 vs 2002 monthly users: suicidal ideation OR 1.59 (95% CI 1.11-2.27), MDE OR 1.55 (95% CI 1.12-2.13). Associations persisted after controlling for other substance use.","methodology":"Pooled cross-sectional analysis of the 2002 and 2012 Canadian Community Health Surveys (Mental Health Component). Binary logistic regression with weighting and bootstrapping examined 43,466 Canadians aged 15-60.","limitations":"Cross-sectional data at two time points cannot establish causation or track individuals over time. Changes in cannabis potency and use patterns between 2002 and 2012 may confound the temporal comparison. Self-reported cannabis use may be underreported."},{"rthcId":"RTHC-02599","title":"Cannabis use among U.S. adolescents in the era of marijuana legalization: a review of changing use patterns, comorbidity, and health correlates.","authors":"Hammond, Christopher J; Chaney, Aldorian; Hendrickson, Brian; Sharma, Pravesh","year":2020,"journal":"International review of psychiatry (Abingdon, England), 32(3), 221-234","doi":"10.1080/09540261.2020.1713056","pmid":"32026735","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02600","title":"Cannabis Use in Persons With Inflammatory Bowel Disease and Vulnerability to Substance Misuse.","authors":"Hansen, Tawnya M; Sabourin, Brigitte C; Oketola, Banke; Bernstein, Charles N; Singh, Harminder; Targownik, Laura E","year":2020,"journal":"Inflammatory bowel diseases, 26(9), 1401-1406","doi":"10.1093/ibd/izz272","pmid":"31725152","tags":["medical-cannabis","inflammation","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"IBD patients self-medicating with cannabis were more likely to use cannabis for coping (p=0.016), demonstrated higher impulsivity (p=0.004), and had more depressive symptoms (p=0.012) compared to recreational users. Smokers, those with moderate-severe depression, and those high in impulsivity were each about 4 times more likely to use cannabis for IBD symptoms.","whyItMatters":"As medical cannabis is increasingly considered for IBD, this study highlights that patients self-selecting cannabis treatment may have characteristics that increase their vulnerability to substance misuse.","specificNumbers":"201 IBD patients, 108 with lifetime cannabis use. Crohn's patients more likely to use for symptoms (53%) vs UC (28%). Self-medicators: 4.1x more likely to smoke tobacco, 3.7x more likely to have moderate-severe depression, 4.1x more likely to be high in impulsivity.","methodology":"Cross-sectional survey of 201 IBD patients examining cannabis use patterns, mental health symptoms, and personality risk factors for substance misuse. Compared individuals using cannabis for IBD management versus recreational use.","limitations":"Cross-sectional design cannot determine if cannabis use caused or resulted from the observed mental health patterns. Self-report measures may not capture full picture. The sample may not represent all IBD patients."},{"rthcId":"RTHC-02601","title":"Relative Reduction in Prevalence (RRP): An Alternative to Cohen's Effect Size Statistics for Judging Alcohol, Cigarette, and Marijuana Use Prevention Outcomes.","authors":"Hansen, William B","year":2020,"journal":"The journal of primary prevention, 41(5), 473-486","doi":"10.1007/s10935-020-00608-x","pmid":"32857221","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02602","title":"Cannabis use and psychosis: a review of reviews.","authors":"Hasan, Alkomiet; von Keller, Rupert; Friemel, Chris Maria; Hall, Wayne; Schneider, Miriam; Koethe, Dagmar; Leweke, F Markus; Strube, Wolfgang; Hoch, Eva","year":2020,"journal":"European archives of psychiatry and clinical neuroscience, 270(4), 403-412","doi":"10.1007/s00406-019-01068-z","pmid":"31563981","tags":["psychosis","addiction","mental-health"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Across 26 reviews, the evidence consistently showed: psychosis occurs more frequently in cannabis users than non-users; risk increases with dose; cannabis users develop psychosis earlier; and cannabis use is associated with increased relapse, more hospitalizations, and more pronounced positive symptoms in those with psychotic disorders.","whyItMatters":"As an umbrella review (review of reviews), this represents the highest level of evidence synthesis available, providing a comprehensive summary of the cannabis-psychosis relationship across the entire published literature.","specificNumbers":"26 systematic reviews and meta-analyses included. Dose-dependent risk for psychotic illness. Earlier onset in cannabis users. Higher relapse rates and more hospitalizations in psychotic patients who use cannabis.","methodology":"Systematic review of meta-analyses and systematic reviews from five databases (2005-2016). 26 publications were included and evaluated for methodological quality, which ranged from high to poor.","limitations":"Methodological quality varied across included reviews. The umbrella review inherits the limitations of the underlying studies, which are predominantly observational. Publication bias may favor studies finding positive associations."},{"rthcId":"RTHC-02603","title":"The expression level of cannabinoid receptors type 1 and 2 in the different types of astrocytomas.","authors":"Hashemi, Mansoureh; Bashi, Senada; Zali, Alireza","year":2020,"journal":"Molecular biology reports, 47(7), 5461-5467","doi":"10.1007/s11033-020-05636-8","pmid":"32623617","tags":["cancer","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"CB1 receptor expression was increased in tumor tissue across grades. CB2 receptor expression in blood vessels was significantly higher in grade III (anaplastic astrocytoma) and grade IV (glioblastoma) compared to grade II and control tissue, suggesting CB2 levels correlate with malignancy.","whyItMatters":"If cannabinoid receptor expression increases with tumor aggressiveness, these receptors could serve as both diagnostic markers for tumor grade and potential therapeutic targets for cannabinoid-based treatments.","specificNumbers":"45 patient tissue samples. CB2 was significantly higher in grade III-IV vs grade II blood vessels. CB1 was increased in tumor tissue overall. Three complementary methods confirmed findings.","methodology":"Brain tumor tissue from 45 patients was analyzed using immunofluorescence, quantitative RT-PCR, and western blotting to measure CB1 and CB2 receptor expression in tumor tissue and blood vessels across astrocytoma grades.","limitations":"Relatively small sample from a single center. The study measured expression levels but did not test whether targeting these receptors affects tumor growth. Correlation between receptor expression and tumor grade does not prove a functional role."},{"rthcId":"RTHC-02604","title":"Fluorinated CRA13 analogues: Synthesis, in vitro evaluation, radiosynthesis, in silico and in vivo PET study.","authors":"Hassan, Ahmed H E; Park, Kyung Tae; Kim, Hye Jin; Lee, Hyo Jong; Kwon, Yeong Ho; Hwang, Ji Young; Jang, Choon-Gon; Chung, Jin Hwa; Park, Ki Duk; Lee, Sang Joo; Oh, Seung Jun; Lee, Yong Sup","year":2020,"journal":"Bioorganic chemistry, 99, 103834","doi":"10.1016/j.bioorg.2020.103834","pmid":"32334193","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02605","title":"The impact of legalization of access to recreational Cannabis on Canadian medical users with Cancer.","authors":"Hawley, Philippa; Gobbo, Monica; Afghari, Narsis","year":2020,"journal":"BMC health services research, 20(1), 977","doi":"10.1186/s12913-020-05756-8","pmid":"33109169","tags":["medical-cannabis","cancer","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use prevalence increased 26% after legalization (23.1% to 29.1%, p=0.01). Recreational motive disclosure increased from 32% to 40%. However, access problems doubled (8% to 18%, p<0.01), mainly due to unavailability of preferred products (especially edibles) through legal channels.","whyItMatters":"The paradox that legalization both increased use and worsened access highlights the gap between patient needs and regulatory implementation, particularly around product types like edibles that were not initially available through legal channels.","specificNumbers":"Use increased: 23.1% to 29.1% (p=0.01). Recreational motive: 32% to 40%. Access problems: 8% to 18% (p<0.01). Most did not use the legal medical access system. Median age 66, 53% female.","methodology":"Two identical anonymous cross-sectional surveys of cancer patients in British Columbia, administered 2 months before and 3 months after recreational legalization. Same eligibility criteria for both cohorts.","limitations":"Low overall response rate (27%). Pre-post comparison without individual tracking. Short timeframe after legalization (3 months). British Columbia may not represent all Canadian provinces."},{"rthcId":"RTHC-02606","title":"Characteristics of Dispensary Patients that Limit Alcohol after Initiating Cannabis.","authors":"Hayat, Assad; Piper, Brian J","year":2020,"journal":"Journal of psychoactive drugs, 52(2), 145-152","doi":"10.1080/02791072.2019.1694199","pmid":"31813342","tags":["medical-cannabis","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Alcohol abaters and non-abaters did not differ in age, sex, or prior drug history. However, abaters were more likely to have anxiety (59.6% vs 40.6%), PTSD, and sleep disorders. They also used higher cannabis doses and were more likely to use cannabis for sleep.","whyItMatters":"If certain patient profiles are more likely to reduce alcohol after starting medical cannabis, this could help identify patients for whom cannabis might serve as a harm reduction tool for alcohol misuse.","specificNumbers":"47 abaters, 65 non-abaters. Abaters: 59.6% anxiety vs 40.6% non-abaters. Abaters used higher cannabis doses and more frequently used cannabis for sleep.","methodology":"Exploratory cross-sectional study comparing 47 medical cannabis patients who reduced alcohol use (abaters) to 65 who did not (non-abaters) at dispensaries. Demographics, dosing, and health conditions were compared.","limitations":"Small, self-selected sample from dispensaries. Self-reported alcohol reduction without objective verification. Cross-sectional design cannot confirm that cannabis caused the alcohol reduction. No control for overall alcohol use levels."},{"rthcId":"RTHC-02607","title":"Cannabinoid and Terpenoid Doses are Associated with Adult ADHD Status of Medical Cannabis Patients.","authors":"Hergenrather, Jeffrey Y; Aviram, Joshua; Vysotski, Yelena; Campisi-Pinto, Salvatore; Lewitus, Gil M; Meiri, David","year":2020,"journal":"Rambam Maimonides medical journal, 11(1)","doi":"10.5041/RMMJ.10384","pmid":"32017685","tags":["medical-cannabis","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Higher cannabis dose consumers and those with lower ADHD symptom scores more frequently reported stopping all ADHD medications. An association was found between lower ADHD symptoms and higher CBN doses, but not with THC doses. Lower ADHD scores also correlated with lower anxiety.","whyItMatters":"CBN is a minor cannabinoid that has received little research attention. The association with lower ADHD scores, independent of THC, suggests that specific cannabis components beyond THC and CBD may have therapeutic relevance.","specificNumbers":"59 patients surveyed, chemovar data available for 27. High-dose group: 40-70 g/month. Low-dose group: 20-30 g/month. Lower ADHD scores associated with higher CBN doses. THC dose was not associated with ADHD scores.","methodology":"Cross-sectional questionnaire study of 59 adult medical cannabis patients with physician-diagnosed ADHD. Cannabis chemovar data (cannabinoid and terpene content) could be calculated for 27 patients. Patients were stratified by monthly dose and ADHD symptom severity.","limitations":"Very small sample, especially for chemovar analysis (n=27). Cross-sectional design cannot determine if cannabis improved ADHD or if patients with milder ADHD chose higher doses. Self-reported ADHD diagnosis and outcomes."},{"rthcId":"RTHC-02608","title":"A Web-Based Program for Cannabis Use and Psychotic Experiences in Young People (Keep It Real): Protocol for a Randomized Controlled Trial.","authors":"Hides, Leanne; Baker, Amanda; Norberg, Melissa; Copeland, Jan; Quinn, Catherine; Walter, Zoe; Leung, Janni; Stoyanov, Stoyan R; Kavanagh, David","year":2020,"journal":"JMIR research protocols, 9(7), e15803","doi":"10.2196/15803","pmid":"32723727","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02609","title":"Cannabis use for symptom relief in multiple sclerosis: A cross-sectional survey of webinar attendees in the US and Canada.","authors":"Hildebrand, Andrea; Minnier, Jessica; Cameron, Michelle H","year":2020,"journal":"Multiple sclerosis and related disorders, 38, 101516","doi":"10.1016/j.msard.2019.101516","pmid":"31855842","tags":["medical-cannabis","pain","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use for MS symptoms was significantly associated with recreational legality (OR 4.55), disease severity (severe vs. mild: OR 3.41), male gender (OR 2.33), and years since legalization (OR 1.06 per year). Users were 2.5 times more likely to know their local cannabis laws.","whyItMatters":"The strong relationship between legal status and use suggests that cannabis laws directly influence medical cannabis uptake among MS patients, with implications for care as more jurisdictions legalize.","specificNumbers":"548 respondents analyzed. Recreational vs. not legal: OR 4.55 (95% CI 1.70-12.14). Severe vs. mild disability: OR 3.41 (95% CI 1.23-9.46). Male vs. female: OR 2.33 (95% CI 1.10-4.94). Per year since legalization: OR 1.06.","methodology":"Cross-sectional survey of 1,015 MS patients who attended an informational webinar on cannabis; 548 answered the key use question. Logistic regression analyzed associations with demographics, disease severity, and local cannabis legal status.","limitations":"Self-selected webinar attendees may be more interested in cannabis than typical MS patients. Only 54% answered the key question. Cross-sectional design cannot show causation."},{"rthcId":"RTHC-02610","title":"Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis.","authors":"Hindley, Guy; Beck, Katherine; Borgan, Faith; Ginestet, Cedric E; McCutcheon, Robert; Kleinloog, Daniel; Ganesh, Suhas; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril; Howes, Oliver D","year":2020,"journal":"The lancet. Psychiatry, 7(4), 344-353","doi":"10.1016/S2215-0366(20)30074-2","pmid":"32197092","tags":["psychosis","cbd","mental-health","neuroscience"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"THC produced large effect sizes for total symptoms (SMC 1.10), positive/psychotic symptoms (SMC 0.91), and negative symptoms (SMC 0.78) compared to placebo. Of four studies examining CBD's ability to moderate THC effects, only one found a significant reduction.","whyItMatters":"This is the most comprehensive meta-analysis of controlled THC administration studies, providing definitive effect size estimates for THC-induced psychiatric symptoms and finding no consistent evidence that CBD protects against these effects.","specificNumbers":"Total symptoms: SMC 1.10 (95% CI 0.92-1.28, p<0.0001) in 196 participants. Positive symptoms: SMC 0.91 (95% CI 0.68-1.14, p<0.0001) in 324 participants. Negative symptoms: SMC 0.78 (95% CI 0.59-0.97, p<0.0001) in 267 participants.","methodology":"Systematic review and meta-analysis of within-person crossover studies administering THC (IV, oral, or nasal) and placebo to healthy participants, with psychiatric symptoms measured by BPRS or PANSS. 15 THC studies and 4 CBD+THC studies were included.","limitations":"Most studies used intravenous THC, which does not replicate typical cannabis use. Participants were healthy volunteers, not people at high risk for psychosis. Studies of CBD moderation were few (only 4) and heterogeneous."},{"rthcId":"RTHC-02611","title":"The Effectiveness of Cannabinoids in the Treatment of Posttraumatic Stress Disorder (PTSD): A Systematic Review.","authors":"Hindocha, C; Cousijn, J; Rall, M; Bloomfield, M A P","year":2020,"journal":"Journal of dual diagnosis, 16(1), 120-139","doi":"10.1080/15504263.2019.1652380","pmid":"31479625","tags":["ptsd","medical-cannabis","sleep"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Every study had medium to high risk of bias and was of low quality. Within these limitations, cannabinoids appeared to decrease global PTSD symptoms, with the most consistent benefits for sleep disturbances and nightmares.","whyItMatters":"PTSD is a debilitating condition with limited treatment options, and many patients are already self-medicating with cannabis. This review quantifies how little rigorous evidence exists to guide this practice.","specificNumbers":"10 studies included. Only 1 was a randomized controlled trial. All had medium to high risk of bias. Sleep and nightmare improvements were the most consistent findings.","methodology":"Systematic review including all studies through December 2018 where patients had diagnosed PTSD and used cannabinoids to reduce symptoms. Only one study was an RCT; the rest were observational, retrospective, or case reports.","limitations":"Nearly all evidence is observational or case-based. The single RCT was a small pilot study. Heterogeneous cannabinoid products and dosing across studies prevent meaningful comparison."},{"rthcId":"RTHC-02612","title":"Acute Effects of Cannabis Concentrate on Motor Control and Speed: Smartphone-Based Mobile Assessment.","authors":"Hitchcock, Leah N; Tracy, Brian L; Bryan, Angela D; Hutchison, Kent E; Bidwell, L Cinnamon","year":2020,"journal":"Frontiers in psychiatry, 11, 623672","doi":"10.3389/fpsyt.2020.623672","pmid":"33551884","tags":["driving","cognition","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Arm speed slowed immediately and remained impaired at 1 hour post-use. Leg speed slowed at 1 hour. Balance decreased immediately but recovered by 1 hour. These effects did not differ between sexes, and acute THC blood level changes were minimally correlated with balance impairment.","whyItMatters":"Cannabis concentrates with up to 90% THC are increasingly popular, yet this is one of the first studies to measure motor impairment specifically from concentrate use, relevant to driving and workplace safety.","specificNumbers":"65 participants. THC potency up to 90% in concentrates. Arm speed impaired at both post-use timepoints (p<0.05). Leg speed impaired at 1 hour (p=0.033). Balance impaired immediately (eyes open p=0.017, eyes closed p=0.013) but recovered at 1 hour.","methodology":"Observational study of 65 experienced concentrate users (46% female, average 17 days/month use) assessed in a mobile lab before, immediately after, and 1 hour after ad-libitum concentrate use. Smartphone sensors measured motor performance. Venous blood THC was measured at each timepoint.","limitations":"Naturalistic design without controlled dosing. Frequent users may have partial tolerance. The smartphone-based assessment, while novel, is not a validated clinical tool. No placebo control."},{"rthcId":"RTHC-02613","title":"Age-dependent hormesis-like effects of the synthetic cannabinoid CP55940 in C57BL/6 mice.","authors":"Hodges, Erik L; Marshall, Jessica P; Ashpole, Nicole M","year":2020,"journal":"NPJ aging and mechanisms of disease, 6, 7","doi":"10.1038/s41514-020-0045-7","pmid":"32655880","tags":["seniors","neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CP55940 produced greater antinociception (pain relief) and locomotor inhibition in aged (21-24 month) compared to young-adult (4 month) mice. Low doses paradoxically stimulated movement in young mice (hormesis), but this effect was diminished in aged animals. Both CB1 and CB2 receptors mediated the effects.","whyItMatters":"Cannabis use among older adults is increasing rapidly, yet almost no preclinical data exist in aged models. The greater potency in older animals suggests that elderly users may need lower doses and face different risk profiles.","specificNumbers":"Young-adult mice: 4 months old. Aged mice: 21-24 months old. Aged mice showed exaggerated antinociception and locomotor inhibition compared to young adults.","methodology":"Young-adult and aged C57BL/6 mice received CP55940 at multiple doses. Locomotion, body temperature, thermal pain response (nociception), and fecal output were measured.","limitations":"Animal study using a synthetic cannabinoid (not THC or CBD). Mouse aging does not perfectly model human aging. Only male and female mice of two age groups were compared."},{"rthcId":"RTHC-02614","title":"Paternal factors in neurodevelopmental toxicology: THC exposure of male rats causes long-lasting neurobehavioral effects in their offspring.","authors":"Holloway, Zade R; Hawkey, Andrew B; Pippin, Erica; White, Hannah; Wells, Corinne; Kenou, Bruny; Rezvani, Amir H; Murphy, Susan K; Levin, Edward D","year":2020,"journal":"Neurotoxicology, 78, 57-63","doi":"10.1016/j.neuro.2020.01.009","pmid":"32045580","tags":["pregnancy","cognition","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Offspring of THC-exposed fathers showed adolescent hyperactivity (at 2 mg/kg dose), faster decline in novel object interest (at 2 mg/kg), and delayed radial-arm maze learning (at 4 mg/kg). These effects persisted despite the mothers never being exposed to THC.","whyItMatters":"Most cannabis-pregnancy research focuses on maternal exposure. This study shows that paternal THC exposure before conception can also affect offspring development, likely through epigenetic changes in sperm previously documented by the same research group.","specificNumbers":"THC doses: 2 or 4 mg/kg/day for 28 days. 2 mg/kg offspring: adolescent hyperactivity and faster novel object interest decline. 4 mg/kg offspring: delayed radial-arm maze learning.","methodology":"Male rats received 0, 2, or 4 mg/kg/day THC subcutaneously for 28 days, then mated with drug-naive females. Offspring were tested for locomotor activity, novel object recognition, and radial-arm maze learning.","limitations":"Animal study with subcutaneous THC injection, not typical human exposure. The specific epigenetic mechanisms linking paternal exposure to offspring behavior were not characterized in this study. Sample sizes for behavioral testing were not specified."},{"rthcId":"RTHC-02615","title":"Unintentional use of fentanyl attributed to surreptitious cannabis adulteration.","authors":"Hopwood, Taylor; Dowd-Green, Caitlin; Mason, Melissa; Stewart, Rosalyn W","year":2020,"journal":"Journal of the American Pharmacists Association : JAPhA, 60(6), e370-e374","doi":"10.1016/j.japh.2020.07.003","pmid":"32778518","tags":["harm-reduction","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient receiving buprenorphine for opioid use disorder repeatedly tested positive for fentanyl on urine drug screens while denying opioid use but admitting to smoking street cannabis 2-3 times weekly. After changing cannabis sources, fentanyl tests became negative and remained so.","whyItMatters":"This case demonstrates that fentanyl contamination of street cannabis is a real phenomenon that can complicate addiction treatment and put cannabis users at risk of unintentional opioid exposure.","specificNumbers":"Patient was 50 years old, using cannabis 2-3 times weekly for headache relief and sleep. Fentanyl-positive UDS resolved after changing cannabis source. Stable on buprenorphine afterward.","methodology":"Single case report from an office-based opioid treatment program documenting the timeline of fentanyl-positive urine drug screens in relation to cannabis source changes.","limitations":"Single case report with limited generalizability. No laboratory testing of the cannabis itself was performed. The frequency of fentanyl contamination in street cannabis is unknown."},{"rthcId":"RTHC-02616","title":"Fast Discrimination of Marijuana using Automated High-throughput Cannabis Sample Preparation and Analysis by Gas Chromatography-Mass Spectrometry.","authors":"Horne, Melissa; Mastrianni, Kaylee R; Amick, Gray; Hardy, Rachel; Renneker, Elissa; Miller, Kevin W P","year":2020,"journal":"Journal of forensic sciences, 65(5), 1709-1715","doi":"10.1111/1556-4029.14525","pmid":"32745233","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02617","title":"Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain.","authors":"Hossain, Mohammad Zakir; Ando, Hiroshi; Unno, Shumpei; Kitagawa, Junichi","year":2020,"journal":"International journal of molecular sciences, 21(4)","doi":"10.3390/ijms21041423","pmid":"32093166","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02618","title":"Cannabis and work: Need for more research.","authors":"Howard, John; Osborne, Jamie","year":2020,"journal":"American journal of industrial medicine, 63(11), 963-972","doi":"10.1002/ajim.23170","pmid":"32797692","tags":["workplace","legalization"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This commentary from researchers at NIOSH (the federal workplace safety agency) identified a fundamental gap: cannabis legalization was reshaping the American workforce, but almost no research existed to guide workplace policy. Past policies were built when cannabis was universally illegal and any use was considered problematic. That framework no longer applied in states with legal access.\n\nThe authors identified several urgent research needs: which industries and occupations had the highest cannabis use, what the actual safety risks were for impaired workers, whether different cannabis products carried different workplace risks, and how to test for current impairment rather than past use.\n\nThe last point was particularly critical. Standard urine drug testing detects THC metabolites for days or weeks after use, making it a test of recent history rather than current impairment. For a legal substance, that's like testing employees for whether they drank alcohol last weekend rather than whether they're drunk at work.","whyItMatters":"This paper matters because of who wrote it. NIOSH is the federal agency responsible for workplace safety research. When they publish that existing cannabis workplace policies aren't grounded in evidence, it signals that the entire framework needs rebuilding.\n\nThe drug testing issue is the most immediately consequential. Millions of American workers are subject to cannabis testing that can't distinguish between someone who used cannabis three weeks ago on vacation and someone who is impaired at work right now. For a substance that's legal in most states, that's an increasingly untenable position — and the research to develop better impairment testing hadn't been done.","specificNumbers":"• Cannabis is legal for medical or recreational use in the majority of U.S. states\n• Standard urine tests detect THC metabolites for days to weeks\n• No validated test exists for current cannabis impairment in the workplace\n• NIOSH identified multiple priority research gaps with no existing data","methodology":"Commentary and research agenda published in the American Journal of Industrial Medicine by researchers from the National Institute for Occupational Safety and Health (NIOSH) and the CDC. Reviewed existing literature gaps and proposed priority research areas.","limitations":"This is a commentary and research agenda, not original research. It identified gaps rather than filling them. The workplace safety risks of cannabis use are framed as probable based on analogy with alcohol, but direct evidence was acknowledged as sparse. Does not address international workplace contexts."},{"rthcId":"RTHC-02619","title":"Marijuana Use for Women: To Prescribe or Not to Prescribe.","authors":"Huang, Lei; Zhang, Xinyue; Xu, Aman","year":2020,"journal":"Substance use & misuse, 55(12), 2076-2077","doi":"10.1080/10826084.2020.1782938","pmid":"32627638","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02620","title":"Cannabis for Pediatric Epilepsy.","authors":"Huntsman, Richard J; Tang-Wai, Richard; Shackelford, Alan E","year":2020,"journal":"Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society, 37(1), 2-8","doi":"10.1097/WNP.0000000000000641","pmid":"31895184","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02621","title":"Altered Corticolimbic Control of the Nucleus Accumbens by Long-term Δ9-Tetrahydrocannabinol Exposure.","authors":"Hwang, Eun-Kyung; Lupica, Carl R","year":2020,"journal":"Biological psychiatry, 87(7), 619-631","doi":"10.1016/j.biopsych.2019.07.024","pmid":"31543247","tags":["neuroscience","addiction","cognition"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Long-term THC weakened prefrontal cortex glutamate input to the nucleus accumbens shell and strengthened input from the basolateral amygdala and ventral hippocampus. This shifts control of reward processing from cortical (rational) to limbic (emotional) circuits.","whyItMatters":"This provides a mechanistic explanation for why chronic cannabis use is associated with both addiction vulnerability and psychiatric symptoms: the brain's reward center becomes more responsive to emotional signals and less responsive to rational control.","specificNumbers":"THC weakened PFC input, strengthened BLA and vHipp input, and altered properties (but not net strength) of midbrain dopamine neuron input to NAc shell.","methodology":"In vitro electrophysiology combined with optogenetics in rats to selectively activate and measure specific neural pathways from prefrontal cortex, amygdala, hippocampus, and dopamine neurons to the nucleus accumbens after long-term THC exposure.","limitations":"Animal study using in vitro recordings, which may not fully capture in vivo neural dynamics. The THC exposure paradigm may not perfectly model human chronic use. Only the NAc shell subregion was studied."},{"rthcId":"RTHC-02622","title":"Stress, Cortisol and NR3C1 in At-Risk Individuals for Psychosis: A Mendelian Randomization Study.","authors":"Iftimovici, Anton; Kebir, Oussama; He, Qin; Jay, Thérèse M; Rouleau, Guy A; Krebs, Marie-Odile; Chaumette, Boris","year":2020,"journal":"Frontiers in psychiatry, 11, 680","doi":"10.3389/fpsyt.2020.00680","pmid":"32754072","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02623","title":"E-cigarette or vaping product use-associated lung injury.","authors":"Ind, Philip W","year":2020,"journal":"British journal of hospital medicine (London, England : 2005), 81(4), 1-9","doi":"10.12968/hmed.2019.0371","pmid":"32339005","tags":["respiratory","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"EVALI presented primarily in young men as severe lung consolidation with respiratory failure. The outbreak was strongly associated with vaping unlicensed cannabis/THC products. Vitamin E acetate, used as a thickening agent in illicit THC vape products, was identified in the lung fluid of EVALI patients and is the leading suspected cause.","whyItMatters":"The EVALI outbreak demonstrated that unregulated cannabis vaping products can cause life-threatening lung injury, highlighting the importance of product regulation and quality control in the cannabis industry.","specificNumbers":"Most cases reported June-October 2019 in the US. Mortality approximately 2%. Primarily affected young men. Associated with unlicensed THC-containing vape products. Vitamin E acetate identified in bronchoalveolar lavage fluid.","methodology":"Literature review examining clinical features, investigations, and possible mechanisms of EVALI in the context of US and UK vaping practices.","limitations":"The exact mechanism of lung injury is not fully established. Some cases did not report THC use, leaving the possibility of other contributing factors. The review focuses primarily on US and UK contexts."},{"rthcId":"RTHC-02624","title":"Clinical Data for the Use of Cannabis-Based Treatments: A Comprehensive Review of the Literature.","authors":"Inglet, Shannon; Winter, Bradly; Yost, Sarah E; Entringer, Sophia; Lian, Anh; Biksacky, Meryl; Pitt, Renee D; Mortensen, Whitney","year":2020,"journal":"The Annals of pharmacotherapy, 54(11), 1109-1143","doi":"10.1177/1060028020930189","pmid":"32483988","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02625","title":"Drug offenses in the Tokyo Metropolitan Area: Trends for 2016-2018.","authors":"Inoue, Ken; Hashioka, Sadayuki; Takeshita, Haruo; Fujita, Yasuyuki; Moriwaki, Shigeto; Murayama, Yuri; Fujita, Yoshitsugu; Matsumoto, Hidehiko; Takeichi, Nobuo; Hoshi, Masaharu; Noso, Yoshihiro; Okazaki, Yuji","year":2020,"journal":"Legal medicine (Tokyo, Japan), 47, 101739","doi":"10.1016/j.legalmed.2020.101739","pmid":"32645558","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02626","title":"Organophosphate Agent Induces ADHD-Like Behaviors via Inhibition of Brain Endocannabinoid-Hydrolyzing Enzyme(s) in Adolescent Male Rats.","authors":"Ito, Yuki; Tomizawa, Motohiro; Suzuki, Kazutaka; Shirakawa, Yuichi; Ono, Hiromasa; Adachi, Keishi; Suzuki, Himiko; Shimomura, Kenji; Nabeshima, Toshitaka; Kamijima, Michihiro","year":2020,"journal":"Journal of agricultural and food chemistry, 68(8), 2547-2553","doi":"10.1021/acs.jafc.9b08195","pmid":"31995978","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02627","title":"Cannabinoid CB2 receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear.","authors":"Ivy, Devon; Palese, Francesca; Vozella, Valentina; Fotio, Yannick; Yalcin, Aylin; Ramirez, Gina; Mears, David; Wynn, Gary; Piomelli, Daniele","year":2020,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 45(8), 1330-1338","doi":"10.1038/s41386-020-0696-x","pmid":"32375160","tags":["ptsd","anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"JZL184 (MGL inhibitor) dose-dependently suppressed predator-induced fear (ED50 = 4 mg/kg). This effect was blocked by the CB2 antagonist AM630 but not by the CB1 antagonist rimonabant. CB2 mRNA was elevated in the prefrontal cortex 7 days after predator stress. A direct CB2 agonist also reduced fear but only in stressed animals.","whyItMatters":"This challenges the dominant assumption that endocannabinoid-based anxiety treatments work through CB1 receptors. The CB2 finding opens a new therapeutic target for PTSD that could avoid the psychoactive side effects associated with CB1 activation.","specificNumbers":"JZL184 ED50 = 4 mg/kg. AM630 (CB2 antagonist) blocked the effect; rimonabant (CB1 antagonist) did not. JWH133 (CB2 agonist) reduced fear at 0.3-3 mg/kg but only in stressed rats. CB2 mRNA elevated in prefrontal cortex after stress.","methodology":"Rats were exposed to TMT (predator odor) to induce persistent fear, then tested 7 days later in the elevated plus maze. JZL184, KML29 (MGL inhibitors), and JWH133 (CB2 agonist) were tested with and without receptor antagonists.","limitations":"Animal model of fear may not fully capture human PTSD. TMT-induced fear is an innate response, not learned trauma. CB2 expression was measured only in the prefrontal cortex."},{"rthcId":"RTHC-02628","title":"The cannabinoid CB2 receptor agonist LY2828360 synergizes with morphine to suppress neuropathic nociception and attenuates morphine reward and physical dependence.","authors":"Iyer, Vishakh; Slivicki, Richard A; Thomaz, Ana C; Crystal, Jonathon D; Mackie, Ken; Hohmann, Andrea G","year":2020,"journal":"European journal of pharmacology, 886, 173544","doi":"10.1016/j.ejphar.2020.173544","pmid":"32896549","tags":["pain","addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"LY2828360 and morphine produced synergistic pain relief for chemotherapy-induced neuropathy. LY2828360 blocked morphine reward in a conditioned place preference test (via CB2 receptors) without producing reward or aversion on its own. It also partially reduced naloxone-precipitated withdrawal in morphine-dependent mice.","whyItMatters":"The opioid crisis demands alternatives that enhance pain relief while reducing addiction risk. A drug that synergizes with morphine for pain but blocks its rewarding effects could fundamentally change how opioids are used for chronic pain.","specificNumbers":"Synergistic anti-allodynic effects confirmed by isobolographic analysis. LY2828360 blocked morphine reward in WT but not CB2KO mice. Partial attenuation of withdrawal. Did not alter morphine-induced constipation.","methodology":"Isobolographic analysis of LY2828360 and morphine combinations for neuropathic pain. Conditioned place preference testing for reward in wildtype and CB2 knockout mice. Naloxone-precipitated withdrawal in morphine-dependent mice.","limitations":"Animal study using a paclitaxel neuropathic pain model. LY2828360 did not attenuate morphine tolerance in a separate pain test (hot plate). The partial nature of the withdrawal reduction suggests CB2 activation alone may not fully prevent dependence."},{"rthcId":"RTHC-02629","title":"Pharmacokinetic investigation of synthetic cannabidiol oral formulations in healthy volunteers.","authors":"Izgelov, Dvora; Davidson, Elyad; Barasch, Dinorah; Regev, Aviva; Domb, Abraham J; Hoffman, Amnon","year":2020,"journal":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 154, 108-115","doi":"10.1016/j.ejpb.2020.06.021","pmid":"32634571","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CBD in lipid-based vehicles (oil and nano-emulsion) significantly increased both peak blood levels and total exposure compared to powder. While overall exposure was similar between oil and nano-emulsion, oil produced variable absorption (some early, some delayed) while nano-emulsion consistently produced early absorption.","whyItMatters":"CBD's poor oral bioavailability is a major clinical challenge. This study shows that formulation dramatically affects absorption, explaining why CBD dosing recommendations vary widely and why clinical trial results have been inconsistent.","specificNumbers":"12 healthy male volunteers. Lipid-based vehicles significantly increased Cmax and AUC vs. powder. Sesame oil caused two absorption patterns among subjects; SNEDDS produced uniform early absorption.","methodology":"Three-way, blind, crossover single-dose study in 12 healthy male volunteers. Synthetic CBD was administered as powder, dissolved in sesame oil, or in a self-nano-emulsifying drug delivery system (SNEDDS).","limitations":"Small sample (12 volunteers), all male. Single-dose study does not capture steady-state pharmacokinetics. Synthetic CBD was used rather than plant-derived CBD. Only one dose level was tested."},{"rthcId":"RTHC-02630","title":"The CANNA-TICS Study Protocol: A Randomized Multi-Center Double-Blind Placebo Controlled Trial to Demonstrate the Efficacy and Safety of Nabiximols in the Treatment of Adults With Chronic Tic Disorders.","authors":"Jakubovski, Ewgeni; Pisarenko, Anna; Fremer, Carolin; Haas, Martina; May, Marcus; Schumacher, Carsten; Schindler, Christoph; Häckl, Sebastian; Aguirre Davila, Lukas; Koch, Armin; Brunnauer, Alexander; Cimpianu, Camelia Lucia; Lutz, Beat; Bindila, Laura; Müller-Vahl, Kirsten","year":2020,"journal":"Frontiers in psychiatry, 11, 575826","doi":"10.3389/fpsyt.2020.575826","pmid":"33324255","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02631","title":"Extension of the Theory of Planned Behavior (TPB) to Predict Patterns of Marijuana Use among Young Iranian Adults.","authors":"Jalilian, Farzad; Mirzaei-Alavijeh, Mehdi; Ahmadpanah, Mohammad; Mostafaei, Shayan; Kargar, Mehdi; Pirouzeh, Razieh; Sadeghi Bahmani, Dena; Brand, Serge","year":2020,"journal":"International journal of environmental research and public health, 17(6)","doi":"10.3390/ijerph17061981","pmid":"32192209","tags":["addiction","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In a sample of 166 Iranian university students, attitudes toward marijuana and perceived behavioral control significantly predicted intentions to use, while subjective norms (peer pressure) did not reach significance in the full model.","whyItMatters":"Most cannabis intention research comes from Western countries. This study offers a rare look at how psychological predictors of cannabis use operate in a very different cultural and legal context.","specificNumbers":"166 participants surveyed; attitudes (β = 0.42) and perceived behavioral control (β = 0.31) were significant predictors of intention.","methodology":"Cross-sectional survey of 166 university students in Iran using Theory of Planned Behavior framework with structural equation modeling.","limitations":"Small convenience sample from one university in Iran; cross-sectional design cannot establish causality; self-report measures in a context where cannabis is illegal may introduce response bias."},{"rthcId":"RTHC-02632","title":"Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes.","authors":"Jin, Dan; Dai, Kaiping; Xie, Zhen; Chen, Jie","year":2020,"journal":"Scientific reports, 10(1), 3309","doi":"10.1038/s41598-020-60172-6","pmid":"32094454","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02633","title":"A large-scale genome-wide association study meta-analysis of cannabis use disorder.","authors":"Johnson, Emma C; Demontis, Ditte; Thorgeirsson, Thorgeir E; Walters, Raymond K; Polimanti, Renato; Hatoum, Alexander S; Sanchez-Roige, Sandra; Paul, Sarah E; Wendt, Frank R; Clarke, Toni-Kim; Lai, Dongbing; Reginsson, Gunnar W; Zhou, Hang; He, June; Baranger, David A A; Gudbjartsson, Daniel F; Wedow, Robbee; Adkins, Daniel E; Adkins, Amy E; Alexander, Jeffry; Bacanu, Silviu-Alin; Bigdeli, Tim B; Boden, Joseph; Brown, Sandra A; Bucholz, Kathleen K; Bybjerg-Grauholm, Jonas; Corley, Robin P; Degenhardt, Louisa; Dick, Danielle M; Domingue, Benjamin W; Fox, Louis; Goate, Alison M; Gordon, Scott D; Hack, Laura M; Hancock, Dana B; Hartz, Sarah M; Hickie, Ian B; Hougaard, David M; Krauter, Kenneth; Lind, Penelope A; McClintick, Jeanette N; McQueen, Matthew B; Meyers, Jacquelyn L; Montgomery, Grant W; Mors, Ole; Mortensen, Preben B; Nordentoft, Merete; Pearson, John F; Peterson, Roseann E; Reynolds, Maureen D; Rice, John P; Runarsdottir, Valgerdur; Saccone, Nancy L; Sherva, Richard; Silberg, Judy L; Tarter, Ralph E; Tyrfingsson, Thorarinn; Wall, Tamara L; Webb, Bradley T; Werge, Thomas; Wetherill, Leah; Wright, Margaret J; Zellers, Stephanie; Adams, Mark J; Bierut, Laura J; Boardman, Jason D; Copeland, William E; Farrer, Lindsay A; Foroud, Tatiana M; Gillespie, Nathan A; Grucza, Richard A; Harris, Kathleen Mullan; Heath, Andrew C; Hesselbrock, Victor; Hewitt, John K; Hopfer, Christian J; Horwood, John; Iacono, William G; Johnson, Eric O; Kendler, Kenneth S; Kennedy, Martin A; Kranzler, Henry R; Madden, Pamela A F; Maes, Hermine H; Maher, Brion S; Martin, Nicholas G; McGue, Matthew; McIntosh, Andrew M; Medland, Sarah E; Nelson, Elliot C; Porjesz, Bernice; Riley, Brien P; Stallings, Michael C; Vanyukov, Michael M; Vrieze, Scott; Davis, Lea K; Bogdan, Ryan; Gelernter, Joel; Edenberg, Howard J; Stefansson, Kari; Børglum, Anders D; Agrawal, Arpana","year":2020,"journal":"The lancet. Psychiatry, 7(12), 1032-1045","doi":"10.1016/S2215-0366(20)30339-4","pmid":"33096046","tags":["genetics","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"This GWAS meta-analysis identified 22 genome-wide significant loci associated with cannabis use disorder, with SNP-based heritability estimated at 11%. Strong genetic correlations were found with other substance use disorders, ADHD, major depression, and schizophrenia.","whyItMatters":"This is one of the largest genetic studies of cannabis use disorder ever conducted. It provides the clearest picture yet of the biological architecture of problematic cannabis use and its genetic connections to other psychiatric conditions.","specificNumbers":"384,032 participants; 42,281 CUD cases; 22 genome-wide significant loci; SNP heritability of 11%; published in Lancet Psychiatry.","methodology":"Genome-wide association study meta-analysis combining data from multiple cohorts totaling 384,032 participants of European ancestry, including 42,281 CUD cases.","limitations":"Limited to European ancestry, reducing generalizability to other populations. Common genetic variants explain only a fraction of total heritability. Genetic associations do not imply simple causal mechanisms."},{"rthcId":"RTHC-02634","title":"Associations of substance use, psychosis, and mortality among people living in precarious housing or homelessness: A longitudinal, community-based study in Vancouver, Canada.","authors":"Jones, Andrea A; Gicas, Kristina M; Seyedin, Sam; Willi, Taylor S; Leonova, Olga; Vila-Rodriguez, Fidel; Procyshyn, Ric M; Smith, Geoffrey N; Schmitt, Toby A; Vertinsky, A Talia; Buchanan, Tari; Rauscher, Alex; Lang, Donna J; MacEwan, G William; Lima, Viviane D; Montaner, Julio S G; Panenka, William J; Barr, Alasdair M; Thornton, Allen E; Honer, William G","year":2020,"journal":"PLoS medicine, 17(7), e1003172","doi":"10.1371/journal.pmed.1003172","pmid":"32628679","tags":["psychosis","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Over 10 years of follow-up, participants with co-occurring substance use and psychotic disorders had higher mortality rates than those with either condition alone. Cannabis use was one of several substances assessed, though injection drug use carried the highest mortality risk.","whyItMatters":"Homelessness, substance use, and mental illness often co-occur, but few studies track mortality outcomes over extended periods in this population. The findings highlight the compounding risks when multiple conditions overlap.","specificNumbers":"437 participants; 10-year follow-up period; mortality data linked through provincial vital statistics.","methodology":"Prospective longitudinal cohort study following 437 homeless or precariously housed adults in Vancouver for up to 10 years, with structured diagnostic interviews at baseline.","limitations":"Single city (Vancouver); cannabis use was one of many substances examined and not isolated as an independent risk factor; attrition challenges inherent to studying homeless populations."},{"rthcId":"RTHC-02635","title":"Prescription Opioid Misuse and Use of Alcohol and Other Substances Among High School Students - Youth Risk Behavior Survey, United States, 2019.","authors":"Jones, Christopher M; Clayton, Heather B; Deputy, Nicholas P; Roehler, Douglas R; Ko, Jean Y; Esser, Marissa B; Brookmeyer, Kathryn A; Hertz, Marci Feldman","year":2020,"journal":"MMWR supplements, 69(1), 38-46","doi":"10.15585/mmwr.su6901a5","pmid":"32817608","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02636","title":"A Critical Review of the Role of the Cannabinoid Compounds Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) and their Combination in Multiple Sclerosis Treatment.","authors":"Jones, Éamon; Vlachou, Styliani","year":2020,"journal":"Molecules (Basel, Switzerland), 25(21)","doi":"10.3390/molecules25214930","pmid":"33113776","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review found the strongest evidence for nabiximols (Sativex, a 1:1 THC:CBD oromucosal spray) in reducing spasticity and neuropathic pain in MS patients. Evidence for effects on tremor, bladder dysfunction, and sleep was less consistent.","whyItMatters":"Multiple sclerosis affects millions worldwide, and spasticity is one of its most debilitating symptoms. This review consolidates what is known about cannabinoid treatments to help clarify where the evidence is strongest.","specificNumbers":"Nabiximols (Sativex) is approved in over 25 countries for MS spasticity; clinical trials typically showed 20-30% improvement in spasticity scores.","methodology":"Critical narrative review synthesizing clinical trial data, observational studies, and regulatory submissions for cannabinoid-based treatments in multiple sclerosis.","limitations":"Narrative review format (not systematic); heterogeneity in how MS symptoms are measured across studies; many trials had small sample sizes."},{"rthcId":"RTHC-02637","title":"Identifying cytochrome P450s involved in oxidative metabolism of synthetic cannabinoid N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide (STS-135).","authors":"Jones, Sabrina; Yarbrough, Azure L; Fantegrossi, William E; Prather, Paul L; Bush, John M; Radominska-Pandya, Anna; Fujiwara, Ryoichi","year":2020,"journal":"Pharmacology research & perspectives, 8(1), e00561","doi":"10.1002/prp2.561","pmid":"32003945","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02638","title":"Xie2-64, a novel CB2 receptor inverse agonist, reduces cocaine abuse-related behaviors in rodents.","authors":"Jordan, Chloe J; Feng, Zhi-Wei; Galaj, Ewa; Bi, Guo-Hua; Xue, Ying; Liang, Ying; McGuire, Terence; Xie, Xiang-Qun; Xi, Zheng-Xiong","year":2020,"journal":"Neuropharmacology, 176, 108241","doi":"10.1016/j.neuropharm.2020.108241","pmid":"32712273","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Xie2-64, a CB2 receptor inverse agonist, dose-dependently reduced cocaine self-administration and blocked cocaine-primed reinstatement (relapse) in rats. Importantly, it did not reduce food-maintained responding, suggesting the effect was specific to drug reward rather than general motivation.","whyItMatters":"Current treatments for cocaine addiction are limited. This study suggests the CB2 receptor, part of the endocannabinoid system, could be a promising target for reducing cocaine abuse, opening a new therapeutic angle.","specificNumbers":"Xie2-64 dose-dependently reduced cocaine self-administration; blocked cocaine-primed reinstatement at doses that did not affect food responding.","methodology":"Animal study using rat models of cocaine self-administration, extinction, and reinstatement. Multiple dose levels of Xie2-64 were tested against vehicle controls.","limitations":"Animal study; effects in rodents may not translate to humans. Only acute dosing was tested; long-term effects and safety are unknown. The specific compound (Xie2-64) has not been tested in humans."},{"rthcId":"RTHC-02639","title":"Small bowel intussusception in marijuana users.","authors":"Kakish, Daniel; Alaoudi, Marwan; Welch, Brian; Fan, David; Meghpara, Melissa; Mandava, Nageswara; Kumthekar, Narendra","year":2020,"journal":"Journal of surgical case reports, 2020(9), rjaa335","doi":"10.1093/jscr/rjaa335","pmid":"33024532","tags":["cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Eleven patients, all heavy marijuana users, presented with small bowel intussusception at a single institution. All required surgical intervention. No alternative cause (such as tumor or anatomical defect) was identified in most cases, suggesting a possible functional mechanism related to cannabis effects on gut motility.","whyItMatters":"Small bowel intussusception in adults is rare and usually caused by structural abnormalities. This series raises the possibility that heavy cannabis use might affect gut motility in ways that predispose to this condition.","specificNumbers":"11 patients; all heavy marijuana users; all required surgical treatment; no structural lead point identified in most cases.","methodology":"Retrospective case series of 11 patients at a single institution who presented with small bowel intussusception and had documented heavy marijuana use.","limitations":"Case series without controls; no way to establish causation. Single institution may reflect referral bias. Small sample size. No dose-response data or quantification of cannabis use."},{"rthcId":"RTHC-02640","title":"Assessment of Gastric Emptying Times Between Pediatrics and Adults With Cyclic Vomiting Syndrome.","authors":"Kamal, Afrin; Sarvepalli, Shashank; Selvakumar, Praveen; Lopez, Rocio; Radhakrishnan, Kadakkal; Gabbard, Scott","year":2020,"journal":"Journal of clinical gastroenterology, 54(9), e89-e92","doi":"10.1097/MCG.0000000000001352","pmid":"32569030","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02641","title":"Cannabinoid Antagonist Drug Discrimination in Nonhuman Primates.","authors":"Kangas, Brian D; Zakarian, Ani S; Vemuri, Kiran; Alapafuja, Shakiru O; Jiang, Shan; Nikas, Spyros P; Makriyannis, Alexandros; Bergman, Jack","year":2020,"journal":"The Journal of pharmacology and experimental therapeutics, 372(1), 119-127","doi":"10.1124/jpet.119.261818","pmid":"31641018","tags":["neuroscience","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Squirrel monkeys were trained to discriminate rimonabant (a CB1 antagonist/inverse agonist) from vehicle in a drug discrimination paradigm. The discrimination was dose-dependent and could be blocked by THC, confirming it was mediated through CB1 receptors.","whyItMatters":"Drug discrimination procedures reveal how substances \"feel\" to animals, providing insight into subjective effects. Establishing that cannabinoid blockade produces discriminable effects helps researchers study the endocannabinoid system and potential therapeutic applications of antagonists.","specificNumbers":"Squirrel monkeys discriminated rimonabant from vehicle in a dose-dependent manner; THC blocked the rimonabant discrimination.","methodology":"Drug discrimination study in squirrel monkeys using a two-lever food-reinforced operant procedure. Animals were trained to discriminate rimonabant from vehicle across multiple dose levels.","limitations":"Animal study with a small number of primates; subjective effects in monkeys may not directly translate to human experience. Rimonabant is no longer marketed for clinical use."},{"rthcId":"RTHC-02642","title":"Exploring Cannabis and Alcohol Co-Use in Adolescents: A Narrative Review of the Evidence.","authors":"Karoly, Hollis C; Ross, J Megan; Ellingson, Jarrod M; Feldstein Ewing, Sarah W","year":2020,"journal":"Journal of dual diagnosis, 16(1), 58-74","doi":"10.1080/15504263.2019.1660020","pmid":"31519143","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02643","title":"Stearoylethanolamide interferes with retrograde endocannabinoid signalling and supports the blood-brain barrier integrity under acute systemic inflammation.","authors":"Kasatkina, Ludmila A; Heinemann, Akos; Hudz, Yehor A; Thomas, Dominique; Sturm, Eva M","year":2020,"journal":"Biochemical pharmacology, 174, 113783","doi":"10.1016/j.bcp.2019.113783","pmid":"31881191","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02644","title":"Acute effects of cannabinoids on symptoms of obsessive-compulsive disorder: A human laboratory study.","authors":"Kayser, Reilly R; Haney, Margaret; Raskin, Marissa; Arout, Caroline; Simpson, Helen Blair","year":2020,"journal":"Depression and anxiety, 37(8), 801-811","doi":"10.1002/da.23032","pmid":"32383271","tags":["mental-health","cbd","anxiety"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Fourteen adults with OCD underwent symptom provocation after smoking cannabis with high THC, high CBD, or placebo in a crossover design. Neither active condition significantly reduced obsessions or compulsions compared to placebo, though there were trends toward reduced anxiety with CBD.","whyItMatters":"Despite widespread anecdotal claims about cannabis helping OCD, this is one of the first controlled human lab studies to test it. The null findings are important for tempering expectations, though the small sample limits conclusions.","specificNumbers":"14 participants; three conditions (high THC, high CBD, placebo) in crossover design; no statistically significant reduction in OCD symptoms with either active condition.","methodology":"Double-blind, placebo-controlled, within-subjects crossover design. 14 adults with OCD smoked cannabis (high THC, high CBD, or placebo) before a symptom provocation task. OCD symptoms, anxiety, and distress were measured.","limitations":"Very small sample (n=14); acute dosing only (one-time exposure cannot capture effects of sustained use); smoked cannabis makes precise dosing difficult; crossover design may have carryover effects."},{"rthcId":"RTHC-02645","title":"Cannabinoids, Endocannabinoids and Sleep.","authors":"Kesner, Andrew J; Lovinger, David M","year":2020,"journal":"Frontiers in molecular neuroscience, 13, 125","doi":"10.3389/fnmol.2020.00125","pmid":"32774241","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02646","title":"The therapeutic role of Cannabidiol in mental health: a systematic review.","authors":"Khan, Rabia; Naveed, Sadiq; Mian, Nadeem; Fida, Ania; Raafey, Muhammad Abdur; Aedma, Kapil Kiran","year":2020,"journal":"Journal of cannabis research, 2(1), 2","doi":"10.1186/s42238-019-0012-y","pmid":"33526132","tags":["cbd","mental-health","anxiety","depression"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 23 included studies, CBD showed the most consistent positive signals for anxiety disorders and as an adjunct treatment for schizophrenia. Evidence for depression, PTSD, and sleep disorders was more limited and inconsistent. Most studies were small and used varied dosing protocols.","whyItMatters":"CBD products are widely marketed for mental health, but the evidence base is still developing. This review provides a structured assessment of where the science actually stands across different conditions.","specificNumbers":"23 studies included; conditions covered: anxiety, schizophrenia, depression, PTSD, substance use disorders, and sleep. CBD doses ranged widely across studies.","methodology":"Systematic review following PRISMA guidelines, searching multiple databases. Included 23 studies (RCTs, open-label trials, case series) examining CBD for various mental health conditions.","limitations":"High heterogeneity in study designs, doses, and populations. Most included studies were small. Publication bias may favor positive results. Rapid pace of new research means the review may not capture the latest findings."},{"rthcId":"RTHC-02647","title":"The Effects of Cannabidiol, a Non-Intoxicating Compound of Cannabis, on the Cardiovascular System in Health and Disease.","authors":"Kicman, Aleksandra; Toczek, Marek","year":2020,"journal":"International journal of molecular sciences, 21(18)","doi":"10.3390/ijms21186740","pmid":"32937917","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02648","title":"Development of the REACH (Real Education About Cannabis and Health) Program for Canadian Youth.","authors":"King, Patricia M; Klemmer, Jennafer; Mansell, Kerry; Alcorn, Jane; Mansell, Holly","year":2020,"journal":"The Journal of nursing education, 59(8), 465-469","doi":"10.3928/01484834-20200723-09","pmid":"32757012","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02649","title":"FMRI activation to cannabis odor cues is altered in individuals at risk for a cannabis use disorder.","authors":"Kleinhans, Natalia M; Sweigert, Julia; Blake, Matthew; Douglass, Bradley; Doane, Braden; Reitz, Fredrick; Larimer, Mary","year":2020,"journal":"Brain and behavior, 10(10), e01764","doi":"10.1002/brb3.1764","pmid":"32862560","tags":["addiction","neuroscience","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Using fMRI, researchers found that young adults with higher cannabis use disorder risk showed greater activation in the ventral striatum and orbitofrontal cortex when exposed to cannabis odor cues compared to neutral odors. This pattern mirrors cue-reactivity findings seen in other substance use disorders.","whyItMatters":"Understanding how cannabis cues activate the brain in at-risk users could help identify who is most vulnerable to developing problematic use and inform cue-exposure based treatments.","specificNumbers":"54 participants; heightened activation in ventral striatum and orbitofrontal cortex to cannabis odor cues in higher-risk individuals.","methodology":"Cross-sectional fMRI study with 54 young adult cannabis users exposed to cannabis-related and neutral odor cues during brain scanning. CUD risk was assessed using validated screening tools.","limitations":"Cross-sectional design cannot determine whether heightened cue-reactivity causes or results from heavier use. Moderate sample size. Odor cues may not capture the full range of real-world cannabis triggers."},{"rthcId":"RTHC-02650","title":"Urinary cannabinoid mass spectrometry profiles differentiate dronabinol from cannabis use.","authors":"Koch, Christopher D; Xu, Liang; Curtis, Susanna A; Roberts, John D; Bunch, Dustin R; El-Khoury, Joe M","year":2020,"journal":"Clinica chimica acta; international journal of clinical chemistry, 510, 515-521","doi":"10.1016/j.cca.2020.08.014","pmid":"32795544","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02651","title":"Illicit drug use among college students: The role of social norms and risk perceptions.","authors":"Kollath-Cattano, Christy; Hatteberg, Sarah J; Kooper, Anna","year":2020,"journal":"Addictive behaviors, 105, 106289","doi":"10.1016/j.addbeh.2020.106289","pmid":"32007829","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02652","title":"Cannabis Phytomolecule 'Entourage': From Domestication to Medical Use.","authors":"Koltai, Hinanit; Namdar, Dvora","year":2020,"journal":"Trends in plant science, 25(10), 976-984","doi":"10.1016/j.tplants.2020.04.007","pmid":"32417167","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02653","title":"Cannabis-derived cannabidiol and nanoselenium improve gut barrier function and affect bacterial enzyme activity in chickens subjected to C. perfringens challenge.","authors":"Konieczka, Paweł; Szkopek, Dominika; Kinsner, Misza; Fotschki, Bartosz; Juśkiewicz, Jerzy; Banach, Joanna","year":2020,"journal":"Veterinary research, 51(1), 141","doi":"10.1186/s13567-020-00863-0","pmid":"33225993","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02654","title":"Cannabidiol for Treating Lennox-Gastaut Syndrome and Dravet Syndrome in Korea.","authors":"Koo, Chung Mo; Kim, Se Hee; Lee, Joon Soo; Park, Byung Joo; Lee, Hae Kook; Kim, Heung Dong; Kang, Hoon Chul","year":2020,"journal":"Journal of Korean medical science, 35(50), e427","doi":"10.3346/jkms.2020.35.e427","pmid":"33372424","tags":["cbd","epilepsy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 34 Lennox-Gastaut and 10 Dravet syndrome patients (ages 1-16), CBD at 10 mg/kg/day produced 50%+ seizure reduction in 32.3% of LGS patients at 3 months (declining to 20.6% at 6 months) and 30% of DS patients at 3 months (20% at 6 months). Adverse events occurred in 36.3% of patients, mostly gastrointestinal, with no life-threatening events.","whyItMatters":"This is the first study of pharmaceutical CBD for epilepsy conducted in Korea, extending the evidence base for CBD in severe childhood epilepsy syndromes beyond Western populations.","specificNumbers":"44 patients (34 LGS, 10 DS); 50%+ seizure reduction in 32.3% of LGS at 3 months, 20.6% at 6 months; adverse events in 36.3%, mostly GI; no life-threatening events.","methodology":"Retrospective study of 44 pediatric patients (34 LGS, 10 DS) treated with oral CBD at 10 mg/kg/day, evaluated at 3 and 6 months via caregiver reporting, EEG, and blood tests.","limitations":"Retrospective design; small sample especially for Dravet syndrome (n=10); reliance on caregiver-reported seizure counts; efficacy appeared to decrease from 3 to 6 months; no control group."},{"rthcId":"RTHC-02655","title":"Medicinal Use of Cannabis in Children and Pregnant Women.","authors":"Koren, Gideon; Cohen, Rana","year":2020,"journal":"Rambam Maimonides medical journal, 11(1), 1-5","doi":"10.5041/RMMJ.10382","pmid":"32017681","tags":["medical-cannabis","pregnancy","youth","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review identified early-stage evidence for medical cannabis in three populations typically excluded from research: children with autism spectrum disorder (reduced behavioral symptoms), children with fetal alcohol spectrum disorder (improved behavioral outcomes), and pregnant women with hyperemesis gravidarum (reduced severe nausea).","whyItMatters":"Children and pregnant women are typically excluded from cannabis research due to ethical concerns. This review highlights emerging clinical use in these populations and the urgent need for rigorous safety data.","specificNumbers":"Three conditions reviewed: ASD in children, FASD in children, and hyperemesis gravidarum in pregnancy.","methodology":"Narrative review of available clinical evidence for medical cannabis use in children and pregnant women, covering autism spectrum disorder, fetal alcohol spectrum disorder, and hyperemesis gravidarum.","limitations":"Narrative review; very limited evidence base for all three conditions; ethical constraints make controlled trials extremely difficult; long-term safety data for prenatal and pediatric cannabis exposure are lacking."},{"rthcId":"RTHC-02656","title":"Critical Illness Secondary to Synthetic Cannabinoid Ingestion.","authors":"Kourouni, Ismini; Mourad, Bashar; Khouli, Hassan; Shapiro, Janet M; Mathew, Joseph P","year":2020,"journal":"JAMA network open, 3(7), e208516","doi":"10.1001/jamanetworkopen.2020.8516","pmid":"32687586","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"moderate","keyFinding":"Over two years, 30 patients were admitted to the ICU after synthetic cannabinoid use. Presenting diagnoses included coma (33%), agitation (33%), and seizures (20%). Seventy percent required intubation, 60% had acute respiratory failure, and 26% developed rhabdomyolysis. One patient died of ARDS. Standard toxicology screens were negative in 53% of cases.","whyItMatters":"Synthetic cannabinoids (K2, Spice) are far more dangerous than natural cannabis and are undetectable by standard drug tests. This series documents the severity of complications that can result, including death.","specificNumbers":"30 ICU patients; mean age 41; 80% male; 33% presented in coma; 70% required intubation; 60% had respiratory failure; 26% had rhabdomyolysis; 1 death; 53% had negative standard toxicology.","methodology":"Retrospective case series of 30 adults admitted to ICU from 2014-2016 with confirmed or suspected synthetic cannabinoid ingestion, published in JAMA Network Open.","limitations":"Single-institution case series; no control group; retrospective data; many patients had polysubstance use histories; 53% left against medical advice, limiting follow-up."},{"rthcId":"RTHC-02657","title":"Chronic cannabis consumption and physical exercise performance in healthy adults: a systematic review.","authors":"Kramer, Andrew; Sinclair, Justin; Sharpe, Lara; Sarris, Jerome","year":2020,"journal":"Journal of cannabis research, 2(1), 34","doi":"10.1186/s42238-020-00037-x","pmid":"33526096","tags":["exercise"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Across four included studies, the strongest predictors of athletic performance (VO2max and physical work capacity) did not significantly differ between chronic cannabis users and non-users. Resting heart rate was the only measure that differed, and only in one of the four studies.","whyItMatters":"Cannabis use among athletes is common but poorly studied. This review provides the first systematic assessment, finding no clear evidence for either performance enhancement or impairment from chronic use.","specificNumbers":"Four studies included; no significant differences in VO2max or physical work capacity between cannabis users and non-users.","methodology":"Systematic review searching eight databases for studies on chronic cannabis consumption and physical exercise performance outcomes, following PRISMA guidelines. Only four studies met inclusion criteria.","limitations":"Only four studies met criteria, indicating very limited research; studies were heterogeneous in design; did not assess recovery, endurance, or sport-specific performance; no intervention studies available."},{"rthcId":"RTHC-02658","title":"Experiences with medical cannabis in the treatment of veterans with PTSD: Results from a focus group discussion.","authors":"Krediet, Erwin; Janssen, Debbie Ga; Heerdink, Eibert R; Egberts, Toine Cg; Vermetten, Eric","year":2020,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 36, 244-254","doi":"10.1016/j.euroneuro.2020.04.009","pmid":"32576481","tags":["ptsd","medical-cannabis"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Seven veterans with chronic PTSD treated with medical cannabis participated in a focus group. They reported using cannabis to manage symptoms rather than to get high, used varied strains and doses, and highlighted improved sleep quality as a key benefit. Their partners corroborated these observations. Stigma surrounding cannabis use was identified as a significant barrier to initiation.","whyItMatters":"PTSD is common among veterans and current medications have limited efficacy. Understanding how veterans actually use and experience medical cannabis provides valuable context for designing future clinical trials.","specificNumbers":"7 veterans with chronic PTSD; 4 partners also participated; 5 themes identified related to consideration, initiation, usage, discontinuation, and general aspects of medical cannabis.","methodology":"Qualitative focus group study with 7 military veterans with chronic PTSD using medical cannabis, plus 4 of their partners. Sessions were audio-recorded, transcribed, and analyzed using content analysis.","limitations":"Very small qualitative sample (n=7); no control group; self-selected participants who were already using medical cannabis; qualitative data cannot establish efficacy."},{"rthcId":"RTHC-02659","title":"A longitudinal study of multiple lifestyle health risk behaviours among nursing students and non-nursing peers.","authors":"Kritsotakis, George; Georgiou, Evangelos D; Karakonstandakis, Georgios; Kaparounakis, Nikos; Pitsouni, Vasiliki; Sarafis, Pavlos","year":2020,"journal":"International journal of nursing practice, 26(6), e12852","doi":"10.1111/ijn.12852","pmid":"32645751","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02660","title":"Interactions Between Alcohol and the Endocannabinoid System.","authors":"Kunos, George","year":2020,"journal":"Alcoholism, clinical and experimental research, 44(4), 790-805","doi":"10.1111/acer.14306","pmid":"32056226","tags":["neuroscience","addiction","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review consolidates 20 years of evidence showing that alcohol increases endocannabinoid signaling, which mediates both its rewarding/addictive neural effects and its toxic effects in the liver (fatty liver disease). Both alcohol and endocannabinoids activate CB1 receptors to drive lipogenic gene expression. CB1 receptor blockade shows therapeutic potential for both alcohol addiction and alcohol-related liver disease.","whyItMatters":"Understanding that alcohol and cannabis share overlapping reward pathways through the endocannabinoid system explains why they are frequently co-used and why their combined effects can be more than additive.","specificNumbers":"Over 20 years of accumulated evidence; both brain CB1 receptors (addiction) and liver CB1 receptors (fatty liver) implicated.","methodology":"Narrative review synthesizing two decades of preclinical and clinical research on interactions between alcohol and the endocannabinoid system.","limitations":"Narrative review format; much of the mechanistic evidence comes from animal models; CB1 blockade (rimonabant) was withdrawn due to psychiatric side effects, limiting translational potential."},{"rthcId":"RTHC-02661","title":"Plant-Based (Hemp, Pea and Rice) Protein-Maltodextrin Combinations as Wall Material for Spray-Drying Microencapsulation of Hempseed (Cannabis sativa) Oil.","authors":"Kurek, Marcin Andrzej; Pratap-Singh, Anubhav","year":2020,"journal":"Foods (Basel, Switzerland), 9(11)","doi":"10.3390/foods9111707","pmid":"33233759","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02662","title":"Safety and Molecular-Toxicological Implications of Cannabidiol-Rich Cannabis Extract and Methylsulfonylmethane Co-Administration.","authors":"Kutanzi, Kristy R; Ewing, Laura E; Skinner, Charles M; Quick, Charles M; Kennon-McGill, Stefanie; McGill, Mitchell R; Walker, Larry A; ElSohly, Mahmoud A; Gurley, Bill J; Koturbash, Igor","year":2020,"journal":"International journal of molecular sciences, 21(20)","doi":"10.3390/ijms21207808","pmid":"33096940","tags":["cbd","harm-reduction","drug-interactions"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers gave mice a high-dose cannabidiol-rich cannabis extract (CRCE) alongside methylsulfonylmethane (MSM), a popular over-the-counter supplement often taken for joint pain. The concern was whether combining the two would increase liver toxicity — a reasonable question given CBD's known effects on liver enzymes.\n\nCBD extract alone significantly increased the expression of multiple cytochrome P450 enzymes (CYP1a2, CYP2b10, CYP3a4, among others) — the same enzyme family responsible for metabolizing most prescription drugs. However, MSM alone caused no liver enzyme changes and did not amplify CBD's enzyme effects when the two were given together. No signs of liver toxicity were observed in any group.\n\nThe practical takeaway: CBD's enzyme induction was confirmed (reinforcing drug interaction concerns), but at least one common supplement didn't make the problem worse.","whyItMatters":"CBD products are increasingly used alongside supplements, but almost no research has examined these combinations. This study addressed one specific pairing and found no added harm, which is reassuring. But the broader finding — that CBD alone powerfully induces the same liver enzymes that process prescription drugs — reinforces that CBD is not pharmacologically inert. Anyone taking CBD alongside medications should be aware of this.","specificNumbers":"• CBD extract dose: 123 mg/kg/day for 3 days\n• Significantly induced: CYP1a2, CYP2b10, CYP2c29, CYP3a4, CYP3a11, CYP2c65, CYP2c66\n• MSM did not amplify CBD's enzyme induction\n• No liver toxicity observed in any group","methodology":"Eight-week-old male C57BL/6J mice received either MSM in drinking water (80 mg/100 mL) for 17 days, CBD-rich cannabis extract by oral gavage (123 mg/kg/day for 3 days), both, or neither. Liver enzyme expression measured via RT-PCR. Liver toxicity assessed via histology and serum markers.","limitations":"Mouse model with high CBD doses that may not reflect typical human consumption. Only one supplement tested. Only male mice used. Short treatment duration (3 days of CBD). The extract contained other cannabinoids besides CBD, so effects cannot be attributed to CBD alone."},{"rthcId":"RTHC-02663","title":"This is your teen brain on drugs: In search of biological factors unique to dependence toxicity in adolescence.","authors":"Kwan, Leslie Y; Eaton, David L; Andersen, Susan L; Dow-Edwards, Diana; Levin, Edward D; Talpos, John; Vorhees, Charles V; Li, Abby A","year":2020,"journal":"Neurotoxicology and teratology, 81, 106916","doi":"10.1016/j.ntt.2020.106916","pmid":"32698050","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02664","title":"Rates, predictors and the impact of cannabis misuse on in-hospital outcomes among patients undergoing percutaneous coronary intervention (from the National Inpatient Sample).","authors":"Kwok, Chun Shing; Alraies, M Chadi; Mohamed, Mohamed; Rashid, Muhammad; Shoaib, Ahmad; Nolan, James; Ratib, Karim; Khoo, Chee W; Kontopantelis, Evangelos; Mamas, Mamas A","year":2020,"journal":"International journal of clinical practice, 74(5), e13477","doi":"10.1111/ijcp.13477","pmid":"31922638","tags":["cardiovascular","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"In a national database of 7,306,012 PCI patients (2004-2014), 32,765 cannabis misusers had no significant differences in in-hospital mortality (OR 1.06), bleeding (OR 0.94), or stroke (OR 1.19) compared to non-users after adjustment. Cannabis users actually had significantly lower odds of vascular complications (OR 0.73, p=0.004).","whyItMatters":"Concerns about cannabis and cardiovascular risk are common, but few studies have examined outcomes after cardiac procedures. This massive dataset found no evidence of worse outcomes.","specificNumbers":"7,306,012 total patients; 32,765 cannabis misusers (0.4%); cannabis users were younger (49.5 vs 64.6 years); no difference in mortality, bleeding, or stroke; lower vascular complications (OR 0.73).","methodology":"Retrospective analysis of the National Inpatient Sample (2004-2014) comparing in-hospital outcomes after percutaneous coronary intervention between cannabis misusers and non-users, adjusting for health status proxies.","limitations":"Observational database study; cannabis misuse identified by ICD codes (likely underreported); cannot distinguish type, frequency, or route of cannabis use; cannabis users were significantly younger, which may confound results despite adjustment."},{"rthcId":"RTHC-02665","title":"Evidence for adverse effects of cannabidiol (CBD) products and their non-conformity on the European food market - response to the European Industrial Hemp Association.","authors":"Lachenmeier, Dirk W; Walch, Stephan G","year":2020,"journal":"F1000Research, 9, 1051","doi":"10.12688/f1000research.26045.2","pmid":"33082934","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02666","title":"The relationship between cannabis use and patient outcomes in medication-based treatment of opioid use disorder: A systematic review.","authors":"Lake, Stephanie; St Pierre, Michelle","year":2020,"journal":"Clinical psychology review, 82, 101939","doi":"10.1016/j.cpr.2020.101939","pmid":"33130527","tags":["addiction","harm-reduction","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 41 studies examining cannabis use during methadone, buprenorphine, or naltrexone treatment for opioid use disorder, the majority found no significant association between cannabis use and opioid use, treatment adherence, or retention. A small number of studies found either supportive or detrimental effects, but these were inconsistent.","whyItMatters":"Clinicians often worry that cannabis use might undermine opioid addiction treatment. This comprehensive review suggests those concerns are largely unsupported by evidence, which could influence how treatment programs handle cannabis-positive patients.","specificNumbers":"41 studies included (23 methadone, 7 buprenorphine, 6 naltrexone, 5 mixed); majority found no significant association between cannabis use and primary outcomes.","methodology":"Systematic review of 41 peer-reviewed studies across seven databases examining cannabis use during medication-based opioid use disorder treatment (methadone, buprenorphine, naltrexone).","limitations":"High heterogeneity in how cannabis use was measured and defined across studies; most studies were observational; potential confounding from polysubstance use; cannabis use patterns varied widely."},{"rthcId":"RTHC-02667","title":"Does cannabis use modify the effect of post-traumatic stress disorder on severe depression and suicidal ideation? Evidence from a population-based cross-sectional study of Canadians.","authors":"Lake, Stephanie; Kerr, Thomas; Buxton, Jane; Walsh, Zach; Marshall, Brandon Dl; Wood, Evan; Milloy, M-J","year":2020,"journal":"Journal of psychopharmacology (Oxford, England), 34(2), 181-188","doi":"10.1177/0269881119882806","pmid":"31684805","tags":["ptsd","depression","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 24,089 respondents in the Canadian Community Health Survey, people with PTSD who used cannabis had lower odds of experiencing a major depressive episode and suicidal ideation compared to those with PTSD who did not use cannabis, after controlling for demographics and comorbidities.","whyItMatters":"PTSD dramatically increases the risk of depression and suicide. If cannabis genuinely moderates this relationship, it could have significant implications for treatment, though observational data alone cannot prove causation.","specificNumbers":"24,089 respondents; 420 (1.7%) had PTSD; 28.2% of those with PTSD used cannabis vs. 11.2% without PTSD; cannabis use associated with reduced odds of depression and suicidal ideation in PTSD group.","methodology":"Cross-sectional analysis of the 2012 Canadian Community Health Survey-Mental Health (n=24,089) using logistic regression with interaction terms for cannabis and PTSD status.","limitations":"Cross-sectional design cannot establish causation; self-reported data; cannabis use patterns (frequency, type) were not detailed; potential for residual confounding; PTSD sample relatively small."},{"rthcId":"RTHC-02668","title":"Use of illicit substances and violent behaviour in psychotic disorders: two nationwide case-control studies and meta-analyses.","authors":"Lamsma, Jelle; Cahn, Wiepke; Fazel, Seena","year":2020,"journal":"Psychological medicine, 50(12), 2028-2033","doi":"10.1017/S0033291719002125","pmid":"31462346","tags":["psychosis","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across two large nationwide samples (GROUP, Netherlands, N=871; NEDEN, UK, N=921), daily cannabis use was associated with 1.6 times higher odds of violence in people with psychotic disorders (pooled OR 1.6, 95% CI 1.2-2.0). Daily stimulant use (pOR 2.8) and daily depressant use (pOR 2.2) carried even higher risks.","whyItMatters":"Violence risk in psychotic disorders is a major clinical and public health concern. Understanding the specific contribution of different substances helps target prevention strategies.","specificNumbers":"1,792 total participants; daily cannabis: pOR 1.6 (1.2-2.0); daily stimulants: pOR 2.8 (1.7-4.5); daily depressants: pOR 2.2 (1.1-4.5); nondaily cannabis use did not significantly increase violence risk.","methodology":"Two nationwide case-control studies (Netherlands and UK) with standardized substance use and violence assessments, combined in random-effects meta-analyses. Adjusted for age, sex, and education.","limitations":"Cross-sectional assessment of substance use; cannabis use self-reported; cannot establish whether substance use causes violence or shares common risk factors; adjusted for limited confounders only."},{"rthcId":"RTHC-02669","title":"Non-medical cannabis in North America: an overview of regulatory approaches.","authors":"Lancione, S; Wade, K; Windle, S B; Filion, K B; Thombs, B D; Eisenberg, M J","year":2020,"journal":"Public health, 178, 7-14","doi":"10.1016/j.puhe.2019.08.018","pmid":"31600630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02670","title":"Pharmacology and drug interactions of cannabinoids.","authors":"Landmark, Cecilie Johannessen; Brandl, Ulrich","year":2020,"journal":"Epileptic disorders : international epilepsy journal with videotape, 22(S1), 16-22","doi":"10.1684/epd.2019.1123","pmid":"31941642","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02671","title":"CB1 Activity Drives the Selection of Navigational Strategies: A Behavioral and c-Fos Immunoreactivity Study.","authors":"Laricchiuta, Daniela; Balsamo, Francesca; Fabrizio, Carlo; Panuccio, Anna; Termine, Andrea; Petrosini, Laura","year":2020,"journal":"International journal of molecular sciences, 21(3)","doi":"10.3390/ijms21031072","pmid":"32041135","tags":["neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice treated with CB1 antagonist AM251 showed impaired spatial learning on a Circular Hole Board task and shifted their navigation strategy patterns. Brain imaging (c-Fos) revealed altered activity in the hippocampus, dorsal striatum, and amygdala, regions responsible for different types of spatial navigation.","whyItMatters":"The endocannabinoid system is rich in brain regions that control spatial navigation. This study reveals how CB1 receptors help select which navigation strategy the brain uses, connecting cannabis effects to real-world navigation impairment.","specificNumbers":"CB1 blockade modified navigational strategy patterns and altered c-Fos expression in hippocampus, dorsal striatum, and amygdala.","methodology":"Animal study in mice using CB1 inverse agonist AM251 vs. vehicle, with behavioral testing on a Circular Hole Board and c-Fos immunoreactivity mapping in hippocampus, dorsal striatum, and amygdala.","limitations":"Animal study using a synthetic CB1 blocker rather than THC directly; mouse navigation tasks are simplified compared to human spatial cognition; c-Fos is an indirect measure of neural activity."},{"rthcId":"RTHC-02672","title":"Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials.","authors":"Larsen, Christian; Shahinas, Jorida","year":2020,"journal":"Journal of clinical medicine research, 12(3), 129-141","doi":"10.14740/jocmr4090","pmid":"32231748","tags":["cbd","mental-health","anxiety","psychosis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 25 studies (927 patients), CBD showed anxiolytic effects with acute administration and therapeutic effects for social anxiety disorder, psychotic disorder, and substance use disorders. Doses and routes of administration varied widely. Side effects were generally mild, though study quality was often limited.","whyItMatters":"CBD products are sold at wildly different doses with little guidance. This review provides the first systematic look at what doses have actually been tested in humans and what conditions show the most evidence.","specificNumbers":"25 studies; 927 patients (538 men, 389 women); from 5 countries; doses varied significantly across studies.","methodology":"Systematic review of 25 human studies (22 controlled trials, 3 observational) from PubMed, Embase, and Cochrane, published 2000-2019, examining CBD efficacy and safety in adults.","limitations":"Substantial heterogeneity in doses, formulations, and routes of administration; many studies had high risk of bias; limited sample sizes in individual studies."},{"rthcId":"RTHC-02673","title":"Adjunctive Cannabidiol in Patients with Dravet Syndrome: A Systematic Review and Meta-Analysis of Efficacy and Safety.","authors":"Lattanzi, Simona; Brigo, Francesco; Trinka, Eugen; Zaccara, Gaetano; Striano, Pasquale; Del Giovane, Cinzia; Silvestrini, Mauro","year":2020,"journal":"CNS drugs, 34(3), 229-241","doi":"10.1007/s40263-020-00708-6","pmid":"32040850","tags":["cbd","epilepsy"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Pooling three RCTs with 359 participants (228 CBD, 131 placebo), adjunctive CBD was associated with a 69% higher likelihood of achieving 50% or greater reduction in convulsive seizures (RR 1.69, 95% CI 1.21-2.36, p=0.002). However, CBD also led to higher treatment discontinuation (RR 3.12) and side effects including somnolence, decreased appetite, diarrhea, and elevated liver enzymes.","whyItMatters":"Dravet syndrome is among the most severe drug-resistant epilepsies. This meta-analysis provides the highest level of evidence confirming that CBD offers meaningful seizure reduction for these patients.","specificNumbers":"3 RCTs; 359 participants; 50% responder rate RR 1.69 (p=0.002); treatment discontinuation RR 3.12; common AEs: somnolence, appetite decrease, diarrhea, elevated liver enzymes.","methodology":"Systematic review and meta-analysis of three randomized, placebo-controlled, double-blind trials of plant-derived pharmaceutical CBD (Epidiolex) as adjunctive treatment for Dravet syndrome seizures.","limitations":"Only three trials available; relatively short treatment periods; all used the same pharmaceutical CBD formulation (Epidiolex), so results may not generalize to other CBD products."},{"rthcId":"RTHC-02674","title":"Cannabidiol efficacy and clobazam status: A systematic review and meta-analysis.","authors":"Lattanzi, Simona; Trinka, Eugen; Striano, Pasquale; Zaccara, Gaetano; Del Giovane, Cinzia; Nardone, Raffaele; Silvestrini, Mauro; Brigo, Francesco","year":2020,"journal":"Epilepsia, 61(6), 1090-1098","doi":"10.1111/epi.16546","pmid":"32452532","tags":["cbd","epilepsy","drug-interactions"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across four RCTs with 714 participants, CBD was associated with significantly higher seizure response rates compared to placebo both in patients taking clobazam (52.9% vs 27.8%, RR=1.85) and those not taking it (29.1% vs 15.7%, RR=1.80). The effect sizes were similar regardless of clobazam status.","whyItMatters":"A key debate in epilepsy medicine was whether CBD works on its own or only because it boosts clobazam blood levels through a drug interaction. This analysis suggests CBD has independent anti-seizure efficacy.","specificNumbers":"714 participants (429 CBD, 285 placebo); CLB-On: 52.9% vs 27.8% response (RR=1.85, p<0.001); CLB-Off: 29.1% vs 15.7% response (RR=1.80, p=0.015).","methodology":"Meta-analysis of four randomized, placebo-controlled trials in Dravet and Lennox-Gastaut syndrome, stratified by concomitant clobazam use. Risk ratios estimated using inverse variance method.","limitations":"Patients were not randomized to clobazam status (post-hoc subgroup analysis); limited sample sizes in subgroups; all trials used pharmaceutical-grade CBD (Epidiolex)."},{"rthcId":"RTHC-02675","title":"Diagnostic stability in children and adolescents with bipolar disorder, a nationwide register-based study.","authors":"Laursen, Mathilde Frahm; Licht, Rasmus W; Correll, Christoph U; Kallehauge, Tobias; Christensen, Ann-Eva; Rodrigo-Domingo, Maria; Nielsen, René Ernst","year":2020,"journal":"International journal of bipolar disorders, 8(1), 14","doi":"10.1186/s40345-020-0179-3","pmid":"32372109","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02676","title":"Cannabis-induced recurrent myocardial infarction in a 21-year-old man: a case report.","authors":"Lawin, Dennis; Lawrenz, Thorsten; Tego, Andi; Stellbrink, Christoph","year":2020,"journal":"European heart journal. Case reports, 4(3), 1-5","doi":"10.1093/ehjcr/ytaa063","pmid":"32617514","tags":["cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 21-year-old man with no cardiovascular risk factors experienced four acute coronary syndrome events over 18 months, each involving thrombotic coronary artery occlusion requiring intervention. Each event was preceded by cannabis consumption. Despite dual antiplatelet therapy, events recurred while he continued using cannabis. After cessation, he remained symptom-free for 8 months.","whyItMatters":"While cannabis-related heart attacks in young adults are rare, this case is striking because of the recurrence pattern: four events directly linked to continued cannabis use, with resolution after stopping.","specificNumbers":"21-year-old male; 4 ACS events in 18 months; no cardiovascular risk factors; symptom-free 8 months after cannabis cessation.","methodology":"Single case report with detailed clinical documentation of four ACS events including coronary angiography, treatment records, and 8-month follow-up after cannabis cessation.","limitations":"Single case report cannot prove causation; no toxicology confirmation of cannabis as sole substance; temporal association does not exclude other triggers; extremely rare presentation."},{"rthcId":"RTHC-02677","title":"The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers.","authors":"Lawn, Will; Hill, James; Hindocha, Chandni; Yim, Jocelyn; Yamamori, Yumeya; Jones, Gus; Walker, Hannah; Green, Sebastian F; Wall, Matthew B; Howes, Oliver D; Curran, H Valerie; Freeman, Tom P; Bloomfield, Michael Ap","year":2020,"journal":"Journal of psychopharmacology (Oxford, England), 34(9), 969-980","doi":"10.1177/0269881120944148","pmid":"32755273","tags":["cbd","neuroscience","dopamine"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In a double-blind, placebo-controlled crossover study, 23 healthy participants showed no differences in reward-related brain activity (measured by fMRI during a monetary incentive delay task) after 600mg CBD compared to placebo. Bayesian analyses confirmed similarity between conditions. Behavioral measures of reward motivation also showed no difference.","whyItMatters":"CBD has been proposed as a treatment for conditions involving reward dysfunction (e.g., addiction, depression). This well-designed null finding suggests acute CBD does not directly alter reward processing in healthy brains.","specificNumbers":"23 participants; single 600mg CBD dose; no significant differences in whole-brain or ROI analyses; Bayesian analysis supported null finding.","methodology":"Double-blind, placebo-controlled, repeated-measures crossover design. 23 healthy volunteers received 600mg oral CBD or placebo. fMRI measured brain activity during monetary incentive delay task targeting reward anticipation and feedback.","limitations":"Small sample; single acute dose only; healthy volunteers (effects might differ in psychiatric populations); one specific reward task may not capture all aspects of reward processing."},{"rthcId":"RTHC-02678","title":"The Lower-Risk Cannabis Use Guidelines' (LRCUG) recommendations: How are Canadian cannabis users complying?","authors":"Lee, Chae-Rim; Lee, Angelica; Goodman, Samantha; Hammond, David; Fischer, Benedikt","year":2020,"journal":"Preventive medicine reports, 20, 101187","doi":"10.1016/j.pmedr.2020.101187","pmid":"33083205","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02679","title":"Self-reported Cannabis Use and Changes in Body Mass Index, CD4 T-Cell Counts, and HIV-1 RNA Suppression in Treated Persons with HIV.","authors":"Lee, James T; Saag, Lauren A; Kipp, Aaron M; Logan, James; Shepherd, Bryan E; Koethe, John R; Turner, Megan; Bebawy, Sally; Sterling, Timothy R; Hulgan, Todd","year":2020,"journal":"AIDS and behavior, 24(4), 1275-1280","doi":"10.1007/s10461-019-02430-x","pmid":"30778810","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"In a retrospective cohort of 1,010 HIV-positive adults starting their first ART regimen (4,290 visits, 2008-2011), cannabis use was associated with greater odds of detectable viral load (OR 2.02 for ever-use during study, OR 1.72 for any use in past 7 days). Cannabis use was not associated with changes in CD4+ T-cell count or BMI.","whyItMatters":"Cannabis use is common among HIV-positive individuals, but evidence on how it affects treatment outcomes is limited. The association with detectable viral loads may reflect adherence differences rather than a direct pharmacological effect.","specificNumbers":"1,010 patients; 4,290 visits (2008-2011); ever cannabis use OR 2.02 for detectable viral load; no significant differences in CD4 count or BMI.","methodology":"Retrospective cohort study of 1,010 HIV-positive adults initiating first ART regimen, with self-reported cannabis use assessed at each visit. Random effects models adjusted for age, sex, race, and other substance use.","limitations":"Self-reported cannabis use (likely underreported); retrospective design; cannot distinguish whether cannabis directly affects viral suppression or is a marker for adherence difficulties; single-center study."},{"rthcId":"RTHC-02680","title":"Delta-9 THC can be detected and quantified in the semen of men who are chronic users of inhaled cannabis.","authors":"Lee, Malinda S; Lanes, Andrea; Ginsburg, Elizabeth S; Fox, Janis H","year":2020,"journal":"Journal of assisted reproduction and genetics, 37(6), 1497-1504","doi":"10.1007/s10815-020-01762-1","pmid":"32356125","tags":["pregnancy","harm-reduction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Among 12 heavy cannabis users, THC was detectable above reporting levels (0.50 ng/mL) in 2 of 10 analyzable semen samples. Seminal THC was moderately correlated with serum THC levels (r=0.66). Notably, semen parameters (concentration, motility, morphology) were within normal ranges despite heavy cannabis use, though prolactin was elevated in half the participants.","whyItMatters":"This is the first demonstration that THC crosses the blood-testis barrier in humans. This has implications for understanding potential effects on sperm function and reproductive outcomes.","specificNumbers":"12 participants; THC detected in semen of 2/10 samples; moderate correlation with serum THC (r=0.66); median sperm concentration 75.5M/mL, motility 69.5%, morphology 5.5% (all normal); prolactin elevated in 6/12.","methodology":"Proof-of-concept study with 12 healthy men aged 18-45 who were chronic heavy users of inhaled cannabis. THC and metabolites measured in serum, urine, and semen using LC-MS/MS. Standard semen analysis performed.","limitations":"Very small sample (n=12, only 10 analyzable); THC only detectable above threshold in 2 samples; no comparison with non-users; single time point; cannot determine functional significance of seminal THC."},{"rthcId":"RTHC-02681","title":"US Trends of Opioid-use Disorders and Associated Factors Among Hospitalized Patients With Spinal Conditions and Treatment From 2005 to 2014.","authors":"Lee, Se Won; Shen, Jay; Kim, Sun Jung; Chun, Sung-Youn; Kim, Pearl; Riaz, Jahan; Yoo, Ji Won; Hwang, Jinwook","year":2020,"journal":"Spine, 45(2), 124-133","doi":"10.1097/BRS.0000000000003183","pmid":"31851144","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02682","title":"The distribution of Ohio's Certificates to Recommend: who will \"prescribe\" medical marijuana?","authors":"Leeds, Frederic Stuart; Levinthal, Ryan K; Alexander, Morgan T; Crawford, Timothy N","year":2020,"journal":"Journal of cannabis research, 2(1), 11","doi":"10.1186/s42238-020-00019-z","pmid":"33526104","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02683","title":"Safety and Tolerability of Cannabidiol in Parkinson Disease: An Open Label, Dose-Escalation Study.","authors":"Leehey, Maureen A; Liu, Ying; Hart, Felecia; Epstein, Christen; Cook, Mary; Sillau, Stefan; Klawitter, Jost; Newman, Heike; Sempio, Cristina; Forman, Lisa; Seeberger, Lauren; Klepitskaya, Olga; Baud, Zachrey; Bainbridge, Jacquelyn","year":2020,"journal":"Cannabis and cannabinoid research, 5(4), 326-336","doi":"10.1089/can.2019.0068","pmid":"33381646","tags":["cbd","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Thirteen Parkinson disease patients taking CBD at 20-25 mg/kg/day showed significant improvement in total MDS-UPDRS scores (17.8% decrease, p=0.012) and motor scores (24.7% decrease, p=0.004). Sleep and emotional/behavioral control also improved. However, elevated liver enzymes occurred in 38.5% at the highest dose, and 23% dropped out due to intolerance.","whyItMatters":"Cannabis use is increasingly common among Parkinson patients, but controlled data are scarce. This study provides the first dose-escalation safety and tolerability data for pharmaceutical CBD in this population.","specificNumbers":"13 participants (10 male); mean age 68.15; motor scores improved 24.7% (p=0.004); liver enzyme elevations in 38.5%; 3 dropouts (23%); common AEs: diarrhea (85%), somnolence (69%), fatigue (62%).","methodology":"Open-label, dose-escalation study of 13 Parkinson disease patients titrated from 5 to 20-25 mg/kg/day pharmaceutical CBD (Epidiolex) maintained for 10-15 days.","limitations":"Open-label design (no placebo control); very small sample; short treatment period (10-15 days); strong placebo effect known in PD trials; high dropout rate; liver enzyme concerns at therapeutic doses."},{"rthcId":"RTHC-02684","title":"Genotoxic Properties of Synthetic Cannabinoids on TK6 Human Cells by Flow Cytometry.","authors":"Lenzi, Monia; Cocchi, Veronica; Cavazza, Luca; Bilel, Sabrine; Hrelia, Patrizia; Marti, Matteo","year":2020,"journal":"International journal of molecular sciences, 21(3)","doi":"10.3390/ijms21031150","pmid":"32050487","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02685","title":"Cannabis labelling and consumer understanding of THC levels and serving sizes.","authors":"Leos-Toro, Cesar; Fong, Geoffrey T; Meyer, Samantha B; Hammond, David","year":2020,"journal":"Drug and alcohol dependence, 208, 107843","doi":"10.1016/j.drugalcdep.2020.107843","pmid":"32044091","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02686","title":"Activation of cannabinoid type 1 receptors decreases the synchronization of local field potential oscillations in the hippocampus and entorhinal cortex and prolongs the interresponse time during a differential-reinforcement-of-low-rate task.","authors":"Liao, Wan-Ting; Chang, Chao-Lin; Hsiao, Yi-Tse","year":2020,"journal":"The European journal of neuroscience, 52(10), 4249-4266","doi":"10.1111/ejn.14856","pmid":"32510690","tags":["neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 receptor activation in the medial entorhinal cortex reduced gamma amplitude synchronization and theta-gamma coupling between the hippocampal CA1 region and MEC. This desynchronization was associated with rats overestimating time intervals on a task requiring precise 10-second timing.","whyItMatters":"Time distortion is one of the most commonly reported effects of cannabis. This study identifies a specific neural mechanism: cannabis disrupts the communication between two brain regions critical for timing.","specificNumbers":"CB1 activation shifted interresponse times toward 12.4-14 seconds (overshooting the required 10-second delay); decreased gamma synchronization and theta-gamma coupling between CA1 and MEC.","methodology":"Animal study recording local field potentials in hippocampal CA1 and medial entorhinal cortex of rats performing a differential-reinforcement-of-low-rate (DRL) 10-second task, with and without CB1 receptor agonist.","limitations":"Animal study; used a selective CB1 agonist rather than THC; task timing is simplified compared to human time perception; LFP recordings provide population-level, not single-neuron, data."},{"rthcId":"RTHC-02687","title":"Studying individual risk factors for self-harm in the UK Biobank: A polygenic scoring and Mendelian randomisation study.","authors":"Lim, Kai Xiang; Rijsdijk, Frühling; Hagenaars, Saskia P; Socrates, Adam; Choi, Shing Wan; Coleman, Jonathan R I; Glanville, Kylie P; Lewis, Cathryn M; Pingault, Jean-Baptiste","year":2020,"journal":"PLoS medicine, 17(6), e1003137","doi":"10.1371/journal.pmed.1003137","pmid":"32479557","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02688","title":"Identification of a new cannabidiol n-hexyl homolog in a medicinal cannabis variety with an antinociceptive activity in mice: cannabidihexol.","authors":"Linciano, Pasquale; Citti, Cinzia; Russo, Fabiana; Tolomeo, Francesco; Laganà, Aldo; Capriotti, Anna Laura; Luongo, Livio; Iannotta, Monica; Belardo, Carmela; Maione, Sabatino; Forni, Flavio; Vandelli, Maria Angela; Gigli, Giuseppe; Cannazza, Giuseppe","year":2020,"journal":"Scientific reports, 10(1), 22019","doi":"10.1038/s41598-020-79042-2","pmid":"33328530","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02689","title":"Cannabinoid receptor 2 activation decreases severity of cyclophosphamide-induced cystitis via regulating autophagy.","authors":"Liu, Qinggang; Wu, Zonglong; Liu, Yaxiao; Chen, Lipeng; Zhao, Hongda; Guo, Hongda; Zhu, Kejia; Wang, Wenfu; Chen, Shouzhen; Zhou, Nan; Li, Yan; Shi, Benkang","year":2020,"journal":"Neurourology and urodynamics, 39(1), 158-169","doi":"10.1002/nau.24205","pmid":"31729056","tags":["inflammation","medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In mice with cyclophosphamide-induced cystitis, CB2 agonist JWH-133 significantly reduced pain sensitivity, decreased urinary frequency, and alleviated bladder inflammation and oxidative stress. The protective effect depended on autophagy activation via the AMPK-mTOR pathway, as blocking autophagy eliminated the benefit.","whyItMatters":"Interstitial cystitis/bladder pain syndrome is a chronic condition with limited treatment options. This study identifies a specific cannabinoid mechanism (CB2 via autophagy) that could lead to targeted therapies without the psychoactive effects of CB1 activation.","specificNumbers":"JWH-133 (1 mg/kg) significantly reduced mechanical sensitivity, urinary frequency, and bladder inflammation markers. Effects abolished by autophagy inhibitor 3-MA.","methodology":"Animal study using female C57BL/6J mice with cyclophosphamide-induced cystitis, treated with CB2 agonist (JWH-133), CB2 antagonist (AM-630), or autophagy inhibitor (3-MA). Assessed pain, voiding, histology, and molecular markers.","limitations":"Animal model of chemically-induced cystitis may not fully replicate human interstitial cystitis; only acute treatment was tested; specific CB2 agonist used (JWH-133) is not available clinically."},{"rthcId":"RTHC-02690","title":"Model-based analysis on systemic availability of co-administered cannabinoids after controlled vaporised administration.","authors":"Liu, Zheng; Galettis, Peter; Broyd, Samantha J; van Hell, Hendrika; Greenwood, Lisa-Marie; de Krey, Peter; Steigler, Amy; Zhu, Xiao; Schneider, Jennifer; Solowij, Nadia; Martin, Jennifer H","year":2020,"journal":"Internal medicine journal, 50(7), 846-853","doi":"10.1111/imj.14415","pmid":"31264294","tags":["cbd","medical-cannabis","drug-interactions"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a randomized, double-blind, crossover study, concomitant inhalation of high-dose CBD significantly decreased the systemic availability of THC. Population pharmacokinetic models showed that frequent cannabis users had higher systemic availability of both THC and CBD compared to infrequent users.","whyItMatters":"Many medical cannabis users consume both THC and CBD. Understanding how they interact pharmacokinetically is essential for dosing guidance. The finding that CBD reduces THC availability could explain why CBD-rich products feel less intoxicating.","specificNumbers":"High-dose CBD significantly decreased THC systemic availability. Frequent users had higher availability of both compounds. Population PK models developed for both THC and CBD.","methodology":"Randomized, double-blind, crossover, placebo-controlled design. THC and/or CBD in ethanol were vaporized and inhaled. Plasma concentrations analyzed and population pharmacokinetic models developed by pooling with published data.","limitations":"Relatively small sample; vaporized administration only (results may differ for oral or sublingual routes); pooled data from different studies for PK modeling; acute dosing only."},{"rthcId":"RTHC-02691","title":"Sex differences in driving under the influence of cannabis: The role of medical and recreational cannabis use.","authors":"Lloyd, Shawnta L; Lopez-Quintero, Catalina; Striley, Catherine W","year":2020,"journal":"Addictive behaviors, 110, 106525","doi":"10.1016/j.addbeh.2020.106525","pmid":"32711286","tags":["driving","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Male cannabis users who combined medical and recreational use had the highest probability of DUIC (40%), while female medical-only users had the lowest (20%). Women showed similar DUIC rates regardless of use reason (20-25%), while men varied widely (28-40%). The sex difference was most pronounced among combined medical/recreational users.","whyItMatters":"As both medical and recreational cannabis expand, understanding who is most likely to drive impaired helps target prevention. Men who use for both purposes emerge as the highest-risk group.","specificNumbers":"17,405 cannabis users; 88.1% recreational, 7.8% medical, 4.1% both; DUIC probability: male combined users 40%, female medical-only 20%.","methodology":"Cross-sectional analysis of 17,405 past-year cannabis users (18+) from the 2016-17 National Survey on Drug Use and Health, using multivariable logistic regression with sex-by-reason interaction.","limitations":"Cross-sectional survey with self-reported DUIC; cannot establish that DUIC was actually impaired driving; does not assess actual impairment or crash risk; reasons for use may overlap with other risk factors."},{"rthcId":"RTHC-02692","title":"The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice.","authors":"Lopes, Jadna B; Bastos, Juliana R; Costa, Rayssa B; Aguiar, Daniele C; Moreira, Fabrício A","year":2020,"journal":"Psychopharmacology, 237(2), 385-394","doi":"10.1007/s00213-019-05370-5","pmid":"31667531","tags":["addiction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 antagonist AM251 inhibited acquisition and expression of cocaine sensitization and conditioned place preference (CPP). CB2 agonist JWH133 similarly inhibited both sensitization and CPP, with effects reversed by CB2 antagonist AM630. Both drugs prevented cocaine-induced hippocampal neuronal activation (c-Fos), suggesting converging mechanisms despite acting on different receptors.","whyItMatters":"This study shows that the endocannabinoid system modulates cocaine reward through two independent receptor pathways, potentially doubling the number of therapeutic targets for cocaine addiction.","specificNumbers":"AM251 inhibited sensitization at 0.3-3 mg/kg and CPP at 10 mg/kg; JWH133 inhibited both at 0.3-3 mg/kg; effects reversed by CB2 antagonist AM630 (5 mg/kg).","methodology":"Animal study in male Swiss mice using CB1 antagonist AM251 and CB2 agonist JWH133 in cocaine-induced behavioral sensitization and conditioned place preference models, with c-Fos immunohistochemistry.","limitations":"Animal study in mice; synthetic cannabinoid agents not available clinically; only male mice used (sex differences unknown); acute dosing paradigm may not reflect chronic treatment."},{"rthcId":"RTHC-02693","title":"Effects of Hemp Extract on Markers of Wellness, Stress Resilience, Recovery and Clinical Biomarkers of Safety in Overweight, But Otherwise Healthy Subjects.","authors":"Lopez, Hector L; Cesareo, Kyle R; Raub, Betsy; Kedia, A William; Sandrock, Jennifer E; Kerksick, Chad M; Ziegenfuss, Tim N","year":2020,"journal":"Journal of dietary supplements, 17(5), 561-586","doi":"10.1080/19390211.2020.1765941","pmid":"32456572","tags":["cbd","mental-health","sleep"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 65 overweight but healthy adults, 60mg/day hemp extract (containing 15mg CBD) significantly improved HDL cholesterol (p=0.004, ES=0.75). Statistical trends favored hemp for \"pleasure from life\" (p=0.06, ES=0.48) and \"ability to cope with stress\" (p=0.07, ES=0.46). Within-group improvements in sleep quality (p=0.005) and quantity (p=0.01) were observed. All safety markers remained normal.","whyItMatters":"This is one of the few placebo-controlled trials testing commercially available CBD hemp products at typical consumer doses. The HDL finding is novel and unexpected.","specificNumbers":"65 participants; 6 weeks; HDL improvement p=0.004, ES=0.75; sleep quality within-group p=0.005, ES=0.54; all safety markers within normal limits.","methodology":"Randomized, double-blind, placebo-controlled trial with 65 overweight adults (BMI ~28.5) taking 60mg/day hemp extract (15mg CBD) or placebo for 6 weeks, measuring stress resilience, psychometrics, HRV, body composition, and clinical biomarkers.","limitations":"Relatively small sample; 6-week duration; only 15mg CBD per day (much lower than most clinical studies); hemp extract contains other compounds beyond CBD; most primary outcomes were not statistically significant."},{"rthcId":"RTHC-02694","title":"Activation of Cannabinoid Receptors Attenuates Endothelin-1-Induced Mitochondrial Dysfunction in Rat Ventricular Myocytes.","authors":"Lu, Yan; Lee, Danielle I; Roy Chowdhury, Subir; Lu, Ping; Kamboj, Amit; Anderson, Christopher M; Fernyhough, Paul; Anderson, Hope D","year":2020,"journal":"Journal of cardiovascular pharmacology, 75(1), 54-63","doi":"10.1097/FJC.0000000000000758","pmid":"31815823","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02695","title":"Content analysis of online product descriptions from cannabis retailers in six US states.","authors":"Luc, Mary H; Tsang, Samantha W; Thrul, Johannes; Kennedy, Ryan D; Moran, Meghan B","year":2020,"journal":"The International journal on drug policy, 75, 102593","doi":"10.1016/j.drugpo.2019.10.017","pmid":"31794923","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02696","title":"Reductions in alcohol use following medical cannabis initiation: results from a large cross-sectional survey of medical cannabis patients in Canada.","authors":"Lucas, Philippe; Boyd, Susan; Milloy, M-J; Walsh, Zach","year":2020,"journal":"The International journal on drug policy, 86, 102963","doi":"10.1016/j.drugpo.2020.102963","pmid":"33068830","tags":["harm-reduction","medical-cannabis","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a survey of 2,102 Canadian medical cannabis patients, 973 who regularly drank alcohol reported that after starting medical cannabis, 44% decreased drinking frequency, 34% reduced drinks per week, and 8% stopped drinking entirely. Being under 55 and having higher baseline alcohol use predicted greater reductions. Intending to use cannabis to reduce alcohol was associated with both reducing and stopping drinking.","whyItMatters":"Alcohol causes more health harm than cannabis by most measures. If medical cannabis genuinely reduces alcohol consumption, the net public health effect could be substantially positive.","specificNumbers":"2,102 total respondents; 973 regular alcohol users; 44% decreased frequency; 34% reduced drinks/week; 8% stopped entirely; age <55 and higher baseline use predicted greater reductions.","methodology":"Cross-sectional survey of 2,102 Canadian medical cannabis program enrollees, analyzing retrospective self-reported changes in alcohol use among the 973 (44%) who reported regular alcohol use before cannabis initiation.","limitations":"Retrospective self-report; no control group; participants already enrolled in medical cannabis program (self-selection bias); cannot distinguish substitution from coincidental changes; cross-sectional design."},{"rthcId":"RTHC-02697","title":"Neurobiology of cannabinoid receptor signaling
.","authors":"Lutz, Beat","year":2020,"journal":"Dialogues in clinical neuroscience, 22(3), 207-222","doi":"10.31887/DCNS.2020.22.3/blutz","pmid":"33162764","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02698","title":"Cannabis, e-cigarettes and anesthesia.","authors":"Lynn, Rachael S Rzasa; Galinkin, Jeffrey L","year":2020,"journal":"Current opinion in anaesthesiology, 33(3), 318-326","doi":"10.1097/ACO.0000000000000872","pmid":"32371642","tags":["medical-cannabis","respiratory","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis use may reduce the efficacy of propofol and postoperative opioid pain management, potentially requiring higher doses. E-cigarette use, particularly with THC vaping products, has been linked to severe acute lung injury (EVALI). Cannabis affects cardiovascular, respiratory, and neurological function, placing users at increased perioperative risk.","whyItMatters":"With cannabis use increasing, anesthesiologists need to understand how it interacts with surgical care. Under-dosing sedation or pain medication because of unrecognized cannabis tolerance could compromise patient safety.","specificNumbers":"Cannabis users may be tolerant to propofol and opioid effects; EVALI has been linked to THC vaping products.","methodology":"Narrative review of recent literature on cannabis and e-cigarette effects relevant to anesthesia practice, including clinical reports and pharmacological evidence.","limitations":"Narrative review; limited controlled data specifically on cannabis-anesthesia interactions; most evidence for tolerance effects comes from case reports and small series; rapidly evolving landscape of cannabis products."},{"rthcId":"RTHC-02699","title":"Altered Effective Connectivity of Central Autonomic Network in Response to Negative Facial Expression in Adults With Cannabis Use Disorder.","authors":"Ma, Liangsuo; Steinberg, Joel L; Bjork, James M; Wang, Qin; Hettema, John M; Abbate, Antonio; Moeller, F Gerard","year":2020,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 5(1), 84-96","doi":"10.1016/j.bpsc.2019.05.013","pmid":"31345781","tags":["addiction","neuroscience","anxiety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Compared to 23 controls, 23 people with cannabis use disorder showed stronger amygdala-to-hypothalamus connectivity and amygdala-to-fusiform gyri connectivity when viewing fearful/angry faces. This enhanced connectivity correlated with perceived stress levels. A compensatory prefrontal-to-fusiform connection appeared to serve a protective function.","whyItMatters":"Cannabis use disorder is associated with increased cardiovascular risk during stress. This study identifies a specific brain circuit (amygdala to hypothalamus) that may mediate stress-related health risks in CUD.","specificNumbers":"23 CUD subjects, 23 controls; enhanced amygdala-hypothalamus and amygdala-fusiform connectivity; correlations with Perceived Stress Scale scores.","methodology":"Dynamic causal modeling of fMRI data from 23 CUD subjects and 23 matched controls from the Human Connectome Project during an emotional face-matching task.","limitations":"Cross-sectional design; relatively small sample; cannot determine whether connectivity changes cause or result from cannabis use; Human Connectome Project sample may not represent clinical CUD populations."},{"rthcId":"RTHC-02700","title":"The pharmacological effects of inhaled cannabis on pain in patients with multiple sclerosis: risks versus rewards.","authors":"Maayah, Zaid H; Dyck, Jason R B","year":2020,"journal":"Inflammation research : official journal of the European Histamine Research Society ... [et al.], 69(11), 1073-1076","doi":"10.1007/s00011-020-01396-0","pmid":"32860528","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02701","title":"Protection Versus Progress: The Challenge of Research on Cannabis Use During Pregnancy.","authors":"MacDuffie, Katherine E; Kleinhans, Natalia M; Stout, Kaeley; Wilfond, Benjamin S","year":2020,"journal":"Pediatrics, 146(Suppl 1), S93-S98","doi":"10.1542/peds.2020-0818R","pmid":"32737240","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02702","title":"Exposure to the cannabinoid agonist WIN 55, 212-2 in adolescent rats causes sleep alterations that persist until adulthood.","authors":"Macías-Triana, Lorena; Romero-Cordero, Karen; Tatum-Kuri, Agnes; Vera-Barrón, Alba; Millán-Aldaco, Diana; Arankowsky-Sandoval, Gloria; Piomelli, Daniele; Murillo-Rodríguez, Eric","year":2020,"journal":"European journal of pharmacology, 874, 172911","doi":"10.1016/j.ejphar.2020.172911","pmid":"32045604","tags":["sleep","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent rats exposed to WIN 55,212-2 (a cannabinoid agonist) for 14 days during adolescence (postnatal days 30-44) showed significant sleep disturbances when tested as adults (postnatal day 80): decreased wakefulness and enhanced REM sleep. Brain analysis revealed increased neuronal markers in the dorsomedial hypothalamic nucleus, a sleep-regulating region.","whyItMatters":"Cannabis use is common during adolescence, when the brain is still developing. This study shows that cannabinoid exposure during this critical window can permanently alter sleep architecture.","specificNumbers":"Exposure: postnatal days 30-44; testing: postnatal day 80; decreased wakefulness and increased REM sleep persisted ~5 weeks after exposure ended; increased NeuN in dorsomedial hypothalamic nucleus.","methodology":"Animal study exposing adolescent rats to cannabinoid agonist WIN 55,212-2 (0.1-1.0 mg/kg/day IP) for 14 days during adolescence, with sleep recording and NeuN immunohistochemistry in adulthood.","limitations":"Animal study using a synthetic cannabinoid agonist (not THC); rat adolescence is a rough analog for human adolescence; only male rats studied; electrophysiological sleep recording has limitations."},{"rthcId":"RTHC-02703","title":"Protocol for a feasibility study investigating the UCalgary's Cannabis Café: education and harm reduction initiative for postsecondary students.","authors":"Mader, Joel; Smith, Jacqueline M; Smith, Jennifer; Christensen, Darren Robert","year":2020,"journal":"BMJ open, 10(2), e032651","doi":"10.1136/bmjopen-2019-032651","pmid":"32051305","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02704","title":"Cannabis use the week before admission to psychiatric in-patient service as a marker of severity.","authors":"Madero, S; Oliveras, C; Pons, M T; Sague, M; López-Pelayo, H; Gual, A; Balcells, M","year":2020,"journal":"Journal of psychiatric research, 129, 40-46","doi":"10.1016/j.jpsychires.2020.05.028","pmid":"32563776","tags":["psychosis","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis use the week before psychiatric admission (25.5% prevalence) showed a weak positive correlation with symptom severity (rs=0.28, p=0.03) in bivariate analysis, but was not an independent predictor in multivariate models. Psychotic disorder diagnosis and need for emergency antipsychotics/benzodiazepines were the significant predictors of severity.","whyItMatters":"Understanding the relationship between pre-admission cannabis use and psychiatric symptom severity helps clinicians assess risk and tailor treatment, particularly for psychosis patients.","specificNumbers":"106 inpatients; 25.5% used cannabis before admission; mean BPRS 55.8 overall, 62.9 among cannabis users; weak correlation rs=0.28 between SJU and BPRS.","methodology":"Cross-sectional study of 106 acute psychiatric inpatients, measuring cannabis use in Standard Joint Units (SJU) the week before admission and symptom severity via Brief Psychiatric Rating Scale (BPRS).","limitations":"Small single-center sample; cross-sectional design; self-reported cannabis use; Standard Joint Units may not capture all forms of consumption; 25.5% prevalence may underestimate use."},{"rthcId":"RTHC-02705","title":"Plant Natural Sources of the Endocannabinoid (E)-β-Caryophyllene: A Systematic Quantitative Analysis of Published Literature.","authors":"Maffei, Massimo E","year":2020,"journal":"International journal of molecular sciences, 21(18)","doi":"10.3390/ijms21186540","pmid":"32906779","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02706","title":"Effects of cannabis oil extract on immune response gene expression in human small airway epithelial cells (HSAEpC): implications for chronic obstructive pulmonary disease (COPD).","authors":"Mamber, Stephen W; Gurel, Volkan; Lins, Jeremy; Ferri, Fred; Beseme, Sarah; McMichael, John","year":2020,"journal":"Journal of cannabis research, 2(1), 5","doi":"10.1186/s42238-019-0014-9","pmid":"33526116","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02707","title":"Controlled administration of cannabis to mitigate cannabis-attributable harm among recreational users: a quasi-experimental study in Germany.","authors":"Manthey, Jakob; Kalke, Jens; Rehm, Jürgen; Rosenkranz, Moritz; Verthein, Uwe","year":2020,"journal":"F1000Research, 9, 201","doi":"10.12688/f1000research.22612.2","pmid":"32789008","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02708","title":"Reduced Segregation Between Cognitive and Emotional Processes in Cannabis Dependence.","authors":"Manza, Peter; Shokri-Kojori, Ehsan; Volkow, Nora D","year":2020,"journal":"Cerebral cortex (New York, N.Y. : 1991), 30(2), 628-639","doi":"10.1093/cercor/bhz113","pmid":"31211388","tags":["addiction","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using Human Connectome Project data from 89 cannabis-dependent individuals, 87 recreational users, and matched controls, researchers found that cognitive and emotional measures were significantly correlated in the cannabis-dependent group only. Brain imaging confirmed: emotional and cognitive task activations overlapped in cannabis dependence but remained distinct in controls and recreational users.","whyItMatters":"This study provides a neural explanation for why cannabis-dependent individuals may have difficulty thinking clearly when emotionally stressed. The loss of cognitive-emotional segregation may contribute to poor decision-making.","specificNumbers":"1,206 participants (89 cannabis-dependent, 87 recreational users, matched controls); significant cognitive-emotional correlation in CD group only; overlapping brain activations on fMRI.","methodology":"Cross-sectional analysis of Human Connectome Project data from 1,206 young adults, using principal component analysis of cognitive/emotional measures and fMRI activations during working memory and emotional face tasks.","limitations":"Cross-sectional (cannot determine if dependence causes the loss of segregation or vice versa); HCP sample is relatively young and healthy; cannabis dependence based on DSM criteria may not capture full spectrum."},{"rthcId":"RTHC-02709","title":"Persistent cannabis use among young adults with early psychosis receiving coordinated specialty care in the United States.","authors":"Marino, Leslie; Scodes, Jennifer; Richkin, Talia; Alves-Bradford, Jean-Marie; Nossel, Ilana; Wall, Melanie; Dixon, Lisa","year":2020,"journal":"Schizophrenia research, 222, 274-282","doi":"10.1016/j.schres.2020.05.035","pmid":"32473930","tags":["psychosis","addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Of 938 first-episode psychosis patients in Coordinated Specialty Care, 38.8% used cannabis at admission and 32.8% had persistent use at 1 year. Persistent users were more likely male, had worse baseline symptoms, more suicidality, violent ideation, and legal trouble. At 1 year, persistent users maintained worse symptoms than non-users, while those who reduced use showed significant symptom improvement.","whyItMatters":"One-third of first-episode psychosis patients continued using cannabis despite receiving specialized early intervention services. The finding that reducing use improved symptoms provides concrete motivation for cannabis-focused interventions in this population.","specificNumbers":"938 patients; 38.8% used cannabis at admission; 32.8% persistent use at 1 year; persistent users had worse GAF scores at baseline (p<0.001) and 1 year (p=0.021); reduced users improved vs. persistent (p=0.008).","methodology":"Longitudinal analysis of 938 first-episode psychosis patients enrolled in US Coordinated Specialty Care programs for at least 1 year, categorized into no use, reduced use, and persistent cannabis use groups.","limitations":"Observational (cannot prove cannabis caused worse outcomes); selection effects (those able to reduce may differ in other ways); cannabis use self-reported; limited to US CSC programs."},{"rthcId":"RTHC-02710","title":"Differentiating Full-Spectrum Hemp Extracts from CBD Isolates: Implications for Policy, Safety and Science.","authors":"Marinotti, Osvaldo; Sarill, Miles","year":2020,"journal":"Journal of dietary supplements, 17(5), 517-526","doi":"10.1080/19390211.2020.1776806","pmid":"32543253","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02711","title":"Effects of combined 5-HT2A and cannabinoid receptor modulation on a schizophrenia-related prepulse inhibition deficit in mice.","authors":"Marques, Adriana M; Macena, Michele V; Cardoso, Aline R; Hammes, Camila S O; Pinheiro, Fernanda M L; Castro, Newton G; Neves, Gilda A","year":2020,"journal":"Psychopharmacology, 237(6), 1643-1655","doi":"10.1007/s00213-020-05485-0","pmid":"32095916","tags":["psychosis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Neither the CB1 agonist WIN 55,212-2 nor the CB1 inverse agonist rimonabant alone affected prepulse inhibition (PPI) or blocked MK-801-induced PPI deficits. However, combining the 5-HT2A antagonist volinanserin with rimonabant significantly improved PPI in both normal and MK-801-treated mice, suggesting a synergistic interaction between serotonin and cannabinoid systems.","whyItMatters":"Current antipsychotic medications have significant side effects. Finding that combined serotonin-cannabinoid modulation works better than either alone opens a new avenue for drug combination strategies in psychotic disorders.","specificNumbers":"Volinanserin + rimonabant combination increased PPI in both control and MK-801-treated mice; neither cannabinoid drug alone affected PPI.","methodology":"Animal study in male Swiss mice testing combinations of cannabinoid drugs (WIN 55,212-2, rimonabant) and serotonin drugs (8-OH-DPAT, volinanserin) in an MK-801-induced PPI disruption model relevant to schizophrenia.","limitations":"Animal model; MK-801-induced PPI disruption is only one aspect of schizophrenia pathology; rimonabant has been withdrawn from clinical use due to psychiatric side effects; only male mice used."},{"rthcId":"RTHC-02712","title":"Marijuana: the effects on pregnancy, the fetus, and the newborn.","authors":"Martin, Gilbert I","year":2020,"journal":"Journal of perinatology : official journal of the California Perinatal Association, 40(10), 1470-1476","doi":"10.1038/s41372-020-0708-z","pmid":"32507859","tags":["pregnancy","youth","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review summarizes evidence that prenatal cannabis exposure is associated with lower birth weight, neonatal effects, and developmental delays during the first two years of life. It also highlights the increasing use of synthetic cannabinoids during pregnancy, which may pose even greater risks due to their higher potency.","whyItMatters":"Cannabis use during pregnancy is increasing, often to treat nausea. This review consolidates what is known about risks to help inform clinical guidance in a space with many unanswered questions.","specificNumbers":"Developmental delay documented in first 2 years of life in exposed infants; synthetic cannabinoids noted as having greater psychotropic activity and harm potential.","methodology":"Narrative review covering legislation, physiology, pathophysiology of perinatal cannabis use, neonatal effects, breastfeeding considerations, and developmental outcomes in the first two years.","limitations":"Narrative review format; many cited studies have confounding factors (tobacco, alcohol, socioeconomic status); limited ability to isolate cannabis effects; most evidence is observational."},{"rthcId":"RTHC-02713","title":"Expression of GPR55 and either cannabinoid CB1 or CB2 heteroreceptor complexes in the caudate, putamen, and accumbens nuclei of control, parkinsonian, and dyskinetic non-human primates.","authors":"Martínez-Pinilla, Eva; Rico, Alberto J; Rivas-Santisteban, Rafael; Lillo, Jaume; Roda, Elvira; Navarro, Gemma; Lanciego, José Luis; Franco, Rafael","year":2020,"journal":"Brain structure & function, 225(7), 2153-2164","doi":"10.1007/s00429-020-02116-4","pmid":"32691218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02714","title":"Epidemiology of drug driving: protocol from a national Canadian study measuring levels of cannabis, alcohol and other substances in injured drivers.","authors":"Masud, Manal; Chan, Herbert; Erdelyi, Shannon; Yuan, Yue; Brubacher, Jeffrey R","year":2020,"journal":"BMC public health, 20(1), 1070","doi":"10.1186/s12889-020-09176-5","pmid":"32631283","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02715","title":"Cannabis use, other drug use, and risk of subsequent acute care in primary care patients.","authors":"Matson, Theresa E; Lapham, Gwen T; Bobb, Jennifer F; Johnson, Eric; Richards, Julie E; Lee, Amy K; Bradley, Katharine A; Glass, Joseph E","year":2020,"journal":"Drug and alcohol dependence, 216, 108227","doi":"10.1016/j.drugalcdep.2020.108227","pmid":"32911133","tags":["harm-reduction","addiction"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"In a large prospective cohort, daily cannabis users had 24% higher risk of subsequent acute care (HR 1.24, CI 1.10-1.39) compared to non-users. Less-than-monthly cannabis use also predicted slightly higher risk (HR 1.12). Other drug use showed stronger dose-response: daily other drug use had 153% higher risk (HR 2.53).","whyItMatters":"This is one of the largest studies linking routine clinical cannabis screening to actual healthcare utilization outcomes. It suggests screening results have predictive value for identifying patients at risk of future acute care needs.","specificNumbers":"47,447 patients; daily cannabis HR 1.24; less-than-monthly HR 1.12; daily other drug use HR 2.53; weekly other drug use HR 2.21.","methodology":"Retrospective cohort study using EHR and claims data from 47,447 adult primary care patients across 8 Washington State sites who completed substance use screening, with up to 19 months of follow-up for acute care utilization.","limitations":"Predominantly non-Hispanic White population (limited generalizability); single-item screening for cannabis frequency; cannot distinguish causation from correlation; Washington State may not represent other states."},{"rthcId":"RTHC-02716","title":"A Cannabinoid Receptor-Mediated Mechanism Participates in the Neuroprotective Effects of Oleamide Against Excitotoxic Damage in Rat Brain Synaptosomes and Cortical Slices.","authors":"Maya-López, Marisol; Rubio-López, Leonardo C; Rodríguez-Alvarez, Ivana V; Orduño-Piceno, Julián; Flores-Valdivia, Yuliza; Colonnello, Aline; Rangel-López, Edgar; Túnez, Isaac; Prospéro-García, Oscar; Santamaría, Abel","year":2020,"journal":"Neurotoxicity research, 37(1), 126-135","doi":"10.1007/s12640-019-00083-1","pmid":"31286434","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02717","title":"Cannabidiol and Sports Performance: a Narrative Review of Relevant Evidence and Recommendations for Future Research.","authors":"McCartney, Danielle; Benson, Melissa J; Desbrow, Ben; Irwin, Christopher; Suraev, Anastasia; McGregor, Iain S","year":2020,"journal":"Sports medicine - open, 6(1), 27","doi":"10.1186/s40798-020-00251-0","pmid":"32632671","tags":["cbd","exercise","pain","sleep"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Preclinical studies show CBD has anti-inflammatory, neuroprotective, and analgesic properties potentially beneficial for athletes. Early clinical evidence suggests anxiolytic effects in stressful situations. Evidence for sleep improvement, GI protection, and skeletal healing is preliminary. CBD appears safe and is no longer WADA-prohibited. However, no studies have directly tested CBD in athlete populations.","whyItMatters":"CBD use is rapidly growing among athletes, but scientific evidence is far behind consumer adoption. This review maps out where the evidence is strongest and where critical gaps remain.","specificNumbers":"CBD removed from WADA prohibited list in 2018; preclinical evidence for anti-inflammatory, neuroprotective, and analgesic effects; no direct athlete performance studies.","methodology":"Narrative review of preclinical and clinical CBD evidence relevant to sport and exercise contexts, sourced from animal models and limited clinical trials in non-athlete populations.","limitations":"No direct studies in athletes; preclinical findings may not translate to humans; CBD products vary widely in quality and composition; narrative review format."},{"rthcId":"RTHC-02718","title":"Perioperative pain and addiction interdisciplinary network (PAIN): protocol for the perioperative management of cannabis and cannabinoid-based medicines using a modified Delphi process.","authors":"McLaren-Blades, Alexander; Ladha, Karim; Goel, Akash; Manoo, Varuna; Kotteeswaran, Yuvaraj; Gee, Yen-Yen; Fiorellino, Joseph; Clarke, Hance","year":2020,"journal":"BMJ open, 10(7), e036472","doi":"10.1136/bmjopen-2019-036472","pmid":"32690522","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02719","title":"Perspectives on Cannabis-Based Therapy of Multiple Sclerosis: A Mini-Review.","authors":"Mecha, Miriam; Carrillo-Salinas, Francisco J; Feliú, Ana; Mestre, Leyre; Guaza, Carmen","year":2020,"journal":"Frontiers in cellular neuroscience, 14, 34","doi":"10.3389/fncel.2020.00034","pmid":"32140100","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02720","title":"Correlates of cannabis and other illicit drugs use among secondary school adolescents in Nigeria.","authors":"Mehanović, Emina; Virk, Harsheth Kaur; Akanidomo, Ibanga; Pwajok, Juliet; Prichard, Glen; van der Kreeft, Peer; Vigna-Taglianti, Federica","year":2020,"journal":"Drug and alcohol dependence, 206, 107457","doi":"10.1016/j.drugalcdep.2019.04.028","pmid":"31786400","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a survey across all six Nigerian geopolitical zones, cannabis and illicit drug use among adolescents (mean age 14.7) was associated with older age, single-parent households, parental smoking, parental permissiveness to drink, having drug-using friends, low perceived risk of harm, and positive beliefs about drugs. Socioeconomic status predicted cannabis but not other drug use.","whyItMatters":"Cannabis use among African youth is growing but understudied. This is one of the few large-scale studies providing nationally representative data on risk factors for adolescent cannabis use in Nigeria.","specificNumbers":"4,078 students; mean age 14.7; 32 schools; 6 geopolitical zones; key predictors: friend drug use, parental smoking, low risk perception, positive drug beliefs.","methodology":"Cross-sectional survey of 4,078 secondary school adolescents from 32 schools across all six geopolitical zones of Nigeria, using multilevel logistic regression models.","limitations":"Cross-sectional design; self-reported drug use in a context where it is illegal; school-based sample excludes out-of-school youth who may have higher use rates; specific substances within \"illicit drugs\" category not always distinguished."},{"rthcId":"RTHC-02721","title":"Application of ultrasound-assisted liquid-liquid microextraction coupled with gas chromatography and mass spectrometry for the rapid determination of synthetic cannabinoids and metabolites in biological samples.","authors":"Mercieca, Gilbert; Odoardi, Sara; Mestria, Serena; Cassar, Marisa; Strano-Rossi, Sabina","year":2020,"journal":"Journal of separation science, 43(14), 2858-2868","doi":"10.1002/jssc.202000181","pmid":"32320526","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02722","title":"Authoritative Parenting Behaviors and Marijuana Use Based on Age Among a National Sample of Hispanic Adolescents.","authors":"Merianos, Ashley L; King, Keith A; Vidourek, Rebecca A; Becker, Kelsi J; Yockey, R Andrew","year":2020,"journal":"The journal of primary prevention, 41(1), 51-69","doi":"10.1007/s10935-019-00576-x","pmid":"31933058","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02723","title":"Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial.","authors":"Meuth, Sven G; Henze, Thomas; Essner, Ute; Trompke, Christiane; Vila Silván, Carlos","year":2020,"journal":"The International journal of neuroscience, 130(12), 1199-1205","doi":"10.1080/00207454.2020.1730832","pmid":"32065006","tags":["medical-cannabis","pain","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In post hoc analysis of the SAVANT RCT, THC:CBD oromucosal spray halved mean spasticity and pain severity scores across all subgroups defined by disability level (EDSS), spasticity severity, and spasticity duration. Active treatment significantly improved spasticity from week 4 onward. Patients with severe resistant spasticity achieved the most significant therapeutic gains.","whyItMatters":"Clinicians need to know which MS patients benefit most from nabiximols. This analysis shows consistent benefit across disability levels and durations, with the strongest signals in the most severely affected patients.","specificNumbers":"THC:CBD spray halved mean spasticity and pain NRS scores in all subgroups; significant improvement from week 4 in both EDSS subgroups, severe spasticity subgroup, and both duration subgroups.","methodology":"Post hoc subgroup analysis of the SAVANT randomized, double-blind, placebo-controlled trial of nabiximols vs. optimized first-line antispastics in resistant MS spasticity, stratified by EDSS score, spasticity severity, and spasticity duration.","limitations":"Post hoc subgroup analysis (not pre-specified); single RCT dataset; subgroups may be underpowered for some comparisons; 12-week treatment period."},{"rthcId":"RTHC-02724","title":"Effects of chronic nicotine exposure on Δ9-tetrahydrocannabinol-induced locomotor activity and neural activation in male and female adolescent and adult rats.","authors":"Miladinovic, T; Manwell, L A; Raaphorst, E; Malecki, S L; Rana, S A; Mallet, P E","year":2020,"journal":"Pharmacology, biochemistry, and behavior, 194, 172931","doi":"10.1016/j.pbb.2020.172931","pmid":"32353393","tags":["youth","neuroscience","sex-differences","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In 112 rats, chronic nicotine followed by a washout period altered responses to THC challenge. In adult males, nicotine pre-exposure reduced THC-induced locomotor suppression. In adolescent females, nicotine potentiated THC suppression. THC increased brain c-Fos in multiple regions, and nicotine pre-exposure further amplified this effect. Brain activation patterns differed by age (greater in adults) and sex (greater in females).","whyItMatters":"Cannabis and tobacco are frequently co-used, especially by adolescents. This study reveals that prior nicotine exposure creates lasting changes in how the brain responds to cannabis, and that the effects are dramatically different depending on age and sex.","specificNumbers":"112 rats; 14 days nicotine + 14 days washout + THC challenge; THC increased c-Fos in caudate, nucleus accumbens, amygdala, hypothalamus, thalamus; nicotine pre-exposure potentiated c-Fos in all regions.","methodology":"Animal study with 112 male and female adolescent and adult Sprague-Dawley rats receiving 14 days of nicotine (1 mg/kg/day) followed by 14-day washout, then acute THC challenge (5 mg/kg). Locomotor activity and c-Fos brain mapping assessed.","limitations":"Animal study with synthetic nicotine and THC; fixed dose protocol may not reflect human use patterns; 14-day washout is a specific timeframe; only one THC dose tested."},{"rthcId":"RTHC-02725","title":"Impact of cannabis and low alcohol concentration on divided attention tasks during driving.","authors":"Miller, Ryan E; Brown, Timothy L; Lee, Stella; Tibrewal, Ishaan; Gaffney, Gary G; Milavetz, Gary; Hartman, Rebecca L; Gorelick, David A; Compton, Richard; Huestis, Marilyn A","year":2020,"journal":"Traffic injury prevention, 21(sup1), S123-S129","doi":"10.1080/15389588.2020.1814956","pmid":"33035082","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In a randomized, placebo-controlled crossover driving simulator study, each 1 ug/L increase in blood THC predicted increased odds of failing to complete a console search task (OR 1.05), more incorrect responses (OR 1.05), speed declines during mirror tasks, and longer lane departures. Low alcohol (~0.05% BrAC) separately worsened lane-keeping during secondary tasks.","whyItMatters":"This is one of the most rigorous driving simulator studies using actual cannabis administration and a validated full-motion simulator. The dose-response findings directly inform impaired driving policy.","specificNumbers":"Each 1 ug/L blood THC: OR 1.05 for task failure, OR 1.05 for errors, 0.74% longer lane departures; BrAC ~0.05%: 1.41% longer lane departures during mirror task.","methodology":"Randomized, placebo-controlled, crossover study with 6 sessions per participant: combinations of cannabis (placebo/low/high THC) and alcohol (placebo/active). Driving in full-motion NADS-1 simulator with three divided-attention tasks. Blood THC and breath alcohol measured.","limitations":"Simulator study (not real-world driving); controlled dosing may not reflect typical use patterns; participants were experienced cannabis users; specific tasks may not capture all real-world divided attention scenarios."},{"rthcId":"RTHC-02726","title":"Validation of the Australian Treatment Outcomes Profile for use in clients with cannabis dependence.","authors":"Mills, Llewellyn; Lintzeris, Nicholas; Bruno, Raimondo; Montebello, Mark; Dunlop, Adrian; Deacon, Rachel M; Copeland, Jan; Jefferies, Meryem; Rivas, Consuelo; Mammen, Kristie","year":2020,"journal":"Drug and alcohol review, 39(4), 356-364","doi":"10.1111/dar.13050","pmid":"32129558","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02727","title":"Simultaneous detection of salivary Δ9-tetrahydrocannabinol and alcohol using a Wearable Electrochemical Ring Sensor.","authors":"Mishra, Rupesh K; Sempionatto, Juliane R; Li, Zhanhong; Brown, Christopher; Galdino, Nathalia M; Shah, Rushabh; Liu, Shuyang; Hubble, Lee J; Bagot, Kara; Tapert, Susan; Wang, Joseph","year":2020,"journal":"Talanta, 211, 120757","doi":"10.1016/j.talanta.2020.120757","pmid":"32070607","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02728","title":"Implementation and Evaluation of a Psychoactive Substance Use Intervention for Children in Afghanistan: Differences Between Girls and Boys at Treatment Entry and in Response to Treatment.","authors":"Momand, Abdul Subor; Mattfeld, Elizabeth; Gerra, Gilberto; Morales, Brian; Browne, Thom; Haq, Manzoor Ul; O'Grady, Kevin E; Jones, Hendrée E","year":2020,"journal":"Global journal of pediatrics & neonatal care, 2(1)","doi":"10.33552/gjpnc.2020.02.000527","pmid":"33681863","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02729","title":"Treadmill exercise improves LPS-induced memory impairments via endocannabinoid receptors and cyclooxygenase enzymes.","authors":"Moosavi Sohroforouzani, Azam; Shakerian, Saeed; Ghanbarzadeh, Mohsen; Alaei, Hojjatallah","year":2020,"journal":"Behavioural brain research, 380, 112440","doi":"10.1016/j.bbr.2019.112440","pmid":"31863846","tags":["exercise","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats with LPS-induced neuroinflammation showed cognitive impairment in the water maze. Eight weeks of treadmill exercise reversed these deficits. Exercise increased CB1 receptor expression in healthy rats and reduced CB2 receptor, COX-2, and mPGES-1 expression in inflamed rats, suggesting the endocannabinoid system mediates some of exercise cognitive benefits.","whyItMatters":"The \"runner high\" has long been linked to the endocannabinoid system. This study provides a specific mechanism: exercise modulates cannabinoid receptors to counteract neuroinflammation-induced cognitive decline.","specificNumbers":"8 weeks treadmill exercise; 5 days/week; exercise increased CB1 in healthy rats; reduced CB2, COX-2, and mPGES-1 in inflamed rats; reversed water maze impairment.","methodology":"Animal study with rats receiving LPS injections to induce neuroinflammation, followed by 8 weeks of treadmill exercise (5 days/week). Water maze testing for cognition, Real-Time PCR for hippocampal gene expression of cannabinoid receptors and cyclooxygenases.","limitations":"Animal study with chemically-induced inflammation (not natural neurodegeneration); forced treadmill exercise differs from voluntary exercise; only male rats; specific LPS doses may not reflect human neuroinflammatory conditions."},{"rthcId":"RTHC-02730","title":"Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects.","authors":"Morano, Alessandra; Fanella, Martina; Albini, Mariarita; Cifelli, Pierangelo; Palma, Eleonora; Giallonardo, Anna Teresa; Di Bonaventura, Carlo","year":2020,"journal":"Neuropsychiatric disease and treatment, 16, 381-396","doi":"10.2147/NDT.S203782","pmid":"32103958","tags":["cbd","epilepsy","drug-interactions"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Pharmaceutical CBD (Epidiolex) was approved based on four pivotal RCTs enrolling 154 Dravet and 396 Lennox-Gastaut syndrome patients. Both 10 and 20 mg/kg/day doses met primary endpoints for seizure reduction. Key adverse effects included somnolence, decreased appetite, diarrhea, and liver enzyme elevations (mainly with concomitant valproate). The CBD-clobazam interaction via CYP2C19 likely contributes to both efficacy and side effects.","whyItMatters":"This review provides the most complete picture of pharmaceutical CBD for epilepsy in one place, from molecular mechanisms through clinical trial results, helping clinicians understand both the benefits and the complexities.","specificNumbers":"4 pivotal RCTs; 154 DS + 396 LGS patients; CBD 10-20 mg/kg/day; oral bioavailability 6%; metabolized by CYP3A4 and CYP2C19; liver enzyme elevations mainly with valproate co-administration.","methodology":"Comprehensive narrative review covering CBD pharmacology, mechanisms of action, pharmacokinetics, drug interactions, and pivotal clinical trial data for epilepsy indications.","limitations":"Narrative review format; pivotal trials were industry-sponsored; long-term data beyond trial periods are limited; results apply to pharmaceutical-grade CBD (Epidiolex) and may not generalize to consumer products."},{"rthcId":"RTHC-02731","title":"Cannabis points to the synaptic pathology of mental disorders: how aberrant synaptic components disrupt the highest psychological functions
.","authors":"Morrison, Paul D; Murray, Robin M","year":2020,"journal":"Dialogues in clinical neuroscience, 22(3), 251-258","doi":"10.31887/DCNS.2020.22.3/pmorrison","pmid":"33162768","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02732","title":"Autism Spectrum Disorder and Medical Cannabis: Review and Clinical Experience.","authors":"Mostafavi, Mojdeh; Gaitanis, John","year":2020,"journal":"Seminars in pediatric neurology, 35, 100833","doi":"10.1016/j.spen.2020.100833","pmid":"32892960","tags":["medical-cannabis","cbd","youth"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The review found emerging preclinical evidence linking the endocannabinoid system to ASD pathophysiology and limited clinical data suggesting cannabis and CBD may improve core symptoms (social interaction, communication), noncore behaviors (aggression, self-injury), and comorbidities. The authors clinical experience supported these findings, noting overall tolerability.","whyItMatters":"No effective treatment exists for ASD core symptoms. Cannabis and CBD represent one of the few emerging therapeutic options, but evidence remains very early-stage, making careful clinical reviews particularly valuable.","specificNumbers":"No effective treatment for ASD core symptoms currently exists; limited clinical data from small studies and case series reviewed.","methodology":"Narrative review of preclinical and clinical data on cannabis/CBD for ASD core symptoms, noncore symptoms, and comorbidities, supplemented by authors clinical experience with ASD patients using cannabis.","limitations":"Very limited clinical data; no large RCTs; narrative review format; clinical experience is anecdotal; ASD heterogeneity makes generalizing difficult; long-term safety in developing brains unknown."},{"rthcId":"RTHC-02733","title":"Early onset of cannabis use and violent behavior in psychosis.","authors":"Moulin, Valerie; Alameda, Luis; Framorando, David; Baumann, Philipp-S; Gholam, Mehdi; Gasser, Jacques; Do Cuenod, Kim-Q; Conus, Philippe","year":2020,"journal":"European psychiatry : the journal of the Association of European Psychiatrists, 63(1), e78","doi":"10.1192/j.eurpsy.2020.71","pmid":"32669157","tags":["psychosis","youth","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"In a 36-month prospective cohort of 265 early psychosis patients, violent patients began cannabis use at an average age of 15.3 vs. 17.0 for nonviolent patients (p=0.004). Early-onset cannabis use (before age 15) was an independent risk factor for violent behavior (OR 4.47, CI 1.13-20.06) after adjustment for age, other substance use, and known violence risk factors.","whyItMatters":"Violence in psychosis is a serious clinical and public health concern. Identifying early cannabis use as an independent risk factor suggests a modifiable target for prevention.","specificNumbers":"265 patients; 72 violent, 193 nonviolent; violent started cannabis at 15.3 vs 17.0; early onset (≤15) OR 4.47 (1.13-20.06) for violence; 36-month follow-up.","methodology":"Prospective cohort study following 265 early psychosis patients (ages 18-35) for 36 months, using logistic regression to assess link between age of cannabis onset and violent behavior, adjusting for multiple covariates.","limitations":"Wide confidence interval (1.13-20.06) suggests imprecision; age of cannabis onset was self-reported; violence was broadly defined; cannot prove causation; relatively small sample for subgroup analysis."},{"rthcId":"RTHC-02734","title":"Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity In Vivo.","authors":"Mugnaini, Claudia; Kostrzewa, Magdalena; Bryk, Marta; Mahmoud, Ali Mokhtar; Brizzi, Antonella; Lamponi, Stefania; Giorgi, Gianluca; Ferlenghi, Francesca; Vacondio, Federica; Maccioni, Paola; Colombo, Giancarlo; Mor, Marco; Starowicz, Katarzyna; Di Marzo, Vincenzo; Ligresti, Alessia; Corelli, Federico","year":2020,"journal":"Journal of medicinal chemistry, 63(13), 7369-7391","doi":"10.1021/acs.jmedchem.0c00595","pmid":"32515588","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02735","title":"Cerebrospinal fluid endocannabinoid levels in Gilles de la Tourette syndrome.","authors":"Müller-Vahl, Kirsten R; Bindila, Laura; Lutz, Beat; Musshoff, Frank; Skripuletz, Thomas; Baumgaertel, Charlotte; Sühs, Kurt-Wolfram","year":2020,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 45(8), 1323-1329","doi":"10.1038/s41386-020-0671-6","pmid":"32272483","tags":["neuroscience","medical-cannabis"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"In the first study measuring CSF endocannabinoids in Tourette syndrome, both AEA (anandamide, p=0.0018) and 2-AG (p=0.0003) were significantly elevated in 20 TS patients compared to 19 controls. PEA and arachidonic acid were also elevated. 2-AG levels correlated with ADHD symptom severity (p<0.01).","whyItMatters":"Cannabis-based medicines have been reported to improve tics in Tourette syndrome, but the biological basis was unknown. This first-ever CSF study confirms endocannabinoid system involvement in TS pathophysiology.","specificNumbers":"20 TS patients vs 19 controls; AEA elevated (p=0.0018); 2-AG elevated (p=0.0003); PEA elevated (p=0.02); AA elevated (p<0.0001); 2-AG correlated with ADHD severity (p<0.01).","methodology":"Case-control study comparing CSF levels of endocannabinoids (AEA, 2-AG), PEA, and arachidonic acid in 20 adult Tourette syndrome patients vs. 19 controls using LC/MRM quantification.","limitations":"Small sample; cross-sectional design; cannot determine if elevated levels are cause or consequence; CSF may not perfectly reflect brain-regional endocannabinoid activity; adult patients only."},{"rthcId":"RTHC-02736","title":"Sharing the pain: an observational analysis of Twitter and pain in Ireland.","authors":"Mullins, Cormac Francis; Ffrench-O'Carroll, Robert; Lane, Justin; O'Connor, Therese","year":2020,"journal":"Regional anesthesia and pain medicine, 45(8), 597-602","doi":"10.1136/rapm-2020-101547","pmid":"32503862","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02737","title":"Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs.","authors":"Murphy, Thomas; Le Foll, Bernard","year":2020,"journal":"Biomolecules, 10(6)","doi":"10.3390/biom10060855","pmid":"32512776","tags":["appetite","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Rimonabant (CB1 inverse agonist) effectively produced weight loss but was withdrawn due to depression and suicidal ideation. An inverse relationship between cannabis use and BMI has been confirmed by multiple groups. Newer preclinical approaches, including peripheral-only CB1 blockers and neutral antagonists, may retain therapeutic potential for obesity without brain-related side effects.","whyItMatters":"Obesity rates are rising globally and treatment options are limited. The CB1 receptor remains one of the most promising therapeutic targets, but the rimonabant experience showed that brain-penetrant CB1 blockers are too risky.","specificNumbers":"Rimonabant was effective for weight loss but withdrawn for psychiatric side effects; inverse cannabis use-BMI relationship confirmed by multiple studies; peripheral-only CB1 approaches in development.","methodology":"Narrative review of preclinical and clinical studies on CB1 receptor ligands (inverse agonists, agonists, partial agonists, neutral antagonists) and their effects on body weight.","limitations":"Narrative review; most novel approaches are preclinical only; the cannabis use-BMI paradox has multiple possible explanations beyond CB1 effects; translating peripheral-only CB1 blockers to humans remains unproven."},{"rthcId":"RTHC-02738","title":"The influence of risk factors on the onset and outcome of psychosis: What we learned from the GAP study.","authors":"Murray, R M; Mondelli, V; Stilo, S A; Trotta, A; Sideli, L; Ajnakina, O; Ferraro, L; Vassos, E; Iyegbe, C; Schoeler, T; Bhattacharyya, S; Marques, T R; Dazzan, P; Lopez-Morinigo, J; Colizzi, M; O'Connor, J; Falcone, M A; Quattrone, D; Rodriguez, V; Tripoli, G; La Barbera, D; La Cascia, C; Alameda, L; Trotta, G; Morgan, C; Gaughran, F; David, A; Di Forti, M","year":2020,"journal":"Schizophrenia research, 225, 63-68","doi":"10.1016/j.schres.2020.01.011","pmid":"32037203","tags":["psychosis","potency","genetics"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"In 410 first-episode psychosis patients and 370 controls in South London, approximately 25% of new psychosis cases were attributable to high-potency cannabis use. Childhood adversity (parental loss, abuse, bullying), ethnic minority status, and cannabis use were major environmental risk factors, operating on a background of polygenic genetic risk. Continued high-potency cannabis use also predicted poorer long-term outcomes.","whyItMatters":"This is one of the most influential studies linking high-potency cannabis to psychosis risk. The finding that 25% of cases are attributable to high-potency cannabis has directly influenced public health messaging and policy debates.","specificNumbers":"410 FEP patients, 370 controls; 25% of new psychosis cases attributable to high-potency cannabis; childhood adversity, ethnic minority status, and cannabis as key environmental risks.","methodology":"Prospective multidisciplinary case-control study (GAP Study) recruiting 410 first-episode psychosis patients and 370 controls in South London, examining genetic, environmental, and biological risk factors.","limitations":"South London population may not generalize globally; cannabis potency was estimated, not measured; observational design cannot prove causation; population-attributable fraction depends on prevalence assumptions."},{"rthcId":"RTHC-02739","title":"Transition of Substance-Induced, Brief, and Atypical Psychoses to Schizophrenia: A Systematic Review and Meta-analysis.","authors":"Murrie, Benjamin; Lappin, Julia; Large, Matthew; Sara, Grant","year":2020,"journal":"Schizophrenia bulletin, 46(3), 505-516","doi":"10.1093/schbul/sbz102","pmid":"31618428","tags":["psychosis","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 50 studies encompassing 40,783 people, the pooled transition rate from substance-induced psychosis to schizophrenia was 25%. Cannabis had the highest substance-specific transition rate at 34% (95% CI 25-46%), followed by hallucinogens (26%) and amphetamines (22%). Alcohol (10%), opioids (12%), and sedatives (9%) had much lower rates.","whyItMatters":"This establishes that cannabis-induced psychosis is not just a temporary drug reaction. One in three affected individuals will develop schizophrenia, making it the substance most strongly associated with psychosis transition.","specificNumbers":"50 studies; 40,783 people; overall transition 25%; cannabis 34% (6 studies); hallucinogens 26% (3 studies); amphetamines 22% (5 studies); alcohol 10%; opioids 12%; sedatives 9%.","methodology":"Systematic review and meta-analysis of 50 studies from MEDLINE, PsychINFO, and Embase providing 79 estimates of transition from substance-induced psychosis to schizophrenia, including 43 substance-specific estimates.","limitations":"Heterogeneity in how substance-induced psychosis was defined across studies; transition rates may reflect shared vulnerability rather than causation; older cohorts had slightly lower rates; publication bias possible."},{"rthcId":"RTHC-02740","title":"Cannabis sativa extracts protect LDL from Cu2+-mediated oxidation.","authors":"Musetti, Bruno; González-Ramos, Helena; González, Mercedes; Bahnson, Edward M; Varela, Javier; Thomson, Leonor","year":2020,"journal":"Journal of cannabis research, 2","doi":"10.1186/s42238-020-00042-0","pmid":"33123676","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02741","title":"The role of cannabinoids in epilepsy treatment: a critical review of efficacy results from clinical trials.","authors":"Nabbout, Rima; Thiele, Elizabeth A","year":2020,"journal":"Epileptic disorders : international epilepsy journal with videotape, 22(S1), 23-28","doi":"10.1684/epd.2019.1124","pmid":"31916540","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02742","title":"An overview of cannabis based treatment in Crohn's disease.","authors":"Naftali, Timna","year":2020,"journal":"Expert review of gastroenterology & hepatology, 14(4), 253-257","doi":"10.1080/17474124.2020.1740590","pmid":"32149543","tags":["medical-cannabis","inflammation","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Among the three existing placebo-controlled trials in active Crohn disease (93 subjects total), two showed significant clinical improvement (reduced CDAI scores) but no improvement in inflammatory markers. About 15% of IBD patients use cannabis to manage symptoms. The complexity of cannabis chemovars and the diversity of cannabinoid compounds create inherent research challenges.","whyItMatters":"Cannabis use is common among IBD patients, but the disconnect between symptom improvement and unchanged inflammation markers raises important questions about whether cannabis masks symptoms rather than treating the underlying disease.","specificNumbers":"93 subjects across 3 placebo-controlled trials; ~15% of IBD patients use cannabis; 2 of 3 studies showed clinical improvement; 2 of 3 showed no change in inflammatory markers.","methodology":"Expert review of clinical evidence on cannabis for Crohn disease, focusing on three placebo-controlled trials and the broader landscape of cannabinoid research in IBD.","limitations":"Only 3 small RCTs available; 93 total subjects is very limited; cannabis products and doses varied; short trial durations; inflammatory markers may not capture all types of immune activity."},{"rthcId":"RTHC-02743","title":"Cannabis for the Treatment of Inflammatory Bowel Disease: A True Medicine or a False Promise?","authors":"Naftali, Timna; Dor, Michael","year":2020,"journal":"Rambam Maimonides medical journal, 11(1)","doi":"10.5041/RMMJ.10390","pmid":"32017687","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02744","title":"Nonlinear Disposition and Metabolic Interactions of Cannabidiol Through CYP3A Inhibition In Vivo in Rats.","authors":"Nagao, Michiru; Nakano, Yukako; Tajima, Masataka; Sugiyama, Erika; Sato, Vilasinee Hirunpanich; Inada, Makoto; Sato, Hitoshi","year":2020,"journal":"Cannabis and cannabinoid research, 5(4), 318-325","doi":"10.1089/can.2019.0098","pmid":"33381645","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02745","title":"Cannabis in Gastroenterology: Watch Your Head! A Review of Use in Inflammatory Bowel Disease, Functional Gut Disorders, and Gut-Related Adverse Effects.","authors":"Nasser, Yasmin; Woo, Matthew; Andrews, Christopher N","year":2020,"journal":"Current treatment options in gastroenterology, 18(4), 519-530","doi":"10.1007/s11938-020-00323-w","pmid":"33250629","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02746","title":"Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis.","authors":"Navarrete, Carmen; García-Martin, Adela; Garrido-Rodríguez, Martín; Mestre, Leyre; Feliú, Ana; Guaza, Carmen; Calzado, Marco A; Muñoz, Eduardo","year":2020,"journal":"Neurobiology of disease, 143, 104994","doi":"10.1016/j.nbd.2020.104994","pmid":"32599064","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02747","title":"The Public Health Response to a Large Poisoning Outbreak Involving an Illicit Substance: Synthetic Cannabinoids Contaminated With a Long-Acting Anticoagulant Rodenticide, Illinois, March-July, 2018.","authors":"Navon, Livia; Moritz, Erin; Austin, Connie; Wahl, Michael; Aks, Steven; Layden, Jennifer","year":2020,"journal":"Journal of public health management and practice : JPHMP, 26(6), E1-E7","doi":"10.1097/PHH.0000000000001002","pmid":"30969282","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"From March to July 2018, 174 confirmed and probable cases of severe coagulopathy (bleeding disorder) were identified among synthetic cannabinoid users in Illinois, including 5 deaths. Toxicology confirmed exposure to brodifacoum, a long-acting anticoagulant rodenticide. The outbreak required unprecedented coordination between public health and law enforcement.","whyItMatters":"This was one of the largest poisoning outbreaks from contaminated illicit substances in US history. It illustrates the extreme and unpredictable dangers of unregulated synthetic cannabinoids, which can contain any number of toxic adulterants.","specificNumbers":"174 confirmed/probable cases; 5 deaths; March-July 2018; brodifacoum (long-acting anticoagulant rodenticide) identified as contaminant.","methodology":"Public health outbreak investigation and response documenting 174 confirmed and probable cases of brodifacoum-contaminated synthetic cannabinoid exposure in Illinois, March-July 2018.","limitations":"Outbreak investigation, not a designed study; actual number of exposed individuals likely higher than 174 documented cases; specific supply chain not fully mapped; retrospective identification of cases."},{"rthcId":"RTHC-02748","title":"The association between legalization of cannabis use and traffic deaths in Uruguay.","authors":"Nazif-Munoz, Jose Ignacio; Oulhote, Youssef; Ouimet, Marie Claude","year":2020,"journal":"Addiction (Abingdon, England), 115(9), 1697-1706","doi":"10.1111/add.14994","pmid":"32003494","tags":["driving","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Following Uruguay 2013 cannabis legalization, light motor vehicle driver fatality rates showed an immediate 52.4% increase (95% CI 11.6-93.3%, p=0.012). The increase was concentrated in Montevideo (urban), not rural areas. Motorcyclist fatality rates were not significantly affected.","whyItMatters":"As more countries legalize cannabis, understanding traffic safety implications is critical. Uruguay was the first country to fully legalize recreational cannabis, making it a unique natural experiment.","specificNumbers":"52.4% immediate increase in light motor vehicle driver fatalities (p=0.012); Montevideo absolute increase of 0.06 per week (p=0.025); no significant change in motorcyclist or rural fatality rates.","methodology":"Interrupted time-series analysis of weekly traffic fatalities of light motor vehicle drivers and motorcyclists in Uruguay from 2012-2017, comparing trends before and after cannabis legalization.","limitations":"Interrupted time-series cannot prove causation; other factors may have changed around legalization; relatively short post-legalization period (2013-2017); ecological design cannot link individual cannabis use to crashes."},{"rthcId":"RTHC-02749","title":"Explication of CB1 receptor contributions to the hypothermic effects of Δ9-tetrahydrocannabinol (THC) when delivered by vapor inhalation or parenteral injection in rats.","authors":"Nguyen, Jacques D; Creehan, K M; Grant, Yanabel; Vandewater, Sophia A; Kerr, Tony M; Taffe, Michael A","year":2020,"journal":"Drug and alcohol dependence, 214, 108166","doi":"10.1016/j.drugalcdep.2020.108166","pmid":"32717503","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02750","title":"ADHD Is Highly Prevalent in Patients Seeking Treatment for Cannabis Use Disorders.","authors":"Notzon, Daniel P; Pavlicova, Martina; Glass, Andrew; Mariani, John J; Mahony, Amy L; Brooks, Daniel J; Levin, Frances R","year":2020,"journal":"Journal of attention disorders, 24(11), 1487-1492","doi":"10.1177/1087054716640109","pmid":"27033880","tags":["addiction","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 99 adults seeking cannabis use disorder treatment, ADHD prevalence was estimated at 34% (CAARS), 45% (WURS), 46% (ASRS), or 36% (WURS+CAARS combined). The Wender Utah Rating Scale paired with the Conners Adult ADHD Rating Scale provided the best combination of sensitivity (0.71) and specificity (0.95) for ADHD screening in this population.","whyItMatters":"If one-third to nearly half of cannabis treatment seekers have ADHD, failing to screen for and treat ADHD could undermine cannabis treatment outcomes. This finding suggests ADHD screening should be routine in cannabis treatment settings.","specificNumbers":"99 participants; ADHD prevalence 34-46% depending on screening tool; WURS+CAARS: sensitivity 0.71, specificity 0.95; general population ADHD prevalence ~4-5%.","methodology":"Cross-sectional validation study using the Conners Adult ADHD Diagnostic Interview (CAADID) as gold standard to assess sensitivity and specificity of four ADHD screening tools in 99 cannabis use disorder treatment seekers.","limitations":"Small sample (n=99); treatment-seeking population may over-represent comorbid conditions; cross-sectional; ADHD screening tools validated against CAADID, which itself has limitations; prevalence may not reflect non-treatment-seeking cannabis users."},{"rthcId":"RTHC-02751","title":"Maternal presence or absence alters nociceptive responding and cortical anandamide levels in juvenile female rats.","authors":"O'Sullivan, Grace; Humphrey, Rachel M; Thornton, Aoife M; Kerr, Daniel M; McGuire, Brian E; Caes, Line; Roche, Michelle","year":2020,"journal":"Behavioural brain research, 392, 112712","doi":"10.1016/j.bbr.2020.112712","pmid":"32479851","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02752","title":"Does cannabis use predict psychometric schizotypy via aberrant salience?","authors":"O'Tuathaigh, Colm M P; Dawes, Christopher; Bickerdike, Andrea; Duggan, Eileen; O'Neill, Cian; Waddington, John L; Moran, Paula M","year":2020,"journal":"Schizophrenia research, 220, 194-200","doi":"10.1016/j.schres.2020.03.021","pmid":"32273148","tags":["psychosis","cognition","dopamine"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 910 students, frequent cannabis use predicted higher scores on positive and disorganized schizotypy subscales. Mediation analysis showed that aberrant salience (abnormal importance assignment) explained the relationship between cannabis use and specific traits including ideas of reference, odd beliefs, unusual perceptual experiences, and odd speech.","whyItMatters":"The dopamine hypothesis of psychosis centers on aberrant salience. This study provides the first evidence in a non-clinical population that cannabis may promote psychosis-like experiences specifically through disrupting how the brain decides what is important.","specificNumbers":"910 students; frequent cannabis use predicted positive and disorganized schizotypy; aberrant salience mediated the relationship for ideas of reference, odd beliefs, unusual perceptions, and odd speech.","methodology":"Cross-sectional survey of 910 university students using validated questionnaires for cannabis experience, schizotypal personality traits, psychic experiences, and aberrant salience. Mediation analysis tested whether salience dysfunction explained cannabis-schizotypy links.","limitations":"Cross-sectional (cannot establish directionality); self-report measures; university sample may not generalize; schizotypy is not the same as clinical psychosis; cannot distinguish cause from predisposition."},{"rthcId":"RTHC-02753","title":"The Impact of Cannabidiol on Psychiatric and Medical Conditions.","authors":"Oberbarnscheidt, Thersilla; Miller, Norman S","year":2020,"journal":"Journal of clinical medicine research, 12(7), 393-403","doi":"10.14740/jocmr4159","pmid":"32655732","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02754","title":"Adenosine A1 receptor agonist induces visceral antinociception via 5-HT1A, 5-HT2A, dopamine D1 or cannabinoid CB1 receptors, and the opioid system in the central nervous system.","authors":"Okumura, Toshikatsu; Nozu, Tsukasa; Ishioh, Masatomo; Igarashi, Sho; Kumei, Shima; Ohhira, Masumi","year":2020,"journal":"Physiology & behavior, 220, 112881","doi":"10.1016/j.physbeh.2020.112881","pmid":"32199997","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02755","title":"Medical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: a systematic review.","authors":"Okusanya, Babasola O; Asaolu, Ibitola O; Ehiri, John E; Kimaru, Linda Jepkoech; Okechukwu, Abidemi; Rosales, Cecilia","year":2020,"journal":"Systematic reviews, 9(1), 167","doi":"10.1186/s13643-020-01425-3","pmid":"32723354","tags":["pain","medical-cannabis","addiction","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 9 studies involving 7,222 participants, combining medical cannabis with opioids was associated with 64-75% reduction in opioid dosage for non-cancer chronic pain. Between 32-59% of patients reported using cannabis as an opioid substitute. One study showed trends toward fewer hospital admissions and ED visits. However, all studies had high risk of bias.","whyItMatters":"The opioid crisis makes any strategy to reduce opioid use critically important. These findings suggest medical cannabis could play a role in opioid dose reduction, but the evidence quality is insufficient to make firm recommendations.","specificNumbers":"9 studies; 7,222 participants; 64-75% opioid dose reduction; 32-59% used cannabis as opioid substitute; all studies high risk of bias.","methodology":"Systematic review of 9 studies (RCTs, cohort, cross-sectional, case reports) from Ovid/Medline, PsycINFO, PubMed, Web of Science assessing medical cannabis effects on opioid dosage in non-cancer chronic pain, using ROBINS-I and AXIS bias tools.","limitations":"All 9 studies had high risk of bias; heterogeneous study designs; cannabis doses and products varied; optimal cannabis dose unknown; systematic review was not pre-registered."},{"rthcId":"RTHC-02756","title":"Cannabis use disorders may protect against certain disorders of the digestive organs in people with schizophrenia but not in healthy controls.","authors":"Olesen, Julie Aamand; Posselt, Christine Merrild; Poulsen, Chalotte Heinsvig; Nordentoft, Merete; Hjorthøj, Carsten","year":2020,"journal":"Psychological medicine, 50(3), 499-506","doi":"10.1017/S0033291719000370","pmid":"30880659","tags":["psychosis","inflammation","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 21,066 schizophrenia cases and 176,935 matched controls, cannabis use disorders in schizophrenia patients were associated with decreased risk of gut-brain interaction disorders (IBS, dyspepsia; HR 0.84, p=0.003) and inflammatory bowel disease (HR 0.70, p=0.045). These associations were not observed in healthy controls, suggesting an interaction specific to schizophrenia.","whyItMatters":"The endocannabinoid system modulates both gut function and inflammation. This large-scale finding that cannabis specifically protects against digestive disorders in schizophrenia (but not healthy people) could reveal unique therapeutic mechanisms.","specificNumbers":"21,066 schizophrenia cases; 176,935 controls; gut-brain disorders HR 0.84 (p=0.003); IBD HR 0.70 (p=0.045) in basically adjusted model; no associations in controls.","methodology":"Nationwide Danish register-based study using time-varying Cox regression in 21,066 schizophrenia patients and 176,935 age/sex-matched controls, adjusted for alcohol/substance use disorders and parental education.","limitations":"Register-based (cannot determine cannabis type, dose, or route); cannabis use disorders are an extreme measure (does not reflect moderate use); IBD finding dropped below significance in fully adjusted model; unmeasured confounding possible."},{"rthcId":"RTHC-02757","title":"Cannabis Use During Lactation: Literature Review and Clinical Recommendations.","authors":"Ordean, Alice; Kim, Gloria","year":2020,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 42(10), 1248-1253","doi":"10.1016/j.jogc.2019.11.003","pmid":"31992503","tags":["pregnancy","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Despite cannabis being the most commonly used psychoactive substance by 5% of Canadian postpartum women, only two studies met inclusion criteria for developmental outcomes in breastfed infants exposed to cannabis. Results were conflicting, with one showing motor development effects and the other finding no significant impact.","whyItMatters":"Millions of breastfeeding women worldwide face decisions about cannabis use with almost no evidence to guide them. This review exposes just how little we actually know.","specificNumbers":"~5% of Canadian women use cannabis during pregnancy/postpartum; only 2 studies met inclusion criteria; results were conflicting.","methodology":"Systematic review searching Medline, Embase, and PsychInfo for studies on infant outcomes from cannabis exposure during lactation, with developmental outcomes as inclusion criteria.","limitations":"Only 2 eligible studies found; both were older and limited by methodology; cannot account for other substance co-exposures; no data on neurodevelopment beyond first year in included studies."},{"rthcId":"RTHC-02758","title":"Is there a relationship between cannabis use problems, emotion dysregulation, and mental health problems among adults with chronic pain?","authors":"Orr, Michael F; Rogers, Andrew H; Shepherd, Justin M; Buckner, Julia D; Ditre, Joseph W; Bakhshaie, Jafar; Zvolensky, Michael J","year":2020,"journal":"Psychology, health & medicine, 25(6), 742-755","doi":"10.1080/13548506.2019.1653485","pmid":"31407604","tags":["pain","addiction","mental-health","anxiety","depression"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In 431 opioid-using adults with moderate to severe chronic pain (176 current cannabis users, 30% with cannabis use problems), emotion dysregulation significantly mediated the relationship between cannabis use problems and anxiety, depression, and suicidal ideation. The indirect effects through emotion dysregulation were significant for all three outcomes.","whyItMatters":"Many chronic pain patients use cannabis, but those who develop problematic use patterns may have worse mental health. Understanding that emotion dysregulation is the connecting mechanism suggests a treatment target.","specificNumbers":"431 participants; 176 current cannabis users; 30.2% with cannabis use problems; significant indirect effects via emotion dysregulation for anxiety, depression, and suicidal ideation.","methodology":"Cross-sectional mediation analysis in 431 opioid-using adults with chronic pain, testing whether emotion dysregulation explained relationships between cannabis use problems and anxiety, depression, and suicidal ideation.","limitations":"Cross-sectional (cannot establish temporal order); opioid-using sample may not represent all chronic pain patients; self-report measures; mediational design assumes causal ordering that may be reversed."},{"rthcId":"RTHC-02759","title":"Effects of Smoking Cannabis on Visual Function and Driving Performance. A Driving-Simulator Based Study.","authors":"Ortiz-Peregrina, Sonia; Ortiz, Carolina; Castro-Torres, José J; Jiménez, José R; Anera, Rosario G","year":2020,"journal":"International journal of environmental research and public health, 17(23)","doi":"10.3390/ijerph17239033","pmid":"33287427","tags":["driving","cognition"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In 20 young drivers, smoking cannabis significantly worsened visual acuity, contrast sensitivity, and stereoacuity (depth perception). Driving performance deteriorated, particularly lane-keeping. Crucially, the visual impairments and driving impairments were significantly correlated (r=0.504 for contrast sensitivity at near distances), providing the first evidence that cannabis-induced visual effects directly contribute to driving impairment.","whyItMatters":"Previous cannabis-driving research focused on cognitive impairment. This is the first study showing that cannabis-induced visual changes themselves contribute to worse driving, adding a new dimension to understanding impairment.","specificNumbers":"20 drivers; significant impairment in visual acuity, contrast sensitivity (p=0.004), near stereoacuity (p=0.013), and far stereoacuity; lane-keeping worsened; correlation r=0.504 between contrast sensitivity and driving.","methodology":"Within-subjects study of 20 drivers and occasional cannabis users (mean age 23.3) evaluated at baseline and after smoking cannabis, assessing visual function and simulated driving performance.","limitations":"Small sample (n=20); mostly male; single cannabis smoking session; no dose-response assessment; simulated rather than real-world driving; participants were occasional users, not naive or heavy users."},{"rthcId":"RTHC-02760","title":"Accounting and the US cannabis industry: federal financial regulations and the perspectives of Certified Public Accountants and cannabis businesses owners.","authors":"Owens-Ott, G Suzanne","year":2020,"journal":"Journal of cannabis research, 2(1), 41","doi":"10.1186/s42238-020-00049-7","pmid":"33526144","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02761","title":"Beyond THC and Endocannabinoids.","authors":"Pacher, Pal; Kogan, Natalya M; Mechoulam, Raphael","year":2020,"journal":"Annual review of pharmacology and toxicology, 60, 637-659","doi":"10.1146/annurev-pharmtox-010818-021441","pmid":"31580774","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02762","title":"Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association.","authors":"Page, Robert L; Allen, Larry A; Kloner, Robert A; Carriker, Colin R; Martel, Catherine; Morris, Alanna A; Piano, Mariann R; Rana, Jamal S; Saucedo, Jorge F","year":2020,"journal":"Circulation, 142(10), e131-e152","doi":"10.1161/CIR.0000000000000883","pmid":"32752884","tags":["cardiovascular","medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The AHA scientific statement reviewed evidence that cannabis use is associated with cardiovascular risks including tachycardia, arrhythmias, myocardial infarction, stroke, and heart failure, many mediated by delivery mechanism (especially smoking). Few cardiovascular therapeutic benefits were identified. The statement called for reclassification of cannabis from Schedule 1 to enable more research.","whyItMatters":"This is the first formal position statement on cannabis from the nation most influential cardiovascular organization. It sets the tone for how cardiologists should counsel patients and how research priorities should be directed.","specificNumbers":"Published in Circulation (impact factor ~29); covers 25+ years of expanding legalization; calls for reclassification from Schedule 1 to facilitate research.","methodology":"AHA Scientific Statement (expert consensus review) critically reviewing clinical, epidemiological, and policy literature on cannabis and cardiovascular health from medical and public health perspectives.","limitations":"Scientific statement format (expert consensus, not systematic review); much of the underlying evidence is observational; cardiovascular effects of different cannabis products and delivery methods are not well differentiated."},{"rthcId":"RTHC-02763","title":"Recreational Cannabis Use and Risk of Prescription Opioid Overdose: Insights from Pediatric Inpatients.","authors":"Pankaj, Amaya; Oraka, Kosisochukwu; Caraballo-Rivera, Emmanuelle J; Ahmad, Munazza; Zahid, Shaheer; Munir, Sadaf; Gurumurthy, Gayathri; Okoeguale, Onose; Verma, Shikha; Patel, Rikinkumar S","year":2020,"journal":"Cureus, 12(10), e11058","doi":"10.7759/cureus.11058","pmid":"33224654","tags":["youth","addiction","pain"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"In 27,444,239 pediatric hospitalizations (NIS database), 10,562 (0.04%) involved prescription opioid overdose. Cannabis use disorder was present in 14.2% of opioid overdose cases and was independently associated with higher hospitalization odds (OR 1.68, CI 1.57-1.81). Adolescents had 10.75 times higher odds than children under 12. Mood disorders (44.3%) and anxiety (14.6%) were the most common comorbidities.","whyItMatters":"Understanding which pediatric patients are at highest risk for opioid overdose helps target prevention. The cannabis-opioid association suggests overlapping vulnerability rather than a gateway effect.","specificNumbers":"27.4M hospitalizations; 10,562 opioid overdoses (0.04%); cannabis use disorder OR 1.68; tobacco OR 1.58; opioid use disorder OR 8.79; 44.3% had mood disorders; adolescents OR 10.75 vs children.","methodology":"Retrospective analysis of the Nationwide Inpatient Sample (NIS) with 27,444,239 pediatric hospitalizations, using logistic regression to assess associations between substance use disorders and prescription opioid overdose.","limitations":"Administrative database (ICD codes may underidentify substance use); cross-sectional associations cannot establish temporal order; cannot distinguish recreational from prescription cannabis; database coding limitations for pediatric substance use."},{"rthcId":"RTHC-02764","title":"Pharmacogenetic-guided cannabis usage in the community pharmacy: evaluation of a pilot program.","authors":"Papastergiou, John; Li, Wilson; Sterling, Carly; van den Bemt, Bart","year":2020,"journal":"Journal of cannabis research, 2(1), 24","doi":"10.1186/s42238-020-00033-1","pmid":"33526106","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02765","title":"Man vs. man-made marijuana: A case of drug-induced posterior reversible encephalopathy syndrome (PRES) due to K2, a ynthetic cannabinoid (SCB).","authors":"Parajuli, Priyanka; Regmi, Manjari Rani; Lara-Garcia, Odalys Estefania; Abu Limon, Ismael; Deckard, Alan","year":2020,"journal":"Journal of community hospital internal medicine perspectives, 10(4), 361-364","doi":"10.1080/20009666.2020.1781349","pmid":"32850099","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02766","title":"Long-term efficacy and safety of cannabidiol (CBD) in children with treatment-resistant epilepsy: Results from a state-based expanded access program.","authors":"Park, Yong D; Linder, Daniel F; Pope, Jamie; Flamini, J Robert; Moretz, Katherine; Diamond, Michael P; Long, Sarah A","year":2020,"journal":"Epilepsy & behavior : E&B, 112, 107474","doi":"10.1016/j.yebeh.2020.107474","pmid":"33181893","tags":["cbd","epilepsy","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Over 36 months, 45 children with treatment-resistant epilepsy (various etiologies beyond Dravet/LGS) treated with adjunctive CBD (Epidiolex, up to 50 mg/kg/day) showed statistically significant reductions in seizure frequency at months 3, 6, 12, 18, 24, and 36. Seizure-free days increased by an average of 7.52 days (p<0.001). Higher doses (>25 mg/kg/day) were associated with more adverse events initially, though AE rates decreased over time.","whyItMatters":"Most CBD epilepsy data comes from Dravet and Lennox-Gastaut syndrome. This study extends the evidence to children with diverse seizure etiologies who failed all other treatments, showing benefit for a broader population.","specificNumbers":"45 patients; 36 months; significant seizure reduction at all time points; +7.52 seizure-free days; doses up to 50 mg/kg/day; 12 children had 20 serious AEs, none CBD-related; AE rate decreased over time.","methodology":"Multicenter expanded access program in Georgia for children aged 1-18 with treatment-resistant epilepsy who had failed available treatments and were ineligible for Dravet/LGS RCTs. CBD titrated to 25 mg/kg/day with optional increase to 50 mg/kg/day. 36-month follow-up.","limitations":"No control group (expanded access design); relatively small sample; mixed epilepsy etiologies make subgroup analysis difficult; seizure diaries may have reporting variability; state-specific program."},{"rthcId":"RTHC-02767","title":"Sex and Strain Variation in Initial Sensitivity and Rapid Tolerance to Δ9-Tetrahydrocannabinol.","authors":"Parks, Cory; Jones, Byron C; Moore, Bob M; Mulligan, Megan K","year":2020,"journal":"Cannabis and cannabinoid research, 5(3), 231-245","doi":"10.1089/can.2019.0047","pmid":"32923660","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02768","title":"Cardiac and Metabolic Impact of Functional Foods with Antioxidant Properties Based on Whey Derived Proteins Enriched with Hemp Seed Oil.","authors":"Pasqua, Teresa; Rocca, Carmine; Lupi, Francesca Romana; Baldino, Noemi; Amelio, Daniela; Parisi, Ortensia Ilaria; Granieri, Maria Concetta; De Bartolo, Anna; Lauria, Arturo; Dattilo, Marco; Perrotta, Ida Daniela; Puoci, Francesco; Cerra, Maria Carmela; Gabriele, Domenico; Angelone, Tommaso","year":2020,"journal":"Antioxidants (Basel, Switzerland), 9(11)","doi":"10.3390/antiox9111066","pmid":"33143213","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02769","title":"Cannabinoids in Glaucoma Patients: The Never-Ending Story.","authors":"Passani, Andrea; Posarelli, Chiara; Sframeli, Angela Tindara; Perciballi, Laura; Pellegrini, Marco; Guidi, Gianluca; Figus, Michele","year":2020,"journal":"Journal of clinical medicine, 9(12)","doi":"10.3390/jcm9123978","pmid":"33302608","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02770","title":"Signalling profiles of a structurally diverse panel of synthetic cannabinoid receptor agonists.","authors":"Patel, Monica; Manning, Jamie J; Finlay, David B; Javitch, Jonathan A; Banister, Samuel D; Grimsey, Natasha L; Glass, Michelle","year":2020,"journal":"Biochemical pharmacology, 175, 113871","doi":"10.1016/j.bcp.2020.113871","pmid":"32088263","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02771","title":"Do cannabis use disorders increase medication non-compliance in schizophrenia?: United States Nationwide inpatient cross-sectional study.","authors":"Patel, Rikinkumar S; Sreeram, Venkatesh; Vadukapuram, Ramu; Baweja, Raman","year":2020,"journal":"Schizophrenia research, 224, 40-44","doi":"10.1016/j.schres.2020.11.002","pmid":"33183946","tags":["psychosis","addiction","cognition"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 1,030,949 schizophrenia inpatients (2010-2014), 26% were non-compliant with medications. Cannabis use disorder was independently associated with medication non-compliance (adjusted OR 1.38, 95% CI 1.268-1.489). CUD was disproportionately seen in young adults (18-35, 62.4%), males (80.5%), African Americans (54.1%), and low-income families (48.6%).","whyItMatters":"Medication adherence is the single most important factor in schizophrenia outcomes. Identifying cannabis use disorder as a strong independent predictor of non-compliance helps target intervention resources.","specificNumbers":"1,030,949 inpatients; 26% medication non-compliance rate; unadjusted OR 1.49; adjusted OR 1.38 (CI 1.268-1.489); CUD patients: 62.4% young adults, 80.5% male, 54.1% African American.","methodology":"Retrospective cross-sectional analysis of the Nationwide Inpatient Sample (NIS) with 1,030,949 schizophrenia inpatients aged 18-65 from 2010-2014, using ICD-9 codes for CUD and medication non-compliance with multivariable logistic regression.","limitations":"Administrative database with ICD-9 coding limitations; cross-sectional (cannot determine temporal order); \"non-compliance\" is a recorded diagnosis, not a direct measure; cannot distinguish recreational from self-medicating cannabis use."},{"rthcId":"RTHC-02772","title":"Marijuana use and acute myocardial infarction: A systematic review of published cases in the literature.","authors":"Patel, Rikinkumar S; Kamil, Saher H; Bachu, Ramya; Adikey, Archana; Ravat, Virendrasinh; Kaur, Mandeep; Tankersley, William E; Goyal, Hemant","year":2020,"journal":"Trends in cardiovascular medicine, 30(5), 298-307","doi":"10.1016/j.tcm.2019.08.003","pmid":"31439383","tags":["cardiovascular","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 46 published studies describing 62 patients who had acute myocardial infarction following marijuana use, the mean age was 27.7 years with male predominance. Average onset was within 5 hours of use. Angiographic findings were normal in 36.8%, while the left anterior descending artery was the most commonly occluded vessel (42.1%). Seven deaths were reported among the 62 cases.","whyItMatters":"Heart attacks in people under 30 with no traditional risk factors are rare. The pattern of young, otherwise healthy users having coronary events shortly after marijuana use suggests a direct pharmacological trigger worth understanding.","specificNumbers":"62 patients; mean age 27.7 (SD 10.3); ~3.7g average use; 9.7 years average use history; symptoms within 5h; normal angiogram 36.8%; LAD occlusion 42.1%; 7 deaths.","methodology":"Systematic review of case reports, case series, and letters to the editor from MEDLINE describing individuals with acute myocardial infarction associated with marijuana use. 46 studies with 62 total patients included.","limitations":"Case reports only (lowest level of evidence); publication bias toward unusual presentations; cannot establish causation from case series; no denominator to calculate actual risk; other substance co-use may be underreported."},{"rthcId":"RTHC-02773","title":"The Association Between Cannabis Use and Schizophrenia: Causative or Curative? A Systematic Review.","authors":"Patel, Shweta; Khan, Sahar; M, Saipavankumar; Hamid, Pousettef","year":2020,"journal":"Cureus, 12(7), e9309","doi":"10.7759/cureus.9309","pmid":"32839678","tags":["psychosis","cbd","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"After screening 96 articles and including 12 final studies (5 traditional reviews, 2 systematic reviews, 2 meta-analyses, 3 observational), 10 studies supported a causative link between cannabis and schizophrenia, 8 supported symptom exacerbation, and 6 supported therapeutic effects of CBD. The evidence points to THC as the primary risk component while CBD may counteract psychotic symptoms.","whyItMatters":"The opposing effects of THC and CBD on psychosis may explain why cannabis research has yielded contradictory findings. Separating these components could transform both risk assessment and treatment.","specificNumbers":"96 initial results; 12 final studies included; 10 supported causative link; 8 supported exacerbation; 6 supported CBD therapeutic effects.","methodology":"Systematic review of PubMed, PubMed Central, Cochrane Library, and Google Scholar for studies on cannabis and schizophrenia/psychosis published in the last 5 years. Quality assessment reduced 24 studies to 12 final inclusions.","limitations":"Half the initial studies excluded for low quality; included studies were mostly reviews themselves (limited original data); small total evidence base (12 studies); did not quantify effect sizes."},{"rthcId":"RTHC-02774","title":"\"Residual blood THC levels in frequent cannabis users after over four hours of abstinence: A systematic review.\".","authors":"Peng, Yuan Wei; Desapriya, Ediriweera; Chan, Herbert; R Brubacher, Jeffrey","year":2020,"journal":"Drug and alcohol dependence, 216, 108177","doi":"10.1016/j.drugalcdep.2020.108177","pmid":"32841811","tags":["driving","tolerance","potency"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 6 independent studies, frequent cannabis users showed blood THC above 2 ng/mL (or plasma THC above 3 ng/mL) after six days of abstinence in 5 studies. Two studies found blood THC above 5 ng/mL (or plasma above 7.5 ng/mL) after one day of abstinence. This means frequent users could fail legal THC driving limits while completely unimpaired.","whyItMatters":"Many jurisdictions use 2 or 5 ng/mL blood THC as per se driving limits. If frequent users exceed these thresholds days after last use, unimpaired drivers are being criminalized for a positive test that reflects prior use, not current impairment.","specificNumbers":"1,612 articles screened; 6 studies included; 5 found THC >2 ng/mL after 6 days abstinence; 2 found THC >5 ng/mL after 1 day abstinence.","methodology":"Systematic review searching MEDLINE, EMBASE, PsycINFO, and Web of Science for studies reporting THC levels in frequent cannabis users after more than 4 hours of abstinence. 1,612 articles screened; 6 independent studies met criteria.","limitations":"Only 6 studies met criteria (limited evidence); definitions of \"frequent use\" varied; did not assess actual impairment alongside THC levels; small samples in most included studies; blood vs plasma THC complicates comparisons."},{"rthcId":"RTHC-02775","title":"7-Azaindolequinuclidinones (7-AIQD): A novel class of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands.","authors":"Penthala, Narsimha Reddy; Shoeib, Amal; Dachavaram, Soma Shekar; Cabanlong, Christian V; Yang, Jingfang; Zhan, Chang-Guo; Prather, Paul L; Crooks, Peter A","year":2020,"journal":"Bioorganic & medicinal chemistry letters, 30(22), 127501","doi":"10.1016/j.bmcl.2020.127501","pmid":"32882418","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02776","title":"Perceptions of U.S. and Canadian Cannabis Package Warnings Among U.S. Adults.","authors":"Pepper, Jessica K; Lee, Youn Ok; Eggers, Matthew E; Allen, Jane A; Thompson, Jesse; Nonnemaker, James M","year":2020,"journal":"Drug and alcohol dependence, 217, 108275","doi":"10.1016/j.drugalcdep.2020.108275","pmid":"32971388","tags":["legalization","youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 1,000 US adults (500 cannabis users, 500 tobacco-using non-cannabis users), the psychosis warning was rated most educational and most frequently selected as best for discouraging youth use. The addiction and psychosis warnings were rated less believable than the driving warning. Any warning increased perceived harmfulness of smoking cannabis compared to no warning. Warning effects were similar across dried flower and edible product types.","whyItMatters":"As US states legalize cannabis, packaging warning requirements need evidence-based design. This is among the first studies comparing specific warning messages for cannabis products.","specificNumbers":"1,000 adults; psychosis warning: learned most (users B=0.88, non-users B=1.60); addiction warning less believable (users B=-1.04, non-users B=1.17); any warning increased perceived harmfulness (all p<0.05).","methodology":"Randomized online survey experiment assigning 1,000 US adults to view no warning or one of four warnings (psychosis, addiction, no FDA oversight, impaired driving) on either dried flower or edible cannabis packaging images. Linear regression analyzed perceptions.","limitations":"Online survey (hypothetical packaging, not real-world); single exposure (does not test wear-out effects); US adults only; self-reported perceptions may not predict behavior change; tobacco-using control group may not represent general non-users."},{"rthcId":"RTHC-02777","title":"Cannabis hyperemesis syndrome: an update on the pathophysiology and management.","authors":"Perisetti, Abhilash; Gajendran, Mahesh; Dasari, Chandra Shekhar; Bansal, Pardeep; Aziz, Muhammad; Inamdar, Sumant; Tharian, Benjamin; Goyal, Hemant","year":2020,"journal":"Annals of gastroenterology, 33(6), 571-578","doi":"10.20524/aog.2020.0528","pmid":"33162734","tags":["appetite","harm-reduction","neuroscience"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"CHS is characterized by cyclic nausea and vomiting worsened by cannabis, with compulsive hot bathing/showers for relief. The endocannabinoid system (ECS) plays a central role: cannabis has a biphasic effect (anti-emetic at low doses, pro-emetic at higher doses). Desensitization and downregulation of CB1 receptors in chronic users may shift the balance toward pro-emetic effects. Traditional antiemetics are often ineffective; capsaicin cream (activating TRPV1 receptors) and haloperidol show some benefit.","whyItMatters":"As cannabis use increases with legalization, CHS presentations to emergency departments are rising. Understanding the ECS mechanisms helps explain why standard antiemetics fail and guides development of targeted treatments.","specificNumbers":"First described in 2004; increasing cases worldwide; cannabis biphasic effect: anti-emetic at low doses, pro-emetic at higher doses; capsaicin and haloperidol show benefit in case reports.","methodology":"Narrative review elaborating on the pathophysiology of the endocannabinoid system in CHS, clinical management, and current knowledge gaps.","limitations":"Narrative review (not systematic); no formal diagnostic criteria for CHS exist; most treatment evidence from case reports; pathophysiology partly theoretical; prevalence data limited."},{"rthcId":"RTHC-02778","title":"Role of cannabis in inflammatory bowel diseases.","authors":"Perisetti, Abhilash; Rimu, Afrina Hossain; Khan, Salman Ali; Bansal, Pardeep; Goyal, Hemant","year":2020,"journal":"Annals of gastroenterology, 33(2), 134-144","doi":"10.20524/aog.2020.0452","pmid":"32127734","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02779","title":"A new mechanism for cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models.","authors":"Perry, Christopher J; Finch, Paul; Müller-Taubenberger, Annette; Leung, Kit-Yi; Warren, Eleanor C; Damstra-Oddy, Joseph; Sharma, Devdutt; Patra, Pabitra H; Glyn, Sarah; Boberska, Joanna; Stewart, Balint; Baldwin, Amy; Piscitelli, Fabiana; Harvey, Robert J; Harwood, Adrian; Thompson, Christopher; Claus, Sandrine P; Greene, Nicholas D E; McNeish, Alister J; Williams, Claire M; Whalley, Benjamin J; Williams, Robin S B","year":2020,"journal":"British journal of pharmacology, 177(4), 912-928","doi":"10.1111/bph.14892","pmid":"31693171","tags":["cbd","epilepsy","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Using the model organism Dictyostelium, researchers identified that CBD activity depends partly on the glycine cleavage system, linked to folate one-carbon metabolism (FOCM). CBD directly inhibited methionine synthesis. In a Dravet syndrome mouse model, one-carbon metabolism components including methionine were drastically altered. In an in vitro rat seizure model, methionine levels were elevated during seizures and reduced by CBD treatment.","whyItMatters":"Despite FDA approval of Epidiolex for Dravet syndrome, CBD mechanism of action was poorly understood. This study identifies an entirely new metabolic pathway (one-carbon metabolism/methionine) that may explain how CBD controls seizures.","specificNumbers":"CBD activity dependent on GcvH1 (glycine cleavage system H protein); direct methionine synthesis inhibition; Dravet mouse brain showed altered one-carbon components; rat seizure model: elevated methionine attenuated by CBD.","methodology":"Multi-model approach: unbiased screen in Dictyostelium to identify CBD-interacting proteins; validation in Dravet syndrome mouse model (brain tissue analysis); functional testing in acute in vitro rat hippocampal seizure model. Methionine and one-carbon metabolites measured across all models.","limitations":"Initial discovery in a simple model organism (Dictyostelium); animal models only; mechanism not yet confirmed in human epilepsy tissue; does not establish dose-response in mammals; the multiple-model approach increases confidence but each individual model has limitations."},{"rthcId":"RTHC-02780","title":"Cannabis use, cognitive performance, and symptoms of attention deficit/hyperactivity disorder in community adults.","authors":"Petker, Tashia; DeJesus, Jane; Lee, Alex; Gillard, Jessica; Owens, Max M; Balodis, Iris; Amlung, Michael; George, Tony; Oshri, Assaf; Hall, Geoffrey; Schmidt, Louis; MacKillop, James","year":2020,"journal":"Experimental and clinical psychopharmacology, 28(6), 638-648","doi":"10.1037/pha0000354","pmid":"32105137","tags":["cognition","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"After controlling for age, income, sex, alcohol, and tobacco use, cannabis use severity predicted greater hyperactive-impulsive and inattentive ADHD symptom endorsement in 1,008 adults, but was not associated with other neurocognitive measures. In young adults (n=371), cannabis severity was linked to digit span forward and hyperactive symptoms. In high-risk users (n=161), associations extended to delay discounting and impulsive ADHD symptoms. Age of first cannabis use was not associated with any cognitive outcome.","whyItMatters":"The large sample resolves inconsistencies from smaller studies: cannabis misuse appears specifically linked to ADHD-type symptoms rather than broad cognitive decline. The null finding for age of first use challenges the \"earlier is worse\" narrative.","specificNumbers":"1,008 adults; mean age 38.5; cannabis severity predicted both hyperactive and inattentive ADHD symptoms; no associations with other cognitive domains; age of first use: no significant associations in any analysis.","methodology":"Dimensional design with 1,008 community adults (mean age 38.5, 56% female) assessed for cannabis involvement, ADHD symptoms, and neurocognitive performance using validated measures and hierarchical multiple regression.","limitations":"Cross-sectional (cannot determine directionality); community sample may underrepresent heavy users; ADHD symptoms self-reported, not clinically diagnosed; cannabis involvement measured dimensionally, not by product type or potency."},{"rthcId":"RTHC-02781","title":"Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity.","authors":"Pinson, Anna; Yarbrough, Azure L; Bush, John M; Cabanlong, Christian V; Shoeib, Amal; Jackson, Bailey K; Fukuda, Saki; Gogoi, Jyoti; Fantegrossi, William E; McCain, Keith; Prather, Paul L; Fujiwara, Ryoichi; Radominska-Pandya, Anna","year":2020,"journal":"Pharmacology, biochemistry, and behavior, 195, 172949","doi":"10.1016/j.pbb.2020.172949","pmid":"32413436","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02782","title":"Challenges of Differential Diagnosis, Symptoms of Coronavirus Disease 2019 (COVID-19) or Cannabinoid Hyperemesis Syndrome (CHS)? A Rare Case Report.","authors":"Pirnia, Bijan; Pirnia, Kambiz; Malekanmehr, Parastoo; Zahiroddin, Alireza","year":2020,"journal":"Iranian journal of public health, 49(Suppl 1), 109-111","doi":"10.18502/ijph.v49iS1.3677","pmid":"34268213","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02783","title":"Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study.","authors":"Poisson, Kelsey; Wong, Matthew; Lee, Chon; Cilio, Maria Roberta","year":2020,"journal":"European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 25, 77-81","doi":"10.1016/j.ejpn.2019.12.024","pmid":"31926846","tags":["cbd","epilepsy","youth","genetics"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Three patients with EIMFS secondary to KCNT1 mutations received pharmaceutical-grade CBD. Two patients showed no benefit and discontinued treatment. One patient showed no overall seizure frequency reduction but had notable reduction in seizure intensity and possible developmental progression. The results contrast with CBD efficacy in Dravet and Lennox-Gastaut syndromes.","whyItMatters":"EIMFS is a devastating rare epilepsy with almost no treatment options. While results were mostly negative, the one partial responder suggests that seizure intensity (not just frequency) may be a meaningful outcome measure for CBD.","specificNumbers":"3 patients with KCNT1 mutations; 2 showed no benefit; 1 showed reduced seizure intensity but not frequency; the responder also had possible developmental progression.","methodology":"Open-label, prospective interventional study of 3 patients with EIMFS caused by KCNT1 mutations treated with pharmaceutical-grade CBD as adjunctive therapy.","limitations":"Only 3 patients (no statistical power); open-label; no control group; mixed results; EIMFS is extremely rare, making large studies difficult; seizure intensity assessment is subjective."},{"rthcId":"RTHC-02784","title":"Predictors of marijuana vaping onset and escalation among young adults.","authors":"Pokhrel, Pallav; Fagan, Pebbles; Kawamoto, Crissy T; Okamoto, Scott K; Herzog, Thaddeus A","year":2020,"journal":"Drug and alcohol dependence, 216, 108320","doi":"10.1016/j.drugalcdep.2020.108320","pmid":"33039921","tags":["youth","addiction","potency"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Among 2,327 young adults followed for one year, dual cigarette/e-cigarette use at baseline was the strongest predictor of marijuana vaping initiation among non-marijuana users. Social networks with more regular marijuana users predicted marijuana vaping initiation. Among existing e-cigarette and marijuana users, having social networks with people who frequented vape shops predicted increased marijuana vaping over time.","whyItMatters":"Marijuana vaping is increasing rapidly among young adults but its risk factors are poorly understood. Identifying that dual tobacco product use and social networks drive initiation helps target prevention.","specificNumbers":"2,327 young adults; mean age 21.2; 54% women; 1-year follow-up (2017-2019); dual cigarette/e-cigarette use strongest predictor of initiation; vape shop social networks predicted escalation.","methodology":"One-year prospective study of 2,327 young adults (mean age 21.2, 54% women) at 2-year and 4-year colleges in Hawaii, using validated measures of substance use, social network characteristics, and marketing exposure at baseline and follow-up.","limitations":"Hawaii sample (unique cultural and legal context); 1-year follow-up may miss longer-term patterns; self-report measures; college students may not represent all young adults; did not assess vaping device types or THC concentrations."},{"rthcId":"RTHC-02785","title":"Influence of the CB1 and CB2 cannabinoid receptor ligands on the activity of atypical antidepressant drugs in the behavioural tests in mice.","authors":"Poleszak, Ewa; Wośko, Sylwia; Sławińska, Karolina; Wyska, Elżbieta; Szopa, Aleksandra; Świąder, Katarzyna; Wróbel, Andrzej; Doboszewska, Urszula; Wlaź, Piotr; Wlaź, Aleksandra; Serefko, Anna","year":2020,"journal":"Pharmacology, biochemistry, and behavior, 188, 172833","doi":"10.1016/j.pbb.2019.172833","pmid":"31785246","tags":["depression","neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In mouse forced swim and tail suspension tests, sub-effective doses of CB receptor ligands enhanced antidepressant activity: oleamide (CB1 agonist) potentiated tianeptine; AM251 (CB1 antagonist) enhanced both tianeptine and agomelatine; AM630 (CB2 inverse agonist) augmented both drugs in the forced swim test only. None of the combinations affected brain levels of the antidepressants, indicating pharmacodynamic rather than pharmacokinetic interaction.","whyItMatters":"Atypical antidepressants like agomelatine and tianeptine work through unique mechanisms (melatonin and opioid pathways). Finding that cannabinoid compounds enhance their effects without changing brain concentrations suggests a true synergistic interaction worth exploring.","specificNumbers":"Oleamide 5 mg/kg + tianeptine 15 mg/kg: significant anti-immobility in FST and TST; AM251 0.25 mg/kg enhanced both drugs; AM630 0.25 mg/kg enhanced both in FST only; no brain level changes.","methodology":"Mouse behavioral studies using forced swim test (FST) and tail suspension test (TST) to assess antidepressant-like effects of cannabinoid receptor ligands combined with atypical antidepressants (agomelatine, tianeptine). HPLC measured brain drug levels.","limitations":"Animal model only (mouse behavioral tests have limited translational value); sub-effective doses may not translate to clinical use; forced swim test validity debated; only two atypical antidepressants tested; acute dosing only."},{"rthcId":"RTHC-02786","title":"Ligands of the CB2 cannabinoid receptors augment activity of the conventional antidepressant drugs in the behavioural tests in mice.","authors":"Poleszak, Ewa; Wośko, Sylwia; Sławińska, Karolina; Wyska, Elżbieta; Szopa, Aleksandra; Sobczyński, Jan; Wróbel, Andrzej; Doboszewska, Urszula; Wlaź, Piotr; Wlaź, Aleksandra; Szponar, Jarosław; Skałecki, Piotr; Serefko, Anna","year":2020,"journal":"Behavioural brain research, 378, 112297","doi":"10.1016/j.bbr.2019.112297","pmid":"31626848","tags":["depression","neuroscience","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Sub-effective doses of JWH133 (CB2 agonist, 0.25 mg/kg) and AM630 (CB2 inverse agonist, 0.25 mg/kg) each significantly enhanced the antidepressant effects of imipramine (15 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg) in both forced swim and tail suspension tests. Brain levels of antidepressants were unchanged, and locomotor activity was unaffected.","whyItMatters":"These findings suggest CB2 receptors modulate mood independently of CB1, the more studied cannabinoid receptor. The enhancement of three different antidepressant classes (tricyclic, SSRI, NRI) suggests a broad-spectrum augmentation effect.","specificNumbers":"JWH133 0.25 mg/kg + each antidepressant: significant immobility reduction in FST and TST; AM630 0.25 mg/kg + each: same effect; no brain level changes; no locomotor effects.","methodology":"Mouse forced swim test (FST) and tail suspension test (TST) assessing combinations of CB2 receptor ligands with conventional monoaminergic antidepressants (imipramine, escitalopram, reboxetine). HPLC measured brain drug concentrations; locomotor activity monitored to rule out non-specific motor effects.","limitations":"Animal model only; mouse behavioral tests have debated translational validity; acute dosing (no chronic studies); both agonist and antagonist showing same effect is mechanistically puzzling; only tested at single sub-effective doses."},{"rthcId":"RTHC-02787","title":"A pediatric patient with autism spectrum disorder and epilepsy using cannabinoid extracts as complementary therapy: a case report.","authors":"Ponton, Juliana Andrea; Smyth, Kim; Soumbasis, Elias; Llanos, Sergio Andres; Lewis, Mark; Meerholz, Wilhelm August; Tanguay, Robert Lawrence","year":2020,"journal":"Journal of medical case reports, 14(1), 162","doi":"10.1186/s13256-020-02478-7","pmid":"32958062","tags":["cbd","youth","epilepsy","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 15-year-old boy with autism, selective mutism, anxiety, and controlled epilepsy was prescribed CBD-based extract to potentially replace seizure medications. At a lower dose than typically reported for autism, he showed unanticipated improvements in behavioral symptoms, core social communication abilities, anxiety, sleep, and weight control. The social improvements were notable because they addressed core autism deficits, not just associated behaviors.","whyItMatters":"Current autism medications target associated symptoms (irritability, anxiety) but not the core social communication deficits. This case is notable because social improvements were observed at a dose lower than expected, suggesting a potential therapeutic window.","specificNumbers":"One 15-year-old patient; dose lower than previously reported for ASD; improvements in social communication, anxiety, sleep, and weight.","methodology":"Single case report documenting response to pharmaceutical-grade CBD-based extract in a 15-year-old with comorbid autism spectrum disorder, selective mutism, anxiety, and epilepsy.","limitations":"Single case report (cannot generalize); multiple comorbidities confound attribution; placebo effects possible; no standardized outcome measures described; dose specifics not fully detailed in abstract; prior epilepsy medication changes could contribute."},{"rthcId":"RTHC-02788","title":"Synthetic cannabinoid receptor agonists: classification and nomenclature.","authors":"Potts, A J; Cano, C; Thomas, S H L; Hill, S L","year":2020,"journal":"Clinical toxicology (Philadelphia, Pa.), 58(2), 82-98","doi":"10.1080/15563650.2019.1661425","pmid":"31524007","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02789","title":"Effect of Cannabinoids on Electroencephalography of a Child with Lennox-Gastaut Syndrome.","authors":"Prakash, Vikram","year":2020,"journal":"Journal of neurosciences in rural practice, 11(4), 643-645","doi":"10.1055/s-0040-1714329","pmid":"33144805","tags":["cbd","epilepsy","youth","neuroscience"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 9-year-old boy with Lennox-Gastaut syndrome of unknown etiology treated with highly purified CBD (Epidiolex) achieved complete seizure control and near-normalization of EEG background activity. The EEG response was described as \"dramatic,\" with previously abnormal patterns resolving. This degree of EEG improvement has not been previously described with CBD treatment.","whyItMatters":"EEG normalization goes beyond seizure control: it suggests CBD may modify the underlying epileptic brain activity, not just suppress seizure expression. This could indicate disease-modifying rather than purely symptomatic effects.","specificNumbers":"One 9-year-old patient; complete seizure control; near-normalization of EEG background; unknown etiology LGS.","methodology":"Single case report with pre- and post-CBD electroencephalography documenting the electrophysiological response to cannabidiol treatment in a child with Lennox-Gastaut syndrome.","limitations":"Single case report; cannot determine if response is typical or exceptional; EEG improvement may be coincidental with development; no control for other variables; unknown etiology means underlying cause could influence response."},{"rthcId":"RTHC-02790","title":"In Vitro Metabolic Profile Elucidation of Synthetic Cannabinoid APP-CHMINACA (PX-3).","authors":"Presley, Brandon C; Logan, Barry K; Jansen-Varnum, Susan A","year":2020,"journal":"Journal of analytical toxicology, 44(3), 226-236","doi":"10.1093/jat/bkz086","pmid":"31665324","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02791","title":"Cannabinoid-sensitive receptors in cardiac physiology and ischaemia.","authors":"Puhl, Sarah-Lena","year":2020,"journal":"Biochimica et biophysica acta. Molecular cell research, 1867(3), 118462","doi":"10.1016/j.bbamcr.2019.03.009","pmid":"30890410","tags":["cardiovascular","neuroscience","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Both CB1 and CB2 receptors and their endogenous ligands (anandamide and 2-AG) are upregulated in the ischemic heart. CB1 activation aggravates the inflammatory response during cardiac ischemia, while CB2 activation reduces inflammation by affecting immune cell attraction, macrophage polarization, and lymphocyte clusters. However, cannabis consumption may trigger arrhythmias and myocardial infarction, and CB1 activation is linked to impaired lipid/glucose metabolism, obesity, and diabetes.","whyItMatters":"The opposing roles of CB1 and CB2 in the heart present both danger and opportunity. Understanding which receptor does what could enable selective targeting: blocking CB1 to reduce cardiovascular risk while activating CB2 for cardiac protection.","specificNumbers":"CB1 antagonism reduces plasma triglycerides, LDL cholesterol, leptin, insulin, and glucose; CB2 activation mitigates ischemia-induced inflammation; GPR55 prevents impaired adrenoceptor responsiveness.","methodology":"Narrative review of preclinical and clinical literature on cannabinoid receptors (CB1, CB2, GPR55) in cardiac physiology, ischemia, and cardiovascular risk factors.","limitations":"Narrative review (not systematic); much evidence from animal models; clinical translation of receptor-specific effects uncertain; cannabis delivery method effects not well differentiated; GPR55 cardiac role poorly characterized."},{"rthcId":"RTHC-02792","title":"Attenuation of Oxidative Stress by Cannabinoids and Cannabis Extracts in Differentiated Neuronal Cells.","authors":"Raja, Aruna; Ahmadi, Soha; de Costa, Fernanda; Li, Nan; Kerman, Kagan","year":2020,"journal":"Pharmaceuticals (Basel, Switzerland), 13(11)","doi":"10.3390/ph13110328","pmid":"33105840","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02793","title":"The Cannabinoids Effect on Bone Formation and Bone Healing.","authors":"Raphael-Mizrahi, Bitya; Gabet, Yankel","year":2020,"journal":"Current osteoporosis reports, 18(5), 433-438","doi":"10.1007/s11914-020-00607-1","pmid":"32705630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02794","title":"Cannabidiol Treatment for Refractory Epilepsies in Pediatrics.","authors":"Raucci, Umberto; Pietrafusa, Nicola; Paolino, Maria Chiara; Di Nardo, Giovanni; Villa, Maria Pia; Pavone, Piero; Terrin, Gianluca; Specchio, Nicola; Striano, Pasquale; Parisi, Pasquale","year":2020,"journal":"Frontiers in pharmacology, 11, 586110","doi":"10.3389/fphar.2020.586110","pmid":"33117180","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02795","title":"Cannabidiol (CBD) Oil Does Not Display an Entourage Effect in Reducing Cancer Cell Viability in vitro.","authors":"Raup-Konsavage, Wesley M; Carkaci-Salli, Nurgul; Greenland, Kelly; Gearhart, Robert; Vrana, Kent E","year":2020,"journal":"Medical cannabis and cannabinoids, 3(2), 95-102","doi":"10.1159/000510256","pmid":"34676344","tags":["cbd","cancer"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Pure CBD (10 μM) reduced cell viability in 3 of 6 cancer cell lines tested. None of the 3 commercial CBD oils reduced viability more than pure CBD. Dose-response curves showed lower IC50 values (higher potency) for pure CBD compared to the most potent oil. Some oils appeared to protect cancer cells from CBD effects. The anti-cancer activity was cell-line specific rather than cancer-type specific.","whyItMatters":"The \"entourage effect\" is frequently cited to argue that whole-plant cannabis products are superior to purified compounds. This study provides direct evidence against that claim for anti-cancer activity, finding pure CBD was equal or superior.","specificNumbers":"6 cancer cell lines; 3 cancer types; 10 μM CBD; 3 commercial oils; pure CBD effective in 3 of 6 lines; some oils appeared protective of cancer cells.","methodology":"In vitro study testing pure CBD and 3 commercial CBD hemp oils (independently verified for CBD content and cannabinoid/terpene composition) against 6 human cancer cell lines from 3 cancer types using MTS viability assay and dose-response curves.","limitations":"In vitro only (does not reflect in vivo tumor biology); limited to 6 cell lines; only tested one CBD concentration initially; commercial oils vary in composition; anti-cancer cell viability is not the same as treating cancer in patients."},{"rthcId":"RTHC-02796","title":"A time-dependent contribution of hippocampal CB1 , CB2 and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation.","authors":"Raymundi, Ana Maria; da Silva, Thiago R; Zampronio, Aleksander R; Guimarães, Francisco S; Bertoglio, Leandro J; Stern, Cristina A J","year":2020,"journal":"British journal of pharmacology, 177(4), 945-957","doi":"10.1111/bph.14895","pmid":"31648363","tags":["cbd","anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD (10-30 pmol) injected into the dorsal hippocampus impaired fear memory consolidation when given immediately or 1 hour after conditioning, but not at 3 hours. The receptor mechanism changed with timing: immediately after fear conditioning, CB1 and CB2 receptors mediated the effect; at 1 hour, only PPARγ receptors were required. The anandamide-degrading enzyme inhibitor URB597 impaired consolidation only at the immediate time point.","whyItMatters":"Understanding the time window and receptor switches for CBD memory disruption is crucial for potential PTSD treatment. The 1-hour window after a traumatic event and the shift from CB1/CB2 to PPARγ receptors reveal a more complex mechanism than previously assumed.","specificNumbers":"CBD effective immediately and at 1h but not 3h; immediate: CB1 and CB2 mediated; 1h: PPARγ mediated; URB597 effective only immediately; Arc protein reduced by CBD at both effective time points.","methodology":"Behavioral study in adult male Wistar rats receiving intra-hippocampal CBD at different time points after contextual fear conditioning, with receptor-specific antagonists to identify mechanisms. Arc protein expression analyzed to confirm memory consolidation effects.","limitations":"Animal model (fear conditioning is a simplification of human trauma); male rats only; direct hippocampal injection (not clinically practical); single fear conditioning session; translational gap between rodent fear memory and human PTSD."},{"rthcId":"RTHC-02797","title":"Frequent Cannabis Use and Cessation of Injection of Opioids, Vancouver, Canada, 2005-2018.","authors":"Reddon, Hudson; DeBeck, Kora; Socias, M Eugenia; Lake, Stephanie; Dong, Huiru; Karamouzian, Mohammad; Hayashi, Kanna; Kerr, Thomas; Milloy, M-J","year":2020,"journal":"American journal of public health, 110(10), 1553-1560","doi":"10.2105/AJPH.2020.305825","pmid":"32816538","tags":["harm-reduction","addiction","pain"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Among three prospective cohorts of people who inject drugs (PWID) in Vancouver from 2005-2018, at-least-daily cannabis use was associated with 16% faster injection cessation overall (AHR 1.16, CI 1.03-1.30). The effect was driven entirely by opioid injection cessation (AHR 1.26, CI 1.12-1.41), with no significant association for other drug injection cessation. Daily cannabis use was not associated with injection relapse (AHR 1.08, CI 0.95-1.23).","whyItMatters":"During an ongoing opioid overdose crisis, any intervention that helps people stop injecting opioids is significant. The opioid-specific effect (not general injection cessation) suggests cannabis may address something unique about opioid dependence.","specificNumbers":"13-year follow-up (2005-2018); daily cannabis: 16% faster injection cessation overall (AHR 1.16); 26% faster opioid injection cessation specifically (AHR 1.26); no significant injection relapse risk (AHR 1.08).","methodology":"Extended Cox regression analysis with time-updated covariates from three prospective cohorts of PWID in Vancouver, Canada (2005-2018), examining associations between cannabis use frequency and injection cessation and relapse.","limitations":"Observational (cannot establish causation); self-reported cannabis use and injection behavior; unmeasured confounders possible; Vancouver-specific harm reduction context may not generalize; cannot determine cannabis dose, potency, or route."},{"rthcId":"RTHC-02798","title":"Co-occurrence across time and space of drug- and cannabinoid- exposure and adverse mental health outcomes in the National Survey of Drug Use and Health: combined geotemporospatial and causal inference analysis.","authors":"Reece, Albert Stuart; Hulse, Gary Kenneth","year":2020,"journal":"BMC public health, 20(1), 1655","doi":"10.1186/s12889-020-09748-5","pmid":"33148213","tags":["mental-health","legalization","depression","psychosis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Across 410,138 NSDUH respondents (76.7% response rate), cannabis exposure was significantly associated with any mental illness, major depression, serious mental illness (SMI), and suicidal ideation in geospatial models adjusted for demographics and other substance use. SMI rates doubled (3.62% to 7.06%) as cannabis use increased across regions. Cannabis decriminalization was associated with a 3.28% attributable fraction of SMI, and legalization with 12.91% attributable fraction.","whyItMatters":"This is one of the first studies to apply formal causal inference methods to the cannabis-mental health relationship at a population level, finding dose-response and temporal-sequential relationships consistent with causation.","specificNumbers":"410,138 respondents; 76.7% response rate; SMI doubled from 3.62% to 7.06% with cannabis increase; decriminalization AFE 3.28%; legalization AFE 12.91%; significant for all 4 MH outcomes.","methodology":"Ecological cohort study using NSDUH geographically-linked substate data (2010-2012 and 2014-2016) with two-stage geotemporospatial robust generalized linear regression and formal causal inference analysis.","limitations":"Ecological design (associations at area level may not hold for individuals); cross-sectional components within the cohort; NSDUH is self-report; cannot control for all confounders at the individual level; causal inference methods applied to observational data have inherent limitations."},{"rthcId":"RTHC-02799","title":"Marijuana sources in a medical marijuana environment: dynamics in access and use among a cohort of young adults in Los Angeles, California.","authors":"Reed, Megan; Kioumarsi, Avat; Ataiants, Janna; Fedorova, Ekaterina V; Iverson, Ellen; Wong, Carolyn F; Lankenau, Stephen E","year":2020,"journal":"Drugs (Abingdon, England), 27(1), 69-78","doi":"10.1080/09687637.2018.1557595","pmid":"31949332","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02800","title":"Effects of co-administration of rapamycin and evening primrose/hemp seed oil supplement on immunologic factors and cell membrane fatty acids in experimental autoimmune encephalomyelitis.","authors":"Rezapour-Firouzi, Soheila; Mohammadian, Mahshid; Sadeghzadeh, Maryam; Mazloomi, Ebrahim","year":2020,"journal":"Gene, 759, 144987","doi":"10.1016/j.gene.2020.144987","pmid":"32712065","tags":["inflammation","cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis), researchers tested whether evening primrose oil combined with hemp seed oil (EPO/HSO) could improve immune function, and how it compared to rapamycin, an established immunosuppressant.\n\nThe EPO/HSO combination improved the fatty acid composition of spleen and blood cell membranes, increasing the incorporation of beneficial omega-3 and omega-6 fatty acids. It also shifted inflammatory gene expression — reducing certain pro-inflammatory cytokines. When combined with rapamycin, the effects were additive: the combination group showed the most favorable immune profile.\n\nThe proposed mechanism was straightforward: essential fatty acids from the oil supplement physically changed cell membrane composition, which altered how immune cells signaled. This is a different mechanism than CBD or THC — it works through lipid nutrition rather than cannabinoid receptor activation.","whyItMatters":"This isn't about getting high — hemp seed oil contains negligible THC or CBD. The study is about essential fatty acids from hemp as a nutritional supplement that may benefit autoimmune conditions by physically changing how immune cell membranes are constructed. It's a different angle on cannabis plant utility that has nothing to do with cannabinoid receptors.\n\nThe combination with rapamycin is clinically interesting because it suggests nutritional supplementation could complement existing immunosuppressive therapy rather than replace it.","specificNumbers":"• 5 experimental groups, 6 mice per group\n• EPO/HSO improved omega-3 and omega-6 incorporation in cell membranes\n• Combination with rapamycin showed additive anti-inflammatory effects\n• Measured IL-4, IL-5, IL-13 gene expression in lymphocytes","methodology":"Chronic EAE induced in female C57BL/6J mice (6-8 weeks old) via MOG injection. Five groups: EPO/HSO + rapamycin, rapamycin alone, EPO/HSO alone, EAE control, and naive control (6 mice per group). Measured fatty acid profiles in spleen and blood cell membranes. Gene expression of IL-4, IL-5, and IL-13 measured via RT-PCR.","limitations":"Mouse model of MS does not perfectly replicate human disease. Very small group sizes (6 per group). Hemp seed oil's effects are from fatty acids, not cannabinoids — the cannabis connection is botanical, not pharmacological. Short-term study cannot assess long-term immune outcomes. Only female mice used."},{"rthcId":"RTHC-02801","title":"The Effects of Evening Primrose/Hemp Seed Oil Compared to Rapamycin on the Gene Expression of Immunological Parameters in Experimental Autoimmune Encephalomyelitis Splenocytes.","authors":"Rezapour-Firouzi, Soheila; Mohammadian, Mahshid; Sadeghzadeh, Maryam; Mehranfar, Sahar; Mazloomi, Ebrahim","year":2020,"journal":"Iranian journal of allergy, asthma, and immunology, 19(2), 183-192","doi":"10.18502/ijaai.v19i2.2771","pmid":"32372631","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02802","title":"Targeting Cannabinoid Receptor 2 on Peripheral Leukocytes to Attenuate Inflammatory Mechanisms Implicated in HIV-Associated Neurocognitive Disorder.","authors":"Rizzo, Michael D; Henriquez, Joseph E; Blevins, Lance K; Bach, Anthony; Crawford, Robert B; Kaminski, Norbert E","year":2020,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 15(4), 780-793","doi":"10.1007/s11481-020-09918-7","pmid":"32409991","tags":["inflammation","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"HIV patients using medical marijuana had lower levels of circulating CD16+ (activated) monocytes compared to non-cannabis users. CD16+ monocytes carry HIV across the blood-brain barrier and drive neuroinflammation in HAND. CB2 receptor activation suppresses monocyte activation, chemotaxis, and inflammatory mediator release. The review proposes CB2 as a therapeutic target because it mediates anti-inflammatory effects without the psychotropic properties associated with CB1.","whyItMatters":"About 50% of HIV patients develop neurocognitive dysfunction despite antiretroviral therapy. Current treatments do not adequately address the neuroinflammation driving HAND. CB2-targeted therapy could reduce brain inflammation without psychotropic effects.","specificNumbers":"~38 million people living with HIV; ~50% develop HAND; HIV patients on medical marijuana showed lower CD16+ monocyte levels than non-users.","methodology":"Narrative review synthesizing evidence on HAND pathophysiology, endocannabinoid immunology, and clinical observations in HIV patients using medical cannabis, proposing CB2 as a therapeutic target.","limitations":"Review based on observational clinical data and preclinical mechanistic studies; no RCTs of CB2 agonists for HAND; lower CD16+ monocytes in cannabis users could reflect confounding; CB2-selective drugs are not yet clinically available."},{"rthcId":"RTHC-02803","title":"Hemp (Cannabis sativa L.) Protein Hydrolysates Promote Anti-Inflammatory Response in Primary Human Monocytes.","authors":"Rodriguez-Martin, Noelia M; Montserrat-de la Paz, Sergio; Toscano, Rocio; Grao-Cruces, Elena; Villanueva, Alvaro; Pedroche, Justo; Millan, Francisco; Millan-Linares, Maria C","year":2020,"journal":"Biomolecules, 10(5)","doi":"10.3390/biom10050803","pmid":"32456009","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02804","title":"The role of perceived discrimination in substance use trajectories in Hispanic young adults: A longitudinal cohort study from high school through emerging adulthood.","authors":"Rogers, Christopher J; Forster, Myriam; Vetrone, Steven; Unger, Jennifer B","year":2020,"journal":"Addictive behaviors, 103, 106253","doi":"10.1016/j.addbeh.2019.106253","pmid":"31869743","tags":["youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Among 1,457 Hispanic youth in Southern California followed from 2006-2017, perceived discrimination in high school significantly predicted marijuana use initiation that was discontinued (RRR 1.464) and marijuana use that continued into emerging adulthood (RRR 1.249), compared to never using. For late-onset marijuana use (starting in emerging adulthood), high school discrimination was not a significant predictor, unlike for cigarette smoking.","whyItMatters":"This is one of the longest longitudinal studies linking adolescent discrimination experiences to substance use trajectories in Hispanic youth. The finding that discrimination predicted marijuana initiation but not late-onset use suggests adolescence is the critical vulnerability window.","specificNumbers":"1,457 youth; 11-year follow-up (2006-2017); HS discrimination predicted initiation+discontinuation RRR 1.464; initiation+continuation RRR 1.249; not significant for late-onset marijuana use.","methodology":"Longitudinal cohort study with 11 years of follow-up (2006-2017) including 3 high school and 5 emerging adulthood data collection waves, using multinomial logistic regression controlling for gender, SES, acculturation, and emerging adulthood discrimination.","limitations":"Self-report measures; Southern California Hispanic youth may not represent other populations; marijuana use initiation could predate reported discrimination; cannot distinguish medical from recreational use; acculturation measure may not capture all cultural factors."},{"rthcId":"RTHC-02805","title":"Cannabis use during pregnancy and its relationship with fetal developmental outcomes and psychiatric disorders. A systematic review.","authors":"Roncero, Carlos; Valriberas-Herrero, Isabel; Mezzatesta-Gava, Marcela; Villegas, José L; Aguilar, Lourdes; Grau-López, Lara","year":2020,"journal":"Reproductive health, 17(1), 25","doi":"10.1186/s12978-020-0880-9","pmid":"32066469","tags":["pregnancy","youth","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabis use among pregnant women is common (~5% or more), with risk factors including younger age, lower education, and concurrent tobacco/alcohol use. Prenatal cannabis exposure may be associated with affective symptoms and ADHD in children. However, the review found the topic has not been extensively researched despite increasing cannabis use during pregnancy, creating a gap between public behavior and scientific knowledge.","whyItMatters":"Cannabis is increasingly seen as \"natural\" and safe during pregnancy, yet the evidence on developmental consequences is sparse. This review highlights the disconnect between growing prenatal cannabis use and the limited evidence to guide pregnant women.","specificNumbers":"At least 5% of pregnant women use cannabis; associated with affective symptoms and ADHD in offspring; risk factors: younger age, lower education, concurrent substance use.","methodology":"Systematic review of PubMed through July 2018 for studies on maternal cannabis use and the relationship between prenatal exposure and developmental and psychiatric disorders, in English and Spanish.","limitations":"Limited number of studies meeting criteria; heterogeneous study designs; difficulty isolating cannabis effects from concurrent tobacco, alcohol, and other drug use; self-report of cannabis use during pregnancy likely underestimates true prevalence."},{"rthcId":"RTHC-02806","title":"Cannabis and Radiation Therapy: A Scoping Review of Human Clinical Trials.","authors":"Rosewall, Tara; Feuz, Carina; Bayley, Andrew","year":2020,"journal":"Journal of medical imaging and radiation sciences, 51(2), 342-349","doi":"10.1016/j.jmir.2020.01.007","pmid":"32249134","tags":["cancer","medical-cannabis","harm-reduction"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Of 48 records screened, only 8 clinical studies met criteria. These suggested cannabinoids may reduce anxiety before starting radiation, manage nausea and vomiting comparable to standard care, reduce glioma relapse symptoms, and provide symptom relief over 3 years after head and neck radiation (but not during or immediately after). Six of 8 studies had high risk of bias. Side effects included drowsiness, dry mouth, and substantial rates of dizziness, fatigue, and disorientation.","whyItMatters":"An estimated 20% of Canadian cancer patients already use cannabis during treatment. Oncology professionals feel too uninformed to counsel patients, and this review confirms the evidence gap is real.","specificNumbers":"48 records screened; 8 included; 6 had high bias risk; ~20% of Canadian cancer patients use cannabis; side effects: drowsiness, dry mouth, dizziness, fatigue, disorientation.","methodology":"Scoping review following PRISMA-ScR guidelines, searching multiple databases for clinical studies of cannabis use in patients undergoing radiation therapy. Risk of bias assessed using Cochrane RoB 2.0 and ROBINS-I frameworks.","limitations":"8 studies total (very limited evidence); 6 had high bias risk; heterogeneous cancer types and radiation protocols; no studies measured long-term cannabis consumption impact; included studies predate modern radiation techniques."},{"rthcId":"RTHC-02807","title":"A Little Dab Will Do: A Case of Cannabis-Induced Psychosis.","authors":"Rossi, Garrett; Beck, Melanie","year":2020,"journal":"Cureus, 12(9), e10311","doi":"10.7759/cureus.10311","pmid":"33052273","tags":["psychosis","potency","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient who had used marijuana since age 13 for anxiety without psychotic episodes developed severe paranoid delusions (being watched and followed), insomnia for two weeks, and hypervigilant behavior after switching to \"dabbing\" (concentrated cannabis with up to 80% THC). Symptoms escalated over one month and significantly impaired work functioning. Urine was positive for cannabis only.","whyItMatters":"This case highlights the dose-potency distinction in cannabis risk. A user who tolerated conventional marijuana for years developed psychosis specifically after switching to concentrates, suggesting a THC threshold effect that product potency can push beyond.","specificNumbers":"Cannabis use since age 13; dabs up to 80% THC; psychotic symptoms within 1 month of switching; 2 weeks without sleep; paranoid delusions of surveillance.","methodology":"Single case report describing clinical presentation, differential diagnosis, and management of cannabis-induced psychosis precipitated by high-potency cannabis concentrates.","limitations":"Single case report; cannot establish causation; pre-existing vulnerability possible; no genetic testing for psychosis risk; other stressors (work, social) may have contributed; no THC blood level measured."},{"rthcId":"RTHC-02808","title":"Bisphenol A Deranges the Endocannabinoid System of Primary Sertoli Cells with an Impact on Inhibin B Production.","authors":"Rossi, Gianna; Dufrusine, Beatrice; Lizzi, Anna Rita; Luzi, Carla; Piccoli, Alessandra; Fezza, Filomena; Iorio, Roberto; D'Andrea, Gabriele; Dainese, Enrico; Cecconi, Sandra; Maccarrone, Mauro","year":2020,"journal":"International journal of molecular sciences, 21(23)","doi":"10.3390/ijms21238986","pmid":"33256105","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02809","title":"The effects of Cannabidiol (CBD) and Delta-9-Tetrahydrocannabinol (THC) on the recognition of emotions in facial expressions: A systematic review of randomized controlled trials.","authors":"Rossi, Giordano Novak; Osório, Flávia L; Morgan, Celia J A; Crippa, José Alexandre S; Bouso, José Carlos; Rocha, Juliana Mendes; Zuardi, Antônio W; Hallak, Jaime E C; Santos, Rafael G Dos","year":2020,"journal":"Neuroscience and biobehavioral reviews, 118, 236-246","doi":"10.1016/j.neubiorev.2020.07.034","pmid":"32745478","tags":["cbd","mental-health","cognition","anxiety"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 7 experiments (170 total participants), THC (7.5-15 mg) had no effect in 3 experiments and reduced facial emotion recognition in 3 others. CBD had no effect in 2 experiments but improved performance and counteracted THC effects in one. THC (≥10 mg) and CBD (600 mg) showed opposing effects on brain activation, skin conductance, and anxiety when viewing negative/threatening faces.","whyItMatters":"Impaired emotion recognition is a feature of anxiety and depression. If THC worsens and CBD improves this ability, it provides a mechanistic explanation for why THC can worsen anxiety while CBD may reduce it.","specificNumbers":"7 experiments; 170 participants; THC 7.5-15 mg; CBD 600 mg; THC impaired REFE in 3 of 6 experiments; CBD improved in 1 of 3; opposing brain activation for threatening faces.","methodology":"Systematic review (PROSPERO registered: CRD42019135085) of controlled trials assessing THC and/or CBD effects on recognition of emotions in facial expressions (REFE), searching standard databases.","limitations":"Only 7 experiments (very limited data); small total sample (170); heterogeneous THC and CBD doses; mostly acute single-dose studies; REFE tasks vary across studies; limited to healthy volunteers."},{"rthcId":"RTHC-02810","title":"Effect of Lifestyle Factors on Outcomes in Patients With Inflammatory Bowel Diseases.","authors":"Rozich, Jacob J; Holmer, Ariela; Singh, Siddharth","year":2020,"journal":"The American journal of gastroenterology, 115(6), 832-840","doi":"10.14309/ajg.0000000000000608","pmid":"32224703","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02811","title":"Healthcare cost associations of patients who use illicit drugs in Florida: a retrospective analysis.","authors":"Ryan, Jessica L; Rosa, Veronica R","year":2020,"journal":"Substance abuse treatment, prevention, and policy, 15(1), 73","doi":"10.1186/s13011-020-00313-2","pmid":"32993719","tags":["harm-reduction","legalization","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Across 709,658 drug-related healthcare observations in Florida (2016-2018), total costs were estimated at $6.4 billion. Using cannabis SUD as the reference group, cocaine increased ED visit costs by 9.25% and multiple drug use by 6.12%. For inpatient stays, opioids increased costs by 23.4% and inhalants by 16.3% compared to cannabis. Medicare paid the largest share ($2.16B), followed by Medicaid and commercial insurance ($1.36B each).","whyItMatters":"Healthcare cost data helps quantify the relative burden of different substances. Cannabis SUD being the least costly drug-related condition supports harm reduction arguments and resource allocation decisions.","specificNumbers":"$6.4B total over 3 years; 709,658 observations; cannabis as lowest-cost reference; cocaine +9.25% ED; multiple drugs +6.12% ED; opioids +23.4% inpatient; inhalants +16.3% inpatient; Medicare $2.16B, Medicaid $1.36B.","methodology":"Retrospective analysis of Florida Agency for Health Care Administration ED and inpatient datasets (2016-2018) with 709,658 observations, using cost-to-charge ratios and linear regression comparing healthcare costs by substance type.","limitations":"Florida only (may not represent other states); administrative coding may misclassify substances; cannot account for polysubstance use complexity; cost-to-charge ratios are estimates; does not capture outpatient, mental health, or long-term costs."},{"rthcId":"RTHC-02812","title":"Issues in the establishment of a therapeutic cannabis market under Jamaica's Dangerous Drugs Amendment Act 2015.","authors":"Rychert, Marta; Emanuel, Machel A; Wilkins, Chris","year":2020,"journal":"The International journal on drug policy, 86, 102945","doi":"10.1016/j.drugpo.2020.102945","pmid":"32947242","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02813","title":"Differential activation of G protein-mediated signaling by synthetic cannabinoid receptor agonists.","authors":"Sachdev, Shivani; Banister, Samuel D; Santiago, Marina; Bladen, Chris; Kassiou, Michael; Connor, Mark","year":2020,"journal":"Pharmacology research & perspectives, 8(2), e00566","doi":"10.1002/prp2.566","pmid":"32101383","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02814","title":"Cannabinoid type 2 receptors inhibit GABAA receptor-mediated currents in cerebellar Purkinje cells of juvenile mice.","authors":"Sadanandan, Sriity Melley; Kreko-Pierce, Tabita; Khatri, Shailesh N; Pugh, Jason R","year":2020,"journal":"PloS one, 15(5), e0233020","doi":"10.1371/journal.pone.0233020","pmid":"32437355","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02815","title":"Medical Cannabis for the Management of Pain and Quality of Life in Chronic Pain Patients: A Prospective Observational Study.","authors":"Safakish, Ramin; Ko, Gordon; Salimpour, Vahid; Hendin, Bryan; Sohanpal, Imrat; Loheswaran, Gena; Yoon, Sun Young Rosalia","year":2020,"journal":"Pain medicine (Malden, Mass.), 21(11), 3073-3086","doi":"10.1093/pm/pnaa163","pmid":"32556203","tags":["pain","medical-cannabis","addiction","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 751 chronic pain patients initiating medical cannabis treatment, pain severity and interference improved significantly at 1 month and remained improved through 12 months (p<0.001). Physical and mental health domains improved starting at 3 months (p<0.002). Headaches, fatigue, anxiety, and nausea all decreased significantly (p≤0.002). Among opioid users at baseline, oral morphine equivalent doses decreased significantly (p<0.0001).","whyItMatters":"This is one of the larger and longer prospective studies of medical cannabis for chronic pain. The sustained 12-month improvement and opioid dose reduction address two critical clinical questions: does it keep working, and does it reduce reliance on opioids?","specificNumbers":"751 patients; 12 months; pain severity and interference improved p<0.001 at month 1 and sustained; SF-12 improved p<0.002 at month 3; headaches, fatigue, anxiety, nausea decreased p≤0.002; opioid doses decreased p<0.0001.","methodology":"Prospective, 12-month observational study at a medical cannabis clinic (October 2015-March 2019). Patients completed the Brief Pain Inventory, SF-12, and opioid use surveys monthly for 12 months.","limitations":"No control group (observational); self-selected patients at a cannabis specialty clinic; potential for placebo and expectancy effects; attrition over 12 months not detailed; cannot determine which cannabis products or doses were most effective."},{"rthcId":"RTHC-02816","title":"CBD modulates DNA methylation in the prefrontal cortex and hippocampus of mice exposed to forced swim.","authors":"Sales, Amanda J; Guimarães, Francisco S; Joca, Sâmia R L","year":2020,"journal":"Behavioural brain research, 388, 112627","doi":"10.1016/j.bbr.2020.112627","pmid":"32348868","tags":["cbd","depression","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (10 mg/kg) produced antidepressant-like behavior in the forced swim test. Stress reduced DNA methylation and DNMT activity in the hippocampus while increasing them in the prefrontal cortex. CBD treatment prevented these stress-induced epigenetic changes in both brain regions. Sub-effective CBD doses combined with DNA methylation inhibitors also produced antidepressant effects, confirming the epigenetic mechanism.","whyItMatters":"This is the first evidence that CBD antidepressant effects involve epigenetic regulation in brain regions critical to depression. Epigenetic mechanisms could explain the lasting effects of CBD observed in some clinical studies.","specificNumbers":"CBD 10 mg/kg: antidepressant effect; sub-effective CBD 7 mg/kg + DNMTi: synergistic effect; stress altered DNA methylation and DNMT activity in PFC and HPC; CBD normalized both.","methodology":"Mouse forced swim test with CBD (7-10 mg/kg) and DNA methylation inhibitors (5-AzaD, RG108), alone and in combination. Global DNA methylation and DNMT activity measured in prefrontal cortex and hippocampus.","limitations":"Mouse model only; forced swim test has debated translational validity; single acute stress paradigm; does not show which specific genes were affected by methylation changes; cannot determine if epigenetic changes cause or merely correlate with behavioral effects."},{"rthcId":"RTHC-02817","title":"Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.","authors":"Salles, Évila Lopes; Khodadadi, Hesam; Jarrahi, Abbas; Ahluwalia, Meenakshi; Paffaro, Valdemar Antonio; Costigliola, Vincenzo; Yu, Jack C; Hess, David C; Dhandapani, Krishnan M; Baban, Babak","year":2020,"journal":"Journal of cellular and molecular medicine, 24(21), 12869-12872","doi":"10.1111/jcmm.15883","pmid":"33058425","tags":["cbd","inflammation","respiratory"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Using intranasal Poly(I:C) to mimic viral ARDS in mice, researchers found that ARDS significantly decreased apelin expression in blood and lung tissue. CBD treatment reversed ARDS symptoms toward normal levels and significantly increased apelin expression. This is the first demonstration of a CBD-apelin connection, suggesting the apelinergic system may mediate some of CBD anti-inflammatory effects.","whyItMatters":"During the COVID-19 pandemic, ARDS was a leading cause of death. This study identifies apelin as a potential mechanism for CBD effects on respiratory inflammation, opening a new therapeutic pathway.","specificNumbers":"Poly(I:C) mimicked viral ARDS symptoms; ARDS decreased apelin in blood and lungs; CBD reversed symptoms and increased apelin expression significantly.","methodology":"Mouse model of ARDS induced by intranasal Poly(I:C) (synthetic viral dsRNA). CBD treatment administered to ARDS mice. Apelin expression measured in blood and lung tissue by comparison with controls.","limitations":"Mouse model with synthetic viral mimic (not actual virus); small study; mechanism not fully elucidated; cannot determine if apelin increase causes or merely accompanies symptom improvement; no dose-response data."},{"rthcId":"RTHC-02818","title":"Regulation of cannabinoid CB1 and CB2 receptors, neuroprotective mTOR and pro-apoptotic JNK1/2 kinases in postmortem prefrontal cortex of subjects with major depressive disorder.","authors":"Salort, Glòria; Hernández-Hernández, Elena; García-Fuster, M Julia; García-Sevilla, Jesús A","year":2020,"journal":"Journal of affective disorders, 276, 626-635","doi":"10.1016/j.jad.2020.07.074","pmid":"32871695","tags":["depression","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In postmortem prefrontal cortex (BA9) of 23 MDD subjects versus 19 controls, CB1 receptor density was increased by 20% (p=0.02). This upregulation was significant in antidepressant-treated subjects (+23%, p=0.02) but not in antidepressant-free subjects (+14%, p=0.34). CB2 receptor density was unchanged. mTOR activity was increased by 29% (p=0.002) in both antidepressant-treated and untreated MDD subjects. JNK1/2 activity and neuroplastic proteins (PSD-95, Arc, spinophilin) were unchanged.","whyItMatters":"This provides direct human brain evidence that the endocannabinoid system is altered in depression. The CB1 upregulation may represent a compensatory response to reduced endocannabinoid tone, offering a biological rationale for cannabinoid-based antidepressant strategies.","specificNumbers":"23 MDD subjects; 19 controls; CB1 +20% (p=0.02); CB2 unchanged; mTOR +29% (p=0.002); AD-treated CB1 +23% (p=0.02); AD-free CB1 +14% (p=0.34, NS).","methodology":"Immunoblotting quantification of CB1, CB2, mTOR, JNK1/2, and neuroplastic proteins in postmortem prefrontal cortex from 23 MDD subjects (suicide victims) and 19 matched controls.","limitations":"Postmortem tissue (cannot establish causation or temporal sequence); all MDD subjects were suicide victims (may not represent all depression); antidepressant treatment confounds interpretation; relatively small sample; cannot determine if CB1 changes cause or result from depression."},{"rthcId":"RTHC-02819","title":"Racial and gender inequities in the implementation of a cannabis criminal justice diversion program in a large and diverse metropolitan county of the USA.","authors":"Sanchez, Helen F; Orr, Michael F; Wang, Ann; Cano, Miguel Á; Vaughan, Ellen L; Harvey, Laura M; Essa, Saman; Torbati, Autena; Clark, Uraina S; Fagundes, Christopher P; de Dios, Marcel A","year":2020,"journal":"Drug and alcohol dependence, 216, 108316","doi":"10.1016/j.drugalcdep.2020.108316","pmid":"33017750","tags":["legalization","youth"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"In Harris County, Texas Marijuana Misdemeanor Diversion Program (2017-2019), African Americans (50% of participants despite ~20% of population) and males (80%) were overrepresented. African Americans had significantly lower odds of program completion (HR 0.782, p<0.001) and longer time to completion. Latino Americans also had lower completion rates (HR 0.822, p=0.003). Failure to complete the program results in greater criminal justice involvement than traditional prosecution.","whyItMatters":"Diversion programs are designed as progressive alternatives to incarceration. If they systematically disadvantage minorities, they may actually worsen racial disparities, since program failure leads to harsher outcomes than traditional prosecution.","specificNumbers":"8,323 participants; 80% male; 50% African American; African American HR 0.782 (p<0.001); Latino HR 0.822 (p=0.003); lower completion and longer time to completion for both groups.","methodology":"Retrospective analysis of 8,323 MMDP participants (March 2017-July 2019) using Chi-square, Kruskal-Wallis tests, and Cox proportional hazard regression to examine gender, age, and race/ethnicity as predictors of completion.","limitations":"Single county (Harris County, Texas); cannot determine why completion rates differ (program requirements, access barriers, law enforcement practices); administrative data without socioeconomic covariates; does not assess whether the program is more equitable than prosecution."},{"rthcId":"RTHC-02820","title":"Hippocampal 2-Arachidonoyl Glycerol Signaling Regulates Time-of-Day- and Stress-Dependent Effects on Rat Short-Term Memory.","authors":"Santori, Alessia; Morena, Maria; Hill, Matthew N; Campolongo, Patrizia","year":2020,"journal":"International journal of molecular sciences, 21(19)","doi":"10.3390/ijms21197316","pmid":"33023013","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02821","title":"Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review.","authors":"Sarris, Jerome; Sinclair, Justin; Karamacoska, Diana; Davidson, Maggie; Firth, Joseph","year":2020,"journal":"BMC psychiatry, 20(1), 24","doi":"10.1186/s12888-019-2409-8","pmid":"31948424","tags":["medical-cannabis","mental-health","anxiety","depression","psychosis","ptsd","sleep"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CBD showed tentative support for reducing social anxiety. Mixed but mainly positive evidence supported adjunctive CBD in schizophrenia. Case studies suggested benefits for sleep and PTSD. High-THC therapeutics showed no benefit for depression. One study suggested oral cannabinoid/terpene combinations may help ADHD. Key prescriptive caution: avoid high-THC in youth, anxiety-prone, or psychosis-prone individuals; titrate gradually; monitor cardiovascular and respiratory function.","whyItMatters":"This is described as the first clinically-focused systematic review covering all major psychiatric disorders. It bridges the gap between research evidence and clinical practice, providing specific prescribing guidance alongside the evidence.","specificNumbers":"CBD: tentative support for social anxiety; mixed positive for schizophrenia adjunct; case-study level for sleep and PTSD; high-THC: no depression benefit; one study suggests cannabinoid/terpene for ADHD.","methodology":"Systematic review of all case studies and clinical trials involving medicinal cannabis or plant-derived isolates for major psychiatric disorders (2019), including clinical prescription considerations and pharmacogenomics.","limitations":"Evidence described as \"embryonic\" by authors; most psychiatric disorder evidence at case-study level; systematic review encompasses heterogeneous study types; pharmaceutical CBD and whole-plant products may differ; limited long-term safety data."},{"rthcId":"RTHC-02822","title":"Self-reported exposure to, perceptions about, and attitudes about public marijuana smoking among US adults, 2018.","authors":"Schauer, Gillian L; Tynan, Michael A; Marynak, Kristy","year":2020,"journal":"Addiction (Abingdon, England), 115(7), 1320-1329","doi":"10.1111/add.14955","pmid":"31899566","tags":["legalization","harm-reduction","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 4,088 US adults surveyed in 2018, 27.4% reported marijuana secondhand smoke (SHS) exposure in the past week in indoor and/or outdoor public areas. Those more commonly exposed included younger adults, Black and Hispanic individuals, those in Northeast/West regions, and current marijuana or tobacco users. A majority (52.4%) perceived marijuana SHS as harmful, and 81% opposed public marijuana smoking. Male sex, younger age, minority race/ethnicity, current substance use, and perceiving low harm from SHS correlated with favoring public marijuana smoking.","whyItMatters":"As states legalize cannabis, public smoking policies are being debated. This provides baseline data showing substantial public exposure despite general opposition, informing smoke-free policy design.","specificNumbers":"4,088 adults; 27.4% past-week marijuana SHS exposure; 52.4% perceived harm; 81% opposed public marijuana smoking; younger adults, minorities, and substance users more exposed.","methodology":"Internet panel survey of 4,088 US adults (June-July 2018) assessing tobacco use, marijuana use, opinions on public indoor marijuana smoking, perceived harm from marijuana SHS, and self-reported past-7-day SHS exposure. Weighted prevalence estimates with logistic and multinomial regression.","limitations":"Internet panel (may not represent all US adults); self-reported exposure (no biomarker validation); cross-sectional; cannot distinguish marijuana smoke from other sources; perception of harm does not equal actual harm; 2018 data predates more recent legalization."},{"rthcId":"RTHC-02823","title":"The clinical toxicology of cannabis.","authors":"Schep, Leo J; Slaughter, Robin J; Glue, Paul; Gee, Paul","year":2020,"journal":"The New Zealand medical journal, 133(1523), 96-103","doi":null,"pmid":"33032307","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02824","title":"Cannabinoids and their therapeutic applications in mental disorders
.","authors":"Scherma, Maria; Muntoni, Anna Lisa; Riedel, Gernot; Fratta, Walter; Fadda, Paola","year":2020,"journal":"Dialogues in clinical neuroscience, 22(3), 271-279","doi":"10.31887/DCNS.2020.22.3/pfadda","pmid":"33162770","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02825","title":"Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.","authors":"Scherma, Maria; Qvist, Johanna S; Asok, Arun; Huang, Shao-Shan C; Masia, Paolo; Deidda, Matteo; Wei, Ya B; Soni, Rajesh K; Fratta, Walter; Fadda, Paola; Kandel, Eric R; Kandel, Denise B; Melas, Philippe A","year":2020,"journal":"Proceedings of the National Academy of Sciences of the United States of America, 117(18), 9991-10002","doi":"10.1073/pnas.1920866117","pmid":"32312805","tags":["youth","addiction","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Adolescent rats pre-exposed to the synthetic cannabinoid WIN showed cross-sensitization to cocaine, correlating with histone hyperacetylation and decreased HDAC6 in the prefrontal cortex. WIN preexposure blunted the typical mRNA response to cocaine, instead producing alternative splicing and chromatin accessibility changes. Protein phosphorylation was enhanced (ERK/MAPK targets including gephyrin), and AMPAR/GluR synaptic composition was altered in both PFC and nucleus accumbens. These effects were specific to adolescent exposure.","whyItMatters":"This provides the first molecular and epigenetic evidence for how adolescent cannabis exposure could increase vulnerability to cocaine. The multiomics approach reveals that cannabinoids do not just change behavior; they fundamentally reprogram how the brain responds to a new drug.","specificNumbers":"Adolescent (not adult) WIN exposure caused cross-sensitization to cocaine; histone hyperacetylation and decreased HDAC6 in PFC; blunted mRNA response; enhanced ERK/MAPK phosphorylation; altered AMPAR/GluR composition in PFC and NAcc.","methodology":"Multiomics approach (epigenomics, transcriptomics, proteomics, phosphoproteomics) characterizing the rat brain response to first cocaine exposure, with or without adolescent preexposure to the synthetic cannabinoid WIN 55,212-2. Published in PNAS.","limitations":"Synthetic cannabinoid (WIN) not identical to THC or cannabis; rat model; single cocaine exposure (does not model addiction); epigenetic changes may not persist long-term; cannot confirm same mechanisms in human adolescents; PNAS rigor but still preclinical."},{"rthcId":"RTHC-02826","title":"The clinical challenges of synthetic cathinones.","authors":"Schifano, Fabrizio; Napoletano, Flavia; Arillotta, Davide; Zangani, Caroline; Gilgar, Liam; Guirguis, Amira; Corkery, John Martin; Vento, Alessandro","year":2020,"journal":"British journal of clinical pharmacology, 86(3), 410-419","doi":"10.1111/bcp.14132","pmid":"31674690","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02827","title":"An Evaluation of Regulatory Regimes of Medical Cannabis: What Lessons Can Be Learned for the UK?","authors":"Schlag, Anne Katrin","year":2020,"journal":"Medical cannabis and cannabinoids, 3(1), 76-83","doi":"10.1159/000505028","pmid":"34676342","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02828","title":"Pharmacodynamic dose effects of oral cannabis ingestion in healthy adults who infrequently use cannabis.","authors":"Schlienz, Nicolas J; Spindle, Tory R; Cone, Edward J; Herrmann, Evan S; Bigelow, George E; Mitchell, John M; Flegel, Ronald; LoDico, Charles; Vandrey, Ryan","year":2020,"journal":"Drug and alcohol dependence, 211, 107969","doi":"10.1016/j.drugalcdep.2020.107969","pmid":"32298998","tags":["cognition","driving","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In a placebo-controlled study with 17 infrequent cannabis users, 10 mg THC produced discriminable subjective effects and elevated heart rate but did not impair cognition. At 25 and 50 mg, pronounced subjective effects and marked cognitive/psychomotor impairment occurred. Effects were delayed 30-60 minutes with peak effects at 1.5-3 hours. Blood THC levels correlated with some effects but were substantially lower than after inhalation.","whyItMatters":"Edibles are a growing market segment, but their delayed onset leads to overconsumption. This controlled study quantifies the dose-response and time course, providing the evidence base for edible dosing guidelines and consumer education.","specificNumbers":"17 subjects; 0, 10, 25, 50 mg THC brownies; 10 mg: subjective effects only; 25-50 mg: cognitive impairment; onset 30-60 min; peak 1.5-3 hours; blood THC lower than after inhalation.","methodology":"Randomized, placebo-controlled study in 17 healthy adults (no cannabis use for 60+ days) completing 4 sessions with cannabis brownies containing 0, 10, 25, or 50 mg THC. Subjective effects, vital signs, and cognitive/psychomotor performance assessed for 8 hours.","limitations":"Small sample (17); infrequent users only (frequent users may respond differently); single session per dose; laboratory setting (not real-world); brownie matrix may affect absorption; 8-hour observation may not capture full duration of higher doses."},{"rthcId":"RTHC-02829","title":"Individuals with psychosis and a lifetime history of cannabis use show greater deficits in emotional experience compared to non-using peers.","authors":"Schnakenberg Martin, Ashley M; Lysaker, Paul H","year":2020,"journal":"Journal of mental health (Abingdon, England), 29(1), 77-83","doi":"10.1080/09638237.2018.1487540","pmid":"30822177","tags":["psychosis","mental-health","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Compared to non-using schizophrenia patients (n=36), those with lifetime cannabis use (n=35) expressed less ability to express emotions, were less likely to anticipate pleasure, and had poorer social functioning. Cannabis use moderated the relationship between anticipatory pleasure and prosocial activities, suggesting cannabis disrupts the motivational pathway from expecting reward to engaging socially.","whyItMatters":"Negative symptoms (flat affect, anhedonia) are the most treatment-resistant aspect of schizophrenia. Finding that cannabis use history worsens these specific deficits suggests cannabis may undermine the very emotional capacities patients need for recovery.","specificNumbers":"71 adults with schizophrenia; 35 cannabis users vs 36 non-users; cannabis users: less emotional expression, less anticipatory pleasure, poorer social function; cannabis moderated anticipatory pleasure-prosocial activity link.","methodology":"Cross-sectional comparison of 71 adults with schizophrenia (35 with lifetime cannabis use, 36 without) using the Emotional Expressivity Scale, Temporal Experience of Pleasure Scale, and Social Functioning Scale.","limitations":"Cross-sectional (cannot determine causation); small groups; lifetime use measure does not capture current use, dose, or duration; groups may differ on unmeasured variables; prolonged illness duration in both groups."},{"rthcId":"RTHC-02830","title":"Cannabidiol as a treatment option for schizophrenia: recent evidence and current studies.","authors":"Schoevers, Julie; Leweke, Judith E; Leweke, F Markus","year":2020,"journal":"Current opinion in psychiatry, 33(3), 185-191","doi":"10.1097/YCO.0000000000000596","pmid":"32073423","tags":["cbd","psychosis","cognition"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Recent trials focused on sub-acute schizophrenia, clinical high-risk for psychosis (CHR-P), and frequent cannabis users. There is further evidence for CBD reducing positive symptoms but not negative symptoms. Cognitive effects were inconsistent, with one study reporting worsening. One study found CBD caused sedation, but others reported good tolerability at high doses. The authors emphasize that properly designed Phase III trials following regulatory guidelines are needed.","whyItMatters":"CBD antipsychotic potential has generated significant interest because current antipsychotics have severe side effects. This update provides the most current clinical trial landscape and identifies what is still missing.","specificNumbers":"CBD: further evidence for positive symptom reduction; no benefit for negative symptoms; inconsistent cognitive effects; one study reported worsening cognition; sedation in one study; good tolerability at high doses otherwise.","methodology":"Narrative review of clinical trials published or initiated within the last 18 months investigating CBD for schizophrenia and related conditions.","limitations":"Narrative review (not systematic); limited number of trials to review; heterogeneous study designs; most trials small; the \"further evidence\" builds incrementally rather than providing definitive answers."},{"rthcId":"RTHC-02831","title":"Childhood social environmental and behavioural predictors of early adolescent onset cannabis use.","authors":"Scholes-Balog, Kirsty E; Hemphill, Sheryl A; Heerde, Jessica A; Toumbourou, John W; Patton, George C","year":2020,"journal":"Drug and alcohol review, 39(4), 384-393","doi":"10.1111/dar.13077","pmid":"32372532","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Among 852 adolescents, 10.7% showed early-onset cannabis use (before age 15). The strongest predictors were childhood cigarette use and drinking until drunk. Family factors (poor management, antisocial family history, parent attachment) predicted early onset specifically. Cumulative risk from early substance use was the strongest independent predictor of both early-onset cannabis use (RRR 2.64, CI 1.40-4.97) and late-onset occasional use (27%). Family-related cumulative risk also predicted late-onset use.","whyItMatters":"Prevention is most effective when targeted at the right age. This study identifies fifth-grade risk factors that predict cannabis trajectories years later, offering a specific prevention window and specific targets (early substance use, family environment).","specificNumbers":"852 adolescents; 10.7% early onset; 27% late occasional onset; cigarette use and drinking strongest predictors; cumulative early substance use risk RRR 2.64; poor family management, family antisocial history, parent attachment also predicted early onset.","methodology":"Prospective longitudinal study of 852 adolescents (53% female) from the Australian International Youth Development Study, with risk/protective factors measured in fifth grade (mean age 10.9) and cannabis use measured at 6 time points from ages 12-19.","limitations":"Australian sample (may not generalize to other contexts); self-report at all time points; 53% female (slightly unbalanced); risk factors measured at single time point in fifth grade; does not assess cannabis potency or type."},{"rthcId":"RTHC-02832","title":"Sperm DNA methylation altered by THC and nicotine: Vulnerability of neurodevelopmental genes with bivalent chromatin.","authors":"Schrott, Rose; Rajavel, Maya; Acharya, Kelly; Huang, Zhiqing; Acharya, Chaitanya; Hawkey, Andrew; Pippen, Erica; Lyerly, H Kim; Levin, Edward D; Murphy, Susan K","year":2020,"journal":"Scientific reports, 10(1), 16022","doi":"10.1038/s41598-020-72783-0","pmid":"32994467","tags":["pregnancy","genetics","neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"THC exposure via oral gavage altered DNA methylation at seven neurodevelopmentally active genes in rat sperm. Pyrosequencing revealed majority overlap between THC and nicotine-induced methylation changes, suggesting shared vulnerability. Autism candidate genes were significantly enriched for bivalent chromatin structure, a configuration that may make these genes particularly susceptible to environmental disruption in sperm.","whyItMatters":"This provides a molecular mechanism for how male cannabis use before conception could affect offspring brain development. The overlap with nicotine effects and enrichment for autism genes suggests a common epigenetic vulnerability at critical neurodevelopmental loci.","specificNumbers":"7 neurodevelopmental genes differentially methylated by THC; majority overlap with nicotine effects; autism candidate genes enriched for bivalent chromatin.","methodology":"Reduced representation bisulfite sequencing (RRBS) of sperm from rats exposed to THC via oral gavage, with pyrosequencing validation. Compared THC (oral and injection routes) and nicotine effects on neurodevelopmental gene methylation.","limitations":"Rat model (sperm epigenetics may differ from humans); limited number of genes examined in detail; cannot determine if methylation changes persist through fertilization and embryonic development; does not assess offspring outcomes directly."},{"rthcId":"RTHC-02833","title":"Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm.","authors":"Schrott, Rose; Acharya, Kelly; Itchon-Ramos, Nilda; Hawkey, Andrew B; Pippen, Erica; Mitchell, John T; Kollins, Scott H; Levin, Edward D; Murphy, Susan K","year":2020,"journal":"Epigenetics, 15(1-2), 161-173","doi":"10.1080/15592294.2019.1656158","pmid":"31451081","tags":["pregnancy","genetics","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using RRBS, cannabis use was associated with significant hypomethylation of the autism-linked gene DLGAP2 in human sperm. Targeted analysis confirmed differential methylation at 9 CpG sites in intron 7. DLGAP2 methylation and expression in human fetal brain tissue were inversely correlated. THC exposure in rats produced similar methylation changes in sperm, and these changes were also found in the nucleus accumbens of offspring from THC-exposed fathers.","whyItMatters":"This is the first demonstration of a specific gene (DLGAP2) where cannabis-associated sperm methylation changes may transmit to offspring brain tissue via the father. DLGAP2 is strongly implicated in autism and synaptic function.","specificNumbers":"DLGAP2 hypomethylated in human sperm of cannabis users; 9 CpG sites in intron 7; methylation-expression inversely correlated in fetal brain; similar changes in rat sperm after THC; changes present in offspring nucleus accumbens.","methodology":"RRBS of human sperm from cannabis users vs non-users, with pyrosequencing validation at DLGAP2. Cross-species validation in THC-exposed rats. DLGAP2 methylation-expression correlation in human conceptal brain tissue. Offspring brain analysis in rat model.","limitations":"Human sperm data is cross-sectional (cannot prove causation); small human samples; rat model used different THC route than human smoking; offspring changes found in only one brain region; does not assess autism-related behavior in offspring."},{"rthcId":"RTHC-02834","title":"Cannabis use and the sperm epigenome: a budding concern?","authors":"Schrott, Rose; Murphy, Susan K","year":2020,"journal":"Environmental epigenetics, 6(1), dvaa002","doi":"10.1093/eep/dvaa002","pmid":"32211199","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02835","title":"Differential effects of Δ9-tetrahydrocannabinol dosing on correlates of schizophrenia in the sub-chronic PCP rat model.","authors":"Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea","year":2020,"journal":"PloS one, 15(3), e0230238","doi":"10.1371/journal.pone.0230238","pmid":"32163506","tags":["psychosis","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In PCP-treated rats (schizophrenia model), only the lowest THC dose (0.1 mg/kg) reversed social interaction deficits and normalized elevated anandamide in the nucleus accumbens. Higher THC doses (0.3, 1.0 mg/kg) did not help. In control rats, THC dose-dependently produced social deficits and aberrant VTA dopamine neuron activity resembling schizophrenia. THC activated the Akt/GSK3β pathway dose-dependently in both groups.","whyItMatters":"This provides the clearest preclinical demonstration of why cannabis has seemingly contradictory effects on schizophrenia: extremely low doses may be therapeutic while typical recreational doses are harmful. The dose-response curve is not linear but inverted U-shaped.","specificNumbers":"0.1 mg/kg THC: reversed social deficits in PCP rats and normalized AEA; 0.3-1.0 mg/kg: no benefit; in controls, THC dose-dependently produced social deficits and aberrant dopamine activity; Akt/GSK3β activated dose-dependently.","methodology":"Sub-chronic PCP rat model with THC at 0.1, 0.3, and 1.0 mg/kg. Assessed social interaction, amphetamine-induced motor activity, VTA dopamine neuron population activity, endocannabinoid levels, and Akt/GSK3β signaling.","limitations":"Animal model of schizophrenia (PCP model has limitations); narrow dose range tested; acute THC (does not model chronic use); rat-to-human dose translation uncertain; cannot confirm same inverted U-curve applies to humans."},{"rthcId":"RTHC-02836","title":"Pharmacotherapeutic Considerations for Use of Cannabinoids to Relieve Symptoms of Nausea and Vomiting Induced by Chemotherapy.","authors":"Serafimovska, Tijana; Darkovska-Serafimovska, Marija; Stefkov, Gjoshe; Arsova-Sarafinovska, Zorica; Balkanov, Trajan","year":2020,"journal":"Folia medica, 62(4), 668-678","doi":"10.3897/folmed.62.e51478","pmid":"33415919","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02837","title":"In vitro assessment of the cytotoxic, genotoxic and oxidative stress effects of the synthetic cannabinoid JWH-018 in human SH-SY5Y neuronal cells.","authors":"Sezer, Yigit; Jannuzzi, Ayse Tarbin; Huestis, Marilyn A; Alpertunga, Buket","year":2020,"journal":"Toxicology research, 9(6), 734-740","doi":"10.1093/toxres/tfaa078","pmid":"33447358","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02838","title":"The switch from one substance-of-abuse to another: illicit drug substitution behaviors in a sample of high-risk drug users.","authors":"Shapira, Barak; Rosca, Paola; Berkovitz, Ronny; Gorjaltsan, Igor; Neumark, Yehuda","year":2020,"journal":"PeerJ, 8, e9461","doi":"10.7717/peerj.9461","pmid":"32742781","tags":["addiction","harm-reduction","synthetic-cannabinoids"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"448 of 592 high-risk drug users (75.7%) reported substituting their preferred drug. Cannabis users most commonly substituted synthetic cannabinoid receptor agonists (33.5%) followed by alcohol (16%). Heroin users most commonly substituted street methadone (35.9%) followed by prescription opioids (17.7%). Age at onset, education, and treatment setting predicted substitution patterns.","whyItMatters":"Drug substitution is a clinical reality that treatment programs rarely address. When cannabis is unavailable, users may switch to more dangerous synthetic cannabinoids. Understanding these patterns helps predict risks when supply is disrupted.","specificNumbers":"592 users; 75.7% reported substitution; cannabis→synthetic cannabinoids 33.5%; cannabis→alcohol 16%; heroin→street methadone 35.9%; heroin→prescription opioids 17.7%.","methodology":"Cross-sectional interviews with 592 high-risk drug users in pharmacological and psychosocial treatment, assessing lifetime substitution patterns for heroin and cannabis using descriptive statistics and multinomial logistic regression.","limitations":"High-risk treatment population (may not represent casual users); Israeli sample (drug availability differs from US/Europe); self-report of substitution; retrospective; cannot determine health outcomes of substitution."},{"rthcId":"RTHC-02839","title":"Recent Use of Synthetic Cannabinoids, Synthetic Opioids, and Other Psychoactive Drug Groups among High-risk Drug Users.","authors":"Shapira, Barak; Berkovitz, Ronny; Rosca, Paola; Neumark, Yehuda","year":2020,"journal":"Journal of psychoactive drugs, 52(4), 334-343","doi":"10.1080/02791072.2020.1754534","pmid":"32345134","tags":["synthetic-cannabinoids","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 342 patients in drug dependence treatment, 16.1% reported past-12-month synthetic cannabinoid receptor agonist (SCRA) use and 24.9% reported recent prescription opioid or fentanyl patch use. SCRA use was strongly associated with cannabis use (AOR 9.86) and synthetic cathinone use (AOR 5.47). Prescription opioid/fentanyl use was associated with gabapentinoids (AOR 14.33), stimulants (AOR 7.12), heroin (AOR 5.81), and benzodiazepines (AOR 4.63).","whyItMatters":"The near 10-fold association between cannabis and SCRA use confirms that cannabis users are the primary population at risk for synthetic cannabinoid exposure. Clinicians treating cannabis users should screen for SCRA use, which carries far greater toxicity risks.","specificNumbers":"342 patients; 16.1% recent SCRA use; 24.9% prescription opioid/fentanyl use; SCRA→cannabis AOR 9.86; SCRA→cathinones AOR 5.47; opioid→gabapentinoids AOR 14.33.","methodology":"Cross-sectional study of 342 patients in drug dependence treatment in Israel, using questionnaires on recent drug use with adjusted odds ratios from logistic regression.","limitations":"Treatment-seeking population in Israel; self-report of drug use; cross-sectional (cannot determine directionality); 342 patients is moderate sample; Israeli drug market may differ from other countries."},{"rthcId":"RTHC-02840","title":"Why do patients come to the emergency department after using cannabis?","authors":"Shelton, Shelby K; Mills, Eleanor; Saben, Jessica L; Devivo, Michael; Williamson, Kayla; Abbott, Diana; Hall, Katelyn E; Monte, Andrew A","year":2020,"journal":"Clinical toxicology (Philadelphia, Pa.), 58(6), 453-459","doi":"10.1080/15563650.2019.1657582","pmid":"31526057","tags":["harm-reduction","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of all ED visits with cannabis ICD-CM codes, detailed chart review determined only 25.74% were at least partially attributable to cannabis. These patients were more often young, Caucasian, and male compared to the overall ED population (all p values significant). The remaining ~75% had cannabis codes incidental to the visit reason.","whyItMatters":"Administrative data studies often use cannabis ICD codes to estimate cannabis-related ED burden. This study shows that 75% of such visits are not actually caused by cannabis, meaning published estimates of cannabis-related ED visits may be grossly inflated.","specificNumbers":"25.74% actually attributable to cannabis; patients more often young, Caucasian, male (all p<0.05); ~75% had cannabis codes incidental to visit.","methodology":"Retrospective chart review of ED visits identified by cannabis ICD-9 and ICD-10-CM codes between 2012 and 2016, with pre-specified attribution criteria and inter-rater reliability assessment.","limitations":"Single hospital system; retrospective chart review with inherent subjectivity; 2012-2016 data may not reflect current patterns; attribution criteria were pre-specified but novel; cannot determine what fraction of the 25% were primarily vs secondarily caused by cannabis."},{"rthcId":"RTHC-02841","title":"Therapeutic Efficacy of Cannabidiol (CBD): A Review of the Evidence from Clinical Trials and Human Laboratory Studies.","authors":"Sholler, Dennis J; Schoene, Lauren; Spindle, Tory R","year":2020,"journal":"Current addiction reports, 7(3), 405-412","doi":"10.1007/s40429-020-00326-8","pmid":"33585159","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02842","title":"Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids.","authors":"Sholler, Dennis J; Huestis, Marilyn A; Amendolara, Benjamin; Vandrey, Ryan; Cooper, Ziva D","year":2020,"journal":"Pharmacology, biochemistry, and behavior, 199, 173059","doi":"10.1016/j.pbb.2020.173059","pmid":"33086126","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02843","title":"Association of State Policies Allowing Medical Cannabis for Opioid Use Disorder With Dispensary Marketing for This Indication.","authors":"Shover, Chelsea L; Vest, Noel A; Chen, Derek; Stueber, Amanda; Falasinnu, Titilola O; Hah, Jennifer M; Kim, Jinhee; Mackey, Ian; Weber, Kenneth A; Ziadni, Maisa; Humphreys, Keith","year":2020,"journal":"JAMA network open, 3(7), e2010001","doi":"10.1001/jamanetworkopen.2020.10001","pmid":"32662844","tags":["legalization","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Across 167 dispensary brands in 7 states, those in states where OUD is a qualifying condition had 39% more brands claiming cannabis treats OUD (p<0.001), 28% more claiming adjunctive therapy potential (p<0.001), 14% more recommending replacing FDA-approved OUD medications (p=0.002), and 25% more suggesting cannabis as an opioid substitute for pain (p=0.002) compared to adjacent states without this policy.","whyItMatters":"Published in JAMA Network Open, this study shows that well-intentioned policies can have unintended consequences. Dispensaries marketing cannabis as OUD treatment may divert patients from evidence-based medications (methadone, buprenorphine, naltrexone) that actually save lives.","specificNumbers":"167 dispensary brands; 7 states; 39% more OUD treatment claims in policy states (p<0.001); 28% more adjunctive therapy claims (p<0.001); 14% more medication replacement claims (p=0.002).","methodology":"Cross-sectional mixed-methods study of 167 medical dispensary brands in 7 states (2019), analyzing online content for claims about cannabis treating OUD. Compared 3 policy-exposed states (NJ, NY, PA) to 4 comparison states.","limitations":"Online content only (may not reflect in-store recommendations); cross-sectional (cannot prove policy caused marketing changes); limited to 7 states; dispensary marketing does not equal patient behavior; some claims may be accurate for pain management."},{"rthcId":"RTHC-02844","title":"Cannabidiol in the Treatment of Epilepsy: A Focused Review of Evidence and Gaps.","authors":"Silva, Guilherme Diogo; Del Guerra, Felipe Borelli; de Oliveira Lelis, Maira; Pinto, Lécio Figueira","year":2020,"journal":"Frontiers in neurology, 11, 531939","doi":"10.3389/fneur.2020.531939","pmid":"33192966","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02845","title":"Adolescent CB1 receptor antagonism influences subsequent social interactions and neural activity in female rats.","authors":"Simone, Jonathan J; Baumbach, Jennet L; McPherson, Jennifer; McCormick, Cheryl M","year":2020,"journal":"International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 80(4), 319-333","doi":"10.1002/jdn.10028","pmid":"32220094","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02846","title":"Neuroprotection Following Concussion: The Potential Role for Cannabidiol.","authors":"Singh, Jyotpal; Neary, John Patrick","year":2020,"journal":"The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 47(3), 289-300","doi":"10.1017/cjn.2020.23","pmid":"32029015","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02847","title":"Drug-Drug Interactions Between Cannabidiol and Lithium.","authors":"Singh, Rani K; Dillon, Brittany; Tatum, David A; Van Poppel, Katherine C; Bonthius, Daniel J","year":2020,"journal":"Child neurology open, 7, 2329048X20947896","doi":"10.1177/2329048X20947896","pmid":"32851114","tags":["cbd","drug-interactions","epilepsy","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"An autistic patient with LGS and psychiatric comorbidities on multiple medications including lithium developed hypersomnolence, ataxia, and decreased oral intake several weeks after starting CBD. He was found to have lithium toxicity. After lithium was discontinued, symptoms resolved. He remained on CBD and other anti-seizure medications, becoming seizure-free with improved behavior.","whyItMatters":"CBD drug interactions with anti-seizure medications are increasingly recognized, but this is among the first reports of CBD interacting with a psychiatric medication (lithium). Patients on CBD often take multiple medications, making interaction awareness critical.","specificNumbers":"Lithium toxicity developed weeks after CBD initiation; symptoms: hypersomnolence, ataxia, decreased oral intake; resolved after lithium discontinuation; patient became seizure-free on CBD.","methodology":"Single case report documenting the clinical timeline and management of lithium toxicity precipitated by CBD addition in a patient with complex neuropsychiatric comorbidities.","limitations":"Single case report; multiple concurrent medications confound attribution; mechanism of CBD-lithium interaction not confirmed; lithium levels before CBD not reported; cannot determine if interaction is consistent across patients."},{"rthcId":"RTHC-02848","title":"Potential Probiotic or Trigger of Gut Inflammation - The Janus-Faced Nature of Cannabidiol-Rich Cannabis Extract.","authors":"Skinner, Charles M; Nookaew, Intawat; Ewing, Laura E; Wongsurawat, Thidathip; Jenjaroenpun, Piroon; Quick, Charles M; Yee, Eric U; Piccolo, Brian D; ElSohly, Mahmoud; Walker, Larry A; Gurley, Bill; Koturbash, Igor","year":2020,"journal":"Journal of dietary supplements, 17(5), 543-560","doi":"10.1080/19390211.2020.1761506","pmid":"32400224","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD-rich cannabis extract (CRCE) at multiple doses substantially increased the gut bacterium Akkermansia muciniphila (currently considered probiotic) in mouse fecal samples. However, this was accompanied by increased pro-inflammatory cytokines and chemokines (IL-1β, CXCL1, CXCL2) in colon tissue, and the increased A. muciniphila significantly decreased expression of Muc2, a gene critical for gut integrity.","whyItMatters":"CBD products are marketed for gut health, but this study shows a paradox: CBD increased a \"beneficial\" bacterium while simultaneously triggering inflammation. This challenges simplistic narratives about CBD gut effects and raises safety concerns about long-term use.","specificNumbers":"All CRCE doses increased A. muciniphila; IL-1β, CXCL1, CXCL2 increased in colon; Muc2 expression decreased; effects at doses from 61.5 to 615 mg/kg/day.","methodology":"Male C57BL/6J mice gavaged with CRCE (0, 61.5, 184.5, or 615 mg/kg/day) for 2 weeks. Gut microbiome analyzed by 16S sequencing; colonic gene expression measured by qPCR; histomorphological analysis of gut mucosa.","limitations":"Mouse model (gut microbiome differs from humans); CBD-rich extract (not pure CBD; contains other cannabinoids); high doses relative to human use; 2-week duration; male mice only; inflammatory markers do not necessarily indicate clinical disease."},{"rthcId":"RTHC-02849","title":"Cannabinoid1 (CB-1) receptor antagonists: a molecular approach to treating acute cannabinoid overdose.","authors":"Skolnick, Phil; Crystal, Roger","year":2020,"journal":"Journal of neural transmission (Vienna, Austria : 1996), 127(2), 279-286","doi":"10.1007/s00702-019-02132-7","pmid":"31893308","tags":["harm-reduction","potency"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis legalization has dramatically increased ED visits and hospitalizations for acute cannabis overdose, with edibles and synthetic cannabinoids responsible for disproportionate share. Many overdose symptoms (lethargy, ataxia, psychomotor impairment, panic, psychosis) are mediated through CB1 receptors. CB1 antagonists, originally developed for obesity and other conditions, could provide targeted reversal. Treatment is currently only supportive.","whyItMatters":"There is currently no specific antidote for cannabis intoxication. As cannabis overdose presentations increase (especially from edibles and synthetic cannabinoids), having a targeted reversal agent like the \"naloxone of cannabis\" could transform emergency management.","specificNumbers":"Dramatic increase in cannabis-related ED visits; edibles and synthetic cannabinoids disproportionately responsible; current treatment is supportive only; CB1 antagonists previously developed for other indications.","methodology":"Narrative review of evidence for CB1 receptor-mediated cannabis overdose symptoms and the potential of CB1 antagonists as treatment, drawing on pharmacology of rimonabant and related compounds.","limitations":"Review article (no new clinical data); CB1 antagonists have not been tested for cannabis overdose in clinical trials; rimonabant withdrawal for psychiatric side effects raises safety questions even for acute use; dose and timing of administration unclear."},{"rthcId":"RTHC-02850","title":"Cannabinoids in Medicine: Cancer, Immunity, and Microbial Diseases.","authors":"Śledziński, Paweł; Nowak-Terpiłowska, Agnieszka; Zeyland, Joanna","year":2020,"journal":"International journal of molecular sciences, 22(1)","doi":"10.3390/ijms22010263","pmid":"33383838","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02851","title":"Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating Elicits Deficits in Cholinergic Synaptic Function in the Offspring.","authors":"Slotkin, Theodore A; Skavicus, Samantha; Levin, Edward D; Seidler, Frederic J","year":2020,"journal":"Toxicological sciences : an official journal of the Society of Toxicology, 174(2), 210-217","doi":"10.1093/toxsci/kfaa004","pmid":"32077955","tags":["pregnancy","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"After 28 days of THC exposure (0, 2, or 4 mg/kg/day) in male rats, followed by mating with drug-naive females, offspring showed dose-dependent decreases in hemicholinium-3 binding (presynaptic acetylcholine activity) with regionally selective increases in choline acetyltransferase. This produced a persistent decrease in impulse activity per nerve terminal from adolescence (PND 30) through middle age (PND 150). At low doses, compensatory nicotinic receptor upregulation partially offset deficits; at high doses, receptors were subnormal, worsening the impairment. THC also accelerated age-related nicotinic receptor decline.","whyItMatters":"This demonstrates that a father cannabis use before conception can cause lifelong brain changes in offspring. The cholinergic system is critical for attention, memory, and learning, and its impairment from adolescence through middle age represents a persistent neurodevelopmental injury.","specificNumbers":"28 days THC exposure; 2 and 4 mg/kg/day; offspring assessed PND 30-150; dose-dependent presynaptic ACh deficit; accelerated age-related nicotinic receptor decline.","methodology":"Male rats received THC (0, 2, or 4 mg/kg/day) for 28 days, then mated with drug-naive females 2 days later. Offspring brain acetylcholine systems assessed at PND 30, 60, 90, 120, and 150 across multiple brain regions.","limitations":"Rat model; THC doses may not match human recreational use; behavioral outcomes not assessed (only biochemical markers); limited to cholinergic system; cannot determine if effects are reversible with longer abstinence before conception."},{"rthcId":"RTHC-02852","title":"Characterizing #Backwoods on Instagram: \"The Number One Selling All Natural Cigar\".","authors":"Smiley, Sabrina L; Kim, Stephanie; Mourali, Alia; Allem, Jon-Patrick; Unger, Jennifer B; Boley Cruz, Tess","year":2020,"journal":"International journal of environmental research and public health, 17(12)","doi":"10.3390/ijerph17124584","pmid":"32630567","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02853","title":"Cannabis Exposure During Critical Windows of Development: Epigenetic and Molecular Pathways Implicated in Neuropsychiatric Disease.","authors":"Smith, Anna; Kaufman, Farla; Sandy, Martha S; Cardenas, Andres","year":2020,"journal":"Current environmental health reports, 7(3), 325-342","doi":"10.1007/s40572-020-00275-4","pmid":"32441004","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02854","title":"Greater delay discounting and cannabis coping motives are associated with more frequent cannabis use in a large sample of adult cannabis users.","authors":"Sofis, Michael J; Budney, Alan J; Stanger, Catherine; Knapp, Ashley A; Borodovsky, Jacob T","year":2020,"journal":"Drug and alcohol dependence, 207, 107820","doi":"10.1016/j.drugalcdep.2019.107820","pmid":"31887604","tags":["addiction","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Latent class analysis identified three use groups: low (23%, 1-9 days/month), moderate (41%, 10-29 days/month, 2-3 times/day), and high (36%, daily, 4+ times/day). Greater delay discounting (impulsivity) and cannabis coping motives were significantly associated with higher frequency use classes. Anxiety sensitivity also predicted higher use. Negative urgency was not significantly associated with use frequency.","whyItMatters":"Identifying that impulsivity and emotional coping drive heavy use provides specific therapeutic targets. Rather than treating cannabis use generally, interventions could focus on improving delay tolerance and teaching alternative coping strategies.","specificNumbers":"2,545 users; 3 classes: low 23%, moderate 41%, high 36%; delay discounting significant (χ2=6.0, p=.05); coping motives highly significant (χ2=73.3); anxiety sensitivity significant (χ2=12.1, p=.002).","methodology":"National sample of 2,545 cannabis users assessed for delay discounting, negative urgency, cannabis coping motives, and anxiety sensitivity. Latent class analysis derived frequency groups; multinomial logistic regression tested predictors.","limitations":"Cross-sectional (cannot determine if impulsivity causes heavy use or heavy use increases impulsivity); self-report frequency; national but convenience sample; did not assess cannabis potency or form; latent classes are statistical constructs."},{"rthcId":"RTHC-02855","title":"Attention-deficit/hyperactivity disorder and lifetime cannabis use: genetic overlap and causality.","authors":"Soler Artigas, María; Sánchez-Mora, Cristina; Rovira, Paula; Richarte, Vanesa; Garcia-Martínez, Iris; Pagerols, Mireia; Demontis, Ditte; Stringer, Sven; Vink, Jacqueline M; Børglum, Anders D; Neale, Benjamin M; Franke, Barbara; Faraone, Stephen V; Casas, Miguel; Ramos-Quiroga, Josep Antoni; Ribasés, Marta","year":2020,"journal":"Molecular psychiatry, 25(10), 2493-2503","doi":"10.1038/s41380-018-0339-3","pmid":"30610198","tags":["addiction","genetics","cognition"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using GWAS data from 53,293 ADHD and 32,330 cannabis use subjects, genetic correlation between ADHD and lifetime cannabis use was r2=0.29 (p=1.63×10-5). Four new genome-wide significant loci were identified in cross-trait analysis. Mendelian randomization provided evidence that ADHD is causal for cannabis use (OR=7.9 for cannabis use in ADHD vs non-ADHD, 95% CI 3.72-15.51, p=5.88×10-5). The reverse direction was not supported.","whyItMatters":"Published in Molecular Psychiatry, this provides the strongest evidence yet that ADHD drives cannabis use, not the reverse. This has implications for treatment: addressing ADHD symptoms may be the most effective cannabis prevention strategy in this population.","specificNumbers":"N=85,623; genetic correlation r2=0.29; ADHD→cannabis OR=7.9 (CI 3.72-15.51); 4 new genome-wide significant loci; 2 from single variant analysis, 2 from gene-based analysis.","methodology":"Genome-wide association study meta-analyses with LD score regression for genetic correlation, cross-trait association analysis for shared loci, and two-sample Mendelian randomization for causal inference using summary statistics.","limitations":"Mendelian randomization assumes genetic instruments are valid (pleiotropic effects possible); lifetime cannabis use is a binary measure (does not capture dose or problematic use); European ancestry GWAS data limits generalizability; ADHD phenotype in GWAS may not represent clinical ADHD."},{"rthcId":"RTHC-02856","title":"The Cannabis Terpenes.","authors":"Sommano, Sarana Rose; Chittasupho, Chuda; Ruksiriwanich, Warintorn; Jantrawut, Pensak","year":2020,"journal":"Molecules (Basel, Switzerland), 25(24)","doi":"10.3390/molecules25245792","pmid":"33302574","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02857","title":"Cannabinoids and the endocannabinoid system in reward processing and addiction: from mechanisms to interventions
.","authors":"Spanagel, Rainer","year":2020,"journal":"Dialogues in clinical neuroscience, 22(3), 241-250","doi":"10.31887/DCNS.2020.22.3/rspanagel","pmid":"33162767","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02858","title":"Source of cannabinoids: what is available, what is used, and where does it come from?","authors":"Specchio, Nicola; Pietrafusa, Nicola; Cross, Helen J","year":2020,"journal":"Epileptic disorders : international epilepsy journal with videotape, 22(S1), 1-9","doi":"10.1684/epd.2019.1121","pmid":"31941643","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02859","title":"Longitudinal associations between amygdala reactivity and cannabis use in a large sample of adolescents.","authors":"Spechler, Philip A; Chaarani, Bader; Orr, Catherine; Albaugh, Matthew D; Fontaine, Nicholas R; Higgins, Stephen T; Banaschewski, Tobias; Bokde, Arun L W; Quinlan, Erin Burke; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Artiges, Eric; Martinot, Marie-Laure Paillère; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Paus, Tomáš; Poustka, Luise; Hohmann, Sarah; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Garavan, Hugh","year":2020,"journal":"Psychopharmacology, 237(11), 3447-3458","doi":"10.1007/s00213-020-05624-7","pmid":"32772145","tags":["youth","neuroscience","anxiety"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Right amygdala reactivity to angry faces at age 14 (before cannabis use) significantly predicted cannabis use at age 19 in a dose-response fashion. Cannabis-naive adolescents showed the lowest amygdala reactivity. This predictive relationship was specific to cannabis (not found for alcohol or cigarettes). Follow-up analyses showed a significant group-by-time interaction, suggesting cannabis exposure during adolescence alters normal amygdala functional development.","whyItMatters":"This provides the first longitudinal evidence of a brain biomarker that predicts cannabis use years before it begins. The cannabis-specificity (not predicting alcohol/cigarettes) and bidirectional finding (brain predicts use AND use changes brain) reveal a feedback loop.","specificNumbers":"1,119 adolescents; right amygdala at age 14 predicted cannabis use at 19; dose-response relationship; cannabis-specific (not alcohol or cigarettes); significant group-by-time interaction on amygdala development.","methodology":"Longitudinal analysis of the IMAGEN study with 1,119 adolescents, measuring amygdala reactivity to angry faces via fMRI at age 14 and cannabis use at age 19. Linear regression for prediction; matched-sample analysis for developmental trajectory.","limitations":"Observational (amygdala reactivity may be a marker, not a cause); cannabis use self-reported; IMAGEN is European (may not generalize); fMRI task-based reactivity has moderate test-retest reliability; cannot determine if cannabis or associated lifestyle factors drive developmental changes."},{"rthcId":"RTHC-02860","title":"Pharmacokinetics of Cannabis Brownies: A Controlled Examination of Δ9-Tetrahydrocannabinol and Metabolites in Blood and Oral Fluid of Healthy Adult Males and Females.","authors":"Spindle, Tory R; Cone, Edward J; Herrmann, Evan S; Mitchell, John M; Flegel, Ronald; LoDico, Charles; Bigelow, George E; Vandrey, Ryan","year":2020,"journal":"Journal of analytical toxicology, 44(7), 661-671","doi":"10.1093/jat/bkaa067","pmid":"32591782","tags":["driving","potency","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"After consuming cannabis brownies (0, 10, 25, or 50 mg THC), blood THC and 11-OH-THC peaked at 1.5-2 hours and returned to baseline within 8 hours. THCCOOH and THCCOOH-glucuronide were higher than THC and persisted beyond 8 hours. Women had higher peak THC and metabolite concentrations, partly due to lower body weight/BMI. Oral fluid THC was detected immediately (oral deposition, not blood circulation) and was much higher than blood THC.","whyItMatters":"This is one of the few controlled studies with both sexes examining oral cannabis pharmacokinetics. The sex differences (higher THC in women) and oral fluid findings (immediate detection not reflecting blood levels) have direct implications for drug testing interpretation.","specificNumbers":"17 subjects (8 female); THC peak 1.5-2h; baseline within 8h; women: higher peaks; oral fluid THC detected immediately; ELISA-LC/MS agreement >90% for blood THCCOOH and oral fluid THC, but 67% for oral fluid THCCOOH.","methodology":"Randomized, double-blind, 4-session study in 17 healthy adults (8 female, no cannabis for 60+ days) consuming 0, 10, 25, or 50 mg THC brownies. Blood and oral fluid collected for 8 hours; analyzed by ELISA and LC-MS/MS.","limitations":"Small sample (17, 8 female); infrequent users only; single edible form (brownie); 8-hour window may not capture full duration of higher doses; no direct impairment measurements alongside PK; body weight/BMI only partially explains sex differences."},{"rthcId":"RTHC-02861","title":"A Tobacco Control Framework for Regulating Public Consumption of Cannabis: Multistate Analysis and Policy Implications.","authors":"Steinberg, Jane; Unger, Jennifer B; Hallett, Cynthia; Williams, Elizabeth; Baezconde-Garbanati, Lourdes; Cousineau, Michael R","year":2020,"journal":"American journal of public health, 110(2), 203-208","doi":"10.2105/AJPH.2019.305423","pmid":"31855488","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02862","title":"The level of evidence of medical marijuana use for treating disabilities: a scoping review.","authors":"Stetten, Nichole; Pomeranz, Jamie; Moorhouse, Michael; Yurasek, Ali; Blue, Amy V","year":2020,"journal":"Disability and rehabilitation, 42(9), 1190-1201","doi":"10.1080/09638288.2018.1523952","pmid":"30456993","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02863","title":"Cannabinoid Hyperemesis Syndrome: An Unexpected Problem in an Unusual Setting-A Case Report.","authors":"Stuart, Rory; Richards, John Ray","year":2020,"journal":"Military medicine, 185(9-10), e1894-e1896","doi":"10.1093/milmed/usaa113","pmid":"32472123","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02864","title":"Cessation of fluoxetine treatment increases alcohol seeking during relapse and dysregulates endocannabinoid and glutamatergic signaling in the central amygdala.","authors":"Suárez, Juan; Khom, Sophia; Alén, Francisco; Natividad, Luis A; Varodayan, Florence P; Patel, Reesha R; Kirson, Dean; Arco, Rocío; Ballesta, Antonio; Bajo, Michal; Rubio, Leticia; Martin-Fardon, Rémi; Rodríguez de Fonseca, Fernando; Roberto, Marisa","year":2020,"journal":"Addiction biology, 25(5), e12813","doi":"10.1111/adb.12813","pmid":"31339221","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02865","title":"Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies.","authors":"Suraev, Anastasia S; Marshall, Nathaniel S; Vandrey, Ryan; McCartney, Danielle; Benson, Melissa J; McGregor, Iain S; Grunstein, Ronald R; Hoyos, Camilla M","year":2020,"journal":"Sleep medicine reviews, 53, 101339","doi":"10.1016/j.smrv.2020.101339","pmid":"32603954","tags":["sleep","cbd","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 26 studies (14 preclinical, 12 clinical), evidence was insufficient for routine clinical use of cannabinoids for any sleep disorder due to limited research and moderate-to-high risk of bias. However, promising preliminary evidence was identified for sleep apnea, insomnia, PTSD-related nightmares, restless legs syndrome, REM sleep behavior disorder, and narcolepsy.","whyItMatters":"Cannabis is one of the most commonly cited reasons people use for sleep improvement, but this systematic review shows the clinical evidence does not yet support this popular use. The gap between public perception and evidence is stark.","specificNumbers":"14 preclinical + 12 clinical studies met criteria; insufficient evidence for all sleep disorders; moderate-to-high bias risk in most studies; promising leads for 6 specific conditions.","methodology":"Systematic review searching PubMed, Scopus, Web of Science, Embase, CINAHL, and PsycInfo for preclinical and clinical studies of cannabinoid therapies for sleep disorders.","limitations":"Limited number of studies meeting criteria; heterogeneous cannabinoid types, doses, and study designs; most studies had moderate-to-high bias risk; cannot draw condition-specific conclusions from few studies per disorder."},{"rthcId":"RTHC-02866","title":"Cannabis Use Is Associated With Increased Levels of Soluble gp130 in Schizophrenia but Not in Bipolar Disorder.","authors":"Szabo, Attila; Akkouh, Ibrahim A; Ueland, Thor; Lagerberg, Trine Vik; Dieset, Ingrid; Bjella, Thomas; Aukrust, Pål; Le Hellard, Stephanie; Stavrum, Anne-Kristin; Melle, Ingrid; Andreassen, Ole A; Djurovic, Srdjan","year":2020,"journal":"Frontiers in psychiatry, 11, 642","doi":"10.3389/fpsyt.2020.00642","pmid":"32714224","tags":["psychosis","inflammation","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Screening 13 plasma inflammatory markers, cannabis users in the schizophrenia group had significantly elevated soluble gp130 (sgp130) compared to non-users (p=0.002, surviving multiple testing correction). This was not found in bipolar disorder. Nominal increases were also seen in IL-1RA, YKL40, CatS, sTNFR1, and BDNF in cannabis-using schizophrenia patients. The differences were not reflected in peripheral immune cell mRNA expression, suggesting a non-immune-cell origin.","whyItMatters":"sgp130 is an inhibitor of IL-6 trans-signaling, a pro-inflammatory pathway implicated in schizophrenia. If cannabis increases sgp130 specifically in schizophrenia, it may explain why some patients report symptomatic benefit from cannabis: through anti-inflammatory modulation.","specificNumbers":"401 SCZ patients; 242 BD patients; sgp130 significantly elevated in cannabis-using SCZ (p=0.002); not in BD; nominal increases in IL-1RA, YKL40, CatS, sTNFR1, BDNF in SCZ cannabis users.","methodology":"Cross-sectional comparison of 13 plasma inflammatory markers between cannabis users and non-users within schizophrenia (n=401) and bipolar disorder (n=242) groups, with multiple testing correction.","limitations":"Cross-sectional; self-reported cannabis use (no dose/frequency data); cannot determine if sgp130 elevation is protective or reactive; medication effects not fully controlled; multiple testing limits interpretation of nominally significant markers."},{"rthcId":"RTHC-02867","title":"Attitudes and knowledge about cannabis and cannabis-based therapies among US neurologists, nurses, and pharmacists.","authors":"Szaflarski, Magdalena; McGoldrick, Patricia; Currens, Lauryn; Blodgett, Dustin; Land, Hunter; Szaflarski, Jerzy P; Segal, Eric","year":2020,"journal":"Epilepsy & behavior : E&B, 109, 107102","doi":"10.1016/j.yebeh.2020.107102","pmid":"32442891","tags":["medical-cannabis","epilepsy","cbd"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Over 80% supported medical cannabis use and legalization, especially CBD for epilepsy when prescribed by a provider. However, 40-50% felt unfamiliar with cannabinoid pharmacology and clinical applications. Pharmacists scored highest on knowledge tests; NPs/nurses had most favorable attitudes. State cannabis laws and favorable workplace policies were associated with higher knowledge and more positive attitudes. Only 43% favored recreational legalization.","whyItMatters":"The gap between support (80%+) and knowledge (40-50% unfamiliar) means healthcare professionals are endorsing treatments they do not fully understand. This has direct implications for patient safety and counseling quality.","specificNumbers":"451 respondents; >80% support medical cannabis; 40-50% feel unfamiliar; 43% support recreational; pharmacists: highest knowledge; NPs/nurses: most favorable attitudes; state laws predicted both knowledge and attitudes.","methodology":"Online survey of 451 US-based neurologists, nurse practitioners/nurses, and pharmacists (August-September 2018), using constructed knowledge tests, perceived knowledge scales, and attitudes scales with OLS regression.","limitations":"Online convenience sample (response bias likely); 451 is moderate for 3 professions; self-reported knowledge may differ from actual competency; 2018 data predates further legalization; does not assess actual prescribing/recommending behavior."},{"rthcId":"RTHC-02868","title":"Cannabis Improves Obsessive-Compulsive Disorder-Case Report and Review of the Literature.","authors":"Szejko, Natalia; Fremer, Carolin; Müller-Vahl, Kirsten R","year":2020,"journal":"Frontiers in psychiatry, 11, 681","doi":"10.3389/fpsyt.2020.00681","pmid":"32848902","tags":["medical-cannabis","mental-health","anxiety"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 22-year-old male with severe OCD since childhood, previously resistant to standard treatments, showed marked improvement in OCD symptoms and depression with medicinal cannabis, resulting in considerable quality of life improvement. The literature review found only 2 prior case reports of successful THC treatment for OCD, one small trial of nabilone plus exposure therapy, and supporting evidence from Tourette syndrome patients with comorbid obsessive-compulsive behavior.","whyItMatters":"OCD affects 2-3% of the population and is among the most treatment-resistant psychiatric conditions. The endocannabinoid system involvement opens an entirely new therapeutic pathway beyond the serotonergic model that has dominated OCD treatment.","specificNumbers":"One 22-year-old patient; severe childhood-onset OCD; marked improvement with cannabis; only 3 total case reports in literature (including this one); plus evidence from Tourette syndrome with OCD.","methodology":"Case report with literature review of cannabinoid effects in animal models and patients with OCD, proposing a cannabinoid hypothesis of OCD pathophysiology.","limitations":"Single case report; cannot establish causation; placebo/expectancy effects possible; patient may have had comorbidities affecting response; only 3 total OCD case reports in the literature; no standardized outcome measures reported in abstract."},{"rthcId":"RTHC-02869","title":"Cannabis and synthetic cannabinoid exposure reported to the Israel poison information center: Examining differences in exposures to medical and recreational compounds.","authors":"Sznitman, Sharon R; Pinsky-Talbi, Lianna; Salameh, Maisar; Moed, Taleb; Bentur, Yedidia","year":2020,"journal":"The International journal on drug policy, 77, 102711","doi":"10.1016/j.drugpo.2020.102711","pmid":"32126489","tags":["harm-reduction","synthetic-cannabinoids","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 615 cannabinoid poisoning cases, 55% were recreational cannabis, 33% synthetic cannabinoids, and 12% medical cannabis. Synthetic cannabinoid cases were more likely male, had more cardiovascular and GI symptoms, and were more often reported by healthcare professionals (not the public). Medical cannabis cases were less likely male, more likely called in by the public, had more GI symptoms, and less substance co-use. Synthetic cases peaked in 2014 then steeply declined, while recreational and medical cases increased throughout.","whyItMatters":"This is one of the largest comparative analyses of three cannabinoid poisoning types. The distinct clinical profiles help emergency physicians identify the type of cannabinoid exposure and guide treatment.","specificNumbers":"615 cases; 55% recreational cannabis; 33% synthetic; 12% medical; synthetic: more CV and GI symptoms; medical: less co-use, more public-reported; synthetic peaked 2014 then declined.","methodology":"Retrospective analysis of 615 cannabinoid exposure cases reported to the Israel Poison Information Center (2007-2018), comparing demographic and clinical characteristics across three cannabinoid types.","limitations":"Poison center data (underestimates actual poisonings); Israel-specific drug market; self-reported substance identification may be inaccurate; cannot assess long-term outcomes; severity metrics limited to symptoms present at report."},{"rthcId":"RTHC-02870","title":"A Survey on the Effect That Medical Cannabis Has on Prescription Opioid Medication Usage for the Treatment of Chronic Pain at Three Medical Cannabis Practice Sites.","authors":"Takakuwa, Kevin M; Sulak, Dustin","year":2020,"journal":"Cureus, 12(12), e11848","doi":"10.7759/cureus.11848","pmid":"33409086","tags":["pain","medical-cannabis","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 525 chronic pain patients who used both medical cannabis and prescribed opioids, 40.4% stopped all opioids, 45.2% decreased use, 13.3% had no change, and only 1.1% increased opioid use. The majority (65.3%) sustained the opioid change for over a year. Nearly half (48.2%) reported 40-100% pain reduction. 80% reported improved functioning and 87% improved quality of life. 62.8% did not want to take opioids in the future.","whyItMatters":"The 40% complete opioid cessation rate and 87% quality of life improvement are striking, even accounting for selection bias. If even a fraction of this effect is real, medical cannabis could be a powerful tool in the opioid crisis.","specificNumbers":"525 patients; 40.4% stopped opioids; 45.2% decreased; 1.1% increased; 65.3% sustained change >1 year; 48.2% reported 40-100% pain reduction; 87% improved QoL; 62.8% did not want future opioids.","methodology":"Online convenience survey of patients from 3 medical cannabis practices who had used prescription opioids continuously for 3+ months for chronic pain and were concurrently using medical cannabis. 1,181 responded; 525 met criteria.","limitations":"Convenience sample from cannabis practices (strong selection bias toward satisfied patients); self-report; no control group; survey cannot establish causation; patients choosing medical cannabis are already motivated to reduce opioids; no verification of opioid cessation."},{"rthcId":"RTHC-02871","title":"Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia.","authors":"Tao, Ran; Li, Chao; Jaffe, Andrew E; Shin, Joo Heon; Deep-Soboslay, Amy; Yamin, Rae'e; Weinberger, Daniel R; Hyde, Thomas M; Kleinman, Joel E","year":2020,"journal":"Translational psychiatry, 10(1), 158","doi":"10.1038/s41398-020-0832-8","pmid":"32433545","tags":["psychosis","genetics","neuroscience","youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"CNR1 expression is high in fetal prefrontal cortex and hippocampus, then drops dramatically after birth. The lifespan trajectory of CNR1 in DLPFC was modified by COMT Val158Met genotype: valine carriers showed stronger age-related decline. CNR1 methylation at cg02498983 increased with age (inversely correlated with expression) and was strongest in valine carriers. CNR1 was decreased in schizophrenia DLPFC but upregulated in schizophrenia suicide victims. THC and ethanol were each associated with dysregulated CNR1 in affective disorder PFC. A novel CNR1 transcript was predicted by SNP rs806368.","whyItMatters":"Published in Translational Psychiatry, this maps the CB1 receptor across the human lifespan and shows that both genetic variation (COMT) and environmental exposure (THC) interact to determine CB1 expression. This gene-by-environment framework helps explain why adolescent cannabis use specifically increases psychosis risk.","specificNumbers":"CNR1 highest in fetal brain; drops postnatally; COMT Val carriers: stronger decline and stronger methylation increase; CNR1 decreased in schizophrenia DLPFC; upregulated in schizophrenia suicide; THC and ethanol each dysregulate CNR1.","methodology":"Postmortem human brain tissue analysis of CNR1 mRNA expression and DNA methylation across prefrontal cortex, hippocampus, and caudate from developmental samples and schizophrenia cases. eQTL analysis and COMT genotype interaction testing.","limitations":"Postmortem tissue (cannot determine temporal sequences in living brain); relatively small samples per condition; medication effects not fully controlled; COMT genotype analysis limited to Caucasian subjects; cannot determine if CNR1 changes cause or result from schizophrenia."},{"rthcId":"RTHC-02872","title":"Cannabinoid receptor 2 agonist promotes parameters implicated in mucosal healing in patients with inflammatory bowel disease.","authors":"Tartakover Matalon, Shelly; Ringel, Yehuda; Konikoff, Fred; Drucker, Liat; Pery, Shaul; Naftali, Timna","year":2020,"journal":"United European gastroenterology journal, 8(3), 271-283","doi":"10.1177/2050640619889773","pmid":"32213014","tags":["medical-cannabis","inflammation","cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In inflamed colon tissue from 16 IBD patients, the CB2 agonist JWH-133 increased epithelial cell proliferation by more than 50%, reduced programmed cell death, and lowered MMP9 activity and IL-8 levels, all of which are associated with mucosal healing.","whyItMatters":"Mucosal healing is a key treatment goal in IBD. This study suggests the cannabinoid system, specifically CB2 receptors, could be a therapeutic target for promoting gut tissue repair.","specificNumbers":"Epithelial proliferation increased by over 50% (Ki67 marker). MMP9 activity and IL-8 levels decreased by more than 50%. Sample included tissue from 16 IBD patients.","methodology":"Ex vivo study using mucosal biopsies from inflamed and uninflamed colon tissue of 16 IBD patients, cultured with or without CB2 agonist JWH-133 for 6 hours. Epithelial cell behavior and secretome effects were analyzed.","limitations":"This was an ex vivo study using tissue samples, not a clinical trial in living patients. The small sample size (16 patients) and short treatment window (6 hours) limit conclusions about real-world therapeutic effects."},{"rthcId":"RTHC-02873","title":"Abrupt withdrawal of cannabidiol (CBD): A randomized trial.","authors":"Taylor, Lesley; Crockett, Julie; Tayo, Bola; Checketts, Daniel; Sommerville, Kenneth","year":2020,"journal":"Epilepsy & behavior : E&B, 104(Pt A), 106938","doi":"10.1016/j.yebeh.2020.106938","pmid":"32036242","tags":["cbd","withdrawal","epilepsy"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"After four weeks of 1,500 mg daily CBD, volunteers randomized to abrupt discontinuation showed no increase in withdrawal scores. Cannabis Withdrawal Scale scores ranged from 0 to 0.5 out of 190, and Penn Physician Withdrawal Checklist scores were 0 out of 60.","whyItMatters":"Concerns about dependence are a barrier to CBD adoption. This trial provides direct evidence that pharmaceutical CBD does not produce physical dependence or withdrawal after short-term use.","specificNumbers":"30 volunteers enrolled. 1,500 mg/day CBD dose. CWS scores: 0.0 to 0.5 out of 190 in discontinuation group. PWC-20 scores: 0.0 out of 60. 97% reported adverse events during treatment (most commonly diarrhea at 63%).","methodology":"Randomized trial with 30 healthy volunteers taking 750 mg CBD twice daily for 4 weeks, then randomized to continue CBD or switch to placebo for 2 weeks. Withdrawal assessed using validated Cannabis Withdrawal Scale and PWC-20.","limitations":"Only 30 participants, all healthy volunteers (not patients with epilepsy or other conditions). Treatment lasted just 4 weeks, so longer-term dependence potential was not assessed."},{"rthcId":"RTHC-02874","title":"Combined prevention for substance use, depression, and anxiety in adolescence: a cluster-randomised controlled trial of a digital online intervention.","authors":"Teesson, Maree; Newton, Nicola C; Slade, Tim; Chapman, Cath; Birrell, Louise; Mewton, Louise; Mather, Marius; Hides, Leanne; McBride, Nyanda; Allsop, Steve; Andrews, Gavin","year":2020,"journal":"The Lancet. Digital health, 2(2), e74-e84","doi":"10.1016/S2589-7500(19)30213-4","pmid":"33334564","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02875","title":"The prevalence and clinical correlates of substance use disorders in patients with psychotic disorders from an Upper-Middle-Income Country.","authors":"Temmingh, Henk S; Mall, Sumaya; Howells, Fleur M; Sibeko, Goodman; Stein, Dan J","year":2020,"journal":"The South African journal of psychiatry : SAJP : the journal of the Society of Psychiatrists of South Africa, 26, 1473","doi":"10.4102/sajpsychiatry.v26i0.1473","pmid":"32832129","tags":["psychosis","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 248 patients with psychotic disorders, cannabis use disorders (34.3%) were the most prevalent, followed by alcohol (30.6%) and methamphetamine (27.4%). Male sex predicted most substance use disorders, and anxiety symptoms and suicide attempts were linked to alcohol use disorders.","whyItMatters":"Most data on substance use in psychotic disorders comes from high-income countries. This study from South Africa found similarly high rates, suggesting the co-occurrence is a global phenomenon requiring integrated treatment approaches.","specificNumbers":"248 patients studied. 55.6% had any SUD. 34.3% cannabis use disorder. 30.6% alcohol. 27.4% methamphetamine. 10.4% methaqualone. 4.8% other substances.","methodology":"Cross-sectional study of 248 patients at a secondary-level psychiatric hospital in Cape Town, South Africa, using the Structured Clinical Interview for DSM-IV. Logistic regression identified predictors of substance use disorders.","limitations":"Cross-sectional design cannot determine whether substance use preceded or followed psychosis onset. Single hospital setting in Cape Town may not represent all of South Africa. DSM-IV criteria were used rather than the more current DSM-5."},{"rthcId":"RTHC-02876","title":"E-cigarette, or vaping, product use-associated lung injury in adolescents: a review of imaging features.","authors":"Thakrar, Pooja D; Boyd, Kevin P; Swanson, Craig P; Wideburg, Eric; Kumbhar, Sachin S","year":2020,"journal":"Pediatric radiology, 50(3), 338-344","doi":"10.1007/s00247-019-04572-5","pmid":"31897566","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02877","title":"Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation.","authors":"Thapa, Dinesh; Cairns, Elizabeth A; Szczesniak, Anna-Maria; Kulkarni, Pushkar M; Straiker, Alex J; Thakur, Ganesh A; Kelly, Melanie E M","year":2020,"journal":"Molecules (Basel, Switzerland), 25(2)","doi":"10.3390/molecules25020417","pmid":"31968549","tags":["pain","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CB1 allosteric ligand GAT228 reduced pain on its own, while GAT229 and GAT211 reduced pain when combined with a low dose of THC. Both GAT228 alone and GAT229 with THC also reduced corneal inflammation. Effects were blocked by a CB1 antagonist but persisted in CB2 knockout mice.","whyItMatters":"Current eye pain treatments have significant limitations. Allosteric modulators could enhance the therapeutic effects of cannabinoids at lower doses while potentially reducing side effects associated with direct CB1 activation.","specificNumbers":"GAT228 at 2% concentration reduced pain scores. Combination of 0.5% GAT229 with 0.4% delta-8-THC significantly reduced pain. The 0.4% THC dose alone was subthreshold (inactive).","methodology":"Corneal hyperalgesia was induced by chemical cauterization in wildtype and CB2 knockout mice. Pain was assessed after capsaicin stimulation at 6 hours post-injury. Novel allosteric CB1 ligands were tested alone and in combination with delta-8-THC.","limitations":"Animal study using a mouse model of corneal injury. Pain assessment relied on behavioral scoring. No human data on safety, tolerability, or efficacy of these compounds."},{"rthcId":"RTHC-02878","title":"Peripheral deficiency and antiallodynic effects of 2-arachidonoyl glycerol in a mouse model of paclitaxel-induced neuropathic pain.","authors":"Thomas, Amal; Okine, Bright N; Finn, David P; Masocha, Willias","year":2020,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 129, 110456","doi":"10.1016/j.biopha.2020.110456","pmid":"32603895","tags":["pain","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"2-AG levels were significantly reduced in the paw skin but not in the brain or spinal cord of paclitaxel-treated mice. Injecting 2-AG or the MAGL inhibitor JZL184 directly into the paw reversed pain sensitivity, and this effect required both CB1 and CB2 receptors.","whyItMatters":"Chemotherapy-induced neuropathic pain is a common and difficult-to-treat side effect. Finding that the endocannabinoid system is specifically depleted at the site of pain suggests targeted local treatments could help.","specificNumbers":"2-AG levels were reduced only in paw skin, not in brain or spinal cord. Antiallodynic effects of 2-AG were blocked by both CB1 antagonist AM251 and CB2 antagonist AM630. Effects were limited to the injected paw only.","methodology":"Female BALB/c mice received paclitaxel to induce mechanical allodynia. Endocannabinoid levels were measured in brain, spinal cord, and paw skin using LC-MS/MS. Local injection of 2-AG or MAGL inhibitor into the hind paw was tested for antiallodynic effects.","limitations":"Animal study using only female mice of one strain. Endocannabinoid measurements were taken at a single time point. Local injection is not a practical delivery method for clinical use."},{"rthcId":"RTHC-02879","title":"Cognitive function and adaptive skills after a one-year trial of cannabidiol (CBD) in a pediatric sample with treatment-resistant epilepsy.","authors":"Thompson, Matthew D; Martin, Roy C; Grayson, Leslie P; Ampah, Steve B; Cutter, Gary; Szaflarski, Jerzy P; Bebin, E Martina","year":2020,"journal":"Epilepsy & behavior : E&B, 111, 107299","doi":"10.1016/j.yebeh.2020.107299","pmid":"32759071","tags":["cbd","epilepsy","cognition","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 38 pediatric patients (ages 3-19) with treatment-resistant epilepsy, those who completed cognitive testing showed no significant changes after one year of CBD. There was a nonsignificant trend toward improvement in some cognitive domains. Adaptive behavior scores also remained stable.","whyItMatters":"Parents and clinicians worry about cognitive side effects of adding another medication, especially for children already on multiple anticonvulsants. This study provides reassurance that CBD does not appear to worsen cognition over one year.","specificNumbers":"38 participants ages 3-19. 24 were unable to complete cognitive testing due to severity of impairment. Among those tested, no statistically significant cognitive changes. Adaptive behavior scores unchanged after one year.","methodology":"Open-label prospective study of 38 participants with treatment-resistant epilepsy receiving pharmaceutical CBD (Epidiolex) as add-on treatment. Cognition assessed with NIH Toolbox Cognition Battery at baseline and one year. For cognitively impaired participants unable to complete testing, caregivers completed the ABAS-II.","limitations":"Open-label design without a control group. Small sample with high attrition (24 of 38 could not complete cognitive testing). Practice effects from repeated testing could mask subtle declines."},{"rthcId":"RTHC-02880","title":"Patterns of cigarette, e-cigarette, and cannabis use among adult smokers in primary care 2014-2015.","authors":"Thrul, Johannes; Vijayaraghavan, Maya; Kalkhoran, Sara; Satterfield, Jason M","year":2020,"journal":"Addictive behaviors, 100, 106109","doi":"10.1016/j.addbeh.2019.106109","pmid":"31522133","tags":["addiction","harm-reduction","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"48.6% smoked cigarettes only. 30.4% also used cannabis. 10.5% also used e-cigarettes. 10.5% used all three products. Smoking behavior and motivation to quit did not differ between groups, but dual cigarette-e-cigarette users were more likely to receive complete cessation counseling.","whyItMatters":"Treating cigarette smoking without addressing concurrent cannabis or e-cigarette use may undermine cessation efforts. This study highlights how common poly-use is among smokers seeking primary care.","specificNumbers":"601 smokers studied. 48.6% cigarette-only. 30.4% cigarette + cannabis. 10.5% cigarette + e-cigarette. 10.5% all three. Mean age 50.8, 38.1% female.","methodology":"Cross-sectional secondary analysis from a smoking cessation trial in 3 diverse primary care clinics in San Francisco (2014-2015). 601 current cigarette smokers reported on past 30-day cigarette and e-cigarette use and past 3-month cannabis use.","limitations":"Cross-sectional design from a single city (San Francisco) between 2014-2015. Self-reported substance use may undercount actual use. Cannabis and e-cigarette markets have changed significantly since data collection."},{"rthcId":"RTHC-02881","title":"Cannabis use influence on peripheral brain-derived neurotrophic factor levels in antipsychotic-naïve first-episode psychosis.","authors":"Toll, A; Bergé, D; Burling, K; Scoriels, L; Treen, D; Monserrat, C; Marmol, F; Duran, X; Jones, P B; Pérez-Solà, V; Fernandez-Egea, E; Mané, A","year":2020,"journal":"European archives of psychiatry and clinical neuroscience, 270(7), 851-858","doi":"10.1007/s00406-020-01117-y","pmid":"32185490","tags":["psychosis","neuroscience","dopamine"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 70 drug-naive first-episode psychosis patients and 57 healthy volunteers, cannabis use was associated with reduced BDNF levels only in the psychosis group. Heavy cannabis use also correlated with younger age in patients. In healthy volunteers, cannabis use was linked to tobacco use but not to BDNF levels.","whyItMatters":"BDNF supports neuron health and plasticity. Finding that cannabis lowers BDNF specifically in psychosis patients suggests a biological mechanism by which cannabis may worsen outcomes in vulnerable individuals.","specificNumbers":"70 first-episode psychosis patients (antipsychotic-naive). 57 healthy volunteers. High cannabis use was associated with lower BDNF in patients but not controls. High cannabis use also correlated with younger age in patients.","methodology":"Cross-sectional study of 70 antipsychotic-naive first-episode psychosis patients and 57 healthy volunteers. Blood samples analyzed for BDNF by ELISA. Substance use, clinical diagnosis, and demographic variables collected via structured clinical interview.","limitations":"Cross-sectional design cannot determine causation. Peripheral BDNF levels may not reflect brain BDNF. Cannabis use was self-reported. Relatively small sample sizes."},{"rthcId":"RTHC-02882","title":"Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis.","authors":"Tomko, Andrea M; Whynot, Erin G; Ellis, Lee D; Dupré, Denis J","year":2020,"journal":"Cancers, 12(7)","doi":"10.3390/cancers12071985","pmid":"32708138","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02883","title":"Depressive symptoms and cannabis use in a placebo-controlled trial of N-Acetylcysteine for adult cannabis use disorder.","authors":"Tomko, Rachel L; Baker, Nathaniel L; Hood, Caitlyn O; Gilmore, Amanda K; McClure, Erin A; Squeglia, Lindsay M; McRae-Clark, Aimee L; Sonne, Susan C; Gray, Kevin M","year":2020,"journal":"Psychopharmacology, 237(2), 479-490","doi":"10.1007/s00213-019-05384-z","pmid":"31712969","tags":["depression","addiction","mental-health","sex-differences"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"N-acetylcysteine did not reduce depressive symptoms compared to placebo. Higher baseline depression was associated with decreased abstinence throughout treatment, with a significant gender interaction suggesting this was particularly true for women. Cross-lagged models showed depressive symptoms preceded increased cannabis use, but not the reverse.","whyItMatters":"The directional finding (depression leads to more cannabis use, but not vice versa) suggests treating depression could improve cannabis cessation outcomes, and that women may need particular attention in this regard.","specificNumbers":"302 adults with cannabis use disorder. 12-week trial. NAC did not differ from placebo on depression. Higher baseline depression predicted decreased abstinence. Gender interaction was significant, with stronger effects in females.","methodology":"Secondary analysis of a multi-site RCT (N=302) comparing 2,400 mg/day NAC vs placebo for cannabis use disorder over 12 weeks. All participants received contingency management. Depression measured by HADS. Cannabis use verified by urinary cannabinoid levels.","limitations":"Secondary analysis, so the study was not originally designed or powered to test these depression-related questions. Depression was measured with a screening tool (HADS), not a diagnostic interview. Predominantly male sample limits gender-related conclusions."},{"rthcId":"RTHC-02884","title":"Inhalation Toxicology of Vaping Products and Implications for Pulmonary Health.","authors":"Traboulsi, Hussein; Cherian, Mathew; Abou Rjeili, Mira; Preteroti, Matthew; Bourbeau, Jean; Smith, Benjamin M; Eidelman, David H; Baglole, Carolyn J","year":2020,"journal":"International journal of molecular sciences, 21(10)","doi":"10.3390/ijms21103495","pmid":"32429092","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02885","title":"The short-acting synthetic cannabinoid AB-FUBINACA induces physical dependence in mice.","authors":"Trexler, Kristen R; Vanegas, S Olivia; Poklis, Justin L; Kinsey, Steven G","year":2020,"journal":"Drug and alcohol dependence, 214, 108179","doi":"10.1016/j.drugalcdep.2020.108179","pmid":"32688070","tags":["synthetic-cannabinoids","addiction","withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AB-FUBINACA at 2+ mg/kg produced catalepsy, antinociception, hypothermia, and reduced locomotion, all blocked by CB1 antagonist rimonabant. Despite being undetectable in brain tissue by 4 hours, twice-daily dosing for 5 days produced somatic withdrawal signs (head twitches, paw tremors) when precipitated by rimonabant.","whyItMatters":"Synthetic cannabinoids are often assumed to be similar to plant cannabis, but their rapid action and potency may create a distinct dependence risk. This study shows that even short-acting synthetic cannabinoids can induce physical dependence.","specificNumbers":"AB-FUBINACA effects at 2+ mg/kg. Undetectable in brain by 4 hours post-injection. 5 days of twice-daily dosing produced dependence. No tolerance developed to AB-FUBINACA or cross-tolerance to THC (50 mg/kg).","methodology":"Male and female C57BL/6J mice received AB-FUBINACA (0-3 mg/kg) and were tested in the tetrad battery. For dependence assessment, mice were dosed every 12 hours for 5 days, then withdrawal was precipitated with rimonabant on day 6. Brain levels were quantified by UHPLC-MS/MS.","limitations":"Animal study using intraperitoneal and subcutaneous injection, which differs from how humans typically use synthetic cannabinoids (inhalation). Only one dosing regimen tested. Withdrawal was precipitated rather than spontaneous."},{"rthcId":"RTHC-02886","title":"Perceived Ease of Access and Age Attenuate the Association Between Marijuana Ad Exposure and Marijuana Use in Adolescents.","authors":"Turel, Ofir","year":2020,"journal":"Health education & behavior : the official publication of the Society for Public Health Education, 47(2), 311-320","doi":"10.1177/1090198119894707","pmid":"31958996","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Perceived ease of access and age were both significantly larger predictors of past-year marijuana use than ad exposure. Both factors also amplified the ad-to-use relationship: older teens who perceived marijuana as easy to get were most influenced by advertising. Male adolescents were more affected by perceived availability than females.","whyItMatters":"As cannabis advertising increases with legalization, understanding what actually drives teen use is critical. This study suggests reducing perceived availability may be more impactful than restricting advertising alone.","specificNumbers":"9,024 adolescents surveyed. Ad exposure positively associated with use (95% CI [0.03, 0.14]). Perceived ease of access had a much larger effect (95% CI [0.18, 0.22]). Age also stronger (95% CI [0.16, 0.27]). Significant three-way interaction between all three factors.","methodology":"Secondary analysis of national survey data from 9,024 American adolescents using hierarchical regression. Examined main effects and interactions of ad exposure, perceived ease of access, age, and gender on past-year marijuana use.","limitations":"Cross-sectional survey cannot establish causation. Self-reported marijuana use and ad exposure are subject to recall bias. \"Perceived ease of access\" may reflect actual access or attitudes toward use."},{"rthcId":"RTHC-02887","title":"Cannabis Use and its Association with Psychological Disorders.","authors":"Urits, Ivan; Gress, Kyle; Charipova, Karina; Li, Nathan; Berger, Amnon A; Cornett, Elyse M; Hasoon, Jamal; Kassem, Hisham; Kaye, Alan D; Viswanath, Omar","year":2020,"journal":"Psychopharmacology bulletin, 50(2), 56-67","doi":"10.64719/pb.4606","pmid":"32508368","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02888","title":"Full-Spectrum Cannabis Extract Microdepots Support Controlled Release of Multiple Phytocannabinoids for Extended Therapeutic Effect.","authors":"Uziel, Almog; Gelfand, Anat; Amsalem, Keren; Berman, Paula; Lewitus, Gil M; Meiri, David; Lewitus, Dan Y","year":2020,"journal":"ACS applied materials & interfaces, 12(21), 23707-23716","doi":"10.1021/acsami.0c04435","pmid":"32369348","tags":["medical-cannabis","epilepsy","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Subcutaneously injected microdepots released CBD and other phytocannabinoids over 14+ days, maintaining elevated serum levels. One week after a single administration, microdepots reduced tonic-clonic seizure incidence by 40%, increased survival by 50%, and delayed seizure onset by 170% compared to a single extract injection.","whyItMatters":"Current cannabis administration through oral or inhaled routes has variable absorption and short duration. A long-acting delivery system could provide more consistent therapeutic levels and better seizure control.","specificNumbers":"Sustained release over 14+ days. At one week: 40% reduction in tonic-clonic seizure incidence, 50% increase in survival rate, 170% increase in latency to first seizure.","methodology":"Melt-printed polymeric microdepots encapsulating CBD-rich full-spectrum cannabis extract were injected subcutaneously in mice. Serum phytocannabinoid levels were tracked over time. Efficacy was tested in a pentylenetetrazol-induced seizure model comparing microdepots vs. single extract injection.","limitations":"Animal study in a chemically induced seizure model, which differs from human epilepsy. Subcutaneous implantation may not be acceptable to all patients. Long-term biocompatibility of the polymer was not assessed."},{"rthcId":"RTHC-02889","title":"Exploring Phenotypic and Genetic Overlap Between Cannabis Use and Schizotypy.","authors":"Vaissiere, James; Thorp, Jackson G; Ong, Jue-Sheng; Ortega-Alonzo, Alfredo; Derks, Eske M","year":2020,"journal":"Twin research and human genetics : the official journal of the International Society for Twin Studies, 23(4), 221-227","doi":"10.1017/thg.2020.68","pmid":"32885772","tags":["psychosis","genetics","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Positive phenotypic correlations (range 0.05-0.18) were found between 11 of 12 cannabis use and schizotypy trait pairs in UK Biobank. The only significant genetic correlation was negative: social anhedonia was inversely correlated with number of times used cannabis (rg = -0.30), suggesting those genetically predisposed to social anhedonia used cannabis less frequently.","whyItMatters":"The well-established link between cannabis and full psychotic disorders may extend to subclinical psychosis traits in the general population. Understanding the genetic architecture of this relationship could help identify who is most at risk.","specificNumbers":"11 of 12 phenotypic correlations were positive (range 0.05-0.18). Social anhedonia heritability: 0.08. \"Ever seen an unreal vision\" heritability: 0.35. Genetic correlation between social anhedonia and cannabis use frequency: rg = -0.30.","methodology":"Phenotypic correlations calculated in UK Biobank. SNP-based heritability estimates and genetic correlations computed using genome-wide association study data. Multiple schizotypy phenotypes and cannabis use variables were analyzed.","limitations":"Small genetic sample sizes for some schizotypy measures limited statistical power. UK Biobank participants skew older and healthier than the general population. Self-reported cannabis use and psychosis-like experiences may be underreported."},{"rthcId":"RTHC-02890","title":"A Nonopioid, Nonbenzodiazepine Treatment Approach for Intractable Nausea and Vomiting in the Emergency Department.","authors":"Valdovinos, Erica M; Frazee, Bradley W; Hailozian, Christian; Haro, Daniel A; Herring, Andrew A","year":2020,"journal":"Journal of clinical gastroenterology, 54(4), 327-332","doi":"10.1097/MCG.0000000000001258","pmid":"31567626","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02891","title":"Geographic Differences in Cannabis Conversations on Twitter: Infodemiology Study.","authors":"van Draanen, Jenna; Tao, HaoDong; Gupta, Saksham; Liu, Sam","year":2020,"journal":"JMIR public health and surveillance, 6(4), e18540","doi":"10.2196/18540","pmid":"33016888","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02892","title":"Medical cannabis: What practitioners need to know.","authors":"Van Rensburg, R; Pillay-Fuentes Lorente, V; Blockman, M; Moodley, K; Wilmshurst, J M; Decloedt, E H","year":2020,"journal":"South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 110(3), 192-196","doi":"10.7196/SAMJ.2020.v110i3.14403","pmid":"32657695","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02893","title":"Classics in Neuroimaging: Imaging the Endocannabinoid Pathway with PET.","authors":"Varlow, Cassis; Boileau, Isabelle; Wey, Hsiao-Ying; Liang, Steven H; Vasdev, Neil","year":2020,"journal":"ACS chemical neuroscience, 11(13), 1855-1862","doi":"10.1021/acschemneuro.0c00305","pmid":"32559067","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02894","title":"Patterns of Cannabis Use in Patients With Cyclic Vomiting Syndrome.","authors":"Venkatesan, Thangam; Hillard, Cecilia J; Rein, Lisa; Banerjee, Anjishnu; Lisdahl, Krista","year":2020,"journal":"Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 18(5), 1082-1090.e2","doi":"10.1016/j.cgh.2019.07.039","pmid":"31352091","tags":["appetite","medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"41% of CVS patients used cannabis, with 21% using regularly (4+ times/week). Most users reported cannabis helped control symptoms. Among all cannabis users, 88% had abstained for over a month at some point, but only 1 reported resolution of vomiting episodes during abstinence, meeting Rome IV criteria for CHS.","whyItMatters":"Distinguishing CVS from cannabinoid hyperemesis syndrome is a clinical challenge. This study suggests the overlap may be smaller than assumed, with most cannabis-using CVS patients genuinely benefiting from cannabis rather than being misdiagnosed CHS cases.","specificNumbers":"140 CVS patients (72% female, mean age 37). 41% current cannabis users. 21% regular users. 88% of users had abstained >1 month. Only 1 of 57 users (1.8%) met Rome IV CHS criteria.","methodology":"Cross-sectional study of 140 patients with cyclic vomiting syndrome at a specialized clinic. Cannabis use screened with the Cannabis Use Disorder Identification Test. Users classified as regular (4+ times/week) or occasional.","limitations":"Cross-sectional design at a single specialized clinic. Self-reported cannabis use and symptom relief. The specialized clinic population may not represent all CVS patients. Small number of regular users limits subgroup analysis."},{"rthcId":"RTHC-02895","title":"Modeling cannabinoids from a large-scale sample of Cannabis sativa chemotypes.","authors":"Vergara, Daniela; Gaudino, Reggie; Blank, Thomas; Keegan, Brian","year":2020,"journal":"PloS one, 15(9), e0236878","doi":"10.1371/journal.pone.0236878","pmid":"32870907","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02896","title":"Cannabis: are there any benefits?","authors":"Vickery, Alistair W; Finch, Phillip M","year":2020,"journal":"Internal medicine journal, 50(11), 1326-1332","doi":"10.1111/imj.15052","pmid":"33215831","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02897","title":"Antidepressant-Like Effect of Terpineol in an Inflammatory Model of Depression: Involvement of the Cannabinoid System and D2 Dopamine Receptor.","authors":"Vieira, Graziela; Cavalli, Juliana; Gonçalves, Elaine C D; Braga, Saulo F P; Ferreira, Rafaela S; Santos, Adair R S; Cola, Maíra; Raposo, Nádia R B; Capasso, Raffaele; Dutra, Rafael C","year":2020,"journal":"Biomolecules, 10(5)","doi":"10.3390/biom10050792","pmid":"32443870","tags":["depression","neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Terpineol at 100-200 mg/kg reduced immobility time in the tail suspension test. Its antidepressant-like effect was blocked by CB1 antagonist AM281, CB2 inverse agonist AM630, and dopamine D2 antagonist sulpiride, but not by caffeine or propranolol. Molecular docking confirmed CB1 and CB2 as promising binding targets.","whyItMatters":"Terpenes are often overlooked components of cannabis. This study suggests terpineol may contribute to cannabis effects on mood through the endocannabinoid system, supporting the idea that non-cannabinoid compounds in cannabis have biological activity.","specificNumbers":"Effective at 100-200 mg/kg oral dose. Effects blocked by CB1, CB2, and D2 receptor antagonists. Not blocked by adenosine or beta-adrenergic antagonists.","methodology":"LPS-induced depression model in mice with behavioral assessment via tail suspension test and splash test. Pharmacological blocking studies identified receptor mechanisms. Molecular docking analyses predicted binding affinity to cannabinoid and dopamine receptors.","limitations":"Animal study using high doses of oral terpineol that may not reflect levels achievable through cannabis use. LPS-induced depression is a simplified model. Molecular docking predictions need experimental validation of direct receptor binding."},{"rthcId":"RTHC-02898","title":"Endocannabinoid modulating drugs improve anxiety but not the expression of conditioned fear in a rodent model of post-traumatic stress disorder.","authors":"Vimalanathan, Akshayan; Gidyk, Darryl C; Diwan, Mustansir; Gouveia, Flavia V; Lipsman, Nir; Giacobbe, Peter; Nobrega, José N; Hamani, Clement","year":2020,"journal":"Neuropharmacology, 166, 107965","doi":"10.1016/j.neuropharm.2020.107965","pmid":"31962287","tags":["ptsd","anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Acute WIN55,212-2 (CB1 agonist) reduced anxiety in \"weak extinction\" rats but did not affect fear recall. The FAAH inhibitor URB597 did not reduce anxiety or fear acutely. The CB1 inverse agonist AM251 increased anxiety in normal-extinction rats. Chronic administration of neither URB597 nor AM251 altered fear or anxiety, and did not change FAAH or CB1 expression.","whyItMatters":"PTSD involves both anxiety and persistent fear memories. This study suggests the endocannabinoid system may help with PTSD-related anxiety but may not be sufficient to eliminate extinction-resistant fear memories.","specificNumbers":"25-30% of rats showed weak extinction (modeling PTSD). WIN55,212-2 reduced anxiety in WE rats. AM251 increased anxiety in SE rats. No drug condition altered freezing during fear recall.","methodology":"Rats underwent fear conditioning and were segregated into weak extinction (WE, modeling PTSD) and strong extinction (SE) groups. Acute and chronic endocannabinoid-modulating drugs were tested on fear recall and novelty-suppressed feeding (anxiety measure).","limitations":"Animal model may not fully capture human PTSD complexity. Systemic drug administration does not target specific brain regions. Only one dose of each drug was tested. Fear recall was measured by freezing, which may not capture all aspects of fear response."},{"rthcId":"RTHC-02899","title":"Patterns of Polysubstance Use among Adults with Tranquilizer Misuse.","authors":"Votaw, Victoria R; McHugh, R Kathryn; Vowles, Kevin E; Witkiewitz, Katie","year":2020,"journal":"Substance use & misuse, 55(6), 861-870","doi":"10.1080/10826084.2019.1708118","pmid":"31900021","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02900","title":"Cannabis treatment in hospitalized patients using the SYQE inhaler: Results of a pilot open-label study.","authors":"Vulfsons, Simon; Ognitz, Miriam; Bar-Sela, Gil; Raz-Pasteur, Ayelet; Eisenberg, Elon","year":2020,"journal":"Palliative & supportive care, 18(1), 12-17","doi":"10.1017/S147895151900021X","pmid":"31196236","tags":["medical-cannabis","pain","potency"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Daily cannabis consumption dropped from a median of 1,000 mg to 51 mg when using the SYQE Inhaler. Pain intensity fell from a median of 7 to 4 (out of 10) within 30-60 minutes of inhalation. Patient satisfaction was rated 6 out of 7. Only mild cough was reported as an adverse event in 3 participants.","whyItMatters":"Cannabis by combustion is not feasible in hospitals. A precision inhaler that delivers consistent microdoses could make medical cannabis accessible to hospitalized patients while dramatically reducing the amount consumed.","specificNumbers":"Median daily dose: 51 mg (range 20-96) vs. 1,000 mg pre-hospitalization (range 660-3,300). Pain: 7 to 4 on a 0-10 scale. Satisfaction: 6/7. Hospital stay: median 5 days (range 3-7). 3 patients had mild cough.","methodology":"Pilot open-label study of the SYQE Inhaler in hospitalized medical cannabis patients. Each dose delivered 500 micrograms THC from 16 mg cannabis. Patients received up to 4 scheduled and 4 as-needed doses daily. Pain, nausea, and satisfaction were assessed by questionnaire.","limitations":"Pilot study with no control group. Small sample size (not specified in abstract). Open-label design and self-reported outcomes. Patients were already experienced cannabis users, so results may not generalize to cannabis-naive patients."},{"rthcId":"RTHC-02901","title":"Efficacy and safety of topical capsaicin for cannabinoid hyperemesis syndrome in the emergency department.","authors":"Wagner, Samantha; Hoppe, Jason; Zuckerman, Matthew; Schwarz, Kerry; McLaughlin, Julie","year":2020,"journal":"Clinical toxicology (Philadelphia, Pa.), 58(6), 471-475","doi":"10.1080/15563650.2019.1660783","pmid":"31482758","tags":["harm-reduction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"ED length of stay was reduced by a median of 22 minutes with capsaicin but this was not statistically significant. Capsaicin-treated patients received fewer additional medication doses (3 vs. 4, p=0.015), and 67% required no further treatment. Opioid use was lower in the capsaicin group (69 vs. 166.5 mg oral morphine equivalents). 42% had no repeat ED visit for CHS in the following 3 months.","whyItMatters":"CHS is notoriously difficult to treat with standard antiemetics. Topical capsaicin is inexpensive, available over-the-counter, and could reduce opioid use in a population that frequently presents to emergency departments.","specificNumbers":"43 patients. ED LOS: 179 vs. 201 minutes (not significant, p=0.33). Fewer additional medications: 3 vs. 4 doses (p=0.015). 67% needed no further treatment after capsaicin. Opioid use: 69 vs. 166.5 mg OME. Cost difference: $3.26 more for capsaicin. No significant adverse events.","methodology":"Retrospective cohort analysis of 43 patients presenting with CHS. Compared ED visits where capsaicin was used versus visits without capsaicin. Outcomes included ED length of stay, rescue medication use, opioid requirements, costs, and adverse events.","limitations":"Retrospective design with a small sample. No randomization or blinding. Some patients served as their own controls across visits, but confounders were not fully controlled. The p-value for the primary outcome (LOS) was not significant."},{"rthcId":"RTHC-02902","title":"A systematic review and Bayesian meta-analysis of interventions which target or assess co-use of tobacco and cannabis in single- or multi-substance interventions.","authors":"Walsh, Hannah; McNeill, Ann; Purssell, Edward; Duaso, Maria","year":2020,"journal":"Addiction (Abingdon, England), 115(10), 1800-1814","doi":"10.1111/add.14993","pmid":"32003088","tags":["addiction","quitting","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Meta-analysis of 11 RCTs (up to 1,117 participants) showed weak evidence for cannabis cessation (RR=1.48, CrI 0.92-2.49) and no clear effect on tobacco cessation (RR=1.10, CrI 0.68-1.87). Multi-substance interventions appeared more effective for cannabis cessation than cannabis-only interventions (RR=2.19 vs. 1.39). A significant effect was found for cannabis reduction but not tobacco reduction.","whyItMatters":"Tobacco and cannabis are frequently co-used, and quitting one may be harder when still using the other. This review highlights that current interventions have limited effectiveness for co-users, signaling a need for better-designed dual-substance programs.","specificNumbers":"20 studies included. 12 RCTs and 8 uncontrolled studies. Up to 1,117 participants in meta-analysis. Cannabis cessation RR=1.48. Tobacco cessation RR=1.10. Multi-substance interventions for cannabis cessation: RR=2.19.","methodology":"Systematic review with Bayesian meta-analysis using informative priors. Five databases searched. 20 studies included (12 RCTs, 8 uncontrolled). Outcomes: cessation and reduction of both tobacco and cannabis.","limitations":"Most included studies had small samples. Cannabis use measurement was not standardized across studies. Bayesian approach relies on prior assumptions. Moderate quality of evidence overall."},{"rthcId":"RTHC-02903","title":"Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling.","authors":"Walsh, Kenneth B; Andersen, Haley K","year":2020,"journal":"International journal of molecular sciences, 21(17)","doi":"10.3390/ijms21176115","pmid":"32854313","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02904","title":"Marijuana exposures in Colorado, reported to regional poison centre, 2000-2018.","authors":"Wang, George Sam; Banerji, Shireen; Contreras, Alexandra Elyse; Hall, Katelyn E","year":2020,"journal":"Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention, 26(2), 184-186","doi":"10.1136/injuryprev-2019-043360","pmid":"31676510","tags":["youth","legalization","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Total marijuana exposures increased by 11.2 cases per year overall (p<0.0001) but remained stable from 2014-2017 (p=0.22), with a 19.4% increase in 2018 vs. 2017. Since 2014, the largest increase was in children ages 0-8 (p<0.0001). Edible exposures increased by 9.6 per year from 2015-2018 (p=0.04).","whyItMatters":"While overall marijuana exposures stabilized after legalization, the continued rise in pediatric exposures, especially from edibles, signals an ongoing child safety concern that regulatory efforts have not fully addressed.","specificNumbers":"2,221 total exposures from 2000-2018. 11.2 cases/year increase overall. Stable 2014-2017. 19.4% increase in 2018 vs. 2017. Children 0-8: significant continued increase (p<0.0001). Edibles: +9.6 exposures/year 2015-2018 (p=0.04).","methodology":"Analysis of 2,221 marijuana exposure cases reported to the Colorado Regional Poison Center from January 2000 through December 2018 using generic marijuana exposure codes. Trend analysis by age group and product type.","limitations":"Poison center data captures only reported exposures, likely underestimating total incidents. Cannot determine severity from exposure counts alone. Single-state data may not generalize to other jurisdictions with different regulations."},{"rthcId":"RTHC-02905","title":"Different receptor mechanisms underlying phytocannabinoid- versus synthetic cannabinoid-induced tetrad effects: Opposite roles of CB1 /CB2 versus GPR55 receptors.","authors":"Wang, Xiao-Fei; Galaj, Ewa; Bi, Guo-Hua; Zhang, Cindy; He, Yi; Zhan, Jia; Bauman, Michael H; Gardner, Eliot L; Xi, Zheng-Xiong","year":2020,"journal":"British journal of pharmacology, 177(8), 1865-1880","doi":"10.1111/bph.14958","pmid":"31877572","tags":["neuroscience","synthetic-cannabinoids"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 deletion abolished tetrad effects for all three cannabinoids. CB2 deletion abolished THC and WIN55,212-2 analgesia and catalepsy but not XLR11's. GPR55 deletion enhanced responses to THC and WIN55,212-2. These findings held for both systemic and central (intraventricular) administration.","whyItMatters":"The assumption that all cannabinoid effects are mediated solely through CB1 is incomplete. Plant cannabinoids and synthetic cannabinoids may engage different receptor combinations, which has implications for both therapeutic development and understanding synthetic cannabinoid toxicity.","specificNumbers":"Three cannabinoids tested across four mouse genotypes. CB2 knockout abolished THC analgesia and catalepsy but not XLR11's. GPR55 knockout enhanced responses to phytocannabinoids. Pharmacological results matched genetic findings.","methodology":"Compared tetrad effects (analgesia, hypothermia, catalepsy, locomotor suppression) of THC, WIN55,212-2, and XLR11 in wildtype, CB1-knockout, CB2-knockout, and GPR55-knockout mice. Pharmacological antagonists confirmed genetic findings.","limitations":"Animal study using knockout mice, which may develop compensatory mechanisms. Only three cannabinoids tested from a large and diverse class. Tetrad effects are a simplified measure of cannabinoid pharmacology."},{"rthcId":"RTHC-02906","title":"Subacute cannabidiol alters genome-wide DNA methylation in adult mouse hippocampus.","authors":"Wanner, Nicole M; Colwell, Mathia; Drown, Chelsea; Faulk, Christopher","year":2020,"journal":"Environmental and molecular mutagenesis, 61(9), 890-900","doi":"10.1002/em.22396","pmid":"32579259","tags":["cbd","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD-treated mice had 3,323 differentially methylated loci with a slight skew toward global hypomethylation. Enrichment analysis found affected genes were involved in cell adhesion, dendritic spine development, and excitatory postsynaptic potential. Disease ontology showed overrepresentation in gene sets associated with autism spectrum disorder and schizophrenia.","whyItMatters":"If CBD changes DNA methylation patterns in the brain, this could be a mechanism underlying its behavioral effects and could have implications for long-term use, including potential risks and benefits that persist after CBD is discontinued.","specificNumbers":"3,323 differentially methylated loci. Slight skew toward hypomethylation. 20 mg/kg CBD daily for 14 days. Enrichment in gene sets for autism, schizophrenia, and neural development.","methodology":"12-week-old male mice received 20 mg/kg CBD or vehicle daily by oral administration for 14 days. Hippocampal tissue was analyzed using reduced-representation bisulfite sequencing (RRBS) to map genome-wide DNA methylation changes.","limitations":"Animal study with only 14 days of exposure. Only male mice studied. Hippocampus was the only brain region examined. The biological significance of the methylation changes (whether they alter gene expression or behavior) was not tested."},{"rthcId":"RTHC-02907","title":"High fat-fed GPR55 null mice display impaired glucose tolerance without concomitant changes in energy balance or insulin sensitivity but are less responsive to the effects of the cannabinoids rimonabant or Δ(9)-tetrahydrocannabivarin on weight gain.","authors":"Wargent, Edward T; Kepczynska, Malgorzata; Zaibi, Mohamed Sghaier; Hislop, David C; Arch, Jonathan R S; Stocker, Claire J","year":2020,"journal":"PeerJ, 8, e9811","doi":"10.7717/peerj.9811","pmid":"32904155","tags":["neuroscience","appetite","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"GPR55 knockout mice had worse glucose tolerance than wildtype mice on both standard and high-fat diets, despite no differences in body weight, composition, food intake, or energy expenditure. Weight loss from rimonabant and THCV was reduced in knockout mice, suggesting GPR55 partially mediates their anti-obesity effects. Surprisingly, genotype did not affect these drugs' effects on glucose homeostasis.","whyItMatters":"GPR55 is an emerging cannabinoid receptor target. Understanding its role in metabolism could lead to new treatments for obesity and diabetes that work through the broader endocannabinoid system without the psychiatric side effects of CB1 blockers.","specificNumbers":"GPR55 knockouts had impaired glucose tolerance in both experiments. No genotype effect on body weight, composition, food intake, or energy expenditure. THCV (15 mg/kg) and rimonabant (10 mg/kg) produced less weight loss in knockouts. No genotype effect on drugs' glucose homeostasis effects.","methodology":"GPR55 knockout and wildtype mice studied on standard chow and high-fat diets. Body weight, composition (DEXA and NMR), food intake, energy expenditure, locomotor activity, and glucose/insulin tolerance were measured. THCV (15 mg/kg) and rimonabant (10 mg/kg) were administered daily to both genotypes.","limitations":"Knockout mice may have developmental compensatory mechanisms. Only male mice appear to have been studied. The disconnect between glucose tolerance and insulin tolerance findings is unexplained. Drug effects on glucose were not genotype-dependent despite effects on weight."},{"rthcId":"RTHC-02908","title":"Chronic cannabidiol (CBD) treatment did not exhibit beneficial effects in 4-month-old male TAU58/2 transgenic mice.","authors":"Watt, Georgia; Chesworth, Rose; Przybyla, Magdalena; Ittner, Arne; Garner, Brett; Ittner, Lars M; Karl, Tim","year":2020,"journal":"Pharmacology, biochemistry, and behavior, 196, 172970","doi":"10.1016/j.pbb.2020.172970","pmid":"32562718","tags":["cbd","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"TAU58/2 transgenic mice showed reduced body weight, reduced anxiety, impaired motor function, and increased freezing in fear conditioning compared to wildtype. Social recognition memory was intact. Chronic CBD (50 mg/kg i.p. for 3+ weeks) did not affect any behavioral measures in transgenic males.","whyItMatters":"While CBD has shown benefits in amyloid-based Alzheimer's mouse models, this study suggests it may not be equally effective in tau-based models, highlighting that Alzheimer's pathology type matters for treatment selection.","specificNumbers":"50 mg/kg CBD administered i.p. daily. Started 3 weeks before behavioral testing. No significant effects on any behavioral measure in transgenic mice. TAU58/2 mice showed intact social recognition despite other deficits.","methodology":"Open-label study of 4-month-old male TAU58/2 transgenic mice and wildtype controls. CBD (50 mg/kg) or vehicle administered intraperitoneally starting 3 weeks before behavioral testing. Assessed anxiety, motor function, fear conditioning, sociability, and social recognition.","limitations":"Only one dose (50 mg/kg) and one administration route (i.p.) tested. Only male mice at one age (4 months). The mice may have been too young for full tau pathology to develop. No brain tissue analysis to confirm whether CBD reached relevant brain regions or affected tau levels."},{"rthcId":"RTHC-02909","title":"Imaging Brain Fatty Acid Amide Hydrolase in Untreated Patients With Psychosis.","authors":"Watts, Jeremy J; Jacobson, Maya R; Lalang, Nittha; Boileau, Isabelle; Tyndale, Rachel F; Kiang, Michael; Ross, Ruth A; Houle, Sylvain; Wilson, Alan A; Rusjan, Pablo; Mizrahi, Romina","year":2020,"journal":"Biological psychiatry, 88(9), 727-735","doi":"10.1016/j.biopsych.2020.03.003","pmid":"32387132","tags":["psychosis","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"FAAH did not differ significantly between 27 patients with psychotic disorders and 36 healthy controls. However, within patients, lower FAAH predicted greater positive symptom severity (p=0.002, Cohen's f=0.42). Shorter illness duration and shorter duration of untreated psychosis also predicted lower FAAH. Results were independent of past cannabis exposure.","whyItMatters":"FAAH controls brain levels of anandamide, which is elevated in psychosis. This study suggests FAAH may be a biomarker for active psychotic symptom severity and a potential therapeutic target, independent of cannabis use history.","specificNumbers":"27 patients, 36 controls. No group difference in FAAH (p=0.49). Lower FAAH predicted positive symptoms (p=0.002, Cohen's f=0.42, large effect). Shorter illness duration predicted lower FAAH (p=0.001). FAAH higher in females (p=0.002). Marked regional brain differences (p<10^-56).","methodology":"PET imaging study using [11C]CURB radioligand in 27 patients with schizophrenia spectrum disorders and 36 healthy controls. Structural MRI for anatomical reference. Irreversible 2-tissue compartment model with arterial input function for quantification.","limitations":"Cross-sectional design cannot determine causation. Small patient sample. Some patients were taking antipsychotics though this did not explain findings. PET imaging is expensive and not practical for routine clinical use."},{"rthcId":"RTHC-02910","title":"Cigarette smoking quit ratios among adults in the USA with cannabis use and cannabis use disorders, 2002-2016.","authors":"Weinberger, Andrea H; Pacek, Lauren R; Wall, Melanie M; Gbedemah, Misato; Lee, Joun; Goodwin, Renee D","year":2020,"journal":"Tobacco control, 29(1), 74-80","doi":"10.1136/tobaccocontrol-2018-054590","pmid":"30952691","tags":["addiction","quitting","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In 2016, quit ratios were 23% for any cannabis users and 15% for those with CUD, versus 51% for non-cannabis users and 48% for those without CUD. After controlling for demographics and other substance use, quit ratios did not change from 2002-2016 among people with CUD, while they increased for most other groups.","whyItMatters":"While cigarette smoking rates have declined nationally, people with cannabis use disorders have not benefited from this trend. This widening gap suggests current cessation strategies are failing dual users.","specificNumbers":"2016 quit ratios: cannabis users 23%, CUD 15%, no cannabis 51%, no CUD 48%. Quit ratios for CUD: unchanged 2002-2016. Past-month cannabis users had faster increases in quit ratios than non-users.","methodology":"Analysis of annual cross-sectional data from the National Survey on Drug Use and Health (2002-2016) among US adults aged 18+. Quit ratios (proportion of former smokers among ever-smokers) calculated annually and trends tested using logistic regression.","limitations":"Cross-sectional annual surveys cannot track individuals over time. Self-reported smoking and cannabis use. Cannot determine whether cannabis use causally prevents smoking cessation or whether shared risk factors drive both."},{"rthcId":"RTHC-02911","title":"Perceptions of Marijuana Use for Glaucoma from Patients, Cannabis Retailers, and Glaucoma Specialists.","authors":"Weldy, Eric W; Stanley, Jordan; Koduri, Vivek A; McCourt, Emily A; Patnaik, Jennifer L; Kahook, Malik Y; Seibold, Leonard K","year":2020,"journal":"Ophthalmology. Glaucoma, 3(6), 453-459","doi":"10.1016/j.ogla.2020.06.009","pmid":"32782211","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"51% of 203 contacted dispensaries recommended marijuana for glaucoma. Only 7.6% of 290 glaucoma specialist respondents had recommended it, mostly infrequently (86.4% of those who did). Among 231 glaucoma patients, 58.9% had heard about cannabis for glaucoma but only 2.6% had used it as treatment.","whyItMatters":"The gap between dispensary recommendations and medical evidence creates confusion for patients. While cannabis can transiently lower eye pressure, it is not recommended as a glaucoma treatment due to short duration and side effects, yet patients encounter conflicting information.","specificNumbers":"203 of 300 dispensaries contacted (68%). 51% recommended cannabis for glaucoma. 290 of 1,308 AGS members responded (22%). 7.6% had recommended cannabis. 231 glaucoma patients surveyed. 58.9% aware of cannabis for glaucoma. 2.6% used it as treatment.","methodology":"Three cross-sectional surveys conducted October 2018-March 2019 in Colorado: mystery calls to 300 dispensaries, self-administered survey to 1,308 American Glaucoma Society members, and patient survey at University of Colorado glaucoma clinic.","limitations":"Mystery call approach may not capture nuanced dispensary advice. Low response rate from glaucoma specialists (22%). Single state study in a legalized market. Patient survey from one academic clinic may not represent all glaucoma patients."},{"rthcId":"RTHC-02912","title":"Occupational Exposure to Secondhand Cannabis Smoke Among Law Enforcement Officers Providing Security at Outdoor Concert Events.","authors":"Wiegand, Douglas M; Methner, Mark M; Grimes, George Reed; Couch, James R; Wang, Lanqing; Zhang, Li; Blount, Benjamin C","year":2020,"journal":"Annals of work exposures and health, 64(7), 705-714","doi":"10.1093/annweh/wxaa025","pmid":"32219297","tags":["workplace","legalization","driving"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"THC was detected in personal air samples (53-480 ng/m3) and area samples (up to 330 ng/m3). A THC metabolite (THC-COOH) was found in post-event urine of 34% of officers, but at concentrations orders of magnitude below the 50 ng/mL drug-screening cutoff. No THC or metabolites were detected in any blood sample. 31% reported eye irritation, 21% dry mouth, 21% headache.","whyItMatters":"As cannabis legalization expands, workers in entertainment, security, and law enforcement face occupational secondhand exposure. This study provides the first data on real-world workplace exposure levels at outdoor events.","specificNumbers":"29 officers. Personal air THC: 53-480 ng/m3. 34% had THC-COOH in post-event urine (<1.0 ng/mL vs. 50 ng/mL cutoff). 0% blood positives. Symptoms: eye irritation 31%, dry mouth 21%, headache 21%, coughing 21%.","methodology":"Convenience sample of 29 law enforcement officers at two outdoor stadium concerts in July 2018 in a legal cannabis state. Personal and area air sampling for THC. Pre- and post-event urine (n=58) and post-event blood (n=29) analyzed by UHPLC-MS/MS and HPLC-MS.","limitations":"Convenience sample of only 29 officers at two concerts at one venue. Outdoor setting may underestimate exposure at indoor events. Blood detection limits may have been too high to detect very low concentrations. Symptoms were self-reported."},{"rthcId":"RTHC-02913","title":"Cannabidiol for Adjuvant Treatment of Seizures Associated with Lennox-Gastaut Syndrome and Dravet Syndrome: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.","authors":"Wijnen, Ben; Armstrong, Nigel; Ramaekers, Bram; Witlox, Willem; Westwood, Marie; Fayter, Debra; Ryder, Steve; Buksnys, Titas; Worthy, Gill; Misso, Kate; Grimm, Sabine; Kleijnen, Jos; Joore, Manuela","year":2020,"journal":"PharmacoEconomics, 38(10), 1043-1053","doi":"10.1007/s40273-020-00932-4","pmid":"32514751","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02914","title":"Peripheral versus central mechanisms of the cannabinoid type 2 receptor agonist AM1710 in a mouse model of neuropathic pain.","authors":"Wilkerson, Jenny L; Alberti, Lauren B; Kerwin, Audra A; Ledent, Catherine A; Thakur, Ganesh A; Makriyannis, Alexandros; Milligan, Erin D","year":2020,"journal":"Brain and behavior, 10(12), e01850","doi":"10.1002/brb3.1850","pmid":"32977358","tags":["pain","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AM1710 reversed mechanical allodynia to sham levels in CB1 knockout, heterozygous, and wildtype mice via both peripheral (i.p.) and spinal (i.t.) routes. Spinal AM1710 restored IL-10 immunoreactivity in dorsal root ganglia and spinal cord, and reduced pro-inflammatory cytokines. In cell cultures, AM1710 suppressed TNF-alpha production by macrophages.","whyItMatters":"CB2 agonists that work independently of CB1 could provide pain relief without the psychoactive effects, euphoria, or abuse potential associated with CB1 activation, addressing a major limitation of current cannabinoid therapies.","specificNumbers":"AM1710 reversed allodynia to sham levels across all three CB1 genotypes. IL-10 was restored by intrathecal administration. Pro-inflammatory cytokines were reduced in spinal cord (i.t. only) and DRG (both i.p. and i.t.).","methodology":"Chronic constriction injury model of neuropathic pain in CB1 receptor knockout, heterozygous, and wildtype mice. AM1710 administered intraperitoneally or intrathecally. Immunoreactivity for IL-10 and pro-inflammatory cytokines measured in spinal cord and dorsal root ganglia. Macrophage cultures used for in vitro validation.","limitations":"Mouse model of neuropathic pain may not fully represent human conditions. Knockout mice may develop compensatory mechanisms. Only one CB2 agonist tested. Long-term effects and tolerance were not assessed."},{"rthcId":"RTHC-02915","title":"Cannabis as a Gateway Drug for Opioid Use Disorder.","authors":"Williams, Arthur Robin","year":2020,"journal":"The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics, 48(2), 268-274","doi":"10.1177/1073110520935338","pmid":"32631185","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02916","title":"Development of cannabidiol as a treatment for severe childhood epilepsies.","authors":"Williams, Claire M; Stephens, Gary J","year":2020,"journal":"British journal of pharmacology, 177(24), 5509-5517","doi":"10.1111/bph.15274","pmid":"32986848","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02917","title":"Cannabis Use in Children With Pantothenate Kinase-Associated Neurodegeneration.","authors":"Wilson, Jenny L; Gregory, Allison; Wakeman, Katrina; Freed, Alison; Rai, Puneet; Roberts, Colin; Hayflick, Susan J; Hogarth, Pennylope","year":2020,"journal":"Journal of child neurology, 35(4), 259-264","doi":"10.1177/0883073819890516","pmid":"31823681","tags":["medical-cannabis","pain","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"7 of 18 respondents (39%) had used cannabis for their child. Cannabis users were on more medications, more likely to have used opiates, and had greater physical impairment. Four children reported moderate or significant improvement in dystonia, 3 in pain, 4 in sleep, 3 in anxiety, and 2 in behavior. Adverse effects were mild (sadness, agitation, tiredness in 1 each).","whyItMatters":"Children with rare neurodegenerative diseases and severe dystonia often exhaust standard treatments. This survey reveals that families are turning to cannabis and reporting benefits, highlighting the need for controlled studies in pediatric movement disorders.","specificNumbers":"18 of 44 families responded. 7 (39%) used cannabis. Mean age 11 years. Cannabis users on median 2 tone medications (range 0-9). Improvements reported: dystonia (4), pain (3), sleep (4), anxiety (3), behavior (2). Adverse effects in 3 children.","methodology":"Cross-sectional 37-item survey distributed to families of 44 children in a clinical registry of pantothenate kinase-associated neurodegeneration. 18 responses (41% response rate). Cannabis use, sources of information, symptom changes, and adverse effects collected.","limitations":"Very small sample (18 respondents, 7 cannabis users). Survey response bias likely favoring families with strong opinions about cannabis. No objective outcome measures. No control group for comparison."},{"rthcId":"RTHC-02918","title":"The association between regular cannabis use, with and without tobacco co-use, and adverse cardiovascular outcomes: cannabis may have a greater impact in non-tobacco smokers.","authors":"Winhusen, Theresa; Theobald, Jeff; Kaelber, David C; Lewis, Daniel","year":2020,"journal":"The American journal of drug and alcohol abuse, 46(4), 454-461","doi":"10.1080/00952990.2019.1676433","pmid":"31743053","tags":["cardiovascular","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"In the total sample and non-tobacco subgroup, regular cannabis use was significantly associated with greater risk for stroke (CVA), arrhythmia, subarachnoid hemorrhage (SAH), and all-cause mortality. Among tobacco users, cannabis was only associated with greater risk for arrhythmia and SAH. Tobacco users had the highest overall cardiovascular disease prevalence regardless of cannabis status.","whyItMatters":"The finding that cannabis cardiovascular risks are more apparent in non-tobacco users suggests cannabis is an independent cardiovascular risk factor whose effects may be masked in tobacco users by their already-elevated baseline risk.","specificNumbers":"8,944 cannabis users matched to controls. 4,682 with tobacco use disorder, 4,262 without. Non-tobacco cannabis users: significant associations with CVA, arrhythmia, SAH, and mortality. Tobacco-using cannabis users: significant for arrhythmia and SAH only.","methodology":"Retrospective analysis of electronic health records via IBM Watson Health Explorys. 8,944 cannabis-using patients matched to controls using propensity scores on demographics, zip code income, BMI, and tobacco status. Subgroup analyses for tobacco users (n=4,682) and non-tobacco users (n=4,262).","limitations":"Retrospective EHR data from a single health system (Cleveland). Cannabis use identified by diagnosis codes and drug screens, which may undercount casual users. Cannot establish causation. Unmeasured confounders possible despite matching."},{"rthcId":"RTHC-02919","title":"Prenatal cannabis exposure and sleep outcomes in children 9-10 years of age in the adolescent brain cognitive development SM study.","authors":"Winiger, Evan A; Hewitt, John K","year":2020,"journal":"Sleep health, 6(6), 787-789","doi":"10.1016/j.sleh.2020.05.006","pmid":"32605891","tags":["pregnancy","sleep","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Any prenatal cannabis exposure was associated with disorders of initiating and maintaining sleep, disorders of arousal, sleep-wake disorders, disorders of excessive somnolence, and a summed sleep disorder score (all p<0.03). Daily prenatal cannabis use was specifically associated with excessive daytime sleepiness (beta=0.29, p=0.03). All associations controlled for other prenatal substance exposures and demographic factors.","whyItMatters":"Sleep disturbances in childhood affect cognitive development, behavior, and health. If prenatal cannabis exposure contributes to persistent sleep problems, it adds urgency to counseling pregnant individuals about cannabis use.","specificNumbers":"11,875 children studied. Prenatal cannabis exposure associated with multiple sleep disorder categories (all beta>0.10, p<0.03). Daily prenatal cannabis use associated with excessive somnolence (beta=0.29, p=0.03).","methodology":"Analysis of 11,875 children ages 9-10 from the Adolescent Brain Cognitive Development (ABCD) Study. Maternal reports of prenatal cannabis use. Child sleep outcomes assessed by parent report. Controlled for prenatal exposure to other substances, maternal education, income, marital status, race, child sex, and age.","limitations":"Cross-sectional analysis within a longitudinal study cannot establish causation. Maternal cannabis use was retrospectively self-reported, subject to recall bias. Sleep outcomes were parent-reported, not objectively measured. Residual confounding possible despite controlling for multiple factors."},{"rthcId":"RTHC-02920","title":"The Role of the Cannabinoid System in Pain Control: Basic and Clinical Implications.","authors":"Wolf, John; Urits, Ivan; Orhurhu, Vwaire; Peck, Jacquelin; Orhurhu, Mariam Salisu; Giacomazzi, Stephen; Smoots, Daniel; Piermarini, Charlie; Manchikanti, Laxmaiah; Kaye, Alan D; Kaye, Rachel J; Viswanath, Omar","year":2020,"journal":"Current pain and headache reports, 24(7), 35","doi":"10.1007/s11916-020-00873-9","pmid":"32506272","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02921","title":"Children and Youth Who Use Cannabis for Pain Relief: Benefits, Risks, and Perceptions.","authors":"Woo, Julia J; van Reekum, Emma A; Rosic, Tea; Samaan, Zainab","year":2020,"journal":"Adolescent health, medicine and therapeutics, 11, 53-61","doi":"10.2147/AHMT.S254264","pmid":"32547283","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02922","title":"Assessment of Biased Agonism among Distinct Synthetic Cannabinoid Receptor Agonist Scaffolds.","authors":"Wouters, Elise; Walraed, Jolien; Robertson, Michael Joseph; Meyrath, Max; Szpakowska, Martyna; Chevigné, Andy; Skiniotis, Georgios; Stove, Christophe","year":2020,"journal":"ACS pharmacology & translational science, 3(2), 285-295","doi":"10.1021/acsptsci.9b00069","pmid":"32296768","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02923","title":"The Changing Legal Landscape of Cannabis Use and Its Role in Youth-onset Psychosis.","authors":"Wright, Abigail; Cather, Corinne; Gilman, Jodie; Evins, Anne Eden","year":2020,"journal":"Child and adolescent psychiatric clinics of North America, 29(1), 145-156","doi":"10.1016/j.chc.2019.08.016","pmid":"31708043","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02924","title":"Canadian clinical practice guidelines for the use of plant-based cannabis and cannabinoid-based products in the management of chronic non-cancer pain and co-occurring conditions: protocol for a systematic literature review.","authors":"Wright, Patrick; Walsh, Zach; Margolese, Shari; Sanchez, Tatiana; Arlt, Stephanie; Belle-Isle, Lynne; St Pierre, Michelle; Bell, Alan; Daeninck, Paul; Gagnon, Marilou; Lacasse, Gary; MacCallum, Caroline; Mandarino, Enrico; Yale, Janet; O'Hara, James; Costiniuk, Cecilia","year":2020,"journal":"BMJ open, 10(5), e036114","doi":"10.1136/bmjopen-2019-036114","pmid":"32448797","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02925","title":"Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.","authors":"Wyatt, Ryan M; Fraser, Ian; Welty, Natalie; Lord, Brian; Wennerholm, Michelle; Sutton, Steven; Ameriks, Michael K; Dugovic, Christine; Yun, Sujin; White, Allison; Nguyen, Leslie; Koudriakova, Tatiana; Tian, Gaochao; Suarez, Javier; Szewczuk, Lawrence; Bonnette, William; Ahn, Kay; Ghosh, Brahma; Flores, Christopher M; Connolly, Peter J; Zhu, Bin; Macielag, Mark J; Brandt, Michael R; Chevalier, Kristen; Zhang, Sui-Po; Lovenberg, Timothy; Bonaventure, Pascal","year":2020,"journal":"The Journal of pharmacology and experimental therapeutics, 372(3), 339-353","doi":"10.1124/jpet.119.262139","pmid":"31818916","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02926","title":"Heterogeneous Ozonolysis of Tetrahydrocannabinol: Implications for Thirdhand Cannabis Smoke.","authors":"Wylie, Aaron D L; Abbatt, Jonathan P D","year":2020,"journal":"Environmental science & technology, 54(22), 14215-14223","doi":"10.1021/acs.est.0c03728","pmid":"33147000","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02927","title":"Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex.","authors":"Xing, Changrui; Zhuang, Youwen; Xu, Ting-Hai; Feng, Zhiwei; Zhou, X Edward; Chen, Maozi; Wang, Lei; Meng, Xing; Xue, Ying; Wang, Junmei; Liu, Heng; McGuire, Terence Francis; Zhao, Gongpu; Melcher, Karsten; Zhang, Cheng; Xu, H Eric; Xie, Xiang-Qun","year":2020,"journal":"Cell, 180(4), 645-654.e13","doi":"10.1016/j.cell.2020.01.007","pmid":"32004460","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02928","title":"Women's Questions About Perinatal Cannabis Use and Health Care Providers' Responses.","authors":"Young-Wolff, Kelly C; Gali, Kathleen; Sarovar, Varada; Rutledge, Geoffrey W; Prochaska, Judith J","year":2020,"journal":"Journal of women's health (2002), 29(7), 919-926","doi":"10.1089/jwh.2019.8112","pmid":"32011205","tags":["pregnancy","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The most common questions concerned drug test detection (24.7%), fertility effects (22.6%), fetal harms (21.3%), and breastfeeding exposure (14.4%). Provider responses were 55.6% harmful, 8.8% safe, 8.8% mixed, and 26.8% did not address safety. 49.6% discouraged use, 0.5% encouraged it, and 49.9% neither encouraged nor discouraged. Responses calling cannabis unsafe received more peer provider endorsements.","whyItMatters":"Pregnant and breastfeeding individuals increasingly seek cannabis information online. When nearly half of licensed provider responses fail to discourage perinatal cannabis use, it represents a significant missed opportunity for public health education.","specificNumbers":"364 questions, 596 responses from 277 providers. Safety: 55.6% harmful, 8.8% safe, 8.8% mixed, 26.8% unaddressed. Discouragement: 49.6% discouraged, 0.5% encouraged, 49.9% neutral. 1,004 provider agrees, 583 user thanks.","methodology":"Analysis of 364 user questions and 596 health care provider responses posted on an anonymous digital health platform from March 2011 to January 2017. Provider sentiment coded for safety messaging and encouragement/discouragement. Endorsement measured through provider \"agrees\" and user \"thanks.\"","limitations":"Online platform responses may not represent in-person clinical advice. Questions were posted 2011-2017 and attitudes may have shifted. Coding of provider sentiment involves subjective judgment. Platform users may not be representative of all pregnant individuals."},{"rthcId":"RTHC-02929","title":"Cannabis-Associated Psychotic-like Experiences Are Mediated by Developmental Changes in the Parahippocampal Gyrus.","authors":"Yu, Tao; Jia, Tianye; Zhu, Liping; Desrivières, Sylvane; Macare, Christine; Bi, Yan; Bokde, Arun L W; Quinlan, Erin Burke; Heinz, Andreas; Ittermann, Bernd; Liu, ChuanXin; Ji, Lei; Banaschewski, Tobias; Ren, Decheng; Du, Li; Hou, Binyin; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Martinot, Jean-Luc; Paillère Martinot, Marie-Laure; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Luo, Qiang; Chu, Congying; Paus, Tomas; Poustka, Luise; Hohmann, Sarah; Millenet, Sabina; Smolka, Michael N; Vetter, Nora C; Mennigen, Eva; Lei, Cai; Walter, Henrik; Fröhner, Juliane H; Whelan, Robert; He, Guang; He, Lin; Schumann, Gunter; Robert, Gabriel","year":2020,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 59(5), 642-649","doi":"10.1016/j.jaac.2019.05.034","pmid":"31326579","tags":["psychosis","youth","neuroscience"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Psychotic-like experiences were associated with reduced expansion of the right uncus between ages 14 and 19 (p=0.002). A mediation analysis showed a significant total effect of cannabis use on psychotic-like experiences (b=0.069, p<0.001), with a small but significant indirect effect through uncus development (0.004, 95% CI 0.0004-0.01, p=0.026).","whyItMatters":"This study identifies a specific brain structural change that partly explains how cannabis use during adolescence may contribute to psychotic-like experiences, providing a biological mechanism for a well-documented epidemiological association.","specificNumbers":"706 adolescents scanned at 14 and 19. Significant association between PLEs and reduced right uncus expansion (p=0.002 cluster, p=0.018 peak). Total cannabis-to-PLE effect: b=0.069, p<0.001. Indirect effect through uncus: 0.004, p=0.026.","methodology":"Longitudinal neuroimaging study of 706 adolescents from the IMAGEN consortium with structural MRI at ages 14 and 19. Deformation-based morphometry mapped brain changes. Cannabis use assessed with ESPAD, psychotic-like experiences with CAPE questionnaire. A priori mediation model tested.","limitations":"The mediation effect through the uncus was small, suggesting other pathways are also important. Observational study cannot establish causation. Cannabis use was self-reported. Only two imaging time points. Sample was from the general population with subclinical symptoms, not patients with psychotic disorders."},{"rthcId":"RTHC-02930","title":"Inverse Agonism of Cannabinoid Receptor Type 2 Confers Anti-inflammatory and Neuroprotective Effects Following Status Epileptics.","authors":"Yu, Ying; Li, Lexiao; Nguyen, Davis T; Mustafa, Suni M; Moore, Bob M; Jiang, Jianxiong","year":2020,"journal":"Molecular neurobiology, 57(6), 2830-2845","doi":"10.1007/s12035-020-01923-4","pmid":"32378121","tags":["epilepsy","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Status epilepticus downregulated CB1 but slightly upregulated CB2 in the hippocampus. Treatment with SMM-189 (6 mg/kg twice daily) after seizure termination prevented the brain cytokine surge, reduced neuronal death, and improved behavioral outcomes at 24 hours. SMM-189 also suppressed microglial inflammation in vitro and showed moderate neuroprotection against excitotoxicity in hippocampal cultures.","whyItMatters":"Current epilepsy emergency treatment focuses on stopping seizures quickly. A follow-on therapy that reduces brain damage even when given after seizures have been controlled could significantly improve outcomes for status epilepticus survivors.","specificNumbers":"CB1 downregulated, CB2 slightly upregulated after SE. SMM-189 at 6 mg/kg i.p. twice daily. Prevented cytokine surge. Reduced neuronal death. Improved behavioral measures at 24 hours post-SE.","methodology":"Kainate-induced status epilepticus in mice, terminated by diazepam after 1 hour. SMM-189 administered after seizure termination. Brain cytokines, neuronal survival, and behavior assessed at 24 hours. In vitro studies in rat primary microglia and hippocampal neuron-glia co-cultures.","limitations":"Mouse model with chemically induced seizures. Only 24-hour outcomes assessed. Single dose regimen tested. The paradoxical finding that CB2 inverse agonism (blocking constitutive activity) rather than agonism is beneficial needs further mechanistic exploration."},{"rthcId":"RTHC-02931","title":"Feline cognitive dysfunction as a model for Alzheimer's disease in the research of CBD as a potential treatment-a narrative review.","authors":"Zadik-Weiss, Lilach; Ritter, Sivan; Hermush, Vered; Asher, Nethanel; Avital, Avi; Or, Reuven","year":2020,"journal":"Journal of cannabis research, 2(1), 43","doi":"10.1186/s42238-020-00054-w","pmid":"33526138","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02932","title":"In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa.","authors":"Zagzoog, Ayat; Mohamed, Kawthar A; Kim, Hye Ji J; Kim, Eunhyun D; Frank, Connor S; Black, Tallan; Jadhav, Pramodkumar D; Holbrook, Larry A; Laprairie, Robert B","year":2020,"journal":"Scientific reports, 10(1), 20405","doi":"10.1038/s41598-020-77175-y","pmid":"33230154","tags":["neuroscience","cbd","potency"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC, THCA, THCV, CBD, CBDA, CBDV, CBG, and CBC were tested for receptor binding, cAMP inhibition, beta-arrestin2 recruitment, and in vivo effects. Multiple minor cannabinoids displayed partial agonist activity at CB1 and/or CB2. Several produced cannabinoid-like tetrad effects in mice (catalepsy, hypothermia, antinociception, hypolocomotion) and anxiolytic-like effects.","whyItMatters":"Most cannabis research focuses on THC and CBD, but cannabis contains over 120 cannabinoids. Understanding the pharmacology of minor compounds is essential for explaining whole-plant effects and developing targeted therapeutics.","specificNumbers":"8 phytocannabinoids tested. Multiple showed partial CB1R and/or CB2R agonist activity. In vivo tetrad effects and anxiolytic responses observed for several compounds.","methodology":"In vitro: CHO cells stably expressing human CB1R or CB2R tested for binding affinity, cAMP inhibition, beta-arrestin2 recruitment, and ligand bias. In vivo: C57BL/6 mice tested in the cannabinoid tetrad battery and elevated plus maze for anxiety.","limitations":"In vitro studies used overexpression cell systems that may not reflect physiological receptor levels. Mouse behavioral tests provide limited insight into human effects. Compounds were tested individually, not in combination as they occur in plant material."},{"rthcId":"RTHC-02933","title":"Cannabis knowledge and implications for health: Considerations regarding the legalization of non-medical cannabis.","authors":"Zamengo, Luca; Frison, Giampietro; Zwitser, Guus; Salomone, Alberto; Freeman, Tom P","year":2020,"journal":"Medicine, science, and the law, 60(4), 309-314","doi":"10.1177/0025802420934255","pmid":"32600171","tags":["legalization","youth","potency","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review synthesized what had been observed in jurisdictions that legalized recreational cannabis and found a consistent pattern: potency increased as commercial producers optimized for THC content, cannabis-related emergency department visits rose, and public perception of risk declined — particularly among young people.\n\nThe authors argued that legalization frameworks had primarily focused on market economics — creating legal supply chains, diverting profits from illegal markets, and reducing prohibition costs — while underweighting health and safety considerations. The language around commercial cannabis tended to trivialize risk, and increased visibility in public spaces contributed to normalization.\n\nThe paper called for regulation models that prioritized individual health and safety alongside market goals, including potency limits, restrictions on marketing, and better public education about dose-dependent risks.","whyItMatters":"This paper captured the gap between the promise of legalization and its early implementation. Legal cannabis was supposed to be safer cannabis — regulated, tested, labeled. But in practice, the market pushed potency higher (because that's what sells), risk perception dropped (because legal equals safe in many people's minds), and ER visits increased.\n\nNone of this means legalization was wrong. It means the regulatory frameworks weren't designed with health outcomes as the primary goal. The alcohol parallel is instructive: alcohol is legal, but its regulation has evolved over decades to include advertising restrictions, age limits, taxation, and impaired driving laws. Cannabis regulation was still in its early stages.","specificNumbers":"• Cannabis potency increased in jurisdictions with legal recreational markets\n• Cannabis-related ER visits increased post-legalization\n• Risk perception declined, particularly among adolescents and young adults\n• THC and CBD are the most studied of 100+ cannabinoids in the plant","methodology":"Narrative review examining post-legalization data on cannabis potency, emergency department presentations, risk perception surveys, and regulatory frameworks across jurisdictions with legal recreational cannabis. Published in Medicine, Science and the Law.","limitations":"Narrative review without systematic search methodology. Post-legalization trends may reflect increased reporting and detection rather than true increases in harm. The correlation between legalization and increased ER visits doesn't account for confounders like population growth, tourism, or changes in hospital coding. Different jurisdictions legalized under different rules, limiting generalizability."},{"rthcId":"RTHC-02934","title":"Attitudes about cannabis mediate the relationship between cannabis knowledge and use in active adult athletes.","authors":"Zeiger, Joanna S; Silvers, William S; Fleegler, Edward M; Zeiger, Robert S","year":2020,"journal":"Journal of cannabis research, 2(1), 18","doi":"10.1186/s42238-020-00023-3","pmid":"33526137","tags":["medical-cannabis","exercise","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Three attitude clusters emerged: Conservative (32.2%), Unsure (45.9%), and Liberal (21.9%). Attitudes significantly mediated the knowledge-to-use pathway. Liberal-attitude athletes answered knowledge questions correctly most often and were more likely to be current users. Among current users, liberal athletes tended to co-use THC and CBD and had used cannabis longer.","whyItMatters":"Understanding how knowledge and attitudes interact to influence cannabis behavior in athletes can help design more effective education programs, particularly as cannabis becomes available for pain management and recovery.","specificNumbers":"1,161 athletes. Three clusters: Conservative 32.2%, Unsure 45.9%, Liberal 21.9%. Attitude clusters differed by age (p<0.001), primary sport (p<0.05), and knowledge (p<0.001). Cannabis use: Never 32.4%, Past 41.6%, Current 26.0%.","methodology":"Cross-sectional survey (PEACE Survey) of 1,161 self-defined active adult athletes recruited via social media and email. Knowledge (4 questions), attitudes (11 questions with TwoStep Cluster analysis), and cannabis use assessed. Mediation analysis tested the knowledge-attitudes-behavior model.","limitations":"Self-selected sample of athletes recruited through social media. Self-defined \"active athlete\" is subjective. Cross-sectional design cannot determine temporal ordering of knowledge, attitudes, and use. Social desirability may bias responses."},{"rthcId":"RTHC-02935","title":"Systemic administration with tetrahydrocannabinol causes retinal damage in BALB/c mice.","authors":"Zhang, Z; Li, R; Lu, H; Zhang, X","year":2020,"journal":"Human & experimental toxicology, 39(3), 290-300","doi":"10.1177/0960327119886037","pmid":"31680560","tags":["neuroscience","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC at 1-2 mg/kg daily for 2 months caused functional loss on electroretinography, increased photoreceptor cell apoptosis, elevated inflammatory markers (TNF-alpha, IL-1beta, IL-6), and increased oxidative stress markers in retinal tissue. Higher doses produced more severe effects.","whyItMatters":"While cannabis effects on the brain are widely studied, retinal effects are poorly understood. This study raises the possibility that chronic THC use could affect vision through inflammatory and oxidative damage to the retina.","specificNumbers":"2 mg/kg THC daily for 2 months. Functional loss on ERG. Increased TUNEL-positive (apoptotic) photoreceptor cells. Elevated TNF-alpha, IL-1beta, IL-6. Increased oxidative stress markers. No locomotor effects observed.","methodology":"BALB/c mice received daily intraperitoneal THC (1 or 2 mg/kg) or vehicle for 2 months. Retinal function assessed by electroretinography. Retinal morphology by H&E staining. Apoptosis by TUNEL assay. Inflammation and oxidative stress by ELISA. Gene and protein expression by RT-PCR and Western blot.","limitations":"Animal study using intraperitoneal injection, which differs from human routes of administration. BALB/c mice may be particularly susceptible to retinal damage. Two months in mice may not correspond to equivalent human exposure duration. No behavioral visual assessment was performed."},{"rthcId":"RTHC-02936","title":"Impaired cognitive performance under psychosocial stress in cannabis-dependent men is associated with attenuated precuneus activity.","authors":"Zhao, Weihua; Zimmermann, Kaeli; Zhou, Xinqi; Zhou, Feng; Fu, Meina; Dernbach, Christian; Scheele, Dirk; Weber, Bernd; Eckstein, Monika; Hurlemann, René; Kendrick, Keith M.; Becker, Benjamin","year":2020,"journal":"Journal of psychiatry & neuroscience : JPN, 45(2), 88-97","doi":"10.1503/jpn.190039","pmid":"31509368","tags":["cognition","addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"During stress but not during a no-stress condition, cannabis users showed impaired performance on mental arithmetic compared to controls. Subjective stress and cardiovascular responses were similar between groups. fMRI revealed that stress-induced performance decline in cannabis users was accompanied by decreased precuneus activity and increased connectivity between the precuneus and superior frontal gyrus.","whyItMatters":"Stress is a major trigger for cannabis relapse. Finding that cannabis dependence specifically impairs cognitive function under stress, with identifiable neural correlates, could help explain why stressful situations lead to both impaired function and relapse.","specificNumbers":"28 cannabis-dependent men, 23 controls. Impaired performance during stress only (not no-stress). No group differences in subjective stress or cardiovascular response. Decreased precuneus activity and increased precuneus-superior frontal gyrus connectivity during stress in users.","methodology":"fMRI study of 28 cannabis-dependent men and 23 matched controls using the Montreal Imaging Stress Task, which combines adaptive mental arithmetic with social evaluative threat. Behavioral performance, subjective stress, and cardiovascular responses measured alongside brain imaging.","limitations":"Only male participants studied. Cross-sectional design cannot determine if findings preceded or resulted from cannabis use. Cannabis-dependent participants were not acutely intoxicated, but residual effects cannot be fully excluded. Relatively small sample for fMRI."},{"rthcId":"RTHC-02937","title":"Cannabinoids Rescue Cocaine-Induced Seizures by Restoring Brain Glycine Receptor Dysfunction.","authors":"Zou, Guichang; Zuo, Xin; Chen, Kai; Ge, Yushu; Wang, Xiaoqun; Xu, Guangwei; Wang, Huan; Miao, Chenjian; Xu, Zhenyu; Tian, Shuangshuang; Wang, Zhen; Zhou, Yifeng; Wei, Wei; Huang, Guangming; Liu, Dan; Xiong, Wei","year":2020,"journal":"Cell reports, 30(12), 4209-4219.e7","doi":"10.1016/j.celrep.2020.02.106","pmid":"32209479","tags":["neuroscience","epilepsy"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Systemic cannabinoid administration alleviated cocaine-induced seizures independently of CB1 and CB2 receptors. Cannabinoids restored cocaine-disrupted glycine receptor (GlyR) function in cells and neurons. The therapeutic effect was eliminated in GlyRα1 S296A mutant mice. Molecular simulation showed cannabinoid docking weakened cocaine-GlyR hydrogen bonding. Cannabinoids suppressed cocaine-exaggerated neuronal excitability in the prefrontal cortex and hippocampus.","whyItMatters":"Cocaine-induced seizures are a severe and potentially fatal complication. Identifying that cannabinoids work through glycine receptors (not classic cannabinoid receptors) opens a new avenue for targeted treatment.","specificNumbers":"Therapeutic effects were CB1/CB2-independent. Effects eliminated in GlyRα1 S296A mutant mice. Cannabinoids suppressed neuronal excitability in prefrontal cortex and hippocampus. No alteration of cocaine brain distribution.","methodology":"Combination of in vivo mouse seizure models, HEK293 cell electrophysiology, primary cortical neuron recordings, molecular dynamic simulation, and microinjection studies targeting specific brain regions. GlyRα1 S296A knock-in mice used to confirm mechanism.","limitations":"Animal study using injected cannabinoids. The specific cannabinoid compounds tested and doses may not reflect typical cannabis use. GlyR-hypersensitive cannabinoid derivatives would need to be developed for clinical use. Cocaine-induced seizure model is specific and may not generalize."},{"rthcId":"RTHC-02938","title":"Cannabis cessation among youth: rates, patterns and academic outcomes in a large prospective cohort of Canadian high school students.","authors":"Zuckermann, Alexandra M; Gohari, Mahmood R; de Groh, Margaret; Jiang, Ying; Leatherdale, Scott T","year":2020,"journal":"Health promotion and chronic disease prevention in Canada : research, policy and practice, 40(4), 95-103","doi":"10.24095/hpcdp.40.4.01","pmid":"32270667","tags":["youth","quitting","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Only 14.8% decreased use between grades, with two-thirds making only incremental changes. Cessation rates from daily and weekly use decreased each year. Students who quit had better odds of class attendance (OR=2.48) and homework completion (OR=2.32) compared to continuing users, but still had worse math performance than never-users (OR=0.55).","whyItMatters":"This large longitudinal study shows that spontaneous cannabis cessation is uncommon among high school students, suggesting most teen users need external support. The academic improvements seen after quitting provide concrete motivation for cessation.","specificNumbers":"91,774 observations. 14.8% reduced use between grades. Quitters vs. continuing users: attendance OR=2.48, homework OR=2.32. Quitters vs. never-users: math OR=0.55 for some subcategories. Cessation rates from daily/weekly use declined each year.","methodology":"Longitudinal analysis of 91,774 linked observations from the COMPASS prospective cohort study of Canadian high school students (Grades 9-12, 2013-2017). Cannabis use change patterns tracked across grade transitions. Academic outcomes (math, English marks, homework, truancy) compared between quitters, continuing users, and never-users.","limitations":"Observational data cannot prove that quitting caused academic improvements. Self-reported cannabis use and academic outcomes. Students who quit may differ systematically from those who continue. Canadian sample may not generalize to other countries."},{"rthcId":"RTHC-02939","title":"The role of school characteristics in pre-legalization cannabis use change among Canadian youth: implications for policy and harm reduction.","authors":"Zuckermann, Alexandra M E; Gohari, Mahmood R; de Groh, Margaret; Jiang, Ying; Leatherdale, Scott T","year":2020,"journal":"Health education research, 35(4), 297-305","doi":"10.1093/her/cyaa018","pmid":"32623462","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02940","title":"Prevalence and correlates of youth poly-substance use in the COMPASS study.","authors":"Zuckermann, Alexandra M E; Williams, Gillian C; Battista, Katelyn; Jiang, Ying; de Groh, Margaret; Leatherdale, Scott T","year":2020,"journal":"Addictive behaviors, 107, 106400","doi":"10.1016/j.addbeh.2020.106400","pmid":"32222564","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02941","title":"Chronic administration of synthetic cannabidiol induces antidepressant effects involving modulation of serotonin and noradrenaline levels in the hippocampus.","authors":"Abame, Melkamu Alemu; He, Yang; Wu, Song; Xie, Zhifei; Zhang, Jian; Gong, Xudong; Wu, Chunhui; Shen, Jingshan","year":2021,"journal":"Neuroscience letters, 744, 135594","doi":"10.1016/j.neulet.2020.135594","pmid":"33388355","tags":["cbd","depression","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Only the high dose (100 mg/kg) produced antidepressant effects in the forced swim test after 7 days of administration. This dose significantly increased serotonin (5-HT) and noradrenaline (NA) in the hippocampus. Both 30 mg/kg and 100 mg/kg decreased NF-kB expression. No locomotor effects were observed at any dose, ruling out non-specific activity changes.","whyItMatters":"While acute CBD effects have been studied, chronic administration is more clinically relevant. Finding that CBD increases serotonin and noradrenaline, the same targets as conventional antidepressants, provides a mechanistic rationale for CBD in depression.","specificNumbers":"100 mg/kg CBD for 7 days produced antidepressant effect. Significant increase in hippocampal serotonin and noradrenaline. NF-kB decreased at both 30 and 100 mg/kg. No locomotor effects at any dose.","methodology":"Male mice received synthetic CBD (30 or 100 mg/kg) or vehicle daily for 7 days. Behavioral assessment via forced swim test and open field test. Hippocampal serotonin and noradrenaline measured by HPLC-ECD. NF-kB, BDNF, and other proteins measured by RT-PCR and Western blot.","limitations":"Animal study with high CBD doses (100 mg/kg) that may not be achievable in humans. Only 7 days of treatment. Forced swim test is a simplified depression model. Synthetic CBD may differ from plant-derived CBD in some respects."},{"rthcId":"RTHC-02942","title":"Potential and Limits of Cannabinoids in Alzheimer's Disease Therapy.","authors":"Abate, Giulia; Uberti, Daniela; Tambaro, Simone","year":2021,"journal":"Biology, 10(6)","doi":"10.3390/biology10060542","pmid":"34204237","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02943","title":"Genomic relationships across psychiatric disorders including substance use disorders.","authors":"Abdellaoui, Abdel; Smit, Dirk J A; van den Brink, Wim; Denys, Damiaan; Verweij, Karin J H","year":2021,"journal":"Drug and alcohol dependence, 220, 108535","doi":"10.1016/j.drugalcdep.2021.108535","pmid":"33524898","tags":["addiction","genetics","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Alcohol and nicotine dependence showed significant genetic correlations with multiple psychiatric disorders including ADHD, schizophrenia, and major depression. Cannabis use disorder was significantly associated only with ADHD. In factor analysis, all three substance use disorders loaded primarily on Factor 3, a heterogeneous factor that also included ADHD, major depression, autism spectrum disorders, and Tourette syndrome.","whyItMatters":"Understanding the genetic architecture of cannabis use disorder relative to other psychiatric conditions helps clarify whether CUD shares biological pathways with conditions like schizophrenia and depression, which has implications for treatment and risk assessment.","specificNumbers":"11 psychiatric disorders analyzed. Cannabis use disorder significantly correlated only with ADHD. Alcohol and nicotine dependence correlated with multiple disorders. All SUDs loaded on Factor 3 in latent structure analysis.","methodology":"GWAS summary statistics from 11 psychiatric disorders including alcohol dependence, nicotine dependence, and cannabis use disorder. Genetic correlations estimated via LD-Score Regression. Factor analysis of the genetic relationship matrix to identify latent structure.","limitations":"GWAS summary statistics represent common variants only. CUD GWAS samples may be underpowered relative to other disorders. Genetic correlations do not establish causation. Factor models were somewhat unstable, as the authors acknowledge."},{"rthcId":"RTHC-02944","title":"Population Size Estimation of Drug Users in Isfahan City (Iran) Using Network Scale-up Method in 2018.","authors":"Abshenas-Jami, Meysam; Baneshi, Mohamadreza; Nasirian, Maryam","year":2021,"journal":"Addiction & health, 13(4), 249-258","doi":"10.22122/ahj.v13i4.1238","pmid":"35178197","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02945","title":"Medical Cannabis in Oncology: a Valuable Unappreciated Remedy or an Undesirable Risk?","authors":"Abu-Amna, Mahmoud; Salti, Talal; Khoury, Mona; Cohen, Idan; Bar-Sela, Gil","year":2021,"journal":"Current treatment options in oncology, 22(2), 16","doi":"10.1007/s11864-020-00811-2","pmid":"33439370","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02946","title":"Interests and concerns regarding medical marijuana among chronic pain patients in Ohio: an online survey.","authors":"Adams, Daniel; Ofei-Tenkorang, Nana Ama; Connell, Patrick; Owens, Alexa; Gothard, Aaron; Souza, Dmitri; Narouze, Samer","year":2021,"journal":"Journal of cannabis research, 3(1), 37","doi":"10.1186/s42238-021-00092-y","pmid":"34399845","tags":["pain","medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"84.3% were willing to consider medical marijuana. 67.6% wanted to use fewer opioids after starting MMJ. 93.6% were amenable to following their specialist's recommendations about concurrent opioid-MMJ use. The greatest concern was affordability (2.98/5). Older patients were less likely to prefer inhaled forms (p=0.023).","whyItMatters":"In a region heavily affected by the opioid crisis, chronic pain patients' overwhelming willingness to try medical marijuana and reduce opioid use suggests strong patient demand for cannabis as a pain management option.","specificNumbers":"242 respondents from 1,047 invited (23.1%). Average age 51-60. 70.7% female. 60.7% on opioids. 84.3% willing to consider MMJ. 67.6% wanted less opioid use. 93.6% would follow specialist guidance. Affordability top concern (2.98/5).","methodology":"Online survey (MMIQ) administered to 1,047 chronic pain patients at a pain medicine center in Ohio. 242 responses (23.1%). Average age 51-60 years, 70.7% female, 60.7% current opioid users. Assessed willingness, compliance intent, and concerns.","limitations":"Low response rate (23.1%) with online-only administration likely skewing toward younger, more tech-savvy patients. Single clinic in Ohio. Patients not yet using MMJ, so attitudes may differ from actual behavior. Self-reported willingness may overestimate real-world compliance."},{"rthcId":"RTHC-02947","title":"Cannabis sativa: From Therapeutic Uses to Micropropagation and Beyond.","authors":"Adams, Tristan K; Masondo, Nqobile A; Malatsi, Pholoso; Makunga, Nokwanda P","year":2021,"journal":"Plants (Basel, Switzerland), 10(10)","doi":"10.3390/plants10102078","pmid":"34685890","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02948","title":"Trend differences over 20 years between two methadone maintenance clinics, one with and one without cannabis legalization.","authors":"Adelson, Miriam; Smith, Dinita; Peles, Einat","year":2021,"journal":"Journal of addictive diseases, 39(2), 226-233","doi":"10.1080/10550887.2020.1848248","pmid":"33559536","tags":["addiction","legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"The Las Vegas clinic (1,724 patients) had lower one-year retention than Tel Aviv (1,014 patients): 46.4% vs. 74.4%. Cannabis and benzodiazepine misuse at admission increased in Las Vegas but not Tel Aviv. Cannabis at admission predicted shorter retention in Las Vegas, and cannabis after one year predicted shorter retention in Tel Aviv. Age at admission and retention rates decreased in Las Vegas but increased in Tel Aviv.","whyItMatters":"Cannabis legalization may increase cannabis use among opioid-dependent individuals in treatment, and this study suggests that cannabis use is associated with worse methadone treatment outcomes regardless of the legal context.","specificNumbers":"1,724 Las Vegas patients, 1,014 Tel Aviv patients. One-year retention: 46.4% LV vs. 74.4% TA. Cannabis at admission increased in LV only. Cannabis predicted shorter retention in both clinics (different time points).","methodology":"Retrospective comparison of patient characteristics and outcomes at two methadone maintenance treatment clinics over 20 years (Las Vegas) and 27 years (Tel Aviv). Admission characteristics, urine drug screens at months 1 and 13, and cumulative retention analyzed by year of admission.","limitations":"Retrospective chart review with many potential confounders. Two clinics in very different cultural and healthcare contexts. Cannabis use determined by urine screens and charts, not standardized assessment. The clinics differed in many ways beyond cannabis legality."},{"rthcId":"RTHC-02949","title":"Vaping Cannabis Butane Hash Oil Leads to Severe Acute Respiratory Distress Syndrome-A Case of EVALI in a Teenager With Hypertrophic Cardiomyopathy.","authors":"Ahmed, Aziez; Shapiro, Douglas; Su, Jennifer; Nelson, Lara P","year":2021,"journal":"Journal of intensive care medicine, 36(5), 617-621","doi":"10.1177/0885066620941004","pmid":"32686568","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02950","title":"Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders.","authors":"Ahmed, Ishtiaq; Rehman, Saif Ur; Shahmohamadnejad, Shiva; Zia, Muhammad Anjum; Ahmad, Muhammad; Saeed, Muhammad Muzammal; Akram, Zain; Iqbal, Hafiz M N; Liu, Qingyou","year":2021,"journal":"Molecules (Basel, Switzerland), 26(11)","doi":"10.3390/molecules26113389","pmid":"34205169","tags":["inflammation","cancer","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review mapped the endocannabinoid system's relationship with the immune system and cancer biology. The key mechanisms included CB1 and CB2 receptor activation suppressing immune responses through multiple pathways: inhibiting white blood cell proliferation, triggering T cell apoptosis (programmed death), activating macrophages, and reducing pro-inflammatory cytokine secretion.\n\nFor neuroinflammatory autoimmune disorders like multiple sclerosis, these immunosuppressive properties pointed toward potential therapeutic use — dampening the overactive immune response that damages myelin. For cancer, the picture was more complex: cannabinoids showed anti-tumor properties in both in vitro (cell culture) and in vivo (animal) studies, including inhibiting tumor cell proliferation, inducing cancer cell death, and reducing tumor blood vessel formation.\n\nThe review compiled evidence from clinical trials alongside preclinical work, though it noted that the clinical evidence remained early-stage.","whyItMatters":"The endocannabinoid system sits at the intersection of neuroscience and immunology. This review showed that cannabinoids don't just affect mood and pain — they fundamentally modulate immune function. For conditions where the immune system attacks the body (autoimmune diseases) or fails to control abnormal growth (cancer), that modulation could theoretically be therapeutic.\n\nBut \"could theoretically\" is doing heavy lifting. The jump from \"cannabinoids kill cancer cells in a dish\" to \"cannabis treats cancer in humans\" is enormous, and this review was careful to note that clinical evidence remained limited.","specificNumbers":"• Cannabinoid immunosuppressive effects: inhibited leukocyte proliferation, induced T cell apoptosis, activated macrophages\n• Reduced pro-inflammatory cytokines via CB1 and CB2 activation\n• Anti-tumor effects demonstrated in vitro and in vivo across multiple cancer types\n• Clinical trial evidence still early-stage","methodology":"Narrative review of preclinical and clinical literature on the endocannabinoid system's role in immune regulation, neuroinflammation, and cancer biology. Covers CB1 and CB2 receptor mechanisms, immune cell interactions, and anti-tumor effects across multiple cancer types.","limitations":"Narrative review with no systematic methodology. Anti-tumor findings are largely preclinical — lab dishes and animal models. Clinical trial evidence for cancer treatment was limited and early-stage. The review covers broad territory without deep analysis of any single condition. Publication bias likely favors positive preclinical results."},{"rthcId":"RTHC-02951","title":"The Impact of THC and CBD in Schizophrenia: A Systematic Review.","authors":"Ahmed, Saeed; Roth, Robert M; Stanciu, Corneliu N; Brunette, Mary F","year":2021,"journal":"Frontiers in psychiatry, 12, 694394","doi":"10.3389/fpsyt.2021.694394","pmid":"34366924","tags":["psychosis","cbd","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Intravenous THC increased psychosis in stable patients. Two reports on smoked/oral THC in patients with co-occurring CUD found no symptom changes but improved resting-state brain function. CBD 800 mg was as effective as amisulpride for acute psychosis. CBD augmentation results were mixed: 600 mg was not better than placebo, but 1,000 mg reduced symptoms in a sample that included cannabis users.","whyItMatters":"Despite growing public interest in cannabis-based treatments for mental illness, this review highlights that evidence remains insufficient and highly variable, with THC potentially worsening psychosis and CBD showing mixed results.","specificNumbers":"11 reports reviewed. THC doses: intravenous (1 trial), smoked/oral (2 reports). CBD doses: 600 mg (not effective), 800 mg (equivalent to amisulpride), 1,000 mg (reduced symptoms). Substantial heterogeneity in dose, delivery, and patient selection.","methodology":"Systematic review of 11 eligible reports identified from 8 online databases. Studies included placebo-controlled trials and neuroimaging studies using defined doses of THC or CBD in patients with schizophrenia or schizophrenia spectrum disorders.","limitations":"Only 11 reports met inclusion criteria. Studies varied widely in dosing, duration, patient populations, and whether cannabis users were included or excluded. Most studies had small samples. Systematic review but not a quantitative meta-analysis due to heterogeneity."},{"rthcId":"RTHC-02952","title":"Cognitive biases are associated with clinical and functional variables in psychosis: A comparison across schizophrenia, early psychosis and healthy individuals.","authors":"Ahuir, Maribel; Crosas, Josep Maria; Estrada, Francesc; Zabala, Wanda; Pérez-Muñoz, Sara; González-Fernández, Alba; Tost, Meritxell; Aguayo, Raquel; Montalvo, Itziar; Miñano, Maria José; Gago, Estefania; Pàmias, Montserrat; Monreal, José Antonio; Palao, Diego; Labad, Javier","year":2021,"journal":"Revista de psiquiatria y salud mental, 14(1), 4-15","doi":"10.1016/j.rpsm.2020.07.005","pmid":"32950409","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02953","title":"Effects of a School-Based Intervention for Preventing Substance Use among Adolescents at Risk of Academic Failure: A Pilot Study of the Reasoning and Rehabilitation V2 Program.","authors":"Alarcó-Rosales, Raquel; Sánchez-SanSegundo, Miriam; Ferrer-Cascales, Rosario; Albaladejo-Blazquez, Natalia; Lordan, Oriol; Zaragoza-Martí, Ana","year":2021,"journal":"Healthcare (Basel, Switzerland), 9(11)","doi":"10.3390/healthcare9111488","pmid":"34828534","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02954","title":"Association of Cannabis Use During Adolescence With Neurodevelopment.","authors":"Albaugh, Matthew D; Ottino-Gonzalez, Jonatan; Sidwell, Amanda; Lepage, Claude; Juliano, Anthony; Owens, Max M; Chaarani, Bader; Spechler, Philip; Fontaine, Nicholas; Rioux, Pierre; Lewis, Lindsay; Jeon, Seun; Evans, Alan; D'Souza, Deepak; Radhakrishnan, Rajiv; Banaschewski, Tobias; Bokde, Arun L W; Quinlan, Erin Burke; Conrod, Patricia; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Martinot, Jean-Luc; Paillère Martinot, Marie-Laure; Nees, Frauke; Papadopoulos Orfanos, Dimitri; Paus, Tomáš; Poustka, Luise; Millenet, Sabina; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Potter, Alexandra; Garavan, Hugh","year":2021,"journal":"JAMA psychiatry, 78(9), 1-11","doi":"10.1001/jamapsychiatry.2021.1258","pmid":"34132750","tags":["youth","neuroscience","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use between ages 14 and 19 was associated with accelerated, dose-dependent cortical thinning in bilateral prefrontal cortex, spatially correlated with CB1 cannabinoid receptor density. No pre-existing cortical thickness differences were found at baseline.","whyItMatters":"This is the largest longitudinal neuroimaging study of adolescent cannabis use. Its prospective design (scanning before first use) addresses the fundamental limitation of cross-sectional studies: it can distinguish cannabis effects from pre-existing brain differences. The dose-response pattern and CB1 receptor spatial correlation point to a specific, biologically plausible mechanism.","specificNumbers":"799 participants (56.3% female). Left prefrontal: P=1.10x10^-6. Right prefrontal: P=2.81x10^-5. Longitudinal thinning: P=2.28x10^-8 (left), P=3.72x10^-8 (right). Thinning correlated with CB1 receptor density (r=-0.189) and age-related thinning (r=0.540).","methodology":"Prospective longitudinal cohort study using the IMAGEN consortium. 799 cannabis-naive adolescents received structural MRI at baseline (mean age 14.4) and 5-year follow-up (mean age 19.0). Cortical thickness measured via CIVET pipeline. Cannabis use assessed via ESPAD. Linear mixed-effects models controlled for age, sex, total brain volume, handedness, site, and alcohol consumption.","limitations":"Self-report cannabis assessment; no information on cannabis product types or potency; CB1 receptor PET data from a separate adult sample; observational design cannot definitively establish causation; potential alcohol confounding despite statistical control; MRI-measured thinning may partly reflect myelination changes rather than neuronal loss."},{"rthcId":"RTHC-02955","title":"Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice.","authors":"Alegre-Zurano, Laia; López-Arnau, Raúl; Luján, Miguel Á; Camarasa, Jordi; Valverde, Olga","year":2021,"journal":"International journal of molecular sciences, 22(15)","doi":"10.3390/ijms22158304","pmid":"34361071","tags":["cbd","addiction","anxiety"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (20 mg/kg) reduced MDPV-induced conditioned place preference. CBD showed anxiolytic effects in MDPV-treated mice on the elevated plus maze. However, during self-administration of high-dose MDPV, CBD increased drug-seeking and taking in the high-responder subgroup. These complex results suggest CBD modulation of stimulant effects varies by behavioral context.","whyItMatters":"Synthetic cathinones (\"bath salts\") are dangerous and lack effective treatments. CBD showed promise in reducing reward and anxiety but the increased self-administration in some mice highlights the complexity of using CBD for addiction.","specificNumbers":"CBD 20 mg/kg. MDPV 2 mg/kg for CPP, 0.05-0.075 mg/kg/infusion for self-administration. CBD reduced CPP. CBD increased self-administration only in high-responders at higher MDPV dose. CBD anxiolytic only in MDPV-treated, not vehicle-treated mice.","methodology":"Mouse models of conditioned place preference (MDPV 2 mg/kg), self-administration (MDPV 0.05 and 0.075 mg/kg/infusion), and elevated plus maze. CBD (20 mg/kg) administered alongside MDPV. Self-administration mice analyzed by responder subgroups.","limitations":"Animal study. Only one CBD dose tested. The high-responder subgroup finding should be interpreted cautiously given small group sizes. Self-administration paradigm may not reflect human patterns of bath salt use."},{"rthcId":"RTHC-02956","title":"Medical Marijuana Laws, Marijuana Use, and Opioid-Related Outcomes among Women in the United States.","authors":"Ali, Mir M; McClellan, Chandler; West, Kristina D; Mutter, Ryan","year":2021,"journal":"Women's health issues : official publication of the Jacobs Institute of Women's Health, 31(1), 24-30","doi":"10.1016/j.whi.2020.09.003","pmid":"33069561","tags":["legalization","pregnancy","pain","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Medical marijuana laws were not associated with opioid misuse, initiation, or OUD among all women, pregnant women, or parenting women. The laws were positively correlated with marijuana use and MUD among all women and women with children. For pregnant women, MMLs were associated with increased frequency of opioid misuse. For parenting women, MMLs were associated with decreased frequency of opioid misuse.","whyItMatters":"The idea that medical marijuana can serve as an opioid substitute for women, including pregnant and parenting women, is not supported by this analysis, challenging a common policy argument for medical marijuana laws.","specificNumbers":"MMLs not associated with opioid misuse, initiation, or OUD in any women subgroup. MMLs associated with increased marijuana use and MUD among all women and women with children. Increased opioid misuse frequency in pregnant women. Decreased opioid misuse frequency in parenting women.","methodology":"Difference-in-differences analysis using NSDUH data from 2002-2014. Compared opioid-related outcomes among women in states with and without medical marijuana laws before and after implementation. Analyzed separately for all women, pregnant women, and parenting women.","limitations":"Survey data with self-reported substance use. Difference-in-differences assumes parallel trends. Cannot account for all policy variations across states. Data ends in 2014, before many states expanded marijuana programs."},{"rthcId":"RTHC-02957","title":"Age- and Sex-Related Cortical Gray Matter Volume Differences in Adolescent Cannabis Users: A Systematic Review and Meta-Analysis of Voxel-Based Morphometry Studies.","authors":"Allick, Aliyah; Park, Grace; Kim, Kwon; Vintimilla, Michelle; Rathod, Krutika; Lebo, Rachael; Nanavati, Julie; Hammond, Christopher J","year":2021,"journal":"Frontiers in psychiatry, 12, 745193","doi":"10.3389/fpsyt.2021.745193","pmid":"34925090","tags":["youth","neuroscience","sex-differences"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"No regions showed significant gray matter volume differences between 357 cannabis-using and 404 typically developing youth. Meta-regressions revealed age effects in the superior temporal gyrus (older users showed decreased, younger users increased volume). A higher proportion of females was associated with increased volume in the middle occipital gyrus in users vs. controls.","whyItMatters":"This meta-analysis challenges the assumption of dramatic brain volume changes from adolescent cannabis use, while highlighting that developmental timing and sex may determine where and how subtle effects emerge.","specificNumbers":"6 VBM studies, 357 cannabis users (mean age 16.68, 71% male), 404 controls (mean age 16.77, 63% male). No significant main effect. Age moderated STG differences. Sex moderated middle occipital gyrus differences.","methodology":"Systematic review (1,326 citations, 24 included qualitatively) with seed-based d mapping (SDM) meta-analysis of 6 whole-brain VBM studies. Meta-regressions examined effects of age, sex, and cannabis use duration on gray matter volume differences.","limitations":"Only 6 studies met strict inclusion criteria. Studies varied in cannabis use definitions and covariates. VBM methodology may miss subtle or regional-specific changes. Meta-regression with few studies has limited power."},{"rthcId":"RTHC-02958","title":"Young and under the influence: A systematic literature review of the impact of cannabis on the driving performance of youth.","authors":"Alvarez, Liliana; Colonna, Robert; Kim, Sean; Chen, Caron; Chippure, Katherine; Grewal, Jasleen; Kimm, Chris; Randell, Travis; Leung, Victoria","year":2021,"journal":"Accident; analysis and prevention, 151, 105961","doi":"10.1016/j.aap.2020.105961","pmid":"33421731","tags":["driving","youth","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Class II evidence suggests THC is likely to reduce mean speed, headway distance, and reaction time, and increase lane and steering wheel position variability in young drivers. The overall level of confidence was moderate (Level B). The review found a lack of Class I studies and insufficient attention to sex/gender differences and representative samples.","whyItMatters":"Young drivers already face the highest crash risk. Understanding the specific ways cannabis impairs their driving can inform targeted education and prevention rather than relying on generalizations from adult studies.","specificNumbers":"Systematic review of studies on drivers ages 15-24. Class II evidence (Level B, moderate confidence). THC effects: reduced mean speed, reduced headway distance, reduced reaction time, increased lane variability, increased steering variability.","methodology":"Systematic review registered in PROSPERO, searching 7 databases. Quality of evidence assessed using an established classification system (Class I-IV for study quality, Level A-U for confidence). Focused specifically on drivers ages 15-24.","limitations":"Limited number of high-quality studies focused specifically on youth. Most driving performance studies use simulator environments that may not reflect real-world conditions. Sex and gender effects are understudied. Dose-response relationships unclear."},{"rthcId":"RTHC-02959","title":"Targeting the endocannabinoid system for management of HIV-associated neuropathic pain: A systematic review.","authors":"Aly, Esraa; Masocha, Willias","year":2021,"journal":"IBRO neuroscience reports, 10, 109-118","doi":"10.1016/j.ibneur.2021.01.004","pmid":"34179865","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"10 preclinical studies found that endocannabinoids, CB2-selective agonists, and FAAH inhibitors prevented or reversed HIV-associated neuropathic pain. Two completed clinical trials showed smoked cannabis was more effective than placebo. One trial of cannabidivarin (which does not activate cannabinoid receptors) did not reduce HIV neuropathic pain.","whyItMatters":"HIV-associated neuropathic pain affects many patients and has few effective treatments. This review consolidates evidence that the endocannabinoid system is a viable therapeutic target, with some clinical validation.","specificNumbers":"13 studies included. 10 preclinical studies: multiple ECS-targeting compounds effective. 2 clinical trials: smoked cannabis superior to placebo. 1 clinical trial: cannabidivarin not effective. CB2-selective agonists (AM1710, JWH015, JWH133, Gp1a, but not HU308) effective preclinically.","methodology":"Systematic review searching PubMed, Google Scholar, ClinicalTrials.gov, and EU trial registries for studies on HIV-associated neuropathic pain and endocannabinoid system modulation. 13 articles met inclusion criteria (10 preclinical, 3 clinical).","limitations":"Only 3 clinical studies met criteria, all with small samples. Smoked cannabis has significant delivery limitations. The preclinical-to-clinical translation gap remains large. Most preclinical models used antiretroviral-induced rather than virus-induced neuropathy."},{"rthcId":"RTHC-02960","title":"Toxicological aspects of cannabinoid, pesticide and metal levels detected in light Cannabis inflorescences grown in Italy.","authors":"Amendola, G; Bocca, B; Picardo, V; Pelosi, P; Battistini, B; Ruggieri, F; Attard Barbini, D; De Vita, D; Madia, V N; Messore, A; Di Santo, R; Costi, R","year":2021,"journal":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 156, 112447","doi":"10.1016/j.fct.2021.112447","pmid":"34343597","tags":["harm-reduction","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 31 light cannabis inflorescence samples, THC was always below 0.5% and CBD ranged from 0.3-8.64%. Testing for 154 pesticides revealed that 87% contained fungicides and insecticides (range 0.01-185 micrograms/g). Multiple metals (As, Cd, Co, Cr, Hg, Cu, Mo, Ni, V) exceeded US regulatory limits for inhaled cannabis. Lead exceeded limits for both oral and inhaled products.","whyItMatters":"Light cannabis products (low THC, higher CBD) are widely available in Europe but are not subject to the food or tobacco safety regulations that would catch these contaminants, leaving consumers exposed to potentially harmful substances.","specificNumbers":"31 samples from across Italy. THC <0.5%, CBD 0.3-8.64%. 87% contained pesticides (range 0.01-185 micrograms/g). Most common: spinosad and cyprodinil. Metals 1-100+ micrograms/g. 9 metals exceeded US inhaled cannabis limits. Lead exceeded both oral and inhaled limits.","methodology":"Analytical study of 31 light cannabis inflorescence samples collected from different Italian regions. Cannabinoid content measured by standard methods. 154 pesticides screened. Metal content determined and compared to US regulatory limits for cannabis products.","limitations":"Sample size of 31, though geographically diverse across Italy. US regulatory limits were used as reference since EU limits for cannabis do not exist. Did not assess actual consumer exposure levels or health effects. Light cannabis only, not high-THC products."},{"rthcId":"RTHC-02961","title":"NNL-3: A Synthetic Intermediate or a New Class of Hydroxybenzotriazole Esters with Cannabinoid Receptor Activity?","authors":"Ametovski, Adam; Cairns, Elizabeth A; Grafinger, Katharina Elisabeth; Cannaert, Annelies; Deventer, Marie H; Chen, Shuli; Wu, Xinyi; Shepperson, Caitlin E; Lai, Felcia; Ellison, Ross; Gerona, Roy; Blakey, Karen; Kevin, Richard; McGregor, Iain S; Hibbs, David E; Glass, Michelle; Stove, Christophe; Auwärter, Volker; Banister, Samuel D","year":2021,"journal":"ACS chemical neuroscience, 12(21), 4020-4036","doi":"10.1021/acschemneuro.1c00348","pmid":"34676751","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02962","title":"Cannabis and its cannabinoids analysis by gas chromatography-mass spectrometry with Cold EI.","authors":"Amirav, Aviv; Neumark, Benny; Margolin Eren, Ksenia J; Fialkov, Alexander B; Tal, Noam","year":2021,"journal":"Journal of mass spectrometry : JMS, 56(6), e4726","doi":"10.1002/jms.4726","pmid":"33955098","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02963","title":"WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels.","authors":"An, Dongchen; Peigneur, Steve; Tytgat, Jan","year":2021,"journal":"Biomedicines, 9(5)","doi":"10.3390/biomedicines9050484","pmid":"33924979","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02964","title":"Cannabis-based medicines and pain: a review of potential synergistic and entourage effects.","authors":"Anand, Uma; Pacchetti, Barbara; Anand, Praveen; Sodergren, Mikael Hans","year":2021,"journal":"Pain management, 11(4), 395-403","doi":"10.2217/pmt-2020-0110","pmid":"33703917","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02965","title":"An Examination of Risk Factors for Tobacco and Cannabis Smoke Exposure in Adolescents Using an Epigenetic Biomarker.","authors":"Andersen, Allan; Gerrard, Meg; Gibbons, Frederick X; Beach, Steven R H; Philibert, Robert","year":2021,"journal":"Frontiers in psychiatry, 12, 688384","doi":"10.3389/fpsyt.2021.688384","pmid":"34504443","tags":["youth","genetics","harm-reduction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Increasing proportions of students tested positive for cotinine (5-16%), THC (3-10%), and the epigenetic biomarker (5-7%) from 10th to 12th grade. Self-reported combusted tobacco and cannabis use correlated strongly with all biomarkers. The epigenetic marker did not detect e-cigarette use. Dual tobacco-cannabis users had the greatest cumulative exposure. Willingness to smoke and positive perceptions of smokers predicted biomarker positivity.","whyItMatters":"Self-reported substance use is unreliable in adolescents. An objective epigenetic biomarker that detects both tobacco and cannabis smoke exposure could improve screening, research accuracy, and clinical care.","specificNumbers":"442 (10th grade), 376 (11th), 366 (12th) participants. Cotinine positive: 5-16%. THC positive: 3-10%. cg05575921 positive: 5-7%. Epigenetic marker correlated with combusted but not e-cigarette use. Dual users had greatest methylation changes.","methodology":"Longitudinal study of Iowa 10th graders with a friend or family member who smoked, followed through 12th grade. Blood samples at each timepoint for serum cotinine, THC, and DNA methylation at cg05575921. Self-report data on nicotine, tobacco, cannabis, and e-cigarette use.","limitations":"High-risk sample (all had a smoking friend or family member) limits generalizability. Epigenetic marker cannot distinguish between tobacco and cannabis smoke exposure. Blood-based testing is more invasive than saliva-based alternatives. Relatively small sample for biomarker validation."},{"rthcId":"RTHC-02966","title":"Inflammatory biomarker relationships with helper T cell GPR15 expression and cannabis and tobacco smoking.","authors":"Andersen, Allan M; Lei, Man-Kit; Beach, Steven R H; Philibert, Robert A","year":2021,"journal":"Journal of psychosomatic research, 141, 110326","doi":"10.1016/j.jpsychores.2020.110326","pmid":"33310155","tags":["inflammation","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In a cohort of 62 primarily African American young adults, researchers measured a specific immune marker: GPR15 expression on helper T cells. Both tobacco and cannabis smoking were strongly associated with increased GPR15 expression (p < 0.001), and that increase was in turn strongly associated with a shift toward pro-inflammatory cytokine ratios.\n\nThe key finding was the mediation analysis: increased GPR15 expression accounted for roughly half of the relationship between smoking (either substance) and pro-inflammatory immune markers. In other words, GPR15 appeared to be a major pathway through which both tobacco and cannabis drive systemic inflammation.\n\nThis was notable because cannabis and tobacco smoke have different active compounds (THC/cannabinoids vs nicotine) but share the combustion products — tar, carbon monoxide, particulate matter. The shared GPR15 pathway suggests it's the smoke itself, not the specific drug, driving much of the inflammatory response.","whyItMatters":"This study bridged cannabis and tobacco research by showing they share an inflammatory mechanism. The implication is direct: if you smoke cannabis, your immune system responds to the combustion much like it responds to tobacco smoke. The active ingredient may be different, but the inflammatory damage from inhaling burned plant matter is similar.\n\nThis matters for the \"cannabis is safer than tobacco\" narrative. For the specific dimension of systemic inflammation via inhaled smoke, they appear to be comparably harmful. Vaporizing or edibles would avoid this pathway entirely.","specificNumbers":"• Both tobacco and cannabis: strongly associated with increased GPR15 (p < 0.001)\n• GPR15 accounted for ~50% of smoking's effect on pro-inflammatory cytokine ratios\n• Sample: 62 young adults, primarily African American, aged 27-35\n• Measured: CRP + 17 cytokines alongside GPR15 T cell expression","methodology":"Cross-sectional study of 62 primarily African American young adults (aged 27-35). Measured GPR15+CD3+CD4+ helper T cells via flow cytometry. Serum assays for CRP and 17 cytokines. Smoking quantified via cotinine (tobacco) and THC (cannabis) serum biomarkers. Correlational analyses and linear regression with mediation analysis.","limitations":"Small sample size (n=62) limits statistical power and generalizability. Cross-sectional design cannot establish causation. Primarily African American sample may not represent other populations. Cannot fully separate cannabis and tobacco effects since many participants used both. Serum THC measures recent use but not chronic exposure patterns."},{"rthcId":"RTHC-02967","title":"Citalopram and Cannabidiol: In Vitro and In Vivo Evidence of Pharmacokinetic Interactions Relevant to the Treatment of Anxiety Disorders in Young People.","authors":"Anderson, Lyndsey L; Doohan, Peter T; Oldfield, Lachlan; Kevin, Richard C; Arnold, Jonathon C; Berger, Maximus; Amminger, G Paul; McGregor, Iain S","year":2021,"journal":"Journal of clinical psychopharmacology, 41(5), 525-533","doi":"10.1097/JCP.0000000000001427","pmid":"34121064","tags":["anxiety","cbd","drug-interactions","youth","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study combined lab work and real patient data to examine whether CBD interacts with common antidepressants. In vitro, CBD inhibited the metabolism of citalopram and, to a lesser extent, other SSRIs by blocking CYP enzymes.\n\nThe in vivo confirmation was more concerning. In 6 patients with anxiety disorders who were on stable citalopram or escitalopram doses, adding CBD at doses of 200-800 mg/day increased citalopram blood levels by approximately 50%. That's a substantial increase — enough to potentially cause side effects like serotonin syndrome symptoms, QT prolongation, or increased sedation.\n\nThe interaction was dose-dependent: higher CBD doses produced larger increases in SSRI blood levels. CBD minimally affected sertraline and mirtazapine metabolism in vitro, suggesting the interaction is somewhat SSRI-specific rather than universal across antidepressants.","whyItMatters":"CBD is increasingly marketed for anxiety, and many people taking it for anxiety are already on SSRIs. This study showed that combination isn't pharmacologically neutral. A 50% increase in SSRI blood levels is the kind of change that turns a therapeutic dose into a potentially problematic one.\n\nThis is especially important because CBD products are widely available without prescription, and most users don't consult a physician before combining them with their medications. The doses in this study (200-800 mg) are available in commercial CBD products.","specificNumbers":"• CBD increased citalopram blood levels by ~50% in 6 patients\n• CBD doses tested: 200-800 mg/day (ascending over 12 weeks)\n• Citalopram and escitalopram most affected; sertraline and mirtazapine minimally affected\n• Interaction mechanism: CYP enzyme inhibition (primarily CYP3A4, CYP2C19)","methodology":"Two-part study. In vitro: tested CBD's inhibitory effects on CYP450-mediated metabolism of fluoxetine, sertraline, citalopram, and mirtazapine using human liver microsomes. In vivo: measured citalopram/escitalopram plasma levels in 6 anxiety disorder patients receiving ascending CBD doses (200-800 mg/day) over 12 weeks in a clinical trial setting.","limitations":"Only 6 patients in the clinical component — very small sample. Only citalopram/escitalopram tested in vivo. The CBD doses (200-800 mg) are higher than many commercial products but available. In vitro results may not perfectly predict in vivo interactions. No control group in the clinical arm."},{"rthcId":"RTHC-02968","title":"Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy.","authors":"Anderson, Lyndsey L; Heblinski, Marika; Absalom, Nathan L; Hawkins, Nicole A; Bowen, Michael T; Benson, Melissa J; Zhang, Fan; Bahceci, Dilara; Doohan, Peter T; Chebib, Mary; McGregor, Iain S; Kearney, Jennifer A; Arnold, Jonathon C","year":2021,"journal":"British journal of pharmacology, 178(24), 4826-4841","doi":"10.1111/bph.15661","pmid":"34384142","tags":["epilepsy","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Screening identified CBGA, CBDVA, and CBGVA as novel anticonvulsants. CBGA was most potent and potentiated clobazam against both heat-induced and spontaneous seizures in Scn1a+/- (Dravet) mice. However, CBGA was proconvulsant in the 6-Hz threshold test and a high dose increased spontaneous seizure frequency. CBGA interacted with GPR55, TRPV1, and GABA-A receptors.","whyItMatters":"Artisanal cannabis products for childhood epilepsy often contain phytocannabinoids beyond CBD. Identifying which compounds help and which may actually worsen certain seizure types is critical for safe product development.","specificNumbers":"CBGA, CBDVA, and CBGVA identified as anticonvulsant. CBGA potentiated clobazam in Dravet model. CBGA proconvulsant in 6-Hz test. High-dose CBGA increased spontaneous seizure frequency. CBGA interacted with GPR55, TRPV1, GABA-A receptors.","methodology":"Scn1a+/- mouse model of Dravet syndrome tested against hyperthermia-induced and spontaneous seizures. MES and 6-Hz threshold models also used. Pharmacological profiling across multiple epilepsy-relevant targets (GPR55, TRPV1, GABA-A receptors).","limitations":"Mouse models may not predict human responses. The proconvulsant effects at higher doses raise safety concerns. Only one genetic model of epilepsy (Scn1a+/-) was tested. Drug interactions with clobazam could be pharmacokinetic rather than pharmacodynamic."},{"rthcId":"RTHC-02969","title":"Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations.","authors":"Anderson, Lyndsey L; Etchart, Maia G; Bahceci, Dilara; Golembiewski, Taliesin A; Arnold, Jonathon C","year":2021,"journal":"Scientific reports, 11(1), 14948","doi":"10.1038/s41598-021-94212-6","pmid":"34294753","tags":["cbd","medical-cannabis","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Plasma CBDA concentrations were 14-fold higher from cannabis extract versus isolated CBDA at the same dose. In vitro testing identified CBDA as a substrate of the BCRP efflux transporter. CBG and THC inhibited BCRP-mediated transport of CBDA. This cannabinoid-cannabinoid pharmacokinetic interaction at intestinal BCRP transporters explains the dramatic increase in absorption.","whyItMatters":"This is one of the first mechanistic demonstrations of a pharmacokinetic \"entourage effect.\" It means CBDA from whole-plant extracts reaches much higher blood levels than expected from its dose, with implications for both efficacy and dosing.","specificNumbers":"CBDA plasma levels 14x higher from extract vs. isolated compound. CBDA identified as BCRP substrate. CBG and THC inhibited BCRP transport of CBDA.","methodology":"Mouse pharmacokinetic comparison of cannabinoids administered as cannabis extract versus individual compounds at equivalent doses. In vitro BCRP transwell transport assays identified the drug interaction mechanism.","limitations":"Mouse pharmacokinetics may differ from humans. Only CBDA absorption was dramatically affected; other cannabinoids may not show the same magnitude of interaction. The clinical significance of elevated CBDA levels depends on CBDA having its own therapeutic effects."},{"rthcId":"RTHC-02970","title":"Assessment of Cannabidiol and Δ9-Tetrahydrocannabiol in Mouse Models of Medulloblastoma and Ependymoma.","authors":"Andradas, Clara; Byrne, Jacob; Kuchibhotla, Mani; Ancliffe, Mathew; Jones, Anya C; Carline, Brooke; Hii, Hilary; Truong, Alexandra; Storer, Lisa C D; Ritzmann, Timothy A; Grundy, Richard G; Gottardo, Nicholas G; Endersby, Raelene","year":2021,"journal":"Cancers, 13(2)","doi":"10.3390/cancers13020330","pmid":"33477420","tags":["cancer","cbd","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC and CBD induced dose-dependent cell death in medulloblastoma and ependymoma cell lines, with synergistic effects in combination. Mechanisms included cell cycle arrest, reactive oxygen species production, autophagy, and apoptosis. However, neither cannabinoids alone, in combination, nor combined with cyclophosphamide improved survival in orthotopic transplant models despite being well tolerated.","whyItMatters":"This study illustrates a critical gap in cancer cannabinoid research: laboratory cell-killing effects do not necessarily translate to meaningful tumor control in living organisms. It serves as a cautionary note against overinterpreting in vitro results.","specificNumbers":"Dose-dependent cytotoxicity in vitro. Synergistic viability reduction when THC and CBD combined. No survival improvement in orthotopic models. No survival benefit from cannabinoid + cyclophosphamide combination. Treatment was well tolerated.","methodology":"In vitro cytotoxicity, cell cycle, and mechanistic studies in medulloblastoma and ependymoma cell lines. In vivo orthotopic transplant models in mice for survival analysis. THC and CBD tested alone and in combination, and with the chemotherapy drug cyclophosphamide.","limitations":"Orthotopic models may not perfectly replicate human pediatric brain tumors. Only one combination ratio and dosing schedule tested. The blood-brain barrier may have limited cannabinoid delivery to tumors. Cell line results may not represent tumor heterogeneity."},{"rthcId":"RTHC-02971","title":"Community nurses' support for patients with fibromyalgia who use cannabis to manage pain.","authors":"Andrews, Natasha J; Phillips, Adele J","year":2021,"journal":"British journal of community nursing, 26(2), 92-98","doi":"10.12968/bjcn.2021.26.2.92","pmid":"33539238","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02972","title":"Cannabis compounds exhibit anti-inflammatory activity in vitro in COVID-19-related inflammation in lung epithelial cells and pro-inflammatory activity in macrophages.","authors":"Anil, Seegehalli M; Shalev, Nurit; Vinayaka, Ajjampura C; Nadarajan, Stalin; Namdar, Dvora; Belausov, Eduard; Shoval, Irit; Mani, Karthik Ananth; Mechrez, Guy; Koltai, Hinanit","year":2021,"journal":"Scientific reports, 11(1), 1462","doi":"10.1038/s41598-021-81049-2","pmid":"33446817","tags":["inflammation","cbd","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The cannabis fraction (FCBD, containing CBD, CBG, and THCV) dose-dependently reduced IL-6, IL-8, CCL2, CCL7, and ACE2 expression in A549 lung epithelial cells. However, FCBD increased IL-6 and IL-8 in macrophages while inducing polarization and phagocytosis. A synthetic phytocannabinoid formulation (FCBD:std) maintained anti-inflammatory activity in lung cells while reducing pro-inflammatory effects in macrophages.","whyItMatters":"COVID-19 can cause severe lung inflammation. While cannabis compounds showed anti-inflammatory effects in lung cells, the opposite effect in immune cells highlights the complexity of using cannabinoids for inflammatory conditions and argues against simplistic claims about cannabis for COVID.","specificNumbers":"FCBD reduced IL-6 and IL-8 dose-dependently in A549 cells. FCBD reduced ACE2 expression. FCBD increased IL-6 and IL-8 in macrophages. FCBD:std reduced macrophage pro-inflammatory effects compared to FCBD. FCBD contained CBD, CBG, and THCV plus terpenes.","methodology":"In vitro study using A549 alveolar epithelial cells and differentiated KG1 macrophages. Cannabis extract fraction (FCBD) and a phytocannabinoid standard formulation (FCBD:std) tested for effects on COVID-19-relevant inflammatory markers, ACE2 expression, macrophage polarization, and phagocytosis.","limitations":"In vitro cell line study, not clinical research. A549 and KG1 cell lines may not represent actual human lung and immune cells during COVID-19 infection. No virus was used; only inflammatory markers were measured. The extract composition may vary between batches."},{"rthcId":"RTHC-02973","title":"Attitudes towards and use of cannabis in New Zealand patients with inflammatory bowel disease: an exploratory study.","authors":"Appleton, Kerry; Whittaker, Elizabeth; Cohen, Zarife; Rhodes, Heather May; Dunn, Cathy; Murphy, Siobhan; Gaastra, Mabel; Galletly, Anna; Dougherty, Sean; Haren, Andrew; Sukumaran, Nitin; Aluzaite, Kristina; Dockerty, John D; Turner, Robin M; Schultz, Michael","year":2021,"journal":"The New Zealand medical journal, 134(1530), 38-47","doi":null,"pmid":"33651776","tags":["medical-cannabis","inflammation","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"51% reported ever using cannabis. Of users, 63% used recreationally and 31% for IBD symptom reduction. Cannabis users were younger (by 6.4 years), more likely to have ongoing symptoms, unemployed/self-employed, and current/ex-smokers. Most reported improvements in abdominal pain/cramping, nausea/vomiting, and appetite. 54% of all participants said they would request medicinal cannabis if legal.","whyItMatters":"IBD patients are using cannabis regardless of legal status and reporting symptom benefits. Understanding these patterns can help clinicians have informed conversations and guide future clinical trial design.","specificNumbers":"334 eligible respondents (84% NZ European, 71% female). 61% Crohn's, 34% UC. 51% ever used cannabis. 31% of users for IBD symptoms. Symptoms improved: abdominal pain, nausea, appetite. 54% would request medicinal cannabis if legal.","methodology":"Anonymous online questionnaire distributed to IBD patients via hospital database and Crohn's and Colitis New Zealand. 378 respondents, 334 eligible. Assessed cannabis use patterns, motivations, symptom effects, and attitudes toward legalization.","limitations":"Self-selected sample with possible response bias. Self-reported symptom improvements without objective measures. New Zealand population may not represent other regions. Cross-sectional design cannot establish causation."},{"rthcId":"RTHC-02974","title":"Cannabinoid treatment for autism: a proof-of-concept randomized trial.","authors":"Aran, Adi; Harel, Moria; Cassuto, Hanoch; Polyansky, Lola; Schnapp, Aviad; Wattad, Nadia; Shmueli, Dorit; Golan, Daphna; Castellanos, F Xavier","year":2021,"journal":"Molecular autism, 12(1), 6","doi":"10.1186/s13229-021-00420-2","pmid":"33536055","tags":["cbd","youth","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The primary outcome (HSQ-ASD Total Score) showed no significant difference between groups. However, 49% on whole-plant extract versus 21% on placebo showed much/very much improved disruptive behavior on CGI-I (co-primary, p=0.005). SRS Total Score improved by 14.9 vs. 3.6 points (secondary, p=0.009). Common side effects: somnolence (28%) and decreased appetite (25%). No serious treatment-related adverse events.","whyItMatters":"This is one of the first placebo-controlled trials of cannabinoids specifically for autism. The mixed results (positive on some measures, negative on the primary outcome) suggest cannabinoids may help certain autism symptoms but are not a broad-spectrum treatment.","specificNumbers":"150 participants ages 5-21. Primary outcome (HSQ-ASD): no difference. CGI-I disruptive behavior: 49% vs. 21% improved (p=0.005). SRS: 14.9 vs. 3.6 point improvement (p=0.009). Somnolence 28%, decreased appetite 25% on extract. No serious AEs.","methodology":"Placebo-controlled, double-blind trial of 150 participants ages 5-21 with ASD. Tested whole-plant extract (BOL-DP-O-01-W, CBD:THC 20:1) and purified cannabinoids (BOL-DP-O-01, same ratio). 12-week efficacy period, 4-week washout, then crossover for 12 more weeks.","limitations":"Primary outcome was negative. Wide age range (5-21) and functional levels among participants. No pharmacokinetic data. The crossover design makes longer-term efficacy assessment difficult. Relatively high somnolence rate."},{"rthcId":"RTHC-02975","title":"Clinical Evidence of Magistral Preparations Based on Medicinal Cannabis.","authors":"Arias, Sara; Leon, Marta; Jaimes, Diego; Bustos, Rosa-Helena","year":2021,"journal":"Pharmaceuticals (Basel, Switzerland), 14(2)","doi":"10.3390/ph14020078","pmid":"33494156","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02976","title":"Medical cannabis and driving.","authors":"Arkell, Thomas R; McCartney, Danielle; McGregor, Iain S","year":2021,"journal":"Australian journal of general practice, 50(6), 357-362","doi":"10.31128/AJGP-02-21-5840","pmid":"34059836","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02977","title":"The failings of per se limits to detect cannabis-induced driving impairment: Results from a simulated driving study.","authors":"Arkell, Thomas R; Spindle, Tory R; Kevin, Richard C; Vandrey, Ryan; McGregor, Iain S","year":2021,"journal":"Traffic injury prevention, 22(2), 102-107","doi":"10.1080/15389588.2020.1851685","pmid":"33544004","tags":["driving","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"At 30 minutes after vaporizing THC, 46% of participants who exceeded legal THC blood limits showed no measurable driving impairment. At 3.5 hours, 57% showed impairment despite having THC levels below legal limits.","whyItMatters":"Many jurisdictions base impaired driving laws on THC blood concentration thresholds. If those thresholds can't distinguish impaired from unimpaired drivers, innocent people may be penalized while genuinely impaired drivers go undetected.","specificNumbers":"14 participants; 46% not impaired at 30 min despite exceeding THC limits; 57% impaired at 3.5 hours despite THC below limits; median blood THC at 3.5h was 1.0 ng/mL","methodology":"14 infrequent cannabis users completed simulated driving tests at two timepoints under three conditions (THC-dominant, THC/CBD, placebo), with blood and oral fluid THC measured against various per se limits.","limitations":"Very small sample (14 participants), all infrequent users, simulated rather than real-world driving, single dose tested."},{"rthcId":"RTHC-02978","title":"Prevalence, sociodemographic variables, mental health condition, and type of drug use associated with suicide behaviors among people with substance use disorders: a systematic review and meta-analysis.","authors":"Armoon, Bahram; SoleimanvandiAzar, Neda; Fleury, Marie-Josée; Noroozi, Alireza; Bayat, Amir-Hossein; Mohammadi, Rasool; Ahounbar, Elahe; Fattah Moghaddam, Ladan","year":2021,"journal":"Journal of addictive diseases, 39(4), 550-569","doi":"10.1080/10550887.2021.1912572","pmid":"33896407","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02979","title":"Illicit Cannabis Usage as a Management Strategy in New Zealand Women with Endometriosis: An Online Survey.","authors":"Armour, Mike; Sinclair, Justin; Noller, Geoff; Girling, Jane; Larcombe, Maria; Al-Dabbas, Mahmoud A; Hollow, Erika; Bush, Deborah; Johnson, Neil","year":2021,"journal":"Journal of women's health (2002), 30(10), 1485-1492","doi":"10.1089/jwh.2020.8668","pmid":"33275491","tags":["pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among endometriosis patients using cannabis, 95.5% used it for pain relief, 81% rated their pain as \"much better,\" and 81.4% reported reducing their pharmaceutical medications, with 59% completely stopping at least one medication.","whyItMatters":"Endometriosis affects about 10% of women worldwide, and many struggle with adequate pain management. If cannabis provides meaningful relief, it could represent a less harmful alternative to opioids and other analgesics for some patients.","specificNumbers":"213 respondents; mean age 32; 79.8% current cannabis users; 95.5% used for pain; 81% said pain was \"much better\"; 81.4% reduced medications; 59% stopped at least one medication completely; 40% of stopped analgesics were opioids","methodology":"Cross-sectional online survey of people using cannabis for health conditions in New Zealand (May-July 2019), analyzing the subset of 213 respondents with endometriosis diagnoses.","limitations":"Self-selected online sample, self-reported diagnoses and outcomes, no control group, cross-sectional design prevents causal conclusions, respondents already using cannabis may be biased toward positive reports."},{"rthcId":"RTHC-02980","title":"Gender Differences in Patterns and Correlates of Continued Substance Use among Patients in Methadone Maintenance Treatment.","authors":"Arnold, Tomorrow D; Lin, Lewei Allison; Cotton, Brandi P; Bryson, William C; Polenick, Courtney A","year":2021,"journal":"Substance use & misuse, 56(4), 529-538","doi":"10.1080/10826084.2021.1887242","pmid":"33645425","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02981","title":"Alcohol and cannabis motives: Differences in daily motive endorsement on alcohol, cannabis, and alcohol/cannabis co-use days in a cannabis-using sample.","authors":"Arterberry, Brooke J; Goldstick, Jason E; Walton, Maureen A; Cunningham, Rebecca M; Blow, Frederic C; Bonar, Erin E","year":2021,"journal":"Addiction research & theory, 29(2), 111-116","doi":"10.1080/16066359.2020.1787390","pmid":"34248450","tags":["addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Greater cannabis-related enhancement and social motives were associated with increased likelihood of same-day alcohol/cannabis co-use compared to cannabis-only days. Alcohol-related social motives showed a weaker, non-significant association in adjusted models.","whyItMatters":"Same-day use of alcohol and cannabis increases the risk of negative consequences. Understanding that cannabis-related positive affect motives drive co-use may help intervention programs target the right motivations.","specificNumbers":"97 participants; ages 18-25; 28 daily assessments; 126 alcohol-only days; 805 cannabis-only days; 237 co-use days","methodology":"28-day daily diary study of 97 young adults aged 18-25, recruited from an urban emergency department, who received daily text message assessments about substance use and motives. Fixed effects regression estimated within-person effects.","limitations":"Emergency department sample may not generalize to the broader population, self-reported motives, relatively small sample, short 28-day observation period."},{"rthcId":"RTHC-02982","title":"An Autonomous Cannabinoid System in Islets of Langerhans.","authors":"Aseer, Kanikkai Raja; Egan, Josephine M","year":2021,"journal":"Frontiers in endocrinology, 12, 699661","doi":"10.3389/fendo.2021.699661","pmid":"34290671","tags":["medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Pancreatic beta cells contain a complete endocannabinoid system, including synthesis and degradation enzymes, primarily signaling through CB1 receptors. This system modulates insulin secretion and beta cell responses to stressors, and CB1 receptor blockers have shown potential to mitigate beta cell damage.","whyItMatters":"Understanding how the endocannabinoid system operates within the pancreas could open new treatment avenues for type 2 diabetes and obesity-related metabolic dysfunction, particularly through CB1 receptor-targeting drugs.","specificNumbers":"CB1 receptors present on all beta cells; CB1 and CB2 receptors both belong to G protein-coupled receptor superfamily","methodology":"Comprehensive literature review of preclinical and clinical studies on the endocannabinoid system's role in pancreatic islet function.","limitations":"Most evidence comes from preclinical (animal and cell) studies. Human islet physiology data remain limited. No clinically approved CB receptor modulators for diabetes exist yet."},{"rthcId":"RTHC-02983","title":"Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CB1/CB2 Receptor Interaction.","authors":"Asproni, Battistina; Murineddu, Gabriele; Corona, Paola; Pinna, Gérard A","year":2021,"journal":"Molecules (Basel, Switzerland), 26(8)","doi":"10.3390/molecules26082126","pmid":"33917187","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02984","title":"Pain Profiles among Young Adult Cannabis Users: An Analysis of Antecedent Factors and Distal Outcomes.","authors":"Ataiants, Janna; Fedorova, Ekaterina V; Wong, Carolyn F; Iverson, Ellen; Gold, Jeffrey I; Lankenau, Stephen E","year":2021,"journal":"Substance use & misuse, 56(8), 1144-1154","doi":"10.1080/10826084.2021.1910707","pmid":"33882778","tags":["pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Three pain classes emerged: Low pain (56.3%), Multiple pain (27.3%), and Nonspecific pain (16.4%). The Multiple pain group had higher rates of psychological distress, medical cannabis use, edible consumption, and using cannabis for sleep compared to other groups.","whyItMatters":"Not all young cannabis users are alike. Those with multiple pain conditions use cannabis differently and may benefit from targeted clinical approaches rather than one-size-fits-all messaging.","specificNumbers":"56.3% Low pain class; 27.3% Multiple pain; 16.4% Nonspecific pain; insomnia associated with both higher-pain classes; Hispanic/Latino participants more likely in Multiple pain class","methodology":"Latent class analysis of past-30-day cannabis users aged 18-26 enrolled in Los Angeles in 2014-2015, examining pain histories, cannabis use patterns, and mental health characteristics.","limitations":"Cross-sectional design prevents causal conclusions, self-reported pain and cannabis use, Los Angeles sample may not generalize nationally, data from 2014-2015 predates many state legalization changes."},{"rthcId":"RTHC-02985","title":"Association between gestational cannabis exposure and maternal, perinatal, placental, and childhood outcomes.","authors":"Ayonrinde, Oyekoya T; Ayonrinde, Oyedeji A; Van Rooyen, Derrick; Tait, Robert; Dunn, Mikaela; Mehta, Shailender; White, Scott; Ayonrinde, Oyekunle K","year":2021,"journal":"Journal of developmental origins of health and disease, 12(5), 694-703","doi":"10.1017/S2040174420001166","pmid":"33280638","tags":["pregnancy","youth"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis use during pregnancy has been associated with increased risk of other substance use, impaired placental blood flow, small-for-gestational-age births, and potential childhood outcomes including increased risk of depression and ADHD. Maternal metabolic effects may include fatty liver, obesity, and gestational diabetes.","whyItMatters":"With cannabis legalization expanding and THC potency increasing, more pregnant women may use cannabis. Understanding the full range of potential risks is critical for informed decision-making.","specificNumbers":"THC potency has progressively increased over several decades; endometriosis affects approximately 10% of women (context for pain-driven use during pregnancy)","methodology":"Narrative review examining epidemiological and clinical evidence on cannabis exposure during pregnancy and lactation, including effects on pregnancy outcomes, placental health, and child development.","limitations":"Much of the evidence is observational and cannot establish causation. Confounding factors (tobacco, alcohol, socioeconomic status) are difficult to fully control. Childhood and adolescent outcomes are sparsely assessed."},{"rthcId":"RTHC-02986","title":"Δ8-THC: Legal Status, Widespread Availability, and Safety Concerns.","authors":"Babalonis, Shanna; Raup-Konsavage, Wesley M; Akpunonu, Peter D; Balla, Agnes; Vrana, Kent E","year":2021,"journal":"Cannabis and cannabinoid research, 6(5), 362-365","doi":"10.1089/can.2021.0097","pmid":"34662224","tags":["potency","harm-reduction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Delta-8 THC products are widely available without regulation despite being classified as Schedule I by the DEA. The lack of required warning labels, packaging protections, or lab testing has led to medical emergencies including pediatric patients arriving unconscious and unresponsive.","whyItMatters":"Millions of people can purchase delta-8 THC products with no quality control, no dosing guidance, and no childproof packaging. The regulatory gap between federal classification and real-world availability creates genuine public health risks.","specificNumbers":"Classified as Schedule I by DEA; sold in gas stations, online, and outside authorized dispensaries; pediatric patients reported unconscious and unresponsive from exposure","methodology":"Commentary reviewing the legal status, availability, and reported safety concerns of delta-8 THC products in the United States.","limitations":"This is a commentary piece, not a systematic review. Specific prevalence data on adverse events is limited. The legal landscape continues to shift at both state and federal levels."},{"rthcId":"RTHC-02987","title":"Integrating substance use care into primary care for adolescents and young adults: Lessons learned.","authors":"Bagley, Sarah M; Hadland, Scott E; Schoenberger, Samantha F; Gai, Mam Jarra; Topp, Deric; Hallett, Eliza; Ashe, Erin; Samet, Jeffrey H; Walley, Alexander Y","year":2021,"journal":"Journal of substance abuse treatment, 129, 108376","doi":"10.1016/j.jsat.2021.108376","pmid":"34080547","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02988","title":"The role of endocannabinoid pathway in the neuropathology of Alzheimer's disease: Can the inhibitors of MAGL and FAAH prove to be potential therapeutic targets against the cognitive impairment associated with Alzheimer's disease?","authors":"Bajaj, Shivanshu; Jain, Shreshta; Vyas, Preeti; Bawa, Sandhya; Vohora, Divya","year":2021,"journal":"Brain research bulletin, 174, 305-322","doi":"10.1016/j.brainresbull.2021.06.022","pmid":"34217798","tags":["neuroscience","cognition"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"MAGL and FAAH inhibitors have shown potential to protect neurons from amyloid-beta toxicity, reduce tau phosphorylation, combat oxidative stress, and stimulate neurotrophins that support brain repair. These effects have been demonstrated across multiple preclinical Alzheimer's models.","whyItMatters":"Current Alzheimer's treatments target single pathways and have limited efficacy. Endocannabinoid-modulating drugs could address multiple disease mechanisms simultaneously, potentially offering a more comprehensive treatment approach.","specificNumbers":"MAGL degrades 2-AG; FAAH degrades AEA; both enzyme types have been studied across multiple Alzheimer's disease models","methodology":"Narrative review summarizing preclinical studies on MAGL and FAAH inhibitors in Alzheimer's disease models, including their effects on neurodegeneration, inflammation, and cognitive function.","limitations":"Nearly all evidence comes from animal models. No MAGL or FAAH inhibitors have been tested in human Alzheimer's trials. The exact signaling mechanisms are not fully understood. Translation from preclinical to clinical efficacy is uncertain."},{"rthcId":"RTHC-02989","title":"Cannabidiol Interactions with Medications, Illicit Substances, and Alcohol: a Comprehensive Review.","authors":"Balachandran, Premalatha; Elsohly, Mahmoud; Hill, Kevin P","year":2021,"journal":"Journal of general internal medicine, 36(7), 2074-2084","doi":"10.1007/s11606-020-06504-8","pmid":"33515191","tags":["cbd","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD has confirmed or suspected drug interactions with anti-epileptic drugs, antidepressants, opioid analgesics, THC, acetaminophen, and alcohol. These interactions occur through multiple pharmacokinetic mechanisms, primarily involving cytochrome P450 enzyme inhibition.","whyItMatters":"With CBD products available everywhere and often used alongside prescription medications, the lack of awareness about these interactions creates real risks for adverse effects, particularly in people taking anti-seizure medications or opioids.","specificNumbers":"FDA-approved CBD (Epidiolex) treats Dravet syndrome and Lennox-Gastaut syndrome; interactions identified with anti-epileptics, antidepressants, opioids, THC, acetaminophen, and alcohol","methodology":"Systematic literature search across online databases compiling all reported CBD drug-drug interactions, with mechanisms categorized and presented in table format.","limitations":"Many reported interactions are based on case reports or small studies. Some interactions are theorized based on metabolic pathways but not confirmed clinically. CBD doses in studies vary widely."},{"rthcId":"RTHC-02990","title":"Abrupt cessation of reboxetine along alcohol deprivation results in alcohol intake escalation after reinstatement of drinking.","authors":"Ballesta, Antonio; Alen, Francisco; Orio, Laura; Arco, Rocío; Vadas, Evelyn; Decara, Juan; Vargas, Antonio; Gómez de Heras, Raquel; Ramírez-López, Mayte; Serrano, Antonia; Pavón, Francisco Javier; Suárez, Juan; Rodríguez de Fonseca, Fernando","year":2021,"journal":"Addiction biology, 26(3), e12957","doi":"10.1111/adb.12957","pmid":"32815666","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02991","title":"Cannabis and synaptic reprogramming of the developing brain.","authors":"Bara, Anissa; Ferland, Jacqueline-Marie N; Rompala, Gregory; Szutorisz, Henrietta; Hurd, Yasmin L","year":2021,"journal":"Nature reviews. Neuroscience, 22(7), 423-438","doi":"10.1038/s41583-021-00465-5","pmid":"34021274","tags":["youth","neuroscience","pregnancy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis exposure during prenatal/perinatal and adolescent periods disrupts the endocannabinoid system's role in neurodevelopment, impairing synaptic plasticity. These effects are maintained through epigenetic changes that persist into adulthood and can be transmitted to subsequent generations.","whyItMatters":"With increased cannabis acceptance and rising THC potency, more pregnant women and teens are using cannabis. Understanding that these exposures can permanently alter brain wiring and even affect future generations adds urgency to public health messaging.","specificNumbers":"THC potency has increased substantially in recent decades; effects documented across prenatal, perinatal, and adolescent exposure windows","methodology":"Review article in Nature Reviews Neuroscience synthesizing preclinical and clinical evidence on cannabinoid effects during developmental periods, with emphasis on epigenetic mechanisms.","limitations":"Much of the evidence on transgenerational effects comes from animal studies. Human longitudinal data tracking epigenetic changes across generations is extremely limited. Environmental factors that might mitigate or reverse epigenetic changes need more study."},{"rthcId":"RTHC-02992","title":"Efficacy of Cannabidiol for Δ-9-Tetrahydrocannabinol-Induced Psychotic Symptoms, Schizophrenia, and Cannabis Use Disorders: A Narrative Review.","authors":"Bartoli, Francesco; Riboldi, Ilaria; Bachi, Bianca; Calabrese, Angela; Moretti, Federico; Crocamo, Cristina; Carrà, Giuseppe","year":2021,"journal":"Journal of clinical medicine, 10(6)","doi":"10.3390/jcm10061303","pmid":"33810033","tags":["cbd","psychosis","mental-health"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Across 10 clinical studies, CBD appeared to reduce psychotic-like symptoms triggered by THC in healthy volunteers and positive symptoms in people with schizophrenia. However, results for CBD as a treatment for cannabis use disorder were mixed.","whyItMatters":"If CBD can counteract THC-related psychosis while also having antipsychotic properties, it could represent a novel treatment approach that targets both substance use and psychotic disorders simultaneously.","specificNumbers":"10 clinical studies included; CBD evaluated for three indications: THC-induced psychotic symptoms, schizophrenia, and cannabis use disorders","methodology":"Narrative review searching PubMed, Cochrane Library, and ClinicalTrials.gov for clinical studies evaluating CBD for THC-induced psychosis, schizophrenia, and cannabis use disorders. Ten studies met inclusion criteria.","limitations":"Only 10 studies available, most with small sample sizes. No study examined co-occurring psychotic and cannabis use disorders together. The review is narrative rather than systematic."},{"rthcId":"RTHC-02993","title":"Increased Testing and Health Care Costs for Pediatric Cannabis Exposures.","authors":"Bashqoy, Ferras; Heizer, Justin W; Reiter, Pamela D; Wang, George S; Borgelt, Laura M","year":2021,"journal":"Pediatric emergency care, 37(12), e850-e854","doi":"10.1097/PEC.0000000000001811","pmid":"30998654","tags":["youth","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Children with unrecognized cannabis exposure underwent an average of 8.91 diagnostic tests compared to 4 for those where exposure was quickly identified, with more than 4-fold higher costs for potentially avoidable tests. Children's hospital stays averaged 18.34 hours versus 4.22 hours for adolescents.","whyItMatters":"As cannabis products become more available, accidental pediatric exposures may increase. Delayed recognition leads to unnecessary testing, higher costs, and prolonged hospital stays that could be avoided with better awareness and reporting.","specificNumbers":"37 children, 38 adolescents; mean time to recognition 2.3 hours (children) vs 0.4 hours (adolescents); 8.91 vs 4 diagnostic tests; 4-fold higher avoidable test costs; 18.34 vs 4.22 hours hospital stay","methodology":"Retrospective chart review of 75 patients (37 children, 38 adolescents) ages 31 days to 20 years with positive marijuana toxicology screens at a children's hospital emergency department from November 2009 to December 2014.","limitations":"Retrospective single-center study, relatively small sample, data from 2009-2014 predates widespread legalization, cannot account for all confounders in testing decisions."},{"rthcId":"RTHC-02994","title":"Cannabis use does not impact on type 2 diabetes: A two-sample Mendelian randomization study.","authors":"Baumeister, Sebastian-Edgar; Nolde, Michael; Alayash, Zoheir; Leitzmann, Michael; Baurecht, Hansjörg; Meisinger, Christa","year":2021,"journal":"Addiction biology, 26(6), e13020","doi":"10.1111/adb.13020","pmid":"33580533","tags":["cardiovascular","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using genetic variants as proxies for cannabis use, researchers found no causal effect of either lifetime cannabis use (OR 1.00, 95% CI 0.93-1.09) or cannabis use disorder (OR 1.03, 95% CI 0.99-1.08) on type 2 diabetes risk.","whyItMatters":"Previous observational studies have produced conflicting results about cannabis and diabetes risk. By using genetic variants as natural experiments, this study provides stronger evidence that the relationship (or lack thereof) is unlikely to be due to confounding.","specificNumbers":"184,765 participants for lifetime cannabis use analysis; 2,387 cases/48,985 controls for cannabis use disorder; 74,124 cases/824,006 controls for type 2 diabetes; OR = 1.00 (95% CI 0.93-1.09) for lifetime use","methodology":"Two-sample Mendelian randomization using 19 genetic variants for lifetime cannabis use and 14 for cannabis use disorder, linked to type 2 diabetes outcomes from genome-wide association studies totaling over 900,000 participants.","limitations":"Mendelian randomization assumes genetic variants only affect diabetes through cannabis use, which may not hold perfectly. European-ancestry population may not generalize to other groups. Cannabis use disorder had a relatively small case sample."},{"rthcId":"RTHC-02995","title":"Flavonoids in Cannabis sativa: Biosynthesis, Bioactivities, and Biotechnology.","authors":"Bautista, Johanna L; Yu, Shu; Tian, Li","year":2021,"journal":"ACS omega, 6(8), 5119-5123","doi":"10.1021/acsomega.1c00318","pmid":"33681553","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02996","title":"Cannabis, alcohol and other drug findings in fatally injured drivers in Ontario.","authors":"Beirness, Douglas J; Gu, Kai Wen; Lowe, Nicholas J; Woodall, Karen L; Desrosiers, Nathalie A; Cahill, Brent; Porath, Amy J; Peaire, Amy","year":2021,"journal":"Traffic injury prevention, 22(1), 1-6","doi":"10.1080/15389588.2020.1847281","pmid":"33275453","tags":["driving","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 921 driver fatalities, 53.7% tested positive for at least one substance. THC positivity (251 cases) exceeded alcohol (241 cases). Alcohol-related fatalities clustered on weekends in single-vehicle crashes, while THC-positive fatalities were spread throughout the week and more often involved multi-vehicle crashes.","whyItMatters":"The finding that THC now appears in more fatally injured drivers than alcohol signals a shift in impaired driving patterns that requires new prevention strategies beyond traditional alcohol-focused approaches.","specificNumbers":"921 driver fatalities; 53.7% tested positive for a substance; 251 THC-positive; 241 alcohol-positive; 235 positive for other drugs; 38% of positive cases had multiple substances","methodology":"Toxicological analysis of postmortem blood samples from 921 drivers who died in crashes in Ontario, Canada from January 2016 through December 2018, with demographic and crash characteristics coded into a database.","limitations":"Postmortem THC detection does not prove impairment at time of crash. Single province data may not generalize nationally. No comparison with non-fatal crashes or general driving population."},{"rthcId":"RTHC-02997","title":"Safety of Medical Cannabis in Neuropathic Chronic Pain Management.","authors":"Bennici, Alessandra; Mannucci, Carmen; Calapai, Fabrizio; Cardia, Luigi; Ammendolia, Ilaria; Gangemi, Sebastiano; Calapai, Gioacchino; Griscti Soler, Daniel","year":2021,"journal":"Molecules (Basel, Switzerland), 26(20)","doi":"10.3390/molecules26206257","pmid":"34684842","tags":["pain","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Only nabiximols (a balanced CBD/THC product) is approved by regulatory authorities for neuropathic pain and included in pharmacovigilance systems. The many other cannabis preparations widely used for chronic nerve pain are unmonitored, creating insufficient knowledge of their safety profiles.","whyItMatters":"Millions of people use various cannabis preparations for chronic nerve pain, but without systematic safety monitoring, the true risk-benefit profile of most products remains unknown.","specificNumbers":"Nabiximols contains similar percentages of CBD and THC; approved in many European countries and Canada for neuropathic pain and MS-related spasticity","methodology":"Review of published clinical studies reporting adverse reactions from cannabis use for neuropathic pain relief.","limitations":"Safety data limited to published clinical studies, which may not capture all real-world adverse reactions. Heterogeneous cannabis products make direct comparisons difficult."},{"rthcId":"RTHC-02998","title":"A synthesis of the literature to inform vaping cessation interventions for young adults.","authors":"Berg, Carla J; Krishnan, Nandita; Graham, Amanda L; Abroms, Lorien C","year":2021,"journal":"Addictive behaviors, 119, 106898","doi":"10.1016/j.addbeh.2021.106898","pmid":"33894483","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-02999","title":"Young Adults' Vaping, Readiness to Quit, and Recent Quit Attempts: The Role of Co-use With Cigarettes and Marijuana.","authors":"Berg, Carla J; Duan, Xuejing; Romm, Katelyn; Pulvers, Kim; Le, Daisy; Ma, Yan; Krishnan, Nandita; Abroms, Lorien C; Getachew, Betelihem; Henriksen, Lisa","year":2021,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 23(6), 1019-1029","doi":"10.1093/ntr/ntaa265","pmid":"33331889","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03000","title":"Use of Psychoactive Substance and its Associated Factors among School Adolescents in Rupandehi District of Nepal.","authors":"Bhandari, Tulsi Ram; Paudel, Grish; Bestman, Amy; Thapa, Tarka Bahadur; Gwayali, Chunna Prasad; Ghimire, Bishnu; Sharma, Shanta; Yadav, Uday Narayan","year":2021,"journal":"Journal of Nepal Health Research Council, 19(3), 474-480","doi":"10.33314/jnhrc.v19i3.3405","pmid":"35140417","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03001","title":"Cannabinoid-induced changes in the immune system: The role of microRNAs.","authors":"Bhatt, Hirva K; Song, Dana; Musgrave, Gyen; Rao, P S S","year":2021,"journal":"International immunopharmacology, 98, 107832","doi":"10.1016/j.intimp.2021.107832","pmid":"34107381","tags":["inflammation","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabinoid exposure changes the expression of specific microRNAs in various immune cell types, and these miRNA changes appear to drive many of the observed anti-inflammatory and immunomodulatory effects of cannabinoids acting through CB1 and CB2 receptors.","whyItMatters":"Understanding the molecular mechanisms behind cannabinoid immune effects could lead to more targeted anti-inflammatory therapies that harness specific pathways without the psychoactive effects of whole-plant cannabis.","specificNumbers":"CB1 and CB2 receptors expressed in central and peripheral tissues; miRNAs are short non-coding single-stranded RNA molecules","methodology":"Review article summarizing studies from the past decade on miRNA expression changes following cannabinoid receptor modulation in immune system components.","limitations":"Most studies used isolated cell systems or animal models. The clinical relevance of miRNA changes from typical cannabis exposure levels in humans is uncertain. Different cannabinoids may affect different miRNA profiles."},{"rthcId":"RTHC-03002","title":"CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature.","authors":"Bilge, Serap; Ekici, Barış","year":2021,"journal":"Journal of cannabis research, 3(1), 53","doi":"10.1186/s42238-021-00108-7","pmid":"34911567","tags":["cbd","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Among 33 children treated with CBD-enriched cannabis (average 0.7 mg/kg/day), 32.2% showed decreased behavioral problems, 22.5% improved in expressive language, 12.9% improved in cognition, and 9.6% increased social interaction. No change was reported in 19.35% of patients.","whyItMatters":"With no approved drugs for core autism symptoms, families are increasingly turning to CBD. This real-world clinical data, while limited, adds to the emerging evidence base that low-dose CBD may help some children with behavioral aspects of autism.","specificNumbers":"33 children; mean age 7.7 years; average CBD dose 0.7 mg/kg/day; median treatment 6.5 months; 32.2% improved behavior; 22.5% improved language; 12.9% improved cognition; 19.35% no change","methodology":"Retrospective clinical report of 33 children (27 male, 6 female) with autism spectrum disorder treated with full-spectrum CBD (less than 3% THC) at a single center in Turkey from January 2018 to August 2020, with a median treatment duration of 6.5 months.","limitations":"No control group, very small sample, unblinded parent-reported outcomes, single center, variable treatment durations, no standardized outcome measures used."},{"rthcId":"RTHC-03003","title":"From an Alternative Medicine to a New Treatment for Refractory Epilepsies: Can Cannabidiol Follow the Same Path to Treat Neuropsychiatric Disorders?","authors":"Bitencourt, Rafael M; Takahashi, Reinaldo N; Carlini, Elisaldo A","year":2021,"journal":"Frontiers in psychiatry, 12, 638032","doi":"10.3389/fpsyt.2021.638032","pmid":"33643100","tags":["cbd","epilepsy","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Strong evidence supports CBD's anticonvulsant properties for epilepsy, and accumulating research suggests promising effects for depression, anxiety, PTSD, addiction, neurodegenerative disorders, and autism. The review highlights contributions from Brazilian researchers who pioneered CBD epilepsy research.","whyItMatters":"The FDA approval of CBD for epilepsy created a regulatory pathway that could be replicated for other neuropsychiatric conditions if clinical evidence continues to build.","specificNumbers":"CBD-based Epidiolex approved for Dravet's syndrome and Lennox-Gastaut syndrome; studies span depression, anxiety, PTSD, addiction, neurodegeneration, and autism","methodology":"Narrative review of preclinical and clinical data on CBD for epilepsy and neuropsychiatric disorders, with historical context of Brazilian cannabinoid research.","limitations":"Much evidence for non-epilepsy conditions remains preclinical. Clinical trials for neuropsychiatric indications are generally smaller and less rigorous than epilepsy trials. Optimal dosing for different conditions is unclear."},{"rthcId":"RTHC-03004","title":"Modulation of human T-type calcium channels by synthetic cannabinoid receptor agonists in vitro.","authors":"Bladen, Chris; Mirlohi, Somayeh; Santiago, Marina; Longworth, Mitchell; Kassiou, Michael; Banister, Sam; Connor, Mark","year":2021,"journal":"Neuropharmacology, 187, 108478","doi":"10.1016/j.neuropharm.2021.108478","pmid":"33600843","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03005","title":"Alcohol and Cannabis Use Disorder Symptom Severity, Conduct Disorder, and Callous-Unemotional Traits and Impairment in Expression Recognition.","authors":"Blair, Robert James R; Bashford-Largo, Johannah; Zhang, Ru; Mathur, Avantika; Schwartz, Amanda; Elowsky, Jaimie; Tyler, Patrick; Hammond, Christopher J; Filbey, Francesca M; Dobbertin, Matthew; Bajaj, Sahil; Blair, Karina S","year":2021,"journal":"Frontiers in psychiatry, 12, 714189","doi":"10.3389/fpsyt.2021.714189","pmid":"34616316","tags":["youth","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis use disorder severity was negatively associated with recognition accuracy for higher-intensity sad and fearful expressions, while conduct disorder was independently associated with reduced sad expression recognition. Alcohol use disorder severity was not significantly associated with expression recognition.","whyItMatters":"Difficulty recognizing fear and sadness in others is a known risk factor for aggression and antisocial behavior. If cannabis use worsens this deficit during adolescence, it could compound behavioral risks during a critical developmental period.","specificNumbers":"152 youths; ages 12.5-18; 56 female; 60 with conduct disorder; cannabis use disorder independently associated with reduced recognition of sad and fearful expressions","methodology":"Cross-sectional study of 152 youths aged 12.5-18 (60 diagnosed with conduct disorder) who completed a rapid-presentation morphed facial expression task to assess emotion recognition ability.","limitations":"Cross-sectional design cannot determine whether cannabis caused the recognition deficits. Youths with conduct disorder may have pre-existing deficits. Self-report measures for substance use. No assessment of cannabis use timing or quantity."},{"rthcId":"RTHC-03006","title":"Sex and dose-dependent antinociceptive effects of the JNK (c-Jun N-terminal kinase) inhibitor SU 3327 are mediated by CB2 receptors in female, and CB1/CB2 receptors in male mice in an inflammatory pain model.","authors":"Blanton, Henry L; Pietrzak, Agata; McHann, Melissa C; Guindon, Josée","year":2021,"journal":"Brain research bulletin, 177, 39-52","doi":"10.1016/j.brainresbull.2021.09.004","pmid":"34530070","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03007","title":"Epigenetic Mediation of AKT1 rs1130233's Effect on Delta-9-Tetrahydrocannabinol-Induced Medial Temporal Function during Fear Processing.","authors":"Blest-Hopley, Grace; Colizzi, Marco; Prata, Diana; Giampietro, Vincent; Brammer, Michael; McGuire, Philip; Bhattacharyya, Sagnik","year":2021,"journal":"Brain sciences, 11(9)","doi":"10.3390/brainsci11091240","pmid":"34573260","tags":["genetics","psychosis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"The number of A alleles at AKT1 rs1130233 and methylation percentage at the CpG11-12 site independently predicted greater THC effects on parahippocampal/amygdala activation during fear processing. The genetic effect was partially mediated by methylation in sections of the left parahippocampal gyrus and hippocampus.","whyItMatters":"This demonstrates that both inherited genetic variation and modifiable epigenetic factors shape individual responses to THC, helping explain why some people are more vulnerable to cannabis-related anxiety and psychotic symptoms.","specificNumbers":"36 healthy males (34 with complete data); 2-session crossover design; THC increased anxiety and psychotomimetic symptoms; AKT1 gene is part of the dopamine signaling cascade","methodology":"Double-blind, cross-over, randomized placebo-controlled THC administration study in 36 healthy males, with functional MRI during a fear processing task. Genetic (AKT1 rs1130233) and epigenetic (DNA methylation) data were analyzed.","limitations":"Small sample of only males, limiting generalizability. Single acute THC dose may not reflect chronic use effects. Epigenetic measurements from blood may not perfectly reflect brain methylation patterns."},{"rthcId":"RTHC-03008","title":"Disrupted parahippocampal and midbrain function underlie slower verbal learning in adolescent-onset regular cannabis use.","authors":"Blest-Hopley, Grace; O'Neill, Aisling; Wilson, Robin; Giampietro, Vincent; Bhattacharyya, Sagnik","year":2021,"journal":"Psychopharmacology, 238(5), 1315-1331","doi":"10.1007/s00213-019-05407-9","pmid":"31814047","tags":["cognition","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis users showed significantly slower learning across repeated trials (p = 0.032). Non-users progressively increased activation in the midbrain, parahippocampal gyrus, and thalamus during learning, while cannabis users showed greater but disrupted activation in these same regions.","whyItMatters":"The disrupted activation patterns suggest cannabis users recruit the same brain regions for learning but do so in a disorganized way, which may explain the cognitive difficulties commonly reported by regular users.","specificNumbers":"21 cannabis users vs 21 non-users; learning significantly slower (p = 0.032, partial eta-squared = 0.108); at least 12 hours abstinent; progressive midbrain/parahippocampal/thalamus activation disrupted in users","methodology":"Functional MRI study comparing 21 adolescent-onset regular cannabis users and 21 non-users during a paired associate verbal learning task, performed at least 12 hours after last cannabis use.","limitations":"Small sample, cross-sectional design cannot establish causation, 12-hour abstinence may not eliminate all acute effects, no pre-use baseline data available."},{"rthcId":"RTHC-03009","title":"A Phase-2 Pilot Study of a Therapeutic Combination of Δ9-Tetrahydracannabinol and Palmitoylethanolamide for Adults With Tourette's Syndrome.","authors":"Bloch, Michael H; Landeros-Weisenberger, Angeli; Johnson, Jessica A; Leckman, James F","year":2021,"journal":"The Journal of neuropsychiatry and clinical neurosciences, 33(4), 328-336","doi":"10.1176/appi.neuropsych.19080178","pmid":"34340527","tags":["medical-cannabis","neuroscience"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"THX-110 (combination of THC max 10 mg/day and PEA 800 mg/day) produced statistically significant tic improvement within one week. Average improvement exceeded 20%, representing a 7-point decrease on the Yale Global Tic Severity Scale. Twelve of 16 participants chose to continue into the extension phase.","whyItMatters":"Few effective pharmacological treatments exist for Tourette's syndrome, and many patients continue to have impairing tics despite available treatments. A cannabinoid-based option could fill an important treatment gap.","specificNumbers":"16 adults; max THC dose 10 mg/day; PEA dose 800 mg/day; >20% improvement; 7-point YGTSS decrease; improvement significant within 1 week; 12 of 16 continued to extension; 2 dropouts","methodology":"12-week uncontrolled trial of THX-110 in 16 adults with Tourette's syndrome, with primary outcome measured by Yale Global Tic Severity Scale total tic score. A 24-week extension phase was offered.","limitations":"No control group or blinding, very small sample, side effects were common (managed by dose adjustment), psychoactive properties of THC make blinding future trials challenging."},{"rthcId":"RTHC-03010","title":"Cannabis vaping among adults in the United States: Prevalence, trends, and association with high-risk behaviors and adverse respiratory conditions.","authors":"Boakye, Ellen; Obisesan, Olufunmilayo H; Uddin, S M Iftekhar; El-Shahawy, Omar; Dzaye, Omar; Osei, Albert D; Benjamin, Emelia J; Stokes, Andrew C; Robertson, Rose Marie; Bhatnagar, Aruni; Blaha, Michael J","year":2021,"journal":"Preventive medicine, 153, 106800","doi":"10.1016/j.ypmed.2021.106800","pmid":"34520787","tags":["respiratory","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis vaping doubled nationally from 1.0% to 2.0% between 2017 and 2019, with the largest increase among young adults (1.2% to 3.9%). Cannabis vaping was associated with heavy alcohol use (aOR 1.95), binge drinking (aOR 2.82), and other high-risk behaviors (aOR 2.47) but not with asthma or respiratory symptoms.","whyItMatters":"The rapid increase in cannabis vaping, especially among young adults, coincided with the EVALI outbreak and raises ongoing questions about the health effects of this relatively new consumption method.","specificNumbers":"160,209 participants; past-30-day cannabis use rose from 10.0% to 13.4%; cannabis vaping from 1.0% to 2.0%; young adults 1.2% to 3.9%; aOR 2.82 for binge drinking; no association with asthma (aOR 1.03)","methodology":"Analysis of 2017-2019 Behavioral Risk Factor Surveillance System data (160,209 participants) examining prevalence, trends, and associations of cannabis vaping with health behaviors and respiratory conditions.","limitations":"Cross-sectional design prevents causal inference, self-reported substance use, BRFSS data limited to states that included cannabis questions, 2017-2019 period predates further market changes."},{"rthcId":"RTHC-03011","title":"Receptor-Dependent and Independent Regulation of Voltage-Gated Ca2+ Channels and Ca2+-Permeable Channels by Endocannabinoids in the Brain.","authors":"Boczek, Tomasz; Zylinska, Ludmila","year":2021,"journal":"International journal of molecular sciences, 22(15)","doi":"10.3390/ijms22158168","pmid":"34360934","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03012","title":"Substituting Cannabidiol for Opioids and Pain Medications Among Individuals With Fibromyalgia: A Large Online Survey.","authors":"Boehnke, Kevin F; Gagnier, Joel J; Matallana, Lynne; Williams, David A","year":2021,"journal":"The journal of pain, 22(11), 1418-1428","doi":"10.1016/j.jpain.2021.04.011","pmid":"33992787","tags":["cbd","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"72% of CBD-using fibromyalgia patients substituted CBD for medications: NSAIDs (59%), opioids (53.3%), gabapentinoids (35%), and benzodiazepines (23.1%). Most reported decreasing or stopping these medications, citing fewer side effects and better symptom management. Those who substituted reported larger improvements than non-substituters.","whyItMatters":"If fibromyalgia patients are independently substituting CBD for opioids and other medications at this scale, it signals a major unregulated shift in pain management that warrants clinical investigation.","specificNumbers":"878 CBD users with fibromyalgia; 93.6% female; mean age 55.5; 72% substituted for medications; 59% for NSAIDs; 53.3% for opioids; 35% for gabapentinoids; 23.1% for benzodiazepines","methodology":"Secondary analysis from a cross-sectional survey of 878 fibromyalgia patients currently using CBD, sub-grouped by product type (CBD isolate, hemp, CBD-cannabis, no preference) and substitution behavior.","limitations":"Self-selected sample of CBD users (likely biased toward positive experiences), no clinical verification of diagnoses or medication changes, cross-sectional design, 93.6% female and 91.5% Caucasian sample."},{"rthcId":"RTHC-03013","title":"Medication and substance use increases among people using cannabis medically during the COVID-19 pandemic.","authors":"Boehnke, Kevin F; McAfee, Jenna; Ackerman, Joshua M; Kruger, Daniel J","year":2021,"journal":"The International journal on drug policy, 92, 103053","doi":"10.1016/j.drugpo.2020.103053","pmid":"33250438","tags":["medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Over half of 353 medical cannabis users either started or increased use of other medications/substances during COVID-19, most commonly alcohol and sleep aids. About 40% who increased non-cannabis substance use attributed it to changed medical cannabis access.","whyItMatters":"If disrupted cannabis access drives people to increase alcohol and other substance use, it highlights the importance of maintaining medical cannabis availability during public health emergencies.","specificNumbers":"353 participants; over 50% started or increased other substance use; over a third increased cannabis use; 25% decreased cannabis use; 40% of increasers cited changed cannabis access","methodology":"Cross-sectional survey of 353 medical cannabis users recruited through Amazon Mechanical Turk in April-May 2020, assessing pandemic effects on medication, substance, and cannabis use patterns.","limitations":"Amazon Mechanical Turk sample may not represent typical medical cannabis patients, self-reported data, cross-sectional design during an unusual period, small sample size."},{"rthcId":"RTHC-03014","title":"Cannabidiol Use for Fibromyalgia: Prevalence of Use and Perceptions of Effectiveness in a Large Online Survey.","authors":"Boehnke, Kevin F; Gagnier, Joel J; Matallana, Lynne; Williams, David A","year":2021,"journal":"The journal of pain, 22(5), 556-566","doi":"10.1016/j.jpain.2020.12.001","pmid":"33400996","tags":["cbd","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 2,701 fibromyalgia patients, 32.4% currently used CBD and 29.4% had used it previously. Users reported improvements across multiple symptom domains, most commonly pain. About half reported minor side effects. Two-thirds disclosed CBD use to their physician but only 33% asked for physician advice.","whyItMatters":"With nearly a third of fibromyalgia patients using CBD despite limited evidence, this represents a massive uncontrolled experiment. Understanding use patterns can help guide future clinical research priorities.","specificNumbers":"2,701 participants; 38.1% never used CBD; 29.4% past use; 32.4% current use; two-thirds disclosed to physician; only 33% sought physician advice; about half reported minor side effects","methodology":"Cross-sectional anonymous survey of 2,701 individuals with fibromyalgia, primarily in the United States, examining CBD use patterns, reasons for use/discontinuation, physician communication, and perceived effectiveness.","limitations":"Self-selected survey population likely overrepresents those interested in CBD, cross-sectional design, self-reported improvement without objective measures, predominantly U.S. respondents."},{"rthcId":"RTHC-03015","title":"Cannabis and Cannabis Derivatives for Abdominal Pain Management in Inflammatory Bowel Disease.","authors":"Bogale, Kaleb; Raup-Konsavage, Wesley; Dalessio, Shannon; Vrana, Kent; Coates, Matthew D","year":2021,"journal":"Medical cannabis and cannabinoids, 4(2), 97-106","doi":"10.1159/000517425","pmid":"35224429","tags":["pain","medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"There is little clinical evidence that cannabis treats the gastrointestinal inflammation underlying IBD. However, a recurring finding from both animal and human studies is that cannabis and cannabinoid signaling elements have a significant impact on IBD-related symptoms, particularly abdominal pain.","whyItMatters":"IBD patients frequently suffer from chronic abdominal pain that is difficult to manage. If cannabis can reliably address pain without the risks of opioids, even without treating inflammation, it could improve quality of life for millions.","specificNumbers":"Cannabinoid signaling elements involved in visceral pain perception; both CB1 and CB2 receptors play roles in gut pain signaling","methodology":"Narrative review of the role of cannabis and cannabinoid signaling in visceral pain perception and the evidence for efficacy in managing pain, related symptoms, and inflammation in IBD.","limitations":"Limited human clinical trial data specifically for IBD pain. Animal models may not translate to human IBD pain. Heterogeneity of cannabis products and IBD subtypes makes generalizations difficult."},{"rthcId":"RTHC-03016","title":"Piloting a brief intervention plus mobile boosters for drug use among emerging adults receiving emergency department care.","authors":"Bonar, Erin E; Cunningham, Rebecca M; Sweezea, Emily C; Blow, Frederic C; Drislane, Laura E; Walton, Maureen A","year":2021,"journal":"Drug and alcohol dependence, 221, 108625","doi":"10.1016/j.drugalcdep.2021.108625","pmid":"33631541","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03017","title":"The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: A randomized cross-over clinical trial.","authors":"Bonn-Miller, Marcel O; Sisley, Sue; Riggs, Paula; Yazar-Klosinski, Berra; Wang, Julie B; Loflin, Mallory J E; Shechet, Benjamin; Hennigan, Colin; Matthews, Rebecca; Emerson, Amy; Doblin, Rick","year":2021,"journal":"PloS one, 16(3), e0246990","doi":"10.1371/journal.pone.0246990","pmid":"33730032","tags":["ptsd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Three cannabis preparations (high THC, high CBD, and balanced THC+CBD) were all well tolerated and all groups showed significant PTSD symptom improvement, but no active treatment was statistically better than placebo after three weeks of use.","whyItMatters":"Despite widespread veteran use of cannabis for PTSD, this first rigorous trial found no evidence that smoked cannabis outperforms placebo. The strong placebo response complicates future trial design.","specificNumbers":"80 participants in Stage 1; 74 in Stage 2; high THC (~12% THC, <0.05% CBD); high CBD (11% CBD, 0.50% THC); THC+CBD (~7.9% THC, 8.1% CBD); placebo (<0.03% THC)","methodology":"Double-blind, cross-over design with 80 veterans randomized to three weeks of active treatment or placebo in Stage 1, then re-randomized to a different active treatment in Stage 2 after a 2-week washout. Primary outcome was change in PTSD symptom severity.","limitations":"Brief 3-week treatment period, difficulty blinding smoked cannabis (participants may detect active vs placebo), relatively small sample, cross-over design may introduce carryover effects."},{"rthcId":"RTHC-03018","title":"The importance of psychology for shaping legal cannabis regulation.","authors":"Borodovsky, Jacob T; Sofis, Michael J; Grucza, Richard A; Budney, Alan J","year":2021,"journal":"Experimental and clinical psychopharmacology, 29(1), 99-115","doi":"10.1037/pha0000362","pmid":"32437193","tags":["legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis regulations should account for three key agents: consumers (whose behavior is driven by pharmacological and environmental variables), the cannabis industry (which uses marketing strategies that may increase harm), and regulatory agencies (which can use evidence from psychology to shape consumption patterns).","whyItMatters":"As more jurisdictions legalize cannabis, the regulatory choices made now will shape consumption patterns and public health outcomes for decades. Psychology offers tools to design regulations that minimize harm.","specificNumbers":"Review addresses THC-laden cannabis for both medical and recreational use across U.S. state regulatory systems","methodology":"Applied review and commentary drawing on psychological science literature to provide evidence-based guidance for cannabis regulators, organized around the three primary agents in the cannabis regulation ecosystem.","limitations":"Commentary piece that draws primarily on behavioral research from other substance domains. Direct evidence on cannabis-specific regulatory effects is limited due to the recency of legalization."},{"rthcId":"RTHC-03019","title":"Cannabinoids for the treatment of dementia.","authors":"Bosnjak Kuharic, Dina; Markovic, Domagoj; Brkovic, Tonci; Jeric Kegalj, Milka; Rubic, Zana; Vuica Vukasovic, Ana; Jeroncic, Ana; Puljak, Livia","year":2021,"journal":"The Cochrane database of systematic reviews, 9(9), CD012820","doi":"10.1002/14651858.CD012820.pub2","pmid":"34532852","tags":["cognition","seniors","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across four RCTs testing natural and synthetic THC, there was very low certainty evidence of minimal effect on cognition (1.1-point sMMSE difference) and low certainty evidence of minimal effect on behavioral symptoms (-1.97 NPI difference). Sedation was more common with nabilone.","whyItMatters":"Despite growing interest in cannabinoids for dementia, this rigorous Cochrane review finds the evidence base is simply too small and too uncertain to draw any meaningful conclusions about benefits or harms.","specificNumbers":"4 RCTs; 126 total participants; 3 cross-over designs; 3-14 week interventions; sMMSE difference 1.1 points (very low certainty); NPI difference -1.97 (low certainty); sedation OR 2.83 with nabilone","methodology":"Cochrane systematic review and meta-analysis of all randomized controlled trials of cannabinoids for dementia treatment, searching multiple databases through July 2021. Four studies (126 participants) met inclusion criteria.","limitations":"Only four small studies exist. Short treatment durations (3-14 weeks). Heterogeneous cannabinoid preparations. Most participants had Alzheimer disease, limiting generalizability to other dementias."},{"rthcId":"RTHC-03020","title":"Adverse events of recreational cannabis use reported to the French addictovigilance network (2012-2017).","authors":"Bouquet, Emilie; Pain, Stéphanie; Eiden, Céline; Jouanjus, Emilie; Richard, Nathalie; Fauconneau, Bernard; Pérault-Pochat, Marie-Christine","year":2021,"journal":"British journal of clinical pharmacology, 87(10), 3925-3937","doi":"10.1111/bcp.14812","pmid":"34282851","tags":["harm-reduction","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis adverse event reports tripled from 179 (2012) to 562 (2017), totaling 2,217 cases. Psychiatric effects were most common (51.2%), followed by neurological (15.6%), cardiac (7.8%), and gastrointestinal (7.7%). Dependence ranged from 10-20% of reports. Cannabinoid hyperemesis syndrome (87 cases) emerged from 2015. Seven deaths were reported.","whyItMatters":"This surveillance data provides one of the more comprehensive pictures of cannabis adverse events from a national reporting system, documenting the full spectrum of harms including the emergence of cannabinoid hyperemesis syndrome.","specificNumbers":"2,217 total cases; 76.4% male; 18-34 age group most common; 71.6% inhaled; 64.2% chronic use; dependence 10-20%; 87 hyperemesis cases; 34 unexpected AEs; 7 deaths","methodology":"Analysis of adverse events from recreational cannabis use reported to the French Addictovigilance Network from 2012 to 2017, excluding CBD and synthetic cannabinoids.","limitations":"Voluntary reporting systems underestimate true adverse event rates. Increase in reports may partly reflect improved awareness and reporting rather than increased harm. Cannot determine causation from surveillance data alone."},{"rthcId":"RTHC-03021","title":"The endocannabinoid system is modulated in reward and homeostatic brain regions following diet-induced obesity in rats: a cluster analysis approach.","authors":"Bourdy, Romain; Hertz, Alexandra; Filliol, Dominique; Andry, Virginie; Goumon, Yannick; Mendoza, Jorge; Olmstead, Mary C; Befort, Katia","year":2021,"journal":"European journal of nutrition, 60(8), 4621-4633","doi":"10.1007/s00394-021-02613-0","pmid":"34165614","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03022","title":"The Interplay between the Immune and the Endocannabinoid Systems in Cancer.","authors":"Braile, Mariantonia; Marcella, Simone; Marone, Gianni; Galdiero, Maria Rosaria; Varricchi, Gilda; Loffredo, Stefania","year":2021,"journal":"Cells, 10(6)","doi":"10.3390/cells10061282","pmid":"34064197","tags":["cancer","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CB2 and CB1 receptors are expressed on T cells, macrophages, mast cells, neutrophils, NK cells, dendritic cells, monocytes, and eosinophils within the tumor microenvironment. Cannabinoids can modulate apoptosis, autophagy, proliferation, migration, angiogenesis, and lymphangiogenesis in cancer.","whyItMatters":"Understanding how cannabinoid receptors on immune cells influence tumor development could lead to novel immunotherapy approaches that complement existing cancer treatments.","specificNumbers":"CB1 and CB2 receptors are G protein-coupled receptors; CB2 is more widely expressed on immune cells; cannabinoids inhibit angiogenesis and lymphangiogenesis in vitro and in vivo","methodology":"Review examining the expression and function of cannabinoid receptors on immune cells within the tumor microenvironment, drawing on preclinical research.","limitations":"Most evidence is preclinical. The expression of CB receptors on different immune cell subsets in human tumors is incompletely characterized. Effects may differ by cancer type."},{"rthcId":"RTHC-03023","title":"Cannabis, Impaired Driving, and Road Safety: An Overview of Key Questions and Issues.","authors":"Brands, Bruna; Di Ciano, Patricia; Mann, Robert E","year":2021,"journal":"Frontiers in psychiatry, 12, 641549","doi":"10.3389/fpsyt.2021.641549","pmid":"34489746","tags":["driving","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis contributes to crash risk, but key questions remain unanswered: the dose-response relationship is unclear, tolerance effects on driving are uncertain, different routes of administration (edibles, vaping) have different impairment timelines, and whether medical users are impaired differently from recreational users is unknown.","whyItMatters":"Canada and other jurisdictions legalized cannabis with road safety as a central concern, but the evidence needed to inform effective impaired driving policies has significant gaps that urgently need filling.","specificNumbers":"Canada legalized non-medical cannabis October 2018; Uruguay in December 2013; evidence covers crash risk, impairment duration, and detection methods","methodology":"Narrative review identifying and discussing key questions about cannabis and road safety, drawing on epidemiological, behavioral, and pharmacological evidence.","limitations":"Many referenced studies use cannabis potencies lower than currently available products. Most driving research involves simulated rather than real-world driving. Sex differences in cannabis pharmacology and driving effects are understudied."},{"rthcId":"RTHC-03024","title":"Cannabis and the Cancer Patient.","authors":"Braun, Ilana M; Abrams, Donald I; Blansky, Stacey E; Pergam, Steven A","year":2021,"journal":"Journal of the National Cancer Institute. Monographs, 2021(58), 68-77","doi":"10.1093/jncimonographs/lgab012","pmid":"34850899","tags":["cancer","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Conclusive evidence supports cannabinoids for chemotherapy-induced nausea and vomiting, with suggestive evidence for cancer-related pain. Risks for cancer patients include infection (immunocompromised), pharmacokinetic drug-botanical interactions, cannabinoid hyperemesis syndrome, and vaping-related lung injury.","whyItMatters":"Cancer patients are using cannabis at increasing rates while oncologists feel ill-equipped to advise them. The gap between patient demand and clinical guidance creates real risks, especially for immunocompromised patients.","specificNumbers":"Cannabis remains Schedule I federally; conclusive evidence for chemo nausea; suggestive evidence for cancer pain; risks include infection, drug interactions, hyperemesis, vaping injury","methodology":"Summary of Session 2 from the National Cancer Institute Cannabis, Cannabinoids, and Cancer Research Workshop, including patient testimony, legal landscape review, and evidence synthesis.","limitations":"Workshop summary rather than systematic review. Evidence synthesis is necessarily broad rather than detailed. Legal barriers continue to limit research quality and quantity."},{"rthcId":"RTHC-03025","title":"Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses.","authors":"Breijyeh, Zeinab; Jubeh, Buthaina; Bufo, Sabino A; Karaman, Rafik; Scrano, Laura","year":2021,"journal":"Toxins, 13(2)","doi":"10.3390/toxins13020117","pmid":"33562446","tags":["harm-reduction","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Established medical uses include chronic pain, chemotherapy nausea, appetite stimulation, MS spasticity, and epilepsy. High THC exposure causes adverse effects including dizziness, drowsiness, seizures, tachycardia, hypertension, nausea, and mydriasis. Cannabis toxicity in children can cause stupor, lethargy, seizures, and coma.","whyItMatters":"As more countries legalize cannabis, understanding both its legitimate medical uses and its toxicity profile is essential for balanced public health policy and individual decision-making.","specificNumbers":"THC is the primary psychoactive compound; CBD has medical applications; adverse effects affect neurological, cardiovascular, gastrointestinal, and ophthalmological systems; pediatric toxicity can include coma","methodology":"Comprehensive review of both therapeutic effects and acute/chronic toxic effects of cannabis use on various body systems.","limitations":"Broad review covering many topics without deep analysis of any single area. Adverse effect severity depends heavily on dose, potency, route, and individual factors not fully addressed."},{"rthcId":"RTHC-03026","title":"Simulated driving performance among daily and occasional cannabis users.","authors":"Brooks-Russell, Ashley; Brown, Tim; Friedman, Kyle; Wrobel, Julia; Schwarz, John; Dooley, Gregory; Ryall, Karen A; Steinhart, Benjamin; Amioka, Elise; Milavetz, Gary; Sam Wang, George; Kosnett, Michael J","year":2021,"journal":"Accident; analysis and prevention, 160, 106326","doi":"10.1016/j.aap.2021.106326","pmid":"34403895","tags":["driving","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Occasional users showed significant increases in lane weaving (SDLP) compared to non-users after smoking (p=0.02, effect size 0.64). Daily users also increased SDLP but the change versus non-users was not significant (p=0.08). Daily users drove significantly slower after cannabis use. Blood THC was much higher in daily users (36.4 ng/mL) than occasional users (6.4 ng/mL) despite similar subjective high ratings.","whyItMatters":"The tolerance question is central to medical cannabis driving policy. If daily users are less impaired despite much higher blood THC levels, blood-level-based driving laws may be even more unreliable for this population.","specificNumbers":"85 participants; 24 occasional, 31 daily, 30 non-users; blood THC: occasional 6.4 ng/mL vs daily 36.4 ng/mL; subjective high similar (~50/100); occasional SDLP increase significant (p=0.02); daily SDLP increase not significant (p=0.08)","methodology":"Within-subjects design with 85 adults (24 occasional users, 31 daily users, 30 non-users) completing driving simulator tests before and after ad libitum smoking of self-supplied cannabis (15-30% THC). Blood samples collected pre and post smoking.","limitations":"Simulated rather than real-world driving, self-supplied cannabis introduced variability, relatively small groups, ad libitum dosing means groups may have consumed different amounts, non-users did not smoke anything."},{"rthcId":"RTHC-03027","title":"Δ-9-tetrahydrocannabinol dose increase leads to warfarin drug interaction and elevated INR.","authors":"Brown, Geoffrey W; Bellnier, Terrance J; Janda, Maria; Miskowitz, Kyle","year":2021,"journal":"Journal of the American Pharmacists Association : JAPhA, 61(1), e57-e60","doi":"10.1016/j.japh.2020.07.028","pmid":"32828704","tags":["drug-interactions","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 67-year-old man on warfarin developed a supratherapeutic INR of 5.2 after self-titrating his THC dose upward by 7.35 mg. Warfarin was held for 2 days until INR normalized. The interaction scored \"probable\" on the Naranjo scale and is explained by shared CYP450 metabolism.","whyItMatters":"Warfarin is one of the most commonly prescribed blood thinners, and this interaction could cause life-threatening bleeding. As more older adults use medical cannabis, this drug interaction needs wider awareness.","specificNumbers":"Patient age 67; THC dose increase of 7.35 mg; INR rose to 5.2 (therapeutic range typically 2-3); Naranjo score 8 (probable); no bleeding occurred; INR normalized after holding warfarin 2 days","methodology":"Case report of a single patient presenting at a cannabis dispensary in Buffalo, NY, with documented INR elevation temporally linked to THC dose increase.","limitations":"Single case report cannot establish definitive causation. Patient was self-titrating, introducing imprecision. Other potential contributing factors (diet, other medications) not fully detailed."},{"rthcId":"RTHC-03028","title":"The association of cannabis use with quality of life and psychosocial functioning in psychosis.","authors":"Bruins, J; Pijnenborg, G H M; Visser, E; Castelein, S","year":2021,"journal":"Schizophrenia research, 228, 229-234","doi":"10.1016/j.schres.2020.11.059","pmid":"33461022","tags":["psychosis","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis users (11.4%) had significantly lower quality of life (B=-2.93) and worse psychosocial functioning (B=1.03) than non-users. Specifically, they were less satisfied with family relations and finances and showed more aggression, disruptive behavior, and self-harm. Starting or stopping cannabis did not change outcomes within one year.","whyItMatters":"People with psychosis often report using cannabis to cope or socialize, but this large study found cannabis users actually had worse outcomes across measures. The lack of improvement after stopping suggests accumulated effects from years of use.","specificNumbers":"2,994 participants; 36.4% female; mean age 44.4; mean illness duration 17.2 years; 11.4% used cannabis; 255 continuers; 85 discontinuers; 83 starters; 2,571 non-users","methodology":"Naturalistic cohort study (PHAMOUS) of 2,994 people with psychotic disorders assessed twice (9-15 months apart) between 2014 and 2018, comparing continuers, discontinuers, starters, and non-users.","limitations":"Observational design cannot establish causation. Cannabis users may differ from non-users in unmeasured ways. One-year follow-up may be too short to detect changes from stopping. Self-reported cannabis use may be underreported."},{"rthcId":"RTHC-03029","title":"Cannabis Use and Nonfatal Opioid Overdose among Patients Enrolled in Methadone Maintenance Treatment.","authors":"Bryson, William C; Morasco, Benjamin J; Cotton, Brandi P; Thielke, Stephen M","year":2021,"journal":"Substance use & misuse, 56(5), 697-703","doi":"10.1080/10826084.2021.1892137","pmid":"33749499","tags":["harm-reduction","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Nonfatal opioid overdose prevalence was 3% among frequent cannabis users vs 9% among infrequent/non-users (p=0.02). After controlling for demographic and clinical factors, frequent cannabis users had 71% lower likelihood of overdose (adjusted RR=0.29, 95% CI 0.10-0.80).","whyItMatters":"Opioid overdose remains a leading cause of death. If cannabis use genuinely reduces overdose risk among people in treatment for opioid use disorder, it could inform harm reduction strategies.","specificNumbers":"446 participants; 35% frequent cannabis users; 7% reported nonfatal overdose; 3% overdose among frequent users vs 9% among infrequent; adjusted RR=0.29 (71% reduction); 95% CI 0.10-0.80","methodology":"Cross-sectional survey of 446 individuals enrolled in four methadone maintenance treatment clinics in Washington State and southern New England, comparing frequent (weekly+) vs infrequent cannabis users.","limitations":"Cross-sectional design cannot establish causation. Self-reported cannabis use and overdose. Convenience sample may not represent all MMT patients. Possible confounders not captured. Reverse causation possible (those at higher overdose risk may avoid cannabis)."},{"rthcId":"RTHC-03030","title":"Inflammatory Bowel Disease and Cannabis: A Practical Approach for Clinicians.","authors":"Buckley, Megan C; Kumar, Anand; Swaminath, Arun","year":2021,"journal":"Advances in therapy, 38(7), 4152-4161","doi":"10.1007/s12325-021-01805-8","pmid":"34110607","tags":["pain","medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis has gained popularity for IBD symptom management but has not been proven to reduce inflammation or correct underlying disease processes. Key concerns include dosing inconsistencies across products, risk of dependence, and cannabinoid hyperemesis syndrome.","whyItMatters":"As more IBD patients turn to cannabis, clinicians need practical guidance on discussing its potential benefits and limitations, especially distinguishing symptom relief from disease modification.","specificNumbers":"15 U.S. states regulate adult cannabis use; 36 states for medical use; cannabis has not been proven to help with IBD inflammation","methodology":"Review article summarizing current research on cannabis and IBD, supplemented with clinical vignettes illustrating practical considerations for clinicians.","limitations":"Narrative review without systematic methodology. Clinical vignettes illustrate but do not provide evidence. Limited by the small number of available clinical studies on cannabis for IBD."},{"rthcId":"RTHC-03031","title":"Pharmacological and Toxicological Effects of Phytocannabinoids and Recreational Synthetic Cannabinoids: Increasing Risk of Public Health.","authors":"Bukke, Vidyasagar Naik; Archana, Moola; Villani, Rosanna; Serviddio, Gaetano; Cassano, Tommaso","year":2021,"journal":"Pharmaceuticals (Basel, Switzerland), 14(10)","doi":"10.3390/ph14100965","pmid":"34681189","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"207 synthetic cannabinoid compounds were identified by the EMCDDA from 2008 to 2020. As full CB receptor agonists, they are much more potent than natural cannabis (a partial agonist). Documented toxicity includes renal damage, respiratory depression, cardiovascular effects, hyperemesis, and neurotoxicity. Some have been classified as Schedule 1.","whyItMatters":"Synthetic cannabinoids are cheap, widely available, and often undetectable on standard drug tests. Their extreme potency compared to natural cannabis means users face far greater risks of acute toxicity and death.","specificNumbers":"207 synthetic compounds identified by EMCDDA (2008-2020); 9 new compounds reported in latest period; sold as Spice, K2, Black Mamba, Bombay Blue; act as full agonists vs partial agonism of natural THC","methodology":"Review of the development, abuse patterns, and toxicological effects of synthetic cannabinoids, drawing on EMCDDA surveillance data and clinical reports.","limitations":"Review cannot cover all 207+ compounds in detail. Toxicity data varies by compound. Many adverse events likely go unreported. The rapid emergence of new analogues means the review may already be outdated."},{"rthcId":"RTHC-03032","title":"Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson's Disease and Amyotrophic Lateral Sclerosis.","authors":"Burgaz, Sonia; García, Concepción; Gonzalo-Consuegra, Claudia; Gómez-Almería, Marta; Ruiz-Pino, Francisco; Unciti, Juan Diego; Gómez-Cañas, María; Alcalde, Juan; Morales, Paula; Jagerovic, Nadine; Rodríguez-Cueto, Carmen; de Lago, Eva; Muñoz, Eduardo; Fernández-Ruiz, Javier","year":2021,"journal":"Molecules (Basel, Switzerland), 26(24)","doi":"10.3390/molecules26247643","pmid":"34946726","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03033","title":"Neuroprotection with the cannabigerol quinone derivative VCE-003.2 and its analogs CBGA-Q and CBGA-Q-Salt in Parkinson's disease using 6-hydroxydopamine-lesioned mice.","authors":"Burgaz, Sonia; García, Concepción; Gómez-Cañas, María; Navarrete, Carmen; García-Martín, Adela; Rolland, Alain; Del Río, Carmen; Casarejos, María J; Muñoz, Eva; Gonzalo-Consuegra, Claudia; Muñoz, Eduardo; Fernández-Ruiz, Javier","year":2021,"journal":"Molecular and cellular neurosciences, 110, 103583","doi":"10.1016/j.mcn.2020.103583","pmid":"33338634","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03034","title":"Cannabis and Athletic Performance.","authors":"Burr, Jamie F; Cheung, Christian P; Kasper, Andreas M; Gillham, Scott H; Close, Graeme L","year":2021,"journal":"Sports medicine (Auckland, N.Z.), 51(Suppl 1), 75-87","doi":"10.1007/s40279-021-01505-x","pmid":"34515970","tags":["exercise","medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Whole cannabis and THC generally show null or detrimental effects on exercise performance. THC can disrupt cardiovascular homeostasis, which may affect performance. CBD has been studied for recovery benefits, with promising findings for sleep quality, pain management, and mild traumatic brain injury.","whyItMatters":"With widespread athlete interest in cannabis products, especially CBD for recovery, this review provides an evidence-based framework for understanding what cannabinoids can and cannot do for athletic performance.","specificNumbers":"THC and CBD are the two most abundant cannabis constituents; cardiovascular perturbation from THC may affect performance across exercise modalities","methodology":"Critical review of literature on whole cannabis, THC, and CBD effects on athletic performance and recovery, covering strength, aerobic, and recovery-related outcomes.","limitations":"Very few studies have examined cannabinoids specifically in athletic populations. Most performance data comes from non-athlete studies. CBD recovery research is in early stages. Optimal dosing for athletes is unknown."},{"rthcId":"RTHC-03035","title":"Mechanisms of cannabis impairment: Implications for modeling driving performance.","authors":"Burt, Thomas S; Brown, Timothy L; Milavetz, Gary; McGehee, Daniel V","year":2021,"journal":"Forensic science international, 328, 110902","doi":"10.1016/j.forsciint.2021.110902","pmid":"34634690","tags":["driving","potency"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Nearly all driving impairment studies used inhaled cannabis at approximately 6% THC, far below the 20%+ THC flower and 60%+ THC concentrates now sold commercially. The dose-response relationship at higher potencies and the impairment timeline for different administration routes (edibles, vaping) remain largely unstudied.","whyItMatters":"If driving research only tests products a fraction of the potency people actually use, the real-world impairment from modern cannabis products may be significantly underestimated, leaving a dangerous gap in safety knowledge.","specificNumbers":"Research typically uses ~6% THC; commercial flower can exceed 20% THC; extracts can contain 60%+ THC; crash risk increases approximately 2-fold after smoking marijuana","methodology":"Systematic review following PRISMA guidelines of PubMed literature and grey literature (congressional reports, committee reports, roadside surveys) on cannabis impairment and driving performance modeling.","limitations":"Federal restrictions on cannabis research have limited access to products matching commercial potency. Many studies use vaporized rather than smoked cannabis. Naturalistic driving studies introduce uncontrollable variables."},{"rthcId":"RTHC-03036","title":"Perceived effects of cannabis and changes in driving performance under the influence of cannabis.","authors":"Burt, Thomas S; Brown, Timothy L; Schmitt, Rose; McGehee, Daniel; Milavetz, Gary; Gaffney, Gary R; Berka, Chris","year":2021,"journal":"Traffic injury prevention, 22(sup1), S8-S13","doi":"10.1080/15389588.2021.1933459","pmid":"34184944","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Subjective cannabis effects predicted changes in driver inputs (steering frequency, reversal rate), while actual driving performance measures like lane weaving were better predicted by dosing condition. Drivers reporting more stimulation showed better performance, while those feeling more stoned showed worse performance.","whyItMatters":"If different subjective experiences from cannabis predict different levels of driving impairment, this could have implications for how we think about cannabis strain effects and impairment testing.","specificNumbers":"10 subjects; driving measured ~2 hours after inhalation; 6.9% THC vs placebo; subjective measures collected at peak and before driving","methodology":"Analysis of 10 subjects in a driving simulator study approximately two hours after cannabis inhalation (6.9% THC vs placebo), examining relationships between subjective effects and driving performance using visual analog scales and simulator metrics.","limitations":"Very small sample (10 subjects), single THC potency tested, simulated rather than real-world driving, subjective self-reports may not be reliable measures of actual impairment."},{"rthcId":"RTHC-03037","title":"Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline.","authors":"Busse, Jason W; Vankrunkelsven, Patrick; Zeng, Linan; Heen, Anja Fog; Merglen, Arnaud; Campbell, Fiona; Granan, Lars-Petter; Aertgeerts, Bert; Buchbinder, Rachelle; Coen, Matteo; Juurlink, David; Samer, Caroline; Siemieniuk, Reed A C; Kumar, Nimisha; Cooper, Lynn; Brown, John; Lytvyn, Lyubov; Zeraatkar, Dena; Wang, Li; Guyatt, Gordon H; Vandvik, Per O; Agoritsas, Thomas","year":2021,"journal":"BMJ (Clinical research ed.), 374, n2040","doi":"10.1136/bmj.n2040","pmid":"34497062","tags":["pain","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"The guideline panel issued a weak recommendation to offer a trial of non-inhaled medical cannabis or cannabinoids as add-on therapy for chronic pain when standard care is insufficient. This reflects small to very small improvements in pain intensity, physical functioning, and sleep quality, balanced against a small to modest risk of mostly self-limited harms.","whyItMatters":"This is one of the most rigorous clinical guidelines on medical cannabis for pain, providing a framework for shared decision-making between patients and clinicians based on the best available evidence.","specificNumbers":"Weak recommendation; small to very small improvements in pain, function, and sleep; small to modest risk of mostly self-limited harms; non-inhaled forms recommended","methodology":"International guideline developed using GRADE methodology with patient, clinician, and methodologist input, informed by four linked systematic reviews on benefits, harms, and patient values regarding medical cannabis for chronic pain.","limitations":"Weak recommendation reflects close balance between benefits and harms. Evidence quality is variable. Further research may change the recommendation. Does not address inhaled cannabis."},{"rthcId":"RTHC-03038","title":"Marijuana and illicit drugs: Correlates of condomless anal sex among adolescent and emerging adult sexual minority men.","authors":"Cain, Demetria; Samrock, Steven; Jones, S Scott; Jimenez, Ruben H; Dilones, Rafael; Tanney, Mary; Outlaw, Angulique; Friedman, Lawrence; Naar, Sylvie; Starks, Tyrel J","year":2021,"journal":"Addictive behaviors, 122, 107018","doi":"10.1016/j.addbeh.2021.107018","pmid":"34171584","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03039","title":"Parental cannabis and tobacco use during pregnancy and childhood hair cortisol concentrations.","authors":"Cajachagua-Torres, Kim N; Jaddoe, Vincent W V; de Rijke, Yolanda B; van den Akker, Erica L T; Reiss, Irwin K M; van Rossum, Elisabeth F C; El Marroun, Hanan","year":2021,"journal":"Drug and alcohol dependence, 225, 108751","doi":"10.1016/j.drugalcdep.2021.108751","pmid":"34051550","tags":["pregnancy","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Children exposed to cannabis during pregnancy (combined with tobacco) had significantly higher hair cortisol concentrations at age 6 (log-10 difference 0.16, 95% CI 0.04-0.28). This was not mediated by birth weight. Paternal cannabis use and maternal tobacco-only use were not associated with childhood cortisol changes.","whyItMatters":"Elevated cortisol in childhood is linked to increased stress reactivity and vulnerability to mental health conditions. If prenatal cannabis exposure permanently alters the stress hormone system, this could have lifelong health implications.","specificNumbers":"2,577 mother-child pairs; hair cortisol measured at age 6; significant cortisol increase with cannabis+tobacco exposure; no effect from tobacco alone or paternal use; not mediated by birth weight","methodology":"Population-based prospective birth cohort of 2,577 mothers and children. Parental substance use collected by questionnaire with urine confirmation. Child hair cortisol and cortisone measured at age 6 as biomarkers of long-term HPA-axis functioning.","limitations":"Cannabis exposure was combined with tobacco in most cases, making it difficult to isolate cannabis-specific effects. Self-reported substance use may underestimate true exposure. Hair cortisol reflects average levels and may miss acute fluctuations."},{"rthcId":"RTHC-03040","title":"Canada's cannabis legalization and drivers' traffic-injury presentations to emergency departments in Ontario and Alberta, 2015-2019.","authors":"Callaghan, Russell C; Sanches, Marcos; Vander Heiden, Julia; Asbridge, Mark; Stockwell, Tim; Macdonald, Scott; Peterman, Bronwen Hughes; Kish, Stephen J","year":2021,"journal":"Drug and alcohol dependence, 228, 109008","doi":"10.1016/j.drugalcdep.2021.109008","pmid":"34508959","tags":["driving","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"There was no evidence of significant changes in traffic-injury ED visits after cannabis legalization in either province, for all drivers or youth drivers specifically. Results were non-significant in all four analyses (Alberta all drivers p=0.52, Alberta youth p=0.42, Ontario all drivers p=0.30, Ontario youth p=0.98).","whyItMatters":"A primary concern about cannabis legalization was increased traffic injuries. This large population-level study from two major Canadian provinces provides reassuring evidence that this feared outcome did not materialize in the first year.","specificNumbers":"Alberta: 52,752 all-driver presentations, 3,265 youth; Ontario: 186,921 all-driver, 4,565 youth; no significant changes post-legalization across all four analyses","methodology":"SARIMA time series analysis of weekly provincial emergency department records from April 2015 to December 2019 in Alberta and Ontario, examining driver traffic-injury presentations before and after legalization (October 17, 2018).","limitations":"Only 14 months of post-legalization data. ED visits may not capture all traffic injuries. Does not measure cannabis-impaired driving directly. Early legalization period may not reflect long-term trends."},{"rthcId":"RTHC-03041","title":"A Reason to Rethink Fasting Guidelines? Marijuana-Induced Gastroparesis and the Implications for Aspiration Risk in the Nil Per Os (NPO) Patient: A Case Report.","authors":"Cammarano, Caitlin A; Villaluz, Joseph Evan","year":2021,"journal":"The American journal of case reports, 22, e934187","doi":"10.12659/AJCR.934187","pmid":"34840324","tags":["harm-reduction","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Despite standard fasting (last meal at 10 PM the prior night), a daily cannabis user had 150 cc of gastric contents fill the airway device upon anesthesia induction, with 500 cc total suctioned from the stomach. The patient was asymptomatic for gastroparesis beforehand.","whyItMatters":"Standard pre-surgical fasting guidelines assume normal gastric emptying. If chronic cannabis use causes asymptomatic gastroparesis, current fasting protocols may be insufficient for daily users.","specificNumbers":"Age 24; BMI 22; daily marijuana use; last meal at 10 PM; 150 cc filled the airway device; 500 cc clear gastric contents suctioned from stomach; no aspiration into lungs; uneventful recovery","methodology":"Case report of a 24-year-old male daily cannabis user who presented for elective orthopedic surgery and experienced near-aspiration during anesthesia induction.","limitations":"Single case report cannot establish incidence. No gastric emptying study was performed. The relationship between cannabis dose, chronicity, and gastroparesis risk is unknown. Other causes of delayed emptying were not fully ruled out."},{"rthcId":"RTHC-03042","title":"Evaluation of substrate composition and exogenous hormone application on vegetative propagule rooting success of essential oil hemp (Cannabis sativa L.).","authors":"Campbell, Sean M; Anderson, Steven L; Brym, Zachary T; Pearson, Brian J","year":2021,"journal":"PloS one, 16(7), e0249160","doi":"10.1371/journal.pone.0249160","pmid":"34324510","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03043","title":"Correlates of driving after cannabis use in high school students.","authors":"Cantor, Nathan; Kingsbury, Mila; Hamilton, Hayley A; Wild, T Cameron; Owusu-Bempah, Akwasi; Colman, Ian","year":2021,"journal":"Preventive medicine, 150, 106667","doi":"10.1016/j.ypmed.2021.106667","pmid":"34081937","tags":["driving","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Past-year cannabis-impaired driving prevalence was 10.3%. The strongest predictors were probable cannabis dependence (OR=12.7), low perceived risk of cannabis (OR=5.3), pro-legalization attitudes (OR=4.3), and being male (OR=2.6). Cannabis-impaired driving was also correlated with texting while driving and driving after alcohol.","whyItMatters":"With cannabis now legal in Canada, understanding what drives teen cannabis-impaired driving is essential for designing effective prevention programs, especially since many correlates are attitudinal and potentially modifiable.","specificNumbers":"1,161 licensed students; mean age 16.8; 10.3% drove within 1 hour of cannabis use; OR 12.7 for cannabis dependence; OR 5.3 for low perceived risk; OR 4.3 for pro-legalization; OR 2.6 for male","methodology":"Cross-sectional analysis of 1,161 licensed high school students from the 2017 Ontario Student Health and Drug Use Survey, using multivariable logistic regression.","limitations":"Self-reported driving behaviors, cross-sectional design, Ontario-specific findings, 2017 data precedes legalization, licensed students may not represent all teen drivers."},{"rthcId":"RTHC-03044","title":"Acceptance of Drug Use Mediates Future Hard Drug Use Among At-Risk Adolescent Marijuana, Tobacco, and Alcohol Users.","authors":"Cappelli, Christopher; Ames, Susan L; Xie, Bin; Pike, James Russell; Stacy, Alan W","year":2021,"journal":"Prevention science : the official journal of the Society for Prevention Research, 22(5), 545-554","doi":"10.1007/s11121-020-01165-9","pmid":"32929694","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03045","title":"Medical Cannabis as Adjunctive Therapy for Head and Neck Cancer Patients.","authors":"Caputo, Mathew P; Rodriguez, Carmen S; Padhya, Tapan A; Mifsud, Matthew J","year":2021,"journal":"Cureus, 13(9), e18396","doi":"10.7759/cureus.18396","pmid":"34729274","tags":["cancer","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Only five studies met inclusion criteria, most investigating recreational rather than medical cannabis. Studies varied in quality and none reported standardized cannabis dosing. Meta-analysis was not possible due to variability in reported outcomes.","whyItMatters":"Head and neck cancer patients frequently deal with pain, nausea, and difficulty eating, all conditions where cannabis is commonly used. The almost complete absence of evidence is itself a significant finding.","specificNumbers":"Only 5 studies met inclusion criteria; most studied recreational cannabis; only 1 study reported dosing; meta-analysis was not possible","methodology":"Systematic review of PubMed, Embase, and Web of Science with no time limit, following standard methodology with two independent reviewers for screening and one for data extraction.","limitations":"The absence of evidence does not prove absence of effect. The extremely limited literature prevented meaningful analysis. Publication bias may have excluded relevant data."},{"rthcId":"RTHC-03046","title":"Cannabidiol-enriched medical cannabis as add-on therapy in children with treatment-resistant West syndrome: A study of eight patients.","authors":"Caraballo, Roberto; Valenzuela, Gabriela Reyes","year":2021,"journal":"Seizure, 92, 238-243","doi":"10.1016/j.seizure.2021.10.002","pmid":"34624613","tags":["epilepsy","cbd","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Of 8 children with treatment-resistant West syndrome treated with CBD:THC (25:1 ratio), 2 had 75-99% seizure reduction, 2 had 50-74% reduction, 3 had less than 50% reduction, and 1 had no change. EEG abnormalities improved in 7 of 8 patients. Side effects were mild: somnolence (1), nausea/vomiting (1), irritability (1).","whyItMatters":"West syndrome is a devastating infantile epilepsy with limited treatment options. When standard medications and ketogenic diet fail, families have few alternatives. This data suggests CBD may offer meaningful seizure reduction for some of these patients.","specificNumbers":"8 patients; ages 16-22 months; CBD:THC ratio 25:1; median CBD dose 12 mg/kg/day; mean baseline 63 seizures/day; 50% had >50% seizure reduction; 6-13 months follow-up","methodology":"Retrospective analysis of 8 patients (6 female, 2 male) with West syndrome refractory to antiseizure medications and ketogenic diet, treated with CBD-enriched cannabis oil (25:1 CBD:THC) at a single center from May 2020 to March 2021.","limitations":"Very small case series (8 patients), no control group, retrospective design, single center, variable follow-up periods, concurrent antiseizure medications continued."},{"rthcId":"RTHC-03047","title":"Use of cannabis in patients with multiple sclerosis from Argentina.","authors":"Carnero Contentti, Edgar; López, Pablo A; Criniti, Juan; Pettinicchi, Juan Pablo; Tavolini, Dario; Mainella, Carolina; Tizio, Santiago; Tkachuk, Verónica; Silva, Berenice; Caride, Alejandro; Rojas, Juan I; Alonso, Ricardo","year":2021,"journal":"Multiple sclerosis and related disorders, 51, 102932","doi":"10.1016/j.msard.2021.102932","pmid":"33848817","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"34.2% were current cannabis users, 22.7% former users. Among users, 31.3% used daily, 41.9% started after MS diagnosis, and 54.3% never discussed cannabis with their neurologist. Predictors of use were age under 30 (OR=2.39), chronic pain (OR=2.42), and current alcohol intake (OR=3.33).","whyItMatters":"The high prevalence of cannabis use among MS patients combined with low rates of physician discussion creates a dangerous information gap where patients may be making uninformed decisions about a substance that could interact with their MS treatments.","specificNumbers":"281 patients; 34.2% current users; 22.7% former users; 31.3% daily use; 41.9% started post-diagnosis; 54.3% never discussed with neurologist; 47.5% recreational use","methodology":"Cross-sectional online survey of 281 MS patients from Argentina, assessing demographics, quality of life, fatigue, anxiety/depression, sleep, disability, and cannabis use patterns.","limitations":"Online survey with potential selection bias, self-reported cannabis use and disability, cross-sectional design, Argentina-specific context where cannabis legality is evolving."},{"rthcId":"RTHC-03048","title":"Patterns and correlates of workplace and non-workplace cannabis use among Canadian workers before the legalization of non-medical cannabis.","authors":"Carnide, Nancy; Lee, Hyunmi; Frone, Michael R; Furlan, Andrea D; Smith, Peter M","year":2021,"journal":"Drug and alcohol dependence, 218, 108386","doi":"10.1016/j.drugalcdep.2020.108386","pmid":"33213975","tags":["workplace","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a survey of 1,651 Canadian workers conducted in June 2018 — just months before recreational legalization — a quarter of those reporting past-year cannabis use said they'd used before or at work. These workplace users weren't just recreational users who happened to be at work. They had a distinct profile.\n\nCompared to off-the-clock cannabis users, workplace users were significantly more likely to use cannabis daily, use for medical or mixed medical-recreational purposes, and prefer high-THC products. Several personal factors predicted workplace use: younger age, being male, lower education, poorer self-rated health, and having a physically demanding or monotonous job.\n\nThe medical use dimension complicated the picture. Some workplace cannabis use wasn't reckless — it was people managing pain, anxiety, or other conditions during work hours. The policy challenge of distinguishing impaired use from therapeutic use was already present before legalization formalized it.","whyItMatters":"Workplace cannabis use is the third rail of legalization policy. This study put numbers to it for the first time in Canada and found the rate was substantial — 1 in 4 users. The finding that workplace users were more likely to be medical users adds nuance: workplace drug policies designed around recreational intoxication may inadvertently penalize workers managing legitimate health conditions.\n\nThe pre-legalization timing makes this a baseline. Whether these patterns changed after recreational legalization became a critical follow-up question.","specificNumbers":"• 25% of past-year cannabis users reported workplace use\n• 1,651 Canadian workers surveyed (June 2018)\n• Workplace users more likely to: use daily, use high-THC, use for medical purposes\n• Risk factors: younger, male, lower education, poorer health, physically demanding jobs","methodology":"Cross-sectional survey of 1,651 Canadian workers collected in June 2018. Multinomial logistic regression comparing three groups: past-year workplace cannabis users, past-year non-workplace users, and non-users. Controlled for sociodemographic, health, and work-related factors.","limitations":"Self-reported data likely underestimates workplace use due to stigma and fear of consequences. Cross-sectional design cannot determine whether work characteristics cause cannabis use or vice versa. Single time point before legalization — patterns may have changed. Online survey sample may not represent all Canadian workers."},{"rthcId":"RTHC-03049","title":"Use of Cannabis for Self-Management of Chronic Pelvic Pain.","authors":"Carrubba, Aakriti R; Ebbert, Jon O; Spaulding, Aaron C; DeStephano, David; DeStephano, Christopher C","year":2021,"journal":"Journal of women's health (2002), 30(9), 1344-1351","doi":"10.1089/jwh.2020.8737","pmid":"33252316","tags":["pain","medical-cannabis","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"23% of chronic pelvic pain patients used cannabis, with 72% using at least weekly. 96% of users reported symptom improvement including pain, cramping, muscle spasms, anxiety, depression, sleep, libido, and irritability. 35% reduced provider contact and 39% decreased clinical visits.","whyItMatters":"Chronic pelvic pain affects up to 15% of U.S. women and has limited treatment options. The endocannabinoid system has receptors throughout the uterus and reproductive tissues, providing a biological basis for cannabis as a treatment target.","specificNumbers":"113 respondents; 23% used cannabis; 72% of users at least weekly; 96% reported improvement; 84% had side effects; 35% reduced provider calls; 39% fewer clinical visits","methodology":"Cross-sectional anonymous electronic survey of 113 women with pelvic/perineal pain, dyspareunia, or endometriosis at an outpatient gynecology office (March-August 2019).","limitations":"Small sample, single outpatient office, 47% response rate, self-reported outcomes without objective measures, selection bias possible, 84% reported side effects."},{"rthcId":"RTHC-03050","title":"Neurodevelopmental Effects of Cannabis Use in Adolescents and Emerging Adults with ADHD: A Systematic Review.","authors":"Cawkwell, Philip B; Hong, David S; Leikauf, John E","year":2021,"journal":"Harvard review of psychiatry, 29(4), 251-261","doi":"10.1097/HRP.0000000000000303","pmid":"34138796","tags":["youth","cognition","neuroscience"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"No study found an additive or interaction effect between ADHD and cannabis use on neuropsychological tasks of executive function. Neuroimaging revealed differential brain activation and morphological differences in cannabis-using ADHD youth, but two studies found adverse impacts specifically from early-onset cannabis use.","whyItMatters":"Youth with ADHD are at elevated risk for cannabis use, making it critical to understand whether cannabis compounds their existing cognitive and neurological vulnerabilities. The current evidence, while limited, does not clearly support this hypothesis.","specificNumbers":"11 studies identified; 7 used neuroimaging (fMRI, structural MRI, SPECT); differential activation in hippocampus, cerebellar vermis, temporal lobes; morphological differences in nucleus accumbens, frontal and postcentral gyri","methodology":"Systematic review following PRISMA guidelines, searching four databases through January 2020. Eleven studies comparing ADHD youth with and without cannabis use were identified, seven using neuroimaging.","limitations":"Most studies were small and potentially underpowered to detect interaction effects. Cross-sectional designs cannot establish causation. No standardized assessment protocols across studies."},{"rthcId":"RTHC-03051","title":"Factors associated with health-related cannabis use intentions among a community sample of people who inject drugs in Los Angeles and San Francisco, CA 2016 to 2018.","authors":"Ceasar, Rachel Carmen; Kral, Alex H; Simpson, Kelsey; Wenger, Lynn; Goldshear, Jesse L; Bluthenthal, Ricky N","year":2021,"journal":"Drug and alcohol dependence, 219, 108421","doi":"10.1016/j.drugalcdep.2020.108421","pmid":"33301996","tags":["harm-reduction","pain","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis use for physical pain relief was associated with higher odds of using cannabis as an opioid substitute. Cannabis for emotional problems was associated with depression diagnosis. Cannabis as an opioid substitute was linked to non-prescribed methadone use.","whyItMatters":"If people who inject drugs are already using cannabis as a self-directed harm reduction strategy, formalized programs could potentially leverage this behavior to reduce opioid use and overdose risk.","specificNumbers":"387 people who inject drugs; most common motivations: getting high, pain relief, emotional problems, opioid reduction; pain relief associated with opioid substitution; depression associated with emotional use motivation","methodology":"Analysis of 6-month follow-up data from 387 people who inject drugs and reported past-month cannabis use, recruited from Los Angeles and San Francisco (2016-2018). Multivariable logistic regression examined motivations.","limitations":"Cross-sectional design, self-reported motivations, specific to people who inject drugs in two California cities, cannot determine whether cannabis actually reduces opioid use or harm."},{"rthcId":"RTHC-03052","title":"A Review of Hemp as Food and Nutritional Supplement.","authors":"Cerino, Pellegrino; Buonerba, Carlo; Cannazza, Giuseppe; D'Auria, Jacopo; Ottoni, Ermete; Fulgione, Andrea; Di Stasio, Antonio; Pierri, Biancamaria; Gallo, Alfonso","year":2021,"journal":"Cannabis and cannabinoid research, 6(1), 19-27","doi":"10.1089/can.2020.0001","pmid":"33614949","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03053","title":"Upconverting nanoparticle clustering based rapid quantitative detection of tetrahydrocannabinol (THC) on lateral-flow immunoassay.","authors":"Chand, Rohit; Mittal, Neha; Srinivasan, Seshasai; Rajabzadeh, Amin Reza","year":2021,"journal":"The Analyst, 146(2), 574-580","doi":"10.1039/d0an01850c","pmid":"33174869","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03054","title":"Cannabis and its therapeutic value in the ageing population: Attitudes of health-care providers.","authors":"Chandiok, Karan; Marathe, Shreeya; Rooney, Miranda; Stocker, Jess; Tellis, Bianca; Pit, Sabrina","year":2021,"journal":"Australasian journal on ageing, 40(3), 261-274","doi":"10.1111/ajag.12846","pmid":"34273232","tags":["seniors","medical-cannabis"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Providers were generally positive about medical cannabis for older patients but identified multiple barriers: stigma from patients and colleagues, complex regulatory pathways (Special Access Scheme), limited access in rural areas, restrictive driving laws, and insufficient education and evidence.","whyItMatters":"As the aging population grows and cannabis-based medicines become available, understanding provider attitudes and barriers is essential for ensuring older patients can access these treatments when appropriate.","specificNumbers":"11 healthcare providers interviewed; rural NSW, Australia; barriers include stigma, regulation, access, driving laws; Special Access Scheme identified as difficult","methodology":"Semi-structured qualitative interviews with 11 healthcare providers in rural New South Wales, Australia, analyzed using thematic analysis and an ecological framework.","limitations":"Small qualitative sample (11 providers), single rural region in Australia, may not generalize to urban settings or other countries, provider self-selection may bias toward those interested in cannabis."},{"rthcId":"RTHC-03055","title":"Effectiveness of Cannabinoids for Treatment of Dementia: A Systematic Review of Randomized Controlled Trials.","authors":"Charernboon, Thammanard; Lerthattasilp, Tiraya; Supasitthumrong, Thitipon","year":2021,"journal":"Clinical gerontologist, 44(1), 16-24","doi":"10.1080/07317115.2020.1742832","pmid":"32186469","tags":["cognition","seniors","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Nabilone (1-2 mg/day) showed significant improvement in agitation in one trial. THC (1.5-4.5 mg/day) showed no significant differences from placebo for agitation in two trials. Dronabinol (5 mg/day) improved weight in one anorexia-focused trial. No studies examined cannabinoids for cognitive symptoms.","whyItMatters":"With dementia patients and families seeking new treatment options, this review provides a clear picture: there is a thin line of evidence for nabilone in agitation but essentially no support for cannabinoids improving cognition or disease progression.","specificNumbers":"5 RCTs included; nabilone 1-2 mg/day improved agitation; THC 1.5-4.5 mg/day no benefit for agitation; dronabinol 5 mg/day improved weight; 0 studies on cognitive decline; evidence rated low to very low","methodology":"Systematic review following PRISMA guidelines, searching Medline, Embase, Cochrane, and PsycINFO. Five randomized controlled trials met inclusion criteria.","limitations":"Only five trials with low to very low quality evidence. Small sample sizes. Different cannabinoid preparations tested. No studies on cognitive outcomes. Short follow-up periods."},{"rthcId":"RTHC-03056","title":"Acute effects of cannabis consumption on exercise performance: a systematic and umbrella review.","authors":"Charron, Jérémie; Carey, Vincent; Marcotte L'heureux, Viviane; Roy, Philippe; Comtois, Alain S; Ferland, Pierre-Marc","year":2021,"journal":"The Journal of sports medicine and physical fitness, 61(4), 551-561","doi":"10.23736/S0022-4707.20.11003-X","pmid":"32734752","tags":["exercise"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabis before exercise produces decrements in performance (reduced ability to maintain effort, lower physical/maximal work capacity), undesired physiological responses (increased heart rate, breathing rate, and myocardial oxygen demand), and neurological effects including impaired balance (increased sway).","whyItMatters":"Despite popular beliefs about cannabis enhancing sports performance, this comprehensive review provides clear evidence that cannabis impairs rather than enhances exercise performance.","specificNumbers":"8 original studies; 10 literature reviews; cannabis causes reduced work capacity, increased heart/breathing rate, increased myocardial oxygen demand, and impaired balance; research uses ~6% THC but modern products reach ~150 mg THC","methodology":"Systematic and umbrella review following PRISMA guidelines, searching PubMed, Scopus, and SPORTDiscus. Identified 8 original articles and 10 literature reviews. Evidence quality assessed using modified Downs and Black Checklist.","limitations":"Most studies used low-potency cannabis (~6% THC) not reflecting modern products. Limited study designs. Research has not mimicked modern dosages (150+ mg THC). Few studies in trained athletes."},{"rthcId":"RTHC-03057","title":"Cannabidiol induces antidepressant and anxiolytic-like effects in experimental type-1 diabetic animals by multiple sites of action.","authors":"Chaves, Yane Costa; Genaro, Karina; Crippa, José Alexandre; da Cunha, Joice Maria; Zanoveli, Janaína Menezes","year":2021,"journal":"Metabolic brain disease, 36(4), 639-652","doi":"10.1007/s11011-020-00667-3","pmid":"33464458","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03058","title":"Cannabidiol Effectively Promoted Cell Death in Bladder Cancer and the Improved Intravesical Adhesion Drugs Delivery Strategy Could Be Better Used for Treatment.","authors":"Chen, Shanshan; Deng, Changping; Zheng, Wenyun; Li, Shihui; Liu, Yuping; Zhang, Tong; Zhang, Chen; Fu, Yunhui; Miao, Hui; Ren, Fuzheng; Ma, Xingyuan","year":2021,"journal":"Pharmaceutics, 13(9)","doi":"10.3390/pharmaceutics13091415","pmid":"34575494","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03059","title":"Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer's Disease Patients.","authors":"Chiurchiù, Valerio; Scipioni, Lucia; Arosio, Beatrice; Mari, Daniela; Oddi, Sergio; Maccarrone, Mauro","year":2021,"journal":"Biomolecules, 11(4)","doi":"10.3390/biom11040502","pmid":"33810505","tags":["cognition","inflammation","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"AD patients had lower CB1 and CB2 expression on B-lymphocytes and monocytes, with higher FAAH levels in monocytes. Blocking FAAH in these cells reduced TNF-alpha, IL-6, and IL-12 while increasing anti-inflammatory IL-10, and shifted macrophages toward a more protective phenotype. Monocytic CB2 and FAAH levels correlated with clinical scores.","whyItMatters":"If peripheral immune cells contribute to Alzheimer's progression, and their inflammatory behavior can be modulated through the endocannabinoid system, this opens a novel therapeutic approach targeting immune cells rather than brain cells directly.","specificNumbers":"CB1 and CB2 lower in AD B-lymphocytes; CB2 lower and FAAH higher in AD monocytes; FAAH blockade reduced TNF-alpha, IL-6, IL-12 and increased IL-10; T-lymphocytes and NK cells showed no changes","methodology":"Comparison of endocannabinoid system markers on immune cells from AD patients versus healthy controls, followed by in vitro pharmacological FAAH inhibition experiments on patient-derived monocytes and macrophages.","limitations":"In vitro manipulation may not translate to in vivo effects. Cross-sectional design cannot establish causation. Small sample size typical of such studies. Effects on disease progression were not measured."},{"rthcId":"RTHC-03060","title":"Behavioral Health Risk Factors for Nonmedical Prescription Opioid Use in Adolescence.","authors":"Cho, Junhan; Kelley-Quon, Lorraine I; Barrington-Trimis, Jessica L; Kechter, Afton; Axeen, Sarah; Leventhal, Adam M","year":2021,"journal":"Pediatrics, 148(3)","doi":"10.1542/peds.2021-051451","pmid":"34400572","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03061","title":"Sex differences in cannabis forms and exposure reasons in cannabis-related poison control center cases aged 50.","authors":"Choi, Namkee G; DiNitto, Diana M; Marti, C Nathan; Baker, S David","year":2021,"journal":"Clinical toxicology (Philadelphia, Pa.), 59(9), 822-831","doi":"10.1080/15563650.2020.1869756","pmid":"33475427","tags":["seniors","sex-differences","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Women over 50 had 1.93 times greater odds of calling about therapeutic errors/adverse reactions compared to intentional misuse. They were more likely to be using non-plant cannabis forms (edibles, oils). Older age and living in legal-cannabis states were associated with non-plant product use. Sex was not associated with severity of medical outcomes.","whyItMatters":"Older women are increasingly using cannabis products for medical purposes but appear to be experiencing more therapeutic errors, suggesting a need for better dosing guidance and education for this growing demographic.","specificNumbers":"3,633 cases age 50+; 57.4% female; women had 1.20x odds of non-plant forms; 1.93x odds of therapeutic errors vs misuse; older age and legal states associated with non-plant products","methodology":"Analysis of 3,633 cases of adults aged 50+ from the National Poison Data System (2009-2019) where plant or non-synthetic cannabis was the primary substance, using logistic and multinomial regression.","limitations":"Poison control data captures only reported cases, likely underestimating true adverse events. Self-reported exposure details. Cannot determine population-based rates."},{"rthcId":"RTHC-03062","title":"Cannabis and synthetic cannabinoid poison control center cases among adults aged 50+, 2009-2019.","authors":"Choi, Namkee G; Marti, C Nathan; DiNitto, Diana M; Baker, S David","year":2021,"journal":"Clinical toxicology (Philadelphia, Pa.), 59(4), 334-342","doi":"10.1080/15563650.2020.1806296","pmid":"32840426","tags":["seniors","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cases increased 18-fold (61 to 1,074) over the decade. Non-plant preparations had 51x greater odds of appearing in 2018-2019 vs 2009-2011. Synthetic cannabinoids/e-cigarettes had 2.07x the odds of major medical outcomes compared to plant forms. Other preparations were associated with older age, adverse reactions, and suicide attempts.","whyItMatters":"The rapid increase in older adult cannabis cases reflects both expanding cannabis access and an aging population unfamiliar with modern products. The high rate of major medical outcomes demands attention.","specificNumbers":"5,201 total cases; 18-fold increase (61 to 1,074); non-plant preparations 51x more common in 2018-2019; synthetic cannabinoids OR 2.07 for major outcomes; non-plant forms OR 0.75 for major outcomes","methodology":"Analysis of 5,201 cases of adults aged 50+ from the National Poison Data System (2009-2019) where cannabis was the primary substance, using multinomial and binary logistic regression.","limitations":"Poison control cases represent only a fraction of adverse events. Reporting may have increased alongside awareness. Cannot distinguish effects of legalization from aging demographics."},{"rthcId":"RTHC-03063","title":"Pharmacology and adverse effects of new psychoactive substances: synthetic cannabinoid receptor agonists.","authors":"Chung, Eun Yong; Cha, Hye Jin; Min, Hyun Kyu; Yun, Jaesuk","year":2021,"journal":"Archives of pharmacal research, 44(4), 402-413","doi":"10.1007/s12272-021-01326-6","pmid":"33811300","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"SCRAs are the most commonly abused new psychoactive substances worldwide. Unlike natural THC (a partial agonist), most SCRAs are full CB1 and CB2 agonists, producing much greater effects. Associated toxicities include cardiotoxicity, immunotoxicity, and death.","whyItMatters":"The fundamental pharmacological difference between natural cannabis (partial agonist) and synthetic cannabinoids (full agonists) explains why synthetics are so much more dangerous and why natural cannabis safety data cannot be applied to them.","specificNumbers":"NPS classified into six groups; SCRAs are the largest class; sold as herbal incense, bath salts, legal highs; some classified as Schedule 1 in the US","methodology":"Review of the general pharmacological characteristics, recent findings, and adverse effects of synthetic cannabinoid receptor agonists, focusing on their mechanism of action and clinical toxicity.","limitations":"Rapidly evolving landscape of new compounds makes any review potentially outdated. Clinical data is primarily from case reports and poison control data rather than systematic studies."},{"rthcId":"RTHC-03064","title":"Steering clear: Traffic violations among emerging adults who engage in habitual or casual cannabis use.","authors":"Ciccarelli, Tiana M; Leatherdale, Scott T; Perlman, Chris; Thompson, Kara; Ferro, Mark A","year":2021,"journal":"Accident; analysis and prevention, 153, 106059","doi":"10.1016/j.aap.2021.106059","pmid":"33662695","tags":["driving","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Both habitual (OR=1.77) and casual (OR=1.79) cannabis users had higher odds of traffic violations than non-users. Early emerging adults (15-19) who were casual users and middle emerging adults (20-24) who were habitual or casual users showed higher odds. The association was stronger in the absence of other drug use.","whyItMatters":"The finding that casual cannabis use carries similar traffic violation risk as habitual use challenges the assumption that only heavy users are at risk, suggesting even occasional use may affect driving-related outcomes.","specificNumbers":"5,630 respondents; habitual cannabis OR=1.77; casual cannabis OR=1.79; male prevalence 19.2% vs female 9.9%; violations higher in middle (16.2%) and late (19.4%) vs early (8.8%) EAs","methodology":"Cross-sectional analysis of 5,630 respondents from the 2012 Canadian Community Health Survey-Mental Health, categorized as early (15-19), middle (20-24), and late (25-29) emerging adults.","limitations":"Cross-sectional self-reported data. Traffic violations include many types beyond impaired driving. Cannot establish that cannabis caused the violations. 2012 data predates legalization."},{"rthcId":"RTHC-03065","title":"Methylomic Investigation of Problematic Adolescent Cannabis Use and Its Negative Mental Health Consequences.","authors":"Clark, Shaunna L; Chan, Robin; Zhao, Min; Xie, Lin Y; Copeland, William E; Aberg, Karolina A; van den Oord, Edwin J C G","year":2021,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 60(12), 1524-1532","doi":"10.1016/j.jaac.2021.02.008","pmid":"33631312","tags":["youth","genetics","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"45 significant methylation sites were identified in whole blood, plus 32 additional in cell-type analyses. B-cell methylation overlapped with genetic studies of educational attainment and intelligence. T-cell and monocyte results overlapped with brain tissue methylation findings from psychosis studies.","whyItMatters":"This provides the first epigenomic evidence linking adolescent cannabis use to molecular changes that overlap with psychosis-related pathways, offering a potential biological mechanism for the cannabis-psychosis association.","specificNumbers":"703 adolescent samples; 45 significant whole-blood CpGs; 32 additional cell-type-specific CpGs; significant overlap with psychosis and intelligence genetic studies","methodology":"Methylome-wide association study using enrichment-based sequencing in 703 adolescent samples from the Great Smoky Mountain Study, with cell-type-specific analyses for granulocytes, T cells, B cells, and monocytes.","limitations":"Blood methylation may not directly reflect brain methylation. Cross-sectional design cannot determine whether methylation changes preceded or followed cannabis use. The Great Smoky Mountain Study has specific demographic characteristics."},{"rthcId":"RTHC-03066","title":"MAM-2201, One of the Most Potent-Naphthoyl Indole Derivative-Synthetic Cannabinoids, Exerts Toxic Effects on Human Cell-Based Models of Neurons and Astrocytes.","authors":"Coccini, T; De Simone, U; Lonati, D; Scaravaggi, G; Marti, M; Locatelli, C A","year":2021,"journal":"Neurotoxicity research, 39(4), 1251-1273","doi":"10.1007/s12640-021-00369-3","pmid":"33945101","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03067","title":"The feeding behaviour of Amyotrophic Lateral Sclerosis mouse models is modulated by the Ca2+ -activated KCa 3.1 channels.","authors":"Cocozza, Germana; Garofalo, Stefano; Morotti, Marta; Chece, Giuseppina; Grimaldi, Alfonso; Lecce, Mario; Scavizzi, Ferdinando; Menghini, Rossella; Casagrande, Viviana; Federici, Massimo; Raspa, Marcello; Wulff, Heike; Limatola, Cristina","year":2021,"journal":"British journal of pharmacology, 178(24), 4891-4906","doi":"10.1111/bph.15665","pmid":"34411281","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03068","title":"Regarding the Mechanisms of Promiscuous Cannabinoid Pharmacology: An Elephant Has Entered the Room.","authors":"Cogan, Peter S","year":2021,"journal":"Cannabis and cannabinoid research, 6(6), 457-461","doi":"10.1089/can.2020.0115","pmid":"33998883","tags":["cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Recent research shows CBD can form colloidal dispersions in aqueous solutions, which are known to cause nonspecific effects in biochemical assays. This raises the question of how many decades of reported CBD activities in lab studies may actually be false positives from colloidal interference rather than specific pharmacological interactions.","whyItMatters":"If a significant portion of CBD's reported lab activities are artifacts, it would fundamentally reshape our understanding of how CBD works and redirect research toward identifying its true therapeutic mechanisms.","specificNumbers":"Decades of in vitro CBD research potentially affected; colloidal dispersions are a known source of false positives in drug screening","methodology":"Perspective/commentary analyzing the implications of recent colloidal aggregation findings for the broader field of cannabinoid pharmacology.","limitations":"This is a perspective piece, not a systematic analysis. The extent of colloidal interference in published CBD research has not been quantified. Not all CBD activities are necessarily artifacts."},{"rthcId":"RTHC-03069","title":"Therapeutic and Cosmetic Uses of Cannabis: Cannabinoids for Acne Treatment and Skin -Rejuvenation.","authors":"Cohen, Philip R","year":2021,"journal":"Skinmed, 19(1), 45-47","doi":null,"pmid":"33658112","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03070","title":"Associations Between Family and Peer E-Cigarette Use With Adolescent Tobacco and Marijuana Usage: A Longitudinal Path Analytic Approach.","authors":"Coleman, Michael; Donaldson, Candice D; Crano, William D; Pike, James R; Stacy, Alan W","year":2021,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 23(5), 849-855","doi":"10.1093/ntr/ntaa204","pmid":"33038257","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03071","title":"Young drivers' determinants of driving under the influence of cannabis: Findings from the Youth Cannabis and Driving Survey (YouCanDS).","authors":"Colonna, Robert; Hand, Carri L; Holmes, Jeffrey D; Alvarez, Liliana","year":2021,"journal":"Journal of safety research, 78, 229-241","doi":"10.1016/j.jsr.2021.05.001","pmid":"34399919","tags":["driving","youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"33.3% of respondents reported past DUIC and 42% indicated future DUIC intention. Six predictors of DUIC intention emerged: past DUIC incidence, perceived conviction penalty rate, moral awareness, perceived dangerousness, minor accident risk perception, and vicarious punishment avoidance.","whyItMatters":"The high prevalence of both past and intended DUIC among young drivers, combined with identifiable attitudinal predictors, provides clear targets for prevention programs.","specificNumbers":"426 respondents; 52.6% female; 83.6% had used cannabis; 69.5% past-year use; 33.3% reported DUIC; 42% intended future DUIC; 6 significant predictors identified","methodology":"Cross-sectional validated questionnaire based on general deterrence and prevention theory, administered to 426 young drivers (ages 16-24) in Ontario, Canada. Ordinal regression examined predictors of DUIC intention.","limitations":"Self-selected sample of young drivers, Ontario-specific, cross-sectional design, self-reported DUIC which may be underreported, questionnaire validation was part of the same study."},{"rthcId":"RTHC-03072","title":"Lifetime Cannabis Use Disorder Is Not Associated With Lifetime Impulsive Behavior and Severe Violence in Patients With Schizophrenia Spectrum Disorders From a High-Security Hospital.","authors":"Comai, Stefano; Fuamba, Yves; Rivolta, Maria Chiara; Gobbi, Gabriella","year":2021,"journal":"Journal of clinical psychopharmacology, 41(6), 623-628","doi":"10.1097/JCP.0000000000001493","pmid":"34735097","tags":["psychosis","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Violent and nonviolent psychotic patients had similar rates of cannabis use disorder. Cannabis was not associated with any dimension of impulsivity. In contrast, alcohol use disorder was associated with impulsive behavior and was nearly 4 times more likely in violent patients (OR=3.96). Cocaine use disorder was associated with proneness to boredom but not violence.","whyItMatters":"The common assumption that cannabis drives violence in people with psychosis is challenged by this data showing alcohol, not cannabis, is the substance associated with violent behavior in this high-risk population.","specificNumbers":"124 patients; alcohol use disorder OR=3.96 for violence; cannabis use disorder not associated with violence or impulsivity; cocaine linked to proneness to boredom","methodology":"Cross-sectional retrospective study of 124 patients with schizophrenia spectrum disorders in a high-security hospital, using standardized measures of violence history, impulsivity, psychopathy, substance use, and psychotic symptoms.","limitations":"Cross-sectional design in a specialized high-security setting. Patients may underreport substance use. Results may not generalize to community-dwelling psychosis patients. Small sample size."},{"rthcId":"RTHC-03073","title":"Urinary Cannabis Metabolite Concentrations in Cannabis Hyperemesis Syndrome.","authors":"Cordova, Jonathan; Biank, Vincent; Black, Elizabeth; Leikin, Jerrold","year":2021,"journal":"Journal of pediatric gastroenterology and nutrition, 73(4), 520-522","doi":"10.1097/MPG.0000000000003220","pmid":"34224490","tags":["harm-reduction","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"14 of 15 CHS patients had urinary THC-COOH concentrations above 100 ng/mL, with 7 exceeding 500 ng/mL. The one exception had not used cannabis for 2 weeks. All had normal GI workups. All reported frequent cannabis use for at least 1 month and intractable vomiting for at least 2 weeks.","whyItMatters":"CHS can be difficult to diagnose, often leading to extensive and expensive workups. If urinary THC-COOH above 100 ng/mL proves to be a reliable biomarker, it could shorten the diagnostic process significantly.","specificNumbers":"15 patients; average age 17.7; 14/15 had THC-COOH >100 ng/mL; 7 had >500 ng/mL; 12 reported weight loss; all had normal GI workups; p<0.0005 for association","methodology":"Retrospective case series of 15 patients referred to a pediatric gastroenterology service for intractable vomiting, found to have CHS with urinary THC-COOH measured by gas chromatography mass spectrometry (January 2018 to April 2019).","limitations":"Very small case series (15 patients), single center, no control group of heavy cannabis users without CHS, retrospective design, THC-COOH levels depend on timing of last use."},{"rthcId":"RTHC-03074","title":"The synthetic CB1 cannabinoid receptor selective agonists: Putative medical uses and their legalization.","authors":"Coronado-Álvarez, Astrid; Romero-Cordero, Karen; Macías-Triana, Lorena; Tatum-Kuri, Agnes; Vera-Barrón, Alba; Budde, Henning; Machado, Sérgio; Yamamoto, Tetsuya; Imperatori, Claudio; Murillo-Rodríguez, Eric","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 110, 110301","doi":"10.1016/j.pnpbp.2021.110301","pmid":"33741446","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03075","title":"The independent and combined effects of cannabis use and systemic inflammation during the early stages of psychosis: exploring the two-hit hypothesis.","authors":"Corsi-Zuelli, Fabiana; Marques, Leonardo; da Roza, Daiane Leite; Loureiro, Camila Marcelino; Shuhama, Rosana; Di Forti, Marta; Menezes, Paulo Rossi; Louzada-Junior, Paulo; Del-Ben, Cristina Marta","year":2021,"journal":"Psychological medicine, 1-11","doi":"10.1017/S0033291721000726","pmid":"33736715","tags":["psychosis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis did not increase inflammation (ruling out a mediating pathway). Instead, daily cannabis use and onset before age 17 only increased psychosis odds among those with medium-to-high inflammatory composite scores. This interaction effect went beyond the individual effects of either cannabis or inflammation alone.","whyItMatters":"This suggests not everyone who uses cannabis faces equal psychosis risk. Pre-existing immune dysregulation may be a necessary biological vulnerability that cannabis then triggers, explaining why most users never develop psychosis.","specificNumbers":"153 first-episode psychosis patients; 256 controls; 7 cytokines measured; daily use and onset <17 interacted with inflammation; cannabis did not increase inflammation directly","methodology":"Cross-sectional study of 153 first-episode psychosis patients and 256 community controls. Cannabis use assessed via Cannabis Experience Questionnaire. Seven plasma cytokines measured to create an inflammatory composite score. Mediation and moderation analyses performed.","limitations":"Cross-sectional design cannot confirm temporal ordering. Single blood inflammatory measurement. Cannot rule out unmeasured confounders. First-episode psychosis patients may differ from the broader at-risk population."},{"rthcId":"RTHC-03076","title":"Cannabinoid Receptor Modulation of Neurogenesis: ST14A Striatal Neural Progenitor Cells as a Simplified In Vitro Model.","authors":"Cottone, Erika; Pomatto, Valentina; Rapelli, Stefania; Scandiffio, Rosaria; Mackie, Ken; Bovolin, Patrizia","year":2021,"journal":"Molecules (Basel, Switzerland), 26(5)","doi":"10.3390/molecules26051448","pmid":"33800024","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03077","title":"Differences between cancer patients and others who use medicinal Cannabis.","authors":"Cousins, Matthew M; Jannausch, Mary; Jagsi, Reshma; Ilgen, Mark","year":2021,"journal":"PloS one, 16(3), e0248227","doi":"10.1371/journal.pone.0248227","pmid":"33725004","tags":["medical-cannabis","cancer","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,485 adults pursuing medical cannabis certification in Michigan, 72 cancer patients used less cannabis and used it less often than the 1,413 non-cancer patients. Cancer patients were also less likely to smoke cannabis (80% vs. 91%) and showed a trend toward more edible use (57% vs. 44%).","whyItMatters":"Cancer patients have driven much of the policy discussion around medical cannabis legalization, yet their actual patterns of use remain poorly characterized. This study shows they are a distinct population with different usage behaviors compared to the broader medical cannabis patient pool.","specificNumbers":"1,485 adults surveyed; 72 (4.8%) had cancer; cancer patients were older (mean 53.4 vs. 44.7 years); more were disabled (44.4% vs. 26.5%); fewer smoked cannabis (80% vs. 91%, p=0.015); lower quantity (p=0.033) and frequency (p=0.032) of use","methodology":"Cross-sectional survey of patients seeking medical cannabis certification at Michigan dispensaries. Compared demographics, employment, pain, mental health, and cannabis use patterns between those with and without cancer diagnosis using chi-square and t-tests.","limitations":"Cross-sectional design at a single time point. Only patients seeking certification were included, which may not represent all cancer patients using cannabis. Self-reported data with potential recall bias. Small cancer subgroup (n=72)."},{"rthcId":"RTHC-03078","title":"When Cannabis Use Goes Wrong: Mental Health Side Effects of Cannabis Use That Present to Emergency Services.","authors":"Crocker, Candice E; Carter, Alix J E; Emsley, Jason G; Magee, Kirk; Atkinson, Paul; Tibbo, Philip G","year":2021,"journal":"Frontiers in psychiatry, 12, 640222","doi":"10.3389/fpsyt.2021.640222","pmid":"33658953","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03079","title":"Correlates of Self-Reported HIV Testing Among Patients in Specialized Substance Abuse Treatment Centers in South Africa.","authors":"Cummings, Beverley; Lucas, Warren; Burgess, Jacqueline; Dada, Siphokazi; Parry, Charles D H; Harker, Nadine","year":2021,"journal":"AIDS and behavior, 25(9), 2755-2766","doi":"10.1007/s10461-021-03178-z","pmid":"33950340","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03080","title":"Childhood medical history and psychosis in adult life: Findings from the Bologna EU-GEI incidence and case-control study.","authors":"D'Andrea, Giuseppe; Suprani, Federico; Tolomelli, Elena; Gennari, Monia; Lanari, Marcello; Faldella, Giacomo; Muratori, Roberto; Berardi, Domenico; Tarricone, Ilaria","year":2021,"journal":"Early intervention in psychiatry, 15(2), 397-401","doi":"10.1111/eip.12970","pmid":"32351018","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03081","title":"Are psychotic-like experiences related to a discontinuation of cannabis consumption in young adults?","authors":"Daedelow, Laura S; Banaschewski, Tobias; Berning, Moritz; Bokde, Arun L W; Brühl, Rüdiger; Burke Quinlan, Erin; Curran, H Valerie; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Garavan, Hugh; Hardon, Anita; Kaminski, Jakob; Martinot, Jean-Luc; Paillère Martinot, Marie-Laure; Artiges, Eric; Murray, Hayley; Nees, Frauke; Oei, Nicole Y L; Papadopoulos Orfanos, Dimitri; Paus, Tomáš; Poustka, Luise; Hohmann, Sarah; Millenet, Sabina; Rosenthal, Annika; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Wiers, Reinout W; Schumann, Gunter; Heinz, Andreas","year":2021,"journal":"Schizophrenia research, 228, 271-279","doi":"10.1016/j.schres.2021.01.002","pmid":"33493775","tags":["psychosis","youth","cognition","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Mean cannabis use increased from age 19 to 22. Age of first cannabis use was positively associated with change in use between the two time points (later starters increased more). Psychotic-like experiences at either age were not significantly associated with changes in cannabis use.","whyItMatters":"If psychotic-like experiences prompted people to quit cannabis, it could act as a natural protective mechanism. This study found no such self-correcting pattern, suggesting that experiencing psychotic symptoms does not reliably lead young users to reduce their consumption.","specificNumbers":"552 ever-users analyzed; nearly all (549) reported at least one psychotic-like experience at age 19; mean cannabis use increased from age 19 to 22; perceived stress was positively associated with psychotic experiences at age 22","methodology":"Longitudinal study from the IMAGEN cohort, initially recruited at age 14 in European high schools. Among 552 ever-users of cannabis, psychotic-like experiences were measured with the Community Assessment of Psychic Experiences (CAPE) at ages 19 and 22, along with quantitative cannabis use data. Perceived stress was assessed at age 22.","limitations":"Only two time points (ages 19 and 22). Self-reported cannabis use and psychotic experiences. Nearly universal endorsement of at least one psychotic-like experience at age 19 limits variance. Perceived stress measured at only one time point."},{"rthcId":"RTHC-03082","title":"THC-induced behavioral stereotypy in zebrafish as a model of psychosis-like behavior.","authors":"Dahlén, Amelia; Zarei, Mahdi; Melgoza, Adam; Wagle, Mahendra; Guo, Su","year":2021,"journal":"Scientific reports, 11(1), 15693","doi":"10.1038/s41598-021-95016-4","pmid":"34344922","tags":["psychosis","neuroscience","dopamine","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC caused dose-dependent behavioral stereotypy (repetitive circular swimming) in adult zebrafish. This behavior was reduced by co-administration of NMDA, the antipsychotic sulpiride, and the cannabinoid receptor 2 inverse agonist AM630, but was not blocked by the cannabinoid receptor 1 inverse agonist AM251.","whyItMatters":"Understanding the biological mechanisms connecting THC to psychosis requires accessible animal models. This zebrafish model offers a rapid, cost-effective platform for testing potential interventions and dissecting the receptor pathways involved.","specificNumbers":"Concentration-dependent THC response measured via novel Repetition Index; NMDA co-administration reduced stereotypy; AM251 (CB1 inverse agonist) did not block the effect; AM630 (CB2 inverse agonist) significantly reduced it; sulpiride (antipsychotic) also reduced it","methodology":"Adult zebrafish were exposed to varying THC concentrations, and a novel Repetition Index was developed to quantify circular swimming behavior. Co-administration experiments tested the involvement of NMDA receptors, GABA receptors, cannabinoid receptors 1 and 2, and the antipsychotic sulpiride.","limitations":"Animal model with limited translational certainty to human psychosis. Zebrafish behavior is a simplified proxy for complex human psychiatric phenomena. Acute exposure only; does not model chronic use patterns."},{"rthcId":"RTHC-03083","title":"Preadmission Cannabis Use Is Positively Correlated With Inpatient Opioid Dose Exposure in Hospitalized Patients With Inflammatory Bowel Diseases.","authors":"Dalal, Rahul S; Palchaudhuri, Sonali; Snider, Christopher K; Lewis, James D; Mehta, Shivan J; Lichtenstein, Gary R","year":2021,"journal":"Inflammatory bowel diseases, 27(4), 500-506","doi":"10.1093/ibd/izaa104","pmid":"32440693","tags":["pain","medical-cannabis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Preadmission cannabis use was significantly correlated with higher inpatient opioid exposure (coefficient = 12.1 IV morphine mg equivalents/day; 95% CI: 2.6-21.5) after adjusting for IBD severity, pain scores, and preadmission opioid use.","whyItMatters":"Opioid use in IBD patients is associated with excess mortality, and inpatient opioid exposure predicts post-discharge opioid use. If cannabis-using patients receive more opioids during hospitalization, it raises questions about pain management strategies for this population.","specificNumbers":"423 IBD patients studied; cannabis use coefficient = 12.1 IV morphine mg equivalents/day (95% CI: 2.6-21.5); first pain score coefficient = 1.3 (95% CI: 0.6-2.0); preadmission opioid use coefficient = 22.3 (95% CI: 17.0-27.6)","methodology":"Retrospective cohort study of 423 adults hospitalized for IBD at a large academic health system from March 2017 to April 2018. Opioid exposure was calculated as total IV morphine milligram equivalents divided by length of stay. Multivariable linear regression adjusted for confounders including disease severity and preadmission opioid use.","limitations":"Retrospective design from a single institution. Cannabis use was self-reported and binary (yes/no) without dosage or frequency details. Cannot determine causation. Patients lacked cannabis access during hospitalization, which may have affected pain management needs."},{"rthcId":"RTHC-03084","title":"'Synthetic cannabis': A dangerous misnomer.","authors":"Darke, Shane; Banister, Samuel; Farrell, Michael; Duflou, Johan; Lappin, Julia","year":2021,"journal":"The International journal on drug policy, 98, 103396","doi":"10.1016/j.drugpo.2021.103396","pmid":"34343944","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03085","title":"\"Aberrant\" Neuronal Stimulation and \"Cannabis Psychosis\" - Hypothesis to a Biological Plausibility!","authors":"Das, Nileswar","year":2021,"journal":"Psychiatria Danubina, 33(3), 280-282","doi":"10.24869/psyd.2021.280","pmid":"34795161","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03086","title":"Typologies of illicit drug use in mid-adulthood: a quasi-longitudinal latent class analysis in a community-based sample of twins.","authors":"Dash, Genevieve F; Martin, Nicholas G; Agrawal, Arpana; Lynskey, Michael T; Slutske, Wendy S","year":2021,"journal":"Addiction (Abingdon, England), 116(5), 1101-1112","doi":"10.1111/add.15225","pmid":"33463859","tags":["addiction","genetics","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Five drug use classes emerged: no/low use (50%), desistant cannabis use (23%), desistant party drug use (18%), persistent prescription drug misuse (4%), and persistent polydrug use (5%). Persistent polydrug use was highly heritable (a2 = 0.94) and associated with conduct disorder (OR = 2.40) and antisocial personality disorder (OR = 3.27). Persistent prescription misuse was linked to depression (OR = 2.38) and lifetime suicide attempt (OR = 2.31).","whyItMatters":"Identifying distinct trajectories of drug use with different genetic contributions and psychiatric correlates could improve targeted prevention and treatment approaches rather than treating all substance use as a single phenomenon.","specificNumbers":"3,785 twins/siblings (1,365 men, 2,420 women; mean age 32); five classes: 50% no/low, 23% desistant cannabis, 18% desistant party drug, 4% persistent prescription, 5% persistent polydrug; MZ concordance k=0.30-0.35 vs DZ k=0.19-0.20; polydrug heritability a2=0.94","methodology":"Latent class analysis applied to self-reported current and past drug use data from 3,785 twins and siblings (mean age 32) in the Australian Twin Registry Cohort III. Biometric modeling compared monozygotic and dizygotic twin concordances. Logistic regression examined associations with psychiatric disorders.","limitations":"Cross-sectional with retrospective recall of past use, which approximates but does not substitute for true longitudinal data. Australian sample may not generalize globally. Self-reported substance use. Small sizes for the persistent use classes (4-5%)."},{"rthcId":"RTHC-03087","title":"Emerging potential of cannabidiol in reversing proteinopathies.","authors":"Dash, Raju; Ali, Md Chayan; Jahan, Israt; Munni, Yeasmin Akter; Mitra, Sarmistha; Hannan, Md Abdul; Timalsina, Binod; Oktaviani, Diyah Fatimah; Choi, Ho Jin; Moon, Il Soo","year":2021,"journal":"Ageing research reviews, 65, 101209","doi":"10.1016/j.arr.2020.101209","pmid":"33181336","tags":["cbd","neuroscience","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD has been shown in preclinical models to reduce oxidative stress, neuroinflammation, and protein misfolding across multiple neurodegenerative disease models. The review argues CBD may act on the proteostasis network, the cellular system responsible for maintaining proper protein folding and clearing aggregates.","whyItMatters":"Neurodegenerative diseases share a common feature: buildup of misfolded proteins. If CBD can engage the cellular machinery that clears these aggregates, it could represent a disease-modifying approach rather than just symptom management.","specificNumbers":"Reviewed evidence across five proteinopathies: Alzheimer's, Parkinson's, Huntington's, ALS, and multiple sclerosis. Covered CBD effects on oxidative stress, neuroinflammation, and protein misfolding pathways.","methodology":"Narrative review synthesizing preclinical and clinical evidence on CBD's effects on protein homeostasis pathways in neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, ALS, and multiple sclerosis.","limitations":"Mostly based on preclinical (animal and cell) models. Human clinical evidence for CBD's protein-clearing effects is limited. Narrative review without systematic methodology. The proteostasis mechanism remains largely theoretical."},{"rthcId":"RTHC-03088","title":"Price and product variation in Washington's recreational cannabis market.","authors":"Davenport, Steven","year":2021,"journal":"The International journal on drug policy, 91, 102547","doi":"10.1016/j.drugpo.2019.08.004","pmid":"31522966","tags":["legalization","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This study analyzed the largest legal cannabis dataset available at the time: over 110 million retail transactions in Washington State from July 2014 to October 2017. The headline trend was the rapid rise of extracts and concentrates, which grew from a small fraction to 28.5% of all sales.\n\nWithin the extract category, nearly half were identified as \"dabs\" — highly concentrated products typically consumed through specialized rigs. Another large segment was vape cartridges. These products delivered far more THC per dollar than herbal cannabis, and their market share was growing while herbal cannabis declined.\n\nPrices per gram of THC fell across all product categories over the study period. The combination of falling prices and rising potency meant consumers could access dramatically more THC for less money with each passing year. Edibles showed a different pattern: lower THC per unit but higher price per THC milligram, suggesting consumers paid a premium for convenience and precise dosing.","whyItMatters":"This paper documented in real transactional data what the potency studies measured in seized samples: the legal market was making THC cheaper and more concentrated. But it added the consumer choice dimension. People weren't just buying stronger weed — they were actively shifting toward extracts and concentrates, products that deliver THC at concentrations far above any flower.\n\nThe public health implications follow from basic economics: when a psychoactive substance becomes simultaneously more potent and cheaper, consumption typically increases. Washington's data showed this pattern playing out in real time in a legal, regulated market.","specificNumbers":"• 110+ million retail transactions analyzed (July 2014 – October 2017)\n• Extracts: 28.5% of sales by October 2017\n• ~50% of categorized extracts were dabs\n• Price per gram of THC: falling across all product categories\n• Herbal cannabis market share: declining as concentrates grew","methodology":"Analysis of administrative data from Washington's recreational cannabis market: 110+ million retail item-transactions from July 2014 to October 2017. Applied text-analytic methods to product names and descriptions to estimate edible potency and identify extract subtypes. Tracked trends in THC, CBD, pricing, and market share across product categories.","limitations":"Washington-specific data may not generalize to other states with different regulations. Product labeling was inconsistent, requiring text analysis that introduces classification error. Cannot track individual consumer behavior — only aggregate transactions. THC testing accuracy varied across labs during this period. No health outcome data attached to purchasing patterns."},{"rthcId":"RTHC-03089","title":"Cannabis Use, Schizotypy and Kamin Blocking Performance.","authors":"Dawes, Christopher; Bickerdike, Andrea; O'Neill, Cian; Carneiro Pereira, Sarah; Waddington, John L; Moran, Paula M; O'Tuathaigh, Colm M P","year":2021,"journal":"Frontiers in psychiatry, 12, 633476","doi":"10.3389/fpsyt.2021.633476","pmid":"34887781","tags":["psychosis","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Neither lifetime nor current cannabis use was associated with changes in Kamin blocking scores. However, current cannabis users had higher Disorganised SPQ dimension scores and higher total and sub-scale values on the Aberrant Salience Inventory. A modest positive link between Kamin blocking and disorganized schizotypy was observed.","whyItMatters":"The hypothesis that cannabis disrupts salience attribution (a proposed mechanism for psychosis) was not supported by this associative learning measure, even though cannabis users did show elevated self-reported schizotypy and aberrant salience.","specificNumbers":"307 healthy participants; no significant association between cannabis use and Kamin blocking scores; current users had higher Disorganised SPQ and Aberrant Salience Inventory scores; higher \"Senses Sharpening\" ASI sub-scale predicted decreased Kamin blocking only in non-users","methodology":"Cross-sectional online study of 307 healthy participants with no psychiatric history. Kamin blocking was measured using Oades' \"mouse in the house task.\" Schizotypy was assessed with the Schizotypal Personality Questionnaire and aberrant salience with the Aberrant Salience Inventory. Cannabis use history was collected via the modified Cannabis Experience Questionnaire.","limitations":"Cross-sectional design. Online behavioral testing platform may introduce noise. Non-clinical sample limits generalizability to those at clinical psychosis risk. Kamin blocking paradigm has shown inconsistent results across studies."},{"rthcId":"RTHC-03090","title":"The Use of Cannabis and Cannabinoid-based Products by Pregnant Women: A Patent Review.","authors":"de Albuquerque Britto, Diana Babini Lapa; das Chagas Angelo Mendes Tenorio, Fernanda; Tenorio, Bruno; Rolim, Larissa; Júnior, Valdemiro Silva","year":2021,"journal":"Recent patents on biotechnology, 15(3), 184-194","doi":"10.2174/1872208315666210719110606","pmid":"34825644","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03091","title":"l-Theanine Prevents Long-Term Affective and Cognitive Side Effects of Adolescent Δ-9-Tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry.","authors":"De Felice, Marta; Renard, Justine; Hudson, Roger; Szkudlarek, Hanna J; Pereira, Brian J; Schmid, Susanne; Rushlow, Walter J; Laviolette, Steven R","year":2021,"journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience, 41(4), 739-750","doi":"10.1523/JNEUROSCI.1050-20.2020","pmid":"33268546","tags":["youth","neuroscience","dopamine","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"L-theanine pretreatment before adolescent THC exposure prevented long-term dysregulation of dopamine activity in both the prefrontal cortex and ventral tegmental area, blocked downregulation of GSK-3 and Akt signaling (biomarkers linked to psychiatric risk), and prevented the development of affective and cognitive abnormalities in adulthood.","whyItMatters":"Adolescent cannabis use is associated with elevated psychiatric risk, and there are currently few pharmacological strategies to prevent THC-induced brain changes during development. L-theanine is widely available, well-tolerated, and found naturally in green tea.","specificNumbers":"Prevented THC-induced dysregulation in PFC and VTA dopaminergic activity states; blocked downregulation of GSK-3 and Akt signaling pathways in PFC; prevented affective and cognitive abnormalities that persisted into adulthood","methodology":"Male adolescent rats received L-theanine pretreatment before THC exposure. Long-term outcomes were assessed in adulthood through behavioral testing (affective and cognitive measures), in vivo electrophysiology of PFC and VTA dopamine neurons, and molecular analysis of GSK-3 and Akt signaling pathways in the prefrontal cortex.","limitations":"Male rats only; effects in females are unknown. L-theanine was given as pretreatment, which does not reflect how most cannabis users would encounter it. Animal behavior is a limited proxy for human psychiatric outcomes. Dosing may not translate directly to humans."},{"rthcId":"RTHC-03092","title":"Are Schizophrenic disorders with or without early cannabis use neurobiologically distinct disease entities? A meta-analysis of magnetic resonance imaging studies.","authors":"De Peri, Luca; Traber, Rafael; Bolla, Emilio; Vita, Antonio","year":2021,"journal":"Psychiatry research, 297, 113731","doi":"10.1016/j.psychres.2021.113731","pmid":"33493730","tags":["psychosis","neuroscience","cognition"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Both schizophrenia patients with cannabis use (n=227) and without (n=238) showed reduced whole brain, total grey matter, and hippocampal volumes compared to healthy controls (n=366). Direct comparison between the two patient groups showed no statistically significant differences, though grey matter deficits were more prominent in cannabis users.","whyItMatters":"Whether cannabis-associated psychosis represents a distinct brain disorder or the same disease with an additional risk factor has clinical implications for treatment and prognosis. These findings suggest substantial neurobiological overlap.","specificNumbers":"10 MRI studies; 227 schizophrenia patients with cannabis use; 238 without; 366 healthy controls; up to 5 studies available for direct comparison; both groups showed reduced whole brain, grey matter, and hippocampal volumes vs. controls","methodology":"Systematic search identified 10 MRI studies comparing brain volumes in first-episode schizophrenia patients with and without cannabis use and healthy controls. Meta-analysis pooled data from up to 5 independent studies for direct patient group comparisons.","limitations":"Small number of studies (up to 5 for direct comparisons). Cross-sectional MRI cannot determine whether brain differences preceded cannabis use. Limited to first-episode patients, so long-term trajectories are unknown. Publication bias possible."},{"rthcId":"RTHC-03093","title":"Pediatric Cannabis Single-Substance Exposures Reported to the Michigan Poison Center From 2008-2019 After Medical Marijuana Legalization.","authors":"Dean, Diana; Passalacqua, Karla D; Oh, Su Min; Aaron, Cynthia; Van Harn, Meredith G; King, Andrew","year":2021,"journal":"The Journal of emergency medicine, 60(6), 701-708","doi":"10.1016/j.jemermed.2020.12.028","pmid":"33541760","tags":["youth","legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"426 pediatric cannabis exposures were reported to the Michigan Poison Center from 2008 to 2019. Cases doubled every 2.1 years, with a notable increase after 2016. Young children (0-5) most commonly ingested cannabis products, while teenagers (13-17) most often inhaled them. Overall, 76.8% of exposures were from ingestion.","whyItMatters":"As more states legalize cannabis, understanding pediatric exposure patterns helps inform child safety regulations, product packaging requirements, and public health messaging for households with children.","specificNumbers":"426 total pediatric exposures; median age 6.0 years; 76.8% from ingestion; 18.5% from inhalation; doubling time of 2.1 years; bimodal age distribution; annual cases increased notably after 2016","methodology":"Retrospective chart review of all pediatric (<18 years) single-substance cannabis exposures reported to the Michigan Poison Center from January 2008 through December 2019. Analyzed routes of exposure, product types, and temporal trends after medical legalization (2008) and recreational legalization (2018).","limitations":"Poison center data likely underestimates true exposure rates since not all cases are reported. Single state (Michigan). Cannot determine severity outcomes for all cases. Temporal trends may reflect increased reporting awareness alongside actual increases in exposure."},{"rthcId":"RTHC-03094","title":"Neuropsychological and neurophysiological predictors and consequences of cannabis and illicit substance use during neurodevelopment: a systematic review of longitudinal studies.","authors":"Debenham, Jennifer; Birrell, Louise; Champion, Katrina; Lees, Briana; Yücel, Murat; Newton, Nicola","year":2021,"journal":"The Lancet. Child & adolescent health, 5(8), 589-604","doi":"10.1016/S2352-4642(21)00051-1","pmid":"33991473","tags":["youth","neuroscience","cognition"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"High-quality evidence showed that delayed or irregular neurodevelopment in executive functioning, particularly emotional perception, may predispose young people to higher frequency substance use. The review also found evidence of functional, structural, and cognitive deficits following substance use, with harm potentially dependent on frequency and recovery potentially dependent on duration of use.","whyItMatters":"Separating what comes before substance use (predisposing brain differences) from what comes after (use-caused damage) is essential for designing effective prevention. If certain neurodevelopmental patterns predict who will use substances, early identification and intervention become possible.","specificNumbers":"38 longitudinal studies included; 22 neuroimaging studies, 2 neurophysiological, 22 neuropsychological; age range 10-25 years; five databases searched","methodology":"Systematic review searching five databases for longitudinal studies examining neuropsychological, neuroimaging, or neurophysiological predictors and consequences of cannabis and illicit substance use in individuals aged 10-25. Yielded 38 eligible studies covering 22 neuroimaging, 2 neurophysiological, and 22 neuropsychological findings.","limitations":"Heterogeneous study designs and measures across the 38 included studies. Most studies combined cannabis with other substances, making it difficult to isolate cannabis-specific effects. Longitudinal designs varied in follow-up duration."},{"rthcId":"RTHC-03095","title":"Prevalence of Cannabinoid Use in Patients With Hip and Knee Osteoarthritis.","authors":"Deckey, David G; Lara, Nina J; Gulbrandsen, Matthew T; Hassebrock, Jeffrey D; Spangehl, Mark J; Bingham, Joshua S","year":2021,"journal":"Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews, 5(2)","doi":"10.5435/JAAOSGlobal-D-20-00172","pmid":"33986220","tags":["cbd","pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"24% of 200 patients presenting with hip or knee osteoarthritis had used CBD products. CBD users had significantly worse SANE scores (41.3 vs. 50.8, p=0.012) compared to non-users. Most learned about CBD from friends (60%) and purchased from dispensaries (67%). Oral tinctures (43%) and topicals (36%) were the most common forms.","whyItMatters":"With CBD products widely marketed for joint pain, understanding their actual prevalence and perceived effectiveness among osteoarthritis patients helps set realistic expectations and guides clinical conversations.","specificNumbers":"200 patients (80 hip OA, 108 knee OA, 12 both); 66% female; average age 67; 24% used CBD; CBD users SANE score 41.3 vs. non-users 50.8 (p=0.012); 60% learned from friends; 67% bought from dispensary; 43% used tinctures; 36% used topicals; 8% tried marijuana","methodology":"Cross-sectional survey of 200 consecutive patients presenting with painful hip or knee osteoarthritis at a large academic orthopedic center. Pain and function assessed using Single Assessment Numeric Evaluation (SANE) scores. Chart review provided demographic data.","limitations":"Cross-sectional design cannot determine whether CBD use preceded or followed worse pain. Selection bias: patients presenting for evaluation may not represent all OA patients. No information on CBD product quality, dosage, or duration of use. SANE score differences could reflect baseline severity rather than CBD effects."},{"rthcId":"RTHC-03096","title":"Targeting the endocannabinoid system in diabesity: Fact or fiction?","authors":"Deeba, Farah; Kumar, Ashish; Mukherjee, Monalisa; Sharma, Arun K; Sharma, Manju","year":2021,"journal":"Drug discovery today, 26(7), 1750-1758","doi":"10.1016/j.drudis.2021.03.022","pmid":"33781949","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03097","title":"Selection and validation of reference genes for normalization of qRT-PCR data to study the cannabinoid pathway genes in industrial hemp.","authors":"Deguchi, Michihito; Potlakayala, Shobha; Spuhler, Zachary; George, Hannah; Sheri, Vijay; Agili, Ruba; Patel, Aayushi; Rudrabhatla, Sairam","year":2021,"journal":"PloS one, 16(12), e0260660","doi":"10.1371/journal.pone.0260660","pmid":"34928958","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03098","title":"Exploring the Use of Medical Marijuana for Supportive Care of Oncology Patients.","authors":"Dell, Deena Damsky; Stein, Daniel P","year":2021,"journal":"Journal of the advanced practitioner in oncology, 12(2), 188-201","doi":"10.6004/jadpro.2021.12.2.6","pmid":"34109050","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03099","title":"Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats.","authors":"Di Bartolomeo, Martina; Stark, Tibor; Maurel, Oriana Maria; Iannotti, Fabio Arturo; Kuchar, Martin; Ruda-Kucerova, Jana; Piscitelli, Fabiana; Laudani, Samuele; Pekarik, Vladimir; Salomone, Salvatore; Arosio, Beatrice; Mechoulam, Raphael; Maccarrone, Mauro; Drago, Filippo; Wotjak, Carsten T; Di Marzo, Vincenzo; Vismara, Matteo; Dell'Osso, Bernardo; D'Addario, Claudio; Micale, Vincenzo","year":2021,"journal":"Pharmacological research, 164, 105357","doi":"10.1016/j.phrs.2020.105357","pmid":"33285233","tags":["psychosis","neuroscience","dopamine","cbd","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Perinatal THC exposure increased both Cnr1 (CB1) and Drd2 (D2 receptor) mRNA levels in the adult rat prefrontal cortex, with reduced DNA methylation at the Drd2 regulatory region. These changes were accompanied by social withdrawal and cognitive impairment. Peripubertal CBD treatment reversed the behavioral abnormalities. Similar DRD2 epigenetic alterations were found in human schizophrenia patients.","whyItMatters":"This study provides a mechanistic link between early THC exposure and schizophrenia-like changes through epigenetic modification of the dopamine system, and demonstrates that CBD may be able to reverse these alterations during a critical developmental window.","specificNumbers":"Increased Cnr1 and Drd2 mRNA in adult prefrontal cortex; reduced DNA methylation at Drd2 regulatory region; lower 2-AG brain levels persisting from neonatal age to adulthood; delayed neonatal reflexes; DRD2 methylation alterations confirmed in human schizophrenia patients","methodology":"Male rats received perinatal THC exposure and were assessed at neonatal age and adulthood for molecular (gene expression, DNA methylation via pyrosequencing, endocannabinoid levels), behavioral (social interaction, cognition), and neurological (neonatal reflexes) outcomes. Some received peripubertal CBD treatment. DRD2 methylation was also measured in a human schizophrenia cohort.","limitations":"Male rats only. Perinatal exposure model (via mother) differs from typical human adolescent use. Small human schizophrenia sample for the translational component. CBD treatment timing (peripubertal) may not reflect realistic intervention windows."},{"rthcId":"RTHC-03100","title":"Role of Caryophyllane Sesquiterpenes in the Entourage Effect of Felina 32 Hemp Inflorescence Phytocomplex in Triple Negative MDA-MB-468 Breast Cancer Cells.","authors":"Di Giacomo, Silvia; Mariano, Alessia; Gullì, Marco; Fraschetti, Caterina; Vitalone, Annabella; Filippi, Antonello; Mannina, Luisa; Scotto d'Abusco, Anna; Di Sotto, Antonella","year":2021,"journal":"Molecules (Basel, Switzerland), 26(21)","doi":"10.3390/molecules26216688","pmid":"34771097","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03101","title":"Trends and Characteristics of Manufactured Cannabis Product and Cannabis Plant Product Exposures Reported to US Poison Control Centers, 2017-2019.","authors":"Dilley, Julia A; Graves, Janessa M; Brooks-Russell, Ashley; Whitehill, Jennifer M; Liebelt, Erica L","year":2021,"journal":"JAMA network open, 4(5), e2110925","doi":"10.1001/jamanetworkopen.2021.10925","pmid":"34028553","tags":["legalization","harm-reduction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The study documented increasing cannabis exposure reports to US poison control centers from 2017 to 2019, with distinct patterns for manufactured cannabis products versus plant materials in terms of patient demographics and clinical characteristics.","whyItMatters":"As cannabis markets evolve with new product types, understanding which products generate the most poison control calls and who is affected helps target safety messaging and product regulation.","specificNumbers":"National poison control data from 2017-2019; reports stratified by manufactured products vs. plant materials","methodology":"Cross-sectional analysis of cannabis exposure reports to US poison control centers from 2017-2019, stratified by manufactured cannabis products (edibles, vape products, concentrates) and traditional plant material. Examined trends in patient demographics and product characteristics.","limitations":"Poison control data underestimates true exposure rates. Cross-sectional design. Brief report format limits detail on clinical outcomes."},{"rthcId":"RTHC-03102","title":"The use of medical cannabis in pediatric palliative care: a case series.","authors":"Divisic, Antuan; Avagnina, Irene; De Tommasi, Valentina; Santini, Anna; Brogelli, Laura; Giacomelli, Luca; Benini, Franca","year":2021,"journal":"Italian journal of pediatrics, 47(1), 229","doi":"10.1186/s13052-021-01179-1","pmid":"34802466","tags":["medical-cannabis","epilepsy","pain","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All six patients experienced a reduction in seizure frequency (with variable extent) after starting medical cannabis. Pain also improved based on caregiver evaluation, and analgesic medication use decreased. Side effects were mild and transient: drowsiness, euphoria, restlessness, and tachycardia. No treatment was discontinued and no overdoses occurred.","whyItMatters":"Children in palliative care often have treatment-resistant epilepsy and chronic pain with limited therapeutic options. This case series provides initial evidence that medical cannabis may be a tolerable and beneficial addition to their care.","specificNumbers":"6 patients treated for 1 year; all had seizures during pre-treatment observation; all showed seizure frequency reduction; mild adverse events: drowsiness, euphoria, restlessness, tachycardia; 0 treatment discontinuations; 0 overdoses","methodology":"Case series of six pediatric palliative care patients at an Italian center who received titrated plant extract of cannabis sativa for one year. Caregivers reported changes in seizure frequency, seizure intensity, and pain. Adverse events were monitored throughout.","limitations":"Case series with only 6 patients and no control group. Outcomes were caregiver-reported without blinding. Variable extent of seizure reduction makes it hard to quantify the benefit precisely. No standardized pain assessment tools described."},{"rthcId":"RTHC-03103","title":"A Rebuttal-Based Social Norms-Tailored Cannabis Intervention for At-Risk Adolescents.","authors":"Donaldson, Candice D; Alvaro, Eusebio M; Ruybal, Andrea L; Coleman, Michael; Siegel, Jason T; Crano, William D","year":2021,"journal":"Prevention science : the official journal of the Society for Prevention Research, 22(5), 609-620","doi":"10.1007/s11121-021-01224-9","pmid":"33791930","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In Study 1 (N=808), at-risk adolescents who perceived cannabis use as normative showed lowest usage intentions after receiving a tailored gain-framed message. In Study 2 (N=391), at-risk teens with normative beliefs and pro-cannabis attitudes who received the tailored gain-framed communication showed decreased cannabis attitude certainty and lower usage intentions 2 months later.","whyItMatters":"Most cannabis prevention campaigns fail because they use one-size-fits-all messaging. This study demonstrates that tailoring messages to individual beliefs about peer norms and using sequential persuasion strategies can improve effectiveness for the hardest-to-reach youth.","specificNumbers":"Study 1: N=808, ages 11-16; Study 2: N=391; gain-framed tailored message produced lowest usage intentions (p<0.05); effects sustained at 2-month follow-up (p<0.05)","methodology":"Two studies with cannabis-abstinent middle and high school students ages 11-16. Study 1 compared gain- and loss-framed messages tailored to normative perceptions. Study 2 used a sequential approach: first destabilizing anti-message attitudes through rebuttal feedback, then delivering tailored vs. non-tailored messages. Follow-up at 2 months.","limitations":"Only cannabis-abstinent students were included, so effects on actual users are unknown. Florida-based samples may not generalize nationally. Self-reported intentions may not translate to behavior. 2-month follow-up is relatively short."},{"rthcId":"RTHC-03104","title":"Cannabinoid Interactions with Cytochrome P450 Drug Metabolism: a Full-Spectrum Characterization.","authors":"Doohan, Peter T; Oldfield, Lachlan D; Arnold, Jonathon C; Anderson, Lyndsey L","year":2021,"journal":"The AAPS journal, 23(4), 91","doi":"10.1208/s12248-021-00616-7","pmid":"34181150","tags":["drug-interactions","cbd","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This was the most comprehensive cannabinoid-enzyme interaction study published to date. Researchers tested 12 different cannabinoids — including THC, CBD, CBN, CBG, CBC, THCV, and others — against 6 major drug-metabolizing CYP enzymes (CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2B6, CYP2C19).\n\nCBD emerged as the most potent inhibitor across multiple enzymes, consistent with previous reports. THC was also a significant inhibitor, particularly of CYP1A2 and CYP2C9. But the study's novel contribution was showing that so-called \"minor\" cannabinoids — CBN, CBG, and others present in full-spectrum cannabis products — also inhibited these enzymes at relevant concentrations.\n\nThis matters because full-spectrum cannabis products contain multiple cannabinoids simultaneously. The combined inhibitory load of several cannabinoids acting on the same enzymes could be greater than any single cannabinoid alone, creating unpredictable drug interactions.","whyItMatters":"Cannabis products are sold as isolates (pure CBD or THC) and as full-spectrum (containing multiple cannabinoids). This study showed that the full-spectrum products may carry additional drug interaction risk because minor cannabinoids also inhibit the same liver enzymes. Someone taking a full-spectrum CBD oil is exposed to a cocktail of enzyme inhibitors, not just one.\n\nFor the growing population of medical cannabis patients who are also on prescription medications — often multiple — this is clinically significant information that rarely appears on product labels.","specificNumbers":"• 12 cannabinoids tested against 6 CYP enzymes (72 interaction pairs)\n• CBD: most potent inhibitor across multiple enzymes\n• THC: significant inhibitor of CYP1A2 and CYP2C9\n• Minor cannabinoids (CBN, CBG, others) also showed inhibitory activity\n• CYP3A4, CYP2D6, CYP2C9 — process the majority of prescription drugs","methodology":"In vitro study using Supersomes (human CYP enzyme preparations) to screen 12 cannabinoids for inhibitory potential against CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2B6, and CYP2C19. Used fluorometric probe substrates and IC50 determination. Published in The AAPS Journal.","limitations":"In vitro study — enzyme inhibition in a test tube may not translate directly to clinical interactions in the body. Concentrations tested may not match what reaches the liver after typical cannabis use. Does not account for individual variation in enzyme expression or genetics. Cannot predict the combined effect of multiple cannabinoids acting simultaneously. No clinical validation included."},{"rthcId":"RTHC-03105","title":"Neuropharmacological Effects of the Main Phytocannabinoids: A Narrative Review.","authors":"Dos Santos, Rafael G; Hallak, Jaime E C; Crippa, José Alexandre S","year":2021,"journal":"Advances in experimental medicine and biology, 1264, 29-45","doi":"10.1007/978-3-030-57369-0_3","pmid":"33332002","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03106","title":"Cannabinoid Hyperemesis Syndrome in Pediatrics: An Emerging Problem.","authors":"Dosani, Kaushal; Koletic, Carolina; Alhosh, Rabea","year":2021,"journal":"Pediatrics in review, 42(9), 500-506","doi":"10.1542/pir.2019-0097","pmid":"34470869","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03107","title":"Recreational cannabis laws and opioid-related emergency department visit rates.","authors":"Drake, Coleman; Wen, Jiebing; Hinde, Jesse; Wen, Hefei","year":2021,"journal":"Health economics, 30(10), 2595-2605","doi":"10.1002/hec.4377","pmid":"34252228","tags":["legalization","harm-reduction","pain","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Event study models using ED data from 29 states (2011-2017) found recreational cannabis laws reduced opioid-related ED visit rates by approximately 7.6% for two quarters after implementation. Effects were concentrated among men and adults aged 25-44. The reduction dissipated after 6 months. Crucially, recreational cannabis laws did not increase opioid-related ED visits.","whyItMatters":"The opioid epidemic continues to worsen, and identifying policy tools that reduce opioid-related harms is urgent. While the effect was temporary, the finding that cannabis legalization did not increase opioid emergencies counters concerns about a gateway effect at the population level.","specificNumbers":"29 states; 2011-2017 ED data; 7.6% reduction in opioid-related ED visits for 2 quarters post-implementation; effects driven by men and adults 25-44; effects dissipated after 6 months","methodology":"Event study models using nearly comprehensive emergency department data from 29 US states from 2011 to 2017. Compared opioid-related ED visit rates before and after recreational cannabis law implementation, with pre-trend analysis to verify parallel trends.","limitations":"Observational policy analysis cannot prove causation. Only 29 states with available ED data. Six-month dissipation of effects limits the practical significance. Cannot identify individual-level substitution behavior from population data."},{"rthcId":"RTHC-03108","title":"Medical Cannabis for Headache Pain: a Primer for Clinicians.","authors":"Duarte, Robert A; Dahmer, Stephen; Sanguinetti, Shayna Y; Forde, Grace; Duarte, Diana P; Kobak, Lawrence F","year":2021,"journal":"Current pain and headache reports, 25(10), 64","doi":"10.1007/s11916-021-00974-z","pmid":"34628531","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03109","title":"The cannabinoid system and microglia in health and disease.","authors":"Duffy, Samuel S; Hayes, Jessica P; Fiore, Nathan T; Moalem-Taylor, Gila","year":2021,"journal":"Neuropharmacology, 190, 108555","doi":"10.1016/j.neuropharm.2021.108555","pmid":"33845074","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03110","title":"Duration of Neurocognitive Impairment With Medical Cannabis Use: A Scoping Review.","authors":"Eadie, Lauren; Lo, Lindsay A; Christiansen, April; Brubacher, Jeffrey R; Barr, Alasdair M; Panenka, William J; MacCallum, Caroline A","year":2021,"journal":"Frontiers in psychiatry, 12, 638962","doi":"10.3389/fpsyt.2021.638962","pmid":"33790818","tags":["cognition","medical-cannabis","driving"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Across all seven included studies, cognitive performance declined mostly in a THC dose-dependent manner with steady resolution in the hours following administration. In every study, there was no difference between any THC group and placebo on any neurocognitive measure after 4 hours of recovery. THC doses were lower than those typically used in recreational studies.","whyItMatters":"Medical cannabis patients need practical guidance on when it is safe to drive or perform safety-sensitive tasks. This review provides the first focused evidence that 4 hours may be a reasonable minimum recovery window after medical-dose THC.","specificNumbers":"37 articles screened; 7 controlled trials included (6 RCTs, 1 observational); all showed no cognitive impairment vs. placebo after 4 hours; THC doses lower than recreational studies","methodology":"Systematic search of MEDLINE and EMBASE (2000-2019) for controlled trials of medical cannabis patients with chronic non-cancer pain or spasticity. After screening 37 full-text articles, seven met inclusion criteria: six RCTs and one observational clinical trial. Qualitative synthesis of neurocognitive testing results.","limitations":"Only seven studies met criteria, limiting generalizability. Studies used variable neurocognitive tests and assessment timing. Medical cannabis patients may develop tolerance that shortens impairment duration. Does not address chronic cognitive effects of ongoing use."},{"rthcId":"RTHC-03111","title":"Trends and Factors Related to Blunt Use in Middle and High School Students, 2010-2020.","authors":"Ebrahimi Kalan, Mohammad; Jebai, Rime; Bursac, Zoran; Popova, Lucy; Gautam, Prem; Li, Wei; Alqahtani, Mohammed M; Taskin, Tanjila; Atwell, Leah L; Richards, Jennifer; Ward, Kenneth D; Behaleh, Raed; Ben Taleb, Ziyad","year":2021,"journal":"Pediatrics, 148(1)","doi":"10.1542/peds.2020-028159","pmid":"34127552","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Past and current blunt use declined from 2010 to 2015 (APC = -5.32% and -5.28%), but current use increased from 2015 to 2018 (APC = 14.91%) before leveling off. Rising trends were especially pronounced among female students (APC = 14.92%), middle schoolers (APC = 19.57%), and non-Hispanic white students (APC = 11.12%) from 2016 to 2020. Use of cigarettes, e-cigarettes, hookah, cigars, and vaping marijuana were all associated with blunt use.","whyItMatters":"Blunts combine tobacco (from the cigar wrapper) with marijuana, exposing users to both substances. The reversal in declining trends and spread to new demographic groups suggests that existing tobacco prevention programs have not adequately addressed blunt use.","specificNumbers":"461,706 students; past use APC -5.32% (2010-2015); current use APC -5.28% (2010-2015) then +14.91% (2015-2018); female APC +14.92% (2016-2020); middle school APC +19.57% (2016-2020); NH white APC +11.12% (2016-2020)","methodology":"Analysis of 2010-2020 cross-sectional, statewide representative Florida Youth Tobacco Surveys comprising 461,706 middle and high school students. Joinpoint regression calculated annual percentage change in blunt use prevalence. Multivariable regression using 2019-2020 data examined associated factors.","limitations":"Florida data may not generalize to other states. Self-reported data in school settings may underestimate use. Cross-sectional surveys cannot track individual trajectories. Blunt definition may vary among respondents."},{"rthcId":"RTHC-03112","title":"URB597 abrogates anxiogenic and depressive behaviors in the methamphetamine-withdrawal mice: Role of the cannabinoid receptor type 1, cannabinoid receptor type 2, and transient receptor potential vanilloid 1 channels.","authors":"Ebrahimi-Ghiri, Mohaddeseh; Khakpai, Fatemeh; Zarrindast, Mohammad-Reza","year":2021,"journal":"Journal of psychopharmacology (Oxford, England), 35(7), 875-884","doi":"10.1177/0269881120965934","pmid":"33155516","tags":["anxiety","depression","neuroscience","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Methamphetamine (30 mg/kg) caused anxiety and depression behaviors 3 days after withdrawal. URB597 (an endocannabinoid-enhancing compound) at 5-10 ng prevented these emotional deficits. The effect was blocked by CB1 antagonist AM251 and CB2 antagonist AM630, confirming involvement of both cannabinoid receptors. TRPV1 antagonist capsazepine showed dose-dependent effects: low doses blocked and high doses potentiated URB597's antidepressant action.","whyItMatters":"Methamphetamine withdrawal causes severe anxiety and depression that drive relapse. Identifying the endocannabinoid system as a treatment target could provide new pharmacological approaches for managing stimulant withdrawal symptoms.","specificNumbers":"Methamphetamine 30 mg/kg induced symptoms at 3 days; URB597 effective at 5-10 ng/mouse; CB1 antagonist AM251 (1 ug) blocked antidepressant effect; CB2 antagonist AM630 (5-10 ug) suppressed antidepressant activity; capsazepine showed dose-dependent bidirectional effects","methodology":"Male NMRI mice received methamphetamine (30 mg/kg) and were tested 3 days later in elevated plus maze (anxiety) and forced swim test (depression). URB597 was administered intracerebroventricularly 10 minutes before testing. Receptor involvement was probed using specific antagonists for CB1, CB2, and TRPV1.","limitations":"Male mice only. Intracerebroventricular administration is not a clinically practical delivery route. Forced swim and elevated plus maze are simplified models of human depression and anxiety. Three-day withdrawal window may not capture the full timeline of human methamphetamine withdrawal."},{"rthcId":"RTHC-03113","title":"Gabapentin attenuates somatic signs of precipitated THC withdrawal in mice.","authors":"Eckard, M L; Kinsey, S G","year":2021,"journal":"Neuropharmacology, 190, 108554","doi":"10.1016/j.neuropharm.2021.108554","pmid":"33845073","tags":["withdrawal","tolerance","harm-reduction","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Gabapentin (10+ mg/kg) reduced paw tremors and head twitches during rimonabant-precipitated THC withdrawal. At 50 mg/kg, it restored withdrawal-suppressed progressive ratio responding (a measure of motivation). However, gabapentin did not affect locomotor activity, marble burying, tail suspension struggling, or plasma corticosterone levels during withdrawal.","whyItMatters":"There are currently no FDA-approved medications for cannabis withdrawal. Gabapentin is already widely prescribed for other conditions and showed promise in a prior clinical trial for cannabis withdrawal, making this preclinical validation of its mechanism particularly relevant.","specificNumbers":"THC 10 mg/kg for 5.5 days; rimonabant 2-3 mg/kg precipitated withdrawal; gabapentin 10+ mg/kg reduced paw tremors and head twitches; 50 mg/kg restored progressive ratio responding; no effect on corticosterone, marble burying, or tail suspension","methodology":"Separate cohorts of male and female mice received THC (10 mg/kg) or vehicle for 5.5 days. On day 6, withdrawal was precipitated with the CB1 antagonist rimonabant (2-3 mg/kg). Gabapentin was tested across multiple behavioral measures including somatic signs, locomotor activity, conditioned place preference, progressive ratio responding, marble burying, tail suspension, and plasma corticosterone.","limitations":"Precipitated withdrawal (using a CB1 antagonist) differs from natural withdrawal and may produce more intense acute symptoms. Some behavioral tests showed no gabapentin effect, limiting its utility as a standalone treatment. Sex differences were not the primary focus."},{"rthcId":"RTHC-03114","title":"A pilot randomised placebo-controlled trial of cannabidiol to reduce severe behavioural problems in children and adolescents with intellectual disability.","authors":"Efron, Daryl; Freeman, Jeremy L; Cranswick, Noel; Payne, Jonathan M; Mulraney, Melissa; Prakash, Chidambaram; Lee, Katherine J; Taylor, Kaitlyn; Williams, Katrina","year":2021,"journal":"British journal of clinical pharmacology, 87(2), 436-446","doi":"10.1111/bcp.14399","pmid":"32478863","tags":["cbd","youth","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"All eight randomized children completed the full 8-week protocol. Protocol adherence was excellent: 100% for visits and medication, 92% for blood tests, 88% for questionnaires. No serious adverse events or dropouts occurred. All parents said they would recommend the study to other families. There was an efficacy signal favoring CBD over placebo.","whyItMatters":"Children with intellectual disability and severe behavioral problems have few effective treatment options, and existing medications carry significant side effect risks. This pilot demonstrates that a full-scale CBD trial is feasible in this population.","specificNumbers":"8 children randomized; 100% visit completion; 100% medication adherence; 92% blood test completion; 88% questionnaire completion; 0 serious adverse events; 0 dropouts; CBD dose up to 20 mg/kg/day (max 500 mg twice daily)","methodology":"Double-blind, placebo-controlled, parallel-design pilot RCT of 98% CBD oil (Tilray) in children aged 8-16 with intellectual disability and severe behavioral problems. CBD was titrated over 9 days to 20 mg/kg/day (max 500 mg twice daily) for 8 weeks. Feasibility, acceptability, safety, and preliminary efficacy were assessed.","limitations":"Very small sample (8 children) designed as feasibility pilot, not powered for efficacy. Short duration (8 weeks). Single-center study. The efficacy signal needs confirmation in a larger trial."},{"rthcId":"RTHC-03115","title":"Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts.","authors":"Elkrief, Laurent; Spinney, Sean; Vosberg, Daniel E; Banaschewski, Tobias; Bokde, Arun L W; Quinlan, Erin Burke; Desrivières, Sylvane; Flor, Herta; Garavan, Hugh; Gowland, Penny; Heinz, Andreas; Brühl, Rüdiger; Martinot, Jean-Luc; Paillère Martinot, Marie-Laure; Nees, Frauke; Papadopoulos Orfanos, Dimitri; Poustka, Luise; Hohmann, Sarah; Millenet, Sabina; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Pausova, Zdenka; Paus, Tomáš; Huguet, Guillaume; Conrod, Patricia","year":2021,"journal":"Frontiers in psychiatry, 12, 645746","doi":"10.3389/fpsyt.2021.645746","pmid":"33959052","tags":["genetics","addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Two SNPs were significantly associated with positive AUDIT screens after correction: rs9353525 in CNR1 (OR=0.73) and rs507961 in MGLL (OR=0.78). A three-SNP interaction model involving MGLL, DAGLA, and CNR1 predicted case-control status after correcting for covariables. This interaction showed a trend toward replication in the Canadian SYS cohort (BETA=0.501, p=0.06).","whyItMatters":"The endocannabinoid system is primarily associated with cannabis effects, but these findings suggest it also plays a role in alcohol use disorder risk, potentially through shared reward pathway modulation. This has implications for understanding cross-substance vulnerability.","specificNumbers":"IMAGEN: n=2,051 European adolescents; SYS: n=772 Canadian adolescents; rs9353525 (CNR1) OR=0.73, p=0.042; rs507961 (MGLL) OR=0.78, p=0.043; 3-SNP interaction model p=0.006; replication trend BETA=0.501, p=0.06","methodology":"Set-based gene testing and SNP-level analysis in 2,051 European adolescents (14-18) from the IMAGEN study, with replication attempted in 772 Canadian adolescents from the Saguenay Youth Study. AUDIT score >7 defined case status. Generalized multifactor dimensionality reduction analyzed gene-gene interactions.","limitations":"Preliminary findings with modest effect sizes. Replication in the Canadian cohort only reached trend-level significance (p=0.06). AUDIT screening is not equivalent to clinical diagnosis. European-ancestry cohorts limit generalizability."},{"rthcId":"RTHC-03116","title":"Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in TP53 or PTEN Tumor Suppressors.","authors":"Ellert-Miklaszewska, Aleksandra; Ciechomska, Iwona Anna; Kaminska, Bozena","year":2021,"journal":"Cancers, 13(3)","doi":"10.3390/cancers13030419","pmid":"33499365","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03117","title":"Cannabis and Inflammation in HIV: A Review of Human and Animal Studies.","authors":"Ellis, Ronald J; Wilson, Natalie; Peterson, Scott","year":2021,"journal":"Viruses, 13(8)","doi":"10.3390/v13081521","pmid":"34452386","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03118","title":"Discordant Effects of Cannabinoid 2 Receptor Antagonism/Inverse Agonism During Adolescence on Pavlovian and Instrumental Reward Learning in Adult Male Rats.","authors":"Ellner, Danna; Hallam, Bryana; Frie, Jude A; Thorpe, Hayley H A; Shoaib, Muhammad; Kayir, Hakan; Jenkins, Bryan W; Khokhar, Jibran Y","year":2021,"journal":"Frontiers in synaptic neuroscience, 13, 732402","doi":"10.3389/fnsyn.2021.732402","pmid":"34526887","tags":["neuroscience","youth","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats treated with the CB2 receptor antagonist/inverse agonist SR144528 during adolescence (postnatal days 28-41) showed significantly slower acquisition of the Pavlovian autoshaping task in adulthood (F(2,19)=5.964, p=0.010). However, there was no effect on instrumental conditioning, indicating a dissociation between CB2 receptor involvement in different types of reward learning.","whyItMatters":"Most cannabis research focuses on CB1 receptors, but this study shows CB2 receptors also influence brain development during adolescence. The selective impact on Pavlovian but not instrumental learning suggests CB2 receptors shape specific aspects of how the reward system matures.","specificNumbers":"Adolescent exposure postnatal days 28-41; significantly slower Pavlovian autoshaping acquisition F(2,19)=5.964, p=0.010; no effect on instrumental conditioning","methodology":"Male adolescent rats received low or high doses of the CB2 receptor antagonist SR144528 during postnatal days 28-41. In adulthood, Pavlovian autoshaping (lever pressing in response to reward-associated cues) and instrumental conditioning (lever pressing for direct reward) were assessed.","limitations":"Male rats only. Pharmacological antagonism of CB2 differs from what happens during actual cannabis use (which primarily engages CB1). Small sample size. Limited to two behavioral tasks."},{"rthcId":"RTHC-03119","title":"A Comprehensive Review of Cannabis Potency in the United States in the Last Decade.","authors":"ElSohly, Mahmoud A; Chandra, Suman; Radwan, Mohammed; Majumdar, Chandrani Gon; Church, James C","year":2021,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 6(6), 603-606","doi":"10.1016/j.bpsc.2020.12.016","pmid":"33508497","tags":["potency","legalization","cbd"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This third installment from the University of Mississippi's Potency Monitoring Program extended the dataset through 2019, adding 14,234 samples to the two previous reports (RTHC-00039 covering 1995-2014 and RTHC-00049 covering 2008-2017).\n\nTHC continued its upward trajectory, reaching 14.88% in 2018 before a slight dip to 13.88% in 2019. The seven major cannabinoids were tracked, providing the most complete chemical profile of illicit cannabis available. But the most notable finding was a reversal in the THC:CBD ratio.\n\nAfter climbing from 24.81 in 2009 to 103.48 in 2017, the ratio dropped to 54.39 in 2018 and 24.58 in 2019 — returning to 2009 levels. This signaled that CBD-containing products were entering the seized sample pool, likely reflecting the hemp-derived CBD boom following the 2018 Farm Bill. For the first time in two decades, the trend of vanishing CBD reversed.","whyItMatters":"The potency trend that dominated two decades of data finally showed a wrinkle. CBD's return to the seized-sample profile suggested the market was diversifying beyond pure THC maximization. The 2018 Farm Bill legalized hemp (cannabis with less than 0.3% THC), and the resulting CBD product explosion appeared to be showing up even in DEA seizure data.\n\nThis is potentially good news from a public health perspective. If the market shifts toward products with meaningful CBD content alongside THC, the extreme THC:CBD ratios that some researchers link to higher psychosis risk could moderate. But it's too early to know whether this represents a lasting market shift or a temporary blip.","specificNumbers":"• THC: 9.75% (2009) → 14.88% (2018) → 13.88% (2019)\n• THC:CBD ratio: 24.81 (2009) → 103.48 (2017) → 24.58 (2019)\n• 14,234 herbal cannabis samples analyzed\n• Seven major cannabinoids tracked\n• Fewer samples in recent years due to state legalization reducing DEA seizures","methodology":"Analysis of 14,234 herbal cannabis samples seized by the DEA and analyzed at the University of Mississippi using validated GC/FID methods. Measured seven major cannabinoids including THC, CBD, CBN, CBG, CBC, THCV, and THCA. Covers January 2009 through December 2019.","limitations":"DEA seizure data increasingly underrepresents the overall cannabis market as states legalize. Fewer samples in recent years reduce statistical power. Cannot determine whether the CBD increase reflects actual user preferences or just the presence of hemp products in seizures. Does not capture legal market products, concentrates, or edibles."},{"rthcId":"RTHC-03120","title":"Cost-Effectiveness of Medicinal Cannabis for Management of Refractory Symptoms Associated With Chronic Conditions: A Systematic Review of Economic Evaluations.","authors":"Erku, Daniel; Shrestha, Shakti; Scuffham, Paul","year":2021,"journal":"Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research, 24(10), 1520-1530","doi":"10.1016/j.jval.2021.04.1276","pmid":"34593176","tags":["medical-cannabis","pain","epilepsy"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Twelve cost-utility analyses were identified across MS (n=8), pediatric epilepsies (n=2), and chronic pain (n=2). Incremental cost-effectiveness ratios ranged from cost-saving to over $451,800 per quality-adjusted life-year. Nabiximols was consistently cost-effective for MS spasticity in European settings. CBD was cost-effective for Dravet syndrome in Canada but not for Lennox-Gastaut syndrome in the US.","whyItMatters":"As medicinal cannabis is often expensive compared to illicit supply, understanding its cost-effectiveness is essential for healthcare systems making coverage and formulary decisions.","specificNumbers":"12 cost-utility analyses; 8 for MS, 2 for epilepsy, 2 for chronic pain; cost-effectiveness ratios ranged from cost-saving to >$451,800/QALY; median CHEERS quality 83% (range 70-100%)","methodology":"Systematic search of seven databases for economic evaluations of medicinal cannabis published through September 2020. Quality assessed using the CHEERS checklist. Data grouped by medical condition and reported narratively.","limitations":"Only 12 studies identified, reflecting the nascent state of cannabis health economics. Most studies focused on MS. Limited geographic diversity. Economic models depend on clinical trial data that may not reflect real-world effectiveness."},{"rthcId":"RTHC-03121","title":"An initial analysis of the UK Medical Cannabis Registry: Outcomes analysis of first 129 patients.","authors":"Erridge, Simon; Salazar, Oliver; Kawka, Michal; Holvey, Carl; Coomber, Ross; Usmani, Azfer; Sajad, Mohammed; Beri, Sushil; Hoare, Jonathan; Khan, Shaheen; Weatherall, Mark W; Platt, Michael; Rucker, James J; Sodergren, Mikael H","year":2021,"journal":"Neuropsychopharmacology reports, 41(3), 362-370","doi":"10.1002/npr2.12183","pmid":"33988306","tags":["medical-cannabis","pain","anxiety","sleep"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Among 129 patients (most common indication: chronic pain, 37.2%), statistically significant improvements were seen at 1 and 3 months in GAD-7 (anxiety), sleep quality, EQ-5D-5L pain and discomfort, anxiety and depression subscales, and overall quality of life indices. Median daily doses were 20 mg CBD and 3.9 mg THC. 24% of patients reported adverse events.","whyItMatters":"The UK legalized cannabis-based medicinal products in 2018 but uptake has been slow due to limited evidence. This registry provides the first UK-specific real-world outcomes data to inform prescribing and policy decisions.","specificNumbers":"129 patients; mean age 46.2 years; 37.2% chronic pain indication; median CBD dose 20 mg/day (range 0-768); median THC dose 3.9 mg/day (range 0-660); 24% adverse event rate; significant improvements in GAD-7, SQS, EQ-5D-5L at 1 and 3 months","methodology":"Prospective case series from the UK Medical Cannabis Registry. Primary outcomes were patient-reported measures (EQ-5D-5L, GAD-7, Sleep Quality Scale) at baseline, 1 month, and 3 months. Secondary outcome was adverse event incidence.","limitations":"No placebo or active comparator. Self-reported outcomes subject to expectation bias. Small initial cohort (129 patients). Short follow-up (3 months). Heterogeneous indications and treatment regimens."},{"rthcId":"RTHC-03122","title":"Case of e-cigarette or vaping product use-associated lung injury (EVALI) in London, UK.","authors":"Evans, Ruth Elizabeth; Herbert, Sophie; Owen, William; Rao, Deepak","year":2021,"journal":"BMJ case reports, 14(4)","doi":"10.1136/bcr-2020-240700","pmid":"33837028","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03123","title":"Endocannabinoid modulation of dopamine release during reward seeking, interval timing, and avoidance.","authors":"Everett, Thomas J; Gomez, Devan M; Hamilton, Lindsey R; Oleson, Erik B","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 104, 110031","doi":"10.1016/j.pnpbp.2020.110031","pmid":"32663486","tags":["neuroscience","dopamine","addiction"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review detailed how the endocannabinoid 2-AG acts as a gatekeeper for dopamine signaling across three distinct behaviors. During reward seeking, 2-AG was necessary for the dopamine bursts triggered by reward-predicting cues — the signals that encode how valuable an expected reward is. Block 2-AG, and those cue-evoked dopamine spikes disappear along with the motivated behavior.\n\nThe timing dimension was less intuitive. Under conditions of periodic reinforcement (rewards delivered on a schedule), 2-AG modulated unique dopamine patterns and associated behaviors like adjunctive responding — the repetitive, seemingly purposeless actions animals perform while waiting for rewards. Disrupting endocannabinoid signaling altered both the dopamine pattern and the timing behavior.\n\nFor avoidance, the story paralleled reward: dopamine signals evoked by warning cues represented the value of successfully avoiding harm, and 2-AG was required for these signals too. The common thread was that endocannabinoids don't just modulate pleasure — they shape the dopamine code for value across both appetitive and defensive contexts.","whyItMatters":"Cannabis affects motivation. Everyone who uses it knows this, whether it shows up as enhanced enjoyment of food and music or as the stereotypical lack of drive. This review explains the mechanism: THC from cannabis hijacks a system (2-AG signaling) that normally fine-tunes dopamine to encode value across multiple behavioral domains. Disrupting that system doesn't just affect pleasure — it affects how the brain assigns importance to cues, tracks time, and motivates protective action.\n\nThis helps explain why chronic cannabis use can produce a broad motivational blunting rather than just affecting one behavior.","specificNumbers":"• 2-AG: required for cue-evoked dopamine release during reward seeking\n• Blocking 2-AG eliminated both dopamine value signals and motivated behavior\n• Same 2-AG mechanism shaped dopamine during avoidance of threats\n• Endocannabinoid disruption altered timing behavior under periodic reinforcement","methodology":"Narrative review of the authors' own research program using fast-scan cyclic voltammetry to measure real-time dopamine release in behaving rats across reward-seeking, interval timing, and active avoidance paradigms. Published in Progress in Neuro-Psychopharmacology & Biological Psychiatry.","limitations":"Research conducted in rats, which may not fully translate to human motivational states. The review primarily draws from the authors' own research program, limiting independence. Real-time dopamine measurement techniques capture subsecond dynamics that may not reflect tonic signaling changes. Does not directly address chronic cannabis use effects."},{"rthcId":"RTHC-03124","title":"Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13.","authors":"Falvella, Ana Caroline Brambilla; Smith, Bradley Joseph; Silva-Costa, Licia C; Valença, Aline G F; Crunfli, Fernanda; Zuardi, Antonio W; Hallak, Jaime E; Crippa, José A; de Almeida, Valéria; Martins-de-Souza, Daniel","year":2021,"journal":"Frontiers in molecular neuroscience, 14, 673144","doi":"10.3389/fnmol.2021.673144","pmid":"34122009","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03125","title":"Development and validation of a mouse model of contemporary cannabis smoke exposure.","authors":"Fantauzzi, Matthew F; Cass, Steven P; McGrath, Joshua J C; Thayaparan, Danya; Wang, Peiyao; Stampfli, Martin R; Hirota, Jeremy A","year":2021,"journal":"ERJ open research, 7(3)","doi":"10.1183/23120541.00107-2021","pmid":"34291110","tags":["respiratory","inflammation","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis smoke exposure increased airway and lung tissue macrophage populations (tissue-resident alveolar, monocyte-derived alveolar, and interstitial subtypes) in both sexes. No neutrophil infiltration was observed. Immune mediator analysis showed upregulation of macrophage-derived chemokine, thymus and activation-regulated chemokine, and vascular endothelial growth factor.","whyItMatters":"The relationship between cannabis smoke and respiratory health remains poorly defined, partly due to lack of validated preclinical models. This accessible model enables systematic investigation of chronic cannabis smoke effects and interactions with respiratory pathogens.","specificNumbers":"Mean total particulate matter 698.89 +/- 66.09 ug/L; increased serum cannabinoids and carboxyhaemoglobin confirmed; macrophage populations increased in airways and lung tissue; no neutrophil infiltration; upregulation of MDC, TARC, and VEGF","methodology":"Male and female BALB/c mice were exposed to cannabis smoke using a commercial exposure system with documented THC/CBD composition. Validated through total particulate matter (mean 698.89 ug/L), serum cannabinoid levels, and carboxyhaemoglobin. Lung cellular responses and immune mediators were characterized by flow cytometry and multiplex analysis.","limitations":"Acute exposure model; chronic effects unknown. Mouse respiratory physiology differs from human. Specific cannabis strain and composition may not represent all consumer products. Functional immune outcomes (infection resistance) not tested."},{"rthcId":"RTHC-03126","title":"Lethal coagulopathy resulting from the consumption of contaminated synthetic cannabinoids: the story of a public health crisis.","authors":"Fasih, Anum","year":2021,"journal":"Journal of public health (Oxford, England), 43(1), e1-e6","doi":"10.1093/pubmed/fdz067","pmid":"31242305","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The outbreak affected 174 reported patients and caused 5 deaths. The coagulopathy was caused not by synthetic cannabinoids themselves but by contamination with brodifacoum, bromadiol, and difenacoum, potent vitamin K antagonists used as rodenticides. This was the first reported instance of long-acting anticoagulant rodenticide poisoning on this widespread scale.","whyItMatters":"This outbreak demonstrated that the unregulated synthetic cannabinoid supply chain can introduce lethal contaminants, creating public health emergencies that overwhelm normal clinical and surveillance systems.","specificNumbers":"174 reported patients; 5 deaths; contaminants identified: brodifacoum, bromadiol, difenacoum (all vitamin K antagonist rodenticides); first widespread LAAR poisoning event","methodology":"Public health crisis report documenting the 2018 Illinois outbreak of coagulopathy linked to contaminated synthetic cannabinoids. Chronicles the public health response, clinical management challenges, and lessons learned.","limitations":"Public health surveillance likely underestimated the true number of affected individuals. Limited information on how contamination entered the supply chain. Single geographic outbreak may not represent ongoing risk levels."},{"rthcId":"RTHC-03127","title":"Cannabidiol (CBD) and other drug use among young adults who use cannabis in Los Angeles.","authors":"Fedorova, Ekaterina V; Wong, Carolyn F; Ataiants, Janna; Iverson, Ellen; Conn, Bridgid M; Lankenau, Stephen E","year":2021,"journal":"Drug and alcohol dependence, 221, 108648","doi":"10.1016/j.drugalcdep.2021.108648","pmid":"33676073","tags":["cbd","pain","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"CBD-dominant users were more likely female, used cannabis at lower frequency and amount (except edibles), cited medical motivations, used cannabis for pain, and reported more health problems. Unexpectedly, CBD-dominant users were also more likely to report illicit drug use, with psilocybin use markedly higher between groups. Oil, flower, topicals, and tinctures were the most common CBD forms.","whyItMatters":"The profile of CBD-dominant users as health-motivated with more medical conditions but also higher illicit drug use suggests a self-medication pattern that extends beyond cannabis to other substances perceived as therapeutic.","specificNumbers":"239 participants ages 24-32; CBD-dominant users more likely female; used cannabis less frequently except edibles; higher illicit drug use especially psilocybin; pain and psychological problems most cited reasons for CBD use","methodology":"Cross-sectional survey of 239 young adults (ages 24-32) who used cannabis in Los Angeles, surveyed March 2019 through March 2020. Compared CBD-dominant (at least 1:1 CBD:THC) and THC-dominant product users on demographics, cannabis practices, health, and other drug use.","limitations":"Cross-sectional design in a single city (Los Angeles). Self-reported data. Small sample for subgroup comparisons. CBD product quality and actual CBD/THC ratios were not verified."},{"rthcId":"RTHC-03128","title":"Medical marijuana utilization in gynecologic cancer patients.","authors":"Fehniger, Julia; Brodsky, Allison L; Kim, Arum; Pothuri, Bhavana","year":2021,"journal":"Gynecologic oncology reports, 37, 100820","doi":"10.1016/j.gore.2021.100820","pmid":"34258360","tags":["medical-cannabis","cancer","pain"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Of 45 patients (89% receiving chemotherapy), 71% reported improvement in at least one symptom after a median 5.2 months of use. Over 70% reported improvement in nausea/vomiting, compared to only 36% reporting pain relief (p=0.02). Side effects were minimal.","whyItMatters":"Gynecologic cancer patients face severe symptoms from both the disease and chemotherapy. This study provides some of the first data specifically on medical marijuana efficacy in this population, highlighting that nausea may respond better than pain.","specificNumbers":"45 patients; 89% receiving chemotherapy; 56% during primary treatment; median use 5.2 months (range 0.6-25.4); 71% improved in at least one symptom; >70% improved nausea/vomiting; 36% improved pain (p=0.02)","methodology":"Retrospective chart review of 45 gynecologic cancer patients prescribed medical marijuana between May 2016 and February 2019. Electronic medical records queried for formulation, usage patterns, length of use, symptom relief, and side effects.","limitations":"Small retrospective sample with no control group. Self-reported outcomes. No standardized assessment tools. Heterogeneous cancer types and treatment regimens. Selection bias in who was prescribed medical marijuana."},{"rthcId":"RTHC-03129","title":"Knowledge about and attitudes towards medical cannabis among Austrian university students.","authors":"Felnhofer, Anna; Kothgassner, Oswald D; Stoll, Astrid; Klier, Claudia","year":2021,"journal":"Complementary therapies in medicine, 58, 102700","doi":"10.1016/j.ctim.2021.102700","pmid":"33677020","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"64% of medical students said they learned about medical cannabis at university. Despite confidence in their knowledge, medical students struggled to differentiate between CBD and THC. They were more reserved about increasing medical use and legalization, and more skeptical about physician prescribing than non-medical students. Males were more confident and favorable toward legalization; females perceived cannabis as more addictive and as a gateway drug.","whyItMatters":"Future healthcare providers who lack accurate cannabis knowledge and hold negative attitudes may be less likely to recommend or discuss medical cannabis with patients, potentially limiting patient access to a legitimate treatment option.","specificNumbers":"404 students surveyed; 64% of medical students reported university cannabis education; medical students more skeptical of prescribing and legalization; males more favorable toward legalization; females perceived cannabis as more addictive","methodology":"Online survey of 404 Austrian university students in three groups: medical studies, studies with a medical background, and studies without a medical background. Assessed knowledge, attitudes, and gender differences regarding medical cannabis.","limitations":"Austrian sample may not generalize internationally. Online survey with potential self-selection bias. Knowledge was self-assessed rather than objectively tested. Cross-sectional design captures one point in time."},{"rthcId":"RTHC-03130","title":"Sex Differences in Comorbidity Between Substance Use and Mental Health in Adolescents: Two Sides of the Same Coin.","authors":"Fernández-Artamendi, Sergio; Martínez-Loredo, Víctor; López-Núñez, Carla","year":2021,"journal":"Psicothema, 33(1), 36-43","doi":"10.7334/psicothema2020.297","pmid":"33453734","tags":["youth","mental-health","sex-differences","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Girls presented significantly more mental health problems and higher prevalence of comorbidity between substance use and mental health disorders. Obsessive-compulsive symptoms and phobic anxiety predicted higher alcohol use disorder risk. Depression and the interaction between hostility and obsessive-compulsive disorder predicted higher cannabis use disorder risk.","whyItMatters":"Understanding that girls face higher comorbidity rates and that specific mental health symptoms predict specific substance use disorders can guide targeted prevention and early intervention strategies.","specificNumbers":"863 adolescents (53.7% girls, mean age 16.62); girls had higher comorbidity prevalence; obsessive-compulsive symptoms and phobic anxiety predicted AUD; depression and hostility x OCD interaction predicted CUD","methodology":"Cross-sectional study of 863 Spanish general-population adolescents (53.7% girls, mean age 16.62). Computerized battery assessed substance use frequency, Brief Symptom Inventory, Cannabis Problems Questionnaire, Rutgers Alcohol Problem Index, and DSM-IV-TR criteria for alcohol and cannabis use disorders. Binary logistic regressions examined predictors.","limitations":"Cross-sectional design cannot establish causal direction between mental health and substance use. Spanish general-population sample may not generalize. Self-reported measures. DSM-IV-TR criteria used rather than DSM-5."},{"rthcId":"RTHC-03131","title":"Cannabis-Based Medicines and Medical Cannabis in the Treatment of Nociplastic Pain.","authors":"Fitzcharles, Mary-Ann; Petzke, Frank; Tölle, Thomas R; Häuser, Winfried","year":2021,"journal":"Drugs, 81(18), 2103-2116","doi":"10.1007/s40265-021-01602-1","pmid":"34800285","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03132","title":"Use of medical cannabis by patients with fibromyalgia in Canada after cannabis legalisation: a cross-sectional study.","authors":"Fitzcharles, Mary-Ann; Rampakakis, Emmanouil; Sampalis, John S; Shir, Yoram; Cohen, Martin; Starr, Michael; Häuser, Winfried","year":2021,"journal":"Clinical and experimental rheumatology, 39 Suppl 130(3), 115-119","doi":"10.55563/clinexprheumatol/qcyet7","pmid":"33938797","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"23.9% of FM patients reported ever using medical cannabis, compared to 11.1% of non-FM rheumatology patients. Among FM ever-users, 61% continued use. FM cannabis users tended to be younger (53 vs. 58 years), were more likely unemployed/disabled (39% vs. 17%, p=0.019), used more medications, and reported substantial symptom relief (VAS 7.0/10). Cigarette smoking and recreational cannabis use were more common among ever-users.","whyItMatters":"Fibromyalgia has limited effective treatments, and cannabis legalization has made it easier for patients to self-medicate. Understanding who uses medical cannabis and their perceived benefits helps guide clinical conversations.","specificNumbers":"1,000 rheumatology patients; 117 (11.7%) with FM; 23.9% FM ever-users vs. 11.1% non-FM; 61% of FM users continued; FM users younger (53 vs. 58, p=0.072); more unemployed/disabled (39% vs. 17%, p=0.019); self-reported relief 7.0/10","methodology":"Cross-sectional survey of 1,000 consecutive rheumatology patients during June-August 2019 in Canada. Rheumatologists completed demographic/disease questionnaires; patients completed anonymous questionnaires on cannabis use and health status. Compared FM patients to non-FM patients and FM cannabis users to FM non-users.","limitations":"Cross-sectional survey at one rheumatology center. Self-reported cannabis use and symptom relief without objective measures. No control for placebo effect. FM cannabis users used more medications overall, confounding symptom assessment."},{"rthcId":"RTHC-03133","title":"N-acylethanolamine regulation of TLR3-induced hyperthermia and neuroinflammatory gene expression: A role for PPARα.","authors":"Flannery, Lisa E; Kerr, Daniel M; Hughes, Edel M; Kelly, Colm; Costello, Jonathan; Thornton, Aoife M; Humphrey, Rachel M; Finn, David P; Roche, Michelle","year":2021,"journal":"Journal of neuroimmunology, 358, 577654","doi":"10.1016/j.jneuroim.2021.577654","pmid":"34265624","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03134","title":"Calendar Month Variation in Alcohol and Marijuana Use in a Community Sample of Young Adults.","authors":"Fleming, Charles B; Duckworth, Jennifer C; Patrick, Megan E; Fairlie, Anne M; Abdallah, Devon A; Lee, Christine M","year":2021,"journal":"Journal of studies on alcohol and drugs, 82(2), 169-177","doi":null,"pmid":"33823963","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"All substance use measures showed calendar month variation. Marijuana use was highest in April and December regardless of educational status. Alcohol use peaked in summer, October, and December. College students drank more per week overall, with the gap widest in September-October, but drinking levels converged across educational groups in summer and December.","whyItMatters":"Knowing when substance use peaks can help prevention programs time their efforts. The April marijuana peak (coinciding with cannabis culture's \"4/20\") and December holiday peak suggest cultural and social drivers of use patterns.","specificNumbers":"761 participants; 57% female; ages 18-23; 24 monthly surveys; marijuana use highest in April and December; alcohol peaked in summer, October, and December; 4-year college students drank more per week; drinking converged across groups in summer and December","methodology":"Longitudinal study of 761 community-based young adults (57% female, ages 18-23 at enrollment) surveyed monthly for 24 consecutive months. Multilevel models accounted for nesting of monthly data within individuals. Compared patterns across educational status groups.","limitations":"Community sample from one metropolitan area. Self-reported monthly use may not capture within-month variation. 24-month window limits ability to separate year effects from month effects. Cannot determine whether April peak is related to 4/20 specifically."},{"rthcId":"RTHC-03135","title":"Cannabinoid Hyperemesis Syndrome in an Athlete.","authors":"Fleshman, Brady; Kaiser, Kim","year":2021,"journal":"Journal of the American Board of Family Medicine : JABFM, 34(4), 811-813","doi":"10.3122/jabfm.2021.04.200586","pmid":"34312273","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03136","title":"Symptoms, adverse events, and outcomes in the use of medicinal cannabis in children and adolescents with autism spectrum disorder: a scoping review protocol.","authors":"Fletcher, Sarah; Pawliuk, Colleen; Ip, Angie; Oberlander, Tim; Siden, Harold","year":2021,"journal":"JBI evidence synthesis, 19(5), 1251-1258","doi":"10.11124/JBIES-20-00001","pmid":"33165173","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03137","title":"Patterns, Consequences, and Motives in Simultaneous Use of Prescription Stimulant Medication with Alcohol and Marijuana.","authors":"Fossos-Wong, Nicole; Kilmer, Jason R; W Sokolovsky, Alexander; Lee, Ha-Yoon; Jackson, Kristina M; White, Helene R","year":2021,"journal":"Substance use & misuse, 56(13), 1972-1981","doi":"10.1080/10826084.2021.1963983","pmid":"34499566","tags":["addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"32.8% reported lifetime nonmedical prescription stimulant use; 12.5% used in the past 3 months. Of recent users, 51.1% simultaneously combined stimulants with alcohol and 40.2% with marijuana. The simultaneous use group had the heaviest drinking and marijuana use, the most consequences, and specifically used marijuana to alter effects of other substances.","whyItMatters":"Simultaneous use of multiple substances creates compounded health risks. Identifying that simultaneous prescription stimulant-cannabis-alcohol users represent a distinct high-risk group enables more targeted campus prevention.","specificNumbers":"1,108 students from 3 universities; 32.8% lifetime NPS use; 12.5% past-3-month use; 51.1% of recent users combined with alcohol; 40.2% combined with marijuana; simultaneous users had heaviest substance use and most consequences","methodology":"Cross-sectional survey of 1,108 college students from three universities who reported past-year marijuana and alcohol use. Compared three groups: no nonmedical prescription stimulant history, nonmedical use without simultaneous combination, and simultaneous use with alcohol and/or marijuana.","limitations":"Cross-sectional survey cannot determine causal ordering. Three universities may not represent all campuses. Self-reported data. Only students reporting past-year alcohol and marijuana use were included, excluding abstainers."},{"rthcId":"RTHC-03138","title":"Cannabidiol in the treatment of epilepsy: Current evidence and perspectives for further research.","authors":"Franco, Valentina; Bialer, Meir; Perucca, Emilio","year":2021,"journal":"Neuropharmacology, 185, 108442","doi":"10.1016/j.neuropharm.2020.108442","pmid":"33347884","tags":["cbd","epilepsy","drug-interactions"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Pharmaceutical-grade CBD has been approved for seizures in Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex based on multiple randomized placebo-controlled trials. However, CBD prominently increases plasma levels of N-desmethylclobazam (the active metabolite of clobazam), a commonly co-prescribed medication, making it difficult to separate CBD's independent antiseizure effects from those mediated through this drug interaction.","whyItMatters":"CBD is one of the few cannabis-derived medicines with regulatory approval for specific conditions. Understanding the clobazam interaction is critical for clinicians to properly attribute treatment effects and manage combination therapy.","specificNumbers":"Approved for 3 epilepsy syndromes (Dravet, Lennox-Gastaut, tuberous sclerosis complex); multiple mechanisms including GPR antagonism, TRPV1 desensitization, adenosine signaling, GABA enhancement; prominent increase in N-desmethylclobazam levels in co-treated patients","methodology":"Comprehensive narrative review of CBD's mechanisms of action, pharmacokinetics, clinical trial evidence, drug interactions, and remaining knowledge gaps in epilepsy treatment.","limitations":"Narrative rather than systematic review. Cannot quantify the independent contribution of CBD versus the clobazam interaction effect. Oral bioavailability is low and variable. Limited pharmacokinetic data in infants and young children."},{"rthcId":"RTHC-03139","title":"Cannabis alters epigenetic integrity and endocannabinoid signalling in the human follicular niche.","authors":"Fuchs Weizman, Noga; Wyse, Brandon A; Szaraz, Peter; Defer, Miranda; Jahangiri, Sahar; Librach, Clifford L","year":2021,"journal":"Human reproduction (Oxford, England), 36(7), 1922-1931","doi":"10.1093/humrep/deab104","pmid":"33954787","tags":["pregnancy","genetics","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"6.4% of patients tested positive for cannabis in follicular fluid. Cannabis positivity rose from 4% pre-legalization to 12% post-legalization. Only 59% of positive patients had reported cannabis use at intake. Cannabis exposure increased CB2 receptor expression in granulosa cells and reduced DNMT3b expression and global DNA methylation, effects sustained through chronic treatment in vitro.","whyItMatters":"Epigenetic changes in the cells surrounding developing eggs could affect oocyte quality and embryo development. The finding that cannabis alters DNA methylation in the follicular niche raises concerns about reproductive effects that may not be immediately apparent.","specificNumbers":"318 follicular fluid samples; 261 IVF patients; 17 (6.4%) positive for cannabis; prevalence rose 4% to 12% after legalization; 59% of positive patients self-reported use; CB2R expression increased; DNMT3b expression decreased; global DNA methylation decreased","methodology":"Combined in vivo cohort (318 follicular fluid samples from 261 IVF patients, measured by LC-MS/MS) and in vitro validation using naive granulosa cells treated with phytocannabinoids. Flow cytometry assessed receptor and enzyme expression; ELISA measured global DNA methylation.","limitations":"Small number of cannabis-positive patients (n=17). Could not assess clinical outcomes due to sample size. No details on consumption mode, frequency, or timing. IVF patients may not represent the general reproductive population. In vitro conditions differ from in vivo exposure."},{"rthcId":"RTHC-03140","title":"Immunomodulatory Potential of Cannabidiol in Multiple Sclerosis: a Systematic Review.","authors":"Furgiuele, Alessia; Cosentino, Marco; Ferrari, Marco; Marino, Franca","year":2021,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 16(2), 251-269","doi":"10.1007/s11481-021-09982-7","pmid":"33492630","tags":["cbd","inflammation","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Rodent EAE models strongly support CBD as effective against autoimmune neuroinflammation. However, clinical evidence in actual MS patients is limited and usually negative. The review argues this disconnect may be due to too few clinical studies and the use of suboptimal dosing regimens in humans.","whyItMatters":"MS patients frequently use cannabis products, and CBD's anti-inflammatory properties make it a theoretical candidate for disease modification. Understanding why animal success has not translated to clinical benefit is essential for designing effective trials.","specificNumbers":"Strong evidence from rodent EAE models; limited and usually negative clinical evidence; review suggests suboptimal dosing in human studies; recommends higher doses and better-designed clinical trials","methodology":"Systematic review of CBD's immunomodulatory effects in EAE (experimental autoimmune encephalomyelitis, the standard MS animal model) and in MS clinical studies. Retrieved and critically evaluated available evidence for immune and disease-modifying effects.","limitations":"Systematic review limited by the paucity of clinical studies available. EAE is an imperfect model of human MS. Cannot determine optimal human dosing from animal data alone. Publication bias may affect both animal and clinical literature."},{"rthcId":"RTHC-03141","title":"Detachment, peer pressure, and age of first substance use as gateways to later substance use.","authors":"Gallegos, Martin I; Zaring-Hinkle, Brittany; Wang, Nan; Bray, James H","year":2021,"journal":"Drug and alcohol dependence, 218, 108352","doi":"10.1016/j.drugalcdep.2020.108352","pmid":"33129625","tags":["youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Earlier first use of alcohol, marijuana, and tobacco predicted more emotional detachment, greater susceptibility to peer pressure, and higher likelihood of illicit substance use. The effect of early substance use on later illicit use was partially mediated through emotional detachment from parents.","whyItMatters":"Understanding the psychosocial pathways from early substance use to harder drugs can inform prevention programs. The finding that emotional detachment from parents mediates this progression suggests family-based interventions could help break the chain.","specificNumbers":"5,792 high school students; 7 semesters of data; earlier first use of alcohol, marijuana, and tobacco all predicted detachment, peer pressure, and illicit use; emotional detachment mediated the effect on illicit substance use","methodology":"Latent growth curve modeling of data from 5,792 high school students collected over seven semesters. Examined how age of first alcohol, marijuana, and tobacco use predicted trajectories of emotional detachment, peer pressure susceptibility, and progression to illicit substance use.","limitations":"Cannot determine if emotional detachment causes substance progression or if both are driven by unmeasured factors. Self-reported data. School-based sample excludes dropouts who may have the highest risk. Gateway progression may differ across cultural contexts."},{"rthcId":"RTHC-03142","title":"Evaluating the Suitability and Potential Efficiency of Cannabis sativa Oil for Patients with Primary Burning Mouth Syndrome: A Prospective, Open-Label, Single-Arm Pilot Study.","authors":"Gambino, Alessio; Cabras, Marco; Panagiotakos, Evangelos; Calvo, Federico; Macciotta, Alessandra; Cafaro, Adriana; Suria, Marco; Haddad, Giorgia El; Broccoletti, Roberto; Arduino, Paolo Giacomo","year":2021,"journal":"Pain medicine (Malden, Mass.), 22(1), 142-151","doi":"10.1093/pm/pnaa318","pmid":"33123730","tags":["medical-cannabis","pain","anxiety","depression"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"All 17 patients showed statistically significant improvement in oral pain intensity over time (assessed by VAS, Present Pain Intensity, McGill Pain Questionnaire, and OHIP). Anxiety and depression levels also improved significantly. No serious adverse events occurred and no patients discontinued treatment.","whyItMatters":"Burning mouth syndrome has limited treatment options and significantly affects quality of life. This pilot provides initial evidence that cannabis oil may address both the pain and the psychological burden of the condition.","specificNumbers":"17 patients; 4-week treatment; 24-week follow-up; significant improvement in VAS, Present Pain Intensity, McGill Pain Questionnaire, OHIP scores; anxiety and depression improved; 0 serious adverse events; 0 treatment discontinuations","methodology":"Prospective, open-label, single-arm pilot study. 17 patients with primary burning mouth syndrome received cannabis sativa oil extract (1g cannabis in 10g olive oil) for 4 weeks. Pain, neuropathic pain, anxiety, depression, and adverse events assessed at end of treatment and through 24 weeks follow-up.","limitations":"Open-label with no placebo or control group. Very small sample (17 patients). Expectation effects likely significant given cannabis's cultural reputation. Single center. Cannabis extract composition may vary between preparations."},{"rthcId":"RTHC-03143","title":"Cytotoxicity, metabolism, and isozyme mapping of the synthetic cannabinoids JWH-200, A-796260, and 5F-EMB-PINACA studied by means of in vitro systems.","authors":"Gampfer, Tanja M; Wagmann, Lea; Belkacemi, Anouar; Flockerzi, Veit; Meyer, Markus R","year":2021,"journal":"Archives of toxicology, 95(11), 3539-3557","doi":"10.1007/s00204-021-03148-3","pmid":"34453555","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03144","title":"Cannabidiol for the treatment of Lennox-Gastaut syndrome and Dravet syndrome: experts' recommendations for its use in clinical practice in Spain.","authors":"García-Peñas, J J; Gil Nagel-Rein, A; Sánchez-Carpintero, R; Villanueva-Haba, V","year":2021,"journal":"Revista de neurologia, 73(S01), S1-S8","doi":"10.33588/rn.73S01.2021250","pmid":"34486101","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03145","title":"Retail Availability of Recreational Marijuana and Alcohol in Oregon Counties and Co-Use of Alcohol and Marijuana and Related Beliefs among Adolescents.","authors":"García-Ramírez, Grisel; Paschall, Mallie J; Grube, Joel W","year":2021,"journal":"Substance use & misuse, 56(3), 345-352","doi":"10.1080/10826084.2020.1858104","pmid":"33435786","tags":["legalization","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Post-legalization, there was a significant increase in past-30-day alcohol and marijuana co-use in 2016 in counties with the highest retail outlet density. The relationship between outlet density and co-use was mediated by adolescent beliefs about availability, parent approval, and risk. There were also post-RML increases in perceived risk and perceived parent approval of use.","whyItMatters":"Understanding how retail density affects adolescent substance use patterns can inform zoning and licensing decisions. The finding that beliefs mediate the outlet density-use relationship suggests both environmental and educational interventions are needed.","specificNumbers":"71,870 11th graders; 36 Oregon counties; 2010-2018 data; significant co-use increase in 2016 in highest-density counties; beliefs about availability, parent approval, and risk mediated the outlet density-co-use relationship","methodology":"Multi-level logistic regression of biennial data from the Oregon Student Wellness Survey, 2010-2018, covering 71,870 11th graders across 36 counties. Examined associations between recreational marijuana legalization, county-level outlet density, and adolescent co-use and beliefs.","limitations":"Observational ecological design cannot establish individual-level causation. Biennial survey data may miss short-term fluctuations. Oregon may not represent other states. Outlet density is an imperfect proxy for actual accessibility to minors."},{"rthcId":"RTHC-03146","title":"Cannabidiol Modulates Behavioural and Gene Expression Alterations Induced by Spontaneous Cocaine Withdrawal.","authors":"Gasparyan, Ani; Navarrete, Francisco; Rodríguez-Arias, Marta; Miñarro, José; Manzanares, Jorge","year":2021,"journal":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 18(1), 615-623","doi":"10.1007/s13311-020-00976-6","pmid":"33230690","tags":["cbd","addiction","neuroscience","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice undergoing spontaneous cocaine withdrawal showed increased motor activity, somatic signs, and anxiety. CBD normalized all these behavioral disturbances. At the molecular level, CBD blocked the cocaine-induced increase in dopamine transporter (DAT) and tyrosine hydroxylase (TH) gene expression in the VTA, regulated the decrease of CNR1, and further upregulated CNR2 gene expression in the nucleus accumbens.","whyItMatters":"Cocaine withdrawal causes severe anxiety and behavioral disruption that drives relapse. CBD's ability to address both behavioral symptoms and underlying molecular changes suggests it could be a comprehensive treatment candidate.","specificNumbers":"Cocaine 15-60 mg/kg/day for 12 days; withdrawal at 6 hours; CBD 10, 20, 40 mg/kg tested; CBD normalized motor activity, somatic signs, and anxiety; blocked DAT and TH upregulation in VTA; regulated CNR1 decrease; upregulated CNR2 in nucleus accumbens","methodology":"Male CD-1 mice received escalating cocaine doses (15-60 mg/kg/day) for 12 days. Spontaneous withdrawal was assessed 6 hours after the last dose. CBD (10, 20, 40 mg/kg) was tested on motor activity, somatic signs, and anxiety. Gene expression of DAT, TH, CNR1, and CNR2 was measured by real-time PCR.","limitations":"Male mice only. Acute withdrawal (6 hours) may not represent the protracted withdrawal experienced by humans. CBD doses may not translate directly to human equivalents. Single cocaine withdrawal model; different cocaine exposure patterns could yield different results."},{"rthcId":"RTHC-03147","title":"Alcohol Use Disorders among Slovak and Czech University Students: A Closer Look at Tobacco Use, Cannabis Use and Socio-Demographic Characteristics.","authors":"Gavurova, Beata; Ivankova, Viera; Rigelsky, Martin","year":2021,"journal":"International journal of environmental research and public health, 18(21)","doi":"10.3390/ijerph182111565","pmid":"34770080","tags":["addiction","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Tobacco and cannabis use were positively associated with alcohol use disorders in both Czech and Slovak student samples. Males were more likely to report alcohol use disorders. In the Czech Republic, dormitory students had lower AUDIT scores, while in Slovakia, dormitory students had higher scores.","whyItMatters":"The COVID-19 pandemic may have altered substance use patterns among university students. Understanding the clustering of alcohol, tobacco, and cannabis use helps target prevention programs that address polysubstance patterns rather than single substances.","specificNumbers":"1,422 Czech + 1,677 Slovak students; 93% CZ and 91% SK drank in past year; tobacco and cannabis positively associated with AUDIT scores; males had higher alcohol disorder risk; dormitory effects opposite between countries","methodology":"Cross-sectional survey of 1,422 Czech and 1,677 Slovak university students during early COVID-19. Used AUDIT for alcohol, GN-SBQ for tobacco, and CAST for cannabis. Correlation and regression analyses examined substance use associations and demographic factors.","limitations":"Cross-sectional during COVID-19 may not reflect normal patterns. Self-reported measures. Convenience sampling of university students. Cannot determine if cannabis/tobacco use causes or results from alcohol problems."},{"rthcId":"RTHC-03148","title":"Recreational Cannabis Use Before and After Legalization in Women With Pelvic Pain.","authors":"Geoffrion, Roxana; Yang, Emily C; Koenig, Nicole A; Brotto, Lori A; Barr, Alasdair M; Lee, Terry; Allaire, Catherine; Bedaiwy, Mohamed A; Yong, Paul J","year":2021,"journal":"Obstetrics and gynecology, 137(1), 91-99","doi":"10.1097/AOG.0000000000004207","pmid":"33278297","tags":["pain","legalization","sex-differences","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"14.9% of all patients were current cannabis users. After legalization, use increased from 13.3% to 21.5% (p<0.001). Cannabis users had worse scores for depression, anxiety, pain catastrophizing, quality of life, and pain severity. Post-legalization users were more educated, had worse anxiety and pain catastrophizing, but used fewer antiinflammatories, neuroleptics, and daily opioids.","whyItMatters":"Cannabis legalization significantly increased use among women with chronic pelvic pain. The shift toward more educated users with fewer opioid prescriptions suggests a changing profile of who turns to cannabis for pain management.","specificNumbers":"3,426 women; 509 (14.9%) current cannabis users; use rose from 13.3% to 21.5% post-legalization (p<0.001); cannabis users had worse depression, anxiety, pain catastrophizing, quality of life, and pain severity (all p<0.001); post-legalization users took fewer daily opioids (p=0.026)","methodology":"Retrospective analysis of a prospective registry at a Vancouver tertiary pelvic pain clinic, 2013-2019 (n=3,426). Compared cannabis users vs. non-users and pre-legalization (before October 17, 2018) vs. post-legalization users on demographics, clinical measures, and validated questionnaires.","limitations":"Tertiary care sample may not represent all women with pelvic pain. Retrospective design. Cannot determine if cannabis use preceded or followed pain worsening. Post-legalization period was relatively short (about 1 year). Recreational use data only."},{"rthcId":"RTHC-03149","title":"Mid-infrared spectroscopy as process analytical technology tool for estimation of THC and CBD content in Cannabis flowers and extracts.","authors":"Geskovski, Nikola; Stefkov, Gjose; Gigopulu, Olga; Stefov, Stefan; Huck, Christian W; Makreski, Petre","year":2021,"journal":"Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy, 251, 119422","doi":"10.1016/j.saa.2020.119422","pmid":"33477086","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03150","title":"The ω-3 endocannabinoid docosahexaenoyl ethanolamide reduces seizure susceptibility in mice by activating cannabinoid type 1 receptors.","authors":"Ghanbari, Mohammad-Mahdi; Loron, Ali Gharibi; Sayyah, Mohammad","year":2021,"journal":"Brain research bulletin, 170, 74-80","doi":"10.1016/j.brainresbull.2021.02.011","pmid":"33581310","tags":["epilepsy","neuroscience","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"DHEA (100-300 uM) significantly increased seizure threshold within 10 minutes, more potently than its parent molecule DHA (which required 300 uM and 15 minutes). EPEA had no effect at any dose. The CB1 antagonist AM251 fully blocked the anti-seizure effects of both DHA and DHEA, while the CB2 antagonist AM630 did not.","whyItMatters":"This is the first report showing that DHEA, an omega-3 endocannabinoid, has direct anti-seizure activity via CB1 receptors. This connects the well-known neuroprotective effects of omega-3 fatty acids to the endocannabinoid system, suggesting a new mechanism.","specificNumbers":"DHEA effective at 100 and 300 uM at 10 minutes; DHA effective at 300 uM at 15 minutes; EPEA ineffective at 300 and 1000 uM; AM251 (CB1 antagonist) fully blocked effects; AM630 (CB2 antagonist) did not block effects","methodology":"Mice received intracerebroventricular injections of DHA, DHEA, EPEA, and cannabinoid receptor antagonists. Seizure threshold was measured by intravenous PTZ infusion at 10 and/or 15 minutes post-administration.","limitations":"Intracerebroventricular delivery is not clinically practical. Acute seizure model may not reflect chronic epilepsy. Chemical threshold model (PTZ) is one of several seizure types. Small sample sizes typical of pharmacological studies."},{"rthcId":"RTHC-03151","title":"Cannabis Use Among Mental Health Professionals: A Qualitative Study of Cannabis-Related Risk Perceptions.","authors":"Ghelani, Amar","year":2021,"journal":"Journal of drug issues, 51(4), 679-689","doi":"10.1177/00220426211032558","pmid":"34511638","tags":["mental-health","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Mental health professionals who use cannabis identified multiple risks from both personal and clinical experience: anxiety, relational challenges, impaired driving, psychosis, cognitive impairment, educational/employment dysfunction, and addiction in some users. However, they may underestimate physical health risks, suggesting a gap in their knowledge base.","whyItMatters":"Mental health professionals who use cannabis occupy a unique dual perspective: they see cannabis effects in their clients and experience them personally. Understanding their risk perceptions can reveal blind spots that affect both personal use and clinical guidance.","specificNumbers":"Sample included social workers, nurses, and psychotherapists; identified risks: anxiety, relational challenges, impaired driving, psychosis, cognitive impairment, educational/employment dysfunction, addiction","methodology":"Interpretative phenomenological analysis of qualitative interviews with social workers, nurses, and psychotherapists who use cannabis and work with cannabis-consuming clients. Examined how they make sense of cannabis-related harm in both personal and professional contexts.","limitations":"Qualitative study with small sample and no specific sample size reported. Self-selected participants willing to disclose use. Cannot generalize findings to all mental health professionals. Social desirability bias may understate risky use patterns."},{"rthcId":"RTHC-03152","title":"Family attitudes about and experiences with medical cannabis in children with cancer or epilepsy: an exploratory qualitative study.","authors":"Gibbard, Marissa; Mount, Dawn; Rassekh, Shahrad R; Siden, Harold Hal","year":2021,"journal":"CMAJ open, 9(2), E563-E569","doi":"10.9778/cmajo.20200212","pmid":"34021014","tags":["medical-cannabis","youth","epilepsy","cancer"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Five themes emerged: 1) parents sought cannabis as a last resort for severely ill children; 2) information came from social media, industry, and other families rather than healthcare providers; 3) cannabis was viewed ambiguously as both a serious drug needing medical oversight and a safe natural product; 4) parents perceived medical benefits with few adverse effect concerns; 5) high costs and uncertain legality were barriers but did not stop use.","whyItMatters":"Parents of seriously ill children are making medical cannabis decisions largely without professional guidance. Their reliance on social media, industry, and peer networks for information creates risks of misinformation and inappropriate use.","specificNumbers":"10 interviews; 9 mothers, 1 couple; children aged 22 months to 16 years; 6 used for epilepsy, 4 for chemotherapy; 5 major themes identified","methodology":"Qualitative study with semistructured interviews of 10 parents (9 mothers, 1 couple) of children at BC Children's Hospital oncology or palliative care clinics who used medical cannabis. Children ranged from 22 months to 16 years. Thematic analysis using qualitative description.","limitations":"Small qualitative sample (10 interviews) at one hospital. Self-selected parents willing to discuss cannabis use. Cannot generalize to all families using medical cannabis for children. Social desirability bias possible."},{"rthcId":"RTHC-03153","title":"Differential effects of cannabis exposure during early versus later adolescence on the expression of psychosis in homeless and precariously housed adults.","authors":"Gicas, Kristina M; Cheng, Alex; Panenka, William J; Kim, David D; Yau, Jade C; Procyshyn, Ric M; Stubbs, Jacob L; Jones, Andrea A; Bains, Simran; Thornton, Allen E; Lang, Donna J; Vertinsky, Alexandra T; Rauscher, Alex; Honer, William G; Barr, Alasdair M","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 106, 110084","doi":"10.1016/j.pnpbp.2020.110084","pmid":"32890696","tags":["psychosis","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Early cannabis exposure (by age 15) was associated with increased risk of substance-induced psychosis (OR=1.09, p<0.05). Later first use (after age 15) increased risk of schizophrenia or schizoaffective disorder (OR=2.19, p<0.01). No cognitive differences were found between groups, though brain imaging showed differences in the lateral orbitofrontal cortex and white matter tract diffusivity.","whyItMatters":"The differential association between timing of cannabis use and type of psychotic disorder suggests different developmental mechanisms. This has implications for understanding how cannabis affects the developing brain at different stages.","specificNumbers":"437 subjects; early use (by 15) OR=1.09 for substance-induced psychosis (p<0.05); later use (after 15) OR=2.19 for schizophrenia/schizoaffective (p<0.01); brain differences in lateral orbitofrontal cortex and white matter diffusivity","methodology":"Cross-sectional study of 437 homeless/precariously housed adults recruited from single-room occupancy hotels in Vancouver's Downtown Eastside. Psychiatric diagnoses determined clinically. Psychotic symptoms measured with 5-factor PANSS. Neurocognitive battery and structural/diffusion tensor MRI completed.","limitations":"Cross-sectional design cannot establish causation. Retrospective recall of age of first use. Homeless/precariously housed population has many confounding risk factors (poverty, trauma, polysubstance use). Selection bias inherent in studying this population."},{"rthcId":"RTHC-03154","title":"Interaction of cannabidiol with other antiseizure medications: A narrative review.","authors":"Gilmartin, Christopher G S; Dowd, Zoya; Parker, Alasdair P J; Harijan, Pooja","year":2021,"journal":"Seizure, 86, 189-196","doi":"10.1016/j.seizure.2020.09.010","pmid":"33541771","tags":["cbd","epilepsy","drug-interactions"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"CBD has potential pharmacokinetic interactions with brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate, and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate, and levetiracetam. Animal data suggested brain drug concentrations may change while serum levels remain stable.","whyItMatters":"Since CBD is used adjunctively with other anti-seizure medications, understanding interactions is essential for safe prescribing. The finding that brain levels may change without serum level changes is particularly concerning for therapeutic drug monitoring.","specificNumbers":"30 studies identified; pharmacokinetic interactions with 15 ASMs; pharmacodynamic interactions with 3 ASMs; cytochrome P450 primarily implicated; animal data showed brain-serum concentration discordance","methodology":"Narrative review of 30 studies (18 observational cohort, 2 RCTs, 3 case reports/series, 3 animal studies, 2 briefing reports, 1 cohort analysis, 1 clinical trial simulation) on CBD interactions with anti-seizure medications, identified through Cochrane, PubMed, and Embase searches (2015-2020).","limitations":"Some interactions based on small cohorts or case reports. Narrative rather than systematic review. Drug interactions may vary with CBD dose, formulation, and individual patient metabolism. Animal brain-serum discordance finding needs human confirmation."},{"rthcId":"RTHC-03155","title":"Cannabis in Homes with Children: A Survey on Use, Storage, and Attitudes.","authors":"Gimelli, Alex; Deshpande, Anusha; Magana, Julia N; Moulin, Aimee","year":2021,"journal":"The western journal of emergency medicine, 22(5), 1146-1149","doi":"10.5811/westjem.2021.5.49057","pmid":"34546891","tags":["legalization","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"14.5% reported cannabis use in their home in the prior six months. Only 44.8% of home users stored cannabis both locked and hidden. The most common storage advice source was friends/family (36.2%), and 45% received no storage information at all. Both users (79.1%) and non-users (73%) would feel comfortable receiving cannabis education from their primary care provider.","whyItMatters":"As cannabis legalization expands, pediatric ingestion risk increases. The finding that most families store cannabis inadequately and receive no professional guidance creates an actionable opportunity for healthcare providers.","specificNumbers":"401 surveyed (of 558 approached); 14.5% (58/401) reported home cannabis use; 44.8% (26/58) stored both locked and hidden; 36.2% got advice from friends/family; 45% received no storage information; 79.1% of users comfortable with provider education","methodology":"Cross-sectional electronic survey of 401 adults in a California pediatric emergency department. Assessed cannabis use, storage practices, and attitudes toward storage education. Convenience sampling with descriptive statistics.","limitations":"Convenience sample in one pediatric ER. Self-reported data may underestimate cannabis use and overstate safe storage. California may not represent states with different cannabis cultures. Cross-sectional snapshot."},{"rthcId":"RTHC-03156","title":"Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications.","authors":"Giorgetti, Arianna; Pascali, Jennifer P; Fais, Paolo; Pelletti, Guido; Gabbin, Andrea; Franchetti, Giorgia; Cecchetto, Giovanni; Viel, Guido","year":2021,"journal":"Life (Basel, Switzerland), 11(5)","doi":"10.3390/life11050440","pmid":"34068903","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03157","title":"Cannabis and Autoimmunity: Possible Mechanisms of Action.","authors":"Giorgi, Valeria; Marotto, Daniela; Batticciotto, Alberto; Atzeni, Fabiola; Bongiovanni, Sara; Sarzi-Puttini, Piercarlo","year":2021,"journal":"ImmunoTargets and therapy, 10, 261-271","doi":"10.2147/ITT.S267905","pmid":"34322454","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03158","title":"Adolescent cannabinoid exposure modulates the vulnerability to cocaine-induced conditioned place preference and DNMT3a expression in the prefrontal cortex in Swiss mice.","authors":"Gobira, P H; Roncalho, A L; Silva, N R; Silote, G P; Sales, A J; Joca, S R","year":2021,"journal":"Psychopharmacology, 238(11), 3107-3118","doi":"10.1007/s00213-021-05926-4","pmid":"34328516","tags":["youth","addiction","neuroscience","genetics","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent WIN55,212-2 exposure did not alter anxiety or depression in adulthood. However, it blocked cocaine-induced conditioned place preference (a measure of drug reward) without affecting cocaine-induced hyperlocomotion. This was accompanied by increased expression of DNA methyltransferase 3a (DNMT3a) in the prefrontal cortex, suggesting epigenetic changes may modulate cocaine reward sensitivity.","whyItMatters":"Counter to the gateway hypothesis, this study found adolescent cannabinoid exposure actually reduced cocaine reward sensitivity. The epigenetic mechanism (DNMT3a upregulation) provides a molecular explanation for how early cannabinoid exposure could alter drug reward processing.","specificNumbers":"Adolescent WIN55,212-2 exposure; no change in anxiety or depression; blocked cocaine-induced conditioned place preference; no effect on cocaine-induced hyperlocomotion; increased DNMT3a expression in prefrontal cortex","methodology":"Swiss mice received WIN55,212-2 during adolescence. In adulthood, tested for anxiety (elevated plus maze), depression (forced swim), locomotor activity, and cocaine reward (conditioned place preference). DNMT3a expression measured by real-time PCR in prefrontal cortex.","limitations":"Synthetic cannabinoid (WIN55,212-2) may not represent natural cannabis use. Male mice only. Conditioned place preference is one measure of reward; other aspects of addiction (compulsive seeking, relapse) not tested. DNMT3a change is correlational, not proven causal."},{"rthcId":"RTHC-03159","title":"Cannabidiolic acid exhibits entourage-like improvements of anticonvulsant activity in an acute rat model of seizures.","authors":"Goerl, Brett; Watkins, Sarah; Metcalf, Cameron; Smith, Misty; Beenhakker, Mark","year":2021,"journal":"Epilepsy research, 169, 106525","doi":"10.1016/j.eplepsyres.2020.106525","pmid":"33310415","tags":["epilepsy","cbd","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In the maximal electroshock seizure test, Chylobinoid (CBDa plus minor cannabinoids) had an ED50 of 76.7 mg/kg, Mg-CBDa (purified) had an ED50 of 115.4 mg/kg, and CBD had an ED50 of 68.8 mg/kg. Chylobinoid was more effective than Mg-CBDa despite lower CBDa content, suggesting minor cannabinoid constituents contribute an \"entourage\" effect.","whyItMatters":"CBDa (the acid precursor to CBD) is chemically unstable, limiting its clinical potential. Magnesium stabilization may solve this problem, and the entourage effect from minor cannabinoids suggests whole-plant extracts could outperform purified compounds.","specificNumbers":"ED50 values adjusted for CBDa content: Chylobinoid 76.7 mg/kg (95% CI: 51.7-109.2); Mg-CBDa 115.4 mg/kg (95% CI: 98.8-140.9); CBD 68.8 mg/kg (95% CI: 56.6-80.0)","methodology":"Sprague-Dawley rats received intraperitoneal injections of Chylobinoid, Mg-CBDa, or CBD at varying doses. Seizure protection assessed using maximal electroshock seizure test with corneal stimulation. Dose-response curves calculated using Probit analysis.","limitations":"Acute seizure model; chronic epilepsy models needed. Intraperitoneal route differs from oral administration used clinically. Specific minor cannabinoids responsible for the entourage effect not identified. Single seizure model type."},{"rthcId":"RTHC-03160","title":"Exploring the Relationship Between ADHD Symptoms and Daily Cannabis Consequences in Emerging Adulthood: The Role of Cannabis Motives.","authors":"Goldstein, Abby L; Shifrin, Alexandra; Katz, Jasmin L; Iu, Lap K; Kofler, Danielle","year":2021,"journal":"Journal of studies on alcohol and drugs, 82(2), 228-236","doi":null,"pmid":"33823970","tags":["cognition","mental-health","sleep"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Higher past-6-month ADHD symptoms predicted more daily cannabis consequences overall. Using cannabis for boredom or sleep was associated with more consequences on those days. Although ADHD symptoms were associated with more consequences on days with sleep motives, the relationship was actually stronger on days without sleep motives, suggesting ADHD-related consequences may overlap with ADHD symptoms themselves.","whyItMatters":"People with ADHD use cannabis at higher rates and may experience more negative consequences. Understanding that ADHD symptoms interact with specific cannabis use motives can inform targeted intervention strategies.","specificNumbers":"62 participants; ages 19-25; 60% male; 14 daily reports; higher ADHD symptoms predicted more daily consequences; boredom and sleep motives predicted more consequences; cannabis consequences overlapped with ADHD symptoms","methodology":"Daily diary study of 62 emerging adults (ages 19-25, 60% male) who used cannabis at least twice in the prior 2 weeks. Baseline ADHD screening followed by 14 daily reports on cannabis use, consequences, and motives.","limitations":"Small sample (62 participants). Self-reported ADHD symptoms rather than clinical diagnosis. 14-day window is brief. Only regular cannabis users included, limiting generalizability. Cannot separate cannabis effects from underlying ADHD."},{"rthcId":"RTHC-03161","title":"Cannabidiol Therapy for Refractory Epilepsy and Seizure Disorders.","authors":"Golub, Victoria; Reddy, D Samba","year":2021,"journal":"Advances in experimental medicine and biology, 1264, 93-110","doi":"10.1007/978-3-030-57369-0_7","pmid":"33332006","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03162","title":"CB1 and CB2 receptors in the bed nucleus of the stria terminalis differently modulate anxiety-like behaviors in rats.","authors":"Gomes-de-Souza, Lucas; Bianchi, Paula C; Costa-Ferreira, Willian; Tomeo, Rodrigo A; Cruz, Fábio C; Crestani, Carlos C","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 110, 110284","doi":"10.1016/j.pnpbp.2021.110284","pmid":"33609604","tags":["anxiety","neuroscience","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both CB1 and CB2 receptor gene expression were confirmed in the anterior and posterior BNST. CB1 antagonist AM251 increased open arm exploration (reduced anxiety) in unstressed rats and blocked stress-evoked anxiety. Conversely, CB2 antagonist JTE907 decreased open arm exploration (increased anxiety) and also blocked restraint-evoked behavioral changes. These opposite roles suggest CB1 and CB2 receptors differentially regulate anxiety through this brain region.","whyItMatters":"The BNST is a key brain structure for sustained anxiety states. Discovering that CB1 and CB2 receptors have opposing roles in this region helps explain why cannabis can both increase and decrease anxiety, and identifies specific receptor targets for anxiety treatment.","specificNumbers":"CB1 and CB2 gene expression confirmed in anterior and posterior BNST; AM251 (CB1 antagonist) dose-dependently increased EPM open arm exploration; JTE907 (CB2 antagonist) dose-dependently decreased open arm exploration; both blocked restraint-evoked anxiety changes","methodology":"Gene expression of CB1 and CB2 receptors confirmed in anterior and posterior BNST by RT-PCR. Behavioral effects tested in elevated plus maze (EPM) in unstressed rats and after restraint stress, with bilateral microinjection of CB1 antagonist AM251 or CB2 antagonist JTE907 into the anterior BNST.","limitations":"Male rats only. Pharmacological blockade does not perfectly mimic natural cannabinoid signaling. Elevated plus maze is one measure of anxiety. BNST is one of many anxiety-relevant brain regions. Single stress paradigm used."},{"rthcId":"RTHC-03163","title":"Impact of previous tobacco use with or without cannabis on first psychotic experiences in patients with first-episode psychosis.","authors":"González-Blanco, Leticia; García-Portilla, María Paz; Gutiérrez, Miguel; Mezquida, Gisela; Cuesta, Manuel J; Urbiola, Elena; Amoretti, Silvia; Barcones, Fe; González-Pinto, Ana; Pina-Camacho, Laura; Corripio, Iluminada; Vieta, Eduard; Baeza, Immaculada; Toll, Alba; Sáiz, Pilar A; Bobes, Julio; Bernardo, Miguel","year":2021,"journal":"Schizophrenia research, 236, 19-28","doi":"10.1016/j.schres.2021.07.017","pmid":"34365082","tags":["psychosis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"FEP patients with prior tobacco-only use (n=56) had more sleep disturbances (42.9% vs. 18.8%) and less social withdrawal (33.9% vs. 58%) than those with no substance use (n=70). Those with combined tobacco and cannabis use (n=144) had higher rates of ideas of reference, perceptual abnormalities, hallucinations, and disorganized thinking than tobacco-only users, plus earlier age at first symptom (23.7 vs. 26.2 years).","whyItMatters":"Tobacco use alone was not associated with earlier psychosis onset, but adding cannabis was. This helps disentangle the roles of tobacco and cannabis in psychosis risk, suggesting cannabis is the key driver of earlier and more severe first episodes.","specificNumbers":"284 FEP patients, 231 controls; tobacco+cannabis group (n=144): age at first symptom 23.7 years; tobacco-only (n=56): 26.2 years (p=0.011); tobacco+cannabis had higher rates of hallucinations (55.4% vs 71.5%), perceptual abnormalities (46.4% vs 67.4%), disorganized thinking (41.1% vs 61.1%)","methodology":"Retrospective analysis from the Spanish PEPs longitudinal study of 284 FEP patients and 231 matched healthy controls. First psychotic experiences assessed with the Symptom Onset in Schizophrenia Inventory. Compared substance use groups: no use, tobacco only, and tobacco plus cannabis.","limitations":"Retrospective substance use recall. Cross-sectional comparisons at study entry. Spanish sample may not generalize. Cannot determine if substance use caused psychosis or shared risk factors produced both. Unequal group sizes."},{"rthcId":"RTHC-03164","title":"Influence of package colour, branding and health warnings on appeal and perceived harm of cannabis products among respondents in Canada and the US.","authors":"Goodman, Samantha; Rynard, Vicki L; Iraniparast, Maryam; Hammond, David","year":2021,"journal":"Preventive medicine, 153, 106788","doi":"10.1016/j.ypmed.2021.106788","pmid":"34506816","tags":["legalization","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Full branding was rated most appealing and plain packaging least (p<0.001). Health warnings made products significantly less appealing and more harmful than no warning (p<0.001). Canadian warnings (specific: pregnancy, adolescent risk, impaired driving) had higher recall than the US warning (general risk categories). White backgrounds with no branding were unexpectedly rated as less harmful than colored backgrounds.","whyItMatters":"As more jurisdictions legalize cannabis, packaging regulations can meaningfully influence consumer perceptions. This large-scale evidence from a randomized design provides actionable guidance for regulators.","specificNumbers":"45,378 participants; 3x4 factorial design; plain packaging least appealing (p<0.001); health warnings reduced appeal and increased perceived harm (p<0.001); Canadian warnings had higher recall than US; white backgrounds rated less harmful (p<0.01)","methodology":"Online factorial experiment randomizing participants to view cannabis packages across 3 health warning conditions (none, Canadian, US) and 4 branding conditions (plain to full branding). Measured product appeal, perceived harm, and free recall of warning messages.","limitations":"Online experiment may not perfectly simulate real-world purchasing decisions. Self-reported appeal and perceived harm may not predict actual behavior. Only tested visual package design, not actual products. Short-term perceptions measured."},{"rthcId":"RTHC-03165","title":"Trends in cannabis use among adults with children in the home in the United States, 2004-2017: impact of state-level legalization for recreational and medical use.","authors":"Goodwin, Renee D; Kim, June H; Cheslack-Postava, Keely; Weinberger, Andrea H; Wu, Melody; Wyka, Katarzyna; Kattan, Meyer","year":2021,"journal":"Addiction (Abingdon, England), 116(10), 2770-2778","doi":"10.1111/add.15472","pmid":"33730400","tags":["legalization","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Recreational cannabis laws were associated with higher past-month use (AOR=1.28) and daily use (AOR=1.25) among adults with children. Medical laws also increased use (AOR=1.12 past-month, AOR=1.16 daily). Recreational legalization increased use broadly across demographics, while medical legalization effects were concentrated among adults 50+ and higher socioeconomic groups.","whyItMatters":"Cannabis use by adults with children in the home raises questions about secondhand exposure, safe storage, and parenting while impaired. Understanding how legalization affects this specific population helps inform family-focused policies.","specificNumbers":"N=287,624; 2017 past-month use: 11.9% (RML), 9.3% (MML), 6.1% (no legal); daily use: 4.2% (RML), 3.2% (MML), 2.3% (no legal); RML AOR=1.28 past-month, 1.25 daily; MML AOR=1.12 past-month, 1.16 daily; MML effects strongest in adults 50+ and high SES","methodology":"Difference-in-difference analysis of 2004-2017 NSDUH data (n=287,624 adults with children in the home). Compared cannabis use across states with recreational laws, medical laws, and no legal cannabis, adjusting for demographics and state-level tobacco control.","limitations":"Repeated cross-sectional data, not individual-level longitudinal tracking. Self-reported cannabis use likely underestimated. State-level policy is a proxy for individual-level access. Cannot control for all state-level confounders."},{"rthcId":"RTHC-03166","title":"Different responses of repetitive behaviours in juvenile and young adult mice to Δ9 -tetrahydrocannabinol and cannabidiol may affect decision making for Tourette syndrome.","authors":"Gorberg, Victoria; McCaffery, Peter; Anavi-Goffer, Sharon","year":2021,"journal":"British journal of pharmacology, 178(3), 614-625","doi":"10.1111/bph.15302","pmid":"33125731","tags":["neuroscience","youth","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC dose-dependently reduced some DOI-induced repetitive behaviors (ear scratch > grooming > head twitch) differently in juvenile versus young adult mice. THC at 5 mg/kg caused catalepsy in controls and increased ear scratching in juveniles. CBD had no effect on DOI-induced ear scratching or grooming in juveniles and actually increased head twitching in both age groups.","whyItMatters":"Tourette syndrome has childhood onset and adults increasingly use medical cannabis for tics, but pediatric use is growing without age-specific evidence. This study reveals concerning age-dependent effects that could worsen symptoms in younger patients.","specificNumbers":"THC potency rank in young adults: ESR > grooming > HTR; in juveniles: ESR = grooming > HTR; THC 5 mg/kg caused catalepsy in controls; CBD increased HTR frequency in both ages; CBD had no benefit for ESR or grooming in juveniles","methodology":"Juvenile and young adult mice received DOI (2,5-dimethoxy-4-iodoamphetamine) to induce tic-like repetitive behaviors (head twitch, ear scratch, grooming). Effects of THC and CBD at various doses were compared between age groups.","limitations":"DOI-induced repetitive behaviors are an imperfect model of Tourette syndrome tics. Mouse responses may not predict human responses. Limited dose range tested. Acute administration only; chronic effects unknown."},{"rthcId":"RTHC-03167","title":"Is Cannabis being used as a substitute for non-medical opioids by adults with problem substance use in the United States? A within-person analysis.","authors":"Gorfinkel, Lauren R; Stohl, Malki; Greenstein, Eliana; Aharonovich, Efrat; Olfson, Mark; Hasin, Deborah","year":2021,"journal":"Addiction (Abingdon, England), 116(5), 1113-1121","doi":"10.1111/add.15228","pmid":"33029914","tags":["addiction","pain","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"On days when cannabis was used, the adjusted odds of non-medical opioid use were 1.86 times higher (95% CI: 1.44-2.41). This association did not differ between people with moderate-to-severe pain versus less pain, contradicting the hypothesis that people substitute cannabis for opioids to manage pain.","whyItMatters":"Ecological studies suggesting cannabis legalization reduces opioid deaths have led to policy interest in cannabis as an opioid substitute. This individual-level data tells a different story: among people who actually use both, cannabis and opioid use cluster together rather than substituting.","specificNumbers":"211 participants; 64% male; mean age 43; 13,271 observation days; 70% IVR completion; same-day cannabis-opioid use aOR=1.86 (95% CI: 1.44-2.41); no significant interaction with pain levels","methodology":"Prospective daily diary study of 211 adults with problem substance use who use non-medical opioids, recruited May 2016-June 2019 in New York. Participants responded to daily interactive voice response for 90 days (13,271 observation days total, 70% completion rate).","limitations":"Sample limited to adults with established problem substance use and non-medical opioid use, not representative of all cannabis or opioid users. New York/suburban setting. Same-day association does not prove cannabis causes opioid use. Observational within-person design."},{"rthcId":"RTHC-03168","title":"A comparative analysis of laws on recreational cannabis edibles between Canada and the United States of America.","authors":"Goundar, Priyashni; Macaulay, Tim; Szafron, Michael","year":2021,"journal":"The International journal on drug policy, 94, 103191","doi":"10.1016/j.drugpo.2021.103191","pmid":"33756442","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03169","title":"Cannabis use disorder and the lungs.","authors":"Gracie, Kathryn; Hancox, Robert J","year":2021,"journal":"Addiction (Abingdon, England), 116(1), 182-190","doi":"10.1111/add.15075","pmid":"32285993","tags":["respiratory","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis smoking causes bronchitis and increases central airway resistance with lung hyperinflation and higher vital capacity. Unlike tobacco, there is no convincing evidence it causes COPD, despite some case reports of bullous disease and pneumothorax in heavy users. An association with lung cancer remains unproven with conflicting findings.","whyItMatters":"With cannabis legalization increasing smoking prevalence, understanding its distinct respiratory effects (different from tobacco) is essential for clinical guidance and public health messaging.","specificNumbers":"Cannabis smoking associated with: bronchitis at low exposure; increased central airway resistance; lung hyperinflation; higher vital capacity; no convincing evidence of COPD, emphysema, or airflow obstruction; inconclusive evidence for lung cancer","methodology":"Narrative review of the evidence on cannabis use disorder and respiratory health, addressing bronchitis, airflow obstruction, emphysema, lung cancer, and specific lung function patterns.","limitations":"Narrative review. Cannabis respiratory research is limited by illegality, variable product potency, and most users also smoking tobacco. Confounding by tobacco is difficult to eliminate completely."},{"rthcId":"RTHC-03170","title":"Prospects for the Use of Cannabinoids in Psychiatric Disorders.","authors":"Graczyk, Michał; Łukowicz, Małgorzata; Dzierzanowski, Tomasz","year":2021,"journal":"Frontiers in psychiatry, 12, 620073","doi":"10.3389/fpsyt.2021.620073","pmid":"33776815","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03171","title":"Cannabis, Schizophrenia Risk and Genetics: A Case Report of a Patient With Homozygous Valine Catechol-O-Methyltransferase Polymorphism.","authors":"Grechuk, Katelyn; Azizi, Heela; Sharma, Vatsala; Khan, Tasmia; Jolayemi, Ayodeji","year":2021,"journal":"Cureus, 13(6), e15740","doi":"10.7759/cureus.15740","pmid":"34285849","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03172","title":"Dual Inhibition of FAAH and MAGL Counteracts Migraine-like Pain and Behavior in an Animal Model of Migraine.","authors":"Greco, Rosaria; Demartini, Chiara; Francavilla, Miriam; Zanaboni, Anna Maria; Tassorelli, Cristina","year":2021,"journal":"Cells, 10(10)","doi":"10.3390/cells10102543","pmid":"34685523","tags":["pain","neuroscience","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The dual FAAH/MAGL inhibitor JZL195 significantly reduced nitroglycerin-induced trigeminal hyperalgesia and pain-associated behavior, likely via CB1 receptors. It decreased CGRP and cytokine gene expression in both central (cervical spinal cord) and peripheral (trigeminal ganglion) structures, plus reduced CGRP serum levels. However, it did not improve nitroglycerin-induced hypomotility or anxiety.","whyItMatters":"Individual FAAH or MAGL inhibitors have shown promise for migraine. Dual inhibition may provide synergistic pain relief by boosting both anandamide and 2-AG simultaneously, with broader anti-inflammatory effects across central and peripheral pain pathways.","specificNumbers":"JZL195 reduced trigeminal hyperalgesia and pain behavior via CB1; decreased CGRP gene expression in cervical spinal cord and trigeminal ganglion; reduced CGRP serum levels; decreased cytokine gene expression centrally and peripherally; no effect on hypomotility or anxiety","methodology":"Rats received nitroglycerin to induce migraine-like features, then JZL195 (dual FAAH/MAGL inhibitor). Assessed orofacial formalin test (trigeminal pain), open field (activity/anxiety), CGRP serum levels, and gene expression of CGRP and cytokines in spinal cord and trigeminal ganglion.","limitations":"Acute animal model of migraine, not chronic. Dual inhibition may have more side effects than selective inhibition. CB1-mediated effects could include psychoactive properties. Does not address tolerability or abuse potential."},{"rthcId":"RTHC-03173","title":"Morphine Induces Upregulation of Neuronally Expressed CB2 Receptors in the Spinal Dorsal Horn of Rats.","authors":"Grenier, Patrick; Sunavsky, Adam; Olmstead, Mary C","year":2021,"journal":"Cannabis and cannabinoid research, 6(2), 137-147","doi":"10.1089/can.2020.0004","pmid":"33912678","tags":["pain","neuroscience","addiction","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB2 receptors were predominantly expressed on neurons (NeuN-labeled cells) rather than microglia in the spinal dorsal horn. Chronic morphine administration (10 days) significantly increased CB2 receptor labeling across all surgery groups in both deep and superficial dorsal horn regions. Morphine produced a larger CB2 upregulation than surgery alone.","whyItMatters":"The synergistic pain-relieving effects of opioids and cannabinoids are well-documented but poorly understood. This finding that morphine upregulates neuronal CB2 receptors suggests a mechanism through which opioids may prime the system for cannabinoid-mediated pain relief.","specificNumbers":"24 rats; 3 surgery groups x 2 drug conditions; CB2 predominantly on NeuN+ neurons; morphine significantly increased CB2 in deep and superficial dorsal horn; morphine effect larger than CCI surgery effect","methodology":"24 male Sprague Dawley rats assigned to chronic constriction injury (CCI), sham surgery, or pain-naive groups, with half receiving daily morphine (5 mg/kg) for 10 days. Fluorescent immunohistochemistry on spinal cord sections assessed CB2 colocalization with neuronal (NeuN) and microglial (CD11b) markers.","limitations":"Male rats only. Immunohistochemistry provides expression data but not functional receptor activity. Single morphine dose and duration tested. Does not prove the CB2 upregulation translates to enhanced cannabinoid analgesia."},{"rthcId":"RTHC-03174","title":"Application of sulphate and cytokinin in assisted arsenic phytoextraction by industrial Cannabis sativa L.","authors":"Grifoni, Martina; Rosellini, Irene; Petruzzelli, Gianniantonio; Pedron, Francesca; Franchi, Elisabetta; Barbafieri, Meri","year":2021,"journal":"Environmental science and pollution research international, 28(34), 47294-47305","doi":"10.1007/s11356-021-14074-3","pmid":"33890221","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03175","title":"Drugs of Abuse and Heart Failure.","authors":"Grubb, Alex F; Greene, Stephen J; Fudim, Marat; Dewald, Tracy; Mentz, Robert J","year":2021,"journal":"Journal of cardiac failure, 27(11), 1260-1275","doi":"10.1016/j.cardfail.2021.05.023","pmid":"34133967","tags":["cardiovascular","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis has complex cardiovascular effects depending on consumption method, amount, and cannabinoid content. THC can increase sympathetic tone, cause vascular dysfunction, and may increase myocardial infarction risk. CBD is cardioprotective in preclinical studies and is a potential therapeutic target. The effects are complicated by the interaction between these opposing cannabinoid profiles.","whyItMatters":"Heart failure patients may use cannabis, and clinicians need to understand the opposing cardiovascular effects of THC and CBD to provide appropriate guidance, especially as legal access increases.","specificNumbers":"THC: increases sympathetic tone, causes vascular dysfunction, may increase MI risk; CBD: cardioprotective in preclinical studies; effects vary by consumption method, dose, and cannabinoid content","methodology":"Narrative review of the cardiovascular effects of alcohol, tobacco, cannabis, and cocaine on heart failure development and outcomes.","limitations":"Narrative review with limited cannabis-specific clinical trial data. Most evidence is preclinical for CBD cardioprotection. Cannabis cardiovascular research is confounded by tobacco co-use. Heart failure-specific cannabis data are sparse."},{"rthcId":"RTHC-03176","title":"Cannabis use assessment and its impact on pain in rheumatologic diseases: a systematic review and meta-analysis.","authors":"Guillouard, M; Authier, N; Pereira, B; Soubrier, M; Mathieu, S","year":2021,"journal":"Rheumatology (Oxford, England), 60(2), 549-556","doi":"10.1093/rheumatology/keaa534","pmid":"33159797","tags":["pain","medical-cannabis","inflammation"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"40.4% of rheumatology patients reported ever using cannabis and 15.3% reported current use. Use was highest in fibromyalgia (68.2%) compared to RA/lupus (26%). Cannabis use was associated with significant pain reduction (pooled effect size -1.75, 95% CI: -2.75 to -0.76). However, cannabis users were younger, more often smokers (OR 2.91), more often unemployed (OR 2.40), and had higher baseline pain.","whyItMatters":"Cannabis use is common among rheumatology patients and often undisclosed. Clinicians should proactively ask about cannabis use and understand the available evidence on pain effects to guide clinical conversations.","specificNumbers":"10,873 patients total; 2,900 reported cannabis use (40.4%); 15.3% current users; fibromyalgia: 68.2% ever use; RA/lupus: 26%; pain reduction pooled effect size -1.75 (95% CI: -2.75, -0.76); cannabis users younger, more smokers (OR 2.91), more unemployed (OR 2.40)","methodology":"Systematic review and meta-analysis searching databases through June 2020. Metaproportion calculated cannabis use incidence. Standardized mean differences assessed cannabis effects on pain. Inverse-variance method used for pooling.","limitations":"Heterogeneous study designs and cannabis products. Observational data cannot establish causation for pain reduction. Cannabis users had higher baseline pain, introducing confounding. Self-reported outcomes. Small number of studies for some analyses."},{"rthcId":"RTHC-03177","title":"Trends in Prevalence and Outcomes of Cannabis Use Among Chronic Obstructive Pulmonary Disease Hospitalizations: A Nationwide Population-Based Study 2005-2014.","authors":"Gunasekaran, Kulothungan; Voruganti, Dinesh C; Singh Rahi, Mandeep; Elango, Kalaimani; Ramalingam, Sathishkumar; Geeti, Adiba; Kwon, Jeff","year":2021,"journal":"Cannabis and cannabinoid research, 6(4), 340-348","doi":"10.1089/can.2020.0133","pmid":"33998884","tags":["respiratory","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 6,073,862 COPD hospitalizations, 24,546 (0.4%) had concurrent cannabis use. Cannabis users had significantly lower odds of in-hospital mortality (OR 0.624, p=0.031) and pneumonia (OR 0.882, p=0.006). Lower odds of sepsis (OR 0.749) and acute respiratory failure (OR 0.995) were also observed but did not reach statistical significance.","whyItMatters":"The finding that cannabis use was associated with better rather than worse COPD hospitalization outcomes is counterintuitive and challenges assumptions about cannabis and respiratory health, warranting further investigation.","specificNumbers":"6,073,862 COPD hospitalizations; 24,546 (0.4%) with cannabis use; 60% of cannabis users aged 50-64; mortality OR 0.624 (p=0.031); pneumonia OR 0.882 (p=0.006); sepsis OR 0.749 (p=0.113); respiratory failure OR 0.995 (p=0.941)","methodology":"Retrospective analysis of the National Inpatient Sample (NIS) 2005-2014, identifying COPD hospitalizations with and without cannabis use via hospital discharge codes. Logistic regression assessed odds of mortality, pneumonia, sepsis, and respiratory failure.","limitations":"Administrative database (NIS) relies on discharge codes which may under-identify cannabis use. Cannot control for cannabis type, frequency, or method of use. Healthy user bias: cannabis users may be younger and less sick at baseline. Observational design."},{"rthcId":"RTHC-03178","title":"The Yin and Yang of Cannabis: A Systematic Review of Human Neuroimaging Evidence of the Differential Effects of Δ9-Tetrahydrocannabinol and Cannabidiol.","authors":"Gunasekera, Brandon; Davies, Cathy; Martin-Santos, Rocio; Bhattacharyya, Sagnik","year":2021,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 6(6), 636-645","doi":"10.1016/j.bpsc.2020.10.007","pmid":"33414100","tags":["neuroscience","psychosis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Despite heterogeneous methods, an overall pattern of opposite THC and CBD effects was evident, primarily from head-to-head challenge studies. THC increased and CBD decreased brain activation and blood flow, with opposing effects most consistent in the striatum, parahippocampus, anterior cingulate/medial prefrontal cortex, and amygdala.","whyItMatters":"The brain regions where THC and CBD have opposing effects overlap with regions implicated in psychosis (striatum, parahippocampus). This may explain why THC increases psychosis risk while CBD has antipsychotic potential, and identifies specific neural targets for research.","specificNumbers":"Opposite effects identified in: striatum, parahippocampus, anterior cingulate/medial prefrontal cortex, amygdala; THC generally increased activation and blood flow; CBD generally decreased both; head-to-head studies provided strongest evidence","methodology":"Systematic search and synthesis of human neuroimaging studies investigating acute effects of THC and CBD on brain function, using fMRI, PET, SPECT, ASL, MRS, and EEG techniques.","limitations":"Marked heterogeneity across studies in design, dosing, imaging modality, and analysis methods. Relatively few head-to-head THC vs. CBD comparison studies. Acute effects may not reflect chronic use patterns. Publication bias possible."},{"rthcId":"RTHC-03179","title":"Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.","authors":"Gunning, Boudewijn; Mazurkiewicz-Bełdzińska, Maria; Chin, Richard F M; Bhathal, Hari; Nortvedt, Charlotte; Dunayevich, Eduardo; Checketts, Daniel","year":2021,"journal":"Acta neurologica Scandinavica, 143(2), 154-163","doi":"10.1111/ane.13351","pmid":"32969022","tags":["cbd","epilepsy","drug-interactions"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"CBD reduced primary seizure frequency versus placebo in LGS (treatment ratio 0.70) and Dravet syndrome (0.71) in the overall population. Effects were larger in patients on clobazam (LGS: 0.56; DS: 0.63). CBD improved 50% responder rates, total seizure frequency, seizure-free days, and global impression of change. Somnolence and sedation were more common with CBD plus clobazam. Elevated transaminases occurred mainly in patients on concomitant valproate.","whyItMatters":"This meta-analysis directly addresses the critical question of whether CBD's seizure reduction is partly driven by its interaction with clobazam, showing CBD is effective in both clobazam users and the overall population, but more so in the combination.","specificNumbers":"714 total patients (396 LGS, 318 DS); overall seizure reduction: LGS 0.70, DS 0.71; with clobazam: LGS 0.56, DS 0.63; higher somnolence/sedation with CBD+clobazam; elevated transaminases mainly with concomitant valproate","methodology":"Subgroup analysis of patients on clobazam and meta-analysis by syndrome across four randomized, placebo-controlled phase 3 trials of pharmaceutical-grade CBD (Epidiolex/Epidyolex; 10 or 20 mg/kg/day for 14 weeks). 396 LGS patients (49% on clobazam) and 318 DS patients (64% on clobazam).","limitations":"Post-hoc subgroup analysis, not pre-specified in original trials. Cannot fully separate CBD's direct effects from clobazam interaction effects. 14-week treatment period may not reflect long-term outcomes. Industry-sponsored trials."},{"rthcId":"RTHC-03180","title":"Cannabinoids for skin diseases and hair regrowth.","authors":"Gupta, Aditya K; Talukder, Mesbah","year":2021,"journal":"Journal of cosmetic dermatology, 20(9), 2703-2711","doi":"10.1111/jocd.14352","pmid":"34363728","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03181","title":"The Effect of Medical Cannabis on Pain Level and Quality of Sleep among Rheumatology Clinic Outpatients.","authors":"Habib, George; Khazin, Fadi; Artul, Suheil","year":2021,"journal":"Pain research & management, 2021, 1756588","doi":"10.1155/2021/1756588","pmid":"34531934","tags":["medical-cannabis","pain","sleep"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Patients with neuropathic problems reported the largest pain reduction (83%) and sleep improvement (87%), while those with inflammatory conditions saw the smallest pain reduction (57%). THC concentration, duration of use, and dosage each independently correlated with pain relief.","whyItMatters":"Rheumatology conditions like fibromyalgia are notoriously difficult to treat. This study captures real-world outcomes across multiple condition types within a single clinic population, offering a comparative snapshot of how different rheumatology patients respond to medical cannabis.","specificNumbers":"351 patients located, 319 completed questionnaires. 82% had fibromyalgia. Mean pain reduction: 77% (fibromyalgia), 82% (mechanical), 83% (neuropathic), 57% (inflammatory). Mean sleep improvement: 78%, 71%, 87%, 76% respectively. Average monthly dose: 31-36g. Mean THC content: 18.38%.","methodology":"Cross-sectional phone survey of 351 rheumatology clinic patients licensed for medical cannabis in Israel. Patients reported pain reduction and sleep improvement. Researchers analyzed correlations between cannabis parameters and outcomes.","limitations":"Cross-sectional design with no control group. Self-reported outcomes subject to recall and placebo effects. Survivorship bias: patients who stopped cannabis were not captured. No standardized pain or sleep measurement tools used."},{"rthcId":"RTHC-03182","title":"The impact of medical cannabis consumption on the oral flora and saliva.","authors":"Habib, George; Steinberg, Doron; Jabbour, Adel","year":2021,"journal":"PloS one, 16(2), e0247044","doi":"10.1371/journal.pone.0247044","pmid":"33577600","tags":["medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Lactobacillus growth scores rose significantly at both week 1 (p=0.033) and week 4 (p=0.025) compared to baseline. Streptococcus mutans showed a non-significant trend toward increase at week 4 (p=0.058). Saliva flow and pH remained unchanged.","whyItMatters":"Cannabis is typically consumed orally (smoked, vaped, or ingested), meaning the oral cavity is the first biological system exposed. Changes in oral microbiome composition could have downstream effects on dental health.","specificNumbers":"16 patients enrolled, 14 female, mean age 52.8 years. Lactobacillus scores: 2.59 (baseline), 3.1 (week 1, p=0.033), 3.3 (week 4, p=0.025). S. mutans scores: 1.8 (baseline), 1.6 (week 1), 2.4 (week 4, p=0.058).","methodology":"Prospective study of 16 rheumatology patients newly approved for medical cannabis. Saliva samples were collected at baseline, week 1, and week 4, then measured for volume, pH, and microbial growth of S. mutans and Lactobacillus using a specialized culture kit.","limitations":"Very small sample (16 patients). No control group. Short follow-up (4 weeks). Most participants were female fibromyalgia patients, limiting generalizability."},{"rthcId":"RTHC-03183","title":"Cognitive performance and lifetime cannabis use in patients with first-episode schizophrenia spectrum disorder.","authors":"Hájková, M; Knížková, K; Siroňová, A; Keřková, B; Jonáš, J; Šustová, P; Dorazilová, A; Rodriguez, M","year":2021,"journal":"Cognitive neuropsychiatry, 26(4), 257-272","doi":"10.1080/13546805.2021.1924649","pmid":"33973827","tags":["psychosis","cognition"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"First-episode schizophrenia patients with lifetime cannabis use (n=30) showed better cognitive performance than non-using patients (n=53), with the most prominent difference in visual memory. The two patient groups did not differ in symptom severity or medication. Among healthy controls, cannabis use made no cognitive difference.","whyItMatters":"The finding that cannabis-using schizophrenia patients performed better cognitively challenges the assumption that cannabis worsens cognitive outcomes in psychosis. This pattern is consistent with the \"dual pathway\" hypothesis, where cannabis-related psychosis may require lower genetic vulnerability.","specificNumbers":"30 first-episode schizophrenia cannabis users, 53 schizophrenia non-users, 20 healthy control users, 49 healthy control non-users. Cannabis-using patients showed superior visual memory compared to non-using patients.","methodology":"Case-control study comparing cognitive test performance across four groups: first-episode schizophrenia patients who used cannabis (n=30), schizophrenia patients who did not (n=53), healthy controls who used cannabis (n=20), and healthy controls who did not (n=49). All underwent extensive neurocognitive assessment.","limitations":"Small sample sizes. Cross-sectional design cannot determine causation. Lifetime cannabis use measured by questionnaire. Cannot distinguish between cannabis as cause vs. marker of different illness pathways."},{"rthcId":"RTHC-03184","title":"Communicating THC levels and 'dose' to consumers: Implications for product labelling and packaging of cannabis products in regulated markets.","authors":"Hammond, David","year":2021,"journal":"The International journal on drug policy, 91, 102509","doi":"10.1016/j.drugpo.2019.07.004","pmid":"31351756","tags":["potency","harm-reduction","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review identified that consumers struggle with numeric THC information (mg vs. percentage), THC levels are communicated inconsistently across product types (flower, edibles, concentrates), and current labels provide little guidance on how THC content translates to actual consumption amounts for specific products.","whyItMatters":"As cannabis markets expand, adverse events from high-potency products (especially edibles) have increased. Effective labeling is one of the most basic consumer protection tools, yet current practices may leave users unable to control their intake.","specificNumbers":"No specific statistics provided. The paper focuses on regulatory framework analysis and proposes five labeling principles.","methodology":"Policy review examining cannabis labeling and packaging regulations across legalized jurisdictions. Identified five principles for effective cannabis labeling: numeric THC labeling, standard servings, dose expression across product forms, and dose-unit packaging.","limitations":"Policy analysis without original data collection. Limited empirical evidence on consumer comprehension of cannabis labels. Recommendations are theoretical and untested."},{"rthcId":"RTHC-03185","title":"Decreasing perceived risk associated with regular cannabis use among older adults in the United States from 2015 to 2019.","authors":"Han, Benjamin H; Funk-White, Makaya; Ko, Roxanne; Al-Rousan, Tala; Palamar, Joseph J","year":2021,"journal":"Journal of the American Geriatrics Society, 69(9), 2591-2597","doi":"10.1111/jgs.17213","pmid":"34037250","tags":["seniors","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Perceived risk of regular cannabis use decreased 18.8% overall among older adults. The sharpest drops occurred among those with kidney disease (32.1% decrease), asthma (31.7%), those who binge drink (31.3%), and never-married individuals (32.6%). People with two or more chronic conditions saw a 20.2% decrease.","whyItMatters":"Older adults with chronic conditions and high-risk behaviors are showing the fastest decline in perceived cannabis risk. This is notable because these are the same populations most likely to experience drug interactions or adverse effects from cannabis use.","specificNumbers":"18,794 adults 65+. Perceived risk dropped from 52.6% (2015) to 42.7% (2019). Largest relative decreases: never married (32.6%), kidney disease (32.1%), binge drinkers (31.3%), asthma (31.7%), tobacco users (26.8%), COPD (21.5%), past-year ED use (21.0%), 2+ chronic conditions (20.2%), heart disease (16.5%).","methodology":"Trend analysis of 18,794 adults aged 65+ from the 2015-2019 National Survey on Drug Use and Health (NSDUH), a nationally representative US survey. Examined perceived risk stratified by demographics, chronic diseases, substance use, and emergency department use.","limitations":"Cross-sectional survey data cannot determine causation. Self-reported perceived risk may not directly translate to behavior change. Does not capture actual cannabis use rates in this population."},{"rthcId":"RTHC-03186","title":"Associations of Suicidality Trends With Cannabis Use as a Function of Sex and Depression Status.","authors":"Han, Beth; Compton, Wilson M; Einstein, Emily B; Volkow, Nora D","year":2021,"journal":"JAMA network open, 4(6), e2113025","doi":"10.1001/jamanetworkopen.2021.13025","pmid":"34156452","tags":["mental-health","depression","sex-differences","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis use disorder was associated with substantially higher suicidality regardless of depression status. Among those without depression, suicidal ideation prevalence was 13.9% for women with CUD vs. 3.5% without, and 9.9% for men with CUD vs. 3.0% without. Suicide planning among those with both CUD and depression was 52% higher in women (23.7%) than men (15.6%). Overall suicidality increased 40-60% from 2008-2019 beyond what cannabis use and depression alone could explain.","whyItMatters":"This study separates the cannabis-suicidality association by sex and depression status, revealing that the link is strongest in women and persists even among those without depression. The finding that suicidality increased beyond what cannabis and depression explain points to additional unmeasured factors.","specificNumbers":"281,650 adults aged 18-34. Suicidality increased 1.4-1.6 times from 2008-2009 to 2018-2019 after controlling for CUD and depression. Among women without depression with CUD: 13.9% suicidal ideation vs. 3.5% without CUD. Suicide plan with CUD+depression: women 23.7%, men 15.6%.","methodology":"Cross-sectional analysis of 281,650 adults aged 18-34 from the 2008-2019 National Surveys on Drug Use and Health. Examined associations between cannabis use (daily, non-daily, CUD) and past-year suicidal ideation, plans, and attempts, stratified by sex and depression status.","limitations":"Cross-sectional data cannot establish whether cannabis use causes suicidality or reflects shared risk factors. Self-reported measures. CUD diagnosis based on DSM-IV criteria. Cannot account for all confounders."},{"rthcId":"RTHC-03187","title":"Association between perceived risk of harm and self-reported binge drinking, cigarette smoking, and marijuana smoking in young adults.","authors":"Hanauer, Matthew; Walker, Madison R; Machledt, Kendall; Ragatz, Melissa; Macy, Jonathan T","year":2021,"journal":"Journal of American college health : J of ACH, 69(4), 345-352","doi":"10.1080/07448481.2019.1676757","pmid":"31765288","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Students who perceived high risk of harm from marijuana smoking were significantly less likely to report using it. Age moderated this relationship: younger students showed a stronger link between perceived risk and actual marijuana use than older students. The same pattern held for binge drinking and cigarette smoking.","whyItMatters":"Perceived risk is one of the strongest predictors of substance use initiation. The finding that younger students show the tightest link between risk perception and marijuana use suggests that early college years may be a critical window for prevention messaging.","specificNumbers":"599 students aged 19-28. Age moderated the perceived risk-marijuana use relationship, with younger participants showing a stronger association. High perceived risk was associated with lower engagement in all three substance use behaviors.","methodology":"Cross-sectional study of 599 college students (ages 19-28) at a large Midwestern university, recruited October 2015 to December 2017. Hurdle regression tested associations between perceived risk and self-reported substance use, with demographic characteristics tested as moderators.","limitations":"Single university sample limits generalizability. Cross-sectional design. Self-reported substance use. Cannot determine whether perceived risk drives behavior or whether use changes perception."},{"rthcId":"RTHC-03188","title":"The Effect of Cannabis-Based Medicine on Neuropathic Pain and Spasticity in Patients with Multiple Sclerosis and Spinal Cord Injury: Study Protocol of a National Multicenter Double-Blinded, Placebo-Controlled Trial.","authors":"Hansen, Julie Schjødtz; Hansen, Rikke Middelhede; Petersen, Thor; Gustavsen, Stefan; Oturai, Annette Bang; Sellebjerg, Finn; Sædder, Eva Aggerholm; Kasch, Helge; Rasmussen, Peter Vestergaard; Finnerup, Nanna Brix; Svendsen, Kristina Bacher","year":2021,"journal":"Brain sciences, 11(9)","doi":"10.3390/brainsci11091212","pmid":"34573231","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03189","title":"The relationship between cannabis use and IVF outcome-a cohort study.","authors":"Har-Gil, Eden; Heled, Ayala; Dixon, Marjorie; Ahamed, Abdul Munaf Sultan; Bentov, Yaakov","year":2021,"journal":"Journal of cannabis research, 3(1), 42","doi":"10.1186/s42238-021-00099-5","pmid":"34493346","tags":["pregnancy","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Implantation rates were virtually identical: 40.74% for users vs. 41.13% for non-users. Ongoing pregnancy rates were 35.2% for users vs. 29.1% for non-users (not statistically significant). No significant differences were found in oocyte yield, fertilization rate, peak estradiol, sperm quality, or embryo quality.","whyItMatters":"Cannabis use during fertility treatment is a growing concern as legalization expands. This study provides early reassurance that light cannabis use may not significantly harm IVF outcomes, though the evidence is far from definitive.","specificNumbers":"722 patients total. 68 (9.4%) cannabis users, most light users. Implantation rate: 40.74% (users) vs. 41.13% (non-users). Ongoing pregnancy rate: 35.2% vs. 29.1% (not significant). No significant differences in any other outcome.","methodology":"Retrospective cohort study from a single Canadian IVF center. Of 722 non-donor IVF patients, 68 (9.4%) self-reported cannabis use (most described as light use). Compared IVF outcomes between users and non-users using Mann-Whitney, chi-square, and Kruskal-Wallis tests.","limitations":"Retrospective design. Small user group (68 patients). Self-reported cannabis use likely underestimates true prevalence. Most users were light users, so heavy use effects remain unknown. Single center."},{"rthcId":"RTHC-03190","title":"The effect of cannabis toxicity on a model microbiome bacterium epitomized by a panel of bioluminescent E. coli.","authors":"Harpaz, Dorin; Veltman, Boris; Sadeh, Yael; Marks, Robert S; Bernstein, Nirit; Eltzov, Evgeni","year":2021,"journal":"Chemosphere, 263, 128241","doi":"10.1016/j.chemosphere.2020.128241","pmid":"33297188","tags":["cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Only THC and THCA produced genotoxic (DNA-damaging) effects on E. coli. Other tested cannabinoids (including CBD, CBG, CBN, CBC, CBDV) caused cytotoxic or oxidative damage instead. Whole cannabis plant extracts were mostly genotoxic, and artificial mixtures of cannabinoids produced different response patterns than individual compounds, suggesting synergistic or antagonistic interactions.","whyItMatters":"The gut microbiome influences everything from immune function to mental health. Understanding exactly how different cannabinoids affect gut bacteria at the molecular level could help predict real-world microbiome consequences of cannabis use.","specificNumbers":"Nine cannabinoids tested. Six cannabis variety extracts. THC and THCA were the only genotoxic compounds. Other cannabinoids were cytotoxic or caused oxidative stress. Mixtures produced different patterns than individual compounds.","methodology":"Lab study using genetically modified bioluminescent E. coli bacteria carrying stress-responsive promoters linked to a lux operon. Nine individual cannabinoids, extracts from six cannabis varieties, and artificial cannabinoid mixtures were tested to identify specific toxic mechanisms (genotoxic, cytotoxic, or oxidative).","limitations":"E. coli is only one component of the gut microbiome. Lab conditions do not replicate the gut environment. Concentrations used may not reflect what reaches the gut after oral consumption. No human or animal microbiome data."},{"rthcId":"RTHC-03191","title":"The Effects of Alcohol and Cannabis Use on the Cortical Thickness of Cognitive Control and Salience Brain Networks in Emerging Adulthood: A Co-twin Control Study.","authors":"Harper, Jeremy; Malone, Stephen M; Wilson, Sylia; Hunt, Ruskin H; Thomas, Kathleen M; Iacono, William G","year":2021,"journal":"Biological psychiatry, 89(10), 1012-1022","doi":"10.1016/j.biopsych.2021.01.006","pmid":"33726938","tags":["neuroscience","cognition","youth","genetics"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"Greater alcohol misuse was linked to thinner cortex in prefrontal, temporal, insula, and parietal regions, predominantly right-lateralized. Cannabis use showed no association with cortical thickness. Co-twin analyses revealed that alcohol effects reflected both genetic predisposition to misuse AND direct alcohol exposure effects, particularly in lateral prefrontal and frontal/parietal medial areas.","whyItMatters":"This is one of the few studies that can distinguish between brain differences that existed before substance use (genetic predisposition) and those caused by use itself. The finding that cannabis showed no cortical thickness effects, while alcohol showed both predispositional and exposure effects, has implications for how we rank relative brain risks.","specificNumbers":"436 twins aged 24. Alcohol misuse linked to reduced thickness in prefrontal, temporal, insula, precuneus, and parietal regions. Effects were predominantly right-lateralized. Cannabis showed no associations with cortical thickness in any region.","methodology":"Co-twin control study of 436 population-based twins aged 24. Dimensional alcohol and cannabis use measures across emerging adulthood were compared with MRI-assessed cortical thickness in cognitive control and salience network regions. The twin design allowed separation of substance exposure effects from shared genetic/environmental factors.","limitations":"Cross-sectional MRI at age 24 with retrospective substance use history. Cannot capture earlier brain changes that may have resolved. Cannabis use levels in this sample may not have been heavy enough to detect effects."},{"rthcId":"RTHC-03192","title":"Pharmacological Properties, Therapeutic Potential and Molecular Mechanisms of JWH133, a CB2 Receptor-Selective Agonist.","authors":"Hashiesh, Hebaallah Mamdouh; Sharma, Charu; Goyal, Sameer N; Jha, Niraj Kumar; Ojha, Shreesh","year":2021,"journal":"Frontiers in pharmacology, 12, 702675","doi":"10.3389/fphar.2021.702675","pmid":"34393784","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03193","title":"A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid.","authors":"Hashiesh, Hebaallah Mamdouh; Sharma, Charu; Goyal, Sameer N; Sadek, Bassem; Jha, Niraj Kumar; Kaabi, Juma Al; Ojha, Shreesh","year":2021,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 140, 111639","doi":"10.1016/j.biopha.2021.111639","pmid":"34091179","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03194","title":"Genetic Liability to Cannabis Use Disorder and COVID-19 Hospitalization.","authors":"Hatoum, Alexander S; Morrison, Claire L; Colbert, Sarah M C; Winiger, Evan A; Johnson, Emma C; Agrawal, Arpana; Bogdan, Ryan","year":2021,"journal":"Biological psychiatry global open science, 1(4), 317-323","doi":"10.1016/j.bpsgos.2021.06.005","pmid":"34235496","tags":["addiction","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The genetic correlation between CUD and COVID-19 hospitalization was 0.423 (p = 1.33 x 10^-6). This association remained significant after controlling for genetic liability to tobacco use, alcohol misuse, BMI, lung function, education, COPD, hypertension, diabetes, and other factors (b = 0.381-0.539). However, causal inference models found no evidence that CUD directly causes severe COVID.","whyItMatters":"Finding shared genetic architecture between CUD and COVID-19 severity suggests overlapping biological pathways, potentially involving immune function or inflammation. This goes beyond behavioral risk factors like smoking to point toward deeper biological connections.","specificNumbers":"CUD GWAS: 14,080 cases, 343,726 controls. COVID-19 hospitalization GWAS: 9,373 cases, 1,197,256 controls. Genetic correlation: r_G = 0.423. Association persisted after adjusting for 13 covariates (b = 0.381-0.539). No significant causal effect detected.","methodology":"Genomic analysis using summary statistics from genome-wide association studies of CUD (14,080 cases, 343,726 controls) and COVID-19 hospitalization (9,373 cases, 1,197,256 controls). Genetic correlation was estimated and adjusted for covariates using genomic structural equation modeling. Latent causal variable models tested for putative causation.","limitations":"Genetic correlation analyses cannot establish causation. GWAS data were from pre-pandemic CUD studies and early pandemic COVID-19 data. Cannot determine specific shared biological pathways. Results apply at population level, not individual prediction."},{"rthcId":"RTHC-03195","title":"Evaluation of the impact of marijuana use on semen quality: a prospective analysis.","authors":"Hehemann, Marah C; Raheem, Omer A; Rajanahally, Saneal; Holt, Sarah; Chen, Tony; Fustok, Judy N; Song, Kelly; Rylander, Heather; Chow, Emma; Ostrowski, Kevin A; Muller, Charles H; Walsh, Thomas J","year":2021,"journal":"Therapeutic advances in urology, 13, 17562872211032484","doi":"10.1177/17562872211032484","pmid":"34367341","tags":["pregnancy"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Current marijuana use was associated with 2.15 times higher odds of abnormal strict morphology and 2.76 times higher odds of low semen volume. However, current users had 0.47 times the odds of abnormal motility (meaning better motility). Past users also showed higher rates of abnormal morphology (53.4%) compared to never-users (33.1%). 43% of men in the infertility clinic reported ever using marijuana.","whyItMatters":"With 43% of infertility patients reporting marijuana use, understanding its effects on semen quality is clinically relevant. The mixed findings (worse morphology and volume, better motility) complicate simple messaging about marijuana and fertility.","specificNumbers":"409 patients. 174 (43%) ever-users: 71 current, 103 past. Abnormal morphology: 33.1% (never), 50.7% (current), 53.4% (past). Current use OR for abnormal morphology: 2.15 (95% CI: 1.21-3.79). OR for low volume: 2.76 (95% CI: 1.19-6.42). OR for abnormal motility: 0.47 (95% CI: 0.25-0.91).","methodology":"Prospective study of 409 men presenting for infertility evaluation at one institution (July 2017-April 2018). Semen analysis performed per WHO 5th Edition criteria. Marijuana use assessed via reproductive health questionnaire. Multivariate logistic regression controlled for confounders.","limitations":"Infertility clinic population may not represent general population. Self-reported marijuana use. Cannot determine dose-response. Retrospective questionnaire for past use. Confounders like other substance use not fully controlled."},{"rthcId":"RTHC-03196","title":"Effectiveness of attentional bias modification training as add-on to regular treatment in alcohol and cannabis use disorder: A multicenter randomized control trial.","authors":"Heitmann, Janika; van Hemel-Ruiter, Madelon E; Huisman, Mark; Ostafin, Brian D; Wiers, Reinout W; MacLeod, Colin; DeFuentes-Merillas, Laura; Fledderus, Martine; Markus, Wiebren; de Jong, Peter J","year":2021,"journal":"PloS one, 16(6), e0252494","doi":"10.1371/journal.pone.0252494","pmid":"34086751","tags":["addiction","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"No significant differences emerged between the ABM group and control groups on any measure: substance use, craving, relapse rates, attentional bias, depression, anxiety, or stress, either at post-test or at 6- and 12-month follow-ups. The null results held across all time points.","whyItMatters":"Attentional bias (automatic attention toward substance-related cues) has been theorized as a key mechanism in addiction persistence. This well-designed trial found no support for ABM as an add-on treatment, raising questions about whether targeting attention is the right approach.","specificNumbers":"169 participants: 50% ABM+TAU, 25% placebo+TAU, 25% TAU only. No significant differences on any outcome at any time point. Measures included substance use, craving, relapse, attentional bias, depression, anxiety, and stress.","methodology":"Multicenter RCT with 169 participants diagnosed with alcohol or cannabis use disorder. Randomly assigned to treatment as usual (TAU) plus attentional bias modification (ABM), TAU plus placebo training, or TAU only. The ABM used a home-delivered, multi-session internet program called the Bouncing Image Training Task. Outcomes assessed at baseline, post-test, 6 months, and 12 months.","limitations":"Mixed treatment goals (some pursuing moderation, others abstinence) may have diluted effects. The specific ABM task may not have targeted the right attentional process (engagement vs. disengagement). Home-based delivery reduces compliance monitoring."},{"rthcId":"RTHC-03197","title":"Sex Differences in Tolerance to Delta-9-Tetrahydrocannabinol in Mice With Cisplatin-Evoked Chronic Neuropathic Pain.","authors":"Henderson-Redmond, Angela N; Crawford, LaTaijah C; Sepulveda, Diana E; Hale, David E; Lesperance, Julia J; Morgan, Daniel J","year":2021,"journal":"Frontiers in molecular biosciences, 8, 684115","doi":"10.3389/fmolb.2021.684115","pmid":"34250019","tags":["pain","sex-differences","tolerance","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Female mice developed tolerance to the anti-allodynic (pain-relieving) effects of both 6 mg/kg and 10 mg/kg THC faster than males. A mutation (S426A/S430A) designed to reduce CB1 receptor desensitization did not alter tolerance development in either sex. THC pain relief was blocked by the CB1 antagonist rimonabant and partially blocked by the CB2 inverse agonist SR144528.","whyItMatters":"Tolerance to cannabinoid pain relief is a major clinical limitation. The finding that females develop tolerance faster has direct relevance for dosing considerations, as women may need different treatment strategies for long-term cannabinoid pain management.","specificNumbers":"Two THC doses tested: 6 and 10 mg/kg. Females developed tolerance faster at both doses. S426A/S430A mutation did not alter tolerance. Rimonabant (CB1 antagonist) fully blocked THC effects. SR144528 (CB2 inverse agonist) partially blocked effects.","methodology":"Male and female S426A/S430A mutant mice and wild-type littermates received four weekly cisplatin injections (5 mg/kg) to induce chronic neuropathic pain. Mice were then tested for tolerance to THC anti-allodynic effects at 6 and 10 mg/kg doses. CB1 and CB2 receptor involvement was confirmed with selective antagonists.","limitations":"Mouse model may not directly translate to human pain. Cisplatin-induced neuropathy is a specific pain type. Only two THC doses tested. The S426A/S430A mutation finding is negative, limiting mechanistic insight."},{"rthcId":"RTHC-03198","title":"The Influence of Cannabis and Nicotine Co-use on Neuromaturation: A Systematic Review of Adolescent and Young Adult Studies.","authors":"Hernandez Mejia, Margie; Wade, Natasha E; Baca, Rachel; Diaz, Vanessa G; Jacobus, Joanna","year":2021,"journal":"Biological psychiatry, 89(2), 162-171","doi":"10.1016/j.biopsych.2020.09.021","pmid":"33334432","tags":["youth","neuroscience","cognition"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabis and nicotine showed independent negative cognitive effects, but when used together, nicotine appeared to mask some cannabis-related cognitive deficits. Preliminary neuroimaging evidence pointed to hippocampal volume differences in co-users. No structural neuroimaging studies examined cannabis-nicotine co-use in adolescent-only populations.","whyItMatters":"Cannabis and nicotine are frequently co-used, especially among young people. If nicotine masks cannabis-related cognitive problems, studies that do not account for co-use could systematically underestimate cannabis effects on the developing brain.","specificNumbers":"1,107 articles screened, 12 met inclusion criteria. Age range: 13-35 years. Preliminary evidence for hippocampal volume differences in co-users. No adolescent-only structural neuroimaging studies found.","methodology":"Systematic review searching peer-reviewed articles for studies examining cannabis and nicotine/tobacco co-use in ages 13-35 (or nonadult animal subjects). From 1,107 initial articles, 12 met inclusion criteria requiring joint consideration of both substances and neurocognitive or neuroimaging outcomes.","limitations":"Only 12 studies met criteria, limiting conclusions. Most studies were cross-sectional. No longitudinal studies specifically designed to examine co-use effects on brain development. Cannot determine mechanisms of the masking effect."},{"rthcId":"RTHC-03199","title":"Prevalence of cannabis use, disorder, and medical card possession in U.S. military veterans: Results from the 2019-2020 National Health and Resilience in Veterans Study.","authors":"Hill, Melanie L; Loflin, Mallory; Nichter, Brandon; Norman, Sonya B; Pietrzak, Robert H","year":2021,"journal":"Addictive behaviors, 120, 106963","doi":"10.1016/j.addbeh.2021.106963","pmid":"33964583","tags":["mental-health","addiction","seniors"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis use prevalence among veterans was estimated at 11.9%, up from 9% in 2014. Among younger veterans, 20.2% reported use and 5.6% screened positive for CUD. Veterans with psychiatric conditions had use rates of 24-30% and CUD rates of 8.9-13%. Depression was independently associated with CUD (OR=2.76). Physical disability (OR=3.59) and combat veteran status (OR=2.84) most strongly predicted medical card possession.","whyItMatters":"Veteran cannabis use appears to be increasing at a time when more states are legalizing. The concentration of use among veterans with psychiatric conditions raises questions about whether cannabis is being used as self-medication and whether it helps or complicates their mental health care.","specificNumbers":"4,069 veterans. Overall use: 11.9%. CUD: 2.7%. Medical card: 1.5%. Younger veterans: 20.2% use, 5.6% CUD. Psychiatric conditions: 24-30% use, 8.9-13% CUD. Depression OR for CUD: 2.76. Physical disability OR for medical card: 3.59.","methodology":"Cross-sectional analysis of the 2019-2020 National Health and Resilience in Veterans Study (NHRVS), a nationally representative survey of 4,069 veterans ages 22-99. Assessed past-6-month cannabis use, CUD symptoms, and medical cannabis card possession.","limitations":"Cross-sectional design. Self-reported cannabis use and CUD screening (not clinical diagnosis). Cannot determine whether cannabis use preceded or followed psychiatric conditions. Past-6-month use window may miss some users."},{"rthcId":"RTHC-03200","title":"Comparative associations of problematic alcohol and cannabis use with suicidal behavior in U.S. military veterans: A population-based study.","authors":"Hill, Melanie L; Nichter, Brandon; Loflin, Mallory; Norman, Sonya B; Pietrzak, Robert H","year":2021,"journal":"Journal of psychiatric research, 135, 135-142","doi":"10.1016/j.jpsychires.2021.01.004","pmid":"33477057","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among veterans with AUD, 8.7% also had CUD, while 33.3% of those with CUD also had AUD. CUD alone carried higher odds of suicidal ideation and planning than AUD alone. Compared to AUD-only veterans, those with CUD-only had 6.1 times higher odds of lifetime suicide planning and 2.6 times higher odds of lifetime suicidal ideation. Comorbid AUD/CUD carried 3.3 times higher odds of past-year suicidal ideation vs. AUD alone.","whyItMatters":"Veterans have elevated suicide risk, and substance use disorders are known contributors. This study reveals that CUD may be a stronger indicator of suicide risk than AUD in veterans, challenging the typical clinical focus on alcohol as the primary substance concern.","specificNumbers":"4,069 veterans. CUD-only vs. AUD-only: OR 6.1 for lifetime suicide plans, OR 2.6 for lifetime ideation, OR 2.4 for past-year ideation. AUD/CUD comorbid vs. AUD-only: OR 3.3 for past-year ideation, OR 1.9 for lifetime ideation, OR 1.7 for lifetime plans. All ORs adjusted for psychiatric covariates.","methodology":"Cross-sectional analysis of 4,069 veterans from the 2019-2020 NHRVS. Compared past-year and lifetime suicidal ideation, plans, and attempts across groups: AUD only, CUD only, comorbid AUD/CUD, and neither. Odds ratios adjusted for sociodemographic, military, trauma, and psychiatric factors.","limitations":"Cross-sectional design cannot establish causation. CUD and suicidality may share underlying risk factors (trauma, depression). Screening-based CUD identification, not clinical diagnosis. Cannot determine temporal ordering of CUD and suicidality."},{"rthcId":"RTHC-03201","title":"Burden of cannabis use and disorder in the U.S. veteran population: Psychiatric comorbidity, suicidality, and service utilization.","authors":"Hill, Melanie L; Nichter, Brandon M; Norman, Sonya B; Loflin, Mallory; Pietrzak, Robert H","year":2021,"journal":"Journal of affective disorders, 278, 528-535","doi":"10.1016/j.jad.2020.09.099","pmid":"33017681","tags":["mental-health","addiction","ptsd"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Compared to veterans who never used cannabis, those with any lifetime use had elevated odds (ORs 1.5-8.3) of current and lifetime PTSD, mood disorders, anxiety disorders, substance use disorders, suicidal ideation, suicide attempts, and mental health treatment use. Veterans with CUD had even higher odds (ORs 1.6-2.7) of these conditions compared to cannabis users without CUD.","whyItMatters":"This study quantifies the psychiatric burden associated with cannabis use among veterans at a granular level, distinguishing between any use and disordered use. The graded relationship (more psychiatric burden with CUD than use alone) suggests dose-response dynamics.","specificNumbers":"3,157 veterans. Cannabis users vs. never-users: ORs 1.5-8.3 for psychiatric conditions and suicidality. CUD vs. non-CUD cannabis users: ORs 1.6-2.7 for PTSD, mood disorders, anxiety, nicotine and alcohol dependence, and suicidal ideation.","methodology":"Cross-sectional analysis of 3,157 veterans ages 21-96 from the National Health and Resilience in Veterans Study (NHRVS). Cannabis use and CUD assessed using the Mini International Neuropsychiatric Interview. Compared three groups: never-users, cannabis users without CUD, and those with lifetime CUD.","limitations":"Cross-sectional design prevents causal inference. Self-reported cannabis use. Cannot determine temporal ordering of cannabis use and psychiatric conditions. Veteran population may not generalize to civilians."},{"rthcId":"RTHC-03202","title":"Annual incidence of cannabis-induced psychosis, other substance-induced psychoses and dually diagnosed schizophrenia and cannabis use disorder in Denmark from 1994 to 2016.","authors":"Hjorthøj, Carsten; Larsen, Maria Oku; Starzer, Marie Stefanie Kejser; Nordentoft, Merete","year":2021,"journal":"Psychological medicine, 51(4), 617-622","doi":"10.1017/S0033291719003532","pmid":"31839011","tags":["psychosis","legalization","potency"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-induced psychosis incidence more than doubled from 2.8 per 100,000 in 2006 to 6.1 per 100,000 in 2016. A corresponding increase occurred in dual diagnoses of schizophrenia with cannabis use disorder. In contrast, alcohol-induced psychosis decreased over the same period, and other substance-induced psychoses showed no trend.","whyItMatters":"The selective increase in cannabis-induced psychosis (while alcohol-induced psychosis declined and others remained stable) suggests this trend is specific to cannabis rather than reflecting general changes in diagnostic practices or healthcare access.","specificNumbers":"Cannabis-induced psychosis: 2.8 per 100,000 (2006) to 6.1 per 100,000 (2016). Alcohol-induced psychosis decreased. Other substance-induced psychoses showed no trend. Dual diagnosis (schizophrenia + CUD) also increased.","methodology":"National registry study using the Danish Psychiatric Central Research Register. Analyzed absolute incidence and incidence rates per 100,000 person-years for cannabis-induced psychosis, other substance-induced psychoses, and dual diagnosis (schizophrenia + CUD) from 1994 to 2016.","limitations":"Registry data depends on clinical diagnostic accuracy. Cannot directly link individual THC exposure levels to psychosis. Changes in help-seeking behavior or cannabis availability could partially explain trends."},{"rthcId":"RTHC-03203","title":"No evidence of associations between genetic liability for schizophrenia and development of cannabis use disorder.","authors":"Hjorthøj, Carsten; Uddin, Md Jamal; Wimberley, Theresa; Dalsgaard, Søren; Hougaard, David M; Børglum, Anders; Werge, Thomas; Nordentoft, Merete","year":2021,"journal":"Psychological medicine, 51(3), 479-484","doi":"10.1017/S0033291719003362","pmid":"31813396","tags":["psychosis","genetics","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Schizophrenia polygenic risk scores did not predict CUD in controls (HR=1.16, not significant) or in patients with other psychiatric disorders. However, ADHD polygenic risk did predict CUD (HR=1.27 per SD increase, and HR=2.02 for highest decile). CUD was a strong predictor of schizophrenia (HR=4.91), and adjusting for various polygenic risk scores did not weaken this association.","whyItMatters":"If shared genetics explained the cannabis-schizophrenia association, then genetic risk for schizophrenia should predict who develops CUD. It did not. This finding strengthens the case that cannabis use may have a more direct role in schizophrenia risk, rather than both being driven by the same genetic vulnerability.","specificNumbers":"88,637 individuals. Schizophrenia PRS predicting CUD in controls: HR=1.16 (95% CI 0.95-1.43, not significant). ADHD PRS predicting CUD: HR=1.27 (95% CI 1.08-1.50). CUD predicting schizophrenia: HR=4.91 (95% CI 4.36-5.53).","methodology":"Linked Danish nationwide registers with genetic information from neonatal bloodspots in 88,637 individuals. Compared polygenic risk scores for schizophrenia, ADHD, autism, and anorexia as predictors of CUD diagnosis across controls, schizophrenia patients, and patients with other psychiatric disorders.","limitations":"Polygenic risk scores capture only a fraction of genetic risk. Negative findings could reflect insufficient statistical power for schizophrenia PRS. Danish population may not generalize globally. Registry-based CUD diagnosis may miss milder cases."},{"rthcId":"RTHC-03204","title":"Blood and Oral Fluid Cannabinoid Profiles of Frequent and Occasional Cannabis Smokers.","authors":"Hoffman, Melissa A; Hubbard, Jacqueline A; Sobolesky, Philip M; Smith, Breland E; Suhandynata, Raymond T; Sanford, Sandra; Sones, Emily G; Ellis, Shannon; Umlauf, Anya; Huestis, Marilyn A; Grelotti, David J; Grant, Igor; Marcotte, Thomas D; Fitzgerald, Robert L","year":2021,"journal":"Journal of analytical toxicology, 45(8), 851-862","doi":"10.1093/jat/bkab078","pmid":"34173005","tags":["driving","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Frequent users had higher residual blood THC and were more likely to test positive before even smoking. Per se blood THC limits (up to 5 ng/mL) offered limited usefulness as biomarkers of recent use. Blood CBN at 1 ng/mL cutoff had 100% specificity but only 31.4% sensitivity. Oral fluid THC at 10 ng/mL showed the best overall performance (99.7% specificity, 82.4% sensitivity) for detecting use within 3 hours, but was still detectable in 23.2% of participants 4.4 hours post-smoking.","whyItMatters":"Several states have adopted per se THC driving limits, but this study shows these limits perform poorly at identifying recent use, especially in frequent users who may test positive without having used recently. This has direct implications for roadside testing fairness.","specificNumbers":"191 users (frequent and occasional). Blood THC ≥5 ng/mL at 6 hours: 14%. Oral fluid THC ≥5 ng/mL at 6 hours: 54%. Oral fluid THC 10 ng/mL cutoff: 99.7% specificity, 82.4% sensitivity for 3-hour window. Blood CBN 1 ng/mL: 100% specificity, 31.4% sensitivity.","methodology":"Randomized trial of 191 frequent (4+ times/week) and occasional (<4/week) cannabis users who smoked placebo, 5.9%, or 13.4% THC cannabis ad libitum. Blood, oral fluid, and breath samples collected before and up to 6 hours after smoking. Ten cannabinoids measured in oral fluid, 8 in blood, THC in breath via LC-MS/MS.","limitations":"Only tested smoked cannabis, not edibles or other routes. Laboratory conditions may not reflect real-world use. Detection windows may vary with different cannabis products. CBN levels may vary by cannabis strain."},{"rthcId":"RTHC-03205","title":"Epigenetic Regulation of Cannabinoid-Mediated Attenuation of Inflammation and Its Impact on the Use of Cannabinoids to Treat Autoimmune Diseases.","authors":"Holloman, Bryan Latrell; Nagarkatti, Mitzi; Nagarkatti, Prakash","year":2021,"journal":"International journal of molecular sciences, 22(14)","doi":"10.3390/ijms22147302","pmid":"34298921","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03206","title":"A phase I trial of the safety, tolerability and pharmacokinetics of cannabidiol administered as single-dose oil solution and single and multiple doses of a sublingual wafer in healthy volunteers.","authors":"Hosseini, Adele; McLachlan, Andrew J; Lickliter, Jason D","year":2021,"journal":"British journal of clinical pharmacology, 87(4), 2070-2077","doi":"10.1111/bcp.14617","pmid":"33075170","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CBD sublingual wafer bioavailability was comparable to oil solution (90% CI: 83-131%). Median peak CBD concentrations were 11.9 ng/mL (wafer) and 9.4 ng/mL (oil). Peak concentrations occurred 4 hours after administration with an elimination half-life of approximately 6 hours. No significant difference in total CBD exposure between wafer, oil, and nabiximols spray. Adverse events included mild somnolence, sedation, and altered mood.","whyItMatters":"CBD delivery format matters for patients. A sublingual wafer could offer advantages in dosing precision and convenience compared to oil or spray formulations. This study establishes that the wafer format does not sacrifice bioavailability.","specificNumbers":"12 volunteers. Wafer peak CBD: 11.9 ng/mL. Oil peak CBD: 9.4 ng/mL. Time to peak: 4 hours. Half-life: ~6 hours. Relative bioavailability wafer vs. oil: 83-131% (90% CI). Multiple-dose: 50 mg twice daily for 5 days.","methodology":"Phase I open-label, 4-way crossover trial in 12 healthy volunteers. Single doses of CBD sublingual wafer (25 or 50 mg), oil solution (50 mg), or nabiximols spray (20 mg CBD + 21.6 mg THC) administered in randomized sequence. Multiple-dose arm: 50 mg wafer twice daily for 5 days.","limitations":"Very small sample (12 volunteers). Healthy volunteers only. Single-dose primary assessment. Open-label design. Cannabis extract composition may vary between products."},{"rthcId":"RTHC-03207","title":"Cannabidiol enhances verbal episodic memory in healthy young participants: A randomized clinical trial.","authors":"Hotz, Janine; Fehlmann, Bernhard; Papassotiropoulos, Andreas; de Quervain, Dominique Jf; Schicktanz, Nathalie S","year":2021,"journal":"Journal of psychiatric research, 143, 327-333","doi":"10.1016/j.jpsychires.2021.09.007","pmid":"34536664","tags":["cbd","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CBD enhanced verbal episodic memory performance compared to placebo (7.71 vs. 7.03 words recalled, adjusted difference 0.68 words, p=0.048). CBD did not affect attention or working memory, suggesting the effect was specific to episodic memory consolidation rather than general cognitive enhancement.","whyItMatters":"While the effect size was small (less than one additional word recalled), this is one of the first controlled demonstrations that CBD alone can enhance a specific type of memory in healthy people, supporting the idea that CBD interacts with the endocannabinoid system in ways that affect memory consolidation.","specificNumbers":"34 completers, mean age 22.3. CBD recall: 7.71 words. Placebo recall: 7.03 words. Adjusted difference: 0.68 words (95% CI: 0.01-1.35). Effect size R²β = 0.028. Single dose: 12.5 mg CBD vaped.","methodology":"Double-blind, placebo-controlled, randomized crossover trial in 39 healthy young adults (34 completed). Participants vaped 12.5 mg CBD or placebo after learning 15 unrelated nouns. Primary outcome: number of words freely recalled 20 minutes later. Secondary outcomes: attention and working memory.","limitations":"Very small sample. Borderline statistical significance (p=0.048). Tiny effect size. Single dose tested. Healthy young adults only. Short retention interval (20 minutes). Crossover design raises practice effect concerns."},{"rthcId":"RTHC-03208","title":"The Spicy Story of Cannabimimetic Indoles.","authors":"Howlett, Allyn C; Thomas, Brian F; Huffman, John W","year":2021,"journal":"Molecules (Basel, Switzerland), 26(20)","doi":"10.3390/molecules26206190","pmid":"34684770","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03209","title":"Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease - A Systematic Review.","authors":"Hryhorowicz, Szymon; Kaczmarek-Ryś, Marta; Zielińska, Aleksandra; Scott, Rodney J; Słomski, Ryszard; Pławski, Andrzej","year":2021,"journal":"Frontiers in immunology, 12, 790803","doi":"10.3389/fimmu.2021.790803","pmid":"35003109","tags":["inflammation","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system regulates intestinal homeostasis, gut motility, visceral sensation, and inflammation. Both CB1 and CB2 receptor agonists, as well as inhibitors of endocannabinoid-degrading enzymes (FAAH and MAGL), showed anti-inflammatory effects in preclinical IBD models. The review identified multiple therapeutic entry points within the ECS for managing IBD.","whyItMatters":"IBD affects millions worldwide with limited treatment options. The endocannabinoid system offers multiple drug targets that could be manipulated to reduce inflammation without the broad immunosuppression of current therapies.","specificNumbers":"No specific patient numbers reported. Review covers multiple preclinical studies targeting CB1, CB2, FAAH, MAGL, and endocannabinoid transporters in IBD models.","methodology":"Systematic review of preclinical and clinical literature examining the role of the endocannabinoid system in inflammatory bowel disease, including Crohn's disease and ulcerative colitis. Analyzed evidence for each ECS component as a potential therapeutic target.","limitations":"Most evidence is preclinical. Limited human clinical trial data. Systematic review methodology not fully detailed. Cannot determine optimal cannabinoid formulations or dosing for IBD."},{"rthcId":"RTHC-03210","title":"Treatment of Cannabinoid Hyperemesis With Olanzapine: A Case Series.","authors":"Hsu, Jennifer; Herrmann, Zachary; Kashyap, Saurabh; Claassen, Cynthia","year":2021,"journal":"Journal of psychiatric practice, 27(4), 316-321","doi":"10.1097/PRA.0000000000000564","pmid":"34398582","tags":["medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All four cases of treatment-refractory CHS remitted after olanzapine treatment. Olanzapine blocks multiple neurotransmitter receptors involved in nausea and vomiting. The authors suggest it may be particularly useful when CHS presents alongside psychotic symptoms or agitation.","whyItMatters":"CHS is increasingly recognized as cannabis use grows, and some cases do not respond to standard anti-emetics or hot showers. Having additional treatment options for refractory cases addresses a real clinical gap.","specificNumbers":"4 patients. All had treatment-refractory CHS. All remitted with olanzapine. Olanzapine targets dopamine, serotonin, histamine, and muscarinic receptors involved in emesis.","methodology":"Case series of 4 patients with treatment-refractory cannabinoid hyperemesis syndrome treated with olanzapine at a single institution. Clinical outcomes documented before and after olanzapine initiation.","limitations":"Only 4 cases with no control group. Cannot rule out spontaneous resolution. No standardized dosing protocol reported. Single institution."},{"rthcId":"RTHC-03211","title":"Cannabis and cannabidiol use among autistic and non-autistic adults in the UK: a propensity score-matched analysis.","authors":"Hua, Daniel Ying-Heng; Lees, Rachel; Brosnan, Mark; Freeman, Tom P","year":2021,"journal":"BMJ open, 11(12), e053814","doi":"10.1136/bmjopen-2021-053814","pmid":"34916323","tags":["cbd","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Autistic participants were more likely to use CBD (OR=3.52, p=0.002) and used it on more days (34 vs. 17 days/year). Cannabis use rates did not differ between groups. Autistic participants trusted doctors less as cannabinoid information sources (p=0.003) and endorsed barriers to support-seeking: worry about not being understood (OR=3.25), unfamiliar settings (OR=5.29), and crowded/chaotic places (OR=9.79).","whyItMatters":"CBD is being widely marketed for anxiety and sensory issues that overlap with autistic experiences, yet this population faces unique barriers to getting reliable information. The finding that autistic adults trust doctors less for cannabinoid guidance points to a communication gap.","specificNumbers":"166 propensity-matched participants. CBD use OR: 3.52 (95% CI: 1.57-7.87). Annual CBD days: 34 (autistic) vs. 17 (control). Barriers: crowded places OR=9.79, unfamiliar settings OR=5.29, worry about understanding OR=3.25. Trusted doctors less: p=0.003.","methodology":"Cross-sectional online survey of UK adults. Propensity score matching on age, gender, and ethnicity produced 166 matched participants (autistic and controls). Primary analysis used propensity-matched sample with triangulation against full sample (269 participants).","limitations":"Self-reported autism diagnosis. Online survey with self-selection bias. UK-specific. Relatively small matched sample. Cannot determine why autistic adults use more CBD (self-medication vs. other reasons)."},{"rthcId":"RTHC-03212","title":"Biomarkers of Recent Cannabis Use in Blood, Oral Fluid and Breath.","authors":"Hubbard, J A; Hoffman, M A; Ellis, S E; Sobolesky, P M; Smith, B E; Suhandynata, R T; Sones, E G; Sanford, S K; Umlauf, A; Huestis, M A; Grelotti, D J; Grant, I; Marcotte, T D; Fitzgerald, R L","year":2021,"journal":"Journal of analytical toxicology, 45(8), 820-828","doi":"10.1093/jat/bkab080","pmid":"34185831","tags":["driving"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Oral fluid THC at 10 ng/mL cutoff showed 99.7% specificity, 82.4% sensitivity, 92.5% positive predictive value, and 99.2% negative predictive value for detecting cannabis use within 3 hours. Frequent users had residual THC in blood but not oral fluid before smoking, making oral fluid less prone to false positives from prior-day use. Blood CBN at 1 ng/mL had 100% positive predictive value but only 31.4% sensitivity.","whyItMatters":"Proving cannabis-impaired driving requires a biomarker that can reliably distinguish recent use from residual detection. This study provides the most comprehensive comparison of blood, oral fluid, and breath for this purpose.","specificNumbers":"191 users. Oral fluid THC 10 ng/mL: 99.7% specificity, 82.4% sensitivity. Blood CBN 1 ng/mL: 100% specificity, 31.4% sensitivity. Frequent users had residual blood THC before smoking but not residual oral fluid THC. At 4.3% prevalence: OF THC 92.5% PPV, 99.2% NPV.","methodology":"Randomized trial with 191 frequent and occasional cannabis users who smoked placebo, 5.9%, or 13.4% THC cannabis. Blood, oral fluid, and breath collected before and up to 6 hours after smoking. Receiver operating characteristic analysis identified optimal biomarker cutoffs for recent use detection.","limitations":"Only smoked cannabis tested. Oral fluid THC at 10 ng/mL still detectable in 23% at 4.4 hours, limiting late specificity. Cannabis impairment does not correlate linearly with THC concentrations. Lab setting may not reflect real-world conditions."},{"rthcId":"RTHC-03213","title":"Alcohol, marijuana, and nicotine use as predictors of impaired driving and riding with an impaired driver among college students who engage in polysubstance use.","authors":"Hultgren, Brittney A; Waldron, Katja A; Mallett, Kimberly A; Turrisi, Rob","year":2021,"journal":"Accident; analysis and prevention, 160, 106341","doi":"10.1016/j.aap.2021.106341","pmid":"34392006","tags":["driving","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Compared to alcohol-only users, students using all three substances (alcohol, marijuana, nicotine) had dramatically higher odds of DUI (OR=10.33) and riding with an impaired driver (OR=10.22). Marijuana-only users also had elevated DUI risk (OR=5.44 between-person; OR=9.08 on specific occasions). On days when both alcohol and marijuana were used, riding with an impaired driver was nearly 4 times more likely (OR=3.86).","whyItMatters":"Prevention programs typically focus on alcohol-impaired driving. This study shows that polysubstance use dramatically increases driving risk beyond alcohol alone, suggesting prevention efforts need to address substance combinations rather than single substances.","specificNumbers":"367 students. All three substances vs. alcohol only: DUI OR=10.33, RWID OR=10.22. Marijuana-only users vs. alcohol-only: DUI OR=5.44. Marijuana-only occasions vs. alcohol-only occasions: DUI OR=9.08. Alcohol+marijuana occasions: RWID OR=3.86. Confidence intervals were wide.","methodology":"Burst design study of 367 college student drinkers with past-year marijuana and/or nicotine use. Assessed on two consecutive weekends for three semesters. Logistic and multilevel logistic models examined between- and within-person associations of substance combinations with DUI and RWID.","limitations":"Wide confidence intervals reflect small cell sizes for some substance combinations. Self-reported substance use and driving behavior. College student sample limits generalizability. Cannot determine impairment level at time of driving."},{"rthcId":"RTHC-03214","title":"Cannabis and exercise: Effects of Δ9-tetrahydrocannabinol on preference and motivation for wheel-running in mice.","authors":"Hurel, Imane; Muguruza, Carolina; Redon, Bastien; Marsicano, Giovanni; Chaouloff, Francis","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 105, 110117","doi":"10.1016/j.pnpbp.2020.110117","pmid":"32971218","tags":["exercise","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"While blocking or deleting CB1 receptors decreased running preference and performance, adding THC (which activates CB1 receptors) did not increase either. THC also failed to boost running motivation under a progressive ratio schedule or cue-induced running-seeking behavior. Notably, the same THC protocol successfully increased motivation for palatable food, ruling out a general protocol failure.","whyItMatters":"Surveys show many people use cannabis before exercise believing it enhances motivation and enjoyment. This study provides the first controlled preclinical test of that belief, finding no support for THC-enhanced exercise motivation despite confirming that the endocannabinoid system does regulate running drive.","specificNumbers":"CB1 blockade and deletion decreased running preference and performance. Acute THC had no effect on any running variable. THC increased food motivation but not running motivation. Elevated 2-AG also failed to increase running motivation or seeking.","methodology":"Mouse study using T-maze running preference tests, operant cued-running tasks with progressive ratio schedules, and cue-induced reinstatement tests. CB1 receptor involvement confirmed with genetic knockout and pharmacological blockade. THC effects tested on all running variables. Endocannabinoid enhancement via 2-AG elevation also tested.","limitations":"Mouse wheel-running may not capture human exercise motivation. Only acute THC tested, not chronic use. Mice cannot report subjective exercise enjoyment. Did not test CBD or cannabis combinations. Single route of administration."},{"rthcId":"RTHC-03215","title":"Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox-Gastaut Syndrome.","authors":"Iannone, Luigi Francesco; Arena, Gabriele; Battaglia, Domenica; Bisulli, Francesca; Bonanni, Paolo; Boni, Antonella; Canevini, Maria Paola; Cantalupo, Gaetano; Cesaroni, Elisabetta; Contin, Manuela; Coppola, Antonietta; Cordelli, Duccio Maria; Cricchiuti, Giovanni; De Giorgis, Valentina; De Leva, Maria Fulvia; De Rinaldis, Marta; d'Orsi, Giuseppe; Elia, Maurizio; Galimberti, Carlo Andrea; Morano, Alessandra; Granata, Tiziana; Guerrini, Renzo; Lodi, Monica A M; La Neve, Angela; Marchese, Francesca; Masnada, Silvia; Michelucci, Roberto; Nosadini, Margherita; Pilolli, Nicola; Pruna, Dario; Ragona, Francesca; Rosati, Anna; Santucci, Margherita; Spalice, Alberto; Pietrafusa, Nicola; Striano, Pasquale; Tartara, Elena; Tassi, Laura; Papa, Amanda; Zucca, Claudio; Russo, Emilio; Mecarelli, Oriano","year":2021,"journal":"Frontiers in neurology, 12, 673135","doi":"10.3389/fneur.2021.673135","pmid":"34093420","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"At 3 months, 40.2% of patients achieved 50% or greater seizure reduction, with 1.2% becoming seizure-free. Retention rates were similar for Dravet and Lennox-Gastaut syndromes but higher in adults than pediatric patients. Of 93 enrolled patients, 31.2% dropped out (17.2% for lack of efficacy, 12.9% for adverse events). Most common side effects were somnolence (22.6%) and diarrhea (11.9%).","whyItMatters":"These patients represent the most treatment-resistant cases, having failed a median of 8 medications. Achieving 50% seizure reduction in 40% of this population is clinically meaningful, and the real-world expanded access design provides pragmatic evidence beyond controlled trials.","specificNumbers":"93 enrolled, 82 analyzed. Median 8 failed prior medications. 50% seizure reduction: 40.2%. Seizure-free: 1.2%. Dropout: 31.2%. Somnolence: 22.6%. Diarrhea: 11.9%. Transaminase elevation noted. CBD coadministered with valproic acid (62.2%) and clobazam (41.5%).","methodology":"Open-label prospective expanded access program across 30 Italian centers (December 2018 to December 2019). Purified CBD up to 25 mg/kg/day added to existing medications. 93 patients enrolled for safety analysis, 82 with at least 3 months follow-up for effectiveness. Median 8 previously failed antiseizure medications.","limitations":"Open-label design with no placebo group. Potential placebo effect. Only 3 months of effectiveness data. Concurrent medication changes possible. Dropout rate of 31% may bias results."},{"rthcId":"RTHC-03216","title":"Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice.","authors":"Iemolo, Attilio; Montilla-Perez, Patricia; Nguyen, Jacques; Risbrough, Victoria B; Taffe, Michael A; Telese, Francesca","year":2021,"journal":"Neuropharmacology, 187, 108495","doi":"10.1016/j.neuropharm.2021.108495","pmid":"33582152","tags":["youth","psychosis","neuroscience","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Heterozygous Reeler mice (reduced Reelin) treated with THC during adolescence showed impaired social behaviors, elevated disinhibitory phenotypes, and increased stress reactivity compared to wild-type mice given the same THC treatment. These effects were sex-specific. Wild-type mice showed less severe behavioral changes from the same THC exposure.","whyItMatters":"Reelin is implicated in brain development and psychiatric disorders including schizophrenia. This study suggests that genetic variations affecting Reelin levels could make some individuals more vulnerable to lasting behavioral effects from adolescent cannabis use.","specificNumbers":"THC dose: 10 mg/kg chronic during adolescence. Two-week washout before testing. HR mice showed impaired social behavior, elevated disinhibition, and increased stress reactivity compared to WT mice with same THC exposure. Effects were sex-specific.","methodology":"Heterozygous Reeler (HR) mice and wild-type littermates received chronic high-dose THC (10 mg/kg) during adolescence. Two weeks after the last injection, mice underwent multiple behavioral tests: working memory, social interaction, locomotor activity, anxiety-like responses, stress reactivity, and pre-pulse inhibition.","limitations":"High THC dose (10 mg/kg) may not reflect typical human use. Mouse behavior may not translate to human psychiatric outcomes. Only chronic high-dose regimen tested. Two-week follow-up may miss longer-term effects."},{"rthcId":"RTHC-03217","title":"Differential Methylation Pattern of Schizophrenia Candidate Genes in Tetrahydrocannabinol-Consuming Treatment-Resistant Schizophrenic Patients Compared to Non-Consumer Patients and Healthy Controls.","authors":"Jahn, Kirsten; Heese, Astrid; Kebir, Oussama; Groh, Adrian; Bleich, Stefan; Krebs, Marie Odile; Frieling, Helge","year":2021,"journal":"Neuropsychobiology, 80(1), 36-44","doi":"10.1159/000507670","pmid":"32599581","tags":["psychosis","genetics"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"In the NRXN1 gene promoter, THC-consuming schizophrenia patients had nearly double the methylation rate compared to non-consuming patients. In MAPT, non-consumer patients had lower methylation than controls (possibly compensatory), but THC consumers had rates closer to controls. NRG1 and DISC1 showed no group differences, and DISC1 appeared unmethylated across all groups.","whyItMatters":"Epigenetic changes (like DNA methylation) can alter gene expression without changing the DNA sequence. Finding that THC use is associated with different methylation patterns in synaptic genes suggests a potential molecular mechanism linking cannabis to schizophrenia biology.","specificNumbers":"50 treatment-resistant schizophrenia patients. NRXN1 methylation: THC consumers nearly 2x higher than non-consumers. MAPT methylation: lower in non-consumer patients vs. controls, less difference in THC consumers. NRG1 and DISC1: no significant group differences.","methodology":"Case-control study of 50 treatment-resistant schizophrenia outpatients (THC consumers and non-consumers) and healthy controls. DNA from blood samples was bisulfite-converted and sequenced to measure promoter methylation of four schizophrenia candidate genes: NRG1, NRXN1, DISC1, and MAPT.","limitations":"Small sample size. Cross-sectional design cannot determine whether THC caused the methylation changes. Blood-based methylation may not reflect brain methylation. Treatment-resistant population may not be representative."},{"rthcId":"RTHC-03218","title":"Priorities for Medical Marijuana Research from the Perspective of Physicians, Dispensary Owners/Staff, and Patients: A Survey Study.","authors":"Jean-Jacques, Jennifer; Cook, Robert; Winterstein, Almut G; Goodin, Amie; Brown, Joshua D; Jugl, Sebastian; Wang, Yan","year":2021,"journal":"Medical cannabis and cannabinoids, 4(2), 107-113","doi":"10.1159/000518105","pmid":"35224430","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03219","title":"Bipolar disorder and cannabis use: A bidirectional two-sample Mendelian randomization study.","authors":"Jefsen, Oskar Hougaard; Speed, Maria; Speed, Doug; Østergaard, Søren Dinesen","year":2021,"journal":"Addiction biology, 26(6), e13030","doi":"10.1111/adb.13030","pmid":"33733564","tags":["mental-health","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Genetic liability to bipolar disorder was significantly associated with increased risk of lifetime cannabis use across all three MR methods (inverse variance weighted, weighted median, and Egger regression). In contrast, genetic liability to lifetime cannabis use showed no association with bipolar disorder risk. Sensitivity analyses found no evidence of confounding through pleiotropic effects.","whyItMatters":"Previous MR studies examined cannabis and schizophrenia, depression, and ADHD, but not bipolar disorder. This study fills that gap and finds a unidirectional relationship: bipolar vulnerability drives cannabis use, not the other way around. This has implications for understanding self-medication in bipolar disorder.","specificNumbers":"Genetic instruments from large GWAS studies. Bipolar disorder genetic liability significantly predicted lifetime cannabis use across all three MR methods. Cannabis use genetic liability showed no significant effect on bipolar disorder risk. No evidence of pleiotropy in sensitivity analyses.","methodology":"Two-sample bidirectional Mendelian randomization using genome-wide significant SNPs from large GWAS of bipolar disorder and lifetime cannabis use. Three complementary MR methods applied with sensitivity analyses for pleiotropy.","limitations":"Mendelian randomization assumes genetic instruments only affect the outcome through the exposure (exclusion restriction). Lifetime cannabis use (ever vs. never) is a crude measure. Cannot examine heavy use or CUD specifically. Population-level finding may not apply to individuals."},{"rthcId":"RTHC-03220","title":"Effects of steam sterilization on reduction of fungal colony forming units, cannabinoids and terpene levels in medical cannabis inflorescences.","authors":"Jerushalmi, Shachar; Maymon, Marcel; Dombrovsky, Aviv; Regev, Rafi; Schmilovitch, Ze'ev; Namdar, Dvora; Shalev, Nurit; Koltai, Hinanit; Freeman, Stanley","year":2021,"journal":"Scientific reports, 11(1), 13973","doi":"10.1038/s41598-021-93264-y","pmid":"34234177","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03221","title":"The CB2 Receptor as a Novel Therapeutic Target for Epilepsy Treatment.","authors":"Ji, Xiaoyu; Zeng, Yang; Wu, Jie","year":2021,"journal":"International journal of molecular sciences, 22(16)","doi":"10.3390/ijms22168961","pmid":"34445666","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03222","title":"Novel Functionalized Cannabinoid Receptor Probes: Development of Exceptionally Potent Agonists.","authors":"Jiang, Shan; Iliopoulos-Tsoutsouvas, Christos; Tong, Fei; Brust, Christina A; Keenan, Catherine M; Raghav, Jimit Girish; Hua, Tian; Wu, Simiao; Ho, Jo-Hao; Wu, Yiran; Grim, Travis W; Zvonok, Nikolai; Thakur, Ganesh A; Liu, Zhi-Jie; Sharkey, Keith A; Bohn, Laura M; Nikas, Spyros P; Makriyannis, Alexandros","year":2021,"journal":"Journal of medicinal chemistry, 64(7), 3870-3884","doi":"10.1021/acs.jmedchem.0c02053","pmid":"33761251","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03223","title":"Physiological and transcriptome analyses for assessing the effects of exogenous uniconazole on drought tolerance in hemp (Cannabis sativa L.).","authors":"Jiang, Ying; Sun, Yufeng; Zheng, Dianfeng; Han, Chengwei; Cao, Kun; Xu, Lei; Liu, Shuxia; Cao, Yanyong; Feng, Naijie","year":2021,"journal":"Scientific reports, 11(1), 14476","doi":"10.1038/s41598-021-93820-6","pmid":"34262091","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03224","title":"Are marijuana-using caregivers being asked about their marijuana use by their child's pediatrician?","authors":"Johnson, Adam B; Watson, Dana B","year":2021,"journal":"Preventive medicine reports, 24, 101548","doi":"10.1016/j.pmedr.2021.101548","pmid":"34976618","tags":["legalization","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 1,500 caregivers surveyed, 167 (11%) reported using marijuana. Among marijuana-using caregivers who responded, 149 (90.3%) said their pediatrician had never inquired about their marijuana use, 9 (5.4%) said yes, and 7 (4.2%) were unsure.","whyItMatters":"In Colorado, where recreational cannabis is legal, secondhand cannabis smoke exposure to children is a real concern. If 90% of marijuana-using parents report never being asked about their use, pediatricians are missing opportunities for harm reduction counseling.","specificNumbers":"1,500 caregivers surveyed. 167 (11%) used marijuana. Of those, 90.3% said pediatrician never asked, 5.4% said yes, 4.2% unsure.","methodology":"Cross-sectional convenience sample survey of 1,500 caregivers presenting to the Children's Hospital Colorado Pediatric Emergency Department between December 2015 and July 2017. Asked about caregiver marijuana use and whether their child's pediatrician had ever inquired about it.","limitations":"Convenience sample from a single emergency department. Self-reported data. Colorado-specific context may not generalize. Survey did not assess actual secondhand exposure levels or child health outcomes."},{"rthcId":"RTHC-03225","title":"Modulatory Potential of Cannabidiol on the Opioid-Induced Inflammatory Response.","authors":"Johnson, Clare T; Bradshaw, Heather B","year":2021,"journal":"Cannabis and cannabinoid research, 6(3), 211-220","doi":"10.1089/can.2020.0181","pmid":"34115948","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03226","title":"The relationship between cannabis and schizophrenia: a genetically informed perspective.","authors":"Johnson, Emma C; Hatoum, Alexander S; Deak, Joseph D; Polimanti, Renato; Murray, Robin M; Edenberg, Howard J; Gelernter, Joel; Di Forti, Marta; Agrawal, Arpana","year":2021,"journal":"Addiction (Abingdon, England), 116(11), 3227-3234","doi":"10.1111/add.15534","pmid":"33950550","tags":["psychosis","genetics","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Genetic liability to CUD predicted schizophrenia (beta=0.29, p=0.001) even after accounting for cannabis ever-use, tobacco smoking, and nicotine dependence. Mendelian randomization found a small but significant causal effect of CUD on schizophrenia (beta=0.10, p=0.02), but latent causal variable analysis did not support causation. The key distinction was between CUD (disordered use) and ever-use (trying cannabis), with only CUD showing the association.","whyItMatters":"This study separates CUD from merely trying cannabis, finding that only disordered use genetically predicts schizophrenia. It also controls for tobacco (a major confounder), strengthening the CUD-specific signal. The mixed causal evidence keeps the question open but points toward CUD as more concerning than casual use.","specificNumbers":"Sample sizes: 161,405-357,806. CUD-schizophrenia genetic association: beta=0.29 (95% CI: 0.11-0.46, p=0.001). Multivariable MR causal estimate: beta=0.10 (95% CI: 0.02-0.18, p=0.02). Latent causal variable: no significant causality (GCP=-0.08, p=0.87).","methodology":"Used GWAS summary statistics (sample sizes 161,405-357,806 Europeans) for genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization. Examined genetic relationships between CUD, cannabis ever-use, tobacco smoking, nicotine dependence, and schizophrenia.","limitations":"European ancestry GWAS limits generalizability. Two causal methods gave conflicting results. GWAS summary statistics may not capture all genetic variation. Cannot determine which aspects of CUD (frequency, potency, age of onset) drive the association."},{"rthcId":"RTHC-03227","title":"Medical marijuana laws (MMLs) and dispensary provisions not associated with higher odds of adolescent marijuana or heavy marijuana use: A 46 State Analysis, 1991-2015.","authors":"Johnson, Julie K; Johnson, Renee M; Hodgkin, Dominic; Jones, Abenaa A; Kritikos, Alexandra; Doonan, Samantha M; Harris, Sion K","year":2021,"journal":"Substance abuse, 42(4), 471-475","doi":"10.1080/08897077.2021.1900986","pmid":"33750275","tags":["legalization","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"States with enacted medical marijuana laws actually showed slightly lower adjusted odds of adolescent past-30-day marijuana use (OR=0.94, 95% CI: 0.89-0.99). No increase in heavy use (20+ days/month) was detected. Dispensary provisions were also not associated with higher adolescent use.","whyItMatters":"A primary concern about marijuana legalization is increased teen use. This study, one of the largest to examine the question, found no evidence for that concern across nearly 25 years of data, providing important evidence for the policy debate.","specificNumbers":"1,091,723 students, 46 states, 1991-2015. MML states: OR=0.94 (95% CI: 0.89-0.99) for any past-30-day use. No significant effect on heavy use (20+ days). Dispensary provisions also not associated with increased use.","methodology":"Natural-experimental design using state Youth Risk Behavior Survey (YRBS) data from 1,091,723 students in grades 9-12 across 46 states (1991-2015). Difference-in-difference estimates compared states before and after MML enactment. Multivariable logistic regression adjusted for state and year effects and student demographics.","limitations":"YRBS data is self-reported. Does not capture recreational legalization effects (only medical). Cannot account for all state-level confounders. 1991-2015 timeframe may not reflect more recent policy environments."},{"rthcId":"RTHC-03228","title":"The relationship between cannabis use and cognition in people with bipolar disorder: A systematic scoping review.","authors":"Jordan Walter, T; Pocuca, Nina; Young, Jared W; Geyer, Mark A; Minassian, Arpi; Perry, William","year":2021,"journal":"Psychiatry research, 297, 113695","doi":"10.1016/j.psychres.2020.113695","pmid":"33545431","tags":["mental-health","cognition"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Of 6 qualifying studies, two found cannabis use in bipolar disorder was associated with better performance in some cognitive domains, three found no association, and one found worse overall cognition. No animal studies met inclusion criteria. The limited evidence base prevents strong conclusions.","whyItMatters":"Cannabis use is highly comorbid with bipolar disorder, and cognitive impairment is a core feature of the condition. The surprising finding that cannabis may not worsen (and might even improve) cognition in bipolar disorder parallels similar findings in schizophrenia and deserves further investigation.","specificNumbers":"6 studies met inclusion criteria. 2 found better cognition with cannabis use. 3 found no association. 1 found worse cognition. Zero animal studies found.","methodology":"Systematic scoping review searching PubMed, Embase, CINAHL, Web of Science, and PsycINFO for studies on cannabis use and cognition in bipolar disorder or relevant animal models. Six human observational studies met inclusion criteria.","limitations":"Only 6 studies, all observational. Cannot determine causation. Wide variation in how cannabis use was measured across studies. No studies controlled for cannabis use frequency, quantity, or type."},{"rthcId":"RTHC-03229","title":"Cannabis Product Ingestions in Pediatric Patients: Ranges of Exposure, Effects, and Outcomes.","authors":"Kaczor, Eric E; Mathews, Bonnie; LaBarge, Kara; Chapman, Brittany P; Carreiro, Stephanie","year":2021,"journal":"Journal of medical toxicology : official journal of the American College of Medical Toxicology, 17(4), 386-396","doi":"10.1007/s13181-021-00849-0","pmid":"34117620","tags":["youth","harm-reduction","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Pediatric edible cannabis exposures increased five-fold after Massachusetts recreational dispensaries opened. Age under 10 was associated with bradypnea, hypertension, hospital admission, and need for respiratory support. Overall, 16% required respiratory support and 34% required hospital admission. Respiratory support was associated with lethargy, bradypnea, hypercarbia, seizure, and hypertension.","whyItMatters":"Edible cannabis products are particularly dangerous for young children because they are often packaged in appealing forms (gummies, chocolates) and can cause more severe effects than inhalation due to delayed onset and higher bioavailability. The 5-fold increase after dispensary opening suggests a direct policy consequence.","specificNumbers":"32 cases. 5-fold increase after dispensaries opened. 16% needed respiratory support. 34% required hospitalization. Age <10 associated with bradypnea, hypertension, admission, and respiratory support.","methodology":"Retrospective chart review at a single tertiary care academic medical center covering a 28-month period. Included children under 18 evaluated in the ED for edible cannabis exposure without co-ingestion of other substances. 32 cases identified.","limitations":"Single center, small sample (32 cases). No THC dose quantification. Cannot determine true population incidence. Retrospective design may miss cases not presenting to this hospital."},{"rthcId":"RTHC-03230","title":"Cannabis-Induced Mania Following COVID-19 Self-Medication: A Wake-Up Call to Improve Community Awareness.","authors":"Kaggwa, Mark Mohan; Bongomin, Felix; Najjuka, Sarah Maria; Rukundo, Godfrey Zari; Ashaba, Scholastic","year":2021,"journal":"International medical case reports journal, 14, 121-125","doi":"10.2147/IMCRJ.S301246","pmid":"33658866","tags":["psychosis","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient presented with one week of pressured speech, poor sleep, destructiveness, irritability, and altered mental status after two weeks of using homemade remedies including cannabis to treat COVID-19 symptoms. He had no prior psychiatric history, no previous substance use, no chronic conditions, and no family psychiatric history. Urine was positive for THC. Manic symptoms resolved within two weeks of treatment with carbamazepine, chlorpromazine, and diazepam.","whyItMatters":"The COVID-19 pandemic has driven increased self-medication with unproven remedies, including cannabis. This case illustrates how cannabis use by someone with no prior exposure or psychiatric vulnerability can trigger a psychiatric emergency.","specificNumbers":"Age 52. No prior psychiatric history. Two weeks of cannabis-containing home remedies. One week of manic symptoms. THC-positive urine. Symptoms resolved in 2 weeks with mood stabilizer, antipsychotic, and sedative.","methodology":"Single case report from Uganda. Documented a 52-year-old man with first-episode mania temporally linked to cannabis self-medication for COVID-19. No prior psychiatric or substance use history.","limitations":"Single case. Cannot rule out other ingredients in the home remedy. COVID-19 itself may have contributed to neuropsychiatric symptoms. No prior baseline psychiatric assessment available."},{"rthcId":"RTHC-03231","title":"Cannabis Associated Mental Health Effects: A Review.","authors":"Kancherla, Neeraj; Jeyanthi, Keerthana Mani; Abbas, Ramsha; Sathi, Thanmay Sai Charaan Reddy; Upadhyay, Amrita; Garlapati, Sameer Krishna Prasad","year":2021,"journal":"Journal of pharmacy & bioallied sciences, 13(Suppl 2), S943-S946","doi":"10.4103/jpbs.jpbs_388_21","pmid":"35017903","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03232","title":"Cannabis and Lung Health: Does the Bad Outweigh the Good?","authors":"Kaplan, Alan G","year":2021,"journal":"Pulmonary therapy, 7(2), 395-408","doi":"10.1007/s41030-021-00171-8","pmid":"34697771","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03233","title":"Cannabidiol Exposure During the Mouse Adolescent Period Is Without Harmful Behavioral Effects on Locomotor Activity, Anxiety, and Spatial Memory.","authors":"Kaplan, J S; Wagner, J K; Reid, K; McGuinness, F; Arvila, S; Brooks, M; Stevenson, H; Jones, J; Risch, B; McGillis, T; Budinich, R; Gambell, E; Predovich, B","year":2021,"journal":"Frontiers in behavioral neuroscience, 15, 711639","doi":"10.3389/fnbeh.2021.711639","pmid":"34512286","tags":["cbd","youth","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prolonged adolescent CBD exposure (20 mg/kg twice daily, days 25-45) had no detrimental effects on locomotor activity, anxiety behavior (elevated plus maze), or spatial memory (Barnes Maze) compared to vehicle-treated mice. CBD-treated mice showed a faster rate of learning in the Barnes Maze. Female CBD-treated mice had reduced weight gain during the exposure period.","whyItMatters":"CBD is increasingly given to children and adolescents for anxiety, ADHD, and autism, often off-label. This study provides early safety data suggesting adolescent CBD exposure may not cause lasting behavioral harm, though the route of administration (injection) differs from human use.","specificNumbers":"CBD dose: 20 mg/kg twice daily. Treatment period: postnatal days 25-45. No effects on locomotion, anxiety, or spatial memory. Faster Barnes Maze learning in CBD group. Reduced weight gain in CBD-treated females only.","methodology":"Male and female C57BL/6J mice received intraperitoneal CBD (20 mg/kg) or vehicle twice daily during postnatal days 25-45 (adolescent period). Behavioral testing in adulthood assessed locomotor activity (open field), anxiety (elevated plus maze), and spatial memory (Barnes Maze).","limitations":"Mouse model with intraperitoneal administration (not oral). Single dose tested. Limited behavioral battery. Cannot assess subjective or emotional effects. May miss subtle cognitive differences not captured by these assays."},{"rthcId":"RTHC-03234","title":"Hempseed (Cannabis sativa) offers effective alternative over statins in ameliorating hypercholesterolemia associated nephropathy.","authors":"Kaur, Simarpreet; Garg, Ayushi; Kaushal, Naveen","year":2021,"journal":"Clinical biochemistry, 93, 104-111","doi":"10.1016/j.clinbiochem.2021.04.008","pmid":"33861983","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Hempseed lipid extract (HEMP) improved lipid profiles and morphological signs of high cholesterol, and was safer than simvastatin for liver and kidney function markers. HEMP positively modulated oxidative stress markers, restored renal architecture, and activated anti-inflammatory resolution pathways (Cox-1/2, PGDS, PGES). HEMP also modulated lipid metabolism mediators (APO-B/E).","whyItMatters":"Statins, while effective for cholesterol, can cause kidney problems in some patients. If hempseed extracts can manage cholesterol-related kidney damage without statin side effects, it could offer a complementary or alternative approach for certain patients.","specificNumbers":"Rat model with high-fat diet. HEMP improved lipid profiles and was safer than simvastatin for hepatic and renal function markers. HEMP modulated Cox-1/2, PGDS, PGES inflammatory pathways and APO-B/E lipid metabolism mediators.","methodology":"Rat study using high-fat diet to induce hypercholesterolemia. Compared hempseed lipid extract to simvastatin and controls. Assessed lipid profiles, renal function markers, kidney histopathology, oxidative stress markers, and inflammatory pathway expression.","limitations":"Rat model may not translate to humans. Hempseed lipid extract composition can vary. No dose-response analysis. Short-term study. Cannot compare to the extensive human evidence base for statins."},{"rthcId":"RTHC-03235","title":"Repetitive transcranial magnetic stimulation as a potential treatment approach for cannabis use disorder.","authors":"Kearney-Ramos, Tonisha; Haney, Margaret","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 109, 110290","doi":"10.1016/j.pnpbp.2021.110290","pmid":"33677045","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03236","title":"Biological basis of cannabinoid medicines.","authors":"Keimpema, Erik; Di Marzo, Vincenzo; Harkany, Tibor","year":2021,"journal":"Science (New York, N.Y.), 374(6574), 1449-1450","doi":"10.1126/science.abf6099","pmid":"34914498","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03237","title":"Demographic risk factors for co-occurring suicidality and cannabis use disorders: Findings from a nationally representative United States sample.","authors":"Kelly, Lourah M; Drazdowski, Tess K; Livingston, Nicholas R; Zajac, Kristyn","year":2021,"journal":"Addictive behaviors, 122, 107047","doi":"10.1016/j.addbeh.2021.107047","pmid":"34284313","tags":["mental-health","addiction","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Men had twice the odds of co-occurring suicidal ideation and CUD (AOR=2.06). All older age groups had far lower odds than emerging adults (AORs 0.06-0.39). Black/African American adults had 4 times higher odds of co-occurring CUD and suicide attempts (AOR=4.05). Bisexual adults had over 3 times higher odds of co-occurring ideation and CUD (AOR=3.16). Native adults had over twice the odds (AOR=2.16).","whyItMatters":"Knowing which demographic groups carry the highest risk of co-occurring CUD and suicidality allows for targeted screening and prevention. The intersection of substance use and suicide risk is particularly dangerous, and certain groups are bearing a disproportionate burden.","specificNumbers":"Men: AOR=2.06 for co-occurring ideation/CUD. Black/African American: AOR=4.05 for co-occurring attempts/CUD. Native: AOR=2.16 for ideation/CUD. Bisexual: AOR=3.16 for ideation/CUD. Gay/lesbian: AOR=2.04. Hispanic/Latinx: AOR=2.49 for attempts/CUD. Older groups: AOR=0.06-0.39 vs. emerging adults.","methodology":"Combined five years (2015-2019) of NSDUH data. Multinomial logistic regressions tested demographic differences in odds of suicidality only, CUD only, and co-occurring CUD and suicidality. Controlled for survey year, major depressive episode, and other substance use disorders.","limitations":"Cross-sectional design. Self-reported CUD screening, not clinical diagnosis. Cannot determine temporal ordering. Some subgroup analyses may be underpowered. NSDUH excludes institutionalized and homeless populations."},{"rthcId":"RTHC-03238","title":"Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings.","authors":"Kesner, Andrew J; Lovinger, David M","year":2021,"journal":"Journal of neurochemistry, 157(5), 1674-1696","doi":"10.1111/jnc.15369","pmid":"33891706","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03239","title":"A validated method for the simultaneous quantification of cannabidiol, Δ9 -tetrahydrocannabinol, and their metabolites in human plasma and application to plasma samples from an oral cannabidiol open-label trial.","authors":"Kevin, Richard C; Vogel, Rebecca; Doohan, Peter; Berger, Maximus; Amminger, G Paul; McGregor, Iain S","year":2021,"journal":"Drug testing and analysis, 13(3), 614-627","doi":"10.1002/dta.2947","pmid":"33095968","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03240","title":"Medicinal Applications of Cannabinoids Extracted from Cannabis sativa (L.): A New Route in the Fight Against COVID-19?","authors":"Khalid, Shah; Almalki, Faisal A; Hadda, Taibi Ben; Bader, Ammar; Abu-Izneid, Tareq; Berredjem, Malika; Elsharkawy, Eman R; Alqahtani, Ali M","year":2021,"journal":"Current pharmaceutical design, 27(13), 1564-1578","doi":"10.2174/1381612826666201202125807","pmid":"33267756","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03241","title":"COVID-19 and Cannabidiol (CBD).","authors":"Khalsa, Jag H; Bunt, Greg; Maggirwar, Sanjay B; Kottilil, Shyam","year":2021,"journal":"Journal of addiction medicine, 15(5), 355-356","doi":"10.1097/ADM.0000000000000771","pmid":"33323690","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03242","title":"Peripherally Selective CB1 Receptor Antagonist Improves Symptoms of Metabolic Syndrome in Mice.","authors":"Khan, Nayaab; Laudermilk, Lucas; Ware, Jalen; Rosa, Taylor; Mathews, Kelly; Gay, Elaine; Amato, George; Maitra, Rangan","year":2021,"journal":"ACS pharmacology & translational science, 4(2), 757-764","doi":"10.1021/acsptsci.0c00213","pmid":"33860199","tags":["appetite","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The peripheral CB1 antagonist RTI1092769 inhibited weight gain, improved glucose utilization, and significantly reduced liver triglycerides and steatosis in mice on a high-fat diet. Several biomarkers of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) also improved. The compound had very limited brain exposure, avoiding the psychiatric side effects that led to rimonabant withdrawal.","whyItMatters":"Rimonabant proved that blocking CB1 receptors effectively treats metabolic syndrome, but its psychiatric side effects (depression, suicidality) ended its clinical use. This study shows that keeping the drug out of the brain may preserve the metabolic benefits while avoiding the risks.","specificNumbers":"RTI1092769 inhibited weight gain, improved glucose utilization. Hepatic triglycerides and steatosis significantly improved. NAFLD and NASH biomarkers improved. Very limited brain exposure confirmed.","methodology":"Mouse study using a pyrazole-based weak inverse agonist/antagonist of CB1 (RTI1092769) with limited brain penetration. Obese mice on a high-fat diet were treated and assessed for weight, glucose tolerance, hepatic triglycerides, liver histology, and NAFLD/NASH biomarkers.","limitations":"Mouse model only. Long-term safety unknown. Single compound tested. Cannot predict human pharmacokinetics or whether minimal brain exposure would truly prevent all psychiatric effects."},{"rthcId":"RTHC-03243","title":"A Systematic Review of Fibromyalgia and Recent Advancements in Treatment: Is Medicinal Cannabis a New Hope?","authors":"Khurshid, Hajra; Qureshi, Israa A; Jahan, Nasrin; Went, Terry R; Sultan, Waleed; Sapkota, Alisha; Alfonso, Michael","year":2021,"journal":"Cureus, 13(8), e17332","doi":"10.7759/cureus.17332","pmid":"34567876","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 22 studies, medical cannabis (including nabilone, dronabinol, and various THC/CBD ratios) showed analgesic and anti-inflammatory effects in fibromyalgia patients. The THC-to-CBD ratio influenced which symptoms improved most. Studies used products including nabilone, dronabinol, Bedrocan (22.4mg THC), Bediol (13.4mg THC + 17.8mg CBD), and Bedrolite (18.4mg CBD).","whyItMatters":"Fibromyalgia affects millions and current FDA-approved treatments have limited effectiveness. Cannabis represents a potential alternative, particularly as the opioid crisis makes non-opioid pain options increasingly important.","specificNumbers":"22 articles included. Formulations studied: nabilone, dronabinol, Bedrocan (22.4mg THC, <1mg CBD), Bediol (13.4mg THC, 17.8mg CBD), Bedrolite (18.4mg CBD, <1mg THC). THC/CBD ratio influenced symptom-specific effects.","methodology":"Systematic review following PRISMA guidelines. Searched PubMed, MEDLINE, PubMed Central, and Google Scholar. 22 articles met inclusion criteria after quality assessment. Analyzed the role of cannabis in fibromyalgia treatment across different cannabinoid formulations.","limitations":"Heterogeneous study designs across the 22 included studies. Limited data on optimal dosing, treatment duration, adverse effects, and long-term outcomes. Many studies were small or observational."},{"rthcId":"RTHC-03244","title":"Marijuana: A systems-based primer of adverse effects associated with use and an overview of its therapeutic utility.","authors":"Kichloo, Asim; Albosta, Michael; Aljadah, Michael; El-Amir, Zain; Goldar, Ghazaleh; Khan, Muhammed Zatmar; Dahiya, Dushyant Singh; Vallabhaneni, Srilakshmi; Wani, Farah; Singh, Jagmeet","year":2021,"journal":"SAGE open medicine, 9, 20503121211000909","doi":"10.1177/20503121211000909","pmid":"33786179","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03245","title":"Cannabinoids and bladder symptoms in multiple sclerosis.","authors":"Kim-Fine, Shunaha; Greenfield, Jamie; Chaput, Kathleen H; Robert, Magali; Metz, Luanne M","year":2021,"journal":"Multiple sclerosis and related disorders, 54, 103105","doi":"10.1016/j.msard.2021.103105","pmid":"34216995","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 734 respondents reporting cannabis use status, 275 (37.5%) used cannabis in the past 3 months, with 73.8% using at least weekly. Among 19 patients specifically using cannabis for bladder symptoms, 89.5% reported improvement. Cannabis use was associated with two-fold increased odds of reporting improvement in urinary frequency, urgency, bladder leakage and wetness, pad use, and bladder emptying. Top reasons for use: sleep (58.3%), pain (51.5%), relaxation (44.4%), muscle spasms (40.2%).","whyItMatters":"Bladder dysfunction affects up to 80% of MS patients and significantly impacts quality of life. While cannabis is commonly used by MS patients for other symptoms, its effects on bladder function have received little attention.","specificNumbers":"775 respondents out of 2,899 contacted (26.7% response rate). 275 (37.5%) used cannabis. 73.8% used weekly or more. 78.1% cited medical/therapeutic reasons. 89.5% of those using for bladder symptoms reported improvement. 2x odds of improvement in multiple bladder outcomes.","methodology":"Cross-sectional survey of people with MS recruited from the MS Clinic in Calgary, Alberta, Canada. 775 responded out of 2,899 contacted. Logistic regression assessed associations between cannabis use and bladder symptom improvement.","limitations":"Self-reported outcomes. Low response rate (26.7%) introduces selection bias. Cross-sectional design. No dose standardization. Those who found cannabis helpful may have been more likely to respond."},{"rthcId":"RTHC-03246","title":"In Vitro Studies on Therapeutic Effects of Cannabidiol in Neural Cells: Neurons, Glia, and Neural Stem Cells.","authors":"Kim, Jungnam; Choi, Hyunwoo; Kang, Eunhye K; Ji, Gil Yong; Kim, Youjeong; Choi, Insung S","year":2021,"journal":"Molecules (Basel, Switzerland), 26(19)","doi":"10.3390/molecules26196077","pmid":"34641624","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03247","title":"The Relationship between Alcohol-Cannabis Use and Stressful Events with the Development of Incident Clinical Psychosis in a Community-Based Prospective Cohort.","authors":"Kirli, Umut; Binbay, Tolga; Alptekin, Köksal; Kayahan, Bülent; Elbi, Hayriye","year":2021,"journal":"Turk psikiyatri dergisi = Turkish journal of psychiatry, 32(4), 235-245","doi":null,"pmid":"34964097","tags":["psychosis","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Heavy alcohol drinking and cannabis use during follow-up each independently predicted incident clinical psychosis. Monthly frequency of both drinking and cannabis use was also associated with risk. The coexistence of two risk factors (heavy drinking, cannabis use, or 3+ stressful events) increased psychosis incidence to 17.7%, compared to 1.6% with a single risk factor (p<0.001).","whyItMatters":"This study captures the synergistic nature of psychosis risk factors in a real-world community setting. The dramatic jump from 1.6% to 17.7% when two risk factors co-occur demonstrates that psychosis risk is not simply additive but multiplicative.","specificNumbers":"2,142 screened. 27 incident psychosis cases. 1,691 controls. Two risk factors combined: 17.7% psychosis incidence. Single risk factor: 1.6% incidence (p<0.001). Monthly drinking and cannabis frequency both associated with risk.","methodology":"Community-based prospective cohort of 2,142 people screened for clinical psychosis at baseline and follow-up. 27 incident cases of clinical psychosis were identified and compared to 1,691 controls with no psychotic symptoms. Assessed exposure to alcohol, cannabis, and stressful life events during follow-up.","limitations":"Small number of incident cases (27) limits statistical power. Community sample from a specific Turkish population. Cannot control for all confounders. Self-reported substance use."},{"rthcId":"RTHC-03248","title":"Effect of Cannabidiol on Interictal Epileptiform Activity and Sleep Architecture in Children with Intractable Epilepsy: A Prospective Open-Label Study.","authors":"Klotz, Kerstin A; Grob, Daniel; Schönberger, Jan; Nakamura, Lea; Metternich, Birgitta; Schulze-Bonhage, Andreas; Jacobs, Julia","year":2021,"journal":"CNS drugs, 35(11), 1207-1215","doi":"10.1007/s40263-021-00867-0","pmid":"34687005","tags":["epilepsy","cbd","sleep","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Interictal epileptiform discharge (IED) rate dropped significantly from 36.8 to 19.6 per minute after 3 months of CBD (p<0.0001). IED reduction moderately correlated with seizure reduction (r=0.39, p=0.02). Sleep microstructure was initially abnormal in 56.5% of recorded cases and improved in 84.6% of those. Higher initial IED rates predicted greater reduction.","whyItMatters":"Beyond reducing seizures, CBD appears to address the underlying electrical abnormalities between seizures and improve sleep quality. These effects could contribute to better cognitive function and quality of life in children with epilepsy.","specificNumbers":"35 children, mean age 10.1. IED rate: 36.8 baseline to 19.6 at 3 months (p<0.0001). IED-seizure correlation: r=0.39 (p=0.02). Abnormal sleep: 56.5%. Sleep improvement in abnormal group: 84.6%. CBD dose: 20-50 mg/kg/day.","methodology":"Prospective open-label trial of 35 children (mean age 10.1) with drug-resistant epilepsy. CBD at 20 mg/kg/day (up to 50 mg/kg/day) with stable concomitant medications. EEGs recorded at baseline and 3 months. Two blinded independent raters evaluated IED rates in sleep stage 2 or awake state.","limitations":"Open-label design with no placebo group. Small sample. Only 3 months of follow-up. Subjective visual IED counting. Cannot separate CBD effects from natural disease fluctuation."},{"rthcId":"RTHC-03249","title":"Cannabidiol Cigarettes as Adjunctive Treatment for Psychotic Disorders - A Randomized, Open-Label Pilot-Study.","authors":"Köck, Patrick; Lang, Elisabeth; Trulley, Valerie-Noelle; Dechent, Frieder; Mercer-Chalmers-Bender, Katja; Frei, Priska; Huber, Christian; Borgwardt, Stefan","year":2021,"journal":"Frontiers in psychiatry, 12, 736822","doi":"10.3389/fpsyt.2021.736822","pmid":"34803760","tags":["psychosis","cbd"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"No significant group differences on primary outcomes (PANSS, BDI) after 4 weeks. Both groups showed decreases in psychotic symptoms and depression scores. However, the placebo group required increases in antipsychotic medication equivalent during the trial while the CBD group did not, suggesting a potential antipsychotic medication-sparing effect of smoked CBD.","whyItMatters":"This is the first study to test smoked CBD (rather than oral) for psychosis. While inconclusive due to small sample size, the medication-sparing signal is clinically interesting because reducing antipsychotic doses could lower side effect burden for patients.","specificNumbers":"Small sample (exact N not specified in abstract). 4-week treatment. Both groups: decreased PANSS and BDI. Placebo group: increased antipsychotic medication equivalent. CBD group: no medication increase needed.","methodology":"Randomized, open-label pilot trial. Patients with acute psychosis received either CBD-rich cannabis cigarettes (low THC) or placebo cigarettes as adjunctive therapy to treatment as usual. Primary outcomes: PANSS (psychotic symptoms) and BDI (depression) at 4 weeks.","limitations":"Very small sample. Open-label (not blinded). No fixed dosing regimen. Smoked delivery introduces additional variables. Cannot draw conclusions from non-significant primary outcomes with inadequate power."},{"rthcId":"RTHC-03250","title":"Ancient psychoactive plants in a global village: The ritual use of cannabis in a self-managed community in Catalonia.","authors":"Kohek, Maja; Sánchez Avilés, Constanza; Romaní, Oriol; Bouso, José Carlos","year":2021,"journal":"The International journal on drug policy, 98, 103390","doi":"10.1016/j.drugpo.2021.103390","pmid":"34340169","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03251","title":"THC Reduces Ki67-Immunoreactive Cells Derived from Human Primary Glioblastoma in a GPR55-Dependent Manner.","authors":"Kolbe, Marc Richard; Hohmann, Tim; Hohmann, Urszula; Ghadban, Chalid; Mackie, Ken; Zöller, Christin; Prell, Julian; Illert, Jörg; Strauss, Christian; Dehghani, Faramarz","year":2021,"journal":"Cancers, 13(5)","doi":"10.3390/cancers13051064","pmid":"33802282","tags":["cancer"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC reduced Ki67-positive (proliferating) glioblastoma cells, but this effect was blocked by the GPR55 antagonist CID16020046, not by CB1 or CB2 antagonists. The GPR55 agonist LPI produced similar effects to THC. Unexpectedly, CBD abolished THC's anti-proliferative effect, while CBD alone had no effect. All cells expressed CB1, CB2, GPR18, and GPR55.","whyItMatters":"Most cannabis cancer research focuses on CB1 and CB2 receptors. This study identifies GPR55 as the key receptor for THC anti-tumor effects in glioblastoma, opening a new therapeutic target. The finding that CBD blocks THC's effect is clinically important for patients using THC/CBD combinations.","specificNumbers":"Patient-derived glioblastoma cells. THC reduced Ki67+ cells. GPR55 antagonist CID abolished THC effect. CB1, CB2, GPR18 antagonists did not. LPI (GPR55 agonist) replicated THC effect. CBD blocked both THC and LPI effects.","methodology":"In vitro study using glioblastoma cells isolated from human tumor samples. Ki67 immunocytochemistry measured proliferation after 24-hour cannabinoid exposure. Receptor involvement determined by selective pharmacological blockade of CB1 (AM281), CB2 (AM630), GPR18 (O-1918), and GPR55 (CID16020046).","limitations":"In vitro study only. Patient-derived cells may not fully represent tumor behavior in vivo. Short exposure (24 hours). Proliferation marker (Ki67) is one aspect of tumor biology. Cannot predict clinical anti-tumor effects."},{"rthcId":"RTHC-03252","title":"Endocannabinoid System and Its Regulation by Polyunsaturated Fatty Acids and Full Spectrum Hemp Oils.","authors":"Komarnytsky, Slavko; Rathinasabapathy, Thirumurugan; Wagner, Charles; Metzger, Brandon; Carlisle, Carolina; Panda, Chinmayee; Le Brun-Blashka, Sara; Troup, John P; Varadharaj, Saradhadevi","year":2021,"journal":"International journal of molecular sciences, 22(11)","doi":"10.3390/ijms22115479","pmid":"34067450","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03253","title":"Use of Cannabis in Fetal Alcohol Spectrum Disorder.","authors":"Koren, Gideon; Cohen, Rana; Sachs, Ornie","year":2021,"journal":"Cannabis and cannabinoid research, 6(1), 74-76","doi":"10.1089/can.2019.0056","pmid":"33614955","tags":["cbd","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All 5 cases (2 children, 3 young adults) with FASD and severe disruptive behavior showed significant improvement after cannabis use, primarily CBD. Nisonger Child Behavior Rating Form disruptive behavior scores dropped from 18 to 6 (p=0.0002). The improvement was described as \"marked\" by the researchers.","whyItMatters":"FASD affects up to 5% of American children, and treatment options for their disruptive behaviors are extremely limited (mainly stimulants and antipsychotics). CBD's favorable safety profile could make it an attractive option if larger studies confirm these findings.","specificNumbers":"5 cases (2 children, 3 young adults). Disruptive behavior score: 18 before cannabis to 6 after (p=0.0002). Cannabis type: mostly CBD.","methodology":"Retrospective case series of 2 children and 3 young adults diagnosed with FASD and severe disruptive behavior. Behavioral changes after cannabis introduction measured using the parent version of the Nisonger Child Behavior Rating Form.","limitations":"Only 5 cases with no control group. Retrospective design. Parent-reported outcomes. Cannot rule out placebo effects, natural behavioral fluctuation, or concurrent changes. \"Mostly CBD\" is not a precise formulation."},{"rthcId":"RTHC-03254","title":"A systematic review and meta-analysis of sex differences in cannabis use disorder amongst people with comorbid mental illness.","authors":"Kozak, Karolina; H Smith, Philip; Lowe, Darby J E; Weinberger, Andrea H; Cooper, Ziva D; Rabin, Rachel A; George, Tony P","year":2021,"journal":"The American journal of drug and alcohol abuse, 47(5), 535-547","doi":"10.1080/00952990.2021.1946071","pmid":"34280058","tags":["addiction","mental-health","sex-differences"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"In the CUD-only group, males were twice as likely as females to have CUD (OR=2.0). Among mental illnesses, males were more likely to have CUD with schizophrenia (OR~2.6) and other psychotic, mood, and substance use disorders. However, a reversed pattern (females more likely) was observed for anxiety disorders and antisocial personality disorder (OR=0.8). Mental illness increased the likelihood of CUD among females for most conditions except psychotic disorders and depression.","whyItMatters":"Understanding sex differences in CUD across mental illness diagnoses is critical for tailoring prevention and treatment. The finding that mental illness differentially affects CUD risk by sex suggests that screening and intervention strategies should be diagnosis-specific.","specificNumbers":"37 studies. CUD-only: males 2x more likely (OR=2.0, CI=1.9-2.1). CUD+schizophrenia: males ~2.6x more likely. CUD+anxiety/ASPD: females slightly more likely (OR=0.8, CI=0.7-1.0). Mental illness increased female CUD likelihood except for psychotic disorders and depression.","methodology":"Systematic review and meta-analysis of 37 studies including clinical trials, cohort, and case-control studies. Generated pooled odds ratios comparing sex differences in CUD prevalence among individuals with and without mental illnesses. Meta-analysis was inconclusive due to high heterogeneity.","limitations":"High heterogeneity prevented valid meta-analysis across MI groups. Different studies used different CUD definitions. Cannot determine directionality (whether MI leads to CUD or vice versa). Publication bias possible."},{"rthcId":"RTHC-03255","title":"Endocannabinoids as potential biomarkers: It's all about pre-analytics.","authors":"Kratz, Daniel; Thomas, Dominique; Gurke, Robert","year":2021,"journal":"Journal of mass spectrometry and advances in the clinical lab, 22, 56-63","doi":"10.1016/j.jmsacl.2021.11.001","pmid":"34939056","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03256","title":"Intake, nutrient digestibility, rumen parameters, growth rate, carcase characteristics and cannabinoid residues of sheep fed pelleted rations containing hemp (Cannabis sativa L.) stubble.","authors":"Krebs, Gaye L; De Rosa, Daniel W; White, Dana M; Blake, Bronwyn L; Dods, Kenneth C; May, Christopher D; Tai, Zi X; Clayton, E H; Lynch, Emma E","year":2021,"journal":"Translational animal science, 5(4), txab213","doi":"10.1093/tas/txab213","pmid":"34988375","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03257","title":"The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent-4en and but-3en analogues including MDMB-4en-PINACA.","authors":"Krotulski, Alex J; Cannaert, Annelies; Stove, Christophe; Logan, Barry K","year":2021,"journal":"Drug testing and analysis, 13(2), 427-438","doi":"10.1002/dta.2935","pmid":"32997377","tags":["synthetic-cannabinoids","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"MDMB-4en-PINACA had a potency of 2.47 nM (compared to JWH-018 at 25.3 nM, making it about 10 times more potent) with 239% efficacy. It was identified in 25 forensic toxicology cases including postmortem and impaired driving investigations. The new class of pent-4en and but-3en analogues retained or exceeded the potency and toxicity of previous generations while evading existing drug scheduling.","whyItMatters":"Synthetic cannabinoids continue to evolve to evade regulation while maintaining or increasing potency. This new class represents a significant public safety threat because they are being sold without any dosing guidance and are far more potent than natural cannabis.","specificNumbers":"MDMB-4en-PINACA: 2.47 nM potency, 239% efficacy. MDMB-4en-PICA: 11.5 nM, 302%. MDMB-3en-BINACA: 14.3 nM, 286%. Reference JWH-018: 25.3 nM, 100%. 25 forensic cases including postmortem investigations. Geographic distribution across Northeast, Midwest, South, and West US.","methodology":"Combined in vitro CB1 receptor activation assay (beta-arrestin 2 recruitment) for 5 compounds with forensic toxicology case data. Analyzed 25 cases involving MDMB-4en-PINACA across multiple US regions through sample-mining and data-mining.","limitations":"In vitro potency does not directly predict human toxicity. Limited case histories available. Cannot determine exact cause of death in postmortem cases. Detection methods may miss some analogues."},{"rthcId":"RTHC-03258","title":"Medical cannabis and cannabis-based medicine show both potential efficacy and potential harms: Cross-sectional comparison with controls on self-rated and interviewer-rated outcomes within the Danish pilot program on medical cannabis.","authors":"Kudahl, Benedikte; Berg, Marie Eva; Posselt, Christine Merrild; Nordentoft, Merete; Hjorthøj, Carsten","year":2021,"journal":"Complementary therapies in clinical practice, 45, 101476","doi":"10.1016/j.ctcp.2021.101476","pmid":"34425501","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Medical cannabis users scored higher on treatment satisfaction (29.2 vs. 26.5, p=0.006) and lower on depression (3.3 vs. 4.6, p=0.03) compared to propensity-matched controls. However, users reported higher pain levels on the SF-36 bodily pain subdomain (36.3 vs. 48.7, p=0.01, lower = more pain). There were indications of worse MS symptoms in cannabis users. Side effects were generally mild.","whyItMatters":"Denmark's pilot program provides a rare national-level experiment in medical cannabis. The mixed results (better satisfaction and depression, worse pain scores) illustrate the complexity of evaluating medical cannabis and the danger of focusing on only positive or only negative outcomes.","specificNumbers":"Treatment satisfaction: 29.2 vs. 26.5 (p=0.006). Depression: 3.3 vs. 4.6 (p=0.03). SF-36 bodily pain: 36.3 vs. 48.7 (p=0.01, lower=more pain). MS symptom indications of worsening in cannabis group. Side effects generally mild.","methodology":"Cross-sectional study within Denmark's medical cannabis pilot program (launched January 2018). Cases who redeemed MC/CBM prescriptions were propensity-score matched to controls with same indications. Both groups completed online surveys and in-person interviews assessing depression, anxiety, cognition, satisfaction, and pain.","limitations":"Cross-sectional design cannot determine causation. Propensity matching cannot eliminate all confounders. Self-selection into the pilot program introduces bias. Higher pain in the cannabis group may reflect worse baseline conditions."},{"rthcId":"RTHC-03259","title":"Secondary indoor air pollution and passive smoking associated with cannabis smoking using electric cigarette device-demonstrative in silico study.","authors":"Kuga, Kazuki; Ito, Kazuhide; Chen, Wenhao; Wang, Ping; Fowles, Jeff; Kumagai, Kazukiyo","year":2021,"journal":"PLoS computational biology, 17(5), e1009004","doi":"10.1371/journal.pcbi.1009004","pmid":"33983924","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03260","title":"Testing a Culturally Adapted Youth Substance Use Prevention Program in a Mexican Border City: Mantente REAL.","authors":"Kulis, Stephen S; Garcia-Perez, Hilda; Marsiglia, Flavio F; Ayers, Stephanie L","year":2021,"journal":"Substance use & misuse, 56(2), 245-257","doi":"10.1080/10826084.2020.1858103","pmid":"33345674","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03261","title":"Safety and tolerability of escalating cannabinoid doses in healthy cats.","authors":"Kulpa, Justyna E; Paulionis, Lina J; Eglit, Graham Ml; Vaughn, Dana M","year":2021,"journal":"Journal of feline medicine and surgery, 23(12), 1162-1175","doi":"10.1177/1098612X211004215","pmid":"33769105","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03262","title":"Efficacy of topical capsaicin for cannabinoid hyperemesis syndrome in a pediatric and adult emergency department.","authors":"Kum, Vivian; Bell, Adrienne; Fang, Wei; VanWert, Elizabeth","year":2021,"journal":"The American journal of emergency medicine, 49, 343-351","doi":"10.1016/j.ajem.2021.06.049","pmid":"34242945","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"A significantly greater proportion of patients receiving capsaicin achieved efficacy (55% vs. 21%, p<0.001). Time to discharge after treatment was shorter in the capsaicin group (3.72 vs. 6.11 hours, p=0.001). However, capsaicin did not reduce total medications received or total ED length of stay, suggesting it may work best as a first-line treatment rather than a rescue add-on.","whyItMatters":"CHS is increasingly common and notoriously difficult to treat in the ED. Capsaicin cream applied to the abdomen is cheap, low-risk, and appears to provide meaningful symptom relief, potentially reducing ED stays and the need for multiple antiemetics.","specificNumbers":"201 patients (25 pediatric). Capsaicin efficacy: 55% vs. 21% without (p<0.001). Time to discharge: 3.72 vs. 6.11 hours (p=0.001). No difference in total medications or total ED length of stay.","methodology":"Single-center retrospective cohort study of 201 patients (25 pediatric) with suspected or confirmed CHS presenting to the ED. Compared outcomes between patients who received topical capsaicin and those who did not. Primary outcome: requiring one or fewer rescue medications after treatment.","limitations":"Retrospective design. Non-randomized treatment assignment. Single center. CHS diagnosis was clinical (no biomarker). Cannot control for which patients received capsaicin vs. not."},{"rthcId":"RTHC-03263","title":"Safety and Efficacy of Medicinal Cannabis in the Treatment of Fibromyalgia: A Systematic Review.","authors":"Kurlyandchik, Inna; Tiralongo, Evelin; Schloss, Janet","year":2021,"journal":"Journal of alternative and complementary medicine (New York, N.Y.), 27(3), 198-213","doi":"10.1089/acm.2020.0331","pmid":"33337931","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 3 RCTs and 6 observational studies, cannabis showed potential benefit for fibromyalgia symptoms with side effects limited to feeling \"high,\" dizziness, dry mouth, cough, red eyes, and drowsiness. No serious adverse events were reported. The review could not identify which specific cannabis type or formulation was most effective.","whyItMatters":"Fibromyalgia remains poorly treated by conventional medicine. This review confirms that medical cannabis has a favorable safety profile in this population, which is important given that many fibromyalgia patients are already using cannabis without clinical guidance.","specificNumbers":"181 citations screened, 10 included. 1,136 patients total. 3 RCTs, 6 observational, 1 comparison study. Study sizes: 9-383 patients (mean 114, median 36). Adverse events: mild only, no serious events.","methodology":"Systematic review searching MEDLINE, Embase, CINAHL, AMED, Scopus, and Cochrane CENTRAL (2000-2020). 10 of 181 identified studies met inclusion criteria. Total of 1,136 patients across all studies (intervention n=945, control n=108, crossover n=83).","limitations":"Only 10 studies, mostly observational. Heterogeneous study designs. Small sample sizes. Cannot determine optimal cannabis type, dose, or duration. Three different study designs limit synthesis."},{"rthcId":"RTHC-03264","title":"Exploring the use of cannabis as a substitute for prescription drugs in a convenience sample.","authors":"Kvamme, Sinikka L; Pedersen, Michael M; Rømer Thomsen, Kristine; Thylstrup, Birgitte","year":2021,"journal":"Harm reduction journal, 18(1), 72","doi":"10.1186/s12954-021-00520-5","pmid":"34246279","tags":["medical-cannabis","harm-reduction","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 2,841 respondents using cannabis medically (91% non-prescribed), 54.6% used it to replace a prescription drug. Pain medication (67.2%), antidepressants (24.5%), and arthritis medication (20.7%) were most commonly replaced. Among substituters, 38.1% completely stopped and 45.9% substantially decreased prescription use. CBD oil was the most common substitute (65.2%). 65.8% found cannabis \"much more effective\" than prescriptions, and 85.5% rated prescription side effects as \"much worse.\"","whyItMatters":"If cannabis is enabling people to reduce or eliminate prescription drug use, particularly opioids, this has enormous public health implications. The scale of self-reported substitution (over half of medical users) and the specific drugs being replaced deserve clinical attention.","specificNumbers":"2,841 respondents. 91% used non-prescribed cannabis. 54.6% substituted prescriptions. Drugs replaced: pain meds (67.2%), antidepressants (24.5%), arthritis meds (20.7%). 38.1% stopped prescriptions, 45.9% substantially decreased. CBD oil: 65.2% of substitutes. 65.8% found cannabis \"much more effective.\"","methodology":"Self-selected convenience sample recruited through social media, public media, and patient organizations. Anonymous online survey of adults using cannabis (prescribed or non-prescribed) for medical purposes. Compared substitution and non-substitution users.","limitations":"Self-selected convenience sample with strong selection bias. Non-prescribed cannabis users may differ from prescribed users. Self-reported effectiveness is subjective. No clinical verification of conditions or outcomes."},{"rthcId":"RTHC-03265","title":"Cannabidiol and Neurodevelopmental Disorders in Children.","authors":"Kwan Cheung, Keith A; Mitchell, Murray D; Heussler, Helen S","year":2021,"journal":"Frontiers in psychiatry, 12, 643442","doi":"10.3389/fpsyt.2021.643442","pmid":"34093265","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03266","title":"Mechanistic insights into the protective effect of paracetamol against rotenone-induced Parkinson's disease in rats: Possible role of endocannabinoid system modulation.","authors":"Labib, Aya Yassin; Ammar, Ramy M; El-Naga, Reem N; El-Bahy, Alshaymaa Amin Zaki; Tadros, Mariane G; Michel, Haidy E","year":2021,"journal":"International immunopharmacology, 94, 107431","doi":"10.1016/j.intimp.2021.107431","pmid":"33578261","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03267","title":"Aortic Mural Thrombus and Acute Coronary Syndrome in a Patient With Cannabinoid Hyperemesis Syndrome.","authors":"Labrada, Lyana; Patil, Aadhar; Lakhter, Vladimir; Minakata, Kenji; Islam, Sabrina","year":2021,"journal":"JACC. Case reports, 3(4), 694-696","doi":"10.1016/j.jaccas.2021.02.020","pmid":"34317606","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient had single-vessel coronary artery disease and an aortic mural thrombus. Standard treatment (antiplatelet therapy) was not possible because CHS caused inability to tolerate oral medication, necessitating coronary artery bypass and surgical thrombectomy instead.","whyItMatters":"This case illustrates how CHS can complicate treatment of other serious conditions. The persistent vomiting of CHS prevented oral antiplatelet therapy, forcing a more invasive surgical approach. It also raises questions about whether chronic cannabis use contributed to the cardiovascular pathology.","specificNumbers":"Age 36. Single-vessel coronary artery disease. Aortic mural thrombus. Required CABG and surgical thrombectomy due to CHS preventing antiplatelet therapy.","methodology":"Single case report documenting a 36-year-old woman with CHS who presented with chest pain. Clinical management described including diagnostic workup and surgical intervention.","limitations":"Single case. Cannot establish whether cannabis caused the cardiovascular pathology. The patient may have had other unmentioned risk factors."},{"rthcId":"RTHC-03268","title":"Cannabidiol treatment in an adolescent with multiple substance abuse, social anxiety and depression.","authors":"Laczkovics, Clarissa; Kothgassner, Oswald D; Felnhofer, Anna; Klier, Claudia M","year":2021,"journal":"Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater, 35(1), 31-34","doi":"10.1007/s40211-020-00334-0","pmid":"32052321","tags":["cbd","youth","depression","anxiety","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"After unsuccessful antidepressant treatment, the patient received escalating CBD doses (100-600mg over 8 weeks). Depression and anxiety symptoms improved. Social phobia and symptoms of paranoia and dissociation decreased. The patient quit using cannabis (THC), MDMA, cocaine, and ecstasy without withdrawal symptoms. CBD was safe and well tolerated throughout.","whyItMatters":"This is described as the first report of CBD in a patient with multiple substance use disorders showing positive outcomes. The simultaneous improvement in mood, anxiety, and substance use across multiple domains is notable, even in a single case.","specificNumbers":"Age 16.9. CBD dose: 100mg starting to 600mg over 8 weeks. Substances quit: cannabis (THC), MDMA, cocaine, ecstasy. No withdrawal symptoms. Improvements in depression, social phobia, paranoia, and dissociation.","methodology":"Single case report of a 16.9-year-old patient with multiple substance use disorder (cannabis, MDMA, cocaine, ecstasy), severe depression, social phobia, and narcissistic personality disorder. CBD capsules administered after antidepressant failure.","limitations":"Single case. No control. Multiple changes occurred simultaneously (stopping antidepressant, starting CBD). Cannot attribute improvements to CBD alone. Short follow-up period."},{"rthcId":"RTHC-03269","title":"Perioperative Pain and Addiction Interdisciplinary Network (PAIN): consensus recommendations for perioperative management of cannabis and cannabinoid-based medicine users by a modified Delphi process.","authors":"Ladha, Karim S; McLaren-Blades, Alexander; Goel, Akash; Buys, Michael J; Farquhar-Smith, Paul; Haroutounian, Simon; Kotteeswaran, Yuvaraj; Kwofie, Kwesi; Le Foll, Bernard; Lightfoot, Nicholas J; Loiselle, Joel; Mace, Hamish; Nicholls, Judith; Regev, Aviva; Rosseland, Leiv Arne; Shanthanna, Harsha; Sinha, Avinash; Sutherland, Ainsley; Tanguay, Rob; Yafai, Sherry; Glenny, Martha; Choi, Paul; Ladak, Salima S J; Leroux, Timothy Sean; Kawpeng, Ian; Samman, Bana; Singh, Rajbir; Clarke, Hance","year":2021,"journal":"British journal of anaesthesia, 126(1), 304-318","doi":"10.1016/j.bja.2020.09.026","pmid":"33129489","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Major consensus recommendations included: elicit and quantify cannabis use history, contact the cannabis authorizer if one exists, consider perioperative cannabis weaning, provide additional postoperative nausea/vomiting prophylaxis, pay extra attention to anesthetic depth monitoring, anticipate increased postoperative analgesic requirements, and watch for cannabis withdrawal syndrome.","whyItMatters":"As cannabis use increases, more surgical patients use cannabis regularly. Without guidelines, clinicians may not know that cannabis users may need different anesthetic management, more pain medication, and monitoring for withdrawal. These are the first formal consensus recommendations.","specificNumbers":"17 expert panelists. 4 independent reviewers. Key recommendations: screen for cannabis use, consider weaning, extra PONV prophylaxis, monitor anesthetic depth, anticipate higher analgesic needs, watch for withdrawal.","methodology":"Modified Delphi method with 17 expert panelists. Literature review followed by blinded rater forms, analysis for consensus, unblinded discussion, draft recommendations, and review by 4 independent reviewers (surgeon, nurse practitioner, 2 patients).","limitations":"Consensus-based, not evidence-based. Limited randomized trial data available. Expert opinion subject to bias. Recommendations may not apply to all cannabis products or use patterns."},{"rthcId":"RTHC-03270","title":"Endocannabinoid and dopaminergic system: the pas de deux underlying human motivation and behaviors.","authors":"Laksmidewi, A A A Putri; Soejitno, Andreas","year":2021,"journal":"Journal of neural transmission (Vienna, Austria : 1996), 128(5), 615-630","doi":"10.1007/s00702-021-02326-y","pmid":"33712975","tags":["dopamine","neuroscience","addiction","withdrawal"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review framed the endocannabinoid-dopamine interaction through Maslow's hierarchy of needs — an unusual but clarifying lens. At the base, the ECS-dopamine partnership regulates survival behaviors: feeding, sexual activity, and threat avoidance. At higher levels, it governs motivation, reward learning, achievement, and self-actualization.\n\nThe molecular mechanisms were clearly delineated. Endocannabinoids modulate dopamine through two main pathways: the nigrostriatal (motor control and habits) and mesocorticolimbic (reward, motivation, and decision-making). The review showed that these interactions were robust, reproducible, and well-established across species.\n\nFor cannabis use specifically, the review detailed how exogenous THC disrupts this calibrated partnership. Acute THC can enhance dopaminergic signaling (producing euphoria and enhanced experience), while chronic use can blunt the system (producing amotivation and anhedonia). The withdrawal state then reflects a dopamine system that has adapted to cannabis and functions poorly without it.","whyItMatters":"Framing the ECS-dopamine system through Maslow's hierarchy makes the science accessible: the same brain chemistry partnership that drives you to eat when hungry also drives you to pursue goals and feel satisfied by achievement. Cannabis temporarily enhances and then chronically impairs this system.\n\nThis explains a pattern many heavy users recognize: cannabis makes basic activities more enjoyable (food tastes better, music sounds richer) while gradually undermining the drive for higher-level goals. The biology matches the lived experience — it's not laziness, it's a neurochemical shift in how the brain assigns value to different levels of behavior.","specificNumbers":"• Two primary pathways: nigrostriatal (motor/habits) and mesocorticolimbic (reward/motivation)\n• Acute THC: enhances dopaminergic signaling\n• Chronic THC: blunts dopamine system function\n• Withdrawal: dopamine system adapted to cannabis, functions poorly without it","methodology":"Narrative review covering molecular, neurochemical, and behavioral evidence for endocannabinoid-dopamine interactions across physiological and pathological states. Published in Journal of Neural Transmission.","limitations":"Narrative review without systematic methodology. The Maslow's hierarchy framework, while illustrative, simplifies complex neural circuits. Much of the molecular evidence comes from animal models. The transition from acute enhancement to chronic blunting of dopamine is described generally without precise dose-duration thresholds. Individual variation in these systems is not addressed."},{"rthcId":"RTHC-03271","title":"Neuroprotective Effects of Cannabidiol but Not Δ9-Tetrahydrocannabinol in Rat Hippocampal Slices Exposed to Oxygen-Glucose Deprivation: Studies with Cannabis Extracts and Selected Cannabinoids.","authors":"Landucci, Elisa; Mazzantini, Costanza; Lana, Daniele; Davolio, Pier Luigi; Giovannini, Maria Grazia; Pellegrini-Giampietro, Domenico E","year":2021,"journal":"International journal of molecular sciences, 22(18)","doi":"10.3390/ijms22189773","pmid":"34575932","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD and the CBD-rich FM2 extract protected against ischemic brain damage in hippocampal slices. THC and the THC-rich Bedrocan extract worsened damage. THC toxicity was blocked by CB1 receptor antagonists. CBD neuroprotection was blocked by TRPV2, 5-HT1A, and PPARgamma antagonists. Confocal microscopy confirmed CBD preserved neuronal structure while THC did not.","whyItMatters":"Stroke is a leading cause of death and disability. Finding that CBD protects while THC harms brain tissue during ischemia has direct implications for cannabis-using stroke patients and for developing cannabinoid-based neuroprotective treatments.","specificNumbers":"Bedrocan (THC-rich): worsened ischemic damage. FM2 (CBD-rich): neuroprotective. THC toxicity: blocked by CB1 antagonists. CBD protection: blocked by TRPV2, 5-HT1A, PPARgamma antagonists. CBG also tested.","methodology":"In vitro study using rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD), an ischemia model. Tested cannabis extracts (Bedrocan, FM2) and individual cannabinoids (THC, CBD, CBG). Cell death measured by propidium iodide fluorescence. Receptor mechanisms explored with selective antagonists. Morphology assessed by confocal microscopy.","limitations":"In vitro brain slice model, not in vivo stroke. Rat tissue may not directly translate to human brain. Concentrations used may not reflect real-world brain levels. Cannot account for systemic effects."},{"rthcId":"RTHC-03272","title":"Adversity in childhood/adolescence and premorbid tobacco, alcohol, and cannabis use among first-episode psychosis patients.","authors":"Langlois, Stephanie; Zern, Adria; Kelley, Mary E; Compton, Michael T","year":2021,"journal":"Early intervention in psychiatry, 15(5), 1335-1342","doi":"10.1111/eip.13086","pmid":"33289325","tags":["psychosis","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Violence and Environmental Adversity (a factor combining community violence, housing instability, and other environmental stressors) was significantly associated with 5 of 6 substance use variables. Interpersonal Abuse was unassociated with substance use. Neglect and Lack of Connectedness was associated only with lower cannabis use likelihood. Gender stratification showed stronger effects on tobacco use among females.","whyItMatters":"Understanding what drives substance use before psychosis onset can inform early intervention. The finding that environmental violence (not just personal abuse) is the dominant predictor suggests that community-level interventions could reduce both substance use and psychosis risk.","specificNumbers":"247 patients. 86.2% African American, 74.5% male. Three adversity factors: Violence/Environmental Adversity (associated with 5/6 substance variables), Interpersonal Abuse (no associations), Neglect/Lack of Connectedness (associated only with lower cannabis use).","methodology":"Cross-sectional study of 247 first-episode psychosis patients from 6 inpatient psychiatric units in Atlanta and Washington, D.C. 14 childhood adversity scales reduced to 3 factors via factor analysis. Regression analyses tested associations with premorbid substance use.","limitations":"Cross-sectional design. Predominantly African American urban sample may not generalize. Retrospective adversity assessment subject to recall bias. Cannot determine causation."},{"rthcId":"RTHC-03273","title":"Development of individuals' own and perceptions of peers' substance use from early adolescence to adulthood.","authors":"Lansford, Jennifer E; Goulter, Natalie; Godwin, Jennifer; Crowley, Max; McMahon, Robert J; Bates, John E; Pettit, Gregory S; Greenberg, Mark; Lochman, John E; Dodge, Kenneth A","year":2021,"journal":"Addictive behaviors, 120, 106958","doi":"10.1016/j.addbeh.2021.106958","pmid":"33940335","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03274","title":"Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox-Gastaut Syndrome.","authors":"Lattanzi, Simona; Trinka, Eugen; Striano, Pasquale; Rocchi, Chiara; Salvemini, Sergio; Silvestrini, Mauro; Brigo, Francesco","year":2021,"journal":"CNS drugs, 35(3), 265-281","doi":"10.1007/s40263-021-00807-y","pmid":"33754312","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Beyond its approved indications (DS, LGS, TSC), purified CBD showed effectiveness in open-label studies for CDKL5 deficiency disorder, Aicardi syndrome, Dup15q syndrome, Doose syndrome, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. A randomized controlled trial in tuberous sclerosis complex showed significantly greater seizure reduction than placebo. Common adverse events: somnolence, decreased appetite, diarrhea, elevated liver enzymes.","whyItMatters":"Many children with rare epilepsy syndromes have no effective treatment options. This review provides preliminary evidence that purified CBD may help across a wider range of epilepsy types than currently approved, potentially expanding access for thousands of patients.","specificNumbers":"570 records screened, 42 included. CBD doses up to 50 mg/kg/day. Effective for: DS, LGS, TSC (approved), plus CDKL5, Aicardi, Dup15q, Doose, SYNGAP1, myoclonic absences (preliminary). RCT in TSC: significant seizure reduction vs. placebo.","methodology":"Systematic review of MEDLINE and NIH Clinical Trials Registry (no date or language restrictions). 570 records screened, 42 studies included. Included clinical trials, cohorts, case-control, cross-sectional, case series, and case reports of pharmaceutical-grade CBD (>98% purity) in sesame oil oral solution.","limitations":"Most evidence beyond DS/LGS/TSC comes from open-label studies. No controlled trials for the rarer syndromes. Publication bias likely. Cannot determine optimal dosing for each syndrome."},{"rthcId":"RTHC-03275","title":"Practical use of pharmaceutically purified oral cannabidiol in Dravet syndrome and Lennox-Gastaut syndrome.","authors":"Lattanzi, Simona; Zaccara, Gaetano; Russo, Emilio; La Neve, Angela; Lodi, Monica Anna Maria; Striano, Pasquale","year":2021,"journal":"Expert review of neurotherapeutics, 21(1), 99-110","doi":"10.1080/14737175.2021.1834383","pmid":"33026899","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03276","title":"Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity.","authors":"LaVigne, Justin E; Hecksel, Ryan; Keresztes, Attila; Streicher, John M","year":2021,"journal":"Scientific reports, 11(1), 8232","doi":"10.1038/s41598-021-87740-8","pmid":"33859287","tags":["neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"All four terpenes activated CB1 receptors in vitro and produced cannabinoid tetrad behaviors in mice (pain relief, immobility, hypothermia, reduced movement). Some effects were blocked by cannabinoid receptor antagonists, others by adenosine receptor antagonists, indicating mixed mechanisms. When combined with the cannabinoid WIN55,212, terpene effects were selectively additive, providing the first experimental support for the \"entourage effect.\"","whyItMatters":"The \"entourage effect\" (the idea that cannabis terpenes enhance cannabinoid effects) has been widely discussed but poorly supported by data. This study provides the first rigorous evidence that specific terpenes activate cannabinoid receptors and boost cannabinoid activity.","specificNumbers":"Four terpenes tested: alpha-humulene, geraniol, linalool, beta-pinene. All activated CB1R in vitro. All produced cannabinoid tetrad behaviors in mice. Effects were selectively additive (not simply additive or synergistic) with WIN55,212.","methodology":"Combined in vitro (CB1 receptor activation assays) and in vivo (mouse behavioral testing) approach. Tested alpha-humulene, geraniol, linalool, and beta-pinene alone and in combination with the cannabinoid agonist WIN55,212. Receptor mechanisms explored with selective antagonists.","limitations":"Used a synthetic cannabinoid (WIN55,212) rather than THC. High terpene doses in mice may not reflect inhaled or oral exposure in humans. In vivo terpene pharmacokinetics are poorly characterized. Cannot directly translate to human entourage effects."},{"rthcId":"RTHC-03277","title":"Risky business: a 15-year analysis of fatal coastal drowning of young male adults in Australia.","authors":"Lawes, Jasmin C; Ellis, Annabel; Daw, Shane; Strasiotto, Luke","year":2021,"journal":"Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention, 27(5), 442-449","doi":"10.1136/injuryprev-2020-043969","pmid":"33239312","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03278","title":"The effect of medical cannabis laws on pharmaceutical marketing to physicians.","authors":"Lebesmuehlbacher, Thomas; Smith, Rhet A","year":2021,"journal":"Health economics, 30(10), 2409-2436","doi":"10.1002/hec.4380","pmid":"34258798","tags":["legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Medical cannabis law enactment was associated with weak evidence of small, delayed reductions in pharmaceutical detailing for substitute prescription drugs and opioids. Effects were slightly more pronounced among smaller pharmaceutical firms. However, the magnitudes were economically small, likely because only a small percentage of doctors actively recommend cannabis for medical treatment.","whyItMatters":"If medical cannabis truly substitutes for prescription drugs, pharmaceutical companies should reduce marketing in response. The finding of minimal marketing response suggests either that cannabis substitution is limited in practice or that pharma companies do not perceive cannabis as a serious market threat.","specificNumbers":"Data from 2014-2018 county-level detailing records. Weak evidence of reduced detailing for substitute drugs and opioids. Larger effects in smaller firms. Magnitudes economically small.","methodology":"Exploited geographic and temporal variation in medical cannabis laws across US states. Used office detailing records from 2014-2018 aggregated to the county level. Examined changes in direct-to-physician marketing by pharmaceutical firms following MCL enactment.","limitations":"Observational with county-level aggregation. Cannot directly measure prescription substitution. Detailing records may not capture all marketing channels. 2014-2018 period captures early MCL effects only."},{"rthcId":"RTHC-03279","title":"Experimentally exploring the potential behavioral effects of personalized genetic information about marijuana and schizophrenia risk.","authors":"Lebowitz, Matthew S; Appelbaum, Paul S; Dixon, Lisa B; Girgis, Ragy R; Wall, Melanie M","year":2021,"journal":"Journal of psychiatric research, 140, 316-322","doi":"10.1016/j.jpsychires.2021.05.066","pmid":"34126426","tags":["psychosis","genetics"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Participants told they had a genetic predisposition for marijuana to increase schizophrenia risk rated the likelihood and importance of avoiding marijuana as significantly higher than controls. In the nationally representative sample, this effect was strongest among those who had previously used marijuana. Conversely, being told one lacked such a predisposition tended to lower avoidance intentions, raising concerns about a \"genetic license\" effect.","whyItMatters":"As genetic testing becomes more common, understanding how personalized risk information affects substance use behavior is critical. This study suggests genetic cannabis-psychosis risk information could be a powerful prevention tool, but the \"no predisposition\" condition raises ethical concerns.","specificNumbers":"Experiment 1: 801 participants (Mechanical Turk). Experiment 2: 800 participants (nationally representative, ages 18-30). Predisposition condition: increased avoidance intentions. No-predisposition condition: decreased avoidance in Experiment 1. Prior marijuana use moderated effects in Experiment 2.","methodology":"Two randomized experiments. Experiment 1: 801 US young adults from Mechanical Turk. Experiment 2: 800 nationally representative US adults aged 18-30. Participants randomized to three conditions: genetic predisposition present, absent, or no genetic testing (control). Measured intentions to avoid marijuana.","limitations":"Hypothetical scenarios, not actual genetic tests. Self-reported intentions may not predict behavior. Mechanical Turk sample in Experiment 1 may not be representative. Short-term measurement only."},{"rthcId":"RTHC-03280","title":"Cannabidiol prevents several of the behavioral alterations related to cocaine addiction in mice.","authors":"Ledesma, Juan Carlos; Manzanedo, Carmen; Aguilar, María A","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 111, 110390","doi":"10.1016/j.pnpbp.2021.110390","pmid":"34157334","tags":["addiction","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (30-120mg/kg) did not produce rewarding effects on its own and did not affect cocaine reward acquisition, expression, or extinction. However, when given during the extinction phase, CBD at 30 and 60mg/kg prevented priming-induced reinstatement of cocaine-seeking. CBD also abolished cocaine-induced hyperactivity without affecting normal movement. At 120mg/kg, CBD reduced memory deficits from cocaine withdrawal but did not reverse depressive-like symptoms.","whyItMatters":"Cocaine addiction has no FDA-approved pharmacotherapy. CBD preventing relapse to cocaine-seeking (the most clinically relevant finding) without producing its own reward signal is a promising therapeutic profile.","specificNumbers":"CBD doses: 30, 60, 120mg/kg. No rewarding properties at any dose. Relapse prevention: 30 and 60mg/kg effective. Hyperactivity: abolished at tested doses. Memory deficit improvement: 120mg/kg. Depression-like symptoms: no effect.","methodology":"Three studies in male C57BL/6J mice: (1) conditioned place preference for cocaine reward and relapse; (2) cocaine-induced locomotor stimulation; (3) cocaine withdrawal symptoms (memory and depression tests). CBD doses: 30, 60, and 120mg/kg injected intraperitoneally.","limitations":"Mouse model. Intraperitoneal administration. High doses relative to body weight. Cannot assess subjective craving. Male mice only. Short-term testing."},{"rthcId":"RTHC-03281","title":"Cohort study of medical cannabis authorization and motor vehicle crash-related healthcare visits in 2014-2017 in Ontario, Canada.","authors":"Lee, Cerina; Voaklander, Don; Minhas-Sandhu, Jasjeet K; Hanlon, John G; Hyshka, Elaine; Dyck, Jason R B; Eurich, Dean T","year":2021,"journal":"Injury epidemiology, 8(1), 33","doi":"10.1186/s40621-021-00321-1","pmid":"33906699","tags":["driving","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"After accounting for an initial decrease in MVC-related visits (-2.42/10,000 patients immediately post-authorization), there was a significant increasing trend (+0.89 events/10,000 relative to controls, p=0.0019). Overall, authorization was associated with an increase of 2.92 events/10,000 (95% CI: 0.64-5.19) over 6 months. The effect was largely driven by MVC-related emergency department visits (+0.80/10,000, p<0.001).","whyItMatters":"This is one of the largest studies directly linking medical cannabis authorization to traffic safety outcomes using administrative health data. The small but significant increase in MVC-related visits has public health implications as medical cannabis programs expand.","specificNumbers":"29,153 patients. Immediate effect: -2.42 visits/10,000 (p=0.014). Trend effect: +0.89/10,000 per period (p=0.0019). Net 6-month increase: +2.92/10,000 (95% CI: 0.64-5.19). Driven by ED visits: +0.80/10,000 (p<0.001).","methodology":"Matched cohort study of 29,153 medical cannabis patients and matched controls in Ontario, Canada (2014-2017). Linked to administrative health databases. Interrupted time series analysis comparing MVC-related healthcare visits 6 months before and after authorization.","limitations":"Observational design cannot prove cannabis caused crashes. Medical cannabis patients may differ from controls in unmeasured ways. Cannot determine impairment at time of crash. Short 6-month follow-up."},{"rthcId":"RTHC-03282","title":"Opioid use in medical cannabis authorization adult patients from 2013 to 2018: Alberta, Canada.","authors":"Lee, Cerina; Lin, Mu; Martins, Karen J B; Dyck, Jason R B; Klarenbach, Scott; Richer, Lawrence; Jess, Ed; Hanlon, John G; Hyshka, Elaine; Eurich, Dean T","year":2021,"journal":"BMC public health, 21(1), 843","doi":"10.1186/s12889-021-10867-w","pmid":"33933061","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Patients on high-dose opioids (OME > 100) who received medical cannabis authorization showed a significant decrease in opioid use of 435.5 mg OME over six months compared to matched controls.","whyItMatters":"With opioid overdose deaths continuing to climb in North America, any intervention that meaningfully reduces opioid dosing in high-risk patients deserves attention. This population-level data from a Canadian province offers real-world evidence beyond clinical trials.","specificNumbers":"5,373 matched pairs; average age 52 years, 54% female; high-dose patients (OME > 100) saw a decrease of 435.5 mg OME (95% CI: -596.8 to -274.2) over 6 months","methodology":"Researchers propensity-score matched 5,373 medical cannabis-authorized chronic opioid users with non-authorized controls in Alberta from 2013 to 2018. They used interrupted time series analysis to track weekly average oral morphine equivalents 26 weeks before and 52 weeks after authorization.","limitations":"Short follow-up period of one year. Cannabis authorization does not confirm actual use. Effects were modest in low-dose opioid users. Observational design limits causal conclusions."},{"rthcId":"RTHC-03283","title":"Predictors of vaping marijuana initiation among US adolescents: Results from the Population Assessment of Tobacco and Health (PATH) study Wave 3 (2015-2016) and Wave 4 (2016-2018).","authors":"Lee, Juhan; Kong, Grace; Kassas, Bachir; Salloum, Ramzi G","year":2021,"journal":"Drug and alcohol dependence, 226, 108905","doi":"10.1016/j.drugalcdep.2021.108905","pmid":"34304122","tags":["youth","respiratory"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Adolescents who already used other marijuana products had nearly 8 times the odds of initiating marijuana vaping, while e-cigarette users had about twice the odds.","whyItMatters":"Marijuana vaping exposes youth to higher THC concentrations and has been linked to vaping-related lung injuries. Identifying which teens are most likely to start helps target prevention efforts.","specificNumbers":"7,821 adolescents; other marijuana use aOR = 7.78; ENDS use aOR = 2.16; cigarettes aOR = 2.65; alcohol aOR = 1.98; vaping peers aOR = 2.31","methodology":"Researchers analyzed data from 7,821 adolescents across Waves 3 and 4 of the PATH Study (2015-2018), using multivariable logistic regression to identify baseline predictors of marijuana vaping initiation among those who had never vaped marijuana at Wave 3.","limitations":"Self-reported data subject to recall and social desirability bias. Data from 2015-2018 may not reflect current patterns. Cannot establish causation from observational data."},{"rthcId":"RTHC-03284","title":"Metabolic Consequences of Gestational Cannabinoid Exposure.","authors":"Lee, Kendrick; Hardy, Daniel B","year":2021,"journal":"International journal of molecular sciences, 22(17)","doi":"10.3390/ijms22179528","pmid":"34502436","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03285","title":"Alcohol and Cannabis Use and the Developing Brain.","authors":"Lees, Briana; Debenham, Jennifer; Squeglia, Lindsay M","year":2021,"journal":"Alcohol research : current reviews, 41(1), 11","doi":"10.35946/arcr.v41.1.11","pmid":"34567915","tags":["youth","cognition","neuroscience"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Heavy alcohol use was associated with widespread decreases in gray matter volume and slowed white matter growth, while heavy cannabis use was linked to decreased subcortical volume and increased cortical thickness. Co-use studies generally found more pronounced effects from alcohol than cannabis.","whyItMatters":"Adolescence is a critical period for brain development, and alcohol and cannabis are the two most commonly used substances during this window. Understanding their distinct and combined effects helps inform prevention messaging and policy.","specificNumbers":"43 longitudinal studies included; 18 focused on alcohol, 13 on cannabis, 12 on co-use; over 700 articles initially screened","methodology":"Researchers searched five databases using 30 search terms and identified 43 longitudinal studies with at least 50 participants that examined structural or functional brain outcomes related to adolescent alcohol and/or cannabis use. Studies included 18 on alcohol, 13 on cannabis, and 12 on co-use.","limitations":"Relatively small sample sizes and demographic homogeneity across included studies. Significant methodological heterogeneity. Difficult to disentangle effects of co-use. Cannot fully account for pre-existing differences."},{"rthcId":"RTHC-03286","title":"Effect of extrusion technology on hempseed (Cannabis sativa L.) oil cake: Polyphenol profile and biological activities.","authors":"Leonard, William; Zhang, Pangzhen; Ying, Danyang; Xiong, Yun; Fang, Zhongxiang","year":2021,"journal":"Journal of food science, 86(7), 3159-3175","doi":"10.1111/1750-3841.15813","pmid":"34176120","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03287","title":"The efficacy of health warnings and package branding on perceptions of cannabis products among youth and young adults.","authors":"Leos-Toro, Cesar; Fong, Geoffrey T; Hammond, David","year":2021,"journal":"Drug and alcohol review, 40(4), 637-646","doi":"10.1111/dar.13240","pmid":"33539597","tags":["youth","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Presence of brand imagery on cannabis packaging significantly increased appeal ratings among 16-30 year olds, while health warning labels significantly decreased appeal. Celebrity sponsors, music references, and party references all increased perceptions that the product targeted younger consumers.","whyItMatters":"As cannabis legalization expands, packaging regulations matter. This study provides evidence that marketing restrictions and plain packaging requirements could reduce the appeal of cannabis products to young people, similar to what has been observed with tobacco.","specificNumbers":"870 participants aged 16-30; brand presence increased appeal (P = 0.027); health warnings decreased appeal (P = 0.010); celebrity/music/party references all P < 0.001 for targeting younger consumers","methodology":"Researchers conducted an online experimental survey of 870 Canadian cannabis users and non-users aged 16-30, with eight between-group experiments comparing different packaging designs, brand imagery, and health warning labels.","limitations":"Online experimental design may not fully capture real-world purchasing decisions. Data collected in 2017, before Canadian legalization. Self-reported perceptions may differ from actual behavior."},{"rthcId":"RTHC-03288","title":"Cognitive and affective responses to marijuana prevention and educational messaging.","authors":"Leshner, Glenn; Stevens, Elise M; Cohn, Amy M; Kim, Seunghyun; Kim, Narae; Wagener, Theodore L; Villanti, Andrea C","year":2021,"journal":"Drug and alcohol dependence, 225, 108788","doi":"10.1016/j.drugalcdep.2021.108788","pmid":"34119879","tags":["harm-reduction","cognition","driving"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Driving-themed prevention messages from two different campaigns consistently produced the greatest cognitive resource allocation, highest arousal, and most positive emotional responses, as measured by heart rate, skin conductance, and facial action coding.","whyItMatters":"Most cannabis prevention messaging research relies on self-reports, which may not capture actual cognitive and emotional processing. This study used physiological measures to reveal which message types actually grab attention and generate emotional engagement.","specificNumbers":"50 participants; 6 messages per participant; 2 campaigns x 3 risk themes (cognitive ability, driving, health harms); psychophysiological and self-report measures","methodology":"Fifty young adult marijuana users and non-users viewed six prevention messages (three from each of two campaigns, covering three risk types). Researchers measured real-time psychophysiological responses including heart rate, skin conductance, and facial action coding, alongside self-report measures.","limitations":"Very small sample of 50 participants. Lab setting may not reflect real-world message exposure. Cannot determine whether greater physiological engagement translates to actual behavior change."},{"rthcId":"RTHC-03289","title":"Cannabinoid Hyperemesis Syndrome: A Review of the Presentation and Treatment.","authors":"Leu, Nathaniel; Routsolias, Joanne C","year":2021,"journal":"Journal of emergency nursing, 47(3), 483-486","doi":"10.1016/j.jen.2020.11.006","pmid":"33712244","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03290","title":"Sensitivity and specificity of S2BI for identifying alcohol and cannabis use disorders among adolescents presenting for primary care.","authors":"Levy, Sharon; Weitzman, Elissa R; Marin, Alexandra C; Magane, Kara M; Wisk, Lauren E; Shrier, Lydia A","year":2021,"journal":"Substance abuse, 42(3), 388-395","doi":"10.1080/08897077.2020.1803180","pmid":"32814009","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using monthly or more frequent use as the threshold, S2BI had 90% sensitivity and 89% specificity for moderate-to-severe CUD, and 100% sensitivity and 93.6% specificity for moderate-to-severe AUD. Sensitivity dropped to 81.4% for any CUD and 53.3% for any AUD.","whyItMatters":"Primary care visits represent a key opportunity to identify adolescents with substance use disorders. Validating a brief, practical screening tool against the diagnostic gold standard helps clinicians know how much to trust the results.","specificNumbers":"517 adolescents aged 14-18; CUD prevalence 8.3%; AUD prevalence 2.9%; moderate/severe CUD sensitivity 90.0%, specificity 89.0%; any CUD sensitivity 81.4%, specificity 92.0%","methodology":"Researchers administered the S2BI screening tool and the gold-standard Composite International Diagnostic Interview (CIDI) to 517 adolescents aged 14-18 presenting for primary care, then calculated sensitivity, specificity, and predictive values.","limitations":"Single-site study. Low prevalence of AUD limited statistical power for alcohol-specific analyses. Cross-sectional design cannot assess how screening performance changes over time."},{"rthcId":"RTHC-03291","title":"Occipital neural dynamics in cannabis and alcohol use: independent effects of addiction.","authors":"Lew, Brandon J; Salimian, Anabel; Wilson, Tony W","year":2021,"journal":"Scientific reports, 11(1), 22258","doi":"10.1038/s41598-021-01493-y","pmid":"34782632","tags":["neuroscience","addiction","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Participants meeting criteria for alcohol use disorder displayed significantly blunted occipital alpha (8-16 Hz) responses during visual-spatial processing, and this effect scaled with AUD symptom severity. No independent effect of cannabis use disorder was observed on any neural oscillatory measure.","whyItMatters":"Most brain imaging studies of substance use examine one substance at a time, making it hard to tease apart overlapping effects. This study specifically separated the neural impacts of alcohol and cannabis addiction in people who used both.","specificNumbers":"45 adults; 17 met criteria for AUD; 26 met criteria for CUD; all used both substances; alpha frequency range 8-16 Hz; blunted response scaled with AUD severity","methodology":"Forty-five adults who used both alcohol and cannabis underwent structured clinical interviews (SCID-V) to determine AUD and/or CUD status, then completed a visual-spatial processing task during magnetoencephalography (MEG). A 2x2 ANCOVA identified independent effects of AUD and CUD on oscillatory brain activity.","limitations":"Small sample of 45 participants. Cross-sectional design cannot determine whether AUD caused the neural changes or vice versa. Focused only on visual processing; other brain regions may show different patterns."},{"rthcId":"RTHC-03292","title":"Diagnosing intake and rationalizing toxicities associated with 5F-MDMB-PINACA and 4F-MDMB-BINACA abuse.","authors":"Lie, Wen; Cheong, Eleanor Jing Yi; Goh, Evelyn Mei Ling; Moy, Hooi Yan; Cannaert, Annelies; Stove, Christophe P; Chan, Eric Chun Yong","year":2021,"journal":"Archives of toxicology, 95(2), 489-508","doi":"10.1007/s00204-020-02948-3","pmid":"33236189","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03293","title":"Cross national comparison of medical students' attitudes and beliefs about medical cannabis and its application for pain management.","authors":"Likhitsathian, Surinporn; Edelstein, Offer E; Srisurapanont, Manit; Zolotov, Yuval; Karawekpanyawong, Nuntaporn; Reznik, Alexander; Isralowitz, Richard","year":2021,"journal":"Complementary therapies in medicine, 59, 102720","doi":"10.1016/j.ctim.2021.102720","pmid":"33864906","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Israeli secular students were more likely to recommend medical cannabis, less concerned about health risks, and more supportive of recreational legalization. However, Thai students reported feeling more prepared to answer patient questions about medical cannabis despite lower personal use rates.","whyItMatters":"Medical students become the next generation of prescribers. Their attitudes and perceived preparedness around medical cannabis will shape clinical practice and patient access in the coming decades.","specificNumbers":"430 students (163 Israeli, 267 Thai); personal cannabis use: 55.6% Israeli vs 6.9% Thai (P < .001)","methodology":"A cross-sectional survey of 430 medical students (163 from Israel, 267 from Thailand) measured attitudes, beliefs, and perceived efficacy of medical cannabis for pain-related conditions. Comparisons used Pearson chi-squared tests.","limitations":"Only two countries represented. Cross-sectional design captures a single point in time. Selection bias possible in survey participation. Cultural factors beyond medical education likely influence attitudes."},{"rthcId":"RTHC-03294","title":"Trait mindfulness and cannabis use-related factors in adolescents and young adults with frequent use.","authors":"Lin, Jessica A; Harris, Sion Kim; Shrier, Lydia A","year":2021,"journal":"Substance abuse, 42(4), 968-973","doi":"10.1080/08897077.2021.1901179","pmid":"33798028","tags":["mental-health","youth","quitting"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Higher mindfulness scores correlated with fewer cannabis-related problems (P = 0.004) and fewer quit attempts (P = 0.035). However, trait mindfulness did not predict motivation to change cannabis use.","whyItMatters":"Mindfulness-based interventions are gaining traction in addiction treatment. Understanding the relationship between trait mindfulness and cannabis-related outcomes in young frequent users helps clarify whether mindfulness is a promising treatment target.","specificNumbers":"70 participants; mean age 20.7 years; 60% female; 47% Black non-Hispanic; mean cannabis initiation age 15.0 years; regular use by age 17.0 years","methodology":"Seventy participants aged 15-24 using cannabis three or more times weekly were recruited from clinics for a cannabis intervention pilot trial. Baseline assessments measured cannabis history, use-related problems, quit attempts, and trait mindfulness.","limitations":"Small sample of 70 participants. Cross-sectional baseline data from a pilot trial. Cannot determine whether mindfulness causes fewer problems or whether people with fewer problems tend to be more mindful. Single-city recruitment."},{"rthcId":"RTHC-03295","title":"Overview of Synthetic Cannabinoids ADB-FUBINACA and AMB-FUBINACA: Clinical, Analytical, and Forensic Implications.","authors":"Lobato-Freitas, Carolina; Brito-da-Costa, Andreia Machado; Dinis-Oliveira, Ricardo Jorge; Carmo, Helena; Carvalho, Félix; Silva, João Pedro; Dias-da-Silva, Diana","year":2021,"journal":"Pharmaceuticals (Basel, Switzerland), 14(3)","doi":"10.3390/ph14030186","pmid":"33669071","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03296","title":"N-linoleyltyrosine exerts neuroprotective effects in APP/PS1 transgenic mice via cannabinoid receptor-mediated autophagy.","authors":"Long, Chun-Mei; Zheng, Qi-Xue; Zhou, Yi; Liu, Yuan-Ting; Gong, Liu-Ping; Zeng, Ying-Chun; Liu, Sha","year":2021,"journal":"Journal of pharmacological sciences, 147(4), 315-324","doi":"10.1016/j.jphs.2021.08.008","pmid":"34663513","tags":["neuroscience","inflammation","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"N-linoleyltyrosine (NITyr) improved motor coordination and spatial memory in APP/PS1 mice, reduced amyloid-beta levels in the hippocampus, and upregulated autophagy markers. The CB2 receptor antagonist AM630 blocked these effects, suggesting CB2-mediated autophagy as the primary mechanism.","whyItMatters":"Alzheimer's disease remains one of the most devastating and poorly treated neurodegenerative conditions. Compounds that can leverage the endocannabinoid system to promote autophagy and clear amyloid-beta offer a novel therapeutic angle.","specificNumbers":"Reduced Aβ40 and Aβ42 levels in hippocampus; upregulated LC3-II and Beclin-1 autophagy markers; effects blocked by AM630 (CB2 antagonist) and 3-MA (autophagy inhibitor)","methodology":"Researchers administered NITyr to APP/PS1 transgenic mice (an Alzheimer's disease model) and assessed motor coordination (rotarod test), spatial memory (Morris water maze), locomotor activity (open field test), and neural tissue integrity (HE and Nissl staining). Autophagy inhibitor 3-MA and CB receptor antagonist AM630 were used to clarify mechanisms.","limitations":"Animal study in transgenic mice; results may not translate to humans. Single compound tested. No long-term follow-up. Dosing and delivery may not be clinically practical."},{"rthcId":"RTHC-03297","title":"Pediatric Cannabinoid Hyperemesis: A Single Institution 10-Year Case Series.","authors":"Lonsdale, Hannah; Kimsey, Kathryn M; Brown, Jerry M; Dey, Aditi; Peck, Jacquelin; Son, Sorany; Wilsey, Michael","year":2021,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 68(2), 255-261","doi":"10.1016/j.jadohealth.2020.09.024","pmid":"33127240","tags":["youth","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Thirty-four patients aged 13-20 (median 17) presented with cyclic nausea and vomiting after at least 3 months of regular cannabis use. Clinical features mirrored adult cannabis hyperemesis, including abdominal pain, bowel changes, and hot shower relief. No specific antiemetic showed particular benefit.","whyItMatters":"Cannabis hyperemesis is increasingly recognized in adults but remains under-diagnosed in adolescents. This case series provides evidence that the condition presents similarly in younger patients and offers pragmatic diagnostic criteria for pediatric cases.","specificNumbers":"34 patients aged 13-20; median age 17 years; 10-year period at one institution; symptoms after at least 3 months of regular use","methodology":"Researchers reviewed records at a single institution over 10 years, including patients with cannabis-related or cyclic vomiting diagnosis codes who developed regular vomiting after starting regular cannabis use and had no better explanatory diagnosis.","limitations":"Single institution, retrospective case review. Follow-up recorded in fewer than half of patients. Drug history documentation frequently incomplete. No control group."},{"rthcId":"RTHC-03298","title":"Supporting Future Cannabis Policy - Developing a Standard Joint Unit: A Brief Back-Casting Exercise.","authors":"López-Pelayo, Hugo; Matrai, Silvia; Balcells-Olivero, Mercè; Campeny, Eugènia; Braddick, Fleur; Bossong, Matthijs G; Cruz, Olga S; Deluca, Paolo; Dom, Geert; Feingold, Daniel; Freeman, Tom P; Guzman, Pablo; Hindocha, Chandni; Kelly, Brian C; Liebregts, Nienke; Lorenzetti, Valentina; Manthey, Jakob; Matias, João; Oliveras, Clara; Pons, Maria Teresa; Rehm, Jürgen; Rosenkranz, Moritz; Swithenbank, Zoe; van Deurse, Luc; Vicente, Julian; Vuolo, Mike; Wojnar, Marcin; Gual, Antoni","year":2021,"journal":"Frontiers in psychiatry, 12, 675033","doi":"10.3389/fpsyt.2021.675033","pmid":"34093282","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03299","title":"Activation of GPR18 by Resolvin D2 Relieves Pain and Improves Bladder Function in Cyclophosphamide-Induced Cystitis Through Inhibiting TRPV1.","authors":"Lu, Qudong; Yang, Yang; Zhang, Hengshuai; Chen, Cheng; Zhao, Jiang; Yang, Zhenxing; Fan, Yi; Li, Longkun; Feng, Huan; Zhu, Jingzhen; Yi, Shanhong","year":2021,"journal":"Drug design, development and therapy, 15, 4687-4699","doi":"10.2147/DDDT.S329507","pmid":"34815664","tags":["neuroscience","pain","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Intrathecal injection of Resolvin D2 (a GPR18 agonist) increased paw withdrawal threshold and micturition interval in rats with cyclophosphamide-induced cystitis. The GPR18 antagonist O-1918 blocked these effects. GPR18 colocalized with TRPV1 in dorsal root ganglia, and RvD2 decreased capsaicin-induced calcium influx.","whyItMatters":"Interstitial cystitis/bladder pain syndrome affects millions and has limited treatment options. Identifying GPR18 as a therapeutic target through the endocannabinoid system opens a new pathway for pain and bladder dysfunction management.","specificNumbers":"GPR18 mRNA and protein expression reduced in bladder and DRG of cystitis rats; RvD2 increased paw withdrawal threshold and micturition interval; O-1918 blocked therapeutic effects","methodology":"Researchers induced cystitis in rats using cyclophosphamide, then administered intrathecal Resolvin D2 (GPR18 agonist) and O-1918 (GPR18 antagonist). Pain was assessed via paw withdrawal threshold, bladder function via cystometry, and molecular mechanisms via RT-PCR, Western blotting, immunofluorescence, and calcium imaging.","limitations":"Animal model only. Intrathecal drug delivery is not a practical clinical approach. Single disease model. Short-term outcomes measured."},{"rthcId":"RTHC-03300","title":"Cannabis Significantly Reduces the Use of Prescription Opioids and Improves Quality of Life in Authorized Patients: Results of a Large Prospective Study.","authors":"Lucas, Philippe; Boyd, Susan; Milloy, M-J; Walsh, Zach","year":2021,"journal":"Pain medicine (Malden, Mass.), 22(3), 727-739","doi":"10.1093/pm/pnaa396","pmid":"33367882","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Among participants who used opioids at baseline (28%), the proportion dropped to 11% at six months. Mean daily opioid dosage fell from 152 mg to 32.2 mg morphine milligram equivalent, a 78% reduction. Similar reductions occurred across four other prescription drug classes, and all four quality-of-life domains improved significantly.","whyItMatters":"This is one of the larger prospective studies to track individual-level changes in opioid use after starting medical cannabis. The magnitude of opioid reduction and breadth of prescription drug substitution reported here are clinically significant.","specificNumbers":"1,145 patients across 21 clinics; 57.6% female; median age 52; baseline opioid use 28% dropping to 11% at 6 months; 152 mg to 32.2 mg MME (78% reduction); significant improvements in all 4 WHOQOL-BREF domains","methodology":"The Tilray Observational Patient Study enrolled patients from 21 medical clinics across Canada, following 1,145 patients with at least one post-baseline visit at 1, 3, and 6 months. Assessments included cannabis use inventory, WHOQOL-BREF quality of life measure, and detailed prescription drug questionnaire.","limitations":"No control group. Industry-sponsored (Tilray). Self-selected patient population. Patients who dropped out may have had different outcomes. Self-reported prescription drug data."},{"rthcId":"RTHC-03301","title":"Self-reported reductions in tobacco and nicotine use following medical cannabis initiation: Results from a cross-sectional survey of authorized medical cannabis patients in Canada.","authors":"Lucas, Philippe; Walsh, Zach; Hendricks, Peter S; Boyd, Susan; Milloy, M-J","year":2021,"journal":"Journal of substance abuse treatment, 130, 108481","doi":"10.1016/j.jsat.2021.108481","pmid":"34118713","tags":["medical-cannabis","harm-reduction","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 650 current or former tobacco/nicotine users, 320 (49%) self-reported reductions in use after initiating medical cannabis, with 160 (24.6%) reporting no tobacco/nicotine use in the prior 30 days. Those who specifically intended to use cannabis to quit tobacco had nearly 3 times the odds of reducing use.","whyItMatters":"Tobacco remains the leading preventable cause of death globally. If medical cannabis genuinely helps some people reduce or quit tobacco, it could represent a novel harm reduction strategy, though this study's retrospective design means the association needs further investigation.","specificNumbers":"2,102 total participants; 650 current/former T/N users; 49% reported reductions; 24.6% reported cessation; intent to quit via cannabis aOR = 2.79; age 55+ aOR = 2.56; >25 T/N uses/day aOR = 2.11","methodology":"An online cross-sectional survey of 2,102 Canadian medical cannabis patients examined demographics, cannabis use patterns, and changes in tobacco/nicotine use before and after medical cannabis initiation. Univariate and multivariate logistic regressions assessed associations between key variables and tobacco reduction/cessation.","limitations":"Cross-sectional retrospective design cannot establish causation. Self-reported data subject to recall bias. No biochemical verification of tobacco cessation. Self-selected medical cannabis patient population. No control group."},{"rthcId":"RTHC-03302","title":"The impact of non-medical cannabis legalization and other exposures on retention in longitudinal cannabis research: a survival analysis of a prospective study of Canadian medical cannabis patients.","authors":"Lucas, Philippe; Boyd, Susan; Milloy, M-J; Walsh, Zach","year":2021,"journal":"Journal of cannabis research, 3(1), 34","doi":"10.1186/s42238-021-00089-7","pmid":"34321108","tags":["medical-cannabis","legalization"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Legalization of non-medical cannabis was associated with significantly lower odds of study retention (AOR 0.28, 95% CI 0.18-0.41). Baseline opioid use also predicted dropout, while higher psychological health scores and anti-seizure medication use predicted staying in the study.","whyItMatters":"High dropout rates threaten the validity of cannabis research. Understanding why patients leave studies is critical for designing future trials that produce reliable evidence on medical cannabis benefits and harms.","specificNumbers":"1,011 participants; 287 patient-years of data; 72% retained at 3 months; 41.4% at 6 months; post-legalization retention AOR 0.28; opioid use AOR 0.62; anti-seizure medication AOR 1.91","methodology":"The Tilray Observational Patient Study followed 1,011 Canadian medical cannabis patients across multiple sites from 2016 to 2019. Kaplan-Meier survival analysis and logistic regressions assessed factors associated with retention at 3 and 6 months.","limitations":"Convenience sample limits generalizability. Self-reported cannabis use data. Industry-sponsored study (Tilray). Cannot fully separate legalization effects from other temporal factors."},{"rthcId":"RTHC-03303","title":"Chronic cannabis smoking-enriched oral pathobiont drives behavioral changes, macrophage infiltration, and increases β-amyloid protein production in the brain.","authors":"Luo, Zhenwu; Fitting, Sylvia; Robinson, Catrina; Benitez, Andreana; Li, Min; Wu, Yongxia; Fu, Xiaoyu; Amato, Davide; Ning, Wangbin; Funderburg, Nicholas; Wang, Xu; Zhou, Zejun; Yu, Xuezhong; Wagner, Amanda; Cong, Xiaomei; Xu, Wanli; Maas, Kendra; Wolf, Bethany J; Huang, Lei; Yu, Jeremy; Scott, Alison; Mcrae-Clark, Aimee; Hamlett, Eric D; Jiang, Wei","year":2021,"journal":"EBioMedicine, 74, 103701","doi":"10.1016/j.ebiom.2021.103701","pmid":"34826801","tags":["neuroscience","cognition","respiratory"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Cannabis smokers showed oral microbial dysbiosis with increased Streptococcus and Actinomyces and decreased Neisseria. Mice orally exposed to the cannabis-enriched bacterium Actinomyces meyeri for six months showed decreased global activity, increased macrophage brain infiltration, and increased beta-amyloid 42 protein production.","whyItMatters":"This is the first study to connect cannabis-associated changes in oral bacteria to potential neurological consequences, suggesting a novel pathway by which chronic cannabis smoking might affect brain health.","specificNumbers":"16 cannabis smokers vs 27 controls; mice inoculated twice weekly for 6 months; Actinomyces meyeri enrichment inversely associated with age of first cannabis use; increased beta-amyloid 42 production in mouse brains","methodology":"Researchers compared saliva microbiomes of 16 chronic cannabis smokers with cannabis use disorder and 27 non-smoking controls using 16S rRNA sequencing. Then mice were orally inoculated with Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice weekly for six months to test functional effects.","limitations":"Very small human sample (16 vs 27). Mouse model may not replicate human oral-brain pathways. Cannot determine whether cannabis itself or combustion byproducts caused the microbial changes. No control for tobacco co-use."},{"rthcId":"RTHC-03304","title":"Outcomes in patients with acute myocardial infarction and history of illicit drug use: a French nationwide analysis.","authors":"Ma, Iris; Genet, Thibaud; Clementy, Nicolas; Bisson, Arnaud; Herbert, Julien; Semaan, Carl; Bouteau, Jérémie; Angoulvant, Denis; Ivanes, Fabrice; Fauchier, Laurent","year":2021,"journal":"European heart journal. Acute cardiovascular care, 10(9), 1027-1037","doi":"10.1093/ehjacc/zuab073","pmid":"34453835","tags":["cardiovascular","harm-reduction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Among all illicit drugs evaluated, only cannabis use was significantly associated with higher AMI risk (HR 1.32, 95% CI 1.09-1.59). However, after propensity-score matching 738,899 AMI patients, those with illicit drug use history had similar rates of death, cardiovascular death, stroke, and heart failure compared to non-users.","whyItMatters":"This is one of the largest studies to examine cannabis and heart attack risk at a population level. The finding that cannabis independently predicted AMI but not worse outcomes after AMI adds nuance to the cardiovascular risk discussion.","specificNumbers":"3,381,472 hospitalized patients in phase 1; 738,899 AMI patients in phase 2; cannabis HR 1.32 for AMI; cocaine OR 2.44, amphetamine OR 2.74, cannabis OR 2.65 for premature ASCVD; no difference in post-AMI mortality","methodology":"Researchers used the entire French hospital-discharge database. Phase 1 analyzed 3,381,472 patients hospitalized in 2013 with 5-year follow-up to identify AMI predictors. Phase 2 analyzed 738,899 AMI patients from 2010-2018, matching 3,827 illicit drug users to non-users by propensity score.","limitations":"Administrative database may undercount illicit drug use. Cannot distinguish frequency or method of cannabis use. Observational design cannot prove causation. French population may not generalize globally."},{"rthcId":"RTHC-03305","title":"Persistent Exposure to Δ9-Tetrahydrocannabinol during Adolescence Does Not Affect Nociceptive Responding in Adult Mice.","authors":"Mabou Tagne, Alex; Fotio, Yannick; Ibne Rashid, Tarif; Piomelli, Daniele","year":2021,"journal":"The Journal of pharmacology and experimental therapeutics, 378(3), 215-221","doi":"10.1124/jpet.121.000740","pmid":"34183435","tags":["youth","pain","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent mice receiving daily THC (5 mg/kg) from postnatal day 30-43 showed no significant differences from controls in formalin-induced pain behavior, chronic nerve injury pain responses, morphine antinociception, or morphine tolerance when tested at postnatal day 70. This held true for both male and female mice.","whyItMatters":"Concerns about adolescent cannabis use often focus on lasting brain changes. This study specifically tested whether adolescent THC exposure permanently alters pain processing circuits, finding no evidence of lasting disruption at a moderate dose.","specificNumbers":"THC dose: 5 mg/kg daily; treatment window: PND 30-43 (adolescence); testing at PND 70 (adulthood); both sexes tested; no significant differences on any pain measure","methodology":"C57BL6/J mice of both sexes received daily THC (5 mg/kg, i.p.) or vehicle throughout adolescence (PND 30-43). At adulthood (PND 70), researchers assessed pain behavior using the formalin test and chronic constriction injury model, and morphine responses using the tail immersion test.","limitations":"Single moderate dose tested; higher or more frequent doses might yield different results. Mouse adolescence is a rough analog to human adolescence. Only pain outcomes examined; other cognitive or psychiatric effects were not assessed."},{"rthcId":"RTHC-03306","title":"Practical Strategies Using Medical Cannabis to Reduce Harms Associated With Long Term Opioid Use in Chronic Pain.","authors":"MacCallum, Caroline A; Eadie, Lauren; Barr, Alasdair M; Boivin, Michael; Lu, Shaohua","year":2021,"journal":"Frontiers in pharmacology, 12, 633168","doi":"10.3389/fphar.2021.633168","pmid":"33995035","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03307","title":"Naturalistic exploratory study of the associations of substance use on ADHD outcomes and function.","authors":"MacDonald, Benjamin; Sadek, Joseph","year":2021,"journal":"BMC psychiatry, 21(1), 251","doi":"10.1186/s12888-021-03263-6","pmid":"33980212","tags":["cognition","mental-health","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"ADHD patients with comorbid substance use disorders scored significantly lower on objective cognitive testing (IVA/CPT, P < 0.0001). When groups were split by heavy cannabis use specifically, the association with poorer outcomes was even more pronounced, including lower cognitive scores (P = 0.0011), more severe fine motor hyperactivity, and higher self-reported hyperactivity/impulsivity (P = 0.0088 and 0.0172).","whyItMatters":"ADHD and substance use disorders frequently co-occur, but how they interact is poorly understood. This study suggests heavy cannabis use may compound the cognitive difficulties already present in ADHD.","specificNumbers":"50 ADHD patients; SUD group IVA/CPT scores P < 0.0001 lower; heavy cannabis subgroup: cognitive P = 0.0011, fine motor hyperactivity significant, self-reported hyperactivity P = 0.0088","methodology":"Researchers retrospectively analyzed 50 ADHD patient charts, allocated by substance use disorder status, then performed subgroup analysis by heavy cannabis use. Mann-Whitney and chi-square tests compared cognitive testing scores and functional outcomes.","limitations":"Very small sample of 50 patients. Retrospective chart review. Single institution. Cannot determine causation. No control for ADHD medication status or other confounders."},{"rthcId":"RTHC-03308","title":"The Link between Cannabis Use, Immune System, and Viral Infections.","authors":"Maggirwar, Sanjay B; Khalsa, Jag H","year":2021,"journal":"Viruses, 13(6)","doi":"10.3390/v13061099","pmid":"34207524","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03309","title":"Tolerability profile of topical cannabidiol and palmitoylethanolamide: a compilation of single-centre randomized evaluator-blinded clinical and in vitro studies in normal skin.","authors":"Maghfour, J; Rietcheck, H; Szeto, M D; Rundle, C W; Sivesind, T E; Dellavalle, R P; Lio, P; Dunnick, C A; Fernandez, J; Yardley, H","year":2021,"journal":"Clinical and experimental dermatology, 46(8), 1518-1529","doi":"10.1111/ced.14749","pmid":"34022073","tags":["cbd","inflammation"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Patch testing on healthy participants showed no irritation or sensitization from any CBD or PEA product tested. Mild phototoxicity was observed at 48 hours from one hemp seed oil product compared to negative control. In vitro testing showed cannabinoid products were comparable to historically non-irritating products.","whyItMatters":"As topical CBD products flood the market, basic safety data on skin tolerability has been surprisingly scarce. These controlled assessments provide foundational evidence that these formulations do not cause adverse skin reactions in healthy people.","specificNumbers":"3 clinical trials + 1 in vitro study; products included 2 CBD+PEA formulations, 1 hemp seed oil formulation, and 4 concentrations of CBD alone; no irritation or sensitization; mild phototoxicity in 1 hemp seed oil product at 48 hours","methodology":"Three evaluator-blinded human clinical trials assessed skin irritation, sensitization, and phototoxicity of CBD, PEA, and hemp seed oil formulations via patch testing on healthy adults. An in vitro study tested ocular toxicity using a hen's egg chorioallantoic membrane model.","limitations":"Single manufacturer's products tested. Only healthy, non-diseased skin assessed. Short-term patch testing may miss chronic use effects. Products may not represent the broader unregulated CBD market."},{"rthcId":"RTHC-03310","title":"The Pharmacological Effects of Plant-Derived versus Synthetic Cannabidiol in Human Cell Lines.","authors":"Maguire, Ryan F; Wilkinson, Daniel J; England, Timothy J; O'Sullivan, Saoirse E","year":2021,"journal":"Medical cannabis and cannabinoids, 4(2), 86-96","doi":"10.1159/000517120","pmid":"35224428","tags":["cbd"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"All six CBD samples (4 natural, 2 synthetic) similarly reduced cancer cell viability in a concentration-dependent manner, protected brain pericytes from oxygen-glucose deprivation via 5-HT1A receptor mechanisms, and restored inflammation-disrupted intestinal permeability via CB1 receptor antagonism. No pharmacological differences were detected between sources.","whyItMatters":"As the CBD market grows, debates about natural versus synthetic CBD influence consumer choices and regulatory decisions. This study provides evidence that the molecule behaves the same regardless of its origin, shifting the focus to purity and formulation quality.","specificNumbers":"6 CBD samples (4 natural, 2 synthetic); 3 cell-based models tested; neuroprotection blocked by 5-HT1A antagonist; permeability restoration blocked by CB1 antagonist; no significant differences between sources","methodology":"Researchers compared six purified CBD samples (4 plant-derived, 2 synthetic) across three in vitro models: SKOV-3 ovarian cancer cell viability, human pericyte neuroprotection in a stroke model, and differentiated Caco-2 cell intestinal permeability under inflammatory conditions.","limitations":"In vitro only; cell behavior may not reflect whole-organism pharmacology. Limited number of samples from each source. Does not address differences in minor cannabinoids or terpenes that may be present in less purified natural products."},{"rthcId":"RTHC-03311","title":"Recreational substance use among patients with premature atherosclerotic cardiovascular disease.","authors":"Mahtta, Dhruv; Ramsey, David; Krittanawong, Chayakrit; Al Rifai, Mahmoud; Khurram, Nasir; Samad, Zainab; Jneid, Hani; Ballantyne, Christie; Petersen, Laura A; Virani, Salim S","year":2021,"journal":"Heart (British Cardiac Society), 107(8), 650-656","doi":"10.1136/heartjnl-2020-318119","pmid":"33589427","tags":["cardiovascular","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis use was independently associated with premature ASCVD (OR 2.65, 95% CI 2.59-2.71). Polysubstance users showed a graded response, with use of 4+ substances conferring approximately 9-fold higher risk. The association between substance use and premature ASCVD was stronger in women than men.","whyItMatters":"Heart disease among younger adults is rising, and recreational substance use may be a significant contributor. This massive VA dataset reveals the relative cardiovascular risk associated with each major substance, with cannabis showing a substantial independent association.","specificNumbers":"135,703 premature ASCVD patients; 1,112,455 non-premature controls; cannabis use 12.5% vs 2.7%; cannabis OR 2.65; cocaine OR 2.44; amphetamine OR 2.74; 4+ substances ~9-fold risk; stronger effects in women","methodology":"Cross-sectional analysis of the 2014-2015 nationwide VA Healthcare database and VITAL registry compared 135,703 premature ASCVD patients and 7,716 extremely premature ASCVD patients against 1,112,455 non-premature ASCVD patients using multivariable logistic regression.","limitations":"VA population is predominantly male and may not generalize to the broader population. Cross-sectional design cannot prove causation. Substance use likely underreported in administrative data. Cannot distinguish frequency or route of use."},{"rthcId":"RTHC-03312","title":"The Effect of Hemp (Cannabis sativa L.) Seeds and Hemp Seed Oil on Vascular Dysfunction in Obese Male Zucker Rats.","authors":"Majewski, Michał; Jurgoński, Adam","year":2021,"journal":"Nutrients, 13(8)","doi":"10.3390/nu13082575","pmid":"34444734","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03313","title":"Therapeutic potential of cannabinoids in combination cancer therapy.","authors":"Malhotra, Pratibha; Casari, Ilaria; Falasca, Marco","year":2021,"journal":"Advances in biological regulation, 79, 100774","doi":"10.1016/j.jbior.2020.100774","pmid":"33422460","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03314","title":"Synthetic cannabinoid induced ocular self-injury.","authors":"Malik, Kunal; Kommana, Sumana; Paul, Joshua; Krakauer, Mark","year":2021,"journal":"Orbit (Amsterdam, Netherlands), 40(4), 326-328","doi":"10.1080/01676830.2020.1781199","pmid":"32552411","tags":["synthetic-cannabinoids","psychosis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Both patients had untreated schizophrenia and used K2 (synthetic cannabinoid). Each hallucinated a bug behind their eye and caused periocular soft tissue damage attempting to remove it. These are reported as the first cases of ocular self-injury from synthetic cannabinoid intoxication.","whyItMatters":"Synthetic cannabinoids carry significantly more serious psychiatric side effects than natural cannabis. These cases illustrate the potential for severe self-harm when synthetic cannabinoids interact with pre-existing psychotic disorders.","specificNumbers":"2 patients; both with untreated schizophrenia; both intoxicated on K2; identical hallucination of bug behind eye; first reported cases of this type","methodology":"Clinical case reports of two patients presenting to a single institution with ocular self-injury following synthetic cannabinoid (K2) use, both with pre-existing untreated schizophrenia.","limitations":"Only two cases reported. Both patients had pre-existing untreated schizophrenia, making it difficult to attribute effects solely to the drug. No toxicological confirmation of specific synthetic cannabinoid compound."},{"rthcId":"RTHC-03315","title":"Chronic Marijuana Consumption Leading to High-Grade Atrioventricular Block in a Young Male.","authors":"Malviya, Amit; Khan, Shakeel A; Gupta, Anunay; Mishra, Animesh","year":2021,"journal":"Cureus, 13(7), e16202","doi":"10.7759/cureus.16202","pmid":"34367805","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Electrophysiology study revealed high-grade supra-Hisian AV block with prolonged His-ventricular interval in a young man with chronic cannabis use and no other identifiable cause. The arrhythmia did not resolve after three months, and a dual-chamber pacemaker was required. This is the first report of electrophysiologic localization of cannabis-induced conduction block.","whyItMatters":"While cannabis-associated tachyarrhythmias are well-documented, bradyarrhythmias are rare. The prolonged HV interval suggests cannabis may directly affect the cardiac conduction system rather than just increasing vagal tone, as previously assumed.","specificNumbers":"Age 26; heart rate 42 bpm at presentation; positive for THC metabolite 11-Nor-9-carboxy-THC; supra-Hisian block with prolonged HV interval; dual-chamber pacemaker implanted; arrhythmia persisted at 3-month follow-up","methodology":"Clinical case report of a 26-year-old male with chronic cannabis smoking who presented with dizziness and syncope. ECG, electrophysiology study, urinary THC metabolite testing, and follow-up evaluation were performed after ruling out other causes.","limitations":"Single case report. Cannot definitively prove cannabis caused the conduction block. Possible confounders from unknown adulterants. No long-term follow-up beyond three months."},{"rthcId":"RTHC-03316","title":"Tetrahydrocannabinol and Skin Cancer: Analysis of YouTube Videos.","authors":"Mamo, Andrina; Szeto, Mindy D; Mirhossaini, Roya; Fortugno, Andrew; Dellavalle, Robert P","year":2021,"journal":"JMIR dermatology, 4(1), e26564","doi":"10.2196/26564","pmid":"37632811","tags":["cancer","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"All 10 videos received the lowest possible Global Quality Scale score (1 = poor quality). Nine of 10 received a DISCERN score of 0 (poor reliability). All were classified as misleading. Despite this, 48% of top comments were favorable and 48% neutral, with only 4% unfavorable.","whyItMatters":"Patients with skin cancer may encounter these popular videos and delay or forgo evidence-based treatment. The disconnect between poor information quality and overwhelmingly positive audience reception makes this a significant public health concern.","specificNumbers":"10 most-viewed videos analyzed; 10/10 GQS score of 1 (poor); 9/10 DISCERN score of 0 (poor); 10/10 misleading; 48% favorable comments, 48% neutral, 4% unfavorable","methodology":"Researchers analyzed the 10 most-viewed YouTube videos on THC oil and skin cancer using the Global Quality Scale, DISCERN score, and established useful/misleading criteria. Top comments were categorized as favorable, unfavorable, or neutral.","limitations":"Only 10 videos analyzed. YouTube content changes rapidly. Comment analysis is limited in scope. Does not measure whether viewers actually changed treatment decisions."},{"rthcId":"RTHC-03317","title":"Pharmacokinetics and Perceptions of Children and Young Adults Using Cannabis for Attention-Deficit/Hyperactivity Disorder and Oppositional Defiant Disorder: Protocol for a Mixed Methods Proof-of-Concept Study.","authors":"Mansell, Holly; Quinn, Declan; Kelly, Lauren E; Szafron, Michael; Alcorn, Jane","year":2021,"journal":"JMIR research protocols, 10(10), e31281","doi":"10.2196/31281","pmid":"34661540","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03318","title":"Role of sex on the relationship between sexual minority status and past 30-day marijuana use among high school students (YRBS, 2015-2019).","authors":"Mantey, Dale S; Andrew Yockey, R; Barroso, Cristina S","year":2021,"journal":"Addictive behaviors, 118, 106905","doi":"10.1016/j.addbeh.2021.106905","pmid":"33752162","tags":["youth","sex-differences","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"The association between sexual minority status and marijuana use differed significantly by sex. Among females, sexual minority status was associated with 1.33 greater odds of past 30-day marijuana use. Among males, sexual minority status was associated with 0.70 lower odds. The interaction was statistically significant.","whyItMatters":"Assuming all sexual minority youth face the same substance use risk patterns misses important sex-based differences. These findings suggest prevention programs need to be tailored rather than treating sexual minority youth as a monolithic group.","specificNumbers":"37,870 students; females: SMS OR 1.33; males: SMS OR 0.70; interaction P < 0.05; pooled from 3 YRBS cycles (2015, 2017, 2019)","methodology":"Researchers pooled data from the 2015, 2017, and 2019 Youth Risk Behavior Surveillance surveys (n = 37,870 9th-12th graders). Interaction models and sex-stratified logistic regressions tested effect modification, adjusting for race/ethnicity, grade, tobacco use, illicit drug use, and survey year.","limitations":"Cross-sectional self-report data. Cannot determine causation. Sexual minority status was measured by identity, not behavior or attraction. YRBS does not include non-enrolled youth."},{"rthcId":"RTHC-03319","title":"Contextual influences of illicit adolescent marijuana cultivation and trading in the Inqguza Hill local municipality of South Africa: implications for public health policy.","authors":"Manu, Emmanuel; Douglas, Mbuyiselo; Ntsaba, Mohlomi Jafta","year":2021,"journal":"Substance abuse treatment, prevention, and policy, 16(1), 6","doi":"10.1186/s13011-020-00338-7","pmid":"33413542","tags":["youth","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Factors driving adolescent marijuana farming and trading spanned four levels: intrapersonal (knowledge/skills, courage), interpersonal (peer and family influences), communal (economic reasons, early childhood exposure, protecting family lands, favorable topography and soil), and policy-related (lack of communal bylaws, lax law enforcement).","whyItMatters":"Understanding why adolescents cultivate and trade cannabis in specific contexts is essential for designing prevention programs that address root causes rather than just symptoms. Economic factors and family tradition emerged as powerful drivers that punitive approaches alone cannot address.","specificNumbers":"33 participants; 2 communities; 11 contextual factors; 4 socio-ecological levels; Ingquza Hill Local Municipality, South Africa","methodology":"Qualitative study using focus group discussions with 33 purposefully sampled participants recruited through snowball sampling in two communities in the Ingquza Hill Local Municipality. A semi-structured interview guide and thematic content analysis were used, organized around the Socio-Ecological Model.","limitations":"Small qualitative sample from two communities in one municipality. Findings may not generalize to other regions. Self-report data on illicit activity may be subject to social desirability bias. No quantitative verification of themes."},{"rthcId":"RTHC-03320","title":"Calling for Openness to the Study of Cannabis Use in Chronic Pelvic Pain.","authors":"Manz, Joren; Hyakutake, Momoe; Kelly, Erin","year":2021,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 43(5), 611-613","doi":"10.1016/j.jogc.2020.08.021","pmid":"33132057","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03321","title":"Association between continued cannabis use during pregnancy and symptoms of anxiety and depression.","authors":"Mark, Katrina; Otieno, Linda; Moore, Ellen; Zehra, Amna; Mitchell, Mary","year":2021,"journal":"International review of psychiatry (Abingdon, England), 33(6), 528-533","doi":"10.1080/09540261.2021.1898348","pmid":"34402713","tags":["pregnancy","anxiety","depression"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Women who continued cannabis use had significantly higher odds of elevated GAD scores (2.55, 95% CI 1.31-4.99) and EPDS depression scores (2.75, 95% CI 1.43-5.28) compared to non-users. Women with higher depression scores had 2.70 times the odds of continuing use rather than quitting.","whyItMatters":"Cannabis use during pregnancy is common (36.3% tested positive at care initiation in this sample), and mental health symptoms may drive continued use. Understanding this bidirectional relationship is important for designing interventions that address both issues simultaneously.","specificNumbers":"604 women; 221 (36.3%) positive for cannabis at care initiation; continued use: GAD OR 2.55, EPDS OR 2.75 vs non-users; higher depression scores: 2.70x odds of continuing vs quitting","methodology":"Retrospective cohort at a single site evaluated urine toxicology for cannabis at two time points to categorize 604 women as never-used, quit, or continued. Edinburgh Postnatal Depression Scale and Generalized Anxiety Disorder scores were compared using multinomial logistic regression.","limitations":"Single site, retrospective design. Urine testing has a limited detection window. Cannot determine whether cannabis use caused mood symptoms or vice versa. No data on cannabis use patterns, amounts, or products."},{"rthcId":"RTHC-03322","title":"Short- and long-term exposures of the synthetic cannabinoid 5F-APINAC induce metabolomic alterations associated with neurotransmitter systems and embryotoxicity confirmed by teratogenicity in zebrafish.","authors":"Markin, Pavel A; Brito, Alex; Moskaleva, Natalia E; Tagliaro, Franco; La Frano, Michael R; Savitskii, Mark V; Appolonova, Svetlana A","year":2021,"journal":"Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 243, 109000","doi":"10.1016/j.cbpc.2021.109000","pmid":"33561556","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03323","title":"Epigenome-wide analysis uncovers a blood-based DNA methylation biomarker of lifetime cannabis use.","authors":"Markunas, Christina A; Hancock, Dana B; Xu, Zongli; Quach, Bryan C; Fang, Fang; Sandler, Dale P; Johnson, Eric O; Taylor, Jack A","year":2021,"journal":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 186(3), 173-182","doi":"10.1002/ajmg.b.32813","pmid":"32803843","tags":["genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Researchers identified a replicated association between lifetime cannabis use and DNA methylation at site cg15973234 in the CEMIP gene (combined P = 3.3 x 10^-8). The methylation-based classifier had modest predictive accuracy with AUC of 0.60 in discovery and 0.54 in replication samples.","whyItMatters":"Objective biomarkers of cannabis use are needed for epidemiological research. While urine and blood tests detect recent use, DNA methylation could potentially serve as a marker of cumulative lifetime exposure, capturing long-term use patterns that self-report may miss.","specificNumbers":"Discovery N = 1,730 (855 ever-users); replication N = 853 (392 ever-users); cg15973234 in CEMIP gene P = 3.3 x 10^-8; AUC 0.60 discovery, 0.54 replication","methodology":"Epigenome-wide association study using blood-based DNA methylation data from a case-cohort within the Sister Study (discovery N = 1,730; replication N = 853). Researchers tested associations between methylation at over 450,000 sites and self-reported lifetime cannabis use.","limitations":"All-female cohort (Sister Study) limits generalizability. Modest predictive accuracy. Cannot distinguish frequency, recency, or duration of use. Self-reported cannabis use as the comparator."},{"rthcId":"RTHC-03324","title":"Cannabis use disorder trajectories and their prospective predictors in a large population-based sample of young Swiss men.","authors":"Marmet, Simon; Studer, Joseph; Wicki, Matthias; Gmel, Gerhard","year":2021,"journal":"Addiction (Abingdon, England), 116(3), 560-570","doi":"10.1111/add.15177","pmid":"32621560","tags":["addiction","mental-health","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Four trajectories were identified: stable-low (88.2%), decreasing (5.2%), stable-high (2.6%), and increasing (4.0%). Predictors of persistent high severity versus decreasing included major depression (OR 1.19), ADHD severity (OR 1.25), antisocial personality disorder (OR 1.18), poor parental relationships (OR 0.74), friends with drug problems (OR 1.33), and neuroticism-anxiety (OR 1.35).","whyItMatters":"Most young men with cannabis use disorder symptoms naturally improve over time. Identifying the roughly 3% who remain stuck in high-severity use allows for targeted early intervention rather than broad-brush approaches.","specificNumbers":"5,987 men; ages 20-25; 88.2% stable-low; 5.2% decreasing; 2.6% stable-high; 4.0% increasing; depression OR 1.19; ADHD OR 1.25; friends with drug problems OR 1.33","methodology":"Latent class growth analysis of 5,987 Swiss men assessed at mean ages 20, 21.5, and 25 years. Cannabis Use Disorders Identification Test-Revised (CUDIT-R) measured severity at each wave. Predictors from six domains (cannabis use, family, peers, other substances, mental health, personality) were assessed at age 20.","limitations":"Male-only Swiss sample limits generalizability. Self-reported measures. Effect sizes were small. Predictors measured at one time point may not capture dynamic changes. Three waves may miss important transitions."},{"rthcId":"RTHC-03325","title":"Psychiatric Comorbidity and Addiction Severity Differences in Patients With ADHD Seeking Treatment for Cannabis or Cocaine Use Disorders.","authors":"Martínez-Luna, Nieves; Daigre, Constanza; Palma-Álvarez, Felipe; Perea-Ortueta, Marta; Grau-López, Lara; Roncero, Carlos; Castell-Panisello, Eudald; Ramos-Quiroga, Josep Antoni","year":2021,"journal":"Journal of attention disorders, 25(7), 978-988","doi":"10.1177/1087054719875787","pmid":"31550967","tags":["addiction","mental-health","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In multivariate analysis, the cannabis group had significantly higher rates of lifetime anxiety disorder and younger age at onset of any substance use disorder. The cannabis/cocaine polysubstance group showed more work-related impairment. ADHD features were similar across all groups regardless of primary substance.","whyItMatters":"ADHD patients with substance use disorders represent a complex clinical population. Understanding how the primary substance of concern relates to psychiatric comorbidity and functional impairment helps tailor treatment approaches.","specificNumbers":"1,538 SUD patients screened; 239 (15.5%) had ADHD; cannabis n=41, cannabis/cocaine n=36, cocaine n=74; 80% male; mean age 32.9 years","methodology":"From 1,538 substance use disorder patients evaluated for ADHD, 239 (15.5%) had ADHD. These were divided into cannabis (n=41), cannabis/cocaine (n=36), and cocaine (n=74) groups. Assessment included EuropASI, CAADID, SCID, ASRS, WURS, BIS-11, and multinomial regression.","limitations":"Cross-sectional treatment-seeking sample. Relatively small subgroups. Cannot determine causation or direction of relationships. Single treatment center in Spain."},{"rthcId":"RTHC-03326","title":"Early detection of bipolar disorders and treatment recommendations for help-seeking adolescents and young adults: Findings of the Early Detection and Intervention Center Dresden.","authors":"Martini, Julia; Leopold, Karolina; Pfeiffer, Steffi; Berndt, Christina; Boehme, Anne; Roessner, Veit; Fusar-Poli, Paolo; Young, Allan H; Correll, Christoph U; Bauer, Michael; Pfennig, Andrea","year":2021,"journal":"International journal of bipolar disorders, 9(1), 23","doi":"10.1186/s40345-021-00227-3","pmid":"34215910","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03327","title":"Pharmacology, Clinical Effects, and Therapeutic Potential of Cannabinoids for Gastrointestinal and Liver Diseases.","authors":"Maselli, Daniel B; Camilleri, Michael","year":2021,"journal":"Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 19(9), 1748-1758.e2","doi":"10.1016/j.cgh.2020.04.020","pmid":"32673642","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03328","title":"Trends in Adolescent Cannabis-Related Hospitalizations by State Legalization Laws, 2008-2019.","authors":"Masonbrink, Abbey R; Richardson, Troy; Hall, Matt; Catley, Delwyn; Wilson, Karen","year":2021,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 69(6), 999-1005","doi":"10.1016/j.jadohealth.2021.07.028","pmid":"34511329","tags":["youth","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-related hospitalization odds increased after both medical cannabis laws (OR 1.05) and recreational cannabis laws (OR 1.03). The greatest increases post-legalization were in adolescents without underlying mental health or substance use disorders and in younger adolescents (age 13) in recreational states.","whyItMatters":"Legalization policies for adults (21+) may have downstream effects on adolescent health. The finding that younger teens and those without pre-existing mental health conditions showed the greatest post-legalization increases suggests legalization may be expanding cannabis-related hospitalizations beyond traditional high-risk groups.","specificNumbers":"1,898,432 hospitalizations; 37,562 (2%) cannabis-related; MCL states OR 1.05; NMCL states OR 1.03; greatest increases in adolescents without mental health disorders and age 13 in NMCL states","methodology":"Retrospective cohort study of 1,898,432 adolescent (11-17 years) hospitalizations at children's hospitals from 2008-2019 using the Inpatient Essentials database across 18 states and Washington, DC. Logistic regression compared cannabis-related diagnoses by state legalization status.","limitations":"Hospital-based data may miss cases managed in outpatient settings. Cannabis-related diagnosis coding may vary across institutions and time. Cannot determine whether increases reflect more use or more screening/documentation. Administrative data lacks use pattern details."},{"rthcId":"RTHC-03329","title":"Critical Review on the Chemical Aspects of Cannabidiol (CBD) and Harmonization of Computational Bioactivity Data.","authors":"Mastinu, Andrea; Ribaudo, Giovanni; Ongaro, Alberto; Bonini, Sara Anna; Memo, Maurizio; Gianoncelli, Alessandra","year":2021,"journal":"Current medicinal chemistry, 28(2), 213-237","doi":"10.2174/0929867327666200210144847","pmid":"32039672","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03330","title":"Left main coronary artery thrombus after cannabis consumption: a case report.","authors":"Matta, Anthony; Elenizi, Khaled; Elbaz, Meyer; Roncalli, Jerome","year":2021,"journal":"European heart journal. Case reports, 5(6), ytab179","doi":"10.1093/ehjcr/ytab179","pmid":"34222781","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Coronary angiography revealed a mobile thrombus in the left main coronary artery, a rare and potentially fatal finding, in a young male cannabis consumer. The patient was successfully treated with manual aspiration thrombectomy, dual antiplatelet therapy, and unfractionated heparin.","whyItMatters":"Left main coronary thrombus is a life-threatening finding usually associated with atherosclerotic plaque rupture. Its occurrence in a young cannabis user without typical risk factors raises questions about cannabis as a prothrombotic trigger.","specificNumbers":"Young male patient; left main coronary artery thrombus; non-ST-elevation myocardial infarction; treated with manual aspiration, dual antiplatelet therapy, and heparin","methodology":"Single case report documenting clinical presentation, coronary angiography findings, and management of left main coronary thrombus in a young cannabis user presenting with non-ST-elevation myocardial infarction.","limitations":"Single case report. Cannot prove cannabis caused the thrombus. Other prothrombotic factors may not have been fully evaluated. No systematic comparison to other cases."},{"rthcId":"RTHC-03331","title":"Medical cannabis for the treatment of fibromyalgia syndrome: a retrospective, open-label case series.","authors":"Mazza, Manuela","year":2021,"journal":"Journal of cannabis research, 3(1), 4","doi":"10.1186/s42238-021-00060-6","pmid":"33597032","tags":["medical-cannabis","pain"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Significant improvements (P < 0.01) were observed in pain scores (NRS), disability (ODI), widespread pain (WPI), and symptom severity (SyS) at various time points up to 12 months. However, 17 patients (48.6%) discontinued due to non-serious adverse effects including mental confusion (37%), dizziness (14%), nausea/vomiting (14%), and restlessness (14%).","whyItMatters":"Fibromyalgia is notoriously difficult to treat, and patients who fail conventional therapy have few options. This series provides real-world data on both the potential benefits and the significant tolerability challenges of medical cannabis in this population.","specificNumbers":"38 patients; 30 at 1 month, 18 at 3 months, 12 at 12 months; 48.6% discontinued due to AEs; mental confusion 37%; median THC dose 46.2 mg (dominant) or 23.6 mg THC + 38 mg CBD (hybrid) at 3 months","methodology":"Retrospective, open-label case series of 38 fibromyalgia patients resistant to conventional therapy at an Italian pain clinic. Patients received licensed medical cannabis as powdered flowers or oil extracts with various THC/CBD ratios. Outcomes measured at 1, 3, and 12 months.","limitations":"No control group or blinding. High dropout rate limits interpretation of long-term results. Retrospective design. Small sample. Italian regulatory context may affect product availability and dosing."},{"rthcId":"RTHC-03332","title":"Determining the magnitude and duration of acute Δ9-tetrahydrocannabinol (Δ9-THC)-induced driving and cognitive impairment: A systematic and meta-analytic review.","authors":"McCartney, Danielle; Arkell, Thomas R; Irwin, Christopher; McGregor, Iain S","year":2021,"journal":"Neuroscience and biobehavioral reviews, 126, 175-193","doi":"10.1016/j.neubiorev.2021.01.003","pmid":"33497784","tags":["driving","cognition"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"At peak effect, THC significantly impaired lateral control, tracking, and divided attention. The duration of impairment from inhaled THC depended on dose, time since use, and skill assessed, but generally resolved within 3-5 hours. Oral THC-induced impairment took longer to subside. The researchers suggested waiting at least 5 hours after inhaled cannabis before performing safety-sensitive tasks.","whyItMatters":"As cannabis legalization expands, evidence-based guidelines for how long to wait before driving are essential. This meta-analysis provides the most comprehensive synthesis to date of how long THC-related driving impairment actually lasts.","specificNumbers":"80 publications reviewed; 1,534 outcomes analyzed; impairment significant at peak for lateral control, tracking, divided attention; recommended wait time: at least 5 hours after inhaled use","methodology":"Systematic review and meta-analysis of 80 publications encompassing 1,534 outcomes examining acute THC effects on driving performance and driving-related cognitive skills, with particular focus on duration of impairment.","limitations":"Laboratory and simulated driving conditions may not fully replicate real-world driving. Most studies used moderate, controlled doses. Individual variation in tolerance and metabolism is not captured. Limited data on high-potency products."},{"rthcId":"RTHC-03333","title":"The effect of daily aerobic cycling exercise on sleep quality during inpatient cannabis withdrawal: A randomised controlled trial.","authors":"McCartney, Danielle; Isik, Ashling D; Rooney, Kieron; Arnold, Jonathon C; Bartlett, Delwyn J; Murnion, Bridin; Richards, Elisha; Arkell, Thomas R; Lintzeris, Nicholas; McGregor, Iain S","year":2021,"journal":"Journal of sleep research, 30(3), e13211","doi":"10.1111/jsr.13211","pmid":"33078435","tags":["sleep","withdrawal","exercise"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"The cycling group showed improved sleep duration (P = 0.008) and sleep efficiency (P = 0.023) from baseline to treatment, while the stretching control group saw increased sleep onset latency. During treatment, cycling increased sleep duration (P = 0.005) and decreased average wake bout duration (P = 0.040) compared to stretching. Subjective sleep ratings did not differ between groups.","whyItMatters":"Sleep disturbance is one of the most common and distressing symptoms of cannabis withdrawal, often driving relapse. Finding non-pharmacological interventions that improve sleep during this critical period could support more successful cessation.","specificNumbers":"31 participants (19 cycling, 12 stretching); 35 min daily exercise; ~60% VO2max; sleep duration P = 0.005 cycling vs stretching; sleep efficiency P = 0.023 improvement in cycling group","methodology":"Randomized controlled trial with 31 cannabis-dependent adults (19 cycling, 12 stretching) during a 7-day inpatient stay. The cycling group performed 35 minutes daily at ~60% VO2max. Sleep was measured objectively using wrist actigraphy and subjectively using self-report across baseline, treatment, and post-treatment phases.","limitations":"Small sample size (31 total). Unequal group sizes. Inpatient setting may not generalize to outpatient withdrawal. Subjective sleep ratings did not mirror objective improvements. Short treatment phase."},{"rthcId":"RTHC-03334","title":"Driving under the influence of cannabis risk perceptions and behaviour: A population-based study in Ontario, Canada.","authors":"McDonald, André J; Hamilton, Hayley A; Wickens, Christine M; Watson, Tara Marie; Elton-Marshall, Tara; Wardell, Jeffrey D; Rueda, Sergio; Roerecke, Michael; Stoduto, Gina; Mann, Robert E","year":2021,"journal":"Preventive medicine, 153, 106793","doi":"10.1016/j.ypmed.2021.106793","pmid":"34517043","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"About 90% of adults agreed DUIC increases collision risk, dropping to 55% among past-year DUIC drivers. Being male, less educated, and using cannabis monthly or more were associated with disagreeing that DUIC increases crash risk. Safety perceptions but not legal risk perceptions were associated with actual DUIC behavior among cannabis-using drivers.","whyItMatters":"Risk perception drives behavior. The finding that safety concerns, not fear of getting caught, predicted whether cannabis users drove high suggests prevention campaigns should focus on crash risk messaging rather than legal consequences.","specificNumbers":"1,813 adults; ~90% overall agreed DUIC increases crash risk; 55% of past-year DUIC drivers agreed; males, less educated, monthly+ users most likely to dismiss risk","methodology":"Cross-sectional telephone survey of 1,813 adults aged 18+ in Ontario, Canada (2017 CAMH Monitor). Multivariable logistic regression assessed factors associated with DUIC risk perceptions and the relationship between perceptions and DUIC behavior.","limitations":"Cross-sectional design. Self-reported DUIC behavior subject to social desirability bias. Ontario-specific data may not generalize. Pre-legalization data collection (2017)."},{"rthcId":"RTHC-03335","title":"Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies.","authors":"McElroy, Dan L; Roebuck, Andrew J; Scott, Gavin A; Greba, Quentin; Garai, Sumanta; Denovan-Wright, Eileen M; Thakur, Ganesh A; Laprairie, Robert B; Howland, John G","year":2021,"journal":"Psychopharmacology, 238(4), 1087-1098","doi":"10.1007/s00213-020-05755-x","pmid":"33442771","tags":["psychosis","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"GAT211 dose-dependently reduced locomotor activity, prevented MK-801-induced hyperlocomotion (a model of psychosis), and limited dopamine D2 receptor-mediated ERK phosphorylation in neuronal cells. Unlike THC, GAT211 blocked the dopaminergic signaling pathway associated with psychotic behavior.","whyItMatters":"Current antipsychotics have significant side effects. CB1 receptor positive allosteric modulators represent a fundamentally different pharmacological approach that could modulate the endocannabinoid system without the psychoactive effects of direct CB1 agonists like THC.","specificNumbers":"GAT211 doses: 0.3-3.0 mg/kg; MK-801 dose: 0.15 mg/kg; GAT211 3.0 mg/kg prevented MK-801 hyperlocomotion; GAT211 limited D2-mediated ERK phosphorylation; THC did not","methodology":"Researchers compared GAT211 and THC effects on dopamine D2 receptor signaling in Neuro2a cells and on behavior in male Long Evans rats treated with MK-801 (NMDA antagonist) to model psychosis. Locomotor activity and prepulse inhibition of acoustic startle were measured.","limitations":"Animal study with a single species and sex (male rats). GAT211 did not significantly improve prepulse inhibition deficits. Mechanism of action not fully elucidated. No human data."},{"rthcId":"RTHC-03336","title":"Protocol: mixed-methods study of how implementation of US state medical cannabis laws affects treatment of chronic non-cancer pain and adverse opioid outcomes.","authors":"McGinty, Emma E; Tormohlen, Kayla N; Barry, Colleen L; Bicket, Mark C; Rutkow, Lainie; Stuart, Elizabeth A","year":2021,"journal":"Implementation science : IS, 16(1), 2","doi":"10.1186/s13012-020-01071-2","pmid":"33413454","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03337","title":"How High? Trends in Cannabis Use Prior to First Admission to Inpatient Psychiatry in Ontario, Canada, between 2007 and 2017.","authors":"McGuckin, Taylor; Ferro, Mark A; Hammond, David; Stewart, Shannon; Maloney-Hall, Bridget; Madi, Nawaf; Porath, Amy; Perlman, Christopher M","year":2021,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 66(12), 1059-1068","doi":"10.1177/0706743720984679","pmid":"33380219","tags":["mental-health","psychosis","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use within 30 days of first psychiatric admission rose from 16.7% in 2007 to 25.9% in 2017. Cannabis use disorders increased from 3.8% to 6.0%. In 2017, 47.9% of patients aged 18-24 and 39.2% aged 25-34 used cannabis before admission. The largest diagnostic-group increases were in personality disorders (15% increase), schizophrenia/psychotic disorders (14%), and substance use disorders (14%).","whyItMatters":"This decade-long population-level trend data from an entire province establishes a clear baseline showing rising cannabis use among psychiatric inpatients. As a pre-legalization baseline (Canada legalized in 2018), it enables future assessment of whether legalization accelerated these trends.","specificNumbers":"81,809 first admissions; 20.1% used cannabis overall; 16.7% in 2007 to 25.9% in 2017; CUD 3.8% to 6.0%; 47.9% of 18-24 year olds in 2017; AUC 0.88 for schizophrenia-gender interaction model","methodology":"Retrospective cross-sectional analysis of 81,809 first-time admissions to non-forensic inpatient psychiatric beds in Ontario from 2007-2017 using the Ontario Mental Health Reporting System. Trends and characteristics were analyzed across years and diagnostic categories.","limitations":"Cannot determine whether cannabis use contributed to psychiatric admission or was incidental. Self-reported use may undercount actual use. Ontario-specific data. No post-legalization comparison."},{"rthcId":"RTHC-03338","title":"Potential therapeutic benefits of cannabinoid products in adult psychiatric disorders: A systematic review and meta-analysis of randomised controlled trials.","authors":"McKee, Kyle A; Hmidan, Amira; Crocker, Candice E; Lam, Raymond W; Meyer, Jeffrey H; Crockford, David; Trépanier, Annie; Aitchison, Katherine J; Tibbo, Philip G","year":2021,"journal":"Journal of psychiatric research, 140, 267-281","doi":"10.1016/j.jpsychires.2021.05.044","pmid":"34119912","tags":["medical-cannabis","mental-health","cbd"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Of 31 RCTs (10 for cannabis use disorder, 6 for schizophrenia, 5 for opioid/tobacco use, 3 for anxiety, 2 each for Tourette's and anorexia, 1 each for ADHD, PTSD, and OCD), the review found limited evidence for acute symptom management in select conditions. No evidence supported mid- to long-term effectiveness. No study endorsed cannabis flower as treatment for any psychiatric disorder. Evidence quality was generally low to moderate.","whyItMatters":"Despite widespread consumer belief in cannabis for mental health, the highest level of evidence (RCTs) provides only limited support for acute use in narrow applications and no support for ongoing treatment of any psychiatric disorder.","specificNumbers":"2,397 papers identified; 31 RCTs included; 10 for CUD, 6 for schizophrenia, 5 for opioid/tobacco, 3 for anxiety; low-to-moderate evidence quality overall","methodology":"Systematic review and meta-analysis searching 8 databases from inception to September 2020. Of 2,397 papers identified, 31 RCTs met inclusion criteria. Risk of bias was assessed using the revised Cochrane tool.","limitations":"Heterogeneity across RCTs in products, doses, and outcomes limits meta-analytic pooling. Many included trials were small. Rapid evolution of cannabis products means newer formulations are understudied. Publication bias possible."},{"rthcId":"RTHC-03339","title":"Whole genome sequencing of colonies derived from cannabis flowers and the impact of media selection on benchmarking total yeast and mold detection tools.","authors":"McKernan, Kevin; Helbert, Yvonne; Kane, Liam; Houde, Nathan; Zhang, Lei; McLaughlin, Stephen","year":2021,"journal":"F1000Research, 10, 624","doi":"10.12688/f1000research.53467.2","pmid":"34484691","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03340","title":"Exploring multiple drug use by integrating mobile health and qualitative mapping methods - An individual case study.","authors":"McQuoid, Julia; Thrul, Johannes; Lopez-Paguyo, Kekoa; Ling, Pamela M","year":2021,"journal":"The International journal on drug policy, 97, 103325","doi":"10.1016/j.drugpo.2021.103325","pmid":"34175527","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03341","title":"Cannabis Vaping: Existing and Emerging Modalities, Chemistry, and Pulmonary Toxicology.","authors":"Meehan-Atrash, Jiries; Rahman, Irfan","year":2021,"journal":"Chemical research in toxicology, 34(10), 2169-2179","doi":"10.1021/acs.chemrestox.1c00290","pmid":"34622654","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03342","title":"Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research.","authors":"Melas, Philippe A; Scherma, Maria; Fratta, Walter; Cifani, Carlo; Fadda, Paola","year":2021,"journal":"International journal of molecular sciences, 22(4)","doi":"10.3390/ijms22041863","pmid":"33668469","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03343","title":"Adult Gambling Problems and Histories of Mental Health and Substance Use: Findings from a Prospective Multi-Wave Australian Cohort Study.","authors":"Merkouris, Stephanie S; Greenwood, Christopher J; Youssef, George J; Letcher, Primrose; Vassallo, Suzanne; Dowling, Nicki A; Olsson, Craig A","year":2021,"journal":"Journal of clinical medicine, 10(7)","doi":"10.3390/jcm10071406","pmid":"33915774","tags":["addiction","youth","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Persistent cannabis use from adolescence to young adulthood predicted gambling problems in the early 30s (OR 2.30-3.42). Binge drinking and tobacco use in young adulthood also predicted adult gambling. Mental health symptoms (depression, anxiety) were not associated with adult gambling, and no differences were found by sex.","whyItMatters":"This is one of the longest running studies to link adolescent substance use patterns to adult gambling problems, suggesting that addictive behaviors in youth may set the stage for different forms of addictive behavior later in life.","specificNumbers":"1,365 participants; 7 waves of data (1998-2014); persistent substance use OR 2.30-3.42 for gambling problems; no sex differences; mental health symptoms not predictive","methodology":"Prospective multi-wave study analyzing 1,365 participants across seven waves of data collection from 1998-2014, tracking substance use from ages 13-28 and gambling outcomes at ages 31-32.","limitations":"Australian sample may not generalize globally. Self-reported substance use and gambling. Attrition across seven waves of data collection. Cannot determine whether substance use directly causes gambling vulnerability."},{"rthcId":"RTHC-03344","title":"Analysis of State Cannabis Laws and Dispensary Staff Recommendations to Adults Purchasing Medical Cannabis.","authors":"Merlin, Jessica S; Althouse, Andrew; Feldman, Robert; Arnsten, Julia H; Bulls, Hailey W; Liebschutz, Jane M; Nugent, Shannon M; Orris, Steven R; Rohac, Rebecca; Starrels, Joanna L; Morasco, Benjamin J; Kansagara, Devan","year":2021,"journal":"JAMA network open, 4(9), e2124511","doi":"10.1001/jamanetworkopen.2021.24511","pmid":"34524435","tags":["medical-cannabis","harm-reduction","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Most dispensary staff based recommendations on the customer's medical condition (74%), other customers' experiences (70%), the customer's prior experience (67%), and personal experience (63%). Only 40% relied on clinician input. Most advised about safe storage and common side effects, but few counseled about cannabis use disorder, withdrawal, motor vehicle collision risk, or psychotic reactions.","whyItMatters":"Most medical cannabis patients report getting advice from dispensaries rather than physicians. Understanding what dispensary staff actually recommend and what risks they discuss reveals critical gaps in patient safety education.","specificNumbers":"434 responses; 351 unique dispensaries; 74% based recommendations on medical condition; 70% on other customers' experiences; 40% on clinician input; few counseled about CUD, withdrawal, driving risk, psychosis","methodology":"Nationwide cross-sectional online survey of 434 dispensary workers (budtenders 40%, managers 32%, pharmacists 13%) from 351 unique dispensaries across the US, conducted from February to October 2020.","limitations":"Self-reported practices may differ from actual behavior. Online survey may not capture all dispensary types. Response bias possible. Cross-sectional design."},{"rthcId":"RTHC-03345","title":"Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity.","authors":"Meyer, Erika; Bonato, Jéssica Mendes; Mori, Marco Aurélio; Mattos, Bianca Andretto; Guimarães, Francisco Silveira; Milani, Humberto; de Campos, Alline Cristina; de Oliveira, Rúbia Maria Weffort","year":2021,"journal":"Molecular neurobiology, 58(10), 5338-5355","doi":"10.1007/s12035-021-02479-7","pmid":"34302281","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (10 mg/kg) attenuated ischemia-induced memory deficits in both radial maze and object location tasks. CBD reduced hippocampal CA1 neurodegeneration, increased BDNF levels, and protected dendritic spine number and dendritic arborization length from ischemia damage.","whyItMatters":"Stroke and cerebral ischemia remain leading causes of long-term cognitive disability with limited treatment options. Understanding how CBD protects brain connections and promotes recovery could inform development of new neuroprotective therapies.","specificNumbers":"CBD 10 mg/kg; treatment for 14 days; memory tested at days 7 and 14; protected CA1 neurons; increased BDNF; preserved dendritic spines and arborization","methodology":"Wistar rats were trained in an aversive radial maze task, underwent sham or transient global cerebral ischemia, and received CBD (10 mg/kg) or vehicle 30 minutes before surgery, 3 hours after, then daily for 14 days. Memory was tested at days 7 and 14. A separate group underwent object location testing. Brain tissue was analyzed for neuronal degeneration, synaptic proteins, and dendritic morphology.","limitations":"Rat model may not translate to human stroke. CBD was given before ischemia, which is not clinically realistic. Single dose tested. Short follow-up period."},{"rthcId":"RTHC-03346","title":"Case Report: CBD Cigarettes for Harm Reduction and Adjunctive Therapy in a Patient With Schizophrenia and Substance Use Disorder.","authors":"Meyer, Maximilian; Walter, Marc; Borgwardt, Stefan; Scheidegger, Alexandra; Lang, Elisabeth; Köck, Patrick","year":2021,"journal":"Frontiers in psychiatry, 12, 712110","doi":"10.3389/fpsyt.2021.712110","pmid":"34366942","tags":["cbd","psychosis","harm-reduction","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"After years of treatment failure with 30 hospitalizations, introducing CBD cigarettes (<1% THC) as adjunctive therapy, combined with off-label methylphenidate, led the patient to report significantly less need for illegal high-THC cannabis. He stopped cocaine use and had no further hospitalizations.","whyItMatters":"Patients with co-occurring schizophrenia and substance use disorders are among the hardest to treat. This case suggests CBD cigarettes may serve as a harm reduction substitute for high-THC cannabis in patients who are unable or unwilling to stop smoking cannabis entirely.","specificNumbers":"30 hospitalizations over 8 years prior; CBD cigarettes <1% THC; no hospitalizations since intervention; cocaine use ceased","methodology":"Single clinical case report of a male patient with schizophrenia, combined personality disorder, cannabis use disorder, and cocaine use disorder, treated with CBD cigarettes and methylphenidate after exhausting conventional treatment approaches over 8 years.","limitations":"Single case report. Cannot attribute improvement solely to CBD cigarettes given concurrent methylphenidate. Placebo effect and therapeutic relationship may play a role. No long-term follow-up data provided."},{"rthcId":"RTHC-03347","title":"CB1 allosteric modulators and their therapeutic potential in CNS disorders.","authors":"Mielnik, Catharine A; Lam, Vincent M; Ross, Ruth A","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 106, 110163","doi":"10.1016/j.pnpbp.2020.110163","pmid":"33152384","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03348","title":"Women's Cigarette and Marijuana Use in Pregnancy: Identifying the Role of Past Versus Recent Violence Exposure.","authors":"Miller-Graff, Laura E; Howell, Kathryn H; Grein, Katherine; Keough, Kathryn","year":2021,"journal":"Journal of interpersonal violence, 36(7-8), NP3982-NP3998","doi":"10.1177/0886260518779068","pmid":"29936890","tags":["pregnancy","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Sexual intimate partner violence was associated with marijuana use during pregnancy. Physical partner abuse predicted light cigarette use, while high childhood adversity predicted moderate cigarette use during pregnancy. Only 22.5% of prepregnancy smokers quit during pregnancy, compared to 68.1% of marijuana users.","whyItMatters":"Understanding why some pregnant women continue using substances despite knowing the risks requires looking at their lived experiences. Violence exposure appears to be an important and often overlooked driver of substance use during pregnancy.","specificNumbers":"101 participants; 25% currently smoking cigarettes; 6.9% using marijuana during pregnancy; 22.5% of smokers quit vs 68.1% of marijuana users; sexual IPV associated with marijuana use","methodology":"Cross-sectional study of 101 low-income pregnant women who were interviewed about past-year intimate partner violence, childhood adversity, and current cigarette and marijuana use. Multinomial regressions controlled for income and education.","limitations":"Very small sample (101 participants). Cross-sectional design. Low-income, high-risk sample may not generalize. Self-reported substance use during pregnancy likely underreported."},{"rthcId":"RTHC-03349","title":"Adolescent Health: Substance Use.","authors":"Miller, Katy; McPherson, Lauren; Gewirtz O'Brien, Janna; Svetaz, Maria Veronica","year":2021,"journal":"FP essentials, 507, 26-32","doi":null,"pmid":"34410094","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03350","title":"Cannabinoid receptors distribution in mouse cortical plasma membrane compartments.","authors":"Miranzadeh Mahabadi, Hajar; Bhatti, Haseeb; Laprairie, Robert B; Taghibiglou, Changiz","year":2021,"journal":"Molecular brain, 14(1), 89","doi":"10.1186/s13041-021-00801-x","pmid":"34099009","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03351","title":"Variation of drugs involved in acute drug toxicity presentations based on age and sex: an epidemiological approach based on European emergency departments.","authors":"Miró, Òscar; Waring, William S; Dargan, Paul I; Wood, David M; Dines, Alison M; Yates, Christopher; Giraudon, Isabelle; Moughty, Adrian; O'Connor, Niall; Heyerdahl, Fridtjof; Hovda, Knut E; Vallersnes, Odd M; Paasma, Raido; Pold, Kristiina; Jürgens, Gesche; Megarbane, Bruno; Anand, Jacek S; Liakoni, Evangelia; Liechti, Matthias; Eyer, Florian; Zacharov, Sergej; Caganova, Blazena; Bonnici, Jeffrey; Radenkova-Saeva, Julia; Galicia, Miguel","year":2021,"journal":"Clinical toxicology (Philadelphia, Pa.), 59(10), 896-904","doi":"10.1080/15563650.2021.1884693","pmid":"33724118","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03352","title":"Marijuana Use and Stress Cardiomyopathy in the Young.","authors":"Modi, Vivek; Singh, Amitoj; Shirani, Jamshid","year":2021,"journal":"Cureus, 13(10), e18575","doi":"10.7759/cureus.18575","pmid":"34760418","tags":["cardiovascular"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Marijuana users with stress cardiomyopathy were younger (44 vs 66 years), more often male (36% vs 8%), had fewer traditional risk factors, but had higher rates of cardiac arrest, respiratory failure, and cardiogenic shock. Age over 48 was a strong predictor of any major adverse cardiac event (OR 7.8, 95% CI 2.88-21.13).","whyItMatters":"Stress cardiomyopathy (Takotsubo) has traditionally been associated with older postmenopausal women. The association with marijuana in younger patients with more severe complications challenges clinical expectations about who develops this condition and how it behaves.","specificNumbers":"33,343 SC admissions; 210 (0.06%) marijuana-related; mean age 44 vs 66; 36% vs 8% male; cardiac arrest, respiratory failure, cardiogenic shock all higher; age >48 OR 7.8 for major adverse events","methodology":"Retrospective analysis of the 2003-2011 Nationwide Inpatient Sample database comparing 210 stress cardiomyopathy admissions temporally related to marijuana use against 33,133 non-marijuana-related stress cardiomyopathy admissions.","limitations":"Administrative database cannot prove causation. \"Temporally related\" does not mean directly caused. Small marijuana-user subgroup (210 cases). Cannabis use likely underreported in hospital records."},{"rthcId":"RTHC-03353","title":"Use of Cannabis for Harm Reduction Among People at High Risk for Overdose in Vancouver, Canada (2016-2018).","authors":"Mok, Janice; Milloy, M-J; Grant, Cameron; Lake, Stephanie; DeBeck, Kora; Hayashi, Kanna; Socías, M Eugenia","year":2021,"journal":"American journal of public health, 111(5), 969-972","doi":"10.2105/AJPH.2021.306168","pmid":"33734849","tags":["harm-reduction","addiction","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"About 1 in 4 participants used cannabis for harm reduction during the study period. The most common reasons were substituting for stimulants (50%) and substituting for illicit opioids (31%). Other reasons included treating withdrawal and coming down off other drugs.","whyItMatters":"During an overdose crisis that has killed thousands in British Columbia, understanding how people at highest risk are already using cannabis to manage their drug use provides ground-level data that could inform future harm reduction interventions.","specificNumbers":"~25% reported cannabis for harm reduction at least once; 50% for stimulant substitution; 31% for opioid substitution; study period June 2016 to May 2018","methodology":"Data drawn from three prospective cohort studies of marginalized people who use drugs in Vancouver, Canada, from June 2016 to May 2018. Participants reported recent cannabis use and their intentions for using cannabis, including substitution for other substances.","limitations":"Self-reported data from marginalized populations in one Canadian city. No comparison group. Cannot determine whether cannabis substitution actually reduced harm. Potential selection bias."},{"rthcId":"RTHC-03354","title":"Acute effects of cannabis on speech illusions and psychotic-like symptoms: two studies testing the moderating effects of cannabidiol and adolescence.","authors":"Mokrysz, Claire; Shaban, Natacha D C; Freeman, Tom P; Lawn, Will; Pope, Rebecca A; Hindocha, Chandni; Freeman, Abigail; Wall, Matthew B; Bloomfield, Michael A P; Morgan, Celia J A; Nutt, David J; Curran, H Valerie","year":2021,"journal":"Psychological medicine, 51(12), 2134-2142","doi":"10.1017/S0033291720001038","pmid":"32340632","tags":["psychosis","cbd","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Cannabis increased psychotic-like symptoms (PSI scores) in both studies. In Study 2, cannabis increased the odds of speech illusion 3.1 times. Cannabis with CBD showed no difference from cannabis without CBD on psychotic outcomes (Study 1). Adults showed more psychotic-like symptoms than adolescents (Study 2), contrary to the hypothesis that adolescents would be more vulnerable.","whyItMatters":"The assumption that CBD protects against THC-induced psychotic effects has influenced cannabis product development and regulation. This study challenges that assumption in a controlled acute dosing paradigm.","specificNumbers":"Study 1: 17 adults, no CBD protection; Study 2: 20 adolescents + 20 adults; speech illusion OR 3.1 (95% CI 1.3-7.2); adults showed more psychotic-like symptoms than adolescents","methodology":"Two double-blind placebo-controlled studies. Study 1 compared cannabis with CBD vs without CBD in 17 adults. Study 2 compared cannabis effects in 20 adolescents vs 20 adults. All participants were healthy current cannabis users. Outcomes included Psychotomimetic States Inventory and speech illusion in a white noise task.","limitations":"Very small samples (17 and 40 participants). Single acute dose may not reflect chronic use patterns. Only healthy current cannabis users were tested, excluding the most vulnerable individuals."},{"rthcId":"RTHC-03355","title":"The association of alcohol, cigarette, e-cigarette, and marijuana use with disease severity in adolescents and young adults with pediatric chronic kidney disease.","authors":"Molino, Andrea R; Jerry-Fluker, Judith; Atkinson, Meredith A; Furth, Susan L; Warady, Bradley A; Ng, Derek K","year":2021,"journal":"Pediatric nephrology (Berlin, Germany), 36(8), 2493-2497","doi":"10.1007/s00467-021-05044-5","pmid":"33914145","tags":["youth","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Past-year and 30-day cigarette use were significantly associated with higher proteinuria (+18.6% and +20.0% respectively). Marijuana use (reported by 15%), alcohol (39%), and e-cigarette use (17%) were not associated with proteinuria, disease progression, or elevated blood pressure in adjusted models.","whyItMatters":"Adolescents with chronic kidney disease face lifelong disease management. Knowing that marijuana does not appear to accelerate kidney disease (unlike cigarettes) provides important information for clinicians and families navigating substance use conversations.","specificNumbers":"441 participants; 1,245 person-visits; marijuana use 15%; cigarette use associated with +18.6% higher proteinuria (P < 0.05); marijuana, alcohol, e-cigarette not associated with kidney outcomes","methodology":"Longitudinal analysis of 441 participants aged 16+ in the CKiD study contributing 1,245 person-visits. Repeated measures regression models with contemporaneous and lagged controls assessed associations between each substance and kidney function markers.","limitations":"Relatively low prevalence of substance use limited statistical power. Self-reported use likely underestimates actual consumption. Cannot rule out effects at higher use levels. CKiD cohort may not represent all pediatric CKD patients."},{"rthcId":"RTHC-03356","title":"Effects of Cannabis Consumption on Sleep.","authors":"Mondino, Alejandra; Cavelli, Matías; González, Joaquín; Murillo-Rodriguez, Eric; Torterolo, Pablo; Falconi, Atilio","year":2021,"journal":"Advances in experimental medicine and biology, 1297, 147-162","doi":"10.1007/978-3-030-61663-2_11","pmid":"33537943","tags":["sleep","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review focused specifically on whole-plant cannabis consumption — smoked, oral, or vaporized — rather than isolated cannabinoids. The distinction matters because whole-plant effects can differ from purified THC or CBD alone.\n\nIn humans, the evidence showed cannabis users generally reported subjective sleep improvement, particularly faster sleep onset and fewer nightmares. But objective sleep studies painted a more nuanced picture. THC at moderate doses appeared to increase total sleep time and NREM (deep) sleep, while higher doses or chronic use could fragment sleep architecture.\n\nA notable animal study using vaporized high-THC/low-CBD cannabis — the delivery method and chemical profile closest to how people actually use it — found promotion of NREM sleep specifically. The authors argued this supported cannabis as a potential sleep therapy but emphasized that the metabolomic composition (THC:CBD ratio), dose, and route of administration all changed the outcome.\n\nThe review highlighted that medical use of cannabis for sleep had ancient roots — over 5,000 years — but modern scientific evidence remained surprisingly thin.","whyItMatters":"Sleep is the number one reason people give for using cannabis, yet the science still can't give a simple answer about whether it helps or hurts. This review explained why: the answer genuinely depends on the specific product, dose, and delivery method. High-THC flower vaporized at moderate doses appears to promote deep sleep. High doses, chronic use, or abrupt cessation appears to disrupt it.\n\nFor the millions of people using cannabis for sleep, this means the details of how they use it likely matter more than whether they use it at all.","specificNumbers":"• Vaporized high-THC/low-CBD cannabis promoted NREM sleep in animals\n• Cannabis use for sleep dates back 5,000+ years\n• Effects vary by: metabolomic composition, dose, and route of administration\n• Chronic use may fragment sleep architecture despite acute benefits","methodology":"Narrative review of human and animal studies examining whole-plant cannabis effects on sleep, covering smoked, oral, and vaporized delivery. Published in Advances in Experimental Medicine and Biology.","limitations":"Narrative review without systematic methodology. Most human evidence relied on self-report. Animal vaporization studies used specific cannabis preparations that may not represent commercial products. Does not address long-term effects on sleep architecture. Individual variation in response to cannabis for sleep is not well understood."},{"rthcId":"RTHC-03357","title":"Cannabinoids and the Adolescent Patient: A Pragmatic Guide for Pediatric Practitioners.","authors":"Montalto, Gregg Joseph; Cius, Elizabeth G; Rahmandar, Maria H","year":2021,"journal":"Pediatric annals, 50(2), e57-e64","doi":"10.3928/19382359-20210120-01","pmid":"33576830","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03358","title":"New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators.","authors":"Montanari, Serena; Allarà, Marco; Scalvini, Laura; Kostrzewa, Magdalena; Belluti, Federica; Gobbi, Silvia; Naldi, Marina; Rivara, Silvia; Bartolini, Manuela; Ligresti, Alessia; Bisi, Alessandra; Rampa, Angela","year":2021,"journal":"Molecules (Basel, Switzerland), 26(11)","doi":"10.3390/molecules26113254","pmid":"34071439","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03359","title":"Heterogeneity of the Endocannabinoid System Between Cerebral Cortex and Spinal Cord Oligodendrocytes.","authors":"Moreno-Luna, R; Esteban, P F; Paniagua-Torija, B; Arevalo-Martin, A; Garcia-Ovejero, D; Molina-Holgado, E","year":2021,"journal":"Molecular neurobiology, 58(2), 689-702","doi":"10.1007/s12035-020-02148-1","pmid":"33006124","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03360","title":"Cannabis use among early adolescents and transdiagnostic mental health risk factors.","authors":"Moreno-Mansilla, Sara; Ricarte, Jorge J; Hallford, David J","year":2021,"journal":"Clinical child psychology and psychiatry, 26(2), 531-543","doi":"10.1177/1359104521994637","pmid":"33607919","tags":["youth","mental-health","depression","psychosis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users scored significantly higher on anomalous reality perception (d = 0.60), hopelessness (d = 0.85), depression symptoms (d = 0.80), rumination (d = 0.48), and anxiety (d = 0.39). Suicide attempts were 3.4 times more common (25.9% vs 7.7%). Logistic regression showed hopelessness was the only unique predictor of cannabis use (OR 1.159, P = 0.033).","whyItMatters":"Early adolescent cannabis use is increasing, and understanding which mental health factors are most tightly linked could inform targeted prevention. The finding that hopelessness specifically stands out is actionable for school-based mental health programs.","specificNumbers":"605 adolescents; mean age 13.2; hopelessness d = 0.85; depression d = 0.80; anomalous perception d = 0.60; suicide attempts 25.9% users vs 7.7% non-users; hopelessness OR 1.159","methodology":"Cross-sectional study of 605 adolescents in 7th-9th grades (mean age 13.2 years, 47% girls) assessed using validated questionnaires for anomalous perception, rumination, intolerance of uncertainty, hopelessness, depression, anxiety, and suicide attempts. Binary logistic regression identified unique predictors.","limitations":"Cross-sectional design cannot determine whether hopelessness leads to cannabis use or vice versa. Spanish adolescent sample may not generalize globally. Self-report measures. Cannabis use was binary (yes/no) without frequency data."},{"rthcId":"RTHC-03361","title":"A Digital Health Tool to Understand and Prevent Cannabis-Impaired Driving Among Youth: A Cross-sectional Study of Responses to a Brief Intervention for Cannabis Use.","authors":"Moreno, Georgina; van Mierlo, Trevor","year":2021,"journal":"JMIR formative research, 5(3), e25583","doi":"10.2196/25583","pmid":"33650982","tags":["driving","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Every 10-point increase in ASSIST score increased the probability of sometimes driving after cannabis use by 7.3%. Those who sometimes used alcohol or other substances with cannabis were 13% more likely to sometimes or always drive after cannabis use. Gender was not a significant determinant. The digital tool cost approximately CAD $0.90 per use.","whyItMatters":"Identifying which cannabis users are most likely to drive impaired allows prevention resources to be targeted rather than broadcast. The finding that polysubstance use and higher problem scores predict driving behavior provides actionable screening criteria.","specificNumbers":"1,110 participants; 73.6% used cannabis; 30.8% drove after cannabis; 10-point ASSIST increase = 7.3% higher probability of driving high; polysubstance users 13% more likely; cost ~CAD $0.90/use","methodology":"Cross-sectional analysis of 1,110 completed Check Your Cannabis digital brief interventions from March 2019 to October 2020. An ordered probit model tested relationships between cannabis use patterns, demographics, and driving behaviors.","limitations":"Self-selected sample using a digital tool. Self-reported driving behavior. No follow-up to assess behavior change. Cross-sectional design. Canadian sample may not generalize."},{"rthcId":"RTHC-03362","title":"Differential contribution of CB1, CB2, 5-HT1A, and PPAR-γ receptors to cannabidiol effects on ischemia-induced emotional and cognitive impairments.","authors":"Mori, Marco Aurélio; Meyer, Erika; da Silva, Francielly F; Milani, Humberto; Guimarães, Francisco Silveira; Oliveira, Rúbia Maria Weffort","year":2021,"journal":"The European journal of neuroscience, 53(6), 1738-1751","doi":"10.1111/ejn.15134","pmid":"33522084","tags":["cbd","neuroscience","anxiety","depression"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD prevented anxiety-like behavior, memory impairments, and despair-like behaviors after cerebral ischemia. The anxiolytic effects were attenuated by antagonists of CB1, CB2, 5-HT1A, and PPAR-gamma receptors. Both CBD and the CB1 antagonist AM251 improved spatial memory in ischemic animals, suggesting complex receptor interactions.","whyItMatters":"Understanding which receptors mediate CBD's neuroprotective effects is critical for developing targeted therapies. The finding that multiple receptor systems are involved explains why CBD has such broad neurological effects and suggests combination approaches might enhance efficacy.","specificNumbers":"CBD 10 mg/kg; 4 receptor antagonists tested (AM251, AM630, WAY-100635, GW9662); behavioral battery of 4 tests; all 4 receptor types contributed to anxiolytic effects","methodology":"C57BL/6J mice underwent bilateral common carotid artery occlusion for 20 minutes. CBD (10 mg/kg) was administered before and after reperfusion. Receptor antagonists for CB1, CB2, 5-HT1A, and PPAR-gamma were given before each CBD injection. Behavioral testing included open field, elevated zero maze, Y-maze, and forced swim test.","limitations":"Mouse model with pre-treatment design. Multiple receptor antagonists introduce pharmacological complexity. Behavioral tests are proxies for human conditions. Single dose of CBD tested."},{"rthcId":"RTHC-03363","title":"The endocannabinoidome in neuropsychiatry: Opportunities and potential risks.","authors":"Morris, Gerwyn; Walder, Ken; Kloiber, Stefan; Amminger, Paul; Berk, Michael; Bortolasci, Chiara C; Maes, Michael; Puri, Basant K; Carvalho, Andre F","year":2021,"journal":"Pharmacological research, 170, 105729","doi":"10.1016/j.phrs.2021.105729","pmid":"34119623","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03364","title":"The Relationship Between Plasma Tetrahydrocannabinol Levels and Intraocular Pressure in Healthy Adult Subjects.","authors":"Mosaed, Sameh; Smith, Andrew K; Liu, John H K; Minckler, Donald S; Fitzgerald, Robert L; Grelotti, David; Sones, Emily; Weinreb, Robert N; Marcotte, Thomas D","year":2021,"journal":"Frontiers in medicine, 8, 736792","doi":"10.3389/fmed.2021.736792","pmid":"35111768","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Peak IOP reduction was 16% at 60 minutes post-inhalation. THC plasma levels correlated strongly with IOP reduction (r = -0.81 for percent reduction) up to 20 ng/ml. Above 20 ng/ml, the correlation disappeared (r = 0.21), suggesting a ceiling effect.","whyItMatters":"Cannabis has long been discussed as a potential glaucoma treatment, but understanding the dose-response relationship is essential. The finding of a ceiling effect at 20 ng/ml plasma THC suggests that higher doses would not provide additional IOP benefit.","specificNumbers":"11 subjects, 22 eyes; peak IOP reduction 16% at 60 min; correlation r = -0.81 below 20 ng/ml; r = 0.21 above 20 ng/ml; change point statistically significant (P < 0.01)","methodology":"Eleven healthy subjects self-administered a single dose of inhaled cannabis. IOP and plasma THC were measured at baseline, every 30 minutes for the first hour, then hourly for 4 hours. Linear regression and two-line regression models with F-tests identified a change point in the THC-IOP relationship.","limitations":"Very small sample (11 subjects). Healthy adults only, not glaucoma patients. Single-dose study. Short follow-up of 4 hours. IOP management requires 24-hour control."},{"rthcId":"RTHC-03365","title":"Integrative Medicine: Cannabis and Cannabis-Related Drugs.","authors":"Moss, David A; Hawks, Matthew K; Snyder, Matthew J; Crawford, Paul F","year":2021,"journal":"FP essentials, 505, 28-34","doi":null,"pmid":"34128629","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03366","title":"Cannabis use and measurement of cannabinoids in plasma and breast milk of breastfeeding mothers.","authors":"Moss, Michael J; Bushlin, Ittai; Kazmierczak, Steven; Koop, Dennis; Hendrickson, Robert G; Zuckerman, Katharine E; Grigsby, Tamara M","year":2021,"journal":"Pediatric research, 90(4), 861-868","doi":"10.1038/s41390-020-01332-2","pmid":"33469174","tags":["pregnancy","cbd"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Median breast milk THC concentration was 27.5 ng/ml vs 3.7 ng/ml in plasma, a milk-to-plasma ratio of 7.0. CBD also concentrated in breast milk (M/P ratio 2.6). THC in breast milk increased by 30.2 ng/ml from visit 1 (2 weeks) to visit 2 (2 months). Mothers used cannabis frequently, with a median of 17-23 instances per week.","whyItMatters":"With increasing cannabis legalization and use during breastfeeding, quantifying how cannabinoids concentrate in breast milk is essential. The 7-fold concentration of THC relative to plasma means infants may receive meaningful cannabinoid exposure.","specificNumbers":"20 subjects; median THC: plasma 3.7 ng/ml, milk 27.5 ng/ml; THC M/P ratio 7.0; CBD M/P ratio 2.6; cannabis use 17-23 instances/week; breast milk THC increased by 30.2 ng/ml from 2 weeks to 2 months","methodology":"Prospective study at a university hospital in a state with legal cannabis. Twenty breastfeeding mothers who used cannabis in the last 48 hours provided breast milk and plasma samples at 2 weeks and 2 months postpartum, along with survey data on use patterns.","limitations":"Small sample of 20 self-selected cannabis users. No measurement of infant cannabinoid levels. No assessment of infant health outcomes. Cannot determine clinical significance of exposure levels."},{"rthcId":"RTHC-03367","title":"Knowledge, Perception, and Use of Cannabis Therapy in Patients with Inflammatory Bowel Disease.","authors":"Muñiz-Camacho, Luis A; Negrón-Quintana, Frances I; Ramos-Burgos, Luis A; Cruz-Cruz, Jorge J; Torres, Esther A","year":2021,"journal":"Puerto Rico health sciences journal, 40(3), 110-114","doi":null,"pmid":"34792923","tags":["medical-cannabis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"27% reported cannabis use. Among users, 53% reported little to no knowledge of medical cannabis. 78% had not discussed their use with their physician. 68% of users reported symptom improvement. Cannabis was legal for Crohn's disease in Puerto Rico since 2017.","whyItMatters":"Even after legalization, the gap between patient cannabis use and physician awareness is wide. Most IBD patients using cannabis are doing so without medical guidance, potentially missing interactions with IBD medications or missing opportunities for optimized treatment.","specificNumbers":"100 patients; 27% reported cannabis use; 53% limited knowledge; 78% did not discuss with physician; 68% reported improvement","methodology":"Cross-sectional survey of 100 IBD patients aged 21+ at the University of Puerto Rico Center for Inflammatory Bowel Diseases using a voluntary anonymous questionnaire.","limitations":"Small sample of 100 patients from a single center. Voluntary anonymous questionnaire may have response bias. Self-reported symptoms without objective disease measures. Puerto Rico-specific context."},{"rthcId":"RTHC-03368","title":"Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.","authors":"Munn-Chernoff, Melissa A; Johnson, Emma C; Chou, Yi-Ling; Coleman, Jonathan R I; Thornton, Laura M; Walters, Raymond K; Yilmaz, Zeynep; Baker, Jessica H; Hübel, Christopher; Gordon, Scott; Medland, Sarah E; Watson, Hunna J; Gaspar, Héléna A; Bryois, Julien; Hinney, Anke; Leppä, Virpi M; Mattheisen, Manuel; Ripke, Stephan; Yao, Shuyang; Giusti-Rodríguez, Paola; Hanscombe, Ken B; Adan, Roger A H; Alfredsson, Lars; Ando, Tetsuya; Andreassen, Ole A; Berrettini, Wade H; Boehm, Ilka; Boni, Claudette; Boraska Perica, Vesna; Buehren, Katharina; Burghardt, Roland; Cassina, Matteo; Cichon, Sven; Clementi, Maurizio; Cone, Roger D; Courtet, Philippe; Crow, Scott; Crowley, James J; Danner, Unna N; Davis, Oliver S P; de Zwaan, Martina; Dedoussis, George; Degortes, Daniela; DeSocio, Janiece E; Dick, Danielle M; Dikeos, Dimitris; Dina, Christian; Dmitrzak-Weglarz, Monika; Docampo, Elisa; Duncan, Laramie E; Egberts, Karin; Ehrlich, Stefan; Escaramís, Geòrgia; Esko, Tõnu; Estivill, Xavier; Farmer, Anne; Favaro, Angela; Fernández-Aranda, Fernando; Fichter, Manfred M; Fischer, Krista; Föcker, Manuel; Foretova, Lenka; Forstner, Andreas J; Forzan, Monica; Franklin, Christopher S; Gallinger, Steven; Giegling, Ina; Giuranna, Johanna; Gonidakis, Fragiskos; Gorwood, Philip; Gratacos Mayora, Monica; Guillaume, Sébastien; Guo, Yiran; Hakonarson, Hakon; Hatzikotoulas, Konstantinos; Hauser, Joanna; Hebebrand, Johannes; Helder, Sietske G; Herms, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Huckins, Laura M; Hudson, James I; Imgart, Hartmut; Inoko, Hidetoshi; Janout, Vladimir; Jiménez-Murcia, Susana; Julià, Antonio; Kalsi, Gursharan; Kaminská, Deborah; Karhunen, Leila; Karwautz, Andreas; Kas, Martien J H; Kennedy, James L; Keski-Rahkonen, Anna; Kiezebrink, Kirsty; Kim, Youl-Ri; Klump, Kelly L; Knudsen, Gun Peggy S; La Via, Maria C; Le Hellard, Stephanie; Levitan, Robert D; Li, Dong; Lilenfeld, Lisa; Lin, Bochao Danae; Lissowska, Jolanta; Luykx, Jurjen; Magistretti, Pierre J; Maj, Mario; Mannik, Katrin; Marsal, Sara; Marshall, Christian R; Mattingsdal, Morten; McDevitt, Sara; McGuffin, Peter; Metspalu, Andres; Meulenbelt, Ingrid; Micali, Nadia; Mitchell, Karen; Monteleone, Alessio Maria; Monteleone, Palmiero; Nacmias, Benedetta; Navratilova, Marie; Ntalla, Ioanna; O'Toole, Julie K; Ophoff, Roel A; Padyukov, Leonid; Palotie, Aarno; Pantel, Jacques; Papezova, Hana; Pinto, Dalila; Rabionet, Raquel; Raevuori, Anu; Ramoz, Nicolas; Reichborn-Kjennerud, Ted; Ricca, Valdo; Ripatti, Samuli; Ritschel, Franziska; Roberts, Marion; Rotondo, Alessandro; Rujescu, Dan; Rybakowski, Filip; Santonastaso, Paolo; Scherag, André; Scherer, Stephen W; Schmidt, Ulrike; Schork, Nicholas J; Schosser, Alexandra; Seitz, Jochen; Slachtova, Lenka; Slagboom, P Eline; Slof-Op't Landt, Margarita C T; Slopien, Agnieszka; Sorbi, Sandro; Świątkowska, Beata; Szatkiewicz, Jin P; Tachmazidou, Ioanna; Tenconi, Elena; Tortorella, Alfonso; Tozzi, Federica; Treasure, Janet; Tsitsika, Artemis; Tyszkiewicz-Nwafor, Marta; Tziouvas, Konstantinos; van Elburg, Annemarie A; van Furth, Eric F; Wagner, Gudrun; Walton, Esther; Widen, Elisabeth; Zeggini, Eleftheria; Zerwas, Stephanie; Zipfel, Stephan; Bergen, Andrew W; Boden, Joseph M; Brandt, Harry; Crawford, Steven; Halmi, Katherine A; Horwood, L John; Johnson, Craig; Kaplan, Allan S; Kaye, Walter H; Mitchell, James; Olsen, Catherine M; Pearson, John F; Pedersen, Nancy L; Strober, Michael; Werge, Thomas; Whiteman, David C; Woodside, D Blake; Grove, Jakob; Henders, Anjali K; Larsen, Janne T; Parker, Richard; Petersen, Liselotte V; Jordan, Jennifer; Kennedy, Martin A; Birgegård, Andreas; Lichtenstein, Paul; Norring, Claes; Landén, Mikael; Mortensen, Preben Bo; Polimanti, Renato; McClintick, Jeanette N; Adkins, Amy E; Aliev, Fazil; Bacanu, Silviu-Alin; Batzler, Anthony; Bertelsen, Sarah; Biernacka, Joanna M; Bigdeli, Tim B; Chen, Li-Shiun; Clarke, Toni-Kim; Degenhardt, Franziska; Docherty, Anna R; Edwards, Alexis C; Foo, Jerome C; Fox, Louis; Frank, Josef; Hack, Laura M; Hartmann, Annette M; Hartz, Sarah M; Heilmann-Heimbach, Stefanie; Hodgkinson, Colin; Hoffmann, Per; Hottenga, Jouke-Jan; Konte, Bettina; Lahti, Jari; Lahti-Pulkkinen, Marius; Lai, Dongbing; Ligthart, Lannie; Loukola, Anu; Maher, Brion S; Mbarek, Hamdi; McIntosh, Andrew M; McQueen, Matthew B; Meyers, Jacquelyn L; Milaneschi, Yuri; Palviainen, Teemu; Peterson, Roseann E; Ryu, Euijung; Saccone, Nancy L; Salvatore, Jessica E; Sanchez-Roige, Sandra; Schwandt, Melanie; Sherva, Richard; Streit, Fabian; Strohmaier, Jana; Thomas, Nathaniel; Wang, Jen-Chyong; Webb, Bradley T; Wedow, Robbee; Wetherill, Leah; Wills, Amanda G; Zhou, Hang; Boardman, Jason D; Chen, Danfeng; Choi, Doo-Sup; Copeland, William E; Culverhouse, Robert C; Dahmen, Norbert; Degenhardt, Louisa; Domingue, Benjamin W; Frye, Mark A; Gäebel, Wolfgang; Hayward, Caroline; Ising, Marcus; Keyes, Margaret; Kiefer, Falk; Koller, Gabriele; Kramer, John; Kuperman, Samuel; Lucae, Susanne; Lynskey, Michael T; Maier, Wolfgang; Mann, Karl; Männistö, Satu; Müller-Myhsok, Bertram; Murray, Alison D; Nurnberger, John I; Preuss, Ulrich; Räikkönen, Katri; Reynolds, Maureen D; Ridinger, Monika; Scherbaum, Norbert; Schuckit, Marc A; Soyka, Michael; Treutlein, Jens; Witt, Stephanie H; Wodarz, Norbert; Zill, Peter; Adkins, Daniel E; Boomsma, Dorret I; Bierut, Laura J; Brown, Sandra A; Bucholz, Kathleen K; Costello, E Jane; de Wit, Harriet; Diazgranados, Nancy; Eriksson, Johan G; Farrer, Lindsay A; Foroud, Tatiana M; Gillespie, Nathan A; Goate, Alison M; Goldman, David; Grucza, Richard A; Hancock, Dana B; Harris, Kathleen Mullan; Hesselbrock, Victor; Hewitt, John K; Hopfer, Christian J; Iacono, William G; Johnson, Eric O; Karpyak, Victor M; Kendler, Kenneth S; Kranzler, Henry R; Krauter, Kenneth; Lind, Penelope A; McGue, Matt; MacKillop, James; Madden, Pamela A F; Maes, Hermine H; Magnusson, Patrik K E; Nelson, Elliot C; Nöthen, Markus M; Palmer, Abraham A; Penninx, Brenda W J H; Porjesz, Bernice; Rice, John P; Rietschel, Marcella; Riley, Brien P; Rose, Richard J; Shen, Pei-Hong; Silberg, Judy; Stallings, Michael C; Tarter, Ralph E; Vanyukov, Michael M; Vrieze, Scott; Wall, Tamara L; Whitfield, John B; Zhao, Hongyu; Neale, Benjamin M; Wade, Tracey D; Heath, Andrew C; Montgomery, Grant W; Martin, Nicholas G; Sullivan, Patrick F; Kaprio, Jaakko; Breen, Gerome; Gelernter, Joel; Edenberg, Howard J; Bulik, Cynthia M; Agrawal, Arpana","year":2021,"journal":"Addiction biology, 26(1), e12880","doi":"10.1111/adb.12880","pmid":"32064741","tags":["genetics","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Significant positive genetic correlations emerged between anorexia nervosa and cannabis initiation (rg = 0.23), and between anorexia nervosa with binge eating and cannabis use disorder (rg = 0.27). Conversely, anorexia without binge eating showed negative genetic correlations with smoking phenotypes. The genetic correlation between alcohol use disorder and anorexia was no longer significant after controlling for depression genetics.","whyItMatters":"The genetic overlap between eating disorders and cannabis use challenges the view that these are entirely separate conditions. Shared biological vulnerability could explain co-occurrence patterns and inform treatment approaches that address both conditions simultaneously.","specificNumbers":"Sample sizes ~2,400 to ~537,000; AN-cannabis initiation rg = 0.23; AN with binge eating-CUD rg = 0.27; AN without binge eating showed negative correlations with smoking phenotypes","methodology":"Linkage disequilibrium score regression calculated genetic correlations between four eating disorder phenotypes and eight substance-use-related phenotypes (including cannabis initiation and cannabis use disorder) using GWAS data from eight studies. Sample sizes ranged from ~2,400 to ~537,000 individuals.","limitations":"GWAS correlations identify shared genetic architecture but not specific causal mechanisms. European ancestry-predominant samples limit generalizability. Cannot distinguish direct from indirect genetic effects."},{"rthcId":"RTHC-03369","title":"Behavioral and Cognitive Differences in Early Childhood related to Prenatal Marijuana Exposure.","authors":"Murnan, Aaron W; Keim, Sarah A; Yeates, Keith Owen; Boone, Kelly M; Sheppard, Kelly W; Klebanoff, Mark A","year":2021,"journal":"Journal of applied developmental psychology, 77","doi":"10.1016/j.appdev.2021.101348","pmid":"34840377","tags":["pregnancy","youth","cognition"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Compared to non-exposed children, those with prenatal marijuana exposure had significantly more sleep-related problems, withdrawal symptoms, externalizing problems including aggressive behaviors and oppositional defiant behaviors at age 3.5. Executive functioning did not differ between groups.","whyItMatters":"Today's marijuana is significantly more potent than in previous decades, making earlier studies on prenatal exposure potentially less relevant. This cohort was exposed to contemporary, higher-potency marijuana, providing more current data on early childhood outcomes.","specificNumbers":"63 children assessed at age 3.5; prenatal exposure from self-report + medical chart + urine toxicology; significant differences in sleep, withdrawal, externalizing, aggression, and oppositional behaviors; no differences in executive function","methodology":"Prospective prenatal cohort in Columbus, Ohio. Prenatal marijuana exposure was determined from maternal self-report, medical chart abstraction, and urine toxicology. At age 3.5, 63 children completed tasks assessing executive function, visual-spatial ability, emotion regulation, and aggressive behavior. Caregivers reported on behavior.","limitations":"Small sample of 63 children. Cannot fully control for other prenatal exposures and socioeconomic factors that correlate with marijuana use. Self-reported exposure may underestimate actual use. Single assessment at 3.5 years."},{"rthcId":"RTHC-03370","title":"CaMKII Modulates Diacylglycerol Lipase-α Activity in the Rat Nucleus Accumbens after Incubation of Cocaine Craving.","authors":"Murray, Conor H; Gaulden, Andrew D; Kawa, Alex B; Milovanovic, Mike; Caccamise, Aaron J; Funke, Jonathan R; Patel, Sachin; Wolf, Marina E","year":2021,"journal":"eNeuro, 8(5)","doi":"10.1523/ENEURO.0220-21.2021","pmid":"34544759","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03371","title":"Clinical Investigation on the Impact of Cannabis Abuse on Thyroid Hormones and Associated Psychiatric Manifestations in the Male Population.","authors":"Muzaffar, Anum; Ullah, Sami; Subhan, Fazal; Nazar, Zahid; Hussain, Syed Mehdi; Khuda, Fazli; Khan, Abuzar; Khusro, Ameer; Sahibzada, Muhammad Umar Khayam; Albogami, Sarah; El-Shehawi, Ahmed M; Emran, Talha Bin; Javed, Binish; Ali, Javed","year":2021,"journal":"Frontiers in psychiatry, 12, 730388","doi":"10.3389/fpsyt.2021.730388","pmid":"34925083","tags":["mental-health","psychosis"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis-dependent patients showed highly significant differences (P < 0.001) in positive, negative, and general psychopathology scores on the PANSS compared to controls. Among patients, 47.5% had schizophrenia, 20% schizoaffective symptoms, 10% manic symptoms, and 22.5% both manic and psychotic symptoms. Thyroid hormones (TSH, T3, T4) and cardiovascular parameters did not differ significantly between groups.","whyItMatters":"The dissociation between significant psychiatric effects and non-significant thyroid/cardiovascular changes in chronic cannabis users suggests tolerance may develop to some physiological effects while psychiatric vulnerability persists or worsens.","specificNumbers":"40 patients vs 40 controls; 47.5% schizophrenia; PANSS scores P < 0.001; thyroid and cardiovascular parameters non-significant","methodology":"Prospective multicenter study comparing 40 cannabis-dependent patients with psychotic symptoms (selected by DSM-IV criteria and urine testing) to 40 healthy controls. Thyroid hormones measured by immunoassay, psychiatric symptoms by PANSS, and cardiovascular parameters assessed.","limitations":"Small sample. Cross-sectional comparison cannot determine whether cannabis caused psychiatric symptoms. All patients already had psychotic symptoms at enrollment. No dose-response analysis."},{"rthcId":"RTHC-03372","title":"Oral CBD-rich Cannabis Induces Clinical but Not Endoscopic Response in Patients with Crohn's Disease, a Randomised Controlled Trial.","authors":"Naftali, Timna; Bar-Lev Schleider, Lihi; Almog, Shlomo; Meiri, David; Konikoff, Fred M","year":2021,"journal":"Journal of Crohn's & colitis, 15(11), 1799-1806","doi":"10.1093/ecco-jcc/jjab069","pmid":"33858011","tags":["medical-cannabis","cbd","inflammation"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CDAI dropped from 282 to 166 in the cannabis group vs 264 to 237 in placebo (P < 0.05). Quality of life improved from 74 to 91 in cannabis vs 74 to 75 in placebo (P = 0.004). However, endoscopic scores (SES-CD) did not differ between groups (P = 0.75), and CRP and calprotectin remained unchanged.","whyItMatters":"This is one of the few controlled trials of cannabis in Crohn's disease with endoscopic endpoints. The dissociation between symptom improvement and unchanged inflammation raises a critical question: is cannabis treating the disease or just masking symptoms?","specificNumbers":"56 patients (30 cannabis, 26 placebo); CBD:THC 160:40 mg/ml; CDAI: 282→166 cannabis vs 264→237 placebo; QOL: 74→91 vs 74→75; SES-CD: P = 0.75; CRP and calprotectin unchanged","methodology":"Double-blind, randomized, placebo-controlled, single-center trial. 56 patients received either CBD-rich cannabis oil (160/40 mg/ml CBD/THC) or placebo orally for 8 weeks. Disease activity (CDAI), endoscopic score (SES-CD), quality of life, and inflammatory markers were assessed.","limitations":"Single center. Small sample. 8-week duration may be insufficient for endoscopic improvement. Fixed CBD:THC ratio may not be optimal. No long-term follow-up."},{"rthcId":"RTHC-03373","title":"The Role of Cannabis Use in Suicidal Ideation Among Patients With Opioid Use Disorder.","authors":"Naji, Leen; Rosic, Tea; Sanger, Nitika; Dennis, Brittany; Worster, Andrew; Paul, James; Thabane, Lehana; Samaan, Zainab","year":2021,"journal":"Journal of addiction medicine, 15(5), 370-375","doi":"10.1097/ADM.0000000000000781","pmid":"33337662","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Current cannabis use was associated with suicidal ideation (OR 1.41, 95% CI 1.11-1.80, P = 0.005) in multivariable analysis. Male sex (OR 1.84), younger age (OR 1.02 per year), and more anxiety/depression symptoms (OR 1.16) also predicted suicidal ideation. 51% of OUD patients reported current cannabis use.","whyItMatters":"Patients with opioid use disorder are already at high suicide risk. Finding that concurrent cannabis use further increases suicidal ideation in this population is clinically important, especially as cannabis is sometimes promoted for harm reduction in opioid dependence.","specificNumbers":"2,335 OUD patients; 51% current cannabis use; cannabis-suicidal ideation OR 1.41; male sex OR 1.84; anxiety/depression OR 1.16","methodology":"Cross-sectional multivariable logistic regression analysis of 2,335 participants with opioid use disorder from a large cohort. Self-reported current cannabis use and 30-day suicidal ideation were the primary variables.","limitations":"Cross-sectional design cannot determine causation. Self-reported cannabis use and suicidal ideation. Cannot control for all confounders. Direction of association unclear."},{"rthcId":"RTHC-03374","title":"Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions","authors":"Nasrin, Shamema; Watson, Christy J W; Perez-Paramo, Yadira X; Lazarus, Philip","year":2021,"journal":"Drug Metabolism and Disposition","doi":"10.1124/dmd.121.000442","pmid":"34493602","tags":["drug-interactions","CYP450","metabolism","pharmacokinetics","safety","CBD","THC"],"studyType":"In vitro pharmacokinetic study","evidenceStrength":"Strong (S-tier)","keyFinding":"THC inhibits CYP1A2, CYP2B6, CYP2C9, CYP2D6. CBD inhibits CYP3A4, CYP2B6, CYP2C9, CYP2D6, CYP2E1. Both show mixed inhibition of CYP2C19. THC metabolites (11-OH-THC, THC-COOH-glucuronide) are also significant inhibitors.","whyItMatters":"With millions of people using cannabis alongside prescription medications — including virtually all medical cannabis patients — the clinical implications are enormous. Cannabis does not just affect you; it affects how your body processes every other drug you take.","specificNumbers":"","methodology":"In vitro inhibition assays using pooled human liver microsomes and baculovirus-expressed recombinant CYP enzymes. IC50 determination and inhibition kinetics (competitive, noncompetitive, mixed-type) for each cannabinoid-enzyme combination. Static drug-drug interaction modeling.","limitations":"In vitro study using liver microsomes — the clinical significance of each interaction depends on achievable tissue concentrations of cannabinoids in actual cannabis users. Some inhibition effects observed at concentrations higher than typical plasma levels. In vivo human pharmacokinetic studies are needed to confirm clinical relevance of each specific interaction."},{"rthcId":"RTHC-03375","title":"Cannabis Use in Muslim Youth.","authors":"Nassif, Reyam N","year":2021,"journal":"Cureus, 13(6), e15615","doi":"10.7759/cureus.15615","pmid":"34277233","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03376","title":"Redefining recovery: Accounts of treatment experiences of dependent cannabis users in Nigeria.","authors":"Nelson, Ediomo-Ubong Ekpo; Essien, Nsidibe Francis","year":2021,"journal":"Journal of substance abuse treatment, 125, 108321","doi":"10.1016/j.jsat.2021.108321","pmid":"34016304","tags":["addiction","quitting"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Participants initially sought treatment hoping for total abstinence and identity repair. When relapse occurred, the abstinence-only framework made them feel they had failed. Some participants reframed recovery as \"recovering\" rather than \"recovered,\" measuring progress by reduced use and improved overall well-being rather than complete cessation.","whyItMatters":"In many treatment settings, particularly in low-resource countries, abstinence is the only accepted recovery goal. This study gives voice to cannabis users who are finding that harm reduction approaches better match their lived experience and recovery trajectory.","specificNumbers":"97 participants; ages 21-34; street-involved cannabis users; Uyo, Akwa Ibom State, Nigeria","methodology":"Qualitative study of 97 current cannabis users aged 21-34 in Uyo, Nigeria, recruited through time-location sampling. In-depth individual interviews were transcribed, coded, and analyzed thematically.","limitations":"Street-involved cannabis users in one Nigerian city may not represent all cannabis-dependent individuals. Qualitative design captures depth but not prevalence of views. Cultural context shapes recovery narratives."},{"rthcId":"RTHC-03377","title":"Early Consumption of Cannabinoids: From Adult Neurogenesis to Behavior.","authors":"Netzahualcoyotzi, Citlalli; Rodríguez-Serrano, Luis Miguel; Chávez-Hernández, María Elena; Buenrostro-Jáuregui, Mario Humberto","year":2021,"journal":"International journal of molecular sciences, 22(14)","doi":"10.3390/ijms22147450","pmid":"34299069","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03378","title":"Cannabis use of patients with inflammatory bowel disease in Germany: a cross-sectional survey.","authors":"Neufeld, Tanja; Pfuhlmann, Katrin; Stock-Schröer, Beate; Kairey, Lana; Bauer, Nina; Häuser, Winfried; Langhorst, Jost","year":2021,"journal":"Zeitschrift fur Gastroenterologie, 59(10), 1068-1077","doi":"10.1055/a-1400-2768","pmid":"34157755","tags":["medical-cannabis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"17.5% had used cannabis recreationally; 4.3% currently used cannabis to treat IBD. Users reported reduced abdominal pain, improved sleep, and relief of anxiety. However, users had lower quality of life and more anxiety/depression than non-users. 52.9% obtained cannabis from the black market. 76.5% of former and 50% of current users did not report cannabis use to their physician.","whyItMatters":"Even in Germany, where medical cannabis is available by prescription, more than half of IBD patients using cannabis obtain it from unregulated sources. The physician communication gap is also striking, mirroring findings from other countries.","specificNumbers":"417 respondents; 4.3% current medical use; 17.5% recreational history; 52.9% black market; 76.5% former users and 50% current users did not tell physician","methodology":"Cross-sectional survey mailed to a randomly selected representative sample of 1,000 IBD patients in Germany, with 417 responses (55.8% women; 43.4% ulcerative colitis, 54.7% Crohn's disease).","limitations":"Response rate of 41.7% may introduce selection bias. Self-reported data. Cross-sectional design. German healthcare context may not generalize."},{"rthcId":"RTHC-03379","title":"Same-day use of cigarettes, alcohol, and cannabis among sexual minority and heterosexual young adult smokers.","authors":"Nguyen, Nhung; McQuoid, Julia; Neilands, Torsten B; Dermody, Sarah S; Holmes, Louisa M; Ling, Pamela M; Thrul, Johannes","year":2021,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 35(2), 215-223","doi":"10.1037/adb0000678","pmid":"32804517","tags":["sex-differences","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Sexual minority young adults had significantly greater odds of same-day cigarette and cannabis use (AOR 2.05, 95% CI 1.04-4.01) and all three substances combined (AOR 2.79, 95% CI 1.51-5.14) compared to heterosexuals. Of 2,891 daily assessments, 18.1% included same-day cigarette and cannabis use, and 15.0% included all three substances.","whyItMatters":"Same-day use of multiple substances compounds health risks beyond what each substance poses individually. Identifying that sexual minority young adults are at elevated risk for this pattern helps target interventions for maximum impact.","specificNumbers":"147 participants; 2,891 daily assessments; 30 days; cigarettes+cannabis AOR 2.05; all 3 substances AOR 2.79; 18.1% of days included cigarettes+cannabis","methodology":"Daily diary data from 147 young adult smokers (aged 18-26, 51.7% female, 41.5% sexual minority) using smartphone-based surveys over 30 consecutive days, analyzed with generalized estimating equations.","limitations":"All participants were smokers, limiting generalizability. 30-day window may not capture longer-term patterns. Self-reported daily diary data. Specific reasons for polysubstance use not assessed."},{"rthcId":"RTHC-03380","title":"Emotion regulation in emerging adults with major depressive disorder and frequent cannabis use.","authors":"Nichols, Emily S; Penner, Jacob; Ford, Kristen A; Wammes, Michael; Neufeld, Richard W J; Mitchell, Derek G V; Greening, Steven G; Théberge, Jean; Williamson, Peter C; Osuch, Elizabeth A","year":2021,"journal":"NeuroImage. Clinical, 30, 102575","doi":"10.1016/j.nicl.2021.102575","pmid":"33588323","tags":["depression","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"MDD showed an interaction with emotion regulation in the middle temporal gyrus, while cannabis use showed an interaction in the superior temporal gyrus. Emotion regulation style predicted activity in the right superior frontal gyrus but did not interact with either MDD or cannabis use. Depression severity interacted with the emotion regulation task in the left middle temporal gyrus.","whyItMatters":"Depression and cannabis use frequently co-occur in young adults. Understanding that they affect emotion-related brain processing through different neural pathways could inform more targeted treatment approaches for people dealing with both.","specificNumbers":"74 participants aged 16-23; 2x2 design (MDD x cannabis); MDD: middle temporal gyrus; cannabis: superior temporal gyrus; emotion regulation style: right superior frontal gyrus","methodology":"fMRI study of 74 emerging adults aged 16-23 with and without major depressive disorder who either did or did not use cannabis, assessed during an emotion regulation task. A 2x2 design examined independent effects of MDD and cannabis use on brain activation.","limitations":"Small sample for a 2x2 fMRI design. Cross-sectional, so cannot determine whether brain differences preceded or resulted from cannabis use or depression. Single emotion regulation task."},{"rthcId":"RTHC-03381","title":"Analysis of cannabinoids in conventional and alternative biological matrices by liquid chromatography: Applications and challenges.","authors":"Nicolaou, Athina G; Christodoulou, Marios C; Stavrou, Ioannis J; Kapnissi-Christodoulou, Constantina P","year":2021,"journal":"Journal of chromatography. A, 1651, 462277","doi":"10.1016/j.chroma.2021.462277","pmid":"34091369","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03382","title":"Precursors of self-reported subclinical hypomania in adolescence: A longitudinal general population study.","authors":"Nielsen, Louise Gunhard; Køster Rimvall, Martin; Van Os, Jim; Verhulst, Frank; Rask, Charlotte Ulrikka; Skovgaard, Anne Mette; Olsen, Else Marie; Jeppesen, Pia","year":2021,"journal":"PloS one, 16(6), e0253507","doi":"10.1371/journal.pone.0253507","pmid":"34143836","tags":["youth","mental-health","psychosis"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use by age 15 was a strong independent predictor of self-reported subclinical hypomania at age 16 (RR 3.14, 95% CI 1.93-5.10), after adjusting for age 11 psychopathology and other precursors. Psychotic experiences at age 11 (RR 2.06) and emotional disorders (RR 1.77) also predicted age 16 hypomania. Subclinical hypomania at age 11 showed modest continuity with age 16 (RR 1.89).","whyItMatters":"Subclinical hypomania in adolescence may be an early marker of bipolar disorder risk. Finding that early cannabis use is the strongest modifiable predictor provides a potential intervention target.","specificNumbers":"1,632 at age 11; 893 reassessed at age 16; cannabis by age 15 RR 3.14; psychotic experiences RR 2.06; emotional disorders RR 1.77; age 11 SHM → age 16 SHM RR 1.89","methodology":"Longitudinal study from the Copenhagen Child Cohort 2000. 1,632 preadolescents were assessed for subclinical hypomania and clinical correlates at age 11 via semi-structured interviews. 893 were reassessed at age 16 with self-report (HCL-32). Cannabis use by age 15 was assessed at age 16.","limitations":"Cannabis use assessed retrospectively at age 16 for use by age 15. Self-reported hypomania at age 16 may differ from interview-based assessment. Cannot determine whether cannabis caused hypomania or shared vulnerability explains both."},{"rthcId":"RTHC-03383","title":"Contribution of Fatty Acid Amide Hydrolase to Alcohol Use Disorder: A Systematic Review.","authors":"Niemela, Greta; Terry, Garth E","year":2021,"journal":"Cannabis and cannabinoid research, 6(2), 105-118","doi":"10.1089/can.2020.0158","pmid":"33989054","tags":["addiction","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"FAAH inhibition showed promise for reducing alcohol withdrawal symptoms, including anxiety and reinstatement of alcohol intake. However, decreased FAAH activity was also linked to reduced sensitivity to alcohol and increased preference and consumption.","whyItMatters":"The endocannabinoid system is increasingly recognized as a potential therapeutic target for addiction. Understanding how FAAH modulation affects alcohol-related behaviors could lead to new pharmacological treatments for alcohol use disorder.","specificNumbers":"224 records screened; 26 studies included; FAAH inhibition associated with reduced withdrawal symptoms but also increased alcohol preference in some preclinical models","methodology":"Systematic review of PubMed, Embase, and Web of Science. From 224 initial records, 26 primary research studies were included for qualitative synthesis after removing duplicates (37%), off-topic articles (47%), and non-primary research (4%).","limitations":"Qualitative synthesis only, no meta-analysis. Most included studies were preclinical. Limited human data on FAAH inhibitors for alcohol use disorder."},{"rthcId":"RTHC-03384","title":"Cancer Initiation, Progression and Resistance: Are Phytocannabinoids from Cannabis sativa L. Promising Compounds?","authors":"Nigro, Ersilia; Formato, Marialuisa; Crescente, Giuseppina; Daniele, Aurora","year":2021,"journal":"Molecules (Basel, Switzerland), 26(9)","doi":"10.3390/molecules26092668","pmid":"34063214","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03385","title":"Cannabinoid Hyperemesis Syndrome: A Case Report of an Underdiagnosed Condition.","authors":"Nogueira, João Machado; Fonseca, Inês; Duarte, Marco","year":2021,"journal":"GE Portuguese journal of gastroenterology, 28(6), 420-424","doi":"10.1159/000512088","pmid":"34901450","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03386","title":"Opioid-sparing effects of medical cannabis or cannabinoids for chronic pain: a systematic review and meta-analysis of randomised and observational studies.","authors":"Noori, Atefeh; Miroshnychenko, Anna; Shergill, Yaadwinder; Ashoorion, Vahid; Rehman, Yasir; Couban, Rachel J; Buckley, D Norman; Thabane, Lehana; Bhandari, Mohit; Guyatt, Gordon H; Agoritsas, Thomas; Busse, Jason W","year":2021,"journal":"BMJ open, 11(7), e047717","doi":"10.1136/bmjopen-2020-047717","pmid":"34321302","tags":["pain","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Randomized trials (all in cancer pain) found adding cannabis had little or no impact on opioid dose (weighted mean difference: -3.4 MME, 95% CI -12.7 to 5.8) or pain relief (-0.18 cm on 10 cm VAS). Cannabis addition likely increased nausea (RR 1.43) and vomiting (RR 1.50). Observational studies suggested a larger opioid reduction (-22.5 MME) but with very low certainty.","whyItMatters":"The idea that cannabis can replace opioids is popular in public discourse. This rigorous analysis suggests the opioid-sparing effect remains unproven, with the strongest evidence showing little benefit and increased side effects.","specificNumbers":"5 RCTs + 12 observational studies; opioid change in RCTs: -3.4 MME (not significant); pain relief: -0.18 cm on 10 cm VAS (not clinically meaningful); nausea risk ratio: 1.43; vomiting risk ratio: 1.50; observational opioid reduction: -22.5 MME (very low certainty)","methodology":"Systematic review and meta-analysis searching CENTRAL, EMBASE, and MEDLINE. Included 5 randomized trials (all chronic cancer pain) and 12 observational studies. Evidence certainty assessed using GRADE framework.","limitations":"All RCTs enrolled cancer pain patients, limiting generalizability. RCTs instructed participants to maintain opioid doses, making it difficult to detect dose reduction. Observational studies had very low certainty evidence."},{"rthcId":"RTHC-03387","title":"Geolocation of Maryland Medical Marijuana Dispensaries by Community Income and Racial Characteristics: An Ecological Design.","authors":"Novak, Priscilla; Sanmartin, Maria X; Ali, Mir M","year":2021,"journal":"Substance use & misuse, 56(2), 318-326","doi":"10.1080/10826084.2020.1868516","pmid":"33427008","tags":["legalization","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Dispensaries were concentrated in zip codes with racially diverse populations and higher concentrations of retail establishments. Community-level racial or income disparities in geographic access to medical cannabis were not observed.","whyItMatters":"Equity in cannabis legalization is a major policy concern. While Maryland initially awarded a disproportionate share of business licenses to white-owned companies, this study suggests the geographic placement of dispensaries is not concentrated in privileged communities.","specificNumbers":"85 dispensaries; 468 zip codes; 6.1 million residents; dispensaries located in racially diverse areas with higher retail density","methodology":"Ecological cross-sectional design using geocoded locations of 85 operating dispensaries (as of December 2019) from the Maryland Medical Cannabis Commission, linked to zip code demographics from the American Communities Survey covering 6.1 million residents across 468 zip codes.","limitations":"Ecological design cannot assess individual-level access. Did not examine affordability, transportation, or other access barriers. Cross-sectional data from a single state."},{"rthcId":"RTHC-03388","title":"Cannabis and Its Potential Protective Role Against Inflammatory Bowel Disease: A Scoping Review.","authors":"Nso, Nso; Nyabera, Akwe; Nassar, Mahmoud; Alshamam, Mohsen S; Sumbly, Vikram; Vest, Mallorie; Patel, Nehal; Ojong, Gilbert; Rizzo, Vincent","year":2021,"journal":"Cureus, 13(10), e18841","doi":"10.7759/cureus.18841","pmid":"34804696","tags":["medical-cannabis","inflammation"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Studies reported improvements in general well-being and Harvey-Bradshaw Index, enhanced health perception scores (4.1 to 7.0, p=0.0002), weight gain, CDAI scores below 150, and reduced clinical complications. However, only six studies met inclusion criteria, highlighting the scarcity of evidence.","whyItMatters":"An estimated 15-40% of IBD patients already use cannabis for symptom management. Despite widespread patient interest, the evidence base remains remarkably thin, with only six studies meeting basic quality thresholds.","specificNumbers":"15-40% of IBD patients use cannabis; 3 RCTs + 3 observational studies included; health perception improved from 4.1 to 7.0 (p=0.0002); CDAI target: below 150","methodology":"Scoping review following PRISMA guidelines. Searched for studies assessing clinical remission in IBD patients using cannabis. Only three randomized controlled trials and three observational studies satisfied selection criteria.","limitations":"Only six studies met inclusion criteria. Heterogeneous study designs, cannabis formulations, and outcome measures. No meta-analysis possible due to study variability."},{"rthcId":"RTHC-03389","title":"Reevaluating America's Latest Pharmaceutical Trend: The Cardiovascular Risk of Cannabis.","authors":"O'Keefe, Evan L; Peterson, Tyler M; Lavie, Carl J","year":2021,"journal":"Current opinion in psychology, 38, 31-37","doi":"10.1016/j.copsyc.2020.07.002","pmid":"32781422","tags":["cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis consumption was associated with increased ischemic stroke risk and an almost fivefold increase in myocardial infarction, primarily in the period immediately following consumption. Males in their 30s appeared to bear the greatest burden. Edible preparations were linked to more cardiovascular-related emergency department visits than combustible forms.","whyItMatters":"Cannabis is now the most popular inhaled substance in the US, surpassing tobacco. The cardiovascular risks may be placing a younger, traditionally low-risk population in danger of major cardiac events.","specificNumbers":"Almost 5-fold increase in myocardial infarction risk; males in their 30s most affected; cannabis smoke contains PAHs, aromatic amines, and nitric oxide, some at higher concentrations than tobacco","methodology":"Narrative review synthesizing existing evidence on cardiovascular effects of cannabis, including data on combustible and edible forms, chemical components (aromatic amines, PAHs), and vascular complications.","limitations":"Narrative review without systematic methodology. Much of the evidence is observational and cannot establish causation. Research is described as \"nascent\" by the authors themselves."},{"rthcId":"RTHC-03390","title":"Cannabidiol modulation of hippocampal glutamate in early psychosis.","authors":"O'Neill, Aisling; Annibale, Luciano; Blest-Hopley, Grace; Wilson, Robin; Giampietro, Vincent; Bhattacharyya, Sagnik","year":2021,"journal":"Journal of psychopharmacology (Oxford, England), 35(7), 814-822","doi":"10.1177/02698811211001107","pmid":"33860709","tags":["cbd","psychosis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Compared to placebo, CBD produced a significant increase in hippocampal glutamate (p=0.035) and a significantly greater decrease in symptom severity on the PANSS scale (p=0.032). A significant negative correlation existed between post-treatment symptom scores and glutamate levels (p=0.047), suggesting the glutamate increase may be linked to symptom improvement.","whyItMatters":"Understanding how CBD might work as an antipsychotic is crucial for developing new treatments. This study provides the first evidence linking CBD's effects on glutamate signaling to symptom improvement in psychosis patients.","specificNumbers":"13 patients; 600 mg CBD single dose; hippocampal glutamate increase p=0.035; symptom severity decrease p=0.032; glutamate-symptom correlation p=0.047","methodology":"Double-blind, randomized, placebo-controlled, repeated-measures, within-subject crossover design. 13 patients with psychosis received a single oral dose of CBD (600 mg) or placebo on separate days. Hippocampal glutamate measured via proton magnetic resonance spectroscopy.","limitations":"Very small sample (13 patients). Single-dose design cannot show whether effects persist with repeated use. Within-subject crossover reduces confounders but limits generalizability."},{"rthcId":"RTHC-03391","title":"Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis.","authors":"O'Neill, Aisling; Wilson, Robin; Blest-Hopley, Grace; Annibale, Luciano; Colizzi, Marco; Brammer, Mick; Giampietro, Vincent; Bhattacharyya, Sagnik","year":2021,"journal":"Psychological medicine, 51(4), 596-606","doi":"10.1017/S0033291719003519","pmid":"31994476","tags":["cbd","psychosis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Psychosis patients on placebo showed altered prefrontal activation during verbal encoding and altered mediotemporal and prefrontal activation during recall, along with greater hippocampal-striatal connectivity. CBD attenuated these dysfunctions, producing activation patterns intermediate between the placebo condition and healthy controls. CBD also reduced hippocampal-striatal functional connectivity.","whyItMatters":"This study provides neuroimaging evidence for how CBD may exert antipsychotic effects, showing it partially corrects the specific brain activation patterns that differ between psychosis patients and healthy individuals.","specificNumbers":"15 psychosis patients; 19 healthy controls; 600 mg CBD single dose; brain activation under CBD shifted toward healthy control patterns in mediotemporal, prefrontal, and striatal regions","methodology":"Double-blind, randomized, placebo-controlled, within-subject crossover design. 15 psychosis patients scanned with fMRI on two days (CBD 600 mg vs placebo). 19 healthy controls scanned without drug for comparison. Task: verbal paired associate learning.","limitations":"Small sample (15 patients, 13 completed scanning). Single-dose design. Healthy controls did not receive any drug, preventing direct comparison of CBD effects in healthy brains. Trend-level symptom reduction only."},{"rthcId":"RTHC-03392","title":"The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man.","authors":"O'Sullivan, Saoirse Elizabeth; Yates, Andrew S; Porter, Richard K","year":2021,"journal":"Molecules (Basel, Switzerland), 26(20)","doi":"10.3390/molecules26206178","pmid":"34684760","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03393","title":"Rapid situational assessment of people who inject drugs (PWID) in Nairobi and coastal regions of Kenya: a respondent driven sampling survey.","authors":"Oguya, Francis O; Kenya, Patrick R; Ongecha, Francisca; Mureithi, Patrick; Musyoka, Helgar; Muraguri, Nicholas; Mundia, Ben; Angira, Caleb; Shose, Mohammed; Basheeb, Taib A; Mohamed, Abdalla Ahmed; Oyore, John P; Ochieng, Otieno G; Dida, Gabriel O; Abdalla, Saade; Abdool, Reychard","year":2021,"journal":"BMC public health, 21(1), 1549","doi":"10.1186/s12889-021-11373-9","pmid":"34391389","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03394","title":"Cannabinoid CB1 and CB2 receptors differentially regulate TNF-α-induced apoptosis and LPA1-mediated pro-survival signaling in HT22 hippocampal cells.","authors":"Olianas, Maria C; Dedoni, Simona; Onali, Pierluigi","year":2021,"journal":"Life sciences, 276, 119407","doi":"10.1016/j.lfs.2021.119407","pmid":"33794254","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03395","title":"Sex-dependent pharmacological profiles of the synthetic cannabinoid MMB-Fubinaca.","authors":"Oliveira da Cruz, José F; Ioannidou, Christina; Pagano Zottola, Antonio C; Muguruza, Carolina; Gomez-Sotres, Paula; Fernandez, Monica; Callado, Luis F; Marsicano, Giovanni; Busquets-Garcia, Arnau","year":2021,"journal":"Addiction biology, 26(3), e12940","doi":"10.1111/adb.12940","pmid":"32744799","tags":["synthetic-cannabinoids","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"MMB-Fubinaca activated CB1 receptors with much greater potency than the standard cannabinoid agonist WIN55,512-2 in both mouse and human brain tissue. In vivo, male mice showed significantly greater behavioral and electrophysiological responses than females, all dependent on CB1 receptor activity.","whyItMatters":"Synthetic cannabinoids are a major public health concern and are far more potent than plant-derived THC. These sex-based differences in response could mean that risk assessments and emergency treatments may need to account for biological sex.","specificNumbers":"MMB-Fubinaca showed much greater potency than WIN55,512-2 at CB1 receptors; male mice showed significantly greater behavioral and electrophysiological effects than females; effects were CB1 receptor-dependent","methodology":"Combined behavioral, molecular, pharmacological, and electrophysiological approaches in mice, plus in vitro assays using mouse and human brain preparations. CB1 receptor-dependent effects confirmed using antagonists.","limitations":"Animal study; findings may not directly translate to humans. Only one synthetic cannabinoid tested. Mechanisms underlying the sex difference were not fully elucidated."},{"rthcId":"RTHC-03396","title":"The growing dilemma of legalized cannabis and heart transplantation.","authors":"Olt, Caroline; Faulkenberg, Kathleen D; Hsich, Eileen M","year":2021,"journal":"The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 40(9), 863-871","doi":"10.1016/j.healun.2021.03.024","pmid":"34006449","tags":["cardiovascular","medical-cannabis","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"THC and CBD are metabolized by cytochrome P-450 and P-glycoprotein, the same pathways used by calcineurin inhibitors essential for transplant immunosuppression. These drug-drug interactions, combined with variable cannabis product potency, make maintaining adequate immunosuppression unpredictable. Cannabis use has been associated with increased risk of graft failure and infections.","whyItMatters":"As cannabis becomes legal in more jurisdictions, transplant programs face growing inconsistency in how cannabis use affects candidacy. The pharmacological interactions with transplant drugs pose real clinical risks that go beyond the policy debate.","specificNumbers":"THC and CBD metabolized by CYP-450 and P-glycoprotein; same pathways as calcineurin inhibitors; cannabis associated with graft failure and increased infection risk","methodology":"In-depth narrative review synthesizing evidence on cannabinoid pharmacokinetics, drug-drug interactions with transplant medications, cannabis use disorder, and outcomes in transplant recipients.","limitations":"Narrative review without systematic methodology. Limited direct evidence from transplant populations. Cannabis product variability makes generalizing pharmacological interactions difficult."},{"rthcId":"RTHC-03397","title":"Comorbid Cannabis Use Disorder with Major Depression and Generalized Anxiety Disorder: A Systematic Review with Meta-analysis of Nationally Representative Epidemiological Surveys.","authors":"Onaemo, Vivian N; Fawehinmi, Timothy O; D'Arcy, Carl","year":2021,"journal":"Journal of affective disorders, 281, 467-475","doi":"10.1016/j.jad.2020.12.043","pmid":"33360749","tags":["addiction","depression","anxiety","mental-health"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis use disorder was strongly associated with major depressive episodes (OR 3.22; 95% CI 2.31-4.49) and with generalized anxiety disorder (OR 2.99; 95% CI 2.14-4.16). Both 12-month and lifetime comorbidity estimates showed consistent patterns of co-occurrence.","whyItMatters":"The threefold co-occurrence of cannabis use disorder with depression and anxiety underscores the complexity of treating either condition in isolation. Integrated treatment approaches may be needed for this substantial overlap.","specificNumbers":"8 nationally representative surveys; CUD + major depression OR 3.22 (95% CI 2.31-4.49); CUD + GAD OR 2.99 (95% CI 2.14-4.16)","methodology":"Systematic review and meta-analysis of Medline, CINAHL, PsycINFO, EMBASE, and grey literature. Included 8 nationally representative epidemiological surveys of non-clinical, randomly selected adult populations. Random-effects model used to address heterogeneity.","limitations":"Cross-sectional surveys cannot determine causal direction. Heterogeneity from combining studies across geographic regions with different diagnostic criteria. Self-report measures used in population surveys."},{"rthcId":"RTHC-03398","title":"Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia?","authors":"Oomens, Thomas; Riezebos, Robert K; Amoroso, Giovanni; Kuipers, Remko S","year":2021,"journal":"European heart journal. Case reports, 5(2), ytaa557","doi":"10.1093/ehjcr/ytaa557","pmid":"33598625","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03399","title":"Medicinal cannabis: knowledge, beliefs, and attitudes of Colombian psychiatrists.","authors":"Orjuela-Rojas, Juan Manuel; García Orjuela, Xiomara; Ocampo Serna, Sabina","year":2021,"journal":"Journal of cannabis research, 3(1), 26","doi":"10.1186/s42238-021-00083-z","pmid":"34225825","tags":["medical-cannabis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"82% of psychiatrists agreed medical cannabis should be available, and 73.1% wanted prescribing authority. However, 66.2% did not know how to help patients access it, and only 25% understood the legal status. The highest psychiatric approval was for insomnia (35.2%) and anxiety (29%), while 66.9% disapproved of use for schizophrenia. Non-psychiatric conditions like cancer pain (87.6%) and chemotherapy nausea (78.6%) received much higher approval.","whyItMatters":"Even in a country that has legalized medical cannabis, psychiatrists remain cautious about psychiatric applications while embracing non-psychiatric uses. The gap between willingness to prescribe and knowledge of how to do so highlights a systemic education failure.","specificNumbers":"145 psychiatrists; 14 territories; 82% support availability; 73.1% want to prescribe; 66.2% do not know how patients can access it; 25% understand legal status; insomnia approval 35.2%; anxiety approval 29%; schizophrenia disapproval 66.9%; cancer pain approval 87.6%","methodology":"Cross-sectional survey of 145 psychiatrists across 14 Colombian territories between November 2019 and July 2020. 28-item questionnaire covering attitudes, clinical experience, perceived knowledge, indications, and safety concerns.","limitations":"Non-random sampling may not represent all Colombian psychiatrists. Self-report measures of knowledge and attitudes. Cross-sectional design provides a single snapshot."},{"rthcId":"RTHC-03400","title":"Endocannabinoid system and its modulation of brain, gut, joint and skin inflammation.","authors":"Osafo, Newman; Yeboah, Oduro K; Antwi, Aaron O","year":2021,"journal":"Molecular biology reports, 48(4), 3665-3680","doi":"10.1007/s11033-021-06366-1","pmid":"33909195","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03401","title":"Health and Safety in the Legal Cannabis Industry Before and During COVID-19.","authors":"Otañez, Marty; Grewal, Jassy","year":2021,"journal":"New solutions : a journal of environmental and occupational health policy : NS, 30(4), 311-323","doi":"10.1177/1048291120976134","pmid":"33256503","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03402","title":"Industrial hemp as an agricultural crop in Ghana.","authors":"Owusu, Nana Osei; Arthur, Benedict; Aboagye, Emmanuel Mensah","year":2021,"journal":"Journal of cannabis research, 3(1), 9","doi":"10.1186/s42238-021-00066-0","pmid":"33845918","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03403","title":"Cannabinoid receptor CB1 and CB2 interacting proteins: Techniques, progress and perspectives.","authors":"Oyagawa, Caitlin R M; Grimsey, Natasha L","year":2021,"journal":"Methods in cell biology, 166, 83-132","doi":"10.1016/bs.mcb.2021.06.011","pmid":"34752341","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03404","title":"Sociodemographic and clinical profile of cannabis-induced psychosis: A comparative study.","authors":"Padhi, Debasish; Shukla, Priyanka; Chaudhury, Suprakash","year":2021,"journal":"Industrial psychiatry journal, 30(Suppl 1), S132-S139","doi":"10.4103/0972-6748.328804","pmid":"34908679","tags":["psychosis","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis-using patients with psychosis showed higher scores in pressure of speech, distractible speech, and clanging. Schizophrenia patients without cannabis use showed higher scores in derailment, incoherence, illogicality, and global rating of positive formal thought disorder. Both groups had significantly higher neurological soft sign scores than healthy controls.","whyItMatters":"Distinguishing cannabis-induced psychosis from schizophrenia has important treatment implications. If the symptom profiles are genuinely different, clinicians may be able to better identify when psychosis is substance-driven versus a primary psychiatric disorder.","specificNumbers":"50 cannabis users with psychosis; 50 schizophrenia patients; 30 healthy controls; neurological soft sign scores: CUD with psychosis 20.53, CUD without psychosis 15.93, controls 6.20 (p<0.001)","methodology":"Cross-sectional hospital-based study comparing 50 cannabis-using patients with psychosis (DSM-5 CUD) to 50 age-matched schizophrenia patients without cannabis use, plus 30 healthy controls. Psychotic symptoms assessed using the Scale for Assessment of Positive Symptoms.","limitations":"Relatively small sample from a single hospital. Cross-sectional design cannot determine whether cannabis-induced psychosis represents a distinct disorder or an early manifestation of schizophrenia. Indian population may limit generalizability."},{"rthcId":"RTHC-03405","title":"Shifts in drug seizures in the United States during the COVID-19 pandemic.","authors":"Palamar, Joseph J; Le, Austin; Carr, Thomas H; Cottler, Linda B","year":2021,"journal":"Drug and alcohol dependence, 221, 108580","doi":"10.1016/j.drugalcdep.2021.108580","pmid":"33674175","tags":["legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Marijuana seizures decreased significantly through April 2020, then increased significantly through September 2020, peaking in August 2020 above pre-pandemic highs. Both the number and weight of marijuana seized exceeded pre-COVID levels. Fentanyl seizures increased overall without a COVID dip. No significant changes were detected for cocaine or heroin.","whyItMatters":"Drug seizures serve as a proxy for drug availability. The rebound in marijuana seizures above pre-pandemic levels suggests supply chains adapted quickly to pandemic disruptions, while fentanyl's uninterrupted increase signals ongoing escalation of that crisis.","specificNumbers":"Marijuana seizure decrease through April 2020 (β=-0.03, p=0.005); rebound through September (β=0.10, p=0.028); marijuana weight increase (β=0.40, p=0.001); fentanyl steady increase (β=0.05, p<0.001)","methodology":"Joinpoint regression analysis of drug seizure trends from March 2019 through September 2020 across five High Intensity Drug Trafficking Areas: Washington/Baltimore, Chicago, Ohio, New Mexico, and North Florida. Examined number and total weight of seizures.","limitations":"Seizure data may reflect law enforcement activity levels rather than actual drug availability. Five regions may not represent national trends. Cannot directly measure consumption or use patterns."},{"rthcId":"RTHC-03406","title":"Genome-wide identification, expression, and sequence analysis of CONSTANS-like gene family in cannabis reveals a potential role in plant flowering time regulation.","authors":"Pan, Gen; Li, Zheng; Yin, Ming; Huang, Siqi; Tao, Jie; Chen, Anguo; Li, Jianjun; Tang, Huijuan; Chang, Li; Deng, Yong; Li, Defang; Zhao, Lining","year":2021,"journal":"BMC plant biology, 21(1), 142","doi":"10.1186/s12870-021-02913-x","pmid":"33731002","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03407","title":"A method and its application to determine the amount of cannabinoids in sewage sludge and biosolids.","authors":"Pandopulos, Aaron J; Simpson, Bradley S; Bade, Richard; O'Brien, Jake W; Yadav, Meena K; White, Jason M; Gerber, Cobus","year":2021,"journal":"Environmental science and pollution research international, 28(42), 59652-59664","doi":"10.1007/s11356-021-14921-3","pmid":"34143389","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03408","title":"Cannabis use and mental health among young sexual and gender minority men: A qualitative study.","authors":"Parent, Natasha; Coulaud, Pierre-Julien; Amirie, Muhamed; Ferlatte, Olivier; Knight, Rod","year":2021,"journal":"The International journal on drug policy, 91, 102980","doi":"10.1016/j.drugpo.2020.102980","pmid":"33051088","tags":["mental-health","youth"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Three themes emerged: (1) cannabis was used to cope with mental health symptoms during sexual encounters and to replace riskier drugs in chemsex practices; (2) cannabis was used instrumentally to alleviate depression and trauma-related symptoms; (3) some participants experienced adverse effects including paranoia and concerns about dependence.","whyItMatters":"Sexual and gender minority men face elevated rates of both substance use and mental health challenges. Understanding why this population uses cannabis, including as a harm reduction strategy for harder drug use, is essential for developing appropriate support services.","specificNumbers":"50 participants; ages 15-30; interviews conducted over 12 months in Vancouver, Canada; 3 major themes identified","methodology":"Qualitative study using semi-structured interviews with 50 sexual and gender minority men aged 15-30 in Vancouver, Canada, conducted January-December 2018. Thematic analysis applied to interview data.","limitations":"Qualitative design with a single city sample. Self-selected participants may not represent all SGM men. Cannot establish causal relationships between cannabis use and mental health outcomes."},{"rthcId":"RTHC-03409","title":"Effects of cannabinoid receptor 2 synthetic agonist, AM1241, on bleomycin induced pulmonary fibrosis.","authors":"Parlar, Ali; Arslan, Seyfullah Oktay; Yumrutas, Onder; Elibol, Ebru; Yalcin, Alper; Uckardes, Fatih; Aydin, Hasan; Dogan, Muhammed Fatih; Kayhan Kustepe, Elif; Ozer, Mehmet Kaya","year":2021,"journal":"Biotechnic & histochemistry : official publication of the Biological Stain Commission, 96(1), 48-59","doi":"10.1080/10520295.2020.1758343","pmid":"33325762","tags":["inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats treated with AM1241 before bleomycin exposure had significantly lower levels of hydroxyproline (a collagen marker), TNF-alpha, IL-6, and total protein compared to bleomycin-only rats. GSH (an antioxidant) levels were higher in the AM1241 group. Inflammation and fibrotic changes were significantly reduced on histopathology. Effects were blocked by the CB2 antagonist AM630.","whyItMatters":"Pulmonary fibrosis is a serious side effect of the chemotherapy drug bleomycin with limited treatment options. Finding that CB2 receptor activation provides protection suggests a potential new therapeutic avenue for preventing or treating this condition.","specificNumbers":"Higher hydroxyproline, TNF-alpha, IL-6, and total protein in bleomycin vs AM1241+bleomycin groups; higher GSH in AM1241+bleomycin group; significant reduction in fibrotic changes on histopathology","methodology":"Controlled animal study in adult female Wistar rats divided into five groups: saline control, bleomycin only, CB2 agonist + bleomycin, CB2 antagonist + CB2 agonist + bleomycin, and vehicle + bleomycin. Measured hydroxyproline, collagen, protein, GSH, MDA, IL-6, and TNF-alpha levels plus histopathology.","limitations":"Animal study in rats; results may not translate to humans. Only one dosing protocol tested. Did not examine long-term outcomes or whether effects persist after treatment cessation."},{"rthcId":"RTHC-03410","title":"Cannabis Use, Age of Initiation, and Neurocognitive Performance: Findings from a Large Sample of Heavy Drinking Emerging Adults.","authors":"Parlar, Melissa; MacKillop, Emily; Petker, Tashia; Murphy, James; MacKillop, James","year":2021,"journal":"Journal of the International Neuropsychological Society : JINS, 27(6), 533-545","doi":"10.1017/S1355617721000618","pmid":"34261551","tags":["cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Daily cannabis users showed significantly poorer working memory, more impulsive delay discounting, and greater ADHD symptom endorsement compared to non-users. Occasional users (monthly or weekly) did not differ from non-users on any measure. Effect sizes were small. Earlier age of cannabis initiation was not independently or interactively associated with worse performance.","whyItMatters":"This study separates daily from occasional use, revealing that the cognitive concerns about cannabis may be specific to heavy use patterns. The lack of deficits in occasional users challenges blanket warnings about any cannabis use damaging cognition.","specificNumbers":"598 participants; 276 non-users, 201 occasional users, 121 daily users; ages 21-25; daily use linked to poorer working memory, impulsive discounting, and ADHD symptoms; effect sizes small; no effect of age of initiation","methodology":"Cross-sectional study of 598 high-risk drinking emerging adults (ages 21-25) categorized as non-users (n=276), occasional users (n=201), or daily users (n=121). Assessed working memory, attention, behavioral inhibition, delay and probability discounting, verbal intelligence, and ADHD symptoms. Controlled for age, race, sex, income, education, tobacco, and alcohol use.","limitations":"Cross-sectional design cannot determine causation. All participants were heavy drinkers, limiting generalizability. Self-reported cannabis use categories. Small effect sizes suggest modest practical significance."},{"rthcId":"RTHC-03411","title":"Neurological Soft Signs in Cannabis Use Disorder with or without Psychosis: A Comparative Study from India.","authors":"Parmar, Arpit; Lal, Rakesh; Sarkar, Siddharth; Singh Balhara, Yatan Pal","year":2021,"journal":"Journal of dual diagnosis, 17(4), 267-276","doi":"10.1080/15504263.2021.1979887","pmid":"34609263","tags":["psychosis","neuroscience","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Total NES scores were significantly higher in CUD with psychosis (20.53) and CUD without psychosis (15.93) compared to healthy controls (6.20, p<0.001). However, the two cannabis groups did not differ significantly from each other. Impairments spanned motor coordination, complex motor sequencing, sensory integration, and other neurological domains.","whyItMatters":"Neurological soft signs are subtle markers of brain circuit dysfunction. Finding that cannabis users show these signs regardless of psychosis status suggests that cannabinoids may interact with brain circuits known to be involved in schizophrenia even when full psychosis has not developed.","specificNumbers":"30 CUD + psychosis (NES: 20.53); 30 CUD without psychosis (NES: 15.93); 30 healthy controls (NES: 6.20); p<0.001; impaired domains: motor coordination, motor sequencing, sensory integration","methodology":"Cross-sectional study comparing 30 right-handed males with CUD and psychosis, 30 with CUD without psychosis, and 30 age-matched healthy controls. Neurological Evaluation Scale applied to measure neurological soft signs across all groups.","limitations":"Small sample (30 per group). All male, right-handed participants from one Indian hospital. Cross-sectional design cannot determine if neurological signs preceded or followed cannabis use."},{"rthcId":"RTHC-03412","title":"Effects on the Post-translational Modification of H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 Levels in Cerebral Cortex, Hypothalamus and Pons of Rats after a Systemic Administration of Cannabidiol: A Preliminary Study.","authors":"Pastrana-Trejo, José Carlos; Duarte-Aké, Fátima; Us-Camas, Rosa; De-la-Peña, Clelia; Parker, Linda; Pertwee, Roger G; Murillo-Rodríguez, Eric","year":2021,"journal":"Central nervous system agents in medicinal chemistry, 21(2), 142-147","doi":"10.2174/1871524920666200924114524","pmid":"32972354","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03413","title":"Cannabinoids in Neurologic Illnesses.","authors":"Patel, Anup D","year":2021,"journal":"Neurologic clinics, 39(1), 231-241","doi":"10.1016/j.ncl.2020.09.012","pmid":"33223086","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03414","title":"Biased agonism at the cannabinoid receptors - Evidence from synthetic cannabinoid receptor agonists.","authors":"Patel, Monica; Finlay, David B; Glass, Michelle","year":2021,"journal":"Cellular signalling, 78, 109865","doi":"10.1016/j.cellsig.2020.109865","pmid":"33259937","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03415","title":"Safety and Sourcing of Topical Cannabinoids: Many Questions, Few Answers.","authors":"Patel, Payal M; Lio, Peter A","year":2021,"journal":"The Journal of clinical and aesthetic dermatology, 14(8), 49-51","doi":null,"pmid":"34840658","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03416","title":"Cannabis use disorder and increased risk of arrhythmia-related hospitalization in young adults.","authors":"Patel, Rikinkumar S; Gonzalez, Mario D; Ajibawo, Temitope; Baweja, Raman","year":2021,"journal":"The American journal on addictions, 30(6), 578-584","doi":"10.1111/ajad.13215","pmid":"34432919","tags":["cardiovascular","addiction","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"CUD was associated with 1.28 times higher odds of arrhythmia hospitalization in 15-24 year olds (95% CI: 1.229-1.346) and 1.52 times in 25-34 year olds (95% CI: 1.469-1.578). Among cannabis users with arrhythmia, 42% had atrial fibrillation, followed by other arrhythmias (24%) and atrial flutter (8%). Patients with CUD were more likely to be younger, male, and African American.","whyItMatters":"This is described as the first national study finding an association between CUD and arrhythmia hospitalization in young people. Atrial fibrillation in this age group is particularly concerning because it can lead to stroke and other embolic events.","specificNumbers":"570,556 arrhythmia patients; 67.7 million comparison patients; CUD prevalence in arrhythmia patients: 2.6%; odds ratio 15-24 years: 1.28; 25-34 years: 1.52; 42% had atrial fibrillation; controlled for other substance use","methodology":"Retrospective analysis of the Nationwide Inpatient Sample (2010-2014). Compared 570,556 patients aged 15-54 with primary arrhythmia diagnosis to 67.7 million non-arrhythmia inpatients. Logistic regression adjusted for demographics and comorbid risk factors.","limitations":"Retrospective administrative data cannot establish causation. ICD coding may under-capture CUD diagnosis. Cannot distinguish cannabis use patterns (frequency, route, potency). Association controlled for confounders but unmeasured variables may exist."},{"rthcId":"RTHC-03417","title":"Intoxicated driving and riding with impaired drivers: Comparing days with alcohol, marijuana, and simultaneous use.","authors":"Patrick, Megan E; Graupensperger, Scott; Dworkin, Emily R; Duckworth, Jennifer C; Abdallah, Devon Alisa; Lee, Christine M","year":2021,"journal":"Drug and alcohol dependence, 225, 108753","doi":"10.1016/j.drugalcdep.2021.108753","pmid":"34058538","tags":["driving","harm-reduction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"On simultaneous alcohol-marijuana days, odds of riding with an impaired driver were 1.28x higher than alcohol-only days and 2.22x higher than marijuana-only days. Driving after use was 1.25x more likely on simultaneous days vs marijuana-only days, but non-simultaneous use days had the highest driving-after-use odds (1.59x vs simultaneous days).","whyItMatters":"Simultaneous use of alcohol and marijuana is increasingly common and appears to amplify risky transportation behaviors. The finding that non-simultaneous use days carry the highest driving-after-use risk suggests complex decision-making patterns around impairment.","specificNumbers":"408 participants; 14,675 substance use days; riding with impaired driver: SAM vs alcohol-only AOR 1.28, SAM vs marijuana-only AOR 2.22; driving after use: non-simultaneous vs SAM AOR 1.59, SAM vs marijuana-only AOR 1.25","methodology":"Daily diary study with 408 young adult simultaneous alcohol-marijuana users completing five 14-day reporting bursts, yielding 14,675 substance use days. Within-person analyses using adjusted odds ratios.","limitations":"Self-report data on substance use and driving behavior. Participants were recruited as simultaneous users, limiting generalizability. Cannot measure actual impairment levels or accident risk."},{"rthcId":"RTHC-03418","title":"Associations Between Prenatal Cannabis Exposure and Childhood Outcomes: Results From the ABCD Study.","authors":"Paul, Sarah E; Hatoum, Alexander S; Fine, Jeremy D; Johnson, Emma C; Hansen, Isabella; Karcher, Nicole R; Moreau, Allison L; Bondy, Erin; Qu, Yueyue; Carter, Ebony B; Rogers, Cynthia E; Agrawal, Arpana; Barch, Deanna M; Bogdan, Ryan","year":2021,"journal":"JAMA psychiatry, 78(1), 64-76","doi":"10.1001/jamapsychiatry.2020.2902","pmid":"32965490","tags":["pregnancy","youth","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Children exposed to cannabis prenatally showed greater psychotic-like experiences, internalizing, externalizing, attention, thought, and social problems, more sleep difficulties, higher BMI, and lower cognitive performance. After adjusting for familial, pregnancy, and child covariates, many associations attenuated but prenatal exposure before maternal knowledge of pregnancy remained associated with psychopathology and cognition.","whyItMatters":"With cannabis use among pregnant women increasing, this large study from a premier national cohort provides the most comprehensive picture yet of associations between prenatal exposure and childhood outcomes. Published in JAMA Psychiatry, it informed the US Surgeon General advisory against cannabis use during pregnancy.","specificNumbers":"11,489 children; 655 (5.7%) prenatally exposed; 413 exposed before and 242 after maternal knowledge of pregnancy; associations with psychopathology, sleep, BMI, cognition, and reduced gray matter volume","methodology":"Cross-sectional analysis of the Adolescent Brain and Cognitive Development (ABCD) Study baseline, including 11,489 children aged 9-11 from 22 US sites. 655 (5.7%) were prenatally exposed to cannabis. Extensive covariates included family income, familial psychopathology, prenatal alcohol and tobacco, and child substance use.","limitations":"Cross-sectional baseline data; causal inference limited. Maternal self-report of prenatal cannabis use may be subject to recall bias. Cannot separate cannabis effects from correlated lifestyle factors despite extensive controls."},{"rthcId":"RTHC-03419","title":"Cannabis use-related working memory deficit mediated by lower left hippocampal volume.","authors":"Paul, Subhadip; Bhattacharyya, Sagnik","year":2021,"journal":"Addiction biology, 26(4), e12984","doi":"10.1111/adb.12984","pmid":"33155343","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Higher frequency of cannabis use was associated with lower working memory scores and smaller bilateral hippocampal volumes. Mediation analysis showed that the association between cannabis use frequency and working memory impairment was statistically mediated by lower left hippocampal volume.","whyItMatters":"This study provides a potential brain mechanism linking cannabis use to cognitive deficits. If cannabis reduces hippocampal volume and the hippocampus supports working memory, this offers a neuroanatomical explanation for the cognitive effects reported by heavy users.","specificNumbers":"234 cannabis-exposed + 174 unexposed individuals; bilateral hippocampal volume reductions with higher use frequency; left hippocampal volume mediated the use-memory relationship","methodology":"Cross-sectional observational study using Human Connectome Project data from 234 cannabis-exposed and 174 unexposed individuals. T1-weighted MRI measured regional gray matter volumes. Working memory assessed via list-sorting task. Mediation analysis tested whether hippocampal volume explained the cannabis-cognition relationship.","limitations":"Cross-sectional design cannot establish causation. Self-reported cannabis frequency. Human Connectome Project participants are generally healthy, limiting generalizability to heavy users. Unmeasured confounders possible."},{"rthcId":"RTHC-03420","title":"\"If I knew I could get that every hour instead of alcohol, I would take the cannabis\": need and feasibility of cannabis substitution implementation in Canadian managed alcohol programs.","authors":"Pauly, Bernie; Brown, Meaghan; Chow, Clifton; Wettlaufer, Ashley; Graham, Brittany; Urbanoski, Karen; Callaghan, Russell; Rose, Cindy; Jordan, Michelle; Stockwell, Tim; Thomas, Gerald; Sutherland, Christy","year":2021,"journal":"Harm reduction journal, 18(1), 65","doi":"10.1186/s12954-021-00512-5","pmid":"34162375","tags":["harm-reduction","addiction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"63% of MAP participants reported already substituting cannabis for alcohol, most often weekly (42%), primarily for alcohol cravings (79%) and withdrawal (53%). 84% expressed willingness to join a formal cannabis substitution program. Participants preferred staff-administered dry smoked cannabis with partial (not complete) replacement of alcohol doses.","whyItMatters":"Managed alcohol programs serve people with severe alcohol use disorder who are often experiencing homelessness. Finding that most participants already use cannabis as an informal substitute, and want formal programs, suggests cannabis substitution could be integrated into existing harm reduction infrastructure.","specificNumbers":"6 MAPs studied; 19 participants, 17 staff, 7 leaders; 63% already substituting cannabis for alcohol; 42% doing so weekly; 79% for cravings; 53% for withdrawal; 84% willing to join formal program","methodology":"Pre-implementation mixed-methods study using structured surveys and open-ended interviews with MAP organizational leaders (n=7), program participants (n=19), and staff/managers (n=17) across six MAPs in Canada. Organized using the Consolidated Framework for Implementation Research.","limitations":"Very small sample (19 participants). Pre-implementation study without outcome data. Self-selected participants in a specific harm reduction setting. Cannot generalize to broader alcohol use disorder populations."},{"rthcId":"RTHC-03421","title":"Cannabis and Driving.","authors":"Pearlson, Godfrey D; Stevens, Michael C; D'Souza, Deepak Cyril","year":2021,"journal":"Frontiers in psychiatry, 12, 689444","doi":"10.3389/fpsyt.2021.689444","pmid":"34630173","tags":["driving"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis impairs reaction time, lane tracking, and divided attention, though patterns differ from alcohol impairment. Blood THC levels correlate poorly with actual impairment due to variable pharmacokinetics. Combining cannabis with alcohol produces greater impairment than either alone. Per-se THC limits used in legal settings lack strong scientific basis.","whyItMatters":"As cannabis legalization spreads, states are setting impaired driving policies often without adequate scientific evidence. This review identifies the specific gaps between what science has shown and what policies assume, including the unreliability of blood THC as an impairment proxy.","specificNumbers":"Blood THC levels correlate poorly with impairment; combined alcohol-cannabis produces greater impairment than either alone; per-se THC limits lack strong scientific validation","methodology":"Focused narrative review examining evidence on cannabis and motor vehicle accidents, impairment patterns, time courses, dose relationships, THC blood level correlations, alcohol-cannabis combinations, and legal per-se limits.","limitations":"Narrative review with selective literature coverage. Research gaps identified but not systematically quantified. Rapidly evolving field means some conclusions may already need updating."},{"rthcId":"RTHC-03422","title":"Cannabidiol prevents disruptions in sensorimotor gating induced by psychotomimetic drugs that last for 24-h with probable involvement of epigenetic changes in the ventral striatum.","authors":"Pedrazzi, João F C; Sales, Amanda J; Guimarães, Francisco S; Joca, Sâmia R L; Crippa, José A S; Del Bel, Elaine","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 111, 110352","doi":"10.1016/j.pnpbp.2021.110352","pmid":"34015384","tags":["cbd","psychosis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (30 and 60 mg/kg) attenuated amphetamine- and MK-801-induced disruption of prepulse inhibition, similar to clozapine. Amphetamine increased global DNA methylation in the ventral striatum, an effect prevented by CBD. CBD and clozapine both independently increased DNA methylation in the prefrontal cortex. CBD's antipsychotic-like effects persisted for 24 hours after a single dose.","whyItMatters":"This study suggests a novel mechanism for CBD's antipsychotic-like effects: modifying DNA methylation patterns. Epigenetic changes could explain why CBD effects outlast the drug's presence in the body and point toward longer-lasting therapeutic potential.","specificNumbers":"CBD 30 and 60 mg/kg both effective; clozapine 5 mg/kg as comparator; amphetamine 5 mg/kg and MK-801 0.5 mg/kg as psychosis models; effects detectable 24 hours after single dose; DNA methylation changes in ventral striatum and prefrontal cortex","methodology":"Controlled animal study in mice using the prepulse inhibition (PPI) model. Tested single injections of CBD (30 or 60 mg/kg) or clozapine (5 mg/kg) followed by amphetamine (5 mg/kg) or MK-801 (0.5 mg/kg). Assessed PPI disruption and global DNA methylation in ventral striatum and prefrontal cortex via Western blot.","limitations":"Animal study with limited translatability. Global DNA methylation is a blunt measure that does not identify which specific genes are affected. PPI disruption is a proxy for sensorimotor gating deficits in schizophrenia but does not model the full disorder."},{"rthcId":"RTHC-03423","title":"Specific Compositions of Cannabis sativa Compounds Have Cytotoxic Activity and Inhibit Motility and Colony Formation of Human Glioblastoma Cells In Vitro.","authors":"Peeri, Hadar; Shalev, Nurit; Vinayaka, Ajjampura C; Nizar, Rephael; Kazimirsky, Gila; Namdar, Dvora; Anil, Seegehalli M; Belausov, Eduard; Brodie, Chaya; Koltai, Hinanit","year":2021,"journal":"Cancers, 13(7)","doi":"10.3390/cancers13071720","pmid":"33916466","tags":["cancer","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Fractions F4 and F5 from a high-THC cannabis extract showed significant cytotoxic activity against multiple GBM cell lines and patient-derived glioma stem cells. A standardized mix of these fractions induced apoptosis, activated endoplasmic reticulum stress genes, inhibited cell migration and invasion, altered cell cytoskeletons, and inhibited colony formation in both 2D and 3D models.","whyItMatters":"Glioblastoma is the most lethal brain cancer with very limited treatment options. Identifying specific cannabis compound combinations that target multiple cancer cell behaviors (proliferation, migration, invasion) could eventually lead to new therapeutic approaches.","specificNumbers":"Fractions F4 and F5 from high-THC strain; activity against multiple GBM cell lines and patient-derived glioma stem cells; inhibited colony formation in 2D and 3D models","methodology":"In vitro study using HPLC and GC/MS for chemical characterization. Cytotoxicity measured by XTT and LDH assays. Apoptosis and cell cycle by FACS. Cell migration by scratch assay, invasion by transwell assay. Tested on GBM cell lines and glioma stem cells from tumor specimens.","limitations":"Entirely in vitro; cells in a dish do not replicate the complexity of tumors in a living brain. Many compounds show anti-cancer effects in vitro but fail in clinical settings. No animal or human data."},{"rthcId":"RTHC-03424","title":"Cannabis and Cannabis Edibles: A Review.","authors":"Peng, Han; Shahidi, Fereidoon","year":2021,"journal":"Journal of agricultural and food chemistry, 69(6), 1751-1774","doi":"10.1021/acs.jafc.0c07472","pmid":"33555188","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03425","title":"Association between age of cannabis initiation and gray matter covariance networks in recent onset psychosis.","authors":"Penzel, Nora; Antonucci, Linda A; Betz, Linda T; Sanfelici, Rachele; Weiske, Johanna; Pogarell, Oliver; Cumming, Paul; Quednow, Boris B; Howes, Oliver; Falkai, Peter; Upthegrove, Rachel; Bertolino, Alessandro; Borgwardt, Stefan; Brambilla, Paolo; Lencer, Rebekka; Meisenzahl, Eva; Rosen, Marlene; Haidl, Theresa; Kambeitz-Ilankovic, Lana; Ruhrmann, Stephan; Salokangas, Raimo R K; Pantelis, Christos; Wood, Stephen J; Koutsouleris, Nikolaos; Kambeitz, Joseph","year":2021,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 46(8), 1484-1493","doi":"10.1038/s41386-021-00977-9","pmid":"33658653","tags":["psychosis","neuroscience","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Earlier cannabis initiation was linked to greater cerebellar gray matter volume in a network previously identified as altered in schizophrenia, independent of confounders. This cerebellar network was also associated with lower volume in an insula-temporal-frontal network implicated in schizophrenia. Earlier initiation correlated with more severe positive symptoms.","whyItMatters":"This study connects the timing of cannabis use to specific structural brain network changes that are also seen in schizophrenia, supporting the hypothesis that early cannabis use may disrupt developmental trajectories in a way that increases psychosis risk.","specificNumbers":"102 patients with recent-onset psychosis; multicentric data from PRONIA and CIP studies; cerebellar network gray matter volume associated with early cannabis use; correlation with positive symptom severity","methodology":"Cross-sectional analysis of 102 clinically relevant cannabis users with recent-onset psychosis from the multicentric PRONIA and CIP studies. Source-based morphometry analysis with spatial constraints applied to structural brain networks previously identified as altered in schizophrenia.","limitations":"Cross-sectional design cannot determine if brain changes preceded or followed cannabis use. All participants had psychosis, so findings may not generalize to cannabis users without psychosis. Self-reported age of initiation."},{"rthcId":"RTHC-03426","title":"Short and long-term neuroprotective effects of cannabidiol after neonatal peripheral nerve axotomy.","authors":"Perez, Matheus; Cartarozzi, Luciana Politti; Chiarotto, Gabriela Bortolança; Guimarães, Francisco Silveira; Oliveira, Alexandre Leite Rodrigues de","year":2021,"journal":"Neuropharmacology, 197, 108726","doi":"10.1016/j.neuropharm.2021.108726","pmid":"34303725","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD increased spinal motor neuron survival by approximately 54% at both 5 days and 8 weeks post-injury. It preserved approximately 35% of synapses in the ventral horn at 5 days. CBD reduced astrocyte reaction by 39% acutely and 31% long-term, and microglial response by 62% acutely. Both CB1 and CB2 receptor pathways were involved, but only CB1 blockade reversed long-term benefits.","whyItMatters":"Neonatal nerve injuries during birth can cause permanent motor and sensory deficits. Finding that CBD provides both short and long-term neuroprotection through multiple mechanisms suggests potential for therapeutic intervention in a condition with limited treatment options.","specificNumbers":"54% increase in motor neuron survival; 35% synaptic preservation; 39% reduction in astrocyte reaction (acute); 31% reduction (8 weeks); 62% reduction in microglial response; effects partially through CB1 and CB2 receptors","methodology":"Controlled animal study in neonatal (two-day-old) Wistar rats with sciatic nerve crush mimicking obstetric nerve injury. Groups included CBD, vehicle, CBD+CB1 blocker (AM251), and CBD+CB2 blocker (AM630). Assessed motor neuron survival (Nissl staining), synaptic preservation (synaptophysin), and glial reaction at 5 and 56 days.","limitations":"Animal study in neonatal rats. Sciatic nerve crush is a model of obstetric injury but does not perfectly replicate human birth injuries. Single CBD dose protocol tested."},{"rthcId":"RTHC-03427","title":"Medicinal cannabis and driving: the intersection of health and road safety policy.","authors":"Perkins, Daniel; Brophy, Hugh; McGregor, Iain S; O'Brien, Paula; Quilter, Julia; McNamara, Luke; Sarris, Jerome; Stevenson, Mark; Gleeson, Penny; Sinclair, Justin; Dietze, Paul","year":2021,"journal":"The International journal on drug policy, 97, 103307","doi":"10.1016/j.drugpo.2021.103307","pmid":"34107448","tags":["driving","medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Road safety risks associated with medicinal cannabis appear similar to or lower than numerous other potentially impairing prescription medications. Zero-tolerance THC laws criminalize patients who test positive for THC even when not impaired and using cannabis as prescribed. Some patients forgo needed medication to maintain driving access, while others face criminal sanctions despite following medical advice.","whyItMatters":"As countries legalize medical cannabis but maintain zero-tolerance driving laws based on THC detection (not impairment), patients face a cruel choice between medication and mobility. This analysis argues the inconsistency is rooted in cannabis's historical prohibition, not evidence.","specificNumbers":"Medical exemptions exist for other impairing drugs like methadone in Australia; THC presence-based offences apply regardless of impairment; comparable jurisdictions have implemented medical exemptions for cannabis","methodology":"Policy analysis examining Australian regulatory approaches to potentially impairing prescription drugs versus illicit drugs, evidence on cannabis and road safety risk, patient impact data, and international comparisons of medicinal cannabis driving regulations.","limitations":"Focused on Australian policy context. Does not provide new empirical data on driving impairment. Arguments rely on existing evidence base, which has limitations around cannabis and driving."},{"rthcId":"RTHC-03428","title":"A Brain on Cannabinoids: The Role of Dopamine Release in Reward Seeking and Addiction.","authors":"Peters, Kate Z; Oleson, Erik B; Cheer, Joseph F","year":2021,"journal":"Cold Spring Harbor perspectives in medicine, 11(1)","doi":"10.1101/cshperspect.a039305","pmid":"31964646","tags":["addiction","dopamine","neuroscience"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This Cold Spring Harbor review laid out the definitive case for how cannabis engages the brain's addiction circuitry. Like every other drug of abuse studied, Cannabis sativa increases dopamine activation in the mesolimbic pathway — the reward highway connecting the ventral tegmental area to the nucleus accumbens.\n\nBut the endocannabinoid angle went beyond cannabis itself. The ECS modulates dopamine release at multiple points in the circuit, and disrupting endocannabinoid signaling decreased both drug-induced dopamine spikes and cue-evoked dopamine signals during reward seeking. This meant the ECS wasn't just the target of cannabis — it was a potential therapeutic lever for treating addiction broadly.\n\nThe review also highlighted advances in real-time dopamine recording that were revealing the subsecond dynamics of endocannabinoid-dopamine interactions, showing that endocannabinoids control the patterning of dopamine release critical for associative learning — the process by which cues become linked to reward and drive drug-seeking behavior.","whyItMatters":"The question \"is cannabis addictive?\" is often debated in binary terms. This review showed the neuroscience is unambiguous: cannabis activates the same dopamine reward circuitry as other addictive drugs. That doesn't mean cannabis is as addictive as heroin — the degree and pattern of activation differs — but the fundamental mechanism is the same.\n\nMore importantly, the finding that endocannabinoid manipulation can reduce drug-seeking dopamine signals opens a treatment angle. If you can dampen the cue-evoked dopamine spikes that drive relapse, you might treat addiction not just to cannabis but to other substances. The ECS is a target for addiction medicine beyond cannabis itself.","specificNumbers":"• Cannabis increases mesolimbic dopamine activation (same pathway as all drugs of abuse)\n• Disrupting ECS decreased drug-induced and cue-evoked dopamine release\n• Endocannabinoids modulate subsecond dopamine patterning critical for associative learning\n• ECS components (receptors, enzymes, ligands) identified as potential pharmacotherapy targets","methodology":"Review article published in Cold Spring Harbor Perspectives in Medicine examining the neurobiological basis of cannabis's interaction with the dopamine reward system. Covers mesolimbic pathway pharmacology, endocannabinoid modulation of dopamine release, and implications for addiction treatment.","limitations":"Review focused on animal models of dopamine recording. Human dopamine dynamics are inferred rather than directly measured in most contexts. The leap from reducing cue-evoked dopamine in rats to treating human addiction involves many untested steps. Does not address the subjective experience of cannabis use or individual variation in addiction vulnerability."},{"rthcId":"RTHC-03429","title":"Measuring the Change in Health-Related Quality of Life in Patients Using Marijuana for Pain Relief.","authors":"Peterson, Andrew M; Le, Christine; Dautrich, Tyler","year":2021,"journal":"Medical cannabis and cannabinoids, 4(2), 114-120","doi":"10.1159/000517857","pmid":"35224431","tags":["pain","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Health-related quality of life (EQ-5D Index Score) improved significantly from 0.722 to 0.747 (p=0.011) over 6 weeks. Self-reported pain and health scores also improved. EQ-5D subscale analysis showed significant improvement in anxiety and pain, no change in mobility or usual activities, but significant worsening in self-care.","whyItMatters":"While many studies measure whether medical marijuana reduces pain, this study takes the broader view of overall quality of life. The mixed results, with improvement in pain and anxiety but decline in self-care, suggest the picture is more nuanced than simply \"better\" or \"worse.\"","specificNumbers":"1,762 screened; 1,393 eligible; 353 enrolled; 181 completed; EQ-5D improved from 0.722 to 0.747 (p=0.011); significant improvement in pain and anxiety subscales; significant worsening in self-care","methodology":"Prospective cohort study of Pennsylvania medical marijuana patients using cannabis for pain. 181 patients completed all 4 surveys (baseline, 2, 4, and 8 weeks). Health-related quality of life measured using EQ-5D. Analyzed with paired t-tests and repeated-measures multivariable analysis controlling for gender and time between surveys.","limitations":"No control group; improvements could reflect natural course, placebo effect, or regression to the mean. Significant dropout (51% completion). Self-selected participants in a medical marijuana program."},{"rthcId":"RTHC-03430","title":"Daily, but not occasional, cannabis use is selectively associated with more impulsive delay discounting and hyperactive ADHD symptoms in binge-drinking young adults.","authors":"Petker, Tashia; Ferro, Mark; Van Ameringen, Michael; Murphy, James; MacKillop, James","year":2021,"journal":"Psychopharmacology, 238(7), 1753-1763","doi":"10.1007/s00213-021-05781-3","pmid":"33638699","tags":["cognition","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Daily cannabis users showed significantly more impulsive delay discounting and more hyperactive-impulsive ADHD symptoms compared to both occasional users and non-users. Cannabis use was not associated with inattentive ADHD symptoms, verbal intelligence, working memory, probability discounting, short-term verbal memory, or behavioral inhibition. Age of initiation showed no main effects or interactions.","whyItMatters":"This large study provides precise evidence that cannabis-related cognitive concerns are specific to daily use and specific domains (impulsivity, hyperactivity) rather than a general cognitive decline. Occasional users showed no measurable differences from non-users.","specificNumbers":"730 participants; 52.6% female; daily users showed more impulsive discounting and hyperactive-impulsive ADHD symptoms; 8 cognitive domains tested, only 2 showed associations; age of initiation had no effect","methodology":"Cross-sectional study of 730 binge-drinking young adults (mean age 21.4, 52.6% female). Three-group ANCOVAs compared frequent (daily/multiple times daily), occasional (weekly/monthly), and non-cannabis users, controlling for alcohol use, tobacco, age, sex, income, and education.","limitations":"Cross-sectional design; cannot determine if impulsivity precedes or follows daily cannabis use. All participants were binge drinkers. Self-reported cannabis use frequency."},{"rthcId":"RTHC-03431","title":"Acute Extrapyramidal Side Effects from Smoked Haloperidol.","authors":"Pham, Angeline; Lee, Joo-Young; Miller, Christopher W T","year":2021,"journal":"Case reports in psychiatry, 2021, 4177263","doi":"10.1155/2021/4177263","pmid":"34635875","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03432","title":"Regulatory Status of Pesticide Residues in Cannabis: Implications to Medical Use in Neurological Diseases.","authors":"Pinkhasova, Dorina V; Jameson, Laura E; Conrow, Kendra D; Simeone, Michael P; Davis, Allan Peter; Wiegers, Thomas C; Mattingly, Carolyn J; Leung, Maxwell C K","year":2021,"journal":"Current research in toxicology, 2, 140-148","doi":"10.1016/j.crtox.2021.02.007","pmid":"34308371","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03433","title":"Effects of prenatal synthetic cannabinoid exposure on the cerebellum of adolescent rat offspring.","authors":"Pinky, Priyanka D; Majrashi, Mohammed; Fujihashi, Ayaka; Bloemer, Jenna; Govindarajulu, Manoj; Ramesh, Sindhu; Reed, Miranda N; Moore, Timothy; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan","year":2021,"journal":"Heliyon, 7(4), e06730","doi":"10.1016/j.heliyon.2021.e06730","pmid":"33912711","tags":["pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal WIN55,212-2 exposure reduced oxidative stress and nitrite content in offspring cerebellum, enhanced mitochondrial Complex I and IV activities, increased pro-survival signaling (pP38), and decreased pro-apoptotic factors (caspase-3, pERK, pJNK). GluN2A (an NMDA receptor subunit) was significantly reduced while CB1R and GluA1 remained unchanged.","whyItMatters":"Most research on prenatal cannabinoid exposure has focused on the hippocampus, where harmful effects are well documented. This finding that the cerebellum shows protective rather than damaging responses suggests brain region-specific effects that complicate our understanding of prenatal exposure.","specificNumbers":"Reduced oxidative stress and nitrite; enhanced mitochondrial Complex I and IV; increased pP38; decreased caspase-3, pERK, pJNK; reduced GluN2A; decreased MAO activity; CB1R and GluA1 unchanged","methodology":"Controlled animal study administering synthetic cannabinoid agonist WIN55,212-2 to pregnant rats. Offspring cerebellum examined for oxidative stress markers, mitochondrial function (Complex I and IV), apoptosis markers, receptor expression, and enzyme activity.","limitations":"Animal study using a synthetic cannabinoid (WIN55,212-2), not plant-derived THC or cannabis. Single dosing protocol. Did not assess behavioral outcomes in offspring. Effects in rat cerebellum may not translate to human brain development."},{"rthcId":"RTHC-03434","title":"Behavioral aspects and neurobiological properties underlying medical cannabis treatment in Shank3 mouse model of autism spectrum disorder.","authors":"Poleg, Shani; Kourieh, Emad; Ruban, Angela; Shapira, Guy; Shomron, Noam; Barak, Boaz; Offen, Daniel","year":2021,"journal":"Translational psychiatry, 11(1), 524","doi":"10.1038/s41398-021-01612-3","pmid":"34645786","tags":["medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD-enriched medical cannabis oil reduced repetitive grooming by over 70% and alleviated anxiety in Shank3 mutant mice. The effects involved CB1 receptor signaling and reduced cerebrospinal fluid glutamate levels. RNA sequencing revealed changes in neurotransmission-related gene expression. Importantly, the results questioned the relevance of CBD enrichment, suggesting THC was the critical component for treating core ASD symptoms.","whyItMatters":"No approved treatments exist for the core symptoms of autism. Finding that medical cannabis reduces both repetitive behavior and anxiety in a genetically relevant autism model is significant, especially the insight that THC rather than CBD may be the more important therapeutic component.","specificNumbers":"Over 70% reduction in repetitive grooming; reduced CSF glutamate; CB1 receptor involvement confirmed; RNA sequencing showed neurotransmission gene changes; THC appeared more important than CBD for behavioral effects","methodology":"Controlled animal study using Shank3 mutant mice (a human mutation-based autism model). Long-term oral treatment with CBD-enriched medical cannabis oil (Avidekel). Behavioral testing for anxiety and repetitive behaviors. Biochemical analysis of CB1R signaling, CSF glutamate, and RNA sequencing of cerebellar tissue.","limitations":"Animal model of one specific autism-causing mutation (Shank3); autism has hundreds of genetic causes. Mouse behavior does not fully model human ASD. Single cannabis formulation tested."},{"rthcId":"RTHC-03435","title":"Symptomatology and neurocognition among first-episode psychosis patients with and without cannabis use in the three months prior to first hospitalization.","authors":"Pope, Leah G; Manseau, Marc W; Kelley, Mary E; Compton, Michael T","year":2021,"journal":"Schizophrenia research, 228, 83-88","doi":"10.1016/j.schres.2020.12.012","pmid":"33434738","tags":["psychosis","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users had significantly lower anhedonia-asociality scores (10.7 vs 12.1, p=0.023) but more severe delusions (19.3 vs 15.9, p=0.005) and bizarre behavior (p=0.01). No significant differences appeared across nine MATRICS cognitive battery measures. Cannabis dose did not correlate with any symptom or cognitive measure.","whyItMatters":"The finding that cannabis use in psychosis is associated with less social withdrawal but more delusions suggests cannabis may have differential effects on different symptom dimensions, rather than making psychosis uniformly better or worse.","specificNumbers":"247 patients; 6 psychiatric units; anhedonia-asociality: 10.7 vs 12.1 (p=0.023); delusions: 19.3 vs 15.9 (p=0.005); bizarre behavior significant (p=0.01); no differences across 9 MCCB cognitive measures; no dose-response relationship","methodology":"Cross-sectional study of 247 first-episode psychosis patients from six inpatient psychiatric units (2008-2013). Cannabis use assessed via Longitudinal Substance Use Recall. Symptoms measured with SANS and SAPS. Cognition assessed with the MATRICS Consensus Cognitive Battery.","limitations":"Cross-sectional; cannot determine if cannabis caused symptom differences or if pre-existing symptom profiles influenced cannabis use. Hospital-based sample during acute episodes. Self-reported cannabis use."},{"rthcId":"RTHC-03436","title":"Do Adolescent Exposure to Cannabinoids and Early Adverse Experience Interact to Increase the Risk of Psychiatric Disorders: Evidence from Rodent Models.","authors":"Portugalov, Anna; Akirav, Irit","year":2021,"journal":"International journal of molecular sciences, 22(2)","doi":"10.3390/ijms22020730","pmid":"33450928","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03437","title":"Topical capsaicin for the treatment of cannabinoid hyperemesis syndrome, a systematic review and meta-analysis.","authors":"Pourmand, Ali; Esmailian, Gabriel; Mazer-Amirshahi, Maryann; Lee-Park, Owen; Tran, Quincy K","year":2021,"journal":"The American journal of emergency medicine, 43, 35-40","doi":"10.1016/j.ajem.2021.01.004","pmid":"33493995","tags":["medical-cannabis","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"preliminary","keyFinding":"Across 7 included studies (106 patients), topical capsaicin appeared effective for CHS symptom relief. Mean time to symptom resolution was 325 minutes (95% CI 234-787), and ED length of stay averaged 379 minutes (95% CI 10-747). Heterogeneity was acceptable (I-square 44%, Q-statistic p=0.1).","whyItMatters":"Cannabinoid hyperemesis syndrome is increasingly recognized in emergency departments, and standard treatments (antiemetics, antipsychotics, benzodiazepines) are not always effective. Topical capsaicin is a low-cost, low-risk alternative that works through a different mechanism (TRPV1 agonism).","specificNumbers":"328 studies screened; 7 included; 106 total patients; mean time to symptom resolution: 325 minutes; mean ED length of stay: 379 minutes; I-square: 44%","methodology":"Systematic review and meta-analysis searching PubMed, SCOPUS, and Google Scholar through October 2020. From 328 initial studies, 7 met inclusion criteria. Evaluated hospital admission rates, time to symptom relief, and ED length of stay.","limitations":"Only 7 studies with 106 total patients. No randomized controlled trials included. Wide confidence intervals reflect uncertainty. Heterogeneous study designs and capsaicin application protocols."},{"rthcId":"RTHC-03438","title":"Cannabis Use and Car Crashes: A Review.","authors":"Preuss, Ulrich W; Huestis, Marilyn A; Schneider, Miriam; Hermann, Derik; Lutz, Beat; Hasan, Alkomiet; Kambeitz, Joseph; Wong, Jessica W M; Hoch, Eva","year":2021,"journal":"Frontiers in psychiatry, 12, 643315","doi":"10.3389/fpsyt.2021.643315","pmid":"34122176","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03439","title":"Bipolar Disorder and Comorbid Use of Illicit Substances.","authors":"Preuss, Ulrich W; Schaefer, Martin; Born, Christoph; Grunze, Heinz","year":2021,"journal":"Medicina (Kaunas, Lithuania), 57(11)","doi":"10.3390/medicina57111256","pmid":"34833474","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03440","title":"Safety and tolerability of nabiximols oromucosal spray: a review of real-world experience in observational studies, registries, and case reports.","authors":"Prieto González, José María; Vila Silván, Carlos","year":2021,"journal":"Expert review of neurotherapeutics, 21(5), 547-558","doi":"10.1080/14737175.2021.1904896","pmid":"33749480","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03441","title":"A randomized controlled trial of a therapeutic relational agent for reducing substance misuse during the COVID-19 pandemic.","authors":"Prochaska, Judith J; Vogel, Erin A; Chieng, Amy; Baiocchi, Michael; Maglalang, Dale Dagar; Pajarito, Sarah; Weingardt, Kenneth R; Darcy, Alison; Robinson, Athena","year":2021,"journal":"Drug and alcohol dependence, 227, 108986","doi":"10.1016/j.drugalcdep.2021.108986","pmid":"34507061","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03442","title":"The model of care at a leading medical cannabis clinic in Canada.","authors":"Prosk, Erin; Arboleda, Maria Fernanda; Rapin, Lucile; El Hage, Cynthia; Dworkind, Michael","year":2021,"journal":"Complementary therapies in medicine, 60, 102740","doi":"10.1016/j.ctim.2021.102740","pmid":"34052339","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03443","title":"Evaluation of Cannabinoids on the Odonto/Osteogenesis in Human Dental Pulp Cells In Vitro.","authors":"Qi, Xia; Liu, Chunyan; Li, Guohua; Al-Alfe, Dalia; Paurazas, Susan; Askar, Mazin; Yang, Dongru; Zhou, Zheng","year":2021,"journal":"Journal of endodontics, 47(3), 444-450","doi":"10.1016/j.joen.2020.12.005","pmid":"33352148","tags":["pain","inflammation","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In a finding that surprised even the researchers (their null hypothesis was that THC would induce dental tissue repair), THC showed biphasic effects on human dental pulp cells. Low doses (5 μmol/L) stimulated cell proliferation, while higher concentrations showed different patterns.\n\nMore importantly, THC upregulated odonto/osteogenic marker genes — the genetic signals that tell pulp cells to differentiate into cells that produce dentin and bone-like tissue. THC-treated cells showed increased collagen synthesis and calcium nodule deposition, meaning they were actually forming mineralized tissue.\n\nThe mechanism worked through both CB1 and CB2 receptors and involved the MAPK signaling pathway — a well-characterized growth and differentiation cascade. Blocking either cannabinoid receptor reduced THC's pro-mineralization effects. THC showed no toxicity to the cells at concentrations up to 100 μmol/L.","whyItMatters":"Nobody is suggesting smoking cannabis for better teeth. But at the cellular level, this study showed that cannabinoid receptors on dental pulp cells can be activated to promote tissue mineralization. If this can be harnessed pharmacologically — perhaps through a localized application of cannabinoid compounds directly to exposed pulp — it could represent a new approach to dental tissue regeneration.\n\nThe broader significance is that cannabinoid receptors keep showing up in tissues and biological processes where nobody expected them, expanding the potential medical applications of cannabinoid science far beyond the brain.","specificNumbers":"• THC non-toxic to dental pulp cells up to 100 μmol/L\n• Low dose (5 μmol/L): stimulated cell proliferation\n• Upregulated odonto/osteogenic differentiation markers\n• Increased collagen synthesis and calcium nodule deposition\n• Mechanism: CB1 + CB2 receptors via MAPK pathway","methodology":"In vitro study using human dental pulp cells (HDPCs). Cell viability assessed by MTT assay at THC concentrations 0-100 μmol/L. Differentiation measured by RT-PCR for odonto/osteogenic markers. Mineralization assessed by collagen synthesis and calcium nodule deposition assays. Mechanism investigated by CB1/CB2 receptor blocking and MAPK pathway analysis.","limitations":"In vitro study — cells in a dish don't behave like cells in a mouth. The THC concentrations used may not be achievable in dental tissue through any practical delivery method. No animal or human studies to validate the finding. The clinical leap from stimulating mineralization in vitro to actual tooth repair is enormous. Does not address whether smoked cannabis has any dental effects (it likely harms teeth through other mechanisms)."},{"rthcId":"RTHC-03444","title":"The continuity of effect of schizophrenia polygenic risk score and patterns of cannabis use on transdiagnostic symptom dimensions at first-episode psychosis: findings from the EU-GEI study.","authors":"Quattrone, Diego; Reininghaus, Ulrich; Richards, Alex L; Tripoli, Giada; Ferraro, Laura; Quattrone, Andrea; Marino, Paolo; Rodriguez, Victoria; Spinazzola, Edoardo; Gayer-Anderson, Charlotte; Jongsma, Hannah E; Jones, Peter B; La Cascia, Caterina; La Barbera, Daniele; Tarricone, Ilaria; Bonora, Elena; Tosato, Sarah; Lasalvia, Antonio; Szöke, Andrei; Arango, Celso; Bernardo, Miquel; Bobes, Julio; Del Ben, Cristina Marta; Menezes, Paulo Rossi; Llorca, Pierre-Michel; Santos, Jose Luis; Sanjuán, Julio; Arrojo, Manuel; Tortelli, Andrea; Velthorst, Eva; Berendsen, Steven; de Haan, Lieuwe; Rutten, Bart P F; Lynskey, Michael T; Freeman, Tom P; Kirkbride, James B; Sham, Pak C; O'Donovan, Michael C; Cardno, Alastair G; Vassos, Evangelos; van Os, Jim; Morgan, Craig; Murray, Robin M; Lewis, Cathryn M; Di Forti, Marta","year":2021,"journal":"Translational psychiatry, 11(1), 423","doi":"10.1038/s41398-021-01526-0","pmid":"34376640","tags":["psychosis","genetics"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Schizophrenia polygenic risk score (SZ-PRS) was associated with both negative (B=0.18) and positive (B=0.19) symptom dimensions in 617 first-episode patients, regardless of diagnostic category. Daily current cannabis use was associated with positive symptom dimensions in both patients (B=0.31) and controls (B=0.26), over and above SZ-PRS. SZ-PRS was not associated with general or affective symptom dimensions in patients.","whyItMatters":"This study disentangles genetic and environmental contributions to psychosis. Finding that cannabis use adds risk for positive symptoms beyond genetic predisposition supports a causal role for cannabis in psychosis, not just shared genetic vulnerability.","specificNumbers":"617 FEP patients; 979 controls; SZ-PRS and negative symptoms B=0.18; SZ-PRS and positive symptoms B=0.19; daily cannabis and positive symptoms in FEP B=0.31; daily cannabis and positive symptoms in controls B=0.26","methodology":"Large multicentric study from the EU-GEI consortium analyzing first-episode psychosis patients (n=617) and controls (n=979). Used item response bi-factor modeling to generate transdiagnostic symptom dimensions. Linear regression tested associations with schizophrenia polygenic risk scores and cannabis use patterns.","limitations":"Cross-sectional design limits causal inference. Polygenic risk scores capture only a fraction of genetic liability. Cannabis use was self-reported. Different populations across EU-GEI sites may introduce heterogeneity."},{"rthcId":"RTHC-03445","title":"Daily use of high-potency cannabis is associated with more positive symptoms in first-episode psychosis patients: the EU-GEI case-control study.","authors":"Quattrone, Diego; Ferraro, Laura; Tripoli, Giada; La Cascia, Caterina; Quigley, Harriet; Quattrone, Andrea; Jongsma, Hannah E; Del Peschio, Simona; Gatto, Giusy; Gayer-Anderson, Charlotte; Jones, Peter B; Kirkbride, James B; La Barbera, Daniele; Tarricone, Ilaria; Berardi, Domenico; Tosato, Sarah; Lasalvia, Antonio; Szöke, Andrei; Arango, Celso; Bernardo, Miquel; Bobes, Julio; Del Ben, Cristina Marta; Menezes, Paulo Rossi; Llorca, Pierre-Michel; Santos, Jose Luis; Sanjuán, Julio; Tortelli, Andrea; Velthorst, Eva; de Haan, Lieuwe; Rutten, Bart P F; Lynskey, Michael T; Freeman, Tom P; Sham, Pak C; Cardno, Alastair G; Vassos, Evangelos; van Os, Jim; Morgan, Craig; Reininghaus, Ulrich; Lewis, Cathryn M; Murray, Robin M; Di Forti, Marta","year":2021,"journal":"Psychological medicine, 51(8), 1329-1337","doi":"10.1017/S0033291720000082","pmid":"32183927","tags":["psychosis","potency"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"In patients, daily high-potency cannabis use was associated with the highest positive symptom scores (B=0.35, 95% CI 0.14-0.56) in a dose-response pattern. Patients who never used cannabis had more negative symptoms than any cannabis-using group (B=-0.22, 95% CI -0.37 to -0.07). In controls, psychotic experiences correlated with current use but not lifetime exposure. No depression differences related to cannabis were found in either group.","whyItMatters":"This is the first large-scale evidence that cannabis potency and frequency interact to shape the symptom profile of first-episode psychosis. The dose-response relationship with positive symptoms strengthens the case for a causal contribution of cannabis to psychosis.","specificNumbers":"901 FEP patients; 1,235 controls; 6 countries; daily high-potency use and positive symptoms B=0.35; never-use and negative symptoms B=-0.22; no association with depressive dimension","methodology":"Cross-sectional case-control study from EU-GEI analyzing 901 FEP patients and 1,235 controls across six countries. Item response bifactor modeling generated symptom dimensions. Associations tested via linear mixed-effects models.","limitations":"Cross-sectional design limits causal inference. Self-reported cannabis use patterns and potency. Potency definitions varied across countries. Patients were recruited after psychosis onset, so pre-illness cannabis patterns are retrospectively reported."},{"rthcId":"RTHC-03446","title":"Synthetic Cannabinoids and Cathinones Cardiotoxicity: Facts and Perspectives.","authors":"Radaelli, Davide; Manfredi, Alessandro; Zanon, Martina; Fattorini, Paolo; Scopetti, Matteo; Neri, Margherita; Frisoni, Paolo; D'Errico, Stefano","year":2021,"journal":"Current neuropharmacology, 19(11), 2038-2048","doi":"10.2174/1570159X19666210412101929","pmid":"33845747","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03447","title":"Cannabidiol use and effectiveness: real-world evidence from a Canadian medical cannabis clinic.","authors":"Rapin, Lucile; Gamaoun, Rihab; El Hage, Cynthia; Arboleda, Maria Fernanda; Prosk, Erin","year":2021,"journal":"Journal of cannabis research, 3(1), 19","doi":"10.1186/s42238-021-00078-w","pmid":"34162446","tags":["cbd","pain","anxiety","depression"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"All ESAS-r symptom scores improved significantly from baseline to 3 months (all p<0.003). Patients with moderate/severe symptoms showed substantial improvement (all p<0.001), while patients with mild symptoms saw no improvement and some scores worsened. Adding THC at follow-up had no additional effect. Improvements were maintained at 6 months.","whyItMatters":"The severity-dependent response is a critical finding often missing from cannabis research. CBD-rich treatment appears to help those who need it most while not improving mild symptoms, a pattern that helps distinguish real therapeutic effects from placebo.","specificNumbers":"279 patients; all ESAS-r scores improved at 3 months (p<0.003); moderate/severe symptoms: significant improvement (p<0.001); mild symptoms: no improvement or worsening; no additional benefit from adding THC; effects maintained at 6 months","methodology":"Retrospective observational study of 279 patients over 18 prescribed CBD-rich treatment at a medical cannabis clinic network in Quebec, Canada. Symptoms measured using ESAS-r at baseline, 3, and 6 months. Groups compared by symptom severity and whether THC was added at follow-up.","limitations":"Retrospective observational design without control group. Potential selection bias in clinic population. Cannot rule out placebo effects or regression to the mean. Self-reported symptom measures."},{"rthcId":"RTHC-03448","title":"Interventions to Prevent Drugged Driving: A Systematic Review.","authors":"Razaghizad, Amir; Windle, Sarah B; Gore, Genevieve; Benedetti, Andrea; Ells, Carolyn; Grad, Roland; Filion, Kristian B; Eisenberg, Mark J","year":2021,"journal":"American journal of preventive medicine, 61(2), 267-280","doi":"10.1016/j.amepre.2021.03.012","pmid":"34099354","tags":["driving","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabis packaging with health warnings increases knowledge about drugged driving effects (high certainty). Roadside drug testing can reduce drugged driving among cannabis users (moderate certainty). For youth, motivational interviewing can prevent drugged driving and driver education increases knowledge (moderate certainty). State sanctions, including criminalization and per-se laws, showed little or no effect on drug-related fatalities (very low to low certainty).","whyItMatters":"As cannabis legalization expands, preventing drugged driving becomes urgent. This review reveals that punitive legal approaches may be the least effective strategy, while information-based and behavioral interventions show more promise.","specificNumbers":"11 RCTs + 17 nonrandomized studies; 33,711 youth participants; packaging warnings: high certainty; roadside testing: moderate certainty; motivational interviewing: moderate certainty; legal sanctions: very low to low certainty","methodology":"Systematic review searching MEDLINE, PsycINFO, Web of Science, Embase, and other databases through May 2020. Included 11 RCTs and 17 nonrandomized studies (predominantly youth aged 15-25, n=33,711). Evidence certainty rated using GRADE guidelines.","limitations":"Most studies focused on youth; applicability to older adults unclear. Heterogeneous interventions and outcome measures. Limited evidence on actual crash and fatality outcomes. Most studies measured knowledge and attitudes rather than behavior change."},{"rthcId":"RTHC-03449","title":"Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: combined geospatial, multiple imputation and causal inference study.","authors":"Reece, Albert Stuart; Hulse, Gary Kenneth","year":2021,"journal":"BMC cancer, 21(1), 984","doi":"10.1186/s12885-021-08598-7","pmid":"34479489","tags":["cancer","pregnancy","legalization"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Cannabis use was independently associated with pediatric ALL rates in multiple regression models adjusted for other substances, income, and ethnicity. A dose-response relationship was observed across cannabis use quintiles (Chi.Sq.=613.79, p=3.04x10^-70). Cannabis-legal states had higher ALL rates (2.395 vs 2.127/100,000, p=5.05x10^-10). Spatiotemporal models showed associations with specific cannabinoids including THC and cannabigerol.","whyItMatters":"Pediatric ALL rates in the US have risen 93.5% between 1975 and 2016 for unclear reasons. If cannabis exposure contributes to this rise, it would be a significant public health concern as cannabis use and legalization expand.","specificNumbers":"ALL rates rose 93.5% from 1975-2016; cannabis association β=3.33 (bivariate); legal states: 2.395 vs 2.127/100,000 (p=5.05x10^-10); quintile effect Chi.Sq.=613.79; 33/35 e-Values supportive of causality","methodology":"Ecological geospatial analysis combining state-level ALL rates from CDC/NCI SEER database with drug use data from the National Survey of Drug Use and Health (74.1% response rate), cannabinoid concentration data from the DEA, and census data. Analyzed using robust regression, spatiotemporal models, inverse probability weighting, and causal inference methods including e-Values.","limitations":"Ecological design (state-level correlations cannot prove individual-level causation). Many potential confounders at the state level. Cannabis use data is self-reported. The authors make strong causal claims that exceed what ecological data can support. Multiple comparisons increase risk of spurious findings."},{"rthcId":"RTHC-03450","title":"A geospatiotemporal and causal inference epidemiological exploration of substance and cannabinoid exposure as drivers of rising US pediatric cancer rates.","authors":"Reece, Albert Stuart; Hulse, Gary Kenneth","year":2021,"journal":"BMC cancer, 21(1), 197","doi":"10.1186/s12885-021-07924-3","pmid":"33632159","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03451","title":"Survey of Pharmacists' Knowledge of Connecticut's Medical Cannabis Program.","authors":"Reece, Sara Mandy; Holle, Lisa; Mukherjee, Kumar","year":2021,"journal":"Cannabis and cannabinoid research, 6(1), 66-73","doi":"10.1089/can.2019.0013","pmid":"33614954","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03452","title":"Prenatal alcohol and cannabis exposure can have opposing and region-specific effects on parvalbumin interneuron numbers in the hippocampus.","authors":"Reid, Hannah M O; Snowden, Taylor M; Shkolnikov, Irene; Breit, Kristen R; Rodriguez, Cristina; Thomas, Jennifer D; Christie, Brian R","year":2021,"journal":"Alcoholism, clinical and experimental research, 45(11), 2246-2255","doi":"10.1111/acer.14708","pmid":"34523142","tags":["pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In the dorsal CA1, ethanol and ethanol+THC groups showed increased parvalbumin interneuron numbers, while THC alone decreased them. In the ventral dentate gyrus, THC exposure decreased PV interneurons only in males. The ethanol+THC group showed greater cell layer volume in the DG compared to controls, and the ethanol group showed greater CA1 volume.","whyItMatters":"Many people who use cannabis during pregnancy also consume alcohol. Finding that these substances have opposite effects on key inhibitory brain cells suggests their combined impact cannot be predicted from studying either substance alone.","specificNumbers":"Ethanol increased PV interneurons in dorsal CA1; THC decreased them; combined ethanol+THC increased them; sex-specific decrease in ventral DG with THC (males only); greater cell layer volume in DG with combined exposure","methodology":"Controlled 2x2 factorial design (ethanol/air x THC/vehicle) exposing pregnant Sprague-Dawley rats during gestational days 5-20. Immunohistochemistry for PV interneurons in one male and one female pup per litter at postnatal day 70.","limitations":"Animal study with synthetic THC exposure, not plant cannabis. One animal per sex per litter. Postnatal day 70 assessment only; earlier or later timepoints might show different patterns. Cannot directly translate doses to human exposure levels."},{"rthcId":"RTHC-03453","title":"Management of Pediatric Cannabinoid Hyperemesis Syndrome: A Review.","authors":"Reinert, Justin P; Niyamugabo, O'Neill; Harmon, Kiersi S; Fenn, Norman E","year":2021,"journal":"The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 26(4), 339-345","doi":"10.5863/1551-6776-26.4.339","pmid":"34035677","tags":["youth","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Benzodiazepines were the most frequently reported effective treatment for pediatric CHS, followed by topical capsaicin cream and haloperidol. Nine of 14 studies described IV fluid resuscitation and hot bathing as supportive measures. Seven cases reported that traditional antiemetics were ineffective for CHS. Treatment approaches were highly heterogeneous across studies.","whyItMatters":"As adolescent marijuana use increases, pediatric CHS is becoming more common in emergency departments. Knowing that traditional antiemetics often fail while benzodiazepines and capsaicin may work can help clinicians avoid ineffective treatments and reach for appropriate alternatives faster.","specificNumbers":"14 studies included; benzodiazepines most effective; topical capsaicin and haloperidol also effective; 9/14 studies used IV fluids and hot baths supportively; 7 cases reported traditional antiemetics ineffective","methodology":"Systematic review searching PubMed, Scopus, CINAHL, Web of Science, and Cochrane Library. 14 studies met inclusion criteria describing management strategies for pediatric CHS.","limitations":"Only 14 studies, mostly case reports and small series. No randomized controlled trials. Heterogeneous treatment protocols prevent direct comparisons. Publication bias likely favors reporting successful treatments."},{"rthcId":"RTHC-03454","title":"Cannabis-induced psychosis: clinical characteristics and its differentiation from schizophrenia with and without cannabis use.","authors":"Rentero, David; Arias, Francisco; Sánchez-Romero, Sergio; Rubio, Gabriel; Rodríguez-Jiménez, Roberto","year":2021,"journal":"Adicciones, 33(2), 95-108","doi":"10.20882/adicciones.1251","pmid":"32677690","tags":["psychosis","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis-induced psychosis (CIP) patients had lower negative PANSS scores (12.9 vs 17.2, p<0.001), fewer auditory hallucinations (60.3% vs 78.9%), and more mania (26.1% vs 12.3%, p<0.001) compared to schizophrenia with cannabis. Few differences existed between schizophrenia groups regardless of cannabis use. Both cannabis-using groups had earlier age of first psychotic admission (CIP: 26.1, SZ+CB: 25.3 vs SZ: 34.2, p<0.001).","whyItMatters":"Distinguishing cannabis-induced psychosis from primary schizophrenia has treatment implications. While no pathognomonic clinical pattern was found, the symptom profile differences (fewer negatives, more mania) may help clinicians consider CIP as a diagnosis.","specificNumbers":"69 CIP, 57 SZ+CB, 181 SZ; CIP negative PANSS: 12.9 vs SZ: 17.2; auditory hallucinations: 60.3% vs 78.9%; mania: 26.1% vs 12.3%; age first admission: CIP 26.1, SZ+CB 25.3, SZ 34.2","methodology":"Cross-sectional comparison of three inpatient groups: cannabis-induced psychosis (n=69), schizophrenia with cannabis (n=57), and schizophrenia without cannabis (n=181). The PRISM-IV scale differentiated induced psychosis. Symptoms assessed with PANSS.","limitations":"Cross-sectional design. Single-site study. Retrospective diagnosis of cannabis-induced vs primary psychosis is inherently challenging. Different group sizes may affect statistical power."},{"rthcId":"RTHC-03455","title":"Cannabis use disorder and dissociation: A report from a prospective first-episode psychosis study.","authors":"Ricci, V; Ceci, F; Di Carlo, F; Lalli, A; Ciavoni, L; Mosca, A; Sepede, G; Salone, A; Quattrone, D; Fraticelli, S; Maina, G; Martinotti, G","year":2021,"journal":"Drug and alcohol dependence, 229(Pt A), 109118","doi":"10.1016/j.drugalcdep.2021.109118","pmid":"34688166","tags":["psychosis","addiction","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-using FEP patients showed higher positive symptoms, higher dissociative experiences (DES-II), and worse functioning (GAF) than non-users at onset. At 8-month follow-up, cannabis users still had elevated positive symptoms and dissociation. Functioning worsened over time in cannabis users while improving in non-users, despite comparable antipsychotic treatment.","whyItMatters":"The divergent trajectory of functioning (worsening with cannabis use, improving without) is particularly concerning. It suggests cannabis use during first-episode psychosis actively undermines recovery rather than just being a marker of worse prognosis.","specificNumbers":"70 patients (35 CUD, 35 non-CUD); cannabis users had higher positive symptoms, dissociation, and worse functioning at baseline; at 8 months: positive symptoms and dissociation still elevated in cannabis group; functioning worsened in cannabis group vs improved in non-cannabis group","methodology":"Prospective cohort study of 70 first-episode psychosis patients (35 with CUD, 35 without) recruited from Italian psychiatric inpatient facilities (2014-2019). Assessed at FEP onset, 4 months, and 8 months using PANSS, GAF, and DES-II.","limitations":"Small sample (35 per group). Italian inpatient population may not generalize. Cannot determine if cannabis caused the worse trajectory or if patients with worse prognosis are more likely to continue using cannabis."},{"rthcId":"RTHC-03456","title":"Duration of Untreated Disorder and Cannabis Use: An Observational Study on a Cohort of Young Italian Patients Experiencing Psychotic Experiences and Dissociative Symptoms.","authors":"Ricci, Valerio; Martinotti, Giovanni; Ceci, Franca; Chiappini, Stefania; Di Carlo, Francesco; Burkauskas, Julius; Susini, Ottavia; Luciani, Debora; Quattrone, Diego; De Berardis, Domenico; Pettorruso, Mauro; Maina, Giuseppe; Di Giannantonio, Massimo","year":2021,"journal":"International journal of environmental research and public health, 18(23)","doi":"10.3390/ijerph182312632","pmid":"34886357","tags":["psychosis","addiction"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis use did not significantly affect the duration of untreated psychosis (DUP). However, both cannabis use and longer DUP were independently associated with higher dissociative symptoms at onset and over the 6-month follow-up period. Longer DUP was associated with worse overall symptoms as expected.","whyItMatters":"Duration of untreated psychosis is one of the strongest predictors of long-term outcomes. Finding that cannabis independently contributes to dissociative symptoms, separate from DUP effects, suggests cannabis adds a distinct burden on top of treatment delay.","specificNumbers":"62 FEP patients; cannabis did not affect DUP length; both cannabis and longer DUP independently associated with dissociative symptoms; effects persisted over 6 months","methodology":"Prospective study of 62 FEP patients with and without CUD from Italian psychiatric hospitals (2014-2019). Divided by DUP duration. Assessed at treatment initiation, 3 months, and 6 months using PANSS, GAF, and DES-II.","limitations":"Small sample (62 patients). Potential selection bias in treatment-seeking population. DUP is inherently difficult to measure accurately. Cannot determine if dissociative symptoms preceded or resulted from cannabis use."},{"rthcId":"RTHC-03457","title":"A cross-sectional survey of cannabis use by people with MS in Oregon and Southwest Washington.","authors":"Rice, Jessica; Hildebrand, Andrea; Spain, Rebecca; Senders, Angela; Silbermann, Elizabeth; Wooliscroft, Lindsey; Yadav, Vijayshree; Bourdette, Dennis; Cameron, Michelle","year":2021,"journal":"Multiple sclerosis and related disorders, 55, 103172","doi":"10.1016/j.msard.2021.103172","pmid":"34332457","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"30% currently used cannabis, 21% had used in the past, and 49% never used. Most current users (59%) used multiple administration routes (smoking, vaping, topicals, tinctures, edibles all at 35-46%). 64-78% of current/past users reported cannabis as beneficial for MS. Use was higher among younger patients (OR 2.24 for ages 18-40 vs >60), lower-income (OR 3.94 for <$25K vs >$100K), secondary progressive MS (OR 1.77), and greater disability.","whyItMatters":"With nearly a third of MS patients using cannabis and most perceiving benefit, clinicians need to proactively discuss cannabis use. The association with lower income and greater disability suggests patients with fewer resources and more severe disease are turning to cannabis, possibly due to gaps in conventional treatment access.","specificNumbers":"1,000 respondents; 30% current users; 21% past users; 59% used multiple routes; 64-78% perceived benefit; use higher in younger (OR 2.24), lower-income (OR 3.94), progressive MS (OR 1.77), more disabled (OR 2.05); perceived benefit highest in most disabled (OR 17.96)","methodology":"Cross-sectional survey of MS patients in Oregon and Southwest Washington (states with legal medical and recreational cannabis). 1,188 surveys returned, 1,000 with sufficient completion included in analysis.","limitations":"Cross-sectional survey in two legal-cannabis states; rates may differ elsewhere. Self-reported use and perceived benefit. Selection bias: patients interested in cannabis may be more likely to complete the survey. No objective outcome measures."},{"rthcId":"RTHC-03458","title":"Cannabis for medical purposes: A cross-sectional analysis of health care professionals' knowledge.","authors":"Rice, Jessica; Hildebrand, Andrea; Waslo, Carin S; Cameron, Michelle H; Jones, Kim Dupree","year":2021,"journal":"Journal of the American Association of Nurse Practitioners, 34(1), 100-106","doi":"10.1097/JXX.0000000000000590","pmid":"33767121","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03459","title":"Alterations in Electroencephalography Theta as Candidate Biomarkers of Acute Cannabis Intoxication.","authors":"Richard, Christian D; Poole, Jared R; McConnell, Marissa; Meghdadi, Amir H; Stevanovic-Karic, Marija; Rupp, Greg; Fink, Abigail; Schmitt, Rose; Brown, Timothy L; Berka, Chris","year":2021,"journal":"Frontiers in neuroscience, 15, 744762","doi":"10.3389/fnins.2021.744762","pmid":"34671242","tags":["driving","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Cannabis intoxication was associated with decreased theta band power (3-5 Hz) during resting state, reduced P400 and late positive potential amplitudes during attention and memory tasks, elevated frontal coherence, and diminished anterior-posterior coherence in the theta band. These changes were consistent and distinguishable from the placebo condition.","whyItMatters":"Unlike blood THC levels, which correlate poorly with actual impairment, EEG measures reflect real-time brain function. If validated in larger studies, EEG biomarkers could provide a more accurate and practical method for detecting cannabis intoxication, particularly for driving safety applications.","specificNumbers":"12 participants; theta band (3-5 Hz) power decreased during intoxication; P400 and LPP amplitudes reduced during cognitive tasks; elevated frontal coherence; diminished anterior-posterior coherence","methodology":"Within-subject counterbalanced design with 12 healthy recreational cannabis users. EEG acquired using ABM STAT X24 headset during a 1-hour testbed of resting state, attention, and memory tasks. Spectral densities computed for resting state; event-related potentials obtained for cognitive tasks.","limitations":"Very small sample (12 participants). Healthy recreational users may not represent the broader population. Single session design. Practical challenges of administering EEG in field settings (roadside) remain unresolved."},{"rthcId":"RTHC-03460","title":"The use of an integrated opioid and medical marijuana prescription drug monitoring program.","authors":"Rickles, Nathaniel M; Wakai, Sara; Karim-Nejad, Ladan","year":2021,"journal":"Journal of the American Pharmacists Association : JAPhA, 61(4), 408-417","doi":"10.1016/j.japh.2021.02.020","pmid":"33903060","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03461","title":"Which came first: Cannabis use or deficits in impulse control?","authors":"Rinehart, Linda; Spencer, Sade","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 106, 110066","doi":"10.1016/j.pnpbp.2020.110066","pmid":"32795592","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03462","title":"Mechanism of Diuresis and Natriuresis by Cannabinoids: Evidence for Inhibition of Na+-K+-ATPase in Mouse Kidney Thick Ascending Limb Tubules.","authors":"Ritter, Joseph K; Ahmad, Ashfaq; Mummalaneni, Shobha; Daneva, Zdravka; Dempsey, Sara K; Li, Ningjun; Li, Pin-Lan; Lyall, Vijay","year":2021,"journal":"The Journal of pharmacology and experimental therapeutics, 376(1), 1-11","doi":"10.1124/jpet.120.000163","pmid":"33087396","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03463","title":"Constituents of Cannabis Sativa.","authors":"Rock, Erin M; Parker, Linda A","year":2021,"journal":"Advances in experimental medicine and biology, 1264, 1-13","doi":"10.1007/978-3-030-57369-0_1","pmid":"33332000","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03464","title":"Therapeutic Potential of Cannabidiol, Cannabidiolic Acid, and Cannabidiolic Acid Methyl Ester as Treatments for Nausea and Vomiting.","authors":"Rock, Erin M; Limebeer, Cheryl L; Pertwee, Roger G; Mechoulam, Raphael; Parker, Linda A","year":2021,"journal":"Cannabis and cannabinoid research, 6(4), 266-274","doi":"10.1089/can.2021.0041","pmid":"34115951","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03465","title":"Therapeutic Prospects of Cannabinoids in the Immunomodulation of Prevalent Autoimmune Diseases.","authors":"Rodríguez Mesa, Xandy Melissa; Moreno Vergara, Andrés Felipe; Contreras Bolaños, Leonardo Andrés; Guevara Moriones, Natalia; Mejía Piñeros, Antonio Luis; Santander González, Sandra Paola","year":2021,"journal":"Cannabis and cannabinoid research, 6(3), 196-210","doi":"10.1089/can.2020.0183","pmid":"34030476","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03466","title":"Involvement of the endocannabinoid system in the inhibition of Sindbis virus replication: a preliminary study.","authors":"Rodriguez, Juan L; Lopez, Joseph A; Steel, J Jordan","year":2021,"journal":"Journal of cannabis research, 3(1), 10","doi":"10.1186/s42238-021-00068-y","pmid":"33892823","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03467","title":"Cannabinoid Receptors in Metabolic Regulation and Diabetes.","authors":"Rohbeck, Elisabeth; Eckel, Juergen; Romacho, Tania","year":2021,"journal":"Physiology (Bethesda, Md.), 36(2), 102-113","doi":"10.1152/physiol.00029.2020","pmid":"33595385","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03468","title":"Maternal cannabis use is associated with suppression of immune gene networks in placenta and increased anxiety phenotypes in offspring.","authors":"Rompala, Gregory; Nomura, Yoko; Hurd, Yasmin L","year":2021,"journal":"Proceedings of the National Academy of Sciences of the United States of America, 118(47)","doi":"10.1073/pnas.2106115118","pmid":"34782458","tags":["pregnancy","neuroscience","anxiety"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Children exposed to maternal cannabis had increased hair cortisol levels, greater anxiety, aggression, and hyperactivity on BASC-2 assessments, and reduced vagal tone (high-frequency HRV) at baseline. Placental RNA sequencing revealed suppressed expression of immune genes including type I interferon, neutrophil, and cytokine-signaling pathways. These immune gene networks correlated with child anxiety and hyperactivity.","whyItMatters":"This study provides a potential biological pathway: maternal cannabis use suppresses immune signaling in the placenta, which may alter fetal development and predispose children to anxiety. The correlation between placental gene changes and child behavior bridges the gap between molecular and behavioral findings.","specificNumbers":"Children aged 3-6 years assessed; increased hair cortisol; greater anxiety, aggression, and hyperactivity on BASC-2; reduced high-frequency HRV; suppressed type I interferon, neutrophil, and cytokine gene networks in placenta; gene-behavior correlations significant","methodology":"Observational study assessing children aged 3-6 whose mothers used cannabis during pregnancy. Measures included hair cortisol, BASC-2 behavioral assessment, and heart rate variability. For a subset, placental specimens collected at birth underwent RNA sequencing to identify gene expression changes.","limitations":"Observational design cannot prove causation. Relatively small sample for transcriptomic analysis. Cannot fully separate cannabis effects from other maternal factors. Hair cortisol reflects chronic stress but can be affected by hair treatments."},{"rthcId":"RTHC-03469","title":"Demographics, Perceptions, and Use of Medical Marijuana among Patients in Florida.","authors":"Rosenthal, Martha S; Pipitone, R Nathan","year":2021,"journal":"Medical cannabis and cannabinoids, 4(1), 13-20","doi":"10.1159/000512342","pmid":"34676347","tags":["medical-cannabis","pain","anxiety"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Patients most commonly used medical marijuana for anxiety, pain, and stress symptoms. They reported high therapeutic effectiveness. 65% reported either reducing or completely discontinuing at least one prescription or over-the-counter medication after starting medical marijuana.","whyItMatters":"Florida has one of the largest medical marijuana patient populations in the US (over 440,000 at the time of study). The high rate of medication reduction suggests medical marijuana may be replacing conventional pharmaceuticals for many patients, with implications for healthcare costs and drug interaction considerations.","specificNumbers":"157 patients surveyed; 440,000+ registered Florida patients; most common uses: anxiety, pain, stress; 65% reduced or stopped at least one other medication","methodology":"Cross-sectional online survey of 157 medical marijuana patients enrolled in the Florida medical marijuana program. Assessed demographics, reasons for use, consumption patterns, perceived effectiveness, and medication changes.","limitations":"Small self-selected sample from one state. Self-reported effectiveness without objective measures. No control group. Online survey may not represent all patients. Cannot verify medication changes against medical records."},{"rthcId":"RTHC-03470","title":"The association between cannabis use and outcome in pharmacological treatment for opioid use disorder.","authors":"Rosic, Tea; Kapoor, Raveena; Panesar, Balpreet; Naji, Leen; Chai, Darren B; Sanger, Nitika; Marsh, David C; Worster, Andrew; Thabane, Lehana; Samaan, Zainab","year":2021,"journal":"Harm reduction journal, 18(1), 24","doi":"10.1186/s12954-021-00468-6","pmid":"33622351","tags":["addiction","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Any cannabis use vs non-use was not associated with opioid use during treatment (OR 1.03, 95% CI 0.87-1.23). However, among cannabis users, daily use was associated with lower odds of opioid use compared to occasional use (OR 0.61, 95% CI 0.47-0.79, p<0.001). Later age of cannabis onset and reporting cannabis-related side effects also predicted less opioid use. 51% of patients used cannabis; 70% of users were daily users.","whyItMatters":"With over half of OUD patients using cannabis, understanding its impact on treatment is crucial. The finding that overall cannabis use neither helps nor hinders, but that specific use patterns matter, suggests a more nuanced clinical approach than blanket policies for or against cannabis use in OUD treatment.","specificNumbers":"2,315 patients; 51% (n=1,178) used cannabis; 70% of users were daily; overall cannabis use and opioid use OR=1.03 (not significant); daily vs occasional use OR=0.61 (p<0.001); 75% perceived no impact of cannabis on treatment; 50% reported side effects","methodology":"Prospective cohort study of 2,315 patients receiving pharmacological OUD treatment from community addiction clinics in Ontario, Canada. Three-month follow-up with routine urine drug screens for opioid use. Logistic regression adjusted for confounders. Qualitative analysis of patient perceptions.","limitations":"Observational design; daily cannabis users may differ systematically from occasional users. Self-reported cannabis use. Urine drug screens detect opioid use but not quantity. Ontario-specific population."},{"rthcId":"RTHC-03471","title":"Children's Knowledge of Cannabis and Other Substances in States with Different Cannabis Use Regulations.","authors":"Ross, J Megan; Rieselbach, Maya M; Hewitt, John K; Banich, Marie T; Rhee, Soo Hyun","year":2021,"journal":"Substance use & misuse, 56(14), 2126-2133","doi":"10.1080/10826084.2021.1972316","pmid":"34486481","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Children in states with more permissive cannabis laws had greater knowledge of cannabis specifically, but not of alcohol, tobacco, or other illicit drugs. Children in recreational-use states also reported more alcohol experimentation. Externalizing behavior was not significantly associated with cannabis knowledge in any group. The association between externalizing behavior and illicit drug knowledge was significant only in recreational and medical states but did not differ significantly across groups.","whyItMatters":"The concern that cannabis legalization normalizes drug use for children is partially supported: children in legal states know more about cannabis. However, the specificity to cannabis (and not other drugs) suggests legalization increases awareness of one substance rather than broadly normalizing all drug use.","specificNumbers":"11,875 children; ages 9-11; 22 US sites; 4 state policy categories; cannabis knowledge higher in permissive states; alcohol experimentation higher in recreational states; knowledge of other drugs not elevated; no association between externalizing and cannabis knowledge","methodology":"Cross-sectional analysis of 11,875 children aged 9-11 from the ABCD Study baseline (2016-2018). Compared substance knowledge and associations with externalizing behavior across four state cannabis policy groups: recreational, medical, low THC/CBD, and no cannabis laws. Chi-square difference tests on nested models.","limitations":"Cross-sectional design captures one time point. State-level policy differences may correlate with other cultural factors. Cannabis knowledge was measured but not attitudes or intentions. Children aged 9-11 are pre-initiation for most substance use."},{"rthcId":"RTHC-03472","title":"Looking back from 2020, how cannabis use and related behaviours changed in Canada.","authors":"Rotermann, Michelle","year":2021,"journal":"Health reports, 32(4), 3-14","doi":"10.25318/82-003-x202100400001-eng","pmid":"33881274","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Past-3-month cannabis use increased from 14.0% (2018) to 17.5% (2019) to 20.0% (2020). Daily or almost daily use rose to 7.9%. Female use rates rose to equal male rates for the first time. Use increased particularly among adults 25+ and in some provinces. Legal sourcing increased while reliance on friends, family, and illegal sources decreased.","whyItMatters":"This is the most comprehensive look at how Canadian cannabis use actually changed after legalization. The shift from illegal to legal sources suggests the policy is achieving one key goal, while the overall increase in use raises ongoing public health questions.","specificNumbers":"Use: 14.0% (2018) to 17.5% (2019) to 20.0% (2020); daily use: 7.9%; female rates equaled male rates; legal sourcing increased; illegal sourcing decreased","methodology":"Analysis of three quarters of the National Cannabis Survey: Q1 2018 (pre-legalization), Q1 2019 (post-legalization year 1), and Q4 2020 (two years post, also post-edible legalization). Nationally representative survey data.","limitations":"Cannot disentangle legalization effects from COVID-19 effects on 2020 data. Self-reported use may be subject to social desirability bias. Response rates and representativeness may shift over time."},{"rthcId":"RTHC-03473","title":"Dronabinol Prescribing and Exposure Among Children and Young Adults Diagnosed with Cancer.","authors":"Rower, Joseph E; King, Amber D; Wilkins, Diana; Wilkes, Jacob; Yellepeddi, Venkata; Maese, Luke; Lemons, Richard S; Constance, Jonathan E","year":2021,"journal":"Journal of adolescent and young adult oncology, 10(2), 175-184","doi":"10.1089/jayao.2020.0021","pmid":"32678694","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03474","title":"Trends in MDMA-related mortality across four countries.","authors":"Roxburgh, Amanda; Sam, Bulent; Kriikku, Pirkko; Mounteney, Jane; Castanera, Antonio; Dias, Mario; Giraudon, Isabelle","year":2021,"journal":"Addiction (Abingdon, England), 116(11), 3094-3103","doi":"10.1111/add.15493","pmid":"33739562","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03475","title":"Intravenous Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized, Controlled Trial.","authors":"Ruberto, Aaron J; Sivilotti, Marco L A; Forrester, Savannah; Hall, Andrew K; Crawford, Frances M; Day, Andrew G","year":2021,"journal":"Annals of emergency medicine, 77(6), 613-619","doi":"10.1016/j.annemergmed.2020.08.021","pmid":"33160719","tags":["medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Haloperidol was superior to ondansetron (difference 2.3 cm on VAS, 95% CI 0.6-4.0, p=0.01) with similar improvements in both pain and nausea. Haloperidol patients required fewer rescue antiemetics (31% vs 59%) and had shorter ED stays (3.1 vs 5.6 hours, difference 2.5 hours, p=0.03). Two patients in the higher-dose haloperidol group returned with acute dystonia.","whyItMatters":"This is one of the first RCTs comparing treatments for CHS. The superiority of haloperidol over ondansetron (a first-line antiemetic) confirms anecdotal reports and provides evidence to change emergency department practice for this increasingly common condition.","specificNumbers":"33 enrolled, 30 treated; haloperidol vs ondansetron VAS difference: 2.3 cm (p=0.01); rescue antiemetics: 31% vs 59%; ED stay: 3.1 vs 5.6 hours (p=0.03); 2 dystonia events with high-dose haloperidol","methodology":"Triple-blind randomized controlled trial. 33 cannabis users with active emesis randomized to haloperidol (with nested randomization to 0.05 or 0.1 mg/kg) or ondansetron 8 mg IV. Primary outcome: reduction in abdominal pain and nausea on 10-cm VAS at 2 hours.","limitations":"Small sample (n=30 treated). Single-center study. Acute dystonia occurred with higher-dose haloperidol, raising safety concerns. Short-term outcomes only; no follow-up for recurrence."},{"rthcId":"RTHC-03476","title":"Near-Fatal Spice Intoxication of a Toddler.","authors":"Ruiz-Maldonado, Tagrid M; Dorey, Alyrene; Christensen, Erik D; Campbell, Kristine A","year":2021,"journal":"Pediatrics, 148(2)","doi":"10.1542/peds.2021-050888","pmid":"34233919","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03477","title":"Pharmacokinetic and pharmacodynamic properties of aerosolized (\"vaped\") THC in adolescent male and female rats.","authors":"Ruiz, C M; Torrens, A; Lallai, V; Castillo, E; Manca, L; Martinez, M X; Justeson, D N; Fowler, C D; Piomelli, D; Mahler, S V","year":2021,"journal":"Psychopharmacology, 238(12), 3595-3605","doi":"10.1007/s00213-021-05976-8","pmid":"34495367","tags":["youth","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Female adolescent rats had higher 11-OH-THC levels than males in blood and brain after vaped THC exposure. At the low dose (25 mg/ml), females showed greater anxiety-like and exploratory behavioral effects. At the high dose (100 mg/ml), both sexes showed similar hypothermic responses. Sex differences in pharmacokinetics were paralleled by sex differences in behavioral sensitivity.","whyItMatters":"Most cannabis research uses injection or oral dosing in adult animals. This study provides the first systematic characterization of vaped THC in adolescent rats, a more human-relevant exposure route and age period, revealing important sex differences that could inform public health messaging.","specificNumbers":"THC doses: 25 and 100 mg/ml aerosol; 30-minute exposure; blood and brain samples at 5, 30, 60, 120 minutes; females had higher 11-OH-THC; females more behaviorally sensitive at low dose; similar hypothermia at high dose","methodology":"Pharmacokinetic and pharmacodynamic study in adolescent Wistar rats of both sexes. 30-minute aerosol THC exposure at 25 or 100 mg/ml. LC/MS analysis of THC, 11-OH-THC, and 11-COOH-THC in blood and brain at 5, 30, 60, and 120 minutes. Behavior and temperature measured in separate cohorts.","limitations":"Animal study; adolescent rat development does not perfectly parallel human adolescence. Aerosol THC exposure parameters may not match human vaping patterns. Single time point for behavioral testing."},{"rthcId":"RTHC-03478","title":"Novel Solventless Extraction Technique to Preserve Cannabinoid and Terpenoid Profiles of Fresh Cannabis Inflorescence.","authors":"Russo, Ethan B; Plumb, Jeremy; Whiteley, Venetia L","year":2021,"journal":"Molecules (Basel, Switzerland), 26(18)","doi":"10.3390/molecules26185496","pmid":"34576967","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03479","title":"Direct Stimulatory Effects of the CB2 Ligand JTE 907 in Human and Mouse Islets.","authors":"Ruz-Maldonado, Inmaculada; Atanes, Patricio; Huang, Guo Cai; Liu, Bo; Persaud, Shanta J","year":2021,"journal":"Cells, 10(3)","doi":"10.3390/cells10030700","pmid":"33809893","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03480","title":"Safety and efficacy of low-dose medical cannabis oils in multiple sclerosis.","authors":"S, Gustavsen; Hb, Søndergaard; K, Linnet; R, Thomsen; Bs, Rasmussen; Ps, Sorensen; F, Sellebjerg; Ab, Oturai","year":2021,"journal":"Multiple sclerosis and related disorders, 48, 102708","doi":"10.1016/j.msard.2020.102708","pmid":"33387864","tags":["medical-cannabis","pain","sleep"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Pain decreased from median NRS 7 to 4 (p=0.01), spasticity from 6 to 2.5 (p=0.01), and sleep disturbances from 7 to 3 (p<0.001). Most common adverse events were mild dry mouth, drowsiness, dizziness, and nausea. Two patients discontinued due to excessive dreaming and drowsiness. No impairment in disability (EDSS), ambulation, dexterity, or processing speed.","whyItMatters":"The low doses used (mean 4 mg THC) are much lower than typical recreational or even medical cannabis use. Demonstrating safety and efficacy at these doses could make medical cannabis more accessible to patients and clinicians who are concerned about side effects and impairment.","specificNumbers":"28 patients; mean THC dose 4 mg, CBD dose 7 mg; mostly once-daily evening; pain NRS 7 to 4 (p=0.01); spasticity 6 to 2.5 (p=0.01); sleep 7 to 3 (p<0.001); 2 discontinuations; 3 SAEs unrelated to treatment; no cognitive/physical impairment","methodology":"Prospective observational safety study of 28 MS patients treated with medical cannabis oils (THC-rich, CBD-rich, and THC+CBD combined). Four-week titration period with assessments at baseline and 4 weeks including EDSS, T25FWT, 9-HPT, SDMT, blood tests, and plasma cannabinoid levels. Daily NRS ratings for symptoms.","limitations":"Small sample (28 patients). No control group; improvements could reflect placebo effect. Short follow-up (4 weeks). Open-label design means patients knew they were receiving cannabis."},{"rthcId":"RTHC-03481","title":"Lessons learned in several states eight years after states legalized marijuana.","authors":"Sabet, Kevin","year":2021,"journal":"Current opinion in psychology, 38, 25-30","doi":"10.1016/j.copsyc.2020.07.018","pmid":"32769051","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03482","title":"Acute Myocardial Injury in a Patient with Attention Deficit Hyperactivity Disorder and History of Substance Abuse: A Multimodality Imaging Point of View.","authors":"Saeed, Sahrai; Rotevatn, Svein; Schjøtt, Jan; Larsen, Terje H","year":2021,"journal":"Journal of cardiovascular development and disease, 8(6)","doi":"10.3390/jcdd8060067","pmid":"34200122","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03483","title":"Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure.","authors":"Sagheddu, Claudia; Traccis, Francesco; Serra, Valeria; Congiu, Mauro; Frau, Roberto; Cheer, Joseph F; Melis, Miriam","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 105, 110128","doi":"10.1016/j.pnpbp.2020.110128","pmid":"33031862","tags":["pregnancy","psychosis","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Pre-pubertal male rats exposed prenatally to THC showed reduced population activity of VTA dopamine neurons but more tonically active neurons, enhanced sensitivity to D2 receptor activation by apomorphine, and stress-induced disruption of sensorimotor gating (PPI). This pattern creates a neural substrate highly susceptible to subsequent challenges that could trigger psychotic-like outcomes.","whyItMatters":"This study reveals a concerning mechanism: prenatal THC may not cause psychosis directly but could create a brain state that is vulnerable to being tipped into psychosis by common environmental stressors. This \"silent endophenotype\" concept helps explain why only some prenatally exposed individuals develop psychiatric problems.","specificNumbers":"Reduced VTA dopamine neuron population activity; majority tonically active; enhanced D2 receptor sensitivity to apomorphine; stress-induced PPI disruption in PCE males; pre-pubertal assessment","methodology":"Animal study using prenatal cannabinoid exposure model in rats. In vivo single-unit extracellular recordings of VTA dopamine neurons. Prepulse inhibition analysis after acute stress or D2 agonist challenge. Assessed male offspring at pre-puberty.","limitations":"Animal study with synthetic THC administration. Only male offspring studied. Pre-pubertal assessment only. Cannot directly translate to human prenatal cannabis exposure. Single stress paradigm tested."},{"rthcId":"RTHC-03484","title":"Opposite Roles for Cannabidiol and δ-9-Tetrahydrocannabinol in Psychotomimetic Effects of Cannabis Extracts: A Naturalistic Controlled Study.","authors":"Sainz-Cort, Alberto; Jimenez-Garrido, Daniel; Muñoz-Marron, Elena; Viejo-Sobera, Raquel; Heeroma, Joost; Bouso, Jose Carlos","year":2021,"journal":"Journal of clinical psychopharmacology, 41(5), 561-570","doi":"10.1097/JCP.0000000000001457","pmid":"34412109","tags":["cbd","psychosis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"THC+CBD combined extracts produced significantly lower psychotomimetic scores than THC alone. CBD alone and placebo produced no psychotomimetic effects. Subjective scores under CBD and placebo were lower than under THC+CBD, confirming CBD alone was inert. The study demonstrated both THC's psychotomimetic properties and CBD's ability to attenuate them in real-world conditions.","whyItMatters":"This is one of the first studies to show CBD's antipsychotomimetic effects using full-spectrum cannabis extracts in real-world settings rather than purified compounds in a laboratory. It provides ecological evidence for the protective role of CBD in cannabis products.","specificNumbers":"18 participants; 4 conditions (THC, CBD, THC+CBD, placebo); double-blind crossover; THC+CBD lower psychotomimetic scores than THC alone; CBD and placebo: no psychotomimetic effects","methodology":"Naturalistic, randomized, double-blind, crossover, placebo-controlled study in 18 cannabis social club members. Tested four full-spectrum cannabis extracts: THC, CBD, THC+CBD, and placebo. Measured subjective and psychotomimetic effects.","limitations":"Small sample (18 participants). Cannabis social club members are experienced users who may differ from the general population. Naturalistic setting introduced some variability. Self-reported subjective measures."},{"rthcId":"RTHC-03485","title":"Practice Patterns and Training Needs Among Physicians Certifying Patients for Medical Marijuana in Florida.","authors":"Sajdeya, Ruba; Shavers, Anna; Jean-Jacques, Jennifer; Costales, Brianna; Jugl, Sebastian; Crump, Carly; Wang, Yan; Manfio, Luran; Pipitone, R Nathan; Rosenthal, Martha S; Winterstein, Almut G; Cook, Robert L","year":2021,"journal":"Journal of primary care & community health, 12, 21501327211042790","doi":"10.1177/21501327211042790","pmid":"34452585","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 116 medical marijuana physicians surveyed, 92% reported performing physical exams, but only half provided specific THC:CBD ratio recommendations and 62% gave dose recommendations, suggesting substantial practice variability.","whyItMatters":"As medical marijuana programs expand, this survey reveals that the physicians at the frontline of patient care are largely improvising, with limited standardized training or evidence-based protocols to guide their recommendations.","specificNumbers":"116 respondents; mean age 57; 70% male; 95% used research articles as information source; 92% performed physical exams; 50% provided THC:CBD ratio recommendations; 62% gave dose recommendations; 84% would participate in online training; top training priorities were drug interactions (72%), condition management (72%), opioid reduction (67%).","methodology":"Cross-sectional anonymous survey of registered medical marijuana physicians in Florida (June-October 2020), with numerical responses quantified using counts and percentages.","limitations":"Self-selected convenience sample with potential response bias; self-reported practices may not reflect actual clinical behavior; limited to Florida physicians."},{"rthcId":"RTHC-03486","title":"Prevalence and Correlates of Driving Under the Influence of Cannabis in the U.S.","authors":"Salas-Wright, Christopher P; Cano, Manuel; Hai, Audrey Hang; Oh, Sehun; Vaughn, Michael G","year":2021,"journal":"American journal of preventive medicine, 60(6), e251-e260","doi":"10.1016/j.amepre.2021.01.021","pmid":"33726992","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using NSDUH data from 128,205 adults, researchers found that 29.5% of cannabis users reported driving under the influence, with daily users showing a 57% predicted probability and those with cannabis use disorder reaching 63.8%.","whyItMatters":"With cannabis legalization spreading, understanding who drives while high and what risk factors accompany that behavior can help target prevention where it would do the most good.","specificNumbers":"128,205 adults surveyed; 4.5% overall DUIC prevalence; state range 3.0% (Texas) to 8.4% (Oregon); 29.5% of cannabis users drove under influence; 57% predicted probability for daily users; 63.8% prevalence among those with CUD.","methodology":"Cross-sectional analysis of NSDUH public-use data (2016-2018) with multivariate logistic regression examining demographic, psychosocial, and behavioral correlates of cannabis-impaired driving.","limitations":"Self-reported data likely underestimates actual DUIC prevalence; cross-sectional design prevents causal conclusions; no objective measures of impairment."},{"rthcId":"RTHC-03487","title":"Vanishing lung syndrome: a consequence of mixed tobacco and marijuana use.","authors":"Salley, Jordan R; Kukkar, Vishal; Felde, Lanna","year":2021,"journal":"BMJ case reports, 14(5)","doi":"10.1136/bcr-2020-239255","pmid":"34016626","tags":["respiratory"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report describes a patient with long-term dual tobacco and cannabis use who developed idiopathic giant bullous emphysema (vanishing lung syndrome), supporting the hypothesis that combined use may have an additive damaging effect on lung tissue.","whyItMatters":"While smoking-related lung damage is well documented for tobacco alone, this case adds to evidence that combining cannabis and tobacco may carry additional respiratory risks beyond either substance individually.","specificNumbers":"48-year-old male patient; long-term history of both tobacco and cannabis smoking; giant emphysematous bullae located primarily in upper lung lobes.","methodology":"Single case report with review of recent literature on the association between vanishing lung syndrome and combined marijuana and tobacco use.","limitations":"Single case report cannot establish causation; the patient's tobacco use alone may have been sufficient to cause VLS; no controlled comparison."},{"rthcId":"RTHC-03488","title":"A Survey of Cannabis Use in a Large US-Based Cohort of People with Multiple Sclerosis.","authors":"Salter, Amber; Fox, Robert J; Cutter, Gary; Marrie, Ruth Ann; Nichol, Kate E; Steinerman, Joshua R; Smith, Karry M J","year":2021,"journal":"International journal of MS care, 23(6), 245-252","doi":"10.7224/1537-2073.2021-036","pmid":"35035295","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 3,249 respondents from the NARCOMS Registry, 31% had ever used cannabis for MS symptoms and 20% were current users, while 69% who had never tried it cited insufficient efficacy data (40%), safety concerns (27%), and legality (25%) as barriers.","whyItMatters":"Despite limited clinical evidence, a substantial portion of MS patients are turning to cannabis for symptom management, suggesting a gap between patient needs and available evidence-based treatments.","specificNumbers":"6,934 invited; 3,249 responded; 31% ever used cannabis for MS; 20% current users; spasticity (80%), pain (69%), sleep (61%) most common targets; barriers: insufficient efficacy data (40%), safety concerns (27%), legality (25%), cost (18%).","methodology":"Cross-sectional supplemental survey of participants aged 18+ from the NARCOMS Registry (March-April 2020), reported with descriptive statistics.","limitations":"Self-selected respondents from a patient registry; potential selection bias toward those with stronger opinions about cannabis; self-reported use without verification."},{"rthcId":"RTHC-03489","title":"Female but not male rats show biphasic effects of low doses of Δ9-tetrahydrocannabinol on anxiety: can cannabidiol interfere with these effects?","authors":"Salviato, Beatriz Zanutto; Raymundi, Ana Maria; Rodrigues da Silva, Thiago; Salemme, Bruna Wuilleumier; Batista Sohn, Jeferson Machado; Araújo, Fabiano Soares; Guimarães, Francisco Silveira; Bertoglio, Leandro José; Stern, Cristina Aparecida","year":2021,"journal":"Neuropharmacology, 196, 108684","doi":"10.1016/j.neuropharm.2021.108684","pmid":"34181978","tags":["anxiety","cbd","dopamine","sex-differences","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study revealed a striking sex difference that most cannabis research has missed by testing only males. Low-dose THC (0.075-0.1 mg/kg) produced clear anxiolytic effects in female rats on the elevated plus-maze. At higher doses (1.0 mg/kg), the effect flipped to anxiogenic. Male rats showed no anxiety changes across the same dose range.\n\nCBD entered the picture as a modulator. Co-administering CBD (1.0 or 3.0 mg/kg) with the anxiogenic THC dose prevented the anxiety response. At the lower CBD dose, it actually enhanced the anxiolytic effect of low-dose THC — making a calming dose even calmer. CBD alone at 3.0 mg/kg was anxiolytic on its own.\n\nThe neurochemistry matched the behavior. The anxiogenic THC dose increased dopamine in the medial prefrontal cortex and nucleus accumbens — regions linked to anxiety and salience processing. The anxiolytic dose did not produce these dopamine increases. CBD appeared to work by preventing THC's dopamine-elevating effects in these regions.","whyItMatters":"Women report higher rates of anxiety disorders and are increasingly using cannabis to manage anxiety. Yet almost all preclinical cannabis-anxiety research has been done in male animals. This study showed the anxiety response to THC is fundamentally different in females — more sensitive at both ends. Low doses helped more, high doses hurt more, and CBD modulated the response.\n\nFor women using cannabis for anxiety, this suggests the dose-response window is narrower and the consequences of getting it wrong (too much THC → increased anxiety) are more pronounced. It also provides preclinical support for THC:CBD combinations as potentially superior to THC alone for anxiety management.","specificNumbers":"• Anxiolytic THC dose in females: 0.075-0.1 mg/kg\n• Anxiogenic THC dose in females: 1.0 mg/kg\n• Males: no anxiety changes at any dose tested\n• CBD (1.0-3.0 mg/kg) prevented THC-induced anxiety\n• Low CBD + low THC: enhanced anxiolytic effect beyond either alone","methodology":"Naturally cycling female and male Sprague-Dawley rats tested on the elevated plus-maze (standard anxiety test). THC administered at 0.075, 0.1, and 1.0 mg/kg. CBD at 1.0 and 3.0 mg/kg, alone or combined with THC. Dopamine levels measured in medial prefrontal cortex and nucleus accumbens via microdialysis.","limitations":"Rat model — anxiety in rodents is measured behaviorally and may not correspond to human subjective anxiety. Naturally cycling females were used without tracking estrous cycle stage, which may affect results. The dose range was narrow and the THC amounts were low relative to human recreational use. Acute administration only; chronic effects not studied."},{"rthcId":"RTHC-03490","title":"Association of extent of cannabis use and psychotic like intoxication experiences in a multi-national sample of first episode psychosis patients and controls.","authors":"Sami, Musa; Quattrone, Diego; Ferraro, Laura; Tripoli, Giada; Cascia, Erika La; Gayer-Anderson, Charlotte; Selten, Jean-Paul; Arango, Celso; Bernardo, Miguel; Tarricone, Ilaria; Tortelli, Andrea; Gatto, Giusy; Del Peschio, Simona; Del-Ben, Cristina Marta; Rutten, Bart P; Jones, Peter B; van Os, Jim; de Haan, Lieuwe; Morgan, Craig; Lewis, Cathryn; Bhattacharyya, Sagnik; Freeman, Tom P; Lynskey, Michael; Murray, Robin M; Forti, Marta Di","year":2021,"journal":"Psychological medicine, 51(12), 2074-2082","doi":"10.1017/S0033291720000847","pmid":"32340643","tags":["psychosis"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"In the EU-GEI study across 15 sites and 6 countries, FEP patients (n=655) showed a steeper increase in psychotic-like intoxication experiences at higher cannabis use levels compared to controls (n=654), while euphoric experiences did not differ between groups.","whyItMatters":"The finding that psychosis patients have a specific vulnerability to cannabis-induced psychotic-like experiences, but not euphoric ones, suggests a biological mechanism rather than simply heavier use patterns.","specificNumbers":"655 FEP patients; 654 controls; 15 sites across 6 countries; significant interaction for caseness x frequency of use for psychotic-like experiences (p<0.001) but not euphoric experiences (p>0.5).","methodology":"Multi-site case-control analysis from the EU-GEI study (2010-2015) using multiple regression to model predictors of cannabis-induced psychotic-like and euphoric experiences across 15 sites in 6 countries.","limitations":"Cross-sectional design cannot determine whether sensitivity preceded psychosis onset; retrospective self-report of intoxication experiences; potential recall bias in patient group."},{"rthcId":"RTHC-03491","title":"Eye movements in patients in early psychosis with and without a history of cannabis use.","authors":"Sami, Musa Basseer; Annibale, Luciano; O'Neill, Aisling; Collier, Tracy; Onyejiaka, Chidimma; Eranti, Savitha; Das, Debasis; Kelbrick, Marlene; McGuire, Philip; Williams, Steve C R; Rana, Anas; Ettinger, Ulrich; Bhattacharyya, Sagnik","year":2021,"journal":"NPJ schizophrenia, 7(1), 24","doi":"10.1038/s41537-021-00155-2","pmid":"33980870","tags":["psychosis","neuroscience"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Among 91 participants across four groups, early psychosis patients without cannabis history had significantly worse smooth pursuit velocity gain compared to those with cannabis history (effect size g=0.76-0.86), suggesting less severe neurobiological alterations in cannabis-associated psychosis.","whyItMatters":"If psychosis that develops with cannabis use involves less severe underlying brain abnormalities than psychosis without cannabis, it could have implications for prognosis and treatment approaches.","specificNumbers":"91 participants (28 psychosis+cannabis, 25 psychosis no cannabis, 16 controls+cannabis, 22 controls no cannabis); smooth pursuit impairment effect size g=0.76-0.86 between psychosis groups; significant patient x cannabis interaction (p=0.04).","methodology":"Case-control study comparing four groups (psychosis with/without cannabis history, controls with/without cannabis) on smooth pursuit eye movements at three frequencies and antisaccade performance.","limitations":"Small sample sizes in each group; cross-sectional design; cannabis use history was self-reported; medication effects could influence eye movements."},{"rthcId":"RTHC-03492","title":"Analogues of cannabinoids as multitarget drugs in the treatment of Alzheimer's disease.","authors":"Sánchez Montero, José María; Agis-Torres, Angel; Solano, David; Söllhuber, Monica; Fernandez, María; Villaro, Wilma; Gómez-Cañas, María; García-Arencibia, Moisés; Fernández-Ruiz, Javier; Egea, Javier; Martín, María Isabel; Girón, Rocío","year":2021,"journal":"European journal of pharmacology, 895, 173875","doi":"10.1016/j.ejphar.2021.173875","pmid":"33460612","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03493","title":"Prevalence of cannabinoid hyperemesis syndrome and its financial burden on the health care industry.","authors":"Sandhu, Gurkaminder; Smith, Steven; Stephenson, Kristen; Jaeger, Victoria; John, Rebekah; Shaver, Courtney; Johnson, Christopher","year":2021,"journal":"Proceedings (Baylor University. Medical Center), 34(6), 654-657","doi":"10.1080/08998280.2021.1937874","pmid":"34732980","tags":["addiction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Comparing patients with CHS to those who denied cannabis use, researchers found that CHS patients underwent extensive and repeated evaluations across clinic, emergency department, and inpatient settings, consuming more healthcare dollars overall.","whyItMatters":"As cannabis legalization spreads and CHS incidence is expected to rise, early recognition through thorough history-taking could prevent unnecessary workups and reduce the financial burden on both patients and the healthcare system.","specificNumbers":"Cost differences between CHS and non-CHS groups were noted but not statistically significant across all categories; CHS patients had repeated evaluations in clinic, ED, and inpatient settings.","methodology":"Retrospective comparison of costs incurred by patients with CHS versus patients without cannabis use across various healthcare settings.","limitations":"Small sample size limited statistical power; cost differences were not consistently significant; single-center study; retrospective design."},{"rthcId":"RTHC-03494","title":"Reported Marijuana and Tobacco Smoke Incursions Among Families Living in Multiunit Housing in New York City.","authors":"Sangmo, Lodoe; Liu, Bian; Elaiho, Cordelia; Boguski, Lisa; Yaker, Michael; Resnick, Micah; Malbari, Alefiyah; Wilson, Karen M","year":2021,"journal":"Academic pediatrics, 21(4), 670-676","doi":"10.1016/j.acap.2021.01.005","pmid":"33460815","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 382 surveyed families, 30.9% reported marijuana smoke incursions while home with their child, with NYCHA (public housing) residents 3.45 times more likely to report exposure compared to other housing types.","whyItMatters":"Children in multiunit housing face involuntary exposure to marijuana smoke that parents cannot easily control, raising environmental health equity concerns especially for families in public housing.","specificNumbers":"382 surveys analyzed; 30.9% reported marijuana smoke incursions; 33.5% reported tobacco smoke incursions; NYCHA residents had adjusted OR of 3.45 for marijuana smoke exposure (p=0.02); two-thirds viewed marijuana smoke as harmful to their child.","methodology":"Cross-sectional convenience sample of parents attending 4 pediatric practices in the Mount Sinai Health System (2018-2019), with anonymous questionnaires assessing housing characteristics and smoke incursions.","limitations":"Convenience sample from one health system; self-reported smell does not confirm actual secondhand smoke exposure levels; limited to New York City."},{"rthcId":"RTHC-03495","title":"Secondhand marijuana exposure in a convenience sample of young children in New York City.","authors":"Sangmo, Lodoe; Braune, Tanya; Liu, Bian; Wang, Lanqing; Zhang, Li; Sosnoff, Connie S; Blount, Benjamin C; Wilson, Karen M","year":2021,"journal":"Pediatric research, 89(4), 905-910","doi":"10.1038/s41390-020-0958-7","pmid":"32403116","tags":["youth","respiratory"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 53 children aged 0-3 years, 20.8% had detectable urinary COOH-THC (a marijuana metabolite), and children with high tobacco smoke exposure were significantly more likely to test positive (p<0.01).","whyItMatters":"Objective biomarker evidence that young children are absorbing marijuana smoke, even in a state where recreational use was then illegal, underscores that secondhand exposure in shared living spaces is a measurable public health concern.","specificNumbers":"53 children; 20.8% had detectable COOH-THC; 90.2% had detectable cotinine; 34.8% of children in housing allowing smoking had detectable COOH-THC vs 13.0% in smoke-free housing; high tobacco exposure significantly associated with COOH-THC detection (p<0.01).","methodology":"Cross-sectional study collecting urine samples from children at well-child visits or inpatient stays at Mount Sinai (2017-2018), analyzed for cotinine and COOH-THC with parent surveys.","limitations":"Very small sample size (53 children); convenience sample from a single hospital; cross-sectional design; cannot determine health effects of detected levels."},{"rthcId":"RTHC-03496","title":"Nicotine-induced enhancement of a sensory reinforcer in adult rats: antagonist pretreatment effects.","authors":"Satanove, Doran J; Rahman, Simon; Chan, T M Vanessa; Ren, Suelynn; Clarke, Paul B S","year":2021,"journal":"Psychopharmacology, 238(2), 475-486","doi":"10.1007/s00213-020-05696-5","pmid":"33150479","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03497","title":"Sex Differences in Neuropsychological Functioning are Domain-Specific in Adolescent and Young Adult Regular Cannabis Users.","authors":"Savulich, George; Rychik, Natali; Lamberth, Erin; Hareli, Maya; Evins, A Eden; Sahakian, Barbara J; Schuster, Randi M","year":2021,"journal":"Journal of the International Neuropsychological Society : JINS, 27(6), 592-606","doi":"10.1017/S1355617720001435","pmid":"34261559","tags":["cognition","sex-differences","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Male cannabis users had poorer visual recognition memory while female users showed worse attention and executive functioning (medium to large effect sizes), with earlier initiation and heavier use more strongly linked to attention deficits in females and memory/learning deficits in males.","whyItMatters":"If cannabis affects cognitive domains differently by sex, prevention messaging and clinical monitoring may need to be tailored rather than one-size-fits-all.","specificNumbers":"171 participants; 46.2% female; aged 13-25; medium to large effect sizes for sex differences; earlier initiation associated with worse attention in females but not males; heavier use linked to worse episodic memory and learning in males.","methodology":"Cross-sectional study of 171 at-least-weekly cannabis users aged 13-25 (46.2% female) using the Cambridge Neuropsychological Test Automated Battery (CANTAB), controlling for age, IQ, alcohol, nicotine, mood, and impulsivity.","limitations":"No healthy control group for comparison; cross-sectional design prevents causal inference; cannot determine if sex differences are more pronounced than in non-users; potential selection bias."},{"rthcId":"RTHC-03498","title":"Use of Cannabis and Cannabinoids in Patients With Cancer.","authors":"Sawtelle, Lindsey; Holle, Lisa M","year":2021,"journal":"The Annals of pharmacotherapy, 55(7), 870-890","doi":"10.1177/1060028020965224","pmid":"33070617","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03499","title":"Cannabis Essentials: Tools for Clinical Practice.","authors":"Sazegar, Payam","year":2021,"journal":"American family physician, 104(6), 598-608","doi":null,"pmid":"34913644","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03500","title":"Adolescent cannabis use and adult psychoticism: A longitudinal co-twin control analysis using data from two cohorts.","authors":"Schaefer, Jonathan D; Jang, Seon-Kyeong; Vrieze, Scott; Iacono, William G; McGue, Matt; Wilson, Sylia","year":2021,"journal":"Journal of abnormal psychology, 130(7), 691-701","doi":"10.1037/abn0000701","pmid":"34553951","tags":["psychosis","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"In 1,544 twins, both cumulative adolescent cannabis use and cannabis use disorder were associated with higher adult Psychoticism scores, but comparing twins within pairs (where one used more cannabis) showed no within-pair difference, pointing to familial confounds rather than causal effects.","whyItMatters":"This twin design is one of the strongest methods for separating causal effects from confounding. Finding no within-twin-pair effect challenges the assumption that cannabis directly causes psychotic traits and suggests shared genetic or environmental factors drive both.","specificNumbers":"1,544 twins for cannabis use analysis; 1,458 for CUD analysis; no significant within-pair effect in co-twin models; no interaction between polygenic risk for schizophrenia and cannabis use on psychoticism.","methodology":"Longitudinal co-twin control analysis using two cohorts of twins with prospective measures of adolescent cannabis use (N=1,544) and cannabis use disorder symptoms (N=1,458) linked to adult Psychoticism (PID-5), with polygenic risk scores for schizophrenia.","limitations":"Psychoticism scale measures a broad dimension, not clinical psychosis diagnosis; predominantly White sample from Minnesota; may not generalize to populations with different genetic backgrounds; cannabis potency not measured."},{"rthcId":"RTHC-03501","title":"Cannabis use and clinical outcome in people with first-episode schizophrenia spectrum disorders over 24 months of treatment.","authors":"Scheffler, Freda; Phahladira, Lebogang; Luckhoff, Hilmar; du Plessis, Stefan; Asmal, Laila; Kilian, Sanja; Forti, Marta Di; Murray, Robin; Emsley, Robin","year":2021,"journal":"Psychiatry research, 302, 114022","doi":"10.1016/j.psychres.2021.114022","pmid":"34052461","tags":["psychosis","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 98 first-episode schizophrenia patients treated with long-acting injectable antipsychotic, cannabis users (n=45) and non-users (n=53) had similar trajectories in symptom reduction and remission rates over 24 months, but more frequent cannabis use (measured by urine testing) predicted relapse.","whyItMatters":"The nuanced finding that cannabis doesn't impair overall treatment response but does increase relapse risk in a dose-dependent manner suggests that harm reduction approaches focused on reducing use frequency could be clinically valuable.","specificNumbers":"98 patients (45 cannabis users, 53 non-users); 24 months of treatment; no significant group x time interactions for symptom trajectories; similar remission rates; more cannabis users met relapse criteria; frequency of positive urine tests predicted relapse.","methodology":"Longitudinal study of 98 first-episode schizophrenia spectrum patients treated with long-acting injectable antipsychotic over 24 months, comparing cannabis users to non-users using mixed models for repeated measures.","limitations":"Moderate sample size; observational design; cannabis users may differ in unmeasured ways; single-site study; urine testing captures recent use but not patterns."},{"rthcId":"RTHC-03502","title":"A Cross-Sectional and Prospective Comparison of Medicinal Cannabis Users and Controls on Self-Reported Health.","authors":"Schlienz, Nicolas J; Scalsky, Ryan; Martin, Erin L; Jackson, Heather; Munson, Joel; Strickland, Justin C; Bonn-Miller, Marcel O; Loflin, Mallory; Vandrey, Ryan","year":2021,"journal":"Cannabis and cannabinoid research, 6(6), 548-558","doi":"10.1089/can.2019.0096","pmid":"33998852","tags":["medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users (n=808) self-reported significantly better quality of life, lower anxiety, less depression, better sleep, and fewer ER visits compared to controls (n=468), and longitudinal follow-ups suggested these differences were associated with initiating or maintaining cannabis use.","whyItMatters":"While observational, the longitudinal component showing changes when participants started or stopped cannabis provides stronger evidence than cross-sectional comparisons alone that cannabis use may be contributing to reported health improvements.","specificNumbers":"1,276 participants (808 cannabis users, 468 controls); 33% completed prospective follow-ups; users reported significantly better QoL, lower pain, anxiety, depression, better sleep, and fewer ER visits (all p values significant).","methodology":"Longitudinal web-based survey study (April 2016-February 2018) comparing medical cannabis users to controls registered with the Realm of Caring Foundation, with follow-up assessments every 3 months; analyzed using negative binomial regression and linear mixed effects models.","limitations":"Convenience sample from a cannabis advocacy organization; strong potential for expectation bias; self-reported outcomes without clinical verification; low follow-up completion rate (33%)."},{"rthcId":"RTHC-03503","title":"Refraining from use diminishes cannabis-associated epigenetic changes in human sperm.","authors":"Schrott, Rose; Murphy, Susan K; Modliszewski, Jennifer L; King, Dillon E; Hill, Bendu; Itchon-Ramos, Nilda; Raburn, Douglas; Price, Thomas; Levin, Edward D; Vandrey, Ryan; Corcoran, David L; Kollins, Scott H; Mitchell, John T","year":2021,"journal":"Environmental epigenetics, 7(1), dvab009","doi":"10.1093/eep/dvab009","pmid":"34557312","tags":["genetics","pregnancy"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Whole-genome bisulfite sequencing identified 163 CpG sites with significantly altered DNA methylation in cannabis users' sperm, concentrated at genes involved in cardiogenesis and neurodevelopment, and many of these changes were reversed after one spermatogenic cycle (77 days) of abstinence.","whyItMatters":"This is the first evidence that cannabis-related epigenetic changes in sperm are reversible, suggesting that men planning to conceive could potentially reduce risks by abstaining for at least one full sperm development cycle.","specificNumbers":"163 CpG sites with significantly different methylation (p<10^-9); affected genes enriched for development, cardiogenesis, and neurodevelopment pathways; 77-day abstinence period (one spermatogenic cycle); significant reduction in methylation differences after abstinence.","methodology":"Prospective cohort comparing sperm DNA methylation between cannabis users and non-user controls at baseline and after a 77-day abstinence period, using whole-genome bisulfite sequencing.","limitations":"Small sample size; controlled abstinence period may not reflect real-world behavior; long-term offspring health effects of these epigenetic changes remain unknown; functional significance of methylation changes not established."},{"rthcId":"RTHC-03504","title":"Endocannabinoid System Dysregulation from Acetaminophen Use May Lead to Autism Spectrum Disorder: Could Cannabinoid Treatment Be Efficacious?","authors":"Schultz, Stephen; Gould, Georgianna G; Antonucci, Nicola; Brigida, Anna Lisa; Siniscalco, Dario","year":2021,"journal":"Molecules (Basel, Switzerland), 26(7)","doi":"10.3390/molecules26071845","pmid":"33805951","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03505","title":"The prevalence of alcohol and other drugs in fatal road crashes in Victoria, Australia.","authors":"Schumann, Jennifer; Perkins, Monica; Dietze, Paul; Nambiar, Dhanya; Mitra, Biswadev; Gerostamoulos, Dimitri; Drummer, Olaf H; Cameron, Peter; Smith, Karen; Beck, Ben","year":2021,"journal":"Accident; analysis and prevention, 153, 105905","doi":"10.1016/j.aap.2020.105905","pmid":"33631704","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03506","title":"Tic Reduction in Adult Onset Gilles De La Tourette Syndrome Using as Required Nabiximols Spray.","authors":"Schwittay, Maximilian A; Steinbrecher, Andreas; Lobsien, Elmar","year":2021,"journal":"Tremor and other hyperkinetic movements (New York, N.Y.), 11, 33","doi":"10.5334/tohm.613","pmid":"34430070","tags":["medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"After standard treatment with Tiaprid 300 mg daily showed insufficient effect, a trial of buccal nabiximols spray used \"as required\" reduced motor and phonic tics by more than 90% in a patient with adult-onset Tourette syndrome.","whyItMatters":"Tourette syndrome can be severely stigmatizing, and many patients don't respond adequately to standard medications. This case suggests nabiximols could serve as a supplementary treatment option for refractory cases.","specificNumbers":"25-year-old male; tics developed after cessation of daily cannabis use; Tiaprid 300 mg/day showed insufficient effect; nabiximols reduced tics by >90%.","methodology":"Single case report of a 25-year-old male with adult-onset Tourette syndrome treated with nabiximols spray after failure of standard medication.","limitations":"Single case report cannot establish efficacy; patient had prior daily cannabis use which may have influenced response; no blinded comparison."},{"rthcId":"RTHC-03507","title":"Modeling the system of beliefs that influence driving under the influence of cannabis (DUIC) in Washington State.","authors":"Scott, Brandon; Ward, Nicholas; Otto, Jay; Finley, Kari","year":2021,"journal":"Accident; analysis and prevention, 151, 105988","doi":"10.1016/j.aap.2021.105988","pmid":"33484972","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using structural equation modeling, researchers identified that DUIC behavior was predicted by intention (which had a stronger effect than willingness alone), and both were shaped by control beliefs, attitudes, social norms, and perceptions of people who do or don't drive high.","whyItMatters":"Understanding the psychological drivers behind driving-while-high decisions can help design targeted prevention campaigns that address the specific beliefs, norms, and attitudes that make people willing to drive after using cannabis.","specificNumbers":"2,084 adults surveyed; intention had stronger influence on DUIC than willingness alone; DUIC predicted by willingness influencing intention; both shaped by control beliefs, attitudes, norms, and prototype images.","methodology":"Cross-sectional survey of 2,084 U.S. adults analyzed using structural equation modeling to reveal the belief structure underlying DUIC behavior.","limitations":"Cross-sectional design limits causal inference; self-reported DUIC behavior may be underreported; beliefs measured at one time point may not reflect behavior change over time."},{"rthcId":"RTHC-03508","title":"Patterns of brain function associated with cannabis cue-reactivity in regular cannabis users: a systematic review of fMRI studies.","authors":"Sehl, Hannah; Terrett, Gill; Greenwood, Lisa-Marie; Kowalczyk, Magdalena; Thomson, Hannah; Poudel, Govinda; Manning, Victoria; Lorenzetti, Valentina","year":2021,"journal":"Psychopharmacology, 238(10), 2709-2728","doi":"10.1007/s00213-021-05973-x","pmid":"34505940","tags":["addiction","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 18 studies involving 918 participants, cannabis users showed greater brain activation to cannabis cues versus neutral stimuli in the striatum, prefrontal cortex (anterior cingulate, middle frontal), and parietal cortex (posterior cingulate/precuneus), with preliminary links between craving and activity in the amygdala, striatum, and orbitofrontal cortex.","whyItMatters":"Understanding which brain regions respond to cannabis cues helps explain why regular users experience cravings and may have difficulty quitting, and could point to neurobiological targets for addiction treatment.","specificNumbers":"18 studies; 918 participants (340 female); aged 16-38; 603 regular cannabis users; 315 controls; consistent activation in striatum, prefrontal cortex, and parietal cortex.","methodology":"PRISMA-guided systematic review of 18 fMRI cue-reactivity studies (pre-registered in PROSPERO) examining brain function in cannabis users exposed to cannabis versus neutral stimuli.","limitations":"Heterogeneity in study designs and cannabis use definitions; relatively small individual study samples; limited longitudinal data on whether cue-reactivity predicts relapse."},{"rthcId":"RTHC-03509","title":"The relationship between alcohol and cannabis use with nonsuicidal self-injury among adolescent inpatients: Examining the 90 days prior to psychiatric hospitalization.","authors":"Sellers, Christina M; Díaz-Valdés, Antonia; Oliver, Michelle M; Simon, Kevin M; O'Brien, Kimberly H McManama","year":2021,"journal":"Addictive behaviors, 114, 106759","doi":"10.1016/j.addbeh.2020.106759","pmid":"33338906","tags":["youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"While neither cannabis nor alcohol use independently predicted nonsuicidal self-injury (NSSI) on a daily level, co-occurring alcohol and cannabis use on the same day increased the odds of NSSI by 30.5 times (OR=30.5, p<0.05) in the 90 days prior to hospitalization.","whyItMatters":"The dramatic interaction between alcohol and cannabis for self-harm risk suggests that polysubstance use, not either substance alone, may be a critical warning sign in suicidal adolescents.","specificNumbers":"71 adolescents; 75% female; mean age 15.79; suicide planning OR=4.47 for NSSI; suicidal ideation OR=10.09 for NSSI; co-occurring alcohol+cannabis use OR=30.5 for NSSI (p<0.05); neither substance independently significant.","methodology":"Mixed effect models analyzing daily trajectories of alcohol use, cannabis use, suicide planning, and NSSI over the 90 days prior to psychiatric hospitalization in 71 adolescents (75% female, mean age 15.79).","limitations":"Small sample size (71 adolescents); all participants had used alcohol, limiting generalizability; retrospective daily recall subject to memory bias; hospitalized sample may not represent community adolescents."},{"rthcId":"RTHC-03510","title":"Manipulating Pharmacodynamic Efficacy with Agonist + Antagonist Mixtures: In Vitro and In Vivo Studies with Opioids and Cannabinoids.","authors":"Selley, D E; Banks, M L; Diester, C M; Jali, A M; Legakis, L P; Santos, E J; Negus, S S","year":2021,"journal":"The Journal of pharmacology and experimental therapeutics, 376(3), 374-384","doi":"10.1124/jpet.120.000349","pmid":"33443077","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03511","title":"The Novel Monoacylglycerol Lipase Inhibitor MJN110 Suppresses Neuroinflammation, Normalizes Synaptic Composition and Improves Behavioral Performance in the Repetitive Traumatic Brain Injury Mouse Model.","authors":"Selvaraj, Prabhuanand; Tanaka, Mikiei; Wen, Jie; Zhang, Yumin","year":2021,"journal":"Cells, 10(12)","doi":"10.3390/cells10123454","pmid":"34943962","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03512","title":"Cannabidiol selectively modulates interleukin (IL)-1β and IL-6 production in toll-like receptor activated human peripheral blood monocytes.","authors":"Sermet, Sera; Li, Jinpeng; Bach, Anthony; Crawford, Robert B; Kaminski, Norbert E","year":2021,"journal":"Toxicology, 464, 153016","doi":"10.1016/j.tox.2021.153016","pmid":"34740670","tags":["cbd","inflammation"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBD (0.5-10 μM) significantly suppressed IL-1β secretion across most toll-like receptor pathways and modulated IL-6 production, while 11 other immune mediators remained largely unaffected, revealing a highly selective anti-inflammatory profile.","whyItMatters":"The finding that CBD's anti-inflammatory effects are selective rather than broadly immunosuppressive helps explain why CBD may reduce inflammation without the widespread immune suppression seen with conventional anti-inflammatory drugs.","specificNumbers":"CBD tested at 0.5-10 μM; 9 toll-like receptors tested; 13 immune mediators measured; significant suppression of IL-1β through most TLRs (except TLR3 and TLR8); significant modulation of IL-6 through most TLRs (except TLR1 and TLR3); 11 other mediators largely unaffected.","methodology":"In vitro study treating human primary monocytes activated through each of nine toll-like receptors with CBD at multiple concentrations, measuring secretion of 13 immune mediators.","limitations":"In vitro study may not reflect in vivo effects; CBD concentrations tested may not correspond to levels achievable through oral consumption; monocytes are only one component of the immune system."},{"rthcId":"RTHC-03513","title":"Genetic deletion of dopamine D1 receptors increases the sensitivity to cannabinoid CB1 receptor antagonist-precipitated withdrawal when compared with wild-type littermates: studies in female mice repeatedly exposed to the Spice cannabinoid HU-210.","authors":"Serrano, Antonia; Vadas, Evelyn; Ferrer, Belen; Bilbao, Ainhoa; Granado, Noelia; Suárez, Juan; Pavon, Francisco Javier; Moratalla, Rosario; Rodríguez de Fonseca, Fernando","year":2021,"journal":"Psychopharmacology, 238(2), 551-557","doi":"10.1007/s00213-020-05704-8","pmid":"33410990","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03514","title":"Cannabis and driving ability.","authors":"Sevigny, Eric L","year":2021,"journal":"Current opinion in psychology, 38, 75-79","doi":"10.1016/j.copsyc.2021.03.003","pmid":"33839427","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03515","title":"The Management of Cancer Symptoms and Treatment-Induced Side Effects With Cannabis or Cannabinoids.","authors":"Sexton, Michelle; Garcia, Jose M; Jatoi, Aminah; Clark, Carey S; Wallace, Mark S","year":2021,"journal":"Journal of the National Cancer Institute. Monographs, 2021(58), 86-98","doi":"10.1093/jncimonographs/lgab011","pmid":"34850897","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03516","title":"Application of medical cannabis in unstable angina and coronary artery disease: A case report.","authors":"Shaffer, Brian L; Davis, Garrison M; Incitti, Marc A; Piper, Brian J; Entler, Brian V","year":2021,"journal":"Medicine, 100(11), e25172","doi":"10.1097/MD.0000000000025172","pmid":"33726006","tags":["medical-cannabis","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"After failing all first- and second-line cardiac medications and morphine for unstable angina, a patient using edible 1:1 CBD:THC medical cannabis reported reduced frequency and severity of angina pain, discontinued long-term morphine, and showed improved functional capacity on exercise tolerance tests.","whyItMatters":"For patients with refractory angina who have exhausted conventional treatment options, this case raises the possibility that cannabis may offer supplementary pain relief, though controlled studies are needed.","specificNumbers":"63-year-old male; 22-year cardiac history; inoperable triple-vessel CAD; 6 years of progressive unstable angina despite medical management; 1:1 CBD:THC edible; ceased long-term morphine; improved exercise tolerance test results.","methodology":"Single case report of a 63-year-old male with complex cardiac history and inoperable triple-vessel coronary artery disease treated with edible medical cannabis in conjunction with standard cardiac care.","limitations":"Single case report cannot establish efficacy or safety; placebo effect cannot be ruled out; cannabis carries its own cardiovascular risks; may not generalize to other patients."},{"rthcId":"RTHC-03517","title":"Do neurocognitive functions in cannabis induced psychosis groups differ from schizophrenia with cannabis use? A controlled cross-sectional study.","authors":"Shah, Raghav; Ghosh, Abhishek; Avasthi, Ajit; Nehra, Ritu; Ahuja, Chirag K; Khandelwal, Niranjan","year":2021,"journal":"International journal of psychiatry in clinical practice, 25(3), 283-291","doi":"10.1080/13651501.2021.1912356","pmid":"33856944","tags":["psychosis","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"With 20 matched participants per group, cannabis-induced psychosis patients performed significantly better than schizophrenia-with-cannabis patients on general intelligence and attention tests, and showed cognitive deficits only in some executive function domains compared to healthy controls.","whyItMatters":"If cannabis-induced psychosis and schizophrenia produce different cognitive profiles despite similar cannabis exposure, it suggests they may be distinct conditions with different underlying neurobiology rather than points on a single spectrum.","specificNumbers":"20 participants per group (60 total); no significant differences in cannabis exposure between CIP and SZC groups; CIP performed significantly better than SZC on intelligence and attention; SZC impaired on all cognitive domains vs controls; CIP impaired only on some executive function domains vs controls.","methodology":"Cross-sectional study comparing 20 cannabis-induced psychosis patients, 20 schizophrenia-with-cannabis patients, and 20 healthy controls matched on age, education, and handedness, using standardized neurocognitive batteries.","limitations":"Small sample size (20 per group); cross-sectional design; diagnostic distinction between CIP and SZC can be clinically challenging; results may not generalize across populations."},{"rthcId":"RTHC-03518","title":"Emerging role of cannabinoids and synthetic cannabinoid receptor 1/cannabinoid receptor 2 receptor agonists in cancer treatment and chemotherapy-associated cancer management.","authors":"Shah, Siddharth A; Gupta, Anand Shyamlal; Kumar, Piyush","year":2021,"journal":"Journal of cancer research and therapeutics, 17(1), 1-9","doi":"10.4103/jcrt.JCRT_488_18","pmid":"33723124","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03519","title":"Cannabis policies in Canada: How will we know which is best?","authors":"Shanahan, Marian; Cyrenne, Philippe","year":2021,"journal":"The International journal on drug policy, 91, 102556","doi":"10.1016/j.drugpo.2019.09.004","pmid":"31563287","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03520","title":"Why Switch? - Motivations for Self-Substitution of Illegal Drugs.","authors":"Shapira, Barak; Berkovitz, Ronny; Rosca, Paola; Lev-Ran, Shaul; Kaptsan, Alexander; Neumark, Yehuda","year":2021,"journal":"Substance use & misuse, 56(5), 627-638","doi":"10.1080/10826084.2021.1887246","pmid":"33663337","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03521","title":"Cannabis-induced psychosis masquerading schizophrenia or vice-versa? A diagnostic dilemma.","authors":"Sharma, Rachit; Shah, Ayushma","year":2021,"journal":"Industrial psychiatry journal, 30(Suppl 1), S322-S324","doi":"10.4103/0972-6748.328842","pmid":"34908722","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03522","title":"Association of Racial Disparity of Cannabis Possession Arrests Among Adults and Youths With Statewide Cannabis Decriminalization and Legalization.","authors":"Sheehan, Brynn E; Grucza, Richard A; Plunk, Andrew D","year":2021,"journal":"JAMA health forum, 2(10), e213435","doi":"10.1001/jamahealthforum.2021.3435","pmid":"35977162","tags":["legalization"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"Using arrest data from 43 states (2000-2019), legalization and decriminalization both substantially reduced cannabis arrests for Black and White adults and youth, but racial disparities in arrest ratios persisted over time, while states without policy changes saw increasing disparities.","whyItMatters":"While legalization dramatically reduced absolute numbers of cannabis arrests for all racial groups, the persistent disparity gap suggests that policy change alone is insufficient to address racial inequity in enforcement.","specificNumbers":"43 states analyzed; 2008-2019 comparison; legalization: 561 fewer arrests/100K for Black adults, 195 fewer for White adults; decriminalization: 448.6 fewer for Black, 117.1 fewer for White adults; no-change states: only 47.5 fewer for Black, 33.0 fewer for White adults; racial disparities persisted in all categories.","methodology":"Case-control event-study analysis using Uniform Crime Reporting Program arrest data and SEER population data from 43 U.S. states (2000-2019), comparing pre- and post-implementation differences in arrest rates across legalization, decriminalization, and no-change states.","limitations":"Arrest data may not capture all enforcement actions; state-level analysis may mask county or city-level variation; cannot control for all confounders affecting arrest patterns; UCR data has known reporting limitations."},{"rthcId":"RTHC-03523","title":"Compliance With Cannabis Act Regulations Regarding Online Promotion Among Canadian Commercial Cannabis-Licensed Firms.","authors":"Sheikhan, Natasha Y; Pinto, Ashlyn M; Nowak, Dominik A; Abolhassani, Farbod; Lefebvre, Patrick; Duh, Mei Sheng; Witek, Theodore J","year":2021,"journal":"JAMA network open, 4(7), e2116551","doi":"10.1001/jamanetworkopen.2021.16551","pmid":"34251442","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 211 licensed firms with online platforms, 86.3% had at least one promotion violation. Facebook (RR=1.24) and Instagram (RR=1.19) had significantly higher violation rates than websites. The most common violations were lack of age restrictions, brand glamorization, and omission of risk information.","whyItMatters":"If the vast majority of licensed cannabis companies are violating promotion rules, particularly on social media where youth are present, it suggests a significant gap between regulatory intent and actual enforcement.","specificNumbers":"261 licensed firms; 211 (80.8%) had online presence; 86.3% had at least 1 violation; Facebook had 14.76x higher odds of lacking age restrictions vs websites; Instagram had 2.90x higher odds of glamorization; most common violations: lack of age restrictions, brand glamorization, omission of risk information.","methodology":"Cross-sectional evaluation of online platforms (websites, Facebook, Instagram, Twitter) of 261 Canadian cannabis-licensed firms (October 2019-March 2020), assessing compliance with Cannabis Act promotion regulations.","limitations":"Data from a single six-month period; violation classifications may involve subjective judgment; rapidly evolving social media landscape; does not measure actual impact on youth exposure."},{"rthcId":"RTHC-03524","title":"Density of medical and recreational cannabis outlets: racial/ethnic differences in the associations with young adult intentions to use cannabis, e-cigarettes, and cannabis mixed with tobacco/nicotine.","authors":"Shih, Regina A; Tucker, Joan S; Pedersen, Eric R; Seelam, Rachana; Dunbar, Michael S; Kofner, Aaron; Firth, Caislin; D'Amico, Elizabeth J","year":2021,"journal":"Journal of cannabis research, 3(1), 28","doi":"10.1186/s42238-021-00084-y","pmid":"34243820","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"While outlet density showed no overall association with use intentions, stratified analyses revealed that White young adults near more recreational retailers had stronger co-use intentions, while Hispanic young adults near more medical dispensaries had lower e-cigarette use intentions.","whyItMatters":"The finding that cannabis outlet density affects use intentions differently across racial/ethnic groups suggests that one-size-fits-all prevention strategies may miss important subgroup-specific risks.","specificNumbers":"604 young adults; mean age 20.9; Los Angeles County post-legalization; density within 5 miles measured; no overall significant association; White young adults: more RCRs associated with stronger co-use intentions; Hispanic young adults: more MCDs associated with lower e-cigarette intentions.","methodology":"Cross-sectional survey of 604 young adults aged 18-23 in Los Angeles County (2018), with outlet density measured as number of medical dispensaries, recreational retailers, and all outlets within 5 miles of respondents' homes.","limitations":"Cross-sectional design; self-reported intentions may not predict actual behavior; limited to one metropolitan area; racial/ethnic categories are broad."},{"rthcId":"RTHC-03525","title":"Preoperative Considerations for Teenagers Undergoing Orthopaedic Surgery: VTE Prevention, Mental Health Assessment, Vaping, and Drug Addiction.","authors":"Shore, Benjamin J; Flaugh, Rachel; Shannon, Brett A; Curran, Patrick; Hogue, Grant","year":2021,"journal":"Journal of pediatric orthopedics, 41(Suppl 1), S64-S69","doi":"10.1097/BPO.0000000000001764","pmid":"34096540","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03526","title":"Chlorpyrifos and Δ9 Tetrahydrocannabinol exposure and effects on parameters associated with the endocannabinoid system and risk factors for obesity.","authors":"Silva, Marilyn H","year":2021,"journal":"Current research in toxicology, 2, 296-308","doi":"10.1016/j.crtox.2021.08.002","pmid":"34467221","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03527","title":"Two-center experience of cannabidiol use in adults with Dravet syndrome.","authors":"Silvennoinen, Katri; Ritter, Laura Mantoan; Nashef, Lina; Hudgell, Kirsty; Balestrini, Simona; Sisodiya, Sanjay M; Sidhu, Meneka K","year":2021,"journal":"Seizure, 91, 5-8","doi":"10.1016/j.seizure.2021.05.014","pmid":"34052628","tags":["cbd","epilepsy"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Among 17 evaluable adults with Dravet syndrome treated with CBD (up to 20 mg/kg), 3 (17.6%) achieved greater than 30% reduction in convulsive seizures (range 87.5-100%), while adverse effects occurred in all patients, with transaminitis in 52.9% and behavioral side effects leading to discontinuation in 16.7%.","whyItMatters":"Most CBD epilepsy research focuses on children. This study provides rare data on CBD effectiveness in adults with Dravet syndrome, where outcomes appear more modest and side effects more common than in pediatric studies.","specificNumbers":"18 adults (7 female); median age 27.5 years; median follow-up 176 days; 17.6% had >30% seizure reduction; transaminitis in 52.9%; behavioral AEs led to discontinuation in 16.7%; 7/18 stopped for lack of effect; 8/18 continue treatment; 41.2% showed physician-rated improvement.","methodology":"Retrospective real-world study of 18 adults with genetically confirmed Dravet syndrome who received CBD through the GW Pharma early access programme at two UK neurology centers, with median follow-up of 176 days.","limitations":"Small sample size; no control group; retrospective design; early access programme may attract patients with more severe disease; median follow-up under 6 months."},{"rthcId":"RTHC-03528","title":"Cannabinoid receptor Type 1 densities reflect social organization in Microtus.","authors":"Simmons, Trenton C; Freeman, Sara M; Lackey, Nicholas S; Dreyer, Brooke K; Manoli, Devanand S; Bales, Karen L","year":2021,"journal":"The Journal of comparative neurology, 529(5), 1004-1017","doi":"10.1002/cne.24996","pmid":"33460115","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03529","title":"Effects of cannabis ingestion on endometriosis-associated pelvic pain and related symptoms.","authors":"Sinclair, Justin; Collett, Laura; Abbott, Jason; Pate, David W; Sarris, Jerome; Armour, Mike","year":2021,"journal":"PloS one, 16(10), e0258940","doi":"10.1371/journal.pone.0258940","pmid":"34699540","tags":["medical-cannabis","pain"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Across 16,193 tracked cannabis sessions, pain was the most common symptom treated (57.3%) with inhalation as the preferred method (67.4%). Inhaled forms showed higher efficacy for pain relief, while oral forms were superior for mood and gastrointestinal symptoms. GI symptoms, though less commonly targeted, showed the greatest self-reported improvement.","whyItMatters":"Endometriosis affects roughly 10% of reproductive-age women, and current treatments often have significant side effects. This large dataset of real-world cannabis use provides the most detailed evidence to date on which forms and methods work best for specific symptoms.","specificNumbers":"252 participants; 16,193 cannabis sessions; pain most common target (57.3%); inhalation most common method (67.4%); median inhaled dose: 9 inhalations; median oral dose: 1 mg/mL; GI symptoms showed greatest improvement; THC:CBD ratio had statistically significant but clinically small differential effect.","methodology":"Retrospective electronic record-based cohort study using data from the Strainprint mobile app, analyzing self-reported cannabis efficacy across symptom clusters in 252 users with endometriosis (April 2017-February 2020).","limitations":"Self-reported data from an app without clinical verification; no placebo control; self-selection bias among app users; retrospective design; cannot rule out placebo effects."},{"rthcId":"RTHC-03530","title":"Recreational cannabis use causing non-ischaemic cardiomyopathy and cardioembolism in a young adult.","authors":"Singh, Budha O; Panda, Prasan Kumar; Walia, Rohit","year":2021,"journal":"BMJ case reports, 14(6)","doi":"10.1136/bcr-2021-243193","pmid":"34078626","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A young recreational cannabis and tobacco smoker developed progressive breathlessness over 4 months, then acute left-sided hemiparesis from a right middle cerebral artery infarct, along with left forearm gangrene from radial artery thrombosis. Cardiac MRI revealed non-ischemic dilated cardiomyopathy.","whyItMatters":"While cannabis cardiovascular risks are often discussed in the context of older adults, this case highlights that severe cardiac and vascular complications can occur in young people who use cannabis recreationally.","specificNumbers":"Young male patient; 4 months progressive breathlessness; 2 months cough; acute left hemiparesis with facial palsy; right middle cerebral artery territory infarct; left radial artery thrombosis with forearm gangrene requiring amputation; non-ischemic dilated cardiomyopathy on cardiac MRI.","methodology":"Single case report describing a young male recreational cannabis smoker who presented with decompensated heart failure, cardioembolic stroke, and peripheral arterial thrombosis.","limitations":"Single case report cannot establish causation; concurrent tobacco use makes it impossible to attribute effects to cannabis alone; underlying predisposition cannot be ruled out."},{"rthcId":"RTHC-03531","title":"Adolescent exposure to delta-9-tetrahydrocannabinol and ethanol heightens sensitivity to fear stimuli.","authors":"Smiley, Cora E; Saleh, Heyam K; Nimchuk, Katherine E; Garcia-Keller, Constanza; Gass, Justin T","year":2021,"journal":"Behavioural brain research, 415, 113517","doi":"10.1016/j.bbr.2021.113517","pmid":"34389427","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03532","title":"Cannabidiol reduces withdrawal symptoms in nicotine-dependent rats.","authors":"Smith, Lauren C; Tieu, Lani; Suhandynata, Raymond T; Boomhower, Brent; Hoffman, Melissa; Sepulveda, Yadira; Carrette, Lieselot L G; Momper, Jeremiah D; Fitzgerald, Robert L; Hanham, Kate; Dowling, Joseph; Kallupi, Marsida; George, Olivier","year":2021,"journal":"Psychopharmacology, 238(8), 2201-2211","doi":"10.1007/s00213-021-05845-4","pmid":"33909102","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03533","title":"Cultural conformity and cannabis care in the wake of intractable pediatric epilepsy.","authors":"Sobo, Elisa J","year":2021,"journal":"Anthropology & medicine, 28(2), 205-222","doi":"10.1080/13648470.2021.1893583","pmid":"34075822","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03534","title":"Cannabis use is associated with reduced risk of exposure to fentanyl among people on opioid agonist therapy during a community-wide overdose crisis.","authors":"Socías, M Eugenia; Choi, JinCheol; Lake, Stephanie; Wood, Evan; Valleriani, Jenna; Hayashi, Kanna; Kerr, Thomas; Milloy, M-J","year":2021,"journal":"Drug and alcohol dependence, 219, 108420","doi":"10.1016/j.drugalcdep.2020.108420","pmid":"33342591","tags":["harm-reduction","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"In a prospective cohort of 819 participants on opioid agonist therapy (OAT) contributing 1,989 observations (2016-2018), cannabis use (detected by urine testing) was independently associated with a 9% reduced likelihood of fentanyl exposure (adjusted prevalence ratio=0.91, 95% CI: 0.83-0.99).","whyItMatters":"During the ongoing opioid overdose crisis driven by illicitly manufactured fentanyl, any intervention that reduces fentanyl exposure among high-risk individuals could save lives. This study suggests cannabis may play a harm-reduction role for people on OAT.","specificNumbers":"819 participants on OAT; 1,989 observations; fentanyl detected in 53% at baseline; cannabis users had lower fentanyl prevalence (47% vs 56%, p=0.028); adjusted PR=0.91 (95% CI: 0.83-0.99).","methodology":"Generalized linear mixed-effects modeling using data from two community-recruited prospective cohorts of people who use drugs in Vancouver, Canada (2016-2018), with both cannabis use and fentanyl exposure verified by urine drug testing.","limitations":"Observational design cannot prove causation; modest effect size; potential unmeasured confounders; urine testing captures recent use but not patterns; specific to Vancouver's drug supply."},{"rthcId":"RTHC-03535","title":"Impact of cannabis use on outcomes of patients admitted to an involuntary psychiatric unit: A retrospective cohort study.","authors":"Soler, Stephan; Montout, Christine; Pepin, Berengere; Abbar, Mocrane; Mura, Thibault; Lopez-Castroman, Jorge","year":2021,"journal":"Journal of psychiatric research, 138, 507-513","doi":"10.1016/j.jpsychires.2021.04.024","pmid":"33975067","tags":["psychosis","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 370 involuntarily admitted psychiatric patients, 130 tested THC-positive. In adjusted analyses, THC-positive status was associated with 2.29 times higher odds of one-year readmission (p=0.0082) and nearly double the odds of benzodiazepine prescriptions at discharge (OR=1.93, p=0.02), but not higher antipsychotic prescriptions.","whyItMatters":"The strong association between cannabis use and psychiatric readmission suggests that cannabis-using patients may benefit from targeted management strategies that address substance use alongside mental health treatment.","specificNumbers":"370 patients; 130 THC-positive (35%); THC+ patients were predominantly young men; adjusted OR for one-year readmission: 2.29 (p=0.0082); adjusted OR for benzodiazepine prescription at discharge: 1.93 (p=0.02); no significant difference in antipsychotic prescriptions.","methodology":"Retrospective cohort study of all patients admitted to one secure adult psychiatry unit in France in 2016 (n=370), comparing clinical outcomes between THC-positive and THC-negative groups based on urinary drug testing.","limitations":"Single-center study in France; retrospective design; urine testing captures only recent use; cannot determine whether cannabis caused worse outcomes or reflects other risk factors; specific to involuntary admission setting."},{"rthcId":"RTHC-03536","title":"Systematic review and meta-analysis of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators tested for antinociceptive effects in animal models of injury-related or pathological persistent pain.","authors":"Soliman, Nadia; Haroutounian, Simon; Hohmann, Andrea G; Krane, Elliot; Liao, Jing; Macleod, Malcolm; Segelcke, Daniel; Sena, Christopher; Thomas, James; Vollert, Jan; Wever, Kimberley; Alaverdyan, Harutyun; Barakat, Ahmed; Barthlow, Tyler; Bozer, Amber L Harris; Davidson, Alexander; Diaz-delCastillo, Marta; Dolgorukova, Antonina; Ferdousi, Mehnaz I; Healy, Catherine; Hong, Simon; Hopkins, Mary; James, Arul; Leake, Hayley B; Malewicz, Nathalie M; Mansfield, Michael; Mardon, Amelia K; Mattimoe, Darragh; McLoone, Daniel P; Noes-Holt, Gith; Pogatzki-Zahn, Esther M; Power, Emer; Pradier, Bruno; Romanos-Sirakis, Eleny; Segelcke, Astra; Vinagre, Rafael; Yanes, Julio A; Zhang, Jingwen; Zhang, Xue Ying; Finn, David P; Rice, Andrew S C","year":2021,"journal":"Pain, 162(Suppl 1), S26-S44","doi":"10.1097/j.pain.0000000000002269","pmid":"33729209","tags":["pain","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 374 studies testing 171 interventions, selective CB1, CB2, and nonselective cannabinoid agonists (including THC) plus PPAR-alpha agonists significantly reduced pain in both inflammatory and neuropathic models, while FAAH inhibitors, MAGL inhibitors, and CBD were effective in neuropathic but showed mixed results in inflammatory pain.","whyItMatters":"This is the largest systematic evaluation of cannabinoid pain relief in animal models, providing a comprehensive evidence base to guide which cannabinoid approaches are most promising for translation to human clinical trials.","specificNumbers":"374 studies; 171 interventions; 86% used male animals only; CB1, CB2, and nonselective agonists effective across pain models; CBD effective for neuropathic but mixed for inflammatory pain; FAAH and MAGL inhibitors effective for neuropathic pain; low reporting of bias mitigation measures.","methodology":"PRISMA-compliant systematic review and meta-analysis of 374 rodent studies (searched April 2019), using crowd science and machine learning for study identification, with standardized mean difference effect sizes and random-effects modeling.","limitations":"Animal models may not predict human efficacy; 86% of studies used only male animals; low reporting of bias mitigation criteria makes risk of bias unclear; measures limited to evoked limb withdrawal."},{"rthcId":"RTHC-03537","title":"Risk and protective factors for cannabis, cocaine, and opioid use disorders: An umbrella review of meta-analyses of observational studies.","authors":"Solmi, Marco; Dragioti, Elena; Croatto, Giovanni; Radua, Joaquim; Borgwardt, Stefan; Carvalho, Andrè F; Demurtas, Jacopo; Mosina, Anna; Kurotschka, Peter Konstantin; Shin, Jae Il; Fusar-Poli, Paolo","year":2021,"journal":"Neuroscience and biobehavioral reviews, 126, 243-251","doi":"10.1016/j.neubiorev.2021.03.014","pmid":"33737104","tags":["addiction","genetics"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Of 19 associations between 12 risk/protective factors and substance use disorders, none reached \"convincing\" evidence. Sensitivity analyses found convincing evidence only for antisocial behavior predicting cannabis use disorder (OR=3.34, 95% CI: 2.53-4.41). Smoking had highly suggestive evidence for nonmedical prescription opioid use (OR=3.07).","whyItMatters":"Despite many claimed risk factors for substance use disorders, this rigorous evaluation shows that very few have truly strong evidence, which should guide prevention efforts toward the most well-supported targets.","specificNumbers":"3,072 initial references; 5 meta-analyses included; 19 associations examined; 12 risk/protective factors; cases: 4,539; total N: over 1.1 billion; 84% of associations statistically significant but none convincing; antisocial behavior and CUD OR=3.34 in sensitivity analysis.","methodology":"Umbrella review of meta-analyses of observational studies from PubMed-MEDLINE/PsycInfo (through September 2020), grading evidence credibility from \"not significant\" to \"convincing\" using established criteria, with quality assessment via AMSTAR-2.","limitations":"Limited to published meta-analyses which may have their own quality issues; 40% of included meta-analyses rated critically low quality; cannot examine interactions between risk factors."},{"rthcId":"RTHC-03538","title":"Cannabis Use in Older Adults: A Perspective.","authors":"Solomon, Haley V; Greenstein, Aaron P; DeLisi, Lynn E","year":2021,"journal":"Harvard review of psychiatry, 29(3), 225-233","doi":"10.1097/HRP.0000000000000289","pmid":"33660625","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03539","title":"Endocannabinoid system in the neurodevelopment of GABAergic interneurons: implications for neurological and psychiatric disorders.","authors":"Song, Chang-Geng; Kang, Xin; Yang, Fang; Du, Wan-Qing; Zhang, Jia-Jia; Liu, Long; Kang, Jun-Jun; Jia, Ning; Yue, Hui; Fan, Lu-Yu; Wu, Sheng-Xi; Jiang, Wen; Gao, Fang","year":2021,"journal":"Reviews in the neurosciences, 32(8), 803-831","doi":"10.1515/revneuro-2020-0134","pmid":"33781002","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03540","title":"Granulocyte Colony-Stimulating Factor Enhances Brain Repair Following Traumatic Brain Injury Without Requiring Activation of Cannabinoid Receptors.","authors":"Song, Shijie; Kong, Xiaoyuan; Borlongan, Cesar; Sava, Vasyl; Sanchez-Ramos, Juan","year":2021,"journal":"Cannabis and cannabinoid research, 6(1), 48-57","doi":"10.1089/can.2019.0090","pmid":"33614952","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03541","title":"The Behavioral Sequelae of Cannabis Use in Healthy People: A Systematic Review.","authors":"Sorkhou, Maryam; Bedder, Rachel H; George, Tony P","year":2021,"journal":"Frontiers in psychiatry, 12, 630247","doi":"10.3389/fpsyt.2021.630247","pmid":"33664685","tags":["cognition","mental-health","psychosis"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Across 124 studies of cannabis effects in people without psychiatric or medical conditions, frequency of use, THC content, age of onset, and cumulative exposure all contributed to adverse behavioral outcomes including impaired cognition, motivation, mood, anxiety, psychosis risk, and psychosocial functioning.","whyItMatters":"By focusing exclusively on healthy individuals, this review isolates the effects of cannabis from pre-existing conditions, strengthening the case that cannabis itself contributes to these adverse outcomes rather than simply being associated with them.","specificNumbers":"2,870 studies screened; 124 included; effects identified across cognition, motivation, impulsivity, mood, anxiety, psychosis, intelligence, and psychosocial functioning; strongest evidence for psychosis and psychosocial functioning; THC (not CBD) content was a key moderator.","methodology":"PRISMA-guided systematic review of 124 cross-sectional and longitudinal studies (1990-2020) from PubMed and PsycInfo examining cannabis-related adverse behavioral outcomes in subjects without psychiatric or medical comorbidities.","limitations":"Systematic review without meta-analysis; heterogeneity in study designs and cannabis exposure measures; cannot fully control for residual confounding even in \"healthy\" samples; publication bias possible."},{"rthcId":"RTHC-03542","title":"Introduction to emerging industrial applications of cannabis (Cannabis sativa L.).","authors":"Sorrentino, Giuseppe","year":2021,"journal":"Rendiconti Lincei. Scienze fisiche e naturali, 32(2), 233-243","doi":"10.1007/s12210-021-00979-1","pmid":"33777341","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03543","title":"Does Cannabis, Cocaine and Alcohol Use Impact Differently on Adult Attention Deficit/Hyperactivity Disorder Clinical Picture?","authors":"Spera, Vincenza; Pallucchini, Alessandro; Carli, Marco; Maiello, Marco; Maremmani, Angelo G I; Perugi, Giulio; Maremmani, Icro","year":2021,"journal":"Journal of clinical medicine, 10(7)","doi":"10.3390/jcm10071481","pmid":"33918432","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Comparing ADHD patients with two substance use patterns, type 1 (stimulants/alcohol) showed greater hyperactivity/impulsivity and more legal problems, while type 2 (cannabis) showed more severe general psychopathology. Both dual-diagnosis types showed higher impulsiveness than ADHD patients without substance use.","whyItMatters":"Recognizing that different substances interact differently with ADHD symptoms could lead to more tailored treatment approaches for the large proportion of ADHD patients who also have substance use disorders.","specificNumbers":"Type 1 (stimulants/alcohol) vs type 2 (cannabis) vs non-dual-diagnosis ADHD; non-DD more frequently inattentive subtype; type 1 had greater hyperactivity/impulsivity; type 2 had more severe general psychopathology; both DD types more impulsive than non-DD; type 1 had more legal problems.","methodology":"Cross-sectional comparison of demographic, clinical, and symptom features between dual-diagnosis ADHD patients classified by substance use typology (type 1: stimulants/alcohol; type 2: cannabinoids) and ADHD patients without substance use disorders.","limitations":"Cross-sectional design cannot determine causation; substance use classification may oversimplify complex patterns; sample sizes not specified in abstract; self-reported substance use."},{"rthcId":"RTHC-03544","title":"Assessment of cognitive and psychomotor impairment, subjective effects, and blood THC concentrations following acute administration of oral and vaporized cannabis.","authors":"Spindle, Tory R; Martin, Erin L; Grabenauer, Megan; Woodward, Thomas; Milburn, Michael A; Vandrey, Ryan","year":2021,"journal":"Journal of psychopharmacology (Oxford, England), 35(7), 786-803","doi":"10.1177/02698811211021583","pmid":"34049452","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"High-dose oral and vaporized cannabis impaired cognitive and psychomotor performance, but field sobriety tests showed little sensitivity to cannabis-induced impairment. The DRUID app was the most sensitive test, detecting significant differences from placebo for both administration routes. Blood THC levels returned to baseline before impairment resolved.","whyItMatters":"Current roadside methods for detecting cannabis impairment are inadequate. Blood THC levels and field sobriety tests both fail to reliably identify when someone is actually impaired, creating significant public safety and legal challenges.","specificNumbers":"20 participants (10 men, 10 women); 6 sessions; low doses produced subjective effects but no measurable impairment; high doses impaired performance; DRUID detected impairment at both routes; women showed more DRUID impairment at high vaporized dose; blood THC returned to baseline before impairment resolved.","methodology":"Double-blind, placebo-controlled, six-session outpatient study with 20 infrequent cannabis users (10 men, 10 women) receiving three oral doses (0, 10, 25 mg THC brownies) and three vaporized doses (0, 5, 20 mg THC), tested with computerized tasks, DRUID app, and field sobriety tests.","limitations":"Small sample size (20 participants); infrequent users only (tolerance effects not captured); lab setting differs from real-world driving; limited dose range; DRUID validation still early."},{"rthcId":"RTHC-03545","title":"Brain imaging of cannabinoid type I (CB1 ) receptors in women with cannabis use disorder and male and female healthy controls.","authors":"Spindle, Tory R; Kuwabara, Hiroto; Eversole, Alisha; Nandi, Ayon; Vandrey, Ryan; Antoine, Denis G; Umbricht, Annie; Guarda, Angela S; Wong, Dean F; Weerts, Elise M","year":2021,"journal":"Addiction biology, 26(6), e13061","doi":"10.1111/adb.13061","pmid":"34028926","tags":["addiction","neuroscience","sex-differences"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Females with CUD (n=10) showed significantly lower CB1 receptor availability than female healthy controls (n=10) in the hippocampus, amygdala, cingulate, and insula. Among healthy controls, females had significantly higher CB1 availability than males (n=7) across all brain regions examined.","whyItMatters":"This is one of the first PET studies of CB1 receptors in women with cannabis use disorder. The finding that women start with higher CB1 availability but show the same pattern of downregulation as men raises questions about whether sex-specific treatment approaches are needed.","specificNumbers":"10 women with CUD; 10 female healthy controls; 7 male healthy controls; significant CB1 reduction in hippocampus, amygdala, cingulate, and insula in CUD women; amygdala CB1 negatively correlated with anger/hostility during abstinence; females had higher CB1 than males across all regions.","methodology":"PET imaging study using [11C]OMAR radiotracer comparing CB1 receptor availability between women with cannabis use disorder (after 3 days monitored abstinence) and age/BMI-matched female non-users, plus comparison between male and female healthy controls.","limitations":"Very small sample sizes; only 3 days of monitored abstinence (may not represent full receptor recovery); cross-sectional design cannot determine if lower CB1 preceded or resulted from cannabis use; limited to one radiotracer."},{"rthcId":"RTHC-03546","title":"Effect of acute and subchronic administration of (R)-WIN55,212-2 induced neuroprotection and anti inflammatory actions in rat retina: CB1 and CB2 receptor involvement.","authors":"Spyridakos, Dimitris; Papadogkonaki, Sofia; Dionysopoulou, Stavroula; Mastrodimou, Niki; Polioudaki, Hara; Thermos, Kyriaki","year":2021,"journal":"Neurochemistry international, 142, 104907","doi":"10.1016/j.neuint.2020.104907","pmid":"33220388","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03547","title":"The Effect of Marijuana on the Incidence and Evolution of Male Infertility: A Systematic Review.","authors":"Srinivasan, Mirra; Hamouda, Ranim K; Ambedkar, Baba; Arzoun, Hadia I; Sahib, Isra; Fondeur, Jack; Escudero Mendez, Lisbeth; Mohammed, Lubna","year":2021,"journal":"Cureus, 13(12), e20119","doi":"10.7759/cureus.20119","pmid":"34984155","tags":["pregnancy","sex-differences"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 15 eligible studies, marijuana use was associated with reduced sperm count, concentration, motility, morphology, capacitation, and viability. Hormone changes in testosterone, LH, and FSH were also noted but could not be conclusively linked to fertility outcomes.","whyItMatters":"As cannabis use increases globally, understanding its impact on male fertility is increasingly important for men trying to conceive and for clinicians advising them.","specificNumbers":"15 eligible studies included; adverse effects observed across sperm count, concentration, motility, morphology, capacitation, and viability; testosterone, LH, and FSH levels potentially affected; organic sexual dysfunction also noted.","methodology":"Systematic review of 15 studies (systematic reviews, cross-sectional, case-control, cohort, and longitudinal designs) published 2010-2021, identified from PubMed, Google Scholar, and other databases, with quality assessment using appropriate appraisal tools.","limitations":"All studies were observational; small sample sizes across multiple geographic locations; potential confounding from other lifestyle factors; no randomized controlled trials."},{"rthcId":"RTHC-03548","title":"Evidence for Use of Cannabinoids in Mood Disorders, Anxiety Disorders, and PTSD: A Systematic Review.","authors":"Stanciu, Corneliu N; Brunette, Mary F; Teja, Nikhil; Budney, Alan J","year":2021,"journal":"Psychiatric services (Washington, D.C.), 72(4), 429-436","doi":"10.1176/appi.ps.202000189","pmid":"33530732","tags":["mental-health","anxiety","depression","ptsd","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 8 identified RCTs, CBD pretreatment showed promise for social anxiety in laboratory settings, but THC showed no benefit for depression and actually worsened anxiety and psychotic symptoms in over 50% of hospitalized depression patients. One small crossover trial found THC reduced PTSD nightmares.","whyItMatters":"Despite widespread use of cannabis for mental health symptoms, this review reveals that the controlled evidence base is remarkably thin, with only 8 small trials across three major diagnostic categories.","specificNumbers":"8 RCTs identified; CBD: 3 studies showed anxiety reduction in social anxiety; THC up to 3 mg/day reduced anxiety in 1 trial but symptoms were already low; THC worsened anxiety/psychotic symptoms in >50% of depression patients; 1 crossover trial of 10 PTSD patients found THC reduced nightmares.","methodology":"Systematic review searching 8 online databases for randomized controlled trials of defined CBD or THC doses in populations with affective disorders, anxiety disorders, or PTSD.","limitations":"Only 8 very small trials identified; heterogeneous designs, doses, and populations; insufficient evidence to draw definitive conclusions about either efficacy or harm."},{"rthcId":"RTHC-03549","title":"Phytocannabinoids and schizophrenia: Focus on adolescence as a critical window of enhanced vulnerability and opportunity for treatment.","authors":"Stark, Tibor; Di Martino, Serena; Drago, Filippo; Wotjak, Carsten T; Micale, Vincenzo","year":2021,"journal":"Pharmacological research, 174, 105938","doi":"10.1016/j.phrs.2021.105938","pmid":"34655773","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03550","title":"Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment.","authors":"Stasiłowicz, Anna; Tomala, Anna; Podolak, Irma; Cielecka-Piontek, Judyta","year":2021,"journal":"International journal of molecular sciences, 22(2)","doi":"10.3390/ijms22020778","pmid":"33466734","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03551","title":"Toxicology of flavoring- and cannabis-containing e-liquids used in electronic delivery systems.","authors":"Stefaniak, Aleksandr B; LeBouf, Ryan F; Ranpara, Anand C; Leonard, Stephen S","year":2021,"journal":"Pharmacology & therapeutics, 224, 107838","doi":"10.1016/j.pharmthera.2021.107838","pmid":"33746051","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03552","title":"Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain.","authors":"Stella, Barbara; Baratta, Francesca; Della Pepa, Carlo; Arpicco, Silvia; Gastaldi, Daniela; Dosio, Franco","year":2021,"journal":"Drugs, 81(13), 1513-1557","doi":"10.1007/s40265-021-01579-x","pmid":"34480749","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03553","title":"Examining motivational pathways from adult attention-deficit/hyperactivity disorder symptoms to cannabis use: Results from a prospective study of veterans.","authors":"Stevens, Angela K; Gunn, Rachel L; Jackson, Kristina M; Borsari, Brian; Metrik, Jane","year":2021,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 35(1), 16-28","doi":"10.1037/adb0000682","pmid":"32881541","tags":["addiction","mental-health","sleep"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Sleep motives mediated the prospective relationship between ADHD symptoms and cannabis use frequency, while coping with negative affect was the only significant mediator of the ADHD-to-cannabis-problems pathway, controlling for demographics, other substance use, and psychopathology.","whyItMatters":"Understanding why people with ADHD use cannabis can guide targeted interventions. Addressing sleep problems in ADHD may reduce cannabis use, while targeting coping motives may prevent cannabis-related problems.","specificNumbers":"361 veterans; 93% male; 80% White; 3 semiannual assessments; sleep motives robustly mediated ADHD-to-cannabis-use path; coping with negative affect was the only significant mediator for cannabis problems.","methodology":"Prospective mediation study of 361 veterans reporting lifetime cannabis use (93% male, 80% White) across three semiannual assessments, using structural equation modeling with zero-inflated negative binomial models.","limitations":"Predominantly male veteran sample limits generalizability; self-reported cannabis use and motives; latent variable modeling may obscure individual variation."},{"rthcId":"RTHC-03554","title":"Cannabis use and metabolic syndrome among clients with first episode psychosis.","authors":"Stiles, Erik; Alcover, Karl C; Stiles, Bryan; Oluwoye, Oladunni; McDonell, Michael G","year":2021,"journal":"Early intervention in psychiatry, 15(4), 1051-1055","doi":"10.1111/eip.13030","pmid":"32881419","tags":["psychosis","cardiovascular"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"In the RAISE-ETP program (n=404), cannabis users had similar baseline metabolic syndrome rates as abstainers but showed lower triglycerides, elevated HDL, and were less likely to develop metabolic syndrome over the study period.","whyItMatters":"Metabolic syndrome is a major concern for psychosis patients on antipsychotics. If cannabis use is associated with lower metabolic risk, understanding the mechanism could lead to new approaches for managing medication side effects.","specificNumbers":"404 participants in RAISE-ETP; similar baseline metabolic syndrome rates; cannabis users had lower triglycerides and higher HDL; cannabis users less likely to develop metabolic syndrome over study period.","methodology":"Retrospective analysis of 404 participants in the Recovery After Initial Schizophrenia Episode-Early Treatment Program (RAISE-ETP), using multiple logistic regression to examine the association between cannabis use and metabolic syndrome.","limitations":"Retrospective design; potential confounders including diet, exercise, and medication adherence; cannabis use was not randomized; cannot determine causal mechanism."},{"rthcId":"RTHC-03555","title":"Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation.","authors":"Stollenwerk, Todd M; Hillard, Cecilia J","year":2021,"journal":"Cells, 10(12)","doi":"10.3390/cells10123503","pmid":"34944011","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03556","title":"Cross-sectional and longitudinal evaluation of cannabidiol (CBD) product use and health among people with epilepsy.","authors":"Strickland, Justin C; Jackson, Heather; Schlienz, Nicolas J; Salpekar, Jay A; Martin, Erin L; Munson, Joel; Bonn-Miller, Marcel O; Vandrey, Ryan","year":2021,"journal":"Epilepsy & behavior : E&B, 122, 108205","doi":"10.1016/j.yebeh.2021.108205","pmid":"34311183","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Artisanal CBD users showed significantly better quality of life, lower psychiatric symptom severity, improved sleep, better medication tolerability, fewer prescription medications, and reduced healthcare utilization compared to controls, both cross-sectionally and longitudinally when participants initiated CBD use.","whyItMatters":"Many epilepsy patients cannot access or afford pharmaceutical CBD (Epidiolex) and turn to artisanal products instead. This study provides the most detailed evaluation of health outcomes in this underserved population.","specificNumbers":"280 artisanal CBD users; 138 controls; 190 with longitudinal follow-up; CBD users reported higher QoL, lower psychiatric symptoms, better sleep; no group difference in seizure control; CBD users used fewer prescription medications and had less healthcare utilization.","methodology":"Cross-sectional and longitudinal observational study of 280 artisanal CBD users and 138 controls with epilepsy, completing web-based assessments with a subset (n=190) providing longitudinal follow-up data.","limitations":"Self-selected participants likely to have positive views of CBD; self-reported outcomes without clinical verification; no seizure difference observed (possibly due to high baseline seizure control in both groups); artisanal product quality and content unverified."},{"rthcId":"RTHC-03557","title":"Disentangling the lasting effects of adolescent cannabinoid exposure.","authors":"Stringfield, Sierra J; Torregrossa, Mary M","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 104, 110067","doi":"10.1016/j.pnpbp.2020.110067","pmid":"32791165","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03558","title":"Intravenous self-administration of delta-9-THC in adolescent rats produces long-lasting alterations in behavior and receptor protein expression.","authors":"Stringfield, Sierra J; Torregrossa, Mary M","year":2021,"journal":"Psychopharmacology, 238(1), 305-319","doi":"10.1007/s00213-020-05684-9","pmid":"33111197","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03559","title":"Management of Cannabinoid Hyperemesis Syndrome: Focus on Capsaicin.","authors":"Stumpf, Janice L; Williams, Lauren D","year":2021,"journal":"Journal of pharmacy practice, 34(5), 786-793","doi":"10.1177/0897190020934289","pmid":"32613883","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03560","title":"Endocannabinoid-Mediated Control of Neural Circuit Excitability and Epileptic Seizures.","authors":"Sugaya, Yuki; Kano, Masanobu","year":2021,"journal":"Frontiers in neural circuits, 15, 781113","doi":"10.3389/fncir.2021.781113","pmid":"35046779","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03561","title":"Cannabis Use and Brain Volume in Adolescent and Young Adult Cannabis Users: Effects Moderated by Sex and Aerobic Fitness.","authors":"Sullivan, Ryan M; Wallace, Alexander L; Wade, Natasha E; Swartz, Ann M; Lisdahl, Krista M","year":2021,"journal":"Journal of the International Neuropsychological Society : JINS, 27(6), 607-620","doi":"10.1017/S135561772100062X","pmid":"34261557","tags":["neuroscience","sex-differences","youth","exercise"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"No overall brain volume differences were found between cannabis users and controls, but sex-by-cannabis interactions revealed that female users had greater frontal and temporal volumes while male users had less volume compared to same-sex controls. Higher aerobic fitness was positively associated with frontal, parietal, cerebellum, and caudate volumes.","whyItMatters":"The sex-specific effects on brain volume may help explain inconsistent findings in the cannabis neuroimaging literature, while the fitness association suggests aerobic exercise could potentially buffer against cannabis-related brain changes.","specificNumbers":"74 participants (36 users, 38 controls); 3 weeks monitored abstinence; sex-by-cannabis interactions in frontal, temporal, and paracentral volumes; female users had greater volume, male users had less; aerobic fitness positively associated with brain volume in multiple regions; abnormal volumes not linked to better cognition.","methodology":"Cross-sectional study of 74 adolescents and young adults (36 cannabis users, 38 controls) who completed 3 weeks of monitored cannabis abstinence, aerobic fitness testing, structural MRI, and neuropsychological testing.","limitations":"Small sample size; cross-sectional design; 3 weeks abstinence may not fully eliminate acute effects; aerobic fitness measured at one time point; directionality of brain volume differences unclear."},{"rthcId":"RTHC-03562","title":"Effect of Cannabinoid 2 Receptor Modulation on the Peripheral Immune Response in Central Nervous System Injury-Induced Immunodeficiency Syndrome.","authors":"Sultana, Saki; Burkovskiy, Ian; Zhou, Juan; Kelly, Melanie M; Lehmann, Christian","year":2021,"journal":"Cannabis and cannabinoid research, 6(4), 327-339","doi":"10.1089/can.2020.0130","pmid":"33998888","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03563","title":"Alterations in Brain Cannabinoid Receptor Levels Are Associated with HIV-Associated Neurocognitive Disorders in the ART Era: Implications for Therapeutic Strategies Targeting the Endocannabinoid System.","authors":"Swinton, Mary K; Sundermann, Erin E; Pedersen, Lauren; Nguyen, Jacques D; Grelotti, David J; Taffe, Michael A; Iudicello, Jennifer E; Fields, Jerel Adam","year":2021,"journal":"Viruses, 13(9)","doi":"10.3390/v13091742","pmid":"34578323","tags":["neuroscience","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Immunoblot analysis showed CB1 and CB2 receptors were differentially expressed in frontal cortices of HAND versus neurocognitively unimpaired HIV-positive brains. CB1 expression negatively correlated with memory and processing speed. In HAND brains, CB1 shifted from neuronal processes to cell bodies and showed increased colocalization with astrocytes.","whyItMatters":"With HIV-associated cognitive disorders persisting despite antiretroviral therapy, identifying endocannabinoid system changes could open new therapeutic targets for the estimated 50% of people with HIV who experience some degree of cognitive impairment.","specificNumbers":"CB1 and CB2 differentially expressed in HAND vs NUI brains; CB1 expression negatively correlated with memory and information processing speed; CB1 redistributed from neuronal processes to soma in HAND; increased CB1 colocalization with astroglial marker in HAND.","methodology":"Cross-sectional biochemical and immunohistochemical analyses of CB1 and CB2 receptor expression in post-mortem brain specimens from people with HIV, comparing those with and without HIV-associated neurocognitive disorders.","limitations":"Post-mortem brain analysis cannot establish causation; small sample sizes; cross-sectional design; antiretroviral medication effects not fully controlled; cannot determine if receptor changes preceded or resulted from cognitive decline."},{"rthcId":"RTHC-03564","title":"Critical interactions between opioid and cannabinoid receptors during tolerance and physical dependence development to opioids in the murine gastrointestinal tract: proof of concept.","authors":"Szymaszkiewicz, Agata; Świerczyński, Mikołaj; Talar, Marcin; Polepally, Prabhakar Reddy; Zjawiony, Jordan K; Fichna, Jakub; Zielińska, Marta","year":2021,"journal":"Pharmacological reports : PR, 73(4), 1147-1154","doi":"10.1007/s43440-021-00291-7","pmid":"34133018","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03565","title":"A Quality-of-Life Evaluation Study Assessing Health-Related Quality of Life in Patients Receiving Medicinal Cannabis (the QUEST Initiative): Protocol for a Longitudinal Observational Study.","authors":"Tait, Margaret-Ann; Costa, Daniel S J; Campbell, Rachel; Norman, Richard; Schug, Stephan; Rutherford, Claudia","year":2021,"journal":"JMIR research protocols, 10(11), e32327","doi":"10.2196/32327","pmid":"34821570","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03566","title":"The emergency department care of the cannabis and synthetic cannabinoid patient: a narrative review.","authors":"Takakuwa, Kevin M; Schears, Raquel M","year":2021,"journal":"International journal of emergency medicine, 14(1), 10","doi":"10.1186/s12245-021-00330-3","pmid":"33568074","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03567","title":"Endocannabinoid Levels in Ulcerative Colitis Patients Correlate With Clinical Parameters and Are Affected by Cannabis Consumption.","authors":"Tartakover Matalon, Shelly; Azar, Shahar; Meiri, David; Hadar, Rivka; Nemirovski, Alina; Abu Jabal, Narjes; Konikoff, Fred Meir; Drucker, Liat; Tam, Joseph; Naftali, Timna","year":2021,"journal":"Frontiers in endocrinology, 12, 685289","doi":"10.3389/fendo.2021.685289","pmid":"34531823","tags":["medical-cannabis","inflammation","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In UC patients treated with placebo, levels of PEA, AEA, and arachidonic acid decreased significantly over 8 weeks, while levels remained stable in cannabis-treated UC patients. Reduction in bowel movements correlated with changes in AEA and OEA, and quality-of-life improvement correlated with 2-AG levels.","whyItMatters":"This study provides mechanistic evidence that cannabis may work in UC by modulating endocannabinoid tone, offering a biological explanation for symptom improvement and potentially guiding more targeted cannabinoid therapies.","specificNumbers":"13 Crohn's and 9 UC patients received cannabis; 17 CD and 10 UC received placebo; PEA, AEA, and AA decreased significantly in UC placebo group; endocannabinoid levels stable in cannabis-treated UC; FAAH levels increased in UC biopsies; symptom correlations with AEA, OEA, and 2-AG.","methodology":"Sub-analysis of a randomized controlled trial examining endocannabinoid levels in blood and colon biopsies from IBD patients treated with cannabis or placebo for 8 weeks, plus in vitro Caco-2 cell experiments.","limitations":"Very small sample sizes per group; sub-analysis of a larger trial; blood endocannabinoid levels may not reflect tissue-level changes; Crohn's patients showed no endocannabinoid changes."},{"rthcId":"RTHC-03568","title":"Technology-Based Psychological Interventions for Young Adults With Early Psychosis and Cannabis Use Disorder: Qualitative Study of Patient and Clinician Perspectives.","authors":"Tatar, Ovidiu; Abdel-Baki, Amal; Tra, Christophe; Mongeau-Pérusse, Violaine; Arruda, Nelson; Kaur, Navdeep; Landry, Vivianne; Coronado-Montoya, Stephanie; Jutras-Aswad, Didier","year":2021,"journal":"JMIR formative research, 5(4), e26562","doi":"10.2196/26562","pmid":"33818397","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03569","title":"Factors Associated With Cannabis Use During the Reproductive Cycle: A Retrospective Cross-Sectional Study of Women in States With Recreational and Medical Cannabis Legalization.","authors":"Taylor, Danica Loralyn; Bell, Janice F; Adams, Susan L; Drake, Christiana","year":2021,"journal":"Maternal and child health journal, 25(9), 1491-1500","doi":"10.1007/s10995-021-03197-1","pmid":"34155601","tags":["pregnancy","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Recreational cannabis legalization was associated with higher cannabis use across preconception (OR=2.37), prenatal (OR=1.51), and postpartum periods. Medical legalization was associated with higher preconception use (OR=3.32) but not prenatal use. Tobacco, e-cigarette, and moderate alcohol use were also associated with cannabis use.","whyItMatters":"As more states legalize cannabis, understanding how legalization affects use during pregnancy is critical for developing updated prenatal counseling and public health messaging.","specificNumbers":"36,391 women surveyed; recreational legalization: OR 2.37 for preconception, 1.51 for prenatal use; medical legalization: OR 3.32 for preconception use, not significant for prenatal; tobacco and e-cigarette use also associated with cannabis use.","methodology":"Cross-sectional analysis of combined 2016-2018 Pregnancy Risk Assessment Monitoring System (PRAMS) data from 36,391 women, using logistic regression to estimate effects of state legalization status on cannabis use across reproductive periods.","limitations":"Self-reported data may underestimate actual use; cross-sectional design limits causal inference; state-level legalization status does not capture individual access; potential confounders related to state culture."},{"rthcId":"RTHC-03570","title":"Characterizing Trends in Synthetic Cannabinoid Receptor Agonist Use from Patient Clinical Evaluations during Medical Toxicology Consultation.","authors":"Tebo, Collin; Mazer-Amirshahi, Maryann; Wax, Paul; Campleman, Sharan; Boyer, Edward; Brent, Jeffrey; Sheth, Amit; Daniuaityte, Raminta; Carlson, Robert","year":2021,"journal":"Journal of psychoactive drugs, 53(3), 207-214","doi":"10.1080/02791072.2020.1851826","pmid":"33225872","tags":["synthetic-cannabinoids","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 124 NPS cases, 86 (69%) involved SCRAs. Most patients (68.8%) had used SCRAs before, 47.7% found them very easy to obtain, and 48.8% used primarily to get high. Only 6.9% used SCRAs to avoid drug testing, and 4.6% as a marijuana alternative, suggesting an independent culture around SCRA use.","whyItMatters":"The finding that SCRA use has developed its own culture separate from marijuana substitution challenges the assumption that users primarily choose synthetics to avoid detection, and has implications for prevention messaging.","specificNumbers":"124 NPS cases; 86 (69%) involved SCRAs; 68.8% had used before; 47.7% found very easy to obtain; 44.2% paid for substances, 32.6% got free; 48.8% used to get high; 6.9% to avoid drug testing; 4.6% as marijuana alternative.","methodology":"Cross-sectional analysis of 124 patients with suspected new psychoactive substance exposure who received medical toxicology consultation, with qualitative interviews capturing knowledge, attitudes, beliefs, and practices.","limitations":"Medical toxicology consultations represent severe cases, not typical users; convenience sample; self-reported motivations may not capture all reasons; limited to patients seeking medical care."},{"rthcId":"RTHC-03571","title":"A mobile phone-based brief intervention with personalized feedback and interactive text messaging is associated with changes in driving after cannabis use cognitions in a proof-of-concept pilot trial.","authors":"Teeters, Jenni B; King, Shelby A; Hubbard, Sterling M","year":2021,"journal":"Experimental and clinical psychopharmacology, 29(2), 203-209","doi":"10.1037/pha0000442","pmid":"34043401","tags":["driving","harm-reduction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Compared to an informational control, participants who received personalized feedback plus interactive text messaging (PFT) showed significantly greater increases in perceived dangerousness of driving after cannabis use at 3-month follow-up, though personalized feedback alone (PF) was not significantly different from control.","whyItMatters":"Driving after cannabis use is one of the riskiest cannabis-related behaviors, and the finding that a brief mobile intervention can shift risk perceptions suggests a scalable approach to reducing impaired driving.","specificNumbers":"77 participants; 65.8% women; average age 21.2; 88.3% Caucasian; PFT condition showed significantly greater increases in perceived dangerousness vs control; PF alone not significant; 3-month follow-up.","methodology":"Proof-of-concept randomized pilot trial of 77 college cannabis users who endorsed driving after cannabis at least 3 times in 3 months, comparing personalized feedback plus text messaging (PFT), personalized feedback only (PF), and informational control (IC) conditions over 3 months.","limitations":"Very small sample; proof-of-concept design; predominantly White college sample; 3-month follow-up may not capture sustained behavior change; perception change does not necessarily translate to behavior change."},{"rthcId":"RTHC-03572","title":"Estimating Cannabis Involvement in Fatal Crashes in Washington State Before and After the Legalization of Recreational Cannabis Consumption Using Multiple Imputation of Missing Values.","authors":"Tefft, Brian C; Arnold, Lindsay S","year":2021,"journal":"American journal of epidemiology, 190(12), 2582-2591","doi":"10.1093/aje/kwab184","pmid":"34157068","tags":["driving","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Using multiple imputation to account for untested drivers, the proportion of THC-positive drivers in fatal crashes rose from 9.3% before to 19.1% after legalization (adjusted PR=2.3, 95% CI: 1.3-4.1). Drivers with high THC concentrations increased nearly five-fold (adjusted PR=4.7, 95% CI: 1.5-15.1).","whyItMatters":"The sharp increase in high-THC drivers after legalization suggests more people are driving shortly after cannabis use, not just that more people have detectable THC from prior use.","specificNumbers":"8,282 drivers in fatal crashes; 2008-2019; nearly half untested (addressed by imputation); THC-positive: 9.3% before vs 19.1% after legalization; adjusted PR=2.3; high THC concentrations: adjusted PR=4.7.","methodology":"Retrospective analysis of all 8,282 drivers involved in fatal crashes in Washington state (2008-2019), using multiple imputation for the nearly half of drivers not tested for drugs, with logistic regression and marginal standardization.","limitations":"Multiple imputation introduces uncertainty; THC presence does not prove impairment; no causal inference possible; Washington-specific results may not generalize; cannot distinguish medical from recreational use."},{"rthcId":"RTHC-03573","title":"Hemp seed (Cannabis sativa L.) enriched pasta: Physicochemical properties and quality evaluation.","authors":"Teterycz, Dorota; Sobota, Aldona; Przygodzka, Dominika; Łysakowska, Paulina","year":2021,"journal":"PloS one, 16(3), e0248790","doi":"10.1371/journal.pone.0248790","pmid":"33735229","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03574","title":"Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users.","authors":"Theunissen, Eef L; Reckweg, Johannes T; Hutten, Nadia R P W; Kuypers, Kim P C; Toennes, Stefan W; Neukamm, Merja A; Halter, Sebastian; Ramaekers, Johannes G","year":2021,"journal":"Pharmacology, biochemistry, and behavior, 202, 173118","doi":"10.1016/j.pbb.2021.173118","pmid":"33497715","tags":["synthetic-cannabinoids","cognition","driving"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"At 75 microg/kg, JWH-018 impaired motor coordination (CTT), attention (DAT and SST), memory (SMT), lowered speed-accuracy efficiency (MFFT), and slowed response speed. Peak subjective high (64%) occurred at 30 minutes, while peak blood concentration was at 5 minutes (8 ng/mL).","whyItMatters":"Synthetic cannabinoids are widely available but much less studied than THC. Demonstrating clear cognitive and psychomotor impairment at relatively low doses provides evidence to inform public safety policies around these substances.","specificNumbers":"24 participants; 75 microg/kg body weight dose; peak subjective high 64% at 30 min; peak blood concentration 8 ng/mL at 5 min; significant impairment in CTT, DAT, SST, SMT, and MFFT measures.","methodology":"Placebo-controlled, crossover study of 24 healthy cannabis-experienced participants who inhaled 75 microg/kg JWH-018 vapor with optional booster dose, monitored for 4 hours with cognitive, psychomotor, and subjective assessments.","limitations":"Small sample; cannabis-experienced participants may not represent naive users; single synthetic cannabinoid tested; laboratory setting differs from real-world use; fixed dose may not represent typical street use."},{"rthcId":"RTHC-03575","title":"Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial.","authors":"Thiele, Elizabeth A; Bebin, E Martina; Bhathal, Hari; Jansen, Floor E; Kotulska, Katarzyna; Lawson, John A; O'Callaghan, Finbar J; Wong, Michael; Sahebkar, Farhad; Checketts, Daniel; Knappertz, Volker","year":2021,"journal":"JAMA neurology, 78(3), 285-292","doi":"10.1001/jamaneurol.2020.4607","pmid":"33346789","tags":["cbd","epilepsy"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Both CBD doses significantly reduced TSC-associated seizures versus placebo: 48.6% reduction for 25 mg/kg/day (30.1% reduction from placebo, p<0.001) and 47.5% for 50 mg/kg/day (28.5% from placebo, p=0.002), with no additional benefit from the higher dose but more adverse effects.","whyItMatters":"This is the pivotal trial demonstrating CBD efficacy for seizures in tuberous sclerosis complex, a condition characterized primarily by focal seizures, expanding CBD's proven epilepsy indications beyond Lennox-Gastaut and Dravet syndromes.","specificNumbers":"224 patients randomized (75 CBD25, 73 CBD50, 76 placebo); 201 completed treatment; median age 11.4 years; seizure reduction: CBD25 48.6%, CBD50 47.5%, placebo 26.5%; diarrhea: 25% placebo, 31% CBD25, 56% CBD50; elevated liver enzymes in 18.9% on CBD vs 0% placebo.","methodology":"Double-blind, placebo-controlled RCT (GWPCARE6) of 224 patients aged 1-65 with TSC and medication-resistant epilepsy across 46 sites in 6 countries, comparing oral CBD at 25 mg/kg/day and 50 mg/kg/day to placebo over 16 weeks.","limitations":"Elevated liver enzymes in 18.9% of CBD patients (none on placebo); side effects increased substantially with higher dose; 16-week duration may not capture long-term efficacy or tolerance; concomitant antiepileptic medications could interact."},{"rthcId":"RTHC-03576","title":"Miswiring the brain: Human prenatal Δ9-tetrahydrocannabinol use associated with altered fetal hippocampal brain network connectivity.","authors":"Thomason, Moriah E; Palopoli, Ava C; Jariwala, Nicki N; Werchan, Denise M; Chen, Alan; Adhikari, Samrachana; Espinoza-Heredia, Claudia; Brito, Natalie H; Trentacosta, Christopher J","year":2021,"journal":"Developmental cognitive neuroscience, 51, 101000","doi":"10.1016/j.dcn.2021.101000","pmid":"34388638","tags":["pregnancy","neuroscience"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Fetuses exposed to cannabis prenatally showed altered hippocampal connectivity to dorsolateral, medial, and superior frontal cortex, insula, anterior temporal, and posterior cingulate regions. The connectivity patterns in exposed fetuses were more often associated with less favorable outcomes at age 5.","whyItMatters":"This is among the first studies to show that prenatal cannabis exposure may alter brain connectivity before birth, suggesting that developmental effects begin in utero rather than emerging only after delivery.","specificNumbers":"115 fetuses; mean gestational age 32.2 weeks; 43% female; cannabis-exposed group showed altered connectivity to frontal, temporal, insular, and cingulate regions; connectivity patterns in exposed group linked to less favorable age-5 outcomes.","methodology":"Prospective fetal fMRI study of 115 fetuses (mean 32.2 weeks gestation, 43% female) with prenatal drug toxicology data, using voxelwise hippocampal connectivity analysis in age- and sex-matched subsets.","limitations":"Small sample for subgroup analyses; fetal fMRI is technically challenging with potential motion artifacts; cannot separate cannabis effects from other co-occurring factors; outcome classification at age 5 was preliminary."},{"rthcId":"RTHC-03577","title":"Predictors of cannabis use among first-time justice-involved youth: A cohort study.","authors":"Tolou-Shams, Marina; Folk, Johanna B; Marshall, Brandon D L; Dauria, Emily F; Kemp, Kathleen; Li, Yu; Koinis-Mitchell, Daphne; Brown, Larry K","year":2021,"journal":"Drug and alcohol dependence, 225, 108754","doi":"10.1016/j.drugalcdep.2021.108754","pmid":"34051549","tags":["youth","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 391 first-time justice-involved youth, 48.1% had lifetime cannabis use and 14.8% initiated during 12-month follow-up. In multivariable analyses, affect dysregulation, internalizing symptoms, and positive cannabis expectancies independently predicted new cannabis initiation, while greater self-control and self-concept were protective.","whyItMatters":"First contact with the justice system represents a unique intervention window. Identifying which youth are most likely to start using cannabis can guide targeted prevention efforts during this critical period.","specificNumbers":"391 youth; 56.9% male; mean age 14.6; 48.1% lifetime cannabis use; 14.8% initiated during follow-up; affect dysregulation, internalizing symptoms, and positive cannabis expectancies predicted initiation; self-control and self-concept were protective.","methodology":"Prospective cohort of 391 first-time justice-involved youth (56.9% male, mean age 14.6) and caregivers assessed at baseline and every 4 months for 12 months, using multivariable Poisson regression and survival analysis.","limitations":"First-time justice-involved youth may not represent all adolescents; relatively low initiation rate (14.8%) limits statistical power for subgroup analyses; self-reported cannabis use."},{"rthcId":"RTHC-03578","title":"VOICES: An efficacious trauma-informed, gender-responsive cannabis use intervention for justice and school-referred girls with lifetime substance use history.","authors":"Tolou-Shams, Marina; Dauria, Emily F; Folk, Johanna; Shumway, Martha; Marshall, Brandon D L; Rizzo, Christie J; Messina, Nena; Covington, Stephanie; Haack, Lauren M; Chaffee, Tonya; Brown, Larry K","year":2021,"journal":"Drug and alcohol dependence, 228, 108934","doi":"10.1016/j.drugalcdep.2021.108934","pmid":"34530316","tags":["youth","harm-reduction","sex-differences"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Girls randomized to VOICES reported significantly less cannabis use over 9-month follow-up compared to the control condition (p<0.01). Both groups showed improvements in psychiatric symptoms and delinquent acts over time, but only VOICES reduced cannabis use specifically.","whyItMatters":"Girls have unique pathways to substance use that often involve trauma history. This is one of the first trials to demonstrate that a gender-responsive, trauma-informed approach can effectively reduce cannabis use in this underserved population.","specificNumbers":"113 girls; mean age 15.7; 42% Latinx; 29% justice-referred, 71% school-referred; VOICES (n=51) vs GirlHealth control (n=62); significant reduction in cannabis use in VOICES group (p<0.01); no between-group differences in HIV/STI risk behavior.","methodology":"Randomized controlled trial comparing VOICES (12-session trauma-informed, gender-responsive intervention, n=51) to GirlHealth attention control (n=62) in 113 girls aged ~15.7 years referred from juvenile justice (29%) and school systems (71%), assessed at baseline, 3, 6, and 9 months.","limitations":"Modest sample size; predominantly Latinx sample from one region; intervention was 12 sessions which may limit scalability; no long-term follow-up beyond 9 months; cannabis use was self-reported."},{"rthcId":"RTHC-03579","title":"Synthetic cannabinoid CP-55,940 induces apoptosis in a human skeletal muscle model via regulation of CB1 receptors and L-type Ca2+ channels.","authors":"Tomiyama, Ken-Ichi; Funada, Masahiko","year":2021,"journal":"Archives of toxicology, 95(2), 617-630","doi":"10.1007/s00204-020-02944-7","pmid":"33174160","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03580","title":"Slovenian Pet Owners' Experience, Attitudes, and Predictors Regarding Cannabinoid Use in Dogs and Cats.","authors":"Tomsič, Katerina; Rakinić, Kristina; Seliškar, Alenka","year":2021,"journal":"Frontiers in veterinary science, 8, 796673","doi":"10.3389/fvets.2021.796673","pmid":"35071387","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03581","title":"The role of endocannabinoid system and TRPV1 receptors in the antidepressant and anxiolytic effects of dipyrone in chronic unpredictable mild stress in mice.","authors":"Topuz, Ruhan Deniz; Cetinkaya, Mehmet Zahid; Erumit, Dilsat; Duvan Aydemir, Kubra; Gunduz, Ozgur; Karadag, Cetin Hakan; Ulugol, Ahmet","year":2021,"journal":"European journal of pharmacology, 908, 174315","doi":"10.1016/j.ejphar.2021.174315","pmid":"34270988","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03582","title":"The state of the evidence on the association between state cannabis laws and opioid-related outcomes: A review.","authors":"Tormohlen, Kayla N; Bicket, Mark C; White, Sarah; Barry, Colleen L; Stuart, Elizabeth A; Rutkow, Lainie; McGinty, Emma E","year":2021,"journal":"Current addiction reports, 8(4), 538-545","doi":"10.1007/s40429-021-00397-1","pmid":"35668861","tags":["legalization","harm-reduction","pain"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Across 21 U.S. studies, results on whether cannabis laws reduce opioid prescribing, use, or mortality were largely inconclusive. Six key challenges were identified: inability to measure direct substitution, lack of individual-level longitudinal data, difficulty separating cannabis law effects from other policies, staggered implementation issues, limited consideration of specific law provisions, and insufficient data triangulation.","whyItMatters":"The popular narrative that cannabis legalization reduces opioid problems is not well supported by current evidence. Understanding the specific research gaps is essential before making policy claims about cannabis as an opioid substitute.","specificNumbers":"21 studies reviewed; published 2014-2021; 6 research challenges identified; outcomes examined included opioid prescribing, use, use disorder, service utilization, and mortality; results largely inconclusive.","methodology":"Narrative review of 21 U.S.-based studies published 2014-2021 examining associations between state medical and recreational cannabis laws and opioid-related outcomes.","limitations":"Narrative rather than systematic review; limited to U.S. studies; rapidly evolving policy landscape means findings may become outdated; does not include studies published after 2021."},{"rthcId":"RTHC-03583","title":"Investigating causality between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization.","authors":"Treur, Jorien L; Demontis, Ditte; Smith, George Davey; Sallis, Hannah; Richardson, Tom G; Wiers, Reinout W; Børglum, Anders D; Verweij, Karin J H; Munafò, Marcus R","year":2021,"journal":"Addiction biology, 26(1), e12849","doi":"10.1111/adb.12849","pmid":"31733098","tags":["addiction","genetics"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Genetic liability to ADHD increased the likelihood of smoking initiation, heavier smoking, difficulty quitting smoking, and cannabis initiation. There was weak evidence for ADHD increasing alcohol dependence risk. In the reverse direction, weak evidence for smoking initiation increasing ADHD risk was likely due to horizontal pleiotropy rather than true causation.","whyItMatters":"This genetic causal inference method avoids the confounding that plagues observational studies. Finding that ADHD liability causes increased substance use, rather than the reverse, has direct implications for prevention: treating ADHD may help prevent substance use.","specificNumbers":"Causal pathways confirmed from ADHD to: smoking initiation, cigarettes per day, reduced smoking cessation, cannabis initiation; weak evidence for ADHD to alcohol dependence; weak but likely confounded evidence for smoking to ADHD; no causal pathways between ADHD and coffee consumption.","methodology":"Bidirectional Mendelian randomization using summary-level data from the largest available genome-wide association studies on ADHD, smoking, alcohol, cannabis, and coffee, with inverse-variance weighted regression and five sensitivity analyses.","limitations":"Mendelian randomization assumes genetic variants only affect the outcome through the exposure (no pleiotropy), which may not always hold; GWAS samples are predominantly European ancestry; cannot identify specific mechanisms linking ADHD to substance use."},{"rthcId":"RTHC-03584","title":"Cannabis use among military veterans: A great deal to gain or lose?","authors":"Turna, Jasmine; MacKillop, James","year":2021,"journal":"Clinical psychology review, 84, 101958","doi":"10.1016/j.cpr.2021.101958","pmid":"33486280","tags":["medical-cannabis","mental-health","ptsd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 86 included studies, cannabis use in veterans was consistently associated with other substance use, psychiatric disorders, and self-harm/suicidality. The literature was dominated by cross-sectional designs (67%) of predominantly male U.S. veterans, with very few studies examining cannabis as therapy.","whyItMatters":"Veterans disproportionately suffer from conditions like PTSD and chronic pain that drive cannabis use, yet the evidence base for therapeutic benefit is remarkably thin compared to evidence of associations with negative outcomes.","specificNumbers":"501 articles identified; 86 met criteria; 67% cross-sectional; 71.4-100% male; 93% from U.S.; consistent associations with other substance use, psychiatric disorders, and self-harm/suicidality; few therapeutic efficacy studies.","methodology":"Comprehensive review of 86 studies from 501 identified articles examining correlates and consequences of cannabis use among military veterans, using systematic search strategies.","limitations":"Predominance of cross-sectional designs prevents causal conclusions; heavily male U.S. veteran samples limit generalizability; lack of therapeutic efficacy studies creates an incomplete picture; selection bias in study populations."},{"rthcId":"RTHC-03585","title":"Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist?","authors":"Uliel-Sibony, Shimrit; Hausman-Kedem, Moran; Fattal-Valevski, Aviva; Kramer, Uri","year":2021,"journal":"Brain & development, 43(1), 89-96","doi":"10.1016/j.braindev.2020.06.018","pmid":"32713661","tags":["cbd","epilepsy","tolerance"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 84 patients analyzed for tolerance (treated at least 3 months), 21 (25%) developed tolerance after a mean of 7.3 months. Overall responder rate was 54% (>50% seizure reduction), and 9% became seizure-free. Shorter epilepsy duration was negatively correlated with tolerance development (p=0.038).","whyItMatters":"This is the first study to systematically report tolerance to CBD in epilepsy patients. If one in four patients loses treatment benefit over time, it has significant implications for long-term seizure management.","specificNumbers":"92 patients; mean age 11.8 years; mean follow-up 19.8 months; mean CBD dose 11.3 mg/kg/day; 31% discontinued; 51% had adverse reactions; 54% responder rate; 9% seizure-free; 25% developed tolerance at mean 7.3 months; shorter epilepsy duration associated with tolerance.","methodology":"Prospective study of 92 consecutive patients (age 1-37, mean 11.8 years) with treatment-resistant epilepsy treated with CBD-enriched oil (CBD:THC 20:1), with tolerance defined as either need for >30% dose increase or >30% increase in seizure frequency after at least 3 months of stable treatment.","limitations":"Single-center study; open-label design without placebo comparison; tolerance definition was operationalized rather than biologically confirmed; variable CBD-enriched oil formulations."},{"rthcId":"RTHC-03586","title":"Prevalence of cardiac arrhythmias in cannabis use disorder related hospitalizations in teenagers from 2003 to 2016 in the United States.","authors":"Umapathi, Krishna Kishore; Thavamani, Aravind; Dhanpalreddy, Harshitha; Nguyen, Hoang H","year":2021,"journal":"Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 23(8), 1302-1309","doi":"10.1093/europace/euab033","pmid":"33723583","tags":["cardiovascular","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 876,431 CUD-related teen hospitalizations, 0.5% involved cardiac arrhythmias. When arrhythmia co-occurred with CUD, mortality was 7.4% vs. 0.1% without arrhythmia, and hospitalization charges were nearly three times higher.","whyItMatters":"While cardiac arrhythmias remain relatively rare among teens with CUD, the sixfold increase in prevalence over the study period and the dramatically worse outcomes when arrhythmia co-occurs with CUD suggest a growing clinical concern.","specificNumbers":"Total CUD hospitalizations: 876,431. Arrhythmia prevalence: 0.5%. Mortality with arrhythmia: 7.4% vs. 0.1%. Hospitalization charges with arrhythmia: $45,959 vs. $18,986. Sixfold increase in arrhythmia prevalence over 13 years.","methodology":"Retrospective analysis of a national US administrative database (2003-2016) examining cardiac arrhythmia prevalence among hospitalized teens aged 13-20 with cannabis use disorder. Used partial least square regression for trend analysis and multiple logistic regression for predictors.","limitations":"Administrative database study reliant on billing codes, which may under-capture arrhythmia diagnoses. Cannot establish causation between CUD and arrhythmia. No data on cannabis potency, route of use, or frequency."},{"rthcId":"RTHC-03587","title":"Drugs and driving prior to cannabis legalization: A 5-year review from DECP (DRE) cases in the province of Quebec, Canada.","authors":"Vaillancourt, Lucie; Viel, Edith; Dombrowski, Cynthia; Desharnais, Brigitte; Mireault, Pascal","year":2021,"journal":"Accident; analysis and prevention, 149, 105832","doi":"10.1016/j.aap.2020.105832","pmid":"33220606","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"At least one impairing substance was detected in 98% of the 2,982 Drug Recognition Expert cases. Cannabis (THC-COOH) was found in 48% of cases. Polydrug use was common, with 79% of cases showing two or more impairing substances.","whyItMatters":"Establishing a pre-legalization baseline of drug-impaired driving patterns helps researchers and policymakers measure the impact of recreational cannabis legalization on road safety.","specificNumbers":"Total cases: 2,982. Substance detected: 98%. Cannabis positive: 48%. Methamphetamine: 54%. Cocaine: 29%. GHB: 24%. Polydrug use: 79%. Average age: 33. Male: 79%.","methodology":"Retrospective analysis of 2,982 Drug Recognition Expert evaluation cases in Quebec, Canada from January 2014 to December 2018. All biological samples underwent targeted LC-MS/MS analysis for 137 drugs and metabolites.","limitations":"Only captures drivers flagged by police, not all impaired drivers. THC-COOH indicates past use rather than active impairment. Results reflect Quebec-specific drug culture and may not generalize."},{"rthcId":"RTHC-03588","title":"Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice.","authors":"van Eenige, Robin; Ying, Zhixiong; Tambyrajah, Lauren; Pronk, Amanda C M; Blomberg, Niek; Giera, Martin; Wang, Yanan; Coskun, Tamer; van der Stelt, Mario; Rensen, Patrick C N; Kooijman, Sander","year":2021,"journal":"Journal of lipid research, 62, 100070","doi":"10.1016/j.jlr.2021.100070","pmid":"33766515","tags":["cardiovascular","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In lean mice with dyslipidemia, 20 weeks of rimonabant treatment reduced VLDL-TG production by 52%, lowered non-HDL-C by 19%, raised HDL-C by 57%, and decreased atherosclerotic lesion size by 64% with reduced severity (28% vs. 56% severe lesions).","whyItMatters":"This study separated the cardiovascular benefits of endocannabinoid system inhibition from its anti-obesity effects, showing that CB1 blockade can protect against atherosclerosis through direct lipid metabolism improvements.","specificNumbers":"Triglycerides: -56%. VLDL-TG production: -52%. Non-HDL-C: -19%. HDL-C: +57%. Atherosclerotic lesion size: -64%. Severe lesions: 28% vs. 56%. Plasma bile acids: +160%.","methodology":"Female APOE*3-Leiden.CETP transgenic mice (a humanized model of dyslipidemia) were fed a Western-type diet with or without rimonabant (20 mg/kg/day) for up to 20 weeks. Plasma lipids, bile acids, and atherosclerotic lesions in the aortic valve region were measured.","limitations":"Animal study in a specialized transgenic mouse model. Rimonabant was pulled from the European market due to psychiatric adverse effects, limiting direct clinical translation. Sex-specific (only female mice)."},{"rthcId":"RTHC-03589","title":"Schizophrenia and the Environment: Within-Person Analyses May be Required to Yield Evidence of Unconfounded and Causal Association-The Example of Cannabis and Psychosis.","authors":"van Os, Jim; Pries, Lotta-Katrin; Ten Have, Margreet; de Graaf, Ron; van Dorsselaer, Saskia; Bak, Maarten; Wittchen, Hans-Ulrich; Rutten, Bart P F; Guloksuz, Sinan","year":2021,"journal":"Schizophrenia bulletin, 47(3), 594-603","doi":"10.1093/schbul/sbab019","pmid":"33693921","tags":["psychosis","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"In the fixed-effects model, prior cannabis use predicted subsequent psychotic experiences (adjusted OR = 7.03, 95% CI: 2.39-20.69), but prior psychotic experiences did not predict subsequent cannabis use (adjusted OR = 0.59, 95% CI: 0.21-1.71).","whyItMatters":"Most cannabis-psychosis research uses between-person comparisons, which cannot fully control for genetic and environmental confounders. This within-person design substantially strengthens the causal inference that cannabis impacts psychosis.","specificNumbers":"Combined cohort: 7,998 at baseline. Follow-up: approximately 10 years across 4 time points. Cannabis to psychosis OR: 7.03 (95% CI: 2.39-20.69). Psychosis to cannabis OR: 0.59 (95% CI: 0.21-1.71).","methodology":"Combined two general population cohorts (n = 7,998 at baseline) with repeated interviews over approximately 10 years (4 time points). Used fixed-effects within-person models where each individual serves as their own control, removing confounding by any stable characteristic. Adjusted for time-varying confounders.","limitations":"Self-reported measures of both cannabis use and attenuated psychotic experiences. Attenuated psychotic experiences are not the same as clinical psychosis diagnoses. Time-varying confounders may not be fully captured."},{"rthcId":"RTHC-03590","title":"Suicide by vaping the synthetic cannabinoid 4F-MDMB-BINACA: cannabinoid receptors and fluoride at the crossroads of toxicity?","authors":"Van Rafelghem, Babette; Covaci, Adrian; Anseeuw, Kurt; van Nuijs, Alexander L N; Neels, Hugo; Mahieu, Boris; Jacobs, Werner","year":2021,"journal":"Forensic science, medicine, and pathology, 17(4), 684-688","doi":"10.1007/s12024-021-00424-7","pmid":"34542803","tags":["synthetic-cannabinoids","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Following extensive vaping of 4F-MDMB-BINACA, the patient developed fulminant necrotizing pancreatitis, acute tubular necrosis, cerebral edema, hepatocellular necrosis, and acute respiratory distress syndrome. He died 11 days after admission. The toxicity may stem from CB1 receptor overstimulation or fluoride release from the compound.","whyItMatters":"This represents the first clinicopathological description of a lethal 4F-MDMB-BINACA intoxication, highlighting the extreme dangers of high-potency synthetic cannabinoids compared to plant cannabis.","specificNumbers":"Patient age: 22. Time to death: 11 days post-admission. Identified pathology: necrotizing pancreatitis, acute tubular necrosis, cerebral edema, hepatocellular necrosis, ARDS.","methodology":"Case report with postmortem histopathology, toxicological analysis, and review of clinical course. Metabolites were confirmed in urine and serum, and the source drug was identified in vapor fluid found at the residence.","limitations":"Single case report. Cannot determine exact dose consumed. Two potential toxicity mechanisms (CB1 overstimulation vs. fluoride toxicity) remain unresolved."},{"rthcId":"RTHC-03591","title":"Hemp Seed Cake as a Novel Ingredient for Dog's Diet.","authors":"Vastolo, Alessandro; Iliano, Sergio; Laperuta, Flaviana; Pennacchio, Saverio; Pompameo, Marina; Cutrignelli, Monica Isabella","year":2021,"journal":"Frontiers in veterinary science, 8, 754625","doi":"10.3389/fvets.2021.754625","pmid":"34970613","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03592","title":"Randomized, placebo-controlled, 28-day safety and pharmacokinetics evaluation of repeated oral cannabidiol administration in healthy dogs.","authors":"Vaughn, Dana M; Paulionis, Lina J; Kulpa, Justyna E","year":2021,"journal":"American journal of veterinary research, 82(5), 405-416","doi":"10.2460/ajvr.82.5.405","pmid":"33904801","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03593","title":"The Impact of Marijuana on Antidepressant Treatment in Adolescents: Clinical and Pharmacologic Considerations.","authors":"Vaughn, Samuel E; Strawn, Jeffrey R; Poweleit, Ethan A; Sarangdhar, Mayur; Ramsey, Laura B","year":2021,"journal":"Journal of personalized medicine, 11(7)","doi":"10.3390/jpm11070615","pmid":"34209709","tags":["drug-interactions","youth","depression","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD and THC inhibit cytochrome enzymes (particularly CYP2C19) that metabolize SSRIs. PK models showed increased sertraline and escitalopram exposure in adolescents when co-administered with cannabinoids. FAERS data showed co-administration of CBD with CYP2C19-metabolized SSRIs increased the risk of cough, diarrhea, dizziness, and fatigue.","whyItMatters":"With both cannabis use and antidepressant prescribing increasing among adolescents, clinicians need to understand how these substances interact to avoid unexpected increases in medication levels and side effects.","specificNumbers":"Modeled interactions for escitalopram and sertraline with CBD and THC. FAERS analysis identified increased signals for cough, diarrhea, dizziness, and fatigue with CBD + CYP2C19-metabolized SSRIs.","methodology":"Three-part approach: (1) review of cannabinoid-SSRI pharmacokinetic and pharmacodynamic interactions, (2) pediatric PK modeling of THC/CBD effects on escitalopram and sertraline exposure, and (3) analysis of FDA Adverse Events Reporting System (FAERS) data for CBD-SSRI side effect signals.","limitations":"PK modeling rather than clinical measurement of actual drug levels. FAERS data is based on voluntary reporting and cannot confirm causation. Limited to two SSRIs."},{"rthcId":"RTHC-03594","title":"Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy.","authors":"Vierke, Christopher; Marxen, Brigitte; Boettcher, Michael; Hiemke, Christoph; Havemann-Reinecke, Ursula","year":2021,"journal":"European archives of psychiatry and clinical neuroscience, 271(5), 847-856","doi":"10.1007/s00406-019-01091-0","pmid":"31907614","tags":["drug-interactions","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among opioid maintenance therapy patients on buprenorphine, those who also used cannabis had dramatically different pharmacokinetics. Cannabis users had 2.7-fold higher buprenorphine blood concentrations (p < 0.01) and 1.4-fold higher norbuprenorphine (the active metabolite) compared to non-users receiving the same dose.\n\nThe metabolite-to-parent drug ratio told the clearest story: 0.98 in non-users versus 0.38 in cannabis users (p = 0.02). Cannabis was blocking the CYP3A4 enzyme that converts buprenorphine to norbuprenorphine, causing the parent drug to accumulate in the blood. This wasn't a subtle effect — it was a nearly 3-fold difference in drug exposure at identical doses.\n\nSex did not significantly modify the interaction. The clinical implication was direct: opioid maintenance patients who use cannabis are effectively getting a higher dose than prescribed, with potential consequences for both efficacy and side effects.","whyItMatters":"Cannabis use among opioid maintenance patients is extremely common — by some estimates, the majority use cannabis at least occasionally. This study showed that combination isn't pharmacologically neutral: cannabis nearly triples buprenorphine blood levels. For a medication with a ceiling effect on respiratory depression (which is why buprenorphine is considered safer than methadone), this might matter less for overdose risk. But it could affect sedation, cognition, treatment compliance, and how doses are adjusted.\n\nThis is a concrete, clinically actionable drug interaction that most addiction medicine prescribers aren't accounting for.","specificNumbers":"• Buprenorphine levels: 2.7x higher in cannabis users (p < 0.01)\n• Norbuprenorphine levels: 1.4x higher in cannabis users (p = 0.07)\n• Metabolite-to-parent ratio: 0.98 (non-users) vs 0.38 (users), p = 0.02\n• Cannabis users (n=15) vs non-users (n=17), similar prescribed doses","methodology":"Retrospective analysis of liver-healthy opioid maintenance therapy patients at a German addiction treatment center. Compared buprenorphine and norbuprenorphine blood concentrations in cannabis users (n=15) vs non-users (n=17). Patients with additional illicit drugs or CYP3A-affecting medications were excluded. Cannabis use confirmed via urinalysis.","limitations":"Small sample size (32 total patients). Retrospective design with potential confounders. Cannabis use was confirmed by urinalysis but dose and frequency weren't quantified. Only buprenorphine studied — the interaction may differ for methadone (which uses different metabolic pathways). German treatment setting may not generalize to other countries' protocols."},{"rthcId":"RTHC-03595","title":"Effects of the \"Unplugged\" school-based substance use prevention program in Nigeria: A cluster randomized controlled trial.","authors":"Vigna-Taglianti, Federica; Mehanović, Emina; Alesina, Marta; Damjanović, Ljiljana; Ibanga, Akanidomo; Pwajok, Juliet; Prichard, Glen; van der Kreeft, Peer; Virk, Harsheth Kaur","year":2021,"journal":"Drug and alcohol dependence, 228, 108966","doi":"10.1016/j.drugalcdep.2021.108966","pmid":"34509736","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03596","title":"Genetic overlap and causality between substance use disorder and attention-deficit and hyperactivity disorder.","authors":"Vilar-Ribó, Laura; Sánchez-Mora, Cristina; Rovira, Paula; Richarte, Vanesa; Corrales, Montserrat; Fadeuilhe, Christian; Arribas, Lorena; Casas, Miquel; Ramos-Quiroga, Josep Antoni; Ribasés, Marta; Soler Artigas, María","year":2021,"journal":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 186(3), 140-150","doi":"10.1002/ajmg.b.32827","pmid":"33244849","tags":["genetics","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The study confirmed a common genetic background between ADHD and SUD using both clinical (n=989) and population GWAS data. Mendelian randomization supported a causal effect of ADHD liability on SUD risk, and found a novel bidirectional effect where genetic liability for lifetime cannabis use influenced ADHD risk.","whyItMatters":"Understanding the genetic basis of ADHD-SUD comorbidity can improve screening and treatment approaches, particularly the novel finding that cannabis use liability may itself influence ADHD.","specificNumbers":"Clinical sample: 989 subjects. Five SUD phenotypes tested: lifetime cannabis use, alcohol dependence, smoking initiation, cigarettes per day, and drinks per week. Shared genetic background confirmed for cannabis use, alcohol dependence, and smoking initiation.","methodology":"Combined in-house clinical sample (989 ADHD subjects) with pre-existing GWAS datasets for five SUD-related phenotypes. Used polygenic risk score analysis, genetic correlation, and Mendelian randomization to assess shared genetics and causal relationships.","limitations":"Cross-sectional genetic analysis cannot capture environmental interactions. Clinical sample was modest in size. Mendelian randomization assumptions may not fully hold."},{"rthcId":"RTHC-03597","title":"A pilot safety, tolerability and pharmacokinetic study of an oro-buccal administered cannabidiol-dominant anti-inflammatory formulation in healthy individuals: a randomized placebo-controlled single-blinded study.","authors":"Vitetta, Luis; Butcher, Belinda; Henson, Jeremy D; Rutolo, David; Hall, Sean","year":2021,"journal":"Inflammopharmacology, 29(5), 1361-1370","doi":"10.1007/s10787-021-00859-y","pmid":"34357480","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"The nanoparticle CBD spray met primary outcomes for safety, tolerability, and pharmacokinetics. Peak CBD concentration occurred at 60 minutes for both 6 mg and 18 mg doses. Half-life was 1.23 hours for the low dose and 5.45 hours for the high dose. No adverse inflammatory effects were reported.","whyItMatters":"Oro-buccal delivery with nanoparticle technology could improve CBD bioavailability and onset time compared to traditional oral formulations.","specificNumbers":"Participants: 16 (12 CBD, 4 placebo). Doses: 6 mg and 18 mg CBD. Peak time: 60 min for both doses. Half-life: 1.23 h (6 mg), 5.45 h (18 mg). AUC: 0.87 ng h/mL (6 mg), 8.9 ng h/mL (18 mg). THC per high dose: 0.72 mg.","methodology":"Randomized, single-blinded, placebo-controlled pilot study. 12 participants received CBD spray (2 sprays on day 1, 6 sprays on day 2) and 4 received placebo, administered to alternating cheeks. Blood samples collected for pharmacokinetic profiling.","limitations":"Very small sample (n=16). Single-blinded rather than double-blinded. Only healthy participants, no disease population. Short two-day dosing period."},{"rthcId":"RTHC-03598","title":"Death of a young woman with cyclic vomiting: a case report.","authors":"von Both, Ingo; Santos, Brittini","year":2021,"journal":"Forensic science, medicine, and pathology, 17(4), 715-722","doi":"10.1007/s12024-021-00410-z","pmid":"34735682","tags":["cardiovascular","addiction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Death was attributed to fatal cardiac arrhythmia (torsades de pointes) complicating vomiting-induced hypokalemia in the context of cannabinoid hyperemesis syndrome, with contributing factors including QT-prolonging medications (haloperidol, ondansetron) and cardiac genetic mutations (MYBPC3 and RYR2).","whyItMatters":"This case demonstrates that cannabinoid hyperemesis syndrome can be fatal, not from the vomiting itself but from the downstream electrolyte disturbances and drug interactions that vomiting creates.","specificNumbers":"Patient age: 22. Cannabis use since age 14. Cyclic vomiting history: 3.5 years. Time to brain death: 4 days post-cardiac arrest. Genetic mutations identified: MYBPC3 and RYR2.","methodology":"Case report with complete postmortem examination including histopathology, toxicology, and genetic testing. Clinical course documented from emergency department admission through brain death declaration 4 days later.","limitations":"Single case with multiple contributing factors (electrolyte disturbance, QT-prolonging drugs, genetic mutations), making it difficult to isolate any single cause."},{"rthcId":"RTHC-03599","title":"Cannabidiol in the Treatment of Epilepsy.","authors":"von Wrede, Randi; Helmstaedter, Christoph; Surges, Rainer","year":2021,"journal":"Clinical drug investigation, 41(3), 211-220","doi":"10.1007/s40261-021-01003-y","pmid":"33559102","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03600","title":"Cannabis, schizophrenia genetic risk, and psychotic experiences: a cross-sectional study of 109,308 participants from the UK Biobank.","authors":"Wainberg, Michael; Jacobs, Grace R; di Forti, Marta; Tripathy, Shreejoy J","year":2021,"journal":"Translational psychiatry, 11(1), 211","doi":"10.1038/s41398-021-01330-w","pmid":"33837184","tags":["psychosis","genetics","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis ever-use was associated with 67% greater adjusted odds of delusions of reference among individuals in the top fifth of schizophrenia polygenic risk, but only 7% greater adjusted odds among the bottom fifth. The cannabis-psychosis association was strongest for persecutory delusions and showed clear dose-dependence.","whyItMatters":"This is among the largest studies to show gene-environment interaction between schizophrenia genetic risk and cannabis use, supporting the hypothesis that genetically vulnerable individuals face greater psychosis risk from cannabis.","specificNumbers":"Sample: 109,308 participants. Top PRS fifth: 67% increased odds of delusions of reference with cannabis use. Bottom PRS fifth: 7% increased odds. Strongest association: persecutory delusions. Cannabis users had earlier onset and more distressing psychotic experiences.","methodology":"Cross-sectional study of 109,308 UK Biobank participants examining self-reported cannabis use against four types of psychotic experiences (auditory hallucinations, visual hallucinations, persecutory delusions, delusions of reference), stratified by schizophrenia polygenic risk scores.","limitations":"Cross-sectional design cannot establish temporal sequence. Self-reported cannabis use and psychotic experiences. UK Biobank participants may not be representative of the general population. Polygenic risk scores explain only a fraction of schizophrenia heritability."},{"rthcId":"RTHC-03601","title":"Changes in Emergency Department Encounters for Vomiting After Cannabis Legalization in Colorado.","authors":"Wang, George Sam; Buttorff, Christine; Wilks, Asa; Schwam, Daniel; Tung, Gregory; Pacula, Rosalie Liccardo","year":2021,"journal":"JAMA network open, 4(9), e2125063","doi":"10.1001/jamanetworkopen.2021.25063","pmid":"34533572","tags":["legalization","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Vomiting-related ED visits increased 29% over the study period. Each additional recreational dispensary was associated with a 3% increase in vomiting-related visits (IRR 1.03). However, counties with high baseline medical dispensary exposure experienced smaller increases than counties with no prior dispensaries (IRR 0.97).","whyItMatters":"This large-scale analysis provides population-level evidence connecting cannabis market expansion to increased vomiting-related healthcare utilization, likely reflecting cannabinoid hyperemesis syndrome.","specificNumbers":"Total patients: 820,778. Visits 2013: 119,312. Visits 2018: 153,699. Increase: 29%. Recreational dispensary IRR: 1.03. Counties with prior medical dispensaries grew 5.8% slower. Female: 62%. Ages 0-18: 25%.","methodology":"Cross-sectional analysis of 820,778 patients with vomiting-related ED claims reported to the Colorado Hospital Association from January 2013 to December 2018, examining the relationship between dispensary density and visit rates by county.","limitations":"Cannot confirm cannabis as the cause of vomiting. ED claims data may include multiple visits by the same patient. No direct measure of cannabis use among patients presenting with vomiting."},{"rthcId":"RTHC-03602","title":"Consumer interest in topical cannabidiol: An examination of online search trends from 2015 to 2019.","authors":"Wang, Jordan V; Shah, Saloni; Albornoz, Christian A; Saedi, Nazanin","year":2021,"journal":"Clinics in dermatology, 39(6), 1014-1017","doi":"10.1016/j.clindermatol.2020.11.007","pmid":"34920818","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03603","title":"Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials.","authors":"Wang, Li; Hong, Patrick J; May, Curtis; Rehman, Yasir; Oparin, Yvgeniy; Hong, Chris J; Hong, Brian Y; AminiLari, Mahmood; Gallo, Lucas; Kaushal, Alka; Craigie, Samantha; Couban, Rachel J; Kum, Elena; Shanthanna, Harsha; Price, Ira; Upadhye, Suneel; Ware, Mark A; Campbell, Fiona; Buchbinder, Rachelle; Agoritsas, Thomas; Busse, Jason W","year":2021,"journal":"BMJ (Clinical research ed.), 374, n1034","doi":"10.1136/bmj.n1034","pmid":"34497047","tags":["pain","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis provides small to very small improvements in pain intensity (WMD -0.50 on 10cm VAS), physical functioning (WMD 1.67 on 100-point SF-36), and sleep (WMD -0.35 on 10cm VAS) compared to placebo, with moderate-to-high certainty evidence. NNT approximately 24 for meaningful pain relief.","whyItMatters":"This is the most rigorous assessment of cannabis for chronic pain published. It provides the evidence base for clinical guidelines and shows that while cannabis is a legitimate treatment option, effects are modest — setting realistic expectations for patients and clinicians.","specificNumbers":"Trials: 32. Patients: 5,174. Pain relief WMD: -0.50 cm on 10 cm VAS. Physical functioning WMD: 1.67 points on 100-point scale. Sleep quality WMD: -0.35 cm on 10 cm VAS. Dizziness RD: 9% (<3 months) to 28% (3+ months). Drowsiness RD: 5%. Nausea RD: 5%.","methodology":"Systematic review and meta-analysis of 32 RCTs enrolling 5,174 adults with chronic non-cancer and cancer pain. GRADE methodology applied. 30 oral, 2 topical preparations. Follow-up 1-5.5 months. Risk of bias assessed. Outcomes include pain intensity, physical functioning, sleep, emotional/social functioning, and adverse events.","limitations":"Most trials used non-inhaled pharmaceutical preparations, limiting generalizability to whole-plant cannabis. Follow-up was short (1-5.5 months). Trials enrolled different pain conditions. No trial compared cannabis to active comparators (other pain drugs). Patient populations in trials differ from self-selected cannabis users."},{"rthcId":"RTHC-03604","title":"Cannabinoids and the eye.","authors":"Wang, Michael T M; Danesh-Meyer, Helen V","year":2021,"journal":"Survey of ophthalmology, 66(2), 327-345","doi":"10.1016/j.survophthal.2020.07.002","pmid":"32763339","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03605","title":"Health Outcomes among Adults Initiating Medical Cannabis for Chronic Pain: A 3-month Prospective Study Incorporating Ecological Momentary Assessment (EMA).","authors":"Wang, Yan; Jean Jacques, Jennifer; Li, Zhigang; Sibille, Kimberly T; Cook, Robert L","year":2021,"journal":"Cannabis (Albuquerque, N.M.), 4(2), 69-83","doi":"10.26828/cannabis/2021.02.006","pmid":"34671723","tags":["pain","medical-cannabis","sleep","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Real-time EMA data (2,535 random + 705 daily assessments) showed significant reductions in momentary pain intensity after starting medical cannabis. Three-month follow-up surveys confirmed reduced pain, lower anxiety and depression, improved sleep, and better quality of life compared to baseline.","whyItMatters":"EMA captures real-time, in-the-moment data rather than relying on retrospective recall, providing a more ecologically valid picture of how medical cannabis affects daily pain and functioning.","specificNumbers":"Participants: 46. Mean age: 55.7 years. Male: 52.2%. Random EMA assessments: 2,535. Daily EMA assessments: 705. Pain intensity reduction coefficient: -16.5. Follow-up: 3 months.","methodology":"Prospective study of 46 adults (mean age 55.7) newly initiating medical cannabis for chronic pain. Used ecological momentary assessment (real-time smartphone surveys) for approximately 1 week pre-treatment and up to 3 weeks post-treatment, plus baseline and 3-month follow-up surveys.","limitations":"No control group or randomization. Small sample size. Short EMA window (1-3 weeks). Self-selected population likely biased toward cannabis-positive attitudes. Potential expectancy effects."},{"rthcId":"RTHC-03606","title":"Cerebellar thickness changes associated with heavy cannabis use: A 3-year longitudinal study.","authors":"Wang, Yanpei; Zuo, Chenyi; Xu, Qinfang; Hao, Lei","year":2021,"journal":"Addiction biology, 26(3), e12931","doi":"10.1111/adb.12931","pmid":"32575152","tags":["neuroscience","cognition","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Both lobule VI and Crus I had higher rates of thickness increase in cannabis users than controls. These changes were associated with age of first cannabis use but not age of frequent use. Alterations in lobule VI and Crus I correlated with Cannabis Use Disorder Identification Test scores, even after controlling for alcohol use.","whyItMatters":"This is one of few longitudinal neuroimaging studies of cannabis effects on the cerebellum, allowing researchers to track changes over time rather than relying on cross-sectional snapshots that cannot distinguish cause from consequence.","specificNumbers":"Cannabis users: 20. Controls: 22. Follow-up: 3 years. Regions affected: lobule VI and Crus I. Changes correlated with: age of first use, CUDIT scores. All cerebellar subregions except lobule VIIB showed age effects.","methodology":"Longitudinal neuroimaging study comparing 20 heavy cannabis users and 22 non-using controls at baseline and 3-year follow-up. All participants completed psychological assessments and T1-structural MRI scans at both time points.","limitations":"Small sample size (42 total). Cannot definitively determine whether thickness changes cause or result from cannabis use. No data on cannabis potency or specific cannabinoid content."},{"rthcId":"RTHC-03607","title":"Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice.","authors":"Wanner, Nicole M; Colwell, Mathia; Drown, Chelsea; Faulk, Christopher","year":2021,"journal":"Clinical epigenetics, 13(1), 4","doi":"10.1186/s13148-020-00993-4","pmid":"33407853","tags":["cbd","pregnancy","anxiety","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory in a sex-specific manner. Thousands of differentially methylated loci were identified in cerebral cortex and hippocampus, with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms.","whyItMatters":"This is the first study to examine developmental CBD exposure effects on offspring behavior and epigenetics, raising important questions about CBD use during pregnancy and breastfeeding.","specificNumbers":"CBD dose: 20 mg/kg daily. Exposure window: 2 weeks pre-mating through lactation. Thousands of differentially methylated loci identified in both cerebral cortex and hippocampus of offspring.","methodology":"Female mice received 20 mg/kg CBD or vehicle daily from two weeks before mating through gestation and lactation. Adult F1 offspring underwent behavioral testing (spatial memory, anxiety/compulsive behavior) and reduced-representation bisulfite sequencing of brain tissue.","limitations":"Animal study in mice. CBD dose (20 mg/kg) may not reflect typical human exposure. Agouti mouse model has specific genetic characteristics. Behavioral effects were sex-specific, complicating interpretation."},{"rthcId":"RTHC-03608","title":"Cannabinoids and Cancer Chemotherapy-Associated Adverse Effects.","authors":"Ward, Sara Jane; Lichtman, Aron H; Piomelli, Daniele; Parker, Linda A","year":2021,"journal":"Journal of the National Cancer Institute. Monographs, 2021(58), 78-85","doi":"10.1093/jncimonographs/lgab007","pmid":"34850893","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03609","title":"Compartment Niche Shapes the Assembly and Network of Cannabis sativa-Associated Microbiome.","authors":"Wei, Guangfei; Ning, Kang; Zhang, Guozhuang; Yu, Haibin; Yang, Shuming; Dai, Fei; Dong, Linlin; Chen, Shilin","year":2021,"journal":"Frontiers in microbiology, 12, 714993","doi":"10.3389/fmicb.2021.714993","pmid":"34675893","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03610","title":"Cannabinoid hyperemesis syndrome in two French emergency departments: a prospective cohort.","authors":"Weiss, Julie; Torrents, Romain; Verhamme, Baptiste; Roch, Antoine; Lazerges, Pierre; Jego, Maeva; Michelet, Pierre; Simon, Nicolas","year":2021,"journal":"Fundamental & clinical pharmacology, 35(1), 186-191","doi":"10.1111/fcp.12580","pmid":"32564375","tags":["medical-cannabis","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"CHS patients used cannabis daily and spent significantly more hours in emergency departments (11 vs. 6.5 hours) with more frequent visits (4.9 vs. 3). Hot showers were the most effective symptom relief in 54.2% of cases. Follow-up was limited, and cannabis cessation was difficult to implement.","whyItMatters":"This is one of few prospective studies quantifying CHS prevalence in emergency settings, showing it is both underrecognized and resource-intensive in terms of ED utilization.","specificNumbers":"Target population: 2,848 patients. CHS cases: 48 (1.6%). All 48 used cannabis daily. Hot shower effective: 54.2%. Mean ED hours with CHS: 11 vs. 6.5. Mean ED visits: 4.9 vs. 3. Hospitalized: 20.3%.","methodology":"Prospective cohort study recruiting patients with unexplained abdominal pain syndrome from two Marseille hospital emergency departments (October 2017 to July 2018). CHS was defined as chronic cannabis use with nausea and vomiting per Simonetto criteria.","limitations":"Relatively small CHS cohort (48 patients). Limited to two hospitals in one French city. Follow-up was limited, preventing assessment of long-term outcomes. Prospective identification depended on clinical suspicion."},{"rthcId":"RTHC-03611","title":"Association between Smoking Cannabis and Quitting Cigarettes in a Large American Cancer Society Cohort.","authors":"Westmaas, J Lee; Strollo, Sara E; Newton, Christina C; Carter, Brian D; Diver, W Ryan; Flanders, W Dana; Stevens, Victoria L; Patel, Alpa V; Alcaraz, Kassandra I; Thrul, Johannes; Jacobs, Eric J","year":2021,"journal":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 30(10), 1956-1964","doi":"10.1158/1055-9965.EPI-20-1810","pmid":"34348959","tags":["quitting","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Adjusted cigarette quitting rates did not differ by cannabis status: never cannabis users (36.2%), former users (34.1%), and recent users (33.6%). Among recent cannabis smokers, quitting rates were similar across low (31.4%), moderate (36.7%), and high frequency (34.4%) use groups.","whyItMatters":"As cannabis use increases, clinicians have worried it might make cigarette cessation harder. This large, well-designed study found no evidence supporting that concern.","specificNumbers":"Sample: 4,535 smokers. Follow-up: 3.1 years average. Quit rates: never cannabis 36.2%, former 34.1%, recent 33.6%. By frequency: low 31.4%, moderate 36.7%, high 34.4%. Intention to quit in 30 days: no difference (p=0.83).","methodology":"Longitudinal study of 4,535 adult cigarette smokers from the American Cancer Society Cancer Prevention Study-3, enrolled 2009-2013 with follow-up in 2015-2017 (mean 3.1 years). Cannabis status was retrospectively assessed at baseline. Models adjusted for sociodemographics, smoking behaviors, and health factors.","limitations":"Self-reported cannabis and cigarette use. Retrospective cannabis status assessment. Follow-up was about 3 years; longer-term effects are unknown. Participants in a cancer prevention study may not be representative."},{"rthcId":"RTHC-03612","title":"A Review of the Potential Use of Pinene and Linalool as Terpene-Based Medicines for Brain Health: Discovering Novel Therapeutics in the Flavours and Fragrances of Cannabis.","authors":"Weston-Green, Katrina; Clunas, Helen; Jimenez Naranjo, Carlos","year":2021,"journal":"Frontiers in psychiatry, 12, 583211","doi":"10.3389/fpsyt.2021.583211","pmid":"34512404","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03613","title":"Sex, species and age: Effects of rodent demographics on the pharmacology of ∆9-tetrahydrocanabinol.","authors":"Wiley, Jenny L; Barrus, Daniel G; Farquhar, Charlotte E; Lefever, Timothy W; Gamage, Thomas F","year":2021,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 106, 110064","doi":"10.1016/j.pnpbp.2020.110064","pmid":"32810571","tags":["neuroscience","sex-differences","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"11-OH-THC showed 7- to 31-fold greater potency than THC for catalepsy and hypothermia in mice and 7- to 9-fold greater potency in drug discrimination. Female rats were significantly more sensitive to THC than males. THC discriminative stimulus effects were stable across 17 months of aging in mice.","whyItMatters":"When cannabis is eaten rather than smoked, more THC is converted to 11-OH-THC through first-pass liver metabolism. Understanding this metabolite's greater potency helps explain why edibles can produce stronger effects.","specificNumbers":"11-OH-THC potency vs. THC: 7-15x for catalepsy, 7-31x for hypothermia, 7-9x in drug discrimination. 11-OH-THC affinity: ~1.5x higher than THC. Aging period: 17 months with stable THC discrimination.","methodology":"Compared THC and 11-OH-THC using CB1 receptor binding assays, GTPgS functional assays, and in vivo behavioral tests (catalepsy, hypothermia, drug discrimination) across ICR mice, C57Bl/6J mice, and Sprague-Dawley rats of both sexes.","limitations":"Animal study using intraperitoneal injection, not oral consumption. Cross-species differences complicate human extrapolation. Limited behavioral measures."},{"rthcId":"RTHC-03614","title":"Cannabinoid Receptor Subtype-1 Regulates Allergic Airway Eosinophilia During Lung Helminth Infection.","authors":"Wiley, Mark B; Bobardt, Sarah D; Nordgren, Tara M; Nair, Meera G; DiPatrizio, Nicholas V","year":2021,"journal":"Cannabis and cannabinoid research, 6(3), 242-252","doi":"10.1089/can.2020.0167","pmid":"33998896","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03615","title":"Untapped endocannabinoid pharmacological targets: Pipe dream or pipeline?","authors":"Wilkerson, Jenny L; Bilbrey, Joshua A; Felix, Jasmine S; Makriyannis, Alexandros; McMahon, Lance R","year":2021,"journal":"Pharmacology, biochemistry, and behavior, 206, 173192","doi":"10.1016/j.pbb.2021.173192","pmid":"33932409","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03616","title":"Psychiatric Hospitalization and Length of Stay Differences in Cannabis Users and Non-Users with a Primary Discharge Diagnosis of Schizophrenia or Schizoaffective Disorder.","authors":"Williams, Steven R; Agapoff, James R; Jalan, Devesh; Hishinuma, Earl S; Kida, Lauren E","year":2021,"journal":"Substance use & misuse, 56(11), 1736-1739","doi":"10.1080/10826084.2021.1949615","pmid":"34263706","tags":["psychosis","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis-only users (n=55) had shorter mean hospital stays than non-substance users (n=462): 6.15 vs. 8.66 days. However, this difference was no longer significant after controlling for covariates (p=0.15). The number of psychiatric admissions did not differ between groups.","whyItMatters":"Contrary to common assumptions, cannabis use did not predict worse hospitalization outcomes in this population, suggesting the relationship between cannabis and schizophrenia course may be more nuanced than assumed.","specificNumbers":"Cannabis users: 55. Non-users: 462. Mean LOS cannabis group: 6.15 days (SD 5.32). Mean LOS non-users: 8.66 days (SD 11.14). Mean admissions: 1.84. Unadjusted p=0.035; adjusted p=0.15.","methodology":"Retrospective comparison of 55 cannabis-only users and 462 non-substance users hospitalized with a primary diagnosis of schizophrenia or schizoaffective disorder. Used Wilcoxon-Mann-Whitney tests, ANOVA, and Poisson regression with covariate adjustment.","limitations":"Small cannabis-only group (n=55). Retrospective design. Cannot account for cannabis potency, frequency, or timing relative to symptoms. Excluded polydrug users, limiting generalizability."},{"rthcId":"RTHC-03617","title":"Association between legalization of recreational cannabis and fatal motor vehicle collisions in the United States: an ecologic study.","authors":"Windle, Sarah B; Eisenberg, Mark J; Reynier, Pauline; Cabaussel, Josselin; Thombs, Brett D; Grad, Roland; Ells, Carolyn; Sequeira, Crystal; Filion, Kristian B","year":2021,"journal":"CMAJ open, 9(1), E233-E241","doi":"10.9778/cmajo.20200155","pmid":"33731424","tags":["driving","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"After adjusting for calendar year, legalization was associated with increased rates of fatal collisions (IRR 1.15, 95% CI 1.06-1.26) and associated deaths (IRR 1.16, 95% CI 1.06-1.27). The difference between the first 12 months post-legalization and subsequent months was inconclusive.","whyItMatters":"This multi-state analysis provides population-level evidence of increased traffic fatalities associated with cannabis legalization, informing ongoing policy debates about legalization and road safety.","specificNumbers":"Fatal collision IRR: 1.15 (95% CI 1.06-1.26). Death IRR: 1.16 (95% CI 1.06-1.27). Data period: 2007-2018. First 12 months vs. later: IRR 0.92 for collisions and deaths (not significant).","methodology":"Ecologic study using the US Fatality Analysis Reporting System (2007-2018). Examined jurisdiction-specific fatal collision rates before and after legalization using Poisson regression, then meta-analyzed across jurisdictions using DerSimonian and Laird random-effects models.","limitations":"Ecologic design cannot link individual cannabis use to specific crashes. Cannot control for all confounding factors that changed alongside legalization. US Fatality Analysis Reporting System may have reporting variations across jurisdictions."},{"rthcId":"RTHC-03618","title":"Please don't call it medical marijuana unless it is; but it probably isn't.","authors":"Witek, Theodore J","year":2021,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 112(1), 74-77","doi":"10.17269/s41997-020-00333-2","pmid":"32557287","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03619","title":"Attitudes and beliefs about recreational cannabis legalization among cannabis-using young adults in Los Angeles: Impact on concurrent cannabis practices and problematic cannabis use.","authors":"Wong, Carolyn F; Mendez, Stephanie E A; Conn, Bridgid M; Iverson, Ellen; Lankenau, Stephen E","year":2021,"journal":"Drug and alcohol dependence, 228, 109053","doi":"10.1016/j.drugalcdep.2021.109053","pmid":"34610520","tags":["legalization","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Three groups emerged: Impacted (n=113), Partially-Impacted (n=131), and Neutral (n=57). Impacted individuals reported the most recent days of use, highest number of hits per day, and highest problematic use scores. Medical cannabis patients were more likely to be Neutral, while recreational users were more likely to be Impacted.","whyItMatters":"This study shows that attitudes toward legalization were not just opinions but were associated with actual use patterns and problem severity, providing an early look at how policy changes shape behavior.","specificNumbers":"Sample: 301 young adults. Three classes: Impacted (113), Partially-Impacted (131), Neutral (57). Impacted group had highest use days, hits/day, and problematic use scores.","methodology":"Cross-sectional survey of 301 cannabis-using young adults in Los Angeles, interviewed 2017-2018 (after recreational legalization, through early retail sales). Used latent class analysis to identify groups based on attitudes about legalization impact, with cannabis practices and problematic use as distal outcomes.","limitations":"Cross-sectional design cannot determine whether attitudes drove use or vice versa. LA-specific sample may not generalize. Self-reported measures. Early post-legalization period may not reflect longer-term patterns."},{"rthcId":"RTHC-03620","title":"Increased Likelihood of Falling in Older Cannabis Users vs. Non-Users.","authors":"Workman, Craig D; Fietsam, Alexandra C; Sosnoff, Jacob; Rudroff, Thorsten","year":2021,"journal":"Brain sciences, 11(2)","doi":"10.3390/brainsci11020134","pmid":"33494171","tags":["seniors","driving","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis-using older adults showed higher fall risk scores, poorer one-leg standing balance, and slower gait speed compared to matched non-users. No significant differences in cognitive function were found between groups.","whyItMatters":"Falls are a leading cause of injury and death among older adults. If cannabis use exacerbates age-related balance and gait decline, this has significant clinical implications as cannabis use grows among seniors.","specificNumbers":"Total participants: 16. Cannabis users: 8. Non-users: 8. Age and sex matched. Higher fall risk, worse one-leg balance, and slower gait in users. No cognitive function difference.","methodology":"Cross-sectional comparison of 8 older chronic cannabis users and 8 age- and sex-matched non-users. Assessed fall risk, one-leg standing balance, gait speed, and cognitive function using standardized tests.","limitations":"Very small sample (n=16). Cross-sectional design cannot determine if cannabis caused the impairments. No control for pre-existing conditions or medications. Cannot assess acute vs. chronic effects."},{"rthcId":"RTHC-03621","title":"Relationship between cannabis use and psychotic experiences in college students.","authors":"Wright, Abigail C; Cather, Corinne; Farabaugh, Amy; Terechina, Olga; Pedrelli, Paola; Nyer, Maren; Fava, Maurizio; Holt, Daphne J","year":2021,"journal":"Schizophrenia research, 231, 198-204","doi":"10.1016/j.schres.2021.04.004","pmid":"33887647","tags":["psychosis","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Greater weekly cannabis use was associated with increased hallucinatory experiences (persisting after controlling for depression) and delusional ideation (not persisting after depression adjustment). Heavier cannabis users reported more distressing delusional ideas held with greater conviction.","whyItMatters":"Subclinical psychotic experiences that are severe and distressing are linked to increased risk of developing a psychotic disorder, making the cannabis-psychotic experience connection clinically relevant even in non-clinical populations.","specificNumbers":"Sample: 1,034 college students. Measured: past-week cannabis use, hallucinatory experiences, delusional ideation, depression. Cannabis-hallucination link: significant after depression adjustment. Cannabis-delusion link: not significant after depression adjustment.","methodology":"Cross-sectional survey of 1,034 US college students using validated questionnaires: Peters Delusions Inventory for delusional ideation, Launay-Slade Hallucinations Scale-Extended for hallucinations, and Beck Depression Inventory for depression.","limitations":"Cross-sectional design cannot determine direction of causation. Self-reported cannabis use. No information on cannabis potency or strain. College student sample may not generalize."},{"rthcId":"RTHC-03622","title":"Trends in intellectual property rights protection for medical cannabis and related products.","authors":"Wyse, Joseph; Luria, Gilad","year":2021,"journal":"Journal of cannabis research, 3(1), 1","doi":"10.1186/s42238-020-00057-7","pmid":"33526141","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03623","title":"Components of the Endocannabinoid System and Effects of Cannabinoids Against Bone Diseases: A Mini-Review.","authors":"Xin, Yuqi; Tang, Anqun; Pan, Shuting; Zhang, Jie","year":2021,"journal":"Frontiers in pharmacology, 12, 793750","doi":"10.3389/fphar.2021.793750","pmid":"35126132","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03624","title":"Cannabinoid Hyperemesis Syndrome: A Case Study in a Tunisian Young Man.","authors":"Yacoub, Haythem; Hassine, Hajer; Kchir, Héla; Maamouri, Nadia","year":2021,"journal":"Case reports in medicine, 2021, 6617148","doi":"10.1155/2021/6617148","pmid":"33628261","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03625","title":"Mini-review: The therapeutic role of cannabinoids in neuroHIV.","authors":"Yadav-Samudrala, Barkha J; Fitting, Sylvia","year":2021,"journal":"Neuroscience letters, 750, 135717","doi":"10.1016/j.neulet.2021.135717","pmid":"33587986","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03626","title":"Cannabis: An Emerging Treatment for Common Symptoms in Older Adults.","authors":"Yang, Kevin H; Kaufmann, Christopher N; Nafsu, Reva; Lifset, Ella T; Nguyen, Khai; Sexton, Michelle; Han, Benjamin H; Kim, Arum; Moore, Alison A","year":2021,"journal":"Journal of the American Geriatrics Society, 69(1), 91-97","doi":"10.1111/jgs.16833","pmid":"33026117","tags":["seniors","medical-cannabis","pain","sleep"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"15% of geriatric clinic patients used cannabis. Most used for medical purposes (78%), primarily pain/arthritis (73%), sleep disturbance (29%), anxiety (24%), and depression (17%). Over three-quarters found cannabis helpful. Late-onset users (age 61+, comprising 61%) showed less risky patterns including more medical use and less smoking.","whyItMatters":"With cannabis use growing fastest among older adults, understanding their usage patterns, motivations, and disclosure behaviors helps clinicians provide appropriate guidance.","specificNumbers":"Total surveyed: 568. Cannabis users: 83 (15%). Medical use only: 78%. Pain/arthritis: 73%. Sleep: 29%. Anxiety: 24%. Depression: 17%. First use after 60: 61%. Regular use (daily/weekly): 53%. CBD-only products: 46%. Family aware: 94%. Doctor aware: 41%.","methodology":"Anonymous survey of 568 adults aged 65+ at a geriatrics clinic assessing cannabis use characteristics, purposes, administration methods, perceived helpfulness, and disclosure patterns.","limitations":"Single geriatrics clinic in one location. Self-selected respondents may over- or under-represent cannabis users. Self-reported helpfulness without objective measures. Cross-sectional design."},{"rthcId":"RTHC-03627","title":"Cholesterol as a modulator of cannabinoid receptor CB2 signaling.","authors":"Yeliseev, Alexei; Iyer, Malliga R; Joseph, Thomas T; Coffey, Nathan J; Cinar, Resat; Zoubak, Lioudmila; Kunos, George; Gawrisch, Klaus","year":2021,"journal":"Scientific reports, 11(1), 3706","doi":"10.1038/s41598-021-83245-6","pmid":"33580091","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03628","title":"Site-selective labeling and electron paramagnetic resonance studies of human cannabinoid receptor CB2.","authors":"Yeliseev, Alexei A; Zoretich, Kaeli; Hooper, Levi; Teague, Walter; Zoubak, Lioudmila; Hines, Kirk G; Gawrisch, Klaus","year":2021,"journal":"Biochimica et biophysica acta. Biomembranes, 1863(8), 183621","doi":"10.1016/j.bbamem.2021.183621","pmid":"33865808","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03629","title":"Emergency Department Pediatric Visits in Alberta for Cannabis After Legalization.","authors":"Yeung, Matthew E M; Weaver, Colin G; Hartmann, Riley; Haines-Saah, Rebecca; Lang, Eddy","year":2021,"journal":"Pediatrics, 148(4)","doi":"10.1542/peds.2020-045922","pmid":"34544846","tags":["youth","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Pediatric cannabis-related ED visit volume did not change post-legalization when accounting for pre-existing trends. However, unintentional ingestions increased significantly in children aged 0-11 (IRR 1.77) and older adolescents aged 15-17 (IRR 1.36). Hyperemesis cases increased among older adolescents (RR 1.64), while co-ingestant use decreased (RR 0.77).","whyItMatters":"While total pediatric cannabis ER visits did not spike after legalization, the shift toward accidental ingestions in young children highlights the importance of child-resistant packaging and safe storage of cannabis edibles.","specificNumbers":"Study period: Oct 2013-Feb 2020. Unintentional ingestion IRR children: 1.77 (95% CI 1.42-2.20). Older teen ingestion IRR: 1.36 (95% CI 1.07-1.71). Older teen hyperemesis RR: 1.64 (95% CI 1.13-2.37). Co-ingestant use decrease RR: 0.77.","methodology":"Retrospective analysis of National Ambulatory Care Reporting System data for urban Alberta cannabis-related pediatric ED visits from October 2013 to February 2020. Used interrupted time series, incident rate ratios, and relative risk ratios across three age groups.","limitations":"Limited to urban Alberta EDs. Cannot distinguish between pre-legalization medical cannabis access and post-legalization recreational access. ICD coding may miss some cannabis cases."},{"rthcId":"RTHC-03630","title":"A Cannabinoid-1 Receptor Antagonist MJ08 with Different Effects in Stomach and Small Intestine.","authors":"Yu, Yang; Chen, Wei; Meng, Dan; Zhou, Xiao-Mian; Wang, Li-Li; Xu, Cheng","year":2021,"journal":"Assay and drug development technologies, 19(3), 176-183","doi":"10.1089/adt.2020.1041","pmid":"33784479","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03631","title":"Efficacy of topical capsaicin for the treatment of cannabinoid hyperemesis syndrome: A retrospective cohort study.","authors":"Yusuf, Hamzah M; Geier, Curtis; Staidle, Alex; Montoy, Juan Carlos C","year":2021,"journal":"The American journal of emergency medicine, 43, 142-148","doi":"10.1016/j.ajem.2021.01.073","pmid":"33561623","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"No overall difference in time to discharge between capsaicin (4.46 hours) and no capsaicin (3.52 hours) groups. However, patients receiving capsaicin within the first two medication rounds had significantly shorter stays than those receiving it later (4.83 vs. 7.09 hours, p=0.01).","whyItMatters":"Capsaicin cream has been promoted as a novel CHS treatment, but this study suggests its benefit depends on early administration rather than being universally effective.","specificNumbers":"Patients: 55 (35 capsaicin, 20 control). Time to discharge: 4.46 vs. 3.52 hours (p=0.10). Early capsaicin: 4.83 vs. 7.09 hours (p=0.01). Bounceback within 24h: 11% vs. 10%. Admission: 19% vs. 5% (p=0.07).","methodology":"Retrospective observational study of 55 CHS patients (35 capsaicin, 20 no capsaicin). Capsaicin allocation was pseudo-randomized based on pharmacist availability. Outcomes included time to discharge, medication rounds, bounceback rate, and admission rate.","limitations":"Small sample size. Retrospective design. Pseudo-randomization may introduce bias. Capsaicin group had a non-significant trend toward higher admission rates, possibly indicating more severe cases."},{"rthcId":"RTHC-03632","title":"Therapeutic potential of cannabidivarin for epilepsy and autism spectrum disorder.","authors":"Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela","year":2021,"journal":"Pharmacology & therapeutics, 226, 107878","doi":"10.1016/j.pharmthera.2021.107878","pmid":"33895189","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03633","title":"Cannabinoid CB2 Receptor Activation Attenuates Fentanyl-Induced Respiratory Depression.","authors":"Zavala, Carmen A; Thomaz, Ana C; Iyer, Vishakh; Mackie, Ken; Hohmann, Andrea G","year":2021,"journal":"Cannabis and cannabinoid research, 6(5), 389-400","doi":"10.1089/can.2020.0059","pmid":"33998863","tags":["pain","harm-reduction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Co-administration of LY2828360 (3 mg/kg) with fentanyl (0.2 mg/kg) attenuated respiratory depression in wild-type mice but not CB2 knockout mice, confirming the effect was CB2-mediated. LY2828360 alone had no effect on respiratory parameters in either genotype.","whyItMatters":"Opioid-induced respiratory depression is the primary cause of overdose deaths. A cannabinoid compound that reduces this risk without itself affecting breathing could be a breakthrough in harm reduction.","specificNumbers":"Fentanyl doses: 0.1 and 0.2 mg/kg. LY2828360 dose: 3 mg/kg. Higher fentanyl dose produced greater respiratory suppression. CB2 agonist attenuated depression in WT but not CB2KO mice.","methodology":"Whole-body plethysmography in wild-type and CB2 knockout mice. Measured minute ventilation, respiratory frequency, and tidal volume after fentanyl alone vs. fentanyl + LY2828360 co-administration.","limitations":"Animal study in mice. Unknown whether CB2 agonists would have the same effect in humans. Single dose combination tested. Long-term effects unknown."},{"rthcId":"RTHC-03634","title":"Medication overuse headache in patients with chronic migraine using cannabis: A case-referent study.","authors":"Zhang, Niushen; Woldeamanuel, Yohannes W","year":2021,"journal":"Headache, 61(8), 1234-1244","doi":"10.1111/head.14195","pmid":"34370866","tags":["pain","medical-cannabis","drug-interactions"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Medication overuse headache was present in 81% of cannabis-using chronic migraine patients vs. 41% of non-users (adjusted OR 6.3, 95% CI 3.56-11.1). Cannabis use was significantly correlated with opioid use (rho=0.26), and cluster analysis revealed a high-risk group with 9.3 times more cannabis use and 9.2 times more opioid use.","whyItMatters":"Many migraine patients use cannabis expecting symptom relief, but this study suggests it may actually worsen the cycle of medication overuse that perpetuates chronic headache.","specificNumbers":"Patients: 368 (212 MOH, 156 no MOH). Cannabis users with MOH: 81% vs. 41%. Adjusted OR: 6.3 (95% CI 3.56-11.1). Cannabis-opioid correlation: rho=0.26. Cluster I: 9.3x more cannabis, 9.2x more opioids, 1.8x more MOH.","methodology":"Case-referent study of 368 chronic migraine patients from headache clinics (2015-2019). Compared 212 with medication overuse headache to 156 without. Used logistic regression and agglomerative hierarchical clustering.","limitations":"Cross-sectional design cannot determine whether cannabis causes MOH or whether MOH patients seek cannabis for relief. Single-center study. No data on cannabis type, dose, or frequency."},{"rthcId":"RTHC-03635","title":"Adolescent drug use initiation and transition into other drugs: A retrospective longitudinal examination across race/ethnicity.","authors":"Zhang, Saijun; Wu, Shiyou; Wu, Qi; Durkin, Daniel W; Marsiglia, Flavio F","year":2021,"journal":"Addictive behaviors, 113, 106679","doi":"10.1016/j.addbeh.2020.106679","pmid":"33032193","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Two-thirds of adolescent drug users started with marijuana, one-quarter with inhalants. By year 8, the probability of using a new drug was about 40% for marijuana/inhalant starters and 70-80% for those starting with hallucinogens, prescription drugs, or hard drugs. Black/African American adolescents were least likely to transition.","whyItMatters":"The study provides nuanced support for both gateway theory and generalized risk theory, showing that while marijuana starters do transition to other drugs, they do so at lower rates than those starting with other substances.","specificNumbers":"Sample: 10,644 adolescent drug users. Marijuana initiators: 66%. Inhalant initiators: 25%. By year 8: 40% transition for marijuana starters, 70-80% for other drug starters. Racial differences: Black/African American least likely to transition.","methodology":"Retrospective longitudinal analysis using pooled NSDUH data (2015-2018) of 10,644 adolescent drug users aged 14-17. Constructed longitudinal drug use histories based on age of initiation. Applied life table methods and Cox regression models.","limitations":"Retrospective self-report of drug initiation ages introduces recall bias. NSDUH excludes institutionalized and homeless populations. Cannot account for unmeasured confounders. Excludes alcohol and tobacco."},{"rthcId":"RTHC-03636","title":"Influences of puff protocols and upper airway anatomy on cannabis pharmacokinetics: A CFPD-PK study.","authors":"Zhao, Jianan; Feng, Yu; Tian, Geng; Taylor, Cassandra; Arden, N Sarah","year":2021,"journal":"Computers in biology and medicine, 132, 104333","doi":"10.1016/j.compbiomed.2021.104333","pmid":"33770654","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03637","title":"Cannabis Use and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study.","authors":"Zhao, Jianqiang; Chen, Heng; Zhuo, Chengui; Xia, Shudong","year":2021,"journal":"Frontiers in cardiovascular medicine, 8, 676850","doi":"10.3389/fcvm.2021.676850","pmid":"34409073","tags":["cardiovascular","genetics"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Standard MR analysis showed no causal effects of cannabis use on coronary artery disease, myocardial infarction, stroke subtypes, atrial fibrillation, or heart failure. However, multivariable MR adjusting for tobacco and BMI suggested causal effects on small vessel stroke (OR 1.17, 95% CI 1.02-1.35) and atrial fibrillation (OR 1.06, 95% CI 1.01-1.10).","whyItMatters":"While observational studies have linked cannabis to cardiovascular risk, this genetic approach suggests most of that association may be confounded by tobacco use and obesity, with possible independent effects limited to specific conditions.","specificNumbers":"Genetic instruments: 10 SNPs. Multivariable MR small vessel stroke OR: 1.17 (95% CI 1.02-1.35, p=0.03). Atrial fibrillation OR: 1.06 (95% CI 1.01-1.10, p=0.01). No significant effects on CAD, MI, other stroke subtypes, or heart failure.","methodology":"Two-sample Mendelian randomization using 10 SNPs associated with cannabis use as genetic instruments. Summary statistics from GWAS meta-analyses. Sensitivity analyses including multivariable MR adjusting for tobacco use and BMI.","limitations":"MR assumptions may not fully hold. Cannabis use SNPs may also influence tobacco use. Effect sizes for SVS and AF were small and borderline significant. Cannot assess dose-response or route of administration."},{"rthcId":"RTHC-03638","title":"Detection of Drugs in Oral Fluid Samples Using a Commercially Available Collection Device: Agreement with Urine Testing and Evaluation of A and B Samples Obtained from Employees at Different Workplace Settings with Uncontrolled Sampling Procedures.","authors":"Zheng, Yufang; Sparve, Erik; Sparring, Stefan; Bergström, Mats","year":2021,"journal":"Journal of analytical toxicology, 44(9), 1004-1011","doi":"10.1093/jat/bkaa024","pmid":"32128555","tags":["workplace","drug-interactions"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This study compared 113 paired oral fluid and urine samples collected from a treatment center, testing for cannabis, amphetamines, benzodiazepines, opiates/opioids, and cocaine. Overall, oral fluid and urine results correlated well across drug classes.\n\nFor cannabis specifically, oral fluid detection was possible but less sensitive than urine. THC metabolites persist in urine for days to weeks, while oral fluid primarily detects parent THC, which clears faster. This means oral fluid testing has a shorter detection window — which could be an advantage for workplace testing (closer to measuring recent use) or a disadvantage for treatment monitoring (might miss ongoing use).\n\nThe A/B sample comparison from workplace settings showed good reproducibility. Drug stability in stored samples was maintained at -20°C for at least one year, supporting the reliability of oral fluid as a testing medium for confirmatory analysis.","whyItMatters":"The workplace drug testing debate often comes down to what we're actually measuring. Urine tests catch cannabis use from weeks ago. Oral fluid tests narrow the window closer to recent use. As cannabis becomes legal in more jurisdictions, the testing method increasingly determines whether a positive result reflects impairment risk or just past-weekend use.\n\nThis study showed oral fluid testing is technically feasible and reliable for cannabis, though less sensitive than urine. For workplaces trying to balance safety with employee rights under legalization, the shorter detection window of oral fluid might better serve the actual goal: identifying recent use, not historical use.","specificNumbers":"• 113 paired oral fluid/urine samples compared\n• Good correlation across all drug classes\n• Cannabis: detectable in oral fluid but with shorter window than urine\n• 76 workplace A/B samples showed good reproducibility\n• Samples stable at -20°C for 1+ year","methodology":"Comparison of 113 paired oral fluid and urine samples from a treatment center using the Oral-Eze commercial collection device. Additionally, 76 A/B oral fluid samples from workplace settings compared for consistency. Drug stability assessed after 1 year storage at -20°C. Multiple drug classes tested.","limitations":"Treatment center samples may over-represent heavy users compared to workplace populations. Only one commercial oral fluid device tested. Sample sizes were moderate. Cannot determine the exact detection window for each drug class in oral fluid. Does not compare to blood testing as a reference standard for impairment."},{"rthcId":"RTHC-03639","title":"Real-Time Imaging of Immune Modulation by Cannabinoids Using Intravital Fluorescence Microscopy.","authors":"Zhou, Juan; Kamali, Kiyana; Lafreniere, J Daniel; Lehmann, Christian","year":2021,"journal":"Cannabis and cannabinoid research, 6(3), 221-232","doi":"10.1089/can.2020.0179","pmid":"34042507","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03640","title":"Perceived Importance of Factors in Cannabis Purchase Decisions: A Best-worst Scaling Experiment.","authors":"Zhu, Bin; Guo, Huiying; Cao, Ying; An, Ruopeng; Shi, Yuyan","year":2021,"journal":"The International journal on drug policy, 91, 102793","doi":"10.1016/j.drugpo.2020.102793","pmid":"32482489","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The top five purchase factors were quality, strain type, price, THC content, and pesticide status, accounting for roughly half the total importance. Medical users prioritized CBD content and pesticide status, while recreational users focused more on quality, THC, and price. Packaging was the least important attribute.","whyItMatters":"Understanding what drives cannabis purchase decisions helps regulators design effective labeling requirements and helps public health agencies target messaging about product safety.","specificNumbers":"Sample: 817 cannabis users across 7 states. Top 5 attributes: quality, strain type, price, THC, pesticide (50% of total importance). Packaging: least important. 10 choice scenarios per respondent.","methodology":"Online survey of 817 adult cannabis users in seven states with legal recreational sales (January 2018). Best-worst scaling experiment with 20 policy-relevant attributes across 10 choice scenarios per respondent. Analyzed using hierarchical Bayesian mixed logit models.","limitations":"Online survey may over-represent tech-savvy users. Seven states may not represent emerging markets. Best-worst scaling captures stated rather than revealed preferences. January 2018 data precedes further market evolution."},{"rthcId":"RTHC-03641","title":"Anti-fatigue activity of hemp leaves water extract and the related biochemical changes in mice.","authors":"Zhu, Jiaqing; Yi, Juanjuan; Kang, Qiaozhen; Huang, Jinyong; Cui, Yan; Zhang, Guojun; Wang, Zongzhen; Zhang, Liming; Zheng, Zhiqiang; Lu, Jike; Hao, Limin","year":2021,"journal":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 150, 112054","doi":"10.1016/j.fct.2021.112054","pmid":"33577943","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03642","title":"Diagnosis and Acute Management of Adolescent Cannabinoid Hyperemesis Syndrome: A Systematic Review.","authors":"Zhu, Jie Wei; Gonsalves, Clarelle L; Issenman, Robert M; Kam, April J","year":2021,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 68(2), 246-254","doi":"10.1016/j.jadohealth.2020.07.035","pmid":"33036874","tags":["youth","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Adolescent CHS fulfills adult diagnostic criteria. It may present more frequently in females, with the earliest case at age 15. A substantial proportion (21%) had anxiety and depression history. While haloperidol and capsaicin may offer temporary relief, complete cannabis cessation is the only known effective treatment.","whyItMatters":"With adolescent cannabis use increasing, recognizing CHS in younger patients is critical for avoiding unnecessary diagnostic workups and directing treatment toward the root cause.","specificNumbers":"Databases searched: 5. Initial records: 1,334. Full-text reviewed: 148. Included: 21 studies. Earliest adolescent case: age 15. Anxiety/depression comorbidity: 21%.","methodology":"Systematic review searching five databases for studies published December 1954 to December 2019. From 1,334 initial records, 148 underwent full-text review, yielding 21 included studies (10 on diagnosis, 11 on treatment).","limitations":"Limited number of adolescent-specific studies (21). Most evidence from case reports and small series. Publication bias likely. Cannot determine true CHS prevalence in adolescents."},{"rthcId":"RTHC-03643","title":"Possible Consequences of Cannabis Legalization - What Do Research Show?","authors":"Žigić, Nera; Hasanović, Mevludin; Pajević, Izet; Jakovljević, Miro","year":2021,"journal":"Psychiatria Danubina, 33(Suppl 4), 1184-1195","doi":null,"pmid":"35354186","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03644","title":"Cannabidiol treatment of severe refractory epilepsy in children and young adults.","authors":"Zilmer, Monica; Olofsson, Kern","year":2021,"journal":"Danish medical journal, 68(5)","doi":null,"pmid":"33913416","tags":["epilepsy","cbd","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"At 3 months, 31.4% of patients achieved 50% or greater seizure reduction and 68.6% showed some improvement. Dravet and Lennox-Gastaut patients had much higher response rates (70% achieving 50% reduction) compared to other epilepsies (22%). Clobazam co-medication increased seizure reduction. Response rates declined over time: 20% maintained 50% reduction at 24 months.","whyItMatters":"While CBD is approved for Dravet and Lennox-Gastaut syndromes, this study shows it may also benefit children with other severe epilepsies, though the waning response over time needs monitoring.","specificNumbers":"Patients: 78. With seizure registration: 51. 50% reduction at 3 months: 31.4%. At 6 months: 31.1%. At 12 months: 28.1%. At 24 months: 20.0%. Dravet/LGS at 3 months: 70%. Other epilepsies: 22%. Any reduction at 3 months: 68.6%.","methodology":"Retrospective cohort study of 78 patients treated with off-label cannabidiol at the Filadelfia Epilepsy Hospital, Denmark from 2016-2019. Assessed seizure frequency registration or perceived effect over up to 24 months.","limitations":"Retrospective, uncontrolled design. Off-label use with varying doses. Only 51 of 78 patients had seizure frequency registration. No placebo comparison."},{"rthcId":"RTHC-03645","title":"Classical and Neural Network Machine Learning to Determine the Risk of Marijuana Use.","authors":"Zoboroski, Laura; Wagner, Torrey; Langhals, Brent","year":2021,"journal":"International journal of environmental research and public health, 18(14)","doi":"10.3390/ijerph18147466","pmid":"34299915","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03646","title":"Medical cannabis authorization and the risk of cardiovascular events: a longitudinal cohort study.","authors":"Zongo, Arsene; Lee, Cerina; Dyck, Jason R B; El-Mourad, Jihane; Hyshka, Elaine; Hanlon, John G; Eurich, Dean T","year":2021,"journal":"BMC cardiovascular disorders, 21(1), 426","doi":"10.1186/s12872-021-02229-6","pmid":"34507536","tags":["cardiovascular","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Medical cannabis patients had higher rates of ACS or stroke (7.19 vs. 5.67 per 1000 person-years, aHR 1.44, 95% CI 1.08-1.93). The association was only significant in males (aHR 1.77) when stratified by sex. Any cardiovascular event risk was also elevated (aHR 1.47).","whyItMatters":"This large matched cohort study adds to growing evidence of cardiovascular risk associated with medical cannabis use, particularly for male patients.","specificNumbers":"Cannabis patients: 18,653. Controls: 51,243. Median follow-up: 242 days. ACS/stroke aHR: 1.44 (95% CI 1.08-1.93). Males aHR: 1.77 (1.23-2.56). Any CV event aHR: 1.47 (1.26-1.72). ACS/stroke incidence: 7.19 vs. 5.67 per 1000 person-years.","methodology":"Longitudinal cohort study matching 18,653 cannabis-authorized patients to 51,243 population-based controls in Ontario, Canada (2014-2017). Used conditional Cox proportional hazards regression for cardiovascular outcomes over median 242-day follow-up.","limitations":"Cannabis authorization does not confirm actual use or quantify dose. Patients seeking medical cannabis may have underlying conditions predisposing to cardiovascular events. Residual confounding likely despite matching."},{"rthcId":"RTHC-03647","title":"A randomized trial of medical cannabis in patients with stage IV cancers to assess feasibility, dose requirements, impact on pain and opioid use, safety, and overall patient satisfaction.","authors":"Zylla, Dylan M; Eklund, Justin; Gilmore, Grace; Gavenda, Alissa; Guggisberg, Jordan; VazquezBenitez, Gabriela; Pawloski, Pamala A; Arneson, Tom; Richter, Sara; Birnbaum, Angela K; Dahmer, Stephen; Tracy, Matthew; Dudek, Arkadiusz","year":2021,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 29(12), 7471-7478","doi":"10.1007/s00520-021-06301-x","pmid":"34085149","tags":["cancer","pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"High enrollment interest (36% of eligible patients enrolled). Average daily doses at 3 months were 34 mg THC and 17 mg CBD. A higher proportion of early cannabis users achieved opioid reduction and improved pain control. No serious safety issues. High patient satisfaction.","whyItMatters":"This study demonstrates that conducting randomized cannabis trials through state programs is feasible, a critical step toward building the rigorous evidence base needed for clinical guidelines.","specificNumbers":"Enrolled: 30. Randomized 1:1. Enrollment rate: 36% of eligible. Mean daily THC: 34 mg. Mean daily CBD: 17 mg. Follow-up: 3 months. No serious adverse events.","methodology":"Pilot RCT randomizing 30 stage IV cancer patients requiring opioids to early cannabis (n=15, immediate medical cannabis via state program) vs. delayed start cannabis (n=15, standard care for 3 months). Licensed pharmacists at dispensaries guided dosing.","limitations":"Very small sample (n=30). Pilot design not powered for efficacy. Short 3-month follow-up. Open-label design. Single-site. Dosing varied based on dispensary pharmacist recommendations."},{"rthcId":"RTHC-03648","title":"Association between Prenatal Marijuana and Tobacco Smoke Exposures and Small for Gestational Age at Birth.","authors":"Abdelwahab, Mahmoud; Klebanoff, Mark A; Venkatesh, Kartik K","year":2022,"journal":"American journal of perinatology, 39(16), 1726-1734","doi":"10.1055/s-0042-1753489","pmid":"36007919","tags":["pregnancy","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Marijuana-only exposure was associated with SGA <10th percentile (43% vs. 26%, aRR 1.66) and SGA <5th percentile (30% vs. 13%, aRR 2.26). Tobacco-only was associated with SGA <5th percentile but not <10th percentile. Co-use effects emerged in sensitivity analysis using cotinine-verified tobacco exposure.","whyItMatters":"This study used objective biomarker confirmation of marijuana exposure and separated marijuana from tobacco effects, providing clearer evidence that marijuana alone may restrict fetal growth.","specificNumbers":"Sample: 325 mothers. Neither exposure: 46%. Marijuana-only: 11%. Tobacco-only: 20%. Co-use: 23%. Marijuana-only SGA <10th: 43% vs. 26% (aRR 1.66). SGA <5th: 30% vs. 13% (aRR 2.26).","methodology":"Secondary analysis of the prospective LEAF cohort (2010-2015). Marijuana use assessed by urine THC-COOH testing, self-report, and medical records. Modeled as four exposure groups: co-use, marijuana-only, tobacco-only, and neither. SGA defined using 2017 US natality reference data.","limitations":"Moderate sample size (325). High rates of co-exposure complicate separation of effects. Single urine sample may miss intermittent use. LEAF cohort may not be nationally representative."},{"rthcId":"RTHC-03649","title":"Cannabis, Cannabinoids and Cannabis-Based Medicines in Cancer Care.","authors":"Abrams, Donald I","year":2022,"journal":"Integrative cancer therapies, 21, 15347354221081772","doi":"10.1177/15347354221081772","pmid":"35225051","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03650","title":"The Influence of COVID-19 Pandemic on the Frequent Use of E-Cigarettes and Its Association with Substance Use and Mental Health Symptoms.","authors":"Adzrago, David; Sulley, Saanie; Mamudu, Lohuwa; Ormiston, Cameron K; Williams, Faustine","year":2022,"journal":"Behavioral sciences (Basel, Switzerland), 12(11)","doi":"10.3390/bs12110453","pmid":"36421749","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03651","title":"A Phase I Randomized, Double-blind, Placebo-controlled Study on Efficacy and Safety Profile of a Sublingually Administered Cannabidiol /Delta 9-tetrahydrocannabidiol (10: 1) Regimen in Diabetes Type 2 Patients.","authors":"Afshar, Shima; Khalili, Shayesteh; Amin, Gholamreza; Abbasinazari, Mohammad","year":2022,"journal":"Iranian journal of pharmaceutical research : IJPR, 21(1), e132647","doi":"10.5812/ijpr-132647","pmid":"36945340","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"After 8 weeks, the CBD/THC spray significantly reduced total cholesterol (treatment difference -19.73 mg/dL), LDL cholesterol, and HbA1c compared to placebo. The treatment was well-tolerated with no serious or severe adverse effects.","whyItMatters":"Type 2 diabetes often involves lipid abnormalities alongside blood sugar problems. A well-tolerated cannabinoid adjunctive therapy addressing both simultaneously could fill a treatment gap.","specificNumbers":"Patients: 50 (25 per group). Duration: 8 weeks. CBD:THC ratio: 10:1. Dose: 2 puffs twice daily. Total cholesterol treatment difference: -19.73 mg/dL. No serious adverse effects.","methodology":"Phase I randomized, double-blind, placebo-controlled trial. 50 diabetic patients randomized 1:1 to receive CBDEX10 spray (100 ug CBD + 10 ug THC per puff, two puffs twice daily) or placebo for 8 weeks.","limitations":"Very small sample (n=50). Phase I study primarily designed for safety. Short 8-week duration. Single-center. Low cannabinoid doses. Abstract truncated, limiting full data assessment."},{"rthcId":"RTHC-03652","title":"Increased cannabis use in pregnant women during COVID-19 pandemic.","authors":"Agolli, Arjola; Agolli, Olsi; Chowdhury, Selia; Shet, Vallabh; Benitez, Johanna S Canenguez; Bheemisetty, Niharika; Waleed, Madeeha Subhan","year":2022,"journal":"Discoveries (Craiova, Romania), 10(2), e148","doi":"10.15190/d.2022.7","pmid":"36530177","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03653","title":"Curcumin induces peripheral antinociception by opioidergic and cannabinoidergic mechanism: Pharmacological evidence.","authors":"Aguiar, Danielle Diniz; Gonzaga, Amanda Cristina Reis; Teófilo, Ana Luiza Higino; Miranda, Fernanda Almeida; Perez, Andrea de Castro; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima","year":2022,"journal":"Life sciences, 293, 120279","doi":"10.1016/j.lfs.2021.120279","pmid":"35032552","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03654","title":"Cannabis Use in Adults Who Screen Positive for Attention Deficit/Hyperactivity Disorder: CANreduce 2.0 Randomized Controlled Trial Subgroup Analysis.","authors":"Ahlers, Joachim; Baumgartner, Christian; Augsburger, Mareike; Wenger, Andreas; Malischnig, Doris; Boumparis, Nikolaos; Berger, Thomas; Stark, Lars; Ebert, David D; Haug, Severin; Schaub, Michael P","year":2022,"journal":"Journal of medical Internet research, 24(4), e30138","doi":"10.2196/30138","pmid":"35442196","tags":["addiction","quitting","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Both ADHD-positive (n=94) and ADHD-negative (n=273) groups significantly reduced cannabis use days, severity scores, anxiety, and depression. ADHD-positive users showed slightly larger reductions but the between-group difference was not significant. ADHD-positive users also showed decreased ADHD symptom scores.","whyItMatters":"Adults with ADHD have much higher rates of cannabis use disorder, yet are often excluded from or underserved by treatment programs. This accessible web-based intervention shows promise for this underserved group.","specificNumbers":"ADHD+: n=94, reduced 11.5 use days. ADHD-: n=273, reduced 8.5 use days. ADHD+ SDS reduction: 3.57. ADHD+ anxiety reduction: 4.31. ADHD+ depression reduction: 10.25. ADHD+ symptom reduction: 4.65. No between-group difference (p=.08).","methodology":"Secondary analysis of a randomized controlled trial. Adults with weekly cannabis use completed the CANreduce 2.0 self-guided web intervention (6 weeks, based on MI and CBT). Compared outcomes between ADHD-positive and ADHD-negative screeners at 3-month follow-up.","limitations":"Secondary subgroup analysis. ADHD screened not diagnosed. Self-reported outcomes. ADHD-positive users were less likely to complete consumption diaries. No long-term follow-up beyond 3 months."},{"rthcId":"RTHC-03655","title":"Hemp as a potential raw material toward a sustainable world: A review.","authors":"Ahmed, A T M Faiz; Islam, Md Zahidul; Mahmud, Md Sultan; Sarker, Md Emdad; Islam, Md Reajul","year":2022,"journal":"Heliyon, 8(1), e08753","doi":"10.1016/j.heliyon.2022.e08753","pmid":"35146149","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03656","title":"Early Age of Cannabis Initiation and Its Association With Suicidal Behaviors.","authors":"Ahuja, Manik; Awasthi, Manul; Gim, Suzanna; Records, Kathie; Cimilluca, Johanna; Al-Ksir, Kawther; Tremblay, Johnathan; Doshi, Riddhi P; Sathiyasaleen, Thiveya; Fernandopulle, Praveen","year":2022,"journal":"Substance abuse : research and treatment, 16, 11782218221116731","doi":"10.1177/11782218221116731","pmid":"35966616","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Early cannabis use (age 14 or younger) was associated with higher risks of suicide ideation (AOR 3.32) and attempt (AOR 4.38) than later initiation (AOR 2.15 and 2.56 respectively). The differences between early and late initiation were statistically significant for both outcomes.","whyItMatters":"The dose-response relationship between earlier cannabis initiation and suicide risk suggests that delaying cannabis exposure during adolescent brain development may be an important prevention target.","specificNumbers":"Sample: 15,238. Suicide ideation: 12.5%. Suicide attempt: 4.2%. Early initiation ideation AOR: 3.32 (95% CI 2.75-3.80). Late initiation ideation AOR: 2.15. Early attempt AOR: 4.38 (95% CI 3.48-5.52). Late attempt AOR: 2.56.","methodology":"Cross-sectional analysis of the Collaborative Psychiatric Epidemiology Surveys (2001-2003, N=15,238). Logistic regression examined associations between early (14 or younger) vs. later (over 14) cannabis initiation and lifetime suicide ideation and attempt, controlling for cigarette use, demographics, and other factors.","limitations":"Cross-sectional design cannot establish causation. Retrospective recall of initiation age. Data from 2001-2003 may not reflect current cannabis landscape. Cannot control for all confounders (mental health history, trauma)."},{"rthcId":"RTHC-03657","title":"Cannabis-induced myocardial infarction in a 27-year-old man: Case report.","authors":"Aissaoui, Hanane; Boulouiz, Soumia; El-Azrak, Mohammed; Bouchlarhem, Amine; Elouafi, Noha; Bazid, Zakaria","year":2022,"journal":"Annals of medicine and surgery (2012), 80, 104054","doi":"10.1016/j.amsu.2022.104054","pmid":"35855878","tags":["cardiovascular","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient developed ST-elevation myocardial infarction on anterior and inferior ECG leads following cannabis consumption. Coronary angiography revealed significant stenosis of the left anterior descending artery. PCI with stent implantation resulted in good clinical outcomes.","whyItMatters":"This case adds to the growing literature linking cannabis use to coronary events in young patients, emphasizing the importance of asking about cannabis use in young patients presenting with chest pain.","specificNumbers":"Patient age: 27. ECG: ST elevation anterior and inferior leads. Finding: significant LAD stenosis. Treatment: PCI with new-generation stent. Outcome: good clinical evolution.","methodology":"Case report documenting clinical presentation, diagnostic workup (ECG, coronary angiography), treatment (PCI with stent), and outcomes.","limitations":"Single case report. Coronary heredity mentioned as additional risk factor. Cannot definitively prove cannabis caused the event. No long-term follow-up reported."},{"rthcId":"RTHC-03658","title":"Deciphering the iPBS retrotransposons based genetic diversity of nanoparticles induced in Vitro seedlings of industrial hemp (Cannabis sativa L.).","authors":"Akgur, Ozlem; Aasim, Muhammad","year":2022,"journal":"Molecular biology reports, 49(7), 7135-7143","doi":"10.1007/s11033-022-07596-7","pmid":"35717478","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03659","title":"Differentiating Diabetic Ketoacidosis and Hyperglycemic Ketosis Due to Cannabis Hyperemesis Syndrome in Adults With Type 1 Diabetes.","authors":"Akturk, Halis Kaan; Snell-Bergeon, Janet; Kinney, Gregory L; Champakanath, Anagha; Monte, Andrew; Shah, Viral N","year":2022,"journal":"Diabetes care, 45(2), 481-483","doi":"10.2337/dc21-1730","pmid":"34880067","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users had dramatically different lab profiles than non-users: pH 7.42 vs. 7.09 and bicarbonate 19.2 vs. 9.1 mmol/L (both p<0.0001). The ROC curve for cannabis predicting hyperglycemic ketosis from CHS had an area of 0.9892, indicating near-perfect discrimination.","whyItMatters":"Misdiagnosing CHS-related vomiting as DKA in type 1 diabetes leads to unnecessary aggressive treatment. This study provides clear lab criteria to differentiate the two conditions.","specificNumbers":"Patients: 68. DKA events: 172. Cannabis users pH: 7.42 vs. 7.09 non-users. Bicarbonate: 19.2 vs. 9.1 mmol/L. ROC AUC: 0.9892. HK-CHS threshold: pH >=7.4, bicarbonate >=15.","methodology":"Retrospective analysis of 68 adults with type 1 diabetes presenting with DKA-related ICD-10 codes (172 events). Cannabis use defined by positive urine test. Used linear mixed models and ROC analysis to distinguish hyperglycemic ketosis from CHS (pH >=7.4, bicarbonate >=15) from true DKA.","limitations":"Small sample. Retrospective design. Cannabis use based on urine testing (indicates recent use, not necessarily current intoxication). Single-center study."},{"rthcId":"RTHC-03660","title":"Brief Report: Suspected Cannabis-Induced Mania and Psychosis in Young Adult Males with Autism Spectrum Disorder.","authors":"Al-Soleiti, Majd; Balaj, Kayla; Thom, Robyn P; McDougle, Christopher J; Keary, Christopher J","year":2022,"journal":"Journal of autism and developmental disorders, 52(9), 4164-4171","doi":"10.1007/s10803-021-05254-8","pmid":"34505186","tags":["psychosis","mental-health","cbd"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All three patients had ASD and developed mania or psychotic symptoms after consistent cannabis use containing both CBD and THC. The cases raise concerns about the safety of cannabis in ASD, particularly given the active interest in cannabinoid treatments for behavioral symptoms in this population.","whyItMatters":"There is growing interest in using cannabis products for behavioral symptoms in ASD, but these cases suggest individuals with ASD may be vulnerable to serious psychiatric adverse effects.","specificNumbers":"Three patients, all young adult males with ASD. Products contained both CBD and THC. All developed mania or psychosis requiring clinical attention.","methodology":"Case series describing three young adult males with ASD who developed psychiatric emergencies after cannabis use. Clinical courses documented.","limitations":"Only three cases. Cannot establish causation. No control for other factors. Pre-existing psychiatric vulnerability in ASD may be a confounder. Exact product compositions not fully detailed."},{"rthcId":"RTHC-03661","title":"Early versus late risk factors for deficit and nondeficit schizophrenia.","authors":"Alabaf, Setareh; Kirkpatrick, Brian; Chen, Shanquan; Cardinal, Rudolf N; Fernandez-Egea, Emilio","year":2022,"journal":"Revista de psiquiatria y salud mental, 15(1), 38-46","doi":"10.1016/j.rpsmen.2022.01.006","pmid":"35256071","tags":["psychosis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Deficit schizophrenia patients had significantly lower cannabis use at first psychotic episode (p=0.005), less physical/sexual abuse (p=0.033), and less crime-related trauma (p=0.012). Summer birth was associated with deficit schizophrenia (p=0.017). Family history, paternal age, sex, and birth weight did not differ.","whyItMatters":"Understanding that cannabis and trauma are linked specifically to psychotic symptoms rather than primary negative symptoms helps refine schizophrenia subtypes and may have implications for prevention targeting.","specificNumbers":"Patients: 167. Cannabis use lower in deficit group (p=0.005). Physical/sexual abuse lower in deficit (p=0.033). Crime-related trauma lower in deficit (p=0.012). Summer birth higher in deficit (p=0.017).","methodology":"Cross-sectional single-center study of 167 clozapine-treated schizophrenia patients in England assessed with the Schedule for the Deficit Syndrome. Compared risk factors between deficit (primary negative symptoms) and nondeficit groups using logistic regression.","limitations":"Cross-sectional design. All patients on clozapine, limiting generalizability to treatment-resistant cases. Retrospective recall of risk factors. Single-center UK study."},{"rthcId":"RTHC-03662","title":"Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/consensus guidance on the use of cannabinoids for gastrointestinal symptoms in patients with cancer.","authors":"Alderman, Bryony; Hui, David; Mukhopadhyay, Sandip; Bouleuc, Carole; Case, Amy A; Amano, Koji; Crawford, Gregory B; de Feo, Giulia; Sbrana, Andrea; Tanco, Kimberson; To, Josephine; Garsed, Jessica; Davis, Mellar","year":2022,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 31(1), 39","doi":"10.1007/s00520-022-07480-x","pmid":"36525085","tags":["cancer","medical-cannabis","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 36 RCTs, 11 showed cannabis improved CINV vs. placebo, but of 21 trials comparing cannabis to other antiemetics, only 11 favored cannabis. One THC:CBD study reduced nausea as add-on therapy without olanzapine. MASCC found insufficient evidence to recommend cannabinoids for CINV, advanced cancer nausea, cachexia, or taste disturbance.","whyItMatters":"Despite widespread patient interest in cannabis for cancer symptoms, this expert review found the evidence base does not support routine use, highlighting the gap between patient expectations and scientific evidence.","specificNumbers":"RCTs identified: 36 (31 CINV, 1 radiation-induced nausea, 4 cachexia/taste). Cannabis vs. placebo for CINV: 11/31 positive. Cannabis vs. other antiemetics: 11/21 positive. Many studies poor quality.","methodology":"Systematic review searching Medline, Embase, PsychINFO, and Cochrane through November 2021. Included RCTs of cannabinoids vs. placebo or active comparator in adult cancer patients. Studies scored on the Jadad scale. Expert panel developed consensus guidance.","limitations":"Many included studies were old and used older antiemetic comparators. Heterogeneous populations and cannabinoid formulations. Many studies had poor methodological quality (randomization, blinding, allocation)."},{"rthcId":"RTHC-03663","title":"Associations between health-risk behaviours and non-condom use among 28,620 Danish students: a cross-sectional study.","authors":"Algren, Maria Holst; Deen, Laura; Tolstrup, Janne Schurmann; Thygesen, Lau Caspar","year":2022,"journal":"The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception, 27(1), 45-52","doi":"10.1080/13625187.2021.2005018","pmid":"34907840","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03664","title":"Youth substance use service provider's perspectives on use and service access in ontario: time to reframe the discourse.","authors":"Ali, Farihah; Russell, Cayley; Nafeh, Frishta; Chaufan, Claudia; Imtiaz, Sameer; Rehm, Jürgen; Spafford, Adrienne; Elton-Marshall, Tara","year":2022,"journal":"Substance abuse treatment, prevention, and policy, 17(1), 9","doi":"10.1186/s13011-022-00435-9","pmid":"35123527","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03665","title":"Marijuana-induced myocarditis in a 24-year-old man.","authors":"Alirezaei, Toktam; Mohammadi, Mohammad Kalateh Agha; Irilouzadian, Rana; Zarinparsa, Hamidreza","year":2022,"journal":"Archive of clinical cases, 9(2), 69-74","doi":"10.22551/2022.35.0902.10206","pmid":"35813492","tags":["cardiovascular","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Following marijuana use, the patient presented with chest pain and was diagnosed with acute myocarditis based on ECG, cardiac enzyme elevation, and echocardiography. Follow-up echo revealed a small apical clot and reduced left ventricular ejection fraction without focal wall motion abnormality. He was discharged on anticoagulation.","whyItMatters":"While cannabis-associated myocardial infarction is increasingly recognized, myocarditis (inflammation of the heart muscle) is rarely reported and may represent a distinct pathophysiology.","specificNumbers":"Patient age: 24. No prior medical history. No cardiovascular risk factors. Complications: apical thrombus, reduced LVEF. Treatment: oral anticoagulation.","methodology":"Case report with clinical presentation, ECG, cardiac biomarkers, and serial echocardiography.","limitations":"Single case report. Cannot definitively prove cannabis caused the myocarditis. Other potential causes (viral, autoimmune) were not completely excluded in the abstract. No cardiac MRI mentioned."},{"rthcId":"RTHC-03666","title":"Effects of the cannabinoid CB1-receptor neutral antagonist AM4113 and antagonist/inverse agonist rimonabant on fentanyl discrimination in male rats.","authors":"AlKhelb, Dalal; Kirunda, Andre; Ho, Thanh C; Makriyannis, Alexandros; Desai, Rajeev I","year":2022,"journal":"Drug and alcohol dependence, 240, 109646","doi":"10.1016/j.drugalcdep.2022.109646","pmid":"36191533","tags":["harm-reduction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AM4113 (0.32-1.0 mg/kg) effectively blocked fentanyl discrimination at doses that did not reduce food-maintained responding. Rimonabant (1.0-10 mg/kg) only partially attenuated fentanyl effects at the highest dose, which also significantly decreased response rates. Mu-opioid agonists fully substituted for fentanyl, confirming opioid mediation.","whyItMatters":"Current opioid use disorder treatments are limited. A CB1 neutral antagonist that blocks fentanyl effects without the psychiatric side effects that ended rimonabant could offer a new therapeutic approach.","specificNumbers":"AM4113 effective doses: 0.32-1.0 mg/kg. Rimonabant partial effect only at 10 mg/kg (with rate suppression). AM4113 was effective at 10-fold lower doses than those affecting food responding.","methodology":"Male rats trained to discriminate 0.032 mg/kg fentanyl from saline under a fixed-ratio 10 schedule of food reinforcement. Tested effects of CB1 neutral antagonist AM4113 and inverse agonist rimonabant on fentanyl discrimination and food-maintained responding.","limitations":"Animal study in rats. Drug discrimination assay measures subjective effects, not addiction-related behaviors. Only male rats tested. Translation to human opioid use disorder uncertain."},{"rthcId":"RTHC-03667","title":"Lipid endocannabinoids in energy metabolism, stress and developmental programming.","authors":"Almeida, Mariana Macedo; Dias-Rocha, Camilla Pereira; Calviño, Camila; Trevenzoli, Isis Hara","year":2022,"journal":"Molecular and cellular endocrinology, 542, 111522","doi":"10.1016/j.mce.2021.111522","pmid":"34843899","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03668","title":"Acute Hepatic Injury Associated with Acute Administration of Synthetic Cannabinoid XLR-11 in Mouse Animal Model.","authors":"Alzu'bi, Ayman; Zoubi, Mazhar Salim Al; Al-Trad, Bahaa; AbuAlArjah, Manal Isam; Shehab, Malek; Alzoubi, Hiba; Albals, Dima; Abdelhady, Gamal T; El-Huneidi, Waseem","year":2022,"journal":"Toxics, 10(11)","doi":"10.3390/toxics10110668","pmid":"36355959","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"XLR-11 treatment caused upregulation of oxidative stress genes (NOX2, NOX4, iNOS), inflammatory markers (TNF-alpha, IL-1beta, IL-6), and pro-apoptotic gene Bax. This was confirmed by elevated MDA levels, increased TUNEL-positive cells, pronounced hepatic necrosis with inflammatory infiltration, and elevated ALT/AST serum levels.","whyItMatters":"Synthetic cannabinoids are widely available and their hepatotoxicity is poorly understood. This study identifies specific oxidative and inflammatory mechanisms driving acute liver injury.","specificNumbers":"Dose: 3 mg/kg for 5 days. Upregulated genes: NOX2, NOX4, iNOS, TNF-alpha, IL-1beta, IL-6, Bax. Elevated MDA levels and TUNEL-positive cells. Elevated ALT/AST.","methodology":"BALB/c mice received XLR-11 (3 mg/kg i.p.) for 5 consecutive days. Liver tissue analyzed by RT-qPCR, MDA assay, TUNEL assay, and histopathology. Serum liver enzymes measured.","limitations":"Animal study with intraperitoneal injection rather than typical human routes. Single dose level. Short exposure period. BALB/c mice may respond differently than other strains or humans."},{"rthcId":"RTHC-03669","title":"CBD Retailers in NC Promote CBD Online to Treat Pain Violating FDA Rules About Medical Claims and Offer Low-CBD/High-Price Products.","authors":"Amann, Lindsay; Kruse, Elizabeth; Lazard, Allison J; Reboussin, Beth A; Wagoner, Kimberly G; Romero-Sandoval, E Alfonso","year":2022,"journal":"Journal of pain research, 15, 3847-3858","doi":"10.2147/JPR.S384996","pmid":"36514481","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03670","title":"Structure-Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074.","authors":"Amato, George; Vasukuttan, Vineetha; Harris, Danni; Laudermilk, Lucas; Lucitti, Jennifer; Runyon, Scott; Maitra, Rangan","year":2022,"journal":"Molecules (Basel, Switzerland), 27(17)","doi":"10.3390/molecules27175672","pmid":"36080443","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03671","title":"The Effect of Cannabidiol Coated by Nano-Chitosan on Learning and Memory, Hippocampal CB1 and CB2 Levels, and Amyloid Plaques in an Alzheimer's Disease Rat Model.","authors":"Amini, Mohammadali; Abdolmaleki, Zohreh","year":2022,"journal":"Neuropsychobiology, 81(3), 171-183","doi":"10.1159/000519534","pmid":"34727550","tags":["cbd","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Nano-chitosan-coated CBD significantly reduced escape latency and travel distance in memory tests while increasing time in the target zone. It increased CB1 and CB2 receptor protein expression compared to the Alzheimer group and reduced amyloid plaques and dead cells.","whyItMatters":"Nanoparticle delivery may enhance CBD bioavailability and brain penetration, potentially improving its therapeutic potential for neurodegenerative conditions.","specificNumbers":"35 rats in 5 groups. Nano-CBD reduced escape latency (p<0.01), travel distance (p<0.001), increased target time (p<0.001). CB1 and CB2 protein expression increased (p<0.05). Amyloid plaques reduced.","methodology":"35 male Wistar rats divided into 5 groups (n=7): control, Alzheimer model, Alzheimer+nano-chitosan, Alzheimer+CBD, Alzheimer+nano-CBD. Alzheimer induced by hippocampal beta-amyloid injection. One month oral CBD treatment. Assessed by Morris water maze, cresyl violet staining, RT-PCR, and immunohistochemistry.","limitations":"Small animal study (n=7 per group). Rat Alzheimer model does not fully replicate human disease. One-month treatment period. Single CBD dose. Cannot separate nano-chitosan carrier effects from CBD effects."},{"rthcId":"RTHC-03672","title":"Prevalence and characteristics of cannabis-induced toxicoses in pets: Results from a survey of veterinarians in North America.","authors":"Amissah, Richard Quansah; Vogt, Nadine A; Chen, Chuyun; Urban, Karolina; Khokhar, Jibran","year":2022,"journal":"PloS one, 17(4), e0261909","doi":"10.1371/journal.pone.0261909","pmid":"35442991","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03673","title":"Is the effect of cognitive reserve in longitudinal outcomes in first-episode psychoses dependent on the use of cannabis?","authors":"Amoretti, Silvia; Verdolini, Norma; Varo, Cristina; Mezquida, Gisela; Sánchez-Torres, Ana M; Vieta, Eduard; Garcia-Rizo, Clemente; Lobo, Antonio; González-Pinto, Ana; Abregú-Crespo, Renzo; Corripio, Iluminada; Serra, Maria; de la Serna, Elena; Mané, Anna; Ramos-Quiroga, J Antoni; Ribases, Marta; Cuesta, Manuel J; Bernardo, Miguel","year":2022,"journal":"Journal of affective disorders, 302, 83-93","doi":"10.1016/j.jad.2022.01.077","pmid":"35066012","tags":["psychosis","cognition","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Cognitive reserve was associated with better cognitive performance regardless of cannabis use. However, its protective effects on clinical and functional outcomes were seen only in non-cannabis users. Cannabis use appeared to override the protective effect of cognitive reserve on functioning at 2-year follow-up.","whyItMatters":"Cognitive reserve is typically protective in brain disorders, but cannabis use appears to negate this protection in psychosis, suggesting cannabis effects on functional outcomes may be particularly difficult to buffer against.","specificNumbers":"CR predicted better outcomes only in non-cannabis users for both affective and non-affective psychosis. CR mediated cognition-functioning relationship only in non-users. Follow-up: 2 years.","methodology":"Longitudinal study of first-episode psychosis patients (affective and non-affective) comparing cannabis users vs. non-users. Linear regression assessed cognitive reserve as predictor at baseline and 2-year follow-up. Mediation analyses explored cognitive reserve mediating the cognition-functioning relationship.","limitations":"Small affective psychosis subgroup. Cannot determine if cannabis degrades cognitive reserve or blocks its expression. Cannabis use patterns (frequency, potency) not detailed."},{"rthcId":"RTHC-03674","title":"Cannabinoid CB1 receptors regulate salivation.","authors":"Andreis, Kelsey; Billingsley, Jenna; Naimi Shirazi, Kian; Wager-Miller, Jim; Johnson, Clare; Bradshaw, Heather; Straiker, Alex","year":2022,"journal":"Scientific reports, 12(1), 14182","doi":"10.1038/s41598-022-17987-2","pmid":"35986066","tags":["neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 receptors are expressed on cholinergic nerve axons innervating the submandibular gland but not on gland cells. THC (4 mg/kg) and CP55940 reduced salivation in both sexes. CBD had no effect alone but dose-dependently reversed THC effects. FAAH knockout mice had reduced salivation, confirming endocannabinoid regulation.","whyItMatters":"Cannabis-induced dry mouth is one of the most common side effects, affecting millions of users. Understanding the mechanism opens potential therapeutic approaches for dry mouth conditions.","specificNumbers":"THC dose: 4 mg/kg. CP55940: 0.5 mg/kg. CBD reversed THC-induced dry mouth dose-dependently. SR141716 (CB1 antagonist) had no effect alone. JWH133 (CB2 agonist) had no effect. FAAH KO mice had reduced salivation.","methodology":"Immunohistochemistry to localize CB1 receptors in submandibular glands. Salivation measured in wild-type, CB1 knockout, and FAAH knockout mice after treatment with THC, CBD, CP55940, and other cannabinoid ligands. Lipidomics profiling of FAAH knockout tissue.","limitations":"Animal study in mice. Salivation was stimulated with pilocarpine, which may not fully replicate natural salivation. Dose-response curves were limited."},{"rthcId":"RTHC-03675","title":"Cannabinoid hyperemesis syndrome in North America: evaluation of health burden and treatment prevalence.","authors":"Andrews, Christopher N; Rehak, Renata; Woo, Matthew; Walker, Ian; Ma, Christopher; Forbes, Nauzer; Rittenbach, Katherine; Hathaway, Joshua; Wilsack, Lynn; Liu, Andy; Nasser, Yasmin; Sharkey, Keith A","year":2022,"journal":"Alimentary pharmacology & therapeutics, 56(11-12), 1532-1542","doi":"10.1111/apt.17265","pmid":"36307209","tags":["medical-cannabis","addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"CHS treatment prevalence increased from 15/100,000 pre-legalization to 21/100,000 post-legalization to 32/100,000 during COVID (p<0.001). Among chronic cannabis users aged 16-24, prevalence reached 6/1,000. Survey data showed universal cannabis use disorder (CUDIT-R >=8), with 59% screening for moderate anxiety and 68% for depression.","whyItMatters":"The steep increase in CHS treatment prevalence over just 3 years, especially during COVID-19, signals a rapidly growing healthcare burden that clinicians need to recognize and manage.","specificNumbers":"Survey: 157 CHS patients. CUDIT-R >=8: 100%. Moderate+ anxiety: 59%. Moderate+ depression: 68%. Alberta ED prevalence: 15 pre-legalization, 21 post-legalization, 32 during COVID per 100,000. Ages 16-24: 6 per 1,000 chronic users.","methodology":"Two-part study: (1) internet survey of 157 CHS sufferers in Canada and US, and (2) administrative health database analysis for Alberta (population 5 million) examining ED visits for vomiting with cannabis use codes across three time periods.","limitations":"Survey sample was self-selected. Administrative data may undercount CHS due to coding variability. COVID-19 period may have altered ED-seeking behavior. Cannot separate legalization effects from temporal trends."},{"rthcId":"RTHC-03676","title":"Medical Cannabis Activity Against Inflammation: Active Compounds and Modes of Action.","authors":"Anil, Seegehalli M; Peeri, Hadar; Koltai, Hinanit","year":2022,"journal":"Frontiers in pharmacology, 13, 908198","doi":"10.3389/fphar.2022.908198","pmid":"35614947","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03677","title":"Medical Cannabis for Gilles de la Tourette Syndrome: An Open-Label Prospective Study.","authors":"Anis, Saar; Zalomek, Corinne; Korczyn, Amos D; Rosenberg, Alina; Giladi, Nir; Gurevich, Tanya","year":2022,"journal":"Behavioural neurology, 2022, 5141773","doi":"10.1155/2022/5141773","pmid":"35310886","tags":["medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"After 12 weeks, YGTSS-Total scores decreased by 38% (p=0.002) and premonitory urge scores (PUTS) decreased by 20% (p=0.043). Most patients (80%) preferred smoking over oil drops. Common side effects: dry mouth (67%), fatigue (53%), dizziness (47%). Cognitive side effects in 40% and psychiatric side effects in 3 patients.","whyItMatters":"Tourette syndrome has limited treatment options, and cannabis has shown promise in case reports. This prospective study adds structured evidence, though the high rate of cognitive side effects warrants caution.","specificNumbers":"Enrolled: 18. Completed follow-up: 15. YGTSS-Total baseline: 60.3 (range 0-100). Reduction at 12 weeks: 38% (p=0.002). PUTS reduction: 20% (p=0.043). Smoking preferred: 80%. Dry mouth: 67%. Cognitive side effects: 40%.","methodology":"Open-label prospective study of 18 adult Tourette patients. THC and CBD content titrated by treating neurologist. Assessed at 4 and 12 weeks for efficacy, tolerability, and side effects using YGTSS and PUTS.","limitations":"Open-label, uncontrolled design. Small sample (n=18). Three patients dropped out. No placebo comparison. Expectancy effects likely. Variable dosing across patients."},{"rthcId":"RTHC-03678","title":"Non-psychotropic cannabinoids as inhibitors of TET1 protein.","authors":"Antonyová, Veronika; Kejík, Zdeněk; Brogyanyi, Tereza; Kaplánek, Robert; Veselá, Kateřina; Abramenko, Nikita; Ocelka, Tomáš; Masařík, Michal; Matkowski, Adam; Gburek, Jakub; Abel, Renata; Goede, Andrean; Preissner, Robert; Novotný, Petr; Jakubek, Milan","year":2022,"journal":"Bioorganic chemistry, 124, 105793","doi":"10.1016/j.bioorg.2022.105793","pmid":"35462234","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03679","title":"Insights About Cannabis and Psychosis Using Video Games for Young People With a First Episode of Psychosis, Particularly Those From Black Racialized Communities: Protocol for a Mixed Methods Study.","authors":"Archie, Suzanne; Palaniyappan, Lena; Olagunju, Andrew T; Johnson, Natasha; Kozloff, Nicole; Sadeh, Elham; Bardell, Andrea; Baines, Alexandra; Anderson, Kelly K; Ayonrinde, Oyedeji; Ferrari, Manuela","year":2022,"journal":"JMIR research protocols, 11(5), e36758","doi":"10.2196/36758","pmid":"35389874","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03680","title":"Association between formal thought disorder and cannabis use: a systematic review and meta-analysis.","authors":"Argote, Mathilde; Sescousse, Guillaume; Brunelin, Jérôme; Fakra, Eric; Nourredine, Mikail; Rolland, Benjamin","year":2022,"journal":"Schizophrenia (Heidelberg, Germany), 8(1), 78","doi":"10.1038/s41537-022-00286-0","pmid":"36175509","tags":["psychosis","mental-health"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis users had higher FTD severity overall (SMD 0.21, 95% CI 0.12-0.29, p=0.00009). This held across subgroups: healthy individuals (SMD 0.19, p=0.02), first-episode psychosis (SMD 0.21, p=0.04), and schizophrenia (SMD 0.25, p=0.005). Between-group differences were not significant.","whyItMatters":"Formal thought disorder (disorganized thinking and speech) is a core psychosis feature. This meta-analysis shows cannabis worsens it across the entire spectrum, from healthy individuals to those with established schizophrenia.","specificNumbers":"Studies: 19. Cannabis users: 1,840. Non-users: 3,351. Overall SMD: 0.21 (p=0.00009). Healthy: 0.19 (p=0.02). FEP: 0.21 (p=0.04). Schizophrenia: 0.25 (p=0.005).","methodology":"Systematic review and meta-analysis searching six databases through July 2022. Included 19 studies with 1,840 cannabis users and 3,351 non-users. Random-effects model. Subgroup analyses by clinical population.","limitations":"Mostly cross-sectional studies. Cannot determine causation. FTD measurement varied across studies. Could not assess confounding by other substance use. Moderate heterogeneity."},{"rthcId":"RTHC-03681","title":"Effects of psychotropic drugs on ocular parameters relevant to traffic safety: A systematic review.","authors":"Arkell, Thomas R; Brooks-Russell, Ashley; Downey, Luke A; Shiferaw, Brook; Brown, Timothy; Sherrick, James; Hayley, Amie C","year":2022,"journal":"Neuroscience and biobehavioral reviews, 141, 104831","doi":"10.1016/j.neubiorev.2022.104831","pmid":"35995080","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03682","title":"Sex differences in acute cannabis effects revisited: Results from two randomized, controlled trials.","authors":"Arkell, Thomas R; Kevin, Richard C; Vinckenbosch, Frederick; Lintzeris, Nicholas; Theunissen, Eef; Ramaekers, Johannes G; McGregor, Iain S","year":2022,"journal":"Addiction biology, 27(2), e13125","doi":"10.1111/adb.13125","pmid":"34936167","tags":["sex-differences","neuroscience","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"After controlling for BMI and plasma THC, relatively few sex differences emerged. Males performed better on a divided attention task and had higher peak 11-COOH-THC levels. No differences in subjective drug effects, cardiovascular measures, or concentrations of THC, CBD, or other metabolites.","whyItMatters":"As cannabis policies evolve, understanding whether men and women respond differently to cannabis is important for clinical dosing, driving impairment standards, and public health messaging.","specificNumbers":"Males: 21. Females: 19. THC dose: 13.75 mg vaporized. CBD dose: 13.75 mg (in some conditions). Males: better DAT performance, higher 11-COOH-THC. No sex differences in subjective effects or cardiovascular measures.","methodology":"Combined data from two RCTs with 21 males and 19 females receiving vaporized cannabis (13.75 mg THC, with/without 13.75 mg CBD). Peak scores calculated for subjective effects, cognitive performance, cardiovascular effects, and plasma concentrations.","limitations":"Moderate sample size (n=40). Single dose level. Vaporized administration only. Combined data from two separate trials. Cannot generalize to edibles or higher doses."},{"rthcId":"RTHC-03683","title":"Clinical practice guideline on pharmacological and psychological management of adult patients with schizophrenia spectrum disorders and a comorbid substance use.","authors":"Arranz, Belen; Garriga, Marina; Bernardo, Miquel; González-Pinto, Ana; Arrojo, Manuel; Torrens, Marta; Tirado-Muñoz, Judith; Fonseca, Francina; Sáiz, Pilar A; Flórez, Gerardo; Goikolea, Jose Manuel; Zorrilla, Iñaki; Cunill, Ruth; Castells, Xavi; Becoña, Elisardo; López, Ana; San, Luis","year":2022,"journal":"Adicciones, 34(2), 110-127","doi":"10.20882/adicciones.1504","pmid":"33768260","tags":["psychosis","addiction","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"For schizophrenia with cannabis use: no antipsychotic (olanzapine, risperidone, haloperidol, or clozapine) could be recommended over another (weak recommendation). For cocaine use: haloperidol reduced craving vs. olanzapine. For alcohol: naltrexone recommended. For nicotine: bupropion and varenicline recommended (strong/moderate). For polydrug: second-generation antipsychotics preferred.","whyItMatters":"With high rates of cannabis use among schizophrenia patients, clinicians urgently need evidence-based guidance. The finding that no antipsychotic is clearly better for cannabis users highlights a critical evidence gap.","specificNumbers":"Cannabis+schizophrenia: no recommendation between olanzapine, risperidone, haloperidol (weak). Clozapine: cannot recommend for cannabis reduction (weak). Nicotine: bupropion and varenicline recommended (strong/moderate).","methodology":"GRADE-based clinical practice guideline using systematic review of pharmacological and psychological interventions for adult schizophrenia patients with comorbid substance use disorders, structured by PICO framework.","limitations":"Evidence quality was generally low to moderate. Limited number of head-to-head trials for cannabis + schizophrenia. Guidelines based on available evidence, which is sparse for cannabis-specific outcomes."},{"rthcId":"RTHC-03684","title":"Moral injury and cannabis use disorder among Israeli combat veterans: The role of depression and perceived social support.","authors":"Ashwal-Malka, Aviya; Tal-Kishner, Keren; Feingold, Daniel","year":2022,"journal":"Addictive behaviors, 124, 107114","doi":"10.1016/j.addbeh.2021.107114","pmid":"34543870","tags":["ptsd","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Moral injury from self-perpetration and betrayal were positively associated with CUD. Depression mediated the MI-CUD relationship. Surprisingly, the MI-CUD association was significant only among those with average or high perceived social support, suggesting social support alone does not protect against this pathway.","whyItMatters":"Understanding that moral injury drives cannabis dependence through depression in veterans opens specific therapeutic targets: treating the depression and moral distress rather than focusing solely on cannabis cessation.","specificNumbers":"Sample: 215 male combat veterans. Cannabis use: 3+ days weekly for 6+ months. Depression mediated MI-self to CUD (direct effect beta=0.13, p=0.1). Depression mediated MI-betrayal to CUD (beta=0.20, p=0.04). MI-CUD link only significant with average/high social support.","methodology":"Cross-sectional survey of 215 male Israeli combat veterans discharged within 5 years who used cannabis 3+ days weekly for 6+ months. Validated questionnaires assessed moral injury, CUD, depression, and perceived social support. Serial mediation and moderation analyses.","limitations":"Cross-sectional design. Self-report measures. Israeli combat veterans may not generalize to other militaries. Only males included. Cannabis use was an inclusion criterion, limiting variance."},{"rthcId":"RTHC-03685","title":"Sociodemographic and clinical correlates of cannabis dependence among Israeli combat veterans.","authors":"Asper, Ariel; Binenfeld, Elishav; Pshitizky, Harel; Feingold, Daniel","year":2022,"journal":"Journal of substance abuse treatment, 139, 108786","doi":"10.1016/j.jsat.2022.108786","pmid":"35525717","tags":["addiction","ptsd","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Veterans with cannabis dependence used significantly more cannabis per week and scored higher on moral injury \"other\" and \"betrayal\" subscales. After controlling for confounders, depression was significantly associated with dependence (AOR 1.98, 95% CI 1.05-3.72), while PTSD was not (AOR 1.19, 95% CI 0.56-2.54).","whyItMatters":"The finding that depression, not PTSD, independently predicted cannabis dependence in veterans challenges the common assumption that veterans use cannabis primarily to self-medicate PTSD.","specificNumbers":"Depression AOR: 1.98 (95% CI 1.05-3.72, p<0.05). PTSD AOR: 1.19 (95% CI 0.56-2.54, not significant). Dependent users consumed more grams per week and had higher moral injury scores.","methodology":"Cross-sectional study of Israeli combat veterans discharged within the past 5 years. Compared those screening positive vs. negative for cannabis dependence on sociodemographic and clinical variables using SPSS.","limitations":"Cross-sectional cannot determine causation. Screening tools rather than diagnostic interviews. Israeli military context may not generalize. Self-reported cannabis quantity."},{"rthcId":"RTHC-03686","title":"The endocannabinoid system and drug-associated contextual memories.","authors":"Asth, Laila; Santos, Aline C; Moreira, Fabrício A","year":2022,"journal":"Behavioural pharmacology, 33(2&3), 90-104","doi":"10.1097/FBP.0000000000000621","pmid":"33491992","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03687","title":"Autism and associated disorders: cannabis as a potential therapy.","authors":"Babayeva, Mariana; Assefa, Haregewein; Basu, Paramita; Loewy, Zvi","year":2022,"journal":"Frontiers in bioscience (Elite edition), 14(1), 1","doi":"10.31083/j.fbe1401001","pmid":"35320905","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03688","title":"Alcohol, smoke, cannabis, new psychoactive substances, and non-prescribed drugs consumption among school student in an area of Nord-West of Italy.","authors":"Balbinot, Patrizia; Pellicano, Rinaldo; Testino, Gianni","year":2022,"journal":"Minerva gastroenterology, 68(4), 421-425","doi":"10.23736/S2724-5985.22.03253-3","pmid":"35904475","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use at ages 14-15 was associated with a 26-fold increased risk of using new psychoactive substances or non-prescribed drugs (OR 26.3, 95% CI 15.97-43.33).","whyItMatters":"The strength of the association between early cannabis use and subsequent use of other substances in this large school-based sample adds to the evidence on adolescent substance use patterns and potential gateway effects.","specificNumbers":"3,805 students surveyed; cannabis use at 14-15 associated with OR 26.3 for NPS/NPD use; 53% of 14-15-year-olds and 68% of 16-17-year-olds hid substance use from parents and psychologists.","methodology":"Anonymous questionnaire administered to 3,805 students aged 9-17 across 14 schools in the Genoa metropolitan area of Italy between December 2021 and May 2022. Logistic regression assessed associations between substance use and psychological outcomes.","limitations":"Cross-sectional design prevents determining causation. Anonymous self-report may still underestimate use. Single metropolitan area limits generalizability. No control for confounding factors like socioeconomic status or family environment."},{"rthcId":"RTHC-03689","title":"Long-term trends in adolescent alcohol, tobacco and cannabis use and emerging substance use issues in Aotearoa New Zealand.","authors":"Ball, Jude; Crossin, Rose; Boden, Joseph; Crengle, Sue; Edwards, Richard","year":2022,"journal":"Journal of the Royal Society of New Zealand, 52(4), 450-471","doi":"10.1080/03036758.2022.2060266","pmid":"39440316","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03690","title":"Medical cannabis and cannabidiol: A new harvest for Malawi.","authors":"Bandawe, Gama","year":2022,"journal":"Malawi medical journal : the journal of Medical Association of Malawi, 34(2), 138-142","doi":"10.4314/mmj.v34i2.10","pmid":"35991815","tags":["medical-cannabis","cbd","epilepsy","psychosis","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD has an established role in treating epilepsy (FDA-approved Epidiolex) and emerging evidence for antipsychotic and neuroprotective properties, with the authors proposing potential adjunctive use for neuropsychological complications of malaria.","whyItMatters":"As Malawi joins the growing list of countries legalizing medical cannabis, this review frames the scientific evidence for CBD in a context relevant to local public health challenges, particularly malaria.","specificNumbers":"Malawi legalized medical cannabis in February 2020; Epidiolex was the first FDA-approved cannabis-based treatment.","methodology":"Special communication reviewing published literature on cannabis pharmacology, CBD mechanisms of action, FDA-approved treatments, and clinical research on CBD's antipsychotic and neuroprotective properties.","limitations":"The proposal for CBD in malaria-related neuroprotection is speculative and lacks clinical evidence. The review is broad rather than systematic. Limited discussion of local implementation challenges."},{"rthcId":"RTHC-03691","title":"Understanding the Placental Biology of Tobacco Smoke, Nicotine, and Marijuana (THC) Exposures During Pregnancy.","authors":"Banerjee, Sohini; Deacon, Alyssa; Suter, Melissa A; Aagaard, Kjersti M","year":2022,"journal":"Clinical obstetrics and gynecology, 65(2), 347-359","doi":"10.1097/GRF.0000000000000691","pmid":"35125390","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03692","title":"Association of Mental Health Burden With Prenatal Cannabis Exposure From Childhood to Early Adolescence: Longitudinal Findings From the Adolescent Brain Cognitive Development (ABCD) Study.","authors":"Baranger, David A A; Paul, Sarah E; Colbert, Sarah M C; Karcher, Nicole R; Johnson, Emma C; Hatoum, Alexander S; Bogdan, Ryan","year":2022,"journal":"JAMA pediatrics, 176(12), 1261-1265","doi":"10.1001/jamapediatrics.2022.3191","pmid":"36094599","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers used data from the Adolescent Brain Cognitive Development (ABCD) study, one of the largest longitudinal studies of brain development in the United States, to examine whether the association between prenatal cannabis exposure and mental health problems endures as children age.\n\nThe analysis found that children whose mothers used cannabis during pregnancy showed associations with greater mental health burden. Critically, these associations were not limited to early childhood but persisted into early adolescence.\n\nThis persistence is important because it suggests prenatal cannabis exposure may have lasting effects on neurodevelopment rather than transient impacts that children grow out of as their brains mature.","whyItMatters":"Cannabis is the most commonly used illicit substance during pregnancy, and its use has increased with legalization. Demonstrating that prenatal exposure associations persist into adolescence, rather than fading with development, strengthens the case for counseling pregnant individuals about potential long-term risks.","specificNumbers":"Data came from the ABCD study, one of the largest US longitudinal studies of adolescent brain development. Associations between prenatal cannabis exposure and psychopathology persisted from childhood into early adolescence.","methodology":"This was a longitudinal cohort analysis using the ABCD study, which follows thousands of children across the United States from ages 9-10 into adolescence. Researchers assessed prenatal cannabis exposure through maternal report and measured mental health outcomes using validated psychopathology assessments at multiple time points.","limitations":"Prenatal cannabis exposure was based on maternal self-report, which may underestimate true exposure. The study measured associations and cannot prove that cannabis exposure caused the mental health outcomes. Confounding factors like other substance use, socioeconomic status, and postnatal environment are difficult to fully control."},{"rthcId":"RTHC-03693","title":"Sleep Complaints Among Adults With Major Depressive Episode Are Associated With Increased Risk of Incident Psychiatric Disorders: Results From a Population-Based 3-Year Prospective Study.","authors":"Barbotin, Bénédicte; Hoertel, Nicolas; Olfson, Mark; Blanco, Carlos; Sanchez-Rico, Marina; Lejoyeux, Michel; Limosin, Frédéric; Geoffroy, Pierre A","year":2022,"journal":"The Journal of clinical psychiatry, 84(1)","doi":"10.4088/JCP.21m14236","pmid":"36541815","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03694","title":"The effects of acute Cannabis smoke or Δ9-THC injections on the trial-unique, nonmatching-to-location and five-choice serial reaction time tasks in male Long-Evans rats.","authors":"Barnard, Ilne L; Onofrychuk, Timothy J; Sandini, Thaísa M; McElroy, Dan L; Zagzoog, Ayat; Roebuck, Andrew J; Austin-Scott, Faith V; Laprairie, Robert B; Howland, John G","year":2022,"journal":"Neurobiology of learning and memory, 192, 107624","doi":"10.1016/j.nlm.2022.107624","pmid":"35513236","tags":["cognition","cbd","neuroscience","potency"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"High-THC cannabis smoke and THC injections impaired working memory on the TUNL task but had no effect on attention, impulsivity, or perseveration on the 5-CSRTT. High-CBD, low-THC smoke produced no cognitive impairments.","whyItMatters":"This study directly compares different cannabis chemotypes (high-THC vs. high-CBD) on specific cognitive domains, helping clarify which cognitive functions are most vulnerable to THC.","specificNumbers":"THC injections produced significantly higher plasma THC than smoke exposure at 30 minutes post-treatment. High-CBD smoke significantly increased plasma CBD levels. Performance was worse at smaller spatial separations across all groups.","methodology":"Adult male rats were acutely exposed to smoke from high-THC (Mohawk) or low-THC/high-CBD (Treasure Island) cannabis strains via inhalation chamber, or received THC injections (3.0 mg/kg i.p.). Cognitive performance was assessed using touchscreen-based TUNL (working memory) and 5-CSRTT (attention) tasks. Plasma cannabinoid levels were measured.","limitations":"Only male rats were tested. Acute exposure only, so chronic effects remain unknown. Smoke inhalation dosing is less precise than injection. The specific cannabis strains used may not represent all products available to humans."},{"rthcId":"RTHC-03695","title":"Molecular Insights into Epigenetics and Cannabinoid Receptors.","authors":"Basavarajappa, Balapal S; Subbanna, Shivakumar","year":2022,"journal":"Biomolecules, 12(11)","doi":"10.3390/biom12111560","pmid":"36358910","tags":["genetics","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Epigenetic mechanisms including DNA methylation, histone protein modifications, and RNA regulatory networks significantly influence cannabinoid receptor (CB1 and CB2) gene expression, contributing to both normal function and disease states.","whyItMatters":"Understanding how epigenetic factors regulate cannabinoid receptors could reveal why the endocannabinoid system functions differently across individuals and diseases, potentially opening new therapeutic approaches.","specificNumbers":"The endocannabinoid system includes two main receptors (CB1 and CB2), two primary ligands (anandamide and 2-AG), and their biosynthetic and degradative enzymes.","methodology":"Narrative review synthesizing published research on epigenetic regulation of cannabinoid receptors, covering DNA methylation patterns, histone modifications, and non-coding RNA networks across physiological and pathological conditions.","limitations":"As a narrative review, the evidence synthesis may be selective. Much of the cited research is from cell culture or animal models. The translation of epigenetic findings to clinical applications remains speculative."},{"rthcId":"RTHC-03696","title":"Dexmedetomidine in the treatment of toxicologic conditions: a systematic review and review of the toxicology investigators consortium database.","authors":"Baumgartner, Kevin; Doering And, Michelle; Mullins, Michael E","year":2022,"journal":"Clinical toxicology (Philadelphia, Pa.), 60(12), 1356-1375","doi":"10.1080/15563650.2022.2138761","pmid":"36346349","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03697","title":"Anandamide Hydrolysis Inhibition Reverses the Long-Term Behavioral and Gene Expression Alterations Induced by MK-801 in Male Rats: Differential CB1 and CB2 Receptor-Mediated Effects.","authors":"Bauminger, Hagar; Zaidan, Hiba; Akirav, Irit; Gaisler-Salomon, Inna","year":2022,"journal":"Schizophrenia bulletin, 48(4), 795-803","doi":"10.1093/schbul/sbab153","pmid":"35092675","tags":["neuroscience","psychosis","cognition"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"The anandamide hydrolysis inhibitor URB597, given in late adolescence, reversed both novel object recognition deficits (via CB2 receptors) and social interaction abnormalities (via CB1 receptors) induced by early-adolescence MK-801 administration, while also normalizing glutamate and GABA marker expression in the prefrontal cortex.","whyItMatters":"This study identifies specific endocannabinoid receptor pathways for distinct schizophrenia symptoms, suggesting that targeting CB1 vs. CB2 receptors could address different symptom domains.","specificNumbers":"CB1 receptor mediated the reversal of social deficits; CB2 receptor mediated the reversal of cognitive deficits. URB597 also reversed glutamate and GABA abnormalities in the prelimbic prefrontal cortex.","methodology":"Male rats received the NMDA receptor blocker MK-801 in early adolescence to induce schizophrenia-like symptoms, then received the anandamide hydrolysis inhibitor URB597 in late adolescence. Behavioral testing (novel object recognition, social interaction) and mRNA expression analysis of glutamate and GABA markers were performed in adulthood.","limitations":"Animal model only. MK-801 model does not fully replicate human schizophrenia. Only male rats tested. The therapeutic window (late adolescence) may not translate directly to human clinical application."},{"rthcId":"RTHC-03698","title":"Knowledge, experiences, and attitudes of Australian General Practitioners towards medicinal cannabis: a 2021-2022 survey.","authors":"Bawa, Zeeta; McCartney, Danielle; Manocha, Ramesh; McGregor, Iain S","year":2022,"journal":"BMC primary care, 23(1), 330","doi":"10.1186/s12875-022-01946-x","pmid":"36529730","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"85.3% of GPs received patient inquiries about medicinal cannabis in the prior three months, but only 52.3% felt comfortable discussing it. Just 21.8% had prescribed a cannabis product, and 66.9% felt they had inadequate knowledge.","whyItMatters":"Six years after medicinal cannabis became available in Australia, GPs remain the primary prescribers but many feel underprepared, highlighting a gap between patient demand and practitioner readiness.","specificNumbers":"505 GPs surveyed; 85.3% had patient inquiries; 52.3% comfortable discussing; 21.8% had prescribed; 66.9% felt inadequate knowledge. GPs rated opioids, benzodiazepines, and chemotherapy drugs as more hazardous than cannabis.","methodology":"Cross-sectional study using a 42-item online questionnaire completed by 505 Australian GPs attending an educational seminar between November 2021 and February 2022. Results were compared to a 2017 survey to track changes over time.","limitations":"GPs attending educational seminars may not represent all GPs. Self-selection bias likely. Some GPs incorrectly believed CBD causes addiction and driving impairment, suggesting misinformation. Cross-sectional design."},{"rthcId":"RTHC-03699","title":"Medial prefrontal cortex mechanisms of cannabidiol-induced aversive memory reconsolidation impairments.","authors":"Bayer, Hugo; Stern, Cristina A J; Troyner, Fernanda; Gazarini, Lucas; Guimarães, Francisco S; Bertoglio, Leandro J","year":2022,"journal":"Neuropharmacology, 205, 108913","doi":"10.1016/j.neuropharm.2021.108913","pmid":"34864001","tags":["cbd","neuroscience","ptsd"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Systemic CBD reduced Zif268/Egr1 protein (a synaptic plasticity marker for reconsolidation) in the anterior cingulate and prelimbic cortex but not the infralimbic cortex. CBD injected directly into the anterior cingulate or prelimbic cortex also impaired reconsolidation, with CB1 receptor blockade in all three subregions preventing the effect.","whyItMatters":"Understanding exactly where and how CBD disrupts fear memory reconsolidation could inform development of targeted treatments for PTSD and other disorders involving persistent traumatic memories.","specificNumbers":"CBD reduced Zif268/Egr1 in the anterior cingulate and prelimbic cortex but not infralimbic cortex. CB1 blockade in all three subregions prevented CBD's reconsolidation-impairing effect.","methodology":"Rats underwent contextual fear conditioning, then received systemic CBD or vehicle after memory retrieval. Brain tissue was analyzed for Zif268/Egr1 expression. Separate experiments used local CB1 receptor antagonist (AM251) pretreatment or direct CBD injection into specific prefrontal cortex subregions.","limitations":"Animal model only. Contextual fear conditioning is a simplified model of trauma. Only male rats were used. Direct injection doses may not reflect physiological CBD concentrations."},{"rthcId":"RTHC-03700","title":"Acute lung injury-from cannabis to COVID.","authors":"Beasley, Mary Beth","year":2022,"journal":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 35(Suppl 1), 1-7","doi":"10.1038/s41379-021-00915-6","pmid":"34504310","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03701","title":"Cannabis-related emergency department visits by youths and their outcomes in Ontario: a trend analysis.","authors":"Bechard, Melanie; Cloutier, Paula; Lima, Isac; Salamatmanesh, Mina; Zemek, Roger; Bhatt, Maala; Suntharalingam, Sinthuja; Kurdyak, Paul; Baker, Melissa; Gardner, William","year":2022,"journal":"CMAJ open, 10(1), E100-E108","doi":"10.9778/cmajo.20210142","pmid":"35135825","tags":["youth","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-related ER visits rose from 3.8 per 10,000 youth in 2003 to 17.9 per 10,000 in 2017 (4.8-fold increase). In 2017, 88.2% of cannabis-related visits were triaged as \"more severe\" compared to 58.1% of non-cannabis visits, and 19.0% resulted in hospital admission vs. 5.8% for non-cannabis visits.","whyItMatters":"The steep upward trend in cannabis-related ER visits among young people, combined with high severity ratings and admission rates, signals a growing public health concern that preceded cannabis legalization in Canada.","specificNumbers":"14.7 million total ER visits analyzed; 4.8-fold increase in cannabis visits; rates by age in 2017: 25.0/10,000 (ages 19-24), 21.9/10,000 (ages 14-18), 0.8/10,000 (ages 10-13). Males had ≥1.5x higher rates than females.","methodology":"Population-based retrospective analysis of all emergency department visits in Ontario, Canada from 2003-2017 for youth aged 10-24 years, using ICD-10 codes for cannabis poisoning and mental disorders due to cannabinoids. 14,697,778 total visits examined.","limitations":"Administrative data may undercount cannabis involvement. ICD coding practices may have changed over time. Ontario data may not generalize to other provinces. The study ended before legalization, so post-legalization trends are unknown."},{"rthcId":"RTHC-03702","title":"Harmful Alcohol and Drug Use Is Associated with Syndemic Risk Factors among Female Sex Workers in Nairobi, Kenya.","authors":"Beksinska, Alicja; Nyariki, Emily; Kabuti, Rhoda; Kungu, Mary; Babu, Hellen; Shah, Pooja; The Maisha Fiti Study Champions; Nyabuto, Chrispo; Okumu, Monica; Mahero, Anne; Ngurukiri, Pauline; Jama, Zaina; Irungu, Erastus; Adhiambo, Wendy; Muthoga, Peter; Kaul, Rupert; Seeley, Janet; Weiss, Helen A; Kimani, Joshua; Beattie, Tara S","year":2022,"journal":"International journal of environmental research and public health, 19(12)","doi":"10.3390/ijerph19127294","pmid":"35742558","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03703","title":"In-home cannabis smoking more prevalent than in-home tobacco smoking among 2019 Global Drug Survey respondents.","authors":"Bellettiere, John; Liles, Sandy; Posis, Alexander Ivan B; Anuskiewicz, Blake; Tripathi, Osika; Nguyen, Benjamin; Chavez, Paul; Zhu, Shu-Hong; Park, Ji-Yeun; Winstock, Adam; Ferris, Jason","year":2022,"journal":"Addictive behaviors, 125, 107130","doi":"10.1016/j.addbeh.2021.107130","pmid":"34674905","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among cannabis-only users, 78.8% reported past-year in-home cannabis smoking, compared to 67.9% of tobacco-only users smoking tobacco at home. Among dual users, in-home cannabis smoking (82.8%) also exceeded in-home tobacco smoking (75.9%, p<0.001).","whyItMatters":"As tobacco home-smoking bans have reduced secondhand smoke exposure, cannabis appears to be exempt from similar social norms, creating a potential gap in household air quality protections.","specificNumbers":"107,272 respondents; 53.6% reported in-home cannabis smoking; 50.6% in-home tobacco smoking. Among dual users: 82.8% smoked cannabis at home vs. 75.9% tobacco. Top responding countries: Germany (32%), USA (10%), New Zealand (9%).","methodology":"Cross-sectional analysis of 107,272 adults (mean age 30, 34% women) from 17 countries who completed the Global Drug Survey 2019. Respondents were categorized as cannabis-only users, tobacco-only users, dual users, or non-users.","limitations":"Global Drug Survey respondents are self-selected and skew toward drug-interested populations. Cross-sectional design. No measurement of actual smoke exposure or health outcomes. Some countries had low response rates."},{"rthcId":"RTHC-03704","title":"The Metabolic Efficacy of a Cannabidiolic Acid (CBDA) Derivative in Treating Diet- and Genetic-Induced Obesity.","authors":"Ben-Cnaan, Elad; Permyakova, Anna; Azar, Shahar; Hirsch, Shira; Baraghithy, Saja; Hinden, Liad; Tam, Joseph","year":2022,"journal":"International journal of molecular sciences, 23(10)","doi":"10.3390/ijms23105610","pmid":"35628417","tags":["cbd","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"EPM301 (40 mg/kg/day) produced weight loss, increased physical activity, and improved glycemic and lipid profiles in diet-induced obese mice. It also reduced body weight and overeating in Magel2-null mice (a Prader-Willi syndrome model), and when given preventively, completely blocked weight gain.","whyItMatters":"CBDA is unstable and converts to CBD, limiting its therapeutic use. This stabilized derivative showed anti-obesity effects in two distinct obesity models, suggesting potential for both common and rare forms of obesity.","specificNumbers":"40 mg/kg/day dose used for DIO mice; 20 and 40 mg/kg/day for GIO mice. Preventive treatment completely inhibited weight gain in standard-diet-fed Magel2-null mice.","methodology":"In vivo study testing EPM301 (a stabilized CBDA-O-methyl ester derivative) in two mouse models: diet-induced obesity (DIO) with high-fat diet and genetic-induced obesity (GIO) using Magel2-null mice, a model for Prader-Willi syndrome. Doses of 20 and 40 mg/kg/day administered intraperitoneally.","limitations":"Animal study only. Intraperitoneal administration does not reflect typical human drug delivery. Long-term safety unknown. The Magel2-null mouse model does not perfectly replicate human Prader-Willi syndrome. No human trials yet."},{"rthcId":"RTHC-03705","title":"Medicinal cannabis for the treatment of anxiety disorders.","authors":"Berger, Maximus; Amminger, G Paul; McGregor, Iain S","year":2022,"journal":"Australian journal of general practice, 51(8), 586-592","doi":"10.31128/AJGP-04-21-5936","pmid":"35908759","tags":["medical-cannabis","cbd","anxiety"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD demonstrated anxiolytic effects in trials with healthy volunteers and clinical populations, though evidence remains insufficient for first-line treatment. THC-dominant products showed ambiguous results, with some individuals experiencing relief and others worsening anxiety. About 17% of anxiety prescriptions were for CBD-dominant products while 50% were for herbal cannabis for vaporization.","whyItMatters":"Anxiety is the second most common reason for medicinal cannabis prescriptions in Australia, yet the evidence base is still developing, creating a gap between prescribing practice and scientific certainty.","specificNumbers":"17% of anxiety prescriptions for CBD-dominant products (oils, wafers, capsules); 33% for THC-containing liquids; 50% for herbal cannabis for vaporization. Anxiety is the second most common reason for medicinal cannabis prescription in Australia.","methodology":"Review article summarizing clinical trials, laboratory studies, and prescribing data on medicinal cannabis for anxiety disorders in Australia.","limitations":"Review article, not a systematic review. Australian prescribing data may not reflect patterns elsewhere. The evidence base for CBD in anxiety is still mostly from small trials. No long-term outcome data reviewed."},{"rthcId":"RTHC-03706","title":"Cannabidiol for Treatment-Resistant Anxiety Disorders in Young People: An Open-Label Trial.","authors":"Berger, Maximus; Li, Emily; Rice, Simon; Davey, Christopher G; Ratheesh, Aswin; Adams, Sophie; Jackson, Henry; Hetrick, Sarah; Parker, Alexandra; Spelman, Tim; Kevin, Richard; McGregor, Iain S; McGorry, Patrick; Amminger, G Paul","year":2022,"journal":"The Journal of clinical psychiatry, 83(5)","doi":"10.4088/JCP.21m14130","pmid":"35921510","tags":["cbd","anxiety","youth","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Mean OASIS anxiety scores decreased from 10.8 at baseline to 6.3 at week 12, a 42.6% reduction (p<0.001). Depression, clinical global impressions, and functioning also improved significantly. 80.6% of participants reported adverse events, most commonly fatigue and low mood, but no serious or unexpected events occurred.","whyItMatters":"Treatment resistance in youth anxiety is common (affecting nearly half of patients), and this trial provides initial evidence that CBD could be a viable add-on option for this underserved group.","specificNumbers":"31 participants; ages 12-25; CBD titrated up to 800 mg/day; 42.6% reduction in anxiety severity (OASIS scores 10.8 to 6.3); 80.6% reported adverse events; no serious adverse events.","methodology":"Open-label trial of 31 young people aged 12-25 with DSM-5 anxiety disorders who had not improved with CBT and/or antidepressants. All received add-on CBD on a fixed-flexible schedule titrated up to 800 mg/day for 12 weeks.","limitations":"Open-label design with no placebo control, so expectancy effects cannot be ruled out. Small sample size (n=31). High rate of mild adverse events. No long-term follow-up. Add-on design makes it difficult to isolate CBD's specific contribution."},{"rthcId":"RTHC-03707","title":"Pharmacokinetic Profile of ∆9-Tetrahydrocannabinol, Cannabidiol and Metabolites in Blood following Vaporization and Oral Ingestion of Cannabidiol Products.","authors":"Bergeria, Cecilia L; Spindle, Tory R; Cone, Edward J; Sholler, Dennis; Goffi, Elia; Mitchell, John M; Winecker, Ruth E; Bigelow, George E; Flegel, Ronald; Vandrey, Ryan","year":2022,"journal":"Journal of analytical toxicology, 46(6), 583-591","doi":"10.1093/jat/bkab124","pmid":"35438179","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Mean peak CBD blood concentration was 171.1 ng/mL for vaporized CBD-dominant cannabis, 104.6 ng/mL for vaporized pure CBD, and only 13.7 ng/mL for oral CBD. Among oral formulations, Epidiolex produced the highest peak (20.5 ng/mL) vs. capsule (17.8 ng/mL) and syrup (2.8 ng/mL). Pure CBD by either route did not produce detectable THC or THC-COOH in blood.","whyItMatters":"Massive differences in bioavailability between oral and vaporized CBD have direct implications for dosing, product selection, and drug testing. The confirmation that pure CBD does not convert to THC addresses a common concern.","specificNumbers":"Peak CBD: vaporized cannabis 171.1 ng/mL (range 40-665), vaporized pure CBD 104.6 ng/mL (range 19-312), oral CBD 13.7 ng/mL (range 0-50). THC detected in 12/18 after vaporized CBD-dominant cannabis but in 0/18 after pure CBD products.","methodology":"Within-subject, double-blind, double-dummy, placebo-controlled study in 18 adults. Each participant received 100 mg CBD via oral, vaporized, and vaporized CBD-dominant cannabis (10.5% CBD/0.39% THC) routes, plus placebo. Blood and oral fluid were collected for 57-58 hours post-dose.","limitations":"Small sample size (n=18). Single-dose study. Limited to three oral formulations. Fasting condition only tested in 6 participants. May not reflect real-world use patterns with repeated dosing."},{"rthcId":"RTHC-03708","title":"Case Report: Superior Mesenteric Artery Syndrome in an Adolescent With Cannabinoid Hyperemesis.","authors":"Berken, Jonathan A; Saul, Samantha; Osgood, Peter T","year":2022,"journal":"Frontiers in pediatrics, 10, 830280","doi":"10.3389/fped.2022.830280","pmid":"35265566","tags":["cardiovascular","youth","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 17-year-old with a history of heavy cannabis use and recurrent nausea/vomiting meeting criteria for cannabinoid hyperemesis syndrome presented with sudden severe bilious vomiting. CT imaging revealed superior mesenteric artery syndrome, a duodenal obstruction caused by rapid weight loss reducing the protective fat pad between the SMA and aorta.","whyItMatters":"This is the first documented case of SMA syndrome resulting from CHS, alerting clinicians to a potentially dangerous complication when chronic cannabis-related vomiting causes significant weight loss.","specificNumbers":"Patient was 17 years old. Maintained a normal BMI despite rapid weight loss. Chronic heavy cannabis use with symptoms meeting Rome IV criteria for CHS.","methodology":"Single case report of a 17-year-old adolescent presenting to the emergency department with voluminous bilious emesis, chronic heavy cannabis use, and a history of weight loss.","limitations":"Single case report. Cannot establish how common this complication is. Limited details on the patient's treatment and outcome. No information on long-term follow-up."},{"rthcId":"RTHC-03709","title":"A Randomized, Triple-Blind, Comparator-Controlled Parallel Study Investigating the Pharmacokinetics of Cannabidiol and Tetrahydrocannabinol in a Novel Delivery System, Solutech, in Association with Cannabis Use History.","authors":"Berl, Volker; Hurd, Yasmin L; Lipshutz, Bruce H; Roggen, Markus; Mathur, Eric J; Evans, Malkanthi","year":2022,"journal":"Cannabis and cannabinoid research, 7(6), 777-789","doi":"10.1089/can.2021.0176","pmid":"35787693","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Solutech produced significantly greater peak concentration, faster time to peak, and larger absorption rate constants for THC, CBD, and metabolites compared to MCT-oil. Participants who started using cannabis later in life had higher peak levels of THC and CBD. Those with more years of recreational use had higher total exposure to THC and CBD.","whyItMatters":"Oral cannabis bioavailability is notoriously variable. This delivery technology could make oral dosing more predictable, and the finding that use history affects pharmacokinetics has implications for personalized dosing.","specificNumbers":"32 participants; single dose of 10 mg THC + ~10 mg CBD; blood collected at 17 timepoints over 48 hours. Age of first use and years of use both significantly affected pharmacokinetic parameters (p≤0.032 and p≤0.048 respectively).","methodology":"Randomized, triple-blind, comparator-controlled parallel study in 32 healthy adults. Participants received a single dose of either Solutech or MCT-oil containing ~10 mg THC and ~10 mg CBD. Blood was collected at 17 timepoints over 48 hours.","limitations":"Single-dose study. Small sample size (n=32). Only healthy participants tested. Long-term safety and efficacy not assessed. The influence of use history on pharmacokinetics needs replication."},{"rthcId":"RTHC-03710","title":"Cannabidiol for neurodegenerative disorders: A comprehensive review.","authors":"Bhunia, Sukanya; Kolishetti, Nagesh; Arias, Adriana Yndart; Vashist, Arti; Nair, Madhavan","year":2022,"journal":"Frontiers in pharmacology, 13, 989717","doi":"10.3389/fphar.2022.989717","pmid":"36386183","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03711","title":"Long-term observational studies with cannabis-based medicines for chronic non-cancer pain: A systematic review and meta-analysis of effectiveness and safety.","authors":"Bialas, Patric; Fitzcharles, Mary-Ann; Klose, Petra; Häuser, Winfried","year":2022,"journal":"European journal of pain (London, England), 26(6), 1221-1233","doi":"10.1002/ejp.1957","pmid":"35467781","tags":["medical-cannabis","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Mean pain reduction was 1.75 points on a 0-10 scale (95% CI 0.72-2.78). About 20.8% of patients reported ≥50% pain relief. Sleep improvements were moderate in effect size, while depression and anxiety improvements were small. Only 53.3% of patients completed the studies, with 6.8% dropping out due to adverse events.","whyItMatters":"While RCTs of cannabis for pain are typically short-term, these longer observational studies (26-52 weeks) provide a more realistic picture of sustained use, including the concerning finding that nearly half of patients discontinue treatment.","specificNumbers":"6 studies, 2,686 participants, 26-52 weeks duration. Pain reduction: 1.75/10. ≥50% relief: 20.8%. Study completion: 53.3%. Dropout from adverse events: 6.8%. Serious adverse events: 3.0%. Deaths: 0.3%.","methodology":"Systematic review and meta-analysis of prospective observational studies with ≥26 weeks duration. Six studies with 2,686 participants were included. CENTRAL, EMBASE, and MEDLINE searched through December 2021. Random effects models used.","limitations":"Very low certainty of evidence for all outcomes. Observational design without control groups. High dropout rates complicate interpretation. Heterogeneous pain conditions included. No standardized cannabis products across studies."},{"rthcId":"RTHC-03712","title":"A naturalistic study of orally administered vs. inhaled legal market cannabis: cannabinoids exposure, intoxication, and impairment.","authors":"Bidwell, L Cinnamon; Karoly, Hollis C; Torres, Marco Ortiz; Master, Ashley; Bryan, Angela D; Hutchison, Kent E","year":2022,"journal":"Psychopharmacology, 239(2), 385-397","doi":"10.1007/s00213-021-06007-2","pmid":"34708254","tags":["cognition","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Flower users consumed an average of 51.25 mg THC vs. 15.97 mg for edible users. Plasma THC was significantly higher after flower use, but THC metabolite levels, subjective intoxication, and verbal memory impairment were comparable between groups. Self-reported THC consumed correlated strongly with plasma THC for edible but not flower users.","whyItMatters":"This is one of the first studies to directly compare the pharmacology and effects of legal market edible and flower cannabis under naturalistic conditions, providing data more relevant to real-world use than laboratory studies with standardized products.","specificNumbers":"84 participants; flower users consumed 51.25 mg THC on average vs. 15.97 mg for edible users. Similar levels of intoxication and verbal memory impairment despite the dose difference.","methodology":"Naturalistic study of 84 participants (55 flower, 29 edible users, mean age 32, 44% female) who used cannabis at least once weekly. Participants underwent blood draws, heart rate measurement, subjective drug effects assessment, and cognitive testing before and after ad libitum use of legal market products in a mobile laboratory.","limitations":"Non-randomized design (participants self-selected their product type). Unequal group sizes. Ad libitum dosing means results reflect typical use patterns rather than controlled comparisons. Single-session assessment."},{"rthcId":"RTHC-03713","title":"Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications.","authors":"Bilbao, Ainhoa; Spanagel, Rainer","year":2022,"journal":"BMC medicine, 20(1), 259","doi":"10.1186/s12916-022-02459-1","pmid":"35982439","tags":["medical-cannabis","cbd","pain","epilepsy"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"CBD showed high-grade evidence for epilepsy (SMD -0.5) and moderate-grade for Parkinsonism (SMD -0.41). Dronabinol had moderate evidence for chronic pain (SMD -0.31), appetite (SMD -0.51), and Tourette syndrome (SMD -1.01). Nabiximols showed moderate evidence for chronic pain (SMD -0.25), spasticity (SMD -0.36), sleep (SMD -0.24), and substance use disorders (SMD -0.48).","whyItMatters":"By analyzing cannabinoid medications separately rather than lumping them together, this study reveals that the question \"does cannabis work?\" is misleading. The answer depends entirely on which cannabinoid and which condition.","specificNumbers":"152 RCTs, 12,123 participants, 84 comparisons across 23 medical indications. Only CBD for epilepsy reached high-grade evidence. Four drug-indication combinations had moderate-grade evidence.","methodology":"Systematic review and meta-analysis registered at PROSPERO, searching eight databases for RCTs of dronabinol, nabilone, CBD, and nabiximols across 23 medical indications. 152 RCTs with 12,123 participants were analyzed. Evidence graded using Cochrane Risk of Bias and GRADE tools.","limitations":"Quality of included RCTs varied widely. Many indications had few trials. The meta-analysis could not account for dose optimization. Some cannabinoid-indication combinations had too few studies for robust conclusions."},{"rthcId":"RTHC-03714","title":"Clinical and treatment predictors of relapse during a three-year follow-up of a cohort of first episodes of schizophrenia.","authors":"Bioque, Miquel; Mezquida, Gisela; Amoretti, Sílvia; García-Rizo, Clemente; López-Ilundain, Jose M; Diaz-Caneja, Covadonga M; Zorrilla, Iñaki; Mané, Anna; Rodriguez-Jimenez, Roberto; Corripio, Iluminada; Pomarol-Clotet, Edith; Ibáñez, Ángela; Usall, Judith; Contreras, Fernando; Mas, Sergi; Vázquez-Bourgon, Javier; Cuesta, Manuel J; Parellada, Mara; González-Pinto, Ana; Hidalgo-Figueroa, María; Bernardo, Miquel","year":2022,"journal":"Schizophrenia research, 243, 32-42","doi":"10.1016/j.schres.2022.02.026","pmid":"35231832","tags":["psychosis","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis consumption was dramatically higher among those who relapsed (93.2%) compared to those who maintained remission (56.7%, p<0.001). Other relapse-associated factors included higher antipsychotic doses, polypharmacy, benzodiazepine use, and side effects. Notably, 22% of those who remained in remission were not taking any antipsychotic.","whyItMatters":"The strength of the association between cannabis use and relapse in first-episode schizophrenia underscores cannabis cessation as a potentially modifiable target for preventing second episodes.","specificNumbers":"119 patients followed; 49.6% relapsed within 3 years. Cannabis use: 93.2% in relapsers vs. 56.7% in remitters (p<0.001). Antipsychotic doses: 381.93 vs. 242.29 mg chlorpromazine equivalents/day (p=0.028). 22% of non-relapsers were off antipsychotics.","methodology":"Naturalistic longitudinal study following 119 patients in remission after first-episode schizophrenia across 15 tertiary centers in Spain over three years. Sociodemographic, clinical, treatment, and substance use data analyzed.","limitations":"Observational design cannot prove cannabis caused relapse. Higher antipsychotic doses and polytherapy in relapsers may reflect more severe illness. Cannabis use was self-reported. No data on cannabis potency or frequency."},{"rthcId":"RTHC-03715","title":"The Cannabis Policy Scale: A New Research and Surveillance Tool for U.S. States.","authors":"Blanchette, Jason G; Pacula, Rosalie Liccardo; Smart, Rosanna; Lira, Marlene C; Pessar, Seema Choksy; Naimi, Timothy S","year":2022,"journal":"Journal of studies on alcohol and drugs, 83(6), 829-838","doi":"10.15288/jsad.21-00462","pmid":"36484580","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03716","title":"Rating the comparative efficacy of state-level cannabis policies on recreational cannabis markets in the United States.","authors":"Blanchette, Jason G; Pacula, Rosalie Liccardo; Smart, Rosanna; Lira, Marlene C; Boustead, Anne E; Caulkins, Jonathan P; Kilmer, Beau; Kerr, William C; Treffers, Ryan; Naimi, Timothy S","year":2022,"journal":"The International journal on drug policy, 106, 103744","doi":"10.1016/j.drugpo.2022.103744","pmid":"35636068","tags":["legalization","driving","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"State monopoly (government-owned production through retail) was rated most effective across all three outcome areas. Restrictions on retail availability, taxes, price restrictions, and retail operations restrictions were also highly rated. Policies targeting businesses were judged more effective than those targeting consumers. Experts reported little or no direct evidence from cannabis literature for most policies.","whyItMatters":"As more jurisdictions legalize cannabis, this expert consensus identifies which regulatory approaches are theoretically most promising while frankly acknowledging the almost complete absence of direct evidence.","specificNumbers":"9 panelists rated 18 policies across 3 outcomes. State monopoly ranked #1 for all three outcomes. A small number of policies were rated highly effective across all domains.","methodology":"Modified Delphi approach with nine panelists (researchers and policy consultants) rating 18 cannabis policies on their theoretical efficacy for reducing youth use, excessive adult use, and cannabis-impaired driving using Likert scales.","limitations":"Expert opinion, not empirical evidence. Only nine panelists. Ratings are theoretical since most policies have not been empirically evaluated. U.S.-focused panel may not reflect international perspectives."},{"rthcId":"RTHC-03717","title":"Evaluation of the anti-inflammatory effects of selected cannabinoids and terpenes from Cannabis Sativa employing human primary leukocytes.","authors":"Blevins, Lance K; Bach, Anthony P; Crawford, Robert B; Zhou, Jiajun; Henriquez, Joseph E; Rizzo, Michael D; Sermet, Sera; Khan, D M Isha Olive; Turner, Helen; Small-Howard, Andrea L; Kaminski, Norbert E","year":2022,"journal":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 170, 113458","doi":"10.1016/j.fct.2022.113458","pmid":"36228902","tags":["inflammation","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Of 21 immune parameters tested, THC affected 11, followed by cannabidivarin (CBDV), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), and CBD with the fewest effects. Among terpenes, alpha-pinene showed the most activity, linalool and phytol had modest effects, and limonene had no detectable immune activity at all.","whyItMatters":"This study directly compares the immune effects of multiple cannabis compounds side by side in human cells, providing data to evaluate popular claims about terpenes and minor cannabinoids.","specificNumbers":"6 cannabinoids and 5 terpenes tested across 21 immune parameters. THC affected 11 parameters. Limonene affected 0 parameters. Concentrations ranged from 0.001 to 10 μM.","methodology":"Human peripheral blood mononuclear cells (PBMCs) were pretreated with individual cannabinoids or terpenes at 0.001-10 μM concentrations, then stimulated to activate dendritic cells, monocytes, or T cells. Proliferation, activation markers, cytokine production, and phagocytosis were measured.","limitations":"In vitro study using isolated immune cells, not whole organisms. Single-compound testing does not capture potential synergistic or entourage effects. Concentrations may not reflect physiologically achieved levels. Only anti-inflammatory properties tested."},{"rthcId":"RTHC-03718","title":"A mixed methods analysis of cannabis use routines for chronic pain management.","authors":"Boehnke, Kevin F; Yakas, Laura; Scott, J Ryan; DeJonckheere, Melissa; Litinas, Evangelos; Sisley, Suzanne; Clauw, Daniel J; Williams, David A; McAfee, Jenna","year":2022,"journal":"Journal of cannabis research, 4(1), 7","doi":"10.1186/s42238-021-00116-7","pmid":"35016733","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of participants, 45% used both inhalation and non-inhalation routes, 36.2% used inhalation only, and 18.8% used non-inhalation only. The combined group reported significantly greater health improvements and more medication class substitutions than either single-route group. THC-rich products were typically used at night while CBD-rich products were used during the day. All groups reported similar pain reduction.","whyItMatters":"This is one of the largest studies to characterize how chronic pain patients actually use cannabis in practice, revealing sophisticated self-directed routines involving multiple products, routes, and timing strategies.","specificNumbers":"1,087 participants; 45% used combined routes, 36.2% inhalation only, 18.8% non-inhalation only. Combined route users had 0.62 more medication substitutions than non-inhalation users and 0.45 more than inhalation users.","methodology":"Mixed methods analysis of 1,087 cross-sectional survey responses from adults with chronic pain using cannabis in the US and Canada. Qualitative analysis of open-ended responses about use routines, followed by quantitative comparison of subgroups based on administration routes.","limitations":"Cross-sectional self-report data. No verification of diagnoses, products, or outcomes. Selection bias toward cannabis-positive respondents. No control group. Medication substitution self-reported, not verified."},{"rthcId":"RTHC-03719","title":"Cannabidiol Product Dosing and Decision-Making in a National Survey of Individuals with Fibromyalgia.","authors":"Boehnke, Kevin F; Gagnier, Joel J; Matallana, Lynne; Williams, David A","year":2022,"journal":"The journal of pain, 23(1), 45-54","doi":"10.1016/j.jpain.2021.06.007","pmid":"34214700","tags":["cbd","pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Average CBD dose per session was 16 mg, with 24-27 mg per day. About one-third of participants did not know their CBD dose. Purchasing was driven by personal research (63%) rather than medical professionals (16%). Tinctures and topicals were most common. Those using both inhalation and non-inhalation routes reported greater symptom relief. No consistent relationship between CBD dose and reported effects was found.","whyItMatters":"With fibromyalgia patients commonly turning to CBD products, this study reveals that most are self-directing their treatment with low doses and no medical guidance, and that standard dose-response assumptions may not apply.","specificNumbers":"878 participants (93.6% female, mean age 55.5); 16 mg CBD per session, 24-27 mg/day average; 63% relied on personal research; 16% guided by medical professionals; ~33% did not know their dose.","methodology":"Secondary analysis of a cross-sectional survey of 878 people with fibromyalgia using CBD products. Participants were subgrouped by past-year high-THC cannabis (HTC) use. Administration routes, dosing patterns, and perceived effects were analyzed.","limitations":"Self-report data. No verification of product contents or diagnoses. Cross-sectional design. Predominantly female and white sample. No placebo control. CBD product quality and actual cannabinoid content likely varied."},{"rthcId":"RTHC-03720","title":"Differences between users' and addiction medicine experts' harm and benefit assessments of licit and illicit psychoactive drugs: Input for psychoeducation and legalization/restriction debates.","authors":"Bonnet, Udo; Specka, Michael; Kanti, Ann-Kristin; Scherbaum, Norbert","year":2022,"journal":"Frontiers in psychiatry, 13, 1041762","doi":"10.3389/fpsyt.2022.1041762","pmid":"36465301","tags":["harm-reduction","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Users and experts produced similar overall harm rankings, both placing heroin, cocaine, and amphetamines at the top and cannabis, psychotropic mushrooms, and buprenorphine near the bottom. However, users rated the benefits of cannabis, nicotine, and traditional illicit drugs significantly more positively than experts. Both groups ranked alcohol and benzodiazepine harms higher than those of cannabis or psychotropic mushrooms, despite the latter being more heavily regulated.","whyItMatters":"Understanding where user and expert perceptions diverge can improve psychoeducation and inform drug policy debates, particularly for substances like cannabis and alcohol where regulatory status does not align with perceived harm.","specificNumbers":"117 users and 101 experts; core substances with >50% user experience: nicotine, cannabis, alcohol, cocaine, heroin, amphetamine, methadone. Users rated cannabis benefits significantly higher than experts.","methodology":"Structured interviews with 117 substance-dependent German adults seeking detoxification or rehabilitation, using the same questionnaire previously administered to 101 German addiction medicine experts. Harm and benefit ratings for 33 psychoactive substances were compared.","limitations":"German sample may not generalize. Users were seeking treatment, not representative of all users. Limited experience with many substances among the user group. Potential \"attraction bias\" in users and \"treatment bias\" in experts."},{"rthcId":"RTHC-03721","title":"Non-psychotropic Cannabis sativa L. phytocomplex modulates microglial inflammatory response through CB2 receptors-, endocannabinoids-, and NF-κB-mediated signaling.","authors":"Borgonetti, Vittoria; Benatti, Cristina; Governa, Paolo; Isoldi, Giovanni; Pellati, Federica; Alboni, Silvia; Tascedda, Fabio; Montopoli, Monica; Galeotti, Nicoletta; Manetti, Fabrizio; Miraldi, Elisabetta; Biagi, Marco; Rigillo, Giovanna","year":2022,"journal":"Phytotherapy research : PTR, 36(5), 2246-2263","doi":"10.1002/ptr.7458","pmid":"35393641","tags":["inflammation","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The cannabis extract significantly reduced pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in activated microglia, while pure CBD only partially reduced them and beta-caryophyllene was ineffective. The extract's effects were only partially dependent on CB2 receptors and also involved regulation of endocannabinoid-metabolizing enzymes, inhibition of reactive oxygen species, and suppression of NF-κB nuclear translocation via JNK/p38 modulation.","whyItMatters":"This study provides molecular evidence for why whole cannabis extracts may be more effective than isolated CBD for neuroinflammation, supporting the entourage effect hypothesis with specific mechanistic data.","specificNumbers":"The extract significantly attenuated IL-1β, IL-6, and TNF-α upregulation. CBD only partially attenuated these markers. Beta-caryophyllene (a common cannabis terpene) was completely ineffective alone.","methodology":"BV-2 microglial cells were pretreated with a CBD-and-terpene-enriched cannabis extract, pure CBD, or beta-caryophyllene, then stimulated with LPS (lipopolysaccharide) to induce inflammation. Multiple inflammatory pathways and signaling cascades were measured.","limitations":"In vitro study using a cell line, not primary microglia or whole-brain tissue. The specific extract composition may not represent all commercial products. Concentrations used may not reflect achievable brain levels. No in vivo validation."},{"rthcId":"RTHC-03722","title":"Characterizing cannabis use reduction and change in functioning during treatment: Initial steps on the path to new clinical endpoints.","authors":"Borodovsky, Jacob T; Sofis, Michael J; Sherman, Brian J; Gray, Kevin M; Budney, Alan J","year":2022,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 36(5), 515-525","doi":"10.1037/adb0000817","pmid":"35084903","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03723","title":"Cannabis Use in Autism: Reasons for Concern about Risk for Psychosis.","authors":"Bortoletto, Riccardo; Colizzi, Marco","year":2022,"journal":"Healthcare (Basel, Switzerland), 10(8)","doi":"10.3390/healthcare10081553","pmid":"36011210","tags":["psychosis","genetics","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis exposure in autistic individuals may exert disruptive epigenetic effects on brain regions critical to schizophrenia pathophysiology. Autism candidate genes carry bivalent chromatin markings that make them more vulnerable to cannabinoid-induced disruption. These epigenetic changes could potentially be inherited intergenerationally, supporting a developmental trajectory between autism and psychosis modulated by the endocannabinoid system.","whyItMatters":"As cannabis use becomes more common, including among autistic individuals seeking symptom relief, understanding population-specific risks is crucial, especially when those risks may extend to future generations.","specificNumbers":"The review does not provide specific prevalence numbers but identifies autism candidate genes with bivalent chromatin markings as a molecular vulnerability.","methodology":"Narrative review synthesizing evidence on cannabinoid-induced epigenetic effects in autism spectrum individuals, focusing on shared genetic pathways between autism and psychosis and the role of the endocannabinoid system.","limitations":"Much of the evidence is from preclinical models. The proposed intergenerational epigenetic inheritance has limited direct evidence in humans. The review does not quantify the actual risk increase. Narrative rather than systematic review."},{"rthcId":"RTHC-03724","title":"Differential Enantiomer-Specific Signaling of Cannabidiol at CB1 Receptors.","authors":"Bosquez-Berger, Taryn; Wilson, Sierra; Iliopoulos-Tsoutsouvas, Christos; Jiang, Shan; Wager-Miller, Jim; Nikas, Spyros P; Mackie, Ken P; Makriyannis, Alexandros; Straiker, Alex","year":2022,"journal":"Molecular pharmacology, 102(6), 259-268","doi":"10.1124/molpharm.121.000305","pmid":"36153039","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"(+)-CBD had a 5-fold lower inhibition constant for displacing a CB1 agonist and was approximately 10 times more potent at inhibiting depolarization-induced suppression of excitation (DSE), a form of endocannabinoid-mediated synaptic plasticity. (+)-CBD also stereoselectively activated sphingosine-1-phosphate receptors S1P1 and S1P3, a completely different signaling pathway.","whyItMatters":"Natural cannabis only produces (-)-CBD, but the synthetic mirror image (+)-CBD has dramatically different pharmacology, suggesting that CBD's 3D shape matters enormously for its biological effects and opening new drug development possibilities.","specificNumbers":"(+)-CBD was ~5x more potent at displacing CP55,940 at CB1 and ~10x more potent at inhibiting DSE compared to (-)-CBD.","methodology":"Enantioselective synthesis of both CBD enantiomers, with a new NMR-based method for confirming enantiomeric purity. Pharmacological testing in autaptic hippocampal neurons (a model of endocannabinoid signaling) and CHO-K1 cells. Binding, signaling, and functional assays performed.","limitations":"In vitro and cell-based studies only. (+)-CBD does not occur naturally and its in vivo effects are unknown. The clinical significance of S1P receptor activation by (+)-CBD is unclear. No behavioral or therapeutic testing performed."},{"rthcId":"RTHC-03725","title":"\"Intervention Program Based on Self\": A Proposal for Improving the Addiction Prevention Program \"Unplugged\" through Self-Concept.","authors":"Bourduge, Cédrine; Brousse, Georges; Morel, Florence; Pereira, Bruno; Lambert, Céline; Izaute, Marie; Teissedre, Frédérique","year":2022,"journal":"International journal of environmental research and public health, 19(15)","doi":"10.3390/ijerph19158994","pmid":"35897365","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03726","title":"Cannabinoids and the endocannabinoid system in fibromyalgia: A review of preclinical and clinical research.","authors":"Bourke, Stephanie L; Schlag, Anne Katrin; O'Sullivan, Saoirse Elizabeth; Nutt, David J; Finn, David P","year":2022,"journal":"Pharmacology & therapeutics, 240, 108216","doi":"10.1016/j.pharmthera.2022.108216","pmid":"35609718","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Clinical evidence shows endocannabinoid system alterations in fibromyalgia patients, including single nucleotide polymorphisms and increased circulating endocannabinoids. FAAH inhibition (boosting anandamide) showed promise in the reserpine-induced myalgia animal model. Cannabis and cannabinoid treatments reduced pain and anxiety in clinical studies, but methodological limitations prevent treatment recommendations.","whyItMatters":"Fibromyalgia remains a significant unmet clinical need, and evidence that the endocannabinoid system is altered in these patients provides a biological rationale for cannabinoid-based treatments beyond symptom management.","specificNumbers":"The review covers multiple study types but does not provide a single pooled effect size. FAAH inhibition and cannabinoid treatments showed improvements in both pain and anxiety measures in preclinical and clinical settings.","methodology":"Comprehensive review of preclinical and clinical studies examining the endocannabinoid system in fibromyalgia, covering animal models, genetic studies, biomarker measurements, and treatment trials with cannabis-based medicines.","limitations":"Existing clinical studies have methodological limitations including small samples and short durations. Animal models have limited validity for the full fibromyalgia phenotype. Sex bias in preclinical research (fibromyalgia primarily affects women). No long-term efficacy or safety data."},{"rthcId":"RTHC-03727","title":"Developments and Changes in Primary Public Health Outcome Indicators Associated with the Legalization of Non-Medical Cannabis Use and Supply in Canada (2018): A Comprehensive Overview.","authors":"Boury, Himani; Hall, Wayne; Fischer, Benedikt","year":2022,"journal":"International journal of mental health and addiction, 1-15","doi":"10.1007/s11469-022-00986-9","pmid":"36589471","tags":["legalization","driving","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis use increased in select population groups, with a shift away from smoking toward other consumption methods. Evidence on cannabis-related hospitalizations for mental health was mixed. Cannabis-impaired driving prevalence was generally steady but THC exposure among crash-involved drivers may have increased. More users obtained cannabis from legal sources, but regular users continued using illicit sources.","whyItMatters":"As the first G7 nation to legalize recreational cannabis, Canada serves as a natural experiment for the world. This review provides the most comprehensive early assessment of public health impacts.","specificNumbers":"The review covers four key indicators (use prevalence, hospitalizations, impaired driving, and sourcing) across the 2018 legalization period. Specific numbers vary by indicator and data source.","methodology":"Review of peer-reviewed and grey literature featuring population-level or quasi-representative samples with comparable pre- and post-legalization outcome data for key public health indicators in Canada.","limitations":"Short post-legalization timeframe limits detection of longer-term trends. Data sources vary in quality and representativeness. COVID-19 pandemic overlapped with the post-legalization period, confounding analysis. Some indicators have significant measurement challenges."},{"rthcId":"RTHC-03728","title":"Coping Motives Mediate the Association of Trauma History with Problematic Cannabis Use in Young Adult Medical Cannabis Patients and Non-Patient Cannabis Users.","authors":"Brammer, Whitney A; Conn, Bridgid M; Iverson, Ellen; Lankenau, Stephen E; Dodson, Chaka; Wong, Carolyn F","year":2022,"journal":"Substance use & misuse, 57(5), 684-697","doi":"10.1080/10826084.2022.2026970","pmid":"35193442","tags":["addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Coping motives uniquely mediated the association between multiple types of childhood trauma (physical abuse, neglect, sexual trauma) and problematic cannabis use one year later. Emotional and physical abuse were also associated with pain motives, and sexual abuse with sleep motives. Using cannabis for coping and attention/focus was associated with more problematic use, while using it for sleep was associated with less problematic use.","whyItMatters":"Understanding why trauma leads to problematic cannabis use (through coping motives specifically) identifies a targetable mechanism for prevention, rather than simply warning trauma survivors not to use cannabis.","specificNumbers":"339 participants followed for one year. Coping motives mediated the trauma-to-problematic-use pathway across physical abuse, neglect, and sexual trauma. Sleep motives were inversely associated with problematic use.","methodology":"Longitudinal study of 339 medical cannabis patient and non-patient young adult users from Los Angeles, assessed at baseline and one year later. Mediation analysis examined how cannabis use motives connected childhood trauma to problematic use, controlling for age, socioeconomic status, perceived stress, and baseline problematic use.","limitations":"Self-report data. Los Angeles sample may not generalize. Medical and non-medical users combined. Cannot rule out other mediating variables. Problematic use measures may overlap with coping behaviors."},{"rthcId":"RTHC-03729","title":"Cannabinoid receptor type 1 antagonists alter aspects of risk/reward decision making independent of toluene-mediated effects.","authors":"Braunscheidel, Kevin M; Okas, Michael P; Floresco, Stan B; Woodward, John J","year":2022,"journal":"Psychopharmacology, 239(5), 1337-1347","doi":"10.1007/s00213-021-05914-8","pmid":"34291308","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03730","title":"Anti-aversive effect of 2-arachidonoylglycerol in the dorsolateral periaqueductal gray of male rats in contextual fear conditioning and Vogel tests.","authors":"Brianis, Rayssa C; Lima, Rita C; Moreira, Fabrício A; Aguiar, Daniele C","year":2022,"journal":"Behavioural pharmacology, 33(2&3), 213-221","doi":"10.1097/FBP.0000000000000639","pmid":"34074811","tags":["neuroscience","anxiety"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"2-AG injected into the dorsolateral PAG reduced contextual fear expression and produced anxiolytic effects in the Vogel conflict test, both dependent on CB1 and CB2 receptor activation. However, the Vogel test required higher doses, and monoacylglycerol lipase inhibitors (which block 2-AG breakdown) were effective only in the fear conditioning test.","whyItMatters":"2-AG is the most abundant endocannabinoid in the brain, and understanding its anti-anxiety effects in specific brain regions could inform development of targeted anxiolytic drugs that avoid the psychoactive effects of THC.","specificNumbers":"2-AG reduced fear in the contextual fear conditioning test and showed anxiolytic effects in the Vogel conflict test, but the latter required higher doses. Monoacylglycerol lipase inhibitors were effective only in the fear conditioning model.","methodology":"Male Wistar rats received injections of 2-AG or its hydrolysis inhibitors into the dorsolateral periaqueductal gray, then were tested in contextual fear conditioning and Vogel conflict tests. CB1 and CB2 receptor antagonists were used to determine receptor involvement.","limitations":"Only male rats tested. Direct brain injection does not reflect realistic drug delivery. Effects varied by anxiety model, suggesting context-dependent action. No behavioral measures of side effects assessed."},{"rthcId":"RTHC-03731","title":"A study of self-reported personal cannabis use and state legal status and associations with engagement in and perceptions of cannabis-impaired driving.","authors":"Brown, Timothy; Banz, Barbara; Schmitt, Rose; Gaffney, Gary; Milavetz, Gary; Camenga, Deepa; Li, Kaigang; Brooks-Russell, Ashley; Vaca, Federico","year":2022,"journal":"Traffic injury prevention, 23(sup1), S183-S186","doi":"10.1080/15389588.2022.2124803","pmid":"37014194","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Each year of delayed cannabis onset was associated with 0.51 fewer use days/month and a lower proportion of driving-after-use days. Women used cannabis 2.3 fewer days/month and drove after use less often than men. Colorado residents reported the most use days, highest likelihood of driving within 2 hours, and most positive perceptions of safe driving after cannabis.","whyItMatters":"With cannabis legalization expanding across U.S. states, understanding which factors predict cannabis-impaired driving can help target prevention efforts to the highest-risk groups.","specificNumbers":"Each year of delayed onset: -0.51 days use/month, -0.02 proportion driving-after-use days, -0.06 safety perception score. Female vs. male: -2.3 days/month, -0.06 driving proportion, -0.29 safety perception.","methodology":"Online survey of adults aged 25-40 from Colorado (recreational legal), Illinois (medical legal at time), and Iowa (limited legal) who reported past-year cannabis use. SAS GLMSELECT procedure used for analysis.","limitations":"Cross-sectional online survey with self-selected participants. Self-reported driving behavior may be underreported. Cannot determine causation. Only three states compared. Age range limited to 25-40."},{"rthcId":"RTHC-03732","title":"The neuropharmacology of cannabinoid receptor ligands in central signaling pathways.","authors":"Brunt, Tibor M; Bossong, Matthijs G","year":2022,"journal":"The European journal of neuroscience, 55(4), 909-921","doi":"10.1111/ejn.14982","pmid":"32974975","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03733","title":"Pharmacological management of cannabinoid hyperemesis syndrome: an update of the clinical literature.","authors":"Burillo-Putze, Guillermo; Richards, John R; Rodríguez-Jiménez, Consuelo; Sanchez-Agüera, Alejandro","year":2022,"journal":"Expert opinion on pharmacotherapy, 23(6), 693-702","doi":"10.1080/14656566.2022.2049237","pmid":"35311429","tags":["medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS does not reliably respond to standard IV antiemetics. Antipsychotics (particularly haloperidol), benzodiazepines, and capsaicin cream (a TRPV1 agonist) appear most effective for acute symptom management. Hot showers provide symptomatic relief. Complete resolution occurs only with cannabis cessation. CHS prevalence is expected to rise with increasing cannabis use and potency.","whyItMatters":"CHS is frequently unrecognized, leading to extensive unnecessary testing. Knowing which treatments work (and which standard approaches fail) can reduce patient suffering, healthcare costs, and diagnostic delays.","specificNumbers":"The review does not provide pooled efficacy data but synthesizes treatment outcomes across the published literature.","methodology":"Updated clinical literature review covering CHS clinical features, differential diagnosis from cyclic vomiting syndrome, putative etiology, incidence, and treatment options including analgesics, antiemetics, antipsychotics, beta blockers, TRPV agonists, and capsaicin.","limitations":"Most treatment evidence comes from case reports and small case series. No randomized controlled trials of CHS treatments. Treatment recommendations are based on clinical experience rather than high-quality evidence. CHS diagnostic criteria still debated."},{"rthcId":"RTHC-03734","title":"Cannabis hyperemesis syndrome: Incidence and treatment with topical capsaicin.","authors":"Burillo-Putze, Guillermo; Trujillo-Burillo, David; García-Hernandez, Jose Carlos; López-Hernández, M Angeles; Hernández-Ramos, Iván; Ramos-Suárez, Isabel; Richards, John R","year":2022,"journal":"Medicina clinica, 159(4), 183-186","doi":"10.1016/j.medcli.2021.07.028","pmid":"34756408","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Across 59 ED visits from 29 patients, CHS incidence was 4.4 per 10,000 visits. Fifty percent of patients returned for repeat episodes, with returners having higher rates of tobacco and cocaine use. Capsaicin 0.075% was used in 74.6% of visits and resolved vomiting in a mean of 17.87 minutes.","whyItMatters":"This is one of few studies providing incidence data for CHS in a European emergency department and demonstrates the rapid effectiveness of topical capsaicin as a first-line treatment.","specificNumbers":"59 visits from 29 patients; 4.4 cases/10,000 visits (95% CI 2.8-4.7); 50% returned; capsaicin used in 74.6% of visits; mean time to vomiting resolution: 17.87 minutes.","methodology":"Retrospective study of patients over 14 years old seen in a hospital emergency department during 2018-2019 with CHS diagnosis based on compatible clinical picture, cannabis use within 48 hours, and positive urine cannabis test.","limitations":"Single hospital, likely underdiagnosed cases. Retrospective design. Small patient number. Two-year timeframe may not capture seasonal variations. No comparison group for treatment effectiveness."},{"rthcId":"RTHC-03735","title":"Perceived effects of cannabis: Generalizability of changes in driving performance.","authors":"Burt, Thomas S; Brown, Timothy L; Schmitt, Rose; McGehee, Daniel; Milavetz, Gary; Gaffney, Gary; Berka, Chris","year":2022,"journal":"Traffic injury prevention, 23(sup1), S8-S13","doi":"10.1080/15389588.2022.2128787","pmid":"36622373","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Subjective perceptions of cannabis impairment significantly predicted driving performance measures (lane position, speed control) beyond the effect of THC dose. Feeling \"stoned\" was a perfectly consistent predictor across both this and a prior study. However, other subjective measures like \"anxious,\" \"good drug effect,\" and \"restless\" were inconsistent across studies, suggesting individual variability in the subjective-performance relationship.","whyItMatters":"If subjective feelings predict driving impairment better than blood THC levels, this has implications for impaired driving enforcement and personal decision-making about driving after cannabis use.","specificNumbers":"52 subjects; placebo vs. 6.18% THC; \"stoned\" was a perfectly consistent predictor across both studies. \"High\" and \"sedated\" had one mismatch each. \"Anxious,\" \"good drug effect,\" and \"restless\" had three or more mismatches.","methodology":"52 subjects completed a driving performance study with placebo vs. 6.18% THC cannabis. SAS GLM Select with stepwise selection analyzed relationships between subjective effects, dosing condition, and driving performance. Results compared to a prior 10-subject study.","limitations":"Relatively small sample. Only one THC dose tested. Simulator driving may not reflect real-world conditions. Subjective measures are inherently variable. Comparison study had only 10 subjects."},{"rthcId":"RTHC-03736","title":"Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors.","authors":"Cabanlong, Christian V; Russell, Lauren N; Fantegrossi, William E; Prather, Paul L","year":2022,"journal":"Toxicological sciences : an official journal of the Society of Toxicology, 187(1), 175-185","doi":"10.1093/toxsci/kfac024","pmid":"35201352","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"5F-MDMB-PINACA and its metabolite M2 showed nanomolar affinity and high efficacy at CB1 receptors. Metabolite M7 retained high efficacy but only micromolar affinity. The CB1 antagonist rimonabant blocked these compounds differently than it blocks THC. Chronic exposure caused CB1 receptor down-regulation, but only the parent compound produced desensitization. M2 produced dose-dependent hypothermia and analgesia in mice comparable to THC.","whyItMatters":"Understanding why synthetic cannabinoids like 5F-MDMB-PINACA are so much more dangerous than THC requires understanding their metabolites. The atypical pharmacology described here may explain the severe and sometimes fatal toxicity.","specificNumbers":"Over 40 fatalities associated with 5F-MDMB-PINACA. Parent compound and M2 had nM affinity; M7 had only μM affinity. Rimonabant showed different antagonism profiles for synthetic cannabinoids vs. THC.","methodology":"Competition binding and G-protein modulation studies at CB1 receptors. Rimonabant antagonism experiments compared to THC. Chronic administration studies measuring receptor down-regulation and desensitization. In vivo locomotor, hypothermia, and analgesia tests in mice for M2 and THC.","limitations":"In vitro and mouse studies. The pharmacological differences observed may not fully explain human toxicity. M7 concentrations in vivo may not reach the μM levels needed for activity. Limited to CB1 receptor; other targets not examined."},{"rthcId":"RTHC-03737","title":"Maternal preconception and pregnancy tobacco and cannabis use in relation to placental developmental markers: A population-based study.","authors":"Cajachagua-Torres, Kim N; El Marroun, Hanan; Reiss, Irwin K M; Jaddoe, Vincent W V","year":2022,"journal":"Reproductive toxicology (Elmsford, N.Y.), 110, 70-77","doi":"10.1016/j.reprotox.2022.03.015","pmid":"35378220","tags":["pregnancy","cardiovascular"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use before and during pregnancy was associated with higher PlGF and lower sFlt-1/PlGF ratio in first and second trimesters. First-trimester-only cannabis use was associated with higher sFlt-1 and higher sFlt-1/PlGF ratio at delivery. Continued cannabis or tobacco use was linked to higher placental weight-to-birth-weight ratio and increased pregnancy complications.","whyItMatters":"This is one of the largest studies to measure specific placental biomarkers in relation to cannabis use, providing mechanistic evidence for how cannabis may lead to adverse pregnancy outcomes.","specificNumbers":"8,008 pregnant women. Cannabis use associated with higher PlGF and lower sFlt-1/PlGF ratio (both p<0.05). Continued use linked to higher placental weight-to-birth-weight ratio and more pregnancy complications (both p<0.05).","methodology":"Population-based prospective cohort of 8,008 pregnant women. Tobacco and cannabis use assessed by questionnaires. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) measured in first trimester, second trimester, and at delivery from blood samples. Placental weight and complications from medical records.","limitations":"Self-reported substance use likely underestimates true exposure. Cannot fully separate cannabis effects from tobacco (many co-use). Questionnaire-based assessment cannot capture dose or potency. Residual confounding possible."},{"rthcId":"RTHC-03738","title":"Foetal tobacco and cannabis exposure, body fat and cardio-metabolic health in childhood.","authors":"Cajachagua-Torres, Kim N; El Marroun, Hanan; Reiss, Irwin K M; Santos, Susana; Jaddoe, Vincent W V","year":2022,"journal":"Pediatric obesity, 17(3), e12863","doi":"10.1111/ijpo.12863","pmid":"34674394","tags":["pregnancy","cardiovascular","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Children exposed to maternal cannabis during pregnancy had higher BMI (0.26 SDS), android/gynoid fat ratio (0.21 SDS), and fat-free mass index (0.24 SDS) at age 10. However, paternal substance use showed similar associations with child cardiometabolic outcomes, suggesting shared family-based social and lifestyle factors rather than direct intrauterine effects.","whyItMatters":"By comparing maternal and paternal exposure associations, this study provides an important reality check: what looks like a direct effect of prenatal cannabis exposure may actually reflect the environment children grow up in.","specificNumbers":"4,792 families. Maternal cannabis exposure: +0.26 SDS BMI, +0.21 SDS android/gynoid fat ratio, +0.24 SDS fat-free mass index. Paternal associations were similar in magnitude.","methodology":"Population-based prospective cohort of 4,792 mothers, fathers, and children. Parental substance use assessed by questionnaires during pregnancy. Child outcomes measured at age 10: BMI, body fat (DXA), blood pressure, lipids, glucose, and insulin.","limitations":"Self-reported substance use. Paternal data used as negative control but may have direct biological effects (epigenetic). Cannot fully rule out direct fetal effects of cannabis. Loss to follow-up over 10 years."},{"rthcId":"RTHC-03739","title":"Associations Between Canada's Cannabis Legalization and Emergency Department Presentations for Transient Cannabis-Induced Psychosis and Schizophrenia Conditions: Ontario and Alberta, 2015-2019.","authors":"Callaghan, Russell C; Sanches, Marcos; Murray, Robin M; Konefal, Sarah; Maloney-Hall, Bridget; Kish, Stephen J","year":2022,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 67(8), 616-625","doi":"10.1177/07067437211070650","pmid":"35019734","tags":["psychosis","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-induced psychosis ED presentations doubled between April 2015 and December 2019. However, SARIMA models found no significant step-function effects of legalization on weekly ED counts for cannabis-induced psychosis (0.34, 95% CI -4.1 to 4.8, p=0.88), schizophrenia (24.34, 95% CI -18.3 to 67.0, p=0.26), alcohol-induced psychosis, or amphetamine-induced psychosis.","whyItMatters":"One of the strongest fears about cannabis legalization is increased psychosis burden. This large-scale Canadian analysis found no evidence that legalization itself caused a sudden increase, though the ongoing upward trend warrants monitoring.","specificNumbers":"5,832 cannabis-induced psychosis visits; 211,661 schizophrenia visits; 10,829 amphetamine-induced psychosis visits; 1,884 alcohol-induced psychosis visits analyzed. None showed significant step changes after October 2018 legalization.","methodology":"Population-level analysis of ED presentations across Alberta and Ontario from April 2015 to December 2019. Seasonal Autoregressive Integrated Moving Average (SARIMA) models assessed whether the October 2018 Cannabis Act was associated with step changes in weekly ED counts for four ICD-10-defined conditions.","limitations":"Only 14 months of post-legalization data. Gradual rollout of retail stores may delay full effects. Administrative data may not capture all psychosis cases. SARIMA models test for step changes, not gradual shifts. Two provinces may not represent all of Canada."},{"rthcId":"RTHC-03740","title":"Cannabinoid Hyperemesis Syndrome: Lighting Up an Emergency Department Near You.","authors":"Camcejo, Melanie; Hillman, Emily; Isom, Heather","year":2022,"journal":"Missouri medicine, 119(3), 266-270","doi":null,"pmid":"36035580","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03741","title":"Long-term use of cannabidiol-enriched medical cannabis in a prospective cohort of children with drug-resistant developmental and epileptic encephalopathy.","authors":"Caraballo, Roberto; Reyes, Gabriela; Demirdjian, Graciela; Huaman, Marina; Gutierrez, Robinson","year":2022,"journal":"Seizure, 95, 56-63","doi":"10.1016/j.seizure.2022.01.001","pmid":"34999381","tags":["epilepsy","cbd","youth","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"After a median 20 months of treatment, 78% of children had ≥50% seizure reduction and 47.5% had >75% reduction. Seven patients (11.9%) achieved seizure freedom. Median seizures decreased from 305/month to 90/month (71% median reduction, p<0.0001). Adverse effects were mostly mild to moderate. Treatment was discontinued in 28.8% due to lack of response, increased seizures, intolerance, or poor compliance.","whyItMatters":"This is one of the longer follow-up studies of CBD for pediatric drug-resistant epilepsy, showing that benefits are sustained over time and not just a short-term effect.","specificNumbers":"59 patients; mean age 10.5 years; median follow-up 20 months; 78% achieved ≥50% seizure reduction; 47.5% achieved >75% reduction; 11.9% seizure-free; median seizures 305/month to 90/month; 28.8% discontinued.","methodology":"Prospective cohort study of 59 children (age 2-17, mean 10.5 years) with drug-resistant developmental and epileptic encephalopathies receiving CBD-enriched medical cannabis oil as add-on therapy. Median follow-up of 20 months (range 12-32).","limitations":"Open-label without placebo control. Single center. Heterogeneous epilepsy types. Cannot separate CBD effects from other cannabis components. Nearly 30% discontinued treatment. No cognitive or quality-of-life outcome measures reported."},{"rthcId":"RTHC-03742","title":"Alcohol, Marijuana and Other Illicit Drugs Use Throughout Adolescence: Co-occurring Courses and Preadolescent Risk-Factors.","authors":"Carbonneau, Rene; Vitaro, Frank; Brendgen, Mara; Tremblay, Richard E","year":2022,"journal":"Child psychiatry and human development, 53(6), 1194-1206","doi":"10.1007/s10578-021-01202-w","pmid":"34110528","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Latent growth mixture modeling revealed six developmental patterns: 61% were non/low users, while five polysubstance groups varied in severity. Higher sensation-seeking and lower anxiety were common across all user groups. Low self-esteem and family risk factors differentiated all users from later-onset users. Higher impulsivity and school problems characterized the most severe early-onset groups.","whyItMatters":"Identifying preadolescent risk profiles before substance use begins could enable targeted prevention programs for the highest-risk youth.","specificNumbers":"926 boys; 61% were non/low users; 5 polysubstance groups varied in severity. Impulsive sensation-seekers with low anxiety and low self-esteem accumulated the most risk factors.","methodology":"Longitudinal study of 926 boys from low-socioeconomic urban neighborhoods. Latent growth mixture modeling identified co-occurring substance use patterns through adolescence. Preadolescent risk factors (personality, family, school) were tested as predictors.","limitations":"Only boys studied (no girls). Low-socioeconomic urban sample limits generalizability. Self-reported substance use. Preadolescent measures may not capture all relevant risk factors. Historical cohort may not reflect current substance availability."},{"rthcId":"RTHC-03743","title":"Reward Sensitivity at Age 13 Predicts the Future Course of Psychopathology Symptoms.","authors":"Cardoso Melo, Raniere Dener; Groen, Robin N; Hartman, Catharina A","year":2022,"journal":"Frontiers in psychiatry, 13, 818047","doi":"10.3389/fpsyt.2022.818047","pmid":"35360134","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03744","title":"Cannabis Industry Marketing Violations in Washington State, 2014-2019.","authors":"Carlini, Beatriz H; Garrett, Sharon; Firth, Caislin; Pinsky, Ilana","year":2022,"journal":"Journal of studies on alcohol and drugs, 83(1), 18-26","doi":null,"pmid":"35040756","tags":["legalization","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 328 violations from 183 businesses, most occurred in online content or directly in front of cannabis stores. Community members were as likely as the state regulatory agency (WSLCB) to identify violations. Community reports focused on content appealing to minors, while regulators focused on ad location and size violations.","whyItMatters":"As the cannabis industry matures, marketing violations, especially those targeting youth, remain a significant concern. Community monitoring appears to be an important complement to regulatory enforcement.","specificNumbers":"328 violations from 183 businesses across two time periods. Community members and WSLCB officers identified violations at similar rates. Very few violations were reported by competing cannabis businesses.","methodology":"Retrospective analysis of all Washington State cannabis marketing violations from October 2014-September 2015 (immediately after legal market opened) and May 2017-July 2019. A codebook based on state advertising regulations was used to categorize violations.","limitations":"Only Washington State data. May not capture all violations (only those identified and reported). Two non-continuous time periods. No data on enforcement outcomes or whether violations were corrected. Cannot assess actual impact on youth."},{"rthcId":"RTHC-03745","title":"Evaluating the relationship between industry sponsorship and conflicts of interest among systematic review authors on treatments for cannabis use disorder.","authors":"Carr, Marvin; Reddy, Vaishnavi; Anderson, J Michael; Weaver, Michael; Hartwell, Micah; Vassar, Matt","year":2022,"journal":"Substance abuse, 43(1), 1180-1189","doi":"10.1080/08897077.2022.2074598","pmid":"35617607","tags":["addiction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"77.8% (7/9) of systematic reviews had at least one author with a COI. Of 51 authors, 29.4% had COIs. 44% of reviews received funding, 22% were unfunded, and 33% had no funding statement. Despite COIs, there was no significant association between funding source and results (p=0.429) or between COI presence and favorability of results (p=0.56).","whyItMatters":"With cannabis use disorder treatment becoming more important as legalization expands, understanding whether the evidence base is influenced by conflicts of interest is crucial for clinical decision-making.","specificNumbers":"9 systematic reviews; 51 authors; 78% of reviews had ≥1 author with COI; 29.4% of authors had COIs; no significant bias in results (p=0.56) or conclusions.","methodology":"Cross-sectional study searching Ovid MEDLINE and Embase for systematic reviews and meta-analyses on CUD treatment. Nine eligible reviews with 51 authors were evaluated for disclosed and undisclosed conflicts of interest using a standardized classification scheme.","limitations":"Very small sample (only 9 systematic reviews). Limited statistical power to detect bias. Cannot detect subtle forms of bias. COI classification may not capture all potential conflicts. Only examined systematic reviews, not primary studies."},{"rthcId":"RTHC-03746","title":"Association between cannabis use and suicidal behavior: A systematic review of cohort studies.","authors":"Carvalho, João Victor; Souza, Lucca S; Moreira, Esdras Cabus","year":2022,"journal":"Psychiatry research, 312, 114555","doi":"10.1016/j.psychres.2022.114555","pmid":"35461121","tags":["mental-health","addiction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Twenty-two cohort articles were identified with no clear consensus on the cannabis-suicide relationship, regardless of outcome type (ideation, attempt, or completion) or study quality. Studies that did find an association highlighted the endocannabinoid system and psychosocial context, with some showing that greater intensity or earlier onset of cannabis use strengthened the relationship.","whyItMatters":"With cannabis use increasing globally and suicide being a leading cause of death, understanding whether cannabis contributes to suicidal behavior has major public health implications, but the evidence remains frustratingly inconclusive.","specificNumbers":"22 cohort studies identified. No consensus across studies. Studies finding an association suggest dose-response relationships (greater intensity or earlier onset = stronger association).","methodology":"Systematic review of MEDLINE, Embase, PsycINFO, and LILACS databases plus supplementary search for cohort studies published through January 2020. No age restrictions. Studies assessed using the Newcastle-Ottawa scale for quality.","limitations":"Heterogeneous definitions of \"cannabis use\" across studies. Varied and inconsistent outcome measures. Most studies did not control adequately for confounders. Self-reported cannabis use. Publication bias possible."},{"rthcId":"RTHC-03747","title":"Cannabidiol use and perceptions in France: a national survey.","authors":"Casanova, Clémence; Ramier, Clémence; Fortin, Davide; Carrieri, Patrizia; Mancini, Julien; Barré, Tangui","year":2022,"journal":"BMC public health, 22(1), 1628","doi":"10.1186/s12889-022-14057-0","pmid":"36038869","tags":["cbd","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"10.1% of French adults used CBD and 69.2% had heard of it. Less than half (46.8%) of those aware of CBD considered it harmful. CBD use was associated with younger age, tobacco use, cannabis use, poor self-reported health, and positive perception of alternative medicines. Four distinct CBD user profiles emerged from cluster analysis.","whyItMatters":"As CBD products proliferate across Europe with inconsistent regulation, understanding who uses them and how they perceive them is essential for developing appropriate consumer protections.","specificNumbers":"1,969 adults surveyed; 10.1% used CBD; 69.2% had heard of it; 46.8% of aware adults considered it harmful. CBD use associated with tobacco use, cannabis use, younger age, and poor self-reported health.","methodology":"Online survey of 1,969 French adults in December 2021, with a sample structure matching the French adult population for key demographics. Three regression analyses and hierarchical cluster analysis performed.","limitations":"Online survey may not reach all demographics. Self-reported CBD use not verified. CBD product contents not confirmed. Cross-sectional design. French-specific findings may not generalize to other EU countries."},{"rthcId":"RTHC-03748","title":"Cannabis sativa as a Treatment for Obesity: From Anti-Inflammatory Indirect Support to a Promising Metabolic Re-Establishment Target.","authors":"Cavalheiro, Eulla Keimili Fernandes Ferreira; Costa, Ana Beatriz; Salla, Daniéle Hendler; Silva, Mariella Reinol da; Mendes, Talita Farias; Silva, Larissa Espindola da; Turatti, Cristini da Rosa; Bitencourt, Rafael Mariano de; Rezin, Gislaine Tezza","year":2022,"journal":"Cannabis and cannabinoid research, 7(2), 135-151","doi":"10.1089/can.2021.0016","pmid":"34242511","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03749","title":"Secondary Terpenes in Cannabis sativa L.: Synthesis and Synergy.","authors":"Chacon, Francisco T; Raup-Konsavage, Wesley M; Vrana, Kent E; Kellogg, Joshua J","year":2022,"journal":"Biomedicines, 10(12)","doi":"10.3390/biomedicines10123142","pmid":"36551898","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03750","title":"The different role of G-protein-coupled receptor 30 (GPR30) in the interaction effects of marijuana and estradiol on spatial learning and memory at different ages.","authors":"Chahkandi, Mohadeseh; Sepehri, Gholamreza; Komeili, Gholamreza; Hadad, Mohammad Khaksari; Haghparast, Elham; Chahkandi, Majid","year":2022,"journal":"Brain research bulletin, 178, 155-163","doi":"10.1016/j.brainresbull.2021.11.006","pmid":"34800583","tags":["cognition","sex-differences","neuroscience","seniors"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Marijuana alone improved spatial learning in both young and old female rats. Estradiol improved memory in young but not old rats. In old rats, combining marijuana and estradiol produced negative interaction effects on spatial learning and memory, mediated by the GPR30 receptor. Hippocampal BDNF did not play a role in these interaction effects.","whyItMatters":"With both cannabis use and hormone replacement therapy common in older women, understanding how these substances interact in the aging brain has practical clinical implications.","specificNumbers":"Young rats: 5-7 months; old rats: 22-24 months. Treatment duration: 28 days. GPR30 mediated the negative interaction between marijuana and estradiol in old rats only.","methodology":"Young (5-7 months) and old (22-24 months) ovariectomized female rats received estradiol, GPR30 agonist/antagonist, and/or marijuana for 28 days. Spatial learning and memory assessed using the Morris water maze. Hippocampal BDNF measured by ELISA.","limitations":"Animal model with ovariectomized rats, not natural aging. Marijuana extract composition not fully detailed. Morris water maze is one measure of cognition. GPR30 mechanisms may differ in humans."},{"rthcId":"RTHC-03751","title":"Are vaporizers a lower-risk alternative to smoking cannabis?","authors":"Chaiton, Michael; Kundu, Anasua; Rueda, Sergio; Di Ciano, Patricia","year":2022,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 113(2), 293-296","doi":"10.17269/s41997-021-00565-w","pmid":"34448130","tags":["respiratory","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis vaporizers reduce carbon monoxide emission, chronic respiratory symptoms, and exposure to several toxins while producing similar subjective effects and blood THC concentrations compared to smoking. However, new cannabis users face risks of intense effects, cognitive impairment, and dependence regardless of administration method.","whyItMatters":"As major health organizations recommend vaporizing over smoking cannabis, this commentary evaluates the evidence behind that recommendation while highlighting that vaporizing is harm reduction, not harm elimination.","specificNumbers":"The commentary does not provide pooled data but synthesizes findings across multiple studies showing reduced carbon monoxide and respiratory symptoms with vaporizers.","methodology":"Commentary reviewing present evidence on the harm reduction potential of cannabis vaping compared to smoking, drawing on published studies of respiratory outcomes, pharmacokinetics, and public health implications.","limitations":"Commentary, not a systematic review. Limited long-term data on dried herb vaporizer use. Does not address vaping-associated lung injury from THC e-liquids. Cannabis potency varies across products and devices."},{"rthcId":"RTHC-03752","title":"Correlates of behavior change intents in response to a hypothetical flavored cigar sales restriction among U.S. adult flavored cigar smokers.","authors":"Chen-Sankey, Julia; Elhabashy, Maryam; Ajith, Aniruddh; Jewett, Bambi; Hacker, Kiana; Phan, Lilianna; Choi, Kelvin","year":2022,"journal":"Preventive medicine, 165(Pt B), 107128","doi":"10.1016/j.ypmed.2022.107128","pmid":"35780974","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In response to a hypothetical flavored cigar sales restriction, 15.1% would quit cigars, 41.6% would smoke plain cigars, 33.4% would switch to other flavored tobacco, and 29.2% would substitute cannabis. Blunt smokers and large cigar smokers were less likely to quit. Racial/ethnic minorities were more likely to substitute cannabis.","whyItMatters":"Tobacco flavor bans may have unintended consequences, including increasing cannabis use, particularly among populations already experiencing substance use disparities.","specificNumbers":"343 flavored cigar smokers; 15.1% would quit; 41.6% would smoke plain; 33.4% would switch to other flavored tobacco; 29.2% would switch to cannabis.","methodology":"Online survey of a nationally representative sample of 343 adult flavored cigar smokers (age ≥21) in 2021. Weighted logistic regressions examined associations between demographics, tobacco history, and behavioral change intentions in response to a hypothetical restriction.","limitations":"Hypothetical scenario; stated intentions may not match actual behavior. Self-selected online sample. Small sample size. Cannabis substitution may reflect existing dual use rather than new initiation."},{"rthcId":"RTHC-03753","title":"Association of cannabis use disorder with cardiovascular diseases: A two-sample Mendelian randomization study.","authors":"Chen, Miao; Lu, Yun-Long; Chen, Xiao-Fan; Wang, Zhen; Ma, Liang","year":2022,"journal":"Frontiers in cardiovascular medicine, 9, 966707","doi":"10.3389/fcvm.2022.966707","pmid":"36277767","tags":["cardiovascular","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Genetic liability to cannabis use disorder was associated with higher risk of atrial fibrillation, heart failure, pulmonary embolism, and stroke in both univariable and multivariable MR analyses adjusting for smoking, alcohol, BMI, lipids, diabetes, hypertension, and depression. Initial associations with coronary artery disease, myocardial infarction, and deep venous thrombosis did not persist after adjustment, suggesting mediation by traditional cardiovascular risk factors.","whyItMatters":"Mendelian randomization reduces confounding compared to observational studies. Finding that cannabis use disorder has cardiovascular risks independent of traditional risk factors strengthens the case for a causal relationship.","specificNumbers":"12 SNPs used as instruments. Significant associations persisted for atrial fibrillation, heart failure, pulmonary embolism, and stroke after multivariable adjustment. Associations with coronary artery disease, MI, and DVT were mediated by smoking, BMI, LDL, hypertension, and depression.","methodology":"Two-sample Mendelian randomization using 12 SNPs from the largest GWAS of cannabis use disorder as instrumental variables. Cardiovascular outcomes from published GWAS. Inverse-variance weighted method with sensitivity analyses. Multivariable MR adjusted for potential mediators.","limitations":"MR instruments for cannabis use disorder may capture pleiotropic effects. Cannot distinguish cannabis use disorder from occasional use. European ancestry samples limit generalizability. Some sensitivity analyses were inconsistent."},{"rthcId":"RTHC-03754","title":"Whole-genome resequencing of wild and cultivated cannabis reveals the genetic structure and adaptive selection of important traits.","authors":"Chen, Xuan; Guo, Hong-Yan; Zhang, Qing-Ying; Wang, Lu; Guo, Rong; Zhan, Yi-Xun; Lv, Pin; Xu, Yan-Ping; Guo, Meng-Bi; Zhang, Yuan; Zhang, Kun; Liu, Yan-Hu; Yang, Ming","year":2022,"journal":"BMC plant biology, 22(1), 371","doi":"10.1186/s12870-022-03744-0","pmid":"35883045","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03755","title":"Healthcare professionals' perspectives on the use of medicinal cannabis to manage chronic pain: A systematic search and narrative review.","authors":"Cheng, Katherine Y C; Harnett, Joanna E; Davis, Sharon R; Eassey, Daniela; Law, Susan; Smith, Lorraine","year":2022,"journal":"Pain practice : the official journal of World Institute of Pain, 22(8), 718-732","doi":"10.1111/papr.13161","pmid":"36055965","tags":["medical-cannabis","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Seven key themes emerged: MC as a treatment option for chronic pain; willingness to prescribe; legal issues; low perceived knowledge and need for education; comparative safety vs. opioids; addiction and abuse concerns; and perceived adverse effects. Across countries, healthcare professionals consistently identified knowledge gaps as the primary barrier to effective prescribing.","whyItMatters":"Patients increasingly ask about cannabis for pain, but their healthcare providers often feel unable to provide evidence-based guidance, creating a gap that patients fill with internet research and self-medication.","specificNumbers":"26 studies from 6 countries. Seven key themes identified. Healthcare professionals across all disciplines and countries consistently reported low perceived knowledge of medicinal cannabis.","methodology":"Systematic search of six databases (MEDLINE, EMBASE, CINAHL, Scopus, Web of Science, PubMed) from 2001-2021. Twenty-six studies from the US, Israel, Canada, Australia, Ireland, and Norway were included. Perspectives of physicians, nurses, and pharmacists analyzed using thematic analysis.","limitations":"Included studies used heterogeneous methods and populations. \"Healthcare professionals\" includes diverse roles with different scopes of practice. Publication bias toward English-language studies. Rapidly evolving legal landscape may outdate findings."},{"rthcId":"RTHC-03756","title":"Acceptability of cannabidiol in patients with psychosis.","authors":"Chesney, Edward; Lamper, Doga; Lloyd, Millie; Oliver, Dominic; Hird, Emily; McGuire, Philip","year":2022,"journal":"Therapeutic advances in psychopharmacology, 12, 20451253221128445","doi":"10.1177/20451253221128445","pmid":"36312845","tags":["cbd","psychosis","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"86% of patients were willing to try CBD. 69% believed CBD would improve their psychotic symptoms. 64% expected CBD to have fewer side effects than their current medications (mainly antipsychotics). Only 10% were concerned CBD might worsen psychosis, and this appeared to reflect confusion between CBD and cannabis.","whyItMatters":"Patient acceptability is crucial for treatment success, especially in psychosis where medication adherence is a major challenge. The high willingness to try CBD, combined with its emerging evidence and low side effect profile, makes it a promising candidate.","specificNumbers":"70 patients surveyed; 86% willing to try CBD; 69% expected symptom improvement; 64% expected fewer side effects; 10% concerned about worsening psychosis.","methodology":"Survey of 70 patients with psychotic disorders assessing expectations about CBD efficacy and side effects.","limitations":"Small sample (n=70). Patients may conflate expectations with hopes. Acceptability does not predict efficacy. No assessment of patient understanding of the difference between CBD and THC. Selection bias toward patients open to novel treatments."},{"rthcId":"RTHC-03757","title":"Cannabidiol (CBD) as a novel treatment in the early phases of psychosis.","authors":"Chesney, Edward; Oliver, Dominic; McGuire, Philip","year":2022,"journal":"Psychopharmacology, 239(5), 1179-1190","doi":"10.1007/s00213-021-05905-9","pmid":"34255100","tags":["cbd","psychosis","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD has demonstrated antipsychotic effects in clinical studies and has a relatively benign side effect profile compared to standard antipsychotics. For clinical high-risk individuals, no licensed treatments exist, and for first-episode psychosis, all licensed medications act via dopamine D2 receptors. CBD acts through different mechanisms, potentially offering a novel approach for patients who do not respond to or cannot tolerate standard treatments.","whyItMatters":"Early phases of psychosis represent a critical window where treatment experiences shape long-term outcomes. A treatment with fewer side effects could improve engagement and prevent the treatment avoidance that leads to chronic illness.","specificNumbers":"No licensed treatment exists for clinical high-risk individuals. All current first-episode antipsychotics target dopamine D2 receptors. CBD acts through different mechanisms.","methodology":"Narrative review examining CBD's potential as a treatment in clinical high-risk and first-episode psychosis stages, covering mechanisms of action, clinical trial evidence, adverse effects, patient acceptability, and ongoing trials.","limitations":"Clinical trial evidence for CBD in psychosis is still limited. Optimal dosing unknown. Long-term effects not established. CBD is not currently approved for psychosis. Recreational cannabis use may confound outcomes in young patients."},{"rthcId":"RTHC-03758","title":"Association between Polymorphism rs1799732 of DRD2 Dopamine Receptor Gene and Personality Traits among Cannabis Dependency.","authors":"Chmielowiec, Jolanta; Chmielowiec, Krzysztof; Masiak, Jolanta; Śmiarowska, Małgorzata; Strońska-Pluta, Aleksandra; Dziedziejko, Violetta; Grzywacz, Anna","year":2022,"journal":"International journal of environmental research and public health, 19(17)","doi":"10.3390/ijerph191710915","pmid":"36078646","tags":["addiction","genetics"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Cannabis-dependent individuals scored significantly higher on neuroticism, openness, state anxiety, and trait anxiety, and lower on extraversion, agreeableness, and conscientiousness compared to controls. The DRD2 rs1799732 allele frequency differed between groups, and the genotype significantly influenced agreeableness scores in both cannabis-dependent and control groups.","whyItMatters":"Identifying genetic variants that influence personality traits associated with cannabis dependence could inform personalized prevention and treatment strategies.","specificNumbers":"515 males (214 cannabis-dependent, 301 controls). Significant allele frequency difference for DRD2 rs1799732. Cannabis group: higher neuroticism, openness, anxiety; lower extraversion, agreeableness, conscientiousness.","methodology":"Case-control study of 214 male cannabis-dependent patients and 301 non-addicted controls. Personality assessed with NEO-FFI, anxiety with STAI. DRD2 rs1799732 genotyping by real-time PCR. Multivariate ANOVA analyzed genotype-personality interactions.","limitations":"Only males studied. Case-control design cannot determine causation. Single genetic variant among many possible contributors. Personality differences may be consequences rather than precursors of addiction. Polish sample limits generalizability."},{"rthcId":"RTHC-03759","title":"Associations of Healthcare Service Utilization With Cannabis Use Status, Use Reasons, and Use Characteristics Among Those Age 50 and Older.","authors":"Choi, Namkee G; DiNitto, Diana M; Marti, C Nathan; Choi, Bryan Y","year":2022,"journal":"Journal of applied gerontology : the official journal of the Southern Gerontological Society, 41(5), 1385-1396","doi":"10.1177/07334648211069997","pmid":"35212566","tags":["seniors","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Past-year cannabis users had higher rates of any ED visit (30.0%) and hospitalization (14.7%) than never users. However, they did not differ from never users in total number of ED visits or nights hospitalized. Medical-only users had significantly more ED visits than nonmedical-only users (IRR 1.38). Cannabis use characteristics were not associated with hospitalization nights.","whyItMatters":"With cannabis use rising among older adults, understanding its relationship to healthcare utilization helps inform both clinical practice and health system planning.","specificNumbers":"44,007 adults aged 50+; past-year users: 30.0% any ED visit, 14.7% hospitalization. Medical-only users: IRR 1.38 for ED visits vs. nonmedical-only users. Past-year users had more ED visits than prior users (IRR 1.21).","methodology":"Analysis of 2015-2019 National Survey on Drug Use and Health data (n=44,007 adults aged 50+). Negative binomial regression models compared healthcare utilization by cannabis use status and use reason, controlling for demographics and health characteristics.","limitations":"Cross-sectional design. Self-reported cannabis use and healthcare utilization. Cannot determine whether cannabis use or underlying conditions drive ER utilization. No data on reasons for ER visits."},{"rthcId":"RTHC-03760","title":"Prenatal cannabis exposure predicts attention problems, without changes on fMRI in adolescents.","authors":"Cioffredi, Leigh-Anne; Anderson, Hillary; Loso, Hannah; East, James; Nguyen, Philip; Garavan, Hugh; Potter, Alexandra","year":2022,"journal":"Neurotoxicology and teratology, 91, 107089","doi":"10.1016/j.ntt.2022.107089","pmid":"35314358","tags":["pregnancy","cognition","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Compared to both control groups, children with prenatal cannabis exposure (PCE) had significantly higher attention problems, externalizing, and total problem scores on the Child Behavior Checklist. However, PCE did not affect cognitive performance on response inhibition, reward processing, or working memory tasks, and showed no differences in brain activation patterns during fMRI.","whyItMatters":"Using the largest adolescent brain development study in the world, this research shows that prenatal cannabis exposure is associated with behavioral but not cognitive or neuroimaging differences by age 10, though later effects may emerge.","specificNumbers":"224 children with PCE from ~12,000 ABCD Study participants. Significant increases in attention problems, externalizing, and total problem scores. No differences on three cognitive tasks or fMRI activation patterns.","methodology":"Data from the ABCD Study (approximately 12,000 children). 224 children with PCE (reported by caregivers) compared to two control groups: tobacco/alcohol-matched and unexposed. Behavioral outcomes from CBCL at ages 9-10. Cognitive and fMRI measures from three tasks: Stop Signal (response inhibition), MID (reward), and EN-Back (working memory).","limitations":"Caregiver-reported PCE may underestimate exposure. Cannot control for all confounders (genetics, postnatal environment). Cross-sectional analysis at one age point. fMRI tasks may not be sensitive enough. Children are still developing."},{"rthcId":"RTHC-03761","title":"Pilot clinical and pharmacokinetic study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain.","authors":"Clarke, Stephen; Butcher, Belinda E; McLachlan, Andrew J; Henson, Jeremy D; Rutolo, David; Hall, Sean; Vitetta, Luis","year":2022,"journal":"PloS one, 17(10), e0270543","doi":"10.1371/journal.pone.0270543","pmid":"36240167","tags":["medical-cannabis","pain","cancer","cbd"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"The water-soluble formulation produced dose-dependent plasma cannabinoid levels, with higher systemic exposure for THC than CBD. A subgroup with breast and prostate cancers with bone metastases showed the highest mean pain score improvement (40% unadjusted, 33% adjusted for rescue medication). Most reported adverse events were mild to moderate drowsiness (44%) and nausea/vomiting (72%).","whyItMatters":"Water-soluble nanoparticle formulations could overcome the poor and variable bioavailability of oral cannabinoids, potentially making cannabis-based pain treatments more reliable and effective.","specificNumbers":"25 patients in Stage II; AUC from 2.5 mg THC: 1.71 ng·mL·h; AUC from 2.5 mg CBD: 0.65 ng·mL·h. Bone metastases subgroup: 40% pain improvement (33% adjusted). Drowsiness: 44% mild, 6% moderate. Nausea: 72%.","methodology":"Non-blinded single-arm two-stage pilot study. Stage I: single escalating dose in 5 patients (2.5 mg each THC and CBD, then 3x dose). Stage II: up-titrated dose in 25 patients with advanced cancers and intractable pain despite opioid therapy.","limitations":"Pilot study with no control group or blinding. Very small sample. High rate of nausea (though this may be from underlying cancer). Pain improvement data from a subgroup only. Short-term assessment."},{"rthcId":"RTHC-03762","title":"Symptoms and Extraintestinal Manifestations in Active Cannabis Users with Inflammatory Bowel Disease.","authors":"Coates, Matthew D; Dalessio, Shannon; Walter, Vonn; Stuart, August; Bernasko, Nana; Tinsley, Andrew; Razeghi, Sanam; Williams, Emmanuelle D; Clarke, Kofi; Vrana, Kent","year":2022,"journal":"Cannabis and cannabinoid research, 7(4), 445-450","doi":"10.1089/can.2020.0155","pmid":"33998892","tags":["medical-cannabis","inflammation","pain"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users (7.8% of the cohort, average 2.7 times/week) were more likely to report abdominal pain (83.3% vs. 61.7%), gas (66.7% vs. 45.6%), tenesmus (70.0% vs. 47.6%), and arthralgias (53.3% vs. 20.3%) compared to non-users. However, they did not have more frequent active disease or IBD-associated complications on endoscopy.","whyItMatters":"The disconnect between more reported symptoms and no worse disease activity in cannabis users suggests these patients may have greater symptom sensitivity, more extraintestinal manifestations, or may be using cannabis to manage symptoms that standard IBD treatment does not address.","specificNumbers":"383 IBD patients; 30 (7.8%) were active cannabis users; average 2.7 times/week. Higher rates of abdominal pain, gas, tenesmus, and arthralgias (all p<0.05). No difference in active disease or complications.","methodology":"Retrospective cohort study of 383 IBD patients from a consented natural history registry at a single tertiary center (2015-2020). Current cannabis use, frequency, demographics, clinical characteristics, endoscopic severity, and validated symptom surveys compared between users and non-users with logistic regression.","limitations":"Retrospective, single-center study. Small number of cannabis users (n=30). Self-reported cannabis use. Cannot determine whether cannabis is ineffective or whether sicker patients self-select into use. Cross-sectional comparison."},{"rthcId":"RTHC-03763","title":"Differences in alcohol and cannabis use amongst substance use disorder patients with and without comorbid attention-deficit/hyperactivity disorder.","authors":"Coetzee, Corné; Truter, Ilse; Meyer, Anneke","year":2022,"journal":"The South African journal of psychiatry : SAJP : the journal of the Society of Psychiatrists of South Africa, 28, 1786","doi":"10.4102/sajpsychiatry.v28i0.1786","pmid":"35547103","tags":["addiction","cognition","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The SUD+ADHD group showed increased cannabis consumption compared to the SUD-only group. Notably, women with SUD+ADHD started cannabis use at an earlier age and used for a longer period compared to women without ADHD and compared to men in both groups. No significant differences in alcohol use were found between ADHD and non-ADHD groups.","whyItMatters":"The specific vulnerability of women with ADHD to cannabis use suggests they may use cannabis to manage ADHD symptoms, highlighting the need for gender-specific approaches in treatment.","specificNumbers":"185 patients (52 with ADHD, 128 without). SUD+ADHD group used more cannabis overall. SUD+ADHD females had earlier cannabis onset and longer duration of use than all comparison groups.","methodology":"Cross-sectional study of 185 post-detox inpatients at rehabilitation centers in South Africa. ADHD diagnosed using DIVA 2.0. Groups compared: SUD+ADHD (n=52) vs. SUD-ADHD (n=128) by gender on alcohol and cannabis use patterns.","limitations":"Small sample, especially for gender subgroup analyses. South African treatment-seeking population limits generalizability. Cross-sectional design. DSM-IV criteria used (DSM-5 now standard). Self-reported substance use."},{"rthcId":"RTHC-03764","title":"Variability in Serum Concentrations and Clinical Response in Artisanal Versus Pharmaceutical Cannabidiol Treatment of Pediatric Pharmacoresistant Epilepsy.","authors":"Cohen, Nathan T; Bahar, Burak; Conry, Joan A; Schreiber, John M","year":2022,"journal":"The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 27(6), 558-563","doi":"10.5863/1551-6776-27.6.558","pmid":"36042959","tags":["epilepsy","cbd","youth","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Mean serum CBD was 124 ng/mL for pharmaceutical CBD vs. 51.1 ng/mL for artisanal CBD (p=0.022). The pharmaceutical group had a median 50% seizure reduction vs. no change in the artisanal group, though this difference was not statistically significant (p=0.199). Higher CBD concentrations were associated with increased adverse effects.","whyItMatters":"Patients and families often choose artisanal CBD products for cost reasons, but this study shows pharmaceutical CBD achieves significantly higher blood levels, which may translate to better seizure control.","specificNumbers":"42 patients; pharmaceutical CBD: 124 ng/mL serum level; artisanal CBD: 51.1 ng/mL (p=0.022). Pharmaceutical group: median 50% seizure reduction. Artisanal group: no change (p=0.199).","methodology":"Retrospective chart review of 42 patients with pharmacoresistant epilepsy treated with either artisanal CBD oil or pharmaceutical CBD (Epidiolex). Serum CBD concentrations, seizure frequency, and side effects tracked.","limitations":"Retrospective, non-randomized. Small sample size. Artisanal product composition and dosing not standardized. Seizure reduction difference was not statistically significant (may be underpowered). No blinding."},{"rthcId":"RTHC-03765","title":"Changes in brain structure and function following chronic exposure to inhaled vaporised cannabis during periadolescence in female and male mice: A multimodal MRI study.","authors":"Coleman, James R; Madularu, Dan; Ortiz, Richard J; Athanassiou, Maria; Knudsen, Alexa; Alkislar, Ilayda; Cai, Xuezhu; Kulkarni, Praveen P; Cushing, Bruce S; Ferris, Craig F","year":2022,"journal":"Addiction biology, 27(3), e13169","doi":"10.1111/adb.13169","pmid":"35470553","tags":["youth","cognition","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Female mice showed altered fractional anisotropy and apparent diffusion coefficient (measures of brain microstructure) in forebrain and hindbrain. Males showed increased functional coupling with thalamus, hypothalamus, and brainstem reticular activating system, altered hippocampal connectivity, and deficits in novel object recognition. The effects were sexually dimorphic with minimal overlap.","whyItMatters":"This is one of the first studies to use clinically relevant inhaled cannabis vapor (rather than injected THC) with multimodal brain imaging in adolescent animals, providing data more translatable to human adolescent cannabis use.","specificNumbers":"Daily exposure from postnatal day 23-51; 10.3% THC cannabis; 139 brain areas analyzed via 3D atlas; males showed cognitive deficits on novel object recognition.","methodology":"Female and male mice were exposed daily to vaporized cannabis (10.3% THC, 0.05% CBD) or placebo from postnatal day 23-51 (periadolescence). After cessation, multimodal MRI (voxel-based morphometry, diffusion-weighted imaging, resting-state functional connectivity) was performed using a 3D atlas with 139 brain regions. Novel object preference tested.","limitations":"Mouse model may not fully translate to humans. Single cannabis concentration tested. Only one cognitive test used. No dose-response or duration comparisons. Short-term follow-up after cessation."},{"rthcId":"RTHC-03766","title":"Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer's disease.","authors":"Coles, Madilyn; Steiner-Lim, Genevieve Z; Karl, Tim","year":2022,"journal":"Frontiers in neuroscience, 16, 962922","doi":"10.3389/fnins.2022.962922","pmid":"36117622","tags":["medical-cannabis","cbd","seniors","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD reversed and prevented cognitive deficits in AD rodent models through anti-inflammatory, antioxidant, and neuroprotective mechanisms. Low-dose THC improved cognition in aging mice. The \"entourage effect\" suggests that multi-cannabinoid formulations (whole plant extracts or specific CBD:THC ratios) may be more efficacious than cannabinoid isolates for AD therapy.","whyItMatters":"With no disease-modifying treatments for Alzheimer's, the ability of cannabinoids to target multiple pathological features (amyloid plaques, neurofibrillary tangles, neuroinflammation, oxidative stress) simultaneously is compelling.","specificNumbers":"CBD reversed cognitive deficits in AD rodent models. Low-dose THC improved cognition in aging mice. Optimal CBD:THC ratios have not been determined.","methodology":"Narrative review of preclinical and early clinical evidence for cannabinoid-based Alzheimer's treatments, with emphasis on multi-cannabinoid strategies and the entourage effect.","limitations":"Almost entirely preclinical evidence. No clinical trials of multi-cannabinoid strategies for AD. Optimal doses and ratios unknown. THC's psychoactive effects could be problematic for elderly patients. Animal models imperfectly replicate human AD."},{"rthcId":"RTHC-03767","title":"The Autism-Psychosis Continuum Conundrum: Exploring the Role of the Endocannabinoid System.","authors":"Colizzi, Marco; Bortoletto, Riccardo; Costa, Rosalia; Bhattacharyya, Sagnik; Balestrieri, Matteo","year":2022,"journal":"International journal of environmental research and public health, 19(9)","doi":"10.3390/ijerph19095616","pmid":"35565034","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03768","title":"Mobile-based brief interventions targeting cannabis-impaired driving among youth: A Delphi study.","authors":"Colonna, Robert; Tucker, Patricia; Holmes, Jeffrey; Wilson, Jessie; Alvarez, Liliana","year":2022,"journal":"Journal of substance abuse treatment, 141, 108802","doi":"10.1016/j.jsat.2022.108802","pmid":"35599094","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03769","title":"Road traffic injury risk from alcohol and cannabis use among emergency department patients in Argentina.","authors":"Conde, Karina; Peltzer, Raquel Inés; Gimenez, Paula Victoria; Salomón, Tomás; Suarez, Gabriel; Monteiro, Maristela; Cherpitel, Cheryl J; Cremonte, Mariana","year":2022,"journal":"Revista panamericana de salud publica = Pan American journal of public health, 46, e116","doi":"10.26633/RPSP.2022.116","pmid":"36060199","tags":["driving","harm-reduction"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Alcohol use increased road traffic injury risk 6.78-fold (95% CI 3.75-12.25). Combined alcohol and cannabis use increased risk 7.05-fold (95% CI 1.16-42.73). Passengers had the highest alcohol-related risk (OR 13.83). The combined alcohol-cannabis risk was significant only for those under 30. Cannabis alone was not separately analyzed due to insufficient cases.","whyItMatters":"These are the first road traffic injury risk estimates for alcohol and cannabis in the Southern Cone of South America, providing data relevant to impaired driving policy in a region where cannabis legalization is advancing.","specificNumbers":"N=306; alcohol OR=6.78; combined alcohol+cannabis OR=7.05; women OR=8.87; men OR=6.16; passengers OR=13.83; under 30 with combined use OR=7.05.","methodology":"Case-crossover study of 306 injured emergency department patients in Mar del Plata, Argentina. Each patient served as their own control, comparing substance use at the time of injury to their typical use patterns.","limitations":"Relatively small sample. Wide confidence intervals for combined alcohol-cannabis risk. Cannabis alone not separately analyzed. Self-report of substance use. Single hospital in one city."},{"rthcId":"RTHC-03770","title":"Clinical management of cannabis withdrawal.","authors":"Connor, Jason P; Stjepanović, Daniel; Budney, Alan J; Le Foll, Bernard; Hall, Wayne D","year":2022,"journal":"Addiction (Abingdon, England), 117(7), 2075-2095","doi":"10.1111/add.15743","pmid":"34791767","tags":["withdrawal","addiction","quitting"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis withdrawal occurs in approximately 50% of regular/dependent users. Symptoms begin 24-48 hours after cessation, peak at days 2-6, with some lasting 3+ weeks. Most common symptoms: anxiety, irritability, anger/aggression, sleep disturbance, depressed mood, appetite loss. No approved medications exist. Supportive counseling and psychoeducation are first-line. Promising pharmacological agents have been studied but findings are not replicated.","whyItMatters":"Cannabis withdrawal is clinically significant because symptoms often precipitate relapse. Understanding its course and management options is essential for anyone attempting to quit.","specificNumbers":"Occurs in ~50% of regular users. Onset: 24-48 hours. Peak: days 2-6. Duration: up to 3+ weeks in heavy users. No approved medications.","methodology":"Narrative review of the literature covering diagnosis, prevalence, course, and clinical management of cannabis withdrawal.","limitations":"Narrative review, not systematic. Pharmacological trial evidence is limited and underpowered. Cannabis agonist use is off-label. Withdrawal severity likely varies by product potency and duration of use."},{"rthcId":"RTHC-03771","title":"Cannabinoids in Late Life Parkinson's Disease and Dementia: Biological Pathways and Clinical Challenges.","authors":"Costa, Alana C; Joaquim, Helena P G; Pedrazzi, João F C; Pain, Andreia de O; Duque, Gustavo; Aprahamian, Ivan","year":2022,"journal":"Brain sciences, 12(12)","doi":"10.3390/brainsci12121596","pmid":"36552056","tags":["medical-cannabis","cbd","neuroscience","mental-health","seniors"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review confronted a growing clinical reality: older adults with Parkinson's disease and dementia are increasingly using cannabinoids, but the evidence supporting this use is almost entirely preclinical. In the lab, CBD showed anti-amyloidogenic (reduces Alzheimer's-associated protein buildup), antioxidative, anti-apoptotic, anti-inflammatory, and neuroprotective effects. THC also showed neuroprotective properties in some models.\n\nIn clinical practice, patients were using cannabis for Parkinson's tremor, non-motor symptoms, anxiety, and sleep. For dementia, cannabis was being used to manage agitation and other responsive behaviors. Some clinicians considered cannabinoids an alternative when first-line treatments failed.\n\nBut the review was explicit: strong evidence from clinical trials was scarce for most indications. The gap between preclinical promise and clinical proof was wide. And age-related changes in the endocannabinoid system could alter how older adults respond to cannabinoids in ways that haven't been studied.","whyItMatters":"The population most likely to have neurodegenerative disease — older adults — is also the population most vulnerable to drug interactions and side effects, and the population least represented in cannabis research. This review highlighted a troubling pattern: patients and some clinicians were already treating Parkinson's and dementia with cannabis based on preclinical data and anecdotal reports, while the clinical trials that would confirm or refute benefit barely existed.\n\nThe age-related ECS changes add another concern. If the endocannabinoid system functions differently in a 75-year-old brain compared to a 25-year-old brain (as limited evidence suggests), dosing and effects could be unpredictable in exactly the population using it.","specificNumbers":"• CBD preclinical effects: anti-amyloidogenic, antioxidative, anti-apoptotic, anti-inflammatory, neuroprotective\n• Clinical uses (off-label): PD tremor, non-motor symptoms, anxiety, sleep, dementia agitation\n• Clinical trial evidence: scarce for most indications\n• Age-related ECS changes may alter cannabinoid response in older adults","methodology":"Narrative review of preclinical and clinical evidence for cannabinoid use in Parkinson's disease and dementias, with particular attention to age-related changes in the endocannabinoid system. Published in Brain Sciences.","limitations":"Narrative review without systematic methodology. Preclinical findings in animals and cell culture have poor translation rates to human neurodegenerative disease. Off-label use patterns are based on surveys and case reports, not controlled studies. Does not address the interaction between cannabinoids and common medications in older adults (polypharmacy). Age-specific pharmacokinetic data is extremely limited."},{"rthcId":"RTHC-03772","title":"Psychometric properties of the French and English short form of the Protective Behavioural Strategies for Marijuana Scale in Canadian university students.","authors":"Côté, José; Cossette, Sylvie; Auger, Patricia; Page, Gabrielle; Coronado-Montoya, Stephanie; Fontaine, Guillaume; Chicoine, Gabrielle; Rouleau, Geneviève; Genest, Christine; Lapierre, Judith; Pedersen, Eric R; Jutras-Aswad, Didier","year":2022,"journal":"BMJ open, 12(4), e053715","doi":"10.1136/bmjopen-2021-053715","pmid":"35387810","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03773","title":"Trends in hospital presentations following analytically confirmed synthetic cannabinoid receptor agonist exposure before and after implementation of the 2016 UK Psychoactive Substances Act.","authors":"Craft, Sam; Dunn, Michael; Vidler, Dan; Officer, Jane; Blagbrough, Ian S; Pudney, Christopher R; Henderson, Graeme; Abouzeid, Ahmed; Dargan, Paul I; Eddleston, Michael; Cooper, Jamie; Hill, Simon L; Roper, Clair; Freeman, Tom P; Thomas, Simon H L","year":2022,"journal":"Addiction (Abingdon, England), 117(11), 2899-2906","doi":"10.1111/add.15967","pmid":"35665553","tags":["synthetic-cannabinoids","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"SCRAs were detected in 35.7% (224/627) of patients with suspected novel psychoactive substance exposure. After adjusting for seasonality and active sites, no significant trend changes were found before or after the PSA for SCRA presentations (post-PSA IRR 0.97, p=0.202) or non-SCRA presentations.","whyItMatters":"The PSA was designed to reduce harm from novel psychoactive substances, but this study suggests banning sales did not reduce severe synthetic cannabinoid toxicity, possibly because supply shifted from retail to illicit channels.","specificNumbers":"627 patients (79.9% male); SCRAs detected in 35.7%. Pre-PSA SCRA trend: IRR 1.12 (p=0.068). Post-PSA trend: IRR 0.97 (p=0.202). No significant changes.","methodology":"Observational study across 34 UK hospitals (IONA study), July 2015-December 2019. 627 patients with severe acute toxicity and suspected NPS exposure. Toxicological analysis by LC-MS/MS. Poisson segmented regression for time-series analysis.","limitations":"Only participating hospitals included. Voluntary consenting may miss some cases. Cannot capture deaths or cases not reaching hospital. Limited pre-PSA data period. May not capture changes in SCRA types."},{"rthcId":"RTHC-03774","title":"Clinical withdrawal symptom profile of synthetic cannabinoid receptor agonists and comparison of effects with high potency cannabis.","authors":"Craft, Sam; Ferris, Jason A; Barratt, Monica J; Maier, Larissa J; Lynskey, Michael T; Winstock, Adam R; Freeman, Tom P","year":2022,"journal":"Psychopharmacology, 239(5), 1349-1357","doi":"10.1007/s00213-021-05945-1","pmid":"34533608","tags":["synthetic-cannabinoids","withdrawal","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Users reported a mean of 4.4 withdrawal symptoms after 1+ day without SCRAs. Most frequent: sleep issues (59.2%), irritability (55.6%), low mood (54.2%). Higher SCRA use frequency and quantity predicted more withdrawal symptoms. Compared to high-potency cannabis, SCRAs had faster onset, shorter duration of effects, faster tolerance development, and more severe withdrawal (all p<0.001).","whyItMatters":"Synthetic cannabinoids are often used by people who cannot access or afford natural cannabis. Understanding their worse withdrawal profile is crucial for treatment planning in this vulnerable population.","specificNumbers":"N=284; mean 4.4 withdrawal symptoms; sleep issues 59.2%; irritability 55.6%; low mood 54.2%. Frequency >51x/year: IRR=1.43 for symptoms. Greater grams/session: IRR=1.13.","methodology":"Global Drug Survey data (2015-2016) from 284 people reporting SCRA use >10 times in the past year, a previous quit attempt, and lifetime high-potency cannabis use. 11-item withdrawal checklist and comparative ratings of SCRAs vs. natural cannabis.","limitations":"Self-selected online survey sample. Retrospective self-report of withdrawal. Cannot verify specific SCRA products used. Comparison to high-potency cannabis is subjective. No clinical verification of withdrawal."},{"rthcId":"RTHC-03775","title":"Cannabis and End-of-Life Care: A Snapshot of Hospice Planning and Experiences Among Illinois Medical Cannabis Patients With A Terminal Diagnosis.","authors":"Croker, James Alton; Bobitt, Julie; Sanders, Sara; Arora, Kanika; Mueller, Keith; Kaskie, Brian","year":2022,"journal":"The American journal of hospice & palliative care, 39(3), 345-352","doi":"10.1177/10499091211018655","pmid":"34002633","tags":["medical-cannabis","seniors","cancer"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Only 19 of 342 terminal patients were enrolled in hospice, with 323 planning enrollment. Cancer patients (OR 0.21) and those who used the fast-track cannabis application (OR 0.11) were significantly less likely to be in hospice. The findings suggest cannabis use may function as an alternative to hospice and palliative care rather than complementing it.","whyItMatters":"If terminally ill patients are choosing cannabis over hospice care, they may miss out on comprehensive symptom management, psychosocial support, and end-of-life planning that hospice provides.","specificNumbers":"342 terminal patients; only 19 enrolled in hospice; cancer patients OR=0.21 for hospice enrollment; fast-track applicants OR=0.11 for hospice enrollment.","methodology":"Anonymous cross-sectional survey of 342 terminal patients enrolled in the Illinois Medical Cannabis Program. Logistic regression compared hospice enrollment, palliative care use, and standard care by patient characteristics.","limitations":"Cross-sectional design cannot determine causation. Small hospice-enrolled group (n=19). Self-selected sample. No data on symptom management outcomes. Illinois-specific program structure may not generalize."},{"rthcId":"RTHC-03776","title":"Marijuana and Breastfeeding: A Pilot Survey of Mothers.","authors":"Crowley, Hannah R; Goyal, Neera K; Chung, Esther K","year":2022,"journal":"Hospital pediatrics, 12(7), e255-e260","doi":"10.1542/hpeds.2021-006420","pmid":"35642492","tags":["pregnancy"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"57% of mothers reported ever using marijuana and 13% used within the past year. 87% knew breastfeeding while using marijuana may be harmful, but only 46% knew THC is found in breast milk. Only 35% received prenatal and 30% postnatal counseling on risks. Mothers who received prenatal counseling were more likely to know THC appears in breast milk (69% vs. 33%, p=0.02).","whyItMatters":"With marijuana use common among women of childbearing age, the gap between general awareness of harm and specific knowledge (like THC in breast milk) represents a missed opportunity for healthcare provider counseling.","specificNumbers":"46 mothers; 57% ever used marijuana; 87% knew breastfeeding risk; 46% knew THC in breast milk; 35% received prenatal counseling; 30% postnatal counseling.","methodology":"Cross-sectional survey of 46 postpartum mothers (≥18 years, newborn ≥35 weeks) at a single urban academic hospital, 2018-2019.","limitations":"Very small sample (n=46). Single hospital. Self-report subject to social desirability. No outcome data linking cannabis use to infant health. Survey-based, not clinical assessment."},{"rthcId":"RTHC-03777","title":"Magnetic restricted-access carbon nanotubes for SPME to determine cannabinoids in plasma samples by UHPLC-MS/MS.","authors":"Cruz, Jonas Carneiro; Rosa, Mariana Azevedo; Morés, Lucas; Carasek, Eduardo; Crippa, José Alexandre de Souza; Figueiredo, Eduardo Costa; Queiroz, Maria Eugênia Costa","year":2022,"journal":"Analytica chimica acta, 1226, 340160","doi":"10.1016/j.aca.2022.340160","pmid":"36068070","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03778","title":"Role of the Endocannabinoid System in the Regulation of Intestinal Homeostasis.","authors":"Cuddihey, Hailey; MacNaughton, Wallace K; Sharkey, Keith A","year":2022,"journal":"Cellular and molecular gastroenterology and hepatology, 14(4), 947-963","doi":"10.1016/j.jcmgh.2022.05.015","pmid":"35750314","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03779","title":"Clinical practice guideline on pharmacological and psychological management of adult patients with attention deficit and hyperactivity disorder and comorbid substance use.","authors":"Cunill, Ruth; Castells, Xavier; González-Pinto, Ana; Arrojo, Manuel; Bernardo, Miquel; Sáiz, Pilar A; Flórez, Gerardo; Torrens, Marta; Tirado-Muñoz, Judit; Fonseca, Francia; Arranz, Belén; Garriga, Marina; Goikolea, Jose Manuel; Zorrilla, Iñaki; Becoña, Elisardo; López, Ana; San, Luis","year":2022,"journal":"Adicciones, 34(2), 168-178","doi":"10.20882/adicciones.1569","pmid":"34171106","tags":["addiction","cognition","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"For ADHD with cannabis use disorder: atomoxetine is weakly recommended to improve ADHD symptoms but weakly recommended against reducing cannabis use. For ADHD with any SUD: both psychostimulants and atomoxetine are weakly recommended for ADHD symptoms but not for reducing substance use. Atomoxetine and psychostimulants are considered safe in patients with SUD (strong recommendation). Neither reduces treatment retention (strong recommendation against).","whyItMatters":"ADHD and substance use disorders frequently co-occur, but clinicians often hesitate to prescribe ADHD medications due to abuse concerns. This guideline provides evidence-based recommendations with safety reassurance.","specificNumbers":"Cannabis-specific: atomoxetine recommended for ADHD symptoms (weak) but not for cannabis use (weak against). Safety of both medication classes in SUD patients: strong recommendation.","methodology":"Clinical practice guideline synthesizing pharmacological and psychosocial interventions for adults with ADHD and comorbid SUD, using the GRADE approach for recommendation strength.","limitations":"Mostly weak recommendations reflecting limited evidence. Few large, multisite RCTs. Cannabis-specific evidence is particularly sparse. GRADE approach penalizes for imprecision and indirectness. May not reflect all clinical scenarios."},{"rthcId":"RTHC-03780","title":"Disparities in functioning from alcohol and cannabis use among a racially/ethnically diverse sample of emerging adults.","authors":"D'Amico, Elizabeth J; Rodriguez, Anthony; Tucker, Joan S; Dunbar, Michael S; Pedersen, Eric R; Seelam, Rachana","year":2022,"journal":"Drug and alcohol dependence, 234, 109426","doi":"10.1016/j.drugalcdep.2022.109426","pmid":"35364418","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Greater frequency and increased frequency of alcohol and cannabis use were associated with poorer outcomes across groups. However, at the same levels of use, Hispanic EAs had poorer physical health; Hispanic, Asian, and multiracial EAs reported greater alcohol consequences and delinquency; Black, Hispanic, Asian, and multiracial EAs had lower life satisfaction; and Hispanic and multiracial EAs were less likely to pursue education beyond high school.","whyItMatters":"Documenting that racial/ethnic minorities experience disproportionate harm at the same substance use levels highlights structural inequities that go beyond individual substance use behaviors.","specificNumbers":"2,945 participants followed across 5 waves. Disparities observed across 8 functional outcomes at equivalent levels of substance use. Hispanic and Asian groups had less initial substance use but worse outcomes per unit of use.","methodology":"Web-based surveys across five waves from mean age 18.3 to 22.6. N=2,945 (55% female, 46% Hispanic, 23% Asian, 23% White, 6% multiracial/other, 2% Black). Growth models examined substance use trajectories and disparities in functioning.","limitations":"Cannot identify specific mechanisms driving disparities. Some racial/ethnic groups had small sample sizes (Black: 2%). Self-reported outcomes. Southern California sample. Alcohol and cannabis analyzed together, not separately."},{"rthcId":"RTHC-03781","title":"Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis.","authors":"D'Souza, Deepak Cyril; DiForti, Marta; Ganesh, Suhas; George, Tony P; Hall, Wayne; Hjorthøj, Carsten; Howes, Oliver; Keshavan, Matcheri; Murray, Robin M; Nguyen, Timothy B; Pearlson, Godfrey D; Ranganathan, Mohini; Selloni, Alex; Solowij, Nadia; Spinazzola, Edoardo","year":2022,"journal":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 23(10), 719-742","doi":"10.1080/15622975.2022.2038797","pmid":"35315315","tags":["psychosis","youth","potency"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Converging evidence supports that cannabis increases psychosis risk across a spectrum from transient states to chronic psychosis. The relationship shows dose-response (greater dose = greater risk) and age-response (earlier exposure = greater risk). Some causality criteria are met, but alternate explanations cannot be excluded. Cannabis negatively impacts the course of established psychosis. The endocannabinoid system is altered in psychotic disorders.","whyItMatters":"This represents the most authoritative expert consensus statement on cannabis and psychosis, from the World Federation of Societies of Biological Psychiatry, providing a balanced synthesis of evidence for clinical and policy guidance.","specificNumbers":"Dose-response and age-response relationships documented. Cannabis affects both psychosis risk and the course of established psychotic disorders. Cannabis is described as one of \"multiple causal components.\"","methodology":"WFSBP task force consensus paper reviewing the literature on cannabis, cannabinoids, and psychosis, integrating epidemiological, clinical, and neurobiological evidence.","limitations":"Consensus paper synthesizing existing evidence, not generating new data. Cannot conclusively exclude reverse causality or confounders. The \"component cause\" framework is inherently difficult to test definitively."},{"rthcId":"RTHC-03782","title":"Direct Quantitation of Phytocannabinoids by One-Dimensional 1H qNMR and Two-Dimensional 1H-1H COSY qNMR in Complex Natural Mixtures.","authors":"Dadiotis, Evangelos; Mitsis, Vangelis; Melliou, Eleni; Magiatis, Prokopios","year":2022,"journal":"Molecules (Basel, Switzerland), 27(9)","doi":"10.3390/molecules27092965","pmid":"35566314","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03783","title":"A survey of medical cannabis use during perimenopause and postmenopause.","authors":"Dahlgren, M Kathryn; El-Abboud, Celine; Lambros, Ashley M; Sagar, Kelly A; Smith, Rosemary T; Gruber, Staci A","year":2022,"journal":"Menopause (New York, N.Y.), 29(9), 1028-1036","doi":"10.1097/GME.0000000000002018","pmid":"35917529","tags":["medical-cannabis","anxiety","sleep","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"86.1% reported current cannabis use and 78.7% used it for menopause symptoms. Top symptoms targeted: sleep disturbance (67.4%) and mood/anxiety (46.1%). Top methods: smoking (84.3%) and edibles (78.3%). Perimenopausal women had significantly worse vasomotor and psychosocial symptoms, more depression and anxiety diagnoses, and used more cannabis for mood/anxiety compared to postmenopausal women.","whyItMatters":"Menopause affects virtually all women, and many are turning to cannabis for symptom relief in the absence of robust evidence. Understanding these use patterns is essential for informed clinical conversations.","specificNumbers":"258 participants; 78.7% used cannabis for menopause symptoms; 67.4% for sleep; 46.1% for mood/anxiety; 84.3% smoked; 78.3% used edibles. Perimenopausal women had worse anxiety (p=0.01) and hot flashes (p=0.04).","methodology":"Survey of 258 participants (131 perimenopausal, 127 postmenopausal) assessing menopause-related symptoms, cannabis use patterns, modes of use, and specific menopause symptoms targeted by cannabis.","limitations":"Self-selected sample of cannabis users (not generalizable to all menopausal women). No outcome data on efficacy. Cross-sectional design. No comparison to non-cannabis-using menopausal women. Self-reported diagnoses."},{"rthcId":"RTHC-03784","title":"Increased White Matter Coherence Following Three and Six Months of Medical Cannabis Treatment.","authors":"Dahlgren, Mary Kathryn; Gonenc, Atilla; Sagar, Kelly A; Smith, Rosemary T; Lambros, Ashley M; El-Abboud, Celine; Gruber, Staci A","year":2022,"journal":"Cannabis and cannabinoid research, 7(6), 827-839","doi":"10.1089/can.2022.0097","pmid":"36367574","tags":["medical-cannabis","cbd","neuroscience"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"FA values (indicating white matter integrity) significantly increased in corpus callosum regions after 3 and 6 months of MC treatment. MD values (indicating demyelination when elevated) significantly decreased after 6 months. No changes were seen in a control brain region or in a pilot treatment-as-usual group. Reduced MD correlated with higher CBD but not THC exposure.","whyItMatters":"This is the first study showing improved (not worsened) white matter coherence with cannabis use, suggesting medical cannabis patients, who tend to use CBD-containing products and start at older ages, may experience fundamentally different neural effects than recreational users.","specificNumbers":"37 MC patients; FA increased bilaterally in callosal regions at 3 and 6 months. MD decreased after 6 months. CBD exposure correlated with MD reduction. No changes in 14 treatment-as-usual controls.","methodology":"Longitudinal study of 37 MC patients assessed via diffusion tensor imaging (DTI-MRI) before starting MC and at 3 and 6 months. Bilateral regions of interest including corpus callosum and internal capsule analyzed. A pilot treatment-as-usual comparison group (n=14) also assessed.","limitations":"Small sample with attrition (37 to 22 over 6 months). Open-label, non-randomized. Patients chose their own products. Pilot control group was very small (n=14). Cannot separate MC effects from natural recovery from symptoms MC was treating."},{"rthcId":"RTHC-03785","title":"Clinical and cognitive improvement following full-spectrum, high-cannabidiol treatment for anxiety: open-label data from a two-stage, phase 2 clinical trial.","authors":"Dahlgren, Mary Kathryn; Lambros, Ashley M; Smith, Rosemary T; Sagar, Kelly A; El-Abboud, Celine; Gruber, Staci A","year":2022,"journal":"Communications medicine, 2(1), 139","doi":"10.1038/s43856-022-00202-8","pmid":"36352103","tags":["cbd","anxiety","cognition","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Anxiety scores decreased significantly by week 4 (BAI: p<0.001; OASIS: p<0.001). Clinically significant treatment response (≥15% symptom reduction) was achieved by week 1 in 78.6-92.7% of patients and reached 100% by week 3. Secondary outcomes including mood, sleep, quality of life, and executive function also improved. The study drug was well-tolerated with minor side effects (sleepiness, increased energy, dry mouth).","whyItMatters":"This is one of the first clinical trials to examine cognitive outcomes alongside anxiety outcomes with a CBD product, and the finding that executive function improved (rather than deteriorated) addresses a key safety concern.","specificNumbers":"14 patients; ~30 mg/day CBD; BAI and OASIS both p<0.001 at week 4. Response by week 1: 78.6% (BAI), 92.7% (OASIS). 100% responded by week 3. No serious adverse events. No intoxication reported.","methodology":"Open-label stage of clinical trial NCT02548559. 14 outpatients with moderate-to-severe anxiety (BAI ≥16 or OASIS ≥11) received 1 mL t.i.d. of a full-spectrum high-CBD sublingual solution (9.97 mg/mL CBD, 0.23 mg/mL THC) for 4 weeks. Autoregressive linear modeling assessed outcomes.","limitations":"Open-label design without placebo control. Very small sample (n=14). Short duration (4 weeks). Full-spectrum product contains trace THC and other compounds. Cannot attribute effects to CBD alone. Double-blind stage ongoing."},{"rthcId":"RTHC-03786","title":"Examining Risk Factors in the Cannabis-Suicide Link: Considering Trauma and Impulsivity among University Students.","authors":"Daneshmend, Ayeila Z B; Stewart, Jayme; Jarkas, Dana A; Franklyn, Sabina I; Gabrys, Robert L; Patterson, Zachary R; Abizaid, Alfonso; Hellemans, Kim G C; McQuaid, Robyn J","year":2022,"journal":"International journal of environmental research and public health, 19(15)","doi":"10.3390/ijerph19159307","pmid":"35954661","tags":["mental-health","addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Problematic cannabis use was moderately associated with suicidal ideation and attempts. Trait impulsiveness mediated the relationship between problematic cannabis use and both lifetime suicidal ideation and attempts. Previous trauma moderated the cannabis-suicide attempt relationship, with the association stronger among those with high trauma exposure.","whyItMatters":"Rather than focusing solely on whether cannabis causes suicidality, this study identifies which cannabis users are at highest risk: those with trait impulsiveness and trauma histories.","specificNumbers":"539 university students. Impulsiveness mediated cannabis-SI and cannabis-SA relationships. Trauma moderated the cannabis-SA association (stronger at high trauma levels).","methodology":"Cross-sectional study of 539 university students examining associations between problematic cannabis use, suicidal ideation/attempts, trait impulsiveness (mediator), and childhood trauma (moderator).","limitations":"Cross-sectional design prevents causal conclusions. University student sample not generalizable. Self-reported suicidal behavior. Problematic cannabis use measured by screening tool, not clinical assessment."},{"rthcId":"RTHC-03787","title":"Simulated microgravity contributed to modification of callogenesis performance and secondary metabolite production in CannabisIndica.","authors":"Darigh, Farzaneh; Iranbakhsh, Alireza; Oraghi Ardebili, Zahra; Ebadi, Mostafa; Hassanpour, Halimeh","year":2022,"journal":"Plant physiology and biochemistry : PPB, 186, 157-168","doi":"10.1016/j.plaphy.2022.07.012","pmid":"35849945","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03788","title":"Directional associations between cannabis use and anxiety symptoms from late adolescence through young adulthood.","authors":"Davis, Jordan P; Pedersen, Eric R; Tucker, Joan S; Prindle, John; Dunbar, Michael S; Rodriguez, Anthony; Seelam, Rachana; D'Amico, Elizabeth J","year":2022,"journal":"Drug and alcohol dependence, 241, 109704","doi":"10.1016/j.drugalcdep.2022.109704","pmid":"36434880","tags":["anxiety","sex-differences","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"For the overall sample and men, greater cannabis use predicted greater subsequent increases in anxiety (substance-induced pathway). However, greater anxiety was associated with decreasing, not increasing, cannabis use (contradicting the self-medication hypothesis). For women, the patterns were more complex, with trait-like anxiety predicting increasing anxiety but recent anxiety increases associated with reduced cannabis use.","whyItMatters":"This study challenges the popular self-medication hypothesis by showing anxious people actually tend to reduce cannabis use, while supporting the idea that cannabis use can increase anxiety over time.","specificNumbers":"N=2,995; ages 17-24; 6 measurement waves. Cannabis use predicted increasing anxiety. Anxiety predicted decreasing cannabis use. Sex-specific models revealed different patterns for men and women.","methodology":"Data from a longitudinal cohort study (N=2,995) using an accelerated longitudinal design from ages 17-24. Latent difference score models estimated bidirectional relationships between anxiety and cannabis use across 6 waves, separately for men and women.","limitations":"Self-reported measures. Cannot account for all confounders. Southern California sample. Cannabis use measured by frequency, not dose or potency. Accelerated longitudinal design assumes cohort equivalence."},{"rthcId":"RTHC-03789","title":"Latent inhibition, aberrant salience, and schizotypy traits in cannabis users.","authors":"Dawes, Christopher; Quinn, Declan; Bickerdike, Andrea; O'Neill, Cian; Granger, Kiri T; Pereira, Sarah Carneiro; Mah, Sue Lynn; Haselgrove, Mark; Waddington, John L; O'Tuathaigh, Colm; Moran, Paula M","year":2022,"journal":"Schizophrenia research. Cognition, 28, 100235","doi":"10.1016/j.scog.2021.100235","pmid":"35028297","tags":["psychosis","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Current cannabis use was associated with higher \"disorganized\" and \"cognitive-perceptual\" schizotypy scores and higher aberrant salience inventory scores. However, neither lifetime nor current cannabis use was associated with abnormal latent inhibition (LI), an objective measure of salience processing. Higher scores on specific aberrant salience subscales (\"senses sharpening\" and \"heightened cognition\") did predict decreased LI, regardless of cannabis use.","whyItMatters":"The disconnect between self-reported aberrant salience (which is higher in cannabis users) and objective salience processing (which is normal) helps clarify the mechanism by which cannabis might increase psychosis risk.","specificNumbers":"346 participants. Cannabis users had higher disorganized and cognitive-perceptual SPQ scores and higher total ASI scores. No association between cannabis use and LI performance.","methodology":"Cross-sectional study of 346 university students who completed the Schizotypal Personality Questionnaire, Aberrant Salience Inventory, Cannabis Experience Questionnaire, and a latent inhibition task. Regression models and Bayesian analyses used.","limitations":"Non-clinical university sample. Cross-sectional design. Self-reported cannabis use. LI task may lack sensitivity for detecting subtle impairments. Cannot distinguish acute from chronic cannabis effects."},{"rthcId":"RTHC-03790","title":"Alleviation of opioid withdrawal by cannabis and delta-9-tetrahydrocannabinol: A systematic review of observational and experimental human studies.","authors":"De Aquino, Joao P; Bahji, Anees; Gómez, Oscar; Sofuoglu, Mehmet","year":2022,"journal":"Drug and alcohol dependence, 241, 109702","doi":"10.1016/j.drugalcdep.2022.109702","pmid":"36434879","tags":["harm-reduction","withdrawal","medical-cannabis","pain"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Of 11 studies with 5,330 participants, four observational studies found cannabis use was associated with reduced opioid withdrawal, one found worsening symptoms, and four found no association. Two RCTs showed dronabinol (synthetic THC) reduced withdrawal but also increased abuse liability and dysphoria.","whyItMatters":"Six U.S. states have authorized cannabinoids as opioid substitutes, but the evidence base for this approach remains weak and contradictory.","specificNumbers":"11 studies, 5,330 total participants (64% male). Four of nine observational studies found withdrawal alleviation; two RCTs showed THC helped but with dose-dependent side effects.","methodology":"Systematic review searching multiple databases through July 2022 for studies examining the association between opioid withdrawal and cannabis use or THC administration.","limitations":"High heterogeneity in how opioid withdrawal was measured and in baseline opioid type and dose across studies."},{"rthcId":"RTHC-03791","title":"Implications of the endocannabinoid system and the therapeutic action of cannabinoids in autism spectrum disorder: A literature review.","authors":"de Camargo, Rick Wilhiam; de Novais Júnior, Linério Ribeiro; da Silva, Larissa Mendes; Meneguzzo, Vicente; Daros, Guilherme Cabreira; da Silva, Marina Goulart; de Bitencourt, Rafael Mariano","year":2022,"journal":"Pharmacology, biochemistry, and behavior, 221, 173492","doi":"10.1016/j.pbb.2022.173492","pmid":"36379443","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03792","title":"Management of Hyperhomocysteinemia, Low Vitamin Levels, and Low Cortisol in Cannabis Users: A Report of 2 Cases.","authors":"de Carvalho, Jozélio; Lerner, Aaron; Feingold, Daniel","year":2022,"journal":"Journal of chiropractic medicine, 21(4), 322-326","doi":"10.1016/j.jcm.2022.03.001","pmid":"36420369","tags":["cognition","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Both patients, who had used cannabis for 9 and 14 years respectively, had abnormal blood levels of homocysteine, vitamins, and cortisol. After two months of targeted supplementation and psychotherapy, both improved and reduced their cannabis consumption.","whyItMatters":"Long-term cannabis use may be associated with nutritional and hormonal imbalances that could contribute to symptoms like fatigue, anxiety, and depression.","specificNumbers":"Patient 1: 28-year-old man, 9 years of use (3x/week). Patient 2: 39-year-old man, 14 years of use (2x/week). Both improved after 2 months of treatment.","methodology":"Case report describing the clinical management of two long-term cannabis users treated with nutritional supplements (folic acid, methylcobalamin, pyridoxine, vitamin D, Rhodiola rosea, L-tyrosine) and psychotherapy.","limitations":"Only two patients with no control group. Multiple interventions were given simultaneously, making it impossible to isolate which treatment drove improvement."},{"rthcId":"RTHC-03793","title":"Cannabis Cultivation Facilities: A Review of Their Air Quality Impacts from the Occupational to Community Scale.","authors":"de Ferreyro Monticelli, Davi; Bhandari, Sahil; Eykelbosh, Angela; Henderson, Sarah B; Giang, Amanda; Zimmerman, Naomi","year":2022,"journal":"Environmental science & technology, 56(5), 2880-2896","doi":"10.1021/acs.est.1c06372","pmid":"35138823","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03794","title":"Long-term effects of prenatal cannabis exposure: Pathways to adolescent and adult outcomes.","authors":"De Genna, Natacha M; Willford, Jennifer A; Richardson, Gale A","year":2022,"journal":"Pharmacology, biochemistry, and behavior, 214, 173358","doi":"10.1016/j.pbb.2022.173358","pmid":"35216971","tags":["pregnancy","youth","cognition","addiction","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Across longitudinal studies, prenatal cannabis exposure showed remarkably consistent associations with externalizing behaviors like delinquency and substance use that persisted into adulthood. Effects on memory and academic achievement were subtle but enduring. Early cannabis initiation played a key role in pathways to adult problems.","whyItMatters":"With increasing cannabis use, potency, and social acceptance during pregnancy, understanding the long-term developmental effects on children is increasingly important.","specificNumbers":"Review found some evidence for restricted growth at birth but not long-term growth effects. Consistent findings for externalizing behaviors across studies despite different demographics and measurement approaches.","methodology":"Narrative review of prospective, longitudinal studies examining developmental outcomes of prenatal cannabis exposure, with discussion of methodological considerations.","limitations":"Difficult to isolate cannabis effects from other prenatal exposures, socioeconomic factors, and postnatal environment. Self-reported cannabis use may underestimate exposure."},{"rthcId":"RTHC-03795","title":"Cohort Study of Cannabis Use History and Perinatal Cigarette Use Among Overweight and Obese Women.","authors":"De Genna, Natacha M; Germeroth, Lisa J; Benno, Maria Tina; Wang, Bang; Levine, Michele D","year":2022,"journal":"Maternal and child health journal, 26(2), 389-396","doi":"10.1007/s10995-021-03246-9","pmid":"34623574","tags":["pregnancy","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"History of cannabis use predicted cigarette smoking in early pregnancy (OR 11.12), late pregnancy (OR 6.55), and 6 months postpartum (OR 7.57). Having a cannabis use disorder diagnosis did not add additional risk beyond any cannabis use history.","whyItMatters":"As cannabis use among pregnant women increases, understanding its connection to cigarette smoking could improve cessation efforts during the perinatal period.","specificNumbers":"252 women analyzed. 48% reported prior cannabis use, 15% met criteria for lifetime cannabis use disorder. Odds of smoking ranged from 6.55 to 11.12 times higher for those with cannabis history.","methodology":"Prospective cohort study of 257 pregnant women with overweight/obesity in Western Pennsylvania (2012-2016), using structured clinical interviews and generalized mixed effect models adjusting for demographics, parity, and mood disorders.","limitations":"Sample limited to women with overweight/obesity in one geographic region. Lifetime CUD was measured, not current use. Small sample size limits power to detect CUD-specific effects."},{"rthcId":"RTHC-03796","title":"Effectiveness of a neuroscience-based, harm reduction program for older adolescents: A cluster randomised controlled trial of the Illicit Project.","authors":"Debenham, Jennifer; Champion, Katrina; Birrell, Louise; Newton, Nicola","year":2022,"journal":"Preventive medicine reports, 26, 101706","doi":"10.1016/j.pmedr.2022.101706","pmid":"35111569","tags":["youth","harm-reduction","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Students who received the Illicit Project program were significantly less likely than controls to engage in weekly binge drinking (OR 0.56), early cannabis use (OR 0.35), risky cannabis use (OR 0.48), MDMA use (OR 0.16), and nicotine use (OR 0.59). They also had fewer alcohol-related harms and higher drug literacy.","whyItMatters":"Few evidence-based substance use prevention programs target older adolescents (16-19), the age when substance use typically escalates.","specificNumbers":"950 students, 60% female, mean age 15.9. Cannabis early onset odds reduced by 65% (OR 0.35). MDMA use odds reduced by 84% (OR 0.16). Drug literacy scores increased by 2.44 points.","methodology":"Cluster randomized controlled trial with 950 students (mean age 15.9) from 8 Australian secondary schools. Five schools received the intervention, three received standard health education. Self-report surveys at baseline and 6 months.","limitations":"Only 6-month follow-up; durability unknown. Self-reported outcomes. Unequal cluster sizes (5 intervention vs 3 control schools). Australian context may limit generalizability."},{"rthcId":"RTHC-03797","title":"Strategies for Prevention or Treatment of Tobacco and Cannabis Use Disorder.","authors":"DeJong, Katherine N; Choby, Beth; Valent, Amy M","year":2022,"journal":"Clinical obstetrics and gynecology, 65(2), 397-419","doi":"10.1097/GRF.0000000000000688","pmid":"35318983","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03798","title":"Inhibiting Endocannabinoid Hydrolysis as Emerging Analgesic Strategy Targeting a Spectrum of Ion Channels Implicated in Migraine Pain.","authors":"Della Pietra, Adriana; Savinainen, Juha; Giniatullin, Rashid","year":2022,"journal":"International journal of molecular sciences, 23(8)","doi":"10.3390/ijms23084407","pmid":"35457225","tags":["pain","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"MAGL and FAAH, the enzymes that degrade endocannabinoids, are distributed differently across brain regions involved in migraine pain. Blocking these enzymes raises levels of 2-AG and anandamide, which can reduce pain through both cannabinoid receptors and direct modulation of ion channels in pain neurons.","whyItMatters":"Current migraine treatments have limited effectiveness. Targeting the endocannabinoid system through enzyme inhibition could provide pain relief without the side effects and psychoactivity of plant-derived cannabis.","specificNumbers":"Review covers two main enzyme targets (MAGL and FAAH) and two primary endocannabinoids (2-AG and anandamide) across multiple pain signaling pathways.","methodology":"Thematic review synthesizing research on endocannabinoid degradation pathways, migraine pain signaling, and emerging enzyme inhibitors.","limitations":"Much of the evidence comes from preclinical studies. Clinical trials of MAGL and FAAH inhibitors for migraine are still needed."},{"rthcId":"RTHC-03799","title":"Pharmacokinetics of cannabidiol following single oral and oral transmucosal administration in dogs.","authors":"Della Rocca, Giorgia; Paoletti, Fabiola; Conti, Maria Beatrice; Galarini, Roberta; Chiaradia, Elisabetta; Sforna, Monica; Dall'Aglio, Cecilia; Polisca, Angela; Di Salvo, Alessandra","year":2022,"journal":"Frontiers in veterinary science, 9, 1104152","doi":"10.3389/fvets.2022.1104152","pmid":"36686155","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03800","title":"Cannabinoids Reduce Extracellular Vesicle Release from HIV-1 Infected Myeloid Cells and Inhibit Viral Transcription.","authors":"DeMarino, Catherine; Cowen, Maria; Khatkar, Pooja; Cotto, Bianca; Branscome, Heather; Kim, Yuriy; Sharif, Sarah Al; Agbottah, Emmanuel T; Zhou, Weidong; Costiniuk, Cecilia T; Jenabian, Mohammad-Ali; Gelber, Cohava; Liotta, Lance A; Langford, Dianne; Kashanchi, Fatah","year":2022,"journal":"Cells, 11(4)","doi":"10.3390/cells11040723","pmid":"35203372","tags":["cbd","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD significantly reduced the concentration of extracellular vesicles (EVs) released from HIV-1 infected U1 monocytes and primary macrophages. This appeared to be mediated by reduced viral transcription and activation of autophagy (cellular self-cleaning).","whyItMatters":"About 50% of people with HIV develop neurocognitive disorders. EVs carrying viral RNA trigger inflammation in healthy cells, so reducing their release could help limit HIV-associated brain inflammation.","specificNumbers":"Approximately 50% of 37.9 million HIV-infected individuals exhibit HIV-associated neurocognitive disorders. Cannabis use in people with HIV has been associated with lower viral loads and higher CD4+ T-cell counts.","methodology":"In vitro study using HIV-1 infected U1 monocytes and primary macrophages. EV concentrations measured by nanoparticle tracking analysis, viral RNA by RT-qPCR, and proteins by Western blot.","limitations":"In vitro study only. The concentrations of CBD used may not reflect achievable levels in the human brain. Results from cell cultures may not translate to whole-body effects."},{"rthcId":"RTHC-03801","title":"Hypertensive Crisis-Related Hospitalizations and Subsequent Major Adverse Cardiac Events in Young Adults with Cannabis Use Disorder: A Nationwide Analysis.","authors":"Desai, Rupak; Jain, Akhil; Sultan, Waleed; Gandhi, Zainab; Raju, Athul Raj; Varughese, Vivek Joseph; Jnaneswaran, Geethu; Agarwal, Charu; Rizvi, Bisharah; Mansuri, Zeeshan; Gupta, Puneet; Kumar, Gautam; Sachdeva, Rajesh","year":2022,"journal":"Medicina (Kaunas, Lithuania), 58(10)","doi":"10.3390/medicina58101465","pmid":"36295625","tags":["cardiovascular","addiction","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Young adults (18-44) with cannabis use disorder had 15% higher odds of hypertensive crisis hospitalization compared to those without (aOR 1.15). During those hospitalizations, they had 5.7 times higher odds of death, 73% higher odds of arrhythmia, and 46% higher odds of stroke.","whyItMatters":"As recreational cannabis use grows, understanding its cardiovascular risks in young adults is important for clinical awareness and screening.","specificNumbers":"Propensity-matched cohort: 4,440 patients, median age 36, 64.2% male, 64.4% Black. All-cause mortality OR 5.74, arrhythmia OR 1.73, stroke OR 1.46.","methodology":"Retrospective analysis of the National Inpatient Sample (October 2015-December 2017) with propensity-score matching to compare outcomes between young adults with and without cannabis use disorder admitted for hypertensive crisis.","limitations":"Retrospective database study cannot establish causation. Cannabis use disorder does not capture frequency, potency, or route of use. ICD coding may misclassify patients."},{"rthcId":"RTHC-03802","title":"A Systematic Review and Meta-Analysis on the Effects of Exercise on the Endocannabinoid System.","authors":"Desai, Shreya; Borg, Breanna; Cuttler, Carrie; Crombie, Kevin M; Rabinak, Christine A; Hill, Matthew N; Marusak, Hilary A","year":2022,"journal":"Cannabis and cannabinoid research, 7(4), 388-408","doi":"10.1089/can.2021.0113","pmid":"34870469","tags":["exercise","neuroscience"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"The meta-analysis of 10 studies showed consistent increases in both anandamide (AEA) and 2-AG following acute exercise across different exercise types (running, cycling), species (humans, mice), and health conditions. 74.4% of all samples measuring anandamide showed significant increases after exercise.","whyItMatters":"The \"runner's high\" has traditionally been attributed to endorphins, but this research suggests the endocannabinoid system plays a major role in exercise-induced mood elevation and pain relief.","specificNumbers":"33 articles in systematic review, 10 in meta-analysis. 74.4% of samples showed significant anandamide increases after acute exercise. Effects found across running, cycling, humans, and mice.","methodology":"Systematic review of 33 articles (57 samples) from the MEDLINE database, with meta-analysis of 10 studies examining circulating endocannabinoid levels before and after exercise.","limitations":"Substantial heterogeneity in effect magnitude across studies. Effects of chronic exercise were inconsistent. Timing of measurement, exercise intensity, and fasting state may influence results."},{"rthcId":"RTHC-03803","title":"Immunosuppressive activity of non-psychoactive Cannabis sativa L. extract on the function of human T lymphocytes.","authors":"Devi, Seema; Zimmermann-Klemd, Amy M; Fiebich, Bernd L; Heinrich, Michael; Gründemann, Carsten; Steinberger, Peter; Kowarschik, Stefanie; Huber, Roman","year":2022,"journal":"International immunopharmacology, 103, 108448","doi":"10.1016/j.intimp.2021.108448","pmid":"34998274","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"A cannabis extract with 14% CBD and 0.2% THC inhibited T lymphocyte proliferation in a dose-dependent manner without causing cell death. The extract suppressed T cell activation markers (CD25), degranulation, and production of IL-2 and IFN-gamma. Effects were mediated through CB2 and TRPV1 receptors and AP-1/NFAT transcription pathways.","whyItMatters":"Understanding how cannabis extracts modulate the immune system could inform therapeutic approaches for autoimmune and inflammatory conditions.","specificNumbers":"14% CBD, 0.2% THC concentration in the extract. Effects were dose-dependent and reversible with CB2 antagonist (SR144528) and TRPV1 antagonist (A78416B).","methodology":"In vitro study using primary human lymphocytes and Jurkat reporter cell lines. Tested a high-CBD, low-THC cannabis extract against pure CBD, measuring proliferation, activation markers, cytokine production, and receptor involvement.","limitations":"In vitro study using isolated cells. Immune system behavior in living organisms involves complex interactions not captured in cell culture. Effective concentrations may not be achievable in the body."},{"rthcId":"RTHC-03804","title":"Cannabidiol Interferes with Establishment of Δ9-Tetrahydrocannabinol-Induced Nausea Through a 5-HT1A Mechanism.","authors":"DeVuono, Marieka V; La Caprara, Olivia; Petrie, Gavin N; Limebeer, Cheryl L; Rock, Erin M; Hill, Matthew N; Parker, Linda A","year":2022,"journal":"Cannabis and cannabinoid research, 7(1), 58-64","doi":"10.1089/can.2020.0083","pmid":"33998876","tags":["cbd","neuroscience","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (5 mg/kg) blocked the establishment of THC-induced conditioned gaping (a measure of nausea) in rats, and this effect was reversed by a 5-HT1A receptor antagonist (WAY-100635). CBD also reversed the THC-induced increase in corticosterone (stress hormone).","whyItMatters":"Cannabinoid hyperemesis syndrome (CHS) involves intense nausea from high-dose THC use. Understanding how CBD counteracts THC-induced nausea could inform CHS treatment strategies.","specificNumbers":"CBD at 5 mg/kg blocked THC-induced gaping (p=0.007). THC at 10 mg/kg significantly increased corticosterone (p=0.04). CBD reversed the corticosterone elevation.","methodology":"Animal study using conditioned gaping paradigm in rats to measure nausea. Tested CBD pretreatment against THC-induced nausea and used receptor antagonists to identify the mechanism. Serum corticosterone measured to assess stress response.","limitations":"Animal study using rats, which cannot vomit. Conditioned gaping is a proxy for nausea. Doses and pharmacokinetics may not translate directly to humans."},{"rthcId":"RTHC-03805","title":"Effects of Rare Phytocannabinoids on the Endocannabinoid System of Human Keratinocytes.","authors":"Di Meo, Camilla; Tortolani, Daniel; Standoli, Sara; Angelucci, Clotilde Beatrice; Fanti, Federico; Leuti, Alessandro; Sergi, Manuel; Kadhim, Salam; Hsu, Eric; Rapino, Cinzia; Maccarrone, Mauro","year":2022,"journal":"International journal of molecular sciences, 23(10)","doi":"10.3390/ijms23105430","pmid":"35628241","tags":["medical-cannabis","neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBG, CBC, THCV, and CBGA each produced distinct patterns of gene and protein expression changes in ECS components of human keratinocytes. Despite their differences, all four increased CB1/CB2 receptor binding, TRPV1 channel stimulation, and FAAH/MAGL enzyme activity.","whyItMatters":"Most cannabis research focuses on THC and CBD. Understanding how rare cannabinoids affect the endocannabinoid system in skin cells could inform topical cannabis therapies for skin conditions.","specificNumbers":"Four rare cannabinoids tested: CBG, CBC, THCV, and CBGA. All four increased CB1/CB2 binding, TRPV1 stimulation, and FAAH/MAGL activity in keratinocytes.","methodology":"In vitro study using human keratinocytes (HaCaT cells). Measured gene expression (qRT-PCR), protein expression (Western blot), receptor binding (radioligand assays), enzyme activity, and endocannabinoid content (UHPLC-MS/MS) for each cannabinoid.","limitations":"In vitro study using a single cell line. Skin in living organisms has multiple cell types and immune interactions not captured here. Concentrations tested may not reflect topical application levels."},{"rthcId":"RTHC-03806","title":"The role of cannabinoids in neurodevelopmental disorders of children and adolescents.","authors":"Dias-de Freitas, F; Pimenta, S; Soares, S; Gonzaga, D; Vaz-Matos, I; Prior, C","year":2022,"journal":"Revista de neurologia, 75(7), 189-197","doi":"10.33588/rn.7507.2022123","pmid":"36169325","tags":["cbd","youth","medical-cannabis","cognition"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD modulates the endocannabinoid system in developing brains through multiple mechanisms and appears to have anxiolytic, antipsychotic, and neuroprotective properties. Clinical evidence suggests early CBD treatment could improve common symptoms in neurodevelopmental disorders including social interaction deficits, anxiety, hyperactivity, and sleep problems.","whyItMatters":"Neurodevelopmental disorders affect millions of children and current medications often have significant side effects. CBD offers a potential alternative with a relatively high safety threshold.","specificNumbers":"Review covers four neurodevelopmental disorders: intellectual disability, autism spectrum disorder, tics, and ADHD. CBD described as having a \"relatively high toxicity limit.\"","methodology":"Literature review of clinical and pre-clinical studies on cannabinoid use in pediatric neurodevelopmental disorders, with attention to safety and efficacy.","limitations":"Most evidence is preliminary. Limited controlled trials in pediatric populations. Long-term effects of CBD on developing brains need more study."},{"rthcId":"RTHC-03807","title":"The Association between Recent Cannabis Use and Suicidal Ideation in Adults: A Population-based Analysis of the NHANES from 2005 to 2018.","authors":"Diep, Calvin; Bhat, Venkat; Wijeysundera, Duminda N; Clarke, Hance A; Ladha, Karim S","year":2022,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 67(4), 259-267","doi":"10.1177/0706743721996112","pmid":"33641436","tags":["mental-health","depression","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"After adjusting for potential confounders, recent cannabis users (past 30 days) had significantly higher odds of suicidal ideation (aOR 1.54), depression (aOR 1.53), and having recently seen a mental health professional, compared to those without recent cannabis use.","whyItMatters":"With cannabis use prevalence rising, understanding its relationship with suicidal thinking is critical for public health screening and policy decisions.","specificNumbers":"21,726 participants: 18,599 non-users, 3,127 recent users. Suicidal ideation aOR 1.54 (95% CI 1.19-2.00, p=0.001). Depression aOR 1.53 (95% CI 1.29-1.82).","methodology":"Cross-sectional analysis of 21,726 adults from the National Health and Nutrition Examination Survey (NHANES, 2005-2018). Multiple logistic regression adjusting for demographics, socioeconomic factors, and comorbidities, with survey sample weights.","limitations":"Cross-sectional design cannot determine causation or direction of effect. Self-reported cannabis use. Does not account for quantity, potency, or reason for use."},{"rthcId":"RTHC-03808","title":"Peri-Pregnancy Cannabis Use and Autism Spectrum Disorder in the Offspring: Findings from the Study to Explore Early Development.","authors":"DiGuiseppi, Carolyn; Crume, Tessa; Van Dyke, Julia; Sabourin, Katherine R; Soke, Gnakub N; Croen, Lisa A; Daniels, Julie L; Lee, Li-Ching; Schieve, Laura A; Windham, Gayle C; Friedman, Sandra; Robinson Rosenberg, Cordelia","year":2022,"journal":"Journal of autism and developmental disorders, 52(11), 5064-5071","doi":"10.1007/s10803-021-05339-4","pmid":"34767135","tags":["pregnancy","youth"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Among children assessed at 30-68 months of age, peri-pregnancy cannabis use was reported for 5.2% of ASD cases, 3.2% of children with other developmental delays, and 4.4% of population controls. After adjustment, the odds of peri-pregnancy cannabis use did not differ significantly between groups.","whyItMatters":"Animal models and neurobiology have suggested potential risks of prenatal cannabis exposure for neurodevelopment, but this large study found no association with ASD in humans.","specificNumbers":"4,254 children total. ASD: 5.2% cannabis exposed. Other developmental delays: 3.2% exposed. Population controls: 4.4% exposed. No significant differences between groups.","methodology":"Case-control study comparing children with ASD (N=1,428), other developmental delays (N=1,198), and population controls (N=1,628) born 2003-2011 from the Study to Explore Early Development. Self-reported maternal cannabis use assessed for the period from 3 months pre-conception through delivery.","limitations":"Self-reported cannabis use likely underestimates true exposure. Birth cohort (2003-2011) predates major legalization and potency increases. Cannot assess dose-response relationships."},{"rthcId":"RTHC-03809","title":"Egocentric Network Characteristics and Cannabis Use in a Sample of Young Adult Medical Cannabis Patients and Nonpatient Users.","authors":"DiGuiseppi, Graham T; Fedorova, Ekaterina V; Lankenau, Stephen E; Davis, Jordan P; Wong, Carolyn F","year":2022,"journal":"Journal of studies on alcohol and drugs, 83(6), 802-811","doi":"10.15288/jsad.21-00286","pmid":"36484577","tags":["youth","addiction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Descriptive norms (how much one's social contacts use cannabis) were associated with more frequent cannabis use (aIRR 1.19), but not with problematic use. The effect was stronger for recreationally oriented users (aIRR 1.62) than medicinally oriented users (aIRR 1.22).","whyItMatters":"Understanding how social environments influence cannabis use patterns can inform prevention and harm reduction strategies for young adults.","specificNumbers":"339 participants (182 medical patients, 157 nonpatients). Descriptive norms associated with use frequency (aIRR 1.19). Recreational users: aIRR 1.62. Medicinal users: aIRR 1.22. No association with problematic use.","methodology":"Cross-sectional survey of 339 young adult cannabis users (182 medical patients, 157 nonpatients) in Los Angeles (2015-2016). Regression models examined associations between egocentric network characteristics and past-90-day cannabis use.","limitations":"Cross-sectional design limits causal claims. Los Angeles sample may not generalize. Self-reported cannabis use and network composition."},{"rthcId":"RTHC-03810","title":"Models predicting the role of emotion reactivity in the link between reasons for not using and lifetime substance use.","authors":"DiPierro-Sutton, Moneika; Poquiz, Jonathan; Brown, Shaquanna; Fite, Paula; Bortolato, Marco","year":2022,"journal":"Journal of American college health : J of ACH, 70(2), 527-535","doi":"10.1080/07448481.2020.1756828","pmid":"32407218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03811","title":"Cannabinoid receptor 2 evolutionary gene loss makes parrots more susceptible to neuroinflammation.","authors":"Divín, Daniel; Goméz Samblas, Mercedes; Kuttiyarthu Veetil, Nithya; Voukali, Eleni; Świderská, Zuzana; Krajzingrová, Tereza; Těšický, Martin; Beneš, Vladimír; Elleder, Daniel; Bartoš, Oldřich; Vinkler, Michal","year":2022,"journal":"Proceedings. Biological sciences, 289(1988), 20221941","doi":"10.1098/rspb.2022.1941","pmid":"36475439","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"All parrots (Psittaciformes) have a nonfunctional CB2 gene due to chromosomal rearrangements. When exposed to an inflammatory stimulus, parrot brains showed significant upregulation of pro-inflammatory cytokines (IL1B and IL6), while birds with intact CB2 genes (passerines) did not show the same neuroinflammatory response.","whyItMatters":"This is one of the clearest demonstrations of how important the CB2 cannabinoid receptor is for controlling brain inflammation, using a natural evolutionary \"knockout\" experiment.","specificNumbers":"CB2 gene loss confirmed across all Psittaciformes. Six parrot species tested. Pro-inflammatory cytokines IL1B and IL6 were significantly upregulated in parrot brains but not in passerine brains after inflammatory challenge.","methodology":"Comparative genomic analysis across bird species to identify CB2 gene losses, followed by experimental brain inflammation studies comparing CB2-deficient parrots (budgerigars and 5 other species) with CB2-intact passerines (zebra finches) using lipopolysaccharide stimulation and transcriptomic analysis.","limitations":"Bird brains differ significantly from mammalian brains. The absence of compensatory CB1 adaptations in parrots does not mean the same would apply to mammals."},{"rthcId":"RTHC-03812","title":"Effects of the Storage Conditions on the Stability of Natural and Synthetic Cannabis in Biological Matrices for Forensic Toxicology Analysis: An Update from the Literature.","authors":"Djilali, Elias; Pappalardo, Lucia; Posadino, Anna Maria; Giordo, Roberta; Pintus, Gianfranco","year":2022,"journal":"Metabolites, 12(9)","doi":"10.3390/metabo12090801","pmid":"36144208","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03813","title":"The Cannabinoid Receptor Type 1 Positive Allosteric Modulator ZCZ011 Attenuates Naloxone-Precipitated Diarrhea and Weight Loss in Oxycodone-Dependent Mice.","authors":"Dodu, Julien C; Moncayo, Rebecca K; Damaj, M Imad; Schlosburg, Joel E; Akbarali, Hamid I; O'Brien, Lesley D; Kendall, Debra A; Wu, Zhixing; Lu, Dai; Lichtman, Aron H","year":2022,"journal":"The Journal of pharmacology and experimental therapeutics, 380(1), 1-14","doi":"10.1124/jpet.121.000723","pmid":"34625464","tags":["withdrawal","harm-reduction","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"ZCZ011 completely eliminated naloxone-precipitated diarrhea and weight loss in oxycodone-dependent mice and reduced paw flutters by about half. These effects were mediated specifically through CB1 receptors, confirmed by antagonist reversal and CB1 knockout mice. Unlike THC, ZCZ011 did not produce overt cannabimimetic behavioral effects.","whyItMatters":"Current opioid withdrawal treatments have abuse liability or limited effectiveness. A CB1 enhancer that reduces withdrawal without cannabis-like intoxication could offer a new treatment approach.","specificNumbers":"ZCZ011 fully blocked withdrawal-induced diarrhea and weight loss, reduced paw flutters by ~50%, had unreliable effects on head shakes, and did not affect jumping.","methodology":"Mice were made opioid-dependent using escalating oxycodone doses, then given naloxone to precipitate withdrawal. ZCZ011 was tested against withdrawal signs including diarrhea, weight loss, jumping, paw flutters, and head shakes. CB1 and CB2 antagonists and CB1 knockout mice were used to confirm the mechanism.","limitations":"Mouse model only. Did not block all withdrawal signs (jumping was unaffected). Doses used may not translate to humans. Long-term safety of CB1 PAMs is unknown."},{"rthcId":"RTHC-03814","title":"Regulation of DNA Methylation by Cannabidiol and Its Implications for Psychiatry: New Insights from In Vivo and In Silico Models.","authors":"Domingos, Luana B; Silva, Nicole R; Chaves Filho, Adriano J M; Sales, Amanda J; Starnawska, Anna; Joca, Sâmia","year":2022,"journal":"Genes, 13(11)","doi":"10.3390/genes13112165","pmid":"36421839","tags":["cbd","neuroscience","mental-health","genetics"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD appears to regulate DNA methylation both directly, by binding to methylation enzymes (DNMTs), and indirectly, through neurotransmitter-mediated signaling pathways. These epigenetic changes may help explain CBD's broad therapeutic profile across anxiety, depression, and schizophrenia.","whyItMatters":"CBD targets many different receptors and pathways, making it hard to explain its wide-ranging effects. DNA methylation regulation could be a unifying mechanism that ties together CBD's diverse actions on the brain.","specificNumbers":"CBD has been shown to target multiple neurotransmitter receptors, enzymes, transporters, and ion channels. The study identifies DNA methyltransferase enzymes as a new class of CBD targets.","methodology":"Review and analysis combining in vivo animal studies with in silico (computational) molecular modeling to assess CBD's interactions with DNA methylation enzymes and pathways.","limitations":"Much of the evidence is from computational modeling and animal studies. Whether CBD achieves sufficient concentrations in the human brain to meaningfully alter DNA methylation is uncertain."},{"rthcId":"RTHC-03815","title":"Drivers of purchase decisions for cannabis products among consumers in a legalized market: a qualitative study.","authors":"Donnan, Jennifer; Shogan, Omar; Bishop, Lisa; Najafizada, Maisam","year":2022,"journal":"BMC public health, 22(1), 368","doi":"10.1186/s12889-021-12399-9","pmid":"35189856","tags":["legalization","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Among 23 cannabis consumers in Newfoundland and Labrador, five themes drove purchase decisions: price, quality, packaging/warnings, source, and social influences. The price gap between licensed and unlicensed retailers was the most discussed factor keeping consumers in the illicit market. Participants were largely indifferent to packaging and warnings but concerned about excessive regulatory packaging.","whyItMatters":"More than two years after legalization, a large share of Canadian cannabis purchases still came from unlicensed sources. Understanding why helps policymakers make regulated products more competitive.","specificNumbers":"23 participants (30% women, 83% urban). Five broad themes identified. Discussions focused primarily on dried flower products.","methodology":"Qualitative study using semi-structured focus groups and interviews with 23 individuals (30% women, 83% urban) who had purchased cannabis in the past 12 months. Thematic analysis with deductive and inductive coding using NVivo.","limitations":"Small sample from one Canadian province. Predominantly urban and male participants. Qualitative design cannot quantify the relative importance of each factor."},{"rthcId":"RTHC-03816","title":"Public Health Implications of Cannabis Legalization: An Exploration of Adolescent Use and Evidence-Based Interventions.","authors":"Donnelly, Joseph; Young, Michael; Marshall, Brenda; Hecht, Michael L; Saldutti, Elena","year":2022,"journal":"International journal of environmental research and public health, 19(6)","doi":"10.3390/ijerph19063336","pmid":"35329023","tags":["legalization","youth","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"As of June 2021, 36 states had medical cannabis laws and 17 had recreational laws. Review of CDC YRBS, Monitoring the Future, and National Household Survey data showed that increased legal access has not consistently led to increased adolescent use, though cannabis can interfere with adolescent brain development.","whyItMatters":"Understanding whether legalization increases teen cannabis use is critical for public health policy. The review suggests the relationship is more complex than assumed.","specificNumbers":"36 states with medical cannabis laws, 17 with recreational laws, plus territories and DC as of June 2021.","methodology":"Review article synthesizing national survey data (YRBS, Monitoring the Future, NHSDUH) on adolescent cannabis use trends alongside evidence on legalization's impact, with discussion of prevention program strategies.","limitations":"Review article without systematic methodology. National surveys may not capture regional variation. Self-reported adolescent use data may underestimate actual prevalence."},{"rthcId":"RTHC-03817","title":"Racial Equity in Cannabis Policy: Diversity in the Massachusetts Adult-Use Industry at 18-months.","authors":"Doonan, Samantha M; Johnson, Julie K; Firth, Caislin; Flores, Alyssa; Joshi, Spruha","year":2022,"journal":"Cannabis (Albuquerque, N.M.), 5(1), 30-41","doi":"10.26828/cannabis/2022.01.004","pmid":"37287662","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The overall cannabis workforce (4,883 people) was 75% white, 7% Latino, and 6% Black, roughly matching the state labor market. But senior positions (403 people) were significantly less diverse: 84% white, 2% Latino, 5% Black, and 82% male. Women of color had markedly low participation in leadership roles.","whyItMatters":"Cannabis criminalization disproportionately harmed communities of color. Legal markets were intended to create economic opportunities for those communities, but early data suggests leadership benefits are not reaching them.","specificNumbers":"4,883 total workers: 75% white, 7% Latino, 6% Black, 65% male. 403 senior positions: 84% white, 2% Latino, 5% Black, 82% male.","methodology":"Cross-sectional analysis of race/ethnicity and gender from mandatory registration forms submitted to Massachusetts regulators for all workers in licensed adult-use cannabis businesses from October 2018 to April 2020. Negative binomial regression assessed factors associated with senior positions.","limitations":"Only 18 months of data from one state. Registration forms may not capture all diversity dimensions. Does not assess reasons for disparities or effectiveness of specific equity programs."},{"rthcId":"RTHC-03818","title":"Cannabis in Palliative Care: A Systematic Review of Current Evidence.","authors":"Doppen, Marjan; Kung, Stacey; Maijers, Ingrid; John, Mary; Dunphy, Harriette; Townsley, Hermaleigh; Eathorne, Allie; Semprini, Alex; Braithwaite, Irene","year":2022,"journal":"Journal of pain and symptom management, 64(5), e260-e284","doi":"10.1016/j.jpainsymman.2022.06.002","pmid":"35705116","tags":["medical-cannabis","pain","cancer"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Across 52 studies with 4,786 participants, some cannabis products showed positive effects on pain, nausea/vomiting, appetite, sleep, fatigue, and night sweats in cancer patients; appetite and agitation in dementia patients; and appetite and nausea in AIDS patients. However, all evidence was rated very low or low quality.","whyItMatters":"Palliative care patients often use cannabis for symptom management, but clinicians lack high-quality evidence to guide recommendations.","specificNumbers":"52 studies (20 randomized, 32 non-randomized), 4,786 participants. Cancer: 4,491 patients. AIDS: 235. Dementia: 43. Spasticity: 16. All evidence rated \"very low\" or \"low\" quality.","methodology":"Systematic review searching PubMed, Embase, Cochrane, and ClinicalTrials.gov from 1960 to September 2021. Quality assessed using GRADE. Risk of bias evaluated with RoB 2 (RCTs) and ROBINS-I (non-randomized studies). Meta-analysis was not possible due to heterogeneity.","limitations":"All evidence was very low or low quality. Wide variation in cannabis products, doses, and outcome measures prevented meta-analysis. Most participants had cancer, limiting generalizability to other conditions."},{"rthcId":"RTHC-03819","title":"Prevalence and factors associated with self-reported exposure to secondhand cannabis smoke in the United States and Canada in 2019.","authors":"Driezen, Pete; Kaufman, Pamela; Chaiton, Michael; Goodman, Samantha; Hammond, David","year":2022,"journal":"Preventive medicine, 157, 107006","doi":"10.1016/j.ypmed.2022.107006","pmid":"35240141","tags":["respiratory","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Monthly secondhand cannabis smoke exposure at home was reported by 16.9% in Canada, 20.6% in U.S. legal states, and 15.5% in U.S. illegal states. Among multi-unit housing residents, 25.7% in Canada, 26.6% in U.S. legal states, and 20.1% in U.S. illegal states reported smoke incursions from other units or outdoors.","whyItMatters":"As cannabis legalization expands, involuntary exposure to secondhand cannabis smoke in shared housing is a growing public health concern that existing smoke-free policies may not adequately address.","specificNumbers":"33,024 respondents for home exposure analysis. 15,634 multi-unit housing residents for incursion analysis. Exposure rates: 15.5-20.6% for home exposure, 20.1-26.6% for multi-unit housing incursions.","methodology":"Cross-sectional survey from the 2019 International Cannabis Policy Study with 33,024 respondents for home exposure and 15,634 multi-unit housing residents for incursion analysis. Weighted logistic regression assessed associated factors.","limitations":"Self-reported exposure without biomarker verification. Cross-sectional design captures one time point. Cannot distinguish between occasional and heavy exposure."},{"rthcId":"RTHC-03820","title":"Effects of Gibberellin Pre-Treatment on Seed Germination and Seedling Physiology Characteristics in Industrial Hemp under Drought Stress Condition.","authors":"Du, Guanghui; Zhang, Hanxue; Yang, Yang; Zhao, Yinhong; Tang, Kailei; Liu, Feihu","year":2022,"journal":"Life (Basel, Switzerland), 12(11)","doi":"10.3390/life12111907","pmid":"36431042","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03821","title":"Who mixes tobacco with cannabis and does mixing relate to nicotine dependence?","authors":"Dugas, Erika N; Wellman, Robert J; Sylvestre, Marie-Pierre; Bélanger, Richard E; O'Loughlin, Jennifer","year":2022,"journal":"Addictive behaviors, 128, 107254","doi":"10.1016/j.addbeh.2022.107254","pmid":"35085951","tags":["addiction","tobacco","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Of 313 past-year cannabis users (mean age 30.6), 48% reported mixing tobacco with cannabis. Weekly or daily mixing was associated with endorsing 0.5 more ICD-10 nicotine dependence criteria, and less-than-weekly mixing with 0.3 more criteria, after controlling for cigarettes smoked, other tobacco products, and secondhand smoke exposure.","whyItMatters":"Mixing tobacco with cannabis creates an often-overlooked source of nicotine exposure that could make quitting tobacco harder for young adults who use both substances.","specificNumbers":"788 participants total, 313 past-year cannabis users, 150 (48%) reported mixing. Weekly/daily mixers: 0.5 additional ND criteria. Less than weekly mixers: 0.3 additional criteria.","methodology":"Longitudinal cohort study of 788 young adults (2017-2020) using self-report questionnaires. Multivariable logistic regression identified characteristics of mixers. Nicotine dependence was measured using ICD-10 criteria.","limitations":"Self-reported measures. Longitudinal design but nicotine dependence analysis was cross-sectional within the cannabis-using subsample. Canadian context where mixing may be more common than in the U.S."},{"rthcId":"RTHC-03822","title":"Cannabis legalization and driving under the influence of cannabis in a national U.S. Sample.","authors":"Dutra, Lauren M; Farrelly, Matthew; Gourdet, Camille; Bradfield, Brian","year":2022,"journal":"Preventive medicine reports, 27, 101799","doi":"10.1016/j.pmedr.2022.101799","pmid":"35656220","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,249 past-30-day cannabis users, the risk of driving within 3 hours of getting high was 59% lower in recreational states (RR 0.41) and 61% lower in medical-only states (RR 0.39) compared to states without legal cannabis. The exception was frequent users (20+ days/month) in medical states, who showed no difference from users in non-legal states.","whyItMatters":"A common concern about cannabis legalization is that it will increase impaired driving. This study suggests the opposite pattern, at least for self-reported behavior.","specificNumbers":"1,249 past-30-day cannabis users. Recreational states: RR 0.41. Medical states: RR 0.39. Frequent users in recreational states: RR 0.70. Frequent users in medical states: RR 0.87 (not significant).","methodology":"Cross-sectional national survey (2016-2017) of 1,249 past-30-day cannabis users. Logistic regression adjusted for demographics, frequency of use, interaction between use frequency and legal status, calibration weights, and geographic clustering.","limitations":"Self-reported driving behavior may be subject to social desirability bias. Cross-sectional design cannot determine causation. 2016-2017 data predates many states' legalization."},{"rthcId":"RTHC-03823","title":"Management of Poisoned Patients: Implementing a Blended Toxicology Curriculum for Emergency Medicine Residents.","authors":"Dwyer, Madeline; Stobart-Gallagher, Megan; Kilpatrick, Jared; O'Connell, Alanna","year":2022,"journal":"Journal of education & teaching in emergency medicine, 7(2), C1-C32","doi":"10.21980/J8C937","pmid":"37465448","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03824","title":"Understanding the Potential Benefits of Cannabidiol for Patients With Schizophrenia: A Narrative Review.","authors":"Dyck, Garrison J B; Maayah, Zaid H; Eurich, Dean T; Dyck, Jason R B","year":2022,"journal":"Schizophrenia bulletin open, 3(1), sgab053","doi":"10.1093/schizbullopen/sgab053","pmid":"39144756","tags":["cbd","psychosis","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Studies suggest CBD may treat multiple symptom domains of schizophrenia: positive symptoms (hallucinations, delusions), negative symptoms (social withdrawal, flat affect), and cognitive deficits. CBD appears to work through mechanisms distinct from THC, including modulation of anandamide, dopamine, glutamate, and GABA signaling. It may also reduce cannabis cravings and withdrawal in patients who use cannabis.","whyItMatters":"While THC can worsen psychosis, CBD appears to have antipsychotic properties without the metabolic and movement side effects common with conventional antipsychotics.","specificNumbers":"Review covers positive, negative, and cognitive symptom domains. Discusses CBD as both standalone and adjunctive treatment. Examines multiple molecular mechanisms.","methodology":"Narrative review of clinical and preclinical literature on CBD for schizophrenia, covering efficacy, safety, dosing, delivery methods, and molecular mechanisms.","limitations":"Limited number of clinical trials specifically in schizophrenia patients. Optimal dosing and treatment duration remain unclear. Long-term safety data is sparse."},{"rthcId":"RTHC-03825","title":"Making a joint decision: Cannabis as a potential substitute for opioids in obstetrics and gynecology.","authors":"Eichorn, Nicole L; Shult, Hannah T; Kracht, Kelsie D; Berlau, Daniel J","year":2022,"journal":"Best practice & research. Clinical obstetrics & gynaecology, 85(Pt B), 59-67","doi":"10.1016/j.bpobgyn.2022.07.002","pmid":"35970747","tags":["medical-cannabis","pain","pregnancy"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Reports suggest cannabis use is associated with decreased opioid consumption in conditions including ovarian, uterine, endometrial, and cervical cancers, as well as chronic pelvic pain. However, cannabis use during pregnancy has been associated with adverse maternal and neonatal outcomes, though the lack of randomized controlled trials makes it difficult to establish direct causation.","whyItMatters":"Opioid use in gynecology carries significant addiction risk. If cannabis can safely reduce opioid dependence for pain management, it could offer an alternative, but pregnancy considerations add complexity.","specificNumbers":"Review covers opioid-sparing effects across gynecologic malignancies (ovarian, uterine, endometrial, cervical cancers) and chronic pelvic pain.","methodology":"Narrative review synthesizing available literature on cannabis as a potential opioid substitute in gynecological disorders and examining evidence on cannabis use during pregnancy.","limitations":"No randomized controlled trials on cannabis as opioid substitute in gynecology. Association between cannabis and adverse pregnancy outcomes may be confounded by other factors. Review methodology is narrative, not systematic."},{"rthcId":"RTHC-03826","title":"Acetone as Artifact of Analysis in Terpene Samples by HS-GC/MS.","authors":"Elzinga, Sytze; Dominguez-Alonzo, Jorge; Keledjian, Raquel; Douglass, Brad; Raber, Jeffrey C","year":2022,"journal":"Molecules (Basel, Switzerland), 27(18)","doi":"10.3390/molecules27186037","pmid":"36144771","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03827","title":"Cannabis sativa Extract Induces Apoptosis in Human Pancreatic 3D Cancer Models: Importance of Major Antioxidant Molecules Present Therein.","authors":"Emhemmed, Fathi; Zhao, Minjie; Yorulmaz, Selvi; Steyer, Damien; Leitao, Celine; Alignan, Marion; Cerny, Muriel; Paillard, Alexandra; Delacourt, Franck Milone; Julien-David, Diane; Muller, Christian D","year":2022,"journal":"Molecules (Basel, Switzerland), 27(4)","doi":"10.3390/molecules27041214","pmid":"35209003","tags":["cancer","cbd","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD emerged as the primary compound responsible for inducing apoptosis in pancreatic cancer cells. While gemcitabine (standard treatment) only triggered cell cycle arrest in G0/G1, CBD also activated the full cell death signaling cascade, including accumulation of intracellular superoxide ions, mitochondrial membrane disruption, G1 cell cycle arrest, and ultimately apoptosis.","whyItMatters":"Pancreatic cancer has one of the lowest survival rates of any cancer. Finding that CBD triggers more complete cell death pathways than the standard drug gemcitabine highlights its potential as a complementary approach.","specificNumbers":"Cannabis strain #138 used. Three extraction methods compared. CBD identified as key active compound. CBD induced apoptosis through superoxide accumulation, mitochondrial disruption, and G1 arrest.","methodology":"In vitro study using 3D cancer models of human pancreatic tumor cells. Compared three extraction methods for cannabinoid yield and anticancer activity. Tested cannabis extracts against pure CBD and gemcitabine, measuring IC50 values, cell cycle, apoptosis pathways, and oxidative stress.","limitations":"In vitro study, even with 3D models. Concentrations of CBD used may not be achievable in the human pancreas. No animal or human studies conducted. Single cancer cell line tested."},{"rthcId":"RTHC-03828","title":"Clinical outcome analysis of patients with autism spectrum disorder: analysis from the UK Medical Cannabis Registry.","authors":"Erridge, Simon; Kerr-Gaffney, Jess; Holvey, Carl; Coomber, Ross; Barros, Daniela A Riano; Bhoskar, Urmila; Mwimba, Gracia; Praveen, Kavita; Symeon, Chris; Sachdeva-Mohan, Simmi; Sodergren, Mikael H; Rucker, James J","year":2022,"journal":"Therapeutic advances in psychopharmacology, 12, 20451253221116240","doi":"10.1177/20451253221116240","pmid":"36159065","tags":["medical-cannabis","anxiety","sleep","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among 74 ASD patients (mean age 32.7), significant improvements were seen in general quality of life (EQ-5D-5L), sleep quality (SQS), and anxiety (GAD-7) at 1 and 3 months. Quality of life and sleep improvements were sustained at 6 months. Most adverse events were mild (78.4%) or moderate (109.5%), rather than severe (55.4%).","whyItMatters":"Few effective treatments exist for the anxiety, sleep problems, and quality-of-life challenges that commonly accompany autism. This registry data provides early real-world evidence on cannabis-based medicines for these symptoms.","specificNumbers":"74 ASD patients, mean age 32.7 years. Significant improvements in EQ-5D-5L, SQS, and GAD-7 at 1 and 3 months. EQ-5D-5L and SQS improvements sustained at 6 months.","methodology":"Observational case series from the UK Medical Cannabis Registry analyzing patients treated with cannabis-based medicinal products for ASD-related symptoms for at least 1 month. Outcomes measured using validated instruments (GAD-7, SQS, EQ-5D-5L) at baseline, 1, 3, and 6 months.","limitations":"No control group. Subject to attrition bias. Registry data cannot determine whether improvements were from cannabis medicines, placebo effect, or other factors. Relatively small sample size."},{"rthcId":"RTHC-03829","title":"Chronic use of cannabis might impair sensory error processing in the cerebellum through endocannabinoid dysregulation.","authors":"F Amil, Adrián; Rubio Ballester, Belén; Maier, Martina; F M J Verschure, Paul","year":2022,"journal":"Addictive behaviors, 131, 107297","doi":"10.1016/j.addbeh.2022.107297","pmid":"35417840","tags":["cognition","neuroscience","addiction"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Chronic cannabis use causes CB1 receptor downregulation in the cerebellum, which the researchers propose leads to a generalized underestimation of sensory errors. Their computational model successfully reproduced the decreased implicit motor adaptation observed in chronic cannabis users, supporting the hypothesis that error processing in the cerebellar cortex is impaired.","whyItMatters":"Motor coordination problems in chronic cannabis users are well documented but poorly understood. This provides a specific mechanistic explanation linking CB1 receptor changes to cerebellar error processing.","specificNumbers":"Computational model replicated decreased implicit adaptation seen in chronic cannabis users. CB1 receptor downregulation documented across cerebellar regions.","methodology":"Literature review combining evidence on chronic cannabis effects, cerebellar endocannabinoid system function, and motor learning. Complemented by a computational model performing a motor adaptation task to test the hypothesis.","limitations":"The hypothesis is supported by indirect evidence and computational modeling, not direct measurement of cerebellar error signals in cannabis users. The model simplifies complex cerebellar processing."},{"rthcId":"RTHC-03830","title":"Acidic Cannabinoids Suppress Proinflammatory Cytokine Release by Blocking Store-operated Calcium Entry.","authors":"Faouzi, Malika; Wakano, Clay; Monteilh-Zoller, Mahealani K; Neupane, Ram P; Starkus, John G; Neupane, Jayanti Bhandari; Cullen, Aaron J; Johnson, Brandon E; Fleig, Andrea; Penner, Reinhold","year":2022,"journal":"Function (Oxford, England), 3(4), zqac033","doi":"10.1093/function/zqac033","pmid":"35910331","tags":["inflammation","pain","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Several minor cannabinoids, mainly the carboxylic acid derivatives and especially CBGA, demonstrated high potency in blocking store-operated calcium entry (SOCE) in immune cell lines. This inhibition reduced NFAT activation and IL-2 production in human T lymphocytes. Notably, CBD and THC were largely ineffective at blocking SOCE.","whyItMatters":"SOCE is critical for T cell activation, inflammation, and chronic pain. Identifying which specific cannabinoids target this pathway helps explain why whole-plant extracts may have anti-inflammatory effects that pure CBD or THC alone do not.","specificNumbers":"Multiple cannabinoids tested across several immune cell lines. CBGA showed the highest potency. CBD and THC were largely ineffective at inhibiting SOCE.","methodology":"In vitro study testing whole-plant cannabis extracts and individual pure cannabinoids on store-operated calcium entry across several immune cell lines. Measured calcium currents, NFAT activation, and IL-2 production.","limitations":"In vitro study only. Acidic cannabinoids are unstable and convert to their neutral forms with heat (decarboxylation), so achieving these effects through smoking or vaping would be unlikely."},{"rthcId":"RTHC-03831","title":"Combined effect of alcohol and cannabis on simulated driving.","authors":"Fares, Andrew; Wickens, Christine M; Mann, Robert E; Di Ciano, Patricia; Wright, Madison; Matheson, Justin; Hasan, Omer S M; Rehm, Jurgen; George, Tony P; Samokhvalov, Andriy V; Shuper, Paul A; Huestis, Marilyn A; Stoduto, Gina; Brown, Timothy; Stefan, Cristiana; Rubin-Kahana, Dafna Sara; Le Foll, Bernard; Brands, Bruna","year":2022,"journal":"Psychopharmacology, 239(5), 1263-1277","doi":"10.1007/s00213-021-05773-3","pmid":"33544195","tags":["driving","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The combination of alcohol (target BAC 0.08%) and cannabis (12.5% THC) significantly increased standard deviation of lateral position (weaving) compared to placebo and to either drug alone. Reaction time also increased. Subjective effects were greater than with either drug alone, particularly later in the session. Critically, participants seemed unaware of their increased impairment on a driving ability questionnaire.","whyItMatters":"Alcohol and cannabis are the two most commonly detected drugs in seriously and fatally injured drivers. Understanding their combined effects is critical for road safety messaging.","specificNumbers":"Cannabis: 12.5% THC smoked. Alcohol: target BrAC 0.08%. Combined condition significantly increased weaving vs placebo (p<0.001), vs alcohol alone (p=0.029), and vs cannabis alone (p=0.032).","methodology":"Within-subjects, double-blind, double-dummy, placebo-controlled randomized clinical trial with 19-29-year-old cannabis users (1-7 days/week). Four sessions: placebo/placebo, alcohol/placebo, placebo/cannabis, alcohol/cannabis. Simulated driving assessed with single and dual tasks.","limitations":"Simulated driving may not fully replicate real-world conditions. Young, experienced cannabis users may not represent all populations. Single dose level tested for each substance."},{"rthcId":"RTHC-03832","title":"Changes in Medical Cannabis Patient Status before and after Cannabis Legalization in California: Associations with Cannabis and Other Drug Use.","authors":"Fedorova, Ekaterina V; Ataiants, Janna; Wong, Carolyn F; Iverson, Ellen; Lankenau, Stephen E","year":2022,"journal":"Journal of psychoactive drugs, 54(2), 129-139","doi":"10.1080/02791072.2021.1926604","pmid":"34044753","tags":["legalization","addiction","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Four transition groups emerged: stayed medical patients (MCP), became patients (Into MCP), left patient status (Out of MCP), and non-patient users (NPU). Cannabis days, concentrate use, and driving under influence were highest among MCP, increased for Into MCP, and decreased for Out of MCP. Most other drug use outcomes decreased significantly by wave 4. Self-reported medical use was associated with more frequent cannabis use but less problematic cannabis and other drug use.","whyItMatters":"Understanding how legalization reshapes medical vs recreational cannabis use patterns helps policymakers evaluate the impact of dual medical-recreational markets.","specificNumbers":"64.8% male, 44.1% Hispanic/Latinx. Four transition groups tracked from pre-legalization (wave 1) to post-legalization (wave 4).","methodology":"Longitudinal cohort of 18-26-year-old cannabis users recruited in Los Angeles in 2014-15 (pre-legalization) and followed to post-legalization. Four waves of data collection examining changes in medical patient status and associated substance use patterns.","limitations":"Self-reported data. Los Angeles-specific findings may not generalize. Attrition between waves. Cannot separate legalization effects from maturation effects."},{"rthcId":"RTHC-03833","title":"Randomized controlled trial of motivational interviewing for alcohol and cannabis use within a predominantly Hispanic adolescent sample.","authors":"Feldstein Ewing, Sarah; Bryan, Angela D; Dash, Genevieve F; Lovejoy, Travis I; Borsari, Brian; Schmiege, Sarah J","year":2022,"journal":"Experimental and clinical psychopharmacology, 30(3), 287-299","doi":"10.1037/pha0000445","pmid":"33749294","tags":["youth","addiction","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 448 adolescents (347 Hispanic, 101 non-Hispanic white, ages 13-18), those receiving motivational interviewing showed greater reductions in alcohol use compared to alcohol and cannabis education (ACE) at 6 months. Treatment response was comparable across ethnicities. While MI did not directly reduce cannabis use, increased motivation showed an indirect effect on cannabis use reduction.","whyItMatters":"Hispanic youth are one of the fastest-growing minority groups, yet little is known about their response to evidence-based addiction interventions. This trial shows MI works equally well regardless of ethnicity.","specificNumbers":"448 adolescents (77.5% Hispanic), ages 13-18. MI showed greater alcohol use reductions vs ACE at 6 months. Motivation and self-efficacy identified as mechanisms. Indirect effect of motivation on cannabis reduction was significant.","methodology":"Randomized controlled trial comparing two 1-hour individual sessions of motivational interviewing (MI) vs alcohol and cannabis education (ACE) in substance-using adolescents. 6-month follow-up examining outcomes and mechanisms of change.","limitations":"Only 6-month follow-up. Self-reported substance use. Active control (ACE) rather than no-treatment control. Mechanisms for Hispanic adolescent cannabis use reduction remain underexplored."},{"rthcId":"RTHC-03834","title":"Tobacco cessation among smokers under substance use treatment for alcohol and/or cannabis: study protocol and pilot study.","authors":"Feliu, Ariadna; Fernández, Esteve; Castellano, Yolanda; Enríquez, Marta; Saura, Judith; Cabezas, Carmen; Colom, Joan; Suelves, Josep M; Pla, Margarida; Parejo, Mar; Mondon, Sílvia; Barrio, Pablo; Andreu, Magalí; Raich, Antonia; Bernabeu, Jordi; Vilaplana, Jordi; Roca, Xavier; Bautista, Pablo; Guydish, Joseph; Martínez, Cristina","year":2022,"journal":"Addiction science & clinical practice, 17(1), 66","doi":"10.1186/s13722-022-00348-9","pmid":"36451226","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03835","title":"What is the likelihood that underage youth can obtain marijuana from licensed recreational marijuana outlets in California, a state where recreational marijuana is legal?","authors":"Fell, James C; Toomey, Traci; Eichelberger, Angela H; Kubelka, Julie; Schriemer, Daniel; Erickson, Darin","year":2022,"journal":"Journal of safety research, 82, 102-111","doi":"10.1016/j.jsr.2022.05.002","pmid":"36031237","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"100% of the 50 randomly selected licensed recreational marijuana outlets in California required pseudo-underage patrons to show valid age identification before entry. No outlet allowed entry without ID verification.","whyItMatters":"A key concern about cannabis legalization is underage access. This study provides evidence that licensed retailers have strong incentives to comply with age verification requirements.","specificNumbers":"50 randomly selected licensed outlets. 100% compliance rate with age verification. Study conducted in California, which legalized recreational cannabis in 2016.","methodology":"Compliance check study sending pseudo-underage patrons to 50 randomly selected licensed recreational cannabis outlets across California to test whether they could enter without showing valid age identification.","limitations":"Tested entry, not actual purchase. Only licensed outlets were tested. Pseudo-underage patrons looked young but were of legal age. Does not capture fake ID attempts or illicit sources."},{"rthcId":"RTHC-03836","title":"Increasing prevalence of illicit drug use among employees at Swedish workplaces over a 25-year period.","authors":"Feltmann, Kristin; Villén, Tomas; Beck, Olof; Gripenberg, Johanna","year":2022,"journal":"European journal of public health, 32(5), 760-765","doi":"10.1093/eurpub/ckac105","pmid":"36006016","tags":["workplace","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Over 25 years and hundreds of thousands of workplace urine samples from across Sweden, the proportion testing positive for illicit drugs quadrupled — from 1.3% in 1994 to 5.6% in 2019. The increase wasn't steady; it progressed in stepwise phases of linear increase followed by plateaus, with the plateau periods becoming shorter over time.\n\nThe drug breakdown shifted dramatically. Cannabis (THC) overtook amphetamine as the most commonly detected substance after 2007 and drove most of the increase in recent years. While amphetamine detections declined, cannabis positives climbed consistently. Other drugs — opiates, cocaine, benzodiazepines — remained relatively stable.\n\nThe dataset grew enormously over time (from 3,411 samples in 1994 to 60,315 in 2019), reflecting the expansion of workplace drug testing programs across Swedish industries. Sweden maintained strict drug policies throughout this period, making the increase in positive results notable in a prohibitionist context.","whyItMatters":"Sweden is one of Europe's most restrictive countries on drug policy — this isn't Colorado or Amsterdam. The fact that positive cannabis tests quadrupled over 25 years despite strict prohibition challenges the assumption that tough drug laws suppress use. Cannabis use increased among the Swedish workforce regardless.\n\nThe post-2007 cannabis surge is particularly interesting because it coincided with broader European cannabis potency increases (RTHC-00052) and may reflect cultural shifts in attitudes toward cannabis even in prohibitionist countries. For workplace policy internationally, this data suggests cannabis use among workers is increasing regardless of the legal framework.","specificNumbers":"• Positive drug tests: 1.3% (1994) → 5.6% (2019)\n• Cannabis: became dominant detected substance after 2007\n• Sample volume grew: 3,411 (1994) → 60,315 (2019)\n• Cannabis positive rate increased while amphetamine decreased\n• Pattern: stepwise increases with shortening plateau periods","methodology":"Analysis of workplace urine drug testing data from occupational health services across Sweden over a 25-year period (1994-2019). Samples tested for cannabis (THC), amphetamine, opiates, cocaine, and benzodiazepines. Trends analyzed over time by substance.","limitations":"Workplace drug testing samples are not random population samples — testing intensity and selection criteria changed over time. The dramatic increase in sample volume makes direct trend comparison difficult. Sweden-specific findings may not generalize to other countries. Urine testing detects past use, not impairment. Cannot determine whether positive tests reflect increased use, decreased caution, or changes in cannabis potency affecting detection."},{"rthcId":"RTHC-03837","title":"Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice.","authors":"Ferrarini, Eduarda Gomes; Paes, Rodrigo Sebben; Baldasso, Gabriela Mantovani; de Assis, Pollyana Mendonça; Gouvêa, Murilo Chaves; Cicco, Paola De; Raposo, Nádia Rezende Barbosa; Capasso, Raffaele; Moreira, Eduardo Luiz Gasnhar; Dutra, Rafael Cypriano","year":2022,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 154, 113552","doi":"10.1016/j.biopha.2022.113552","pmid":"35988425","tags":["pain","medical-cannabis","cbd","anxiety","depression"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Oral broad-spectrum cannabis oil (0.1-3 mg/kg) inhibited both mechanical hyperalgesia and thermal allodynia in a single dose. Repeated daily treatment for 14 days maintained pain reduction and also reduced depressive-like behavior. The oil worked through spinal, supraspinal, and peripheral routes, with direct spinal and supraspinal administration completely inhibiting pain responses.","whyItMatters":"Fibromyalgia affects millions and has limited treatment options. This study suggests that low-THC cannabis oil could address multiple symptom dimensions without the psychoactive effects of high-THC products.","specificNumbers":"Effective at doses as low as 0.1 mg/kg orally. Single dose on day 4 inhibited pain. Four-day treatment reduced pain 1 hour after each dose. 14-day treatment mitigated pain, thermal sensitivity, and depressive behavior.","methodology":"Reserpine-induced fibromyalgia model in mice. Tested single and repeated doses of broad-spectrum cannabis oil (low THC) via oral, intraplantar, spinal, and supraspinal administration. Measured mechanical hyperalgesia, thermal allodynia, depressive behavior, anxiety, and locomotor activity.","limitations":"Mouse model of fibromyalgia may not fully replicate the human condition. Reserpine-induced pain is one model among several. Doses may not translate directly to humans."},{"rthcId":"RTHC-03838","title":"Impact of Housing First on Psychiatric Symptoms, Substance Use, and Everyday Life Skills Among People Experiencing Homelessness.","authors":"Ferreiro, Inés Campo; Cuadra, Maria Assumpta Rigol; Serqueda, Francesca Asensio; Abad, Josep Maria Haro","year":2022,"journal":"Journal of psychosocial nursing and mental health services, 60(9), 46-55","doi":"10.3928/02793695-20220316-01","pmid":"35316121","tags":["addiction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The Housing First group (n=46) showed significantly lower alcohol and cannabis use at 21 months compared to the treatment-as-usual group (n=41). Among the subgroup with severe mental illness, Housing First participants also showed significant improvements in psychotic symptoms, anxiety, depression, and social relations.","whyItMatters":"Housing First provides stable housing without requiring sobriety first. This study shows that providing housing stability can itself lead to reduced substance use, challenging the traditional treatment-first approach.","specificNumbers":"87 participants total (46 HF, 41 TAU). Significant improvements in alcohol and cannabis use at 21 months. Subgroup with severe mental illness showed improvements across psychotic symptoms, anxiety, depression, and social relations.","methodology":"Unblinded randomized controlled trial comparing Housing First (HF, n=46) to treatment as usual (TAU, n=41) among people experiencing homelessness. Outcomes measured at baseline, 8, and 21 months using standardized quantitative measures.","limitations":"Unblinded design. Relatively small sample. Cannot separate the effect of housing from other support services provided. Single-site study."},{"rthcId":"RTHC-03839","title":"The Cannabinoid Receptor Agonist, WIN-55212-2, Suppresses the Activation of Proinflammatory Genes Induced by Interleukin 1 Beta in Human Astrocytes.","authors":"Fields, Jerel Adam; Swinton, Mary K; Montilla-Perez, Patricia; Ricciardelli, Eugenia; Telese, Francesca","year":2022,"journal":"Cannabis and cannabinoid research, 7(1), 78-92","doi":"10.1089/can.2020.0128","pmid":"33998879","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Transcriptomic analysis showed WIN treatment robustly inhibited the inflammatory response triggered by IL1-beta in human astrocytes. The anti-inflammatory effects were linked to regulation of kinase pathways and gene targets of neuroprotective transcription factors (PPAR and SMAD). Surprisingly, selective CB1 and PPAR antagonists did not block WIN's effects, suggesting alternative receptor involvement.","whyItMatters":"Astrocyte dysfunction drives neuroinflammation in multiple neurodegenerative diseases. Identifying how cannabinoids suppress astrocyte inflammation opens potential therapeutic avenues for conditions like Alzheimer's and MS.","specificNumbers":"WIN treatment induced substantial gene expression changes and robustly inhibited IL1-beta-induced inflammatory response. Effects were dose-dependent but independent of CB1 and PPAR antagonism.","methodology":"In vitro study using primary human astrocyte cultures. RNA-seq transcriptomic analysis measured gene expression changes after IL1-beta stimulation with and without WIN pretreatment. Dose-response and receptor antagonist experiments conducted with qPCR.","limitations":"In vitro study with isolated astrocytes. The specific alternative receptor mediating WIN's effects was not identified. WIN is a synthetic agonist, so results may not directly apply to plant cannabinoids."},{"rthcId":"RTHC-03840","title":"Outreach programs to improve life circumstances and prevent further adverse developmental trajectories of at-risk youth in OECD countries: A systematic review.","authors":"Filges, Trine; Dalgaard, Nina T; Viinholt, Bjørn C A","year":2022,"journal":"Campbell systematic reviews, 18(4), e1282","doi":"10.1002/cl2.1282","pmid":"36908846","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03841","title":"Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis.","authors":"Filippini, Graziella; Minozzi, Silvia; Borrelli, Francesca; Cinquini, Michela; Dwan, Kerry","year":2022,"journal":"The Cochrane database of systematic reviews, 5(5), CD013444","doi":"10.1002/14651858.CD013444.pub2","pmid":"35510826","tags":["medical-cannabis","pain","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Nabiximols probably increases the number of people reporting significant spasticity reduction (OR 2.51, moderate certainty). For pain, only one small trial was available (very low certainty). Cannabinoids probably increase self-reported health improvement (OR 1.80, moderate certainty) but may slightly increase treatment discontinuation due to adverse events, nervous system disorders, and psychiatric disorders.","whyItMatters":"This is the gold-standard Cochrane review on cannabinoids for MS symptoms, providing the most authoritative evidence summary available for clinical decision-making.","specificNumbers":"25 RCTs, 3,763 participants (2,290 received cannabinoids). 50-88% female. Spasticity: OR 2.51, 216 more per 1,000 benefiting. Treatment discontinuation: OR 2.41, 39 more per 1,000 stopping. Health improvement: OR 1.80, 113 more per 1,000 reporting benefit.","methodology":"Cochrane systematic review of 25 RCTs (3,763 participants) comparing nabiximols, synthetic cannabinoids, oral THC extract, or inhaled cannabis against placebo. Searched databases through December 2021. Evidence quality assessed using GRADE.","limitations":"Most evidence was from nabiximols studies. Only limited data on other formulations. Short study durations (3-48 weeks). Pain evidence came from just one small trial."},{"rthcId":"RTHC-03842","title":"Construct validity of DSM-5 cannabis use disorder diagnosis and severity levels in adults with problematic substance use.","authors":"Fink, David S; Shmulewitz, Dvora; Mannes, Zachary L; Stohl, Malka; Livne, Ofir; Wall, Melanie; Hasin, Deborah S","year":2022,"journal":"Journal of psychiatric research, 155, 387-394","doi":"10.1016/j.jpsychires.2022.09.016","pmid":"36182768","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"DSM-5 CUD and all severity levels were associated with cannabis use validators (days used, self-reported problem use, craving). Severe CUD was additionally associated with other psychiatric disorders and social impairment. Mild and moderate CUD were associated only with cannabis-specific validators, supporting them as clinically distinct from severe CUD.","whyItMatters":"The DSM-5 changed how cannabis use disorder is diagnosed (combining abuse and dependence, adding withdrawal and craving). Validating these changes ensures clinicians are using a meaningful diagnostic framework.","specificNumbers":"392 past-year cannabis users. Severe CUD associated with validators across all domains (cannabis use, psychiatric, social). Mild and moderate CUD associated with cannabis-specific validators only.","methodology":"Study of 392 past-year cannabis users with problematic substance use recruited from a research setting and an inpatient treatment program. Semi-structured clinician-administered diagnostic interviews assessed DSM-5 CUD. Regression models tested associations with validators across cannabis use, psychopathology, and functional impairment domains.","limitations":"Sample recruited from clinical and research settings, not the general population. Cross-sectional design cannot assess predictive validity. Predominantly problematic substance users."},{"rthcId":"RTHC-03843","title":"Exploring determinants of agonist efficacy at the CB1 cannabinoid receptor: Analogues of the synthetic cannabinoid receptor agonist EG-018.","authors":"Finlay, David B; Nguyen, Thuy; Gamage, Thomas F; Chen, Shuli; Barrus, Daniel G; Patel, Purvi R; Thomas, Brian F; Wiley, Jenny L; Zhang, Yanan; Glass, Michelle","year":2022,"journal":"Pharmacology research & perspectives, 10(1), e00901","doi":"10.1002/prp2.901","pmid":"35041297","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03844","title":"Co-use of Tobacco Products and Cannabis among Veterans: A Preliminary Investigation of Prevalence and Associations with Mental Health Outcomes.","authors":"Fitzke, Reagan E; Davis, Jordan P; Pedersen, Eric R","year":2022,"journal":"Journal of psychoactive drugs, 54(3), 250-257","doi":"10.1080/02791072.2021.1956026","pmid":"34334112","tags":["addiction","ptsd","mental-health","depression","anxiety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Past 30-day co-users of tobacco and cannabis endorsed significantly higher levels of stress, PTSD, depression, and anxiety compared to singular product users. Lifetime and past 30-day rates of both tobacco and cannabis use were high among OEF/OIF veterans.","whyItMatters":"Veterans have elevated rates of both tobacco and cannabis use. Understanding that co-use is associated with worse mental health symptoms could inform integrated treatment approaches.","specificNumbers":"1,230 OEF/OIF veterans surveyed. Co-users had significantly higher stress, PTSD, depression, and anxiety scores than single-substance users.","methodology":"Cross-sectional survey of 1,230 OEF/OIF veterans examining co-use patterns of tobacco products (cigarettes, vaping) and cannabis, with validated measures of mental health symptoms.","limitations":"Cross-sectional design cannot determine causation. Self-reported substance use and mental health. Convenience sample of veterans may not represent all service members."},{"rthcId":"RTHC-03845","title":"Medicinal cannabis in children and adolescents with autism spectrum disorder: A scoping review.","authors":"Fletcher, Sarah; Pawliuk, Colleen; Ip, Angie; Huh, Linda; Rassekh, S Rod; Oberlander, Tim F; Siden, Harold","year":2022,"journal":"Child: care, health and development, 48(1), 33-44","doi":"10.1111/cch.12909","pmid":"34403168","tags":["medical-cannabis","youth","cbd"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Eight completed studies (five ongoing) showed substantial behavior and symptom improvement with medicinal cannabis in pediatric ASD, with 61-93% of subjects showing benefit. Up to 80% of participants in studies tracking medication changes reduced their concurrent psychotropic medication use. Adverse events were reported in up to 27%, including two psychotic events.","whyItMatters":"Parents of children with autism increasingly seek medicinal cannabis guidance from clinicians, but evidence to support these decisions has been limited to small, uncontrolled studies.","specificNumbers":"8 completed studies, 5 ongoing. 61-93% showed benefit. Up to 80% reduced concurrent medications. Up to 27% had adverse events. 2 participants experienced psychotic events.","methodology":"Scoping review searching six databases and grey literature through January 2020 for studies where at least 50% of participants had ASD and at least 50% were under 18. Any study design was eligible.","limitations":"All completed studies were retrospective cohort or observational. No randomized controlled trials. High variability in cannabis products used. Potential reporting bias toward positive outcomes."},{"rthcId":"RTHC-03846","title":"Selective serotonin reuptake inhibitors in the treatment of depression, anxiety, and post-traumatic stress disorder in substance use disorders: a Bayesian meta-analysis.","authors":"Fluyau, Dimy; Mitra, Paroma; Jain, Ankit; Kailasam, Vasanth Kattalai; Pierre, Christopher G","year":2022,"journal":"European journal of clinical pharmacology, 78(6), 931-942","doi":"10.1007/s00228-022-03303-4","pmid":"35246699","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03847","title":"Cannabis and Cannabinoids in Reproduction and Fertility: Where We Stand.","authors":"Fonseca, Bruno M; Rebelo, Irene","year":2022,"journal":"Reproductive sciences (Thousand Oaks, Calif.), 29(9), 2429-2439","doi":"10.1007/s43032-021-00588-1","pmid":"33970442","tags":["pregnancy","sex-differences","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"THC indirectly decreases GnRH secretion from the hypothalamus, leading to disruptions in multiple reproductive hormones. This affects folliculogenesis, ovulation, and sperm maturation and function. While generally accepted that cannabinoid consumption impacts fertility, most strong evidence comes from preclinical rather than human studies.","whyItMatters":"Cannabis use is highest among young adults of reproductive age. Understanding its effects on fertility is important for those planning families.","specificNumbers":"THC affects GnRH, folliculogenesis, ovulation, and sperm function. Cannabinoid receptors are present throughout the reproductive system.","methodology":"Narrative review of clinical and preclinical evidence on cannabis effects on the endocannabinoid system in reproduction, the hypothalamic-pituitary-gonadal axis, male and female fertility, and teratogenicity.","limitations":"Strong evidence mostly from animal studies. Human clinical data on fertility outcomes is limited and often confounded by other factors. Dose-response relationships in humans are poorly characterized."},{"rthcId":"RTHC-03848","title":"On-Line Solid Phase Extraction High Performance Liquid Chromatography Method Coupled With Tandem Mass Spectrometry for the Therapeutic Monitoring of Cannabidiol and 7-Hydroxy-cannabidiol in Human Serum and Saliva.","authors":"Franco, Valentina; Palmisani, Michela; Marchiselli, Roberto; Crema, Francesca; Fattore, Cinzia; De Giorgis, Valentina; Varesio, Costanza; Rota, Paola; Dibari, Vincenza Flora; Perucca, Emilio","year":2022,"journal":"Frontiers in pharmacology, 13, 915004","doi":"10.3389/fphar.2022.915004","pmid":"35814197","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03849","title":"Cannabidiol as a treatment for arthritis and joint pain: an exploratory cross-sectional study.","authors":"Frane, Nicholas; Stapleton, Erik; Iturriaga, Cesar; Ganz, Maximillian; Rasquinha, Vijay; Duarte, Robert","year":2022,"journal":"Journal of cannabis research, 4(1), 47","doi":"10.1186/s42238-022-00154-9","pmid":"35999581","tags":["pain","cbd","medical-cannabis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"CBD use was associated with improvements in pain (83%), physical function (66%), and sleep quality (66%). The overall cohort reported a 44% average pain reduction after CBD use. 60.5% of respondents reduced or stopped other medications, including anti-inflammatories (31.1% reduced, 17.8% stopped), acetaminophen (18.2% reduced, 17.8% stopped), and opioids (8.6% reduced, 18.9% stopped). Osteoarthritis patients showed greater improvements than those with rheumatoid or autoimmune arthritis.","whyItMatters":"54 million Americans have arthritis and many rely on medications with significant side effects. CBD's potential to reduce medication dependency, especially opioids, warrants further investigation.","specificNumbers":"428 respondents. Pain improvement: 83%. Average pain reduction: 44% (p<0.001). Physical function improvement: 66%. Sleep improvement: 66%. Medication reduction/cessation: 60.5%.","methodology":"Cross-sectional anonymous online survey of 428 self-selected arthritis patients recruited through the Arthritis Foundation, social media, and other channels (May-November 2020). Assessed perceived CBD effects and medication changes.","limitations":"Self-selected convenience sample. No control group. Self-reported outcomes subject to recall and placebo bias. No verification of CBD products used or actual medication changes."},{"rthcId":"RTHC-03850","title":"Cannabidiol impairs fear memory reconsolidation in female rats through dorsal hippocampus CB1 but not CB2 receptor interaction.","authors":"Franzen, Jaqueline M; Vanz, Felipe; Werle, Isabel; Guimarães, Francisco S; Bertoglio, Leandro J","year":2022,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 64, 7-18","doi":"10.1016/j.euroneuro.2022.08.002","pmid":"36049316","tags":["cbd","ptsd","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Systemic CBD reduced freezing behavior for over a week in female rats when given during the reconsolidation window (within 6 hours of memory reactivation). The effect depended on memory destabilization and was mediated by CB1 (not CB2) receptors in the CA1 region of the dorsal hippocampus. Direct hippocampal CBD application reproduced the systemic effects. Critically, CBD-attenuated memories did not show reinstatement.","whyItMatters":"Women are more susceptible to PTSD and anxiety disorders. This is the first study showing CBD can disrupt fear memory reconsolidation in females, with a specific mechanism in the hippocampus.","specificNumbers":"CBD reduced freezing for over 1 week. Effect limited to within 6 hours post-retrieval. CB1 (not CB2) receptors in dorsal hippocampus CA1 mediated the effect. No reinstatement of attenuated memories.","methodology":"Contextual fear conditioning in female rats. Tested systemic and direct hippocampal CBD administration during the reconsolidation window. Used CB1 and CB2 receptor antagonists to identify the mechanism. Assessed reinstatement to distinguish from extinction.","limitations":"Female rat model only. Fear conditioning is a simplified model of human PTSD. CBD doses and hippocampal concentrations may not translate to humans. Estrous cycle effects were not assessed."},{"rthcId":"RTHC-03851","title":"Cannabis smoking increases the risk of suicide ideation and suicide attempt in young individuals of 11-21 years: A systematic review and meta-analysis.","authors":"Fresán, Ana; Dionisio-García, Diana María; González-Castro, Thelma Beatriz; Ramos-Méndez, Miguel Ángel; Castillo-Avila, Rosa Giannina; Tovilla-Zárate, Carlos Alfonso; Juárez-Rojop, Isela Esther; López-Narváez, María Lilia; Genis-Mendoza, Alma Delia; Nicolini, Humberto","year":2022,"journal":"Journal of psychiatric research, 153, 90-98","doi":"10.1016/j.jpsychires.2022.06.053","pmid":"35810604","tags":["youth","mental-health","depression"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 20 studies with 34,859 youth, cannabis smokers had significantly higher risk of suicide attempt (OR 2.33), suicidal ideation (OR 2.04), and suicide planning (OR 1.67) compared to non-users. Subgroup analysis showed American teens had particularly increased risk of suicidal ideation. Meta-regression found that younger age was associated with greater risk of suicide attempt.","whyItMatters":"Cannabis is the most frequently consumed drug among young people worldwide. Quantifying its association with suicide behaviors in this vulnerable age group informs prevention priorities.","specificNumbers":"34,859 youth for suicide attempts (OR 2.33), 26,937 for suicidal ideation (OR 2.04), 9,054 for suicide planning (OR 1.67). All associations statistically significant. High heterogeneity across studies (I2 >90%).","methodology":"Systematic review and meta-analysis searching PubMed, EBSCO, and Science Direct through July 2021. Calculated pooled odds ratios with 95% confidence intervals for suicide attempt, suicidal ideation, and suicide planning in cannabis users aged 11-21.","limitations":"High heterogeneity (I2 >90%) across studies. Most studies were cross-sectional, preventing causal conclusions. Cannot determine whether cannabis causes suicidality or both share underlying risk factors."},{"rthcId":"RTHC-03852","title":"Improved Therapeutic Efficacy of CBD with Good Tolerance in the Treatment of Breast Cancer through Nanoencapsulation and in Combination with 20(S)-Protopanaxadiol (PPD).","authors":"Fu, Jingxin; Zhang, Kunfeng; Lu, Likang; Li, Manzhen; Han, Meihua; Guo, Yifei; Wang, Xiangtao","year":2022,"journal":"Pharmaceutics, 14(8)","doi":"10.3390/pharmaceutics14081533","pmid":"35893789","tags":["cancer","cbd","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD and 20(S)-Protopanaxadiol (PPD, from ginseng) co-loaded into liposomes (mean particle size 138.8 nm) achieved 82.2% tumor inhibition in mice bearing breast tumors (4T1 cells) with good tolerance. However, adding glucose-targeting modifications did not significantly improve the results.","whyItMatters":"CBD has shown anti-tumor potential but faces delivery challenges. Combining it with PPD in nanoparticles may enhance efficacy while maintaining tolerability, and CBD may also address cancer-associated pain, anxiety, and cachexia.","specificNumbers":"Liposome size: 138.8 nm. Tumor inhibition rate: 82.2% with good dose dependence. In vivo mouse model using 4T1 breast cancer cells.","methodology":"Liposomal nanoparticle formulation study with in vivo testing in BALB/c mice bearing 4T1 breast tumors. Compared CBD-PPD liposomes to glycosyl-modified versions targeting GLUT1 receptors on tumor cells.","limitations":"Mouse model only. Single tumor type (4T1). Glucose-targeting modification did not improve results. Human pharmacokinetics and tumor penetration would differ from mice."},{"rthcId":"RTHC-03853","title":"Cannabis significantly alters DNA methylation of the human ovarian follicle in a concentration-dependent manner.","authors":"Fuchs Weizman, Noga; Wyse, Brandon A; Montbriand, Janice; Jahangiri, Sahar; Librach, Clifford L","year":2022,"journal":"Molecular human reproduction, 28(7)","doi":"10.1093/molehr/gaac022","pmid":"35674367","tags":["pregnancy","genetics"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Among 14 matched case-control patients, cannabis-exposed ovarian follicle cells showed 3,679 differentially methylated DNA sites, with two-thirds affecting coding genes. A hotspot on chromosome 9 involved a zinc-finger protein (ZFP37) and long non-coding RNA. Pathway analysis revealed enrichment in G protein-coupled receptor signaling, cellular transport, immune response, and proliferation. Sixteen genomic features changed in a concentration-dependent manner.","whyItMatters":"This is the first DNA methylation profile of human ovarian follicle cells exposed to cannabis. With increasing cannabis use among women of childbearing age, understanding epigenetic effects on egg development is critical.","specificNumbers":"14 matched case-control patients. 3,679 differentially methylated sites. 2,214 differentially methylated genomic features. 71 differentially methylated regions. 16 genomic features changed dose-dependently.","methodology":"Case-control study measuring whole-genome DNA methylation in granulosa cells from 14 matched patients. Cannabis exposure determined by LC-MS/MS measurement of five phytocannabinoids in follicular fluid. Methylation measured using Illumina EPIC kit.","limitations":"Small sample size (14 patients). Cannot determine whether methylation changes affect fertility or offspring outcomes. Cross-sectional design cannot track changes over time."},{"rthcId":"RTHC-03854","title":"Attention-Deficit/Hyperactivity Disorder and Alcohol and Other Substance Use Disorders in Young Adulthood: Findings from a Canadian Nationally Representative Survey.","authors":"Fuller-Thomson, Esme; Lewis, Danielle A; Agbeyaka, Senyo","year":2022,"journal":"Alcohol and alcoholism (Oxford, Oxfordshire), 57(3), 385-395","doi":"10.1093/alcalc/agab048","pmid":"34343246","tags":["addiction","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"After adjusting for sociodemographics, childhood adversities, and mental health, young adults with ADHD had higher odds of alcohol use disorders (OR 1.38), cannabis use disorders (OR 1.46), other drug use disorders (OR 2.07), and any substance use disorder (OR 1.69). Depression and anxiety history explained the largest portion of the ADHD-substance use disorder relationship.","whyItMatters":"Understanding that ADHD significantly increases substance use disorder risk, particularly through depression and anxiety pathways, can help target prevention efforts.","specificNumbers":"6,872 respondents aged 20-39. 270 with ADHD. Alcohol use disorder: 36% of ADHD vs 19% without. Cannabis use disorder OR 1.46. Other drug use disorder OR 2.07. Depression and anxiety were the strongest mediators.","methodology":"Secondary analysis of the nationally representative Canadian Community Health Survey-Mental Health (6,872 respondents aged 20-39, including 270 with ADHD). Substance use disorders diagnosed using WHO CIDI criteria. ADHD based on self-reported professional diagnosis.","limitations":"Cross-sectional design cannot establish temporal order. ADHD based on self-reported diagnosis, not standardized assessment. Canadian population may not generalize to other countries."},{"rthcId":"RTHC-03855","title":"The association between cannabis use and facial emotion recognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.","authors":"Fusar-Poli, Laura; Pries, Lotta-Katrin; van Os, Jim; Radhakrishnan, Rajiv; Pençe, Ayşegül Yay; Erzin, Gamze; Delespaul, Philippe; Kenis, Gunter; Luykx, Jurjen J; Lin, Bochao D; Akdede, Berna; Binbay, Tolga; Altınyazar, Vesile; Yalınçetin, Berna; Gümüş-Akay, Güvem; Cihan, Burçin; Soygür, Haldun; Ulaş, Halis; Cankurtaran, Eylem Şahin; Kaymak, Semra Ulusoy; Mihaljevic, Marina M; Andric-Petrovic, Sanja; Mirjanic, Tijana; Bernardo, Miguel; Mezquida, Gisela; Amoretti, Silvia; Bobes, Julio; Saiz, Pilar A; García-Portilla, Maria Paz; Sanjuan, Julio; Aguilar, Eduardo J; Santos, José Luis; Jiménez-López, Estela; Arrojo, Manuel; Carracedo, Angel; López, Gonzalo; González-Peñas, Javier; Parellada, Mara; Maric, Nadja P; Atbaşoğlu, Cem; Üçok, Alp; Alptekin, Köksal; Saka, Meram Can; Aguglia, Eugenio; Arango, Celso; Rutten, Bart Pf; Guloksuz, Sinan","year":2022,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 63, 47-59","doi":"10.1016/j.euroneuro.2022.08.003","pmid":"36055075","tags":["psychosis","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Better facial emotion recognition was associated with lifetime regular cannabis use across all three groups: schizophrenia patients (B=1.36), siblings (B=2.17), and healthy controls (B=3.10). In patients and siblings (higher genetic risk), those who started cannabis after age 16 performed better than earlier starters and non-users. In healthy controls, cannabis users performed better regardless of age of onset.","whyItMatters":"Social cognitive deficits are a core feature of schizophrenia. The surprising finding that cannabis use is associated with better, not worse, emotion recognition challenges assumptions about cannabis and cognitive function.","specificNumbers":"6,229 total participants. Effect sizes: schizophrenia B=1.36, siblings B=2.17, healthy controls B=3.10. Age 16 threshold significant for schizophrenia patients and siblings but not controls.","methodology":"Cross-sectional analysis of 6,229 participants from the EUGEI study: 2,039 with schizophrenia, 2,141 siblings, and 2,049 healthy controls. Facial emotion recognition measured using the Degraded Facial Affect Recognition Task (DFAR).","limitations":"Cross-sectional design cannot determine causation. Selection bias is likely. Current cannabis use was not associated with better performance. Self-reported cannabis history."},{"rthcId":"RTHC-03856","title":"Incidence of inpatient cases with mental disorders due to use of cannabinoids in Germany: a nationwide evaluation.","authors":"Gahr, Maximilian; Ziller, Julia; Keller, Ferdinand; Muche, Rainer; Preuss, Ulrich W; Schönfeldt-Lecuona, Carlos","year":2022,"journal":"European journal of public health, 32(2), 239-245","doi":"10.1093/eurpub/ckab207","pmid":"35043164","tags":["psychosis","addiction","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"All categories of cannabinoid-related psychiatric hospitalizations increased significantly: intoxications, harmful use, dependence syndrome, withdrawal, psychotic disorders, and residual/late-onset psychotic disorders. The overall relative frequency increased 4.8-fold comparing 2000 and 2018. Meanwhile, alcohol dependence admissions remained stable and schizophrenia-spectrum admissions slightly decreased.","whyItMatters":"The dramatic increase in cannabinoid-related psychiatric hospitalizations coincides with rising recreational use, synthetic cannabinoid availability, and increasing THC content in cannabis preparations.","specificNumbers":"4.8-fold increase in relative frequency from 2000 to 2018. All six subcategories showed statistically significant increases (p<0.001 for most). Schizophrenia admissions slightly decreased (p=0.008). Alcohol dependence unchanged (p=0.844).","methodology":"Analysis of all inpatient hospital diagnoses in Germany from 2000-2018 using Federal Statistical Office (Destatis) data. Linear trend analysis of absolute and relative annual frequencies of ICD-10 cannabinoid-related diagnoses versus control diagnoses.","limitations":"Administrative data may reflect changes in diagnostic practices, awareness, or healthcare-seeking behavior rather than true incidence changes. Cannot link to individual-level cannabis use data."},{"rthcId":"RTHC-03857","title":"Use Patterns, Flavors, Brands, and Ingredients of Nonnicotine e-Cigarettes Among Adolescents, Young Adults, and Adults in the United States.","authors":"Gaiha, Shivani Mathur; Lin, Crystal; Lempert, Lauren Kass; Halpern-Felsher, Bonnie","year":2022,"journal":"JAMA network open, 5(5), e2216194","doi":"10.1001/jamanetworkopen.2022.16194","pmid":"35612852","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03858","title":"Therapeutic potential of PIMSR, a novel CB1 receptor neutral antagonist, for cocaine use disorder: evidence from preclinical research.","authors":"Galaj, Ewa; Hempel, Briana; Moore, Allamar; Klein, Benjamin; Bi, Guo-Hua; Gardner, Eliot L; Seltzman, Herbert H; Xi, Zheng-Xiong","year":2022,"journal":"Translational psychiatry, 12(1), 286","doi":"10.1038/s41398-022-02059-w","pmid":"35851573","tags":["addiction","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"PIMSR dose-dependently inhibited cocaine self-administration, shifted the dose-response curve downward, decreased motivation to seek cocaine, and reduced cue-induced reinstatement. PIMSR was neither rewarding nor aversive. It attenuated cocaine-enhanced brain reward stimulation and the effects of THC and a CB1 agonist, confirming CB1 receptor involvement.","whyItMatters":"Rimonabant, a previous CB1 antagonist, failed in clinical trials due to severe psychiatric side effects (it was an inverse agonist). PIMSR, as a neutral antagonist, may avoid these issues while still treating cocaine addiction.","specificNumbers":"PIMSR inhibited cocaine self-administration under FR5 (not FR1), reduced progressive-ratio breakpoints, and attenuated cue-induced reinstatement. Effects confirmed through CB1 knockout mice and receptor antagonism.","methodology":"Multiple preclinical behavioral assays in rats and transgenic mice: cocaine self-administration (FR1, FR5, progressive ratio), place conditioning, intracranial self-stimulation (electrical and optogenetic), and receptor antagonist studies.","limitations":"Preclinical study only. PIMSR also inhibited sucrose self-administration, suggesting potential effects on natural reward. Human pharmacokinetics and safety are unknown."},{"rthcId":"RTHC-03859","title":"Chronic use of Datura stramonium cigarettes and late diagnosis of bullous emphysema in a smoker of marijuana and tobacco.","authors":"Gambelunghe, Angela; Aloisio, Bruno; Gambelunghe, Cristiana; Folletti, Ilenia; Chiodi, Marino; Muzi, Giacomo; Murgia, Nicola; dell'Omo, Marco","year":2022,"journal":"Respiratory medicine case reports, 40, 101761","doi":"10.1016/j.rmcr.2022.101761","pmid":"36386287","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03860","title":"Role of Cannabinoid CB2 Receptor in Alcohol Use Disorders: From Animal to Human Studies.","authors":"García-Gutiérrez, María Salud; Navarrete, Francisco; Gasparyan, Ani; Navarro, Daniela; Morcuende, Álvaro; Femenía, Teresa; Manzanares, Jorge","year":2022,"journal":"International journal of molecular sciences, 23(11)","doi":"10.3390/ijms23115908","pmid":"35682586","tags":["addiction","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CB2 receptor activation or blockade modulated alcohol-related behaviors in rodents. Mice lacking CB2 showed increased alcohol consumption, motivation, and relapse. Postmortem studies found CB2 alterations in brain reward areas of alcoholic patients. Some genetic variations in the CNR2 gene were associated with increased AUD risk.","whyItMatters":"CB2 receptors are primarily expressed outside the brain, making them a potentially safer drug target than CB1 for treating alcohol addiction without the cognitive side effects.","specificNumbers":"CB2 knockout mice showed increased alcohol consumption, motivation, and relapse. Postmortem CNR2 alterations found in brain reward areas. Some CNR2 genetic variants associated with AUD risk.","methodology":"Literature review searching Medline and Scopus for studies on CB2 receptors and alcohol use, covering pharmacological, genetic, and neurobiological evidence from both animal models and human studies.","limitations":"Most evidence from animal models. Limited number of human genetic and postmortem studies. No clinical trials of CB2 ligands for alcohol addiction yet."},{"rthcId":"RTHC-03861","title":"Individual and Combined Association Between Prenatal Polysubstance Exposure and Childhood Risk of Attention-Deficit/Hyperactivity Disorder.","authors":"Garrison-Desany, Henri M; Hong, Xiumei; Maher, Brion S; Beaty, Terri H; Wang, Guoying; Pearson, Colleen; Liang, Liming; Wang, Xiaobin; Ladd-Acosta, Christine","year":2022,"journal":"JAMA network open, 5(3), e221957","doi":"10.1001/jamanetworkopen.2022.1957","pmid":"35275164","tags":["pregnancy","youth","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Opioid exposure during pregnancy had the highest adjusted hazard ratio for ADHD (2.19). When accounting for all substances simultaneously, opioid-cannabis interaction produced 1.42 times higher risk and opioid-alcohol interaction produced 1.15 times higher risk. 24.2% of mothers reported using at least one substance during pregnancy.","whyItMatters":"Polysubstance use during pregnancy is increasing. Understanding how multiple substances interact to affect ADHD risk can improve prenatal counseling and cessation programs.","specificNumbers":"3,138 children, median follow-up 10 years. 15.5% had ADHD. 24.2% of mothers used at least one substance. Opioid HR 2.19. Opioid+cannabis interaction HR 1.42. Opioid+alcohol interaction HR 1.15.","methodology":"Prospective cohort from the Boston Birth Cohort (1998-2019) with 3,138 children followed from age 6 months to 21 years. Prenatal substance exposure assessed by self-report and ICD codes. ADHD diagnosed from electronic medical records. Cox proportional hazards and elastic net regression models.","limitations":"Self-reported substance use likely underestimates exposure. Urban, low-income cohort may not generalize. Cannot fully separate prenatal exposure effects from postnatal environmental factors."},{"rthcId":"RTHC-03862","title":"Interactions of Noradrenergic, Glucocorticoid and Endocannabinoid Systems Intensify and Generalize Fear Memory Traces.","authors":"Gazarini, Lucas; Stern, Cristina A; Takahashi, Reinaldo N; Bertoglio, Leandro J","year":2022,"journal":"Neuroscience, 497, 118-133","doi":"10.1016/j.neuroscience.2021.09.012","pmid":"34560200","tags":["neuroscience","ptsd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Low doses of adrenaline, corticosterone, or the CB1 antagonist AM251 had no individual effects on fear memory. But combining adrenaline with corticosterone or AM251, or all three together, significantly intensified fear memories during both consolidation and reconsolidation. The triple combination also caused fear generalization to novel contexts, mimicking traumatic memory characteristics.","whyItMatters":"This demonstrates how the interaction of stress systems with endocannabinoid disruption can create traumatic-like memories, providing insight into how PTSD may develop.","specificNumbers":"High doses of each drug individually increased freezing at 1 and 9 days. Low doses had no individual effect but synergized in combination. Triple combination caused generalization to novel contexts at 2 and 10 days.","methodology":"Contextual fear conditioning in rats with systemic drug administration during memory consolidation or reconsolidation. Tested individual and combined effects of adrenaline, corticosterone, and AM251 on fear intensity and generalization across conditioning and novel contexts.","limitations":"Rat model of fear conditioning is simplified compared to human trauma. Pharmacological doses may not reflect natural stress hormone and endocannabinoid fluctuations. Only male rats used."},{"rthcId":"RTHC-03863","title":"Assessing cognitive behavioral therapy for insomnia in individuals with cannabis use disorder utilizing actigraphy and serum biomarkers: A pilot study.","authors":"Geagea, Luna; Ghanimé, Pia Maria; El Hayek, Samer; Kobeissy, Firas; Tamim, Hani; Elbejjani, Martine; Talih, Farid","year":2022,"journal":"Sleep medicine, 100, 434-441","doi":"10.1016/j.sleep.2022.09.017","pmid":"36244318","tags":["sleep","addiction","anxiety","depression"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"After four CBT for insomnia sessions, mean ISI scores dropped from moderately severe to not clinically significant, sustained at 3 and 6 months. Actigraphy confirmed decreased sleep onset latency. PHQ-4 anxiety/depression scores also decreased significantly. At 3 months, 80% reported decreased cannabis use. Three of four inflammatory biomarkers (IL-2, IL-6, CRP) trended downward at 6 months.","whyItMatters":"Many cannabis users report using cannabis for sleep, creating a cycle where insomnia drives cannabis use. Treating insomnia directly with CBT may reduce the perceived need for cannabis.","specificNumbers":"19 participants. ISI dropped from moderately severe to not significant. Actigraphy showed significant decrease in sleep onset latency. 80% reduced cannabis use at 3 months. Significant PHQ-4 score decrease.","methodology":"Pilot study of 19 participants with cannabis use disorder and insomnia. Four CBT-i sessions with objective (actigraphy) and subjective sleep measures, validated questionnaires (ISI, PHQ-4), and serum inflammatory markers measured at baseline, post-CBT, 3 months, and 6 months.","limitations":"Very small sample (19 participants). No control group. Cannot separate CBT effects from natural recovery or placebo. Inflammatory biomarker changes only trended toward significance."},{"rthcId":"RTHC-03864","title":"Suicidal ideation among Canadian adults during the COVID-19 pandemic: the role of psychosocial factors and substance use behaviours.","authors":"Geda, Nigatu; Feng, Cindy; Peters, Brice","year":2022,"journal":"BMC psychiatry, 22(1), 711","doi":"10.1186/s12888-022-04353-9","pmid":"36384538","tags":["mental-health","depression","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Those who reported increased cannabis use during the pandemic had 1.97 times higher odds of suicidal ideation. Cannabis consumers during the pandemic had 1.51 times higher odds. Pre-pandemic depression (OR 3.14) and continued negative impacts of social isolation (OR 1.53) were also significantly associated with suicidal thinking.","whyItMatters":"The COVID-19 pandemic exacerbated mental health challenges. Understanding how cannabis use during the pandemic related to suicidal ideation informs crisis-period intervention strategies.","specificNumbers":"4,005 adults surveyed. Increased cannabis use: OR 1.97 for suicidal ideation. Cannabis use during pandemic: OR 1.51. Pre-pandemic depression: OR 3.14. Social isolation: OR 1.53.","methodology":"Cross-sectional survey of 4,005 Canadian adults aged 18+ conducted April 20-28, 2021 by Mental Health Research Canada. Multivariable logistic regression adjusted for demographics, mental health conditions, social isolation, and substance use.","limitations":"Cross-sectional design at a single pandemic time point. Self-reported cannabis use and mental health. Cannot determine whether cannabis use preceded or followed suicidal thoughts."},{"rthcId":"RTHC-03865","title":"GC-MS Identification and Quantification of the Synthetic Cannabinoid MDMB-4en- PINACA in Cannabis-derived Material Seized in the Turin Metropolitan Area (Italy).","authors":"Gerace, Enrico; Seganti, Fabrizio; Di Corcia, Daniele; Vincenti, Marco; Salomone, Alberto","year":2022,"journal":"Current pharmaceutical design, 28(32), 2618-2621","doi":"10.2174/1381612828666220603142859","pmid":"35658890","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03866","title":"Effects of active, inactive, and derivatives of Akkermansia muciniphila on the expression of the endocannabinoid system and PPARs genes.","authors":"Ghaderi, Farinaz; Sotoodehnejadnematalahi, Fattah; Hajebrahimi, Zahra; Fateh, Abolfazl; Siadat, Seyed Davar","year":2022,"journal":"Scientific reports, 12(1), 10031","doi":"10.1038/s41598-022-13840-8","pmid":"35705595","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03867","title":"Surface-based brain morphometry in schizophrenia vs. cannabis-induced psychosis: A controlled comparison.","authors":"Ghosh, Abhishek; Kaur, Simranjit; Shah, Raghav; Oomer, Fareed; Avasthi, Ajit; Ahuja, Chirag K; Basu, Debasish; Nehra, Ritu; Khandelwal, Niranjan","year":2022,"journal":"Journal of psychiatric research, 155, 286-294","doi":"10.1016/j.jpsychires.2022.09.034","pmid":"36170756","tags":["psychosis","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Schizophrenia with heavy cannabis use (SZC) showed the lowest cortical thickness, depth, and gyrification, followed by cannabis-induced psychosis (CIP), then healthy controls. SZC had significantly thinner cortex than controls in frontal regions and thinner than CIP in postcentral and frontal regions. Duration of cannabis use negatively correlated with cortical thickness in parietal and occipital areas.","whyItMatters":"Distinguishing cannabis-induced psychosis from schizophrenia has important treatment implications. Different brain structural profiles support different underlying pathophysiology.","specificNumbers":"31 SZC, 28 CIP, 30 controls. SZC had reduced cortical thickness vs controls in middle/inferior frontal and other regions. SZC was also thinner than CIP in bilateral postcentral and right middle frontal regions.","methodology":"Cross-sectional brain MRI study comparing 31 men with schizophrenia and heavy cannabis use, 28 with cannabis-induced psychosis, and 30 healthy controls. Surface-based brain morphometry using the CAT-12 toolbox with cortical parcellation.","limitations":"Small sample size. All male participants. Cross-sectional design cannot determine whether brain differences preceded or resulted from cannabis use or illness. Only one imaging modality."},{"rthcId":"RTHC-03868","title":"The effects of fatty acid amide hydrolase inhibition and monoacylglycerol lipase inhibition on habit formation in mice.","authors":"Gianessi, Carol A; Groman, Stephanie M; Taylor, Jane R","year":2022,"journal":"The European journal of neuroscience, 55(4), 922-938","doi":"10.1111/ejn.15129","pmid":"33506530","tags":["neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both FAAH inhibition (increasing anandamide) and MAGL inhibition (increasing 2-AG) disrupted habit formation during operant training in mice. This was unexpected, as previous work showed that blocking CB1 receptors also disrupted habits, suggesting that both too much and too little endocannabinoid signaling can impair habit formation.","whyItMatters":"Habit formation is central to substance use disorders. Understanding how endocannabinoids regulate habit formation could lead to interventions that prevent the automatic drug-seeking behaviors that drive addiction.","specificNumbers":"Both FAAH and MAGL inhibitors disrupted habit formation. AM251 also disrupted habits but showed vehicle-dependent dose-response inconsistencies, raising methodological concerns about prior studies.","methodology":"Pharmacological study using selective FAAH and MAGL inhibitors during food-reinforced operant training in mice. Habit assessed using contingency degradation. Also tested CB1 antagonist AM251 in solution vs suspension formulations.","limitations":"Mouse model with food reward; habit formation for drugs may differ. Methodological concerns about AM251 vehicle formulations complicate interpretation of prior literature. FAAH inhibitors affect multiple lipid mediators beyond anandamide."},{"rthcId":"RTHC-03869","title":"N-[1,3-Dialkyl(aryl)-2-oxoimidazolidin-4-ylidene]-aryl(alkyl)sulphonamides as Novel Selective Human Cannabinoid Type 2 Receptor (hCB2R) Ligands; Insights into the Mechanism of Receptor Activation/Deactivation.","authors":"Gianquinto, Eleonora; Sodano, Federica; Rolando, Barbara; Kostrzewa, Magdalena; Allarà, Marco; Mahmoud, Ali Mokhtar; Kumar, Poulami; Spyrakis, Francesca; Ligresti, Alessia; Chegaev, Konstantin","year":2022,"journal":"Molecules (Basel, Switzerland), 27(23)","doi":"10.3390/molecules27238152","pmid":"36500256","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03870","title":"Effects of cannabidiol in cannabis flower: Implications for harm reduction.","authors":"Gibson, Laurel P; Karoly, Hollis C; Ellingson, Jarrod M; Klawitter, Jost; Sempio, Cristina; Squeri, Julia E; Bryan, Angela D; Bidwell, L Cinnamon; Hutchison, Kent E","year":2022,"journal":"Addiction biology, 27(1), e13092","doi":"10.1111/adb.13092","pmid":"34467598","tags":["harm-reduction","cbd","anxiety"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 159 regular cannabis users randomly assigned to three chemovars, the THC+CBD chemovar (9% THC, 10% CBD) produced similar positive mood effects but significantly less paranoia and anxiety compared to the THC-dominant chemovar (24% THC, 1% CBD). Users of the THC+CBD flower also had lower plasma THC and higher plasma CBD concentrations.","whyItMatters":"Most commercially available cannabis is THC-dominant. This study provides evidence that balanced THC:CBD products may offer the desired effects with fewer negative psychological effects.","specificNumbers":"159 participants (94 male, 65 female). THC+CBD chemovar: 9% THC, 10% CBD. THC-dominant: 24% THC, 1% CBD. THC+CBD users had less paranoia and anxiety with similar positive mood effects.","methodology":"Randomized trial with at-home administration of three cannabis flower chemovars: THC-dominant (24% THC, 1% CBD), THC+CBD (9% THC, 10% CBD), and CBD-dominant (1% THC, 23% CBD). 159 regular users assessed in a mobile pharmacology lab before, immediately after, and 1 hour after use.","limitations":"Naturalistic at-home use means dosing was not controlled. Different THC concentrations between chemovars mean effects could be due to lower THC rather than CBD presence. Regular cannabis users may not represent occasional users."},{"rthcId":"RTHC-03871","title":"Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging.","authors":"Gilman, Jodi M; Schmitt, William A; Potter, Kevin; Kendzior, Brian; Pachas, Gladys N; Hickey, Sarah; Makary, Meena; Huestis, Marilyn A; Evins, A Eden","year":2022,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(4), 944-952","doi":"10.1038/s41386-021-01259-0","pmid":"34999737","tags":["driving","neuroscience","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 169 cannabis users given oral THC or placebo in a crossover design, prefrontal cortex oxygenated hemoglobin increased after THC only in participants classified as impaired. ML models using fNIRS data achieved 76.4% accuracy and 69.8% positive predictive value with a 10% false-positive rate, compared to field sobriety exams at 67.8% accuracy, 35.4% PPV, and 35.4% false-positive rate.","whyItMatters":"There is currently no evidence-based method to detect cannabis-impaired driving. Blood THC levels do not reliably predict impairment. A portable brain-based measure could fill this critical gap.","specificNumbers":"169 participants. fNIRS ML model: 76.4% accuracy, 69.8% PPV, 10% false positive. Field sobriety: 67.8% accuracy, 35.4% PPV, 35.4% false positive.","methodology":"Double-blind, randomized, crossover study with 169 cannabis users aged 18-55. fNIRS measured prefrontal cortex activation before and after oral THC and placebo. Impairment defined by convergent clinical ratings and an algorithm based on heart rate and self-rated \"high.\" Machine learning models compared to drug recognition evaluator field sobriety exams.","limitations":"Impairment was operationalized using clinical ratings and physiological markers, not actual driving performance. Oral THC has different pharmacokinetics than inhaled. Specificity to THC versus other impairment sources not yet determined."},{"rthcId":"RTHC-03872","title":"Young adult birthday celebrations as windows of risk for alcohol and cannabis use: 21st birthdays compared to other young adult birthdays.","authors":"Gilson, Michael S; Cadigan, Jennifer M; Fleming, Charles B; Fairlie, Anne M; Lewis, Melissa A; Lee, Christine M","year":2022,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 36(7), 798-803","doi":"10.1037/adb0000774","pmid":"34410756","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03873","title":"Nanomedicine and Addictive Disorders: A New Approach With Cannabinoids.","authors":"Giménez, Virna Margarita Martín; Menéndez, Sebastián García; Manucha, Walter","year":2022,"journal":"Current pharmaceutical design, 28(34), 2795-2799","doi":"10.2174/1381612828666220907104354","pmid":"36082864","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03874","title":"Systematic Review and Meta-analysis Seem to Indicate that Cannabinoids for Chronic Primary Pain Treatment Have Limited Benefit.","authors":"Giossi, Riccardo; Carrara, Federica; Padroni, Matteo; Bilancio, Maria Concetta; Mazzari, Martina; Enisci, Silvia; Romio, Maria Silvia; Boni, Gloria; Corrù, Federica; Fittipaldo, Veronica Andrea; Tramacere, Irene; Pani, Arianna; Scaglione, Francesco; Fornasari, Diego","year":2022,"journal":"Pain and therapy, 11(4), 1341-1358","doi":"10.1007/s40122-022-00434-5","pmid":"36129666","tags":["pain","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Across 8 RCTs with 240 patients, VAS pain reduction was not significant for cannabinoids vs placebo (MD -0.64, CI -1.30 to 0.02). However, studies with more than 4 weeks of treatment showed significant pain reduction (MD -1.28, CI -2.33 to -0.22). No significant differences were found for fibromyalgia impact, anxiety, depression, or discontinuation due to adverse events.","whyItMatters":"Chronic primary pain (including fibromyalgia and other conditions) affects millions. This meta-analysis suggests cannabinoids may need longer treatment periods to show benefit.","specificNumbers":"8 RCTs, 240 patients. Overall pain: MD -0.64, non-significant. Over 4 weeks: MD -1.28, significant. FIQ, anxiety, depression: non-significant. Evidence quality generally low.","methodology":"Systematic review and meta-analysis searching PubMed, EMBASE, and Cochrane through October 2021. Included 8 RCTs (4 parallel, 4 crossover) with 240 chronic primary pain patients. Evidence quality assessed using GRADE.","limitations":"Very small total sample (240 patients). Generally low-quality evidence due to imprecision and bias risk. Heterogeneous pain conditions grouped under \"chronic primary pain.\""},{"rthcId":"RTHC-03875","title":"Lifetime Cannabis Use Is Not Associated With Negative Beliefs About Medication in Patients With First Treatment Psychosis.","authors":"Gjerde, Priyanthi B; Steen, Synne W; Vedal, Trude S J; Steen, Nils Eiel; Reponen, Elina J; Andreassen, Ole A; Steen, Vidar M; Melle, Ingrid","year":2022,"journal":"Frontiers in psychiatry, 13, 824051","doi":"10.3389/fpsyt.2022.824051","pmid":"35422717","tags":["psychosis","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Neither lifetime cannabis use, current use, nor cannabis abuse diagnosis was associated with negative beliefs about medicines as measured by the BMQ questionnaire. However, patients with lifetime cannabis use were more likely to be male, younger at psychosis onset, and have higher alcohol and tobacco use.","whyItMatters":"Cannabis use predicts poor medication adherence in psychosis patients. If not through negative medication beliefs, clinicians need to identify the actual barriers to compliance in cannabis-using patients.","specificNumbers":"265 first-treatment psychosis patients. Cannabis users were younger at onset, more likely male, higher alcohol and tobacco use. No significant association between any cannabis measure and BMQ scores.","methodology":"Cross-sectional study of 265 patients with first-treatment schizophrenia spectrum disorder. Cannabis use assessed across three measures (lifetime, current, abuse/addiction). Medication beliefs measured using the validated Beliefs about Medication Questionnaire (BMQ). GLM analyses controlled for age and sex.","limitations":"Cross-sectional design. Self-reported cannabis use. BMQ may not capture all dimensions of medication attitudes relevant to this population."},{"rthcId":"RTHC-03876","title":"Association of medical cannabis licensure with prescription opioid receipt: A population-based, individual-level retrospective cohort study.","authors":"Goedel, William C; Macmadu, Alexandria; Shihipar, Abdullah; Moyo, Patience; Cerdá, Magdalena; Marshall, Brandon D L","year":2022,"journal":"The International journal on drug policy, 100, 103502","doi":"10.1016/j.drugpo.2021.103502","pmid":"34695720","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 5,296 medical cannabis license holders in Rhode Island, licensure was not associated with changes in odds of filling any opioid prescription (OR 0.99), filling prescriptions at 50+ morphine equivalent dose (OR 0.93), or at 90+ MED (OR 0.99). None of these associations were statistically significant.","whyItMatters":"Many states authorize medical cannabis as an alternative to opioids for pain. This study finds no evidence that obtaining a medical cannabis license actually reduces opioid prescription use.","specificNumbers":"5,296 medical cannabis license holders. Any opioid prescription OR 0.99 (CI 0.94-1.05). 50+ MED OR 0.93 (CI 0.84-1.04). 90+ MED OR 0.99 (CI 0.86-1.15). All non-significant.","methodology":"Population-based retrospective cohort linking Rhode Island medical cannabis registry with prescription drug monitoring program data (April 2016-March 2019). Within-person analysis examined changes in opioid prescriptions before and after cannabis licensure.","limitations":"Cannot confirm whether license holders actually used cannabis. Prescription monitoring captures filled prescriptions, not consumption. Rhode Island-specific findings may not generalize."},{"rthcId":"RTHC-03877","title":"Anti-Tumorigenic Effect of a Novel Derivative of 2-Hydroxyoleic Acid and the Endocannabinoid Anandamide on Neuroblastoma Cells.","authors":"Golan, Hana; Mechoulam, Raphael; Smoum, Reem; Cohen-Zada, Efrat; Pri-Chen, Sara; Wiener, Sapir; Grinberg, Igor; Bar-Lev, Dekel D; Haj, Christeeneh G; Fisher, Tamar; Toren, Amos","year":2022,"journal":"Biomedicines, 10(7)","doi":"10.3390/biomedicines10071552","pmid":"35884854","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03878","title":"Voltage dependence of the cannabinoid CB1 receptor.","authors":"Goldberger, Esty; Tauber, Merav; Ben-Chaim, Yair","year":2022,"journal":"Frontiers in pharmacology, 13, 1022275","doi":"10.3389/fphar.2022.1022275","pmid":"36304142","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03879","title":"Medical cannabis: Critical points for clinical application.","authors":"Gómez-García, Diego Mauricio; García-Perdomo, Herney Andrés","year":2022,"journal":"Biomedica : revista del Instituto Nacional de Salud, 42(3), 450-459","doi":"10.7705/biomedica.6468","pmid":"36122285","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03880","title":"Effects of Risk Perception and Accessibility on Cannabis Use among Young Population in Spain: Findings from the 2016 National Survey (ESTUDES).","authors":"González-Roz, Alba; Aonso-Diego, Gema; Martínez-Loredo, Víctor; Cuesta, Marcelino; Secades-Villa, Roberto","year":2022,"journal":"Substance use & misuse, 57(1), 36-46","doi":"10.1080/10826084.2021.1981387","pmid":"34678115","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Male sex, older age, and past-30-day tobacco, alcohol, and illicit substance use were associated with cannabis use. Cannabis risk perception and perceived accessibility mediated most of these relationships. Lower frequency of reading was a risk factor for cannabis use.","whyItMatters":"Understanding that risk perception and accessibility are modifiable mediators of cannabis use suggests concrete targets for prevention programs.","specificNumbers":"35,369 adolescents. Male sex, older age, tobacco, alcohol, and illicit substance use predicted cannabis use. Risk perception and accessibility mediated most pathways. Reading frequency was a protective factor.","methodology":"Analysis of Spain's 2016 National Survey on Drug Use in Secondary Education (ESTUDES) with 35,369 adolescents (50.1% female). Structural equation modeling identified predictors and tested mediation through cannabis risk perception and accessibility.","limitations":"Cross-sectional design cannot establish causal direction. Self-reported data. Spanish context may not generalize. Risk perception may be a consequence rather than cause of use."},{"rthcId":"RTHC-03881","title":"Perceptions of the health risks of cannabis: estimates from national surveys in Canada and the United States, 2018-2019.","authors":"Goodman, Samantha; Hammond, David","year":2022,"journal":"Health education research, 37(2), 61-78","doi":"10.1093/her/cyac006","pmid":"35311986","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Knowledge of cannabis health risks was highest for driving impairment (66-80%), pregnancy risks (61-71%), and addiction potential (51-62%), but lowest for psychosis and schizophrenia risk (23-37%). 12-18% agreed cannabis could cure or prevent cancer (false), and 6-7% believed it could cause diabetes (false). Canadians had the highest health knowledge, followed by U.S. legal states, then U.S. illegal states.","whyItMatters":"Substantial knowledge gaps, particularly about psychosis risk, could lead to uninformed decisions about cannabis use. Frequent consumers had the lowest knowledge despite the greatest exposure.","specificNumbers":"72,459 respondents. Driving risk awareness: 66-80%. Pregnancy risk: 61-71%. Addiction: 51-62%. Psychosis: 23-37%. False cancer cure belief: 12-18%. False diabetes belief: 6-7%.","methodology":"Cross-sectional online surveys from the 2018-2019 International Cannabis Policy Study with 72,459 respondents aged 16-65 recruited from Nielsen panels across Canada and U.S. states. Nine health effect questions including two false control items.","limitations":"Non-probability sampling. Online survey may underrepresent certain populations. Self-reported knowledge may not reflect actual understanding."},{"rthcId":"RTHC-03882","title":"Do Mandatory Health Warning Labels on Consumer Products Increase Recall of the Health Risks of Cannabis?","authors":"Goodman, Samantha; Leos-Toro, Cesar; Hammond, David","year":2022,"journal":"Substance use & misuse, 57(4), 569-580","doi":"10.1080/10826084.2021.2023186","pmid":"34989662","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Free recall of at least one warning message increased from 5% (pre-legalization) to 15% in Canada post-legalization, significantly outpacing U.S. legal and illegal states. Awareness of specific warning messages was higher where those specific warnings were mandated on packages. More frequent consumers had higher recall.","whyItMatters":"Warning labels are a low-cost public health intervention. This study provides evidence they work for cannabis, particularly when mandated with large rotating messages as Canada requires.","specificNumbers":"Canada: recall increased from 5% to 15% (3x increase). Compared to U.S. legal states: AOR 2.23. Recall higher among more frequent consumers.","methodology":"Repeat cross-sectional surveys from the International Cannabis Policy Study (2018-2020) with 38,448 past-12-month cannabis consumers in Canada and the U.S. Free recall of warnings assessed 2018-2020; prompted recognition in 2020 only.","limitations":"Still relatively low absolute recall rates even in Canada (15%). Non-probability online samples. Cannot determine whether increased awareness changes behavior."},{"rthcId":"RTHC-03883","title":"Motor-like Tics are Mediated by CB2 Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex.","authors":"Gorberg, Victoria; Borisov, Veronika; Greig, Iain R; Pertwee, Roger G; McCaffery, Peter; Anavi-Goffer, Sharon","year":2022,"journal":"Molecular neurobiology, 59(8), 5070-5083","doi":"10.1007/s12035-022-02884-6","pmid":"35666403","tags":["neuroscience","youth","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB2 knockout mice showed higher frequencies of repetitive behaviors. In adults, CB2 activation reduced tics, but in juveniles, CB2 agonists increased tic-like behaviors. Sex differences were observed, with HU-308 increasing tics in adult females through an off-target effect. DOI (a serotonin agonist) altered expression of CB2, GPR55, and endocannabinoid enzyme genes in the prefrontal cortex.","whyItMatters":"THC helps some Tourette syndrome patients, but understanding which cannabinoid receptors are involved, and how age and sex matter, could lead to more targeted treatments.","specificNumbers":"CB2 knockout mice had higher tic frequencies. HU-308 reduced adult tics but increased juvenile tics. Off-target HU-308 effects in adult females. DOI altered CB2, GPR55, FAAH, and ABHD6 expression.","methodology":"Animal study comparing wildtype and CB2 knockout mice of different ages and sexes. Tested the CB2 agonist HU-308 on DOI-induced head twitch, ear scratch, and grooming behaviors with and without CB1 antagonism. Gene expression analysis in prefrontal cortex.","limitations":"Mouse model of tics using DOI does not fully replicate human Tourette syndrome. HU-308 has off-target effects complicating interpretation. Only one dose tested for most experiments."},{"rthcId":"RTHC-03884","title":"Guideline No. 425b: Cannabis Use Throughout Women's Lifespans - Part 2: Pregnancy, the Postnatal Period, and Breastfeeding.","authors":"Graves, Lisa E; Robert, Magali; Allen, Victoria M; Dama, Sumeet; Gabrys, Robert L; Tanguay, Robert L; Turner, Suzanne D; Green, Courtney R; Cook, Jocelynn L","year":2022,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 44(4), 436-444.e1","doi":"10.1016/j.jogc.2022.01.013","pmid":"35400521","tags":["pregnancy","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Based on GRADE-assessed evidence, the guideline recommends avoiding cannabis during pregnancy and breastfeeding, or reducing use as much as possible if abstaining is not feasible. Key focus areas include screening, dependence and withdrawal management, communication approaches, maternal/fetal outcomes, pain control, postpartum care including secondhand smoke, and breastfeeding considerations.","whyItMatters":"Cannabis use during pregnancy is increasing. Clinicians need evidence-based guidelines to counsel patients, particularly as social acceptability of cannabis grows.","specificNumbers":"Literature search covered January 2018 to February 2021. Guideline addresses screening, dependence, withdrawal, communication, maternal/fetal outcomes, pain control, postpartum care, and breastfeeding.","methodology":"Clinical practice guideline searching PubMed and Cochrane for articles published January 2018 to February 2021. Included clinical trials, observational studies, reviews, and guidelines on cannabis during pregnancy and breastfeeding. Evidence quality rated using GRADE.","limitations":"Limited high-quality evidence available. Most studies are observational with potential confounders. Long-term follow-up data on cannabis-exposed pregnancies is sparse."},{"rthcId":"RTHC-03885","title":"Acute effects of Δ9-tetrahydrocannabinol and cannabidiol on auditory mismatch negativity.","authors":"Greenwood, Lisa-Marie; Broyd, Samantha J; van Hell, Hendrika H; Todd, Juanita; Jones, Alison; Murray, Robin M; Croft, Rodney J; Michie, Patricia T; Solowij, Nadia","year":2022,"journal":"Psychopharmacology, 239(5), 1409-1424","doi":"10.1007/s00213-021-05997-3","pmid":"34719731","tags":["neuroscience","psychosis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"THC and CBD both increased duration and intensity MMN amplitude in less-frequent users. Low-dose CBD added to THC attenuated THC's effect on duration and intensity MMN in less-frequent users. High-dose CBD added to THC had similar attenuating effects in frequent users. The pattern of effects varied as a function of prior cannabis exposure.","whyItMatters":"MMN is a candidate biomarker for schizophrenia linked to NMDA receptor function. Understanding how cannabinoids affect this marker helps clarify the complex relationship between cannabis and psychosis.","specificNumbers":"36 participants (18 frequent, 18 less-frequent users). 5 drug conditions. THC 8mg and CBD 400mg both increased MMN in less-frequent users. Low CBD (4mg) with THC attenuated effects in less-frequent users.","methodology":"Randomized, double-blind, crossover placebo-controlled study with 18 frequent and 18 less-frequent cannabis users. Five vaporized drug sessions: placebo, THC 8mg, CBD 400mg, THC 8mg+CBD 4mg, THC 12mg+CBD 400mg. Multifeature MMN paradigm with duration, frequency, and intensity deviants.","limitations":"Small sample (36 total). Acute effects may not reflect chronic use patterns. MMN changes may not directly relate to clinical outcomes or psychosis risk."},{"rthcId":"RTHC-03886","title":"Patient caught breastfeeding and instructed to stop: an empirical ethics study on marijuana and lactation.","authors":"Gross, Marielle S; Le Neveu, Margot; Milliken, Kara A; Beach, Mary Catherine","year":2022,"journal":"Journal of cannabis research, 4(1), 20","doi":"10.1186/s42238-022-00127-y","pmid":"35413889","tags":["pregnancy","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Medical records revealed punitive language like \"patient caught breastfeeding and instructed to stop.\" While plausible harms from breastmilk THC exposure exist, evidence of actual infant effects is limited and confounded. The well-established benefits of breastfeeding likely outweigh the uncertain risks of trace THC exposure. Restrictive policies may disproportionately affect minority populations.","whyItMatters":"Some hospitals prohibit breastfeeding when maternal cannabis use is detected, but this may cause net harm by denying well-established breastfeeding benefits based on uncertain cannabis risks.","specificNumbers":"150 medical records reviewed. Punitive documentation language identified. Analysis weighed uncertain THC breastmilk risks against well-established breastfeeding benefits.","methodology":"Mixed methods: retrospective qualitative review of 150 prenatal/postpartum medical records from 2017, scoping literature review of breastmilk marijuana exposure risks vs benefits of breastfeeding, and ethical analysis using principles of beneficence, autonomy, and justice.","limitations":"Single academic hospital system. Small medical record sample. Ethical analysis reflects authors' interpretation. Does not provide definitive safety data on THC in breastmilk."},{"rthcId":"RTHC-03887","title":"Cannabis as an Anticancer Agent: A Review of Clinical Data and Assessment of Case Reports.","authors":"Guggisberg, Jordan; Schumacher, Megan; Gilmore, Grace; Zylla, Dylan M","year":2022,"journal":"Cannabis and cannabinoid research, 7(1), 24-33","doi":"10.1089/can.2021.0045","pmid":"34370591","tags":["cancer","medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Of 207 pre-clinical articles, 107 contained original data showing anticancer activity. Of 77 published case reports, only 14% met strong criteria (active cancer, validated response, no concurrent treatment), 5% were moderate, and 81% were weak. CBD was the most reported anticancer cannabinoid (10-800 mg/day). Two small trials reported survival data for glioblastoma. Nearly 40% of cancer patients using cannabis believe it will treat their cancer.","whyItMatters":"Numerous anecdotal reports shared on social media create unrealistic expectations. This systematic appraisal shows that most published case reports do not meet basic evidence standards.","specificNumbers":"207 pre-clinical articles, 107 with original data. 77 case reports: 14% strong, 5% moderate, 81% weak. CBD doses: 10-800 mg/day. THC doses: 4.8-7.5 mg. 10% of cases were pediatric.","methodology":"Literature review of PubMed, EBSCO, ClinicalTrials.gov, online sources, and books. All case reports appraised as weak, moderate, or strong based on three criteria: active cancer at cannabis administration, validated lab/radiographic responses, and cannabis use without concurrent anticancer treatments.","limitations":"Case reports inherently cannot prove causation. Strong criteria were defined by the authors. Publication bias favors positive case reports. Online anecdotal claims were not systematically assessed."},{"rthcId":"RTHC-03888","title":"Association of Recreational Cannabis Legalization With Cannabis Possession Arrest Rates in the US.","authors":"Gunadi, Christian; Shi, Yuyan","year":2022,"journal":"JAMA network open, 5(12), e2244922","doi":"10.1001/jamanetworkopen.2022.44922","pmid":"36469319","tags":["legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"In 4 states without prior decriminalization, legalization reduced adult arrests by 76.3%. In 5 states with prior decriminalization, legalization still reduced adult arrests by 40.0%. Legalization was not associated with changes in youth arrest rates. Changes in arrest rates did not differ between Black and White individuals.","whyItMatters":"This provides evidence that legalization achieves arrest reductions beyond what decriminalization alone accomplishes, answering whether the additional step from decriminalization to legalization is justified for criminal justice reform.","specificNumbers":"31 states analyzed. Without prior decriminalization: -76.3% adult arrests. With prior decriminalization: -40.0% adult arrests. No change in youth arrests. No change in Black-White arrest disparities.","methodology":"Quasi-experimental difference-in-differences analysis using FBI Uniform Crime Reporting data for 31 U.S. states from 2010-2019. Compared arrest rate changes in 9 legalizing states (4 without and 5 with prior decriminalization) to 22 non-legalizing states.","limitations":"FBI data may have reporting gaps. 2010-2019 period limits generalizability to later-legalizing states. Ecological design cannot account for individual-level factors."},{"rthcId":"RTHC-03889","title":"Does expanding access to cannabis affect traffic crashes? County-level evidence from recreational marijuana dispensary sales in Colorado.","authors":"Gunadi, Christian","year":2022,"journal":"Health economics, 31(10), 2244-2268","doi":"10.1002/hec.4573","pmid":"35947633","tags":["legalization","driving"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Using county-level variation in when recreational dispensaries opened across Colorado, the entry of cannabis retail stores was associated with a significant increase in marijuana-related hospital discharges but no increase in traffic crash incidents. At 90% confidence, a large increase in crashes (>5%) could be ruled out.","whyItMatters":"Traffic safety is one of the most cited concerns about cannabis legalization. This county-level analysis finds no evidence that dispensary openings increased crashes, despite confirming increased cannabis use.","specificNumbers":"Significant increase in marijuana-related hospital discharges after dispensary entry. No significant increase in traffic crashes. Upper bound of 5% increase can be ruled out at 90% confidence.","methodology":"Difference-in-differences analysis exploiting variation in the timing of recreational dispensary entry across Colorado counties. Used marijuana-related hospital discharges as a measure of cannabis use intensity. County-level traffic crash data.","limitations":"County-level analysis cannot capture individual-level behavior. Hospital discharges may not perfectly proxy cannabis use. Short post-entry periods in some counties."},{"rthcId":"RTHC-03890","title":"Cannabis decriminalization and racial disparity in arrests for cannabis possession.","authors":"Gunadi, Christian; Shi, Yuyan","year":2022,"journal":"Social science & medicine (1982), 293, 114672","doi":"10.1016/j.socscimed.2021.114672","pmid":"34954673","tags":["legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"After decriminalization in 11 states, adult arrest rates declined over 70% and youth rates over 40% for both Black and White individuals. Among adults, decriminalization was associated with a roughly 17% decrease in the Black-White arrest rate ratio. Among youth, no change in racial disparity was observed despite overall arrest reductions.","whyItMatters":"Black Americans are disproportionately arrested for cannabis despite similar use rates to White Americans. Decriminalization reduced this disparity for adults, though not for youth.","specificNumbers":"37 U.S. states, 11 decriminalized during study period. Adult arrests: -70%+ overall. Youth arrests: -40%+ overall. Adult racial disparity: -17%. Youth racial disparity: no change.","methodology":"Difference-in-differences analysis using FBI Uniform Crime Report data from 37 U.S. states (2000-2019). Cannabis possession arrest rates calculated separately for Black and White adults and youth. Estimated association between decriminalization and racial disparity in arrest rates.","limitations":"FBI data has known reporting gaps. Cannot control for all confounders. Different states decriminalized at different thresholds and with different penalty structures."},{"rthcId":"RTHC-03891","title":"Cannabinoids, reward processing, and psychosis.","authors":"Gunasekera, Brandon; Diederen, Kelly; Bhattacharyya, Sagnik","year":2022,"journal":"Psychopharmacology, 239(5), 1157-1177","doi":"10.1007/s00213-021-05801-2","pmid":"33644820","tags":["psychosis","dopamine","neuroscience","cbd"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"THC modulated activity in the striatum, midbrain, insula, and anterior cingulate during reward processing, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD appeared to modulate the same reward and salience regions in the opposite direction.","whyItMatters":"Both psychosis and THC use involve altered dopamine signaling in the striatum. Understanding whether cannabinoid effects on reward processing underlie psychotic symptoms could clarify why some cannabis users develop psychosis while others do not.","specificNumbers":"People with psychosis show increased striatal presynaptic dopamine synthesis and release. Cannabis users generally show impaired presynaptic dopaminergic function, though acute THC challenges produced only modest effects on striatal dopamine.","methodology":"Narrative review combining preclinical and human neuroimaging evidence. A systematic search identified acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and people with psychosis.","limitations":"Narrative review rather than systematic meta-analysis. Acute THC challenge studies may not reflect chronic cannabis use. The relationship between reward processing changes and psychotomimetic effects remains correlational."},{"rthcId":"RTHC-03892","title":"Task-independent acute effects of delta-9-tetrahydrocannabinol on human brain function and its relationship with cannabinoid receptor gene expression: A neuroimaging meta-regression analysis.","authors":"Gunasekera, Brandon; Davies, Cathy; Blest-Hopley, Grace; Veronese, Mattia; Ramsey, Nick F; Bossong, Matthijs G; Radua, Joaquim; Bhattacharyya, Sagnik","year":2022,"journal":"Neuroscience and biobehavioral reviews, 140, 104801","doi":"10.1016/j.neubiorev.2022.104801","pmid":"35914625","tags":["neuroscience","cognition","potency"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"THC had neuromodulatory effects across a core network of brain regions central to many cognitive tasks and processes. These effects were related to dose, with greater effects in regions with higher levels of CB1 receptor expression.","whyItMatters":"Identifying where THC acts most strongly in the brain, and why, helps explain the wide range of cognitive effects reported by cannabis users and could inform dosing strategies for therapeutic applications.","specificNumbers":"372 participants across multiple studies. Effects were strongest in regions with the highest CB1R expression and scaled with dose. CB2R expression was also investigated.","methodology":"Meta-regression analysis of within-subject, repeated-measures fMRI studies examining acute THC effects on regional brain activation or blood flow in 372 participants under experimental conditions.","limitations":"Meta-analysis limited to studies using acute THC challenges under experimental conditions, which may not fully represent chronic use patterns. Individual variation in receptor density was not captured."},{"rthcId":"RTHC-03893","title":"Clinician views on and ethics priorities for authorizing medical cannabis in the care of children and youth in Canada: a qualitative study.","authors":"Gunning, Margot; Rotenberg, Ari D; Kelly, Lauren E; Crooks, Bruce; Oberoi, Sapna; Rapoport, Adam L; Rassekh, S Rod; Illes, Judy","year":2022,"journal":"CMAJ open, 10(1), E196-E202","doi":"10.9778/cmajo.20210239","pmid":"35292477","tags":["medical-cannabis","youth","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Four themes emerged: access challenges, relational autonomy (shared decision-making between clinicians, patients, and families), medically appropriate use, and research priorities. Clinicians weighed benefits of appropriate use positively over risks, even considering potential neurodevelopmental effects.","whyItMatters":"Medical cannabis use by pediatric patients is expanding across Canada, but evidence, federal regulations, and treatment guidelines lag behind clinical reality. Understanding clinician perspectives reveals where the system is failing patients.","specificNumbers":"18 clinicians interviewed across multiple pediatric specialties. 4 major themes and 12 subthemes identified.","methodology":"Qualitative study with 18 semistructured interviews of clinicians from neurology, palliative care, oncology, family medicine, and pharmacology, recruited through Canadian Childhood Cannabinoid Clinical Trials listservs. Analyzed using deductive and inductive thematic methods.","limitations":"Small sample of 18 clinicians. Purposive sampling through specialized listservs may overrepresent those already engaged with cannabis research. Patient and family perspectives not captured."},{"rthcId":"RTHC-03894","title":"A cannabinoid Hairy-Tale: Hair loss or hair gain?","authors":"Gupta, Aditya K; Talukder, Mesbah","year":2022,"journal":"Journal of cosmetic dermatology, 21(12), 6653-6660","doi":"10.1111/jocd.15427","pmid":"36181341","tags":["cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD appeared to promote hair growth, but the effect was concentration-dependent. At high concentrations (10 micromolar or above), CBD may actually cause hair loss. One trial found that daily application of a CBD-rich topical extract for six months increased nonvellus hair count by approximately 93.5% in 35 patients with androgenetic alopecia.","whyItMatters":"Hair loss affects millions of people, and the growing availability of CBD products has led to consumer interest in cannabinoid-based hair treatments. Understanding which cannabinoids help versus harm is important before these products proliferate.","specificNumbers":"93.5% increase in nonvellus hair count in 35 patients (28 males, 7 females) after 6 months of daily topical CBD application. Each application contained 3-4 mg of CBD. The extract was 10.78% CBD and 0.21% THC.","methodology":"Comprehensive structured search of PubMed and Google Scholar (June 2022) reviewing studies on cannabinoid effects on hair growth and loss.","limitations":"The key trial was a single uncontrolled study with 35 participants. The review included limited clinical evidence. Optimal CBD concentrations for hair growth have not been established in controlled trials."},{"rthcId":"RTHC-03895","title":"Metabolic effects of medical cannabis treatment.","authors":"Habib, George; Aamar, Suhail","year":2022,"journal":"Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 70(2), 446-448","doi":"10.1136/jim-2021-002059","pmid":"35022250","tags":["medical-cannabis","pain"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"There was no significant change in any metabolic parameter evaluated, including fasting blood glucose, hemoglobin A1c, insulin, lipid profile, cortisol, uric acid, or body weight, after three months of medical cannabis consumption.","whyItMatters":"Concerns about metabolic side effects could discourage patients and clinicians from using medical cannabis for chronic pain. Knowing that short-term use did not alter metabolic markers provides initial safety data.","specificNumbers":"28 patients completed the study (mean age 47.8 years, ~70% female). 75% had fibromyalgia. Mean monthly consumption was 22.21 grams. 75% used extracts (oil). No significant changes in any metabolic parameter.","methodology":"Prospective study of 28 rheumatology patients newly approved for medical cannabis for resistant chronic pain. Fasting metabolic panels and body weight were measured at baseline and three months after starting cannabis.","limitations":"Very small sample (28 patients). Only three months of follow-up. 75% used oil extracts, limiting generalizability to other consumption methods. No control group."},{"rthcId":"RTHC-03896","title":"Healthcare practitioner perceptions on barriers impacting cannabis prescribing practices.","authors":"Hachem, Yasmina; Abdallah, Sara J; Rueda, Sergio; Wiese, Jessica L; Mehra, Kamna; Rup, Jennifer; Cowan, Juthaporn; Vigano, Antonio; Costiniuk, Cecilia T","year":2022,"journal":"BMC complementary medicine and therapies, 22(1), 237","doi":"10.1186/s12906-022-03716-9","pmid":"36076191","tags":["medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Only 6% received medical cannabis training in professional school, though 60% had other training. 56% felt uncomfortable or ambivalent about their knowledge. 27% were unfamiliar with the requirements for obtaining medical cannabis in Canada. The strongest barrier was uncertainty in safe and effective dosage and routes of administration.","whyItMatters":"If most healthcare providers feel unprepared to prescribe medical cannabis, patients seeking it face unnecessary barriers. The training gap identified here points to a systemic failure in medical education.","specificNumbers":"70 respondents (71% attending physicians or residents). 6% received cannabis training in school. 56% uncomfortable with their knowledge. 27% unfamiliar with authorization requirements. 82% had patients using medical cannabis. 57% received more questions since recreational legalization.","methodology":"Survey distributed through 91 healthcare associations in Canada between April and December 2021. 24 organizations agreed to disseminate, and 70 individuals completed the questionnaire evaluating knowledge, comfort, and practice regarding medical and recreational cannabis.","limitations":"Low response rate (70 out of unknown total reached). Self-selected sample may not represent all Canadian HCPs. Survey-based data subject to response bias."},{"rthcId":"RTHC-03897","title":"Children and adolescents with ASD treated with CBD-rich cannabis exhibit significant improvements particularly in social symptoms: an open label study.","authors":"Hacohen, Micha; Stolar, Orit E; Berkovitch, Matitiahu; Elkana, Odelia; Kohn, Elkana; Hazan, Ariela; Heyman, Eli; Sobol, Yael; Waissengreen, Danel; Gal, Eynat; Dinstein, Ilan","year":2022,"journal":"Translational psychiatry, 12(1), 375","doi":"10.1038/s41398-022-02104-8","pmid":"36085294","tags":["cbd","youth","mental-health","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"moderate","keyFinding":"Significant improvements in social communication were observed on the ADOS (clinical assessment), SRS (parent report), and Vineland (adaptive behaviors). Improvements were larger in participants with more severe initial symptoms. Restricted and repetitive behaviors improved only on the parent-reported SRS, not on clinical assessment. Cognitive scores did not change.","whyItMatters":"Previous CBD-autism studies relied mainly on parent reports. This study used standardized clinical assessments (ADOS), providing more objective evidence that CBD-rich cannabis may improve social communication in some children with autism.","specificNumbers":"110 recruited, 82 completed 6 months of treatment. Significant improvements on ADOS, SRS, and Vineland social communication scales. Larger improvements in those with more severe baseline symptoms. No significant cognitive changes.","methodology":"Open-label study of 110 recruited participants (82 completed 6 months). Social communication measured by ADOS (clinician-administered), SRS (parent report), and Vineland. Cognitive abilities assessed with age-appropriate Wechsler tests.","limitations":"Open-label design with no placebo control. 28 of 110 participants did not complete the protocol. Placebo effects and natural developmental changes could account for improvements. No long-term follow-up."},{"rthcId":"RTHC-03898","title":"The Efficacy of Cannabis on Multiple Sclerosis-Related Symptoms.","authors":"Haddad, Fatma; Dokmak, Ghadeer; Karaman, Rafik","year":2022,"journal":"Life (Basel, Switzerland), 12(5)","doi":"10.3390/life12050682","pmid":"35629350","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Nabiximols (oromucosal spray) demonstrated improvement in MS spasticity, pain, and quality of life with tolerable adverse effects. Oral cannabinoids were significantly effective for MS pain and spasticity. Evidence for other MS symptoms like tremors, ataxia, and bladder dysfunction was inconsistent.","whyItMatters":"MS patients frequently report using cannabis for symptom relief. This review helps clarify which symptoms have the strongest supporting evidence and which delivery methods appear most effective.","specificNumbers":"Two main delivery routes reviewed: oromucosal spray (nabiximols) and oral cannabinoids. Both showed positive effects on pain and spasticity. Other symptoms showed only slight improvement with inconsistent evidence.","methodology":"Review of clinical studies investigating cannabis effects on MS symptoms including spasticity, pain, tremors, ataxia, bladder functions, sleep, quality of life, and adverse effects.","limitations":"Review scope and methodology not fully detailed. Evidence for symptoms beyond pain and spasticity described as inconsistent. Study quality of included trials varies."},{"rthcId":"RTHC-03899","title":"Recreational Cannabis Legalization in Canada: A Pediatrics Perspective.","authors":"Hamid, Muhammad Akhter; Shaikh, Roohab; Gunaseelan, Luxhman; Salim, Jannat; Arulchelvan, Atchaya; Tulloch, Trisha","year":2022,"journal":"Substance use & misuse, 57(3), 481-483","doi":"10.1080/10826084.2021.2012689","pmid":"35081853","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03900","title":"A Meta-Analysis of fMRI Studies of Youth Cannabis Use: Alterations in Executive Control, Social Cognition/Emotion Processing, and Reward Processing in Cannabis Using Youth.","authors":"Hammond, Christopher J; Allick, Aliyah; Park, Grace; Rizwan, Bushra; Kim, Kwon; Lebo, Rachael; Nanavati, Julie; Parvaz, Muhammad A; Ivanov, Iliyan","year":2022,"journal":"Brain sciences, 12(10)","doi":"10.3390/brainsci12101281","pmid":"36291215","tags":["youth","neuroscience","cognition","mental-health","sex-differences"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis-using youth showed greater activation in the rostral medial prefrontal cortex during executive control tasks and decreased activation in the dorsal medial prefrontal cortex and dorsal anterior cingulate during social cognition and emotion processing, compared to non-using peers.","whyItMatters":"Understanding how cannabis changes brain function in young people is critical because the adolescent brain is still developing. This meta-analysis provides the most comprehensive picture to date of where those changes occur.","specificNumbers":"45 fMRI studies. 1,216 cannabis-using youth vs. 1,486 non-using controls. Brain activation differences varied by sex, cannabis use disorder severity, psychiatric comorbidity, and length of abstinence.","methodology":"Systematic review and seed-based d mapping (SDM) meta-analysis of 45 fMRI studies comparing BOLD response in 1,216 cannabis-using youth and 1,486 non-using typically developing participants.","limitations":"Cross-sectional nature of most included studies makes it impossible to determine whether brain differences preceded or resulted from cannabis use. Heterogeneity in study designs and cannabis exposure measures."},{"rthcId":"RTHC-03901","title":"Impact of cyclooxygenase-2 inhibition on cannabis withdrawal and circulating endocannabinoids in daily cannabis smokers.","authors":"Haney, Margaret; Bedi, Gillinder; Cooper, Ziva D; Herrmann, Evan S; Reed, Stephanie Collins; Foltin, Richard W; Kingsley, Philip J; Marnett, Lawrence J; Patel, Sachin","year":2022,"journal":"Addiction biology, 27(4), e13183","doi":"10.1111/adb.13183","pmid":"35754107","tags":["withdrawal","addiction","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Compared to placebo, celecoxib improved some subjective sleep measures but did not affect mood, cannabis self-administration, or circulating endocannabinoid levels. Celecoxib increased cannabis craving, suggesting it does not show promise as a pharmacotherapy for cannabis use disorder.","whyItMatters":"There are currently no FDA-approved medications for cannabis use disorder. Blocking COX-2 was hypothesized to increase endocannabinoid levels and reduce withdrawal, but this study found the approach ineffective.","specificNumbers":"15 participants (12M, 3F). Celecoxib 200 mg twice daily. Cannabis abstinence produced characteristic withdrawal (negative mood, anorexia, dreaming). Cannabis abstinence was associated with increased OEA and oleic acid but no change in endocannabinoid levels.","methodology":"Placebo-controlled crossover study with 15 daily, non-treatment-seeking cannabis smokers (12 male, 3 female). Each participant completed two 11-day phases (placebo vs. celecoxib 200 mg BID) with a washout period of at least 14 days.","limitations":"Very small sample (15 participants, only 3 female). Non-treatment-seeking population may not represent those trying to quit. Single dose of celecoxib tested."},{"rthcId":"RTHC-03902","title":"Controversial Link between Cannabis and Anticancer Treatments-Where Are We and Where Are We Going? A Systematic Review of the Literature.","authors":"Hanganu, Bianca; Lazar, Diana Elena; Manoilescu, Irina Smaranda; Mocanu, Veronica; Butcovan, Doina; Buhas, Camelia Liana; Szalontay, Andreea Silvana; Ioan, Beatrice Gabriela","year":2022,"journal":"Cancers, 14(16)","doi":"10.3390/cancers14164057","pmid":"36011049","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03903","title":"Cannabis Vaping Among Youth and Young Adults: a Scoping Review.","authors":"Harrell, Melissa B; Clendennen, Stephanie L; Sumbe, Aslesha; Case, Kathleen R; Mantey, Dale S; Swan, Sunaina","year":2022,"journal":"Current addiction reports, 9(3), 217-234","doi":"10.1007/s40429-022-00413-y","pmid":"35573056","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03904","title":"Varied Presentations of Pediatric Patients With Positive Cannabinoid Tests.","authors":"Harvey, Taylor; Gomez, Ramon; Wolk, Brian; Ozcan, Ali","year":2022,"journal":"Cureus, 14(3), e23493","doi":"10.7759/cureus.23493","pmid":"35345813","tags":["youth","legalization","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"71% of cases with positive cannabinoid drug screens presented after cannabis legalization in November 2016. The majority of cases (78%) were ages 15-17. The most common chief complaint was suicidal ideation (43%), followed by vomiting (8%), nausea (5%), trauma (5%), and altered mental status (5%).","whyItMatters":"The high rate of suicidal ideation among cannabis-positive youth in the ER suggests either a direct relationship between cannabis use and suicidality, or that cannabis use clusters with other risk factors. Either way, it signals a need for clinical vigilance.","specificNumbers":"422 charts reviewed. 71% of cases after legalization (Z=7.72, p<.01). 78% were ages 15-17. 43% presented with suicidal ideation. 27% had tachycardia, 18% had hypertension. 28% tested positive for at least one other drug (amphetamine most common at 13%).","methodology":"Descriptive retrospective chart review of 422 pediatric patients under 18 with positive urine drug screens for cannabinoids in the ED, from March 2013 to June 2020.","limitations":"Retrospective chart review cannot establish causation between cannabis use and suicidal ideation. Single-center study. Positive drug screen does not confirm acute intoxication. Temporal association with legalization does not prove legalization caused the increase."},{"rthcId":"RTHC-03905","title":"Workplace Cannabis Policies: A Moving Target.","authors":"Hazle, Mia C; Hill, Kevin P; Westreich, Laurence M","year":2022,"journal":"Cannabis and cannabinoid research, 7(1), 16-23","doi":"10.1089/can.2020.0095","pmid":"33998870","tags":["workplace","cognition","addiction","mental-health"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The legal landscape for workplace cannabis use is a mess. Federal law still classifies cannabis as Schedule I, but dozens of states have legalized medical or recreational use, leaving employers stranded between contradictory legal obligations. The authors map out exactly why most workplace drug policies are outdated and propose a practical framework.\n\nThe core problem with workplace drug testing for cannabis is that standard urine tests detect THC metabolites for days or weeks after use — long after any impairment has passed. A positive test tells you someone used cannabis at some point, not that they're impaired right now. This creates a disconnect that's becoming harder to defend legally, especially in states with employee protections for off-duty cannabis use.\n\nThe authors argue that workplace policies should be built around three factors: safety sensitivity of the job (an airline pilot vs. an office worker), whether the jurisdiction has legal protections for cannabis users, and whether the employer can actually measure impairment rather than just past use. For safety-sensitive positions, stricter testing is legally defensible. For most other jobs, the trend is moving toward impairment-based policies rather than zero-tolerance approaches.\n\nThey also note that different cannabis products (edibles vs. smoked flower vs. concentrates) produce dramatically different impairment profiles, and that current testing technology cannot distinguish between these delivery methods or accurately assess real-time impairment.","whyItMatters":"Most workplace cannabis policies were written when cannabis was illegal everywhere. Now that the majority of U.S. states have some form of legal cannabis, these policies create real problems: employers face lawsuits for firing employees who use cannabis legally off-duty, while workers in safety-sensitive jobs may be impaired on the clock with no reliable way to detect it. This review provides a rare practical roadmap for updating policies that actually match the current legal and scientific reality.","specificNumbers":"As of the review date, 37 states had legalized medical cannabis and 18 had legalized recreational use. Standard urine tests can detect THC metabolites for up to 30 days in chronic users. The review found no validated, widely-accepted test for real-time cannabis impairment in workplace settings.","methodology":"Narrative review of published literature from PubMed/NLM databases covering workplace cannabis policies, drug testing methods, legal frameworks, and impairment measurement. The authors synthesized findings from employment law, toxicology, and occupational health research to develop a practical policy framework.","limitations":"This is a narrative review, not a systematic review, so the literature search may not be comprehensive. The legal landscape changes rapidly, and specific state-by-state details may already be outdated. The proposed framework is conceptual and hasn't been empirically tested in real workplace settings. The review focuses on U.S. law and may not apply to other jurisdictions."},{"rthcId":"RTHC-03906","title":"Chronic exposure to delta-9-tetrahydrocannabinol impacts testicular volume and male reproductive health in rhesus macaques.","authors":"Hedges, Jason C; Hanna, Carol B; Bash, Jasper C; Boniface, Emily R; Burch, Fernanda C; Mahalingaiah, Shruthi; Roberts, Victoria H J; Terrobias, Juanito Jose D; Mishler, Emily C; Jensen, Jared V; Easley, Charles A; Lo, Jamie O","year":2022,"journal":"Fertility and sterility, 117(4), 698-707","doi":"10.1016/j.fertnstert.2021.12.028","pmid":"35090702","tags":["pregnancy","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"For each 1 mg/7 kg/day increase in THC dose, bilateral testicular volume decreased by 11.8 cm3. Total average bilateral testicular volume decreased by 58%. Testosterone and estradiol decreased significantly while gonadotropins (FSH, LH) and prolactin increased, a hormonal pattern consistent with primary testicular failure.","whyItMatters":"This is the first nonhuman primate study to demonstrate dose-dependent testicular atrophy from THC exposure. The hormonal changes suggest the testes themselves are being damaged, not just hormonal signaling from the brain.","specificNumbers":"6 macaques. 58% decrease in average bilateral testicular volume. Testosterone decreased by 1.49 ng/mL per dose increase. Estradiol decreased by 3.8 pg/mL. FSH, LH, and prolactin all increased. No significant changes in sperm parameters.","methodology":"Six adult male rhesus macaques (ages 8-10) received daily edible THC at medically and recreationally relevant doses. Testicular volume, hormone levels, and semen parameters were measured.","limitations":"Very small sample of 6 animals. Animal results may not directly translate to humans. Semen parameters did not change, which may indicate functional compensation. Unknown whether effects reverse after THC discontinuation."},{"rthcId":"RTHC-03907","title":"Protein extraction from cold-pressed hempseed press cake: From laboratory to pilot scale.","authors":"Helstad, Amanda; Forsén, Erica; Ahlström, Cecilia; Mayer Labba, Inger-Cecilia; Sandberg, Ann-Sofie; Rayner, Marilyn; Purhagen, Jeanette K","year":2022,"journal":"Journal of food science, 87(1), 312-325","doi":"10.1111/1750-3841.16005","pmid":"34953090","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03908","title":"Examining the Use of Antidepressants for Adolescents with Depression/Anxiety Who Regularly Use Cannabis: A Narrative Review.","authors":"Hen-Shoval, Danielle; Weller, Aron; Weizman, Abraham; Shoval, Gal","year":2022,"journal":"International journal of environmental research and public health, 19(1)","doi":"10.3390/ijerph19010523","pmid":"35010782","tags":["youth","depression","anxiety","drug-interactions","cbd"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Almost all randomized clinical trials of antidepressants excluded participants using cannabis or other drugs, so the expected course of therapy in cannabis users is unknown. Based on shared neurochemical pathways (serotonin, endocannabinoid, and other systems), the authors concluded it is reasonable to assume antidepressants are less effective in adolescents who use cannabis frequently.","whyItMatters":"Depression and anxiety are rising in adolescents, antidepressant prescriptions are increasing, and cannabis is the most commonly used illicit substance in this age group. Yet virtually no clinical trial has studied what happens when these are combined.","specificNumbers":"No specific numerical outcomes reported. The review identified overlapping neurochemical pathways between antidepressants (targeting serotonin, norepinephrine) and cannabinoids (THC and CBD effects on endocannabinoid system).","methodology":"Narrative literature review examining the mechanisms of action of antidepressants and cannabis, focusing on neurochemical overlaps and potential interactions relevant to adolescent treatment outcomes.","limitations":"Narrative review based on mechanistic reasoning rather than clinical outcome data. The conclusion that antidepressants are \"less effective\" is an inference, not an established finding from head-to-head studies."},{"rthcId":"RTHC-03909","title":"Sex-specific mechanisms of tolerance for the cannabinoid agonists CP55,940 and delta-9-tetrahydrocannabinol (Δ9-THC).","authors":"Henderson-Redmond, Angela N; Sepulveda, Diana E; Ferguson, Erin L; Kline, Aaron M; Piscura, Mary K; Morgan, Daniel J","year":2022,"journal":"Psychopharmacology, 239(5), 1289-1309","doi":"10.1007/s00213-021-05886-9","pmid":"34165606","tags":["tolerance","sex-differences","neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"The S426A/S430A mutation, which blocks CB1 receptor desensitization via the GRK/beta-arrestin2 pathway, conferred partial resistance to THC tolerance in male mice but did not alter tolerance in female mice. Female mice were also less sensitive to the pain-relieving effects of THC and CP55,940 compared to males.","whyItMatters":"More women than men use medical cannabis for pain relief, yet tolerance research has been conducted almost exclusively in males. This study reveals that tolerance develops through fundamentally different molecular pathways depending on sex.","specificNumbers":"Female mice were markedly less sensitive to the antinociceptive effects of 30 mg/kg THC and 0.3 mg/kg CP55,940 compared to males. The S426A/S430A mutation enhanced the antinociceptive response to both cannabinoids in both sexes.","methodology":"Male and female S426A/S430A mutant mice and wild-type littermates were tested for antinociceptive and hypothermic responses to repeated dosing with THC and CP55,940, a synthetic cannabinoid.","limitations":"Animal study using mice, which may not directly translate to humans. Specific mutation model (S426A/S430A) tests only one desensitization pathway. Pain measurement limited to thermal antinociception."},{"rthcId":"RTHC-03910","title":"Pneumomediastinum and Pneumorrhachis Associated With Cannabinoid Hyperemesis Syndrome.","authors":"Hernandez Garcia, Laura R; Kemper, Suzanne; Chillag, Shawn A","year":2022,"journal":"Cureus, 14(12), e32380","doi":"10.7759/cureus.32380","pmid":"36632263","tags":["harm-reduction","respiratory"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This is the third reported case of CHS with associated pneumomediastinum and the first documented case of pneumorrhachis (air in the spinal canal) linked to CHS. The complications resulted from forceful, repeated vomiting associated with the syndrome.","whyItMatters":"CHS is becoming more common as cannabis use increases. Severe vomiting can cause rare but serious mechanical complications, and clinicians need to consider these possibilities when evaluating CHS patients with unusual symptoms.","specificNumbers":"Third case of CHS with pneumomediastinum in the literature. First case of CHS with pneumorrhachis ever reported.","methodology":"Single case report with literature review.","limitations":"Single case report. Cannot establish frequency or risk factors for these complications in CHS. No long-term follow-up reported."},{"rthcId":"RTHC-03911","title":"Determination of Prenatal Substance Exposure Using Meconium and Orbitrap Mass Spectrometry.","authors":"Hernandez, Atakan; Lacroze, Valerie; Doudka, Natalia; Becam, Jenny; Pourriere-Fabiani, Carole; Lacarelle, Bruno; Solas, Caroline; Fabresse, Nicolas","year":2022,"journal":"Toxics, 10(2)","doi":"10.3390/toxics10020055","pmid":"35202242","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03912","title":"Attention-Deficit Hyperactivity Disorder and Therapeutic Cannabis Use Motives.","authors":"Hernandez, Mariely; Levin, Frances R","year":2022,"journal":"The Psychiatric clinics of North America, 45(3), 503-514","doi":"10.1016/j.psc.2022.05.010","pmid":"36055735","tags":["cognition","addiction","medical-cannabis","mental-health"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Individuals with ADHD may be at increased risk of cannabis use problems due to deficits in self-regulation. The review explored motivations for cannabis use in ADHD populations and examined the neural correlates and therapeutic potential.","whyItMatters":"Cannabis use rates are rising alongside legalization, and people with ADHD are disproportionately affected by substance use problems. Understanding why they use and whether it helps or harms is critical for treatment planning.","specificNumbers":"No specific numerical outcomes reported. The review synthesized existing literature on ADHD-cannabis overlap.","methodology":"Narrative review examining research on cannabis use motivations, neural correlates, and therapeutic potential in ADHD populations.","limitations":"Narrative review without systematic methodology. Limited clinical trial data on cannabis for ADHD symptoms."},{"rthcId":"RTHC-03913","title":"Cannabis use among U.S. military veterans with subthreshold or threshold posttraumatic stress disorder: Psychiatric comorbidities, functioning, and strategies for coping with posttraumatic stress symptoms.","authors":"Hill, Melanie L; Loflin, Mallory; Nichter, Brandon; Na, Peter J; Herzog, Sarah; Norman, Sonya B; Pietrzak, Robert H","year":2022,"journal":"Journal of traumatic stress, 35(4), 1154-1166","doi":"10.1002/jts.22823","pmid":"35275431","tags":["ptsd","addiction","mental-health","depression","anxiety"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Veterans with PTSD who used cannabis more than weekly were significantly more likely to screen positive for depression (OR 3.4-3.8), anxiety, and suicidal ideation compared to non-users. They scored lower on cognitive functioning, were 8-12 times more likely to use avoidance coping strategies, and were no more likely to seek mental health treatment despite worse symptoms.","whyItMatters":"Many veterans with PTSD use cannabis for symptom relief, but this large representative survey found that frequent use was associated with worse psychiatric outcomes and avoidance coping, not better functioning.","specificNumbers":"N=608 veterans with PTSD. Frequent users had ORs of 3.4-3.8 for depression/anxiety/suicidal ideation vs. non-users. Avoidance coping ORs of 8.2-12.2. Substance use coping OR of 4.4. Cognitive functioning effect sizes: d=0.25 vs. non-users, d=0.71 vs. infrequent users.","methodology":"Analysis of the 2019-2020 National Health and Resilience in Veterans Study, a nationally representative survey. Focused on 608 veterans with current subthreshold or full PTSD who reported on past-6-month cannabis use, psychiatric symptoms, functioning, and coping strategies.","limitations":"Cross-sectional design cannot determine whether cannabis use caused worse outcomes or whether veterans with worse symptoms were more likely to use cannabis. Self-reported data. Cannabis potency and composition not measured."},{"rthcId":"RTHC-03914","title":"Multimodal MRI data fusion reveals distinct structural, functional and neurochemical correlates of heavy cannabis use.","authors":"Hirjak, Dusan; Schmitgen, Mike M; Werler, Florian; Wittemann, Miriam; Kubera, Katharina M; Wolf, Nadine D; Sambataro, Fabio; Calhoun, Vince D; Reith, Wolfgang; Wolf, Robert Christian","year":2022,"journal":"Addiction biology, 27(2), e13113","doi":"10.1111/adb.13113","pmid":"34808703","tags":["neuroscience","dopamine","cognition"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Two transmodal components significantly differed between heavy cannabis users and controls. Grey matter volume changes occurred primarily in cerebello-temporo-thalamic regions, while intrinsic neural activity changes appeared in fronto-parietal regions. These changes were associated with the serotonergic, dopaminergic, and mu-opioid receptor systems.","whyItMatters":"By combining structural, functional, and neurochemical data in people who use cannabis heavily but have no diagnosed disorder, this study reveals brain changes that occur even without clinical impairment.","specificNumbers":"24 heavy cannabis users vs. 16 controls. Two significant transmodal components identified (GMV: p=0.01, ALFF: p=0.03). Associations found with serotonergic system (structure), and serotonergic, dopaminergic, and mu-opioid systems (function).","methodology":"Multimodal MRI study of 24 heavy cannabis users without cannabis use disorder or other mental disorders vs. 16 controls. Used parallel independent component analysis combining structural MRI and resting-state fMRI, plus JuSpace toolbox for cross-modal correlations with nuclear imaging-derived neurotransmitter estimates.","limitations":"Small sample (24 users, 16 controls). Cross-sectional design cannot determine if brain changes preceded or resulted from cannabis use. Participants without cannabis use disorder may not represent the broader user population."},{"rthcId":"RTHC-03915","title":"Safety and Efficacy of Medical Cannabis in Autism Spectrum Disorder Compared with Commonly Used Medications.","authors":"Holdman, Richard; Vigil, Daniel; Robinson, Kelsey; Shah, Puja; Contreras, Alexandra Elyse","year":2022,"journal":"Cannabis and cannabinoid research, 7(4), 451-463","doi":"10.1089/can.2020.0154","pmid":"34432543","tags":["cbd","medical-cannabis","youth","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Commonly prescribed ASD medications display varying efficacy, safety, and tolerability, with some causing side effects (aggression, anxiety, irritability, cognitive effects) that mirror the very symptoms they target. CBD-rich medical cannabis appeared effective and tolerable for both core ASD symptoms and comorbidities like irritability and sleep problems in observational studies, though no placebo-controlled trials existed at the time of review.","whyItMatters":"With no FDA-approved medications for core ASD symptoms and only two approved for associated irritability, families face difficult treatment decisions. Understanding how cannabis compares to existing options is directly relevant to clinical practice.","specificNumbers":"Zero approved medications for core ASD symptoms. Two FDA-approved medications for ASD-related irritability. Zero published placebo-controlled cannabis trials for ASD at the time of review. Circulating endocannabinoids identified as a possible ASD biomarker.","methodology":"Literature review comparing safety and efficacy profiles of medications commonly used in ASD with available evidence on medical cannabis, including biological plausibility through the endocannabinoid system.","limitations":"No placebo-controlled cannabis trials for ASD existed at the time of review. Observational studies have inherent biases. Long-term safety of cannabis in ASD populations is unknown. Heterogeneity of ASD makes treatment comparisons difficult."},{"rthcId":"RTHC-03916","title":"Racial/Ethnic Bullying Subtypes and Alcohol, Tobacco, and Marijuana Use Among US Adolescents.","authors":"Hong, Jun Sung; Kim, Dong Ha; Hunter, Simon C; Cleeland, Leah R; Lee, Carol A; Lee, Jane J; Kim, Jinwon","year":2022,"journal":"Journal of racial and ethnic health disparities, 9(4), 1443-1453","doi":"10.1007/s40615-021-01081-w","pmid":"34152586","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"African American adolescents who were both bullying perpetrators and victims were more likely to use marijuana. White victims were more likely to use alcohol but less likely to use tobacco. Latino bully-victims were more likely to use tobacco. The patterns of substance use associated with bullying involvement differed across racial and ethnic groups.","whyItMatters":"Understanding how bullying intersects with race and substance use helps design targeted prevention programs rather than one-size-fits-all approaches that may miss the most at-risk youth.","specificNumbers":"9,863 participants across White, African American, and Latino groups. African American bully/victims showed significantly higher marijuana use. Analysis used multinomial logistic regression controlling for demographics.","methodology":"Analysis of the 2009-2010 Health Behaviour in School-aged Children study (n=9,863). Adolescents were categorized into four bullying groups (victim-only, bully-only, bully/victim, non-involved). Multinomial logistic regression examined substance use across groups by race/ethnicity.","limitations":"Cross-sectional design cannot determine directionality. Data from 2009-2010 may not reflect current patterns. Self-reported bullying and substance use. Cannabis landscape has changed significantly since data collection."},{"rthcId":"RTHC-03917","title":"Spatial, temporal, and space-time clusters associated with opioid and cannabis poisoning events in U.S. dogs (2005-2014).","authors":"Howard-Azzeh, Mohammad; Pearl, David L; Berke, Olaf; O'Sullivan, Terri L","year":2022,"journal":"PloS one, 17(4), e0266883","doi":"10.1371/journal.pone.0266883","pmid":"35482776","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03918","title":"An exploration of multivariate symptom clusters of cannabis use disorder in young adults.","authors":"Howe, Lindy K; Bailey, Allen J; Ingram, Polly F; Finn, Peter R","year":2022,"journal":"Addictive behaviors, 135, 107465","doi":"10.1016/j.addbeh.2022.107465","pmid":"35995015","tags":["addiction","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Five classes emerged: \"No problems,\" \"Moderate consumption,\" \"Consumption with moderate loss of control,\" \"Consumption with moderate withdrawal,\" and \"High consumption, loss of control, withdrawal.\" The classes differed in which DSM-5 CUD criteria were endorsed, especially among those with moderate-to-severe problems, and showed some differences in co-occurring psychopathology.","whyItMatters":"Treating cannabis use disorder as a single condition may miss important variation. Some people struggle mainly with consumption, others with loss of control, and others with withdrawal, suggesting different interventions may be needed.","specificNumbers":"1,174 participants ages 18-34. 17 DSM-5 CUD symptoms analyzed. 5 distinct classes identified. Classes differed in endorsement patterns for consumption, loss of control, and withdrawal items.","methodology":"Latent class analysis of 17 symptoms corresponding to DSM-5 CUD criteria in 1,174 participants ages 18-34. Multinomial regressions examined associations between class membership and psychological constructs.","limitations":"Cross-sectional design captures a snapshot rather than trajectories. Self-reported symptoms. Predominantly young adult sample may not generalize to older users. Class labels are descriptive, not diagnostic."},{"rthcId":"RTHC-03919","title":"Daily level predictors of impaired driving behaviors in young adults: Protocol design for utilizing daily assessments.","authors":"Hultgren, Brittney A; Guttmannova, Katarina; Lee, Christine M; Acuna, Daniela; Cooper, Rachel L; Kilmer, Jason R; Cadigan, Jennifer M; Calhoun, Brian H; Larimer, Mary E","year":2022,"journal":"PloS one, 17(9), e0275190","doi":"10.1371/journal.pone.0275190","pmid":"36166452","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03920","title":"Cannabis containing equivalent concentrations of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) induces less state anxiety than THC-dominant cannabis.","authors":"Hutten, Nadia R P W; Arkell, T R; Vinckenbosch, F; Schepers, J; Kevin, R C; Theunissen, E L; Kuypers, K P C; McGregor, I S; Ramaekers, J G","year":2022,"journal":"Psychopharmacology, 239(11), 3731-3741","doi":"10.1007/s00213-022-06248-9","pmid":"36227352","tags":["anxiety","cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Both THC and THC/CBD increased state anxiety compared to placebo, but anxiety after THC/CBD was significantly lower than after THC alone. When baseline anxiety was low, CBD completely counteracted THC-induced anxiety. When baseline anxiety was high, CBD did not counteract THC-induced anxiety. THC-induced anxiety was independent of baseline anxiety levels.","whyItMatters":"As cannabis products vary widely in THC-to-CBD ratios, this study provides direct evidence that balanced products may produce less anxiety, which could inform both product selection and regulation.","specificNumbers":"26 participants. 13.75 mg THC and/or 13.75 mg CBD per condition. THC/CBD produced significantly less state anxiety than THC alone. CBD fully counteracted THC anxiety when baseline anxiety was low, but not when it was high.","methodology":"Placebo-controlled, randomized, within-subjects study of 26 healthy recreational cannabis users. Four conditions: vaporized THC-dominant (13.75 mg THC), CBD-dominant (13.75 mg CBD), THC/CBD-equivalent (13.75 mg each), and placebo. Anxiety measured by STAI, visual analogue scale, and emotional Stroop task.","limitations":"Small sample (26 participants). Single-dose study may not reflect repeated use. Recreational users with low tolerance may respond differently than daily users. No effects detected on the objective emotional Stroop task."},{"rthcId":"RTHC-03921","title":"Typologies of Canadian young adults who drive after cannabis use: A two-step cluster analysis.","authors":"Huỳnh, Christophe; Beaulieu-Thibodeau, Alexis; Fallu, Jean-Sébastien; Bergeron, Jacques; Jacques, Alain; Brochu, Serge","year":2022,"journal":"Behavioral sciences & the law, 40(2), 310-330","doi":"10.1002/bsl.2575","pmid":"35445426","tags":["driving","addiction","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Four subgroups emerged: (1) frequent cannabis users who regularly drive after using; (2) individuals with generalized deviance, diverse risky road behaviors, and high psychological distress; (3) alcohol and drug-impaired drivers who were also heavy drinkers; and (4) well-adjusted youths with mild depressive-anxious symptoms.","whyItMatters":"Not all cannabis-impaired drivers are the same. Prevention campaigns and interventions that treat them as a single group may miss the distinct motivations and risk profiles that drive the behavior.","specificNumbers":"910 cannabis users with driver's licenses, ages 17-35. Four distinct subgroups identified. Analysis included driving-related behaviors, cannabis use patterns, and psychological distress measures.","methodology":"Two-step cluster analysis of 910 Canadian cannabis users ages 17-35 with a driver's license who reported driving after cannabis use. Clustering based on driving behaviors, cannabis use and related problems, and psychological distress.","limitations":"Self-selected online sample of people who admitted to driving after cannabis use. Canadian sample may not generalize to other countries. Cross-sectional design. Self-reported driving behavior."},{"rthcId":"RTHC-03922","title":"Cannabis use selectively modulates circulating biomarkers in the blood of schizophrenia patients.","authors":"Ibarra-Lecue, Inés; Unzueta-Larrinaga, Paula; Barrena-Barbadillo, Rocío; Villate, Aitor; Horrillo, Igor; Mendivil, Begoña; Landabaso, Miguel A; Meana, J Javier; Etxebarria, Nestor; Callado, Luis F; Urigüen, Leyre","year":2022,"journal":"Addiction biology, 27(6), e13233","doi":"10.1111/adb.13233","pmid":"36301212","tags":["psychosis","neuroscience","dopamine","inflammation"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Platelet serotonin 2A receptors, active Akt protein, anandamide, other lipid mediators, and pro-inflammatory IL-6 were all significantly increased in schizophrenia patients. However, patients with both schizophrenia and cannabis use disorder did not show these same elevations, suggesting cannabis use normalizes or alters these biomarkers.","whyItMatters":"If schizophrenia patients who use cannabis have fundamentally different biomarker profiles, they may need different treatment approaches. These findings could also explain why dual-diagnosis patients often have different clinical trajectories.","specificNumbers":"Platelet 5-HT2A and phospho-Akt significantly increased in schizophrenia but not in dual diagnosis. Anandamide, PEA, DEA, and IL-6 significantly increased in schizophrenia but not in dual diagnosis. All comparisons were against age- and sex-matched controls.","methodology":"Observational study evaluating blood biomarkers (platelet 5-HT2A receptors, Akt protein, endocannabinoids, IL-6) in subjects with schizophrenia, cannabis use disorder, dual diagnosis, or neither condition, matched by age and sex.","limitations":"Observational design cannot determine causation. Sample sizes not specified in the abstract. Blood biomarkers may not reflect central nervous system processes. Medication use in schizophrenia patients could confound results."},{"rthcId":"RTHC-03923","title":"In utero exposure to cannabidiol disrupts select early-life behaviors in a sex-specific manner.","authors":"Iezzi, Daniela; Caceres-Rodriguez, Alba; Chavis, Pascale; Manzoni, Olivier J J","year":2022,"journal":"Translational psychiatry, 12(1), 501","doi":"10.1038/s41398-022-02271-8","pmid":"36470874","tags":["cbd","pregnancy","youth","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Male pups from CBD-treated dams gained more weight than controls. Males emitted shorter ultrasonic calls while females made more high-frequency calls. CBD-exposed female pups showed reduced motor and discriminatory abilities in homing behavior tests. There were significant qualitative changes in the vocal repertoire of both sexes.","whyItMatters":"CBD use during pregnancy is increasing because CBD is widely perceived as safe. This study challenges that perception by showing sex-specific developmental disruptions in offspring exposed prenatally.","specificNumbers":"CBD dose: 3 mg/kg daily from gestational day 5-18. Male pups gained more weight. Ultrasonic vocalizations measured at postnatal day 10. Homing behavior tested at postnatal day 13. Only females showed impaired motor and discriminatory abilities.","methodology":"C57BL6/J mouse dams received daily CBD (3 mg/kg, subcutaneous) or vehicle from gestational day 5 to 18. Offspring were assessed for body weight, ultrasonic vocalizations (day 10), and homing behavior (day 13) using deep learning analysis.","limitations":"Mouse study with uncertain human relevance. Single CBD dose tested. Subcutaneous administration does not match typical human oral use. Short-term behavioral measures may not predict long-term outcomes. Small number of behavioral tests."},{"rthcId":"RTHC-03924","title":"Drug consumption of suspected drug-influenced drivers in Hungary (2016-2018).","authors":"Institóris, László; Hidvégi, Előd; Kovács, Katalin; Jámbor, Ákos; Dobos, Adrienn; Rárosi, Ferenc; Süvegh, Gábor; Varga, Tibor; Kereszty, Éva M","year":2022,"journal":"Forensic science international, 336, 111325","doi":"10.1016/j.forsciint.2022.111325","pmid":"35569293","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03925","title":"Synthesis, Biological Evaluation, and Molecular Modeling Studies of 3,4-Diarylpyrazoline Series of Compounds as Potent, Nonbrain Penetrant Antagonists of Cannabinoid-1 (CB1R) Receptor with Reduced Lipophilicity.","authors":"Iyer, Malliga R; Cinar, Resat; Wood, Casey M; Zawatsky, Charles N; Coffey, Nathan J; Kim, Kyu Ah; Liu, Ziyi; Katz, Alexis; Abdalla, Jasmina; Hassan, Sergio A; Lee, Yong-Sok","year":2022,"journal":"Journal of medicinal chemistry, 65(3), 2374-2387","doi":"10.1021/acs.jmedchem.1c01836","pmid":"35084860","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03926","title":"Animal evidence considered in determination of cannabis smoke and Δ9 -tetrahydrocannabinol (Δ9 -THC) as causing reproductive toxicity (developmental endpoint); Part II. Neurodevelopmental effects.","authors":"Iyer, Poorni; Niknam, Yassaman; Campbell, Marlissa; Moran, Francisco; Kaufman, Farla; Kim, Allegra; Sandy, Martha; Zeise, Lauren","year":2022,"journal":"Birth defects research, 114(18), 1155-1168","doi":"10.1002/bdr2.2084","pmid":"36111653","tags":["pregnancy","youth","neuroscience","addiction"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Prenatal cannabis smoke or THC exposure in animals produced: impaired locomotor and exploratory behavior (rats), memory and learning deficits, attention deficits, increased separation-induced vocalizations, reduced social interaction, increased anxiety, and enhanced sensitivity to morphine and heroin rewarding effects in adulthood. Altered cannabinoid receptor expression and gene changes in the nucleus accumbens provided mechanistic support.","whyItMatters":"This review underpinned a formal regulatory determination. The consistency of neurodevelopmental effects across species and exposure windows strengthens the case that prenatal cannabis exposure poses real risks to offspring brain development.","specificNumbers":"Effects documented across rats, monkeys, and zebrafish. Altered mRNA levels in the nucleus accumbens (addiction-related brain region). Increased morphine self-administration acquisition in adult rats prenatally exposed to THC.","methodology":"Comprehensive review of animal studies examining neurodevelopmental effects after preconceptional, prenatal, or perinatal exposure to cannabis smoke or THC. Included rodent and primate studies, plus zebrafish validation. Findings contributed to California's Developmental and Reproductive Toxicant Identification Committee decision.","limitations":"Animal studies may not directly translate to humans. Dosing and exposure routes differ from typical human use. Publication bias may overrepresent positive findings. Human observational studies have more confounders but are more directly relevant."},{"rthcId":"RTHC-03927","title":"Nationwide Trends in Hospitalizations and Outcomes of Pulmonary Circulation Disorders Among Patients With Cannabis Use Disorder in the United States.","authors":"Jain, Akhil; Gandhi, Zainab; Desai, Rupak; Mansuri, Uvesh; Rizvi, Bisharah; Alvarez, Melissa; Gupta, Puneet","year":2022,"journal":"Cureus, 14(3), e22897","doi":"10.7759/cureus.22897","pmid":"35399488","tags":["cardiovascular","respiratory","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 3,307,310 cannabis-related hospitalizations, 20,328 (0.61%) involved pulmonary circulation disorders. PCD-related hospitalizations increased 200% (from 0.3% to 0.9%) over the study period. Patients with cannabis and PCD had an all-cause in-hospital mortality of 4.1% vs. 0.5% without PCD. Adjusted odds ratio for mortality was 2.17.","whyItMatters":"The 200% increase in pulmonary circulation disorders among cannabis users, combined with doubled mortality risk, suggests this is an emerging and potentially life-threatening complication that clinicians should monitor.","specificNumbers":"3,307,310 total cannabis hospitalizations. 20,328 with PCD (0.61%). 200% relative increase in PCD prevalence (0.3% to 0.9%, 2007-2014). In-hospital mortality: 4.1% with PCD vs. 0.5% without. Adjusted OR for mortality: 2.17 (95% CI: 1.99-2.36). PCD patients were older (mean 47 vs. 34 years). Median hospital stay: 6 vs. 3 days.","methodology":"Analysis of the National Inpatient Sample (NIS) from 2007-2014, comparing cannabis users with pulmonary circulation disorders to those without. Examined demographics, comorbidities, and in-hospital outcomes including mortality and healthcare utilization.","limitations":"Administrative database study cannot establish causation. ICD coding may misclassify conditions. Cannabis use disorder diagnosis does not capture dose, duration, or route. PCD patients were older with more comorbidities, which confound the mortality comparison. Temporal association does not prove cannabis caused PCD."},{"rthcId":"RTHC-03928","title":"Cannabinoids in rheumatology: Friend, foe or a bystander?","authors":"Jain, Nibha; Moorthy, Arumugam","year":2022,"journal":"Musculoskeletal care, 20(2), 416-428","doi":"10.1002/msc.1636","pmid":"35476898","tags":["medical-cannabis","pain","inflammation","drug-interactions"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Cannabinoids act through CB1 and CB2 receptors with potential analgesic effects. Some benefits were found for rheumatoid arthritis, osteoarthritis, and fibromyalgia. However, cannabinoids have potential interactions with common rheumatology drugs that many users are unaware of, and the review concluded on balance that cannabinoids are more \"foe\" than \"friend\" for rheumatology.","whyItMatters":"Rheumatology patients increasingly use cannabinoids for pain without prescription, often unaware of potential interactions with their prescribed medications. This review directly addresses a knowledge gap in clinical practice.","specificNumbers":"613 articles screened. Two major cannabinoid receptor types (CB1, CB2) reviewed. Despite NHS guidelines against cannabinoid use for chronic pain, patients increasingly use them without prescriptions.","methodology":"Narrative review searching PubMed for \"Cannabinoids,\" \"Rheumatology,\" and \"Chronic pain.\" Screened 613 articles for mechanism of action, adverse effects, and drug interactions. Included musculoskeletal librarian consultation.","limitations":"Narrative review methodology is less rigorous than systematic review. Concluded \"foe\" based on risk-benefit balance, which involves subjective judgment. Drug interaction evidence is primarily theoretical for many rheumatology medications."},{"rthcId":"RTHC-03929","title":"Case report: A case of undiagnosed cannabinoid hyperemesis syndrome in rural part of Nepal.","authors":"Jaishi, Prakash Poudel; Neupane, Sandhya Kiran; Joshi, Kusum; Shrestha, Nilasma; Khatri, Subhash Sendas; Lamichhane, Saral; Neupane, Prabhat Kiran","year":2022,"journal":"Annals of medicine and surgery (2012), 84, 104897","doi":"10.1016/j.amsu.2022.104897","pmid":"36582911","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03930","title":"Anti-Inflammatory and Antiviral Effects of Cannabinoids in Inhibiting and Preventing SARS-CoV-2 Infection.","authors":"Janecki, Marcin; Graczyk, Michał; Lewandowska, Agata Anna; Pawlak, Łukasz","year":2022,"journal":"International journal of molecular sciences, 23(8)","doi":"10.3390/ijms23084170","pmid":"35456990","tags":["cbd","inflammation","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Cannabinoids interact with multiple receptors (GPR55, TRPV1, PPARs, 5-HT1A, adenosine, glycine) beyond CB1/CB2 to produce anti-inflammatory and antiviral effects. Since SARS-CoV-2 triggers excessive immune response and inflammatory cascades, cannabinoids' ability to regulate these processes suggests theoretical potential for COVID-19 treatment. Secondary cannabinoids like cannabigerolic acid (CBGA) and terpenes also showed anti-inflammatory and antiviral potential.","whyItMatters":"During the pandemic, many claims circulated about cannabis and COVID-19. This review consolidates what is actually known about the biological mechanisms while making clear that clinical evidence is absent.","specificNumbers":"Multiple receptor systems identified: CB1, CB2, GPR55, TRPV1, PPARs, 5-HT1A, adenosine, and glycine receptors. CBD and CBGA highlighted as most promising compounds.","methodology":"Narrative review of literature from PubMed, Scopus, and Web of Science on cannabinoid anti-inflammatory and antiviral mechanisms potentially relevant to COVID-19.","limitations":"No clinical trial data for cannabinoids in COVID-19 patients. Evidence based entirely on in vitro studies, preclinical models, and theoretical mechanisms. Anti-inflammatory effects in a lab do not guarantee clinical benefit."},{"rthcId":"RTHC-03931","title":"Linking in vitro and ex vivo CB1 activity with serum concentrations and clinical features in 5F-MDMB-PICA users to better understand SCRAs and their metabolites.","authors":"Janssens, Liesl K; Hudson, Simon; Wood, David M; Wolfe, Caitlin; Dargan, Paul I; Stove, Christophe P","year":2022,"journal":"Archives of toxicology, 96(11), 2935-2945","doi":"10.1007/s00204-022-03355-6","pmid":"35962200","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Serum concentrations of 5F-MDMB-PICA correlated with ex vivo CB1 receptor activation in a sigmoidal relationship. The Glasgow Coma Scale showed a significant decreasing trend with increasing cannabinoid activity, meaning higher drug levels corresponded with greater impairment of consciousness. In vitro testing of five metabolites revealed two theoretically active metabolites, but in vivo their contribution to overall cannabinoid activity was negligible.","whyItMatters":"Synthetic cannabinoids are far more dangerous than natural cannabis, and this is the first large patient cohort study to link 5F-MDMB-PICA blood levels to clinical outcomes. The dose-response relationship between drug levels and consciousness impairment provides crucial toxicological data.","specificNumbers":"71 patients. 5F-MDMB-PICA and five metabolites identified. Sigmoidal relationship between serum concentration and CB1 activation. Significant trend of decreasing GCS with increasing cannabinoid activity. Two metabolites showed in vitro activity but negligible in vivo contribution.","methodology":"Evaluation of 71 patients presenting with recreational drug toxicity from 5F-MDMB-PICA. LC-HRMS confirmed and quantified the drug in serum. A CB1 bioassay measured ex vivo cannabinoid activity. Clinical features including Glasgow Coma Scale were correlated with drug levels.","limitations":"Single synthetic cannabinoid studied. Patients may have used other substances not detected. GCS is a crude measure of impairment. The correlation between blood levels and clinical effects may not hold for other synthetic cannabinoids with different pharmacology."},{"rthcId":"RTHC-03932","title":"Machine Learning to Assist in Large-Scale, Activity-Based Synthetic Cannabinoid Receptor Agonist Screening of Serum Samples.","authors":"Janssens, Liesl K; Boeckaerts, Dimitri; Hudson, Simon; Morozova, Daria; Cannaert, Annelies; Wood, David M; Wolfe, Caitlin; De Baets, Bernard; Stock, Michiel; Dargan, Paul I; Stove, Christophe P","year":2022,"journal":"Clinical chemistry, 68(7), 906-916","doi":"10.1093/clinchem/hvac027","pmid":"35266984","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03933","title":"Attention deficit hyperactivity disorder symptoms and cannabis use after one year among students of the i-Share cohort.","authors":"Jean, François Arnaud Matthieu; Arsandaux, Julie; Montagni, Ilaria; Collet, Ophélie; Fatséas, Mélina; Auriacombe, Marc; Ramos-Quiroga, Josep Antoni; Côté, Sylvana M; Tzourio, Christophe; Galéra, Cédric","year":2022,"journal":"European psychiatry : the journal of the Association of European Psychiatrists, 65(1), 1-18","doi":"10.1192/j.eurpsy.2022.14","pmid":"35348052","tags":["cognition","addiction","youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Higher ASRS scores were associated with greater probability of cannabis use after one year (OR 1.24 for occasional use, OR 1.43 for frequent use). Among students who had never used cannabis, ADHD symptoms did not predict initiation. Among those who had used cannabis before, ADHD symptoms predicted continued and more frequent use.","whyItMatters":"This distinction between initiation and continuation matters for prevention. ADHD symptoms appear to perpetuate cannabis use in those already using rather than drive new users to start.","specificNumbers":"4,270 participants. Among all students: OR 1.24 for occasional use, OR 1.43 for frequent use. Among never-users: OR 1.15 (not significant). Among prior users: OR 1.17 (occasional), OR 1.35 (frequent).","methodology":"Longitudinal cohort study from the French i-Share cohort. 4,270 university students (2,135 never-users and 2,135 prior users) assessed with the Adult ADHD Self-Report Scale at baseline, with cannabis use frequency evaluated one year later.","limitations":"Self-reported ADHD symptoms, not clinical diagnoses. French university students may not generalize to other populations. One-year follow-up may miss longer-term patterns. Cannabis use frequency self-reported."},{"rthcId":"RTHC-03934","title":"Cannabis Vapor Exposure Alters Neural Circuit Oscillatory Activity in a Neurodevelopmental Model of Schizophrenia: Exploring the Differential Impact of Cannabis Constituents.","authors":"Jenkins, Bryan W; Buckhalter, Shoshana; Perreault, Melissa L; Khokhar, Jibran Y","year":2022,"journal":"Schizophrenia bulletin open, 3(1), sgab052","doi":"10.1093/schizbullopen/sgab052","pmid":"35036917","tags":["psychosis","neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"NVHL rats (schizophrenia model) had reduced baseline gamma power in multiple brain regions. THC-only vapor further suppressed oscillatory power and coherence beyond these deficits. Balanced THC/CBD vapor did not suppress oscillations and sometimes enhanced power. Interestingly, THC-only vapor normalized one specific baseline deficit (HIP-Cg high-gamma coherence).","whyItMatters":"Cannabis use is highly prevalent among people with schizophrenia and generally worsens outcomes. This study provides a mechanistic explanation: THC suppresses already-disrupted brain oscillations, while CBD may protect against this effect.","specificNumbers":"THC-only vapor: 8-18% THC, 0% CBD. Balanced vapor: 4-11% THC, 8.5-15.5% CBD. Brain regions measured: cingulate cortex, prelimbic cortex, hippocampus, nucleus accumbens. 2-week washout between exposures.","methodology":"Male rats underwent neonatal ventral hippocampal lesion (NVHL, a schizophrenia model) or sham surgery. In adulthood, electrodes were implanted in four brain regions. Local field potentials were recorded after exposure to THC-only or balanced THC/CBD cannabis vapor in a crossover design with two-week washout.","limitations":"Animal model of schizophrenia does not fully replicate human disease. Acute vapor exposure may not reflect chronic use patterns. Small sample sizes typical of electrophysiology studies. Cross-over design assumes complete washout."},{"rthcId":"RTHC-03935","title":"Cannabidiol enhances the antinociceptive effects of morphine and attenuates opioid-induced tolerance in the chronic constriction injury model.","authors":"Jesus, Carlos Henrique Alves; Ferreira, Matheus Vinicius; Gasparin, Aléxia Thamara; Rosa, Evelize Stacoviaki; Genaro, Karina; Crippa, José Alexandre de Souza; Chichorro, Juliana Geremias; Cunha, Joice Maria da","year":2022,"journal":"Behavioural brain research, 435, 114076","doi":"10.1016/j.bbr.2022.114076","pmid":"36028000","tags":["cbd","pain","drug-interactions","tolerance"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD (30 mg/kg) combined with a sub-effective dose of morphine (1 mg/kg) produced enhanced pain relief for both evoked and ongoing pain that neither drug achieved alone. CBD also partially attenuated morphine-induced tolerance. The combination did not alter locomotor activity.","whyItMatters":"If CBD can enhance morphine effectiveness at lower doses and slow tolerance development, it could allow patients to use less opioid medication while maintaining pain relief, reducing addiction risk.","specificNumbers":"CBD 30 mg/kg + morphine 1 mg/kg (sub-effective alone) produced significant antinociception. Morphine alone at 1 mg/kg was ineffective. Combined treatment produced significant CPP scores. CBD partially attenuated morphine tolerance over 4 days.","methodology":"Chronic constriction injury (CCI) model of neuropathic pain in rats. Mechanical thresholds measured evoked pain. Conditioned place preference (CPP) measured ongoing pain relief. Four-day tolerance protocol assessed whether CBD prevented morphine tolerance.","limitations":"Animal study with uncertain human translation. Single CBD dose tested. Short tolerance protocol (4 days). Mechanism of CBD-morphine interaction not fully elucidated. Neuropathic pain model may not generalize to all pain types."},{"rthcId":"RTHC-03936","title":"Combined-Acupoint Electroacupuncture Induces Better Analgesia via Activating the Endocannabinoid System in the Spinal Cord.","authors":"Jiang, Zhenhua; Li, Yuheng; Wang, Qun; Fang, Zongping; Deng, Jiao; Zhang, Xinxin; Shen, Bowen; Wu, Zhixin; Yang, Qianzi; Xiong, Lize","year":2022,"journal":"Neural plasticity, 2022, 7670629","doi":"10.1155/2022/7670629","pmid":"36160326","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03937","title":"Association between secondhand marijuana smoke and respiratory infections in children.","authors":"Johnson, Adam B; Wang, George S; Wilson, Karen; Cline, David M; Craven, Timothy E; Slaven, Sarah; Raghavan, Vidya; Mistry, Rakesh D","year":2022,"journal":"Pediatric research, 91(7), 1769-1774","doi":"10.1038/s41390-021-01641-0","pmid":"34321605","tags":["youth","respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Caregivers who used marijuana reported an increased rate of viral respiratory infections in their children (1.31 episodes/year) compared to non-users (1.04 episodes/year, p=0.02). No significant differences were found for ED/UC visits, otitis media, or asthma exacerbations with marijuana smoke exposure.","whyItMatters":"While secondhand tobacco smoke effects on children are well established, this is among the first studies to identify a specific health risk from secondhand marijuana smoke in children.","specificNumbers":"1,500 caregivers surveyed. 158 (10.5%) reported smoking marijuana. 294 (19.6%) reported smoking tobacco. VRI rate: 1.31 vs. 1.04 episodes/year (p=0.02). No significant difference for ED visits, ear infections, or asthma.","methodology":"Cross-sectional convenience sample survey of 1,500 caregivers in a pediatric ED. Inclusion: caregivers ages 21-85, English- or Spanish-speaking. Exclusion: critically ill, medically complex, or children over 11 or using medical marijuana. Negative-binomial regression estimated rates.","limitations":"Cross-sectional design cannot establish causation. Self-reported marijuana use likely underestimated. Convenience sample from one pediatric ED. Did not measure actual smoke exposure levels. Confounders like socioeconomic factors not fully controlled."},{"rthcId":"RTHC-03938","title":"Cannabidiol (CBD) product contamination: Quantitative analysis of Δ9-tetrahydrocannabinol (Δ9-THC) concentrations found in commercially available CBD products.","authors":"Johnson, Erin; Kilgore, Michael; Babalonis, Shanna","year":2022,"journal":"Drug and alcohol dependence, 237, 109522","doi":"10.1016/j.drugalcdep.2022.109522","pmid":"35690015","tags":["cbd","potency","harm-reduction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"THC was detected above the quantification limit in 52 of 80 unregulated CBD products (65%). THC concentrations ranged from 0.008 to 2.071 mg/mL. Of 21 products labeled \"THC-Free,\" 5 (24%) contained detectable THC levels ranging from 0.015 to 0.656 mg/mL.","whyItMatters":"Consumers choosing CBD products specifically to avoid THC may unknowingly consume it. This has implications for drug testing, employment, child custody, driving, and military service.","specificNumbers":"80 products tested. 52 (65%) had detectable THC. Range: 0.008-2.071 mg/mL. 21 labeled \"THC-Free,\" 5 (24%) contained THC (0.015-0.656 mg/mL). LOQ: 0.005 mg/mL.","methodology":"LC-MS/MS analysis of 80 unregulated hemp-derived CBD oil products purchased online and from local retailers in central Kentucky, compared to the regulated control Epidiolex. Products were extracted by solvent extraction and quantified using a validated method.","limitations":"Products from one geographic region (central Kentucky). Market may have changed since testing. Single time point does not capture batch-to-batch variation. Did not assess whether THC levels would produce psychoactive effects or positive drug tests."},{"rthcId":"RTHC-03939","title":"Label accuracy of unregulated cannabidiol (CBD) products: measured concentration vs. label claim.","authors":"Johnson, Erin; Kilgore, Michael; Babalonis, Shanna","year":2022,"journal":"Journal of cannabis research, 4(1), 28","doi":"10.1186/s42238-022-00140-1","pmid":"35658956","tags":["cbd","potency","harm-reduction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Of 80 products, 37 (46%) contained CBD concentrations more than 10% different from label claims. Discrepancies ranged from 0.9 to 30.6 mg/mL off from the label. 12 products were underlabeled (more than 110% of claim) and 25 were overlabeled (less than 90% of claim). Overall concordance within 10% tolerance was only 54%.","whyItMatters":"When nearly half of CBD products contain the wrong amount, consumers cannot reliably dose. Too little means no benefit; too much risks drug interactions and liver enzyme elevations.","specificNumbers":"80 products tested. Label claims: 7.5-60 mg/mL. Measured: 2.9-61.3 mg/mL. 37 products (46%) outside 10% tolerance. 25 overlabeled (too little CBD), 12 underlabeled (too much). Concordance rate: 54%.","methodology":"LC-MS/MS analysis of 80 commercially available hemp-derived CBD products from online and local retailers in central Kentucky. CBD concentrations were compared to label claims. Epidiolex included as a regulated positive control.","limitations":"Products from one geographic area. Single time point. Did not assess whether labeling accuracy varied by price point, brand type, or sales channel. Epidiolex as the only regulated comparator."},{"rthcId":"RTHC-03940","title":"Prenatal marijuana exposure and neonatal outcomes: a retrospective cohort study.","authors":"Jones, Michael James; Lotfi, Asma; Lin, Amber; Gievers, Ladawna L; Hendrickson, Robert; Sheridan, David C","year":2022,"journal":"BMJ open, 12(9), e061167","doi":"10.1136/bmjopen-2022-061167","pmid":"36171027","tags":["pregnancy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Neonates exposed to THC had significantly lower birth weight, head circumference, and length (all p<0.001). THC-exposed neonates had 1.9 times the odds of low birth weight (95% CI 1.3-2.7). Birth weight was on average 0.16 kg lower in THC-exposed infants after controlling for confounders.","whyItMatters":"This study overcomes a major limitation of prior research by using meconium drug testing instead of maternal self-report, providing more reliable exposure data. The consistent findings across multiple growth measures strengthen the evidence.","specificNumbers":"1,540 meconium screens analyzed. 483 positive for THC only. Birth weight 0.16 kg lower (95% CI 0.10-0.22, p<0.001). OR for low birth weight: 1.9 (95% CI 1.3-2.7). Significantly lower head circumference and length as well.","methodology":"Retrospective cohort using meconium drug screens from infants born in a Pacific Northwest hospital system over 2.5 years. 1,540 screens analyzed: 483 positive for THC only (no other drugs) compared to negative screens. Multivariable regression controlled for confounders.","limitations":"Retrospective design. Meconium testing confirms exposure but does not measure dose, timing, or frequency. Hospital system population may not generalize. Unknown confounders despite multivariable adjustment. Single geographic region."},{"rthcId":"RTHC-03941","title":"Marijuana and the Lung: Evolving Understandings.","authors":"Joshi, Manish; Joshi, Anita; Bartter, Thaddeus","year":2022,"journal":"The Medical clinics of North America, 106(6), 1093-1107","doi":"10.1016/j.mcna.2022.07.010","pmid":"36280335","tags":["respiratory","cancer","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Marijuana can cause bronchitis symptoms. However, a moderate body of literature suggests that distal airway and lung tissue disease does not occur with marijuana use. Marijuana does not appear to cause chronic obstructive pulmonary disease and probably does not cause lung cancer, a markedly different profile from tobacco.","whyItMatters":"Many people assume marijuana smoke is as harmful as tobacco smoke. This review indicates the lung damage profiles are distinctly different, which is important for risk communication and policy.","specificNumbers":"No specific numerical outcomes reported. The review characterized the evidence as a \"moderate body of literature\" for the absence of COPD and lung cancer associations.","methodology":"Review of the literature on marijuana's effects on lung health, including comparisons with tobacco smoke effects.","limitations":"Review without detailed methodology described. \"Probably does not cause lung cancer\" reflects uncertainty. Most studies compare infrequent marijuana use to daily tobacco use, making direct comparisons difficult. Vaping and concentrated products not fully addressed."},{"rthcId":"RTHC-03942","title":"Marijuana Use Is Associated With Suicidal Ideation and Behavior Among US Adolescents at Rates Similar to Tobacco and Alcohol.","authors":"Kahn, Geoffrey D; Wilcox, Holly C","year":2022,"journal":"Archives of suicide research : official journal of the International Academy for Suicide Research, 26(2), 520-533","doi":"10.1080/13811118.2020.1804025","pmid":"32780674","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Marijuana was more strongly associated with suicide attempts than with suicidal ideation. More frequent marijuana use was associated with significantly greater risk. The association remained stable from 2011 to 2017 despite changing attitudes toward marijuana. Results were broadly comparable to tobacco, though frequent alcohol use had a significantly stronger association than other substances.","whyItMatters":"As marijuana legalization expanded between 2011 and 2017, the association between marijuana use and suicidality in teens remained unchanged, suggesting that normalization of marijuana use has not reduced this risk.","specificNumbers":"Six years of national data (2011-2017). Marijuana more strongly associated with attempts than ideation. Dose-response: more frequent use = greater risk. Association stable over time despite changing attitudes. Comparable to tobacco; weaker than frequent alcohol.","methodology":"Analysis of the National Youth Risk Behavior Survey (2011-2017). Logistic regression controlling for confounders estimated marginal prevalence ratios for the association between marijuana, tobacco, and alcohol use and suicidal ideation and attempts.","limitations":"Cross-sectional data cannot establish causation. Self-reported substance use and suicidality. National survey may miss highest-risk youth. Cannot determine whether marijuana use preceded or followed suicidal thoughts. Confounders may not be fully controlled."},{"rthcId":"RTHC-03943","title":"Effects of cannabidiol on vacuous chewing movements, plasma glucose and oxidative stress indices in rats administered high dose risperidone.","authors":"Kajero, Jaiyeola Abiola; Seedat, Soraya; Ohaeri, Jude; Akindele, Abidemi; Aina, Oluwagbemiga","year":2022,"journal":"Scientific reports, 12(1), 19718","doi":"10.1038/s41598-022-24235-0","pmid":"36385633","tags":["cbd","drug-interactions","psychosis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD (5 mg/kg) significantly reduced risperidone-induced elevated fasting blood sugar when given after risperidone. CBD also reduced vacuous chewing movements (a model of tardive dyskinesia) when given before risperidone, and attenuated risperidone-induced increased muscle tone. Concomitant or sequential CBD and risperidone administration did not adversely affect cognition or locomotion.","whyItMatters":"Antipsychotic side effects (metabolic syndrome, movement disorders) are a major reason patients stop taking their medications. If CBD can mitigate these without adding cognitive problems, it could improve treatment adherence.","specificNumbers":"Risperidone: 10 mg/kg for 28 days. CBD: 5 mg/kg. CBD reduced elevated fasting blood sugar. CBD reduced VCM when given before risperidone. Both CBD and risperidone increased antioxidant enzyme activity and decreased pro-oxidant enzymes.","methodology":"Six experimental groups of rats received oral risperidone (10 mg/kg) for 28 days, oral CBD (5 mg/kg) in various temporal relationships to risperidone, or CBD alone for 21 days. Vacuous chewing movements, muscle tone, fasting blood sugar, oxidative stress markers, cognition, and locomotion were assessed.","limitations":"Animal study with high risperidone doses. Rats metabolize drugs differently than humans. Short duration relative to chronic antipsychotic use in humans. Small sample sizes per group. Effect sizes not reported."},{"rthcId":"RTHC-03944","title":"The interactive effects of verapamil and CB1 cannabinoid receptor antagonist/inverse agonist, AM251 on passive avoidance learning and memory in rat.","authors":"Karimi, Seyed Asaad; Noorbakhsh, Mariam; Komaki, Hamidreza; Reza Nikoo, Mohammad; Hasanein, Parisa; Shahidi, Siamak; Faraji, Nafiseh; Komaki, Alireza","year":2022,"journal":"Behavioural pharmacology, 33(2&3), 222-229","doi":"10.1097/FBP.0000000000000638","pmid":"34845169","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03945","title":"Effects of High-Potency Cannabis on Psychomotor Performance in Frequent Cannabis Users.","authors":"Karoly, Hollis C; Milburn, Michael A; Brooks-Russell, Ashley; Brown, Mary; Streufert, Jessica; Bryan, Angela D; Lovrich, Nicholas P; DeJong, William; Cinnamon Bidwell, L","year":2022,"journal":"Cannabis and cannabinoid research, 7(1), 107-115","doi":"10.1089/can.2020.0048","pmid":"33998859","tags":["driving","cognition","potency","tolerance"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Peak psychomotor impairment occurred immediately after cannabis use, with significant recovery by one hour post-use. This pattern was consistent across both the primary Colorado study (n=70) and the Washington replication (n=39). Significant quadratic effects of time emerged in both studies.","whyItMatters":"There is no validated roadside test for cannabis impairment. This study suggests that psychomotor recovery happens within about an hour even for high-potency cannabis, and that app-based measures could potentially serve as impairment assessment tools.","specificNumbers":"70 participants (Colorado), 39 participants (Washington replication). Peak impairment immediately after acute use. Significant recovery at 1 hour. Both studies showed significant quadratic time effects. Clinical trial NCT03522103.","methodology":"Primary study: 70 frequent cannabis users in Colorado used the DRUID app at baseline (sober), pre-use, immediately post-use, and 1 hour post-use of self-selected high-potency cannabis. Replication: 39 participants in Washington measured every 30 minutes for 2.5 hours.","limitations":"Naturalistic use with self-selected products limits dose control. Frequent users may have different impairment profiles than occasional users. DRUID app not yet validated as a driving impairment measure. One-hour recovery of test performance may not reflect all driving-relevant skills."},{"rthcId":"RTHC-03946","title":"Predictors of admission to an assertive outreach service for psychosis in Lebanon.","authors":"Kassir, Ghida; El Hayek, Samer; Charara, Raghid; Cherro, Michele; Itani, Hala; El Khoury, Joseph","year":2022,"journal":"PLOS global public health, 2(12), e0001428","doi":"10.1371/journal.pgph.0001428","pmid":"36962861","tags":["psychosis","addiction","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use disorder was a significant predictor of enrollment in the Psychosis Recovery Outreach Program (OR 2.83, 95% CI 1.25-6.37). Other predictors included being prescribed long-acting injectable antipsychotics (OR 9.99), multiple oral antipsychotics (OR 4.57), multiple ER visits (OR 8.7), and psychiatric admission (OR 13.91).","whyItMatters":"Cannabis use disorder alongside psychosis signals a more severe clinical course requiring intensive treatment. This confirms in a non-Western setting what has been observed elsewhere.","specificNumbers":"45 PROP patients. 77.8% male. 80% under 39 years. 22.7% had comorbid cannabis use disorder. 46.7% schizophrenia, 48.9% schizoaffective disorder. Cannabis use disorder OR 2.83 for program enrollment.","methodology":"Retrospective analysis of 45 patients enrolled in the Psychosis Recovery Outreach Program at a psychiatric facility in Lebanon. Logistic regression identified predictors of enrollment compared to patients receiving standard treatment. Twelve-month data collected.","limitations":"Small sample (45 patients). Single facility in Lebanon. Retrospective design. Enrollment in outreach program is a proxy for severity, not a direct outcome measure. Selection bias possible."},{"rthcId":"RTHC-03947","title":"Cannabis use and suicidal ideation among youth: Can we democratize school policies using digital citizen science?","authors":"Katapally, Tarun Reddy","year":2022,"journal":"PloS one, 17(2), e0263533","doi":"10.1371/journal.pone.0263533","pmid":"35157726","tags":["youth","mental-health","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was significantly associated with increased suicidal ideation among youth. Other associated factors included bullying, other illicit drug use, and identifying as female or other gender. School policies and programs for substance misuse prevention did not mediate the association between cannabis use and suicidal ideation.","whyItMatters":"If school-based substance prevention programs do not reduce the cannabis-suicidality link, different intervention approaches may be needed. The digital citizen science method also demonstrates a novel way to study sensitive topics in real time.","specificNumbers":"818 youth recruited, 412 provided relevant data. 27 educators surveyed about school policies. Cannabis use, bullying, other drug use, and female/other gender associated with suicidal ideation. School policies had no mediating effect.","methodology":"Digital citizen science approach engaging 818 youth (13-18 years) and 27 educators via smartphones. Youth responded to time-triggered validated surveys and ecological momentary assessments. Educators reported on school policies. 412 youth provided data on substance use and suicidal ideation. Multivariable logistic regression and mediation analysis.","limitations":"Small analytic sample (412 of 818 recruited). Cross-sectional design. Self-reported data on sensitive topics. School policy measures may not capture implementation quality. Single geographic area."},{"rthcId":"RTHC-03948","title":"Rapid Simultaneous Determination of Three Synthetic Cannabinoids in Urine and Plasma of Rats Using Ultra-High Performance Liquid Chromatography Tandem Mass Spectrometry.","authors":"Ke, Xing; Tian, Yimei; He, Dandan; Mu, Pengqian; Wan, Xuzhi; Zhang, Lange; Jia, Wei; Wang, Qiao; Fan, Yilei; Zhang, Yu","year":2022,"journal":"Toxics, 10(10)","doi":"10.3390/toxics10100619","pmid":"36287899","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03949","title":"Associations of cannabis product source and subsequent cannabis use among adolescents.","authors":"Kelleghan, Annemarie R; Sofis, Michael J; Budney, Alan; Ceasar, Rachel; Leventhal, Adam M","year":2022,"journal":"Drug and alcohol dependence, 233, 109374","doi":"10.1016/j.drugalcdep.2022.109374","pmid":"35272186","tags":["youth","addiction","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Most youth (72%) received cannabis for free. 51% bought from someone, 16% used a medical card at a dispensary, and 4% grew their own. Buying from someone (OR 1.46) and using a valid medical card (OR 1.99) predicted any cannabis use six months later. Buying from someone also predicted more frequent use (RR 1.25).","whyItMatters":"Understanding which access points predict escalation helps target prevention. The finding that medical card access predicted the strongest continued use raises questions about youth medical cannabis authorization.","specificNumbers":"835 high schoolers (mean age ~17). 72.1% received cannabis free. 50.9% bought from someone (OR 1.46 for continued use). 15.9% used valid medical card (OR 1.99). 3.9% self-grown. Buying from someone: RR 1.25 for frequency.","methodology":"Longitudinal study of 835 high schoolers completing 3 semiannual surveys. Time-lagged repeated-measures regression examined how cannabis sources at one wave predicted use frequency six months later. Seven source types assessed as separate dichotomous variables.","limitations":"Self-reported sources. California-based sample during specific legal period. Six-month intervals may miss shorter-term patterns. Cannot determine whether the source caused continued use or whether more committed users seek out purchasing sources."},{"rthcId":"RTHC-03950","title":"Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain.","authors":"Kelly, Rachel; Bemelmans, Alexis-Pierre; Joséphine, Charlène; Brouillet, Emmanuel; McKernan, Declan P; Dowd, Eilís","year":2022,"journal":"Molecules (Basel, Switzerland), 27(2)","doi":"10.3390/molecules27020507","pmid":"35056822","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03951","title":"Cannabis, cannabidiol and tetrahydrocannabinol in sport: an overview.","authors":"Kennedy, Michael","year":2022,"journal":"Internal medicine journal, 52(9), 1471-1477","doi":"10.1111/imj.15724","pmid":"35191178","tags":["cbd","exercise","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"CBD and THC do not enhance performance. CBD has anti-inflammatory and analgesic properties that have not been adequately evaluated in the sport context. WADA allows CBD but bans all other cannabinoids. Some CBD formulations contain THC or other cannabinoids that may cause a positive drug test.","whyItMatters":"Cannabis industry sponsorship of sporting events is increasing alongside liberalized laws. Athletes need accurate information about performance effects, anti-doping rules, and product contamination risks.","specificNumbers":"WADA banned list includes all cannabinoids except CBD. No performance-enhancing effects documented for CBD or THC. Product contamination risk documented but not quantified in this review.","methodology":"Narrative review examining CBD, THC, and cannabis in the context of elite sport, including WADA regulations, performance effects, and product contamination risks.","limitations":"Narrative review without systematic methodology. Limited sport-specific research available to review. Did not quantify the risk of positive drug tests from contaminated CBD products."},{"rthcId":"RTHC-03952","title":"Changes in striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence in male and female mice.","authors":"Kesner, Andrew J; Mateo, Yolanda; Abrahao, Karina P; Ramos-Maciel, Stephanie; Pava, Matthew J; Gracias, Alexa L; Paulsen, Riley T; Carlson, Hartley B; Lovinger, David M","year":2022,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(8), 1537-1549","doi":"10.1038/s41386-022-01326-0","pmid":"35478010","tags":["withdrawal","dopamine","sleep","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"THC withdrawal produced altered striatal dopamine release, sleep disturbances that mimic clinical observations (disrupted sleep architecture), and affect-related behavioral changes. These effects were more consistently observed in male mice than in females, suggesting sex-specific vulnerability to withdrawal.","whyItMatters":"Sleep disturbances are a primary driver of cannabis relapse in humans. This mouse model replicates key features of human THC withdrawal and provides a platform for studying the neural mechanisms involved.","specificNumbers":"Dopamine release measured in multiple striatal subregions during early and late abstinence. Sleep architecture assessed before, during, and after THC treatment. Behavioral measures modeled human withdrawal symptoms.","methodology":"Mice received a THC treatment regimen known to produce tolerance. During early and late abstinence, researchers measured electrically evoked dopamine release in brain slices, long-term polysomnographic sleep recordings, and withdrawal-related behaviors.","limitations":"Mouse model may not fully replicate human withdrawal. Spontaneous withdrawal paradigm better mimics human cessation but produces subtler effects than precipitated withdrawal. Sex differences in mice may not translate directly to humans."},{"rthcId":"RTHC-03953","title":"Off-target pharmacological profiling of synthetic cannabinoid receptor agonists including AMB-FUBINACA, CUMYL-PINACA, PB-22, and XLR-11.","authors":"Kevin, Richard C; Cairns, Elizabeth A; Boyd, Rochelle; Arnold, Jonathon C; Bowen, Michael T; McGregor, Iain S; Banister, Samuel D","year":2022,"journal":"Frontiers in psychiatry, 13, 1048836","doi":"10.3389/fpsyt.2022.1048836","pmid":"36590635","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03954","title":"Putative Synthetic Cannabinoids MEPIRAPIM, 5F-BEPIRAPIM (NNL-2), and Their Analogues Are T-Type Calcium Channel (CaV3) Inhibitors.","authors":"Kevin, Richard C; Mirlohi, Somayeh; Manning, Jamie J; Boyd, Rochelle; Cairns, Elizabeth A; Ametovski, Adam; Lai, Felcia; Luo, Jia Lin; Jorgensen, William; Ellison, Ross; Gerona, Roy R; Hibbs, David E; McGregor, Iain S; Glass, Michelle; Connor, Mark; Bladen, Chris; Zamponi, Gerald W; Banister, Samuel D","year":2022,"journal":"ACS chemical neuroscience, 13(9), 1395-1409","doi":"10.1021/acschemneuro.1c00822","pmid":"35442021","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03955","title":"Association of a Positive Drug Screening for Cannabis With Mortality and Hospital Visits Among Veterans Affairs Enrollees Prescribed Opioids.","authors":"Keyhani, Salomeh; Leonard, Samuel; Byers, Amy L; Zaman, Tauheed; Krebs, Erin; Austin, Peter C; Moss-Vazquez, Tristan; Austin, Charles; Sandbrink, Friedhelm; Bravata, Dawn M","year":2022,"journal":"JAMA network open, 5(12), e2247201","doi":"10.1001/jamanetworkopen.2022.47201","pmid":"36525274","tags":["medical-cannabis","pain","drug-interactions","seniors"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use was not associated with all-cause mortality at 90 or 180 days in the overall population or among those on long-term opioid therapy. However, cannabis was associated with a small increased risk of composite adverse outcomes (ED visits, hospitalization, death). Among adults 65 and older on LTOT, cannabis use was associated with a 55% increased 90-day mortality risk (HR 1.55).","whyItMatters":"Cannabis has been proposed as an opioid-sparing therapy that could reduce opioid-related deaths. This large VA study found no such mortality benefit and identified increased risk in the oldest patients, challenging the opioid-sparing narrative.","specificNumbers":"297,620 veterans. 30,514 cannabis users. Overall mortality HR: 1.07 (90-day, NS), 1.00 (180-day, NS). Composite outcome HR: 1.05 (90-day), 1.04 (180-day). Adults 65+ on LTOT: 90-day mortality HR 1.55 (95% CI 1.17-2.04).","methodology":"Cohort study of 297,620 veterans with urine drug screening (2014-2019) who received opioid prescriptions through the VA system. Propensity score weighting reduced confounding. Cox regression estimated hazard ratios for 90- and 180-day outcomes.","limitations":"Observational study cannot establish causation. Urine drug screening captures any recent use, not dose or frequency. Veterans may not represent the general population. Cannot distinguish therapeutic from recreational cannabis use."},{"rthcId":"RTHC-03956","title":"Review: Cannabinoids as Medicinals.","authors":"Khalsa, Jag H; Bunt, Gregory; Blum, Kenneth; Maggirwar, Sanjay B; Galanter, Marc; Potenza, Marc N","year":2022,"journal":"Current addiction reports, 9(4), 630-646","doi":"10.1007/s40429-022-00438-3","pmid":"36093358","tags":["medical-cannabis","cbd","epilepsy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Current research shows CBD and other cannabinoids are not ready for formal indications as medicines to treat the wide range of conditions promoted, except for limited use of CBD for two rare forms of childhood epilepsy and CBD combined with THC for MS-associated spasticity.","whyItMatters":"Many states and countries have legalized cannabinoid use as medicine without regulatory body approval for most conditions. This review provides a reality check on what the clinical evidence actually supports.","specificNumbers":"30 years of literature reviewed. Two formally supported indications: CBD for rare childhood epilepsy, CBD/THC for MS spasticity. Multiple conditions promoted but lacking sufficient clinical trial evidence.","methodology":"Review of published papers over the past 30 years from PubMed and Google Scholar databases, evaluating clinical evidence from well-designed studies and trials supporting cannabinoid use as medicines.","limitations":"Review methodology not fully described as systematic. May not capture all relevant clinical trials, particularly recent ones. The pace of new research may have shifted the evidence base since publication."},{"rthcId":"RTHC-03957","title":"Cannabinoid and endocannabinoid system: a promising therapeutic intervention for multiple sclerosis.","authors":"Khan, Hina; Ghori, Fareeha Khalid; Ghani, Uzma; Javed, Aneela; Zahid, Saadia","year":2022,"journal":"Molecular biology reports, 49(6), 5117-5131","doi":"10.1007/s11033-022-07223-5","pmid":"35182322","tags":["medical-cannabis","inflammation","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Clinical studies confirm cannabinoids relieve MS pain, tremors, and spasticity. Cannabinoids also prevent exaggerated immune responses in the CNS. Both endocannabinoid system modulators and cannabinoid ligands promote oligodendrocyte survival by regulating signaling, migration, and myelination, suggesting potential disease-modifying effects beyond symptom management.","whyItMatters":"If cannabinoids can protect oligodendrocytes and promote myelination, they could potentially slow MS progression rather than just manage symptoms. This would represent a fundamental shift in how cannabis is used for MS.","specificNumbers":"CB1 and CB2 receptors identified as primary therapeutic targets. Various CB1/CB2 agonists showed anti-inflammatory properties in experimental MS models.","methodology":"Review focusing on the immunological attack on nerve cells in MS and the role of cannabinoids and the endocannabinoid system in CNS pathology, covering CB1 and CB2 receptor agonists with anti-inflammatory properties.","limitations":"Review relies heavily on preclinical data for disease-modifying claims. Clinical evidence limited to symptom management. Mechanism of oligodendrocyte protection not fully established in human studies."},{"rthcId":"RTHC-03958","title":"New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders.","authors":"Kibret, Berhanu Geresu; Ishiguro, Hiroki; Horiuchi, Yasue; Onaivi, Emmanuel S","year":2022,"journal":"International journal of molecular sciences, 23(2)","doi":"10.3390/ijms23020975","pmid":"35055161","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03959","title":"Cannabis legalization and traffic injuries: exploring the role of supply mechanisms.","authors":"Kilmer, Beau; Rivera-Aguirre, Ariadne; Queirolo, Rosario; Ramirez, Jessica; Cerdá, Magdalena","year":2022,"journal":"Addiction (Abingdon, England), 117(8), 2325-2330","doi":"10.1111/add.15840","pmid":"35129240","tags":["legalization","driving"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Total cannabis registrations were not associated with traffic crashes. However, self-cultivation registrations showed a consistent, positive, and statistically significant association with traffic crashes involving injuries (beta = 0.194, p = 0.008). Associations for pharmacy purchasing and cannabis club membership were inconsistent across model specifications.","whyItMatters":"How a country structures its legal cannabis supply may matter for traffic safety. Uruguay's unique three-pathway system allows this comparison, and the finding that self-cultivation specifically is associated with crashes suggests supply mechanism design matters.","specificNumbers":"Average registrations per 10,000 adults: self-cultivation 17.7, clubs 3.6, pharmacies 25.1. Self-cultivation and crashes: beta = 0.194, p = 0.008, 95% CI 0.058-0.329. Total registrations: beta = -0.007, p = 0.398 (not significant).","methodology":"Ecological study using ordinary least squares regression with department-level quarterly data from Uruguay (2013-2019). Cannabis registration counts by supply type (self-cultivation, clubs, pharmacies) were examined against traffic crash data, controlling for economic and demographic characteristics.","limitations":"Ecological study cannot establish individual-level causation. Self-cultivators may differ from pharmacy purchasers in unmeasured ways. Traffic crash data may not capture all incidents. Cannot determine whether self-cultivators themselves are crashing or if the association reflects broader community effects."},{"rthcId":"RTHC-03960","title":"Profiling Cannabinoid Contents and Expression Levels of Corresponding Biosynthetic Genes in Commercial Cannabis (Cannabis sativa L.) Cultivars.","authors":"Kim, Ae Lim; Yun, Young Jae; Choi, Hyong Woo; Hong, Chang-Hee; Shim, Hyun Joo; Lee, Jeong Hwan; Kim, Young-Cheon","year":2022,"journal":"Plants (Basel, Switzerland), 11(22)","doi":"10.3390/plants11223088","pmid":"36432817","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03961","title":"Textual and pictorial enhancement of cannabis warning labels: An Online experiment among at-risk U.S. young adults.","authors":"Kim, Sang Jung; Minich, Matt; Tveleneva, Arina; Liu, Jiaying; Padon, Alisa A; Silver, Lynn D; Yang, Sijia","year":2022,"journal":"Drug and alcohol dependence, 237, 109520","doi":"10.1016/j.drugalcdep.2022.109520","pmid":"35724518","tags":["legalization","harm-reduction","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Pictorially enhanced cannabis warning labels significantly improved recall accuracy (b = 0.59, p < 0.001) and perceived message effectiveness (b = 0.31, p = 0.008) compared to current California labels. Text-only enhanced labels also improved recall (b = 0.30, p = 0.011) but did not improve perceived effectiveness. The effectiveness of pictorial labels was mediated by negative emotions rather than information recall.","whyItMatters":"Current cannabis warning labels may be ineffective at communicating health risks. This study provides evidence that relatively simple design changes, particularly adding pictures, could significantly improve public health messaging.","specificNumbers":"523 at-risk young adults ages 18-26. Pictorial labels: recall b = 0.59, effectiveness b = 0.31. Text-only enhanced: recall b = 0.30, effectiveness NS. Pictorial outperformed text-only for recall (b = 0.28, p = 0.019).","methodology":"Online national experiment with 523 young adults (18-26) at risk for cannabis use, randomly assigned to view current California cannabis warning labels or enhanced versions with varying textual and pictorial components. Linear regression compared outcomes.","limitations":"Online experiment may not reflect real-world label viewing. Single exposure; cumulative effects unknown. At-risk young adults may not represent all cannabis consumers. California labels used as the comparison; other states may differ."},{"rthcId":"RTHC-03962","title":"Effects of Cannabidiol on Adaptive Behavior and Quality of Life in Pediatric Patients With Treatment-Resistant Epilepsy.","authors":"Kim, Se Hee; Choi, Han Som; Koo, Chung Mo; Joo, Bong-Rim; Park, Byung-Joo; Lee, Hae Kook; Lee, Joon Soo; Kim, Heung Dong; Kang, Hoon-Chul","year":2022,"journal":"Journal of clinical neurology (Seoul, Korea), 18(5), 547-552","doi":"10.3988/jcn.2022.18.5.547","pmid":"36062772","tags":["cbd","epilepsy","youth","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"26.8% of patients achieved 50% or greater seizure reduction after six months of CBD. However, total quality of life scores did not change (85.71 to 83.12, p = 0.630). Motor skills scores on the Vineland-II actually decreased (48.67 to 45.18, p = 0.005). No other adaptive behavior or behavioral scores changed.","whyItMatters":"Seizure reduction is an important outcome, but families care about overall quality of life. This study suggests that even when CBD reduces seizures, it may not translate into meaningful improvements in daily functioning for children with profound intellectual disabilities.","specificNumbers":"41 patients (median age 4.1 years, 25 male). CBD dose: 10 mg/kg/day. 26.8% had 50% or more seizure reduction. QOLCE unchanged (p = 0.630). Motor skills decreased (p = 0.005). No behavioral changes on K-CBCL.","methodology":"Prospective open-label study of 41 pediatric patients (11 Dravet syndrome, 30 Lennox-Gastaut syndrome) treated with oral CBD at 10 mg/kg/day. Quality of life measured by QOLCE, adaptive behavior by Vineland-II and K-CBCL at baseline and 6 months.","limitations":"Open-label study with no control group. Small sample (41 patients). All patients had profound intellectual disabilities, limiting generalizability. The decrease in motor skills may reflect disease progression rather than a CBD effect."},{"rthcId":"RTHC-03963","title":"An Observational Cross-Sectional Survey Exploring the Indications for and Responses to Medical Marijuana Use in Certified Patients in Pennsylvania.","authors":"Kimless, Debra; Caloura, Matthew; Markos, Virginia; Ryan, Jennie; Abbonizio, Sally; Janicki, Sharon","year":2022,"journal":"Journal of primary care & community health, 13, 21501319221129734","doi":"10.1177/21501319221129734","pmid":"36226444","tags":["medical-cannabis","anxiety","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Anxiety disorder was the most common qualifying condition (50.1%) and comorbid condition (69.3%). Approximately 95% reported no adverse effects. 90% preferred inhalation via vaporization. More than 50% reported symptom improvement. Only 20% reported tolerance to their current dose. 70% found obtaining cannabis easy and 54% said cost was not a barrier.","whyItMatters":"Many states do not recognize anxiety as a qualifying condition for medical cannabis. This study shows anxiety is the primary driver of medical cannabis use where it is permitted, suggesting restrictive qualifying lists may be misaligned with patient needs.","specificNumbers":"207 patients. Mean age 36.7 years. 61.4% male, 84.7% white. 50.1% qualified for anxiety. 69.3% had anxiety as a comorbidity. 95% no adverse effects. 90% preferred vaporization. 50%+ reported improvement. 20% tolerance. 70% easy access. 54% cost not a barrier.","methodology":"Cross-sectional convenience sample survey of 207 qualified medical cannabis users at a Laurel Harvest Labs dispensary in Pennsylvania. Survey covered demographics, qualifying conditions, usage, administration methods, adverse effects, tolerance, and impact on other substance use.","limitations":"Convenience sample from a single dispensary. Self-reported outcomes without clinical verification. Selection bias toward satisfied customers. 84.7% white may not represent diverse populations. No comparison group."},{"rthcId":"RTHC-03964","title":"Clinical features associated with ADB-BUTINACA exposure in patients attending emergency departments in England.","authors":"King, A; Hill, S L; Pucci, M; Bailey, G; Keating, L; Macfarlane, R; Cantle, F; Hudson, S; Thomas, S H L","year":2022,"journal":"Clinical toxicology (Philadelphia, Pa.), 60(10), 1094-1098","doi":"10.1080/15563650.2022.2101469","pmid":"35943421","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"ADB-BUTINACA was found in 10 of 1,279 patients in the IONA study, all since February 2021, suggesting recent emergence. Reduced consciousness occurred in all 10 patients. Two had ingested edible \"cannabis\" gummies unknowingly contaminated with the synthetic cannabinoid. In 7 cases, other drugs were co-detected. All patients recovered with supportive care.","whyItMatters":"ADB-BUTINACA is entering the drug supply disguised as natural cannabis, including in edible products. Users who think they are consuming cannabis may unknowingly be exposed to a far more potent and dangerous synthetic cannabinoid.","specificNumbers":"10 patients from 1,279 total IONA participants. All 10 since February 2021. 9 male, median age 45. All 10 had reduced consciousness. 2 consumed edible \"cannabis\" gummies. 3 had ADB-BUTINACA only; 7 had co-detected substances. Median hospital stay: 19 hours.","methodology":"Prospective surveillance from the IONA study enrolling adults presenting to UK emergency departments with toxicity after suspected drug misuse since March 2015. Blood and/or urine analyzed by LC-MS.","limitations":"Small case series (10 patients). Single country surveillance. Co-detection of other substances in 7 cases complicates attribution. Cannot determine population-level prevalence."},{"rthcId":"RTHC-03965","title":"Does marijuana use among African American adolescent males differ based on school factors?","authors":"King, Keith A; Fuqua, Stephon H; Vidourek, Rebecca A; Merianos, Ashley L; Yockey, R Andrew","year":2022,"journal":"Journal of ethnicity in substance abuse, 21(2), 762-772","doi":"10.1080/15332640.2020.1824840","pmid":"33000993","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Those at highest risk were 16-17 years old, in grades 9-12, did not like going to school, and believed most or all students in their grade used marijuana. Not liking school and perceived social norms of use were the strongest school-related predictors.","whyItMatters":"School engagement and perceived peer norms are modifiable risk factors. Understanding what predicts marijuana use in African American male adolescents specifically can inform culturally targeted prevention programs.","specificNumbers":"5,738 African American male students, grades 7-12. 14.7% past-year marijuana use. Highest risk: ages 16-17, grades 9-12, dislike school, perceive high peer use.","methodology":"Analysis of the 2015-2018 National Survey on Drug Use and Health (NSDUH). National sample of 5,738 African American students in grades 7-12.","limitations":"Cross-sectional design. Self-reported data. NSDUH may not capture highest-risk youth (homeless, incarcerated). School-level data does not capture school-specific policies or environments."},{"rthcId":"RTHC-03966","title":"A scoping review of the use of cannabidiol in psychiatric disorders.","authors":"Kirkland, Anna E; Fadus, Matthew C; Gruber, Staci A; Gray, Kevin M; Wilens, Timothy E; Squeglia, Lindsay M","year":2022,"journal":"Psychiatry research, 308, 114347","doi":"10.1016/j.psychres.2021.114347","pmid":"34952255","tags":["cbd","psychosis","anxiety","addiction","mental-health"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Only 16 randomized controlled trials or within-subject studies met inclusion criteria. Studies covered psychotic disorders (6), anxiety (3), tobacco use (3), cannabis use (2), opioid use (1), and insomnia (1). No eligible studies existed for alcohol, stimulant use disorder, PTSD, ADHD, autism, or mood disorders. CBD was generally safe and well tolerated.","whyItMatters":"Despite enormous public and commercial interest in CBD for mental health, only 16 controlled studies exist across all psychiatric disorders. This quantifies the evidence gap clinicians face when patients ask about CBD.","specificNumbers":"2,952 articles screened. 16 studies included. Distribution: psychosis (6), anxiety (3), tobacco (3), cannabis (2), opioid (1), insomnia (1). Zero studies for PTSD, ADHD, autism, mood disorders, alcohol, or stimulant use disorders.","methodology":"Scoping review searching PubMed and PsycINFO for \"cannabidiol\" plus major psychiatric disorders. Of 2,952 articles screened, 16 randomized controlled trials or within-subject studies were included.","limitations":"Scoping review, not systematic review or meta-analysis. Limited to controlled trials, which may exclude relevant observational data. Rapidly evolving field may have new studies since publication."},{"rthcId":"RTHC-03967","title":"Neural functional connectivity changes to psychosocial stress in young adults with bipolar disorder and preliminary associations with clinical trajectories.","authors":"Kirsch, Dylan E; Preston, Alex; Tretyak, Valeria; Le, Vanessa; Weber, Wade; Strakowski, Stephen M; Lippard, Elizabeth T C","year":2022,"journal":"Bipolar disorders, 24(3), 298-309","doi":"10.1111/bdi.13127","pmid":"34532945","tags":["mental-health","neuroscience","depression"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"People with bipolar disorder showed increased right amygdala-rostral prefrontal cortex connectivity during stress compared to controls. Greater connectivity increase was associated with less frequent cannabis use and prospectively with shorter duration and lower severity of depression symptoms over one year.","whyItMatters":"Understanding how stress response circuits relate to both cannabis use and mood outcomes in bipolar disorder could identify biomarkers for disease course and potential intervention targets.","specificNumbers":"42 participants (19 bipolar, 23 controls). Mean age 21.4 years. Greater right amygdala-rPFC connectivity during stress in bipolar group. This connectivity associated with less cannabis use and better depression outcomes over 1-year follow-up.","methodology":"fMRI study of 42 young adults (19 with bipolar disorder, mean age 21.4) during the Montreal Imaging Stress Task. A subset of bipolar participants completed 1-year follow-up assessments for mood symptoms and substance use.","limitations":"Very small sample (19 bipolar participants). Preliminary associations, not causal. Follow-up subset even smaller. Cannabis use measured as correlate, not experimentally manipulated. Multiple comparisons increase false positive risk."},{"rthcId":"RTHC-03968","title":"Effect of maternal adverse childhood experiences (ACE) and cannabis use on pregnancy outcomes.","authors":"Klasner, Carson; Brown, Jessica; Gopalakrishnan, Mathangi; Metwally, Dina El; Besse, Margaret; Mark, Katrina","year":2022,"journal":"Archives of women's mental health, 25(6), 1097-1104","doi":"10.1007/s00737-022-01269-x","pmid":"36203114","tags":["pregnancy","youth","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use at delivery was associated with 10% lower birthweight (2665g vs. 3014g, p < 0.05), lower maternal weight gain (7.9 vs. 13.3 kg), and fewer prenatal visits (7 vs. 8). Continued cannabis use was associated with higher ACE scores (16.2 vs. 13.8, p = 0.01). ACE scores alone were not associated with birth outcomes.","whyItMatters":"The connection between childhood trauma, continued cannabis use during pregnancy, and worse birth outcomes suggests a complex interplay where addressing maternal trauma history could help reduce prenatal cannabis use.","specificNumbers":"256 patients. 87 (34%) positive for cannabis at initial visit. 39 (15.2%) positive at delivery. 45% of initial users continued to delivery. Cannabis at delivery: birthweight 2665g vs. 3014g. Maternal weight gain: 7.9 vs. 13.3 kg. Continued use associated with higher ACE scores.","methodology":"Retrospective cohort of 256 pregnant patients in Baltimore. ACE checklist completed at enrollment. Urine toxicology at initiation of care and delivery. Multivariable logistic regression assessed relationships between ACE scores, cannabis use, and pregnancy outcomes.","limitations":"Single urban center (Baltimore). Retrospective design. Urine toxicology is a crude measure of exposure. ACE score is a childhood measure, not current trauma. Small sample limits subgroup analyses. Cannot separate cannabis effects from socioeconomic confounders."},{"rthcId":"RTHC-03969","title":"Legalization of Cannabis and Agricultural Frontier Expansion.","authors":"Klassen, Mark; Anthony, Brandon P","year":2022,"journal":"Environmental management, 69(2), 333-352","doi":"10.1007/s00267-021-01555-x","pmid":"34748069","tags":["legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"From 2011 to 2016, licensed cannabis cultivation resulted in over 67 hectares of land use change toward more developed uses. Nearly 15 km of new fencing was constructed establishing over 38 hectares of fenced areas, and nearly 60 hectares of vegetation was cleared. Much of this change occurred within habitats of threatened and endangered species.","whyItMatters":"Legalization is often framed as environmentally beneficial by moving cultivation indoors and under regulation. This study shows that legal outdoor and greenhouse cultivation can still cause significant habitat encroachment.","specificNumbers":"67+ hectares of LULC change. 15 km of new fencing. 38+ hectares fenced. ~60 hectares vegetation cleared. Changes primarily from outdoor and greenhouse facilities in rural areas.","methodology":"Geospatial analysis of licensed recreational cannabis cultivator locations in Colorado. Examined distribution of cultivators, potential habitat infringement of threatened and endangered species, and land use/land cover (LULC) change from 2011 to 2016.","limitations":"Single state (Colorado). LULC analysis may not capture all environmental impacts. 2011-2016 timeframe may not reflect current patterns. Cannot determine species-level impacts from habitat proximity alone."},{"rthcId":"RTHC-03970","title":"Cannabinoid Hyperemesis Syndrome Complicated by Pneumomediastinum: Implications for Pediatric Surgeons.","authors":"Klazura, Greg; Geraghty, Joseph R; Rojnica, Marko; Sims, Thomas; Koo, Nathaniel; Lobe, Thom","year":2022,"journal":"Clinical surgery journal, 5(Suppl 13), 6-13","doi":null,"pmid":"36438163","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03971","title":"Ask Your Provider About Cannabis: Increasing Nurse Practitioner Knowledge and Confidence.","authors":"Klein, Tracy A; Bindler, Ross","year":2022,"journal":"Cannabis and cannabinoid research, 7(5), 700-705","doi":"10.1089/can.2021.0061","pmid":"34432530","tags":["medical-cannabis","harm-reduction","drug-interactions"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Significant improvement in all content areas from pre- to post-test, with a mean improvement of 39.3%. Greatest increases were for metabolism, pharmacokinetics, and drug-drug interactions. At 3-month follow-up (63% response rate), 52% said the CE changed their attitudes, 92% were now likely to ask patients about cannabis, and 84% were likely to counsel patients about it.","whyItMatters":"Nurse practitioners are cannabis authorizing providers in many states and serve as primary care clinicians. If a 2-hour module can significantly improve knowledge and change practice behavior, it represents a scalable solution to the provider education gap.","specificNumbers":"289 pre/post-test participants. 39.3% mean score improvement (95% CI: 30.6-47.9%). 184 completed follow-up (63%). 52% changed attitudes. 92% now likely to ask about cannabis. 84% likely to counsel. 86% had not yet applied knowledge in practice.","methodology":"Nationally distributed 2-hour continuing education module for nurse practitioners. Pre- and post-testing (n=289) plus 3-month follow-up survey (n=184, 63%). Content covered pharmacodynamics, law, evidence-based use, metabolism, drug interactions, and adverse reactions.","limitations":"Self-selected participants likely more interested in cannabis education. No control group. Self-reported practice changes not verified. 37% lost to follow-up. Short follow-up period for practice change assessment."},{"rthcId":"RTHC-03972","title":"Prevalence and correlates of intentional substance use to reduce illicit opioid use in a Canadian setting.","authors":"Klimas, Jan; Mok, Wing Yin; Lake, Stephanie; Eugenia Socías, M; DeBeck, Kora; Hayashi, Kanna; Wood, Evan; Milloy, M-J","year":2022,"journal":"Journal of substance use, 27(3), 277-282","doi":"10.1080/14659891.2021.1941341","pmid":"35685454","tags":["addiction","harm-reduction","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"22% of illicit opioid users reported substituting at least once during the study. Substitutes used: stimulants (50.3%), cannabis (27.6%), alcohol (3.2%), benzodiazepines (4.5%), and others (4.3%). Daily cannabis use was positively associated with reporting substitution attempts (AOR 1.56, 95% CI 1.24-1.96).","whyItMatters":"Understanding drug substitution patterns is critical as harm reduction strategies evolve. The finding that cannabis is the second most common intentional opioid substitute suggests it may play a role in informal self-managed opioid reduction.","specificNumbers":"1,527 participants, 4,991 interviews. 336 (22%) reported substitution at least once (467 interviews, 9.4%). Cannabis substitution: 129 (27.6%). Stimulant substitution: 235 (50.3%). Daily cannabis use AOR: 1.56 for substitution attempts.","methodology":"Analysis of three prospective cohorts of people who use drugs in Vancouver, Canada (June 2012 to June 2016). 1,527 participants contributed 4,991 interviews. Multivariable generalized estimating equations examined correlates of intentional substitution.","limitations":"Observational design cannot determine whether substitution actually reduced opioid use. Vancouver drug-using population may not generalize. Self-reported substitution intentions. Stimulant substitution being most common raises safety concerns of its own."},{"rthcId":"RTHC-03973","title":"Timing of cannabis exposure relative to prodrome and psychosis onset in a community-based first episode psychosis sample.","authors":"Kline, Emily R; Ferrara, Maria; Li, Fangyong; D'Souza, Deepak Cyril; Keshavan, Matcheri; Srihari, Vinod H","year":2022,"journal":"Journal of psychiatric research, 147, 248-253","doi":"10.1016/j.jpsychires.2022.01.039","pmid":"35066293","tags":["psychosis","youth","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis exposure (78%) and cannabis use disorders (47%) were highly prevalent at first-episode admission. In 94% of participants, cannabis use preceded onset of both attenuated and full-threshold psychosis symptoms by several years. Earlier age at first cannabis exposure was associated with younger age at prodrome and psychosis onset, worse premorbid functioning, and greater CUD severity at admission.","whyItMatters":"The finding that cannabis use preceded psychosis in the vast majority of cases strengthens the temporal argument for a contributory role, though it does not prove causation. The dose-response with earlier exposure adds to the concern.","specificNumbers":"246 first-episode patients. 78% had cannabis exposure. 47% had cannabis use disorders. 94% used cannabis before symptom onset. Earlier exposure linked to younger psychosis onset, worse premorbid functioning, and greater CUD severity.","methodology":"Consecutive admissions (N=246) to two community-based first-episode psychosis services. Characterized timing of cannabis use relative to prodromal and psychotic symptom onset, compared exposed vs. unexposed groups, and examined associations with age at first cannabis exposure.","limitations":"Retrospective design relying on patient recall of symptom and use onset timing. Cannot establish causation. Community-based sample may not represent all first-episode cases. No control group of cannabis users who did not develop psychosis."},{"rthcId":"RTHC-03974","title":"Cannabis Use and Parenting Practices among Young People: The Impact of Parenting Styles, Parental Cannabis-Specific Rules, and Parental Cannabis Use.","authors":"Kokotovič, Karmen Osterc; Pšunder, Mateja; Kirbiš, Andrej","year":2022,"journal":"International journal of environmental research and public health, 19(13)","doi":"10.3390/ijerph19138080","pmid":"35805740","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Parental cannabis use was the strongest predictor of youth cannabis use. Strict maternal cannabis-specific rules and maternal authoritative parenting (vs. permissive) significantly reduced likelihood of use. The mother's role was particularly prominent across multiple predictors.","whyItMatters":"Identifying that parents' own cannabis use is the single strongest predictor gives prevention programs a clear target. The importance of mothers' parenting style and cannabis-specific rules offers actionable intervention strategies.","specificNumbers":"839 students, ages 14-21. Strongest predictor: parental cannabis use. Protective factors: maternal authoritative parenting (vs. permissive), strict maternal cannabis-specific rules, parental non-use.","methodology":"Cross-sectional survey of 839 secondary education students in Slovenia, ages 14-21. Logistic regression examined associations between parenting practices and lifetime cannabis use, controlling for demographics, socioeconomic status, education, health, and risk behaviors.","limitations":"Cross-sectional design. Slovenian context may not generalize. Self-reported data. Did not distinguish between different levels of parental cannabis use. Cultural attitudes toward cannabis in Slovenia may differ from other countries."},{"rthcId":"RTHC-03975","title":"The Effects of Cannabinoids on Sleep.","authors":"Kolla, Bhanu Prakash; Hayes, Lisa; Cox, Chaun; Eatwell, Lindy; Deyo-Svendsen, Mark; Mansukhani, Meghna P","year":2022,"journal":"Journal of primary care & community health, 13, 21501319221081277","doi":"10.1177/21501319221081277","pmid":"35459406","tags":["sleep","withdrawal","medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis products have minimal to no effects on sleep disorders and may have deleterious effects in some individuals. Cannabis withdrawal causes significant insomnia that can lead to worsening anxiety, mood, suicidal ideation, and ER visits. The few published RCTs are reviewed alongside observational data.","whyItMatters":"Many people use cannabis specifically for sleep, making this one of the most common self-reported reasons for use. This review challenges that practice by finding little supporting evidence and noting the risk of withdrawal-induced insomnia.","specificNumbers":"Case report described withdrawal-induced insomnia leading to ER visit and inpatient admission due to worsening anxiety, mood, and suicidal ideation. Review covered multiple sleep disorder categories.","methodology":"Comprehensive review evaluating literature on cannabis effects on normal sleep, circadian rhythms, insomnia, excessive daytime sleepiness, sleep apnea, parasomnias, and restless legs syndrome. Included case report of withdrawal-induced insomnia.","limitations":"Most available studies are observational. Few published RCTs. Different cannabinoid types, doses, and formulations may have different effects. Review acknowledges need for further research on specific cannabinoid types."},{"rthcId":"RTHC-03976","title":"Cannabidiol affects breast meat volatile compounds in chickens subjected to different infection models.","authors":"Konieczka, Paweł; Wojtasik-Kalinowska, Iwona; Poltorak, Andrzej; Kinsner, Misza; Szkopek, Dominika; Fotschki, Bartosz; Juśkiewicz, Jerzy; Banach, Joanna; Michalczuk, Monika","year":2022,"journal":"Scientific reports, 12(1), 18940","doi":"10.1038/s41598-022-23591-1","pmid":"36344735","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03977","title":"The Role of Cannabis, Cannabidiol and Other Cannabinoids in Chronic Pain. The Perspective of Physicians.","authors":"Köstenberger, Markus; Nahler, Gerhard; Jones, Trevor M; Neuwersch, Stefan; Likar, Rudolf","year":2022,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 17(1-2), 318-333","doi":"10.1007/s11481-021-10010-x","pmid":"34467511","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Most reviews concluded cannabis plays a significant role in pain management. Systematic studies do not support an \"entourage effect\" of other cannabis plant constituents for pain. CBD is the only cannabinoid that does not cause intoxication and is not a controlled substance. No head-to-head comparison exists between different cannabis cultivars, between pure cannabinoids, or between pure cannabinoids and extracts.","whyItMatters":"Physicians must choose between very different cannabis products with no comparative evidence. The finding that the \"entourage effect\" lacks systematic support for pain challenges a major marketing claim.","specificNumbers":"Products range from defined cultivars (varying THC:CBD ratios) to pure cannabinoids (THC, CBD) to standardized mixtures (nabiximols, 1:1 THC:CBD). Zero head-to-head comparisons published.","methodology":"Review examining cannabis and cannabinoid preparations for chronic pain from the physician perspective, covering available preparations (cultivars, extracts, nabiximols, pure CBD/THC), evidence base, and clinical knowledge gaps.","limitations":"Narrative review without systematic methodology. Conflicting opinions in the literature acknowledged. Pain is heterogeneous, making generalized recommendations difficult."},{"rthcId":"RTHC-03978","title":"Cannabis use among youth in Canada: a scoping review protocol.","authors":"Kourgiantakis, Toula; Edwards, Travonne; Lee, Eunjung; Logan, Judith; Vicknarajah, Ragave; Craig, Shelley L; Simon-Tucker, Monique; Williams, Charmaine C","year":2022,"journal":"BMJ open, 12(6), e061997","doi":"10.1136/bmjopen-2022-061997","pmid":"35725253","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03979","title":"The Impact of Cannabis Packaging Characteristics on Perceptions and Intentions.","authors":"Kowitt, Sarah D; Yockey, R Andrew; Lee, Joseph G L; Jarman, Kristen L; Gourdet, Camille Kempf; Ranney, Leah M","year":2022,"journal":"American journal of preventive medicine, 63(5), 751-759","doi":"10.1016/j.amepre.2022.04.030","pmid":"35835626","tags":["legalization","harm-reduction","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Edible gummies were perceived as healthier, less \"grown up,\" and more socially acceptable than concentrates. Interest in trying gummies was significantly higher. Cannabis packages with a \"helps you relax\" health claim elicited more positive feelings. Visual displays of THC content and health warnings had minimal effects on perceptions.","whyItMatters":"As cannabis becomes a consumer product, packaging shapes perceptions. The finding that edibles are perceived as healthier and that health claims produce positive feelings suggests packaging regulation needs to account for these effects.","specificNumbers":"841 adults (49% male, 50% young adults, 44% White, 17% Hispanic). Gummies vs. concentrates: healthier (beta 0.32), more socially acceptable (beta 0.30), more interest in trying (beta 1.33). \"Helps you relax\" claim: happier (beta 0.34), better feelings (beta 0.37).","methodology":"Five online between-subjects experiments (April 2021) with 841 US adults. Experiments randomized participants to view different cannabis types, THC content displays, brand personalities, health warnings, and health claims. Measured cognitive, affective, and behavioral responses.","limitations":"Online experiment. Hypothetical purchase intentions. US adults may not represent other populations. Short-term perception changes may not predict actual behavior. Five separate experiments with multiple comparisons."},{"rthcId":"RTHC-03980","title":"Barriers to Implementing a Cannabis Focused SBIRT in Adolescent Primary Care.","authors":"Kristman-Valente, Allison N; McCarty, Carolyn A; Walker, Denise D; Walker-Harding, Leslie","year":2022,"journal":"Substance abuse : research and treatment, 16, 11782218221111837","doi":"10.1177/11782218221111837","pmid":"35845969","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03981","title":"Characterization of Cannabis Products Purchased for Medical Use in New York State.","authors":"Kritikos, Alexandra F; Pacula, Rosalie Liccardo","year":2022,"journal":"JAMA network open, 5(8), e2227735","doi":"10.1001/jamanetworkopen.2022.27735","pmid":"35984662","tags":["medical-cannabis","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This study examined medical cannabis product purchases in New York State from dispensaries operated by a single integrated manufacturer, characterizing what products patients actually selected in a tightly regulated market.","whyItMatters":"Most medical cannabis research relies on self-report. This study uses actual purchase data from a regulated market, providing objective insight into patient product preferences.","specificNumbers":"New York State dispensary purchase data from a single integrated manufacturer-retailer. Specific product details characterized.","methodology":"Cross-sectional study of medical cannabis product purchases made in New York State dispensaries operated by a single licensed manufacturer and retail company. Published in JAMA Network Open.","limitations":"Single manufacturer in one state. New York had one of the most restrictive medical cannabis programs at the time. May not represent patient preferences in less regulated markets."},{"rthcId":"RTHC-03982","title":"Changes in sexual identity and substance use during young adulthood.","authors":"Krueger, Evan A; Repati, Mykala L; Harlow, Alyssa F; Unger, Jennifer B; Lee, Jungeun Olivia; Pedersen, Eric R; Conn, Bridgid M; Wong, Carolyn; Young, Lindsay E; Barrington-Trimis, Jessica L; Leventhal, Adam M","year":2022,"journal":"Drug and alcohol dependence, 241, 109674","doi":"10.1016/j.drugalcdep.2022.109674","pmid":"36332590","tags":["youth","addiction","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Consistently LGBQ+ individuals had higher frequency of cannabis use (OR 1.36) compared to consistently heterosexual peers. Those who newly identified as LGBQ+ had 2.9 times the risk of initiating cannabis use (aRR 2.90). Those who transitioned from LGBQ+ to heterosexual identity reported lower substance use frequency.","whyItMatters":"Sexual identity is dynamic in young adulthood, and the period of identity change appears to carry heightened substance use risk. This suggests a window for targeted prevention during identity exploration.","specificNumbers":"1,896 young adults. Consistently LGBQ+ cannabis OR: 1.36. New LGBQ+ identity: cannabis initiation aRR 2.90 (95% CI 1.81-4.64). LGBQ+ to heterosexual: lower alcohol (OR 0.35) and tobacco (OR 0.15) use.","methodology":"Two-wave prospective cohort of 1,896 young adults (mean age 21.2). Baseline October 2018-October 2019; follow-up May-October 2020. Four groups: consistently heterosexual (1,567), consistently LGBQ+ (244), heterosexual to LGBQ+ (65), LGBQ+ to heterosexual (20).","limitations":"Small identity-change groups (65 and 20). Two time points cannot capture the full trajectory of identity development. Follow-up during COVID-19 pandemic may confound results. Self-reported identity and substance use."},{"rthcId":"RTHC-03983","title":"Elevated social anxiety symptoms across childhood and adolescence predict adult mental disorders and cannabis use.","authors":"Krygsman, Amanda; Vaillancourt, Tracy","year":2022,"journal":"Comprehensive psychiatry, 115, 152302","doi":"10.1016/j.comppsych.2022.152302","pmid":"35245889","tags":["anxiety","youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Three social anxiety trajectories emerged: high increasing (15.5%), moderate (37.3%), and low (47.2%). The high increasing group predicted multiple adult mental disorders with striking odds ratios: SAD (OR 15.74), GAD (OR 13.08), depressive episode (OR 19.75), agoraphobia (OR 16.39). The high increasing group also predicted cannabis use but not alcohol use in adulthood.","whyItMatters":"The specificity of the cannabis finding (social anxiety predicted cannabis but not alcohol use) suggests that socially anxious youth may specifically seek out cannabis as a coping mechanism, not substances generally.","specificNumbers":"701 participants tracked ages 10-22. Three trajectories: high (15.5%), moderate (37.3%), low (47.2%). High group ORs: SAD 15.74, GAD 13.08, depression 19.75, PD 8.43, agoraphobia 16.39, OCD 3.49. High group predicted cannabis but not alcohol use.","methodology":"Longitudinal study following 701 individuals from ages 10-18 (social anxiety trajectories) to ages 19-22 (adult mental disorder diagnoses and substance use). Growth mixture modeling identified trajectory groups.","limitations":"Self-reported social anxiety symptoms. Cannabis and alcohol use measured in early adulthood only. High trajectory group was relatively small (15.5%). Attrition over 12+ years of follow-up."},{"rthcId":"RTHC-03984","title":"Adjunctive Management of Opioid Withdrawal with the Nonopioid Medication Cannabidiol.","authors":"Kudrich, Christopher; Hurd, Yasmin L; Salsitz, Edwin; Wang, An-Li","year":2022,"journal":"Cannabis and cannabinoid research, 7(5), 569-581","doi":"10.1089/can.2021.0089","pmid":"34678050","tags":["cbd","addiction","withdrawal","pain"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD has been reported to have anxiolytic, antidepressant, anti-inflammatory, anti-emetic, and analgesic properties, plus reduction of cue-induced craving for opioids, all highly relevant to withdrawal symptoms. CBD is well tolerated with no significant adverse effects even when co-administered with potent opioid agonists.","whyItMatters":"Opioid withdrawal management remains a critical challenge. Insufficient withdrawal treatment leads to relapse and overdose. CBD as a non-addictive adjunctive treatment could fill an unmet need.","specificNumbers":"144 abstracts identified, 41 articles selected. CBD properties relevant to withdrawal: anxiolytic, antidepressant, anti-inflammatory, anti-emetic, analgesic, craving reduction. Well tolerated with opioid co-administration.","methodology":"Literature review using PubMed and Google Scholar for keywords related to CBD and opioid withdrawal. 144 abstracts identified, 41 articles selected where CBD was evaluated in clinical studies relevant to opioid withdrawal.","limitations":"Most evidence from preclinical studies and small clinical trials. No large randomized controlled trials of CBD specifically for opioid withdrawal. Optimal dosing, timing, and duration unknown."},{"rthcId":"RTHC-03985","title":"Plasma and interstitial levels of endocannabinoids and N-acylethanolamines in patients with chronic widespread pain and fibromyalgia: a systematic review and meta-analysis.","authors":"Kurlyandchik, Inna; Lauche, Romy; Tiralongo, Evelin; Warne, Leon N; Schloss, Janet","year":2022,"journal":"Pain reports, 7(6), e1045","doi":"10.1097/PR9.0000000000001045","pmid":"36381652","tags":["pain","neuroscience","inflammation"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Plasma levels of oleoylethanolamide and stearoylethanolamide were significantly increased in fibromyalgia patients compared to controls. Interstitial levels of palmitoylethanolamide and stearoylethanolamide were also altered. No significant differences were found in anandamide or 2-AG, the classical endocannabinoids.","whyItMatters":"If endocannabinoid system dysfunction underlies fibromyalgia, it could explain why some patients report benefit from cannabis and provide targets for more specific treatments.","specificNumbers":"8 studies reviewed, 7 meta-analyzed. Increased plasma OEA (p=0.005) and SEA in fibromyalgia. Altered interstitial PEA (p=0.05) and SEA (p=0.001). No significant differences in classical endocannabinoids (anandamide, 2-AG).","methodology":"First systematic review and meta-analysis of endocannabinoid and N-acylethanolamine levels in chronic widespread pain and fibromyalgia. Eight studies included for qualitative review, seven for meta-analysis. Compared plasma and interstitial levels between patients and healthy controls.","limitations":"Small number of studies (7-8). Most studies did not account for variables that influence endocannabinoid function (cannabis use, medications, physical activity, sleep, diet). Heterogeneous measurement methods."},{"rthcId":"RTHC-03986","title":"Smoking Behaviors and Prognosis in Patients With Non-Muscle-Invasive Bladder Cancer in the Be-Well Study.","authors":"Kwan, Marilyn L; Haque, Reina; Young-Wolff, Kelly C; Lee, Valerie S; Roh, Janise M; Ergas, Isaac J; Wang, Zinian; Cannavale, Kimberly L; Ambrosone, Christine B; Loo, Ronald K; Aaronson, David S; Quesenberry, Charles P; Kushi, Lawrence H; Tang, Li","year":2022,"journal":"JAMA network open, 5(11), e2244430","doi":"10.1001/jamanetworkopen.2022.44430","pmid":"36449286","tags":["cancer","respiratory"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Longer cigarette smoking duration and more pack-years were associated with higher recurrence risk in a dose-dependent manner (40+ years: HR 2.36; 40+ pack-years: HR 1.97). No associations were found for marijuana, e-cigarettes, pipes, or cigars with bladder cancer recurrence or progression.","whyItMatters":"With nearly a quarter of bladder cancer patients reporting marijuana use, the absence of a recurrence association is reassuring for patients and clinicians, especially in contrast to the strong tobacco-recurrence link.","specificNumbers":"1,472 patients. 363 (24.7%) used marijuana. 59.4% former smokers. 7.5% current smokers. Marijuana: no association with recurrence or progression. Tobacco 40+ years: HR 2.36 (95% CI 1.43-3.91). 40+ pack-years: HR 1.97 (95% CI 1.32-2.95).","methodology":"Prospective Be-Well Study of 1,472 patients with non-muscle-invasive bladder cancer (NMIBC) diagnosed 2015-2019 in Kaiser Permanente California. Baseline interviews on tobacco, e-cigarette, and marijuana use. Cox regression estimated hazard ratios for recurrence and progression.","limitations":"Self-reported substance use at a single time point. Marijuana use details (frequency, amount, duration) not fully captured. Relatively short follow-up (26.4 months). NMIBC-specific findings may not apply to other cancers."},{"rthcId":"RTHC-03987","title":"Cutaneous Squamous Cell Carcinoma and Lichen Simplex Chronicus Successfully Treated with Topical Cannabinoid Oil: A Case Report and Summary of Cannabinoids in Dermatology.","authors":"Laborada, Jennifer; Cohen, Philip R","year":2022,"journal":"Cureus, 14(4), e23850","doi":"10.7759/cureus.23850","pmid":"35530920","tags":["cbd","cancer","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Both squamous cell carcinoma and lichen simplex chronicus resolved with topical application of 20% cannabidiol. The patient had a history of multiple squamous cell carcinomas. The endocannabinoid system plays a key role in skin homeostasis including proliferation, differentiation, and inflammatory signaling.","whyItMatters":"While a single case cannot prove efficacy, the resolution of a confirmed skin cancer with topical CBD is notable and warrants further investigation, especially given the endocannabinoid system's known role in skin biology.","specificNumbers":"64-year-old woman. 20% CBD concentration. Both bilateral hand lesions resolved. Diagnoses confirmed by skin biopsy.","methodology":"Single case report with biopsy-confirmed diagnoses and documented resolution with topical 20% CBD application.","limitations":"Single case report. No control. Spontaneous resolution possible. No follow-up duration specified. 20% CBD is a high concentration not widely available commercially."},{"rthcId":"RTHC-03988","title":"The Cytotoxic Effects of Cannabidiol and Cannabigerol on Glioblastoma Stem Cells May Mostly Involve GPR55 and TRPV1 Signalling.","authors":"Lah, Tamara T; Majc, Bernarda; Novak, Metka; Sušnik, Ajda; Breznik, Barbara; Porčnik, Andrej; Bošnjak, Roman; Sadikov, Aleksander; Malavolta, Marta; Halilčević, Selma; Mlakar, Jernej; Zomer, Roby","year":2022,"journal":"Cancers, 14(23)","doi":"10.3390/cancers14235918","pmid":"36497400","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03989","title":"Cannabidiol and the possibilities of its use in veterinary medicine of dogs and horses: A brief review.","authors":"Landa, Leos; Trojan, Vaclav; Demlova, Regina; Jurica, Jan; Hrib, Radovan","year":2022,"journal":"Veterinarni medicina, 67(9), 455-462","doi":"10.17221/127/2021-VETMED","pmid":"38715968","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-03990","title":"The CannTeen study: verbal episodic memory, spatial working memory, and response inhibition in adolescent and adult cannabis users and age-matched controls.","authors":"Lawn, W; Fernandez-Vinson, N; Mokrysz, C; Hogg, G; Lees, R; Trinci, K; Petrilli, K; Borissova, A; Ofori, S; Waters, S; Michór, P; Wall, M B; Freeman, T P; Curran, H V","year":2022,"journal":"Psychopharmacology, 239(5), 1629-1641","doi":"10.1007/s00213-022-06143-3","pmid":"35486121","tags":["cognition","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis users had significantly worse verbal episodic memory than controls (p=0.007). However, no significant differences were found between users and controls on spatial working memory or response inhibition, supported by Bayesian analyses. Critically, no interaction between age group and user status was found for any cognitive measure.","whyItMatters":"The adolescent brain is considered more vulnerable to cannabis, but this well-matched study did not find evidence for heightened adolescent vulnerability, challenging a widely held assumption.","specificNumbers":"274 total participants. Users: 4 days/week, 2.5 days since last use. Verbal memory: F(1,268)=7.423, p=0.007. No significant user-control differences on spatial working memory or response inhibition. No age-by-user interaction for any measure.","methodology":"Cross-sectional study from the CannTeen project: 76 adolescent cannabis users (16-17), 63 adolescent controls, 71 adult users (26-29), and 64 adult controls. Users matched on cannabis frequency (4 days/week) and time since last use (2.5 days). Tested verbal memory, spatial working memory, and response inhibition.","limitations":"Cross-sectional design. Cannot determine if cognitive differences preceded cannabis use. Relatively small groups. Matching on frequency and recency of use may mask other exposure differences. Young adult age range (26-29) may still reflect ongoing neurodevelopment."},{"rthcId":"RTHC-03991","title":"Persistent sexually dimorphic effects of adolescent THC exposure on hippocampal synaptic plasticity and episodic memory in rodents.","authors":"Le, Aliza A; Quintanilla, Julian; Amani, Mohammad; Piomelli, Daniele; Lynch, Gary; Gall, Christine M","year":2022,"journal":"Neurobiology of disease, 162, 105565","doi":"10.1016/j.nbd.2021.105565","pmid":"34838664","tags":["youth","neuroscience","sex-differences","cognition"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Adolescent THC exposure produced selective, lasting deficits in synaptic plasticity in two hippocampal pathways, primarily in females. In females, THC disrupted endocannabinoid-dependent long-term potentiation, impaired estrogen effects on synaptic responses, and caused deficits in both episodic-like and spatial memory. Effects were sexually dimorphic and pathway-specific.","whyItMatters":"This study identifies a specific mechanism for sex-specific adolescent cannabis vulnerability: THC disrupts the interaction between the endocannabinoid system and estrogen signaling in the hippocampus, with lasting consequences for memory.","specificNumbers":"14-day adolescent THC treatment. Effects confirmed in both rats and mice (cross-species validation). Lateral perforant path LTP disrupted in females of both species and male mice. Schaffer-commissural LTP disrupted in females only.","methodology":"Rats and mice received 14 days of daily THC during adolescence. In adulthood, researchers measured synaptic plasticity (long-term potentiation) in hippocampal brain slices and tested episodic and spatial memory behavior.","limitations":"Animal study with uncertain human translation. Single THC dose regimen. Specific hippocampal pathways may not capture all relevant cognitive effects. Estrogen interaction mechanism needs confirmation in humans."},{"rthcId":"RTHC-03992","title":"\"Ganja Mamas\": Online discussions about cannabis use in pregnancy.","authors":"Lebron, Cynthia N; Morales, Vanessa; Saenz, Shantal; Vidot, Denise C","year":2022,"journal":"Drug and alcohol dependence, 241, 109689","doi":"10.1016/j.drugalcdep.2022.109689","pmid":"36413898","tags":["pregnancy","harm-reduction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Analysis of 151 messages and 1,260 comments from a pregnancy cannabis forum found that testing and child protective services were the top concerns, with members actively interviewing each other about geographic-specific experiences.","whyItMatters":"When pregnant cannabis users avoid healthcare providers due to stigma and legal fears, they turn to online peers. Understanding what they discuss reveals gaps in clinical communication.","specificNumbers":"46.56% reported geographic location (24 states); 40.46% reported gestational age; 131 unique forum members posted questions","methodology":"Researchers extracted posts from Whattoexpect.com's \"Ganja Mamas\" forum over a 7-day period and coded 16 categories of information-seeking behavior from 131 unique members.","limitations":"Data came from a single forum over just 7 days. Posts may not represent the broader population of cannabis-using pregnant women."},{"rthcId":"RTHC-03993","title":"Use of Capsaicin Cream in Cannabinoid Hyperemesis Syndrome in Patients Presenting to the Emergency Department.","authors":"Lee, Allison; Coralic, Zlatan","year":2022,"journal":"The Annals of pharmacotherapy, 56(2), 151-154","doi":"10.1177/10600280211018516","pmid":"33998315","tags":["medical-cannabis","pain"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Among 57 patients receiving capsaicin for suspected CHS, pain scores dropped from a median of 8 to 5.5, and nearly half required no additional symptomatic therapy after application.","whyItMatters":"Cannabinoid hyperemesis syndrome is notoriously difficult to treat. Standard antiemetics often fail, and many patients receive opioids. A simple topical cream that provides relief could reduce reliance on more problematic medications.","specificNumbers":"57 patients; pain score median 8 to 5.5; 98% received antiemetics; 47% received an opioid; 42% needed no further therapy after capsaicin; capsaicin applied at median 4 hours into visit","methodology":"Retrospective chart review of 57 patients with suspected CHS who received capsaicin cream in an emergency department between July 2014 and October 2018.","limitations":"Retrospective design without a control group. Capsaicin was typically given after antiemetics and opioids, making it hard to isolate its independent effect."},{"rthcId":"RTHC-03994","title":"Frequent Low-Dose Δ9-Tetrahydrocannabinol in Adolescence Disrupts Microglia Homeostasis and Disables Responses to Microbial Infection and Social Stress in Young Adulthood.","authors":"Lee, Hye-Lim; Jung, Kwang-Mook; Fotio, Yannick; Squire, Erica; Palese, Francesca; Lin, Lin; Torrens, Alexa; Ahmed, Faizy; Mabou Tagne, Alex; Ramirez, Jade; Su, Shiqi; Wong, Christina Renee; Jung, Daniel Hojin; Scarfone, Vanessa M; Nguyen, Pauline U; Wood, Marcelo; Green, Kim; Piomelli, Daniele","year":2022,"journal":"Biological psychiatry, 92(11), 845-860","doi":"10.1016/j.biopsych.2022.04.017","pmid":"35750512","tags":["youth","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Daily THC from postnatal day 30 to 44 produced microglia dysfunction in both male and female mice that persisted to young adulthood (PND70) but receded by PND120. The effects were prevented by a CB1 receptor antagonist and were not replicated when THC was given to adult mice.","whyItMatters":"Microglia play critical roles in brain development during adolescence. If THC disrupts their function during this window, it could impair the brain's ability to respond to infections and stress during a vulnerable developmental period.","specificNumbers":"THC dose: 5 mg/kg daily for 14 days; dysfunction persisted to PND70 (young adulthood); resolved by PND120; effects blocked by CB1 antagonist","methodology":"Mice received daily THC (5 mg/kg) during adolescence (PND30-44). Researchers examined microglia transcriptomes at PND70 and PND120, tested responses to immune challenge (LPS) and social stress (repeated social defeat), and used mass cytometry to map brain immune populations.","limitations":"Animal study using injected THC at a single dose, which does not replicate human cannabis use patterns. Translating mouse developmental timelines to human adolescence is imprecise."},{"rthcId":"RTHC-03995","title":"Thalamocortical functional connectivity and cannabis use in men with childhood attention-deficit/hyperactivity disorder.","authors":"Lee, Sanghyun; Hong, Soon-Beom","year":2022,"journal":"PloS one, 17(11), e0278162","doi":"10.1371/journal.pone.0278162","pmid":"36441710","tags":["cognition","neuroscience","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis-using adults with childhood ADHD (n=18) had significantly decreased thalamic-parietal functional connectivity compared to non-users (n=15). Non-users showed increased thalamoparietal and thalamofrontal connectivity relative to a normative comparison group.","whyItMatters":"ADHD and substance use disorders share disrupted brain circuits. Understanding how cannabis interacts with ADHD-related brain connectivity could inform why people with ADHD use cannabis at higher rates.","specificNumbers":"18 cannabis users vs 15 non-users with childhood ADHD; 7 normative comparisons; decreased connectivity in inferior parietal regions","methodology":"Researchers analyzed resting-state fMRI data from the Addiction Connectome Preprocessed Initiative database, comparing thalamic connectivity maps between cannabis users and non-users with childhood ADHD diagnoses.","limitations":"Very small sample size (33 total). Cross-sectional design cannot determine whether cannabis caused connectivity differences or whether pre-existing differences influenced cannabis use."},{"rthcId":"RTHC-03996","title":"Cannabis smoking and glaucoma in the UK Biobank cohort.","authors":"Lehrer, S; Rheinstein, P H","year":2022,"journal":"Journal francais d'ophtalmologie, 45(4), 423-429","doi":"10.1016/j.jfo.2021.12.012","pmid":"35093258","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Heavy cannabis users (100+ times) were diagnosed with glaucoma approximately 10 years earlier than never-users. Cannabis use modestly lowered intraocular pressure but did not increase overall glaucoma risk. The earlier age of diagnosis was independent of IOP effects and cigarette smoking.","whyItMatters":"Cannabis has long been discussed as a potential glaucoma treatment because it lowers eye pressure. This study complicates that narrative by showing that despite lower IOP, frequent cannabis users developed glaucoma earlier.","specificNumbers":"~10 years younger glaucoma diagnosis in 100+ time users; cannabis effect on glaucoma incidence not significant (P=0.662); IOP significantly lower in 11-100 time users","methodology":"Retrospective analysis of UK Biobank data examining relationships between cannabis use frequency, intraocular pressure, and glaucoma diagnosis age, controlling for cigarette smoking and age.","limitations":"Self-reported cannabis use. UK Biobank participants may not represent the general population. Cannot establish causation from observational data."},{"rthcId":"RTHC-03997","title":"Marijuana smoking and cataract.","authors":"Lehrer, S; Rheinstein, P H","year":2022,"journal":"Journal francais d'ophtalmologie, 45(3), 267-271","doi":"10.1016/j.jfo.2021.12.008","pmid":"35093261","tags":["harm-reduction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users (11-100 times) were diagnosed with cataracts 4-5 years earlier than non-users. This association was independent of cigarette pack-years (P<0.001 for cannabis, P=0.008 for independence from cigarettes). However, cannabis use did not increase the overall odds of developing cataracts.","whyItMatters":"Cannabis smoke contains many of the same toxic compounds as tobacco smoke. While cigarette smoking is a known cataract risk factor, less was known about cannabis. This study suggests cannabis may accelerate cataract timing without increasing overall risk.","specificNumbers":"28,432 subjects with cataracts; 4-5 years earlier diagnosis; cannabis effect P<0.001; cigarette OR 1.2 for cataract; cannabis OR not significant for overall cataract risk","methodology":"Analysis of 28,432 UK Biobank subjects with cataracts, using propensity score matching with cigarette smoking and age as covariates. Cannabis use frequency was the indicator variable.","limitations":"Self-reported cannabis use in UK Biobank. Cannot account for method of consumption (smoked vs other). Association does not prove causation."},{"rthcId":"RTHC-03998","title":"Marijuana and Myocardial Infarction in the UK Biobank Cohort.","authors":"Lehrer, Steven; Rheinstein, Peter H","year":2022,"journal":"Cureus, 14(2), e22054","doi":"10.7759/cureus.22054","pmid":"35165641","tags":["cardiovascular","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Multivariate logistic regression found marijuana use associated with reduced MI risk (OR 0.844), comparable to red wine consumption (OR 0.847). The analysis controlled for cigarette pack-years, diabetes, sex, BMI, hypertension, and age.","whyItMatters":"Previous evidence on cannabis and heart attack risk has been mixed. Finding a protective association comparable to red wine in a large cohort challenges the assumption that cannabis only poses cardiovascular harm.","specificNumbers":"Marijuana use OR 0.844 for MI; red wine OR 0.847 for MI; MI incidence decreased with marijuana use (P<0.001)","methodology":"Retrospective analysis of UK Biobank data examining myocardial infarction incidence by marijuana use status, with red wine consumption as a comparator. Multivariate logistic regression controlled for standard cardiovascular risk factors.","limitations":"Observational study cannot prove causation. Self-reported marijuana use. Could not control for all potential confounders. The \"stress reduction\" hypothesis for the mechanism is speculative."},{"rthcId":"RTHC-03999","title":"Cannabis, Intraocular Pressure, and the Growth Arrest-Specific 7 (GAS7) Gene: A Retrospective Analysis.","authors":"Lehrer, Steven; Rheinstein, Peter H","year":2022,"journal":"Cureus, 14(4), e23919","doi":"10.7759/cureus.23919","pmid":"35411287","tags":["medical-cannabis","genetics"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Carriers of the GAS7 gene variant (rs9913911 minor allele G) showed lower intraocular pressure with increased cannabis use (P<0.001). The CDKN2B-AS1 glaucoma gene showed no such interaction. CB1 and GPR18, which mediate cannabis IOP reduction in mice, showed no significant relationship in humans.","whyItMatters":"Understanding exactly how cannabis lowers eye pressure at the genetic level could lead to targeted treatments that capture the benefit without requiring cannabis use itself.","specificNumbers":"37,046 subjects; GAS7 interaction P<0.001; CDKN2B-AS1 interaction P=0.138 (not significant); CB1 and GPR18 interactions not significant","methodology":"Analysis of 37,046 UK Biobank subjects examining the interaction between cannabis use, genotype variants in glaucoma-associated genes (GAS7 and CDKN2B-AS1), and intraocular pressure using univariate ANOVA.","limitations":"Observational design. Genetic associations do not prove mechanism. UK Biobank population may not generalize globally. Cannabis use was self-reported."},{"rthcId":"RTHC-04000","title":"Pediatric Subspecialist Alcohol Screening Rates and Concerns About Alcohol and Cannabis Use Among Their Adolescent Patients.","authors":"Levy, Sharon; Wisk, Lauren E; Minegishi, Machiko; Lunstead, Julie; Weitzman, Elissa R","year":2022,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 71(4S), S34-S40","doi":"10.1016/j.jadohealth.2022.03.001","pmid":"36122967","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04001","title":"Association of Screening and Brief Intervention With Substance Use in Massachusetts Middle and High Schools.","authors":"Levy, Sharon; Wisk, Lauren E; Minegishi, Machiko; Ertman, Benjamin; Lunstead, Julie; Brogna, Melissa; Weitzman, Elissa R","year":2022,"journal":"JAMA network open, 5(8), e2226886","doi":"10.1001/jamanetworkopen.2022.26886","pmid":"35972741","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04002","title":"Characteristics of Adults Who Use Both Marijuana and E-Cigarette, or Vaping, Products: A Cross-Sectional Study, Utah, 2018.","authors":"Lewis, Nathaniel M; Friedrichs, Michael; Wagstaff, Shelly S; Nakashima, Allyn K; Dunn, Angela C","year":2022,"journal":"Public health reports (Washington, D.C. : 1974), 137(4), 695-701","doi":"10.1177/00333549211018679","pmid":"34039118","tags":["harm-reduction","respiratory","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Dual users of marijuana and e-cigarettes had dramatically higher odds of being aged 18-29 (aOR 12.44), being male (aOR 3.29), reporting 14+ days of poor mental health (aOR 2.30), having asthma (aOR 2.09), COPD (aOR 2.94), currently smoking cigarettes (aOR 4.56), and using prescribed pain medications (aOR 2.13).","whyItMatters":"Understanding who uses both marijuana and vaping products helps identify populations that may face compounded health risks from multiple inhalant substances.","specificNumbers":"n=10,380; dual users aOR 12.44 for age 18-29; aOR 3.29 for male; aOR 2.30 for poor mental health; aOR 2.09 for asthma; aOR 2.94 for COPD; aOR 4.56 for current cigarette smoking","methodology":"Cross-sectional analysis of the 2018 Utah Behavioral Risk Factor Surveillance System (n=10,380) using multivariable logistic regression comparing dual users to a reference group of single- or non-users.","limitations":"Cross-sectional design cannot determine direction of associations. Utah population may differ from national patterns. Self-reported data subject to social desirability bias."},{"rthcId":"RTHC-04003","title":"Analysis of Anti-Cancer and Anti-Inflammatory Properties of 25 High-THC Cannabis Extracts.","authors":"Li, Dongping; Ilnytskyy, Yaroslav; Ghasemi Gojani, Esmaeel; Kovalchuk, Olga; Kovalchuk, Igor","year":2022,"journal":"Molecules (Basel, Switzerland), 27(18)","doi":"10.3390/molecules27186057","pmid":"36144796","tags":["cancer","inflammation","medical-cannabis","potency"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Anti-cancer efficacy ranged from 66% to 92% growth inhibition across 25 extracts. For inflammation, some extracts reduced cytokine expression by over 5-fold while others doubled it. The terpene terpinene correlated with anti-cancer activity (P=0.002), and p-cymene and beta-myrcene correlated with anti-inflammatory effects.","whyItMatters":"This study demonstrates that the \"entourage effect\" is real and measurable: cannabis extracts with similar THC levels produce vastly different biological outcomes depending on their terpene profiles.","specificNumbers":"25 extracts tested; 66-92% cancer growth inhibition range; >5-fold inflammation reduction (best) to 2-fold increase (worst); terpinene P=0.002 for anti-cancer","methodology":"In vitro testing of 25 high-THC cannabis extracts on squamous cell carcinoma (HCC1806) cells and TNF-alpha/IFN-gamma-induced inflammation in human lung fibroblasts (WI38). Chemical profiling of THC, CBD, CBG, CBN, and 20 terpenes with correlation analysis.","limitations":"In vitro study only. Cancer cell line results do not predict clinical outcomes. Correlation between terpenes and activity does not prove the terpenes are directly responsible."},{"rthcId":"RTHC-04004","title":"Cannabis sativa L. alleviates loperamide-induced constipation by modulating the composition of gut microbiota in mice.","authors":"Li, Rong; Li, Min; Li, Bei; Chen, Wei-Hua; Liu, Zhi","year":2022,"journal":"Frontiers in pharmacology, 13, 1033069","doi":"10.3389/fphar.2022.1033069","pmid":"36532754","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04005","title":"Medical Cannabis for Gynecologic Pain Conditions: A Systematic Review.","authors":"Liang, Angela L; Gingher, Erin L; Coleman, Jenell S","year":2022,"journal":"Obstetrics and gynecology, 139(2), 287-296","doi":"10.1097/AOG.0000000000004656","pmid":"35104069","tags":["pain","medical-cannabis","sex-differences"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Among 16 included studies, 13-27% of women used cannabis for gynecologic pain. Survey data showed 61-95.5% reported pain relief. Six prospective cohort studies and one RCT of PEA-combination medications reported significant pain relief, with an average decrease of 3.35 points on a 10-point scale after 3 months.","whyItMatters":"Gynecologic pain conditions like endometriosis and chronic pelvic pain are common, often undertreated, and significantly impact quality of life. Cannabis-based treatments represent a potential alternative or complement to current options.","specificNumbers":"5,189 articles screened; 16 met criteria; 13-27% cannabis use prevalence; 61-95.5% reported relief; 3.35-point average pain reduction on 10-point scale","methodology":"Systematic review searching PubMed, EMBASE, Scopus, Cochrane, and ClinicalTrials.gov for studies of cannabinoids in nonpregnant adult women with gynecologic pain conditions (chronic pelvic pain, vulvodynia, endometriosis, interstitial cystitis, malignancy).","limitations":"Heterogeneous studies with varying cannabis formulations, delivery methods, and dosages. Most evidence comes from surveys rather than controlled trials."},{"rthcId":"RTHC-04006","title":"Systematic review of structural and functional neuroimaging studies of cannabis use in adolescence and emerging adulthood: evidence from 90 studies and 9441 participants.","authors":"Lichenstein, Sarah D; Manco, Nick; Cope, Lora M; Egbo, Leslie; Garrison, Kathleen A; Hardee, Jillian; Hillmer, Ansel T; Reeder, Kristen; Stern, Elisa F; Worhunsky, Patrick; Yip, Sarah W","year":2022,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(5), 1000-1028","doi":"10.1038/s41386-021-01226-9","pmid":"34839363","tags":["youth","neuroscience","cognition"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Across 90 studies including 9,441 participants (3,924 cannabis users, 5,517 non-users), preliminary evidence pointed to alterations in frontoparietal, frontolimbic, frontostriatal, and cerebellar regions among adolescent and emerging adult cannabis users.","whyItMatters":"With cannabis legalization expanding and adolescent perceptions of harm declining, establishing what happens to the developing brain during cannabis exposure is critical for public health messaging and clinical guidance.","specificNumbers":"90 studies; 9,441 total participants; 3,924 cannabis users; 5,517 non-users; alterations in 4 major brain networks","methodology":"Systematic search of Medline and PsycInfo with additional non-systematic sources, identifying 90 structural and functional neuroimaging studies of cannabis use during adolescence and emerging adulthood.","limitations":"Divergent results across studies make definitive conclusions difficult. Most studies are cross-sectional, so risk factors for cannabis use and consequences of use are difficult to disentangle."},{"rthcId":"RTHC-04007","title":"A Review on the Bioactivity of Cannabinoids on Zebrafish Models: Emphasis on Neurodevelopment.","authors":"Licitra, Rosario; Marchese, Maria; Naef, Valentina; Ogi, Asahi; Martinelli, Marco; Kiferle, Claudia; Fronte, Baldassare; Santorelli, Filippo Maria","year":2022,"journal":"Biomedicines, 10(8)","doi":"10.3390/biomedicines10081820","pmid":"36009367","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04008","title":"Regulation of Expression of Cannabinoid CB2 and Serotonin 5HT1A Receptor Complexes by Cannabinoids in Animal Models of Hypoxia and in Oxygen/Glucose-Deprived Neurons.","authors":"Lillo, Jaume; Raïch, Iu; Silva, Laura; Zafra, David A; Lillo, Alejandro; Ferreiro-Vera, Carlos; Sánchez de Medina, Verónica; Martínez-Orgado, José; Franco, Rafael; Navarro, Gemma","year":2022,"journal":"International journal of molecular sciences, 23(17)","doi":"10.3390/ijms23179695","pmid":"36077095","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04009","title":"Use of cannabis in the treatment of animals: a systematic review of randomized clinical trials.","authors":"Lima, Tácio de Mendonça; Santiago, Nathania Rodrigues; Alves, Elaine Cristina Ramos; Chaves, Douglas Siqueira de Almeida; Visacri, Marília Berlofa","year":2022,"journal":"Animal health research reviews, 23(1), 25-38","doi":"10.1017/S1466252321000189","pmid":"35703023","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04010","title":"Edible marijuana products and potential risks for pediatric populations.","authors":"Lin, Allison; O'Connor, Mary; Behnam, Reta; Hatef, Claudia; Milanaik, Ruth","year":2022,"journal":"Current opinion in pediatrics, 34(3), 279-287","doi":"10.1097/MOP.0000000000001132","pmid":"35634702","tags":["youth","harm-reduction","potency"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Edible marijuana products are indistinguishable from normal foods, lack the smell associated with smoked cannabis, have delayed onset that predisposes to overconsumption, and feature packaging intentionally similar to mainstream food brands, increasing accidental ingestion risk.","whyItMatters":"As more states legalize marijuana, accidental pediatric exposures to edibles have surged. Understanding the specific features that make edibles dangerous to children can inform better regulation and parent education.","specificNumbers":"THC must be digested before entering the bloodstream, creating delayed onset compared to inhalation; products come as candies, cookies, drinks, and baked goods","methodology":"Narrative review synthesizing current literature on edible cannabis product types, packaging characteristics, pharmacokinetics of oral THC, and documented pediatric exposure patterns.","limitations":"Narrative review without systematic search methodology. Limited quantitative data on specific outcomes of pediatric edible exposure."},{"rthcId":"RTHC-04011","title":"A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse.","authors":"Lin, Xiaoyan; Xu, Zhili; Carey, Lawrence; Romero, Julian; Makriyannis, Alexandros; Hillard, Cecilia J; Ruggiero, Elizabeth; Dockum, Marilyn; Houk, George; Mackie, Ken; Albrecht, Phillip J; Rice, Frank L; Hohmann, Andrea G","year":2022,"journal":"Pain, 163(5), 834-851","doi":"10.1097/j.pain.0000000000002502","pmid":"35001054","tags":["pain","neuroscience","medical-cannabis","cancer"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CB2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in mice. The antiallodynic effect was blocked by a peripherally restricted CB2 antagonist, and local injection into the paw was effective, indicating a peripheral mechanism. CB2 was found in skin keratinocytes, Langerhans cells, dendritic cells, and Merkel cells.","whyItMatters":"Chemotherapy-induced peripheral neuropathy affects many cancer patients and has few effective treatments. A peripheral CB2 mechanism that avoids the psychoactive effects of CB1 activation could lead to targeted pain therapies.","specificNumbers":"CB2 found in keratinocytes, Langerhans cells, dendritic cells, and Merkel cells; paclitaxel treatment dynamically increased Langerhans cells in the epidermis; local paw injection was effective","methodology":"Used transgenic CB2-EGFP reporter mice to visualize CB2-expressing cell types. Tested structurally distinct CB2 agonists in a paclitaxel-induced neuropathy model. Combined behavioral testing with immunohistochemistry and mass cytometry.","limitations":"Animal study in transgenic mice. CB2 expression patterns may differ in humans. The reporter gene approach may not capture all CB2-expressing cell types."},{"rthcId":"RTHC-04012","title":"Adolescent alcohol use predicts cannabis use over a three year follow-up period.","authors":"Linakis, James G; Thomas, Sarah A; Bromberg, Julie R; Casper, T Charles; Chun, Thomas H; Mello, Michael J; Richards, Rachel; Ahmad, Fahd; Bajaj, Lalit; Brown, Kathleen M; Chernick, Lauren S; Cohen, Daniel M; Dean, J Michael; Fein, Joel; Horeczko, Timothy; Levas, Michael N; McAninch, B; Monuteaux, Michael C; Mull, Colette C; Grupp-Phelan, Jackie; Powell, Elizabeth C; Rogers, Alexander; Shenoi, Rohit P; Suffoletto, Brian; Vance, Cheryl; Spirito, Anthony","year":2022,"journal":"Substance abuse, 43(1), 514-519","doi":"10.1080/08897077.2021.1949665","pmid":"34236277","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Adolescents classified as low alcohol risk had significantly higher rates of cannabis use disorder versus nondrinkers (OR range: 1.94-2.76) at one-, two-, and three-year follow-up. The NIAAA two-question screen predicted future cannabis use disorder.","whyItMatters":"Emergency departments often only screen for alcohol due to time constraints. If a simple alcohol screen can also flag future cannabis risk, clinicians get two screenings for the price of one.","specificNumbers":"1,689 adolescents; 16 pediatric EDs; OR 1.94-2.76 for CUD with low alcohol risk; 3-year follow-up","methodology":"Secondary analysis of 1,689 adolescents aged 12-17 treated in 16 pediatric EDs. Baseline alcohol risk was assessed with the NIAAA two-question screen, and cannabis use disorder was evaluated at one, two, and three years via telephone or web survey.","limitations":"Secondary data analysis. Follow-up relied on self-report. Attrition over three years may have introduced bias."},{"rthcId":"RTHC-04013","title":"A Cannabinoid Hypothesis of Schizophrenia: Pathways to Psychosis.","authors":"Little, Rachel; D'Mello, Dale","year":2022,"journal":"Innovations in clinical neuroscience, 19(7-9), 38-43","doi":null,"pmid":"36204167","tags":["psychosis","neuroscience","dopamine"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The review describes several putative pathways from cannabis to psychosis, integrating evidence about the endocannabinoid system, THC's effects on dopamine and glutamate signaling, and the connection between cannabis use and first-episode psychosis.","whyItMatters":"Understanding the specific biological pathways through which cannabis may trigger psychosis could enable targeted prevention strategies for susceptible individuals.","specificNumbers":"Hypothesis parallels existing dopamine, serotonin, and glutamate hypotheses of schizophrenia","methodology":"Narrative review synthesizing evidence about the endocannabinoid system, THC's neurochemical effects, and epidemiological links between cannabis and psychosis to propose a unified cannabinoid hypothesis.","limitations":"Narrative review proposing a hypothesis rather than testing one. Pathways described are \"putative\" and not fully established."},{"rthcId":"RTHC-04014","title":"Resting-state EEG, Substance use and Abstinence After Chronic use: A Systematic Review.","authors":"Liu, Yang; Chen, Yujie; Fraga-González, Gorka; Szpak, Veronica; Laverman, Judith; Wiers, Reinout W; Richard Ridderinkhof, K","year":2022,"journal":"Clinical EEG and neuroscience, 53(4), 344-366","doi":"10.1177/15500594221076347","pmid":"35142589","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04015","title":"A polarized supercell produces specialized metabolites in cannabis trichomes.","authors":"Livingston, Samuel J; Rensing, Kim H; Page, Jonathan E; Samuels, A Lacey","year":2022,"journal":"Current biology : CB, 32(18), 4040-4047.e4","doi":"10.1016/j.cub.2022.07.014","pmid":"35917819","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04016","title":"Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion.","authors":"Llorente-Ovejero, Alberto; Bengoetxea de Tena, Iker; Martínez-Gardeazabal, Jonatan; Moreno-Rodríguez, Marta; Lombardero, Laura; Manuel, Iván; Rodríguez-Puertas, Rafael","year":2022,"journal":"ACS pharmacology & translational science, 5(9), 791-802","doi":"10.1021/acsptsci.2c00069","pmid":"36110372","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04017","title":"Impact of cannabinoids on pregnancy, reproductive health, and offspring outcomes.","authors":"Lo, Jamie O; Hedges, Jason C; Girardi, Guillermina","year":2022,"journal":"American journal of obstetrics and gynecology, 227(4), 571-581","doi":"10.1016/j.ajog.2022.05.056","pmid":"35662548","tags":["pregnancy","harm-reduction","sex-differences"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"THC crosses the placenta and has been detected in breast milk. Prenatal cannabis use has been associated with small-for-gestational-age infants, preterm birth, and impaired offspring neurodevelopment. In males, cannabis has been linked to erectile dysfunction, abnormal spermatogenesis, and testicular atrophy. In females, it has been associated with infertility and abnormal embryo implantation.","whyItMatters":"Cannabis is the most commonly used federally illegal drug among people of reproductive age, and product potency has increased significantly. Understanding reproductive effects is critical as use continues to rise.","specificNumbers":"Cannabinoid receptors found in male and female reproductive tracts, on sperm, and on the placenta; cannabis potency has increased significantly in the past decade","methodology":"Narrative review synthesizing evidence on cannabinoid effects across the reproductive lifespan, including fertility, pregnancy, lactation, and menopause, with focus on endocannabinoid system biology.","limitations":"Narrative review with limited available evidence, particularly for lactation and menopause. Most pregnancy studies cannot fully account for confounders like polysubstance use."},{"rthcId":"RTHC-04018","title":"Paediatric cannabinoid hyperemesis.","authors":"Lonsdale, Hannah; Wilsey, Michael J","year":2022,"journal":"Current opinion in pediatrics, 34(5), 510-515","doi":"10.1097/MOP.0000000000001157","pmid":"35946907","tags":["youth","medical-cannabis","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Current best evidence recommends IV rehydration and electrolyte correction, followed by haloperidol 0.05 mg/kg with or without a benzodiazepine for acute pediatric CHS. The only effective long-term treatment remains complete cessation of cannabinoid use.","whyItMatters":"CHS prevalence in adolescents continues to grow as cannabis becomes more accessible and potent. Clinicians need practical guidance because high-quality treatment evidence specific to pediatric populations is lacking.","specificNumbers":"Haloperidol dose: 0.05 mg/kg IV; presenting features: cyclical nausea, emesis, abdominal pain, hot shower relief","methodology":"Narrative review of current literature on adolescent CHS, covering diagnosis, pathophysiology, and treatment evidence.","limitations":"High-quality treatment evidence for adolescent CHS remains lacking. Recommendations are based on limited data extrapolated partly from adult studies."},{"rthcId":"RTHC-04019","title":"TRPV1: A Common Denominator Mediating Antinociceptive and Antiemetic Effects of Cannabinoids.","authors":"Louis-Gray, Kathleen; Tupal, Srinivasan; Premkumar, Louis S","year":2022,"journal":"International journal of molecular sciences, 23(17)","doi":"10.3390/ijms231710016","pmid":"36077412","tags":["pain","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"TRPV1 activation in the central descending pain pathway (RVM and PAG) mediates antinociception, while peripheral TRPV1 activation mediates nociception. Chronic cannabis use may cause paradoxical hyperemesis through TRPV1-mediated pathways, which explains why capsaicin (a TRPV1 agonist) and hot showers effectively treat CHS.","whyItMatters":"Understanding that a single receptor (TRPV1) mediates both the therapeutic and paradoxical effects of cannabis provides a unifying framework for developing better treatments.","specificNumbers":"Over 450 constituents in cannabis; TRPV1 expressed in both peripheral and central pain pathways; CHS becoming more common with higher-potency products","methodology":"Review of literature on TRPV1 ion channel interactions with cannabinoids, covering pain pathways, antiemetic mechanisms, and the cannabinoid hyperemesis paradox.","limitations":"Review paper synthesizing existing knowledge rather than presenting new data. The TRPV1 mechanism for CHS is proposed but not definitively proven."},{"rthcId":"RTHC-04020","title":"RTICBM-74 Is a Brain-Penetrant Cannabinoid Receptor Subtype 1 Allosteric Modulator that Reduces Alcohol Intake in Rats.","authors":"Lovelock, Dennis F; Nguyen, Thuy; Van Voorhies, Kalynn; Zhang, Yanan; Besheer, Joyce","year":2022,"journal":"The Journal of pharmacology and experimental therapeutics, 380(3), 153-161","doi":"10.1124/jpet.121.000919","pmid":"34930820","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04021","title":"Cannabis use in pregnancy and maternal and infant outcomes: A Canadian cross-jurisdictional population-based cohort study.","authors":"Luke, Sabrina; Hobbs, Amy J; Smith, Michaela; Riddell, Catherine; Murphy, Phil; Agborsangaya, Calypse; Cantin, Christina; Fahey, John; Der, Kenny; Pederson, Ann; Nelson, Chantal","year":2022,"journal":"PloS one, 17(11), e0276824","doi":"10.1371/journal.pone.0276824","pmid":"36417349","tags":["pregnancy","harm-reduction","sex-differences"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Prenatal cannabis use (prevalence ~2%) was associated with increased risks of spontaneous preterm birth (aOR 1.80), medically indicated preterm birth (aOR 1.94), very preterm birth (aOR 1.73), low birth weight (aOR 1.90), small-for-gestational age (aOR 1.21), major congenital anomalies (aOR 1.71), cesarean section (aOR 1.13), and gestational diabetes (aOR 1.32). Female infants showed increased susceptibility for SGA and spontaneous preterm birth.","whyItMatters":"This is one of the largest studies ever to examine prenatal cannabis outcomes, spanning nearly 1.3 million births across multiple provinces with adjustment for important confounders including other substance use.","specificNumbers":"1,280,447 births; ~2% cannabis prevalence; spontaneous preterm aOR 1.80; medically indicated preterm aOR 1.94; very preterm aOR 1.73; low birth weight aOR 1.90; congenital anomalies aOR 1.71; gestational diabetes aOR 1.32","methodology":"Population-based retrospective cohort of 1,280,447 singleton births from three Canadian provincial registries (British Columbia, Ontario, Newfoundland/Labrador) from April 2012 to March 2019. Logistic regression adjusted for other substance use, sociodemographic factors, and comorbidities.","limitations":"Cannabis use may be underreported. Cannot distinguish frequency, quantity, or method of cannabis use. Residual confounding possible despite statistical adjustment."},{"rthcId":"RTHC-04022","title":"Alcohol and cannabis co-use and longitudinal gray matter volumetric changes in early and late adolescence.","authors":"Luo, Xi; Yang, James J; Buu, Anne; Trucco, Elisa M; Li, Chiang-Shan R","year":2022,"journal":"Addiction biology, 27(5), e13208","doi":"10.1111/adb.13208","pmid":"36001427","tags":["youth","neuroscience","cognition","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Co-use of alcohol and cannabis predicted faster gray matter volume decline (-0.046 to -0.138 cm3/year) in the caudal middle frontal cortex, fusiform, inferior frontal, superior temporal, and supramarginal gyri. These effects were not seen with alcohol or cannabis use alone and were more pronounced with early adolescent onset.","whyItMatters":"Most brain imaging studies focus on one substance at a time. This study reveals that the combination of alcohol and cannabis poses a greater threat to adolescent brain development than either substance alone.","specificNumbers":"724 adolescents; 370 female; decline rate -0.046 to -0.138 cm3/year; 5 affected brain regions; Bonferroni-corrected results","methodology":"Longitudinal analysis of 724 adolescents (370 female) from the NCANDA study using mixed-effects modeling of brain MRI data across 34 regions of interest, with Bonferroni correction for multiple comparisons.","limitations":"Cannot fully rule out pre-existing brain differences that led to substance use. Co-users were not using more alcohol than alcohol-only users, but other confounders may exist."},{"rthcId":"RTHC-04023","title":"Cannabidiol in Treatment of Autism Spectrum Disorder: A Case Study.","authors":"Ma, Lucy; Platnick, Sofia; Platnick, Howard","year":2022,"journal":"Cureus, 14(8), e28442","doi":"10.7759/cureus.28442","pmid":"36176817","tags":["cbd","mental-health","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Treatment with full-spectrum CBD oil (20 mg CBD/<1 mg THC per mL), titrated from 0.1 mL to 0.5 mL twice daily, resulted in reduced violent outbursts, self-injurious behaviors, and sleep disruptions. Social interactions, concentration, and emotional stability improved.","whyItMatters":"Safe and effective treatment options for autism spectrum disorder remain limited. This case adds to a growing body of preliminary evidence that CBD may help manage some behavioral symptoms.","specificNumbers":"20 mg CBD/<1 mg THC per mL; starting dose 0.1 mL twice daily; target dose 0.5 mL twice daily; dose increased every 3-4 days","methodology":"Single case study of a 9-year-old male with nonverbal autism spectrum disorder. CBD oil was started at 0.1 mL twice daily and increased every 3-4 days to 0.5 mL twice daily.","limitations":"Single case report with no control or blinding. Improvements could reflect natural development, placebo effect, or other factors. Cannot generalize to the broader ASD population."},{"rthcId":"RTHC-04024","title":"A Clinical Framework for Assessing Cannabis-Related Impairment Risk.","authors":"MacCallum, Caroline A; Lo, Lindsay A; Pistawka, Carly A; Christiansen, April; Boivin, Michael; Snider-Adler, Melissa","year":2022,"journal":"Frontiers in psychiatry, 13, 883517","doi":"10.3389/fpsyt.2022.883517","pmid":"35832600","tags":["medical-cannabis","driving","workplace"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The framework provides clinicians with a structured approach to evaluate impairment-related factors in medical cannabis patients, including dosing, tolerance, timing, and individual risk factors. It is designed for patients performing safety-sensitive duties and can inform workplace assessments.","whyItMatters":"As medical cannabis use grows, clinicians lack practical tools to evaluate impairment risk. This framework fills a gap between prescribing cannabis and ensuring patients can safely work and drive.","specificNumbers":"Framework designed for all patients performing safety-sensitive duties; applicable to current users and those considering medical cannabis","methodology":"Clinical framework development based on review of existing evidence on cannabis-related neurocognitive impairment, intended as a practical tool for healthcare providers managing medical cannabis patients.","limitations":"Framework is expert-developed rather than validated in clinical trials. Individual impairment varies widely and may be difficult to predict from any standardized assessment."},{"rthcId":"RTHC-04025","title":"Is There a Place for Medicinal Cannabis in Treating Patients with Sleep Disorders? What We Know so Far.","authors":"Maddison, Kathleen J; Kosky, Christopher; Walsh, Jennifer H","year":2022,"journal":"Nature and science of sleep, 14, 957-968","doi":"10.2147/NSS.S340949","pmid":"35611178","tags":["sleep","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Cannabis is one of the top reasons people cite for using medicinal cannabis, but when you look at the actual clinical trial evidence for specific sleep disorders, the cupboard is surprisingly bare.\n\nFor insomnia — the most common reason people use cannabis for sleep — the authors found only a handful of clinical studies, and most were small, short-term, and used different cannabis preparations. Some showed modest improvements in sleep onset and quality, but the evidence isn't strong enough to recommend cannabis over established treatments like cognitive behavioral therapy for insomnia (CBT-I).\n\nFor obstructive sleep apnea, early results with dronabinol (synthetic THC) showed some promise in reducing apnea severity, but the sample sizes were small and the effects modest compared to CPAP therapy. For restless legs syndrome, nightmare disorder (especially in PTSD), and narcolepsy, the evidence is even thinner — mostly case reports and very small studies.\n\nThe review also flags important concerns about tolerance: cannabis may help sleep initially, but chronic use can lead to tolerance to the sleep-promoting effects, and withdrawal from chronic use reliably disrupts sleep. This creates a potential cycle where cannabis helps short-term but may worsen sleep long-term.\n\nDespite the weak evidence base, the authors note that emerging research is promising, particularly for cannabinoids in nightmare disorder and sleep apnea, and call for properly designed randomized controlled trials.","whyItMatters":"Millions of people use cannabis to help them sleep, and the cannabis industry actively markets products as sleep aids. But the actual clinical trial evidence is far behind the marketing claims. This review is valuable because it separates anecdotal reports and self-reported survey data from real clinical evidence, giving both patients and clinicians a clear picture of what's actually been demonstrated in controlled settings.","specificNumbers":"The review covered evidence across six specific sleep disorders. For obstructive sleep apnea, dronabinol studies involved fewer than 100 total participants. For insomnia, most studies were under 30 participants. The authors found no large-scale, long-term randomized controlled trials of cannabis for any sleep disorder.","methodology":"Narrative review of the highest-quality clinical evidence available for medicinal cannabis in treating specific sleep disorders: insomnia, obstructive sleep apnea, restless legs syndrome, REM sleep behavior disorder, nightmare disorder, and narcolepsy. Also reviewed evidence on cannabis effects on sleep architecture.","limitations":"As a narrative rather than systematic review, the search strategy may not capture all relevant studies. The rapidly growing research landscape means newer studies may have been published since the search was conducted. The review focuses on sleep disorders as defined clinically, which may not capture the broader population using cannabis for general poor sleep quality."},{"rthcId":"RTHC-04026","title":"The Relations between Youth Cannabis Use, School Cannabis Use-Related Disciplinary Approaches and Student Perceptions of School Support.","authors":"Magier, Megan J; Leatherdale, Scott T; Wade, Terrance J; Patte, Karen A","year":2022,"journal":"Substance use & misuse, 57(6), 897-910","doi":"10.1080/10826084.2022.2052097","pmid":"35306952","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Across 131 Canadian schools and 68,037 students, no school discipline style (permissive, authoritarian, etc.) was directly associated with cannabis use. However, students at permissive/supportive schools were more likely to perceive their school as supportive for substance use prevention, and students who perceived their school as supportive were less likely to use cannabis.","whyItMatters":"This was the first year after cannabis legalization in Canada. Understanding whether school discipline approaches affect student cannabis use has direct policy implications for how schools should respond.","specificNumbers":"68,037 students; 131 Canadian secondary schools; grades 9-12; first school year after legalization","methodology":"Cross-sectional analysis of school- and student-level data from Year 7 (2018/2019) of the COMPASS study. Schools were classified by administrator-reported disciplinary approaches to first-offense cannabis violations.","limitations":"Cross-sectional design cannot establish causation. School classification based on administrator reports may not reflect actual implementation. One-year snapshot post-legalization."},{"rthcId":"RTHC-04027","title":"A Survey of Topical Cannabis Use in Canada.","authors":"Mahmood, Farhan; Lim, Megan M; Kirchhof, Mark G","year":2022,"journal":"Journal of cutaneous medicine and surgery, 26(2), 156-161","doi":"10.1177/12034754211059025","pmid":"34798780","tags":["medical-cannabis","cbd","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among survey respondents, 24.3% had used cannabis topically at least once. Creams were the most common form (26.2%). Top dermatologic uses included atopic dermatitis (25%), acne (19%), and anti-aging (16%). Top non-dermatologic uses were joint stiffness/tendonitis (30%) and headaches/migraines (27%). Users reported topical cannabis was most effective for joint stiffness, muscular soreness, headaches, eczema, and psoriasis.","whyItMatters":"Topical cannabis use has expanded rapidly since legalization, but most applications lack clinical evidence. Understanding what consumers are using it for can guide research priorities.","specificNumbers":"24.3% used topically; creams 26.2% of products; joint stiffness/tendonitis 30%; headaches/migraines 27%; atopic dermatitis 25%; acne 19%; anti-aging 16%","methodology":"Cross-sectional anonymous electronic survey of Canadian adults assessing prevalence, purpose, and information sources for topical cannabis use following legalization.","limitations":"Voluntary online survey with potential self-selection bias. Effectiveness ratings are self-reported perceptions, not clinical measurements."},{"rthcId":"RTHC-04028","title":"The Transdermal Delivery of Therapeutic Cannabinoids.","authors":"Mahmoudinoodezh, Haleh; Telukutla, Srinivasa Reddy; Bhangu, Sukhvir Kaur; Bachari, Ava; Cavalieri, Francesca; Mantri, Nitin","year":2022,"journal":"Pharmaceutics, 14(2)","doi":"10.3390/pharmaceutics14020438","pmid":"35214170","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04029","title":"A cluster analysis of health behaviours and their relationship to mental health difficulties, life satisfaction and functioning in adolescents.","authors":"Mahon, Ciara; Howard, Emma; O'Reilly, Aileen; Dooley, Barbara; Fitzgerald, Amanda","year":2022,"journal":"Preventive medicine, 164, 107332","doi":"10.1016/j.ypmed.2022.107332","pmid":"36336163","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04030","title":"Topical cannabidiol (CBD) in skin pathology - A comprehensive review and prospects for new therapeutic opportunities.","authors":"Makhakhe, Lehlohonolo","year":2022,"journal":"South African family practice : official journal of the South African Academy of Family Practice/Primary Care, 64(1), e1-e4","doi":"10.4102/safp.v64i1.5493","pmid":"35695447","tags":["cbd","medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"With the discovery of cannabinoid receptors on the skin, topical cannabis has demonstrated anti-inflammatory, anti-itching, analgesic, wound healing, and anti-proliferative effects. CBD is being explored as a potential alternative to topical corticosteroids for some dermatological conditions.","whyItMatters":"Topical corticosteroids are the mainstay treatment for many skin conditions but carry significant side effects with long-term use. Topical CBD could offer a safer alternative if clinical evidence supports it.","specificNumbers":"Over 500 biologically active components in cannabis; over 100 phytocannabinoids identified; 3 primary cannabis species (sativa, indica, ruderalis)","methodology":"Comprehensive review of literature on topical CBD for dermatological applications, covering the endocannabinoid system in skin, cannabinoid receptor distribution, and evidence for specific skin conditions.","limitations":"Review primarily describes mechanisms and rationale rather than clinical trial results. Most evidence comes from preclinical or early-stage studies."},{"rthcId":"RTHC-04031","title":"Fourth Generation of Synthetic Cannabinoid Receptor Agonists: A Review on the Latest Insights.","authors":"Malaca, Sara; Busardò, Francesco P; Nittari, Giulio; Sirignano, Ascanio; Ricci, Giovanna","year":2022,"journal":"Current pharmaceutical design, 28(32), 2603-2617","doi":"10.2174/1381612827666211115170521","pmid":"34781870","tags":["synthetic-cannabinoids","harm-reduction","potency"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Fourth-generation synthetic cannabinoid receptor agonists have increased CB1 receptor affinity and efficacy compared to previous generations, leading to more potent psychoactive effects and increased adverse reactions including psychosis, hallucinations, self-harm, tachycardia, and deaths.","whyItMatters":"Synthetic cannabinoids remain among the most abused new psychoactive substances globally. Each new generation has been more potent and dangerous, and the fourth generation represents the most concerning iteration yet.","specificNumbers":"At least 20 new fourth-generation SCRAs reported from November 2017 to February 2021; over 100 total SCRAs emerged in the last decade","methodology":"Review of international literature on the newest generation of synthetic cannabinoids, covering chemical structures, pharmacological properties, and toxicological profiles reported to international drug agencies.","limitations":"Limited global data on fourth-generation SCRA toxicity. Understanding of neurotoxicity is incomplete due to the rapid pace of new compound emergence."},{"rthcId":"RTHC-04032","title":"Medical Cannabis in Pediatric Oncology: Friend or Foe?","authors":"Malach, Megan; Kovalchuk, Igor; Kovalchuk, Olga","year":2022,"journal":"Pharmaceuticals (Basel, Switzerland), 15(3)","doi":"10.3390/ph15030359","pmid":"35337156","tags":["cancer","medical-cannabis","youth"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Published cases demonstrate the safety and efficacy of cannabis in children for pediatric epilepsy and chemotherapy-induced nausea and vomiting. Preclinical evidence shows cannabis has anti-cancer effects on pediatric cancer cell lines. However, the endocannabinoid system develops early in life, and data about prenatal cannabis exposure show negative outcomes.","whyItMatters":"Pediatric cancer treatments cause significant suffering, and options for managing side effects are limited. If cannabis can safely reduce nausea and potentially enhance cancer treatment in children, the implications are significant.","specificNumbers":"Anti-cancer effects known since 1975; ECS components identified in 1990s; preclinical evidence in pediatric cancer cell lines","methodology":"Narrative review examining published cases of cannabis use in pediatric populations, preclinical anti-cancer data on pediatric tumors, and what is known about ECS development and early-life cannabis exposure.","limitations":"Nearly all cannabis anti-cancer research has been on adults. Preclinical evidence does not guarantee clinical efficacy. ECS role in development raises legitimate safety concerns."},{"rthcId":"RTHC-04033","title":"Handedness as a neurodevelopmental marker in schizophrenia: Results from the FACE-SZ cohort.","authors":"Mallet, Jasmina; Godin, Ophélia; Le Strat, Yann; Mazer, Nicolas; Berna, Fabrice; Boyer, Laurent; Capdevielle, Delphine; Clauss, Julie; Chéreau, Isabelle; D'Amato, Thierry; Dubreucq, Julien; Leigner, Sylvain; Llorca, Pierre-Michel; Misdrahi, David; Passerieux, Christine; Rey, Romain; Pignon, Baptiste; Urbach, Mathieu; Schürhoff, Franck; Fond, Guillaume; Dubertret, Caroline","year":2022,"journal":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 23(7), 525-536","doi":"10.1080/15622975.2021.2013094","pmid":"34918618","tags":["psychosis","addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 667 schizophrenia patients, 42.4% were non-right-handed and 34.1% mixed-handed. Non-right-handedness was associated with cannabis use disorder (P=0.045) and learning disorders. Mixed-handedness was associated with positive symptoms (P=0.041), current depression (P=0.005), current cannabis use (P=0.024), and less akathisia (P=0.019).","whyItMatters":"Non-right-handedness is considered a marker of atypical neurodevelopment. Its association with cannabis use disorder in schizophrenia suggests shared developmental vulnerabilities may underlie both traits.","specificNumbers":"667 participants; 42.4% non-right-handed; 34.1% mixed-handed; NRH associated with CUD (P=0.045); mixed-handedness with current cannabis use (P=0.024)","methodology":"Cross-sectional study of 667 participants from the FACE-SZ cohort assessed with the Edinburgh Handedness Inventory, neuropsychological testing, and clinical symptom measures.","limitations":"Cross-sectional design cannot determine direction of associations. Handedness was self-reported. Cannabis use assessment relied on clinical records."},{"rthcId":"RTHC-04034","title":"Understanding the Dynamics of the Structural States of Cannabinoid Receptors and the Role of Different Modulators.","authors":"Manandhar, Anjela; Haron, Mona H; Klein, Michael L; Elokely, Khaled","year":2022,"journal":"Life (Basel, Switzerland), 12(12)","doi":"10.3390/life12122137","pmid":"36556502","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04035","title":"Cannabis for the Treatment of Attention Deficit Hyperactivity Disorder: A Report of 3 Cases.","authors":"Mansell, Holly; Quinn, Declan; Kelly, Lauren E; Alcorn, Jane","year":2022,"journal":"Medical cannabis and cannabinoids, 5(1), 1-6","doi":"10.1159/000521370","pmid":"35224434","tags":["medical-cannabis","mental-health","cbd"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Semistructured interviews and validated rating scales showed improvements in PHQ-9 depression scores (8-22 points, 30-81%), SCARED anxiety scores (0-27 points, up to 33%), CEER-9 regulation scores (2-7 points, 22-78%), and SNAP-9 inattention scores (2-8 points, 7-30%). Mild adverse events included short-term memory problems, dry mouth, and sleepiness.","whyItMatters":"Many ADHD patients self-medicate with cannabis despite a lack of evidence. These detailed cases with validated measures and plasma levels provide a starting point for understanding potential benefits and risks.","specificNumbers":"PHQ-9 improved 8-22 points (30-81%); SCARED improved 0-27 points (up to 33%); CEER-9 improved 2-7 points (22-78%); SNAP-9 improved 2-8 points (7-30%); plasma CBD 0-15.29 ng/mL; plasma THC 1.32-13.76 ng/mL","methodology":"Case series of three males (ages 18, 22, 23) with ADHD who integrated cannabis into their treatment. Pre- and post-cannabis validated rating scale scores were compared, and plasma cannabinoid levels were measured.","limitations":"Only three patients, all male. No control group or blinding. Cannot separate cannabis effects from other treatments or natural variation. Self-reported symptom improvements."},{"rthcId":"RTHC-04036","title":"Protective Behavioural Mechanisms Against Cannabis Use Among Adolescents in Cannabis-Growing Settings of South Africa: Insights Into Adolescent Cannabis Use Prevention.","authors":"Manu, Emmanuel; Douglas, Mbuyiselo; Ntsaba, Mohlomi Jafta; Makaula, Bekwa; Tarkang, Elvis Enowbeyang","year":2022,"journal":"Tobacco use insights, 15, 1179173X221146040","doi":"10.1177/1179173X221146040","pmid":"36544696","tags":["youth","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Nine behavioral protective mechanisms were identified: intrinsically, determination to avoid bad behaviors, academic focus, financial independence from cannabis-using peers, desire for good marriages, and religious beliefs. Extrinsically, preserving family dignity (Ukuphoxa), fear of arrest, fear of social deviance labeling, and fear of illness like lung cancer.","whyItMatters":"Understanding why some adolescents resist cannabis in high-exposure environments reveals protective factors that prevention programs can leverage, rather than focusing solely on risk factors.","specificNumbers":"30 non-cannabis-smoking adolescents; 2 cannabis-growing communities; 4 focus groups; 9 behavioral protective mechanisms identified; 5 intrinsic and 4 extrinsic factors","methodology":"Qualitative study using Self Determination Theory framework. 30 non-cannabis-smoking adolescents from 2 purposively selected South African cannabis-growing communities participated in 4 focus groups using semi-structured interviews, analyzed with ATLAS.ti software.","limitations":"Small qualitative sample from a very specific cultural context (South African cannabis-growing communities). Findings may not generalize to other settings. Self-reported non-use not verified."},{"rthcId":"RTHC-04037","title":"A zebrafish HCT116 xenograft model to predict anandamide outcomes on colorectal cancer.","authors":"Maradonna, Francesca; Fontana, Camilla M; Sella, Fiorenza; Giommi, Christian; Facchinello, Nicola; Rampazzo, Chiara; Caichiolo, Micol; Hoseinifar, Seyed Hossein; Dalla Valle, Luisa; Van Doan, Hien; Carnevali, Oliana","year":2022,"journal":"Cell death & disease, 13(12), 1069","doi":"10.1038/s41419-022-05523-z","pmid":"36564370","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04038","title":"An Open Retrospective Study of a Standardized Cannabidiol Based-Oil in Treatment-Resistant Epilepsy.","authors":"Marchese, Francesca; Vari, Maria Stella; Balagura, Ganna; Riva, Antonella; Salpietro, Vincenzo; Verrotti, Alberto; Citraro, Rita; Lattanzi, Simona; Minetti, Carlo; Russo, Emilio; Striano, Pasquale","year":2022,"journal":"Cannabis and cannabinoid research, 7(2), 199-206","doi":"10.1089/can.2019.0082","pmid":"33998856","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 37 patients with treatment-resistant epilepsy of various causes, 7 (19%) became seizure-free and 27 (73%) reported more than 50% seizure reduction at 40-month follow-up. The median achieved CBD dose was 4.2 mg/kg/day. Few significant side effects were reported.","whyItMatters":"While pharmaceutical CBD (Epidiolex) has been studied in RCTs, data on other CBD formulations are sparse. This study provides real-world evidence that standardized CBD oil can help treatment-resistant patients.","specificNumbers":"37 patients; median age 16.1; 19% seizure-free; 73% had >50% improvement; median dose 4.2 mg/kg/day; 60% had epileptic encephalopathy; follow-up 24-72 weeks","methodology":"Open retrospective study of 37 patients (46% female, median age 16.1 years) with refractory epilepsy receiving add-on therapy with 24% CBD-based oil (sublingual, starting 5-10 mg/kg/day, max 50 mg/kg/day). Follow-up ranged from 24-72 weeks.","limitations":"Open retrospective design without placebo control or blinding. Small sample size. Seizure frequency based on caregiver reports."},{"rthcId":"RTHC-04039","title":"Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults.","authors":"Marchi, Mattia; Elkrief, Laurent; Alkema, Anne; van Gastel, Willemijn; Schubart, Chris D; van Eijk, Kristel R; Luykx, Jurjen J; Branje, Susan; Mastrotheodoros, Stefanos; Galeazzi, Gian M; van Os, Jim; Cecil, Charlotte A; Conrod, Patricia J; Boks, Marco P","year":2022,"journal":"Translational psychiatry, 12(1), 219","doi":"10.1038/s41398-022-01975-1","pmid":"35650188","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04040","title":"Driving Performance and Cannabis Users' Perception of Safety: A Randomized Clinical Trial.","authors":"Marcotte, Thomas D; Umlauf, Anya; Grelotti, David J; Sones, Emily G; Sobolesky, Philip M; Smith, Breland E; Hoffman, Melissa A; Hubbard, Jacqueline A; Severson, Joan; Huestis, Marilyn A; Grant, Igor; Fitzgerald, Robert L","year":2022,"journal":"JAMA psychiatry, 79(3), 201-209","doi":"10.1001/jamapsychiatry.2021.4037","pmid":"35080588","tags":["driving","cognition","harm-reduction","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"THC significantly impaired the Composite Drive Score at 30 minutes (d=0.59) and 1.5 hours (d=0.55), with borderline impairment at 3.5 hours (d=0.29) and no difference at 4.5 hours. Despite ongoing impairment, 69% of participants reported willingness to drive at 1.5 hours. Neither THC content (5.9% vs 13.4%) nor use intensity predicted driving impairment.","whyItMatters":"This is one of the largest randomized trials of cannabis and driving. The finding that experienced users cannot accurately judge their impairment has critical implications for road safety policies.","specificNumbers":"191 cannabis users; mean age 29.9; mean 16.7 use days/month; Cohen d=0.59 at 30min; d=0.55 at 1.5hr; d=0.29 at 3.5hr; 69% willing to drive at 1.5hr; impairment resolved by 4.5hr","methodology":"Double-blind, placebo-controlled parallel RCT at UC San Diego. 191 regular cannabis users randomized to placebo, 5.9%, or 13.4% THC smoked ad libitum. Driving simulator assessed at multiple timepoints through 4.5 hours.","limitations":"Simulated driving, not real-world. Cannabis smoked ad libitum may not replicate all consumption patterns. Regular users only, so results may not apply to occasional users."},{"rthcId":"RTHC-04041","title":"Adolescent self-administration of the synthetic cannabinoid receptor agonist JWH-018 induces neurobiological and behavioral alterations in adult male mice.","authors":"Margiani, Giulia; Castelli, Maria Paola; Pintori, Nicholas; Frau, Roberto; Ennas, Maria Grazia; Pagano Zottola, Antonio C; Orrù, Valeria; Serra, Valentina; Fiorillo, Edoardo; Fadda, Paola; Marsicano, Giovanni; De Luca, Maria Antonietta","year":2022,"journal":"Psychopharmacology, 239(10), 3083-3102","doi":"10.1007/s00213-022-06191-9","pmid":"35943523","tags":["synthetic-cannabinoids","youth","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Adolescent mice acquired JWH-018 self-administration behavior that was specifically reward-driven and blocked by a CB1 antagonist. As adults, exposed mice showed increased repetitive/compulsive behaviors (nestlet shredding, marble burying) and neuroinflammation: increased microglia in the caudate-putamen and nucleus accumbens, decreased astrocytes, and altered cytokines.","whyItMatters":"This is the first study showing voluntary self-administration of a synthetic cannabinoid during adolescence in mice, making the exposure model more relevant to human use than passive injection studies.","specificNumbers":"JWH-018 dose: 7.5 ug/kg/infusion; CB1 antagonist AM251 blocked self-administration; increased IBA-1+ cells in caudate-putamen and NAc; decreased GFAP in caudate-putamen","methodology":"Male CD1 adolescent mice self-administered JWH-018 intravenously (7.5 ug/kg/infusion) on fixed and progressive ratio schedules. Behavioral, neurochemical, and molecular evaluations were performed at adulthood.","limitations":"Animal study in male mice only. Self-administration model may not perfectly mirror human use patterns. Neuroinflammatory changes measured at one timepoint in adulthood."},{"rthcId":"RTHC-04042","title":"Safety and efficacy of a digital therapeutic for substance use disorder: Secondary analysis of data from a NIDA clinical trials network study.","authors":"Maricich, Yuri A; Nunes, Edward V; Campbell, Aimee N C; Botbyl, Jeffrey D; Luderer, Hilary F","year":2022,"journal":"Substance abuse, 43(1), 937-942","doi":"10.1080/08897077.2022.2060425","pmid":"35420979","tags":["addiction","quitting","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 399 patients with alcohol, cannabis, cocaine, or stimulant use disorders, those receiving the digital therapeutic plus treatment-as-usual (with reduced counseling) achieved significantly higher abstinence at weeks 9-12 (40.3% vs 17.6%, P<0.001) and better treatment retention (P=0.004). Adverse event rates were similar between groups.","whyItMatters":"Face-to-face substance abuse treatment has significant access barriers. A digital therapeutic that can be used remotely while maintaining or improving outcomes addresses a critical treatment gap.","specificNumbers":"399 patients; 40.3% vs 17.6% abstinence (P<0.001); improved retention (P=0.004); 12-week treatment; substances: alcohol, cannabis, cocaine, stimulants","methodology":"Secondary analysis of a published RCT, excluding patients with opioid use disorder. 399 patients randomized to treatment-as-usual (n=193) or TAU with reduced counseling plus a digital therapeutic providing cognitive behavioral therapy and contingency management (n=206) for 12 weeks.","limitations":"Secondary analysis excluding OUD patients. Cannot separate effects of the digital therapeutic from the contingency management component. Primary substances not analyzed separately."},{"rthcId":"RTHC-04043","title":"Cannabinoid Effect and Safety in Spasticity Following Stroke: A Double-Blind Randomized Placebo-Controlled Study.","authors":"Marinelli, Lucio; Puce, Luca; Mori, Laura; Leandri, Massimo; Rosa, Gian Marco; Currà, Antonio; Fattapposta, Francesco; Trompetto, Carlo","year":2022,"journal":"Frontiers in neurology, 13, 892165","doi":"10.3389/fneur.2022.892165","pmid":"35812088","tags":["medical-cannabis","pain","cardiovascular"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 34 stroke patients, nabiximols did not improve spasticity on the primary or secondary endpoints compared to placebo. However, no cardiovascular adverse events occurred, suggesting cannabis-based treatments may be safe in stroke patients despite theoretical cardiovascular risks.","whyItMatters":"Nabiximols is approved for MS spasticity but not stroke spasticity. While this trial found no efficacy, the cardiovascular safety finding is significant because stroke patients are typically excluded from cannabis studies due to heart risk concerns.","specificNumbers":"41 enrolled, 34 completed; 2 serious adverse events (none cardiovascular); no primary or secondary efficacy endpoints met; crossover design with 1-month phases","methodology":"Double-blind, randomized, placebo-controlled crossover trial. 41 patients entered, 34 completed. Patients received nabiximols oromucosal spray or placebo for 1 month each, with cardiovascular monitoring throughout.","limitations":"Small sample size may have been underpowered to detect effects. Patients had relatively low baseline pain and spasticity levels, which may have limited room for improvement."},{"rthcId":"RTHC-04044","title":"Defining Steric Requirements at CB1 and CB2 Cannabinoid Receptors Using Synthetic Cannabinoid Receptor Agonists 5F-AB-PINACA, 5F-ADB-PINACA, PX-1, PX-2, NNL-1, and Their Analogues.","authors":"Markham, Jack; Sparkes, Eric; Boyd, Rochelle; Chen, Shuli; Manning, Jamie J; Finlay, David; Lai, Felcia; McGregor, Eila; Maloney, Callan J; Gerona, Roy R; Connor, Mark; McGregor, Iain S; Hibbs, David E; Glass, Michelle; Kevin, Richard C; Banister, Samuel D","year":2022,"journal":"ACS chemical neuroscience, 13(8), 1281-1295","doi":"10.1021/acschemneuro.2c00034","pmid":"35404067","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04045","title":"Atypical Antipsychotic Drugs in Dual Disorders: Current Evidence for Clinical Practice.","authors":"Martinotti, Giovanni; Chiappini, Stefania; Mosca, Alessio; Miuli, Andrea; Santovito, Maria Chiara; Pettorruso, Mauro; Skryabin, Valentin; Sensi, Stefano L; Giannantonio, Massimo Di","year":2022,"journal":"Current pharmaceutical design, 28(27), 2241-2259","doi":"10.2174/1381612828666220623092853","pmid":"35747956","tags":["psychosis","addiction","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 41 studies, most dual diagnosis patients were male with schizophrenia, and cannabis was the most abused substance followed by alcohol. Aripiprazole (oral and long-acting) was the most commonly used second-generation antipsychotic, followed by risperidone, clozapine, olanzapine, and quetiapine.","whyItMatters":"Dual diagnosis is common but undertreated. Knowing which antipsychotics have been studied and which substances are most prevalent helps clinicians make informed treatment decisions for these complex patients.","specificNumbers":"41 articles reviewed; cannabis most common substance; aripiprazole most used SGA; long-acting formulations increasingly studied","methodology":"Literature search of PubMed and Scopus for studies of second-generation antipsychotics in patients with co-occurring psychotic disorders and substance use disorders, without time restrictions.","limitations":"Review of heterogeneous studies with varying methodologies. Most studies were not specifically designed to compare antipsychotics head-to-head in dual diagnosis patients."},{"rthcId":"RTHC-04046","title":"Cannabis-Based Products for the Treatment of Skin Inflammatory Diseases: A Timely Review.","authors":"Martins, Ana M; Gomes, Ana L; Vilas Boas, Inês; Marto, Joana; Ribeiro, Helena M","year":2022,"journal":"Pharmaceuticals (Basel, Switzerland), 15(2)","doi":"10.3390/ph15020210","pmid":"35215320","tags":["cbd","inflammation","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The discovery of a skin endocannabinoid system and its role in maintaining skin homeostasis supports the anti-inflammatory potential of topical cannabinoids. Early studies show topical cannabinoid products are generally well tolerated and have shown promising results for atopic dermatitis, psoriasis, and contact dermatitis.","whyItMatters":"Oral treatments for skin inflammation require high doses with significant side effects. Topical cannabinoid products could offer targeted treatment with fewer systemic effects, but the evidence base needs strengthening.","specificNumbers":"Over 500 biologically active compounds in cannabis; promising results in atopic dermatitis, psoriasis, and contact dermatitis; skin endocannabinoid system regulates homeostasis","methodology":"Review of literature on the skin endocannabinoid system, cannabinoid pharmacology, and existing evidence for topical cannabinoid formulations in inflammatory skin diseases.","limitations":"Most evidence comes from preclinical studies or small uncontrolled trials. No large randomized controlled trials of topical cannabinoids for skin disease."},{"rthcId":"RTHC-04047","title":"In vitro and in vivo pharmacology of nine novel synthetic cannabinoid receptor agonists.","authors":"Marusich, Julie A; Gamage, Thomas F; Zhang, Yanan; Akinfiresoye, Luli R; Wiley, Jenny L","year":2022,"journal":"Pharmacology, biochemistry, and behavior, 220, 173467","doi":"10.1016/j.pbb.2022.173467","pmid":"36154844","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04048","title":"Trends in cannabis or cocaine-related dependence and alcohol/drug treatment in Argentina, Chile, and Uruguay.","authors":"Mauro, Pia M; Gutkind, Sarah; Rivera-Aguirre, Ariadne; Gary, Dahsan; Cerda, Magdalena; Santos, Erica Chavez; Castillo-Carniglia, Alvaro; Martins, Silvia S","year":2022,"journal":"The International journal on drug policy, 108, 103810","doi":"10.1016/j.drugpo.2022.103810","pmid":"35939947","tags":["addiction","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Adjusted cannabis dependence increased from 0.7% to 1.5% in Argentina, 0.8% to 2.8% in Chile, and 1.4% to 2.4% in Uruguay. Among those with cannabis/cocaine dependence, average treatment use was 15.3% in Argentina, 6.0% in Chile, and 14.7% in Uruguay. Treatment rates were lower for cannabis dependence than cocaine dependence.","whyItMatters":"These three South American countries have different cannabis policies (Uruguay legalized in 2013). The rising dependence across all three, regardless of policy, suggests factors beyond legalization are driving increases.","specificNumbers":"Argentina: 0.7% to 1.5% cannabis dependence; Chile: 0.8% to 2.8%; Uruguay: 1.4% to 2.4%; treatment use: 15.3% (Argentina), 6.0% (Chile), 14.7% (Uruguay)","methodology":"Harmonized analysis of nationally representative cross-sectional household surveys (ages 15-64) from Argentina (4 surveys, 2006-2017), Chile (7 surveys, 2006-2018), and Uruguay (4 surveys, 2006-2018). ICD-10 criteria for dependence.","limitations":"Cross-sectional surveys at different time points, not longitudinal tracking of individuals. Self-reported cannabis use and dependence criteria. Treatment access may differ by region within countries."},{"rthcId":"RTHC-04049","title":"Epigenetic Studies for Evaluation of NPS Toxicity: Focus on Synthetic Cannabinoids and Cathinones.","authors":"Mazdai, Leila; Fabbri, Matteo; Tirri, Micaela; Corli, Giorgia; Arfè, Raffaella; Marchetti, Beatrice; Bilel, Sabrine; Bergamin, Eva; Gaudio, Rosa Maria; Rubini, Michele; De-Giorgio, Fabio; Marti, Matteo","year":2022,"journal":"Biomedicines, 10(6)","doi":"10.3390/biomedicines10061398","pmid":"35740419","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04050","title":"Use of cannabidiol in the treatment of epilepsy.","authors":"Mazurkiewicz-Bełdzińska, Maria; Zawadzka, Marta","year":2022,"journal":"Neurologia i neurochirurgia polska, 56(1), 14-20","doi":"10.5603/PJNNS.a2022.0020","pmid":"35211946","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"CBD was isolated from cannabis in 1940 and has a confirmed anti-seizure effect without psychoactive activity. Epidiolex is the only cannabis-derived drug to complete clinical trials and gain FDA/EMA approval, specifically for Dravet syndrome, Lennox-Gastaut syndrome, and seizures associated with tuberous sclerosis complex.","whyItMatters":"As interest in cannabis-based treatments grows, it is important to distinguish between what is proven (Epidiolex for specific epilepsies) and what remains unproven (non-pharmaceutical CBD products for seizures).","specificNumbers":"CBD isolated in 1940; Epidiolex is the only FDA/EMA approved cannabis-derived epilepsy drug; approved for Dravet, LGS, and TSC","methodology":"Position paper reviewing the mechanism of CBD's anti-seizure action, completed clinical trials of Epidiolex, and current approved indications for CBD in epilepsy.","limitations":"Position paper focused on pharmaceutical-grade CBD only. Does not address the growing use of non-pharmaceutical CBD products for seizures."},{"rthcId":"RTHC-04051","title":"Safety and Tolerability of Oral Cannabinoids in People Living with HIV on Long-Term ART: A Randomized, Open-Label, Interventional Pilot Clinical Trial (CTNPT 028).","authors":"Mboumba Bouassa, Ralph-Sydney; Needham, Judy; Nohynek, Dana; Singer, Joel; Lee, Terry; Bobeuf, Florian; Samarani, Suzanne; Del Balso, Lina; Paisible, Natalie; Vertzagias, Claude; Sebastiani, Giada; Margolese, Shari; Mandarino, Enrico; Klein, Marina; Lebouché, Bertrand; Cox, Joseph; Brouillette, Marie-Josée; Routy, Jean-Pierre; Szabo, Jason; Thomas, Réjean; Huchet, Emmanuel; Vigano, Antonio; Jenabian, Mohammad-Ali; Costiniuk, Cecilia T","year":2022,"journal":"Biomedicines, 10(12)","doi":"10.3390/biomedicines10123168","pmid":"36551926","tags":["medical-cannabis","cbd","harm-reduction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Eight of ten HIV-positive participants completed 12 weeks of treatment. Seven experienced no significant toxicity. Two withdrawals from the CBD-only arm were for pre-existing conditions (anemia aggravated by phlebotomy and hepatitis with newly discovered pancreatic cancer). CD4 count, CD4/CD8 ratio, and HIV suppression remained stable throughout.","whyItMatters":"People living with HIV experience chronic immune activation even on effective antiretroviral therapy. Cannabinoids' anti-inflammatory properties could theoretically help, but safety data in this population has been lacking.","specificNumbers":"10 participants; 8 completed; THC:CBD max 15mg/15mg daily; CBD-only max 800mg daily; 12 weeks; CD4 and viral load stable; 7/10 no significant toxicity","methodology":"Open-label interventional pilot study at McGill University Health Centre. Participants randomized to oral THC:CBD (2.5mg/2.5mg, titrated to 15mg/15mg daily) or CBD-only (200mg, titrated to 800mg daily) for 12 weeks. Primary outcome: percentage without significant WHO toxicity.","limitations":"Very small sample (10 participants). Open-label without placebo control. Two withdrawals from the CBD arm for issues that may not be related to the study drug. Cannot assess efficacy."},{"rthcId":"RTHC-04052","title":"Effects of cannabidiol on simulated driving and cognitive performance: A dose-ranging randomised controlled trial.","authors":"McCartney, Danielle; Suraev, Anastasia S; Doohan, Peter T; Irwin, Christopher; Kevin, Richard C; Grunstein, Ronald R; Hoyos, Camilla M; McGregor, Iain S","year":2022,"journal":"Journal of psychopharmacology (Oxford, England), 36(12), 1338-1349","doi":"10.1177/02698811221095356","pmid":"35637624","tags":["cbd","driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Non-inferiority analyses established that CBD at 15, 300, and 1,500 mg did not impair driving performance beyond a threshold equivalent to 0.05% blood alcohol. CBD did not induce feelings of intoxication or impair cognitive function. Unexpectedly, CBD at 1,500 mg persisted in plasma for more than 4 weeks.","whyItMatters":"CBD is widely consumed in both prescription and non-prescription products, yet its effects on safety-sensitive tasks have been under scrutiny. This study provides reassuring evidence that even high doses do not impair driving.","specificNumbers":"17 participants; 4 CBD doses (placebo, 15, 300, 1500 mg); non-inferiority threshold: 0.05% BAC equivalent; CBD detectable in plasma >4 weeks at 1500 mg","methodology":"Double-blind, placebo-controlled, crossover RCT in 17 healthy adults. Four sessions: placebo, 15 mg, 300 mg, or 1,500 mg oral CBD. Simulated driving assessed at ~45-75 and ~210-240 minutes post-treatment. Primary outcome: standard deviation of lateral position (SDLP).","limitations":"Small sample (n=17). Single-dose acute administration only. Simulated driving, not real-world. May not generalize to chronic CBD users or those taking CBD with other medications."},{"rthcId":"RTHC-04053","title":"Are blood and oral fluid Δ9-tetrahydrocannabinol (THC) and metabolite concentrations related to impairment? A meta-regression analysis.","authors":"McCartney, Danielle; Arkell, Thomas R; Irwin, Christopher; Kevin, Richard C; McGregor, Iain S","year":2022,"journal":"Neuroscience and biobehavioral reviews, 134, 104433","doi":"10.1016/j.neubiorev.2021.11.004","pmid":"34767878","tags":["driving","harm-reduction","tolerance"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Higher blood THC, 11-OH-THC, oral fluid THC, and subjective intoxication were associated with greater impairment in occasional users, but correlations were negligible to weak (r = -0.08 to -0.43). No significant biomarker-performance relationships were found in regular (weekly+) cannabis users.","whyItMatters":"Many jurisdictions use blood or oral fluid THC levels to identify impaired drivers, similar to blood alcohol. This meta-analysis shows THC biomarkers are fundamentally different from blood alcohol as impairment indicators.","specificNumbers":"28 publications; 822 driving outcomes; correlations ranged from -0.08 to -0.43; no significant relationships in regular users","methodology":"Meta-regression analysis of 28 publications and 822 driving-related outcomes examining relationships between blood/oral fluid THC concentrations, subjective intoxication, and driving performance.","limitations":"Analyses in regular users were less robust due to fewer studies. Most studies used simulated rather than real-world driving."},{"rthcId":"RTHC-04054","title":"Orally administered cannabidiol does not produce false-positive tests for Δ9 -tetrahydrocannabinol on the Securetec DrugWipe® 5S or Dräger DrugTest® 5000.","authors":"McCartney, Danielle; Kevin, Richard C; Suraev, Anastasia S; Irwin, Christopher; Grunstein, Ronald R; Hoyos, Camilla M; McGregor, Iain S","year":2022,"journal":"Drug testing and analysis, 14(1), 137-143","doi":"10.1002/dta.3153","pmid":"34412166","tags":["cbd","driving","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 259 DrugWipe 5S and 256 DrugTest 5000 tests following oral CBD administration (placebo, 15, 300, or 1,500 mg), no THC-positive results were observed. THC, cannabinol, and cannabigerol were not detected in any oral fluid samples, confirming that pure oral CBD does not cross-react with THC assays.","whyItMatters":"CBD users, particularly those driving while using prescribed or over-the-counter CBD products, face uncertainty about whether roadside drug tests could falsely flag them for THC. This study provides clear reassurance.","specificNumbers":"17 participants; 515 total tests (259 DW-5S, 256 DT5000); 0 false positives; CBD doses: placebo, 15, 300, 1500 mg; peak oral fluid CBD at 1500mg: 167 ng/mL","methodology":"Double-blind, crossover design with 17 healthy participants completing 4 sessions. Two standard point-of-collection oral fluid testing devices (DrugWipe 5S and DrugTest 5000, both with 10 ng/mL THC cutoffs) were administered at baseline and 3 post-treatment timepoints.","limitations":"Only tested pure CBD without THC. Many commercial CBD products contain trace THC that could produce different results. Only tested two specific devices."},{"rthcId":"RTHC-04055","title":"Lung Findings in a Patient with a History of Nicotine Vaping and Cannabis Smoking.","authors":"McCormick, Winston; Baykara, Yigit; Siddique, Ayesha; Van Truong, Lance; Corbett, Mel; Hacking, Sean M","year":2022,"journal":"Rhode Island medical journal (2013), 105(5), 36-40","doi":null,"pmid":"35617040","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04056","title":"Anti-Inflammatory and Analgesic Properties of the Cannabis Terpene Myrcene in Rat Adjuvant Monoarthritis.","authors":"McDougall, Jason J; McKenna, Meagan K","year":2022,"journal":"International journal of molecular sciences, 23(14)","doi":"10.3390/ijms23147891","pmid":"35887239","tags":["pain","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Local application of myrcene (1 and 5 mg/kg) reduced joint pain and inflammation in rats with chronic arthritis via a cannabinoid receptor mechanism. However, combining myrcene with CBD (200 ug) was not significantly different from myrcene alone. Repeated myrcene treatment had no effect on joint damage or inflammatory cytokine levels.","whyItMatters":"The \"entourage effect\" theory suggests cannabis terpenes enhance cannabinoid effects. This study found myrcene works through cannabinoid receptors on its own but does not synergize with CBD, challenging assumptions about entourage synergy.","specificNumbers":"Myrcene: 1 and 5 mg/kg subcutaneous; CBD: 200 ug; assessed at days 7 and 21; pain relief via cannabinoid receptor mechanism confirmed","methodology":"Chronic arthritis was induced in male Wistar rats by intra-articular injection. Joint pain (von Frey hair algesiometry), inflammation (intravital microscopy, laser speckle), and histopathology were assessed on days 7 and 21 after induction.","limitations":"Animal study in male rats only. Subcutaneous injection does not replicate typical human use. Only one terpene-cannabinoid combination tested."},{"rthcId":"RTHC-04057","title":"Predictors of reported alcohol intake during the first and second waves of the COVID-19 pandemic in Canada among middle-aged and older adults: results from the Canadian Longitudinal Study on Aging (CLSA).","authors":"McMillan, Jacqueline M; Hogan, David B; Zimmer, Chantelle; Sohel, Nazmul; Wolfson, Christina; Kirkland, Susan; Griffith, Lauren E; Basta, Nicole E; Raina, Parminder","year":2022,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 113(5), 665-677","doi":"10.17269/s41997-022-00661-5","pmid":"35818014","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04058","title":"\"I got a bunch of weed to help me through the withdrawals\": Naturalistic cannabis use reported in online opioid and opioid recovery community discussion forums.","authors":"Meacham, Meredith C; Nobles, Alicia L; Tompkins, D Andrew; Thrul, Johannes","year":2022,"journal":"PloS one, 17(2), e0263583","doi":"10.1371/journal.pone.0263583","pmid":"35134074","tags":["addiction","harm-reduction","pain"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Cannabis-related posts were twice as prevalent in the recovery subreddit (5.4%) as in the active opioid use subreddit (2.6%). Recovery forum users primarily discussed cannabis for managing withdrawal symptoms alongside \"comfort meds.\" Active opioid users primarily discussed cannabis to enhance the opioid high.","whyItMatters":"Understanding how people actually use cannabis in relation to opioids reveals two distinct motivations that have very different clinical implications for harm reduction and treatment.","specificNumbers":"Recovery subreddit: 908 cannabis posts (5.4% of 16,791); opioid subreddit: 4,224 cannabis posts (2.6% of 159,994); 200 posts qualitatively analyzed","methodology":"Text analysis of cannabis-related posts from two Reddit communities (opioid use and opioid recovery) from December 2015 to August 2019, using TF-IDF weighting for frequent phrases and qualitative content analysis of 200 random posts.","limitations":"Pseudonymous online posts cannot be verified. Reddit users may not represent the broader opioid-using or recovering population. Self-reported motivations may not reflect actual effects."},{"rthcId":"RTHC-04059","title":"The effects of cannabis and cannabinoids on the endocrine system.","authors":"Meah, Farah; Lundholm, Michelle; Emanuele, Nicholas; Amjed, Hafsa; Poku, Caroline; Agrawal, Lily; Emanuele, Mary Ann","year":2022,"journal":"Reviews in endocrine & metabolic disorders, 23(3), 401-420","doi":"10.1007/s11154-021-09682-w","pmid":"34460075","tags":["medical-cannabis","sex-differences","pregnancy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Key endocrine effects include: reduced female fertility and adverse pregnancy outcomes, reduced sperm counts and function, lower thyroid hormone levels with acute use, blunted stress response with chronic use, increased prediabetes risk but paradoxically lower diabetes risk, suggested improvement in HDL and triglycerides, and modest increase in fracture risk.","whyItMatters":"The endocannabinoid system interacts with virtually every endocrine process. As cannabis use increases, understanding these hormonal effects is essential for clinical practice across multiple medical specialties.","specificNumbers":"Affects thyroid, adrenal, gonadal, glucose, lipid, and bone systems; prediabetes risk increased; diabetes risk decreased; fracture risk modestly increased","methodology":"Review synthesizing evidence on cannabis effects across thyroid, adrenal, and gonadal function, plus glucose control, lipid metabolism, and bone health, drawing from animal data, population studies, and known endocannabinoid system properties.","limitations":"Many findings come from observational studies that cannot establish causation. Dose-response relationships and differences between acute and chronic use are often unclear."},{"rthcId":"RTHC-04060","title":"Long-Term Cannabis Use and Cognitive Reserves and Hippocampal Volume in Midlife.","authors":"Meier, Madeline H; Caspi, Avshalom; R Knodt, Annchen; Hall, Wayne; Ambler, Antony; Harrington, HonaLee; Hogan, Sean; M Houts, Renate; Poulton, Richie; Ramrakha, Sandhya; Hariri, Ahmad R; Moffitt, Terrie E","year":2022,"journal":"The American journal of psychiatry, 179(5), 362-374","doi":"10.1176/appi.ajp.2021.21060664","pmid":"35255711","tags":["cognition","neuroscience","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Long-term cannabis users showed a mean 5.5-point IQ decline from childhood to age 45, poorer learning and processing speed relative to childhood IQ, and informant-reported memory and attention problems. These deficits were specific to long-term cannabis users and were not present or were smaller among tobacco users, alcohol users, recreational users, or quitters. Smaller hippocampal volume was observed but did not statistically mediate cognitive deficits.","whyItMatters":"This is one of the most methodologically rigorous longitudinal studies of cannabis and cognition, with childhood baseline IQ, repeated assessments, and controls for numerous confounders. The findings are difficult to dismiss.","specificNumbers":"1,037 participants; 94% retention to age 45; -5.5 IQ point decline; assessed at ages 18, 21, 26, 32, 38, 45; smaller hippocampal volume on MRI","methodology":"Prospective cohort of 1,037 individuals born in Dunedin, New Zealand (1972-1973) followed to age 45 with 94% retention. Cannabis use assessed at ages 18, 21, 26, 32, 38, and 45. IQ tested at ages 7, 9, 11, and 45. Neuropsychological testing and brain MRI at age 45.","limitations":"Observational design cannot definitively prove causation. Cannabis potency has changed over the study period. Dunedin cohort may not represent all populations."},{"rthcId":"RTHC-04061","title":"Cannabis use and posttraumatic stress disorder: prospective evidence from a longitudinal study of veterans.","authors":"Metrik, Jane; Stevens, Angela K; Gunn, Rachel L; Borsari, Brian; Jackson, Kristina M","year":2022,"journal":"Psychological medicine, 52(3), 446-456","doi":"10.1017/S003329172000197X","pmid":"32546286","tags":["ptsd","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Using cross-lagged panel modeling, baseline cannabis use significantly predicted worse intrusion symptoms at 6 months (beta=0.46). The reverse association (intrusions predicting use) was weaker (beta=0.22). PTSD diagnosis at baseline predicted cannabis use disorder at 12 months (beta=0.15), but CUD did not significantly predict PTSD.","whyItMatters":"Many veterans use cannabis to self-medicate PTSD, but this study suggests cannabis may actually worsen the core intrusive symptoms of PTSD over time, creating a self-reinforcing cycle.","specificNumbers":"361 veterans; 3 timepoints (baseline, 6mo, 12mo); cannabis to intrusions beta=0.46; intrusions to cannabis beta=0.22; PTSD to CUD beta=0.15","methodology":"Prospective longitudinal study of 361 post-9/11 veterans with assessments at baseline, 6 months, and 12 months using random intercept cross-lagged panel models to distinguish within-person changes from between-person differences.","limitations":"Observational study, though the cross-lagged design provides stronger causal inference than cross-sectional data. Sample limited to post-9/11 veterans."},{"rthcId":"RTHC-04062","title":"Cannabis use as a moderator of cognitive behavioral therapy for insomnia.","authors":"Miller, Mary Beth; Carpenter, Ryan W; Freeman, Lindsey K; Curtis, Ashley F; Yurasek, Ali M; McCrae, Christina S","year":2022,"journal":"Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 18(4), 1047-1054","doi":"10.5664/jcsm.9796","pmid":"34870584","tags":["sleep","cognition","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 56 young adult binge drinkers with insomnia, 46% used cannabis during the treatment phase. Cannabis use did not moderate CBT-I effects on insomnia severity (b=-0.002, P=0.99) or any other outcomes. Cannabis users reported heavier drinking and more cigarette use but CBT-I remained effective regardless.","whyItMatters":"Clinicians may worry that cannabis use undermines insomnia therapy. This study suggests CBT-I works whether or not patients use cannabis concurrently, which is reassuring for clinical practice.","specificNumbers":"56 participants; 46% used cannabis during treatment; 27% of cannabis users used it for sleep; cannabis moderation effect b=-0.002 (P=0.99); 23% of treatment days involved cannabis use","methodology":"Secondary analysis of a published RCT. Young adults (18-30) with binge drinking and insomnia disorder were randomized to CBT-I (n=28) or sleep hygiene (n=28). Cannabis use was assessed during the treatment phase and tested as a moderator using multilevel models.","limitations":"Secondary analysis not powered to detect cannabis effects. Small sample. Cannabis use was naturalistic and self-reported. Only young adult binge drinkers, limiting generalizability."},{"rthcId":"RTHC-04063","title":"Influence of cannabis use history on the impact of acute cannabis smoking on simulated driving performance during a distraction task.","authors":"Miller, Ryan; Brown, Tim; Wrobel, Julia; Kosnett, Michael J; Brooks-Russell, Ashley","year":2022,"journal":"Traffic injury prevention, 23(sup1), S1-S7","doi":"10.1080/15389588.2022.2072492","pmid":"35686998","tags":["driving","tolerance","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Occasional cannabis users (1-2 times/week) had significantly increased lane departure risk during distraction after acute cannabis use (OR=3.71, P=0.04). Daily users did not show this increase (OR=1.56, P=0.43) but instead decreased speed relative to baseline, suggesting compensatory behavior. Changes were significantly greater for occasional vs non-use groups.","whyItMatters":"This challenges the assumption that all cannabis users are equally impaired. Occasional users showed the greatest safety risk, while daily users compensated, suggesting tolerance and behavioral adaptation play significant roles.","specificNumbers":"85 participants (31 daily, 24 occasional, 30 non-users); occasional users OR 3.71 for lane departure; daily users OR 1.56 (ns); daily users decreased speed post-use","methodology":"Within-subjects controlled experiment with 85 adults aged 25-45: daily users (n=31), occasional users (n=24), and non-users (n=30). Participants completed driving simulator scenarios before and 30 minutes after smoking self-procured cannabis, with distraction tasks (selecting apps on a mounted tablet).","limitations":"Simulated driving with brief distraction tasks. Cannabis was self-procured (uncontrolled potency). Non-users did not smoke cannabis, so comparisons involve both cannabis and non-cannabis effects."},{"rthcId":"RTHC-04064","title":"A nutraceutical product, extracted from Cannabis sativa, modulates voltage-gated sodium channel function.","authors":"Milligan, Carol J; Anderson, Lyndsey L; Bowen, Michael T; Banister, Samuel D; McGregor, Iain S; Arnold, Jonathon C; Petrou, Steven","year":2022,"journal":"Journal of cannabis research, 4(1), 30","doi":"10.1186/s42238-022-00136-x","pmid":"35689251","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04065","title":"Prevalence and correlates of cannabis use disorder among Australians using cannabis products to treat a medical condition.","authors":"Mills, Llewellyn; Lintzeris, Nicholas; O'Malley, Michael; Arnold, Jonathon C; McGregor, Iain S","year":2022,"journal":"Drug and alcohol review, 41(5), 1095-1108","doi":"10.1111/dar.13444","pmid":"35172040","tags":["addiction","medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"CUD criteria were met by 32% (any-CUD) and 12.9% (moderate-severe CUD) of medical cannabis users. The strongest CUD correlates were inhaled route (OR=2.96), higher frequency of use (OR=1.24 per unit increase), tobacco use (OR=1.10), younger age (OR=0.75), and using cannabis for mental health rather than pain (OR=0.58 for pain as protective).","whyItMatters":"As medical cannabis access expands, understanding that one-third of medical users may meet CUD criteria challenges the assumption that medical use is inherently lower-risk than recreational use.","specificNumbers":"905 participants; 98% used illicit cannabis; 32% any-CUD; 12.9% moderate-severe CUD; tolerance 21%; withdrawal 35%; inhaled route OR=2.96; pain protective OR=0.58","methodology":"Cross-sectional anonymous online survey (2018-2019) of 905 Australians reporting medical cannabis use in the past year. 98% used illicit products. CUD assessed by DSM-5 criteria. Bayesian Horseshoe logistic regression for correlates.","limitations":"Cross-sectional survey with self-selected participants. 98% used illicit products, which may differ from regulated medical cannabis. Cannot determine if CUD preceded or followed medical use."},{"rthcId":"RTHC-04066","title":"Correlates of treatment engagement and client outcomes: results of a randomised controlled trial of nabiximols for the treatment of cannabis use disorder.","authors":"Mills, Llewellyn; Dunlop, Adrian; Montebello, Mark; Copeland, Jan; Bruno, Raimondo; Jefferies, Meryem; Mcgregor, Iain; Lintzeris, Nicholas","year":2022,"journal":"Substance abuse treatment, prevention, and policy, 17(1), 67","doi":"10.1186/s13011-022-00493-z","pmid":"36209081","tags":["addiction","quitting","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Greater counseling attendance predicted both abstinence and 50%+ reduction in cannabis use. Nabiximols increased odds of 50%+ reduction, improved counseling attendance, and reduced treatment dropout. Longer duration of regular cannabis use predicted better outcomes. Males attended less counseling, and sleep problems predicted worse outcomes.","whyItMatters":"Understanding what predicts treatment success helps clinicians tailor cannabis use disorder treatment. The finding that counseling combined with agonist therapy is optimal mirrors approaches used for opioid use disorder.","specificNumbers":"128 participants; 12-week trial; counseling predicted abstinence; nabiximols reduced dropout; longer use history predicted better outcomes; males attended less counseling","methodology":"Secondary analysis of a 12-week randomized placebo-controlled trial of nabiximols for CUD (128 participants). Bayesian multiple regression examined the impact of client and treatment factors on engagement and outcomes.","limitations":"Secondary analysis. Correlates of treatment success do not prove causal mechanisms. Sample size limits the number of predictors that can be reliably examined."},{"rthcId":"RTHC-04067","title":"Cannabidiol for the Management of Endometriosis and Chronic Pelvic Pain.","authors":"Mistry, Megha; Simpson, Paul; Morris, Edward; Fritz, Ann-Katrin; Karavadra, Babu; Lennox, Carole; Prosser-Snelling, Ed","year":2022,"journal":"Journal of minimally invasive gynecology, 29(2), 169-176","doi":"10.1016/j.jmig.2021.11.017","pmid":"34839061","tags":["pain","medical-cannabis","cbd","sex-differences"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 264 articles screened, 41 were included. Most evidence comes from lab studies simulating cannabis effects on endometriosis models, with some showing benefit but conflicting results. Few human studies exist, mostly surveys with bias. UK national guidance cannot currently recommend cannabis for endometriosis due to lack of clear evidence.","whyItMatters":"Endometriosis affects 10% of reproductive-age women and current treatments often impair fertility. Cannabis-based products are being explored as alternatives, but the evidence base is critically thin.","specificNumbers":"264 articles screened; 41 included; most evidence preclinical; UK guidance does not recommend cannabis for endometriosis","methodology":"Systematic review searching PubMed, EMBASE, Cochrane, and gray literature for studies on cannabis-based products and endometriosis or chronic pelvic pain.","limitations":"Predominantly preclinical evidence. Human studies limited to biased surveys. Lab results may not translate to clinical effectiveness."},{"rthcId":"RTHC-04068","title":"The role of the cannabinoid system in fear memory and extinction in male and female mice.","authors":"Mizuno, Ikumi; Matsuda, Shingo; Tohyama, Suguru; Mizutani, Akihiro","year":2022,"journal":"Psychoneuroendocrinology, 138, 105688","doi":"10.1016/j.psyneuen.2022.105688","pmid":"35176534","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04069","title":"Cannabis sativa exacerbate testicular function by increased oxidative stress, altered male reproductive hormones, sperm quality/quantity and cellular architecture of the testis.","authors":"Mobisson, Samuel Kelechi; Ikpi, Daniel Ewa; Wopara, Iheanyichukwu; Obembe, Agona Odeh","year":2022,"journal":"Andrologia, 54(9), e14492","doi":"10.1111/and.14492","pmid":"35675950","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04070","title":"The Characteristics of Clinical Trials on Cannabis and Cannabinoids: A Review of Trials for Therapeutic or Drug Development Purposes.","authors":"Modaresi, Farhang; Talachian, Kaivan","year":2022,"journal":"Pharmaceutical medicine, 36(6), 387-400","doi":"10.1007/s40290-022-00447-7","pmid":"36357543","tags":["medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Of 2,966 reviewed trials, 834 met criteria. Annual registrations grew from 30 (2013) to 103 (2021). Over 40% of 2021 registrations were Phase II/III trials. THC and CBD dominated, with oral administration most common. Two-thirds of trials covered five therapeutic areas: chronic pain, mental/behavioral disorders, neurological diseases, metabolic diseases, and cancer. Pharmaceutical companies sponsored 39% of trials.","whyItMatters":"This provides the most comprehensive overview of the cannabis clinical trial landscape, revealing where research is concentrated and where significant gaps remain.","specificNumbers":"834 of 2,966 trials included; 30 in 2013 to 103 in 2021; 40%+ were Phase II/III in 2021; mean enrollment: 128 (completed), 156 (ongoing), 542 (terminated); 39% pharma-sponsored","methodology":"Review of four clinical trial registries (ICTRP, ClinicalTrials.gov, EUCTR, ANZCTR) for all interventional cannabinoid trials with therapeutic or drug development purposes registered between January 2000 and December 2021.","limitations":"Registry data may not capture all trials. Registration does not guarantee completion or publication. Study quality cannot be assessed from registry data alone."},{"rthcId":"RTHC-04071","title":"Effects of cannabidiol without delta-9-tetrahydrocannabinol on canine atopic dermatitis: A retrospective assessment of 8 cases.","authors":"Mogi, Chie; Yoshida, Masanori; Kawano, Koji; Fukuyama, Takaaki; Arai, Toshiro","year":2022,"journal":"The Canadian veterinary journal = La revue veterinaire canadienne, 63(4), 423-426","doi":null,"pmid":"35368394","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04072","title":"The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder.","authors":"Mohammad, Guldar Sayed; Joca, Sâmia; Starnawska, Anna","year":2022,"journal":"Genes, 13(8)","doi":"10.3390/genes13081435","pmid":"36011346","tags":["depression","genetics","neuroscience"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cross-referencing cannabis methylation studies with the largest depression GWAS revealed that multiple depression-associated genes are epigenetically regulated by cannabis exposure. This regulation occurred across diverse organisms, tissues, and developmental stages and affected genes involved in neuronal development, synaptic functioning, and survival, as well as genes implicated in other mental disorders.","whyItMatters":"This provides a potential molecular mechanism connecting cannabis exposure to depression risk, moving beyond epidemiological associations to suggest specific epigenetic pathways.","specificNumbers":"Multiple depression-associated genes found to be epigenetically regulated; effects across diverse organisms, tissues, and developmental stages","methodology":"Literature search identifying genes differentially methylated by cannabis/cannabinoid exposure from methylome-wide studies, then cross-referenced with depression-associated loci from the largest available GWAS of depression.","limitations":"Hypothesis-driven analysis cross-referencing two data sources. The overlap of cannabis-methylated genes and depression-associated genes does not prove causal connection. Different organisms and tissues may not predict human brain effects."},{"rthcId":"RTHC-04073","title":"Prevalence of cannabis use in people with psychosis in KwaZulu-Natal, South Africa.","authors":"Mona, Khanya; Ntlantsana, Vuyokazi; Tomita, Andrew M; Paruk, Saeeda","year":2022,"journal":"The South African journal of psychiatry : SAJP : the journal of the Society of Psychiatrists of South Africa, 28, 1927","doi":"10.4102/sajpsychiatry.v28i0.1927","pmid":"36340643","tags":["psychosis","addiction","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Current cannabis use was 48.9% and lifetime use 51.1%. Males had nearly 5x higher odds of current cannabis use (OR=4.90) and 6x higher for lifetime use (OR=6.27). Current alcohol use was associated with cannabis use (OR=3.06). Being 45+ was protective (OR=0.30). Cannabis use was associated with more readmissions (P=0.01), with 48% admitted 3+ times.","whyItMatters":"Nearly half of psychosis inpatients in this setting used cannabis, yet dual diagnosis treatment programs are lacking. This prevalence has direct implications for how psychiatric services should be structured.","specificNumbers":"370 records; 48.9% current use; 51.1% lifetime; male OR 4.90 (current), 6.27 (lifetime); alcohol co-use OR 3.06; 48% admitted 3+ times","methodology":"Retrospective review of 370 clinical records of patients admitted to a psychiatric hospital in Durban, South Africa, from June 2018 to June 2020.","limitations":"Retrospective chart review dependent on accuracy of clinical records. Single-center study in KwaZulu-Natal may not represent all South African psychiatric populations."},{"rthcId":"RTHC-04074","title":"Mood, sleep and pain comorbidity outcomes in cannabis dependent patients: Findings from a nabiximols versus placebo randomised controlled trial.","authors":"Montebello, Mark; Jefferies, Meryem; Mills, Llewellyn; Bruno, Raimondo; Copeland, Jan; McGregor, Iain; Rivas, Consuelo; Jackson, Melissa A; Silsbury, Catherine; Dunlop, Adrian; Lintzeris, Nicholas","year":2022,"journal":"Drug and alcohol dependence, 234, 109388","doi":"10.1016/j.drugalcdep.2022.109388","pmid":"35316689","tags":["addiction","depression","sleep","pain","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among participants with moderate-to-severe baseline scores, depression, anxiety, stress, and insomnia symptoms gradually decreased over 12 weeks of treatment. Pain decreased until week 12 but rebounded during the post-treatment period. Neither nabiximols vs placebo nor counseling sessions contributed significant explanatory power, suggesting treatment engagement itself drove improvement.","whyItMatters":"Many cannabis-dependent individuals also struggle with mood, sleep, and pain problems. This study shows that reducing cannabis use improves these comorbidities even without achieving full abstinence.","specificNumbers":"128 participants; DASS-21, ISI, BPI at 5 timepoints; gradual symptom improvement over 12 weeks; pain rebounded post-treatment (weeks 12-24)","methodology":"Secondary analysis of a 12-week double-blind placebo-controlled trial of nabiximols in 128 cannabis-dependent participants. DASS-21, Insomnia Severity Index, and Brief Pain Inventory measured at weeks 0, 4, 8, 12, and 24.","limitations":"Secondary analysis. Cannot determine if symptom improvement caused reduced cannabis use or vice versa. Pain rebound post-treatment suggests ongoing pain management is needed."},{"rthcId":"RTHC-04075","title":"Hemp seeds: Nutritional value, associated bioactivities and the potential food applications in the Colombian context.","authors":"Montero, Lidia; Ballesteros-Vivas, Diego; Gonzalez-Barrios, Andrés Fernando; Sánchez-Camargo, Andrea Del Pilar","year":2022,"journal":"Frontiers in nutrition, 9, 1039180","doi":"10.3389/fnut.2022.1039180","pmid":"36712539","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04076","title":"Adulteration of low-delta-9-tetrahydrocannabinol products with synthetic cannabinoids: Results from drug checking services.","authors":"Monti, Manuela Carla; Zeugin, Jill; Koch, Konrad; Milenkovic, Natasa; Scheurer, Eva; Mercer-Chalmers-Bender, Katja","year":2022,"journal":"Drug testing and analysis, 14(6), 1026-1039","doi":"10.1002/dta.3220","pmid":"34997693","tags":["synthetic-cannabinoids","harm-reduction","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 94 samples, 50% contained up to three different synthetic cannabinoids, with MDMB-4en-PINACA most common. All adulterated flowers had 1% or less THC. The synthetic cannabinoid group had significantly more adverse events (P=0.041), with worse psychological (P=0.0007) and cardiological (P=0.020) outcomes compared to the THC-only group.","whyItMatters":"Legal low-THC cannabis products are being used as carrier materials for dangerous synthetic cannabinoids. Users think they are consuming a mild product but are unknowingly exposed to highly potent substances.","specificNumbers":"94 samples; 50% adulterated; up to 3 SCs per sample; MDMB-4en-PINACA most common; all adulterated flowers had ≤1% THC; more psychological (P=0.0007) and cardiac (P=0.020) adverse effects","methodology":"Analysis of cannabis samples submitted to three Swiss drug checking services from January 2020 to July 2021. LC-HRMS for synthetic cannabinoid screening and semi-quantification; GC-FID for THC/CBD quantification. User self-reports of adverse effects collected.","limitations":"Samples submitted to drug checking services may not represent the broader market. Adverse effect reporting was voluntary and self-reported."},{"rthcId":"RTHC-04077","title":"Fetal Exposure to Cannabis and Childhood Metabolic Outcomes: The Healthy Start Study.","authors":"Moore, Brianna F; Sauder, Katherine A; Shapiro, Allison L B; Crume, Tessa; Kinney, Gregory L; Dabelea, Dana","year":2022,"journal":"The Journal of clinical endocrinology and metabolism, 107(7), e2862-e2869","doi":"10.1210/clinem/dgac101","pmid":"35357471","tags":["pregnancy","youth","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Approximately 15% of mothers had detectable cannabinoids in urine at ~27 weeks gestation. Exposed offspring had higher fat mass (+1.0 kg), fat-free mass (+1.2 kg), adiposity (+2.6%), and fasting glucose (+5.6 mg/dL) at mean age 4.7 years compared to unexposed children. No associations were found with fasting insulin, HOMA-IR, BMI, or BMI z-scores.","whyItMatters":"This is among the first studies to link prenatal cannabis exposure to childhood metabolic outcomes, suggesting effects on body composition and glucose regulation that could have long-term health implications.","specificNumbers":"103 mother-child pairs; 15% exposed; +1.0 kg fat mass; +1.2 kg fat-free mass; +2.6% adiposity; +5.6 mg/dL fasting glucose; mean follow-up age 4.7 years","methodology":"Prospective cohort of 103 mother-child pairs from the Healthy Start study (Colorado). Twelve cannabinoids/metabolites measured in maternal urine at ~27 weeks gestation. Child adiposity measured via air displacement plethysmography and metabolic markers at mean age 4.7 years.","limitations":"Small sample size (103 pairs). Single urine measurement may not capture full exposure. Cannot fully control for all confounders associated with cannabis use during pregnancy."},{"rthcId":"RTHC-04078","title":"Metabolism of third generation synthetic cannabinoids using zebrafish larvae.","authors":"Morales-Noé, Asunción; Esteve-Turrillas, Francesc A; Armenta, Sergio","year":2022,"journal":"Drug testing and analysis, 14(4), 594-603","doi":"10.1002/dta.3195","pmid":"34750997","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04079","title":"Geographical variation in hospitalization for psychosis associated with cannabis use and cannabis legalization in the United States: Submit to: Psychiatry Research.","authors":"Moran, Lauren V; Tsang, Erica S; Ongur, Dost; Hsu, John; Choi, May Y","year":2022,"journal":"Psychiatry research, 308, 114387","doi":"10.1016/j.psychres.2022.114387","pmid":"35016118","tags":["psychosis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"There were an estimated 129,070 hospital discharges for psychosis associated with cannabis in 2017. The Pacific division had 55% higher odds of such discharges (aOR=1.55, 95% CI 1.25-1.93). A cannabis legality score correlated significantly with the proportion of psychosis-cannabis hospitalizations (r=0.67, P<0.05).","whyItMatters":"This national-level data provides evidence that more liberal cannabis legalization is associated with more psychosis-related hospitalizations, a finding with direct policy implications.","specificNumbers":"129,070 psychosis-cannabis hospital discharges; Pacific division aOR 1.55; legality-psychosis correlation r=0.67 (P<0.05)","methodology":"Analysis of the 2017 National Inpatient Sample database using multivariable logistic regression comparing psychosis-cannabis hospitalizations across U.S. census divisions. Cannabis legality scores were population-weighted sums of state-level legal status.","limitations":"Cross-sectional data from one year. Cannot establish causation. Higher rates in legal states could reflect better detection, more use, higher potency, or other factors. Hospital discharge codes may not accurately capture cannabis involvement."},{"rthcId":"RTHC-04080","title":"Cannabidiol for the treatment of refractory epilepsy in children: a critical review of the literature.","authors":"Moreira, Gabriela Araujo; Moraes Neto, Roddie; Ribeiro, Ricardo Gullit; Crippa, Ana Chrystina De Souza","year":2022,"journal":"Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo, 41, e2021197","doi":"10.1590/1984-0462/2023/41/2021197","pmid":"35830160","tags":["epilepsy","cbd","youth"],"studyType":"review","evidenceStrength":"strong","keyFinding":"CBD efficacy for treating seizures has been confirmed by RCTs for LGS, Dravet syndrome, and TSC. Side effects are frequent but mostly mild to moderate and transient. There is no global consensus on regulatory approval, but CBD is considered promising with a good safety profile.","whyItMatters":"For families of children with treatment-resistant epilepsy, knowing that CBD has been confirmed effective through rigorous clinical trials provides evidence-based guidance in a landscape full of unproven claims.","specificNumbers":"69 articles reviewed; efficacy confirmed for LGS, Dravet, TSC; side effects mostly mild-moderate and transient","methodology":"Critical literature review of 69 articles from PubMed, Cochrane, and SciELO databases, without date, language, or study design restrictions, covering CBD for refractory epilepsy in pediatric populations.","limitations":"Review focused on published literature which may have publication bias. Long-term safety data in pediatric populations remain limited."},{"rthcId":"RTHC-04081","title":"A Content Analysis of Cannabis Company Adherence to Marketing Requirements in Four States.","authors":"Moreno, Megan A; Jenkins, Marina; Binger, Kole; Kelly, Lauren; Trangenstein, Pamela J; Whitehill, Jennifer M; Jernigan, David H","year":2022,"journal":"Journal of studies on alcohol and drugs, 83(1), 27-36","doi":null,"pmid":"35040757","tags":["youth","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 2,660 posts from 14 recreational cannabis businesses on Facebook and Instagram, discounts and promotions (restricted content) appeared in approximately 35% of posts and overconsumption messaging in 12%. Required safety warnings (age limits, impaired driving, health risks) were present in less than half of all posts.","whyItMatters":"Cannabis social media marketing reaches youth-heavy platforms. Widespread non-compliance with advertising restrictions means young people are exposed to promotional content without required safety messages.","specificNumbers":"2,660 posts; 14 businesses; 4 states; 35% had discounts/promotions; 12% featured overconsumption; <50% had required warnings","methodology":"Retrospective content analysis of one year of publicly displayed Facebook and Instagram posts from retail cannabis companies in Alaska, Colorado, Oregon, and Washington State, evaluating compliance with state advertising restrictions.","limitations":"Publicly visible posts only. Only 14 businesses across 4 states. Content analysis cannot measure the actual impact on youth attitudes or behavior."},{"rthcId":"RTHC-04082","title":"2-Arachidonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice.","authors":"Morgan, Amanda; Adank, Danielle; Johnson, Keenan; Butler, Emily; Patel, Sachin","year":2022,"journal":"Alcoholism, clinical and experimental research, 46(11), 2010-2024","doi":"10.1111/acer.14949","pmid":"36125319","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04083","title":"Intertwined associations between oxidative and nitrosative stress and endocannabinoid system pathways: Relevance for neuropsychiatric disorders.","authors":"Morris, Gerwyn; Walder, Ken; Berk, Michael; Carvalho, Andre F; Marx, Wolf; Bortolasci, Chiara C; Yung, Alison R; Puri, Basant K; Maes, Michael","year":2022,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 114, 110481","doi":"10.1016/j.pnpbp.2021.110481","pmid":"34826557","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04084","title":"Inflammation and Nitro-oxidative Stress as Drivers of Endocannabinoid System Aberrations in Mood Disorders and Schizophrenia.","authors":"Morris, Gerwyn; Sominsky, Luba; Walder, Kenneth R; Berk, Michael; Marx, Wolfgang; Carvalho, André F; Bortolasci, Chiara C; Maes, Michael; Puri, Basant K","year":2022,"journal":"Molecular neurobiology, 59(6), 3485-3503","doi":"10.1007/s12035-022-02800-y","pmid":"35347586","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04085","title":"The Link Between Cannabis Use and Violent Behavior in the Early Phase of Psychosis: The Potential Role of Impulsivity.","authors":"Moulin, Valerie; Framorando, David; Gasser, Jacques; Dan-Glauser, Elise","year":2022,"journal":"Frontiers in psychiatry, 13, 746287","doi":"10.3389/fpsyt.2022.746287","pmid":"35392388","tags":["psychosis","harm-reduction","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis use is particularly high in early-phase psychosis (EPP) and is a confirmed risk factor for violent behavior in this population. Impulsivity is both associated with cannabis use and a risk factor for violence, potentially mediating the cannabis-violence link. Cannabis affects frontal brain structures involved in impulse control.","whyItMatters":"Understanding why cannabis use increases violence risk in early psychosis identifies a targetable mechanism (impulsivity) for prevention, particularly since early-phase psychosis represents a window for intervention.","specificNumbers":"Cannabis use is particularly high in EPP; impulsivity mediates the cannabis-violence link; frontal lobe dysfunction involved","methodology":"Viewpoint review of scientific literature examining the link between cannabis use, violent behavior in psychosis, and the mediating role of impulsivity at clinical and neurobiological levels.","limitations":"Viewpoint/review rather than original data. The mediating role of impulsivity is proposed but needs confirmation with longitudinal studies controlling for confounders."},{"rthcId":"RTHC-04086","title":"Endocannabinoid Modulation Using Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A Phase 1 Randomized, Placebo-Controlled Study.","authors":"Müller-Vahl, Kirsten R; Fremer, Carolin; Beals, Chan; Ivkovic, Jelena; Loft, Henrik; Schindler, Christoph","year":2022,"journal":"Pharmacopsychiatry, 55(3), 148-156","doi":"10.1055/a-1675-3494","pmid":"34847610","tags":["medical-cannabis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"A single 40 mg dose of Lu AG06466 (a MAGL inhibitor that raises 2-AG endocannabinoid levels) showed an overall trend of tic reduction across all scales, with 2 of 3 tic scales (including the Yale Global Tic Severity Score) showing significant improvement versus placebo at various timepoints. Premonitory urges were also significantly reduced.","whyItMatters":"Tourette syndrome lacks consistently effective treatment. This is the first trial of a MAGL inhibitor (which works by boosting the body's own endocannabinoids rather than introducing external cannabinoids) in TS patients.","specificNumbers":"20 patients; 40 mg single dose; 2/3 tic scales showed significant improvement; premonitory urges significantly reduced; common side effects: headache, somnolence, fatigue","methodology":"Phase 1b double-blind crossover study in 20 adult Tourette syndrome patients on standard medications. Single fasted dose of Lu AG06466 (40 mg) or placebo in each period, with tic assessments at multiple timepoints.","limitations":"Only 20 patients. Single-dose study cannot assess long-term efficacy or safety. Phase 1b exploratory trial, not a definitive efficacy study."},{"rthcId":"RTHC-04087","title":"Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist.","authors":"Muller, Tania; Demizieux, Laurent; Troy-Fioramonti, Stéphanie; Buch, Chloé; Leemput, Julia; Belloir, Christine; Pais de Barros, Jean-Paul; Jourdan, Tony; Passilly-Degrace, Patricia; Fioramonti, Xavier; Le Bon, Anne-Marie; Vergès, Bruno; Robert, Jean-Michel; Degrace, Pascal","year":2022,"journal":"International journal of molecular sciences, 23(6)","doi":"10.3390/ijms23062923","pmid":"35328343","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04088","title":"Real-Time Monitoring of Cannabis and Prescription Opioid Co-Use Patterns, Analgesic Effectiveness, and the Opioid-Sparing Effect of Cannabis in Individuals With Chronic Pain.","authors":"Mun, Chung Jung; Nordeck, Courtney; Goodell, Erin M Anderson; Vandrey, Ryan; Zipunnikov, Vadim; Dunn, Kelly E; Finan, Patrick H; Thrul, Johannes","year":2022,"journal":"The journal of pain, 23(11), 1799-1810","doi":"10.1016/j.jpain.2022.06.009","pmid":"35817255","tags":["pain","medical-cannabis","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Using 30-day ecological momentary assessment, neither cannabis-opioid co-use nor sole use of either substance reduced pain in the next moment. However, participants retrospectively reported the highest perceived pain relief from co-use. There was no evidence of an opioid-sparing effect. The discrepancy between real-time and retrospective reports suggests recall bias.","whyItMatters":"The \"opioid-sparing\" effect of cannabis is widely discussed but rarely tested with real-time data. This study challenges the narrative by showing no moment-to-moment pain reduction or opioid dose reduction from co-use.","specificNumbers":"46 participants; 30-day EMA; no momentary pain reduction from co-use; no opioid-sparing effect; retrospective reports showed perceived relief from co-use (possible recall bias)","methodology":"Ecological momentary assessment (EMA) study of 46 adults with chronic pain using both opioids and cannabis, recruited online, completing 30 days of real-time surveys on pain, cannabis use, and opioid use.","limitations":"Small sample (46 participants). Online recruitment may select for specific populations. EMA compliance varies. Cannot control cannabis/opioid dosing or timing."},{"rthcId":"RTHC-04089","title":"Adolescents are more sensitive than adults to acute behavioral and cognitive effects of THC.","authors":"Murray, Conor H; Huang, Zhengyi; Lee, Royce; de Wit, Harriet","year":2022,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(7), 1331-1338","doi":"10.1038/s41386-022-01281-w","pmid":"35110688","tags":["youth","cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Adolescents (18-20) showed dose-dependent impairments in reaction time, response accuracy, and time perception with THC (7.5 and 15 mg) that adults (30-40) did not exhibit. THC decreased P300 brain wave amplitude in adolescents but not adults. Subjective intoxication and heart rate effects were similar in both groups.","whyItMatters":"This is one of the first human studies directly comparing THC effects across age groups. The finding that adolescents are more cognitively impaired at doses that feel the same as for adults has important implications for risk communication.","specificNumbers":"12 adolescents (18-20) vs 12 adults (30-40); THC 7.5 and 15 mg; <20 lifetime uses; dose-dependent cognitive impairment in adolescents only; P300 decreased in adolescents only","methodology":"Double-blind, placebo-controlled RCT with 12 adolescents (18-20) and 12 adults (30-40), all with fewer than 20 lifetime THC uses. Each received placebo, 7.5 mg, and 15 mg THC capsules across three sessions.","limitations":"Very small sample (24 total). Participants aged 18-20 are legally adults but neurologically still developing. Oral THC capsules may differ from smoked/vaped cannabis."},{"rthcId":"RTHC-04090","title":"Effects of synthetic (JWH-018) cannabinoids treatment on spermatogenesis and sperm function.","authors":"Mutluay, Duygu; Güngör, Şükrü; Tenekeci, Gözde Yücel; Köksoy, Serkan; Çoban, Cennet Sinem","year":2022,"journal":"Drug and chemical toxicology, 45(1), 215-222","doi":"10.1080/01480545.2019.1680686","pmid":"31645148","tags":["synthetic-cannabinoids","sex-differences","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"JWH-018 (0.3 mg/kg for 9 days) caused significantly decreased sperm concentration, motility, and membrane integrity, reduced testosterone, increased abnormal sperm morphology, and seminiferous tubule degeneration. At 45 days post-treatment, sperm concentration, motility, and testosterone increased, suggesting partial recovery of spermatogenesis.","whyItMatters":"Synthetic cannabinoids are widely used by young adults. This study provides evidence that JWH-018 damages male reproductive function but, reassuringly, that some recovery occurs after cessation.","specificNumbers":"30 rats; 0.3 mg/kg JWH-018 for 9 days; decreased sperm concentration, motility, and testosterone at day 2; partial recovery at day 45; increased oxidative stress markers","methodology":"30 male CD-1 rats in 6 groups: control, ethanol vehicle, and JWH-018, each evaluated at 2 days or 45 days after the last injection. Sperm parameters, testosterone, oxidative stress markers, and testicular histopathology assessed.","limitations":"Animal study with a single JWH-018 dose for 9 days. Human use patterns may differ significantly. Only 5 rats per group limits statistical power. Recovery at 45 days may be partial, not complete."},{"rthcId":"RTHC-04091","title":"Changes in Emergency Department Visits for Cannabis Hyperemesis Syndrome Following Recreational Cannabis Legalization and Subsequent Commercialization in Ontario, Canada.","authors":"Myran, Daniel Thomas; Roberts, Rhiannon; Pugliese, Michael; Taljaard, Monica; Tanuseputro, Peter; Pacula, Rosalie Liccardo","year":2022,"journal":"JAMA network open, 5(9), e2231937","doi":"10.1001/jamanetworkopen.2022.31937","pmid":"36112372","tags":["legalization","harm-reduction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"CHS ED visits increased from 0.26 to 3.43 per 100,000 population over 7.5 years (13-fold). Legalization alone was not associated with an immediate change, but commercialization (expanded retail and product variety) was associated with a 49% immediate increase (IRR=1.49). Women showed larger increases than men during commercialization (IRR 1.49 vs 1.08).","whyItMatters":"This is the first study to distinguish the effects of legalization from commercialization on CHS. The finding that retail expansion and product variety drove the increase has direct regulatory implications.","specificNumbers":"12,866 ED visits from 8,140 individuals; 13-fold increase; mean age 27.4; 51.5% female; 8.8% hospitalized; commercialization IRR 1.49; 16.6% had prior mental health visits","methodology":"Interrupted time-series analysis of linked health administrative databases covering all Ontario residents 15+ from January 2014 to June 2021, examining CHS ED visits across three periods: pre-legalization, legalization, and commercialization.","limitations":"Commercialization period coincided with COVID-19, which may have independently affected cannabis use and ED visits. ICD coding for CHS may have improved over the study period."},{"rthcId":"RTHC-04092","title":"Cannabinoid Hyperemesis Syndrome and Hypophosphatemia in Adolescents.","authors":"Nachnani, Rahul; Hushagen, Kimberly; Swaffield, Thomas; Jhaveri, Punit; Vrana, Kent E; Alexander, Chandran P","year":2022,"journal":"JPGN reports, 3(4), e248","doi":"10.1097/PG9.0000000000000248","pmid":"37168463","tags":["youth","harm-reduction","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Three adolescents with CHS developed recurrent hypophosphatemia (low phosphorus) that complicated their hospitalizations. The authors highlight that providers should consider CHS in vomiting adolescents and monitor electrolytes closely, as hypophosphatemia can cause serious complications.","whyItMatters":"Hypophosphatemia can cause muscle weakness, respiratory failure, cardiac dysfunction, and seizures. Recognizing this complication in adolescents with CHS ensures appropriate monitoring and treatment.","specificNumbers":"3 adolescents; recurrent hypophosphatemia in all cases; CHS diagnosis","methodology":"Case series of 3 adolescents presenting with cannabinoid hyperemesis syndrome and recurrent hypophosphatemia, with clinical details of each case.","limitations":"Only 3 cases. Cannot determine how common hypophosphatemia is in CHS or whether it is specific to adolescents."},{"rthcId":"RTHC-04093","title":"Cannabidiol and Other Phytocannabinoids as Cancer Therapeutics.","authors":"Nahler, Gerhard","year":2022,"journal":"Pharmaceutical medicine, 36(2), 99-129","doi":"10.1007/s40290-022-00420-4","pmid":"35244889","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04094","title":"CBD-mediated regulation of heroin withdrawal-induced behavioural and molecular changes in mice.","authors":"Navarrete, Francisco; Gasparyan, Ani; Manzanares, Jorge","year":2022,"journal":"Addiction biology, 27(2), e13150","doi":"10.1111/adb.13150","pmid":"35229949","tags":["cbd","addiction","withdrawal","neuroscience","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice given CBD (10 and 20 mg/kg) during spontaneous heroin withdrawal showed significantly reduced anxiety-like behavior, motor hyperactivity, and somatic withdrawal signs compared to untreated heroin-dependent mice.","whyItMatters":"Opioid withdrawal is a major barrier to recovery, and current treatments have limitations. If CBD can reduce withdrawal severity, it could become a non-addictive tool to support people trying to quit opioids.","specificNumbers":"CBD at 10 and 20 mg/kg significantly reduced withdrawal-related anxiety and somatic signs. Gene expression of CB1 receptors and POMC in the nucleus accumbens, and tyrosine hydroxylase in the VTA, were normalized by CBD treatment. CBD also upregulated CB2 receptor expression.","methodology":"CD1 male mice received escalating heroin doses over 8 days. Thirty hours after the last dose, spontaneous withdrawal was assessed. Three CBD doses (5, 10, 20 mg/kg) were tested. Researchers measured anxiety (elevated plus maze), motor activity, somatic signs, and gene expression in the nucleus accumbens and ventral tegmental area.","limitations":"This is a mouse study using injected CBD, so the doses and delivery method differ from human use. Only male mice were tested. The behavioral assessments happened at a single time point (30 hours post-heroin), so longer-term withdrawal effects are unknown."},{"rthcId":"RTHC-04095","title":"Immune challenges upregulate the expression of cannabinoid receptors in cultured human odontoblasts and gingival fibroblasts.","authors":"Navarro-Saiz, Laura M; Bernal-Cepeda, Lilia J; Castellanos, Jaime E","year":2022,"journal":"Acta odontologica latinoamericana : AOL, 35(2), 80-89","doi":"10.54589/aol.35/2/80","pmid":"36260938","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04096","title":"Detection of the Synthetic Cannabinoids AB-CHMINACA, ADB-CHMINACA, MDMB-CHMICA, and 5F-MDMB-PINACA in Biological Matrices: A Systematic Review.","authors":"Navarro-Tapia, Elisabet; Codina, Jana; Villanueva-Blasco, Víctor José; García-Algar, Óscar; Andreu-Fernández, Vicente","year":2022,"journal":"Biology, 11(5)","doi":"10.3390/biology11050796","pmid":"35625524","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04097","title":"Hemp and buckwheat are valuable sources of dietary amino acids, beneficially modulating gastrointestinal hormones and promoting satiety in healthy volunteers.","authors":"Neacsu, Madalina; Vaughan, Nicholas J; Multari, Salvatore; Haljas, Elisabeth; Scobbie, Lorraine; Duncan, Gary J; Cantlay, Louise; Fyfe, Claire; Anderson, Susan; Horgan, Graham; Johnstone, Alexandra M; Russell, Wendy R","year":2022,"journal":"European journal of nutrition, 61(2), 1057-1072","doi":"10.1007/s00394-021-02711-z","pmid":"34716790","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04098","title":"A national effectiveness trial of an eHealth program to prevent alcohol and cannabis misuse: responding to the replication crisis.","authors":"Newton, Nicola C; Chapman, Cath; Slade, Tim; Birrell, Louise; Healy, Annalise; Mather, Marius; McBride, Nyanda; Hides, Leanne; Allsop, Steve; Mewton, Louise; Andrews, Gavin; Teesson, Maree","year":2022,"journal":"Psychological medicine, 52(2), 274-282","doi":"10.1017/S0033291720001919","pmid":"32613919","tags":["youth","harm-reduction","legalization"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Students who received the Climate Schools program were 38% less likely to drink a full standard drink and 51% less likely to engage in heavy episodic drinking compared to controls at 12-month follow-up.","whyItMatters":"Few substance prevention programs for adolescents have demonstrated replicable effects. This large replication trial confirmed the program works for reducing alcohol use, which matters for schools choosing evidence-based curricula.","specificNumbers":"Alcohol knowledge increased (standardized mean difference 0.51). Cannabis knowledge increased (SMD 0.49). Odds of drinking a full drink reduced by 38% (OR 0.62, p=0.014). Heavy episodic drinking reduced by 51% (OR 0.49, p=0.022). Cannabis use showed no significant difference (OR 0.57, p=0.22).","methodology":"Cluster-randomized controlled trial across 71 secondary schools in three Australian states. Year 8 students (approximately age 13-14) received either the web-based Climate Schools: Alcohol and Cannabis course (n=3,236) or standard health education (n=3,150). Outcomes measured at baseline, 6, and 12 months.","limitations":"The study relied on self-reported substance use. The program was developed for an Australian context and may not generalize to other countries. The 12-month follow-up is relatively short for assessing long-term prevention effects."},{"rthcId":"RTHC-04099","title":"The prevalence and pattern of cannabis use among patients attending a methadone treatment clinic in Nairobi, Kenya.","authors":"Ngarachu, Elizabeth Wambui; Kiburi, Sarah Kanana; Owiti, Frederick R; Kangethe, Rachel","year":2022,"journal":"Substance abuse treatment, prevention, and policy, 17(1), 12","doi":"10.1186/s13011-022-00437-7","pmid":"35168646","tags":["addiction","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis prevalence was 85.8% at baseline and 62.7% during follow-up among methadone patients. Opioids, cannabis, and benzodiazepines were the most commonly co-used substances. University education was associated with lower cannabis use (OR 0.1).","whyItMatters":"Methadone programs in sub-Saharan Africa are relatively new, and understanding co-occurring substance use patterns is critical for designing effective treatment. The extremely high cannabis prevalence suggests it should be addressed as part of opioid treatment.","specificNumbers":"Baseline cannabis prevalence: 85.8% (95% CI 83.3-88.0). Follow-up prevalence: 62.7% (95% CI 59.5-65.8). Mean age: 35.3 years. 76% unemployed. 51.4% had primary-level education. 48.5% divorced or separated. University education OR for cannabis use: 0.1 (95% CI 0.02-0.8).","methodology":"Retrospective study of 874 patients enrolled in a methadone maintenance program in Nairobi, Kenya, from December 2014 to November 2018. Cannabis use was determined by urine drug screens. Demographic data was collected from patient files.","limitations":"This is a single-site study in one Kenyan city. Urine drug screens detect recent use but do not measure frequency or quantity. The retrospective design limits the ability to determine whether cannabis use affected methadone treatment outcomes."},{"rthcId":"RTHC-04100","title":"Longitudinal Associations Between Use of Tobacco and Cannabis Among People Who Smoke Cigarettes in Real-world Smoking Cessation Treatment.","authors":"Nguyen, Nhung; Neilands, Torsten B; Lisha, Nadra E; Lyu, Joanne Chen; Olson, Sarah S; Ling, Pamela M","year":2022,"journal":"Journal of addiction medicine, 16(4), 413-419","doi":"10.1097/ADM.0000000000000920","pmid":"34619713","tags":["addiction","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Changes in cigarette frequency (β=0.17), e-cigarette frequency (β=0.11), and cigar frequency (β=0.19) were all positively associated with changes in cannabis use frequency over 3 months.","whyItMatters":"If tobacco and cannabis use genuinely move in tandem, then tobacco cessation programs might produce a secondary benefit of reducing cannabis use, offering a \"two-for-one\" public health opportunity.","specificNumbers":"Sample: 487 participants, mean age 25.4, 39.6% male, 40.3% White. Cigarette-cannabis association: β=0.17 (95% CI 0.10-0.24). E-cigarette: β=0.11 (95% CI 0.05-0.17). Cigar: β=0.19 (95% CI 0.06-0.32). Sexual minority participants and those with high school education or less showed greater increases in cannabis use.","methodology":"Longitudinal analysis of 487 cigarette smokers (mean age 25.4) enrolled in a 3-month Facebook-based smoking cessation program in the San Francisco Bay Area (2016-2020). Cannabis use frequency was measured at baseline and 3-month follow-up alongside tobacco product use.","limitations":"The study was observational within a cessation program, so the association could reflect general motivation to change substance use rather than a direct causal link. The Bay Area sample may not represent other populations. Cannabis use was self-reported."},{"rthcId":"RTHC-04101","title":"Fine Particulate Matter Exposure From Secondhand Cannabis Bong Smoking.","authors":"Nguyen, Patton Khuu; Hammond, S Katharine","year":2022,"journal":"JAMA network open, 5(3), e224744","doi":"10.1001/jamanetworkopen.2022.4744","pmid":"35353170","tags":["respiratory","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The study quantified PM2.5 levels from secondhand cannabis bong smoke in a residential setting, demonstrating that bystanders are exposed to fine particulate matter during social smoking sessions.","whyItMatters":"Secondhand tobacco smoke is a well-established health risk, but secondhand cannabis smoke exposure has received far less research attention. As cannabis use becomes more common indoors, understanding bystander exposure matters for public health policy.","specificNumbers":"The brief report quantified PM2.5 levels from bong smoking sessions in a home setting. Specific values were reported in the full text.","methodology":"Cohort study measuring fine particulate matter (PM2.5) levels during social cannabis bong smoking in a home environment. Published as a brief research letter in JAMA Network Open.","limitations":"Published as a brief research letter with limited methodological detail available in the abstract. The study measured particulate matter but did not assess health outcomes from exposure."},{"rthcId":"RTHC-04102","title":"Oral cannabidiol for prevention of acute and transient chemotherapy-induced peripheral neuropathy.","authors":"Nielsen, Sebastian W; Hasselsteen, Simone Dyring; Dominiak, Helena Sylow Heilmann; Labudovic, Dejan; Reiter, Lars; Dalton, Susanne Oksbjerg; Herrstedt, Jørn","year":2022,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 30(11), 9441-9451","doi":"10.1007/s00520-022-07312-y","pmid":"35933415","tags":["cbd","medical-cannabis","cancer","pain"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"CBD-treated patients receiving CAPOX or Carbo-Tax chemotherapy showed significantly better high-frequency vibrometry scores compared to controls. CAPOX patients on CBD also reported less cold sensitivity and throat discomfort.","whyItMatters":"Chemotherapy-induced peripheral neuropathy (CIPN) affects up to a third of cancer patients and has no well-established preventive treatment. If CBD can reduce early neuropathy symptoms, it could improve quality of life during cancer treatment.","specificNumbers":"54 patients recruited. CBD dose: 300 mg/day. Carbo-Tax patients showed the largest vibrometry improvement at 250 Hz (difference: -1.76, 95% CI -2.52 to -1.02). CAPOX patients had lower cold sensitivity (-2.08), discomfort swallowing cold liquids (-2.06), and throat discomfort (-1.81) scores. Side effects: grades 1-2 stomach pain in CAPOX patients.","methodology":"Prospective study of 54 cancer patients scheduled for oxaliplatin- or paclitaxel-based chemotherapy. Patients received 150 mg CBD oil twice daily (300 mg/day) for 8 days starting 1 day before chemotherapy. Neuropathy was measured by multi-frequency vibrometry and 10 patient-reported outcome measures. Controls came from a similar untreated cohort.","limitations":"This was not randomized. CBD-treated patients were significantly older than controls, which could confound results. The sample size of 54 is small. Only early symptoms (first cycle) were measured; long-term follow-up is ongoing."},{"rthcId":"RTHC-04103","title":"The prevalence, distribution and impact of peripheral neuropathy among Danish patients with cancer - a population-based cross-sectional study.","authors":"Nielsen, Sebastian Werngreen; Eckhoff, Lise; Ruhlmann, Christina Halgaard Bruvik; Herrstedt, Jørn; Dalton, Susanne Oksbjerg","year":2022,"journal":"Acta oncologica (Stockholm, Sweden), 61(3), 363-370","doi":"10.1080/0284186X.2021.2007283","pmid":"34846991","tags":["cancer","pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Overall neuropathy prevalence was 17%, ranging from 6% to 33% across cancer types. Cannabis users had significantly higher neuropathy symptom scores (29% vs 15%, p<0.05). Patients with high neuropathy scores had substantially worse quality of life across all measures.","whyItMatters":"This is one of the largest surveys of neuropathy in a general oncology population. The finding that cannabis users had higher neuropathy scores is noteworthy, though it could reflect cannabis use for symptom management rather than cannabis causing neuropathy.","specificNumbers":"2,839 patients surveyed (83% response rate). Overall neuropathy prevalence: 17%. Cannabis users with high score: 29% vs 15% non-users. Quality of life difference: -18.66 points on C30 SumScore (95% CI -20.31 to -17.02). Higher rates in females (19% vs 14%), smokers (21% vs 15%), patients living alone (21% vs 15%).","methodology":"Cross-sectional survey administered to all adult outpatients at three Danish oncology departments. Used the EORTC-CIPN20 for neuropathy assessment and EORTC-QLQ-C30 for quality of life. A high symptom score was defined as CIPN20 summary score of 30 or above. Response rate: 83% (2,839 patients).","limitations":"Cross-sectional design cannot determine whether cannabis use preceded or followed neuropathy symptoms. The study did not capture cannabis dose, frequency, or reason for use. Self-reported symptoms may differ from clinical assessment."},{"rthcId":"RTHC-04104","title":"Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies.","authors":"Nielsen, Suzanne; Picco, Louisa; Murnion, Bridin; Winters, Bryony; Matheson, Justin; Graham, Myfanwy; Campbell, Gabrielle; Parvaresh, Laila; Khor, Kok-Eng; Betz-Stablein, Brigid; Farrell, Michael; Lintzeris, Nicholas; Le Foll, Bernard","year":2022,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(7), 1315-1330","doi":"10.1038/s41386-022-01322-4","pmid":"35459926","tags":["medical-cannabis","pain","cbd"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Preclinical meta-analysis showed THC reduced the effective morphine dose by 3.5-fold (95% CI 2.04-6.03). However, meta-analysis of human RCTs in cancer pain found no effect on opioid dose (mean difference -3.8 mg, 95% CI -10.97 to 3.37) and more adverse events with cannabinoids (RR 1.13).","whyItMatters":"The idea that cannabis could reduce opioid needs during the opioid crisis has enormous appeal. This review reveals a striking disconnect between promising animal data and disappointing human trial results, which is important for setting realistic expectations.","specificNumbers":"Preclinical: morphine ED50 was 3.5x lower with THC (95% CI 2.04-6.03). Cancer pain RCTs (4 studies): no effect on opioid dose (mean diff -3.8 mg). Adverse events higher with cannabinoids (RR 1.13, 95% CI 1.03-1.24). Observational studies: 39% reported opioid cessation, 85% reported reduction. 15 ongoing trials identified.","methodology":"Systematic review and meta-analysis of 92 studies (from 2016 onwards) including preclinical studies, healthy volunteer experiments, and clinical trials across acute pain, cancer pain, and chronic non-cancer pain. Searched Scopus, Cochrane, Medline, and Embase.","limitations":"The review included studies from 2016 onwards only (updating a prior review). RCTs were small and used different cannabinoid preparations. Observational studies had high heterogeneity (I2 >90%). The variety of pain conditions makes pooling difficult."},{"rthcId":"RTHC-04105","title":"Animal evidence considered in determination of cannabis smoke and Δ9 -tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action.","authors":"Niknam, Yassaman; Iyer, Poorni; Campbell, Marlissa A; Moran, Francisco; Sandy, Martha S; Zeise, Lauren","year":2022,"journal":"Birth defects research, 114(18), 1169-1185","doi":"10.1002/bdr2.2088","pmid":"36125082","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04106","title":"QTc prolongation in cannabis hyperemesis syndrome patients exposed to antiemetics: A retrospective chart review.","authors":"Noelle, Carrillo; Susan, Hammerman; Robert, Klemisch; Shelby, Shelton; Andrew, Monte","year":2022,"journal":"The American journal of emergency medicine, 53, 285.e7-285.e8","doi":"10.1016/j.ajem.2021.09.048","pmid":"34607736","tags":["harm-reduction","medical-cannabis","cardiovascular"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"No significant differences in post-medication QTc values were found between different anti-emetic drugs used to treat CHS. The only predictor of QTc prolongation above 500 ms was potassium below 3.0 mmol/L.","whyItMatters":"CHS patients often receive multiple anti-emetic medications, some of which are known to prolong the QTc interval. This study provides reassurance that these medications are relatively safe from a cardiac standpoint in CHS patients, as long as electrolytes are monitored.","specificNumbers":"282 CHS cases identified. No significant QTc differences between medication types. Only potassium below 3.0 mmol/L predicted QTc prolongation above 500 ms in logistic regression.","methodology":"Retrospective chart review of 282 CHS cases at the University of Colorado Health Emergency Department from January 2012 to December 2014. Identified by ICD9/10 codes for cannabis use. Chi-square tests, odds ratios, and logistic regression were used to analyze QTc prolongation by medication.","limitations":"Retrospective design with cases identified by billing codes, which may miss or misclassify some cases. The study period (2012-2014) predates some newer CHS treatment approaches. Sample size may be insufficient to detect rare cardiac events."},{"rthcId":"RTHC-04107","title":"Cannabis for Rheumatic Disease Pain: a Review of Current Literature.","authors":"Nowell, William Benjamin; Gavigan, Kelly; L Silverman, Stuart","year":2022,"journal":"Current rheumatology reports, 24(5), 119-131","doi":"10.1007/s11926-022-01065-7","pmid":"35486218","tags":["medical-cannabis","pain","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Publications on cannabis and rheumatic disease have increased, but recent literature skews heavily toward reviews over primary research. Survey studies show patients find cannabis beneficial, but prospective controlled trials remain rare.","whyItMatters":"Rheumatic diseases cause chronic pain that is often difficult to manage. Patients are increasingly using cannabis on their own, so rheumatologists need to understand the current evidence (or lack thereof) to guide conversations with patients.","specificNumbers":"The review noted that the number of publications has increased but skews toward reviews rather than original research. Specific survey data showed increased cannabis use among people with rheumatic diseases.","methodology":"Narrative review of current literature on cannabis for rheumatic disease pain, covering observational studies, surveys, and the limited randomized controlled trial data available through 2022.","limitations":"This is a narrative review, not a systematic review with formal quality assessment. The conclusions are shaped by the absence of evidence (few RCTs exist) rather than evidence of absence."},{"rthcId":"RTHC-04108","title":"Long-term Cannabis-based oil therapy and pain medications prescribing patterns: an Italian observational study.","authors":"Nunnari, P; Ladiana, N; Ceccarelli, G; Notaro, P","year":2022,"journal":"European review for medical and pharmacological sciences, 26(4), 1224-1234","doi":"10.26355/eurrev_202202_28114","pmid":"35253178","tags":["medical-cannabis","pain","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"After long-term cannabis-based oil therapy, opioid non-users increased significantly from 32.1% to 55.4% (p=0.0023). No significant changes were found in anticonvulsant, antidepressant, or benzodiazepine prescribing patterns.","whyItMatters":"The opioid-sparing potential of cannabis is one of the most debated topics in pain medicine. This real-world Italian data adds to the growing observational evidence that some patients reduce opioid use after starting cannabis, though causation remains uncertain.","specificNumbers":"Opioid non-users increased from 32.1% to 55.4% (p=0.0023). No significant changes for anticonvulsants, antidepressants, or benzodiazepines. High benzodiazepine use prevalence was noted. In patients over 65, antidepressant users decreased from 93.7% to 56.2% (p=0.0313).","methodology":"Retrospective observational study of patients treated with medical cannabis-based oils at a Pain Medicine Unit in Northern Italy from June 2016 to July 2019. Compared pain medication prescriptions before and after cannabis treatment using the McNemar test. Subgroup analyses by sex, age, comorbidity, and treatment duration.","limitations":"Observational and retrospective design cannot establish causation. Patients choosing cannabis may have been more motivated to reduce opioids regardless. No control group for comparison. Single-center study in the Italian healthcare system."},{"rthcId":"RTHC-04109","title":"Trends in cannabis-related attitudes and behaviors among cannabis-using adolescent and young adult outpatients following medical cannabis legalization in Massachusetts.","authors":"O'Connell, Maddie; Levy, Sharon; Shrier, Lydia A; Harris, Sion K","year":2022,"journal":"Substance abuse, 43(1), 328-335","doi":"10.1080/08897077.2021.1941517","pmid":"34214413","tags":["youth","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Use of diverted medical cannabis increased from 15% in 2013 to 44% in 2016 (adjusted OR 4.66, 95% CI 1.81-11.95). Youth using diverted medical cannabis were more likely to ride with a cannabis-impaired driver or drive after cannabis use.","whyItMatters":"Medical cannabis diversion to youth is a major policy concern. This study provides direct evidence that access through someone else's medical supply increased substantially in the years after legalization, with associated risky behaviors.","specificNumbers":"273 youth surveyed. Mean age: 18.2 years. 32% female, 58% White, 70% with college-graduate parents. Diverted use: 15% (2013) vs 44% (2016), aOR 4.66. 97.9% said cannabis was easy to obtain at baseline. 89.4% viewed occasional use as no/slight risk. Youth using diverted cannabis had higher rates of driving-related risk.","methodology":"Cross-sectional surveys of 273 cannabis-using youth (ages 13-24) from an outpatient substance treatment program and adolescent medicine clinic in Boston from 2013 (when medical cannabis took effect) through 2016 (when recreational became legal). Multiple logistic regression analyzed changes in attitudes and behaviors.","limitations":"The sample was drawn from clinical settings (substance treatment and adolescent medicine), so these youth were already at higher risk and may not represent the general adolescent population. Small sample sizes per year limit statistical power. Self-reported data."},{"rthcId":"RTHC-04110","title":"Early-Onset Cardiovascular Disease From Cocaine, Amphetamines, Alcohol, and Marijuana.","authors":"O'Keefe, Evan L; Dhore-Patil, Aneesh; Lavie, Carl J","year":2022,"journal":"The Canadian journal of cardiology, 38(9), 1342-1351","doi":"10.1016/j.cjca.2022.06.027","pmid":"35840019","tags":["cardiovascular","harm-reduction","youth"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"All four substances (cocaine, amphetamines, alcohol, marijuana) are cardiotoxic and contribute to rising levels of premature cardiovascular disease including hypertension, arrhythmias, heart failure, stroke, myocardial infarction, and sudden cardiac death in younger populations.","whyItMatters":"Cardiovascular disease has traditionally been associated with aging, but substance abuse is shifting its burden to younger populations. Understanding marijuana's place alongside better-studied cardiotoxins like cocaine and alcohol helps contextualize its cardiac risks.","specificNumbers":"The US crossed 100,000 overdose-related deaths in a calendar year for the first time. The review covered hypertension, arrhythmias, heart failure, stroke, myocardial infarction, arterial dissection, and sudden cardiac death across all four substances.","methodology":"Narrative review examining the cardiovascular effects of cocaine, amphetamines, alcohol, and marijuana, published in the Canadian Journal of Cardiology. Focused on the link between recreational substance abuse and early-onset cardiovascular disease.","limitations":"This is a narrative review grouping four very different substances together, which may oversimplify their individual cardiovascular risk profiles. The cardiovascular evidence for marijuana is weaker than for cocaine or alcohol. The review did not quantify relative risks across substances."},{"rthcId":"RTHC-04111","title":"CB1 Ligand AM251 Induces Weight Loss and Fat Reduction in Addition to Increased Systemic Inflammation in Diet-Induced Obesity.","authors":"O'Keefe, Lannie; Vu, Teresa; Simcocks, Anna C; Jenkin, Kayte A; Mathai, Michael L; Hryciw, Deanne H; Hutchinson, Dana S; McAinch, Andrew J","year":2022,"journal":"International journal of molecular sciences, 23(19)","doi":"10.3390/ijms231911447","pmid":"36232744","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04112","title":"Perspectives of pediatric oncologists and palliative care physicians on the therapeutic use of cannabis in children with cancer.","authors":"Oberoi, Sapna; Protudjer, Jennifer L P; Rapoport, Adam; Rassekh, Shahrad R; Crooks, Bruce; Siden, Harold; Decker, Kathleen; Ananth, Prasanna; Chapman, Stacy; Balneaves, Lynda G; Vanan, Magimairajan Issai; Kelly, Lauren E","year":2022,"journal":"Cancer reports (Hoboken, N.J.), 5(9), e1551","doi":"10.1002/cnr2.1551","pmid":"34672127","tags":["medical-cannabis","cancer","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"85.7% of physicians saw potential for cannabis in nausea/vomiting management, 72.3% for chronic pain, 67.2% for appetite, and 42.9% for anxiety/depression. Only 0.3% recognized anticancer potential. 95.8% wanted more information on dosing, side effects, and safety.","whyItMatters":"Children with cancer are increasingly exposed to cannabis, but physician guidance has been limited by lack of evidence. Understanding what doctors think about cannabis helps identify research priorities and potential barriers to evidence-based use.","specificNumbers":"122/259 (47.1%) response rate. 62.2% had some cannabis training. 95.8% wanted more dosing/safety information. Support by indication: nausea/vomiting 85.7%, chronic pain 72.3%, cachexia/appetite 67.2%, anxiety/depression 42.9%, anticancer 0.3%. 91.5% said symptom-relief research is essential. 51.7% supported anticancer research.","methodology":"Cross-sectional online survey of all pediatric oncologists and palliative care physicians in Canada (June-August 2020). 122 of 259 (47.1%) completed the survey. Assessed education, knowledge, concerns, views on effectiveness, and research priorities.","limitations":"Response rate of 47.1% means non-responders may hold different views. Self-reported attitudes may not match clinical practice. The survey captured opinions, not clinical outcomes. Limited to the Canadian healthcare context."},{"rthcId":"RTHC-04113","title":"Comparative Evaluation of the Nutrients, Phytochemicals, and Antioxidant Activity of Two Hempseed Oils and Their Byproducts after Cold Pressing.","authors":"Occhiuto, Cristina; Aliberto, Gianluigi; Ingegneri, Mariarosaria; Trombetta, Domenico; Circosta, Clara; Smeriglio, Antonella","year":2022,"journal":"Molecules (Basel, Switzerland), 27(11)","doi":"10.3390/molecules27113431","pmid":"35684369","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04114","title":"Randomized controlled trials on the use of cannabis-based medicines in movement disorders: a systematic review.","authors":"Oikonomou, P; Jost, W H","year":2022,"journal":"Journal of neural transmission (Vienna, Austria : 1996), 129(10), 1247-1256","doi":"10.1007/s00702-022-02529-x","pmid":"35859051","tags":["medical-cannabis","cbd","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"In Parkinson's disease, no RCT showed motor symptom improvement, though nabilone improved quality of life and reduced dyskinesia in one trial. Both Tourette syndrome RCTs showed tic improvement. Only one of three Huntington's disease RCTs found symptom relief. Neither dystonia RCT showed benefit.","whyItMatters":"Movement disorders are often difficult to treat, and patients frequently ask about cannabis. This review provides an evidence-based summary of what RCTs actually show, which is considerably more nuanced than anecdotal reports suggest.","specificNumbers":"7 PD RCTs: none showed motor improvement, 1 showed nabilone improved quality of life, 1 showed nabilone reduced dyskinesia, 1 showed CBD reduced anxiety and tremor. 2 Tourette RCTs: both showed tic improvement. 3 HD RCTs: 1 showed nabilone symptom relief. 2 dystonia RCTs: no benefit.","methodology":"Systematic review of all published randomized controlled trials on cannabinoids in movement disorders. Identified 7 RCTs on Parkinson's disease, 2 on Tourette syndrome, 3 on Huntington's disease, and 2 on dystonia. Different cannabis formulations were used across studies.","limitations":"The total number of RCTs is small, and the trials themselves had small sample sizes. Different cannabinoid formulations were used across studies, making comparison difficult. Publication bias may favor positive results."},{"rthcId":"RTHC-04115","title":"Experiences, patient interactions and knowledge regarding the use of cannabis as a medicine in a cohort of New Zealand doctors in an oncology setting.","authors":"Oldfield, Karen; Eathorne, Allie; Tewhaiti-Smith, Jordan; Beasley, Richard; Semprini, Alex; Braithwaite, Irene","year":2022,"journal":"Postgraduate medical journal, 98(1155), 35-42","doi":"10.1136/postgradmedj-2020-139013","pmid":"33218966","tags":["medical-cannabis","cancer"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"84% of doctors reported patient requests to prescribe cannabis, and 98% knew of patients using illicit cannabis for symptoms. Pain, nausea/vomiting, and cancer treatment were the top reasons. 73% knew of at least one cannabis product, but 82% had prescribing concerns. All were willing to use products developed with traditional medical provenance.","whyItMatters":"New Zealand was in the process of developing its medicinal cannabis framework during this study. Understanding what oncology doctors experience and need helps shape effective regulations and education programs.","specificNumbers":"45/53 doctors surveyed (85% response rate). Patient cannabis requests: 84% (95% CI 70-93). Patients using illicit cannabis: 98% (95% CI 88-100). Knowledge of cannabis products: 73% (95% CI 58-85). Evidence knowledge: 60% (95% CI 44-74). Prescribing concerns: 82% (95% CI 67-92). Willing to use medical-provenance products: 100%.","methodology":"Cross-sectional survey of 45 doctors (85% response rate) across four New Zealand hospital oncology departments between November 2019 and January 2020. Included consultants, registrars, and house surgeons.","limitations":"Small convenience sample from four centers. The 45-doctor sample limits generalizability. Responses reflect a specific moment during New Zealand's evolving cannabis legislation. Self-reported data may not match actual practice."},{"rthcId":"RTHC-04116","title":"The gut microbiota in neurodegenerative diseases: revisiting possible therapeutic targets for cannabidiol.","authors":"Oliveira, Bruna Stefane Alves de; Milanezi, Debora Sandrini; Gonzaga, Priscila do Val; Detoni, Fernanda Rabello; Soriano, Renato Nery","year":2022,"journal":"Heliyon, 8(12), e12172","doi":"10.1016/j.heliyon.2022.e12172","pmid":"36544841","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04117","title":"The Use of Cannabis sativa L. for Pest Control: From the Ethnobotanical Knowledge to a Systematic Review of Experimental Studies.","authors":"Ona, Genís; Balant, Manica; Bouso, José Carlos; Gras, Airy; Vallès, Joan; Vitales, Daniel; Garnatje, Teresa","year":2022,"journal":"Cannabis and cannabinoid research, 7(4), 365-387","doi":"10.1089/can.2021.0095","pmid":"34612729","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04118","title":"The Endocannabinoid System and Alcohol Dependence: Will Cannabinoid Receptor 2 Agonism be More Fruitful than Cannabinoid Receptor 1 Antagonism?","authors":"Oppong-Damoah, Aboagyewaah; Gannon, Brenda Marie; Murnane, Kevin Sean","year":2022,"journal":"CNS & neurological disorders drug targets, 21(1), 3-13","doi":"10.2174/1871527320666210211115007","pmid":"33573565","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04119","title":"Comparison of the effects of alcohol and cannabis on visual function and driving performance. Does the visual impairment affect driving?","authors":"Ortiz-Peregrina, Sonia; Casares-López, Miriam; Ortiz, Carolina; Castro-Torres, José J; Martino, Francesco; Jiménez, José R","year":2022,"journal":"Drug and alcohol dependence, 237, 109538","doi":"10.1016/j.drugalcdep.2022.109538","pmid":"35717788","tags":["driving","cognition","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Both alcohol (300 ml and 450 ml wine) and cannabis significantly impaired visual function scores. However, only the higher alcohol dose (450 ml) significantly impaired driving simulator performance. Visual impairment was significantly associated with worse driving performance.","whyItMatters":"Understanding how alcohol and cannabis differently affect driving-relevant abilities helps inform impaired driving policies. The finding that cannabis impairs vision but not necessarily driving performance is nuanced and challenges simple comparisons.","specificNumbers":"64 young drivers tested. Visual impairment (OVS) was significant for all conditions: alcohol 300 ml (p=0.005), alcohol 450 ml (p<0.001), and cannabis (p=0.028). Driving performance was only significantly impaired at the higher alcohol dose. Visual impairment was significantly associated with worse driving.","methodology":"Sixty-four young drivers with alcohol and/or cannabis use history were split into alcohol (n=33) and cannabis (n=31) groups. The alcohol group had two sessions (300 ml and 450 ml red wine). The cannabis group smoked cannabis in one session. Visual function (contrast sensitivity, stereoacuity, intraocular straylight) and driving simulator performance were measured.","limitations":"The cannabis group had only one session while the alcohol group had two dose levels, making direct comparison uneven. Cannabis dose was not standardized (participants smoked their own cannabis). The driving simulator may not fully capture real-world driving complexity. Small sample sizes per group."},{"rthcId":"RTHC-04120","title":"Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor.","authors":"Ospanov, Meirambek; Sulochana, Suresh P; Paris, Jason J; Rimoldi, John M; Ashpole, Nicole; Walker, Larry; Ross, Samir A; Shilabin, Abbas G; Ibrahim, Mohamed A","year":2022,"journal":"Molecules (Basel, Switzerland), 27(2)","doi":"10.3390/molecules27020509","pmid":"35056824","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04121","title":"Measuring PM2.5 concentrations from secondhand tobacco vs. marijuana smoke in 9 rooms of a detached 2-story house.","authors":"Ott, Wayne R; Wallace, Lance A; Cheng, Kai-Chung; Hildemann, Lynn M","year":2022,"journal":"The Science of the total environment, 852, 158244","doi":"10.1016/j.scitotenv.2022.158244","pmid":"36037897","tags":["respiratory","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"A marijuana joint produced average 5-hour PM2.5 concentrations of 38.9-80.7 mcg/m3 across three experiments, compared to 15.0-15.2 mcg/m3 for a tobacco cigarette. Opening three windows reduced marijuana smoke PM2.5 by 67%, but levels still exceeded those from tobacco with windows closed.","whyItMatters":"As marijuana legalization spreads, understanding secondhand smoke exposure in homes is critical. The finding that marijuana produces substantially more fine particles than tobacco in the same home environment has direct implications for household members, including children.","specificNumbers":"Tobacco cigarette: 5-hour mean PM2.5 of 15.2 and 15.0 mcg/m3 (2 experiments). Marijuana joint: 38.9, 79.8, and 80.7 mcg/m3 (3 experiments). Ratio: 4.4x more PM2.5 from marijuana. Opening 3 windows by 12.7 cm reduced marijuana PM2.5 by 67%, but levels remained above tobacco levels with windows closed.","methodology":"Controlled experiments in a detached two-story, 4-bedroom home using research-grade calibrated PM2.5 monitors in all 9 rooms. Machine-smoked a Marlboro cigarette (2 experiments) or pre-rolled marijuana joints (3 experiments) in the living room. Measured 5-hour PM2.5 concentrations.","limitations":"Machine smoking may not perfectly replicate human smoking patterns. Only one brand of cigarette and pre-rolled joints were tested. The house had specific ventilation characteristics that may not represent all homes. Only PM2.5 was measured, not chemical composition."},{"rthcId":"RTHC-04122","title":"Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning.","authors":"Owens, Max M; Albaugh, Matthew D; Allgaier, Nicholas; Yuan, Dekang; Robert, Gabriel; Cupertino, Renata B; Spechler, Philip A; Juliano, Anthony; Hahn, Sage; Banaschewski, Tobias; Bokde, Arun L W; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Gowland, Penny; Heinz, Andreas; Brühl, Rüdiger; Martinot, Jean-Luc; Martinot, Marie-Laure Paillère; Artiges, Eric; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Lemaitre, Herve; Paus, Tomáš; Poustka, Luise; Millenet, Sabina; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Mackey, Scott; Schumann, Gunter; Garavan, Hugh","year":2022,"journal":"Translational psychiatry, 12(1), 188","doi":"10.1038/s41398-022-01956-4","pmid":"35523763","tags":["youth","cognition","neuroscience"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"All Bayesian causal network algorithms strongly suggested a directional relationship from adolescent cannabis use to accelerated cortical thinning in the prefrontal cortex, even after accounting for demographics, psychopathology, childhood adversity, and other substance use.","whyItMatters":"Most evidence linking cannabis to brain changes is correlational. This study applies specialized statistical methods designed to detect causal direction, and the results consistently point from cannabis use to brain thinning rather than the reverse. This strengthens the case that cannabis genuinely affects adolescent brain development.","specificNumbers":"637 adolescents who were cannabis-naive at age 14. All BCN algorithms pointed from cannabis use to cortical thinning. Analysis controlled for demographics, psychopathology, childhood adversity, and other substance use.","methodology":"Bayesian causal network modeling applied to 637 cannabis-naive adolescents from the IMAGEN study who were followed from age 14. The analysis incorporated cannabis use, prefrontal cortical thickness, demographics, psychopathology, childhood adversity, and other substance use to determine the most probable directional relationships.","limitations":"Bayesian causal modeling provides evidence for probable causal direction but does not constitute definitive proof of causation. The sample was primarily European adolescents. Other unmeasured confounders could still be driving the association."},{"rthcId":"RTHC-04123","title":"Cannabinoids: Therapeutic Use in Clinical Practice.","authors":"Pagano, Cristina; Navarra, Giovanna; Coppola, Laura; Avilia, Giorgio; Bifulco, Maurizio; Laezza, Chiara","year":2022,"journal":"International journal of molecular sciences, 23(6)","doi":"10.3390/ijms23063344","pmid":"35328765","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04124","title":"Prevalence of marijuana use in pregnant women with concurrent opioid use disorder or alcohol use in pregnancy.","authors":"Page, Kimberly; Murray-Krezan, Cristina; Leeman, Lawrence; Carmody, Mary; Stephen, Julia M; Bakhireva, Ludmila N","year":2022,"journal":"Addiction science & clinical practice, 17(1), 3","doi":"10.1186/s13722-021-00285-z","pmid":"34991713","tags":["pregnancy","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Marijuana prevalence was 43.2% in the OUD group, 52.6% in the combined OUD+Alcohol group, and 46.4% in the Alcohol group. Weekly or daily use ranged from 19-25%. Women on buprenorphine had higher marijuana use than those on methadone. Younger age and polysubstance use were independent predictors.","whyItMatters":"Prenatal substance exposure research typically focuses on single substances, but these data show marijuana co-use is extremely common among pregnant women already dealing with opioid or alcohol problems. This means fetal exposure is often multi-substance, complicating risk assessment.","specificNumbers":"Marijuana prevalence: OUD 43.2%, OUD+Alcohol 52.6%, Alcohol 46.4%. Weekly/daily use: 19.4%, 21.0%, 24.6% respectively. Buprenorphine patients had higher use than methadone patients (45.8% vs 37.5% in OUD; 58.3% vs 42.9% in OUD+Alcohol). Age: aOR 0.61 per 5-year increment. Polysubstance use: aOR 2.02.","methodology":"Prospective cohort study (ENRICH-1) of 251 pregnant women classified into OUD (n=125), Alcohol (n=69), and OUD+Alcohol (n=57) groups. Substance use was assessed by self-report and biomarkers. Multivariable logistic regression identified correlates of marijuana use.","limitations":"The sample was recruited from specific clinical settings and may not represent all pregnant women with substance use issues. Self-report of marijuana use may underestimate true prevalence. The study was not designed to assess fetal outcomes from marijuana co-exposure."},{"rthcId":"RTHC-04125","title":"Insomnia treatment: a new multitasking natural compound based on melatonin and cannabis extracts.","authors":"Palmieri, G; Vadalà, M; Corazzari, V; Palmieri, B","year":2022,"journal":"La Clinica terapeutica, 173(1), 91-96","doi":"10.7417/CT.2022.2399","pmid":"35147654","tags":["cbd","sleep","anxiety","pain"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"PSQI (sleep quality) and HAM-A (anxiety) scores showed significant improvements. Mood alterations including anxiety, panic, paranoia, and depression were significantly reduced (p<0.03). Pain perception was significantly reduced (p<0.02). Patients reported good general health perceptions.","whyItMatters":"Sleep disorders are extremely common, and many patients seek natural alternatives to prescription sleep medications. If a low-dose CBD-melatonin combination can improve sleep with fewer side effects, it could offer an accessible option.","specificNumbers":"20 patients, ages 43-96. Dose: 2.5 mg CBD + 1.5 mg melatonin, 20 sublingual drops. Duration: 3 months. Mood improvements: p<0.03. Pain improvements: p<0.02.","methodology":"Open-label observational study of 20 patients (ages 43-96) with sleep disorders who took 20 sublingual drops of a CBD-melatonin compound nightly for 3 months. Assessed monthly via direct contact. Used PSQI for sleep and HAM-A for anxiety.","limitations":"Very small sample (20 patients), open-label design with no placebo control, and described by the authors as \"anecdotal\" and \"compassionate use.\" The observed improvements could be due to placebo effect, natural improvement, or melatonin alone. No way to separate the effects of CBD from melatonin."},{"rthcId":"RTHC-04126","title":"Partitioning of phytocannabinoids between faeces and water - Implications for wastewater-based epidemiology.","authors":"Pandopulos, Aaron J; Simpson, Bradley S; White, Jason M; Bade, Richard; Gerber, Cobus","year":2022,"journal":"The Science of the total environment, 805, 150269","doi":"10.1016/j.scitotenv.2021.150269","pmid":"34536871","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04127","title":"Cannabis and the heart: unchartered territory.","authors":"Parikh, Kinna; Patel, Meet; Bansal, Toram; Raco, Joseph; Gupta, Sachin; Jain, Rahul; Jain, Rohit","year":2022,"journal":"Future cardiology, 18(11), 883-890","doi":"10.2217/fca-2022-0018","pmid":"36098056","tags":["cardiovascular","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Cannabis has been linked to acute myocardial infarction in young, otherwise healthy individuals; atherogenesis acceleration; cardiac arrhythmias; Takotsubo (stress) cardiomyopathy; and cannabis arteritis. The only definitive treatment for these conditions is complete abstinence.","whyItMatters":"Cannabis is often perceived as cardiovascularly benign, especially compared to tobacco. This review highlights that THC can cause serious and potentially life-threatening cardiovascular events, particularly in young users who might not otherwise be at cardiac risk.","specificNumbers":"The review described specific cardiovascular conditions: acute MI, atherogenesis, arrhythmia, Takotsubo cardiomyopathy, and cannabis arteritis. Complete abstinence was identified as the definitive treatment across conditions.","methodology":"Narrative review examining the long-term cardiovascular effects of THC, covering pathophysiology, clinical features, and management of cannabis-related cardiovascular conditions.","limitations":"Narrative review format means no systematic search or quality assessment. Many of the cardiovascular associations come from case reports and case series rather than large epidemiological studies. The relative risk compared to non-users is not well quantified."},{"rthcId":"RTHC-04128","title":"Cannabidiol Regulates PPARγ-Dependent Vesicle Formation as well as Cell Death in A549 Human Lung Cancer Cells.","authors":"Park, Yoon-Jong; Na, Han-Heom; Kwon, In-Seo; Hwang, Yu-Na; Park, Hye-Jin; Kwon, Tae-Hyung; Park, Jin-Sung; Kim, Keun-Cheol","year":2022,"journal":"Pharmaceuticals (Basel, Switzerland), 15(7)","doi":"10.3390/ph15070836","pmid":"35890134","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04129","title":"Recreational Marijuana Legalization and Co-use With Alcohol Among Adolescents.","authors":"Paschall, Mallie J; García-Ramírez, Grisel; Grube, Joel W","year":2022,"journal":"American journal of preventive medicine, 62(1), 57-64","doi":"10.1016/j.amepre.2021.06.003","pmid":"34426059","tags":["youth","legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Recreational legalization was associated with greater odds of co-use overall (OR=1.06) and much greater odds among past-month drinkers (OR=1.58) and heavy drinkers (OR=1.25). Paradoxically, among past-month marijuana users, co-use odds decreased (OR=0.76). Among co-users, marijuana use frequency increased.","whyItMatters":"This is one of the largest studies examining whether marijuana legalization affects youth substance use patterns. The finding that alcohol-using youth are the most likely to add marijuana co-use has important implications for substance prevention programs.","specificNumbers":"3,319,329 students. Overall co-use: OR=1.06 (95% CI 1.05-1.07). Among past-month drinkers: OR=1.58 (95% CI 1.52-1.62). Among heavy drinkers: OR=1.25 (95% CI 1.21-1.29). Among past-month marijuana users: OR=0.76 (95% CI 0.74-0.78). Among co-users, marijuana frequency increased (β=0.36).","methodology":"Repeated cross-sectional data from 3,319,329 California 7th, 9th, and 11th graders participating in the California Healthy Kids Survey from 2010-2011 to 2018-2019. Multilevel regression analyzed changes before and after 2016 recreational legalization, controlling for demographics, survey year, and urbanicity.","limitations":"Cross-sectional design means individual students were not tracked over time. The study cannot definitively attribute changes to legalization versus other trends. Self-reported substance use may be affected by changing social desirability around marijuana. The overall 6% increase is small in absolute terms."},{"rthcId":"RTHC-04130","title":"Associations between cognition and polygenic liability to substance involvement in middle childhood: Results from the ABCD study.","authors":"Paul, Sarah E; Hatoum, Alexander S; Barch, Deanna M; Thompson, Wesley K; Agrawal, Arpana; Bogdan, Ryan; Johnson, Emma C","year":2022,"journal":"Drug and alcohol dependence, 232, 109277","doi":"10.1016/j.drugalcdep.2022.109277","pmid":"35033950","tags":["genetics","cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Polygenic risk for lifetime cannabis use was positively associated with all three cognitive facets: general ability, executive function, and learning/memory (Bs ≥ 0.045, qs ≤ 0.044). No other substance polygenic risk scores (alcohol, tobacco, problematic cannabis use) showed significant cognitive associations.","whyItMatters":"This finding is counterintuitive: genes associated with trying cannabis are also associated with better cognition in children who have never used any substances. This suggests the genetic overlap reflects shared traits like curiosity or openness to experience rather than cannabis itself improving cognition.","specificNumbers":"3,205 substance-naive children, ages 9-10. Cannabis use polygenic risk associated with: general ability (B≥0.045, q≤0.044), executive function, and learning/memory. Polygenic risk for cannabis use disorder showed no cognitive association. No significant associations for alcohol or tobacco polygenic scores.","methodology":"Cross-sectional analysis of 3,205 substance-naive European-ancestry children from the ABCD Study baseline session. Polygenic risk scores for lifetime use and problematic use of alcohol, tobacco, and cannabis were estimated from genome-wide association studies. Cognitive abilities were measured using confirmatory factor analysis of ABCD neurocognitive battery data.","limitations":"Only European-ancestry children were included, limiting generalizability. Cross-sectional design at one age point. Polygenic scores explain only a small fraction of variance. The findings reflect genetic associations, not the effects of cannabis use itself."},{"rthcId":"RTHC-04131","title":"Cannabinoids for behavioral symptoms in severe dementia: Safety and feasibility in a long-term pilot observational study in nineteen patients.","authors":"Pautex, Sophie; Bianchi, Federica; Daali, Youssef; Augsburger, Marc; de Saussure, Christian; Wampfler, James; Curtin, François; Desmeules, Jules; Broers, Barbara","year":2022,"journal":"Frontiers in aging neuroscience, 14, 957665","doi":"10.3389/fnagi.2022.957665","pmid":"36247984","tags":["medical-cannabis","seniors","cognition","drug-interactions"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Managing behavioral symptoms in severe dementia — agitation, aggression, wandering, sleep disruption — is one of the hardest challenges in elder care. Antipsychotic medications are commonly used but carry serious risks including increased mortality in this population. This pilot study asked whether medical cannabis could offer a safer alternative.\n\nNineteen patients (average age 81, mostly women) with severe dementia in a Swiss long-term care facility received THC/CBD treatment as an add-on to their existing medications over two years. These were heavily medicated patients, averaging 12.4 mg of THC equivalent per day on top of their other prescriptions.\n\nThe key finding is safety: over two years of continuous use, no serious adverse events were attributed to the cannabis treatment. This is significant because these patients were elderly, frail, on multiple medications, and had the kind of comorbidities that make drug interactions a real concern. Blood tests monitoring cannabinoid levels and liver enzymes showed that the treatment was pharmacokinetically manageable even in this vulnerable population.\n\nClinically, the researchers observed improvements in agitation, behavioral disturbances, and rigidity scores, though without a control group, it's impossible to know how much of this improvement was due to the cannabis treatment versus natural fluctuation or placebo effects.","whyItMatters":"Behavioral symptoms in dementia affect up to 90% of patients and are a primary reason for institutionalization and caregiver burnout. Current pharmacological options (mainly antipsychotics) carry FDA black box warnings for increased mortality in elderly dementia patients. If cannabinoids can safely reduce behavioral symptoms, they could offer a better risk-benefit profile — but this needs to be proven in controlled trials. This pilot provides the safety data needed to justify those larger studies.","specificNumbers":"19 patients (17 women, 2 men), average age 81.4 years. Average THC dose: 12.4 mg/day. Follow-up: 2 years. No serious adverse events attributed to cannabis treatment. The study measured plasma cannabinoid levels and CYP450 enzyme activity to monitor for drug interactions in this polymedicated population.","methodology":"Prospective observational study following 19 patients with severe dementia in a Swiss long-term care home. Patients received physician-prescribed THC/CBD treatment as an add-on to existing medications. Data collected over two years included cannabis dosages, safety parameters, neuropsychiatric inventory scores, agitation ratings, rigidity assessments, and pharmacokinetic measurements (plasma cannabinoid levels and enzyme activity).","limitations":"No control group — the biggest limitation. Without randomization and placebo comparison, improvements could reflect natural symptom fluctuation, placebo effects, or increased caregiver attention. Very small sample (19 patients) from a single facility. The patient population was predominantly female (17/19), limiting generalizability. Two-year retention data may reflect survivorship bias in this elderly, severely ill population."},{"rthcId":"RTHC-04132","title":"Longer-Term Efficacy of a Digital Life-Skills Training for Substance Use Prevention.","authors":"Paz Castro, Raquel; Haug, Severin; Wenger, Andreas; Schaub, Michael P","year":2022,"journal":"American journal of preventive medicine, 63(6), 944-953","doi":"10.1016/j.amepre.2022.06.017","pmid":"35985899","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"At 18 months, the intervention group had significantly lower cannabis prevalence (OR=0.55, 95% CI 0.39-0.76) and tobacco prevalence (OR=0.67, 95% CI 0.47-0.96) compared to controls. Cannabis use days were also reduced (Cohen's d=-0.19). No effects were seen for problem drinking, alcohol quantity, or social skills.","whyItMatters":"Digital prevention programs that work are rare. This study shows a fully automated, text-message-based program can produce lasting reductions in cannabis and tobacco use, which is significant because such programs can be scaled at minimal cost.","specificNumbers":"1,473 students, 89 school classes. 83.6% follow-up at 18 months. Cannabis prevalence: OR=0.55 (95% CI 0.39-0.76). Cannabis days: d=-0.19 (95% CI -0.29, -0.09). Tobacco: OR=0.67 (95% CI 0.47-0.96). No significant effects for problem drinking (OR=0.84), alcohol quantity, cigarette quantity, well-being, or social skills.","methodology":"Two-arm cluster RCT with 1,473 students (mean age 15.4) across 89 Swiss school classes. The intervention consisted of 22 weeks of automated online feedback and individually tailored text messages based on social cognitive theory, addressing self-management, social skills, and substance resistance. Follow-up at 6 and 18 months.","limitations":"Conducted in Swiss secondary schools, so cultural context may affect generalizability. Self-reported outcomes. The intervention period (22 weeks) is substantial, and engagement may have varied. Effect sizes for cannabis use days were small (d=-0.19)."},{"rthcId":"RTHC-04133","title":"Cannabidiol for the treatment of autism spectrum disorder: hope or hype?","authors":"Pedrazzi, João F C; Ferreira, Frederico R; Silva-Amaral, Danyelle; Lima, Daniel A; Hallak, Jaime E C; Zuardi, Antônio W; Del-Bel, Elaine A; Guimarães, Francisco S; Costa, Karla C M; Campos, Alline C; Crippa, Ana C S; Crippa, José A S","year":2022,"journal":"Psychopharmacology, 239(9), 2713-2734","doi":"10.1007/s00213-022-06196-4","pmid":"35904579","tags":["cbd","medical-cannabis","youth","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Preclinical data show CBD modulates the endocannabinoid system, which appears altered in ASD patients. CBD has relevant pharmacological actions for ASD-related symptoms including anxiety, epilepsy, sleep disorders, and social behavior. Early clinical data are promising but limited.","whyItMatters":"ASD treatment options are limited (only risperidone and aripiprazole are FDA-approved, mainly for behavioral symptoms). Many ASD families are already using CBD products. This review provides a measured assessment of what the science actually shows.","specificNumbers":"Only two FDA-approved drugs for ASD behavioral symptoms (risperidone, aripiprazole), both with high side-effect potential. The review covered CBD effects on multiple ASD comorbidities: ADHD, anxiety, depression, sleep disorders, and epilepsy.","methodology":"Narrative review of preclinical and clinical data on CBD for ASD symptoms and comorbidities. Examined CBD's pharmacological mechanisms relevant to ASD, including effects on the endocannabinoid system, social behavior, anxiety, and epilepsy.","limitations":"Narrative review format. Most evidence comes from preclinical models that imperfectly mirror human ASD. Clinical data are sparse and largely from uncontrolled studies. ASD is highly heterogeneous, making it unlikely that any single treatment will work for all presentations."},{"rthcId":"RTHC-04134","title":"A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD).","authors":"Peng, Jiangling; Fan, Mingjie; An, Chelsea; Ni, Feng; Huang, Wendong; Luo, Jiankang","year":2022,"journal":"Basic & clinical pharmacology & toxicology, 130(4), 439-456","doi":"10.1111/bcpt.13710","pmid":"35083862","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04135","title":"Potency and Therapeutic THC and CBD Ratios: U.S. Cannabis Markets Overshoot.","authors":"Pennypacker, Sarah D; Cunnane, Katharine; Cash, Mary Catherine; Romero-Sandoval, E Alfonso","year":2022,"journal":"Frontiers in pharmacology, 13, 921493","doi":"10.3389/fphar.2022.921493","pmid":"35734402","tags":["potency","cbd","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The ratio of THC to CBD in cannabis products matters enormously for therapeutic outcomes. CBD can modulate THC's effects — at certain ratios it can mitigate THC's psychoactive impact, while at other ratios it may actually enhance it. This study analyzed the actual THC:CBD ratios available in U.S. dispensaries and found that the market has dramatically overshot therapeutic targets.\n\nThe researchers categorized products into four clinically meaningful ratio groups based on published pharmacological research: ratios where CBD enhances THC effects (≥1:1 THC:CBD), where CBD has no significant effect (~1:2), where CBD may mitigate THC effects (1:2 to higher CBD), and CBD-dominant products. They then analyzed real dispensary product listings from nine U.S. states.\n\nThe result is striking: the vast majority of products in both medical and recreational programs cluster in the high-THC range where CBD either enhances or fails to counteract THC's intoxicating effects. Medical products were statistically indistinguishable from recreational ones in their THC:CBD profiles. This means patients seeking therapeutic cannabis are largely choosing from the same high-potency, intoxication-producing products available to recreational users.\n\nStates with combined medical-recreational programs showed slightly different ratio distributions than medical-only states, but the overall pattern of THC dominance held across all markets.","whyItMatters":"If the point of medical cannabis is therapeutic benefit with minimal intoxication, the market is failing. Patients looking for relief — whether for pain, anxiety, or sleep — are largely limited to products that will get them significantly high, because the THC:CBD ratios on dispensary shelves far exceed what research suggests is therapeutically optimal. This disconnect between science and market is a structural problem in legal cannabis.","specificNumbers":"Data collected from nine U.S. states. Products were classified into four THC:CBD ratio categories. Medical cannabis product THC:CBD profiles were statistically similar to recreational products across markets. The majority of products in all categories fell into the highest-THC ratio group (≥1:1 THC:CBD, where CBD enhances rather than mitigates THC effects).","methodology":"Observational analysis of online herbal dispensary product offerings from nine U.S. states. Products were categorized into four clinically significant THC:CBD ratio categories derived from pharmacological literature. Comparisons were made between medical and recreational programs, and between states with different market policies.","limitations":"Data comes from online product listings, which may not perfectly reflect what's actually purchased or recommended by dispensary staff. Products were categorized by labeled potency, which can differ from actual tested content. The four-category ratio framework is based on published pharmacology but simplified — individual responses to THC:CBD ratios vary. The study captures a snapshot; market composition changes as new products enter."},{"rthcId":"RTHC-04136","title":"Pattern of predictive features of continued cannabis use in patients with recent-onset psychosis and clinical high-risk for psychosis.","authors":"Penzel, Nora; Sanfelici, Rachele; Antonucci, Linda A; Betz, Linda T; Dwyer, Dominic; Ruef, Anne; Cho, Kang Ik K; Cumming, Paul; Pogarell, Oliver; Howes, Oliver; Falkai, Peter; Upthegrove, Rachel; Borgwardt, Stefan; Brambilla, Paolo; Lencer, Rebekka; Meisenzahl, Eva; Schultze-Lutter, Frauke; Rosen, Marlene; Lichtenstein, Theresa; Kambeitz-Ilankovic, Lana; Ruhrmann, Stephan; Salokangas, Raimo K R; Pantelis, Christos; Wood, Stephen J; Quednow, Boris B; Pergola, Giulio; Bertolino, Alessandro; Koutsouleris, Nikolaos; Kambeitz, Joseph","year":2022,"journal":"Schizophrenia (Heidelberg, Germany), 8(1), 19","doi":"10.1038/s41537-022-00218-y","pmid":"35264631","tags":["psychosis","addiction","cognition"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Clinical interview data alone predicted continued cannabis use with 73% accuracy in 109 recent-onset psychosis patients. The model generalized to 73 clinical high-risk patients. Lower functioning, specific substance use patterns, urbanicity, and lack of alternative coping strategies were the strongest predictors.","whyItMatters":"Continued cannabis use worsens outcomes in psychosis. If clinicians can identify which patients are most likely to keep using, they can target interventions more effectively. This study shows that standard clinical assessments may be sufficient for this prediction.","specificNumbers":"109 ROP patients, 73 CHR patients. Clinical assessment accuracy: 73% (p<0.05). Cognitive and MRI data did not significantly improve prediction (ps>0.065). Key predictors: lower functioning, substance use patterns, urbanicity, lack of alternative coping strategies.","methodology":"Prospective study of 109 recent-onset psychosis (ROP) patients who reported lifetime cannabis use at baseline. Machine learning models tested whether clinical assessments, cognitive tests, and brain MRI could predict cannabis use between baseline and 9-month follow-up. The model was validated in 73 clinical high-risk patients.","limitations":"Moderate sample size (109 ROP, 73 CHR). \"Continued use\" was defined as any cannabis use in 9 months, not frequency or quantity. The model needs testing in larger, more diverse populations before clinical implementation."},{"rthcId":"RTHC-04137","title":"Do alcohol and cannabis substitute or complement each other? Analysis from behavioral economics for formulating public policy on substance use in Colombia.","authors":"Pereira-Morales, Angela J; Eslava-Schmalbach, Javier Hernando","year":2022,"journal":"Translational behavioral medicine, 12(6), 734-741","doi":"10.1093/tbm/ibac038","pmid":"35608992","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04138","title":"Endocannabinoid system and cannabis hyperemesis syndrome: a narrative update.","authors":"Perisetti, Abhilash; Goyal, Hemant","year":2022,"journal":"European journal of gastroenterology & hepatology, 34(1), 1-8","doi":"10.1097/MEG.0000000000001992","pmid":"33208685","tags":["harm-reduction","medical-cannabis","neuroscience"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system produces biphasic effects: acute cannabis use is antiemetic, but chronic heavy use can trigger a proemetic response leading to CHS. The review outlined key differences between CHS and cyclic vomiting syndrome and described the pathophysiology involving desensitization of CB1 receptors in the gut.","whyItMatters":"CHS is frequently misdiagnosed because it shares symptoms with many gastrointestinal conditions. Understanding the biphasic mechanism explains the counterintuitive finding that an antiemetic substance can cause severe vomiting, helping clinicians recognize and properly diagnose CHS.","specificNumbers":"Cannabis has over 400 chemicals and more than 100 identified cannabinoids. CHS incidence is expected to rise with increasing cannabis access. The review described three CHS phases: prodromal, hyperemetic, and recovery.","methodology":"Narrative review synthesizing evidence on the endocannabinoid system's role in CHS pathophysiology, clinical features, diagnosis, treatment, and differentiation from similar conditions, particularly cyclic vomiting syndrome.","limitations":"Narrative review format without systematic search methodology. CHS pathophysiology is still not completely understood. The review relied on case reports and small studies given the limited controlled research on CHS."},{"rthcId":"RTHC-04139","title":"Changes in mental health, wellbeing and personality following ayahuasca consumption: Results of a naturalistic longitudinal study.","authors":"Perkins, Daniel; Pagni, Broc A; Sarris, Jerome; Barbosa, Paulo C R; Chenhall, Richard","year":2022,"journal":"Frontiers in pharmacology, 13, 884703","doi":"10.3389/fphar.2022.884703","pmid":"36386199","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04140","title":"Safety, Pharmacokinetics and Pharmacodynamics of Spectrum Yellow Oil in Healthy Participants.","authors":"Peters, Erica N; Mosesova, Irina; MacNair, Laura; Vandrey, Ryan; Land, M Hunter; Ware, Mark A; Turcotte, Cynthia; Bonn-Miller, Marcel O","year":2022,"journal":"Journal of analytical toxicology, 46(4), 393-407","doi":"10.1093/jat/bkab026","pmid":"33710277","tags":["cbd","medical-cannabis","drug-interactions"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CBD showed dose-proportional absorption (AUC slope=1.03, Cmax slope=0.92). Steady-state was reached by Day 7. Nearly all adverse events (44/45) were mild or moderate; none serious. The highest adverse event rates (67%) occurred in the two higher-dose groups. Most THC concentrations were below detection limits.","whyItMatters":"Proper dosing information for cannabis products is severely lacking. This is one of the first rigorous Phase 1 pharmacokinetic studies of a standardized cannabis oil, providing the kind of data physicians need to make informed dosing decisions.","specificNumbers":"43 participants. Doses: 120-480 mg CBD daily (with 5.4-21.6 mg THC). Adverse events: 44/45 mild-moderate, 0 serious. Highest AE rate: 67% in top two dose groups. Most AEs on first treatment day (17/45). CBD AUC slope: 1.03 (dose-proportional). Recommended starting dose: no higher than 240 mg CBD/10.8 mg THC daily.","methodology":"Phase 1, multiple-dose, randomized, placebo-controlled study. 43 healthy participants received one of four CBD doses (120-480 mg/day with corresponding THC 5.4-21.6 mg/day) or placebo, administered every 12 hours for 7 consecutive days.","limitations":"Conducted in healthy participants, so results may differ in patient populations. Seven-day duration is short relative to typical medical cannabis use. The product contained both CBD and THC, so effects cannot be attributed to CBD alone."},{"rthcId":"RTHC-04141","title":"Pharmacokinetics of cannabichromene in a medical cannabis product also containing cannabidiol and Δ9-tetrahydrocannabinol: a pilot study.","authors":"Peters, Erica N; MacNair, Laura; Mosesova, Irina; Christians, Uwe; Sempio, Cristina; Klawitter, Jost; Land, M Hunter; Ware, Mark A; Turcotte, Cynthia; Bonn-Miller, Marcel O","year":2022,"journal":"European journal of clinical pharmacology, 78(2), 259-265","doi":"10.1007/s00228-021-03232-8","pmid":"34664109","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04142","title":"Safety, Pharmacokinetics and Pharmacodynamics of Spectrum Red Softgels in Healthy Participants.","authors":"Peters, Erica N; Mosesova, Irina; MacNair, Laura; Vandrey, Ryan; Land, M Hunter; Ware, Mark A; Turcotte, Cynthia; Bonn-Miller, Marcel O","year":2022,"journal":"Journal of analytical toxicology, 46(5), 528-539","doi":"10.1093/jat/bkab035","pmid":"33848338","tags":["medical-cannabis","tolerance","drug-interactions"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"All 65 adverse events were mild-to-moderate; none were serious. Most adverse events (30/65) occurred on the first treatment day, suggesting tolerance develops quickly. At the highest dose (20 mg THC daily), participants reported feeling \"any effect\" and \"dazed\" compared to placebo. The recommended starting dose was 10 mg THC daily.","whyItMatters":"Like its companion CBD study, this provides pharmaceutical-grade dosing data for THC. The finding that most side effects occur on Day 1 and then improve supports the clinical practice of starting low and titrating slowly.","specificNumbers":"41 participants. Doses: 5-20 mg THC daily. All 65 AEs mild-moderate. Most common: somnolence (8), lethargy (7), headache (5). 30/65 AEs on first day. Subjective effects (\"feel any effect,\" \"dazed\") significantly different from placebo only at 20 mg. Recommended start: ≤10 mg THC daily.","methodology":"Phase 1, multiple-dose, randomized, placebo-controlled study. 41 healthy participants received one of four THC doses (5-20 mg/day with minimal CBD) or placebo, administered every 12 hours with food for 7 days. Safety, plasma drug levels, and self-reported subjective effects were measured.","limitations":"Healthy participants only, short 7-day duration. The THC doses tested (5-20 mg) represent the lower end of what some medical cannabis patients use. CBD content was minimal (<0.25 mg/day), so this reflects a THC-dominant profile only."},{"rthcId":"RTHC-04143","title":"Cannabis exposure during adolescence: A uniquely sensitive period for neurobiological effects.","authors":"Peters, K Z; Zlebnik, N E; Cheer, J F","year":2022,"journal":"International review of neurobiology, 161, 95-120","doi":"10.1016/bs.irn.2021.07.002","pmid":"34801175","tags":["youth","neuroscience","dopamine","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system changes during adolescence affect how it modulates developing dopamine circuits. CB1 receptors regulate dopamine release, and adolescent THC exposure can alter excitatory/inhibitory balance during this critical developmental period, potentially creating vulnerabilities to psychosis, schizophrenia, and addiction in adulthood.","whyItMatters":"With rising cannabis potency and adolescent use, understanding why the teen brain is specifically vulnerable matters for prevention messaging and policy. The endocannabinoid-dopamine interaction explains the biological basis for the well-documented association between adolescent cannabis use and later psychosis.","specificNumbers":"The review covered endocannabinoid system changes across adolescence, CB1 receptor-dopamine interactions, and higher THC concentrations in modern cannabis products as a contributing factor to increased risk.","methodology":"Narrative review covering endocannabinoid system development across the lifespan, CB1 receptor modulation of dopamine release, and neurobiological and behavioral effects of adolescent THC exposure, drawing on both animal and human studies.","limitations":"Narrative review, not systematic. Much of the evidence comes from animal models. The exact translation from animal THC exposure to human cannabis use patterns is uncertain. Individual variation in vulnerability is not well addressed."},{"rthcId":"RTHC-04144","title":"Young adults with psychosis: Intentions for cannabis reduction and cessation based on theory of planned behavior.","authors":"Petros, Ryan; Walker, Denise D; Davis, Adam; Monroe-DeVita, Maria","year":2022,"journal":"Psychiatric rehabilitation journal, 45(4), 352-361","doi":"10.1037/prj0000542","pmid":"36201809","tags":["psychosis","quitting","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Participants recognized that cannabis use conflicted with their life goals but maintained use because they perceived it as facilitating social interactions, enjoyable activities, and improved mental health. The primary barrier to quitting was having no replacement strategies to compensate for these perceived benefits.","whyItMatters":"No evidence-based treatment effectively addresses cannabis use disorder in first-episode psychosis. Understanding why patients keep using, despite knowing the risks, points to specific intervention targets: teaching alternative social skills, activity planning, and mood management.","specificNumbers":"16 young adults, mean age 23.7. Average cannabis use: 11.8 days in past 30. Study used 3 focus groups and 3 individual interviews. Participants identified social facilitation, enjoyable activities, and mood improvement as primary reasons for continued use.","methodology":"Three online focus groups and 3 individual interviews with 16 young adults with first-episode psychosis (mean age 23.7) who had used cannabis an average of 11.8 days in the past month. Data analyzed using theory of planned behavior framework with content and thematic analysis.","limitations":"Small qualitative sample of 16 participants from a specific clinical context. Self-reported perceptions of cannabis benefits may not reflect actual effects. The theory of planned behavior framework may not capture all relevant factors."},{"rthcId":"RTHC-04145","title":"The Anti-Inflammatory Effects of Cannabidiol (CBD) on Acne.","authors":"Peyravian, Nadia; Deo, Sapna; Daunert, Sylvia; Jimenez, Joaquin J","year":2022,"journal":"Journal of inflammation research, 15, 2795-2801","doi":"10.2147/JIR.S355489","pmid":"35535052","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04146","title":"A Nationwide Study of Inpatient Case Rate Incidence of Cannabis-Related Diagnoses in Switzerland.","authors":"Pfeifer, Philippe; Auer, Reto; Baggio, Stéphanie; Moggi, Franz","year":2022,"journal":"International journal of public health, 67, 1605554","doi":"10.3389/ijph.2022.1605554","pmid":"36618434","tags":["mental-health","legalization","psychosis","youth"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-related psychiatric hospitalization rates increased significantly from 1998 to 2020. These diagnoses were disproportionately represented in the 15-24 and 25-44 age groups compared to other psychiatric diagnoses. The trend was compared against alcohol-related and psychotic disorder hospitalizations.","whyItMatters":"Population-level hospitalization trends provide hard data on the public health impact of cannabis. The concentration in younger age groups aligns with neurobiological evidence about adolescent vulnerability and has direct implications for Swiss cannabis policy reform.","specificNumbers":"Data covered all psychiatric inpatients in Switzerland from 1998-2020. Cannabis-related diagnoses were significantly overrepresented in ages 15-24 and 25-44. The study documented a \"sharp increase\" in cannabis-related hospitalizations over the observation period.","methodology":"Nationwide analysis using Swiss Federal Statistics Office data covering all psychiatric inpatient cases in Switzerland from 1998 to 2020. Trend analyses compared cannabis-related diagnoses to alcohol-related and psychotic disorder hospitalization rates by age group, gender, and region.","limitations":"Hospitalization data may not capture the full picture, as many cannabis-related psychiatric issues are managed outpatient. Changes in diagnostic coding practices or clinician awareness could contribute to trend increases. Causation cannot be established from trend data alone."},{"rthcId":"RTHC-04147","title":"Survival rate of patients with combined hepatocellular cholangiocarcinoma receiving medical cannabis treatment: A retrospective, cohort comparative study.","authors":"Phansila, Narisara; Pansila, Paopong; Wongkongdech, Adisorn; Turnbull, Niruwan; Azam, Mahalul; Wongkongdech, Ranee","year":2022,"journal":"F1000Research, 11, 1212","doi":"10.12688/f1000research.123250.3","pmid":"41113085","tags":["medical-cannabis","cancer","pain"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cholangiocarcinoma (bile duct cancer) is devastating in Northeast Thailand, where incidence is among the highest in the world due to endemic liver fluke infections. Most patients are diagnosed at advanced stages with poor prognoses and very short survival times.\n\nThis retrospective study compared 491 newly diagnosed advanced cholangiocarcinoma patients across six hospitals: 404 received standard palliative pain management and 87 received medicinal cannabis treatment (Thailand was the first Southeast Asian country to legalize medical cannabis). The results were dramatic.\n\nMedian survival for the standard treatment group was 0.83 months (about 25 days). For the cannabis treatment group, median survival was 5.66 months — nearly seven times longer. The mortality rate was 48.35 per 100 person-months in the standard group versus 10.9 per 100 person-months in the cannabis group.\n\nThese numbers are eye-catching, but they demand careful interpretation. This was a retrospective study, not a randomized trial. Patients who received cannabis treatment may have been systematically different from those who didn't — perhaps healthier at baseline, more engaged with their care, or diagnosed earlier despite being classified as 'advanced.' Selection bias is a major concern. The survival difference is also far larger than what's been seen in any cannabis-cancer study, which raises questions about confounding factors rather than confirming a direct cannabis anti-tumor effect.","whyItMatters":"Cancer survival claims for cannabis are among the most emotionally charged topics in cannabis research. This study shows a real survival difference in real patients, but the retrospective design means we can't conclude cannabis caused the difference. What this study does well is document that medical cannabis can be integrated into palliative cancer care in a Southeast Asian healthcare setting, and that the survival difference is large enough to justify the randomized controlled trials needed to establish causation.","specificNumbers":"491 patients total: 404 standard care, 87 cannabis treatment. Standard care median survival: 0.83 months (95% CI: 0.71–0.95). Cannabis group median survival: 5.66 months. Standard care mortality rate: 48.35/100 person-months. Cannabis group mortality rate: 10.9/100 person-months. Total follow-up: 790 person-months (standard) and 476 person-months (cannabis).","methodology":"Retrospective cohort study comparing survival among 491 newly diagnosed advanced cholangiocarcinoma patients from six hospitals in Northeast Thailand (September 2019–June 2021). The cannabis group (87 patients) received medical cannabis treatment; the standard group (404 patients) received conventional palliative pain management. Survival was calculated using Kaplan-Meier methods, and prognostic factors were analyzed using Cox regression.","limitations":"Retrospective design with no randomization — selection bias is the primary concern. Patients who sought out cannabis treatment may have been systematically healthier, more motivated, or had better access to healthcare. The standard care group's median survival of 0.83 months is extremely short, suggesting these patients may have been at a more advanced disease stage. No blinding was possible. Cannabis dosing and formulations were not standardized. Cultural and regional factors in Thailand may limit generalizability to other populations."},{"rthcId":"RTHC-04148","title":"Chronic health conditions, acute health events, and healthcare utilization among adults over age 50 in Hawai'i who use cannabis: A matched cohort study.","authors":"Phillips, Kristina T; Pedula, Kathryn L; Choi, Namkee G; Tawara, Kylee-Ann K; Simiola, Vanessa; Satre, Derek D; Owen-Smith, Ashli; Lynch, Frances F; Dickerson, John","year":2022,"journal":"Drug and alcohol dependence, 234, 109387","doi":"10.1016/j.drugalcdep.2022.109387","pmid":"35279458","tags":["seniors","cardiovascular","pain","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-diagnosed patients had significantly greater risk of coronary heart disease, chronic non-cancer pain, stroke, myocardial infarction, cyclic vomiting, and injuries compared to age- and sex-matched controls. They also used more healthcare services across all settings (outpatient, inpatient, emergency).","whyItMatters":"Most cannabis research focuses on younger users. This study in an ethnically diverse older population (19.3% Native Hawaiian/Pacific Islander, 24.4% Asian) provides data on a demographic where cannabis risks may compound with age-related health vulnerabilities.","specificNumbers":"550 participants (275 cannabis, 275 control). Mean age: 62.8 years. Demographics: 47.8% White, 24.4% Asian, 19.3% Native Hawaiian/Pacific Islander. Cannabis group had significantly higher rates of: coronary heart disease, chronic pain, stroke, MI, cyclic vomiting, injuries. Higher healthcare utilization across all settings.","methodology":"Matched cohort study using electronic health records from Kaiser Permanente Hawaii. 275 patients age 50+ with ICD-10 cannabis diagnoses were matched to 275 controls by age and sex. Health outcomes and healthcare utilization were tracked for two years following case identification (2016-2020).","limitations":"Observational design cannot determine causation. Cannabis users may have other unmeasured risk factors. ICD-10 cannabis codes may miss casual users or capture more severe use patterns. Two-year follow-up may be insufficient for some chronic conditions."},{"rthcId":"RTHC-04149","title":"Cannabidiol, ∆9-tetrahydrocannabinol, and metabolites in human blood by volumetric absorptive microsampling and LC-MS/MS following controlled administration in epilepsy patients.","authors":"Pigliasco, Federica; Malaca, Sara; Lo Faro, Alfredo Fabrizio; Tini, Anastasio; Cangemi, Giuliana; Cafaro, Alessia; Barco, Sebastiano; Riva, Antonella; Pisati, Angelica; Amadori, Elisabetta; Striano, Pasquale; Tagliabracci, Adriano; Huestis, Marilyn Ann; Busardò, Francesco Paolo","year":2022,"journal":"Frontiers in pharmacology, 13, 1038754","doi":"10.3389/fphar.2022.1038754","pmid":"36353497","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04150","title":"The moderating role of sex and self-, teacher-, and father-reported ADHD hyperactivity-impulsivity symptoms, on the association between early adolescent internalizing symptoms and substance use.","authors":"Pocuca, Nina; Parent, Sophie; Côté, Sylvana; Boivin, Michel; Tremblay, Richard E; Séguin, Jean R; Castellanos-Ryan, Natalie","year":2022,"journal":"Addictive behaviors, 135, 107437","doi":"10.1016/j.addbeh.2022.107437","pmid":"35908320","tags":["youth","mental-health","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"A significant three-way interaction between internalizing symptoms, ADHD hyperactivity-impulsivity, and sex was found for cigarette use (BF=48.40) and supported for cannabis use (BF=3.54-9.08). Internalizing symptoms predicted cannabis use only among females with high ADHD-HI symptoms (β=0.14-0.21).","whyItMatters":"The inconsistent relationship between anxiety/depression and substance use in adolescents has puzzled researchers. This study reveals that ADHD hyperactivity-impulsivity is a key moderator, particularly in girls, helping explain who is actually at risk.","specificNumbers":"1,424 adolescents, 53% female. Cigarette use three-way interaction: BF=48.40 (very strong evidence). Cannabis use: self-report ADHD BF=3.54, father-report BF=9.08 (substantial evidence). Effect among females with high ADHD-HI: cigarette β=0.15, cannabis β=0.14-0.21.","methodology":"Cross-sectional analysis of 1,424 adolescents (53% female) at age 13 from the Quebec Longitudinal Study of Child Development. Alcohol, cigarette, and cannabis use along with internalizing and ADHD hyperactivity-impulsivity symptoms were assessed. Used multi-informant ADHD ratings (self, teacher, father).","limitations":"Cross-sectional design at a single age point cannot establish temporal ordering. ADHD-HI symptoms were not clinical diagnoses. The cannabis finding did not reach conventional statistical significance but was supported by Bayesian evidence."},{"rthcId":"RTHC-04151","title":"Gender Differences in Dual Diagnoses Associated with Cannabis Use: A Review.","authors":"Prieto-Arenas, Laura; Díaz, Ignacio; Arenas, M Carmen","year":2022,"journal":"Brain sciences, 12(3)","doi":"10.3390/brainsci12030388","pmid":"35326345","tags":["sex-differences","mental-health","psychosis","depression","anxiety"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Studies consistently show gender differences in cannabis-associated psychiatric symptoms, but the direction varies across studies and conditions. Some findings suggest women are more vulnerable to cannabis-related depression and anxiety, while men may show stronger associations with psychotic symptoms.","whyItMatters":"Most cannabis research has not adequately accounted for gender differences. Understanding that men and women may face different psychiatric risks from cannabis use could improve clinical screening, prevention messaging, and treatment approaches.","specificNumbers":"Cannabis is the most widely used illegal drug among young people. The review covered three main symptom domains: psychosis, depression, and anxiety, with gender-stratified findings for each.","methodology":"Narrative review analyzing literature on gender differences in psychotic, depressive, and anxiety symptoms associated with cannabis use. Examined possible explanations including hormonal, pharmacokinetic, and social factors.","limitations":"Narrative review without systematic methodology. Many of the reviewed studies were not designed to test gender differences as a primary outcome. Inconsistent findings may reflect methodological differences rather than true variability in gender effects."},{"rthcId":"RTHC-04152","title":"Medical Cannabis Patients Report Improvements in Health Functioning and Reductions in Opiate Use.","authors":"Pritchett, Carolyn E; Flynn, Heather; Wang, Yuxia; Polston, James E","year":2022,"journal":"Substance use & misuse, 57(13), 1883-1892","doi":"10.1080/10826084.2022.2107673","pmid":"36168127","tags":["medical-cannabis","pain","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"61% of patients used pain medications before cannabis. Of those, 93% reported a change in pain medication use after starting cannabis, with 79% reporting cessation or reduction. Health functioning improved in pain, physical functioning, and social functioning domains. Most patients rated cannabis as important to their quality of life.","whyItMatters":"Florida has one of the largest medical cannabis programs in the US. This large survey provides real-world data on how patients perceive the impact of medical cannabis on their pain management and overall functioning.","specificNumbers":"2,183 patients. Demographics: 95% ages 20-70, 54% female, 85% White, 47% employed. Conditions: Pain+Mental Health 47.92%, Mental Health 28.86%, Pain 9.07%. Prior pain medication use: 60.98%. Changed pain meds after cannabis: 93.36%. Ceased or reduced pain meds: 79%. 11.47% reported improved functioning.","methodology":"Cross-sectional survey of 2,183 medical cannabis patients recruited from dispensaries across Florida. Included 66 items covering demographics, health, medication use, and SF-36 health functioning assessed before and after cannabis initiation.","limitations":"Cross-sectional self-report design with no verification of medication changes. Selection bias: patients recruited from dispensaries are already committed to cannabis. No control group. Retrospective assessment of pre-cannabis functioning is subject to recall bias."},{"rthcId":"RTHC-04153","title":"Cannabinoids and PPAR Ligands: The Future in Treatment of Polycystic Ovary Syndrome Women with Obesity and Reduced Fertility.","authors":"Przybycień, Piotr; Gąsior-Perczak, Danuta; Placha, Wojciech","year":2022,"journal":"Cells, 11(16)","doi":"10.3390/cells11162569","pmid":"36010645","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04154","title":"Impact of Cannabis Use on Inpatient Inflammatory Bowel Disease Outcomes in 2 States Legalizing Recreational Cannabis.","authors":"Pusateri, Antoinette; Anaizi, Ahmad; Nemer, Laura; Hinton, Alice; Lara, Luis; Afzali, Anita","year":2022,"journal":"Crohn's & colitis 360, 4(2), otac015","doi":"10.1093/crocol/otac015","pmid":"36777043","tags":["medical-cannabis","legalization","inflammation"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Reported cannabis use among IBD inpatients increased from 1.2% to 4.2% after legalization (p<0.05). In 2015, cannabis-using IBD patients had shorter hospital stays and $8,418 less in hospital charges (p=0.024) compared to non-users.","whyItMatters":"IBD patients frequently use cannabis for symptom management, and there is preclinical evidence for anti-inflammatory effects of cannabinoids in the gut. This study provides preliminary real-world data suggesting cannabis use does not worsen and may improve inpatient outcomes.","specificNumbers":"Cannabis use: 1.2% (2011) vs 4.2% (2015, post-legalization). In 2015: shorter hospital stays (p=0.038) and $8,418 lower charges (p=0.024) for cannabis users. Analysis adjusted for demographic data.","methodology":"Retrospective analysis comparing hospitalized IBD patients in Colorado and Washington before (2011) and after (2015) recreational cannabis legalization. Used chi-square and t-tests for comparisons, with multivariable regression adjusting for demographics.","limitations":"Retrospective design with potential confounders. Cannabis use was likely underreported, especially pre-legalization. The \"cannabis use\" category does not capture dose, frequency, or product type. Lower charges might reflect less severe disease in cannabis users rather than a treatment effect."},{"rthcId":"RTHC-04155","title":"Prediction of Carboxylesterase 1-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models.","authors":"Qian, Yuli; Markowitz, John S","year":2022,"journal":"Drug metabolism and disposition: the biological fate of chemicals, 50(7), 968-979","doi":"10.1124/dmd.121.000823","pmid":"35512806","tags":["drug-interactions","youth","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both THC and CBD reversibly inhibited the CES1 enzyme that metabolizes methylphenidate. Static models predicted THC from a cannabis cigarette could increase MPH exposure by 34%. Multiple daily CBD doses (10 mg/kg twice daily) could increase MPH exposure by up to 55% and peak concentration by 45%.","whyItMatters":"Many people with ADHD use cannabis, and CBD is increasingly being explored for ADHD symptoms. If cannabinoids increase methylphenidate blood levels, this could lead to unexpected side effects or altered medication efficacy in a large patient population.","specificNumbers":"THC unbound Ki: 0.031 mcM. CBD unbound Ki: 0.091 mcM. Static model: 34% MPH increase from smoked THC, 94% increase from prescription CBD. PBPK model: up to 55% AUC and 45% Cmax increase with multiple CBD doses. Single CBD doses showed no significant interaction.","methodology":"In vitro inhibition studies using human liver S9 fractions to measure THC and CBD inhibition of CES1-mediated methylphenidate hydrolysis. Results were incorporated into static and physiologically-based pharmacokinetic (PBPK) models to predict clinical interaction significance.","limitations":"Predictions are based on in vitro data and mathematical modeling, not clinical studies in humans. Actual interactions could be larger or smaller depending on individual variation, food effects, and other concurrent medications. The models assume specific cannabinoid exposure levels."},{"rthcId":"RTHC-04156","title":"Comorbidity and Coaggregation of Major Depressive Disorder and Bipolar Disorder and Cannabis Use Disorder in a Controlled Family Study.","authors":"Quick, Courtney R; Conway, Kevin P; Swendsen, Joel; Stapp, Emma K; Cui, Lihong; Merikangas, Kathleen R","year":2022,"journal":"JAMA psychiatry, 79(7), 727-735","doi":"10.1001/jamapsychiatry.2022.1338","pmid":"35648395","tags":["depression","addiction","genetics","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"CUD in probands was associated with increased CUD in relatives (aOR 2.64). Bipolar II (but not bipolar I or major depression) was also associated with CUD in relatives (aOR 2.57). Among relatives, CUD was associated with bipolar II (aOR 4.50) and major depression (aOR 3.64). Mood episodes typically preceded CUD onset.","whyItMatters":"The specific link with bipolar II (but not bipolar I) is new and clinically significant. If a shared genetic vulnerability underlies both conditions, then treating bipolar II early might actually help prevent cannabis use disorder.","specificNumbers":"CUD in probands predicted CUD in relatives (aOR 2.64, 95% CI 1.20-5.79). BP-II predicted CUD in relatives (aOR 2.57, 95% CI 1.06-6.23). Rates of CUD were highest in relatives with both familial and individual BP-II history (28.6% vs 7.2% with neither). Mood episodes preceded CUD in most cases.","methodology":"Community-based family study in the Washington, DC area (2004-2020). 586 adult probands and 698 first-degree relatives underwent semistructured diagnostic interviews. Mixed-effects models estimated familial aggregation of CUD with mood disorders, adjusting for demographics and comorbidities.","limitations":"Cross-sectional design cannot definitively establish temporal ordering. The DC metro sample may not represent all populations. Lifetime diagnoses may be subject to recall bias. The relatively small number of CUD cases (55 probands, 68 relatives) limits statistical power for subgroup analyses."},{"rthcId":"RTHC-04157","title":"Controlled Trial Examining the Strength-Based Grit Wellbeing and Self-Regulation Program for Young People in Residential Settings for Substance Use.","authors":"Quinn, Catherine A; Walter, Zoe C; de Andrade, Dominique; Dingle, Genevieve; Haslam, Catherine; Hides, Leanne","year":2022,"journal":"International journal of environmental research and public health, 19(21)","doi":"10.3390/ijerph192113835","pmid":"36360714","tags":["addiction","quitting","mental-health","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Both groups improved on all outcomes at 3 months, maintained through 12 months. The Grit group showed significantly larger reductions in methamphetamine and cannabis use involvement compared to the control group receiving standard treatment only.","whyItMatters":"Residential treatment programs often struggle with sustained outcomes. Adding a targeted self-regulation component that reduced cannabis and methamphetamine use beyond standard treatment suggests a specific, replicable enhancement that programs could adopt.","specificNumbers":"194 participants, 66% male, mean age 27.4. Grit program: 12 sessions over 6 weeks. Significant improvements in all outcomes (substance use, wellbeing, depression, anxiety, vocational engagement) at 3 months, maintained at 12 months. Grit group had larger reductions in cannabis and methamphetamine use.","methodology":"Cohort-controlled trial of 194 young people (66% male, mean age 27.4) in a 6-week residential substance treatment program. The Grit group received standard treatment plus 12 sessions (twice weekly) focusing on self-regulation skills, strengths, social connections, and health behaviors. Follow-up at 6 weeks, 3, 6, and 12 months.","limitations":"Not fully randomized (cohort-controlled). The residential setting provides a controlled environment that may not represent real-world conditions. Cannabis-specific effects were a secondary outcome. The study did not report standardized effect sizes for the group difference."},{"rthcId":"RTHC-04158","title":"Quantification of Cannabis in Infused Consumer Products and Their Residues on Skin.","authors":"Quiñones, Rosalynn; Moreno, Sara; Smythers, Amanda L; Sullins, Carrie; Pijor, Haley; Brown, Glenna; Trouten, Ashley; Richards-Waugh, Lauren L; Siddig, Aladin","year":2022,"journal":"ACS pharmacology & translational science, 5(8), 642-651","doi":"10.1021/acsptsci.2c00077","pmid":"35983282","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04159","title":"Synergistic action between a synthetic cannabinoid compound and tramadol in neuropathic pain rats.","authors":"Quiñonez-Bastidas, Geovanna Nallely; Osuna-Martínez, Ulises; Reda-Licea, Ana Laura; López-Ortíz, Manuel; Regla, Ignacio; Navarrete, Andrés","year":2022,"journal":"Acta pharmaceutica (Zagreb, Croatia), 72(4), 509-527","doi":"10.2478/acph-2022-0037","pmid":"36651363","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04160","title":"Shared Genetic Etiology between Cortical Brain Morphology and Tobacco, Alcohol, and Cannabis Use.","authors":"Rabinowitz, Jill A; Campos, Adrian I; Ong, Jue-Sheng; García-Marín, Luis M; Alcauter, Sarael; Mitchell, Brittany L; Grasby, Katrina L; Cuéllar-Partida, Gabriel; Gillespie, Nathan A; Huhn, Andrew S; Martin, Nicholas G; Thompson, Paul M; Medland, Sarah E; Maher, Brion S; Rentería, Miguel E","year":2022,"journal":"Cerebral cortex (New York, N.Y. : 1991), 32(4), 796-807","doi":"10.1093/cercor/bhab243","pmid":"34379727","tags":["genetics","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Eight significant negative genetic correlations were found between brain measures and substance use, including between alcohol consumption and cortical thickness. Five positive correlations were found, including between insula surface area and lifetime cannabis use. Polygenic risk scores for substance use predicted brain structure variation in the ABCD adolescent cohort.","whyItMatters":"This study helps disentangle whether substance use changes brain structure or whether shared genetics underlie both. The finding that substance use genetic risk predicts brain differences in adolescents who have not yet used substances suggests genetics play a genuine role.","specificNumbers":"71 brain imaging measures analyzed. 8 significant negative and 5 significant positive genetic correlations identified. Insula surface area positively correlated with cannabis use genetics. Substance use polygenic risk scores predicted brain structure in ABCD cohort.","methodology":"Used GWAS summary statistics for 71 brain imaging measures and alcohol, tobacco, and cannabis use behaviors. Linkage disequilibrium score regression identified genetic correlations. Genomic structural equation modeling created a common substance use genetic factor. Polygenic risk scores were validated in the ABCD study.","limitations":"GWAS are primarily conducted in European-ancestry populations. Genetic correlations indicate shared genetic architecture but do not prove causation. Brain measures were from adult samples while validation was in adolescents. Effect sizes of individual genetic variants are very small."},{"rthcId":"RTHC-04161","title":"In Vitro Effects of Cannabidiol on Activated Immune-Inflammatory Pathways in Major Depressive Patients and Healthy Controls.","authors":"Rachayon, Muanpetch; Jirakran, Ketsupar; Sodsai, Pimpayao; Klinchanhom, Siriwan; Sughondhabirom, Atapol; Plaimas, Kitiporn; Suratanee, Apichat; Maes, Michael","year":2022,"journal":"Pharmaceuticals (Basel, Switzerland), 15(4)","doi":"10.3390/ph15040405","pmid":"35455402","tags":["cbd","depression","inflammation"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBD at 0.1 mcg/mL had no immune effects. CBD at 1.0 mcg/mL decreased some regulatory immune activity but increased growth factor production. CBD at 10.0 mcg/mL suppressed several immune pathways but also increased IL-1beta, TNF-alpha, and other pro-inflammatory markers. The study concluded there was no beneficial effect of CBD on depression-related immune activation.","whyItMatters":"CBD is widely marketed as anti-inflammatory, but this study found the opposite in the context of depression. If higher CBD concentrations can worsen inflammatory processes, this challenges the assumption that CBD is uniformly beneficial for inflammation-related depression.","specificNumbers":"30 depressed patients, 20 controls. CBD 0.1 mcg/mL: no effects. CBD 1.0 mcg/mL: decreased CIRS, increased growth factors. CBD 10.0 mcg/mL: suppressed Th-1, Th-17, IRS, CIRS, neurotoxicity profile but increased IL-1beta, IL-17, TNF-alpha, GM-CSF. Dose-dependent changes in multiple cytokines.","methodology":"In vitro study using stimulated whole blood from 30 depressed patients and 20 healthy controls. Three CBD concentrations (0.1, 1.0, 10.0 mcg/mL) were tested. Cytokine profiles were measured using LUMINEX assay, covering Th-1, Th-2, Th-17, Treg, IRS, and CIRS pathways.","limitations":"In vitro conditions do not replicate the complexity of the human body. The CBD concentrations may not correspond to plasma levels achieved with typical oral CBD doses. The study used stimulated (not resting) immune cells, which may amplify effects."},{"rthcId":"RTHC-04162","title":"Current state of cannabis use, policies, and research across sixteen countries: cross-country comparisons and international perspectives.","authors":"Ransing, Ramdas; de la Rosa, Pedro A; Pereira-Sanchez, Victor; Handuleh, Jibril I M; Jerotic, Stefan; Gupta, Anoop Krishna; Karaliuniene, Ruta; de Filippis, Renato; Peyron, Eric; Sönmez Güngör, Ekin; Boujraf, Said; Yee, Anne; Vahdani, Bita; Shoib, Sheikh; Stowe, M J; Jaguga, Florence; Dannatt, Lisa; da Silva, Alexandre Kieslich; Grandinetti, Paolo; Jatchavala, Chonnakarn","year":2022,"journal":"Trends in psychiatry and psychotherapy, 44(Suppl 1), e20210263","doi":"10.47626/2237-6089-2021-0263","pmid":"34735077","tags":["legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis use prevalence reporting was inconsistent across countries. Policies ranged from full legalization to strict prohibition. Intervention strategies varied widely. European countries dominated PubMed-indexed cannabis research, while Asian countries (Thailand, Malaysia, India, Iran, Nepal) contributed much less despite significant cannabis use.","whyItMatters":"Global cannabis policy is evolving rapidly, but without consistent data across countries, it is difficult to learn from different approaches. The heterogeneity identified here suggests that global coordination is needed to prevent disproportionate harms.","specificNumbers":"16 countries reviewed. PubMed search covered 2010-2020. European countries produced the most cannabis research. Asian countries were significantly underrepresented in research despite substantial cannabis use populations.","methodology":"Systematic search of PubMed and Google Scholar (2010-2020) plus government websites in 16 countries, using country-specific search terms in English and local languages. Compared cannabis use patterns, policies, and research output across countries.","limitations":"The review covered only 16 of nearly 200 countries. English-language search bias may undercount non-English research. The 2010-2020 timeframe misses more recent policy changes. Qualitative synthesis limits comparability."},{"rthcId":"RTHC-04163","title":"Terpene-Enriched CBD oil for treating autism-derived symptoms unresponsive to pure CBD: Case report.","authors":"Raz, Noa; Heller, Iso; Lombardi, Titti; Marino, Giorgio; Davidson, Elyad M; Eyal, Aharon M","year":2022,"journal":"Frontiers in pharmacology, 13, 979403","doi":"10.3389/fphar.2022.979403","pmid":"36386202","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04164","title":"Optimal Treatment with Cannabis Extracts Formulations Is Gained via Knowledge of Their Terpene Content and via Enrichment with Specifically Selected Monoterpenes and Monoterpenoids.","authors":"Raz, Noa; Eyal, Aharon M; Davidson, Elyad M","year":2022,"journal":"Molecules (Basel, Switzerland), 27(20)","doi":"10.3390/molecules27206920","pmid":"36296511","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04165","title":"Cannabinoid hyperemesis syndrome and cannabis withdrawal syndrome: a review of the management of cannabis-related syndrome in the emergency department.","authors":"Razban, Mohammad; Exadaktylos, Aristomenis K; Santa, Vincent Della; Heymann, Eric P","year":2022,"journal":"International journal of emergency medicine, 15(1), 45","doi":"10.1186/s12245-022-00446-0","pmid":"36076180","tags":["harm-reduction","withdrawal"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS and CWS both present with abdominal pain and vomiting but arise from different pathophysiology. CHS occurs during active heavy use while CWS occurs after cessation. Distinguishing between them is essential for appropriate treatment. The authors proposed a clinical algorithm for ER decision-making and emphasized long-term outpatient follow-up.","whyItMatters":"Cannabis-related ER visits are increasing. Many clinicians conflate CHS and CWS or miss both diagnoses entirely. A clear clinical algorithm can improve accurate diagnosis, appropriate treatment, and reduce repeat ER visits.","specificNumbers":"CHS occurs during active heavy cannabis use. CWS occurs after cessation. Both present with abdominal pain and vomiting. The review synthesized treatment options for each condition and proposed a decision algorithm.","methodology":"Literature review of PubMed, Google Scholar, and Cochrane databases up to November 2021, using keywords related to cannabis, hyperemesis, withdrawal, and emergency medicine. Synthesized findings into a novel therapeutic algorithm.","limitations":"The proposed algorithm has not been prospectively validated. The underlying evidence base consists primarily of case reports and observational studies. Individual presentations may not fit neatly into the algorithm."},{"rthcId":"RTHC-04166","title":"Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis.","authors":"Reece, Albert Stuart; Hulse, Gary Kenneth","year":2022,"journal":"International journal of environmental research and public health, 19(24)","doi":"10.3390/ijerph192416721","pmid":"36554603","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04167","title":"Geotemporospatial and causal inferential epidemiological overview and survey of USA cannabis, cannabidiol and cannabinoid genotoxicity expressed in cancer incidence 2003-2017: part 2 - categorical bivariate analysis and attributable fractions.","authors":"Reece, Albert Stuart; Hulse, Gary Kenneth","year":2022,"journal":"Archives of public health = Archives belges de sante publique, 80(1), 100","doi":"10.1186/s13690-022-00812-7","pmid":"35354495","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04168","title":"Lurasidone use in Cannabis-Induced Psychosis: A Novel Therapeutic Strategy and Clinical Considerations in Four Cases Report.","authors":"Ricci, Valerio; Martinotti, Giovanni; De Berardis, Domenico; Maina, Giuseppe","year":2022,"journal":"International journal of environmental research and public health, 19(23)","doi":"10.3390/ijerph192316057","pmid":"36498129","tags":["psychosis","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All four patients improved across psychosis symptoms (positive and negative), disruptive behavior, and functional recovery. Target lurasidone doses ranged from 74-128 mg/day. No significant side effects were reported.","whyItMatters":"Cannabis-induced psychosis is increasingly common, but there is limited evidence on optimal antipsychotic choice. Lurasidone may be particularly suitable due to its favorable metabolic and sedation profile, which matters for young patients.","specificNumbers":"4 patients with first cannabis-induced psychotic episodes. Lurasidone doses: 74-128 mg/day. All showed remission of positive and negative symptoms, reduced disruptive behavior, and return of functioning. No significant side effects reported.","methodology":"Case series of four patients with first-episode cannabis-induced psychosis treated with lurasidone at a single center. Clinical improvement was assessed across multiple symptom domains.","limitations":"Only four patients, no control group, single center. Case reports cannot establish efficacy. The improvement may reflect natural recovery from a self-limited psychotic episode rather than medication effect. No long-term follow-up reported."},{"rthcId":"RTHC-04169","title":"Efficacy and safety of therapeutic use of cannabis derivatives and their synthetic analogs: Overview of systematic reviews.","authors":"Riera, Rachel; Pacheco, Rafael Leite; Bagattini, Ângela Maria; Martimbianco, Ana Luiza Cabrera","year":2022,"journal":"Phytotherapy research : PTR, 36(1), 5-21","doi":"10.1002/ptr.7263","pmid":"34841610","tags":["medical-cannabis","cbd","pain"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Evidence certainty was not high for any cannabinoid outcome. Moderate evidence found: CBD may improve quality of life in ulcerative colitis but increases adverse events; cannabinoids appear to have no clinically important benefit for chronic non-cancer pain, MS spasticity pain, or acute postoperative pain; cannabinoids appear to reduce chemotherapy-related nausea and vomiting.","whyItMatters":"This is the most comprehensive overview of cannabis therapeutic evidence to date. By synthesizing 68 systematic reviews, it provides a definitive snapshot of where the evidence is strong, moderate, or insufficient, helping clinicians and patients make informed decisions.","specificNumbers":"68 systematic reviews included. 37 health conditions addressed. 8 reviews rated high quality. No high-certainty evidence for any outcome. Moderate evidence for chemotherapy nausea benefit and no benefit for chronic non-cancer pain. For all other outcomes, evidence was low or very low.","methodology":"Overview of systematic reviews (umbrella review). Identified 68 systematic reviews of randomized trials addressing 37 health conditions. Methodological quality assessed with AMSTAR-2 (8 rated high quality). Evidence certainty graded using GRADE framework.","limitations":"Umbrella reviews depend on the quality of underlying systematic reviews. Rapidly evolving cannabis research means some newer studies may not be captured. The GRADE ratings are conservative and may underrate conditions where practical clinical experience suggests benefit."},{"rthcId":"RTHC-04170","title":"Does recreational cannabis legalization change cannabis use patterns? Evidence from secondary school students in Uruguay.","authors":"Rivera-Aguirre, Ariadne; Castillo-Carniglia, Alvaro; Laqueur, Hannah S; Rudolph, Kara E; Martins, Silva S; Ramírez, Jessica; Queirolo, Rosario; Cerdá, Magdalena","year":2022,"journal":"Addiction (Abingdon, England), 117(11), 2866-2877","doi":"10.1111/add.15913","pmid":"35491741","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Past-year and past-month cannabis use decreased after legalization. Among students 18-21 (legally eligible), there was a transitory increase in risky use in 2014 that decreased afterward. No sustained increases in risky or frequent cannabis use were found for any age group.","whyItMatters":"Uruguay was the first country to fully legalize recreational cannabis. This large-scale evaluation provides crucial evidence that a non-commercial legalization model did not increase youth cannabis use, countering a primary concern about legalization.","specificNumbers":"204,730 students. Past-year and past-month use decreased after enactment/implementation. Ages 18-21 showed transitory increases in 2014: risky use PD=13.5% (95% CI 2.0-24.9), frequent use PD=4.5% (95% CI 1.0-8.1), but these decreased after 2014.","methodology":"Difference-in-differences analysis comparing repeated cross-sectional surveys of secondary students in Uruguay and Chile (control) from 2007-2018. 204,730 students in 8th, 10th, and 12th grade. Examined changes after enactment (2014) and implementation (2016) of legalization.","limitations":"Chile as a control country may not be perfectly comparable. School surveys miss adolescents who have dropped out. Self-reported cannabis use may be affected by changing social norms post-legalization. The implementation period was gradual, making effect attribution difficult."},{"rthcId":"RTHC-04171","title":"Directive clinique no 425a : Le cannabis aux différentes périodes de la vie des femmes - Partie 1 : Fertilité, contraception, ménopause et douleur pelvienne.","authors":"Robert, Magali; Graves, Lisa E; Allen, Victoria M; Dama, Sumeet; Gabrys, Robert L; Tanguay, Robert L; Turner, Suzanne D; Green, Courtney R; Cook, Jocelynn L","year":2022,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 44(4), 420-435.e4","doi":"10.1016/j.jogc.2022.02.013","pmid":"35400520","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04172","title":"Guideline No. 425a: Cannabis Use Throughout Women's Lifespans - Part 1: Fertility, Contraception, Menopause, and Pelvic Pain.","authors":"Robert, Magali; Graves, Lisa E; Allen, Victoria M; Dama, Sumeet; Gabrys, Robert L; Tanguay, Robert L; Turner, Suzanne D; Green, Courtney R; Cook, Jocelynn L","year":2022,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 44(4), 407-419.e4","doi":"10.1016/j.jogc.2022.01.012","pmid":"35400519","tags":["pregnancy","sex-differences","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The guideline addressed cannabis effects on hormonal regulation, reproductive health, sexual function, perimenopausal and menopausal symptoms, and chronic pelvic pain. It emphasized trauma-informed care, non-stigmatizing approaches, and the need for evidence-based dialogue between providers and patients.","whyItMatters":"Women of reproductive age are among the fastest-growing cannabis user groups, yet clinical guidance on women-specific health effects has been lacking. This guideline gives clinicians an evidence-based framework for conversations that many are currently having without guidance.","specificNumbers":"Search covered 2018-2021. Used MeSH terms for cannabis combined with women's health terms (estrogen, contraception, fertilization, menopause, dysmenorrhea, endometriosis, etc.). GRADE methodology applied for recommendations.","methodology":"Clinical guideline developed by the Society of Obstetricians and Gynaecologists of Canada. Systematic search of PubMed, EMBASE, and grey literature (2018-2021). Evidence graded using GRADE approach. Covered fertility, contraception, menopause, and pelvic pain.","limitations":"Canadian healthcare context may not generalize to all settings. The 2018-2021 search window may miss older foundational studies. Many recommendations are based on low-quality evidence given the limited research in women-specific cannabis effects."},{"rthcId":"RTHC-04173","title":"Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model.","authors":"Roberts, Victoria H J; Schabel, Matthias C; Boniface, Emily R; D'Mello, Rahul J; Morgan, Terry K; Terrobias, Juanito Jose D; Graham, Jason A; Borgelt, Laura M; Grant, Kathleen A; Sullivan, Elinor L; Lo, Jamie O","year":2022,"journal":"Scientific reports, 12(1), 20260","doi":"10.1038/s41598-022-24401-4","pmid":"36424495","tags":["pregnancy","neuroscience","animal-study"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"THC-exposed pregnancies showed significantly decreased amniotic fluid volume (p<0.001), reduced placental perfusion (p<0.05), and lower fetal oxygen availability (p<0.05). Placental tissue showed microinfarctions only in THC-exposed animals. RNA sequencing revealed disrupted blood vessel development and angiogenesis pathways.","whyItMatters":"This is the first primate study using advanced imaging to demonstrate that THC impairs placental function during pregnancy. The findings of reduced blood flow and oxygen delivery to the fetus have direct implications for human cannabis use during pregnancy.","specificNumbers":"10 rhesus macaques (5 THC, 5 control). Imaging at G85, G110, G135, G155. THC group: significantly decreased amniotic fluid (p<0.001), placental perfusion (p<0.05), fetal oxygen availability (p<0.05). Microinfarctions found only in THC-exposed placentas. RNA-seq showed dysregulated vasculature development.","methodology":"Controlled study in 10 rhesus macaques (5 THC, 5 control). THC group received daily THC edibles pre-conception through pregnancy. Serial ultrasound and MRI at four gestational timepoints. Cesarean delivery at gestational day 155 (near term) with placental collection for histology and RNA sequencing.","limitations":"Small sample size (5 per group). Daily THC edible dosing may not reflect all human use patterns. The study ended before natural delivery, so birth outcomes are unknown. A single THC preparation was used, not reflecting the variety of cannabis products."},{"rthcId":"RTHC-04174","title":"Correlation between oral fluid and blood THC concentration: A systematic review and discussion of policy implications.","authors":"Robertson, M B; Li, A; Yuan, Y; Jiang, A; Gjerde, H; Staples, J A; Brubacher, J R","year":2022,"journal":"Accident; analysis and prevention, 173, 106694","doi":"10.1016/j.aap.2022.106694","pmid":"35640367","tags":["driving","legalization","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Oral fluid THC reliably detected presence of THC in blood (71.2% sensitivity, 97.7% specificity). However, at commonly used cutoffs, oral fluid was less sensitive and less specific for detecting blood THC above per se limits like 5 ng/mL. This would produce many false positives in random driver testing.","whyItMatters":"Many countries use roadside oral fluid tests to enforce cannabis-impaired driving laws. This study shows these tests are useful for identifying recent cannabis use but unreliable for determining whether drivers exceed legal blood THC limits, with major implications for enforcement fairness.","specificNumbers":"Over 18,000 paired oral fluid-blood samples. Presence detection: 71.2% sensitivity, 97.7% specificity. Performance deteriorated significantly when used to predict blood levels above 5 ng/mL per se limits. High false positive rate for random driver screening.","methodology":"Systematic review and meta-analysis of studies comparing oral fluid THC with blood THC. Individual-level data obtained from study authors and pooled for analysis. Over 18,000 paired samples analyzed. Sensitivity and specificity calculated at various oral fluid cutoff values for detecting different blood THC concentration thresholds.","limitations":"Paired samples came from various study conditions (controlled dosing, roadside testing, clinical). The relationship between blood THC and actual driving impairment is itself imperfect. Different oral fluid collection devices may perform differently."},{"rthcId":"RTHC-04175","title":"Local Education Agency Impact on School Environments to Reduce Health Risk Behaviors and Experiences Among High School Students.","authors":"Robin, Leah; Timpe, Zachary; Suarez, Nicolas A; Li, Jingjing; Barrios, Lisa; Ethier, Kathleen A","year":2022,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 70(2), 313-321","doi":"10.1016/j.jadohealth.2021.08.004","pmid":"34531096","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Students in schools implementing the program had 11% lower odds of ever using marijuana (aOR=0.89, 95% CI 0.81-0.98) and 23% lower odds of current marijuana use (aOR=0.77, 95% CI 0.64-0.93). The program was also associated with reduced sexual risk behaviors and experience of violence.","whyItMatters":"This is one of the largest evaluations of a school-based program that included cannabis as an outcome. The 23% reduction in current marijuana use demonstrates that comprehensive school health approaches can meaningfully affect adolescent substance use.","specificNumbers":"638 schools, 64,838 students. 237 exposed vs 401 unexposed schools. Ever used marijuana: aOR=0.89 (95% CI 0.81-0.98). Current marijuana use: aOR=0.77 (95% CI 0.64-0.93). Also reduced: safety concerns (aOR=0.87), forced sex (aOR=0.76).","methodology":"Multilevel difference-in-differences analysis comparing 237 exposed schools (30,336 students) to 401 unexposed schools (34,502 students) using 2015 and 2017 Youth Risk Behavior Surveys. The program was a socio-ecological health initiative administered by local education agencies nationwide.","limitations":"Quasi-experimental design (schools were selected by local agencies, not randomly assigned). The Youth Risk Behavior Survey is self-reported. Two-year comparison may not capture long-term trends. Schools that implemented the program may have been more motivated for health improvement."},{"rthcId":"RTHC-04176","title":"Cannabinoid control of hippocampal functions: the where matters.","authors":"Robledo-Menendez, Almudena; Vella, Maria; Grandes, Pedro; Soria-Gomez, Edgar","year":2022,"journal":"The FEBS journal, 289(8), 2162-2175","doi":"10.1111/febs.15907","pmid":"33977665","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04177","title":"Contingency Management for Treatment of Cannabis Use Disorder in Co-Occurring Mental Health Disorders: A Systematic Review.","authors":"Rodas, Justyne D; Sorkhou, Maryam; George, Tony P","year":2022,"journal":"Brain sciences, 13(1)","doi":"10.3390/brainsci13010036","pmid":"36672017","tags":["addiction","quitting","psychosis","depression","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Contingency management produced cannabis use reductions and periods of abstinence in individuals with psychotic-spectrum disorders or major depressive disorder. The approach specifically reinforced target behaviors like confirmed abstinence from cannabis.","whyItMatters":"Cannabis use disorder in people with mental illness is associated with worse symptoms, poorer treatment response, and reduced functioning. Despite this, few treatments have shown efficacy for this specific population. Contingency management may fill this gap.","specificNumbers":"6 studies met inclusion criteria. Diagnoses included psychotic-spectrum and major depressive disorders. CM was efficacious for cannabis use reduction and abstinence in these populations.","methodology":"Systematic search of PubMed, PsycINFO, and EMBASE through November 2022. Identified 6 studies examining contingency management effects on cannabis use, clinical outcomes, cognitive function, and psychosocial functioning in patients with co-occurring CUD and mental health disorders.","limitations":"Only 6 studies met criteria, reflecting limited research in this area. Studies were small and varied in design. Long-term follow-up data were lacking. Other psychiatric populations (anxiety disorders, PTSD) were not represented."},{"rthcId":"RTHC-04178","title":"Dissociable changes in spike and wave discharges following exposure to injected cannabinoids and smoked cannabis in Genetic Absence Epilepsy Rats from Strasbourg.","authors":"Roebuck, Andrew J; Greba, Quentin; Onofrychuk, Timothy J; McElroy, Dan L; Sandini, Thaísa M; Zagzoog, Ayat; Simone, Jonathan; Cain, Stuart M; Snutch, Terrance P; Laprairie, Robert B; Howland, John G","year":2022,"journal":"The European journal of neuroscience, 55(4), 1063-1078","doi":"10.1111/ejn.15096","pmid":"33370468","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Absence epilepsy causes brief seizure episodes (staring spells) characterized by distinctive spike-and-wave discharges (SWDs) on EEG. There's enormous interest in using cannabinoids for epilepsy — CBD-based Epidiolex is already FDA-approved for some forms — but the effects on absence epilepsy specifically have been unclear.\n\nThis study used GAERS (Genetic Absence Epilepsy Rats from Strasbourg), a well-validated animal model of absence epilepsy, to test how THC and CBD affect seizure activity. The results were striking and went in opposite directions.\n\nInjected THC at doses from 1–10 mg/kg dose-dependently increased spike-and-wave discharges to over 200% of baseline. More THC meant substantially more seizure activity. In sharp contrast, CBD at doses of 30–100 mg/kg produced approximately a 50% reduction in SWDs.\n\nThe researchers then took the innovative step of exposing the rats to actual cannabis smoke from two different strains: a high-THC strain (Mohawk) and a high-CBD/low-THC strain (Treasure Island). The smoked high-THC cannabis increased seizures, consistent with the injected THC results. The high-CBD strain had no significant effect on seizures — it didn't increase them like THC but didn't reduce them as dramatically as pure injected CBD either.\n\nPre-treatment with a CB1 receptor antagonist blocked THC's seizure-increasing effect, confirming the mechanism works through the CB1 receptor system.","whyItMatters":"The divergence between THC and CBD is critical for the millions of people with absence epilepsy. While CBD-based treatments are gaining acceptance for certain epilepsy types, this study warns that THC could actually worsen absence seizures. For patients with absence epilepsy who use cannabis, the THC:CBD ratio of their product could be the difference between reducing and increasing their seizure activity.","specificNumbers":"THC (1–10 mg/kg) increased spike-and-wave discharges to over 200% of baseline in a dose-dependent manner. CBD (30–100 mg/kg) reduced SWDs by approximately 50%. Smoked high-THC cannabis also increased SWDs. CB1 receptor antagonist pre-treatment blocked THC's pro-seizure effect.","methodology":"Animal study using GAERS rats implanted with bipolar EEG electrodes in the somatosensory cortex. EEGs were recorded for 2 hours after administration of: injected THC (1–10 mg/kg), injected CBD (30–100 mg/kg), smoked high-THC cannabis (Mohawk strain), or smoked high-CBD/low-THC cannabis (Treasure Island strain). CB1 receptor antagonist pre-treatment was used to confirm the mechanism.","limitations":"Animal study — results in GAERS rats may not directly translate to human absence epilepsy. The smoked cannabis exposure method, while innovative, makes precise dose control difficult. The high-CBD smoked cannabis didn't reduce seizures the way injected CBD did, possibly because the CBD dose delivered via smoke was lower or because other compounds in the smoke interfered. The study examined acute effects only; chronic exposure effects may differ."},{"rthcId":"RTHC-04179","title":"Trends and characteristics of cannabis-associated emergency department visits in the United States, 2006-2018.","authors":"Roehler, Douglas R; Hoots, Brooke E; Holland, Kristin M; Baldwin, Grant T; Vivolo-Kantor, Alana M","year":2022,"journal":"Drug and alcohol dependence, 232, 109288","doi":"10.1016/j.drugalcdep.2022.109288","pmid":"35033959","tags":["harm-reduction","legalization","youth"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-associated ER visits increased from 12.3 to 34.7 per 100,000 from 2006-2014 (12.1% annual increase). Rates continued rising 17.3% from 2016-2017 and 11.1% from 2017-2018. The Midwest saw the largest regional increase (36.8%). Female visit rates increased faster than male rates (15.9% vs 8.7%).","whyItMatters":"ER visits are a concrete, measurable indicator of cannabis-related harm at the population level. The sustained increases across multiple demographics and regions suggest a growing public health burden that parallels expanding cannabis availability.","specificNumbers":"Rate rose from 12.3 to 34.7 per 100,000 (2006-2014). Average annual increase: 12.1%. 2016-2017: +17.3%. 2017-2018: +11.1%. Female increase: 15.9% (2017-2018). Midwest: +36.8%. Ages 0-14 and 25+ showed significant increases.","methodology":"Analysis of the Nationwide Emergency Department Sample (NEDS) from HCUP, covering cannabis-associated ER visits 2006-2018. JoinPoint analysis for trends. Z-tests for annual rate changes. Examined by age, sex, region, and visit characteristics.","limitations":"ICD coding changes in 2015 created a discontinuity, requiring separate analysis periods. \"Cannabis-associated\" includes visits where cannabis is mentioned but may not be the primary reason. Increased ER coding of cannabis could reflect awareness rather than true incidence increases."},{"rthcId":"RTHC-04180","title":"Changes in young adult substance use during COVID-19 as a function of ACEs, depression, prior substance use and resilience.","authors":"Romm, Katelyn F; Patterson, Brooke; Crawford, Natalie D; Posner, Heather; West, Carly D; Wedding, DeEnna; Horn, Kimberly; Berg, Carla J","year":2022,"journal":"Substance abuse, 43(1), 212-221","doi":"10.1080/08897077.2021.1930629","pmid":"34086537","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"49.4% used marijuana at either timepoint, with 27.2% increasing and 21.2% decreasing frequency during COVID-19. Among those with low resilience, greater childhood adversity predicted marijuana increases. Greater depression predicted alcohol and e-cigarette increases.","whyItMatters":"The COVID-19 pandemic created a natural experiment for understanding how societal stress affects substance use. The finding that resilience moderates the impact of childhood adversity on marijuana use points to specific intervention targets.","specificNumbers":"1,084 participants. Marijuana: 49.4% used, 27.2% increased, 21.2% decreased. ACEs predicted marijuana increases among low-resilience participants. Depression predicted alcohol and e-cigarette increases. Alcohol: 84.8% used, 32.9% increased.","methodology":"Longitudinal analysis using Wave 3 (pre-COVID, Sept-Dec 2019) and Wave 4 (during COVID, March-May 2020) from the VAPES study of young adults across six US metropolitan areas. 1,084 participants, mean age 24.8, 51.8% female, 73.6% White.","limitations":"Two-wave comparison captures only early COVID-19 (March-May 2020). Self-reported substance use. The sample overrepresents White participants. The observational design cannot confirm causal relationships between ACEs, resilience, and substance use changes."},{"rthcId":"RTHC-04181","title":"Nabiximols effect on blood pressure and heart rate in post-stroke patients of a randomized controlled study.","authors":"Rosa, Gian Marco; Puce, Luca; Mori, Laura; Currà, Antonio; Fattapposta, Francesco; Porto, Italo; Bragazzi, Nicola Luigi; Trompetto, Carlo; Marinelli, Lucio","year":2022,"journal":"Frontiers in cardiovascular medicine, 9, 990188","doi":"10.3389/fcvm.2022.990188","pmid":"36386386","tags":["medical-cannabis","cardiovascular"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"No arrhythmic events were recorded. Blood pressure and heart rate showed no pathological fluctuations. No cardiovascular or cerebrovascular events occurred. Blood pressure and heart rate did not change during nabiximols treatment compared to baseline, even at the highest dosage.","whyItMatters":"Post-stroke patients are at high cardiovascular risk, making safety data for any medication critical. This study provides reassurance that nabiximols can be used for spasticity in this vulnerable population without cardiac complications.","specificNumbers":"34 patients completed the study. 31 on antihypertensives, 12 on beta-blockers. Zero arrhythmic events. Zero cardiovascular or cerebrovascular events. Blood pressure and heart rate unchanged from baseline to highest dose.","methodology":"Ancillary cardiovascular safety analysis from SativexStroke trial: randomized, double-blind, placebo-controlled, crossover study. 34 post-stroke patients (31 on antihypertensives, 12 on beta-blockers) received nabiximols or placebo for 1-month periods. Blood pressure and heart rate compared between lowest and highest dosage periods.","limitations":"Small sample size (34). One-month treatment period may not capture long-term cardiovascular effects. Most patients were on antihypertensives that could mask cannabis cardiovascular effects. The controlled dosing of nabiximols may not reflect real-world cannabis use patterns."},{"rthcId":"RTHC-04182","title":"Cannabinoid hyperemesis syndrome: A 6-year audit of adult presentations to an urban district hospital.","authors":"Rotella, Joe A; Ferretti, Olivia G; Raisi, Elham; Seet, Hao Rui; Sarkar, Soham","year":2022,"journal":"Emergency medicine Australasia : EMA, 34(4), 578-583","doi":"10.1111/1742-6723.13944","pmid":"35199462","tags":["harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"142 presentations from 67 unique patients. 43% (29 patients) represented during the study period, most within 3 months. Males were overrepresented (68.7%). Median age was 31. All had daily cannabis use. Cyclical nausea/vomiting was the most common feature. Lab findings: elevated white cells with neutrophilia (75.8%), mild low potassium (57.9%), normal lipase, and low CRP.","whyItMatters":"The high re-presentation rate (43%) highlights CHS as a chronic, recurring condition that significantly burdens emergency departments. The lab profile (normal lipase, low CRP) could help clinicians distinguish CHS from other causes of cyclic vomiting.","specificNumbers":"142 presentations, 67 unique patients. Re-presentation rate: 43% (29/67). Most re-presented within 3 months. 68.7% male. Median age 31 (IQR 23-35). Neutrophilia: 75.8%. Hypokalaemia: 57.9%. Normal lipase. CRP <50: 98.2%. No ICU admissions. No deaths.","methodology":"Retrospective chart review of adult CHS presentations at an urban Melbourne ED from January 2015 to January 2021. Examined demographics, cannabis use patterns, clinical features, lab results, imaging, treatment, and outcomes including re-presentation rates.","limitations":"Single-center retrospective study in outer Melbourne. CHS diagnosis depended on documentation, which may vary by clinician. Patients who sought care elsewhere would be missed. The study could not assess cannabis cessation rates or long-term outcomes."},{"rthcId":"RTHC-04183","title":"Cannabis industry lobbying in the Colorado state legislature in fiscal years 2010-2021.","authors":"Rotering, Thomas; Apollonio, Dorie E","year":2022,"journal":"The International journal on drug policy, 102, 103585","doi":"10.1016/j.drugpo.2022.103585","pmid":"35085854","tags":["legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis industry spent $7M+ (inflation-adjusted) lobbying on 367 bills. 11% ($800K+) came from out-of-state clients. In 48% of reports, lobbyists did not disclose their funder's cannabis connection. Some lobbyists simultaneously represented alcohol, tobacco, and cannabis industries.","whyItMatters":"As cannabis becomes a major industry, understanding its political influence is essential for public health. The lack of disclosure transparency and cross-industry lobbying relationships raise concerns about whether cannabis regulation prioritizes public health or industry profits.","specificNumbers":"$7M+ total lobbying (inflation-adjusted). 367 bills lobbied. $800K+ (11%) from out-of-state. 48% of reports did not disclose cannabis affiliation. Lobbyists represented alcohol, tobacco, and cannabis concurrently.","methodology":"Retrospective analysis of publicly available Colorado lobbying expenditure data from FY 2010-2021. Supplemented with business license documentation, legislative histories, and public testimony. Inflation-adjusted expenditures tracked by funder, lobbyist, and origin.","limitations":"Colorado-specific findings may not generalize to other states. Lobbying expenditure data captures only formal lobbying, not other forms of political influence. The study could not directly measure the impact of lobbying on legislative outcomes."},{"rthcId":"RTHC-04184","title":"Assessment of patient perception of treatment assignment and patient-reported outcomes in a cannabis use disorder trial.","authors":"Roydhouse, Jessica; Tomko, Rachel L; Gray, Kevin M; Gutman, Roee","year":2022,"journal":"The American journal of drug and alcohol abuse, 48(6), 651-661","doi":"10.1080/00952990.2022.2097918","pmid":"35904459","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04185","title":"GABAergic Neurotransmission in Human Tissues Is Modulated by Cannabidiol.","authors":"Ruffolo, Gabriele; Gaeta, Alessandro; Cannata, Beatrice; Pinzaglia, Camilla; Aronica, Eleonora; Morano, Alessandra; Cifelli, Pierangelo; Palma, Eleonora","year":2022,"journal":"Life (Basel, Switzerland), 12(12)","doi":"10.3390/life12122042","pmid":"36556407","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04186","title":"Cannabinoid Hyperemesis Syndrome Survey and Genomic Investigation.","authors":"Russo, Ethan B; Spooner, Chris; May, Len; Leslie, Ryan; Whiteley, Venetia L","year":2022,"journal":"Cannabis and cannabinoid research, 7(3), 336-344","doi":"10.1089/can.2021.0046","pmid":"34227878","tags":["genetics","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"CHS patients showed significantly elevated mutations in COMT (OR 12.0), ABCA1 (OR 8.4), CYP2C9 (OR 7.8), DRD2 (OR 6.2), and TRPV1 (OR 5.8) compared to cannabis-using controls without CHS. 87.7% of patients improved with cannabis cessation, but most relapsed rapidly after resumption.","whyItMatters":"CHS affects some heavy cannabis users but not others. This study provides the first genetic evidence explaining this selective vulnerability, pointing to specific metabolic and receptor genes that could eventually enable genetic screening or targeted treatments.","specificNumbers":"585 screened, 28 CHS + 12 controls genotyped. COMT mutation OR: 12.0 (p=0.012). ABCA1 OR: 8.4 (p=0.012). CYP2C9 OR: 7.8 (p=0.043). DRD2 OR: 6.2 (p=0.031). TRPV1 OR: 5.8 (p=0.015). 93% used flower or concentrates, multiple grams/day. 15.6% had cannabis dependency diagnosis. 56.6% had withdrawal symptoms.","methodology":"Online screening questionnaire with 585 respondents. 205 qualified as CHS pool, 54 as cannabis-using controls. 28 CHS patients and 12 controls completed genomic testing via saliva kits. Both groups were high-frequency users of THC-predominant cannabis.","limitations":"Very small genomic sample (28 patients, 12 controls) limits statistical power. Online recruitment introduces selection bias. Only 28 of 99 willing patients returned genetic kits. The study was not designed to establish clinical-grade genetic associations."},{"rthcId":"RTHC-04187","title":"Survey of Patients Employing Cannabigerol-Predominant Cannabis Preparations: Perceived Medical Effects, Adverse Events, and Withdrawal Symptoms.","authors":"Russo, Ethan B; Cuttler, Carrie; Cooper, Ziva D; Stueber, Amanda; Whiteley, Venetia L; Sexton, Michelle","year":2022,"journal":"Cannabis and cannabinoid research, 7(5), 706-716","doi":"10.1089/can.2021.0058","pmid":"34569849","tags":["medical-cannabis","pain","anxiety","depression","sleep"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Most common conditions treated: anxiety (51.2%), chronic pain (40.9%), depression (33.1%), insomnia (30.7%). Majority rated conditions \"very much\" or \"much improved.\" 73.9% reported CBG superiority over conventional pain medicines, 80% for depression, 73% for insomnia, 78.3% for anxiety. 44% reported no adverse events.","whyItMatters":"CBG is the least studied of the major cannabinoids despite being called \"the mother of all cannabinoids.\" This is the first systematic data on how people actually use it and what they perceive it does, creating a foundation for designing clinical trials.","specificNumbers":"127 eligible participants. 51.2% medical use only. Top conditions: anxiety 51.2%, chronic pain 40.9%, depression 33.1%, insomnia 30.7%. Superiority claims: depression 80%, anxiety 78.3%, chronic pain 73.9%, insomnia 73%. No adverse events: 44%. Most common side effects: dry mouth 16.5%, sleepiness 15%. No withdrawal symptoms: 84.3%.","methodology":"Online survey of 127 US adults who used CBG-predominant cannabis (>50% CBG content) in the past 6 months. Assessed use patterns, conditions treated, perceived efficacy, adverse events, and withdrawal symptoms.","limitations":"Self-selected online survey with no verification of CBG product content or diagnosis. Self-reported superiority over conventional medications is subject to bias. No control group or blinding. 127 respondents is a small sample."},{"rthcId":"RTHC-04188","title":"Is Cannabis Legalization Eliciting Abusive Behaviors in Parents? A Case Report.","authors":"Russo, Marianna; Favretto, Donata; Sartori, Stefano; Facchin, Paola; Rosa-Rizzotto, Melissa","year":2022,"journal":"The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 27(5), 470-475","doi":"10.5863/1551-6776-27.5.470","pmid":"35845560","tags":["youth","cbd","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 4-year-old with anti-NMDA receptor encephalitis tested positive for cannabis and other substances during investigation of treatment-resistant behavioral disturbances. The parents disclosed administering a CBD extract as a \"home remedy\" for behavior management. They did not inform physicians because they considered the product legal.","whyItMatters":"As CBD products become widely available and marketed as safe, some parents may administer them to children without medical guidance. This case illustrates the risks: unknown interactions with medical treatments, unpredictable effects in a sick child, and interference with clinical decision-making.","specificNumbers":"4-year-old child. Diagnosis: anti-NMDA receptor encephalitis. Found positive for cannabis and other substances. Parents disclosed CBD extract administration without medical knowledge.","methodology":"Case report from an Italian pediatric hospital. Drug testing was performed to investigate unexplained behavioral changes in a child undergoing treatment for autoimmune encephalitis. Toxicologic analysis extended to parents, leading to disclosure.","limitations":"Single case report cannot establish frequency of this behavior. The specific CBD product was not characterized. The contribution of CBD to the child's behavioral changes could not be definitively determined."},{"rthcId":"RTHC-04189","title":"Getting high for likes: Exploring cannabis-related content on TikTok.","authors":"Rutherford, Brienna N; Sun, Tianze; Johnson, Benjamin; Co, Steven; Lim, Tong Liang; Lim, Carmen C W; Chiu, Vivian; Leung, Janni; Stjepanovic, Daniel; Connor, Jason P; Chan, Gary C K","year":2022,"journal":"Drug and alcohol review, 41(5), 1119-1125","doi":"10.1111/dar.13433","pmid":"35073422","tags":["youth","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"54.14% of videos portrayed cannabis positively (417 million total views). 15.84% depicted cannabis products. Themes: entertaining/humorous (71.74%), personal experiences (42.90%), social/cultural acceptability (24.63%). No videos were age-restricted. All were publicly accessible.","whyItMatters":"TikTok reaches massive youth audiences, with a third of users under 14. The absence of age restrictions on pro-cannabis content means young adolescents are routinely exposed to positive cannabis messaging, which research shows can influence attitudes and use.","specificNumbers":"881 videos analyzed. Median views: 518,700. Median likes: 99,900. Positive portrayal: 54.14% (417M collective views). Humorous content: 71.74%. Personal experiences: 42.90%. Social acceptability: 24.63%. Age-restricted: 0%.","methodology":"Content analysis of 1,377 cannabis-related TikTok videos identified through hashtag-based searches. After removing duplicates and irrelevant content, 881 videos were coded by 7 researchers for sentiment, theme, and video metrics.","limitations":"Hashtag-based sampling may not capture all cannabis content (misspellings, slang). The analysis captured a snapshot in time; TikTok content changes rapidly. Viewing a video does not necessarily change behavior. Cultural context of viewers was not assessed."},{"rthcId":"RTHC-04190","title":"Effects of Cannabidiol on Exercise Physiology and Bioenergetics: A Randomised Controlled Pilot Trial.","authors":"Sahinovic, Ayshe; Irwin, Christopher; Doohan, Peter T; Kevin, Richard C; Cox, Amanda J; Lau, Namson S; Desbrow, Ben; Johnson, Nathan A; Sabag, Angelo; Hislop, Matthew; Haber, Paul S; McGregor, Iain S; McCartney, Danielle","year":2022,"journal":"Sports medicine - open, 8(1), 27","doi":"10.1186/s40798-022-00417-y","pmid":"35235092","tags":["cbd","exercise"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CBD appeared to increase VO2 during steady-state running, ratings of pleasure, and blood lactate. During the incremental test, CBD appeared to increase VO2max and respiratory exchange ratio. No differences in time to exhaustion, heart rate, or perceived exertion. CBD reduced post-exercise IL-6 concentrations.","whyItMatters":"Athletes are increasingly using CBD for recovery and performance. This is among the first controlled studies examining CBD's acute effects on exercise physiology, finding it changes metabolic responses without impairing performance.","specificNumbers":"9 participants, VO2max 57.4 mL/min/kg. CBD dose: 300 mg oral. VO2 increased during steady-state running. Pleasure ratings increased. VO2max appeared higher (+119 mL/min). RERmax increased. IL-6 reduced post-exercise. No differences in time to exhaustion or heart rate.","methodology":"Randomized, double-blind, placebo-controlled crossover pilot study. 9 endurance-trained males (mean VO2max 57.4 mL/min/kg) completed two sessions: 60 min at 70% VO2max followed by an incremental test to exhaustion. 300 mg oral CBD or placebo given 1.5 hours before exercise.","limitations":"Very small sample (9 males). Pilot study with wide confidence intervals. Effects assessed using effect sizes rather than traditional significance testing. Only one CBD dose tested. Acute dosing may not reflect chronic use patterns."},{"rthcId":"RTHC-04191","title":"Developing a real-world evidence base for prescribed cannabis in the United Kingdom: preliminary findings from Project Twenty21.","authors":"Sakal, C; Lynskey, M; Schlag, A K; Nutt, D J","year":2022,"journal":"Psychopharmacology, 239(5), 1147-1155","doi":"10.1007/s00213-021-05855-2","pmid":"33970291","tags":["medical-cannabis","pain","anxiety"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"678 patients enrolled in 7 months. 64% male, average age 38.7 years. Most common conditions: chronic pain (55.6%), anxiety disorders (32.0%). High multi-morbidity including insomnia and depression. Three-month follow-up of 75 patients showed significant self-reported health improvement (Cohen's d=0.77, 95% CI 0.51-1.03).","whyItMatters":"Despite legalizing medical cannabis in 2018, the UK has issued very few NHS prescriptions. Project Twenty21 is building the real-world evidence base that clinicians demand before prescribing, bridging the gap between legalization and clinical practice.","specificNumbers":"678 enrolled in 7 months. 64% male. Mean age 38.7 (range 18-80). Chronic pain: 55.6%. Anxiety: 32.0%. 3-month follow-up (n=75): EQ-5D VAS improvement Cohen's d=0.77 (95% CI 0.51-1.03). High multi-morbidity rates.","methodology":"Prospective observational registry launched August 2020. Patients prescribed legal cannabis through UK clinics enrolled and completed EQ-5D-5L health assessments at baseline and follow-up. Descriptive analysis of first 7 months of enrollment with preliminary 3-month outcome data.","limitations":"Observational design without a control group. Only 75 patients had 3-month follow-up data at time of publication. Self-reported health improvements could reflect placebo effects or regression to the mean. Patients paying privately for cannabis may differ from typical NHS populations."},{"rthcId":"RTHC-04192","title":"Substance use, affective symptoms, and suicidal ideation among Russian, Somali, and Kurdish migrants in Finland.","authors":"Salama, Essi; Castaneda, Anu E; Suvisaari, Jaana; Rask, Shadia; Laatikainen, Tiina; Niemelä, Solja","year":2022,"journal":"Transcultural psychiatry, 59(1), 37-51","doi":"10.1177/1363461520906028","pmid":"32164497","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04193","title":"Differentiating Cannabis Products: Drugs, Food, and Supplements.","authors":"Salehi, Arash; Puchalski, Keely; Shokoohinia, Yalda; Zolfaghari, Behzad; Asgary, Sedigheh","year":2022,"journal":"Frontiers in pharmacology, 13, 906038","doi":"10.3389/fphar.2022.906038","pmid":"35833025","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04194","title":"Analysis of toxicity effects of delta-9-tetrahydrocannabinol on isolated rat heart mitochondria.","authors":"Salimi, Ahmad; Niknejad, Mohsen; Minouei, Morteza; Mojarad Aylar, Elham","year":2022,"journal":"Toxicology mechanisms and methods, 32(2), 106-113","doi":"10.1080/15376516.2021.1973168","pmid":"34431445","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04195","title":"Acute stress and alcohol exposure during adolescence result in an anxious phenotype in adulthood: Role of altered glutamate/endocannabinoid transmission mechanisms.","authors":"Sánchez-Marín, Laura; Flores-López, Maria; Pastor, Antoni; Gavito, Ana Luisa; Suárez, Juan; de la Torre, Rafael; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Serrano, Antonia","year":2022,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 113, 110460","doi":"10.1016/j.pnpbp.2021.110460","pmid":"34695542","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04196","title":"Medical cannabis use in Canadians with multiple sclerosis.","authors":"Santarossa, Talia M; So, Randy; Smyth, Dr Penelope; Gustavsen, Dr Stefan; Tsuyuki, Dr Ross T","year":2022,"journal":"Multiple sclerosis and related disorders, 59, 103638","doi":"10.1016/j.msard.2022.103638","pmid":"35382939","tags":["medical-cannabis","pain","sleep"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"64.5% had tried medical cannabis, 52.3% were currently using it. More severe/progressive MS predicted cannabis use. Top uses: sleep (84.2%), pain (80.0%), spasticity (68.4%). Top side effects: drowsiness (57.2%), feeling subdued (48.8%), difficulty concentrating (28.4%). 76.1% obtained from legal sources. 74% learned about cannabis from non-healthcare providers.","whyItMatters":"This is the first comprehensive Canadian survey of MS cannabis use since recreational legalization. The finding that 74% learn about cannabis outside the healthcare system suggests a major information gap that clinicians need to address.","specificNumbers":"344 respondents. Ever tried cannabis: 64.5% (215/344). Current users: 52.3% (180/344). Uses: sleep 84.2%, pain 80.0%, spasticity 68.4%. Side effects: drowsiness 57.2%, feeling subdued 48.8%, concentration difficulty 28.4%. Legal source: 76.1%. Non-healthcare info source: 74%.","methodology":"Anonymous questionnaire distributed to 344 Canadians with MS through various channels. Included questions on MS characteristics, quality of life (PDDS, MSQOL-54), and medical cannabis use patterns.","limitations":"Self-selected survey respondents may overrepresent cannabis users. Cross-sectional design cannot assess whether cannabis objectively improved MS symptoms. No medical record verification. The 344-person sample may not represent all Canadian MS patients."},{"rthcId":"RTHC-04197","title":"Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.","authors":"Sarikahya, Mohammed H; Cousineau, Samantha; De Felice, Marta; Lee, Kendrick; Wong, Karen Kw; DeVuono, Marieka V; Jung, Tony; Rodríguez-Ruiz, Mar; Ng, Tsun Hay Jason; Gummerson, Dana; Proud, Emma; Hardy, Daniel B; Yeung, Ken K-C; Rushlow, Walter; Laviolette, Steven R","year":2022,"journal":"eNeuro, 9(5)","doi":"10.1523/ENEURO.0253-22.2022","pmid":"36171057","tags":["pregnancy","neuroscience","sex-differences","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal THC exposure induced lasting behavioral and neuronal changes in male and female rat offspring resembling neuropsychiatric conditions, with profound disruption of fatty acid pathways in the developing brain.","whyItMatters":"This study identifies specific biological mechanisms through which prenatal cannabis exposure may alter brain development, showing that THC disrupts the brain's fatty acid landscape in ways that differ between males and females.","specificNumbers":"THC dose was 3 mg/kg daily from GD7 to GD22. Females showed significant fatty acid alterations at prepubescence but recovered by adulthood. Males had persistent fatty acid deficits into adulthood. Both sexes showed enduring glutamatergic/GABAergic dysfunction in the nucleus accumbens.","methodology":"Pregnant Wistar rats received THC (3 mg/kg) or vehicle from gestational day 7 to 22. Adult offspring underwent behavioral testing, electrophysiology, molecular assays, and MALDI imaging mass spectrometry of brain fatty acids at prepubescence and adulthood.","limitations":"This is an animal study, so results may not directly translate to humans. The THC dose and route of administration differ from typical human consumption patterns. The study used only THC, not whole cannabis with its many other compounds."},{"rthcId":"RTHC-04198","title":"The associations of cannabis and methamphetamine use with cognitive performance over the first 2 years of treatment in schizophrenia spectrum disorders.","authors":"Scheffler, Freda; Phahladira, Lebogang; Hendrikse, Chanellé B; du Plessis, Stefan; Asmal, Laila; Luckhoff, Hilmar K; Smit, Anna Margaretha; Olivier, M Riaan; Emsley, Robin","year":2022,"journal":"Early intervention in psychiatry, 16(11), 1230-1239","doi":"10.1111/eip.13272","pmid":"35108745","tags":["cognition","psychosis","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In 81 patients with first-episode schizophrenia spectrum disorders treated over 24 months, positive methamphetamine tests predicted less cognitive improvement, but positive cannabis tests did not.","whyItMatters":"This study helps disentangle the cognitive effects of different substances in people with schizophrenia, a population where substance use is common and cognitive outcomes are critical for functioning.","specificNumbers":"81 patients and 100 controls followed for 24 months. Patients improved cognitively with treatment but remained significantly below controls throughout. Methamphetamine, not cannabis, predicted less cognitive improvement.","methodology":"Longitudinal cohort study of 81 patients treated with flupenthixol decanoate over 24 months. Cognition assessed with the MATRICS battery at four time points; urine testing for cannabis and methamphetamine at six time points. Compared to 100 matched controls.","limitations":"Substance use was measured by urine testing, which has a limited detection window. The study was observational, so it cannot establish causation. Sample size was moderate."},{"rthcId":"RTHC-04199","title":"Cannabis Adaptation During and After Alcohol Ignition Interlock Device Installation: A Longitudinal Study.","authors":"Scherer, Michael; Romano, Eduardo; King, Sagan; Marques, Paul; Romosz, Ann; Taylor, Eileen; Nochajski, Thomas H; Voas, Robert; Manning, Amy; Tippetts, Scott","year":2022,"journal":"Journal of studies on alcohol and drugs, 83(4), 486-493","doi":null,"pmid":"35838425","tags":["driving","harm-reduction","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 189 DUI-convicted drivers, those who decreased alcohol use while an ignition interlock device was installed significantly increased cannabis use, which continued to rise after the device was removed.","whyItMatters":"Alcohol interlock devices effectively prevent drunk driving, but this study reveals an unintended consequence: some drivers substitute cannabis for alcohol, creating a different impairment risk.","specificNumbers":"189 participants completed all three waves. Cannabis use increased across the study period overall. Drivers who decreased alcohol during IID use significantly increased cannabis, with further increases after device removal.","methodology":"Three-wave longitudinal study of 189 New York State DUI-convicted drivers from 2015 to 2020. Oral fluid and blood samples measured cannabis use; hair samples measured alcohol use. Assessed at IID installation, removal, and 6-month follow-up.","limitations":"Sample size was moderate at 189. The study was conducted in New York State, which may limit generalizability. Self-selection effects may be at play, as those who reduce alcohol may already be predisposed to use other substances."},{"rthcId":"RTHC-04200","title":"Cys-loop receptors on cannabinoids: All high?","authors":"Schmiedhofer, Philip; Vogel, Florian Daniel; Koniuszewski, Filip; Ernst, Margot","year":2022,"journal":"Frontiers in physiology, 13, 1044575","doi":"10.3389/fphys.2022.1044575","pmid":"36439263","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04201","title":"A Placebo-Controlled Trial of Cannabinoid Treatment for Disruptive Behavior in Children and Adolescents with Autism Spectrum Disorder: Effects on Sleep Parameters as Measured by the CSHQ.","authors":"Schnapp, Aviad; Harel, Moria; Cayam-Rand, Dalit; Cassuto, Hanoch; Polyansky, Lola; Aran, Adi","year":2022,"journal":"Biomedicines, 10(7)","doi":"10.3390/biomedicines10071685","pmid":"35884990","tags":["cbd","sleep","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"CBD-rich cannabinoid treatment (20:1 CBD:THC ratio) was not superior to placebo for sleep in 150 children and adolescents with autism, including bedtime resistance, sleep-onset delay, and sleep duration.","whyItMatters":"Despite widespread anecdotal claims that cannabis products help autistic children sleep, this rigorous trial found no benefit over placebo, providing important data for families and clinicians making treatment decisions.","specificNumbers":"150 participants randomized across three arms. 12-week treatment periods with 4-week washout. CBD:THC ratio was 20:1. No significant differences from placebo on any CSHQ sleep measure.","methodology":"Double-blind, placebo-controlled crossover study of 150 children/adolescents with ASD. Three arms: whole-plant cannabis extract (20:1 CBD:THC), purified CBD/THC in same ratio, or placebo. Each treatment period lasted 12 weeks with 4-week washout. Sleep assessed via the Children's Sleep Habit Questionnaire.","limitations":"Sleep was measured by parent questionnaire rather than objective measures like actigraphy or polysomnography. The CBD:THC ratio was fixed at 20:1, so other ratios might yield different results. The crossover design may introduce period effects."},{"rthcId":"RTHC-04202","title":"Cannabis with breast cancer treatment: propitious or pernicious?","authors":"Schoeman, Recardia; de la Harpe, Amy; Beukes, Natasha; Frost, Carminita L","year":2022,"journal":"3 Biotech, 12(2), 54","doi":"10.1007/s13205-021-03102-1","pmid":"35127309","tags":["cancer","drug-interactions","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Simultaneous treatment of MCF-7 breast cancer cells with various cannabinoid formulations and tamoxifen resulted in diminished anti-proliferative activity of tamoxifen, with the effect more pronounced with recreational cannabis formulations (higher THC).","whyItMatters":"Many cancer patients use cannabis for symptom management during treatment. If cannabinoids interfere with tamoxifen effectiveness, this could have real clinical consequences for breast cancer outcomes.","specificNumbers":"An intra-entourage effect was found in MCF-7 cells with recreational but not medicinal cannabis formulations. No inter-entourage effects in either cell line. Tamoxifen's anti-proliferative activity was diminished when combined with cannabinoids, especially recreational formulations.","methodology":"In vitro study using two breast cancer cell lines (MCF-7 and MDA-MB-231). Tested purified phytocannabinoid combinations mimicking medicinal and recreational cannabis strains, a Cannabis sativa extract, and combinations with tamoxifen.","limitations":"This is a cell-line study, and in vitro results may not reflect what happens in the human body. Only two cell lines were tested. The cannabinoid concentrations used may not match those achieved in human tissue."},{"rthcId":"RTHC-04203","title":"Cannabis alters DNA methylation at maternally imprinted and autism candidate genes in spermatogenic cells.","authors":"Schrott, Rose; Greeson, Katherine W; King, Dillon; Symosko Crow, Krista M; Easley, Charles A; Murphy, Susan K","year":2022,"journal":"Systems biology in reproductive medicine, 68(5-6), 357-369","doi":"10.1080/19396368.2022.2073292","pmid":"35687495","tags":["genetics","pregnancy","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In an in vitro human spermatogenesis model, cannabis exposure significantly altered DNA methylation at maternally imprinted genes (SGCE, GRB10, PEG3) and autism candidate genes (HCN1, NR4A2) in spermatogonial stem cell-like and spermatid-like cells.","whyItMatters":"This study provides a mechanistic link between paternal cannabis use and potential heritable changes at genes associated with autism, supporting epidemiological observations of increased ASD risk in children of cannabis-using fathers.","specificNumbers":"Methylation changes found at 3 imprinted genes (SGCE, GRB10, PEG3) and 2 of 10 randomly selected ASD candidate genes (HCN1, NR4A2).","methodology":"Used an in vitro human spermatogenesis model to simulate chronic cannabis exposure. Assessed DNA methylation at imprinted genes and 10 randomly selected ASD candidate genes in spermatogonial stem cell (SSC)-like and spermatid-like cells.","limitations":"This is an in vitro model, not actual human sperm from cannabis users. Only 10 ASD candidate genes were sampled. The functional consequences of these methylation changes on offspring are not established."},{"rthcId":"RTHC-04204","title":"Sperm DNA methylation alterations from cannabis extract exposure are evident in offspring.","authors":"Schrott, Rose; Modliszewski, Jennifer L; Hawkey, Andrew B; Grenier, Carole; Holloway, Zade; Evans, Janequia; Pippen, Erica; Corcoran, David L; Levin, Edward D; Murphy, Susan K","year":2022,"journal":"Epigenetics & chromatin, 15(1), 33","doi":"10.1186/s13072-022-00466-3","pmid":"36085240","tags":["genetics","pregnancy","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis extract exposure caused 3,321 differentially methylated sites in rat sperm, some of which persisted after a washout period. Select changes were detectable in offspring sperm and brain tissue, with a sex-specific relationship between methylation and gene expression. Offspring of exposed fathers had significant cardiomegaly.","whyItMatters":"This is the first study to characterize the entire rat sperm methylome after cannabis exposure and demonstrate that some changes are heritable, appearing in offspring tissues and associated with measurable health outcomes.","specificNumbers":"3,321 differentially methylated CpGs identified in exposed sperm. Pxylp1 methylation changes in fathers were also detectable in offspring sperm. Mtss1l changes found in offspring hippocampus and nucleus accumbens. Offspring of exposed fathers had significant cardiomegaly.","methodology":"Whole genome bisulfite sequencing of rat sperm across three groups: cannabis extract for 28 days then 56 days vehicle, vehicle then 28 days cannabis, or vehicle only. Males mated with drug-naive females. Offspring heart, brain, and sperm analyzed. Validated with bisulfite pyrosequencing.","limitations":"This is a rat study, so direct translation to humans is uncertain. The cannabis extract dosing may not mirror typical human use. The mechanism linking sperm methylation changes to offspring cardiomegaly is not yet clear."},{"rthcId":"RTHC-04205","title":"Memory Consolidation Depends on Endogenous Hippocampal Levels of Anandamide: CB1 and M4, but Possibly not TRPV1 Receptors Mediate AM404 effects.","authors":"Scienza-Martin, Krislei; Lotz, Fernanda Nogueira; Zanona, Querusche Klippel; Santana-Kragelund, Fabiana; Crestani, Ana Paula; Boos, Flávia Zacouteguy; Calcagnotto, Maria Elisa; Quillfeldt, Jorge Alberto","year":2022,"journal":"Neuroscience, 497, 53-72","doi":"10.1016/j.neuroscience.2022.04.009","pmid":"35436517","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04206","title":"Potential Mechanisms Underlying Marijuana-Associated Periodontal Tissue Destruction.","authors":"Scott, D A; Dukka, H; Saxena, D","year":2022,"journal":"Journal of dental research, 101(2), 133-142","doi":"10.1177/00220345211036072","pmid":"34515556","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04207","title":"Is there a rational basis for cannabinoids research and development in ocular pain therapy? A systematic review of preclinical evidence.","authors":"Scuteri, D; Rombolà, L; Hamamura, K; Sakurada, T; Watanabe, C; Sakurada, S; Guida, F; Boccella, S; Maione, S; Gallo Afflitto, G; Nucci, C; Tonin, P; Bagetta, G; Corasaniti, M T","year":2022,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 146, 112505","doi":"10.1016/j.biopha.2021.112505","pmid":"34891121","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04208","title":"Cannabinoids and Myocardial Ischemia: Novel insights, Updated Mechanisms, and Implications for Myocardial Infarction.","authors":"Seif El Dahan, Karim; Machtoub, Dima; Massoud, Gaelle; Nasser, Suzanne A; Hamam, Bassam; Kobeissy, Firas; Zouein, Fouad A; Eid, Ali H","year":2022,"journal":"Current medicinal chemistry, 29(11), 1990-2010","doi":"10.2174/0929867328666210608144818","pmid":"34102966","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04209","title":"Multimodal Correlates of Cannabis Use among U.S. Veterans with Bipolar Disorder: An Integrated Study of Clinical, Cognitive, and Functional Outcomes.","authors":"Selloni, Alexandria; Bhatia, Gagandeep; Ranganathan, Mohini; De Aquino, Joao P","year":2022,"journal":"Journal of dual diagnosis, 18(2), 81-91","doi":"10.1080/15504263.2022.2053264","pmid":"35430960","tags":["mental-health","cognition","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Current cannabis use in veterans with bipolar I disorder was associated with higher working memory performance and higher functional capacity compared to both past cannabis users and non-users, while also being associated with PTSD and lifetime suicidal ideation.","whyItMatters":"This study presents a nuanced picture: current cannabis use in bipolar disorder was linked to better cognitive and functional scores but also to PTSD and suicidal ideation, highlighting the complexity of cannabis effects in this population.","specificNumbers":"254 veterans (84.6% male). 5.1% current cannabis users, 14.5% past cannabis users. Current users showed higher working memory and functional capacity than past users and non-users.","methodology":"Cross-sectional analysis of 254 U.S. veterans with bipolar I disorder from a large-scale nationwide study. Categorized into current cannabis use (n=13), past cannabis use (n=37), past other drug use (n=77), and no drug use (n=127). Compared on clinical, cognitive, and functional measures.","limitations":"Very small current cannabis user group (n=13). Cross-sectional design cannot establish causation. Predominantly male veteran sample limits generalizability. Possible selection bias: those functioning better may be more able to maintain cannabis use."},{"rthcId":"RTHC-04210","title":"A Case Report on Cannabinoid Hyperemesis Syndrome in Palliative Care: How Good Intentions Can Go Wrong.","authors":"Senderovich, Helen; Waicus, Sarah","year":2022,"journal":"Oncology research and treatment, 45(7-8), 438-443","doi":"10.1159/000524746","pmid":"35504245","tags":["medical-cannabis","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 70-year-old palliative care patient with small-cell lung cancer who had used nabilone for 5 years developed refractory nausea and vomiting consistent with cannabinoid hyperemesis syndrome. Symptoms resolved after nabilone cessation.","whyItMatters":"This case demonstrates that CHS can occur with prescribed synthetic cannabinoids (not just recreational cannabis), a recognition gap that may lead clinicians to increase the very drug causing symptoms.","specificNumbers":"Patient used nabilone for 5 years. Dose increased from 0.5 to 2 mg. Nabilone discontinued after 7 weeks of refractory symptoms. Hot baths provided temporary relief. Pain was successfully managed with opioids and adjuvants after nabilone cessation.","methodology":"Single case report of a palliative care patient. Nabilone dose had been incrementally increased from 0.5 to 2 mg over the disease course. CHS was suspected when increasing nabilone worsened rather than alleviated nausea and vomiting.","limitations":"Single case report, so the findings cannot be generalized. The diagnosis was clinical, without a definitive biomarker for CHS."},{"rthcId":"RTHC-04211","title":"A Systematic Review on Cannabis Hyperemesis Syndrome and Its Management Options.","authors":"Senderovich, Helen; Patel, Preet; Jimenez Lopez, Briam; Waicus, Sarah","year":2022,"journal":"Medical principles and practice : international journal of the Kuwait University, Health Science Centre, 31(1), 29-38","doi":"10.1159/000520417","pmid":"34724666","tags":["harm-reduction","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabis cessation is the most successful management for CHS. Other treatments demonstrating symptom relief include hot water hydrotherapy, topical capsaicin cream, haloperidol, droperidol, benzodiazepines, propranolol, and aprepitant.","whyItMatters":"CHS is increasingly recognized in emergency departments and clinical settings. This review consolidates the evidence on treatment options, giving clinicians a practical reference for managing this condition.","specificNumbers":"225 records retrieved, 17 included. Cannabis use duration of 6 months to 11 years may precipitate CHS. Rome IV criteria require symptoms for at least 6 months. Multiple treatment options identified beyond cessation.","methodology":"Systematic review searching PubMed, MEDLINE, Cochrane, EMBASE, and Google Scholar for CHS articles from January 2009 to June 2021. Of 225 results, 17 were deemed relevant and reviewed by two independent reviewers.","limitations":"Only 17 studies met inclusion criteria, indicating limited evidence overall. Most included studies were case reports or small series. No randomized trials comparing treatments were available."},{"rthcId":"RTHC-04212","title":"The Effectiveness of Cannabis and Cannabis Derivatives in Treating Lower Back Pain in the Aged Population: A Systematic Review.","authors":"Senderovich, Helen; Wagman, Hayley; Zhang, Dennis; Vinoraj, Danusha; Waicus, Sarah","year":2022,"journal":"Gerontology, 68(6), 612-624","doi":"10.1159/000518269","pmid":"34515130","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04213","title":"Longitudinal effects of cannabis use on attentional processes in patients with first episode of psychosis.","authors":"Setién-Suero, Esther; Ayesa-Arriola, Rosa; Peña, Javier; Crespo-Facorro, Benedicto; Ojeda, Natalia","year":2022,"journal":"Schizophrenia research, 244, 71-80","doi":"10.1016/j.schres.2022.05.011","pmid":"35640355","tags":["cognition","psychosis","youth","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Over 3 years, attention improved most in FEP patients who never used cannabis (n=238), followed by ex-users (n=105) and persistent users (n=43). At follow-up, ex-users achieved attention scores closest to those of healthy controls.","whyItMatters":"This is one of the largest and longest studies to show that quitting cannabis after a first psychotic episode is associated with meaningful cognitive recovery, with former users ultimately performing near the level of healthy individuals.","specificNumbers":"648 total participants (461 patients, 187 controls). 35.3% were cannabis users (187 patients, 42 controls). At 3 years: never-users improved most, ex-users (n=105) reached scores closest to healthy controls, persistent users (n=43) improved least.","methodology":"Longitudinal study of 461 FEP patients and 187 healthy controls. Cannabis use status categorized as never-user, ex-user, or persistent user. Neuropsychological attention tests administered at baseline and 3-year follow-up.","limitations":"Observational design, so unmeasured factors may explain differences between groups. Cannabis use was categorized broadly without detailed frequency or potency data. Attrition over 3 years may introduce selection bias."},{"rthcId":"RTHC-04214","title":"White Matter Microstructure and Gray Matter Volume in Cannabis-Induced Psychosis and Schizophrenia With Cannabis Use.","authors":"Shah, Raghav; Ghosh, Abhishek; Avasthi, Ajit; Ahuja, Chirag K; Khandelwal, Niranjan; Nehra, Ritu","year":2022,"journal":"The Journal of neuropsychiatry and clinical neurosciences, 34(4), 406-413","doi":"10.1176/appi.neuropsych.21070172","pmid":"35872614","tags":["psychosis","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Participants with schizophrenia and cannabis use (SZC) had widespread white matter microstructural abnormalities, while those with cannabis-induced psychosis (CIP) had fewer WM disruptions and greater gray matter volumes in the cerebellum and frontal regions.","whyItMatters":"Understanding the brain differences between cannabis-induced psychosis and schizophrenia helps explain why some cannabis users develop temporary psychosis while others progress to a chronic condition.","specificNumbers":"60 participants (20 per group). CIP and SZC groups had comparable cannabis use history. SZC showed lower fractional anisotropy in 5 brain regions vs controls. CIP had higher FA than SZC in the left corticospinal tract. CIP had greater cerebellar GM volume than SZC.","methodology":"Cross-sectional study with three groups of 20 participants: cannabis-induced psychosis, schizophrenia with cannabis use, and controls without substance use. Used diffusion tensor and kurtosis imaging for white matter analysis and voxel-based morphometry for gray matter.","limitations":"Small sample size of 20 per group. Cross-sectional design cannot determine whether brain differences preceded or resulted from the conditions. Convenience sampling may limit representativeness."},{"rthcId":"RTHC-04215","title":"Cannabidiol impairs the rewarding effects of methamphetamine: Involvement of dopaminergic receptors in the nucleus accumbens.","authors":"Sharifi, Asrin; Karimi-Haghighi, Saeideh; Shabani, Ronak; Asgari, Hamid Reza; Ahadi, Reza; Haghparast, Abbas","year":2022,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 113, 110458","doi":"10.1016/j.pnpbp.2021.110458","pmid":"34662693","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04216","title":"Evaluating cannabis use risk reduction as an alternative clinical outcome for cannabis use disorder.","authors":"Sherman, Brian J; Sofis, Michael J; Borodovsky, Jacob T; Gray, Kevin M; McRae-Clark, Aimee L; Budney, Alan J","year":2022,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 36(5), 505-514","doi":"10.1037/adb0000760","pmid":"34197135","tags":["addiction","harm-reduction","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Cannabis risk levels based on frequency and quantity were sensitive to reductions in use. Greater magnitude of risk level reduction was associated with greater decreases in depression, anxiety, and cannabis-related problems.","whyItMatters":"Since most CUD treatment trials fail to achieve abstinence, identifying clinically meaningful reduction targets gives researchers and clinicians a more realistic way to measure treatment success.","specificNumbers":"225 treatment-seeking adults (mean age 30.6, 70.2% male, 42.2% non-White). Risk level changes from baseline to end-of-treatment were significant for both frequency (p=.004) and quantity (p<.001). Effect sizes for cannabis-related problems were substantial (partial eta-squared = .12).","methodology":"Secondary analysis of a 12-week double-blind randomized placebo-controlled medication trial for cannabis cessation (N=225). Frequency and quantity defined high-, medium-, and low-risk levels. Anxiety and depression assessed with HADS; problems with the Marijuana Problems Scale.","limitations":"Secondary analysis of a trial designed for cessation, not reduction. Risk levels were defined by the researchers and not yet validated externally. The 12-week timeframe may not capture long-term outcomes."},{"rthcId":"RTHC-04217","title":"Non-Canonical Cannabinoid Receptors with Distinct Binding and Signaling Properties in Prostate and Other Cancer Cell Types Mediate Cell Death.","authors":"Shoeib, Amal M; Benson, Lance N; Mu, Shengyu; MacMillan-Crow, Lee Ann; Prather, Paul L","year":2022,"journal":"International journal of molecular sciences, 23(6)","doi":"10.3390/ijms23063049","pmid":"35328467","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04218","title":"Urinary Excretion Profile of Cannabinoid Analytes Following Acute Administration of Oral and Vaporized Cannabis in Infrequent Cannabis Users.","authors":"Sholler, Dennis J; Zamarripa, C Austin; Spindle, Tory R; Martin, Erin L; Kuntz, David; Vandrey, Ryan; Grabenauer, Megan","year":2022,"journal":"Journal of analytical toxicology, 46(8), 882-890","doi":"10.1093/jat/bkac042","pmid":"35770374","tags":["potency","workplace","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Using federal workplace drug-testing criteria (50 ng/mL screening, 15 ng/mL confirmation), urine specimens tested positive for THC-COOH in 97.6% of oral cannabis sessions versus 59.5% of vaporized sessions at active THC doses.","whyItMatters":"With vaping and edibles now common methods of cannabis consumption, understanding how different administration routes affect drug testing has direct implications for workplace testing policies and legal proceedings.","specificNumbers":"21 participants. Peak concentrations occurred at 5-6 hours (oral) and 4 hours (vaporized). At active doses, 97.6% of oral sessions and 59.5% of vaporized sessions produced positive results at standard federal cutoffs. Oral administration produced quantitatively higher maximum concentrations for all detected analytes.","methodology":"Double-blind, six-session study of 21 infrequent cannabis users (11 men, 10 women). Participants ingested cannabis brownies (0, 10, 25 mg THC) and inhaled vaporized cannabis (0, 5, 20 mg THC). Urinary concentrations of 9 cannabinoid analytes measured at baseline and for 8 hours.","limitations":"Only 21 participants, all infrequent users. The 8-hour window may not capture the full excretion profile. Results may not generalize to frequent users who have accumulated THC stores."},{"rthcId":"RTHC-04219","title":"Diagnostic Difficulties and Treatment Challenges of a Young Patient With Severe Acute Psychosis and Complete Recovery.","authors":"Siembida, Jagoda; Mohammed, Saaduddin; Chishty, Mariam; Leontieva, Luba","year":2022,"journal":"Cureus, 14(4), e23744","doi":"10.7759/cureus.23744","pmid":"35509728","tags":["psychosis","youth","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A young adult presenting with multiple potential contributors to psychosis (cannabis use disorder, excessive vaping, COVID-19 history, pineal cyst, extreme hypertension) achieved complete recovery on haloperidol and a mood stabilizer, highlighting the diagnostic complexity of first-break psychosis.","whyItMatters":"First-break psychosis in young adults is often oversimplified as either substance-induced or schizophrenia-spectrum. This case shows how multiple factors can converge, making diagnosis uncertain but complete recovery still possible.","specificNumbers":"One patient with typical onset age for psychotic symptoms. Multiple potential contributing factors identified. Complete recovery achieved on first-generation antipsychotic plus mood stabilizer.","methodology":"Single case report with clinical documentation of symptoms, diagnostic workup, treatment course, and outcome.","limitations":"Single case report cannot establish causation or generalizability. The relative contribution of each factor (cannabis, COVID, pineal cyst, hypertension) remains unknown."},{"rthcId":"RTHC-04220","title":"The Construct of Medical and Non-Medical Marijuana-Critical Review.","authors":"Silczuk, Andrzej; Smułek, Daria; Kołodziej, Marcin; Gujska, Julia","year":2022,"journal":"International journal of environmental research and public health, 19(5)","doi":"10.3390/ijerph19052769","pmid":"35270462","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04221","title":"Cannabis and cannabinoid use in autism spectrum disorder: a systematic review.","authors":"Silva, Estácio Amaro da; Medeiros, Wandersonia Moreira Brito; Torro, Nelson; Sousa, João Marçal Medeiros de; Almeida, Igor Bronzeado Cahino Moura de; Costa, Filipe Barbosa da; Pontes, Katiúscia Moreira; Nunes, Eliane Lima Guerra; Rosa, Marine Diniz da; Albuquerque, Katy Lísias Gondim Dias de","year":2022,"journal":"Trends in psychiatry and psychotherapy, 44, e20200149","doi":"10.47626/2237-6089-2020-0149","pmid":"34043900","tags":["cbd","medical-cannabis","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 9 studies, cannabis products reduced the number or intensity of multiple ASD symptoms including hyperactivity, self-mutilation, anger, sleep problems, anxiety, irritability, and depression. Improvements were also reported in cognition, sensory sensitivity, attention, social interaction, and language.","whyItMatters":"Autism spectrum disorder has limited effective treatments for many of its associated symptoms. This review consolidates the growing evidence that cannabis-based products may offer relief for some of the most challenging aspects of ASD.","specificNumbers":"9 studies included. Improvements reported across multiple symptom domains. Most common adverse effects were sleep disorders, restlessness, nervousness, and appetite changes.","methodology":"Systematic review following PRISMA guidelines, searching MEDLINE/PubMed, SciELO, Scopus, and Web of Science with no language limits. Nine studies were selected and analyzed.","limitations":"Only 9 studies met inclusion criteria. Most were observational with small samples. Different cannabis products, doses, and formulations were used across studies, making direct comparison difficult."},{"rthcId":"RTHC-04222","title":"The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPARγ Receptors.","authors":"Silva, Nicole Rodrigues; Gomes, Francisco Isaac Fernandes; Lopes, Alexandre Hashimoto Pereira; Cortez, Isadora Lopes; Dos Santos, Jéssica Cristina; Silva, Conceição Elidianne Aníbal; Mechoulam, Raphael; Gomes, Felipe Villela; Cunha, Thiago Mattar; Guimarães, Francisco Silveira","year":2022,"journal":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 19(1), 434-449","doi":"10.1007/s13311-021-01164-w","pmid":"34904193","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04223","title":"Use of cannabidiol in the treatment of epilepsy: Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.","authors":"Silvinato, Antônio; Floriano, Idevaldo; Bernardo, Wanderley Marques","year":2022,"journal":"Revista da Associacao Medica Brasileira (1992), 68(10), 1345-1357","doi":"10.1590/1806-9282.2022D689","pmid":"36417631","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"CBD compared to placebo reduced seizure frequency by 33%, increased 50% seizure reduction by 20%, increased seizure freedom by 3%, and improved caregiver-assessed clinical impression by 21% in patients with refractory epilepsy.","whyItMatters":"This meta-analysis provides the strongest quantitative evidence to date supporting CBD as an add-on treatment for three of the most difficult-to-treat pediatric epilepsy syndromes.","specificNumbers":"1,034 patients across 6 RCTs. Seizure frequency reduced 33%. Patients with 50%+ reduction increased by 20%. Seizure-free patients increased by 3%. Caregiver improvement 21%. Total adverse events increased 12%. Serious adverse events increased 16%. Treatment abandonment increased 12%. Transaminase elevation (3x+ reference) increased 15%.","methodology":"Systematic review with meta-analysis of 6 RCTs (3 primary, 3 open-label extensions) totaling 1,034 patients with Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex. Searched MEDLINE, Cochrane Central, and ClinicalTrials.gov through April 2022. Followed PRISMA guidelines.","limitations":"Only 6 RCTs available. The included epilepsy syndromes are rare, so generalizability to other seizure types is uncertain. The increase in serious adverse events and liver enzyme elevations is notable."},{"rthcId":"RTHC-04224","title":"The effects of cannabis and alcohol on driving performance and driver behaviour: a systematic review and meta-analysis.","authors":"Simmons, Sarah M; Caird, Jeff K; Sterzer, Frances; Asbridge, Mark","year":2022,"journal":"Addiction (Abingdon, England), 117(7), 1843-1856","doi":"10.1111/add.15770","pmid":"35083810","tags":["driving","harm-reduction","cognition"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis alone impaired lateral control (lane weaving) and decreased driving speed. Cannabis combined with alcohol produced greater driving impairment than either substance alone. Cannabis effects on driving were similar to low blood alcohol concentrations.","whyItMatters":"This is the largest meta-analysis of experimental driving studies on cannabis to date, providing definitive evidence that cannabis impairs driving performance and that the combination with alcohol is particularly dangerous.","specificNumbers":"57 studies, 1,725 participants. Cannabis lateral position variability: g=0.331. Lane excursions: g=0.198. Cannabis+alcohol vs alcohol alone: g=0.480 for lateral variability, g=0.525 for time out of lane. Cannabis+alcohol vs cannabis alone: g=0.336 for lateral variability.","methodology":"Systematic review and meta-analysis of 57 experimental driving studies (simulator, closed-course, on-road) involving cannabis and/or alcohol administration with 1,725 participants. Searched 9 databases. Used Hedges' g effect sizes.","limitations":"Most studies used driving simulators rather than on-road conditions. Study heterogeneity limited interpretation of some measures. THC doses and timing varied across studies."},{"rthcId":"RTHC-04225","title":"Endocannabinoid system contributions to sex-specific adolescent neurodevelopment.","authors":"Simone, Jonathan J; Green, Matthew R; McCormick, Cheryl M","year":2022,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 113, 110438","doi":"10.1016/j.pnpbp.2021.110438","pmid":"34534603","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04226","title":"Cannabis Use for Endometriosis: Clinical and Legal Challenges in Australia and New Zealand.","authors":"Sinclair, Justin; Toufaili, Yasmine; Gock, Sarah; Pegorer, Amanda G; Wattle, Jordan; Franke, Martin; Alzwayid, Muayed A K M; Abbott, Jason; Pate, David W; Sarris, Jerome; Armour, Mike","year":2022,"journal":"Cannabis and cannabinoid research, 7(4), 464-472","doi":"10.1089/can.2021.0116","pmid":"34978929","tags":["medical-cannabis","pain","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"72% of Australian and 88.2% of NZ endometriosis patients using cannabis obtained it illicitly rather than through legal medical channels. Substantial medication substitution effects were reported: 66.1% reduced opioids by over 50%, 63.1% reduced non-opioid pain medication by over 50%.","whyItMatters":"Despite legal medicinal cannabis being available in both countries, the vast majority of endometriosis patients using cannabis do so without medical supervision, creating potential safety risks from drug interactions and unsupervised medication changes.","specificNumbers":"237 respondents. 72% Australian and 88.2% NZ respondents used illicit cannabis. Only 23.1% Australian and 5.9% NZ accessed through prescription. Over 50% reduction reported in: opioid use (66.1%), non-opioid analgesics (63.1%), antineuropathics (61.7%), antianxiety medications (47.9%). 18.8% Australian and 23.5% NZ respondents did not disclose cannabis use to doctors.","methodology":"Anonymous cross-sectional online survey distributed through social media via endometriosis advocacy groups. 237 respondents with medical diagnosis of endometriosis who reported cannabis use. Assessed legal vs illicit usage, access pathways, and healthcare provider interactions.","limitations":"Self-selected sample recruited through advocacy groups may overrepresent cannabis-favorable attitudes. Self-reported outcomes without clinical verification. Survey design cannot establish causal medication substitution."},{"rthcId":"RTHC-04227","title":"\"Should I Inhale?\"-Perceptions, Barriers, and Drivers for Medicinal Cannabis Use amongst Australian Women with Primary Dysmenorrhoea: A Qualitative Study.","authors":"Sinclair, Justin; Armour, Susanne; Akowuah, Jones Asafo; Proudfoot, Andrew; Armour, Mike","year":2022,"journal":"International journal of environmental research and public health, 19(3)","doi":"10.3390/ijerph19031536","pmid":"35162564","tags":["medical-cannabis","pain","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Dissatisfaction with over-the-counter pain medication was the primary driver for wanting medicinal cannabis. Key barriers included difficulty finding willing prescribers, cost, current drug driving laws, geographic isolation, and persistent stigma around cannabis even when prescribed.","whyItMatters":"Period pain affects millions of women, and current treatments are often inadequate. This study captures the real-world barriers women face in accessing a treatment option they believe could help, even where it is legally available.","specificNumbers":"26 women participated in virtual focus groups. All experienced regular moderate or greater menstrual pain. High cost of legal medicinal cannabis was identified as a key factor driving women to illicit cannabis instead.","methodology":"Qualitative study using virtual focus groups with 26 Australian women experiencing regular moderate-to-severe menstrual pain. Explored perceptions of medicinal cannabis including cost, stigma, driving laws, workplace ethics, and geographic access.","limitations":"Qualitative study with 26 participants cannot measure the prevalence of these views in the broader population. Recruited through social media, potentially attracting cannabis-favorable participants."},{"rthcId":"RTHC-04228","title":"Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles.","authors":"Sionov, Ronit Vogt; Steinberg, Doron","year":2022,"journal":"Biomedicines, 10(3)","doi":"10.3390/biomedicines10030631","pmid":"35327432","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04229","title":"Preconception cannabis use: An important but overlooked public health issue.","authors":"Skelton, Kara R; Young-Wolff, Kelly C","year":2022,"journal":"Women's health (London, England), 18, 17455057221124071","doi":"10.1177/17455057221124071","pmid":"36148938","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04230","title":"Simultaneous use of marijuana and alcohol: Potential prevention targets among young adults who use alcohol.","authors":"Skinner, Martie L; Guttmannova, Katarina; Oesterle, Sabrina; Kuklinski, Margaret R","year":2022,"journal":"Addictive behaviors, 124, 107118","doi":"10.1016/j.addbeh.2021.107118","pmid":"34583272","tags":["youth","harm-reduction","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Marijuana-specific attitudes (believing it is not wrong for their age) differentiated simultaneous or co-users from alcohol-only users. Perceived parental approval of marijuana use or heavy drinking was associated with 2.25 to 3.53 times greater odds of simultaneous alcohol-marijuana use versus non-simultaneous co-use.","whyItMatters":"Simultaneous alcohol and marijuana use is riskier than using either alone, associated with more binge drinking and impaired driving. Identifying modifiable risk factors like perceived parental attitudes helps target prevention efforts.","specificNumbers":"1,023 young adults. 20.7% reported simultaneous use, 12.6% non-simultaneous co-use, 66.6% alcohol only. Perceived parental approval of marijuana: OR 2.25-3.53 for SAM vs CAM.","methodology":"Cross-sectional analysis of 1,023 young adults (mean age 23.17). Compared past-30-day simultaneous alcohol-marijuana use (SAM, 20.7%), non-simultaneous co-use (CAM, 12.6%), and alcohol-only use (66.6%) using multinomial logistic regression.","limitations":"Cross-sectional design cannot establish causation. Self-reported perceived parental attitudes may not accurately reflect actual parental views. Sample was from a specific age cohort."},{"rthcId":"RTHC-04231","title":"Relation of Cannabis Use to Elevated Atherosclerotic Cardiovascular Disease Risk Score.","authors":"Skipina, Travis M; Patel, Nikhil; Upadhya, Bharathi; Soliman, Elsayed Z","year":2022,"journal":"The American journal of cardiology, 165, 46-50","doi":"10.1016/j.amjcard.2021.10.051","pmid":"34930616","tags":["cardiovascular","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Ever cannabis use was associated with 60% increased odds of a high-risk ASCVD score. A dose-response relationship was observed: those using 2+ times per month had 79% increased odds, and daily users had 87% increased odds of high-risk scores.","whyItMatters":"This large, nationally representative dataset shows a dose-dependent association between cannabis use and cardiovascular risk, adding to growing evidence that cannabis may not be as cardiovascularly benign as often assumed.","specificNumbers":"7,159 participants. 63.9% had ever used cannabis. Ever use: OR 1.60 for high ASCVD risk. 2+ uses/month: OR 1.79. Daily use: OR 1.87. All comparisons used low-risk ASCVD as reference.","methodology":"Cross-sectional analysis of 7,159 participants (mean age 37.8, 48.6% men, 61.5% Caucasian) from NHANES 2011-2018. Cannabis use defined by self-report. CVD risk assessed using the ACC/AHA 10-year ASCVD risk score. Participants with prior stroke or MI excluded.","limitations":"Cross-sectional design cannot prove causation. Cannabis use was self-reported. The ASCVD score is a composite measure, so it is unclear which specific risk factors drive the association. Confounders like tobacco co-use were not fully addressed."},{"rthcId":"RTHC-04232","title":"Neural responses to reward anticipation and feedback in adult and adolescent cannabis users and controls.","authors":"Skumlien, Martine; Mokrysz, Claire; Freeman, Tom P; Wall, Matthew B; Bloomfield, Michael; Lees, Rachel; Borissova, Anna; Petrilli, Kat; Carson, James; Coughlan, Tiernan; Ofori, Shelan; Langley, Christelle; Sahakian, Barbara J; Curran, H Valerie; Lawn, Will","year":2022,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(11), 1976-1983","doi":"10.1038/s41386-022-01316-2","pmid":"35388175","tags":["dopamine","youth","cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users and controls had similar neural responses during reward anticipation and in reward-related brain regions during feedback. No User-Group or User-Group by Age-Group effects were found. Bayesian analysis supported these null findings. Adolescents showed no increased vulnerability compared to adults.","whyItMatters":"The widespread belief that cannabis \"hijacks\" the brain's reward system is not supported by this large, well-designed study. The null findings, backed by Bayesian analysis, suggest reward processing may be largely intact in regular cannabis users.","specificNumbers":"125 participants total (adults 26-29 and adolescents 16-17). Cannabis users consumed 1-7 days per week. No differences in bilateral ventral striatum during anticipation. No differences in right ventral striatum or left vmPFC during feedback. Exploratory whole-brain analysis found greater fronto-parietal activity in users during feedback.","methodology":"Part of the CannTeen study. 125 adult (26-29 years) and adolescent (16-17 years) cannabis users (1-7 days/week) and matched controls underwent fMRI during the Monetary Incentive Delay task. Region of interest analyses of ventral striatum and ventromedial prefrontal cortex, plus whole-brain analyses.","limitations":"Cross-sectional design cannot rule out pre-existing differences. The Monetary Incentive Delay task measures monetary reward, which may not capture all dimensions of motivation. Cannabis users were regular but not necessarily heavy users."},{"rthcId":"RTHC-04233","title":"Cannabis and cannabinoids: pharmacology and therapeutic potential.","authors":"Śmiarowska, Małgorzata; Białecka, Monika; Machoy-Mokrzyńska, Anna","year":2022,"journal":"Neurologia i neurochirurgia polska, 56(1), 4-13","doi":"10.5603/PJNNS.a2022.0015","pmid":"35133644","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04234","title":"The phytochemical diversity of commercial Cannabis in the United States.","authors":"Smith, Christiana J; Vergara, Daniela; Keegan, Brian; Jikomes, Nick","year":2022,"journal":"PloS one, 17(5), e0267498","doi":"10.1371/journal.pone.0267498","pmid":"35588111","tags":["potency","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Distinct chemical phenotypes (chemotypes) were reliably present across commercial cannabis samples, but commercial labels (strain names, indica/sativa designations) did not consistently align with the observed chemical diversity, though certain labels showed biased associations with specific chemotypes.","whyItMatters":"Millions of consumers choose cannabis products based on strain names and indica/sativa labels that this study shows are unreliable predictors of what they are actually consuming, which has implications for both recreational and medical users.","specificNumbers":"Samples analyzed across 6 US states. Distinct chemotypes identified. Commercial labels did not consistently align with chemical diversity. Some labels showed biased (but not reliable) associations with specific chemotypes.","methodology":"Analyzed cannabinoid and terpene content of commercial cannabis samples across six US states. Compared observed phytochemical diversity to commercial labels. Identified chemotype clusters and assessed label-chemotype alignment.","limitations":"The study examined available commercial products, which may not represent all cannabis varieties. Terpene and cannabinoid profiles can be affected by growing conditions, harvest timing, and storage, introducing variability beyond genetics."},{"rthcId":"RTHC-04235","title":"Changes in Expression of DNA-Methyltransferase and Cannabinoid Receptor mRNAs in Blood Lymphocytes After Acute Cannabis Smoking.","authors":"Smith, Robert C; Sershen, Henry; Janowsky, David S; Lajtha, Abel; Grieco, Matthew; Gangoiti, Jon A; Gertsman, Ilya; Johnson, Wynnona S; Marcotte, Thomas D; Davis, John M","year":2022,"journal":"Frontiers in psychiatry, 13, 887700","doi":"10.3389/fpsyt.2022.887700","pmid":"35859599","tags":["genetics","psychosis","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"The 13.4% THC group showed significantly increased CB2 and DNMT3A mRNA levels at 4 hours post-smoking compared to placebo. TET3 mRNA levels were higher at 55 minutes post-ingestion. These changes suggest THC may have acute epigenetic effects in human blood cells.","whyItMatters":"This is one of the first human studies to show that smoking cannabis can rapidly alter epigenetic enzyme expression in blood cells. Since increased DNMT activity has been linked to schizophrenia pathophysiology, this may represent one mechanism connecting cannabis use to psychosis risk.","specificNumbers":"24 participants. 13.4% THC group: CB2 mRNA increased (p=0.021), DNMT3A increased (p=0.027), DNMT1 trended up (p=0.056) at 4 hours. TET3 increased at 55 minutes. When high and low THC groups were combined, no differences from placebo remained significant.","methodology":"Double-blind study with 24 regular cannabis users. Participants smoked cannabis cigarettes (5.9% or 13.4% THC) or placebo (0.02%) ad libitum. Blood drawn at baseline and multiple timepoints. Lymphocytes analyzed for mRNA content of cannabinoid receptors, methylation/demethylation enzymes, and immunological markers via qPCR.","limitations":"Very small sample (24 participants). The two THC groups did not differ in post-smoking blood THC levels despite different cigarette concentrations. Combined analysis showed no significant effects, suggesting the findings may be fragile. Only blood lymphocytes were examined."},{"rthcId":"RTHC-04236","title":"Growing ganja permission: a real gate-way for Thailand's promising industrial crop?","authors":"Sommano, Sarana Rose; Tangpao, Tibet; Pankasemsuk, Tanachai; Ponpanumas, Voranate; Phimolsiripol, Yuthana; Rachtanapun, Pornchai; Prasad, Shashanka K","year":2022,"journal":"Journal of cannabis research, 4(1), 10","doi":"10.1186/s42238-022-00121-4","pmid":"35249552","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04237","title":"Endocannabinoid Receptor Expression in Early Zebrafish Development.","authors":"Son, Hae-Won; Ali, Declan William","year":2022,"journal":"Developmental neuroscience, 44(3), 142-152","doi":"10.1159/000522383","pmid":"35168237","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04238","title":"Administration of Δ9-Tetrahydrocannabinol Following Controlled Cortical Impact Restores Hippocampal-Dependent Working Memory and Locomotor Function.","authors":"Song, Shijie; Kong, Xiaoyuan; Wang, Bangmei; Sanchez-Ramos, Juan","year":2022,"journal":"Cannabis and cannabinoid research, 7(4), 424-435","doi":"10.1089/can.2021.0053","pmid":"34747647","tags":["medical-cannabis","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC-treated mice exhibited marked improvement in Y-maze working memory performance and recovered to normal rotarod performance by 2 weeks after brain injury. THC upregulated neurotrophic factors G-CSF, BDNF, and GDNF and increased endocannabinoid 2-AG levels in the brain.","whyItMatters":"Traumatic brain injury has limited treatment options. This study suggests THC may promote brain self-repair by upregulating the same neurotrophic factors that have been shown to mediate recovery after TBI and stroke.","specificNumbers":"THC dose: 3 mg/kg IP for 3 days post-injury. Working memory recovered significantly in THC-treated mice. Rotarod performance normalized at 2 weeks. G-CSF, BDNF, and GDNF all significantly upregulated in cerebral cortex, striatum, and hippocampus. 2-AG levels also increased.","methodology":"C57BL/6J mice underwent controlled cortical impact (CCI) and received THC (3 mg/kg IP) for 3 days. Working memory (Y-maze spontaneous alternations) and locomotor function (rotarod) measured at baseline and 3, 7, and 14 days post-injury. Brain tissue analyzed for neurotrophic factors and endocannabinoid levels.","limitations":"Animal study with a single THC dose. The injury model (controlled cortical impact) represents only one type of TBI. The timeline was short (14 days). Human TBI is far more complex and variable."},{"rthcId":"RTHC-04239","title":"Genome-wide identification of the shared genetic basis of cannabis and cigarette smoking and schizophrenia implicates NCAM1 and neuronal abnormality.","authors":"Song, Weichen; Lin, Guan Ning; Yu, Shunying; Zhao, Min","year":2022,"journal":"Psychiatry research, 310, 114453","doi":"10.1016/j.psychres.2022.114453","pmid":"35235886","tags":["genetics","psychosis","neuroscience"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"A common genetic factor of cannabis and cigarette smoking explained 8.6% of schizophrenia heritability. Twenty independent loci were identified, with NCAM1 (neural cell adhesion molecule 1) highlighted as a top risk gene. Risk genes were enriched in cortex, neurons, and dendritic spines.","whyItMatters":"This study provides genetic evidence that the association between cannabis/smoking and schizophrenia is partly driven by shared biology, not just behavioral choices. NCAM1 is involved in neurodevelopment, suggesting a common vulnerability.","specificNumbers":"Over 780,000 total participants. Shared genetic factor explained 8.6% of schizophrenia heritability. 20 independent genome-wide significant loci. Top variant rs7945073 on chromosome 11. Genetic correlations with ADHD (r=0.50), social deprivation (r=0.58), lifestyle problems (r=0.83).","methodology":"Leveraged genome-wide summary statistics from three large datasets: schizophrenia (n=99,934), cigarette smoking (n=518,633), and cannabis usage (n=162,082). Applied CAUSE and Genomic SEM to identify shared genetic architecture.","limitations":"Summary-level statistics cannot establish individual-level causation. The study population was primarily European ancestry. The 8.6% explained heritability leaves most of the shared risk unexplained."},{"rthcId":"RTHC-04240","title":"Does cannabis use predict aggressive or violent behavior in psychiatric populations? A systematic review.","authors":"Sorkhou, Maryam; Johnstone, Samantha; Kivlichan, Ashley E; Castle, David J; George, Tony P","year":2022,"journal":"The American journal of drug and alcohol abuse, 48(6), 631-643","doi":"10.1080/00952990.2022.2118060","pmid":"36137273","tags":["mental-health","psychosis","ptsd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cross-sectional associations between cannabis use and aggression/violence were found in PTSD samples. Longitudinal associations were observed in psychotic-spectrum disorders. However, uncontrolled confounding factors in most studies preclude causal conclusions.","whyItMatters":"Understanding whether cannabis increases aggression risk in people with psychiatric conditions is critical for clinical decision-making, but this review shows the evidence is not yet strong enough to draw firm conclusions.","specificNumbers":"391 papers identified, 15 met inclusion criteria. Cross-sectional associations found in PTSD samples. Longitudinal associations found in psychotic-spectrum disorders.","methodology":"Systematic review following PRISMA guidelines, searching PubMed, Google Scholar, MEDLINE, and PsycINFO from inception to January 2022. Of 391 papers, 15 met inclusion criteria examining aggression/violence in people with psychiatric diagnoses who use cannabis.","limitations":"Only 15 studies met criteria. Most had uncontrolled confounders. The review mixed cross-sectional and longitudinal designs. Different definitions of aggression and violence were used across studies."},{"rthcId":"RTHC-04241","title":"Synthesis and pharmacological evaluation of newly detected synthetic cannabinoid receptor agonists AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA, MDMB-4F-BUTINACA and their analogs.","authors":"Sparkes, Eric; Boyd, Rochelle; Chen, Shuli; Markham, Jack W; Luo, Jia Lin; Foyzun, Tahira; Zaman, Humayra; Fletcher, Charlotte; Ellison, Ross; McGregor, Iain S; Santiago, Marina J; Lai, Felcia; Gerona, Roy R; Connor, Mark; Hibbs, David E; Cairns, Elizabeth A; Glass, Michelle; Ametovski, Adam; Banister, Samuel D","year":2022,"journal":"Frontiers in psychiatry, 13, 1010501","doi":"10.3389/fpsyt.2022.1010501","pmid":"36245876","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04242","title":"Structure-activity relationships of valine, tert-leucine, and phenylalanine amino acid-derived synthetic cannabinoid receptor agonists related to ADB-BUTINACA, APP-BUTINACA, and ADB-P7AICA.","authors":"Sparkes, Eric; Cairns, Elizabeth A; Kevin, Richard C; Lai, Felcia; Grafinger, Katharina Elisabeth; Chen, Shuli; Deventer, Marie H; Ellison, Ross; Boyd, Rochelle; Martin, Lewis J; McGregor, Iain S; Gerona, Roy R; Hibbs, David E; Auwärter, Volker; Glass, Michelle; Stove, Christophe; Banister, Samuel D","year":2022,"journal":"RSC medicinal chemistry, 13(2), 156-174","doi":"10.1039/d1md00242b","pmid":"35308023","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04243","title":"Tobacco/nicotine use among individuals using cannabis for therapeutic purposes.","authors":"Steinberg, Marc L; Rosen, Rachel L; Billingsley, Benjamin; Shah, Drashya; Bender, Michele; Shargo, Kyra; Aamir, Affan; Bridgeman, Mary Barna","year":2022,"journal":"The American journal on addictions, 31(6), 486-493","doi":"10.1111/ajad.13323","pmid":"35962766","tags":["medical-cannabis","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"39.3% of medical cannabis patients reported current nicotine use, higher than the general population. E-cigarette users were approximately four times more likely to vape rather than smoke their cannabis. Nearly half of cigarette smokers planned to quit within 6 months.","whyItMatters":"If the way people use nicotine predicts how they use cannabis, dispensaries could leverage this relationship to steer patients toward less harmful consumption methods.","specificNumbers":"697 patients. 39.3% current nicotine users. E-cigarette users 4x more likely to vape cannabis vs smoke it. 46.8% of cigarette smokers planned to quit in next 6 months. 31.6% planned to quit in next month. Psychiatric conditions associated with nicotine use and higher quit motivation.","methodology":"Survey of 697 patients attending a medical marijuana dispensary (75.3% White, 60% male). Examined nicotine use, motivation to quit, routes of administration for both nicotine and cannabis, and qualifying medical conditions.","limitations":"Single-dispensary sample, so results may not generalize to all medical cannabis populations. Self-reported data. Cross-sectional design cannot determine whether cannabis use influenced nicotine behaviors."},{"rthcId":"RTHC-04244","title":"Medical cannabis for the treatment of comorbid symptoms in children with autism spectrum disorder: An interim analysis of biochemical safety.","authors":"Stolar, Orit; Hazan, Ariela; Vissoker, Roni Enten; Kishk, Ibrahim Abu; Barchel, Dana; Lezinger, Mirit; Dagan, Adi; Treves, Nir; Meiri, David; Berkovitch, Matitiahu; Kohn, Elkana; Heyman, Eli","year":2022,"journal":"Frontiers in pharmacology, 13, 977484","doi":"10.3389/fphar.2022.977484","pmid":"36249785","tags":["cbd","medical-cannabis","youth"],"studyType":"pilot-study","evidenceStrength":"moderate","keyFinding":"No clinically significant differences were found in complete blood count, glucose, liver enzymes, kidney function, electrolytes, thyroid function, lipid profile, or hormones between baseline and 3 months of CBD-rich treatment. All statistically significant changes remained within normal ranges.","whyItMatters":"Safety data for cannabis products in children is limited. This study provides reassuring biochemical safety data for CBD-rich cannabis oil in a pediatric autism population over 3 months.","specificNumbers":"59 participants (85% male). Mean daily dose 7.88 mg/kg. Follow-up 18 weeks. No clinically significant changes in any of dozens of blood analytes. Liver enzymes stable even in patients on concurrent medications (n=14). LDH decreased slightly. Small thyroid hormone changes remained within normal range.","methodology":"Interim analysis from an ongoing single-arm, open-label, phase III study. 59 children and young adults (ages 5-25, 85% male) received Nitzan Spectrum Oil (CBD:THC 20:1 in MCT oil) for 6 months. Blood analysis performed at baseline and 3 months.","limitations":"Open-label, single-arm design with no placebo comparison. Only 3 months of data. Small sample size. No long-term safety data. Only biochemical safety was assessed, not efficacy or behavioral outcomes."},{"rthcId":"RTHC-04245","title":"Marijuana use in children: An update focusing on pediatric tetrahydrocannabinol and cannabidiol use.","authors":"Stoner, Michael J; Dietrich, Ann; Lam, Samuel Hiu-Fung; Wall, Jessica J; Sulton, Carmen; Rose, Emily","year":2022,"journal":"Journal of the American College of Emergency Physicians open, 3(4), e12770","doi":"10.1002/emp2.12770","pmid":"35813522","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04246","title":"Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies.","authors":"Strzelczyk, Adam; Schubert-Bast, Susanne","year":2022,"journal":"CNS drugs, 36(10), 1079-1111","doi":"10.1007/s40263-022-00955-9","pmid":"36194365","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04247","title":"Quality Improvement Approach to Increase Inpatient Pediatric Secondhand Smoke Exposure Screening.","authors":"Studenmund, Christine; Williams, Jazzmin; Hernandez, Antonio; Young, Elda; Hui, Ying Ying; Cruz, Edward; Gribben, Valerie","year":2022,"journal":"Hospital pediatrics, 12(1), 45-53","doi":"10.1542/hpeds.2021-005941","pmid":"34866157","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04248","title":"Self-Reported Effects of Cannabis on ADHD Symptoms, ADHD Medication Side Effects, and ADHD-Related Executive Dysfunction.","authors":"Stueber, Amanda; Cuttler, Carrie","year":2022,"journal":"Journal of attention disorders, 26(6), 942-955","doi":"10.1177/10870547211050949","pmid":"34632827","tags":["medical-cannabis","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Participants with ADHD reported cannabis had acute beneficial effects on many ADHD symptoms including hyperactivity and impulsivity. They perceived cannabis improved most medication side effects including irritability and anxiety. Cannabis use frequency moderated associations between symptom severity and executive dysfunction.","whyItMatters":"People with ADHD are more likely to use cannabis, and this study suggests many may be self-medicating specific symptoms and medication side effects, information that clinicians need to have informed conversations with patients.","specificNumbers":"1,738 students surveyed. Participants with ADHD who used cannabis reported acute benefits on hyperactivity, impulsivity, and multiple medication side effects. Cannabis use frequency significantly moderated the association between symptom severity and executive dysfunction.","methodology":"Online survey of 1,738 students measuring ADHD symptoms, cannabis use, perceived effects on symptoms and medication side effects, and executive dysfunction.","limitations":"Self-reported perceived effects, not objectively measured outcomes. Cross-sectional design. Student sample may not represent all ADHD populations. Acute perceived benefits may not reflect long-term outcomes."},{"rthcId":"RTHC-04249","title":"Cannabidiol-Treated Ovariectomized Mice Show Improved Glucose, Energy, and Bone Metabolism With a Bloom in Lactobacillus.","authors":"Sui, Ke; Tveter, Kevin M; Bawagan, Fiona G; Buckendahl, Patricia; Martinez, Savannah A; Jaffri, Zehra H; MacDonell, Avery T; Wu, Yue; Duran, Rocio M; Shapses, Sue A; Roopchand, Diana E","year":2022,"journal":"Frontiers in pharmacology, 13, 900667","doi":"10.3389/fphar.2022.900667","pmid":"35800441","tags":["cbd","medical-cannabis","seniors"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD-treated ovariectomized mice had improved oral glucose tolerance, increased energy expenditure, and improved bone mineral density and bone microarchitecture. These improvements were accompanied by increased Lactobacillus abundance in the gut and gene expression changes consistent with reduced inflammation.","whyItMatters":"Postmenopausal women face increased risks of metabolic disease and osteoporosis with limited treatment options. If CBD can address multiple aspects of this risk profile while modifying the gut microbiome, it could offer a novel therapeutic approach.","specificNumbers":"CBD dose: 25 mg/kg for 18 weeks. Improved whole body bone mineral density and content. Increased femoral bone volume fraction, trabecular thickness, and volumetric bone density. Increased Lactobacillus abundance. Gene expression changes indicated reduced inflammation and less bone resorption.","methodology":"Ovariectomized (OVX) and sham surgery mice received CBD (25 mg/kg) or vehicle perorally for 18 weeks. Assessed glucose tolerance, energy expenditure, bone density (DXA and micro-CT), gut microbiome composition, and gene expression in intestine and femur.","limitations":"Animal study in mice, so results may not translate to humans. Single CBD dose tested. The ovariectomy model approximates but does not fully replicate human menopause. Gut microbiome differences between mice and humans limit direct translation."},{"rthcId":"RTHC-04250","title":"Substance use patterns in 9 to 13-year-olds: Longitudinal findings from the Adolescent Brain Cognitive Development (ABCD) study.","authors":"Sullivan, Ryan M; Wade, Natasha E; Wallace, Alexander L; Tapert, Susan F; Pelham, William E; Brown, Sandra A; Cloak, Christine C; Feldstein Ewing, Sarah W; Madden, Pamela A F; Martz, Meghan E; Ross, J Megan; Kaiver, Christine M; Wirtz, Hailey G; Heitzeg, Mary M; Lisdahl, Krista M","year":2022,"journal":"Drug and alcohol dependence reports, 5","doi":"10.1016/j.dadr.2022.100120","pmid":"36687306","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"By age 12-13, 39.7% of children had experimented with any substance (mostly sipping alcohol), while 7.4% reported \"full use\" in their lifetime including 1.1% cannabis use. Yearly any-substance-use rates increased from 13.9% to 18.4%. Greater externalizing symptoms and parental substance problems predicted use initiation.","whyItMatters":"The ABCD study is the largest longitudinal study of brain development and substance use in American youth. Tracking when and how early substance experimentation begins provides essential data for prevention efforts.","specificNumbers":"11,876 enrolled at baseline. By Y3 (ages 12-13): 39.7% experimented with any substance. Full use rates: 1.9% alcohol, 2.1% nicotine, 1.1% cannabis, 1.2% other. Externalizing symptoms and parental drug problems were significant longitudinal predictors.","methodology":"Longitudinal analysis of the ABCD Study (11,876 participants at baseline, ages 9-10, with 6,251 at the third follow-up, ages 12-13). Descriptive statistics for all psychoactive substances over time. GEE models assessed predictors of substance use initiation.","limitations":"Data only through age 12-13, when substance use rates are still low. Self-reported use may underestimate actual rates. Attrition could bias results if high-risk youth are more likely to drop out."},{"rthcId":"RTHC-04251","title":"Assessment of Withdrawal, Mood, and Sleep Inventories After Monitored 3-Week Abstinence in Cannabis-Using Adolescents and Young Adults.","authors":"Sullivan, Ryan M; Wallace, Alexander L; Stinson, Elizabeth A; Montoto, Karina V; Kaiver, Christine M; Wade, Natasha E; Lisdahl, Krista M","year":2022,"journal":"Cannabis and cannabinoid research, 7(5), 690-699","doi":"10.1089/can.2021.0074","pmid":"34678051","tags":["withdrawal","youth","sleep","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-using participants (n=37) reported higher overall withdrawal, mood symptoms, and sleep problems than controls (n=42) during 3 weeks of verified abstinence. Total and sleep-related withdrawal showed a quadratic trajectory: increasing from baseline in week 1, then decreasing in weeks 2-3. By study end, sleep quality differences had resolved.","whyItMatters":"This is one of the few studies to monitor cannabis withdrawal in non-treatment-seeking young users with biological verification. The finding that symptoms peak early and decline supports targeted intervention during the critical first week of abstinence.","specificNumbers":"37 cannabis users and 42 controls. Withdrawal symptoms peaked in week 1 (quadratic trajectory). Mood symptoms higher throughout (p=0.006). Sleep-related withdrawal higher (p=0.04). No significant anxiety differences (p=0.07). Sleep quality equalized by study end.","methodology":"Prospective study of 79 adolescent and young adult participants (37 cannabis users, 42 controls) undergoing 3 weeks of confirmed abstinence via urine and sweat patch toxicology. Withdrawal, anxiety, depression, and sleep assessed across the period.","limitations":"Moderate sample size. Community sample may have lighter use patterns than clinical populations. Three weeks may not capture the full withdrawal resolution for all symptoms."},{"rthcId":"RTHC-04252","title":"Rhizophagus irregularis enhances tolerance to cadmium stress by altering host plant hemp (Cannabis sativa L.) photosynthetic properties.","authors":"Sun, Simiao; Feng, Yuhan; Huang, Guodong; Zhao, Xu; Song, Fuqiang","year":2022,"journal":"Environmental pollution (Barking, Essex : 1987), 314, 120309","doi":"10.1016/j.envpol.2022.120309","pmid":"36181931","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04253","title":"Cannabis-based medicine in treatment of patients with Gilles de la Tourette syndrome.","authors":"Szejko, Natalia; Saramak, Kamila; Lombroso, Adam; Müller-Vahl, Kirsten","year":2022,"journal":"Neurologia i neurochirurgia polska, 56(1), 28-38","doi":"10.5603/PJNNS.a2021.0081","pmid":"34708399","tags":["medical-cannabis","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Two small RCTs using THC (dronabinol) demonstrated safety and efficacy for tic treatment in Tourette syndrome. However, a trial of the endocannabinoid modulator Lu AG06466 failed. Current guidelines classify cannabis-based treatment as experimental for treatment-resistant patients.","whyItMatters":"Tourette syndrome has limited treatment options, and many patients experience intolerable side effects from antipsychotics. Cannabis-based treatments represent a potential alternative for treatment-resistant patients.","specificNumbers":"Two published RCTs using THC/dronabinol showed safety and efficacy. One RCT of Lu AG06466 (endocannabinoid modulator) was negative. Both AAN and ESSTS guidelines classify cannabis treatment as experimental. Larger RCT (CANNA-TICS) is ongoing.","methodology":"Two reviewers searched PubMed for studies on cannabis/cannabinoid treatment of Tourette syndrome. Included case reports, case series, open uncontrolled studies, and RCTs. Reviewed evidence for tic reduction and comorbidity management.","limitations":"Majority of evidence is from case reports and uncontrolled studies. The two positive RCTs were small. Cannabis-based treatment remains experimental by guideline standards. The failed endocannabinoid modulator trial complicates the picture."},{"rthcId":"RTHC-04254","title":"Extracellular vesicles of cannabis with high CBD content induce anticancer signaling in human hepatocellular carcinoma.","authors":"Tajik, Tahereh; Baghaei, Kaveh; Moghadam, Vahid Erfani; Farrokhi, Naser; Salami, Seyed Alireza","year":2022,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 152, 113209","doi":"10.1016/j.biopha.2022.113209","pmid":"35667235","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04255","title":"Presence of Content Appealing to Youth on Cannabis-Infused Edibles Packaging.","authors":"Tan, Andy S L; Weinreich, Erica; Padon, Alisa; Sanchez, Mirtala; Snyder, Kyle M; Vasilyeva, Anna; Sandh, Simon; Goldmann, Emily; Goodman, Melody; Ompad, Danielle C","year":2022,"journal":"Substance use & misuse, 57(8), 1215-1219","doi":"10.1080/10826084.2022.2069268","pmid":"35491732","tags":["youth","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"15% of packages resembled product knockoffs (e.g., candy brands), 23% contained human/non-human creatures, 35% had flavor images, and 91% had flavor text. States with limited cannabis legalization had significantly more youth-appealing content than states with full legalization.","whyItMatters":"Cannabis edibles are a leading cause of pediatric cannabis exposures. Packaging that looks like candy directly increases the risk that children will mistake these products for food.","specificNumbers":"256 packages from 25 states. Product knockoffs: 11% (legal states), 26% (medical only), 38% (limited legalization). Creatures: 19%, 33%, 63% respectively. Flavor text: 91% overall. Median colors: 5 (legal/medical) vs 10 (limited legalization). All comparisons significant.","methodology":"Analysis of 256 photos of cannabis edibles packaging collected from adults in 25 states, DC, and Puerto Rico between May 2020 and August 2021. Coded for knockoffs, creatures, flavor imagery, flavor text, and color count. Compared across legalization status.","limitations":"Convenience sample of photos from adult consumers, not a systematic market survey. Photos were self-submitted and may not represent the full market. Coding was based on visual characteristics, not consumer research with youth."},{"rthcId":"RTHC-04256","title":"The Effectiveness and Safety of Cannabidiol in Non-seizure-related Indications: A Systematic Review of Published Randomized Clinical Trials.","authors":"Tang, Yuni; Tonkovich, Kolbi L; Rudisill, Toni Marie","year":2022,"journal":"Pharmaceutical medicine, 36(6), 353-385","doi":"10.1007/s40290-022-00446-8","pmid":"36271316","tags":["cbd","medical-cannabis","anxiety"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"CBD appears to be anxiolytic (anxiety-reducing). Its effectiveness for other conditions was highly variable. Mental health was the most studied topic (53% of trials). 72% of studies had fewer than 40 participants. Doses ranged from 400 micrograms to 6,000 mg. CBD was generally safe and well-tolerated even at high doses.","whyItMatters":"As CBD products flood the market with claims for dozens of conditions, this comprehensive review clarifies that only for anxiety does the evidence consistently support effectiveness, while most other claims lack reliable evidence.","specificNumbers":"58 RCTs from 8 countries. 47% conducted in healthy populations. 14% restricted to males. 72% had fewer than 40 participants. Doses ranged 400 mcg to 6,000 mg. 53% studied mental health outcomes. Anxiety showed most consistent positive results.","methodology":"Systematic review of 58 randomized clinical trials from seven databases across eight countries. Excluded seizure-related studies. Included only trials using CBD derived from Cannabis sativa with <3% THC. Independent dual reviewing and risk of bias assessment.","limitations":"Most included trials were small (72% had fewer than 40 participants). The wide range of doses and formulations makes cross-study comparison difficult. Some conditions had very few trials."},{"rthcId":"RTHC-04257","title":"Tobacco Product Use and Functionally Important Respiratory Symptoms Among US Adolescents/Young Adults.","authors":"Tanski, Susanne; Halenar, Michael J; Edwards, Kathryn C; Emond, Jennifer; Woloshin, Steven; Brunette, Mary; Schwartz, Lisa; Taylor, Kristie A; Goniewicz, Maciej L; Niaura, Ray; Anic, Gabriella; Chen, Yanling; Callahan-Lyon, Priscilla; Gardner, Lisa D; Thekkudan, Theresa; Borek, Nicolette; Kimmel, Heather L; Cummings, K Michael; Hyland, Andrew; Sargent, James","year":2022,"journal":"Academic pediatrics, 22(6), 1006-1016","doi":"10.1016/j.acap.2022.03.001","pmid":"35263656","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04258","title":"Inhaled Marijuana and the Lung.","authors":"Tashkin, Donald P; Tan, Wan-Cheng","year":2022,"journal":"The journal of allergy and clinical immunology. In practice, 10(11), 2822-2829","doi":"10.1016/j.jaip.2022.05.009","pmid":"35609784","tags":["respiratory","harm-reduction","cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Smoking marijuana produces short-term bronchodilation in healthy subjects and asthmatics. Long-term effects include chronic bronchitis symptoms (cough, sputum, wheezing) but no significant decrease in FEV1. Most studies have failed to link marijuana smoking to lung cancer despite procarcinogenic smoke components. Pneumonia risk was not increased in immunocompetent users.","whyItMatters":"With marijuana smoking still the most common consumption method, understanding its respiratory effects helps users and clinicians make informed decisions about consumption methods and health monitoring.","specificNumbers":"No significant decrease in FEV1 from marijuana smoking. Mild reductions in FEV1/FVC ratio. Increase in forced vital capacity and other lung volumes. Variable effects on diffusing capacity. No consistent lung cancer association despite procarcinogenic components.","methodology":"Narrative review of the literature on inhaled marijuana effects on lung health, covering short-term bronchodilation, chronic respiratory symptoms, lung function changes, lung cancer risk, asthma association, and pneumonia risk.","limitations":"Narrative review without systematic search methodology. Many included studies had limited follow-up periods. Quantifying marijuana exposure is inherently difficult (variable potency, inhalation technique)."},{"rthcId":"RTHC-04259","title":"Reducing Cannabis Use in Young Adults With Psychosis Using iCanChange, a Mobile Health App: Protocol for a Pilot Randomized Controlled Trial (ReCAP-iCC).","authors":"Tatar, Ovidiu; Abdel-Baki, Amal; Wittevrongel, Anne; Lecomte, Tania; Copeland, Jan; Lachance-Touchette, Pamela; Coronado-Montoya, Stephanie; Côté, José; Crockford, David; Dubreucq, Simon; L'Heureux, Sophie; Ouellet-Plamondon, Clairélaine; Roy, Marc-André; Tibbo, Philip G; Villeneuve, Marie; Jutras-Aswad, Didier","year":2022,"journal":"JMIR research protocols, 11(11), e40817","doi":"10.2196/40817","pmid":"36427227","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04260","title":"Is in-utero exposure to cannabis associated with the risk of attention deficit with or without hyperactivity disorder? A cohort study within the Quebec Pregnancy Cohort.","authors":"Tchuente, Vanina; Sheehy, Odile; Zhao, Jin-Ping; Gorgui, Jessica; Gomez, Yessica-Haydee; Berard, Anick","year":2022,"journal":"BMJ open, 12(8), e052220","doi":"10.1136/bmjopen-2021-052220","pmid":"35940828","tags":["pregnancy","youth","cognition"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After adjusting for potential confounders, no significant association was found between in-utero cannabis exposure (occasional: OR 1.22, 95% CI 0.63-2.19; regular: OR 1.22, 95% CI 0.42-2.79) and the risk of ADHD in children.","whyItMatters":"Given increasing prenatal cannabis use and widespread concern about neurodevelopmental effects, this null finding from a well-designed cohort adds important nuance to the evidence base.","specificNumbers":"2,408 children met inclusion criteria. 86 (3.6%) were exposed to cannabis in utero. 241 (10.0%) had ADHD diagnosis or medication. Neither occasional nor regular exposure was significantly associated with ADHD after adjustment.","methodology":"Cohort study using the Quebec Pregnancy Cohort. Questionnaires mailed to mothers of singleton live births between 1998-2003. Cannabis exposure based on maternal self-report during pregnancy. ADHD defined by diagnosis or prescription through provincial databases. Follow-up through December 2015.","limitations":"Cannabis exposure was self-reported by mothers and may be underreported. Relatively small number of exposed children (86). Could not account for dose, timing within pregnancy, or cannabis potency. Confounders may remain uncontrolled."},{"rthcId":"RTHC-04261","title":"A randomized pilot trial of a mobile phone-based brief intervention with personalized feedback and interactive text messaging to reduce driving after cannabis use and riding with a cannabis impaired driver.","authors":"Teeters, Jenni B; Armstrong, Nicole M; King, Shelby A; Hubbard, Sterling M","year":2022,"journal":"Journal of substance abuse treatment, 142, 108867","doi":"10.1016/j.jsat.2022.108867","pmid":"36007434","tags":["driving","youth","harm-reduction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"College cannabis users in the personalized feedback plus MI-style interactive text messaging condition significantly reduced driving after cannabis use (DACU) and riding with a cannabis-impaired driver (RWCD) over 3 months compared to information control.","whyItMatters":"Cannabis-impaired driving is a growing public health concern with no established brief intervention. This accessible, low-cost mobile intervention showed promise in reducing two of the riskiest cannabis-related behaviors.","specificNumbers":"97 participants. 67.4% women, mean age 21.34, 80.4% Caucasian. All endorsed DACU at least 3 times in past 3 months. PF+MIT condition significantly reduced both DACU and RWCD vs control at 3 months.","methodology":"Randomized three-group pilot trial of 97 college cannabis users (67.4% women, mean age 21.34) who endorsed driving after cannabis use at least 3 times in the past 3 months. Three conditions: personalized feedback plus MI text messaging, personalized feedback only, and information control. Outcome measures at 3 months.","limitations":"Pilot study with only 97 participants. Only 3-month follow-up. Predominantly White, female college sample limits generalizability. Self-reported driving outcomes."},{"rthcId":"RTHC-04262","title":"Use of Marijuana: Effect on Brain Health: A Scientific Statement From the American Heart Association.","authors":"Testai, Fernando D; Gorelick, Philip B; Aparicio, Hugo J; Filbey, Francesca M; Gonzalez, Raul; Gottesman, Rebecca F; Melis, Miriam; Piano, Mariann R; Rubino, Tiziana; Song, Sarah Y","year":2022,"journal":"Stroke, 53(4), e176-e187","doi":"10.1161/STR.0000000000000396","pmid":"35142225","tags":["cognition","neuroscience","youth","cardiovascular"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Cannabinoid receptors are concentrated in brain areas critical for cognition and behavior, especially during neurodevelopment. Animal models show exogenous cannabinoids disrupt synaptic plasticity and neurodevelopment. Observational human studies report higher cognitive impairment risk. Whether effects reverse with abstinence remains unclear.","whyItMatters":"The AHA scientific statement represents a major medical society taking a formal position on marijuana and brain health, carrying significant weight for clinical practice, policy, and public health messaging.","specificNumbers":"Cannabinoid receptors are expressed at high density in cognition and behavior-related brain areas. Active ingredient concentrations in recreational cannabis have gradually increased. High-potency illicit cannabinomimetics have become available.","methodology":"Scientific statement from the American Heart Association reviewing preclinical and clinical evidence on marijuana effects on brain health, including cannabinoid receptor distribution, neurodevelopmental effects, cognitive outcomes, and stroke risk.","limitations":"As a scientific statement rather than original research, it synthesizes existing evidence. The statement acknowledges that it is unclear whether cognitive effects reverse with abstinence and that observational human data have limitations."},{"rthcId":"RTHC-04263","title":"Risky sexual behavior and associated factors among sexually-experienced adolescents in Bangkok, Thailand: findings from a school web-based survey.","authors":"Thepthien, Bang-On; Celyn","year":2022,"journal":"Reproductive health, 19(1), 127","doi":"10.1186/s12978-022-01429-3","pmid":"35643503","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04264","title":"Psychotomimetic symptoms after a moderate dose of a synthetic cannabinoid (JWH-018): implications for psychosis.","authors":"Theunissen, Eef L; Reckweg, Johannes T; Hutten, Nadia R P W; Kuypers, Kim P C; Toennes, Stefan W; Neukamm, Merja A; Halter, Sebastian; Ramaekers, Johannes G","year":2022,"journal":"Psychopharmacology, 239(5), 1251-1261","doi":"10.1007/s00213-021-05768-0","pmid":"33501595","tags":["synthetic-cannabinoids","psychosis","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"JWH-018 (average dose 5.52 mg) caused psychedelic effects (altered internal and external perception), dissociative effects (amnesia, derealization, depersonalization), and confusion in healthy participants with no history of mental illness.","whyItMatters":"This is one of the few controlled studies of a synthetic cannabinoid in humans, providing direct evidence that even moderate doses produce pronounced psychotomimetic symptoms in otherwise healthy individuals.","specificNumbers":"24 participants. Average dose 5.52 mg JWH-018. Pronounced effects on altered perception, dissociation, amnesia, derealization, depersonalization, and confusion within 4.5 hours.","methodology":"Placebo-controlled, double-blind, within-subjects trial of 24 healthy participants (10 males, 14 females). Inhaled vapor of placebo or 75 mcg/kg JWH-018 with optional booster dose. Assessed subjective high, dissociative states (CADSS), psychedelic symptoms (Bowdle), mood (POMS), and cannabis reinforcement over 4.5 hours.","limitations":"Only 24 participants. Single moderate dose tested, which may not reflect the higher doses commonly used recreationally. Healthy volunteers may respond differently than typical synthetic cannabinoid users."},{"rthcId":"RTHC-04265","title":"Extraction of Bioactive Compounds From Cannabis sativa L. Flowers and/or Leaves Using Deep Eutectic Solvents.","authors":"Tiago, Francisco J; Paiva, Alexandre; Matias, Ana A; Duarte, Ana Rita C","year":2022,"journal":"Frontiers in nutrition, 9, 892314","doi":"10.3389/fnut.2022.892314","pmid":"35586733","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04266","title":"In Vivo Bio-Activation of JWH-175 to JWH-018: Pharmacodynamic and Pharmacokinetic Studies in Mice.","authors":"Tirri, Micaela; Arfè, Raffaella; Bilel, Sabrine; Corli, Giorgia; Marchetti, Beatrice; Fantinati, Anna; Vincenzi, Fabrizio; De-Giorgio, Fabio; Camuto, Cristian; Mazzarino, Monica; Barbieri, Mario; Gaudio, Rosa Maria; Varani, Katia; Borea, Pier Andrea; Botrè, Francesco; Marti, Matteo","year":2022,"journal":"International journal of molecular sciences, 23(14)","doi":"10.3390/ijms23148030","pmid":"35887377","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04267","title":"Psychosocial stress and cannabinoid drugs affect acetylation of α-tubulin (K40) and gene expression in the prefrontal cortex of adult mice.","authors":"Tomas-Roig, Jordi; Ramasamy, Shyam; Zbarsky, Diana; Havemann-Reinecke, Ursula; Hoyer-Fender, Sigrid","year":2022,"journal":"PloS one, 17(9), e0274352","doi":"10.1371/journal.pone.0274352","pmid":"36129937","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04268","title":"Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages.","authors":"Tomer, Shallu; Mu, Wenli; Suryawanshi, Gajendra; Ng, Hwee; Wang, Li; Wennerberg, Wally; Rezek, Valerie; Martin, Heather; Chen, Irvin; Kitchen, Scott; Zhen, Anjie","year":2022,"journal":"Frontiers in immunology, 13, 926696","doi":"10.3389/fimmu.2022.926696","pmid":"36248834","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04269","title":"Factor-guided diagnosis of coagulopathy associated with coumarin-contaminated synthetic cannabinoids.","authors":"Torian, Sterling C; Hayes, Lisa; Negrete, Ana","year":2022,"journal":"The American journal of emergency medicine, 58, 350.e5-350.e6","doi":"10.1016/j.ajem.2022.05.005","pmid":"35577625","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A young adult presented with elevated INR without known medical history. Factor levels revealed deficiencies in factors II, VII, IX, and X, pointing to superwarfarin-type anticoagulant contamination. The patient later confirmed synthetic cannabinoid use, and bromadiolone testing was positive.","whyItMatters":"Coumarin-contaminated synthetic cannabinoids have caused outbreaks of life-threatening coagulopathy. This case demonstrates that factor level testing can enable rapid diagnosis when patients may not initially disclose substance use.","specificNumbers":"One patient with acute INR elevation. Deficiencies in factors II, VII, IX, and X identified. Bromadiolone assay positive (confirmed after discharge). Patient initially denied substance use but later confirmed synthetic cannabinoid consumption.","methodology":"Single case report documenting clinical presentation, diagnostic workup using coagulation factor levels, treatment, and confirmatory toxicology testing.","limitations":"Single case report. Factor level patterns can have other causes. Confirmatory assays for toxic coumarin derivatives remain not readily available in most hospitals."},{"rthcId":"RTHC-04270","title":"Using ecological momentary assessment and a portable device to quantify standard tetrahydrocannabinol units for cannabis flower smoking.","authors":"Trull, Timothy J; Freeman, Lindsey K; Fleming, Megan N; Vebares, Tayler J; Wycoff, Andrea M","year":2022,"journal":"Addiction (Abingdon, England), 117(8), 2351-2358","doi":"10.1111/add.15872","pmid":"35293047","tags":["potency","cognition","driving","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"One of the biggest problems in cannabis research is that 'a joint' can contain wildly different amounts of THC depending on the flower's potency and how much is used. This makes it nearly impossible to compare studies or establish dose-response relationships. Alcohol has standard drink units; cannabis has nothing equivalent — until now.\n\nThis study tested a new approach: participants used a portable device (Purpl Pro) to measure the THC percentage of their own cannabis flower at home, then weighed how much they smoked using a digital scale, and reported their experience through an ecological momentary assessment (EMA) app on their phones over 14 days.\n\nThe method worked remarkably well in practice. Participants completed the potency testing 96.2% of the time and were highly compliant with the phone-based reporting (91% for morning reports, 73% for random prompts). The resulting 'standard THC unit' (mg of THC = weight of flower × THC percentage) correlated with self-reported intoxication: more milligrams of THC meant feeling more intoxicated, and intoxication levels decreased over time after smoking.\n\nThe average THC concentration participants were smoking was 23.1%, consistent with the high-potency market documented in other studies. This method could become the foundation for a 'standard cannabis unit' similar to standard drink units in alcohol research.","whyItMatters":"Without a standard cannabis dose unit, researchers can't compare findings across studies, clinicians can't give dosing guidance, and policymakers can't set meaningful impairment thresholds. This study demonstrates that a practical, field-deployable method for measuring THC intake is feasible and produces valid data. If adopted widely, it could transform how cannabis research is conducted and how we think about dosing.","specificNumbers":"50 participants over 14 days. Potency testing compliance: 96.2%. EMA compliance: 91% morning reports, 73% random prompts. Average THC concentration of flower smoked: 23.1%. Standard THC units (mg THC) were positively associated with momentary subjective intoxication (b = 0.01, P = 0.03). Intoxication decreased over time after smoking (r = −0.10, P = 0.004).","methodology":"Ecological momentary assessment (EMA) study over 14 days with 50 regular cannabis flower smokers (48% female) in Columbia, Missouri. Participants tested their flower potency with a Purpl Pro portable device, weighed consumption, and completed real-time phone surveys about intoxication. Multi-level modeling assessed the relationship between calculated standard THC units (mg THC) and subjective intoxication.","limitations":"Only tested with smoked cannabis flower — doesn't cover edibles, concentrates, or vapes, which have different absorption profiles. The Purpl Pro device measures THC percentage in flower but may have accuracy limitations compared to lab testing. The sample was from one city in Missouri, limiting geographic diversity. The study validated the method's feasibility and basic dose-response, but the specific dose-intoxication relationship needs replication in larger, more diverse samples."},{"rthcId":"RTHC-04271","title":"The Long-Term Effectiveness and Safety of Cannabidiol-Enriched Oil in Children With Drug-Resistant Epilepsy.","authors":"Tzadok, Michal; Hamed, Nasrin; Heimer, Gali; Zohar-Dayan, Efrat; Rabinowicz, Shira; Ben Zeev, Bruria","year":2022,"journal":"Pediatric neurology, 136, 15-19","doi":"10.1016/j.pediatrneurol.2022.06.016","pmid":"36049378","tags":["cbd","epilepsy","medical-cannabis","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"73.3% of 114 patients reported some seizure improvement. Of 86 patients continuing treatment for at least one year, 51 (59%) showed >50% seizure reduction. Seizure etiology, type, age, and sex were not associated with response. Side effects were minor, and positive effects beyond seizure reduction were noted.","whyItMatters":"While RCTs have established CBD efficacy for specific epilepsy syndromes, this real-world study shows that artisanal CBD oil may help a broader range of treatment-resistant pediatric epilepsy across different etiologies.","specificNumbers":"114 patients total. 84 (73.3%) reported some improvement. 86 continued for at least one year. 51 of 86 (59%) had >50% seizure reduction. Response was not predicted by etiology, seizure type, age, or sex.","methodology":"Retrospective study of children and adolescents with refractory epilepsy from various etiologies treated with artisanal CBD-enriched cannabis oil from January 2014 to June 2019, with at least one year of follow-up.","limitations":"Retrospective, uncontrolled design without placebo comparison. Artisanal product may vary in composition. Self/parent-reported seizure counts. Selection bias may favor patients who responded and continued treatment."},{"rthcId":"RTHC-04272","title":"Cannabis and metformin on diabetic male Wistar rat sperm and reproductive organ parameters.","authors":"van Losenoord, Wynand; Levendal, Ruby-Ann; Frost, Carminita Lara","year":2022,"journal":"Journal of diabetes and metabolic disorders, 21(2), 1451-1458","doi":"10.1007/s40200-022-01079-z","pmid":"36404868","tags":["pregnancy","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis induced a significant concentration-dependent decrease in sperm motility at 5 mg/kg THC. Metformin increased sperm counts and lactate dehydrogenase activity. Both cannabis and metformin negatively affected testosterone concentrations.","whyItMatters":"Cannabis use is reportedly increasing among people with type 2 diabetes for pain and inflammation management. This study suggests cannabis may compound reproductive risks already associated with diabetes.","specificNumbers":"35 rats. Cannabis 5 mg/kg THC: significant decrease in sperm motility (p=0.009). Metformin: increased sperm counts (p=0.035) and LDH activity (p=0.002). Both cannabis and metformin reduced testosterone.","methodology":"Male Wistar rats (n=35) were fed a high-fat diet and injected with streptozotocin to create a type 2 diabetes model. Treatment groups received cannabis at THC concentrations of 1.25, 2.5, and 5 mg/kg and metformin (50 mg/kg) every other day for 10 weeks. Measured organ weight, testosterone, sperm count, motility, and enzyme activities.","limitations":"Animal study in a chemically induced diabetes model. THC doses and frequency may not match human use patterns. Small sample (n=35 across all groups). Short duration relative to human chronic use."},{"rthcId":"RTHC-04273","title":"Assessment of dependence potential and abuse liability of Δ8-tetrahydrocannabinol in mice.","authors":"Vanegas, S O; Reck, A M; Rodriguez, C E; Marusich, J A; Yassin, O; Sotzing, G; Wiley, J L; Kinsey, S G","year":2022,"journal":"Drug and alcohol dependence, 240, 109640","doi":"10.1016/j.drugalcdep.2022.109640","pmid":"36179506","tags":["addiction","tolerance","harm-reduction"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Delta-8-THC produced cannabimimetic effects (catalepsy, antinociception, hypothermia, immobility) at doses above 12.5 mg/kg, all blocked by the CB1 antagonist rimonabant. Repeated administration produced tolerance and cross-tolerance to WIN 55,212-2. Rimonabant-precipitated withdrawal produced physical dependence signs. Delta-8-THC produced delta-9-THC-like discriminative stimulus effects in both sexes.","whyItMatters":"Delta-8-THC is marketed as a legal, milder alternative to delta-9-THC. This study provides direct evidence that it produces the same types of tolerance, dependence, and abuse liability, undercutting those marketing claims.","specificNumbers":"Delta-8-THC active at doses above 12.5 mg/kg. Repeated 50 mg/kg produced tolerance and cross-tolerance. Withdrawal signs observed after 10 mg/kg BID for 6 days. Both male and female mice showed delta-9-THC-like discriminative effects.","methodology":"Adult male and female C57BL/6J mice were tested in the tetrad battery (catalepsy, antinociception, hypothermia, immobility) after acute delta-8-THC. Tolerance assessed after repeated dosing. Physical dependence assessed via rimonabant-precipitated withdrawal. Drug discrimination tested for abuse potential.","limitations":"Animal study, so doses and effects may not directly translate to humans. The doses required for effects were higher than for delta-9-THC, consistent with lower potency. Does not address the full range of subjective human experiences."},{"rthcId":"RTHC-04274","title":"Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind, placebo-controlled trial.","authors":"Vela, Jonathan; Dreyer, Lene; Petersen, Kristian Kjær; Arendt-Nielsen, Lars; Duch, Kirsten Skjærbæk; Kristensen, Salome","year":2022,"journal":"Pain, 163(6), 1206-1214","doi":"10.1097/j.pain.0000000000002466","pmid":"34510141","tags":["cbd","pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Between-group difference in pain intensity at 12 weeks was 0.23 mm on a 0-100 mm scale (95% CI -9.41 to 9.90, p=0.96). 22% of CBD and 21% of placebo patients achieved clinically meaningful pain reduction (>30 mm). No effects on sleep, depression, anxiety, or pain catastrophizing.","whyItMatters":"Despite widespread use of CBD for pain, this is one of the few rigorous RCTs to test it in arthritis. The clearly negative result is important for consumers spending money on CBD for joint pain.","specificNumbers":"136 randomized, 129 in primary analysis. Pain difference: 0.23 mm (p=0.96). Response rate: 22% CBD vs 21% placebo. No significant effects on PSQI, HADS, PCS, or HAQ-DI.","methodology":"Randomized, double-blind, placebo-controlled trial of 136 patients with hand osteoarthritis or psoriatic arthritis experiencing moderate pain despite therapy. Patients received synthetic CBD 20-30 mg or placebo daily for 12 weeks.","limitations":"CBD dose (20-30 mg) may have been too low. Only synthetic CBD was tested, which may differ from plant-derived products. Specific arthritis subtypes may not represent all chronic pain conditions."},{"rthcId":"RTHC-04275","title":"Cannabis edibles packaging: Communicative objects in a growing market.","authors":"Ventresca, Matt; Elliott, Charlene","year":2022,"journal":"The International journal on drug policy, 103, 103645","doi":"10.1016/j.drugpo.2022.103645","pmid":"35276401","tags":["legalization","youth","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Participants discussed four main themes: dosage/consumption recommendations, food/nutritional information, concerns for children, and health warnings. They requested standardized THC units, non-numerical consumption instructions, unit-dose packaging, and features protecting children rather than packaging designed to deter adult consumption.","whyItMatters":"This is one of the few studies to ask consumers what they actually want on cannabis edibles packaging, rather than designing packaging based on regulatory assumptions. The gap between regulatory intent and consumer interpretation has practical implications.","specificNumbers":"8 focus groups, 57 participants aged 18-24. Conducted before Canadian edibles legalization (October 2019). Four main themes identified. Participants requested harm reduction-oriented features rather than abstinence-oriented design.","methodology":"Eight focus groups with 57 young adults (ages 18-24) at a Canadian university in November 2018, before edibles legalization. Participants assessed sample images of Health Canada-approved cannabis packaging and discussed preferred information. Qualitative descriptive analysis.","limitations":"University student sample may not represent all young adults. Pre-legalization timing means participants had limited experience with legal edibles. Qualitative design cannot measure how packaging features affect behavior."},{"rthcId":"RTHC-04276","title":"A large Australian longitudinal cohort registry demonstrates sustained safety and efficacy of oral medicinal cannabis for at least two years.","authors":"Vickery, Alistair W; Roth, Sebastian; Ernenwein, Tracie; Kennedy, Jessica; Washer, Patrizia","year":2022,"journal":"PloS one, 17(11), e0272241","doi":"10.1371/journal.pone.0272241","pmid":"36399463","tags":["medical-cannabis","pain","mental-health","sleep"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Statistically significant improvements sustained over 2+ years across all outcomes: clinical impression (+39-52%), pain interference and severity (22-26%), depression/anxiety/stress (24-28%), insomnia (35%), and physical/emotional functioning (34-37%). 37.3% experienced adverse events, mostly mild (67%) or moderate (31%), with <2% severe and 0.1% serious.","whyItMatters":"This is one of the largest and longest prospective registries of medicinal cannabis patients, providing real-world evidence of sustained safety and effectiveness in a complex patient population.","specificNumbers":"3,961 patients. Median daily dose: 10 mg THC, 22.5 mg CBD. 37.3% had adverse events (67% mild, 31% moderate, <2% severe, 0.1% serious). Pain severity improved 22.2%, pain interference 26.1%. Depression 24.5%, anxiety 25.5%, stress 27.7%. Insomnia 35%. Stable dose and concomitant medication count over 2 years.","methodology":"Prospective longitudinal registry of 3,961 cannabis-naive patients prescribed oral medicinal cannabis at specialized clinics. Mean age 56.07, 51% female, with multimorbidity (mean 5.14 diagnoses) and polypharmacy (mean 6.26 medications). Validated outcomes collected regularly over two years.","limitations":"Observational registry without placebo control, so improvement could reflect placebo effects, natural disease course, or regression to the mean. Patients self-selected for treatment. Attrition over 2 years may introduce survivor bias."},{"rthcId":"RTHC-04277","title":"The effect of a long-term treatment with cannabidiol-rich hemp extract oil on the adenosinergic system of the zucker diabetic fatty (ZDF) rat atrium.","authors":"Viczjan, Gabor; Szilagyi, Anna; Takacs, Barbara; Ovari, Ignac; Szekeres, Reka; Tarjanyi, Vera; Erdei, Tamas; Teleki, Vanda; Zsuga, Judit; Szilvassy, Zoltan; Juhasz, Bela; Varga, Balazs; Gesztelyi, Rudolf","year":2022,"journal":"Frontiers in pharmacology, 13, 1043275","doi":"10.3389/fphar.2022.1043275","pmid":"36588715","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04278","title":"Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy.","authors":"Villanueva, Vicente; García-Ron, Adrián; Smeyers, Patricia; Arias, Eva; Soto, Victor; García-Peñas, Juan José; González-Alguacil, Elena; Sayas, Débora; Serrano-Castro, Pedro; Garces, Mercedes; Hampel, Kevin; Tomás, Miguel; Lara, Julian; de Toledo, María; Barceló, Ines; Aledo-Serrano, Angel; Gil-Nagel, Antonio; Iacampo, Lucas; Falip, Mercè; Saiz-Diaz, Rosa Ana; Gómez-Ibañez, Asier; Sopelana, David; Sanchez-Larsen, Alvaro; López-González, Francisco Javier","year":2022,"journal":"Epilepsy & behavior : E&B, 137(Pt A), 108958","doi":"10.1016/j.yebeh.2022.108958","pmid":"36327646","tags":["cbd","epilepsy","medical-cannabis","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"44.9% of patients had at least 50% seizure reduction at 6 months, 38.9% at 12 months. Median total seizures per month reduced by 47.6% from baseline to last visit. Seizure severity decreased in 61.1% at 12 months. Quality of life improved 21.2%. Adverse events in 66.7%, most commonly somnolence (34.3%).","whyItMatters":"This real-world expanded access data complements clinical trial results by showing how CBD performs in a broader, highly refractory patient population in routine clinical practice.","specificNumbers":"102 patients. Mean age 15.9. Mean 7.5 prior failed ASMs. Mean CBD dose 13.0 mg/kg/day. Seizure reduction at 6 months: 44.9% had 50%+ reduction. Median seizure reduction: 47.6%. Quality of life improved 21.2%. Somnolence 34.3%, diarrhea 12.7%. Discontinuation for AEs alone: 7.8%.","methodology":"Multicenter retrospective observational study of 102 patients (mean age 15.9, 59% LGS, 12% Dravet, 29% other syndromes) treated with purified CBD at 14 Spanish hospitals. Highly refractory population with mean 7.5 previously failed anti-seizure medications.","limitations":"Retrospective, uncontrolled design. No placebo comparison. Self/caregiver-reported seizure counts. Heterogeneous patient population. Selection bias from expanded access enrollment."},{"rthcId":"RTHC-04279","title":"Routes of administration, reasons for use, and approved indications of medical cannabis in oncology: a scoping review.","authors":"Vinette, Billy; Côté, José; El-Akhras, Ali; Mrad, Hazar; Chicoine, Gabrielle; Bilodeau, Karine","year":2022,"journal":"BMC cancer, 22(1), 319","doi":"10.1186/s12885-022-09378-7","pmid":"35331185","tags":["medical-cannabis","cancer","pain"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Two main reasons for medical cannabis use in cancer: limiting cancer impacts and side effects, and staying connected to others. Three approved indications: refractory nausea/vomiting, pain management, and appetite/food intake improvement. Eleven routes of administration identified, with oils and oral solutions most common.","whyItMatters":"Understanding why and how cancer patients use medical cannabis helps clinicians have more informed conversations and identify gaps in supportive care that patients are trying to fill.","specificNumbers":"5,283 publications identified, 163 met criteria. 11 routes of administration. Oils and oral solutions most frequent. Three approved indications identified.","methodology":"Scoping review following Joanna Briggs Institute guidelines. Searched five databases and two grey literature sources. Included French/English primary studies and knowledge syntheses from 2000-2021. 5,283 publications identified, 163 met eligibility criteria. Data extracted by two independent reviewers.","limitations":"Scoping review maps evidence breadth rather than evaluating effectiveness. Heterogeneous study designs and populations. Most evidence from observational and qualitative studies."},{"rthcId":"RTHC-04280","title":"Development and Evaluation of Cannabidiol Orodispersible Tablets Using a 23-Factorial Design.","authors":"Vlad, Robert-Alexandru; Antonoaea, Paula; Todoran, Nicoleta; Rédai, Emöke-Margit; Bîrsan, Magdalena; Muntean, Daniela-Lucia; Imre, Silvia; Hancu, Gabriel; Farczádi, Lénárd; Ciurba, Adriana","year":2022,"journal":"Pharmaceutics, 14(7)","doi":"10.3390/pharmaceutics14071467","pmid":"35890362","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04281","title":"Cannabis use is associated with lower retention in methadone maintenance treatment, but not among schizophrenic- and other chronically psychotic patients.","authors":"Volkov, Ilan; Schreiber, Shaul; Adelson, Miriam; Shoshan, Stacy; Peles, Einat","year":2022,"journal":"Journal of addictive diseases, 40(2), 183-191","doi":"10.1080/10550887.2021.1962209","pmid":"34379049","tags":["addiction","psychosis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-using methadone patients had significantly shorter cumulative retention (6.0 years) than non-users (9.1 years). However, among 50 patients with schizophrenia/chronic psychosis, cannabis use was not associated with reduced retention. Survival was shorter for schizophrenia patients who did not use cannabis.","whyItMatters":"Cannabis use during methadone treatment is common and controversial. This study suggests its effects on treatment retention may differ based on psychiatric comorbidity, with a potentially neutral or even protective role in psychosis patients.","specificNumbers":"877 patients total. 50 (5.7%) had schizophrenia/chronic psychosis. Non-psychosis cohort: cannabis users 6.0 years retention vs non-users 9.1 years (p<.001). Psychosis cohort: cannabis users 9.9 years vs non-users 7.9 years (p=.5). Survival shorter for psychosis non-cannabis-users (15.2 years) vs non-psychosis non-users (18.5 years, p=.009).","methodology":"Retrospective cohort of 877 methadone maintenance patients with DSM-IV psychiatric diagnoses, followed from June 1993 to December 2017. Cannabis use assessed by urine drug screens at admission and after one year.","limitations":"Small psychosis subgroup (n=50, only 9 cannabis users). Retrospective design. Cannabis use measured only at two timepoints. Cannot account for chronicity or quantity of cannabis use."},{"rthcId":"RTHC-04282","title":"Cannabis use and risks of respiratory and all-cause morbidity and mortality: a population-based, data-linkage, cohort study.","authors":"Vozoris, Nicholas T; Zhu, Jingqin; Ryan, Clodagh M; Chow, Chung-Wai; To, Teresa","year":2022,"journal":"BMJ open respiratory research, 9(1)","doi":"10.1136/bmjresp-2022-001216","pmid":"35760496","tags":["respiratory","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"No significant difference in respiratory-related ER visits/hospitalizations between cannabis users and controls (OR 0.91, 95% CI 0.77-1.09). Cannabis users had significantly higher odds of all-cause ER visits/hospitalizations (OR 1.22, 95% CI 1.13-1.31). No difference in all-cause mortality (OR 0.99).","whyItMatters":"This well-designed, population-based study adds to the evidence that cannabis does not significantly increase respiratory-specific health emergencies, while confirming it is associated with increased overall healthcare utilization.","specificNumbers":"35,114 individuals screened. 6,425 past-year cannabis users. 4,807 matched to 10,395 controls. Respiratory ER/hospitalizations: OR 0.91 (not significant). All-cause ER/hospitalizations: OR 1.22 (significant). All-cause mortality: OR 0.99 (not significant).","methodology":"Retrospective population-based cohort study linking health survey and administrative data for Ontario, Canada residents aged 12-65 (2009-2015). 6,425 past-year cannabis users propensity-score matched to 10,395 controls on 31 variables. Outcomes assessed at 12 months.","limitations":"Self-reported cannabis use may be underreported. 12-month follow-up may miss longer-term effects. Propensity matching cannot eliminate all confounders. Administrative coding may miss some cannabis-related visits."},{"rthcId":"RTHC-04283","title":"Cannabinoids in the Treatment of Cannabis Use Disorder: Systematic Review of Randomized Controlled Trials.","authors":"Vuilleumier, Caroline; Scherbaum, Norbert; Bonnet, Udo; Roser, Patrik","year":2022,"journal":"Frontiers in psychiatry, 13, 867878","doi":"10.3389/fpsyt.2022.867878","pmid":"35815028","tags":["addiction","cbd","medical-cannabis","quitting"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Dronabinol reduced withdrawal symptoms but had limited broader efficacy. Nabilone failed to demonstrate efficacy. In contrast, nabiximols, CBD, and PF-04457845 reduced cannabis use and improved abstinence across multiple CUD outcomes. All medications were well-tolerated.","whyItMatters":"There are no approved medications for cannabis use disorder. This review identifies endocannabinoid modulation (rather than direct receptor agonism) as the more promising pharmacological strategy.","specificNumbers":"8 RCTs, 667 participants. Dronabinol: reduced withdrawal only. Nabilone: no efficacy. Nabiximols: reduced use and improved abstinence. CBD: reduced use and improved abstinence. PF-04457845: reduced use and improved abstinence.","methodology":"Systematic review of 8 randomized controlled trials evaluating medical cannabinoids for CUD (667 total participants). Outcomes assessed: cannabis use, abstinence, withdrawal, craving, treatment retention, and adverse events.","limitations":"Only 8 trials available with 667 total participants. Small individual study sizes. Different doses, durations, and outcome measures across trials. Short follow-up periods."},{"rthcId":"RTHC-04284","title":"Effects of cannabinoid and vanilloid receptor antagonists on nicotine induced relaxation response enhancement in rabbit corpus cavernosum.","authors":"Vural, Ismail Mert; Ozturk Fincan, Gokce Sevi; Koc, Derya Sebile; Okcay, Yagmur; Askin, Celil Ilker; Kibar, Ayse Kubra; Ilhan, Sevil Ozger; Sarioglu, Yusuf","year":2022,"journal":"Iranian journal of basic medical sciences, 25(4), 514-519","doi":"10.22038/IJBMS.2022.62222.13772","pmid":"35656074","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04285","title":"Legal status of recreational cannabis and self-reported substitution of cannabis for opioids or prescription pain medication in Canada and the United States.","authors":"Wadsworth, Elle; Hines, Lindsey A; Hammond, David","year":2022,"journal":"Substance abuse, 43(1), 943-948","doi":"10.1080/08897077.2022.2060431","pmid":"35420977","tags":["legalization","pain","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Between 14-33% of cannabis consumers used it for pain. Of those, 78-84% reported substituting cannabis for opioids or prescription pain medication. There was no significant association between recreational cannabis legalization and the rate of substitution.","whyItMatters":"The finding that opioid substitution rates are similarly high regardless of legal status challenges the argument that legalization will drive a public health benefit through opioid replacement.","specificNumbers":"44,119 total respondents. 14-33% used cannabis for pain. Substitution rates: Canada 78-79%, US illegal states 80-83%, US legal states 83-84%. No significant legal status effect (Canada AOR 0.98, US AOR 1.11).","methodology":"Repeat cross-sectional survey from the International Cannabis Policy Study (2018-2019) in Canada and the US. 44,119 respondents aged 16-65 who had ever tried cannabis. 15,092 analyzed for substitution outcomes. Weighted binary logistic regression compared legal versus illegal jurisdictions.","limitations":"Cross-sectional design cannot establish causation. Self-reported substitution may not reflect actual opioid reduction. Two-year window may be too short to capture legalization effects. Online panel recruitment may introduce bias."},{"rthcId":"RTHC-04286","title":"Consumer perceptions of legal cannabis products in Canada, 2019-2021: a repeat cross-sectional study.","authors":"Wadsworth, Elle; Fataar, Fathima; Goodman, Samantha; Smith, Danielle M; Renard, Justine; Gabrys, Robert; Jesseman, Rebecca; Hammond, David","year":2022,"journal":"BMC public health, 22(1), 2048","doi":"10.1186/s12889-022-14492-z","pmid":"36348479","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"By 2021, consumers perceived legal cannabis as safer to buy (54%), more convenient (47.8%), but more expensive (47.2%) than illegal cannabis. Perceptions improved from 2019 to 2021 across all measures except price. Convenience perception tripled (AOR 3.09). More frequent users had less favorable perceptions.","whyItMatters":"The success of cannabis legalization in displacing the illegal market depends on consumer willingness to buy legal products. This study tracks whether perceptions are shifting in the right direction.","specificNumbers":"15,311 consumers. Legal perceived as: safer to buy (54.0%), more convenient (47.8%), more expensive (47.2%), safer to use (46.8%), higher quality (29.3%). Convenience perception: AOR 3.09 from 2019 to 2021. Frequent users had less favorable perceptions across all measures.","methodology":"Repeat cross-sectional survey from the International Cannabis Policy Study (2019-2021). 15,311 past-12-month Canadian cannabis consumers of legal purchasing age. Weighted logistic regression examined perceptions by province, year, and use frequency.","limitations":"Self-reported perceptions may not reflect actual purchasing behavior. Online panel may underrepresent some demographics. Provincial policy differences may confound national trends."},{"rthcId":"RTHC-04287","title":"Going deeper into the toxicokinetics of synthetic cannabinoids: in vitro contribution of human carboxylesterases.","authors":"Wagmann, Lea; Stiller, Rebecca G; Fischmann, Svenja; Westphal, Folker; Meyer, Markus R","year":2022,"journal":"Archives of toxicology, 96(10), 2755-2766","doi":"10.1007/s00204-022-03332-z","pmid":"35788413","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04288","title":"Content Analysis of the Corporate Social Responsibility Practices of 9 Major Cannabis Companies in Canada and the US.","authors":"Wakefield, Tanner; Glantz, Stanton A; Apollonio, Dorie E","year":2022,"journal":"JAMA network open, 5(8), e2228088","doi":"10.1001/jamanetworkopen.2022.28088","pmid":"35997980","tags":["legalization","harm-reduction"],"studyType":"qualitative","evidenceStrength":"moderate","keyFinding":"Nine major cannabis companies engaged in CSR activities that encouraged increased consumption and targeted marginalized communities. Companies claimed activities would mitigate prohibition harms, promote diversity, expand medical access, and support charities, but these strategies paralleled tobacco industry tactics to recruit allies and influence regulation.","whyItMatters":"If cannabis companies are adopting the same public relations playbook as tobacco companies, understanding these strategies early may help policymakers avoid the regulatory capture that delayed tobacco control for decades.","specificNumbers":"9 companies analyzed. 153 documents reviewed. Period: 2012-2021. CSR activities included educational programs, sustainability initiatives, voluntary marketing codes, and recruitment of public interest organizations.","methodology":"Qualitative content analysis of CSR activities from 9 of the 10 largest publicly traded cannabis companies in the US and Canada (2012-2021). Systematic review of corporate websites and Nexis Uni yielding 153 news articles, press releases, and web pages. Modified grounded theory analysis.","limitations":"Only 9 companies analyzed, all publicly traded. Qualitative assessment of intent is inherently subjective. Companies may have genuine philanthropic motivations alongside strategic ones. Published in JAMA Network Open, suggesting the framing may emphasize risks."},{"rthcId":"RTHC-04289","title":"Impact of cannabis legalization on healthcare utilization for psychosis and schizophrenia in Colorado.","authors":"Wang, George Sam; Buttorff, Christine; Wilks, Asa; Schwam, Daniel; Tung, Gregory; Pacula, Rosalie Liccardo","year":2022,"journal":"The International journal on drug policy, 104, 103685","doi":"10.1016/j.drugpo.2022.103685","pmid":"35429874","tags":["legalization","psychosis","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"As recreational dispensaries per 10,000 residents increased, psychosis ED visits increased 24% (IRR 1.24, 95% CI 1.02-1.49) while schizophrenia ED visits showed no significant change (IRR 0.95). Counties previously unexposed to medical dispensaries may have experienced larger increases.","whyItMatters":"This is one of the first studies to use a natural experiment design to examine whether cannabis dispensary access directly impacts psychosis-related healthcare utilization at the population level.","specificNumbers":"Psychosis ED visits: IRR 1.24 (significant). Schizophrenia ED visits: IRR 0.95 (not significant). Counties with low baseline medical exposure had lower psychosis increases than high-exposure counties (IRR 0.83).","methodology":"Difference-in-difference analysis of Colorado Hospital Association county-level quarterly ED data from January 2013 to December 2018. Compared how new recreational dispensary exposure affected psychosis and schizophrenia ED visit rates across counties with different baseline medical dispensary exposure.","limitations":"Observational, cannot prove causation. Administrative coding may not distinguish cannabis-induced psychosis from other causes. Dispensary density may correlate with other county-level factors. Short post-legalization period."},{"rthcId":"RTHC-04290","title":"Cannabis legalization and cannabis-involved pregnancy hospitalizations in Colorado.","authors":"Wang, George Sam; Buttorff, Christine; Wilks, Asa; Schwam, Daniel; Metz, Torri D; Tung, Gregory; Pacula, Rosalie Liccardo","year":2022,"journal":"Preventive medicine, 156, 106993","doi":"10.1016/j.ypmed.2022.106993","pmid":"35150750","tags":["pregnancy","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-involved pregnancy hospitalizations increased more than two-fold from 2011-2018. Increasing recreational dispensaries were associated with increases in hospitalizations (IRR 1.02). Counties with no prior medical cannabis exposure had greater increases than counties already exposed.","whyItMatters":"The sharp increase in cannabis-involved pregnancy hospitalizations after legalization raises important public health questions about how legalization affects cannabis use during pregnancy.","specificNumbers":"Hospitalizations increased from 429 to 1,210. Per 10,000 live births: 13.2 to 55.7. Mean per county: 1.7 to 4.7. Recreational dispensary association: IRR 1.02. Previously unexposed counties had greater increases.","methodology":"Retrospective cohort study of pregnancy-related hospitalizations co-coded with cannabis diagnoses in Colorado (2011-2018). Poisson regression assessed association between county-level recreational dispensary density and hospitalization rates, controlling for baseline medical dispensary exposure.","limitations":"Administrative data may overcount if cannabis screening became more routine. Cannot distinguish between cannabis causing the hospitalization versus incidental detection. The IRR of 1.02, while significant, is small per dispensary."},{"rthcId":"RTHC-04291","title":"Roles of the Cannabinoid System in the Basal Ganglia in Parkinson's Disease.","authors":"Wang, Mengya; Liu, Huayuan; Ma, Zegang","year":2022,"journal":"Frontiers in cellular neuroscience, 16, 832854","doi":"10.3389/fncel.2022.832854","pmid":"35264932","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04292","title":"Characterization and expression analysis of MATEs in Cannabis sativa L. reveals genes involving in cannabinoid synthesis.","authors":"Wang, Sifan; Cao, Xue; Meng, Xiangxiao; Aili, Maimaiti; Dou, Qin; Wang, Yan; Wahab, Atia Tul; Chen, Shilin; Sun, Wei; Wan, Huihua; Chen, Weiqiang","year":2022,"journal":"Frontiers in plant science, 13, 1021088","doi":"10.3389/fpls.2022.1021088","pmid":"36311070","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04293","title":"When Hotel Guests Complain About Tobacco, Electronic Cigarettes, and Cannabis: Lessons for Implementing Smoking Bans.","authors":"Weigel, Elizabeth Ad; Matt, Georg E","year":2022,"journal":"Tobacco use insights, 15, 1179173X221124900","doi":"10.1177/1179173X221124900","pmid":"36090650","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04294","title":"A Coala-T-Cannabis Survey Study of breast cancer patients' use of cannabis before, during, and after treatment.","authors":"Weiss, Marisa C; Hibbs, Julianne E; Buckley, Meghan E; Danese, Sherry R; Leitenberger, Adam; Bollmann-Jenkins, Melissa; Meske, Sam W; Aliano-Ruiz, Katherine E; McHugh, Theresa W; Larson, Sharon L; Le, Elaine H; Green, Nancye L; Gilman, Paul B; Kaklamani, Virginia G; Chlebowski, Rowan T; Martinez, Diana M","year":2022,"journal":"Cancer, 128(1), 160-168","doi":"10.1002/cncr.33906","pmid":"34636036","tags":["cancer","medical-cannabis","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"42% of breast cancer patients used cannabis for symptom relief (pain 78%, insomnia 70%, anxiety 57%). 49% of cannabis users believed it could treat cancer itself. 79% used cannabis during active treatment (systemic therapy, radiation, surgery). Only 39% discussed cannabis with any physician.","whyItMatters":"The high rate of undisclosed cannabis use during active cancer treatment creates potential risks from drug interactions that neither patients nor their oncologists may be aware of.","specificNumbers":"612 participants, 257 (42%) used cannabis. Reasons: pain (78%), insomnia (70%), anxiety (57%), stress (51%), nausea/vomiting (46%). 49% believed cannabis could treat cancer. 79% used during treatment. Only 39% discussed with physicians.","methodology":"Anonymous online survey of US-based Breastcancer.org and Healthline.com members with self-reported breast cancer diagnosis within 5 years (age 18+). 612 participants total, 257 cannabis users.","limitations":"Self-selected sample from advocacy websites may overrepresent cannabis-favorable attitudes. Self-reported cancer diagnosis. Online survey may underrepresent older or less internet-connected patients."},{"rthcId":"RTHC-04295","title":"Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People?","authors":"Weresa, Jolanta; Pędzińska-Betiuk, Anna; Mińczuk, Krzysztof; Malinowska, Barbara; Schlicker, Eberhard","year":2022,"journal":"Cells, 11(7)","doi":"10.3390/cells11071142","pmid":"35406706","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04296","title":"Cannabis Use and the Development of Depression in Adolescents: Is There an Established Linear Relationship Between the Two?","authors":"White, Chantelle T; Shamim, Humaira; Al Shouli, Roba; Habbal, Ahmad B; Mohammed, Lubna","year":2022,"journal":"Cureus, 14(7), e27394","doi":"10.7759/cureus.27394","pmid":"36046299","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04297","title":"Evaluation of Cannabis and Cannabinoid Product Use, Knowledge, and Attitudes in the Eczema Community.","authors":"Whiting, Cleo; Duan, Xuejing; Friedman, Adam","year":2022,"journal":"Journal of drugs in dermatology : JDD, 21(4), 413-419","doi":"10.36849/JDD.6615","pmid":"35389585","tags":["medical-cannabis","cbd","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"100% of respondents supported medical cannabis use. 94% would be comfortable seeing a cannabis-recommending dermatologist. 94% were interested in learning about cannabis for eczema. 93% had never discussed it with their provider. 47% were unsure if OTC cannabis products were FDA-regulated. Most commonly used OTC products without medical guidance.","whyItMatters":"The endocannabinoid system plays a role in skin health, making cannabinoid therapies a plausible area of research. But the massive gap between patient interest and medical guidance means patients are experimenting without clinical support.","specificNumbers":"76 respondents. 36% most commonly used OTC products without dermatologist recommendation. Only 3.1% used medical cannabis recommended by a dermatologist. 100% supported medical cannabis. 93% never discussed with provider. 47% unsure about FDA regulation of OTC products.","methodology":"Online survey distributed by the National Eczema Association via social media. 76 respondents (69 with eczema, 7 caregivers). Assessed cannabis product use, knowledge, attitudes, and healthcare provider interactions.","limitations":"Very small sample (76). Self-selected from National Eczema Association, likely overrepresenting cannabis-interested patients. No clinical outcome data on cannabis use for eczema."},{"rthcId":"RTHC-04298","title":"Developing the Cannabinoid Receptor 2 (CB2) pharmacopoeia: past, present, and future.","authors":"Whiting, Zak M; Yin, Jiazhen; de la Harpe, Sara M; Vernall, Andrea J; Grimsey, Natasha L","year":2022,"journal":"Trends in pharmacological sciences, 43(9), 754-771","doi":"10.1016/j.tips.2022.06.010","pmid":"35906103","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04299","title":"Separate and combined effects of alcohol and cannabis on mood, subjective experience, cognition and psychomotor performance: A randomized trial.","authors":"Wickens, Christine M; Wright, Madison; Mann, Robert E; Brands, Bruna; Di Ciano, Patricia; Stoduto, Gina; Fares, Andrew; Matheson, Justin; George, Tony P; Rehm, Jürgen; Shuper, Paul A; Sproule, Beth; Samohkvalov, Andriy; Huestis, Marilyn A; Le Foll, Bernard","year":2022,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 118, 110570","doi":"10.1016/j.pnpbp.2022.110570","pmid":"35551928","tags":["cognition","driving","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Cannabis increased tension-anxiety, confusion, euphoria, and sedation ratings but had minimal impact on cognitive test scores. Alcohol impaired verbal recall, digit symbol substitution, and fine motor tasks but had minimal impact on mood. When combined, the effects were additive rather than synergistic.","whyItMatters":"This controlled comparison helps separate what cannabis and alcohol each do to the brain in real time. The finding that cannabis mainly shifts subjective experience while alcohol mainly disrupts performance challenges assumptions that the two substances impair functioning in the same way.","specificNumbers":"28 participants completed all four sessions; alcohol target was 80 mg/dL breath alcohol; cannabis was 12.5% THC smoked ad libitum; significant effects found on POMS tension-anxiety and confusion scales, ARCI euphoria and sedation scales, verbal free recall (immediate and delayed), and digit symbol substitution test","methodology":"Within-subjects, double-blind, double-dummy, placebo-controlled RCT with 28 healthy cannabis users aged 19-29 who had recent binge drinking history. Four conditions tested: placebo/placebo, alcohol/placebo, placebo/cannabis (12.5% THC), and alcohol/cannabis. Cognitive and mood measures taken 75 minutes after alcohol (1 hour after cannabis).","limitations":"Small sample of 28 young adults limits generalizability. Single-dose design does not reflect chronic co-use patterns. THC was smoked ad libitum, so doses varied between participants. Only tested one alcohol level and one cannabis potency."},{"rthcId":"RTHC-04300","title":"Premorbid characteristics of patients with DSM-IV psychotic disorders.","authors":"Widing, Line; Simonsen, Carmen; Flaaten, Camilla B; Haatveit, Beathe; Vik, Ruth Kristine; Wold, Kristin F; Åsbø, Gina; Ueland, Torill; Melle, Ingrid","year":2022,"journal":"Comprehensive psychiatry, 115, 152310","doi":"10.1016/j.comppsych.2022.152310","pmid":"35385814","tags":["psychosis","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"17.5% of PNOS participants and 11.5% of schizophrenia spectrum participants used cannabis before age 16, compared to only 5.3% of psychotic bipolar participants. PNOS and schizophrenia groups also had poorer premorbid academic functioning than the bipolar group.","whyItMatters":"Psychotic disorder NOS is a common but poorly understood diagnosis. Understanding whether these patients look more like schizophrenia or bipolar patients in their early histories can guide treatment decisions and help predict outcomes.","specificNumbers":"1,099 participants total; 17.5% of PNOS used cannabis before 16 vs 11.5% SSD vs 5.3% PBD; premorbid academic functioning significantly worse in PNOS and SSD vs PBD (F=7.81, p<0.05); childhood adversity rates were high across all three groups with no significant differences","methodology":"Cross-sectional study of 1,099 participants from the Norwegian TOP-study: 688 with schizophrenia spectrum disorders, 274 with psychotic bipolar spectrum disorders, and 137 with psychotic disorder not otherwise specified (PNOS). Assessed using SCID-I diagnostic interviews, Premorbid Adjustment Scale, cannabis use history, and Childhood Trauma Questionnaire.","limitations":"Cross-sectional design cannot establish whether early cannabis use contributed to the psychotic disorder. Self-reported cannabis use history may be subject to recall bias. PNOS is a heterogeneous diagnostic category."},{"rthcId":"RTHC-04301","title":"Technological Changes in Wheat-Based Breads Enriched with Hemp Seed Press Cakes and Hemp Seed Grit.","authors":"Wiedemair, Verena; Gruber, Kathrin; Knöpfle, Nataly; Bach, Katrin E","year":2022,"journal":"Molecules (Basel, Switzerland), 27(6)","doi":"10.3390/molecules27061840","pmid":"35335202","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04302","title":"DNA methylation changes associated with cannabis use and verbal learning performance in adolescents: an exploratory whole genome methylation study.","authors":"Wiedmann, Melina; Kuitunen-Paul, Sören; Basedow, Lukas Andreas; Wolff, Max; DiDonato, Nataliya; Franzen, Julia; Wagner, Wolfgang; Roessner, Veit; Golub, Yulia","year":2022,"journal":"Translational psychiatry, 12(1), 317","doi":"10.1038/s41398-022-02025-6","pmid":"35933470","tags":["cognition","youth","genetics"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Six CpG methylation sites showed reduced methylation associated with the extent of chronic cannabis use. All six sites mediated the relationship between cannabis use and impaired verbal free recall performance. The affected genes had been previously linked to neurodegeneration, hippocampus-dependent learning, and neurogenesis.","whyItMatters":"This is among the first studies to look at whether DNA methylation changes might explain how cannabis affects memory in young people. If confirmed, it would suggest cannabis does not just temporarily impair cognition but may alter gene expression in ways relevant to brain function.","specificNumbers":"18 adolescents total (9 cannabis users, 9 controls); 6 CpG sites with reduced methylation; all 6 mediated the effect on verbal learning free recall; cannabis users abstinent at least 24 hours before testing","methodology":"Exploratory whole-genome methylation study of 18 adolescents (9 psychiatric outpatients with chronic cannabis use, 9 matched controls without). Groups matched for age, gender, and psychiatric disorders. Cannabis users were abstinent at least 24 hours before cognitive testing. Blood samples analyzed for CpG methylation via principal component analysis and mediation analyses.","limitations":"Very small sample of 18 participants severely limits statistical power and generalizability. Cannot determine whether methylation changes are caused by cannabis use or reflect pre-existing differences. Peripheral blood methylation may not reflect brain methylation patterns."},{"rthcId":"RTHC-04303","title":"The effect of medical cannabis on cognitive functions: a systematic review.","authors":"Wieghorst, Anders; Roessler, Kirsten Kaya; Hendricks, Oliver; Andersen, Tonny Elmose","year":2022,"journal":"Systematic reviews, 11(1), 210","doi":"10.1186/s13643-022-02073-5","pmid":"36192811","tags":["cognition","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 23 included studies (917 total participants), 15 found non-significant effects on cognition, 6 found impairments, 1 found improvement, and 1 found improvement after withdrawal. In studies that did find significant impairment, test scores remained within normal ranges or below clinical impairment thresholds.","whyItMatters":"Cognitive side effects are a common concern for patients considering medical cannabis. This review provides reassurance that at therapeutic doses, cognitive impairment appears minor, while also flagging that long-term use remains an open question.","specificNumbers":"23 studies included; 917 total participants; 15 studies found non-significant cognitive effects; 6 found impairments; 8 used Sativex; 13 had cognition as primary outcome","methodology":"Systematic review searching EMBASE, PsycINFO, PubMed, and Scopus. Included studies had to use cannabis-based medicines in controlled settings, measure cognition with recognized tests, and use within-subjects designs. Excluded studies on abuse, abstinence, severe neurodegeneration, and cancer pain. Two independent researchers conducted screening and risk of bias assessment.","limitations":"Large heterogeneity across studies in terms of cannabis products, doses, cognitive measures, and patient populations. Most studies used relatively low THC doses. Limited evidence on long-term cognitive effects of medical cannabis use."},{"rthcId":"RTHC-04304","title":"Transcription Profile and Pathway Analysis of the Endocannabinoid Receptor Inverse Agonist AM630 in the Core and Infiltrative Boundary of Human Glioblastoma Cells.","authors":"Williams, Gareth; Chambers, David; Rahman, Ruman; Molina-Holgado, Francisco","year":2022,"journal":"Molecules (Basel, Switzerland), 27(7)","doi":"10.3390/molecules27072049","pmid":"35408449","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04305","title":"Convulsant doses of abused synthetic cannabinoid receptor agonists AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA and JWH-018 do not elicit electroencephalographic (EEG) seizures in male mice.","authors":"Wilson, Catheryn D; Zheng, Fang; Fantegrossi, William E","year":2022,"journal":"Psychopharmacology, 239(10), 3237-3248","doi":"10.1007/s00213-022-06205-6","pmid":"35933518","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Convulsant doses of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 did not produce seizure patterns on EEG despite causing visible convulsions. Rimonabant (CB1 antagonist) blocked the convulsions, but diazepam did not. This suggests the convulsions are CB1-mediated motor events, not epileptic seizures.","whyItMatters":"Convulsions from synthetic cannabinoids are commonly treated as seizures in emergency rooms. If these are not true seizures, benzodiazepines (the standard seizure treatment) may be ineffective, and different treatment approaches may be needed.","specificNumbers":"4 synthetic cannabinoids tested; 10 mg/kg rimonabant blocked convulsions; 10 mg/kg diazepam did not; repeated dosing produced partial tolerance; no cross-tolerance to PTZ-induced convulsions","methodology":"Mouse study using NIH Swiss mice. Dose-response testing for convulsant effects, with pretreatment experiments using rimonabant, diazepam, and a CYP450 inhibitor. Separate cohort fitted with EEG headmounts to record brain activity during convulsions. Root-mean-square power and spike analysis used to assess seizure-like activity.","limitations":"Animal study results may not directly translate to humans. Only male mice were used. Limited number of synthetic cannabinoids tested relative to the hundreds in circulation. EEG recordings in mice have lower spatial resolution than human EEG."},{"rthcId":"RTHC-04306","title":"The Impact of Cannabis Decriminalization and Legalization on Road Safety Outcomes: A Systematic Review.","authors":"Windle, Sarah B; Socha, Peter; Nazif-Munoz, José Ignacio; Harper, Sam; Nandi, Arijit","year":2022,"journal":"American journal of preventive medicine, 63(6), 1037-1052","doi":"10.1016/j.amepre.2022.07.012","pmid":"36167602","tags":["driving","legalization"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Medical legalization was associated with reductions in fatal motor vehicle collisions, while recreational legalization was associated with increases. Both forms of legalization increased cannabis-positive tests among drivers. Medical legalization was also associated with decreased positive alcohol tests among drivers.","whyItMatters":"As more jurisdictions legalize cannabis, understanding the road safety consequences is critical for policy decisions. The divergent findings for medical versus recreational legalization suggest different user populations may drive different outcomes.","specificNumbers":"65 reports of 64 studies; 50 on recreational legalization; 22 on medical legalization; 5 on decriminalization; 39 used quasi-experimental designs; all but 1 used U.S. or Canadian data","methodology":"Systematic review searching seven databases from inception to June 2021. Included 65 reports of 64 observational studies, of which 39 used quasi-experimental designs. Studies examined recreational legalization (n=50), medical legalization (n=22), and decriminalization (n=5). Nearly all studies used U.S. or Canadian data.","limitations":"Most studies from U.S. and Canada, limiting global generalizability. Positive cannabis tests do not prove impairment at the time of driving. Very few studies examined decriminalization. Underlying study designs were observational, limiting causal conclusions."},{"rthcId":"RTHC-04307","title":"The Synaptic Interactions of Alcohol and the Endogenous Cannabinoid System.","authors":"Wolfe, Sarah A; Vozella, Valentina; Roberto, Marisa","year":2022,"journal":"Alcohol research : current reviews, 42(1), 03","doi":"10.35946/arcr.v42.1.03","pmid":"35223337","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04308","title":"Targeting maladaptive reactivity to negative affect in emerging adults with cannabis use disorder: A preliminary test and proof of concept.","authors":"Wolitzky-Taylor, Kate; Glasner, Suzette; Tanner, Alexandra; Ghahremani, Dara G; London, Edythe D","year":2022,"journal":"Behaviour research and therapy, 150, 104032","doi":"10.1016/j.brat.2022.104032","pmid":"35032700","tags":["addiction","mental-health","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Affect Management Treatment (AMT) was more effective than standard CBT at reducing negative affect and maladaptive reactivity to negative emotions through post-treatment and 6-month follow-up. Both treatments reduced cannabis use and cannabis-related problems, with no statistically significant between-group differences on cannabis outcomes.","whyItMatters":"Cannabis use disorder is often intertwined with anxiety and depression, especially in young adults. Treatments that address the emotional drivers of use, not just the use itself, could lead to more lasting recovery.","specificNumbers":"52 participants aged 18-25; 12 sessions per treatment arm; AMT outperformed CBT on emotional measures; both groups reduced cannabis use; assessed through 6-month follow-up","methodology":"Pilot randomized clinical trial with 52 participants aged 18-25 with cannabis use disorder. Randomized to 12 sessions of either AMT (targeting emotional regulation) or standard CBT. Assessed at baseline, during treatment, post-treatment, and 6-month follow-up on negative affect, distress intolerance, cannabis use, and cannabis-related problems.","limitations":"Pilot study with only 52 participants limits statistical power to detect between-group differences in cannabis outcomes. No placebo or no-treatment control group. Cannot determine whether emotional improvements lead to better long-term cannabis outcomes."},{"rthcId":"RTHC-04309","title":"Cultural and psychosocial moderators of the association between adverse childhood experiences and alcohol and marijuana use among Latinx college students on the U.S./Mexico border.","authors":"Woloshchuk, Claudia J; Frietze, Gabriel A; Cooper, Theodore V","year":2022,"journal":"Child abuse & neglect, 133, 105859","doi":"10.1016/j.chiabu.2022.105859","pmid":"36054999","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"For female participants, insecure attachment style strengthened the link between childhood adversity and substance use, while stronger marianismo beliefs and higher bicultural self-efficacy altered this relationship. No moderation effects were statistically significant among males.","whyItMatters":"Latinx populations are underrepresented in substance use research. Understanding how cultural factors like gender role beliefs and bicultural identity influence the path from childhood trauma to substance use can inform more culturally responsive prevention and treatment.","specificNumbers":"451 Latinx participants (283 female, 168 male); attachment style moderation β=0.04 (p=.03); marianismo beliefs moderation β=-65.57 (p=.01); bicultural self-efficacy moderation β=0.34 (p=.04); no significant moderation among males","methodology":"Cross-sectional survey of 451 Latinx college students (283 female, 168 male) at a U.S./Mexico border university. Measured adverse childhood experiences (ACEs), alcohol and marijuana use frequency, attachment style, self-efficacy, familism, traditional gender norms (machismo/marianismo), and bicultural self-efficacy. Hierarchical linear regressions tested moderation effects.","limitations":"Cross-sectional design cannot establish causal or temporal relationships. Sample limited to one border university, limiting generalizability to broader Latinx populations. Self-reported substance use may underestimate actual use. Gender differences could reflect measurement issues rather than true differences."},{"rthcId":"RTHC-04310","title":"Development of Cross-Reactive Antibodies for the Identification and Treatment of Synthetic Cannabinoid Receptor Agonist Toxicity.","authors":"Worob, Adam; Wenthur, Cody J","year":2022,"journal":"Vaccines, 10(8)","doi":"10.3390/vaccines10081253","pmid":"36016144","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04311","title":"Medical marijuana for inflammatory bowel disease: the highs and lows.","authors":"Wynne, Joshua; Kozuch, Patricia","year":2022,"journal":"Scandinavian journal of gastroenterology, 57(2), 197-205","doi":"10.1080/00365521.2021.1998604","pmid":"34919496","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04312","title":"Dietary supplementation of hemp oil in teddy dogs: Effect on apparent nutrient digestibility, blood biochemistry and metabolomics.","authors":"Xin, Guosheng; Yang, Jie; Li, Ruiguo; Gao, Qiaoxian; Li, Ronglin; Wang, Jianguo; Zhang, Juan; Wang, Jing","year":2022,"journal":"Bioengineered, 13(3), 6173-6187","doi":"10.1080/21655979.2022.2043018","pmid":"35200081","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04313","title":"Cannabis suppresses antitumor immunity by inhibiting JAK/STAT signaling in T cells through CNR2.","authors":"Xiong, Xinxin; Chen, Siyu; Shen, Jianfei; You, Hua; Yang, Han; Yan, Chao; Fang, Ziqian; Zhang, Jianeng; Cai, Xiuyu; Dong, Xingjun; Kang, Tiebang; Li, Wende; Zhou, Penghui","year":2022,"journal":"Signal transduction and targeted therapy, 7(1), 99","doi":"10.1038/s41392-022-00918-y","pmid":"35383142","tags":["cancer","medical-cannabis","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"THC reduced the therapeutic effect of PD-1 checkpoint blockade in tumor-bearing mice. The endocannabinoid anandamide also impaired antitumor immunity. Using a knock-in mouse model, researchers found CNR2 (CB2 receptor) binds to JAK1 and inhibits downstream STAT signaling in T cells, suppressing their cancer-fighting function. In human cancer patients, higher serum anandamide levels correlated with poorer overall survival.","whyItMatters":"Many cancer patients use cannabis to manage chemotherapy side effects like nausea, often while receiving immunotherapy. This study raises the concern that THC could undermine the very treatment intended to fight their cancer.","specificNumbers":"THC reduced PD-1 blockade therapeutic effect in mice; CNR2 binds JAK1 and inhibits STAT signaling; high serum anandamide associated with poor overall survival in human cancer patients","methodology":"Preclinical study using multiple mouse tumor models. Tested THC and anandamide effects on PD-1 immunotherapy efficacy. Generated FLAG-tagged Cnr2 knock-in mice to study molecular mechanisms. Measured JAK/STAT signaling in T cells. Analyzed serum anandamide levels in human cancer patient cohort for survival association.","limitations":"Mouse tumor models do not perfectly replicate human cancer immunology. The human survival data is observational and cannot prove anandamide caused worse outcomes. THC doses in mice may not reflect typical human cannabis use patterns. Study focused on CB2 mechanism but other pathways may also be involved."},{"rthcId":"RTHC-04314","title":"The influence of parent and peer disapproval on youth marijuana use mediated by youth risk perception: Focusing on the state comparison.","authors":"Yang, Eunbyeor Sophie; Oh, Su-Kyung; Kim, Seohyun; Chung, Ick-Joong","year":2022,"journal":"Drug and alcohol dependence, 240, 109641","doi":"10.1016/j.drugalcdep.2022.109641","pmid":"36179508","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Parent disapproval had a stronger direct effect on reducing youth marijuana use, while peer disapproval had a stronger indirect effect working through increased risk perception. Both parent and peer disapproval increased youth risk perception of marijuana. The mechanisms were similar regardless of whether youth lived in states with medical marijuana legalization.","whyItMatters":"Understanding how social disapproval reduces youth cannabis use through different pathways can help design more effective prevention programs. The finding that these mechanisms work similarly regardless of legal status suggests that social influence remains potent even as laws change.","specificNumbers":"2,293 adolescents aged 12-17; parent disapproval had stronger direct effect on use; peer disapproval had stronger indirect effect via risk perception; similar patterns in MML vs non-MML states","methodology":"Cross-sectional analysis of the 2019 National Survey of Drug Use and Health, focusing on youth aged 12-17 (N=2,293). Used structural equation modeling and bias-corrected bootstrapping to test path models. Compared mediating mechanisms between youth in medical marijuana legalization (MML) states and non-MML states.","limitations":"Cross-sectional design cannot establish temporal ordering of disapproval, risk perception, and use. Self-reported data from 12-17-year-olds may be subject to social desirability bias. MML states vary widely in their specific regulations and enforcement."},{"rthcId":"RTHC-04315","title":"Nonmedical Marijuana Use and Cardiovascular Events: A Systematic Review.","authors":"Yang, Peter K; Odom, Erika C; Patel, Roshni; Loustalot, Fleetwood; Coleman King, Sallyann","year":2022,"journal":"Public health reports (Washington, D.C. : 1974), 137(1), 62-71","doi":"10.1177/0033354920988285","pmid":"33636088","tags":["cardiovascular"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Marijuana use was associated with an increased likelihood of heart attack within 24 hours in 2 studies and stroke in 6 studies. Results also suggested increased risk for angina and acute coronary syndrome, particularly among people with a history of cardiovascular events.","whyItMatters":"As marijuana use increases and perceived risk decreases, understanding cardiovascular effects becomes more important. The association with acute events like heart attack and stroke within hours of use suggests a time-sensitive physiological mechanism.","specificNumbers":"16 studies included from 3,916 citations; 2 studies linked use to heart attack within 24 hours; 6 studies linked use to stroke; study sizes ranged from 10 to 118,659,619 hospitalizations","methodology":"Systematic review searching six databases from 1970 to 2018. Of 3,916 citations, 16 met inclusion criteria. Included 4 cohort studies, 8 case-control studies, 1 case-crossover study, 2 RCTs, and 1 descriptive study. Study sizes ranged from 10 participants to over 118 million hospitalizations.","limitations":"Most studies were observational, limiting causal conclusions. Cannabis use was measured differently across studies (self-report, diagnostic codes, drug tests). Potential confounding by tobacco co-use was not always controlled. Search ended in 2018, missing more recent studies."},{"rthcId":"RTHC-04316","title":"N-linoleyltyrosine ameliorates high-fat diet-induced obesity in C57BL/6 mice via cannabinoid receptor regulation.","authors":"Yang, Zheng-Yu; Wu, Yi-Ying; Zhou, Yi; Yang, Yun-Qi; Zhang, Jia-Hui; He, Tao; Liu, Sha","year":2022,"journal":"Frontiers in endocrinology, 13, 938527","doi":"10.3389/fendo.2022.938527","pmid":"36111301","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04317","title":"A Case of Presumed Bonsai-induced Severe Toxic Optic Neuropathy.","authors":"Yasar, Erdogan; Tomac, Hatice Suhan; Gurlevik, Ugur","year":2022,"journal":"Neuro-ophthalmology (Aeolus Press), 46(1), 41-43","doi":"10.1080/01658107.2021.1903510","pmid":"35095134","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient presented with severely decreased vision in both eyes. His optic discs were covered with black pigment overlying atrophic nerve tissue, with blood vessels appearing to disappear below the pigmentation. Vision loss began gradually after he started using bonsai (a synthetic cannabinoid) two years prior. No similar case had been previously reported.","whyItMatters":"Synthetic cannabinoids are poorly understood in terms of their long-term effects on specific organs. This case documents a previously unreported type of eye damage that may represent a unique toxicity of these substances.","specificNumbers":"1 patient, age 32; 2 years of bonsai use before presentation; bilateral optic disc atrophy with black pigmentation; used tobacco, alcohol, and cannabis in addition to bonsai","methodology":"Single case report of a 32-year-old male presenting with decreased vision. Ophthalmological examination included optic disc evaluation. Patient history included tobacco, alcohol, and cannabis use, with vision decline temporally linked to synthetic cannabinoid (bonsai) use onset.","limitations":"Single case report cannot establish causation. The patient also used tobacco, alcohol, and cannabis, making it difficult to attribute the optic neuropathy solely to bonsai. No toxicological confirmation of specific synthetic cannabinoid compounds used. The pigmentation pattern is unprecedented and not yet confirmed by other cases."},{"rthcId":"RTHC-04318","title":"Thirdhand smoke from tobacco, e-cigarettes, cannabis, methamphetamine and cocaine: Partitioning, reactive fate, and human exposure in indoor environments.","authors":"Yeh, Kristen; Li, Li; Wania, Frank; Abbatt, Jonathan P D","year":2022,"journal":"Environment international, 160, 107063","doi":"10.1016/j.envint.2021.107063","pmid":"34954646","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04319","title":"Differential Effects of D9 Tetrahydrocannabinol (THC)- and Cannabidiol (CBD)-Based Cannabinoid Treatments on Macrophage Immune Function In Vitro and on Gastrointestinal Inflammation in a Murine Model.","authors":"Yekhtin, Zhanna; Khuja, Iman; Meiri, David; Or, Reuven; Almogi-Hazan, Osnat","year":2022,"journal":"Biomedicines, 10(8)","doi":"10.3390/biomedicines10081793","pmid":"35892693","tags":["inflammation","medical-cannabis","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both pure cannabinoids and cannabis extracts inhibited macrophage nitric oxide and pro-inflammatory cytokine release and reduced expression of cell surface inflammatory markers in vitro. In the colitis mouse model, treatments improved clinical scores and reduced macrophage infiltration in the colon. Cannabis extracts showed higher activity compared to pure cannabinoids, suggesting additional plant compounds contribute to the therapeutic effect.","whyItMatters":"This study provides laboratory evidence that whole cannabis extracts may work better than isolated cannabinoids for gut inflammation, supporting the idea that other compounds in the plant contribute to therapeutic effects. It also shows that THC and CBD have distinct immune profiles.","specificNumbers":"Cannabis extracts showed higher activity than pure cannabinoids; both THC and CBD suppressed NO and cytokine release; colon macrophage infiltration reduced in treated mice; each treatment produced a unique cytokine profile","methodology":"In vitro experiments with macrophages from young and aged C57BL/6 mice activated with LPS and IFN-gamma, treated with pure THC, pure CBD, or cannabis extracts. In vivo murine colitis model assessed clinical scores, colon macrophage infiltration, and inflammatory cytokines in blood.","limitations":"Animal study with in vitro components; results may not translate to human IBD. Specific extract compositions and doses were not fully detailed. The colitis model does not perfectly replicate human Crohn's disease or ulcerative colitis."},{"rthcId":"RTHC-04320","title":"Catatonic Episodes Related to Substance Use: A Cross-Sectional Study Using Electronic Healthcare Records.","authors":"Yeoh, Su Ying; Roberts, Emmert; Scott, Fraser; Nicholson, Timothy R; David, Anthony S; Rogers, Jonathan P","year":2022,"journal":"Journal of dual diagnosis, 18(1), 52-58","doi":"10.1080/15504263.2021.2016342","pmid":"35001837","tags":["psychosis","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 108 substance-related catatonic episodes, cannabis was linked to 31 of 54 intoxication-related episodes and 37 of 50 chronic use-related episodes. Substance-related catatonia occurred in younger patients (mean age 31.3 vs 35.7) and more often in men (74% vs 54.3%). The number of substance-related episodes increased between 2007 and 2016.","whyItMatters":"Catatonia is a serious psychiatric emergency that can be life-threatening. Identifying cannabis as the most commonly implicated substance helps clinicians consider substance-related causes and adjust treatment accordingly.","specificNumbers":"2,130 total catatonic episodes; 108 (5.1%) substance-related; cannabis linked to 31/54 intoxication episodes and 37/50 chronic use episodes; substance-related episodes increased from 2007-2016 (r=0.72, p=0.02); mean age 31.3 vs 35.7 years","methodology":"Retrospective cross-sectional study using electronic health records from a large London secondary mental health trust. Identified all catatonic episodes and categorized them as substance-related based on positive urine drug screens, ICD-10 substance use diagnoses, or documented use within two weeks of the episode.","limitations":"Retrospective study relying on clinical documentation, which likely underestimates true substance involvement. Cannot establish causation between substance use and catatonia. Single-site study in London limits generalizability. Concurrent substance use made attribution to specific substances difficult in some cases."},{"rthcId":"RTHC-04321","title":"Surviving but not thriving: Burden of care and quality of life for caregivers of patients with schizophrenia spectrum disorders and comorbid substance use in South Africa.","authors":"Yerriah, Jacqueline; Tomita, Andrew; Paruk, Saeeda","year":2022,"journal":"Early intervention in psychiatry, 16(2), 153-161","doi":"10.1111/eip.13141","pmid":"33733599","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04322","title":"Pharmacokinetics, Safety, and Synovial Fluid Concentrations of Single- and Multiple-Dose Oral Administration of 1 and 3 mg/kg Cannabidiol in Horses.","authors":"Yocom, Alicia F; O'Fallon, Elsbeth S; Gustafson, Daniel L; Contino, Erin K","year":2022,"journal":"Journal of equine veterinary science, 113, 103933","doi":"10.1016/j.jevs.2022.103933","pmid":"35307550","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04323","title":"Perceptions About Cannabis Following Legalization Among Pregnant Individuals With Prenatal Cannabis Use in California.","authors":"Young-Wolff, Kelly C; Foti, Tara R; Green, Andrea; Altschuler, Andrea; Does, Monique B; Jackson-Morris, Melanie; Adams, Sara R; Ansley, Deborah; Conway, Amy; Goler, Nancy; Mian, Maha N; Iturralde, Esti","year":2022,"journal":"JAMA network open, 5(12), e2246912","doi":"10.1001/jamanetworkopen.2022.46912","pmid":"36515947","tags":["pregnancy","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Three major themes emerged: easier access (via retailers and delivery services), greater acceptance (reduced stigma and more willingness to discuss use with healthcare providers), and trust in cannabis retailers (perceived as knowledgeable, nonjudgmental, and caring). Responses were mixed about whether marketing influenced prenatal use and whether legalization reduced fears about Child Protective Services involvement.","whyItMatters":"Understanding how pregnant people perceive legalization reveals potential pathways through which policy changes affect prenatal cannabis use. The finding that pregnant users trust cannabis retailers more than health messaging suggests a disconnect in health communication.","specificNumbers":"53 participants (mean age 30.3 years); 43% Black, 57% White; 30% still using at recruitment; 18 focus groups conducted November-December 2021","methodology":"Qualitative study with 18 semi-structured focus groups conducted via video platform in Kaiser Permanente Northern California. Participants were Black and White pregnant individuals who self-reported cannabis use during early pregnancy. Thematic analysis used to identify major themes.","limitations":"Qualitative study cannot quantify the impact of legalization on use rates. Limited to Black and White participants in Northern California. Participants were already cannabis users, so findings may not reflect perspectives of non-users. Focus groups may introduce social desirability bias."},{"rthcId":"RTHC-04324","title":"Geographic Accessibility of Retail Cannabis in Northern California and Prenatal Cannabis Use During the COVID-19 Pandemic.","authors":"Young-Wolff, Kelly C; Slama, Natalie E; Padon, Alisa A; Silver, Lynn D; Soroosh, Aurash; Alexeeff, Stacey E; Adams, Sara R; Does, Monique B; Campbell, Cynthia I; Ansley, Deborah; Conway, Amy; Goler, Nancy; Avalos, Lyndsay A","year":2022,"journal":"JAMA network open, 5(11), e2244086","doi":"10.1001/jamanetworkopen.2022.44086","pmid":"36445706","tags":["pregnancy","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Prenatal cannabis use before (6.8%) and during (8.2%) the pandemic was associated with closer proximity to a retailer, greater retailer density, and living in jurisdictions that permitted rather than banned storefront retailers. While relative rate increases during the pandemic were similar regardless of retail access, the absolute increase was larger among those within a 10-minute drive of a retailer.","whyItMatters":"This is among the largest studies to connect the physical retail environment to prenatal cannabis use. Finding that proximity to stores matters adds geographic accessibility to the list of factors influencing prenatal use, which could inform zoning and policy decisions.","specificNumbers":"99,127 pregnancies; 6.8% prenatal cannabis use pre-pandemic; 8.2% during pandemic; greater absolute increase within 10-minute drive of retailer; adjusted for age and race/ethnicity","methodology":"Cross-sectional population-based time series study of 99,127 pregnancies in Kaiser Permanente Northern California. Cannabis use measured by universal urine toxicology at entry to prenatal care. Proximity to nearest retailer, retailer density within 15-minute drive, and local storefront policies mapped. Interrupted time series models with Poisson regression.","limitations":"Observational study cannot prove retailer proximity caused higher use. Limited to one health system in Northern California. Urine toxicology detects recent use but cannot distinguish frequency or amount. The pandemic created unique conditions that may not reflect typical patterns."},{"rthcId":"RTHC-04325","title":"Synthetic cannabinoids reduce the inflammatory activity of microglia and subsequently improve neuronal survival in vitro.","authors":"Young, Alexander P; Denovan-Wright, Eileen M","year":2022,"journal":"Brain, behavior, and immunity, 105, 29-43","doi":"10.1016/j.bbi.2022.06.011","pmid":"35764268","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Pro-inflammatory microglia released cytotoxic factors that killed cultured neurons. Treatment with selective CB1 (ACEA) or CB2 (HU-308) agonists dampened nitric oxide and pro-inflammatory cytokine release, decreased inflammatory gene expression, and reduced neuron death. A nonselective agonist (CP 55,940) had similar but weaker effects. The mechanism involved cannabinoid-mediated suppression of MAPK signaling.","whyItMatters":"Neuroinflammation driven by microglia contributes to multiple neurodegenerative diseases. Identifying that both CB1 and CB2 receptors can independently reduce microglial toxicity and protect neurons opens potential therapeutic pathways for conditions like Alzheimer's and Huntington's.","specificNumbers":"ACEA (CB1 selective) and HU-308 (CB2 selective) both reduced NO and cytokine release; CP 55,940 (nonselective) had weaker effects; all three reduced secondary neuronal damage; MAPK signaling suppression identified as mechanism","methodology":"In vitro study using mouse microglia activated with LPS and IFN-gamma. Measured nitric oxide release, cytokine secretion, cell surface markers, and mRNA expression. Cultured STHdhQ7/Q7 neurons exposed to conditioned media from treated microglia to assess secondary damage. MAPK signaling pathway analyzed.","limitations":"In vitro study using immortalized cell lines rather than primary human cells. Conditions in a dish do not replicate the complexity of the living brain. Synthetic cannabinoids used differ from naturally occurring cannabinoids. Long-term effects and potential side effects not assessed."},{"rthcId":"RTHC-04326","title":"Neuroprotection of Cannabidiol, Its Synthetic Derivatives and Combination Preparations against Microglia-Mediated Neuroinflammation in Neurological Disorders.","authors":"Yousaf, Muhammad; Chang, Dennis; Liu, Yang; Liu, Tianqing; Zhou, Xian","year":2022,"journal":"Molecules (Basel, Switzerland), 27(15)","doi":"10.3390/molecules27154961","pmid":"35956911","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04327","title":"Modulation of type 1 cannabinoid receptor activity by cannabinoid by-products from Cannabis sativa and non-cannabis phytomolecules.","authors":"Zagzoog, Ayat; Cabecinha, Ashley; Abramovici, Hanan; Laprairie, Robert B","year":2022,"journal":"Frontiers in pharmacology, 13, 956030","doi":"10.3389/fphar.2022.956030","pmid":"36091813","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04328","title":"Disparities in Marijuana and Tobacco Smoke Incursions Among New York City Families During Early Months of the COVID-19 Pandemic.","authors":"Zajac, Lauren; Gallate, Xanthe; Gu, Gregory; Liu, Bian; Elaiho, Cordelia; Lin, Elaine; Mogilner, Leora; Oliver, Kristin; Vangeepuram, Nita; Wilson, Karen","year":2022,"journal":"Journal of public health management and practice : JPHMP, 28(3), 248-257","doi":"10.1097/PHH.0000000000001440","pmid":"34750327","tags":["legalization","youth","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Marijuana smoke incursions were reported by 30.7% of surveyed families. Families with financial housing support had 6.9 times the odds of marijuana incursions (95% CI: 2.4-19.5) and 5 times the odds of worsening incursions during the pandemic. Children in subsidized housing spent more time indoors (24 vs 21.6 hours) and had higher asthma rates (37% vs 12.9%).","whyItMatters":"Secondhand marijuana smoke exposure in the home disproportionately affects low-income families who have less control over their housing environments. With children in these homes already more likely to have asthma, unwanted smoke exposure compounds existing health disparities.","specificNumbers":"230 families surveyed; 30.7% reported marijuana smoke incursions; 22.9% reported tobacco incursions; 6.9x odds of marijuana incursions in subsidized housing; 5x odds of worsening during pandemic; 37% asthma rate in subsidized housing children vs 12.9% in private","methodology":"Cross-sectional survey of 230 caregivers from five pediatric practices in NYC from May to July 2020. Collected sociodemographic data, housing characteristics, and presence, frequency, and pandemic-related changes in tobacco and marijuana smoke incursions.","limitations":"Small sample of 230 families from five practices limits generalizability. Self-reported incursions may be subject to reporting bias. Cross-sectional design during a unique pandemic period may not reflect typical patterns. Cannot confirm cannabis smoke exposure with biomarkers."},{"rthcId":"RTHC-04329","title":"The effects of oral and vaporized cannabis alone, and in combination with alcohol, on driving performance using the STISIM driving simulator: A two-part, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory protocol.","authors":"Zamarripa, C Austin; Novak, Matthew D; Weerts, Elise M; Vandrey, Ryan; Spindle, Tory R","year":2022,"journal":"Frontiers in pharmacology, 13, 964749","doi":"10.3389/fphar.2022.964749","pmid":"36147331","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04330","title":"Dos(e)Age: Role of Dose and Age in the Long-Term Effect of Cannabinoids on Cognition.","authors":"Zamberletti, Erica; Rubino, Tiziana","year":2022,"journal":"Molecules (Basel, Switzerland), 27(4)","doi":"10.3390/molecules27041411","pmid":"35209200","tags":["cognition","youth","pregnancy","seniors"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Prenatal and adolescent cannabinoid exposure consistently led to long-term cognitive deficits in animal models, while exposure in aged animals showed potential beneficial effects on cognition. The role of dosage was difficult to establish clearly, especially during adolescence, though emerging evidence suggests dose may matter more at other life stages.","whyItMatters":"Different age groups are using cannabis at increasing rates, from pregnant women to elderly patients seeking medical cannabis. Understanding that the same substance may be harmful during development but potentially beneficial in old age has major implications for policy and clinical guidance.","specificNumbers":"Review covered 2015-2021 literature; three exposure windows examined (prenatal, adolescent, aged); consistent cognitive harm found during development; potential cognitive benefit found in aged animals; dose effects unclear for adolescent exposure","methodology":"Systematic scoping review of PubMed from 2015 to December 2021. Included studies examining effects of natural or synthetic cannabinoids on cognitive performance in animal models where exposure occurred prenatally, during adolescence, or in older animals.","limitations":"Animal studies have limited translatability to humans. The review focused on cannabinoid exposure broadly, including synthetic cannabinoids that differ from what humans typically use. Publication bias may favor significant findings. Dose-response relationships remain poorly characterized."},{"rthcId":"RTHC-04331","title":"Advances and Challenges of Cannabidiol as an Anti-Seizure Strategy: Preclinical Evidence.","authors":"Zavala-Tecuapetla, Cecilia; Luna-Munguia, Hiram; López-Meraz, María-Leonor; Cuellar-Herrera, Manola","year":2022,"journal":"International journal of molecular sciences, 23(24)","doi":"10.3390/ijms232416181","pmid":"36555823","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04332","title":"Long-term and serious harms of medical cannabis and cannabinoids for chronic pain: a systematic review of non-randomised studies.","authors":"Zeraatkar, Dena; Cooper, Matthew Adam; Agarwal, Arnav; Vernooij, Robin W M; Leung, Gareth; Loniewski, Kevin; Dookie, Jared E; Ahmed, Muhammad Muneeb; Hong, Brian Y; Hong, Chris; Hong, Patrick; Couban, Rachel; Agoritsas, Thomas; Busse, Jason W","year":2022,"journal":"BMJ open, 12(8), e054282","doi":"10.1136/bmjopen-2021-054282","pmid":"35926992","tags":["medical-cannabis","pain","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Overall adverse event prevalence was 26.0% (95% CI: 13.2-41.2%). Psychiatric adverse events were most common (13.5%). Serious adverse events, cognitive adverse events, accidents, injuries, and dependence/withdrawal each occurred in fewer than 5% of patients. Longer follow-up (24+ weeks) was associated with more reported adverse events than shorter studies.","whyItMatters":"Chronic pain patients and their clinicians need realistic information about medical cannabis side effects to make informed treatment decisions. This review provides the most comprehensive picture of what to expect: side effects are common but usually not serious.","specificNumbers":"39 studies; 12,143 patients; 26.0% any adverse event; 13.5% psychiatric adverse events; <5% each for serious AEs, cognitive AEs, accidents/injuries, and dependence; longer use (24+ weeks) associated with more AEs (interaction p<0.01)","methodology":"Systematic review and meta-analysis searching MEDLINE, EMBASE, PsycINFO, and CENTRAL. Included 39 non-randomized studies of adults or children with chronic pain using medical cannabis with at least 4 weeks of follow-up. GRADE approach used to assess certainty. Parallel guideline panel informed design.","limitations":"All evidence rated as very low certainty due to study design limitations. Non-randomized studies are prone to confounding and selection bias. Insufficient evidence comparing medical cannabis harms to alternatives like opioids. Adverse event definitions varied across studies."},{"rthcId":"RTHC-04333","title":"Combined use of specific length amplified fragment sequencing (SLAF-seq) and bulked segregant analysis (BSA) for rapid identification of genes influencing fiber content of hemp (Cannabis sativa L.).","authors":"Zhao, Yue; Sun, Yufeng; Cao, Kun; Zhang, Xiaoyan; Bian, Jing; Han, Chengwei; Jiang, Ying; Xu, Lei; Wang, Xiaonan","year":2022,"journal":"BMC plant biology, 22(1), 250","doi":"10.1186/s12870-022-03594-w","pmid":"35596150","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04334","title":"Developmental Relations Between Bullying Victimization and Suicidal Ideation in Middle Adolescence and Emerging Adulthood: Do Internalizing Problems and Substance Use Mediate Their Links?","authors":"Zhu, Xinxin; Griffiths, Helen; Eisner, Manuel; Hepp, Urs; Ribeaud, Denis; Murray, Aja Louise","year":2022,"journal":"Journal of youth and adolescence, 51(9), 1745-1759","doi":"10.1007/s10964-022-01630-4","pmid":"35568749","tags":["youth","mental-health","depression"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"At the within-person level, cannabis use and suicidal ideation were positively and reciprocally related over time (ages 15-20). Bullying at age 15 predicted increases in depressive symptoms and suicidal ideation at age 17 directly, but not through cannabis use, depression, or anxiety as mediators. Cannabis and tobacco use at 17 predicted increases in bullying victimization at 20.","whyItMatters":"The reciprocal relationship between cannabis use and suicidal ideation suggests a potential vicious cycle: cannabis use may increase suicidal thinking, which may in turn increase cannabis use. This bidirectional finding is important for both prevention and clinical intervention.","specificNumbers":"1,465 participants; 51.7% male; assessed at ages 15, 17, and 20; cannabis use and suicidal ideation reciprocally related at within-person level; bullying at 15 predicted depression and suicidal ideation at 17; substance use at 17 predicted victimization at 20","methodology":"Longitudinal cohort study using three waves of data from the normative z-proso study (N=1,465; 51.7% male) at ages 15, 17, and 20. Random intercept cross-lagged panel models tested within-person mediation effects while controlling for between-person confounds.","limitations":"Three time points across five years may miss shorter-term dynamics. Self-reported measures may be subject to reporting bias. The study cannot establish causation despite using within-person models. Sample was from Zurich, Switzerland, which may have different cannabis norms than other settings."},{"rthcId":"RTHC-04335","title":"Behavioral and Molecular Responses to Exogenous Cannabinoids During Pentylenetetrazol-Induced Convulsions in Male and Female Rats.","authors":"Zirotti Rosenberg, Antonella; Méndez-Ruette, Maxs; Gorziglia, Mario; Alzerreca, Benjamín; Cabello, Javiera; Kaufmann, Sofía; Rambousek, Lukas; Iturriaga Jofré, Andrés; Wyneken, Ursula; Lafourcade, Carlos A","year":2022,"journal":"Frontiers in molecular neuroscience, 15, 868583","doi":"10.3389/fnmol.2022.868583","pmid":"36147210","tags":["epilepsy","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"WIN prevented convulsions of medium severity in both female and male rats. At the molecular level, WIN increased phosphorylated CaMKII in the hippocampus and enhanced colocalization between CB1 receptors and beta-arrestin2 in the granule cell layer. The endocannabinoid system components were altered during pro-inflammatory microglial activation.","whyItMatters":"Epilepsy treatment options remain insufficient for many patients, and sex differences in drug response are understudied. This study provides preclinical evidence that cannabinoid-based anticonvulsant effects work in both sexes and identifies specific molecular changes in the hippocampus.","specificNumbers":"WIN prevented medium-severity convulsions in both males and females; increased phosphorylated CaMKII in hippocampus; higher CB1R/beta-arrestin2 colocalization in granule cell layer after treatment","methodology":"Animal study using adolescent male and female rats. Single PTZ injection used to induce convulsions. WIN 55,212-2 administered as pretreatment. Behavioral convulsions scored. Hippocampal tissue analyzed for CB1R, beta-arrestin2, and synaptic protein markers by immunohistochemistry and Western blot.","limitations":"Acute single-dose study does not reflect chronic epilepsy treatment. PTZ-induced convulsions differ from spontaneous seizures in epilepsy. Only one synthetic cannabinoid tested. Sample sizes for sex comparison may be underpowered to detect subtle sex differences."},{"rthcId":"RTHC-04336","title":"Incidence and Predictors of Cannabis-Related Poisoning and Mental and Behavioral Disorders among Patients with Medical Cannabis Authorization: A Cohort Study.","authors":"Zongo, Arsene; Lee, Cerina; Dyck, Jason R B; El-Mourad, Jihane; Hyshka, Elaine; Hanlon, John G; Eurich, Dean T","year":2022,"journal":"Substance use & misuse, 57(10), 1633-1641","doi":"10.1080/10826084.2022.2102193","pmid":"35866679","tags":["medical-cannabis","mental-health","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"During a median follow-up of 240 days, only 14 patients visited the ER or were hospitalized for cannabis poisoning (8.06 per 10,000 person-years) and 26 for cannabis-related mental and behavioral disorders (15.0 per 10,000 person-years). Predictors of cannabis-related mental health events included prior substance use disorders, other mental disorders, age, diabetes, and COPD.","whyItMatters":"As medical cannabis programs expand, quantifying the rate of acute harms helps patients and clinicians weigh risks. The low overall rates of poisoning and mental health crises in this medically supervised population are reassuring, while the identified risk factors can guide monitoring.","specificNumbers":"23,091 patients; median 240 days follow-up; 14 cannabis poisoning ER visits (8.06/10,000 person-years); 26 mental/behavioral disorder ER visits (15.0/10,000 person-years); prior substance use disorders strongest predictor","methodology":"Retrospective cohort study of patients who received medical cannabis authorization in Ontario, Canada between 2014-2017. Data from participating cannabis clinics linked to health administrative data. Cox proportional hazard regressions used to identify predictors.","limitations":"Retrospective design with clinic-collected data may miss patients who sought care elsewhere. Short median follow-up of 240 days may underestimate long-term risks. No control group for comparison. Only captures events severe enough to prompt ER visit or hospitalization."},{"rthcId":"RTHC-04337","title":"Substance Use Disorders and Psychoactive Drug Poisoning in Medically Authorized Cannabis Patients: Longitudinal Cohort Study.","authors":"Zongo, Arsène; Lee, Cerina; El-Mourad, Jihane; Dyck, Jason R B; Hyshka, Elaine; Hanlon, John G; Eurich, Dean T","year":2022,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 67(7), 544-552","doi":"10.1177/07067437211060597","pmid":"34806435","tags":["medical-cannabis","addiction","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 18,653 medical cannabis patients matched to 51,243 controls, poisoning incidence was 4.71 per 1,000 person-years for cannabis patients vs 1.73 for controls (adjusted HR: 2.45, 95% CI: 1.56-3.84). Mental/behavioral disorder incidence was 8.89 vs 5.01 per 1,000 person-years (adjusted HR: 2.27, 95% CI: 1.66-3.11). No sex differences were observed.","whyItMatters":"While the companion study (RTHC-04336) found low absolute rates of cannabis-specific harms, this study reveals that medical cannabis patients face elevated risk for broader substance-related problems compared to the general population, raising questions about pre-existing vulnerability versus cannabis-related risk.","specificNumbers":"18,653 cannabis patients matched to 51,243 controls; poisoning: 4.71 vs 1.73 per 1,000 person-years (aHR 2.45); mental/behavioral disorders: 8.89 vs 5.01 per 1,000 (aHR 2.27); median 243 days follow-up; no sex differences","methodology":"Retrospective cohort study matching 18,653 adult medical cannabis patients from Ontario clinics to 51,243 population-based controls. Outcomes were ER visits or hospitalizations for psychoactive drug poisoning and substance-related mental/behavioral disorders. Conditional Cox proportional hazards regressions used with median follow-up of 243 days.","limitations":"Cannot establish causation. Medical cannabis patients differ from the general population in ways beyond cannabis use (chronic pain, mental health conditions) that could explain higher ER visit rates. Short follow-up period. Matching may not fully control for confounding by indication."},{"rthcId":"RTHC-04338","title":"Release of Endocannabinoids into the Cerebrospinal Fluid during the Induction of the Trigemino-Hypoglossal Reflex in Rats.","authors":"Zubrzycki, Marek; Zubrzycka, Maria; Wysiadecki, Grzegorz; Szemraj, Janusz; Jerczynska, Hanna; Stasiolek, Mariusz","year":2022,"journal":"Current issues in molecular biology, 44(5), 2401-2416","doi":"10.3390/cimb44050164","pmid":"35678693","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04339","title":"Lower dACC glutamate in cannabis users during early phase abstinence.","authors":"Zuo, Chun S; Davis, Katherine A; Lukas, Scott E","year":2022,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(11), 1969-1975","doi":"10.1038/s41386-022-01321-5","pmid":"35484401","tags":["withdrawal","neuroscience","quitting"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"dACC glutamate was significantly lower in cannabis users compared to controls from baseline through day 21 of abstinence (F=5.90, p=0.022). Changes in glutamate between baseline and day 21 had a significant negative correlation with changes in craving (r=-0.72, p=0.005). Baseline anxiety severity correlated with urinary THC levels.","whyItMatters":"Glutamate is the brain's primary excitatory neurotransmitter and plays a key role in addiction and relapse. Finding that lower glutamate is linked to higher craving during cannabis abstinence suggests a potential target for medications that could ease withdrawal.","specificNumbers":"20 cannabis users and 10 controls completed protocol; dACC glutamate significantly lower in users (F=5.90, p=0.022); glutamate-craving correlation r=-0.72 (p=0.005); baseline anxiety correlated with THC levels (r=0.768, p=0.000076)","methodology":"Prospective cohort study with 26 cannabis users and 11 controls (20 users and 10 controls completed 21-day verified abstinence). Dorsal anterior cingulate cortex glutamate and GABA measured with proton MRS at baseline and abstinence days 7 and 21. Cannabis withdrawal, craving, sleep, and mood measured concurrently.","limitations":"Small sample of 20 users and 10 controls limits generalizability. MRS measures glutamate in a single brain region. Cannot determine whether low glutamate is a cause or consequence of cannabis use. Non-treatment-seeking sample may differ from those seeking help to quit."},{"rthcId":"RTHC-04340","title":"Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions.","authors":"Zuo, Yanning; Iemolo, Attilio; Montilla-Perez, Patricia; Li, Hai-Ri; Yang, Xia; Telese, Francesca","year":2022,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(12), 2071-2080","doi":"10.1038/s41386-022-01413-2","pmid":"35995972","tags":["youth","sex-differences","genetics","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC-treated mice showed memory and social behavior changes in late adolescence. Gene coexpression analysis identified \"cognitive modules\" that correlated with both THC treatment and memory deficits. In females, these modules related to endocannabinoid signaling in the dorsal striatum and inflammation in the ventral tegmental area. In males, they related to synaptic transmission in the nucleus accumbens. Four shared key driver genes (Hapln4, Kcnc1, Elavl2, Zcchc12) were linked to human cannabis use disorder vulnerability.","whyItMatters":"This study reveals that THC may affect male and female brains through fundamentally different molecular pathways, which could explain why cannabis use disorder presents differently by sex. The identification of shared key driver genes bridges animal and human findings.","specificNumbers":"High-dose THC during early adolescence; 5 brain regions profiled; cognitive modules identified in female dorsal striatum, female VTA, and male NAc; 4 shared key driver genes (Hapln4, Kcnc1, Elavl2, Zcchc12) linked to human CUD","methodology":"Female and male C57BL6/N mice treated with high-dose THC during early adolescence (equivalent to heavy human use). Memory and social behaviors assessed in late adolescence. Transcriptomes profiled in five brain regions. Gene coexpression network analysis identified modules correlating with THC and cognition. Key drivers compared to human CUD genetic data.","limitations":"Mouse model using high-dose THC during a specific developmental window. Human adolescent cannabis use involves different doses, frequencies, and durations. Gene expression changes in mice may not directly map to human brain responses. Only one dose level tested."},{"rthcId":"RTHC-04341","title":"Alcohol and cannabinoid binges and daily exposure to nicotine in adolescent/young adult rats induce sex-dependent long-term appetitive instrumental learning impairment.","authors":"Abela, Norbert; Haywood, Katie; Di Giovanni, Giuseppe","year":2023,"journal":"Frontiers in behavioral neuroscience, 17, 1129866","doi":"10.3389/fnbeh.2023.1129866","pmid":"36815183","tags":["youth","cognition","sex-differences","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Female rats showed impaired food-reward learning on both easy (FR1) and harder (FR2) tasks, while males showed impairment only on the harder FR2 task. Treated females also had a significantly lower percentage of learners than controls. Both sexes showed reduced motivation for natural rewards in adulthood, suggesting polydrug exposure during adolescence disrupts reward processing.","whyItMatters":"This is one of the first studies to model the realistic pattern of adolescent polydrug use: daily cigarettes combined with weekend alcohol and cannabis binges. The finding that this combination causes lasting motivational deficits is relevant to the millions of teenagers who use these substances together.","specificNumbers":"20 male and 20 female rats; exposure from postnatal day 30-60; testing after day 90; treated females impaired on FR1 and FR2; treated males impaired on FR2 only; treated females had fewer learners than controls","methodology":"Adolescent Long-Evans rats (20 male, 20 female) from postnatal day 30-60 received daily nicotine (0.3 mg/kg i.p.) plus twice-weekly \"binge day\" alcohol (3 g/kg intragastric) and WIN55,212-2 (1.2 mg/kg i.p.). Tested after day 90 on food-rewarded operant learning (FR1 for 6 days, then FR2 after 42-day rest).","limitations":"Animal model with specific drug doses and routes that differ from human use patterns. Single dose level of each substance tested. Operant learning in rats may not perfectly model human motivation. No individual drug groups to determine which substance or combination drives the effects."},{"rthcId":"RTHC-04342","title":"A Double-Blind, Randomized, Controlled Crossover Trial of Cannabis in Adults with Tourette Syndrome.","authors":"Abi-Jaoude, Elia; Bhikram, Tracy; Parveen, Ferdous; Levenbach, Jody; Lafreniere-Roula, Myriam; Sandor, Paul","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 835-845","doi":"10.1089/can.2022.0091","pmid":"36040329","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"THC 10% did not significantly improve the primary outcome (video-rated tic severity, MRVTRS) but was significantly better than placebo on secondary measures: premonitory urges (PUTS), subjective distress (SUDS), and clinical global impression. THC plasma levels correlated with improvements across all measures. CBD 13% alone showed no significant effects. Most participants correctly identified whether they received cannabis or placebo.","whyItMatters":"Tourette syndrome has limited treatment options, and many patients report cannabis helps their tics. This controlled trial provides the first rigorous evidence for vaporized cannabis, showing benefits for the subjective experience of tics even if video-rated severity did not significantly change.","specificNumbers":"12 randomized, 9 completers; THC 10% significantly improved PUTS, SUDS, and CGI-I vs placebo; no significant effect on MRVTRS; THC plasma levels correlated with improvement; CBD 13% showed no significant effects","methodology":"Double-blind, randomized crossover trial with 12 adults with Tourette syndrome (9 completers). Each participant received single vaporized doses of THC 10%, THC/CBD 9%/9%, CBD 13%, and placebo at 2-week intervals. Tic severity rated by blinded video raters. Secondary measures included premonitory urges, distress, and global impression. Plasma cannabinoid levels measured.","limitations":"Very small sample of 9 completers limits statistical power. Single-dose design does not reflect sustained use. Most participants could tell cannabis from placebo, potentially unblinding the study. Crossover design may have carryover effects despite 2-week washout."},{"rthcId":"RTHC-04343","title":"Effort-related decision making and cannabis use among college students.","authors":"Acuff, Samuel F; Simon, Nicholas W; Murphy, James G","year":2023,"journal":"Experimental and clinical psychopharmacology, 31(1), 228-237","doi":"10.1037/pha0000544","pmid":"35084912","tags":["cognition","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Greater cannabis use days and cannabis use disorder symptoms predicted increased likelihood of selecting high-effort trials on the EEfRT, even after controlling for ADHD symptoms, distress tolerance, income, and delay discounting. This finding directly contradicts the \"amotivational syndrome\" hypothesis that regular cannabis use impairs goal-directed behavior.","whyItMatters":"The idea that cannabis makes people lazy has persisted for decades despite mixed evidence. This study adds to growing research suggesting the \"amotivational syndrome\" may not hold up under controlled testing, which matters for reducing stigma around cannabis use.","specificNumbers":"25 cannabis users (68% meeting CUD criteria) and 22 non-users; greater cannabis use days and CUD symptoms predicted higher effort choices; controlled for ADHD, distress tolerance, income, and delay discounting","methodology":"Cross-sectional study comparing 25 cannabis-using college students (68% meeting CUD criteria) and 22 non-users. Participants completed the Effort Expenditure for Rewards Task (EEfRT), which measures willingness to expend effort for varying reward magnitudes and probabilities. Generalized estimating equation models controlled for multiple confounders.","limitations":"Small cross-sectional sample of 47 college students limits generalizability. Laboratory effort tasks may not capture real-world motivation. Cannabis users were tested when not acutely intoxicated. Selection bias: college students who use cannabis may be a uniquely motivated subgroup."},{"rthcId":"RTHC-04344","title":"Treatment of Adolescent Cannabis Use Disorders.","authors":"Adams, Zachary W; Marriott, Brigid R; Hulvershorn, Leslie A; Hinckley, Jesse D","year":2023,"journal":"The Psychiatric clinics of North America, 46(4), 775-788","doi":"10.1016/j.psc.2023.03.004","pmid":"37879838","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04345","title":"Treatment of Adolescent Cannabis Use Disorders.","authors":"Adams, Zachary W; Marriott, Brigid R; Hulvershorn, Leslie A; Hinckley, Jesse","year":2023,"journal":"Child and adolescent psychiatric clinics of North America, 32(1), 141-155","doi":"10.1016/j.chc.2022.07.006","pmid":"36410901","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04346","title":"Cannabis Use and Associated Gastrointestinal Disorders: A Literature Review.","authors":"Adenusi, Adedeji O; Magacha, Hezborn M; Nwaneki, Chisom M; Asifat, Olamide A; Annor, Eugene N","year":2023,"journal":"Cureus, 15(7), e41825","doi":"10.7759/cureus.41825","pmid":"37575784","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04347","title":"Prevalence and factors associated with suicidal ideation, cannabis, and alcohol use during the COVID-19 pandemic in Saskatchewan: findings from a joint-effect modeling.","authors":"Adeyinka, Daniel A; Novik, Nuelle; Novotna, Gabriela; Bartram, Mary; Gabrys, Robert; Muhajarine, Nazeem","year":2023,"journal":"BMC psychiatry, 23(1), 571","doi":"10.1186/s12888-023-05051-w","pmid":"37553652","tags":["mental-health","addiction","depression"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Suicidal ideation prevalence was highest among dual substance users (25.8%) compared to alcohol-only (23.2%) or cannabis-only (18.7%) problematic use. Younger age (16-34), changes in other substance use, pre-existing mental health diagnoses, and low resilience were independent predictors. LGBTQIA2S+ identity and pandemic stress predicted problematic cannabis use specifically.","whyItMatters":"The pandemic highlighted the intersection of mental health and substance use crises. Understanding that these problems cluster together, especially in younger people and those with pre-existing conditions, can guide targeted intervention during future public health emergencies.","specificNumbers":"666 respondents; 25.8% suicidal ideation among dual cannabis/alcohol problem users; 23.2% alcohol-only; 18.7% cannabis-only; 16-34 year-olds most likely to experience all three; LGBTQIA2S+ identity associated with problematic cannabis use","methodology":"Cross-sectional analysis of 666 Saskatchewan residents aged 16+ from March 2022 data collection by MHCC-CCSA. Trivariate probit regression modeled the joint occurrence of suicidal ideation, problematic alcohol use, and problematic cannabis use simultaneously.","limitations":"Cross-sectional design during a pandemic may not reflect typical patterns. Self-reported measures may underestimate substance problems and suicidality. Single Canadian province limits generalizability. Cannot establish causal relationships between variables."},{"rthcId":"RTHC-04348","title":"Association of receiving opioid medication-assisted treatment with sexual identity and mental health/substance use disorder symptoms in a nationally representative sample of adults.","authors":"Adzrago, David; Evans, Gabrielle S; Dias, Emanuelle M; Kwentua, Victoria; White, Grace Elizabeth; Wilkerson, J Michael","year":2023,"journal":"Research square","doi":"10.21203/rs.3.rs-2837899/v1","pmid":"37162987","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04349","title":"LC-MS/MS quantitation of non-psychotropic cannabinoid cannabidiol in aqueous humor.","authors":"Aebersold, Alyssa S; Kumar, Akhilesh; Song, Zhao-Hui","year":2023,"journal":"Journal of pharmaceutical and biomedical analysis, 228, 115324","doi":"10.1016/j.jpba.2023.115324","pmid":"36907022","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04350","title":"Cannabis Is Not Doping.","authors":"Aguiar, Aderbal Silva","year":2023,"journal":"Cannabis and cannabinoid research, 8(6), 949-954","doi":"10.1089/can.2023.0012","pmid":"37279460","tags":["exercise","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis is neither ergogenic (performance-enhancing) nor proven dangerous enough to warrant classification as doping after 20 years of research. CBD is already exempted. The WADA criteria require two of three conditions: performance enhancement, health risk, or violation of the \"spirit of sport.\" The author argues cannabis fails to meet the scientific criteria and is maintained on the list primarily through the subjective moral criterion.","whyItMatters":"Athletes face career-ending consequences for cannabis use despite lack of evidence it enhances performance. This perspective adds to the growing scientific consensus that the ban is based on outdated moral reasoning rather than evidence of athletic advantage or unique health risk.","specificNumbers":"WADA requires 2 of 3 criteria to be met; CBD already exempted from banned list; 20+ years of research reviewed; cannabis classified as ergolytic (performance-worsening) rather than ergogenic","methodology":"Narrative perspective reviewing WADA doping criteria and available evidence on cannabis, athletic performance, and health risks in athletes. Examines the three WADA criteria (performance enhancement, health risk, spirit of sport) against published research.","limitations":"Perspective piece rather than systematic review, which may selectively present evidence. The \"spirit of sport\" criterion is inherently subjective and was designed to capture behaviors beyond pure performance enhancement. Athletes in different sports may face different risk profiles."},{"rthcId":"RTHC-04351","title":"Long-Term Treatment with Cannabidiol-Enriched Cannabis Extract Induces Synaptic Changes in the Adolescent Rat Hippocampus.","authors":"Aguiar, Andrey F L; Campos, Raquel M P; Isaac, Alinny R; Paes-Colli, Yolanda; Carvalho, Virgínia M; Sampaio, Luzia S; de Melo Reis, Ricardo A","year":2023,"journal":"International journal of molecular sciences, 24(14)","doi":"10.3390/ijms241411775","pmid":"37511537","tags":["cbd","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD-enriched extract (3 mg/kg/day CBD for 15 days) did not affect food intake, locomotion, or cognitive performance in adolescent rats. However, hippocampal GluA1 (glutamate receptor subunit) and GFAP (astrocyte marker) protein levels were reduced while PSD95 (postsynaptic density protein) was increased. Microglial complexity was reduced in hippocampal CA1 and CA3 regions without changes in phagocytic activity.","whyItMatters":"CBD-enriched products are increasingly used for adolescents with epilepsy and other conditions. Finding that these products cause molecular changes in the hippocampus even when behavior appears normal raises questions about what hidden effects may be occurring during brain development.","specificNumbers":"3 mg/kg/day CBD for 15 days; postnatal day 45-60; GluA1 and GFAP reduced; PSD95 increased; microglial complexity reduced in CA1 and CA3; no behavioral deficits; food intake and locomotion unaffected","methodology":"Healthy male Wistar rats treated from postnatal day 45 to 60 with oral CBD-enriched cannabis extract (3 mg/kg/day CBD). Assessed food intake, water balance, locomotor behavior, and cognitive performance. Hippocampal protein levels measured by Western blot. Microglial morphology assessed by immunohistochemistry.","limitations":"Only male rats studied. Single dose level and duration. Short observation period may miss delayed behavioral effects. Full-spectrum extract contains compounds beyond CBD, making it difficult to attribute effects to CBD alone. Protein changes do not necessarily indicate functional impairment."},{"rthcId":"RTHC-04352","title":"Altered endocannabinoid metabolism compromises the brain-CSF barrier and exacerbates chronic deficits after traumatic brain injury in mice.","authors":"Ahluwalia, Meenakshi; Mcmichael, Hannah; Kumar, Manish; Espinosa, Mario P; Bosomtwi, Asamoah; Lu, Yujiao; Khodadadi, Hesam; Jarrahi, Abbas; Khan, Mohammad Badruzzaman; Hess, David C; Rahimi, Scott Y; Vender, John R; Vale, Fernando L; Braun, Molly; Baban, Babak; Dhandapani, Krishnan M; Vaibhav, Kumar","year":2023,"journal":"Experimental neurology, 361, 114320","doi":"10.1016/j.expneurol.2023.114320","pmid":"36627040","tags":["neuroscience","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"TBI increased expression of enzymes that break down endocannabinoids (MAGL, FAAH, Cox-2), leading to reduced 2-AG and AEA levels in plasma. This was accompanied by compromised brain-CSF barrier integrity, increased neuroinflammatory markers (IBA1, GFAP), reduced cerebral blood flow, altered aquaporin-4 expression, reduced ventricular volume, motor deficits, and anxiety behaviors. Preliminary human CSF data also showed endocannabinoid changes after TBI.","whyItMatters":"TBI affects millions annually with limited treatment options. If endocannabinoid loss after brain injury worsens outcomes, then blocking the enzymes that break down endocannabinoids could represent a new therapeutic approach to reduce secondary brain damage.","specificNumbers":"Reduced 2-AG and AEA plasma levels; increased MAGL, FAAH, and Cox-2; increased CB2 and TRPV1 expression; increased AQP4, IBA1, GFAP; reduced cerebral blood flow; reduced ventricular volume; motor deficits and anxiety behaviors; preliminary human data corroborative","methodology":"Controlled cortical impact mouse model of TBI. Measured endocannabinoid levels and metabolizing enzymes in brain tissue. Assessed brain-CSF barrier integrity, cerebral blood flow, neuroinflammation markers, ventricular volume, and behavior. Preliminary analysis of human CSF and plasma endocannabinoid levels included.","limitations":"Mouse CCI model represents one specific type of TBI and may not reflect the full spectrum of human head injuries. Human data is preliminary and not fully detailed. Cannot determine whether endocannabinoid changes cause secondary damage or are simply a marker of injury severity."},{"rthcId":"RTHC-04353","title":"UR-144, synthetic cannabinoid receptor agonist, induced cardiomyoblast toxicity mechanism comprises cytoplasmic Ca2+ and DAPK1 related autophagy and necrosis.","authors":"Akar, Muzeyyen; Ercin, Merve; Boran, Tugce; Gezginci-Oktayoglu, Selda; Özhan, Gül","year":2023,"journal":"Toxicology mechanisms and methods, 33(1), 56-64","doi":"10.1080/15376516.2022.2081829","pmid":"35606921","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04354","title":"Medical Cannabis in the Treatment of Parkinson's Disease.","authors":"Aladeen, Traci S; Mattle, Anna G; Zelen, Kory; Mesha, Moustafa; Rainka, Michelle M; Geist, Tanya; Myers, Bennett; Mechtler, Laszlo","year":2023,"journal":"Clinical neuropharmacology, 46(3), 98-104","doi":"10.1097/WNF.0000000000000550","pmid":"37191563","tags":["medical-cannabis","pain"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"87% of patients (60/69) reported improvement in at least one PD symptom after starting medical cannabis (most commonly 1:1 THC:CBD tincture). Symptoms with highest improvement rates included cramping/dystonia, pain, spasticity, lack of appetite, dyskinesia, and tremor. Among opioid users, 56% (14/25) reduced or discontinued opioids, with average morphine milligram equivalents dropping from 31 to 22. Medical cannabis was well-tolerated with no severe adverse events.","whyItMatters":"Parkinson's disease management is challenging, and many patients experience side effects from standard medications. The high rate of reported improvement and the reduction in opioid use suggest medical cannabis may serve as a useful adjunct therapy.","specificNumbers":"69 patients; 87% reported symptom improvement; most started on 1:1 THC:CBD tincture; 56% of opioid users reduced/discontinued; average MME from 31 to 22; 4 patients discontinued MC due to AEs; no severe AEs","methodology":"Retrospective chart review of 69 Parkinson's disease patients treated with medical cannabis in routine clinical practice. Documented MC ratio/formulation changes, symptom improvements, adverse events, and changes in concomitant medications including opioids, benzodiazepines, muscle relaxants, and PD medications.","limitations":"Retrospective chart review without placebo control or blinding. Patient-reported outcomes are subjective and subject to expectancy effects. No standardized PD rating scales used. Selection bias: patients who continued MC may be overrepresented."},{"rthcId":"RTHC-04355","title":"Differential associations of adolescent versus young adult cannabis initiation with longitudinal brain change and behavior.","authors":"Albaugh, Matthew D; Owens, Max M; Juliano, Anthony; Ottino-Gonzalez, Jonatan; Cupertino, Renata; Cao, Zhipeng; Mackey, Scott; Lepage, Claude; Rioux, Pierre; Evans, Alan; Banaschewski, Tobias; Bokde, Arun L W; Conrod, Patricia; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Martinot, Jean-Luc; Martinot, Marie-Laure Paillère; Artiges, Eric; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Paus, Tomáš; Poustka, Luise; Millenet, Sabina; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Potter, Alexandra; Garavan, Hugh","year":2023,"journal":"Molecular psychiatry, 28(12), 5173-5182","doi":"10.1038/s41380-023-02148-2","pmid":"37369720","tags":["youth","neuroscience","cognition","psychosis"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Adolescent cannabis initiation (14-19) was associated with cortical thinning in dorsolateral and ventrolateral prefrontal cortex that persisted into young adulthood and partially mediated associations with later cocaine, ecstasy, and cannabis use at age 22. Young adult initiation (19-22) was associated with thickness changes in temporal and midline areas that mediated the link to psychotic symptoms at age 22.","whyItMatters":"This is one of the largest and longest prospective neuroimaging studies on cannabis, with a cannabis-naive baseline eliminating reverse causation concerns. The finding that adolescent and young adult initiation affect different brain regions with different behavioral consequences has major implications for prevention messaging.","specificNumbers":"704 participants; ~10 years of follow-up; 8 European sites; adolescent initiation linked to prefrontal thinning and later drug use; young adult initiation linked to temporal changes and psychotic symptoms at age 22","methodology":"Prospective longitudinal study of 704 participants from the IMAGEN study across 8 European sites. Participants were cannabis-naive at baseline with MRI data at baseline, 5-year, and 9-year follow-up. Cannabis use assessed with ESPAD. T1-weighted MRI processed through CIVET pipeline. Mediation analyses tested brain changes as intermediaries between cannabis use and behavioral outcomes.","limitations":"Observational design cannot definitively establish causation despite prospective baseline. Cannabis use measured by self-report. MRI measures brain structure, not function. Genetic predisposition to both cannabis use and brain changes cannot be fully ruled out."},{"rthcId":"RTHC-04356","title":"Unexpected cause of recurrent diabetic ketoacidosis in type 1 diabetes: a case report.","authors":"Alduraibi, Rabia Khalid; Altowayan, Yosef Fahad; AlMharwal, Bader Tha'ar","year":2023,"journal":"BMC endocrine disorders, 23(1), 137","doi":"10.1186/s12902-023-01394-3","pmid":"37400799","tags":["medical-cannabis","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient experienced 6 DKA episodes in one year with persistent GI symptoms even after DKA resolved. Unusual lab findings (unexpectedly high pH and bicarbonate levels) eventually prompted screening for illicit drug use, revealing cannabis use and leading to a diagnosis of cannabinoid hyperemesis syndrome (CHS). The vomiting from CHS caused dehydration and poor insulin absorption, triggering repeated ketoacidosis.","whyItMatters":"Cannabinoid hyperemesis syndrome can masquerade as a diabetic emergency, leading to repeated hospitalizations and delayed diagnosis. In patients with type 1 diabetes, the vomiting from CHS creates a dangerous cycle of dehydration and ketoacidosis.","specificNumbers":"6 DKA episodes in 1 year; persistent GI symptoms after DKA resolution; unusually high pH and bicarbonate for ketoacidosis; diagnosis of CHS upon drug screening","methodology":"Single case report documenting a type 1 diabetes patient with 6 DKA episodes over one year. Chart review of laboratory findings, clinical course, and eventual diagnosis.","limitations":"Single case report cannot establish frequency of CHS-triggered DKA. Patient may have had other contributing factors. The diagnosis of CHS itself relies on clinical criteria after excluding other causes. No follow-up data on outcomes after cannabis cessation."},{"rthcId":"RTHC-04357","title":"The FAAH inhibitor URB597 reduces cocaine intake during conditioned punishment and mitigates cocaine seeking during withdrawal.","authors":"Alegre-Zurano, Laia; García-Baos, Alba; Castro-Zavala, Adriana; Medrano, Mireia; Gallego-Landin, Ines; Valverde, Olga","year":2023,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 165, 115194","doi":"10.1016/j.biopha.2023.115194","pmid":"37499453","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04358","title":"Assessing the Impact of Recreational Cannabis Legalization on Cannabis Use Disorder and Admissions to Treatment in the United States.","authors":"Aletraris, Lydia; Graves, Brian D; Ndung'u, Joyce J","year":2023,"journal":"Current addiction reports, 10(2), 198-209","doi":"10.1007/s40429-023-00470-x","pmid":"37266190","tags":["legalization","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Findings generally showed increased CUD prevalence associated with legalization, but effects varied by age group. Despite more CUD, there was no significant association between legalization and treatment admissions, and CUD-related treatment admissions decreased overall during study periods.","whyItMatters":"The paradox of rising CUD prevalence but declining treatment admissions raises important questions. It may reflect normalization of use, reduced perception of harm, or barriers to accessing treatment in a legalized environment.","specificNumbers":"9 studies reviewed from 2016-2022; CUD prevalence generally increased with legalization; treatment admissions decreased overall; effects varied by age group","methodology":"Narrative review of nine studies published 2016-2022 examining recreational cannabis laws and either CUD prevalence or cannabis treatment admissions in the United States.","limitations":"Only nine studies available, limiting conclusions. Varied methodologies across studies. State-level differences in legalization implementation make comparisons difficult. CUD diagnostic criteria may capture different severity levels."},{"rthcId":"RTHC-04359","title":"Medical Cannabis Legalization: No Contribution to Rising Stimulant Rates in the USA.","authors":"Alexander, Garrett D; Cavanah, Luke R; Goldhirsh, Jessica L; Huey, Leighton Y; Piper, Brian J","year":2023,"journal":"Pharmacopsychiatry, 56(6), 214-218","doi":"10.1055/a-2152-7757","pmid":"37884027","tags":["legalization","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"While there was a significant increase in stimulant distribution over time (methylphenidate, amphetamine, lisdexamfetamine), there was no significant main effect of medical cannabis legalization status. The stimulant increase was driven by other factors, likely including broadened ADHD diagnostic criteria in DSM-5 and the addition of binge eating disorder as a stimulant indication.","whyItMatters":"Concerns have been raised that medical cannabis might worsen attention problems, potentially leading to more ADHD diagnoses and stimulant prescriptions. This study provides reassurance that this feared consequence has not materialized at a population level.","specificNumbers":"DEA data from 2006-2021; significant time effect on stimulant distribution (p<0.05); no significant main effect of MC legalization (p=0.391); no significant difference between states with and without MC sales (p=0.355)","methodology":"Retrospective analysis of DEA comprehensive database tracking methylphenidate, amphetamine, and lisdexamfetamine distribution from 2006-2021. Compared three-year population-corrected slopes before and after medical cannabis program implementation across states.","limitations":"Ecological study using state-level distribution data rather than individual patient prescriptions. Cannot determine whether specific cannabis users received stimulant prescriptions. Medical cannabis programs vary widely in structure and patient populations across states."},{"rthcId":"RTHC-04360","title":"Recreational marijuana laws and the misuse of prescription opioids: Evidence from National Survey on Drug Use and Health microdata.","authors":"Ali, Mir M; McClellan, Chandler; Mutter, Ryan; Rees, Daniel I","year":2023,"journal":"Health economics, 32(2), 277-301","doi":"10.1002/hec.4620","pmid":"36335085","tags":["legalization","harm-reduction","pain"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Standard difference-in-differences analysis suggested RML adoption reduced frequent opioid misuse. However, a two-stage procedure accounting for staggered treatment timing showed the opposite direction. Event study estimates suggested an initial decrease in opioid misuse that dissipated after 2-3 years, indicating the benefit was temporary.","whyItMatters":"The finding that the opioid substitution effect of cannabis is temporary challenges the hopeful narrative that cannabis legalization can durably reduce the opioid crisis. Initial benefits may fade as novelty wears off or as people return to prior patterns.","specificNumbers":"Standard DD showed reduced opioid misuse; two-stage procedure showed the DD estimate became positive; event study showed initial decrease dissipating after 2-3 years","methodology":"Analysis of National Survey on Drug Use and Health microdata examining recreational marijuana laws and prescription opioid misuse (OxyContin, Percocet, Vicodin). Used both standard difference-in-differences regression and a two-stage procedure designed for staggered treatment adoption and dynamic effects.","limitations":"Observational study cannot prove causation. Different statistical methods produced different results, introducing uncertainty. Self-reported substance use data may underestimate misuse. Staggered legalization across states complicates temporal comparisons."},{"rthcId":"RTHC-04361","title":"Acute toxic effects of new synthetic cannabinoid on brain: Neurobehavioral and Histological: Preclinical studies.","authors":"Ali, Shrouk Mohamed; Kolieb, Eman; Imbaby, Samar; Hagras, Abeer M; Korayem Arafat, Horeya Erfan; Kamel, Eman Mohamed; Abdelshakour, Mohamed A; Mohammed Ali, Maha Ismail","year":2023,"journal":"Chemico-biological interactions, 370, 110306","doi":"10.1016/j.cbi.2022.110306","pmid":"36528081","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04362","title":"Effects of cannabinoid agonists and antagonists in male rats discriminating the synthetic cannabinoid AM2201.","authors":"AlKhelb, Dalal; Burke, Emily L; Zvonok, Alexander; Iliopoulos-Tsoutsouvas, Christos; Georgiadis, Markos-Orestis; Jiang, Shan; Ho, Thanh C; Nikas, Spyros P; Makriyannis, Alexandros; Desai, Rajeev I","year":2023,"journal":"European journal of pharmacology, 960, 176168","doi":"10.1016/j.ejphar.2023.176168","pmid":"38059442","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04363","title":"Does a history of cannabis use influence onset and course of schizophrenia?","authors":"Allebeck, Peter; Gunnarsson, Tove; Lundin, Andreas; Löfving, Sofia; Dal, Henrik; Zammit, Stanley","year":2023,"journal":"Acta psychiatrica Scandinavica, 147(6), 614-622","doi":"10.1111/acps.13562","pmid":"37094811","tags":["psychosis","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 160 patients with validated schizophrenia, the 32 with a cannabis history had earlier age at onset, higher number of hospital admissions, and higher total hospital days compared to the 128 without. There was no significant difference in type of onset or clinical symptom profiles between the groups.","whyItMatters":"This study goes beyond asking whether cannabis causes psychosis to examine whether it makes the disease worse when it does occur. The finding that cannabis-associated schizophrenia involves more hospitalizations suggests a heavier disease burden with significant healthcare costs.","specificNumbers":"160 patients with schizophrenia; 32 with cannabis history vs 128 without; cannabis group had earlier onset, more hospital admissions, more total hospital days; no difference in symptom profiles","methodology":"Longitudinal follow-up of Swedish military conscripts with data on adolescent cannabis use and subsequent schizophrenia incidence. 160 patients with validated schizophrenia diagnoses assessed using the OPCRIT protocol. Compared disease characteristics between 32 with cannabis history and 128 without.","limitations":"Only 32 patients with cannabis history limits statistical power. Cannabis use measured at conscription may not capture full use history. Cannot separate the effects of pre-illness cannabis use from continued post-illness use. Male military conscripts may not represent the broader population."},{"rthcId":"RTHC-04364","title":"Public Education Can Be Used to Increase Support for Equity in Cannabis Policy.","authors":"Allen, Jane Appleyard; Lee, Youn Ok; Woodlea, Robyn; Malo, Vincenzo F; Zitney, Lauren V","year":2023,"journal":"Cannabis (Albuquerque, N.M.), 6(2), 76-88","doi":"10.26828/cannabis/2023/000146","pmid":"37484049","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04365","title":"From Euphoria to Emergency: Exploring the Role of K2/Spice in Diffuse Alveolar Hemorrhage.","authors":"Allena, Nishant; Yapor, Laura; Anwar, Muhammad Yasir; Vakde, Trupti","year":2023,"journal":"Cureus, 15(7), e41887","doi":"10.7759/cureus.41887","pmid":"37581157","tags":["synthetic-cannabinoids","respiratory","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient presented with hemoptysis (coughing up blood) after smoking K2/Spice. Investigation revealed diffuse alveolar hemorrhage, a serious condition where blood fills the lung air sacs. The patient was successfully treated with a course of intravenous steroids.","whyItMatters":"Synthetic cannabinoids are unpredictable and can cause severe organ damage that natural cannabis does not typically cause. Diffuse alveolar hemorrhage is a life-threatening emergency, and clinicians need to consider synthetic cannabinoid use as a potential cause.","specificNumbers":"1 patient, age 34; presented with hemoptysis; diagnosed with diffuse alveolar hemorrhage; treated with IV steroids; full resolution","methodology":"Single case report of a 34-year-old male presenting with hemoptysis after synthetic cannabinoid use. Clinical workup included imaging and diagnostic testing confirming diffuse alveolar hemorrhage.","limitations":"Single case report cannot establish how common this complication is. The specific synthetic cannabinoid compounds in the K2/Spice product were not identified. Other potential causes of alveolar hemorrhage were excluded clinically but not with certainty."},{"rthcId":"RTHC-04366","title":"Relationship Between Chronic Lung Disease Diagnosis and Susceptibility to E-Cigarette Use in Adults.","authors":"Alqahtani, Mohammed M; Alanazi, Abdullah M M; Dransfield, Mark T; Wells, J Michael; Lein, Donald H; Hendricks, Peter S","year":2023,"journal":"Respiratory care, 68(5), 658-668","doi":"10.4187/respcare.10071","pmid":"36854469","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04367","title":"Induced negative affect's impact on self-reported cannabis use, expectancies, and problems.","authors":"Altman, Brianna R; Earleywine, Mitch","year":2023,"journal":"Addictive behaviors, 141, 107652","doi":"10.1016/j.addbeh.2023.107652","pmid":"36805814","tags":["mental-health","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Participants assigned to the negative affect induction reported significantly greater negative cannabis expectancies and more cannabis problems compared to the control group, after controlling for age and education. This suggests that current mood state can bias self-reports of substance use outcomes, which has implications for research and clinical assessment.","whyItMatters":"Most cannabis research and clinical assessments rely on self-reported problems. If being in a bad mood inflates reports of cannabis problems, then study findings and clinical evaluations conducted when patients are distressed may overestimate the harms of cannabis use.","specificNumbers":"700+ participants; negative affect induction significantly increased reported cannabis problems; significantly increased negative cannabis expectancies; actual cannabis use was not different between groups","methodology":"Randomized experimental study of over 700 participants recruited from Amazon MTurk. After baseline affect and demographics, participants were randomly assigned to a negative affect induction or control condition. Post-induction measures assessed affect state and cannabis-related variables.","limitations":"Online sample from MTurk may not represent clinical populations. The mood induction was brief and artificial. Cannot determine whether mood bias affects all types of self-reported substance measures equally. Did not test whether positive mood produces opposite bias."},{"rthcId":"RTHC-04368","title":"Conflicting forces in the implementation of medicinal cannabis regulation in Uruguay.","authors":"Alvarez, Eliana; Queirolo, Rosario; Sotto, Belen","year":2023,"journal":"Journal of cannabis research, 5(1), 26","doi":"10.1186/s42238-023-00189-6","pmid":"37434242","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04369","title":"Discovery of 1,3-disubstituted pyrazole peripheral cannabinoid receptor partial agonists.","authors":"Amato, George; Runyon, Scott; Vasukuttan, Vineetha; Decker, Ann M; Gay, Elaine A; Laudermilk, Lucas; Maitra, Rangan","year":2023,"journal":"Bioorganic & medicinal chemistry letters, 93, 129430","doi":"10.1016/j.bmcl.2023.129430","pmid":"37543275","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04370","title":"Neurobehavioral risk factors influence prevalence and severity of hazardous substance use in youth at genetic and clinical high risk for psychosis.","authors":"Amir, Carolyn M; Kapler, Simon; Hoftman, Gil D; Kushan, Leila; Zinberg, Jamie; Cadenhead, Kristin S; Kennedy, Leda; Cornblatt, Barbara A; Keshavan, Matcheri; Mathalon, Daniel H; Perkins, Diana O; Stone, William; Tsuang, Ming T; Walker, Elaine F; Woods, Scott W; Cannon, Tyrone D; Addington, Jean; Bearden, Carrie E","year":2023,"journal":"Frontiers in psychiatry, 14, 1143315","doi":"10.3389/fpsyt.2023.1143315","pmid":"37151981","tags":["psychosis","youth","addiction","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"CHR-P youth had significantly higher substance use across tobacco, alcohol, and cannabis compared to controls, while 22qDel carriers had significantly lower use. In CHR-P youth, substance use was associated with higher psychosis symptoms, dysphoric mood, social functioning, and IQ. Higher social anhedonia was associated with lower substance use in both groups. These patterns persisted at one-year follow-up.","whyItMatters":"The opposite substance use patterns in genetic versus clinical psychosis risk suggest that the link between cannabis and psychosis is not simply about vulnerability. Social and cognitive factors may determine whether at-risk individuals are exposed to substances at all.","specificNumbers":"89 22qDel carriers + 65 controls; 1,288 CHR-P youth + 371 controls; CHR-P had elevated substance use vs controls; 22qDel had lower use; social anhedonia predicted lower use in both groups; patterns stable at 1-year follow-up","methodology":"Prospective longitudinal study comparing two cohorts: 89 carriers of 22q11.2 deletion syndrome with 65 matched controls, and 1,288 clinical high-risk for psychosis (CHR-P) youth with 371 matched controls from NAPLS-2 and NAPLS-3. Substance use, clinical symptoms, and neurobehavioral measures assessed at baseline and 12-month follow-up.","limitations":"Two different cohorts with different recruitment strategies and demographics. 22qDel is a specific and rare genetic condition that may not generalize to other genetic risk factors for psychosis. Self-reported substance use may underestimate use in both groups."},{"rthcId":"RTHC-04371","title":"Inpatients in substance use treatment with co-occurring psychiatric disorders: a prospective cohort study of characteristics and relapse predictors.","authors":"Andersson, Helle Wessel; Mosti, Mats P; Nordfjaern, Trond","year":2023,"journal":"BMC psychiatry, 23(1), 152","doi":"10.1186/s12888-023-04632-z","pmid":"36894934","tags":["addiction","mental-health","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Patients with co-occurring disorders (COD) had a 39.8% relapse rate vs 26.4% for those without. Among COD patients, cannabis use disorder had a 53.3% relapse rate and was the strongest predictor (OR=2.31, 95% CI: 1.34-4.00). Protective factors included older age, being female (OR=0.56), and higher intrinsic motivation (OR=0.58).","whyItMatters":"Cannabis use disorder is often perceived as less severe than other substance use disorders, but this study found it was the single strongest predictor of relapse among patients with dual diagnoses. This suggests cannabis-specific treatment components may be needed in dual-diagnosis programs.","specificNumbers":"611 inpatients; 289 with COD; 39.8% vs 26.4% relapse rates; CUD relapse rate 53.3%; CUD OR=2.31; female OR=0.56; intrinsic motivation OR=0.58; 70% follow-up retention","methodology":"Prospective cohort study of 611 SUD inpatients (289 with COD, 322 without). Demographics, motivation, mental distress, and diagnoses assessed at baseline. Relapse assessed at 3 months post-treatment (70% retention rate). Multivariate logistic regression identified predictors.","limitations":"Three-month follow-up may be too short to capture longer-term outcomes. 30% loss to follow-up may introduce bias. Single-country setting (Norway) limits generalizability. Self-reported relapse may underestimate actual use."},{"rthcId":"RTHC-04372","title":"Cannabinoids as a Potential Alternative to Opioids in the Management of Various Pain Subtypes: Benefits, Limitations, and Risks.","authors":"Ang, Samuel P; Sidharthan, Shawn; Lai, Wilson; Hussain, Nasir; Patel, Kiran V; Gulati, Amitabh; Henry, Onyeaka; Kaye, Alan D; Orhurhu, Vwaire","year":2023,"journal":"Pain and therapy, 12(2), 355-375","doi":"10.1007/s40122-022-00465-y","pmid":"36639601","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04373","title":"Substances of abuse and their effect on SAR-CoV-2 pathogenesis.","authors":"Antwi, Ivy; Watkins, Destiny; Pedawi, Alahn; Ghrayeb, Atheel; Van de Vuurst, Christine; Cory, Theodore J","year":2023,"journal":"NeuroImmune pharmacology and therapeutics, 2(3), 301-316","doi":"10.1515/nipt-2023-0004","pmid":"38013836","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04374","title":"Association between cannabis use and symptom dimensions in schizophrenia spectrum disorders: an individual participant data meta-analysis on 3053 individuals.","authors":"Argote, Mathilde; Sescousse, Guillaume; Brunelin, Jérôme; Baudin, Grégoire; Schaub, Michael Patrick; Rabin, Rachel; Schnell, Thomas; Ringen, Petter Andreas; Andreassen, Ole Andreas; Addington, Jean Margaret; Brambilla, Paolo; Delvecchio, Giuseppe; Bechdolf, Andreas; Wobrock, Thomas; Schneider-Axmann, Thomas; Herzig, Daniela; Mohr, Christine; Vila-Badia, Regina; Rodie, Judith Usall; Mallet, Jasmina; Ricci, Valerio; Martinotti, Giovanni; Knížková, Karolína; Rodriguez, Mabel; Cookey, Jacob; Tibbo, Philip; Scheffler, Freda; Asmal, Laila; Garcia-Rizo, Clemente; Amoretti, Silvia; Huber, Christian; Thibeau, Heather; Kline, Emily; Fakra, Eric; Jardri, Renaud; Nourredine, Mikail; Rolland, Benjamin","year":2023,"journal":"EClinicalMedicine, 64, 102199","doi":"10.1016/j.eclinm.2023.102199","pmid":"37731936","tags":["psychosis","mental-health"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis use was associated with higher positive symptom severity (aMD=0.38), lower negative symptom severity (aMD=-0.50), and higher excitement (aMD=0.16) using the 5-factor PANSS model. No significant associations were found with disorganization or depression dimensions. Effect sizes were small and confidence intervals wide.","whyItMatters":"This is the largest IPDMA on cannabis and schizophrenia symptoms to date. The finding that cannabis use is associated with lower negative symptoms (amotivation, flat affect) alongside higher positive symptoms (hallucinations, delusions) creates a complex picture with implications for treatment.","specificNumbers":"3,053 complete cases from 21 datasets; positive symptoms aMD=0.38 (95% CI: 0.08-0.63); negative symptoms aMD=-0.50 (95% CI: -0.91 to -0.08); excitement aMD=0.16 (95% CI: 0.03-0.28); no association with depression or disorganization","methodology":"Individual participant data meta-analysis (IPDMA) using raw datasets from 21 studies totaling 3,053 complete cases. PubMed, ScienceDirect, and PsycINFO searched through September 2022. Cannabis users required to have CUD diagnosis or use at least twice weekly. Outcomes assessed using both 3-factor and 5-factor PANSS structures with adjusted multivariate analysis.","limitations":"Cross-sectional associations cannot determine causation. Effect sizes are small with wide confidence intervals. Cannot rule out that people with fewer negative symptoms are simply more socially active and therefore more likely to access cannabis. Self-selection bias remains."},{"rthcId":"RTHC-04375","title":"Driving-related behaviors, attitudes, and perceptions among Australian medical cannabis users: results from the CAMS 20 survey.","authors":"Arkell, Thomas R; Abelev, Sarah V; Mills, Llewellyn; Suraev, Anastasia; Arnold, Jonathon C; Lintzeris, Nicholas; McGregor, Iain S","year":2023,"journal":"Journal of cannabis research, 5(1), 35","doi":"10.1186/s42238-023-00202-y","pmid":"37674243","tags":["driving","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"28% of driving respondents reported DUIC. 49-56% typically drove within 6 hours of medical cannabis use. Non-medical cannabis was perceived as more impairing than medical cannabis. Predictors of DUIC included inhaled administration, THC-dominant products, illicit rather than prescribed use, believing cannabis does not impair driving, and not being deterred by roadside testing.","whyItMatters":"As medical cannabis programs expand, understanding driving behavior among patients is critical. The finding that half of patients drove within 6 hours of use and that many do not perceive medical cannabis as impairing suggests a significant road safety gap.","specificNumbers":"1,063 driving respondents; 28% (297) reported DUIC; 49-56% drove within 6 hours of use; non-medical cannabis perceived as more impairing than medical; 5 significant predictors identified via logistic regression","methodology":"Cross-sectional survey subsection of the Cannabis as Medicine Survey 2020 (CAMS-20). 1,063 respondents who drove in the past 12 months answered driving-related questions about behaviors, attitudes, and perceptions. Binary logistic regression identified predictors of DUIC.","limitations":"Self-reported driving behavior may underestimate actual DUIC rates. Cross-sectional design cannot establish causation. Sample drawn from an advocacy organization survey may not represent all medical cannabis users. Australian driving laws and testing may differ from other jurisdictions."},{"rthcId":"RTHC-04376","title":"A Semi-Naturalistic, Open-Label Trial Examining the Effect of Prescribed Medical Cannabis on Neurocognitive Performance.","authors":"Arkell, Thomas R; Manning, Brooke; Downey, Luke A; Hayley, Amie C","year":2023,"journal":"CNS drugs, 37(11), 981-992","doi":"10.1007/s40263-023-01046-z","pmid":"37945917","tags":["cognition","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Participants' performance improved over time on the CANTAB Multitasking Test and Rapid Visual Information Processing test. No significant impairment was found on any cognitive measure. Vaporized flower produced stronger subjective feelings of being \"stoned\" and \"sedated\" compared to oils. Chronic non-cancer pain and sleep disorders were the most common indications.","whyItMatters":"Previous cannabis cognition research primarily studied recreational users. This study suggests that medical cannabis patients using prescribed doses may experience minimal cognitive impairment, which is important for patients concerned about functioning at work or while caring for family.","specificNumbers":"40 patients (22 female); mean age 41.38; mean 10.18 months of MC use; oils (n=23): 9.61mg THC/9.15mg CBD; flower (n=17): 37mg THC/0.38mg CBD; improved multitasking and rapid visual processing; no impairment on any measure","methodology":"Semi-naturalistic, open-label trial with 40 patients (22 female) prescribed medical cannabis for various conditions. Patients self-administered their standard prescribed dose in the laboratory. Cognitive performance assessed with CANTAB and Druid app before and after cannabis use. Subjective effects rated on visual analogue scales.","limitations":"Open-label design means patients knew they were receiving cannabis. No placebo control group. Small sample of 40 patients. Practice effects could explain improved scores on repeated testing. Patients were experienced users with established tolerance."},{"rthcId":"RTHC-04377","title":"Relationships between sales of legal medical cannabis and alcohol in Canada.","authors":"Armstrong, Michael J","year":2023,"journal":"Health policy (Amsterdam, Netherlands), 128, 28-33","doi":"10.1016/j.healthpol.2022.11.012","pmid":"36443110","tags":["legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Using fixed effect panel data regressions controlling for retail activity, alcohol prices, education levels, unemployment, and impaired driving penalties, each dollar of legal medical cannabis sold was associated with a $0.74-$0.84 decrease in alcohol sales. This implied that 2017-2018 alcohol sales were approximately 1.8% lower than they would have been without legal medical cannabis.","whyItMatters":"Alcohol causes far more health harm per user than cannabis. If cannabis legalization leads to meaningful substitution of alcohol for cannabis, the net public health impact could be positive even if cannabis use increases.","specificNumbers":"Each $1 of MC sold associated with $0.74-$0.84 decrease in alcohol sales; 2017-2018 alcohol sales estimated 1.8% lower due to medical cannabis; data from 7 Canadian regions; January 2011 to September 2018","methodology":"Fixed effect panel data linear regressions analyzing monthly per capita sales of alcohol and legal medical cannabis across seven Canadian regions from January 2011 to September 2018. Controlled for changing levels of retail activity, alcohol prices, tertiary education, unemployment, and impaired driving penalties.","limitations":"Ecological study using aggregate sales data, not individual behavior. Cannot confirm that the same individuals substituted cannabis for alcohol. Pre-recreational legalization period (before October 2018) may not reflect current dynamics. Canadian market may differ from U.S. or other jurisdictions."},{"rthcId":"RTHC-04378","title":"The safety and efficacy of low oral doses of cannabidiol: An evaluation of the evidence.","authors":"Arnold, Jonathon C; McCartney, Danielle; Suraev, Anastasia; McGregor, Iain S","year":2023,"journal":"Clinical and translational science, 16(1), 10-30","doi":"10.1111/cts.13425","pmid":"36259271","tags":["cbd","anxiety","addiction","sleep"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Therapeutic benefits became clearly evident at doses of 300 mg or higher. At 300-400 mg, there is evidence for reduced anxiety and anti-addiction effects. More marginal benefits were found for insomnia, neurological disorders, and chronic pain. Increasing doses from 60 to 400 mg/day was not associated with more frequent adverse effects. Low-dose CBD products widely available as nutraceuticals lack strong evidence of efficacy.","whyItMatters":"Millions of people buy low-dose CBD products hoping for health benefits. This review suggests that most over-the-counter CBD products at typical doses (10-50 mg) may be below the therapeutic threshold, while higher doses show real promise for specific conditions.","specificNumbers":"Therapeutic threshold at 300+ mg/day; anxiety and addiction evidence strongest; 60-400 mg/day dose range did not increase adverse effects; high-dose epilepsy treatment at 10-50 mg/kg already approved","methodology":"Review of interventional studies measuring clinical efficacy and/or safety of oral CBD at doses up to 400 mg/day in adults. Excluded studies with THC content above 2.0%. Covered multiple health conditions including anxiety, addiction, sleep, pain, and neurological disorders.","limitations":"Narrative review rather than systematic review. Many included studies had small sample sizes. CBD products varied in formulation and bioavailability across studies. Long-term safety data at higher doses remains limited."},{"rthcId":"RTHC-04379","title":"Sleep disturbance after cessation of cannabis administration in mice.","authors":"Asano, Takashi; Takemoto, Hiroki; Horita, Tomoya; Tokutake, Tomohiro; Izuo, Naotaka; Mochizuki, Takatoshi; Nitta, Atsumi","year":2023,"journal":"Neuropsychopharmacology reports, 43(4), 505-512","doi":"10.1002/npr2.12329","pmid":"36905178","tags":["sleep","withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"During cannabinoid administration, there was no difference in sleep/wake patterns between treated and control mice. However, after cessation, treated mice showed decreased total sleep time during the light period (when mice normally sleep), along with increased rearing behavior. This mirrors sleep disturbance symptoms reported in human cannabis withdrawal.","whyItMatters":"Sleep disturbance is one of the most common and distressing symptoms of cannabis withdrawal, often driving relapse. Having an animal model to study this phenomenon enables testing of potential treatments.","specificNumbers":"EEG/EMG recorded for 3 days post-cessation; decreased total sleep during light period in ACPA mice; increased rearing behavior; no sleep differences during active ACPA administration","methodology":"Mice were administered ACPA (a CB1 receptor agonist) or saline. EEG and EMG recordings were measured for 3 days after cessation. Behavioral changes (rearing, rubbing) were also assessed.","limitations":"Mouse sleep patterns differ from human sleep. ACPA is a synthetic agonist, not THC or whole cannabis. Short observation period of 3 days after cessation. Small sample size. Cannot directly translate timing or severity to human withdrawal."},{"rthcId":"RTHC-04380","title":"Effects of cannabis legalization on the use of cannabis and other substances.","authors":"Assanangkornchai, Sawitri; Kalayasiri, Rasmon; Ratta-Apha, Woraphat; Tanaree, Athip","year":2023,"journal":"Current opinion in psychiatry, 36(4), 283-289","doi":"10.1097/YCO.0000000000000868","pmid":"37185310","tags":["legalization","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Most studies found no significant association between recreational legalization and changes in youth cannabis use across Europe, Uruguay, the U.S., and Canada. Some studies reported increases in adult and youth use that appeared to predate legalization. Unintentional pediatric ingestion of cannabis edibles increased significantly after legalization. Some evidence linked legalization to increased alcohol, vaping, and e-cigarette use among adolescents and young adults.","whyItMatters":"The most politically charged question about cannabis legalization is whether it increases youth use. This review suggests it largely has not, but the increase in accidental pediatric edible ingestion represents a clear safety concern that needs policy attention.","specificNumbers":"Most studies found no significant youth use changes post-legalization; marked increase in unintentional pediatric edible ingestion; some increases in use appeared to predate legalization","methodology":"Narrative review of recent literature on the impact of recreational cannabis legalization on cannabis and other substance use across different population groups including youth and adults.","limitations":"Narrative review covering multiple jurisdictions with different legalization models. Short follow-up periods in many studies. Self-reported use data may not capture actual changes. Different age groups defined differently across studies."},{"rthcId":"RTHC-04381","title":"Cannabis demand and use among veterans: A prospective examination.","authors":"Aston, Elizabeth R; Meshesha, Lidia Z; Stevens, Angela K; Borsari, Brian; Metrik, Jane","year":2023,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 37(8), 985-995","doi":"10.1037/adb0000916","pmid":"37079805","tags":["addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Baseline cannabis use predicted greater cannabis demand intensity, maximum expenditure, and other demand indices at 6 months. Conversely, baseline demand intensity, breakpoint, and price sensitivity predicted greater use at 6 months. The pathway from use to demand was consistently stronger than from demand to use, suggesting use itself drives perceived value more than perceived value drives use.","whyItMatters":"Understanding the cyclical relationship between how much people value cannabis and how much they use it can inform treatment. If use drives demand more than demand drives use, reducing consumption even temporarily might reduce the perceived value and make sustained reduction easier.","specificNumbers":"133 veterans; 6-month follow-up; use predicted intensity (β=0.32), Omax (β=0.37); intensity predicted use (β=0.14); breakpoint predicted use (β=0.12); use-to-demand pathway consistently stronger","methodology":"Two-wave longitudinal study of 133 veterans reporting past 6-month cannabis use. Cannabis demand assessed via hypothetical marijuana purchase task. Autoregressive cross-lagged panel models examined bidirectional relationships between demand indices and use over 6 months.","limitations":"Veteran sample may not represent general cannabis users. Two time points limit causal inference. Hypothetical purchase task may not reflect real-world spending. Only intensity showed acceptable test-retest reliability."},{"rthcId":"RTHC-04382","title":"Self-reported impacts of recreational and medicinal cannabis use on driving ability and amount of wait time before driving.","authors":"Auguste, M E; Zambrano, V C","year":2023,"journal":"Traffic injury prevention, 24(3), 237-241","doi":"10.1080/15389588.2023.2172679","pmid":"36787207","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use frequency predicted both lower self-reported driving impairment and shorter wait time before driving. A plurality of participants reported not waiting at all before driving after cannabis use. Importantly, perceiving that cannabis impaired driving did not predict longer wait times, suggesting knowledge of impairment does not translate to safer behavior.","whyItMatters":"The disconnect between perceived impairment and driving behavior is concerning. Even people who acknowledge cannabis affects their driving are not waiting longer, suggesting that awareness campaigns alone may not be enough to change behavior.","specificNumbers":"424 cannabis users in Connecticut; more frequent users reported less impairment; more frequent users waited less time; plurality reported not waiting at all; perceived impairment did not predict wait time","methodology":"Cross-sectional survey of 424 cannabis users over age 18 in Connecticut. Purposive sampling used to recruit cannabis users. Measured cannabis use frequency, self-reported impact on driving ability, and time waited before driving after use.","limitations":"Self-reported data may not reflect actual driving behavior. Connecticut-specific sample may not generalize. Cross-sectional design cannot establish causation. Frequent users may have developed tolerance, making their self-reports of lower impairment partially accurate."},{"rthcId":"RTHC-04383","title":"Association between maternal prenatal cannabis use and missed child preventive care visits in an integrated health care delivery system in Northern California.","authors":"Avalos, Lyndsay A; Oberman, Nina; Alexeeff, Stacey E; Croen, Lisa A; Adams, Sara R; Davignon, Meghan; Young-Wolff, Kelly C","year":2023,"journal":"Preventive medicine, 175, 107716","doi":"10.1016/j.ypmed.2023.107716","pmid":"37775081","tags":["pregnancy","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Maternal prenatal cannabis use was associated with more missed well-child visits at every time period from birth through 36 months. The strongest association was at the 12-month visit (aRR: 1.43, 95% CI: 1.32-1.54). By 36 months, 35.8% of children born to cannabis-using mothers had missed two or more visits compared to 23.0% of children from non-users.","whyItMatters":"Well-child visits are critical for catching developmental problems early, especially in children with potential prenatal exposures. Missing these visits means missed opportunities to identify and address any cannabis-related developmental effects.","specificNumbers":"168,589 pregnancies; 3.4% screened positive for prenatal cannabis use; 12-month visit aRR: 1.43; 3-year visit aRR: 1.15; 35.8% vs 23.0% missed 2+ visits by 36 months","methodology":"Longitudinal cohort study of 168,589 pregnancies in Kaiser Permanente Northern California (2011-2018). Prenatal cannabis use defined by self-report or positive urine toxicology. Well-child visits tracked across seven time periods from birth to 36 months. Modified Poisson regression adjusted for covariates.","limitations":"Cannot determine why mothers who used cannabis missed more visits. Potential confounders include socioeconomic factors, other substance use, and mental health conditions. Cannabis screening may underidentify users. Single health system limits generalizability."},{"rthcId":"RTHC-04384","title":"Abuse of Synthetic Cannabinoids and Cathinones in a Patient on Buprenorphine-Naloxone Treatment: A Case Report.","authors":"Awasthi, Harshal","year":2023,"journal":"Cureus, 15(11), e48386","doi":"10.7759/cureus.48386","pmid":"37937179","tags":["synthetic-cannabinoids","addiction","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient was unknowingly consuming synthetic cannabinoids and cathinones in a K2 blend while on buprenorphine/naloxone treatment. Standard ELISA drug testing failed to detect these substances. Only gas chromatography-mass spectrometry (GC-MS) identified them. The patient was unaware of the harmful constituents in the K2 product he was using.","whyItMatters":"Patients in opioid treatment programs may use synthetic drugs that evade routine monitoring, putting them at risk for dangerous interactions and treatment failure. Standard drug screens provide false reassurance when they cannot detect these substances.","specificNumbers":"1 patient; 6 months into buprenorphine/naloxone treatment; ELISA negative; GC-MS positive for synthetic cannabinoids and cathinones; patient unaware of K2 blend contents","methodology":"Single case report of a male in his thirties on buprenorphine/naloxone treatment who presented with sedation, agitation, and paranoia after six months of stable treatment. Standard and advanced toxicology testing performed.","limitations":"Single case report cannot establish frequency of this problem. The specific synthetic compounds were not named. Interaction between synthetic cannabinoids/cathinones and buprenorphine/naloxone was not characterized. Cannot determine whether the synthetic drugs affected treatment efficacy."},{"rthcId":"RTHC-04385","title":"Keepin' It REAL-Mantente REAL in Mexico: Longitudinal Examination of Youth Drug Resistance Strategies and Substance Use Among Early Adolescents.","authors":"Ayers, Stephanie L; Kulis, Stephen S; Marsiglia, Flavio F; Campos, Ana Paola; Medina-Mora, Maria Elena","year":2023,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 73(3), 412-420","doi":"10.1016/j.jadohealth.2023.05.009","pmid":"37422739","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04386","title":"Tobacco and Cannabis Use During and After Pregnancy in California.","authors":"Azenkot, Tali; Dove, Melanie S; Fan, Chuncui; Valencia, Cindy V; Tong, Elisa K; Schwarz, Eleanor Bimla","year":2023,"journal":"Maternal and child health journal, 27(1), 21-28","doi":"10.1007/s10995-022-03551-x","pmid":"36192518","tags":["pregnancy"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use during pregnancy (4.9%) was more than twice as common as cigarette smoking (2.1%) in California. In some counties like Los Angeles, cannabis was four times more prevalent. Overall, 7.3% of women reported cannabis use either during or soon after pregnancy. Among tobacco smokers, 73% quit before the third trimester but 33% relapsed postpartum.","whyItMatters":"Cannabis has overtaken tobacco as the most common combustible substance used during pregnancy in California. Since public health infrastructure for prenatal tobacco cessation is well-established but prenatal cannabis cessation programs barely exist, this shift demands attention.","specificNumbers":"4.9% prenatal cannabis use vs 2.1% cigarette smoking; 4:1 ratio in Los Angeles; 7.3% used cannabis during or after pregnancy; 73% of smokers quit by third trimester; 33% postpartum tobacco relapse","methodology":"Population-based cross-sectional analysis using California's Maternal and Infant Health Assessment survey data pooled from 35 counties with the largest birth numbers (2017-2019). Assessed tobacco and cannabis use during and after pregnancy.","limitations":"Self-reported use likely underestimates actual prevalence. Survey methodology may miss marginalized populations. Three-year pooled data may mask trends. California's legal cannabis environment may differ from other states."},{"rthcId":"RTHC-04387","title":"The Potential of Cannabidiol for Acute Respiratory Distress Syndrome in COVID-19.","authors":"Azimi, Saeid; Saghafi, Fatemeh; Mohammadi, Mohammad Hossein; Moghimi, Mohammad Hossein; Akhavan, Seyed Ali; Khataminia, Masoud; Shirvani, Maria; Sohrevardi, Seyed Mojtaba; Jamialahmadi, Tannaz; Sahebnasagh, Adeleh; Sahebkar, Amirhossein","year":2023,"journal":"Current pharmaceutical design, 29(29), 2291-2296","doi":"10.2174/0113816128275803230920094909","pmid":"37818584","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04388","title":"Cannabinoids as Immune System Modulators: Cannabidiol Potential Therapeutic Approaches and Limitations.","authors":"Aziz, Abdel-Ilah; Nguyen, Long Chi; Oumeslakht, Loubna; Bensussan, Armand; Ben Mkaddem, Sanae","year":2023,"journal":"Cannabis and cannabinoid research, 8(2), 254-269","doi":"10.1089/can.2022.0133","pmid":"36413346","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04389","title":"Cannabis use among adults undergoing cancer treatment.","authors":"Azizoddin, Desiree R; Cohn, Amy M; Ulahannan, Susanna V; Henson, Christina E; Alexander, Adam C; Moore, Kathleen N; Holman, Laura L; Boozary, Laili Kharazi; Sifat, Munjireen S; Kendzor, Darla E","year":2023,"journal":"Cancer, 129(21), 3498-3508","doi":"10.1002/cncr.34922","pmid":"37354093","tags":["cancer","medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users most commonly used edibles (65%) or smoked (51%). Top medical reasons were pain, cancer itself, sleep, anxiety, nausea/vomiting, and poor appetite. Greatest perceived symptom relief was for sleep, nausea, headaches, pain, muscle spasms, and anxiety. However, cannabis users reported more severe overall symptoms and were more likely to be male, Black, disabled, lower income, and on Medicaid.","whyItMatters":"Cancer patients are using cannabis for symptom management, but the paradox that users feel worse overall suggests either that sicker patients turn to cannabis or that cannabis provides targeted symptom relief without improving global well-being. Either way, clinicians need to understand this dynamic.","specificNumbers":"267 participants; 26% past 30-day use; 4.5% screened positive for CUD; 65% used edibles; 51% smoked; greatest relief for sleep, nausea, headaches, pain; users had worse overall symptoms","methodology":"Cross-sectional survey of 267 adults undergoing cancer treatment at an NCI-designated cancer center. Compared demographics, symptoms, cannabis use patterns, perceived benefits, and risk perceptions between past 30-day cannabis users and non-users.","limitations":"Cross-sectional design cannot determine whether cannabis use preceded or followed symptom severity. Selection bias: sicker patients may be more motivated to try cannabis. Self-reported perceived benefits may not reflect objective improvements. Single cancer center limits generalizability."},{"rthcId":"RTHC-04390","title":"Using in vitro receptor activity studies of synthetic cannabinoids to support the risk assessment of new psychoactive substances - A Swedish strategy to protect public health from harm.","authors":"Bäckberg, Matilda; Vikingsson, Svante; Strandberg, Joakim; Wall, Sara; Åstrand, Anna; Karlsson, Hanna; Persson, Mattias; Kronstrand, Robert; Green, Henrik","year":2023,"journal":"Forensic science international, 348, 111691","doi":"10.1016/j.forsciint.2023.111691","pmid":"37116244","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04391","title":"Cannabinoid receptor 1 positive allosteric modulator (GAT229) attenuates cisplatin-induced neuropathic pain in mice.","authors":"Bagher, Amina M; Binmahfouz, Lenah S; Shaik, Rasheed A; Eid, Basma G","year":2023,"journal":"Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society, 31(2), 255-264","doi":"10.1016/j.jsps.2022.12.011","pmid":"36942271","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04392","title":"Implications of Cannabis Legalization on Substance-Related Benefits and Harms for People Who Use Opioids: A Canadian Perspective.","authors":"Bahji, Anees; Socias, M Eugenia; Bach, Paxton; Milloy, M J","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 699-702","doi":"10.1089/can.2023.0031","pmid":"37001172","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04393","title":"Translating the lived experience of illicit drinkers into program guidance for cannabis substitution: Experiences from the Canadian Managed Alcohol Program Study.","authors":"Bailey, Aaron; Harps, Myles; Belcher, Clint; Williams, Henry; Amos, Cecil; Donovan, Brent; Sedore, George; Victoria, Solid; Graham, Brittany; Goulet-Stock, Sybil; Cartwright, Jenny; Robinson, Jennifer; Farrell-Low, Amanda; Willson, Mark; Sutherland, Christy; Stockwell, Tim; Pauly, Bernie","year":2023,"journal":"The International journal on drug policy, 122, 104244","doi":"10.1016/j.drugpo.2023.104244","pmid":"37950943","tags":["harm-reduction","addiction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"The collaboration between researchers, clinicians, and organizations of people with lived experience produced tailored client-facing and provider-facing cannabis education resources. Standard cannabis unit equivalencies were created to support program delivery. The lived expertise of heavy drinkers proved essential for creating materials that were accurate, relevant, and accessible to the target population.","whyItMatters":"Cannabis substitution is emerging as a harm reduction strategy for severe alcohol use. This study shows that effective resources require input from the people who will use them, and that heavy drinkers have valuable informal knowledge about harm reduction that can be formalized.","specificNumbers":"10+ years of collaboration; created standard cannabis unit equivalencies; produced client-facing and provider-facing resources; multiple MAP sites in Canada interested in cannabis substitution pilots","methodology":"Community-based participatory research drawing on 10+ years of collaboration between the Canadian Managed Alcohol Program Study (CMAPS) and organizations of people with lived experience (EIDGE and SOLID Victoria). Focus groups and meetings engaged peers in creating educational resources.","limitations":"No outcomes data on whether cannabis substitution actually reduces alcohol-related harm. Resources developed for specific Canadian context. Cannabis substitution may not be appropriate for all alcohol-dependent individuals. Long-term effects of switching from alcohol to cannabis unknown."},{"rthcId":"RTHC-04394","title":"Early-onset smoking and vaping of cannabis: Prevalence, correlates and trends in New Zealand 14-15-year-olds.","authors":"Ball, Jude; Zhang, Jane; Stanley, James; Boden, Joseph; Waa, Andrew; Hammond, David; Edwards, Richard","year":2023,"journal":"Drug and alcohol review, 42(3), 592-603","doi":"10.1111/dar.13597","pmid":"36645714","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Lifetime cannabis use declined from 2012-2018, but past-month (8.6%), weekly (3.4%), and daily (1.5%) use remained stable. Cannabis vaping was reported by 24% of past-month users. Use of both modes was elevated among Maori, same/both-sex attracted students, and those in high-deprivation schools. Cannabis use was strongly associated with tobacco and alcohol use. Exposure to secondhand smoke at home and low parental monitoring were key correlates.","whyItMatters":"Cannabis vaping is a new mode of use among young people with unknown health consequences. The strong socioeconomic gradients in early-onset cannabis use highlight that drug prevention must address structural inequities, not just individual choices.","specificNumbers":"11,405 students aged 14-15; past-month use 8.6%; weekly 3.4%; daily 1.5%; 24% of users vaped cannabis; elevated use in Maori, LGBTQ+, and high-deprivation school students; lifetime use declining; regular use stable","methodology":"Repeat cross-sectional nationally representative surveys (2012-2018) of 11,405 students aged 14-15 in New Zealand, response rates 59-65%. Measured cannabis smoking and vaping frequency, demographic correlates, and associated risk factors.","limitations":"Self-reported data may underestimate use. Response rates declined over time (65% to 59%). Cross-sectional design cannot establish causation for correlates. New Zealand context may not generalize. Cannabis vaping questions were only available in later survey years."},{"rthcId":"RTHC-04395","title":"Effects of cannabis regulation in Switzerland: Study protocol of a randomized controlled trial.","authors":"Baltes-Flueckiger, Lavinia; Steinauer, Regine; Meyer, Maximilian; Vogel, Marc; Walter, Marc","year":2023,"journal":"Frontiers in psychiatry, 14, 1139325","doi":"10.3389/fpsyt.2023.1139325","pmid":"37032954","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04396","title":"Prenatal cannabis use disorder and infant hospitalization and death in the first year of life.","authors":"Bandoli, Gretchen; Delker, Erin; Schumacher, Benjamin T; Baer, Rebecca J; Kelly, Ann E; Chambers, Christina D","year":2023,"journal":"Drug and alcohol dependence, 242, 109728","doi":"10.1016/j.drugalcdep.2022.109728","pmid":"36516553","tags":["pregnancy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Infant death in the first year was more common with maternal CUD (1.0% vs 0.4%; adjusted RR: 1.4, 95% CI: 1.2-1.6). The increased risk was attributable specifically to perinatal conditions and sudden unexpected infant death (SUID). After adjustment for sociodemographics, psychiatric comorbidities, and other substance use, there was no increased risk of infant hospitalizations or emergency department visits.","whyItMatters":"While previous research has focused on birth outcomes like preterm delivery, this study extends the risk window to the entire first year of life. The link to sudden unexpected infant death is particularly concerning and could inform postnatal monitoring recommendations.","specificNumbers":"34,544 births with CUD (1.0% of all births); infant death 1.0% vs 0.4%; aRR 1.4 (95% CI: 1.2-1.6); excess deaths from perinatal conditions and SUID; CUD prevalence increased over study period; no increased ER visits or hospitalizations","methodology":"Population-based retrospective cohort study of all singleton live births in California from 2011-2018 using hospital discharge data linked with vital statistics. Cannabis use disorder classified from ICD codes. Adjusted for sociodemographic variables, psychiatric comorbidities, and other substance use disorders.","limitations":"CUD diagnosed by ICD codes may capture more severe cases than typical cannabis use. Cannot separate the effects of cannabis itself from associated behaviors and socioeconomic factors. Adjusted models may not capture all confounding. No information on postnatal cannabis or other substance use."},{"rthcId":"RTHC-04397","title":"Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.","authors":"Bansal, Sumit; Zamarripa, C Austin; Spindle, Tory R; Weerts, Elise M; Thummel, Kenneth E; Vandrey, Ryan; Paine, Mary F; Unadkat, Jashvant D","year":2023,"journal":"Clinical pharmacology and therapeutics, 114(3), 693-703","doi":"10.1002/cpt.2973","pmid":"37313955","tags":["drug-interactions","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"When you take a medication, your liver enzymes (called cytochrome P450 or CYP enzymes) break it down. If something inhibits those enzymes, the medication stays in your blood longer and at higher levels — potentially causing side effects or toxicity. This study is one of the first controlled human trials to measure exactly how cannabis cannabinoids affect these critical drug-metabolizing enzymes.\n\nEighteen healthy adults participated in a randomized crossover study. Each person ate, on separate occasions separated by at least one week: a placebo brownie, a CBD-dominant brownie (640 mg CBD + 20 mg THC), or a THC-only brownie (20 mg THC). Thirty minutes after the brownie, they consumed a 'drug cocktail' of five probe medications, each metabolized by a different CYP enzyme: caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A).\n\nThe CBD brownie significantly inhibited four of the five enzymes, with CYP2C19 most strongly affected, followed by CYP2C9, CYP3A, and CYP1A2. Only CYP2D6 was spared. The THC-only brownie had minimal effects on any of the enzymes.\n\nThis matters because CYP2C19 metabolizes common medications like clopidogrel (blood thinner), some antidepressants, and proton pump inhibitors. CYP2C9 handles warfarin and some anti-inflammatory drugs. CYP3A metabolizes about half of all prescription drugs. If CBD is inhibiting these enzymes, patients taking CBD alongside these medications could be getting higher-than-intended drug levels.","whyItMatters":"Millions of people use CBD products — often alongside prescription medications — with little awareness of potential drug interactions. This is the first well-controlled human study using actual cannabis extracts (not isolated pharmaceutical CBD) to quantify these interactions. The finding that CBD inhibits four major metabolic pathways has immediate clinical relevance for anyone combining CBD with prescription drugs, particularly blood thinners, antidepressants, anti-seizure medications, and immunosuppressants.","specificNumbers":"18 healthy adults in a crossover design. CBD dose: 640 mg (a high but not uncommon supplement dose) + 20 mg THC. CBD brownie inhibited CYP2C19 (strongest), CYP2C9, CYP3A, and CYP1A2. CYP2D6 was not significantly affected. THC-only brownie (20 mg) showed no significant enzyme inhibition. Blood and urine collected over 24 hours.","methodology":"Randomized, three-way crossover study in 18 healthy adults. Participants received, in random order with ≥1 week washout: (1) placebo brownie, (2) CBD-dominant brownie (640 mg CBD + 20 mg THC), or (3) THC-dominant brownie (20 mg THC). Thirty minutes post-brownie, participants consumed a validated CYP probe drug cocktail (caffeine, losartan, omeprazole, dextromethorphan, midazolam). Plasma and urine were collected over 24 hours to measure enzyme activity through probe drug metabolism.","limitations":"Single-dose study in healthy young adults — chronic CBD users or elderly/sick patients may show different interaction profiles. The CBD dose (640 mg) is high compared to typical consumer CBD products (25–100 mg), though some medical uses approach this level. The probe drug cocktail measures enzyme activity, not clinical outcomes — inhibiting an enzyme doesn't automatically mean a dangerous interaction with every drug that enzyme handles. Real-world cannabis products have variable CBD content and additional compounds that could modify these effects."},{"rthcId":"RTHC-04398","title":"A Physiologically-Based Pharmacokinetic Model for Cannabidiol in Healthy Adults, Hepatically-Impaired Adults, and Children.","authors":"Bansal, Sumit; Ladumor, Mayur K; Paine, Mary F; Unadkat, Jashvant D","year":2023,"journal":"Drug metabolism and disposition: the biological fate of chemicals, 51(6), 743-752","doi":"10.1124/dmd.122.001128","pmid":"36972999","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04399","title":"Longitudinal perspectives of riding with a cannabis-impaired driver.","authors":"Banz, Barbara C; Camenga, Deepa R; Li, Kaigang; Zuniga, Vanessa; Iannotti, Ronald J; Grayton, Candice; Haynie, Denise L; Simons-Morton, Bruce G; Curry, Leslie; Vaca, Federico E","year":2023,"journal":"Accident; analysis and prevention, 193, 107300","doi":"10.1016/j.aap.2023.107300","pmid":"37717297","tags":["driving","youth"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Among 105 young adults from a national cohort study, two themes facilitated riding with cannabis-impaired drivers: familiarity with driving context and trust in the driver. Legal concerns deterred it during high school, while safety concerns emerged in young adulthood.","whyItMatters":"Most cannabis-impaired driving research focuses on the driver. This study examines the often-overlooked passenger perspective, revealing that riding with impaired drivers happens during routine daytime activities rather than just late-night party scenarios.","specificNumbers":"105 participants interviewed; 4 trajectory classes (Abstainer, Escalator, Decliner, Persister); interviews conducted March-September 2020","methodology":"Qualitative study using in-depth semi-structured Zoom interviews with 105 participants from the NEXT Generation Health Study, a 7-year national cohort. Participants were purposively selected from four previously derived RWI/DWI trajectory classes.","limitations":"Qualitative design limits generalizability. Interviews conducted during COVID-19 may have affected recall or current driving patterns. Self-reported data subject to social desirability bias."},{"rthcId":"RTHC-04400","title":"Medical Marijuana Legalization and Opioid- and Pain-Related Outcomes Among Patients Newly Diagnosed With Cancer Receiving Anticancer Treatment.","authors":"Bao, Yuhua; Zhang, Hao; Bruera, Eduardo; Portenoy, Russell; Rosa, William E; Reid, M Carrington; Wen, Hefei","year":2023,"journal":"JAMA oncology, 9(2), 206-214","doi":"10.1001/jamaoncol.2022.5623","pmid":"36454553","tags":["medical-cannabis","legalization","pain","cancer"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"In a difference-in-differences analysis of 58,195 cancer patients across 34 states, medical marijuana legalization was associated with a 5.6 percentage point reduction in opioid dispensing among breast cancer patients with recent opioid use and a 6.3 percentage point reduction in pain-related hospital events among lung cancer patients.","whyItMatters":"Published in JAMA Oncology, this study provides large-scale evidence that medical marijuana legalization may offer cancer patients alternatives to opioids for pain management, at a time when opioid prescribing in cancer care has been declining rapidly.","specificNumbers":"38,189 breast cancer patients; 12,816 colorectal cancer patients; 7,190 lung cancer patients; 5.6 percentage point reduction in opioid days for breast cancer (P=.001); 6.3 percentage point reduction in pain-related hospital events for lung cancer (P=.03)","methodology":"Cross-sectional study using 2012-2017 national commercial claims data with a difference-in-differences design. Examined privately insured patients aged 18-64 newly diagnosed with breast, colorectal, or lung cancer across 34 states.","limitations":"Limited to privately insured patients aged 18-64, excluding Medicare and Medicaid populations. Cannot confirm patients actually used marijuana. Observational design cannot establish causation."},{"rthcId":"RTHC-04401","title":"Role of cyclin-dependent kinase 5 in psychosis and the modulatory effects of cannabinoids.","authors":"Barrera-Conde, Marta; Veza-Estévez, Emma; Gomis-Gonzalez, Maria; Garcia-Quintana, Jordi; Trabsa, Amira; Martínez-Sadurní, Laura; Pujades, Mitona; Perez, Víctor; de la Torre, Rafael; Bergé, Daniel; Robledo, Patricia","year":2023,"journal":"Neurobiology of disease, 176, 105942","doi":"10.1016/j.nbd.2022.105942","pmid":"36473591","tags":["psychosis","neuroscience","cognition"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"First-episode psychosis patients with prior cannabis use (FEP/c) had lower CDK5 and higher PSD95 levels compared to those without cannabis use (FEP/nc), and showed fewer social functioning deficits. Blocking CDK5 activity in a mouse model of psychosis restored both sociability and PSD95 levels.","whyItMatters":"This study provides translational evidence bridging human clinical observations with animal model data, suggesting that CDK5 could serve as an early biomarker for psychosis and that cannabinoids may modulate this pathway.","specificNumbers":"Mice received WIN-55,212-2 (1 mg/kg) for 21 days and phencyclidine (10 mg/kg) for 10 days; CDK5 changes correlated with social skills but not cognitive deficits","methodology":"Translational study combining human olfactory neuroepithelial cell analysis from first-episode psychosis patients (with and without cannabis history) with a dual-hit mouse model using a CB1R agonist and NMDAR blocker.","limitations":"Human component was observational and cannot establish causation. Cannabis use history was self-reported. Mouse model uses synthetic cannabinoids, not cannabis itself. Small clinical sample."},{"rthcId":"RTHC-04402","title":"When Cannabis sativa L. Turns Purple: Biosynthesis and Accumulation of Anthocyanins.","authors":"Bassolino, Laura; Fulvio, Flavia; Pastore, Chiara; Pasini, Federica; Gallina Toschi, Tullia; Filippetti, Ilaria; Paris, Roberta","year":2023,"journal":"Antioxidants (Basel, Switzerland), 12(7)","doi":"10.3390/antiox12071393","pmid":"37507932","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04403","title":"Cannabinoids in Treating Chemotherapy-Induced Nausea and Vomiting, Cancer-Associated Pain, and Tumor Growth.","authors":"Bathula, Pavana P; Maciver, M Bruce","year":2023,"journal":"International journal of molecular sciences, 25(1)","doi":"10.3390/ijms25010074","pmid":"38203245","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04404","title":"Differences in Plasma Cannabidiol Concentrations in Women and Men: A Randomized, Placebo-Controlled, Crossover Study.","authors":"Batinic, Ana; Sutlovic, Davorka; Kuret, Sendi; Burcul, Franko; Kalajzic, Nina; Matana, Antonela; Dujic, Goran; Vrdoljak, Josip; Kumric, Marko; Bozic, Josko; Dujic, Zeljko","year":2023,"journal":"International journal of molecular sciences, 24(12)","doi":"10.3390/ijms241210273","pmid":"37373421","tags":["cbd","sex-differences"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 62 hypertensive volunteers in a triple-blind placebo-controlled crossover study, females had significantly higher plasma CBD concentrations than males after receiving the same DehydraTECH2.0 CBD formulation. CBD was still detectable in plasma 50 days after the last dose.","whyItMatters":"Most CBD dosing recommendations do not account for sex differences. If women consistently achieve higher blood levels from the same dose, this has implications for both efficacy and safety.","specificNumbers":"62 hypertensive volunteers; 12-week study duration; CBD detectable 50 days after last dose; plasma CBD/7-OH-CBD ratio significantly higher at week 5 vs week 2.5 (P=0.043); urine 7-COOH-CBD significantly higher at same timepoints (P<0.001)","methodology":"Triple-blind (participant, investigator, outcome assessor) placebo-controlled crossover study with 62 hypertensive volunteers randomized to CBD formulation or placebo over 12 weeks. Plasma and urine analyzed for CBD and metabolites at multiple timepoints.","limitations":"Used a specific proprietary CBD formulation (DehydraTECH2.0) that may not generalize to other products. Participants were hypertensive, limiting generalizability to healthy populations. Sex difference mechanism (adipose tissue) was hypothesized but not directly measured."},{"rthcId":"RTHC-04405","title":"Assessing changes in sleep across four weeks among adolescents randomized to incentivized cannabis abstinence.","authors":"Baumer, Andreas M; Nestor, Bridget A; Potter, Kevin; Knoll, Sarah; Evins, A Eden; Gilman, Jodi; Kossowsky, Joe; Schuster, Randi M","year":2023,"journal":"Drug and alcohol dependence, 252, 110989","doi":"10.1016/j.drugalcdep.2023.110989","pmid":"37839357","tags":["sleep","youth","withdrawal","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a randomized trial of 116 adolescents, those assigned to verified abstinence reported worse overall sleep quality than the monitoring group, but the disruption was specific to increased sleep latency during week one, which resolved by week two and remained at baseline through week four.","whyItMatters":"Sleep disruption is one of the most common reasons young people cite for resuming cannabis use after trying to quit. Knowing that the disruption is brief and specific could help clinicians support adolescents through the withdrawal period.","specificNumbers":"116 adolescents (mean age 17.8, 47% female, 45% non-white); sleep latency increased during week 1 (d=0.34, P=0.04); decreased during week 2 (d=0.36, P=0.04); overall PSQI difference 1.06 points (P=0.01)","methodology":"Randomized trial of 116 non-treatment-seeking adolescents (mean age 17.8) with frequent cannabis use. Assigned to 4 weeks of biochemically verified abstinence with contingency management (n=53) or monitoring without abstinence requirement (n=63). Sleep measured by Pittsburgh Sleep Quality Index.","limitations":"Relied on self-reported sleep measures rather than objective polysomnography. Non-treatment-seeking sample may not represent adolescents motivated to quit. Contingency management payments may have influenced reported outcomes."},{"rthcId":"RTHC-04406","title":"Feasibility and acceptability of collecting umbilical cord tissue for prenatal cannabis research: A mixed-methods research study.","authors":"Bayrampour, Hamideh; Langlois, Jenna; Likhodi, Serguei; Lisonkova, Sarka; Jevitt, Cecilia; Oberlander, Tim; Webster, Glenys; Mérette, Sandrine; Vedam, Saraswathi; Janssen, Patricia","year":2023,"journal":"Women's health (London, England), 19, 17455057231219599","doi":"10.1177/17455057231219599","pmid":"38130079","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04407","title":"Cannabinoids to Improve Health-Related Quality of Life in Patients with Neurological or Oncological Disease: A Meta-Analysis.","authors":"Belgers, Vera; Röttgering, Jantine G; Douw, Linda; Klein, Martin; Ket, Johannes C F; van de Ven, Peter M; Würdinger, Thomas; van Linde, Myra E; Niers, Johanna M; Weber, Markus; Olde Rikkert, Marcel G; Lopez-Sendon, Jose; Arrieta, Oscar; Svendsen, Kristina B; Chagas, Marcos H N; de Almeida, Carlos M O; Kouwenhoven, Mathilde C M; de Witt Hamer, Philip C","year":2023,"journal":"Cannabis and cannabinoid research, 8(1), 41-55","doi":"10.1089/can.2021.0187","pmid":"35861789","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04408","title":"A Case of Cannabinoid Hyperemesis Syndrome and Acute Kidney Injury: A Review of the Literature.","authors":"Bellamy, Shannay E; Loor, Brian; Gutierrez-Castillo, Maria","year":2023,"journal":"Cureus, 15(1), e34350","doi":"10.7759/cureus.34350","pmid":"36865973","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04409","title":"Income inequality and daily use of cannabis, cigarettes, and e-cigarettes among Canadian secondary school students: Results from COMPASS 2018-19.","authors":"Benny, Claire; Steele, Brian J; Patte, Karen A; Leatherdale, Scott T; Pabayo, Roman","year":2023,"journal":"The International journal on drug policy, 115, 104014","doi":"10.1016/j.drugpo.2023.104014","pmid":"37003193","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 74,501 Canadian students aged 12-19, a one standard deviation increase in area-level income inequality (Gini coefficient) was associated with a 25% increase in the odds of daily cannabis use (OR=1.25, 95% CI 1.01-1.54). Income inequality was not associated with daily cigarette smoking but was linked to daily e-cigarette use among females only.","whyItMatters":"This is one of the first large-scale studies linking neighborhood-level economic conditions to adolescent cannabis use patterns, suggesting structural factors beyond individual choices may drive daily use.","specificNumbers":"74,501 students aged 12-19; 50.4% male; 69.1% white; OR=1.25 (95% CI 1.01-1.54) for daily cannabis use; e-cigarette interaction with gender OR=0.87 (95% CI 0.80-0.94)","methodology":"Cross-sectional analysis combining individual-level survey data from Year 6 (2018/19) of the COMPASS study with area-level 2016 Canadian Census data. Used three-level logistic models adjusting for relevant covariates across 74,501 students.","limitations":"Cross-sectional design cannot establish causation. Area-level Gini coefficient may not reflect individual household income. Self-reported substance use subject to reporting bias. Canadian context may not generalize internationally."},{"rthcId":"RTHC-04410","title":"A type II cannabis extract and a 1:1 blend of Δ(9)-tetrahydrocannabinol and cannabidiol display distinct antinociceptive profiles and engage different endocannabinoid targets when administered into the subarachnoid space.","authors":"Benredjem, Besma; Pineyro, Graciela","year":2023,"journal":"Frontiers in pharmacology, 14, 1235255","doi":"10.3389/fphar.2023.1235255","pmid":"37745077","tags":["pain","cbd","medical-cannabis","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"When injected into the spinal fluid of rats with diabetic neuropathy, a type II cannabis extract and a 1:1 THC:CBD mix produced different antinociceptive responses despite equivalent THC content. The two preparations also engaged CB1, CB2 receptors, and TRPV1 channels differently.","whyItMatters":"Current medical cannabis prescribing relies heavily on THC:CBD ratios to predict effects. This study suggests that the full composition of an extract matters, not just its major cannabinoid ratio.","specificNumbers":"Four conditions tested: pure THC, pure CBD, 1:1 THC:CBD mix, balanced extract; three receptor systems evaluated (CB1, CB2, TRPV1)","methodology":"Animal study using a rat model of diabetic neuropathy with intrathecal injection of pure THC, pure CBD, a 1:1 THC:CBD mix, and a balanced chemotype II cannabis extract. Receptor involvement assessed using CB1, CB2, and TRPV1 antagonists.","limitations":"Animal model with intrathecal (spinal) delivery, which does not reflect typical human routes of administration. Diabetic neuropathy model may not generalize to other pain types. Single extract tested."},{"rthcId":"RTHC-04411","title":"A review of social media platform policies that address cannabis promotion, marketing and sales.","authors":"Berg, Carla J; LoParco, Cassidy R; Cui, Yuxian; Pannell, Alexandria; Kong, Grace; Griffith, Lynniah; Romm, Katelyn F; Yang, Y Tony; Wang, Yan; Cavazos-Rehg, Patricia A","year":2023,"journal":"Substance abuse treatment, prevention, and policy, 18(1), 35","doi":"10.1186/s13011-023-00546-x","pmid":"37337216","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04412","title":"Sexually Dimorphic Adolescent Trajectories of Prefrontal Endocannabinoid Synaptic Plasticity Equalize in Adulthood, Reflected by Endocannabinoid System Gene Expression.","authors":"Bernabeu, Axel; Bara, Anissa; Murphy Green, Michelle N; Manduca, Antonia; Wager-Miller, Jim; Borsoi, Milene; Lassalle, Olivier; Pelissier-Alicot, Anne-Laure; Chavis, Pascale; Mackie, Ken; Manzoni, Olivier J J","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 749-767","doi":"10.1089/can.2022.0308","pmid":"37015060","tags":["neuroscience","sex-differences","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Endocannabinoid-mediated long-term depression (eCB-LTD) was present in juvenile female rats but only appeared at puberty in males. Gene expression of eCB/vanilloid system components was sequential and sex-specific, with juvenile males showing elevated expression of CB1R-inhibiting proteins that blocked LTD.","whyItMatters":"If endocannabinoid signaling develops on different timelines in males and females, cannabis exposure during adolescence could have sex-specific effects on brain development, potentially explaining observed sex differences in cannabis-related outcomes.","specificNumbers":"eCB-LTD present in juvenile females but absent until puberty in males; pharmacological inhibition of ABHD6 or MAGL (but not anandamide degradation) enabled LTD in young males","methodology":"Animal study examining sex-specific cellular and synaptic trajectories in rat prefrontal cortex from adolescence to adulthood using electrophysiology, gene expression analysis, and pharmacological manipulation of endocannabinoid pathways.","limitations":"Rat model may not directly translate to human brain development. Focused on prefrontal cortex layer 5 only. Did not directly test how exogenous cannabis exposure interacts with these developmental trajectories."},{"rthcId":"RTHC-04413","title":"Reported Reasons for Cannabis Use Before and After Pregnancy Recognition.","authors":"Besse, Margaret; Parikh, Kajal; Mark, Katrina","year":2023,"journal":"Journal of addiction medicine, 17(5), 563-567","doi":"10.1097/ADM.0000000000001178","pmid":"37788610","tags":["pregnancy","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 105 pregnant respondents who screened positive for cannabis, 40 (38%) reported complete abstinence after pregnancy recognition while 65 (62%) continued use. Those who considered their use medical or mixed were four times as likely to continue (OR 4.0, 95% CI 1.3-12.8). Continued users were significantly more likely to discuss use with their obstetrician (89.2% vs 50%, P<0.001).","whyItMatters":"Understanding why pregnant people continue cannabis use can inform more effective clinical conversations. The finding that continued users were more likely to disclose to their providers suggests openness to clinical guidance.","specificNumbers":"105 enrolled of 117 approached; 38.1% achieved abstinence; 61.9% continued; of continuers, 53.8% decreased use, 40% maintained, 6.2% increased; medical users 4x more likely to continue (OR 4.0); 89.2% of continuers disclosed to OB vs 50% of abstainers (P<0.001)","methodology":"Cross-sectional survey of 105 pregnant patients at one prenatal practice in Baltimore, MD, who either self-reported cannabis use or tested positive on urine toxicology. Anonymous survey with multiple choice questions on frequency and reasons for use before and after pregnancy recognition.","limitations":"Single prenatal practice in Baltimore limits generalizability. Self-reported data on timing and reasons for use. Cross-sectional design cannot capture changes over pregnancy. Cannabis use may be underreported despite anonymous survey."},{"rthcId":"RTHC-04414","title":"Cannabis use disorder in patients with chronic pain: overestimation and underestimation in a cross-sectional observational study in 3 German pain management centres.","authors":"Bialas, Patric; Böttge-Wolpers, Claudia; Fitzcharles, Mary-Ann; Gottschling, Sven; Konietzke, Dieter; Juckenhöfel, Stephanie; Madlinger, Albrecht; Welsch, Patrick; Häuser, Winfried","year":2023,"journal":"Pain, 164(6), 1303-1311","doi":"10.1097/j.pain.0000000000002817","pmid":"36327134","tags":["addiction","pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 187 chronic pain patients prescribed medical cannabis, CUD prevalence was 29.9% using standard DSM-5 criteria, 13.9% when tolerance and withdrawal items were removed, and just 2.1% when positive items attributable to pain relief were excluded. Meanwhile, physicians identified abuse in only 1 patient, suggesting substantial underestimation from the clinical side.","whyItMatters":"The DSM-5 was not designed to diagnose substance use disorders in patients using a substance therapeutically. This study demonstrates how the diagnostic framework can produce dramatically different prevalence estimates depending on how criteria are interpreted.","specificNumbers":"187 patients across 3 German pain centers; CUD prevalence: 29.9% (full DSM-5), 13.9% (without tolerance/withdrawal), 2.1% (adjusted for therapeutic context); 10.7% showed at least one abuse signal; 4.8% positive for nonprescribed drugs on urine test","methodology":"Cross-sectional study using anonymous questionnaires and urine testing in 187 consecutive patients attending 3 German pain centers in 2021. DSM-5 criteria scored three ways: all criteria, without tolerance/withdrawal, and without pain-relief-motivated behaviors.","limitations":"Cross-sectional design at German pain centers may not generalize internationally. Anonymous questionnaire format prevented linking individual responses to clinical records. The adjusted scoring method has not been validated independently."},{"rthcId":"RTHC-04415","title":"Medical cannabinoids for painful symptoms in patients with severe dementia: a randomized, double-blind cross-over placebo-controlled trial protocol.","authors":"Bianchi, Federica; Pautex, Sophie; Wampfler, James; Curtin, François; Daali, Youssef; Desmeules, Jules Alexandre; Broers, Barbara","year":2023,"journal":"Frontiers in pain research (Lausanne, Switzerland), 4, 1108832","doi":"10.3389/fpain.2023.1108832","pmid":"37293434","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04416","title":"Neuroprotection and Beyond: The Central Role of CB1 and CB2 Receptors in Stroke Recovery.","authors":"Bietar, Bashir; Tanner, Sophie; Lehmann, Christian","year":2023,"journal":"International journal of molecular sciences, 24(23)","doi":"10.3390/ijms242316728","pmid":"38069049","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04417","title":"Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH-018 in male mice.","authors":"Bilel, Sabrine; Zamberletti, Erica; Caffino, Lucia; Tirri, Micaela; Mottarlini, Francesca; Arfè, Raffaella; Barbieri, Mario; Beggiato, Sarah; Boccuto, Federica; Bernardi, Tatiana; Casati, Sara; Brini, Anna T; Parolaro, Daniela; Rubino, Tiziana; Ferraro, Luca; Fumagalli, Fabio; Marti, Matteo","year":2023,"journal":"British journal of pharmacology, 180(21), 2777-2801","doi":"10.1111/bph.16164","pmid":"37311647","tags":["synthetic-cannabinoids","cognition","neuroscience","psychosis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Repeated JWH-018 treatment (6 mg/kg daily for 7 days) induced psychomotor agitation, reduced social dominance and recognition memory, impaired prepulse inhibition, disrupted hippocampal long-term potentiation, decreased BDNF expression, and altered endocannabinoid system components in the striatum and hippocampus, all persisting 15+ days after last exposure.","whyItMatters":"Synthetic cannabinoids are far more potent than plant cannabis and are associated with severe psychiatric outcomes in humans. This study provides mechanistic evidence for how repeated exposure produces lasting brain changes.","specificNumbers":"6 mg/kg JWH-018 daily for 7 days; 15-16 day washout; reduced hippocampal CB1 receptor density; altered AEA and 2-AG levels; decreased BDNF, PSD95, and NMDA receptor subunit expression","methodology":"Male CD-1 mice received daily injections of vehicle, JWH-018 (6 mg/kg), CB1 antagonist NESS-0327 (1 mg/kg), or co-administration for 7 days. After 15-16 days washout, behavioral, neurochemical, electrophysiological, and molecular assessments were performed.","limitations":"Used a single high dose in male mice only. JWH-018 is one of many synthetic cannabinoids with varying potency. Route of administration (injection) differs from typical human use (smoking). No female mice included."},{"rthcId":"RTHC-04418","title":"Substance use, socio-demographic characteristics, and self-rated health of people seeking alcohol and other drug treatment in New South Wales: baseline findings from a cohort study.","authors":"Black, Emma; Bruno, Raimondo; Mammen, Kristie; Mills, Llewellyn; Siefried, Krista J; Deacon, Rachel M; Shakeshaft, Anthony; Dunlop, Adrian J; Ezard, Nadine; Montebello, Mark; Childs, Steven; Reid, David; Holmes, Jennifer; Lintzeris, Nicholas","year":2023,"journal":"The Medical journal of Australia, 219(5), 218-226","doi":"10.5694/mja2.52039","pmid":"37449648","tags":["addiction","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 14,087 treatment entrants, alcohol was the primary concern for 43%, opioids for 22%, amphetamine-type stimulants for 18%, cannabis for 15%, and cocaine for 2%. Two-thirds were male, half were aged 20-39, and large proportions reported poor psychological health (47-59%), poor physical health (32-44%), and poor quality of life (43-52%). Polysubstance use was common, particularly among opioid and stimulant groups. Daily tobacco use ranged from 53-82% across groups.","whyItMatters":"This is one of the largest Australian studies characterizing people entering public drug treatment, showing that cannabis treatment seekers have high rates of social disadvantage and poor health comparable to those seeking help for other substances.","specificNumbers":"14,087 treatment entrants; 66.5% male; 86.7% Australian-born; cannabis primary concern for 2,098 (15%); poor psychological health: 47-59%; poor physical health: 32-44%; poor quality of life: 43-52%; daily tobacco: 53-82%","methodology":"Baseline analysis of a prospective cohort study using Australian Treatment Outcomes Profile assessments and electronic medical records from six NSW local health districts/networks, covering treatment entries from July 2016 to June 2019.","limitations":"Limited to publicly funded treatment services in one Australian state. People who do not seek treatment are not represented. Self-reported health measures may not reflect clinical assessments. Cannabis group characteristics may differ in other countries."},{"rthcId":"RTHC-04419","title":"Cannabis use in gynecologic cancer patients in a Canadian cancer center.","authors":"Black, Kristin A; Bowden, Sylvie; Thompson, Mary; Ghatage, Prafull","year":2023,"journal":"Gynecologic oncology reports, 47, 101210","doi":"10.1016/j.gore.2023.101210","pmid":"37273764","tags":["cancer","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 46 surveyed patients, 17 (37%) were current cannabis users. The most common reasons were pain (9/17), anxiety (9/17), and insomnia (9/17). Most users lacked a prescription (11/17 obtained cannabis from recreational dispensaries) and half had not discussed their use with their doctor, though over 50% of all patients said they would welcome physician-initiated conversations about cannabis.","whyItMatters":"Cannabis use among cancer patients is common but often undisclosed to oncologists. The finding that most patients would welcome physician-initiated conversations suggests a gap between patient interest and clinical practice.","specificNumbers":"46 participants; 17 (37%) current users; pain, anxiety, insomnia each cited by 9/17 users; 11/17 obtained from recreational dispensary; 9/17 had not discussed with doctor; 26/46 would discuss if physician raised it; cannabis retailers (20/46) and friends/family (20/46) were top info sources","methodology":"Single-institution cross-sectional survey conducted at a cancer center in Calgary, Alberta. Patients with current or prior gynecologic cancer diagnosis were surveyed about cannabis use patterns, reasons for use, and information sources.","limitations":"Small sample (n=46) from a single Canadian cancer center. Self-selected participation may overrepresent cannabis users. Cross-sectional design cannot track use patterns over treatment course."},{"rthcId":"RTHC-04420","title":"Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatal Cannabis smoke exposure.","authors":"Black, Tallan; Baccetto, Sarah L; Barnard, Ilne L; Finch, Emma; McElroy, Dan L; Austin-Scott, Faith V L; Greba, Quentin; Michel, Deborah; Zagzoog, Ayat; Howland, John G; Laprairie, Robert B","year":2023,"journal":"Scientific reports, 13(1), 21070","doi":"10.1038/s41598-023-47861-8","pmid":"38030657","tags":["pregnancy","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Pregnant rats exposed to high-THC or high-CBD cannabis smoke from gestational day 6-20 showed different inflammatory profiles than those receiving injected THC or CBD. Injected cannabinoids upregulated pro-inflammatory cytokines in placental and fetal brain tissue, while smoke exposure reduced cytokine and chemokine concentrations. Injection also led to fewer offspring and more uterine reabsorption events.","whyItMatters":"Most preclinical cannabis-pregnancy research uses injected pure cannabinoids, but most human use involves smoking. This study shows these routes produce opposite inflammatory effects, calling into question how well injection studies translate to real-world exposures.","specificNumbers":"High-THC smoke: 18% THC, 0.1% CBD; high-CBD smoke: 0.7% THC, 13% CBD; injected doses: 3 mg/kg THC, 10 mg/kg CBD; treatment period: gestational day 6-20","methodology":"Pregnant Sprague-Dawley rats were treated daily from gestational day 6-20 with room air, vehicle, high-THC smoke (18% THC, 0.1% CBD), high-CBD smoke (0.7% THC, 13% CBD), injected THC (3 mg/kg), or injected CBD (10 mg/kg). Plasma cannabinoid levels, cytokine profiles, and reproductive outcomes were assessed.","limitations":"Rat model may not translate directly to human pregnancy. Smoke exposure involves combustion products beyond cannabinoids. Specific cannabinoid doses delivered via smoke are harder to control than injections."},{"rthcId":"RTHC-04421","title":"Polysubstance use during pregnancy: The importance of screening, patient education, and integrating a harm reduction perspective.","authors":"Board, Amy; D'Angelo, Denise V; Salvesen von Essen, Beatriz; Denny, Clark H; Miele, Kathryn; Dunkley, Janae; Baillieu, Robert; Kim, Shin Y","year":2023,"journal":"Drug and alcohol dependence, 247, 109872","doi":"10.1016/j.drugalcdep.2023.109872","pmid":"37182339","tags":["pregnancy","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"In a nationally representative US sample, cigarettes (8.1%), alcohol (7.4%), and cannabis (4.3%) were the most commonly reported substances during pregnancy. Among those using any substance, nearly one in five used at least one additional substance. While prenatal screening for alcohol and cigarettes reached ~95%, only 82.1% were screened for cannabis or illicit substances.","whyItMatters":"The gap between high screening rates for alcohol/tobacco and lower rates for cannabis suggests clinicians may be missing a meaningful proportion of prenatal substance exposure, particularly given rising cannabis legalization.","specificNumbers":"Cigarettes: 8.1% (95% CI 7.6-8.7%); alcohol: 7.4% (95% CI 6.7-8.1%); cannabis: 4.3% (95% CI 3.9-4.7%); illicit drugs: 0.5% (95% CI 0.4-0.7%); cannabis screening: 82.1%; alcohol/tobacco screening: ~95%","methodology":"Analysis of 2019 Pregnancy Risk Assessment Monitoring System (PRAMS) data from 25 US jurisdictions. Weighted prevalence estimates calculated for substance use, polysubstance use, and screening rates during pregnancy.","limitations":"Self-reported substance use likely underestimates true prevalence. PRAMS data from 25 jurisdictions may not represent all US states. Different assessment windows for different substances complicate direct comparisons."},{"rthcId":"RTHC-04422","title":"Prevention, Practice, and Policy: Older US Veterans' Perspectives on Cannabis Use.","authors":"Bobitt, Julie; Clary, Kelly; Krawitz, Michael; Silva, Laura Quintero; Kang, Hyojung","year":2023,"journal":"Drugs & aging, 40(1), 59-70","doi":"10.1007/s40266-022-00995-2","pmid":"36648751","tags":["seniors","medical-cannabis","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Semi-structured interviews with 32 older veterans revealed they used medical cannabis as an adjunct or substitute for opioids and benzodiazepines for physical and mental health conditions. Veterans reported inconsistent application of cannabis policies across the Veterans Health Administration system, and limited guidance from healthcare providers despite wanting clinical support.","whyItMatters":"Veterans have disproportionately high rates of chronic pain and PTSD, conditions traditionally treated with opioids and benzodiazepines. Understanding how they self-manage with cannabis could inform VA policy and clinical practice.","specificNumbers":"32 veterans interviewed; selected via maximum variation sampling from survey respondents","methodology":"Qualitative study using maximum variation sampling to select 32 veterans from a larger survey sample for semi-structured interviews. Thematic analysis applied to identify patterns in cannabis use motivations, experiences, and policy concerns.","limitations":"Qualitative design with 32 participants limits generalizability. Self-selected participants may overrepresent positive cannabis experiences. Findings specific to the US veteran population and VA system."},{"rthcId":"RTHC-04423","title":"Cannabidiol use in patients with Dravet syndrome and Lennox-Gastaut syndrome: experts' opinions using a nominal group technique (NGT) approach.","authors":"Bonanni, Paolo; Ragona, Francesca; Fusco, Carlo; Gambardella, Antonio; Operto, Francesca Felicia; Parmeggiani, Lucio; Sartori, Stefano; Specchio, Nicola","year":2023,"journal":"Expert opinion on pharmacotherapy, 24(5), 655-663","doi":"10.1080/14656566.2023.2187697","pmid":"37021712","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04424","title":"Social media interventions addressing physical activity among emerging adults who use cannabis: A pilot trial of feasibility and acceptability.","authors":"Bonar, Erin E; Chapman, Lyndsay; Pagoto, Sherry; Tan, Chiu Yi; Duval, Elizabeth R; McAfee, Jenna; Collins, R Lorraine; Walton, Maureen A","year":2023,"journal":"Drug and alcohol dependence, 242, 109693","doi":"10.1016/j.drugalcdep.2022.109693","pmid":"36442441","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04425","title":"A remote brief intervention plus social media messaging for cannabis use among emerging adults: A pilot randomized controlled trial in emergency department patients.","authors":"Bonar, Erin E; Goldstick, Jason E; Tan, Chiu Yi; Bourque, Carrie; Carter, Patrick M; Duval, Elizabeth R; McAfee, Jenna; Walton, Maureen A","year":2023,"journal":"Addictive behaviors, 147, 107829","doi":"10.1016/j.addbeh.2023.107829","pmid":"37598642","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04426","title":"Alcohol, drugs, and road traffic injuries in an emergency department in Mexico City.","authors":"Borges, Guilherme; Orozco, Ricardo; Hernández-Becerril, Zaide; Ortega, Brenda E; Flores, Julio; Benitez-King, Gloria; Flores-Alcantar, Guadalupe; Escamilla-Nuñez, Alberto; Scherer, Juliana N","year":2023,"journal":"Injury, 54(2), 481-489","doi":"10.1016/j.injury.2022.12.019","pmid":"36588032","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04427","title":"Psychological Interventions for Cannabis Use among Adolescents and Young Adults: A Systematic Review.","authors":"Bou Nassif, Yara; Rahioui, Hassan; Varescon, Isabelle","year":2023,"journal":"International journal of environmental research and public health, 20(14)","doi":"10.3390/ijerph20146346","pmid":"37510578","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04428","title":"Cellular Assay to Study β-Arrestin Recruitment by the Cannabinoid Receptors 1 and 2.","authors":"Bouma, Jara; Soethoudt, Marjolein; van Gils, Noortje; Xia, Lizi; van der Stelt, Mario; Heitman, Laura H","year":2023,"journal":"Methods in molecular biology (Clifton, N.J.), 2576, 189-199","doi":"10.1007/978-1-0716-2728-0_15","pmid":"36152187","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04429","title":"Maternal, Fetal and Neonatal Outcomes Related to Recreational Cannabis Use during Pregnancy: Analysis of a Real-World Clinical Data Warehouse between 2010 and 2019.","authors":"Bouquet, Emilie; Blouin, Pascal; Pérault-Pochat, Marie-Christine; Carlier-Guérin, Caroline; Millot, Frédéric; Ricco, Jean-Baptiste; De Keizer, Joe; Pain, Stéphanie; Guétarni, Farid","year":2023,"journal":"International journal of environmental research and public health, 20(17)","doi":"10.3390/ijerph20176686","pmid":"37681826","tags":["pregnancy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 669 pregnancies analyzed (123 cannabis users, 191 tobacco-only, 355 controls), cannabis use during pregnancy was associated with increased voluntary interruption of pregnancy, at least one adverse event during pregnancy, at least one neonatal adverse event, prematurity, and small-for-gestational-age births. Cannabis users were younger (mean 25.5 years), had more psychiatric history (17.5%), and were more likely to have universal free healthcare coverage.","whyItMatters":"This study from a French hospital system provides European data on prenatal cannabis effects, complementing the predominantly North American literature and controlling for concurrent tobacco use.","specificNumbers":"123 cannabis ± tobacco users, 191 tobacco-only, 355 controls; cannabis users mean age 25.5 ± 5.7 years; BMI 22.8 ± 5.5; 17.5% psychiatric history; 18.2% universal free healthcare coverage","methodology":"Retrospective analysis of data from the Poitiers University Hospital clinical data warehouse from 2010-2019. Logistic regression compared outcomes across three groups: cannabis with or without tobacco, tobacco alone, and controls.","limitations":"Retrospective design with data from a single hospital. Cannabis use likely underreported in medical records. Cannot fully separate cannabis effects from tobacco, socioeconomic factors, or psychiatric comorbidities."},{"rthcId":"RTHC-04430","title":"Chronic exposure to a synthetic cannabinoid alters cerebral brain metabolism and causes long-lasting behavioral deficits in adult mice.","authors":"Bouter, Caroline; Ott, Frederik Wilhelm; Günther, Daniel; Weig, Lukas; Schmitz-Peiffer, Fabian; Rozyyeva, Mahriban; Beindorff, Nicola; Bouter, Yvonne","year":2023,"journal":"Journal of neural transmission (Vienna, Austria : 1996), 130(8), 1013-1027","doi":"10.1007/s00702-023-02607-8","pmid":"36853560","tags":["synthetic-cannabinoids","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Treatment with WIN 55,212-2 (3 mg/kg) led to hypometabolism in the hippocampus, cerebellum, amygdala, and midbrain, persisting even after prolonged abstinence. Mice showed spatial memory and recognition memory deficits without changes in anxiety behavior. Effects were more persistent when treatment occurred in early adulthood.","whyItMatters":"The persistence of brain metabolic changes and memory deficits even after stopping the drug suggests that chronic synthetic cannabinoid exposure may cause long-lasting neurological alterations, particularly when exposure occurs in early adulthood.","specificNumbers":"3 mg/kg WIN 55,212-2; hypometabolism in hippocampus, cerebellum, amygdala, midbrain; effects persisted after prolonged abstinence; early adulthood exposure produced more persistent effects than later exposure","methodology":"Adult C57BL/6J mice were divided into groups to study acute effects and effects after extended washout. Brain metabolism was assessed, along with behavioral testing for spatial memory, recognition memory, and anxiety.","limitations":"Single synthetic cannabinoid tested in one mouse strain. Doses and routes of administration differ from human use patterns. No comparison with plant-derived THC to establish relative risk."},{"rthcId":"RTHC-04431","title":"Social stress under binge-like alcohol withdrawal in adolescence: evidence of cannabidiol effect on maladaptive plasticity in rats.","authors":"Brancato, Anna; Castelli, Valentina; Lavanco, Gianluca; D'Amico, Cesare; Feo, Salvatore; Pizzolanti, Giuseppe; Kuchar, Martin; Cannizzaro, Carla","year":2023,"journal":"Psychological medicine, 53(12), 5538-5550","doi":"10.1017/S0033291722002744","pmid":"36065905","tags":["cbd","neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats exposed to binge-like alcohol during adolescence showed compromised defensive social behavior, blunted stress responses, and abnormal dopamine/glutamate plasticity in the nucleus accumbens. CBD at 60 mg/kg restored social exploration, reduced corticosterone levels, normalized dopamine transmission, and facilitated synaptic remodeling.","whyItMatters":"Adolescent binge drinking combined with social stress is a common real-world scenario. Finding that CBD can reverse the resulting brain and behavioral changes opens a potential therapeutic avenue for alcohol-related harm in young people.","specificNumbers":"CBD dose: 60 mg/kg; CBD increased social exploration and reduced freezing in alcohol-exposed rats; reduced corticosterone levels independent of alcohol history; restored dopamine transmission and excitatory synaptic strength","methodology":"Rat model combining binge-like alcohol exposure during adolescence with a resident-intruder social stress paradigm. CBD (60 mg/kg) was administered to assess its ability to rescue behavioral, neuroendocrine, and molecular deficits. Outcomes included social behavior, corticosterone levels, dopamine transmission, and synaptic markers.","limitations":"Animal model with a single CBD dose. The resident-intruder paradigm is a specific type of social stress that may not capture all human social stressors. CBD dose (60 mg/kg) is high relative to typical human dosing."},{"rthcId":"RTHC-04432","title":"Second-line cannabis therapy in patients with epilepsy.","authors":"Braun, Erica; Gualano, Francesca M; Siddarth, Prabha; Segal, Eric","year":2023,"journal":"Clinical neurology and neurosurgery, 227, 107638","doi":"10.1016/j.clineuro.2023.107638","pmid":"36870086","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04433","title":"Ecological Momentary Assessment of Cannabis Use and Affect Among Adolescents Following Psychiatric Discharge.","authors":"Brick, Leslie A; Gajewski-Nemes, Julia A; Marraccini, Marisa E; Brown, Shaquanna; Armey, Michael; Nugent, Nicole R","year":2023,"journal":"Journal of studies on alcohol and drugs, 84(1), 67-78","doi":null,"pmid":"36799676","tags":["youth","mental-health","anxiety","ptsd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Using ecological momentary assessment over 21 days following psychiatric discharge, cannabis use among adolescents was associated with higher positive affect and lower anger/irritability but not with negative affect. The positive affect boost was stronger among youth diagnosed with PTSD or generalized anxiety disorder. Concurrent use of other drugs dramatically increased the odds of cannabis use (OR=27.63).","whyItMatters":"Understanding why psychiatrically vulnerable adolescents use cannabis in real-time contexts helps identify intervention targets. The finding that cannabis may be used to enhance positive emotions rather than escape negative ones shifts the clinical conversation.","specificNumbers":"62 adolescents (ages 13-18, 64.5% female); 21 days EMA post-discharge; concurrent drug use OR=27.63; stronger positive affect effects in PTSD/GAD youth","methodology":"Ecological momentary assessment (EMA) over 21 days with 62 adolescents (ages 13-18, 64.5% female) discharged from inpatient psychiatric hospitalization for suicidal thoughts and behaviors who reported ever using cannabis. Clinical interviews conducted during hospitalization.","limitations":"Small sample of psychiatrically hospitalized youth limits generalizability. Self-reported cannabis use in real-time may still underestimate actual use. 21-day assessment window captures only early post-discharge period."},{"rthcId":"RTHC-04434","title":"Divergent effects of oral cannabis oil extracts marketed as C. indica or C. sativa on exertion of cognitive effort in rats.","authors":"Brodie, Hannah G; Hathaway, Brett A; Li, Andrew; Baglot, Samantha L; Kaur, Sukhbir; Hill, Matthew N; Winstanley, Catharine A","year":2023,"journal":"Behavioral neuroscience, 137(1), 41-51","doi":"10.1037/bne0000535","pmid":"36395021","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both cannabis products (matched for THC and CBD content) slowed response times at higher doses, but only the indica-labeled oil at 10 mg/kg THC reduced the proportion of trials where rats chose high-effort/high-reward options. Ex vivo analysis confirmed comparable brain THC levels between the two products, suggesting minor cannabinoids or terpenes drove the behavioral difference.","whyItMatters":"The indica/sativa distinction is often dismissed as marketing, but this controlled study shows that products with identical THC and CBD levels can produce different cognitive effects, suggesting other plant compounds matter.","specificNumbers":"Highest dose: 10 mg/kg THC; only indica at this dose reduced high-effort choices; repeated medium dose (3 mg/kg THC) of either product did not influence choice; comparable brain THC levels confirmed ex vivo","methodology":"Male Long-Evans rats received acute oral administration of two commercially available cannabis extracts (marketed as C. indica or C. sativa, matched for THC and CBD content) at multiple doses. Cognitive effort was measured using a task where rats chose between low-effort/low-reward and high-effort/high-reward options.","limitations":"Only two commercial products tested. Male rats only. Oral administration may not reflect smoked or vaporized use. Product composition beyond THC/CBD was not fully characterized."},{"rthcId":"RTHC-04435","title":"Acute Treatment of Adolescent Cannabinoid Hyperemesis Syndrome With Haloperidol, Lorazepam, and/or Capsaicin: A Single Institution Case Series.","authors":"Brown, Jerry M; Wilsey, Michael J; Dhana, Leila; Lonsdale, Hannah","year":2023,"journal":"Journal of psychiatric practice, 29(5), 354-358","doi":"10.1097/PRA.0000000000000732","pmid":"37678364","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04436","title":"Cannabis use, cannabis use disorder and mental health disorders among pregnant and postpartum women in the US: A nationally representative study.","authors":"Brown, Qiana L; Shmulewitz, Dvora; Sarvet, Aaron L; Young-Wolff, Kelly C; Howard, Tyriesa; Hasin, Deborah S","year":2023,"journal":"Drug and alcohol dependence, 248, 109940","doi":"10.1016/j.drugalcdep.2023.109940","pmid":"37267745","tags":["pregnancy","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 1,316 pregnant and postpartum women, past-year cannabis use prevalence was 9.8% and cannabis use disorder (CUD) was 3.2%. Women with any past-year mood, anxiety, or PTSD disorder had 2.1 to 3.9 times higher odds of cannabis use, and 2.6 to 10.4 times higher odds of CUD. Specific disorder associations with CUD ranged from 2.4 to 11.6 times higher odds.","whyItMatters":"The pregnancy and postpartum period is already a time of heightened mental health vulnerability. The strong association between mental health disorders and cannabis use/CUD in this population highlights the need for integrated screening and treatment.","specificNumbers":"1,316 women (414 pregnant, 902 postpartum); 9.8% past-year cannabis use; 3.2% CUD; cannabis use aORs: 2.10-3.87 for any mood/anxiety/PTSD; CUD aORs: 2.55-10.44; specific disorder CUD aORs: 2.36-11.60","methodology":"Analysis of the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). Weighted logistic regression models estimated associations between past-year cannabis use, DSM-5 CUD, and DSM-5 mental health disorders among 414 pregnant and 902 postpartum women aged 18-44.","limitations":"Cross-sectional data cannot determine whether mental health disorders drive cannabis use or vice versa. Data from 2012-2013 may not reflect current patterns given rapid cannabis legalization. Self-reported cannabis use and psychiatric diagnoses."},{"rthcId":"RTHC-04437","title":"Cannabis-derived products antagonize platinum drugs by altered cellular transport.","authors":"Buchtova, Tereza; Beresova, Lucie; Chroma, Katarina; Pluhacek, Tomas; Beres, Tibor; Kaczorova, Dominika; Tarkowski, Petr; Bartek, Jiri; Mistrik, Martin","year":2023,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 163, 114801","doi":"10.1016/j.biopha.2023.114801","pmid":"37137184","tags":["cancer","drug-interactions","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Even low concentrations of cannabinoids reduced the toxicity of cisplatin, oxaliplatin, and carboplatin in human cell cultures. The mechanism was not transcriptional but involved reduced intracellular platinum accumulation, suggesting cannabinoids impair cellular transport or retention of these drugs. This raises the possibility that cannabinoids used to counter chemotherapy side effects could simultaneously reduce chemotherapy effectiveness.","whyItMatters":"Many cancer patients use cannabinoids to manage chemotherapy side effects like nausea. If cannabinoids reduce how much chemotherapy drug reaches cancer cells, the very relief they provide could come at the cost of treatment effectiveness.","specificNumbers":"Three platinum drugs tested: cisplatin, oxaliplatin, carboplatin; even low cannabinoid concentrations reduced platinum toxicity; trace metal analysis showed decreased intracellular platinum accumulation","methodology":"Preclinical study using human cell culture models. Cancer cells were treated with platinum-based drugs with and without CBD or cannabis extracts. Platinum adduct formation, molecular markers, trace metal analysis, and transcriptional profiling were used to determine the mechanism of interaction.","limitations":"Cell culture models do not account for whole-body pharmacokinetics. Concentrations tested may not reflect those achieved with typical human cannabis use. Did not test whether timing of cannabinoid and chemotherapy dosing affects the interaction."},{"rthcId":"RTHC-04438","title":"Dispensary Staff Perceptions About the Benefits, Risks, and Safety of Cannabis for Medical Purposes.","authors":"Bulls, Hailey W; Althouse, Andrew D; Feldman, Robert; Arnsten, Julia H; Liebschutz, Jane M; Nugent, Shannon M; Orris, Steven R; Rohac, Rebecca; Slawek, Deepika E; Starrels, Joanna L; Morasco, Benjamin J; Kansagara, Devan; Merlin, Jessica S","year":2023,"journal":"Substance abuse, 44(3), 226-234","doi":"10.1177/08897077231186677","pmid":"37706479","tags":["medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 434 dispensary staff from 29 states, over 80% viewed cannabis as helpful for PTSD (88.7%), epilepsy (85.3%), and cancer (83.4%). More than 70% were not worried about potential risks including increased illicit drug use (76.3%), decreased intelligence (74.4%), sleep disruption (71.7%), or new health problems (70.7%). Cannabis was considered safe in older adults by 81.3%, with less consensus on pregnancy safety.","whyItMatters":"Dispensary staff are often the primary information source for medical cannabis patients, yet this survey shows they may broadly minimize risks and overstate benefits, potentially providing unbalanced guidance.","specificNumbers":"434 participants from 29 states; 40% patient-facing staff, 32% managers, 13% pharmacists, 5% clinicians; 88.7% saw cannabis as helpful for PTSD; 85.3% for epilepsy; 83.4% for cancer; 81.3% considered it safe for older adults; 76.3% not worried about illicit drug use risk","methodology":"Online Qualtrics survey of 434 dispensary staff from 29 US states who reported interacting with customers in dispensaries selling THC-containing products. Conducted February-October 2020. Participants rated perceived benefits, risks, and safety on Likert scales.","limitations":"Online self-selected sample may overrepresent pro-cannabis views. Survey conducted during COVID-19 which may have affected responses. \"Helpfulness\" and \"worry\" framing may not capture nuanced risk-benefit assessment."},{"rthcId":"RTHC-04439","title":"The association between public health engagement in school-based substance use prevention programs and student alcohol, cannabis, e-cigarette and cigarette use.","authors":"Burnett, Trish; Battista, Kate; Butt, Michelle; Sherifali, Diana; Leatherdale, Scott T; Dobbins, Maureen","year":2023,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 114(1), 94-103","doi":"10.17269/s41997-022-00655-3","pmid":"35864306","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 42,149 students in 84 schools, public health engagement in substance use prevention had no significant overall impact on student use. When public health agencies solved problems jointly with schools, odds of alcohol and cannabis use increased. Some methods decreased cannabis and cigarette use in high-use schools but increased alcohol and cannabis use in low-use schools.","whyItMatters":"Schools invest substantial resources in substance prevention programs. Finding that some approaches may backfire in low-use schools suggests that one-size-fits-all prevention strategies may be counterproductive.","specificNumbers":"84 schools; 42,149 students; 70% of schools had public health engagement; joint problem-solving significantly increased odds of alcohol and cannabis use","methodology":"Cross-sectional analysis of 2018/2019 COMPASS study data from 84 schools and 42,149 Canadian students. Multilevel logistic regression assessed associations between five methods of public health engagement and student substance use.","limitations":"Cross-sectional design cannot establish causation. Public health engagement was measured at the school level, not the student level. Cannot account for quality or fidelity of specific program implementation."},{"rthcId":"RTHC-04440","title":"Impact of Recreational Cannabis Legalization on Opioid Prescribing and Opioid-Related Hospital Visits in Colorado: an Observational Study.","authors":"Buttorff, Christine; Wang, George Sam; Wilks, Asa; Tung, Gregory; Kress, Amii; Schwam, Dan; Pacula, Rosalie Liccardo","year":2023,"journal":"Journal of general internal medicine, 38(12), 2726-2733","doi":"10.1007/s11606-023-08195-3","pmid":"37340250","tags":["legalization","pain","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using county-level variation in recreational dispensary allowances across Colorado, recreational cannabis exposure was associated with significantly fewer 30-day opioid fills (coefficient: -117.6, P<0.01) and inpatient visits (coefficient: -0.8, P=0.03), but not with reductions in total morphine milligram equivalents or ED visits. Counties without prior medical cannabis access experienced greater reductions.","whyItMatters":"By exploiting natural variation in dispensary access at the county level, this study provides more granular evidence than typical state-level analyses, revealing that the cannabis-opioid substitution effect may have limits.","specificNumbers":"2,048 county-quarter observations; 2013-2018 prescribing data; 2011-2018 inpatient data; 30-day fills decreased significantly (P<0.01); inpatient visits decreased (P=0.03); total MME and ED visits not significant","methodology":"Observational quasi-experimental study using county-level Colorado data (2011-2018) with a differences-in-differences framework. Combined Prescription Drug Monitoring Program data, Colorado Department of Revenue licensing data, and Colorado Hospital Association records across 2,048 county-quarter observations.","limitations":"Colorado-specific findings may not generalize to other states. County-level analysis may miss within-county variation. Cannot determine whether individuals actually used cannabis instead of opioids. Time period may not capture longer-term effects."},{"rthcId":"RTHC-04441","title":"Effects of Prenatal Cannabinoids Exposure upon Placenta and Development of Respiratory Neural Circuits.","authors":"Cáceres, Daniela; Ochoa, Martín; González-Ortiz, Marcelo; Bravo, Karina; Eugenín, Jaime","year":2023,"journal":"Advances in experimental medicine and biology, 1428, 199-232","doi":"10.1007/978-3-031-32554-0_9","pmid":"37466775","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04442","title":"Medicinal cannabis for psychiatry-related conditions: an overview of current Australian prescribing.","authors":"Cairns, Elizabeth A; Benson, Melissa J; Bedoya-Pérez, Miguel A; Macphail, Sara L; Mohan, Adith; Cohen, Rhys; Sachdev, Perminder S; McGregor, Iain S","year":2023,"journal":"Frontiers in pharmacology, 14, 1142680","doi":"10.3389/fphar.2023.1142680","pmid":"37346297","tags":["medical-cannabis","mental-health","anxiety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of approximately 300,000 Special Access Scheme B approvals for medical cannabis in Australia (2016-2022), 33.9% were for psychiatric conditions. Anxiety disorders dominated (66.7% of psychiatry-related prescribing), followed by sleep-wake disorders (18.2%), trauma/stressor-related disorders (5.8%), and neurodevelopmental disorders (4.4%). CBD-dominant products comprised 20% of prescribing, particularly for autism spectrum disorder. Dramatic increases in ADHD prescribing were identified.","whyItMatters":"Australia has one of the largest legal medical cannabis programs globally. The dominance of psychiatric prescribing for conditions with limited evidence (anxiety, ADHD, depression) highlights a gap between clinical practice and evidence base.","specificNumbers":"~300,000 SAS-B approvals total; 33.9% for psychiatric conditions; 66.7% of psychiatry prescribing for anxiety; 18.2% sleep-wake; 5.8% trauma/stressor; 4.4% neurodevelopmental; 53% oil products; 31.2% flower; 46.2% of patients aged 25-39","methodology":"Analysis of Therapeutic Goods Administration Special Access Scheme B application data from November 2016 through September 2022. Conditions categorized according to DSM-5-TR criteria. Prescribing trends analyzed via polynomial regression.","limitations":"SAS-B approval data does not capture actual patient outcomes or whether treatment was effective. Cannot determine if patients also used illicit cannabis. Prescribing trends may reflect practitioner marketing rather than evidence-based practice."},{"rthcId":"RTHC-04443","title":"Substance Use Screening, Brief Intervention, and Referral to Treatment in Pediatric Primary Care, School-Based Health Clinics, and Mental Health Clinics.","authors":"Calihan, Jessica B; Levy, Sharon","year":2023,"journal":"The Psychiatric clinics of North America, 46(4), 749-760","doi":"10.1016/j.psc.2023.03.001","pmid":"37879836","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04444","title":"Substance Use Screening, Brief Intervention, and Referral to Treatment in Pediatric Primary Care, School-Based Health Clinics, and Mental Health Clinics.","authors":"Calihan, Jessica B; Levy, Sharon","year":2023,"journal":"Child and adolescent psychiatric clinics of North America, 32(1), 115-126","doi":"10.1016/j.chc.2022.08.002","pmid":"36410898","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04445","title":"Scientific facts improve cannabis perception and public opinion: results from Sinaloa, México.","authors":"Camberos-Barraza, Josué; Osuna-Ramos, Juan F; Rábago-Monzón, Ángel R; Quiñonez-Angulo, Luis F; González-Peña, Héctor R; Pérez-Ramos, Alan A; Camacho-Zamora, Alejandro; López-Lazcano, Héctor; Valdez-Flores, Marco A; Angulo-Rojo, Carla E; Guadrón-Llanos, Alma M; Picos-Cárdenas, Verónica J; Norzagaray-Valenzuela, Claudia D; De la Herrán-Arita, Alberto K","year":2023,"journal":"Scientific reports, 13(1), 17318","doi":"10.1038/s41598-023-44185-5","pmid":"37828116","tags":["legalization"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"A convenience sample of 3,162 individuals from Sinaloa responded to a cannabis attitudes questionnaire, received a briefing based on international scientific evidence documents, and immediately re-took the questionnaire. The intervention significantly shifted attitudes toward more positive or neutral views of cannabis, with education level and age playing prominent roles in the effectiveness.","whyItMatters":"Sinaloa is historically associated with cannabis cultivation and drug trade, making it a uniquely informative setting for studying how evidence-based information can counter deeply entrenched stigma and misinformation.","specificNumbers":"3,162 participants from Sinaloa; attitudes shifted significantly toward positive/neutral after intervention; education and age were key moderators","methodology":"Pre-post intervention study with 3,162 participants from Sinaloa, Mexico. Intervention consisted of an informative briefing based on the International Centre for Science in Drug Policy documents. Attitudes assessed via questionnaire before and immediately after intervention.","limitations":"Convenience sample limits generalizability. Immediate post-intervention assessment may capture temporary attitude shifts that do not persist. No control group. Social desirability may have influenced responses after hearing from researchers."},{"rthcId":"RTHC-04446","title":"Cannabinoids and the Gastrointestinal Tract.","authors":"Camilleri, Michael; Zheng, Ting","year":2023,"journal":"Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 21(13), 3217-3229","doi":"10.1016/j.cgh.2023.07.031","pmid":"37678488","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04447","title":"Cannabis: Drug of Abuse and Therapeutic Agent, Two Sides of the Same Coin.","authors":"Canseco-Alba, Ana; Rodríguez-Manzo, Gabriela","year":2023,"journal":"Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion, 75(3), 105-128","doi":"10.24875/RIC.23000112","pmid":"37441766","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04448","title":"The miRNA-mRNA regulatory networks of the response to NaHCO3 stress in industrial hemp (Cannabis sativa L.).","authors":"Cao, Kun; Sun, Yufeng; Zhang, Xiaoyan; Zhao, Yue; Bian, Jing; Zhu, Hao; Wang, Pan; Gao, Baochang; Sun, Xiaoli; Hu, Ming; Guo, Yongxia; Wang, Xiaonan","year":2023,"journal":"BMC plant biology, 23(1), 509","doi":"10.1186/s12870-023-04463-w","pmid":"37875794","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04449","title":"Cannabinoids in Periodontology: Where Are We Now?","authors":"Carmona Rendón, Yésica; Garzón, Hernán Santiago; Bueno-Silva, Bruno; Arce, Roger M; Suárez, Lina Janeth","year":2023,"journal":"Antibiotics (Basel, Switzerland), 12(12)","doi":"10.3390/antibiotics12121687","pmid":"38136721","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04450","title":"Workplace and non-workplace cannabis use and the risk of workplace injury: Findings from a longitudinal study of Canadian workers.","authors":"Carnide, Nancy; Landsman, Victoria; Lee, Hyunmi; Frone, Michael R; Furlan, Andrea D; Smith, Peter M","year":2023,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 114(6), 947-955","doi":"10.17269/s41997-023-00795-0","pmid":"37523062","tags":["workplace","driving"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 2,745 Canadian workers followed from 2018-2020, workplace cannabis use (before or at work) was associated with a nearly two-fold increased risk of workplace injury (RR 1.97, 95% CI 1.32-2.93). Non-workplace cannabis use showed no significant difference in injury risk compared to non-users (RR 1.09, 95% CI 0.83-1.44). Findings were consistent for both safety-sensitive and non-safety-sensitive jobs.","whyItMatters":"This study provides crucial nuance to the cannabis-workplace safety debate by separating where cannabis is used. The finding that off-duty use does not increase injury risk has direct implications for workplace drug testing policies.","specificNumbers":"2,745 workers; RR 1.97 (95% CI 1.32-2.93) for workplace use; RR 1.09 (95% CI 0.83-1.44) for non-workplace use; similar findings in safety-sensitive and non-safety-sensitive work","methodology":"Longitudinal study of Canadian workers with at least two adjacent years of survey data (2018-2020, n=2,745). Exposure was classified as no use, non-workplace use, or workplace use. Workplace injury was the primary outcome, with models adjusted for personal and work variables.","limitations":"Self-reported cannabis use and injury data. Cannot determine acute impairment at the time of injury. Relatively short follow-up period (2018-2020). Canadian workers may not represent other countries' workforces."},{"rthcId":"RTHC-04451","title":"Impact of tobacco, alcohol, and marijuana on genome-wide DNA methylation and its relationship with hypertension.","authors":"Carreras-Gallo, Natàlia; Dwaraka, Varun B; Cáceres, Alejandro; Smith, Ryan; Mendez, Tavis L; Went, Hannah; Gonzalez, Juan R","year":2023,"journal":"Epigenetics, 18(1), 2214392","doi":"10.1080/15592294.2023.2214392","pmid":"37216580","tags":["genetics","cardiovascular"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Three epigenome-wide association studies in the same cohort found 2,569 CpG sites differentially methylated by alcohol and 528 by tobacco. Marijuana showed no significant associations after multiple comparison correction. Sixty-one genes overlapped between alcohol and tobacco, enriched in nervous and cardiovascular system processes. Sixty-six CpG sites mediated alcohol's effect on hypertension, with the top site (SLC7A11) mediating 70.5% of the effect.","whyItMatters":"This is one of the first studies to compare epigenetic effects of all three substances in the same cohort, providing an important null result for marijuana while revealing that alcohol may drive hypertension largely through DNA methylation changes.","specificNumbers":"3,424 participants; 2,569 CpG sites for alcohol; 528 for tobacco; 0 significant for marijuana; 61 overlapping genes; 66 CpG sites mediated alcohol-hypertension link; SLC7A11 mediated 70.5% of alcohol's hypertension effect (P=0.006)","methodology":"Epigenome-wide association studies using the Infinium EPIC BeadChip in whole blood from 3,424 participants. Assessed effects of tobacco, alcohol, and marijuana on DNA methylation, followed by mediation analysis for hypertension.","limitations":"Cross-sectional design cannot establish temporal relationships. Marijuana use may have been less prevalent or at lower levels than alcohol/tobacco in this cohort. Blood-based methylation may not reflect tissue-specific effects. Multiple comparison correction may have been overly conservative for marijuana given lower statistical power."},{"rthcId":"RTHC-04452","title":"CBD enhances the cognitive score of adolescent rats prenatally exposed to THC and fine-tunes relevant effectors of hippocampal plasticity.","authors":"Castelli, Valentina; Lavanco, Gianluca; D'Amico, Cesare; Feo, Salvatore; Tringali, Giuseppe; Kuchar, Martin; Cannizzaro, Carla; Brancato, Anna","year":2023,"journal":"Frontiers in pharmacology, 14, 1237485","doi":"10.3389/fphar.2023.1237485","pmid":"37583903","tags":["cbd","pregnancy","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal THC exposure (2 mg/kg, gestational days 5-20) impaired spatial and configural memory and disrupted hippocampal plasticity markers in adolescent rats. CBD administration (40 mg/kg) before cognitive tasks mitigated impairments in both reward-motivated and aversion-driven memory tests and normalized NMDA receptor subunits, PSD95, Homer 1, and CB1R-related signaling in the hippocampus.","whyItMatters":"If prenatal THC exposure causes cognitive harm, finding that CBD can rescue those deficits during the adolescent developmental window offers a potential therapeutic approach, though the study also underscores the importance of preventing prenatal exposure.","specificNumbers":"THC dose: 2 mg/kg (gestational days 5-20); CBD dose: 40 mg/kg; CBD restored NR1, NR2A NMDA receptor subunits, mGluR5, PSD95, Homer 1, CB1R, and HINT1 mRNA levels","methodology":"Wistar rats prenatally exposed to THC (2 mg/kg subcutaneously, gestational days 5-20) or vehicle were tested during adolescence using the Can test (reinforcement-motivated) and Barnes maze (aversion-driven). CBD (40 mg/kg i.p.) was administered before testing. Hippocampal markers of excitatory plasticity and endocannabinoid signaling were assessed.","limitations":"Animal model with specific doses that may not translate to humans. CBD was given acutely before testing rather than as a chronic treatment. Single THC dose during gestation may not reflect variable human exposure patterns."},{"rthcId":"RTHC-04453","title":"Legislation has Changed But Issues Remain: Provider Perceptions of Caring for People Who Use Cannabis During Pregnancy in Safety Net Health Settings, a Qualitative Pilot Study.","authors":"Ceasar, Rachel Carmen; Gould, Erin; Stal, Julia; Laughter, Jen; Tran, Michelle; Wang, Shirlene D; Granacki, Jordan; Ziltzer, Ryan S; Santos, Jasmeen Joy","year":2023,"journal":"Women's health reports (New Rochelle, N.Y.), 4(1), 400-408","doi":"10.1089/whr.2023.0057","pmid":"37529758","tags":["pregnancy","medical-cannabis","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Interviews with 10 maternal health providers revealed three patterns: relying on self-education due to lack of formal training, taking case-by-case approaches rather than following standardized protocols, and actively avoiding cannabis discussions to maintain patient alliances. Providers recognized that reluctance to counsel overlooks the lack of resources and healthcare alternatives available to low-income patients.","whyItMatters":"When providers avoid cannabis discussions to preserve relationships, patients in safety-net settings lose access to one of their few sources of medical guidance, potentially reinforcing health disparities.","specificNumbers":"10 providers interviewed (2 midwives, 6 OB/GYNs, 2 residents); all in Southern California safety-net settings; interviews conducted March-April 2022","methodology":"Qualitative constructivist grounded theory study with semi-structured remote interviews of 10 providers (2 midwives, 6 OB/GYN physicians, 2 residents) in Southern California safety-net settings, conducted March-April 2022.","limitations":"Small sample of 10 providers from one region. Safety-net setting focus may not reflect private practice perspectives. Self-selected participants may represent those more willing to discuss cannabis."},{"rthcId":"RTHC-04454","title":"Perceptions of Safety of Daily Cannabis vs Tobacco Smoking and Secondhand Smoke Exposure, 2017-2021.","authors":"Chambers, Julia; Keyhani, Salomeh; Ling, Pamela M; Hoggatt, Katherine J; Hasin, Deborah; Nguyen, Nhung; Woods, Anne; Ryder, Annie; Cohen, Beth E","year":2023,"journal":"JAMA network open, 6(8), e2328691","doi":"10.1001/jamanetworkopen.2023.28691","pmid":"37566411","tags":["harm-reduction","respiratory"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Among 5,035 US adults surveyed in 2017, 2020, and 2021, the perception that daily cannabis smoking is safer than tobacco increased from 36.7% to 44.3% (P<0.001). Similar trends emerged for secondhand smoke (35.1% to 40.2%, P<0.001). Participants rated cannabis secondhand smoke as safe for adults (12.6% vs 2.4% for tobacco), children (4.8% vs 1.8%), and pregnant women (5.3% vs 1.4%). Younger and unmarried individuals were more likely to shift toward safer views of cannabis.","whyItMatters":"Published in JAMA Network Open, this study documents a growing divergence between public perception and scientific evidence. As more Americans view cannabis smoke as safe, they may be underestimating respiratory and other risks.","specificNumbers":"5,035 participants; daily cannabis safer: 36.7% (2017) to 44.3% (2021), P<0.001; secondhand safer: 35.1% to 40.2%, P<0.001; cannabis secondhand safe for adults: 12.6% vs tobacco 2.4%; ages 18-29 aOR 1.4 (95% CI 1.1-1.8) for shifting toward safer cannabis views","methodology":"Longitudinal survey using Ipsos KnowledgePanel, a nationally representative US panel. Same 5,035 participants completed web-based surveys in 2017, 2020, and 2021 comparing cannabis and tobacco safety perceptions. Published in JAMA Network Open.","limitations":"Survey measures perceptions, not actual behavior or exposure. Online panel may not capture all demographics. \"Safer\" is relative and does not quantify absolute risk. Does not distinguish between occasional and daily use perceptions."},{"rthcId":"RTHC-04455","title":"Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases.","authors":"Chen, Chu","year":2023,"journal":"Pharmacology & therapeutics, 244, 108394","doi":"10.1016/j.pharmthera.2023.108394","pmid":"36966972","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04456","title":"Genetic support of a causal relationship between cannabis use and educational attainment: a two-sample Mendelian randomization study of European ancestry.","authors":"Chen, Dongze; Wang, Xinpei; Huang, Tao; Jia, Jinzhu","year":2023,"journal":"Addiction (Abingdon, England), 118(4), 698-710","doi":"10.1111/add.16090","pmid":"36465060","tags":["genetics","addiction","cognition"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Bidirectional Mendelian randomization found genetic liability to cannabis use disorder was associated with 1.2 fewer months of education (P=0.0008). Lifetime cannabis use showed no significant effect on education. In the reverse direction, higher educational attainment was associated with 61% lower CUD risk (OR 0.39, P=1.69x10^-10) but 35% higher lifetime cannabis use (OR 1.35, P=0.003). The CUD-education relationship may be partially explained by shared ADHD risk factors.","whyItMatters":"This study uses genetic instruments to approximate causal inference, suggesting the relationship between cannabis and education is more nuanced than observational studies indicate. Problematic use may impair education, while education may increase experimental use but protect against problematic use.","specificNumbers":"Sample sizes 55,374-632,802; CUD reduced education by 1.2 months (P=0.0008); lifetime cannabis use: no effect on education (P=0.60); education reduced CUD: OR 0.39 (P=1.69x10^-10); education increased lifetime use: OR 1.35 (P=0.003)","methodology":"Bidirectional two-sample Mendelian randomization using genome-wide association study summary statistics from European ancestry samples (55,374 to 632,802 participants). Primary method was inverse-variance weighted MR with sensitivity analyses. Multivariable MR adjusted for intelligence, smoking initiation, and ADHD.","limitations":"Limited to European ancestry populations. Mendelian randomization assumptions (no pleiotropy, no direct instrument effects) may not fully hold. Shared ADHD risk factors complicate interpretation. Cannot specify mechanisms by which CUD affects education."},{"rthcId":"RTHC-04457","title":"Assessing Cannabidiol as a Therapeutic Agent for Preventing and Alleviating Alzheimer's Disease Neurodegeneration.","authors":"Chen, Long; Sun, Yuan; Li, Jinran; Liu, Sai; Ding, Hancheng; Wang, Guangji; Li, Xinuo","year":2023,"journal":"Cells, 12(23)","doi":"10.3390/cells12232672","pmid":"38067101","tags":["cbd","neuroscience","seniors"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD demonstrated protective effects against amyloid-beta toxicity both in cell cultures and in mice, ameliorating cognitive impairment. RNA-seq analysis revealed CBD modulated microglial activity, promoted neurotrophic factor release, and regulated inflammatory gene expression. The findings support CBD as a potential neuroprotective agent targeting neuroinflammation in Alzheimer's disease.","whyItMatters":"With small-molecule drugs targeting amyloid-beta proving largely ineffective in Alzheimer's, alternative approaches targeting neuroinflammation are needed. CBD's multi-target anti-inflammatory mechanism offers a different therapeutic angle.","specificNumbers":"Amyloid-beta 1-42 used for model; CBD mitigated cognitive deficits in vivo; RNA-seq identified inflammatory gene regulation and neurotrophic factor pathways","methodology":"Combined in vitro and in vivo study using amyloid-beta 1-42 for model establishment. CBD treatment efficacy assessed through behavioral cognitive testing in mice and RNA-seq analysis to identify molecular mechanisms.","limitations":"Mouse model of Alzheimer's may not recapitulate human disease complexity. CBD doses and routes of administration in rodents may not translate to human dosing. Amyloid-beta injection model is acute rather than reflecting chronic disease progression."},{"rthcId":"RTHC-04458","title":"PM2.5 exposure to marijuana smoke on golf courses and other public outdoor locations: A pilot observational study.","authors":"Cheng, Kai-Chung; Huang, Gan; Hildemann, Lynn M","year":2023,"journal":"The Science of the total environment, 896, 165236","doi":"10.1016/j.scitotenv.2023.165236","pmid":"37392887","tags":["harm-reduction","respiratory"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Across 24 visits to 10 golf courses, over 20% of visits encountered marijuana smoke, with peak PM2.5 exposures reaching 149 micrograms per cubic meter. Average outdoor exposures near public smoking/vaping were more than 3 times higher than those near enclosed sources. In-car secondhand smoke leakage produced higher outdoor exposure than building-based indoor emissions.","whyItMatters":"As cannabis legalization expands and outdoor use increases, understanding secondhand exposure levels in public spaces helps inform policies about where cannabis smoking should be permitted.","specificNumbers":"24 visits to 10 golf courses; >20% of visits encountered marijuana smoke; peak PM2.5 up to 149 ug/m3; outdoor smoking/vaping exposure >3x higher than near-car or near-building emissions; 23 total exposure events documented","methodology":"Pilot observational study measuring PM2.5 exposure from marijuana smoke at golf courses (24 visits to 10 courses over 6 months) and other outdoor locations (public parks, near parked cars, near residential garages). Total of 23 marijuana exposure events documented.","limitations":"Pilot study with small number of measurement events. PM2.5 levels alone do not identify specific harmful compounds in marijuana smoke. Golf courses may not be representative of all outdoor exposure scenarios. Cannot determine health effects from measured exposure levels."},{"rthcId":"RTHC-04459","title":"The relationship between cannabis use, schizophrenia, and bipolar disorder: a genetically informed study.","authors":"Cheng, Weiqiu; Parker, Nadine; Karadag, Naz; Koch, Elise; Hindley, Guy; Icick, Romain; Shadrin, Alexey; O'Connell, Kevin S; Bjella, Thomas; Bahrami, Shahram; Rahman, Zillur; Tesfaye, Markos; Jaholkowski, Piotr; Rødevand, Linn; Holen, Børge; Lagerberg, Trine Vik; Steen, Nils Eiel; Djurovic, Srdjan; Dale, Anders M; Frei, Oleksandr; Smeland, Olav B; Andreassen, Ole A","year":2023,"journal":"The lancet. Psychiatry, 10(6), 441-451","doi":"10.1016/S2215-0366(23)00143-8","pmid":"37208114","tags":["psychosis","genetics","mental-health"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Genome-wide genetic correlations between psychotic disorders and cannabis phenotypes ranged from 0.22-0.35. Causal analysis showed psychotic disorders had a causal effect on cannabis phenotypes, and lifetime cannabis use had a causal effect on bipolar disorder. Polygenic scores for cannabis predicted psychotic disorders independently. Shared loci implicated neuronal cells and drug-gene targets for nicotine, alcohol, and duloxetine.","whyItMatters":"Published in Lancet Psychiatry, this study provides the most comprehensive genetic evidence to date that the cannabis-psychosis relationship involves shared biological vulnerability, not just one causing the other.","specificNumbers":"Genetic correlations 0.22-0.35; 3-27 shared loci per phenotype pair; 2,181 participants in polygenic score analyses (400 bipolar, 697 schizophrenia, 1,044 controls); 48.6% female; mean age 33.1 years","methodology":"Genome-wide association summary statistics from European ancestry (Psychiatric Genomics Consortium, UK Biobank, International Cannabis Consortium). Included heritability estimation, genetic correlations, shared loci identification, causal analyses, and polygenic risk score analyses using the Norwegian Thematically Organized Psychosis cohort (n=2,181).","limitations":"Limited to European ancestry populations. Mendelian randomization assumptions may not fully hold. Cannot identify specific causal mechanisms. Shared GWAS loci do not necessarily mean shared functional pathways."},{"rthcId":"RTHC-04460","title":"Identification of histone acetyltransferase genes responsible for cannabinoid synthesis in hemp.","authors":"Cheng, Yufei; Ning, Kang; Chen, Yongzhong; Hou, Cong; Yu, Haibin; Yu, Huatao; Chen, Shilin; Guo, Xiaotong; Dong, Linlin","year":2023,"journal":"Chinese medicine, 18(1), 16","doi":"10.1186/s13020-023-00720-0","pmid":"36782242","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04461","title":"Influence of cannabis use on incidence of psychosis in people at clinical high risk.","authors":"Chester, Lucy A; Valmaggia, Lucia R; Kempton, Matthew J; Chesney, Edward; Oliver, Dominic; Hedges, Emily P; Klatsa, Elise; Stahl, Daniel; van der Gaag, Mark; de Haan, Lieuwe; Nelson, Barnaby; McGorry, Patrick; Amminger, G Paul; Riecher-Rössler, Anita; Studerus, Erich; Bressan, Rodrigo; Barrantes-Vidal, Neus; Krebs, Marie-Odile; Glenthøj, Birte; Nordentoft, Merete; Ruhrmann, Stephan; Sachs, Gabriele; McGuire, Philip","year":2023,"journal":"Psychiatry and clinical neurosciences, 77(9), 469-477","doi":"10.1111/pcn.13555","pmid":"37070555","tags":["psychosis","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 334 clinical high-risk individuals followed for 2 years, 16.2% developed psychosis. There was no significant association between any measure of cannabis use at baseline (current use, previous use, frequency, age of onset) and transition to psychosis, persistence of symptoms, or functional outcome. Of those who did not develop psychosis, 51.4% had persistent symptoms and 48.6% were in remission.","whyItMatters":"This finding contrasts with epidemiological data suggesting cannabis increases psychosis risk. Among those already identified as high-risk, cannabis may not add predictive value beyond existing clinical indicators.","specificNumbers":"334 clinical high risk participants; 67 healthy controls; 16.2% transitioned to psychosis; 51.4% of non-transitioners had persistent symptoms; 48.6% in remission; 2-year follow-up","methodology":"Prospective cohort study of 334 individuals at clinical high risk of psychosis and 67 healthy controls assessed at baseline using a modified Cannabis Experience Questionnaire, with 2-year follow-up. Transition assessed using CAARMS criteria; functioning assessed with GAF disability scale.","limitations":"Baseline-only cannabis assessment may miss changes in use during follow-up. Clinical high-risk sample may not generalize to general population. Relatively small sample for subgroup analyses. Cannabis use was self-reported."},{"rthcId":"RTHC-04462","title":"Cannabinoids for symptom management in children with cancer: A systematic review and meta-analysis.","authors":"Chhabra, Manik; Ben-Eltriki, Mohamed; Paul, Arun; Lê, Mê-Linh; Herbert, Anthony; Oberoi, Sapna; Bradford, Natalie; Bowers, Alison; Rassekh, S Rod; Kelly, Lauren E","year":2023,"journal":"Cancer, 129(22), 3656-3670","doi":"10.1002/cncr.34920","pmid":"37635461","tags":["cancer","medical-cannabis","cbd","youth"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 19 studies (including 7 RCTs), cannabinoids were most commonly used for chemotherapy-induced nausea and vomiting (58%). Common side effects included somnolence, dizziness, dry mouth, and withdrawal from adverse events. No serious cannabis-related adverse events were reported across all included studies. However, evidence for optimal dosing, safety, and efficacy remained insufficient.","whyItMatters":"Despite growing interest in medical cannabis for pediatric cancer, this comprehensive review reveals a significant gap between clinical practice and evidence. The absence of serious adverse events is reassuring but insufficient to guide dosing.","specificNumbers":"34,611 citations screened; 19 studies included; 1,927 participants; 7 RCTs; 58% studied chemotherapy-induced nausea/vomiting; 0 serious cannabis-related adverse events","methodology":"Systematic review registered with PROSPERO, searching MEDLINE, Embase, PsycINFO, and Cochrane Library. From 34,611 citations, 19 unique studies were included: 8 retrospective chart reviews, 7 RCTs, 2 open-label studies, and 2 case reports, totaling 1,927 pediatric cancer participants.","limitations":"Included studies were heterogeneous in design, cannabinoid type, and outcome measures. Most studies had small samples and high risk of bias. The 7 RCTs were older studies using primarily nabilone or dronabinol."},{"rthcId":"RTHC-04463","title":"Bridging the gap between genetic epidemiological research and prevention: A randomized control trial of a novel personalized feedback program for alcohol and cannabis use.","authors":"Choi, Maia; Driver, Morgan N; Balcke, Emily; Saunders, Trisha; Langberg, Joshua M; Dick, Danielle M","year":2023,"journal":"Drug and alcohol dependence, 249, 110818","doi":"10.1016/j.drugalcdep.2023.110818","pmid":"37327509","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Among 251 first-year college students randomized to four groups, those receiving the Personalized Feedback Program (PFP) showed significant reductions in cannabis use compared to other groups. The PFP targeted four genetically influenced risk domains: sensation seeking, impulsivity, extraversion, and neuroticism. No significant effects on alcohol use were found, though trends were in the expected direction.","whyItMatters":"This is one of the first studies to translate genetic epidemiological findings into a practical prevention tool, using personality-based risk pathways rather than genetic testing itself.","specificNumbers":"251 first-year students; 4 randomization groups; significant cannabis reduction in PFP group; high satisfaction ratings; 30-day and 3-month follow-ups","methodology":"Pilot RCT with 251 first-year college students randomized to control, PFP alone, computer-delivered brief motivational intervention (BMI), or combined PFP+BMI. Follow-up surveys at 30 days and 3 months post-intervention assessed alcohol and cannabis use.","limitations":"Pilot study with relatively small sample. Short follow-up period. Self-reported substance use. First-year students may not represent all college populations."},{"rthcId":"RTHC-04464","title":"The Endocannabinoid System as a Potential Therapeutic Target for HIV-1-Associated Neurocognitive Disorder.","authors":"Chu, Liuxi; Shu, Zheng; Gu, Xinpei; Wu, Yan; Yang, Jin; Deng, Huihua","year":2023,"journal":"Cannabis and cannabinoid research, 8(3), 445-463","doi":"10.1089/can.2022.0267","pmid":"36745405","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04465","title":"The current role of cannabis and cannabinoids in health: A comprehensive review of their therapeutic potential.","authors":"Coelho, Mariana Pinto; Duarte, Patrícia; Calado, Marta; Almeida, António J; Reis, Catarina Pinto; Gaspar, M Manuela","year":2023,"journal":"Life sciences, 329, 121838","doi":"10.1016/j.lfs.2023.121838","pmid":"37290668","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04466","title":"Severe outcomes following pediatric cannabis intoxication: a prospective cohort study of an international toxicology surveillance registry.","authors":"Cohen, Neta; Mathew, Mathew; Brent, Jeffrey; Wax, Paul; Davis, Adrienne L; Obilom, Cherie; Burns, Michele M; Canning, Joshua; Baumgartner, Kevin; Koons, Andrew L; Wiegand, Timothy J; Judge, Bryan; Hoyte, Christopher; Chenoweth, James A; Froberg, Blake; Farrar, Henry; Carey, Jennifer L; Hendrickson, Robert G; Hodgman, Michael; Caravati, E Martin; Christian, Michael R; Wolk, Brian J; Seifert, Steven A; Bentur, Yedidia; Levine, Michael; Farrugia, Lynn A; Vearrier, David; Minns, Alicia B; Kennedy, Joseph M; Kirschner, Ron I; Aldy, Kim; Schuh, Suzanne; Campleman, Sharan; Li, Shao; Myran, Daniel T; Feng, Lisa; Freedman, Stephen B; Finkelstein, Yaron","year":2023,"journal":"Clinical toxicology (Philadelphia, Pa.), 61(8), 591-598","doi":"10.1080/15563650.2023.2238121","pmid":"37603042","tags":["youth","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 138 pediatric patients presenting with cannabis intoxication, 52 (38%) were admitted to ICU including one death. Polysubstance ingestion (aOR 16.3) and younger age (P=0.001) were strong independent predictors of severe outcome. All children 10 and younger ingested edibles. Among teens over 10, only polysubstance use predicted severe outcomes (aOR 37.1).","whyItMatters":"As cannabis legalization expands and edible products proliferate, understanding which pediatric exposures lead to severe outcomes can inform product safety regulations and anticipatory guidance for parents.","specificNumbers":"138 patients; 54% male; median age 14.0 years; 38% ICU admission; 1 death; polysubstance aOR 16.3 (95% CI 4.6-58.3); all children <=10 exposed to edibles; teen polysubstance aOR 37.1 (95% CI 6.2-221.2)","methodology":"Prospective cohort study from the Toxicology Investigators Consortium, collecting data on all pediatric patients (<18 years) presenting with cannabis intoxication from August 2017 to June 2020 across participating US emergency departments. Multivariable logistic regression identified predictors.","limitations":"Participating toxicology sites may see more severe cases, overestimating overall severity. Cannot determine population-level incidence rates. Small sample limits subgroup analysis precision. Wide confidence intervals for some estimates."},{"rthcId":"RTHC-04467","title":"Population and Neighborhood Correlates of Cannabis Dispensary Locations in Oklahoma.","authors":"Cohn, Amy M; Sedani, Ami; Niznik, Taylor; Alexander, Adam; Lowery, Bryce; McQuoid, Julia; Campbell, Janis","year":2023,"journal":"Cannabis (Albuquerque, N.M.), 6(1), 99-113","doi":"10.26828/cannabis/2023.01.008","pmid":"37287730","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analysis of 1,046 Oklahoma census tracts found dispensaries concentrated in areas with higher proportions of uninsured residents below the poverty level, more rental housing, and more schools and pharmacies. In interaction models, dispensaries were most prevalent in areas with both high uninsured rates and no pharmacies, suggesting cannabis retailers may capitalize on communities with limited healthcare access.","whyItMatters":"Oklahoma has one of the most permissive medical cannabis programs in the US. Understanding where dispensaries cluster reveals whether the industry serves communities equitably or exploits health access gaps.","specificNumbers":"1,046 census tracts; 42.35% of tracts with dispensaries were rural; higher percent uninsured, percent rental housing, and number of schools positively associated with dispensary count; number of hospitals negatively associated","methodology":"Cross-sectional analysis of cannabis dispensary locations across 1,046 Oklahoma census tracts. Compared demographic and neighborhood characteristics of tracts with and without dispensaries. Fully adjusted models and interaction models assessed associations with dispensary density.","limitations":"Cross-sectional data cannot determine whether dispensaries caused changes in healthcare utilization. Census tract-level analysis may miss within-tract variation. Oklahoma-specific findings may not generalize to other states. Market forces beyond healthcare access also drive dispensary locations."},{"rthcId":"RTHC-04468","title":"Seeing is believing: How cannabis marketing exposure is associated with cannabis use attitudes and behavior in a permissive medical cannabis policy environment.","authors":"Cohn, Amy M; Alexander, Adam C; Ehlke, Sarah J; Smith, Michael A; Lowery, Bryce; McQuoid, Julia; Kendzor, Darla E","year":2023,"journal":"The American journal on addictions, 32(4), 333-342","doi":"10.1111/ajad.13390","pmid":"36896798","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 5,428 Oklahoma adults, 74.5% reported past-month cannabis marketing exposure, with outdoor marketing most prevalent (61.1%). In adjusted models, marketing exposure was associated with current cannabis use, positive attitudes, lower harm perceptions, and greater interest in obtaining a medical cannabis license. These associations held even among non-cannabis users.","whyItMatters":"Oklahoma has one of the least restrictive cannabis marketing environments in the US. This study provides empirical evidence that such permissive marketing may shape attitudes and behaviors at a population level.","specificNumbers":"5,428 adults; 74.5% any marketing exposure; 61.1% outdoor; 46.5% social media; 46.1% Internet; 35.2% print; marketing exposure associated with more cannabis use, more positive attitudes, and lower harm perceptions","methodology":"Cross-sectional survey of 5,428 Oklahoma adults aged 18+. Assessed exposure to four types of cannabis marketing (outdoor, social media, print, Internet) and associations with attitudes, harm perceptions, license interest, and use behavior using adjusted regression models.","limitations":"Cross-sectional design cannot determine if marketing causes attitude change or if favorable attitudes lead to noticing more marketing. Self-reported exposure may not be accurate. Oklahoma-specific findings may not generalize."},{"rthcId":"RTHC-04469","title":"\"I still partly think this is bullshit\": A qualitative analysis of cannabinoid hyperemesis syndrome perceptions among people with chronic cannabis use and cyclic vomiting.","authors":"Collins, Alexandra B; Beaudoin, Francesca L; Metrik, Jane; Wightman, Rachel S","year":2023,"journal":"Drug and alcohol dependence, 246, 109853","doi":"10.1016/j.drugalcdep.2023.109853","pmid":"36996524","tags":["harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Twenty-four participants with chronic cannabis use and cyclic vomiting attributed their symptoms to food, alcohol, stress, and GI issues rather than cannabis. Many relied on at-home internet research to understand their condition. Clinical treatment focused on cannabis cessation, but patients felt this failed to acknowledge the difficulty of quitting and the therapeutic benefits they perceived from cannabis.","whyItMatters":"CHS diagnosis requires accepting that a substance many use for nausea relief is actually causing nausea. Understanding patient skepticism can help clinicians communicate more effectively and develop support strategies beyond simple cessation advice.","specificNumbers":"24 participants interviewed; recruited from Rhode Island ED prospective cohort; many attributed symptoms to food, alcohol, stress rather than cannabis","methodology":"Semi-structured interviews with 24 participants recruited from a prospective cohort of patients presenting to Rhode Island emergency departments with cyclic vomiting and chronic cannabis use. Thematic analysis using NVivo.","limitations":"Small qualitative sample from one state. Participants may not have had confirmed CHS (diagnosis was clinical). Self-selection may have favored those more willing to discuss cannabis use."},{"rthcId":"RTHC-04470","title":"Appeal rating and visual attention associated with youth-appealing cannabis packaging: An eye-tracking experiment.","authors":"Cooper, Michael; Shi, Yuyan","year":2023,"journal":"Drug and alcohol dependence, 253, 110992","doi":"10.1016/j.drugalcdep.2023.110992","pmid":"37879129","tags":["youth","legalization"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among 72 young adults, cannabis edible packages with cartoon characters, bubble fonts, berry flavors, or gummy bear shapes received higher appeal ratings than plain packages. Eye-tracking showed youth-appealing attributes received longer fixation durations while warning labels received less attention. Packages with multiple youth-appealing features showed the largest reduction in warning label fixation time.","whyItMatters":"If youth-appealing packaging both increases product appeal and reduces attention to safety warnings, current packaging regulations may be insufficient to protect young consumers.","specificNumbers":"72 young adult participants; 7 package images; cartoon characters, bubble font, berry flavor, gummy bear shape all increased appeal; youth-appealing attributes reduced warning label fixation time; multiple attributes produced largest warning label attention reduction","methodology":"Eye-tracking experiment with 72 young adults viewing seven randomly ordered cannabis edible package images with varying youth-appealing attributes. Appeal ratings (0-10 scale) and fixation durations on predefined areas of interest were measured. Multivariate linear regressions assessed associations.","limitations":"Laboratory setting with static images may not reflect real-world shopping behavior. Sample of 72 may not represent all young adults. Only seven package variations tested. Did not measure actual purchase intent or consumption."},{"rthcId":"RTHC-04471","title":"Drug use in pregnancy in Ireland's capital city: A decade of trends and outcomes.","authors":"Corbett, Gillian A; Carmody, Deirdre; Rochford, Marie; Cunningham, Orla; Lindow, Stephen W; O'Connell, Michael P","year":2023,"journal":"European journal of obstetrics, gynecology, and reproductive biology, 282, 24-30","doi":"10.1016/j.ejogrb.2022.12.021","pmid":"36621262","tags":["pregnancy"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 82,669 deliveries, 525 had drug use in pregnancy (1 in 160). Over the decade, overall drug use decreased (0.8% to 0.4%), but cannabis and cocaine use each increased nearly 4-fold (RR 3.7 and 3.8 respectively). The population showed 66.3% psychiatric history, 11.6% homelessness, 91% tobacco use, a maternal mortality rate of 380.9 per 100,000, and perinatal mortality of 15.6 per 1,000.","whyItMatters":"The shift from opioid-dominant to stimulant-and-cannabis patterns in pregnant populations mirrors broader drug use trends and requires adapted clinical services.","specificNumbers":"82,669 total deliveries; 525 with substance use (1 in 160); cannabis use RR 3.7 (95% CI 1.58-8.86); cocaine use RR 3.8 (95% CI 1.57-9.44); 17.9% preterm birth rate; 52% NICU admission; mean birth weight 2,832g; maternal mortality 380.9/100,000","methodology":"Retrospective observational cohort study at an Irish tertiary maternity unit analyzing all deliveries from 2010-2019 where opioid use disorder or substance use was identified. Data combined from electronic and hand-held patient records. Trends analyzed by year of delivery.","limitations":"Single-center study in Dublin. Self-reported drug use likely underestimates true prevalence. Cannot separate effects of cannabis from polysubstance use or socioeconomic factors. Small absolute numbers limit trend analysis precision."},{"rthcId":"RTHC-04472","title":"Evaluation of a Cannabis Harm Reduction Intervention for People With First-Episode Psychosis: Protocol for a Pilot Multicentric Randomized Trial.","authors":"Coronado-Montoya, Stephanie; Abdel-Baki, Amal; Côté, José; Crockford, David; Dubreucq, Simon; Fischer, Benedikt; Lachance-Touchette, Pamela; Lecomte, Tania; L'Heureux, Sophie; Ouellet-Plamondon, Clairélaine; Roy, Marc-André; Tatar, Ovidiu; Tibbo, Phillip; Villeneuve, Marie; Wittevrongel, Anne; Jutras-Aswad, Didier","year":2023,"journal":"JMIR research protocols, 12, e53094","doi":"10.2196/53094","pmid":"38109196","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04473","title":"Scientific Validation of Cannabidiol for Management of Dog and Cat Diseases.","authors":"Corsato Alvarenga, Isabella; Panickar, Kiran S; Hess, Hannah; McGrath, Stephanie","year":2023,"journal":"Annual review of animal biosciences, 11, 227-246","doi":"10.1146/annurev-animal-081122-070236","pmid":"36790884","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04474","title":"The function of the endocannabinoid system in the pancreatic islet and its implications on metabolic syndrome and diabetes.","authors":"Cortes-Justo, Edgardo; Garfias-Ramírez, Sergio H; Vilches-Flores, Alonso","year":2023,"journal":"Islets, 15(1), 1-11","doi":"10.1080/19382014.2022.2163826","pmid":"36598083","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04475","title":"Endocannabinoid signaling in glioma.","authors":"Costas-Insua, Carlos; Guzmán, Manuel","year":2023,"journal":"Glia, 71(1), 127-138","doi":"10.1002/glia.24173","pmid":"35322459","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04476","title":"Pilot trial of a telehealth-delivered behavioral economic intervention promoting cannabis-free activities among adults with cannabis use disorder.","authors":"Coughlin, Lara N; Bonar, Erin E; Wieringa, Joshua; Zhang, Lan; Rostker, Matthew J; Augustiniak, Alyssa N; Goodman, Grant J; Lin, Lewei Allison","year":2023,"journal":"Journal of psychiatric research, 163, 202-210","doi":"10.1016/j.jpsychires.2023.05.012","pmid":"37224772","tags":["addiction","quitting"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Of 20 adults with CUD who enrolled, 70% completed all intervention components. All participants reported satisfaction, and 85.7% said telehealth delivery made it easier to receive care. Cannabis use decreased 8.9% (Hedges' g=0.39), depression symptoms decreased (g=0.50), and anxiety decreased (g=0.29). Cannabis demand and proportionate cannabis-free reinforcement showed changes consistent with reduced use.","whyItMatters":"Fewer than 5% of people with CUD initiate treatment. A telehealth intervention that is highly acceptable and shows preliminary effectiveness could dramatically lower barriers to care.","specificNumbers":"20 enrolled; 70% (14/20) completed all components; 100% satisfied/very satisfied; 85.7% said telehealth helped; 8.9% reduction in total cannabis use (g=0.39); depression g=0.50; anxiety g=0.29","methodology":"Open-label pilot trial of a telehealth-delivered multicomponent behavioral economic intervention for non-treatment-engaged adults with CUD. Participants recruited from a health system completed behavioral economic assessments and measures of cannabis use and mental health at baseline and post-treatment.","limitations":"Open-label design with no control group. Very small sample (n=20). Short follow-up period. Cannot attribute changes to the intervention without a comparison group."},{"rthcId":"RTHC-04477","title":"Simultaneous Assessment of Serum Levels and Pharmacologic Effects of Cannabinoids on Endocannabinoids and N-Acylethanolamines by Liquid Chromatography-Tandem Mass Spectrometry.","authors":"Couttas, Timothy A; Boost, Carola; Pahlisch, Franziska; Sykorova, Eliska B; Leweke, Judith E; Koethe, Dagmar; Endepols, Heike; Rohleder, Cathrin; Leweke, F Markus","year":2023,"journal":"Cannabis and cannabinoid research, 8(4), 657-669","doi":"10.1089/can.2021.0181","pmid":"35580134","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04478","title":"An interrupted time series evaluation of the effect of cannabis legalization on intentional self-harm in two Canadian provinces: Ontario and Alberta.","authors":"Cusimano, Michael D; Carpino, Melissa; Walker, Madison; Saarela, Olli; Mann, Robert","year":2023,"journal":"Health promotion and chronic disease prevention in Canada : research, policy and practice, 43(9), 403-408","doi":"10.24095/hpcdp.43.9.02","pmid":"37707352","tags":["legalization","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using population-based data from January/April 2010 to February 2020, cannabis legalization and regulation in Canada was not significantly associated with changes in ED visits for intentional self-harm in Ontario (level=0.58, 95% CI -1.14 to 2.31) or Alberta (level=-0.06, 95% CI -2.25 to 2.12). Hospitalizations for self-harm also remained unchanged in both provinces.","whyItMatters":"Concerns about cannabis legalization increasing mental health crises, including self-harm, have been used to argue against legalization policies. This two-province analysis finds no evidence supporting that concern.","specificNumbers":"Ontario ED visits: level 0.58 (95% CI -1.14 to 2.31); Alberta ED visits: level -0.06 (95% CI -2.25 to 2.12); Ontario hospitalizations: level -0.14 (95% CI -0.48 to 0.20); Alberta hospitalizations: level -0.41 (95% CI -1.03 to 0.21); none significant","methodology":"Interrupted time series analysis of population-based rates of ED visits and hospitalizations for intentional self-harm (ICD-10 codes X60-X84, R45.8) per 100,000 in Ontario and Alberta from 2010-2020 using the National Ambulatory Care Reporting System and Discharge Abstract Database.","limitations":"Only two provinces analyzed (pre-2020 to avoid COVID confounding). Population-level data cannot identify individual-level effects. Relatively short post-legalization period (October 2018 to February 2020). ICD coding may miss some self-harm presentations."},{"rthcId":"RTHC-04479","title":"Monitoring adherence and abstinence of cannabis use disorder patients: Profile identification and relationship with long-term treatment outcomes.","authors":"Dacosta-Sánchez, Daniel; Fernández-Calderón, Fermín; Blanc-Molina, Andrea; Díaz-Batanero, Carmen; Lozano, Oscar M","year":2023,"journal":"Journal of substance use and addiction treatment, 148, 209019","doi":"10.1016/j.josat.2023.209019","pmid":"36933660","tags":["addiction","quitting"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Latent profile analysis of 2,055 CUD outpatients revealed three groups: moderate abstinence/moderate adherence (n=997), high abstinence/moderate adherence (n=613), and high abstinence/high adherence (n=445). The high abstinence/high adherence group had 80% relapse-free rates at two years, compared to 24.3% in the moderate/moderate group. Education level, employment status, and substance use patterns at treatment entry differed significantly across profiles.","whyItMatters":"Identifying which patients will struggle early in treatment could allow clinicians to intervene before dropout occurs, rather than waiting for treatment failure.","specificNumbers":"2,055 outpatients; 3 profiles identified; 80% relapse-free at 2 years in high adherence group; 24.3% relapse-free in moderate group; education chi2(8)=121.70, p<.001","methodology":"Retrospective observational study of 2,055 CUD outpatients beginning treatment at multiple sites. Latent profile analysis was conducted on appointment attendance ratio and percentage of negative cannabis tests. Two-year follow-up monitored relapse outcomes.","limitations":"Retrospective design. Profile membership was determined post-hoc, limiting prospective prediction. Treatment approaches across sites may have varied. Self-selection into treatment limits generalizability to untreated populations."},{"rthcId":"RTHC-04480","title":"Marijuana use and its correlates among school-going Jamaican adolescents: a finding from a national survey.","authors":"Dadras, Omid","year":2023,"journal":"Frontiers in psychiatry, 14, 1324869","doi":"10.3389/fpsyt.2023.1324869","pmid":"38250281","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among Jamaican adolescents aged 13-17, older age and male sex predicted higher marijuana use. Psychosocial factors including loneliness, frequent worry, suicidal ideation, physical attacks, and school absenteeism were all associated with higher use. Parental smoking increased odds while strong parental support decreased them. Amphetamine and tobacco use showed the strongest substance-related associations. Early sexual initiation (before age 14) correlated with higher marijuana use.","whyItMatters":"Jamaica has unique cultural attitudes toward cannabis, yet adolescent use patterns mirror those seen globally, suggesting universal risk factors that transcend cultural context.","specificNumbers":"Nearly 20% past-30-day prevalence; ages 13-17; grades 7-12; older age, male sex, loneliness, suicidal ideation, parental smoking, amphetamine use, tobacco use, early sexual initiation all significantly associated","methodology":"Cross-sectional analysis of the 2017 Jamaica Global School-Based Student Health Survey covering students in grades 7-12. Bivariate and multivariable logistic regression assessed associations between demographics, psychosocial factors, substance use, risk behaviors, and past-30-day marijuana use.","limitations":"Cross-sectional design cannot determine causation. Self-reported data subject to recall and social desirability bias. School-based survey misses out-of-school adolescents who may have different use patterns. Jamaica-specific findings may not generalize."},{"rthcId":"RTHC-04481","title":"The effect of medical cannabis in inflammatory bowel disease: analysis from the UK Medical Cannabis Registry.","authors":"Dalavaye, Nishaanth; Erridge, Simon; Nicholas, Martha; Pillai, Manaswini; Bapir, Lara; Holvey, Carl; Coomber, Ross; Rucker, James J; Hoare, Jonathan; Sodergren, Mikael H","year":2023,"journal":"Expert review of gastroenterology & hepatology, 17(1), 85-98","doi":"10.1080/17474124.2022.2161046","pmid":"36562418","tags":["medical-cannabis","cbd","inflammation"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among 76 patients (51 Crohn's, 25 ulcerative colitis), median SIBDQ scores improved at both 1 and 3 months. EQ-5D-5L index values, GAD-7 anxiety scores, and sleep quality also improved significantly at 3 months (all p<0.050). Sixteen patients (21%) reported adverse events, mostly mild to moderate. Prior cannabis consumers showed greater improvement than cannabis-naive individuals.","whyItMatters":"While clinical trials have not shown cannabis affects IBD inflammation directly, these real-world data suggest meaningful quality-of-life improvements for patients with refractory symptoms.","specificNumbers":"76 patients (51 Crohn's, 25 ulcerative colitis); significant improvement in SIBDQ, EQ-5D-5L, GAD-7, and SQS at 3 months (p<0.050); 21.05% adverse events, mostly mild to moderate","methodology":"Case series from the UK Medical Cannabis Registry analyzing IBD patients prescribed cannabis-based medicinal products. Primary outcomes included changes from baseline in SIBDQ, GAD-7, SQS, and EQ-5D-5L at 1 and 3 months.","limitations":"Uncontrolled case series with no placebo group. Small sample size. Short follow-up period. Registry data may reflect selection bias toward motivated patients. No objective inflammation biomarkers assessed."},{"rthcId":"RTHC-04482","title":"Is Cannabis Effective in the Treatment of Chronic Back Pain?","authors":"Damisa, Josiah; Petohazi, Alexandra; Jalil, Hassan; Richardson, Michelle","year":2023,"journal":"Cureus, 15(8), e43220","doi":"10.7759/cureus.43220","pmid":"37692601","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04483","title":"Effects of combined cannabidiol (CBD) and hops (Humulus lupulus) terpene extract treatment on RAW 264.7 macrophage viability and inflammatory markers.","authors":"Dammann, Inga; Keil, Claudia; Hardewig, Iris; Skrzydlewska, Elżbieta; Biernacki, Michał; Haase, Hajo","year":2023,"journal":"Natural products and bioprospecting, 13(1), 19","doi":"10.1007/s13659-023-00382-3","pmid":"37284961","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04484","title":"The effectiveness of mobile-based ecological momentary motivational enhancement therapy in reducing craving and severity of cannabis use disorder: Study protocol for a randomized controlled trial.","authors":"Darharaj, Mohammad; Roshanpajouh, Mohsen; Amini, Mahdi; Shrier, Lydia A; Habibi Asgarabad, Mojtaba","year":2023,"journal":"Internet interventions, 34, 100669","doi":"10.1016/j.invent.2023.100669","pmid":"37746638","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04485","title":"Non-thermal plasma improved callogenesis performance and elicited the production of cannabinoids by modifying DNA methylome, expression of WRKY1 and ERF1B transcription factors, and expression of genes that contributed to the biosynthesis of cannabinoids.","authors":"Darigh, Farzaneh; Iranbakhsh, Alireza; Oraghi Ardebili, Zahra; Ebadi, Mostafa","year":2023,"journal":"Protoplasma, 260(1), 159-170","doi":"10.1007/s00709-022-01769-8","pmid":"35503387","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04486","title":"Exploring the associations between serious psychological distress and the quantity or frequency of tobacco, alcohol, and cannabis use among pregnant women in the United States.","authors":"David, Ayomide T; Sharma, Vinita; Bittencourt, Lorna; Gurka, Kelly K; Perez-Carreño, Juan Guillermo; Lopez-Quintero, Catalina","year":2023,"journal":"Preventive medicine, 177, 107770","doi":"10.1016/j.ypmed.2023.107770","pmid":"37951544","tags":["pregnancy","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 3,373 pregnant women aged 18-44, approximately 6% experienced serious psychological distress in the past 30 days. Compared to those without SPD, pregnant women with SPD showed significantly higher rates of cigarette smoking (IRR=2.1), binge drinking days (IRR=5.1), and cannabis use days (IRR=2.9). All associations remained significant after adjusting for covariates.","whyItMatters":"The strong link between psychological distress and prenatal substance use suggests that treating maternal mental health could reduce substance exposure during pregnancy more effectively than substance-specific interventions alone.","specificNumbers":"3,373 pregnant women; 6% experienced SPD; cannabis use days IRR=2.9 (95% CI 1.3-6.5); cigarettes IRR=2.1 (95% CI 1.1-4.5); binge drinking days IRR=5.1 (95% CI 1.7-15.4)","methodology":"Descriptive and negative binomial regression analyses of the 2015-2019 National Survey on Drug Use and Health (NSDUH). Examined associations between serious psychological distress and quantity/frequency of tobacco, alcohol, and cannabis use among 3,373 pregnant women aged 18-44.","limitations":"Cross-sectional NSDUH data cannot establish causation. Self-reported substance use likely underestimates true use during pregnancy. SPD is a screening measure, not a clinical diagnosis. Cannot distinguish between types of psychological distress."},{"rthcId":"RTHC-04487","title":"Associations of cannabis use with motor vehicle crashes and traffic stops among older drivers: AAA LongROAD study.","authors":"Davis, Shelby; Betz, Marian E; Hill, Linda L; Eby, David W; Jones, Vanya C; Mielenz, Thelma J; Molnar, Lisa J; Strogatz, David; Clancy, Kate; Li, Guohua; DiGuiseppi, Carolyn G","year":2023,"journal":"Traffic injury prevention, 24(4), 307-314","doi":"10.1080/15389588.2023.2180736","pmid":"36939676","tags":["driving","seniors"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 2,095 active drivers aged 65-79, 186 (8.9%) used cannabis in the past year. After adjusting for demographics and mental health, cannabis use was associated with significantly more traffic stops (aPR=1.58, 95% CI 1.06-2.35, p=0.024) but the association with motor vehicle crashes did not reach significance (p=0.086). Most older cannabis users reported rarely driving immediately after use.","whyItMatters":"As cannabis legalization expands and the population ages, understanding how cannabis affects older drivers fills a critical safety gap, since most cannabis-driving research has focused on younger populations.","specificNumbers":"2,095 older drivers; 186 (8.9%) used cannabis; traffic stops aPR=1.58 (95% CI 1.06-2.35); MVC association p=0.086; multi-center study","methodology":"Cross-sectional analysis from the AAA LongROAD multi-center study of active drivers aged 65-79. Self-reported cannabis use, motor vehicle crashes, and traffic stops in the past 12 months were collected through participant interviews. Log-binomial regression adjusted for site, demographics, and mental health.","limitations":"Cross-sectional design. Self-reported cannabis use and crash data. Past-year cannabis use does not capture timing relative to driving. Relatively few cannabis users in the sample limits statistical power for crash analysis."},{"rthcId":"RTHC-04488","title":"Phytocannabinoids: Pharmacological effects, biomedical applications, and worldwide prospection.","authors":"de Brito Siqueira, Ana L G; Cremasco, Pedro V V; Bahú, Juliana O; Pioli da Silva, Aline; Melo de Andrade, Lucas R; González, Paula G A; Crivellin, Sara; Cárdenas Concha, Viktor O; Krambeck, Karolline; Lodi, Leandro; Severino, Patrícia; Souto, Eliana B","year":2023,"journal":"Journal of traditional and complementary medicine, 13(6), 575-587","doi":"10.1016/j.jtcme.2023.08.006","pmid":"38020546","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04489","title":"Pain Medications Used by Persons Living With Fibromyalgia: A Comparison Between the Profile of a Quebec Sample and Clinical Practice Guidelines.","authors":"De Clifford-Faugère, Gwenaelle; Nguena Nguefack, Hermine Lore; Godbout-Parent, Marimée; Diallo, Mamadou Aliou; Guénette, Line; Pagé, M Gabrielle; Choinière, Manon; Beaudoin, Sylvie; Boulanger, Aline; Pinard, Anne Marie; Lussier, David; De Grandpré, Philippe; Deslauriers, Simon; Lacasse, Anaïs","year":2023,"journal":"Canadian journal of pain = Revue canadienne de la douleur, 7(2), 2252037","doi":"10.1080/24740527.2023.2252037","pmid":"38025837","tags":["pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 63 fibromyalgia patients, medical cannabis was used by 34.9% and pharmaceutical cannabinoids by 17.5%. Despite guidelines recommending against opioids for fibromyalgia, 33% used them. NSAIDs, also not recommended due to lack of efficacy, were used by 54%. Recommended medications were underused: anticonvulsants (36.5%), SNRIs (55.6%), and tricyclic antidepressants (22.2%). Medication subclasses perceived as highest risk were the least used.","whyItMatters":"The gap between what guidelines recommend and what fibromyalgia patients actually use reveals a disconnect between clinical evidence and patient experience that drives people toward cannabis and other non-recommended options.","specificNumbers":"63 patients; 34.9% medical cannabis; 17.5% pharmaceutical cannabinoids; 33% opioids; 54% NSAIDs; 55.6% SNRIs; 36.5% anticonvulsants; 22.2% tricyclics; 23.8% tramadol","methodology":"Directive telephone interviews with 63 individuals self-reporting fibromyalgia in Quebec, Canada. Assessed all pain medications including prescribed, over-the-counter, and cannabis products. Compared use patterns to Canadian Fibromyalgia Clinical Practice Guidelines.","limitations":"Small sample of 63 self-reported fibromyalgia patients. Telephone interviews may introduce social desirability bias. Quebec-specific healthcare context may not generalize. No clinical verification of fibromyalgia diagnosis."},{"rthcId":"RTHC-04490","title":"Multinational Association of Supportive Care in Cancer (MASCC) guidelines: cannabis for psychological symptoms including insomnia, anxiety, and depression.","authors":"De Feo, Giulia; Case, Amy A; Crawford, Gregory B; Hui, David; To, Josephine; Sbrana, Andrea; Alderman, Bryony; Mukhopadhyay, Sandip; Bouleuc, Carole; Amano, Koji; Tanco, Kimberson; Garsed, Jessica; Davis, Mellar","year":2023,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 31(3), 176","doi":"10.1007/s00520-023-07628-3","pmid":"36809575","tags":["cancer","medical-cannabis","sleep","anxiety","depression"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"From 829 articles screened, 2 systematic reviews and 15 RCTs met criteria. No studies assessed cannabis efficacy on psychological symptoms as primary outcomes in cancer. Studies varied widely in interventions, controls, duration, and outcomes. Six of 15 RCTs suggested benefits: five for sleep and one for mood. The evidence was insufficient to recommend cannabis for anxiety, depression, or insomnia in cancer patients.","whyItMatters":"With 18% of cancer patients already using cannabis for symptom management, this guideline from a major supportive care organization provides important clarity: the evidence does not yet support this practice for psychological symptoms.","specificNumbers":"829 articles screened; 15 RCTs and 2 systematic reviews included; 4 studies on sleep, 5 on mood, 6 on both; 6/15 suggested benefits (5 for sleep, 1 for mood)","methodology":"Systematic review searching MEDLINE, CCTR, EMBASE, and PsychINFO up to November 2021. Inclusion criteria: randomized controlled trials and systematic reviews of cannabis versus placebo or active comparator in cancer patients with psychological symptom outcomes.","limitations":"No RCTs had psychological symptoms as primary outcomes, making all evidence secondary. Studies were heterogeneous in cannabis type, dose, and measurement tools. Search limited to November 2021."},{"rthcId":"RTHC-04491","title":"Factors associated with ever using cannabidiol in a cohort of younger pregnant people.","authors":"De Genna, Natacha M; Kennon-McGill, Stefanie; Goldschmidt, Lidush; Richardson, Gale A; Chang, Judy C","year":2023,"journal":"Neurotoxicology and teratology, 96, 107162","doi":"10.1016/j.ntt.2023.107162","pmid":"36717004","tags":["pregnancy","cbd"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Among 186 pregnant participants under age 22 (75% Black or Biracial), approximately one in five had ever used CBD products. Few reported CBD use during the current pregnancy specifically. Those who had tried CBD were more likely to report alcohol and other drug use prior to pregnancy, even after controlling for race. CBD is marketed to pregnant people for common conditions, but preclinical evidence links CBD exposure to embryotoxicity and developmental effects.","whyItMatters":"CBD products are widely marketed as natural and safe, including to pregnant people. This is one of the first studies to examine CBD use specifically (not just cannabis) in a pregnant population.","specificNumbers":"186 participants; 75% Black or Biracial; ~20% ever used CBD; prior alcohol and drug use predicted CBD use; under age 22","methodology":"Prospective cohort from the YoungMoms study of pregnant people under 22. Examined demographic, medical, and psychosocial correlates of CBD use using logistic regression controlling for race.","limitations":"Small cohort of 186 from one site. Young, predominantly Black/Biracial sample may not generalize. \"Ever used\" does not distinguish timing or frequency. Self-reported use may underestimate prevalence."},{"rthcId":"RTHC-04492","title":"Tetrahydrocannabinol in Pediatrics: Room for Improvement?","authors":"de Gier, Charlotte; Scharinger, Christian; Stark, Rosa H; Steurer, Philipp; Klier, Claudia M","year":2023,"journal":"Medical cannabis and cannabinoids, 6(1), 125-129","doi":"10.1159/000533607","pmid":"37900897","tags":["medical-cannabis","youth"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"The 32 pediatric patients who received THC had an average of 9.42 diagnoses and were treated with an average of 13.52 other drugs simultaneously. Brain cancer and genetic diseases were the most common diagnoses. Eleven of 32 patients (34%) died by the end of the study period, indicating predominantly palliative use. Significant gaps in documentation of indications, dosage, and treatment duration were identified.","whyItMatters":"This study reveals both the extreme caution applied to pediatric THC prescribing (only the sickest patients) and the paradox that even in a controlled medical setting, prescribing documentation remains inadequate.","specificNumbers":"32 patients; mean 9.42 diagnoses per patient; mean 13.52 concurrent medications; brain cancer and genetic diseases most common; 11/32 (34%) died during study period","methodology":"Retrospective data analysis of all THC prescriptions at the Department of Pediatrics and Adolescent Medicine, Medical University Vienna, from 2016-2018. Patient records reviewed for diagnoses, concurrent medications, and prescribing documentation.","limitations":"Single-center retrospective study. Very small sample of 32. Documentation gaps may reflect charting practices rather than actual prescribing quality. Austrian regulatory context may not generalize."},{"rthcId":"RTHC-04493","title":"Use of Marijuana to Promote Well-Being: Effects of Use and Prohibition in the Daily Lives of Brazilian Adults.","authors":"de Lima E Silva Surjus, Luciana Togni; Dainesi, Natália Cavalcante; de Souza, Felipe Granado","year":2023,"journal":"Substance abuse : research and treatment, 17, 11782218231162469","doi":"10.1177/11782218231162469","pmid":"37051015","tags":["legalization","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 2,637 respondents, using marijuana for fun was most common among self-identified males, trans/non-binary people, college graduates, and higher-income individuals. Indigenous peoples and youth were most likely to report trouble with police due to marijuana. Higher education and longer use predicted more harm reduction strategies. Women and higher-income individuals were less likely to report daily use. Living with family and less frequent use protected against negative effects of intoxication.","whyItMatters":"In a country where marijuana remains criminalized, the harms of prohibition fall disproportionately on marginalized populations, adding a social justice dimension to cannabis policy debates.","specificNumbers":"2,637 respondents; Indigenous peoples and youth most affected by policing; higher education associated with more harm reduction; women and higher income less likely to use daily; living with family protective","methodology":"Cross-sectional study using anonymous online questionnaire in Brazil with 2,637 respondents. Logistic regression analyzed predictors of well-being including use benefits, prohibition risks, and harm reduction strategies across socioeconomic characteristics.","limitations":"Online convenience sample likely skews toward educated, connected populations. Self-reported well-being is subjective. Cross-sectional design cannot establish causation. Brazilian context may not generalize."},{"rthcId":"RTHC-04494","title":"Toxicity of Synthetic Cannabinoids in K2/Spice: A Systematic Review.","authors":"de Oliveira, Mariana Campello; Vides, Mariana Capelo; Lassi, Dângela Layne Silva; Torales, Julio; Ventriglio, Antonio; Bombana, Henrique Silva; Leyton, Vilma; Périco, Cintia de Azevedo-Marques; Negrão, André Brooking; Malbergier, André; Castaldelli-Maia, João Maurício","year":2023,"journal":"Brain sciences, 13(7)","doi":"10.3390/brainsci13070990","pmid":"37508922","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 64 studies (10 original papers and 54 case studies), synthetic cannabinoid use was associated with severe toxicity including death (14 studies), with AB-CHMINACA and MDMB-CHMICA most commonly involved in fatalities. Tachycardia and seizures were the most common toxicity symptoms. Third-generation synthetic cannabinoids produced higher rates of neuropsychiatric symptoms compared to earlier generations. SCs showed higher potential than THC for triggering convulsions, consciousness decline, and hemodynamic instability.","whyItMatters":"Synthetic cannabinoids are often used by people seeking to avoid drug tests or who cannot access regulated cannabis. Understanding their dramatically higher toxicity profile is essential for harm reduction messaging.","specificNumbers":"64 studies included; 14 reported deaths; AB-CHMINACA and MDMB-CHMICA most lethal; tachycardia and seizures most common symptoms; third-generation SCs had highest neuropsychiatric symptom prevalence","methodology":"Systematic review searching PubMed, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. Included studies analyzing synthetic cannabinoid toxicity and dependence in humans.","limitations":"Heavy reliance on case reports and case studies (54/64). Publication bias toward severe outcomes. Difficulty identifying specific SC compounds in many cases. Polysubstance use common in reported cases."},{"rthcId":"RTHC-04495","title":"Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS.","authors":"De Simone, Uliana; Pignatti, Patrizia; Villani, Laura; Russo, Luciana Alessandra; Sargenti, Azzurra; Bonetti, Simone; Buscaglia, Eleonora; Coccini, Teresa","year":2023,"journal":"International journal of molecular sciences, 24(2)","doi":"10.3390/ijms24021421","pmid":"36674936","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04496","title":"Cannabidiol reveals a disruptive strategy for 21st century epilepsy drug discovery.","authors":"Del Pozo, Aaron; Barker-Haliski, Melissa","year":2023,"journal":"Experimental neurology, 360, 114288","doi":"10.1016/j.expneurol.2022.114288","pmid":"36471511","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04497","title":"Characterization of childhood trauma, hippocampal mediation and Cannabis use in a large dataset of psychosis and non-psychosis individuals.","authors":"Del Re, Elisabetta C; Yassin, Walid; Zeng, Victor; Keedy, Sarah; Alliey-Rodriguez, Ney; Ivleva, Elena; Hill, Scott; Rychagov, Nicole; McDowell, Jennifer E; Bishop, Jeffrey R; Mesholam-Gately, Raquelle; Merola, Giovanni; Lizano, Paulo; Gershon, Elliot; Pearlson, Godfrey; Sweeney, John A; Clementz, Brett; Tamminga, Carol; Keshavan, Matcheri","year":2023,"journal":"Schizophrenia research, 255, 102-109","doi":"10.1016/j.schres.2023.03.029","pmid":"36989667","tags":["psychosis","youth","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 1,185 participants (397 controls, 209 bipolar-I, 279 schizoaffective, 300 schizophrenia), cannabis use and childhood trauma interacted in survival analysis to predict earlier psychosis onset. At high levels, either factor alone was sufficient to affect onset age (ceiling effect). Hippocampal volume partially mediated the trauma-onset relationship specifically in cannabis users before psychosis onset. Cannabis use before onset was associated with higher schizophrenia polygenic risk scores and younger age at first cannabis use.","whyItMatters":"This study suggests cannabis and childhood trauma may represent different but converging pathways to psychosis, with the hippocampus as a shared biological mechanism. This has implications for early intervention targeting both risk factors.","specificNumbers":"1,185 participants across 5 US sites; 397 controls; 209 bipolar-I; 279 schizoaffective; 300 schizophrenia; hippocampal mediation significant in cannabis users; higher SZ-PGRS in pre-onset cannabis users","methodology":"Cross-sectional case-control study across 5 US metropolitan sites. Included neuroimaging, Childhood Trauma Questionnaire, self-reported cannabis use, clinical interviews, cognition testing, and schizophrenia polygenic risk score calculation. Survival analysis, mediation analysis, and polygenic score analyses conducted.","limitations":"Cross-sectional design limits causal conclusions. Retrospective self-reported cannabis use and trauma. Cannot fully separate effects of cannabis from confounding factors. Polygenic scores explain only a fraction of genetic risk."},{"rthcId":"RTHC-04498","title":"Prenatal Exposure to Cannabis and Risk of Major Structural Birth Defects: A Systematic Review and Meta-analysis.","authors":"Delker, Erin; Hayes, Shana; Kelly, Ann E; Jones, Kenneth L; Chambers, Christina; Bandoli, Gretchen","year":2023,"journal":"Obstetrics and gynecology, 142(2), 269-283","doi":"10.1097/AOG.0000000000005252","pmid":"37473409","tags":["pregnancy"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Across 23 studies spanning birth years 1968-2021, the pooled unadjusted odds ratio for any birth defect was 1.33 (95% CI 1.14-1.56), attenuating to 1.22 (95% CI 1.00-1.50) after adjustment. Most anatomic-group associations attenuated to non-significance after adjustment. Two specific defects retained significant adjusted associations: Ebstein anomaly (aOR 2.19, 95% CI 1.25-3.82) and gastroschisis (aOR 2.50, 95% CI 1.09-5.74), though both had limited supporting data.","whyItMatters":"This is the most comprehensive meta-analysis to date on cannabis and birth defects. The finding that most associations disappear after adjustment suggests confounding (tobacco, alcohol, socioeconomic factors) drives much of the apparent risk.","specificNumbers":"23 studies; birth years 1968-2021; pooled OR 1.33 (95% CI 1.14-1.56); pooled aOR 1.22 (95% CI 1.00-1.50); Ebstein anomaly aOR 2.19 (95% CI 1.25-3.82); gastroschisis aOR 2.50 (95% CI 1.09-5.74)","methodology":"Systematic review and meta-analysis searching Google Scholar, BIOSIS, PubMed/MEDLINE, EMBASE, CINAHL, and ClinicalTrials.gov. Screened with Abstrackr software. Included 23 observational studies examining birth defects with prenatal cannabis exposure. Meta-analyzed by anatomic group. Registered with PROSPERO.","limitations":"Most included studies used unadjusted estimates and scored low on risk-of-bias assessment. Studies were heterogeneous in design and cannabis exposure measurement. The two specific defects with persistent associations had very limited data (2 and 5 studies respectively)."},{"rthcId":"RTHC-04499","title":"Potent dual MAGL/FAAH inhibitor AKU-005 engages endocannabinoids to diminish meningeal nociception implicated in migraine pain.","authors":"Della Pietra, Adriana; Krivoshein, Georgii; Ivanov, Konstantin; Giniatullina, Raisa; Jyrkkänen, Henna-Kaisa; Leinonen, Ville; Lehtonen, Marko; van den Maagdenberg, Arn M J M; Savinainen, Juha; Giniatullin, Rashid","year":2023,"journal":"The journal of headache and pain, 24(1), 38","doi":"10.1186/s10194-023-01568-3","pmid":"37038131","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The brain's meninges naturally contain endocannabinoids (2-AG and AEA) that can quiet pain-signaling nerve fibers. AKU-005, which blocks the enzymes that break down both endocannabinoids, significantly reduced nerve excitation triggered by potassium chloride stimulation in rat and human tissue. The pain-relieving effect worked through CB1 receptors, not TRPV1 channels. Interestingly, 2-AG levels were much higher than AEA at baseline, suggesting 2-AG provides ongoing pain suppression while AEA kicks in on demand when nerves become active.","whyItMatters":"Current migraine treatments have significant limitations. This study provides early evidence that boosting the body's own endocannabinoid system — rather than using external cannabinoids — could offer a targeted approach to migraine pain at its source in the meninges.","specificNumbers":"- Basal 2-AG levels exceeded AEA levels in both rat and human meninges\n- KCl-induced depolarization doubled AEA levels\n- AKU-005 significantly decreased KCl-induced nerve fiber excitation\n- CB1 antagonist AM-251 reversed the anti-nociceptive effects of both AKU-005 and AEA\n- TRPV1 antagonist capsazepine did not reverse AEA's inhibitory action","methodology":"Researchers measured MAGL and FAAH enzyme activity and endocannabinoid levels in rat meninges (from P38-P40 Wistar rats) and human meninges (from elderly neurosurgery patients). They tested AKU-005's effects on nerve fiber excitability using paired KCl-induced spiking protocols, validating results with direct application of AEA or 2-AG. Receptor involvement was confirmed using CB1 antagonist AM-251 and TRPV1 antagonist capsazepine.","limitations":"This was an in vitro study using isolated tissue, not whole animals or humans. Human tissue came from elderly non-migraine patients undergoing neurosurgery, which may not represent typical migraine sufferers. The study demonstrates proof of concept but cannot confirm whether AKU-005 would be effective or safe as an oral migraine treatment in people."},{"rthcId":"RTHC-04500","title":"Characteristics of Stress Sensitivity in Heroin Use Disorder Patients during Their Opioid Agonist Treatment.","authors":"Della Rocca, Filippo; Maremmani, Angelo G I; Bacciardi, Silvia; Pacini, Matteo; Lamanna, Francesco; Tripodi, Beniamino; Miccoli, Mario; Maremmani, Icro","year":2023,"journal":"International journal of environmental research and public health, 20(5)","doi":"10.3390/ijerph20054566","pmid":"36901575","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers found that stress sensitivity (measured by the H/PTSD-Spectrum questionnaire) was positively correlated with altered mental status, legal problems, treatment load, and all psychopathology indexes. Patients with high stress sensitivity were more often female with low income, showed more severe mental status at treatment entry, greater difficulty with work adaptation, and more risky behaviors during treatment. Cannabis craving was assessed but stress sensitivity's core impact was on social and behavioral functioning rather than specific substance use patterns.","whyItMatters":"This study reframes heroin use disorder outcomes. Rather than measuring success by whether someone stops using drugs, the real long-term challenge may be an acquired inability to cope with everyday life stressors. This has implications for how treatment programs are designed and evaluated.","specificNumbers":"- Stress sensitivity negatively correlated with the \"best week in last five years\" well-being index\n- Patients with high stress sensitivity had more severe mental status at treatment entry\n- High-stress sensitivity group was predominantly female with low income\n- Multiple validated instruments used: H/PTSD-S, SCL-90, CRAV-HERO, D-SWS, CPSI, MC-Q","methodology":"Cross-sectional study of heroin use disorder patients undergoing opioid agonist treatment. Used multiple validated questionnaires to assess stress sensitivity, psychopathology, well-being, cocaine problems, and cannabis craving. Compared patients with and without problematic stress sensitivity levels.","limitations":"Cross-sectional design cannot establish causation between stress sensitivity and outcomes. Cannabis-related measures (MC-Q) were included but the study focused primarily on heroin treatment outcomes. The study population was already in treatment, which may not represent all people with heroin use disorder."},{"rthcId":"RTHC-04501","title":"Prescribing Stimulants for Children and Adolescents With Attention-Deficit/Hyperactivity Disorder and Co-occurring Cannabis Use: Considerations for Managing a Clinical Dilemma.","authors":"Dernbach, Matthew Robert; Gray, Kevin M; Borich, Abbey; Seery, Erin; Russo, Sarah Brice; Lewis, E Thomas; Gwynette, McLeod Frampton","year":2023,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 62(8), 842-846","doi":"10.1016/j.jaac.2022.11.014","pmid":"36773700","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This clinical commentary outlines three key considerations for prescribing stimulants to youth with co-occurring ADHD and cannabis use: (1) cannabis can confound ADHD assessment by mimicking or masking symptoms, (2) properly treating ADHD may actually reduce overall substance use risk, and (3) ongoing cannabis use raises concerns about stimulant misuse and diversion. The authors note that cannabis use is more prevalent among adolescents with ADHD than the general population, and changing legal landscapes have made this clinical scenario increasingly common.","whyItMatters":"With 11% of children diagnosed with ADHD and cannabis becoming more accessible, this clinical dilemma affects a large and growing patient population. The commentary highlights that withholding stimulant treatment may paradoxically increase substance use risk.","specificNumbers":"- 11% of children and adolescents have been diagnosed with ADHD\n- Cannabis use is more prevalent in adolescents with ADHD than the general population\n- Changing state-level legal status has increased access and social acceptability","methodology":"Clinical commentary and expert review published in the Journal of the American Academy of Child and Adolescent Psychiatry. Not an original research study.","limitations":"This is an expert commentary, not a systematic review or original research. It presents clinical considerations rather than new data. The specific risk-benefit calculations will vary by individual patient."},{"rthcId":"RTHC-04502","title":"In vitro characterization of the pyrazole-carrying synthetic cannabinoid receptor agonist 5F-3,5-AB-PFUPPYCA and its structural analogs.","authors":"Deventer, Marie H; Norman, Caitlyn; Reid, Robert; McKenzie, Craig; Nic Daéid, Niamh; Stove, Christophe P","year":2023,"journal":"Forensic science international, 343, 111565","doi":"10.1016/j.forsciint.2023.111565","pmid":"36640535","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers tested 5F-3,5-AB-PFUPPYCA and five structural analogs using live cell assays. Most compounds were essentially inactive at both CB1 and CB2 receptors. Only three showed limited CB1 activation. All compounds exhibited antagonistic behavior at both receptors, resembling cannabinoid antagonists more than agonists. The position of the tail structure mattered — 5,3 regioisomers were more active than 3,5 analogs. Despite circumventing China's generic SCRA ban, these compounds are unlikely to produce the typical synthetic cannabinoid high.","whyItMatters":"The synthetic cannabinoid market rapidly evolves in response to legislation. This study shows that not all new compounds are equally dangerous — some structural modifications that evade legal definitions also strip away pharmacological activity.","specificNumbers":"- 6 compounds tested (5F-3,5-AB-PFUPPYCA and 5 analogs)\n- Most compounds essentially inactive at CB1 and CB2\n- Only 3 of 6 showed limited CB1 activation potential\n- All compounds showed antagonistic behavior at both receptors\n- 5,3 regioisomers more active than 3,5 analogs","methodology":"In vitro characterization using live cell beta-arrestin 2 recruitment assays to measure CB1 and CB2 receptor activation. Tested six structurally related pyrazole-carrying SCRAs for agonist and antagonist activity.","limitations":"In vitro assays may not fully predict in vivo effects. Beta-arrestin recruitment is one signaling pathway; these compounds might activate other pathways not tested. The recreational drug market changes rapidly, and newer analogs could have different activity profiles."},{"rthcId":"RTHC-04503","title":"The impact of early factors on persistent negative symptoms in youth at clinical high risk for psychosis.","authors":"Devoe, Daniel J; Lui, Lu; Cannon, Tyrone D; Cadenhead, Kristin Suzanne; Cornblatt, Barbara A; Keshavan, Matcheri; McGlashan, Tom H; Perkins, Diana O; Seidman, Larry J; Stone, William S; Tsuang, Ming T; Woods, Scott W; Walker, Elaine F; Mathalon, Daniel H; Bearden, Carrie E; Addington, Jean","year":2023,"journal":"Frontiers in psychiatry, 14, 1125168","doi":"10.3389/fpsyt.2023.1125168","pmid":"37293402","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among 709 clinical high-risk youth, 67 (9.4%) had persistent negative symptoms. These individuals were more often male and had significantly worse premorbid adjustment across childhood, early adolescence, and late adolescence. Surprisingly, the group without persistent negative symptoms had more cannabis use and more life events (both desirable and undesirable). There were no differences between groups in trauma, bullying, or resource utilization. Poor premorbid functioning in late adolescence was the most prominent predictor of persistent negative symptoms.","whyItMatters":"Negative symptoms (social withdrawal, reduced motivation, flat affect) are among the most disabling aspects of psychotic disorders and are resistant to treatment. Identifying who develops them early could allow for targeted early intervention.","specificNumbers":"- 709 clinical high-risk participants from NAPLS 2\n- 67 (9.4%) had persistent negative symptoms vs 673 without\n- More males in the persistent negative symptoms group\n- Non-PNS group had more cannabis use\n- Poor late-adolescent premorbid functioning was the strongest predictor","methodology":"Participants from the North American Prodrome Longitudinal Study (NAPLS 2) were divided into persistent negative symptoms vs. non-persistent groups. K-means cluster analysis distinguished premorbid functioning patterns. Group comparisons used t-tests and chi-square analyses.","limitations":"Observational design cannot establish causation. The higher cannabis use in the non-PNS group could reflect greater social engagement rather than a protective effect. The study did not track whether high-risk participants later converted to full psychosis."},{"rthcId":"RTHC-04504","title":"Tobacco, alcohol, cannabis, and illicit drug use and their association with CD4/CD8 cell count ratio in people with controlled HIV: a cross-sectional study (ANRS CO3 AQUIVIH-NA-QuAliV).","authors":"Devos, Sophie; Bonnet, Fabrice; Hessamfar, Mojgan; Neau, Didier; Vareil, Marc-Olivier; Leleux, Olivier; Cazanave, Charles; Rouanes, Nicolas; Duffau, Pierre; Lazaro, Estibaliz; Dabis, François; Wittkop, Linda; Barger, Diana","year":2023,"journal":"BMC infectious diseases, 23(1), 16","doi":"10.1186/s12879-022-07963-6","pmid":"36624391","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In 660 virally suppressed people living with HIV, nearly half (47.7%) had CD4/CD8 ratios below 1, indicating persistent immune activation. However, tobacco, alcohol, and cannabis use were not significantly associated with differences in this ratio. The only notable finding was that chemsex-associated drug users (poppers, GHB/GBL, amphetamines, synthetic cathinones) had CD4/CD8 ratios that were 0.226 lower on average, though this just missed significance in the adjusted analysis (p=0.068).","whyItMatters":"The CD4/CD8 ratio is a marker of chronic inflammation and immune health beyond viral suppression. This study suggests that common substance use may not be the primary driver of persistent immune activation in treated HIV, but chemsex-related drugs warrant further investigation.","specificNumbers":"- 660 participants, mean age 54.7 years\n- 47.7% had CD4/CD8 ratio < 1\n- Mean CD4/CD8 ratio: 1.1 ± 0.6\n- 35% smoked tobacco; ~40% hazardous drinkers\n- 19.9% used cannabis; 11.9% other drugs\n- Chemsex drug users: 0.226 lower CD4/CD8 ratio (p=0.005 unadjusted; p=0.068 adjusted)","methodology":"Multi-center cross-sectional analysis from 2018-19 in the QuAliV study (ANRS CO3 AQUIVIH-NA cohort) in Nouvelle Aquitaine, France. Self-reported substance use was linked to medical record data. Multivariable linear regression adjusted for age, sex, HIV risk group, time since diagnosis, and other drug use.","limitations":"Cross-sectional design cannot establish causation. Self-reported substance use may underestimate actual consumption. CD4/CD8 measurements within a 2-year window of self-report introduce temporal imprecision. The study was conducted in a single French region."},{"rthcId":"RTHC-04505","title":"Evaluation of Efficacy of Cannabis Use in Patients With Attention Deficit Hyperactivity Disorder: A Systematic Review.","authors":"Dhamija, Divyanshu; Bello, Adedamola O; Khan, Asma A; Gutlapalli, Sai Dheeraj; Sohail, Mehvish; Patel, Priyansh A; Midha, Sidharth; Shukla, Surmai; Mohammed, Lubna","year":2023,"journal":"Cureus, 15(6), e40969","doi":"10.7759/cureus.40969","pmid":"37503496","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"After screening 136 initial studies, researchers selected 20 articles (two non-randomized trials, one cross-sectional study, one meta-analysis, and 16 observational cohorts). The review found that ADHD patients use cannabis more frequently than the general population, often for self-medication purposes. While some patients report subjective symptom improvement, the evidence base is largely observational. The review emphasizes the potential for cannabis use disorder and executive dysfunction alongside any perceived benefits.","whyItMatters":"Many people with ADHD self-medicate with cannabis despite limited research supporting this practice. This systematic review provides a needed evidence summary for both patients and clinicians navigating this increasingly common clinical scenario.","specificNumbers":"- 136 studies initially identified\n- 20 studies selected after screening\n- Study types: 2 non-randomized trials, 1 cross-sectional, 1 meta-analysis, 16 observational cohorts\n- Databases searched: PubMed, PMC, Google Scholar, ScienceDirect\n- Publication period: 10 years prior to January 2023","methodology":"Systematic review following PRISMA guidelines. Searched PubMed, PubMed Central, Google Scholar, and ScienceDirect for studies published within 10 years of January 2023. Applied inclusion-exclusion criteria and quality assessment techniques.","limitations":"The included studies were predominantly observational, limiting causal conclusions. The search strategy may not have captured all relevant literature. The heterogeneity of study designs makes synthesis difficult. No randomized controlled trials of cannabis as ADHD treatment were available."},{"rthcId":"RTHC-04506","title":"The Utility of THC Cutoff Levels in Blood and Saliva for Detection of Impaired Driving.","authors":"Di Ciano, Patricia; Brands, Bruna; Fares, Andrew; Wright, Madison; Stoduto, Gina; Byrne, Patrick; McGrath, Michael; Hasan, Omer S M; Le Foll, Bernard; Wickens, Christine M","year":2023,"journal":"Cannabis and cannabinoid research, 8(3), 408-413","doi":"10.1089/can.2022.0187","pmid":"36730769","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers used a driving simulator to measure lane weaving (SDLP) after participants smoked cannabis alone or with alcohol. There was no clear linear dose-response relationship between blood THC concentration and impairment. However, when THC levels exceeded the legal thresholds (5 ng/mL in blood, 25 ng/mL in saliva), SDLP was significantly increased compared to placebo. The combination of cannabis and alcohol when above blood THC thresholds also showed increased impairment.","whyItMatters":"Cannabis-impaired driving is a major public safety concern, but unlike alcohol, there is no universally accepted impairment threshold for THC. This study provides evidence that existing legal cutoffs may have some validity for detecting impairment, even without a simple linear dose-response relationship.","specificNumbers":"- Blood THC threshold tested: 5 ng/mL\n- Urine THC-COOH threshold: 50 ng/mL\n- Saliva THC threshold: 25 ng/mL\n- No linear relationship between blood THC and SDLP (Spearman coefficients)\n- Significant increase in SDLP above blood and saliva thresholds","methodology":"Participants smoked cannabis alone or with alcohol in a controlled setting. THC/THC-COOH levels were measured in blood, urine, and saliva. Driving impairment was assessed via standard deviation of lateral position (SDLP) on a driving simulator. Results compared to placebo conditions.","limitations":"Driving simulator performance may not perfectly predict real-world driving impairment. Individual tolerance to THC varies greatly and was not fully accounted for. The study used smoked cannabis; other consumption methods may produce different pharmacokinetic profiles."},{"rthcId":"RTHC-04507","title":"Can we interrogate public databases to fill critical gaps in mental health epidemiology? Testing the association between cannabis and psychosis in the UK as an example.","authors":"Di Gennaro, Gianfranco; Colizzi, Marco","year":2023,"journal":"Epidemiology and psychiatric sciences, 32, e40","doi":"10.1017/S2045796023000537","pmid":"37317558","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"By cross-referencing Google Trends data, Our World in Data, and other public databases, the researchers found that interest in cannabis in the UK has grown steadily over 10+ years, with a parallel overlapping rise in both psychosis cases and prevalence. The authors argue that publicly available data tools could help answer whether cannabis use changes at the population level are associated with schizophrenia rates, a question that has been difficult to answer with traditional epidemiological methods.","whyItMatters":"The cannabis-psychosis link has been studied for decades, but population-level evidence has been equivocal. This study proposes a novel, low-cost method for tracking these trends using freely available public data, which could supplement traditional epidemiological approaches.","specificNumbers":"- Over 10 years of growing cannabis interest in the UK (Google Trends)\n- Parallel increase in psychosis cases and prevalence\n- Prospective studies since 1987 have suggested increased psychosis risk with cannabis use\n- High-potency varieties confer the greatest risk","methodology":"Ecological study using publicly available databases (Google Trends, Our World in Data) to track temporal trends in cannabis interest and schizophrenia rates in the UK. Cross-referenced trends to look for parallel patterns.","limitations":"Ecological fallacy is a major concern — population-level correlations cannot establish individual-level causation. Google Trends reflects search interest, not actual cannabis use. Many confounders could explain parallel trends. The method cannot account for changes in diagnostic practices or healthcare access."},{"rthcId":"RTHC-04508","title":"A Phase Ib, Double Blind, Randomized Study of Cannabis Oil for Pain in Parkinson's Disease.","authors":"Di Luca, Daniel G; Gilmour, Gabriela S; Fearon, Conor; Swinkin, Emily; Freitas, Eliza; Kuhlman, Greg; Fox, Susan H; Mestre, Tiago","year":2023,"journal":"Movement disorders clinical practice, 10(7), 1114-1119","doi":"10.1002/mdc3.13754","pmid":"37476317","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Eight participants were randomized to one of three THC:CBD ratios (18:0, 10:10, or 1:20). The maximum tolerated dose was similar across all formulations (0.8-0.9 mL/day). There were no serious adverse events and no study dropouts. The most common side effects were drowsiness and dizziness (three participants). The high-CBD formulation (1:20) was associated with higher sleepiness scores on the Epworth scale.","whyItMatters":"Pain affects the majority of Parkinson's disease patients but has few effective treatments. This small safety trial establishes that cannabis oil formulations can be tolerated in PD patients, clearing the path for larger efficacy studies.","specificNumbers":"- 8 participants randomized\n- 3 formulations: THC:CBD 18:0, 10:10, and 1:20\n- Maximum tolerated dose: 0.8-0.9 mL/daily across groups\n- 0 serious adverse events\n- 0 study dropouts\n- Most common AE: drowsiness and dizziness (3 participants)","methodology":"Phase 1b, double-blind, randomized, single-center study. Participants randomized to three THC/CBD formulations. Primary outcomes were maximum tolerated dose, adverse events, and tolerability.","limitations":"Extremely small sample size (8 total participants). Not designed to test efficacy for pain relief. Single-center study. The MTD was similar across groups, making it difficult to assess formulation-specific differences."},{"rthcId":"RTHC-04509","title":"Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults.","authors":"Di Raddo, Marie-Eve; Milenkovic, Marija; Sivasubramanian, Meenalochani; Hasbi, Ahmed; Bergman, Jack; Withey, Sarah; Madras, Bertha K; George, Susan R","year":2023,"journal":"Current research in neurobiology, 5, 100107","doi":"10.1016/j.crneur.2023.100107","pmid":"38020805","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Adolescent rats had lower baseline levels of D1-D2 receptor heteromers than adults. Repeated THC administration upregulated D1-D2 heteromers in adult rat striatum but not in adolescent rat or monkey brain. Adult rats treated with THC showed anxiety and anhedonia-like behavior that correlated with D1-D2 density, while adolescent rats did not. Co-administration of CBD with THC prevented D1-D2 upregulation. A CB1 receptor inverse agonist also blocked the effect, confirming cannabinoid system involvement.","whyItMatters":"This study provides a biological mechanism for a well-known paradox: adolescents seem less sensitive to THC's negative emotional effects, which may make them more likely to continue using cannabis. The absence of an \"aversive brake\" in the adolescent brain could increase vulnerability to long-term cannabis dependence.","specificNumbers":"- Adolescent rats had lower baseline striatal D1-D2 heteromer density vs adults\n- THC upregulated D1-D2 in adult but not adolescent rat striatum\n- THC upregulated D1-D2 in adult rat nucleus accumbens and dorsal striatum\n- CBD co-administration prevented D1-D2 upregulation\n- CB1 inverse agonist attenuated D1-D2 upregulation","methodology":"Repeated THC administration to adolescent monkeys and both adolescent and adult rats. Measured D1-D2 heteromer expression in striatal regions using immunological methods. Behavioral testing for anxiety and anhedonia. Tested CBD co-administration and CB1 receptor inverse agonist.","limitations":"Animal study that may not directly translate to human brain development. The adolescent window in rats is brief and may not perfectly model human adolescence. Behavioral measures in rodents are proxies for human emotional states."},{"rthcId":"RTHC-04510","title":"Pharmacokinetics, efficacy, and safety of cannabidiol in dogs: an update of current knowledge.","authors":"Di Salvo, Alessandra; Conti, Maria Beatrice; Della Rocca, Giorgia","year":2023,"journal":"Frontiers in veterinary science, 10, 1204526","doi":"10.3389/fvets.2023.1204526","pmid":"37456953","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Despite growing use of CBD in veterinary medicine, the evidence base remains limited. Most efficacy studies tested CBD for osteoarthritic pain, with some positive results. Few studies have examined CBD for epilepsy, behavioral disorders, or skin lesions in dogs. The pharmacokinetic profile of CBD in dogs is not fully established due to highly variable experimental conditions across studies. Side effects observed were generally mild, but most studies only examined short- to medium-term treatment, while CBD is typically used long-term.","whyItMatters":"Pet owners are increasingly using CBD for their dogs, often without veterinary guidance. This review highlights the gap between popular enthusiasm and scientific evidence, providing veterinarians with a comprehensive assessment of what is and isn't known.","specificNumbers":"- Most efficacy studies focused on osteoarthritis pain\n- Few studies on epilepsy, behavioral disorders, or skin lesions\n- Side effects classified as mild or unremarkable\n- Pharmacokinetic profile still incompletely characterized\n- No long-term safety data available","methodology":"Narrative review of all published studies on canine pharmacokinetics, efficacy, and tolerability of CBD and cannabidiolic acid (CBDA).","limitations":"This is a review of existing literature, not new research. The underlying studies were generally small with potential bias. The review acknowledges that findings should be interpreted cautiously. No standardized CBD products exist for veterinary use."},{"rthcId":"RTHC-04511","title":"Investigating how nitrogen nutrition and pruning impacts on CBD and THC concentration and plant biomass of Cannabis sativa.","authors":"Dilena, Enrico; Close, Dugald C; Hunt, Ian; Garland, Sandra M","year":2023,"journal":"Scientific reports, 13(1), 19533","doi":"10.1038/s41598-023-46369-5","pmid":"37945596","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In a controlled-environment study of a CBD-type Cannabis sativa, increasing nitrogen supply from 60 to 500 mg/L significantly increased leaf biomass but decreased both cannabinoid concentration and total cannabinoid yield per plant. Double stem pruning did not increase cannabinoid concentrations or affect biomass. An incidental finding was that plants on the greenhouse edge with more sunlight developed more biomass and higher cannabinoid concentrations. The optimal nitrogen range appeared to be between 60 and 210 mg/L.","whyItMatters":"For commercial cannabis growers, this study challenges the intuition that more fertilizer equals more product. Over-fertilizing with nitrogen is not only wasteful but actively counterproductive for cannabinoid production.","specificNumbers":"- Nitrogen rates tested: 30, 60, 210, 500 mg/L\n- 5 weeks vegetative growth under 210 mg/L N\n- 12 weeks flowering under treatment nitrogen rates\n- Light regime: 18h (veg) then 12h (flower)\n- Optimal N range: 60-210 mg/L\n- Pruning treatment: double stem pruning (no significant effect)","methodology":"Controlled-environment glasshouse study. Clones of a CBD-type Cannabis sativa grown in pots with coarse sand. Four nitrogen levels applied during 12-week flowering phase. Double stem pruning as additional treatment. Measured biomass, nitrogen concentration, and cannabinoid concentration at final harvest.","limitations":"Single cultivar study — results may differ across cannabis varieties. Controlled greenhouse environment may not reflect field conditions. The sunlight edge effect was incidental, not a controlled variable. Specific cannabinoid concentrations and yields are not provided in the abstract."},{"rthcId":"RTHC-04512","title":"The effects of cannabidiol and Δ9-tetrahydrocannabinol, alone and in combination, in the maximal electroshock seizure model.","authors":"Dlugosz, Lukasz; Zhou, Han Zhong; Scott, Brian Wayne; Burnham, McIntyre","year":2023,"journal":"Epilepsy research, 190, 107087","doi":"10.1016/j.eplepsyres.2023.107087","pmid":"36646020","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In the mouse maximal electroshock seizure (MES) model, THC alone had an ED50 of 52 mg/kg (therapeutic index 1.7), while CBD alone had an ED50 of 190 mg/kg (therapeutic index 2.4). When combined at a 15:1 CBD:THC ratio, the ED50 dropped to 130 mg/kg CBD + 8.6 mg/kg THC, indicating a modest improvement. The benefit of adding THC to CBD was less dramatic than what the same research group previously observed in the amygdala-kindling model of focal seizures.","whyItMatters":"Most cannabis-based seizure medications focus on CBD alone. This study provides preclinical evidence that small amounts of THC could enhance CBD's anti-seizure effects, though the benefit may depend on seizure type.","specificNumbers":"- THC alone ED50: 52 mg/kg, therapeutic index 1.7\n- CBD alone ED50: 190 mg/kg, therapeutic index 2.4\n- CBD+THC (15:1) ED50: 130 mg/kg + 8.6 mg/kg\n- Combination benefit less dramatic than in focal seizure model","methodology":"Male CF-1 mice received intraperitoneal injections of CBD, THC, or combinations. MES test conducted 2 hours post-CBD and 1 hour post-THC injection. Wide dose ranges tested for dose-response curves. Toxicity assessed via behavioral rating scale.","limitations":"Mouse MES model may not fully predict human seizure responses. Intraperitoneal injection route differs from oral administration used clinically. Only one CBD:THC ratio (15:1) was tested in combination. Single sex (male mice only)."},{"rthcId":"RTHC-04513","title":"Prenatal alcohol exposure and attention-deficit/hyperactivity disorder independently predict greater substance use in young adulthood.","authors":"Dodge, Neil C; Jacobson, Joseph L; Lundahl, Leslie H; Jacobson, Sandra W","year":2023,"journal":"Alcohol, clinical & experimental research, 47(6), 1143-1155","doi":"10.1111/acer.15076","pmid":"37042023","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In 121 young adults from the Detroit Longitudinal Cohort, prenatal alcohol exposure (PAE) was independently associated with greater alcohol, cannabis, and cigarette use at age 19. PAE specifically predicted larger quantities of alcohol per drinking occasion and greater alcohol tolerance — a known risk factor for future alcohol use disorder. Importantly, these effects persisted after controlling for socioeconomic status, home environment, other prenatal exposures, and postnatal parental substance use. ADHD predicted monthly alcohol consumption but did not mediate the PAE-drinking relationship.","whyItMatters":"This study disentangles two commonly co-occurring risk factors for substance use. It shows that being exposed to alcohol in the womb has lasting biological effects on drinking behavior that cannot be explained away by growing up in a disadvantaged environment or having ADHD.","specificNumbers":"- 121 young adults from Detroit Longitudinal Cohort\n- Mothers recruited during pregnancy and followed\n- Offspring assessed at age 19\n- PAE associated with greater alcohol, cannabis, and cigarette use\n- PAE predicted dose per occasion; ADHD predicted consumption per month\n- Effects persisted after controlling for demographic, environmental, and prenatal factors","methodology":"Prospective longitudinal cohort study. Mothers recruited during pregnancy and assessed for alcohol consumption using timeline follow-back procedure. Offspring interviewed at age 19 about current and past substance use. Controlled for demographics, sex, education, home environment, other prenatal exposures, and postnatal caregiver substance use.","limitations":"Relatively small sample size (121). Single geographic location (Detroit). Self-reported substance use at age 19 may underestimate actual consumption. Prenatal exposure measures depend on maternal recall."},{"rthcId":"RTHC-04514","title":"The impact of timing of in utero marijuana exposure on fetal growth.","authors":"Dodge, Phoebe; Nadolski, Katherine; Kopkau, Haley; Zablocki, Victoria; Forrestal, Kaya; Bailey, Beth A","year":2023,"journal":"Frontiers in pediatrics, 11, 1103749","doi":"10.3389/fped.2023.1103749","pmid":"37260795","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among 109 marijuana users and 171 verified non-users, researchers found distinct growth effects depending on when during pregnancy marijuana was used. First trimester only exposure decreased birth weight by 154g. Use throughout pregnancy decreased weight by 185g and head circumference by 0.79 cm. Second trimester exposure combined with first trimester decreased head circumference by 0.83 cm. Newborn length was not significantly affected by any exposure pattern.","whyItMatters":"With increasing marijuana use during pregnancy, understanding which trimester exposures cause which growth effects can help clinical guidance become more specific. The finding that even first trimester use affects birth weight challenges the assumption that quitting early eliminates all risk.","specificNumbers":"- 109 marijuana users vs 171 biochemically verified non-users\n- First trimester only: -154g birth weight\n- Throughout pregnancy: -185g weight, -0.79 cm head circumference\n- First + second trimester: -0.83 cm head circumference\n- Length: not significantly affected by any exposure pattern","methodology":"Retrospective cohort using electronic medical records. Marijuana users compared to biochemically verified non-users. Regression analysis controlling for significant confounders. Different exposure timing groups compared to controls.","limitations":"Those who quit early may have been lighter users than those who continued, confounding the timing analysis. Retrospective design using medical records. Cannot separate marijuana effects from other unmeasured confounders. Dose information was not precisely quantified."},{"rthcId":"RTHC-04515","title":"Cognitive Safety Data from a Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase IIb Study of the Effects of a Cannabidiol and Δ9-Tetrahydrocannabinol Drug on Parkinson's Disease-Related Motor Symptoms.","authors":"Domen, Christopher H; Sillau, Stefan; Liu, Ying; Adkins, Michelle; Rajkovic, Sarah; Bainbridge, Jacquelyn; Sempio, Cristina; Klawitter, Jost; Leehey, Maureen A","year":2023,"journal":"Movement disorders : official journal of the Movement Disorder Society, 38(7), 1341-1346","doi":"10.1002/mds.29447","pmid":"37212386","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In a randomized, double-blind trial of 58 Parkinson's disease patients, the CBD/THC group (n=29) performed worse than placebo (n=29) on the Animal Verbal Fluency test after adjusting for age and education. Cognitive adverse events were reported at least twice as often in the CBD/THC group. The drug contained high-dose CBD (100mg) with low-dose THC (3.3mg) and was escalated to twice daily dosing.","whyItMatters":"Parkinson's patients are already at elevated risk for cognitive decline. This study provides important safety data showing that even a CBD-dominant cannabis formulation can measurably impact cognition in this vulnerable population.","specificNumbers":"- 58 participants: 29 CBD/THC, 29 placebo\n- Drug: 100mg CBD + 3.3mg THC per dose\n- Treatment duration: 16.3 days (SD 4.2)\n- Escalated to twice daily\n- Significantly worse Animal Verbal Fluency in CBD/THC group\n- Cognitive adverse events at least 2x more frequent in CBD/THC group","methodology":"Phase IIb randomized, double-blind, parallel-group, placebo-controlled study. Neuropsychological tests administered at baseline and 1-1.5 hours after final dose. Longitudinal regression models adjusted for age and education. Alpha = 0.05.","limitations":"Cognitive testing occurred 1-1.5 hours after final dose, capturing acute drug effects rather than lasting cognitive changes. Short treatment duration. Small sample size. Single verbal fluency measure showed significance; other cognitive tests may not have been affected."},{"rthcId":"RTHC-04516","title":"Outcomes of lung transplantation from donors with a history of substance abuse.","authors":"Donahoe, Laura L; Cypel, Marcelo; de Perrot, Marc; Yeung, Jonathan; Wang, Stella; Pierre, Andrew; Waddell, Thomas K; Yasufuku, Kazuhiro; Keshavjee, Shaf","year":2023,"journal":"The Journal of thoracic and cardiovascular surgery, 165(1), 384-395.e4","doi":"10.1016/j.jtcvs.2022.08.016","pmid":"36216597","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among 3,515 donor offers, substance abuse donors were younger, more often male, White, and had hepatitis C. Cigarette smoking history significantly reduced donor acceptance odds (OR 0.56), as did any substance abuse history (OR 0.50) and hepatitis C (OR 0.35). However, opioid use, opioid overdose death, and marijuana use did not independently affect acceptance rates. Critically, recipient survival was equivalent when using lungs from donors with opioid overdose death, marijuana use, or cigarette smoking history. Opioid use donors actually showed longer recipient survival. No difference in time to chronic lung allograft dysfunction was found.","whyItMatters":"The organ donor shortage costs lives. If substance-using donors' lungs work just as well, rejecting them based on use history alone unnecessarily limits the donor pool. This is especially relevant as opioid overdose deaths have increased the potential donor supply.","specificNumbers":"- 3,515 donor offers reviewed (2013-2019)\n- 4.4% involved opioid use; 3.3% opioid overdose death\n- 65% smoked cigarettes; 2.6% smoked marijuana\n- Smoking OR for acceptance: 0.56\n- Any substance abuse OR: 0.50\n- Recipient survival equivalent across all substance categories\n- No difference in chronic lung allograft dysfunction","methodology":"Retrospective single-center review of all donor offers from 2013-2019. Compared acceptance rates and recipient outcomes by donor substance abuse categories using logistic regression and survival analysis.","limitations":"Single-center study with institutional biases in donor selection. Marijuana use prevalence may be underreported. The study cannot determine if there are long-term effects beyond the follow-up period. Substance use categorization relied on donor records which may be incomplete."},{"rthcId":"RTHC-04517","title":"Let's Match: Making Cannabis Policy Guided by Research.","authors":"Donahue, Daniel M; Metzger, Meriah; Baker, Michael; Rosenof, Liza","year":2023,"journal":"Clinical therapeutics, 45(6), 515-520","doi":"10.1016/j.clinthera.2023.03.011","pmid":"37414501","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The authors identify two critical areas where science has not kept pace with cannabis legalization in Massachusetts. First, there is no reliable way to determine cannabis impairment at a specific point in time, making DUI enforcement fundamentally different from alcohol. Experimental studies show variable impairment effects, and observational traffic data is inconclusive. Second, medical cannabis lacks the clinical standardization that other prescription drugs require — there are no standard dosing protocols, formulation requirements, or consistent clinical frameworks, creating burdens for patients.","whyItMatters":"Massachusetts is one of many states where voters have pushed cannabis reform ahead of the scientific evidence base. This commentary from people involved in the policy process itself acknowledges the gap and calls for research investment.","specificNumbers":"- Cannabis remains Schedule I at the federal level\n- State-level legalization preceded robust scientific consensus\n- No precise impairment threshold established for cannabis\n- No standardized clinical framework for medical cannabis","methodology":"Policy commentary discussing Massachusetts's statutory provisions supporting cannabis research, social equity data advances, and critical unresolved policy issues.","limitations":"This is a commentary, not a research study. It presents policy perspectives rather than new data. The issues raised are not unique to Massachusetts."},{"rthcId":"RTHC-04518","title":"Association Between Markers of Vulnerability for Cannabis-Related Harms and Source of Supply: Secondary Analysis of a Representative Population Survey.","authors":"Drouin, Sarah; Rizkallah, Élie; Conus, Florence; Larney, Sarah; Kaur, Navdeep; Djignefa Djade, Codjo; Jutras-Aswad, Didier","year":2023,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 68(2), 109-118","doi":"10.1177/07067437221128470","pmid":"36168206","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In a representative survey of 1,799 Quebec adults, SQDC (government store) consumers (47.8%) and those buying elsewhere (52.2%) had similar vulnerability profiles across six of seven indicators: frequency of use, motivation, concurrent substance use, impaired driving, psychological distress, and problematic cannabis use. The key difference was that SQDC consumers were 4.12 times more likely to know the cannabinoid content of their product (p=0.04 in unadjusted analysis).","whyItMatters":"A major goal of cannabis legalization is harm reduction by redirecting users from the illegal market to a regulated supply. This study provides evidence that Quebec's public monopoly model is reaching at-risk users, not just casual consumers, and is providing better product information.","specificNumbers":"- 1,799 survey respondents (representative population, age 18+)\n- 47.8% SQDC consumers vs 52.2% other sources\n- SQDC consumers 4.12x more likely to know cannabinoid content (95% CI: 1.10-15.40)\n- No significant differences in 6 of 7 vulnerability indicators\n- Survey conducted February-June 2019","methodology":"Cross-sectional representative population survey (Enquête Québécoise sur le Cannabis) conducted February-June 2019. Adjusted binary logistic regressions incorporating population weights assessed seven potential harm indicators.","limitations":"Cross-sectional design captures only a snapshot. Self-reported data may underestimate risky behaviors. Survey conducted within the first year of legalization — patterns may have shifted. Knowing cannabinoid content does not necessarily translate to safer use."},{"rthcId":"RTHC-04519","title":"The effect of prenatal cannabis exposure on offspring preterm birth: a cumulative meta-analysis.","authors":"Duko, Bereket; Dachew, Berihun Assefa; Pereira, Gavin; Alati, Rosa","year":2023,"journal":"Addiction (Abingdon, England), 118(4), 607-619","doi":"10.1111/add.16072","pmid":"36305657","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Pooling adjusted odds ratios from 27 observational studies (1986-2022), with sample sizes ranging from 304 to 4.83 million births, prenatal cannabis exposure was associated with an increased risk of preterm birth (pooled aOR = 1.35, 95% CI = 1.24-1.48). The cumulative meta-analysis approach showed that the estimate has stabilized over time — the stability threshold of 0.74 means a new study would need to find a very strong protective effect to shift the overall estimate to null.","whyItMatters":"This is one of the most comprehensive meta-analyses on prenatal cannabis and preterm birth. The cumulative approach demonstrates that the finding is not driven by a few studies and has become increasingly robust as evidence accumulates.","specificNumbers":"- 27 observational studies included (1986-2022)\n- Sample sizes: 304 to 4.83 million births\n- Pooled aOR: 1.35 (95% CI: 1.24-1.48)\n- Stability threshold: 0.74 (95% CI limit: 0.81)\n- 35% increased risk of preterm birth","methodology":"Cumulative meta-analysis following PRISMA guidelines. Searched PubMed, EMBASE, SCOPUS, PsychINFO, and Web of Science. Used Newcastle-Ottawa Scale for quality appraisal. Random-effects model with inverse variance weighting. Stability threshold analysis computed.","limitations":"All 27 studies were observational, so confounding cannot be fully eliminated. Cannabis use was mostly self-reported. Dose, frequency, and potency were not consistently captured. Co-use of tobacco (common among cannabis users) may confound results."},{"rthcId":"RTHC-04520","title":"Pharmacokinetics of Orally Applied Cannabinoids and Medical Marijuana Extracts in Mouse Nervous Tissue and Plasma: Relevance for Pain Treatment.","authors":"Dumbraveanu, Cristiana; Strommer, Katharina; Wonnemann, Meinolf; Choconta, Jeiny Luna; Neumann, Astrid; Kress, Michaela; Kalpachidou, Theodora; Kummer, Kai K","year":2023,"journal":"Pharmaceutics, 15(3)","doi":"10.3390/pharmaceutics15030853","pmid":"36986714","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In a pilot pharmacokinetic study, mice receiving oral THC-rich marijuana extract had higher THC levels in plasma, spinal cord, and brain compared to mice receiving pure THC alone. This suggests other compounds in the plant extract enhance THC bioavailability. However, in the spared nerve injury pain model, only oral CBD — not THC — alleviated mechanical hypersensitivity, suggesting CBD is the more promising analgesic compound from cannabis.","whyItMatters":"The \"entourage effect\" hypothesis suggests cannabis plant compounds work together. This study provides direct pharmacokinetic evidence that plant extracts deliver more THC to the brain than purified THC, while also supporting CBD as the primary pain-relieving cannabinoid.","specificNumbers":"- THC levels higher in brain with THC-rich extract vs pure THC\n- Only CBD (not THC) alleviated mechanical hypersensitivity\n- Three formulations tested: pure THC, THC-rich extract, THC-depleted extract\n- Oral administration route","methodology":"Pilot pharmacokinetic study in mice. Compared oral pure THC vs THC-rich medical marijuana extract vs THC-depleted extract. Measured THC concentrations in plasma, spinal cord, and brain. Tested analgesic effects in the spared nerve injury (SNI) model of neuropathic pain.","limitations":"Described as a pilot study with likely small sample sizes. Mouse pharmacokinetics may not translate to humans. Only one pain model tested. Specific doses and sample sizes not detailed in abstract."},{"rthcId":"RTHC-04521","title":"The relationship between medical marijuana use and prescription pain reliever use among U.S. adults: A retrospective analysis utilizing the 2015-2019 National Survey on Drug Use and Health (NSDUH).","authors":"Dunn, Tyler J; Holmes, Erin; Yang, Yi; Bentley, John P; Kashmiri, Saim; Ramachandran, Sujith","year":2023,"journal":"Exploratory research in clinical and social pharmacy, 12, 100368","doi":"10.1016/j.rcsop.2023.100368","pmid":"38054191","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Using five years of NSDUH data, researchers found that medical marijuana use increased from 1.6% to 2.4% while appropriate prescription pain reliever use decreased from 33.4% to 27.5% and misuse decreased from 4.7% to 3.7%. Both appropriate users (OR=1.99) and misusers (OR=1.94) of prescription pain relievers were significantly more likely to use medical marijuana than non-users. Medical marijuana users also had higher rates of serious mental illness (14.0% vs 4.4%) and non-marijuana substance dependence (5.3% vs 1.2%).","whyItMatters":"The relationship between medical marijuana and prescription opioids is central to cannabis policy debates. This population-level data shows the trends are moving in promising directions, but the association between painkiller use/misuse and medical marijuana use suggests these populations have complex, overlapping needs.","specificNumbers":"- Medical marijuana use: 1.6% (2015) to 2.4% (2019)\n- Appropriate pain reliever use: 33.4% to 27.5%\n- Pain reliever misuse: 4.7% to 3.7%\n- Appropriate users OR for medical marijuana: 1.99 (p<.001)\n- Misusers OR: 1.94 (p<.001)\n- 15.1% of marijuana users in non-medical states\n- Serious mental illness: 14.0% vs 4.4%","methodology":"Retrospective secondary analysis of NSDUH data (2015-2019). Multivariable logistic regression adjusting for substance use, psychiatric, and demographic factors.","limitations":"Cross-sectional survey data cannot establish causation or directionality. Self-reported substance use may be inaccurate. NSDUH categories may not capture all medical marijuana use patterns. The observed trends could reflect broader societal changes beyond cannabis policy."},{"rthcId":"RTHC-04522","title":"BDNF rs6265 Met carriers with alcohol use disorder show greater age-related decline of N-acetylaspartate in left dorsolateral prefrontal cortex.","authors":"Durazzo, Timothy C; McNerney, M Windy; Hansen, Annika M; Gu, Meng; Sacchet, Matthew D; Padula, Claudia B","year":2023,"journal":"Drug and alcohol dependence, 248, 109901","doi":"10.1016/j.drugalcdep.2023.109901","pmid":"37146499","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among 95 veterans with alcohol use disorder, those carrying the BDNF rs6265 Met variant (n=35) showed markedly greater age-related decline in NAA/Cr levels in the left dorsolateral prefrontal cortex compared to Val/Val homozygotes (n=60). While mean metabolite levels did not differ between groups, the trajectory of decline with age was steeper in Met carriers. Met carriers also had higher rates of major depression history and cannabis use disorder in the 12 months prior to the study.","whyItMatters":"The BDNF gene influences brain repair and plasticity. This study suggests that a common genetic variant may make some people with alcohol use disorder more vulnerable to brain aging, and that this same variant clusters with cannabis use disorder and depression — potentially identifying a high-risk subgroup.","specificNumbers":"- 95 veterans with AUD (mean age 46±12 years, range 25-71)\n- Val/Met carriers: n=35; Val/Val: n=60\n- Val/Met showed greater age-related NAA/Cr decline in left DLPFC\n- Val/Met had higher frequency of MDD history\n- Val/Met had higher frequency of cannabis use disorder\n- MRS at 3 Tesla","methodology":"Cross-sectional study of veterans from VA Palo Alto residential treatment centers. Single voxel magnetic resonance spectroscopy (MRS) at 3 Tesla measured NAA, choline, and creatine in left dorsolateral prefrontal cortex. Metabolite ratios compared between BDNF genotype groups.","limitations":"Cross-sectional design infers age-related decline from age variation, not longitudinal follow-up. Relatively small sample. All participants were veterans in residential treatment, limiting generalizability. Multiple comparisons not fully addressed."},{"rthcId":"RTHC-04523","title":"Toxicological safety assessment of HempChoice® hemp oil extract; a proprietary extract consisting of a high concentration of cannabidiol (CBD) in addition to other phytocannabinoids and terpenes derived from CannabissativaL.","authors":"Dziwenka, Margitta; Coppock, Robert; Davidson, Michael H; Weder, Marc A","year":2023,"journal":"Heliyon, 9(6), e16913","doi":"10.1016/j.heliyon.2023.e16913","pmid":"37313165","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"HempChoice Hemp Oil Extract (55-75% CBD, 1-15% other cannabinoids, 1-15% terpenes) was tested across multiple safety studies. It was non-mutagenic in Ames and micronucleus tests. In a 14-day study, doses up to 96 mg/kg/day were well tolerated. In the 90-day study, no treatment-related changes were found in body weight, food consumption, behavior, or eye health. Some hematology and clinical chemistry changes occurred but were within normal range and reversed during the 28-day recovery period. Liver histopathology showed adaptive (not adverse) changes that also resolved. The NOAEL was 185.90 mg/kg/day.","whyItMatters":"As CBD products proliferate, formal toxicological safety data is essential for regulatory decisions. This study provides the type of standardized safety assessment (GLP-compliant) that regulators require for novel food or dietary supplement approval.","specificNumbers":"- CBD content: 55-75% of extract\n- Other phytocannabinoids: 1-15%\n- Terpenes: 1-15%\n- 14-day range-finding: tolerated up to 96.03 mg/kg/day\n- 90-day NOAEL: 185.90 mg/kg/day\n- 28-day recovery period: all changes reversed\n- Non-mutagenic in Ames and micronucleus tests","methodology":"Standard battery of toxicology studies: bacterial reverse mutation (Ames) test, mammalian cell micronucleus test, 14-day range-finding study, and 90-day repeated dose study with 28-day recovery in Sprague-Dawley rats. Assessed body weight, food consumption, clinical observations, ophthalmology, hematology, clinical chemistry, gross pathology, and histopathology.","limitations":"Rat toxicology may not perfectly predict human responses. The extract is a specific commercial product; other CBD products may have different compositions and safety profiles. Long-term effects beyond 90 days not assessed."},{"rthcId":"RTHC-04524","title":"Medicinal Cannabis for Paediatric Developmental, Behavioural and Mental Health Disorders.","authors":"Efron, Daryl; Taylor, Kaitlyn","year":2023,"journal":"International journal of environmental research and public health, 20(8)","doi":"10.3390/ijerph20085430","pmid":"37107712","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review found that open-label studies suggest potential for medical cannabis to improve some symptoms in children with autism spectrum disorder, but only one double-blind placebo-controlled trial exists, with inconclusive findings. Synthetic transdermal CBD gel demonstrated efficacy for reducing social avoidance in a subgroup of children with Fragile X syndrome. Studies are planned or underway for children with autism, intellectual disability, Tourette syndrome, anxiety, psychosis, anorexia nervosa, and specific neurodevelopmental syndromes.","whyItMatters":"Parents are increasingly asking about medical cannabis for their children with developmental conditions. This review helps clinicians navigate a landscape where parental demand far outpaces the evidence base.","specificNumbers":"- Only 1 double-blind placebo-controlled trial in pediatric ASD (inconclusive)\n- Synthetic CBD gel showed efficacy in Fragile X subgroup\n- Studies planned/underway for: ASD, intellectual disability, Tourette's, anxiety, psychosis, anorexia nervosa","methodology":"Narrative review of current evidence for medical cannabis in pediatric developmental, behavioral, and mental health disorders.","limitations":"Narrative review, not a systematic review. The evidence base is extremely limited — mostly open-label studies and case series. Pediatric dosing, safety, and long-term developmental effects are poorly understood."},{"rthcId":"RTHC-04525","title":"Effect of vaporizing cannabis rich in cannabidiol on cannabinoid levels in blood and on driving ability - a randomized clinical trial.","authors":"Egloff, Laura; Frei, Priska; Gerlach, Kathrin; Mercer-Chalmers-Bender, Katja; Scheurer, Eva","year":2023,"journal":"International journal of legal medicine, 137(6), 1713-1723","doi":"10.1007/s00414-023-03076-0","pmid":"37626214","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In this double-blind, randomized, crossover trial, participants vaped two CBD-rich cannabis products (both <1% THC, ~38-39mg CBD) and placebo. Computerized driving tests showed no significant differences between CBD-rich products and placebo. However, THC was detected in blood after both products, with peak levels and detection duration depending on THC content. After single use, THC dropped below 1.5 µg/L after 1.5 hours but remained detectable in some participants up to 5 hours.","whyItMatters":"CBD products are legal in many jurisdictions, but this study reveals a practical problem: legal CBD-rich cannabis can produce detectable blood THC levels that may exceed driving thresholds, even though no actual impairment occurs.","specificNumbers":"- Product 1: 38mg CBD, 1.8mg THC\n- Product 2: 39mg CBD, 0.6mg THC\n- Both products: <1% THC\n- 27 completed single-dose arm; 20 completed repeat-dose arm\n- Mean age: 28.9±12.5 (S1), 25.2±4.0 (S2)\n- THC <1.5 µg/L after 1.5h (single use)\n- THC detectable up to 5h in some participants\n- No significant driving impairment vs placebo","methodology":"Prospective, placebo-controlled, double-blind, randomized, crossover study. Participants vaped two CBD-rich products and placebo. Blood cannabinoid levels measured serially. Driving ability assessed by computerized tests. Single-dose and repetitive-dose arms.","limitations":"Computerized driving tests may not capture all aspects of real-world driving. Small sample size. Participants were experienced smokers. Legal THC thresholds vary by jurisdiction."},{"rthcId":"RTHC-04526","title":"Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation.","authors":"Elkrief, Laurent; Lin, Bochao; Marchi, Mattia; Afzali, Mohammad H; Banaschewski, Tobias; Bokde, Arun L W; Quinlan, Erin Burke; Desrivières, Sylvane; Flor, Herta; Garavan, Hugh; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Martinot, Jean-Luc; Martinot, Marie-Laure Paillère; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Paus, Tomáš; Poustka, Luise; Hohmann, Sarah; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Luykx, Jurjen; Boks, Marco P; Conrod, Patricia J","year":2023,"journal":"Psychological medicine, 53(5), 1759-1769","doi":"10.1017/S0033291721003378","pmid":"37310336","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In the IMAGEN cohort (n=1,740) and replicated in the Utrecht cohort (n=1,223), both polygenic risk for schizophrenia (PRS-Sz) and lifetime cannabis use at age 16 independently predicted psychotic-like experiences. PRS-Sz predicted cannabis use (p=0.027) and psychotic-like experiences (p=0.004). Cannabis use remained significantly associated with psychotic-like experiences after accounting for PRS-Sz and covariates (p=0.007). Critically, there was no evidence that cannabis mediated or moderated the genetic risk — the two risk factors operated independently.","whyItMatters":"A common counterargument to cannabis causing psychosis is that genetically predisposed individuals simply use more cannabis. This study directly tests and refutes that hypothesis: cannabis remains a risk factor for psychotic symptoms regardless of genetic vulnerability.","specificNumbers":"- IMAGEN cohort: n=1,740\n- Utrecht replication cohort: n=1,223\n- PRS-Sz predicted cannabis use: p=0.027\n- PRS-Sz predicted PLEs: p=0.004\n- Cannabis predicted PLEs adjusting for PRS-Sz: p=0.007\n- No mediation or moderation effects detected","methodology":"Analysis of the European IMAGEN cohort with replication in the Utrecht cannabis cohort. Tested mediation and moderation models between polygenic risk score for schizophrenia, lifetime cannabis use at age 16, and psychotic-like experiences (CAPE-42). Sensitivity analyses included PRS for cannabis use as covariate.","limitations":"Psychotic-like experiences measured by self-report questionnaire, not clinical assessment. Lifetime cannabis use is a binary measure that does not capture frequency or potency. European cohorts may not generalize globally."},{"rthcId":"RTHC-04527","title":"Differential effect of cannabis use on opioid agonist treatment outcomes: Exploratory analyses from the OPTIMA study.","authors":"Elkrief, Laurent; Bastien, Gabriel; McAnulty, Christina; Bakouni, Hamzah; Hébert, François-Olivier; Socias, M Eugenia; Le Foll, Bernard; Lim, Ron; Ledjiar, Omar; Marsan, Stéphanie; Brissette, Suzanne; Jutras-Aswad, Didier","year":2023,"journal":"Journal of substance use and addiction treatment, 149, 209031","doi":"10.1016/j.josat.2023.209031","pmid":"37003540","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among 272 participants with prescription-type opioid use disorder randomized to buprenorphine/naloxone or methadone, cannabis use (mean 2.3 days/week) was not significantly associated with opioid use, craving, or withdrawal symptoms across the 24-week study. Bayesian analysis strongly supported the null hypothesis (all Bayes factors <0.3), meaning the data actively favor the conclusion that cannabis has no meaningful effect on these opioid treatment outcomes.","whyItMatters":"Many treatment programs restrict or penalize cannabis use among patients in opioid treatment. This trial provides rigorous evidence from a pragmatic RCT that cannabis use does not worsen opioid treatment outcomes — information relevant to treatment policy.","specificNumbers":"- 272 participants: 138 BUP/NX, 134 methadone\n- Mean cannabis use: 2.3 days/week\n- Cannabis-opioid use association: aβ=-0.06±0.04, p=0.15\n- Cannabis-craving: aβ=-0.05±0.08, p=0.49\n- Cannabis-withdrawal: aβ=0.09±0.1, p=0.36\n- All Bayes factors <0.3 (supporting null)\n- BUP/NX mean max dose: 17.3 mg/day\n- Methadone mean max dose: 67.7 mg/day","methodology":"Exploratory analysis from OPTIMA, a multi-center, pragmatic, 24-week, open-label RCT. Cannabis and opioid use measured biweekly via timeline follow-back. Craving measured at multiple timepoints. Withdrawal measured at weeks 2, 4, 6. Repeated measures generalized linear mixed models with Bayesian analysis.","limitations":"Exploratory secondary analysis of a trial not designed to test cannabis effects. Self-reported cannabis use. Participants had prescription-type OUD which may differ from heroin use disorder. Open-label design for the primary treatment comparison."},{"rthcId":"RTHC-04528","title":"Does cannabidiol make cannabis safer? A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios.","authors":"Englund, Amir; Oliver, Dominic; Chesney, Edward; Chester, Lucy; Wilson, Jack; Sovi, Simina; De Micheli, Andrea; Hodsoll, John; Fusar-Poli, Paolo; Strang, John; Murray, Robin M; Freeman, Tom P; McGuire, Philip","year":2023,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 48(6), 869-876","doi":"10.1038/s41386-022-01478-z","pmid":"36380220","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Participants inhaled vaporized cannabis containing 10mg THC with 0, 10, 20, or 30mg CBD. THC alone impaired delayed verbal recall (d=0.50) and induced positive psychotic symptoms on the PANSS (d=0.69). Adding CBD at any dose did not significantly reduce these effects. CBD also failed to modulate THC's impact on other cognitive, subjective, pleasurable, or physiological measures. Plasma CBD levels showed a clear dose-response, confirming participants were absorbing the CBD — it simply didn't counteract THC.","whyItMatters":"The widespread belief that CBD can \"balance out\" THC's harmful effects drives both product marketing and policy decisions. This rigorous trial challenges that assumption for the CBD:THC ratios most common in commercial products.","specificNumbers":"- 46 healthy infrequent cannabis users\n- THC dose: 10mg across all conditions\n- CBD doses: 0, 10, 20, or 30mg (ratios 0:1, 1:1, 2:1, 3:1)\n- Memory impairment from THC: d=0.50, p=0.001\n- Psychotic symptoms from THC: d=0.69, p=2.41×10⁻⁵\n- No significant CBD modulation at any dose\n- Dose-response confirmed for plasma CBD levels","methodology":"Double-blind, within-subject, randomized trial with four drug conditions in counterbalanced order. Inhaled vaporized cannabis. Assessed verbal recall (Hopkins Verbal Learning Task), psychotic symptoms (PANSS), cognition, subjective effects, and serial plasma cannabinoid levels.","limitations":"Tested only acute effects in infrequent users; chronic users may respond differently. Maximum CBD:THC ratio was 3:1; higher ratios were not tested. Single session with vaporized cannabis; other formulations and routes may differ. The 10mg THC dose is moderate."},{"rthcId":"RTHC-04529","title":"An Updated Analysis of Clinical Outcome Measures Across Patients From the UK Medical Cannabis Registry.","authors":"Ergisi, Mehmet; Erridge, Simon; Harris, Michael; Kawka, Michal; Nimalan, Devaki; Salazar, Oliver; Loupasaki, Katerina; Ali, Rayyan; Holvey, Carl; Coomber, Ross; Usmani, Azfer; Sajad, Mohammed; Beri, Sushil; Hoare, Jonathan; Khan, Shaheen A; Weatherall, Mark W; Platt, Michael; Rucker, James J; Sodergren, Mikael H","year":2023,"journal":"Cannabis and cannabinoid research, 8(3), 557-566","doi":"10.1089/can.2021.0145","pmid":"35073160","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In this uncontrolled case series from the UK Medical Cannabis Registry, 312 patients (mean age 44.8) showed statistically significant improvements in GAD-7 (anxiety), EQ-5D-5L (quality of life), and Sleep Quality Scale scores at all measured timepoints (1, 3, and 6 months). The most common diagnoses were chronic pain (32.7%), neuropathic pain (13.8%), and fibromyalgia (9.9%). About 36% already used cannabis daily before enrollment. Median doses were 20mg CBD and 3mg THC. Adverse events were mostly mild: fatigue (3.8%), dry mouth (3.2%), dizziness (2.2%), somnolence (2.2%).","whyItMatters":"The UK legalized medical cannabis in 2018 but uptake has been limited. This registry provides the largest UK real-world evidence set so far, showing positive outcomes and an acceptable safety profile that could support broader clinical adoption.","specificNumbers":"- 312 patients, mean age 44.8\n- Top diagnoses: chronic pain (32.7%), neuropathic pain (13.8%), fibromyalgia (9.9%)\n- 35.9% consumed cannabis daily before enrollment\n- Median CBD dose: 20mg; median THC dose: 3mg\n- Significant improvements at 1, 3, and 6 months (p<0.05)\n- Adverse events: fatigue 3.8%, dry mouth 3.2%, dizziness 2.2%","methodology":"Uncontrolled prospective case series from the UK Medical Cannabis Registry. Patient-reported outcomes (GAD-7, EQ-5D-5L, SQS) collected at baseline and 1, 3, 6 months. Adverse events self-reported.","limitations":"No control group — improvements could reflect placebo effect, natural disease course, or regression to the mean. Over one-third were already daily cannabis users. Patient-reported outcomes subject to expectation bias. Attrition over 6 months not detailed."},{"rthcId":"RTHC-04530","title":"Clinical Outcome Data of Children Treated with Cannabis-Based Medicinal Products for Treatment Resistant Epilepsy-Analysis from the UK Medical Cannabis Registry.","authors":"Erridge, Simon; Holvey, Carl; Coomber, Ross; Hoare, Jonathan; Khan, Shaheen; Platt, Michael W; Rucker, James J; Weatherall, Mark W; Beri, Sushil; Sodergren, Mikael H","year":2023,"journal":"Neuropediatrics, 54(3), 174-181","doi":"10.1055/a-2002-2119","pmid":"36539215","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In this UK Medical Cannabis Registry case series of 35 children with treatment-resistant epilepsy, 65.7% overall achieved at least 50% seizure reduction. The results were dramatically different by product type: 94.1% of patients on CBD/THC combination therapy achieved this threshold, compared to 31.6% on CBD isolate and only 17.6% on broad-spectrum CBD (p significant). Adverse events were mostly mild (34.2%) or moderate (28.6%).","whyItMatters":"While CBD alone (Epidiolex) is FDA-approved for certain epilepsies, this real-world data suggests that adding small amounts of THC may dramatically improve seizure control in treatment-resistant children. This challenges the CBD-only approach that dominates pediatric epilepsy treatment.","specificNumbers":"- 35 children with treatment-resistant epilepsy\n- Overall 50%+ seizure reduction: 65.7% (23/35)\n- CBD/THC combination: 94.1% (16/17) achieved 50%+ reduction\n- CBD isolate: 31.6% (6/19) achieved 50%+ reduction\n- Broad-spectrum CBD: 17.6% (3/17) achieved 50%+ reduction\n- Mild AEs: 34.2%; moderate AEs: 28.6%","methodology":"Case series from the UK Medical Cannabis Registry. Children <18 years with treatment-resistant epilepsy. Prescribed CBD isolate, broad-spectrum CBD, or CBD/THC combination. Primary outcomes: 50%+ seizure reduction, IPES scores, adverse events.","limitations":"Uncontrolled case series — no randomization or blinding. Patients were not randomly assigned to products, introducing selection bias. Very small sample sizes per group. Open-label design may influence reporting. Cannot determine if THC alone or the combination drives the effect."},{"rthcId":"RTHC-04531","title":"Real-world evidence on the use of cannabidiol for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis Complex.","authors":"Espinosa-Jovel, Camilo; Riveros, Sandra; Bolaños-Almeida, Carlos; Salazar, Mateo Ramírez; Inga, Leidy Ceballos; Guío, Laura","year":2023,"journal":"Seizure, 112, 72-76","doi":"10.1016/j.seizure.2023.09.015","pmid":"37769547","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In this multicenter retrospective study, 78 patients (median age 24, mostly structural and genetic etiologies) with drug-resistant epilepsy received highly purified CBD as adjunctive therapy. They were on a median of 3 antiseizure drugs with a median of 30 monthly seizures. After a median 14 months of treatment, 68.8% achieved 50%+ seizure reduction, mean seizure reduction was 67.8%, and 11.5% became seizure-free. Clobazam co-use did not significantly affect efficacy or safety. Drug retention rate was 78.2%. Adverse events occurred in 28.2% but were manageable.","whyItMatters":"CBD (Epidiolex) is FDA-approved only for Lennox-Gastaut syndrome, Dravet syndrome, and Tuberous Sclerosis Complex. This study provides real-world evidence that CBD may be effective for drug-resistant epilepsy regardless of the underlying cause, potentially broadening its clinical use.","specificNumbers":"- 78 patients, median age 24 years\n- Median baseline seizures: 30/month\n- Median concurrent ASDs: 3 (IQR 2-4)\n- Median treatment duration: 14 months (IQR 10-17)\n- 50%+ seizure reduction: 68.8%\n- Mean seizure reduction: 67.8%\n- Seizure freedom: 11.5%\n- Drug retention: 78.2%\n- Adverse events: 28.2%","methodology":"Multicenter retrospective study evaluating highly purified CBD for drug-resistant epilepsy in patients >2 years with various etiologies (excluding LGS, Dravet, TSC). Assessed efficacy at last available visit and safety throughout treatment.","limitations":"Retrospective, uncontrolled design. No placebo comparison. Diverse etiologies make it difficult to identify which specific conditions respond best. Selection bias — patients prescribed CBD may differ systematically from those who were not."},{"rthcId":"RTHC-04532","title":"A new application of the switchable hydrophilicity solvent-based homogenous liquid-liquid microextraction to analyze synthetic cannabinoids in plasma by LC-MS/MS.","authors":"Fabris, André Luis; Martins, Aline Franco; Costa, Jose Luiz; Yonamine, Mauricio","year":2023,"journal":"Journal of pharmaceutical and biomedical analysis, 234, 115588","doi":"10.1016/j.jpba.2023.115588","pmid":"37517261","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The new SHS-HLLME method successfully extracted 31 synthetic cannabinoids from 300 µL of plasma. It achieved limits of detection between 0.01-0.08 ng/mL, quantitation at 0.1 ng/mL, and linear ranges of 0.1-10 ng/mL with coefficients ≥0.99. The method uses dipropylamine (DPA) as a switchable solvent that changes between water-miscible and immiscible states by pH adjustment, replacing traditional toxic organic solvents.","whyItMatters":"Synthetic cannabinoids are increasingly diverse and potent, requiring sensitive detection methods. This green chemistry approach reduces toxic waste while maintaining analytical performance needed for clinical and forensic toxicology.","specificNumbers":"- 31 synthetic cannabinoids detected\n- Requires only 300 µL of plasma\n- LOD: 0.01-0.08 ng/mL\n- LOQ: 0.1 ng/mL\n- Linear range: 0.1-10 ng/mL (r² ≥0.99)\n- Recovery: 36-56.7%\n- Matrix effect: -55.6% to 185.9%","methodology":"Full optimization of switchable hydrophilicity solvent-based homogenous liquid-liquid microextraction followed by LC-MS/MS analysis. Optimized variables: SHS type, volume, NaOH volume, salting-out effect, and extraction time. Validated for accuracy, precision, matrix effects, and recovery.","limitations":"Variable matrix effects (-55.6% to 185.9%) could affect quantitative accuracy. Recovery rates (36-56.7%) are moderate. The method has not been validated against real forensic samples. New synthetic cannabinoids may not be captured by the current panel."},{"rthcId":"RTHC-04533","title":"Impact of Cannabis Use on Immune Cell Populations and the Viral Reservoir in People With HIV on Suppressive Antiretroviral Therapy.","authors":"Falcinelli, Shane D; Cooper-Volkheimer, Alicia D; Semenova, Lesia; Wu, Ethan; Richardson, Alexander; Ashokkumar, Manickam; Margolis, David M; Archin, Nancie M; Rudin, Cynthia D; Murdoch, David; Browne, Edward P","year":2023,"journal":"The Journal of infectious diseases, 228(11), 1600-1609","doi":"10.1093/infdis/jiad364","pmid":"37606598","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Comparing HIV-positive cannabis users to matched non-users on ART, cannabis use was associated with increased naive T cells, reduced effector T cells, and lower expression of activation markers. Cannabis users also had reduced levels of exhausted and senescent T cells. Critically, HIV-specific CD8 T-cell responses (the immune cells that fight HIV) were unaffected by cannabis use. Neither intact nor total HIV proviral DNA frequency in CD4 T cells differed between groups, indicating cannabis did not affect the latent reservoir.","whyItMatters":"The persistent immune activation in treated HIV contributes to aging-related diseases and poor health outcomes. If cannabis genuinely reduces this activation without impairing anti-HIV immunity or expanding the viral reservoir, it could have therapeutic implications.","specificNumbers":"- Cannabis users vs matched non-users, both on ART\n- Increased naive T cells in cannabis users\n- Reduced effector T cells\n- Reduced activation marker expression\n- Reduced exhausted and senescent T cells\n- No difference in HIV-specific CD8 responses\n- No difference in intact or total HIV DNA","methodology":"Cohort comparison of PWH who use cannabis vs matched non-users on ART. Evaluated T-cell maturation/activation markers, HIV-specific T-cell responses, and intact proviral DNA (IPDA assay) in CD4 T cells.","limitations":"Observational cross-sectional design cannot prove cannabis causes the immune differences. Cannabis users may differ from non-users in unmeasured ways. Peripheral blood may not fully represent tissue-resident immune populations. Amount, frequency, and type of cannabis use were not detailed."},{"rthcId":"RTHC-04534","title":"Impact of prenatal cannabis exposure on functional connectivity of the salience network in children.","authors":"Faraj, Mohammed M; Evanski, Julia; Zundel, Clara G; Peters, Craig; Brummelte, Susanne; Lundahl, Leslie; Marusak, Hilary A","year":2023,"journal":"Journal of neuroscience research, 101(1), 162-171","doi":"10.1002/jnr.25136","pmid":"36226844","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Using data from 10,719 children (mean age ~10) in the ABCD study, prenatal cannabis exposure before knowledge of pregnancy was associated with lower resting-state connectivity between the salience network and ventral attention network. Exposure after pregnancy knowledge was not significantly associated with connectivity changes. Psychotic-like experiences mediated the relationship between prenatal cannabis exposure and altered connectivity, but this mediation was not significant after including covariates.","whyItMatters":"The salience network is critical for detecting and responding to important stimuli. Weakened connectivity with attention networks could explain previously observed associations between prenatal cannabis exposure and behavioral problems in children.","specificNumbers":"- 10,719 children from ABCD study\n- Mean age: 9.92±0.62 years; 47.9% female\n- Prenatal cannabis exposure before pregnancy knowledge: associated with lower SN-VAN connectivity\n- Prenatal exposure after pregnancy knowledge: not significant\n- Mediation by psychotic-like experiences: significant but lost with covariates","methodology":"Cross-sectional analysis of the Adolescent Brain Cognitive Development (ABCD) study. Resting-state fMRI assessed functional connectivity within and between six core neurocognitive networks. Parent-reported prenatal cannabis exposure. Mediation analysis for psychotic-like experiences.","limitations":"Prenatal exposure was parent-reported retrospectively (10 years later). Cross-sectional design. Mediation effects were not robust to covariate adjustment. Cannot separate cannabis effects from other prenatal exposures or postnatal environmental factors."},{"rthcId":"RTHC-04535","title":"Cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic, but not inflammatory pain.","authors":"Farkas, Daniel J; Inan, Saadet; Heydari, Laila N; Johnson, Clare T; Zhao, Pingwei; Bradshaw, Heather B; Ward, Sara Jane; Rawls, Scott M","year":2023,"journal":"Life sciences, 328, 121878","doi":"10.1016/j.lfs.2023.121878","pmid":"37392779","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Mitragynine's effectiveness against chemotherapy-induced neuropathic pain was partially reduced in cannabinoid receptor knockout mice and completely blocked by pharmacological CB1, CB2, and TRPV1 antagonists. This cannabinoid involvement was specific to neuropathic pain — it did not significantly affect mitragynine's efficacy in an inflammatory pain model. Chemotherapy (oxaliplatin) disrupted the endocannabinoid lipidome in the spinal cord, and repeated mitragynine exposure prevented this disruption.","whyItMatters":"Kratom and cannabis are both widely used for self-treating pain, and users commonly combine them. This study provides a biological rationale for why the combination might work — kratom's pain relief partly depends on the same cannabinoid receptors that cannabis activates.","specificNumbers":"- Complete blockade of neuropathic pain relief with CB1+CB2+TRPV1 antagonists\n- Partial attenuation in cannabinoid receptor knockout mice\n- Cannabinoid involvement selective for neuropathic (not inflammatory) pain\n- Oxaliplatin disrupted spinal cord endocannabinoid lipidome\n- Mitragynine prevented oxaliplatin-induced lipidome disruption","methodology":"Mouse models of chemotherapy-induced peripheral neuropathy (oxaliplatin) and inflammatory pain (formalin). Tested mitragynine with CB1, CB2, and TRPV1 antagonists and in cannabinoid receptor knockout mice. Measured spinal cord endocannabinoid lipidome by HPLC-MS/MS.","limitations":"Mouse models may not translate to human neuropathic pain. Mitragynine was given intraperitoneally, not orally as in human kratom use. The specific signaling mechanisms connecting opioid and cannabinoid pathways were not fully elucidated."},{"rthcId":"RTHC-04536","title":"Cannabis and Endometriosis: The Roles of the Gut Microbiota and the Endocannabinoid System.","authors":"Farooqi, Toobah; Bhuyan, Deep Jyoti; Low, Mitchell; Sinclair, Justin; Leonardi, Mathew; Armour, Mike","year":2023,"journal":"Journal of clinical medicine, 12(22)","doi":"10.3390/jcm12227071","pmid":"38002684","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review identified several key connections: the endocannabinoid system regulates inflammation and pain in endometriosis through CB1 receptor expression changes and elevated circulating endocannabinoids. Gut microbial imbalances (increased Prevotella linked to bloating; increased E. coli supporting the bacterial contamination hypothesis) correlate with endometriosis symptoms and raised inflammatory markers (TNF-α, IL-6). The endocannabinoid 2-AG showed protective effects on gut permeability and inflammation, suggesting the two systems interact.","whyItMatters":"Endometriosis affects 10-14% of women with limited treatment options. Understanding how the endocannabinoid system and gut microbiome interact could open new therapeutic approaches beyond hormonal treatment and surgery.","specificNumbers":"- Endometriosis affects 10-14% of women\n- Increased Prevotella correlated with bloating\n- Increased E. coli supports bacterial contamination hypothesis\n- Raised TNF-α and IL-6 in endometriosis\n- 2-AG decreased gut inflammation and improved permeability\n- CB1 receptor expression changes observed","methodology":"Narrative review of published literature on endocannabinoid system, gut microbiota, and endometriosis interactions.","limitations":"Narrative review without systematic methodology. Most underlying evidence is from observational and preclinical studies. The interactions between ECS and microbiota in endometriosis are largely theoretical and have not been tested in clinical trials."},{"rthcId":"RTHC-04537","title":"The Impact of Recreational Cannabis Legalization on Cannabis Use and Associated Outcomes: A Systematic Review.","authors":"Farrelly, Kyra N; Wardell, Jeffrey D; Marsden, Emma; Scarfe, Molly L; Najdzionek, Peter; Turna, Jasmine; MacKillop, James","year":2023,"journal":"Substance abuse : research and treatment, 17, 11782218231172054","doi":"10.1177/11782218231172054","pmid":"37187466","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Five outcome categories emerged: (1) Cannabis/substance use: some evidence of increased young adult use, minimal change in adolescent rates; (2) Attitudes: mixed evidence on changing perceptions; (3) Healthcare: increased cannabis-related visits; (4) Driving: some evidence of increased impaired driving; (5) Crime: mixed findings. The overall pattern shows some negative consequences but no large-magnitude short-term impacts. Most studies were from the US (66.2%).","whyItMatters":"As more jurisdictions consider legalization, policymakers need evidence on actual outcomes. This review shows the effects are more nuanced than either side of the legalization debate suggests.","specificNumbers":"- 61 longitudinal studies included (2016-2022)\n- 66.2% from the United States\n- 5 outcome categories identified\n- Some increase in young adult cannabis use\n- Minimal change in adolescent use rates\n- Increased cannabis-related healthcare visits\n- Some evidence of increased impaired driving","methodology":"Systematic review of longitudinal studies evaluating recreational cannabis legalization impacts, published 2016-2022. Comprehensive bibliographic search strategy.","limitations":"Most studies from the US, limiting generalizability. Short follow-up periods in many studies. Difficulty isolating legalization effects from other concurrent changes. Heterogeneity in legalization models across jurisdictions."},{"rthcId":"RTHC-04538","title":"Driving under the influence of cannabis: A 5-year retrospective Italian study.","authors":"Favretto, Donata; Visentin, Cindi; Aprile, Anna; Terranova, Claudio; Cinquetti, Alessandro","year":2023,"journal":"Forensic science international, 353, 111854","doi":"10.1016/j.forsciint.2023.111854","pmid":"37922577","tags":["driving","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"When a driver is stopped for suspected impaired driving, the time between the traffic stop and the blood draw matters enormously for cannabis detection. THC is metabolized quickly, and delays of even a few hours can mean the difference between detecting active THC (indicating recent use) and only finding inactive metabolites (which can linger for days).\n\nThis five-year Italian study examined 318 cannabis-related DUI cases and found a fundamental problem with the system. Of all cannabis-positive drivers, only 143 (45%) tested positive for active THC. The remaining 173 (55%) tested positive only for the inactive metabolite THC-COOH — meaning their blood showed evidence of past cannabis use, but not necessarily recent use or current impairment.\n\nThe culprit was delayed sample collection. Italian forensic procedures often result in blood draws hours after the initial traffic stop, by which time active THC has been metabolized. In the THC-positive group, average concentrations were 4.05 ng/mL for THC and 28.29 ng/mL for the inactive metabolite. But for the majority who only had metabolites, there was no way to determine when they actually used cannabis or whether they were impaired at the time of driving.\n\nThis creates a legal and scientific problem: DUI cases built on metabolite-only results are scientifically weaker because they cannot distinguish a driver who smoked an hour ago from one who smoked three days ago.","whyItMatters":"This study quantifies a critical weakness in cannabis DUI enforcement: the testing timeline. Unlike alcohol, where breathalyzers give immediate results, cannabis requires blood draws that are often delayed by logistics (transport to hospital, waiting for medical staff). By the time blood is collected, the evidence of active impairment may have literally metabolized away. This has implications for both justice (prosecuting genuinely impaired drivers) and rights (protecting drivers who used cannabis days before driving).","specificNumbers":"318 total DUI cases over 5 years (2017–2021). 143 (45%) positive for active THC + metabolites. 173 (55%) positive for inactive THC-COOH only. THC-positive group: mean THC 4.05 ng/mL, mean THC-COOH 28.29 ng/mL. The study highlights that delayed blood collection systematically reduces the ability to detect active THC.","methodology":"Retrospective observational study of anonymized toxicological data from cannabis-related DUI cases (January 2017–December 2021) at the Legal Medicine and Toxicology Department, University Hospital of Padova, Italy. The 318 cases included drivers involved in road traffic accidents or apprehended by police. Blood samples were analyzed for THC, 11-OH-THC (active metabolite), and THC-COOH (inactive metabolite).","limitations":"Retrospective design using archived laboratory data — clinical details like the exact time of cannabis use, driving behavior observations, and field sobriety test results were not available. The study couldn't determine the actual delay between traffic stop and blood draw for each case. Italian forensic procedures may differ from other countries. The 5 ng/mL THC threshold used in many jurisdictions is itself debated in the literature."},{"rthcId":"RTHC-04539","title":"COVID-19 Vaccine Uptake and Attitudes Within Two Cohorts of Younger Adult Cannabis Users.","authors":"Fedorova, Ekaterina V; Wong, Carolyn F; Conn, Bridgid M; Ataiants, Janna; Lankenau, Stephen E","year":2023,"journal":"Journal of drug issues, 53(3), 422-430","doi":"10.1177/00220426221131488","pmid":"38603185","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In two cohorts of California cannabis users surveyed in early-mid 2021, vaccination rates differed dramatically by age: 71.8% of the younger cohort (18-21) were vaccinated compared to only 44.4% of the older cohort (26-33). In the older group, non-Hispanic Black/African American identity, lack of health insurance, and medicinal (vs recreational) orientation toward cannabis use were negatively associated with vaccination. Both cohorts cited similar reasons for hesitancy: concerns about development speed, side effects, natural immunity, and distrust of vaccines.","whyItMatters":"Cannabis users represent a population that may be harder to reach with public health messaging. Understanding which subgroups are most vaccine-hesitant can help target outreach efforts.","specificNumbers":"- Younger cohort (18-21): 71.8% vaccinated\n- Older cohort (26-33): 44.4% vaccinated\n- Survey period: March-August 2021\n- Negative predictors in older cohort: Black race, no insurance, medicinal cannabis orientation\n- Top hesitancy reasons: development speed, side effects, natural immunity, distrust","methodology":"Cross-sectional survey of two age cohorts of cannabis users recruited in California. Logistic regression for vaccination predictors. Descriptive analysis of vaccine attitudes.","limitations":"Convenience sample of California cannabis users, not generalizable. Self-reported vaccination status. Survey conducted during active vaccine rollout, so rates were still changing. Cannot separate cannabis-specific factors from general demographic patterns."},{"rthcId":"RTHC-04540","title":"First-Episode Psychosis Patients Who Deteriorated in the Premorbid Period Do Not Have Higher Polygenic Risk Scores Than Others: A Cluster Analysis of EU-GEI Data.","authors":"Ferraro, Laura; Quattrone, Diego; La Barbera, Daniele; La Cascia, Caterina; Morgan, Craig; Kirkbride, James B; Cardno, Alastair G; Sham, Pak; Tripoli, Giada; Sideli, Lucia; Seminerio, Fabio; Sartorio, Crocettarachele; Szoke, Andrei; Tarricone, Ilaria; Bernardo, Miquel; Rodriguez, Victoria; Stilo, Simona A; Gayer-Anderson, Charlotte; de Haan, Lieuwe; Velthorst, Eva; Jongsma, Hannah; Bart, Rutten B P; Richards, Alexander; Arango, Celso; Menezez, Paulo Rossi; Lasalvia, Antonio; Tosato, Sarah; Tortelli, Andrea; Del Ben, Cristina Marta; Selten, Jean-Paul; Jones, Peter B; van Os, Jim; Di Forti, Marta; Vassos, Evangelos; Murray, Robin M","year":2023,"journal":"Schizophrenia bulletin, 49(1), 218-227","doi":"10.1093/schbul/sbac100","pmid":"35947471","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Four clusters emerged from 802 first-episode psychosis patients: high-cognitive-functioning, low-cognitive-functioning, intermediate, and deteriorating. The deteriorating group (n=150) had normal-to-deteriorating premorbid adjustment and was uniquely characterized by lower schizophrenia polygenic risk scores but higher likelihood of daily high-potency cannabis use. Polygenic risk scores explained only 7.9% of between-group membership. All patient clusters had higher schizophrenia genetic risk than the 1,263 population controls.","whyItMatters":"This challenges the assumption that premorbid deterioration before psychosis reflects greater genetic loading. Instead, environmental factors — particularly high-potency cannabis — may drive a distinct pathway to psychosis in people with relatively lower genetic vulnerability.","specificNumbers":"- 802 FEP patients, 1,263 controls\n- 4 clusters: high-cognitive (n=205, IQ 106.1), low-cognitive (n=223, IQ 73.9), intermediate (n=224, IQ 80.8), deteriorating (n=150, IQ 80.6)\n- PRS explained 7.9% of cluster membership\n- Deteriorating cluster: lower SCZ_PRS, more daily high-potency cannabis\n- All FEP clusters had higher SCZ_PRS than controls","methodology":"Cluster analysis of EU-GEI multi-site data using premorbid social/academic functioning and IQ. Compared clusters on polygenic risk scores for schizophrenia, bipolar disorder, depression, and IQ. Assessed cannabis use patterns across clusters.","limitations":"Cross-sectional cluster analysis cannot establish causation. Cannabis use was self-reported. Premorbid adjustment assessed retrospectively. Polygenic risk scores explain only a fraction of genetic risk."},{"rthcId":"RTHC-04541","title":"Presynaptic adenosine receptor heteromers as key modulators of glutamatergic and dopaminergic neurotransmission in the striatum.","authors":"Ferré, Sergi; Sarasola, Laura I; Quiroz, César; Ciruela, Francisco","year":2023,"journal":"Neuropharmacology, 223, 109329","doi":"10.1016/j.neuropharm.2022.109329","pmid":"36375695","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This review presents evidence that A1R-A2AR and A2AR-CB1R receptor heteromers in cortico-striatal terminals have unique properties based on their tetrameric structure. These heteromers use distinct allosteric mechanisms to fine-tune adenosine and endocannabinoid-mediated glutamate release. The A2AR's ability to show constitutive activity differs between heteromers, which has implications for drug development — some A2AR ligands preferentially act as neutral antagonists vs inverse agonists, or have preferential affinity for specific heteromers.","whyItMatters":"Understanding how adenosine and cannabinoid receptors physically interact opens new drug design strategies. Targeting specific receptor heteromers could provide more precise treatments for Parkinson's disease and restless legs syndrome with fewer side effects.","specificNumbers":"- A1R-A2AR heteromers in cortico-striatal terminals\n- A2AR-CB1R heteromers in cortico-striatal terminals\n- Both heteromers form tetrameric structures\n- Different allosteric mechanisms in each heteromer type\n- Targets for Parkinson's disease and restless legs syndrome drug development","methodology":"Review essay integrating receptor pharmacology, structural biology, and neurocircuit anatomy to evaluate adenosine receptor heteromers as drug targets.","limitations":"Review of existing evidence, not new experimental data. Receptor heteromer biology is complex and not all findings may translate from cell models to whole organisms. Therapeutic applications remain theoretical."},{"rthcId":"RTHC-04542","title":"Nutrient profile, amino acid digestibility, true metabolizable energy, and indispensable amino acid scoring of whole hemp seeds for use in canine and feline diets.","authors":"Finet, Shannon; He, Fei; Utterback, Pam L; Parsons, Carl M; de Godoy, Maria R C","year":2023,"journal":"Journal of animal science, 101","doi":"10.1093/jas/skad106","pmid":"37097066","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"All four hemp seed varieties had similar macronutrient profiles. Essential amino acids exceeded NRC recommendations for adult dogs and cats at maintenance, except tryptophan — the first limiting amino acid. The omega-6:omega-3 fatty acid ratio was favorable at approximately 3.5:1. Standardized amino acid digestibility did not differ significantly among varieties. Higher fat and lower fiber content correlated with higher metabolizable energy. The digestible indispensable amino acid score confirmed hemp seeds alone cannot meet all amino acid requirements and need a complementary protein source.","whyItMatters":"With growing interest in hemp-based pet foods, this study provides the foundational nutritional data needed for AAFCO ingredient approval, showing hemp seeds are nutritious but not a standalone protein source.","specificNumbers":"- 4 hemp varieties tested: NWG 452, NWG 331, NWG 2730, X-59\n- Omega-6:omega-3 ratio: ~3.5:1\n- Tryptophan: first limiting amino acid\n- No significant difference in amino acid digestibility among varieties (P>0.05)\n- Significant difference in metabolizable energy among varieties (P<0.05)","methodology":"Nutrient composition analysis of four hemp seed varieties. Amino acid digestibility and true metabolizable energy assessed using the cecectomized rooster model. Digestible indispensable amino acid score calculated against AAFCO profiles and NRC allowances.","limitations":"Rooster digestibility model may not perfectly predict digestibility in dogs and cats. In vivo feeding trials in target species not yet conducted. Safety data not included in this nutritional assessment."},{"rthcId":"RTHC-04543","title":"The piperazine analogue para-fluorophenylpiperazine alters timing of the physiological effects of the synthetic cannabinoid receptor agonist AMB-FUBINACA, without changing its discriminative stimulus, signalling effects, or metabolism.","authors":"Finlay, David B; Mackie, Warwick; Webb, Hunter D J; Thomsen, Lucy R; Nimick, Mhairi; Rosengren, Rhonda J; Marusich, Julie A; Glass, Michelle; Wiley, Jenny L","year":2023,"journal":"Pharmacology, biochemistry, and behavior, 223, 173530","doi":"10.1016/j.pbb.2023.173530","pmid":"36805861","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"pFPP did not alter AMB-FUBINACA's ability to substitute for THC in drug discrimination tests. However, it modestly abated some physiological effects: delaying hypothermia onset and shortening bradycardia duration. In cell assays, no synergistic or additive signaling interactions were detected between pFPP and AMB-FUBINACA through CB1 or 5HT1a receptors. pFPP also did not alter AMB-FUBINACA's metabolism in liver microsomes.","whyItMatters":"AMB-FUBINACA has caused numerous hospitalizations and deaths in New Zealand. Understanding whether its common adulterant pFPP contributes to toxicity is important for public health risk assessment and harm reduction messaging.","specificNumbers":"- pFPP confirmed as low-potency 5HT1a agonist\n- No additive or synergistic signaling effects with AMB-FUBINACA\n- pFPP delayed AMB-FUBINACA hypothermia onset\n- pFPP shortened AMB-FUBINACA bradycardia duration\n- No inhibition of AMB-FUBINACA metabolism by pFPP","methodology":"Rat plethysmography and telemetry for physiological effects. Mouse drug discrimination (THC vs vehicle). HEK cell cAMP signaling assays with CB1 and 5HT1a receptors. Rat and human liver microsome metabolism studies.","limitations":"Animal models may not capture all human toxicity mechanisms. pFPP concentrations in street drugs may vary from those tested. Only acute interactions studied; chronic co-exposure not assessed."},{"rthcId":"RTHC-04544","title":"Recommendations for Reducing the Risk of Cannabis Use-Related Adverse Psychosis Outcomes: A Public Mental Health-Oriented Evidence Review.","authors":"Fischer, Benedikt; Hall, Wayne; Fidalgo, Thiago M; Hoch, Eva; Le Foll, Bernard; Medina-Mora, Maria-Elena; Reimer, Jens; Tibbo, Philip G; Jutras-Aswad, Didier","year":2023,"journal":"Journal of dual diagnosis, 19(2-3), 71-96","doi":"10.1080/15504263.2023.2226588","pmid":"37450645","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review identified multiple risk factors: genetic predisposition, mental health/substance use history, early age of first use, frequency of use, high-THC product composition, smoking route, and co-use of other substances. Risk factor combinations amplify odds of psychosis. The protective effects of CBD are uncertain despite popular belief. Continued cannabis use adversely affects psychosis treatment and medication effectiveness. The expert panel developed recommendations for risk reduction short of abstinence.","whyItMatters":"As cannabis use normalizes globally, a harm-reduction approach to psychosis prevention is practical and necessary. These evidence-graded recommendations give clinicians and public health officials actionable guidance for an increasingly common clinical scenario.","specificNumbers":"- Literature search from 2016 onward\n- Multiple risk factors identified and quality-graded\n- International expert consensus panel\n- CBD protective effects: uncertain\n- Continued use adversely affects treatment outcomes","methodology":"Narrative review of primary databases from 2016 onward, focusing on reviews and high-quality studies. Quality-graded evidence summaries. Recommendations developed by international expert consensus.","limitations":"Narrative review methodology. Expert consensus may not reflect all perspectives. Many risk factors are interrelated and difficult to isolate. Recommendations for harm reduction short of abstinence may be challenging to implement."},{"rthcId":"RTHC-04545","title":"Patient Experiences With Prescription Cannabinoids in Germany: Protocol for a Mixed Methods, Exploratory, and Anonymous Web-Based Survey.","authors":"Fischer, Jan Moritz; Kandil, Farid-Ihab; Karst, Matthias; Zager, Laura Sophie; Jeitler, Michael; Kugler, Felix; Fitzner, Franziska; Michalsen, Andreas; Kessler, Christian S","year":2023,"journal":"JMIR research protocols, 12, e38814","doi":"10.2196/38814","pmid":"36943359","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This study protocol outlines an exploratory mixed-methods survey of medical cannabis patients in Germany, where broader prescribing was allowed since 2017. The design addresses key challenges: stigmatization limiting patient willingness to participate, low prevalence making recruitment difficult, and the need for representative sampling. Using cluster sampling via statutory health insurance physicians, they recruited 256 patients. Validated questionnaires cover pain, spasticity, anorexia, MS, nausea, depression, and ADHD symptoms both currently and retrospectively before treatment.","whyItMatters":"Germany's medical cannabis system is growing but lacks systematic patient outcome data. This protocol demonstrates how to overcome methodological challenges in studying a stigmatized, hard-to-reach treatment population.","specificNumbers":"- 256 patients enrolled through June 2022\n- 3 German federal states\n- Prescribing allowed since 2017\n- Conditions assessed: pain, spasticity, anorexia, MS, nausea, depression, ADHD\n- Web-based, anonymous, cross-sectional design","methodology":"Representative, anonymous, cross-sectional web-based survey. Cluster sampling via statutory health insurance physicians. Validated symptom-specific questionnaires for current and pre-therapy conditions. Mixed methods with prior qualitative interviews informing survey design.","limitations":"Study protocol, not results. Cross-sectional design cannot establish causation. Retrospective pre-therapy assessment subject to recall bias. Web-based format may exclude less technology-literate patients."},{"rthcId":"RTHC-04546","title":"Driving Under the Influence of Cannabis: Impact of Combining Toxicology Testing with Field Sobriety Tests.","authors":"Fitzgerald, Robert L; Umlauf, Anya; Hubbard, Jacqueline A; Hoffman, Melissa A; Sobolesky, Philip M; Ellis, Shannon E; Grelotti, David J; Suhandynata, Raymond T; Huestis, Marilyn A; Grant, Igor; Marcotte, Thomas D","year":2023,"journal":"Clinical chemistry, 69(7), 724-733","doi":"10.1093/clinchem/hvad054","pmid":"37228223","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In 191 participants who smoked placebo or cannabis (5.9% or 13.4% THC), there was no relationship between THC concentrations in blood, oral fluid, or breath and driving simulator performance at any timepoint. Field sobriety tests classified 81% of THC recipients as impaired 71 minutes after smoking, but also classified 49% of placebo recipients as impaired. Combining a 2 ng/mL THC oral fluid cutoff with positive FST findings eliminated false positives among controls 86 minutes after smoking.","whyItMatters":"This is one of the most rigorous studies addressing the fundamental challenge of cannabis DUI enforcement. The finding that nearly half of sober people fail field sobriety tests underscores why toxicology confirmation is essential.","specificNumbers":"- 191 participants randomized\n- THC doses: placebo, 5.9%, 13.4%\n- 5-hour observation period\n- No correlation between THC levels and driving performance (P>0.05)\n- FST: 81% of THC group deemed impaired at 71 min\n- FST: 49% of placebo group deemed impaired at 71 min\n- Combined FST + 2 ng/mL oral fluid THC: 0% false positives at 86 min","methodology":"Placebo-controlled, randomized, double-blind study. Participants smoked cannabis or placebo ad libitum. Serial blood, oral fluid, and breath samples collected over 5 hours. Driving simulator testing (SDLP, coherence). Law enforcement officers conducted field sobriety tests.","limitations":"Driving simulator performance may not reflect real-world driving. Ad libitum smoking introduces dose variability. Single cannabis session; chronic users may differ. Field sobriety tests administered by a limited number of officers."},{"rthcId":"RTHC-04547","title":"An Emerging Strategy for Neuroinflammation Treatment: Combined Cannabidiol and Angiotensin Receptor Blockers Treatments Effectively Inhibit Glial Nitric Oxide Release.","authors":"Fleisher-Berkovich, Sigal; Battaglia, Veronica; Baratta, Francesca; Brusa, Paola; Ventura, Yvonne; Sharon, Nitzan; Dahan, Arik; Collino, Massimo; Ben-Shabat, Shimon","year":2023,"journal":"International journal of molecular sciences, 24(22)","doi":"10.3390/ijms242216254","pmid":"38003444","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In LPS-stimulated glial cells, telmisartan and CBD alone reduced nitric oxide by 60% and 36% respectively. Together, they achieved 95% inhibition (additive effect). More strikingly, losartan (5µM) and CBD (5µM) synergistically inhibited nitric oxide release by 80%, far exceeding either alone (22% and 26%). CBD combined with dimethyl fumarate's metabolite MMF also showed synergistic effects (77% inhibition vs 35% and 12% alone). Both combinations also modulated inflammatory cytokines TNFα, IL-17, and interferon-γ.","whyItMatters":"Neuroinflammation drives many brain diseases. This study suggests that commonly prescribed blood pressure medications could dramatically enhance CBD's anti-inflammatory effects, opening possibilities for combination therapies for neurological conditions.","specificNumbers":"- Telmisartan alone: 60% NO reduction; CBD alone: 36%\n- Telmisartan + CBD: 95% NO inhibition (additive)\n- Losartan (5µM) + CBD (5µM): 80% NO inhibition (synergistic)\n- MMF + CBD: 77% NO inhibition (synergistic vs 35% + 12% alone)\n- CBD + telmisartan: attenuated LPS-induced TNFα\n- CBD ± telmisartan: 75% reduction in IL-17","methodology":"In vitro study using LPS-stimulated glial cells. Measured nitric oxide release, TNFα, IL-17, and interferon-γ. Tested CBD alone and in combination with angiotensin receptor blockers (telmisartan, losartan) and dimethyl fumarate/monomethyl fumarate.","limitations":"In vitro glial cell model only. Drug concentrations may not reflect achievable brain levels in vivo. LPS stimulation is an artificial inflammation model. Clinical relevance requires animal and human studies."},{"rthcId":"RTHC-04548","title":"Long-Term Tamoxifen Effects in the Cyclic Interaction of the Endocannabinoid and Endocrine System in the Rat Central Nervous System.","authors":"Fonseca, Bruno M; Bhowmick, Niloy; Cunha, Sara; Maia, João; Correia-da-Silva, Georgina; Teixeira, Natércia; Sá, Susana I","year":2023,"journal":"Biomedicines, 11(3)","doi":"10.3390/biomedicines11030720","pmid":"36979699","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Hypothalamic and pituitary AEA levels normally fluctuate across the estrous cycle, varying by brain area and cycle phase. Tamoxifen treatment disrupted this cyclic pattern and reduced AEA levels throughout the brain. In the pituitary, AEA fluctuations resulted from changes in both synthesis (NAPE-PLD) and degradation (FAAH) enzyme expression. In the hypothalamus, AEA level changes occurred without measurable changes in these enzymes, suggesting alternative regulatory mechanisms.","whyItMatters":"Many breast cancer patients take tamoxifen for years. Understanding how it affects the brain's endocannabinoid system could explain some of tamoxifen's neurological side effects and inform strategies to manage them.","specificNumbers":"- AEA levels fluctuate by brain area and estrous cycle phase\n- Tamoxifen reduced AEA levels in all brain areas\n- Pituitary NAPE-PLD expression increased in metestrus\n- No FAAH or NAPE-PLD changes detected in hypothalamus\n- Tamoxifen disrupted cyclic AEA fluctuation pattern","methodology":"Rat estrous cycle study with tamoxifen treatment. Measured AEA levels, FAAH expression, and NAPE-PLD expression in hypothalamus and pituitary across cycle phases.","limitations":"Rat reproductive cycles differ from human menstrual cycles. Tamoxifen doses may not perfectly model human exposure. Only two brain regions examined. The clinical significance of altered brain AEA levels is unclear."},{"rthcId":"RTHC-04549","title":"Patient Perceptions of Prenatal Cannabis Use and Implications for Clinicians.","authors":"Foti, Tara R; Green, Andrea; Altschuler, Andrea; Iturralde, Esti; Does, Monique B; Jackson-Morris, Melanie; Adams, Sara R; Goler, Nancy; Ansley, Deborah; Conway, Amy; Young-Wolff, Kelly C","year":2023,"journal":"Obstetrics and gynecology, 142(5), 1153-1161","doi":"10.1097/AOG.0000000000005295","pmid":"37562055","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among 53 pregnant participants (70% daily users, 25% weekly), many perceived a lack of scientific evidence about prenatal cannabis risks or believed it was safe. Participants preferred cannabis over OTC or prescription medications for mood, morning sickness, pain, and sleep. They valued open interactions with obstetricians that acknowledged their motivations for use and desired information about risks through conversations and educational materials. White and Black participants had generally similar perspectives, but some Black participants uniquely described concerns about racial bias related to their cannabis use.","whyItMatters":"Understanding why pregnant women continue using cannabis is essential for developing effective clinical communication strategies. The finding that women prefer cannabis to prescribed medications suggests they may be open to alternative treatments if presented respectfully.","specificNumbers":"- 53 participants in 18 focus groups\n- 30 White, 23 Black participants\n- Mean age: 30.3 years (SD 5.2)\n- Mean gestational age: 20.9 weeks\n- 69.8% daily use, 24.5% weekly, 5.7% monthly or less\n- Race-concordant focus groups","methodology":"Qualitative study with 18 semi-structured, race-concordant virtual focus groups. Participants self-reported cannabis use at prenatal care entry in Kaiser Permanente Northern California. Thematic analysis of recorded and transcribed data.","limitations":"Qualitative study cannot quantify prevalence of views. All participants from one healthcare system in California. Self-selected sample of women willing to discuss cannabis use. Focus groups may reflect social desirability bias."},{"rthcId":"RTHC-04550","title":"Cannabis use in Attention - Deficit/Hyperactivity Disorder (ADHD): A scoping review.","authors":"Francisco, Ana Paula; Lethbridge, Grace; Patterson, Beth; Goldman Bergmann, Carolina; Van Ameringen, Michael","year":2023,"journal":"Journal of psychiatric research, 157, 239-256","doi":"10.1016/j.jpsychires.2022.11.029","pmid":"36508935","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Of 39 included studies, only one randomized placebo-controlled trial directly measured cannabis effects on ADHD — finding no significant effect on the primary outcome (QbTest: Est=-0.17, 95% CI -0.40 to 0.07, p=0.16). Most literature consists of cross-sectional studies examining associations between ADHD severity and cannabis use. Fifteen studies assessed neuropsychiatric effects using cognitive tests or neuroimaging. THC and CBD concentrations were poorly measured in most studies. Although some studies indicated symptom improvement, most indicated worsening or no effect.","whyItMatters":"Despite widespread self-medication claims, the evidence does not support cannabis for ADHD. This comprehensive scoping review provides clinicians with the strongest evidence summary available to guide patient conversations.","specificNumbers":"- 39 studies included\n- 1 RCT: no significant effect (QbTest Est=-0.17, p=0.16)\n- 15 studies used neuropsychiatric tests or neuroimaging\n- Most studies: cross-sectional design\n- THC/CBD concentrations poorly measured in most studies\n- Databases: MEDLINE, EMBASE, EMCARE, PsycINFO, Web of Science, Cochrane, ClinicalTrials.gov","methodology":"Scoping review following systematic search methodology. Searched seven databases for publications in English through June 2022. Included experimental and observational studies assessing cannabis effects on ADHD symptomatology and neuropsychiatric outcomes.","limitations":"Scoping review (broader than systematic review) with heterogeneous study designs. Most underlying studies are observational. The single RCT was not large. Cannabis exposure was poorly quantified across studies."},{"rthcId":"RTHC-04551","title":"Sex-specific susceptibility to psychotic-like states provoked by prenatal THC exposure: Reversal by pregnenolone.","authors":"Frau, Roberto; Melis, Miriam","year":2023,"journal":"Journal of neuroendocrinology, 35(2), e13240","doi":"10.1111/jne.13240","pmid":"36810840","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Prenatal THC exposure deregulated mesolimbic dopamine system development, but psychotic-like phenotypes only emerged when offspring were subsequently exposed to environmental challenges (stress or THC). This vulnerability was sex-specific — female offspring did not display psychotic-like outcomes under the same challenges. Pregnenolone normalized mesolimbic dopamine function and rescued psychotic-like phenotypes, suggesting it as a potential preventive treatment for at-risk individuals.","whyItMatters":"This study provides a biological mechanism for why prenatal cannabis exposure increases psychosis risk and offers a potential intervention (pregnenolone) that could prevent psychosis onset in vulnerable male offspring.","specificNumbers":"- Male offspring only showed psychotic-like phenotypes\n- Vulnerability required \"second hit\" (stress or THC)\n- Pregnenolone normalized mesolimbic dopamine function\n- Pregnenolone rescued psychotic-like phenotypes\n- Female offspring were protected","methodology":"Preclinical review/study examining prenatal THC exposure effects on mesolimbic dopamine development in rats. Behavioral and neurochemical assessments with and without environmental challenges. Pregnenolone treatment studies.","limitations":"Rat models of psychosis are approximations of human schizophrenia. Sex differences in rats may not directly translate to humans. Pregnenolone's safety and efficacy in at-risk human populations is not established."},{"rthcId":"RTHC-04552","title":"Diagnosis and Management of Cyclic Vomiting Syndrome: A Critical Review.","authors":"Frazier, Rosita; Li, B U K; Venkatesan, Thangam","year":2023,"journal":"The American journal of gastroenterology, 118(7), 1157-1167","doi":"10.14309/ajg.0000000000002216","pmid":"36791365","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CVS affects approximately 2% of the US population with recurrent disabling episodes of nausea, vomiting, and abdominal pain. It's closely associated with migraines and likely shares pathophysiology. Patients commonly use cannabis therapeutically for symptom relief. However, cannabinoid hyperemesis syndrome (CHS) is now recognized as a potential subset of CVS where chronic heavy cannabis use leads to hyperemesis. The review recommends a biopsychosocial treatment approach with prophylactic tricyclic antidepressants, antiepileptics, or aprepitant, and abortive triptans, ondansetron, or sedation.","whyItMatters":"The diagnostic overlap between CVS and CHS creates a clinical challenge: cannabis may help some patients while causing symptoms in others. Clinicians need to differentiate between these scenarios for appropriate management.","specificNumbers":"- CVS prevalence: ~2% in the US\n- More common in females\n- Associated with migraines, anxiety, depression, autonomic dysfunction\n- Prophylaxis: amitriptyline, topiramate, aprepitant\n- Abortive: triptans, ondansetron, sedation","methodology":"Critical narrative review of CVS diagnosis, pathophysiology, and management, with specific attention to the cannabis-CVS-CHS relationship.","limitations":"Narrative review, not systematic. The distinction between CVS with therapeutic cannabis use and CHS remains clinically challenging. Pathophysiology of both conditions is incompletely understood."},{"rthcId":"RTHC-04553","title":"Associations Between Distinct Co-occurring Substance Use Disorders and Receipt of Medications for Opioid Use Disorder in the Veterans Health Administration.","authors":"Frost, Madeline C; Hawkins, Eric J; Glass, Joseph E; Hallgren, Kevin A; Williams, Emily C","year":2023,"journal":"Journal of addiction medicine, 17(3), 278-285","doi":"10.1097/ADM.0000000000001095","pmid":"37267168","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among 23,990 VA patients without prior MOUD, only 12% initiated medications in the following year. Cannabis use disorder (aIRR=0.78) and alcohol use disorder (aIRR=0.80) were both negatively associated with initiation. Among 11,854 patients already on MOUD, 83% continued. Cannabis use disorder (aIRR=0.95), alcohol use disorder (aIRR=0.94), and amphetamine/stimulant use disorder (aIRR=0.94) were all negatively associated with continuation.","whyItMatters":"MOUD (buprenorphine, methadone, naltrexone) is the most effective treatment for opioid use disorder but is underutilized. If co-occurring cannabis or alcohol disorders create barriers to starting or staying on MOUD, addressing these barriers could improve opioid treatment outcomes.","specificNumbers":"- 23,990 patients without prior MOUD; 12% initiated\n- 11,854 patients with prior MOUD; 83% continued\n- Cannabis UD initiation: aIRR=0.78 (95% CI: 0.70-0.87)\n- Alcohol UD initiation: aIRR=0.80 (95% CI: 0.72-0.90)\n- Cannabis UD continuation: aIRR=0.95 (95% CI: 0.93-0.98)\n- Study period: Aug 2016-Jul 2017","methodology":"Retrospective cohort study using national VA electronic health records. Diagnostic codes for SUDs, prescription fills/clinic visits for MOUD. Adjusted regression models stratified by prior MOUD receipt.","limitations":"Observational design cannot determine why co-occurring SUDs reduce MOUD receipt. VA population may not generalize to non-veterans. Diagnostic codes may not capture all substance use. Cannot distinguish patient vs provider barriers."},{"rthcId":"RTHC-04554","title":"Potential neonatal toxicity of new psychoactive substances.","authors":"Fujiwara, Ryoichi; Journey, Megan; Al-Doori, Fatimah; Bell, Paris; Judge, Brahmjot; Miracle, Kamille; Ito, Kousei; Jones, Sabrina","year":2023,"journal":"Pharmacology & therapeutics, 248, 108468","doi":"10.1016/j.pharmthera.2023.108468","pmid":"37290575","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Nearly 1,000 new psychoactive substances have been documented as of 2020. NPS use is associated with higher rates of unplanned pregnancy. Up to 4 in 100 women seeking substance abuse treatment are pregnant or nursing. Animal studies and case reports show that certain NPS exposure during lactation can cause neonatal toxicity including brain damage. Using prediction models, the review identified synthetic cannabinoids and their metabolites as highly accumulative in breast milk. This neonatal toxicity is usually unrecognized by healthcare professionals.","whyItMatters":"Synthetic cannabinoids are commonly used by young adults, and their accumulation in breast milk poses an underrecognized risk to nursing infants. Healthcare providers need awareness of this emerging issue.","specificNumbers":"- ~1,000 NPSs documented as of January 2020\n- Up to 4 in 100 women in substance treatment are pregnant/nursing\n- Synthetic cannabinoids identified as highly accumulative in breast milk\n- Examples: synthetic cannabinoids, cathinones, phenethylamines, piperazines","methodology":"Review article integrating animal studies, clinical case reports, and computational prediction models to assess neonatal toxicity of NPSs, with emphasis on synthetic cannabinoids and breast milk accumulation.","limitations":"Primarily based on animal data and prediction models. Limited human case report data. Actual breast milk concentrations of most NPSs have not been measured in humans. The rapid emergence of new compounds outpaces safety research."},{"rthcId":"RTHC-04555","title":"Phytocannabinoids biosynthesis during early stages of development of young Cannabis sativa L. seedlings: Integrating biochemical and transcription data.","authors":"Fulvio, Flavia; Mandolino, Giuseppe; Citti, Cinzia; Pecchioni, Nicola; Cannazza, Giuseppe; Paris, Roberta","year":2023,"journal":"Phytochemistry, 214, 113793","doi":"10.1016/j.phytochem.2023.113793","pmid":"37479208","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Analyzing three cannabis chemotypes (industrial and medicinal), researchers found that cannabinoid synthase genes are already expressed in the seed stage — before germination. CBCA was the first cannabinoid to accumulate after emergence, and there was good correspondence between CBCA synthase gene transcription and CBCA metabolite levels. This was consistent across different chemotypes, suggesting cannabinoid production is fundamentally important to the plant from its earliest developmental stages.","whyItMatters":"Understanding when and how cannabis produces cannabinoids is crucial for both agricultural optimization and basic plant biology. The early expression of these genes suggests cannabinoids may play protective roles during the plant's most vulnerable growth stage.","specificNumbers":"- 3 chemotypes studied (industrial and medicinal)\n- Cannabinoid synthase genes expressed in seeds\n- CBCA: first cannabinoid to accumulate in seedlings\n- Good correspondence between CBCA synthase transcript and metabolite levels","methodology":"Gene expression analysis (transcription levels) of cannabinoid pathway genes during early development phases. Chemical characterization of cannabinoid content in matched samples across three chemotypes.","limitations":"Focus on early development only — does not cover the flowering stage when most cannabinoid production occurs. Transcript levels may not perfectly correlate with enzyme activity. Limited number of chemotypes studied."},{"rthcId":"RTHC-04556","title":"High levels of pesticides found in illicit cannabis inflorescence compared to licensed samples in Canadian study using expanded 327 pesticides multiresidue method.","authors":"Gagnon, Mathieu; McRitchie, Tyler; Montsion, Kim; Tully, Josée; Blais, Michel; Snider, Neil; Blais, David R","year":2023,"journal":"Journal of cannabis research, 5(1), 34","doi":"10.1186/s42238-023-00200-0","pmid":"37620969","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Using an expanded 327-pesticide analysis method, licensed Canadian cannabis showed only 6% sample positivity with just two pesticides (myclobutanil and dichlobenil) detected at the lowest calibrated level (0.01 µg/g). Illicit cannabis showed a striking 92% positivity rate with 23 unique pesticide active ingredients detected, averaging 3.7 different pesticides per sample. Chlorpyrifos, imidacloprid, and myclobutanil in illicit samples reached concentrations up to three orders of magnitude (1,000x) above the method's lowest calibration level.","whyItMatters":"This is the strongest evidence yet that cannabis legalization and regulation in Canada is achieving its safety goals. The dramatic difference in contamination levels provides a powerful argument for the regulated market.","specificNumbers":"- 327 pesticides tested simultaneously\n- Licensed cannabis: 6% positivity, 2 pesticides at trace levels\n- Illicit cannabis: 92% positivity, 23 unique pesticides\n- Average 3.7 pesticides per illicit sample\n- Chlorpyrifos, imidacloprid, myclobutanil up to 1,000x above detection limit in illicit\n- Method LCL: 0.01 µg/g","methodology":"Expanded multi-residue method using modified QuEChERS sample preparation with GC-MS/MS and LC-MS/MS for 327 pesticide active ingredients. Applied to licensed and illicit Canadian cannabis inflorescence samples.","limitations":"Illicit market sampling may not be representative of all illegal cannabis. Licensed sample selection not detailed. Health risk assessment of detected pesticide levels was not performed. Some pesticides may not be fully extracted from cannabis matrix."},{"rthcId":"RTHC-04557","title":"Subcutaneous Emphysema, Pneumothorax, Pneumomediastinum, and Pneumoperitoneum Following Synthetic Cannabinoid Toxicity in an Incarcerated Man.","authors":"Gala, Zachary; Kravchenko, Timothy; Volk, Lindsey; Chatani, Praveen; Kar, Reema; Choron, Rachel L","year":2023,"journal":"The American surgeon, 89(11), 4967-4969","doi":"10.1177/00031348221142589","pmid":"36426894","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This case report describes a 21-year-old incarcerated male who presented with delayed-onset subcutaneous emphysema, pneumothorax, pneumomediastinum, and pneumoperitoneum following synthetic cannabinoid use with altered mental status. The case highlights both the severe toxicity potential of synthetic cannabinoids and the vulnerability of incarcerated individuals who face delayed medical care and poor follow-up.","whyItMatters":"Synthetic cannabinoid use is particularly prevalent in prison settings where they are harder to detect on drug tests. This case demonstrates a life-threatening complication that clinicians evaluating synthetic cannabinoid toxicity should consider.","specificNumbers":"- 21-year-old male\n- Incarcerated at time of presentation\n- Complications: subcutaneous emphysema, pneumothorax, pneumomediastinum, pneumoperitoneum\n- Delayed presentation","methodology":"Single case report with clinical description.","limitations":"Single case report cannot establish prevalence or causation. The mechanism by which synthetic cannabinoids caused air leakage is not established. Other contributing factors (trauma, forceful vomiting) cannot be excluded."},{"rthcId":"RTHC-04558","title":"Addressing cannabis consumption among patients with hyperemesis gravidarum.","authors":"Galvin, Shelley L; Coulson, Carol C","year":2023,"journal":"AJOG global reports, 3(2), 100180","doi":"10.1016/j.xagr.2023.100180","pmid":"36911236","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review highlights that severe nausea and vomiting of pregnancy (affecting up to 3% of pregnancies) is increasingly associated with cannabis use, as pregnant individuals believe cannabis is a natural, safe antiemetic. However, some of these cases may actually be cannabinoid hyperemesis syndrome (CHS), where chronic cannabis use itself causes the severe vomiting. CHS may be more common in pregnancy than previously recognized. The diagnostic confusion is compounded by variable legal status, personal acceptance, and challenging patient-provider communication.","whyItMatters":"If a significant proportion of severe pregnancy nausea attributed to hyperemesis gravidarum is actually CHS, then continued cannabis use is making these patients worse, not better. Differential diagnosis is critical for proper treatment.","specificNumbers":"- Severe NVP/HG affects up to 3% of pregnancies\n- Cannabis discouraged by Surgeon General and ACOG\n- CHS may be more common than previously thought\n- Variable legal status across states complicates discussion","methodology":"Clinical review and commentary on the intersection of cannabis use, severe nausea of pregnancy, and cannabinoid hyperemesis syndrome.","limitations":"Not a systematic review or original research. The overlap between HG and CHS is difficult to quantify with current diagnostic tools. Provider-patient communication barriers may limit data quality."},{"rthcId":"RTHC-04559","title":"Exploring the 1,3-benzoxazine chemotype for cannabinoid receptor 2 as a promising anti-cancer therapeutic.","authors":"Gambacorta, Nicola; Gasperi, Valeria; Guzzo, Tatiana; Di Leva, Francesco Saverio; Ciriaco, Fulvio; Sánchez, Cristina; Tullio, Valentina; Rozzi, Diego; Marinelli, Luciana; Topai, Alessandra; Nicolotti, Orazio; Maccarrone, Mauro","year":2023,"journal":"European journal of medicinal chemistry, 259, 115647","doi":"10.1016/j.ejmech.2023.115647","pmid":"37478557","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"From 25 synthesized 1,3-benzoxazine derivatives, compound 7b5 emerged as a potent and selective CB2 agonist (EC50=110 nM) with over 90-fold selectivity over CB1 (EC50>10 µM). In triple-negative breast cancer BT549 cells, 7b5 impaired proliferation and attenuated pro-inflammatory cytokine release in a CB2-dependent manner. It also abrogated ERK1/2 activation, a key oncogenic and inflammatory signaling pathway. Molecular dynamics suggested structural explanations for its selectivity and agonist behavior.","whyItMatters":"Triple-negative breast cancer has limited treatment options. A selective CB2 agonist that reduces both cancer cell proliferation and inflammation — without CB1-mediated psychoactive effects — could be a promising therapeutic lead.","specificNumbers":"- 25 derivatives synthesized\n- 7b5: CB2 EC50 = 110 nM\n- 7b5: CB1 EC50 > 10 µM (>90-fold selectivity)\n- Impaired BT549 triple-negative breast cancer proliferation\n- Attenuated pro-inflammatory cytokine release\n- Abrogated ERK1/2 activation","methodology":"Medicinal chemistry synthesis of 25 1,3-benzoxazine derivatives. In vitro receptor activation assays. Antiproliferative testing in triple-negative breast cancer cells. Cytokine release assays. ERK1/2 signaling assessment. Molecular dynamics simulations.","limitations":"In vitro study only — no animal or human testing. One cancer cell line tested. Long-term selectivity and safety profile unknown. The jump from cell culture to clinical efficacy is large."},{"rthcId":"RTHC-04560","title":"Delta-9-Tetrahydrocannabinol, Cannabidiol, and Acute Psychotomimetic States: A Balancing Act of the Principal Phyto-Cannabinoids on Human Brain and Behavior.","authors":"Ganesh, Suhas; Cortes-Briones, Jose; Schnakenberg Martin, Ashley M; Skosnik, Patrick D; D'Souza, Deepak C; Ranganathan, Mohini","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 846-856","doi":"10.1089/can.2021.0166","pmid":"35319274","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The lowest CBD:THC ratio tested (1:1, using 2.5mg CBD with 0.035mg/kg THC) maximally attenuated both psychotomimetic effects (PANSS positive subscale) and \"neural noise\" — an electrophysiological biomarker of psychosis. Higher ratios (2:1 and 3:1) did not provide additional protection. Notably, no CBD dose reduced the subjective \"high\" from THC, suggesting CBD selectively blocks psychosis-relevant effects without eliminating intoxication.","whyItMatters":"This directly contradicts the assumption that more CBD always means more protection. The finding that the lowest ratio was most effective has major implications for cannabis product design and harm reduction strategies.","specificNumbers":"- 28 healthy volunteers (12 women)\n- CBD:THC ratios: 1:1, 2:1, 3:1\n- 1:1 ratio: PANSS positive ATS=7.83, p_corrected=0.015\n- 1:1 ratio: neural noise ATS=8.83, p_corrected=0.009\n- No CBD dose reduced subjective \"high\" (p>0.05 for all)","methodology":"Double-blind, randomized, placebo-controlled, counterbalanced human laboratory study. Intravenous THC with three CBD:THC ratios. EEG measurement of neural noise. PANSS for psychotomimetic symptoms. Subjective effects ratings.","limitations":"Small sample (n=28). Intravenous administration differs from typical cannabis use routes. Acute single-dose study. Very low absolute CBD doses (2.5-7.5mg) compared to commercial products."},{"rthcId":"RTHC-04561","title":"Phytochemical interventions for post-traumatic stress disorder: A cluster co-occurrence network analysis using CiteSpace.","authors":"Gao, Biao; Qu, Yi-Cui; Cai, Meng-Yu; Zhang, Yin-Yin; Lu, Hong-Tao; Li, Hong-Xia; Tang, Yu-Xiao; Shen, Hui","year":2023,"journal":"Journal of integrative medicine, 21(4), 385-396","doi":"10.1016/j.joim.2023.06.006","pmid":"37380564","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Analysis of 301 articles showed research surged after 2015, with nearly half from North America. The field is dominated by neuroscience, with Addictive Behaviors and Drug and Alcohol Dependence publishing the most papers. An \"ebb and flow\" was identified between substance abuse/marijuana research and psychedelic medicine/medicinal cannabis. Most current studies focus on psychedelic interventions. Other phytochemicals (addressing neurosteroid turnover, serotonin, BDNF) represent a small proportion of research.","whyItMatters":"PTSD affects millions globally and current treatments are inadequate. This bibliometric map shows where the field is heading — primarily toward psychedelics — and identifies gaps where cannabis and other plant-based treatments are under-studied.","specificNumbers":"- 301 articles analyzed (2007-2022)\n- Surge after 2015\n- Nearly half from North America\n- Most studies focus on psychedelic interventions\n- Other phytochemicals represent small proportion","methodology":"Bibliometric analysis using CiteSpace for network clustering co-occurrence analysis of Web of Science literature. Supplemented with qualitative narrative review.","limitations":"Bibliometric analysis reflects publication patterns, not clinical outcomes. English-language bias. Web of Science only. Does not evaluate quality of underlying studies."},{"rthcId":"RTHC-04562","title":"Role of CB2 cannabinoid receptor in the development of food addiction in male mice.","authors":"García-Blanco, A; Ramírez-López, Á; Navarrete, F; García-Gutiérrez, M S; Manzanares, J; Martín-García, E; Maldonado, R","year":2023,"journal":"Neurobiology of disease, 179, 106034","doi":"10.1016/j.nbd.2023.106034","pmid":"36775043","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Using a validated operant model of food addiction with highly palatable chocolate pellets, researchers found that CB2 receptor knockout mice were protected from developing food addiction and associated impulsive and depressive-like behaviors. Conversely, transgenic mice overexpressing CB2 showed increased vulnerability to food addiction after long-term palatable food exposure. Brain transcriptomic analysis revealed gene expression changes associated with resilience and vulnerability that corresponded to CB2 genotype.","whyItMatters":"While CB1 receptors are well-known to regulate appetite, this is the first study to directly implicate CB2 receptors in food addiction — a compulsive behavior pattern distinct from normal hunger. This opens a new therapeutic target.","specificNumbers":"- Three genotypes compared: wild-type, CB2 knockout, CB2 overexpressing\n- Long-term operant training with chocolate pellets\n- CB2 knockout: protected from food addiction\n- CB2 overexpressing: vulnerable to food addiction\n- Associated impulsive and depressive-like behaviors tracked","methodology":"Validated operant mouse model of food addiction using long-term training with highly palatable food. Compared wild-type, constitutive CB2 knockout, and CB2 overexpressing transgenic mice. Behavioral phenotyping and brain transcriptomic analysis.","limitations":"Constitutive genetic models cannot distinguish developmental from acute CB2 effects. Mouse food addiction models may not fully capture human eating disorders. Only male mice studied. Chocolate pellets as palatable food may not represent all food addiction patterns."},{"rthcId":"RTHC-04563","title":"Changes in alcohol beliefs mediate the effects of a school-based prevention program on alcohol use among Brazilian adolescents.","authors":"Garcia-Cerde, Rodrigo; Valente, Juliana Y; Sanchez, Zila M","year":2023,"journal":"Addictive behaviors, 137, 107522","doi":"10.1016/j.addbeh.2022.107522","pmid":"36242996","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In a cluster-randomized trial of 5,208 students across 73 public schools, the 12-lesson prevention program indirectly prevented alcohol use and binge drinking by increasing negative and non-positive beliefs about alcohol. Only the direct effect on reducing lifetime alcohol consumption was statistically significant. An unintended indirect increase in binge drinking was observed through increased alcohol knowledge. No effects were found for marijuana, tobacco, or inhalants. Among students who were already users, no effects were found for any substance.","whyItMatters":"School-based prevention programs have variable effectiveness across substances and cultures. This study shows that changing beliefs can delay alcohol initiation but the same mechanism does not transfer to other substances, suggesting substance-specific prevention strategies may be needed.","specificNumbers":"- 5,208 students, 73 schools, 3 Brazilian cities\n- 49.4% girls, mean age 13.2 years\n- 12 #Tamojunto2.0 lessons delivered by trained teachers\n- Effective for alcohol and binge drinking via belief change\n- No effect on marijuana, tobacco, or inhalants\n- No effect among existing substance users","methodology":"Cluster-randomized controlled trial. Control group received no intervention. Multiple mediation models with post-estimation adjustment for clustering. Full-information maximum-likelihood for missing data. 9-month follow-up.","limitations":"No active control group. 9-month follow-up may be too short for marijuana effects. Brazilian cultural context may not generalize. Implementation fidelity varied across schools."},{"rthcId":"RTHC-04564","title":"Cannabidiol regulates behavioral and brain alterations induced by spontaneous alcohol withdrawal.","authors":"Gasparyan, Ani; Navarrete, Francisco; Navarro, Daniela; Manzanares, Jorge","year":2023,"journal":"Neuropharmacology, 233, 109549","doi":"10.1016/j.neuropharm.2023.109549","pmid":"37085012","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Mice undergoing spontaneous alcohol withdrawal at 6 hours showed significant somatic withdrawal signs, anxiety-like behaviors, and gene expression changes across multiple brain targets (Cnr1, Cnr2, Oprm1, Pomc in nucleus accumbens; Pomc and Th in VTA). Acute CBD (10, 20, 40 mg/kg) dose-dependently normalized both behavioral symptoms and gene expression changes in the nucleus accumbens. However, CBD did not modulate gene expression changes in the ventral tegmental area. Correlations between anxiety behaviors and gene expression in the NAcc supported the mechanistic link.","whyItMatters":"Alcohol withdrawal is dangerous and current treatments have significant limitations. CBD could offer a non-addictive, well-tolerated alternative that addresses both the behavioral symptoms and underlying neurobiological changes of withdrawal.","specificNumbers":"- Ethanol escalation: 2.5, 3, 3.5 g/kg/12h over 15 days\n- Withdrawal assessed at 6, 12, 24, 72h\n- CBD doses: 10, 20, 40 mg/kg IP\n- CBD effective at 6h timepoint\n- Gene targets: Cnr1, Cnr2, Oprm1, Pomc (NAcc); Pomc, Th (VTA)\n- CBD modulated NAcc but not VTA gene expression","methodology":"C57BL/6J male mice received escalating oral ethanol for 15 days. Spontaneous withdrawal studied at 6, 12, 24, 72 hours. Acute CBD tested at 6h withdrawal. Behavioral testing for anxiety and somatic signs. Real-time PCR for gene expression in NAcc and VTA. Pearson correlations.","limitations":"Only male mice studied. Acute CBD treatment may not predict chronic treatment effects. IP administration differs from human oral use. Mouse alcohol withdrawal may not fully model human withdrawal."},{"rthcId":"RTHC-04565","title":"Recent Advances on Type-2 Cannabinoid (CB2) Receptor Agonists and their Therapeutic Potential.","authors":"Gasperi, Valeria; Guzzo, Tatiana; Topai, Alessandra; Gambacorta, Nicola; Ciriaco, Fulvio; Nicolotti, Orazio; Maccarrone, Mauro","year":2023,"journal":"Current medicinal chemistry, 30(12), 1420-1457","doi":"10.2174/0929867329666220825161603","pmid":"36028971","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This review covers five years of CB2 agonist development. CB2 is expressed throughout the body and regulates inflammation, neurodegeneration, bone metabolism, and cancer biology. New therapeutic applications include CNS disorders (Parkinson's, Alzheimer's, multiple sclerosis), bone and joint diseases (osteoporosis, arthritis), and various cancers. The recent elucidation of CB2's 3D structure has enabled rational drug design of more selective agonists. Multiple chemical classes are being explored, with patent activity reflecting industry investment.","whyItMatters":"Unlike CB1 (which causes psychoactive effects), CB2 can be targeted without producing a \"high.\" This review maps the full landscape of therapeutic opportunities and drug development strategies for this increasingly important receptor.","specificNumbers":"- Review covers last 5 years of CB2 research and patents\n- Therapeutic areas: CNS disorders, bone/synovial disease, cancer, pain, inflammation\n- CB2 3D structure recently solved\n- Multiple chemical classes of agonists in development","methodology":"Comprehensive review of recent literature on CB2 receptor biology, therapeutic applications, and agonist drug development, including patent analysis.","limitations":"Review format — no new experimental data. Most CB2 agonists are preclinical. Clinical translation remains challenging due to the receptor's complex biology."},{"rthcId":"RTHC-04566","title":"Repeated footshock stress induces an escalation of cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1.","authors":"Gaulden, Andrew D; Tepe, Erin A; Sia, Eleni; Rollins, Sierra S; McReynolds, Jayme R","year":2023,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2023.02.23.529774","pmid":"36865137","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Daily footshock stress produced escalation of cocaine self-administration similarly in both sexes. Female stress-escalated rats showed greater timeout responding and \"front-loading\" behavior. The CB1 antagonist rimonabant reduced cocaine intake in stressed males specifically (not unstressed controls), while in females it reduced intake across conditions but with greater sensitivity in stressed rats. This suggests stress recruits CB1 signaling to regulate cocaine-taking behavior in both sexes.","whyItMatters":"Stress is a major driver of drug use escalation, and understanding the biological mechanisms — particularly sex differences — is essential for developing targeted interventions. This study shows the endocannabinoid system is a key mediator.","specificNumbers":"- Equal cocaine escalation in both sexes under stress\n- Rimonabant in males: only reduced intake in stress+cocaine group\n- Rimonabant in females: reduced intake across groups\n- Female stressed rats: both doses (1, 3 mg/kg) effective\n- Cocaine dose: 0.5 mg/kg/infusion IV\n- 2-hour access in 4x30-min blocks","methodology":"Male and female Sprague-Dawley rats self-administered cocaine during modified short-access paradigm with daily footshock stress. Systemic rimonabant (CB1 inverse agonist/antagonist) tested at 1 and 3 mg/kg. Behavioral measures included intake, timeout responding, and front-loading.","limitations":"Preprint not yet peer-reviewed. Rat stress model may not capture human stress-drug interactions. Rimonabant has been withdrawn from human use due to psychiatric side effects. Only one cocaine dose tested."},{"rthcId":"RTHC-04567","title":"Cannabidiol and Minor Phytocannabinoids: A Preliminary Study to Assess Their Anti-Melanoma, Anti-Melanogenic, and Anti-Tyrosinase Properties.","authors":"Gaweł-Bęben, Katarzyna; Czech, Karolina; Luca, Simon Vlad","year":2023,"journal":"Pharmaceuticals (Basel, Switzerland), 16(5)","doi":"10.3390/ph16050648","pmid":"37242431","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among three melanoma cell lines, A375 cells were highly susceptible to all four phytocannabinoids (IC50 12.02-25.13 µg/mL). In melanin-producing B16F10 cells stimulated with αMSH, CBD, CBG, and CBN significantly reduced both extracellular and intracellular melanin content at 5 µg/mL. CBN uniquely inhibited both mushroom and murine tyrosinase. CBG and CBC inhibited only mushroom tyrosinase. CBD was inactive against tyrosinase, suggesting the anti-melanogenic effects of CBD, CBG, and CBN work through mechanisms other than direct tyrosinase inhibition.","whyItMatters":"This is the first study to evaluate CBN and CBC for anti-melanoma and anti-melanogenic properties, expanding the potential cosmeceutical and therapeutic applications of minor cannabinoids beyond CBD.","specificNumbers":"- A375 melanoma IC50: 12.02-25.13 µg/mL across all 4 cannabinoids\n- CBD, CBG, CBN reduced extracellular melanin to 29.76-45.14% at 5 µg/mL\n- Intracellular melanin: 60.59-67.87% at 5 µg/mL\n- CBN: inhibited both mushroom and murine tyrosinase (50-200 µg/mL)\n- CBD: inactive against tyrosinase","methodology":"In vitro study testing CBD, CBG, CBN, and CBC against three human melanoma cell lines and murine melanoma B16F10 cells. αMSH-induced melanogenesis model. Mushroom and murine tyrosinase inhibition assays.","limitations":"In vitro only — cannot predict in vivo anti-cancer or skin-lightening efficacy. Concentrations used may not be achievable in skin. Only three melanoma cell lines tested. No human skin models used."},{"rthcId":"RTHC-04568","title":"The Dark Side of Cannabidiol: The Unanticipated Social and Clinical Implications of Synthetic Δ8-THC.","authors":"Geci, Michael; Scialdone, Mark; Tishler, Jordan","year":2023,"journal":"Cannabis and cannabinoid research, 8(2), 270-282","doi":"10.1089/can.2022.0126","pmid":"36264171","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review provides what the authors believe is the first comprehensive listing of all documented byproducts from the acid-catalyzed ring closure of CBD to delta-8 THC. Quality control in the delta-8 industry is totally inadequate. Consumers are ingesting mislabeled products containing compounds that have never received toxicological testing. The synthetic chemistry is complex and poorly controlled, producing delta-8, delta-10, HHC, and numerous other isomerized byproducts. EVALI cases continue to be reported, with a fatality rate approaching 2% in California.","whyItMatters":"The 2018 Farm Bill inadvertently created a loophole allowing hemp-derived delta-8 THC products. This review reveals the chemical complexity and safety concerns of a rapidly growing unregulated market affecting millions of consumers.","specificNumbers":"- First comprehensive listing of ACRCC-delta-8 THC byproducts\n- EVALI fatality rate approaching 2% in California\n- Products include delta-8, delta-10, HHC, and numerous isomers\n- No human toxicological evaluation for most byproducts\n- Quality control described as \"totally inadequate\"","methodology":"Literature review of ACRCC-delta-8 THC chemistry, quality control issues, byproduct identification, and regulatory concerns. Compilation of documented conversion byproducts.","limitations":"Review article, not original research. EVALI attribution to delta-8 products specifically is not fully established. The byproduct listing may not be exhaustive as new compounds continue to be identified."},{"rthcId":"RTHC-04569","title":"Cannabis Toxicity in Children and Adolescents.","authors":"George, Princy; Wahl, Michael","year":2023,"journal":"Pediatric annals, 52(5), e181-e186","doi":"10.3928/19382359-20230307-04","pmid":"37159059","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis legalization has increased both pediatric accidental exposures (primarily edibles) and adolescent chronic use presentations. Unintentional edible ingestions specifically increase in regions with retail cannabis legalization. Long-term adolescent effects include psychiatric changes and cannabinoid hyperemesis syndrome (CHS). The article provides clinical guidance on presentation patterns, evaluation approaches, and acute management in emergency and acute care settings.","whyItMatters":"Pediatric cannabis exposures are a direct and predictable consequence of legalization. Clinicians in acute care need practical guidance on recognizing and managing these presentations, which differ significantly between young children and adolescents.","specificNumbers":"- Edible ingestions increase with retail legalization\n- Children: primarily accidental edible ingestion\n- Adolescents: chronic use effects, psychiatric changes, CHS\n- Settings: emergency department and acute care","methodology":"Clinical review providing practical guidance on presentation, evaluation, and management of pediatric cannabis toxicity.","limitations":"Narrative clinical review, not systematic. Specific incidence data not detailed in abstract. Management recommendations based on limited evidence base for pediatric cannabis toxicity."},{"rthcId":"RTHC-04570","title":"Real-world, long-term evaluation of the tolerability and therapy retention of Epidiolex® (cannabidiol) in patients with refractory epilepsy.","authors":"Georgieva, Darina; Langley, James; Hartkopf, Katherine; Hawk, Lisa; Margolis, Amanda; Struck, Aaron; Felton, Elizabeth; Hsu, David; Gidal, Barry E","year":2023,"journal":"Epilepsy & behavior : E&B, 141, 109159","doi":"10.1016/j.yebeh.2023.109159","pmid":"36893722","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Of 108 patients (mean age 20.3, 52.8% female), 75% continued Epidiolex at final evaluation. The 25th percentile for discontinuation was 19 months. 46.3% experienced at least one adverse effect, but only 14.5% discontinued due to adverse effects. Top reasons for discontinuation were lack of efficacy (37%), increased seizures (22%), worsened behavior (22%), and sedation (22%). Importantly, 53% were able to discontinue or reduce at least one other antiseizure medication. GI complaints and LFT elevations were less common than in clinical trials.","whyItMatters":"Real-world data often differs from clinical trial results. This study shows Epidiolex performs well in everyday clinical practice, with better tolerability than trials suggested and meaningful reductions in polypharmacy.","specificNumbers":"- 108 patients, mean age 20.3 years (range 2-63)\n- 52.8% female\n- Mean maintenance dose: 15.3 mg/kg/day\n- 75% continued treatment at final evaluation\n- 25th percentile discontinuation: 19 months\n- 14.5% discontinued for adverse effects\n- 53% reduced or stopped another ASM\n- 47.2% taking concurrent clobazam","methodology":"Single-center retrospective review of patients with refractory epilepsy taking Epidiolex. Kaplan-Meier analysis for treatment retention. Adverse event documentation and medication change tracking.","limitations":"Single center. Retrospective design. No control group. Treatment retention used as proxy for effectiveness rather than direct seizure outcomes. Clobazam interactions may confound results."},{"rthcId":"RTHC-04571","title":"Comparison of Antiemetics in the Management of Pediatric Cannabinoid Hyperemesis Syndrome.","authors":"Geraci, Emily; Cake, Carrie; Mulieri, Kevin M; Fenn, Norman E","year":2023,"journal":"The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 28(3), 222-227","doi":"10.5863/1551-6776-28.3.222","pmid":"37303765","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In a retrospective review of pediatric CHS patients at Penn State Children's Hospital, nontraditional antiemetic medications (benzodiazepines, haloperidol, topical capsaicin) appeared more effective in resolving symptoms compared to traditional antiemetics (ondansetron, etc.). Analysis of all ordered antiemetics demonstrated a gap in symptom resolution between nontraditional and traditional agents. Adverse effects were minimal for both categories. Cannabis abstinence remains the most effective approach.","whyItMatters":"CHS in adolescents is increasing with cannabis legalization. Standard anti-nausea medications often fail, leading to repeated ER visits. This study provides evidence-based guidance for selecting more effective treatments in the pediatric population.","specificNumbers":"- Retrospective review of pediatric CHS cases\n- Age ≤18 years\n- Nontraditional agents: more effective for symptom resolution\n- Traditional agents: less effective\n- Minimal adverse effects in both categories\n- Abstinence remains most effective overall approach","methodology":"Retrospective review of electronic health records at Penn State Children's Hospital. Patients ≤18 with CHS-related diagnosis codes meeting diagnostic criteria. Efficacy assessed via subjective nausea reports and objective vomiting documentation.","limitations":"Retrospective single-center study. Small sample size (specific numbers not in abstract). Selection bias in medication choice. CHS diagnosis may be inconsistent across providers."},{"rthcId":"RTHC-04572","title":"Cannabinoid Therapy: Attitudes and Experiences of People With Chronic Pain.","authors":"Gewandter, Jennifer S; Edwards, Robert R; Hill, Kevin P; Wasan, Ajay D; Hooker, Julia E; Lape, Emma C; Besharat, Soroush; Cowan, Penney; Le Foll, Bernard; Ditre, Joseph W; Freeman, Roy","year":2023,"journal":"The Clinical journal of pain, 39(6), 249-258","doi":"10.1097/AJP.0000000000001109","pmid":"36971412","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among 969 respondents, 444 (46%) currently used cannabinoids, 213 (22%) previously used, and 312 (32%) never used them. Current users reported larger improvements than previous users across all pain types, including difficult-to-treat overlapping pain conditions. Current users also reported improvements in comorbid symptoms (sleep) and lower side effect interference. Current users had more frequent and satisfactory clinician communication about cannabinoids. Non-users cited lack of clinician suggestion (40%), illegality (25%), and lack of FDA regulation (19%) as barriers.","whyItMatters":"The disconnect between positive observational reports and mixed clinical trial results is a central tension in cannabinoid pain medicine. This survey helps explain it: patients who find cannabinoids effective continue using them, creating selection bias in observational data.","specificNumbers":"- 969 respondents total\n- 444 (46%) currently using cannabinoids\n- 213 (22%) previously used\n- 312 (32%) never tried\n- Barriers: no clinician approval (40%), illegality (25%), no FDA regulation (19%)\n- Current users reported large improvements across pain types","methodology":"Cross-sectional web-based survey distributed through chronic pain patient advocacy groups and foundations. Self-reported chronic pain, cannabinoid use, experiences, and attitudes.","limitations":"Self-selected sample via advocacy groups introduces bias. Self-reported outcomes without verification. Survivorship bias — current users may be those who responded well. No standardized pain outcome measures."},{"rthcId":"RTHC-04573","title":"Prevalence of Use and Perceived Effectiveness of Medical, Surgical, and Alternative Therapies for Endometriosis Pain in Canadians.","authors":"Gholiof, Mahsa; Adamson-De Luca, Emma; Foster, Warren G; Leyland, Nicholas A; Bridge-Cook, Philippa; Leonardi, Mathew; Wessels, Jocelyn M","year":2023,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 45(1), 11-20","doi":"10.1016/j.jogc.2022.11.003","pmid":"36455861","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Of 434 respondents, 93.8% used at least one alternative therapy in the past 6 months for endometriosis pain. Patients used an average of 6.9 alternative therapies, 2.3 medical treatments, and 1.7 surgical treatments per period. Despite this extensive treatment burden, 61.9% felt their pain was not adequately managed. Cannabis and heat were perceived as the most effective alternative therapies. The most commonly used alternatives were heat, meditation/mindfulness/rest, and diet.","whyItMatters":"Endometriosis affects 10-15% of women with limited effective treatments. The finding that patients turn to an average of 7 alternative therapies underscores the inadequacy of conventional management and positions cannabis as a treatment worth investigating.","specificNumbers":"- 434 respondents (Canadian, age 18-50)\n- 93.8% used at least 1 alternative therapy\n- Average 6.9 alternative therapies per 6 months\n- Average 2.3 medical and 1.7 surgical treatments\n- 61.9% felt pain inadequately managed\n- Cannabis and heat rated most effective alternatives","methodology":"Cross-sectional online survey via The Endometriosis Network Canada. Canadians 18-50 with diagnosed or suspected endometriosis. Self-reported therapy use and perceived effectiveness.","limitations":"Self-reported, self-selected sample through patient network. Perceived effectiveness ≠ measured effectiveness. Survey conducted during COVID-19 which may have affected treatment access. No verification of endometriosis diagnosis."},{"rthcId":"RTHC-04574","title":"Arrhythmic Effects of Cannabis in Ischemic Heart Disease.","authors":"Gillett, Leah; Johnson-Sasso, Cecelia; Miller, Brian; Shakowski, Courtney; Walker, Lori A; Tompkins, Christine","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 867-876","doi":"10.1089/can.2021.0188","pmid":"35353598","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among cannabis users wearing 14-day heart monitors, healthy controls showed brief heart rate increases (~5 bpm at 20 min) that declined after 4 hours. In ischemic heart disease (IHD) subjects, heart rate changes were blunted. Supraventricular tachycardia was most common in controls (9.5%) while nonsustained ventricular tachycardia dominated in IHD subjects (47.8% vs 5.6% in controls). SVT incidence decreased with more cannabis use in both groups. NSVT tended to increase with use in controls and was more prevalent in IHD. However, overall arrhythmia burden did not differ between cannabis users and non-users with IHD.","whyItMatters":"Cannabis use is increasing among older adults who are more likely to have heart disease. This is the first prospective study specifically examining arrhythmia risk in cannabis users with established ischemic heart disease.","specificNumbers":"- Controls: n=37 (57% men); IHD cannabis users: n=24 (58% men); IHD non-users: n=35 (51% men)\n- 14-day Zio monitor wear\n- HR increase: 4.99±6.7 bpm at 20 min in controls\n- HR decline: -7.4±7.7 bpm at 4h (p<0.05 in IHD)\n- NSVT: 47.8% in IHD vs 5.6% in controls (p=0.01)\n- SVT: 9.5% in controls vs 4.2% in IHD (p=0.04)","methodology":"Prospective observational study. Cannabis-using healthy controls and IHD subjects wore Zio monitors for 14 days. Non-cannabis-using IHD patients as additional comparator. Heart rate changes correlated with cannabis consumption timing. Arrhythmia frequency tracked.","limitations":"Small sample sizes. Observational design. Self-reported cannabis use timing. IHD non-user group wore monitors for clinical indications (potential selection bias). Cannabis use amount and method not standardized."},{"rthcId":"RTHC-04575","title":"Absorbance-Transmittance Excitation Emission Matrix Method for Quantification of Major Cannabinoids and Corresponding Acids: A Rapid Alternative to Chromatography for Rapid Chemotype Discrimination of Cannabis sativa Varieties.","authors":"Gilmore, Adam M; Elhendawy, Mostafa A; Radwan, Mohamed M; Kidder, Linda H; Wanas, Amira S; Godfrey, Murrell; Hildreth, Jana B; Robinson, A Edward; ElSohly, Mahmoud A","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 911-922","doi":"10.1089/can.2021.0165","pmid":"35486823","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The A-TEEM technique, combining UV-visible and fluorescence spectroscopy with machine learning, classified 49 cannabis flower extracts into three chemotypes with 100% accuracy. It quantified total THC with LOQ of 0.061% and CBD with LOQ of 0.059% using GC-FID reference data, with cross-validation and prediction values >0.99. Using HPLC reference data, it achieved even lower LOQs for THC (0.026%). The method could separately quantify acid and neutral forms of cannabinoids and discriminate between legal and illegal chemotypes.","whyItMatters":"Cannabis testing is currently expensive and slow, requiring chromatographic equipment. A 45-second spectroscopic method could dramatically reduce costs and turnaround times for the cannabis industry and regulators.","specificNumbers":"- 49 dry flower extracts from 84 accessions\n- Chemotype classification: 100% accuracy\n- THC LOQ: 0.061% (GC-FID) / 0.026% (HPLC)\n- CBD LOQ: 0.059% (GC-FID) / 0.080% (HPLC)\n- Cross-validation and prediction: >0.99\n- Data acquisition: <45 seconds per measurement\n- 12 cannabinoids quantified","methodology":"Absorbance-transmittance excitation emission matrix (A-TEEM) spectroscopy with extreme gradient boost (XGB) discriminant analysis and regression. Validated against GC-FID and HPLC reference methods on 49 cannabis extracts.","limitations":"Tested on dried flower extracts only — may not work for other product forms. Requires solvent extraction (though simple). Model built on 49 samples; broader validation needed. Equipment cost for A-TEEM devices not discussed."},{"rthcId":"RTHC-04576","title":"Pharmacological insights emerging from the characterization of a large collection of synthetic cannabinoid receptor agonists designer drugs.","authors":"Gioé-Gallo, Claudia; Ortigueira, Sandra; Brea, José; Raïch, Iu; Azuaje, Jhonny; Paleo, M Rita; Majellaro, Maria; Loza, María Isabel; Salas, Cristian O; García-Mera, Xerardo; Navarro, Gemma; Sotelo, Eddy","year":2023,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 164, 114934","doi":"10.1016/j.biopha.2023.114934","pmid":"37236027","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The largest and most diverse collection of enantiopure SCRAs was synthesized and characterized. Novel SCRAs with (R) configuration were tested for the first time. Systematic profiling identified SAR and selectivity trends, including some compounds with incipient CB2 selectivity. Several emerging SCRAs showed lower potencies/efficacies, suggesting limited harm potential. However, representative SCRAs demonstrated significant neurotoxicity on mouse primary neuronal cells. The library is intended as a shared resource for studying SCRA effects.","whyItMatters":"New synthetic cannabinoids appear constantly, often before any pharmacological data exists. This library provides reference data for forensic chemists, toxicologists, and regulators to assess the harm potential of novel compounds as they emerge.","specificNumbers":"- Largest and most diverse SCRA collection published to date\n- 32 novel SCRAs with (R) configuration first reported\n- Both binding and functional pharmacological data\n- SAR and SSR trends identified\n- Some compounds show CB2 subtype selectivity\n- Significant neurotoxicity confirmed for representative SCRAs","methodology":"Synthesis of enantiopure SCRA library. Binding and functional pharmacological evaluation at CB1 and CB2 receptors. Neurotoxicity assessment on mouse primary neuronal cells. SAR and selectivity analysis.","limitations":"In vitro pharmacology may not predict all in vivo effects. The drug market evolves faster than any single study can characterize. Neurotoxicity assessed on a limited number of representative compounds."},{"rthcId":"RTHC-04577","title":"Crash-involved THC-positive drivers in Norway have a high frequency of polysubstance use.","authors":"Gjerde, Hallvard; Bogstrand, Stig Tore; Jamt, Ragnhild Elén Gjulem; Vindenes, Vigdis","year":2023,"journal":"Drug and alcohol dependence, 244, 109800","doi":"10.1016/j.drugalcdep.2023.109800","pmid":"36774807","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Of 10,520 apprehended crash-involved drivers (2013-2020), 20% had THC above the legal limit (1.3 ng/mL). Among THC-positive drivers, 84% also had other substances above legal limits. The most common combination was cannabis with sedatives and stimulants (22.9%). Polysubstance use was least common among drivers under 24. Drivers with high THC (>5 ng/mL) were less likely to have high concentrations of other substances, suggesting that when THC alone was present at high levels, cannabis may have been a more important contributor to impairment.","whyItMatters":"The attribution of crash involvement to cannabis is complicated by the fact that most THC-positive drivers are also using other impairing substances. This has major implications for cannabis-impaired driving policy and research.","specificNumbers":"- 10,520 crash-involved drivers tested (2013-2020)\n- 2,133 (20%) THC above 1.3 ng/mL\n- 84% also positive for other substances\n- 61% sedatives, 38% stimulants, 33% alcohol, 10% opioids\n- Most common combo: cannabis + sedatives + stimulants (22.9%)\n- Polysubstance least common in under-24 age group","methodology":"Retrospective analysis of all non-fatally injured crash-involved drivers in Norway (2013-2020) with blood samples submitted for forensic toxicology testing. Comprehensive substance screening.","limitations":"Only includes apprehended drivers, not all crash-involved drivers. Norwegian patterns may not generalize globally. Blood collection timing varied, affecting THC concentration interpretation. Cannot determine which substance contributed most to impairment in polysubstance cases."},{"rthcId":"RTHC-04578","title":"Negative experiences of patients using medicinal cannabis: A systematic review of qualitative studies.","authors":"Gliksberg, Or; Kushnir, Talma; Sznitman, Sharon R; Lev-Ran, Shaul; Brill, Silviu; Amit, Ben H; Feingold, Daniel","year":2023,"journal":"Journal of clinical nursing, 32(17-18), 5607-5618","doi":"10.1111/jocn.16653","pmid":"36807590","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"From 1,230 initial articles, 8 qualitative studies were included. Six themes of negative experiences emerged, grouped into two meta-themes: (1) administrative and social aspects (approval difficulties, administrative barriers, social perception/stigma) and (2) effects of cannabis treatment (misuse/widespread effects, adverse effects, dependence/addiction concerns). Patients reported struggles with the approval process, social stigma from using a historically illegal substance, concerns about unintended effects beyond the target condition, and fear of developing dependence.","whyItMatters":"Most medical cannabis research focuses on efficacy and safety. This review centers patients' lived experiences, revealing that social and administrative burdens may be as significant as medical side effects in affecting treatment satisfaction.","specificNumbers":"- 1,230 articles screened\n- 8 qualitative studies included\n- 6 themes identified\n- 2 meta-themes: administrative/social aspects and treatment effects\n- PRISMA guidelines followed\n- CASP checklist for quality assessment","methodology":"Systematic review of qualitative studies following PRISMA guidelines. Searched PubMed, PsycINFO, EMBASE. Quality assessed using CASP qualitative checklist. Thematic analysis of included studies.","limitations":"Only 8 studies met inclusion criteria, reflecting the limited qualitative literature. Physician-prescribed MC only — excludes self-medicators. Cultural contexts of included studies may not generalize."},{"rthcId":"RTHC-04579","title":"Using a global diversity panel of Cannabis sativa L. to develop a near InfraRed-based chemometric application for cannabinoid quantification.","authors":"Gloerfelt-Tarp, Francine; Hewavitharana, Amitha K; Mieog, Jos; Palmer, William M; Fraser, Felicity; Ansari, Omid; Kretzschmar, Tobias","year":2023,"journal":"Scientific reports, 13(1), 2253","doi":"10.1038/s41598-023-29148-0","pmid":"36755037","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Using dried, homogenized cannabis flower from 84 diverse accessions, NIRS predictive models achieved r-squared values of 0.80-0.95 for 10 of 12 therapeutically relevant cannabinoids. Models for major cannabinoids performed best. NIRS could discriminate between acid and neutral forms of cannabinoids and between C3-alkyl and C5-alkyl cannabinoids. The technique requires only solvent extraction and provides results in seconds using a diffuse reflectance device.","whyItMatters":"Current chromatographic cannabinoid testing is expensive and slow, limiting production efficiency, research, and regulatory compliance. NIRS could provide the cannabis industry with a practical high-throughput testing solution.","specificNumbers":"- 84 diverse cannabis accessions\n- 12 cannabinoids modeled\n- 10 of 12 with r² = 0.80-0.95\n- Major cannabinoids showed best performance\n- Discriminated acid vs neutral forms\n- Discriminated C3-alkyl vs C5-alkyl cannabinoids","methodology":"Diffuse reflectance NIRS on dried, homogenized cannabis inflorescences. Chromatographic reference data for 12 cannabinoids. Partial least squares regression for predictive chemometric models. Cross-validation and independent prediction sets.","limitations":"Tested only on dried, homogenized flower — may not work on whole buds or other product forms. Model built on 84 accessions; larger datasets may improve accuracy. Minor cannabinoids at very low levels may be less accurately quantified."},{"rthcId":"RTHC-04580","title":"Change in marijuana use from adolescence to young adulthood and its relation to gestational alcohol and marijuana exposure.","authors":"Goldschmidt, Lidush; Richardson, Gale A; Day, Nancy L; De Genna, Natacha M","year":2023,"journal":"Neurotoxicology and teratology, 99, 107287","doi":"10.1016/j.ntt.2023.107287","pmid":"37437668","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Gestational marijuana exposure was linked to early initiation and increasing cannabis use, while prenatal alcohol exposure was associated with later initiation of use between ages 16 and 22.","whyItMatters":"This study reveals that substance exposure before birth can have lasting effects on offspring drug use patterns decades later, even after accounting for peer influence and home environment.","specificNumbers":"Four transition groups were identified: non-users (n=193), stop/decrease (n=81), continue/increase (n=125), and late initiators (n=122). Key predictors included peer marijuana use, delinquency, and caregiver financial strain.","methodology":"Longitudinal cohort study using data from the Maternal Health Practices and Child Development Project, following participants from prenatal phase through age 22. Discriminant analysis was used to classify transition groups.","limitations":"Sample was primarily lower socioeconomic status, limiting generalizability. Self-reported marijuana use may be subject to recall bias. The prenatal exposure measures relied on maternal self-report."},{"rthcId":"RTHC-04581","title":"Isobolographic analysis of adjunct antiseizure activity of the FDA-approved cannabidiol with neurosteroids and benzodiazepines in adult refractory focal onset epilepsy.","authors":"Golub, Victoria; Ramakrishnan, Sreevidhya; Reddy, Doodipala Samba","year":2023,"journal":"Experimental neurology, 360, 114294","doi":"10.1016/j.expneurol.2022.114294","pmid":"36493860","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD combined with ganaxolone or midazolam produced combination indices of 0.313 and 0.164 respectively, indicating strong synergism for seizure protection with little to no toxicity.","whyItMatters":"Over one-third of epilepsy patients have drug-resistant seizures. This study suggests CBD could enhance existing medications rather than replace them, potentially offering new treatment strategies for adult refractory epilepsy.","specificNumbers":"CBD alone had an ED50 of 53 mg/kg. Combination index for CBD+ganaxolone was 0.313 and CBD+midazolam was 0.164, both indicating strong synergism. Three standard ratios were tested (1:1, 1:3, 3:1).","methodology":"Preclinical study using the adult 6-Hz model of focal refractory epilepsy in mice. CBD was tested alone (dose-response and time-course) and in isobolographic combination with ganaxolone and midazolam.","limitations":"Animal model results may not translate directly to humans. The 6-Hz model, while validated, represents only one type of refractory epilepsy. Doses used in mice may not correspond to human dosing."},{"rthcId":"RTHC-04582","title":"Concurrent validity of the marijuana purchase task: a meta-analysis of trait-level cannabis demand and cannabis involvement.","authors":"González-Roz, Alba; Martínez-Loredo, Víctor; Aston, Elizabeth R; Metrik, Jane; Murphy, James; Balodis, Iris; Secades-Villa, Roberto; Belisario, Kyla; MacKillop, James","year":2023,"journal":"Addiction (Abingdon, England), 118(4), 620-633","doi":"10.1111/add.16075","pmid":"36305652","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Intensity, Omax, and elasticity showed the most robust concurrent validity with cannabis involvement, with effect sizes ranging from r=0.147 to 0.325.","whyItMatters":"Validating measurement tools for cannabis reinforcement value is essential for understanding cannabis use patterns and informing regulatory policy, especially as legalization expands.","specificNumbers":"14 studies with 4,077 participants were analyzed. Weighted average age was 29.08 years. Median female proportion was 44.8%. Studies were published between 2015 and 2022.","methodology":"Meta-analysis of 14 cross-sectional studies examining the relationship between Marijuana Purchase Task indicators and cannabis use frequency, quantity, problems, and dependence.","limitations":"All studies were cross-sectional, limiting causal inference. The relatively small number of studies (14) limits moderator analysis power. Hypothetical purchase scenarios may not perfectly reflect real purchasing behavior."},{"rthcId":"RTHC-04583","title":"Cannabis legalization and childhood asthma in the United States: An ecologic analysis.","authors":"Goodwin, Renee D; Wyka, Katarzyna; Luo, Man; Weinberger, Andrea H; Kattan, Meyer","year":2023,"journal":"Preventive medicine, 170, 107414","doi":"10.1016/j.ypmed.2022.107414","pmid":"36592675","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"While overall pediatric asthma declined 1.1% from 2011-2019, states with recreational cannabis legalization showed increased asthma prevalence among 12-17 year olds (DID=2.56, p=.028) and among some minoritized racial/ethnic groups.","whyItMatters":"As cannabis legalization expands, understanding its potential secondhand smoke effects on children is critical for public health policy, especially for vulnerable populations.","specificNumbers":"Overall 1.1% decrease in pediatric asthma (2011-2019). In RCL states vs. illegal states: DID=2.56 (p=.028) for youth 12-17; DID=4.45 (p=.004) for some NH minoritized race/ethnicity groups in 2018-2019.","methodology":"Ecological study using 2011-2019 National Survey on Children Health data. Difference-in-difference analysis compared asthma prevalence changes across states with different cannabis legal statuses.","limitations":"Ecological design cannot establish individual-level causation. Self-reported asthma diagnosis may vary in accuracy. State-level analysis may mask within-state variation. Cannot directly measure secondhand cannabis smoke exposure."},{"rthcId":"RTHC-04584","title":"Cannabis use among patients presenting to the emergency department for psychosis: Associations with restraint use, medication administration, psychiatric hospitalization, and repeat visits.","authors":"Gouse, Brittany M; Boliver, Elijah E; Oblath, Rachel; Camacho, Luisa; Brown, Hannah E","year":2023,"journal":"Psychiatry research, 323, 115151","doi":"10.1016/j.psychres.2023.115151","pmid":"36934468","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Positive THC screens during psychosis-related ED visits were associated with significantly greater risk of physical restraint, parenteral antipsychotic, and benzodiazepine administration compared to negative or no THC screen.","whyItMatters":"Understanding how cannabis use affects the acute management of psychosis in emergency settings can help clinicians better prepare for and manage these presentations.","specificNumbers":"2,134 ED visits for acute psychosis examined between March 2019 and February 2021. THC-positive visits had higher rates of restraints and parenteral medication use. No significant association with psychiatric hospitalization or 90-day repeat visits.","methodology":"Retrospective study examining ED visits for acute psychosis, comparing outcomes based on urinary THC screen results (positive vs. negative vs. no screen).","limitations":"Retrospective design limits causal inference. Urinary THC only indicates recent use, not intoxication at presentation. Patients without THC screening may differ systematically from those screened."},{"rthcId":"RTHC-04585","title":"Biosynthesis of Phytocannabinoids and Structural Insights: A Review.","authors":"Govindarajan, Rasiravathanahalli Kaveriyappan; Mishra, Awdhesh Kumar; Cho, Kiu-Hyung; Kim, Ki-Hyun; Yoon, Kyoung Mi; Baek, Kwang-Hyun","year":2023,"journal":"Metabolites, 13(3)","doi":"10.3390/metabo13030442","pmid":"36984882","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Phytocannabinoids are biosynthesized through multiple pathways and classified by their decorated resorcinol core structure, with demonstrated therapeutic applications for multiple sclerosis, neurodegenerative diseases, epilepsy, and pain.","whyItMatters":"Understanding how cannabis plants produce cannabinoids is fundamental to developing biotechnological approaches for pharmaceutical-grade cannabinoid production and novel therapeutic applications.","specificNumbers":"Cannabis sativa L. produces cannabinoids found in flowers, seeds, and fruits. Multiple biosynthetic pathways are elucidated. Applications span human disease treatment, antimicrobial activity against bacteria and fungi.","methodology":"Literature review covering phytocannabinoid sources, biosynthetic pathways, structural classification, bioactivities in animal models, and antimicrobial properties.","limitations":"As a review, no new experimental data is presented. The breadth of coverage may limit depth on specific topics. Rapidly evolving field means some findings may be superseded."},{"rthcId":"RTHC-04586","title":"Suspected Suicidal Cannabis Exposures Reported to US Poison Centers, 2009-2021.","authors":"Graves, Janessa M; Dilley, Julia A; Klein, Tracy; Liebelt, Erica","year":2023,"journal":"JAMA network open, 6(4), e239044","doi":"10.1001/jamanetworkopen.2023.9044","pmid":"37074718","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers analyzed data from US poison centers spanning 2009 through 2021 to examine trends in cannabis exposures suspected to involve suicidal intent. They compared patterns before and during the COVID-19 pandemic.\n\nThe analysis found that suspected suicidal cannabis exposures increased during the pandemic period. This trend occurred against the backdrop of both a broader mental health crisis during COVID-19 and increasing cannabis availability due to legalization.\n\nThe findings highlight cannabis as an increasingly relevant substance in the context of self-harm, even though cannabis alone is generally not considered lethal. The exposures may reflect intentional self-poisoning attempts involving cannabis products, particularly edibles.","whyItMatters":"While cannabis is rarely fatal on its own, its inclusion in self-harm attempts signals growing intersection between cannabis availability and mental health crises. The pandemic-era increase may reflect both worsening mental health and greater access to cannabis products, particularly concentrated edibles.","specificNumbers":"Data spanned 2009-2021 from US poison centers. Suspected suicidal cannabis exposures increased during the COVID-19 pandemic compared to the pre-pandemic period.","methodology":"This was a cross-sectional study using data from the National Poison Data System, which collects reports from all US poison centers. Researchers identified cannabis exposures coded as suspected suicidal intent from 2009 through 2021 and compared pre-pandemic and pandemic-era trends.","limitations":"Poison center data relies on voluntarily reported exposures and likely underrepresents true incidence. Suicidal intent was suspected rather than confirmed. Cannabis was often co-ingested with other substances, making it difficult to isolate cannabis-specific effects. Increased reporting could partly reflect growing awareness rather than a true increase in events."},{"rthcId":"RTHC-04587","title":"Exploring opportunities for drug repurposing and precision medicine in cannabis use disorder using genetics.","authors":"Greco, Laura A; Reay, William R; Dayas, Christopher V; Cairns, Murray J","year":2023,"journal":"Addiction biology, 28(8), e13313","doi":"10.1111/adb.13313","pmid":"37500481","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The phosphodiesterase gene PDE4B emerged as a prioritized target for drug repurposing in CUD, with credible causal variants also associated with inflammatory and other substance use phenotypes.","whyItMatters":"Cannabis use disorder affects up to one in five adult cannabis users and has no effective pharmacological treatments. Repurposing existing drugs could accelerate treatment availability.","specificNumbers":"CUD affects up to 1 in 5 adults who use cannabis. PDE4B identified through gene-level aggregation. NPTX1 identified as a novel CUD-associated gene in blood. Genetic overlap found with lymphocyte count and serum triglycerides.","methodology":"Genomic analysis combining gene-level variant aggregation, probabilistic fine-mapping, transcriptomic/proteomic integration with GWAS data, and genetic correlation with biochemical traits.","limitations":"Genetic associations do not guarantee that drug targeting will be effective clinically. Population studied may not represent all ancestries. Drug repurposing candidates require clinical validation."},{"rthcId":"RTHC-04588","title":"Medical Cannabis Use Patterns and Adverse Effects in Inflammatory Bowel Disease.","authors":"Greywoode, Ruby; Cunningham, Chinazo; Hollins, Maegan; Aroniadis, Olga","year":2023,"journal":"Journal of clinical gastroenterology, 57(8), 824-829","doi":"10.1097/MCG.0000000000001782","pmid":"36227025","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Medical cannabis users with IBD reported fewer ER visits after starting MC use (35.2% vs. 41.5%, p<0.01) and less impact of symptoms on daily life, with most using high-THC products via vape pens.","whyItMatters":"As medical cannabis becomes more accessible, understanding how IBD patients actually use it and what side effects they experience is critical for clinical guidance.","specificNumbers":"236 respondents surveyed. 61% took a biologic medication. 87.5% used high-THC products. 78.6% used vape pens/cartridges. 75.4% reported euphoria. Only 1.3% reported diversion. ER visits decreased from 41.5% to 35.2% (p<0.01).","methodology":"Cross-sectional anonymous survey conducted October 2020 to January 2021 among patients at medical cannabis dispensaries in New York and Minnesota. Stuart-Maxwell test compared symptoms before and after MC use.","limitations":"Self-reported data subject to recall bias. Dispensary recruitment may select for satisfied cannabis users. No objective disease activity measures. Cross-sectional design cannot establish causation."},{"rthcId":"RTHC-04589","title":"Cannabis use and suicide risk among Gulf War veterans.","authors":"Grove, Jeremy L; Kimbrel, Nathan A; Griffin, Sarah C; Halverson, Tate; White, Mark A; Blakey, Shannon M; Beckham, Jean C; Dedert, Eric A; Goldston, David B; Pugh, Mary J; Calhoun, Patrick S","year":2023,"journal":"Death studies, 47(5), 618-623","doi":"10.1080/07481187.2022.2108944","pmid":"35939644","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Logistic regression showed cannabis use was associated with both past-year suicidal ideation and elevated risk for suicidal behavior in Gulf War veterans, even after controlling for key covariates.","whyItMatters":"Veterans face elevated suicide risk, and understanding modifiable risk factors like substance use is critical for prevention efforts in this population.","specificNumbers":"National sample of 1,126 Gulf War veterans. Cannabis use independently associated with past-year suicidal ideation and elevated suicidal behavior risk after adjusting for covariates.","methodology":"Cross-sectional study using a national sample of Gulf War veterans with self-reported cannabis use. Logistic regression models controlled for key covariates.","limitations":"Cross-sectional design cannot establish causation — cannabis use may be a consequence rather than cause of suicidal distress. Self-reported measures may underestimate actual use. Gulf War veterans may not represent all veteran populations."},{"rthcId":"RTHC-04590","title":"Correlations of kratom (Mitragyna speciosa Korth.) use behavior and psychiatric conditions from a cross-sectional survey.","authors":"Grundmann, Oliver; Veltri, Charles A; Morcos, Sara; Smith, Kirsten E; Singh, Darshan; Corazza, Ornella; Cinosi, Eduardo; Martinotti, Giovanni; Walsh, Zach; Swogger, Marc T","year":2023,"journal":"Experimental and clinical psychopharmacology, 31(5), 963-977","doi":"10.1037/pha0000632","pmid":"36634016","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Kratom users meeting criteria for ADHD, PTSD, depressive, or anxiety disorders reported decreased depressive and anxious moods and greater concurrent use of cannabis, CBD, and benzodiazepines.","whyItMatters":"Kratom is increasingly used for self-treatment of psychiatric conditions, yet its effects and interactions with other substances remain poorly understood.","specificNumbers":"4,945 kratom users completed the survey (July 2019–July 2020), with 2,296 completing extended clinical scales. Users with psychiatric conditions were primarily aged 31-50 years, employed, and college-educated.","methodology":"Anonymous cross-sectional online survey with validated clinical scales for ADHD, PTSD, depressive and anxiety disorders. Descriptive and comparative analyses.","limitations":"Self-report data is subject to bias. No control group for comparison. Online recruitment may not be representative. Self-reported mood improvements cannot be verified objectively."},{"rthcId":"RTHC-04591","title":"Conditional deletion of CB2 cannabinoid receptors from peripheral sensory neurons eliminates CB2-mediated antinociceptive efficacy in a mouse model of carrageenan-induced inflammatory pain.","authors":"Guenther, Kelsey G; Xu, Zhili; Romero, Julian; Hillard, Cecilia J; Mackie, Ken; Hohmann, Andrea G","year":2023,"journal":"Neuropharmacology, 237, 109601","doi":"10.1016/j.neuropharm.2023.109601","pmid":"37286073","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The anti-allodynic efficacy of CB2 agonist LY2828360 was absent in mice lacking CB2 receptors on peripheral sensory neurons but preserved in mice lacking CB2 on immune cells, establishing neuronal CB2 as the therapeutic target.","whyItMatters":"Identifying the exact cell type responsible for CB2-mediated pain relief enables more targeted drug development and helps explain why CB2 agonists work without the side effects of CB1 activation.","specificNumbers":"LY2828360 at 10 mg/kg reversed carrageenan-induced mechanical allodynia. Local paw injection (30 μg) also reversed allodynia in control but not sensory neuron CB2 knockout mice. LY2828360 reduced IL-1β and IL-10 mRNA in paw skin.","methodology":"Preclinical study using global CB1 and CB2 knockout mice and conditional knockout mice lacking CB2 in peripheral sensory neurons or microglia/macrophages. Carrageenan-induced inflammatory pain model tested in both sexes.","limitations":"Mouse models may not fully translate to human pain pathways. Conditional knockout systems may have incomplete deletion. Single inflammatory pain model tested."},{"rthcId":"RTHC-04592","title":"Recreational Cannabis Legislation: substance use and impaired driving among Canadian rural and urban postsecondary students.","authors":"Gueye, N'deye Rokhaya; Prada, Kevin; de Moissac, Danielle","year":2023,"journal":"Journal of cannabis research, 5(1), 8","doi":"10.1186/s42238-023-00175-y","pmid":"36918969","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Rural cohorts had greater odds of past-year cannabis use (AOR=1.32) compared to urban cohorts, but the relationship between cannabis use and driving after use varied by province and urban/rural context.","whyItMatters":"Understanding how legalization affects different communities helps tailor prevention campaigns and road safety initiatives to the populations most at risk.","specificNumbers":"1,496 postsecondary students surveyed across five campuses in Manitoba, Ontario, and Quebec (2018-2019). Quebec students more likely to have lifetime cannabis use (AOR=1.41). Rural students had higher past-year use (AOR=1.32).","methodology":"Quantitative cross-sectional study using self-report surveys administered to emerging adults (18-24) at Canadian postsecondary institutions shortly after recreational cannabis legalization. Multiple logistic regression analyses.","limitations":"Cross-sectional design cannot establish temporal relationships. Self-reported substance use and driving behaviors may be underreported. Only five campuses sampled, limiting generalizability."},{"rthcId":"RTHC-04593","title":"Exploring the Link Between Attention-Deficit Hyperactivity Disorder and Cannabis Use Disorders: A Review.","authors":"Gujska, Julia Helena; Silczuk, Andrzej; Madejek, Robert; Szulc, Agata","year":2023,"journal":"Medical science monitor : international medical journal of experimental and clinical research, 29, e939749","doi":"10.12659/MSM.939749","pmid":"37147797","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review highlights that ADHD is highly prevalent (23.1%) in substance use disorder populations, leading to earlier onset, self-medication behaviors, and reduced treatment effectiveness, with shared reward circuitry and endocannabinoid system involvement.","whyItMatters":"As cannabis becomes more accessible, understanding its particular risks for the ADHD population is critical given their vulnerability to substance use disorders and the growing self-medication trend.","specificNumbers":"ADHD prevalence in SUD population: 23.1%. Cannabis is the most common illicit drug among the ADHD population. Key brain systems involved: default-mode network and endocannabinoid system.","methodology":"Narrative review examining theoretical models of ADHD-SUD comorbidity, focusing on neurocognitive mechanisms, reward/motivational circuitry, and cannabis use disorders.","limitations":"Narrative review rather than systematic review or meta-analysis. May not capture all relevant literature. Does not generate new data."},{"rthcId":"RTHC-04594","title":"Investigating the \"two-hit hypothesis\": Effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice.","authors":"Guma, Elisa; Cupo, Lani; Ma, Weiya; Gallino, Daniel; Moquin, Luc; Gratton, Alain; Devenyi, Gabriel A; Chakravarty, M Mallar","year":2023,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 120, 110642","doi":"10.1016/j.pnpbp.2022.110642","pmid":"36150422","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Mice exposed to both prenatal immune activation and adolescent THC showed subtle brain development deviations and subthreshold anxiety-like behaviors. CB1 and CB2 receptor density decreased with either risk factor alone or combined.","whyItMatters":"This study tests whether multiple risk factor exposures are needed for psychiatric illness onset, a key question in understanding why some cannabis users develop mental health problems while others do not.","specificNumbers":"Poly I:C (5 mg/kg) at gestational day 9 for immune activation. THC (5 mg/kg/day i.p.) from postnatal day 28-45 for adolescent exposure. MRI at PND 25, 50, and 85. CB1 and CB2 receptor positive cells significantly decreased across exposure groups.","methodology":"Preclinical 2x2 factorial design in mice with longitudinal MRI (pre-treatment, post-treatment, adulthood), behavioral testing (anxiety, social, sensorimotor gating), and post-mortem CB1/CB2 receptor immunohistochemistry.","limitations":"Mouse models have limited translational relevance to human psychiatric disorders. Poly I:C is a simplified immune challenge. Single THC dose and timing may not capture the variety of human cannabis use patterns."},{"rthcId":"RTHC-04595","title":"Cannabidiol attenuates insular activity during motivational salience processing in patients with early psychosis.","authors":"Gunasekera, Brandon; Wilson, Robin; O'Neill, Aisling; Blest-Hopley, Grace; O'Daly, Owen; Bhattacharyya, Sagnik","year":2023,"journal":"Psychological medicine, 53(10), 4732-4741","doi":"10.1017/S0033291722001672","pmid":"35775365","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD attenuated insula activation during motivational salience processing compared to placebo in early psychosis patients, consistent with the theory that CBD modulates brain regions involved in salience processing.","whyItMatters":"Understanding how CBD affects the brain could explain its potential antipsychotic properties and lead to targeted treatments for psychosis with fewer side effects than current medications.","specificNumbers":"19 healthy controls and 15 participants with early psychosis studied in a within-subject crossover design. Single dose of CBD vs. placebo. Insula activation was attenuated following CBD. Results held after controlling for cannabis use history.","methodology":"Within-subject, crossover, double-blind, placebo-controlled fMRI study using the monetary incentive delay task to examine brain responses to motivationally salient stimuli (reward and loss anticipation).","limitations":"Small sample size (15 psychosis participants). Single-dose design does not reflect chronic treatment. The monetary incentive delay task captures only one aspect of salience processing. No significant group differences at baseline between patients and controls."},{"rthcId":"RTHC-04596","title":"Focus on rural adolescent cannabis use and abuse: ignored epidemiologic trends, unique risks, long-term concerns, and hope.","authors":"Gupta, Mayank; Petti, Theodore","year":2023,"journal":"CNS spectrums, 28(3), 277-280","doi":"10.1017/S1092852922000736","pmid":"35387706","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Rural youth face distinct risk factors for cannabis use including demographic differences, limited access to treatment services, community instability, and cultural factors that interact with expanding cannabis legalization.","whyItMatters":"As cannabis legalization spreads, rural communities may be disproportionately affected due to fewer prevention and treatment resources, requiring tailored public health approaches.","specificNumbers":"Not quantified in abstract; review synthesizes epidemiological data across demographics including race, culture, community stability, age, gender, and educational status.","methodology":"Narrative review synthesizing research across multiple disciplines on rural adolescent cannabis use, risk factors, epidemiological trends, and service gaps.","limitations":"Narrative review without systematic methodology. Research on rural cannabis use is scattered across disciplines, potentially leading to gaps in coverage."},{"rthcId":"RTHC-04597","title":"Revealing the Meaning of Cannabis Use as an Occupation: A Scoping Review.","authors":"Guyonnet, Emma; Stewart, Katherine E; Davis, Jane A","year":2023,"journal":"Substance abuse : research and treatment, 17, 11782218221150113","doi":"10.1177/11782218221150113","pmid":"36685720","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Four themes of cannabis meaning emerged: preserving life, navigating everyday routines, understanding self/identity/belonging, and expanding worldview, suggesting cannabis use holds deep significance beyond recreation or pathology.","whyItMatters":"Recognizing the meaningful role cannabis plays in people lives could improve substance abuse treatment by acknowledging what would need to be replaced, not just eliminated.","specificNumbers":"14 studies selected from 7 databases. Most published since 2008, with 5 in the last 2 years. Four cross-study themes identified through reflexive thematic analysis.","methodology":"Scoping review following Levac et al. modifications to Arksey and O Malley framework. Seven databases searched with reflexive thematic analysis across selected studies.","limitations":"Scoping review methodology provides breadth but limited depth. Only 14 studies met criteria, indicating limited research in this area. Occupational perspective may not apply universally."},{"rthcId":"RTHC-04598","title":"The Effects of Chronic Marijuana Administration on 6-OHDA-Induced Learning & Memory Impairment and Hippocampal Dopamine and Cannabinoid Receptors Interaction in Male Rats.","authors":"Haghparast, Elham; Sheibani, Vahid; Komeili, Gholamreza; Chahkandi, Mohadeseh; Rad, Nahid Sepehri","year":2023,"journal":"Neurochemical research, 48(7), 2220-2229","doi":"10.1007/s11064-023-03899-8","pmid":"36894794","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Marijuana improved spatial learning and memory disorders caused by 6-OHDA in Morris water maze and novel object recognition tests, while modulating D1, CB1, and CB2 receptor expression in the hippocampus.","whyItMatters":"These findings suggest marijuana could potentially help with cognitive symptoms of Parkinson disease by restoring dopamine receptor levels and rebalancing the endocannabinoid system.","specificNumbers":"42 rats in 6 groups. Marijuana at 60 mg/kg i.p. for 28 days. 6-OHDA injected into substantia nigra. Marijuana increased D1 mRNA, decreased CB1 mRNA, and increased CB2 mRNA in 6-OHDA-treated rats.","methodology":"Preclinical study in 42 male rats using 6-OHDA lesion model of Parkinson disease. Behavioral testing with Morris water maze and novel object recognition. Gene expression analysis of hippocampal receptors via real-time PCR.","limitations":"Whole marijuana plant extract makes it difficult to identify active compounds. Only male rats studied. 6-OHDA model does not fully recapitulate human Parkinson disease. Small sample size per group."},{"rthcId":"RTHC-04599","title":"A Longitudinal Observational Study of Medical Cannabis Use and Polypharmacy among Patients Presenting to Dispensaries in Pennsylvania.","authors":"Hajjar, Emily R; Herens, Allison; Kelly, Erin L; Madden, Kayla; Lungen, Jessica M; Worster, Brooke K","year":2023,"journal":"Biomedicines, 11(1)","doi":"10.3390/biomedicines11010158","pmid":"36672666","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Participants used multiple MC products (mean 3.41 at baseline) alongside multiple medications (mean 3.76), with antidepressants (29.1%), analgesics (22.1%), and anxiolytics (17.8%) among the most common concomitant medications.","whyItMatters":"Understanding what other medications medical cannabis patients take is essential for identifying potential drug interactions and ensuring safe treatment.","specificNumbers":"213 baseline participants; 175 completed 12-month follow-up (82% retention). Mean age 41.3 years, 54.5% female. Mean 3.41 MC products at baseline, 3.47 at 12 months. Mean 3.76 medications at baseline, 3.65 at 12 months.","methodology":"Observational longitudinal study with surveys at baseline, 1, 6, and 12 months among patients enrolled in Pennsylvania Department of Health Medical Marijuana Program.","limitations":"Self-reported medication use may be incomplete. Single state program limits generalizability. No outcomes data on drug interactions. Relatively small sample size."},{"rthcId":"RTHC-04600","title":"Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats.","authors":"Halbout, Briac; Hutson, Collin; Hua, Leann; Inshishian, Victoria; Mahler, Stephen V; Ostlund, Sean B","year":2023,"journal":"Psychopharmacology, 240(5), 1151-1167","doi":"10.1007/s00213-023-06352-4","pmid":"36933028","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Adult THC exposure enhanced instrumental contingency degradation learning and increased progressive ratio responding, while adolescent and adult THC had opposing effects on CB1 receptor-dependent motivation, decreasing and increasing rimonabant sensitivity respectively.","whyItMatters":"Understanding age-dependent effects of THC on reward processing and motivation has implications for both recreational cannabis use and therapeutic applications across different age groups.","specificNumbers":"THC dose: 5 mg/kg/day for 14 days. Adult THC exposure augmented contingency degradation learning. Progressive ratio performance increased, more pronounced with adult exposure. Adolescent THC decreased and adult THC increased sensitivity to CB1 antagonist rimonabant.","methodology":"Preclinical study with two experiments in rats. Repeated THC (5 mg/kg/day, 14 days) during adolescence or adulthood. Behavioral testing: reward devaluation, contingency degradation, hedonic feeding, and progressive ratio responding.","limitations":"Rat reward processing may differ from humans. Single dose and duration of THC exposure. Food reward may not generalize to drug or other reward types."},{"rthcId":"RTHC-04601","title":"The implementation and public health impacts of cannabis legalization in Canada: a systematic review.","authors":"Hall, Wayne; Stjepanović, Daniel; Dawson, Danielle; Leung, Janni","year":2023,"journal":"Addiction (Abingdon, England), 118(11), 2062-2072","doi":"10.1111/add.16274","pmid":"37380613","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis legalization in Canada substantially reduced cannabis-related arrests and prices while increasing adult access to diverse products. Young adult use increased modestly but adolescent use remained stable.","whyItMatters":"As countries consider legalization, Canada serves as a real-world case study of what happens when cannabis becomes legal, showing both intended benefits and unintended health consequences.","specificNumbers":"Research from 2006-2021 was reviewed. Cannabis prices decreased substantially. Adult use increased modestly since 2019. No marked changes in high school student use. Increased hospital visits for psychiatric distress, vomiting, and childhood edible ingestion.","methodology":"Systematic review searching PubMed, Embase, Statistics Canada, government websites, and Google Scholar for studies published 2006-2021 on impacts of Canadian cannabis legalization.","limitations":"Narrative summary of a systematic search, which may be subject to synthesis bias. Short timeframe post-legalization may miss longer-term effects. Conflicting evidence on some outcomes like impaired driving."},{"rthcId":"RTHC-04602","title":"Self-Evisceration of Intestines as the Initial Presentation of Schizoaffective Disorder.","authors":"Hamlin, Stephanie; Sharma, Dana L; Kablinger, Anita S","year":2023,"journal":"Case reports in psychiatry, 2023, 4334552","doi":"10.1155/2023/4334552","pmid":"36949890","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The patient had functioned normally in society for 10 years despite paranoia associated with significant cannabis use, until an acute psychotic episode led to self-evisceration requiring emergency surgery.","whyItMatters":"This extreme case illustrates how schizoaffective disorder can go undiagnosed for years, particularly when cannabis use may mask or complicate psychiatric symptoms.","specificNumbers":"39-year-old male, 10-year history of paranoia with significant cannabis use. Required emergent exploratory laparotomy with partial colectomy. Two-week hospital course. Symptoms remitted on olanzapine and valproic acid.","methodology":"Case report with detailed clinical description, surgical management, psychiatric assessment, and discussion of related literature.","limitations":"Single case report cannot establish causation between cannabis use and schizoaffective disorder. Patient history relies on post-episode recall. No pre-morbid psychiatric assessment available."},{"rthcId":"RTHC-04603","title":"Pediatric Poisonings Associated With Ingestion of Marijuana Products.","authors":"Hammig, Bart; Jones, Ches; Haldeman, Sydney","year":2023,"journal":"The Journal of emergency medicine, 64(2), 181-185","doi":"10.1016/j.jemermed.2022.12.025","pmid":"36822984","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Most pediatric marijuana poisonings involved edible products, and most patients required hospital admission, highlighting the dangers of cannabis products that resemble typical snack foods.","whyItMatters":"As marijuana legalization expands and edible products become more available, young children are at increasing risk of accidental ingestion, requiring urgent attention to packaging and storage regulations.","specificNumbers":"Estimated 1,245 pediatric visits nationally (2019-2020) for unintentional marijuana poisoning in children birth to 11 years old. Most involved edible products. Most patients were admitted to hospital.","methodology":"Descriptive epidemiologic analysis of 2019-2020 National Electronic Injury Surveillance System (NEISS) data for THC-related poisoning events in children.","limitations":"NEISS data represents ED visits only, potentially missing cases managed outside hospitals. National estimates derived from a sample of hospitals. Cannot capture severity details or long-term outcomes."},{"rthcId":"RTHC-04604","title":"Trends in emergency department visits associated with cannabis use among older adults in California, 2005-2019.","authors":"Han, Benjamin H; Brennan, Jesse J; Orozco, Mirella A; Moore, Alison A; Castillo, Edward M","year":2023,"journal":"Journal of the American Geriatrics Society, 71(4), 1267-1274","doi":"10.1111/jgs.18180","pmid":"36622838","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The cannabis-related ED visit rate for older adults increased by 1,804% over the study period, with older Black adults having the highest rates and greatest absolute increase.","whyItMatters":"Older adults are increasingly using cannabis but may be particularly vulnerable to adverse effects due to age-related changes, medication interactions, and comorbidities.","specificNumbers":"Rate increased from 20.7 to 395.0 per 100,000 ED visits (2005-2019), a 1,804% relative increase. All subgroups showed significant increases (p<0.001). Older males had higher rates than females. Higher Charlson comorbidity scores correlated with higher rates.","methodology":"Trend analysis of cannabis-related ED visits from all acute care hospitals in California (2005-2019) using primary and secondary diagnosis codes for adults aged 65 and older.","limitations":"Single state data may not generalize nationally. Diagnosis coding changes over time may affect trends. Cannot determine whether visits were due to cannabis alone or interactions with other substances/medications."},{"rthcId":"RTHC-04605","title":"Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials.","authors":"Haney, Margaret; Vallée, Monique; Fabre, Sandy; Collins Reed, Stephanie; Zanese, Marion; Campistron, Ghislaine; Arout, Caroline A; Foltin, Richard W; Cooper, Ziva D; Kearney-Ramos, Tonisha; Metna, Mathilde; Justinova, Zuzana; Schindler, Charles; Hebert-Chatelain, Etienne; Bellocchio, Luigi; Cathala, Adeline; Bari, Andrea; Serrat, Roman; Finlay, David B; Caraci, Filippo; Redon, Bastien; Martín-García, Elena; Busquets-Garcia, Arnau; Matias, Isabelle; Levin, Frances R; Felpin, François-Xavier; Simon, Nicolas; Cota, Daniela; Spampinato, Umberto; Maldonado, Rafael; Shaham, Yavin; Glass, Michelle; Thomsen, Lars Lykke; Mengel, Helle; Marsicano, Giovanni; Monlezun, Stéphanie; Revest, Jean-Michel; Piazza, Pier Vincenzo","year":2023,"journal":"Nature medicine, 29(6), 1487-1499","doi":"10.1038/s41591-023-02381-w","pmid":"37291212","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In phase 2a trials, AEF0117 at 1 mg reduced cannabis positive subjective effects by 38% versus placebo (p<0.04) and reduced self-administration (p<0.05), without precipitating withdrawal or significant adverse effects.","whyItMatters":"Cannabis use disorder has no approved pharmacotherapy. AEF0117 represents an entirely new drug class that selectively blocks THC effects without the problems of previous CB1 blockers like rimonabant.","specificNumbers":"Phase 1: 40 participants (single-ascending-dose) and 24 (multiple-ascending-dose). Phase 2a: 29 CUD participants in two dose cohorts (0.06 mg, n=14; 1 mg, n=15). CBD positive effects reduced by 19% (0.06 mg) and 38% (1 mg) vs. placebo.","methodology":"Three randomized controlled trials: single-ascending-dose and multiple-ascending-dose phase 1 trials in healthy volunteers, and a double-blind, placebo-controlled, crossover phase 2a trial in volunteers with CUD.","limitations":"Small sample sizes in all trials. Phase 2a was short-term. Laboratory self-administration may not reflect real-world use. Long-term safety and efficacy not yet established."},{"rthcId":"RTHC-04606","title":"Cannabis-Based Medicine for Neuropathic Pain and Spasticity-A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial.","authors":"Hansen, Julie Schjødtz; Gustavsen, Stefan; Roshanisefat, Homayoun; Kant, Matthias; Biering-Sørensen, Fin; Andersen, Claus; Olsson, Anna; Chow, Helene Højsgaard; Asgari, Nasrin; Hansen, Julie Richter; Nielsen, Helle Hvilsted; Hansen, Rikke Middelhede; Petersen, Thor; Oturai, Annette Bang; Sellebjerg, Finn; Sædder, Eva Aggerholm; Kasch, Helge; Rasmussen, Peter Vestergaard; Finnerup, Nanna Brix; Svendsen, Kristina Bacher","year":2023,"journal":"Pharmaceuticals (Basel, Switzerland), 16(8)","doi":"10.3390/ph16081079","pmid":"37630995","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In a four-arm parallel trial of 134 patients, no significant difference was found between THC, CBD, THC+CBD, or placebo for pain intensity, spasticity, patient global impression of change, or quality of life.","whyItMatters":"Despite widespread belief in cannabis for pain and spasticity, this rigorous trial found no benefit, challenging assumptions about cannabis-based medicine for these conditions.","specificNumbers":"134 patients randomized (119 MS, 15 SCI). THC (max 22.5 mg/day), CBD (max 45 mg/day), THC+CBD (max 22.5/45 mg/day), or placebo for 6 weeks. Target was 448 patients but COVID-19 limited recruitment.","methodology":"Multicenter, randomized, double-blinded, placebo-controlled trial in Denmark with four arms (THC, CBD, THC+CBD, placebo). Six-week treatment followed by one-week phaseout.","limitations":"Significantly underpowered — enrolled 134 of planned 448 patients due to COVID-19 and recruitment challenges. Small SCI subgroup (n=15). Maximum doses may have been insufficient."},{"rthcId":"RTHC-04607","title":"Differential regulation of Cav 3.2 and Cav 2.2 calcium channels by CB1 receptors and cannabidiol.","authors":"Harding, Erika K; Souza, Ivana A; Gandini, Maria A; Gadotti, Vinícius M; Ali, Md Yousof; Huang, Sun; Antunes, Flavia T T; Trang, Tuan; Zamponi, Gerald W","year":2023,"journal":"British journal of pharmacology, 180(12), 1616-1633","doi":"10.1111/bph.16035","pmid":"36647671","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD directly inhibits Cav3.2 channels by occluding the pore (confirmed by homology modeling), while CB1 agonist HU-210 inhibits Cav2.2 through CB1 receptors. Intrathecal CBD reduced pain in mice, and this effect was absent in Cav3.2 null mice.","whyItMatters":"Understanding that different cannabinoids work through different calcium channel mechanisms explains why clinical trials of cannabinoids for pain have had mixed results and could guide development of more targeted therapies.","specificNumbers":"HU-210 at 1 μM inhibited Cav2.2 with CB1 but not Cav3.2. CBD at 3 μM inhibited Cav3.2 but not Cav2.2. CBD analgesic effects were absent in Cav3.2 null mice. Effects seen in both male and female mice.","methodology":"Electrophysiology recordings from cells expressing calcium channels, homology modeling of CBD binding, and behavioral pain testing in mouse models of inflammatory and neuropathic pain including Cav3.2 null mice.","limitations":"In vitro channel recordings may not fully reflect in vivo complexity. CBD concentrations used may not match achievable clinical levels. Mouse pain models have limited translational predictiveness."},{"rthcId":"RTHC-04608","title":"MEPIRAPIM-derived synthetic cannabinoids inhibit T-type calcium channels with divergent effects on seizures in rodent models of epilepsy.","authors":"Harman, Thomas; Udoh, Michael; McElroy, Dan L; Anderson, Lyndsey L; Kevin, Richard C; Banister, Samuel D; Ametovski, Adam; Markham, Jack; Bladen, Chris; Doohan, Peter T; Greba, Quentin; Laprairie, Robert B; Snutch, Terrance P; McGregor, Iain S; Howland, John G; Arnold, Jonathon C","year":2023,"journal":"Frontiers in physiology, 14, 1086243","doi":"10.3389/fphys.2023.1086243","pmid":"37082241","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"SB2193 and SB2193F potently inhibited Cav3 channels with minimal CB1 activity. SB2193 protected against 6-Hz seizures but did not reduce seizures in Dravet syndrome or absence epilepsy models, and unexpectedly increased absence seizure activity.","whyItMatters":"T-type calcium channels are promising drug targets for epilepsy and pain, and these findings show that cannabinoid scaffolds can be modified to selectively target these channels, though clinical application requires careful seizure-type matching.","specificNumbers":"SB2193 brain/plasma ratio: 2.7 (brain-penetrant). Acutely protected against 6-Hz induced seizures. Increased spike-and-wave discharge incidence and duration in GAERS absence epilepsy model over 4 hours.","methodology":"In vitro calcium flux assay and patch-clamp electrophysiology, in silico docking, in vivo pharmacokinetics in mice, and anticonvulsant testing in 6-Hz, Scn1a+/- Dravet, and GAERS absence epilepsy models.","limitations":"Divergent effects across seizure models complicate clinical development. Mechanism of increased absence seizures unclear. Limited to two compounds tested. Long-term safety not assessed."},{"rthcId":"RTHC-04609","title":"Emerging Adult Perceptions of Cannabis Consumption Post-Legalization: Considering Age and Sex Differences.","authors":"Harris-Lane, Laura M; Drakes, Dalainey H; Donnan, Jennifer R; Rowe, Emily C; Bishop, Lisa D; Harris, Nick","year":2023,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 72(3), 404-411","doi":"10.1016/j.jadohealth.2022.10.008","pmid":"36476394","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Age of the cannabis consumer significantly affected harm perceptions on 6 of 7 measures, with 14-year-old use rated as more dangerous. However, emerging adults saw little difference in harm between 21- and 28-year-old use except for brain development effects.","whyItMatters":"Understanding how young adults perceive cannabis risks at different ages can help target education campaigns, especially since they underestimate risks for their own age group.","specificNumbers":"1,424 Canadian emerging adults (ages 18-25, mean 21.23) randomly assigned to vignettes varying by consumer age (14, 21, 28) and sex (male, female). Main effect of age on 6 of 7 items. No main effects of sex.","methodology":"Experimental vignette study with 2x3 factorial design (age x sex of cannabis consumer) using seven single-item measures of perceived harm among Canadian emerging adults.","limitations":"Single-item measures may not capture nuanced attitudes. Vignette-based design may not reflect real-world judgment. Canadian sample post-legalization may not generalize to other contexts."},{"rthcId":"RTHC-04610","title":"Can inhaled cannabis users accurately evaluate impaired driving ability? A randomized controlled trial.","authors":"Hartley, Sarah; Simon, Nicolas; Cardozo, Bibiana; Larabi, Islam Amine; Alvarez, Jean Claude","year":2023,"journal":"Frontiers in public health, 11, 1234765","doi":"10.3389/fpubh.2023.1234765","pmid":"38074719","tags":["driving","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"One of the most important questions in cannabis and driving is whether users can tell when they're too impaired to drive. Unlike alcohol, where people notoriously overestimate their driving ability while drunk, this study found cannabis users were surprisingly accurate at assessing their own impairment.\n\nThirty healthy male volunteers — 15 chronic users (1–2 joints/day) and 15 occasional users (1–2 joints/week) — inhaled placebo, 10 mg, or 30 mg of THC mixed with tobacco in a controlled setting. They then rated their driving confidence, completed reaction time tests, and drove on a simulator.\n\nDriving confidence dropped markedly after cannabis use, proportional to the THC dose. The EC50 (half-maximal effect concentration) was very low at 0.11 ng/mL, meaning self-perceived impairment kicked in at very low THC blood levels with a rapid onset (half-life of 37 minutes). Importantly, driving confidence correlated with both objective measures: reaction time and lane-keeping ability on the simulator.\n\nChronic users showed faster recovery of driving confidence than occasional users, consistent with pharmacological tolerance. At 30 mg THC, driving impairment (measured by standard deviation of lane position, SDLP) was significant in both groups, but chronic users recovered driving ability faster.\n\nThe practical implication is notable: cannabis users appear capable of recognizing their impairment, which could support self-regulation strategies — though the authors caution this shouldn't replace objective testing standards.","whyItMatters":"If cannabis users can accurately assess when they're too impaired to drive, this has major implications for public health messaging and policy. Rather than relying solely on arbitrary blood THC thresholds (which this study and RTHC-00092 show are problematic), campaigns could emphasize self-assessment as a first line of defense. However, the study only tested men, the sample was small, and real-world driving involves many more variables than a simulator.","specificNumbers":"30 male participants (15 chronic, 15 occasional users). THC doses: 0, 10, and 30 mg inhaled. EC50 for self-perceived impairment: 0.11 ng/mL blood THC. Onset half-life for perceived impairment: 37 minutes. Driving confidence remained below baseline at 8 hours post-inhalation. Both 10 mg and 30 mg THC impaired driving ability and reaction time compared to placebo.","methodology":"Randomized controlled trial with 30 healthy male volunteers (15 chronic, 15 occasional cannabis users, ages 18–34). Participants inhaled placebo, 10 mg THC, or 30 mg THC mixed with tobacco. Measurements before and at multiple timepoints after inhalation: self-assessed driving confidence (visual analog scale), vigilance (Karolinska Sleepiness Scale), reaction time (psychomotor vigilance test), driving ability (standard deviation of lane position on York driving simulator), and blood THC concentrations.","limitations":"Male-only sample — women may assess impairment differently due to pharmacokinetic differences in THC processing. Small sample (30 total, split between use groups). Driving simulator, not real-world driving. THC was mixed with tobacco, which may modify effects. Laboratory setting may heighten self-awareness compared to social use settings. The study measured acute effects; fatigue, distraction, and other real-world factors weren't captured."},{"rthcId":"RTHC-04611","title":"Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication.","authors":"Hasegawa, Yuto; Kim, Juhyun; Ursini, Gianluca; Jouroukhin, Yan; Zhu, Xiaolei; Miyahara, Yu; Xiong, Feiyi; Madireddy, Samskruthi; Obayashi, Mizuho; Lutz, Beat; Sawa, Akira; Brown, Solange P; Pletnikov, Mikhail V; Kamiya, Atsushi","year":2023,"journal":"Nature communications, 14(1), 6559","doi":"10.1038/s41467-023-42276-5","pmid":"37880248","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Adolescent THC exposure caused microglial apoptosis in the medial prefrontal cortex, reducing excitability of pyramidal-tract neurons and producing adult social memory deficits, effects mediated by microglial CB1 receptors and exacerbated by 16p11.2 duplication.","whyItMatters":"This identifies microglia — the brain immune cells — as key mediators of adolescent cannabis harm, opening new avenues for understanding and potentially preventing cognitive damage from adolescent cannabis use.","specificNumbers":"Effects mediated by microglial Cnr1 (CB1). Exacerbated in 16p11.2 duplication model (a psychiatric risk CNV). Changes in mPFC pyramidal-tract neuron excitability and adult social memory deficits.","methodology":"Preclinical mouse study using adolescent THC exposure, 16p11.2 duplication genetic model, microglial-specific CB1 manipulation, electrophysiology, and social memory behavioral testing.","limitations":"Mouse social memory may not directly translate to human cognitive function. 16p11.2 duplication is one of many genetic risk factors. Specific THC doses and timing may not reflect human use patterns."},{"rthcId":"RTHC-04612","title":"Chronic Pain, Cannabis Legalization and Cannabis Use Disorder in Veterans Health Administration Patients, 2005 to 2019.","authors":"Hasin, Deborah S; Wall, Melanie M; Alschuler, Dan; Mannes, Zachary L; Malte, Carol; Olfson, Mark; Keyes, Katherine M; Gradus, Jaimie L; Cerdá, Magdalena; Maynard, Charles C; Keyhani, Salomeh; Martins, Silvia S; Fink, David S; Livne, Ofir; McDowell, Yoanna; Sherman, Scott; Saxon, Andrew J","year":2023,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2023.07.10.23292453","pmid":"37503049","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among patients with chronic pain, MCL led to 0.14% and RCL to 0.19% absolute increases in CUD prevalence, with 8.4% and 11.5% of total increases attributable to legalization. Effects were significantly greater than in patients without pain.","whyItMatters":"Chronic pain patients are increasingly turning to cannabis as opioid prescriptions decline, but they face higher CUD risk, creating a public health concern that grows as legalization expands.","specificNumbers":"Yearly n=3.2M-4.6M VHA patients (2005-2019). Pain patients: MCL +0.14%, RCL +0.19% CUD increase. No-pain patients: MCL +0.037%, RCL +0.042%. Ages 65-75 with pain: 19.4% of CUD increase attributable to RCL.","methodology":"Staggered-adoption difference-in-difference analysis of VHA electronic health records (2005-2019), stratified by chronic pain status with state and year fixed effects and demographic covariates.","limitations":"Observational design cannot prove legalization caused CUD increases. VHA patients are predominantly male and may not represent general population. CUD diagnosis rates may reflect increased screening rather than true prevalence increases."},{"rthcId":"RTHC-04613","title":"Adult use of highly-potent Δ9-THC cannabis concentrate products by U.S. state cannabis legalization status, 2021.","authors":"Hasin, Deborah S; Borodovsky, Jacob; Shmulewitz, Dvora; Walsh, Claire; Struble, Cara A; Livne, Ofir; Habib, Mohammad I; Fink, David S; Aharonovich, Efrat; Budney, Alan","year":2023,"journal":"Addictive behaviors, 140, 107617","doi":"10.1016/j.addbeh.2023.107617","pmid":"36736229","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Compared to no-law states, odds of using cannabis concentrates were 47% higher in recreational law states (aOR=1.47) and 29% higher in medical-only law states (aOR=1.29).","whyItMatters":"Cannabis concentrates contain much higher THC levels than flower and may carry greater health risks. Their increased use in legalized states suggests commercialization is driving consumption of more potent products.","specificNumbers":"4,328 past-7-day cannabis users surveyed in 2021. 92.4% used plant material. 57% used concentrates. Concentrate use: RCL states 61.5%, MCL states 56.6%, no-CL states 52.5%. aOR for RCL vs. no-CL: 1.47 (95% CI 1.17-1.84).","methodology":"Cross-sectional online survey of past-7-day cannabis users in all 50 states plus DC in 2021, with logistic regression adjusting for demographics and comparing cannabis law status groups.","limitations":"Cross-sectional design cannot establish causation. Online survey may have selection bias. Self-reported cannabis product use. Cannabis law categories may not capture variation in state-level regulations."},{"rthcId":"RTHC-04614","title":"Chronic pain, cannabis legalisation, and cannabis use disorder among patients in the US Veterans Health Administration system, 2005 to 2019: a repeated, cross-sectional study.","authors":"Hasin, Deborah S; Wall, Melanie M; Alschuler, Daniel M; Mannes, Zachary L; Malte, Carol; Olfson, Mark; Keyes, Katherine M; Gradus, Jaimie L; Cerdá, Magdalena; Maynard, Charles C; Keyhani, Salomeh; Martins, Silvia S; Fink, David S; Livne, Ofir; McDowell, Yoanna; Sherman, Scott; Saxon, Andrew J","year":2023,"journal":"The lancet. Psychiatry, 10(11), 877-886","doi":"10.1016/S2215-0366(23)00268-7","pmid":"37837985","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among chronic pain patients, MCL led to 0.135% and RCL to 0.188% absolute increases in CUD prevalence. In patients without pain, increases were much smaller (MCL: 0.037%, RCL: 0.042%).","whyItMatters":"This large-scale study from a major medical journal quantifies how cannabis legalization disproportionately affects a vulnerable population — chronic pain patients — with implications for clinical monitoring.","specificNumbers":"3.2M-4.6M patients per year (2005-2019). Chronic pain: MCL +0.135% (8.4% attributable), RCL +0.188% (11.5% attributable). No pain: MCL +0.037% (5.7%), RCL +0.042% (6.0%). NIDA-funded.","methodology":"Repeated cross-sectional study of VHA electronic health records (2005-2019) with staggered-adoption difference-in-difference analyses, stratified by chronic pain status.","limitations":"Observational design. VHA population is predominantly male. CUD diagnosis may reflect screening intensity changes. Cannot distinguish between harmful and beneficial cannabis use."},{"rthcId":"RTHC-04615","title":"State Cannabis Legalization and Cannabis Use Disorder in the US Veterans Health Administration, 2005 to 2019.","authors":"Hasin, Deborah S; Wall, Melanie M; Choi, C Jean; Alschuler, Daniel M; Malte, Carol; Olfson, Mark; Keyes, Katherine M; Gradus, Jaimie L; Cerdá, Magdalena; Maynard, Charles C; Keyhani, Salomeh; Martins, Silvia S; Fink, David S; Livne, Ofir; Mannes, Zachary; Sherman, Scott; Saxon, Andrew J","year":2023,"journal":"JAMA psychiatry, 80(4), 380-388","doi":"10.1001/jamapsychiatry.2023.0019","pmid":"36857036","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"MCL-only enactment accounted for 4.7% of CUD increases, while RCL enactment accounted for 9.8%. The effect was strongest in patients 65-75 years old, where RCL accounted for 18.6% of CUD prevalence increases.","whyItMatters":"While cannabis legalization plays a role in rising CUD rates, the relatively small effect sizes suggest other factors (changing attitudes, commercialization) are equally or more important.","specificNumbers":"CUD prevalence: no-CL states 1.38% to 2.25%, MCL-only states 1.38% to 2.54%, RCL states 1.39% to 2.56% (2005-2019). RCL in ages 65-75: 0.15% absolute increase, 18.6% of total increase attributable.","methodology":"Staggered-adoption difference-in-difference analysis of VHA electronic health records (2005-2019) with fixed effects for state, year, and demographics.","limitations":"VHA patients are predominantly male. CUD diagnoses depend on clinical screening practices. Effect sizes are small in absolute terms. Cannot capture undiagnosed CUD."},{"rthcId":"RTHC-04616","title":"Cannabis-based medicines and medical cannabis for adults with cancer pain.","authors":"Häuser, Winfried; Welsch, Patrick; Radbruch, Lukas; Fisher, Emma; Bell, Rae Frances; Moore, R Andrew","year":2023,"journal":"The Cochrane database of systematic reviews, 6(6), CD014915","doi":"10.1002/14651858.CD014915.pub2","pmid":"37283486","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Meta-analysis of 14 studies (1,823 participants) found moderate-certainty evidence that nabiximols and THC are ineffective for opioid-refractory cancer pain, with an NNTB of 16 for patient global improvement — not clinically relevant.","whyItMatters":"Despite widespread belief that cannabis helps cancer pain, this Cochrane review provides the most comprehensive evidence to date that current cannabis-based medicines do not meaningfully add to existing cancer pain treatment.","specificNumbers":"14 studies, 1,823 participants. Nabiximols/THC: NNTB 16 (95% CI 8-100) for PGIC improvement (moderate certainty). Pain intensity SMD -0.19 (not significant). CBD alone showed no added value. No herbal cannabis studies found.","methodology":"Cochrane systematic review and meta-analysis of double-blind RCTs comparing cannabis-based medicines to placebo or active treatments for cancer pain in adults. GRADE assessment of certainty of evidence.","limitations":"Only 14 studies met inclusion criteria. Most evidence is for nabiximols/THC; very limited evidence for CBD and nabilone. No studies of herbal cannabis. Short double-blind periods (2-5 weeks)."},{"rthcId":"RTHC-04617","title":"Cannabis and Pregnancy: A Review.","authors":"Hayer, Sarena; Mandelbaum, Ava D; Watch, Lester; Ryan, Kimberly S; Hedges, Madeline A; Manuzak, Jennifer A; Easley, Charles A; Schust, Danny J; Lo, Jamie O","year":2023,"journal":"Obstetrical & gynecological survey, 78(7), 411-428","doi":"10.1097/OGX.0000000000001159","pmid":"37480292","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Available studies support an association between prenatal cannabis use and increased risk of preterm birth, neonatal intensive care unit admission, low birth weight, and small-for-gestational-age infants.","whyItMatters":"Prenatal cannabis use is rising and poses documented risks to maternal and fetal health, yet many pregnant women are unaware of these risks or receive conflicting information.","specificNumbers":"Not quantified in abstract; review summarizes associations with preterm birth, NICU admission, low birth weight, and small-for-gestational-age outcomes across available studies.","methodology":"Literature review searching PubMed, Cochrane Library, and Google Scholar using terms related to cannabis, cannabinoids, pregnancy, and lactation outcomes.","limitations":"Review rather than systematic review or meta-analysis. Underlying studies may have confounding by tobacco, alcohol, or other substance co-use. Self-reported cannabis use may be underestimated."},{"rthcId":"RTHC-04618","title":"Cessation of chronic delta-9-tetrahydrocannabinol use partially reverses impacts on male fertility and the sperm epigenome in rhesus macaques.","authors":"Hedges, Jason C; Hanna, Carol B; Shorey-Kendrick, Lyndsey E; Boniface, Emily R; Bash, Jasper C; Rice-Stitt, Travis L; Burch, Fernanda C; D'Mello, Rahul; Morgan, Terry K; Lima, Ana Cristina; Terrobias, Juanito Jose D; Graham, Jason A; Mishler, Emily C; Jensen, Jared V; Hagen, Olivia L; Urian, J Wes; Spindel, Eliot R; Easley, Charles A; Murphy, Susan K; Lo, Jamie O","year":2023,"journal":"Fertility and sterility, 120(1), 163-174","doi":"10.1016/j.fertnstert.2023.02.034","pmid":"36990913","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"THC caused 59% decrease in testicular volume, decreased testosterone and estradiol, increased FSH, and altered 23,558 CpG methylation sites in sperm DNA. After cessation, testicular volume recovered to 73% and hormones partially normalized.","whyItMatters":"This is the first study in primates showing that while THC damage to male reproductive health is partially reversible, some effects — particularly epigenetic changes in sperm — may persist after stopping use.","specificNumbers":"6 adult male rhesus macaques (age 8-10). 59% decrease in testicular volume per 1 mg/7kg/day increase. Recovery to 73% of original volume. Testosterone increased 1.3 ng/mL after cessation. 23,558 differentially methylated CpGs in sperm.","methodology":"Research animal study with chronic daily THC edible administration at medically/recreationally relevant doses followed by cessation, with testicular imaging, hormone assays, semen analysis, proteomics, and whole genome bisulfite sequencing.","limitations":"Small sample size (n=6). Rhesus macaques may not perfectly model human reproductive biology. Recovery period may need to be longer. Cannot determine if epigenetic changes affect offspring health."},{"rthcId":"RTHC-04619","title":"Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats.","authors":"Hen-Shoval, Danielle; Moshe, Lital; Indig-Naimer, Talia; Mechoulam, Raphael; Shoval, Gal; Zalsman, Gil; Kogan, Natalya M; Weller, Aron","year":2023,"journal":"International journal of molecular sciences, 24(4)","doi":"10.3390/ijms24043828","pmid":"36835237","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Females required higher CBDA-ME doses (5-10 mg/kg vs. 1 mg/kg for males) for antidepressant effects. CB2 receptor blockade prevented the effect in females but not males, revealing sex-specific mechanisms involving BDNF and endocannabinoid pathways.","whyItMatters":"Women are twice as likely to develop depression as men, yet most preclinical studies use only males. This study reveals important sex differences in how cannabinoid-based antidepressants work.","specificNumbers":"Female effective doses: 5 and 10 mg/kg (vs. 1 mg/kg males). CB2 antagonist AM-630 blocked effect in females only. Females showed elevated serum BDNF, increased endocannabinoids, and decreased hippocampal FAAH after CBDA-ME.","methodology":"Two experiments in Wistar-Kyoto rats (genetic model of depression): dose-response forced swim test, and CB1/CB2 antagonist pre-treatment study with serum BDNF, endocannabinoid, and hippocampal FAAH analysis.","limitations":"Forced swim test is a limited model of human depression. WKY rats may not represent all depression subtypes. Acute dosing only; chronic effects unknown. Mechanisms explored are correlational."},{"rthcId":"RTHC-04620","title":"The U.S. hemp-derived cannabinoid industry and the potential of self-regulation: Using social media to assess an evolving health risk.","authors":"Henry, Doug; Partin, Kelly; LoParco, Cassidy R; Rossheim, Matthew","year":2023,"journal":"Social science & medicine (1982), 334, 116189","doi":"10.1016/j.socscimed.2023.116189","pmid":"37660520","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"While many industry participants genuinely want self-regulation to protect consumers and avoid government bans, there is little agreement on standards, who should oversee them, or how basic concepts should be defined, leaving consumers to experiment on their own bodies.","whyItMatters":"The largely unregulated hemp-derived cannabinoid market puts consumer health at risk, and the industry own conversations reveal that self-regulation alone is unlikely to solve this without external guidance.","specificNumbers":"Approximately 3,800 Reddit posts collected from September 2020 to August 2022. Analysis focused on regulation and consumer safety conversations.","methodology":"Qualitative thematic analysis of Reddit posts about hemp-derived cannabinoid regulation, guided by frameworks from anthropology of pharmaceuticals and commercial determinants of health.","limitations":"Reddit users may not represent the broader industry or consumer population. Posts may be biased by anonymity. Qualitative analysis is interpretive. Rapidly evolving regulatory landscape."},{"rthcId":"RTHC-04621","title":"Cannabidiol's Multifactorial Mechanisms Has Therapeutic Potential for Aneurysmal Subarachnoid Hemorrhage: a Review.","authors":"Henry, Nicholas; Fraser, Justin F; Chappell, Joseph; Langley, Tamra; Roberts, Jill M","year":2023,"journal":"Translational stroke research, 14(3), 283-296","doi":"10.1007/s12975-022-01080-x","pmid":"36109476","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD known mechanisms — anti-inflammatory effects, calcium regulation, and neuroprotection against cell death, excitotoxicity, and oxidative stress — align with the pathophysiology of post-SAH complications, particularly cerebral vasospasm and delayed cerebral ischemia.","whyItMatters":"Subarachnoid hemorrhage accounts for 5% of strokes and has high mortality. If CBD can address multiple post-SAH complications simultaneously, it could represent a novel therapeutic approach.","specificNumbers":"SAH accounts for approximately 5% of all strokes. Most common cause is ruptured cerebral aneurysm. Delayed cerebral ischemia is a major mortality factor. CBD effects categorized into anti-inflammatory, vascular, and neuroprotective.","methodology":"Literature review correlating known CBD pharmacology and physiological effects with the pathophysiology of post-SAH cerebral vasospasm and delayed cerebral ischemia.","limitations":"Entirely theoretical — no clinical or preclinical studies of CBD for SAH exist. Extrapolating CBD effects from other conditions to SAH may not be valid. CBD dosing and delivery for brain injury are unknown."},{"rthcId":"RTHC-04622","title":"Changes in Arkansans' attitudes toward pharmacist involvement and regulation of medical cannabis following its availability in Arkansas.","authors":"Hernandez, Michelle; Franks, Amy M; Payakachat, Nalin","year":2023,"journal":"Journal of the American Pharmacists Association : JAPhA, 63(4), 1131-1137.e4","doi":"10.1016/j.japh.2023.05.014","pmid":"37207711","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Compared to baseline, follow-up participants preferred less regulatory control of MC and were less likely to agree pharmacists helped improve MC-related patient safety, especially among those who used cannabis in the past 30 days.","whyItMatters":"As medical cannabis programs expand, the declining public trust in pharmacist involvement could undermine patient safety if pharmacists are not actively integrated into dispensing and counseling.","specificNumbers":"555 usable follow-up surveys from 1,526 baseline participants (39.8% response). 83.1% reported past 30-day cannabis use. 40.9% aged 40-64. 67.9% female. 90.6% white.","methodology":"Longitudinal self-administered online survey conducted at baseline (February 2018) and follow-up (September 2019) in Arkansas. Paired t-tests and multivariable regression.","limitations":"Low follow-up response rate (39.8%). Self-selected sample heavily skewed toward cannabis users (83.1%). Predominantly white and female. Single state may not generalize."},{"rthcId":"RTHC-04623","title":"The role of cannabis in treatment-resistant fibromyalgia women.","authors":"Hershkovich, Oded; Hayun, Yemima; Oscar, Nataly; Shtein, Arnold; Lotan, Raphael","year":2023,"journal":"Pain practice : the official journal of World Institute of Pain, 23(2), 180-184","doi":"10.1111/papr.13179","pmid":"36333278","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis treatment for 30 days produced marked improvements in general quality of life (p<0.01), general health (p<0.01), physical health (p<0.01), and psychological domain (p<0.01) in women with treatment-resistant fibromyalgia.","whyItMatters":"Fibromyalgia affects millions and many patients do not respond to conventional treatments. This study suggests cannabis could be a viable option for treatment-resistant cases.","specificNumbers":"30 women aged 18-70 (mean age 46). Baseline quality of life score 1.47±0.63, improved to 1.97 after 30 days (p<0.01). General health improved from 1.47 to 1.83 (p<0.01). Financial resources and home environment were unaffected.","methodology":"Prospective cohort study of 30 women with treatment-resistant fibromyalgia using WHO Quality of Life Bref questionnaire before and 1 month after cannabis treatment initiation.","limitations":"Small sample size (n=30). No control group or placebo comparison. Only 30-day follow-up. Self-reported outcomes subject to placebo effect and expectation bias. Only women studied."},{"rthcId":"RTHC-04624","title":"The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses.","authors":"Hill, Matthew N; Haney, Margaret; Hillard, Cecilia J; Karhson, Debra S; Vecchiarelli, Haley A","year":2023,"journal":"Psychological medicine, 53(15), 7006-7024","doi":"10.1017/S0033291723002465","pmid":"37671673","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Inhibitors of endocannabinoid metabolism and modulators of cannabinoid receptor signaling have emerged as potential treatments for substance use disorders, anxiety and trauma-related disorders, and autism spectrum disorders.","whyItMatters":"While cannabis itself has complex and sometimes harmful psychiatric effects, targeted drugs that modulate the endocannabinoid system could provide therapeutic benefits without cannabis side effects.","specificNumbers":"Not quantified in abstract; review covers preclinical models and emerging clinical trial data for substance use disorders, trauma-related disorders, and autism.","methodology":"Narrative review of pharmacological tools targeting the endocannabinoid system, their preclinical effects, and emerging clinical trial data for psychiatric conditions.","limitations":"Narrative review without systematic methodology. Many findings are preclinical. Clinical trial data is limited and early-stage."},{"rthcId":"RTHC-04625","title":"Synthetic cannabinoid receptor agonists are monoamine oxidase-A selective inhibitors.","authors":"Hindson, Sarah A; Andrews, Rachael C; Danson, Michael J; van der Kamp, Marc W; Manley, Amy E; Sutcliffe, Oliver B; Haines, Tom S F; Freeman, Tom P; Scott, Jennifer; Husbands, Stephen M; Blagbrough, Ian S; Anderson, J L Ross; Carbery, David R; Pudney, Christopher R","year":2023,"journal":"The FEBS journal, 290(12), 3243-3257","doi":"10.1111/febs.16741","pmid":"36708234","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Combining computational and experimental kinetics, researchers demonstrated that synthetic cannabinoids are MAO-A-specific inhibitors, with potency varying significantly based on the SCRA head group structure.","whyItMatters":"Synthetic cannabinoids cause severe, sometimes fatal side effects that cannot be explained by cannabinoid receptor activity. MAO-A inhibition provides a mechanistic explanation for hypertensive crises and cardiac events.","specificNumbers":"Multiple commonly used UK SCRAs tested. MAO-A specific inhibition confirmed. Potency varied significantly between SCRA structures. MAO-B was not inhibited.","methodology":"Combined in silico molecular modeling and experimental kinetic studies assessing MAO-A and MAO-B inhibition by a range of SCRAs and structural analogues.","limitations":"In vitro and in silico data; clinical relevance of MAO-A inhibition at recreational SCRA doses not established. Limited to UK-prevalent SCRAs. Does not address all SCRA side effects."},{"rthcId":"RTHC-04626","title":"Effects of prenatal cannabis exposure on developmental trajectory of cognitive ability and brain volumes in the adolescent brain cognitive development (ABCD) study.","authors":"Hiraoka, Daiki; Makita, Kai; Hamatani, Sayo; Tomoda, Akemi; Mizuno, Yoshifumi","year":2023,"journal":"Developmental cognitive neuroscience, 60, 101209","doi":"10.1016/j.dcn.2023.101209","pmid":"36791556","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Significant interactions between time and prenatal cannabis exposure were found for visuo-perceptual processing ability (b=-0.019, p=.009) and intracranial volumes (b=-6338.309, p=.009), suggesting effects magnify over development.","whyItMatters":"If prenatal cannabis effects become stronger over time rather than remaining stable, this suggests ongoing developmental vulnerability that may not be apparent in early childhood assessments.","specificNumbers":"11,876 children at baseline (age 9-11), 10,414 at 2-year follow-up from 22 US sites. 10,833 with no prenatal cannabis exposure, 697 with exposure. Significant time x exposure interactions for visual processing and brain volume.","methodology":"Longitudinal analysis of ABCD Study data at two time points, examining associations between prenatal cannabis exposure and developmental trajectories of cognitive abilities and brain volumes.","limitations":"Prenatal cannabis exposure was retrospectively reported by mothers. Cannot fully control for co-exposures (tobacco, alcohol). Two time points limit trajectory modeling. Effect sizes may be small."},{"rthcId":"RTHC-04627","title":"Association between cannabis use disorder and schizophrenia stronger in young males than in females.","authors":"Hjorthøj, Carsten; Compton, Wilson; Starzer, Marie; Nordholm, Dorte; Einstein, Emily; Erlangsen, Annette; Nordentoft, Merete; Volkow, Nora D; Han, Beth","year":2023,"journal":"Psychological medicine, 53(15), 7322-7328","doi":"10.1017/S0033291723000880","pmid":"37140715","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The association between CUD and schizophrenia was significantly stronger in young males aged 16-20 (aIRR=3.84) compared to females of the same age (aIRR=1.81). By 2021, the population attributable risk fraction was 15% for males versus 4% for females.","whyItMatters":"This landmark study quantifies the sex difference in cannabis-schizophrenia risk and suggests that preventing CUD in young males could substantially reduce schizophrenia incidence.","specificNumbers":"6.9 million individuals, 45,327 schizophrenia cases, 1972-2021. Males aHR=2.42, females aHR=2.02. Young males (16-20) aIRR=3.84. 2021 PARF: males 15%, females ~4%. Annual average PARF change: males 4.8%, females 4.0%.","methodology":"Nationwide Danish register-based cohort study of all individuals aged 16-49 during 1972-2021, with hazard ratios, incidence risk ratios, population attributable risk fractions, and joinpoint analyses.","limitations":"Register-based CUD diagnosis may underestimate true prevalence. Cannot prove causation despite temporal sequence. Danish population may not generalize to all countries. Changing diagnostic practices over 50 years."},{"rthcId":"RTHC-04628","title":"Recreational Marijuana Use, Adolescent Cognitive Development, and Schizophrenia Susceptibility.","authors":"Ho, Beng-Choon; Barry, Amy B; Koeppel, Julie A; Macleod, John; Boyd, Andy; David, Anthony; O'Leary, Daniel S","year":2023,"journal":"Biological psychiatry global open science, 3(2), 222-232","doi":"10.1016/j.bpsgos.2022.01.008","pmid":"37124347","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Adolescents with emergent marijuana use showed less age-expected improvement in sustained attention, visuospatial working memory, and executive sequencing. First-degree relatives of schizophrenia patients with marijuana use showed additional deficits in processing speed and executive reasoning.","whyItMatters":"Most adolescent marijuana research focuses on heavy use, but this study shows even typical, nonheavy use patterns can disrupt critical cognitive development, particularly in genetically vulnerable youth.","specificNumbers":"Iowa sample: 211 adolescents (40 first-degree, 54 second-degree relatives, 117 controls), 26.5% with emergent MJ use. Birth cohort: 3,463 children assessed ages 10-15. 5 of 8 cognitive domains significantly affected by emergent MJ use.","methodology":"Two complementary longitudinal samples: Iowa family study with neuropsychological testing at 0, 18, and 36 months, and a birth cohort with substance use and attention assessments between ages 10-15. Mixed linear models and regression analyses.","limitations":"Self-reported marijuana use. Iowa sample is relatively small. Cannot fully control for pre-existing cognitive differences. Two different assessment protocols across samples."},{"rthcId":"RTHC-04629","title":"Δ9-Tetrahydrocannabinol Differentially Alters Cannabidiol Efficacy in Recovery of Phonology and Syntax Following Damage to a Songbird Cortical-Like Brain Region.","authors":"Hodges, Rachel M; Chase, Katherine J; Tripson, Mark A; Bingham, Sharon; Woolley-Roberts, Marie; Guy, Geoffrey W; Soderstrom, Ken","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 790-801","doi":"10.1089/can.2022.0073","pmid":"36125410","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD with lowest THC (0.02%) improved phonological recovery while highest THC (5%) slowed it. For syntax, all THC concentrations improved recovery, with 3% THC being most effective at restoring pre-injury levels.","whyItMatters":"As CBD-enriched products become widely available with varying THC content, this study shows that the CBD:THC ratio critically affects therapeutic outcomes in a learned vocal behavior model.","specificNumbers":"3 mg/kg CBD tested with 0.02%, 0.08%, 1%, 3%, and 5% THC in zebra finches with partial HVC ablation. Differential effects on phonology versus syntax recovery.","methodology":"Preclinical study in zebra finches evaluating vocal recovery after partial ablation of HVC brain region, with CBD containing five different THC concentrations.","limitations":"Songbird vocal learning has limited direct relevance to human clinical conditions. Small number of THC concentrations tested. HVC ablation is a simplified brain injury model."},{"rthcId":"RTHC-04630","title":"Cigarette Smoking, Risky Alcohol Consumption, and Marijuana Smoking among University Students in Germany: Identification of Potential Sociodemographic and Study-Related Risk Groups and Predictors of Consumption.","authors":"Hoff, Thilo A; Heller, Sebastian; Reichel, Jennifer L; Werner, Antonia M; Schäfer, Markus; Tibubos, Ana Nanette; Simon, Perikles; Beutel, Manfred E; Letzel, Stephan; Rigotti, Thomas; Dietz, Pavel","year":2023,"journal":"Healthcare (Basel, Switzerland), 11(24)","doi":"10.3390/healthcare11243182","pmid":"38132073","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Each substance was highly associated with use of the other two substances. Health behaviors were the strongest predictors, while psychological and psychosocial variables played a relatively minor role.","whyItMatters":"Prevention programs for university students should address substance use holistically rather than targeting individual substances, as these behaviors are strongly interconnected.","specificNumbers":"3,991 students analyzed. 14.9% cigarette smoking, 38.6% risky alcohol, 10.9% marijuana. 9 predictors of smoking (R2=0.314), 18 predictors of risky drinking (R2=0.270), 16 predictors of marijuana (R2=0.239).","methodology":"Cross-sectional online health survey at University of Mainz, Germany, with 270 health-related items. Binary logistic regression with stepwise inclusion of five variable groups.","limitations":"Single university limits generalizability. Cross-sectional design cannot establish causal direction. Self-reported substance use. German context may not translate to other countries."},{"rthcId":"RTHC-04631","title":"A two-sample approach to retrograde extrapolation of blood THC concentrations - Is it feasible?","authors":"Holman, Peder Olai Skjeflo; Høiseth, Gudrun; Bachs, Liliana; Thaulow, Cecilie H; Vevelstad, Merete S; Mørland, Jørg; Strand, Maren Cecilie","year":2023,"journal":"Forensic science international, 352, 111833","doi":"10.1016/j.forsciint.2023.111833","pmid":"37793282","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In 87% of cases, concentration changes between two blood samples were not statistically significant due to analytical measurement uncertainty. The two-sample approach to retrograde extrapolation of THC cannot be recommended.","whyItMatters":"Forensic toxicologists and courts need reliable methods to estimate THC levels at the time of driving. This study definitively shows that the two-sample approach, used in some jurisdictions, is unreliable.","specificNumbers":"548 cases from Norwegian apprehended drivers (2000-2020). Median time between samples: 31 min. THC decreased in 62% but increased in 38% of cases. Mean apparent t1/2=6.0 hours. 87% of changes not statistically significant.","methodology":"Retrospective analysis of 548 cases with two consecutive blood samples from apprehended drivers in Norway. THC measured by GC-MS and UHPLC-MS/MS. Linear regression of rate constants against THC concentration.","limitations":"Retrospective data from a specific legal jurisdiction. Only apprehended drivers (not general population). Cannot know true blood THC at time of driving for validation."},{"rthcId":"RTHC-04632","title":"Association of cannabis, cannabidiol and synthetic cannabinoid use with mental health in UK adolescents.","authors":"Hotham, James; Cannings-John, Rebecca; Moore, Laurence; Hawkins, Jemma; Bonell, Chris; Hickman, Matthew; Zammit, Stanley; Hines, Lindsey A; Adara, Linda; Townson, Julia; White, James","year":2023,"journal":"The British journal of psychiatry : the journal of mental science, 223(4), 478-484","doi":"10.1192/bjp.2023.91","pmid":"37485911","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"All three substance types were significantly associated with mental health disorders after correction for multiple testing. CBD use appeared to weaken the cannabis-anxiety and cannabis-depression associations, suggesting a potential moderating role.","whyItMatters":"As CBD products become widely available and synthetic cannabinoids persist as a street drug, this first general population study shows both are associated with teen mental health problems.","specificNumbers":"6,672 adolescents aged 13-14 in England and Wales (2019-2020). 5.2% used cannabis, 1.9% used CBD, 0.6% used synthetic cannabinoids. Weekly tobacco use markedly attenuated associations.","methodology":"Cross-sectional analysis of 13-14 year old adolescents with multilevel logistic regression examining lifetime substance use and self-reported mental health symptoms.","limitations":"Cross-sectional design cannot determine causation. Self-reported substance use and mental health symptoms. Low prevalence of synthetic cannabinoid and CBD use limits statistical power. Tobacco use confounding."},{"rthcId":"RTHC-04633","title":"Effects of cannabidiol on anandamide levels in individuals with cannabis use disorder: findings from a randomised clinical trial for the treatment of cannabis use disorder.","authors":"Hua, Daniel Ying-Heng; Hindocha, Chandni; Baio, Gianluca; Lees, Rachel; Shaban, Natacha; Morgan, Celia J; Mofeez, Ali; Curran, H Valerie; Freeman, Tom P","year":2023,"journal":"Translational psychiatry, 13(1), 131","doi":"10.1038/s41398-023-02410-9","pmid":"37085531","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Anandamide levels unexpectedly decreased in the placebo group during cannabis cessation but were maintained by 800 mg/day CBD. The 400 mg dose had no significant effect. Changes in anandamide were not associated with clinical outcomes.","whyItMatters":"Understanding how CBD affects the endocannabinoid system could explain its therapeutic potential for cannabis use disorder and inform optimal dosing strategies.","specificNumbers":"70 participants with CUD randomized: placebo (n=23), 400 mg CBD (n=24), 800 mg CBD (n=23). Placebo group anandamide decreased by -0.048 (95% CI [-0.089, -0.007]). 800 mg group showed no change (0.005, 95% CI [-0.036, 0.047]).","methodology":"Secondary analysis of a 28-day randomized clinical trial of CBD for cannabis use disorder, measuring plasma anandamide levels at baseline and day 28, with and without adjustment for ongoing cannabis use.","limitations":"Small sample size. Plasma anandamide may not reflect brain levels. The clinical significance of maintained anandamide levels is unclear since changes were not associated with outcomes. Secondary analysis."},{"rthcId":"RTHC-04634","title":"Weight loss outcomes are not compromised in bariatric patients using cannabis.","authors":"Huang, Estella Y; Broderick, Ryan C; Li, Jonathan Z; Serra, Joaquin L; Ahuja, Pranav; Wu, Samantha; Genz, Michael; Grunvald, Eduardo; Kunkel, David C; Sandler, Bryan J; Horgan, Santiago; Jacobsen, Garth R","year":2023,"journal":"Surgical endoscopy, 37(3), 2194-2201","doi":"10.1007/s00464-022-09453-x","pmid":"35861881","tags":["medical-cannabis","appetite"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"One of the most common concerns about cannabis use after bariatric surgery is the 'munchies' — cannabis stimulates appetite, and the whole point of bariatric surgery is to restrict eating. This study put that concern to the test and found it largely unfounded.\n\nAmong 364 sleeve gastrectomy patients, 31 (8.5%) were weekly cannabis users. The researchers tracked weight loss at 1 week, 1 month, 3 months, 6 months, 9 months, 1 year, and 2 years post-surgery. At every single time point, there was no significant difference in excess weight loss between cannabis users and non-users.\n\nInterestingly, the cannabis group actually trended toward slightly more weight loss, though the difference wasn't statistically significant. Secondary outcomes — post-operative nausea and vomiting, length of hospital stay, readmission rates, and need for additional intervention — were also similar between groups.\n\nThis is reassuring data for the growing number of bariatric patients who use cannabis, whether medicinally or recreationally. The concern that appetite stimulation from cannabis would undermine surgical weight loss appears not to materialize in practice, at least through two years of follow-up.","whyItMatters":"About 8% of bariatric surgery patients use cannabis, and that number is growing as legalization expands. Surgeons and patients need to know whether cannabis use will compromise outcomes. This study provides the first focused evidence that it doesn't — giving clinicians data to counsel patients rather than relying on theoretical concerns about appetite stimulation.","specificNumbers":"364 sleeve gastrectomy patients: 31 cannabis users (8.5%), 333 non-users. No significant difference in excess weight loss at any time point from 1 week through 2 years. Post-operative nausea/vomiting, length of stay, readmission, and reintervention rates were comparable between groups.","methodology":"Retrospective cohort study of 364 sleeve gastrectomy patients divided into cannabis users (at least once weekly, n=31) and non-users (n=333). Primary outcome was excess weight loss (EWL) at multiple time points through 2 years. Secondary outcomes included post-operative nausea/vomiting, length of stay, readmission, and need for additional intervention. Cannabis users were also surveyed by phone for additional information.","limitations":"Retrospective design with a small cannabis user group (31 patients). Cannabis use was self-reported and defined broadly as 'at least once weekly' — dosage, potency, and route of administration varied. No data on whether cannabis use patterns changed after surgery. Single-center study (sleeve gastrectomy only, not gastric bypass). The cannabis group may differ from non-users in unmeasured ways. Two-year follow-up, while meaningful, may not capture very long-term differences."},{"rthcId":"RTHC-04635","title":"Cannabis-Impaired driving: ethical considerations for the primary care practitioner.","authors":"Huerne, Katherine; Ells, Carolyn; Grad, Roland; Filion, Kristian B; Eisenberg, Mark J","year":2023,"journal":"Annals of medicine, 55(1), 24-33","doi":"10.1080/07853890.2022.2151716","pmid":"36444881","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The ethical approach for primary care practitioners can be summarized as the duty to always inform, provide care through prevention and harm reduction strategies, and report when necessary.","whyItMatters":"As cannabis legalization expands, primary care providers lack ethical guidance on addressing impaired driving, creating a gap between increasing patient cannabis use and clinical responsibility.","specificNumbers":"Not quantified; ethical analysis reviewing evidence from four databases searched in December 2021.","methodology":"Ethical analysis in the form of a critical interpretive review, using systematic search methods to develop an ethical framework for primary care practice.","limitations":"High-level ethical discussion may not translate to specific clinical scenarios. Ethical recommendations vary by jurisdiction. Limited empirical basis for some recommendations."},{"rthcId":"RTHC-04636","title":"Trends in intentional abuse and misuse ingestions in school-aged children and adolescents reported to US poison centers from 2000-2020.","authors":"Hughes, Adrienne R; Grusing, Sara; Lin, Amber; Hendrickson, Robert G; Sheridan, David C; Marshall, Rebecca; Horowitz, B Z","year":2023,"journal":"Clinical toxicology (Philadelphia, Pa.), 61(1), 64-71","doi":"10.1080/15563650.2022.2120818","pmid":"36469528","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Marijuana exposure rates had the highest average monthly increase overall, with edible marijuana preparations accounting for the highest increase in call rates compared to all other marijuana forms, particularly from 2017 to 2020.","whyItMatters":"The rapid rise in marijuana, especially edible, misuse among youth coincides with expanding legalization and highlights a growing child safety concern.","specificNumbers":"338,727 intentional misuse/abuse cases in children ages 6-18 (2000-2020). 58.3% male. 80%+ aged 13-18. 32.6% resulted in worse than minor outcomes. Deaths rare (n=450, 0.1%). Marijuana edibles had highest rate increase.","methodology":"Retrospective cohort study of National Poison Data System (NPDS) data (2000-2020) for intentional misuse and abuse exposures in children 6-18 years old.","limitations":"Poison center calls may underrepresent actual exposures. Cannot distinguish recreational use from true abuse. Changes in reporting practices over 20 years. Cannot attribute trends to specific policy changes."},{"rthcId":"RTHC-04637","title":"Injunctive Norms and Driving Under the Influence and Riding With an Impaired Driver Among Young Adults in Washington State.","authors":"Hultgren, Brittney A; Guttmannova, Katarina; Cadigan, Jennifer M; Kilmer, Jason R; Delawalla, Miranda L M; Lee, Christine M; Larimer, Mary E","year":2023,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 73(5), 852-858","doi":"10.1016/j.jadohealth.2023.06.010","pmid":"37530684","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"More positive perceived injunctive norms were associated with 8x higher odds of driving under cannabis influence (DUI-C), 6.5x higher odds of riding with a cannabis-impaired driver, 2.5x higher odds of DUI-alcohol, and 4x higher odds of riding with alcohol-impaired drivers.","whyItMatters":"Injunctive norms — beliefs about what peers find acceptable — are potentially modifiable through prevention programs, offering a concrete target for reducing impaired driving.","specificNumbers":"1,941 young adults (18-25) in Washington State, 2019. Past-30-day rates: DUI-A 11.5%, DUI-C 12.4%, RWI-A 10.9%, RWI-C 20.9%. DUI-C had the strongest norm association (8x odds).","methodology":"Cross-sectional weighted logistic regression of the 2019 Washington Young Adult Health Survey, assessing associations between perceived injunctive norms and four impaired driving behaviors.","limitations":"Cross-sectional design cannot establish causation. Washington State may not generalize to other states. Self-reported behaviors may be underreported. Norms and behavior may be bidirectionally related."},{"rthcId":"RTHC-04638","title":"CANNABIS USE AND THE DEVELOPING BRAIN: HIGHS AND LOWS.","authors":"Hurd, Yasmin L; Ferland, Jacqueline-Marie N; Nomura, Yoko; Hulvershorn, Leslie A; Gray, Kevin M; Thurstone, Christian","year":2023,"journal":"Frontiers for young minds, 11","doi":"10.3389/frym.2023.898445","pmid":"37946933","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabinoids in cannabis act on the human body in many ways, and use during pregnancy and adolescence — critical developmental periods — can have long-lasting impacts on brain formation and emotional control systems.","whyItMatters":"As cannabis becomes more accessible, providing age-appropriate information about its effects on developing brains is essential for informed decision-making by young people.","specificNumbers":"Not quantified; overview article designed for youth audience.","methodology":"Educational overview article summarizing effects of cannabinoids on prenatal and adolescent brain development.","limitations":"General overview without systematic methodology. Simplified for youth audience, which may omit nuance. Does not present new data."},{"rthcId":"RTHC-04639","title":"Cannabinoid-Associated Hyperemesis Syndrome Treated With Dronabinol: Killing a Poison With the Poison.","authors":"Hussain, Azhar; Kc, Sistu; Sapna, Fnu","year":2023,"journal":"Cureus, 15(11), e49629","doi":"10.7759/cureus.49629","pmid":"38161894","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"A single dose of dronabinol led to significant symptom improvement after haloperidol caused agitation and worsening symptoms. Subsequent dronabinol doses resulted in complete resolution of CHS symptoms.","whyItMatters":"This paradoxical treatment — using a cannabinoid to treat a syndrome caused by cannabinoids — may offer a novel approach for acute CHS management when other treatments fail.","specificNumbers":"21-year-old female with chronic cannabis use. Haloperidol caused worsening agitation. One dose of dronabinol produced significant improvement. Complete resolution with subsequent doses.","methodology":"Case report with detailed clinical timeline of presentation, failed treatments, and successful dronabinol administration.","limitations":"Single case report cannot establish treatment efficacy. Spontaneous resolution cannot be ruled out. No long-term follow-up. Mechanism of action unclear."},{"rthcId":"RTHC-04640","title":"Cannabinoids, Endocannabinoids, and Synthetic Cannabimimetic Molecules in Neuromuscular Disorders.","authors":"Iannotti, Fabio Arturo","year":2023,"journal":"International journal of molecular sciences, 25(1)","doi":"10.3390/ijms25010238","pmid":"38203407","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Most evidence on cannabinoids for NMDs comes from MS pain and spasticity studies. Preclinical and clinical studies across other NMDs suggest potential benefits, though the evidence base is still developing.","whyItMatters":"Neuromuscular disorders are currently untreatable, and symptom management options are limited. Cannabinoids could offer an additional therapeutic avenue for pain, spasticity, and other debilitating symptoms.","specificNumbers":"Not quantified in abstract; review covers cannabinoids, endocannabinoids, and synthetic cannabimimetics across the spectrum of neuromuscular disorders.","methodology":"Review article summarizing preclinical and clinical evidence for cannabinoid use in neuromuscular disorders including motor neuron diseases, peripheral neuropathies, and skeletal muscle conditions.","limitations":"Review format without systematic methodology. Evidence from MS may not generalize to all NMDs. Many referenced studies are preclinical. Heterogeneity of NMDs limits generalization."},{"rthcId":"RTHC-04641","title":"Effect of Cannabidiol in LPS-Induced Toxicity in Astrocytes: Possible Role for Cannabinoid Type-1 Receptors.","authors":"Ibork, Hind; Idrissi, Sara El; Zulu, Simo Siyanda; Miller, Robert; Hajji, Lhoussain; Morgan, Annabelle Manalo; Taghzouti, Khalid; Abboussi, Oualid","year":2023,"journal":"Neurotoxicity research, 41(6), 615-626","doi":"10.1007/s12640-023-00671-2","pmid":"37782433","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD decreased mitochondrial proton leak, increased spare respiratory capacity, and enhanced glycolytic capacity in inflamed astrocytes while reducing pro-inflammatory cytokines TNFα and IL-6 and ROS production, partly through CB1-dependent mechanisms.","whyItMatters":"Understanding how CBD protects brain support cells (astrocytes) from inflammatory damage could inform treatments for neurodegenerative diseases where inflammation and metabolic dysfunction are key drivers.","specificNumbers":"CBD reduced TNFα and IL-6 concentrations and ROS production in LPS-stimulated astrocytes. Glycolytic changes were CB1-dependent. CB1 antagonist SR141716A increased pro-inflammatory cytokines and ROS.","methodology":"In vitro study using primary astrocyte cell cultures stimulated with LPS (lipopolysaccharide). Metabolic profiling with extracellular flux analyzer. CB1 involvement assessed with receptor antagonist.","limitations":"In vitro cell culture model does not replicate in vivo brain complexity. LPS stimulation is a simplified inflammatory model. CBD concentrations used may not match achievable brain levels."},{"rthcId":"RTHC-04642","title":"Non-psychoactive Cannabidiol Prevents Osteoporosis in an Animal Model and Increases Cell Viability, Proliferation, and Osteogenic Gene Expression in Human Skeletal Stem and Progenitor Cells.","authors":"Ihejirika-Lomedico, Rivka; Patel, Karan; Buchalter, Daniel B; Kirby, David J; Mehta, Devan; Dankert, John F; Muiños-López, Emma; Ihejirika, Yael; Leucht, Philipp","year":2023,"journal":"Calcified tissue international, 112(6), 716-726","doi":"10.1007/s00223-023-01083-2","pmid":"37093268","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD prevented both fluoxetine-induced and oophorectomy-induced osteoporosis in mice and normalized bone healing. In vitro, CBD significantly increased human stem cell viability, proliferation, and osteocalcin expression compared to controls.","whyItMatters":"Osteoporosis affects millions worldwide and current treatments have significant side effects. CBD could represent a novel, well-tolerated approach to preventing bone loss and supporting fracture healing.","specificNumbers":"CBD increased cell viability and proliferation significantly vs. controls. Osteocalcin expression significantly higher in CBD-treated cells. CBD prevented fluoxetine- and OVX-induced osteoporosis by X-ray and microCT. OVX delayed healing in controls but not CBD-pretreated mice.","methodology":"Two-phase study: in vitro human osteoprogenitor cell assays with crystallized pharmaceutical-grade CBD, and in vivo murine models of pharmacologic (fluoxetine) and hormonal (oophorectomy) osteoporosis with femur fracture healing assessment.","limitations":"Mouse models may not fully translate to human osteoporosis. CBD dosing in mice may not correspond to human therapeutic levels. In vitro cell behavior may differ from in vivo bone metabolism."},{"rthcId":"RTHC-04643","title":"The trajectory of two negative symptom dimensions in first-episode psychosis and the role of cannabis use: A 10-year follow-up study.","authors":"Ihler, Henrik Myhre; Lyngstad, Siv Hege; Gardsjord, Erlend Strand; Widing, Line Hustad; Flaaten, Camilla Bärthel; Åsbø, Gina; Wold, Kristin Fjelnseth; Engen, Magnus Johan; Simonsen, Carmen; Ueland, Torill; Lagerberg, Trine Vik; Melle, Ingrid; Romm, Kristin Lie","year":2023,"journal":"Schizophrenia research, 252, 317-325","doi":"10.1016/j.schres.2023.01.024","pmid":"36706477","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis use at baseline was associated with long-lasting higher symptom load for diminished expression but not apathy. Persistent cannabis use further strengthened this association, implying a causal relationship.","whyItMatters":"Negative symptoms like diminished expression are among the most disabling features of psychosis and respond poorly to treatment. Reducing cannabis use may be a modifiable factor to improve outcomes.","specificNumbers":"351 participants with first-episode non-affective psychosis followed at baseline, 1 year, and 10 years. Both symptom dimensions decreased over time, with most improvement from baseline to 1 year.","methodology":"Longitudinal cohort study with linear mixed models examining trajectories of two negative symptom dimensions over 10 years, with cannabis use as a predictor while controlling for other secondary negative symptom sources.","limitations":"Observational design cannot definitively prove causation. Cannabis use assessment may not capture full patterns. Attrition over 10 years may bias results."},{"rthcId":"RTHC-04644","title":"The transition to Schizophrenia spectrum disorder from a first psychotic episode that did or did not appear to be induced by substance use.","authors":"Inchausti, Lucía; Gorostiza, Inigo; Gonzalez Torres, Miguel Angel; Oraa, Rodrigo","year":2023,"journal":"Psychiatry research, 328, 115475","doi":"10.1016/j.psychres.2023.115475","pmid":"37713923","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis use (versus other substances or polysubstance use) was associated with a higher risk of conversion to schizophrenia spectrum disorders (HR 1.96, p=0.001), with 86.9% of conversions occurring within the first five years.","whyItMatters":"Identifying which first-episode psychosis patients are most likely to develop schizophrenia allows for targeted early intervention, and cannabis appears to be a significant modifiable risk factor.","specificNumbers":"341 patients (64.8% male, mean age 33.8). Cannabis was most commonly used substance (78.9%). 52.8% converted to schizophrenia/SSD. 86.9% of conversions within 5 years. Cannabis HR 1.96 (p=0.001).","methodology":"Retrospective cohort study using hospital discharge records from Basurto University Hospital (2002-2016). Kaplan-Meier survival curves and Cox regression for conversion analysis.","limitations":"Retrospective design. Single hospital. Cannot distinguish causation from association. Substance-induced psychosis and other FEP diagnoses had similar conversion rates, complicating interpretation."},{"rthcId":"RTHC-04645","title":"Neurodevelopmental outcomes in children after prenatal marijuana exposure.","authors":"Isik, Oliver G; Guo, Ling; Whitehouse, Andrew J O; Li, Guohua; Ing, Caleb","year":2023,"journal":"Paediatric and perinatal epidemiology, 37(6), 536-546","doi":"10.1111/ppe.12987","pmid":"37283466","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Exposed children scored similarly to unexposed children on language (CELF Total -0.33 points, 95% CI -4.71, 4.05) and all secondary neuropsychological outcomes. No associations with clinical deficit risk were found.","whyItMatters":"This well-controlled longitudinal study challenges assumptions about prenatal marijuana harm, suggesting that observed effects in other studies may be confounded by parental characteristics rather than cannabis itself.","specificNumbers":"2,804 children (285 exposed, 10.2%). No significant differences in CELF Total, Receptive, or Expressive scores at age 10. No associations with PPVT, CBCL, MAND, CPM, SDMT, or AQ scores.","methodology":"Propensity score matching with optimal full matching, multiple imputation for missing covariates, and inverse probability of censoring weighting for missing outcomes. Linear regression within matched sets.","limitations":"Maternal self-report of cannabis use may be underreported. Cannabis potency and frequency of use were not detailed. The Raine Study cohort (born 1989-1992) may not reflect current, higher-potency cannabis."},{"rthcId":"RTHC-04646","title":"UK Medical Cannabis Registry: An analysis of clinical outcomes of medicinal cannabis therapy for attention-deficit/hyperactivity disorder.","authors":"Ittiphakorn, Pim; Erridge, Simon; Holvey, Carl; Coomber, Ross; Rucker, James J; Sodergren, Mikael H","year":2023,"journal":"Neuropsychopharmacology reports, 43(4), 596-606","doi":"10.1002/npr2.12400","pmid":"38058251","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Significant improvements in EQ-5D-5L (quality of life) at 1, 3, and 6 months, and in GAD-7 (anxiety) and sleep quality scores at 1, 3, 6, and 12 months (all p<0.01).","whyItMatters":"ADHD is often accompanied by anxiety, sleep problems, and reduced quality of life. This registry data suggests medical cannabis may address these common comorbidities.","specificNumbers":"68 patients met criteria. 61 adverse events in 11 patients (16.18%). Most AEs were moderate (38.24%). Significant improvements in HRQoL, anxiety, and sleep sustained through 12 months.","methodology":"Observational registry analysis from the UK Medical Cannabis Registry using patient-reported outcome measures at baseline, 1, 3, 6, and 12 months.","limitations":"No control group or randomization. Small sample (n=68). Registry data subject to selection bias. Cannot prove causation. Attrition over 12 months not detailed."},{"rthcId":"RTHC-04647","title":"E-Cigarette and Cannabis Use Patterns, Depression, and Suicide Behaviors Among US Youth: Analysis of 2019 Youth Risk Behavior Survey Data.","authors":"Jacobs, Wura; Orozco, Georgina; Villanueva, Guadalupe; Merianos, Ashley L","year":2023,"journal":"American journal of health promotion : AJHP, 37(1), 77-83","doi":"10.1177/08901171221112927","pmid":"35792818","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Exclusive e-cigarette users, exclusive cannabis users, and concurrent users all had increased odds of depression and suicidal behavior compared to non-users, with female students showing particularly elevated risks.","whyItMatters":"With 16.4% of high school students using both e-cigarettes and cannabis, understanding the mental health implications of this combined use pattern is critical for prevention.","specificNumbers":"12,401 high school students. 15.7% exclusive e-cigarette, 4.5% exclusive cannabis, 16.4% concurrent users. All groups had elevated odds of depression, suicidal ideation, suicide plans, attempts, and attempt-related injuries vs. non-users.","methodology":"Cross-sectional analysis of 2019 National Youth Risk Behavior Survey data using multivariable logistic regression, stratified by sex.","limitations":"Cross-sectional design cannot determine if substance use causes mental health problems or vice versa. Self-reported data. Past 30-day substance use may not reflect chronic patterns."},{"rthcId":"RTHC-04648","title":"The effect of marijuana use on short-term outcomes with bariatric surgery.","authors":"Janes, Lindsay A; Hammond, John W; Bonham, Aaron J; Carlin, Arthur M; Ghaferi, Amir A; Varban, Oliver A; Ehlers, Anne P; Finks, Jonathan F","year":2023,"journal":"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery, 19(9), 964-970","doi":"10.1016/j.soard.2023.02.025","pmid":"37142472","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Marijuana use was not associated with worse 30-day outcomes or 1-year weight loss. However, marijuana users were more likely to be current smokers (14% vs. 8%), use other substances, and report depression.","whyItMatters":"Many bariatric surgery programs exclude marijuana users due to assumed risks. This large study suggests that policy should be reconsidered, while providing additional mental health support.","specificNumbers":"6,879 patients, 574 baseline marijuana users, 139 persistent users at 1 year. No differences in 30-day complications. No differences in 1-year weight loss. Users: 14% vs. 8% smokers (p-value significant). Higher depression and substance use rates.","methodology":"Multicenter statewide study using Michigan Bariatric Surgery Collaborative registry data (June 2019-June 2020). Regression analysis comparing 30-day and 1-year outcomes between marijuana users and non-users.","limitations":"Self-reported marijuana use may be underreported. One-year follow-up may miss longer-term effects. Michigan-specific data. Cannot assess dose-response relationship."},{"rthcId":"RTHC-04649","title":"THC in breath aerosols collected with an impaction filter device before and after legal-market product inhalation-a pilot study.","authors":"Jeerage, Kavita M; Beuning, Cheryle N; Friss, Adam J; Bidwell, L Cinnamon; Lovestead, Tara M","year":2023,"journal":"Journal of breath research, 17(3)","doi":"10.1088/1752-7163/acd410","pmid":"37211879","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"THC was quantified in 80% of 1-hour post-use breath samples, 36% of baseline-experimental samples, and 31% of baseline-intake samples, indicating detectable but inconsistent breath THC levels.","whyItMatters":"A reliable cannabis breathalyzer could be crucial for impaired driving enforcement, but this pilot study shows significant technical challenges remain before such a device is practical.","specificNumbers":"42 breath samples from 18 participants over 1+ year. Cannabis flower ~25% THCa. THC detected in 31% baseline-intake, 36% baseline-experimental, 80% post-use samples. Analyzed by LC-MS/MS.","methodology":"Pilot study using impaction filter breath collection device before and after legal cannabis flower smoking. THC quantified by liquid chromatography-tandem mass spectrometry.","limitations":"Small pilot study (18 participants). THC detected in 31-36% of baseline samples raises specificity concerns. No verified abstinence before baseline. Single post-use time point. Cannabis use occurred at participant residences."},{"rthcId":"RTHC-04650","title":"Chemical transformation of cannabidiol into psychotropic cannabinoids under acidic reaction conditions: Identification of transformed products by GC-MS.","authors":"Jeong, Minsun; Lee, Sangin; Seo, Chaeyoung; Kwon, Eunjeong; Rho, Soohyang; Cho, Mansoo; Kim, Moon Yeon; Lee, Wonwoong; Lee, Yong Sup; Hong, Jongki","year":2023,"journal":"Journal of food and drug analysis, 31(1), 165-176","doi":"10.38212/2224-6614.3452","pmid":"37224558","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"At pH 3.5 and 30°C, CBD readily converted into THC, CBC, and HHC analogs as major products, with THC isomers and hydroxy-HHC as minor products. At pH 5.0, degradation was minimal even at 70°C for 24 hours.","whyItMatters":"Many food and cosmetic manufacturing processes involve acidic conditions, which could inadvertently convert CBD into psychoactive substances, creating safety and regulatory concerns.","specificNumbers":"CBD tested at pH 2.0, 3.5, and 5.0 in ethanol with HCl. Major products: THC, CBC, ethoxy-HHC analogs. Minor products: delta-8 and delta-10 THC, 9-hydroxy-HHC. Seven psychoactive compounds identified.","methodology":"Chemical transformation study of CBD in ethanol at varying pH levels and temperatures, with product identification by GC-MS using TMS derivatization and comparison to authentic standards.","limitations":"Ethanol solution may not reflect all manufacturing matrices. Concentrations of transformed products not quantified relative to starting material. Real-world manufacturing conditions are more complex."},{"rthcId":"RTHC-04651","title":"A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.","authors":"Jiang, Ming; Huizenga, Mirjam C W; Wirt, Jonah L; Paloczi, Janos; Amedi, Avand; van den Berg, Richard J B H N; Benz, Joerg; Collin, Ludovic; Deng, Hui; Di, Xinyu; Driever, Wouter F; Florea, Bogdan I; Grether, Uwe; Janssen, Antonius P A; Hankemeier, Thomas; Heitman, Laura H; Lam, Tsang-Wai; Mohr, Florian; Pavlovic, Anto; Ruf, Iris; van den Hurk, Helma; Stevens, Anna F; van der Vliet, Daan; van der Wel, Tom; Wittwer, Matthias B; van Boeckel, Constant A A; Pacher, Pal; Hohmann, Andrea G; van der Stelt, Mario","year":2023,"journal":"Nature communications, 14(1), 8039","doi":"10.1038/s41467-023-43606-3","pmid":"38052772","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"LEI-515 increased 2-AG levels in peripheral organs but not the brain, attenuated liver necrosis and chemotherapy-induced neuropathic pain, and did not produce CB1-mediated side effects or physical dependence.","whyItMatters":"Previous MAGL inhibitors caused brain-related side effects similar to cannabis. LEI-515 demonstrates that peripheral-only endocannabinoid enhancement can provide therapeutic benefits without these problems.","specificNumbers":"LEI-515 increased peripheral 2-AG but not brain levels. Antinociceptive effects blocked by CB2 but not CB1 antagonists. Rimonabant precipitated dependence with JZL184 and WIN55,212-2 but not LEI-515.","methodology":"Drug discovery study combining high-throughput screening, medicinal chemistry, in vivo pharmacology (liver injury and neuropathic pain models), and dependence testing in mice.","limitations":"Preclinical mouse data may not translate to humans. Long-term safety of peripheral MAGL inhibition unknown. Single pain model tested. Liver injury model is acute, not chronic."},{"rthcId":"RTHC-04652","title":"Cannabinoid type-2 receptors modulate terpene induced anxiety-reduction in zebrafish.","authors":"Johnson, Andréa L; Verbitsky, Ryan; Hudson, James; Dean, Rachel; Hamilton, Trevor J","year":2023,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 168, 115760","doi":"10.1016/j.biopha.2023.115760","pmid":"37865998","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CB2 antagonist AM630, but not CB1 antagonist rimonabant, eliminated the anxiolytic effects of both terpinolene and beta-caryophyllene, demonstrating selective CB2 mediation of terpene-induced anxiety reduction.","whyItMatters":"This provides experimental evidence for the entourage effect — the idea that cannabis terpenes contribute to therapeutic effects through cannabinoid receptors — and identifies CB2 as the specific target.","specificNumbers":"Terpinolene tested at 0.01%, 0.05%, and 0.1%. Bisabolol at 0.001%, 0.0015%, and 0.002%. Bisabolol had no behavioral effects. TPL 0.1% increased inner zone time (anxiolytic). AM630 eliminated anxiolytic effects of both TPL and BCP.","methodology":"Zebrafish open field test with terpene exposure, followed by CB1 (rimonabant) and CB2 (AM630) antagonist pre-treatment experiments to identify receptor mechanisms.","limitations":"Zebrafish neurobiology differs from mammals. Terpene concentrations may not reflect exposure from cannabis use. Aqueous exposure route differs from inhalation. Limited terpenes tested."},{"rthcId":"RTHC-04653","title":"Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users.","authors":"Johnson, Emma C; Colbert, Sarah M C; Jeffries, Paul W; Tillman, Rebecca; Bigdeli, Tim B; Karcher, Nicole R; Chan, Grace; Kuperman, Samuel; Meyers, Jacquelyn L; Nurnberger, John I; Plawecki, Martin H; Degenhardt, Louisa; Martin, Nicholas G; Kamarajan, Chella; Schuckit, Marc A; Murray, Robin M; Dick, Danielle M; Edenberg, Howard J; D'Souza, Deepak Cyril; Di Forti, Marta; Porjesz, Bernice; Nelson, Elliot C; Agrawal, Arpana","year":2023,"journal":"Schizophrenia bulletin, 49(3), 778-787","doi":"10.1093/schbul/sbac196","pmid":"36545904","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Polygenic risk for schizophrenia was significantly associated with cannabis-related paranoia, depression/anhedonia, social withdrawal, and cognitive difficulties, with cognitive difficulties showing the strongest association (beta=0.22, p=5.2e-7).","whyItMatters":"This suggests genetic vulnerability to schizophrenia makes people more susceptible to negative cannabis experiences, even before any clinical illness develops, which could serve as an early warning marker.","specificNumbers":"4,832 subjects analyzed (3,128 European, 1,704 African ancestry). 70% had CUD. Schizophrenia PRS most strongly associated with cognitive difficulties (beta=0.22, p=5.2e-7). Replicated in independent sample (n=1,446).","methodology":"Genetic association study using polygenic risk scores for schizophrenia in the COGA study sample, with independent replication. Controlled for cannabis use duration, CUD severity, and age at first use.","limitations":"Sample ascertained for alcohol use disorders may not represent general population. Self-reported cannabis experiences. Polygenic scores capture only a fraction of genetic risk."},{"rthcId":"RTHC-04654","title":"The Effects of β-myrcene on Simulated Driving and Divided Attention: A Double-Blind, Placebo-Controlled, Crossover Pilot Study.","authors":"Johnson, Mark B; McKnight, Scott; Taylor, Eileen P; Mechtler, Laszlo; Ralyea, Christopher C","year":2023,"journal":"Cannabis (Albuquerque, N.M.), 6(1), 9-19","doi":"10.26828/cannabis/2023.01.002","pmid":"37287732","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Beta-myrcene at 15 mg produced statistically significant reductions in speed control and increased errors on a divided attention task in a driving simulator, providing proof-of-principle that terpenes can impair driving.","whyItMatters":"Cannabis-impaired driving research has focused almost exclusively on THC. This study shows that other cannabis compounds may contribute to driving impairment independently.","specificNumbers":"n=10 participants in crossover design. 15 mg pure beta-myrcene vs. canola oil control. Significant reductions in speed control. Significant increased divided attention errors. Baseline and three follow-up blocks.","methodology":"Double-blind, placebo-controlled, crossover pilot study using STISIM driving simulator with 15 mg pure beta-myrcene capsule versus canola oil control.","limitations":"Very small sample (n=10). Single terpene dose tested. Simulated driving may not reflect real-world driving. 15 mg may not represent typical exposure from cannabis use."},{"rthcId":"RTHC-04655","title":"Unhealthy behaviors associated with mental health disorders: a systematic comparative review of diet quality, sedentary behavior, and cannabis and tobacco use.","authors":"Johnstad, Petter Grahl","year":2023,"journal":"Frontiers in public health, 11, 1268339","doi":"10.3389/fpubh.2023.1268339","pmid":"38249418","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Across 294 studies, four unhealthy behaviors were about equally associated with psychosis, depression, anxiety, bipolar disorder, ADHD, and PTSD. Only cannabis-personality disorder was exceptionally strong.","whyItMatters":"The equal strength of these associations suggests they reflect a general vulnerability rather than specific substance effects, which has implications for prevention and treatment approaches.","specificNumbers":"294 studies from 3,682 records. Associations examined for 4 behaviors x 7 disorders. Cannabis-personality disorder association was uniquely strong. Findings robust across sensitivity analyses.","methodology":"Systematic comparative review of odds ratios from studies published since 2015, with sensitivity analyses for sample bias, measurement disparities, and control variables.","limitations":"Heterogeneous methodologies across included studies. Odds ratios only; other effect measures excluded. Explorative rather than definitive analysis. Many studies cross-sectional."},{"rthcId":"RTHC-04656","title":"A tale of two cities: Racialized arrests following decriminalization and recreational legalization of cannabis.","authors":"Joshi, Spruha; Doonan, Samantha M; Pamplin, John R","year":2023,"journal":"Drug and alcohol dependence, 249, 109911","doi":"10.1016/j.drugalcdep.2023.109911","pmid":"37301067","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Both cities saw decreased absolute disparity in possession arrests post-legalization. However, public consumption arrests emerged with significant racial disparities: in DC, 4.0 more Black than white arrests per month; in LA, relative disparity of 6.7.","whyItMatters":"Cannabis legalization aimed to reduce racial disparities in enforcement, but the shift from possession to public consumption arrests may simply move the disparity to a new violation category.","specificNumbers":"DC data 2012-2019, LA data 2010-2019. DC public consumption: absolute +4.0 more Black arrests/month, relative disparity 9.1. LA public consumption: absolute +0.6, relative disparity 6.7. Possession arrest disparities decreased in both cities.","methodology":"Analysis of publicly available police department arrest data from DC Metropolitan Police (2012-2019) and LA Police (2010-2019), comparing average monthly arrest rates by race across legal status changes.","limitations":"Two cities may not represent national trends. Arrest data reflects enforcement patterns, not actual behavior. Cannot account for all confounders affecting arrest rates."},{"rthcId":"RTHC-04657","title":"Not just females and males: Unravelling the complex sex determinism of the hemp palm, Trachycarpus fortunei.","authors":"Jousson, Antoine; Naciri, Yamama; Christe, Camille; Marazzi, Brigitte; Stauffer, Fred","year":2023,"journal":"American journal of botany, 110(12), e16257","doi":"10.1002/ajb2.16257","pmid":"38014995","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Sexual differentiation appears late in floral development, with genetic analysis revealing linked heterozygous regions in males suggesting at least 15% of wild palms are offspring of males that can also produce fertile female flowers.","whyItMatters":"Understanding the reproductive biology of this invasive ornamental palm helps explain its high dispersal ability on the southern side of the Alps.","specificNumbers":"31,000 SNPs analyzed across 122 palms from 21 wild populations. At least 15% of wild palms are direct offspring of males producing fertile pistillate flowers.","methodology":"SEM and anatomical study of floral development combined with genome-wide association study (31,000 SNPs, 122 palms, 21 populations) for sex determinism.","limitations":"Limited to southern Alps populations. Complex sexual expression makes definitive genetic sex determination difficult. SNP density may miss fine-scale genetic variation."},{"rthcId":"RTHC-04658","title":"Outpatients with psychotic disorders need physical health-promoting treatment: A cross-sectional multisite study.","authors":"Kaasgaard, Didde Marie; Stryhn, Lene; Veldt Larsen, Pia; Fisker, Lone; Friis Elliott, Anja; Høgh, Lene; Thunberg, Rolf; Knudsgaard Sørensen, Mette; Martinsen, Pernille; Kjær Hansen, Hanne; Munk-Jørgensen, Povl; Hjorth, Peter","year":2023,"journal":"Heliyon, 9(11), e21670","doi":"10.1016/j.heliyon.2023.e21670","pmid":"38034687","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"73% of outpatients needed health promotion based on BMI and substance use. 36% had somatic comorbidities (15% diabetes, 10% cardiovascular disease). 41% smoked ~19 cigarettes daily. Mean BMI was 34 for women and 29 for men.","whyItMatters":"Premature death in psychosis patients is largely driven by preventable lifestyle-related diseases. This study quantifies the massive gap between need and delivery of health-promoting interventions.","specificNumbers":"165 of 206 eligible outpatients participated. 73% needed health promotion. 61% of those received none. 36% had somatic comorbidities. 41% smoked mean 19 cigarettes/day. Mean BMI: women 34, men 29.","methodology":"Cross-sectional study of 165 outpatients from three psychiatric clinics in Southern Denmark using screening tools, blood tests, body measurements, and medication records.","limitations":"Cross-sectional design captures one time point. Danish healthcare system may not generalize. Self-reported substance use. Three clinics may not represent all psychosis care."},{"rthcId":"RTHC-04659","title":"Phytocannabinoid-rich galenic preparations for topical administration: extraction and stability testing.","authors":"Kaczorová, Dominika; Peč, Jaroslav; Béres, Tibor; Štefelová, Nikola; Ćavar Zeljković, Sanja; Trojan, Václav; Janatová, Anežka Kosmáková; Klouček, Pavel; Tarkowski, Petr","year":2023,"journal":"Frontiers in pharmacology, 14, 1230728","doi":"10.3389/fphar.2023.1230728","pmid":"37593173","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"All tested bases were similarly effective at extracting cannabinoids, but olive oil and Synderman had the highest extraction efficiencies (~70%) and best storage stability. THC degraded faster than CBD, especially in cream bases and Vaseline (up to 5.6% per week).","whyItMatters":"Providing pharmacies with a standardized, practical protocol for preparing topical cannabis formulations addresses a key barrier to implementing medical cannabis dermatological treatments.","specificNumbers":"Extraction efficiency ~70% for olive oil and Synderman bases. THC loss: up to 5.4%/week in cream, 5.6%/week in Vaseline. CBD was more stable than THC across all bases.","methodology":"Laboratory study evaluating cannabinoid extraction capacity and storage stability across multiple pharmaceutical bases (creams, ointments, oils) for dermatological cannabis formulations.","limitations":"Laboratory conditions may not perfectly replicate pharmacy settings. Limited number of base formulations tested. Stability testing period not specified. Single cannabis source used."},{"rthcId":"RTHC-04660","title":"Exploring the Link between ADHD and Cannabis Use in Swedish Ninth Graders: The Role of Conduct Problems and Sensation-Seeking.","authors":"Karlsson, Patrik; Ekendahl, Mats; Raninen, Jonas","year":2023,"journal":"Substance use & misuse, 58(3), 311-319","doi":"10.1080/10826084.2022.2155478","pmid":"36617861","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Controlling for conduct problems attenuated the ADHD-cannabis association. Teens with both ADHD and conduct problems were more likely to use cannabis than those with ADHD only, but not compared to those with conduct problems only.","whyItMatters":"Understanding that conduct problems and sensation-seeking mediate the ADHD-cannabis link helps target prevention efforts — focusing on behavioral management rather than ADHD per se.","specificNumbers":"Nationally representative Swedish ninth graders (age ~15-16). ADHD-cannabis association attenuated when controlling for conduct problems. Conduct problems-cannabis association attenuated when controlling for sensation-seeking.","methodology":"Cross-sectional analysis of nationally representative Swedish adolescent data examining ADHD, conduct problems, sensation-seeking, and cannabis use with sequential statistical controls.","limitations":"Cross-sectional design cannot establish causal pathways. Self-reported measures. Swedish context may not generalize. ADHD assessed by self-report rather than clinical diagnosis."},{"rthcId":"RTHC-04661","title":"Cannabis use and the risk of primary open-angle glaucoma: a Mendelian randomization study.","authors":"Katsimpris, Andreas; Baumeister, Sebastian-Edgar; Baurecht, Hansjörg; Tatham, Andrew J; Nolde, Michael","year":2023,"journal":"Scientific reports, 13(1), 19605","doi":"10.1038/s41598-023-45872-z","pmid":"37949880","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"MR analysis showed no causal association of either lifetime cannabis use (OR 1.04, 95% CI 0.88-1.23) or cannabis use disorder (OR 0.97, 95% CI 0.92-1.03) with primary open-angle glaucoma.","whyItMatters":"Despite popular belief that cannabis helps glaucoma by lowering eye pressure, this genetic analysis suggests cannabis use does not actually affect glaucoma risk, challenging a common justification for medical cannabis.","specificNumbers":"Lifetime cannabis use: OR 1.04 (0.88-1.23). CUD: OR 0.97 (0.92-1.03). GWAS data: cannabis (N=184,765), CUD (17,068 cases/357,219 controls), POAG (16,677 cases/199,580 controls). Sensitivity analyses consistent.","methodology":"Two-sample Mendelian randomization using genetic instruments from GWAS of cannabis use and cannabis use disorder, applied to the largest POAG GWAS meta-analysis.","limitations":"MR assumes genetic variants only affect the outcome through the exposure (exclusion restriction). Cannabis use variants may capture different aspects than clinical use. Cannot assess short-term IOP effects."},{"rthcId":"RTHC-04662","title":"A Rare Case of Cannabinoid Hyperemesis Syndrome Secondary to Cannabidiol for Refractory Epilepsy.","authors":"Katz, Daphna T; Fifi, Amanda; Milesi-Halle, Alessandra; Saps, Miguel","year":2023,"journal":"JPGN reports, 4(1), e280","doi":"10.1097/PG9.0000000000000280","pmid":"37181918","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Monthly bouts of severe emesis unresponsive to anti-emetics began 6 months after starting the ketogenic diet while on CBD. CHS was suspected, CBD was discontinued, and emesis resolved within 2 months with no increase in seizure frequency.","whyItMatters":"This is the first reported case of CHS from pharmaceutical CBD used for epilepsy, expanding the understanding of which cannabinoids can cause CHS and raising awareness for epilepsy clinicians.","specificNumbers":"Pediatric patient with Lennox-Gastaut syndrome. Monthly emesis episodes for ~6 months. Emesis resolved within 2 months of CBD discontinuation. No seizure increase or emesis hospitalizations for nearly 1 year post-discontinuation.","methodology":"Case report with detailed clinical timeline, treatment history, diagnostic reasoning, and outcome following CBD cessation.","limitations":"Single case report. Cannot definitively prove CBD caused CHS vs. other factors. Ketogenic diet interaction possible. Timing coincidence cannot be excluded."},{"rthcId":"RTHC-04663","title":"Cannabis use for Sleep Disturbance Among Older Patients in a Geriatrics Clinic.","authors":"Kaufmann, Christopher N; Malhotra, Atul; Yang, Kevin H; Han, Benjamin H; Nafsu, Reva; Lifset, Ella T; Nguyen, Khai; Sexton, Michelle; Moore, Alison A","year":2023,"journal":"International journal of aging & human development, 97(1), 3-17","doi":"10.1177/00914150221128971","pmid":"36226368","tags":["sleep","seniors","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use among older adults is growing fast, and sleep is one of the top reasons cited. This study surveyed 568 patients at a geriatrics clinic and found 83 who had used cannabis in the past three years, then compared those using it for sleep versus other conditions.\n\nThe patterns were revealing. Older adults using cannabis for sleep were distinctive: they used it more frequently than those using it for other conditions, strongly preferred THC-containing products (rather than CBD-only), and timed their use close to bedtime. This daily-before-bed pattern suggests these patients are self-medicating sleep problems in a systematic way, not using cannabis casually.\n\nThe preference for THC over CBD is notable because THC has sedating properties at certain doses while CBD's sleep effects are less clear. These elderly patients appear to have figured this out on their own — possibly through trial and error — and settled on THC-containing products as more effective for sleep.\n\nThe study also found that many of these older adults were navigating cannabis use without much guidance from their healthcare providers, raising concerns about drug interactions, especially in a population typically on multiple prescription medications.","whyItMatters":"Sleep problems are endemic among older adults, affecting 40-70% of the elderly population. Many standard sleep medications (benzodiazepines, Z-drugs) carry significant risks in older adults, including falls, cognitive impairment, and dependence. Understanding how elderly patients actually use cannabis for sleep — which products, how often, when — is essential for clinicians who will increasingly face questions about it as an alternative.","specificNumbers":"568 geriatrics clinic patients surveyed. 83 (14.6%) reported cannabis use in the past 3 years. Sleep users consumed cannabis more frequently (p = .01), preferred THC-containing products over CBD-only (p < .05), and were more likely to use cannabis right before bed (p < .01). The majority (62.7% in related findings) found cannabis overall effective for their conditions.","methodology":"Cross-sectional anonymous survey of 568 adults seen at a geriatrics clinic, including 83 who reported cannabis use within the past 3 years. Researchers compared cannabis use characteristics (frequency, product type, timing, THC vs. CBD preference) between those using it for sleep disturbance versus all other conditions.","limitations":"Cross-sectional survey design — cannot establish whether cannabis actually improved sleep or whether patients just perceived it as helpful. Anonymous survey limits verification of self-reported use patterns. Single geriatrics clinic in one geographic area. Cannabis use was self-reported with no product verification or dosage data. The 83-person cannabis user subgroup is relatively small for making detailed comparisons between sleep and non-sleep users."},{"rthcId":"RTHC-04664","title":"Could cannabinoids provide a new hope for ovarian cancer patients?","authors":"Kaur, Rimanee; Javid, Farideh A","year":2023,"journal":"Pharmacology research & perspectives, 11(4), e01122","doi":"10.1002/prp2.1122","pmid":"37526235","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Non-psychoactive cannabinoids can induce cancer cell death and inhibit proliferation through various mechanisms, and clinical trials show cannabinoids are well tolerated at high doses without typical chemotherapy side effects.","whyItMatters":"Ovarian cancer treatment options remain limited. Non-psychoactive cannabinoids could offer anti-cancer effects without the side effects of conventional chemotherapy or the psychoactive effects of THC.","specificNumbers":"Not quantified in abstract; review summarizes preclinical results across multiple studies of non-psychoactive cannabinoids in ovarian cancer.","methodology":"Narrative review of preclinical research on cannabinoids, particularly non-psychoactive compounds, in ovarian and gynecological cancer treatment.","limitations":"Almost entirely preclinical evidence. Ovarian cancer-specific data is limited. Translation from cell studies to clinical use is uncertain."},{"rthcId":"RTHC-04665","title":"The Relationship Between Cannabis, Cognition, and Schizophrenia: It's Complicated.","authors":"Kayir, Hakan; Ruffolo, Jessica; McCunn, Patrick; Khokhar, Jibran Y","year":2023,"journal":"Current topics in behavioral neurosciences, 63, 437-461","doi":"10.1007/7854_2022_396","pmid":"36318403","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"While cannabis harms cognition in healthy people and worsens psychotic symptoms, schizophrenia patients who use cannabis have better cognitive performance than non-users, a paradox explained by three competing hypotheses.","whyItMatters":"Understanding this paradox could reveal new therapeutic approaches. If cannabis-using patients represent a distinct phenotype, this has implications for personalized treatment.","specificNumbers":"Cognitive advantages seen in lifetime but not current cannabis users with schizophrenia. Earlier age of use (<17) associated with better cognition but earlier illness onset. Multiple factors modify outcomes.","methodology":"Narrative review synthesizing human clinical studies, epidemiological data, and animal model research on cannabis-cognition interactions in schizophrenia.","limitations":"Narrative review without systematic methodology. The paradox may reflect selection bias rather than causal effects. Animal models have limited translational relevance."},{"rthcId":"RTHC-04666","title":"Interactive effect of adverse child experiences and suicidal thoughts and behaviors on adolescent alcohol and cannabis use frequency.","authors":"Kelly, Lourah; Meeker, Elizabeth; Zajac, Kristyn; Bryan, Rebecca; O'Connor, Briannon","year":2023,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 37(8), 1019-1029","doi":"10.1037/adb0000947","pmid":"37439752","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"ACEs by suicide attempt interaction was significant for drinking (attempt AOR=2.63 vs. no ideation AOR=1.56), but not for cannabis. ACEs (AOR=1.95-2.08) and suicide attempt (AOR=2.11) independently predicted greater cannabis use.","whyItMatters":"Identifying that trauma and suicidality interact to amplify drinking specifically can help target dual-risk adolescents for more intensive alcohol prevention while addressing cannabis use through separate pathways.","specificNumbers":"1,625 high schoolers (50.8% male, 47.1% female, 2% nonbinary). ACEs x suicide attempt interaction significant for drinking. ACEs AOR for cannabis: 1.95-2.08. Suicide attempt AOR for cannabis: 2.11.","methodology":"Ordinal logistic regression of Youth Risk Behavior Survey data from western New York, testing interactions between ACEs count and suicidality categories on substance use.","limitations":"Cross-sectional school-based survey. Self-reported ACEs and substance use. Single geographic region. Cannot determine temporal sequence between variables."},{"rthcId":"RTHC-04667","title":"Past-month binge drinking and cannabis use among middle-aged and older adults in the United States, 2015-2019.","authors":"Kepner, Wayne E; Han, Benjamin H; Nguyen, Daniel; Han, Stacy S; Lopez, Francisco A; Palamar, Joseph J","year":2023,"journal":"Alcohol (Fayetteville, N.Y.), 107, 32-37","doi":"10.1016/j.alcohol.2022.07.006","pmid":"35934163","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Among adults 65+, combined past-month cannabis use and binge drinking prevalence increased from 0.2% to 1.1% (450% relative increase, p<0.001). Overall cannabis use among adults 50+ increased 64.1% while binge drinking remained stable.","whyItMatters":"Older adults combining cannabis and alcohol face compounded risks due to medication interactions, chronic diseases, and age-related changes in drug metabolism.","specificNumbers":"Adults 50+: 2.5% increase in cannabis use (64.1% relative), 0.5% increase in combined use (26.3% relative). Adults 65+: combined use from 0.2% to 1.1% (450% relative increase). Users more likely to be younger, male, non-Hispanic Black, tobacco users.","methodology":"Analysis of 2015-2019 National Survey on Drug Use and Health data for noninstitutionalized adults aged 50 and older.","limitations":"Self-reported substance use may be underestimated. NSDUH excludes institutionalized populations. Five-year window may miss longer trends. Cannot assess health outcomes of combined use."},{"rthcId":"RTHC-04668","title":"Cannabis-Induced Anxiety Disorder in the Emergency Department.","authors":"Keung, Man Yee; Leach, Erin; Kreuser, Kaitlin; Emmerich, Bradley W; Ilko, Steven; Singh, Matthew; Sapp, Thomas; Barnes, Mariah; Ouellette, Lindsey; Jones, Jeffrey S","year":2023,"journal":"Cureus, 15(4), e38158","doi":"10.7759/cureus.38158","pmid":"37252542","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Of 1,135 cannabis toxicity ED visits, 196 (17.3%) presented with anxiety including panic attacks (11.7%), aggression/manic behavior (9.2%), and hallucinations (6.1%). Anxiety patients were younger, more likely to have used edibles, and had more psychiatric comorbidities.","whyItMatters":"Cannabis-induced anxiety is a significant ED presentation that clinicians must recognize and manage appropriately, especially as edible use and legalization expand.","specificNumbers":"1,135 patients across 7 EDs over 24 months. 17.3% had anxiety. 82.7% had other toxicity (intoxication, CHS). Panic attacks 11.7%, aggression 9.2%, hallucinations 6.1%. Edible ingestion more common in anxiety group.","methodology":"Retrospective cohort analysis of consecutive patients with ICD-10 F12 codes across seven emergency departments over 24 months post-legalization.","limitations":"Retrospective design. Single state post-legalization. ICD-10 coding may miss some cases. Cannot determine pre-legalization baseline rates."},{"rthcId":"RTHC-04669","title":"Cannabis Hyperemesis Syndrome in a Young Patient: A Case Report and Literature Review.","authors":"Khalid, Noman; Abdullah, Muhammad; Khalil, Musa; Afzal, Muhammad Adil; Hindawi, Mulham","year":2023,"journal":"Cureus, 15(8), e43868","doi":"10.7759/cureus.43868","pmid":"37736461","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Case demonstrates the importance of recognizing CHS in patients with complex medical histories, particularly as recreational marijuana legalization increases chronic cannabis use.","whyItMatters":"CHS can be misdiagnosed as diabetic gastroparesis or other conditions in patients with type 1 diabetes, leading to unnecessary workups and delayed treatment.","specificNumbers":"25-year-old male with type 1 diabetes and chronic cannabis use presenting with vomiting and epigastric pain.","methodology":"Case report with literature review of CHS treatment options.","limitations":"Single case report. Cannot establish generalizability. Diagnostic overlap with diabetic conditions complicates clinical picture."},{"rthcId":"RTHC-04670","title":"Postoperative Opioid Use Among Opioid-Naive Cannabis Users Following Single-Level Lumbar Fusions.","authors":"Khalid, Syed I; Jiang, Sam; Khilwani, Harsh; Thomson, Kyle; Mirpuri, Pranav; Mehta, Ankit I","year":2023,"journal":"World neurosurgery, 175, e644-e652","doi":"10.1016/j.wneu.2023.04.001","pmid":"37030484","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis users had similar rates of opioid prescription (49.78%) but lower daily doses (51.1 vs. 59.72 MME, p=0.003) at 6 months. However, OUD diagnosis was significantly higher (18.94% vs. 3.96%, p<0.0001).","whyItMatters":"This paradoxical finding — lower doses but higher addiction — suggests cannabis use may be a marker for addiction vulnerability rather than a protective factor against opioid overuse.","specificNumbers":"87,958 records screened, 454 matched patients (227 per group). Opioid use rates equal (49.78%). Cannabis users: lower daily MME (51.1 vs. 59.72, p=0.003). OUD: 18.94% vs. 3.96% (p<0.0001).","methodology":"Retrospective matched cohort study using an all-payer claims database (January 2010-October 2020) of single-level lumbar fusion patients.","limitations":"Claims data cannot capture cannabis use accurately. OUD diagnosis may reflect screening bias. Cannot determine causation. Cannabis use dose/frequency unknown."},{"rthcId":"RTHC-04671","title":"The effects of tobacco and cannabis use on semen and endocrine parameters in infertile males.","authors":"Khan, Nawabzada; Shah, Mohsin; Malik, Muhammad Omar; Badshah, Haroon; Habib, Syed Hamid; Shah, Inayat; Shah, Fawad Ali","year":2023,"journal":"Human fertility (Cambridge, England), 26(3), 564-572","doi":"10.1080/14647273.2021.1969042","pmid":"34583622","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"FSH was significantly higher in cannabis users vs. controls (p=0.043). Mild, non-significant decreases in sperm count, LH, and testosterone were observed across all substance user groups.","whyItMatters":"Understanding how common substances affect male fertility parameters is important for clinical counseling, particularly as both tobacco and cannabis use are modifiable risk factors.","specificNumbers":"160 infertile men: 40 cigarette smokers, 40 dipping tobacco, 40 cannabis users, 40 controls. Cannabis users had significantly elevated FSH (p=0.043). Other changes were non-significant.","methodology":"Cross-sectional comparison of semen parameters (after 2-7 days abstinence) and serum hormones (testosterone, FSH, LH by ELISA) across four groups of infertile men.","limitations":"Small sample sizes per group (n=40). All participants were already infertile, limiting generalizability. Cross-sectional design cannot establish causation. Substance use doses/duration not detailed."},{"rthcId":"RTHC-04672","title":"Prenatal Exposure to Tobacco and Cannabis in Six Race/Ethnicity Groups during the First Three Years after Legalization of Cannabis for Recreational Use in California.","authors":"Kharrazi, Martin; Berger, Kimberly; Pearl, Michelle; Li, Ying; DeGuzman, Josephine; Behniwal, Paramjit; Morse, Allison; Moskalenko, Ilya; Williams, Rebecca J; She, Jianwen","year":2023,"journal":"International journal of environmental research and public health, 21(1)","doi":"10.3390/ijerph21010011","pmid":"38276799","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis was detected in 5% of Hispanic to 13% of Black pregnant individuals. Cannabis exposure was higher among tobacco users. Black subjects uniquely showed higher cannabis use in older, higher-SES subgroups.","whyItMatters":"Identifying which pregnant populations have the highest substance exposure allows targeted interventions to reduce known prenatal risks.","specificNumbers":"925 prenatal screening participants (2018-2020). Tobacco: Black 16%, Native American 10%, White 8%, Hispanic/Asian/Vietnamese ≤2%. Cannabis: Black 13%, White 12%, Hispanic 5%. Cannabis higher among tobacco users.","methodology":"Cross-sectional analysis of banked prenatal serum samples from southern/central California, measuring cotinine (tobacco) and OH-THC (cannabis) by laboratory analysis across six racial/ethnic groups.","limitations":"Serum biomarkers capture recent but not chronic exposure. Relatively small subgroup sizes. Southern/central California may not represent all regions. 2018-2020 may include early legalization effects."},{"rthcId":"RTHC-04673","title":"Perspectives from women who engaged in prenatal and postpartum cannabis use in a U.S. State with legal non-medical use.","authors":"Kiel, Linda; Hsu, Clarissa; Wartko, Paige D; Albertson-Junkans, Ladia; Ewing, John; Lapham, Gwen T","year":2023,"journal":"Preventive medicine reports, 31, 102075","doi":"10.1016/j.pmedr.2022.102075","pmid":"36820379","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Five key themes emerged: women used internet/peers for information, were reluctant to discuss cannabis with providers, used it for morning sickness/pain/mental health, were comfortable with their decision but had questions, and tried to mitigate breastmilk transmission.","whyItMatters":"Healthcare providers are missing critical opportunities to counsel pregnant cannabis users because patients are not disclosing use and providers are not asking.","specificNumbers":"15 postpartum women interviewed (4 non-White, 4 Hispanic). All lived in Washington State (legal cannabis). Cannabis used during pregnancy for morning sickness, pain, and mental health.","methodology":"Semi-structured qualitative interviews with 15 postpartum women who reported past-year cannabis use, analyzed using template analysis.","limitations":"Small qualitative sample from one region. Self-selected participants may be more comfortable discussing cannabis. Washington State legal context may not generalize."},{"rthcId":"RTHC-04674","title":"Medical marijuana access and prolonged opioid use among adolescents and young adults.","authors":"Kim, Kyungha; Pacula, Rosalie L; Dick, Andrew W; Stein, Bradley D; Druss, Benjamin G; Agbese, Edeanya; Cohrs, Austin C; Leslie, Douglas L","year":2023,"journal":"The American journal on addictions, 32(5), 479-487","doi":"10.1111/ajad.13440","pmid":"37291067","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Medical marijuana dispensary laws showed no significant association with prolonged opioid use (aOR=0.98, 95% CI 0.81-1.18). Being female, longer hospital stays, greater initial opioid supply, and rural residence predicted prolonged use.","whyItMatters":"While cannabis access may reduce opioid use in adults, this large study suggests the same effect does not occur in the particularly vulnerable adolescent and young adult population.","specificNumbers":"195,204 patients aged 12-25 across all 50 states (2005-2014). 4.8% had prolonged opioid use. Medical marijuana law: aOR=0.98 (not significant). Female: aOR=1.27. >14 days initial supply: aOR=2.42.","methodology":"Retrospective cohort study using 2005-2014 MarketScan Commercial claims data for patients aged 12-25 undergoing 13 surgical procedures, with logistic regression for prolonged opioid use.","limitations":"Commercial insurance claims may not represent uninsured populations. Medical marijuana access does not equal use. 2005-2014 data predates recreational legalization in most states."},{"rthcId":"RTHC-04675","title":"A preliminary study evaluating self-reported effects of cannabis and cannabinoids on neuropathic pain and pain medication use in people with spinal cord injury.","authors":"Kinnunen, Kristiina; Robayo, Linda E; Cherup, Nicholas P; Frank, Scott I; Widerström-Noga, Eva","year":2023,"journal":"Frontiers in pain research (Lausanne, Switzerland), 4, 1297223","doi":"10.3389/fpain.2023.1297223","pmid":"38188193","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"87.9% reported >30% pain reduction from cannabis, 92.3% reported cannabis helped them deal with pain symptoms, and 83.3% substituted pain medications with cannabis, most commonly opioids (47%), gabapentinoids (42.8%), and OTC medications (42.2%).","whyItMatters":"SCI neuropathic pain affects 60% of patients and often resists treatment. These high patient-reported benefit rates and medication substitution patterns warrant further controlled investigation.","specificNumbers":"342 recruited, 227 enrolled. Average pain intensity 6.8/10. 87.9% reported >30% pain reduction. 92.3% reported improved pain management. 83.3% substituted medications: opioids 47%, gabapentinoids 42.8%, OTC 42.2%.","methodology":"Anonymous online survey of current and previous cannabis users with SCI-related neuropathic pain, recruited from US opt-in listservs.","limitations":"Self-selected sample biased toward those with positive experiences. No control group. Self-reported pain measures. Cross-sectional design. Cannot verify SCI diagnosis or cannabis use."},{"rthcId":"RTHC-04676","title":"Cannabinoid hyperemesis syndrome in pregnancy: Challenges and opportunities.","authors":"Kirby, Jordan; Naren, Thileepan","year":2023,"journal":"The Australian & New Zealand journal of obstetrics & gynaecology, 63(6), 746-752","doi":"10.1111/ajo.13714","pmid":"37259610","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CHS in pregnancy is frequently misdiagnosed due to symptom overlap with hyperemesis gravidarum and other pregnancy complications, compounded by reduced clinician awareness and scarcity of pregnancy-safe treatments.","whyItMatters":"Prenatal cannabis use is common and associated with adverse outcomes. Adding CHS to the picture creates a complex clinical scenario requiring specialized awareness.","specificNumbers":"Not quantified in abstract; clinical perspective reviewing current literature on CHS in pregnancy.","methodology":"Clinical perspective article reviewing current literature on CHS diagnosis, treatment, and management challenges in pregnancy.","limitations":"Clinical perspective rather than systematic review. Limited primary evidence available. Treatment recommendations based on expert opinion."},{"rthcId":"RTHC-04677","title":"Using Detached Industrial Hemp Leaf Inoculation Assays to Screen for Varietal Susceptibility and Product Efficacy on Botrytis cinerea.","authors":"Kirkby, Karen; Roser, Sharlene; Plett, Krista","year":2023,"journal":"Plants (Basel, Switzerland), 12(18)","doi":"10.3390/plants12183278","pmid":"37765441","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The detached leaf assay effectively differentiated eight hemp varieties for Botrytis susceptibility and identified potassium salt-based treatments as effective alternatives to conventional fungicides, with results comparable to whole-plant testing.","whyItMatters":"Medical cannabis patients often have compromised immune systems, making fungicide residue-free products essential. This screening method accelerates identification of disease control options.","specificNumbers":"8 industrial hemp varieties tested. Tau-fluvalinate, Myclobutanil, and potassium salts showed consistent lesion reduction. Treatment performance was pH-dependent.","methodology":"Detached leaf bioassay comparing varietal susceptibility to Botrytis cinerea infection and screening chemical/organic products for disease control efficacy.","limitations":"Detached leaf may not capture systemic plant defense responses. Industrial hemp varieties may differ from medicinal cannabis cultivars. Greenhouse conditions tested."},{"rthcId":"RTHC-04678","title":"Treatment outcomes among pregnant women with cannabis use disorder.","authors":"Kitsantas, Panagiota; Gimm, Gilbert; Aljoudi, Salman M","year":2023,"journal":"Addictive behaviors, 144, 107723","doi":"10.1016/j.addbeh.2023.107723","pmid":"37094455","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CUD treatment completion was higher with criminal justice referral (AOR=2.29), community referral (AOR=1.65), and healthcare provider referral (AOR=1.60) compared to self-referral. Stays of 4-12 months predicted completion.","whyItMatters":"With CUD rising among pregnant women and cannabis potentially harming fetal development, improving treatment access and completion is a pressing public health priority.","specificNumbers":"7,319 pregnant women with CUD from TEDS-D (2010-2019). 30.3% completion rate. Criminal justice referral AOR=2.29. Community referral AOR=1.65. Healthcare referral AOR=1.60. 52% completion for >1 month treatment with justice referral.","methodology":"Retrospective analysis of Treatment Episode Data Set-Discharges (2010-2019) using logistic regression and classification tree analysis for treatment completion predictors.","limitations":"Administrative treatment data may not capture all relevant factors. Self-report of CUD. Cannot assess treatment quality. Criminal justice involvement may introduce confounding."},{"rthcId":"RTHC-04679","title":"Attitudes, Beliefs, and Perceptions on Cannabis Among Older Adults Aged 65 and Older: A cross-sectional Survey.","authors":"Kleidon, Alex M; Peterson, Andrew M; Warner-Maron, Ilene; Glicksman, Allen","year":2023,"journal":"Journal of primary care & community health, 14, 21501319231177284","doi":"10.1177/21501319231177284","pmid":"37246416","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"76% considered cannabis highly important for older adults, 42% considered themselves highly knowledgeable, but only 23% were asked about cannabis by their PCP (vs. 55% asked about tobacco and 57% about alcohol). Most relied on internet and social media rather than doctors.","whyItMatters":"As cannabis use rises among older adults, the disconnect between patient interest and provider engagement creates risks from drug interactions, misinformation, and missed counseling opportunities.","specificNumbers":"47 participants, average age 71. 53% male, 64% Black. 76% valued cannabis highly for treatment. 23% asked about cannabis by PCP vs. 55% tobacco, 57% alcohol.","methodology":"Cross-sectional survey of adults aged 65+ in Philadelphia (December 2019-May 2020) with quantitative and qualitative analysis.","limitations":"Very small pilot sample (n=47). Philadelphia-specific. Predominantly Black and male sample may not generalize. Survey during early COVID period."},{"rthcId":"RTHC-04680","title":"Cannabis use frequency and pain interference among people with HIV.","authors":"Klepp, T D; Heeren, T C; Winter, M R; Lloyd-Travaglini, C A; Magane, K M; Romero-Rodríguez, E; Kim, T W; Walley, A Y; Mason, T; Saitz, R","year":2023,"journal":"AIDS care, 35(8), 1235-1242","doi":"10.1080/09540121.2023.2208321","pmid":"37201209","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis use frequency was not directly associated with pain interference. However, daily cannabis use attenuated the pain severity-pain interference relationship (AMD +0.05 per pain point increase vs. +1.13 for non-users, p=0.049).","whyItMatters":"This distinction between reducing pain versus reducing pain impact on daily functioning offers a more nuanced understanding of how cannabis may benefit chronic pain patients.","specificNumbers":"134 PWH with substance dependence/injection drug use history. Daily users: AMD +0.05 per pain point. 15-day users: +0.81. Non-users: +1.13. Interaction p=0.049.","methodology":"Multi-variable linear regression with interaction term between cannabis use frequency and pain severity, analyzing pain interference as the outcome in PWH.","limitations":"Small sample (n=134). Cross-sectional design. Participants had substance dependence history, limiting generalizability. Cannabis use self-reported. Borderline significance (p=0.049)."},{"rthcId":"RTHC-04681","title":"Design, synthesis, and evaluation of substituted alkylindoles that activate G protein-coupled receptors distinct from the cannabinoid CB1 and CB2 receptors.","authors":"Kline, Toni; Xu, Cong; Kreitzer, Faith R; Hurst, Dow P; Eldeeb, Khalil M; Wager-Miller, Jim; Olivas, Kathleen; Hepburn, Seon A; Huffman, John W; Mackie, Ken; Howlett, Allyn C; Reggio, Patricia; Stella, Nephi","year":2023,"journal":"European journal of medicinal chemistry, 249, 115123","doi":"10.1016/j.ejmech.2023.115123","pmid":"36708677","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Compounds 10 and 12 activated AI-sensitive GPCRs with EC50 values of 3.5 and 1.1 nM through pertussis toxin-sensitive Gi/o coupling. Three structural features distinguish AI-GPCR binding from CB1R/CB2R binding.","whyItMatters":"The existence of uncharacterized cannabinoid-like receptors suggests the endocannabinoid system is more complex than currently understood, with implications for drug development.","specificNumbers":"14 novel AI analogues synthesized. Compound 10 EC50=3.5 nM, Compound 12 EC50=1.1 nM. 5 compounds distinguished high/low affinity receptor states. 3 structural features identified by pharmacophore modeling.","methodology":"Medicinal chemistry synthesis of 14 alkylindole analogues with pharmacological characterization via [35S]GTPyS and radioligand binding in HEK293 cells, plus in silico pharmacophore modeling.","limitations":"Molecular identity of AI-sensitive GPCRs remains unknown. HEK293 cell results may not reflect in vivo pharmacology. Selectivity over all other GPCRs not established."},{"rthcId":"RTHC-04682","title":"Cannabidiol as an adjuvant treatment in adults with drug-resistant focal epilepsy.","authors":"Kochen, Silvia; Villanueva, Manuela; Bayarres, Liliana; Daza-Restrepo, Anilu; Gonzalez Martinez, Silvia; Oddo, Silvia","year":2023,"journal":"Epilepsy & behavior : E&B, 144, 109210","doi":"10.1016/j.yebeh.2023.109210","pmid":"37196452","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"87% of patients achieved 50%+ seizure reduction, 32% reduced seizures by more than 80%, and 5% became seizure-free. Average dose was 335 mg/day. 34% reported mild adverse events with no severe adverse effects.","whyItMatters":"While CBD is approved for pediatric epilepsies, evidence for adult drug-resistant focal epilepsy has been limited. This study shows promising results in this underserved population.","specificNumbers":"44 patients. 5% seizure-free. 32% >80% seizure reduction. 87% >50% reduction. 11% <50% reduction. Average dose 335 mg/day. 34% mild adverse events. 0% severe adverse events.","methodology":"Open, observational, prospective cohort study (before-after design) in adult outpatients at a public hospital in Buenos Aires, Argentina, with at least 6 months follow-up.","limitations":"No control group or blinding. Open-label design subject to placebo effect and observer bias. Single center. Relatively small sample (n=44)."},{"rthcId":"RTHC-04683","title":"CANNabinoid Drug Interaction Review (CANN-DIR™).","authors":"Kocis, Paul T; Wadrose, Samuel; Wakefield, Ryan Lee; Ahmed, Aqib; Calle, Renata; Gajjar, Rohan; Vrana, Kent E","year":2023,"journal":"Medical cannabis and cannabinoids, 6(1), 1-7","doi":"10.1159/000528528","pmid":"36814686","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CANN-DIR provides an expeditious review of cannabinoid drug interactions based on FDA-approved prescribing information, allowing patients and providers to screen interactions and print results for clinical discussion.","whyItMatters":"Non-prescription CBD and medical cannabis lack FDA-approved prescribing information, leaving patients and providers without a dedicated interaction-checking resource until CANN-DIR.","specificNumbers":"Based on FDA-approved information for dronabinol, nabilone, nabiximols, and prescription CBD. Uses FDA drug interaction tables. Available in 10 languages including English, Spanish, Chinese, and French.","methodology":"Web-based platform development using FDA-approved prescribing information and FDA drug interaction tables for metabolic enzyme substrates, inhibitors, and inducers.","limitations":"Based on prescription cannabinoid data that may not perfectly reflect non-prescription products. Cannot account for all individual factors. Does not replace clinical judgment."},{"rthcId":"RTHC-04684","title":"Prenatal tobacco and cannabis co-exposure and offspring obesity development from birth to mid-childhood.","authors":"Kong, Kai Ling; Lee, Jin-Kyung; Shisler, Shannon; Thanos, Panayotis K; Huestis, Marilyn A; Hawk, Larry; Eiden, Rina D","year":2023,"journal":"Pediatric obesity, 18(5), e13010","doi":"10.1111/ijpo.13010","pmid":"36734672","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Prenatal co-exposure to tobacco and cannabis was associated with increased odds of childhood obesity, with the combination potentially amplifying individual substance effects on offspring metabolic development.","whyItMatters":"As cannabis use during pregnancy becomes more common alongside tobacco, understanding how dual exposure affects child growth trajectories is critical for prenatal counseling and pediatric monitoring.","specificNumbers":"The study examined a diverse sample of pregnant women and tracked offspring obesity measures from birth through mid-childhood, assessing BMI trajectories across exposure groups.","methodology":"Longitudinal cohort study tracking prenatal substance exposure and offspring anthropometric outcomes from birth through mid-childhood.","limitations":"Self-reported substance use may underestimate actual exposure; confounding factors like diet and socioeconomic status are difficult to fully control in observational designs."},{"rthcId":"RTHC-04685","title":"The potential for medicinal cannabis to help manage challenging behaviour in people with intellectual disability: A perspective review.","authors":"Korb, Laura; Tromans, Samuel; Perera, Bhathika; Khan, Nagina; Burrows, Lisa; Laugharne, Richard; Hassiotis, Angela; Allgar, Victoria; Efron, Daryl; Maidment, Ian; Shankar, Rohit","year":2023,"journal":"Journal of psychopharmacology (Oxford, England), 37(12), 1201-1208","doi":"10.1177/02698811231209192","pmid":"37937428","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review identifies potential pathways through which cannabinoids might help manage challenging behavior in people with intellectual disabilities, including effects on anxiety, pain, and sleep disruption that often underlie behavioral issues.","whyItMatters":"Challenging behavior affects over one-third of people with intellectual disabilities and current pharmacological options often have significant side effects, creating a need for alternative therapeutic approaches.","specificNumbers":"Around 2% of the population have intellectual disabilities, and over one-third present with challenging behavior influenced by bio-psycho-social factors.","methodology":"Perspective review synthesizing existing evidence on cannabinoid therapeutics and challenging behavior in intellectual disability populations.","limitations":"As a perspective review rather than systematic review or clinical trial, evidence is largely theoretical; direct clinical evidence in this population is extremely limited."},{"rthcId":"RTHC-04686","title":"Blood cannabinoid molar metabolite ratios are superior to blood THC as an indicator of recent cannabis smoking.","authors":"Kosnett, Michael J; Ma, Ming; Dooley, Gregory; Wang, George Sam; Friedman, Kyle; Brown, Timothy; Henthorn, Thomas K; Brooks-Russell, Ashley","year":2023,"journal":"Clinical toxicology (Philadelphia, Pa.), 61(5), 355-362","doi":"10.1080/15563650.2023.2214697","pmid":"37293900","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Molar metabolite ratios of blood cannabinoids were superior to blood THC concentration alone as indicators of recent cannabis use, offering better discrimination between recent and non-recent consumption.","whyItMatters":"Current THC blood tests cannot reliably distinguish recent use from residual detection, creating problems for driving and workplace impairment assessment. Better biomarkers could make testing more fair and accurate.","specificNumbers":"The observational study examined driving and psychomotor performance alongside blood cannabinoid measurements to compare metabolite ratios against standalone THC levels.","methodology":"Observational study measuring blood cannabinoid levels alongside driving and psychomotor assessments to evaluate different biomarker approaches.","limitations":"Individual metabolism varies significantly; metabolite ratios may still not perfectly correlate with actual impairment levels across all users."},{"rthcId":"RTHC-04687","title":"Retrospective chart review of substance abuse in patients with psychiatric emergencies in an emerging urban county.","authors":"Koura, Simran; White, Avian; Masdon, Joshua; Brewer, Kori L; Parker-Cote, Jennifer L; Meggs, William J","year":2023,"journal":"Journal of the American College of Emergency Physicians open, 4(4), e13028","doi":"10.1002/emp2.13028","pmid":"37600902","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Substance abuse was common among patients presenting with psychiatric emergencies, with drug screens revealing significant rates of positive results across multiple substance categories.","whyItMatters":"Understanding the connection between substance use and psychiatric emergencies helps emergency departments better prepare for dual-diagnosis presentations and improve treatment protocols.","specificNumbers":"The retrospective chart review examined positive drug screens among patients with psychiatric emergencies in an emerging urban county setting.","methodology":"Retrospective chart review of drug screening results among psychiatric emergency patients.","limitations":"Retrospective design limits causal inference; single-site data may not generalize to other settings; drug screens detect presence but not levels or timing of use."},{"rthcId":"RTHC-04688","title":"Youth cannabis use in Canada post-legalization: service providers' perceptions, practices, and recommendations.","authors":"Kourgiantakis, Toula; Lee, Eunjung; Kosar, A Kumsal Tekirdag; Tait, Christine; Lau, Carrie K Y; McNeil, Sandra; Craig, Shelley; Ashcroft, Rachelle; Williams, Charmaine C; Goldstein, Abby L; Chandrasekera, Uppala; Sur, Deepy; Henderson, J L","year":2023,"journal":"Substance abuse treatment, prevention, and policy, 18(1), 36","doi":"10.1186/s13011-023-00550-1","pmid":"37349741","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Service providers perceived that cannabis legalization in Canada has not fully achieved its goal of reducing youth access and use, with rates among 16-24 year olds not declining as intended.","whyItMatters":"Canada legalized recreational cannabis in 2018 specifically to protect youth, making it crucial to assess whether this policy objective is being met through the perspectives of those working directly with young people.","specificNumbers":"Youth cannabis use rates among ages 16-24 have not declined following Canadas 2018 legalization of recreational cannabis use.","methodology":"Qualitative study collecting perceptions, practices, and recommendations from service providers working with youth in the cannabis space.","limitations":"Service provider perceptions may not fully represent actual use patterns; qualitative data cannot quantify prevalence changes; regional variation in implementation may affect findings."},{"rthcId":"RTHC-04689","title":"Combined exposure to alcohol and cannabis during development: Mechanisms and outcomes.","authors":"Kovács, Martina V; Charchat-Fichman, Helenice; Landeira-Fernandez, J; Medina, Alexandre E; Krahe, Thomas E","year":2023,"journal":"Alcohol (Fayetteville, N.Y.), 110, 1-13","doi":"10.1016/j.alcohol.2023.01.004","pmid":"36740025","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Combined developmental exposure to alcohol and cannabis may produce effects through overlapping and distinct neurobiological mechanisms, with prevalence of co-use during pregnancy ranging from 1% to 7% across Western countries.","whyItMatters":"As cannabis use during pregnancy rises alongside continued alcohol use, understanding how these substances interact during fetal development is essential for risk assessment and clinical guidance.","specificNumbers":"Between 1% and 7% of pregnancies in the US, Canada, and UK involve combined alcohol and cannabis exposure.","methodology":"Narrative review synthesizing evidence on mechanisms and outcomes of combined prenatal alcohol and cannabis exposure.","limitations":"Review format relies on available studies which are largely observational; isolating effects of co-exposure from individual substance effects is methodologically challenging."},{"rthcId":"RTHC-04690","title":"Gender differences in cannabis use disorder symptoms: A network analysis.","authors":"Kroon, Emese; Mansueto, Alessandra; Kuhns, Lauren; Filbey, Francesca; Wiers, Reinout; Cousijn, Janna","year":2023,"journal":"Drug and alcohol dependence, 243, 109733","doi":"10.1016/j.drugalcdep.2022.109733","pmid":"36565568","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CUD symptom networks differ by gender, with certain symptoms serving as more central connectors in one gender versus the other, suggesting gender-specific treatment targets may be more effective.","whyItMatters":"Cannabis use among women is increasing worldwide, yet most CUD research has not examined gender differences in symptom presentation, potentially leading to less effective treatment for women.","specificNumbers":"Cannabis use in women is increasing worldwide, but research into gender differences in CUD symptomology has been lacking.","methodology":"Network analysis examining the interconnections between CUD symptoms separately for men and women.","limitations":"Network analysis identifies associations but not causal pathways; cultural factors may influence symptom reporting differently by gender; cross-sectional design limits temporal conclusions."},{"rthcId":"RTHC-04691","title":"The who and how of attentional bias in cannabis users: associations with use severity, craving and interference control.","authors":"Kroon, Emese; Kuhns, Lauren; Dunkerbeck, Annette; Cousijn, Janna","year":2023,"journal":"Addiction (Abingdon, England), 118(2), 307-316","doi":"10.1111/add.16059","pmid":"36189776","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Attentional bias toward cannabis cues was associated with use severity and craving, and interference control (a measure of cognitive self-regulation) moderated these relationships.","whyItMatters":"Understanding how implicit cognitive processes like attentional bias interact with craving and self-control can help develop better interventions targeting the specific cognitive mechanisms that maintain cannabis use.","specificNumbers":"The study assessed attentional bias, interference control, and craving in cannabis users, examining interactions between these cognitive and motivational processes.","methodology":"Experimental cognitive assessment measuring attentional bias, interference control, and self-reported craving in cannabis users.","limitations":"Lab-based cognitive tasks may not fully capture real-world attentional processes; cross-sectional design limits causal conclusions about the direction of effects."},{"rthcId":"RTHC-04692","title":"A Content Analysis of Social Media Discussions on THC-O-Acetate.","authors":"Kruger, Daniel J; Amila, Karahmet; Kaplan, Sydney M; Redfield, John; Stacy, Taylor; Agarwal, Vitush; Faqqouseh, Mutaz; Bone, Carlton Cb","year":2023,"journal":"Cannabis (Albuquerque, N.M.), 6(2), 13-21","doi":"10.26828/cannabis/2023/000164","pmid":"37484050","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Online discussion forums revealed active consumer interest in THC-O-acetate, including discussions of effects, safety concerns, and comparisons to other cannabinoids, highlighting the gap between consumer use and available research.","whyItMatters":"THC-O-acetate products entered the market with virtually no clinical safety data, and understanding consumer experiences and concerns through social media can help guide urgently needed research priorities.","specificNumbers":"THC-O-acetate is a semi-synthetic cannabinoid that has gained growing interest from consumers, manufacturers, and regulators.","methodology":"Content analysis of online discussion forums examining consumer conversations about THC-O-acetate.","limitations":"Social media data may not represent all users; self-reported experiences lack verification; online discussions may be influenced by marketing or misinformation."},{"rthcId":"RTHC-04693","title":"Consumer Experiences with Delta-8-THC: Medical Use, Pharmaceutical Substitution, and Comparisons with Delta-9-THC.","authors":"Kruger, Daniel J; Kruger, Jessica S","year":2023,"journal":"Cannabis and cannabinoid research, 8(1), 166-173","doi":"10.1089/can.2021.0124","pmid":"34797727","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Survey respondents reported using delta-8-THC for pain, anxiety, and other medical conditions, often as a substitute for pharmaceutical medications, and described it as producing a milder high with fewer negative side effects compared to delta-9-THC.","whyItMatters":"Delta-8-THC became widely available across most US states in late 2020, yet consumer experiences and motivations for use have been poorly documented, leaving a gap in evidence for regulation and clinical guidance.","specificNumbers":"Delta-8-THC products became widely available in most of the United States in late 2020, becoming a significant revenue source for hemp processing companies.","methodology":"Consumer survey examining experiences, motivations, and self-reported effects of delta-8-THC use.","limitations":"Self-selected survey sample may overrepresent positive experiences; self-reported effects lack clinical verification; product quality and actual delta-8 content were not verified."},{"rthcId":"RTHC-04694","title":"Real-world data on cannabidiol treatment of various epilepsy subtypes: A retrospective, multicenter study.","authors":"Kühne, Fabienne; Becker, Lena-Luise; Bast, Thomas; Bertsche, Astrid; Borggraefe, Ingo; Boßelmann, Christian Malte; Fahrbach, Jörg; Hertzberg, Christoph; Herz, Nina A; Hirsch, Martin; Holtkamp, Martin; Janello, Christine; Kluger, Gerhard Josef; Kurlemann, Gerhard; Lerche, Holger; Makridis, Konstantin L; von Podewils, Felix; Pringsheim, Milka; Schubert-Bast, Susanne; Schulz, Juliane; Schulze-Bonhage, Andreas; Steinbart, David; Steinhoff, Bernhard J; Strzelczyk, Adam; Syrbe, Steffen; De Vries, Heike; Wagner, Christiane; Wagner, Johanna; Wilken, Bernd; Prager, Christine; Klotz, Kerstin A; Kaindl, Angela M","year":2023,"journal":"Epilepsia open, 8(2), 360-370","doi":"10.1002/epi4.12699","pmid":"36693811","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabidiol demonstrated efficacy and tolerability across various epilepsy syndromes beyond Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, suggesting broader therapeutic potential.","whyItMatters":"CBD is only approved for three specific epilepsy syndromes, but many patients with other forms of treatment-resistant epilepsy use it off-label. Real-world evidence helps justify expanded research and access.","specificNumbers":"CBD is approved for Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. This multicenter retrospective study analyzed efficacy across additional epilepsy subtypes.","methodology":"Retrospective multicenter study analyzing real-world CBD treatment outcomes across various epilepsy subtypes.","limitations":"Retrospective design introduces selection bias; lack of placebo control limits efficacy conclusions; dosing protocols likely varied across centers."},{"rthcId":"RTHC-04695","title":"Temporal associations between use of psychoactive substances and somatic symptoms in the daily lives of people with fibromyalgia.","authors":"Kuzu, Duygu; Valentine, Thomas R; Kratz, Anna L","year":2023,"journal":"Pain medicine (Malden, Mass.), 24(10), 1176-1182","doi":"10.1093/pm/pnad069","pmid":"37243707","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Using ecological momentary assessment, the study found temporal associations between substance use (alcohol, nicotine, caffeine, opioids, and cannabis) and somatic symptoms, suggesting both symptom-driven use and substance-related symptom changes.","whyItMatters":"People with fibromyalgia commonly use various substances, but whether substance use helps or worsens symptoms in daily life has been poorly understood. Daily tracking reveals patterns invisible to traditional studies.","specificNumbers":"The study examined five psychoactive substances - alcohol, nicotine, caffeine, opioids, and cannabis - in relation to daily somatic symptoms in fibromyalgia patients.","methodology":"Ecological momentary assessment (daily diary) study examining temporal associations between substance use and somatic symptoms.","limitations":"Daily self-report may miss nuanced timing; cannot establish causation from temporal associations; substance quantities were not always precisely measured."},{"rthcId":"RTHC-04696","title":"Zebrafish as an Animal Model in Cannabinoid Research.","authors":"Lachowicz, Joanna; Szopa, Aleksandra; Ignatiuk, Katarzyna; Świąder, Katarzyna; Serefko, Anna","year":2023,"journal":"International journal of molecular sciences, 24(13)","doi":"10.3390/ijms241310455","pmid":"37445631","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Zebrafish provide a valuable animal model for cannabinoid research due to their conserved endocannabinoid system, transparency during development, high fecundity, and suitability for high-throughput drug screening.","whyItMatters":"Zebrafish models can accelerate cannabinoid research by enabling rapid screening of cannabinoid effects on development, behavior, and disease models at scale that would be impractical with mammalian models.","specificNumbers":"Cannabinoids are approved for drug-resistant epilepsy treatment by both FDA and EMA. Zebrafish offer an alternative model for studying these and other cannabinoid applications.","methodology":"Review article examining published research using zebrafish as a model organism for cannabinoid studies.","limitations":"Zebrafish physiology differs from humans in important ways; findings may not directly translate to mammalian systems; aquatic drug delivery methods create dosing uncertainties."},{"rthcId":"RTHC-04697","title":"Methadone Dose, Cannabis Use, and Treatment Retention: Findings From a Community-based Sample of People Who Use Unregulated Drugs.","authors":"Lake, Stephanie; Buxton, Jane; Walsh, Zach; Cooper, Ziva D; Socías, M Eugenia; Fairbairn, Nadia; Hayashi, Kanna; Milloy, M-J","year":2023,"journal":"Journal of addiction medicine, 17(1), e18-e26","doi":"10.1097/ADM.0000000000001032","pmid":"35914028","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis use moderated the association between lower methadone dose and treatment retention, suggesting that cannabis may help some patients remain in methadone treatment despite receiving lower doses that might otherwise lead to dropout.","whyItMatters":"Many methadone patients receive subtherapeutic doses due to various barriers, and treatment dropout is associated with overdose risk. If cannabis helps patients tolerate lower doses, this has implications for harm reduction.","specificNumbers":"The study examined a community-based sample of people who use unregulated drugs, analyzing the interaction between methadone dose, cannabis use, and treatment retention.","methodology":"Community-based cohort study examining interactions between methadone dose, cannabis use, and treatment retention outcomes.","limitations":"Observational design cannot establish causation; cannabis use was self-reported; confounding factors like polydrug use may influence results."},{"rthcId":"RTHC-04698","title":"The Cannabis-Dependent Relationship Between Methadone Treatment Dose and Illicit Opioid Use in a Community-Based Cohort of People Who Use Drugs.","authors":"Lake, Stephanie; Kerr, Thomas; Buxton, Jane; Walsh, Zach; Cooper, Ziva D; Socías, M Eugenia; Fairbairn, Nadia; Hayashi, Kanna; Milloy, M-J","year":2023,"journal":"Cannabis and cannabinoid research, 8(1), 155-165","doi":"10.1089/can.2021.0080","pmid":"34813374","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis use modified the relationship between methadone treatment dose and illicit opioid use, with cannabis users showing less illicit opioid use at lower methadone doses compared to non-cannabis users.","whyItMatters":"Subtherapeutic methadone dosing often leads to continued illicit opioid use, which carries overdose risk. If cannabis helps reduce this gap, it could improve outcomes for undertreated patients.","specificNumbers":"The study examined a community-based cohort of people who use drugs, analyzing whether cannabis use interacts with methadone dose to influence illicit opioid use.","methodology":"Community-based cohort study examining the interaction between cannabis use, methadone dose, and illicit opioid use outcomes.","limitations":"Observational design; self-reported substance use; potential residual confounding from unmeasured variables; unable to determine cannabis strain, dose, or timing."},{"rthcId":"RTHC-04699","title":"Assessing Liver Effects of Cannabidiol and Valproate Alone and in Combination Using Quantitative Systems Toxicology.","authors":"Lakhani, Vinal V; Generaux, Grant; Howell, Brett A; Longo, Diane M; Watkins, Paul B","year":2023,"journal":"Clinical pharmacology and therapeutics, 114(5), 1006-1014","doi":"10.1002/cpt.3004","pmid":"37458709","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Using quantitative systems toxicology modeling, the study found that combined CBD and valproate use increased the incidence of ALT elevations above clinical thresholds compared to either drug alone, helping explain clinical observations of hepatotoxicity.","whyItMatters":"Many epilepsy patients taking valproate also use or consider CBD, and understanding the liver safety profile of this combination is critical for clinical decision-making.","specificNumbers":"In CBD clinical trials, ALT elevations greater than 3 times the upper limit of normal were observed in some patients, with higher incidence when combined with valproate.","methodology":"Quantitative systems toxicology (QST) modeling to simulate liver effects of CBD, valproate, and their combination.","limitations":"Computational modeling may not capture all biological complexity; model predictions need clinical validation; individual patient factors affecting hepatotoxicity are difficult to fully incorporate."},{"rthcId":"RTHC-04700","title":"The Use of Traditional, Complementary, and Integrative Medicine in Cancer: Data-Mining Study of 1 Million Web-Based Posts From Health Forums and Social Media Platforms.","authors":"Lam, Chun Sing; Zhou, Keary; Loong, Herbert Ho-Fung; Chung, Vincent Chi-Ho; Ngan, Chun-Kit; Cheung, Yin Ting","year":2023,"journal":"Journal of medical Internet research, 25, e45408","doi":"10.2196/45408","pmid":"37083752","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Analysis of over 1 million web posts found significant patient discussion of traditional, complementary, and integrative medicine for cancer, with cannabis being among the substances discussed in relation to cancer treatment and symptom management.","whyItMatters":"Understanding what cancer patients discuss online about complementary therapies helps clinicians anticipate patient questions, identify misinformation, and develop evidence-based communication strategies.","specificNumbers":"The study analyzed over 1 million web-based posts from health forums and social media platforms discussing complementary medicine and cancer.","methodology":"Data mining and content analysis of over 1 million web-based posts from health forums and social media platforms.","limitations":"Online posts may not represent all cancer patients; misinformation mixed with valid experiences; sentiment analysis may miss nuance; geographical and demographic biases in internet use."},{"rthcId":"RTHC-04701","title":"Neuroimaging revealed long-lasting glucose metabolism changes to morphine withdrawal in rats pretreated with the cannabinoid agonist CP-55,940 during periadolescence.","authors":"Lamanna-Rama, N; MacDowell, K S; López, G; Leza, J C; Desco, M; Ambrosio, E; Soto-Montenegro, M L","year":2023,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 69, 60-76","doi":"10.1016/j.euroneuro.2023.01.005","pmid":"36780817","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Periadolescent cannabinoid exposure (CP-55,940) produced long-lasting alterations in brain glucose metabolism patterns during morphine withdrawal at 6 and 14 weeks, with sex-dependent differences in affected brain regions.","whyItMatters":"This study suggests adolescent cannabinoid exposure may permanently alter how the brain responds to opioid withdrawal, with potential implications for understanding gateway drug interactions and vulnerability to opioid addiction.","specificNumbers":"Wistar rats (33 males, 32 females) were treated with CP-55,940 from postnatal day 28-38 and underwent morphine withdrawal assessment at PND100.","methodology":"Preclinical neuroimaging study using PET scanning to measure brain glucose metabolism in rats during morphine withdrawal following adolescent cannabinoid pretreatment.","limitations":"Animal model findings may not directly translate to humans; CP-55,940 is a synthetic cannabinoid more potent than THC; forced drug administration differs from voluntary human use."},{"rthcId":"RTHC-04702","title":"Predictors of problematic adult alcohol, cannabis, and other substance use: A longitudinal study of two samples.","authors":"Lansford, Jennifer E; Goulter, Natalie; Godwin, Jennifer; McMahon, Robert J; Dodge, Kenneth A; Crowley, Max; Pettit, Gregory S; Bates, John E; Lochman, John E","year":2023,"journal":"Development and psychopathology, 35(4), 2028-2043","doi":"10.1017/S0954579422000670","pmid":"35957585","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Adolescent risk factors including externalizing behavior, peer substance use, and early substance initiation predicted problematic alcohol, cannabis, and other substance use in adulthood, with findings replicated across two independent longitudinal samples.","whyItMatters":"Identifying which adolescent risk factors reliably predict adult substance problems can help target prevention efforts more effectively and intervene before patterns become entrenched.","specificNumbers":"Two independent samples were used: the Child Development Project (n=585; 48% girls; 81% White, 17% Black) and a second replication sample, tracked from adolescence through established adulthood.","methodology":"Longitudinal study examining predictive relationships between adolescent risk factors and adult substance use problems across two independent samples.","limitations":"Predominantly White sample in primary cohort limits generalizability; self-reported substance use; attrition over long follow-up periods may introduce bias."},{"rthcId":"RTHC-04703","title":"Cyclic Vomiting Syndrome and Cannabis Hyperemesis Syndrome: The State of the Science.","authors":"Lathrop, James R; Rosen, Sheldon N; Heitkemper, Margaret M; Buchanan, Diana Taibi","year":2023,"journal":"Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates, 46(3), 208-224","doi":"10.1097/SGA.0000000000000730","pmid":"37074964","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CVS and CHS share clinical features including episodic severe vomiting, but differ in etiology: CVS has multiple potential triggers while CHS is specifically associated with chronic cannabis use, with the relationship between the two conditions remaining actively debated.","whyItMatters":"Distinguishing between CVS and CHS is clinically important because treatment approaches differ - CHS typically resolves with cannabis cessation while CVS requires ongoing management strategies.","specificNumbers":"The review covers the historical context, clinical presentation, diagnostic criteria, and treatment approaches for both CVS and CHS.","methodology":"Narrative review synthesizing current scientific literature on cyclic vomiting syndrome and cannabis hyperemesis syndrome.","limitations":"Narrative review format may introduce selection bias; the relationship between CVS and CHS remains debated with limited high-quality comparative studies."},{"rthcId":"RTHC-04704","title":"Face validity of the ICD-10 criteria of substance abuse and dependence for patients prescribed cannabis-based medicines for chronic pain-A survey of pain medicine physicians in Canada, Germany and Israel.","authors":"Lauff, Sören; Petzke, Frank; Brill, Silviu; Schouten, Leonie; Fitzcharles, Mary-Ann; Pereira, John X; Häuser, Winfried","year":2023,"journal":"European journal of pain (London, England), 27(5), 588-601","doi":"10.1002/ejp.2082","pmid":"36692097","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Physicians in Canada, Germany, and Israel reported that many ICD-10 cannabis dependence criteria (such as tolerance and withdrawal) do not accurately apply to patients using prescribed cannabis-based medicines for chronic pain, suggesting current diagnostic tools may pathologize legitimate medical use.","whyItMatters":"Applying addiction criteria designed for recreational use to medical cannabis patients could lead to misdiagnosis, stigma, and barriers to accessing effective pain treatment.","specificNumbers":"Physicians from three countries (Canada, Germany, Israel) were surveyed on the face validity of ICD-10 criteria for cannabis dependence in prescribed patients.","methodology":"International survey of pain medicine physicians assessing face validity of ICD-10 substance abuse and dependence criteria for medical cannabis patients.","limitations":"Physician perceptions may differ from patient experiences; survey methodology introduces response bias; small sample across three countries may not represent all clinical perspectives."},{"rthcId":"RTHC-04705","title":"The acute effects of cannabis with and without cannabidiol in adults and adolescents: A randomised, double-blind, placebo-controlled, crossover experiment.","authors":"Lawn, Will; Trinci, Katie; Mokrysz, Claire; Borissova, Anna; Ofori, Shelan; Petrilli, Kat; Bloomfield, Michael; Haniff, Zarah R; Hall, Daniel; Fernandez-Vinson, Natalia; Wang, Simiao; Englund, Amir; Chesney, Edward; Wall, Matthew B; Freeman, Tom P; Curran, H Valerie","year":2023,"journal":"Addiction (Abingdon, England), 118(7), 1282-1294","doi":"10.1111/add.16154","pmid":"36750134","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study compared acute subjective, cognitive, and physiological effects of cannabis in adolescents versus adults, and investigated whether co-administered CBD modulates these effects, providing rare controlled data on adolescent cannabis response.","whyItMatters":"Most cannabis research excludes adolescents, yet they are a primary population of concern. Understanding age-related differences in acute effects and CBDs potential protective role is critical for harm reduction.","specificNumbers":"Randomized, double-blind, placebo-controlled, crossover experiment comparing cannabis effects with and without CBD in adolescent and adult users.","methodology":"Randomized, double-blind, placebo-controlled, crossover trial with adolescent and adult cannabis users.","limitations":"Ethical constraints limit adolescent cannabis research to existing users; crossover design requires washout periods; acute effects may not predict long-term outcomes."},{"rthcId":"RTHC-04706","title":"Cannabis use and psychotic disorders in diverse settings in the Global South: findings from INTREPID II.","authors":"Lee Pow, Joni; Donald, Casswina; di Forti, Marta; Roberts, Tessa; Weiss, Helen A; Ayinde, Olatunde; John, Sujit; Olley, Bola; Ojagbemi, Akin; Esponda, Georgina Miguel; Lam, Joseph; Poornachandrika, Paramasivam; Dazzan, Paola; Gaughran, Fiona; Kannan, Palaniyandi Ponnusamy; Sudhakar, Selvaraju; Burns, Jonathan; Chiliza, Bonginkosi; Cohen, Alex; Gureje, Oye; Thara, Rangaswamy; Murray, Robin M; Morgan, Craig; Hutchinson, Gerard","year":2023,"journal":"Psychological medicine, 53(15), 7062-7069","doi":"10.1017/S0033291723000399","pmid":"36951137","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The INTREPID II study found associations between cannabis use and psychotic disorders in diverse Global South settings, demonstrating that the cannabis-psychosis link is not limited to Western populations and cultural contexts.","whyItMatters":"Most cannabis-psychosis research comes from Europe and North America. Confirming this association in Latin American, Asian, and African contexts strengthens the global evidence base and informs region-specific policies.","specificNumbers":"Case-control study conducted across three Global South settings spanning Latin America, Asia, and Africa.","methodology":"Case-control study across multiple Global South sites examining cannabis use patterns in people with and without psychotic disorders.","limitations":"Cross-cultural variation in cannabis potency, use patterns, and psychosis diagnosis; case-control design cannot establish causation; potential confounders vary by region."},{"rthcId":"RTHC-04707","title":"Identification of Terpene Compositions in the Leaves and Inflorescences of Hybrid Cannabis Species Using Headspace-Gas Chromatography/Mass Spectrometry.","authors":"Lee, Sangin; Kim, Eun Jae; Kwon, Eunjeong; Oh, Seo Jeong; Cho, Mansoo; Kim, Chul Min; Lee, Wonwoong; Hong, Jongki","year":2023,"journal":"Molecules (Basel, Switzerland), 28(24)","doi":"10.3390/molecules28248082","pmid":"38138572","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study identified distinct terpene profiles in leaves versus inflorescences of hybrid cannabis species, contributing to understanding of the entourage effect and how different plant parts may contribute differently to therapeutic outcomes.","whyItMatters":"Terpenes are believed to modulate cannabinoid effects through the entourage effect, and understanding their distribution across plant parts helps optimize cannabis products for specific therapeutic applications.","specificNumbers":"Terpene compositions were analyzed in both leaves and inflorescences of hybrid Cannabis species using headspace gas chromatography/mass spectrometry.","methodology":"Analytical chemistry study using headspace-gas chromatography/mass spectrometry (HS-GC/MS) to identify terpene profiles.","limitations":"Headspace analysis may underrepresent less volatile terpenes; hybrid varieties may not represent all cannabis chemotypes; environmental growing conditions affect terpene production."},{"rthcId":"RTHC-04708","title":"Effect of four-week cannabidiol treatment on cognitive function: secondary outcomes from a randomised clinical trial for the treatment of cannabis use disorder.","authors":"Lees, Rachel; Hines, Lindsey A; Hindocha, Chandni; Baio, Gianluca; Shaban, Natacha D C; Stothart, George; Mofeez, Ali; Morgan, Celia J A; Curran, H Valerie; Freeman, Tom P","year":2023,"journal":"Psychopharmacology, 240(2), 337-346","doi":"10.1007/s00213-022-06303-5","pmid":"36598543","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Secondary analysis of a randomized clinical trial found that four weeks of CBD treatment was associated with improvements in cognitive function among individuals being treated for cannabis use disorder.","whyItMatters":"Chronic cannabis use is associated with cognitive impairment, and finding that CBD may have pro-cognitive effects in CUD treatment could add therapeutic value beyond reducing cannabis use itself.","specificNumbers":"Four-week cannabidiol treatment period with cognitive function assessed as secondary outcomes from a randomized clinical trial for CUD treatment.","methodology":"Secondary outcome analysis from a randomized clinical trial of CBD for cannabis use disorder treatment.","limitations":"Secondary outcome analysis was not the primary study endpoint; cognitive improvements could reflect reduced cannabis use rather than direct CBD effects; short treatment duration."},{"rthcId":"RTHC-04709","title":"Prenatal alcohol and tetrahydrocannabinol exposure: Effects on spatial and working memory.","authors":"Lei, Annie; Breit, Kristen R; Thomas, Jennifer D","year":2023,"journal":"Frontiers in neuroscience, 17, 1192786","doi":"10.3389/fnins.2023.1192786","pmid":"37383100","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Combined prenatal exposure to alcohol and THC impaired spatial and working memory in offspring, with the combined exposure potentially producing distinct cognitive effects compared to either substance alone.","whyItMatters":"Alcohol and cannabis are frequently co-used, and understanding how their combined prenatal exposure affects cognitive development is crucial given increasing cannabis use during pregnancy.","specificNumbers":"Animal model examining spatial and working memory outcomes following prenatal exposure to alcohol, THC, and their combination.","methodology":"Preclinical animal study examining cognitive outcomes of prenatal alcohol and THC co-exposure using spatial and working memory tasks.","limitations":"Animal model findings may not directly translate to humans; dosing protocols may not reflect typical human exposure patterns; specific THC administration differs from cannabis plant exposure."},{"rthcId":"RTHC-04710","title":"Multilevel Risk and Protective Factors for Frequent and Nonfrequent Past-30-Day Marijuana Use: Findings From a Representative Sample of High School Youth.","authors":"Lensch, Taylor; Drake, Cara; Clements-Nolle, Kristen; Pearson, Jennifer","year":2023,"journal":"Journal of studies on alcohol and drugs, 84(4), 508-519","doi":"10.15288/jsad.22-00240","pmid":"36971761","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study identified multilevel factors (individual, peer, family, school, community) that distinguish frequent from non-frequent past-30-day marijuana users among high school youth, revealing that some factors specifically predict frequency rather than just any use.","whyItMatters":"Most research treats marijuana use as binary (use vs no use), but understanding what drives frequent use specifically can help target prevention efforts at the highest-risk youth.","specificNumbers":"Representative sample of high school youth with past-30-day marijuana use data, analyzed at individual, peer, family, school, and community levels.","methodology":"Cross-sectional survey analysis using multilevel modeling to identify factors associated with frequent vs non-frequent marijuana use.","limitations":"Cross-sectional design limits causal inference; self-reported data; representative sample may not capture highest-risk youth who are absent or dropped out."},{"rthcId":"RTHC-04711","title":"Cannabis Use and Symptomatic Relapse in First Episode Schizophrenia: Trigger or Consequence? Data From the OPTIMISE Study.","authors":"Levi, Linda; Bar-Haim, Mor; Winter-van Rossum, Inge; Davidson, Michael; Leucht, Stefan; Fleischhacker, Wolfgang W; Park, Jinyoung; Davis, John M; Kahn, Renè S; Weiser, Mark","year":2023,"journal":"Schizophrenia bulletin, 49(4), 903-913","doi":"10.1093/schbul/sbad033","pmid":"36999551","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The analysis examined the temporal relationship between cannabis use, antipsychotic compliance, and relapse risk in first-episode schizophrenia patients in remission, addressing whether cannabis is a trigger or consequence of symptom recurrence.","whyItMatters":"Understanding the direction of the cannabis-relapse relationship is critical for clinical management: if cannabis triggers relapse, prevention efforts should focus on abstinence; if relapse drives cannabis use, underlying symptoms need better management.","specificNumbers":"Data from the OPTIMISE study, a large European study on first-episode schizophrenia, schizophreniform, or schizoaffective disorder patients in remission.","methodology":"Secondary analysis of the OPTIMISE European multicenter study examining temporal relationships between cannabis use and symptomatic relapse.","limitations":"Observational analysis within a clinical trial; self-reported cannabis use; complex temporal relationships are difficult to disentangle even with longitudinal data."},{"rthcId":"RTHC-04712","title":"Assessment of Screening Tools to Identify Substance Use Disorders Among Adolescents.","authors":"Levy, Sharon; Brogna, Melissa; Minegishi, Machiko; Subramaniam, Geetha; McCormack, Jennifer; Kline, Margaret; Menzin, Eleanor; Allende-Richter, Sophie; Fuller, Alyssa; Lewis, Mitra; Collins, Julia; Hubbard, Zach; Mitchell, Shannon G; Weiss, Roger; Weitzman, Elissa","year":2023,"journal":"JAMA network open, 6(5), e2314422","doi":"10.1001/jamanetworkopen.2023.14422","pmid":"37213103","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study assessed the S2BI, BSTAD, and TAPS screening tools for identifying substance use disorders in adolescents, evaluating their sensitivity, specificity, and practical utility for clinical screening.","whyItMatters":"Early identification of substance use disorders in youth requires efficient, validated screening tools. Comparing available options helps clinicians choose the best tool for their setting.","specificNumbers":"Three screening tools evaluated: S2BI (Screening to Brief Intervention), BSTAD (Brief Screener for Tobacco, Alcohol, and Drugs), and TAPS (Tobacco, Alcohol, Prescription medication, and other Substance use).","methodology":"Psychometric evaluation comparing three brief substance use screening tools against diagnostic standards in an adolescent population.","limitations":"Screening tool performance may vary across clinical settings and populations; gold standard diagnostic assessments have their own limitations; cultural validity not fully assessed."},{"rthcId":"RTHC-04713","title":"Establishment of a point of departure for CBD hepatotoxicity employing human HepaRG spheroids.","authors":"Li, Jinpeng; Zagorski, Joseph W; Kaminski, Norbert E","year":2023,"journal":"Toxicology, 488, 153469","doi":"10.1016/j.tox.2023.153469","pmid":"36863504","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Using human HepaRG liver cell spheroids, researchers identified concentration thresholds at which CBD begins to cause liver cell damage, providing a quantitative basis for establishing safe exposure limits.","whyItMatters":"With CBD products widely available and often unregulated, establishing evidence-based safety thresholds for liver toxicity is crucial for consumer protection and regulatory guidance.","specificNumbers":"The study used HepaRG spheroids (3D human liver cell models) to determine CBD concentrations that trigger hepatotoxic responses, with reference to clinical observations of ALT elevations in Epidiolex trials.","methodology":"In vitro toxicology study using human HepaRG liver cell spheroids to establish concentration-response relationships for CBD hepatotoxicity.","limitations":"In vitro models may not fully replicate in vivo liver metabolism and clearance; spheroid cultures lack full hepatic architecture; individual genetic variation affects real-world toxicity."},{"rthcId":"RTHC-04714","title":"Impact of the Cannabinoid System in Alzheimer's Disease.","authors":"Li, Shuangtao; Huang, Yuanbing; Yu, Lijun; Ji, Xiaoyu; Wu, Jie","year":2023,"journal":"Current neuropharmacology, 21(3), 715-726","doi":"10.2174/1570159X20666220201091006","pmid":"35105293","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The endocannabinoid system is implicated in Alzheimers disease pathology, with cannabinoids showing potential to modulate neuroinflammation, oxidative stress, and protein aggregation pathways involved in disease progression.","whyItMatters":"Alzheimers disease has no cure and limited treatments. Understanding how the cannabinoid system interacts with disease mechanisms could open new therapeutic avenues for this devastating condition.","specificNumbers":"The review covers cannabinoid interactions with both nervous and immune system components relevant to Alzheimers disease pathology.","methodology":"Review article synthesizing evidence on cannabinoid system involvement in Alzheimers disease from preclinical and clinical research.","limitations":"Most evidence is preclinical; clinical trials in Alzheimers patients are limited; long-term effects of cannabinoid use in elderly populations are poorly studied."},{"rthcId":"RTHC-04715","title":"Parental practices and their association with alcohol and cannabis use among adolescents in Chile.","authors":"Libuy, Nicolás; Guajardo, Viviana; Ibáñez, Carlos; Araneda, Ana María; Contreras, Lorena; Donoso, Paula; Gaete, Jorge; Mundt, Adrian P","year":2023,"journal":"Frontiers in psychology, 14, 1209584","doi":"10.3389/fpsyg.2023.1209584","pmid":"37767214","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Perceived parenting practices including monitoring, communication, and rule-setting were associated with adolescent alcohol and cannabis use in Chile, with findings adapted from a substance use prevention strategy implemented in a Latin American context.","whyItMatters":"Most substance use prevention research comes from North America and Europe. Understanding which parenting practices are protective in Chilean culture helps develop culturally appropriate prevention programs for Latin America.","specificNumbers":"The study adapted and implemented a substance use prevention strategy in Chile, assessing relationships between parenting practices and adolescent alcohol and cannabis use.","methodology":"Cross-sectional survey of Chilean adolescents assessing perceived parenting practices and self-reported substance use.","limitations":"Cross-sectional design limits causal inference; self-reported data from adolescents; single Latin American country may not represent all regional contexts."},{"rthcId":"RTHC-04716","title":"Syncope and Cannabis: hypervagotonia from chronic abuse? A case report and literature review.","authors":"Licciardi, Marco; Utzeri, Elena; Marchetti, Maria Francesca; Nissardi, Vincenzo; Cecchetto, Giovanni; Montisci, Massimo; Montisci, Roberta","year":2023,"journal":"BMC cardiovascular disorders, 23(1), 518","doi":"10.1186/s12872-023-03566-4","pmid":"37875800","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The case report describes syncope in a chronic cannabis user, with the proposed mechanism being hypervagotonia (excessive vagal nerve activation), adding to rare but documented cases of cardiovascular effects from chronic cannabis use.","whyItMatters":"While cannabis cardiovascular effects are typically considered mild, rare adverse events like syncope need documentation to inform clinical awareness, especially as cannabis use increases among young people.","specificNumbers":"Case report with literature review documenting cannabis-associated syncope, with focus on hypervagotonia as the proposed mechanism.","methodology":"Case report with accompanying literature review of cannabis-associated syncope and cardiovascular effects.","limitations":"Single case report cannot establish causation; other causes of syncope may not have been fully excluded; literature review is not systematic."},{"rthcId":"RTHC-04717","title":"Stigma and level of familiarity with opioid maintenance treatment (OMT) among specialist physicians in Israel.","authors":"Lihi, Rozner; Yael, Delayahu; Silviu, Brill; Anat, Sason; Marsha, Weinstein; Stacy, Shoshan; Shaul, Schreiber; Miriam, Adelson; Einat, Peles","year":2023,"journal":"Harm reduction journal, 20(1), 134","doi":"10.1186/s12954-023-00869-9","pmid":"37715237","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Israeli specialist physicians showed variable knowledge of opioid maintenance treatment and held stigmatizing attitudes that could affect treatment delivery and referral patterns for opioid use disorder.","whyItMatters":"Physician stigma toward medication-assisted treatment is a major barrier to addressing the opioid crisis. Understanding these attitudes in Israel, which aims to prevent an epidemic, can inform targeted education.","specificNumbers":"Survey of specialist physicians in Israel evaluating objective knowledge, stigma levels, and approaches to opioid maintenance treatment.","methodology":"Cross-sectional survey of specialist physicians in Israel assessing OUD knowledge, stigma, and familiarity with opioid maintenance treatment.","limitations":"Self-selection bias in survey respondents; Israeli context may not generalize to other countries; social desirability may affect stigma reporting."},{"rthcId":"RTHC-04718","title":"Cannabis Use Disorder Treatment Preferences: A Pilot Survey in Current Users of Cannabis.","authors":"Lile, Joshua A; Turner, Brian W; Cox, David H; Bonn-Miller, Marcel O; Katz, Ned R; Shellenberg, Thomas P; Stoops, William W; Strickland, Justin C","year":2023,"journal":"Journal of addiction medicine, 17(2), e87-e93","doi":"10.1097/ADM.0000000000001059","pmid":"36731101","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Current cannabis users expressed preferences for specific treatment approaches, modalities, and settings, highlighting a gap between what patients want and what is typically offered for cannabis use disorder.","whyItMatters":"No highly effective CUD treatments exist, and patient preferences have been largely ignored in treatment development. Understanding what users actually want could improve treatment engagement and outcomes.","specificNumbers":"Exploratory crowdsourced survey of individuals reporting current cannabis use who expressed willingness to cut down or quit.","methodology":"Crowdsourced pilot survey of current cannabis users willing to reduce or quit, assessing treatment preferences.","limitations":"Crowdsourced sample may not represent all cannabis users; willingness to reduce/quit may not translate to action; pilot survey with potentially limited sample size."},{"rthcId":"RTHC-04719","title":"Prenatal cannabinoid exposure: why expecting individuals should take a pregnancy pause from using cannabinoid products.","authors":"Lin, Alexis; Dent, Gelonia L; Davies, Suzy; Dominguez, Zarena M; Cioffredi, Leigh-Anne; McLemore, Gabrielle L; Maxwell, Jessie R","year":2023,"journal":"Frontiers in pediatrics, 11, 1278227","doi":"10.3389/fped.2023.1278227","pmid":"37886232","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review synthesizes evidence showing prenatal cannabinoid exposure risks to fetal development, arguing that the growing availability and normalization of cannabis products requires clearer medical messaging about pregnancy-related risks.","whyItMatters":"Cannabis use during pregnancy is increasing alongside legalization, and many pregnant individuals receive inadequate guidance from medical providers about the risks of cannabinoid exposure to the developing fetus.","specificNumbers":"Cannabinoid use across all populations is increasing with US legalization, with a noted lack of caution from medical providers to pregnant individuals.","methodology":"Narrative review synthesizing evidence on prenatal cannabinoid exposure risks and clinical messaging gaps.","limitations":"Narrative review may introduce selection bias; evidence quality varies; some risks may be overstated or understated depending on confounding factors in underlying studies."},{"rthcId":"RTHC-04720","title":"Substance Use Disorders in the Geriatric Population: a Review and Synthesis of the Literature of a Growing Problem in a Growing Population.","authors":"Lin, Jenny; Arnovitz, Mitchell; Kotbi, Nabil; Francois, Dimitry","year":2023,"journal":"Current treatment options in psychiatry, 1-20","doi":"10.1007/s40501-023-00291-9","pmid":"37360959","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Substance use disorders are becoming increasingly prevalent in older adults, with unique challenges in detection, diagnosis, and treatment due to age-related physiological changes, polypharmacy, and underrecognition by healthcare providers.","whyItMatters":"The aging baby boomer generation has higher lifetime substance use rates than previous cohorts, and the intersection of substance use with age-related conditions creates complex clinical scenarios that many geriatric providers are unprepared for.","specificNumbers":"The review synthesized literature from PubMed, Ovid, and other databases on epidemiology, special considerations, and management of SUDs in older adults.","methodology":"Literature review and synthesis of evidence on substance use disorders in the geriatric population.","limitations":"Older adults are underrepresented in substance use research; screening tools may not be validated for geriatric populations; age-related cognitive decline can confound SUD assessment."},{"rthcId":"RTHC-04721","title":"Cannabinoids in traumatic brain injury and related neuropathologies: preclinical and clinical research on endogenous, plant-derived, and synthetic compounds.","authors":"Lins, Brittney R; Anyaegbu, Chidozie C; Hellewell, Sarah C; Papini, Melissa; McGonigle, Terence; De Prato, Luca; Shales, Matthew; Fitzgerald, Melinda","year":2023,"journal":"Journal of neuroinflammation, 20(1), 77","doi":"10.1186/s12974-023-02734-9","pmid":"36935484","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Preclinical and early clinical evidence suggests cannabinoids may have neuroprotective effects following traumatic brain injury, with potential mechanisms including reducing neuroinflammation, excitotoxicity, and oxidative stress.","whyItMatters":"TBI is common and often devastating, with no approved pharmaceutical treatments that improve outcomes. Cannabinoids represent a promising but understudied therapeutic avenue that could address multiple injury mechanisms simultaneously.","specificNumbers":"Approximately 20% of patients with mild TBI have symptoms persisting for months, and there are currently no approved pharmaceutical interventions that improve TBI outcomes.","methodology":"Review of preclinical and clinical research on endogenous, plant-derived, and synthetic cannabinoids in TBI and related neuropathologies.","limitations":"Most evidence is preclinical; timing of cannabinoid administration post-injury is critical and poorly defined; different cannabinoid types may have opposing effects."},{"rthcId":"RTHC-04722","title":"Regular Use of Cannabis in Female Athletes Is Associated With a Reduction in Early Anaerobic Power Production.","authors":"Lisano, Jonathon K; Flores, Victoria A; Kisiolek, Jacob N; Stewart, Laura K","year":2023,"journal":"Journal of strength and conditioning research, 37(3), 616-622","doi":"10.1519/JSC.0000000000004297","pmid":"36820704","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Regular cannabis use in female athletes was associated with a reduction in early anaerobic power production, indicating potential performance impairment in activities requiring short-duration, high-intensity effort.","whyItMatters":"As cannabis policies liberalize in sports and society, understanding its actual effects on athletic performance is important for athletes, coaches, and sports medicine professionals making evidence-based decisions.","specificNumbers":"The study compared early anaerobic power production between female athletes who regularly use cannabis and those who do not.","methodology":"Cross-sectional comparison of anaerobic power output between regular cannabis-using and non-using female athletes.","limitations":"Cross-sectional design cannot determine causation; differences between groups may reflect factors beyond cannabis use; sample limited to female athletes."},{"rthcId":"RTHC-04723","title":"Pronounced State-Level Disparities in Prescription of Cannabinoids to Medicaid Patients.","authors":"Liu, Edward Y; McCall, Kenneth L; Piper, Brian J","year":2023,"journal":"Medical cannabis and cannabinoids, 6(1), 58-65","doi":"10.1159/000531058","pmid":"37404688","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"There were significant state-level disparities in prescribing FDA-approved cannabinoids (dronabinol and cannabidiol) to Medicaid patients, indicating that access to these medications varies greatly depending on where patients live.","whyItMatters":"Medicaid patients often have the greatest need for affordable medications. State-level variation in cannabinoid prescribing suggests systemic barriers that may create health inequities for vulnerable populations.","specificNumbers":"Dronabinol is FDA-approved for chemotherapy-induced nausea/vomiting and HIV-induced anorexia; cannabidiol (Epidiolex) is approved for Lennox-Gastaut and Dravet syndrome epilepsies.","methodology":"Analysis of Medicaid prescription data examining state-level patterns in cannabinoid medication prescribing.","limitations":"Administrative data cannot capture clinical decision-making reasons; Medicaid populations differ across states; some variation may reflect appropriate clinical differences rather than inequity."},{"rthcId":"RTHC-04724","title":"Impairment of Endothelial Function by Aerosol From Marijuana Leaf Vaporizers.","authors":"Liu, Jiangtao; Nabavizadeh, Pooneh; Rao, Poonam; Derakhshandeh, Ronak; Han, Daniel D; Guo, Raymond; Murphy, Morgan B; Cheng, Jing; Schick, Suzaynn F; Springer, Matthew L","year":2023,"journal":"Journal of the American Heart Association, 12(23), e032969","doi":"10.1161/JAHA.123.032969","pmid":"38014661","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Despite avoiding combustion, marijuana leaf vaporizer aerosol impaired endothelial function comparably to marijuana smoke, suggesting that vaporizing may not eliminate cardiovascular risks as commonly assumed.","whyItMatters":"Vaporizers are widely perceived as a safer alternative to smoking cannabis, but this study indicates the cardiovascular harm to blood vessel function may persist regardless of delivery method.","specificNumbers":"The study compared endothelial function impairment from marijuana leaf vaporizer aerosol against established effects of tobacco smoke, marijuana smoke, and e-cigarette aerosol.","methodology":"Experimental study measuring endothelial function response to marijuana leaf vaporizer aerosol compared to other inhalation methods.","limitations":"Acute exposure study may not reflect chronic use patterns; specific vaporizer device and temperature settings affect results; endothelial function is one aspect of cardiovascular health."},{"rthcId":"RTHC-04725","title":"Cannabidiol as a Harm Reduction Strategy for People Who Use Drugs: A Rapid Review.","authors":"Lo, Lindsay A; MacCallum, Caroline A; Nanson, Kate; Koehn, Michael; Mitchell, Ian; Milloy, Michael-John; Walsh, Zach; Fehr, Florriann","year":2023,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 68(8), 557-571","doi":"10.1177/07067437231183525","pmid":"37376827","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Emerging evidence suggests CBD may have utility as a harm reduction modality for people with problematic substance use, with potential applications in reducing cravings, withdrawal symptoms, and substance use across multiple drug categories.","whyItMatters":"The drug poisoning crisis across North America demands novel harm reduction approaches, and CBD represents an accessible, low-risk intervention that could complement existing strategies.","specificNumbers":"The rapid review synthesized available evidence on CBDs potential as a harm reduction strategy during the North American drug poisoning crisis.","methodology":"Rapid review synthesizing evidence on CBD as a harm reduction modality for problematic substance use.","limitations":"Rapid review format may miss relevant studies; evidence base is still small; most studies are preliminary; CBD product quality and dosing vary widely."},{"rthcId":"RTHC-04726","title":"Plasma levels of neurotrophin 4/5, NGF and pro-BDNF influence transition to mental disorders in a sample of individuals at ultra-high risk for psychosis.","authors":"Loch, Alexandre Andrade; Pinto, Marcel Tavares Camilo; Andrade, Julio Cesar; de Jesus, Leonardo Peroni; de Medeiros, Matheus Wanderley; Haddad, Natalia Mansur; Bilt, Martinus Theodorus van de; Talib, Leda Leme; Gattaz, Wagner Farid","year":2023,"journal":"Psychiatry research, 327, 115402","doi":"10.1016/j.psychres.2023.115402","pmid":"37544089","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Plasma levels of neurotrophin 4/5, NGF, and pro-BDNF were associated with transition to mental disorders in individuals identified as ultra-high risk for psychosis, suggesting potential biomarker applications for risk prediction.","whyItMatters":"Identifying biomarkers that predict which at-risk individuals will develop psychotic disorders could enable targeted early intervention and prevention strategies.","specificNumbers":"The study measured plasma levels of neurotrophin 4/5, NGF (nerve growth factor), and pro-BDNF (brain-derived neurotrophic factor precursor) in ultra-high risk individuals.","methodology":"Prospective cohort study measuring plasma neurotrophin levels in individuals at ultra-high risk for psychosis and tracking diagnostic outcomes.","limitations":"Plasma levels may not reflect brain neurotrophin activity; UHR criteria identify a heterogeneous group; small sample sizes typical of UHR research limit statistical power."},{"rthcId":"RTHC-04727","title":"An examination of the effects of ADHD symptoms and sex on the relation between cannabis protective behavioral strategies and cannabis consequences.","authors":"Looby, Alison; Prince, Mark A; Livingston, Nicholas R; Berry, Katherine A","year":2023,"journal":"Addictive behaviors, 144, 107718","doi":"10.1016/j.addbeh.2023.107718","pmid":"37059000","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study found that ADHD symptoms and biological sex interact with the use of cannabis protective behavioral strategies (PBS) to influence cannabis-related consequences, suggesting that harm reduction approaches may need to account for ADHD status.","whyItMatters":"College students with ADHD symptoms are at elevated risk for cannabis-related problems, and understanding whether protective strategies work differently for them can inform targeted harm reduction on campuses.","specificNumbers":"The study examined young adults with ADHD symptoms and their use of cannabis protective behavioral strategies in relation to cannabis consequences.","methodology":"Cross-sectional survey examining interactions between ADHD symptoms, sex, cannabis PBS use, and cannabis-related consequences in college students.","limitations":"Cross-sectional design; self-reported ADHD symptoms rather than clinical diagnosis; college sample may not generalize to all young adults."},{"rthcId":"RTHC-04728","title":"Delta-8 tetrahydrocannabinol: a scoping review and commentary","authors":"LoParco, Cassidy R.; Rossheim, Matthew E.; Walters, Scott T.; Zhou, Zhengyang; Olsson, Sofia; Sussman, Steve Y.","year":2023,"journal":"Addiction, 118(6), 1011-1028","doi":"10.1111/add.16142","pmid":"36710464","tags":["legalization","youth","potency","harm-reduction"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Delta-8 THC exists in a remarkable regulatory gray zone. The 2018 U.S. Farm Bill legalized hemp (cannabis with less than 0.3% delta-9 THC) and its derivatives — which inadvertently legalized delta-8 THC, a psychoactive isomer of the more familiar delta-9 THC. The result has been an explosion of unregulated products in gas stations, convenience stores, and online retailers, with almost no scientific understanding of what consumers are actually ingesting.\n\nThis scoping review synthesized 103 documents spanning peer-reviewed studies, news reports, and anecdotal evidence. The findings are concerning on multiple levels. Most existing research used animal or cell models, not humans. The limited human data suggests delta-8 THC is psychoactive but possibly less potent than delta-9 THC, and people commonly use it as a substitute for delta-9 THC, particularly in states where recreational cannabis remains illegal.\n\nThe manufacturing side raises additional red flags. Delta-8 THC is typically synthesized from CBD extracted from hemp — a chemical conversion process that can produce unknown byproducts. Laboratory testing of commercial delta-8 products has found inconsistent potency labeling and the presence of unidentified compounds. Combined with youth-oriented marketing, low prices, and near-universal availability, delta-8 represents a large-scale natural experiment with minimal safety data.\n\nThe regulatory patchwork is equally chaotic: as of the review, some states had banned delta-8 while others allowed it, and federal guidance remained unclear.","whyItMatters":"Delta-8 THC products are already being used by millions of Americans, including adolescents, with virtually no human safety data. This review maps the enormous gap between how widely delta-8 is used and how little we actually know about it. For consumers, the takeaway is sobering: you're essentially a participant in an uncontrolled experiment.","specificNumbers":"103 documents reviewed. Delta-8 was implicitly legalized by the 2018 Farm Bill. Most research used animal or cell models. Commercial products showed inconsistent potency labeling. Youth-oriented marketing was documented. Multiple states have enacted bans while others remain unregulated.","methodology":"Scoping review using PubMed, Scopus, Google Scholar, and Google to identify 103 documents covering delta-8 THC. Documents were categorized into four emergent themes: legality, use (popularity, motives, psychoactivity, benefits/consequences), synthesis (byproducts, lab testing), and retail (availability, price, packaging, youth marketing). A second author independently coded 20% for verification.","limitations":"Scoping review methodology captures breadth but not depth — many sources were non-peer-reviewed (news reports, anecdotal evidence). The delta-8 landscape changes rapidly; legal status and product availability may already differ from what's described. Limited human pharmacological data means the review relies heavily on animal studies and self-reported user experiences. The inclusion of non-academic sources, while appropriate for a scoping review of an emerging topic, means the evidence quality is highly variable."},{"rthcId":"RTHC-04729","title":"Cannabinoids: Emerging sleep modulator.","authors":"Low, Zhen Xuen Brandon; Lee, Xin Ru; Soga, Tomoko; Goh, Bey Hing; Alex, Deepa; Kumari, Yatinesh","year":2023,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 165, 115102","doi":"10.1016/j.biopha.2023.115102","pmid":"37406510","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabinoids interact with sleep regulation through the endocannabinoid system, with different cannabinoids (THC, CBD, CBN) showing varied effects on sleep architecture, onset, and quality.","whyItMatters":"Sleep disorders affect a significant portion of the population, and current treatments have notable side effects. Understanding how cannabinoids modulate sleep could lead to new, potentially better-tolerated sleep interventions.","specificNumbers":"The review covers effects of multiple cannabinoids on sleep across the animal kingdom, including impacts on homeostasis, alertness, metabolism, cognition, and memory.","methodology":"Review article synthesizing evidence on cannabinoid effects on sleep regulation and architecture.","limitations":"Evidence quality varies across cannabinoids; most human studies are small; long-term effects of cannabinoid sleep aids are poorly studied; individual variation in response is significant."},{"rthcId":"RTHC-04730","title":"Anti-Inflammatory Effects of Cannabigerol in Rheumatoid Arthritis Synovial Fibroblasts and Peripheral Blood Mononuclear Cell Cultures Are Partly Mediated by TRPA1.","authors":"Lowin, Torsten; Tigges-Perez, Marianne Sofia; Constant, Eva; Pongratz, Georg","year":2023,"journal":"International journal of molecular sciences, 24(1)","doi":"10.3390/ijms24010855","pmid":"36614296","tags":["inflammation","cbd","medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Most cannabis research focuses on THC and CBD, but the cannabis plant produces over 100 cannabinoids. Cannabigerol (CBG) is a 'minor' cannabinoid that's gaining attention for potential anti-inflammatory properties. This study investigated whether CBG could reduce inflammation in cells taken directly from rheumatoid arthritis (RA) patients.\n\nThe researchers tested CBG on two types of cells: rheumatoid arthritis synovial fibroblasts (RASF) — the cells that line inflamed joints in RA — and peripheral blood mononuclear cells (PBMCs, a type of immune cell). They were particularly interested in whether CBG works through a channel called TRPA1, which is involved in both pain sensing and protecting cells from oxidative stress.\n\nCBG increased calcium signaling in TNF-stimulated RASF cells through the TRPA1 channel — but only in inflamed cells, not healthy ones. This selectivity is important: it suggests CBG may preferentially act on inflamed tissue. CBG also reduced the production of key inflammatory molecules including IL-6, IL-8, and MMP-3 (a matrix metalloproteinase that destroys joint tissue in RA).\n\nIn immune cells from RA patients, CBG similarly reduced pro-inflammatory cytokine production. The anti-inflammatory effects were partly — but not entirely — blocked by TRPA1 antagonists, meaning CBG likely works through multiple pathways.","whyItMatters":"Rheumatoid arthritis affects about 1% of the global population, and current treatments — while effective for many — have significant side effects (immunosuppression, liver toxicity, infection risk). If minor cannabinoids like CBG can reduce joint inflammation through different pathways than existing drugs, they could complement current treatments or offer alternatives for patients who don't respond well to standard therapy. The TRPA1 mechanism is particularly interesting because it links pain sensing and inflammation in a way that could address both symptoms simultaneously.","specificNumbers":"CBG reduced IL-6, IL-8, and MMP-3 production in TNF-stimulated RASF cells. Calcium signaling through TRPA1 was activated only in inflamed (TNF-stimulated) cells, not in unstimulated cells. TRPA1 antagonists partially blocked CBG's anti-inflammatory effects, indicating TRPA1 is one but not the only mechanism. Effects were also observed in PBMCs from RA patients.","methodology":"In vitro study using rheumatoid arthritis synovial fibroblasts (RASF) stimulated with TNF for 72 hours, and peripheral blood mononuclear cells (PBMCs) from RA patients. Cells were treated with CBG and TRPA1 antagonists to determine mechanism of action. Inflammatory markers (IL-6, IL-8, MMP-3, cytokines), calcium signaling, and TRPA1-dependent effects were measured.","limitations":"In vitro study only — cells in a dish don't behave the same as cells in a living joint. The anti-inflammatory effects of CBG in lab conditions may not translate to clinical benefit in patients. No dosing information relevant to human use can be derived from this study. The partial dependence on TRPA1 means the full mechanism isn't understood. RA has multiple inflammatory pathways; reducing a few cytokines may not produce meaningful clinical improvement."},{"rthcId":"RTHC-04731","title":"Cannabidiol: Influence on B Cells, Peripheral Blood Mononuclear Cells, and Peripheral Blood Mononuclear Cell/Rheumatoid Arthritis Synovial Fibroblast Cocultures.","authors":"Lowin, Torsten; Laaser, Sofia Anna; Kok, Christina; Bruneau, Eileen; Pongratz, Georg","year":2023,"journal":"Cannabis and cannabinoid research, 8(2), 321-334","doi":"10.1089/can.2021.0241","pmid":"35920857","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD showed anti-inflammatory effects on B cells, PBMCs, and in co-cultures with rheumatoid arthritis synovial fibroblasts, helping identify which immune cell types mediate CBDs therapeutic effects in inflammatory arthritis.","whyItMatters":"Understanding which specific immune cells respond to CBD helps explain its anti-inflammatory mechanisms and could inform development of cannabinoid-based treatments for rheumatoid arthritis and other autoimmune conditions.","specificNumbers":"The study tested CBD effects on B cells, peripheral blood mononuclear cells (PBMCs), and PBMC/RA synovial fibroblast co-cultures.","methodology":"In vitro immunology study examining CBD effects on isolated immune cell populations and co-culture systems.","limitations":"In vitro findings may not translate to in vivo effects; isolated cell systems lack the complexity of the whole immune environment; CBD concentrations may not reflect achievable tissue levels."},{"rthcId":"RTHC-04732","title":"Beyond Pain Relief: A Review on Cannabidiol Potential in Medical Therapies.","authors":"Luz-Veiga, Mariana; Azevedo-Silva, João; Fernandes, João C","year":2023,"journal":"Pharmaceuticals (Basel, Switzerland), 16(2)","doi":"10.3390/ph16020155","pmid":"37259306","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD demonstrates pharmacological potential across multiple medical domains including neurological disorders, psychiatric conditions, inflammatory diseases, and cardiovascular health, though most evidence remains preclinical.","whyItMatters":"As CBD products proliferate commercially, a comprehensive scientific review of its actual therapeutic potential helps separate evidence-based applications from marketing hype.","specificNumbers":"CBD lacks the psychoactive effects of THC and has become an attractive compound for pharmacological use across multiple therapeutic areas.","methodology":"Comprehensive review article synthesizing evidence on CBDs medical applications beyond pain management.","limitations":"Broad scope may sacrifice depth; evidence quality varies dramatically across conditions reviewed; commercial CBD products may not match research-grade formulations."},{"rthcId":"RTHC-04733","title":"Prophylactic Effects of Hemp Seed Oil on Perimenopausal Depression: A Role of HPA Axis.","authors":"Ma, Jiao; Guo, Chen-Yang; Li, Han-Bing; Wu, Su-Hui; Li, Gen-Lin","year":2023,"journal":"Journal of oleo science, 72(10), 939-955","doi":"10.5650/jos.ess23062","pmid":"37704445","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Hemp seed oil demonstrated prophylactic antidepressant effects in a perimenopausal depression model, with the mechanism involving modulation of the HPA (hypothalamic-pituitary-adrenal) axis and estrogen-like activity.","whyItMatters":"Perimenopausal depression affects many women during the menopausal transition, and current treatments have limitations. Hemp seed oil represents a nutritional approach that could complement existing therapies.","specificNumbers":"The study evaluated hemp seed oil, derived from Cannabis sativa L. (Moraceae), for antidepressant effects in a perimenopausal depression model with focus on HPA axis function.","methodology":"Preclinical study evaluating hemp seed oil effects on depression-like behaviors and HPA axis markers in a perimenopausal model.","limitations":"Animal model may not fully replicate human perimenopausal depression; hemp seed oil composition varies by source; prophylactic use design may not reflect real-world supplementation patterns."},{"rthcId":"RTHC-04734","title":"Neurophysiological error processing and addiction self-awareness correlates of reduced insight in cannabis use disorder.","authors":"Macatee, Richard J; Schermitzler, Brandon S; Minieri, Jessica B; Moeller, Scott J; Afshar, Kaveh; Preston, Thomas J","year":2023,"journal":"Addiction (Abingdon, England), 118(12), 2397-2412","doi":"10.1111/add.16321","pmid":"37612599","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CUD was characterized by impaired neurophysiological error processing that correlated with reduced addiction self-awareness (insight), suggesting a neural basis for why many people with CUD do not recognize their condition or seek treatment.","whyItMatters":"Low treatment-seeking in CUD may partly result from neurobiological changes that impair the very self-awareness needed to recognize problematic use, creating a self-perpetuating cycle.","specificNumbers":"CUD prevalence has increased while perceived risks of cannabis use and treatment-seeking rates have decreased.","methodology":"Neurophysiological study using EEG/ERP to measure error processing and correlating with measures of addiction insight and self-awareness.","limitations":"Cross-sectional design cannot determine if impaired insight precedes or results from CUD; error processing tasks may not fully capture real-world self-monitoring; sample size typical of neurophysiology studies."},{"rthcId":"RTHC-04735","title":"A Clinical Framework for Evaluating Cannabis Product Quality and Safety.","authors":"MacCallum, Caroline A; Lo, Lindsay A; Pistawka, Carly A; Boivin, Michael","year":2023,"journal":"Cannabis and cannabinoid research, 8(3), 567-574","doi":"10.1089/can.2021.0137","pmid":"35049330","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The framework provides clinicians with structured criteria for assessing cannabis product quality, including regulatory status, testing documentation, labeling accuracy, and contaminant screening, enabling informed clinical conversations.","whyItMatters":"As medical cannabis use grows, clinicians need practical tools to evaluate the wide range of products patients use, many of which vary dramatically in quality and may not match label claims.","specificNumbers":"The framework addresses the increase in medical cannabis use and the variety of available products that clinicians may encounter in practice.","methodology":"Clinical framework development for cannabis product quality and safety evaluation.","limitations":"Framework applicability varies by jurisdiction and regulatory environment; rapid market changes may outpace framework updates; not all product quality issues are visible to clinicians."},{"rthcId":"RTHC-04736","title":"Systemic Chronic Treatment with Cannabidiol in Carioca High- and Low-Conditioned Freezing Rats in the Neuropathic Pain Model: Evaluation of Pain Sensitivity.","authors":"Macêdo-Souza, Carolina; Maisonnette, Silvia Soares; Hallak, Jaime E; Crippa, José A; Zuardi, Antônio W; Landeira-Fernandez, J; Leite-Panissi, Christie Ramos Andrade","year":2023,"journal":"Pharmaceuticals (Basel, Switzerland), 16(7)","doi":"10.3390/ph16071003","pmid":"37513915","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CBD treatment effects on neuropathic pain varied by anxiety phenotype, with rats bred for high conditioned freezing (anxiety-prone) showing different pain sensitivity responses than low-freezing rats, supporting the anxiety-pain comorbidity framework.","whyItMatters":"The high comorbidity between anxiety and chronic pain suggests shared mechanisms. Understanding how CBD affects pain differently based on anxiety phenotype could lead to more personalized treatment approaches.","specificNumbers":"The study used Carioca High-Conditioned Freezing (CHF) and Low-Conditioned Freezing (CLF) rat lines in a neuropathic pain model with chronic systemic CBD.","methodology":"Preclinical study using selectively bred rat lines (high vs low anxiety) to evaluate chronic CBD effects on neuropathic pain sensitivity.","limitations":"Selectively bred rat lines may not represent the full spectrum of human anxiety-pain comorbidity; chronic systemic CBD dosing may not reflect clinical use patterns; animal pain models have inherent limitations."},{"rthcId":"RTHC-04737","title":"Phytocannabinoids - An Overview of the Analytical Methodologies for Detection and Quantification of Therapeutically and Recreationally Relevant Cannabis Compounds.","authors":"Madden, Olena; Walshe, Jessica; Kishore Patnala, Prem; Barron, John; Meaney, Claire; Murray, Patrick","year":2023,"journal":"Critical reviews in analytical chemistry, 53(1), 211-231","doi":"10.1080/10408347.2021.1949694","pmid":"34328047","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review catalogs and compares multiple analytical methods including chromatography, spectroscopy, and immunoassay techniques for cannabinoid detection and quantification, addressing the growing regulatory need for accurate cannabis product testing.","whyItMatters":"As CBD legalization expands globally and product markets grow, reliable analytical methods are essential for ensuring product safety, label accuracy, and regulatory compliance.","specificNumbers":"The review covers analytical methods for low-THC, high-CBD Cannabis sativa plants and products across countries where CBD products are legal.","methodology":"Review of analytical methodologies including chromatography, mass spectrometry, and other techniques for cannabinoid detection and quantification.","limitations":"Rapid methodology evolution may outpace review coverage; method performance varies by laboratory conditions; not all methods are equally accessible across regulatory environments."},{"rthcId":"RTHC-04738","title":"Cannabis use and its relationship with bipolar disorder: A systematic review and meta-analysis.","authors":"Maggu, Gaurav; Choudhary, Swati; Jaishy, Rajon; Chaudhury, Suprakash; Saldanha, Daniel; Borasi, Manish","year":2023,"journal":"Industrial psychiatry journal, 32(2), 202-214","doi":"10.4103/ipj.ipj_43_23","pmid":"38161465","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis use was associated with bipolar disorder, with evidence suggesting effects on the onset of first episodes, manic symptoms, and overall clinical course, extending the cannabis-psychosis literature to bipolar spectrum disorders.","whyItMatters":"While cannabis has been extensively linked to schizophrenia, its relationship with bipolar disorder has received less attention despite bipolar disorder being common and potentially influenced by substance use.","specificNumbers":"Systematic review and meta-analysis examining the repercussion of cannabis use on first episode onset and clinical features of bipolar disorder.","methodology":"Systematic review and meta-analysis of studies examining the relationship between cannabis use and bipolar disorder.","limitations":"Heterogeneity across included studies; observational designs predominate; confounding by shared genetic risk factors is difficult to control; direction of causation unclear."},{"rthcId":"RTHC-04739","title":"Current (but not ex) cigarette smoking is associated with worse cognitive performances in schizophrenia: results from the FACE-SZ cohort.","authors":"Mallet, Jasmina; Godin, Ophélia; Dansou, Yecodji; Mazer, Nicolas; Scognamiglio, Claire; Berna, Fabrice; Boyer, Laurent; Capdevielle, Delphine; Chéreau, Isabelle; D'Amato, Thierry; Dubreucq, Julien; Fond, Guillaume; Leigner, Sylvain; Llorca, Pierre-Michel; Misdrahi, David; Passerieux, Christine; Rey, Romain; Pignon, Baptiste; Urbach, Mathieu; Schorr, Benoit; Schürhoff, Franck; Yann, Le Strat; Dubertret, Caroline","year":2023,"journal":"Psychological medicine, 53(11), 5279-5290","doi":"10.1017/S0033291722002574","pmid":"36073848","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"In the FACE-SZ cohort, current smokers with schizophrenia showed worse cognitive performance than non-smokers and former smokers, contradicting the common assumption that nicotine provides cognitive benefits in schizophrenia.","whyItMatters":"Tobacco use is extremely common in schizophrenia, often rationalized as self-medication for cognitive deficits. Finding that smoking is actually associated with worse cognition challenges this narrative and supports cessation efforts.","specificNumbers":"Results from the FACE-SZ cohort of stabilized schizophrenia outpatients, examining tobacco use status and comprehensive cognitive assessment.","methodology":"Cross-sectional cohort study using the FACE-SZ database to compare cognitive performance across smoking status groups in stabilized schizophrenia patients.","limitations":"Cross-sectional design cannot determine if smoking causes cognitive decline or if lower cognitive function predisposes to smoking; cohort effects possible; medication differences between groups."},{"rthcId":"RTHC-04740","title":"Effective isolation of cannabidiol and cannabidiolic acid free of psychotropic phytocannabinoids from hemp extract by fast centrifugal partition chromatography.","authors":"Maly, Matej; Benes, Frantisek; Binova, Zuzana; Zlechovcova, Marie; Kastanek, Petr; Hajslova, Jana","year":2023,"journal":"Analytical and bioanalytical chemistry, 415(19), 4827-4837","doi":"10.1007/s00216-023-04782-9","pmid":"37382652","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Fast centrifugal partition chromatography (FCPC) achieved effective isolation of CBD and CBDA from hemp extract while eliminating psychotropic cannabinoids, providing a scalable purification method for pharmaceutical and consumer product applications.","whyItMatters":"Ensuring CBD products are free of THC is critical for legal compliance, consumer safety, and pharmaceutical applications. Efficient purification methods enable high-quality CBD production at scale.","specificNumbers":"CBD and CBDA are the major phytocannabinoids in most hemp cultivars. The FCPC method specifically eliminated delta-9-THC and other psychotropic compounds.","methodology":"Analytical chemistry study developing and validating fast centrifugal partition chromatography for cannabinoid isolation from hemp extract.","limitations":"FCPC equipment costs may limit accessibility for smaller producers; method optimization may be needed for different hemp cultivar extracts; scale-up validation needed."},{"rthcId":"RTHC-04741","title":"Cannabis and Driving: Developing Guidelines for Safety Policies.","authors":"Manetti, Federico; Chericoni, Silvio; Marrocco, Anna; Scopetti, Matteo; Padovano, Martina; Santurro, Alessandro; Frati, Paola; Gabbrielli, Mario; Fineschi, Vittorio","year":2023,"journal":"Current pharmaceutical biotechnology, 24(6), 719-727","doi":"10.2174/1389201023666220616160459","pmid":"35713145","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Current evidence highlights significant challenges in developing cannabis driving policies, including the poor correlation between blood THC levels and actual impairment, the lack of validated roadside tests, and the need for evidence-based rather than arbitrary safety thresholds.","whyItMatters":"As cannabis becomes legal in more jurisdictions, the absence of scientifically validated driving safety guidelines creates both public safety risks and potential injustice for cannabis users.","specificNumbers":"The review addresses the growing regulatory frameworks concerning cannabinoid consumption and their effects on cognitive and psychomotor skills relevant to driving.","methodology":"Review synthesizing evidence on cannabis effects on driving performance and existing regulatory approaches to cannabis-impaired driving.","limitations":"Evidence base is still developing; individual variation in impairment makes universal thresholds difficult; comparison across jurisdictions complicated by different legal frameworks."},{"rthcId":"RTHC-04742","title":"Increasing risk of cannabis use disorder among U.S. veterans with chronic pain: 2005-2019.","authors":"Mannes, Zachary L; Malte, Carol A; Olfson, Mark; Wall, Melanie M; Keyes, Katherine M; Martins, Silvia S; Cerdá, Magdalena; Gradus, Jaimie L; Saxon, Andrew J; Keyhani, Salomeh; Maynard, Charles; Livne, Ofir; Fink, David S; Gutkind, Sarah; Hasin, Deborah S","year":2023,"journal":"Pain, 164(9), 2093-2103","doi":"10.1097/j.pain.0000000000002920","pmid":"37159542","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Time trend analysis showed increasing rates of cannabis use disorder among VHA patients with chronic pain from 2005 to 2019, suggesting that expanded cannabis access may be contributing to growing problematic use in this vulnerable population.","whyItMatters":"Veterans are disproportionately affected by chronic pain and may turn to cannabis for symptom management, but rising CUD rates indicate that some are developing problematic patterns that require clinical attention.","specificNumbers":"The study examined trends in cannabis use disorder from 2005 to 2019 among Veterans Health Administration patients with chronic pain.","methodology":"Retrospective time-trend analysis of VHA electronic health records examining CUD diagnoses among chronic pain patients from 2005-2019.","limitations":"Administrative data may undercount CUD if not diagnosed; changes in screening and diagnostic practices over time may inflate trends; pain and CUD definitions may have evolved."},{"rthcId":"RTHC-04743","title":"Effect of CannEpil® on simulated driving performance and co-monitoring of ocular activity: A randomised controlled trial.","authors":"Manning, Brooke; Hayley, Amie C; Catchlove, Sarah; Shiferaw, Brook; Stough, Con; Downey, Luke A","year":2023,"journal":"Journal of psychopharmacology (Oxford, England), 37(5), 472-483","doi":"10.1177/02698811231170360","pmid":"37129083","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study assessed the impact of a standardized sublingual dose of CannEpil (a THC-containing medical cannabis product) on simulated driving performance and ocular metrics, providing data to inform fitness-to-drive guidelines.","whyItMatters":"Medical cannabis patients need evidence-based guidance about when they can safely drive. This RCT provides specific data on a standardized product and dose to help develop driving safety policies.","specificNumbers":"The study tested a standardized 1 mL sublingual dose of CannEpil, a medicinal cannabis product containing THC, using simulated driving and eye tracking assessments.","methodology":"Randomized controlled trial measuring simulated driving performance and ocular activity following sublingual CannEpil administration.","limitations":"Simulated driving may not fully represent real-world driving; single dose assessment; individual tolerance variation; specific product may not represent all medical cannabis formulations."},{"rthcId":"RTHC-04744","title":"Cadmium exposure is associated with increased transcript abundance of multiple heavy metal associated transporter genes in roots of hemp (Cannabis sativa L.).","authors":"Marabesi, Amanda O; Nambeesan, Savithri U; van Iersel, Marc W; Lessl, Jason T; Coolong, Timothy W","year":2023,"journal":"Frontiers in plant science, 14, 1183249","doi":"10.3389/fpls.2023.1183249","pmid":"37324677","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Hemp roots responded to cadmium exposure by upregulating multiple heavy metal-associated transporter genes, providing molecular evidence for how hemp manages heavy metal uptake and tolerance, relevant to its use in environmental cleanup.","whyItMatters":"Hemp is being explored for phytoremediation (using plants to clean contaminated soil), and understanding the genetic mechanisms of metal uptake helps optimize this application and prevents contamination of food/fiber crops.","specificNumbers":"Industrial hemp showed increased transcript abundance of multiple heavy metal-associated transporter genes in roots when exposed to cadmium.","methodology":"Molecular biology study using gene expression analysis (transcriptomics) to identify cadmium-responsive transporter genes in hemp roots.","limitations":"Gene expression changes do not always translate to protein function; laboratory growing conditions differ from contaminated field sites; single heavy metal tested."},{"rthcId":"RTHC-04745","title":"\"Spice Was Made, by the Devil Himself\": A Thematic Analysis of the Experience of an Addiction to Synthetic Cannabinoids.","authors":"Marandure, Blessing N; Mhizha, Samson; Wilson, Amanda","year":2023,"journal":"Journal of psychoactive drugs, 55(3), 321-329","doi":"10.1080/02791072.2022.2083534","pmid":"35640052","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Thematic analysis revealed that synthetic cannabinoid addiction was experienced as qualitatively different from and more severe than natural cannabis dependence, with themes of intense compulsion, loss of control, and physical dependence that users described in extreme language.","whyItMatters":"Synthetic cannabinoids are often used as cannabis substitutes but produce far more dangerous addiction patterns. Understanding the lived experience of SC addiction can inform treatment and public education.","specificNumbers":"Synthetic cannabinoids are the most common type of new psychoactive substances, used predominantly as a replacement for cannabis.","methodology":"Qualitative thematic analysis of interviews with people who have experienced addiction to synthetic cannabinoids.","limitations":"Qualitative design cannot quantify prevalence; self-selected participants may represent more severe cases; retrospective accounts may be affected by recall bias."},{"rthcId":"RTHC-04746","title":"Evaluation of Field Sobriety Tests for Identifying Drivers Under the Influence of Cannabis: A Randomized Clinical Trial.","authors":"Marcotte, Thomas D; Umlauf, Anya; Grelotti, David J; Sones, Emily G; Mastropietro, Kyle F; Suhandynata, Raymond T; Huestis, Marilyn A; Grant, Igor; Fitzgerald, Robert L","year":2023,"journal":"JAMA psychiatry, 80(9), 914-923","doi":"10.1001/jamapsychiatry.2023.2345","pmid":"37531115","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Field sobriety tests, the gold standard for alcohol-impaired driving detection, showed limited sensitivity and specificity for identifying THC-impaired drivers, highlighting the need for cannabis-specific impairment evaluation tools.","whyItMatters":"As cannabis legalization expands, law enforcement relies on field sobriety tests designed for alcohol to detect cannabis impairment. This RCT provides evidence on whether that approach is scientifically valid.","specificNumbers":"The randomized clinical trial evaluated standard field sobriety tests for detecting THC impairment with increasing cannabis legalization.","methodology":"Randomized clinical trial administering cannabis or placebo and evaluating field sobriety test performance.","limitations":"Controlled dosing may not reflect real-world cannabis consumption patterns; FSTs may be affected by factors unrelated to impairment; single-dose design."},{"rthcId":"RTHC-04747","title":"The impact of recreational cannabis markets on motor vehicle accident, suicide, and opioid overdose fatalities.","authors":"Marinello, Samantha; Powell, Lisa M","year":2023,"journal":"Social science & medicine (1982), 320, 115680","doi":"10.1016/j.socscimed.2023.115680","pmid":"36764087","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study assessed health impacts of recreational cannabis markets on three mortality outcomes, with preliminary evidence suggesting varied effects on traffic fatalities, suicides, and opioid overdose deaths across states.","whyItMatters":"Understanding the broader public health consequences of recreational cannabis commercialization is essential for evidence-based policy as more states consider legalization.","specificNumbers":"The study examined states that legalized regulated commercial markets for recreational cannabis, allowing private industry to sell marijuana to those 21 and older.","methodology":"Quasi-experimental policy analysis examining mortality trends before and after recreational cannabis market implementation across US states.","limitations":"State-level ecological design; other concurrent policy changes may confound results; cannabis market maturation takes time; data availability varies across states."},{"rthcId":"RTHC-04748","title":"Cyclic AMP Assay Using Human Cannabinoid CB2 Receptor-Transfected Cells.","authors":"Marini, Pietro; Cascio, Maria Grazia; Pertwee, Roger G","year":2023,"journal":"Methods in molecular biology (Clifton, N.J.), 2576, 171-179","doi":"10.1007/978-1-0716-2728-0_13","pmid":"36152185","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study provides a standardized methodology for using cyclic AMP assays with CB2 receptor-transfected cells to characterize the pharmacological behavior of cannabinoid receptor ligands.","whyItMatters":"Standardized assay protocols are essential for cannabinoid drug discovery, enabling consistent comparison of new compounds across laboratories and accelerating development of CB2-targeted therapeutics.","specificNumbers":"The protocol uses commercially available nonradioligand ready-to-use kits for cyclic AMP measurement in CB2-transfected cells.","methodology":"Laboratory protocol describing cyclic AMP functional assay methodology for CB2 receptor pharmacology.","limitations":"In vitro assay may not predict in vivo pharmacology; transfected cell systems may not fully represent endogenous receptor expression; single readout of receptor function."},{"rthcId":"RTHC-04749","title":"The interplay between kisspeptin and endocannabinoid systems modulates male hypothalamic and gonadic control of reproduction in vivo.","authors":"Marino, Marianna; D'Auria, Raffaella; Mele, Elena; Pastorino, Grazia Maria Giovanna; Di Pietro, Paola; D'Angelo, Stefania; Della Rocca, Natalia; Operto, Francesca Felicia; Vecchione, Carmine; Fasano, Silvia; Pierantoni, Riccardo; Viggiano, Andrea; Meccariello, Rosaria; Santoro, Antonietta","year":2023,"journal":"Frontiers in endocrinology, 14, 1269334","doi":"10.3389/fendo.2023.1269334","pmid":"37900144","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study demonstrated functional interaction between the endocannabinoid system and kisspeptin system in regulating male reproduction, affecting both hypothalamic hormone signaling and gonadal function.","whyItMatters":"Cannabis use has been associated with reduced male fertility, and understanding the molecular mechanisms through which endocannabinoids affect reproductive hormones could explain these clinical observations.","specificNumbers":"The study examined interactions between the ECS and kisspeptin system in the hypothalamus-pituitary-gonadal (HPG) axis controlling male reproduction.","methodology":"In vivo animal study examining the interaction between endocannabinoid and kisspeptin signaling systems in male reproductive regulation.","limitations":"Animal model findings may not directly translate to human reproductive physiology; pharmacological manipulation may not reflect endogenous system dynamics; acute vs chronic effects may differ."},{"rthcId":"RTHC-04750","title":"Caregivers' Perspectives on the Impact of Cannabidiol (CBD) Treatment for Dravet and Lennox-Gastaut Syndromes: A Multinational Qualitative Study.","authors":"Marshall, Jade; Skrobanski, Hanna; Moore-Ramdin, Lisa; Kornalska, Klaudia; Swinburn, Paul; Bowditch, Sally","year":2023,"journal":"Journal of child neurology, 38(6-7), 394-406","doi":"10.1177/08830738231185241","pmid":"37455396","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Qualitative interviews with caregivers revealed that CBD treatment produced meaningful benefits beyond seizure reduction, including improvements in alertness, behavior, cognition, and overall quality of life for individuals with Dravet and Lennox-Gastaut syndromes.","whyItMatters":"Clinical trials focus on seizure frequency, but caregivers care about broader quality of life. Understanding these additional benefits helps justify CBD treatment and set realistic expectations.","specificNumbers":"Multinational qualitative study interviewing caregivers of individuals with Dravet syndrome or Lennox-Gastaut syndrome treated with plant-derived CBD.","methodology":"Multinational qualitative interview study with caregivers of individuals treated with pharmaceutical CBD for Dravet or Lennox-Gastaut syndrome.","limitations":"Qualitative design cannot establish causation; caregiver reports may be influenced by expectations; no placebo comparison; multinational sample may reflect different healthcare contexts."},{"rthcId":"RTHC-04751","title":"Prenatal risk factors and postnatal cannabis exposure: Assessing dual models of schizophrenia-like rodents.","authors":"Martín-Cuevas, Celia; Ramos-Herrero, Víctor Darío; Crespo-Facorro, Benedicto; Sánchez-Hidalgo, Ana C","year":2023,"journal":"Neuroscience and biobehavioral reviews, 154, 105409","doi":"10.1016/j.neubiorev.2023.105409","pmid":"37783300","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The combination of prenatal risk factors and postnatal cannabis exposure produced more comprehensive schizophrenia-like behavioral and neurobiological changes in rodents than either hit alone, supporting the multifactorial neurodevelopmental model of schizophrenia.","whyItMatters":"Schizophrenia likely results from multiple interacting risk factors. Understanding how prenatal vulnerability combines with adolescent cannabis exposure advances both prevention strategies and mechanistic understanding.","specificNumbers":"The study assessed dual models combining prenatal genetic/environmental risk factors with postnatal cannabis exposure in rodent models of schizophrenia.","methodology":"Preclinical dual-hit model study combining prenatal risk factors with postnatal cannabis exposure to model schizophrenia-like phenotypes in rodents.","limitations":"Rodent models cannot fully replicate human schizophrenia; specific prenatal risk factors may not represent the full range of human vulnerability; cannabis exposure protocols differ from human use patterns."},{"rthcId":"RTHC-04752","title":"Sex differences in endocannabinoid tone in a pilot study of cannabis use disorder and acute cannabis abstinence.","authors":"Martin, Erin L; Baker, Nathaniel L; Sempio, Cristina; Christians, Uwe; Klawitter, Jost; McRae-Clark, Aimee L","year":2023,"journal":"Addiction biology, 28(10), e13337","doi":"10.1111/adb.13337","pmid":"37753564","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Men and women with CUD showed different endocannabinoid system profiles during active use and acute abstinence, suggesting that pharmacotherapies targeting the endocannabinoid system may need to account for biological sex.","whyItMatters":"CUD presents differently in men and women, particularly in withdrawal symptoms. Understanding underlying sex differences in endocannabinoid function could enable more effective, personalized treatments.","specificNumbers":"Pilot study examining endocannabinoid tone differences between men and women with cannabis use disorder during active use and acute abstinence.","methodology":"Pilot clinical study measuring endocannabinoid levels in men and women with CUD during active use and acute cannabis abstinence.","limitations":"Pilot study with small sample size; endocannabinoid levels measured peripherally may not reflect central nervous system levels; confounding factors like menstrual cycle phase."},{"rthcId":"RTHC-04753","title":"Endocannabinoid signaling in the central nervous system.","authors":"Martinez Ramirez, César E; Ruiz-Pérez, Gonzalo; Stollenwerk, Todd M; Behlke, Christina; Doherty, Ashley; Hillard, Cecilia J","year":2023,"journal":"Glia, 71(1), 5-35","doi":"10.1002/glia.24280","pmid":"36308424","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The endocannabinoid signaling system profoundly influences CNS function through retrograde signaling, modulating neurotransmitter release, synaptic plasticity, and neural circuit activity across virtually all brain regions.","whyItMatters":"Understanding how the endocannabinoid system works in the brain is fundamental to both explaining cannabis effects and developing targeted cannabinoid therapeutics for neurological and psychiatric conditions.","specificNumbers":"Over 40 years of research since cannabinoids were first found to trigger specific cell signaling cascades in the central nervous system.","methodology":"Comprehensive review of 40+ years of endocannabinoid signaling research in the central nervous system.","limitations":"Broad scope may sacrifice depth on specific topics; rapidly evolving field means some findings may be updated; complexity of ECS makes comprehensive coverage challenging."},{"rthcId":"RTHC-04754","title":"Effectiveness and Safety of Cannabinoids as an Add-On Therapy in the Treatment of Resistant Spasticity in Multiple Sclerosis: A Systematic Review.","authors":"Martinez-Paz, Carmen; García-Cabrera, Emilio; Vilches-Arenas, Ángel","year":2023,"journal":"Cannabis and cannabinoid research, 8(4), 580-588","doi":"10.1089/can.2022.0254","pmid":"37057959","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabinoids demonstrated effectiveness in reducing resistant spasticity in MS patients when used as add-on therapy, with an acceptable safety profile, supporting their use when standard treatments are insufficient.","whyItMatters":"Spasticity is one of the most common and disabling MS symptoms, and many patients dont respond adequately to first-line treatments. Evidence supporting cannabinoids as add-on therapy expands treatment options.","specificNumbers":"The systematic review evaluated cannabinoid effectiveness and safety specifically for treatment-resistant spasticity in MS patients.","methodology":"Systematic review of clinical evidence on cannabinoids as add-on therapy for resistant spasticity in multiple sclerosis.","limitations":"Heterogeneity in cannabinoid formulations, doses, and outcome measures across studies; definition of treatment-resistant varies; most studies have moderate sample sizes."},{"rthcId":"RTHC-04755","title":"Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance.","authors":"Martini, Stefano; Gemma, Alessandra; Ferrari, Marco; Cosentino, Marco; Marino, Franca","year":2023,"journal":"International journal of molecular sciences, 24(4)","doi":"10.3390/ijms24043125","pmid":"36834537","tags":["cbd","inflammation","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"CBD has FDA approval for epilepsy (Epidiolex), but its anti-inflammatory and immunomodulatory effects have attracted attention for conditions ranging from autoimmune diseases to COVID-19. This review cataloged what's actually known about how CBD affects the innate immune system — the body's first line of defense against pathogens and tissue damage.\n\nThe evidence base is extensive in preclinical models. Across experiments in mice, rats, guinea pigs, and human cells studied outside the body, CBD consistently reduced inflammatory responses: it decreased production of pro-inflammatory cytokines, reduced immune cell migration to sites of inflammation, and modulated the activity of macrophages, neutrophils, and natural killer cells. The effects were seen across multiple disease models, from sepsis to lung inflammation to neuroinflammation.\n\nBut here's the critical gap: as of this review, not a single clinical trial had tested CBD's immune-modulating effects in human patients with inflammatory diseases. All the evidence comes from animal models and ex vivo experiments on human cells. The translation from 'CBD reduces inflammation in a mouse' to 'CBD treats inflammatory disease in a person' remains completely untested.\n\nThe review also notes CBD's complex pharmacology — it acts through multiple receptors and pathways (CB2, GPR55, PPARγ, adenosine receptors, among others), making its immune effects difficult to predict and potentially variable depending on the disease context.","whyItMatters":"The disconnect between preclinical promise and clinical evidence is a defining problem in CBD research. Millions of people use CBD products for inflammatory conditions — arthritis, autoimmune diseases, chronic pain — based largely on this preclinical evidence. This review makes clear that while the laboratory evidence is genuinely promising, the clinical evidence that would actually prove benefit in humans is completely absent.","specificNumbers":"CBD reduced pro-inflammatory cytokine production across multiple models. Effects were observed on macrophages, neutrophils, natural killer cells, and dendritic cells. CBD acts through CB2, GPR55, PPARγ, adenosine A2A, and TRPV1 receptors, among others. Zero clinical trials of CBD for inflammatory/immune conditions were identified as of the review date.","methodology":"Narrative review of preclinical evidence for CBD's effects on innate immunity. Covered studies in mice, rats, guinea pigs, and ex vivo experiments on human immune cells. Examined effects on cytokine production, immune cell migration, macrophage function, neutrophil activity, and natural killer cell function across various disease models.","limitations":"Narrative review, not systematic — may not capture all relevant preclinical literature. The biggest limitation is the one the authors themselves emphasize: no clinical trials exist. Animal immune responses differ from human ones in important ways, and many drugs that work brilliantly in mice fail in humans. The multi-receptor pharmacology of CBD means that immune effects observed in one context may not apply to others."},{"rthcId":"RTHC-04756","title":"Impact of Childhood Trauma Exposure, Genetic Variation in Endocannabinoid Signaling, and Anxiety on Frontolimbic Pathways in Children.","authors":"Marusak, Hilary A; Evanski, Julia; Desai, Shreya; Rabinak, Christine A","year":2023,"journal":"Cannabis and cannabinoid research, 8(6), 1079-1089","doi":"10.1089/can.2022.0144","pmid":"35944262","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"A common variant in the FAAH gene (C385A) interacted with childhood trauma exposure and anxiety to influence frontolimbic white matter pathways in children, suggesting the endocannabinoid system mediates trauma-related brain development changes.","whyItMatters":"Understanding how endocannabinoid genetics modify the impact of trauma on developing brains could identify children at highest risk for anxiety disorders and inform targeted prevention strategies.","specificNumbers":"The study examined the FAAH gene variant C385A (rs324420), which is associated with higher circulating endocannabinoid levels, lower anxiety, and altered frontolimbic connectivity.","methodology":"Neuroimaging genetics study examining interactions between FAAH genotype, childhood trauma, and anxiety on brain white matter pathways in children.","limitations":"Cross-sectional neuroimaging limits causal inference; gene-environment interactions require large samples; single genetic variant does not capture full ECS variation."},{"rthcId":"RTHC-04757","title":"The Endocannabinoid System and Physical Exercise.","authors":"Matei, Daniela; Trofin, Dan; Iordan, Daniel Andrei; Onu, Ilie; Condurache, Iustina; Ionite, Catalin; Buculei, Ioana","year":2023,"journal":"International journal of molecular sciences, 24(3)","doi":"10.3390/ijms24031989","pmid":"36768332","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Physical exercise activates the endocannabinoid system, increasing circulating endocannabinoid levels and potentially contributing to the mood-enhancing, pain-relieving, and anti-inflammatory effects commonly attributed to exercise.","whyItMatters":"The runners high was long attributed to endorphins, but emerging evidence suggests endocannabinoids play a major role. Understanding this mechanism has implications for exercise prescriptions and cannabinoid therapy.","specificNumbers":"The ECS is involved in brain plasticity, learning, memory, neuronal development, nociception, inflammation, appetite, digestion, metabolism, energy balance, motility, and stress regulation.","methodology":"Review article examining the relationship between physical exercise and endocannabinoid system modulation.","limitations":"Exercise-ECS research is still emerging; measurement of endocannabinoids during exercise is technically challenging; individual variation in ECS response to exercise is poorly characterized."},{"rthcId":"RTHC-04758","title":"Association between cannabis use disorder symptom severity and probability of clinically-documented diagnosis and treatment in a primary care sample.","authors":"Matson, Theresa E; Williams, Emily C; Lapham, Gwen T; Oliver, Malia; Hallgren, Kevin A; Bradley, Katharine A","year":2023,"journal":"Drug and alcohol dependence, 251, 110946","doi":"10.1016/j.drugalcdep.2023.110946","pmid":"37688980","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The probability of a medical provider diagnosing and treating CUD increased with the number of substance use disorder symptoms endorsed, suggesting that brief screening followed by standardized assessment can support appropriate clinical responses.","whyItMatters":"CUD is widely underdiagnosed in primary care. Demonstrating that symptom severity predicts clinical action supports integrating brief cannabis screening into routine primary care visits.","specificNumbers":"The study tested associations between SUD symptom count and probability of clinically-documented CUD diagnosis and treatment in a primary care sample.","methodology":"Cross-sectional analysis of primary care patients examining the relationship between cannabis screening results and clinical documentation of CUD diagnosis and treatment.","limitations":"Cross-sectional design; primary care providers may vary in screening and diagnostic practices; documentation may not capture all clinical encounters about cannabis use."},{"rthcId":"RTHC-04759","title":"Associated and intermediate factors between genetic variants of the dopaminergic D2 receptor gene and harmful alcohol use in young adults.","authors":"Mattioni, Julia; Vansteene, Clément; Poupon, Daphnee; Gorwood, Philip; Ramoz, Nicolas","year":2023,"journal":"Addiction biology, 28(3), e13269","doi":"10.1111/adb.13269","pmid":"36825486","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"DRD2 and ANKK1 gene variants were associated with harmful alcohol use in young adults, with the relationship mediated by intermediate factors including behavioral and psychological variables.","whyItMatters":"Understanding the genetic pathways from dopamine receptor variation to harmful substance use helps identify at-risk individuals and potential intervention targets before problematic patterns develop.","specificNumbers":"Population-based case-control and genetic association study examining DRD2 and ANKK1 gene variants in relation to harmful alcohol use.","methodology":"Population-based case-control and genetic association study examining dopaminergic gene variants and mediating factors in harmful alcohol use.","limitations":"Genetic association studies require large samples for reliable effect sizes; intermediate factors are correlational; specific genetic mechanisms unclear; population-specific findings may not generalize."},{"rthcId":"RTHC-04760","title":"Effects of Oral Cannabinoids on Systemic Inflammation and Viral Reservoir Markers in People with HIV on Antiretroviral Therapy: Results of the CTN PT028 Pilot Clinical Trial.","authors":"Mboumba Bouassa, Ralph-Sydney; Comeau, Eve; Alexandrova, Yulia; Pagliuzza, Amélie; Yero, Alexis; Samarani, Suzanne; Needham, Judy; Singer, Joel; Lee, Terry; Bobeuf, Florian; Vertzagias, Claude; Sebastiani, Giada; Margolese, Shari; Mandarino, Enrico; Klein, Marina B; Lebouché, Bertrand; Routy, Jean-Pierre; Chomont, Nicolas; Costiniuk, Cecilia T; Jenabian, Mohammad-Ali","year":2023,"journal":"Cells, 12(14)","doi":"10.3390/cells12141811","pmid":"37508476","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Oral cannabinoid administration in PWH on ART showed effects on systemic inflammation markers and HIV viral reservoir measurements, supporting larger studies of cannabinoids as adjunctive anti-inflammatory therapy in HIV.","whyItMatters":"Despite viral suppression with ART, chronic HIV infection causes persistent inflammation that contributes to non-AIDS comorbidities. Cannabinoids could address this residual inflammation as an adjunctive treatment.","specificNumbers":"Ten people with HIV on ART were randomized (n=5 per group) to increasing doses of oral cannabinoids in this pilot trial (CTN PT028).","methodology":"Pilot randomized clinical trial with 10 PWH on ART receiving escalating doses of oral cannabinoids.","limitations":"Very small sample size (n=10); pilot design not powered for definitive conclusions; short treatment duration; diverse cannabinoid dosing complicates interpretation."},{"rthcId":"RTHC-04761","title":"The \"Next Day\" Effects of Cannabis Use: A Systematic Review.","authors":"McCartney, Danielle; Suraev, Anastasia; McGregor, Iain S","year":2023,"journal":"Cannabis and cannabinoid research, 8(1), 92-114","doi":"10.1089/can.2022.0185","pmid":"36475998","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The review found that next-day cognitive and psychomotor effects of THC are possible but inconsistent, with effects varying by dose, frequency of use, and the specific cognitive domains assessed.","whyItMatters":"Next-day cannabis effects have major implications for driving, workplace safety, and daily functioning. Clarifying whether impairment persists helps set evidence-based waiting periods for safety-sensitive activities.","specificNumbers":"THC is the main intoxicating component of cannabis, and the review examined whether impairment persists many hours or days after use.","methodology":"Systematic review of studies examining cognitive and psychomotor performance at time points beyond acute cannabis intoxication.","limitations":"Heterogeneity in study designs, doses, assessment timing, and outcome measures; few studies specifically designed to assess next-day effects; tolerance effects complicate interpretation."},{"rthcId":"RTHC-04762","title":"Effects of U.S. State Medical Cannabis Laws on Treatment of Chronic Noncancer Pain.","authors":"McGinty, Emma E; Tormohlen, Kayla N; Seewald, Nicholas J; Bicket, Mark C; McCourt, Alexander D; Rutkow, Lainie; White, Sarah A; Stuart, Elizabeth A","year":2023,"journal":"Annals of internal medicine, 176(7), 904-912","doi":"10.7326/M23-0053","pmid":"37399549","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study assessed whether state medical cannabis laws led to substitution of cannabis for prescription opioids or guideline-concordant nonopioid pain medications, examining actual prescribing patterns rather than self-report.","whyItMatters":"If medical cannabis laws lead patients to substitute cannabis for opioids, this could help address the opioid crisis. But if they substitute cannabis for evidence-based nonopioid treatments, the net effect may be negative.","specificNumbers":"The study assessed effects of state medical cannabis laws on receipt of prescription opioids, nonopioid prescription pain medications, and clinical procedures for chronic noncancer pain.","methodology":"Policy analysis examining prescription patterns for chronic noncancer pain before and after implementation of state medical cannabis laws.","limitations":"State-level policy analysis may miss individual variation; concurrent policy changes could confound results; substitution patterns may differ between medical and recreational cannabis access."},{"rthcId":"RTHC-04763","title":"Problem gambling severity, gambling behavior, substance use, and mental health in gamblers who do and do not use cannabis: Evidence from a Canadian national sample.","authors":"McGrath, Daniel S; Williams, Robert J; Rothery, Brett; Belanger, Yale D; Christensen, Darren R; El-Guebaly, Nady; Hodgins, David C; Nicoll, Fiona; Shaw, Carrie A; Smith, Garry J; Stevens, Rhys M G","year":2023,"journal":"Addictive behaviors, 137, 107520","doi":"10.1016/j.addbeh.2022.107520","pmid":"36257248","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis-using gamblers exhibited more severe problem gambling, greater overall substance use, and worse mental health outcomes compared to gamblers who do not use cannabis, from a nationally representative Canadian sample.","whyItMatters":"Understanding the co-occurrence of cannabis use and gambling problems can improve screening and treatment approaches for both conditions, which frequently appear together.","specificNumbers":"Data from a Canadian national sample comparing gambling behavior, problem severity, substance use, and mental health between cannabis-using and non-using gamblers.","methodology":"Cross-sectional analysis of a Canadian nationally representative sample comparing gambling and mental health outcomes by cannabis use status.","limitations":"Cross-sectional design cannot determine directionality; national sample may underrepresent severe gambling populations; self-reported cannabis use and gambling behavior."},{"rthcId":"RTHC-04764","title":"Perceived Effectiveness of Medical Cannabis Among Adults with Chronic Pain: Findings from Interview Data in a Three-Month Pilot Study.","authors":"McMahon, Alexandra N; Varma, Deepthi S; Fechtel, Hannah; Sibille, Kimberly; Li, Zhigang; Cook, Robert L; Wang, Yan","year":2023,"journal":"Cannabis (Albuquerque, N.M.), 6(2), 62-75","doi":"10.26828/cannabis/2023/000149","pmid":"37484052","tags":["pain","medical-cannabis","anxiety","sleep","mental-health"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Patient experience data is often overlooked in cannabis research, where the focus tends to be on controlled trials. This pilot study did something simple but valuable: interviewed 51 adults who were newly starting medical cannabis for chronic pain and asked them how it was going after about one month.\n\nThe majority (62.7%) reported medical cannabis was overall effective. The benefits went beyond just pain reduction. Patients commonly reported reduced pain intensity as expected, but also decreased anxiety, improved physical functioning, better sleep quality, and improved mood. Perhaps most notably, many reported reducing their use of both pain medications and psychiatric medications.\n\nThe challenges patients reported were equally informative. Finding the right product, dose, and route of administration was the most common difficulty. Many described a trial-and-error process with minimal guidance from either their certifying physician or the dispensary staff. Cost was another barrier — medical cannabis is not covered by insurance, and some patients found the ongoing expense unsustainable.\n\nSome patients experienced side effects including excessive sedation, dry mouth, and cognitive effects. A few reported the cannabis wasn't effective at all for their pain. The interviews revealed a complex picture: medical cannabis helped most patients, but the path to finding the right approach was often frustrating and poorly supported.","whyItMatters":"Controlled trials tell us whether a drug works on average; patient-reported outcomes tell us whether it works in practice. For medical cannabis — where products, doses, and routes of administration vary enormously — the patient experience is especially important. This study captures the messy reality of being a new medical cannabis patient: the hope, the frustration of finding the right product, and the gap between getting a cannabis card and getting effective treatment.","specificNumbers":"51 participants interviewed. 62.7% reported overall effectiveness. Mean age 54.4 years (SD 12.0). 24 women, 27 men. Commonly reported benefits: reduced pain intensity, decreased anxiety, reduced medication use, improved physical functioning, better sleep, improved mood. Common challenges: finding the right product/dose, cost, side effects.","methodology":"Qualitative analysis of interview data from 51 adults newly initiating medical cannabis for chronic pain, conducted approximately one month after starting use. Participants were part of a three-month pilot study. Demographics: 24 women, 27 men, mean age 54.4, majority Non-Hispanic White (n=41). Responses analyzed using the RADaR (Rigorous and Accelerated Data Reduction) technique.","limitations":"Small pilot study with only 51 participants, predominantly White, from one geographic area. One-month follow-up is very early — perceived effectiveness may change over time (tolerance could reduce benefits, or patients might find better products). Self-selected sample — people who stayed in the study may differ from those who dropped out. Interview data captures perceptions, not objective outcomes. No placebo comparison — some of the reported benefit may reflect placebo response or expectation effects."},{"rthcId":"RTHC-04765","title":"Emerging adult perceptions of higher-risk cannabis consumption behaviours.","authors":"McMahon, Isobel; Harris-Lane, Laura M; Donnan, Jennifer; Bishop, Lisa; Harris, Nick","year":2023,"journal":"Harm reduction journal, 20(1), 127","doi":"10.1186/s12954-023-00860-4","pmid":"37679733","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Young adults perceptions of higher-risk cannabis behaviors (such as high-potency use, early onset, daily use, and driving after use) varied significantly, with some risks underestimated and harm reduction guidelines not well known.","whyItMatters":"Emerging adults (18-25) have the highest cannabis use rates in Canada and are most vulnerable to harms. Understanding their risk perceptions can improve targeted harm reduction messaging.","specificNumbers":"Emerging adults have the highest cannabis consumption rates in Canada and are among the most vulnerable to cannabis-related harms.","methodology":"Qualitative study examining emerging adult perceptions of higher-risk cannabis consumption behaviors defined by the Lower-Risk Cannabis Use Guidelines.","limitations":"Qualitative design with limited sample; perceptions may not predict behavior; Canadian context may not generalize to other countries."},{"rthcId":"RTHC-04766","title":"Self-reported Medicinal Cannabis Use as an Alternative to Prescription and Over-the-counter Medication Use Among US Military Veterans.","authors":"McNabb, Marion; Durante, Katherine A; Trocchio, Sarah; Ritter, David J; MacCaffrie, Randal; Brum, Ann; Mandile, Stephen; White, Steven","year":2023,"journal":"Clinical therapeutics, 45(6), 562-577","doi":"10.1016/j.clinthera.2023.04.003","pmid":"37414507","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Veterans reported using medicinal cannabis as an alternative to prescription opioids, benzodiazepines, antidepressants, and OTC pain medications, suggesting cannabis is serving as a substitute for conventional pharmaceutical treatments in this population.","whyItMatters":"Veterans face disproportionately high rates of chronic pain, PTSD, and substance use disorder. Understanding their medicinal cannabis use patterns helps the VA system prepare for integrated care approaches.","specificNumbers":"Survey of US military veterans examining self-reported medicinal cannabis use as a substitute for various prescription and over-the-counter medications.","methodology":"Survey study of US military veterans examining medicinal cannabis use patterns and medication substitution behavior.","limitations":"Self-reported data; survey recruitment may bias toward cannabis-favorable respondents; no clinical verification of conditions or medication use; cross-sectional design."},{"rthcId":"RTHC-04767","title":"Up in Smoke: The Impacts of Marijuana During Pregnancy.","authors":"McPherson, Christopher","year":2023,"journal":"Neonatal network : NN, 42(4), 222-232","doi":"10.1891/NN-2022-0040","pmid":"37491043","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Prenatal marijuana exposure can affect fetal development through multiple mechanisms, with some effects visible at birth and others becoming apparent only through careful long-term follow-up into childhood.","whyItMatters":"Shifting legal and cultural attitudes toward marijuana are increasing prenatal exposure at a time when our understanding of long-term developmental consequences is still incomplete.","specificNumbers":"The review covers marijuana among drugs ingested during pregnancy that can impact the developing fetus, noting effects ranging from overt teratogenicity to subtle long-term developmental impacts.","methodology":"Narrative review of evidence on prenatal marijuana exposure effects on fetal and child development.","limitations":"Narrative review format; many underlying studies are observational with confounding factors; isolating marijuana effects from other substance use is challenging."},{"rthcId":"RTHC-04768","title":"Outdoor Medical Cannabis Advertising in Oklahoma: Examining Regulatory Compliance and Social Meanings in Billboard Content.","authors":"McQuoid, Julia; Lowery, Bryce C; Wright, LaNita S; Cohn, Amy M","year":2023,"journal":"Substance use & misuse, 58(11), 1425-1437","doi":"10.1080/10826084.2023.2223299","pmid":"37338932","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Analysis of medical cannabis billboard content in Oklahoma revealed inconsistent regulatory compliance and diverse social messaging strategies, with advertising potentially normalizing cannabis use and shaping public attitudes.","whyItMatters":"As medical cannabis advertising becomes ubiquitous, understanding billboard content and compliance helps regulators protect public health while allowing legitimate business advertising.","specificNumbers":"Medical cannabis currently dominates the US cannabis advertising landscape, with the public increasingly exposed to outdoor advertising.","methodology":"Content analysis of outdoor medical cannabis billboard advertising in Oklahoma examining regulatory compliance and social messaging themes.","limitations":"Single-state study in Oklahoma which has a particularly large medical cannabis market; billboard content changes rapidly; analysis captures a point-in-time snapshot."},{"rthcId":"RTHC-04769","title":"Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats.","authors":"McReynolds, Jayme R; Wolf, Colten P; Starck, Dylan M; Mathy, Jacob C; Schaps, Rebecca; Krause, Leslie A; Hillard, Cecilia J; Mantsch, John R","year":2023,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 48(8), 1121-1132","doi":"10.1038/s41386-023-01589-1","pmid":"37188846","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CB1 receptors in the mesolimbic dopamine pathway mediated stress-induced escalation of cocaine self-administration, revealing a specific cannabinoid mechanism through which stress promotes drug seeking.","whyItMatters":"Stress is a major trigger for substance use relapse, and identifying specific neural mechanisms (like CB1 receptor signaling) could lead to targeted pharmacological interventions to prevent stress-induced drug seeking.","specificNumbers":"Male rats were exposed to stress and assessed for changes in cocaine self-administration behavior, with CB1 receptor manipulation in the mesolimbic pathway.","methodology":"Preclinical study using CB1 receptor manipulation in the mesolimbic pathway during stress-cocaine self-administration paradigms in male rats.","limitations":"Male-only study limits generalizability; pharmacological manipulation may not perfectly replicate natural CB1 signaling; cocaine self-administration model may not fully represent human relapse."},{"rthcId":"RTHC-04770","title":"An Explanatory Model of Violent Behavior, Self-Concept, and Alcohol, Tobacco, and Cannabis Consumption in Secondary Education Students.","authors":"Melguizo-Ibáñez, Eduardo; González-Valero, Gabriel; Badicu, Georgian; Clemente, Filipe Manuel; Silva, Ana Filipa; Puertas-Molero, Pilar","year":2023,"journal":"BioMed research international, 2023, 1971858","doi":"10.1155/2023/1971858","pmid":"37096221","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study found significant relationships between violent behavior, self-concept dimensions, and consumption of alcohol, tobacco, and cannabis among secondary students, with physical activity engagement providing protective benefits.","whyItMatters":"Understanding how substance use, violent behavior, and self-concept interact during adolescence can inform comprehensive school-based prevention programs that address multiple risk behaviors simultaneously.","specificNumbers":"The study examined two models of relationships between violent behavior, self-concept, and substance use (alcohol, tobacco, and cannabis) in secondary education students.","methodology":"Cross-sectional explanatory model examining relationships between violence, self-concept, and substance use in secondary students.","limitations":"Cross-sectional design limits causal inference; self-reported data; cultural context of the sample may not generalize globally."},{"rthcId":"RTHC-04771","title":"Criminal Justice Referrals to Cannabis Use Disorder Treatment among Adolescents and Young Adults following Recreational Cannabis Legalization in the United States.","authors":"Mennis, Jeremy; Stahler, Gerald J; McKeon, Thomas P","year":2023,"journal":"Journal of addiction medicine, 17(6), 725-728","doi":"10.1097/ADM.0000000000001219","pmid":"37934545","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The proportion of CUD treatment referrals from the criminal justice system declined after recreational cannabis legalization for both adolescents (12-17) and young adults (18-24), reflecting changing enforcement patterns.","whyItMatters":"Many youth enter cannabis treatment through criminal justice mandates rather than clinical need. Declining criminal justice referrals after legalization may reflect more appropriate treatment allocation or may reduce treatment access for some youth.","specificNumbers":"The study examined criminal justice referral proportions for CUD treatment among adolescents (12-17) and young adults (18-24) before and after state recreational legalization.","methodology":"Policy analysis examining changes in criminal justice referral proportions to CUD treatment following state recreational cannabis legalization.","limitations":"Treatment system data may not capture all CUD cases; referral changes could reflect enforcement, legislative, or treatment system changes; state variation in implementation."},{"rthcId":"RTHC-04772","title":"Recreational cannabis legalization alters associations among cannabis use, perception of risk, and cannabis use disorder treatment for adolescents and young adults.","authors":"Mennis, Jeremy; McKeon, Thomas P; Stahler, Gerald J","year":2023,"journal":"Addictive behaviors, 138, 107552","doi":"10.1016/j.addbeh.2022.107552","pmid":"36413909","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"After recreational legalization, the relationships between risk perception, cannabis use, and CUD treatment changed, with potential implications for how young people evaluate cannabis harm and seek treatment.","whyItMatters":"If legalization changes how young people perceive cannabis risk and relate to treatment, public health responses must adapt to this new landscape rather than relying on pre-legalization approaches.","specificNumbers":"The study investigated changes in associations among adolescent and young adult perception of risk, cannabis use, and CUD treatment following recreational legalization.","methodology":"Policy analysis examining changes in associations between risk perception, cannabis use, and CUD treatment before and after recreational legalization.","limitations":"Ecological analysis cannot determine individual-level causal pathways; risk perception measurement may vary across surveys; concurrent cultural changes may confound legalization effects."},{"rthcId":"RTHC-04773","title":"Exploring preferences for different modes of cannabis use during early pregnancy: A qualitative study.","authors":"Mian, Maha N; Foti, Tara R; Green, Andrea; Iturralde, Esti; Altschuler, Andrea; Does, Monique B; Jackson-Morris, Melanie; Adams, Sara R; Satre, Derek D; Ansley, Deborah; Young-Wolff, Kelly C","year":2023,"journal":"Addictive behaviors, 146, 107812","doi":"10.1016/j.addbeh.2023.107812","pmid":"37490827","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Pregnant individuals expressed distinct preferences among cannabis delivery methods (smoking, vaping, edibles, topicals) during early pregnancy, influenced by perceived safety, convenience, and symptom management needs.","whyItMatters":"Different cannabis delivery methods produce different exposure profiles for the developing fetus. Understanding maternal preferences helps develop targeted harm reduction messaging for those who continue to use during pregnancy.","specificNumbers":"Focus group study conducted with Kaiser Permanente Northern California pregnant individuals examining cannabis use patterns and mode preferences.","methodology":"Qualitative focus group study with pregnant individuals examining preferences and perceptions regarding modes of prenatal cannabis use.","limitations":"Qualitative design with specific HMO population; participants willing to discuss cannabis use may not represent all pregnant users; focus groups may introduce social desirability bias."},{"rthcId":"RTHC-04774","title":"Cannabis Use Among U.S. Military Veterans Following Residential Substance Use Disorder Treatment.","authors":"Mian, Maha N; Chan Osilla, Karen; Blonigen, Daniel","year":2023,"journal":"Military medicine, 188(11-12), e3591-e3598","doi":"10.1093/milmed/usad216","pmid":"37294846","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Veterans cannabis use patterns after residential SUD treatment were predicted by specific treatment factors, suggesting opportunities to improve post-treatment cannabis outcomes through targeted intervention during residential stays.","whyItMatters":"Cannabis use during and after addiction treatment is increasingly common among veterans, and understanding predictors of post-treatment use can inform treatment planning in VA residential programs.","specificNumbers":"The study examined descriptive patterns of cannabis use and treatment predictors of outcomes among US military veterans following residential SUD treatment.","methodology":"Retrospective cohort study examining cannabis use patterns and treatment predictors following residential SUD treatment in US veterans.","limitations":"Retrospective design; VA treatment population may not represent all veterans; cannabis use was secondary to primary SUD treatment in many cases."},{"rthcId":"RTHC-04775","title":"Improving Quality of Life During Chemotherapy: Cannabinoids, Cryotherapy, and Scalp Cooling.","authors":"Michel, Alissa; Lee, Richard T; Salehi, Elahe; Accordino, Melissa K","year":2023,"journal":"American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 43, e390428","doi":"10.1200/EDBK_390428","pmid":"37267515","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabinoids, cryotherapy, and scalp cooling each address different chemotherapy side effects (nausea/vomiting, neuropathy, and alopecia respectively), and their combined use represents a multifaceted approach to improving QOL during cancer treatment.","whyItMatters":"Chemotherapy side effects significantly impact patient quality of life and treatment adherence. Non-pharmacological and cannabinoid-based supportive care options can complement standard antiemetic and supportive protocols.","specificNumbers":"Chemotherapy-induced nausea and vomiting, chemotherapy-induced peripheral neuropathy, and chemotherapy-induced alopecia are among the most distressing side effects affecting quality of life.","methodology":"Review article examining evidence for cannabinoids, cryotherapy, and scalp cooling as supportive care during chemotherapy.","limitations":"Different levels of evidence across the three interventions; cannabinoid evidence is more established for nausea than other applications; review scope is broad."},{"rthcId":"RTHC-04776","title":"Characteristics Associated With Cannabis Use Initiation by Late Childhood and Early Adolescence in the Adolescent Brain Cognitive Development (ABCD) Study.","authors":"Miller, Alex P; Baranger, David A A; Paul, Sarah E; Hatoum, Alexander S; Rogers, Cynthia; Bogdan, Ryan; Agrawal, Arpana","year":2023,"journal":"JAMA pediatrics, 177(8), 861-863","doi":"10.1001/jamapediatrics.2023.1801","pmid":"37358866","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers analyzed data from the ABCD study to identify which children were most likely to begin using cannabis by late childhood or early adolescence. Early-onset cannabis use is a known risk factor for later substance use problems and developmental difficulties.\n\nThe study identified multiple characteristics associated with early initiation, spanning individual traits, family factors, and environmental influences. These risk factors help build a profile of which young people may be most vulnerable to early cannabis exposure.\n\nIdentifying these characteristics before cannabis use begins is valuable because it could inform targeted prevention efforts aimed at the highest-risk populations rather than universal messaging that may be less effective.","whyItMatters":"Early-onset cannabis use is consistently linked to worse outcomes than initiation in later adolescence or adulthood. Identifying who is most at risk before they start using could allow prevention resources to be directed where they are most needed, potentially reducing the population-level burden of early cannabis exposure.","specificNumbers":"The ABCD study enrolled approximately 12,000 children across 21 US sites. Researchers assessed characteristics associated with cannabis initiation by late childhood and early adolescence.","methodology":"This was a longitudinal cohort analysis using the ABCD study, which enrolled approximately 12,000 children ages 9-10 at 21 sites across the United States. Researchers assessed multiple domains of potential risk factors and tracked which participants initiated cannabis use during the follow-up period through early adolescence.","limitations":"The ABCD cohort, while large, may not be fully representative of all US youth. Self-reported cannabis use in children may be underreported due to social desirability bias. The study identified associations with early use but cannot prove these characteristics caused earlier initiation."},{"rthcId":"RTHC-04777","title":"Prenatal cocaine exposure and substance use disorder in emerging adulthood at age 21.","authors":"Min, Meeyoung O; Minnes, Sonia; Kim, Sun-Kyung; Kim, June-Yung; Singer, Lynn T","year":2023,"journal":"Drug and alcohol dependence, 242, 109736","doi":"10.1016/j.drugalcdep.2022.109736","pmid":"36516550","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Individuals prenatally exposed to cocaine showed increased rates of substance use disorder at age 21, suggesting that prenatal drug exposure effects extend into emerging adulthood and may predispose to addiction vulnerability.","whyItMatters":"Understanding long-term consequences of prenatal substance exposure helps identify at-risk populations for early intervention and informs prenatal counseling about lasting developmental impacts.","specificNumbers":"The study followed individuals with prenatal cocaine exposure to age 21, assessing substance use disorder outcomes in emerging adulthood.","methodology":"Prospective longitudinal study following individuals with prenatal cocaine exposure from birth to age 21, assessing SUD outcomes.","limitations":"Longitudinal attrition; difficult to isolate cocaine exposure from other prenatal substance use and postnatal environmental factors; SUD at 21 may reflect ongoing development rather than final outcomes."},{"rthcId":"RTHC-04778","title":"MICROGLIAL CELL EXPRESSION OF THE TYPE 2 CANNABINOID RECEPTOR REGULATES IMMUNE-MEDIATED NEUROINFLAMMATION.","authors":"Moe, Alison; Rayasam, Aditya; Sauber, Garrett; Shah, Ravi K; Yuan, Cheng-Yin; Szabo, Aniko; Moore, Bob M; Colonna, Marco; Cui, Weiguo; Romero, Julian; Zamora, Anthony E; Hillard, Cecilia J; Drobyski, William R","year":2023,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2023.08.10.552854","pmid":"37645843","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"CB2 receptor expression on microglial cells plays a regulatory role in immune-mediated neuroinflammation, with potential therapeutic implications for conditions ranging from immunotherapy side effects to neurodegenerative diseases.","whyItMatters":"Neuroinflammation is a complication of cancer immunotherapies and a driver of neurodegenerative diseases. Understanding how microglial CB2 receptors control this inflammation could lead to targeted cannabinoid interventions.","specificNumbers":"Neuroinflammation complicates immunotherapies including checkpoint inhibitors, CAR-T therapy, and graft-versus-host disease after stem cell transplantation.","methodology":"Research examining the role of CB2 receptor expression on microglia in regulating neuroinflammatory responses.","limitations":"Microglial CB2 expression varies by activation state and disease context; targeting CB2 specifically on microglia is technically challenging; translation from models to clinical application is early."},{"rthcId":"RTHC-04779","title":"Exposure to Δ9-tetrahydrocannabinol leads to a rise in caspase-3, morphological changes in microglial, and astrocyte reactivity in the cerebellum of rats.","authors":"Mohammadpanah, Mojtaba; Farrokhi, Sheida; Sani, Mojtaba; Moghaddam, Meysam Hassani; Bayat, Amir-Hossein; Boroujeni, Mahdi Eskandarian; Abdollahifar, Mohammad-Amin; Fathi, Mobina; Vakili, Kimia; Nikpour, Fatemeh; Omran, Hossein Salehi; Ahmadirad, Hossein; Ghorbani, Zeynab; Peyvandi, Ali Asghar; Aliaghaei, Abbas","year":2023,"journal":"Toxicology research, 12(6), 1077-1094","doi":"10.1093/toxres/tfad098","pmid":"38145099","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"THC at 10 mg/kg caused increased caspase-3 (apoptosis marker), altered microglial morphology, and astrocyte reactivity in the cerebellum, demonstrating both neurotoxic and neuroinflammatory effects in this brain region.","whyItMatters":"The cerebellum is critical for motor coordination and increasingly recognized for cognitive and emotional functions. THC-induced changes here could explain motor and cognitive effects of cannabis use.","specificNumbers":"10 mg/kg THC dose in male rats was assessed using stereology, Sholl analysis, immunofluorescence, and real-time qPCR for cerebellar changes.","methodology":"Preclinical histological study using multiple techniques (stereology, Sholl analysis, immunofluorescence, RT-qPCR) to assess THC effects on rat cerebellum.","limitations":"Single high dose in rats; acute exposure may not represent chronic human use patterns; rat cerebellar development differs from human; 10 mg/kg is a relatively high dose."},{"rthcId":"RTHC-04780","title":"Mental Health Conditions- and Substance Use-Associated Emergency Department Visits during the COVID-19 Pandemic in Nevada, USA.","authors":"Mojtahedi, Zahra; Guo, Ying; Kim, Pearl; Khawari, Parsa; Ephrem, Hailey; Shen, Jay J","year":2023,"journal":"International journal of environmental research and public health, 20(5)","doi":"10.3390/ijerph20054389","pmid":"36901398","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"COVID-19 pandemic impacts on mental health and substance use-related ED visits in Nevada revealed complex patterns, with some conditions increasing and others decreasing, reflecting the pandemics multifaceted effects on behavioral health.","whyItMatters":"Understanding how the pandemic affected behavioral health ED utilization helps health systems prepare for future disruptions and address ongoing mental health and substance use impacts.","specificNumbers":"The study examined ED visits for mental health conditions and substance use during the COVID-19 pandemic in Nevada, USA, compared to pre-pandemic trends.","methodology":"Retrospective analysis of emergency department visit data comparing mental health and substance use presentations before and during the COVID-19 pandemic in Nevada.","limitations":"Single-state data may not represent national trends; ED visit changes may reflect avoidance of healthcare rather than true prevalence changes; pandemic affected data collection and coding."},{"rthcId":"RTHC-04781","title":"Use of Cannabis as a Harm Reduction Strategy Among People Who Use Drugs: A Cohort Study.","authors":"Mok, Janice; Milloy, M-J; Grant, Cameron; Lake, Stephanie; DeBeck, Kora; Hayashi, Kanna; Kerr, Thomas; Socías, M Eugenia","year":2023,"journal":"Cannabis and cannabinoid research, 8(4), 670-678","doi":"10.1089/can.2021.0229","pmid":"35647886","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Participants in the cohort used cannabis intentionally as a harm reduction strategy, reporting reduced use of more harmful substances like opioids, stimulants, and alcohol when using cannabis as a substitute or complement.","whyItMatters":"With limited access to evidence-based harm reduction services, understanding how people self-manage substance use risks with cannabis could inform pragmatic public health approaches.","specificNumbers":"Cohort study of people who use drugs, examining cannabis as a harm reduction strategy amid limited access to evidence-based interventions.","methodology":"Prospective cohort study examining patterns and motivations for cannabis use as a harm reduction strategy among people who use drugs.","limitations":"Self-reported harm reduction behavior; cohort may not represent all PWUD; cannot establish that cannabis substitution actually reduces overall harm; potential for cannabis use disorder."},{"rthcId":"RTHC-04782","title":"Association Between Stimulant Treatment and Substance Use Through Adolescence Into Early Adulthood.","authors":"Molina, Brooke S G; Kennedy, Traci M; Howard, Andrea L; Swanson, James M; Arnold, L Eugene; Mitchell, John T; Stehli, Annamarie; Kennedy, Edward H; Epstein, Jeffery N; Hechtman, Lily T; Hinshaw, Stephen P; Vitiello, Benedetto","year":2023,"journal":"JAMA psychiatry, 80(9), 933-941","doi":"10.1001/jamapsychiatry.2023.2157","pmid":"37405756","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The study examined the long-debated question of whether stimulant treatment for ADHD influences later substance use, using data from the landmark Multimodal Treatment Study of ADHD (MTA) to track outcomes through adolescence and early adulthood.","whyItMatters":"Parents and clinicians worry that stimulant medications for ADHD could predispose children to later substance use. This long-term data from the gold-standard ADHD treatment study addresses these concerns directly.","specificNumbers":"Data from the Multimodal Treatment Study of ADHD (MTA), the largest and longest ADHD treatment trial, following participants from childhood through early adulthood.","methodology":"Long-term follow-up analysis from the MTA randomized trial examining associations between stimulant treatment duration/intensity and subsequent substance use.","limitations":"Post-randomization treatment was not controlled; observational follow-up phase limits causal conclusions; substance use measures may miss some patterns; attrition over long follow-up."},{"rthcId":"RTHC-04783","title":"Adolescent Cannabis Use, Comorbid Attention-Deficit/Hyperactivity Disorder, and Other Internalizing and Externalizing Disorders.","authors":"Molinero, Karla; Hinckley, Jesse D","year":2023,"journal":"The Psychiatric clinics of North America, 46(4), 691-702","doi":"10.1016/j.psc.2023.03.007","pmid":"37879832","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Adolescent cannabis use frequently co-occurs with ADHD, anxiety, depression, and conduct disorders, and thorough diagnostic evaluation is needed to determine whether symptoms reflect cannabis effects, underlying disorders, or both.","whyItMatters":"Comorbid cannabis use and psychiatric disorders in adolescents complicate diagnosis and treatment. Understanding these overlaps is essential for clinicians to provide appropriate care.","specificNumbers":"Cannabis use often co-occurs with ADHD and other internalizing (anxiety, depression) and externalizing (conduct, oppositional) disorders in adolescents.","methodology":"Clinical review examining comorbidity between adolescent cannabis use, ADHD, and other psychiatric disorders.","limitations":"Review format; individual clinical presentations vary significantly; distinguishing cannabis effects from underlying disorders is inherently challenging."},{"rthcId":"RTHC-04784","title":"Adolescent Cannabis Use, Comorbid Attention-Deficit/Hyperactivity Disorder, and Other Internalizing and Externalizing Disorders.","authors":"Molinero, Karla; Hinckley, Jesse D","year":2023,"journal":"Child and adolescent psychiatric clinics of North America, 32(1), 57-68","doi":"10.1016/j.chc.2022.07.003","pmid":"36410906","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis use commonly co-occurs with ADHD and other internalizing/externalizing disorders in adolescents, requiring thorough diagnostic evaluation for appropriate pharmacologic and psychosocial treatment planning.","whyItMatters":"Comorbid cannabis use and psychiatric disorders in adolescents require careful diagnostic evaluation to determine symptom origins and plan appropriate interventions.","specificNumbers":"Cannabis use often co-occurs with ADHD and other internalizing and externalizing disorders in adolescents requiring comprehensive assessment.","methodology":"Clinical review on comorbidity between adolescent cannabis use, ADHD, and other psychiatric disorders.","limitations":"Appears to be a duplicate database entry of RTHC-04783; review format with inherent limitations in generalizability."},{"rthcId":"RTHC-04785","title":"A chestnut-hemp type-II sourdough to improve technological, nutritional, and sensory properties of gluten-free bread.","authors":"Montemurro, Marco; Beccaccioli, Marzia; Perri, Giuseppe; Rizzello, Carlo Giuseppe; Reverberi, Massimo; Pontonio, Erica","year":2023,"journal":"International journal of food microbiology, 404, 110322","doi":"10.1016/j.ijfoodmicro.2023.110322","pmid":"37454506","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Combining chestnut and hemp flour in a type-II sourdough process produced gluten-free bread with improved texture, nutritional profile, and sensory qualities compared to standard gluten-free formulations.","whyItMatters":"Gluten-free products often suffer from poor nutrition and taste. Using hemp flour in sourdough fermentation offers a natural way to improve quality while providing beneficial nutrients like omega fatty acids and plant protein.","specificNumbers":"The study used chestnut and hemp flour alternatives to improve GF bread quality, avoiding long ingredient lists typical of current GF products.","methodology":"Food science study developing and evaluating a chestnut-hemp type-II sourdough for gluten-free bread production.","limitations":"Single product formulation; consumer acceptance may vary by market; hemp flour availability and cost may limit commercial adoption; regulatory status of hemp in food varies by country."},{"rthcId":"RTHC-04786","title":"Associations between Prenatal and Postnatal Exposure to Cannabis with Cognition and Behavior at Age 5 Years: The Healthy Start Study.","authors":"Moore, Brianna F; Salmons, Kaytlyn A; Hoyt, Adrienne T; Swenson, Karli S; Bates, Emily A; Sauder, Katherine A; Shapiro, Allison L B; Wilkening, Greta; Kinney, Gregory L; Neophytou, Andreas M; Sempio, Cristina; Klawitter, Jost; Christians, Uwe; Dabelea, Dana","year":2023,"journal":"International journal of environmental research and public health, 20(6)","doi":"10.3390/ijerph20064880","pmid":"36981794","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Both prenatal cannabis exposure and postnatal secondhand cannabis exposure were associated with cognitive and behavioral differences at age 5, with postnatal exposure representing a previously understudied risk factor.","whyItMatters":"Most research focuses on prenatal cannabis exposure, but this study highlights that postnatal secondhand exposure during early childhood may also influence development, expanding the window of concern beyond pregnancy.","specificNumbers":"The Healthy Start Study assessed associations between prenatal and postnatal cannabis exposure and cognition and behavior outcomes at age 5.","methodology":"Prospective cohort study (Healthy Start) examining prenatal and postnatal cannabis exposure associations with cognitive and behavioral outcomes at age 5.","limitations":"Observational design with potential confounders; postnatal exposure measurement may not fully capture secondhand cannabis smoke/vapor levels; age 5 assessment is early for detecting some effects."},{"rthcId":"RTHC-04787","title":"Pharmacokinetics of Oral Minor Cannabinoids in Blood and Brain.","authors":"Moore, Catherine F; Weerts, Elise M; Kulpa, Justyna; Schwotzer, Daniela; Dye, Wendy; Jantzi, Jacob; McDonald, Jacob D; Lefever, Timothy W; Bonn-Miller, Marcel O","year":2023,"journal":"Cannabis and cannabinoid research, 8(S1), S51-S61","doi":"10.1089/can.2023.0066","pmid":"37721988","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Oral administration of minor cannabinoids produced distinct pharmacokinetic profiles in blood and brain, with each compound showing different absorption, distribution, and elimination patterns relevant to their therapeutic and recreational use.","whyItMatters":"Minor cannabinoids are increasingly consumed in oral products, but their pharmacokinetics have been poorly characterized. Understanding how they reach the brain informs dosing, safety, and regulatory decisions.","specificNumbers":"The study examined THCV, CBC, CBN, and delta-8-THC pharmacokinetics in blood and brain following oral formulations (edibles, tinctures).","methodology":"Pharmacokinetic study measuring blood and brain levels of minor cannabinoids (THCV, CBC, CBN, delta-8-THC) after oral administration.","limitations":"Animal pharmacokinetics may not directly translate to humans; oral bioavailability varies by formulation; limited number of minor cannabinoids tested."},{"rthcId":"RTHC-04788","title":"Early onset frontotemporal dementia following cannabis abuse: a case report.","authors":"Moshfeghinia, Reza; Oji, Bahare; Hosseinzadeh, Mehrnaz; Pourfridoni, Mohammad; Ahmadi, Jamshid","year":2023,"journal":"BMC psychiatry, 23(1), 484","doi":"10.1186/s12888-023-04956-w","pmid":"37391735","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"A patient with long-term heavy cannabis use developed early-onset behavioral variant frontotemporal dementia (bvFTD), with the case report exploring whether chronic cannabis exposure may have contributed to or accelerated neurodegenerative processes.","whyItMatters":"While cannabis is sometimes explored as a treatment for neurodegeneration, this case raises the possibility that chronic heavy use could itself contribute to neurodegenerative processes in vulnerable individuals.","specificNumbers":"Case report of early-onset frontotemporal dementia in a patient with chronic cannabis abuse history. FTD involves impairment to frontal and temporal lobe neurons.","methodology":"Clinical case report with literature review examining the association between chronic cannabis use and early-onset frontotemporal dementia.","limitations":"Single case report cannot establish causation; genetic and other environmental factors may have contributed; temporal association does not prove cannabis caused FTD."},{"rthcId":"RTHC-04789","title":"Tetrahydrocannabinol and Cannabidiol in Tourette Syndrome.","authors":"Mosley, Philip E; Webb, Lachlan; Suraev, Anastasia; Hingston, Leah; Turnbull, Tracy; Foster, Kelley; Ballard, Emma; Gomes, Lauren; Mohan, Adith; Sachdev, Perminder S; Kevin, Richard; Gordon, Rebecca; Benson, Melissa; McGregor, Iain S","year":2023,"journal":"NEJM evidence, 2(9), EVIDoa2300012","doi":"10.1056/EVIDoa2300012","pmid":"38320199","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The double-blind trial examined whether THC with CBD co-administration improved tics in Tourette syndrome, with CBD potentially improving the side-effect profile and safety of the THC component.","whyItMatters":"Tourette syndrome has limited treatment options and many patients report self-medicating with cannabis. Rigorous clinical trial data is needed to evaluate whether cannabinoids should be formally recommended.","specificNumbers":"Double-blind trial of THC with CBD co-administration in Tourette syndrome, which is characterized by chronic motor and vocal tics.","methodology":"Double-blind clinical trial evaluating THC and CBD for Tourette syndrome tic reduction and safety.","limitations":"Trial details (sample size, duration) from abstract are limited; previous evidence was preliminary; tic assessment tools may not capture all symptom dimensions."},{"rthcId":"RTHC-04790","title":"Cannabis during pregnancy: A way to transfer an impairment to later life.","authors":"Motamedi, Sina; Amleshi, Reza Saboori; Javar, Behnoush Akbari; Shams, Parisa; Kohlmeier, Kristi A; Shabani, Mohammad","year":2023,"journal":"Birth defects research, 115(15), 1327-1344","doi":"10.1002/bdr2.2207","pmid":"37318343","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Cannabis exposure during gestation or the perinatal period is associated with later-life mental health issues appearing across developmental stages, with effects mediated through disruption of the endocannabinoid systems role in neurodevelopment.","whyItMatters":"Public perception often diverges from medical guidance on cannabis during pregnancy. This review provides the scientific basis for why abstinence is recommended, with effects potentially spanning decades.","specificNumbers":"The review covers epidemiological studies showing mental health impacts from prenatal cannabis that manifest during childhood, adolescence, and adulthood.","methodology":"Narrative review of epidemiological and mechanistic evidence on prenatal cannabis exposure and later-life mental health outcomes.","limitations":"Observational studies dominate; isolating cannabis effects from confounders is challenging; long follow-up periods introduce attrition and measurement challenges."},{"rthcId":"RTHC-04791","title":"Isolation of Biologically Active Compounds from Cannabis sativa L. Inflorescences by Using Different Extraction Solvents and Evaluation of Antimicrobial Activity.","authors":"Motiejauskaitė, Dovilė; Ullah, Sana; Kundrotaitė, Algimanta; Žvirdauskienė, Renata; Bakšinskaitė, Aušra; Barčauskaitė, Karolina","year":2023,"journal":"Antioxidants (Basel, Switzerland), 12(5)","doi":"10.3390/antiox12050998","pmid":"37237864","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Extraction solvent choice significantly affected both the yield and composition of bioactive compounds from hemp inflorescences, with certain solvents producing extracts with notable antimicrobial properties.","whyItMatters":"Optimizing extraction methods is essential for producing consistent, high-quality hemp products with reliable bioactive compound profiles for therapeutic and commercial applications.","specificNumbers":"Multiple organic solvents were compared for extraction of phytocannabinoids and other biologically active compounds from hemp inflorescences.","methodology":"Comparative extraction study using different organic solvents to isolate bioactive compounds from hemp flowers, with antimicrobial activity testing.","limitations":"Laboratory-scale extraction may not directly scale to commercial production; antimicrobial testing was in vitro; different hemp cultivars would produce different results."},{"rthcId":"RTHC-04792","title":"Association between cannabis use and risk of diabetes mellitus type 2: A systematic review and meta-analysis.","authors":"Mousavi, Seyed Ehsan; Tondro Anamag, Farhad; Sanaie, Sarvin","year":2023,"journal":"Phytotherapy research : PTR, 37(11), 5092-5108","doi":"10.1002/ptr.7973","pmid":"37526051","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The systematic review and meta-analysis found mixed evidence regarding cannabis use and type 2 diabetes risk, with cannabis affecting glucose regulation and insulin secretion through multiple pathways that may produce different effects depending on use patterns.","whyItMatters":"With both cannabis use and diabetes prevalence increasing globally, understanding their relationship is important for clinical guidance and public health messaging.","specificNumbers":"Cannabis affects metabolism via pathways including glucose regulation and insulin secretion, but studies on the cannabis-diabetes association have been discrepant.","methodology":"Systematic review and meta-analysis of studies examining the association between cannabis use and type 2 diabetes mellitus risk.","limitations":"Heterogeneity in study designs and definitions of cannabis use; confounding by lifestyle factors; different metabolic effects of acute vs chronic use."},{"rthcId":"RTHC-04793","title":"Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor.","authors":"Mugnaini, Claudia; Kostrzewa, Magdalena; Casini, Marta; Kumar, Poulami; Catallo, Valeria; Allarà, Marco; Guastaferro, Laura; Brizzi, Antonella; Paolino, Marco; Tafi, Andrea; Kapatais, Christelos; Giorgi, Gianluca; Vacondio, Federica; Mor, Marco; Corelli, Federico; Ligresti, Alessia","year":2023,"journal":"Molecules (Basel, Switzerland), 28(13)","doi":"10.3390/molecules28134958","pmid":"37446625","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Through systematic substitution pattern modification of 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide, researchers identified new compounds with high CB2 receptor affinity and selectivity, functioning as either agonists or inverse agonists.","whyItMatters":"Selective CB2 receptor drugs could treat inflammation and pain without psychoactive effects. Discovering new selective ligands expands the toolkit for cannabinoid drug development.","specificNumbers":"The 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide scaffold produced derivatives acting as CB2 agonists or inverse agonists with high selectivity.","methodology":"Medicinal chemistry study systematically modifying a chemical scaffold to optimize CB2 receptor affinity and selectivity.","limitations":"In vitro receptor binding does not guarantee in vivo efficacy; ADMET properties need assessment; translation from binding studies to therapeutic candidates is a long process."},{"rthcId":"RTHC-04794","title":"CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders - Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study.","authors":"Müller-Vahl, Kirsten R; Pisarenko, Anna; Szejko, Natalia; Haas, Martina; Fremer, Carolin; Jakubovski, Ewgeni; Musil, Richard; Münchau, Alexander; Neuner, Irene; Huys, Daniel; van Elst, Ludger Tebartz; Schröder, Christoph; Ringlstetter, Rieke; Koch, Armin; Jenz, Eva Beate; Großhennig, Anika","year":2023,"journal":"Psychiatry research, 323, 115135","doi":"10.1016/j.psychres.2023.115135","pmid":"36878177","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"The prospective, multicenter, randomized, double-blind, placebo-controlled phase IIIb trial (CANNA-TICS) evaluated nabiximols efficacy and safety for chronic tic disorders, providing rigorous evidence for cannabinoid treatment of Tourette syndrome.","whyItMatters":"This is the largest and most rigorous clinical trial of a cannabinoid medication for Tourette syndrome, potentially leading to the first cannabinoid-based treatment specifically approved for tic disorders.","specificNumbers":"Prospective, multicenter, randomized, double-blind, placebo-controlled, phase IIIb superiority study of oral nabiximols in adults with chronic tic disorders.","methodology":"Phase IIIb multicenter randomized double-blind placebo-controlled superiority trial of nabiximols for chronic tic disorders.","limitations":"Phase IIIb design; adult-only population while tics often affect children; nabiximols availability varies by country; treatment duration may not capture long-term outcomes."},{"rthcId":"RTHC-04795","title":"Influence of prenatal cannabinoid exposure on early development and beyond.","authors":"Mulligan, Megan K; Hamre, Kristin M","year":2023,"journal":"Advances in drug and alcohol research, 3, 10981","doi":"10.3389/adar.2023.10981","pmid":"38389825","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Prenatal cannabis exposure influences neurodevelopmental trajectories through endocannabinoid system disruption, with effects potentially extending well beyond the neonatal period despite public perception that cannabis is safe during pregnancy.","whyItMatters":"Many women of reproductive age believe cannabis is safe during pregnancy, contrary to medical guidance. This review bridges the gap between public perception and scientific evidence.","specificNumbers":"Public perception diverges from medical guidance of abstinence before, during, and after pregnancy, with many women of reproductive age believing cannabis use during pregnancy is safe.","methodology":"Review examining evidence on prenatal cannabinoid exposure effects on early development and beyond.","limitations":"Review format; much evidence is observational; disentangling cannabis effects from socioeconomic and other substance use factors remains challenging."},{"rthcId":"RTHC-04796","title":"Association between Cannabis Use Disorder and Mental Health Disorders in the Adolescent Population: A Cohort Study.","authors":"Muñoz-Galán, Regina; Lana-Lander, Irene; Coronado, Marta; Segura, Lidia; Colom, Joan","year":2023,"journal":"European addiction research, 29(5), 344-352","doi":"10.1159/000530331","pmid":"37586355","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Adolescents with cannabis use disorder showed increased risk for developing subsequent mental health disorders, with early initiation and dependent use patterns identified as important risk factors.","whyItMatters":"This is one of few cohort studies tracking mental health disorder development specifically associated with adolescent cannabis use disorder, providing temporal evidence stronger than cross-sectional studies.","specificNumbers":"Cohort study examining mental health disorder development associated with early cannabis initiation and dependent use patterns in adolescents.","methodology":"Prospective cohort study tracking adolescents with cannabis use disorder for subsequent mental health disorder development.","limitations":"Cohort design cannot fully prove causation; shared risk factors may explain both CUD and mental health disorders; assessment intervals may miss some transitions."},{"rthcId":"RTHC-04797","title":"Application of Paper-Based Microfluidic Analytical Devices (µPAD) in Forensic and Clinical Toxicology: A Review.","authors":"Musile, Giacomo; Grazioli, Cristian; Fornasaro, Stefano; Dossi, Nicolò; De Palo, Elio Franco; Tagliaro, Franco; Bortolotti, Federica","year":2023,"journal":"Biosensors, 13(7)","doi":"10.3390/bios13070743","pmid":"37504142","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Paper-based microfluidic devices offer promising rapid, sensitive, and cost-effective approaches for point-of-need drug detection in forensic and clinical toxicology settings.","whyItMatters":"Rapid on-the-spot drug detection could transform forensic and clinical practice by enabling immediate results at the point of need rather than requiring laboratory analysis with long turnaround times.","specificNumbers":"The review covers paper-based microfluidic analytical devices for use in nonspecialized laboratories and at the point of need.","methodology":"Review of paper-based microfluidic analytical device technology for forensic and clinical toxicology applications.","limitations":"Technology is still developing; sensitivity and specificity may not match laboratory methods; environmental conditions can affect paper-based assay performance; regulatory approval for clinical use is pending."},{"rthcId":"RTHC-04798","title":"Exploring Roles of Stakeholders in Combating Substance Abuse in the DIMAMO Surveillance Site, South Africa.","authors":"Muthelo, Livhuwani; Mbombi, Masenyani Oupa; Mphekgwana, Peter; Mabila, Linneth Nkateko; Dhau, Inos; Tlouyamma, Joseph; Nemuramba, Rathani; Mashaba, Reneilwe Given; Mothapo, Katlego; Ntimana, Cairo Bruce; Maimela, Eric","year":2023,"journal":"Substance abuse : research and treatment, 17, 11782218221147498","doi":"10.1177/11782218221147498","pmid":"36875745","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Multiple stakeholders including families, South Africa Police Service, and social workers play distinct but interconnected roles in addressing substance abuse in the rural DIMAMO surveillance site, with resource limitations constraining effectiveness.","whyItMatters":"Rural communities in developing countries face unique substance abuse challenges with limited resources. Understanding stakeholder roles helps optimize the multi-sector response needed in resource-constrained settings.","specificNumbers":"The study examined stakeholder roles in the DIMAMO surveillance site in Limpopo Province, South Africa, where substance abuse prevalence is increasing.","methodology":"Qualitative study exploring stakeholder roles and perspectives on substance abuse in a rural South African surveillance site.","limitations":"Single rural site in South Africa; stakeholder perspectives may not capture user experiences; qualitative design limits generalizability; cultural context is specific."},{"rthcId":"RTHC-04799","title":"Driving under the influence of cannabis, alcohol, and illicit drugs among adults in the United States from 2016 to 2020.","authors":"Myers, Matthew G; Bonar, Erin E; Bohnert, Kipling M","year":2023,"journal":"Addictive behaviors, 140, 107614","doi":"10.1016/j.addbeh.2023.107614","pmid":"36652810","tags":["driving","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using nationally representative NSDUH data, over 1 in 10 US adults reported DUI of any substance annually. Cannabis-impaired driving did not increase in the general population, but among past-year cannabis users it decreased (AOR 0.95). Meanwhile, alcohol-impaired driving declined overall (AOR 0.96). Females and adults ages 26-34 and 65+ showed increasing trends for driving under the influence of non-cannabis drugs.","whyItMatters":"As cannabis legalization spreads, a key public health concern is whether more use translates to more impaired driving. This national data suggests the relationship is not straightforward: more people used cannabis, but the rate of driving impaired among users went down.","specificNumbers":"Over 1 in 10 US adults reported past-year DUI of any substance. DUIA peaked at 8.7% in 2017 and declined (AOR 0.96). Past-year cannabis use rose 29.1%. DUIC among users declined (AOR 0.95).","methodology":"Analysis of National Survey on Drug Use and Health data from 2016-2020, using nationally representative samples of non-institutionalized US adults. Prevalence estimates and adjusted logistic regressions characterized temporal trends overall and among demographic subpopulations.","limitations":"Self-reported data likely underestimates actual DUI prevalence. The study period ends in 2020, so COVID-19 may have influenced driving patterns. Cannot distinguish between levels of impairment or crash risk."},{"rthcId":"RTHC-04800","title":"Transition to Schizophrenia Spectrum Disorder Following Emergency Department Visits Due to Substance Use With and Without Psychosis.","authors":"Myran, Daniel T; Harrison, Lyndsay D; Pugliese, Michael; Solmi, Marco; Anderson, Kelly K; Fiedorowicz, Jess G; Perlman, Christopher M; Webber, Colleen; Finkelstein, Yaron; Tanuseputro, Peter","year":2023,"journal":"JAMA psychiatry, 80(11), 1169-1174","doi":"10.1001/jamapsychiatry.2023.3582","pmid":"37755727","tags":["psychosis","mental-health","youth"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 9.8 million people without prior psychosis, those with ER visits for substance-induced psychosis had a 163-fold increased risk of transitioning to schizophrenia (3-year risk: 18.5% vs 0.1%). Cannabis-induced psychosis had the highest transition risk (aHR 241.6). Even substance use ER visits without psychosis carried a 9.8-fold risk, and because they were far more common, they accounted for 3 times more total transitions than psychosis visits.","whyItMatters":"This is one of the largest studies to quantify the pathway from substance-related ER visits to schizophrenia. The finding that cannabis carried the highest transition risk among all substances, and that even non-psychotic substance use visits predicted elevated risk, has major implications for early intervention.","specificNumbers":"9.8 million people studied. 407,737 ER visits for substance use. 13,784 (3.4%) involved psychosis. Substance-induced psychosis: 163-fold risk, 18.5% three-year transition rate. Cannabis psychosis: aHR 241.6. Non-psychotic substance use: 9.8-fold risk, 1.4% three-year rate, but 3x more total transitions (9,969 vs 3,029).","methodology":"Population-based retrospective cohort study of 9.8 million individuals aged 14-65 in Ontario, Canada (January 2008 to March 2022), with no prior psychotic disorder. Used cause-specific hazard models to estimate transition risk to schizophrenia spectrum disorder.","limitations":"Observational design cannot prove causation. Relies on ER diagnostic coding which may miss or misclassify cases. Ontario has universal healthcare which may limit generalizability to other systems. Cannot account for frequency or potency of substance use."},{"rthcId":"RTHC-04801","title":"Cannabis-Involved Traffic Injury Emergency Department Visits After Cannabis Legalization and Commercialization.","authors":"Myran, Daniel T; Gaudreault, Adrienne; Pugliese, Michael; Manuel, Douglas G; Tanuseputro, Peter","year":2023,"journal":"JAMA network open, 6(9), e2331551","doi":"10.1001/jamanetworkopen.2023.31551","pmid":"37672273","tags":["driving","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Annual rates of cannabis-involved traffic injury ER visits rose from 0.18 to 1.01 per 1,000 total motor vehicle collisions. Legalization with restrictions was associated with a 94% increase (aRR 1.94), while the commercialization/COVID period saw a 223% increase (aRR 3.23). Cannabis involvement remained rare overall (0.04% of traffic injury ER visits) compared to alcohol (0.8%). Males, ages 19-21, lowest-income neighborhoods, and prior cannabis-related ER visits were risk factors.","whyItMatters":"As jurisdictions legalize cannabis, tracking traffic safety outcomes is critical. This study suggests that the retail expansion phase, not initial legalization, may be when impaired driving increases most, though confounding with COVID-era changes in driving patterns complicates interpretation.","specificNumbers":"947,604 traffic injury ER visits total. 426 (0.04%) had cannabis involvement. 7,564 (0.8%) had alcohol involvement. 475% increase in cannabis-involved rate over the study period. Males: aOR 3.38. Ages 19-21: aOR 4.67. Prior cannabis ER visit: aOR 8.03.","methodology":"Repeated cross-sectional study of all traffic injury ER visits in Ontario, Canada (2010-2021) across three periods: pre-legalization, legalization with restrictions, and commercialization. Used quasi-Poisson models adjusting for season and time trends.","limitations":"Cannabis involvement was documented in only 0.04% of visits, so small absolute changes produce large relative changes. The commercialization period coincided with COVID-19, confounding the analysis. Relies on clinician documentation of cannabis involvement, which likely underestimates true prevalence."},{"rthcId":"RTHC-04802","title":"Association between non-medical cannabis legalization and emergency department visits for cannabis-induced psychosis.","authors":"Myran, Daniel T; Pugliese, Michael; Roberts, Rhiannon L; Solmi, Marco; Perlman, Christopher M; Fiedorowicz, Jess; Tanuseputro, Peter; Anderson, Kelly K","year":2023,"journal":"Molecular psychiatry, 28(10), 4251-4260","doi":"10.1038/s41380-023-02185-x","pmid":"37500826","tags":["psychosis","legalization","youth","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Across 6,300 ER visits for cannabis-induced psychosis, restricted legalization showed no change relative to pre-legalization. Commercialization was associated with an immediate 30% increase (IRR 1.30). The increase was driven by youth above the legal purchase age (19-24, IRR 1.63) but not below it (15-18, IRR 0.73, nonsignificant). No changes were seen in cocaine or methamphetamine psychosis ER visits, serving as negative controls.","whyItMatters":"This study provides a nuanced message: it is not legalization per se that may increase psychosis risk, but rather the commercial expansion phase with more retail stores, more product types, and likely more potent products. The finding that youth above but not below legal purchase age drove the increase suggests retail access matters.","specificNumbers":"6,300 ER visits for cannabis-induced psychosis. Commercialization: IRR 1.30 (95% CI 1.02-1.66). Youth 19-24: IRR 1.63 (95% CI 1.27-2.08). Youth 15-18: IRR 0.73 (not significant). No changes in cocaine or methamphetamine psychosis visits.","methodology":"Population-based study using health administrative data for all ER visits in Ontario, Canada (population 14.3 million) across three periods: pre-legalization (Jan 2014-Sep 2018), legalization with restrictions (Oct 2018-Feb 2020), and commercialization (Mar 2020-Sep 2021). Segmented regression with cocaine and methamphetamine psychosis as controls.","limitations":"The commercialization period overlapped with COVID-19, which may have independently affected substance use and mental health. Cannot determine whether potency changes, increased access, or other factors drove the increase. Relies on ER diagnostic coding."},{"rthcId":"RTHC-04803","title":"Acute care related to cannabis use during pregnancy after the legalization of nonmedical cannabis in Ontario.","authors":"Myran, Daniel Thomas; Roberts, Rhiannon; Pugliese, Michael; Corsi, Daniel; Walker, Mark; El-Chaâr, Darine; Tanuseputro, Peter; Simpson, Andrea","year":2023,"journal":"CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 195(20), E699-E708","doi":"10.1503/cmaj.230045","pmid":"37220929","tags":["pregnancy","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The mean quarterly rate of cannabis-related acute care during pregnancy rose from 11.0 to 20.0 per 100,000 pregnancies after legalization (IRR 1.82). Mental health acute care decreased and non-cannabis substance use care did not change, serving as controls. Cannabis-related acute care during pregnancy was associated with 9.7-fold higher odds of hyperemesis gravidarum, 1.93-fold higher odds of preterm birth, and 1.94-fold higher odds of NICU admission.","whyItMatters":"With cannabis legalization spreading globally, understanding impacts on vulnerable populations like pregnant people is critical. While the relative increase was large, the absolute numbers remained small. The association with preterm birth and NICU stays adds urgency to prenatal screening discussions.","specificNumbers":"Rate rose from 11.0 to 20.0 per 100,000 pregnancies (IRR 1.82). Post-legalization quarterly increase: 1.13 per 100,000 pregnancies. Cannabis-related visits: 9.73x odds of hyperemesis gravidarum, 1.93x odds of preterm birth (16.9% vs 7.2%), 1.94x odds of NICU admission (31.5% vs 13.0%).","methodology":"Population-based repeated cross-sectional study in Ontario, Canada (Jan 2015-Jul 2021). Segmented regression comparing cannabis-related acute care trends to mental health and non-cannabis substance use controls. Multivariable logistic regression for neonatal outcomes.","limitations":"Cannot determine if the increase reflects more cannabis use, more willingness to disclose, or better clinical detection. Observational design cannot establish whether cannabis caused the adverse neonatal outcomes. COVID-19 overlapped with part of the study period."},{"rthcId":"RTHC-04804","title":"Prevalence of cannabis use disorder among individuals using medical cannabis at admission to inpatient treatment for substance use disorders.","authors":"N S Gendy, Marie; Taisir, Radia; Sousa, Sarah; Costello, Jean; Rush, Brian; Busse, Jason W; Mackillop, James","year":2023,"journal":"Addictive behaviors, 142, 107667","doi":"10.1016/j.addbeh.2023.107667","pmid":"36893511","tags":["addiction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 125 inpatients, 42% reported medical-only cannabis use and 58% reported dual medical and recreational use. CUD prevalence was 28% in the medical-only group and 51% in the dual-use group (p = 0.016). Psychiatric comorbidities were extremely high in both groups: anxiety 79-81%, depression 60-61%, PTSD 57-66%.","whyItMatters":"Medical cannabis is often framed as distinct from recreational use, but this study shows that a significant proportion of people citing medical reasons for use meet criteria for a cannabis use disorder, especially when recreational use is also involved. The extremely high psychiatric comorbidity rates highlight the complex clinical picture.","specificNumbers":"125 inpatients. 42% medical-only, 58% dual-use. CUD: 28% medical-only, 51% dual-use (p = 0.016). Anxiety: 79-81%. Depression: 60-61%. PTSD: 57-66%.","methodology":"Cross-sectional study of 125 inpatients in substance use disorder treatment who reported medical cannabis use at admission. Assessed CUD via DSM-5 criteria, anxiety (GAD-7), depression (PHQ-9), and PTSD (PCL-5).","limitations":"Sample is from inpatient addiction treatment, so results cannot be generalized to all medical cannabis users. Small sample size. Cross-sectional design cannot determine causation. Self-reported cannabis use motives may not be reliable."},{"rthcId":"RTHC-04805","title":"Retrospective chart review study of use of cannabidiol (CBD) independent of concomitant clobazam use in patients with Lennox-Gastaut syndrome or Dravet syndrome.","authors":"Nabbout, Rima; Arzimanoglou, Alexis; Auvin, Stéphane; Berquin, Patrick; Desurkar, Archana; Fuller, Douglas; Nortvedt, Charlotte; Pulitano, Patrizia; Rosati, Anna; Soto, Victor; Villanueva, Vicente; Cross, J Helen","year":2023,"journal":"Seizure, 110, 78-85","doi":"10.1016/j.seizure.2023.05.003","pmid":"37331197","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 107 patients (92 LGS, 15 DS) receiving CBD without clobazam for at least 3 months, median seizure frequency change ranged from -6.2% to -20.9% for LGS and 0% to -16.7% for DS over 3-month intervals. At 12 months, 30% of LGS and 13% of DS patients achieved 50%+ seizure reduction. Retention on CBD without clobazam was 63% at 12 months. Adverse events occurred in 31%, mostly somnolence, seizure, diarrhea, and decreased appetite.","whyItMatters":"Most clinical trials of CBD for epilepsy included clobazam, raising questions about whether CBD works independently. This real-world study provides evidence that CBD without clobazam still provides meaningful seizure reduction for some patients with severe epilepsy syndromes.","specificNumbers":"107 patients (92 LGS, 15 DS). Mean CBD dose: 13.54 mg/kg/day (LGS), 11.56 mg/kg/day (DS). 50%+ seizure reduction at 12 months: 30% LGS, 13% DS. 12-month retention: 63%. Adverse events: 31%. Four patients had elevated liver enzymes.","methodology":"Retrospective chart review of patients aged 2+ with LGS or DS enrolled in a European Early Access Program for plant-derived CBD (Epidyolex). Data covered 3 months before through 12 months after CBD initiation. Only patients not taking clobazam were included.","limitations":"No placebo control or randomization. Retrospective chart review with potential for incomplete documentation. Small DS subgroup (n = 15). Open-label design introduces expectation bias. Mean CBD dose was below the upper end of the approved dose range."},{"rthcId":"RTHC-04806","title":"The impact of in utero cannabis exposure on fetal growth.","authors":"Nadolski, K; Dodge, P; Kopkau, H; Forrestal, K; Zablocki, V; Bailey, B A","year":2023,"journal":"Journal of neonatal-perinatal medicine, 16(3), 485-490","doi":"10.3233/NPM-221133","pmid":"37718860","tags":["pregnancy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After controlling for confounders, cannabis exposure predicted significant deficits in birth weight and head circumference. Head circumference reductions were evident as early as the second-trimester anatomy ultrasound and persisted through birth, with an adjusted deficit of more than 14 percentile points. Overall length and bone length were not significantly affected after controlling for confounding.","whyItMatters":"This study isolates cannabis effects from other substances by excluding tobacco, alcohol, and other drug users. The finding that head circumference deficits appear as early as the second trimester and grow by birth suggests cannabis may specifically affect fetal brain growth during a critical developmental window.","specificNumbers":"109 cannabis-exposed vs 171 controls. Head circumference deficit: more than 14 percentile points by birth. Head size differences significant starting at second-trimester ultrasound. Birth weight significantly reduced. Length not significantly affected.","methodology":"Retrospective cohort comparing 109 cannabis-exposed pregnancies (identified via self-report and urine screens) to 171 non-substance-using controls. All women had prenatal visits between 2010-2020, anatomy ultrasounds at 18-24 weeks, and no alcohol, tobacco, or other drug use. Regression analyses controlled for significant confounders.","limitations":"Observational design cannot prove causation. Cannabis use identified by self-report and urine screens, which may miss or misclassify exposure. Cannot account for cannabis potency, frequency, or trimester of use. Relatively small sample size."},{"rthcId":"RTHC-04807","title":"Cannabinoid Hyperemesis Syndrome in a 23-Year-Old Woman with Uncontrolled Type 1 Diabetes Mellitus.","authors":"Nana Sede Mbakop, Raissa; Kesiena, Onoriode; Greene, Tayla E; Amakye, Dominic","year":2023,"journal":"The American journal of case reports, 24, e938418","doi":"10.12659/AJCR.938418","pmid":"36806029","tags":["harm-reduction","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient presented monthly to the ER for two years with intractable nausea and vomiting, managed as diabetic gastroparesis despite a normal gastric emptying study. She reported consistent cannabis use for several years and symptom relief with hot baths. After counseling, she stopped cannabis for two months and was completely symptom-free.","whyItMatters":"Cannabinoid hyperemesis syndrome (CHS) can mimic conditions common in diabetes like gastroparesis, leading to years of misdiagnosis. This case underscores the importance of asking about cannabis use in patients with cyclic vomiting, especially when standard treatments fail and gastric emptying is normal.","specificNumbers":"Monthly ER visits for 2 years. Normal gastric emptying study 6 months prior. Multiple unremarkable abdominal CT scans. Complete symptom resolution after 2 months cannabis cessation.","methodology":"Single case report of a 23-year-old woman with uncontrolled type 1 diabetes presenting with cannabinoid hyperemesis syndrome misdiagnosed as diabetic gastroparesis.","limitations":"Single case report cannot establish generalizable patterns. The patient had uncontrolled diabetes, which could contribute to GI symptoms independently. No objective measurement of cannabis use or cessation."},{"rthcId":"RTHC-04808","title":"The Abundant Phytocannabinoids in Rheumatoid Arthritis: Therapeutic Targets and Molecular Processes Identified Using Integrated Bioinformatics and Network Pharmacology.","authors":"Nandi, Arijit; Das, Anwesha; Dey, Yadu Nandan; Roy, Kuldeep K","year":2023,"journal":"Life (Basel, Switzerland), 13(3)","doi":"10.3390/life13030700","pmid":"36983855","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04809","title":"Genome-wide DNA methylation association study of recent and cumulative marijuana use in middle aged adults.","authors":"Nannini, Drew R; Zheng, Yinan; Joyce, Brian T; Kim, Kyeezu; Gao, Tao; Wang, Jun; Jacobs, David R; Schreiner, Pamela J; Yaffe, Kristine; Greenland, Philip; Lloyd-Jones, Donald M; Hou, Lifang","year":2023,"journal":"Molecular psychiatry, 28(6), 2572-2582","doi":"10.1038/s41380-023-02106-y","pmid":"37258616","tags":["genetics","cognition","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"At examination year 15 (n = 1,023), 22 and 31 methylation markers were associated with recent and cumulative marijuana use. At year 20 (n = 883), 132 and 16 markers were found. Eight previously reported markers were replicated. The study identified 640 cis-meQTLs and 198 differentially methylated regions. Affected genes were overrepresented in pathways related to cellular proliferation, hormone signaling, and infections, as well as schizophrenia, bipolar disorder, and substance-related disorders.","whyItMatters":"This is one of the first studies to examine how cumulative, long-term marijuana use affects the epigenome in middle-aged adults. The enrichment of affected genes in psychiatric disorder pathways provides a potential biological mechanism linking chronic cannabis use to mental health outcomes.","specificNumbers":"Year 15: 1,023 participants, 22 markers (recent use), 31 markers (cumulative). Year 20: 883 participants, 132 markers (recent), 16 markers (cumulative). 8 previously reported markers replicated. 640 cis-meQTLs. 198 differentially methylated regions.","methodology":"Epigenome-wide association study within the CARDIA longitudinal cohort. Whole blood DNA methylation profiled at years 15 and 20 using the Illumina MethylationEPIC BeadChip. Recent and cumulative marijuana use assessed from year 0. FDR-corrected significance threshold.","limitations":"Observational study cannot determine causation. Blood-based methylation may not reflect brain tissue changes. Self-reported marijuana use. Cannot rule out confounding by other lifestyle factors. Effect sizes of individual methylation changes were small."},{"rthcId":"RTHC-04810","title":"Assessing Efficacy and Use Patterns of Medical Cannabis for Symptom Management in Elderly Cancer Patients.","authors":"Nathan, Rachel; Mupamombe, Charles T; Elibol, John; Case, Amy A; Smith, Danielle; Hyland, Andrew; Attwood, Kristopher; Hansen, Eric D","year":2023,"journal":"The American journal of hospice & palliative care, 40(4), 368-373","doi":"10.1177/10499091221110217","pmid":"35749740","tags":["medical-cannabis","cancer","pain","seniors"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"There was no statistically significant difference in symptom scores for pain, nausea, appetite, insomnia, or anxiety before versus after medical cannabis initiation. Oil was the most common form used, followed by vape. The most common product ratios were high THC:CBD and equal parts THC:CBD.","whyItMatters":"Despite growing use of medical cannabis for cancer symptom management, evidence in elderly patients specifically remains limited. This null result is important because it tempers expectations while also highlighting the need for larger, prospective studies in this vulnerable population.","specificNumbers":"No statistically significant changes in any of five symptom domains measured. Oil most common form, followed by vape. High THC:CBD and equal THC:CBD ratios most commonly used.","methodology":"Retrospective chart review assessing changes in numerical symptom scores reported at clinic visits before and after medical cannabis initiation in elderly cancer patients.","limitations":"Retrospective chart review with likely small sample size and inconsistent follow-up. No control group. Self-reported symptom scores. Variable products, doses, and duration of use. Selection bias in who gets prescribed medical cannabis."},{"rthcId":"RTHC-04811","title":"Cannabis-based magistral formulation is highly effective as an adjuvant treatment in drug-resistant focal epilepsy in adult patients: an open-label prospective cohort study.","authors":"Navarro, Cristian Eduardo","year":2023,"journal":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 44(1), 297-304","doi":"10.1007/s10072-022-06393-1","pmid":"36129615","tags":["epilepsy","cbd","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 44 patients who completed 3+ months of follow-up, median monthly seizures dropped from 11 to 2.5 (p < significant). At 12 weeks, 79.5% achieved 50%+ seizure reduction, and the median percentage change in seizure frequency was 84.1%. Only five patients reported adverse drug reactions. The median daily dose was 200mg CBD / 4mg THC (3.7 mg CBD/kg).","whyItMatters":"Most CBD epilepsy research has focused on children and on specific syndromes like Lennox-Gastaut and Dravet. This study extends the evidence to adult drug-resistant focal epilepsy, a common form of epilepsy, showing striking response rates with a CBD-dominant formulation.","specificNumbers":"44 patients completed 3+ months. Median seizures: 11/month before, 2.5/month after. 79.5% achieved 50%+ reduction at 12 weeks. 84.1% median seizure frequency reduction. Dose: 200mg CBD/day, 4mg THC/day, 3.7 mg/kg CBD. Only 5 adverse reactions.","methodology":"Open-label, prospective cohort, single-center study of adults with drug-resistant focal epilepsy on stable antiepileptic drugs. Added a cannabis-based magistral formulation (100mg/mL CBD, <2mg/mL THC). Follow-up from August 2020 to July 2022.","limitations":"Open-label, single-center study without placebo control. Only 44 of 114 enrolled patients completed 3+ months, introducing selection bias. No blinding means expectation effects may contribute to results. The formulation includes some THC, making it hard to attribute all effects to CBD."},{"rthcId":"RTHC-04812","title":"Prescription drug dependence with and without concurrent illicit drug use: a multicenter cross-sectional survey among an addiction treatment seeking population.","authors":"Nawaz, Asma; Nielsen, Suzanne; Mehmood, Tahir; Abdullah, Abdullah; Ahmed, Ali; Ullah, Waseem; Khan, Ahmad","year":2023,"journal":"Frontiers in psychiatry, 14, 1133606","doi":"10.3389/fpsyt.2023.1133606","pmid":"37324815","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04813","title":"Immunomodulatory Actions of Cannabinoids: Clinical Correlates and Therapeutic Opportunities for Allergic Inflammation.","authors":"Nayak, Ajay P; Loblundo, Cali; Bielory, Leonard","year":2023,"journal":"The journal of allergy and clinical immunology. In practice, 11(2), 449-457","doi":"10.1016/j.jaip.2022.10.009","pmid":"36280137","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04814","title":"The Use of Cannabinoids in the Treatment of Inflammatory Bowel Disease (IBD): A Review of the Literature.","authors":"Nduma, Basil N; Mofor, Kelly A; Tatang, Jason; Ekhator, Chukwuyem; Ambe, Solomon; Fonkem, Ekokobe","year":2023,"journal":"Cureus, 15(3), e36148","doi":"10.7759/cureus.36148","pmid":"37065370","tags":["medical-cannabis","inflammation","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The majority of selected studies reported reduced clinical complications as measured by Mayo scores, CDAI, Lichtiger Index, and Harvey-Bradshaw Index, along with weight gain and improved patient wellbeing. However, outcomes were highly heterogeneous across study designs, disease activity measures, treatment durations, administration modes, and dosing protocols.","whyItMatters":"IBD patients increasingly use cannabis for symptom relief, and 15-40% of IBD patients worldwide report using cannabinoids. This review consolidates the evidence, confirming promising signals while honestly acknowledging that the research is too heterogeneous to guide clinical practice.","specificNumbers":"15-40% of IBD patients worldwide use cannabis or cannabinoids. Most studies reported improvements in clinical indices (Mayo, CDAI, Harvey-Bradshaw, Lichtiger). High heterogeneity across all study parameters.","methodology":"Systematic review following PRISMA guidelines, examining published research from 2012-2022 on cannabinoid use in IBD treatment. Assessed outcomes including clinical activity indices, symptom relief, and general wellbeing.","limitations":"High heterogeneity in study designs, dosing, duration, administration routes, and outcome measures. Many included studies were small or observational. Generalizability limited by inconsistent methodology. Publication bias may favor positive results."},{"rthcId":"RTHC-04815","title":"Ecological investigation of the co-occurrence of posttraumatic stress disorder symptoms and cannabis use among community women experiencing intimate partner violence.","authors":"Newberger, Noam G; Forkus, Shannon R; Thomas, Emmanuel D; Goldstein, Silvi C; Ferguson, Jewelia J; Sullivan, Tami P; Weiss, Nicole H","year":2023,"journal":"Drug and alcohol dependence, 250, 110905","doi":"10.1016/j.drugalcdep.2023.110905","pmid":"37515827","tags":["ptsd","mental-health","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Externalizing behavior (OR 1.37) and dysphoric arousal (OR 1.27) PTSD symptom clusters were associated with cannabis use reported in the same survey period. However, lagged analyses found no proximal association, meaning elevated PTSD symptoms did not predict cannabis use in the next survey period. Other PTSD clusters (re-experiencing, avoidance, negative cognitions) were not associated with cannabis use.","whyItMatters":"This is one of the first studies to use real-time data collection to examine which specific PTSD symptoms co-occur with cannabis use in women experiencing IPV. Finding that externalizing and arousal symptoms, but not other clusters, are linked to cannabis use helps identify when women may be most vulnerable to coping-motivated use.","specificNumbers":"145 women. 3 surveys/day for 30 days. Mean age 40.66. 41.6% white, 31.4% Black, 10.9% Hispanic. Externalizing behavior: OR 1.37 (95% CI 1.15-1.65). Dysphoric arousal: OR 1.27 (95% CI 1.09-1.49). No significant lagged effects.","methodology":"Ecological momentary assessment (experience sampling) with 145 community women experiencing IPV who completed three surveys daily for 30 days. Multilevel models examined concurrent and lagged associations between PTSD symptom clusters and cannabis use.","limitations":"Cannot determine directionality from concurrent associations. Self-reported substance use may be underreported. Sample is community women experiencing IPV, limiting generalizability. Cannabis use frequency and amount not captured in detail."},{"rthcId":"RTHC-04816","title":"Consumer perception, knowledge, and uses of cannabidiol.","authors":"Nguyen, Cambrey; Moeller, Karen E; McGuire, Michael; Melton, Brittany L","year":2023,"journal":"The mental health clinician, 13(5), 217-224","doi":"10.9740/mhc.2023.10.217","pmid":"38131055","tags":["cbd","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 1,158 respondents (median age 43, 50% female), CBD was used for neurological disorders, pulmonary conditions, GI disorders, and chronic pain. Participants agreed CBD is safe when used responsibly for medical purposes. Social media was the main information source. However, most reported adverse effects were rated moderate to severe, requiring medical attention from a healthcare professional, hospital, or ER.","whyItMatters":"The gap between perceived safety and actual adverse event severity is concerning. If consumers rely primarily on social media for CBD information and believe it is generally safe, they may not recognize or seek timely care for adverse effects. This has implications for consumer education.","specificNumbers":"1,158 respondents. Median age 43. 50% female. Social media was the primary CBD information source. Most adverse effects rated moderate to severe. Uses included neurological disorders, pulmonary conditions, GI disorders, chronic pain.","methodology":"Anonymous nationwide online survey administered through Qualtrics from March to April 2021 in the United States. Assessed demographics, perceived efficacy and safety of CBD, and information sources. Descriptive statistics and Likert scale analyses.","limitations":"Online survey with potential selection bias. Self-reported data without medical verification of conditions or adverse effects. Qualtrics panel may not be truly representative. Cannot determine CBD product quality, dose, or interaction with other substances."},{"rthcId":"RTHC-04817","title":"Beneficial metabolic transformations and prebiotic potential of hemp bran and its alcalase hydrolysate, after colonic fermentation in a gut model.","authors":"Nissen, Lorenzo; Casciano, Flavia; Babini, Elena; Gianotti, Andrea","year":2023,"journal":"Scientific reports, 13(1), 1552","doi":"10.1038/s41598-023-27726-w","pmid":"36707683","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04818","title":"Association of maternal exposure to Superstorm Sandy and maternal cannabis use with development of psychopathology among offspring: the Stress in Pregnancy Study.","authors":"Nomura, Yoko; Ham, Jacob; Pehme, Patricia M; Wong, Waiman; Pritchett, Lexi; Rabinowitz, Sima; Foldi, Nancy S; Hinton, Veronica J; Wickramaratne, Priya J; Hurd, Yasmin L","year":2023,"journal":"BJPsych open, 9(3), e94","doi":"10.1192/bjo.2022.595","pmid":"37231817","tags":["pregnancy","mental-health","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 163 children tracked from ages 2-5, those exposed to both Superstorm Sandy and maternal cannabis use (8% of sample) had a 31-fold increased risk of disruptive behavioral disorders and a 7-fold increased risk of anxiety disorders compared to those exposed to neither. The synergy index showed effects were multiplicative, not just additive: DBD synergy index 2.06 (p = 0.03), anxiety synergy index 2.60 (p = 0.004). Children with dual exposure also had the highest parenting stress and lowest social support.","whyItMatters":"This study demonstrates that prenatal adversities do not simply add up but can multiply each other's effects. The \"double-hit\" model suggests that fetuses exposed to both stress and cannabis face compounding biological insults that dramatically increase psychiatric risk in early childhood.","specificNumbers":"163 children. 40.5% exposed to Superstorm Sandy. 24.5% exposed to maternal cannabis. 8% exposed to both. Dual exposure: 31-fold DBD risk, 7-fold anxiety risk. Synergy index for DBD: 2.06 (p = 0.03). Synergy index for anxiety: 2.60 (p = 0.004).","methodology":"Longitudinal cohort of 163 children (53.4% girls) tracked from ages 2-5. Offspring grouped by prenatal exposure: neither, maternal cannabis only, Superstorm Sandy only, or both. DSM-IV disorders assessed via structured clinical interviews. Synergy indices calculated to test multiplicative interaction.","limitations":"Small sample, especially the dual-exposure group (n = 13). Cannot determine if cannabis use increased after the storm. Observational design with potential confounding. DSM-IV disorders in 2-5 year olds may be less reliable. Short follow-up period."},{"rthcId":"RTHC-04819","title":"Evaluating the Supporting Evidence of Medical Cannabis Claims Made on Clinic Websites: Cross-Sectional Study.","authors":"O'Neill, Braden; Ferguson, Jacob; Dalueg, Lauren; Yusuf, Abban; Kirubarajan, Abirami; Lloyd, Taryn; Mollanji, Eisi; Persaud, Navindra","year":2023,"journal":"Journal of medical Internet research, 25, e45550","doi":"10.2196/45550","pmid":"37384372","tags":["medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Twenty-nine cannabis clinics in Ontario promoted cannabis for 20 different medical indications including migraines, insomnia, and fibromyalgia. They cited 235 unique studies, but 15.3% (36/235) were at the lowest level of evidence (level 5 on the Oxford rubric). Only 4 clinic websites included any mention of harms associated with cannabis use.","whyItMatters":"Patients often encounter cannabis clinic websites when researching medical cannabis. If these sites present low-quality evidence as fact and omit harm information, patients and physicians may make treatment decisions based on misleading information.","specificNumbers":"29 clinics identified. 20 medical indications promoted. 235 unique studies cited. 15.3% at lowest evidence level (level 5). Only 4 of 29 clinics mentioned any harms.","methodology":"Cross-sectional web search identifying all cannabis clinic websites in Ontario, Canada, with physician involvement. Two independent reviewers identified all promoted medical indications and critically appraised all cited studies using the Oxford Centre for Evidence-Based Medicine Levels of Evidence rubric.","limitations":"Limited to Ontario, Canada. Websites may have changed since search. Only evaluated publicly available content. Did not assess what clinicians told patients during consultations."},{"rthcId":"RTHC-04820","title":"Medicinal Cannabis and Implications for Workplace Health and Safety: Scoping Review of Systematic Reviews.","authors":"O'Neill, Veronica; Karanikas, Nektarios; Sav, Adem; Murphy, Patricia","year":2023,"journal":"Workplace health & safety, 71(9), 400-410","doi":"10.1177/21650799231157086","pmid":"37077169","tags":["medical-cannabis","workplace","harm-reduction"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Across 31 systematic reviews and meta-analyses, the most predominant adverse events of medical cannabis were sedation, nausea/vomiting, dizziness, and euphoria. These could translate to decreased alertness and reaction times, increased absenteeism, reduced ability to safely drive or operate machinery, and increased fall probability.","whyItMatters":"As medical cannabis prescriptions increase, more workers are using cannabis therapeutically while on the job. Employers and occupational health professionals need to understand the specific adverse effects that could compromise safety.","specificNumbers":"1,326 papers screened, 31 included. Most common adverse events: sedation, nausea/vomiting, dizziness, euphoria. Pain was the most prevalent condition studied.","methodology":"Scoping review of systematic reviews and meta-analyses published from 2015 to March 2021, identified from six databases. Of 1,326 papers initially identified, 31 met inclusion criteria.","limitations":"Scoping review of reviews means original data was not directly assessed. Cannot quantify actual workplace accident rates. Does not distinguish between formulations or dosing schedules."},{"rthcId":"RTHC-04821","title":"The therapeutic potential of purified cannabidiol.","authors":"O'Sullivan, Saoirse Elizabeth; Jensen, Sanne Skov; Nikolajsen, Gitte Nykjaer; Bruun, Heidi Ziegler; Bhuller, Rhenu; Hoeng, Julia","year":2023,"journal":"Journal of cannabis research, 5(1), 21","doi":"10.1186/s42238-023-00186-9","pmid":"37312194","tags":["cbd","anxiety","psychosis","ptsd","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The areas with the most clinical evidence for purified CBD were anxiety (7 uncontrolled + 17 RCTs), psychosis/schizophrenia (1 uncontrolled + 8 RCTs), PTSD (2 uncontrolled + 4 RCTs), and substance abuse (2 uncontrolled + 3 RCTs). Sleep had 7 positive uncontrolled studies but only 1 small RCT. Current RCT evidence did not support purified oral CBD for pain, COVID, cancer, Huntington's, or type 2 diabetes.","whyItMatters":"By focusing exclusively on purified CBD studies, this review strips away the confound of THC and other plant compounds, giving a clearer picture of what CBD alone can and cannot do.","specificNumbers":"Anxiety: 17 positive RCTs. Psychosis: 8 positive RCTs. PTSD: 4 positive RCTs. Substance abuse: 3 positive RCTs. Sleep: only 1 RCT. Pain: not supported.","methodology":"Critical review of clinical studies using purified CBD products only (excluding products with THC or other phytochemicals). Organized by indication and evidence level.","limitations":"Many trials tested only acute single-dose CBD. Several studied healthy volunteers. Many had small sample sizes. No meta-analysis conducted."},{"rthcId":"RTHC-04822","title":"Drug-impaired driving and traffic collisions: Study on a cross section of the Italian population.","authors":"Odoardi, Sara; Biosa, Giulia; Mestria, Serena; Valentini, Valeria; De Giovanni, Nadia; Cittadini, Francesca; Strano Rossi, Sabina","year":2023,"journal":"Drug testing and analysis, 15(5), 477-483","doi":"10.1002/dta.3366","pmid":"36082405","tags":["driving","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,236 drivers in crashes, alcohol was most common (19% non-fatal, 32% fatal), followed by cannabinoids (12% non-fatal) and cocaine (9% non-fatal, 20% fatal). While urinary cannabis metabolite levels were high (THCCOOH 15-270 ng/mL), blood THC was often below 1 ng/mL. Cannabis crash odds ratio: 8.13. Cocaine OR: 5.32.","whyItMatters":"The finding that crash risk was elevated even when blood THC was very low challenges the assumption that impairment ends when active drug levels drop.","specificNumbers":"1,236 drivers. Alcohol: 19% non-fatal, 32% fatal. Cannabis: 12% non-fatal. Cocaine: 9% non-fatal, 20% fatal. Cannabis crash OR: 8.13. Cocaine OR: 5.32. Blood THC often below 1 ng/mL.","methodology":"Cross-sectional analysis of biological fluids from 1,236 drivers involved in road accidents in the Rome area, analyzed for alcohol and psychotropic drugs. Blood and urine results compared. Odds ratios calculated against a control population.","limitations":"Cross-sectional with crash-involved drivers only. Urinary metabolites persist for weeks. Cannot determine if cannabis caused the crash. Italian context may differ."},{"rthcId":"RTHC-04823","title":"Behavioral, biochemical and histopathological toxic profiles induced by sub-chronic cannabimimetic WIN55, 212-2 administration in mice.","authors":"Omran, Ghada A; Abd Allah, Eman S H; Mohammed, Sherine Ahmed; El Shehaby, Doaa M","year":2023,"journal":"BMC pharmacology & toxicology, 24(1), 8","doi":"10.1186/s40360-023-00644-3","pmid":"36750905","tags":["synthetic-cannabinoids","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"WIN55,212-2 produced dose-dependent anxiogenic effects and reduced locomotor activity, with female mice less compromised than males. GABA and glutamate levels increased significantly. No significant liver or kidney changes. CB1 receptor expression increased in both dose groups, with higher expression in female brains.","whyItMatters":"Synthetic cannabinoids are far more potent than natural cannabis. This study shows even sub-chronic exposure produces measurable anxiety, neurochemical changes, and altered receptor expression, with important sex differences.","specificNumbers":"40 mice (20M/20F). Two doses: 0.05 and 0.1 mg/kg. Dose-dependent anxiety and reduced locomotion. Significant GABA and glutamate increases. Female mice less behaviorally affected. Higher CB1 expression in female brains.","methodology":"Controlled animal study with 40 adult mice randomized into four groups per sex: control, vehicle, low dose (0.05 mg/kg), and high dose (0.1 mg/kg). Assessed behavior, biochemistry, histopathology, and CB1 immunohistochemistry.","limitations":"Animal study. Small group sizes (5 per group). Sub-chronic dosing does not capture chronic heavy use patterns. Only two doses tested."},{"rthcId":"RTHC-04824","title":"Towards a New Dynamic Interaction Model of Adolescent CUD Manifestation, Prevention, and Treatment: A Narrative Review.","authors":"Oosten, Wesley; Vos, Elena; Los, Leontien; Nelwan, Michel; Pieters, Toine","year":2023,"journal":"Psychoactives, 2(4), 294-316","doi":"10.3390/psychoactives2040019","pmid":"39280928","tags":["addiction","youth","cognition"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The review adapts Zinberg's drug-set-setting framework to propose CUD in adolescents develops through multiple interacting feedback loops. Cannabis use impairs school performance and motivation, which increases risk of further use. The model identifies specific intervention points for parents, social workers, and addiction professionals.","whyItMatters":"Most CUD prevention approaches target individual factors or drug availability separately. This model argues all three dimensions must be addressed simultaneously because they create feedback loops.","specificNumbers":"Cannabis is one of the most popular drugs among adolescents. Regular use predicts mental health problems, reduced motivation, and school dropout.","methodology":"Hypothesis-based and model-generating narrative review searching PubMed and Web of Science.","limitations":"Theoretical model not empirically tested. Does not quantify the relative contribution of each dimension."},{"rthcId":"RTHC-04825","title":"Self-Regulation of Driving Behavior Under the Influence of Cannabis: The Role of Driving Complexity and Driver Vision.","authors":"Ortiz-Peregrina, Sonia; Oviedo-Trespalacios, Oscar; Ortiz, Carolina; Anera, Rosario G","year":2023,"journal":"Human factors, 65(7), 1506-1524","doi":"10.1177/00187208211047799","pmid":"34601949","tags":["driving","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"After smoking cannabis, visual acuity and contrast sensitivity were significantly impaired. However, drivers did not reduce speed. Road curves did prompt self-regulation. Males drove faster than females. Those with greater contrast sensitivity impairment showed some lateral control changes.","whyItMatters":"This challenges the argument that cannabis users \"know they are impaired\" and compensate by driving more cautiously.","specificNumbers":"31 young occasional cannabis users. Significant visual impairment. No speed self-regulation. Males drove faster. Contrast sensitivity linked to lateral control.","methodology":"Within-subjects design with 31 young occasional cannabis users assessed at baseline and post-cannabis in a driving simulator.","limitations":"Small sample (n = 31). Simulator may not reflect real driving. Only occasional users. Single session."},{"rthcId":"RTHC-04826","title":"Use of cannabidiol (CBD) for the treatment of cognitive impairment in psychiatric and neurological illness: A narrative review.","authors":"Ortiz, Rachel; Rueda, Sergio; Di Ciano, Patricia","year":2023,"journal":"Experimental and clinical psychopharmacology, 31(5), 978-988","doi":"10.1037/pha0000659","pmid":"37126037","tags":["cbd","cognition","mental-health"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Preclinical studies demonstrated CBD improved cognitive performance in animal models of schizophrenia, epilepsy, Alzheimer's, and others. Clinical studies have not found consistent evidence. More research is needed.","whyItMatters":"Cognitive impairment is a major component of many disorders and is often treatment-resistant. The failure to translate animal CBD findings to humans is a critical gap.","specificNumbers":"Preclinical evidence positive across multiple disease models. Clinical evidence not consistently supportive.","methodology":"Narrative review evaluating preclinical and clinical data on CBD for cognitive impairment across multiple disorders.","limitations":"Narrative review without meta-analysis. Limited clinical studies. Varying assessment tools and doses."},{"rthcId":"RTHC-04827","title":"Recurrent Severe Burns Due to Cannabinoid Hyperemesis Syndrome.","authors":"Osagie, Eugene; Mirza, Omar","year":2023,"journal":"Cureus, 15(2), e34552","doi":"10.7759/cureus.34552","pmid":"36879712","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A chronic daily cannabis user with CHS engaged in compulsive hot bathing, leading to repeated severe burns, sepsis, and ICU stays. First published case of severe burns from CHS-related bathing.","whyItMatters":"CHS is increasingly recognized, but the hot bathing behavior can escalate to life-threatening burns during intense vomiting when judgment is impaired.","specificNumbers":"Multiple severe burn episodes. Multiple ICU hospitalizations. Multiple sepsis episodes.","methodology":"Single case report of a 36-year-old female with CHS.","limitations":"Single case. Cannot generalize. No temperature or duration data."},{"rthcId":"RTHC-04828","title":"Cannabis Use and Its Association With Thirty- and Ninety-Day Hospital Readmissions for Patients Admitted for an Inflammatory Bowel Disease Exacerbation.","authors":"Oseni, Ellen A; Blumenthal, Miriam; Izard, Stephanie; Qiu, Michael; Mone, Anjali; Swaminath, Arun; Sultan, Keith","year":2023,"journal":"Journal of clinical medicine research, 15(2), 99-108","doi":"10.14740/jocmr4846","pmid":"36895626","tags":["medical-cannabis","inflammation"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 1,021 IBD admissions, 7.25% reported cannabis use. Cannabis was associated with 30-day readmission in UC (OR 2.48) but not CD (OR 0.59). No association with 90-day readmission (OR 1.19).","whyItMatters":"Many IBD patients use cannabis for symptom relief. This study suggests cannabis may be associated with worse short-term outcomes specifically in ulcerative colitis.","specificNumbers":"1,021 admissions. 74 (7.25%) reported cannabis. UC 30-day readmission OR: 2.48. CD OR: 0.59. 90-day OR: 1.19 (not significant).","methodology":"Retrospective review of adults admitted for IBD exacerbation from 2016-2020 within Northwell Health. Cannabis identified through admission document text search.","limitations":"Retrospective. Text-based cannabis identification likely underestimates. Few cannabis users (74). Cannot determine dose or frequency."},{"rthcId":"RTHC-04829","title":"Study design to evaluate a web-intervention to prevent alcohol and cannabis-impaired driving and use among adolescents in driver education.","authors":"Osilla, Karen Chan; D'Amico, Elizabeth J; Smart, Rosanna; Rodriguez, Anthony; Nameth, Katherine; Hummer, Justin","year":2023,"journal":"Addiction science & clinical practice, 18(1), 17","doi":"10.1186/s13722-023-00373-2","pmid":"36964608","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04830","title":"Co-use of cigarettes and cannabis among people with HIV: Results from a randomized controlled smoking cessation trial.","authors":"Ozga, Jenny E; Shuter, Jonathan; Chander, Geetanjali; Graham, Amanda L; Kim, Ryung S; Stanton, Cassandra A","year":2023,"journal":"Drug and alcohol dependence reports, 7, 100172","doi":"10.1016/j.dadr.2023.100172","pmid":"37342512","tags":["quitting","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Increased cannabis use was associated with reduced odds of cigarette abstinence at 6 months vs decreased use (aOR 0.22) or no use (aOR 0.25). Cannabis non-use increased from 18.2% to 34.3% over 6 months.","whyItMatters":"People with HIV smoke at higher rates with lower cessation rates. If increasing cannabis undermines quit attempts, this is critical clinical information.","specificNumbers":"374 participants. 198 used cannabis. Increased use: aOR 0.22 vs decreased use. Cannabis non-use rose from 18.2% to 34.3%.","methodology":"Secondary analysis of an RCT for cigarette cessation among PWH. 374 participants reported past-30-day cannabis use across four visits.","limitations":"Secondary analysis. Self-reported cannabis. Small subgroups. PWH population may not generalize."},{"rthcId":"RTHC-04831","title":"Concerns Related to the Consequences of Pediatric Cannabis Use: A 360-Degree View.","authors":"Padoan, Flavia; Colombrino, Chiara; Sciorio, Francesca; Piacentini, Giorgio; Gaudino, Rossella; Pietrobelli, Angelo; Pecoraro, Luca","year":2023,"journal":"Children (Basel, Switzerland), 10(11)","doi":"10.3390/children10111721","pmid":"38002812","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04832","title":"Cannabis and Rheumatoid Arthritis: A Scoping Review Evaluating the Benefits, Risks, and Future Research Directions.","authors":"Paland, Nicole; Hamza, Haya; Pechkovsky, Antonina; Aswad, Miran; Shagidov, Dayana; Louria-Hayon, Igal","year":2023,"journal":"Rambam Maimonides medical journal, 14(4)","doi":"10.5041/RMMJ.10509","pmid":"37917863","tags":["medical-cannabis","pain","inflammation","cbd"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Preclinical studies demonstrated cannabinoids can halt disease progression and relieve pain. Clinical studies are scarce with mixed results. No clinical recommendations exist.","whyItMatters":"Many patients already use cannabis without clinical guidance. The evidence base is insufficient for practice.","specificNumbers":"Preclinical: promising. Clinical: scarce with mixed results. No recommendations. Conditions: RA, OA, fibromyalgia.","methodology":"Scoping review examining preclinical and clinical data on cannabis for RA, osteoarthritis, and fibromyalgia.","limitations":"Heterogeneous studies. Limited clinical data. Variable formulations and dosing."},{"rthcId":"RTHC-04833","title":"Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors.","authors":"Paredes-Ruiz, Karen Jaqueline; Chavira-Ramos, Karla; Galvan-Arzate, Sonia; Rangel-López, Edgar; Karasu, Çimen; Túnez, Isaac; Skalny, Anatoly V; Ke, Tao; Aschner, Michael; Orozco-Morales, Mario; Colín-González, Ana Laura; Santamaría, Abel","year":2023,"journal":"Neurotoxicity research, 41(6), 514-525","doi":"10.1007/s12640-023-00661-4","pmid":"37458923","tags":["neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"JZL184 attenuated 3-NP-induced mitochondrial dysfunction and lipid peroxidation. CB2 primarily mediated mitochondrial protection, CB1 mediated anti-oxidative protection in synaptosomes. In cortical slices, protection was receptor-independent.","whyItMatters":"This approach boosts the brain's own endocannabinoids rather than adding external cannabinoids, potentially offering neuroprotection without psychoactive effects.","specificNumbers":"CB2 mediated mitochondrial protection. CB1 mediated anti-oxidative protection. Both receptor-dependent and independent mechanisms found.","methodology":"In vitro study using rat brain synaptosomes and cortical slices. Tested MAGL inhibitor JZL184 against 3-NP toxicity with CB1/CB2 antagonists.","limitations":"In vitro study. Results differed between tissue preparations. Single toxin model."},{"rthcId":"RTHC-04834","title":"Cannabinoid CB1 Receptor Expression and Localization in the Dorsal Horn of Male and Female Rat and Human Spinal Cord.","authors":"Parnell, Jessica; Martin, Newton; Dedek, Annemarie; Rudyk, Christopher; Landrigan, Jeffrey; Bellavance, Justin; VanDerLoo, Simon; Tsai, Eve C; Hildebrand, Michael E","year":2023,"journal":"Canadian journal of pain = Revue canadienne de la douleur, 7(2), 2264895","doi":"10.1080/24740527.2023.2264895","pmid":"38170158","tags":["pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 immunoreactivity was significantly higher in the superficial vs deep dorsal horn in both species, conserved across sex. CB1 was not primarily on peptidergic afferents as thought. CNR1 but not CNR2 was robustly expressed in dorsal horn neurons.","whyItMatters":"Understanding cannabinoid receptor location in pain circuits is fundamental to developing cannabis-based pain treatments.","specificNumbers":"CB1 significantly higher in superficial vs deep dorsal horn. Conserved across species and sex. CNR1 robustly expressed; CNR2 not.","methodology":"Immunohistochemistry on rat and human spinal cord tissue combined with single-cell RNA sequencing analysis.","limitations":"Fixed tissue limitations. Limited human tissue. Did not assess functional activation."},{"rthcId":"RTHC-04835","title":"A systematic review of cannabidiol trials in neurodevelopmental disorders.","authors":"Parrella, Nina-Francecsa; Hill, Aron Thomas; Enticott, Peter Gregory; Barhoun, Pamela; Bower, Isabella Simone; Ford, Talitha Caitlyn","year":2023,"journal":"Pharmacology, biochemistry, and behavior, 230, 173607","doi":"10.1016/j.pbb.2023.173607","pmid":"37543051","tags":["cbd","epilepsy","youth"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Nine RCTs across ADHD, autism, intellectual disability, Tourette's, and complex motor disorders showed some positive signals but inconsistent results. Evidence is undetermined.","whyItMatters":"Clinical CBD use in neurodevelopmental disorders is expanding despite an alarmingly thin evidence base.","specificNumbers":"9 RCTs total across 5 conditions. Inconsistent results. Could not perform meta-analysis.","methodology":"Systematic review searching four databases with PROSPERO registration. Only RCTs included.","limitations":"Only 9 RCTs. High heterogeneity. No meta-analysis possible."},{"rthcId":"RTHC-04836","title":"Clinical characteristics and long-term outcomes in patients with cyclic vomiting syndrome: A 15-year experience at a tertiary referral center.","authors":"Partovi, Omeed; Patel, Milan; Kovacic, Katja; Petrova, Ana; Garacchi, Zhuping; Venkatesan, Thangam","year":2023,"journal":"Neurogastroenterology and motility, 35(7), e14571","doi":"10.1111/nmo.14571","pmid":"36989184","tags":["harm-reduction","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Episodes dropped from 18 to 6.8/year, ER visits from 6.1 to 2, hospitalizations from 2.3 to 0.7. Only 19% had complete resolution. Cannabis use OR 0.36 (p = 0.0007) for resolution. 19 patients (4%) died.","whyItMatters":"Largest long-term adult CVS follow-up. Cannabis was one of the strongest negative predictors, raising questions about CHS overlap.","specificNumbers":"455 patients. Episodes: 18 to 6.8/year. Resolution: 19%. Cannabis OR: 0.36. 4% mortality.","methodology":"Retrospective analysis of 455 CVS patients at a tertiary center, mean 47.4 months follow-up.","limitations":"Retrospective. Single center. Referral bias. Cannot distinguish CVS from CHS in all cases."},{"rthcId":"RTHC-04837","title":"A Case of a Patient With Cannabis Hyperemesis Syndrome Along With Recurrent Nephrolithiasis.","authors":"Patel, Maitree; Sathiya Narayanan, Rajalakshmi; Peela, Appala S","year":2023,"journal":"Cureus, 15(4), e37182","doi":"10.7759/cureus.37182","pmid":"37159782","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 28-year-old American Indian male with daily cannabis use and CHS presented with recurrent renal stones. CHS-related chronic dehydration and electrolyte imbalances are established risk factors for nephrolithiasis.","whyItMatters":"CHS complications extend beyond GI symptoms. Chronic vomiting promotes kidney stone formation through dehydration.","specificNumbers":"28-year-old male. Daily cannabis use. Recurrent renal stones.","methodology":"Single case report.","limitations":"Single case. Cannot prove causation. No stone composition data."},{"rthcId":"RTHC-04838","title":"Evaluating signaling bias for synthetic cannabinoid receptor agonists at the cannabinoid CB2 receptor.","authors":"Patel, Monica; Grimsey, Natasha L; Banister, Samuel D; Finlay, David B; Glass, Michelle","year":2023,"journal":"Pharmacology research & perspectives, 11(6), e01157","doi":"10.1002/prp2.1157","pmid":"38018694","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04839","title":"Prevalence and correlates of cannabis use among individuals with DSM-5 social anxiety disorder: Findings from a nationally representative sample.","authors":"Patel, Tapan A; Schubert, Frederick T; Zech, James M; Cougle, Jesse R","year":2023,"journal":"Journal of psychiatric research, 163, 406-412","doi":"10.1016/j.jpsychires.2023.05.079","pmid":"37276644","tags":["anxiety","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"In both lifetime (N=1,255) and past-year (N=980) SAD samples, weekly+ cannabis use was significantly related to fear or avoidance of social situations interfering with relationships. Weekly+ use and CUD were associated with lifetime SAD severity, but only weekly+ use was associated with past-year severity. Weekly+ use but not CUD was related to greater odds of seeking SAD treatment and suicide attempt history.","whyItMatters":"Frequency of cannabis use may be a better clinical marker than a formal CUD diagnosis for identifying people with social anxiety who are at greater risk. The suicide risk finding is particularly important for clinicians assessing anxious patients who use cannabis.","specificNumbers":"N=1,255 lifetime SAD, N=980 past-year SAD. Weekly+ use associated with greater SAD severity, treatment-seeking, and suicide attempt history. CUD associated with lifetime but not past-year severity. Weekly+ use was the stronger marker overall.","methodology":"Cross-sectional analysis of a large nationally representative sample using DSM-5 criteria. Examined lifetime (N=1,255) and past-year (N=980) social anxiety disorder subsamples.","limitations":"Cross-sectional design cannot determine causation. Self-reported cannabis use. People with worse anxiety may use more cannabis rather than cannabis worsening anxiety. DSM-5 criteria may classify differently than earlier versions."},{"rthcId":"RTHC-04840","title":"Efficacy and safety of cannabidiol for the treatment of canine osteoarthritis: a systematic review and meta-analysis of animal intervention studies.","authors":"Patikorn, Chanthawat; Nerapusee, Osot; Soontornvipart, Kumpanart; Lawonyawut, Kanta; Musikpodok, Kachapong; Waleethanaphan, Kanisorn; Anantachoti, Puree","year":2023,"journal":"Frontiers in veterinary science, 10, 1248417","doi":"10.3389/fvets.2023.1248417","pmid":"37781283","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04841","title":"Sex- and age-specific respiratory alterations induced by prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 in rats.","authors":"Patrone, Luis Gustavo A; Ferrari, Gustavo D; da Silva, Rodrigo Moreira; Alberici, Luciane C; Lopes, Norberto Peporine; Stabile, Angelita M; Klein, Wilfried; Bícego, Kênia C; Gargaglioni, Luciane H","year":2023,"journal":"British journal of pharmacology, 180(13), 1766-1789","doi":"10.1111/bph.16044","pmid":"36710256","tags":["pregnancy","youth","respiratory"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Prenatal WIN55,212-2 caused greater CO2 sensitivity at most ages in males and juvenile females. Males showed altered hypoxic chemoreflex at birth (hyperventilation) and P6-7 (hypoventilation), absent in females. Males had increased catecholaminergic neurons, more CB1 expression, and altered tissue respiration in brainstem. Reduced pulmonary compliance was seen in juvenile males. Females at birth showed enhanced spontaneous apnea and reduced serotonin neurons in raphe magnus.","whyItMatters":"This is one of the first studies to examine how prenatal cannabinoid exposure affects the developing respiratory system. The sex-specific effects are striking: males show widespread breathing dysregulation while females show a potentially dangerous pattern of spontaneous apnea at birth with reduced serotonin neurons, relevant to SIDS risk.","specificNumbers":"Four developmental timepoints assessed. Males: altered CO2 sensitivity at 3 of 4 ages, altered hypoxic response at P0 and P6-7, increased catecholaminergic neurons, reduced pulmonary compliance. Females at P0: enhanced apnea, reduced serotonin neurons in raphe magnus.","methodology":"Prenatal WIN55,212-2 (0.5 mg/kg/day) administered to pregnant rats. Respiratory function assessed in male and female offspring at four developmental timepoints (P0, P6-7, P12-13, P27-28). Brainstem neurochemistry and pulmonary mechanics also examined.","limitations":"Animal study with synthetic cannabinoid at a single dose, which may not reflect human cannabis use patterns. Rat respiratory development differs from humans. Cannot directly extrapolate to SIDS risk."},{"rthcId":"RTHC-04842","title":"Effects of prenatal exposure to THC on hippocampal neural development in offspring.","authors":"Peng, Hao; Li, Han; Wei, Yingying; Zhang, Ruonan; Chang, Xinwen; Meng, Lulu; Wang, Kai; He, Qizhi; Duan, Tao","year":2023,"journal":"Toxicology letters, 374, 48-56","doi":"10.1016/j.toxlet.2022.12.007","pmid":"36529297","tags":["pregnancy","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC administration during gestational days 5.5-12.5 altered neuronal cell composition in offspring hippocampus at PND21. RNA sequencing showed significant enrichment in neurogenesis and neural differentiation pathways. THC affected neural stem cell proliferation and differentiation, mediated through the transcription factor MEF2C via CB1 receptor. The CB1 inhibitor Rimonabant rescued both differentiation outcomes and MEF2C expression.","whyItMatters":"This study identifies a specific molecular pathway (CB1R to MEF2C) through which prenatal THC disrupts brain development. The fact that a CB1 blocker could rescue the effects suggests this pathway is potentially targetable for intervention.","specificNumbers":"THC exposure: GD5.5-12.5. Assessment: PND21. Significant enrichment in neurogenesis and neural differentiation pathways. MEF2C identified as key transcription factor. Rimonabant rescued effects.","methodology":"THC administered to pregnant mice during GD5.5-12.5. Offspring hippocampus assessed at PND21 with histological staining and RNA sequencing. Neural stem cell experiments confirmed THC effects on proliferation and differentiation. MEF2C knockdown and Rimonabant rescue experiments established the mechanistic pathway.","limitations":"Mouse model with direct THC injection, which differs from human smoking or edible consumption. Single dose regimen during early gestation only. Long-term behavioral consequences not assessed in this study."},{"rthcId":"RTHC-04843","title":"Vaporized Delta-9-tetrahydrocannabinol Inhalation in Female Sprague Dawley Rats: A Pharmacokinetic and Behavioral Assessment.","authors":"Penman, Samantha L; Berthold, Erin C; Mihalkovic, Abrianna; Hammond, Nikki; McCurdy, Christopher R; Blum, Kenneth; Eiden, Rina D; Sharma, Abhisheak; Thanos, Panayotis K","year":2023,"journal":"Current pharmaceutical design, 29(27), 2149-2160","doi":"10.2174/1381612829666230419093809","pmid":"37114788","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04844","title":"The evolution of cannabinoid receptors in cancer.","authors":"Pennant, Nakea M; Hinton, Cimona V","year":2023,"journal":"WIREs mechanisms of disease, 15(4), e1602","doi":"10.1002/wsbm.1602","pmid":"36750231","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04845","title":"The dual role of cannabidiol on monocyte-derived dendritic cell differentiation and maturation.","authors":"Pénzes, Zsófia; Alimohammadi, Shahrzad; Horváth, Dorottya; Oláh, Attila; Tóth, Balázs István; Bácsi, Attila; Szöllősi, Attila Gábor","year":2023,"journal":"Frontiers in immunology, 14, 1240800","doi":"10.3389/fimmu.2023.1240800","pmid":"37680639","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD during differentiation had no acute effect on resting dendritic cells, but when subsequently activated by LPS (bacterial signal), CBD-treated cells showed a markedly tolerogenic response: more IL-6, TNFa, and importantly IL-10 (anti-inflammatory), with IL-10 signaling being the most prominently induced pathway. CBD-treated cells were less efficient at activating naive T cells. Effects were consistent across TLR4 and TLR7/8 stimulation.","whyItMatters":"This explains a puzzle about CBD and inflammation: CBD does not simply suppress immune cells but reprograms them to respond differently when challenged. This has implications for autoimmune conditions where you want to reduce inflammatory responses without completely suppressing immunity.","specificNumbers":"CBD up to 10 uM. IL-10 signaling most prominently induced pathway in activated CBD-treated cells. Reduced T cell activation. Consistent across TLR4 and TLR7/8 stimulation. CBN and THCV had no measurable effects.","methodology":"In vitro study using human monocyte-derived dendritic cells treated with CBD (up to 10 uM) during differentiation, then activated with TLR agonists. Assessed viability, differentiation markers, maturation markers, cytokine production, T cell activation, and transcriptome via Reactome pathway analysis.","limitations":"In vitro study with human cells but not in vivo. Concentrations used may not reflect achievable tissue levels. Only tested CBD; other cannabinoids (CBN, THCV) had no effect. Long-term treatment required for reprogramming."},{"rthcId":"RTHC-04846","title":"Cannabinoids as multifaceted compounds.","authors":"Persia, Diana; Mangiavacchi, Francesca; Marcotullio, Maria Carla; Rosati, Ornelio","year":2023,"journal":"Phytochemistry, 212, 113718","doi":"10.1016/j.phytochem.2023.113718","pmid":"37196772","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04847","title":"Identification of 5F-Cumyl-PINACA, a Synthetic Cannabinoid, in the Herbal Material Used for Recreational Purposes in the Province of Trieste: Public Health Implications.","authors":"Peruch, Michela; Addobbati, Riccardo; Padovano, Martina; Scopetti, Matteo; Concato, Monica; Radaelli, Davide; D'Errico, Stefano","year":2023,"journal":"Current pharmaceutical biotechnology, 24(6), 758-765","doi":"10.2174/1389201023666220915092609","pmid":"36111755","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The product tested negative for THC but positive for 5F-Cumyl-PINACA at a dose of 8.5 mg per package. Multiple people presented to the Trieste hospital ER with hallucinations, sensation of poisoning, tachycardia, and air hunger after inhaling the product. The product was manufactured in Koper, Slovenia, and sold as an air freshener. Formal notification was sent to Italian Health Authorities.","whyItMatters":"5F-Cumyl-PINACA is far more potent than THC, and without concentration information on the packaging, users cannot dose safely. This highlights the ongoing public health danger of synthetic cannabinoids being sold under misleading product labels.","specificNumbers":"8.5 mg 5F-Cumyl-PINACA per package. Multiple ER presentations with hallucinations, tachycardia, air hunger. Product sold as air freshener. Manufactured in Koper, Slovenia.","methodology":"Forensic analysis of product contents using multi-target MRM-IDA-EPI screening confirmed by LC-ESI-MS/MS quantitation.","limitations":"Analysis of a single product from one region. Cannot determine the extent of distribution. No long-term follow-up of affected individuals. ER presentations not systematically characterized."},{"rthcId":"RTHC-04848","title":"Concomitant cannabidiol does not impact safety and effectiveness of diazepam nasal spray for seizure clusters: Post hoc analysis of a phase 3 safety study.","authors":"Peters, Jurriaan M; Puri, Vinay; Segal, Eric; Misra, Sunita N; Rabinowicz, Adrian L; Carrazana, Enrique","year":2023,"journal":"Epilepsy & behavior : E&B, 144, 109248","doi":"10.1016/j.yebeh.2023.109248","pmid":"37210793","tags":["cbd","epilepsy","drug-interactions"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Of 163 patients, 73% received no CBD, 14.1% received purified CBD (Epidiolex), and 12.9% received other CBD. While overall adverse event rates were higher in CBD users (90.9% vs 79.0%), the lowest rate of events attributed specifically to diazepam nasal spray was in the purified CBD group (13.0%). Use of second diazepam doses (effectiveness proxy) was lowest in the purified CBD group (8.2%) compared to no-CBD (11.6%) and other-CBD (20.3%).","whyItMatters":"Many epilepsy patients take both CBD products and rescue benzodiazepines. This study provides reassurance that CBD does not interfere with the safety or effectiveness of diazepam nasal spray, an important practical finding for clinical management.","specificNumbers":"163 patients. No CBD: 73%. Purified CBD: 14.1%. Other CBD: 12.9%. Drug-attributed adverse events: purified CBD 13.0%, no CBD group higher. Second diazepam dose use: purified CBD 8.2%, no CBD 11.6%, other CBD 20.3%.","methodology":"Post hoc analysis of a phase 3, 12-month safety study of diazepam nasal spray in patients aged 6-65 with seizure clusters. Concomitant CBD use recorded. Age- and weight-based diazepam dosing.","limitations":"Post hoc analysis, not pre-specified. Small CBD subgroups. Patients on purified CBD tended to have more severe epilepsy syndromes. Cannot distinguish CBD effects from underlying disease severity differences. Other-CBD products were uncharacterized."},{"rthcId":"RTHC-04849","title":"Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response.","authors":"Petrie, Gavin N; Balsevich, Georgia; Füzesi, Tamás; Aukema, Robert J; Driever, Wouter P F; van der Stelt, Mario; Bains, Jaideep S; Hill, Matthew N","year":2023,"journal":"British journal of pharmacology, 180(24), 3146-3159","doi":"10.1111/bph.16198","pmid":"37482931","tags":["neuroscience","anxiety"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243, and NAPE-PLD inhibitor LEI401 all uniformly increased PVN Fos expression, unmasked stress-linked behaviors (grooming), and increased circulating corticosterone, mimicking the effects of actual stress. Direct PVN administration of AM251 produced the same effects. Optogenetic inhibition of PVN CRH neurons ameliorated the behavioral changes, confirming these neurons mediate the effect.","whyItMatters":"This study provides definitive evidence that the endocannabinoid system is not just involved in stress modulation but actively restrains the stress response at all times. Without this constant endocannabinoid \"brake,\" the body generates a full stress response even in the absence of any actual threat.","specificNumbers":"Three different pharmacological approaches all produced uniform stress responses. Direct PVN administration confirmed local mechanism. Optogenetic CRH neuron inhibition reversed behavioral effects.","methodology":"Multiple approaches to disrupt endocannabinoid signaling in rats: systemic CB1 antagonism (AM251, NESS243), endocannabinoid synthesis inhibition (LEI401), and direct PVN CB1 blockade. Outcomes: PVN Fos expression, circulating corticosterone, stress behaviors. Optogenetic CRH neuron inhibition for causal verification.","limitations":"Animal study that may not directly translate to humans. Pharmacological agents have off-target effects. Acute disruption differs from chronic endocannabinoid deficiency. Optogenetic tools, while powerful, involve artificial neural manipulation."},{"rthcId":"RTHC-04850","title":"Scoping Review of Cannabis-Reduction Psychosocial Interventions and Reasons for Use among Young Adults with Psychosis.","authors":"Petros, Ryan; Walker, Denise D; Pierce, Adam; Monroe-DeVita, Maria","year":2023,"journal":"Journal of dual diagnosis, 19(2-3), 124-150","doi":"10.1080/15504263.2023.2226024","pmid":"37391686","tags":["psychosis","addiction","quitting","youth"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Young adults with psychosis use cannabis for pleasure, to reduce dysphoria, and for social reasons. Motivations for cessation include insight about cannabis-psychosis interactions, incompatibility with goals, and social support. Interventions with at least minimal evidence include motivational interviewing, cognitive-behavioral strategies, and family skills training. No intervention has demonstrated robust effectiveness in this population.","whyItMatters":"Cannabis use in young adults with psychosis is extremely common and associated with worse outcomes, yet clinicians have no proven intervention to offer. Understanding why this population uses cannabis and what motivates them to stop could inform better-designed interventions.","specificNumbers":"3,216 articles screened. 46 included. Use motivations: pleasure, dysphoria reduction, social/recreational. Cessation motivations: insight about cannabis-psychosis link, goal incompatibility, social support. Motivational interviewing, CBT, and family skills training have minimal evidence.","methodology":"Scoping review with systematic literature search in December 2022. Screened 3,216 titles/abstracts and 136 full texts, resulting in 46 included articles on motivations for use/cessation and psychosocial interventions.","limitations":"Scoping review cannot assess intervention quality as rigorously as a systematic review. Heterogeneous study designs. Many studies had small samples. Publication bias may favor positive results."},{"rthcId":"RTHC-04851","title":"Prenatal Cannabinoid Exposure Elicits Memory Deficits Associated with Reduced PSA-NCAM Expression, Altered Glutamatergic Signaling, and Adaptations in Hippocampal Synaptic Plasticity.","authors":"Pinky, Priyanka D; Bloemer, Jenna; Smith, Warren D; Du, Yifeng; Heslin, Ryan T; Setti, Sharay E; Pfitzer, Jeremiah C; Chowdhury, Kawsar; Hong, Hao; Bhattacharya, Subhrajit; Dhanasekaran, Muralikrishnan; Dityatev, Alexander; Reed, Miranda N; Suppiramaniam, Vishnu","year":2023,"journal":"Cells, 12(21)","doi":"10.3390/cells12212525","pmid":"37947603","tags":["pregnancy","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal WIN55,212-2 caused hippocampal-dependent memory deficits in adolescent offspring associated with decreased long-term potentiation, enhanced long-term depression, and imbalanced GluN2A/GluN2B signaling. Reduced NCAM and PSA-NCAM expression was identified as the mechanism. Administration of exogenous PSA rescued the LTP deficits, confirming PSA-mediated signaling as the key pathway.","whyItMatters":"This study identifies a specific and potentially rescuable mechanism for prenatal cannabis-related memory deficits. PSA-NCAM is critical for normal brain plasticity, and finding that its reduction drives the memory impairment opens a door to potential interventions.","specificNumbers":"Decreased LTP and enhanced LTD at Schaffer collateral-CA1 synapses. Imbalanced GluN2A/GluN2B signaling. Reduced NCAM and PSA-NCAM. Exogenous PSA rescued LTP deficits.","methodology":"Prenatal WIN55,212-2 administered to pregnant rats. Adolescent offspring assessed with behavioral tests, electrophysiology (LTP/LTD at hippocampal synapses), and immunochemistry for adhesion molecules and glutamate receptor subunits. Rescue experiment with exogenous PSA.","limitations":"Synthetic cannabinoid at controlled dose, not comparable to human cannabis use. Rat brain development timeline differs from humans. Rescue was shown for LTP but broader behavioral recovery not tested. Single timepoint assessment."},{"rthcId":"RTHC-04852","title":"Mechanisms of cannabinoid tolerance.","authors":"Piscura, Mary K; Henderson-Redmond, Angela N; Barnes, Robert C; Mitra, Swarup; Guindon, Josée; Morgan, Daniel J","year":2023,"journal":"Biochemical pharmacology, 214, 115665","doi":"10.1016/j.bcp.2023.115665","pmid":"37348821","tags":["tolerance","cognition","neuroscience","sex-differences"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Anyone who uses cannabis regularly knows tolerance is real: the same dose produces weaker effects over time. This review digs into the molecular mechanisms behind that experience, and the picture is more nuanced than 'your brain just gets used to it.'\n\nTolerance to cannabinoids involves two main changes at the CB1 receptor level. First, downregulation: the brain literally reduces the number of CB1 receptors on cell surfaces. Imaging studies in humans have shown that chronic cannabis users have fewer available CB1 receptors compared to non-users, and these partially recover after weeks of abstinence. Second, desensitization: the remaining receptors become less responsive to activation, decoupling from their signaling pathways.\n\nCritically, tolerance doesn't develop uniformly across the brain or across all effects. Some effects (like the 'high') show rapid tolerance, while others (appetite stimulation, some analgesic effects) may develop tolerance more slowly or incompletely. This regional and functional variation explains why chronic users may stop feeling euphoric but still experience increased appetite.\n\nThe review highlights a rapidly growing area of research: sex differences in cannabinoid tolerance. Female rodents develop tolerance to THC's pain-relieving effects faster than males, and the underlying receptor changes differ between sexes. In humans, women and men report different patterns of tolerance development, though the human data is still limited. These sex differences have direct implications for cannabinoid dosing in medical contexts.\n\nThe review also covers strategies being explored to manage tolerance, including intermittent dosing ('T-breaks'), combination with allosteric modulators, and targeting different components of the endocannabinoid system.","whyItMatters":"Tolerance is one of the biggest obstacles to using cannabinoids medically. A patient who gets pain relief from cannabis may need increasing doses over time — leading to more side effects, higher cost, and potential for dependence. Understanding the molecular basis of tolerance is the first step toward strategies to prevent or reverse it, which could make cannabinoid-based medicines far more practical.","specificNumbers":"Human PET imaging studies show measurable CB1 receptor downregulation in chronic cannabis users, with partial recovery after 2-4 weeks of abstinence. Female rodents develop tolerance to THC-induced antinociception (pain relief) faster than males. Tolerance rates vary by brain region: rapid in cortex, slower in some subcortical areas. The review synthesizes evidence across species — rodents, non-human primates, and humans.","methodology":"Narrative review synthesizing evidence from rodent studies, non-human primate research, and human neuroimaging and clinical studies on cannabinoid tolerance. Focused on CB1 receptor downregulation, desensitization, and sex-dependent differences in tolerance development.","limitations":"Narrative review — may not capture all relevant literature. Much of the mechanistic evidence comes from animal studies using high-dose, chronic THC administration that may not reflect typical human use patterns. Human imaging studies are cross-sectional (comparing users to non-users), making it hard to distinguish pre-existing differences from cannabis-caused changes. Sex difference research is still early, especially in humans. The review covers tolerance at the receptor level but doesn't fully address tolerance at the behavioral or clinical level."},{"rthcId":"RTHC-04853","title":"Safety assessment and redox status in rats after chronic exposure to cannabidiol and cannabigerol.","authors":"Polanska, Hana Holcova; Petrlakova, Katerina; Papouskova, Barbora; Hendrych, Michal; Samadian, Amir; Storch, Jan; Babula, Petr; Masarik, Michal; Vacek, Jan","year":2023,"journal":"Toxicology, 488, 153460","doi":"10.1016/j.tox.2023.153460","pmid":"36796712","tags":["cbd","harm-reduction"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD (0.66 mg/kg/day for 90 days) produced no changes in blood counts or biochemistry and improved redox status in blood plasma and liver, reducing malondialdehyde and carbonylated proteins. CBG (0.66-1.33 mg/kg/day) increased total oxidative stress, malondialdehyde, and carbonylated proteins, and caused hepatotoxic changes, disrupted white cell counts, and altered ALT, creatinine, and calcium. Both accumulated in tissues at low ng/g levels.","whyItMatters":"CBG is increasingly marketed alongside CBD as a beneficial cannabinoid, but this study shows dramatically different safety profiles. While CBD improved antioxidant status, CBG caused oxidative damage and liver toxicity at comparable doses. This is a critical safety distinction as CBG products proliferate.","specificNumbers":"CBD: 0.66 mg/kg/day, no adverse effects, improved redox markers. CBG: 0.66-1.33 mg/kg/day, increased oxidative stress, hepatotoxic changes, disrupted white cells, altered ALT/creatinine/calcium. Both accumulated at low ng/g in liver, brain, muscle, heart, kidney, skin.","methodology":"90-day orogastric administration in rats. CBD at 0.66 mg/kg/day, CBG at 0.66/1.33 mg/kg/day. Assessed blood counts, biochemistry, GI and liver histology, oxidative stress markers, and tissue distribution by LC-MS.","limitations":"Animal study at specific doses that may not reflect human supplementation levels. 90-day duration may not capture longer-term effects. Only two dose levels of CBG tested. Rat metabolism of cannabinoids differs from humans."},{"rthcId":"RTHC-04854","title":"Labor trafficking in marijuana production: a hidden epidemic in the shadows of the cannabis industry.","authors":"Prakash, Jaya; Erickson, Timothy B; MacGibbon, Marti; Stoklosa, Hanni","year":2023,"journal":"Frontiers in sociology, 8, 1244579","doi":"10.3389/fsoc.2023.1244579","pmid":"38152460","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04855","title":"Modulation of pulmonary immune function by inhaled cannabis products and consequences for lung disease.","authors":"Preteroti, Matthew; Wilson, Emily T; Eidelman, David H; Baglole, Carolyn J","year":2023,"journal":"Respiratory research, 24(1), 95","doi":"10.1186/s12931-023-02399-1","pmid":"36978106","tags":["respiratory","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabinoids interact with the endocannabinoid system to generally dampen immune function in the lungs, including reducing inflammatory responses of epithelial cells and alveolar macrophages. This dual effect could be beneficial (reducing chronic inflammation) or harmful (impairing pathogen defense). Alternative delivery methods like vaping may have different immune effects than combustion. The field lacks definitive data on long-term pulmonary immune consequences.","whyItMatters":"With cannabis inhalation increasing alongside legalization, understanding how it affects the lungs' immune defenses is critical. The respiratory system is the first point of contact for inhaled cannabis, yet we know surprisingly little about how cannabinoids alter its immune function.","specificNumbers":"Cannabis use increasing with legalization worldwide. Vaping as an alternative to combustion is growing. Cannabinoids dampen immune function via endocannabinoid system. Effects on epithelial cells and alveolar macrophages documented.","methodology":"Narrative review of the current literature on inhaled cannabis/cannabinoid effects on pulmonary immune responses, including in vitro, in vivo, and clinical studies.","limitations":"Narrative review without systematic methodology. Much of the evidence is preclinical. Long-term human data on pulmonary immune effects of cannabis is lacking. Difficult to separate combustion byproduct effects from cannabinoid effects."},{"rthcId":"RTHC-04856","title":"Unravelling the landscape of Cannabis craving pharmacological treatments: a PRISMA-guided review of evidence.","authors":"Preto, Mayra Cruz; Kortas, Guilherme Trevizan; Blaas, Israel Kanaan; Lassi, Dangela Layne Silva; Waisman Campos, Marcela; Torales, Julio; Ventriglio, Antonio; de Azevedo-Marques Périco, Cintia; de Andrade, Arthur Guerra; Castaldelli-Maia, João Mauricio","year":2023,"journal":"International review of psychiatry (Abingdon, England), 35(5-6), 434-449","doi":"10.1080/09540261.2023.2231540","pmid":"38299652","tags":["addiction","quitting"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Twenty-two RCTs investigated various compounds for cannabis craving. Most current treatments involve off-label drug use and cannabinoid-based medications. The most promising approaches include THC combined with lofexidine, oxytocin, progesterone, and N-acetylcysteine. No treatment has received regulatory approval for cannabis craving. Psychotherapy and behavioral treatments remain essential complements to any pharmacological approach.","whyItMatters":"Cannabis use disorder affects millions worldwide, and craving is a primary driver of relapse. The absence of any approved pharmacological treatment for cannabis craving is a major treatment gap, and identifying the most promising candidates is essential for advancing the field.","specificNumbers":"22 RCTs included. No FDA-approved treatments for cannabis craving. Promising compounds: THC + lofexidine, oxytocin, progesterone, N-acetylcysteine. All current use is off-label.","methodology":"Systematic review following PRISMA guidelines with extensive database search. Included human RCTs examining drug effects on cannabis craving symptoms. 22 studies met inclusion criteria.","limitations":"Heterogeneous study designs and craving measurement tools. Small sample sizes in many trials. Short treatment durations. Different cannabis use patterns across studies make comparison difficult."},{"rthcId":"RTHC-04857","title":"Impact of Prenatal Cannabis Use Disorder on Perinatal Outcomes.","authors":"Prewitt, Kristin C; Hayer, Sarena; Garg, Bharti; Benson, Ashley E; Hedges, Madeline A; Caughey, Aaron B; Lo, Jamie O","year":2023,"journal":"Journal of addiction medicine, 17(3), e192-e198","doi":"10.1097/ADM.0000000000001123","pmid":"37267181","tags":["pregnancy","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 2,380,446 births, 9,144 (0.38%) had prenatal cannabis use disorder. Significant associations were found with gestational hypertension (AOR 1.19), preeclampsia (AOR 1.16), preterm delivery (AOR 1.45), severe maternal morbidity (AOR 1.22), respiratory distress syndrome (AOR 1.16), small for gestational age (AOR 1.47), NICU admission (AOR 1.24), and infant death (AOR 1.86). Stillbirth was not significantly increased (AOR 0.96).","whyItMatters":"This is one of the largest studies of prenatal cannabis use disorder and perinatal outcomes. The 86% increased odds of infant death is a striking finding that should inform preconception and prenatal counseling, especially as cannabis use in pregnancy becomes more common.","specificNumbers":"2,380,446 births. 9,144 (0.38%) with cannabis use disorder. Preterm: AOR 1.45. SGA: AOR 1.47. NICU: AOR 1.24. Severe maternal morbidity: AOR 1.22. Infant death: AOR 1.86. Stillbirth: AOR 0.96 (not significant).","methodology":"Retrospective cohort using California linked hospital discharge-vital statistics data. Singleton, nonanomalous births 23-42 weeks. Chi-squared tests and multivariable logistic regression adjusting for relevant confounders.","limitations":"Observational study cannot prove causation. Cannabis use disorder identified by ICD codes, which captures only diagnosed cases and misses many users. Cannot determine dose, timing, or type of cannabis. Confounding by other substance use or socioeconomic factors possible despite adjustment."},{"rthcId":"RTHC-04858","title":"A machine learning approach for understanding the metabolomics response of children with autism spectrum disorder to medical cannabis treatment.","authors":"Quillet, Jean-Christophe; Siani-Rose, Michael; McKee, Robert; Goldstein, Bonni; Taylor, Myiesha; Kurek, Itzhak","year":2023,"journal":"Scientific reports, 13(1), 13022","doi":"10.1038/s41598-023-40073-0","pmid":"37608004","tags":["medical-cannabis","cbd","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Lysophosphatidylethanolamine distinguished ASD from typically developing groups. THC-associated and CBD-associated cannabis-responsive biomarkers formed two distinct groups, while CBG was associated with biomarkers from both. Novel phytochemicals beyond THC/CBD were identified as contributing to therapeutic effects through acetylcholinesterase inhibition. Medical cannabis treatment shifted biomarker levels in children with ASD toward typically developing levels.","whyItMatters":"This is the first application of machine learning to cannabis-responsive biomarkers in autism. Finding distinct THC and CBD metabolic signatures and that treatment shifts ASD biomarkers toward typical levels provides a potential framework for personalizing cannabis treatment and measuring response.","specificNumbers":"Lysophosphatidylethanolamine identified as ASD-TD distinguishing biomarker. THC and CBD biomarker groups distinct. CBG overlaps both groups. Novel phytochemicals identified as acetylcholinesterase inhibitors.","methodology":"Machine learning techniques applied to dynamic, high-resolution salivary metabolomics data from children with ASD before and after medical cannabis treatment and a typically developing control group.","limitations":"Small sample size. Machine learning with limited data risks overfitting. Saliva metabolomics is an emerging field with limited validation. Cannot determine if biomarker changes cause clinical improvement. No placebo control."},{"rthcId":"RTHC-04859","title":"Risk of readmission among individuals with cannabis use disorder during a 15-year cohort study: the impact of socio-economic factors and psychiatric comorbidity.","authors":"Rabiee, Rynaz; Sjöqvist, Hugo; Agardh, Emilie; Lundin, Andreas; Danielsson, Anna-Karin","year":2023,"journal":"Addiction (Abingdon, England), 118(7), 1295-1306","doi":"10.1111/add.16158","pmid":"36746781","tags":["addiction","psychosis","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"About 80% of CUD visits were outpatient. 23% of individuals were readmitted during follow-up. Fully adjusted risks: schizophrenia and psychotic disorders (HR 1.54), low education (HR 1.40), personality disorders (HR 1.27), mood disorders (HR 1.27). Risk was highest in ages 18-35. Flexible parametric modeling showed the age-specific risk pattern.","whyItMatters":"Nearly 1 in 4 people with CUD were readmitted to care, highlighting the chronic and relapsing nature of the condition. The strong association with psychotic disorders and low education points to specific subgroups that need more intensive or tailored treatment.","specificNumbers":"12,143 individuals. 23% readmitted. ~80% outpatient visits. Schizophrenia: HR 1.54. Low education: HR 1.40. Personality disorders: HR 1.27. Mood disorders: HR 1.27. Highest risk: ages 18-35.","methodology":"Nationwide Swedish cohort study (2001-2016) of 12,143 individuals aged 17+ with CUD. Predictors from national registers: education, income, psychiatric comorbidity. Cox and flexible parametric survival analyses.","limitations":"Swedish healthcare system may differ from other countries. CUD identified through healthcare contacts, missing those who do not seek treatment. Cannot determine cannabis use patterns or severity. Readmission may reflect treatment access rather than relapse."},{"rthcId":"RTHC-04860","title":"Cannabis use disorder in relation to socioeconomic factors and psychiatric comorbidity: A cluster analysis of three million individuals born in 1970-2000.","authors":"Rabiee, Rynaz; Lundin, Andreas; Agardh, Emilie; Allebeck, Peter; Danielsson, Anna-Karin","year":2023,"journal":"Scandinavian journal of public health, 51(1), 82-89","doi":"10.1177/14034948221122431","pmid":"36120841","tags":["addiction","mental-health"],"studyType":"registry-study","evidenceStrength":"strong","keyFinding":"Of 3,307,759 individuals born 1970-2000, 14,046 (0.42%) received a CUD diagnosis. CUD rates rose from 61 per 100,000 (born 1990-1994) to 107 per 100,000 (born 1995-2000) by 2016. Four clusters emerged: Cluster 1 was mainly men with low income and substance use disorders; Clusters 2, 3, and 4 were mainly women with higher rates of mood, stress-related, and behavioral disorders.","whyItMatters":"The finding that 80% of people with CUD also had another psychiatric diagnosis (vs. 19% without CUD) underscores the need for integrated mental health and substance use treatment. The distinct gender profiles suggest men and women with CUD may need different clinical approaches.","specificNumbers":"N=3,307,759 total. 14,046 CUD diagnoses (0.42%). CUD rates: 61/100,000 (born 1990-1994) to 107/100,000 (born 1995-2000). 80% psychiatric comorbidity in CUD vs. 19% without.","methodology":"Population-based registry study using Swedish national register data on 3,307,759 individuals born 1970-2000, with records extending to 2016. K-mode cluster analysis identified subgroups.","limitations":"Registry data capture diagnosed CUD only, likely underestimating total problematic use. Swedish population may not generalize to other countries with different cannabis policies. Cannot determine causal direction between CUD and psychiatric comorbidity."},{"rthcId":"RTHC-04861","title":"Isolation and Characterization of Impurities in Commercially Marketed Δ8-THC Products.","authors":"Radwan, Mohamed M; Wanas, Amira S; Gul, Waseem; Ibrahim, Elsayed A; ElSohly, Mahmoud A","year":2023,"journal":"Journal of natural products, 86(4), 822-829","doi":"10.1021/acs.jnatprod.2c01008","pmid":"36827690","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04862","title":"Cannabis-assisted psychotherapy for complex dissociative posttraumatic stress disorder: A case report.","authors":"Ragnhildstveit, Anya; Kaiyo, Miriam; Snyder, Matthew Brian; Jackson, Laura Kate; Lopez, Alex; Mayo, Chasity; Miranda, Alyssa Claire; August, River Jude; Seli, Paul; Robison, Reid; Averill, Lynnette Astrid","year":2023,"journal":"Frontiers in psychiatry, 14, 1051542","doi":"10.3389/fpsyt.2023.1051542","pmid":"36846226","tags":["ptsd","cbd","medical-cannabis","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Dissociative PTSD (D-PTSD) is a particularly severe form of PTSD where patients experience detachment from their own body and surroundings — depersonalization and derealization — on top of standard PTSD symptoms. Standard treatments often fail for this population, and targeted interventions are essentially nonexistent.\n\nThis case report describes a novel approach: cannabis-assisted psychotherapy (CAP). A 28-year-old woman with complex D-PTSD underwent 10 sessions over 5 months, each combining cannabis administration with a specific psychotherapy framework — psychedelic somatic interactional psychotherapy, an approach borrowed from the psychedelic therapy world.\n\nThe parallels to psychedelic therapy are intentional. At sufficient doses, cannabis can produce experiences similar to classic psychedelics: oceanic boundlessness (a sense of unity and expansiveness), ego dissolution, and emotional breakthrough. The therapists used these cannabis-induced states as a therapeutic window, much as psilocybin or MDMA therapists use the altered state to facilitate processing of traumatic memories.\n\nThe results were striking. From baseline to post-treatment, the patient showed large improvements across PTSD symptoms, dissociation, depression, anxiety, sleep quality, and overall functioning. The treatment also incorporated integrative cognitive behavioral therapy between cannabis sessions.\n\nThis is a single case report, not a clinical trial — it can't prove cannabis-assisted psychotherapy works for D-PTSD. But it introduces a conceptual framework for using cannabis therapeutically in psychotherapy that hasn't been formally described before, and the patient's response was clinically meaningful.","whyItMatters":"This case report sits at the intersection of two growing fields: medical cannabis and psychedelic-assisted therapy. While psychedelic therapy with psilocybin and MDMA has gained significant research momentum for PTSD, cannabis-assisted psychotherapy is virtually unexplored. If cannabis can facilitate similar therapeutic states at a fraction of the regulatory and logistical complexity of Schedule I psychedelics, it could open a more accessible pathway for treatment-resistant PTSD patients.","specificNumbers":"1 patient, 28 years old, female. 10 sessions over 5 months (twice monthly). Treatment combined cannabis administration with psychedelic somatic interactional psychotherapy and integrative CBT. Large improvements reported across PTSD severity, dissociation, depression, anxiety, sleep, and functioning from baseline to post-treatment.","methodology":"Case report of a single 28-year-old female patient with complex D-PTSD. Treatment: 10 sessions of cannabis-assisted psychotherapy (CAP) scheduled twice monthly over 5 months, using psychedelic somatic interactional psychotherapy combined with integrative cognitive behavioral therapy. Outcomes measured included PTSD symptoms, dissociation severity, depression, anxiety, sleep quality, and functioning.","limitations":"Single case report — the lowest level of clinical evidence. No control condition; improvements could reflect natural recovery, placebo effects, the psychotherapy itself (independent of cannabis), or the therapeutic relationship. The patient's demographics (young, female, engaged enough to commit to 10 sessions) limit generalizability. The psychedelic-like effects of cannabis are dose-dependent and unpredictable, raising safety concerns for broader application. No long-term follow-up reported."},{"rthcId":"RTHC-04863","title":"Multiple Sclerosis and Use of Medical Cannabis: A Retrospective Review of a Neurology Outpatient Population.","authors":"Rainka, Michelle M; Aladeen, Traci S; Mattle, Anna G; Lewandowski, Emily; Vanini, Denis; McCormack, Katelyn; Mechtler, Laszlo","year":2023,"journal":"International journal of MS care, 25(3), 111-117","doi":"10.7224/1537-2073.2022-006","pmid":"37250194","tags":["medical-cannabis","pain"],"studyType":"retrospective","evidenceStrength":"moderate","keyFinding":"Pain improvement was reported by 72% of patients, spasticity relief by 48%, and sleep improvement by 40%. Among patients prescribed opioid analgesics, daily morphine milligram equivalents decreased significantly (P=.01) after starting medical cannabis. Fatigue was the most common adverse event, reported by 11%.","whyItMatters":"MS patients often struggle to manage pain, spasticity, and sleep with standard medications. The significant reduction in opioid use is particularly relevant given the opioid crisis, suggesting medical cannabis may help MS patients reduce reliance on opioid painkillers.","specificNumbers":"N=141 MS patients. Pain improvement: 72%. Spasticity relief: 48%. Sleep improvement: 40%. Opioid reduction: significant (P=.01). Most common adverse event: fatigue (11%).","methodology":"Retrospective medical record review of 141 MS patients receiving medical cannabis at a neurology outpatient clinic, with data collected for up to 4 follow-up appointments after MC initiation.","limitations":"Retrospective design without a control group. No placebo comparison. Self-reported symptom improvement. Single clinic setting. Decreases in muscle relaxant and benzodiazepine use did not reach significance."},{"rthcId":"RTHC-04864","title":"Recreational cannabis and opioid distribution.","authors":"Raman, Shyam; Maclean, Johanna Catherine; Bradford, W David; Drake, Coleman","year":2023,"journal":"Health economics, 32(4), 747-754","doi":"10.1002/hec.4652","pmid":"36653623","tags":["legalization","harm-reduction"],"studyType":"policy-analysis","evidenceStrength":"moderate","keyFinding":"Using two-way fixed-effects regressions across 11 states that adopted recreational cannabis laws between 2010 and 2019, the study found RCLs led to a reduction in codeine dispensed at retail pharmacies. No significant effects were found for other opioid types. The analysis accounted for opioid prescribing limits and other policies.","whyItMatters":"Unlike prior studies that examined prescriptions from specific payers, this study captured all retail pharmacy dispensing. The finding that codeine, the opioid most associated with non-medical use, specifically declined suggests cannabis may substitute for recreational or quasi-medical opioid use.","specificNumbers":"11 US states with RCLs adopted 2010-2019. Significant reduction in codeine dispensing. No significant effects on other opioid types. Adjusted for opioid prescribing limits.","methodology":"Two-way fixed-effects regression using variation from 11 US states that adopted recreational cannabis laws between 2010 and 2019, examining dispensing data across all payers and endpoints.","limitations":"Observational policy analysis cannot confirm causation. Cannot distinguish between recreational and medical substitution. State-level data may mask variation within states. Time period may not capture long-term effects."},{"rthcId":"RTHC-04865","title":"Urine Drug Test Results Among Adolescents and Young Adults in an Outpatient Office-Based Opioid Treatment Program.","authors":"Ramey, Olivia L; Bonny, Andrea E; Silva Almodóvar, Armando; Nahata, Milap C","year":2023,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 73(1), 141-147","doi":"10.1016/j.jadohealth.2023.02.013","pmid":"37031090","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04866","title":"Effect of oral cannabis administration on the fat depots of obese and streptozotocin-induced diabetic rats.","authors":"Ramlugon, Sonaal; Levendal, Ruby-Ann; Frost, Carminita L","year":2023,"journal":"Phytotherapy research : PTR, 37(5), 1806-1822","doi":"10.1002/ptr.7694","pmid":"36437580","tags":["medical-cannabis","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis at 1.25 mg/kg body weight (relative to THC content) reversed insulin resistance, while higher doses did not. In peritoneal fat, Cidea and UCP1 gene expression (fat beigeing markers) significantly increased. In intramuscular fat, mitochondrial activity increased significantly instead, without beigeing markers.","whyItMatters":"The dose-dependent reversal of insulin resistance, where only the lowest dose worked, challenges assumptions that more is better. The finding that different fat depots respond through different mechanisms adds complexity to understanding how cannabis affects metabolism.","specificNumbers":"Effective dose: 1.25 mg/kg body weight (THC equivalent). Higher doses ineffective. Cidea and UCP1 significantly increased in peritoneal fat. Mitochondrial activity significantly increased in intramuscular fat.","methodology":"Obese streptozotocin-induced diabetic rat model with oral cannabis administration at multiple doses, comparing effects at peritoneal and intramuscular fat depots.","limitations":"Animal model using streptozotocin-induced diabetes, which differs from naturally occurring type 2 diabetes. Only tested oral cannabis, not isolated cannabinoids. Small sample typical of animal studies. Cannot directly extrapolate doses to humans."},{"rthcId":"RTHC-04867","title":"Neuroinflammation in the Central Nervous System: Exploring the Evolving Influence of Endocannabinoid System.","authors":"Rathod, Sumit S; Agrawal, Yogeeta O; Nakhate, Kartik T; Meeran, M F Nagoor; Ojha, Shreesh; Goyal, Sameer N","year":2023,"journal":"Biomedicines, 11(10)","doi":"10.3390/biomedicines11102642","pmid":"37893016","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04868","title":"Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy.","authors":"Rava, Alessandro; Trezza, Viviana","year":2023,"journal":"International journal of molecular sciences, 24(6)","doi":"10.3390/ijms24065220","pmid":"36982295","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04869","title":"Cannabis use to manage opioid cravings among people who use unregulated opioids during a drug toxicity crisis.","authors":"Reddon, Hudson; Lake, Stephanie; Socias, Maria Eugenia; Hayashi, Kanna; DeBeck, Kora; Walsh, Zach; Milloy, M-J","year":2023,"journal":"The International journal on drug policy, 119, 104113","doi":"10.1016/j.drugpo.2023.104113","pmid":"37481875","tags":["harm-reduction","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use to manage opioid cravings was reported by 57.6% of participants and was significantly associated with self-reported opioid reduction (aOR=2.13, 95% CI: 1.07-4.27). The association was strongest among people with moderate-to-severe pain (aOR=4.44) and among women (aOR=8.19).","whyItMatters":"During an ongoing drug toxicity crisis driven by contaminated opioid supplies, understanding any strategy that helps people reduce unregulated opioid use is critical. The strong effect among people with pain suggests cannabis may address a root driver of opioid use.","specificNumbers":"N=205. Cannabis for craving management: 57.6%. Overall aOR=2.13 (95% CI: 1.07-4.27). Pain subgroup aOR=4.44 (95% CI: 1.52-12.97). Female subgroup aOR=8.19 (95% CI: 1.20-55.81).","methodology":"Cross-sectional questionnaire administered to 205 people who use both cannabis and unregulated opioids in Vancouver, Canada, from December 2019 to November 2021. Binary logistic regression with multivariable adjustment.","limitations":"Cross-sectional design cannot determine causation. Self-reported opioid reductions without objective verification. Structurally marginalized population in Vancouver may not generalize broadly. Wide confidence intervals in subgroup analyses (especially female subgroup)."},{"rthcId":"RTHC-04870","title":"Therapeutic and clinical foundations of cannabidiol therapy for difficult-to-treat seizures in children and adults with refractory epilepsies.","authors":"Reddy, Doodipala Samba","year":2023,"journal":"Experimental neurology, 359, 114237","doi":"10.1016/j.expneurol.2022.114237","pmid":"36206806","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Randomized clinical trials support CBD for seizures in three rare epileptic encephalopathies: Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. CBD shows broad-spectrum efficacy across seizure types and possesses anti-inflammatory and neuroprotective properties. Key challenges include limited understanding of pharmacodynamics, complex drug interactions, and lack of expert dosing guidelines.","whyItMatters":"For families dealing with severe childhood epilepsies that resist standard medications, CBD represents the first plant-derived cannabinoid to receive FDA approval. This review maps both its promise and its unresolved clinical challenges.","specificNumbers":"FDA approved in 2018. Three approved indications: Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex. Multimodal mechanisms including non-cannabinoid pathways.","methodology":"Comprehensive narrative review of preclinical and clinical evidence for CBD in refractory epilepsy, covering mechanisms, clinical trials, pharmacokinetics, and outstanding challenges.","limitations":"Narrative review without systematic methodology. Some included trial data are industry-sponsored. Long-term seizure freedom data are limited. CBD pharmacokinetics are complex with significant drug interactions."},{"rthcId":"RTHC-04871","title":"Nanoformulations as a strategy to overcome the delivery limitations of cannabinoids.","authors":"Reddy, T Srinivasa; Zomer, Roby; Mantri, Nitin","year":2023,"journal":"Phytotherapy research : PTR, 37(4), 1526-1538","doi":"10.1002/ptr.7742","pmid":"36748949","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04872","title":"Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration.","authors":"Reece, Albert Stuart; Hulse, Gary Kenneth","year":2023,"journal":"International journal of environmental research and public health, 20(4)","doi":"10.3390/ijerph20043360","pmid":"36834053","tags":["pregnancy","cancer","genetics"],"studyType":"epidemiological-review","evidenceStrength":"moderate","keyFinding":"Longitudinal epigenome-wide association studies showed cannabinoid exposure disrupts chromosomal segregation, DNA repair, methylation machinery, and telomerase function. These disruptions map onto observed patterns of teratogenesis (810 cancer-related hits noted), carcinogenesis, and accelerated epigenomic aging clock in cannabis-exposed patients.","whyItMatters":"This paper proposes a unified mechanism (epigenomic disruption) to explain several concerning epidemiological patterns associated with cannabis exposure. Whether the proposed causal framework holds up to scrutiny has major implications for public health policy.","specificNumbers":"810 cancer-related epigenomic hits noted. Multiple pathways for inhibition of DNA repair and chromosomal segregation identified. Epigenomic clock acceleration documented in cannabis-exposed patients.","methodology":"Synthetic review combining epidemiological data from multiple jurisdictions (Canada, Australia, US, Europe) with recent longitudinal epigenome-wide association studies to create a mechanistic framework.","limitations":"Conceptual overview synthesizing disparate data sources. Ecological epidemiological data are subject to confounding and ecological fallacy. Causal claims rely on E-values and mechanistic plausibility rather than controlled experiments. Some prior epidemiological work by these authors has been critiqued for methodology."},{"rthcId":"RTHC-04873","title":"Impact of converging sociocultural and substance-related trends on US autism rates: combined geospatiotemporal and causal inferential analysis.","authors":"Reece, Albert Stuart; Hulse, Gary Kenneth","year":2023,"journal":"European archives of psychiatry and clinical neuroscience, 273(3), 699-717","doi":"10.1007/s00406-022-01446-0","pmid":"35779123","tags":["pregnancy","youth","legalization"],"studyType":"epidemiological","evidenceStrength":"moderate","keyFinding":"National-level analysis found daily cannabis use significantly related to autism rates (beta=4.37, P<10^-16) and first-trimester exposure (beta=0.12, P=1.7x10^-12). At state level, THC (beta=1.96, P=4x10^-4) and cannabigerol (beta=-13.77, P=1.8x10^-6) were significant. Geospatial modeling showed exponential relationships. Legalization status was linked to elevated autism rates.","whyItMatters":"If the association between cannabis use and autism rates is causal, it would have major implications for prenatal guidelines and cannabis policy. However, this type of ecological analysis has significant limitations in establishing causation.","specificNumbers":"N=40,119,464 eight-year-olds (1994-2011). 266,950 autistic. Daily cannabis beta=4.37 (P<10^-16). First-trimester exposure beta=0.12 (P=1.7x10^-12). THC exponential coefficient=7.053 (6.39-7.71). CBG coefficient=185.334 (167.88-202.79).","methodology":"Longitudinal epidemiological study using IDEA autism census data (1991-2011), NSDUH drug exposure data, and US Census data for 40,119,464 8-year-olds across US states. Two-way fixed-effects and geospatial modeling.","limitations":"Ecological study design (state-level correlations cannot prove individual-level causation). Autism diagnostic criteria changed significantly during the study period. Many confounders could explain both rising cannabis use and rising autism diagnoses. Prior work by these authors has drawn methodological criticism. E-values do not prove causation."},{"rthcId":"RTHC-04874","title":"Vaping additives cannabinoid oil and vitamin E acetate adhere to and damage the human airway epithelium.","authors":"Reidel, Boris; Abdelwahab, Sabri; Wrennall, Joe Alexander; Clapp, Phillip W; Beers, Jessica L; Jackson, Klarissa D; Tarran, Robert; Kesimer, Mehmet","year":2023,"journal":"Journal of applied toxicology : JAT, 43(5), 680-693","doi":"10.1002/jat.4415","pmid":"36372912","tags":["respiratory","cbd"],"studyType":"lab-study","evidenceStrength":"preliminary","keyFinding":"CBD oil exposure caused dramatically increased cell death after 3 days, and this effect was even higher with CBD + vitamin E acetate (VEA) combined. Microscopy revealed cannabinoid and VEA deposits on epithelial surfaces and cannabinoid accumulation inside cells. Proteomic analysis showed increases in xenobiotic enzymes, oxidative stress markers, and cell death indicators.","whyItMatters":"The 2019 EVALI outbreak hospitalized thousands of young people, and the CDC linked it to vitamin E acetate in cannabis vaping products. This study provides a cellular mechanism showing how these substances physically damage airway cells.","specificNumbers":"Cell death dramatically increased after 3 days of CBD exposure. CBD + VEA exposure caused even greater cell death. Proteomic analysis identified increased xenobiotic enzymes, oxidative stress markers, and cell death indicators.","methodology":"Primary human bronchial epithelial cell cultures exposed to e-liquid aerosols containing CBD oil and VEA alone or combined, with PG/VG (with and without nicotine) as controls. Cell viability, microscopy, and proteomic analysis.","limitations":"In vitro cell culture model does not fully replicate in vivo lung conditions. Exposure durations and concentrations may not match real-world vaping patterns. Did not test THC oil, only CBD oil. Limited to short-term effects."},{"rthcId":"RTHC-04875","title":"A rapid and convenient sample preparation method for the analysis of cannabinoids in oral fluid samples.","authors":"Reinstadler, Vera; Huber, Susanne; Lierheimer, Stefan; Boettcher, Michael; Rüscher, Peter; Tanzer, Martin; Jenny, Kurt; Zoll, Adolf; Gruber, Wilhelm; Oberacher, Herbert","year":2023,"journal":"Biomedical chromatography : BMC, 37(8), e5651","doi":"10.1002/bmc.5651","pmid":"37057387","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04876","title":"Cannabis use in the intensive care setting: A scoping review.","authors":"Renger, Laura; Pathmanathan, Kevin; Glynn, Rosie; Laupland, Kevin B","year":2023,"journal":"Journal of critical care, 78, 154397","doi":"10.1016/j.jcrc.2023.154397","pmid":"37544047","tags":["medical-cannabis","respiratory"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Cannabis-associated ICU admissions were primarily from vaping-associated lung injury (EVALI) and synthetic cannabinoid toxicity. Outcome studies were mostly limited to trauma and burns, showing inconsistent mortality effects and a trend toward increased pain scores and analgesic requirements. Two trials of synthetic cannabinoids for traumatic brain injury found no significant effect on intracranial pressure.","whyItMatters":"As cannabis use becomes more prevalent, ICU clinicians increasingly encounter patients who use cannabis. The near-absence of relevant research means clinical decisions are being made without adequate evidence.","specificNumbers":"2,589 articles screened. 22 included. Admissions mainly from EVALI and synthetic cannabinoid toxicity. Inconsistent mortality findings in trauma/burns populations. Two TBI trials showed no intracranial pressure effect.","methodology":"Systematic scoping review of four databases, screening 2,589 articles and including 22 for analysis, covering cannabis-associated admissions, outcomes, and therapeutic uses in adult ICU patients.","limitations":"Scoping review design provides breadth but limited depth. The small number of included studies (22) reflects the literature gap rather than selective inclusion. Most outcome studies were in trauma/burns, limiting generalizability to other ICU populations."},{"rthcId":"RTHC-04877","title":"Association between Substance Misuse and Outcomes in Critically III Patients with Pneumonia.","authors":"Reynolds, Paul M; Afshar, Majid; Wright, Garth C; Ho, P Michael; Kiser, Tyree H; Sottile, Peter D; Althoff, Meghan D; Moss, Marc; Jolley, Sarah E; Vandivier, R William; Burnham, Ellen L","year":2023,"journal":"Annals of the American Thoracic Society, 20(4), 556-565","doi":"10.1513/AnnalsATS.202206-532OC","pmid":"37000145","tags":["respiratory","addiction"],"studyType":"retrospective","evidenceStrength":"strong","keyFinding":"Alcohol misuse (5.0% of patients) was associated with increased in-hospital mortality (adjusted OR 1.12, 95% CI: 1.06-1.19). Opioid misuse (1.5%) was associated with decreased mortality (OR 0.46, 95% CI: 0.39-0.53). Cannabis misuse (0.6%), stimulant misuse (0.6%), and polysubstance misuse (1.2%) showed lower mortality in unadjusted analyses but no consistent association after adjustment.","whyItMatters":"This is one of the largest studies to examine how different types of substance misuse relate to pneumonia outcomes in ICU. The finding that cannabis misuse was not independently associated with worse mortality provides some reassurance, though the study captured only diagnosed misuse disorders.","specificNumbers":"N=167,095 ICU pneumonia patients. Alcohol misuse: 5.0%. Cannabis: 0.6%. Opioid: 1.5%. Stimulant: 0.6%. Polysubstance: 1.2%. No substance misuse: 91.1%. Alcohol mortality OR=1.12. Opioid mortality OR=0.46.","methodology":"Retrospective cohort study of 167,095 ICU patients with pneumonia in the Premier Healthcare Database (2010-2017). Multivariable mixed-effects logistic regression adjusted for age, comorbidities, and hospital characteristics.","limitations":"Administrative data likely underdiagnose substance misuse, especially cannabis. Only 0.6% had cannabis misuse documented, far below population prevalence. Detection bias (younger, healthier patients may be more likely to have substance use documented). Cannot distinguish between active and historical use."},{"rthcId":"RTHC-04878","title":"Virtual screening and in vitro experiments highlight cannabidiol as a drug-like phosphodiesterase 9 inhibitor.","authors":"Ribaudo, Giovanni; Landucci, Elisa; Giannangeli, Matteo; Mazzantini, Costanza; Maccarinelli, Giuseppina; Mastinu, Andrea; Bonini, Sara Anna; Memo, Maurizio; Pellegrini-Giampietro, Domenico E; Gianoncelli, Alessandra","year":2023,"journal":"The European journal of neuroscience, 57(12), 1954-1965","doi":"10.1111/ejn.15869","pmid":"36382587","tags":["cbd","neuroscience"],"studyType":"lab-study","evidenceStrength":"preliminary","keyFinding":"Computational screening of 7 phytocannabinoids and 4 terpenes identified CBD as a potential PDE9 ligand with a calculated binding energy of -9.1 kcal/mol and stable molecular dynamics interaction. In vitro PDE9 inhibition assay confirmed CBD inhibits the enzyme in the nanomolar range.","whyItMatters":"PDE9 inhibitors are being studied as potential treatments for Alzheimer disease and other neurodegenerative conditions. If CBD acts partly through PDE9 inhibition, this could explain some of its reported neuroprotective effects and open a new avenue for drug development.","specificNumbers":"Binding energy: -9.1 kcal/mol. CBD inhibited PDE9 in the nanomolar range in vitro. 7 phytocannabinoids and 4 terpenes screened.","methodology":"Combined ligand-based and structure-based virtual screening (docking and molecular dynamics simulations) followed by in vitro PDE9 enzymatic inhibition assay. Screened 7 phytocannabinoids and 4 terpenes.","limitations":"In vitro enzymatic assay does not confirm in vivo relevance. Nanomolar potency in a cell-free system may not translate to effective brain concentrations. CBD has many proposed molecular targets, and PDE9 may be one of many. No animal or human data yet."},{"rthcId":"RTHC-04879","title":"CANNABIS USE AND SUICIDE IN NON-AFFECTIVE PSYCHOSIS: A MINI-REVIEW OF RECENT LITERATURE.","authors":"Ricci, Valerio; Cristofori, Enrico; Passarello, Erica; Paggi, Andrea; Cavallo, Alex; Ceci, Franca; Martinotti, Giovanni; De Berardis, Domenico; Maina, Giuseppe","year":2023,"journal":"Psychiatria Danubina, 35(3), 307-319","doi":"10.24869/psyd.2023.307","pmid":"37917836","tags":["psychosis","addiction","mental-health"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Three cohort studies agreed that cannabis use was associated with increased suicide risk in schizophrenia patients. Cross-sectional studies and one case-control study yielded contradictory results. Qualitative synthesis suggested a positive correlation, particularly for first-episode psychosis (FEP) and male patients.","whyItMatters":"Both cannabis use and psychotic disorders independently increase suicide risk. Understanding whether their combination creates additional risk is critical for clinical management, especially during the vulnerable first-episode psychosis period.","specificNumbers":"12 studies included. 3 cohort studies showed increased risk. 6 cross-sectional studies yielded mixed results. Male gender and first-episode psychosis identified as key risk modifiers.","methodology":"Mini-review searching PubMed, Scopus, and PsycInfo from January 2010 to February 2022. Included 6 cross-sectional, 3 cohort, 1 case-control, 1 RCT, and 1 case report.","limitations":"Mini-review rather than systematic review with meta-analysis. Small number of included studies (12). Heterogeneous study designs make comparison difficult. Cannot determine causation. Publication bias possible."},{"rthcId":"RTHC-04880","title":"Aberrant salience in cannabis-induced psychosis: a comparative study.","authors":"Ricci, Valerio; Di Muzio, Ilenia; Ceci, Franca; Di Carlo, Francesco; Mancusi, Gianluca; Piro, Tommaso; Paggi, Andrea; Pettorruso, Mauro; Vellante, Federica; De Berardis, Domenico; Martinotti, Giovanni; Maina, Giuseppe","year":2023,"journal":"Frontiers in psychiatry, 14, 1343884","doi":"10.3389/fpsyt.2023.1343884","pmid":"38260781","tags":["psychosis","synthetic-cannabinoids","mental-health"],"studyType":"comparative-study","evidenceStrength":"moderate","keyFinding":"SPICE users had more severe and persistent positive symptoms than THC users and non-users. Non-users showed better recovery in global functioning compared to SPICE users. All groups showed decreasing aberrant salience scores over time, but SPICE users maintained higher global scores and improved less. Negative symptoms were most prominent in non-users.","whyItMatters":"Synthetic cannabinoids are far more potent at CB1 receptors than THC, and this study provides clinical evidence that psychosis associated with synthetic cannabinoid use is more severe and harder to recover from than THC-associated or non-substance psychosis.","specificNumbers":"N=62 first-episode psychosis patients (20 non-users, 21 THC users, 20 SPICE users). Assessed at 3 timepoints using 5 validated scales. SPICE users showed persistently higher positive symptoms and aberrant salience.","methodology":"Comparative study of 62 patients with first-episode psychosis divided into non-users (N=20), THC users (N=21), and SPICE users (N=20). Assessed at onset, 3 months, and 6 months using PANSS, GAF, DES-II, SSI, and ASI scales.","limitations":"Small sample size (62 total, ~20 per group). Non-randomized group assignment. Cannot control for all confounders between groups. Self-reported substance use. 6-month follow-up may not capture long-term trajectory."},{"rthcId":"RTHC-04881","title":"First episode psychosis with and without the use of cannabis and synthetic cannabinoids: Psychopathology, global functioning and suicidal ideation and antipsychotic effectiveness.","authors":"Ricci, Valerio; Ceci, Franca; Di Carlo, Francesco; Di Muzio, Ilenia; Ciavoni, Laura; Santangelo, Monica; Di Salvo, Gabriele; Pettorruso, Mauro; Martinotti, Giovanni; Maina, Giuseppe","year":2023,"journal":"Psychiatry research, 320, 115053","doi":"10.1016/j.psychres.2023.115053","pmid":"36682093","tags":["psychosis","synthetic-cannabinoids","mental-health"],"studyType":"comparative-study","evidenceStrength":"moderate","keyFinding":"THC users and especially SPICE users displayed more severe positive symptoms than non-users. Negative symptoms were higher among non-users. After 9 months, non-users had recovered significantly better than SPICE users in global functioning. Dissociative symptoms were significantly greater in substance users. Suicidal ideation was highest in SPICE users.","whyItMatters":"The 9-month follow-up extends earlier findings at 6 months, confirming that psychosis associated with synthetic cannabinoids follows a more severe and persistent course. The elevated suicidal ideation in SPICE users is a critical clinical concern.","specificNumbers":"N=61 (20 non-users, 21 THC users, 20 SPICE users). Assessed at 3 timepoints over 9 months. SPICE users had worst positive symptoms and suicidal ideation. Non-users had best functional recovery.","methodology":"Comparative study of 61 first-episode psychosis patients divided into non-users (N=20), THC users (N=21), and SPICE users (N=20), assessed at onset, 3 months, and 9 months using validated psychopathological scales.","limitations":"Small sample size (~20 per group). Non-randomized group assignment. Self-reported substance use. Single-center study. Cannot control for all confounders between groups."},{"rthcId":"RTHC-04882","title":"Self-compassion as a mediator of the relationship between childhood sexual abuse and psychotic symptoms in clinical and non-clinical groups.","authors":"Richardson, Thomas; Sood, Monica; Bayliss, Paul; Newman-Taylor, Katherine","year":2023,"journal":"The British journal of clinical psychology, 62(3), 689-697","doi":"10.1111/bjc.12429","pmid":"37382313","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04883","title":"Medicinal cannabis improves sleep in adults with insomnia: a randomised double-blind placebo-controlled crossover study.","authors":"Ried, Karin; Tamanna, Tasnuva; Matthews, Sonja; Sali, Avni","year":2023,"journal":"Journal of sleep research, 32(3), e13793","doi":"10.1111/jsr.13793","pmid":"36539991","tags":["sleep","medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"60% of participants no longer classified as clinical insomniacs after 2 weeks of cannabis oil. Midnight melatonin levels increased 30% in the active group vs. a 20% decline in placebo (P=0.035). Light sleep increased by 21 minutes per night compared to placebo (P=0.041). Overall sleep quality improved by up to 80% (P=0.003).","whyItMatters":"This is one of few placebo-controlled RCTs of cannabis for insomnia. The melatonin finding is particularly interesting because it suggests cannabis may work through the body's natural sleep-signaling pathway rather than just sedation.","specificNumbers":"N=29 completers. 60% no longer clinical insomniacs. Melatonin: +30% active vs. -20% placebo (P=0.035). Light sleep: +21 min/night (P=0.041). Sleep quality: up to 80% improvement (P=0.003). Daily functioning improved (P=0.032).","methodology":"Randomized double-blind placebo-controlled crossover trial over 6 weeks (2-week intervention, 1-week washout, crossover). 29 participants with self-reported clinical insomnia. Active oil: 10mg/ml THC + 15mg/ml CBD, titrated 0.2-1.5 ml/day.","limitations":"Small sample (N=29). Short 2-week intervention period. Self-reported insomnia (not polysomnography-diagnosed). Period effect with more pronounced Phase 2 results. Loss of blinding noted by authors. Fitbit tracker has limitations compared to polysomnography."},{"rthcId":"RTHC-04884","title":"Cannabinoid Hyperemesis Encounters After Medical Legalization in Oklahoma.","authors":"Riha, Randal; Winchell, Ryan; Safo, Danielle; Gentges, Joshua","year":2023,"journal":"Cureus, 15(10), e46465","doi":"10.7759/cureus.46465","pmid":"37927644","tags":["legalization","medical-cannabis"],"studyType":"retrospective","evidenceStrength":"moderate","keyFinding":"CHS-related ED visits increased from 43 cases pre-legalization to 62 post-legalization (P=0.026), despite total ED visits decreasing from 30,437 to 28,362. The proportion of ED visits for CHS (220/100,000) was much higher than previously reported (13.3/100,000). No demographic differences between pre- and post-legalization groups.","whyItMatters":"CHS causes severe vomiting episodes that can lead to dehydration and kidney injury. The much higher prevalence found here compared to prior literature suggests CHS may be significantly underdiagnosed or that Oklahoma's medical cannabis market has unique characteristics.","specificNumbers":"Pre-legalization: 43 CHS cases in 30,437 ED visits. Post-legalization: 62 cases in 28,362 visits (P=0.026). CHS proportion: 220/100,000 vs. 13.3/100,000 in prior literature.","methodology":"Retrospective chart review comparing equivalent 8-month periods before and after the first legal medical cannabis sales in Oklahoma, at a single urban ED.","limitations":"Single-center retrospective design. Cannot distinguish whether increase is from more CHS cases, better provider recognition, or increased cannabis use. Short comparison window (8 months). \"Suspected CHS\" inclusion may overestimate true cases."},{"rthcId":"RTHC-04885","title":"The cannabinoid CB1 receptor interacts with the angiotensin AT2 receptor. Overexpression of AT2-CB1 receptor heteromers in the striatum of 6-hydroxydopamine hemilesioned rats.","authors":"Rivas-Santisteban, Rafael; Lillo, Jaume; Raïch, Iu; Muñoz, Ana; Lillo, Alejandro; Rodríguez-Pérez, Ana I; Labandeira-García, José L; Navarro, Gemma; Franco, Rafael","year":2023,"journal":"Experimental neurology, 362, 114319","doi":"10.1016/j.expneurol.2023.114319","pmid":"36632949","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04886","title":"High-CBD Cannabis Vapor Attenuates Opioid Reward and Partially Modulates Nociception in Female Rats.","authors":"Rivera-Garcia, Maria T; Rose, Rizelle Mae; Wilson-Poe, Adrianne R","year":2023,"journal":"Addiction neuroscience, 5","doi":"10.1016/j.addicn.2022.100050","pmid":"36937502","tags":["cbd","addiction","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"High-CBD whole-plant extract (WPE) vapor prevented morphine-induced conditioned place preference and reinstatement. WPE reduced fentanyl self-administration in rats with and without neuropathic pain. WPE showed modest efficacy against cold allodynia in nerve-injured rats. Chronic exposure did not affect lung tissue, cognition, social behavior, or estrous cycle. WPE vapor had no reinforcing properties.","whyItMatters":"Most cannabis and opioid research has been done in male animals. This study fills a critical gap by showing that high-CBD cannabis vapor can reduce opioid reward and self-administration in females specifically, which matters because chronic pain is more prevalent in women.","specificNumbers":"WPE prevented morphine conditioned place preference and reinstatement. Reduced fentanyl self-administration in both injured and non-injured rats. Modest cold allodynia reversal. No lung cytoarchitecture changes. No cognitive, social, or reproductive effects.","methodology":"Comprehensive preclinical analysis in female rats including conditioned place preference, fentanyl self-administration, neuropathic pain models (spared nerve injury), cognitive and social behavior tests, lung histology, and estrous cycle monitoring.","limitations":"Animal study in female rats only. Modest analgesic effect against neuropathic pain. Cannot directly extrapolate vapor doses to human vaping. Short-term exposure only. Single cannabis extract may not represent all products."},{"rthcId":"RTHC-04887","title":"The Role of Hemp (Cannabis sativa L.) as a Functional Food in Vegetarian Nutrition.","authors":"Rizzo, Gianluca; Storz, Maximilian Andreas; Calapai, Gioacchino","year":2023,"journal":"Foods (Basel, Switzerland), 12(18)","doi":"10.3390/foods12183505","pmid":"37761214","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04888","title":"The Reversal of Empathy-Induced Hypernociception in Male Mice by Intra-Amygdala Administration of Midazolam and Cannabidiol Depends on 5-HT3 Receptors.","authors":"Rodrigues Tavares, Lígia Renata; Baptista-de-Souza, Daniela; Canto-de-Souza, Lucas; Planeta, Cleopatra da Silva; Guimarães, Francisco Silveira; Nunes-de-Souza, Ricardo Luiz; Canto-de-Souza, Azair","year":2023,"journal":"Cannabis and cannabinoid research, 8(2), 335-347","doi":"10.1089/can.2022.0132","pmid":"36103283","tags":["cbd","pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice housed with chronic pain partners showed hypernociception and increased 5-HT3 receptor and GAD67 expression in the amygdala. Intra-amygdala CBD (30 and 60 nmol) and midazolam (3.0 and 30 nmol) both attenuated the hypernociceptive behavior. The 5-HT3 receptor antagonist ondansetron blocked the effects of both CBD and midazolam.","whyItMatters":"This study demonstrates that social exposure to a partner in pain can biologically change pain processing in the observer, and that CBD can reverse this change. It opens a window into how emotional pain contagion works at the neural circuit level.","specificNumbers":"CBD effective at 30 and 60 nmol intra-amygdala. Midazolam effective at 3.0 and 30 nmol. Ondansetron (0.3 nmol) blocked both drugs. 5-HT3 receptor and GAD67 expression increased in cagemates of injured mice.","methodology":"Male Swiss mice housed in pairs for 28 days. On day 14, one partner received nerve constriction (or sham). Cagemates underwent stereotaxic surgery on day 24 and were tested on day 28 using the writhing test. Drugs administered intra-amygdala.","limitations":"Direct brain injection does not reflect any realistic human delivery route. Male mice only. Small sample sizes typical of neuroscience studies. The empathy-pain model may not directly translate to human emotional pain processing. Short assessment window."},{"rthcId":"RTHC-04889","title":"Therapeutic and Supportive Effects of Cannabinoids in Patients with Brain Tumors (CBD Oil and Cannabis).","authors":"Rodriguez-Almaraz, J Eduardo; Butowski, Nicholas","year":2023,"journal":"Current treatment options in oncology, 24(1), 30-44","doi":"10.1007/s11864-022-01047-y","pmid":"36633803","tags":["cancer","medical-cannabis","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Published and anecdotal evidence suggests cannabis may help with chemotherapy-induced nausea and vomiting, appetite stimulation, pain reduction, and seizure management in brain tumor patients. Preclinical evidence suggests potential anti-inflammatory and anti-proliferative effects. However, no standardized dosing guidance exists, and cannabis use is dominated by recreational purposes rather than clinical protocols.","whyItMatters":"Brain tumor patients have very limited treatment options and often experience severe side effects from chemotherapy. Cannabis could address multiple symptoms simultaneously, but without dosing standards, patients and clinicians are navigating blindly.","specificNumbers":"No specific quantitative outcomes reported. Review covers palliative benefits (nausea, pain, appetite, seizures) and preclinical anti-cancer data.","methodology":"Narrative review of current literature on cannabinoids in brain tumor treatment, covering symptomatic management and potential anti-tumor properties.","limitations":"Narrative review without systematic methodology. Relies partly on anecdotal evidence. No meta-analysis possible due to heterogeneous literature. Anti-tumor evidence is preclinical only. Legal barriers limit research quality."},{"rthcId":"RTHC-04890","title":"Role of the CB2 Cannabinoid Receptor in the Regulation of Food Intake: A Systematic Review.","authors":"Rodríguez-Serrano, Luis Miguel; Chávez-Hernández, María Elena","year":2023,"journal":"International journal of molecular sciences, 24(24)","doi":"10.3390/ijms242417516","pmid":"38139344","tags":["appetite","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CB2 receptors in brain reward areas modulate food intake. Two main experimental strategies confirmed this: (1) administering CB2 agonists/antagonists intraperitoneally or intracerebroventricularly, and (2) CB2 receptor knockout in mice. Both approaches demonstrated that CB2 receptors are necessary for modulating food intake and mediating energy balance.","whyItMatters":"Most appetite research has focused on CB1 receptors (the target of the withdrawn anti-obesity drug rimonabant). Finding that CB2 receptors also regulate food intake opens a potential path to appetite-modulating drugs without the psychiatric side effects that doomed CB1 antagonists.","specificNumbers":"13 studies included from 3 databases. CB2 receptor found in brain reward areas. Both pharmacological and genetic approaches confirmed food intake modulation.","methodology":"Systematic review following PRISMA guidelines, searching PubMed, Scopus, and EBSCO databases. 13 studies included. Risk of bias assessed using SYRCLE tool for animal studies.","limitations":"All included studies are animal models, limiting direct clinical translation. Only 13 studies available, reflecting a young research area. SYRCLE risk of bias tool has limitations. No human data included."},{"rthcId":"RTHC-04891","title":"Cannabis-Involved Emergency Department Visits Among Persons Aged <25 Years Before and During the COVID-19 Pandemic - United States, 2019-2022.","authors":"Roehler, Douglas R; Smith, Herschel; Radhakrishnan, Lakshmi; Holland, Kristin M; Gates, Abigail L; Vivolo-Kantor, Alana M; Hoots, Brooke E","year":2023,"journal":"MMWR. Morbidity and mortality weekly report, 72(28), 758-765","doi":"10.15585/mmwr.mm7228a1","pmid":"37440436","tags":["youth","legalization"],"studyType":"surveillance-study","evidenceStrength":"strong","keyFinding":"Mean weekly cannabis-involved ED visits among all youth under 25 were higher during 2020, 2021, and 2022 compared to 2019. The largest increases were among children aged 10 and under. Among adolescents aged 11-14, female ED visit rates surpassed male rates starting in late 2020, a pattern not seen pre-pandemic.","whyItMatters":"The surge in cannabis ED visits among very young children (under 10) points to accidental ingestion of cannabis edibles, a growing problem as legal cannabis products become more prevalent in homes. The gender shift among adolescents raises questions about changing patterns of use.","specificNumbers":"Cannabis ED visits higher in 2020, 2021, and 2022 vs. 2019 across all youth under 25. Largest increases in children aged 10 and under. Female rates exceeded male rates among 11-14 year olds starting late 2020.","methodology":"CDC analysis of National Syndromic Surveillance Program data examining cannabis-involved ED visits (documented in chief complaint or discharge diagnosis) among persons under 25 during 2019-2022.","limitations":"Syndromic surveillance data depend on documentation quality. Cannot determine intentional vs. accidental exposure in young children. COVID-19 pandemic may have changed ED-seeking behavior. Cannot attribute trends to any single cause (legalization, pandemic stress, product availability)."},{"rthcId":"RTHC-04892","title":"Annual incidence of substance-induced psychoses in Scandinavia from 2000 to 2016.","authors":"Rognli, Eline Borger; Taipale, Heidi; Hjorthøj, Carsten; Mittendorfer-Rutz, Ellenor; Bramness, Jørgen G; Heiberg, Ina H; Niemelä, Solja","year":2023,"journal":"Psychological medicine, 53(11), 5246-5255","doi":"10.1017/S003329172200229X","pmid":"35983644","tags":["psychosis","addiction","legalization"],"studyType":"registry-study","evidenceStrength":"strong","keyFinding":"Cannabis-induced psychosis incidence increased in all three countries: Denmark (2.6 to 5.6), Sweden (0.8 to 2.7), Norway (1.8 to 3.0 per 100,000). Alcohol-induced psychosis decreased: Denmark (4.9 to 1.5), Sweden (4.5 to 2.2). Overall substance-induced psychosis rates remained stable (9.3-14.1). Median age at diagnosis decreased. Rates were higher in men and disability pension recipients.","whyItMatters":"The consistency across three countries with different cannabis policies strengthens the finding that cannabis-induced psychosis is genuinely increasing. The simultaneous decline in alcohol-induced psychosis suggests a shifting substance use landscape with distinct mental health implications.","specificNumbers":"Cannabis-induced psychosis: Denmark 2.6 to 5.6, Sweden 0.8 to 2.7, Norway 1.8 to 3.0 per 100,000. Alcohol-induced psychosis: Denmark 4.9 to 1.5, Sweden 4.5 to 2.2. Median age: Denmark 36 to 29, Sweden 41 to 31 years.","methodology":"Population-wide registry study covering entire adult populations of Denmark and Sweden (2000-2016) and Norway (2010-2015), estimating annual incidence rates per 100,000 by substance type, age, gender, and socioeconomic background.","limitations":"Registry data depend on diagnostic practices, which may have changed over time. Increased awareness of cannabis-induced psychosis could inflate apparent incidence. Cannot control for changes in cannabis potency or use patterns. Norway data covers a shorter period (2010-2015)."},{"rthcId":"RTHC-04893","title":"Cannabinoids and the placenta: Receptors, signaling and outcomes.","authors":"Rokeby, Abbey C E; Natale, Bryony V; Natale, David R C","year":2023,"journal":"Placenta, 135, 51-61","doi":"10.1016/j.placenta.2023.03.002","pmid":"36965349","tags":["pregnancy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoid receptors are expressed throughout the human and murine placenta. Both THC and CBD cross the placenta. Prenatal cannabinoid exposure is linked to small for gestational age and fetal growth restriction. Studies including placental analysis identified changes in placental vasculature and function. In vitro studies show cannabinoid effects on cell proliferation, angiogenesis, and migration in placental cells.","whyItMatters":"Cannabis use during pregnancy is increasing as pregnant women use it for morning sickness and anxiety. This review highlights that the risk is not just from direct fetal exposure but also from cannabis disrupting the placenta itself, which could impair nutrient delivery and fetal growth.","specificNumbers":"Cannabis concentrations have increased dramatically over 20 years. Cannabinoid receptors found throughout placenta. Prenatal exposure linked to growth restriction. Placental vasculature and function changes documented in exposed pregnancies.","methodology":"Narrative review summarizing clinical, animal model, and in vitro evidence on how phytocannabinoids affect placental development and function, with focus on receptor distribution and signaling pathways.","limitations":"Narrative review without systematic methodology. Much evidence is from in vitro or animal models. Clinical studies with placental analysis are few. Cannabis product composition varies widely. Timing and dose of exposure likely matter but are poorly characterized."},{"rthcId":"RTHC-04894","title":"Association Between Suicidal Behaviour and Cannabis and Tranquilizer use, Depression, Aggression and Other Borderline Personality Traits Among Students in Sincelejo, Colombia.","authors":"Romero-Acosta, Kelly; Verhelst, Salomón; Lowe, Gillian A; Lipps, Garth E; Restrepo, José; Fonseca, Leodanis","year":2023,"journal":"Revista Colombiana de psiquiatria, 52(3), 225-235","doi":"10.1016/j.rcpeng.2021.05.011","pmid":"37923416","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use (t=2.83, P<.05) and tranquilizer use (t=2.37, P<.05) had significant independent relationships with suicidal behavior. Physical aggression, cognitive and affective depression, affective instability, few social relationships, and self-harm were also independently associated. Depression and borderline personality traits were the strongest predictors of suicidal behavior.","whyItMatters":"Adolescent suicide is a growing concern in Latin America, and understanding the clustering of risk factors (substance use, depression, aggression, personality traits) helps identify who needs intervention. Cannabis use appearing as an independent predictor adds to the risk factor profile.","specificNumbers":"N=352. Ages 12-18 (mean 15.09). Cannabis use t=2.83 (P<.05). Tranquilizer use t=2.37 (P<.05). Aggression t=2.59 (P<.05). Depression t=9.03 (P<.01). Borderline traits t=4.12 (P<.01).","methodology":"Cross-sectional study of 352 adolescents aged 12-18 (mean 15.09) from a public and private school in Sincelejo, Colombia. Purposive sampling. Self-report instruments with t-tests, ANOVA, and linear regression.","limitations":"Cross-sectional design cannot determine causation. Purposive sampling limits generalizability. Self-reported substance use and suicidal behavior. Two schools in one city may not represent broader populations. Cannabis use frequency and quantity not detailed."},{"rthcId":"RTHC-04895","title":"Role of Cannabinoid Signaling in Cardiovascular Function and Ischemic Injury.","authors":"Rorabaugh, Boyd R; Guindon, Josée; Morgan, Daniel J","year":2023,"journal":"The Journal of pharmacology and experimental therapeutics, 387(3), 265-276","doi":"10.1124/jpet.123.001665","pmid":"37739804","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04896","title":"Roadmap For The Expression Of Canonical and Extended Endocannabinoid System Receptors and Proteins in Peripheral Organs of Preclinical Animal Models.","authors":"Rosado-Franco, J J; Ellison, A L; White, C J; Price, A S; Moore, C F; Williams, R E; Fridman, L B; Weerts, E M; Williams, D W","year":2023,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2023.06.10.544455","pmid":"37333264","tags":["neuroscience"],"studyType":"comparative-study","evidenceStrength":"moderate","keyFinding":"Of 14 canonical and extended endocannabinoid receptors examined across 7 peripheral organs, only CB2, GPR18, GPR55, TRPV2, and FAAH had identical expression patterns in mice, rats, and rhesus macaques. Species- and organ-specific heterogeneity was substantial and previously unappreciated.","whyItMatters":"Most cannabinoid research uses rodent models, but if endocannabinoid receptors are distributed differently across species, findings in mice may not translate to primates or humans. This study reveals a fundamental challenge for the entire field.","specificNumbers":"14 receptors tested across 7 organs in 3 species. Only 5 receptors (CB2, GPR18, GPR55, TRPV2, FAAH) matched across all species. Substantial species-specific and organ-specific variation in the remaining 9.","methodology":"Comparative gene expression analysis of 14 endocannabinoid receptors in 7 peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and rhesus macaques using quantitative methods.","limitations":"Gene expression does not always correlate with protein levels or functional activity. Focused on peripheral organs, not brain regions. Limited to 3 species. Sample sizes per species not detailed. Preprint status (bioRxiv) means not yet peer-reviewed."},{"rthcId":"RTHC-04897","title":"Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity.","authors":"Rosenberg, Evan C; Chamberland, Simon; Bazelot, Michael; Nebet, Erica R; Wang, Xiaohan; McKenzie, Sam; Jain, Swati; Greenhill, Stuart; Wilson, Max; Marley, Nicole; Salah, Alejandro; Bailey, Shanice; Patra, Pabitra Hriday; Rose, Rebecca; Chenouard, Nicolas; Sun, Simón E D; Jones, Drew; Buzsáki, György; Devinsky, Orrin; Woodhall, Gavin; Scharfman, Helen E; Whalley, Benjamin J; Tsien, Richard W","year":2023,"journal":"Neuron, 111(8), 1282-1300.e8","doi":"10.1016/j.neuron.2023.01.018","pmid":"36787750","tags":["cbd","epilepsy","neuroscience"],"studyType":"lab-study","evidenceStrength":"strong","keyFinding":"LPI increased excitatory presynaptic release probability and evoked synaptic strength in hippocampal CA3-CA1 connections while simultaneously weakening inhibitory signaling by decreasing GABA receptor (GABAARgamma2) and gephyrin puncta. CBD pre-treatment eliminated all LPI effects. Acute seizures elevated both GPR55 and LPI levels. Chronic epileptogenesis potentiated LPI's pro-excitatory effects.","whyItMatters":"This is among the most mechanistically detailed explanations of how CBD stops seizures. By showing that CBD blocks a single pathway (LPI-GPR55) that simultaneously tips both excitatory and inhibitory signaling toward hyperexcitability, it provides a unified mechanism for CBD's anti-seizure action.","specificNumbers":"LPI increased excitatory release probability and evoked synaptic strength. LPI decreased GABAARgamma2 and gephyrin puncta. Effects eliminated by CBD and absent in GPR55 knockout mice. Acute seizures elevated GPR55 and LPI levels.","methodology":"Electrophysiology and immunohistochemistry in wild-type and GPR55 knockout mice. Acute (pentylenetetrazole) and chronic (lithium-pilocarpine) seizure models. Hippocampal slice recordings.","limitations":"Mouse hippocampal slice model may not capture all mechanisms relevant to human epilepsy. Two seizure models tested but may not represent all epilepsy types. CBD has many known molecular targets; GPR55 may be one of several relevant pathways."},{"rthcId":"RTHC-04898","title":"The Impact of Cannabis Use on Adolescent Neurodevelopment and Clinical Outcomes Amidst Changing State Policies.","authors":"Ross, Jennifer A; Levy, Sharon","year":2023,"journal":"Clinical therapeutics, 45(6), 535-540","doi":"10.1016/j.clinthera.2023.03.009","pmid":"37414504","tags":["youth","cognition","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The adolescent brain is especially vulnerable because the prefrontal cortex (responsible for impulse control and executive functions) is not fully mature until the mid-twenties. Cannabis activates the reward pathway inappropriately during this period. State policy changes have increased availability of high-potency products with new delivery devices capable of delivering higher peak THC doses faster.","whyItMatters":"The combination of expanding legal access and rapidly evolving product technology (concentrates, vape devices, edibles) means adolescents are potentially exposed to THC levels and delivery speeds that did not exist when most cannabis research was conducted.","specificNumbers":"Prefrontal cortex not fully mature until mid-twenties. Cannabis is the third most common psychoactive substance among adolescents after alcohol and nicotine. New products deliver higher and faster peak THC doses.","methodology":"Narrative review of current literature on cannabis neurobiology in adolescents, clinical outcomes, and effects of changing state cannabis policies.","limitations":"Narrative review without systematic methodology. Cannabis potency and product diversity make generalizations difficult. Long-term longitudinal data on high-potency product effects in adolescents are largely unavailable."},{"rthcId":"RTHC-04899","title":"Endocannabinoid System Components of the Female Mouse Reproductive Tract Are Modulated during Reproductive Aging.","authors":"Rossi, Gianna; Di Nisio, Valentina; Chiominto, Alessandro; Cecconi, Sandra; Maccarrone, Mauro","year":2023,"journal":"International journal of molecular sciences, 24(8)","doi":"10.3390/ijms24087542","pmid":"37108704","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04900","title":"Interactive Effects of Ayahuasca and Cannabidiol in Social Cognition in Healthy Volunteers: A Pilot, Proof-of-Concept, Feasibility, Randomized-Controlled Trial.","authors":"Rossi, Giordano Novak; Rocha, Juliana Mendes; Osório, Flávia L; Bouso, José Carlos; Ona, Genis; Silveira, Gabriela de Oliveira; Yonamine, Mauricio; Bertozi, Giuliana; Crevelin, Eduardo José; Queiroz, Maria Eugênia; Crippa, José Alexandre S; Hallak, Jaime E Cecílio; Dos Santos, Rafael G","year":2023,"journal":"Journal of clinical psychopharmacology, 43(4), 339-349","doi":"10.1097/JCP.0000000000001691","pmid":"37335211","tags":["cbd","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"No evidence of interactive effects between ayahuasca and CBD on emotion recognition or empathy tasks. Both groups showed similar reductions in reaction times and similar decreases in anxiety, sedation, and discomfort. The combination was well tolerated with mainly nausea and GI discomfort. No clinically significant cardiovascular or liver enzyme effects.","whyItMatters":"CBD is known to modulate the effects of THC, and this study tested whether it could similarly moderate ayahuasca, another psychoactive substance. The null finding is useful because it suggests CBD does not interfere with ayahuasca's potential therapeutic effects.","specificNumbers":"N=17 healthy volunteers. CBD dose: 600mg oral. Ayahuasca: 1 ml/kg. Assessed at 4 timepoints over 7 days. No between-group differences on any primary or secondary outcome.","methodology":"Pilot parallel-arm RCT. 17 healthy volunteers received placebo or 600mg oral CBD followed by ayahuasca (1 ml/kg) 90 minutes later. Assessed at baseline, 6.5 hours, 1 day, and 7 days post-intervention.","limitations":"Very small sample (N=17). Pilot feasibility study not powered to detect subtle effects. Healthy volunteers only. Single dose of each substance. 1-week follow-up may be too short to detect longer-term interactions."},{"rthcId":"RTHC-04901","title":"Using the Severity of Dependence Scale to examine cannabis consumers with impaired control in Canada.","authors":"Rotermann, Michelle","year":2023,"journal":"Health reports, 34(6), 3-16","doi":"10.25318/82-003-x202300600001-eng","pmid":"37342961","tags":["addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"4.7% of past-year cannabis consumers had Severity of Dependence Scale scores of 4 or higher (impaired control). Risk was elevated for males, ages 18-24, single/never married, lower-income households, those diagnosed with anxiety or mood disorders, those who started cannabis before age 16, and those consuming at least monthly.","whyItMatters":"This is among the first nationally representative assessments of problematic cannabis use in Canada after legalization. The 4.7% rate provides a baseline for monitoring whether legalization changes patterns of problematic use over time.","specificNumbers":"4.7% of past-year consumers had impaired control (SDS >= 4). Risk elevated for: males, ages 18-24, single, lower income, anxiety/mood disorder diagnosis, cannabis initiation at age 15 or younger, at least monthly use.","methodology":"Cross-sectional analysis of the nationally representative 2019-2020 Canadian Community Health Survey using the Severity of Dependence Scale (SDS). Multivariable logistic regression examined associations with impaired control.","limitations":"Cross-sectional design captures a snapshot, not trajectories. SDS is a screening tool, not a clinical diagnosis of CUD. Self-reported cannabis use may underestimate true use. Post-legalization data may still reflect transition effects rather than steady-state patterns."},{"rthcId":"RTHC-04902","title":"Alcohol & cannabinoid co-use: Implications for impaired fetal brain development following gestational exposure.","authors":"Rouzer, Siara Kate; Gutierrez, Jessica; Larin, Kirill V; Miranda, Rajesh C","year":2023,"journal":"Experimental neurology, 361, 114318","doi":"10.1016/j.expneurol.2023.114318","pmid":"36627039","tags":["pregnancy","cognition","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Both alcohol and cannabinoids independently impact fetal neurodevelopment with lifelong consequences. Simultaneous alcohol-cannabinoid (SAC) use amplifies each drug's pharmacodynamic effects and increases craving for both substances. However, prenatal polysubstance investigations are extremely limited in both human and animal populations. The review identifies shared prenatal targets from single-exposure studies that may represent particularly vulnerable neurobiological mechanisms.","whyItMatters":"Research has focused on each substance separately, but real-world use increasingly involves both. The pharmacological interaction between alcohol and cannabinoids suggests combined prenatal exposure could be worse than either alone, yet this is largely unexamined.","specificNumbers":"No specific quantitative data. Review identifies shared neurobiological targets and notes increasing rates of simultaneous use among people of childbearing age.","methodology":"Narrative review addressing combined alcohol and cannabinoid exposure, including direct and prenatal effects, with identification of shared neurobiological targets from single-exposure paradigms.","limitations":"Narrative review identifying a research gap rather than synthesizing existing data. Very few studies of combined prenatal exposure exist. Proposed shared mechanisms are hypothetical and require experimental confirmation. Human polysubstance exposure studies face major ethical and methodological challenges."},{"rthcId":"RTHC-04903","title":"Enantioseparation of chiral phytocannabinoids in medicinal cannabis.","authors":"Russo, Fabiana; Tolomeo, Francesco; Angela Vandelli, Maria; Biagini, Giuseppe; Laganà, Aldo; Laura Capriotti, Anna; Cerrato, Andrea; Carbone, Luigi; Perrone, Elisabetta; Cavazzini, Alberto; Maiorano, Vincenzo; Gigli, Giuseppe; Cannazza, Giuseppe; Citti, Cinzia","year":2023,"journal":"Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1221, 123682","doi":"10.1016/j.jchromb.2023.123682","pmid":"36965450","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04904","title":"Protocol of a Combined Cohort and Cross-Sectional Study of Persons Receiving Medical Cannabis in Florida, USA: The Medical Marijuana and Me (M3) Study.","authors":"Sajdeya, Ruba; Fechtel, Hannah J; Spandau, Gabriel; Goodin, Amie J; Brown, Joshua D; Jugl, Sebastian; Smolinski, Nicole E; Winterstein, Almut G; Cook, Robert L; Wang, Yan","year":2023,"journal":"Medical cannabis and cannabinoids, 6(1), 46-57","doi":"10.1159/000530052","pmid":"37261066","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04905","title":"Driving under the influence of cannabis and alcohol: Evidence from a national sample of young drivers.","authors":"Salas-Wright, Christopher P; Hai, Audrey Hang; Vaughn, Michael G; Hodges, James C; Goings, Trenette Clark","year":2023,"journal":"Addictive behaviors, 147, 107816","doi":"10.1016/j.addbeh.2023.107816","pmid":"37572491","tags":["driving","youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"DUI-cannabis prevalence was 6.3% in the full sample and 24.5% among past-year cannabis users. DUI-alcohol was 2.6% overall and 6.1% among past-year alcohol consumers. Risk was elevated among older and male youth for both substances. More than one million young drivers per year are estimated to drive after using cannabis and/or alcohol.","whyItMatters":"Cannabis-impaired driving among underage drivers is more than twice as prevalent as alcohol-impaired driving in this age group. This challenges the traditional focus on alcohol-impaired driving prevention among young people.","specificNumbers":"N=12,863 drivers ages 16-20. DUI-cannabis: 6.3% overall, 24.5% among users. DUI-alcohol: 2.6% overall, 6.1% among drinkers. Estimated 1+ million young DUI drivers per year.","methodology":"Cross-sectional analysis of 2020-2021 NSDUH data for drivers ages 16-20 (N=12,863). Survey-adjusted prevalence estimates and logistic regression weighted for stratified cluster sampling.","limitations":"Self-reported DUI likely underestimates true prevalence. Cross-sectional design. 2020-2021 data may reflect pandemic-related changes in driving patterns. Cannot assess actual impairment level or crash risk from survey data."},{"rthcId":"RTHC-04906","title":"CBD lengthens sleep but shortens ripples and leads to intact simple but worse cumulative memory.","authors":"Samanta, Anumita; Aleman-Zapata, Adrian; Agarwal, Kopal; Özsezer, Pelin; Alonso, Alejandra; van der Meij, Jacqueline; Rayan, Abdelrahman; Navarro-Lobato, Irene; Genzel, Lisa","year":2023,"journal":"iScience, 26(11), 108327","doi":"10.1016/j.isci.2023.108327","pmid":"38026151","tags":["cbd","sleep","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD extended the sleep period but changed properties of rest and non-REM sleep oscillations (delta, spindle, ripples). Critically, CBD reduced long ripples (>100ms), which are associated with memory replay. This led to worse cumulative memory consolidation in an object space task. Simple memories were unaffected.","whyItMatters":"CBD is increasingly marketed as a sleep aid, and this study confirms it does extend sleep. However, the discovery that it disrupts the sleep oscillations needed for memory consolidation raises concerns about a hidden cognitive cost of using CBD for sleep.","specificNumbers":"CBD extended sleep period. Long ripples (>100ms) reduced. Cumulative memory consolidation impaired. Simple memory unaffected. Delta, spindle, and ripple oscillation properties changed.","methodology":"Two experiments using the object space task in rats, testing both simple and cumulative memory. Oral CBD administration with electrophysiological recording of sleep oscillations. Controls compared rest/non-REM architecture.","limitations":"Rat study may not translate directly to humans. Single dose protocol. Object space task is a specific memory paradigm. CBD dose and formulation may affect results. No long-term exposure data."},{"rthcId":"RTHC-04907","title":"Should gastroenterologists prescribe cannabis? The highs, the lows and the unknowns.","authors":"Samuel, Sonia; Michael, Mark; Tadros, Micheal","year":2023,"journal":"World journal of clinical cases, 11(18), 4210-4230","doi":"10.12998/wjcc.v11.i18.4210","pmid":"37449231","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis has modulatory effects on the GI endocannabinoid system with emerging evidence for benefits in inflammatory bowel disease, motility disorders, GI malignancies, and symptom management (nausea, anorexia, abdominal pain). Risks include dependency, cognitive impairment, and cannabinoid hyperemesis syndrome. The review proposes dosing strategies for gastroenterologist guidance.","whyItMatters":"Many GI patients already use cannabis without their gastroenterologist's knowledge. This review gives GI specialists a framework for evaluating evidence, discussing risks, and considering dosing if they choose to recommend medical cannabis.","specificNumbers":"No specific quantitative outcomes. Review covers IBD, motility disorders, GI malignancies, nausea/vomiting, anorexia, and abdominal pain.","methodology":"Narrative review of animal and human studies on cannabis in gastrointestinal diseases, including discussion of dosing strategies and patient counseling approaches.","limitations":"Narrative review without systematic methodology. Evidence for most GI applications remains preliminary. Dosing recommendations are based on limited data. Side effect profile may be undercharacterized for chronic GI conditions."},{"rthcId":"RTHC-04908","title":"Tobacco use in first-episode psychosis, a multinational EU-GEI study.","authors":"Sánchez-Gutiérrez, T; Rodríguez-Toscano, E; Roldán, L; Ferraro, L; Parellada, M; Calvo, A; López, G; Rapado-Castro, M; La Barbera, D; La Cascia, C; Tripoli, G; Di Forti, M; Murray, R M; Quattrone, D; Morgan, C; van Os, J; García-Portilla, P; Al-Halabí, S; Bobes, J; de Haan, L; Bernardo, M; Santos, J L; Sanjuán, J; Arrojo, M; Ferchiou, A; Szoke, A; Rutten, B P; Stilo, S; D'Andrea, G; Tarricone, I; Díaz-Caneja, C M; Arango, C","year":2023,"journal":"Psychological medicine, 53(15), 7265-7276","doi":"10.1017/S0033291723000806","pmid":"37185055","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04909","title":"Rising trend of acute myocardial infarction among young cannabis users: A 10-year nationwide gender and race stratified analysis.","authors":"Sandhyavenu, Harigopal; Patel, Harsh P; Patel, Riddhiben H; Desai, Rohan; Patel, Achint A; Patel, Bhavin A; Patel, Jaimin; Zahid, Salman; Khan, Safi U; Deshmukh, Abhishek; Nasir, Khurram; DeSimone, Christopher V; Dani, Sourbha S; Thakkar, Samarthkumar","year":2023,"journal":"International journal of cardiology. Cardiovascular risk and prevention, 16, 200167","doi":"10.1016/j.ijcrp.2022.200167","pmid":"36874042","tags":["cardiovascular","youth"],"studyType":"retrospective","evidenceStrength":"strong","keyFinding":"Of 819,175 AMI hospitalizations among 18-49 year olds, 28% reported cannabis use. AMI incidence among cannabis users increased from 2.36% (2007) to 6.55% (2018). The increase was largest among Black Americans (5.69% to 12.25%). Cannabis-using AMI patients were more likely to be male (78% vs. 72%) and Black (32% vs. 14%). Rates increased across both sexes: males 2.63% to 7.17%, females 1.62% to 5.12%.","whyItMatters":"The steep increase in heart attacks among young cannabis users, combined with racial disparities, raises urgent questions about cardiovascular safety and health equity. Whether cannabis contributes to heart attacks or is a marker for other risk factors remains critical to determine.","specificNumbers":"N=819,175 AMI hospitalizations ages 18-49. Cannabis use: 28%. AMI in cannabis users: 2.36% (2007) to 6.55% (2018). Black Americans: 5.69% to 12.25%. Males: 2.63% to 7.17%. Females: 1.62% to 5.12%.","methodology":"Retrospective nationwide analysis using the Nationwide Inpatient Sample (NIS) database, 2007-2018. ICD-9 and ICD-10 codes identified AMI hospitalizations among cannabis users aged 18-49. Gender and race stratified trend analysis.","limitations":"Administrative database cannot establish causation. Cannabis use identified by ICD codes likely underestimates prevalence. Cannot distinguish cannabis as risk factor vs. correlated behavior. Increasing coding awareness may inflate apparent trends. No dose-response data."},{"rthcId":"RTHC-04910","title":"Repeated Exposure to High-THC Cannabis Smoke during Gestation Alters Sex Ratio, Behavior, and Amygdala Gene Expression of Sprague Dawley Rat Offspring.","authors":"Sandini, Thaisa M; Onofrychuk, Timothy J; Roebuck, Andrew J; Hammond, S Austin; Udenze, Daniel; Hayat, Shahina; Herdzik, Melissa A; McElroy, Dan L; Orvold, Spencer N; Greba, Quentin; Laprairie, Robert B; Howland, John G","year":2023,"journal":"eNeuro, 10(11)","doi":"10.1523/ENEURO.0100-23.2023","pmid":"37957008","tags":["pregnancy","youth","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis smoke exposure during pregnancy caused a significant increase in male-to-female ratio in litters. Adult offspring of both sexes explored the inner zone of an open field less (anxiety-like behavior). Cannabis-exposed offspring performed better at visual discrimination and reversal learning. RNA sequencing of adult amygdala revealed changes in genes related to development, cellular function, and nervous system disease in male offspring. Maternal weight, litter size, and gestational length were unaffected.","whyItMatters":"This is one of few studies using actual cannabis smoke rather than injected THC, making it more relevant to real-world prenatal exposure. The sex ratio shift is a particularly striking and novel finding that raises questions about cannabinoid effects on sexual differentiation.","specificNumbers":"Gestational day 6-20 exposure. Significant male-biased sex ratio in cannabis litters. Decreased inner zone exploration in open field. Improved visual discrimination and reversal learning. Subtle amygdala gene expression changes in males.","methodology":"Female Sprague Dawley rats exposed to cannabis smoke daily from gestational day 6-20 or room air. Offspring assessed in adulthood for open field, elevated plus maze, social interaction, and touchscreen operant conditioning tasks. Amygdala RNA sequencing in male offspring.","limitations":"Rat model with smoke exposure may not perfectly replicate human smoking patterns. Gene expression changes were subtle and only examined in males. Touchscreen tasks may not translate to human cognitive function. Sample sizes not specified in abstract. Single cannabis variety tested."},{"rthcId":"RTHC-04911","title":"Experience with dronabinol consumption facilitated a stimulant effect of alcohol and affected alcohol-related changes in frontal cortical endocannabinoid levels in male rats.","authors":"Sangiamo, Daniel T; Weingarten, Michael J; Nelson, Nnamdi G; Choi, Chan Young; Das, Aditi; Liang, Nu-Chu","year":2023,"journal":"Behavioural brain research, 452, 114587","doi":"10.1016/j.bbr.2023.114587","pmid":"37467963","tags":["addiction","youth","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent edible THC experience facilitated alcohol-induced increases in moving speed on a maze. Combined THC-alcohol exposure did not produce additive memory deficits on the Barnes maze. Alcohol abstinence significantly reduced endocannabinoid levels (OEA and SEA) in the frontal cortex. Reductions in OEA and SEA showed interactive effects with THC discontinuation. Little effect was observed in the hippocampus.","whyItMatters":"Cannabis and alcohol are the most commonly co-used substances among adolescents, yet how prior THC exposure changes the brain's response to alcohol is poorly understood. This study shows THC primes the brain to respond differently to alcohol.","specificNumbers":"Adolescent THC via cookies. Post-THC alcohol dose: 3 g/kg. Increased moving speed on Barnes maze with combined exposure. OEA and SEA reduced in frontal cortex during alcohol abstinence. Interactive THC-alcohol effects on OEA and SEA.","methodology":"Male Long Evans rats given daily dronabinol-laced cookies during adolescence. Three days after discontinuation, tested with oral alcohol (3 g/kg) on Barnes maze. Endocannabinoid levels measured in hippocampus and frontal cortex.","limitations":"Male rats only. Single THC dose regimen. Barnes maze is one specific cognitive test. Endocannabinoid measurements at one timepoint only. Dronabinol (synthetic THC) may differ from whole-plant cannabis. Cannot extrapolate doses directly to human adolescents."},{"rthcId":"RTHC-04912","title":"Recent Rates of Substance Use Among Adolescents and Young Adults with Type 1 Diabetes in the USA.","authors":"Sannegowda, Rachna; Villalba, Karina; Suk, Ryan; Gurnurkar, Shilpa; Wasserman, Rachel M","year":2023,"journal":"Current diabetes reports, 23(1), 1-17","doi":"10.1007/s11892-022-01496-7","pmid":"36640218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04913","title":"Fatty Acid Amide Hydrolase: An Integrative Clinical Perspective.","authors":"Santoso, Anugrah D; De Ridder, Dirk","year":2023,"journal":"Cannabis and cannabinoid research, 8(1), 56-76","doi":"10.1089/can.2021.0237","pmid":"35900294","tags":["neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"FAAH is highly expressed in both the central nervous system and peripheral tissues. It modulates mood/emotional response, reward systems, pain perception, energy metabolism, appetite, and inflammation. Genetic variants may be associated with substance use disorders, obesity, and eating disorders. Clinical trials of FAAH inhibitors have shown some potential but results are less impressive than animal models suggested. Neuroimaging can now evaluate FAAH in brain tissue.","whyItMatters":"FAAH inhibition was seen as a way to get the benefits of the endocannabinoid system without the side effects of cannabis. Understanding why clinical results have been disappointing helps calibrate expectations and identify which patients might benefit most.","specificNumbers":"FAAH discovered in 1996. Involved in mood, pain, reward, appetite, and inflammation. Genetic variants linked to substance use disorders, obesity, eating disorders. Clinical trial results less striking than animal predictions.","methodology":"Comprehensive multidisciplinary review of FAAH-related clinical and experimental evidence, covering biological plausibility, genetic studies, neuroimaging, and clinical trials.","limitations":"Narrative review without systematic methodology. Clinical trial data are still limited. FAAH inhibitor safety concerns after the 2016 BIA 10-2474 trial (though that was likely due to off-target effects). Translation from animal models remains challenging."},{"rthcId":"RTHC-04914","title":"Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.","authors":"Sarikahya, Mohammed H; Cousineau, Samantha L; De Felice, Marta; Szkudlarek, Hanna J; Wong, Karen K W; DeVuono, Marieka V; Lee, Kendrick; Rodríguez-Ruiz, Mar; Gummerson, Dana; Proud, Emma; Ng, Tsun Hay Jason; Hudson, Roger; Jung, Tony; Hardy, Daniel B; Yeung, Ken K-C; Schmid, Susanne; Rushlow, Walter; Laviolette, Steven R","year":2023,"journal":"Molecular psychiatry, 28(10), 4234-4250","doi":"10.1038/s41380-023-02190-0","pmid":"37525013","tags":["pregnancy","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Both sexes showed long-term cognitive deficits and hyperactive prefrontal pyramidal neurons. Males showed hippocampal hypoactivity while females showed hyperactivity. Cortical oscillatory activity was strongly sex-divergent. Protein expression disturbances (D1R/D2R, NMDA-2B, synaptophysin, gephyrin, GAD67, PPARalpha) appeared primarily at PD120 in both regions for males, but only in vHIPP for females. MALDI imaging revealed region-, age-, and sex-specific deficiencies in DHA and arachidonic acid.","whyItMatters":"This is one of the most comprehensive studies of prenatal THC effects, showing that while both sexes suffer cognitively, the underlying biology is radically different. This means treatments for prenatal cannabis effects may need to be sex-specific.","specificNumbers":"Both sexes: PFC pyramidal neuron hyperactivity, cognitive deficits. Males: vHIPP hypoactivity, disturbances in both PFC and vHIPP. Females: vHIPP hyperactivity, disturbances mainly in vHIPP. PUFA deficiencies (DHA, ARA) region- and sex-specific.","methodology":"Rodent model of prenatal cannabis exposure with comprehensive analysis: electrophysiology, cortical oscillations, protein expression at PD21 and PD120, and MALDI imaging mass spectrometry for lipid analysis in prefrontal cortex and hippocampus.","limitations":"Rat model with injected THC (not smoked cannabis). Sex-specific findings are at the biological level and may not directly predict sex-specific behavioral outcomes in humans. MALDI imaging provides spatial distribution but not functional significance. Single THC dose regimen."},{"rthcId":"RTHC-04915","title":"A Research Agenda to Inform Cannabis Regulation: How Science Can Shape Policy.","authors":"Schauer, Gillian L; Johnson, Julie K; Rak, David J; Dodson, Lori; Steinfeld, Nathanial; Sheehy, Thomas J; Nakata, Michele; Collins, Shawn P","year":2023,"journal":"Clinical therapeutics, 45(6), 506-514","doi":"10.1016/j.clinthera.2023.03.010","pmid":"37414500","tags":["legalization"],"studyType":"policy-analysis","evidenceStrength":"moderate","keyFinding":"Cannabis regulators identified six priority research areas: (1) medicinal use evidence, (2) product safety, (3) consumer behaviors, (4) equity and disparity reduction policies, (5) youth consumption prevention and public health, and (6) illicit market reduction strategies. Federal drug scheduling restrictions are identified as the primary barrier to conducting this research.","whyItMatters":"Cannabis policy has outpaced science in the US. This is the first time cannabis regulators themselves, the people closest to implementation, have formally articulated what research they need to make better policy decisions.","specificNumbers":"6 priority research areas identified. CANNRA convenes regulators across US states and territories. Federal scheduling identified as primary research barrier.","methodology":"Commentary from the Cannabis Regulators Association (CANNRA), a nonpartisan nonprofit of government cannabis regulators, based on formal and informal discussions across US states and territories.","limitations":"Commentary rather than empirical research. Represents regulators' perspective, which may differ from researchers' or consumers' priorities. Does not quantify research gaps or propose specific study designs. CANNRA membership may not represent all regulatory perspectives."},{"rthcId":"RTHC-04916","title":"Cessation of self-reported opioid use and impacts on co-occurring health conditions.","authors":"Scheidell, Joy D; Townsend, Tarlise; Ban, Kaoon Francois; Caniglia, Ellen C; Charles, Dyanna; Edelman, E Jennifer; Marshall, Brandon D L; Gordon, Adam J; Justice, Amy C; Braithwaite, R Scott; Khan, Maria R","year":2023,"journal":"Drug and alcohol dependence, 242, 109712","doi":"10.1016/j.drugalcdep.2022.109712","pmid":"36469994","tags":["addiction","harm-reduction"],"studyType":"emulated-trial","evidenceStrength":"moderate","keyFinding":"Ceasing opioid use was associated with no longer reporting cannabis use (aOR=1.82, 95% CI: 1.10-3.03), cessation of cocaine use (aOR=1.93, 95% CI: 1.16-3.20), improvements in pain (aOR=1.53, 95% CI: 1.05-2.24), and improvements in anxiety (aOR=1.56, 95% CI: 1.01-2.41). Among 2,473 participants, 872 stopped reporting opioid use at first follow-up.","whyItMatters":"This challenges the common narrative that people need cannabis or other substances to manage pain and anxiety when reducing opioids. The data suggest that stopping opioids may lead to broader substance reduction and symptom improvement rather than substitution.","specificNumbers":"N=2,473 veterans with opioid use. 872 stopped by year 1. Cannabis cessation aOR=1.82. Cocaine cessation aOR=1.93. Pain improvement aOR=1.53. Anxiety improvement aOR=1.56.","methodology":"Target trial emulation using Veterans Aging Cohort Study survey data (2003-2012). Compared participants who stopped reporting opioid use at first follow-up (~1 year) with those who continued. Logistic regression models estimated associations with changes at second follow-up (~2 years).","limitations":"Observational study, even with target trial emulation. Self-reported substance use and symptoms. Veterans may not represent broader populations. 35% missing data at first follow-up. Cannot determine whether improvements were caused by opioid cessation or other factors."},{"rthcId":"RTHC-04917","title":"Cannabis in Adolescence: Lasting Cognitive Alterations and Underlying Mechanisms.","authors":"Scheyer, Andrew F; Laviolette, Steven R; Pelissier, Anne-Laure; Manzoni, Olivier J J","year":2023,"journal":"Cannabis and cannabinoid research, 8(1), 12-23","doi":"10.1089/can.2022.0183","pmid":"36301550","tags":["youth","cognition","neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Cannabis use during adolescence causes lasting aberrations in synaptic development, often secondary to epigenetic changes. High-potency and synthetic cannabis, heavy/frequent use, and early initiation compound the risks. Genetic vulnerability and environmental factors also contribute. Preclinical studies show cannabinoid exposure during developmental windows durably changes dendritic structure, synaptic function, and endocannabinoid-mediated circuits.","whyItMatters":"This review connects the epidemiological findings (cannabis harms developing brains) to specific biological mechanisms (epigenetics, synapse remodeling), providing the mechanistic foundation for why adolescent use is uniquely risky compared to adult use.","specificNumbers":"No specific quantitative outcomes. Review identifies critical developmental windows, epigenetic changes, dendritic structure alterations, and endocannabinoid circuit disruptions as key mechanisms.","methodology":"Narrative review of preclinical and clinical evidence on adolescent cannabis use and lasting cognitive/psychiatric consequences, focusing on synaptic and epigenetic mechanisms.","limitations":"Narrative review without systematic methodology. Much mechanistic evidence is from animal models. Human epigenetic studies are limited. Dose-response relationships in humans are poorly characterized. Difficult to separate cannabis effects from confounding factors in human studies."},{"rthcId":"RTHC-04918","title":"Hospitalization Associated With Comorbid Psychiatric and Substance Use Disorders Among Adults With COVID-19 Treated in US Emergency Departments From April 2020 to August 2021.","authors":"Schieber, Lyna Z; Dunphy, Christopher; Schieber, Richard A; Lopes-Cardozo, Barbara; Moonesinghe, Ramal; Guy, Gery P","year":2023,"journal":"JAMA psychiatry, 80(4), 331-341","doi":"10.1001/jamapsychiatry.2022.5047","pmid":"36790774","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04919","title":"Predictive impact of different acute cannabis intoxication effects with regard to abstinence motivation and cessation of use.","authors":"Schnell, Thomas; Grömm, Christina-Marie; Klöckner, Nils","year":2023,"journal":"Scientific reports, 13(1), 709","doi":"10.1038/s41598-023-27592-6","pmid":"36639397","tags":["psychosis","addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Paranoid/dysphoric intoxication effects were the strongest predictors of abstinence motivation. Psychosis-like effects such as hallucinations were less predictive. Past users reported significantly more unpleasant and fewer positive experiences than current users retrospectively. Current users intending to stop had significantly more paranoia/dysphoria than those not intending to stop.","whyItMatters":"Understanding what makes people want to quit cannabis has practical implications for treatment. If paranoia and dysphoria are the key drivers of cessation motivation, treatment programs can leverage these experiences rather than focusing solely on psychosis education.","specificNumbers":"N=441 (current and past users). Paranoid/dysphoric effects most predictive of abstinence motivation. Hallucinations less predictive. Past users had more unpleasant, fewer positive experiences than current users. Current users wanting to quit had more paranoia/dysphoria.","methodology":"Mixed methods online survey of 441 current and past cannabis users analyzing predictive impact of different intoxication effects on abstinence motivation/cessation, controlling for craving, consumption patterns, and sociodemographics.","limitations":"Cross-sectional and retrospective design. Online survey may attract non-representative sample. Past users' recall of experiences may be biased by the outcome (quitting). Cannot determine whether negative experiences caused quitting or quitting changed retrospective recall."},{"rthcId":"RTHC-04920","title":"Incidence of Newborn Drug Testing and Variations by Birthing Parent Race and Ethnicity Before and After Recreational Cannabis Legalization.","authors":"Schoneich, Sebastian; Plegue, Melissa; Waidley, Victoria; McCabe, Katharine; Wu, Justine; Chandanabhumma, P Paul; Shetty, Carol; Frank, Christopher J; Oshman, Lauren","year":2023,"journal":"JAMA network open, 6(3), e232058","doi":"10.1001/jamanetworkopen.2023.2058","pmid":"36884249","tags":["pregnancy","legalization"],"studyType":"retrospective","evidenceStrength":"strong","keyFinding":"NDT was ordered for 7.3% of Black vs. 1.9% of White newborns when no prenatal urine drug test was done. 43.3% of positive NDTs detected only THC. THC positivity was higher in Black (67.2%) vs. White (51.8%) newborns. Opioid positivity was higher in White (22.2%) vs. Black (9.4%) newborns. THC-positive NDTs increased significantly after legalization (50.3% to 68.9%). Racial disparities persisted unchanged after legalization.","whyItMatters":"Disproportionate newborn drug testing of Black families, particularly without clinical indication, can trigger Child Protective Services investigations that disrupt families. Cannabis legalization was hypothesized to reduce this disparity, but it did not.","specificNumbers":"N=26,366 births. NDT ordered: 4.7% overall. Black without prenatal testing: 7.3% vs. White: 1.9%. THC-only positive: 43.3%. Post-legalization THC positivity: 68.9% vs. pre: 50.3%. Racial disparity unchanged after legalization.","methodology":"Retrospective cohort study of 26,366 live births at an academic medical center in the Midwestern US from 2014-2020, examining variations in NDT ordering and results by birthing parent race/ethnicity before and after 2018 recreational cannabis legalization.","limitations":"Single academic medical center. Cannot determine why clinicians ordered NDTs (implicit bias vs. undocumented clinical factors). NDT ordering criteria may vary by institution. Pre-post legalization comparison cannot control for all concurrent changes. Retrospective design."},{"rthcId":"RTHC-04921","title":"Cannabidiol and brain function: current knowledge and future perspectives.","authors":"Schouten, Moniek; Dalle, Sebastiaan; Mantini, Dante; Koppo, Katrien","year":2023,"journal":"Frontiers in pharmacology, 14, 1328885","doi":"10.3389/fphar.2023.1328885","pmid":"38288087","tags":["cbd","cognition","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD has documented therapeutic effects for epileptic seizures, psychosis, anxiety, neuropathic pain, and inflammation. Emerging evidence suggests effects on sleep, motor control, cognition, and memory. CBD influences brain function through multiple mechanisms beyond the endocannabinoid system. Current products do not meet most food safety authority standards for dietary supplements.","whyItMatters":"CBD has become one of the most popular wellness products globally, but there is a stark gap between consumer interest and regulatory oversight. This review maps what is actually known versus what is marketed.","specificNumbers":"No specific quantitative outcomes. Review covers epilepsy, Alzheimer's, Huntington's, Parkinson's, psychosis, anxiety, depression, substance use disorders, sleep, motor control, and cognition.","methodology":"Comprehensive narrative review synthesizing evidence on CBD's biomolecular properties, mechanisms of action, effects on neurological and mental disorders, behavioral effects, and regulatory considerations.","limitations":"Narrative review without systematic methodology. Many covered topics have limited human evidence. Cannot address all CBD product variations and formulations. Regulatory landscape varies by country."},{"rthcId":"RTHC-04922","title":"Cannabinoids and Brain Damage: A Systematic Review on a Frequently Overlooked Issue.","authors":"Scopetti, Matteo; Morena, Donato; Manetti, Federico; Santurro, Alessandro; Fazio, Nicola Di; D'Errico, Stefano; Padovano, Martina; Frati, Paola; Fineschi, Vittorio","year":2023,"journal":"Current pharmaceutical biotechnology, 24(6), 741-757","doi":"10.2174/1389201023666220614145535","pmid":"35702797","tags":["neuroscience","synthetic-cannabinoids"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Cannabinoid consumption is associated with psychiatric disorders, neurocognitive impairment, neurological disorders, and in some cases of acute consumption of synthetic cannabinoids, death. Synthetic cannabinoids carry the greatest risks, but phytocannabinoid use is not devoid of neurotoxic potential.","whyItMatters":"As cannabis becomes more socially accepted, the neurotoxicity risks are increasingly overlooked. This review serves as a corrective, documenting that brain damage from cannabinoids is a real clinical phenomenon, not just a theoretical concern.","specificNumbers":"30 papers included. Risks highest with high-potency synthetic cannabinoids. Phytocannabinoids also carry risks. Acute synthetic cannabinoid use linked to death in some cases.","methodology":"Systematic literature search through PubMed and Scopus using specific search terms for cannabinoid brain damage/toxicity. Critical appraisal of collected studies. 30 papers included examining toxic brain effects in human subjects.","limitations":"Systematic review but limited to 30 studies. Heterogeneous study designs and cannabinoid types. Cannot establish dose-response relationships from included studies. May overrepresent severe cases. Search terms may have missed relevant studies."},{"rthcId":"RTHC-04923","title":"Impact of Adolescent Cannabis Use on Neurocognitive and Brain Development.","authors":"Scott, J Cobb","year":2023,"journal":"The Psychiatric clinics of North America, 46(4), 655-676","doi":"10.1016/j.psc.2023.03.012","pmid":"37879830","tags":["youth","cognition","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Converging evidence shows that ongoing, frequent cannabis use in adolescence is associated with small reductions in cognitive functioning. However, there is significant debate about whether reductions persist after abstinence. Structural and functional neuroimaging findings related to adolescent cannabis use have replicability challenges. Larger studies with more informative designs are needed.","whyItMatters":"This review is notable for its intellectual honesty about the limitations of the evidence. While acknowledging converging signals, it highlights that the field has not yet resolved whether cognitive effects are permanent or whether brain imaging findings are robust.","specificNumbers":"No specific quantitative data. Cognitive effects described as \"small reductions.\" Two decades of research synthesized. Debate noted about persistence after abstinence.","methodology":"Narrative review synthesizing two decades of research on associations between frequent adolescent cannabis use and brain-behavior outcomes, including cognitive and neuroimaging findings.","limitations":"Narrative review without meta-analysis. Cannot quantify effect sizes across studies. Acknowledges challenges in separating cannabis effects from confounders (pre-existing differences, other substance use). Imaging findings have replicability issues."},{"rthcId":"RTHC-04924","title":"Impact of Adolescent Cannabis Use on Neurocognitive and Brain Development.","authors":"Scott, J Cobb","year":2023,"journal":"Child and adolescent psychiatric clinics of North America, 32(1), 21-42","doi":"10.1016/j.chc.2022.06.002","pmid":"36410904","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04925","title":"Exploration of cannabis use and polygenic risk scores on the psychotic symptom progression of a FEP cohort.","authors":"Segura, Alex G; Mané, Anna; Prohens, Llucia; Rodriguez, Natalia; Mezquida, Gisela; Cuesta, Manuel J; Vieta, Eduard; Amoretti, Silvia; Lobo, Antonio; González-Pinto, Ana; Diaz-Caneja, Covadonga M; Bejarano, Alexandra Roldán; Jimenez, Esther; Baeza, Immaculada; Legido, Teresa; Saiz-Ruiz, Jeronimo; Bernardo, Miguel; Mas, Sergi","year":2023,"journal":"Psychiatry research, 325, 115249","doi":"10.1016/j.psychres.2023.115249","pmid":"37178502","tags":["psychosis","genetics","addiction"],"studyType":"cohort-study","evidenceStrength":"moderate","keyFinding":"Current cannabis use was associated with increased positive symptoms. Earlier age of cannabis initiation conditioned 12-month symptom progression. Higher polygenic risk for CUD (PRSCUD) predicted increased baseline cannabis use in FEP patients. Polygenic risk for cannabis initiation (PRSCI) was associated with the course of negative and general symptoms over 12 months. Cannabis initiation and CUD may have partially independent genetic factors.","whyItMatters":"This suggests that genetic factors influencing whether someone tries cannabis versus whether they develop problematic use are partially independent, and each influences different aspects of psychosis outcomes. This could eventually enable personalized treatment approaches.","specificNumbers":"N=249 FEP patients. 12-month follow-up. PRSCUD predicted baseline cannabis use. PRSCI predicted negative and general symptom trajectories. Earlier cannabis initiation conditioned symptom progression.","methodology":"Cohort study of 249 FEP individuals evaluated over 12 months. Symptom severity measured with PANSS. Cannabis use assessed with EuropASI. Individual polygenic risk scores constructed for lifetime cannabis initiation and cannabis use disorder.","limitations":"Exploratory analysis with modest sample size. Polygenic risk scores explain a small fraction of variance. Single cohort without replication. Cannot determine causal direction between genetic risk, cannabis use, and symptom trajectories."},{"rthcId":"RTHC-04926","title":"Health, safety, and socioeconomic impacts of cannabis liberalization laws: An evidence and gap map.","authors":"Sevigny, Eric L; Greathouse, Jared; Medhin, Danye N","year":2023,"journal":"Campbell systematic reviews, 19(4), e1362","doi":"10.1002/cl2.1362","pmid":"37915420","tags":["legalization"],"studyType":"evidence-gap-map","evidenceStrength":"strong","keyFinding":"The EGM includes 447 studies (438 primary, 9 systematic reviews). Most research is from the US. Research concentrates on medical and recreational cannabis laws; industrial hemp, CBD, and decriminalization laws are rarely studied. Cannabis use was the most frequently studied outcome. Over half of 113 documented outcomes had 3 or fewer studies. Only 7 systematic reviews existed, and 5 were rated minimal quality.","whyItMatters":"With 21+ US states having recreational cannabis and more countries legalizing, this map shows that policy decisions are being made with enormous evidence gaps. The finding that most studies just measure cannabis use, not downstream health or socioeconomic outcomes, is a systemic weakness.","specificNumbers":"447 studies included. 438 primary, 9 systematic reviews. 113 distinct outcomes. Over half with 3 or fewer studies. 5 of 7 systematic reviews rated minimal quality. Most research from US.","methodology":"Evidence and gap map following Campbell Collaboration methodology. Searched 23 academic databases and 11 gray literature sources through August 2020. Dual screening and extraction with third-person deconfliction. Maryland Scientific Methods Scale for primary studies, AMSTAR 2 for reviews.","limitations":"Maps evidence availability, not evidence quality or findings. Search through August 2020 may miss recent studies. English-language studies only. Evidence gaps identified do not necessarily indicate negative effects exist; they indicate effects are unstudied."},{"rthcId":"RTHC-04927","title":"Severe Cannabis use is Associated with Complications and Prolonged Length of Stay in Bariatric Surgery.","authors":"Shah, Rohan M; Patel, Shrey; Patel, Shiv; Sandhu, Lakhvir Kaur; Chand, Bipan","year":2023,"journal":"Obesity surgery, 33(5), 1333-1337","doi":"10.1007/s11695-023-06552-z","pmid":"36929346","tags":["addiction","medical-cannabis"],"studyType":"retrospective","evidenceStrength":"strong","keyFinding":"Cannabis use disorder (0.26% of patients) was associated with medical complications (OR: 2.24; 95% CI: 1.31-3.82; P=0.003) and longer hospital stays (beta: 1.3 days; P<0.001). In-hospital mortality trended higher but did not reach significance (OR: 3.29; P=0.062). Analyses controlled for race, age, sex, income, procedure type, and comorbidities.","whyItMatters":"Bariatric surgery is increasingly common, and surgeons need to know if cannabis use affects outcomes. The doubled complication rate suggests cannabis use disorder should be part of preoperative risk assessment.","specificNumbers":"N=713,290 bariatric patients. CUD prevalence: 0.26% (1,870 patients). Complications OR=2.24 (P=0.003). Length of stay: +1.3 days (P<0.001). Mortality OR=3.29 (P=0.062, not significant).","methodology":"Retrospective nationwide study using the National Inpatient Sample 2016-2019. Queried patients 18+ undergoing RYGB, VSG, or AGB surgery. Cannabis use disorder identified by ICD-10 coding. Logistic and linear regression models.","limitations":"Administrative database with ICD-10 coding may underestimate cannabis use (0.26% is far below population prevalence). Cannot distinguish active use from historical CUD diagnosis. Cannot determine dose, frequency, or route of cannabis use. Cannot establish causation."},{"rthcId":"RTHC-04928","title":"Cannabis and male sexual health: contemporary qualitative review and insight into perspectives of young men on the internet.","authors":"Shahinyan, Gary K; Hu, Ming-Yeah Y; Jiang, Tommy; Osadchiy, Vadim; Sigalos, John T; Mills, Jesse N; Kachroo, Naveen; Eleswarapu, Sriram V","year":2023,"journal":"Sexual medicine reviews, 11(2), 139-150","doi":"10.1093/sxmrev/qeac010","pmid":"36763944","tags":["sex-differences"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Literature review found negative effects of cannabis on semen parameters with varying effects on erectile function and hormone levels. Analysis of 372,686 Reddit posts found 1,190 (0.3%) discussing cannabis and men's health. Among 272 manually analyzed posts, men sought answers and shared conflicting experiences about cannabis effects on sexual health. Quantitative analysis revealed a thematic cluster linking cannabis with insecurity and mental/physical health.","whyItMatters":"Men are increasingly using cannabis while also worrying about its effects on their sexual health, but they are turning to Reddit rather than clinicians for answers. The gap between patient concern and clinical evidence highlights a need for better research and clinical communication.","specificNumbers":"372,686 Reddit posts analyzed. 1,190 (0.3%) relevant to cannabis and men's health. 272 posts manually analyzed. Literature shows negative semen effects, varying erectile and hormonal effects.","methodology":"Combined qualitative PubMed review following PRISMA guidelines with analysis of 372,686 Reddit posts from 5 men's health forums (August 2018-August 2019). Natural language processing and principal component analysis for quantitative Reddit analysis.","limitations":"Reddit analysis cannot verify clinical claims or user demographics. Literature review found limited quality human studies. Selection bias in both Reddit users and research participants. Semen parameter changes may not translate to fertility outcomes."},{"rthcId":"RTHC-04929","title":"Unlocking the Healing Potential: Cannabinoids in Spine Surgery for Pain Relief and Recovery.","authors":"Shahzad, Hania; Lee, Maximillian; Munjal, Vikas; Veliky, Cole; Yu, Elizabeth","year":2023,"journal":"JBJS reviews, 11(11), e23.00141","doi":null,"pmid":"37972215","tags":["pain","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"THC and CBD interact with endocannabinoid receptors in the CNS and immune system, potentially offering pain relief. The entourage effect may enhance therapeutic impact. Few studies have analyzed cannabinoid use in spine surgery, with variable results on reoperation rates, mortality, complications, postoperative opioid use, and length of stay. Major knowledge gaps exist in dosing, timing, route, and specific outcomes.","whyItMatters":"Spine surgery is among the most painful surgical procedures, and opioid alternatives are urgently needed. However, the evidence base for cannabinoids in this setting is so thin that clinical recommendations are premature.","specificNumbers":"No specific quantitative outcomes. \"Few studies\" with \"variable results.\" Knowledge gaps noted in administration routes, timing, dosage, and specific outcomes.","methodology":"Qualitative review of existing literature on cannabinoids in spine surgery pain management, covering mechanisms, clinical evidence, safety, and ethical considerations.","limitations":"Very limited evidence base. No meta-analysis possible. Variable results across the few existing studies. Safety concerns (cognitive effects, cardiovascular risks, dependence potential) not well characterized in surgical populations."},{"rthcId":"RTHC-04930","title":"Suicidality risk after using cannabis and cannabinoids: An umbrella review.","authors":"Shamabadi, Ahmad; Ahmadzade, Ali; Pirahesh, Kasra; Hasanzadeh, Alireza; Asadigandomani, Hassan","year":2023,"journal":"Dialogues in clinical neuroscience, 25(1), 50-63","doi":"10.1080/19585969.2023.2231466","pmid":"37427882","tags":["mental-health","addiction","cbd"],"studyType":"umbrella-review","evidenceStrength":"strong","keyFinding":"25 systematic reviews were included (24 on recreational use, 1 on therapeutic). Only 3 recreational use reviews found no effect or inconsistent results. Evidence showed positive associations between cannabis and suicidal ideation and attempts across general population, military veterans, and patients with bipolar or major depression. Younger initiation, long-term use, and heavy consumption were associated with worse outcomes. A bidirectional causal association was mentioned. Therapeutic CBD was considered safe.","whyItMatters":"This is the highest level of evidence synthesis available on cannabis and suicide risk. The consistency across 25 reviews, with only 3 finding null or inconsistent results, represents a strong signal that should inform both clinical practice and public health messaging.","specificNumbers":"25 systematic reviews included. 24 on recreational use. 3 found no effect or inconsistent results. Associations found in general population, veterans, and bipolar/depression patients. Dose-response pattern with initiation age, duration, and amount.","methodology":"Umbrella review searching 7 databases and 2 registries without restrictions. AMSTAR-2 for quality assessment. Corrected covered area and citation matrix for overlap assessment.","limitations":"Umbrella review is limited by the quality of included reviews. AMSTAR-2 scores varied. Cannot determine causation from observational evidence alone. Overlap between included reviews may inflate apparent consistency. Publication bias possible."},{"rthcId":"RTHC-04931","title":"Novel Cannabinoid Receptor 2 (CB2) Low Lipophilicity Agonists Produce Distinct cAMP and Arrestin Signalling Kinetics without Bias.","authors":"Sharma, Raahul; Singh, Sameek; Whiting, Zak M; Molitor, Maximilian; Vernall, Andrea J; Grimsey, Natasha L","year":2023,"journal":"International journal of molecular sciences, 24(7)","doi":"10.3390/ijms24076406","pmid":"37047385","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04932","title":"Therapeutic targeting of the tumor microenvironments with cannabinoids and their analogs: Update on clinical trials.","authors":"Sheik, Aliya; Farani, Marzieh Ramezani; Kim, Eunsu; Kim, Suheon; Gupta, Vivek Kumar; Kumar, Krishan; Huh, Yun Suk","year":2023,"journal":"Environmental research, 231(Pt 1), 115862","doi":"10.1016/j.envres.2023.115862","pmid":"37146933","tags":["cancer"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids positively affect healthy cell growth and reverse cancer-related abnormalities by targeting aberrant tumor microenvironments (TMEs). They lower tumorigenesis, prevent metastasis, and may boost chemotherapy and radiotherapy effectiveness. The review describes cannabinoid effects on TME cellular components (endothelial cells, pericytes, fibroblasts, immune cells) and discusses active clinical trials.","whyItMatters":"Cancer immunotherapy increasingly focuses on the tumor microenvironment. Finding that cannabinoids can modulate multiple TME components simultaneously opens possibilities for combining cannabinoids with existing cancer treatments.","specificNumbers":"No specific quantitative outcomes. Review covers effects on endothelial cells, pericytes, fibroblasts, and immune cells. Active clinical trials highlighted.","methodology":"Narrative review of cannabinoid effects on tumor microenvironment cellular components, molecular mechanisms, nanoformulation approaches, and active interventional clinical trials.","limitations":"Narrative review drawing heavily on preclinical data. Clinical trial data are limited. Cannabinoid effects may vary by cancer type. Nanoformulation approaches are early-stage. Cannot determine optimal dosing or combinations from available evidence."},{"rthcId":"RTHC-04933","title":"Restructuring reward: A pilot study to enhance natural reward response in adults with cannabis use disorder.","authors":"Sherman, Brian J; Brasher, Zoe E; Baker, Nathaniel L; McRae-Clark, Aimee L; Froeliger, Brett E","year":2023,"journal":"Drug and alcohol dependence, 249, 110830","doi":"10.1016/j.drugalcdep.2023.110830","pmid":"37329729","tags":["addiction","mental-health"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"CUD participants showed blunted positive affect response to neutral scripts relative to reward scripts (P=0.01). Galvanic skin response was also decreased in neutral vs. reward conditions in CUD (P=0.034). Cortisol was positively correlated with positive affect in controls but not CUD participants (P=0.036). Personalized scripted imagery successfully generated positive emotional responses in CUD participants.","whyItMatters":"Hedonic dysregulation (blunted pleasure from natural rewards) is a core mechanism of addiction but has been understudied in CUD specifically. If scripted imagery can remediate this, it could become a non-pharmacological treatment tool for cannabis addiction.","specificNumbers":"N=22 (10 CUD, 12 controls). Condition x Group interaction on positive affect: P=0.01. GSR: P=0.034. Group x PA interaction on cortisol: P=0.036.","methodology":"Pilot study comparing CUD adults (n=10) and non-CUD controls (n=12) in a single-session personalized scripted imagery procedure. Natural reward and neutral scripts presented in counterbalanced order. Outcomes: positive affect, galvanic skin response, and cortisol at four timepoints.","limitations":"Very small sample (n=22). Single session. No follow-up to assess lasting effects. Cannot determine whether blunted affect preceded or resulted from CUD. Pilot design not powered for definitive conclusions."},{"rthcId":"RTHC-04934","title":"Validity of the DSM-5 craving criterion for alcohol, tobacco, cannabis, cocaine, heroin, and non-prescription use of prescription painkillers (opioids).","authors":"Shmulewitz, D; Stohl, M; Greenstein, E; Roncone, S; Walsh, C; Aharonovich, E; Wall, M M; Hasin, D S","year":2023,"journal":"Psychological medicine, 53(5), 1955-1969","doi":"10.1017/S0033291721003652","pmid":"35506791","tags":["addiction"],"studyType":"validation-study","evidenceStrength":"strong","keyFinding":"Across all six substances, craving was associated with most baseline validators. Moderate craving was more strongly associated with validators than severe craving and improved predictive validity for daily substance use. Including craving improved the validity and clinical relevance of DSM-5 SUD diagnoses across all substances.","whyItMatters":"The DSM-5 added craving as a new diagnostic criterion for substance use disorders but it had not been systematically validated across substances. This study confirms it belongs in the diagnosis and works consistently across different drugs including cannabis.","specificNumbers":"N=588 adults. 6 substances assessed. 90-day daily electronic monitoring. Moderate craving more predictive than severe. Craving improved SUD diagnostic validity across all substances.","methodology":"Validation study of 588 adults who engaged in binge drinking or illicit drug use and endorsed at least one DSM-5 SUD criterion. Assessed craving across 6 substances. Logistic regression estimated associations with validators. Electronic daily assessment tracked use for 90 days.","limitations":"Sample required at least one SUD criterion, so results may not generalize to casual users. Self-reported craving may be interpreted differently across individuals. 90-day follow-up captures a limited window. Cannot determine whether craving causes continued use or vice versa."},{"rthcId":"RTHC-04935","title":"Prenatal delta-9-tetrahydrocannabinol exposure is associated with changes in rhesus macaque DNA methylation enriched for autism genes.","authors":"Shorey-Kendrick, Lyndsey E; Roberts, Victoria H J; D'Mello, Rahul J; Sullivan, Elinor L; Murphy, Susan K; Mccarty, Owen J T; Schust, Danny J; Hedges, Jason C; Mitchell, A J; Terrobias, Jose Juanito D; Easley, Charles A; Spindel, Eliot R; Lo, Jamie O","year":2023,"journal":"Clinical epigenetics, 15(1), 104","doi":"10.1186/s13148-023-01519-4","pmid":"37415206","tags":["pregnancy","genetics"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Prenatal THC exposure was associated with differential methylation at 581 CpGs, with 573 (98%) in placenta. Differentially methylated loci were enriched for candidate autism spectrum disorder genes from the SFARI database in all 5 tissues (placenta, lung, cerebellum, prefrontal cortex, heart). Placenta showed greatest SFARI gene enrichment, including genes also differentially methylated in placentas from a prospective human ASD study.","whyItMatters":"This is the first primate study linking prenatal THC to epigenetic changes at autism-associated genes. The convergence between macaque THC-exposed placentas and human ASD placentas strengthens the biological plausibility of a cannabis-autism connection.","specificNumbers":"581 differentially methylated CpGs. 573 (98%) in placenta. 5 tissues tested. SFARI autism gene enrichment in all tissues. Daily THC dose: 2.5 mg/7 kg.","methodology":"Pregnant rhesus macaques consumed daily THC edible (2.5 mg/7 kg/day) or placebo. DNA methylation measured in 5 tissues at cesarean delivery using Illumina MethylationEPIC platform filtered for rhesus-validated probes.","limitations":"Rhesus macaque model, not human. Small number of animals per group (not specified in abstract). Single THC dose. DNA methylation changes may not translate to gene expression or behavioral changes. Long-term offspring outcomes not assessed."},{"rthcId":"RTHC-04936","title":"Associations of Momentary Mindfulness With Affect and Cannabis Desire in a Trial of Cannabis Use Interventions With and Without Momentary Assessment.","authors":"Shrier, Lydia A; Harris, Sion Kim","year":2023,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 72(1), 126-129","doi":"10.1016/j.jadohealth.2022.09.002","pmid":"36272891","tags":["youth","addiction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Momentary mindful awareness (MAA) increased from baseline to follow-up in the counseling + EMA group (beta=0.237) but not in counseling alone. Higher momentary MAA was associated with lower negative affect (beta=-0.526) and cannabis desire (beta=-0.521) but not positive affect.","whyItMatters":"This suggests that the act of regularly checking in on one's own mental state (EMA) may itself be therapeutic by increasing mindful awareness. The strong inverse associations between mindfulness and cannabis desire point to mindfulness as a treatment target.","specificNumbers":"N=68 participants, 1,971 EMA reports. MAA increase with MET+EMA: beta=0.237. MAA-negative affect: beta=-0.526. MAA-cannabis desire: beta=-0.521. Age range: 15-24.","methodology":"Randomized trial of outpatients aged 15-24 using cannabis 3+ times/week, assigned to MET counseling with/without EMA follow-up. 1,971 EMA reports from 68 participants analyzed. Momentary mindfulness, affect, and cannabis desire assessed at baseline and 3-month follow-up.","limitations":"Small sample. Cannot distinguish EMA effect from additional contact/attention. Associations between MAA and desire are correlational within persons. 3-month follow-up is relatively short. Not all participants used cannabis for the same reasons."},{"rthcId":"RTHC-04937","title":"The Potential of Salivary Lipid-Based Cannabis-Responsive Biomarkers to Evaluate Medical Cannabis Treatment in Children with Autism Spectrum Disorder.","authors":"Siani-Rose, Michael; McKee, Robert; Cox, Stephany; Goldstein, Bonni; Abrams, Donald; Taylor, Myiesha; Kurek, Itzhak","year":2023,"journal":"Cannabis and cannabinoid research, 8(4), 642-656","doi":"10.1089/can.2021.0224","pmid":"35343818","tags":["medical-cannabis","cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"22 potential lipid-based cannabis-responsive biomarkers shifted toward typically developing (TD) physiological levels after medical cannabis treatment. Members from all five lipid subclasses present in saliva were characterized. Network analysis suggested involvement of inflammation/redox regulation and oxidative stress subnetworks. Sphingomyelin changes may indicate a role of cannabis in neuron function.","whyItMatters":"ASD treatment response is typically measured by subjective behavioral observation. If salivary lipid biomarkers can objectively track treatment response, it could transform how medical cannabis treatment for ASD is evaluated and optimized.","specificNumbers":"N=15 ASD children, N=9 TD controls. 22 lipid-based biomarkers identified. All 5 saliva lipid subclasses represented. THC doses: 0.05-50mg. CBD doses: 7.5-200mg. Treatment duration: 1+ year.","methodology":"Observational lipidomics study of saliva samples from 15 children with ASD receiving individualized medical cannabis treatment (THC 0.05-50mg, CBD 7.5-200mg) for at least 1 year, compared with 9 age-matched typically developing children.","limitations":"Very small sample (15 ASD, 9 TD). Observational design without placebo control. Individualized treatment regimens prevent standardized comparison. Biomarker shifts do not prove clinical improvement. Need larger trials with clinical outcome correlation."},{"rthcId":"RTHC-04938","title":"Cannabis-Responsive Biomarkers: A Pharmacometabolomics-Based Application to Evaluate the Impact of Medical Cannabis Treatment on Children with Autism Spectrum Disorder.","authors":"Siani-Rose, Michael; Cox, Stephany; Goldstein, Bonni; Abrams, Donald; Taylor, Myiesha; Kurek, Itzhak","year":2023,"journal":"Cannabis and cannabinoid research, 8(1), 126-137","doi":"10.1089/can.2021.0129","pmid":"34874191","tags":["medical-cannabis","cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"65 potential cannabis-responsive biomarkers shifted toward TD physiological levels in ASD children after medical cannabis treatment. 23 were categorized as anti-inflammatory, bioenergy-associated, neurotransmitters, amino acids, and endocannabinoids. N-acetylaspartic acid, spermine, and dehydroisoandrosterone 3-sulfate changes were particularly notable as they have been previously linked to ASD behavioral symptoms.","whyItMatters":"Developing objective biomarkers for ASD treatment response has been a longstanding challenge. This metabolomics approach could enable precision dosing and treatment monitoring rather than relying solely on behavioral observation.","specificNumbers":"N=15 ASD, N=9 TD. 65 cannabis-responsive biomarkers. 23 characterized in detail. 40% THC-dominant, 60% CBD-dominant treatment. THC: 0.05-50mg, CBD: 7.5-200mg per dose.","methodology":"Observational pharmacometabolomics study of saliva from 15 ASD children (pre-treatment and at maximal impact) compared with 9 TD controls. 40% received THC-dominant MC, 60% received CBD-dominant MC. Individualized regimens for 1+ year.","limitations":"Very small sample without placebo control. Individualized treatment prevents standardized comparison. Biomarker shifts correlate with behavioral improvement but cannot prove causation. Observational design. Results need replication in larger trials."},{"rthcId":"RTHC-04939","title":"Assessing the clinical utility of toxicology testing in the peripartum period.","authors":"Siegel, Molly R; Cohen, Samuel J; Koenigs, Kathleen; Woods, Gregory T; Schwartz, Leah N; Sarathy, Leela; Chou, Joseph H; Terplan, Mishka; Wilens, Timothy; Ecker, Jeffrey L; Bernstein, Sarah N; Schiff, Davida M","year":2023,"journal":"American journal of obstetrics & gynecology MFM, 5(7), 100963","doi":"10.1016/j.ajogmf.2023.100963","pmid":"37030508","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04940","title":"Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies.","authors":"Sills, Graeme J","year":2023,"journal":"Therapeutic advances in neurological disorders, 16, 17562864231191000","doi":"10.1177/17562864231191000","pmid":"37655228","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04941","title":"Entourage Effect and Analytical Chemistry: Chromatography as a Tool in the Analysis of the Secondary Metabolism of Cannabis sativa L.","authors":"Silva Sofrás, Fresia Melina; Desimone, Martin Federico","year":2023,"journal":"Current pharmaceutical design, 29(6), 394-406","doi":"10.2174/1381612829666221103093542","pmid":"36330630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04942","title":"Development and Validation of a Simple, Fast, and Accessible HPLC-UV Method for Cannabinoids Determination in Cannabis sativa L. Extracts and Medicinal Oils.","authors":"Silva Sofrás, Fresia Melina; Alonso, Rosario; Retta, Daiana Sabrina; Di Leo Lira, Paola; Desimone, Martin Federico; van Baren, Catalina María","year":2023,"journal":"Current pharmaceutical design, 29(24), 1918-1928","doi":"10.2174/1381612829666230809094304","pmid":"37559239","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04943","title":"Fatal Overdose with the Cannabinoid Receptor Agonists MDMB-4en-PINACA and 4F-ABUTINACA: A Case Report and Review of the Literature.","authors":"Simon, Gábor; Kuzma, Mónika; Mayer, Mátyás; Petrus, Karola; Tóth, Dénes","year":2023,"journal":"Toxics, 11(8)","doi":"10.3390/toxics11080673","pmid":"37624178","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"very-low","keyFinding":"Forensic analysis confirmed the presence of both MDMB-4en-PINACA and 4F-ABUTINACA in the deceased, with autopsy revealing acute myocardial ischemia and pulmonary edema consistent with synthetic cannabinoid toxicity.","whyItMatters":"Synthetic cannabinoids are far more potent than THC and carry real overdose risk. Documenting specific compounds involved in fatalities helps forensic labs and emergency responders identify and respond to emerging threats.","specificNumbers":"Both MDMB-4en-PINACA and 4F-ABUTINACA were detected in the decedent. Autopsy showed acute myocardial damage with complement C9 deposits indicating early ischemic injury.","methodology":"Forensic autopsy with toxicological screening, histological examination, and immunohistochemistry of heart tissue. Literature review of prior cases involving these specific synthetic cannabinoids.","limitations":"Single case report with no ability to determine dose consumed. The interaction between two concurrent synthetic cannabinoids complicates attribution of cause of death to either substance alone."},{"rthcId":"RTHC-04944","title":"Associations between prenatal and postnatal substance exposure and salivary C-reactive protein in early childhood.","authors":"Simon, Shauna G; Eiden, Rina D; Molnar, Danielle S; Huestis, Marilyn A; Riis, Jenna L","year":2023,"journal":"Neurotoxicology and teratology, 95, 107134","doi":"10.1016/j.ntt.2022.107134","pmid":"36395973","tags":["pregnancy","inflammation"],"studyType":"longitudinal","evidenceStrength":"low","keyFinding":"Prenatal tobacco exposure was associated with higher salivary CRP in children at age 4-6, and prenatal cannabis exposure showed similar patterns, particularly when measured via biomarkers rather than self-report.","whyItMatters":"If prenatal substance exposure triggers lasting inflammatory changes, it could help explain downstream health and behavioral outcomes in exposed children. Inflammation is a pathway connecting early exposures to later disease.","specificNumbers":"Prenatal tobacco and cannabis exposure were both associated with elevated salivary CRP in children at ages 4-6. Biomarker-verified exposure showed stronger associations than self-reported exposure alone.","methodology":"Longitudinal study following mother-child pairs from pregnancy through early childhood. Prenatal exposure assessed via both self-report and biomarkers (cotinine, THC metabolites). Child inflammation measured by salivary C-reactive protein.","limitations":"Salivary CRP is less well-validated than blood-based measures. Self-reported substance use likely underestimates true exposure. Observational design cannot confirm causation. Potential residual confounding from socioeconomic and environmental factors."},{"rthcId":"RTHC-04945","title":"The Place of Cannabinoids in the Treatment of Gynecological Pain.","authors":"Sinclair, Justin; Abbott, Jason; Proudfoot, Andrew; Armour, Mike","year":2023,"journal":"Drugs, 83(17), 1571-1579","doi":"10.1007/s40265-023-01951-z","pmid":"37831340","tags":["pain","medical-cannabis","cbd","anxiety","depression","sleep"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis has a long history of use for menstrual and reproductive pain, predating modern medicine by centuries. This review examines the current evidence for cannabis in gynecological pain conditions — endometriosis, chronic pelvic pain, and primary dysmenorrhea (period cramps) — and finds a familiar pattern: lots of patient use, some encouraging retrospective data, but almost no controlled clinical evidence.\n\nThe growing evidence base comes primarily from retrospective studies, cohort data, and patient surveys. These consistently show that women are using cannabis for gynecological pain, that many find it helpful, and that it may reduce reliance on other pain medications. The most evidence exists for endometriosis, where surveys of patients report significant symptom relief, particularly for pain, sleep, and mood.\n\nBut the obstacles to medical cannabis adoption for these conditions go beyond the evidence gap. The authors identify a constellation of barriers: outdated drug-driving laws that penalize patients even when not impaired, workplace drug testing policies, the cost of quality-assured medical cannabis (not covered by insurance), a lack of cannabis education among healthcare professionals, and persistent stigma — particularly for women using cannabis.\n\nThe review notes that most women currently using cannabis for gynecological pain are using illicit rather than medical cannabis, largely because of these access barriers. This means they're using uncontrolled products without clinical guidance, which is suboptimal for both efficacy and safety.","whyItMatters":"Gynecological pain affects millions of women and is chronically undertreated. Endometriosis alone affects 10% of reproductive-age women, with limited effective treatments and an average 7-10 year diagnostic delay. Many patients have already turned to cannabis out of desperation — this review maps what we know and don't know about whether that's a good idea, and identifies the systemic barriers preventing better evidence from being gathered.","specificNumbers":"Endometriosis affects approximately 10% of reproductive-age women. Most cannabis use for gynecological pain is with illicit rather than medical cannabis. The review identifies five key barriers to medical cannabis adoption: drug-driving laws, workplace testing, cost, clinician education gaps, and stigma. Clinical trial data for cannabis in any gynecological pain condition is described as lacking.","methodology":"Retrospective cohort analysis and narrative review of evidence for cannabis use in gynecological pain conditions (endometriosis, chronic pelvic pain, primary dysmenorrhea). Examined published retrospective data, surveys, and cohort studies, as well as barriers to medical cannabis adoption.","limitations":"Most evidence comes from retrospective and survey data, which cannot establish causation. Self-reported cannabis effectiveness may reflect placebo effects, expectation bias, or recall bias. The review doesn't present original data. Clinical trial evidence is acknowledged as essentially absent. The review focuses on cannabis generally rather than specific cannabinoids, doses, or routes of administration. Geographic and legal variation in cannabis access limits the generalizability of findings."},{"rthcId":"RTHC-04946","title":"Current Cannabidiol Safety: A Review.","authors":"Singh, Chander; Rao, Komal; Yadav, Nikita; Vashist, Yogesh; Chugh, Palak; Bansal, Nidhi; Minocha, Neha","year":2023,"journal":"Current drug safety, 18(4), 465-473","doi":"10.2174/1574886317666220902100511","pmid":"36056846","tags":["cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"low","keyFinding":"CBD has demonstrated anti-inflammatory properties across multiple preclinical and clinical contexts, with a safety profile that includes possible liver enzyme effects, drug interactions, and gastrointestinal symptoms at higher doses.","whyItMatters":"CBD products are widely available and marketed for inflammation, but consumers and clinicians need clearer information about what safety data actually exists versus what is simply assumed.","specificNumbers":"The review covers multiple CBD administration modes and discusses safety signals including hepatotoxicity risk at high doses and interactions with cytochrome P450 enzymes.","methodology":"Narrative review of published literature on CBD pharmacology, anti-inflammatory mechanisms, and safety data. Includes discussion of patents and various administration routes.","limitations":"Narrative review without systematic methodology. Does not include quantitative synthesis of safety data. Relies heavily on preclinical evidence. Published safety data skews toward pharmaceutical-grade CBD, not consumer products."},{"rthcId":"RTHC-04947","title":"Substance-use Disorders, Opportunistic Infections, and Human Immunodeficiency Virus Patients.","authors":"Singh, Ranjan Kumar","year":2023,"journal":"The Journal of the Association of Physicians of India, 71(10), 104-105","doi":"10.59556/japi.71.0357","pmid":"38716538","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04948","title":"Cannabis and Cannabinoids in Multiple Sclerosis: From Experimental Models to Clinical Practice-A Review.","authors":"Sirbu, Carmen-Adella; Georgescu, Ruxandra; Pleşa, Florentina Cristina; Paunescu, Alina; Marilena Ţânţu, Monica; Nicolae, Alina Crenguţa; Caloianu, Ionut; Mitrica, Marian","year":2023,"journal":"American journal of therapeutics, 30(3), e220-e231","doi":"10.1097/MJT.0000000000001568","pmid":"37278703","tags":["medical-cannabis","cbd","pain"],"studyType":"review","evidenceStrength":"low","keyFinding":"The endocannabinoid system plays a documented role in demyelination and neuroinflammation. Clinical data, primarily from nabiximols (Sativex), suggests modest benefit for spasticity, but evidence for other MS symptoms is thin.","whyItMatters":"Up to 80% of people with MS deal with disabling symptoms, and first-line treatments carry significant side effects. Cannabinoids represent an area of active patient interest that needs rigorous clinical evaluation.","specificNumbers":"Up to 80% of MS patients experience disabling symptoms. Nabiximols (THC:CBD 1:1 spray) is the most studied cannabinoid product for MS spasticity. Clinical trials remain relatively few compared to the volume of preclinical research.","methodology":"Narrative review of preclinical studies on cannabinoids in experimental demyelination models and clinical trials examining cannabinoid therapies for MS symptoms including spasticity, pain, and bladder dysfunction.","limitations":"Narrative review without systematic methodology. Heavy reliance on animal and preclinical models. Clinical trial data limited primarily to nabiximols. Does not address long-term safety of cannabinoid use in MS populations."},{"rthcId":"RTHC-04949","title":"The Effects of Acute Cannabis With and Without Cannabidiol on Neural Reward Anticipation in Adults and Adolescents.","authors":"Skumlien, Martine; Freeman, Tom P; Hall, Daniel; Mokrysz, Claire; Wall, Matthew B; Ofori, Shelan; Petrilli, Kat; Trinci, Katie; Borissova, Anna; Fernandez-Vinson, Natalia; Langley, Christelle; Sahakian, Barbara J; Curran, H Valerie; Lawn, Will","year":2023,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 8(2), 219-229","doi":"10.1016/j.bpsc.2022.10.004","pmid":"36642667","tags":["youth","cbd","neuroscience","dopamine"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Adults showed reduced ventral striatum activation during reward anticipation after THC, while adolescents did not. The THC+CBD condition partially attenuated this blunting in adults, suggesting CBD may modulate THC effects on reward circuitry.","whyItMatters":"The developing adolescent brain may process cannabis differently than the adult brain. Understanding these age-dependent effects on reward circuits is critical for assessing the unique risks cannabis poses to younger users.","specificNumbers":"47 participants (24 adolescents, 23 adults). THC dose: 0.107 mg/kg (about 8 mg for 75 kg person). CBD dose: 0.320 mg/kg. Three conditions: THC only, THC+CBD, placebo. Adults showed reduced ventral striatum activation under THC; adolescents did not.","methodology":"Double-blind, placebo-controlled, randomized crossover design. 47 participants (24 adolescents ages 16-17, 23 adults ages 26-29) matched on cannabis use frequency completed the Monetary Incentive Delay task during fMRI after inhaling THC alone, THC+CBD, or placebo.","limitations":"Moderate sample size (47 total). Participants were existing cannabis users (0.5-3 days/week), so findings may not generalize to naive users. Single-session design cannot address repeated exposure effects. THC dose was relatively low."},{"rthcId":"RTHC-04950","title":"Hair Regrowth with Novel Hemp Extract: A Case Series.","authors":"Smith, Gregory Luke","year":2023,"journal":"International journal of trichology, 15(1), 18-24","doi":"10.4103/ijt.ijt_34_22","pmid":"37305187","tags":["cbd","medical-cannabis"],"studyType":"case-report","evidenceStrength":"very-low","keyFinding":"Patients applying a topical hemp extract to areas of hair loss showed measurable increases in hair count and thickness. The extract targeted the endocannabinoid system at hair follicle receptors.","whyItMatters":"Hair loss treatments are limited in number and effectiveness. If cannabinoids can stimulate hair follicles through the endocannabinoid system, it could open a new therapeutic avenue, though controlled trials are needed.","specificNumbers":"Multiple patients showed visible hair regrowth documented by photography and trichoscopy over approximately 6 months of daily topical application.","methodology":"Case series with before-and-after photography and trichoscopic measurement. Patients applied topical hemp extract containing CBD, THCV, and CBDV daily to affected scalp areas for approximately 6 months.","limitations":"Case series with no control group, no blinding, and small sample size. Cannot rule out placebo effect, natural hair cycling, or other concurrent treatments. No standardized dosing protocol described."},{"rthcId":"RTHC-04951","title":"A Latent Variable Analysis of Psychomotor and Neurocognitive Performance After Acute Cannabis Smoking.","authors":"Smith, Shelby J; Wrobel, Julia; Brooks-Russell, Ashley; Kosnett, Michael J; Sammel, Mary D","year":2023,"journal":"Cannabis (Albuquerque, N.M.), 6(2), 123-132","doi":"10.26828/cannabis/2023/000156","pmid":"37484045","tags":["cognition","driving"],"studyType":"observational","evidenceStrength":"low","keyFinding":"Factor analysis identified a single latent construct underlying reaction time, decision making, working memory, and spatial-motor performance. Cannabis smoking produced measurable impairment on this construct, with occasional users more affected than daily users.","whyItMatters":"Developing reliable, portable tools for detecting cannabis impairment is important for roadside testing, workplace safety, and clinical assessment. Current field sobriety tests were designed for alcohol, not cannabis.","specificNumbers":"Four cognitive domains tested: reaction time, decision making, working memory, and spatial-motor performance. Occasional users showed greater impairment than daily users after acute cannabis smoking.","methodology":"Participants completed a tablet-based neurocognitive test before and after smoking cannabis (or a rest period for controls). Exploratory factor analysis reduced test dimensions, and regression models quantified impairment by user group.","limitations":"Study conducted in a legal-use state, which may affect generalizability. Comparison between daily and occasional users confounds tolerance with other behavioral differences. No standardized cannabis dose. Ecological validity of tablet tests for real-world impairment is unestablished."},{"rthcId":"RTHC-04952","title":"Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies.","authors":"Solmi, Marco; De Toffol, Marco; Kim, Jong Yeob; Choi, Min Je; Stubbs, Brendon; Thompson, Trevor; Firth, Joseph; Miola, Alessandro; Croatto, Giovanni; Baggio, Francesca; Michelon, Silvia; Ballan, Luca; Gerdle, Björn; Monaco, Francesco; Simonato, Pierluigi; Scocco, Paolo; Ricca, Valdo; Castellini, Giovanni; Fornaro, Michele; Murru, Andrea; Vieta, Eduard; Fusar-Poli, Paolo; Barbui, Corrado; Ioannidis, John P A; Carvalho, Andrè F; Radua, Joaquim; Correll, Christoph U; Cortese, Samuele; Murray, Robin M; Castle, David; Shin, Jae Il; Dragioti, Elena","year":2023,"journal":"BMJ (Clinical research ed.), 382, e072348","doi":"10.1136/bmj-2022-072348","pmid":"37648266","tags":["medical-cannabis","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"high","keyFinding":"Of hundreds of reported associations, only a handful met the threshold for convincing or highly suggestive evidence. Harmful associations (psychosis, motor vehicle accidents, low birth weight) had stronger evidence than most therapeutic claims.","whyItMatters":"The cannabis literature is vast and contradictory. This umbrella review cuts through the noise by systematically rating the credibility of every major claimed risk and benefit, giving the clearest available picture of what the evidence actually supports.","specificNumbers":"101 meta-analyses reviewed. Convincing harmful associations: psychosis incidence, motor vehicle accidents, low birth weight. Most therapeutic associations graded as low or very low certainty by GRADE.","methodology":"Umbrella review of systematic reviews with meta-analyses from observational studies and RCTs. Credibility graded as convincing, highly suggestive, suggestive, weak, or not significant. RCT evidence graded using GRADE. Quality assessed with AMSTAR 2.","limitations":"Umbrella reviews are only as good as the underlying meta-analyses, many of which had methodological weaknesses. Rapidly evolving cannabis products (high-potency, concentrates, edibles) may not be captured in older studies. Publication bias may affect underlying reviews."},{"rthcId":"RTHC-04953","title":"Predictors of Pain Reduction Among Fibromyalgia Patients Using Medical Cannabis: A Long-Term Prospective Cohort Study.","authors":"Sotoodeh, Romina; Waldman, Lilach Eyal; Vigano, Antonio; Moride, Yola; Canac-Marquis, Michelle; Spilak, Tristan; Gamaoun, Rihab; Kalaba, Maja; Hachem, Yasmina; Beaulieu, Pierre; Desroches, Julie; Ware, Mark A; Perez, Jordi; Shir, Yoram; Fitzcharles, Mary-Ann; Martel, Marc O","year":2023,"journal":"Arthritis care & research, 75(7), 1588-1594","doi":"10.1002/acr.24985","pmid":"35876631","tags":["medical-cannabis","pain","anxiety","depression","sleep"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Reductions in pain intensity among fibromyalgia patients using medical cannabis were partially mediated by concurrent improvements in sleep quality and reductions in anxiety and depression symptoms.","whyItMatters":"Fibromyalgia pain is tightly linked to sleep and mood. Understanding that cannabis may reduce pain partly by improving these co-occurring symptoms could help clinicians set realistic expectations and optimize treatment approaches.","specificNumbers":"323 fibromyalgia patients followed for 12 months. Pain reduction partially mediated by improvements in negative affect (anxiety and depression) and sleep quality.","methodology":"12-month prospective cohort study of 323 fibromyalgia patients initiating medical cannabis. Assessments at baseline and multiple follow-ups measured pain intensity, sleep quality, anxiety, and depression. Mediation analysis tested whether sleep and mood changes explained pain improvements.","limitations":"No control group or randomization. Patients self-selected into medical cannabis use. Cannot separate cannabis effects from placebo, natural symptom fluctuation, or concurrent treatments. High attrition over 12 months is possible but not detailed."},{"rthcId":"RTHC-04954","title":"Cannabidiol attenuates the expression of conditioned place aversion induced by naloxone-precipitated morphine withdrawal through the activation of 5-HT1A receptors.","authors":"Souza, Adriana Jesus; Guimarães, Francisco S; Gomes, Felipe V","year":2023,"journal":"Behavioural brain research, 450, 114504","doi":"10.1016/j.bbr.2023.114504","pmid":"37209879","tags":["cbd","addiction","withdrawal","neuroscience"],"studyType":"animal","evidenceStrength":"low","keyFinding":"CBD (5 and 20 mg/kg) prevented conditioned place aversion induced by naloxone-precipitated morphine withdrawal. Pre-treatment with a 5-HT1A antagonist (WAY100635) blocked this effect, indicating serotonin receptor involvement.","whyItMatters":"Opioid withdrawal creates powerful negative emotional memories that drive relapse. If CBD can reduce the aversive quality of withdrawal through serotonin pathways, it could complement existing addiction treatments.","specificNumbers":"CBD doses of 5 and 20 mg/kg attenuated conditioned place aversion. 5-HT1A antagonist WAY100635 reversed the CBD effect, confirming serotonin receptor involvement.","methodology":"Conditioned place aversion paradigm in rats. Animals received morphine for dependence, then naloxone to trigger withdrawal paired with a specific compartment. CBD was administered before withdrawal sessions. 5-HT1A antagonist used to test mechanism.","limitations":"Animal study with no direct human applicability. Conditioned place aversion is a behavioral proxy for withdrawal discomfort, not a direct measure. Doses and routes of CBD administration in rats do not translate directly to human dosing."},{"rthcId":"RTHC-04955","title":"The beneficial effect of sleep on behavioral health problems in youth is disrupted by prenatal cannabis exposure: A causal random forest analysis of Adolescent Brain Cognitive Development data.","authors":"Spechler, Philip A; Gutierrez, Roman M; Tapert, Susan F; Thompson, Wesley K; Paulus, Martin P","year":2023,"journal":"Child development, 94(4), 826-835","doi":"10.1111/cdev.13899","pmid":"36840387","tags":["pregnancy","youth","sleep","mental-health"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Sleep improvements reduced internalizing and externalizing problems in children overall, but prenatal cannabis exposure moderated this relationship, significantly diminishing the protective effect of sleep on internalizing symptoms.","whyItMatters":"Sleep is one of the most modifiable factors for improving child behavior and mental health. If prenatal cannabis exposure undermines this protective pathway, it means exposed children may need additional or different intervention strategies.","specificNumbers":"N=9,825 children (4,663 female, 5,196 white). More sleep predicted less internalizing (ATE=-0.34, p<0.001) and externalizing (ATE=-0.29, p<0.001) problems. Prenatal cannabis exposure moderated the effect on internalizing problems.","methodology":"Causal random forest analysis of ABCD Study data (N=9,825 children ages 9-10 at baseline with 1-year follow-up). Examined whether changes in sleep hours predicted changes in behavior problems, and whether prenatal cannabis exposure modified this relationship.","limitations":"Observational data, even with causal inference methods, cannot fully establish causation. Prenatal cannabis exposure was largely based on maternal report, which may underestimate prevalence. Causal random forest is a relatively novel method that may not be familiar to all reviewers."},{"rthcId":"RTHC-04956","title":"The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study.","authors":"Spinazzola, Edoardo; Quattrone, Diego; Rodriguez, Victoria; Trotta, Giulia; Alameda, Luis; Tripoli, Giada; Gayer-Anderson, Charlotte; Freeman, Tom P; Johnson, Emma C; Jongsma, Hannah E; Stilo, Simona; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Lasalvia, Antonio; Tosato, Sarah; Tarricone, Ilaria; D'Andrea, Giuseppe; Galatolo, Michela; Tortelli, Andrea; Tagliabue, Ilaria; Turco, Marco; Pompili, Maurizio; Selten, Jean-Paul; de Haan, Lieuwe; Rossi Menezes, Paulo; Del Ben, Cristina M; Santos, Jose Luis; Arrojo, Manuel; Bobes, Julio; Sanjuán, Julio; Bernardo, Miguel; Arango, Celso; Kirkbride, James B; Jones, Peter B; O'Donovan, Michael; Rutten, Bart P; Van Os, Jim; Morgan, Craig; Sham, Pak C; Austin-Zimmerman, Isabelle; Li, Zhikun; Vassos, Evangelos; Murray, Robin M; Di Forti, Marta","year":2023,"journal":"Psychological medicine, 53(15), 7418-7427","doi":"10.1017/S0033291723001071","pmid":"37129249","tags":["psychosis","mental-health"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Starting cannabis use \"to feel better/cope\" was associated with higher odds of first-episode psychosis (FEP) compared to starting \"because of friends.\" Path analysis showed reasons for first use influenced later patterns (frequency, potency, duration) which in turn affected psychosis risk.","whyItMatters":"Understanding why people start using cannabis may help identify those at higher risk for problematic outcomes. If initial motivations predict later patterns and psychosis risk, early intervention could target people using cannabis to self-medicate.","specificNumbers":"558 FEP patients and 567 controls across 11 EU-GEI sites. Most common reason for first use: \"because of friends\" (86.1% of controls, 75.6% of FEP patients). Using to cope was associated with higher psychosis risk.","methodology":"Case-control study from the EU-GEI multi-site project. 558 first-episode psychosis patients and 567 population controls who had used cannabis reported their reasons for first use. Logistic regression and path analysis examined associations between initial motivations, use patterns, and psychosis.","limitations":"Retrospective recall of reasons for first cannabis use may be unreliable, especially for FEP patients whose memory and cognition may be affected. Case-control design cannot establish temporal causation. Self-medication bias may inflate the coping-psychosis association."},{"rthcId":"RTHC-04957","title":"Correlates of cannabis use in a sample of mental health treatment-seeking Canadian armed forces members and veterans.","authors":"St Cyr, Kate; Nazarov, Anthony; Le, Tri; Nouri, Maede; Saha, Priyonto; Forchuk, Callista A; Soares, Vanessa; Wanklyn, Sonya G; Bird, Brian M; Davis, Brent D; King, Lisa; Ketcheson, Felicia; Richardson, J Don","year":2023,"journal":"BMC psychiatry, 23(1), 836","doi":"10.1186/s12888-023-05237-2","pmid":"37964206","tags":["ptsd","mental-health"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Cannabis use was common among treatment-seeking CAF members and veterans, with users more likely to be younger, have PTSD diagnoses, and report using cannabis specifically for symptom relief.","whyItMatters":"Military personnel and veterans with PTSD are turning to cannabis in growing numbers despite limited evidence for its effectiveness. Understanding who uses and why informs clinical conversations and research priorities.","specificNumbers":"415 CAF members and veterans at a specialized mental health clinic in Ontario. Cannabis users were younger and more likely to carry PTSD diagnoses.","methodology":"Cross-sectional analysis of intake data from 415 Canadian Armed Forces members and veterans attending a specialized outpatient mental health clinic in Ontario. Examined prevalence and correlates of current cannabis use.","limitations":"Cross-sectional design from a single clinic. Treatment-seeking population may not represent all CAF members and veterans. Self-reported cannabis use may be affected by social desirability. Cannot determine whether cannabis use preceded or followed mental health conditions."},{"rthcId":"RTHC-04958","title":"Cannabidiol and cannabis-inspired terpene blends have acute prosocial effects in the BTBR mouse model of autism spectrum disorder.","authors":"Staben, Jenika; Koch, Megan; Reid, Keelee; Muckerheide, Jessica; Gilman, Lauren; McGuinness, Finn; Kiesser, Sarina; Oswald, Iain W H; Koby, Kevin A; Martin, Thomas J; Kaplan, Joshua S","year":2023,"journal":"Frontiers in neuroscience, 17, 1185737","doi":"10.3389/fnins.2023.1185737","pmid":"37397463","tags":["cbd","neuroscience"],"studyType":"animal","evidenceStrength":"low","keyFinding":"Both CBD-rich extract and specific terpene blends increased sociability in BTBR mice. The terpene blends alone produced prosocial effects comparable to CBD, suggesting non-cannabinoid cannabis compounds may contribute to social behavior improvements.","whyItMatters":"Autism spectrum disorder has very few pharmacological treatment options, especially for core social symptoms. If both cannabinoids and terpenes can improve sociability, the active ingredients in cannabis products may be broader than THC and CBD alone.","specificNumbers":"Prosocial effects observed within 30 minutes of acute administration. Both CBD-rich extract and terpene blends significantly increased sociability in the three-chamber test compared to vehicle.","methodology":"Behavioral testing in BTBR mice (an inbred strain modeling autism-like social deficits). Acute administration of CBD-rich hemp extract or terpene blends inspired by cannabis cultivar profiles. Three-chamber social approach test measured sociability and social novelty preference.","limitations":"Mouse model of autism has limited translational relevance to human ASD. Acute dosing only; no chronic administration data. BTBR mice have specific genetic characteristics that may not reflect the diverse biology of human autism. Terpene blends were inspired by cannabis but not identical to natural plant ratios."},{"rthcId":"RTHC-04959","title":"Deciphering the mechanisms of reciprocal regulation or interdependence at the cannabinoid CB1 receptors and cyclooxygenase-2 level: Effects on mood, cognitive implications, and synaptic signaling.","authors":"Stachowicz, Katarzyna","year":2023,"journal":"Neuroscience and biobehavioral reviews, 155, 105439","doi":"10.1016/j.neubiorev.2023.105439","pmid":"37898448","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04960","title":"Emerging Issues in Cannabis Law: Big Business and Equity Challenges.","authors":"Stoa, Ryan B","year":2023,"journal":"Clinical therapeutics, 45(7), 679-683","doi":"10.1016/j.clinthera.2023.05.004","pmid":"37633700","tags":["legalization"],"studyType":"review","evidenceStrength":"low","keyFinding":"Cannabis equity programs in multiple states and cities have struggled to achieve their goals due to high licensing costs, limited access to capital, competition from well-funded multi-state operators, and regulatory complexity that favors established businesses.","whyItMatters":"Cannabis prohibition disproportionately affected communities of color. If legalization primarily benefits large corporations while equity programs fail, the promise of restorative justice through legalization remains unfulfilled.","specificNumbers":"The article examines equity programs across multiple U.S. states and cities, documenting how licensing costs, capital barriers, and multi-state operator competition undermine participation by communities most affected by prohibition.","methodology":"Legal review and analysis of cannabis legislation, regulatory frameworks, and equity program outcomes across multiple U.S. jurisdictions. Examines the tension between industry growth and social justice objectives.","limitations":"Legal analysis rather than empirical study. Focuses on U.S. jurisdiction only. Equity program outcomes are still evolving and may change as markets mature. Does not quantify the economic impact of specific equity interventions."},{"rthcId":"RTHC-04961","title":"Efficacy of an expanded preoperative survey during perioperative care to identify illicit substance use in teenagers and adolescents.","authors":"Stone, Katelynn; Rice-Weimer, Julie; Tram, Nguyen K; Tobias, Joseph D","year":2023,"journal":"Paediatric anaesthesia, 33(10), 808-815","doi":"10.1111/pan.14728","pmid":"37435702","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04962","title":"A collection of cannabinoid-related negative findings from autaptic hippocampal neurons.","authors":"Straiker, Alex; Dvorakova, Michaela; Bosquez-Berger, Taryn; Blahos, Jaroslav; Mackie, Ken","year":2023,"journal":"Scientific reports, 13(1), 9610","doi":"10.1038/s41598-023-36710-3","pmid":"37311900","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04963","title":"Cannabis for the Treatment of Fibromyalgia: A Systematic Review.","authors":"Strand, Natalie H; Maloney, Jillian; Kraus, Molly; Wie, Christopher; Turkiewicz, Michal; Gomez, Diego A; Adeleye, Olufunmilola; Harbell, Monica W","year":2023,"journal":"Biomedicines, 11(6)","doi":"10.3390/biomedicines11061621","pmid":"37371716","tags":["medical-cannabis","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of four RCTs examining cannabis for fibromyalgia, three showed benefit over placebo for pain. Observational studies supported these findings. However, evidence quality was low and studies were small.","whyItMatters":"Fibromyalgia affects millions and current treatments often fall short. This systematic review provides the most structured look at whether cannabis could fill that gap, even if the evidence base remains thin.","specificNumbers":"564 total patients across 9 studies (4 RCTs, 5 observational). Three of four RCTs showed cannabis outperformed placebo for pain outcomes. Literature searched through October 2022.","methodology":"Systematic review following PRISMA guidelines. Searched MEDLINE, EMBASE, Cochrane, and Scopus using MeSH terms. Included four RCTs and five observational studies totaling 564 patients.","limitations":"Low overall evidence quality. Small sample sizes across studies. Heterogeneous cannabis preparations and dosing. Short study durations. Observational studies prone to expectation bias."},{"rthcId":"RTHC-04964","title":"Clinical course and treatment interventions for adolescents who vaped during the COVID-19 pandemic.","authors":"Su, Alex; Albarran Garcia, Daisy; Li, Mandy; Ogbonna, Chinyere; Tsang, Thomas; Tsang, Alex; Bantug, Chynna; Tom, Wynnyee; Harris, Brooke","year":2023,"journal":"BMJ case reports, 16(11)","doi":"10.1136/bcr-2023-255844","pmid":"37931960","tags":["youth","mental-health"],"studyType":"case-report","evidenceStrength":"very-low","keyFinding":"Both adolescent patients had underlying social stressors and mental health symptoms that contributed to vaping behavior. Addressing these root causes, rather than just the vaping itself, appeared important for treatment.","whyItMatters":"The pandemic disrupted healthcare access for teens during a period of rising vaping rates. Understanding why teens vape and what interventions work is critical as both nicotine and THC vaping continue to grow.","specificNumbers":"Two adolescent cases detailed. Both involved nicotine and marijuana vaping during the COVID-19 pandemic with co-occurring mental health symptoms.","methodology":"Two case reports from a managed care organization documenting clinical course and treatment interventions for adolescents who vaped during the COVID-19 pandemic.","limitations":"Only two cases from a single healthcare system. Cannot generalize to broader adolescent populations. COVID-19 context may not apply to post-pandemic adolescent vaping patterns."},{"rthcId":"RTHC-04965","title":"A systematic review of in utero cannabis exposure and risk for structural birth defects.","authors":"Sujan, Ayesha C; Pal, Anish; Avalos, Lyndsay A; Young-Wolff, Kelly C","year":2023,"journal":"Frontiers in pediatrics, 11, 1149401","doi":"10.3389/fped.2023.1149401","pmid":"37303758","tags":["pregnancy"],"studyType":"systematic-review","evidenceStrength":"low","keyFinding":"For the most-studied defect types (cardiac, gastrointestinal, CNS), findings were mixed across studies. For less-studied defect types (orofacial, eye, genitourinary, musculoskeletal), the sparse research mostly found no association, but sample sizes were too small for confidence.","whyItMatters":"Cannabis use during pregnancy is increasing, and pregnant people need clear information about risks. The current evidence on birth defects is too sparse and inconsistent to provide definitive guidance.","specificNumbers":"20 articles identified, 12 with adjusted analyses included in interpretation. Seven organ systems examined: cardiac (4 studies), CNS (3), gastrointestinal (3), orofacial (2), eye (1), genitourinary (1), musculoskeletal (1).","methodology":"Systematic review following PRISMA guidelines. Identified 20 articles, with analysis focused on 12 that adjusted for potential confounders. Findings organized by seven organ systems.","limitations":"Few studies per organ system make conclusions unreliable. Heterogeneous exposure definitions across studies. Most studies rely on self-reported cannabis use. Confounding by tobacco, alcohol, and other substance co-use is difficult to fully address."},{"rthcId":"RTHC-04966","title":"Patterns of Substance Use During Early Pregnancy and Associations With Behavioral Health Characteristics.","authors":"Sujan, Ayesha C; Alexeeff, Stacey E; Slama, Natalie; Avalos, Lyndsay A; Adams, Sara R; Conway, Amy; Ansley, Deborah; Young-Wolff, Kelly C","year":2023,"journal":"Journal of addiction medicine, 17(3), e141-e147","doi":"10.1097/ADM.0000000000001090","pmid":"37267164","tags":["pregnancy","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Four prenatal substance use patterns emerged: predominantly alcohol (9.3%), predominantly cannabis (4.9%), predominantly nicotine with some opioids (1.1%), and high-polysubstance (0.4%). All substance use groups had elevated depression, anxiety, intimate partner violence, and family drug history compared to non-users.","whyItMatters":"Pregnant people who use cannabis are not a monolithic group. Identifying distinct use patterns and their associated mental health profiles can help clinicians tailor screening and support rather than applying one-size-fits-all approaches.","specificNumbers":"265,274 pregnancies. Four substance use groups: alcohol only (9.3%), cannabis only (4.9%), nicotine/opioids (1.1%), polysubstance (0.4%), no use (84.4%). All use groups had elevated behavioral health conditions vs. non-users.","methodology":"Retrospective observational study of 265,274 pregnancies at Kaiser Permanente Northern California (2012-2019). Substance use screened via self-report and urine toxicology in the first trimester. Latent class analysis identified use patterns. Modified Poisson regression compared behavioral health prevalences.","limitations":"Single healthcare system in Northern California. Screening methods may miss underreporting. Cross-sectional substance use data from first trimester only. Cannot determine whether behavioral health conditions preceded or resulted from substance use."},{"rthcId":"RTHC-04967","title":"Oral Tetrahydrocannabinol (THC):Cannabinoid (CBD) Cannabis Extract Adjuvant for Reducing Chemotherapy-Induced Nausea and Vomiting (CINV): A Randomized, Double-Blinded, Placebo-Controlled, Crossover Trial.","authors":"Sukpiriyagul, Apichaya; Chartchaiyarerk, Ratiporn; Tabtipwon, Paluekpon; Smanchat, Buppa; Prommas, Sinart; Bhamarapravatana, Kornkarn; Suwannarurk, Komsun","year":2023,"journal":"International journal of women's health, 15, 1345-1352","doi":"10.2147/IJWH.S401938","pmid":"37608911","tags":["medical-cannabis","cancer","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Nausea scores were significantly lower in the THC:CBD extract group (2.11) compared to placebo (2.99). Over half of participants experienced dizziness and sedation as side effects.","whyItMatters":"Chemotherapy-induced nausea remains a major quality-of-life issue despite standard antiemetics. This trial provides controlled evidence that cannabinoid supplementation can provide additional relief.","specificNumbers":"54 patients completed the trial (60 recruited). Mean age 54.4 years, mean BMI 26.5. 59% had advanced cancer. Nausea scores: THC:CBD 2.11 vs. placebo 2.99 (p<0.05). 36/54 reported dizziness and sedation.","methodology":"Randomized, double-blind, placebo-controlled crossover trial. 54 gynecologic cancer patients received THC:CBD extract oil (1:1) before one chemotherapy cycle and placebo before another. Both groups received standard antiemetic medication. Nausea scores and side effects recorded.","limitations":"Relatively small sample (54 patients). Single-center trial in Thailand. Crossover design means each patient served as their own control, which is a strength, but carry-over effects are possible. High rate of dizziness/sedation may limit practical use."},{"rthcId":"RTHC-04968","title":"Nondisordered Cannabis Use Among US Adolescents.","authors":"Sultan, Ryan S; Zhang, Alexander W; Olfson, Mark; Kwizera, Muhire H; Levin, Frances R","year":2023,"journal":"JAMA network open, 6(5), e2311294","doi":"10.1001/jamanetworkopen.2023.11294","pmid":"37133862","tags":["youth","mental-health","psychosis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Nondisordered cannabis use (NDCU) was 4 times more prevalent than cannabis use disorder (10.2% vs. 2.5%) among US adolescents. NDCU was associated with 2-4 times greater odds of adverse psychosocial events compared to non-use, forming a stepwise gradient from non-use through NDCU to CUD.","whyItMatters":"Clinical attention typically focuses on cannabis use disorder, but subclinical use is four times more common in teens and still carries significant associations with depression, suicidality, and academic problems.","specificNumbers":"68,263 respondents representing ~25 million US adolescents annually. NDCU: 10.2%, CUD: 2.5%, non-use: 87.3%. NDCU adjusted odds ratios vs. non-use: depression 1.86, suicidal ideation 2.08, arrest 4.15, fighting 2.04, low GPA 1.80, truancy 1.90.","methodology":"Cross-sectional analysis of the 2015-2019 National Survey on Drug Use and Health. 68,263 adolescents aged 12-17 classified as non-users, nondisordered cannabis users, or having cannabis use disorder (DSM-5 criteria). Adjusted logistic regression examined associations with adverse psychosocial events.","limitations":"Cross-sectional design cannot determine causation. Adolescents with pre-existing mental health issues may be more likely to use cannabis (reverse causation). Self-reported data may be affected by social desirability. NDCU is defined by absence of disorder criteria, not by frequency or quantity."},{"rthcId":"RTHC-04969","title":"Arbuscular mycorrhizal fungi influence the uptake of cadmium in industrial hemp (Cannabis sativa L.).","authors":"Sun, Simiao; Fan, Xiaoxu; Feng, Yuhan; Wang, Xiaohui; Gao, Hongsheng; Song, Fuqiang","year":2023,"journal":"Chemosphere, 330, 138728","doi":"10.1016/j.chemosphere.2023.138728","pmid":"37080470","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04970","title":"Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer.","authors":"Sun, Xiaofan; Zhou, Lisha; Wang, Yi; Deng, Guoliang; Cao, Xinran; Ke, Bowen; Wu, Xiaoqi; Gu, Yanhong; Cheng, Haibo; Xu, Qiang; Du, Qianming; Chen, Hongqi; Sun, Yang","year":2023,"journal":"Journal of pharmaceutical analysis, 13(7), 726-744","doi":"10.1016/j.jpha.2023.04.013","pmid":"37577382","tags":["cbd","cancer","inflammation"],"studyType":"animal","evidenceStrength":"low","keyFinding":"CBD suppressed M2-like (immunosuppressive) macrophages and promoted M1-like (anti-tumor) macrophages within tumors. This shift enhanced macrophage-tumor cell interactions and improved response to anti-PD-1 immunotherapy in xenografted mice.","whyItMatters":"Many colorectal tumors resist immunotherapy because their immune environment is suppressive. If CBD can reprogram that environment, it could potentially make existing immunotherapies work better.","specificNumbers":"CBD shifted macrophage balance from M2 (immunosuppressive) to M1 (anti-tumor). CBD inhibited PI3K-AKT signaling and shifted macrophage metabolism from oxidative phosphorylation to glycolysis. CBD plus anti-PD-1 showed enhanced anti-tumor response vs. either treatment alone.","methodology":"Single-cell RNA sequencing and single-cell ATAC sequencing of colorectal tumors in mice treated with CBD. Mechanistic studies examined macrophage metabolic reprogramming. Combination experiments tested CBD plus anti-PD-1 antibody in tumor-bearing mice.","limitations":"Mouse study with limited translational relevance. Xenograft models do not fully recapitulate human tumor microenvironments. CBD doses in mice may not reflect achievable human exposures. No clinical validation."},{"rthcId":"RTHC-04971","title":"Psychopathology and Pattern of Remission of Cannabis-Induced Psychotic Disorder.","authors":"Suresh, P N; Menon, Vikas; Suresh, Rohith; Uvais, N A","year":2023,"journal":"The primary care companion for CNS disorders, 25(2)","doi":"10.4088/PCC.22m03350","pmid":"37115153","tags":["psychosis","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"low","keyFinding":"Cannabis-induced psychotic disorder presented primarily with positive symptoms (hostility, excitement, grandiosity) and minimal affective symptoms. Both positive and negative symptoms showed significant improvement after one week in hospital and one month post-discharge with cannabis cessation.","whyItMatters":"Understanding the symptom profile and recovery trajectory of cannabis-induced psychosis helps clinicians distinguish it from primary psychotic disorders and set appropriate treatment expectations.","specificNumbers":"56 male patients, mean age 22.2 years. Predominant positive symptoms: hostility, excitement, grandiosity. Total duration of cannabis use and family history of substance use correlated with severity. Significant symptom improvement at both 1-week and 1-month follow-ups.","methodology":"Prospective cohort study of 56 male patients admitted with new-onset psychosis and cannabis use at a tertiary care hospital in Kerala, India (January-June 2019). Assessed at admission, 1 week, and 1 month using PANSS and CGI-S.","limitations":"All-male sample limits generalizability. Single center in India. No long-term follow-up to assess relapse or transition to primary psychotic disorder. No comparison group of non-cannabis psychosis patients. Relatively small sample."},{"rthcId":"RTHC-04972","title":"Opioid and healthcare service use in medical cannabis patients with chronic pain: a prospective study.","authors":"Sznitman, Sharon; Mabouk, Carolyn; Said, Zahi; Vulfsons, Simon","year":2023,"journal":"BMJ supportive & palliative care, 13(e2), e464-e468","doi":"10.1136/bmjspcare-2020-002661","pmid":"34521640","tags":["medical-cannabis","pain","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"low","keyFinding":"Patients filled fewer opioid prescriptions at 6-month follow-up compared to the 6 months before starting medical cannabis. The reduction was statistically significant but of small effect size. No changes in non-opioid medications or healthcare utilization.","whyItMatters":"The opioid-sparing potential of medical cannabis is one of its most cited justifications. This small study adds to the mixed evidence, finding a real but modest reduction.","specificNumbers":"68 patients. Opioid prescriptions decreased from baseline to 6-month follow-up with small effect size. No significant changes in other medication types or healthcare service utilization.","methodology":"Retrospective cohort study using medical records of 68 Israeli patients with chronic pain who initiated medical cannabis. Compared prescription fills and healthcare service use 6 months before vs. 6 months after starting treatment. Paired t-tests for within-patient comparisons.","limitations":"Very small sample (68 patients). No control group. Retrospective design using medical records. Cannot account for other changes in pain management. Small effect size questions clinical significance. Israeli medical cannabis system differs from other countries."},{"rthcId":"RTHC-04973","title":"Prenatal cannabinoid exposure and early language development.","authors":"Talavera-Barber, Maria M; Morehead, Evlyn; Ziegler, Katherine; Hockett, Christine; Elliott, Amy J","year":2023,"journal":"Frontiers in pediatrics, 11, 1290707","doi":"10.3389/fped.2023.1290707","pmid":"38078314","tags":["pregnancy","cognition","youth"],"studyType":"prospective-cohort","evidenceStrength":"low","keyFinding":"Late-exposed infants (2nd/3rd trimester) scored significantly higher on expressive and receptive language subscales at 12 months compared to unexposed infants. Early-exposed infants (1st trimester only) showed higher gross motor scores. No differences in visual reception.","whyItMatters":"This counterintuitive finding challenges the assumption that all prenatal cannabis effects are negative. However, the authors note these early scores may not predict long-term outcomes and could reflect altered neural connectivity patterns.","specificNumbers":"69 exposed, 138 unexposed infants. Late exposure: higher expressive language (95% CI: 2.54-12.76, p=0.004) and receptive language (95% CI: 0.39-8.72, p=0.03). Early exposure: higher gross motor scores (95% CI: 1.75-13, p=0.01). Mean maternal age: 23.7 (early) and 22.8 (late) years.","methodology":"Prospective cohort from the Safe Passage Study. 69 cannabis-exposed infants matched with 138 unexposed controls. Cognitive screening at 12 months using the Mullen Scale of Early Learning. Multiple linear regression adjusted for covariates.","limitations":"Small sample size. Observational design with potential unmeasured confounders. Cannabis-using mothers differed demographically from controls. 12-month assessments are very early and may not predict later development. Co-use of tobacco was common in the exposed group."},{"rthcId":"RTHC-04974","title":"Subchronic oral toxicity assessment of a cannabis extract.","authors":"Tallon, Mark J; Child, Robert","year":2023,"journal":"Regulatory toxicology and pharmacology : RTP, 144, 105496","doi":"10.1016/j.yrtph.2023.105496","pmid":"37734651","tags":["cbd"],"studyType":"animal","evidenceStrength":"moderate","keyFinding":"CBD was tolerated up to 460 mg/kg/day in males over 90 days. Some non-adverse organ and tissue changes occurred, and all changes except those at the highest dose reversed during the 35-day recovery period. Prenatal screening showed reduced body weight at the highest dose but no malformations.","whyItMatters":"As CBD products proliferate in consumer markets, establishing formal safety limits through standard toxicology testing provides a scientific basis for regulatory decisions about acceptable doses.","specificNumbers":"NOAEL: 460 mg/kg/day (males), 230 mg/kg/day (females). 14-day tolerance up to 460 mg/kg/day. 90-day study with 35-day off-dose recovery. Prenatal study showed reduced body weight at highest dose but no gross abnormalities.","methodology":"Three toxicology experiments in Sprague-Dawley rats: prenatal development screening, 14-day sighting study, and OECD-compliant 90-day subchronic oral toxicity study with 35-day recovery period. Doses: 0, 30, 115, 230, and 460 mg/kg/day of CBD isolate.","limitations":"Animal study with uncertain human translation. Used purified CBD isolate, not whole-plant extract. Standard safety factors (typically 100x) are applied when extrapolating animal NOAELs to human recommended doses. Sex differences in NOAEL suggest hormonal interactions not fully understood."},{"rthcId":"RTHC-04975","title":"Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis.","authors":"Talwar, Ashna; Estes, Emily; Aparasu, Rajender; Reddy, Doodipala Samba","year":2023,"journal":"Experimental neurology, 359, 114238","doi":"10.1016/j.expneurol.2022.114238","pmid":"36206805","tags":["cbd","epilepsy","youth"],"studyType":"meta-analysis","evidenceStrength":"high","keyFinding":"CBD treatment was significantly more effective than placebo (OR=2.45, 95% CI: 1.81-3.32). Subgroup analysis showed benefit in all three syndromes: Dravet (OR=2.26), Lennox-Gastaut (OR=2.98), and tuberous sclerosis complex (OR=1.99). Higher adverse event rates were seen with CBD, especially with clobazam co-therapy.","whyItMatters":"Refractory epilepsy in children is devastating and treatment options are limited. This meta-analysis strengthens the evidence base for CBD as both standalone and adjunct therapy across the three approved indications.","specificNumbers":"6 RCTs included. Pooled OR for 50%+ seizure reduction: 2.45 (p<0.01). By syndrome: Dravet 2.26, LGS 2.98, TSC 1.99. Adverse events increased (OR=1.81), serious adverse events (OR=2.86). Common side effects: diarrhea, somnolence, sedation.","methodology":"Systematic review and meta-analysis of 6 RCTs meeting eligibility criteria from 1,183 screened articles. All studies used pharmaceutical-grade oral CBD (Epidiolex) at 10-50 mg/kg/day for up to 16 weeks. Subgroup analyses by syndrome and clobazam co-therapy.","limitations":"Only 6 RCTs available. All used one product (Epidiolex) at specific doses. Treatment duration limited to 16 weeks. Clobazam interaction complicates interpretation of whether CBD alone or the CBD-clobazam combination drives efficacy. Increased serious adverse events warrant careful monitoring."},{"rthcId":"RTHC-04976","title":"Making informed choices about cannabis use during pregnancy and lactation: A qualitative study of information use.","authors":"Taneja, Shipra; Panday, Janelle; Popoola, Anuoluwa; Greyson, Devon; McDonald, Sarah D; Patel, Tejal; Vanstone, Meredith","year":2023,"journal":"Birth (Berkeley, Calif.), 50(3), 504-512","doi":"10.1111/birt.12668","pmid":"35848512","tags":["pregnancy"],"studyType":"qualitative","evidenceStrength":"low","keyFinding":"Participants deliberately sought information about cannabis risks during pregnancy but found it inadequate. Online sources and social networks were primary information channels. Healthcare providers were not viewed as knowledgeable or supportive sources on this topic.","whyItMatters":"Pregnant people are making decisions about cannabis with inadequate information and without clinical support. Understanding their information needs and barriers is essential for developing better guidance.","specificNumbers":"52 participants interviewed. Most searched for risk information. Online material and social networks were the primary sources. Clinicians were rarely described as helpful. Participants overwhelmingly described available information as insufficient.","methodology":"Qualitative study with semi-structured interviews of 52 pregnant and lactating people in Canada who decided to start, stop, or continue cannabis use. Recruited from prenatal clinics and social media. Inductive analysis focused on information-seeking and decision-making.","limitations":"Qualitative study cannot quantify prevalence of information gaps. Canadian healthcare context may differ from other countries. Self-selected sample may overrepresent people motivated to seek information. Social desirability may affect interview responses."},{"rthcId":"RTHC-04977","title":"Transcriptomic and metabolomic analyses reveal the differential accumulation of phenylpropanoids and terpenoids in hemp autotetraploid and its diploid progenitor.","authors":"Tang, Qing; Xu, Ying; Gao, Feng; Xu, Ying; Cheng, Chaohua; Deng, Canhui; Chen, Jiquan; Yuan, Xiaoge; Zhang, Xiaoyu; Su, Jianguang","year":2023,"journal":"BMC plant biology, 23(1), 616","doi":"10.1186/s12870-023-04630-z","pmid":"38049730","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-04978","title":"Altered glial expression of the cannabinoid 1 receptor in the subiculum of a mouse model of Alzheimer's disease.","authors":"Terradillos, Itziar; Bonilla-Del Río, Itziar; Puente, Nagore; Serrano, Maitane; Mimenza, Amaia; Lekunberri, Leire; Anaut-Lusar, Ilazki; Reguero, Leire; Gerrikagoitia, Inmaculada; Ruiz de Martín Esteban, Samuel; Hillard, Cecilia J; Grande, María T; Romero, Julián; Elezgarai, Izaskun; Grandes, Pedro","year":2023,"journal":"Glia, 71(4), 866-879","doi":"10.1002/glia.24312","pmid":"36437738","tags":["neuroscience","cognition"],"studyType":"animal","evidenceStrength":"low","keyFinding":"CB1 receptor expression increased in reactive microglia surrounding amyloid plaques in the subiculum of 5xFAD mice. In astrocytes, CB1 labeling rose proportionally to cell size (reactive astrocytes are larger), keeping receptor density effectively constant.","whyItMatters":"The endocannabinoid system is involved in neuroinflammation, and understanding how CB1 receptors change in glial cells during Alzheimer's pathology could identify therapeutic targets for modulating the neuroinflammatory response.","specificNumbers":"CB1 receptor expression increased in reactive microglia in 5xFAD mice vs. controls. In astrocytes, CB1 labeling increased proportionally to perimeter of reactive astrocytes. Microglial CB1 was found closely surrounding amyloid plaques and dystrophic neurites.","methodology":"Immuno-electron microscopy examining CB1 receptor localization in microglia and astrocytes in the subiculum of 5xFAD/CB2-EGFP mice (Alzheimer's model) versus controls. Quantitative analysis of receptor density relative to glial cell morphology.","limitations":"Mouse model of Alzheimer's disease (5xFAD) overexpresses mutant human genes and may not fully recapitulate human AD pathology. Observational study of receptor expression without functional testing. Only examined the subiculum, one of many affected brain regions."},{"rthcId":"RTHC-04979","title":"Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases.","authors":"Thapa, Dinesh; Warne, Leon N; Falasca, Marco","year":2023,"journal":"International journal of molecular sciences, 24(19)","doi":"10.3390/ijms241914677","pmid":"37834122","tags":["medical-cannabis"],"studyType":"review","evidenceStrength":"low","keyFinding":"Historical records from multiple cultures document cannabis use for nausea, vomiting, diarrhea, and inflammatory bowel conditions. Modern research confirms endocannabinoid system involvement in gut function, with THC:CBD preparations showing promise for inflammation and motility.","whyItMatters":"Understanding the historical use of cannabis for gut conditions provides context for modern research directions and highlights that this is not a new therapeutic concept but one that was interrupted by prohibition.","specificNumbers":"Reviews evidence from multiple cultural traditions spanning thousands of years. Discusses the endocannabinoidome as an expanded system beyond classical endocannabinoid signaling in gastrointestinal modulation.","methodology":"Narrative review combining ethnomedicinal history of cannabis for gastrointestinal conditions with modern pharmacological understanding of the endocannabinoid system and expanded endocannabinoidome in gut function.","limitations":"Narrative review without systematic methodology. Historical accounts lack the rigor of modern clinical evidence. Modern evidence for cannabinoids in GI conditions remains primarily preclinical. Optimal formulations and dosing for GI conditions are unknown."},{"rthcId":"RTHC-04980","title":"Cannabis and adverse cardiovascular events: A systematic review and meta-analysis of observational studies","authors":"Theerasuwipakorn, Nonthikorn; et al.","year":2023,"journal":"Toxicology Reports, 10, 537-543","doi":"10.1016/j.toxrep.2023.04.011","pmid":"37168078","tags":["cardiovascular","legalization","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"As cannabis legalization expands globally, the cardiovascular safety question becomes increasingly urgent. Does cannabis use increase the risk of heart attacks and strokes? This meta-analysis pulled together 20 observational studies encompassing over 183 million patients to find out.\n\nThe headline findings split in two directions. For acute myocardial infarction (heart attack), cannabis use was not significantly associated with increased risk — the pooled odds ratio was 1.29 but the confidence interval crossed 1.0, meaning the association wasn't statistically reliable. For stroke, however, the picture was different: cannabis use was significantly associated with increased risk.\n\nThe magnitude and clinical significance of the stroke finding deserve careful interpretation. Observational studies can't prove causation — cannabis users may differ from non-users in ways that independently affect stroke risk (smoking tobacco, other substance use, socioeconomic factors). The researchers used standard methods to assess and control for confounding, but residual confounding is always a concern with observational data.\n\nThe overall prevalence of cannabis use in this massive dataset was 1.9%, and the median follow-up was 6.2 years. The male predominance in the sample (23.7%) likely reflects the demographics of cardiovascular events rather than cannabis use patterns.\n\nThis meta-analysis lands in a contentious space. Some prior studies have suggested cannabis increases cardiovascular risk, while others found no association. This analysis, by virtue of its massive sample size, provides the most statistically powered answer to date — and it suggests the risk is real for stroke but uncertain for heart attack.","whyItMatters":"This is the largest meta-analysis of cannabis and cardiovascular risk ever conducted. With over 183 million patients, it has statistical power that individual studies lack. The finding that stroke risk is elevated while heart attack risk is not suggests cannabis may affect the cardiovascular system in specific ways — possibly through effects on blood vessel function, blood pressure regulation, or clotting — rather than through a general increase in cardiovascular disease.","specificNumbers":"20 studies, 183,410,651 patients. Cannabis use prevalence: 1.9%. Median age: 42.4 years. Median follow-up: 6.2 years. Acute MI: pooled OR 1.29 (95% CI crossing 1.0, not significant). Stroke: significantly associated with cannabis use (pooled OR reported as significant). 23.7% male in the overall sample.","methodology":"Systematic review and meta-analysis of 20 observational studies including 183,410,651 patients. Searched PubMed, Scopus, and Cochrane Library databases. Data on effect estimates combined via random-effects meta-analysis using the DerSimonian and Laird method with generic inverse-variance strategy. Outcomes: acute myocardial infarction and stroke.","limitations":"All included studies were observational — the association between cannabis and stroke cannot be confirmed as causal. Residual confounding is a major concern: cannabis users may differ from non-users in smoking habits, other drug use, and socioeconomic factors that independently affect cardiovascular risk. The definition of 'cannabis use' varied across studies (current vs. ever, frequency, route of administration). The very low proportion of males (23.7%) in the overall sample is unusual and may reflect specific study populations. Publication bias is possible."},{"rthcId":"RTHC-04981","title":"An exploratory follow-up study of cannabis use and decision-making under various risk conditions within adolescence.","authors":"Thompson, Erin L; Adams, Ashley R; Pacheco-Colón, Ileana; Lopez-Quintero, Catalina; Limia, Jorge M; Pulido, William; Granja, Karen; Paula, Dayana C; Gonzalez, Ingrid; Ross, J Megan; Duperrouzel, Jacqueline C; Hawes, Samuel W; Gonzalez, Raul","year":2023,"journal":"Neuropsychology, 37(5), 544-556","doi":"10.1037/neu0000897","pmid":"36939602","tags":["youth","cognition"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Baseline performance on the Game of Dice Task (explicit risk decision-making) predicted greater escalation in cannabis use frequency and cannabis-related problems over 2 years. Decision-making under ambiguous risk (Iowa Gambling Task) did not predict cannabis outcomes.","whyItMatters":"Understanding which cognitive abilities protect against or predict cannabis escalation in adolescence could inform targeted prevention programs, particularly in underrepresented Hispanic populations.","specificNumbers":"401 adolescents (90% Hispanic), ages 14-17, five assessments over 2 years. GDT performance predicted cannabis use escalation (beta=0.200, p=0.008) and problem escalation (beta=0.388, p=0.035). IGT and Cups Task were not predictive.","methodology":"Longitudinal study with five biannual assessments of 401 adolescents (90% Hispanic, ages 14-17 at baseline). Three decision-making tasks assessed (Iowa Gambling Task, Game of Dice Task, Cups Task). Latent growth curve modeling examined bidirectional associations.","limitations":"Exploratory analyses requiring replication. Predominantly Hispanic sample in one geographic area. Cannabis use measures relied on self-report. The distinction between ambiguous and explicit risk tasks, while theoretically meaningful, may reflect other cognitive differences."},{"rthcId":"RTHC-04982","title":"Prenatal cannabis use and its impact on offspring neuro-behavioural outcomes: A systematic review.","authors":"Thompson, Mary; Vila, Merima; Wang, Li; Thabane, Lehana; Shea, Alison K","year":2023,"journal":"Paediatrics & child health, 28(1), 8-16","doi":"10.1093/pch/pxac079","pmid":"36865761","tags":["pregnancy","cognition","youth"],"studyType":"systematic-review","evidenceStrength":"low","keyFinding":"Meta-analyses showed no significant associations between prenatal cannabis exposure and attention, global IQ, reading, written comprehension, spelling, or mathematics. Individual studies of heavy use showed some differences, but these disappeared when outcomes were pooled.","whyItMatters":"Prenatal cannabis exposure is increasing and parents need evidence about risks. This comprehensive review suggests the cognitive effects, if any, may be smaller than commonly assumed, though evidence quality is low.","specificNumbers":"28 studies, 523,107 total patients. Pooled standardized mean differences (all non-significant): attention -0.27, IQ -0.16, reading -0.05, written comprehension -0.09, spelling -0.04, mathematics -0.01. Evidence graded as very low quality.","methodology":"Systematic review with meta-analyses following standard guidelines. Searched MEDLINE, EMBASE, PsychINFO, CINAHL, and ClinicalTrials.gov. 28 studies included (n=523,107 patients). Random-effects models used when at least three studies reported the same outcome. GRADE assessment applied.","limitations":"Very low-quality evidence by GRADE assessment. Significant heterogeneity across studies. Cohort redundancy (multiple papers from the same cohorts) limited meta-analysis. Heavy use subgroups showed effects that disappeared when pooled. Self-reported exposure likely misclassified many participants."},{"rthcId":"RTHC-04983","title":"Program Evaluation to Aid Choice of Aripiprazole or Risperidone for Hospitalized Adolescents with Cannabis Use Disorder and Psychosis.","authors":"Thurstone, Christian; Loh, Ryan; Foreman, Kristina; Thurstone, Christian A; Wolf, Chelsea","year":2023,"journal":"Journal of child and adolescent psychopharmacology, 33(8), 332-336","doi":"10.1089/cap.2023.0053","pmid":"37861990","tags":["youth","psychosis"],"studyType":"retrospective-cohort","evidenceStrength":"low","keyFinding":"Adolescents prescribed aripiprazole had a mean length of stay of 5.8 days compared to 9.7 days for risperidone (p=0.002). The length of stay index was also significantly lower for aripiprazole (0.79 vs. 1.4, p=0.004).","whyItMatters":"Co-occurring cannabis use and psychosis in adolescents is increasing, and clinicians lack evidence to guide antipsychotic choice for this specific population. These preliminary data suggest aripiprazole may resolve acute symptoms faster.","specificNumbers":"110 adolescents. Aripiprazole: mean stay 5.8 days, index 0.79. Risperidone: mean stay 9.7 days, index 1.4. Both differences significant (p=0.002 and p=0.004 respectively).","methodology":"Retrospective chart review of 110 adolescents (ages 13-21) hospitalized for psychosis with co-occurring cannabis use disorder. Compared outcomes between those prescribed risperidone versus aripiprazole. Nonrandomized quality improvement project.","limitations":"Nonrandomized design with potential selection bias in medication choice. Retrospective chart review. Cannot control for illness severity, cannabis use patterns, or other medications. Single-center data."},{"rthcId":"RTHC-04984","title":"Who responds to a multi-component treatment for cannabis use disorder? Using multivariable and machine learning models to classify treatment responders and non-responders.","authors":"Tomko, Rachel L; Wolf, Bethany J; McClure, Erin A; Carpenter, Matthew J; Magruder, Kathryn M; Squeglia, Lindsay M; Gray, Kevin M","year":2023,"journal":"Addiction (Abingdon, England), 118(10), 1965-1974","doi":"10.1111/add.16226","pmid":"37132085","tags":["addiction","quitting"],"studyType":"secondary-analysis","evidenceStrength":"moderate","keyFinding":"Both multivariable logistic regression and machine learning models (random forest, gradient boosting) had limited ability to classify CUD treatment responders versus non-responders. Prediction accuracy was modest, indicating that commonly measured variables do not strongly predict treatment response.","whyItMatters":"CUD treatments have limited efficacy overall. If clinicians could identify who will respond to which treatment approach, they could personalize care and improve outcomes. This study shows current predictive tools fall short.","specificNumbers":"Multi-site clinical trial data used. Multiple machine learning approaches tested (random forest, gradient boosting, logistic regression). All achieved modest classification accuracy for treatment response.","methodology":"Secondary analysis of a National Drug Abuse Treatment Clinical Trials Network multi-site outpatient trial. Adult CUD patients were assessed with multivariable logistic regression and machine learning models (random forest, gradient boosting) to predict treatment response.","limitations":"Secondary analysis limited to variables collected in the original trial. Treatment was a specific multi-component protocol that may not generalize. Machine learning models can overfit to training data. Modest sample sizes may limit model performance."},{"rthcId":"RTHC-04985","title":"Systematic Review: Polysubstance Prevalence Estimates Reported during Pregnancy, US, 2009-2020.","authors":"Tran, Emmy L; England, Lucinda J; Park, Youngjoo; Denny, Clark H; Kim, Shin Y","year":2023,"journal":"Maternal and child health journal, 27(3), 426-458","doi":"10.1007/s10995-023-03592-w","pmid":"36752906","tags":["pregnancy"],"studyType":"systematic-review","evidenceStrength":"low","keyFinding":"Polysubstance use during pregnancy involved diverse combinations, with cannabis commonly appearing alongside other substances. Prevalence estimates varied widely depending on screening method and population studied.","whyItMatters":"Most prenatal substance use research focuses on single substances, but real-world use often involves combinations. Understanding polysubstance patterns is essential for accurate risk assessment and targeted interventions.","specificNumbers":"Literature from 2009-2020 reviewed. Cannabis was a common component of prenatal polysubstance use patterns alongside tobacco, alcohol, opioids, and stimulants.","methodology":"Systematic review following PRISMA guidelines. Searched four databases for articles published January 2009 to June 2020 reporting prenatal exposure to two or more substances in the US.","limitations":"Heterogeneous study designs and exposure definitions across included studies. Prevalence estimates are highly sensitive to screening methods used. Many studies relied on self-report. Publication date cutoff (2020) may miss recent trends."},{"rthcId":"RTHC-04986","title":"Phytochemical Comparison of Medicinal Cannabis Extracts and Study of Their CYP-Mediated Interactions with Coumarinic Oral Anticoagulants.","authors":"Treyer, Andrea; Reinhardt, Jakob K; Eigenmann, Daniela Elisabeth; Oufir, Mouhssin; Hamburger, Matthias","year":2023,"journal":"Medical cannabis and cannabinoids, 6(1), 21-31","doi":"10.1159/000528465","pmid":"36814687","tags":["cbd","drug-interactions","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"If you take a blood thinner like warfarin and use cannabis, this study has important implications. The researchers tested cannabis extracts from four different chemotypes — varieties with different ratios of THC, CBD, and other cannabinoids — to see how they affected the liver enzymes (CYP2C9 and CYP3A4) responsible for metabolizing common blood-thinning medications.\n\nAll four cannabis extract types inhibited these enzymes, meaning all of them could potentially increase blood thinner levels in the body. But the degree of inhibition varied substantially between chemotypes. This variation matters because patients using medical cannabis may switch products or strains without realizing they're changing their drug interaction risk.\n\nThe study specifically tested interactions with three coumarin-type anticoagulants: warfarin (most common in the U.S.), phenprocoumon, and acenocoumarol (more common in Europe). Both THC and CBD individually inhibited these pathways, but whole-plant extracts showed interaction profiles that couldn't be predicted simply from their THC and CBD content — suggesting other compounds in the plant contribute to drug interactions.\n\nThis is a critical safety finding for the significant number of patients who use both cannabis and anticoagulant medications, particularly elderly patients with atrial fibrillation or mechanical heart valves where anticoagulation must be precisely controlled.","whyItMatters":"Warfarin has one of the narrowest therapeutic windows of any commonly prescribed drug — too little and blood clots form, too much and dangerous bleeding occurs. If cannabis extracts inhibit the enzymes that metabolize warfarin, patients could unknowingly push their blood levels into the danger zone. This study shows the risk is real and varies by cannabis product type, which is especially concerning because patients rarely consult their anticoagulation clinic about cannabis use.","specificNumbers":"Four cannabis chemotypes tested. Both CYP2C9 and CYP3A4 were inhibited by all extract types. Pure THC and CBD both showed inhibitory activity. Three coumarin anticoagulants tested: warfarin, phenprocoumon, acenocoumarol. Inhibition profiles varied between chemotypes, meaning product-switching could change interaction risk.","methodology":"In vitro study using pooled, mixed-gender human liver microsomes. Cannabis extracts were prepared from four chemotypes, either commercially obtained or prepared via ethanol extraction with overnight decarboxylation. Extracts were characterized for cannabinoid content using NMR and HPLC-PDA-ELSD-ESIMS. CYP inhibition was assessed using tolbutamide (CYP2C9) and testosterone (CYP3A4) as probe substrates, with warfarin, phenprocoumon, and acenocoumarol as clinically relevant model compounds.","limitations":"In vitro study using liver microsomes — not a clinical trial in patients. Enzyme inhibition in a test tube doesn't always predict clinically significant interactions in living patients. The extracts were tested at concentrations that may or may not reflect what reaches the liver after normal cannabis use. No patient outcomes (bleeding events, INR changes) were measured. The four chemotypes represent a fraction of the enormous variety of cannabis products available."},{"rthcId":"RTHC-04987","title":"Implementation and Preliminary Evaluation of a 12-Week Cognitive Behavioural and Motivational Enhancement Group Therapy for Cannabis Use Disorder.","authors":"Trick, Leanne; Butler, Kevin; Bourgault, Zoe; Vandervoort, Julianne; Le Foll, Bernard","year":2023,"journal":"Substance abuse : research and treatment, 17, 11782218231205840","doi":"10.1177/11782218231205840","pmid":"37904747","tags":["withdrawal","addiction","mental-health","quitting"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis use disorder (CUD) is increasingly recognized as a real clinical condition, but treatment options have been slow to develop. This study evaluated a structured 12-week outpatient group therapy program at Toronto's Centre for Addiction and Mental Health — one of Canada's premier addiction treatment centers.\n\nThe program combined two evidence-based approaches: cognitive behavioral therapy (CBT), which helps patients identify and change thought patterns and behaviors that drive cannabis use, and motivational enhancement therapy (MET), which builds internal motivation to change. The group format added peer support and shared accountability.\n\nThe results were encouraging across the board. After treatment, participants showed lower cannabis use, more days of abstinence, fewer cannabis-related problems, reduced cravings, less severe withdrawal symptoms, and improved self-efficacy (confidence in their ability to stay abstinent). Depression and anxiety scores also improved.\n\nTreatment retention — always a challenge in addiction treatment — was assessed by tracking clinic attendance. Client satisfaction, measured by anonymous feedback, was positive. The researchers also explored what predicted better outcomes and retention, looking for patterns that could help match patients to treatment.\n\nThis is important practical evidence because most cannabis treatment research has tested individual therapy. Group therapy is more cost-effective and more widely scalable, making it relevant for the many treatment programs facing long waitlists for cannabis-related concerns.","whyItMatters":"As cannabis use increases and more people develop problematic use patterns, accessible treatment options are urgently needed. Individual therapy is effective but expensive and limited in availability. This group-based CBT+MET program showed meaningful improvements in a real-world clinical setting, offering a scalable model that other treatment centers could adopt. The combination of reduced use AND improved mental health symptoms is particularly valuable since depression and anxiety commonly co-occur with CUD.","specificNumbers":"12-week program. Treatment setting: outpatient group therapy at Centre for Addiction and Mental Health, Toronto. Post-treatment improvements: lower cannabis use, more abstinence days, reduced craving, fewer withdrawal symptoms, improved self-efficacy, lower depression and anxiety scores. Client satisfaction was positive. Specific effect sizes and retention rates were measured but detailed in the full paper.","methodology":"Retrospective observational cohort study using medical records and self-report assessments from treatment-seeking cannabis users at the Centre for Addiction and Mental Health, Toronto. Pre- and post-treatment measures: cannabis use, cannabis-related problems, craving, withdrawal symptoms, self-efficacy, depression, and anxiety. Treatment retention calculated from attendance records. Client satisfaction assessed via anonymous feedback survey. Exploratory analyses examined predictors of outcomes and retention.","limitations":"Retrospective design without a control group — improvements could partly reflect natural recovery, regression to the mean, or motivation to change that existed before treatment began. Self-report measures are subject to social desirability bias, especially in a treatment setting. No long-term follow-up to assess whether improvements persisted after the 12-week program ended. Single-center study at a well-resourced addiction hospital — results may differ in less specialized settings."},{"rthcId":"RTHC-04988","title":"Location and home rules of cannabis use - Findings from marijuana use and environmental survey 2020, a nationally representative survey in the United States.","authors":"Tripathi, Osika; Bellettiere, John; Liles, Sandy; Shi, Yuyan","year":2023,"journal":"Preventive medicine reports, 35, 102289","doi":"10.1016/j.pmedr.2023.102289","pmid":"37408996","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis was most commonly used at home, and many households lacked rules restricting indoor cannabis use. This creates potential secondhand and thirdhand exposure risks for non-users including children.","whyItMatters":"As cannabis legalization expands, understanding where people use and who is exposed secondhand is critical for public health policy, particularly regarding children and non-consenting adults.","specificNumbers":"Nationally representative US sample from 2020. Most cannabis use occurred at home. Many households reported no rules restricting indoor cannabis combustion or aerosolization.","methodology":"Cross-sectional analysis of the Marijuana Use and Environmental Survey 2020, a nationally representative US survey. Examined locations of cannabis use, presence of other people during use, and household rules about cannabis.","limitations":"Cross-sectional survey with self-reported data. Social desirability may affect reporting. Survey conducted in 2020 during COVID-19, which may have increased home-based use. Cannot measure actual secondhand exposure levels from survey data alone."},{"rthcId":"RTHC-04989","title":"Cannabis use as a potential mediator between childhood adversity and first-episode psychosis: results from the EU-GEI case-control study.","authors":"Trotta, Giulia; Rodriguez, Victoria; Quattrone, Diego; Spinazzola, Edoardo; Tripoli, Giada; Gayer-Anderson, Charlotte; Freeman, Tom P; Jongsma, Hannah E; Sideli, Lucia; Aas, Monica; Stilo, Simona A; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Lasalvia, Antonio; Tosato, Sarah; Tarricone, Ilaria; D'Andrea, Giuseppe; Tortelli, Andrea; Schürhoff, Franck; Szöke, Andrei; Pignon, Baptiste; Selten, Jean-Paul; Velthorst, Eva; de Haan, Lieuwe; Llorca, Pierre-Michel; Rossi Menezes, Paulo; Del Ben, Cristina M; Santos, Jose Luis; Arrojo, Manuel; Bobes, Julio; Sanjuán, Julio; Bernardo, Miquel; Arango, Celso; Kirkbride, James B; Jones, Peter B; Richards, Alexander; Rutten, Bart P; Van Os, Jim; Austin-Zimmerman, Isabelle; Li, Zhikun; Morgan, Craig; Sham, Pak C; Vassos, Evangelos; Wong, Chloe; Bentall, Richard; Fisher, Helen L; Murray, Robin M; Alameda, Luis; Di Forti, Marta","year":2023,"journal":"Psychological medicine, 53(15), 7375-7384","doi":"10.1017/S0033291723000995","pmid":"38078747","tags":["psychosis","mental-health"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Cannabis use acted as a partial mediator between childhood adversity and first-episode psychosis. Different patterns of cannabis use (frequency, potency, duration) contributed to this mediating pathway, suggesting adversity may increase psychosis risk partly through promoting problematic cannabis use.","whyItMatters":"Understanding whether cannabis use is a mechanism linking childhood adversity to psychosis could inform prevention. If adversity increases psychosis risk partly by promoting cannabis use, targeting substance use in trauma-exposed youth could reduce psychosis incidence.","specificNumbers":"881 first-episode psychosis patients and 1,231 controls from the EU-GEI study across Europe. Cannabis use patterns partially mediated the childhood adversity-psychosis association.","methodology":"Case-control study using EU-GEI data. 881 first-episode psychosis patients and 1,231 controls. Detailed cannabis use histories collected. Mediation analysis tested whether cannabis use patterns explained part of the adversity-psychosis association.","limitations":"Case-control design limits causal inference. Retrospective assessment of both childhood adversity and cannabis use history. Mediation analysis assumes temporal ordering that cannot be confirmed. Other mediating pathways (e.g., stress, other substances) not fully examined."},{"rthcId":"RTHC-04990","title":"A comprehensive evaluation of adverse childhood experiences, social-emotional impairments, and neurodevelopmental disorders in cannabis-use disorder: Implications for clinical practice.","authors":"Trovini, Giada; Amici, Emanuela; Bauco, Piergiorgio; Matrone, Marta; Lombardozzi, Ginevra; Giovanetti, Valeria; Kotzalidis, Georgios D; De Filippis, Sergio","year":2023,"journal":"European psychiatry : the journal of the Association of European Psychiatrists, 66(1), e77","doi":"10.1192/j.eurpsy.2023.2436","pmid":"37702087","tags":["addiction","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Adverse childhood experiences (ACEs), social-emotional impairments (SEIs), and neurodevelopmental disorders (NDs) were highly prevalent among CUD patients. Those with pre-CUD-onset ACEs, SEIs, or NDs differed significantly from those without, suggesting these conditions shape vulnerability to cannabis use disorder.","whyItMatters":"If ACEs, neurodevelopmental conditions, and social-emotional problems precede cannabis use disorder in most cases, prevention efforts should target these upstream vulnerabilities rather than focusing solely on cannabis availability.","specificNumbers":"323 patients with CUD, ages 12-35, mean age 22.94, 64.5% male. Non-premorbid group: 52 patients. The majority had pre-CUD-onset ACEs, SEIs, or neurodevelopmental disorders.","methodology":"Cross-sectional study of 323 inpatients and outpatients (ages 12-35, mean 22.9, 64.5% male) with current or past cannabis use disorder. Assessed for ACEs, SEIs, and NDs. Compared those with pre-CUD-onset conditions to those without.","limitations":"Cross-sectional design cannot confirm temporal ordering despite attempting to identify pre-CUD conditions. Recall bias for childhood events. Clinical sample may not represent all people with CUD. Single-interview assessment."},{"rthcId":"RTHC-04991","title":"Sperm capacitation and transcripts levels are altered by in vitro THC exposure.","authors":"Truong, Vivien B; Davis, Ola S; Gracey, Jade; Neal, Michael S; Khokhar, Jibran Y; Favetta, Laura A","year":2023,"journal":"BMC molecular and cell biology, 24(1), 6","doi":"10.1186/s12860-023-00468-3","pmid":"36823609","tags":["sex-differences"],"studyType":"in-vitro","evidenceStrength":"very-low","keyFinding":"Physiologically relevant THC concentrations altered sperm capacitation (a key step for fertilization) and changed gene expression patterns in bull sperm used as a translational model for human sperm.","whyItMatters":"Cannabis use is highest among reproductive-age males. If THC directly affects sperm function, it has implications for male fertility that are relevant to a large population of users.","specificNumbers":"Physiologically relevant THC concentrations used. Sperm capacitation was impaired. Transcript levels were altered in THC-treated sperm compared to controls.","methodology":"In vitro study using bull sperm of known fertility as a translational model. Sperm were treated with physiologically relevant THC concentrations. Assessed capacitation, physiological parameters, and transcript levels.","limitations":"In vitro study using bull sperm, not human. Laboratory conditions do not replicate the reproductive tract environment. Acute THC exposure may not reflect chronic cannabis use patterns. Transcript changes may not translate to functional fertility outcomes."},{"rthcId":"RTHC-04992","title":"Prenatal substance use in the rural and Appalachian state: Project WATCH study 2020-2022.","authors":"Umer, Amna; Garrow, Jana; Nesbitt, Makena; Lilly, Christa; Lefeber, Candice; Breyel, Janine; John, Collin","year":2023,"journal":"The Journal of rural health : official journal of the American Rural Health Association and the National Rural Health Care Association, 39(4), 804-815","doi":"10.1111/jrh.12752","pmid":"36823403","tags":["pregnancy"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis was identified as both a standalone prenatal exposure category and a component of multiple polysubstance patterns (cannabis alone, opioids+cannabis, cannabis+stimulants, opioids+cannabis+stimulants) in a population-based birth cohort from West Virginia.","whyItMatters":"Rural Appalachian populations face disproportionate substance use challenges. Understanding the specific patterns, including where cannabis fits, is essential for designing appropriate prenatal interventions in underserved regions.","specificNumbers":"34,309 births in West Virginia (2020-2022). Nine substance use categories: no use, opioids, cannabis, sedatives/hypnotics, stimulants, opioids+cannabis, opioids+stimulants, cannabis+stimulants, opioids+cannabis+stimulants.","methodology":"Population-based cohort (Project WATCH) of all 34,309 women who gave birth in West Virginia between February 2020 and June 2022. Substance use identified through self-report, medical records, and drug screening. Nine substance use categories defined.","limitations":"Single-state data from a region with unique substance use dynamics. Screening methods may miss some use. Short time window (2020-2022) overlapping with COVID-19 pandemic. Does not assess pregnancy outcomes associated with different substance use patterns."},{"rthcId":"RTHC-04993","title":"Identification of a novel fatty acid binding protein-5-CB2 receptor-dependent mechanism regulating anxiety behaviors in the prefrontal cortex.","authors":"Uzuneser, Taygun C; Szkudlarek, Hanna J; Jones, Matthew J; Nashed, Mina G; Clement, Timothy; Wang, Hehe; Ojima, Iwao; Rushlow, Walter J; Laviolette, Steven R","year":2023,"journal":"Cerebral cortex (New York, N.Y. : 1991), 33(6), 2470-2484","doi":"10.1093/cercor/bhac220","pmid":"35650684","tags":["anxiety","neuroscience"],"studyType":"animal","evidenceStrength":"low","keyFinding":"The FABP-5 inhibitor SBFI-103 reduced anxiety-like behaviors when administered to the rat prefrontal cortex. This anxiolytic effect was blocked by a CB2 receptor antagonist, identifying a novel FABP5-CB2 receptor pathway in anxiety regulation.","whyItMatters":"Current anxiety medications have significant limitations. Discovering a new endocannabinoid pathway (FABP5-CB2) in the prefrontal cortex that regulates anxiety could open a novel drug development avenue that avoids the psychoactive effects of THC.","specificNumbers":"Acute intra-prefrontal cortex SBFI-103 reduced anxiety behaviors. CB2 receptor antagonist reversed the effect, confirming CB2 dependence.","methodology":"Behavioral pharmacology in rats. SBFI-103 (FABP-5 inhibitor) was injected into the prelimbic prefrontal cortex. Anxiety assessed using standard behavioral tests. CB2 receptor antagonist used to determine mechanism.","limitations":"Rat study with direct brain injection, not a clinically feasible route. Unknown whether systemic FABP-5 inhibition would produce the same effect. CB2 receptor role in brain function is still debated. Single behavioral paradigm."},{"rthcId":"RTHC-04994","title":"Cannabis-opioid interaction in the treatment of fibromyalgia pain: an open-label, proof of concept study with randomization between treatment groups: cannabis, oxycodone or cannabis/oxycodone combination-the SPIRAL study.","authors":"van Dam, Cornelis Jan; van Velzen, Monique; Kramers, Cornelis; Schellekens, Arnt; Olofsen, Erik; Niesters, Marieke; Dahan, Albert","year":2023,"journal":"Trials, 24(1), 64","doi":"10.1186/s13063-023-07078-6","pmid":"36707893","tags":["medical-cannabis","pain","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The SPIRAL study randomized fibromyalgia patients to three arms: cannabis alone, oxycodone alone, or cannabis+oxycodone combination. The trial examined whether combining cannabis with opioids could maintain pain relief while reducing opioid consumption.","whyItMatters":"If cannabis can allow lower opioid doses while maintaining pain control, it could reduce opioid-related harms in chronic pain populations. This is the first trial directly testing this combination approach in fibromyalgia.","specificNumbers":"Three treatment arms: cannabis alone, oxycodone alone, cannabis+oxycodone combination. Pharmaceutical-grade cannabis used. Proof-of-concept design.","methodology":"Single-center, randomized, three-arm, open-label, proof-of-concept study. Fibromyalgia patients randomized to pharmaceutical-grade cannabis, oxycodone, or cannabis/oxycodone combination.","limitations":"Open-label design introduces significant expectation bias. Single-center. Proof-of-concept with likely small sample. Fibromyalgia results may not generalize to other chronic pain conditions. Pharmaceutical-grade cannabis may not reflect commercial products."},{"rthcId":"RTHC-04995","title":"Nausea and vomiting of pregnancy and prenatal cannabis use in a Michigan sample.","authors":"Vanderziel, Alyssa; Anthony, James C; Barondess, David; Kerver, Jean M; Alshaarawy, Omayma","year":2023,"journal":"American journal of obstetrics & gynecology MFM, 5(12), 101171","doi":"10.1016/j.ajogmf.2023.101171","pmid":"37778699","tags":["pregnancy"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Women experiencing nausea and vomiting of pregnancy were more likely to use cannabis prenatally. The study documented increasing cannabis potency and decreasing risk perception alongside state-level recreational legalization.","whyItMatters":"Morning sickness is a primary reason pregnant women report using cannabis. Understanding this connection is important as legalization reduces perceived risk and cannabis potency increases.","specificNumbers":"Over 70% of pregnancies experience nausea and vomiting. Cannabis potency (THC concentration) increased from 10% in 2009 to 14% in 2019. State-level legalization may contribute to increased use and reduced risk perception.","methodology":"Cross-sectional analysis of a Michigan pregnancy cohort. Assessed associations between nausea/vomiting of pregnancy and prenatal cannabis use. Contextualized within trends of increasing THC potency and changing legalization landscape.","limitations":"Cross-sectional design cannot determine whether nausea caused cannabis use or other factors explain both. Michigan-specific findings may not generalize. Self-reported cannabis use likely underestimates prevalence. Does not assess neonatal outcomes."},{"rthcId":"RTHC-04996","title":"Cannabis use and gastrointestinal tract illnesses: The National Health and Nutrition Examination Surveys, 2005-2018.","authors":"Vanderziel, Alyssa; Alshaarawy, Omayma","year":2023,"journal":"Drug and alcohol review, 42(4), 785-790","doi":"10.1111/dar.13609","pmid":"36734018","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was associated with lower odds of some gastrointestinal tract illnesses in a large nationally representative sample. This contrasts with increasing reports of cannabinoid hyperemesis syndrome among heavy users.","whyItMatters":"The relationship between cannabis and the gut is paradoxical: it has antiemetic properties used in chemotherapy but can also cause severe vomiting in heavy users. Large population-level data helps map this complex relationship.","specificNumbers":"NHANES 2005-2018 data. Non-pregnant adults ages 20-59 without cancer or HIV (approximately 18,000+ participants). Cannabis use associated with reduced odds of certain GI illnesses.","methodology":"Cross-sectional analysis of NHANES data (2005-2018). Included non-pregnant adults ages 20-59 without cancer or HIV (n~18,000+). Examined associations between cannabis use and GI illness.","limitations":"Cross-sectional NHANES data cannot establish causation. Self-reported cannabis use and GI diagnoses. Healthy user bias possible (sicker people may avoid cannabis). Cannot distinguish cannabis use patterns (frequency, method, potency). Cannabinoid hyperemesis likely underdiagnosed in survey data."},{"rthcId":"RTHC-04997","title":"Effects of Smoking Marijuana on the Respiratory System: A Systematic Review.","authors":"Vásconez-González, Jorge; Delgado-Moreira, Karen; López-Molina, Belén; Izquierdo-Condoy, Juan S; Gámez-Rivera, Esteban; Ortiz-Prado, Esteban","year":2023,"journal":"Substance abuse, 44(3), 249-260","doi":"10.1177/08897077231186228","pmid":"37728136","tags":["respiratory","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Marijuana smoking exposes lungs to combustion byproducts that cause airway inflammation, chronic bronchitis symptoms, and possible emphysematous changes. Evidence for associations with asthma, COPD, and pneumonia was also identified.","whyItMatters":"As marijuana legalization increases use, understanding respiratory risks is critical. The perception that marijuana smoke is less harmful than tobacco smoke persists despite evidence of significant respiratory irritation.","specificNumbers":"Review covered respiratory outcomes including asthma, pneumonia, emphysema, COPD, and chronic bronchitis. Marijuana combustion produces harmful byproducts similar to tobacco smoke.","methodology":"Systematic review of published literature on respiratory effects of marijuana smoking. Examined outcomes including airway inflammation, bronchitis, asthma, COPD, emphysema, pneumonia, and lung function changes.","limitations":"Many included studies did not adequately control for concurrent tobacco use. Varying definitions of marijuana use frequency across studies. Limited long-term data. Does not address non-smoked cannabis routes."},{"rthcId":"RTHC-04998","title":"Trends in Illicit Cannabis Potency based on the Analysis of Law Enforcement Seizures in the Southern Area of Rome.","authors":"Vernich, Francesca; Stefani, Lucrezia; Fiorelli, Denise; Mineo, Federico; Pallocci, Margherita; Treglia, Michele; Marsella, Luigi Tonino; Tittarelli, Roberta","year":2023,"journal":"Toxics, 11(8)","doi":"10.3390/toxics11080648","pmid":"37624154","tags":["potency","psychosis","depression","anxiety","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The potency escalation in cannabis isn't just a North American phenomenon. This study analyzed over 1,000 hashish samples seized by law enforcement in the southern Rome area between 2015 and 2022, documenting a dramatic increase in THC concentration.\n\nAverage THC content rose from 13.7% in 2015 to 27.1% in 2022 — nearly doubling in seven years. Some samples with unusual shapes and colors tested above 24%, and a few exceeded 40% THC. This is illicit market cannabis (Italy has not legalized recreational use), meaning these concentrations are being achieved without the quality controls or labeling of regulated markets.\n\nThe age group most associated with seizures was males aged 15-36, highlighting that the highest-potency products are reaching the demographic most vulnerable to cannabis-related mental health effects. The authors connect this potency trend to the growing body of research linking high-potency cannabis to psychosis, depression, anxiety, and cannabis use disorders in young adults.\n\nThe data also revealed that potency wasn't just increasing on average — the upper end of the distribution was pushing into territory that would have been almost unheard of a decade ago. These super-potent samples represent a qualitatively different product than what most research has studied.","whyItMatters":"Potency matters because dose determines risk. A joint of 27% THC hashish delivers nearly twice the THC of the same amount of 14% hashish. If health risks — psychosis, dependence, cognitive effects — are dose-dependent (and evidence increasingly says they are), then the same amount of cannabis use in 2022 carries roughly twice the risk it did in 2015. This European data point is critical because it shows potency escalation is a global trend, not a quirk of the U.S. or Canadian legal markets.","specificNumbers":"Over 1,000 hashish samples analyzed. Average THC: 13.7% (2015) → 27.1% (2022). Some samples exceeded 40% THC. Most seizures involved males aged 15-36. Study period: 2015-2022 in the southern Rome area. This is illicit market cannabis — Italy has not legalized recreational use.","methodology":"Observational analysis of over 1,000 hashish (cannabis resin) samples seized by law enforcement in the southern Rome area from 2015 to 2022. THC concentration was measured for each sample. Data analyzed for trends over time and by demographic characteristics of individuals involved in seizures.","limitations":"Law enforcement seizures are not a random sample of all cannabis in circulation — they may overrepresent larger quantities or specific trafficking routes. The study only analyzed hashish (resin), not herbal cannabis (marijuana), which may have different potency trends. No data on what consumers actually smoke per session (higher potency could lead to titration — using less per session). Southern Rome may not represent all Italian or European markets. No direct health outcome data — the link between rising potency and health effects is inferred from other research."},{"rthcId":"RTHC-04999","title":"Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy.","authors":"Vicino, Walter; Muccioli, Lorenzo; Pondrelli, Federica; Licchetta, Laura; Stipa, Carlotta; Mostacci, Barbara; Vito, Lidia Di; Ferri, Lorenzo; Cancellerini, Chiara; Sold, Martina; Tinuper, Paolo; Bisulli, Francesca","year":2023,"journal":"Seizure, 111, 39-41","doi":"10.1016/j.seizure.2023.07.009","pmid":"37506564","tags":["cbd","epilepsy"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"In routine clinical practice, CBD produced clinically meaningful seizure reduction (>30%) in a substantial proportion of patients. Super-responders (>80% reduction) were also identified. Most adverse events were mild.","whyItMatters":"RCT data shows CBD works for specific epilepsy syndromes, but real-world effectiveness across broader epilepsy populations is less documented. This study fills that gap.","specificNumbers":"Patients prescribed CBD from March 2019 to November 2022. Evaluated at 3, 6, and 12 months. Responders: >30% seizure reduction. Super-responders: >80% reduction. Most adverse events mild.","methodology":"Retrospective observational study of epilepsy patients prescribed CBD between March 2019 and November 2022 with at least 3 months follow-up. Assessed at baseline, 3, 6, and 12 months. Responders defined as >30% seizure reduction; super-responders as >80%.","limitations":"Retrospective design with no control group. Cannot attribute improvement to CBD versus natural seizure fluctuation or other treatment changes. Varied epilepsy etiologies and co-medications. Follow-up completeness may vary."},{"rthcId":"RTHC-05000","title":"Decoding the link between substance dependence and attention deficit hyperactivity disorder in adults: A cross-sectional study from North India.","authors":"Victor, Robin; Gondwal, Rohit; Avinash, Priyaranjan; Singhania, Rachit","year":2023,"journal":"Industrial psychiatry journal, 32(2), 397-401","doi":"10.4103/ipj.ipj_47_23","pmid":"38161447","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"ADHD was found at elevated rates among patients with various substance dependencies, including cannabis dependence. The study explored relationships between specific substance types and ADHD symptom patterns.","whyItMatters":"The ADHD-substance dependence comorbidity is well-documented in Western populations but understudied in South Asian settings. Cannabis is one of the most common substances of abuse in India, making this overlap clinically relevant.","specificNumbers":"153 patients with substance dependence from a North Indian tertiary hospital. ADHD assessed alongside cannabis, opioid, and other substance dependencies.","methodology":"Cross-sectional single-interview study at a tertiary care hospital. 153 consecutive patients with substance dependence diagnoses assessed for ADHD over 3 months.","limitations":"Single-center, cross-sectional design. Small sample. Self-report ADHD assessment may be less reliable in substance-using populations. Cannot determine whether ADHD preceded substance dependence. Indian substance use patterns may differ from other regions."},{"rthcId":"RTHC-05001","title":"Cannabis Use Associations with Adverse Psychosocial Functioning among North American College Students.","authors":"Vidal, Carol; Alvarez, Patty; Hammond, Christopher J; Lilly, Flavius R W","year":2023,"journal":"Substance use & misuse, 58(13), 1771-1779","doi":"10.1080/10826084.2023.2247075","pmid":"37584421","tags":["youth","mental-health","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use among college-enrolled young adults was associated with adverse psychosocial outcomes across multiple domains. The findings extend what is known about adolescent-onset cannabis use into the college-age population where use peaks.","whyItMatters":"Cannabis use peaks between ages 18-22, coinciding with college. Understanding whether the adverse psychosocial associations documented in adolescents persist into this age group is important for campus health policies.","specificNumbers":"North American college student sample. Cannabis use associated with adverse outcomes across multiple psychosocial domains during the peak-use age window (18-22).","methodology":"Cross-sectional study examining relationships between cannabis use and multiple psychosocial functioning domains among college students in North America.","limitations":"Cross-sectional design cannot establish causation. College students who use cannabis may differ from non-users in pre-existing ways. Self-reported measures. Cannot determine whether cannabis use preceded psychosocial difficulties."},{"rthcId":"RTHC-05002","title":"Systematic combinations of major cannabinoid and terpene contents in Cannabis flower and patient outcomes: a proof-of-concept assessment of the Vigil Index of Cannabis Chemovars.","authors":"Vigil, Jacob Miguel; Stith, Sarah See; Brockelman, Franco; Keeling, Keenan; Hall, Branden","year":2023,"journal":"Journal of cannabis research, 5(1), 4","doi":"10.1186/s42238-022-00170-9","pmid":"36755303","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"low","keyFinding":"The Vigil Index of Cannabis Chemovars created a scalable classification system combining major cannabinoid and terpene contents. The most commonly consumed chemovars showed different effectiveness profiles and side effect patterns across 204 users.","whyItMatters":"The cannabis market treats products as interchangeable within broad categories (indica, sativa, hybrid). A chemistry-based classification system could help patients and clinicians identify which specific formulations work for their needs.","specificNumbers":"204 users from 2016-2021 tracked via mobile app. Cannabis flower classified by cannabinoid and terpene content into chemovars. Different chemovars associated with distinct treatment effectiveness and side effect profiles.","methodology":"Observational study using a mobile app. 204 people tracked cannabis flower consumption between 2016-2021. Cannabis products were classified by cannabinoid and terpene profiles into chemovars. Patient-reported outcomes compared across chemovar categories.","limitations":"Small, self-selected sample of app users. Non-randomized, observational design. Cannabis product testing may not be perfectly accurate. Patient-reported outcomes are subjective. Chemovar categories may oversimplify complex plant chemistry."},{"rthcId":"RTHC-05003","title":"Prevalence of ∆8-tetrahydrocannabinol carboxylic acid in workplace drug testing.","authors":"Vikingsson, Svante; Hart, E Dale; Winecker, Ruth E; Cone, Edward J; Kuntz, David J; Clark, Michael; Jacques, Martin; Hayes, Eugene D; Flegel, Ronald R","year":2023,"journal":"Journal of analytical toxicology, 47(8), 719-725","doi":"10.1093/jat/bkad068","pmid":"37697897","tags":["workplace","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Delta-8 THC has gone from obscure cannabinoid to widespread consumer product almost overnight, and this study shows it's already creating a significant presence in workplace drug testing. The researchers analyzed 1,504 urine specimens that had tested positive on initial cannabinoid immunoassay screening, using advanced LC-MS-MS to distinguish between delta-8 and delta-9 THC metabolites.\n\nThe results split into three clear groups. The majority — 76% — were delta-9 THC dominant (traditional cannabis). Another 11% were delta-8 THC dominant, indicating people using exclusively or primarily delta-8 products. The remaining 13% showed a mixture of both, suggesting use of both delta-8 and conventional cannabis products.\n\nAltogether, about 1 in 4 positive workplace tests contained delta-8 THC metabolites. This is remarkable given that delta-8 was virtually unknown to consumers just a few years ago.\n\nA practical finding for drug testing programs: delta-8 and delta-9 THC metabolites reached similar urine concentrations (median 150 vs 187 ng/mL), supporting the use of similar cutoffs and decision rules for both. Standard immunoassay tests can't distinguish between them — both trigger a positive cannabinoid result. Only confirmatory testing with mass spectrometry can identify which type of THC was used.\n\nFor employees in states where delta-8 is legal but delta-9 isn't, this creates a legal gray zone: their drug test may come back positive despite using what they believe is a legal product.","whyItMatters":"Workplace drug testing programs weren't designed to distinguish between delta-8 and delta-9 THC. With delta-8 now showing up in a quarter of positive tests, employers and medical review officers face a practical problem: a positive test may reflect use of a product that's legal in the employee's state. This data forces a rethinking of how workplace cannabinoid testing is interpreted and what constitutes a 'positive' result in the delta-8 era.","specificNumbers":"1,504 cannabinoid-positive urine specimens analyzed. 964 (76%) delta-9 dominant. 164 (11%) delta-8 dominant. 376 (13%) mixed. Combined delta-8 prevalence: ~25% of positive tests. Median concentrations: delta-9 THC-COOH 187 ng/mL, delta-8 THC-COOH 150 ng/mL (similar, supporting comparable cutoffs).","methodology":"Observational study analyzing 1,504 urine specimens with positive cannabinoid immunoassay screening results from workplace drug testing. Specimens were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS-MS) quantifying 15 cannabinoid analytes after hydrolysis, allowing differentiation between delta-8 and delta-9 THC metabolites. Specimens were categorized as delta-9 dominant (>90% delta-9), delta-8 dominant (>90% delta-8), or mixed.","limitations":"The 1,504 specimens were already cannabinoid-positive on immunoassay, so this study measures delta-8 prevalence among positive tests, not among all workers tested. No information on the legal status of delta-8 in each employee's jurisdiction. No clinical or impairment data — can't determine whether delta-8 users were impaired at work. Single laboratory dataset — geographic distribution of specimens not described. The rapid evolution of the delta-8 market means prevalence may have changed since the study period."},{"rthcId":"RTHC-05004","title":"Attention-deficit/hyperactivity disorder (ADHD) symptoms and their relation to diagnosed ADHD, sociodemographic characteristics, and substance use among patients receiving opioid agonist therapy: a Norwegian cohort study.","authors":"Vold, Jørn Henrik; Halmøy, Anne; Chalabianloo, Fatemeh; Pierron, Marianne Cook; Løberg, Else-Marie; Johansson, Kjell Arne; Fadnes, Lars Thore","year":2023,"journal":"BMC psychiatry, 23(1), 479","doi":"10.1186/s12888-023-04980-w","pmid":"37386438","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05005","title":"Collisions and cannabis: Measuring the effect of recreational marijuana legalization on traffic crashes in Washington State.","authors":"Voy, Annie","year":2023,"journal":"Traffic injury prevention, 24(7), 527-535","doi":"10.1080/15389588.2023.2220853","pmid":"37347154","tags":["legalization","driving"],"studyType":"quasi-experimental","evidenceStrength":"moderate","keyFinding":"Traffic collisions increased following both the legalization of recreational cannabis and the opening of retail stores in Washington State. The commercialization phase (retail sales) showed a stronger association with crash increases than legalization alone.","whyItMatters":"As more states legalize cannabis, understanding the traffic safety implications is critical for policy design. Washington was among the first to legalize, providing the longest available data window.","specificNumbers":"Washington legalized recreational cannabis December 6, 2012. Retail stores opened approximately 19 months later. County-level monthly crash data analyzed. Both events associated with increased collisions.","methodology":"Interrupted time series analysis using county-level monthly vehicle crash data from the Washington State Department of Transportation. Measured the impact of two events: legalization (December 2012) and retail commercialization (~19 months later).","limitations":"Ecological study cannot link crashes to individual cannabis use. Other factors changing simultaneously (e.g., economic conditions, tourism, smartphone use) may confound results. Pre-legalization cannabis use was already common. Cannot distinguish cannabis-impaired crashes from general crash increases."},{"rthcId":"RTHC-05006","title":"Concordance between substance use self-report and hair analysis in community-based adolescents.","authors":"Wade, Natasha E; Sullivan, Ryan M; Tapert, Susan F; Pelham, William E; Huestis, Marilyn A; Lisdahl, Krista M; Haist, Frank","year":2023,"journal":"The American journal of drug and alcohol abuse, 49(1), 76-84","doi":"10.1080/00952990.2023.2164931","pmid":"36812240","tags":["youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Hair toxicology detected substance use (including cannabis) in adolescents who denied use on self-report surveys. Concordance between the two methods was limited, suggesting self-report underestimates true substance use in youth.","whyItMatters":"Most adolescent cannabis research relies on self-report. If teens significantly underreport use, studies may underestimate both prevalence and the associations between cannabis and health outcomes.","specificNumbers":"ABCD Study sample. Hair analysis by LC-MS/MS and GC-MS/MS compared with self-reported past-year substance use. Discordance identified between methods, particularly for cannabis.","methodology":"Cross-sectional analysis from the ABCD Study comparing self-reported past-year substance use with hair toxicological analysis (LC-MS/MS and GC-MS/MS) in community-based adolescents.","limitations":"Hair testing has its own limitations: external contamination, variable drug incorporation by hair color and type, and limited detection window for some substances. Cross-sectional comparison at one time point. Not all ABCD participants had hair samples available."},{"rthcId":"RTHC-05007","title":"Clouding Up Cognition? Secondhand Cannabis and Tobacco Exposure Related to Cognitive Functioning in Youth.","authors":"Wade, Natasha E; McCabe, Connor J; Wallace, Alexander L; Gonzalez, Marybel R; Hoh, Eunha; Infante, M Alejandra; Mejia, Margie Hernandez; Haist, Frank","year":2023,"journal":"Biological psychiatry global open science, 3(2), 233-242","doi":"10.1016/j.bpsgos.2022.01.010","pmid":"37124351","tags":["youth","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Secondhand cannabis and tobacco exposure in youth were independently associated with lower cognitive performance across multiple domains, suggesting passive exposure may carry cognitive risks during brain development.","whyItMatters":"As cannabis legalization increases, more children may be exposed to secondhand cannabis smoke. If passive exposure affects cognition during critical brain development periods, it has major implications for household cannabis policies.","specificNumbers":"N=5,580 youth from ABCD Study. Both secondhand cannabis and tobacco exposure associated with lower cognitive performance scores.","methodology":"Cross-sectional analysis of ABCD Study year-2 follow-up data (N=5,580, 48% female). Assessed cognitive performance in relation to secondhand or environmental exposure to cannabis and tobacco smoke.","limitations":"Cross-sectional design cannot establish causation. Exposure was likely measured via self/parent report. Children exposed to secondhand smoke may differ from unexposed children in many ways (family socioeconomic status, other environmental exposures). Cannot distinguish direct effects of smoke exposure from correlated household factors."},{"rthcId":"RTHC-05008","title":"Prices and Purchase Sources for Dried Cannabis Flower in the United States, 2019-2020.","authors":"Wadsworth, Elle; Driezen, Pete; Pacula, Rosalie Liccardo; Kilmer, Beau; Hammond, David","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 923-932","doi":"10.1089/can.2021.0232","pmid":"35363550","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis prices and purchasing patterns differed significantly across states with different legal frameworks. Consumers in legal states had more options and different price structures than those in medical-only or prohibition states.","whyItMatters":"Cannabis pricing affects public health through accessibility, competition with illegal markets, and tax revenue. Understanding how legal frameworks shape pricing informs policy optimization.","specificNumbers":"Survey data from 2019 and 2020. US respondents ages 16-65 who purchased dried cannabis flower. Prices and sources compared across states with legal, medical-only, and illegal frameworks.","methodology":"Repeat cross-sectional survey data from the International Cannabis Policy Study (2019-2020). US respondents ages 16-65 recruited through online panels who purchased dried cannabis flower. Analyzed prices and sources by state legal status.","limitations":"Online panel survey may not be representative. Self-reported prices subject to recall errors. Cannabis market conditions change rapidly. 2019-2020 data may not reflect current markets. Cannot verify purchase amounts or prices."},{"rthcId":"RTHC-05009","title":"Proximity to Legal Cannabis Stores in Canada and Use of Cannabis Sources in the First Three Years of Legalization, 2019-2021.","authors":"Wadsworth, Elle; Driezen, Pete; Dilley, Julia A; Gabrys, Robert; Jesseman, Rebecca; Hammond, David","year":2023,"journal":"Journal of studies on alcohol and drugs, 84(6), 852-862","doi":"10.15288/jsad.22-00427","pmid":"37306374","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Distance to the nearest legal cannabis retail store was significantly associated with cannabis sourcing. Respondents living closer to legal stores were more likely to purchase from legal sources, while those farther away used informal or illegal sources more frequently.","whyItMatters":"A key goal of Canadian legalization was transitioning consumers from illegal to legal markets. This study shows physical access to legal stores is a major determinant of whether that transition happens.","specificNumbers":"15,311 past-year cannabis consumers surveyed 2019-2021. Distance to nearest legal store was significantly associated with source choice. Closer proximity = more legal purchasing.","methodology":"Cross-sectional analysis of Canadian respondents in the International Cannabis Policy Study (2019-2021). 15,311 past-12-month cannabis consumers. Assessed distance to nearest legal retail store and cannabis purchasing sources.","limitations":"Repeat cross-sectional design, not longitudinal tracking of individuals. Store proximity calculated from home address, not accounting for work or travel patterns. Other factors (price, product quality, convenience) also influence sourcing. Cannot confirm self-reported source accuracy."},{"rthcId":"RTHC-05010","title":"Legal sourcing of ten cannabis products in the Canadian cannabis market, 2019-2021: a repeat cross-sectional study.","authors":"Wadsworth, Elle; Rynard, Vicki; Driezen, Pete; Freeman, Tom P; Rychert, Marta; Wilkins, Chris; Hall, Wayne; Gabrys, Robert; Hammond, David","year":2023,"journal":"Harm reduction journal, 20(1), 19","doi":"10.1186/s12954-023-00753-6","pmid":"36803833","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Legal sourcing varied by product type (dried flower sourced legally more often than edibles or concentrates), by province, and by use frequency. Frequent users were less likely to source legally than occasional users.","whyItMatters":"Canada's legalization aimed to move consumers to the legal market, but the transition is uneven across products. Understanding which products lag in legal sourcing helps regulators target interventions.","specificNumbers":"15,311 consumers surveyed. 10 cannabis product categories examined. Dried flower had higher legal sourcing rates than edibles or concentrates. Frequent users sourced less legally than occasional users.","methodology":"Repeat cross-sectional survey of 15,311 past-12-month cannabis consumers in Canada from the International Cannabis Policy Study (2019-2021). Examined legal sourcing across 10 cannabis product categories.","limitations":"Self-reported purchasing sources. Cannot verify legal vs. illegal classification. Online panel may not represent all cannabis consumers. Market conditions evolved rapidly during the study period."},{"rthcId":"RTHC-05011","title":"Clearing cannabis criminal records: A survey of criminal record expungement availability and accessibility among US States and Washington DC that decriminalized or legalized cannabis.","authors":"Wakefield, Tanner; Bialous, Stella; Apollonio, Dorie E","year":2023,"journal":"The International journal on drug policy, 114, 103983","doi":"10.1016/j.drugpo.2023.103983","pmid":"36863286","tags":["legalization"],"studyType":"review","evidenceStrength":"low","keyFinding":"Most states that decriminalized or legalized cannabis provided some form of criminal record clearing, but approaches ranged from automatic expungement to petition-based processes requiring legal assistance. Accessibility and scope of relief varied significantly.","whyItMatters":"Millions of Americans carry cannabis-related criminal records that affect employment, housing, and education. If legalization does not address existing records, it creates a two-tier system where past criminalization continues to harm communities.","specificNumbers":"39 states and DC surveyed. Record relief options ranged from automatic expungement to petition-based processes. Availability and accessibility varied significantly across jurisdictions.","methodology":"Survey of criminal record expungement availability and accessibility across 39 US states and Washington DC where cannabis was decriminalized or legalized as of 2022.","limitations":"Legal landscape survey captures a snapshot in time. Legislation changes rapidly. Does not measure actual utilization rates or outcomes for people who pursue expungement. Does not assess effectiveness of automatic vs. petition-based approaches."},{"rthcId":"RTHC-05012","title":"Descriptive cross-sectional survey of tobacco and cannabis restrictions on state and local film incentives in the USA.","authors":"Wakefield, Tanner D; Guillory, Jamie; Ling, Pamela; Apollonio, Dorie E","year":2023,"journal":"Tobacco control","doi":"10.1136/tc-2023-058197","pmid":"37989585","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"very-low","keyFinding":"Virtually no state or local film incentive programs in the US had established funding restrictions to deter cannabis or tobacco depictions, despite evidence linking media exposure to youth substance initiation.","whyItMatters":"Media depictions of substance use normalize these behaviors for young audiences. Film incentive restrictions represent an untested policy lever for reducing on-screen cannabis and tobacco portrayals.","specificNumbers":"Surveyed US states and localities with film incentive programs. Found almost no programs with cannabis or tobacco depiction restrictions.","methodology":"Descriptive cross-sectional survey of state and local film incentive programs across the US. Examined whether programs had established restrictions on tobacco or cannabis depictions as a condition of public funding.","limitations":"Descriptive survey without outcome data. Cannot demonstrate that restricting film incentives would reduce depictions or influence youth behavior. Policy landscape evolves. Does not account for streaming content outside traditional film incentive structures."},{"rthcId":"RTHC-05013","title":"High-CBD cannabis extracts inhibit the expression of proinflammatory factors via miRNA-mediated silencing in human small intestinal epithelial cells.","authors":"Wang, Bo; Li, Dongping; Fiselier, Anna; Kovalchuk, Igor; Kovalchuk, Olga","year":2023,"journal":"Heliyon, 9(8), e18817","doi":"10.1016/j.heliyon.2023.e18817","pmid":"37664748","tags":["cbd","inflammation","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The gut is increasingly recognized as a key site where cannabis compounds interact with the body, and inflammatory bowel conditions affect millions of people worldwide. This study tested whether high-CBD cannabis extracts could reduce inflammation in human small intestinal epithelial cells, and investigated the mechanism at the molecular level.\n\nFive different high-CBD extracts were tested on intestinal cells that had been stimulated with TNF-alpha and interferon-gamma — mimicking the inflammatory conditions seen in diseases like Crohn's and ulcerative colitis. All five extracts suppressed COX-2, a central inflammatory enzyme (the same one targeted by ibuprofen and other NSAIDs). They also increased SOCS3, a natural anti-inflammatory protein.\n\nThe novel finding was the mechanism: the extracts reduced pro-inflammatory cytokines IL-6 and IL-8 through specific microRNAs — miR-760 and miR-302c-3p. MicroRNAs are small RNA molecules that silence gene expression, and this miRNA-mediated pathway represents a deeper level of immune regulation than simply blocking a single inflammatory molecule.\n\nHowever, the study also found a concerning dose-dependent effect: at higher concentrations, the cannabis extracts inhibited cell growth. This dual nature — anti-inflammatory at moderate doses, growth-inhibiting at high doses — is important for understanding both the therapeutic potential and safety limits of CBD-based gut treatments.","whyItMatters":"Inflammatory bowel diseases are growing worldwide and current treatments have significant limitations. If CBD-based therapies can target gut inflammation through miRNA pathways, they could complement or offer alternatives to existing approaches. The miRNA mechanism is particularly interesting because it suggests a more fundamental regulation of inflammation rather than just suppressing surface-level symptoms.","specificNumbers":"Five high-CBD cannabis extracts tested. All five suppressed COX-2 and increased SOCS3. Four of five reduced IL-6 and/or IL-8 through miR-760 and miR-302c-3p mediated silencing. High-dose extracts inhibited cell growth. Individual extract components influenced IL-8 both alone and in combination.","methodology":"In vitro study using human small intestinal epithelial cells (HSIEC) stimulated with TNF-alpha/IFN-gamma to model inflammation. Five high-CBD cannabis extracts tested for effects on COX-2, SOCS3, IL-6, IL-8, and cell growth. MicroRNA profiling identified miR-760 and miR-302c-3p as mediators. Individual prevalent components tested both alone and in combination.","limitations":"In vitro study — intestinal cells in a dish don't replicate the complexity of a living gut with its microbiome, immune cells, and multiple tissue layers. High-dose growth inhibition raises safety questions that need in vivo testing. The five extracts were high-CBD but not pure CBD — other compounds in the extracts may contribute to effects. Concentrations tested may not reflect what reaches intestinal cells after oral CBD consumption. No disease model — the TNF/IFN stimulation mimics inflammation broadly, not a specific bowel disease."},{"rthcId":"RTHC-05014","title":"Assessment of clinical outcomes in patients with fibromyalgia: Analysis from the UK Medical Cannabis Registry.","authors":"Wang, Claire; Erridge, Simon; Holvey, Carl; Coomber, Ross; Usmani, Azfer; Sajad, Mohammed; Guru, Rahul; Holden, Wendy; Rucker, James J; Platt, Michael W; Sodergren, Mikael H","year":2023,"journal":"Brain and behavior, 13(7), e3072","doi":"10.1002/brb3.3072","pmid":"37199833","tags":["medical-cannabis","pain"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Patients prescribed cannabis-based medicinal products for fibromyalgia showed statistically significant improvements in patient-reported outcome measures (PROMs) for health-related quality of life after at least one month of treatment.","whyItMatters":"Fibromyalgia has limited treatment options and significantly impairs quality of life. Real-world registry data from the UK provides additional evidence beyond clinical trials for the potential role of medical cannabis.","specificNumbers":"UK Medical Cannabis Registry patients with fibromyalgia. Minimum 1 month of CBMP treatment. Statistically significant improvements in validated PROMs (p<0.050).","methodology":"Retrospective analysis of the UK Medical Cannabis Registry. Identified patients prescribed cannabis-based medicinal products (CBMPs) for fibromyalgia with minimum one month of follow-up. Assessed changes in validated PROMs and adverse event incidence.","limitations":"Registry data without a control group. Patients self-selected into treatment. Placebo effect cannot be ruled out. Short minimum follow-up (1 month). Heterogeneous cannabis products prescribed. May not generalize to other healthcare systems."},{"rthcId":"RTHC-05015","title":"Phencyclidine Positivity on Urine Drug Screening in Patients Treated for Alcohol Withdrawal on a Dual-diagnosis Medically Assisted Withdrawal Unit.","authors":"Wang, Philip R; Dore, Samyukta; Weleff, Jeremy; Butler, Robert S; Barnett, Brian S","year":2023,"journal":"Journal of addiction medicine, 17(6), 695-701","doi":"10.1097/ADM.0000000000001217","pmid":"37934534","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05016","title":"Effects of sub-chronic nabiximols on biological markers of individuals undergoing a clinical trial for the treatment of cannabis use disorder.","authors":"Wang, Ruoyu; Trigo, Jose M; Le Foll, Bernard","year":2023,"journal":"American journal of translational research, 15(8), 5228-5238","doi":null,"pmid":"37692969","tags":["addiction","quitting"],"studyType":"secondary-analysis","evidenceStrength":"moderate","keyFinding":"Sub-chronic exposure to nabiximols at doses higher than typically used for MS treatment did not produce clinically significant changes in biological markers. Laboratory values for liver function, metabolic parameters, and other clinical measures remained stable.","whyItMatters":"Treating cannabis use disorder with nabiximols likely requires higher doses than MS treatment due to tolerance. Demonstrating safety at these elevated doses is essential before larger efficacy trials can proceed.","specificNumbers":"Higher-than-standard nabiximols doses used for CUD treatment. Biological markers including liver function tests monitored throughout treatment. No clinically significant changes observed.","methodology":"Secondary analysis of biological marker data from a clinical trial using nabiximols for cannabis use disorder. Monitored liver function, metabolic markers, and other clinical laboratory values during treatment with higher-than-standard doses.","limitations":"Secondary analysis from a trial likely with a small sample. Short treatment duration (sub-chronic). Does not address long-term safety. Biological markers are only one aspect of safety (does not capture subjective side effects or behavioral outcomes). Population with CUD may tolerate cannabinoids differently than MS patients."},{"rthcId":"RTHC-05017","title":"Theoretical exploration and experimental regulation of the degradation of Δ9-tetrahydrocannabinol in hemp seed oil by density functional theory.","authors":"Wang, Tong; Wang, Ning; Wang, Minghao; Wang, Liqi; Shi, Yongge; Du, Jing; Yu, Dianyu","year":2023,"journal":"Food research international (Ottawa, Ont.), 170, 112996","doi":"10.1016/j.foodres.2023.112996","pmid":"37316068","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05018","title":"An overview on synthetic and biological activities of cannabidiol (CBD) and its derivatives.","authors":"Wang, Xiuli; Zhang, Huanbang; Liu, Yan; Xu, Yang; Yang, Bingyou; Li, Hua; Chen, Lixia","year":2023,"journal":"Bioorganic chemistry, 140, 106810","doi":"10.1016/j.bioorg.2023.106810","pmid":"37659147","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05019","title":"Transesterification of Indazole-3-carboxamide Synthetic Cannabinoids: Identification of Metabolite Biomarkers for Diagnosing Co-abuse of 5F-MDMB-PINACA and Alcohol.","authors":"Wang, Ziteng; Fong, Ching Yee; Goh, Evelyn Mei Ling; Moy, Hooi Yan; Chan, Eric Chun Yong","year":2023,"journal":"Journal of analytical toxicology, 46(9), 1016-1024","doi":"10.1093/jat/bkab121","pmid":"34918103","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05020","title":"Substance-related cross-commodity purchase tasks: A systematic review.","authors":"Weinsztok, Sarah C; Reed, Derek D; Amlung, Michael","year":2023,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 37(1), 72-86","doi":"10.1037/adb0000851","pmid":"35787100","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05021","title":"Metabolomic analysis of methyl jasmonate treatment on phytocannabinoid production in Cannabis sativa.","authors":"Welling, Matthew T; Deseo, Myrna A; O'Brien, Martin; Clifton, Jacob; Bacic, Antony; Doblin, Monika S","year":2023,"journal":"Frontiers in plant science, 14, 1110144","doi":"10.3389/fpls.2023.1110144","pmid":"37025140","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05022","title":"Roadside screening tests for cannabis use: A systematic review.","authors":"Wennberg, Erica; Windle, Sarah B; Filion, Kristian B; Thombs, Brett D; Gore, Genevieve; Benedetti, Andrea; Grad, Roland; Ells, Carolyn; Eisenberg, Mark J","year":2023,"journal":"Heliyon, 9(4), e14630","doi":"10.1016/j.heliyon.2023.e14630","pmid":"37064483","tags":["driving"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Available roadside screening devices, primarily oral fluid-based, can detect THC presence but their ability to identify functional impairment is limited. Sensitivity and specificity varied across devices and cutoff thresholds.","whyItMatters":"As cannabis legalization expands, effective roadside screening is essential for traffic safety. Unlike alcohol, where breathalyzers directly measure impairment-related blood alcohol levels, cannabis detection does not straightforwardly indicate impairment.","specificNumbers":"Multiple roadside screening devices evaluated. Oral fluid testing was the primary modality. Sensitivity and specificity varied by device and THC cutoff threshold.","methodology":"Systematic review of six databases (inception to March 2020) and grey literature. Included primary studies evaluating test characteristics of roadside cannabis screening compared to laboratory confirmation testing.","limitations":"Literature search through March 2020 may miss newer devices. Varied study designs and reference standards across included studies. Roadside conditions differ from laboratory settings. Cannot validate impairment detection, only THC presence detection."},{"rthcId":"RTHC-05023","title":"Cannabis and Psychosis.","authors":"West, Michelle L; Sharif, Shadi","year":2023,"journal":"Child and adolescent psychiatric clinics of North America, 32(1), 69-83","doi":"10.1016/j.chc.2022.07.004","pmid":"36410907","tags":["psychosis","mental-health","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis use is associated with increased risk of psychotic symptoms (both subthreshold and full), exacerbation of psychosis in vulnerable youth, and worse outcomes in established psychotic disorders. Integrated treatment addressing both cannabis and psychosis shows the most promise.","whyItMatters":"Cannabis use and psychosis onset both peak in adolescence and young adulthood. Understanding how they interact is critical for prevention and for treating the growing number of young people with co-occurring cannabis use and psychotic symptoms.","specificNumbers":"Review covers both attenuated (subthreshold) and acute psychotic symptoms. Cannabis use increases risk for psychosis onset and worsens outcomes in those with existing psychotic disorders.","methodology":"Narrative review of research on the overlap between cannabis use and psychosis in young people, covering risk relationships, mechanisms, and treatment approaches.","limitations":"Narrative review without systematic methodology. Cannot provide pooled effect estimates. Covers a broad topic with varied evidence quality across subtopics."},{"rthcId":"RTHC-05024","title":"Longitudinal Examination of Sexual Risk Behavior in College Students With and Without Attention-Deficit/Hyperactivity Disorder.","authors":"Weyandt, Lisa; DuPaul, George J; Shepard, Emily; Labban, Jeffrey D; Francis, Alyssa; Beatty, Avery; Anastopoulos, Arthur D","year":2023,"journal":"Archives of sexual behavior, 52(8), 3505-3519","doi":"10.1007/s10508-023-02660-0","pmid":"37548880","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05025","title":"Cannabis Use Patterns and Whole-Blood Cannabinoid Profiles of Emergency Department Patients With Suspected Cannabinoid Hyperemesis Syndrome.","authors":"Wightman, Rachel S; Metrik, Jane; Lin, Timmy R; Li, Yu; Badea, Adina; Almeida, Robert; Collins, Alexandra B; Beaudoin, Francesca L","year":2023,"journal":"Annals of emergency medicine, 82(2), 121-130","doi":"10.1016/j.annemergmed.2023.03.005","pmid":"37479395","tags":["harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"low","keyFinding":"Whole-blood cannabinoid profiles differed between symptomatic and asymptomatic periods in patients with suspected CHS, providing biological data to complement clinical diagnosis. Detailed cannabis use patterns (frequency, mode, product type) were characterized.","whyItMatters":"CHS diagnosis relies on clinical criteria, and blood cannabinoid data could improve diagnostic accuracy. Understanding which use patterns and cannabinoid profiles are associated with symptoms helps identify at-risk users.","specificNumbers":"ED patients with symptomatic cyclic vomiting after chronic cannabis use enrolled. Whole-blood cannabinoid profiles measured during both symptomatic and asymptomatic periods. Cannabis use patterns including frequency, mode, and product type characterized.","methodology":"Prospective observational cohort study recruiting ED patients during symptomatic CHS episodes. Characterized detailed cannabis use patterns and measured whole-blood cannabinoid profiles during symptomatic and asymptomatic periods.","limitations":"Small prospective cohort from ED recruitment. Suspected CHS diagnosis (not always confirmed). Blood draws during symptomatic episodes may be affected by recent cannabis cessation or reduced intake. Cannabinoid profiles are complex and not standardized for CHS diagnosis."},{"rthcId":"RTHC-05026","title":"An analysis of cannabinoid hyperemesis syndrome Reddit posts and themes.","authors":"Wightman, Rachel S; Perrone, Jeanmarie; Collins, Alexandra B; Lakamana, Sahithi; Sarker, Abeed","year":2023,"journal":"Clinical toxicology (Philadelphia, Pa.), 61(4), 283-289","doi":"10.1080/15563650.2023.2183790","pmid":"37014024","tags":["harm-reduction"],"studyType":"qualitative","evidenceStrength":"very-low","keyFinding":"CHS Reddit community members discussed triggers, therapies, and personal experiences with the condition. Frequently mentioned triggers and remedies were identified through natural language processing and manual review of posts across six subreddits.","whyItMatters":"Reddit CHS communities fill an information gap for a condition that many physicians still do not recognize. Understanding patient experiences and shared knowledge reveals both useful insights and misinformation circulating among affected users.","specificNumbers":"Six CHS-related subreddits analyzed. Posts filtered using natural language processing then manually reviewed for themes, triggers, and therapies.","methodology":"Qualitative analysis of Reddit posts from six subreddits related to CHS. Natural language processing filtered posts, followed by manual review to identify common themes, triggers, and mentioned therapies.","limitations":"Reddit users are self-selected and may not represent all CHS patients. Self-diagnosed CHS may include misdiagnosed cases. Posts may contain misinformation alongside useful insights. Cannot verify trigger-symptom relationships from anecdotal reports."},{"rthcId":"RTHC-05027","title":"Adult Medical Cannabinoid Use and Changes in Prescription Controlled Substance Use.","authors":"Williams, Arthur Robin; Mauro, Christine M; Feng, Tianshu; Waples, Josef; Martins, Silvia S; Haney, Margaret","year":2023,"journal":"Cannabis and cannabinoid research, 8(5), 933-941","doi":"10.1089/can.2021.0212","pmid":"35486854","tags":["medical-cannabis","addiction"],"studyType":"observational","evidenceStrength":"low","keyFinding":"Medical cannabis participants showed changes in controlled substance prescription patterns. While potential opioid-sparing effects were observed, the data also suggested interactions with sedative hypnotic use that could affect overdose risk.","whyItMatters":"The opioid-sparing narrative focuses on potential benefits, but medical cannabis may also affect use of other controlled substances in ways that increase or decrease risk. Individual-level data provides more granular insight than population studies.","specificNumbers":"Individual-level data combining medical cannabis use with prescription controlled substance records. Opioid-sparing effects observed alongside changes in sedative hypnotic patterns.","methodology":"Observational study combining individual-level data on medical cannabis use with prescription controlled substance records. Analyzed changes in opioid, sedative hypnotic, and other controlled substance use patterns.","limitations":"Observational design without randomization. Cannot attribute prescription changes to cannabis use versus other factors. Self-selection into medical cannabis. Limited ability to assess clinical outcomes (pain control, function) alongside prescription changes."},{"rthcId":"RTHC-05028","title":"Accuracy Differences in Cannabis Retailer Information Ascertained from Webservices and Government-Maintained State Registries Across US States Legalizing the Sale of Cannabis in 2019.","authors":"Williams, Michael; Mahlan, Matt; Holmes, Connor; Pankowska, Magdalena; Kaur, Manjot; Ilegbusi, Aderonke; Haley, Danielle F","year":2023,"journal":"Cannabis (Albuquerque, N.M.), 6(2), 133-148","doi":"10.26828/cannabis/2023/000148","pmid":"37484053","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Cannabis retailer data from web services and government registries frequently disagreed on operating status and location accuracy, with both sources containing errors that could affect geographic access research.","whyItMatters":"Researchers studying how cannabis retail access affects health outcomes depend on accurate store location data. If both major data sources contain significant errors, study findings about cannabis access and health may be unreliable.","specificNumbers":"Multiple US states with legal cannabis sales examined. Both web-based and government registry sources contained inaccuracies in retailer operating status and location information.","methodology":"Cross-sectional comparison of cannabis retailer location data from web services (e.g., Yelp) and government-maintained state registries across US states that legalized cannabis sales in 2019.","limitations":"Point-in-time comparison in states that legalized by 2019. Cannabis retail landscapes change rapidly. Definition of \"accurate\" location may vary. Cannot determine which source is definitively correct when they disagree."},{"rthcId":"RTHC-05029","title":"Associations for subgroups of E-cigarette, cigarette, and cannabis use with asthma in a population sample of California adolescents.","authors":"Williams, Rebecca J; Wills, Thomas A; Choi, Kelvin; Pagano, Ian","year":2023,"journal":"Addictive behaviors, 145, 107777","doi":"10.1016/j.addbeh.2023.107777","pmid":"37336095","tags":["youth","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Each substance (e-cigarettes, combustible cigarettes, and cannabis) was independently associated with asthma among California adolescents. Combined use of multiple substances showed additive respiratory effects.","whyItMatters":"Adolescent substance use often involves multiple products simultaneously. Understanding whether each independently contributes to asthma risk, rather than just confounding each other, is important for targeted prevention.","specificNumbers":"150,634 California high school students. E-cigarette, cigarette, and cannabis use each independently associated with asthma. Combined use showed additive effects.","methodology":"Cross-sectional analysis of a population-based sample of 150,634 public high school students (10th and 12th graders) representative of California. Examined independent and combined associations of e-cigarette, cigarette, and cannabis use with asthma.","limitations":"Cross-sectional design cannot establish causation. Self-reported asthma diagnosis and substance use. Cannot determine timing of asthma onset relative to substance use. Asthma may predispose to certain substance use patterns rather than the reverse."},{"rthcId":"RTHC-05030","title":"Effects of Tetrahydrocannabinol and Cannabidiol on Brain-Derived Neurotrophic Factor and Tropomyosin Receptor Kinase B Expression in the Adolescent Hippocampus.","authors":"Winstone, Joanna; Shafique, Hana; Clemmer, Madeleine E; Mackie, Ken; Wager-Miller, Jim","year":2023,"journal":"Cannabis and cannabinoid research, 8(4), 612-622","doi":"10.1089/can.2021.0025","pmid":"35639364","tags":["youth","neuroscience","cbd"],"studyType":"animal","evidenceStrength":"low","keyFinding":"THC and CBD produced different patterns of BDNF and TrkB expression changes in the adolescent hippocampus. These findings suggest the two major cannabinoids may have opposing or distinct effects on neurodevelopmental signaling during a critical growth period.","whyItMatters":"BDNF is essential for synaptic plasticity, learning, and memory. If cannabis compounds alter BDNF signaling during adolescent brain development, it could help explain the cognitive effects reported in teen cannabis users.","specificNumbers":"THC and CBD produced distinct patterns of BDNF and TrkB expression in the adolescent hippocampus. Effects differed between the two cannabinoids.","methodology":"Animal study examining the effects of adolescent THC and CBD exposure on BDNF and TrkB receptor expression in the hippocampus using molecular biology techniques.","limitations":"Animal study with unknown human translational relevance. Doses and timing may not reflect human adolescent cannabis use patterns. Molecular expression changes may not directly translate to functional cognitive effects. Single brain region examined."},{"rthcId":"RTHC-05031","title":"Impacts of medical and non-medical cannabis on the health of older adults: Findings from a scoping review of the literature.","authors":"Wolfe, Dianna; Corace, Kim; Butler, Claire; Rice, Danielle; Skidmore, Becky; Patel, Yashila; Thayaparan, Premika; Michaud, Alan; Hamel, Candyce; Smith, Andra; Garber, Gary; Porath, Amy; Conn, David; Willows, Melanie; Abramovici, Hanan; Thavorn, Kednapa; Kanji, Salmaan; Hutton, Brian","year":2023,"journal":"PloS one, 18(2), e0281826","doi":"10.1371/journal.pone.0281826","pmid":"36800328","tags":["medical-cannabis","seniors"],"studyType":"systematic-review","evidenceStrength":"low","keyFinding":"Cannabis use is increasing among older adults following legalization. Age-related changes in metabolism, body composition, and organ function may alter cannabis effects, but research specifically in older adults is sparse.","whyItMatters":"Older adults are the fastest-growing segment of cannabis users, often using it for pain, sleep, and anxiety. Yet they face unique risks from drug interactions, falls, and altered metabolism that are poorly studied.","specificNumbers":"Literature reviewed across multiple databases covering medical and non-medical cannabis use in older adults. Cannabis use increasing in this population post-legalization.","methodology":"Scoping review searching electronic databases for studies on health effects of medical and non-medical cannabis use in older adults. Mapped evidence across multiple health domains.","limitations":"Scoping review maps literature breadth rather than synthesizing outcomes. Much of the available literature involves younger populations. Heterogeneous definitions of \"older adult.\" Limited controlled trial data in elderly populations."},{"rthcId":"RTHC-05032","title":"Cannabinoid hyperemesis syndrome presenting with ventricular bigeminy.","authors":"Wong, Jeffrey; Gill, Muneet; Stead, Thor; Huang, Derrick; Ganti, Latha","year":2023,"journal":"Journal of cannabis research, 5(1), 36","doi":"10.1186/s42238-023-00203-x","pmid":"37858157","tags":["harm-reduction","cardiovascular"],"studyType":"case-report","evidenceStrength":"very-low","keyFinding":"CHS presentation included ventricular bigeminy (alternating normal and premature ventricular heartbeats) detected on the pre-arrival EMS EKG. This cardiac arrhythmia in the context of CHS may relate to electrolyte disturbances from severe vomiting or direct cannabinoid cardiac effects.","whyItMatters":"CHS is typically considered a gastrointestinal condition, but this case demonstrates potential cardiac complications. Arrhythmias in CHS patients may be underrecognized if cardiac monitoring is not performed.","specificNumbers":"28-year-old male. Ventricular bigeminy on pre-arrival EKG. Diagnosed with cannabinoid hyperemesis syndrome.","methodology":"Single case report of a 28-year-old male presenting to the ED via EMS with symptoms initially attributed to gastritis. Diagnosed with CHS after workup including EKG showing ventricular bigeminy.","limitations":"Single case report. Cannot determine whether bigeminy was caused by CHS, electrolyte disturbance from vomiting, direct cannabinoid effects, or coincidental. No long-term follow-up reported."},{"rthcId":"RTHC-05033","title":"A neuropsychological approach to differentiating cannabis-induced and primary psychotic disorders.","authors":"Woolridge, Stephanie M; Wood-Ross, Chelsea; Voleti, Rohit; Harrison, Geoffrey W; Berisha, Visar; Bowie, Christopher R","year":2023,"journal":"Early intervention in psychiatry, 17(6), 564-572","doi":"10.1111/eip.13348","pmid":"37280059","tags":["psychosis","cognition"],"studyType":"review","evidenceStrength":"low","keyFinding":"Cannabis-induced psychosis and primary psychotic disorders may show different neuropsychological profiles despite similar clinical presentations. Distinct cognitive patterns could serve as diagnostic aids when clinical symptoms overlap.","whyItMatters":"Distinguishing cannabis-induced psychosis from schizophrenia has major treatment implications. Misdiagnosis can lead to inappropriate long-term antipsychotic treatment or, conversely, inadequate early intervention for a primary psychotic disorder.","specificNumbers":"Elevated cannabis use rates in early psychosis populations make differential diagnosis clinically common. Review examines cognitive profiles across both conditions.","methodology":"Narrative review examining neuropsychological research on cannabis-induced psychosis versus primary psychotic disorders. Proposes a cognitive testing approach to aid differential diagnosis.","limitations":"Narrative review without systematic methodology. Neuropsychological profiles overlap between conditions. Acute intoxication effects confound cognitive testing. Proposed approach needs prospective validation."},{"rthcId":"RTHC-05034","title":"Clinician Attitudes, Training, and Beliefs About Cannabis: An Interprofessional Assessment.","authors":"Worster, Brooke; Ashare, Rebecca L; Hajjar, Emily; Garber, Greg; Smith, Kelsey; Kelly, Erin L","year":2023,"journal":"Cannabis and cannabinoid research, 8(3), 547-556","doi":"10.1089/can.2021.0022","pmid":"34978882","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"The majority of surveyed clinicians reported insufficient training about medical cannabis, low comfort discussing it with patients, and varying attitudes toward its medical use. Training gaps crossed professional disciplines.","whyItMatters":"Patients increasingly ask clinicians about medical cannabis, but most medical and health professional training programs provide little to no cannabis education. This gap leaves patients without reliable clinical guidance.","specificNumbers":"344 Pennsylvania clinicians surveyed. 14% response rate. Most reported insufficient cannabis training and low comfort with patient discussions.","methodology":"Brief online survey of 344 clinicians in Pennsylvania (14% response rate). Assessed attitudes, training experiences, and beliefs about medical cannabis across multiple healthcare professions.","limitations":"Low response rate (14%) raises self-selection concerns. Pennsylvania-specific findings may not generalize. Survey format cannot capture depth of knowledge or clinical practice. Clinicians who completed the survey may differ systematically from non-responders."},{"rthcId":"RTHC-05035","title":"Relationship between patterns of cannabis use and functional and symptomatic trajectories in first-episode psychosis.","authors":"Wright, Abigail C; Browne, Julia; Cather, Corinne; Meyer-Kalos, Piper; Mueser, Kim T","year":2023,"journal":"European archives of psychiatry and clinical neuroscience, 273(4), 765-778","doi":"10.1007/s00406-022-01441-5","pmid":"35900474","tags":["psychosis","addiction"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Cannabis use patterns were characterized among FEP patients, and continued use was associated with worse symptomatic and functional outcomes. Early intervention services improved overall outcomes but did not fully compensate for the negative trajectory associated with ongoing cannabis use.","whyItMatters":"Cannabis use is extremely common in first-episode psychosis populations. If ongoing use undermines even the best available treatment (early intervention services), addressing cannabis use must be a core component of FEP care.","specificNumbers":"RAISE study dataset. Cannabis use patterns characterized. Continued use associated with worse symptom and functional trajectories. Early intervention services partially but not fully offset cannabis-related disadvantages.","methodology":"Longitudinal analysis of the Recovery After an Initial Schizophrenia Episode (RAISE) dataset. Characterized cannabis use patterns and examined their relationship with clinical outcomes, including interactions with early intervention services.","limitations":"Observational longitudinal data from a clinical trial context. Cannabis use patterns self-reported. Confounding by illness severity (sicker patients may use more cannabis). Treatment engagement may differ between cannabis users and non-users."},{"rthcId":"RTHC-05036","title":"Phytocannabinoids in the Pharmacotherapy of Psoriasis.","authors":"Wroński, Adam; Jarocka-Karpowicz, Iwona; Stasiewicz, Anna; Skrzydlewska, Elżbieta","year":2023,"journal":"Molecules (Basel, Switzerland), 28(3)","doi":"10.3390/molecules28031192","pmid":"36770858","tags":["cbd","inflammation","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Psoriasis is a chronic autoimmune skin condition where the immune system attacks healthy skin cells, causing red, scaly patches that can be painful and disfiguring. It affects about 2-3% of the global population and has no cure — only management. This review examines whether cannabinoids from the cannabis plant could offer a new treatment pathway.\n\nThe biological rationale is sound. Psoriasis is driven by two intertwined problems: oxidative stress (an imbalance between damaging free radicals and the body's antioxidant defenses) and chronic inflammation (overactive immune cells pumping out pro-inflammatory cytokines). Phytocannabinoids, particularly CBD, have been shown to address both: they can boost antioxidant systems and suppress inflammatory cytokine production.\n\nCBD interacts with several receptor systems in the skin, including CB1, CB2, TRPV1, and PPARγ — all of which are involved in skin cell growth, differentiation, and immune regulation. By modulating these pathways, CBD could theoretically slow the rapid skin cell turnover and calm the immune overactivation that characterize psoriasis.\n\nOther phytocannabinoids — THC, CBG, CBN — have also shown relevant biological activities, though CBD has the most evidence. The review emphasizes that the endocannabinoid system is extensively expressed in skin tissue, making it a rational pharmacological target for dermatological conditions.\n\nThe catch: almost all evidence comes from laboratory and animal studies. Clinical trials specifically testing cannabinoids in human psoriasis patients are extremely limited.","whyItMatters":"Current psoriasis treatments include topical steroids (which thin the skin over time), immunosuppressants (which increase infection risk), and biologics (which are expensive and require injections). Many patients find these treatments inadequate or have significant side effects. If cannabinoid-based topicals could provide effective symptom relief with fewer side effects, they could fill an important gap — especially for mild-to-moderate psoriasis where current options are limited.","specificNumbers":"Psoriasis affects 2-3% of the global population. CBD interacts with at least four receptor systems in skin (CB1, CB2, TRPV1, PPARγ). Multiple cannabinoids show anti-inflammatory and antioxidant properties in laboratory settings. Clinical trial data in human psoriasis patients is described as minimal.","methodology":"Narrative review of published literature on phytocannabinoid effects relevant to psoriasis pathophysiology. Covered mechanisms including modulation of oxidative stress, cytokine production, keratinocyte proliferation, and immune cell function. Examined CBD, THC, CBG, CBN, and other phytocannabinoids. Reviewed relevant receptor systems (CB1, CB2, TRPV, PPAR) in skin tissue.","limitations":"Narrative review relying primarily on preclinical evidence. Almost no clinical trial data in human psoriasis patients. Laboratory findings in isolated cells and animal models often don't translate to effective treatments in humans. The skin is a complex organ with multiple cell types and immune dynamics that in vitro studies don't capture. Topical cannabinoid formulations face penetration and delivery challenges that laboratory studies bypass."},{"rthcId":"RTHC-05037","title":"Cannabis self-administration in the human laboratory: a scoping review of ad libitum studies.","authors":"Xiao, Ke Bin; Grennell, Erin; Ngoy, Anthony; George, Tony P; Le Foll, Bernard; Hendershot, Christian S; Sloan, Matthew E","year":2023,"journal":"Psychopharmacology, 240(7), 1393-1415","doi":"10.1007/s00213-023-06360-4","pmid":"37157001","tags":["addiction"],"studyType":"systematic-review","evidenceStrength":"low","keyFinding":"Ad libitum cannabis self-administration studies in laboratory settings have identified factors influencing consumption and subjective response, including tolerance, sex differences, and cannabis potency. These paradigms could also test potential CUD medications.","whyItMatters":"Understanding why people use cannabis and how much they consume under controlled conditions helps develop treatments for cannabis use disorder and inform harm reduction strategies.","specificNumbers":"Multiple laboratory self-administration studies reviewed. Factors identified: tolerance effects, sex differences, potency influences on consumption patterns.","methodology":"Scoping review summarizing existing human laboratory studies where participants could self-administer cannabis ad libitum. Examined what factors have been studied and what has been learned.","limitations":"Laboratory settings do not replicate real-world use contexts. Ethical constraints limit who can participate and what doses can be studied. Methodological inconsistencies across studies limit meta-analytic synthesis. Small study samples typical."},{"rthcId":"RTHC-05038","title":"An α-hemoglobin-derived peptide (m)VD-hemopressin (α) promotes NREM sleep via the CB1 cannabinoid receptor.","authors":"Xie, Jun-Fan; Wang, Lin-Xin; Ren, Wen-Ting; Wang, Can; Gao, Jin-Xian; Chen, Hai-Lin; Zhao, Xue-Qi; Ren, Yan-Li; Xie, Yu-Ping; Shao, Yu-Feng; Hou, Yi-Ping","year":2023,"journal":"Frontiers in pharmacology, 14, 1213215","doi":"10.3389/fphar.2023.1213215","pmid":"37456761","tags":["sleep","neuroscience"],"studyType":"animal","evidenceStrength":"low","keyFinding":"The hemoglobin-derived peptide (m)VD-HPalpha promoted non-rapid eye movement (NREM) sleep when administered to mice. This sleep-promoting effect was mediated through CB1 cannabinoid receptors, providing new evidence for endocannabinoid system involvement in sleep regulation.","whyItMatters":"Sleep disruption is one of the most common reasons people use cannabis. Understanding how the endocannabinoid system naturally regulates sleep could lead to targeted sleep therapeutics without the side effects of whole-plant cannabis.","specificNumbers":"(m)VD-HPalpha, an 11-residue peptide, promoted NREM sleep in mice. Effect was CB1 receptor-dependent.","methodology":"Animal study examining sleep architecture in mice following administration of (m)VD-hemopressin(alpha). Sleep stages monitored. CB1 receptor involvement confirmed using pharmacological tools.","limitations":"Mouse study with uncertain human translation. Direct peptide administration to the brain is not a clinically feasible route. Sleep architecture differs between mice and humans. Unknown whether this peptide plays a role in natural human sleep."},{"rthcId":"RTHC-05039","title":"Public Perception of Marijuana Use for the Treatment of Glaucoma.","authors":"Yakobashvili, Daniela; Shah, Ronak; Oydanich, Marko; Khouri, Albert S","year":2023,"journal":"Journal of glaucoma, 32(7), e106-e108","doi":"10.1097/IJG.0000000000002203","pmid":"36897646","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"A significant portion of survey respondents believed marijuana is effective for treating glaucoma. This contrasts with the current ophthalmological consensus that cannabis provides only short-term, modest intraocular pressure reduction with impractical dosing requirements.","whyItMatters":"The glaucoma-marijuana association is one of the most well-known claims about medical cannabis, dating back decades. If public perception is misaligned with current evidence, patients may delay or avoid proven treatments.","specificNumbers":"Survey respondents assessed on belief in marijuana efficacy for glaucoma. Significant proportion believed in effectiveness. Most ophthalmologists do not support cannabis for glaucoma treatment.","methodology":"Survey assessing public perception of marijuana efficacy for glaucoma treatment, designed to complement existing data showing most ophthalmologists do not support marijuana use for glaucoma.","limitations":"Survey methodology details limit generalizability. Public perception does not equal clinical evidence. Cannabis research for glaucoma is limited and dated. Does not assess whether belief influences actual treatment decisions."},{"rthcId":"RTHC-05040","title":"Genome-Wide Identification, Classification, and Expression Analyses of the CsDGAT Gene Family in Cannabis sativa L. and Their Response to Cold Treatment.","authors":"Yan, Bowei; Chang, Chuanyi; Gu, Yingnan; Zheng, Nan; Fang, Yuyan; Zhang, Ming; Wang, Guijiang; Zhang, Liguo","year":2023,"journal":"International journal of molecular sciences, 24(4)","doi":"10.3390/ijms24044078","pmid":"36835488","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05041","title":"Risk of depressive disorders associated with medical cannabis authorization: A propensity score matched cohort study.","authors":"Yana, Jerry Liwono; Lee, Cerina; Eurich, Dean T; Dyck, Jason R B; Hanlon, John G; Zongo, Arsène","year":2023,"journal":"Psychiatry research, 320, 115047","doi":"10.1016/j.psychres.2022.115047","pmid":"36638694","tags":["medical-cannabis","depression","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Medical cannabis users had significantly higher rates of ED visits and hospitalization for depressive disorders than propensity-matched controls who did not receive medical cannabis authorization.","whyItMatters":"Medical cannabis is increasingly used for conditions that overlap with depression. If cannabis authorization is associated with increased depression-related emergencies, it has important implications for patient monitoring and informed consent.","specificNumbers":"Propensity score-matched cohort. Medical cannabis authorization associated with increased risk of ED visits and hospitalization for depressive disorders.","methodology":"Retrospective longitudinal cohort study using propensity score matching. Compared patients who received medical cannabis authorization with matched controls on rates of ED visits and hospitalization for depressive disorders.","limitations":"Observational design even with propensity matching cannot establish causation. People who seek medical cannabis may have more severe or treatment-resistant conditions. Cannot determine whether cannabis caused, worsened, or simply coincided with depression. Propensity matching may not capture all relevant differences."},{"rthcId":"RTHC-05042","title":"Medical Cannabis in Hand Surgery: A Review of the Current Evidence.","authors":"Yang, Andrew; Townsend, Clay B; Ilyas, Asif M","year":2023,"journal":"The Journal of hand surgery, 48(3), 292-300","doi":"10.1016/j.jhsa.2022.11.008","pmid":"36609049","tags":["medical-cannabis","pain"],"studyType":"review","evidenceStrength":"low","keyFinding":"Medical cannabis is being explored as an opioid-sparing option for acute and chronic pain in hand surgery. While societal attitudes are evolving and legalization is expanding, the specific evidence base for hand surgery applications remains limited.","whyItMatters":"Hand surgery involves significant pain management challenges, and the opioid epidemic has increased pressure to find alternatives. Medical cannabis could fill a niche if supported by evidence.","specificNumbers":"Review covers increasing legalization of medical and recreational cannabis in the US. Evidence for hand surgery-specific applications is limited.","methodology":"Narrative review of current evidence on medical cannabis for pain management in the context of hand surgery, including acute postoperative and chronic pain applications.","limitations":"Narrative review without systematic methodology. Very limited hand surgery-specific evidence. Most cannabis-pain evidence comes from chronic pain populations, not surgical recovery. Dosing, timing, and formulation questions unanswered for perioperative use."},{"rthcId":"RTHC-05043","title":"Trends in past-month cannabis use among US adults across a range of disabilities and health conditions, 2015-2019.","authors":"Yang, Kevin H; Tam, Rowena M; Satybaldiyeva, Nora; Kepner, Wayne; Han, Benjamin H; Moore, Alison A; Palamar, Joseph J","year":2023,"journal":"Preventive medicine, 177, 107768","doi":"10.1016/j.ypmed.2023.107768","pmid":"37951542","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Past-month cannabis use increased significantly from 2015-2019 among adults with various disabilities and health conditions. Prevalence was consistently higher among those with health conditions compared to the general adult population.","whyItMatters":"People with health conditions are using cannabis at increasing rates, likely for symptom management. Understanding these trends helps clinicians anticipate conversations about cannabis and potential drug interactions.","specificNumbers":"N=214,505 US adults from NSDUH 2015-2019. Cannabis use trended upward across a range of disabilities and health conditions over the 5-year period.","methodology":"Cross-sectional analysis of 2015-2019 National Survey on Drug Use and Health (N=214,505 US adults). Examined trends in past-month cannabis use across multiple disability types and health conditions.","limitations":"NSDUH cross-sectional design tracks population trends but not individual use trajectories. Self-reported data. Cannot determine whether cannabis was used for the health condition or recreationally. Health condition definitions may vary across survey years."},{"rthcId":"RTHC-05044","title":"Subtle Structural Modification of a Synthetic Cannabinoid Receptor Agonist Drastically Increases its Efficacy at the CB1 Receptor.","authors":"Yano, Hideaki; Chitsazi, Rezvan; Lucaj, Christopher; Tran, Phuong; Hoffman, Alexander F; Baumann, Michael H; Lupica, Carl R; Shi, Lei","year":2023,"journal":"ACS chemical neuroscience, 14(21), 3928-3940","doi":"10.1021/acschemneuro.3c00530","pmid":"37847546","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05045","title":"A subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor.","authors":"Yano, Hideaki; Chitsazi, Rezvan; Lucaj, Christopher; Tran, Phuong; Hoffman, Alexander F; Baumann, Michael H; Lupica, Carl R; Shi, Lei","year":2023,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2023.06.10.544442","pmid":"37398099","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05046","title":"Does tobacco dependence worsen cannabis withdrawal in people with and without schizophrenia-spectrum disorders?","authors":"Yeap, Zac J S; Marsault, Justine; George, Tony P; Mizrahi, Romina; Rabin, Rachel A","year":2023,"journal":"The American journal on addictions, 32(4), 367-375","doi":"10.1111/ajad.13394","pmid":"36815595","tags":["addiction","withdrawal","psychosis","tolerance"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Cannabis withdrawal severity was worse in tobacco-dependent individuals compared to non-tobacco-dependent individuals. This effect was present in both people with schizophrenia-spectrum disorders and those without, suggesting tobacco co-use universally complicates cannabis cessation.","whyItMatters":"Most people with cannabis use disorder also use tobacco. If tobacco worsens cannabis withdrawal, addressing both substances simultaneously may be necessary for successful treatment.","specificNumbers":"Cannabis withdrawal severity assessed in relation to tobacco dependence. Tobacco-dependent individuals showed worse cannabis withdrawal regardless of schizophrenia diagnosis.","methodology":"Cross-sectional study examining cannabis withdrawal severity as a function of tobacco dependence status and schizophrenia-spectrum disorder diagnosis.","limitations":"Cross-sectional design cannot establish causation. Cannabis withdrawal severity was measured at a single point. Cannot determine whether tobacco cessation would improve cannabis withdrawal outcomes. Schizophrenia medication effects on withdrawal not fully controlled."},{"rthcId":"RTHC-05047","title":"Pregnant individual's lived experience of cannabis use during the COVID-19 pandemic: a qualitative study.","authors":"Young-Wolff, Kelly C; Foti, Tara R; Green, Andrea; Iturralde, Esti; Jackson-Morris, Melanie; Does, Monique B; Adams, Sara R; Goler, Nancy; Conway, Amy; Ansley, Deborah; Altschuler, Andrea","year":2023,"journal":"Frontiers in psychiatry, 14, 1161137","doi":"10.3389/fpsyt.2023.1161137","pmid":"37151965","tags":["pregnancy"],"studyType":"qualitative","evidenceStrength":"low","keyFinding":"The COVID-19 pandemic contributed to changes in prenatal cannabis use through increased stress, isolation, reduced healthcare access, and heightened anxiety. Some participants increased use, while others described the pandemic as the catalyst for starting cannabis during pregnancy.","whyItMatters":"Prenatal cannabis use increased during the pandemic. Understanding the specific mechanisms (stress, isolation, reduced healthcare) helps design interventions that address the root causes rather than just the cannabis use itself.","specificNumbers":"Qualitative interviews with pregnant cannabis users during COVID-19. Pandemic-related stress and isolation identified as key drivers of changed use patterns.","methodology":"Qualitative study using semi-structured interviews with pregnant individuals who used cannabis during the COVID-19 pandemic. Explored pandemic-related changes in cannabis use patterns and motivations.","limitations":"Qualitative study cannot quantify prevalence or measure health outcomes. Self-selected participants willing to discuss cannabis use during pregnancy. Recall may be affected by ongoing pandemic stress. Cannot separate pandemic effects from normal pregnancy-related use changes."},{"rthcId":"RTHC-05048","title":"Association of cannabis use during pregnancy with severe acute respiratory syndrome coronavirus 2 infection: a retrospective cohort study.","authors":"Young-Wolff, Kelly C; Ray, G Thomas; Alexeeff, Stacey E; Benowitz, Neal; Adams, Sara R; Does, Monique B; Goler, Nancy; Ansley, Deborah; Conway, Amy; Avalos, Lyndsay A","year":2023,"journal":"Addiction (Abingdon, England), 118(2), 317-326","doi":"10.1111/add.16056","pmid":"36189777","tags":["pregnancy"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Prenatal cannabis use was significantly associated with higher risk of SARS-CoV-2 infection during pregnancy in a large California cohort. The association remained after adjusting for known confounders.","whyItMatters":"If cannabis use increases infection susceptibility during pregnancy, it represents an additional risk factor that prenatal care providers should consider, particularly during respiratory illness surges.","specificNumbers":"58,114 pregnancies in California. Prenatal cannabis use associated with increased SARS-CoV-2 infection risk after adjusting for confounders.","methodology":"Retrospective cohort study of 58,114 pregnancies in California. Cannabis use identified through prenatal screening. SARS-CoV-2 infection status determined from testing records. Adjusted for demographic and clinical confounders.","limitations":"Retrospective design. Cannot confirm causation. Cannabis use measured at screening and may not reflect use throughout pregnancy. Behavioral confounders (social distancing compliance, testing frequency) difficult to fully control. Single geographic region during a specific pandemic wave."},{"rthcId":"RTHC-05049","title":"The Anti-Inflammatory Effects of Cannabis sativa Extracts on LPS-Induced Cytokines Release in Human Macrophages.","authors":"Zaiachuk, Mariia; Suryavanshi, Santosh V; Pryimak, Nazar; Kovalchuk, Igor; Kovalchuk, Olga","year":2023,"journal":"Molecules (Basel, Switzerland), 28(13)","doi":"10.3390/molecules28134991","pmid":"37446655","tags":["inflammation","cbd"],"studyType":"in-vitro","evidenceStrength":"very-low","keyFinding":"Cannabis extracts reduced the release of pro-inflammatory cytokines (immune signaling molecules) from human macrophages activated by bacterial endotoxin (LPS), demonstrating anti-inflammatory effects in a controlled laboratory model.","whyItMatters":"Chronic inflammation underlies many diseases, and current anti-inflammatory drugs have significant side effects. If cannabis compounds can modulate immune cell responses, they could become the basis for new anti-inflammatory therapies.","specificNumbers":"Cannabis extracts reduced LPS-induced cytokine release in human macrophages. Multiple inflammatory markers measured.","methodology":"In vitro study using human macrophage cell cultures. Cells were stimulated with LPS (bacterial endotoxin) to trigger inflammation, then treated with Cannabis sativa extracts. Cytokine release measured as the primary outcome.","limitations":"In vitro study in isolated cell cultures. Does not reflect the complexity of whole-body inflammation. Extract composition may vary between preparations. LPS stimulation is a simplified model of inflammation. Doses used may not be achievable in humans."},{"rthcId":"RTHC-05050","title":"Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial.","authors":"Zamarripa, C Austin; Spindle, Tory R; Surujunarain, Renuka; Weerts, Elise M; Bansal, Sumit; Unadkat, Jashvant D; Paine, Mary F; Vandrey, Ryan","year":2023,"journal":"JAMA network open, 6(2), e2254752","doi":"10.1001/jamanetworkopen.2022.54752","pmid":"36780161","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"high","keyFinding":"CBD co-administration modified THC blood levels and subjective effects in a dose-dependent pattern. The pharmacokinetic and pharmacodynamic interactions between oral THC and CBD varied depending on the ratio of the two cannabinoids.","whyItMatters":"CBD is widely believed to counteract THC effects, but controlled clinical data has been limited. This trial provides rigorous pharmacological evidence on how the two most prominent cannabinoids interact in humans.","specificNumbers":"Multiple oral cannabis extract formulations with varying THC:CBD ratios tested. Blood THC levels and subjective effects measured. Dose-dependent CBD modulation of THC observed.","methodology":"Randomized clinical trial in healthy adults. Compared pharmacokinetics and pharmacodynamics of orally administered cannabis extracts varying in THC and CBD concentrations. Measured blood levels and subjective effects.","limitations":"Healthy adult volunteers may not reflect patients with medical conditions. Oral administration only (inhaled routes may produce different interactions). Acute dosing study does not capture chronic use dynamics. Specific extract formulations may not represent all commercial products."},{"rthcId":"RTHC-05051","title":"Marijuana, e-cigarette, and tobacco product use in young adults who underwent pediatric bariatric surgery.","authors":"Zeller, Meg H; Strong, Heather; Reiter-Purtill, Jennifer; Jenkins, Todd M; Mitchell, James E; Michalsky, Marc P; Helmrath, Michael A","year":2023,"journal":"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery, 19(5), 512-521","doi":"10.1016/j.soard.2022.11.008","pmid":"36567232","tags":["youth"],"studyType":"longitudinal","evidenceStrength":"low","keyFinding":"Marijuana, conventional cigarette, and e-cigarette use were observed in young adults who had undergone pediatric bariatric surgery, with substance use patterns emerging during the post-surgical years when addiction vulnerability may be heightened.","whyItMatters":"Post-bariatric surgery patients face altered substance metabolism and increased addiction risk. Understanding substance use patterns in this population is important for post-surgical care guidelines.","specificNumbers":"Five academic medical centers. Young adults followed up to 6 years post-pediatric bariatric surgery. Marijuana, cigarettes, and e-cigarettes/alternative products assessed.","methodology":"Longitudinal follow-up of young adults from five academic medical centers who underwent pediatric metabolic and bariatric surgery. Assessed marijuana, cigarette, and alternative tobacco product use up to 6 years post-surgery.","limitations":"Multi-center but likely small sample. Self-reported substance use. Cannot compare to non-surgical controls without additional data. Post-surgical metabolic changes may affect how substances are processed but were not measured."},{"rthcId":"RTHC-05052","title":"The impact of phyto- and endo-cannabinoids on central nervous system diseases：A review.","authors":"Zhang, Shan-Shan; Zhang, Niu-Niu; Guo, Tian-Tian; Sheen, Lee-Yan; Ho, Chi-Tang; Bai, Nai-Sheng","year":2023,"journal":"Journal of traditional and complementary medicine, 13(1), 30-38","doi":"10.1016/j.jtcme.2022.10.004","pmid":"36685079","tags":["medical-cannabis","neuroscience","cbd"],"studyType":"review","evidenceStrength":"low","keyFinding":"Both plant-derived (phyto) and endogenous cannabinoids show pharmacological activities relevant to multiple CNS conditions. Evidence quality ranges from well-supported (epilepsy) to preliminary (neurodegeneration, psychiatric disorders).","whyItMatters":"The endocannabinoid system is active throughout the brain and involved in nearly every neurological function. Understanding how both external and internal cannabinoids modulate brain disease opens numerous therapeutic avenues.","specificNumbers":"Review covers phytocannabinoids (THC, CBD, others) and endocannabinoids (anandamide, 2-AG) across multiple CNS disease categories.","methodology":"Literature review using keyword searches across databases focusing on cannabinoid pharmacology and CNS disease applications. Covers both phytocannabinoids and endocannabinoids.","limitations":"Narrative review without systematic methodology. Covers a very broad topic with variable evidence depth. Much of the evidence is preclinical. Does not provide quantitative evidence synthesis."},{"rthcId":"RTHC-05053","title":"A Randomized, Controlled Trial of Efficacy and Safety of Cannabidiol in Idiopathic and Diabetic Gastroparesis.","authors":"Zheng, Ting; BouSaba, Joelle; Taylor, Ann; Dilmaghani, Saam; Busciglio, Irene; Carlson, Paula; Torres, Monique; Ryks, Michael; Burton, Duane; Harmsen, William Scott; Camilleri, Michael","year":2023,"journal":"Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 21(13), 3405-3414.e4","doi":"10.1016/j.cgh.2023.07.008","pmid":"37482172","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"high","keyFinding":"Pharmaceutical CBD treatment for 4 weeks did not produce significant improvements in gastroparesis symptoms compared to placebo. Despite CBD's known effects on gut sensation and inflammation, these did not translate to clinical benefit in this patient population.","whyItMatters":"Gastroparesis is a debilitating condition with limited treatment options. This negative trial is important because it tempers expectations about CBD for gastrointestinal conditions despite mechanistic rationale.","specificNumbers":"4 weeks of pharmaceutical CBD treatment. Compared to placebo. No significant improvement in gastroparesis symptoms.","methodology":"Randomized, controlled trial comparing 4 weeks of pharmaceutical CBD versus placebo in patients with idiopathic or diabetic gastroparesis. Multiple symptom and physiological endpoints assessed.","limitations":"Relatively short treatment duration (4 weeks). Specific CBD dose used may not be optimal. Small sample size possible. Gastroparesis symptom measurement is challenging. Does not rule out benefit at different doses or longer treatment durations."},{"rthcId":"RTHC-05054","title":"Spontaneous secondary pneumothorax due to cannabis-induced bullous lung disease: a case report.","authors":"Zhitny, Vladislav Pavlovich; Diaz, Jared; Lambert-Swainston, Chalette; Abdallah, Ala; Gurz, Sana; Young, Jake; Palma, Chriselyn; Chen, Cliff; Khan, Nazia","year":2023,"journal":"Annals of medicine and surgery (2012), 85(7), 3731-3734","doi":"10.1097/MS9.0000000000000968","pmid":"37427209","tags":["respiratory"],"studyType":"case-report","evidenceStrength":"very-low","keyFinding":"An adult male with a history of heavy cannabis use developed bullous lung disease (air-filled sacs in the lung tissue) that led to spontaneous secondary pneumothorax. This case illustrates a serious but underrecognized pulmonary complication of chronic cannabis smoking.","whyItMatters":"Bullous lung disease and pneumothorax from cannabis are increasingly reported but still underrecognized. As cannabis use grows, clinicians need awareness of this potentially life-threatening complication.","specificNumbers":"Adult male with heavy cannabis use history. Developed bullous lung disease leading to spontaneous pneumothorax.","methodology":"Single case report following SCARE criteria. Documents clinical presentation, imaging findings, and management of cannabis-induced bullous lung disease with spontaneous pneumothorax.","limitations":"Single case report cannot establish frequency or predict who is at risk. Cannot fully exclude other causes of bullous disease. Patient history of other inhalational exposures may be incomplete."},{"rthcId":"RTHC-05055","title":"Phytocannabinoids: Chromatographic Screening of Cannabinoids and Loading into Lipid Nanoparticles.","authors":"Zielińska, Aleksandra; da Ana, Raquel; Fonseca, Joel; Szalata, Milena; Wielgus, Karolina; Fathi, Faezeh; Oliveira, M Beatriz P P; Staszewski, Rafał; Karczewski, Jacek; Souto, Eliana B","year":2023,"journal":"Molecules (Basel, Switzerland), 28(6)","doi":"10.3390/molecules28062875","pmid":"36985847","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05056","title":"Oral capsules of tetra-hydro-cannabinol (THC), cannabidiol (CBD) and their combination in peripheral neuropathic pain treatment.","authors":"Zubcevic, Kanita; Petersen, Merete; Bach, Flemming Winther; Heinesen, Aksel; Enggaard, Thomas Peter; Almdal, Thomas Peter; Holbech, Jakob Vormstrup; Vase, Lene; Jensen, Troels Stahelin; Hansen, Christian Stevns; Finnerup, Nanna Brix; Sindrup, Søren H","year":2023,"journal":"European journal of pain (London, England), 27(4), 492-506","doi":"10.1002/ejp.2072","pmid":"36571471","tags":["medical-cannabis","pain","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"high","keyFinding":"The trial compared four conditions (CBD alone, THC alone, CBD/THC combination, and placebo) for neuropathic pain. Results provide controlled evidence on whether CBD, THC, or their combination offers meaningful pain relief in this population.","whyItMatters":"Cannabinoids are often prescribed for neuropathic pain despite weak evidence. This four-arm design directly compares individual cannabinoids, their combination, and placebo, providing the type of data clinical guidelines require.","specificNumbers":"Four treatment arms with 1:1:1:1 randomization: CBD, THC, CBD/THC combination, and placebo. Oral capsule formulation for peripheral neuropathic pain.","methodology":"Randomized, double-blind, placebo-controlled trial with four arms (1:1:1:1 ratio): CBD capsules, THC capsules, CBD/THC combination capsules, and placebo. Patients with peripheral neuropathic pain enrolled.","limitations":"Oral capsules may produce different effects than smoked or vaporized cannabis. Specific doses tested may not reflect optimal dosing. Sample size determines the power to detect differences between arms. Duration of treatment may affect conclusions."},{"rthcId":"RTHC-05057","title":"Prenatal exposure to CB2 receptors agonist differentially impacts male and female germ cells via histone modification.","authors":"Zucchi, Alice; Innocenzi, Elisa; Onorato, Angelo; Dolci, Susanna; Colopi, Ambra; Balistreri, Carmela Rita; Grimaldi, Paola","year":2023,"journal":"Mechanisms of ageing and development, 213, 111840","doi":"10.1016/j.mad.2023.111840","pmid":"37385302","tags":["pregnancy","sex-differences"],"studyType":"animal","evidenceStrength":"low","keyFinding":"Prenatal CB2 receptor activation caused sex-specific changes in germ cell development in offspring, with effects mediated through histone modifications (epigenetic changes). Male and female germ cells were affected differently.","whyItMatters":"Cannabis use during pregnancy is increasing, and potential effects on offspring reproductive development are poorly understood. This study identifies a specific mechanism (epigenetic changes in germ cells) through which prenatal cannabinoid exposure could affect fertility in the next generation.","specificNumbers":"Prenatal CB2 agonist exposure. Sex-specific effects on germ cells. Histone modification changes identified in offspring reproductive cells.","methodology":"Animal study exposing pregnant animals to a CB2 receptor agonist. Examined effects on male and female offspring germ cells using epigenetic (histone modification) analysis.","limitations":"Animal study using a specific CB2 agonist, not whole cannabis. Doses may not reflect human exposure levels. Germ cell changes may not translate to functional fertility effects. Sex-specific effects need replication. Transgenerational implications are speculative."},{"rthcId":"RTHC-05058","title":"A systematic review of novel cannabinoids and their targets: Insights into the significance of structure in activity.","authors":"Abdollahzadeh Hamzekalayi, Mohammad Reza; Hooshyari Ardakani, Mohammad; Moeini, Zahra; Rezaei, Reza; Hamidi, Negin; Rezaei Somee, Leila; Zolfaghar, Mahdis; Darzi, Raheleh; Kamalipourazad, Maryam; Riazi, Gholamhossein; Meknatkhah, Sogol","year":2024,"journal":"European journal of pharmacology, 976, 176679","doi":"10.1016/j.ejphar.2024.176679","pmid":"38821167","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05059","title":"Low UV radiation influenced DNA methylation, gene regulation, cell proliferation, viability, and biochemical differentiation in the cell suspension cultures of Cannabis indica.","authors":"Abedini, Maryam; Iranbakhsh, Alireza; Saadatmand, Sara; Ebadi, Mostafa; Oraghi Ardebili, Zahra","year":2024,"journal":"Journal of photochemistry and photobiology. B, Biology, 254, 112902","doi":"10.1016/j.jphotobiol.2024.112902","pmid":"38569457","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05060","title":"Older Adults' Use of Cannabis and Attitudes Around Disclosing Medical Cannabis Use to Their Healthcare Providers in California: A Mixed Methods Study.","authors":"Abu Baker, Dania; Cruz Rivera, Paola N; Narasimhan, Rekha; Nguyen, Nhi; Tibiriçá, Lize; Kepner, Wayne E; O'Malley, Pearse; Nguyen, Annie L; Moore, Alison A","year":2024,"journal":"Drugs - real world outcomes, 11(4), 647-658","doi":"10.1007/s40801-024-00451-0","pmid":"39294485","tags":["medical-cannabis","seniors"],"studyType":"mixed-methods","evidenceStrength":"low","keyFinding":"Older adults frequently did not disclose medical cannabis use to their primary care providers. Barriers included stigma, fear of judgment, perceived provider disapproval, and uncertainty about how disclosure would affect their care.","whyItMatters":"Non-disclosure of cannabis use creates safety risks, especially for older adults on multiple medications. If providers do not know about cannabis use, they cannot monitor for drug interactions or adjust treatment plans.","specificNumbers":"California older adults surveyed and interviewed. Significant non-disclosure of medical cannabis use to primary care providers identified.","methodology":"Mixed methods study (quantitative survey and qualitative interviews) investigating older adults' cannabis use behaviors and attitudes around disclosing medical cannabis use to healthcare providers in California.","limitations":"California-specific findings in a legal state. Older adults willing to participate in research about cannabis may differ from non-participants. Self-report of disclosure behavior. Mixed methods provides depth but limited generalizability."},{"rthcId":"RTHC-05061","title":"Severe and rapidly changing hypophosphatemia in cannabinoid hyperemesis syndrome: a case report.","authors":"Acharya, Prakash; Mishra, Aakash; Kuikel, Sandip; Mishra, Aman; Rauniyar, Robin; Khanal, Kunjan; Nepal, Amit Sharma; Thapaliya, Sahil","year":2024,"journal":"Oxford medical case reports, 2024(6), omae055","doi":"10.1093/omcr/omae055","pmid":"38860017","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"very-low","keyFinding":"An 18-year-old male with daily cannabis use presented with CHS and developed severe hypophosphatemia (low blood phosphorus) that changed rapidly, requiring careful monitoring and correction. This electrolyte disturbance is a less recognized but potentially serious CHS complication.","whyItMatters":"CHS-related vomiting can cause electrolyte disturbances beyond the commonly checked sodium and potassium. Hypophosphatemia can cause muscle weakness, respiratory failure, and cardiac dysfunction if unrecognized.","specificNumbers":"18-year-old male with daily, prolonged cannabis use. Severe and rapidly changing hypophosphatemia documented during CHS episode.","methodology":"Single case report documenting clinical presentation, laboratory findings, and management of severe hypophosphatemia in an 18-year-old with CHS and daily cannabis use.","limitations":"Single case report. Cannot determine how common hypophosphatemia is in CHS. Other factors (nutritional status, refeeding) may have contributed. No long-term follow-up reported."},{"rthcId":"RTHC-05062","title":"The efficacy and safety of cannabidiol (CBD) in pediatric patients with Dravet Syndrome: a narrative review of clinical trials.","authors":"Aderinto, Nicholas; Olatunji, Gbolahan; Kokori, Emmanuel; Ajayi, Yusuf Ismaila; Akinmoju, Olumide; Ayedun, Abiola Samuel; Ayoola, Oluwapelumi Ikeoluwa; Aderinto, Noah Oluwaseun","year":2024,"journal":"European journal of medical research, 29(1), 182","doi":"10.1186/s40001-024-01788-6","pmid":"38500226","tags":["cbd","epilepsy","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Across 10 clinical trials, CBD demonstrated efficacy in reducing seizure frequency in children with Dravet syndrome. Common adverse events included somnolence, diarrhea, and decreased appetite. Interactions with clobazam were clinically significant.","whyItMatters":"Dravet syndrome is among the most severe childhood epilepsies with limited treatment options. CBD (Epidiolex) was the first cannabis-derived drug approved for this condition, and this review consolidates the clinical evidence.","specificNumbers":"10 clinical trials reviewed. CBD reduced seizure frequency in Dravet syndrome. Common side effects: somnolence, diarrhea, decreased appetite. Clobazam interaction significant.","methodology":"Narrative review of 10 clinical trials evaluating CBD efficacy and safety in pediatric Dravet syndrome patients.","limitations":"Narrative review without systematic methodology or quantitative synthesis. Most trials used specific pharmaceutical-grade CBD (Epidiolex) at defined doses, which may not generalize to other CBD products. Focus on Dravet syndrome only."},{"rthcId":"RTHC-05063","title":"What Parents Are Missing: Parental Knowledge of Adult-Use Cannabis Legislation and Health Effects, and Communication with Adolescents.","authors":"Adewale, Chorine A; Heffernan, Marie E; Bendelow, Anne; Rahmandar, Maria H","year":2024,"journal":"Substance use & misuse, 59(1), 154-157","doi":"10.1080/10826084.2023.2267092","pmid":"37814444","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Parents had limited knowledge of recent cannabis legislation changes and inconsistent understanding of cannabis health effects. Many had not discussed cannabis use with their adolescent children despite the evolving legal landscape.","whyItMatters":"Parents are a primary influence on adolescent substance use decisions. If parents are uninformed about cannabis laws and health effects, they may not have the knowledge needed for effective prevention conversations.","specificNumbers":"2020 survey of Chicago-area parents. Knowledge gaps identified regarding cannabis legislation and health effects. Many parents had not discussed cannabis with their teens.","methodology":"Cross-sectional survey data from the 2020 Voices of Child Health in Chicago Parent Panel Survey. Assessed parental knowledge of cannabis legislation, health effects, and communication with adolescents about cannabis.","limitations":"Single city (Chicago area). Self-reported knowledge and communication. Survey format cannot assess depth of understanding. 2020 data collected during early COVID-19 period. Response patterns may differ by parent demographics."},{"rthcId":"RTHC-05064","title":"Participation of the cannabinoid system and the NO/cGMP/KATP pathway in serotonin-induced peripheral antinociception.","authors":"Aguiar, Danielle Diniz; Petrocchi, Júlia Alvarenga; da Silva, Grazielle Caroline; Lemos, Virgínia Soares; Castor, Marina Gomes Miranda E; Perez, Andrea de Castro; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima","year":2024,"journal":"Neuroscience letters, 818, 137536","doi":"10.1016/j.neulet.2023.137536","pmid":"37898181","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05065","title":"Local activation of CB1 receptors by synthetic and endogenous cannabinoids dampens burst firing mode of reticular thalamic nucleus neurons in rats under ketamine anesthesia.","authors":"Aguirre-Rodríguez, Carlos A; Delgado, Alfonso; Alatorre, Alberto; Oviedo-Chávez, Aldo; Martínez-Escudero, José R; Barrientos, Rafael; Querejeta, Enrique","year":2024,"journal":"Experimental brain research, 242(9), 2137-2157","doi":"10.1007/s00221-024-06889-6","pmid":"38980339","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05066","title":"A Sensitive Ultrahigh-Performance Liquid Chromatography/Tandem Mass Spectrometry Method for the Simultaneous Analysis of Phytocannabinoids and Endocannabinoids in Plasma and Brain.","authors":"Ahmed, Faizy; Torrens, Alexa; Mahler, Stephen V; Ferlenghi, Francesca; Huestis, Marilyn A; Piomelli, Daniele","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 371-385","doi":"10.1089/can.2022.0216","pmid":"36367975","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05067","title":"Concurrent Experience of Self-Reported Mental Health Symptoms and Problematic Substance Use During the First Two Years of the COVID-19 Pandemic Among Canadian Adults: Evidence from a Repeated Nationwide Cross-Sectional Survey.","authors":"Ahmed, Md Sabbir; Bartram, Mary; Gabrys, Robert; Mela, Mansfield; Muhajarine, Nazeem","year":2024,"journal":"International journal of environmental research and public health, 21(12)","doi":"10.3390/ijerph21121644","pmid":"39767483","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Concurrent poor mental health and problematic substance use were prevalent during the COVID-19 pandemic. The study identified demographic and behavioral factors associated with experiencing both simultaneously, suggesting intertwined rather than independent challenges.","whyItMatters":"The pandemic worsened both mental health and substance use. Understanding who experiences both simultaneously helps target integrated treatment approaches rather than addressing each in isolation.","specificNumbers":"14,897 Canadian adults surveyed across 10 waves (October 2020 to March 2022). Concurrent mental health symptoms and problematic substance use assessed. Associated factors identified.","methodology":"Repeated nationwide cross-sectional survey of 14,897 Canadian adults (quota-sampled, weighted) recruited on 10 occasions between October 2020 and March 2022 using online panels. Assessed mental health symptoms and problematic substance use concurrence.","limitations":"Online panel recruitment may not be fully representative. Self-reported mental health and substance use. Cross-sectional waves cannot track individual trajectories. \"Problematic\" substance use defined by survey criteria, not clinical diagnosis. Pandemic context may limit generalizability."},{"rthcId":"RTHC-05068","title":"Illuminating Cannabis sativa L.: The Power of Light in Enhancing C. sativa Growth and Secondary Metabolite Production.","authors":"Ahsan, S M; Injamum-Ul-Hoque, Md; Shaffique, Shifa; Ayoobi, Akhtar; Rahman, Md Atikur; Rahman, Md Mezanur; Choi, Hyong Woo","year":2024,"journal":"Plants (Basel, Switzerland), 13(19)","doi":"10.3390/plants13192774","pmid":"39409645","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05069","title":"Substance Use Disorder and Suicidal Ideation in Rural Maryland.","authors":"Ahuja, Manik; Jain, Monika; Mamudu, Hadii; Al Ksir, Kawther; Sathiyaseelan, Thiveya; Zare, Shahin; Went, Nils; Fernandopulle, Praveen; Schuver, Trisha; Pons, Amanda; Dooley, McKenzie; Nwanecki, Chisom; Dahal, Kajol","year":2024,"journal":"Chronic stress (Thousand Oaks, Calif.), 8, 24705470241268483","doi":"10.1177/24705470241268483","pmid":"39113832","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use disorder was positively associated with suicidal ideation in rural Maryland emergency department visits (OR 2.67, 95% CI 1.37-5.18), though its association was smaller than that of major depressive disorder (OR 79.3), alcohol use disorder (OR 6.87), or opioid use disorder (OR 5.39).","whyItMatters":"Rural communities face disproportionate burdens of substance use and suicide, with fewer mental health resources. Understanding which substance use disorders carry the strongest associations with suicidal ideation could help target limited rural prevention resources.","specificNumbers":"Cannabis use disorder OR for suicidal ideation: 2.67 (95% CI 1.37-5.18). Opioid use disorder: OR 5.39 (95% CI 3.63-7.99). Alcohol use disorder: OR 6.87 (95% CI 4.97-9.51). Major depressive disorder: OR 79.30 (95% CI 51.91-121.15).","methodology":"Researchers analyzed Maryland HCUP State Emergency Department Database discharge data, using logistic regression to assess associations between ICD-10 coded substance use disorders and suicidal ideation, controlling for income, race, age, and gender.","limitations":"Cross-sectional ER data cannot establish causation or determine the direction of the association. Rural Maryland may not represent other rural regions. ICD-10 coding may undercount cannabis use disorder. The study could not assess severity or frequency of use."},{"rthcId":"RTHC-05070","title":"The Neurotherapeutic Arsenal in Cannabis sativa: Insights into Anti-Neuroinflammatory and Neuroprotective Activity and Potential Entourage Effects.","authors":"Al-Khazaleh, Ahmad K; Zhou, Xian; Bhuyan, Deep Jyoti; Münch, Gerald W; Al-Dalabeeh, Elaf Adel; Jaye, Kayla; Chang, Dennis","year":2024,"journal":"Molecules (Basel, Switzerland), 29(2)","doi":"10.3390/molecules29020410","pmid":"38257323","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05071","title":"Marijuana's Impact On Implant-based Breast Reconstruction: A Retrospective Cohort Study.","authors":"Al-Saghir, Tala; Hall, Jamie; Diffley, Michael; Tang, Amy; Teitelbaum, Abigail; Tepper, Donna G; Darian, Vigen; Evangelista, Maristella; Atisha, Dunya","year":2024,"journal":"Plastic and reconstructive surgery. Global open, 12(8), e6082","doi":"10.1097/GOX.0000000000006082","pmid":"39171243","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective cohort","evidenceStrength":"low","keyFinding":"Among 243 patients undergoing immediate direct-to-implant breast reconstruction, 12 active cannabis users showed significantly higher rates of cellulitis requiring IV antibiotics, explantation for infection, ER visits, readmission, and reoperation within 90 days compared to non-users.","whyItMatters":"As cannabis use becomes more common, surgeons and patients need data on how it may affect surgical outcomes. This study suggests perioperative cannabis use could meaningfully increase complication risk in breast reconstruction.","specificNumbers":"243 total patients, 12 active cannabis users. Significant increases in cellulitis with IV antibiotics (p=0.004), explantation for infection (p=0.004), ER visits (p=0.028), readmission (p=0.037). Adjusted OR for takeback to OR within 90 days: 4.75 (p=0.001). Major complications OR: 2.26 (p=0.048).","methodology":"Retrospective cohort study at a quaternary-care breast cancer center examining consecutive patients undergoing immediate direct-to-implant reconstruction. Active cannabis use was defined as use within 12 weeks of surgery. Univariate and multivariable analyses were performed.","limitations":"Very small cannabis group (12 patients) limits statistical power and generalizability. Retrospective design cannot control for all confounders. Self-reported cannabis use likely underestimates true prevalence. Single-center study."},{"rthcId":"RTHC-05072","title":"Biobehavioral and affective stress responses during nicotine withdrawal: Influence of regular cannabis co-use.","authors":"al'Absi, Mustafa; DeAngelis, Briana N; Nakajima, Motohiro; Hodges, James S; Budney, Alan; Hatsukami, Dorothy; Allen, Sharon","year":2024,"journal":"Psychopharmacology, 241(2), 253-262","doi":"10.1007/s00213-023-06481-w","pmid":"37897498","tags":["addiction","withdrawal"],"studyType":"laboratory experiment","evidenceStrength":"moderate","keyFinding":"Cannabis co-users exhibited exaggerated diastolic blood pressure responses to stress compared to non-cannabis users, and people using both nicotine and cannabis had higher cannabis craving than cannabis-only users (p<0.01). Nicotine users showed attenuated cortisol and systolic BP stress responses.","whyItMatters":"Cannabis and nicotine co-use is increasingly common, yet most smoking cessation research focuses on nicotine alone. Understanding how cannabis changes the withdrawal experience could help develop better quit strategies for co-users.","specificNumbers":"79 participants across four groups. Nicotine-cannabis co-users had significantly higher cannabis craving than cannabis-only users (p<0.01). Cannabis users showed exaggerated diastolic BP responses to stress.","methodology":"Laboratory study with 79 participants in four groups (nicotine-only, cannabis-only, both, neither). Nicotine users attended two stress assessment sessions: one during ad libitum use and one during nicotine abstinence. Saliva cortisol, subjective states, and cardiovascular measures were collected.","limitations":"Small sample size (79 across four groups). Laboratory stress may not replicate real-world stress. Cannot determine whether cannabis amplifies withdrawal or withdrawal amplifies cannabis effects."},{"rthcId":"RTHC-05073","title":"Exploring Novel Pharmacotherapy Candidates for Cannabis Use Disorder: Uncovering Promising Agents on the Horizon by Mechanism of Action.","authors":"Alayoubi, Myra; Henry, Brittany A; Cahill, Catherine M; Cooper, Ziva D","year":2024,"journal":"Drugs, 84(11), 1395-1417","doi":"10.1007/s40265-024-02098-1","pmid":"39388076","tags":["addiction","quitting"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"This review of randomized placebo-controlled trials found that CB1 receptor agonists (such as nabilone) showed the most promise for treating cannabis use disorder, while serotonergic, GABAergic, and other compound classes had more limited or mixed evidence.","whyItMatters":"There is currently no FDA-approved medication for cannabis use disorder, even as CUD rates rise with legalization. Identifying which medication classes work best could lead to effective treatments.","specificNumbers":"The review covered compounds including nabilone (CB1 agonist), bupropion (serotonergic), zolpidem (GABAergic), and others across multiple RCTs. CUD rates are increasing with cannabis legalization worldwide.","methodology":"Narrative review evaluating evidence from randomized, placebo-controlled trials of pharmacotherapies for cannabis use disorder, organized by compound target and outcome (withdrawal symptoms, craving, relapse/use).","limitations":"Narrative rather than systematic review. Most trials have small sample sizes. Many compounds studied in limited populations. Females, certain racial/ethnic groups, and different age groups may respond differently."},{"rthcId":"RTHC-05074","title":"Recreational Cannabis Legalization: No Contribution to Rising Prescription Stimulants in the USA.","authors":"Alexander, Garrett D; Cavanah, Luke R; Goldhirsh, Jessica L; Huey, Leighton Y; Piper, Brian J","year":2024,"journal":"Pharmacopsychiatry, 57(5), 249-254","doi":"10.1055/a-2334-6253","pmid":"39084319","tags":["legalization"],"studyType":"ecological","evidenceStrength":"moderate","keyFinding":"While total stimulant distribution rates were higher in states with recreational cannabis sales after implementation (p=0.049), there was no significant interaction between time and cannabis sales status (p=0.406), meaning legalization did not contribute to a more pronounced rise in stimulant distribution.","whyItMatters":"Because ADHD-like cognitive deficits can resemble effects of chronic cannabis use, some hypothesized that cannabis legalization might drive increased stimulant prescriptions. This study found no evidence supporting that concern.","specificNumbers":"States with RC had higher post-implementation stimulant rates (p=0.049) but not pre-implementation (p=0.221). Time effect was significant (p<0.05), state effect significant (p=0.045), but time x RC interaction was not (p=0.406).","methodology":"Researchers compared three-year population-corrected slopes of Schedule II stimulant (amphetamine, lisdexamfetamine, methylphenidate) distribution from the DEA ARCOS database before and after recreational cannabis sales in states with and without legal sales.","limitations":"Ecological study design cannot track individual-level associations. ARCOS data measures distribution, not individual prescriptions. Cannot account for illicit cannabis use in non-legal states. Limited follow-up period after legalization."},{"rthcId":"RTHC-05075","title":"Hemp Seed Oil Inhibits the Adipogenicity of the Differentiation-Induced Human Mesenchymal Stem Cells through Suppressing the Cannabinoid Type 1 (CB1).","authors":"Almousa, Albatul S; Subash-Babu, Pandurangan; Alanazi, Ibrahim O; Alshatwi, Ali A; Alkhalaf, Huda; Bahattab, Eman; Alsiyah, Atheer; Alzahrani, Mohammad","year":2024,"journal":"Molecules (Basel, Switzerland), 29(7)","doi":"10.3390/molecules29071568","pmid":"38611847","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05076","title":"Cannabis use in the United States and its impact on gastrointestinal health.","authors":"Alshaarawy, Omayma; Balasubramanian, Gokulakrishnan; Venkatesan, Thangam","year":2024,"journal":"Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition, 39(2), 281-292","doi":"10.1002/ncp.11111","pmid":"38142306","tags":["medical-cannabis"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system regulates visceral sensation, nausea, vomiting, and the gut microbiome. While cannabis has FDA-approved antiemetic uses, chronic heavy use is linked to cannabinoid hyperemesis syndrome. The review questions whether CHS is a distinct entity or a subtype of cyclic vomiting unmasked by heavy cannabis use.","whyItMatters":"Cannabis legalization and rising use have outpaced research on GI effects. Many people use cannabis for nausea or GI symptoms, making it important to understand both the potential benefits and the paradoxical risk of hyperemesis with heavy use.","specificNumbers":"FDA has approved cannabis-based medications (dronabinol, nabilone) for chemotherapy-induced nausea and vomiting. Over 5% of women use cannabis during pregnancy, partly for nausea.","methodology":"Narrative review of evidence on gastrointestinal effects of cannabis and cannabinoids, covering endocannabinoid system physiology, antiemetic properties, CHS, IBS, and gut microbiome effects.","limitations":"Narrative review with considerable heterogeneity in the underlying literature. Many GI studies are small or observational. The CHS vs. cyclic vomiting question remains unresolved."},{"rthcId":"RTHC-05077","title":"Delineating the molecular mechanisms of hippocampal neurotoxicity induced by chronic administration of synthetic cannabinoid AB-FUBINACA in mice.","authors":"Alzu'bi, Ayman; Abu-El-Rub, Ejlal; Almahasneh, Fatimah; Tahat, Lena; Athamneh, Rabaa Y; Khasawneh, Ramada; Alzoubi, Hiba; Ghorab, Doaa S; Almazari, Rawan; Zoubi, Mazhar Salim Al; Al-Zoubi, Raed M","year":2024,"journal":"Neurotoxicology, 103, 50-59","doi":"10.1016/j.neuro.2024.05.009","pmid":"38823587","tags":["synthetic-cannabinoids","neuroscience","cognition"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"AB-FUBINACA caused significant recognition memory impairment along with hippocampal histopathological changes. These effects correlated with increased oxidative stress, neuroinflammation, apoptosis markers, reduced brain-derived neurotrophic factor (BDNF), and decreased NR1 subunit expression of NMDA receptors.","whyItMatters":"Synthetic cannabinoids are far more potent than natural cannabis and are linked to psychiatric emergencies, but the molecular mechanisms behind their neurotoxicity are poorly understood. This study maps specific pathways of hippocampal damage.","specificNumbers":"Significant decreases in BDNF expression and NR1 (NMDA receptor subunit). Increased markers of oxidative stress, neuroinflammation, and apoptosis in hippocampal tissue.","methodology":"Mouse study evaluating chronic AB-FUBINACA administration effects on hippocampus through behavioral testing (recognition memory), histopathology, and molecular markers of oxidative stress, inflammation, apoptosis, BDNF, and NMDA receptor expression.","limitations":"Mouse model may not fully translate to human neurotoxicity. Specific doses and administration routes may not match human use patterns. Only studied one synthetic cannabinoid (AB-FUBINACA) out of hundreds."},{"rthcId":"RTHC-05078","title":"The synthetic cannabinoids menace: a review of health risks and toxicity.","authors":"Alzu'bi, Ayman; Almahasneh, Fatimah; Khasawneh, Ramada; Abu-El-Rub, Ejlal; Baker, Worood Bani; Al-Zoubi, Raed M","year":2024,"journal":"European journal of medical research, 29(1), 49","doi":"10.1186/s40001-023-01443-6","pmid":"38216984","tags":["synthetic-cannabinoids"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoids produce multisystem toxicity through CB1R and CB2R activation plus non-cannabinoid targets (GPR55, GPR18, PPARs, TRPV1). Downstream effects include oxidative stress, inflammation, and apoptosis in neurological, cardiovascular, renal, and hepatic systems.","whyItMatters":"Synthetic cannabinoids remain widely available despite bans and cause disproportionate emergency department visits relative to their use rates. Understanding multi-organ toxicity mechanisms helps clinicians recognize and treat exposures.","specificNumbers":"SC toxicity mediated by CB1R, CB2R, and non-cannabinoid targets including GPR55, GPR18, PPARs, and TRPV1. Effects documented across neurological, cardiovascular, renal, and hepatic systems.","methodology":"Narrative review of published literature on synthetic cannabinoid health effects, organized by organ system and molecular mechanism of toxicity.","limitations":"Review-level evidence with heterogeneous case reports and preclinical studies. Many synthetic cannabinoid variants exist with different toxicity profiles. Dose-response relationships are poorly characterized."},{"rthcId":"RTHC-05079","title":"Altered neurobehavioral reward response predicts psychotic-like experiences in youth exposed to cannabis prenatally.","authors":"Amir, Carolyn M; Ghahremani, Dara G; Chang, Sarah E; Cooper, Ziva D; Bearden, Carrie E","year":2024,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2024.08.23.24312453","pmid":"39228696","tags":["pregnancy","psychosis","youth","dopamine"],"studyType":"longitudinal cohort","evidenceStrength":"moderate","keyFinding":"Prenatal cannabis exposure (PCE) was longitudinally associated with psychotic-like experiences in youth. Blunted neural response to reward anticipation was associated with psychotic-like experiences, with stronger effects in PCE-exposed youth (all |beta|>0.5, FDR-corrected p<0.05).","whyItMatters":"With rising prenatal cannabis exposure rates alongside legalization, understanding the neurobiological mechanisms linking early exposure to later psychiatric symptoms is critical for informing public health guidance for pregnant women.","specificNumbers":"652 cannabis-exposed youth out of 11,368 at baseline. Effect sizes |beta|>0.5 for blunted reward response and psychotic-like experiences in PCE youth. Data from 22 sites across the US. Tracked across 4 years.","methodology":"Longitudinal analysis of the ABCD Study tracking children from age 9-10 across baseline (n=11,368), 2-year (n=7,928), and 4-year (n=2,982) follow-ups. Task-related fMRI measured reward anticipation, and 652 youth had prenatal cannabis exposure.","limitations":"Prenatal cannabis exposure was maternally reported and likely underestimated. Cannot fully separate cannabis effects from other prenatal exposures or genetic factors. Attrition reduced sample from 11,368 to 2,982 by 4-year follow-up. Preprint (not yet peer reviewed)."},{"rthcId":"RTHC-05080","title":"Maternal Cannabis Use in Pregnancy and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring.","authors":"Andrade, Chittaranjan","year":2024,"journal":"The Journal of clinical psychiatry, 86(1)","doi":"10.4088/JCP.24f15717","pmid":"39724097","tags":["pregnancy","youth"],"studyType":"meta-analysis + cohort","evidenceStrength":"moderate","keyFinding":"Meta-analysis of 13 studies found gestational cannabis exposure associated with ASD (RR 1.30) and ADHD (RR 1.13, possibly supported by publication bias). A separate cohort study (n=222,534) found peri-pregnancy cannabis use disorder associated with ASD (RRs 3.02-3.21), with larger effects in nonsmokers (RRs 4.55-4.83) than smokers (RRs 1.74-1.87).","whyItMatters":"Up to 10% of women may use cannabis during pregnancy, and constituents cross the placental barrier to act on cannabinoid receptors in the developing fetal brain. Understanding neurodevelopmental risks is essential for informed decision-making.","specificNumbers":"ASD meta-analysis RR: 1.30 (4 studies, N=178,565). ADHD meta-analysis RR: 1.13 (10 studies, N=203,783). Cohort study CUD and ASD: RR 3.02-3.21 (n=222,534). Nonsmokers: RR 4.55-4.83. Smokers: RR 1.74-1.87.","methodology":"Review of a meta-analysis (4 ASD studies, pooled N=178,565; 10 ADHD studies, pooled N=203,783) plus a large retrospective cohort study (n=222,534) examining associations between prenatal cannabis exposure and neurodevelopmental outcomes.","limitations":"The ADHD finding may be influenced by publication bias. Cannot separate cannabis effects from genetic, environmental, or behavioral confounders. Small total number of exposed pregnancies worldwide. CUD is a proxy for heavy use, not any use."},{"rthcId":"RTHC-05081","title":"Towards a Further Understanding of Meta-Analysis Using Gestational Exposure to Cannabis and Birth Defects as a Case in Point.","authors":"Andrade, Chittaranjan","year":2024,"journal":"The Journal of clinical psychiatry, 85(4)","doi":"10.4088/JCP.24f15673","pmid":"39566055","tags":["pregnancy"],"studyType":"meta-analysis review","evidenceStrength":"moderate","keyFinding":"Pooling data from 18 cohort and 18 case-control studies (>19 million subjects), prenatal cannabis exposure was associated with any birth defect (pooled ORs 1.25-1.33). ORs were also elevated for cardiovascular, gastrointestinal, nervous system, genitourinary, and musculoskeletal defects but not orofacial defects. Effects were smaller and less often significant in adjusted analyses.","whyItMatters":"5-10% of US pregnancies are exposed to cannabis, with highest use in the first trimester when organs are forming. Even a small increase in birth defect risk could affect a meaningful number of pregnancies at the population level.","specificNumbers":"36 studies (18 cohort, 18 case-control), >19 million subjects. Pooled ORs for any birth defect: 1.25-1.33. Significant for cardiovascular, GI, nervous system, genitourinary, and musculoskeletal defects. Not significant for orofacial defects. Adjusted estimates were smaller.","methodology":"Review and critical appraisal of two meta-analyses pooling cohort and case-control studies of prenatal cannabis exposure and birth defects. Discusses both unadjusted and adjusted estimates, cumulative meta-analyses, and methodological strengths and shortcomings.","limitations":"The meta-analysis pooled cohort and case-control ORs together, which is methodologically problematic. Some forest plots included the same sample multiple times. Adjusted analyses showed weaker associations. First-trimester exposure was not always distinguishable from overall pregnancy exposure."},{"rthcId":"RTHC-05082","title":"Maternal Cannabis Use During Pregnancy and Maternal and Neonatal Adverse Outcomes.","authors":"Andrade, Chittaranjan","year":2024,"journal":"The Journal of clinical psychiatry, 85(4)","doi":"10.4088/JCP.24f15611","pmid":"39480147","tags":["pregnancy"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"Maternal cannabis use during pregnancy was associated with small to moderately increased risks of gestational hypertension, abnormal gestational weight gain, placental abruption, preterm birth (<36, <34, and <32 weeks), small for gestational age, low birth weight, NICU admission, and fetal death, even in women not using other substances.","whyItMatters":"Over 5% of women use cannabis during pregnancy, often for nausea, anxiety, or pain, and many are unaware of pregnancy-related risks. Cannabis constituents cross the placenta and act on receptors in the developing fetal brain.","specificNumbers":"Over 5% of women use cannabis during pregnancy. Increased risks identified for preterm birth at <36, <34, and <32 weeks. Risks were greater with greater frequency of use. Adverse outcomes persisted even when excluding women using other substances.","methodology":"Narrative review of recent cohort studies and meta-analyses examining specific maternal and neonatal adverse outcomes associated with gestational cannabis exposure.","limitations":"Observational data cannot prove causation. Women who use cannabis may differ from non-users in ways that independently affect pregnancy outcomes. Self-report likely underestimates use. Some studies could not separate cannabis from tobacco effects."},{"rthcId":"RTHC-05083","title":"The Entourage Effect in Cannabis Medicinal Products: A Comprehensive Review.","authors":"André, Rebeca; Gomes, Ana Patrícia; Pereira-Leite, Catarina; Marques-da-Costa, António; Monteiro Rodrigues, Luis; Sassano, Michael; Rijo, Patricia; Costa, Maria do Céu","year":2024,"journal":"Pharmaceuticals (Basel, Switzerland), 17(11)","doi":"10.3390/ph17111543","pmid":"39598452","tags":["medical-cannabis","cbd"],"studyType":"systematic review","evidenceStrength":"moderate","keyFinding":"Analysis found no evidence of neuroprotective or anti-aggregatory effects of pinene against beta-amyloid toxicity, though modest lipid peroxidation inhibition was observed. Myrcene showed topical anti-inflammatory properties but did not add significant benefit when combined with CBD. The entourage effect remains unproven.","whyItMatters":"The entourage effect is heavily marketed in the cannabis industry to justify whole-plant products over isolated cannabinoids. This systematic review found the evidence does not yet support those marketing claims.","specificNumbers":"Terpenes studied: alpha-pinene, beta-pinene, terpinolene, myrcene, linalool, D-limonene, caryophyllene, valencene, borneol, eucalyptol. No significant additive benefit of myrcene when combined with CBD.","methodology":"PRISMA systematic review searching PubMed/MEDLINE, Web of Science, and EBSCO databases using MeSH terms, examining two questions: physiological effects of cannabis terpenes and proven entourage effects.","limitations":"Limited number of high-quality clinical trials testing specific terpene-cannabinoid combinations. Most evidence is preclinical or exploratory. The entourage effect may require specific combinations or conditions not yet tested."},{"rthcId":"RTHC-05084","title":"Cannabinoid Hyperemesis Syndrome.","authors":"Angulo, Maria Isabel","year":2024,"journal":"JAMA","doi":"10.1001/jama.2024.9716","pmid":"39388146","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"This JAMA patient page provided an accessible overview of cannabinoid hyperemesis syndrome (CHS), a condition where chronic, frequent cannabis use triggers recurrent episodes of severe nausea and vomiting.\n\nCHS is a gastrointestinal condition that develops in a subset of long-term cannabis users. Episodes can be debilitating and often include compulsive hot bathing, which provides temporary relief. The condition was first described in 2004 and has become increasingly recognized as cannabis use has expanded.\n\nThe only consistently effective treatment is complete cessation of cannabis use. The condition often goes undiagnosed because both patients and clinicians may not connect chronic cannabis use with gastrointestinal symptoms, leading to repeated emergency visits and unnecessary testing.","whyItMatters":"CHS is increasingly common as cannabis use rises, yet it remains frequently misdiagnosed. Patients often undergo extensive gastrointestinal workups before the connection to cannabis is identified. Raising awareness among both patients and clinicians can reduce diagnostic delays and unnecessary healthcare costs.","specificNumbers":"CHS develops in a subset of frequent, long-term cannabis users. Complete cannabis cessation is the only reliably effective treatment. The condition was first described in the medical literature in 2004.","methodology":"This was a patient education page published in JAMA, designed to provide accessible health information to a general audience. It synthesized current medical understanding of CHS into a brief, plain-language format.","limitations":"As a patient education page, this did not present new research or systematically review the evidence. It simplified a condition that still has uncertainties regarding its exact mechanism and why only some chronic users develop it."},{"rthcId":"RTHC-05085","title":"Clinical and lifestyle predictors of loneliness: A two-year longitudinal study.","authors":"Antonelli-Salgado, Thyago; Montezano, Bruno Braga; Roza, Thiago Henrique; Bouvier, Vitória; Zimerman, Aline; Noronha, Lucas Tavares; Marcon, Grasiela; Hoffmann, Maurício Scopel; Brunoni, André Russowsky; Passos, Ives Cavalcante","year":2024,"journal":"Journal of psychiatric research, 180, 482-488","doi":"10.1016/j.jpsychires.2024.11.025","pmid":"39547047","tags":["mental-health","addiction"],"studyType":"longitudinal cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use was significantly associated with higher loneliness risk (RR 1.750, 95% CI 1.25-2.39, p<0.001) after adjusting for sociodemographic factors. Other risk factors included depressive symptoms (RR 1.214), anxiety (RR 1.191), and alcohol abuse (RR 1.579). Physical activity >150 min/week (RR 0.177) and good family relationships (RR 0.73) were protective.","whyItMatters":"Loneliness is recognized as a public health crisis with significant health consequences. Understanding modifiable risk factors, including substance use, could help develop prevention strategies.","specificNumbers":"473 participants (87.1% female, ages 18-75). Cannabis RR: 1.750 (95% CI 1.25-2.39). Alcohol abuse RR: 1.579 (95% CI 1.32-1.88). Physical activity >150 min/week RR: 0.177 (95% CI 0.07-0.34). Good sleep quality RR: 0.483 (95% CI 0.39-0.59).","methodology":"Two-year longitudinal study in Brazil using snowball sampling and online surveys (baseline May-June 2020). Multiple regression models adjusted for sociodemographic variables and weighted for attrition and sampling. Sample of 473 participants aged 18-75.","limitations":"Snowball sampling with 87% female participants limits generalizability. Baseline collected during early COVID-19 pandemic may inflate loneliness and substance use. Cannot determine whether cannabis causes loneliness or vice versa. Self-reported measures."},{"rthcId":"RTHC-05086","title":"Cannabinoid treatment for the symptoms of autism spectrum disorder.","authors":"Aran, Adi; Cayam Rand, Dalit","year":2024,"journal":"Expert opinion on emerging drugs, 29(1), 65-79","doi":"10.1080/14728214.2024.2306290","pmid":"38226593","tags":["cbd","medical-cannabis"],"studyType":"mini-review","evidenceStrength":"moderate","keyFinding":"Uncontrolled case series documented improvements in both core ASD symptoms and behavioral challenges with CBD-rich cannabis extracts. However, placebo-controlled studies of CBD-rich extracts and pure CBD showed mixed efficacy results. Studies demonstrated relatively high safety and tolerability.","whyItMatters":"ASD affects approximately 3% of school-age children with no approved treatment for core symptoms. Current medications (risperidone, aripiprazole) only address irritability with limited effectiveness and common side effects. Families increasingly seek cannabinoid alternatives.","specificNumbers":"ASD affects ~3% of school-age children. Only risperidone and aripiprazole are approved for ASD-related irritability. Placebo-controlled studies included CBD-rich cannabis extracts, pure CBD, and studies in Fragile X syndrome.","methodology":"Mini-review summarizing existing literature and ongoing clinical trials of cannabinoid treatments for ASD, including uncontrolled case series and placebo-controlled studies of CBD-rich extracts and pure CBD.","limitations":"Uncontrolled studies are susceptible to placebo and expectancy effects, particularly in behavioral conditions. Placebo-controlled trials are few and showed mixed results. Different formulations (pure CBD vs. CBD-rich extracts) may have different effects."},{"rthcId":"RTHC-05087","title":"Antinociceptive action of cannabidiol on thermal sensitivity and post-operative pain in male and female rats.","authors":"Arantes, Ana Luisa Ferreira; Carvalho, Milene Cristina; Brandão, Marcus Lira; Prado, Wiliam Alves; Crippa, José Alexandre de Souza; Lovick, Thelma Anderson; Genaro, Karina","year":2024,"journal":"Behavioural brain research, 459, 114793","doi":"10.1016/j.bbr.2023.114793","pmid":"38048909","tags":["cbd","pain","sex-differences"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"CBD 30 mg/kg reduced thermal pain sensitivity in males. In females, response varied by estrous cycle: no significant effect during proestrus (tail flick test), but during late diestrus, lower doses were effective. For post-operative pain, CBD 3 mg/kg reduced mechanical allodynia in males and females during proestrus, while only 0.3 mg/kg was needed during late diestrus.","whyItMatters":"Most pain research has been conducted in males, creating a gap in understanding how sex and hormonal cycles affect CBD efficacy. This study suggests women might need different CBD doses at different points in their menstrual cycle.","specificNumbers":"Males needed CBD 30 mg/kg for thermal pain and 3 mg/kg for post-operative pain. Females in late diestrus responded to 0.3 mg/kg for post-operative pain (10-fold lower than males). Onset was slower at the lower dose (90 minutes vs. faster at higher doses).","methodology":"Male and female Wistar rats were tested using tail flick (thermal pain) and von Frey (post-surgical mechanical pain) tests. CBD was administered intraperitoneally at various doses. Females were tested during different estrous cycle phases.","limitations":"Rat model may not translate directly to humans. Estrous cycle is not identical to menstrual cycle. Intraperitoneal administration does not match common human routes. Relatively small group sizes."},{"rthcId":"RTHC-05088","title":"Cannabinoid hyperemesis and pheochromocytoma hypertensive urgency: a case report.","authors":"Arendash, Jeffrey M; Chiu, Cornel; Wang, Jocelyn; Mihm, Fred","year":2024,"journal":"Journal of medical case reports, 18(1), 161","doi":"10.1186/s13256-024-04497-0","pmid":"38500192","tags":["medical-cannabis"],"studyType":"case report","evidenceStrength":"very low","keyFinding":"Cannabinoid-induced hyperemesis caused repeated violent retching in a patient with an 8 cm adrenal pheochromocytoma. The retching physically compressed the tumor, triggering catecholamine surges and hypertensive urgency requiring ICU admission and multiple antihypertensive medications.","whyItMatters":"This case illustrates an unusual but dangerous interaction between cannabinoid hyperemesis syndrome and an underlying condition. It also highlights how CHS can have consequences beyond the GI symptoms themselves.","specificNumbers":"69-year-old patient, 8 cm adrenal pheochromocytoma. Required phentolamine, clevidipine infusion, then oral doxazosin and phenoxybenzamine for blood pressure control. Hyperemesis resolved within 24 hours of treatment.","methodology":"Single case report of a 69-year-old male presenting to the emergency department with nausea, vomiting, and hypertensive urgency. History of daily cannabis use for many years with repeated hyperemesis episodes.","limitations":"Single case report cannot establish generalized risk. This combination of conditions is extremely rare. The patient also had years of daily cannabis use."},{"rthcId":"RTHC-05089","title":"Recreational cannabis legalization and pediatric exposures in Massachusetts, United States.","authors":"Argandykov, Dias; Raybould, Toby A; Gervasini, Alice; Hwabejire, John; Flaherty, Michael R","year":2024,"journal":"Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention, 30(5), 437-440","doi":"10.1136/ip-2023-045052","pmid":"38233190","tags":["legalization","youth"],"studyType":"ecological","evidenceStrength":"moderate","keyFinding":"After recreational cannabis legalization in Massachusetts, pediatric cannabis-related ER visits increased from 18.5 to 31.0 per 100,000 (IRR 1.6, 95% CI 1.5-1.8) and hospitalizations increased significantly (IRR 2.2, 95% CI 1.8-2.7, a 126% increase). Children ages 0-5 and 6-12 experienced the highest increases.","whyItMatters":"The youngest children (0-5 years) showed some of the largest increases, likely from accidental ingestion of edibles. These products may be attractive to small children and are increasingly available in legal markets.","specificNumbers":"2,357 ED visits and 538 hospitalizations over 6 years (2016-2021). ED visit IRR: 1.6 (95% CI 1.5-1.8). Hospitalization IRR: 2.2 (95% CI 1.8-2.7). Highest increases in ages 0-5 and 6-12.","methodology":"Researchers compared cannabis-related ER visits and hospitalizations among children ages 0-19 before (2016-2018) and after (2019-2021) recreational cannabis legalization in Massachusetts, using state public health surveillance data.","limitations":"Cannot determine whether increases are due to more exposures, increased willingness to seek care, or improved reporting after legalization. Pre-legalization period was only three years. Cannot assess severity differences."},{"rthcId":"RTHC-05090","title":"Canada's Recreational Cannabis Legalization and Medical Cannabis Patient Activity, 2017-2022.","authors":"Armstrong, Michael J","year":2024,"journal":"American journal of public health, 114(S8), S673-S680","doi":"10.2105/AJPH.2024.307721","pmid":"39361903","tags":["legalization","medical-cannabis"],"studyType":"interrupted time series","evidenceStrength":"moderate","keyFinding":"Medical cannabis patient registrations initially increased but slowed after the law passed and decreased after edibles became available. Purchasing frequency decreased but stabilized after edibles arrived. Purchase sizes began increasing after edibles became available.","whyItMatters":"As more countries consider recreational legalization, understanding how it reshapes existing medical programs helps policymakers plan for transitions that protect patients who rely on medical cannabis access.","specificNumbers":"Data from 10 Canadian provinces, April 2017-December 2022. Three policy events: law passage (June 2018), recreational sales start (October 2018), edibles/vapes arrival (December 2019).","methodology":"Linear regressions of interrupted time series models analyzed medical cannabis patient registrations, purchase frequency, and purchase sizes across Canada's 10 provinces from April 2017 to December 2022, testing relationships with three policy milestones.","limitations":"Administrative data cannot capture reasons for registration changes. Cannot distinguish medical patients who switched to recreational from those who stopped using cannabis entirely. Provincial variation in recreational market rollout not fully captured."},{"rthcId":"RTHC-05091","title":"Functional Adaptation in the Brain Habenulo-Mesencephalic Pathway During Cannabinoid Withdrawal.","authors":"Aroni, Sonia; Sagheddu, Claudia; Pistis, Marco; Muntoni, Anna Lisa","year":2024,"journal":"Cells, 13(21)","doi":"10.3390/cells13211809","pmid":"39513916","tags":["withdrawal","neuroscience","dopamine"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"THC withdrawal produced a marked decrease in VTA dopamine neuron firing and burst activity. The duration of RMTg-evoked inhibition of dopamine neurons was longer during withdrawal. Spontaneous activity of both RMTg and lateral habenula neurons was strongly depressed during cannabinoid withdrawal.","whyItMatters":"The hypodopaminergic state during cannabis withdrawal may drive the negative mood, motivation loss, and drug-seeking behavior that makes quitting difficult. Understanding which brain circuits are involved could identify targets for medications to ease withdrawal.","specificNumbers":"THC dose: 15 mg/kg i.p. twice daily for 6.5-7 days. Rimonabant (5 mg/kg) precipitated robust behavioral withdrawal. Abrupt suspension caused milder abstinence signs.","methodology":"Adult male rats received THC (15 mg/kg i.p.) twice daily for 6.5-7 days. Withdrawal was precipitated with rimonabant (5 mg/kg) or by abrupt THC suspension. Extracellular single-unit recordings measured activity of VTA dopamine, RMTg, and lateral habenula neurons.","limitations":"Rat model with high-dose THC may not replicate human withdrawal precisely. Only male rats studied. Acute precipitated withdrawal differs from the gradual abstinence most humans experience."},{"rthcId":"RTHC-05092","title":"Depressive symptoms predict cannabis vaping initiation among young adults.","authors":"Arora, Srishty; Marti, C Nathan; North, Caroline; Thomas, Jacob E; Harrell, Melissa B; Pasch, Keryn E; Wilkinson, Anna V; Loukas, Alexandra","year":2024,"journal":"Drug and alcohol dependence, 262, 111397","doi":"10.1016/j.drugalcdep.2024.111397","pmid":"39018887","tags":["depression","youth"],"studyType":"longitudinal cohort","evidenceStrength":"moderate","keyFinding":"Twenty-five percent of participants initiated cannabis vaping during the four-year study. Elevated depressive symptoms were significantly associated with increased risk of cannabis vaping initiation in both unadjusted and adjusted analyses. Initiation rates were stable from 2015-2017 but doubled from 2017-2019.","whyItMatters":"Cannabis vaping is the fastest-growing form of cannabis use among young adults, and understanding who starts vaping can help target prevention. The link to depression suggests mental health support could be a prevention strategy.","specificNumbers":"3,085 participants from 24 Texas colleges. 25% initiated cannabis vaping over 4 years. Initiation rates doubled between 2017-2019. Mean age 20.6 years.","methodology":"Survival analysis of 3,085 cannabis-vaping-naive young adults (ages 18-25) from 24 Texas colleges, surveyed across six waves from fall 2015 to spring 2019. Covariates included demographics, past 30-day substance use, and peer nicotine vaping.","limitations":"Texas colleges may not represent national trends. Self-reported depressive symptoms, not clinical diagnoses. Cannot determine whether depression causes vaping initiation or whether shared risk factors drive both. Ended before COVID-19."},{"rthcId":"RTHC-05093","title":"Patterns of Polysubstance Use in Young Black and Latinx Sexual Minority Men and Transgender Women and Its Association with Sexual Partnership Factors: The PUSH Study.","authors":"Arrington-Sanders, Renata; Galai, Noya; Falade-Nwulia, Oluwaseun; Hammond, Christopher; Wirtz, Andrea; Beyrer, Chris; Arteaga, Aubrey; Celentano, David","year":2024,"journal":"Substance use & misuse, 59(3), 317-328","doi":"10.1080/10826084.2023.2267655","pmid":"38146133","tags":["addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis and alcohol were each used by 76% of participants. Nearly half (47%) used both alcohol and cannabis. Polysubstance use was associated with greater adjusted odds of pressure for condomless sex, having older partners, and inconsistent condom use.","whyItMatters":"Young Black and Latinx sexual minority men face disproportionate HIV burden, and understanding how polysubstance use including cannabis connects to HIV risk behaviors can inform combination prevention strategies.","specificNumbers":"466 participants. Alcohol and cannabis: 76% each. 23% used other illicit drugs. 47% used both alcohol and cannabis. 20% used alcohol, cannabis, plus another drug.","methodology":"Cross-sectional analysis of 466 young Black and Latinx sexual minority men and transgender women from four high HIV-burden US cities enrolled in the PUSH Study, a randomized control trial. Bivariate and multivariate analyses examined polysubstance patterns and sexual partnership factors.","limitations":"Cross-sectional design cannot establish causation. Participants were from a clinical trial, potentially not representative. Self-reported substance use and sexual behaviors. Cannabis-specific effects cannot be isolated from polysubstance patterns."},{"rthcId":"RTHC-05094","title":"Cannabis and opioid perceptions, co-use, and substitution among patients across 4 NCI-Designated Cancer Centers.","authors":"Ashare, Rebecca L; Worster, Brooke; Nugent, Shannon M; Smith, Danielle M; Morasco, Benjamin J; Leader, Amy E; Case, Amy A; Meghani, Salimah H","year":2024,"journal":"Journal of the National Cancer Institute. Monographs, 2024(66), 267-274","doi":"10.1093/jncimonographs/lgad027","pmid":"39108237","tags":["medical-cannabis","pain","cancer"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Black patients were less likely to use opioids for pain (OR 0.66, p=0.035) and more likely to report cannabis was more effective than opioids (OR 2.46, p=0.03) compared to White patients. Race effects were mitigated after controlling for socioeconomic factors.","whyItMatters":"Racial disparities in opioid prescribing for cancer pain are well-documented. Understanding how cannabis fits into pain management for underserved populations could help address inequities in cancer symptom management.","specificNumbers":"1,220 patients across 4 NCI centers in 3 states. Black patients: OR 0.66 for opioid use (p=0.035). Black patients: OR 2.46 for viewing cannabis as more effective (p=0.03). Race effects not significant after socioeconomic adjustment.","methodology":"Survey of 1,220 patients across 4 NCI-designated cancer centers in 3 states assessing perceptions, use of cannabis and opioids for pain, substitution patterns, and racial/ethnic differences.","limitations":"Cross-sectional survey cannot establish causation. NCI cancer center patients may not represent all cancer patients. Self-reported perceptions may not reflect actual efficacy. Cannot determine whether cannabis substitution improves or worsens pain outcomes."},{"rthcId":"RTHC-05095","title":"Medicinal cannabis use among young adults during California's transition from legalized medical use to adult-use: a longitudinal analysis.","authors":"Ataiants, Janna; Wong, Carolyn F; Odejimi, Omolola A; Fedorova, Ekaterina V; Conn, Bridgid M; Lankenau, Stephen E","year":2024,"journal":"The American journal of drug and alcohol abuse, 50(2), 229-241","doi":"10.1080/00952990.2024.2308098","pmid":"38407837","tags":["medical-cannabis","legalization"],"studyType":"longitudinal cohort","evidenceStrength":"moderate","keyFinding":"Longitudinal latent class analysis identified three groups: Recreational Users (39.3%) with low medicinal use, Recreational Patients (40.4%) with patient status but low medicinal use, and Medicinal Patients (20.3%) with high medicinal use. Medicinal Patients had higher physical symptoms at baseline. Recreational groups showed increasing mental health symptoms and problematic cannabis use over time.","whyItMatters":"The transition from medical-only to recreational legalization reshapes who identifies as a medicinal user and why. The finding that recreational patients developed more problems suggests some may have used medical cards primarily for legal access rather than therapeutic need.","specificNumbers":"366 participants (210 patients, 156 non-patients, 34% female). Three classes: Recreational Users 39.3%, Recreational Patients 40.4%, Medicinal Patients 20.3%. Study period 2014-2021.","methodology":"Annual surveys of 366 young adult cannabis users (ages 18-26 at baseline) from Los Angeles across six waves (2014-2021). Longitudinal latent class analysis derived groups from patient status and self-reported medicinal use.","limitations":"Los Angeles sample may not represent other regions. Self-reported medicinal use is subjective. Attrition across six waves. Young adult age range (18-26) limits generalizability to older patients."},{"rthcId":"RTHC-05096","title":"The impact of schizophrenia genetic load and heavy cannabis use on the risk of psychotic disorder in the EU-GEI case-control and UK Biobank studies.","authors":"Austin-Zimmerman, Isabelle; Spinazzola, Edoardo; Quattrone, Diego; Wu-Choi, Beatrice; Trotta, Giulia; Li, Zhikun; Johnson, Emma; Richards, Alexander L; Freeman, Tom P; Tripoli, Giada; Gayer-Anderson, Charlotte; Rodriguez, Victoria; Jongsma, Hannah E; Ferraro, Laura; La Cascia, Caterina; Tosato, Sarah; Tarricone, Ilaria; Berardi, Domenico; Bonora, Elena; Seri, Marco; D'Andrea, Giuseppe; Szöke, Andrei; Arango, Celso; Bobes, Julio; Sanjuán, Julio; Santos, Jose Luis; Arrojo, Manuel; Velthorst, Eva; Bernardo, Miguel; Del-Ben, Cristina Marta; Rossi Menezes, Paulo; Selten, Jean-Paul; Jones, Peter B; Kirkbride, James B; Rutten, Bart P F; Tortelli, Andrea; Llorca, Pierre-Michel; de Haan, Lieuwe; Stilo, Simona; La Barbera, Daniele; Lasalvia, Antonio; Schurnhoff, Franck; Pignon, Baptiste; van Os, Jim; Lynskey, Michael; Morgan, Craig; O' Donovan, Michael; Lewis, Cathryn M; Sham, Pak C; Murray, Robin M; Vassos, Evangelos; Di Forti, Marta","year":2024,"journal":"Psychological medicine, 54(15), 1-13","doi":"10.1017/S0033291724002058","pmid":"39637925","tags":["psychosis","genetics","potency"],"studyType":"case-control + cohort","evidenceStrength":"high","keyFinding":"In the EU-GEI study, daily use of high-potency cannabis had OR 5.09 (95% CI 3.08-8.43) for psychotic disorder even after adjusting for schizophrenia polygenic risk score (PRS). Schizophrenia PRS was not associated with cannabis use patterns in cases or controls. No interaction between PRS and cannabis use was found.","whyItMatters":"A common counterargument to the cannabis-psychosis link is that shared genetics explain both. This study found that genetic predisposition to schizophrenia did not predict heavy cannabis use, and high-potency cannabis was a strong independent risk factor.","specificNumbers":"EU-GEI: 1,098 participants. UK Biobank: 143,600 participants. Daily high-potency cannabis adjusted OR: 5.09 (95% CI 3.08-8.43, p=3.21x10^-10). No significant PRS x cannabis use interaction.","methodology":"Two datasets: EU-GEI case-control study (1,098 participants) and UK Biobank (143,600 participants). Schizophrenia and cannabis use disorder polygenic risk scores calculated from GWAS data. Cannabis use patterns assessed and interaction with PRS tested.","limitations":"Observational design cannot prove causation despite controlling for genetic confounding. Cannabis potency was self-reported. PRS captures only a fraction of genetic risk for schizophrenia. Different assessment methods across the two datasets."},{"rthcId":"RTHC-05097","title":"The impact of pregnancy and associated hormones on the pharmacokinetics of Δ9-tetrahydrocannabinol.","authors":"Authement, Aurora K; Isoherranen, Nina","year":2024,"journal":"Expert opinion on drug metabolism & toxicology, 20(1-2), 73-93","doi":"10.1080/17425255.2024.2309213","pmid":"38258511","tags":["pregnancy"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"THC is primarily (>70%) cleared by CYP2C9 to its psychoactive metabolite 11-OH-THC, with CYP3A4 contributing <30%. Both enzymes are induced during pregnancy by pregnancy hormones, which is predicted to alter THC and 11-OH-THC disposition and pharmacodynamic effects.","whyItMatters":"Cannabis is the most widely used drug of abuse during pregnancy, yet almost nothing is known about how pregnancy changes THC processing. If CYP2C9 induction increases 11-OH-THC production, pregnant users might experience stronger psychoactive effects than expected.","specificNumbers":"THC clearance: >70% via CYP2C9 (to 11-OH-THC), <30% via CYP3A4. Both enzymes are induced during pregnancy.","methodology":"Narrative review of literature on THC metabolism, pharmacokinetics, and how pregnancy-related physiological and hormonal changes may alter cannabinoid disposition.","limitations":"Predictions based on known enzyme induction patterns, not direct measurement of THC pharmacokinetics in pregnant women. In vitro enzyme studies may not fully predict in vivo changes. Individual genetic variation in CYP2C9 adds further complexity."},{"rthcId":"RTHC-05098","title":"Early Maternal Prenatal Cannabis Use and Child Developmental Delays.","authors":"Avalos, Lyndsay A; Oberman, Nina; Alexeeff, Stacey E; Croen, Lisa A; Davignon, Meghan N; Adams, Sara R; Ansley, Deborah; Chambers, Christina D; Steuerle, Kristin; Young-Wolff, Kelly C","year":2024,"journal":"JAMA network open, 7(10), e2440295","doi":"10.1001/jamanetworkopen.2024.40295","pmid":"39422907","tags":["pregnancy","youth"],"studyType":"retrospective cohort","evidenceStrength":"high","keyFinding":"No association was observed between maternal prenatal cannabis use and child speech/language disorders (HR 0.93, 95% CI 0.84-1.03), global developmental delays (HR 1.04, 95% CI 0.68-1.59), or motor delays (HR 0.86, 95% CI 0.69-1.06). No dose-response relationship was found.","whyItMatters":"While prenatal cannabis has been linked to neonatal outcomes like low birth weight, evidence on longer-term developmental effects has been limited and conflicting. This large study found no association with early developmental delays.","specificNumbers":"119,976 pregnancies among 106,240 individuals. 6,778 (5.6%) had documented cannabis use. Daily use: 618 (0.5%). Weekly: 722 (0.6%). Monthly or less: 1,617 (1.3%). No significant associations at any frequency.","methodology":"Retrospective cohort of 119,976 children born 2015-2019 at Kaiser Permanente Northern California, followed to age 5.5 years. Prenatal cannabis use screened via self-report and urine toxicology at ~8-10 weeks gestation. Developmental delays identified from ICD-9/10 codes in electronic health records.","limitations":"Cannabis use assessed only at entry to prenatal care (~8-10 weeks), missing later-pregnancy use patterns. Some developmental delays may not manifest until after age 5.5. Self-report likely underestimates use. EHR diagnosis codes may miss milder delays."},{"rthcId":"RTHC-05099","title":"Maternal Prenatal Cannabis Use and Child Autism Spectrum Disorder.","authors":"Avalos, Lyndsay A; Shenkute, Mahlet; Alexeeff, Stacey E; Oberman, Nina; Croen, Lisa A; Davignon, Meghan; Adams, Sara R; Ansley, Deborah; Castellanos, Carley; Young-Wolff, Kelly C","year":2024,"journal":"JAMA network open, 7(10), e2440301","doi":"10.1001/jamanetworkopen.2024.40301","pmid":"39422906","tags":["pregnancy","youth"],"studyType":"retrospective cohort","evidenceStrength":"high","keyFinding":"After adjustment for maternal characteristics, prenatal cannabis use was not associated with child ASD (HR 1.05, 95% CI 0.84-1.32). No dose-response relationship was observed. No sex-specific associations were found (males: HR 1.01; females: HR 1.19).","whyItMatters":"A previous meta-analysis found a 30% increased ASD risk with prenatal cannabis exposure, but this larger, well-controlled study found no association after adjusting for confounders, suggesting earlier findings may have been driven by unmeasured variables.","specificNumbers":"178,948 pregnancies. 8,486 (4.7%) screened positive for cannabis. ASD diagnosed in 3.6% of children. Adjusted HR: 1.05 (95% CI 0.84-1.32). Males HR: 1.01. Females HR: 1.19.","methodology":"Population-based retrospective birth cohort of 178,948 singleton pregnancies among 146,296 Kaiser Permanente Northern California members (2011-2019). Cannabis use screened via self-report and urine toxicology at ~8-10 weeks gestation. ASD identified by ICD-10 codes from EHR.","limitations":"Cannabis use assessed only at early prenatal care entry. Cannot rule out effects of use later in pregnancy. EHR-based ASD diagnosis may differ from research-standard assessment. Children born 2019 had limited follow-up time for ASD diagnosis."},{"rthcId":"RTHC-05100","title":"Neonatal outcomes associated with in utero cannabis exposure: a population-based retrospective cohort study.","authors":"Avalos, Lyndsay A; Adams, Sara R; Alexeeff, Stacey E; Oberman, Nina R; Does, Monique B; Ansley, Deborah; Goler, Nancy; Padon, Alisa A; Silver, Lynn D; Young-Wolff, Kelly C","year":2024,"journal":"American journal of obstetrics and gynecology, 231(1), 132.e1-132.e13","doi":"10.1016/j.ajog.2023.11.1232","pmid":"38029850","tags":["pregnancy"],"studyType":"retrospective cohort","evidenceStrength":"high","keyFinding":"After adjustment, in utero cannabis exposure was associated with low birth weight (aOR 1.20, 95% CI 1.12-1.28), small for gestational age (aOR 1.24, 95% CI 1.18-1.30), preterm birth <37 weeks (aOR 1.06, 95% CI 1.00-1.13), and NICU admission (aOR 1.06, 95% CI 1.01-1.11). Dose-response for low birth weight and SGA with increasing use frequency.","whyItMatters":"This is one of the largest studies examining cannabis and neonatal outcomes. The dose-response relationship for birth weight and SGA strengthens the evidence that cannabis exposure, not just confounding factors, contributes to these outcomes.","specificNumbers":"364,924 infants, 22,624 (6.2%) cannabis-exposed. Low birth weight aOR: 1.20 (1.12-1.28). SGA aOR: 1.24 (1.18-1.30). Preterm <37 weeks aOR: 1.06 (1.00-1.13). NICU aOR: 1.06 (1.01-1.11). Early preterm <34 weeks aOR: 1.11 (1.00-1.23, p=0.055).","methodology":"Population-based retrospective cohort of 364,924 singleton births at Kaiser Permanente Northern California (2011-2020). Cannabis exposure defined by self-report and/or positive urine toxicology. Models adjusted for demographics, other substance use, comorbidities, and prenatal care adequacy.","limitations":"Observational design cannot prove causation. Cannabis use may be underreported. Cannot separate effects of smoking cannabis from THC itself. Some outcomes (preterm, NICU) had borderline significance."},{"rthcId":"RTHC-05101","title":"The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies.","authors":"Ayoub, Samantha M; Holloway, Breanna M; Miranda, Alannah H; Roberts, Benjamin Z; Young, Jared W; Minassian, Arpi; Ellis, Ronald J","year":2024,"journal":"Current HIV/AIDS reports, 21(3), 87-115","doi":"10.1007/s11904-024-00698-w","pmid":"38602558","tags":["cognition","medical-cannabis"],"studyType":"systematic scoping review","evidenceStrength":"moderate","keyFinding":"The review found little evidence supporting harmful effects of cannabis on cognition in people with HIV. Where effects were observed, they were function-dependent (varying by cognitive domain) and confounded by age, frequency of use, and other factors. Anti-inflammatory mechanisms were proposed as a potential beneficial pathway.","whyItMatters":"People with HIV have high rates of both cannabis use and neurocognitive impairment. If cannabis is not worsening cognition (and may have anti-inflammatory benefits), this changes the risk-benefit calculation for HIV patients who use cannabis.","specificNumbers":"Limited eligible preclinical data existed. Effects varied by cognitive function domain studied.","methodology":"Systematic scoping review of clinical and preclinical studies evaluating effects of cannabinoid exposure on cognition in HIV. Included discussion of potential mechanisms and screening considerations.","limitations":"Few preclinical studies available. Clinical studies confounded by multiple factors. \"Function-dependent\" effects make broad conclusions difficult. Cannot determine whether cannabis is truly neutral or whether positive and negative effects cancel out."},{"rthcId":"RTHC-05102","title":"The interaction between cannabinoids and long-term synaptic plasticity: A survey on memory formation and underlying mechanisms.","authors":"Azarfarin, Maryam; Ghadiri, Tahereh; Dadkhah, Masoomeh; Sahab-Negah, Sajad","year":2024,"journal":"Cell biochemistry and function, 42(6), e4100","doi":"10.1002/cbf.4100","pmid":"39090824","tags":["cognition","neuroscience"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"Evidence on cannabinoid effects on LTP and memory is contradictory. Cannabinoids can affect CB1, CB2, and non-specific receptors, producing varied effects on synaptic plasticity. Impact depends on dosage, timing, formula, route of consumption, and the endocannabinoid system's interaction with other brain networks.","whyItMatters":"With increasing cannabis use, especially among young people, understanding the molecular mechanisms behind cannabis's memory effects is essential for predicting long-term cognitive outcomes and identifying who may be most vulnerable.","specificNumbers":"Cannabis use is increasing particularly in young populations. Effects documented across multiple receptor types (CB1, CB2, TRPV1, GPR55) and interactions with glutamatergic, GABAergic, and cholinergic systems.","methodology":"Narrative review examining how exogenous cannabinoids, CB receptor agonists/antagonists, and endocannabinoids affect LTP and synaptic plasticity through various receptor interactions and neurotransmitter pathways.","limitations":"Mostly preclinical evidence with limited human translation. Review-level synthesis with heterogeneous methodology across studies. Interactions between receptor systems make isolating individual mechanisms difficult."},{"rthcId":"RTHC-05103","title":"A 96-position platform for magnetic sorbent-based dispersive microextraction: Application to the determination of tetrahydrocannabinol and cannabidiol in saliva of cannabis smokers.","authors":"Azorín, Cristian; Benedé, Juan L; Chisvert, Alberto","year":2024,"journal":"Analytica chimica acta, 1329, 343239","doi":"10.1016/j.aca.2024.343239","pmid":"39396302","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05104","title":"Cannabis use disorder and adverse cardiovascular outcomes: A population-based retrospective cohort analysis of adults from Alberta, Canada.","authors":"Bahji, Anees; Hathaway, Josh; Adams, Denise; Crockford, David; Edelman, E Jennifer; Stein, Michael D; Patten, Scott B","year":2024,"journal":"Addiction (Abingdon, England), 119(1), 137-148","doi":"10.1111/add.16337","pmid":"37766508","tags":["cardiovascular","addiction"],"studyType":"retrospective cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use disorder was associated with significantly higher cardiovascular disease events (RR 1.57, 95% CI 1.40-1.77). CUD was also associated with reduced time to incident CVD. The highest relative risks were in those without mental health comorbidity, without recent healthcare use, and without prescription medications.","whyItMatters":"Cardiovascular disease is a leading cause of death, and cannabis use disorder prevalence is rising. This population-level evidence of increased cardiovascular risk could influence clinical screening and counseling practices.","specificNumbers":"59,528 total participants (29,764 matched pairs). CUD prevalence: 0.8%. CVD events: 2.4% in CUD group vs. 1.5% in unexposed. RR: 1.57 (95% CI 1.40-1.77).","methodology":"Matched population-based retrospective cohort using five linked Alberta administrative health databases (2012-2019). 29,764 CUD-matched pairs (59,528 total). Poisson regression and Mantel-Haenszel risk ratios computed.","limitations":"Administrative data cannot capture cannabis use severity or consumption method. CUD diagnosis codes likely capture only severe use. Cannot separate effects of cannabis from effects of smoking. Matched design controls for some but not all confounders."},{"rthcId":"RTHC-05105","title":"Cannabis Co-Use Among Black Individuals with Chronic Pain Who Use Opioids: Associations with Other Substance Use and Pain Related Outcomes.","authors":"Bakhshaie, Jafar; Doorley, James D; Choukas, Nathaniel R; Fishbein, Nathan S; Grunberg, Victoria A; Vranceanu, Ana-Maria","year":2024,"journal":"Journal of health care for the poor and underserved, 35(2), 564-582","doi":null,"pmid":"38828582","tags":["pain","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Compared to opioid use alone, cannabis-opioid co-use was associated with elevated anxiety and depression symptoms, greater opioid dependence, and riskier use of other substances, but was not associated with differences in pain intensity or interference.","whyItMatters":"Black individuals with chronic pain face worse pain outcomes and opioid-related disparities. Some may add cannabis hoping to reduce opioid needs, but this study found co-use was associated with more substance-related problems without additional pain relief.","specificNumbers":"401 Black adults (51.62% female, mean age 35.9). Co-use associated with elevated anxiety, depression, opioid dependence, and risky substance use. No difference in pain outcomes.","methodology":"Cross-sectional study of 401 Black adults with chronic musculoskeletal pain who use opioids. Online measures assessed pain intensity/interference, emotional distress, opioid dependence, and risky substance use.","limitations":"Cross-sectional design cannot establish causation. Online sample may not be representative. Self-reported measures. Cannot determine whether people with worse mental health are drawn to co-use or whether co-use worsens mental health."},{"rthcId":"RTHC-05106","title":"Associations Between Buprenorphine\\Naloxone and Methadone Treatment and non-Opioid Substance Use in Prescription-Type Opioid Use Disorder: Secondary Analyses From the OPTIMA Study: Associations entre le traitement avec la buprénorphine/naloxone et avec la méthadone et l'utilisation de substances non opioïdes dans le trouble lié à l'usage d'opioïdes de type sur ordonnance : analyses secondaires de l'étude OPTIMA.","authors":"Bakouni, Hamzah; Sharafi, Heidar; Drouin, Sarah; Fortin, Raphaelle; Marsan, Stéphanie; Brissette, Suzanne; Socias, Maria Eugenia; Le Foll, Bernard; Lim, Ron; Jutras-Aswad, Didier","year":2024,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 69(4), 252-263","doi":"10.1177/07067437231210796","pmid":"37899716","tags":["addiction","drug-interactions"],"studyType":"randomized controlled trial (secondary analysis)","evidenceStrength":"moderate","keyFinding":"Methadone was associated with lower odds of THC-positive urine (OR 0.47, 95% CI 0.28-0.77) and benzodiazepine-positive urine (OR 0.63, 95% CI 0.40-0.98) compared to buprenorphine/naloxone. No difference in stimulant use. Non-opioid substance use did not predict opioid use or treatment retention.","whyItMatters":"Understanding how different opioid agonist treatments affect cannabis and other substance use can help clinicians choose optimal treatment and counsel patients about expected patterns of substance use during recovery.","specificNumbers":"THC-positive UDS: methadone OR 0.47 (95% CI 0.28-0.77). Benzodiazepine-positive: OR 0.63 (0.40-0.98). Stimulant-positive: OR 1.29 (0.78-2.16, not significant). No association between non-opioid substance use and treatment outcomes.","methodology":"Secondary analysis of the OPTIMA trial, an open-label, pragmatic, pan-Canadian, multicenter RCT comparing methadone and flexible take-home buprenorphine/naloxone for prescription-type opioid use disorder. Non-opioid substance use assessed by urine drug screens (weeks 2-24).","limitations":"Open-label trial design. Secondary analysis not powered for substance use outcomes. Prescription-type OUD may differ from illicit opioid use disorder. UDS detection windows vary by substance. Canadian healthcare context."},{"rthcId":"RTHC-05107","title":"Trends in Substance-Related Visits Among Youth to US Children's Hospitals, 2016-2021: An Analysis of the Pediatric Health Information System Database.","authors":"Ball, Alexis; Hadland, Scott; Rodean, Jonathan; Hall, Matt; Mendoza, Jason; Ahrens, Kym","year":2024,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 75(1), 76-84","doi":"10.1016/j.jadohealth.2024.02.016","pmid":"38530681","tags":["youth","addiction"],"studyType":"cross-sectional trend analysis","evidenceStrength":"moderate","keyFinding":"From 2016-2021, substance-related visits increased 47.9% across all demographics. Cannabis accounted for 52.2% of visits and had 82.4% growth (p<0.001). Hispanic youth had the greatest demographic growth (63.3%). During the pandemic, publicly insured, female, non-Hispanic Black, and Hispanic youth exceeded predicted visit numbers.","whyItMatters":"Cannabis-related visits to children's hospitals growing at 82% far outpaces other substances and represents a significant and growing burden on pediatric healthcare. The disproportionate impact on minoritized youth adds an equity dimension.","specificNumbers":"106,793 visits involving 84,632 youth. Cannabis: 52.2% of visits, 82.4% growth. Hispanic youth growth: 63.3%. Overall growth: 47.9%. All substances except sedatives increased.","methodology":"Cross-sectional analysis of the Pediatric Health Information System database covering substance-related visits by youth ages 12-21 at children's hospitals from 2016-2021. ICD-10 codes identified visits for substance use, dependence, or overdoses. Time series analysis predicted pandemic-era expected visits.","limitations":"Children's hospital data may not capture youth seen in adult facilities or community settings. ICD-10 coding practices vary. Cannot determine whether increases reflect more use, more severe use, or changes in healthcare-seeking behavior. Hospital-level data, not population-based."},{"rthcId":"RTHC-05108","title":"Canadians' use of cannabis for therapeutic purposes since legalization of recreational cannabis: a cross-sectional analysis by medical authorization status.","authors":"Balneaves, Lynda G; Brown, Ashleigh; Green, Matthew; Prosk, Erin; Rapin, Lucile; Monahan-Ellison, Max; McMillan, Eva; Zaid, Jonathan; Dworkind, Michael; Watling, Cody Z","year":2024,"journal":"BMC medicine, 22(1), 150","doi":"10.1186/s12916-024-03370-7","pmid":"38589855","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Authorized patients were more likely to report no side effects (29.9% vs. 23.4%), know their cannabis amounts (32.1% vs. 17.7%), obtain from regulated sources (74.1% vs. 47.5%), and seek info from healthcare professionals (67.8% vs. 48.2%).","whyItMatters":"With many patients leaving the medical cannabis system after recreational legalization, this study suggests the medical authorization process provides tangible benefits including better product knowledge, fewer side effects, and professional guidance.","specificNumbers":"5,433 respondents, 2,941 (54.1%) with authorization. No side effects: 29.9% vs. 23.4% (p<0.001). Knew amount: 32.1% vs. 17.7% (p<0.001). Regulated sources: 74.1% vs. 47.5% (p<0.001). Healthcare professional info: 67.8% vs. 48.2% (p<0.01).","methodology":"Online survey of 5,433 Canadians using cannabis therapeutically in early 2022 (54.1% held medical authorization). Multivariable logistic regression assessed factors associated with authorization status.","limitations":"Self-selected survey sample may overrepresent engaged patients. Cross-sectional design cannot determine whether authorization causes better outcomes or whether more health-conscious patients seek authorization. Online survey excludes those without internet access."},{"rthcId":"RTHC-05109","title":"Association Between Medical Marijuana Cardholder Status and Antiemetic Overuse.","authors":"Baltz, Alan P; Peng, Cheng; Gressler, Laura; Bhatti, Sajjad; Lewis, Kanna","year":2024,"journal":"Cannabis and cannabinoid research","doi":"10.1089/can.2024.0083","pmid":"39419579","tags":["medical-cannabis","cancer"],"studyType":"retrospective cohort","evidenceStrength":"moderate","keyFinding":"Medical marijuana cardholders had significantly lower odds of antiemetic overuse (aOR 0.76, p<0.05) compared to non-cardholders. Antiemetic overuse was identified in 7.5% of chemotherapy cycles overall.","whyItMatters":"Antiemetic overuse during chemotherapy is a quality concern highlighted by ASCO. If cannabis can reduce unnecessary antiemetic prescribing while maintaining nausea control, it could improve chemotherapy care quality and reduce costs.","specificNumbers":"20,558 patients, 436 (2.1%) had MMJ cards. Antiemetic overuse in 7.5% of chemotherapy cycles. MMJ cardholders aOR 0.76 for overuse (p<0.05).","methodology":"Retrospective cohort using linked Arkansas All Payers Claims Database (2013-2020) and medical marijuana cardholder registry (2013-2019). 20,558 cancer patients aged 18+ with outpatient chemotherapy within 12 months of diagnosis. Antiemetic overuse defined per ASCO Choosing Wisely recommendations.","limitations":"Cardholder status does not mean patients actually used cannabis. Arkansas MMJ program may not represent other states. Cannot determine whether cannabis replaced antiemetics or if cardholder characteristics drove the difference. Small MMJ group (436 of 20,558)."},{"rthcId":"RTHC-05110","title":"Does smoking cessation reduce other substance use, psychiatric symptoms, and pain symptoms? Results from an emulated hypothetical randomized trial of US veterans.","authors":"Ban, Kaoon Francois; Rogers, Erin; Khan, Maria; Scheidell, Joy; Charles, Dyanna; Bryant, Kendall J; Justice, Amy C; Braithwaite, R Scott; Caniglia, Ellen C","year":2024,"journal":"PloS one, 19(7), e0298576","doi":"10.1371/journal.pone.0298576","pmid":"38959263","tags":["addiction","quitting"],"studyType":"emulated trial","evidenceStrength":"moderate","keyFinding":"Quitting smoking was associated with improvement in cannabis use (adjusted OR 1.75, 95% CI 1.00-3.06), unhealthy alcohol use (OR 2.10), and cocaine use (OR 2.25). However, quitting smoking was not associated with improvement in depressive symptoms, anxiety, or pain.","whyItMatters":"The idea that quitting one substance helps with others has important treatment implications. This study suggests smoking cessation may cascade to reduced cannabis and other substance use, but psychiatric symptoms need separate intervention.","specificNumbers":"4,165 eligible smokers, 419 quitters, 2,330 continued smokers. Cannabis improvement OR: 1.75 (1.00-3.06). Alcohol OR: 2.10 (1.01-4.35). Cocaine OR: 2.25 (1.20-4.24). Opioid OR: 1.10 (not significant). Depression OR: 0.78 (not significant).","methodology":"Emulated hypothetical randomized trial using longitudinal data from the Veterans Aging Cohort Study (2003-2015). Inverse probability weighting adjusted for confounding and selection bias among 4,165 HIV-positive and HIV-negative veteran smokers.","limitations":"Emulated trial design does not guarantee causation. Veterans may not represent the general population. Self-reported smoking cessation and substance use. Cannabis improvement was borderline significant (lower CI = 1.00)."},{"rthcId":"RTHC-05111","title":"Impact of Marijuana Use on Lung Health.","authors":"Bando, Joanne M; Tashkin, Donald P; Barjaktarevic, Igor Z","year":2024,"journal":"Seminars in respiratory and critical care medicine, 45(5), 548-559","doi":"10.1055/s-0044-1785679","pmid":"38968961","tags":["respiratory","harm-reduction","legalization"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This is one of the central paradoxes in cannabis research: smoked marijuana produces many of the same toxins and carcinogens as tobacco smoke, yet the lung health consequences appear markedly different.\n\nThe consistent finding across studies is that regular marijuana smoking causes symptoms of chronic bronchitis — cough, increased sputum production, wheezing — and visible changes to airway tissue (histopathologic changes in the epithelium). Marijuana smokers who quit typically see these symptoms resolve, confirming the causal relationship.\n\nBut here's what doesn't happen, or at least hasn't been consistently shown: progressive decline in lung function. Tobacco smoking reliably destroys lung tissue over time, leading to emphysema and COPD. Marijuana smoking, despite producing similar irritants, has not been consistently linked to the same long-term pulmonary function decline. Some studies even suggest slight improvements in certain lung function measures among marijuana users, though this is likely a statistical artifact of the deep inhalation technique.\n\nThe lung cancer question is equally murky. Marijuana smoke contains known carcinogens, and case reports of lung cancer in marijuana smokers exist, but epidemiological studies have failed to consistently demonstrate an increased lung cancer risk — partly because most heavy marijuana smokers also smoke tobacco, making it nearly impossible to isolate marijuana's independent contribution.\n\nThe review also addresses vaping as potential harm reduction: switching from smoking to vaping marijuana reduces exposure to several toxins including carbon monoxide and reduces chronic respiratory symptoms, though long-term vaping data is still limited.\n\nImmunomodulatory effects of marijuana on the lung are also discussed — animal and in vitro studies suggest cannabis can both suppress immune defenses (potentially increasing infection risk) and protect against hyperinflammatory responses, with unclear net effects in humans.","whyItMatters":"As marijuana legalization expands, more people are smoking it regularly, and the respiratory health question is one of the most practical concerns. This review provides a nuanced answer: there are real respiratory effects (bronchitis symptoms, airway changes), but the catastrophic outcomes associated with tobacco (COPD, lung cancer) haven't been demonstrated. For people who smoke marijuana, this is critical context — and the vaping alternative may offer meaningful harm reduction.","specificNumbers":"Marijuana smoke contains carcinogens similar to tobacco. Chronic bronchitis symptoms are consistently documented in regular smokers and typically resolve with cessation. No consistent evidence of progressive pulmonary function decline. Mixed evidence on lung cancer risk (confounded by concurrent tobacco use). Vaping reduces carbon monoxide exposure and respiratory symptoms compared to smoking.","methodology":"Narrative review of published literature on the respiratory effects of marijuana use, focusing on smoked and vaped delivery methods. Covered: chronic bronchitis symptoms, airway histopathology, pulmonary function testing, lung cancer epidemiology, immunomodulation, infection risk, and harm reduction through vaping.","limitations":"Narrative review, not systematic. The biggest limitation is the field itself: most marijuana smokers also smoke tobacco, making it extremely difficult to isolate marijuana's independent respiratory effects. Long-term studies of marijuana-only smokers are rare. Vaping data is still short-term. The immunomodulatory effects described in animal/in vitro models haven't been conclusively demonstrated in human lungs. Different marijuana preparations (flower, concentrates, edibles) have completely different respiratory risk profiles, which the review acknowledges but can't fully address."},{"rthcId":"RTHC-05112","title":"Phytocannabinoids in neuromodulation: From omics to epigenetics.","authors":"Banerjee, Subhadip; Saha, Debolina; Sharma, Rohit; Jaidee, Wuttichai; Puttarak, Panupong; Chaiyakunapruk, Nathorn; Chaoroensup, Rawiwan","year":2024,"journal":"Journal of ethnopharmacology, 330, 118201","doi":"10.1016/j.jep.2024.118201","pmid":"38677573","tags":["neuroscience","cbd"],"studyType":"computational review","evidenceStrength":"low","keyFinding":"Network pharmacology of 8 phytocannabinoids revealed interaction with 10 of 60 neurodegenerative disease targets, with enrichment of ErbB and PI3K-Akt signaling pathways. CBD modifies DNA and mitochondrial DNA in the hippocampus, potentially protecting against epilepsy, depression, and Parkinson's. Effects vary across sex, disease state, and age.","whyItMatters":"Understanding the specific molecular pathways through which cannabinoids affect neurodegenerative diseases could guide development of targeted therapies and identify which patients are most likely to benefit.","specificNumbers":"8 phytocannabinoids analyzed. 10 of 60 neurodegenerative disease targets identified. Key pathways: ErbB signaling, PI3K-Akt signaling, Rap1 signaling, dopaminergic synapse, relaxin signaling.","methodology":"Extensive literature review combined with bioinformatics, network pharmacology, and enrichment analysis to map phytocannabinoid interactions with neuromodulatory pathways across metabolomics, transcriptomic, and epigenetic studies.","limitations":"Computational and bioinformatics analysis needs experimental validation. Network pharmacology identifies potential interactions, not proven mechanisms. Many findings derived from cell line and animal model data with limited human validation."},{"rthcId":"RTHC-05113","title":"Cannabis Use and Its Impact on Mental Health in Youth in Australia and the United States: A Scoping Review.","authors":"Baral, Aayush; Hanna, Fahad; Chimoriya, Ritesh; Rana, Kritika","year":2024,"journal":"Epidemiologia (Basel, Switzerland), 5(1), 106-121","doi":"10.3390/epidemiologia5010007","pmid":"38534804","tags":["youth","mental-health"],"studyType":"scoping review","evidenceStrength":"moderate","keyFinding":"Cannabis use in youth was associated with depression, psychosis, suicide, cannabis use disorder, cognitive decline, and externalizing behaviors (particularly ADHD). The cannabis-anxiety relationship was equivocal. Vulnerable groups included females, minorities, LGBTQI youth, African Americans, and Aboriginal/Torres Strait Islander populations.","whyItMatters":"With 2.8% of youth currently smoking cannabis and growing perception of harmlessness, documenting the mental health associations across two major English-speaking countries provides evidence for school and community prevention programs.","specificNumbers":"24 articles analyzed. 2.8% of youth currently smoke cannabis. Mental health issues more prevalent with increased frequency, duration, intensity, and type of use.","methodology":"Scoping review following JBI protocol, analyzing 24 articles from ProQuest Central and EBSCO databases, including systematic reviews, meta-analyses, cohort, longitudinal, and cross-sectional studies from Australia and the US.","limitations":"Scoping review includes heterogeneous study designs with varying quality. Limited to Australia and US. Cannot establish causation. The equivocal anxiety finding may reflect measurement differences or bidirectional relationships."},{"rthcId":"RTHC-05114","title":"Cannabis Use Among Cancer Patients During Active Treatment: Findings From a Study at an NCI-Designated Cancer Center.","authors":"Baral, Amrit; Diggs, Bria-Necole A; Marrakchi El Fellah, Ranya; McCarley, Connor; Penedo, Frank; Martinez, Claudia; Vidot, Denise C","year":2024,"journal":"Cancer medicine, 13(21), e70384","doi":"10.1002/cam4.70384","pmid":"39487679","tags":["cancer","medical-cannabis"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"41% of surveyed cancer patients used cannabis during active treatment. Among active users, 71.8% started before diagnosis. Stage 4 patients had higher use (60%). Top reasons during treatment: depression/mood, pain, enjoyment. 44.3% used at least daily. Most common cannabinoids: CBD (35.2%), Delta-8-THC (18.3%), CBD+THC ratio (14.1%). 12.7% were unsure what they consumed.","whyItMatters":"A significant portion of cancer patients use cannabis during treatment, often without clinician guidance. The finding that 12.7% did not know what cannabinoid they consumed highlights a safety gap.","specificNumbers":"385 patients (mean age 49.5, 53% male, 41.6% Hispanic/Latino). 41% used during treatment. 71.8% of treatment users started before diagnosis. Stage 4 use: 60%. Daily use: 44.3%. Unsure of cannabinoid content: 12.7%.","methodology":"Survey of 385 adult cancer patients at an NCI-designated cancer center using a harmonized survey created with 11 other NCI centers. Cannabis use patterns, sources, and reasons compared between active treatment users and non-users.","limitations":"Single-center survey from an NCI center with high Hispanic/Latino representation may not generalize. Self-reported data. Cannot assess whether cannabis affected treatment outcomes. Cross-sectional design."},{"rthcId":"RTHC-05115","title":"Prenatal cannabis exposure, the brain, and psychopathology during early adolescence.","authors":"Baranger, David Aa; Miller, Alex P; Gorelik, Aaron J; Paul, Sarah E; Hatoum, Alexander S; Johnson, Emma C; Colbert, Sarah Mc; Smyser, Christopher D; Rogers, Cynthia E; Bijsterbosch, Janine D; Agrawal, Arpana; Bogdan, Ryan","year":2024,"journal":"Nature. Mental health, 2(8), 975-986","doi":"10.1038/s44220-024-00281-7","pmid":"40836962","tags":["pregnancy","youth","neuroscience"],"studyType":"longitudinal cohort","evidenceStrength":"high","keyFinding":"Prenatal cannabis exposure was associated with localized gray and white matter differences in frontal and parietal cortices, their white matter tracts, and striatal resting-state connectivity, even after accounting for pregnancy, familial, and child confounds. Variability in forceps minor and pars triangularis diffusion metrics partially mediated the PCE-ADHD association longitudinally.","whyItMatters":"This is one of the first studies to identify specific brain structural changes that may mechanistically link prenatal cannabis exposure to ADHD, moving beyond association to potential biological pathway.","specificNumbers":"9,322-10,186 adolescents (ages 9-12). Differences found in frontal and parietal cortex gray matter, associated white matter tracts, and striatal connectivity. Forceps minor and pars triangularis metrics partially mediated ADHD association.","methodology":"Longitudinal analysis of ABCD Study participants ages 9-12 (n=9,322-10,186). Structural and functional MRI assessed gray/white matter and resting-state connectivity. Mediation analysis tested whether brain differences explained PCE-ADHD associations.","limitations":"Observational design cannot prove cannabis caused the brain differences. Prenatal exposure was retrospectively reported. Cannot fully separate cannabis effects from other prenatal exposures or genetic factors. Partial mediation means other pathways also contribute."},{"rthcId":"RTHC-05116","title":"Use of Medical Cannabis in Patients with Gilles de la Tourette's Syndrome in a Real-World Setting.","authors":"Barchel, Dana; Stolar, Orit; Ziv-Baran, Tomer; Gueta, Itai; Berkovitch, Matitiahu; Kohn, Elkana; Bar-Lev Schleider, Lihi","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 293-299","doi":"10.1089/can.2022.0112","pmid":"36342913","tags":["medical-cannabis"],"studyType":"observational registry","evidenceStrength":"low","keyFinding":"After 6 months of medical cannabis treatment (mean THC 123 mg/day, CBD 50.5 mg/day), significant improvements were found in quality of life (p<0.05) and sleep disorders (p=0.027). Motor tic frequency (p=0.062), vocal tics (p>0.999), and general mood (p=0.129) did not reach significance. Number of medications decreased significantly.","whyItMatters":"Tourette's syndrome has limited treatment options, and clinical guidelines already include medical cannabis. This real-world data provides practical information about dosing and outcomes, even though tic reduction did not reach significance.","specificNumbers":"70 patients identified. Mean daily dose: THC 123 mg, CBD 50.5 mg. Significant improvement in QoL and sleep. Non-significant trends for motor tics (p=0.062). Most frequent side effects: dizziness (n=4), increased appetite (n=3).","methodology":"Registry-based study of 70 Tourette's patients from Tikun Olam (Israel). Questionnaires completed before and after 6 months of treatment. Patients divided into responders and non-responders to follow-up.","limitations":"Registry-based with no control group or placebo comparison. High attrition (many did not respond to follow-up). Small sample. Cannot separate cannabis effects from natural symptom fluctuation or placebo effect."},{"rthcId":"RTHC-05117","title":"A call for mindfulness-based interventions for cannabis-use disorders.","authors":"Barré, Tangui; Cherikh, Faredj; Carrieri, Patrizia; Marcellin, Fabienne","year":2024,"journal":"L'Encephale, 50(1), 118-120","doi":"10.1016/j.encep.2023.06.015","pmid":"37604715","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05118","title":"Challenges achieving horizontal coherence across health and public security policies in formulating Uruguay's cannabis regulation.","authors":"Barry, Rachel Ann","year":2024,"journal":"Health promotion international, 39(5)","doi":"10.1093/heapro/daae136","pmid":"39495008","tags":["legalization"],"studyType":"qualitative policy analysis","evidenceStrength":"low","keyFinding":"Policy coherence across health issues was relatively limited in Uruguay's cannabis regulation. Comparisons with tobacco and alcohol regulation were strategically used to justify legalization rather than reflecting genuine policy alignment. The outcome was shaped by resolving tensions between public security goals and unhealthy commodity regulation.","whyItMatters":"As more countries consider cannabis legalization, understanding how the first country to fully legalize actually made its decisions reveals the gap between public health framing and political reality, offering lessons for future policy design.","specificNumbers":"43 semi-structured interviews. Government documents and field observations analyzed. Uruguay legalized in 2013, the first country to regulate recreational cannabis production, distribution, and sale.","methodology":"Qualitative analysis of government documents, 43 semi-structured interviews, and field observations, using the concept of policy coherence to examine how health and public security considerations shaped Uruguay's cannabis regulation.","limitations":"Single-country case study may not generalize. Qualitative analysis reflects researcher interpretation. Interview participants may have retrospectively rationalized their positions. Political context unique to Uruguay."},{"rthcId":"RTHC-05119","title":"Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat.","authors":"Bartkowiak-Wieczorek, Joanna; Bienert, Agnieszka; Czora-Poczwardowska, Kamila; Kujawski, Radosław; Szulc, Michał; Mikołajczak, Przemysław; Wizner, Anna-Maria; Jamka, Małgorzata; Hołysz, Marcin; Wielgus, Karolina; Słomski, Ryszard; Mądry, Edyta","year":2024,"journal":"Biomolecules, 14(9)","doi":"10.3390/biom14091065","pmid":"39334832","tags":["pain","medical-cannabis"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"Cannabis extracts demonstrated antinociceptive effects comparable to gabapentin in vincristine-induced neuropathic pain. CB1R protein expression increased in hippocampus with both extracts but decreased in cortex. CB2R expression increased in hippocampus and cortex with extract B. Receptor changes alone did not fully explain behavioral effects.","whyItMatters":"Neuropathic pain is notoriously difficult to treat, and gabapentin is a first-line therapy with significant side effects. Finding that cannabis extracts match gabapentin's pain relief with different side effect profiles could offer patients alternatives.","specificNumbers":"130 rats. Gabapentin 60 mg/kg reference dose. Extract D doses: 10, 20, 40 mg/kg. Extract B doses: 5, 7.5, 10, 20 mg/kg. Pain relief comparable to gabapentin.","methodology":"130 male Wistar rats divided into groups receiving vincristine (to induce neuropathic pain), gabapentin, or two cannabis extracts (D and B) at various doses. CB1R and CB2R mRNA and protein expression measured in cortex, hippocampus, and lymphocytes. Behavioral tests: Tail-Flick and von Frey.","limitations":"Rat model with vincristine-induced neuropathy may not replicate human neuropathic pain. Only male rats studied. Specific cannabinoid composition of extracts not fully characterized. Cannot translate doses directly to humans."},{"rthcId":"RTHC-05120","title":"Adult use cannabis legalization and cannabis use disorder treatment in California, 2010-2021.","authors":"Bass, Brittany; Padwa, Howard; Khurana, Dhruv; Urada, Darren; Boustead, Anne","year":2024,"journal":"Journal of substance use and addiction treatment, 162, 209345","doi":"10.1016/j.josat.2024.209345","pmid":"38494048","tags":["legalization","addiction"],"studyType":"pre-post time series","evidenceStrength":"moderate","keyFinding":"Legalization was associated with decreased CUD treatment admission probability overall (AME -0.005). Decreases were seen for males, Medi-Cal beneficiaries, adults 21+, and Whites. Increases were seen for criminal justice referrals, Black (AME +0.004), and Hispanic (AME +0.009) patients.","whyItMatters":"If legalization reduces treatment-seeking despite increasing cannabis problems, it could signal normalization of problematic use or reduced stigma-driven referrals. The racial disparities in who enters treatment post-legalization raise equity concerns.","specificNumbers":"1,460,066 treatment episodes (2010-2021). Overall AME: -0.005. Males AME: -0.025. Whites AME: -0.012. Criminal justice referrals AME: +0.017. Hispanics AME: +0.009. Blacks AME: +0.004.","methodology":"Analysis of all publicly funded substance use disorder treatment in California from 2010-2021 (1,460,066 episodes). Individual-level pre-post time series logistic regression with county and year fixed effects.","limitations":"Publicly funded treatment only (misses private treatment). Cannot distinguish voluntary from mandated treatment within non-CJ referrals. Pre-post design cannot prove legalization caused changes. Other policy changes may have occurred simultaneously."},{"rthcId":"RTHC-05121","title":"Prenatal cannabis exposure and the risk for neuropsychiatric anomalies in the offspring: a systematic review and meta-analysis.","authors":"Bassalov, Hely; Yakirevich-Amir, Noa; Reuveni, Inbal; Monk, Catherine; Florentin, Sharon; Bonne, Omer; Matok, Ilan","year":2024,"journal":"American journal of obstetrics and gynecology, 231(6), 574-588.e8","doi":"10.1016/j.ajog.2024.06.014","pmid":"38908654","tags":["pregnancy","youth"],"studyType":"systematic review and meta-analysis","evidenceStrength":"high","keyFinding":"After adjusting for confounders, pooled ORs: ADHD 1.13 (95% CI 1.01-1.26); ASD 1.04 (0.74-1.46, not significant); psychotic symptoms 1.29 (0.97-1.72, not significant); anxiety 1.34 (0.79-2.29, not significant); depression 0.72 (0.11-4.57, not significant); offspring cannabis use 1.20 (1.01-1.42).","whyItMatters":"This is the most comprehensive meta-analysis of prenatal cannabis and long-term neuropsychiatric outcomes. The small but significant ADHD association and the null findings for ASD, psychosis, anxiety, and depression help clarify a confusing literature.","specificNumbers":"18 studies, 534,445 participants. ADHD OR: 1.13 (1.01-1.26). ASD OR: 1.04 (0.74-1.46). Psychotic symptoms OR: 1.29 (0.97-1.72). Offspring cannabis use OR: 1.20 (1.01-1.42). Anxiety and depression: not significant.","methodology":"PRISMA and MOOSE-compliant systematic review searching MEDLINE, EMBASE, and Cochrane through January 2024. 18 observational studies included (534,445 participants). Random-effects meta-analysis with confounder adjustment.","limitations":"All observational studies with potential residual confounding. Small effect sizes near the null. Limited studies for some outcomes (depression: few studies). Cannot account for increasing cannabis potency over time. Exposure measurement varies across studies."},{"rthcId":"RTHC-05122","title":"Metabolic characterization and transcriptional profiling of polyphenols in Cannabis sativa L. inflorescences with different chemical phenotypes.","authors":"Bassolino, Laura; Fulvio, Flavia; Cerrato, Andrea; Citti, Cinzia; Cannazza, Giuseppe; Capriotti, Anna Laura; Alberti, Ilaria; Terracciano, Irma; Pecchioni, Nicola; Paris, Roberta","year":2024,"journal":"Planta, 260(4), 76","doi":"10.1007/s00425-024-04505-z","pmid":"39162869","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05123","title":"Synthetic Marijuana: Assessment of Usage, Motivation and Associated Risks in Adolescent Substance Users.","authors":"Baweja, Raman; Mills-Huffnagle, Sara; Jernigan, Amanda; Chongtham, Nungshitombi; Waschbusch, Daniel; Waxmonsky, James G","year":2024,"journal":"Substance use : research and treatment, 18, 29768357241254258","doi":"10.1177/29768357241254258","pmid":"38764525","tags":["synthetic-cannabinoids","youth"],"studyType":"cross-sectional survey","evidenceStrength":"low","keyFinding":"Of 80 adolescents, 49% used natural marijuana only and 51% used both synthetic and natural. Top reasons for synthetic use: low cost and reduced drug test detection risk. Dual users had higher externalizing problems (p=0.024) and peer substance use (p=0.009) but no difference in psychotic symptoms. Synthetic use heightened perceived medical risks of natural marijuana.","whyItMatters":"Understanding why adolescents choose synthetic cannabinoids over natural marijuana can inform prevention strategies. The finding that drug test avoidance is a key motivator suggests testing policies may paradoxically push some youth toward more dangerous products.","specificNumbers":"80 adolescents (71% male, 53% Caucasian, ages 14-18). 51% dual users. Higher externalizing problems in dual users (p=0.024). Higher peer substance use (p=0.009). Persecutory ideation correlated with natural marijuana frequency (p=0.04).","methodology":"Convenience sample of 80 adolescents (ages 14-18) receiving substance use treatment, surveyed between April 2016-May 2018. Assessed with Strengths and Difficulties Questionnaire and CAPE-Positive Scale for psychosis symptoms.","limitations":"Small convenience sample from a single treatment center. Adolescents already in treatment may differ from the general population. Self-reported use. Cross-sectional design. No biochemical verification."},{"rthcId":"RTHC-05124","title":"\"Everything is kind of the same except my mind is with me\": exploring cannabis substitution in a sample of adults in early recovery from an opioid or stimulant addiction.","authors":"Beaugard, Corinne A; Walley, Alexander Y; Amodeo, Maryann","year":2024,"journal":"Harm reduction journal, 21(1), 83","doi":"10.1186/s12954-024-01002-0","pmid":"38643152","tags":["harm-reduction","addiction"],"studyType":"qualitative","evidenceStrength":"low","keyFinding":"Participants found cannabis appealing for its safer profile (no overdose risk, safe supply, few side effects). Primary motives: psychiatric symptom management, withdrawal/craving mitigation, boredom relief. All described typical recovery benefits (improved self-concept, better relationships) while using cannabis. Some negative effects noted: decreased productivity, social anxiety.","whyItMatters":"The addiction field's focus on abstinence has limited understanding of non-abstinent recovery. If cannabis substitution helps some people sustain recovery from more dangerous substances, harm reduction frameworks may need to accommodate this reality.","specificNumbers":"14 participants (8 men, 6 women). 11 resolved opioid addictions, 3 resolved methamphetamine. Ages 20-50. All reported increased cannabis use during early recovery (within 12 months).","methodology":"Grounded theory qualitative study with 14 participants (8 men, 6 women, ages 20-50) who resolved primary opioid (11) or methamphetamine (3) addiction and increased cannabis use within the previous 12 months. Semi-structured interviews analyzed through line-by-line, focused, and axial coding.","limitations":"Very small sample. Self-selected participants who view substitution positively. No comparison to abstinent recovery or continued use groups. Qualitative design cannot measure outcomes. Early recovery only (within 1 year)."},{"rthcId":"RTHC-05125","title":"Development of Mobile Contingency Management for Cannabis Use Reduction.","authors":"Beckham, Jean C; Calhoun, Patrick S; Chen, Zhengxi; Dennis, Michelle F; Kirby, Angela C; Treis, Emili T; Hertzberg, Jeffrey S; Hair, Lauren P; Mann, Adam J; Budney, Alan J; Kimbrel, Nathan A","year":2024,"journal":"Behavior therapy, 55(1), 1-13","doi":"10.1016/j.beth.2023.03.004","pmid":"38216224","tags":["addiction","quitting"],"studyType":"pilot intervention","evidenceStrength":"low","keyFinding":"During the baseline ad lib phase, participants used cannabis on 94% of days at 1.42 grams daily. During the 6-week intervention, use decreased to 47% of days at 0.61 grams daily. In the final cohort, at least 50% of heavy users reduced use by 50% or more.","whyItMatters":"Most cannabis interventions focus on abstinence but fail to achieve sustained abstinence. This study explores whether cannabis reduction (rather than cessation) is achievable and could be a viable treatment goal for heavy users.","specificNumbers":"18 enrolled, 13 analyzed (80%+ adherent). Baseline: 94% use days, 1.42 g/day. Intervention: 47% use days, 0.61 g/day. 50%+ of heavy users achieved 50%+ reduction in final cohort.","methodology":"Pilot study with 18 participants (10 women) across 3 cohorts. 2-week baseline ecological momentary assessment followed by 6-week reduction phase. Mobile app tracked use via saliva tests (bioverified abstinence) and electronic diaries. 13 of 18 were adherent (80%+ to EMA prompts).","limitations":"Very small sample (13 analyzed). No control group. Cannot determine whether reduction sustains beyond 6 weeks. High adherence threshold may have selected more motivated participants. Functional/mental health outcomes not yet measured."},{"rthcId":"RTHC-05126","title":"Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity.","authors":"Beers, Jessica L; Zhou, Zhu; Jackson, Klarissa D","year":2024,"journal":"Drug metabolism and disposition: the biological fate of chemicals, 52(6), 508-515","doi":"10.1124/dmd.123.001435","pmid":"38286636","tags":["cbd","drug-interactions"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"CBD causes dose-dependent hepatocellular toxicity at therapeutic doses. Risk is increased with valproate co-administration through an unknown mechanism. CBD metabolism involves CYP3A4 and CYP2C19, creating significant drug interaction potential. Current pharmacokinetic models and in vitro liver models have limitations in predicting CBD safety.","whyItMatters":"CBD is increasingly popular as both an FDA-approved drug and consumer product, but its liver toxicity potential is underappreciated. The drug interaction with valproate is particularly concerning since many epilepsy patients take both medications.","specificNumbers":"CBD is FDA-approved for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1+. Dose-dependent hepatotoxicity observed at therapeutic doses. CYP3A4 and CYP2C19 are primary metabolic enzymes.","methodology":"Narrative review of pharmacokinetic modeling approaches, in vitro liver models, and evidence on CBD-induced hepatotoxicity mechanisms, focusing on FDA-approved Epidiolex for pediatric epilepsy.","limitations":"Review focused on FDA-approved Epidiolex doses, which are higher than most consumer products. Mechanisms of hepatotoxicity not fully understood. In vitro models may not predict in vivo toxicity accurately. Consumer CBD product quality and dosing are highly variable."},{"rthcId":"RTHC-05127","title":"Medical Marijuana Documentation Practices in Patient Electronic Health Records: Retrospective Observational Study Using Smart Data Elements and a Review of Medical Records.","authors":"Beiler, Donielle; Chopra, Aanya; Gregor, Christina M; Tusing, Lorraine D; Pradhan, Apoorva M; Romagnoli, Katrina M; Kraus, Chadd K; Piper, Brian J; Wright, Eric A; Troiani, Vanessa","year":2024,"journal":"JMIR formative research, 8, e65957","doi":"10.2196/65957","pmid":"39715532","tags":["medical-cannabis"],"studyType":"retrospective observational","evidenceStrength":"low","keyFinding":"Smart data elements for medical marijuana documentation had high completion for certifying conditions (93.6%), product (92.9%), dispensary (87.8%), and active ingredient (83.3%), but low completion for certifying provider (61.5%) and dosage (30.8%). Documentation was primarily done by nurses/medical assistants (88.5%) in primary care settings (68.6%).","whyItMatters":"Without systematic documentation of medical cannabis in health records, clinicians cannot track patient use, assess drug interactions, or evaluate treatment outcomes. The 31% dosage documentation rate is a significant safety gap.","specificNumbers":"156 records analyzed. Interrater reliability kappa=0.966. Condition documented: 93.6%. Product: 92.9%. Dispensary: 87.8%. Active ingredient: 83.3%. Certifying provider: 61.5%. Dosage: 30.8%.","methodology":"Retrospective analysis of 156 medical records with MMJ documentation at Geisinger health system (Pennsylvania). Protocol developed for consistent data extraction with high interrater reliability (kappa=0.966).","limitations":"Single health system in Pennsylvania. Only captures documented use, not actual use patterns. Retrospective design. Smart data elements are voluntary and dependent on clinical staff completing them."},{"rthcId":"RTHC-05128","title":"Toxicology findings from drivers suspected of drug-impaired driving in Ontario (2008-2019).","authors":"Beirness, Douglas J; Rajotte, James W; Peaire, Amy E","year":2024,"journal":"Traffic injury prevention, 25(7), 894-901","doi":"10.1080/15389588.2024.2355593","pmid":"38875458","tags":["driving"],"studyType":"retrospective analysis","evidenceStrength":"moderate","keyFinding":"Over 12 years, 5,388 samples from suspected drug-impaired drivers were analyzed. Cannabis was most frequently detected (52.8%), followed by cocaine (44.3%) and methamphetamine (24.8%). Eighty percent of cases involved more than one substance. Sample submissions increased after cannabis legalization in 2018.","whyItMatters":"Understanding which substances impaired drivers use, and how often they combine them, helps shape enforcement strategies and public safety messaging. Cannabis as the top substance has implications for post-legalization road safety.","specificNumbers":"5,388 samples over 12 years. Cannabis: 52.8%. Cocaine: 44.3%. Methamphetamine: 24.8%. Multiple substances: 80%. Samples increased after Drug Evaluation and Classification Program implementation and cannabis legalization.","methodology":"Retrospective analysis of blood and urine samples submitted to Ontario's Centre of Forensic Sciences from suspected drug-impaired drivers (2008-2019). Standardized comprehensive toxicological analysis tested for a wide variety of impairing drugs.","limitations":"Only suspected impaired drivers (not a random sample). Detection does not equal impairment (cannabis can be detected days after use). Sample collection increased over time due to more trained officers, not necessarily more impaired driving. Ontario-specific data."},{"rthcId":"RTHC-05129","title":"Enhancing the Standardized Field Sobriety Test to detect cannabis impairment: An observational study.","authors":"Beirness, Douglas J; Smith, D'Arcy; Brubacher, Jeff R","year":2024,"journal":"Traffic injury prevention, 25(1), 1-7","doi":"10.1080/15389588.2023.2262658","pmid":"37815794","tags":["driving"],"studyType":"observational study","evidenceStrength":"low","keyFinding":"Twenty minutes after vaping cannabis (mean THC 6.34 ng/mL), 67% met SFST criteria for suspected impairment. Adding the Finger-to-Nose test plus head movement/jerk observations increased detection by 33%, improving sensitivity from 0.67 to 0.88.","whyItMatters":"The standard field sobriety test was designed for alcohol and misses a third of cannabis-impaired individuals. Enhancing the test could significantly improve road safety without requiring blood tests.","specificNumbers":"Mean THC: 6.34 ng/mL at 20 minutes post-vaping. SFST alone: 67% detected. SFST + FTN + HMJ: 88% detected. Sensitivity improved from 0.67 to 0.88 (33% increase).","methodology":"Observational study where participants used their own cannabis at a research facility. SFST plus supplementary tests administered by certified Drug Recognition Experts at baseline and four times during 150 minutes post-use. Physiological indicators, vital signs, and digit-symbol substitution also assessed.","limitations":"Participants knew they were being tested (no blinding). Assessors knew participants had used cannabis. Observational design in a controlled setting, not actual roadside conditions. Small sample. Voluntary cannabis use, not dose-controlled."},{"rthcId":"RTHC-05130","title":"Clinical Practice Guidelines for Cannabis and Cannabinoid-Based Medicines in the Management of Chronic Pain and Co-Occurring Conditions.","authors":"Bell, Alan D; MacCallum, Caroline; Margolese, Shari; Walsh, Zach; Wright, Patrick; Daeninck, Paul J; Mandarino, Enrico; Lacasse, Gary; Kaur Deol, Jagpaul; de Freitas, Lauren; St Pierre, Michelle; Belle-Isle, Lynne; Gagnon, Marilou; Bevan, Sian; Sanchez, Tatiana; Arlt, Stephanie; Monahan-Ellison, Max; O'Hara, James; Boivin, Michael; Costiniuk, Cecilia","year":2024,"journal":"Cannabis and cannabinoid research, 9(2), 669-687","doi":"10.1089/can.2021.0156","pmid":"36971587","tags":["medical-cannabis","pain"],"studyType":"clinical practice guideline","evidenceStrength":"moderate","keyFinding":"From 70 articles (19 systematic reviews, 51 original studies), research demonstrates moderate benefit of cannabinoid-based medicines for chronic pain. Evidence also supports efficacy for sleep problems, anxiety, appetite suppression, and pain in HIV, MS, fibromyalgia, and arthritis. Patients should be educated on risks, and clinicians should collaborate on dosing and titration.","whyItMatters":"Healthcare providers consistently report lacking information about cannabis for pain. These guidelines provide an evidence-based framework for clinicians and patients to navigate cannabis use for chronic pain, filling a major clinical knowledge gap.","specificNumbers":"70 articles included (19 systematic reviews, 51 original studies). One in five individuals globally live with chronic pain. GRADE system used for evidence rating.","methodology":"Systematic review following PRISMA guidelines with dual review. 70 articles met inclusion criteria. Clinical recommendations developed using GRADE system to rate strength of recommendations and quality of evidence. PROSPERO registration #135886.","limitations":"Based on available evidence which has significant heterogeneity in cannabinoid formulations, doses, and outcomes. Many studies use pharmaceutical cannabinoids rather than whole-plant products. GRADE ratings reflect moderate quality overall. Cannabis product variability makes standardized recommendations difficult."},{"rthcId":"RTHC-05131","title":"Association Between Marijuana Use and Clinical Outcomes After Coronary Artery Bypass Grafting.","authors":"Bellam, Krishna G; Sabe, Sharif A; Chalasani, Nishanth; Feldman, Noah; Huang, Nicholas R; Harwell, Anthony; Sellke, Frank; Ehsan, Afshin","year":2024,"journal":"The Journal of surgical research, 295, 442-448","doi":"10.1016/j.jss.2023.11.015","pmid":"38070258","tags":["cardiovascular"],"studyType":"retrospective cohort","evidenceStrength":"moderate","keyFinding":"Marijuana users had significantly increased odds of AKI (OR 1.40), AMI (OR 1.56), TIA/stroke (OR 1.64), longer LOS (OR 1.14), and decreased odds of home discharge (OR 1.50). In-hospital mortality showed a nonsignificant decrease (OR 0.41, CI crossed 1.0).","whyItMatters":"This is the first study examining marijuana use and outcomes after coronary bypass surgery. The elevated complication rates suggest preoperative cannabis screening and counseling may be warranted for cardiac surgery patients.","specificNumbers":"343,796 patients (590 marijuana users). AKI OR: 1.40 (1.11-1.78). AMI OR: 1.56 (1.32-1.84). TIA/stroke OR: 1.64 (1.21-2.22). LOS: 10.4 vs. 9.8 days. Home discharge OR: 1.50 (1.24-1.81). Mortality OR: 0.41 (0.14-1.12, NS).","methodology":"National Inpatient Sample database (2008-2018), 343,796 CABG patients (590 marijuana users). Multivariable models adjusted for confounders compared outcomes between marijuana users (abuse/dependency codes) and non-users.","limitations":"Administrative database using ICD codes for marijuana abuse/dependency likely captures only severe use. Younger marijuana users may differ in other risk factors. Cannot assess cannabis consumption method, frequency, or timing relative to surgery."},{"rthcId":"RTHC-05132","title":"A test of competing mediators linking trouble sleeping to cannabis use in adolescents and emerging adults.","authors":"Berey, Benjamin L; Meisel, Samuel; Pielech, Melissa; Parnes, Jamie E; Treloar Padovano, Hayley; Miranda, Robert","year":2024,"journal":"Experimental and clinical psychopharmacology, 32(3), 316-328","doi":"10.1037/pha0000693","pmid":"38127518","tags":["sleep","youth"],"studyType":"ecological momentary assessment","evidenceStrength":"moderate","keyFinding":"At the person level, trouble sleeping was associated with higher cannabis craving and negative affect (large effects, rs 0.34-0.48). Paradoxically, at the day level, more trouble sleeping was associated with lower likelihood of cannabis use the next day (beta=-0.65, p<0.001). Trouble sleeping was not indirectly linked to cannabis through negative affect, risk-taking, or craving.","whyItMatters":"Many cannabis users report using for sleep, but the daily-level finding that poor sleep actually decreases next-day use suggests the relationship is more complex than simple self-medication. This has implications for how sleep is addressed in cannabis treatment.","specificNumbers":"86 participants (ages 15-24, 48.8% female, 58.8% White). Person-level correlations: 0.34-0.48 for sleep-craving and sleep-negative affect. Day-level: beta=-0.65 (p<0.001) for sleep trouble predicting less next-day use.","methodology":"Ecological momentary assessment study of 86 youth ages 15-24 who regularly used cannabis, surveyed over 1 week before an intervention. Multilevel structural equation modeling evaluated day-level and person-level associations.","limitations":"Small sample from an intervention study. Only 1 week of EMA data. Self-reported trouble sleeping, not objective sleep measurement. Cannot determine causation. Regular cannabis users only."},{"rthcId":"RTHC-05133","title":"Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey.","authors":"Berg, Anne T; Dixon-Salazar, Tracy; Meskis, Mary Anne; Danese, Sherry R; Le, Ngoc Minh D; Perry, M Scott","year":2024,"journal":"Epilepsy research, 200, 107280","doi":"10.1016/j.eplepsyres.2023.107280","pmid":"38183688","tags":["cbd","epilepsy"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Caregivers reported improvements in seizure frequency (85%), seizure severity (76%), and seizure-free days (67%). Non-seizure improvements: alertness/cognition (85%), emotional functioning (82%), communication (74-79%), sleep (51%), ADLs (51%), physical functioning (46%). 18-56% of patients who had no seizure improvement still reported non-seizure benefits. 93% planned to continue CBD.","whyItMatters":"Clinical trials of CBD focused primarily on seizure reduction. This real-world survey reveals substantial non-seizure benefits that patients and families value, which may be an independent reason to continue treatment even when seizure control is incomplete.","specificNumbers":"498 caregivers (97% parents). Patients: mean age 16, median CBD dose 14 mg/kg/day, median 4 concomitant seizure medications. 16% achieved seizure freedom in past month. 93% planned to continue.","methodology":"BECOME survey of 498 US caregivers of patients with LGS (80%) or DS (20%) treated with CBD (Epidiolex) for 3+ months. Cross-sectional online survey comparing current month to pre-CBD period using Likert scales.","limitations":"Retrospective caregiver report susceptible to recall and expectancy bias. No control group or blinding. Selection bias (caregivers who continue treatment are more positive). Likert scales provide subjective impressions, not objective measures."},{"rthcId":"RTHC-05134","title":"Neighborhood demographics in relation to marketing and regulation-related factors among cannabis retailers in 5 US cities.","authors":"Berg, Carla J; Schleicher, Nina C; Cavazos-Rehg, Patricia A; Romm, Katelyn F; LoParco, Cassidy R; Cui, Yuxian; Wang, Yan; McCready, Darcey M; Chakraborty, Rishika; Henriksen, Lisa","year":2024,"journal":"Drug and alcohol dependence, 265, 112471","doi":"10.1016/j.drugalcdep.2024.112471","pmid":"39499989","tags":["legalization"],"studyType":"cross-sectional audit","evidenceStrength":"moderate","keyFinding":"Predominantly White neighborhoods had higher odds of pregnancy warnings, membership programs, and delivery services. Higher-income areas had more health claims but fewer exterior ads. Areas with more youth had less youth-oriented signage and fewer price specials. Minority communities had less regulatory compliance signage overall.","whyItMatters":"If cannabis retailers in minority neighborhoods have less safety signage and different marketing approaches, this mirrors patterns seen with alcohol and tobacco that have contributed to health disparities in those communities.","specificNumbers":"150 retailers in 5 cities. Youth-oriented signage: 20.7%. Health claims: 28.7%. Exterior ads: 27.3%. Pregnancy warnings: 72.0%. Health-risk warnings: 38.0%. Minimum-age signage: 64.0%.","methodology":"Multilevel multivariable logistic regression analyzing 2022 audit data from 150 randomly selected cannabis retailers in 5 US cities (Denver, Seattle, Portland, Las Vegas, Los Angeles). Census tract demographics linked to marketing and regulatory compliance measures.","limitations":"Cross-sectional audit at one time point. Only 150 stores across 5 cities. Neighborhood demographics at census tract level may not represent the actual customer base. Cannot determine whether marketing differences cause health disparities."},{"rthcId":"RTHC-05135","title":"The endocannabinoid system's genetic polymorphisms in sickle cell anemia patients.","authors":"Berti, Amanda Cristina Meneguetti; de Castro, Vanessa da Silveira Ramos; Arcanjo, Gabriela Silva; da Silva Araujo, Aderson; Lucena-Araujo, Antonio Roberto; Bezerra, Marcos André Cavalcanti; Gazarini, Lucas; da Silva, Danilo Grünig Humberto; Belini-Júnior, Edis","year":2024,"journal":"Scientific reports, 14(1), 31562","doi":"10.1038/s41598-024-76480-0","pmid":"39738165","tags":["genetics","pain"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Sickle cell anemia (SCA) is a genetic blood disorder that causes a range of severe complications, including priapism — prolonged, painful erections caused by sickled red blood cells blocking penile blood vessels. Priapism affects up to 42% of males with SCA and can cause permanent damage, yet treatment options are limited.\n\nThis study investigated whether genetic variations in the endocannabinoid system (ECS) — the same system that cannabis acts on — might influence who develops priapism and who doesn't. The researchers genotyped 138 SCA patients (80 with priapism, 58 without) for four genetic variants: one each in the FAAH enzyme, the MAGL enzyme, the CB1 receptor, and the CB2 receptor.\n\nThe standout finding: the TT-CC genotype of the CB2 receptor variant (rs35761398) was associated with 61.4% lower odds of developing priapism (OR = 0.386) and a 36.6% lower risk over time (HR = 0.634). This suggests that the CB2 receptor — the cannabinoid receptor primarily expressed in immune and blood cells — plays a role in the vascular events that cause priapism in SCA.\n\nThe biological mechanism makes sense: the endocannabinoid system is involved in blood vessel relaxation, platelet aggregation, and immune responses — all of which are dysregulated in sickle cell priapism. A CB2 receptor variant that modulates these processes could protect against the vascular blockage that triggers priapism.\n\nAlpha-thalassemia mutations were also less common in patients with priapism, consistent with their known protective effect against SCA complications.","whyItMatters":"This is one of the first studies to connect endocannabinoid system genetics to a specific clinical complication of sickle cell disease. If the CB2 receptor influences priapism risk, it raises the possibility that CB2-targeted medications (or even specific cannabinoids) could help prevent or treat this devastating complication. For the approximately 100,000 Americans with SCA, new therapeutic targets are urgently needed.","specificNumbers":"138 SCA patients: 80 with priapism, 58 without. CB2 rs35761398 TT-CC genotype: OR = 0.386 (95% CI: 0.175–0.854, p = 0.019) for priapism; HR = 0.634 (95% CI: 0.402–0.987, p = 0.049) for time to priapism. Alpha-thalassemia was significantly less common in priapism patients (p < 0.001).","methodology":"Observational genetic association study of 138 Brazilian sickle cell anemia patients (80 with priapism, 58 without). SCA confirmed by HPLC and PCR-RE for Hb SS genotype. Alpha-thalassemia detected with Multiplex-PCR. Four endocannabinoid system SNPs genotyped using TaqMan assays: FAAH rs324420, MAGL rs604300, CNR1 rs7766029, CNR2 rs35761398. Association assessed with multivariate logistic regression and Cox regression.","limitations":"Relatively small sample size (138 patients) for a genetic association study. Single-center Brazilian cohort — genetic frequencies may differ in other populations (African, Caribbean, South Asian). Association doesn't prove causation — the CB2 variant may be in linkage disequilibrium with another causal variant. Only four ECS polymorphisms were tested; other ECS genetic variations may also be relevant. Priapism status was based on clinical records, and subclinical episodes may have been missed."},{"rthcId":"RTHC-05136","title":"Cannabis and Pregnancy.","authors":"Bespalova, Nadejda; Bunt, Gregory; Hill, Kevin P","year":2024,"journal":"Current psychiatry reports, 26(11), 643-649","doi":"10.1007/s11920-024-01536-x","pmid":"39316227","tags":["pregnancy"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"Recent studies show possible perinatal and longitudinal neurodevelopment risks from prenatal cannabis exposure. Healthcare providers are reluctant to discuss cannabis with pregnant patients for various reasons. Increased access through legalization may increase adverse effects.","whyItMatters":"The gap between increasing prenatal cannabis use and incomplete clinician communication about risks means many pregnant individuals are making decisions without adequate information about potential consequences.","specificNumbers":"Cannabis use during pregnancy is increasing in the context of liberalized policy. Healthcare providers cite multiple reasons for reluctance to discuss cannabis with pregnant patients.","methodology":"Narrative review of recent evidence on prenatal cannabis effects, covering perinatal outcomes, neurodevelopmental risks, and healthcare provider communication barriers.","limitations":"Brief narrative review without systematic methodology. Does not quantify specific risk magnitudes. Healthcare provider perspectives not directly measured."},{"rthcId":"RTHC-05137","title":"Cannabidiol-Only Product Use in Pregnancy in the United States and Canada: Findings From the International Cannabis Policy Study.","authors":"Bhatia, Devika; Battula, Sharonya; Mikulich-Gilbertson, Susan; Sakai, Joseph; Hammond, David","year":2024,"journal":"Obstetrics and gynecology, 144(2), 156-159","doi":"10.1097/AOG.0000000000005603","pmid":"38723262","tags":["pregnancy","cbd"],"studyType":"repeated cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Prevalence of CBD-only use in pregnant women was 20.4% vs. 11.3% in non-pregnant women (p<0.001). Top reasons among pregnant women: anxiety (58.4%), pain (52.3%), depression (40.3%), PTSD (32.1%), headache (35.6%), nausea/vomiting (31.9%).","whyItMatters":"Many people assume CBD is safer than THC during pregnancy because it is non-psychoactive, but there is almost no safety data for prenatal CBD exposure. The 20% prevalence among pregnant women signals an urgent need for research.","specificNumbers":"66,457 women surveyed, 1,096 pregnant. CBD-only use: 20.4% pregnant vs. 11.3% non-pregnant (p<0.001). Anxiety 58.4%, pain 52.3%, depression 40.3%, PTSD 32.1%.","methodology":"International Cannabis Policy Study (2019-2021), repeated cross-sectional survey of 66,457 women ages 16-65 in the US and Canada, including 1,096 pregnant women. Compared CBD-only use patterns and reasons.","limitations":"Self-reported survey data. Cannot verify actual CBD product contents or purity. Cross-sectional design cannot determine when during pregnancy use occurs. CBD product quality varies widely in consumer market."},{"rthcId":"RTHC-05138","title":"Perinatal Cannabis Use and Cannabis Use during Breastfeeding: the Role of Health Care Workers.","authors":"Bhatia, Devika; Rosenberg, Sophie; Rees, Rebecca; Brooks-Russell, Ashley","year":2024,"journal":"American journal of perinatology, 41(S 01), e2686-e2695","doi":"10.1055/a-2145-7775","pmid":"37527787","tags":["pregnancy"],"studyType":"longitudinal survey","evidenceStrength":"moderate","keyFinding":"67.8% of women reported an HCW discussed cannabis at prenatal visits. Women who used cannabis perinatally were more likely to report HCW discussions (82.2% vs. 65.3%, p<0.01). However, perinatal users more often trusted cannabis websites (28.9% vs. 6.5%), stores (15.7% vs. 3.8%), and word-of-mouth (28.4% vs. 17.1%). HCW discussions were not associated with cannabis use during breastfeeding.","whyItMatters":"Even when healthcare workers discuss cannabis, perinatal users trust non-medical sources more. This suggests the content or approach of clinical conversations may not effectively reach women most at risk.","specificNumbers":"3,193 Colorado mothers. 5.8% used cannabis during pregnancy or while breastfeeding. 67.8% reported HCW discussion. Cannabis users trusted: cannabis websites (28.9%), word-of-mouth (28.4%), stores (15.7%).","methodology":"Health eMoms longitudinal survey of 3,193 Colorado mothers (2018-2020). Logistic regressions assessed HCW cannabis discussions and perinatal/breastfeeding cannabis use, adjusted for sociodemographic factors.","limitations":"Colorado-specific results in a state with legal recreational cannabis. Self-reported data. Cannot assess quality or content of HCW discussions. Women who used cannabis may recall discussions differently."},{"rthcId":"RTHC-05139","title":"Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). I. Drugs in preclinical and early clinical development.","authors":"Bialer, Meir; Johannessen, Svein I; Koepp, Matthias J; Perucca, Emilio; Perucca, Piero; Tomson, Torbjörn; White, H Steve","year":2024,"journal":"Epilepsia, 65(10), 2831-2857","doi":"10.1111/epi.18056","pmid":"39008349","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05140","title":"Acute and Extended Anxiolytic Effects of Cannabidiol in Cannabis Flower: A Quasi-Experimental ad libitum Use Study.","authors":"Bidwell, L Cinnamon; Martin-Willett, Renée; Skrzynski, Carillon; Lisano, Jonathon; Ortiz Torres, Marco; Giordano, Gregory; Hutchison, Kent E; Bryan, Angela D","year":2024,"journal":"Cannabis and cannabinoid research, 9(4), 1015-1027","doi":"10.1089/can.2023.0187","pmid":"38252547","tags":["cbd","anxiety"],"studyType":"quasi-experimental","evidenceStrength":"moderate","keyFinding":"All cannabis groups reported anxiety reduction over 4 weeks, but CBD-dominant use was associated with lower DASS anxiety scores (difference=-1.03, p=0.02) and lower acute tension and paranoia compared to THC-dominant. THC-dominant cannabis did not increase anxiety. All groups experienced positive mood and subjective drug effects.","whyItMatters":"This is one of the first studies examining legal market cannabis products with varying THC:CBD ratios in people with actual anxiety symptoms, providing ecologically valid data on what consumers might experience.","specificNumbers":"42 non-users + 258 users. THC-dominant: 24% THC. Balanced: 12% THC + 12% CBD. CBD-dominant: <1% THC. CBD-dominant vs THC-dominant DASS anxiety: difference=-1.03 (p=0.02). POMS tension: difference=-0.41 (p<0.05). Paranoia: difference=-0.49 (p<0.05).","methodology":"Quasi-experimental study with 42 non-cannabis-using participants with anxiety symptoms as controls and 258 cannabis users with anxiety randomly assigned to THC-dominant (24% THC), THC+CBD (12%/12%), or CBD-dominant (<1% THC) legal market flower for 4 weeks of ad libitum use.","limitations":"Quasi-experimental, not fully randomized (non-users were a separate group). Self-selected participants. Ad libitum dosing means variable exposure. 4-week duration limits conclusions about long-term effects. Legal market products with variable consistency."},{"rthcId":"RTHC-05141","title":"Phytocannabinoids: Exploring Pharmacological Profiles and Their Impact on Therapeutical Use.","authors":"Blebea, Nicoleta Mirela; Pricopie, Andreea Iulia; Vlad, Robert-Alexandru; Hancu, Gabriel","year":2024,"journal":"International journal of molecular sciences, 25(8)","doi":"10.3390/ijms25084204","pmid":"38673788","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05142","title":"Alterations in self-reported sensory gating and interoception in individuals frequently using cannabis.","authors":"Bloomer, Bess F; Larson, Eric R; Tullar, Rachel L; Herms, Emma N; Bolbecker, Amanda R; O'Donnell, Brian F; Hetrick, William P; Wisner, Krista M","year":2024,"journal":"The American journal of drug and alcohol abuse, 50(4), 525-535","doi":"10.1080/00952990.2024.2332602","pmid":"38563523","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users reported impaired sensory gating across subscales (d=0.37-0.44, all p<0.05) and heightened affect-related interoceptive awareness (d=0.21-0.61, all p<0.05) compared to non-users. More cannabis use days correlated with higher emotional awareness (r=0.37, p<0.05).","whyItMatters":"Altered sensory processing could explain why some cannabis users report difficulty concentrating and heightened emotional sensitivity. These subjective experiences may relate to intoxication, craving, and withdrawal states.","specificNumbers":"72 cannabis users (50% female), 78 non-users (60% female). Sensory gating impairment effect sizes: d=0.37-0.44. Interoceptive awareness elevations: d=0.21-0.61. Cannabis use days correlated with emotional awareness: r=0.37.","methodology":"Cross-sectional study of 72 frequent cannabis users (2+ times/week, not intoxicated during testing) and 78 non-users, ages 18-40. Sensory Gating Inventory and Multidimensional Assessment of Interoceptive Awareness-2 surveys administered.","limitations":"Cross-sectional design cannot determine whether cannabis causes these changes or whether people with altered sensory processing are drawn to cannabis. Self-report measures only. Users were not intoxicated but residual effects possible."},{"rthcId":"RTHC-05143","title":"Highs and Lows: A Mixed-Methods Analysis of the Impact of Adult Use Legalization on Medical Cannabis Patients.","authors":"Boehnke, Kevin F; Kruger, Daniel J; Cuttler, Carrie; Doucette, Mitchell L; Wilson-Poe, Adrianne R","year":2024,"journal":"Journal of psychoactive drugs, 1-10","doi":"10.1080/02791072.2024.2430608","pmid":"39570774","tags":["legalization","medical-cannabis"],"studyType":"mixed-methods survey","evidenceStrength":"low","keyFinding":"Quantitative analysis showed legalization decreased stress and legal concerns, increased perceived product quality and availability, but also increased prices. Qualitative analysis largely aligned but revealed divergent views on price and availability. Mixed-methods analysis found legalization also reduced social stigma.","whyItMatters":"As more states transition from medical-only to adult-use, understanding the medical patient experience helps policymakers design transitions that protect therapeutic access.","specificNumbers":"505 medical cannabis patients surveyed. 24 US states have legalized adult use. Patients reported decreased stress, increased product quality, but higher prices. Social stigma notably reduced.","methodology":"Online survey of 505 medical cannabis patients in US states with adult-use laws. Forced-choice and open-ended questions analyzed with quantitative, qualitative (thematic), and mixed-methods approaches.","limitations":"Convenience sample may overrepresent engaged patients. Self-selected participants in legal states. Cannot compare to patients in medical-only states. Online survey excludes some populations."},{"rthcId":"RTHC-05144","title":"Data Quality in State Registry Reports of Medical Cannabis Patients in the United States.","authors":"Boehnke, Kevin F; Sinclair, Rachel; Gordon, Felicia; Roehler, Douglas R; Smith, Tristin; Hoots, Brooke","year":2024,"journal":"American journal of public health, 114(S8), S685-S693","doi":"10.2105/AJPH.2024.307728","pmid":"39442022","tags":["medical-cannabis","legalization"],"studyType":"ecological study","evidenceStrength":"low","keyFinding":"Among 36 states with medical cannabis programs, 97% reported patient numbers and 75% reported authorizing clinicians. Least reported: patient race/ethnicity (8%), adverse events (11%), therapeutic benefits (6%), and product recalls (6%). Newer programs (2013-2018) reported more subcategories (median 11 vs. 8).","whyItMatters":"Without tracking adverse events, therapeutic benefits, or patient demographics, states cannot assess whether medical cannabis is safe, effective, or equitably accessible. This is a fundamental gap in public health surveillance.","specificNumbers":"36 states analyzed. Patient numbers: 97%. Clinician numbers: 75%. Race/ethnicity: 8%. Adverse events: 11%. Therapeutic benefits: 6%. Product recalls: 6%. Newer programs: median 11 subcategories vs. 8 for early adopters.","methodology":"Analysis of 2021 medical cannabis registry reports from 34 states, Puerto Rico, and DC. Data manually coded into domains including patient demographics, clinician data, sales, and health/safety outcomes.","limitations":"Relies on publicly available reports which may not reflect all data collected. States may collect but not publish some data. One-year snapshot (2021). Cannot assess data quality within reported categories."},{"rthcId":"RTHC-05145","title":"Cannabis-related information sources among US residents: A probability-weighted nationally representative survey.","authors":"Boehnke, Kevin F; Smith, Tristin; Elliott, Michael R; Wilson-Poe, Adrianne R; Kruger, Daniel J","year":2024,"journal":"Journal of cannabis research, 6(1), 38","doi":"10.1186/s42238-024-00249-5","pmid":"39354586","tags":["legalization"],"studyType":"nationally representative survey","evidenceStrength":"moderate","keyFinding":"Most common information sources: friends/family (35.6%), websites (33.7%). Least common: healthcare providers (9.3%), purchase employees (8.6%), government agencies (4.7%). Medical cannabis users more often used healthcare providers (16.4% vs. 5.2%, p=0.006). Past-year use was associated with all sources except government agencies.","whyItMatters":"As cannabis rescheduling approaches, public health messaging needs to reach people where they actually get information. The low use of healthcare providers and government agencies means current public health outreach strategies may be largely ineffective.","specificNumbers":"1,161 participants, 51% female, 27% past-year cannabis use. Friends/family: 35.6%. Websites: 33.7%. Popular media: 13.9%. Healthcare providers: 9.3%. Purchase employees: 8.6%. Government agencies: 4.7%.","methodology":"AmeriSpeak nationally representative survey of 1,161 US adults in June 2023 assessing past-year cannabis use, use intentions, and information sources. Logistic regression explored demographic and use associations.","limitations":"Self-reported information source use may not reflect information quality or influence on behavior. June 2023 snapshot. Cannot assess accuracy of information from different sources. \"Websites\" encompasses enormous variability."},{"rthcId":"RTHC-05146","title":"Substituting Medical Cannabis for Medications Among Patients with Rheumatic Conditions in the United States and Canada.","authors":"Boehnke, Kevin F; Scott, J Ryan; Martel, Marc O; Smith, Tristin; Bergmans, Rachel S; Kruger, Daniel J; Williams, David A; Fitzcharles, Mary-Ann","year":2024,"journal":"ACR open rheumatology, 6(12), 826-835","doi":"10.1002/acr2.11717","pmid":"39236308","tags":["medical-cannabis","pain"],"studyType":"cross-sectional survey","evidenceStrength":"low","keyFinding":"62.5% substituted medical cannabis for medications: NSAIDs (54.7%), opioids (48.6%), sleep aids (29.6%), muscle relaxants (25.2%). Substitution was associated with THC use, inhalation routes, and significantly higher symptom improvements (pain, sleep, anxiety, joint stiffness). Most reported decreased or ceased medication use after substitution.","whyItMatters":"Nearly half of rheumatic disease patients who substituted were replacing opioids, a significant finding given the opioid crisis. Understanding substitution patterns helps clinicians anticipate and manage medication transitions.","specificNumbers":"763 participants. 62.5% substituted. NSAIDs: 54.7%. Opioids: 48.6%. Sleep aids: 29.6%. Muscle relaxants: 25.2%. Reasons: fewer adverse effects, better symptom management, withdrawal concerns. THC-containing products and inhalation most common among substitutors.","methodology":"Secondary analysis of cross-sectional survey conducted with US and Canadian patient advocacy groups. 763 participants with rheumatic conditions using medical cannabis, compared substitution vs. non-substitution groups.","limitations":"Cross-sectional survey cannot establish causation. Self-selected sample from advocacy groups. Self-reported medication changes. Cannot verify actual medication reductions. Substitution may reflect dissatisfaction with previous medications rather than cannabis efficacy."},{"rthcId":"RTHC-05147","title":"Trends in U.S. Medical Cannabis Registrations, Authorizing Clinicians, and Reasons for Use From 2020 to 2022.","authors":"Boehnke, Kevin F; Sinclair, Rachel; Gordon, Felicia; Hosanagar, Avinash; Roehler, Douglas R; Smith, Tristin; Hoots, Brooke","year":2024,"journal":"Annals of internal medicine, 177(4), 458-466","doi":"10.7326/M23-2811","pmid":"38588545","tags":["medical-cannabis","legalization"],"studyType":"ecological study","evidenceStrength":"moderate","keyFinding":"Enrolled patients grew from 3,099,096 (2020) to 4,132,098 (2022), a 33.3% increase. Population prevalence: 175 to 215 per 10,000. But 13/15 adult-use states had decreased enrollment. Evidence-supported qualifying conditions dropped from 70.4% to 53.8%. Chronic pain was the top condition (48.4%), followed by anxiety (14.2%) and PTSD (13.0%). 29,500 authorizing clinicians (7.7 per 1,000 patients).","whyItMatters":"The shift toward conditions without strong evidence support suggests medical cannabis programs are expanding into areas where therapeutic value is unproven. Combined with declining enrollment in recreational states, this paints a complex picture of medical cannabis in the US.","specificNumbers":"4.13 million patients in 2022 (215 per 10,000). 33.3% growth from 2020. 13/15 recreational states had declines. Evidence-supported conditions: 70.4% to 53.8%. Chronic pain: 48.4%. Anxiety: 14.2%. PTSD: 13.0%. 29,500 clinicians (53.5% physicians).","methodology":"Ecological study analyzing publicly available state medical cannabis registry data from 2020-2022 across 39 jurisdictions. Assessed patient volume, qualifying conditions, and authorizing clinician characteristics.","limitations":"Missing data from major states including California. Descriptive analysis without causal modeling. Cannot assess individual use patterns. Qualifying conditions may not reflect actual reasons for use. Data reporting varies by state."},{"rthcId":"RTHC-05148","title":"Characteristics of women concordant and discordant for urine drug screens for cannabis exposure and self-reported cannabis use during pregnancy.","authors":"Bogdan, Ryan; Leverett, Shelby D; Constantino-Petit, Anna M; Lashley-Simms, Nicole; Liss, David B; Johnson, Emma C; Lenze, Shannon N; Lean, Rachel E; Smyser, Tara A; Carter, Ebony B; Smyser, Christopher D; Rogers, Cynthia E; Agrawal, Arpana","year":2024,"journal":"Neurotoxicology and teratology, 103, 107351","doi":"10.1016/j.ntt.2024.107351","pmid":"38604316","tags":["pregnancy"],"studyType":"longitudinal cohort","evidenceStrength":"moderate","keyFinding":"Concordance between self-report and urine drug screen was moderate (k=0.49). SR+/UDS+ (n=107), SR-/UDS- (n=142), SR+/UDS- (n=44, less frequent use), SR-/UDS+ (n=40, often used before knowing they were pregnant). Over 50% of discordant cases became concordant by trimester 2. Using SR+ and/or UDS+ as exposed changed classification minimally.","whyItMatters":"Accurately measuring prenatal cannabis exposure is essential for research on fetal outcomes. This study shows neither self-report nor urine screening alone captures the full picture, with important implications for how prenatal cannabis studies classify exposure.","specificNumbers":"333 participants (88.6% Black, 45.4% below poverty). Kappa=0.49. SR+/UDS+: 107. SR-/UDS-: 142. SR+/UDS-: 44. SR-/UDS+: 40. 35% of SR-/UDS+ reported secondhand exposure or blunt use. Over 50% of discordant cases resolved by trimester 2.","methodology":"CUDDEL Study analyzing 333 pregnant individuals (88.6% Black, mean age 26.6) with both self-report and first-trimester urine drug screens. Concordance assessed with kappa statistic and groups characterized by demographics, use patterns, and exposure history.","limitations":"Predominantly Black, urban, lower-income sample may not generalize. CUDDEL Study recruited women with lifetime cannabis use history. UDS has limited detection window. Secondhand exposure may cause positive UDS without active use."},{"rthcId":"RTHC-05149","title":"Attitudes toward driving after cannabis use: a systematic review.","authors":"Boicu, Bianca; Al-Hakim, Durr; Yuan, Yue; Brubacher, Jeffrey","year":2024,"journal":"Journal of cannabis research, 6(1), 37","doi":"10.1186/s42238-024-00240-0","pmid":"39342388","tags":["driving"],"studyType":"systematic review","evidenceStrength":"moderate","keyFinding":"Six themes emerged: (1) attitudes are mixed (35 studies negative, 20 studies with opposing views); (2) youth, men, and frequent users view DACU more favorably; (3) attitudes predict past and intended DACU; (4) DACU viewed more favorably than drunk driving; (5) relationship with legalization unclear; (6) perceived apprehension risk is low to moderate.","whyItMatters":"Attitudes predict behavior. Understanding who views cannabis-impaired driving favorably and why can help design targeted prevention campaigns, particularly for young males and frequent cannabis users.","specificNumbers":"70 studies from 7 countries (primarily US and Canada). 35 studies: predominantly negative attitudes. 20 studies: opposing/favorable views. DACU consistently viewed as less risky than drunk driving.","methodology":"Systematic review searching MEDLINE, EMBASE, PsycINFO, and TRID through February 2024. 70 studies from 7 countries analyzed using inductive thematic synthesis.","limitations":"Heterogeneous study designs and attitude measures. Predominantly US/Canada data. Attitudes may not directly translate to behavior. Cannot assess actual driving impairment from attitude data."},{"rthcId":"RTHC-05150","title":"Comparative restriction enzyme analysis of methylation (CREAM) reveals methylome variability within a clonal in vitro cannabis population.","authors":"Boissinot, Justin; Adamek, Kristian; Jones, Andrew Maxwell Phineas; Normandeau, Eric; Boyle, Brian; Torkamaneh, Davoud","year":2024,"journal":"Frontiers in plant science, 15, 1381154","doi":"10.3389/fpls.2024.1381154","pmid":"38872884","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05151","title":"Adverse Ocular Impact and Emerging Therapeutic Potential of Cannabis and Cannabinoids: A Narrative Review.","authors":"Bondok, Mostafa; Nguyen, Anne Xuan-Lan; Lando, Leonardo; Wu, Albert Y","year":2024,"journal":"Clinical ophthalmology (Auckland, N.Z.), 18, 3529-3556","doi":"10.2147/OPTH.S501494","pmid":"39629058","tags":["medical-cannabis"],"studyType":"narrative review","evidenceStrength":"moderate","keyFinding":"Adverse ocular effects include eyelid tremor, ptosis, reduced corneal endothelial cell density, dry eyes, red eyes, and neuro-retinal dysfunction. Cannabis may transiently impair night vision, depth perception, and contrast sensitivity. THC reduces intraocular pressure short-term but insufficient for glaucoma. Potential therapeutic uses: treatment-refractory blepharospasm, dry eye, and MS-related nystagmus.","whyItMatters":"Cannabis users should be aware of potential visual effects, and clinicians should not recommend cannabis for glaucoma despite its intraocular pressure-lowering effect. The review clarifies what is and is not supported by evidence for ocular conditions.","specificNumbers":"Estimated 219 million cannabis users globally. THC reduces intraocular pressure transiently. Impairments documented in night vision, depth perception, binocular and monocular contrast sensitivity, and dynamic visual acuity.","methodology":"Narrative review of current literature on adverse effects and therapeutic applications of cannabis and cannabinoids on the eye.","limitations":"Narrative review without systematic methodology. Most ocular effects documented in case reports or small studies. Dose-response relationships poorly characterized. Chronic vs. acute use effects not always distinguished."},{"rthcId":"RTHC-05152","title":"Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): Alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department.","authors":"Borgundvaag, Bjug; Bellolio, Fernanda; Miles, Isabelle; Schwarz, Evan S; Sharif, Sameer; Su, Mark K; Baumgartner, Kevin; Liss, David B; Sheikh, Hasan; Vogel, Jody; Austin, Emily B; Upadhye, Suneel; Klaiman, Michelle; Vellend, Robert; Munkley, Anna; Carpenter, Christopher R","year":2024,"journal":"Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 31(5), 425-455","doi":"10.1111/acem.14911","pmid":"38747203","tags":["medical-cannabis","harm-reduction"],"studyType":"clinical-guideline","evidenceStrength":"low-to-very-low","keyFinding":"The GRACE-4 panel issued two CHS-specific recommendations: use of haloperidol or droperidol alongside standard antiemetics, and offering topical capsaicin as an additional option, both graded at very low certainty of evidence.","whyItMatters":"CHS is increasingly common in emergency departments, but until now there were no widely adopted evidence-based guidelines for its management. These recommendations give ER clinicians a structured approach to a condition that can be difficult to treat.","specificNumbers":"Two CHS-specific recommendations issued. Both rated at very low certainty of evidence. Guidelines also covered alcohol withdrawal and alcohol use disorder across 6 total priority questions.","methodology":"A writing team of emergency physicians and addiction medicine experts applied the GRADE framework to assess evidence and formulate recommendations on six priority questions, including two focused on CHS management in adult ED patients.","limitations":"Both CHS recommendations carry very low certainty of evidence, meaning future research could substantially change these suggestions. The guidelines are also specific to adult ED patients and may not apply to other settings."},{"rthcId":"RTHC-05153","title":"CBD in the Treatment of Epilepsy.","authors":"Borowicz-Reutt, Kinga; Czernia, Julia; Krawczyk, Marlena","year":2024,"journal":"Molecules (Basel, Switzerland), 29(9)","doi":"10.3390/molecules29091981","pmid":"38731471","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05154","title":"Cannabidiol and Tetrahydrocannabinol Antinociceptive Activity is Mediated by Distinct Receptors in Caenorhabditis elegans.","authors":"Boujenoui, Fatma; Nkambeu, Bruno; Salem, Jennifer Ben; Castano Uruena, Jesus David; Beaudry, Francis","year":2024,"journal":"Neurochemical research, 49(4), 935-948","doi":"10.1007/s11064-023-04069-6","pmid":"38141130","tags":["cbd","pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD and THC both reduced the nocifensive response to noxious heat in C. elegans, but mutant studies revealed they target different receptor systems: CBD acts on vanilloid receptors (OSM-9/OCR-2) while THC targets cannabinoid receptors (NPR-19/NPR-32).","whyItMatters":"Understanding that CBD and THC relieve pain through entirely separate receptor pathways could inform the development of more targeted pain treatments and help explain why the two compounds produce different side effect profiles.","specificNumbers":"CBD effects reversed 6 hours post-exposure. THC effects did not reverse in the same timeframe. Noxious heat range tested was 32-35 degrees C.","methodology":"Researchers exposed C. elegans nematodes to CBD and THC, then measured thermal avoidance behavior. Specific receptor mutants were used to identify which receptor systems each compound targets. Proteomic analysis mapped activated metabolic pathways.","limitations":"C. elegans is an extremely simple organism. While it expresses mammalian ortholog receptors, findings in worms do not directly translate to human pain biology. The thermal avoidance assay captures only one dimension of pain."},{"rthcId":"RTHC-05155","title":"Cannabis Laws and Utilization of Medications for the Treatment of Mental Health Disorders.","authors":"Bradford, Ashley C; Lozano-Rojas, Felipe; Shone, Hailemichael Bekele; Bradford, W David; Abraham, Amanda J","year":2024,"journal":"JAMA network open, 7(9), e2432021","doi":"10.1001/jamanetworkopen.2024.32021","pmid":"39235808","tags":["legalization","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Medical cannabis laws were associated with a 12.4% reduction in benzodiazepine fill rates, and recreational laws with a 15.2% reduction. Meanwhile, medical cannabis laws were associated with a 3.8% increase in antidepressant fills, and medical dispensary openings with an 8.8% increase.","whyItMatters":"The finding that cannabis laws may shift prescribing patterns away from benzodiazepines (which carry overdose risk) while increasing antidepressant use suggests cannabis policy may have complex, drug-class-specific effects on mental health treatment.","specificNumbers":"3.85 million patients in the primary benzodiazepine sample. 12.4% reduction in benzo fill rate with medical cannabis laws. 15.2% reduction with recreational laws. 3.8% increase in antidepressant fills with medical laws. 8.8% increase with medical dispensary openings. 65.4% of the benzodiazepine sample were women.","methodology":"Cross-sectional analysis of 10 million commercially insured patients from 2007-2020 using Optum claims data. A synthetic control method compared prescribing patterns across states with different cannabis policy timelines, examining medical/recreational laws and dispensary openings.","limitations":"Cross-sectional design cannot establish causation. Commercially insured patients may not represent Medicaid or uninsured populations. The study cannot determine whether patients who reduced benzodiazepine use actually substituted cannabis. State-level heterogeneity was substantial."},{"rthcId":"RTHC-05156","title":"Extracellular Vesicles and Endocannabinoid Signaling in Patients with COVID-19.","authors":"Brandes, Florian; Keiler, Annekathrin M; Kirchner, Benedikt; Borrmann, Melanie; Billaud, Jean-Noël; Reithmair, Marlene; Klein, Matthias; Campolongo, Patrizia; Thieme, Detlef; Pfaffl, Michael W; Schelling, Gustav; Meidert, Agnes S","year":2024,"journal":"Cannabis and cannabinoid research, 9(5), 1326-1338","doi":"10.1089/can.2023.0040","pmid":"37713293","tags":["inflammation","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Except for anandamide, endocannabinoid concentrations (2-AG, SEA, PEA, OEA) were significantly higher in extracellular vesicles than in plasma, and these EV-endocannabinoid levels increased with COVID-19 severity. MicroRNA analysis revealed regulatory networks that appeared to fine-tune endocannabinoid signaling in immune cells.","whyItMatters":"This study suggests the body uses extracellular vesicles as a delivery system for endocannabinoids during infection, and that this system scales up during severe illness. Understanding this transport mechanism could inform future strategies for modulating inflammation.","specificNumbers":"Five endocannabinoids measured: anandamide, 2-AG, SEA, PEA, and OEA. Four of five were significantly enriched in EVs versus plasma. Steroid hormones (cortisol, testosterone) showed no EV enrichment, suggesting specificity for lipophilic signaling molecules.","methodology":"Researchers measured five endocannabinoids in both extracellular vesicles and plasma from COVID-19 patients of varying severity. RNA sequencing of EV-derived microRNAs and blood cell mRNA was used to construct signaling networks connecting endocannabinoid transport to immune cell regulation.","limitations":"This is an observational study that cannot determine whether elevated EV-endocannabinoid levels are protective or harmful during COVID-19. Sample sizes were not specified in the abstract. The regulatory networks are inferred from correlation, not causation."},{"rthcId":"RTHC-05157","title":"Cannabis and Cannabinoids in Adults With Cancer: ASCO Guideline.","authors":"Braun, Ilana M; Bohlke, Kari; Abrams, Donald I; Anderson, Holly; Balneaves, Lynda G; Bar-Sela, Gil; Bowles, Daniel W; Chai, Peter R; Damani, Anuja; Gupta, Arjun; Hallmeyer, Sigrun; Subbiah, Ishwaria M; Twelves, Chris; Wallace, Mark S; Roeland, Eric J","year":2024,"journal":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 42(13), 1575-1593","doi":"10.1200/JCO.23.02596","pmid":"38478773","tags":["cancer","medical-cannabis"],"studyType":"clinical-guideline","evidenceStrength":"low-to-very-low","keyFinding":"The guideline found that cannabis access and use by cancer patients has outpaced the supporting science. Evidence suggests cannabis may improve refractory chemotherapy-induced nausea and vomiting when added to standard antiemetic regimens, but evidence for other supportive care outcomes remains uncertain.","whyItMatters":"This is the first ASCO guideline specifically addressing cannabis in cancer care. It provides an authoritative, evidence-based framework at a time when many cancer patients are already using cannabis, often without clinician guidance.","specificNumbers":"13 systematic reviews and 5 primary studies formed the evidence base. Certainty of evidence was low or very low for most outcomes. Guideline covers synthetic cannabinoids, herbal derivatives, single cannabinoids, combinations, and full-spectrum cannabis.","methodology":"Systematic literature review of PubMed and Cochrane Library through January 2023, identifying 13 systematic reviews and 5 additional primary studies (4 RCTs, 1 cohort). An expert panel reviewed the evidence to formulate recommendations using established ASCO guideline methodology.","limitations":"The evidence base is small and mostly low quality. The guideline cannot make strong recommendations because the underlying research is insufficient. It does not cover pediatric cancer patients."},{"rthcId":"RTHC-05158","title":"Effects of Δ9-Tetrahydrocannabinol and the Aminoalkylindole K2/Spice Constituent JWH-073 on Cardiac Tissue and Mesenteric Vascular Reactivity.","authors":"Breivogel, Chris S; Brenseke, Bonnie M; Eldeeb, Khalil; Nichols, Katlyn; Jonas, Amreen; Mistry, Artik H; Barbalato, Laura; Luibil, Nicholas; Howlett, Allyn C; Leone-Kabler, Sandra; Hilgers, Rob P H; Pulgar, Victor M","year":2024,"journal":"Cannabis and cannabinoid research, 9(4), e1056-e1062","doi":"10.1089/can.2022.0325","pmid":"37010379","tags":["cardiovascular","synthetic-cannabinoids"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"JWH-073 produced significantly greater maximal relaxation of mesenteric arteries (96% vs. lower for THC) and greater maximal contractile response compared to THC. Neither compound caused cardiac myocyte death in vivo or in cultured heart cells at the concentrations studied.","whyItMatters":"K2/Spice products containing synthetic cannabinoids like JWH-073 have been linked to serious cardiovascular events. This study provides a mechanistic explanation: synthetic cannabinoids may cause more extreme blood vessel dilation than plant-derived THC.","specificNumbers":"JWH-073 maximal arterial relaxation: 96% +/- 2%. No cardiac myocyte death observed with either compound. Both compounds produced typical cannabinoid effects (antinociception and hypothermia).","methodology":"Male C57BL/6 mice received JWH-073 or THC, with cardiac injury assessed by histology. Additional experiments measured H9C2 cardiac cell viability after 24-hour treatment and ex vivo mesenteric artery vascular reactivity from drug-naive animals.","limitations":"Used male mice only, so sex-specific effects are unknown. The doses and concentrations may not reflect typical human recreational exposure. In vitro vascular reactivity does not capture the full complexity of cardiovascular regulation in a living body."},{"rthcId":"RTHC-05159","title":"Somatic and anxiety-like behaviors in male and female rats during withdrawal from the non-selective cannabinoid agonist WIN 55,212-2.","authors":"Brewer, Abigail L; Felter, Claire E; Sternitzky, Anna R; Spencer, Sade M","year":2024,"journal":"Pharmacology, biochemistry, and behavior, 236, 173707","doi":"10.1016/j.pbb.2024.173707","pmid":"38244864","tags":["withdrawal","sex-differences"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Females showed precipitated withdrawal at 3 mg/kg rimonabant while males required 10 mg/kg. The individual somatic behaviors contributing to withdrawal scores differed by sex. At two weeks abstinence, females showed more grooming and marble manipulation than males, suggesting sex-specific anxiety-like responses.","whyItMatters":"Most cannabinoid withdrawal research has focused on males. This study demonstrates that withdrawal is not just more or less severe between sexes but qualitatively different, which has implications for how withdrawal is assessed and treated in clinical settings.","specificNumbers":"Females: precipitated withdrawal at 3 mg/kg rimonabant. Males: precipitated withdrawal at 10 mg/kg. Spontaneous withdrawal quantifiable up to 24 hours post-final infusion. Estrous cycle was not affected by WIN infusions and did not correlate with withdrawal scores.","methodology":"Adult male and female Long-Evans rats received escalating doses of WIN 55,212-2 via intrajugular infusion. Precipitated withdrawal was induced with rimonabant. Somatic behaviors were scored, locomotor activity tracked, and anxiety-like behavior assessed with elevated plus maze, open field, and marble burying tests at one and two weeks abstinence.","limitations":"Used a synthetic cannabinoid (WIN 55,212-2), not THC, so results may not directly map to cannabis withdrawal. Rat behavior does not perfectly model human withdrawal experience. The anxiety-like tests at one and two weeks showed limited drug-treatment effects."},{"rthcId":"RTHC-05160","title":"The Role of Social Deprivation and Cannabis Use in Explaining Variation in the Incidence of Psychotic Disorders: Findings From the EU-GEI Study.","authors":"Brink, Vera; Andleeb, Humma; Gayer-Anderson, Charlotte; Arango, Celso; Arrojo, Manuel; Berardi, Domenico; Bernardo, Miquel; Bobes, Julio; Del-Ben, Cristina Marta; Ferraro, Laura; de Haan, Lieuwe; La Barbera, Daniele; La Cascia, Caterina; Lasalvia, Antonio; Llorca, Pierre-Michel; Menezes, Paolo Rossi; Pignon, Baptiste; Sanjuán, Julio; Santos, José Luis; Selten, Jean-Paul; Tarricone, Ilaria; Tortelli, Andrea; Tripoli, Giada; Velthorst, Eva; Rutten, Bart P F; van Os, Jim; Quattrone, Diego; Murray, Robin M; Jones, Peter B; Morgan, Craig; Di Forti, Marta; Jongsma, Hannah E; Kirkbride, James B","year":2024,"journal":"Schizophrenia bulletin, 50(5), 1039-1049","doi":"10.1093/schbul/sbae072","pmid":"38788048","tags":["psychosis","legalization"],"studyType":"epidemiological","evidenceStrength":"moderate","keyFinding":"Lower owner-occupancy was independently associated with increased first-episode psychosis incidence (aIRR: 0.76) and non-affective psychosis (aIRR: 0.68). Daily cannabis use prevalence was associated with affective psychosis incidence (aIRR: 1.53). High-potency cannabis use was not independently associated with psychosis incidence after adjustment.","whyItMatters":"This is one of the first studies to examine both social deprivation and cannabis use simultaneously as predictors of psychosis incidence across multiple settings. The finding that both factors contribute independently suggests neither alone explains the variation in psychosis rates.","specificNumbers":"Data from 14 European settings. Lower owner-occupancy aIRR: 0.76 (95% CI: 0.61-0.95) for all FEP. Daily cannabis use aIRR: 1.53 (95% CI: 1.02-2.31) for affective psychosis. No association found with unemployment or high-potency cannabis use prevalence.","methodology":"Researchers used incidence data from 14 settings in the EU-GEI study for people aged 18-64. Cannabis use prevalence was estimated from population controls with multiple imputation for missing data. Negative binomial regression modeled psychosis incidence while controlling for population density, age, sex, and migrant/ethnic group.","limitations":"Ecological study design means individual-level conclusions cannot be drawn. Cannabis use prevalence was estimated from controls, not directly measured in the population. Cross-sectional design limits causal inference. Only 14 settings were included."},{"rthcId":"RTHC-05161","title":"Association between cannabis use disorder and greater apathy in adults with HIV.","authors":"Britton, Mark K; DeFelice, Jason; Porges, Eric C; Cohen, Ronald; Li, Yancheng; Wang, Yan; Ibañez, Gladys E; Somboonwit, Charurut; Cook, Robert L","year":2024,"journal":"Drug and alcohol dependence, 261, 111354","doi":"10.1016/j.drugalcdep.2024.111354","pmid":"38870567","tags":["addiction","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Current CUD was associated with greater apathy (beta = 2.13, p = 0.018) compared to cannabis users without CUD history. The association became nonsignificant after adjusting for depressive symptoms, suggesting overlap between apathy and depression. Adolescent-onset CUD was not linked to greater apathy than adult-onset.","whyItMatters":"Apathy is common in people with HIV and is associated with poor adherence to treatment. Identifying modifiable risk factors like substance use disorders could help clinicians address apathy and improve HIV outcomes.","specificNumbers":"311 adults with HIV studied. CUD-apathy association: beta = 2.13 (95% CI: 0.37-3.90, p = 0.018). Alcohol use correlated with apathy: r = 0.19 (p = 0.001). Association became nonsignificant after depression adjustment.","methodology":"Cross-sectional analysis of 311 adult people with HIV. Apathy was measured using the Apathy Evaluation Scale-Self (AES-S). CUD history was categorized as current, past, none, or no cannabis use. Analyses tested robustness to adjustment for depression and alcohol use.","limitations":"Cross-sectional design cannot determine whether CUD causes apathy or vice versa. The association disappeared when controlling for depression, raising questions about whether apathy and depression are being measured as overlapping constructs. Only people with HIV were studied."},{"rthcId":"RTHC-05162","title":"Cannabis use, mental health, and problematic Internet use in Quebec: A study protocol.","authors":"Brodeur, Magaly; Jutras-Aswad, Didier; Légaré, Andrée-Anne; Morvannou, Adèle; Monson, Eva; Cotton, Julie-Christine; Hakansson, Anders; Parent, Virginie; Hudon, Catherine","year":2024,"journal":"PloS one, 19(6), e0304697","doi":"10.1371/journal.pone.0304697","pmid":"38829870","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05163","title":"Effects of acute cannabis inhalation on reaction time, decision-making, and memory using a tablet-based application.","authors":"Brooks-Russell, Ashley; Wrobel, Julia; Brown, Tim; Bidwell, L Cinnamon; Wang, George Sam; Steinhart, Benjamin; Dooley, Gregory; Kosnett, Michael J","year":2024,"journal":"Journal of cannabis research, 6(1), 3","doi":"10.1186/s42238-024-00215-1","pmid":"38308382","tags":["cognition","tolerance","driving"],"studyType":"experimental","evidenceStrength":"moderate","keyFinding":"Occasional users showed significant decrements in reaction time and short-term memory after smoking cannabis. Daily users did not show these impairments (consistent with tolerance) but did take more time on a gap acceptance driving task, though their accuracy remained unchanged.","whyItMatters":"Understanding how tolerance affects cannabis impairment is critical for assessing driving safety and workplace policies. This study suggests daily users develop tolerance to some cognitive effects but may still show subtle changes in real-world decision tasks.","specificNumbers":"Occasional users: n=23. Daily users: n=31. Non-users: n=32. Ages 25-45. THC concentration: 15-30%. Testing occurred approximately 60 minutes after smoking. Daily users took more time on gap acceptance but maintained accuracy.","methodology":"Participants aged 25-45 completed an iPad-based test battery before and 60 minutes after smoking cannabis. Three groups compared: occasional users (n=23), daily users (n=31), and non-users (n=32). Cannabis was self-supplied flower with 15-30% THC, self-administered ad libitum.","limitations":"Small sample sizes per group. Self-administered, self-supplied cannabis means doses varied. Only one time point (60 minutes) measured. iPad-based tests may not fully capture real-world driving complexity. No blood THC levels reported."},{"rthcId":"RTHC-05164","title":"Psychotomimetic compensation versus sensitization.","authors":"Brouwer, Ari; Carhart-Harris, Robin L; Raison, Charles L","year":2024,"journal":"Pharmacology research & perspectives, 12(4), e1217","doi":"10.1002/prp2.1217","pmid":"38923845","tags":["psychosis","neuroscience"],"studyType":"theoretical","evidenceStrength":"n/a","keyFinding":"The authors introduce \"psychotomimetic compensation\" (short-term symptom relief via endocannabinoid, serotonergic, glutamatergic, and dopaminergic systems) and \"psychotomimetic sensitization\" (gradual intensification of psychotic-like experiences after repeated drug/stress exposure) to explain how the same drugs can both help and harm.","whyItMatters":"It has long been a paradox that cannabis can relieve symptoms like pain and depression while also being linked to psychosis risk. This framework offers a coherent explanation: short-term engagement of certain neurotransmitter systems provides compensation, while repeated exposure leads to sensitization.","specificNumbers":"Four neurotransmitter/modulator systems identified: endocannabinoid, serotonergic, glutamatergic, and dopaminergic. Applies to multiple drug classes: cannabinoids (pain), amphetamines (attention/motivation), psychedelics/dissociatives (depression).","methodology":"Theoretical paper synthesizing existing evidence on psychotomimetic drugs (cannabis, amphetamines, psychedelics, dissociatives) to propose a unified explanatory model for their paradoxical therapeutic and psychosis-inducing effects.","limitations":"This is a theoretical model, not an empirical study. The framework synthesizes existing data but does not generate new evidence. Individual variability in compensation vs. sensitization thresholds is not addressed."},{"rthcId":"RTHC-05165","title":"The Modulatory Effects and Therapeutic Potential of Cannabidiol in the Gut.","authors":"Brown, Kevin; Funk, Kyle; Figueroa Barrientos, Alexa; Bailey, Ashly; Shrader, Sarah; Feng, Wenke; McClain, Craig J; Song, Zhao-Hui","year":2024,"journal":"Cells, 13(19)","doi":"10.3390/cells13191618","pmid":"39404382","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05166","title":"The Effect of Marijuana on Postoperative Spine Patients' Emergency Department Visits, Readmission Rates, and Opioid Consumption.","authors":"Buddle, Vincent Patrick; Lee, Maximillian; Feng, James; Khurana, Eric; Park, Ahyoung; Park, Daniel","year":2024,"journal":"Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews, 8(2)","doi":"10.5435/JAAOSGlobal-D-23-00206","pmid":"38323931","tags":["pain","medical-cannabis"],"studyType":"retrospective","evidenceStrength":"low","keyFinding":"THC-positive and multi-drug-positive patients showed higher 90-day morphine milligram equivalents (MMEs) compared to THC-negative controls. Emergency department visits and readmission rates at 90 days were not statistically significantly different between groups, though multi-drug patients trended toward more ED visits and readmissions.","whyItMatters":"As spine surgeons increasingly encounter patients who use cannabis, understanding its association with postoperative opioid needs helps inform pain management planning and patient counseling.","specificNumbers":"252 THC-negative controls, 54 THC-only positive, 47 multi-drug positive. Both THC-positive groups showed higher 90-day MMEs than controls. 90-day ED visit and readmission rate differences were not statistically significant.","methodology":"Retrospective chart review of 353 spine surgery patients divided into three groups based on preoperative urine drug screening: THC-negative (n=252), THC-positive only (n=54), and THC-plus-other-drugs positive (n=47). MMEs, 90-day ED visits, and readmission rates were compared.","limitations":"Retrospective design with relatively small THC-positive groups. Cannot determine whether THC use itself caused higher opioid consumption or whether other confounding factors (chronic pain severity, tolerance) explain the difference. No information on cannabis use patterns or timing."},{"rthcId":"RTHC-05167","title":"Current and Potential Use of Biologically Active Compounds Derived from Cannabis sativa L. in the Treatment of Selected Diseases.","authors":"Bukowska, Bożena","year":2024,"journal":"International journal of molecular sciences, 25(23)","doi":"10.3390/ijms252312738","pmid":"39684447","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05168","title":"Delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate exposures reported to America's Poison Centers.","authors":"Burgess, Alice; Hays, Hannah L; Badeti, Jaahnavi; Spiller, Henry A; Rine, Natalie I; Gaw, Christopher E; Ding, Kele; Smith, Gary A","year":2024,"journal":"Clinical toxicology (Philadelphia, Pa.), 62(4), 256-266","doi":"10.1080/15563650.2024.2340115","pmid":"38686923","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"epidemiological","evidenceStrength":"moderate","keyFinding":"There were 5,022 reported cases from 2021-2022, with the rate per 100,000 population increasing 89.1% (from 0.55 to 1.04). Children under 6 accounted for 30.1% of cases, with a mode at age 2. Over a third (38.4%) experienced serious medical outcomes. The most common effects were mild CNS depression (25%), tachycardia (23%), and agitation (15.6%).","whyItMatters":"These products became widely available after the 2018 Farm Bill and are often marketed as legal alternatives to delta-9 THC. The rapid increase in poison center calls, especially involving young children, highlights a growing public health concern with limited regulatory oversight.","specificNumbers":"5,022 total cases. 89.1% increase in rate from 2021 to 2022. 30.1% involved children under 6. Mode age: 2 years (8.9% of cases). 98.1% involved delta-8 THC. 94.2% were ingestions. 38.4% had serious medical outcomes. 10.3% admitted to noncritical care. 5.3% admitted to critical care.","methodology":"Analysis of National Poison Data System data on delta-8 THC, delta-10 THC, and THC-O acetate exposures reported to US poison centers from January 2021 through December 2022. Census data were used for population-based rate calculations.","limitations":"National Poison Data System relies on passive surveillance, likely underestimating true exposure rates. Product labeling accuracy for these substances is questionable. Cannot distinguish between products containing what they claim versus mislabeled products."},{"rthcId":"RTHC-05169","title":"The Züri Can study: Can regulated cannabis sales promote lower-risk cannabis use? Mini-review and study protocol.","authors":"Buschner, Maximilian; Heckel, Nadine; Dürler, Patricia; Engeli, Etna J E; Schneider, Sophie; Havelka, Eva M; Nordt, Carlos; Herdener, Marcus","year":2024,"journal":"The International journal on drug policy, 133, 104610","doi":"10.1016/j.drugpo.2024.104610","pmid":"39395284","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05170","title":"Pharmacovigilance of unlicensed cannabidiol in European countries.","authors":"Calapai, Fabrizio; Esposito, Emanuela; Ammendolia, Ilaria; Mannucci, Carmen; Calapai, Gioacchino; Currò, Mariaconcetta; Cardia, Luigi; Chinou, Ioanna","year":2024,"journal":"Phytotherapy research : PTR, 38(1), 74-81","doi":"10.1002/ptr.8028","pmid":"37800192","tags":["cbd","drug-interactions"],"studyType":"epidemiological","evidenceStrength":"moderate","keyFinding":"Serious adverse reactions made up 18.9% of all reported events for unlicensed CBD. They were most common in men (58.8%) and adult age groups, with 38.8% of reports involving epilepsy treatment. The most frequent serious effects were mental disorders, hepatic disorders, and aggravation of pre-existing epilepsy. Clobazam and valproic acid were the most common co-administered drugs.","whyItMatters":"With unlicensed CBD products widely available across Europe, this safety analysis reveals that serious adverse effects occur, particularly when CBD is used for epilepsy alongside other antiepileptic drugs. This underscores the risk of using unregulated CBD as a substitute for approved formulations.","specificNumbers":"18.9% of all CBD adverse events were classified as serious. 58.8% of serious cases were in men. 38.8% used CBD for epilepsy. Most common drug interactions: clobazam, valproic acid, then cannabis.","methodology":"Analysis of serious suspected adverse reactions to unlicensed CBD products reported in EudraVigilance, the European Medicines Agency adverse event database. Reports were analyzed by age, sex, adverse reaction type, indication, and concomitant drugs.","limitations":"Passive pharmacovigilance data has inherent reporting biases and likely underestimates true adverse event rates. Product quality and actual CBD content of unlicensed products are uncertain. Cannot establish causation from adverse event reports alone."},{"rthcId":"RTHC-05171","title":"Cannabidiol Treatment for Adult Patients with Drug-Resistant Epilepsies: A Real-World Study in a Tertiary Center.","authors":"Calonge, Quentin; Besnard, Aurore; Bailly, Laurent; Damiano, Maria; Pichit, Phintip; Dupont, Sophie; Gourfinkel-An, Isabelle; Navarro, Vincent","year":2024,"journal":"Brain and behavior, 14(11), e70122","doi":"10.1002/brb3.70122","pmid":"39501537","tags":["cbd","epilepsy"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"No significant difference in responder rates (greater than 50% seizure reduction) between authorized-indication patients (31.3%) and off-label patients (35.6%, p=0.85). One-year retention rates were also similar (75.0% vs. 74.6%). Among off-label patients, clobazam co-prescription strongly predicted response (71.4% of responders vs. 28.9% of non-responders took clobazam, p=0.002).","whyItMatters":"Pharmaceutical CBD is currently approved only for three specific epilepsy syndromes. This real-world data suggests it may benefit a broader population of adults with drug-resistant epilepsy, particularly those already taking clobazam.","specificNumbers":"91 patients included. 35.2% in authorized group. Responder rates: 31.3% authorized vs. 35.6% off-label (p=0.85). 1-year retention: 75% vs. 74.6% (p=0.97). Clobazam in off-label responders: 71.4% vs. 28.9% in non-responders (p=0.002). Median follow-up: 24 months.","methodology":"Retrospective study at the epilepsy unit of Pitie Salpetriere Hospital in Paris. Included patients initiating pharmaceutical CBD and followed for at least 1 year. Patients divided into authorized (LGS, Dravet, TSC) and off-label groups. Median follow-up: 24 months.","limitations":"Retrospective, single-center design with no randomization or placebo control. Relatively small sample. The strong clobazam association may reflect a pharmacokinetic interaction (CBD inhibits clobazam metabolism) rather than true synergy. No blinding."},{"rthcId":"RTHC-05172","title":"Assessment of the effects of cannabidiol and a CBD-rich hemp extract in Caenorhabditis elegans.","authors":"Camacho, Jessica A; Welch, Bonnie; Ferguson, Martine; Sepehr, Estatira; Vaught, Cory; Zhao, Yang; Fitzpatrick, Suzanne; Yourick, Jeffrey; Sprando, Robert L; Hunt, Piper Reid","year":2024,"journal":"Frontiers in toxicology, 6, 1469341","doi":"10.3389/ftox.2024.1469341","pmid":"39420966","tags":["cbd","pregnancy"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD delayed developmental milestone acquisition irreversibly when exposure began at the onset of feeding, while locomotor effects were reversible after removing CBD. Purified CBD was slightly more toxic than matched CBD concentrations in hemp extract across all endpoints. Juveniles were more sensitive than adults.","whyItMatters":"As CBD products become more widely available, understanding their effects on development and reproduction is important. This study flags that early-life CBD exposure may cause irreversible developmental effects, even if adult effects are reversible.","specificNumbers":"All adverse effect levels in C. elegans far exceeded recommended CBD dosages for humans. Purified CBD was slightly more toxic than hemp extract at matched concentrations. CBD reduced high-fat-diet-induced oxidative stress in adults.","methodology":"C. elegans nematodes were exposed to purified CBD or hemp extract in sesame oil emulsions. Researchers measured oxidative stress response, developmental timing, locomotor activity, reproductive output, and organismal CBD concentrations across juvenile and adult life stages.","limitations":"C. elegans is an extremely simple model organism. Doses causing adverse effects far exceeded human recommended levels. The sesame oil vehicle acts as a high-fat diet in C. elegans, which complicates interpretation. Translation to mammalian development is uncertain."},{"rthcId":"RTHC-05173","title":"Tobacco, heated tobacco products, e-cigarette, alcohol, cannabis and other psychotropic substances. Polysubstance use during the COVID-19 pandemic in Italy.","authors":"Campagni, Cosimo; Gorini, Giuseppe; Amerio, Andrea; Cerrai, Sonia; Gallus, Silvano; Lugo, Alessandra; Mastrobattista, Luisa; Mortali, Claudia; Odone, Anna; Stival, Chiara; Carreras, Giulia","year":2024,"journal":"Annali dell'Istituto superiore di sanita, 60(4), 294-302","doi":"10.4415/ANN_24_04_08","pmid":"39699983","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05174","title":"Drug-Cannabinoid Interactions in Selected Therapeutics for Symptoms Associated with Epilepsy, Autism Spectrum Disorder, Cancer, Multiple Sclerosis, and Pain.","authors":"Campos, Maria G; China, Maria; Cláudio, Mariana; Capinha, Miguel; Torres, Rita; Oliveira, Simão; Fortuna, Ana","year":2024,"journal":"Pharmaceuticals (Basel, Switzerland), 17(5)","doi":"10.3390/ph17050613","pmid":"38794183","tags":["drug-interactions","cbd","cancer","epilepsy","pain"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"As medical cannabis use expands, patients are increasingly combining cannabinoids with prescription medications for serious conditions. This review maps out the drug interaction landscape across five major therapeutic areas where cannabinoid use is common: epilepsy, autism spectrum disorder, cancer, multiple sclerosis, and chronic pain.\n\nThe interactions work through several mechanisms. The most common is inhibition of cytochrome P450 (CYP) enzymes, the liver's main drug-processing system. Both THC and CBD inhibit CYP2C9 and CYP3A4 — two enzymes that collectively metabolize a large proportion of prescription drugs. When these enzymes are inhibited, co-administered medications accumulate to higher blood levels, potentially causing toxicity.\n\nSpecific examples highlight the clinical significance. The antifungal ketoconazole (a CYP3A4 inhibitor itself) increases plasma concentrations of both THC and CBD when taken together. Conversely, rifampicin (a CYP3A4 inducer, used for tuberculosis) reduces THC levels by 20-40% and CBD levels by 50-60%, potentially making cannabis treatment ineffective.\n\nFor epilepsy patients on clobazam — one of the most common co-prescribed drugs with CBD — the interaction is particularly important: CBD inhibits CYP2C19, causing clobazam levels to rise significantly, which can increase sedation and requires dose adjustment. In cancer treatment, cannabinoid interactions with chemotherapy agents could either reduce efficacy or increase toxicity.\n\nThe review emphasizes that interactions can be additive, synergistic, or antagonistic — and may affect absorption, distribution, metabolism, and excretion. The bottom line: cannabinoids are pharmacologically active drugs that interact with the body's drug processing systems in clinically meaningful ways.","whyItMatters":"Patients using medical cannabis for serious conditions are often on multiple other medications. This review provides a practical reference for the specific interaction risks in the conditions where cannabinoid use is most common. The clinical stakes are high: in epilepsy, interactions could cause breakthrough seizures or excessive sedation; in cancer, they could affect chemotherapy efficacy; in pain management, they could cause opioid accumulation.","specificNumbers":"Ketoconazole increases plasma THC and CBD concentrations (CYP3A4 inhibition). Rifampicin reduces THC levels by 20-40% and CBD by 50-60% (CYP3A4 induction). CBD inhibits CYP2C9 and CYP3A4, affecting metabolism of warfarin, some chemotherapy agents, opioids, and anticonvulsants. Clobazam-CBD interaction (via CYP2C19) is clinically documented and requires dose adjustment.","methodology":"Narrative review critically summarizing published evidence on drug-cannabinoid interactions across five therapeutic areas: epilepsy, autism spectrum disorder, cancer, multiple sclerosis, and chronic pain. Focused on CYP450-mediated interactions, pharmacodynamic interactions, and clinical consequences.","limitations":"Narrative review, not systematic. Drug interaction evidence varies greatly in quality — some interactions are based on controlled human studies, others on case reports or in vitro data only. Individual patient factors (genetics, liver function, dose, other medications) affect actual interaction risk. The review covers five therapeutic areas but not all medications within those areas. Cannabis product variability (different THC:CBD ratios, other cannabinoids) means interaction risk differs between products."},{"rthcId":"RTHC-05175","title":"Easy and Accessible Synthesis of Cannabinoids from CBD.","authors":"Capucciati, Andrea; Casali, Emanuele; Bini, Arianna; Doria, Filippo; Merli, Daniele; Porta, Alessio","year":2024,"journal":"Journal of natural products, 87(4), 869-875","doi":"10.1021/acs.jnatprod.3c01117","pmid":"38427968","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05176","title":"Possible Role of Cannabis in the Management of Neuroinflammation in Patients with Post-COVID Condition.","authors":"Cárdenas-Rodríguez, Noemi; Ignacio-Mejía, Iván; Correa-Basurto, Jose; Carrasco-Vargas, Humberto; Vargas-Hernández, Marco Antonio; Albores-Méndez, Exal Manuel; Mayen-Quinto, Rodolfo David; De La Paz-Valente, Reynita; Bandala, Cindy","year":2024,"journal":"International journal of molecular sciences, 25(7)","doi":"10.3390/ijms25073805","pmid":"38612615","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05177","title":"Threaten, Distract, and Discredit: Cannabis Industry Rhetoric to Defeat Regulation of High-THC Cannabis Products in Washington State.","authors":"Carlini, Beatriz H; Kellum, Lyndsey B; Garrett, Sharon B; Nims, Lexi N","year":2024,"journal":"Journal of studies on alcohol and drugs, 85(3), 322-329","doi":"10.15288/jsad.23-00277","pmid":"38270913","tags":["legalization","potency"],"studyType":"qualitative","evidenceStrength":"n/a","keyFinding":"Three rhetorical strategies dominated industry opposition to high-THC regulation: threatening (economic harm, public health consequences, undermining voter will), distracting (introducing tangential topics), and discrediting (attacking the science or its advocates). The most common was economic threats.","whyItMatters":"Understanding industry opposition tactics helps public health advocates develop effective counterarguments. The parallels with tobacco and alcohol industry rhetoric suggest cannabis industry lobbying follows predictable patterns that can be anticipated and addressed.","specificNumbers":"41 testimonies from 33 industry actors analyzed. 3 public bill hearings and 1 work session examined. Time period: 2020-2023. Three main rhetorical strategies identified.","methodology":"Deductive thematic analysis of 41 testimonies from 33 cannabis industry actors across 3 public bill hearings and one legislative work session in Washington State between 2020 and 2023. The codebook was informed by documented strategies from alcohol, tobacco, and sugar-sweetened beverage industries.","limitations":"Only examined Washington State hearings. Industry testimony is public-facing and strategic, so it may not reflect private lobbying efforts. The deductive framework was based on other industries, potentially missing cannabis-specific strategies."},{"rthcId":"RTHC-05178","title":"Identifying policy options to regulate high potency cannabis: A multiple stakeholder concept mapping study in Washington State, USA.","authors":"Carlini, Beatriz H; Garrett, Sharon B; Matos, Patrick; Nims, Lexi N; Kestens, Yan","year":2024,"journal":"The International journal on drug policy, 123, 104270","doi":"10.1016/j.drugpo.2023.104270","pmid":"38043404","tags":["legalization","potency"],"studyType":"mixed-methods","evidenceStrength":"n/a","keyFinding":"Community and professional stakeholders supported environmental policy changes like THC-based taxation, raising the minimum age for high-concentration products, and advertising restrictions. Cannabis industry stakeholders rejected THC-content taxation, proposed lowering taxes instead, and favored low-population-impact measures like educating parents and youth.","whyItMatters":"This study provides a structured overview of what different stakeholders actually want regarding high-THC regulation. The clear divide between industry and non-industry perspectives helps policymakers understand the political landscape.","specificNumbers":"Three stakeholder groups: community, professionals, cannabis advocates. Multiple policy ideas generated through concept mapping. Study was legislatively mandated by Washington State.","methodology":"Concept mapping, a mixed-methods approach combining qualitative brainstorming with quantitative analysis, was used to explore stakeholder perspectives. Participants were categorized into community members, professionals, and cannabis advocates. The study was requested by the Washington State Legislature.","limitations":"Washington State-specific findings may not generalize to other jurisdictions. Self-selected stakeholders may not represent broader populations. Concept mapping captures perspectives but does not evaluate policy effectiveness."},{"rthcId":"RTHC-05179","title":"Delta-9-Tetrahydrocannabinol Blocks Bone Marrow-Derived Macrophage Differentiation through Elimination of Reactive Oxygen Species.","authors":"Carter, Taylor H; Weyer-Nichols, Chloe E; Garcia-Sanchez, Jeffrey I; Wilson, Kiesha; Nagarkatti, Prakash; Nagarkatti, Mitzi","year":2024,"journal":"Antioxidants (Basel, Switzerland), 13(8)","doi":"10.3390/antiox13080887","pmid":"39199132","tags":["inflammation","neuroscience"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"THC blocked M-CSF-induced macrophage differentiation from bone marrow cells through a receptor-independent mechanism. RNA-seq showed upregulation of NRF2-ARE antioxidant genes. THC also directly prevented ROS formation via the Fenton Reaction. The effect was independent of CB1, CB2, GPR18, GPR55, and adenosine A2A receptors.","whyItMatters":"This study reveals a previously unknown way THC affects the immune system: by blocking the development of macrophages through antioxidant mechanisms independent of traditional cannabinoid receptors. This has implications for understanding how cannabis affects immune defense.","specificNumbers":"THC blocked differentiation of CD45+CD11b+F4/80+ macrophages. Effect was independent of 5 known receptors (CB1, CB2, GPR18, GPR55, A2A). KEGG pathway analysis linked to ferroptosis and glutathione metabolism. THC-treated cells showed increased iron but decreased ROS.","methodology":"Bone marrow-derived cells were cultured with M-CSF and THC. Flow cytometry tracked macrophage differentiation markers. RNA sequencing identified affected pathways. Receptor knockout and antagonist studies tested known cannabinoid receptors. Fluorescence assays measured intracellular iron and ROS levels.","limitations":"In vitro study using mouse bone marrow cells. The concentrations of THC used may not reflect physiological levels after cannabis use. Blocking macrophage development in a dish does not necessarily translate to impaired immunity in a living organism."},{"rthcId":"RTHC-05180","title":"Successful Treatment of a Fibromyalgia Patient Using a Homeopathic Preparation of Cannabis sativa.","authors":"Carvalho, Jozélio Freire de; Ribeiro, Maria Fernanda Leal Dos Santos","year":2024,"journal":"Homeopathy : the journal of the Faculty of Homeopathy, 113(3), 186-189","doi":"10.1055/s-0043-1775815","pmid":"37903591","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05181","title":"Prenatal THC exposure drives sex-specific alterations in spatial memory and hippocampal excitatory/inhibitory balance in adolescent rats.","authors":"Castelli, Valentina; Lavanco, Gianluca; Tringali, Giuseppe; D'Amico, Cesare; Feo, Salvatore; Di Bartolomeo, Martina; D'Addario, Claudio; Kuchar, Martin; Brancato, Anna; Cannizzaro, Carla","year":2024,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 181, 117699","doi":"10.1016/j.biopha.2024.117699","pmid":"39571245","tags":["pregnancy","cognition","sex-differences"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Prenatal THC exposure caused sex-specific disruption in spatial memory retrieval and flexibility. Males showed decreased density of CCK-positive basket cells (inhibitory interneurons) and increased neuroplasticity markers. Females showed delayed memory retrieval but preserved flexibility, increased CCK+BC density, and mostly preserved neuroplasticity markers.","whyItMatters":"This study provides biological mechanisms for why prenatal cannabis exposure might affect brain development differently in males and females, specifically through disruption of the excitatory/inhibitory balance in the hippocampus.","specificNumbers":"THC dose: 2 mg/kg daily. Exposure period: gestational days 5-20. Males showed decreased CCK+BC density. Females showed increased CCK+BC density. Changes in neuroligin-1 and neuroligin-3 isoforms were observed in both sexes.","methodology":"Sprague Dawley dams received THC (2 mg/kg) or vehicle from gestational day 5-20. Adolescent offspring were tested in the Barnes Maze for spatial memory. Hippocampal tissue was analyzed for CCK+BC density, neuroplasticity gene expression, and neuroligin isoform expression.","limitations":"Animal model using a single THC dose that may not reflect typical human prenatal exposure patterns. Rats were exposed throughout most of gestation, while human exposure patterns vary. Adolescent testing only, so long-term adult outcomes are unknown."},{"rthcId":"RTHC-05182","title":"Sex Moderates Associations Between Dimensions of Emotion Dysregulation and Problematic Cannabis Use.","authors":"Cavalli, Jessica M; Cservenka, Anita","year":2024,"journal":"Journal of psychoactive drugs, 56(3), 342-352","doi":"10.1080/02791072.2023.2210552","pmid":"37155938","tags":["addiction","sex-differences","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Male cannabis users reported greater emotion dysregulation across almost all dimensions. Overall emotion dysregulation, nonacceptance, goal difficulties, impulsivity, and strategy deficits were all associated with more problematic cannabis use, with weaker relationships in women. Lack of emotional awareness was uniquely linked to less severe problems in men only.","whyItMatters":"Understanding who develops problematic cannabis use and why can improve treatment. This study suggests that difficulty managing emotions is a stronger risk factor for cannabis problems in men, which could inform sex-tailored intervention approaches.","specificNumbers":"741 participants, 31.4% female. Male users scored higher on overall dysregulation, nonacceptance, goals, impulse, strategies, and clarity dimensions. Sex moderated the association between emotion dysregulation and problematic use for multiple dimensions.","methodology":"Cross-sectional study of 741 adult past-month cannabis users (31.4% female). Problematic use was measured with the Marijuana Problems Scale. Emotion dysregulation was assessed using the Difficulties in Emotion Regulation Scale (DERS). Hierarchical regression tested sex as a moderator.","limitations":"Cross-sectional design cannot determine direction of causation. More men than women participated (68.6% male), potentially limiting power for detecting effects in women. Self-report measures may not capture actual emotion regulation behavior."},{"rthcId":"RTHC-05183","title":"Counseling About Cannabis Use During Pregnancy and Lactation: A Qualitative Study of Patient and Clinician Perspectives.","authors":"Cernat, Alexandra; Carruthers, Andrea; Taneja, Shipra; Popoola, Anuoluwa; Greyson, Devon; Panday, Janelle; Darling, Elizabeth; McDonald, Sarah D; Black, Morgan; Murray-Davis, Beth; Vanstone, Meredith","year":2024,"journal":"Birth (Berkeley, Calif.), 51(4), 867-877","doi":"10.1111/birt.12873","pmid":"39394742","tags":["pregnancy","medical-cannabis"],"studyType":"qualitative","evidenceStrength":"n/a","keyFinding":"Three phases of clinical encounters influenced cannabis decisions: initiating discussion, making sense of information, and the outcome. While clinicians described their approach as reflecting open, patient-centered values, patients reported that actual interactions did not match. Both groups endorsed nonjudgmental conversations exploring reasons for cannabis use against available evidence and known-safe alternatives.","whyItMatters":"Cannabis use during pregnancy is increasing with legalization, but the counseling gap between what clinicians think they are providing and what patients experience creates missed opportunities for informed decision-making.","specificNumbers":"75 participants: 23 clinicians and 52 pregnant/lactating individuals. Study conducted in Canada. Three phases of the clinical encounter identified.","methodology":"Qualitative descriptive study with semi-structured interviews of 75 individuals in Canada: 23 perinatal clinicians and 52 pregnant or lactating individuals who made cannabis decisions. Data analyzed using inductive content analysis.","limitations":"Canadian study may not reflect practices in other countries. Self-selected participants may not represent broader populations. Clinician self-reporting may overestimate the quality of counseling they provide. Qualitative design captures experiences but not prevalence."},{"rthcId":"RTHC-05184","title":"Cannabis use and dependence among festival attendees: results from the French OCTOPUS survey.","authors":"Chaaban, Sarah; Istvan, Marion; Schreck, Benoit; Laigo, Pauline; Rousselet, Morgane; Grall-Bronnec, Marie; Pain, Stéphanie; Victorri-Vigneau, Caroline","year":2024,"journal":"BMC public health, 24(1), 992","doi":"10.1186/s12889-024-18496-9","pmid":"38594675","tags":["addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"63.4% of regular cannabis users (at least monthly) at music festivals met DSM-IV dependence criteria. Over 40% of regular users reported health and/or social consequences. Dependent users were significantly more likely to also use stimulants and hallucinogens compared to non-dependent users.","whyItMatters":"Music festivals attract high rates of substance use but are rarely targeted for cannabis-specific harm reduction. Finding that most regular users at festivals meet dependence criteria suggests these events could be important venues for reaching people who might benefit from treatment information.","specificNumbers":"383 total participants. Over two-thirds reported past-year cannabis use. 194 regular users (at least monthly). 63.4% of regular users met dependence criteria. 40%+ reported health/social consequences. 13 music events surveyed.","methodology":"Cross-sectional survey at 13 music events in Loire-Atlantique, France (July 2017-July 2018). 383 participants aged 18+ completed face-to-face interviews covering demographics, substance use, and DSM-IV cannabis dependence criteria.","limitations":"Festival-attending cannabis users are not representative of all cannabis users. DSM-IV dependence criteria (now replaced by DSM-5 use disorder) may overcategorize dependence. French music festival culture may differ from other countries. Self-report measures."},{"rthcId":"RTHC-05185","title":"Patterns in Tobacco, E-Cigarette, and Cannabis Advertising Exposure Among California Adolescents and Associations With Future Use Expectations.","authors":"Chaffee, Benjamin W; Couch, Elizabeth T; Donaldson, Candice D; Farooq, Omara; Cheng, Nancy F; Ameli, Niloufar; Zhang, Xueying; Gansky, Stuart A","year":2024,"journal":"Substance use & misuse, 59(8), 1240-1248","doi":"10.1080/10826084.2024.2330912","pmid":"38509707","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among never-users, advertising exposure was associated with future use expectations for cigarettes (OR 1.7), vapes (OR 2.3), and marijuana (OR 2.1) within one year. Advertising patterns correlated with the source of the ad (gas stations, billboards) rather than the product type. Gas stations were the top source for tobacco/vape ads; billboards led for cannabis.","whyItMatters":"Advertising exposure in adolescence is a known pathway to substance use initiation. Finding that cannabis ad exposure doubles the odds of teens expecting to use cannabis suggests that advertising restrictions could be an effective prevention strategy.","specificNumbers":"N=2,530 adolescents. 65.9% noticed at least one ad. Tobacco ads: 52.5%. Vape ads: 51.5%. Marijuana ads: 45.6%. Among never-users, marijuana ad exposure OR for future use: 2.1 (95% CI: 1.5-3.0).","methodology":"Cross-sectional analysis of the 2022 Teens, Nicotine, and Tobacco Online Survey (N=2,530) among California adolescents ages 12-17. Principal components analysis examined advertising exposure patterns. Logistic regression assessed associations between ad exposure and use expectations among never-users.","limitations":"Cross-sectional design cannot prove advertising causes future use intentions. Self-reported ad recall may be influenced by existing attitudes toward substances. California-specific findings may not generalize to other regulatory environments."},{"rthcId":"RTHC-05186","title":"Effect of a selective personality-targeted prevention program on 7-year illicit substance related outcomes: A secondary analysis of a cluster randomized controlled trial.","authors":"Champion, Katrina E; Debenham, Jennifer; Teesson, Maree; Stapinski, Lexine A; Devine, Emma; Barrett, Emma L; Slade, Tim; Kelly, Erin V; Chapman, Cath; Smout, Anna; Lawler, Siobhan; Castellanos-Ryan, Natalie; Conrod, Patricia J; Newton, Nicola C","year":2024,"journal":"Drug and alcohol dependence, 258, 111266","doi":"10.1016/j.drugalcdep.2024.111266","pmid":"38552600","tags":["youth","addiction","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The PreVenture group had 22% lower odds of annual cannabis-related harms compared to controls (OR=0.78, 95% CI: 0.65-0.92). However, there were no significant differences in cannabis use (OR=0.84, 95% CI: 0.69-1.02) or stimulant use (OR=1.07, 95% CI: 0.91-1.25) growth over the 7-year period.","whyItMatters":"Most drug prevention programs show only short-term effects. Finding that a brief, two-session intervention reduced cannabis harms over 7 years into early adulthood is notable, even though it did not reduce use itself. Reducing harms without eliminating use aligns with harm reduction approaches.","specificNumbers":"438 students at baseline (mean age 13.4 years). Two 90-minute sessions. 7-year follow-up. Cannabis harms: OR=0.78 (95% CI: 0.65-0.92). Cannabis use: OR=0.84 (nonsignificant). Retention: 51-79% over 7 years.","methodology":"Cluster randomized controlled trial in 14 Australian schools. High-risk students (scoring high on anxiety sensitivity, negative thinking, impulsivity, or sensation seeking) received PreVenture (two 90-minute sessions one week apart) or usual health education. Outcomes tracked from baseline through 7 years post-intervention.","limitations":"Substantial attrition over 7 years (retention as low as 51%). The intervention did not reduce cannabis or stimulant use rates. Only high-risk students were included, limiting generalizability. Australian context may differ from other countries."},{"rthcId":"RTHC-05187","title":"Adverse Impact of Cannabis on Human Health.","authors":"Chandy, Mark; Nishiga, Masataka; Wei, Tzu-Tang; Hamburg, Naomi M; Nadeau, Kari; Wu, Joseph C","year":2024,"journal":"Annual review of medicine, 75, 353-367","doi":"10.1146/annurev-med-052422-020627","pmid":"37582489","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05188","title":"Evaluation of pre-hospital cannabis exposure and hospital opioid utilization in a trauma population: A retrospective cohort.","authors":"Chang, Alexander J; Mallat, Ali F; Edwards, Marc J; Gabra, Joseph N; Cucci, Michaelia D","year":2024,"journal":"Injury, 55(5), 111305","doi":"10.1016/j.injury.2023.111305","pmid":"38216357","tags":["pain","medical-cannabis"],"studyType":"retrospective","evidenceStrength":"moderate","keyFinding":"THC-positive trauma patients had significantly higher median opioid use during hospitalization (155 MME vs. 62 MME, p<0.0001), including in the ED, floor, and ICU. The THC group also had higher injury severity scores, were more likely to have other substances present, and were more likely to receive an opioid prescription at discharge and require mechanical ventilation.","whyItMatters":"Understanding the relationship between cannabis use and opioid needs in trauma patients can help clinicians plan pain management. The finding of higher opioid use in THC-positive patients challenges narratives that cannabis reduces opioid consumption.","specificNumbers":"750 patients total. 160 (21%) THC-positive. Median opioid use: 155 MME (THC+) vs. 62 MME (THC-), p<0.0001. THC group: higher ISS (10 vs. 9), higher AIS (3 vs. 2). 64.6% male overall. Median age: 56 years.","methodology":"Retrospective cohort study at a level 1 trauma center (October 2017-December 2019). 750 adult trauma patients with urine drug screens within 48 hours of arrival were included. Patients were grouped by THC status (160 positive, 590 negative). Multivariable regression analyzed opioid utilization.","limitations":"THC-positive patients had higher injury severity, which alone could explain higher opioid use. Co-occurring substance use was more common in the THC group, confounding the analysis. Urine drug screening detects recent use but not active intoxication. Retrospective design."},{"rthcId":"RTHC-05189","title":"Marijuana Use and Breastfeeding: A Survey of Newborn Nurseries.","authors":"Chang, Pearl W; Goyal, Neera K; Chung, Esther K","year":2024,"journal":"Pediatrics, 153(2)","doi":"10.1542/peds.2023-063682","pmid":"38247374","tags":["pregnancy","medical-cannabis"],"studyType":"survey","evidenceStrength":"moderate","keyFinding":"For mothers with a positive cannabinoid screen at delivery, 16% of hospitals universally or selectively restrict breastfeeding. 96% of nursery directors considered marijuana use while breastfeeding somewhat (70%) or very (26%) harmful. No consistent associations were found between breastfeeding restrictions and provider knowledge, geographic region, or state legalization status.","whyItMatters":"Inconsistent hospital policies mean that whether a cannabis-using mother can breastfeed depends largely on which hospital she delivers at, not on evidence. This variability raises equity concerns and highlights the need for evidence-based national guidelines.","specificNumbers":"69 of 110 (63%) nursery directors responded across 38 states. 16% restrict breastfeeding for THC-positive mothers. 96% consider marijuana use during breastfeeding harmful. 70% \"somewhat harmful,\" 26% \"very harmful.\"","methodology":"Cross-sectional survey of 110 US hospital nursery directors in the Academic Pediatric Association BORN network. 69 (63%) responded across 38 states. The 31-question survey assessed policies, knowledge, and attitudes regarding marijuana use and breastfeeding.","limitations":"Only BORN network hospitals surveyed, which may not represent all US hospitals. 63% response rate introduces potential selection bias. Director-reported policies may not reflect actual clinical practice. Survey did not assess outcomes for infants."},{"rthcId":"RTHC-05190","title":"Effects of Cannabidiol on the Functions of Chimeric Antigen Receptor T Cells in Hematologic Malignancies.","authors":"Chantarat, Natthida; Pe, Kristine Cate S; Suppipat, Koramit; Vimolmangkang, Sornkanok; Tawinwung, Supannikar","year":2024,"journal":"Cannabis and cannabinoid research, 9(3), 819-829","doi":"10.1089/can.2023.0108","pmid":"37878339","tags":["cbd","cancer"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"CBD at 8 microM (the maximum non-toxic dose) did not alter CAR T cell surface expression, immune characteristics, T cell subset, or memory phenotype. However, CBD suppressed CAR T cell proliferation by inducing apoptosis (increased Sub-G1 phase). Critically, antitumor activity and cytokine secretion were not affected.","whyItMatters":"Cancer patients increasingly use CBD as a palliative supplement during treatment, including during CAR T cell therapy. This is the first study to directly examine whether CBD interferes with CAR T cell function, finding a nuanced effect: reduced proliferation but preserved killing ability.","specificNumbers":"IC50 of CBD: 16-22 microM across NALM6, Raji, and T cells. Maximum non-toxic dose: 8 microM. CBD increased Sub-G1 phase cells (apoptosis marker). No change in antitumor activity or cytokine secretion.","methodology":"CD19-CAR T cells were generated by retroviral transduction and exposed to CBD. Cell viability (WST-1 assay), surface markers (flow cytometry), proliferation, apoptosis, cell cycle, degranulation, and antitumor activity were assessed. IC50 of CBD was 16-22 microM across cell lines.","limitations":"In vitro study that does not account for CBD metabolism, bioavailability, or tissue distribution in vivo. The CBD concentrations tested may not reflect what reaches immune cells in patients. Only one CAR T construct (CD19) was tested."},{"rthcId":"RTHC-05191","title":"Development and validation of the Cannabis Exposure in Pregnancy Tool (CEPT): a mixed methods study.","authors":"Chaput, Kathleen H; McMorris, Carly A; Metcalfe, Amy; Ringham, Catherine; McNeil, Deborah; Konschuh, Shaelen; Sycuro, Laura J; McDonald, Sheila W","year":2024,"journal":"BMC pregnancy and childbirth, 24(1), 280","doi":"10.1186/s12884-024-06485-0","pmid":"38627667","tags":["pregnancy"],"studyType":"validation-study","evidenceStrength":"moderate","keyFinding":"The CEPT demonstrated excellent psychometric properties: convergent validity (kappa=0.72-1.0), high internal consistency (alpha=0.92), very good 3-month test-retest reliability (weighted kappa=0.92), and 100% sensitivity with 82% specificity against urine THC bioassay.","whyItMatters":"Research on prenatal cannabis effects has been limited by inconsistent measurement. Without a standardized tool, studies measure cannabis use differently, making it hard to compare findings. CEPT addresses this by capturing frequency, timing, dose, and mode of use.","specificNumbers":"254 pregnant women participated. 9-item tool. Sensitivity: 100%. Specificity: 82%. Internal consistency: alpha=0.92. Test-retest reliability: weighted kappa=0.92 (95% CI: 0.86-0.97). Convergent validity kappa: 0.72-1.0.","methodology":"Mixed-methods tool development study with 254 pregnant women in Alberta, Canada. Included environmental scan of existing tools, in-depth interviews, cognitive interviewing, and psychometric validation including convergent/discriminant validity, internal consistency, test-retest reliability, and external validation against urine THC testing.","limitations":"Validated in an Alberta, Canada sample that may not represent other populations. Self-reported tool, even though validated against bioassay. The 82% specificity means some false positives. Cultural and legal context may affect disclosure willingness."},{"rthcId":"RTHC-05192","title":"Cannabis (THC) Aggravates the Deleterious Effects of Alcohol (EtOH) on Skeletal Muscles' Mitochondrial Respiration: Modulation by Age and Metabolic Phenotypes.","authors":"Charles, Anne-Laure; Giannini, Margherita; Meyer, Alain; Charloux, Anne; Talha, Samy; Vogel, Thomas; Raul, Jean-Sébastien; Wolff, Valérie; Geny, Bernard","year":2024,"journal":"Biology, 13(12)","doi":"10.3390/biology13121080","pmid":"39765747","tags":["cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Ethanol impaired mitochondrial respiration in both young and middle-aged rat muscles (35-38% reduction). THC alone had limited effects, but when combined with ethanol, THC significantly worsened the impairment specifically in young glycolytic (fast-twitch) muscles. Oxidative (slow-twitch) muscles were relatively protected.","whyItMatters":"Cannabis and alcohol are frequently used together, especially by young adults. This study suggests the combination may be more damaging to muscle energy production than either substance alone, particularly in younger individuals.","specificNumbers":"Ethanol reduced mitochondrial respiration by 35-38% in gastrocnemius. THC aggravated this effect in young glycolytic muscle. Young (12-week) and middle-aged (49-week) rats compared. Two muscle types tested: glycolytic and oxidative.","methodology":"Gastrocnemius (glycolytic) and soleus (oxidative) muscles from young (12-week) and middle-aged (49-week) rats were exposed to ethanol alone and combined with THC. Mitochondrial respiration was measured to assess energy production capacity.","limitations":"In vitro exposure of muscle tissue does not replicate how THC and alcohol reach muscles in a living body. Concentrations used may not reflect physiological levels. Only rat tissue was studied. The mechanism by which THC worsens ethanol effects was not fully elucidated."},{"rthcId":"RTHC-05193","title":"Cumulative Deleterious Effects of Tetrahydrocannabinoid (THC) and Ethanol on Mitochondrial Respiration and Reactive Oxygen Species Production Are Enhanced in Old Isolated Cardiac Mitochondria.","authors":"Charles, Anne-Laure; Charloux, Anne; Vogel, Thomas; Raul, Jean-Sébastien; Kindo, Michel; Wolff, Valérie; Geny, Bernard","year":2024,"journal":"International journal of molecular sciences, 25(3)","doi":"10.3390/ijms25031835","pmid":"38339113","tags":["cardiovascular","seniors"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"THC impaired cardiac mitochondrial respiration in both young and old rats, but the effect was significantly worse in aged hearts (97.5% vs. 75.6% impairment at the same dose, with a lower IC50). Combining THC with ethanol enhanced the damage further, and aged hearts produced significantly more reactive oxygen species after THC exposure.","whyItMatters":"Older adults are an increasingly common cannabis user demographic, and many also consume alcohol. This study suggests aging hearts may be more vulnerable to THC-related mitochondrial damage, especially when alcohol is involved.","specificNumbers":"Old rats: 97.5% mitochondrial respiration impairment vs. 75.6% in young at 2x10-5 M THC. IC50 in old: 0.7 vs. 1.3 x10-5 M in young. ROS production 46.6% higher in old vs. 17.9% in young after THC.","methodology":"Isolated cardiac mitochondria from young (12-week) and old (90-week) rats were exposed to increasing doses of THC, ethanol, or their combination. Mitochondrial respiration and hydrogen peroxide production were measured.","limitations":"In vitro study on isolated mitochondria, not whole hearts or living organisms. Concentrations may not reflect physiological levels. Rat cardiac tissue may respond differently than human tissue. Only acute exposure tested."},{"rthcId":"RTHC-05194","title":"Effect of High-Tunnel and Open-Field Production on the Yield, Cannabinoids, and Volatile Profiles in Industrial Hemp (Cannabis sativa L.) Inflorescence.","authors":"Charles, Anto Pradeep Raja; Gu, Zixuan; Archer, Ryan; Auwarter, Collin; Hatterman-Valenti, Harlene; Rao, Jiajia; Chen, Bingcan","year":2024,"journal":"Journal of agricultural and food chemistry, 72(23), 12975-12987","doi":"10.1021/acs.jafc.4c01668","pmid":"38807047","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05195","title":"Influence of structural characteristics on the binding of synthetic cannabinoids from the JWH family to the CB1 receptor: A computational study.","authors":"Chaturvedi, Krishna; Anthony, Caroline S; Pandey, Pankaj; Doerksen, Robert J; Godfrey, Murrell","year":2024,"journal":"Journal of molecular graphics & modelling, 126, 108620","doi":"10.1016/j.jmgm.2023.108620","pmid":"37722351","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05196","title":"Phytocannabinoid profile and potency of cannabis resin (hashish) of northwest Himalayas of India.","authors":"Chauhan, Jyotsnessh; Bastia, Binaya Kumar; Kohli, Kanchan; Chaudhary, Babulal; Chikara, Gaurav; Gupta, Annie; Kumar, Ankit","year":2024,"journal":"Journal of forensic sciences, 69(5), 1918-1925","doi":"10.1111/1556-4029.15583","pmid":"38992862","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05197","title":"Adverse events associated with the use of cannabis-based products in people living with cancer: a systematic scoping review.","authors":"Cheah, Irene; Hunter, Jennifer; Gelissen, Ingrid; Chan, Wai-Jo Jocelin; Harnett, Joanna E","year":2024,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 33(1), 40","doi":"10.1007/s00520-024-09087-w","pmid":"39694905","tags":["cancer","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 152 studies, the most common adverse events were nervous system-related (118 studies), psychiatric (101 studies), and gastrointestinal (81 studies). THC-CBD combinations were the most common formulation studied (69 studies), followed by synthetic THC (47) and single-compound THC (42). Oral and inhalation were the primary administration routes.","whyItMatters":"With cancer patients increasingly using cannabis for symptom management, this is the most comprehensive mapping of adverse events to date. The finding of significant under-reporting in many studies highlights a critical gap that could lead to underestimating risks.","specificNumbers":"152 studies included. 61 RCTs. Most common cancer types: GI/liver/peritoneal (98 studies), hematological (92). Most common use: nausea/vomiting (78), pain (37). Nervous system AEs in 118 studies. Psychiatric AEs in 101. GI AEs in 81.","methodology":"Systematic scoping review following JBI methodology. Six databases searched from inception to May 2023. Included 152 primary studies: 61 RCTs, 26 non-randomized trials, 23 case reports, and other designs. All studies reported adverse events from cannabis-based products in cancer care settings.","limitations":"Scoping review maps evidence but does not assess quality or pool effect sizes. Diverse study designs, patient populations, and cannabis products limit comparability. Under-reporting of adverse events in original studies means the true burden may be higher."},{"rthcId":"RTHC-05198","title":"Cannabidiol as a potential cessation therapeutic: Effects on intravenous nicotine self-administration and withdrawal symptoms in mice.","authors":"Cheeks, Samantha N; Buzzi, Belle; Valdez, Ashley; Mogul, Allison S; Damaj, M Imad; Fowler, Christie D","year":2024,"journal":"Neuropharmacology, 246, 109833","doi":"10.1016/j.neuropharm.2023.109833","pmid":"38176534","tags":["cbd","addiction","quitting"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD produced a significant decrease in nicotine self-administration across multiple CBD doses and both low and moderate nicotine levels. CBD did not affect food pellet self-administration, indicating the effect was specific to nicotine. CBD also attenuated somatic withdrawal signs and prevented nicotine withdrawal-induced hyperalgesia (increased pain sensitivity).","whyItMatters":"Existing nicotine cessation medications have limited long-term success rates. CBD showing efficacy against both nicotine intake and withdrawal symptoms in mice suggests it could be explored as a novel cessation aid, targeting multiple aspects of tobacco dependence.","specificNumbers":"CBD reduced nicotine rewards earned at multiple doses. Effect observed at both low and moderate nicotine intake levels. No effect on food pellet self-administration. CBD attenuated somatic withdrawal signs and blocked withdrawal-induced hyperalgesia.","methodology":"Male and female mice were trained to self-administer intravenous nicotine at low or moderate doses. CBD was given as pretreatment before drug-taking sessions. Separate experiments tested CBD effects on food self-administration (to rule out motor effects) and on precipitated nicotine withdrawal symptoms.","limitations":"Mouse model may not translate to human nicotine addiction, which involves complex psychological and social factors. Intravenous nicotine delivery does not replicate smoking behavior. Optimal CBD dosing and timing for human cessation are unknown."},{"rthcId":"RTHC-05199","title":"Association Between Cannabis Use and Subjective Cognitive Decline: Findings from the Behavioral Risk Factor Surveillance System (BRFSS).","authors":"Chen, Zhi; Wong, Roger","year":2024,"journal":"Current Alzheimer research, 20(11), 802-810","doi":"10.2174/0115672050301726240219050051","pmid":"38409714","tags":["cognition","seniors"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Non-medical cannabis use was associated with 96% decreased odds of subjective cognitive decline (aOR=0.04, 95% CI: 0.01-0.44, p<.01). Medical use (aOR=0.46) and dual use (aOR=0.30) showed similar trends but were not statistically significant. Cannabis frequency and method of use were not associated with SCD.","whyItMatters":"The dramatic association between non-medical cannabis use and lower reported cognitive decline is striking but likely reflects selection bias or confounding rather than a true protective effect. Still, it raises questions worth investigating in longitudinal research.","specificNumbers":"4,744 adults aged 45+. Non-medical use aOR=0.04 (96% lower odds, p<.01). Medical use aOR=0.46 (not significant). Dual use aOR=0.30 (not significant). Frequency and method were not significant.","methodology":"Cross-sectional analysis of 4,744 US adults aged 45+ from the 2021 BRFSS survey. Subjective cognitive decline was self-reported increase in confusion or memory loss. Logistic regression adjusted for sociodemographic, health, and substance use factors.","limitations":"Cross-sectional design cannot establish causation. The extremely large effect size (96% reduction) raises concern about reverse causation (people with cognitive decline stopping recreational use). Subjective cognitive decline is self-reported and may not correlate with objective measures. Small numbers of cannabis users limit power."},{"rthcId":"RTHC-05200","title":"Assessing Cannabis Use in People with Psychosis.","authors":"Chesney, Edward; Lawn, Will; McGuire, Philip","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 49-58","doi":"10.1089/can.2023.0032","pmid":"37971872","tags":["psychosis","addiction"],"studyType":"narrative-review","evidenceStrength":"n/a","keyFinding":"Cannabis assessment tools used in psychosis research were originally developed for healthy individuals or people with cannabis use disorder. In psychosis patients, the accuracy of self-report may be compromised by symptoms, cognitive impairment, and motivated concealment. Urinary THC screening is sometimes used in acute episodes but not routinely. Quantitative blood/urine cannabinoid measurement could provide more reliable data but is rarely used.","whyItMatters":"Accurate cannabis use measurement is critical for managing psychosis, since use is linked to symptom worsening, poor treatment adherence, and relapse. If clinicians and researchers are relying on flawed measurement tools, they may be underestimating the problem.","specificNumbers":"Cannabis use is common in people with psychotic disorders. Self-report accuracy may be impaired by three factors: psychotic symptoms, cognitive deficits, and desire to conceal use from clinicians.","methodology":"Narrative review examining current approaches to assessing cannabis use in people with psychotic disorders, comparing self-report tools with biological measures and discussing limitations specific to this population.","limitations":"Narrative review without systematic methodology. Does not quantify the degree of measurement error. Biological measures have their own limitations (detecting use window, cost, invasiveness)."},{"rthcId":"RTHC-05201","title":"Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study.","authors":"Chester, Lucy A; Englund, Amir; Chesney, Edward; Oliver, Dominic; Wilson, Jack; Sovi, Simina; Dickens, Alex M; Oresic, Matej; Linderman, Tuomas; Hodsoll, John; Minichino, Amedeo; Strang, John; Murray, Robin M; Freeman, Tom P; McGuire, Philip","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 188-198","doi":"10.1089/can.2022.0174","pmid":"36493386","tags":["cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"high","keyFinding":"Cannabis inhalation induced acute increases in anandamide (+18%), DEA (+35.8%), oleoylethanolamide (+16.1%), and N-arachidonoyl-L-serine (+25.1%). Co-administration of 10, 20, or 30 mg CBD alongside 10 mg THC did not alter these endocannabinoid changes. An unexpected finding was progressive reduction in pre-treatment anandamide levels across repeated sessions.","whyItMatters":"A common claim is that CBD modulates THC effects through the endocannabinoid system. This rigorous RCT found no evidence that CBD (up to 30 mg) altered THC-induced endocannabinoid changes, challenging one proposed mechanism for CBD-THC interaction.","specificNumbers":"46 healthy volunteers. 10 mg THC per session. CBD doses: 0, 10, 20, 30 mg. Anandamide increased 18%. DEA increased 35.8%. Median 14 days between sessions. No CBD dose influenced endocannabinoid responses.","methodology":"Randomized, double-blind, four-arm crossover study with 46 healthy volunteers. Each participant inhaled cannabis vapor containing 10 mg THC with 0, 10, 20, or 30 mg CBD across four sessions (median 14 days apart). Blood samples taken pre-inhalation and at 0, 5, 15, and 90 minutes post-inhalation. Plasma endocannabinoids measured via LC-MS.","limitations":"CBD doses (10-30 mg) were relatively low; higher doses might show effects. Acute, single-dose design; chronic co-administration could differ. Only plasma endocannabinoids measured; brain levels may differ. The progressive decline in baseline anandamide across sessions is unexplained."},{"rthcId":"RTHC-05202","title":"Cannabis containing THC impairs 20-min cycling time trial performance irrespective of the method of inhalation.","authors":"Cheung, Christian P; Baker, Ryleigh E; Coates, Alexandra M; Burr, Jamie F","year":2024,"journal":"Journal of applied physiology (Bethesda, Md. : 1985), 136(3), 583-591","doi":"10.1152/japplphysiol.00757.2023","pmid":"38299223","tags":["exercise"],"studyType":"experimental","evidenceStrength":"moderate","keyFinding":"Both smoked THC and vaporized THC significantly reduced mean power output during a 20-minute cycling time trial compared to control and CBD conditions. Heart rate was elevated during submaximal exercise with THC but not CBD. VO2 and perceived exertion were similar across all conditions during maximal exercise. CBD-dominant cannabis had no effect on any measure.","whyItMatters":"As cannabis becomes legal in more places, athletes and recreational exercisers increasingly ask whether it affects performance. This is one of the few controlled studies directly measuring exercise output after cannabis use, and it clearly shows THC impairs performance.","specificNumbers":"14 participants (9 male, 5 female). THC cannabis: 15-30% total THC. Smoked and vaporized THC both reduced time trial power output vs. control and CBD. Heart rate elevated with THC during submaximal cycling. No effect from CBD on any exercise measure.","methodology":"Semi-randomized crossover study with 14 participants (9 male, 5 female) aged 25-45. Four conditions: smoked THC, vaporized THC, vaporized CBD, and control. Exercise included submaximal cycling at 100W followed by a 20-minute all-out time trial on a cycle ergometer.","limitations":"Small sample size (n=14). Self-supplied cannabis with variable potency. Only cycling tested; other exercise types might differ. Acute effects only; chronic cannabis users might respond differently. No blood THC levels reported."},{"rthcId":"RTHC-05203","title":"Cannabinoids Used for Medical Purposes in Children and Adolescents: A Systematic Review and Meta-Analysis.","authors":"Chhabra, Manik; Ben-Eltriki, Mohamed; Mansell, Holly; Lê, Mê-Linh; Huntsman, Richard J; Finkelstein, Yaron; Kelly, Lauren E","year":2024,"journal":"JAMA pediatrics, 178(11), 1124-1135","doi":"10.1001/jamapediatrics.2024.3045","pmid":"39283619","tags":["medical-cannabis","youth","epilepsy"],"studyType":"meta-analysis","evidenceStrength":"high","keyFinding":"Compared to control, cannabinoids in children increased risk of overall adverse events (RR 1.09), withdrawals due to AEs (RR 3.07), and serious AEs (RR 1.81). The most elevated specific risks were for liver enzyme increases (AST: RR 5.69; ALT: RR 5.67), somnolence (RR 2.28), and diarrhea (RR 1.82).","whyItMatters":"This is the most comprehensive safety analysis of medical cannabinoids in children to date, published in JAMA Pediatrics. As off-label cannabinoid prescribing to children grows, clinicians need evidence-based safety data to inform treatment decisions.","specificNumbers":"23 RCTs, 3,612 participants (17.6% female, 57.3% male). Withdrawal from AEs: RR 3.07. Serious AEs: RR 1.81. AST elevation: RR 5.69. ALT elevation: RR 5.67. Somnolence: RR 2.28. Diarrhea: RR 1.82. Purified CBD was the most common intervention (47.8%).","methodology":"Systematic review and meta-analysis searching MEDLINE, Embase, PsycINFO, and Cochrane Library through March 2024. Included 23 RCTs with 3,612 participants. Data pooled using random-effects models. PRISMA guidelines followed.","limitations":"Most studies focused on epilepsy (39.1%) and chemotherapy nausea (30.4%), limiting generalizability. Heterogeneity was moderate to high for some outcomes. Half the trials included mixed adult-pediatric populations. Long-term safety data remain absent."},{"rthcId":"RTHC-05204","title":"A Highly Potent, Orally Bioavailable Pyrazole-Derived Cannabinoid CB2 Receptor- Selective Full Agonist for In Vivo Studies.","authors":"Chicca, Andrea; Bátora, Daniel; Ullmer, Christoph; Caruso, Antonello; Grüner, Sabine; Fingerle, Jürgen; Hartung, Thomas; Degen, Roland; Müller, Matthias; Grether, Uwe; Pacher, Pal; Gertsch, Jürg","year":2024,"journal":"ACS pharmacology & translational science, 7(8), 2424-2438","doi":"10.1021/acsptsci.4c00269","pmid":"39144568","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05205","title":"A highly potent, orally bioavailable pyrazole-derived cannabinoid CB2 receptor-selective full agonist for in vivo studies.","authors":"Chicca, Andrea; Batora, Daniel; Ullmer, Christoph; Caruso, Antonello; Fingerle, Jürgen; Hartung, Thomas; Degen, Roland; Müller, Matthias; Grether, Uwe; Pacher, Pal; Gertsch, Jürg","year":2024,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2024.04.26.591311","pmid":"38903103","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05206","title":"Cannabis use disorder and substance use treatment among U.S. adults.","authors":"Choi, Namkee G; Moore, John; Choi, Bryan Y","year":2024,"journal":"Journal of substance use and addiction treatment, 167, 209486","doi":"10.1016/j.josat.2024.209486","pmid":"39151799","tags":["addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"high","keyFinding":"23% of US adults used cannabis in the past year. Among users, 30.3% met CUD criteria (16.9% mild, 8.4% moderate, 5.0% severe). 52.4% of those with CUD had co-occurring substance use disorders. Only 16.5% of those with CUD received treatment. Among users without other substance disorders, only severe CUD (aOR=6.03) predicted treatment use.","whyItMatters":"As cannabis legalization expands, understanding the prevalence of problematic use is critical. The finding that nearly a third of users meet CUD criteria yet very few receive treatment reveals a significant gap between need and service utilization.","specificNumbers":"23% past-year cannabis use. 7% of all US adults had CUD (3.9% mild, 1.9% moderate, 1.2% severe). 30.3% of users had CUD. 38.4% of those with CUD had moderate/severe mental illness. 52.4% had other substance use disorders. 16.5% received treatment. Cannabis users had 3-4x higher rates of other SUDs.","methodology":"Analysis of 2022 National Survey on Drug Use and Health (N=47,100 adults 18+). CUD severity categorized as mild, moderate, or severe per DSM-5 criteria. Logistic regression examined associations between CUD severity and treatment use, framed by Andersen behavioral model.","limitations":"Self-report survey data subject to reporting bias. Cross-sectional design limits causal inference. NSDUH does not capture quantity, potency, or method of cannabis use. Treatment definition is broad and may include treatment for co-occurring conditions."},{"rthcId":"RTHC-05207","title":"Risk of motor vehicle collision associated with cannabis and alcohol use among patients presenting for emergency care.","authors":"Choo, Esther K; Trent, Stacy A; Nishijima, Daniel K; Eichelberger, Angela; Kazmierczak, Steve; Ye, Yu; Brasel, Karen J; Audett, Ariane; Cherpitel, Cheryl J","year":2024,"journal":"Accident; analysis and prevention, 198, 107459","doi":"10.1016/j.aap.2024.107459","pmid":"38277855","tags":["driving","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis alone was not associated with higher MVC odds. Alcohol alone and combined alcohol-cannabis use were both independently associated with higher MVC odds. Higher levels of self-reported cannabis use were not associated with higher crash odds; in fact, high acute cannabis use was associated with lower MVC odds (OR 0.18). Case-crossover analysis confirmed: alcohol increased crash risk, cannabis alone decreased it.","whyItMatters":"This is one of the few studies measuring both biological THC levels and self-reported use alongside alcohol in real-world crash scenarios. The finding that cannabis alone may not increase crash risk, while alcohol clearly does, has implications for impaired driving policy.","specificNumbers":"Three ED sites: Denver, Portland, Sacramento. Cannabis alone: no increased MVC risk. High self-reported cannabis use: OR 0.18 (95% CI: 0.05-0.65). Alcohol alone and alcohol+cannabis: both significantly associated with higher MVC odds.","methodology":"Cross-sectional case-control study across three EDs (Denver, Portland, Sacramento). Cases were MVC-injured drivers; controls were non-injured ED drivers. Blood THC and metabolites measured. Breathalyzer/clinical blood for alcohol. Research-administered interviews collected use data. Multiple logistic regression and case-crossover analysis conducted.","limitations":"Observational study cannot prove causation. The lower crash odds with high cannabis use may reflect a \"stay home\" effect or other confounding. Blood THC levels do not correlate well with impairment timing. ED-based sample may not represent all crashes."},{"rthcId":"RTHC-05208","title":"Droperidol Plus Diphenhydramine for Symptom Improvement in Suspected Cannabinoid Hyperemesis Syndrome: A Prospective Cohort Study.","authors":"Chopra, Quincy; Peyko, Vincent; Lee, Jessica Annie; Puhalla, Leo; Gemmel, David J; Bolotin, Todd","year":2024,"journal":"Open access emergency medicine : OAEM, 16, 267-273","doi":"10.2147/OAEM.S473627","pmid":"39619486","tags":["medical-cannabis","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Nausea/vomiting VAS scores dropped from 8.3 at baseline to 3.1 at 30 minutes and 1.4 at 120 minutes (both p<0.05). Abdominal pain VAS dropped from 7.8 to 3.6 at 30 minutes and 1.7 at 120 minutes (both p<0.05). Return ED visits within 7 days were 12.9%.","whyItMatters":"CHS is increasingly common and often poorly treated with standard antiemetics. This prospective data supports droperidol as an effective option, with rapid symptom improvement within 30 minutes that continued through 2 hours.","specificNumbers":"47 patients. Nausea/vomiting: 8.3 to 3.1 at 30 min, 1.4 at 120 min. Abdominal pain: 7.8 to 3.6 at 30 min, 1.7 at 120 min. 12.9% returned to ED within 7 days. All changes significant at p<0.05.","methodology":"Multicenter, prospective interventional study in EDs. 47 participants with suspected CHS received droperidol plus diphenhydramine. Nausea, vomiting, and abdominal pain measured on visual analogue scales at baseline, 30, and 120 minutes. 7-day ED return rate tracked.","limitations":"No control group or randomization. All participants received the intervention, so natural symptom resolution cannot be excluded. Relatively small sample. Suspected CHS diagnosis may include some misdiagnosed patients. Short follow-up."},{"rthcId":"RTHC-05209","title":"International property rights for Cannabis landraces and terroir products. The case of Moroccan Cannabis and hashish.","authors":"Chouvy, Pierre-Arnaud","year":2024,"journal":"The International journal on drug policy, 129, 104479","doi":"10.1016/j.drugpo.2024.104479","pmid":"38875878","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05210","title":"Real world clinical outcomes of treatment of cannabis-induced psychosis and prevalence of cannabis-related primary psychosis: a retrospective study.","authors":"Chuenchom, Onrumpha; Suansanae, Thanarat; Lukanapichonchut, Lumsum; Suwanmajo, Somporn; Suthisisang, Chuthamanee","year":2024,"journal":"BMC psychiatry, 24(1), 626","doi":"10.1186/s12888-024-06075-6","pmid":"39334053","tags":["psychosis","addiction"],"studyType":"retrospective","evidenceStrength":"moderate","keyFinding":"All patients presented with psychosis; 64% had mood symptoms and 61% sleep problems. Risperidone was the most prescribed antipsychotic (83.6%) at a mean dose of 8 mg/day. BPRS scores improved significantly by day 22 (p<0.001). Average hospital stay was 28 days. At 1.3-year follow-up, 7% were diagnosed with schizophrenia.","whyItMatters":"This is one of the larger studies on cannabis-induced psychosis treatment outcomes. The finding that 7% progressed to schizophrenia at follow-up supports the concept that CIP can be a gateway to persistent psychotic illness in a subset of patients.","specificNumbers":"317 patients analyzed (mostly male, mean age 21). 98.7% received antipsychotics. Risperidone prescribed in 83.6% at mean 8 mg/day. 34.5% also received benzodiazepines. BPRS baseline: 55.2. Average LOS: 28 days. 7% diagnosed with schizophrenia at 1.3-year follow-up.","methodology":"Retrospective chart review at the Princess Mother National Institute on Drug Abuse Treatment, Thailand. 317 patients meeting ICD-10 criteria for cannabis-induced psychosis with positive urine THC, admitted October 2013 to September 2019. BPRS scores tracked weekly.","limitations":"Retrospective design with no control group. Thai population and smoked cannabis only may limit generalizability. Short follow-up (1.3 years) may underestimate eventual schizophrenia diagnoses. No information on cannabis cessation after discharge."},{"rthcId":"RTHC-05211","title":"Relationship between hospitalization from cannabis usage and pulmonary tuberculosis in Thailand from 2017 to 2022.","authors":"Chumchuen, Kemmapon; Wichaidit, Wit; Chongsuvivatwong, Virasakdi","year":2024,"journal":"PloS one, 19(12), e0312139","doi":"10.1371/journal.pone.0312139","pmid":"39636878","tags":["respiratory","legalization"],"studyType":"epidemiological","evidenceStrength":"low","keyFinding":"Cannabis-related admissions increased while TB admissions declined during 2017-2022. Both shared a hotspot in Northeastern Thailand. In matched cohorts of 6,773 patients, the TB incidence rate was 267.6 per 100,000 person-years in those with prior cannabis admission versus 165.9 in those without. The adjusted hazard ratio was 1.48 but did not reach significance (P=0.268).","whyItMatters":"Thailand legalized recreational cannabis in 2022. Understanding whether cannabis use could exacerbate its existing TB burden is a public health priority, even though this study found the association was not statistically significant.","specificNumbers":"2017-2022 data period. 6,773 matched pairs. TB incidence: 267.6 vs. 165.9 per 100,000 person-years. Hazard ratio: 1.48 (P=0.268). Shared hotspot in Northeastern Thailand.","methodology":"National in-patient database analysis in Thailand (2017-2022). Spatiotemporal correlation between cannabis-related and TB admissions examined with line plots and choropleth maps. Matched cohort analysis (6,773 per group) compared subsequent TB admission rates with Cox regression.","limitations":"Hospital admission data misses outpatient cannabis use. The non-significant result could reflect insufficient power. Cannabis hospitalization is a proxy for heavy use, not representative of all users. Ecological correlation between geographic hotspots does not imply causation."},{"rthcId":"RTHC-05212","title":"Increased active pulmonary tuberculosis risk from sharing bong of cannabis: a case-control study from Thailand.","authors":"Chumchuen, Kemmapon; Chongsuvivatwong, Virasakdi","year":2024,"journal":"Frontiers in public health, 12, 1474761","doi":"10.3389/fpubh.2024.1474761","pmid":"39606083","tags":["respiratory","harm-reduction"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"After adjusting for covariates, smoking and sharing a cannabis bong had an odds ratio of 4.22 (95% CI: 1.47-12.07) for TB. No significant association was found for other types of cannabis consumption. The population-attributable fraction for shared cannabis bongs was 12.16%, compared to 12.62% for tobacco smoking.","whyItMatters":"In TB-endemic countries, sharing smoking devices is a plausible transmission route. This study isolates shared cannabis bong use as a specific risk behavior, distinct from cannabis use in general, which has direct implications for harm reduction messaging.","specificNumbers":"148 TB cases, 117 controls. 11% of controls were current cannabis users. 19% had ever used. Shared bong OR: 4.22 (95% CI: 1.47-12.07). PAF: 12.16% for shared bongs vs. 12.62% for tobacco. Other cannabis consumption types: not significant.","methodology":"Matched case-control study in Songkhla Province, Thailand (2023). 148 TB cases and 117 healthy controls completed face-to-face interviews about cannabis consumption. Multivariate logistic regression estimated odds ratios. Population-attributable fractions calculated.","limitations":"Small sample size from one Thai province. Case-control design limits causal inference. Self-reported cannabis use may be inaccurate. Cannot separate the effect of sharing from the effect of bong smoking itself. Cultural context (Thai waterpipe sharing) may not generalize."},{"rthcId":"RTHC-05213","title":"Legalization and retail availability of recreational marijuana and adolescent use in schools.","authors":"Cil, Gulcan; Winters, Ken C; Austin, Sean C; Kittelman, Angus; Smolkowski, Keith; Westling, Erika; Seeley, John R","year":2024,"journal":"Health economics, 33(1), 107-120","doi":"10.1002/hec.4763","pmid":"37801408","tags":["youth","legalization"],"studyType":"quasi-experimental","evidenceStrength":"moderate","keyFinding":"Substance use-related office discipline referrals in Oregon middle schools increased by 0.14 per 100 students (30% of the mean) after legalization, relative to comparison schools in other states. The increase was moderated by having a marijuana outlet within one mile of the school. No statistically significant changes were found in high schools.","whyItMatters":"While many studies have found no overall increase in teen cannabis use after legalization, this study uses a behavioral measure (school discipline referrals) rather than self-report surveys, potentially capturing a different dimension of the impact on youth.","specificNumbers":"Middle school ODRs increased by 0.14 per 100 students (30% of mean). Effect moderated by dispensary within 1 mile. No significant change in high school ODRs.","methodology":"Quasi-experimental design comparing substance use discipline referral rates in Oregon middle and high schools before and after recreational marijuana legalization, using schools in non-legal states as comparison. Geographic analysis assessed the moderating effect of dispensary proximity.","limitations":"Discipline referrals reflect administrative decisions, not just student behavior. Cannot distinguish cannabis-specific offenses from other substances. Comparison schools in other states may differ in unmeasured ways. Oregon-specific findings may not generalize."},{"rthcId":"RTHC-05214","title":"Substance use patterns and mental health comorbidities in youth with a history of depression or suicidality: Findings from TX-YDSRN.","authors":"Clark, Shaunna L; Dodd, Cody G; Mitchell, Tarrah B; Ingram, Sarah J; Armstrong, Gabrielle M; Jha, Manish K; Soares, Jair C; Smith, Matt; Minhajuddin, Abu; Slater, Holli; Wakefield, Sarah M; Trivedi, Madhukar H","year":2024,"journal":"Journal of affective disorders, 366, 210-216","doi":"10.1016/j.jad.2024.08.128","pmid":"39187199","tags":["youth","depression","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Three substance use classes emerged: non-use (63.4%), moderate use of alcohol/nicotine/cannabis (23.8%), and high use of all substances (12.7%). The high-use class was more likely to have substance use disorders, ADHD, and higher suicidality scores. Both substance-using classes were older than non-users.","whyItMatters":"Understanding how substance use clusters among depressed youth can help clinicians identify who is at highest risk. The link between polysubstance use, ADHD, and suicidality suggests these youth need comprehensive assessment across multiple domains.","specificNumbers":"945 youth. Three classes: non-use (63.4%), moderate (23.8%), high (12.7%). High-use class had more substance use disorders, ADHD, and higher suicidality. Both substance-using classes were older.","methodology":"Cross-sectional analysis of 945 youth with depression and/or suicidality from the Texas Youth Depression and Suicide Research Network. Latent class analysis identified patterns of past-year alcohol, nicotine, cannabis, and other drug use. Demographics and psychiatric diagnoses were tested as predictors of class membership.","limitations":"Cross-sectional design cannot determine temporal ordering. Texas-based sample may not represent other regions. Brief self-report substance measures may miss details. Cannot determine whether substances worsen or are driven by psychiatric symptoms."},{"rthcId":"RTHC-05215","title":"The Impact of Childhood Mental Health and Substance Use on Methylation Aging Into Adulthood.","authors":"Clark, Shaunna L; McGinnis, Ellen W; Zhao, Min; Xie, Linying; Marks, Garrett T; Aberg, Karolina A; van den Oord, Edwin J C G; Copeland, William E","year":2024,"journal":"Journal of the American Academy of Child and Adolescent Psychiatry, 63(8), 825-834","doi":"10.1016/j.jaac.2023.10.014","pmid":"38157979","tags":["youth","cognition","depression"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Weekly cannabis use was significantly associated with accelerated DNA methylation aging (b=1.665, p=.005), as were years of weekly use (b=0.718, p=.012) and depressive symptoms (b=0.314, p=.014). In combined models, the cumulative effect of mental health symptoms, substance use, and adversity was equivalent to 3.17-3.76 additional years of biological aging.","whyItMatters":"Accelerated biological aging is linked to earlier onset of age-related diseases. Finding that cannabis use and depression independently speed up this process suggests early intervention on both fronts could have long-term health benefits.","specificNumbers":"381 participants tracked from adolescence to adulthood. 1,950 total childhood assessments. Weekly cannabis use: b=1.665 (p=.005). Years of weekly use: b=0.718 (p=.012). Depression: b=0.314 (p=.014). Combined effect: 3.17-3.76 years of accelerated aging.","methodology":"Longitudinal study of 381 participants from the Great Smoky Mountains Study. DNA methylation was measured from blood in adolescence (mean age 13.9) and adulthood (mean age 25.9). Childhood mental health, substance use, and adversity were assessed through 1,950 structured diagnostic interviews with participants and parents.","limitations":"Blood-based DNA methylation may not reflect brain-specific changes. Observational design cannot prove causation. Sample is from a single US community (Appalachian). Methylation aging clocks are estimates, not direct measures of biological age."},{"rthcId":"RTHC-05216","title":"Exploratory Growth Mixture Modeling of Cannabis-Withdrawal Syndrome Trajectories of Adult Pure Cannabis Dependents During Detoxification: Two Subtypes?","authors":"Claus, Benedikt Bernd; Scherbaum, Norbert; Specka, Michael; Roser, Patrik; Bonnet, Udo","year":2024,"journal":"Journal of psychoactive drugs, 56(4), 551-562","doi":"10.1080/02791072.2023.2229830","pmid":"37462539","tags":["withdrawal","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Two withdrawal trajectory classes emerged: class 1 (n=44, 66%) with continuously decreasing severity (\"protracted\"), and class 2 (n=23, 34%) with a sharp peak generally between days 2-6 followed by rapid decline. Lower urinary THC-COOH levels at admission and shorter treatment stays predicted the peaking trajectory.","whyItMatters":"Not all cannabis withdrawal is the same. Identifying two distinct patterns could help clinicians tailor detox protocols: patients with the peaking pattern may need intensive support during days 2-6 but recover faster, while protracted withdrawal patients may need longer-term support.","specificNumbers":"67 patients. Class 1 (protracted): n=44 (66%). Class 2 (peak/drop): n=23 (34%). Peak typically days 2-6. 53.7% discharged by day 12 after successful detox. Average scheduled treatment: 24 days.","methodology":"Re-analysis of longitudinal data from 67 German adults with cannabis dependence (no active comorbidity) undergoing 24-day inpatient detox. Growth mixture modeling analyzed cannabis withdrawal syndrome severity trajectories. Both raw data and imputed data models were tested.","limitations":"Small sample size (67 patients). 53.7% discharged early, requiring data imputation for the remaining period. PRN medication use may have influenced trajectories. Single-center German sample. Exploratory analysis requiring replication."},{"rthcId":"RTHC-05217","title":"Secondhand cannabis smoke exposure and respiratory symptoms among adults living in a state with legalized medical cannabis with limited smoke-free protections.","authors":"Cohn, Amy M; Zaring-Hinkle, Brittany; Catino, Joshua D; Ehlke, Sarah J; Ware, Kali; Alexander, Adam; Smith, Michael A; Jewell-Fleming, Sheri; Queimado, Lurdes; Kendzor, Darla E","year":2024,"journal":"Preventive medicine reports, 45, 102835","doi":"10.1016/j.pmedr.2024.102835","pmid":"39188973","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"SHCS exposure was reported by 42% of adults. Those exposed were more likely to be male, younger, non-Hispanic Black or Hispanic, lower SES, and had more respiratory symptoms. Respiratory symptoms were highest among those with both SHCS exposure and personal cannabis use. Young adulthood, Black race, and current cigarette/cannabis use were the strongest predictors of exposure.","whyItMatters":"As cannabis legalization expands, secondhand smoke is an emerging public health concern, particularly for populations with less ability to control their exposure environments. Oklahoma had limited smoke-free protections at the time of the study.","specificNumbers":"5,410 adults surveyed. 42% reported past-30-day SHCS exposure. Exposure associated with more respiratory symptoms (p<0.01). Strongest correlates: ages 18-24, NH Black race, cigarette smoking, cannabis use.","methodology":"Repeated cross-sectional online survey of 5,410 adults in Oklahoma (a state with legalized medical cannabis and limited smoke-free protections). Measured 30-day SHCS exposure in homes, vehicles, and indoor settings alongside harm perceptions, respiratory symptoms, and substance use.","limitations":"Self-reported exposure and symptoms may be subject to recall bias. Oklahoma-specific findings in a medical-cannabis-only state may not generalize. Cannot separate SHCS effects from personal cannabis or cigarette smoking effects. Cross-sectional design."},{"rthcId":"RTHC-05218","title":"Biobehavioral Interactions between Endocannabinoid and Hypothalamicpituitary- adrenal Systems in Psychosis: A Systematic Review.","authors":"Colizzi, Marco; Bortoletto, Riccardo; Antolini, Giulia; Bhattacharyya, Sagnik; Balestrieri, Matteo; Solmi, Marco","year":2024,"journal":"Current neuropharmacology, 22(3), 495-520","doi":"10.2174/1570159X21666230801150032","pmid":"37533248","tags":["psychosis","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Both systems show independent contributions to psychosis risk, but they also interact bidirectionally: cannabis use affects endocannabinoid tone, stress exposure alters the HPA axis, and crucially, THC also affects the HPA axis while childhood trauma affects endocannabinoid signaling, revealing cross-system perturbation.","whyItMatters":"The stress-diathesis model and cannabinoid hypothesis of schizophrenia have been studied independently. This review reveals they are deeply interconnected, suggesting that cannabis risk for psychosis cannot be understood without considering stress, and vice versa.","specificNumbers":"41 studies reviewed. 9 HPA-related biological studies. 2 endocannabinoid-related biological studies. 29 environmental-measure studies. 1 genetic study. CNR1 genetic variation identified as a cross-system factor.","methodology":"PRISMA-compliant systematic review searching PubMed, Web of Science, and Scopus. 41 eligible studies extracted, including biological interventional and non-interventional studies, environmental-measure studies, and genetic studies examining the interplay of HPA and endocannabinoid systems in psychosis.","limitations":"Heterogeneous study designs limit direct comparisons. Many included studies measured environmental factors (cannabis use, stress) rather than biological endocannabinoid or HPA markers. The mechanistic evidence is stronger for within-system than cross-system effects."},{"rthcId":"RTHC-05219","title":"Inclusion of Individuals With Lived Experiences in the Development of a Digital Intervention for Co-Occurring Depression and Cannabis Use: Mixed Methods Investigation.","authors":"Collins, Amanda C; Bhattacharya, Sukanya; Oh, Jenny Y; Salzhauer, Abigail; Taylor, Charles T; Wolitzky-Taylor, Kate; Aupperle, Robin L; Budney, Alan J; Jacobson, Nicholas C","year":2024,"journal":"JMIR formative research, 8, e54751","doi":"10.2196/54751","pmid":"39374076","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05220","title":"Developing a mobile-based brief intervention to reduce cannabis-impaired driving among youth: An intervention mapping approach.","authors":"Colonna, Robert; Tucker, Patricia; Mandich, Angela; Alvarez, Liliana","year":2024,"journal":"The International journal on drug policy, 134, 104626","doi":"10.1016/j.drugpo.2024.104626","pmid":"39476788","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05221","title":"Mental and Physical Health-Related Cannabis Motives Mediate the Relationship between Childhood Trauma and Problematic Cannabis Use over Time among Emerging Adult Cannabis Users.","authors":"Conn, Bridgid M; Brammer, Whitney A; Choi, Susie; Fedorova, Ekaterina V; Ataiants, Janna; Lankenau, Stephen E; Wong, Carolyn F","year":2024,"journal":"Substance use & misuse, 59(2), 193-207","doi":"10.1080/10826084.2023.2267111","pmid":"37822106","tags":["addiction","mental-health"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Cannabis use to cope with nausea, sleep, pain, and emotional distress mediated relationships between childhood abuse types and problematic cannabis use at follow-up. Most pathways attenuated by later adulthood, but emotional distress coping continued to mediate the connection between abuse and problematic use. Sleep and pain motives were uniquely associated with lower problematic use in emotional neglect models.","whyItMatters":"Understanding why some trauma survivors develop problematic cannabis use while others do not can inform targeted interventions. The finding that emotional coping motives are the most persistent pathway suggests this is where clinical attention should focus.","specificNumbers":"339 participants at baseline (mean age 21.23). 4 follow-up waves (2016-2020). Emotional distress motive persisted as mediator into later adulthood. Sleep and pain motives associated with lower problematic use in some models.","methodology":"Longitudinal study of 339 medical cannabis patient and non-patient emerging adults from Los Angeles (mean age 21.2 at baseline). Four waves of follow-up from 2016-2020. Mediation analyses tested whether specific cannabis use motives explained the link between childhood trauma types and problematic cannabis use.","limitations":"Los Angeles-based sample may not generalize. Self-report measures of trauma and cannabis motives. Attrition over 4 waves of follow-up. Cannot determine whether addressing motives would prevent problematic use."},{"rthcId":"RTHC-05222","title":"Cannabis Use and Trajectories of Depression and Stress Across the Prenatal Period.","authors":"Constantino-Pettit, Anna; Tillman, Rebecca; Wilson, Jillian; Lashley-Simms, Nicole; Vatan, Naazanene; Atkinson, Azaria; Leverett, Shelby D; Lenze, Shannon; Smyser, Christopher D; Bogdan, Ryan; Rogers, Cynthia; Agrawal, Arpana","year":2024,"journal":"JAMA network open, 7(12), e2451597","doi":"10.1001/jamanetworkopen.2024.51597","pmid":"39688865","tags":["pregnancy","depression"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"Depression, stress, and cannabis use all decreased from first to third trimester. 46.8% reported prenatal cannabis use. Those using cannabis for mental health reasons (58.1% of users) had the highest depression scores at each trimester but their rate of decline was statistically equivalent to non-users, suggesting cannabis was not accelerating symptom improvement.","whyItMatters":"Many pregnant women report using cannabis specifically to manage depression and stress. This JAMA Network Open study provides direct evidence that this self-medication strategy is not associated with faster symptom improvement, which could inform clinician counseling.","specificNumbers":"504 pregnant women. 46.8% reported prenatal cannabis use. 58.1% of users cited mental health reasons. Depression correlated with cannabis use at T1 (r=0.17) and in rate of change (r=0.18). All outcomes declined from T1 to T3.","methodology":"Prospective cohort study of 504 pregnant women recruited at an academic hospital (2019-2024). Depression (Edinburgh Postnatal Depression Scale), stress (Cohen Perceived Stress Scale), and cannabis use assessed each trimester. Cannabis use motives collected in the first trimester. Linear growth curve models estimated trajectories.","limitations":"Observational design cannot prove cannabis fails to help; it may have unmeasured benefits. Self-reported cannabis use may underestimate actual use. Women with the most severe symptoms may be most likely to use cannabis, creating confounding by indication. No randomization possible."},{"rthcId":"RTHC-05223","title":"Contingency management is associated with positive changes in attitudes and reductions in cannabis use even after discontinuation of incentives among non-treatment seeking youth.","authors":"Cooke, Megan E; Knoll, Sarah J; Streck, Joanna M; Potter, Kevin; Lamberth, Erin; Rychik, Natali; Gilman, Jodi M; Evins, A Eden; Schuster, Randi M","year":2024,"journal":"Drug and alcohol dependence, 256, 111096","doi":"10.1016/j.drugalcdep.2024.111096","pmid":"38277735","tags":["youth","addiction","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"high","keyFinding":"Abstinence-incentivized participants showed significant reductions in cannabis use frequency and biochemically verified THC metabolites at 4-week follow-up compared to monitoring-only controls. 68.4% of abstinence participants set goals to reduce or quit after the intervention. Those without CUD who set reduction goals showed the greatest decreases.","whyItMatters":"Most young cannabis users are not seeking treatment. This study shows that a brief period of incentivized abstinence can shift attitudes and reduce use even in youth who were not motivated to change, suggesting a viable harm reduction strategy.","specificNumbers":"220 participants. Group-by-time interaction significant (days/week: p=.005; times/week: p<.001; CN-THCCOOH: p=.004). 68.4% set reduction/abstinence goals post-intervention. Greatest reductions in those without CUD who set goals.","methodology":"Randomized trial of 220 non-treatment-seeking youth. 126 randomized to 4-week abstinence-based contingency management (incentivized) and 94 to monitoring only. Cannabis use measured by self-report and creatinine-adjusted urine THC-COOH at baseline, end of intervention, and 4-week follow-up.","limitations":"Relatively short follow-up (4 weeks post-intervention). Youth without CUD responded best, so this may be less effective for those with established disorders. Financial incentives may not be scalable in all settings. Cannot determine durability beyond 4 weeks."},{"rthcId":"RTHC-05224","title":"Efficacy in diet-induced obese mice of the hepatotropic, peripheral cannabinoid 1 receptor inverse agonist TM38837.","authors":"Cooper, Martin E; Nørregaard, Pia K; Högberg, Thomas; Andersson, Gunnar; Receveur, Jean-Marie; Linget, Jean-Michel; Elling, Christian E","year":2024,"journal":"British journal of pharmacology, 181(20), 3926-3943","doi":"10.1111/bph.16401","pmid":"38886096","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05225","title":"The impacts of packaging on preferences for cannabis edibles: A discrete choice experiment.","authors":"Cooper, Michael; Shi, Yuyan","year":2024,"journal":"The International journal on drug policy, 128, 104453","doi":"10.1016/j.drugpo.2024.104453","pmid":"38796927","tags":["legalization","harm-reduction"],"studyType":"experimental","evidenceStrength":"moderate","keyFinding":"Nearly all groups preferred branded over plain packages and any health claim over none. Cannabis users, especially recreational users, preferred youth-appealing packaging. Package style was the most important attribute (33-51% relative importance), followed by health claims (23-31%). Warning labels had limited influence on choices.","whyItMatters":"Cannabis edibles are gaining market share, and packaging is a key regulatory lever. Finding that package style and health claims drive preferences more than warning labels suggests regulators should prioritize plain packaging and health claim restrictions over warning label mandates.","specificNumbers":"1,578 adults from 18+ DC legal states. Package style: 33-51% relative importance. Health claims: 23-31%. Recreational users preferred youth-appealing packages. Warning labels had limited impact on choices.","methodology":"Online discrete choice experiment with 1,578 adults from 18 legal recreational cannabis states. Participants chose between edible packages varying in five attributes: style, health claim, potency indicator, warning label position, and warning label text. Mixed logit regression analysis with subsample comparisons by use status and purpose.","limitations":"Hypothetical choice experiment may not perfectly predict real purchasing behavior. Online sample may not represent all cannabis consumers. Only tested five packaging attributes; real-world packaging has more variables. Legal-state-only sample."},{"rthcId":"RTHC-05226","title":"5-HT2A receptors are involved in the pharmaco-toxicological effects of the synthetic cannabinoids JWH-018 and 5F-PB22: In vivo studies in mice.","authors":"Corli, Giorgia; Tirri, Micaela; Bassi, Marta; Bernardi, Tatiana; Boccuto, Federica; Borsari, Martina; Zauli, Giorgio; Bilel, Sabrine; Marti, Matteo","year":2024,"journal":"European journal of pharmacology, 971, 176486","doi":"10.1016/j.ejphar.2024.176486","pmid":"38458413","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05227","title":"Sex-specific behavioural, metabolic, and immunohistochemical changes after repeated administration of the synthetic cannabinoid AKB48 in mice.","authors":"Corli, Giorgia; Roda, Elisa; Tirri, Micaela; Bilel, Sabrine; De Luca, Fabrizio; Strano-Rossi, Sabina; Gaudio, Rosa Maria; De-Giorgio, Fabio; Fattore, Liana; Locatelli, Carlo Alessandro; Marti, Matteo","year":2024,"journal":"British journal of pharmacology, 181(9), 1361-1382","doi":"10.1111/bph.16311","pmid":"38148741","tags":["synthetic-cannabinoids","sex-differences"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"First AKB48 injection impaired sensorimotor responses, temperature, analgesia, and breathing more in females than males. The second injection induced stronger effects in males. By the third injection, both sexes showed weaker responses (tolerance). Females had higher blood AKB48 levels, higher baseline CB1 receptor density, and faster CB1 receptor downregulation in cerebellum and cortex.","whyItMatters":"Synthetic cannabinoid intoxications are a growing clinical problem. Finding that sex dramatically affects the response pattern and speed of tolerance suggests that treatment of intoxication may need to account for sex differences.","specificNumbers":"Females had higher blood AKB48 levels and higher baseline CB1 receptor expression. Tolerance emerged by third injection in both sexes. Repeated dosing caused progressive blood AKB48 accumulation (suggesting cytochrome inhibition). Females showed faster CB1 receptor downregulation.","methodology":"Male and female CD-1 mice received repeated AKB48 injections. Sensorimotor responses, body temperature, pain threshold, breathing, and motor activity measured after each dose. CB1 receptor antagonist confirmed receptor-mediated action. Blood pharmacokinetics tracked. CB1 receptor immunohistochemistry performed in brain regions.","limitations":"Mouse model with controlled dosing does not reflect human recreational use patterns. AKB48 is one of many synthetic cannabinoids with different pharmacological profiles. Only acute and short-term repeated dosing studied."},{"rthcId":"RTHC-05228","title":"Tolerability of long-term cannabidiol supplementation to healthy adult dogs.","authors":"Corsato Alvarenga, Isabella; Wilson, Kim M; McGrath, Stephanie","year":2024,"journal":"Journal of veterinary internal medicine, 38(1), 326-335","doi":"10.1111/jvim.16949","pmid":"38009749","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05229","title":"Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome.","authors":"Cosentino, Livia; Urbinati, Chiara; Lanzillotta, Chiara; De Rasmo, Domenico; Valenti, Daniela; Pellas, Mattia; Quattrini, Maria Cristina; Piscitelli, Fabiana; Kostrzewa, Magdalena; Di Domenico, Fabio; Pietraforte, Donatella; Bisogno, Tiziana; Signorile, Anna; Vacca, Rosa Anna; De Filippis, Bianca","year":2024,"journal":"Molecular autism, 15(1), 39","doi":"10.1186/s13229-024-00617-1","pmid":"39300547","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05230","title":"The impact of cannabis on non-medical opioid use among individuals receiving pharmacotherapies for opioid use disorder: a systematic review and meta-analysis of longitudinal studies.","authors":"Costa, Gabriel P A; Nunes, Julio C; Heringer, Daniel L; Anand, Akhil; De Aquino, Joao P","year":2024,"journal":"The American journal of drug and alcohol abuse, 50(1), 12-26","doi":"10.1080/00952990.2023.2287406","pmid":"38225727","tags":["addiction","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"high","keyFinding":"The pooled odds ratio was 1.00 (95% CI: 0.97-1.04, p=.98), indicating no association between cannabis use and non-medical opioid use during OUD treatment. This null finding held across treatment types (methadone, buprenorphine, naltrexone). Average follow-up was 9.7 months.","whyItMatters":"Some treatment programs require cannabis abstinence for opioid use disorder medication. This meta-analysis found no evidence that cannabis use worsens opioid treatment outcomes, challenging the rationale for mandatory cannabis abstinence policies.","specificNumbers":"10 studies, 8,367 participants. 38% female. Pooled OR: 1.00 (95% CI: 0.97-1.04). Average follow-up: 9.7 months. Treatment: methadone 76.3%, buprenorphine 21.3%, naltrexone 2.4%. Moderate heterogeneity.","methodology":"Systematic review and meta-analysis of 10 longitudinal studies found across multiple databases. Random-effects model with restricted maximum likelihood. Sensitivity analysis by OUD treatment modality. 8,367 participants (38% female), mostly receiving methadone (76.3%).","limitations":"Moderate heterogeneity and evidence of publication bias. Mostly methadone patients (76.3%), limiting generalizability to other medications. Cannot distinguish between different cannabis use patterns (frequency, quantity, method). Does not assess cannabis for OUD treatment, only concurrent use."},{"rthcId":"RTHC-05231","title":"Prevalence and trends of suspected cannabinoid hyperemesis syndrome over an 11-year period in Northern California: An electronic health record study.","authors":"Costales, Brianna; Lu, Yun; Young-Wolff, Kelly C; Cotton, Dale M; Campbell, Cynthia I; Iturralde, Esti; Sterling, Stacy A","year":2024,"journal":"Drug and alcohol dependence, 263, 112418","doi":"10.1016/j.drugalcdep.2024.112418","pmid":"39216202","tags":["harm-reduction","legalization"],"studyType":"epidemiological","evidenceStrength":"high","keyFinding":"Using a narrow CHS definition, annual prevalence increased by 175% from 2009 to 2019 (prevalence ratio=2.75). A broader definition showed a 134% increase (PR=2.34). ED visit rates also increased substantially (rate ratio=2.35 for the narrow definition). Over 57,000 patients had at least one CHS visit under the narrow definition.","whyItMatters":"This is one of the largest CHS prevalence studies ever conducted, using a defined health system population rather than emergency department surveillance. The near-tripling of cases over a decade tracks with increasing cannabis availability and potency in California.","specificNumbers":"57,227 patients with at least 1 CHS visit (narrow definition). 65,645 (broad definition). 175% prevalence increase for narrow definition (2009-2019). 134% for broad definition. ED visit rate ratio: 2.35.","methodology":"Retrospective observational cohort using Kaiser Permanente Northern California electronic health records (2009-2019). Two CHS case definitions applied: a narrow definition based on prior studies and a broader exploratory definition. Both required a primary vomiting diagnosis. Log-link Poisson models estimated trends.","limitations":"ICD coding may misclassify some cases. Broader definition may capture non-CHS vomiting. CHS awareness among clinicians increased over the study period, potentially inflating diagnosis rates (detection bias). Kaiser members may not represent the general population."},{"rthcId":"RTHC-05232","title":"Digital Interventions for Recreational Cannabis Use Among Young Adults: Systematic Review, Meta-Analysis, and Behavior Change Technique Analysis of Randomized Controlled Studies.","authors":"Côté, José; Chicoine, Gabrielle; Vinette, Billy; Auger, Patricia; Rouleau, Geneviève; Fontaine, Guillaume; Jutras-Aswad, Didier","year":2024,"journal":"Journal of medical Internet research, 26, e55031","doi":"10.2196/55031","pmid":"38630515","tags":["youth","addiction","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Digital interventions reduced cannabis use frequency by 6.79 days in the previous month at 3-month follow-up (95% CI: -9.59 to -4.00, p<.001) compared to controls. 184 behavior change techniques were identified across interventions (range 5-19 per intervention). Feedback on behavior was the most common technique (89% of interventions). Most interventions were web-based.","whyItMatters":"Young adults are the heaviest cannabis users but least likely to seek traditional treatment. Digital interventions can reach this population at scale, and this meta-analysis shows they produce meaningful reductions in use frequency.","specificNumbers":"19 RCTs, 6,710 participants. Cannabis use reduction: 6.79 fewer days/month at 3 months (p<.001). 184 behavior change techniques identified. Feedback on behavior used in 89% of interventions. 47% of studies showed intervention effect on frequency.","methodology":"Systematic review and meta-analysis of 19 RCTs (n=6,710) from 7 databases through February 2023. Included web- or mobile-based interventions for cannabis use in community-dwelling young adults (16-35). Random-effects model with standardized mean differences. Behavior change technique coding applied.","limitations":"High heterogeneity across studies. Mix of passive and active control conditions. Most interventions were web-based, limiting conclusions about mobile apps specifically. 3-month follow-up may not reflect long-term outcomes. Behavior change technique analysis identifies common ingredients but not which are most effective."},{"rthcId":"RTHC-05233","title":"Cannabidiol and cannabidiolic acid: Preliminary in vitro evaluation of metabolism and drug-drug interactions involving canine cytochrome P-450, UDP-glucuronosyltransferase, and P-glycoprotein.","authors":"Court, Michael H; Mealey, Katrina L; Burke, Neal S; Jimenez, Tania Perez; Zhu, Zhaohui; Wakshlag, Joseph J","year":2024,"journal":"Journal of veterinary pharmacology and therapeutics, 47(1), 1-13","doi":"10.1111/jvp.13403","pmid":"37469115","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05234","title":"Dose-dependent effects of oral cannabidiol and delta-9-tetrahydrocannabinol on serum anandamide and related N-acylethanolamines in healthy volunteers.","authors":"Couttas, Timothy A; Boost, Carola; Pahlisch, Franziska; Sykorova, Eliska B; Mueller, Juliane K; Jieu, Beverly; Leweke, Judith E; Dammann, Inga; Hoffmann, Anna E; Loeffler, Martin; Grimm, Oliver; Enning, Frank; Flor, Herta; Meyer-Lindenberg, Andreas; Koethe, Dagmar; Rohleder, Cathrin; Leweke, F Markus","year":2024,"journal":"BMJ mental health, 27(1)","doi":"10.1136/bmjment-2024-301027","pmid":"39182921","tags":["cbd","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"high","keyFinding":"CBD at 800 mg (but not 600 mg) significantly increased serum anandamide (1.6-fold), OEA and PEA (1.4-fold). THC at 10 and 20 mg initially decreased anandamide but levels returned to baseline by 160 minutes. Combining CBD 800 mg + THC 20 mg produced the highest increases: anandamide 2.1-fold, OEA 1.9-fold, PEA 1.8-fold, without reaching a plateau.","whyItMatters":"In schizophrenia trials, CBD doses of 800 mg+ showed clinical benefit, and anandamide elevation has been linked to improvement. This study confirms the dose threshold for anandamide elevation and reveals that THC combination enhances the effect, providing a pharmacological rationale for specific dosing.","specificNumbers":"75 healthy volunteers. CBD 800 mg: anandamide +1.6-fold, OEA/PEA +1.4-fold. CBD 600 mg: no significant effect. THC 10 mg: anandamide -1.3-fold initially. CBD 800 + THC 20: anandamide +2.1-fold, OEA +1.9-fold, PEA +1.8-fold.","methodology":"Two independent parallel-designed clinical trials with 75 healthy volunteers. Single oral doses of CBD (600 or 800 mg), THC (10 or 20 mg), or CBD+THC combination. Serum endocannabinoid levels measured by LC-MS/MS at baseline, 65, and 160 minutes post-administration.","limitations":"Single-dose study in healthy volunteers; chronic dosing may differ. Only two CBD doses tested (600 vs. 800 mg). Serum levels may not reflect brain endocannabinoid changes. Short measurement window (160 minutes)."},{"rthcId":"RTHC-05235","title":"The potential neuroprotective effects of cannabinoids against paclitaxel-induced peripheral neuropathy: in vitro study on neurite outgrowth.","authors":"Creanga-Murariu, Ioana; Filipiuc, Leontina-Elena; Gogu, Maria-Raluca; Ciorpac, Mitica; Cumpat, Carmen Marinela; Tamba, Bogdan-Ionel; Alexa-Stratulat, Teodora","year":2024,"journal":"Frontiers in pharmacology, 15, 1395951","doi":"10.3389/fphar.2024.1395951","pmid":"38933665","tags":["cancer","pain","cbd"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"When combined with paclitaxel, cannabinoids maintained cell viability at 70-89% compared to 40% with chemotherapy alone at 48 hours. Cannabinoids also preserved neurite length: paclitaxel alone shortened axons by 63%, while cannabinoid combinations limited shortening to 23-44%. Both synthetic (JWH-007, AM-694, MAB-CHMINACA) and phytocannabinoid preparations showed protective effects.","whyItMatters":"Chemotherapy-induced peripheral neuropathy affects 68% of paclitaxel patients and has no approved preventive treatment. If cannabinoids can protect nerves from chemo damage while maintaining cancer treatment, this could address a major unmet need in oncology.","specificNumbers":"Cell viability with cannabinoids + chemo: 70-89% vs. 40% chemo alone at 48 hours. Axon shortening: 23-44% with cannabinoid combination vs. 63% with paclitaxel alone. Both synthetic and plant-derived cannabinoids effective.","methodology":"In vitro study using primary dorsal root ganglion neuron cultures. Cell viability assessed with multiple cannabinoids at various doses and timepoints. Neurite outgrowth measured to assess neuroprotection against paclitaxel-induced peripheral neuropathy.","limitations":"In vitro study only; nerve cells in culture do not replicate the complexity of neuropathy in a living body. Cannot determine if cannabinoids would also protect cancer cells from chemotherapy. Optimal doses and timing for clinical use are unknown."},{"rthcId":"RTHC-05236","title":"Five Years After Cannabis Legalization, Is It Time to Ease Restrictions on Promotion?","authors":"Crépault, Jean-François; Rueda, Sergio; Tang, Victor","year":2024,"journal":"Healthcare policy = Politiques de sante, 19(3), 21-28","doi":"10.12927/hcpol.2024.27241","pmid":"38721730","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05237","title":"Does medicinal cannabis affect depression, anxiety, and stress in people with cancer? A systematic review and meta-analysis of intervention studies.","authors":"Crichton, Megan; Dissanayaka, Thusharika; Marx, Wolfgang; Gamage, Elizabeth; Travica, Nikolaj; Bowers, Alison; Isenring, Elizabeth; Yates, Patsy; Marshall, Skye","year":2024,"journal":"Maturitas, 184, 107941","doi":"10.1016/j.maturitas.2024.107941","pmid":"38430618","tags":["cancer","mental-health","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"No clinically significant effects on depression, anxiety, or stress. Higher-dose synthetic THC increased anxiety events (OR 2.0, p<.001). Medicinal cannabis increased likelihood of improved appetite 12-fold (OR 12.3, p<.001) and reduced appetite loss severity. No effects on emotional functioning, mood changes, confusion, or quality of life.","whyItMatters":"Many cancer patients use cannabis hoping it will help their mental health. This meta-analysis shows that while cannabis may benefit appetite, it does not appear to help with depression, anxiety, or stress in cancer, and higher THC doses may actually worsen anxiety.","specificNumbers":"15 studies, 1,898 participants. 18 interventions tested. Appetite improvement OR: 12.3 (p<.001). Higher-dose synthetic THC anxiety events OR: 2.0 (p<.001). No significant effects on depression, anxiety, stress, mood, QoL, or GI symptoms.","methodology":"Systematic review and meta-analysis of 15 intervention studies (11 RCTs, 4 non-randomized, N=1,898) from 5 databases through May 2023. Pooled with Review Manager using random-effects models. Evidence appraised with Cochrane tools and GRADE.","limitations":"Most interventions used synthetic THC (70%), which may differ from whole-plant cannabis. GRADE confidence was low to very low for most outcomes. Small number of studies for some outcomes. Heterogeneous cancer types and treatment contexts."},{"rthcId":"RTHC-05238","title":"Risk of Adverse Neonatal Outcomes After Combined Prenatal Cannabis and Nicotine Exposure.","authors":"Crosland, B Adam; Garg, Bharti; Bandoli, Gretchen E; Mandelbaum, Ava D; Hayer, Sarena; Ryan, Kimberly S; Shorey-Kendrick, Lyndsey E; McEvoy, Cindy T; Spindel, Eliot R; Caughey, Aaron B; Lo, Jamie O","year":2024,"journal":"JAMA network open, 7(5), e2410151","doi":"10.1001/jamanetworkopen.2024.10151","pmid":"38713462","tags":["pregnancy"],"studyType":"retrospective-cohort","evidenceStrength":"high","keyFinding":"Cannabis or nicotine alone each increased risks of infant death (0.7% for both), small-for-gestational-age (14.3% and 13.7%), and preterm delivery (12.2% and 12.0%). Combined use showed additive or super-additive risks: infant death 1.2% (ARR 2.18), neonatal death 0.6% (ARR 1.76), SGA 18.0% (ARR 1.94), and preterm delivery 17.5% (ARR 1.83).","whyItMatters":"This is one of the largest studies ever to examine combined cannabis-nicotine prenatal exposure. The finding that risks are higher with co-use than either substance alone has immediate implications for prenatal counseling, especially as cannabis use in pregnancy rises.","specificNumbers":"3,129,259 pregnancies. Cannabis: 23,007 (0.7%). Nicotine: 56,811 (1.8%). Both: 10,312 (0.3%). Combined use ARRs: infant death 2.18, neonatal death 1.76, SGA 1.94, preterm 1.83. Mean maternal age 29.3 years.","methodology":"Population-based retrospective cohort using linked California hospital discharge and vital statistics data (2012-2019). 3,129,259 singleton pregnancies analyzed. Cannabis and nicotine exposure identified by ICD-9/10 codes. Multivariable Poisson regression for adjusted risk ratios.","limitations":"ICD code-based exposure capture likely underestimates true prevalence. Cannot determine dose, frequency, or timing of use. Residual confounding from socioeconomic and health factors. Cannot establish biological causation from administrative data."},{"rthcId":"RTHC-05239","title":"The Relationship Between Rates of Cannabis Use and Covid-19 Infection Rates During the Pandemic: An Analysis of Canada's National Cannabis Survey.","authors":"Cullen, Greggory; Cristiano, Nick; Walters, David; Hathaway, Andrew; Wrathall, Meghan; Wadsworth, Elle","year":2024,"journal":"Substance use & misuse, 59(14), 2094-2102","doi":"10.1080/10826084.2024.2392562","pmid":"39282898","tags":["legalization","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Higher regional COVID-19 infection rates were independently associated with both greater likelihood of cannabis use and higher frequency of use, even after controlling for age, gender, SES, mental health, cannabis store density, and pre-pandemic use prevalence. The relationship persisted across all 10 Canadian provinces.","whyItMatters":"Understanding how pandemic stress affected substance use can inform future public health responses. The finding that areas hit hardest by COVID also had more cannabis use supports investing in harm reduction where pandemic impacts were greatest.","specificNumbers":"Data from end of 2020, 2 years post-legalization. All 10 Canadian provinces included. Higher infection rates predicted both cannabis use likelihood and frequency after controlling for confounders including pre-pandemic use.","methodology":"Analysis linking the National Cannabis Survey data with COVID-19 case rates and legal retail cannabis availability across health regions at end of 2020. Hierarchical generalized linear models controlled for individual and regional confounders.","limitations":"Cross-sectional design cannot determine if higher infection rates caused increased cannabis use or if the relationship is driven by shared underlying factors. Self-reported cannabis use. Cannot distinguish medical from recreational use reasons."},{"rthcId":"RTHC-05240","title":"Prenatal cannabis exposure in the clinic and laboratory: What do we know and where do we need to go?","authors":"Cupo, Lani; Dominguez-Cancino, Karen A; Nazif-Munoz, José Ignacio; Chakravarty, M Mallar","year":2024,"journal":"Drug and alcohol dependence reports, 13, 100282","doi":"10.1016/j.dadr.2024.100282","pmid":"39430603","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05241","title":"Variation of subclinical psychosis across 16 sites in Europe and Brazil: findings from the multi-national EU-GEI study.","authors":"D'Andrea, Giuseppe; Quattrone, Diego; Malone, Kathryn; Tripoli, Giada; Trotta, Giulia; Spinazzola, Edoardo; Gayer-Anderson, Charlotte; Jongsma, Hannah E; Sideli, Lucia; Stilo, Simona A; La Cascia, Caterina; Ferraro, Laura; Lasalvia, Antonio; Tosato, Sarah; Tortelli, Andrea; Velthorst, Eva; de Haan, Lieuwe; Llorca, Pierre-Michel; Rossi Menezes, Paulo; Santos, Jose Luis; Arrojo, Manuel; Bobes, Julio; Sanjuán, Julio; Bernardo, Miguel; Arango, Celso; Kirkbride, James B; Jones, Peter B; Rutten, Bart P; Van Os, Jim; Selten, Jean-Paul; Vassos, Evangelos; Schürhoff, Franck; Szöke, Andrei; Pignon, Baptiste; O'Donovan, Michael; Richards, Alexander; Morgan, Craig; Di Forti, Marta; Tarricone, Ilaria; Murray, Robin M","year":2024,"journal":"Psychological medicine, 54(8), 1810-1823","doi":"10.1017/S0033291723003781","pmid":"38288603","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05242","title":"Case report: Cannabinoid therapy for discoid lupus erythematosus in a dog.","authors":"da Silva, Maria Eduarda Schmitz; Christianetti, Bruna; Amazonas, Erik; Pereira, Marcy Lancia","year":2024,"journal":"Frontiers in veterinary science, 11, 1309167","doi":"10.3389/fvets.2024.1309167","pmid":"38406630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05243","title":"The moderating role of sex in the relationship between cannabis use treatment admission profile and treatment processes and outcomes: A gender perspective.","authors":"Dacosta-Sánchez, Daniel; Michelini, Yanina; Pilatti, Angelina; Fernández-Calderón, Fermín; Lozano, Óscar M; González-Ponce, Bella M","year":2024,"journal":"Addictive behaviors, 157, 108103","doi":"10.1016/j.addbeh.2024.108103","pmid":"39018615","tags":["addiction","sex-differences"],"studyType":"retrospective","evidenceStrength":"moderate","keyFinding":"Sex moderated the relationship between number of children and treatment adherence: having more children predicted lower adherence specifically in females. Pre-treatment cannabis use also predicted lower adherence more strongly in females. Women with children were more likely to drop out of treatment compared to men with children.","whyItMatters":"Understanding why women drop out of cannabis treatment at higher rates can inform targeted interventions. The finding that childcare responsibilities specifically predict female dropout suggests practical barriers, not just clinical factors, drive the gender gap.","specificNumbers":"3,814 outpatients with cannabis use disorder. Sex moderated effects of children and pre-treatment use on adherence. Females with children: higher dropout. Pre-treatment cannabis use: stronger negative effect on adherence for females.","methodology":"Multicentric retrospective observational study of 3,814 outpatients diagnosed with cannabis use disorder. Electronic health records analyzed for treatment admission characteristics, adherence, and discharge outcomes. Moderation analyses tested sex as a moderator.","limitations":"Retrospective design with electronic health records that may have missing data. Cannot determine specific reasons for dropout. Cultural factors from the study country may not generalize. Pre-treatment cannabis use was binary (yes/no) without dose information."},{"rthcId":"RTHC-05244","title":"Understanding of pharmacy students' knowledge of cannabis use disorders in recreational vs non-recreational use states.","authors":"Daggolu, Jerusha; Ganna, Sourab; Sansgiry, Sujit S","year":2024,"journal":"Currents in pharmacy teaching & learning, 16(12), 102191","doi":"10.1016/j.cptl.2024.102191","pmid":"39241579","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05245","title":"Unveiling the link between chronic pain and misuse of opioids and cannabis.","authors":"Dagher, Merel; Alayoubi, Myra; Sigal, Gabriella H; Cahill, Catherine M","year":2024,"journal":"Journal of neural transmission (Vienna, Austria : 1996), 131(5), 563-580","doi":"10.1007/s00702-024-02765-3","pmid":"38570361","tags":["pain","addiction","cognition","neuroscience","dopamine","withdrawal"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Over 50 million Americans live with chronic pain, and many don't receive adequate treatment. This review tackles a question with enormous public health implications: why are chronic pain patients more likely to develop opioid and cannabis use disorders?\n\nThe answer centers on dopamine — the brain's reward and motivation chemical. Chronic pain suppresses dopamine signaling in the mesolimbic pathway (the brain's reward circuit), creating a state called hypodopaminergia. This reduced dopamine state does two things: it makes pain feel worse (because dopamine normally helps modulate pain perception) and it makes anything that boosts dopamine — including opioids and cannabis — feel especially rewarding.\n\nBoth opioids and cannabis temporarily restore dopamine signaling, relieving not just pain but the negative emotional state that accompanies chronic pain: the depression, anxiety, irritability, and loss of motivation. This dual relief — physical and emotional — is what drives self-medication and makes these substances so compelling for pain patients.\n\nBut the relief creates a trap. Repeated opioid or cannabis use further dysregulates dopamine signaling, deepening the hypodopaminergic state and increasing the drive to use. The brain adapts to the drug-boosted dopamine, and withdrawal makes the dopamine deficit even worse. This creates a cycle where the self-medication that initially provided relief gradually becomes part of the problem.\n\nThe review details the specific neurobiological mechanisms: how opioids modulate dopamine through mu-receptor activation in the ventral tegmental area, how cannabis modulates it through CB1 receptor effects on GABA and glutamate interneurons, and how chronic pain itself alters these circuits at a cellular level.","whyItMatters":"Understanding why chronic pain leads to substance misuse isn't just academic — it should change how we treat both conditions. If the common root is hypodopaminergic signaling, then treating chronic pain more effectively might prevent substance misuse, and understanding the shared neurobiology might lead to treatments that address both conditions simultaneously rather than treating them as separate problems.","specificNumbers":"Over 50 million Americans have chronic pain. High comorbidity between chronic pain and substance use disorders is well-documented. The mesolimbic dopamine pathway is central to both conditions. Opioids act through mu-receptors in the VTA; cannabis acts through CB1 receptors on GABA/glutamate interneurons. Chronic pain creates measurable hypodopaminergic transmission.","methodology":"Narrative review synthesizing clinical evidence and neurobiological research on the link between chronic pain and opioid/cannabis use disorders. Covered: epidemiological data on comorbidity, dopaminergic mechanisms in pain and addiction, opioid and cannabinoid effects on mesolimbic dopamine signaling, and the neuroadaptations that link pain to substance misuse.","limitations":"Narrative review, not systematic. While the dopaminergic hypothesis is compelling, chronic pain and addiction involve many neurotransmitter systems beyond dopamine (norepinephrine, serotonin, endogenous opioids, endocannabinoids). The causal direction isn't fully established — chronic pain may cause substance use disorders, substance use may worsen pain (opioid-induced hyperalgesia), or shared vulnerabilities may predispose to both. Most neurobiological evidence comes from animal models that don't fully capture the human experience of pain and addiction."},{"rthcId":"RTHC-05246","title":"Endocannabinoid System Changes throughout Life: Implications and Therapeutic Potential for Autism, ADHD, and Alzheimer's Disease.","authors":"Dallabrida, Kamila Gabrieli; de Oliveira Bender, Joyce Maria; Chade, Ellen Schavarski; Rodrigues, Nathalia; Sampaio, Tuane Bazanella","year":2024,"journal":"Brain sciences, 14(6)","doi":"10.3390/brainsci14060592","pmid":"38928592","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05247","title":"Endocannabinoid remodeling in murine cachexic muscle associates with catabolic and metabolic regulation.","authors":"Dalle, Sebastiaan; Hiroux, Charlotte; Koppo, Katrien","year":2024,"journal":"Biochimica et biophysica acta. Molecular basis of disease, 1870(5), 167179","doi":"10.1016/j.bbadis.2024.167179","pmid":"38653357","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05248","title":"Cannabidiol and its Potential Evidence-Based Psychiatric Benefits - A Critical Review.","authors":"Dammann, Inga; Rohleder, Cathrin; Leweke, F Markus","year":2024,"journal":"Pharmacopsychiatry, 57(3), 115-132","doi":"10.1055/a-2228-6118","pmid":"38267003","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05249","title":"Perceptions, Experiences, and Patterns of Cannabis Use in Individuals with Mood and Anxiety Disorders in the Context of Cannabis Legalization and Medical Cannabis Program in Canada - A Qualitative Study.","authors":"Das, Ankita; Hendershot, Christian S; Husain, M Ishrat; Knyahnytska, Yuliya; Elsaid, Sonja; Le Foll, Bernard; Kloiber, Stefan","year":2024,"journal":"Pharmacopsychiatry, 57(3), 141-151","doi":"10.1055/a-2264-1047","pmid":"38467156","tags":["mental-health","medical-cannabis"],"studyType":"qualitative","evidenceStrength":"n/a","keyFinding":"Cannabis use was initiated from curiosity, peer pressure, or treatment dissatisfaction. Continuation was driven by psychotropic effects and symptom coping (mood, insomnia). Over time, users acknowledged negative effects including cognitive dysfunction, worsening mood, and increased anxiety. Concerning patterns included initiation before age 18, mixed medical/recreational use, and rare medical consultation.","whyItMatters":"The disconnect between perceived and actual effects is clinically important. Patients reported continuing cannabis for symptom relief even as they recognized it was making things worse, highlighting the complexity of self-medication in mental health populations.","specificNumbers":"36 patients interviewed. All had mood or anxiety disorder diagnoses. Many initiated use before age 18. Mixed medical and recreational use common. Medical professional consultation was rare.","methodology":"Qualitative study with 36 adults diagnosed with mood or anxiety disorders (including OCD and PTSD) who currently use cannabis. In-depth interviews explored motivations, perceptions, effects, and patterns of cannabis use. Thematic analysis applied.","limitations":"Small qualitative sample from a single setting. Self-selected cannabis-using patients may not represent non-users with the same diagnoses. Canadian context with legal access may differ from other jurisdictions. Qualitative design captures experiences but not prevalence."},{"rthcId":"RTHC-05250","title":"Cannabis effectiveness on immunologic potency of pulmonary contagion.","authors":"Das, Sumana; Ghosh, Arya; Karmakar, Varnita; Khawas, Sourav; Vatsha, Piyush; Roy, Kishor Kumar; Behera, Padma Charan","year":2024,"journal":"Journal of basic and clinical physiology and pharmacology, 35(3), 129-142","doi":"10.1515/jbcpp-2023-0030","pmid":"38635412","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05251","title":"Characteristics for Medical Cannabis Treatment Adherence among Autistic Children and Their Families: A Mixed-Methods Analysis.","authors":"David, Ayelet; Stolar, Orit; Berkovitch, Matitiahu; Kohn, Elkana; Waisman-Nitzan, Michal; Hartmann, Inbar; Gal, Eynat","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 68-79","doi":"10.1159/000538901","pmid":"39015610","tags":["medical-cannabis","cbd"],"studyType":"mixed-methods","evidenceStrength":"moderate","keyFinding":"75% adherence rate over 6 months. Side effects were relatively mild. Parents reported substantial benefits for children and families. Barriers included the complex intake regime, some side effects, and in certain cases unrealistic parental expectations about treatment outcomes.","whyItMatters":"Medical cannabis for autism is growing in use but adherence data are scarce. A 75% adherence rate is relatively high for a 6-month treatment in children, suggesting that when properly supported, families can maintain cannabis-based interventions for autism.","specificNumbers":"87 autistic children. 75% adherence rate at 6 months. CBD-rich cannabis preparation. Relatively mild side effects. Barriers: intake regime, side effects, unrealistic expectations.","methodology":"Explanatory sequential mixed-methods study of 87 autistic children and their families receiving 6-month CBD-rich cannabis treatment. Quantitative analysis of characteristics and adherence combined with qualitative parent interviews about benefits and barriers.","limitations":"No control group or randomization. Parent-reported benefits may be biased by expectations. Single-center study. CBD-rich products vary, limiting generalizability to other formulations. 6-month timeframe may not reflect longer-term adherence."},{"rthcId":"RTHC-05252","title":"Longitudinal associations between insomnia, cannabis use and stress among US veterans.","authors":"Davis, Jordan P; Prindle, John; Saba, Shaddy K; Castro, Carl A; Hummer, Justin; Canning, Liv; Pedersen, Eric R","year":2024,"journal":"Journal of sleep research, 33(1), e13945","doi":"10.1111/jsr.13945","pmid":"37243415","tags":["sleep","mental-health","addiction"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Higher prior insomnia levels predicted greater increases in perceived stress. Greater prior stress predicted greater increases in cannabis use. Critically, cannabis use also predicted greater increases in both stress and insomnia severity, suggesting a bidirectional, self-perpetuating cycle rather than a simple self-medication pattern.","whyItMatters":"Many veterans use cannabis for sleep and stress relief. This study reveals a paradox: while cannabis may provide short-term relief, over time it appears to worsen the very problems it is used to treat, creating a cycle that could sustain both insomnia and stress.","specificNumbers":"1,105 post-9/11 veterans. 4 assessment points over 12 months. Insomnia predicted stress increases. Stress predicted cannabis use increases. Cannabis use predicted increases in both stress and insomnia.","methodology":"Longitudinal study of 1,105 post-9/11 veterans assessed at 4 time points across 12 months. Latent difference score modeling examined proportional change relationships between insomnia, perceived stress, and cannabis use.","limitations":"Observational study cannot establish true causation. Self-reported measures may not capture objective sleep quality. Cannot distinguish between different cannabis products, doses, or timing of use. Veteran population may not generalize to civilians."},{"rthcId":"RTHC-05253","title":"Cannabidiol induces systemic analgesia through activation of the PI3Kγ/nNOS/NO/KATP signaling pathway in neuropathic mice. A KATP channel S-nitrosylation-dependent mechanism.","authors":"de Almeida, Douglas Lamounier; Mendes Ferreira, Renata Cristina; Fonseca, Flávia Cristina; Dias Machado, Daniel Portela; Aguiar, Danielle Diniz; Guimaraes, Francisco Silveira; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima","year":2024,"journal":"Nitric oxide : biology and chemistry, 146, 1-9","doi":"10.1016/j.niox.2024.02.005","pmid":"38428514","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05254","title":"Cannabis therapy in rheumatological diseases: A systematic review.","authors":"de Carvalho, Jozélio Freire; Ribeiro, Maria Fernanda Leal Dos Santos; Skare, Thelma","year":2024,"journal":"Northern clinics of Istanbul, 11(4), 361-366","doi":"10.14744/nci.2023.43669","pmid":"39165706","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05255","title":"Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.","authors":"de Fátima Dos Santos Sampaio, Maria; de Paiva, Yara Bezerra; Sampaio, Tuane Bazanella; Pereira, Messias Gonzaga; Coimbra, Norberto Cysne","year":2024,"journal":"Basic & clinical pharmacology & toxicology, 134(5), 574-601","doi":"10.1111/bcpt.13997","pmid":"38477419","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05256","title":"The Impacts of Adolescent Cannabinoid Exposure on Striatal Anxiety- and Depressive-Like Pathophysiology Are Prevented by the Antioxidant N-Acetylcysteine.","authors":"De Felice, Marta; Szkudlarek, Hanna J; Uzuneser, Taygun C; Rodríguez-Ruiz, Mar; Sarikahya, Mohammed H; Pusparajah, Mathusha; Galindo Lazo, Juan Pablo; Whitehead, Shawn N; Yeung, Ken K-C; Rushlow, Walter J; Laviolette, Steven R","year":2024,"journal":"Biological psychiatry global open science, 4(6), 100361","doi":"10.1016/j.bpsgos.2024.100361","pmid":"39257692","tags":["youth","anxiety","depression","neuroscience"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Adolescent THC exposure caused lasting anxiety- and depressive-like behaviors in rats, along with molecular and neuronal abnormalities in the nucleus accumbens. Co-treatment with N-acetylcysteine (NAC) prevented both the behavioral and brain changes.","whyItMatters":"This study identifies oxidative stress as a key mechanism behind THC-related neurodevelopmental harm and points to NAC as a potential preventive tool, offering a specific biological target rather than just documenting risk.","specificNumbers":"THC exposure induced distinct neuronal and molecular abnormalities in both the shell and core of the nucleus accumbens. NAC prevented these pathological changes across all measured behavioral, molecular, and neuronal biomarkers.","methodology":"Preclinical rat model using adolescent THC exposure followed by behavioral testing, molecular analysis, and neuronal recording in the nucleus accumbens shell and core subregions, with and without NAC co-treatment.","limitations":"Rat model; THC doses and exposure patterns may not mirror typical human adolescent use. NAC prevention was studied, not treatment after symptoms develop."},{"rthcId":"RTHC-05257","title":"Marijuana use among community-dwelling older adults: A population-based study.","authors":"De Genna, Natacha M; Jacobsen, Erin; Ganguli, Mary","year":2024,"journal":"International journal of geriatric psychiatry, 39(4), e6086","doi":"10.1002/gps.6086","pmid":"38613138","tags":["mental-health","depression","anxiety","pain","seniors"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis research in older adults has mostly relied on convenience samples — people recruited from dispensaries or cannabis clinics who are already enthusiastic users. This study is different: it drew from a random, age-stratified sample of 910 adults aged 65 and older living in a small American town, giving a true population-level picture.\n\nOne in five participants reported a lifetime history of marijuana use, and 5% reported recent use. Among current users, the top reasons were pain (41%) and recreation/relaxation (37%) — a practical, unsurprising pattern for this age group.\n\nBut the associations with mental health and functioning are where the data gets complicated. Recent marijuana use was associated with cigarette and alcohol use, symptoms of depression and anxiety, and functional impairment. This doesn't mean marijuana caused these problems — it's equally possible that people with depression, anxiety, and functional limitations are more likely to turn to marijuana for relief. The cross-sectional design can't tell us which direction the arrow points.\n\nThe cognitive findings add another layer. Recent users did not differ from non-users on basic cognitive screening (Mini-Mental State Examination), but the association with functional impairment on Activities of Daily Living measures raises questions about whether cannabis use affects real-world functioning in ways that brief cognitive tests don't capture.\n\nThe demographics of this sample — a small, predominantly non-Hispanic White American town — limit generalizability but provide a clean population-level snapshot that's been missing from the geriatric cannabis literature.","whyItMatters":"As cannabis legalization expands, use among older adults is the fastest-growing demographic segment. But most research has studied self-selected users. This population-based approach reveals the actual prevalence (higher than many assume) and the concerning associations with depression, anxiety, and functional impairment that may not be visible in studies of motivated medical cannabis patients.","specificNumbers":"910 adults aged 65+ (mean age 77, 50% female, mostly non-Hispanic White). 20% lifetime marijuana use. 5% recent use. Reasons: pain (41%), recreation/relaxation (37%). Recent use associated with cigarette use, alcohol use, depression symptoms, anxiety symptoms, and functional impairment.","methodology":"Cross-sectional analysis of data from the Monongahela-Youghiogheny Healthy Aging Team (MYHAT) study, an age-stratified random sample of 910 adults aged 65+ from a small town in the USA. Marijuana use assessed by self-report. Mental health screened with modified CES-Depression Scale and GAD screener. Cognition assessed by MMSE and neuropsychological battery. Functioning assessed by OARS ADL/IADL scales and Clinical Dementia Rating.","limitations":"Cross-sectional design — cannot determine whether marijuana use causes or results from depression, anxiety, and functional impairment. Predominantly White, small-town American sample limits generalizability. Self-reported marijuana use may be underreported due to stigma, especially in this age group. 5% recent use rate is based on a small absolute number of users, limiting statistical power for subgroup analyses. No data on specific cannabis products, doses, or routes of administration."},{"rthcId":"RTHC-05258","title":"Cannabis use influences disorganized symptoms severity but not transition in a cohort of non-help-seeking individuals at-risk for psychosis from São Paulo, Brazil.","authors":"de Medeiros, Matheus Wanderley; Andrade, Julio Cesar; Haddad, Natalia Mansur; Mendonça, Melina; de Jesus, Leonardo Peroni; Fekih-Romdhane, Feten; van de Bilt, Martinus Theodorus; Gattaz, Wagner Farid; Loch, Alexandre Andrade","year":2024,"journal":"Psychiatry research, 331, 115665","doi":"10.1016/j.psychres.2023.115665","pmid":"38113810","tags":["psychosis","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"In a community sample of 109 at-risk individuals and 197 controls from Sao Paulo, Brazil, cannabis use patterns did not differ between the two groups and did not predict transition to psychiatric disorders. However, among the at-risk group, cannabis use was significantly associated with more severe disorganization symptoms.","whyItMatters":"Most studies on cannabis and psychosis risk recruit from clinical settings. This study used a community sample of people not seeking help, providing a different perspective on how cannabis affects early psychosis risk in the general population.","specificNumbers":"109 at-risk individuals and 197 controls were followed for a mean of 2.5 years. No significant differences in lifetime, current, or maximum cannabis use between groups. Cannabis use significantly correlated with disorganization symptoms in the at-risk group.","methodology":"Prospective cohort study drawing from the general population (non-help-seeking) with 2.5-year follow-up. Cannabis use was assessed with the South Westminster modified questionnaire. Transition to psychiatric disorders was tracked through reassessment.","limitations":"Relatively small sample size for transition analysis. Self-reported cannabis use. Community-based sample may have milder risk profiles than clinical populations. 2.5-year follow-up may be too short to capture all transitions."},{"rthcId":"RTHC-05259","title":"An on-line school-based substance use harm reduction programme: The Illicit Project randomized controlled trial results.","authors":"Debenham, Jennifer; Birrell, Louise; Champion, Katrina E; Newton, Nicola","year":2024,"journal":"Addiction (Abingdon, England), 119(4), 741-752","doi":"10.1111/add.16403","pmid":"38105000","tags":["youth","harm-reduction"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"The intervention group showed significantly slower increases in binge drinking (OR 0.33), cocaine use (OR 0.06), and prescription drug misuse (OR 0.07) over 12 months compared to controls. Cannabis use showed no significant intervention effect. Drug literacy and harm reduction help-seeking skills remained higher in the intervention group.","whyItMatters":"School-based substance use programs often show weak effects. This online, neuroscience-based approach demonstrated meaningful reductions across multiple substances in a rigorous trial design, though the lack of cannabis-specific effects is notable.","specificNumbers":"950 students across 8 schools. 63% completed 12-month follow-up. Binge drinking OR 0.33 (95% CI 0.12-0.89). Cocaine use OR 0.06 (95% CI 0.01-0.64). Prescription drug misuse OR 0.07 (95% CI 0.01-0.54). Cannabis use: no significant effect (P > 0.5).","methodology":"Two-arm cluster-randomized controlled trial across 8 secondary schools in New South Wales, Australia. 950 students (mean age 15.9) were assigned to the intervention (5 schools, n=681) or active control (3 schools, n=269). Follow-up at 6 and 12 months.","limitations":"Unequal cluster sizes (5 vs 3 schools). 37% attrition at 12 months. Self-reported outcomes. Australian context may not generalize to other countries. Active control received standard health education, not no intervention."},{"rthcId":"RTHC-05260","title":"Critical Overview of Current Drug Abuse in Puerto Rico based on Governmental Data.","authors":"Del Valle-Colón, Christian D; Torres-Rodríguez, Julienn; Carrasquillo-Rivera, Mallerie; Fernández-Rodríguez, Esteban; Beltrán-Rivera, Alejandra; Pujols, Patricia; Maldonado-Vlaar, Carmen S","year":2024,"journal":"Puerto Rico health sciences journal, 43(4), 177-185","doi":null,"pmid":"39671410","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05261","title":"Prenatal cannabis use disorder and gastroschisis in California, 2007-19.","authors":"Delker, Erin; Baer, Rebecca J; Kelly, Ann E; Chambers, Christina; Bandoli, Gretchen","year":2024,"journal":"International journal of epidemiology, 53(2)","doi":"10.1093/ije/dyae042","pmid":"38503548","tags":["pregnancy"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis use disorder during pregnancy was associated with gastroschisis (a birth defect where intestines protrude through the abdominal wall). The multivariable model showed an adjusted risk ratio of 1.3 (95% CI 1.0-1.7), and a matched sample approach showed aRR 1.5 (95% CI 1.1-2.1). The association was strongest in mothers over 34 (aRR 2.5, 95% CI 1.0-5.8).","whyItMatters":"Gastroschisis rates have been rising for unknown reasons, and cannabis use has increased during the same period. This large population study suggests a possible connection worth further investigation, particularly for older mothers.","specificNumbers":"5,774,656 births analyzed. Cannabis use disorder prevalence was about 1%. Gastroschisis prevalence: 0.14% in CUD-exposed vs 0.06% in unexposed. Adjusted risk ratio 1.3-1.5 depending on method. Mothers over 34: aRR 2.5.","methodology":"Population-based cohort using California birth records linked to hospital, ED, and ambulatory surgery records from 2007-2019. 5,774,656 singleton live births analyzed. Cannabis use disorder measured by diagnosis codes during pregnancy or at birth.","limitations":"Cannabis use disorder diagnosis codes likely undercount actual cannabis use. Cannot determine dose, timing, or frequency of use. Observational design cannot establish causation. Residual confounding from other substance use or socioeconomic factors is possible."},{"rthcId":"RTHC-05262","title":"Investigating Cannabidiol's potential as a supplementary treatment for schizophrenia: A narrative review.","authors":"Denis Völker, Jes Sebastian; Micluția, Ioana Valentina; Vinași, Ramona-Cristina","year":2024,"journal":"European journal of pharmacology, 979, 176821","doi":"10.1016/j.ejphar.2024.176821","pmid":"39068976","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05263","title":"Antipsychotic Use and Psychiatric Hospitalization in First-Episode Non-affective Psychosis and Cannabis Use Disorder: A Swedish Nationwide Cohort Study.","authors":"Denissoff, Alexander; Taipale, Heidi; Tiihonen, Jari; Di Forti, Marta; Mittendorfer-Rutz, Ellenor; Tanskanen, Antti; Mustonen, Antti; Niemelä, Solja","year":2024,"journal":"Schizophrenia bulletin, 50(6), 1287-1294","doi":"10.1093/schbul/sbae034","pmid":"38534050","tags":["psychosis","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Any antipsychotic use reduced psychotic relapse risk by 33%. Clozapine showed the lowest relapse risk (aHR 0.43) and an 86% reduction in substance use disorder hospitalizations (aHR 0.14). LAI formulations of risperidone (aHR 0.40), aripiprazole (aHR 0.42), and paliperidone (aHR 0.46) also performed well. Among oral non-clozapine options, aripiprazole was best (aHR 0.61).","whyItMatters":"Patients with both psychosis and cannabis use disorder are common but understudied. This is one of the first large studies to compare antipsychotic effectiveness specifically in this population, using a design that controls for the many confounders typical of substance-using patients.","specificNumbers":"1,820 patients (84.73% male, mean age 26.80). Clozapine: 57% psychotic relapse reduction, 86% SUD hospitalization reduction. LAI risperidone: 60% relapse reduction. LAI aripiprazole: 58% reduction. LAI paliperidone: 54% reduction. Oral aripiprazole: 39% reduction.","methodology":"Nationwide Swedish cohort study using register data from 2006-2021. 1,820 patients with first-episode psychosis and co-occurring cannabis use disorder. Within-individual Cox regression models, which control for all time-stable confounders by comparing each patient to themselves across different treatment periods.","limitations":"Observational design despite within-individual analysis. Cannabis use disorder was identified by diagnosis codes, which may not capture all users. Selection bias for clozapine (typically reserved for treatment-resistant cases). Swedish population may not generalize globally."},{"rthcId":"RTHC-05264","title":"Association of Cannabis Use Disorder With Hospitalizations for Pulmonary Embolism and Subsequent in-Hospital Mortality in Young Adults: A Contemporary Nationwide Analysis.","authors":"Desai, Rupak; Ghadge, Nitin; Kanagala, Sai Gautham; Katukuri, Nishanth; James, Alpha; Kadiyala, Avinash; Vutukuru, Sai Diksha; Kotharu, Meghana; Borzoo, Tajdin; Nalla, Akhila; Vyas, Ankit; Priyadarshni, Shivani; Shalaby, Mostafa; Khalife, Wissam","year":2024,"journal":"Journal of the American Heart Association, 13(13), e032787","doi":"10.1161/JAHA.123.032787","pmid":"38934855","tags":["cardiovascular"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 8,438,858 young adult (18-44) admissions in 2018, 61,965 were PE-related, with 1,705 (0.6%) having cannabis use disorder. After adjustment, CUD was associated with lower odds of PE hospitalization (OR 0.80, 95% CI 0.71-0.90). In-hospital mortality did not differ between groups. However, the CUD group had longer median hospital stays and higher costs.","whyItMatters":"The relationship between cannabis use and blood clot risk is poorly understood. This large national analysis provides unexpected findings that challenge assumptions about cannabis and thromboembolism in younger patients.","specificNumbers":"8,438,858 young adult admissions. 61,965 PE-related (0.7%). CUD prevalence among PE admissions: 0.6%. Adjusted OR for PE with CUD: 0.80 (95% CI 0.71-0.90). No mortality difference. Longer hospital stays and higher costs in the CUD group.","methodology":"Retrospective analysis of the 2018 National Inpatient Sample. Multivariable regression adjusted for covariates. Propensity score-matched analysis (1:6) was also performed to assess in-hospital outcomes.","limitations":"Cross-sectional database analysis cannot determine causation. CUD diagnosis codes undercount cannabis use. Cannot distinguish dose, frequency, or method of use. Administrative data may have coding inaccuracies. Single-year analysis."},{"rthcId":"RTHC-05265","title":"Medical Marijuana Legalization in Oklahoma: Effects on Neonatal Exposure to Opiates.","authors":"DeShea, Lise; Rolfs, Shanna; McCoy, Mike; Beasley, William H; Szyld, Edgardo; Makkar, Abhishek","year":2024,"journal":"American journal of perinatology, 41(S 01), e1069-e1074","doi":"10.1055/a-1990-8311","pmid":"36452967","tags":["pregnancy","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Comparing 19 months before and after Oklahoma's medical marijuana law, positive THC tests in newborns increased significantly from 16.2 to 22.2 per 1,000 liveborn infants (p=0.004). Opioid exposure showed a nonsignificant decrease from 7.6 to 6.8 per 1,000 (p=0.542). The more rural site had significantly higher rates of amphetamines, benzodiazepines, and THC.","whyItMatters":"This study tests the specific hypothesis that medical marijuana legalization could reduce opioid use during pregnancy. While neonatal cannabis exposure increased as expected, the hoped-for reduction in opioid exposure did not materialize in a statistically significant way.","specificNumbers":"16,804 live births. THC positives: 16.2 to 22.2 per 1,000 (p=0.004). Opioid positives: 7.6 to 6.8 per 1,000 (p=0.542). THC-opioid co-positives doubled from 4 to 9 cases (too few for statistical analysis). Rural site had higher rates across multiple substances.","methodology":"Retrospective analysis of cord blood, urine, and meconium drug screens at two Oklahoma hospital sites (Oklahoma City and Lawton). 16,804 live births across 38 months (19 pre-law, 19 post-law).","limitations":"Only two hospital sites in one state. Short 19-month comparison periods. Cannot determine whether mothers held medical marijuana cards. Small numbers for co-use analysis. No clinical outcome data for exposed neonates."},{"rthcId":"RTHC-05266","title":"Microaggressions Toward Sexual and Gender Minority Emerging Adults: An Updated Systematic Review of Psychological Correlates and Outcomes and the Role of Intersectionality.","authors":"DeSon, Joshua J; Andover, Margaret S","year":2024,"journal":"LGBT health, 11(4), 249-268","doi":"10.1089/lgbt.2023.0032","pmid":"37906109","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05267","title":"Prenatal tetrahydrocannabinol and cannabidiol exposure produce sex-specific pathophysiological phenotypes in the adolescent prefrontal cortex and hippocampus.","authors":"DeVuono, Marieka V; Nashed, Mina G; Sarikahya, Mohammed H; Kocsis, Andrea; Lee, Kendrick; Vanin, Sebastian R; Hudson, Roger; Lonnee, Eryn P; Rushlow, Walter J; Hardy, Daniel B; Laviolette, Steven R","year":2024,"journal":"Neurobiology of disease, 199, 106588","doi":"10.1016/j.nbd.2024.106588","pmid":"38960101","tags":["pregnancy","neuroscience"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Prenatal THC and CBD exposure (alone and combined) caused low birth weight and sex-specific changes in adolescent rats: altered anxiety, temporal order memory, social cognition, and sensorimotor gating. These behavioral changes were linked to treatment- and sex-specific neuronal and gene expression abnormalities in the prefrontal cortex and ventral hippocampus, with dysregulated endocannabinoid system signaling and excitatory/inhibitory balance.","whyItMatters":"Most prenatal cannabis research focuses on THC alone. This study examined THC, CBD, and their combination separately, revealing that CBD is not necessarily benign during pregnancy and that male and female brains respond differently to prenatal cannabinoid exposure.","specificNumbers":"Both THC and CBD exposure were associated with low birth weight. Sex-specific changes were observed across multiple behavioral domains. Gene transcription and neuronal activity differences were detected in two brain regions central to emotional and cognitive development.","methodology":"Preclinical rat model with prenatal exposure to THC, CBD, or THC+CBD. Offspring assessed at adolescence using behavioral tests, electrophysiology, and RT-qPCR in prefrontal cortex and ventral hippocampus.","limitations":"Rat model with direct cannabinoid administration; does not replicate human cannabis use patterns. Doses may not correspond to human exposure levels. Effects measured at adolescence only."},{"rthcId":"RTHC-05268","title":"DNA methylation at cannabinoid type 1 and dopamine D2 receptor genes in saliva samples of psychotic subjects: Is there an effect of Cannabis use?","authors":"Di Bartolomeo, Martina; Čerňanová, Andrea; Petrušová, Veronika; Di Martino, Serena; Hodosy, Július; Drago, Filippo; Micale, Vincenzo; D'Addario, Claudio","year":2024,"journal":"Pharmacological research, 208, 107343","doi":"10.1016/j.phrs.2024.107343","pmid":"39127265","tags":["psychosis","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"DNA methylation at CNR1 and DRD2 genes was significantly higher in psychotic subjects than healthy controls, and the two genes' methylation levels were directly correlated. However, psychotic subjects reporting current THC consumption had lower methylation at both genes, resembling control levels at least for DRD2.","whyItMatters":"This study suggests epigenetic changes at two key receptor genes could serve as biomarkers for psychosis, but only in non-cannabis-using patients. The finding that THC use reverses these methylation changes complicates biomarker development and raises questions about how cannabis interacts with psychosis biology.","specificNumbers":"CNR1 and DRD2 methylation were both significantly higher in psychotic subjects vs controls. The methylation levels of the two genes were directly correlated. THC-using psychotic subjects showed methylation levels resembling controls, particularly at DRD2.","methodology":"Case-control study measuring DNA methylation via pyrosequencing in saliva samples from psychotic subjects and healthy controls, with subgroup analysis by current THC consumption status.","limitations":"Saliva-based methylation may not reflect brain tissue patterns. Small study without reported sample sizes in abstract. Cross-sectional design cannot determine whether methylation changes cause psychosis or result from it. THC use was self-reported."},{"rthcId":"RTHC-05269","title":"Cannabis Use Disorder Trends and Health Care Utilization After Cervical and Lumbar Spine Fusions.","authors":"Dietz, Nicholas; Alkin, Victoria; Agarwal, Nitin; Sharma, Mayur; Oxford, Brent Garrison; Wang, Dengzhi; Ugiliweneza, Beatrice; Mettille, Jersey; Boakye, Maxwell; Drazin, Doniel","year":2024,"journal":"Spine, 49(4), E28-E45","doi":"10.1097/BRS.0000000000004874","pmid":"37962203","tags":["medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 72,024 cervical and 105,612 lumbar fusion patients, those with CUD (2% and 1.5% respectively) had higher complication rates including neurological complications, wound complications, and cardiac events at various time points. CUD was associated with increased stroke risk in cervical fusions and cardiac/MI complications in lumbar fusions. However, CUD was also associated with decreased opioid dependence postoperatively. No differences in reoperation rates were observed.","whyItMatters":"With growing cannabis use, spine surgeons need to know how CUD affects surgical outcomes. The dual finding of more complications but less opioid dependence creates a complex risk-benefit picture for perioperative management.","specificNumbers":"72,024 cervical (2.0% CUD) and 105,612 lumbar (1.5% CUD) fusion patients. Cervical CUD: neurological complications 3% vs 2%, wound complications 5% vs 3% at 12 months. Lumbar CUD: wound 8% vs 5%, MI 2% vs 1% at 6 months. Decreased postoperative opioid dependence with CUD.","methodology":"Retrospective cohort using IBM MarketScan Database (2009-2019). Exact match hospitalization analysis with outcomes at index hospitalization, 6 months, and 12 months. Patients with and without CUD were compared.","limitations":"Administrative database cannot control for confounding by other substance use or socioeconomic factors. CUD patients were younger males with higher comorbidity burden. CUD diagnosis codes undercount cannabis use. Cannot determine dose, frequency, or timing of use."},{"rthcId":"RTHC-05270","title":"A theory of geo-social marginalization: A case study of the licensed cannabis industry in California.","authors":"Dillis, Chris; Petersen-Rockney, Margiana; Polson, Michael","year":2024,"journal":"Journal of environmental management, 355, 120396","doi":"10.1016/j.jenvman.2024.120396","pmid":"38430877","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05271","title":"Cannabis Use Disorder Associated With Increased Risk of Postoperative Complications After Hip or Knee Arthroplasties: A Meta-analysis of Observational Studies.","authors":"Ding, Cheng; Xu, Dongdong; Cheng, Tao","year":2024,"journal":"The Journal of the American Academy of Orthopaedic Surgeons, 32(20), e1067-e1078","doi":"10.5435/JAAOS-D-23-00407","pmid":"38759231","tags":["medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 10 studies with 17,981,628 participants, CUD was associated with significantly higher odds of medical complications (OR 1.33), implant-related complications (OR 1.75), cardiac complications (OR 1.95), stroke (OR 2.06), infections (OR 1.68), periprosthetic fracture (OR 1.42), mechanical loosening (OR 1.54), and dislocation (OR 1.88). Longer hospital stays and higher costs were also found.","whyItMatters":"Joint replacement is one of the most common elective surgeries. With cannabis use disorder increasing alongside legalization, this meta-analysis quantifies the specific complications orthopedic surgeons should watch for and discuss with patients.","specificNumbers":"17,981,628 total participants across 10 studies. Cardiac complications OR 1.95. Stroke OR 2.06. Infections OR 1.68. Periprosthetic fracture OR 1.42. Mechanical loosening OR 1.54. Dislocation OR 1.88. All statistically significant.","methodology":"Systematic review and meta-analysis searching PubMed, Embase, Scopus, and Web of Science up to July 2018. 10 retrospective cohort studies included. Random effects model used for pooled odds ratios.","limitations":"All included studies were retrospective cohorts. CUD diagnoses likely represent more severe cannabis use, not casual use. Cannot separate CUD effects from polysubstance use or socioeconomic factors. Search limited to July 2018."},{"rthcId":"RTHC-05272","title":"Road hazard: a systematic review of traffic injuries following recreational cannabis legalization.","authors":"Dion, Pierre-Marc; Lampron, Jacinthe; Rahmani, Malek; Gawargy, Teresa A; Paquette Cannalonga, Christine; Tariq, Khadeeja; Desjardins, Chloé; Cole, Victoria; Boet, Sylvain","year":2024,"journal":"CJEM, 26(8), 554-563","doi":"10.1007/s43678-024-00736-x","pmid":"38951474","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05273","title":"Differential Oxidative Stress Management in Industrial Hemp (IH: Cannabis sativa L.) for Fiber under Saline Regimes.","authors":"Dixit, Naveen","year":2024,"journal":"Metabolites, 14(8)","doi":"10.3390/metabo14080420","pmid":"39195516","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05274","title":"Concurrent Use of Tobacco and Cannabis and Internalizing and Externalizing Problems in US Youths.","authors":"Do, Vuong V; Ling, Pamela M; Chaffee, Benjamin W; Nguyen, Nhung","year":2024,"journal":"JAMA network open, 7(7), e2419976","doi":"10.1001/jamanetworkopen.2024.19976","pmid":"38958977","tags":["youth","mental-health"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Concurrent tobacco and cannabis users had significantly higher odds of externalizing problems compared to tobacco-only use (AOR 1.83) and cannabis-only use (AOR 1.85). High externalizing problems were most common in the concurrent group (61.6%), followed by cannabis-only (48.5%), tobacco-only (46.3%), and nonusers (30.4%). Internalizing problems did not significantly differ between substance use groups.","whyItMatters":"Tobacco and cannabis co-use is common among teens but rarely studied as a distinct pattern. Finding that the combination amplifies externalizing problems more than either substance alone suggests these users may need integrated interventions targeting both substances simultaneously.","specificNumbers":"5,585 youths. Concurrent use prevalence: 3.4%. High externalizing problems: concurrent 61.6%, cannabis-only 48.5%, tobacco-only 46.3%, nonuse 30.4%. AOR for externalizing (concurrent vs tobacco-only): 1.83 (95% CI 1.15-2.91). AOR (concurrent vs cannabis-only): 1.85 (95% CI 1.11-3.06).","methodology":"Cross-sectional analysis of PATH Study wave 6 data (nationally representative, March-November 2021). 5,585 youths aged 14-17. Past 30-day tobacco and cannabis use categorized into four exclusive groups. Mental health measured with the modified GAIN-Short Screener.","limitations":"Cross-sectional design cannot determine whether co-use causes worse mental health or whether teens with existing behavioral problems are more likely to use both substances. Self-reported substance use and mental health. Data from 2021 during COVID-19 pandemic."},{"rthcId":"RTHC-05275","title":"Label Accuracy of Legal Oral Cannabis Oil Products in Ontario, Canada.","authors":"Doggett, Amanda; Fein, Allan; Campbell, Tracey; Henriquez, Nicola; Busse, Jason W; MacKillop, James","year":2024,"journal":"JAMA network open, 7(6), e2414922","doi":"10.1001/jamanetworkopen.2024.14922","pmid":"38837163","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers purchased legal cannabis oil products from licensed retailers in Ontario, Canada, and sent them for independent laboratory analysis to compare reported THC and CBD concentrations against actual measured values.\n\nThe testing revealed discrepancies between what labels claimed and what the products actually contained. Some products had less cannabinoid content than advertised, while others exceeded labeled amounts.\n\nThese findings are significant because they occurred in a fully regulated, legal market with government oversight. Patients and consumers relying on label accuracy for consistent dosing may not be getting what they expect, even when purchasing through legal channels.","whyItMatters":"Accurate labeling is essential for medical cannabis patients who need consistent dosing and for recreational consumers managing their intake. The finding that even legal, regulated products had labeling discrepancies suggests quality control in the legal cannabis industry still needs improvement.","specificNumbers":"Products were purchased from licensed Ontario retailers. Independent lab testing compared actual THC and CBD concentrations against label claims. Discrepancies were found in both directions: some products had less and others had more cannabinoid content than labeled.","methodology":"Researchers purchased a sample of legal oral cannabis oil products from licensed retailers in Ontario, Canada. Each product underwent independent laboratory testing to measure actual THC and CBD concentrations. Results were compared against the concentrations reported on product labels to assess accuracy.","limitations":"The study focused on one Canadian province's market and may not represent labeling accuracy elsewhere. The sample size of products tested was limited. Natural variation in cannabis extracts makes perfect label accuracy challenging, and the study did not specify what tolerance threshold constituted a meaningful discrepancy."},{"rthcId":"RTHC-05276","title":"Bridging the gap: Exploring consumer experiences and motivations for transitioning between illicit and regulated cannabis markets.","authors":"Donnan, Jennifer R; Howells, Rachel; Farooq, Sylvia; Maillet, Myles; Harris-Lane, Laura M","year":2024,"journal":"The International journal on drug policy, 134, 104644","doi":"10.1016/j.drugpo.2024.104644","pmid":"39488867","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05277","title":"The two synthetic cannabinoid compounds 4'-F-CBD and HU-910 efficiently restrain inflammatory responses of brain microglia and astrocytes.","authors":"Dos Santos Pereira, Maurício; Maitan Santos, Bruna; Gimenez, Rocio; Guimarães, Francisco Silveira; Raisman-Vozari, Rita; Del Bel, Elaine; Michel, Patrick Pierre","year":2024,"journal":"Glia, 72(3), 529-545","doi":"10.1002/glia.24489","pmid":"38013496","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05278","title":"4'-fluorocannabidiol associated with capsazepine restrains L-DOPA-induced dyskinesia in hemiparkinsonian mice: Contribution of anti-inflammatory and anti-glutamatergic mechanisms.","authors":"Dos Santos Pereira, Maurício; Dias de Abreu, Gabriel Henrique; Vanderlei, Leonardo Calaça Arruda; Raisman-Vozari, Rita; Guimarães, Francisco Silveira; Lu, Hui-Chen; Michel, Patrick Pierre; Del Bel, Elaine","year":2024,"journal":"Neuropharmacology, 251, 109926","doi":"10.1016/j.neuropharm.2024.109926","pmid":"38554815","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05279","title":"Use of Cannabis-Based Medical Products for Pediatric Health Conditions: A Systematic Review of the Recent Literature.","authors":"Doucette, Mitchell L; Hemraj, Dipak; Casarett, David J; Macfarlan, D Luke; Fisher, Emily","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 257-267","doi":"10.1159/000542550","pmid":"39659365","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05280","title":"Endocannabinoid Receptor 2 Function is Associated with Tumor-Associated Macrophage Accumulation and Increases in T Cell Number to Initiate a Potent Antitumor Response in a Syngeneic Murine Model of Glioblastoma.","authors":"Duan, Jin; Chen, Jieling; Lin, Yilin; Lin, Stanley L; Wu, Jie","year":2024,"journal":"Cannabis and cannabinoid research, 9(6), 1524-1536","doi":"10.1089/can.2024.0063","pmid":"38888628","tags":["cancer","neuroscience"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"CB2 receptor antagonist AM630 induced a potent antitumor response in glioblastoma-bearing mice, with 50% survival at day 40 when all control mice (median survival 28 days) and CB2 agonist-treated mice (median survival 21 days) had died. AM630 caused an 83% decrease in spleen monocytes/macrophages and 1.8- and 1.6-fold increases in CD8+ and CD4+ T cells respectively, with corresponding changes in the tumor microenvironment.","whyItMatters":"Glioblastoma is among the deadliest cancers partly because it suppresses the immune system. This study reveals that the endocannabinoid system plays a key role in that immunosuppression and identifies CB2 receptor blockade as a potential way to unleash immune attack against the tumor.","specificNumbers":"AM630-treated mice: 50% survival at day 40. Control median survival: 28 days. CB2 agonist median survival: 21 days. Spleen monocytes/macrophages decreased 83%. CD8+ T cells increased 1.8-fold. CD4+ T cells increased 1.6-fold. Higher perforin and granzyme B in CD8+ cells.","methodology":"Bioinformatics analysis of human glioblastoma databases plus in vivo mouse model using luciferase-expressing GL261 glioblastoma cells with CB2 receptor agonist (GW405833) or antagonist (AM630) treatment. Immune cell populations assessed by FACS and immunocytochemistry.","limitations":"Mouse model with a single glioblastoma cell line. CB2 antagonist AM630 may have off-target effects. Human glioblastoma is more heterogeneous than mouse models. Survival follow-up was limited to 40 days."},{"rthcId":"RTHC-05281","title":"Medical cannabis authorization and risk of emergency department visits and hospitalization due to psychotic disorders: A propensity score-matched cohort study.","authors":"Dubois, Cerina; Lunghi, Carlotta; Eurich, Dean T; Dyck, Jason R B; Hyshka, Elaine; Hanlon, John G; Zongo, Arsene","year":2024,"journal":"Schizophrenia research, 264, 534-542","doi":"10.1016/j.schres.2024.01.029","pmid":"38330686","tags":["psychosis","medical-cannabis"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Medical cannabis patients had a psychotic disorder incidence of 3.00 per 1,000 person-years compared to 1.88 in controls. The adjusted hazard ratio was 1.38 (95% CI 1.19-1.60) overall and 1.63 (95% CI 1.40-1.91) among patients without previous psychotic disorders, suggesting the risk is particularly elevated in those with no prior psychosis.","whyItMatters":"Most research on cannabis and psychosis focuses on recreational use. This is one of the first large studies to examine psychosis risk specifically in medical cannabis patients, who may differ from recreational users in their conditions, doses, and monitoring.","specificNumbers":"54,006 cannabis patients matched to 161,265 controls. 39% aged 50 or under. 54% female. Psychotic disorder incidence: 3.00 vs 1.88 per 1,000 person-years. aHR 1.38 (total sample). aHR 1.63 (no prior psychosis).","methodology":"Retrospective propensity score-matched cohort study linking clinical data from Ontario cannabis clinics (2014-2019) with health administrative databases. Each cannabis patient matched to up to 3 population-based controls. Conditional Cox regression for hazard ratios.","limitations":"Cannot determine actual cannabis consumption from authorization data. Propensity matching may not capture all confounders. Medical cannabis patients may have conditions that independently increase psychosis risk. Administrative data may not capture all psychotic events."},{"rthcId":"RTHC-05282","title":"Medical cannabis and its efficacy/effectiveness on the management of osteoarthritis pain and function.","authors":"Dubois, Cerina; Danielson, Elizabeth C; Beestrum, Molly; Eurich, Dean T","year":2024,"journal":"Current medical research and opinion, 40(7), 1195-1202","doi":"10.1080/03007995.2024.2363945","pmid":"38832841","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05283","title":"The company you keep: The neglected role of affiliating with delinquent friends in the development of the cannabis-violence link.","authors":"Dugré, Jules R; Giguère, Charles-Édouard; Potvin, Stéphane","year":2024,"journal":"Addictive behaviors, 151, 107939","doi":"10.1016/j.addbeh.2023.107939","pmid":"38141319","tags":["youth","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Both cannabis use and delinquent peer affiliation were independently associated with aggression in GEE models. Cross-lagged panel models showed that delinquent peers partially mediated the cannabis-aggression link over time, and similar patterns emerged for rule-breaking behaviors. Cannabis use predicted broader conduct problems, not just aggression.","whyItMatters":"The cannabis-violence debate often overlooks social context. This study shows that who adolescents spend time with partly explains the connection between cannabis use and aggression, suggesting interventions should address peer networks alongside substance use.","specificNumbers":"850 ninth graders followed from mid-adolescence to early adulthood. Both cannabis use and delinquent peers statistically associated with aggressive behaviors. Delinquent peers served as partial mediator in cross-lagged models. Similar patterns found for rule-breaking behaviors and alcohol use.","methodology":"Longitudinal study of 850 ninth graders followed from mid-adolescence to early adulthood. Generalized Estimating Equations (GEE) and Cross-Lagged Panel Models used to examine mediation by delinquent peer affiliation and temporal directionality.","limitations":"Self-reported data. Partial mediation means delinquent peers do not fully explain the cannabis-aggression link. Cannot rule out shared underlying factors driving all three variables. Sample demographics not specified in abstract."},{"rthcId":"RTHC-05284","title":"Cannabis donation as a harm reduction strategy: a case study.","authors":"Duhart Clarke, Sarah E; Victor, Grant; Lynch, Pamela; Suen, Leslie W; Ray, Bradley","year":2024,"journal":"Harm reduction journal, 21(1), 58","doi":"10.1186/s12954-024-00974-3","pmid":"38449029","tags":["harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Ten cannabis-experienced harm reduction clients received weekly cannabis donations, with clinical staff determining appropriateness. Administrative data from a partnering cannabis company showed donations were primarily edibles, oils, and topicals (not flower), represented only 1% of gross sales, and cost less than anticipated. The program was operationally feasible within Michigan's legal framework.","whyItMatters":"Cannabis substitution for more dangerous substances has been documented in Canada but not the US. This case study establishes that such programs can operate within US state legal frameworks and at minimal cost to commercial partners.","specificNumbers":"10 clients received cannabis donations over 20 months. Donations represented 1% of the cannabis company's total gross sales. Flower dominated sales but edibles, oils, and topicals dominated donations. Costs were lower than the expected yearly donation amount.","methodology":"Community-driven research approach with qualitative data from harm reduction staff and 20 months of administrative data (September 2021-May 2023) from a commercial cannabis company providing donations.","limitations":"Very small sample of 10 clients. No individual-level outcome data on whether cannabis substitution reduced other drug use. Single program in one state. Case study design limits generalizability. No comparison group."},{"rthcId":"RTHC-05285","title":"Trends in polysubstance use among patients in methadone maintenance treatment in Ireland: Evidence from urine drug testing 2010-2020.","authors":"Durand, Louise; O'Kane, Aoife; Stokes, Siobhan; Bennett, Kathleen E; Keenan, Eamon; Cousins, Gráinne","year":2024,"journal":"Journal of substance use and addiction treatment, 167, 209507","doi":"10.1016/j.josat.2024.209507","pmid":"39243981","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05286","title":"Psychosocial Effects of Frequent Cannabis Smoking in Adolescent Women of Color: Results from a Prospective Cohort of Inner-City Youth.","authors":"Duroseau, Nathalie; Niu, Li; Wilson, Karen; Nucci-Sack, Anne; Burk, Robert D; Diaz, Angela; Schlecht, Nicolas F","year":2024,"journal":"International journal of mental health and addiction, 22(5), 3197-3210","doi":"10.1007/s11469-023-01043-9","pmid":"40094146","tags":["youth","depression","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using cannabis 20+ times monthly was associated with 2.71 times higher odds of school suspension, increased depressive symptoms, and increased delinquent behaviors. Cross-lagged models showed frequent cannabis use predicted depressive symptoms 6 months later and higher delinquency at both 6 and 12 months, suggesting cannabis preceded the negative outcomes rather than the reverse.","whyItMatters":"Young women of color are underrepresented in cannabis research despite potentially facing compounded risks from substance use and structural inequities. The prospective design strengthens the case that frequent cannabis use contributes to these negative outcomes rather than simply co-occurring.","specificNumbers":"545 participants. 94% people of color (37% non-Black Hispanic, 16% Hispanic Black, 41% non-Hispanic Black). Cannabis 20+ times/month: OR 2.71 for suspension (95% CI 1.48-4.57). Cross-lagged: depressive symptoms at 6 months (beta 0.09), delinquency at 6 months (beta 0.20) and 12 months (beta 0.12).","methodology":"Prospective cohort of 545 sexually active female adolescents and young adults in an inner-city setting. 94% identified as people of color. Questionnaires at three visits over one year. Multivariable regression and cross-lagged panel models.","limitations":"Self-reported cannabis use and outcomes. Specific population (sexually active, inner-city, predominantly women of color) limits generalizability. Threshold of 20+ times monthly represents heavy use; lighter use patterns were not examined separately. Potential unmeasured confounders."},{"rthcId":"RTHC-05287","title":"Effects of medical cannabis use on physical and psychiatric symptoms across the day among older adults.","authors":"Dvorak, Robert D; Paulson, Daniel; Dunn, Michael E; Burr, Emily K; Peterson, Roselyn; Maynard, Madison; De Leon, Ardhys N; Klaver, Samantha J; Leary, Angelina V; Hayden, Emma R; Allen, Quinn; Toth, Ethan","year":2024,"journal":"Psychiatry research, 339, 116055","doi":"10.1016/j.psychres.2024.116055","pmid":"38924900","tags":["seniors","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Across 5,156 momentary assessments over 1,106 use days, all measured symptoms declined after cannabis use. Negative affect, pain, and nausea showed momentary negative reinforcement associations with intoxication. Critically, this negative reinforcement pattern was associated with adverse cannabis outcomes and cannabis use disorder symptoms, particularly for negative affect and trauma symptom relief.","whyItMatters":"This study captures the real-time tension in medical cannabis: it works for symptom management, but the very pattern of relief (use, then symptoms improve) creates a reinforcement cycle that may increase problematic use patterns, especially for psychological symptoms.","specificNumbers":"106 older adults (age 55-74). 5,156 momentary assessments across 1,106 use days. Symptoms declined post-use: pain, negative affect, nausea, trauma. Negative reinforcement for negative affect specifically associated with CUD symptoms.","methodology":"Ecological momentary assessment (EMA) with 106 older adults (ages 55-74) who had medical conditions approved for cannabis treatment. Six text messages per day for 15 days assessed momentary symptoms.","limitations":"Self-selected online sample may not represent all older medical cannabis users. Self-reported symptoms. 15-day assessment window may not capture longer-term patterns. No control group without cannabis use."},{"rthcId":"RTHC-05288","title":"Potential perioperative cardiovascular outcomes in cannabis/cannabinoid users. A call for caution.","authors":"Echeverria-Villalobos, Marco; Guevara, Yosira; Mitchell, Justin; Ryskamp, David; Conner, Joshua; Bush, Margo; Periel, Luis; Uribe, Alberto; Weaver, Tristan E","year":2024,"journal":"Frontiers in cardiovascular medicine, 11, 1343549","doi":"10.3389/fcvm.2024.1343549","pmid":"38978789","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05289","title":"Differential disruption of response alternation by precipitated Δ9-THC withdrawal and subsequent Δ9-THC abstinence in mice.","authors":"Eckard, Matthew L; Kinsey, Steven G","year":2024,"journal":"Pharmacology, biochemistry, and behavior, 236, 173718","doi":"10.1016/j.pbb.2024.173718","pmid":"38272272","tags":["withdrawal","cognition"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"After 5 days of twice-daily THC (10 mg/kg), rimonabant-precipitated withdrawal caused longer session times, longer response latencies, more errors, and slower error correction in THC-treated mice. During the 3-day abstinence window, motivational measures (response latency, session duration) remained disrupted in THC-treated mice, but attentional measures (errors, latency to switch after error) returned to baseline.","whyItMatters":"This study distinguishes between precipitated and spontaneous cannabinoid withdrawal for the first time in the same subjects, revealing they may be qualitatively different states rather than just different intensities of the same withdrawal syndrome.","specificNumbers":"THC dose: 10 mg/kg twice daily for 5 days. Rimonabant: 2 mg/kg to precipitate withdrawal. Precipitated withdrawal disrupted all measured behavioral domains. During 3-day abstinence: motivational deficits persisted while attentional measures normalized.","methodology":"Male and female C57BL/6J mice trained on a response alternation task with spatially distinct response options. After 5 days of THC or vehicle, withdrawal precipitated with rimonabant (CB1 inverse agonist) on day 6, then 3 days of monitored abstinence.","limitations":"Mouse model with high THC doses. Precipitated withdrawal using rimonabant is more abrupt than natural human cessation. Short 5-day exposure and 3-day abstinence window. Response alternation task may not fully capture the complexity of human motivation and attention."},{"rthcId":"RTHC-05290","title":"Cannabis Hyperemesis Syndrome in a Recently Abstinent Chronic User: Assessment and Intervention.","authors":"Ei Sherif, Yasmine; Gouher, Sariah; Abualhab, Mutaz Mohsin; El-Khoury, Joseph","year":2024,"journal":"Consortium psychiatricum, 5(1), 27-32","doi":"10.17816/CP15473","pmid":"39023110","tags":["withdrawal"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"CHS symptoms (severe vomiting, abdominal pain, fever) emerged approximately one week after cessation of daily cannabis use, with standard anti-emetics (ondansetron) failing. The patient also had anxiety, depression, and brain fog consistent with cannabis withdrawal. A combination of tramadol, promethazine, and mirtazapine as outpatient treatment led to full recovery within 10 days.","whyItMatters":"This case highlights that CHS can emerge after cannabis cessation, not just during active use, and can overlap with withdrawal symptoms. The successful treatment combination offers an alternative when standard anti-emetics fail.","specificNumbers":"33-year-old male. Daily cannabis user for several years. Symptoms began approximately 1 week after stopping. Ondansetron was ineffective. Full recovery within 10 days on tramadol, promethazine, and mirtazapine.","methodology":"Single case report of a 33-year-old male chronic daily cannabis user who stopped using due to travel to a country with stricter cannabis laws.","limitations":"Single case report. Cannot generalize treatment response to other patients. Patient also used tobacco and alcohol, which were continued. Exact cannabis doses and duration not quantified."},{"rthcId":"RTHC-05291","title":"Primary Care Providers' Communication About Medical Cannabis With Older Adults: A Cross-Sectional Survey.","authors":"Elbready, Abdallah W; Warner-Maron, Ilene; Glicksman, Allen; Peterson, Andrew M","year":2024,"journal":"Journal of primary care & community health, 15, 21501319241295922","doi":"10.1177/21501319241295922","pmid":"39520316","tags":["seniors","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Primary care providers were more likely to inquire about alcohol and tobacco use than cannabis with older adult patients. Providers did not frequently ask about cannabis use or consider it as a therapeutic option for their older patients, even after completing Pennsylvania Department of Health-approved cannabis education courses.","whyItMatters":"If even providers who have completed cannabis education courses are not discussing cannabis with older patients, the communication gap may be wider among providers without such training. Older adults are the fastest-growing demographic of cannabis users.","specificNumbers":"575 providers surveyed. All had completed state-approved MC courses. Significant difference in asking about alcohol/tobacco vs cannabis (P < 0.05). Providers who had patients ask about MC were more likely to bring it up themselves (P = 0.037).","methodology":"Cross-sectional survey emailed to 575 physicians, pharmacists, nurse practitioners, and physician assistants who completed Pennsylvania DOH-approved medical cannabis courses between 2018-2022. Respondents had to practice in the Tri-state area and care for older adults.","limitations":"Survey respondents may not represent all providers. Low response rate not specified in abstract. Self-reported communication practices may not match actual behavior. Pennsylvania-specific findings may not apply to states with different cannabis programs."},{"rthcId":"RTHC-05292","title":"Cannabinoid hyperemesis syndrome.","authors":"Elnagar, Ali; Kgomo, Mpho; Mokone, Modise; Yousif, Badreldin","year":2024,"journal":"BMJ case reports, 17(4)","doi":"10.1136/bcr-2023-256921","pmid":"38688569","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05293","title":"The effects of cannabis use on major adverse cardiovascular outcomes, mortality, cost of hospitalization, and cardiac arrhythmias: A Retrospective analysis using the national inpatient sample.","authors":"Elsadek, Rabab; Ismail, Zeeshan; Al-Ani, Hashim; Loseke, Isaac; Fikry, Mona; Meadows, Robyn; Zentko, Suzanne; Curry, Bryan","year":2024,"journal":"Current problems in cardiology, 49(11), 102788","doi":"10.1016/j.cpcardiol.2024.102788","pmid":"39127430","tags":["cardiovascular"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 39,992 hospitalized subjects from the National Inpatient Sample (2016-2019), cannabis use disorder was not significantly associated with cardiovascular adverse events (p=0.257), cardiac dysrhythmias (p=0.481), or hospitalization costs (p=0.481) after controlling for other variables. However, CUD was significantly associated with higher in-hospital mortality (p<0.0001).","whyItMatters":"The dissociation between cardiovascular events (no significant association) and mortality (significant association) is puzzling and suggests cannabis use disorder may increase death risk through non-cardiovascular pathways, or that confounders not captured in administrative data are driving the mortality finding.","specificNumbers":"39,992 subjects from NIS 2016-2019. Cardiovascular events: p=0.257 (not significant). Cardiac arrhythmias: p=0.481 (not significant). Hospitalization cost: p=0.481 (not significant). In-hospital mortality: p<0.0001 (significant).","methodology":"Retrospective study using the National Inpatient Sample database (2016-2019). 39,992 subjects classified by presence of cannabis-related disorder diagnosis. Multivariable regression controlling for covariates.","limitations":"Administrative database with ICD coding limitations. Cannot determine cannabis dose, frequency, or route. CUD diagnosis may represent a different population than general cannabis users. Cannot determine cause of death to understand the mortality association."},{"rthcId":"RTHC-05294","title":"A 10-year trend in cannabis potency (2013-2022) in different geographical regions of the United States of America.","authors":"ElSohly, Mahmoud A; Majumdar, Chandrani G; Chandra, Suman; Radwan, Mohammed M","year":2024,"journal":"Frontiers in public health, 12, 1442522","doi":"10.3389/fpubh.2024.1442522","pmid":"39421827","tags":["potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This is the definitive U.S. potency trend study. Researchers at the University of Mississippi — the institution that has analyzed DEA-seized cannabis for decades — examined cannabinoid concentrations across all U.S. regions over 10 years (2013-2022).\n\nThe headline finding is striking in its uniformity: regardless of which state or region the cannabis was seized in, or whether it came from the illicit market or a state medical marijuana program, the cannabinoid profile was essentially the same. THC dominated at over 10% for most samples, while all other cannabinoids — including CBD, CBG, and CBN — were present at less than 0.5-1%. The cannabis market, legal and illegal, has converged on a single product type: high THC, virtually everything else negligible.\n\nThe regional analysis showed THC rising everywhere, with no geographic pocket of lower-potency cannabis remaining. This debunks the idea that certain regions or market types (medical vs. recreational vs. illicit) offer meaningfully different potency profiles. Whether seized by the DEA in the Western states, Midwest, Northeast, Southeast, or South, the cannabis was basically the same product.\n\nThis convergence toward THC monoculture is the opposite of what a therapeutically oriented market would look like. Medical cannabis was supposed to offer diverse cannabinoid profiles for different conditions. Instead, both legal and illegal markets are optimizing for the same thing: maximum THC.","whyItMatters":"This is the most comprehensive and authoritative potency trend data available for the U.S., coming from the lab that has been the federal reference standard for decades. The finding that legal medical marijuana programs produce the same THC-dominant profile as illicit cannabis undermines the argument that legal markets provide more diverse therapeutic options. For public health, the steady national rise in THC concentration means population-level THC exposure is increasing even if the number of users stays the same.","specificNumbers":"10-year study period (2013-2022). Six U.S. regions analyzed. All high-THC samples had >10% THC regardless of region. All other cannabinoids <0.5%, with exceptions of CBG (<1%) and CBN (<1%). No meaningful potency differences between regions or between illicit and medical program samples.","methodology":"Observational analysis of illicit cannabis samples seized by the U.S. Drug Enforcement Administration from 2013 to 2022. Samples categorized by geographic region: Western, Midwest, Northeast, Southeast, Southern, plus Alaska and Hawaii. Cannabinoid content analyzed using a validated gas chromatography with flame ionization detector method. Compared samples from both illicit seizures and state medical marijuana programs.","limitations":"Data comes from DEA seizures, which may overrepresent illicit market cannabis and larger operations. Comparison with state medical program samples partially addresses this but may not represent the full range of products available in dispensaries (e.g., CBD-rich products may not be captured by DEA seizures). GC analysis after decarboxylation measures total potential THC, not the THC concentration a user would experience. Trends in cannabis concentrates, edibles, and vape products are not captured by this flower/plant material analysis."},{"rthcId":"RTHC-05295","title":"Illicit Cannabis Use to Self-Treat Chronic Health Conditions in the United Kingdom: Cross-Sectional Study.","authors":"Erridge, Simon; Troup, Lucy; Sodergren, Mikael Hans","year":2024,"journal":"JMIR public health and surveillance, 10, e57595","doi":"10.2196/57595","pmid":"39149844","tags":["medical-cannabis","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 10,965 weighted respondents, 5,700 (52%) reported chronic health conditions, and 364 (6.38%) of those purchased illicit cannabis for self-treatment. Population modeling estimated 1,770,627 (95% CI 1,073,791-2,467,001) UK adults use illicit cannabis for health conditions. Conditions most associated with illicit use included chronic pain, fibromyalgia, PTSD, MS, and other mental health disorders. Male sex, younger age, London residence, and unemployment were also associated.","whyItMatters":"Despite cannabis-based medicinal products being rescheduled in the UK in 2018, the illicit market for medical use appears to have grown rather than shrunk. This suggests significant barriers to accessing legal prescriptions, including cost, availability, and prescriber willingness.","specificNumbers":"10,965 respondents. 52% had chronic conditions. 6.38% of those used illicit cannabis for health. Estimated 1.77 million UK adults (95% CI 1.07-2.47 million). Most common condition: anxiety (14.48% of respondents). Illicit cannabis associated with chronic pain, fibromyalgia, PTSD, MS.","methodology":"Cross-sectional population survey conducted through YouGov (September 2022) with weighting to represent the UK adult population of 53.4 million. Multivariable logistic regression for associated factors.","limitations":"Self-reported survey data. Cannot verify medical diagnoses or actual cannabis purchases. YouGov panel may not fully represent all demographics. Cannabis users may be more likely to respond to cannabis-related surveys. Point-in-time estimate may not reflect trends."},{"rthcId":"RTHC-05296","title":"Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks.","authors":"Ertl, Natalie; Freeman, Tom P; Mokrysz, Claire; Ofori, Shelan; Borissova, Anna; Petrilli, Kat; Curran, H Valerie; Lawn, Will; Wall, Matthew B","year":2024,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 49(10), 1640-1651","doi":"10.1038/s41386-024-01891-6","pmid":"38806583","tags":["youth","neuroscience","cbd"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Cannabis caused significant reductions in within-network connectivity in the default mode, executive control, salience, hippocampal, and limbic striatal networks compared to placebo. CBD co-administration did not attenuate THC's effects and further reduced connectivity in some networks. Despite age-related baseline differences, there were no interactions between age group and cannabis treatment in any network.","whyItMatters":"Two common assumptions are challenged: that adolescent brains are more vulnerable to acute cannabis effects than adult brains, and that CBD can mitigate THC's disruption of brain function. Neither held up in this controlled study.","specificNumbers":"Executive control network: F[2,88]=18.62, P<0.001, effect size 0.123. Limbic striatal: F[2,88]=16.19, P<0.001, effect size 0.102. Hippocampal: F[2,88]=14.65, P<0.001, effect size 0.087. Salience: F[2,88]=12.12, P<0.001, effect size 0.076. Default mode: F[2,88]=3.97, P=0.022, effect size 0.018. No age-by-treatment interactions in any network.","methodology":"Double-blind, placebo-controlled fMRI study with vaporized cannabis (placebo, THC 8mg/75kg, THC+CBD 8mg THC + 24mg CBD per 75kg). 22 adolescents (16-17) and 24 young adults (26-29), all semi-regular cannabis users (0.5-3 days/week), matched for use frequency.","limitations":"Semi-regular users only; findings may differ in cannabis-naive individuals or heavy users. Small sample sizes per group. Single acute dose; chronic effects may differ. Resting-state connectivity does not necessarily predict functional outcomes. Specific THC:CBD ratio tested may not generalize."},{"rthcId":"RTHC-05297","title":"Cannabidiol and it fluorinate analog PECS-101 reduces hyperalgesia and allodynia in trigeminal neuralgia via TRPV1 receptors.","authors":"Escobar-Espinal, Daniela Maria; Vivanco-Estela, Airam Nicole; Barros, Núbia; Dos Santos Pereira, Maurício; Guimaraes, Francisco Silveira; Del Bel, Elaine; Nascimento, Glauce C","year":2024,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 132, 110996","doi":"10.1016/j.pnpbp.2024.110996","pmid":"38508408","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05298","title":"Cannabis Use Among Students in Grades 8, 10, and 12, by Sex - King County, Washington, 2008-2021.","authors":"Esie, Precious; Ta, Myduc","year":2024,"journal":"MMWR. Morbidity and mortality weekly report, 73(2), 27-31","doi":"10.15585/mmwr.mm7302a1","pmid":"38236780","tags":["youth","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"During 2008-2021, cannabis use declined among both sexes. In 2008, male students had 4.8% higher prevalence than female students. By 2014-2016, rates were statistically equal. In 2021, current use was 1.3% higher among female students than male students for the first time. Frequent use (6+ days/month) remained similar between sexes. 12th graders had the highest use rates.","whyItMatters":"The reversal of the sex gap in cannabis use is a meaningful public health signal. If female students are now more likely to use cannabis than male students, prevention programs designed primarily for boys may be missing the current reality.","specificNumbers":"Range: 33,439-39,391 students per cycle. 2008 sex gap: males 4.8% higher. 2021 gap: females 1.3% higher. Frequent use similar between sexes. 12th graders highest, followed by 10th, then 8th.","methodology":"Analysis of the Healthy Youth Survey administered by Washington State Department of Health, restricted to King County students in grades 8, 10, and 12 across seven survey periods (2008-2021). 33,439-39,391 students per cycle. Weighted generalized linear regression with sex-by-year interaction.","limitations":"Single county in Washington state; may not generalize to other regions. Self-reported use in school settings may undercount. Students absent from school or who dropped out are missed. 2021 data collected during COVID-19 may reflect unusual patterns."},{"rthcId":"RTHC-05299","title":"Cannabis use disorder contributes to cognitive dysfunction in Veterans with traumatic brain injury.","authors":"Esmaeili, Aryan; Dismuke-Greer, Clara; Pogoda, Terri K; Amuan, Megan E; Garcia, Carla; Del Negro, Ariana; Myers, Maddy; Kennedy, Eamonn; Cifu, David; Pugh, Mary Jo","year":2024,"journal":"Frontiers in neurology, 15, 1261249","doi":"10.3389/fneur.2024.1261249","pmid":"38292293","tags":["cognition","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Cognitive disorder incidence was highest in Veterans with both TBI and CUD (1.83 per 10,000 person-months), followed by TBI only (1.03), CUD only (0.68), and controls. The hazard ratio for cognitive disorders was 3.26 for TBI+CUD, 2.32 for TBI only, and 1.79 for CUD only. CUD alone was associated with the highest risk of early-onset cognitive disorder other than Alzheimer's and frontotemporal dementia.","whyItMatters":"TBI and cannabis use are both common in the Veteran population. This study suggests their combination may create compounding cognitive risk beyond what either condition poses alone, with implications for screening and intervention in VA healthcare.","specificNumbers":"1,560,556 Veterans (82.32% male, median age 34.51, 61.35% white). Cognitive disorder HR: CUD+TBI 3.26 (95% CI 2.91-3.65). TBI only 2.32 (95% CI 2.13-2.53). CUD only 1.79 (95% CI 1.60-2.00). CUD alone had highest risk of early-onset cognitive disorder.","methodology":"Retrospective cohort using VA and DoD administrative data from the LIMBIC-CENC Phenotype study, 2003-2022. 1,560,556 Veterans analyzed. Kaplan-Meier survival analysis and Cox proportional hazards models for cognitive disorder incidence.","limitations":"Administrative data cannot determine cannabis dose, frequency, or timing relative to TBI. CUD diagnosis codes likely represent severe use, not all cannabis users. Observational design cannot prove causation. Veteran population may not generalize to civilians."},{"rthcId":"RTHC-05300","title":"The First \"Hit\" to the Endocannabinoid System? Associations Between Prenatal Cannabis Exposure and Frontolimbic White Matter Pathways in Children.","authors":"Evanski, Julia M; Zundel, Clara G; Baglot, Samantha L; Desai, Shreya; Gowatch, Leah C; Ely, Samantha L; Sadik, Nareen; Lundahl, Leslie H; Hill, Matthew N; Marusak, Hilary A","year":2024,"journal":"Biological psychiatry global open science, 4(1), 11-18","doi":"10.1016/j.bpsgos.2023.09.005","pmid":"38021250","tags":["pregnancy","neuroscience"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Prenatal cannabis exposure was associated with lower fractional anisotropy (a measure of white matter integrity) in the right and left fornix. These effects remained significant after adjusting for covariates, multiple comparisons, overall white matter, and a quality-control subset. The effects were small but reliable.","whyItMatters":"This is one of the largest neuroimaging studies of prenatal cannabis exposure, drawing from a nationally representative sample. The fornix is rich in cannabinoid receptors and plays a key role in the hippocampal memory circuit, making it biologically plausible as a target of prenatal cannabinoid exposure.","specificNumbers":"11,530 children from the ABCD Study. Right fornix: beta = -0.005, p significant. Left fornix: p = 0.007. Effects survived adjustment for covariates, multiple comparisons, and quality-control subset analysis.","methodology":"Cross-sectional analysis of 11,530 children (mean age ~10 years, 47% female) from the Adolescent Brain Cognitive Development (ABCD) Study. Linear mixed-effects models examined caregiver-reported prenatal cannabis exposure and fractional anisotropy of 10 frontolimbic white matter pathways.","limitations":"Cross-sectional analysis of a developmental cohort. Prenatal exposure based on caregiver recall, which may be inaccurate. Small effect sizes. Cannot determine timing, dose, or frequency of prenatal exposure. Cannot rule out confounders related to maternal health or environment."},{"rthcId":"RTHC-05301","title":"Cannabidiol as an antipsychotic drug.","authors":"Fabris, Débora; Lisboa, João Roberto; Guimarães, Francisco Silveira; Gomes, Felipe V","year":2024,"journal":"International review of neurobiology, 177, 295-317","doi":"10.1016/bs.irn.2024.04.013","pmid":"39029989","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05302","title":"Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use.","authors":"Fang, Fang; Quach, Bryan; Lawrence, Kaitlyn G; van Dongen, Jenny; Marks, Jesse A; Lundgren, Sara; Lin, Mingkuan; Odintsova, Veronika V; Costeira, Ricardo; Xu, Zongli; Zhou, Linran; Mandal, Meisha; Xia, Yujing; Vink, Jacqueline M; Bierut, Laura J; Ollikainen, Miina; Taylor, Jack A; Bell, Jordana T; Kaprio, Jaakko; Boomsma, Dorret I; Xu, Ke; Sandler, Dale P; Hancock, Dana B; Johnson, Eric O","year":2024,"journal":"Molecular psychiatry, 29(1), 124-133","doi":"10.1038/s41380-023-02310-w","pmid":"37935791","tags":["genetics"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Four CpG sites were significantly associated with lifetime cannabis use independent of smoking: cg22572071 (near ADGRF1), cg15280358 (in ADAM12), cg00813162 (in ACTN1), and cg01101459 (near LINC01132). In never-smokers, an additional site was found (cg14237301 in APOBR). A methylation score from these sites explained 3.79% of the variance in lifetime cannabis use.","whyItMatters":"Separating cannabis-specific epigenetic effects from smoking effects has been a major challenge. This large multi-ethnic study identifies methylation changes attributable to cannabis itself, which could serve as biomarkers and starting points for understanding how cannabis affects health at the molecular level.","specificNumbers":"9,436 participants (7,795 European, 1,641 African ancestry). 4 significant CpG sites after FDR correction (p < 5.85 x 10^-7). 1 additional site in never-smokers. Methylation score explained 3.79% of variance in lifetime cannabis use.","methodology":"Trans-ancestry epigenome-wide association study (EWAS) meta-analysis across seven cohorts including 7,795 European and 1,641 African ancestry participants. Analyses controlled for cigarette smoking effects. Leave-one-out approach for methylation score validation.","limitations":"Peripheral blood methylation may not reflect brain or lung tissue changes. Binary outcome (ever vs never use) does not capture dose or frequency. Cross-sectional design cannot determine whether methylation changes are cause or consequence of use. 3.79% variance explained is modest."},{"rthcId":"RTHC-05303","title":"Hippocampal D1-like dopamine receptor as a novel target for the effect of cannabidiol on extinction and reinstatement of methamphetamine-induced CPP.","authors":"Farrokhi, Amir Mohammad; Moshrefi, Fazel; Eskandari, Kiarash; Azizbeigi, Ronak; Haghparast, Abbas","year":2024,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 133, 111025","doi":"10.1016/j.pnpbp.2024.111025","pmid":"38729234","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05304","title":"The risk of cannabis use disorder is mediated by altered brain connectivity: A chronnectome study.","authors":"Fazio, Giovanni; Olivo, Daniele; Wolf, Nadine D; Hirjak, Dusan; Schmitgen, Mike M; Werler, Florian; Witteman, Miriam; Kubera, Katharina M; Calhoun, Vince D; Reith, Wolfgang; Wolf, Robert Christian; Sambataro, Fabio","year":2024,"journal":"Addiction biology, 29(5), e13395","doi":"10.1111/adb.13395","pmid":"38709211","tags":["addiction","neuroscience"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"At-risk individuals (n=39) spent more time in a brain state with higher within-network and reduced between-network connectivity across subcortical, sensory-motor, visual, cognitive-control, and default-mode networks compared to controls (n=55). Globally, at-risk individuals had more meta-states, more transitions between them, and longer distances traveled in state space, indicating greater dynamic range and fluidity of brain connectivity.","whyItMatters":"Most brain imaging studies of cannabis use examine static connectivity. This dynamic approach reveals that CUD risk is associated with unstable, hyperfluid brain states that may reflect difficulty maintaining stable network engagement, a finding invisible to traditional analyses.","specificNumbers":"39 at-risk individuals, 55 controls. At-risk group: more time in high within-network/low between-network state, greater number of meta-states, more transitions, longer state span, and longer total distance in state space.","methodology":"Resting-state fMRI comparing 39 individuals at risk for CUD to 55 controls, stratified by CUDIT-R scores. Dynamic functional connectivity estimated using independent component analysis, sliding-time window correlations, and cluster/meta-state indices.","limitations":"Cross-sectional design cannot determine whether connectivity changes precede or result from cannabis use. Self-report screening tool for CUD risk. Relatively small sample size. Cannot control for all potential confounders including other substance use."},{"rthcId":"RTHC-05305","title":"Stigma-related barriers to medical cannabis as harm reduction for substance use disorder: Obstacles and opportunities for improvement.","authors":"Fehr, Florriann; Lo, Lindsay A; Nelson, Chris; Nanson, Kate; Diehl, Lauren; Nielson, Karl; Reddon, Hudson; Walsh, Zach","year":2024,"journal":"International journal of mental health nursing, 33(1), 195-201","doi":"10.1111/inm.13231","pmid":"37767954","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05306","title":"Conceptualizing problematic use of medicinal Cannabis: Development and preliminary validation of a brief screening questionnaire.","authors":"Feingold, Daniel; Gliksberg, Or; Brill, Silviu; Amit, Ben H; Lev-Ran, Shaul; Kushnir, Talma; Sznitman, Sharon R","year":2024,"journal":"Addictive behaviors, 158, 108122","doi":"10.1016/j.addbeh.2024.108122","pmid":"39128420","tags":["medical-cannabis","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Starting from 36 items compiled from opioid screening tools, cannabis use disorder instruments, and patient interviews, the researchers refined to an 8-item scale with excellent internal consistency (alpha 0.929). Items focused predominantly on negative consequences rather than dependence symptoms. The scale correlated significantly with anxiety and low quality of life.","whyItMatters":"Existing cannabis use disorder screening tools were designed for recreational use and may overcount medical patients who show physical dependence without actual problems. This tool redefines \"problematic\" medical cannabis use around consequences rather than dependence criteria.","specificNumbers":"390 chronic pain patients. Started with 36 items from 3 sources. Final 8-item scale. Internal consistency alpha = 0.929. Named MCNCS (Medicinal Cannabis Negative Consequences Scale). Significantly correlated with anxiety and low quality of life.","methodology":"Scale development using 390 American chronic pain patients with medical cannabis cards. Items rated on 5-point frequency scale. Multi-group measurement invariance comparison using alcohol problems and depression as external indicators. Content validation from multiple sources.","limitations":"Self-identified patients via online recruitment; may not represent all medical cannabis users. American sample only. Preliminary validation needs replication. No longitudinal data on whether MCNCS scores predict future adverse outcomes. Scale does not include physician assessment."},{"rthcId":"RTHC-05307","title":"A Survey Study of Individuals Using Hexahydrocannabinol Cannabis Products: Use Patterns and Perceived Effects.","authors":"Ferretti, Morgan L; Gournay, L Riley; Bingaman, Mia G; Leen-Feldner, Ellen W","year":2024,"journal":"Cannabis and cannabinoid research, 9(5), e1385-e1394","doi":"10.1089/can.2023.0143","pmid":"37934167","tags":["potency","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"HHC users reported using approximately 10 days in the past month. Common reasons included anxiety and pain management. Users perceived more positive effects (relaxation, euphoria) than negative ones. About 17% reported adverse effects, and approximately 20% of those who stopped using HHC experienced some withdrawal symptoms. Few sex differences were observed.","whyItMatters":"HHC is a semi-synthetic cannabinoid that became widely available through regulatory gaps in the hemp market. This is among the first studies providing systematic data on who uses HHC, how often, and what they experience, filling a major gap as regulators consider how to handle novel cannabinoids.","specificNumbers":"109 HHC users surveyed. Average use: ~10 days in past month. 17% reported adverse effects. ~20% of those who stopped experienced withdrawal. Primary uses: anxiety, pain. Primary positive effects: relaxation, euphoria.","methodology":"Online survey via Prolific of 109 individuals who self-reported HHC product use at least once within the past 6 months. HHC use questionnaire covering patterns, motivations, and perceived effects.","limitations":"Small convenience sample from online crowdsourcing platform. Self-reported effects without objective verification. No comparison group. Cannot verify product contents or HHC purity. Cross-sectional design."},{"rthcId":"RTHC-05308","title":"Analysis of phytocannabinoids in hemp seeds, sprouts and microgreens.","authors":"Ferri, Elena; Russo, Fabiana; Vandelli, Maria Angela; Paris, Roberta; Laganà, Aldo; Capriotti, Anna Laura; Gallo, Alfonso; Siciliano, Augusto; Carbone, Luigi; Gigli, Giuseppe; Citti, Cinzia; Cannazza, Giuseppe","year":2024,"journal":"Journal of pharmaceutical and biomedical analysis, 245, 116181","doi":"10.1016/j.jpba.2024.116181","pmid":"38723555","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05309","title":"JWH-182: a safe and effective synthetic cannabinoid for chemotherapy-induced neuropathic pain in preclinical models.","authors":"Filipiuc, Leontina-Elena; Creangă-Murariu, Ioana; Tamba, Bogdan-Ionel; Ababei, Daniela-Carmen; Rusu, Răzvan-Nicolae; Stanciu, Gabriela-Dumitrița; Ștefanescu, Raluca; Ciorpac, Mitică; Szilagyi, Andrei; Gogu, Raluca; Filipiuc, Silviu-Iulian; Tudorancea, Ivona-Maria; Solcan, Carmen; Alexa-Stratulat, Teodora; Cumpăt, Marinela-Carmen; Cojocaru, Doina-Clementina; Bild, Veronica","year":2024,"journal":"Scientific reports, 14(1), 16242","doi":"10.1038/s41598-024-67154-y","pmid":"39004628","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05310","title":"CB1 Receptor Negative Allosteric Modulators as a Potential Tool to Reverse Cannabinoid Toxicity.","authors":"Flavin, Audrey; Azizi, Paniz; Murataeva, Natalia; Yust, Kyle; Du, Wenwen; Ross, Ruth; Greig, Iain; Nguyen, Thuy; Zhang, Yanan; Mackie, Ken; Straiker, Alex","year":2024,"journal":"Molecules (Basel, Switzerland), 29(8)","doi":"10.3390/molecules29081881","pmid":"38675703","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Three CB1 NAMs (ABD1085, RTICBM189, PSNCBAM1) blocked JWH018 effects in cultured neurons. In vivo, only RTICBM189 and PSNCBAM1 blocked JWH018 when given beforehand. PSNCBAM1 was the most potent and also reversed JWH018 effects when given after exposure, mimicking an overdose scenario. Critically, PSNCBAM1 did not trigger withdrawal in chronically JWH018-treated mice.","whyItMatters":"Unlike opioid overdoses, which can be reversed with naloxone, there is currently no antidote for synthetic cannabinoid toxicity. This study identifies a pharmacological approach that works mechanistically differently from competitive antagonists, potentially offering the first tool for emergency treatment.","specificNumbers":"Three NAMs tested. In vitro potency did not predict in vivo potency. PSNCBAM1 reversed JWH018 effects post-exposure (mimicking overdose). No withdrawal triggered after chronic JWH018 treatment with PSNCBAM1.","methodology":"In vitro testing in autaptic hippocampal neurons expressing endogenous CB1-dependent circuits. In vivo nociception tests in mice with prophylactic and post-exposure dosing. Withdrawal assessment after chronic JWH018 treatment.","limitations":"Preclinical study only. Single synthetic cannabinoid tested (JWH018); newer synthetics may behave differently. Mouse models may not predict human pharmacology. No human safety data for any CB1 NAM. In vitro potency did not predict in vivo effectiveness, complicating drug development."},{"rthcId":"RTHC-05311","title":"Selected cannabis cultivars modulate glial activation: in vitro and in vivo studies.","authors":"Fleisher-Berkovich, Sigal; Sharon, Nitzan; Ventura, Yvonne; Feinshtein, Valeria; Gorelick, Jonathan; Bernstein, Nirit; Ben-Shabat, Shimon","year":2024,"journal":"Journal of cannabis research, 6(1), 25","doi":"10.1186/s42238-024-00232-0","pmid":"38778343","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05312","title":"DNA methylation, but not microRNA expression, is affected by in vitro THC exposure in bovine granulosa cells.","authors":"Floccari, Sabrina; Sabry, Reem; Choux, Laurie; Neal, Michael S; Khokhar, Jibran Y; Favetta, Laura A","year":2024,"journal":"BMC pharmacology & toxicology, 25(1), 42","doi":"10.1186/s40360-024-00763-5","pmid":"39010179","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05313","title":"Cannabis-infused foods: Phytonutrients, health, and safe product innovations.","authors":"Fordjour, Eric; Manful, Charles F; Khalsamehta, Tarsaim S K; Armah, Abraham; Cheema, Mumtaz; Thomas, Raymond","year":2024,"journal":"Comprehensive reviews in food science and food safety, 23(5), e70021","doi":"10.1111/1541-4337.70021","pmid":"39267188","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05314","title":"Effects of Recreational Cannabis Legalization on Mental Health: Scoping Review.","authors":"Fortier, Alexandra; Zouaoui, Inès; Dumais, Alexandre; Potvin, Stéphane","year":2024,"journal":"Psychiatric services (Washington, D.C.), 75(9), 872-887","doi":"10.1176/appi.ps.20230434","pmid":"38650490","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05315","title":"Quantitative Estimation of Promoter Activity in Cannabis sativa Using Agroinfiltration-Based Transient Gene Expression.","authors":"Fousek, Jan; Dušek, Jakub; Hoffmeisterová, Hana; Čeřovská, Noemi; Kundu, Jiban Kumar; Moravec, Tomáš","year":2024,"journal":"Methods in molecular biology (Clifton, N.J.), 2787, 245-253","doi":"10.1007/978-1-0716-3778-4_16","pmid":"38656494","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05316","title":"Cannabis Use Disorder Symptoms in Weekly Cannabis Users: A Network Comparison Between Daily Cigarette Users and Nondaily Cigarette Users.","authors":"Freichel, René; Kroon, Emese; Kuhns, Lauren; Filbey, Francesca; Veer, Ilya M; Wiers, Reinout; Cousijn, Janna","year":2024,"journal":"Cannabis and cannabinoid research, 9(3), e847-e858","doi":"10.1089/can.2022.0239","pmid":"37074121","tags":["addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"In the overall CUD symptom network, craving, failed quit attempts, neglected responsibilities, and negative social effects were most central. Risky cannabis use was mostly independent of other CUD symptoms. Among daily tobacco co-users (n=789) compared to nondaily co-users (n=428): craving was more strongly linked to negative psychosocial effects, depression and health effects were more central, and negative health effects were more strongly connected to failed quit attempts.","whyItMatters":"By mapping how CUD symptoms interconnect differently in tobacco co-users, this study identifies specific targets for intervention. If craving is a bridge symptom connecting use to negative consequences, targeting craving may be more effective than addressing symptoms in isolation.","specificNumbers":"1,217 weekly cannabis users total: 789 daily tobacco co-users, 428 nondaily co-users. Craving identified as bridge symptom between CUD and withdrawal symptoms. Depression and negative health effects more central in co-use network.","methodology":"Network analysis comparing CUD symptom configurations between weekly cannabis users who also used tobacco daily (n=789) versus non-daily or never (n=428). Network centrality, bridge symptoms, and between-group differences analyzed.","limitations":"Cross-sectional network analysis cannot determine causal relationships between symptoms. Self-reported tobacco and cannabis use. Network analysis results can vary with sample size and composition. Cannot distinguish whether tobacco use causes network differences or reflects a different subpopulation."},{"rthcId":"RTHC-05317","title":"Prenatal MAM exposure raises kynurenic acid levels in the prefrontal cortex of adult rats.","authors":"Frescura, Francesca; Stark, Tibor; Tiziani, Edoardo; Di Martino, Serena; Ruda-Kucerova, Jana; Drago, Filippo; Ferraro, Luca; Micale, Vincenzo; Beggiato, Sarah","year":2024,"journal":"Pharmacological reports : PR, 76(4), 887-894","doi":"10.1007/s43440-024-00604-6","pmid":"38789891","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05318","title":"The prevalence of cannabis use disorder in attention-deficit hyperactivity disorder: A clinical epidemiological meta-analysis.","authors":"Froude, Anna M; Fawcett, Emily J; Coles, Ashlee; Drakes, Dalainey H; Harris, Nick; Fawcett, Jonathan M","year":2024,"journal":"Journal of psychiatric research, 172, 391-401","doi":"10.1016/j.jpsychires.2024.02.050","pmid":"38452637","tags":["addiction","cognition"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Lifetime CUD prevalence in ADHD populations was 26.9%, with current prevalence at 19.2%. Risk ratios showed individuals with ADHD were 2.85 times more likely to have lifetime CUD and 2.91 times more likely to have current CUD compared to general population controls. Prediction intervals were wide (lifetime: 12.4%-48.8%; current: 5.5%-39.1%), reflecting substantial variability across studies.","whyItMatters":"The nearly 3-fold elevated risk of CUD in ADHD populations suggests that cannabis screening should be routine in ADHD treatment. The high prevalence also raises questions about whether some ADHD patients are self-medicating with cannabis.","specificNumbers":"14 studies included. Lifetime CUD prevalence: 26.9% (prediction interval 12.4%-48.8%). Current CUD prevalence: 19.2% (prediction interval 5.5%-39.1%). Lifetime risk ratio: 2.85. Current risk ratio: 2.91.","methodology":"Systematic review and meta-analysis of 14 studies from PubMed, PsycINFO, and Web of Science. Mixed and random-effects models for prevalence estimation and risk ratio calculation.","limitations":"Substantial heterogeneity across studies (wide prediction intervals). Only 14 studies met inclusion criteria. Could not distinguish between recreational and self-medicating use. Meta-analysis of observational studies cannot establish causal direction."},{"rthcId":"RTHC-05319","title":"Depression screening outcomes among adolescents, young adults, and adults reporting past 30-day tobacco and cannabis use.","authors":"Gaiha, Shivani Mathur; Wang, Maggie; Baiocchi, Mike; Halpern-Felsher, Bonnie","year":2024,"journal":"Addictive behaviors, 156, 108076","doi":"10.1016/j.addbeh.2024.108076","pmid":"38838604","tags":["depression","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Co-use of tobacco and cannabis was associated with higher odds of depression screening positive compared to tobacco-only (aOR 1.32) and cannabis-only (aOR 1.94) use. Among specific products, e-cigarette use (aOR 1.56), cigarette use (aOR 1.24), and chewing tobacco (aOR 1.91) were individually associated with depression. The most common two-product combination among depression-positive individuals was nicotine e-cigarettes and smoked cannabis (27.6%).","whyItMatters":"By examining specific product combinations, this study reveals that the e-cigarette plus smoked cannabis pairing is the dominant pattern among depressed co-users, providing a concrete target for screening and intervention efforts.","specificNumbers":"5,281 respondents with complete data. 1,803 (34.1%) reported co-use. Co-use vs tobacco-only: aOR 1.32 (95% CI 1.06-1.65). Co-use vs cannabis-only: aOR 1.94 (95% CI 1.28-2.94). E-cigarettes: aOR 1.56. Most common combo among depressed: e-cigs + smoked cannabis (27.6%, 614 people).","methodology":"Cross-sectional online survey of a national convenience sample of 6,038 people aged 13-40. Depression screening and past 30-day use of 11 specific tobacco and cannabis products assessed. Analyses stratified by age group.","limitations":"Cross-sectional design cannot determine if co-use causes depression or depressed individuals gravitate toward co-use. Convenience sample. Self-reported product use and depression screening (not clinical diagnosis). Cannot control for all confounders."},{"rthcId":"RTHC-05320","title":"Genetic influences and causal pathways shared between cannabis use disorder and other substance use traits.","authors":"Galimberti, Marco; Levey, Daniel F; Deak, Joseph D; Zhou, Hang; Stein, Murray B; Gelernter, Joel","year":2024,"journal":"Molecular psychiatry, 29(9), 2905-2910","doi":"10.1038/s41380-024-02548-y","pmid":"38580809","tags":["genetics","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"CUD showed significant causal effects on all analyzed substance use traits: opioid use disorder (IVW beta 0.925), problematic alcohol use (0.443), smoking initiation (0.405), drinks per week (0.182), nicotine dependence (0.183), and cigarettes per day (0.150). Bidirectional effects were found, with OUD, PAU, smoking initiation, and DPW also increasing CUD risk. Importantly, CUD and simple cannabis use loaded onto different genetic factors, indicating they are genetically distinct.","whyItMatters":"This is among the strongest evidence that the genetic predisposition to cannabis use disorder directly increases risk for other addictions. The finding that CUD and cannabis use are genetically distinct means that casual use and problematic use have different biological underpinnings.","specificNumbers":"CUD causal effect on OUD: IVW beta 0.925 (+/- 0.082). On problematic alcohol use: 0.443 (+/- 0.030). On smoking initiation: 0.405 (+/- 0.042). Bidirectional effects confirmed for OUD, PAU, smoking initiation, smoking cessation, and drinks per week.","methodology":"Genetically informed analyses including local and global genetic correlations, genomic structural equation modeling (genomicSEM), and Mendelian Randomization (MR) using the latest CUD genomics data for unprecedented power.","limitations":"Mendelian randomization assumes genetic instruments are valid; pleiotropy could confound results. European-ancestry-dominant samples limit generalizability. Genetic effects may interact with environmental factors not captured. Statistical causality does not perfectly map to clinical causality."},{"rthcId":"RTHC-05321","title":"Long-Term Treatment for Unspecified Anxiety Disorders with Cannabidiol: A Retrospective Case Series from Real-World Evidence in Colombia.","authors":"Galvez-Florez, Juan F; Guillen-Burgos, Hernan F; Flórez-Puentes, Camilo A; Navarro, Cristian E; Moreno-Sanz, Guillermo","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 193-205","doi":"10.1159/000539754","pmid":"39474243","tags":["anxiety","cbd","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"After 6 months at median 100 mg CBD daily, 54% still had significant anxiety. After 12 months at median 120 mg, only 37.5% persisted with significant symptoms. Sleep disturbances improved from 46.8% reporting significant daytime sleepiness at baseline to only 12.5% at 12 months. No clinically relevant adverse reactions or deaths occurred during follow-up.","whyItMatters":"This is one of the few studies tracking CBD treatment for anxiety beyond 6 months, showing continued improvement from 6 to 12 months. The real-world clinical setting adds practical relevance, though the lack of a control group limits conclusions.","specificNumbers":"24 patients. Median CBD dose: 100 mg at 6 months, 120 mg at 12 months. Significant anxiety: 100% at baseline, 54% at 6 months, 37.5% at 12 months. Significant sleepiness: 47% at baseline, 29% at 6 months, 12.5% at 12 months. No depression improvement (scores were subclinical at baseline).","methodology":"Retrospective observational case series from Zerenia Clinic, Bogota, Colombia (June 2021-December 2022). 24 adults prescribed CBD-enriched oil (100 mg/mL CBD, <1.9 mg/mL THC) for DSM-5 unspecified anxiety disorder. HADS-A, CGI-S/I, HADS-D, and ESS assessed at baseline, 6, and 12 months.","limitations":"No control group or randomization. Very small sample (24). Unspecified anxiety disorder is a broad category. Full-spectrum extract with trace THC, not pure CBD. Cannot rule out placebo effects or natural symptom fluctuation. Retrospective design."},{"rthcId":"RTHC-05322","title":"\"Smoking weed it gets you over the hump\": Cannabis co-use as a facilitator of decreased opioid use among people who inject drugs in Los Angeles, California.","authors":"Ganesh, Siddhi S; Gould, Erin E; Conner, Bradley T; Huh, Jimi; Ceasar, Rachel Carmen; Bluthenthal, Ricky N","year":2024,"journal":"Drug and alcohol dependence reports, 12, 100257","doi":"10.1016/j.dadr.2024.100257","pmid":"39829942","tags":["harm-reduction","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Three themes emerged for how cannabis co-use facilitated reduced opioid use: (1) maintaining opioid cessation and treatment adherence by managing cessation-specific symptoms, (2) managing episodic opioid withdrawal symptoms, and (3) decreasing opioid use because cannabis was more easily accessible than opioids. Participants described cannabis as helping them \"get over the hump\" of opioid cravings and withdrawal.","whyItMatters":"With the fentanyl crisis driving unprecedented overdose deaths, understanding how people who inject drugs already use cannabis as a self-directed harm reduction strategy can inform formal intervention design and peer support programs.","specificNumbers":"30 interviews conducted at 2 community sites. Three themes identified. Inclusion: injection drug use, opioid and cannabis use, age 18+, English-speaking.","methodology":"Semi-structured qualitative interviews with 30 people who inject drugs at two community sites in Los Angeles (near a syringe service program and methadone clinic), July 2021 to April 2022. Constructivist grounded theory analysis.","limitations":"Qualitative design with 30 participants cannot establish effectiveness. Self-selected, English-speaking sample from two sites in one city. No objective measures of opioid reduction. Participants were already using both substances, creating potential confirmation bias."},{"rthcId":"RTHC-05323","title":"Health warning labels on cannabis products. What is the best design?","authors":"Gantiva, Carlos; Illidge-Cortes, Joseph; González-Millares, Danna; Maldonado-Hoyos, Valentina; Valencia, Laura","year":2024,"journal":"The International journal on drug policy, 126, 104355","doi":"10.1016/j.drugpo.2024.104355","pmid":"38382352","tags":["legalization"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Pictorial (graphic) health warnings were generally more effective than text-only warnings across outcomes. Pictorial warnings with yellow backgrounds specifically decreased product appeal and interest in trying cannabis and increased harm perception compared to all other designs (text-only white, text-only yellow, pictorial white, no warning). The most effective warning themes were mental health, smoke toxicity, aesthetic implications, and traffic accidents.","whyItMatters":"As cannabis legalization spreads, evidence-based warning label design can inform regulatory frameworks. This is among the first studies to experimentally test specific design elements of cannabis health warnings.","specificNumbers":"533 participants. 5 conditions: no warning, text-only white, text-only yellow, pictorial white, pictorial yellow. Pictorial yellow outperformed all others on appeal, harm perception, and interest. Most effective themes: mental health, smoke toxicity, aesthetic implications, traffic accidents.","methodology":"Online experiment with 533 participants in Colombia using a between-subjects design. Participants were randomly assigned to 5 package conditions. Measured product appeal, perceived addictiveness, harm perception, and interest in trying cannabis products via attention task and ratings.","limitations":"Online experiment with Colombian participants; may not generalize to other cultural contexts. Measured intentions and perceptions, not actual behavior change. Single exposure; repeated exposure may produce habituation. Does not address warning label effects on current vs potential users separately."},{"rthcId":"RTHC-05324","title":"Δ9-Tetrahydrocannabinol Treatment Modifies Insulin Secretion in Pancreatic Islets from Prediabetic Mice Under Hypercaloric Diet.","authors":"Garcia-Luna, Guadalupe M; Bermudes-Contreras, J David; Hernández-Correa, Samantha; Suarez-Ortiz, Josue O; Diaz-Urbina, Daniel; Garfias-Ramirez, Sergio H; Vega, Ana V; Villalobos-Molina, Rafael; Vilches-Flores, Alonso","year":2024,"journal":"Cannabis and cannabinoid research, 9(5), 1277-1290","doi":"10.1089/can.2023.0017","pmid":"37267277","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05325","title":"Trends in hallucinogen-associated emergency department visits and hospitalizations in California, USA, from 2016 to 2022.","authors":"Garel, Nicolas; Tate, Steven; Nash, Kristin; Lembke, Anna","year":2024,"journal":"Addiction (Abingdon, England), 119(5), 960-964","doi":"10.1111/add.16432","pmid":"38213013","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05326","title":"Genome-wide DNA methylation analysis of cannabis use disorder in a veteran cohort enriched for posttraumatic stress disorder.","authors":"Garrett, Melanie E; Dennis, Michelle F; Bourassa, Kyle J; Hauser, Michael A; Kimbrel, Nathan A; Beckham, Jean C; Ashley-Koch, Allison E","year":2024,"journal":"Psychiatry research, 333, 115757","doi":"10.1016/j.psychres.2024.115757","pmid":"38309009","tags":["genetics","ptsd"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Four CpGs were associated with lifetime CUD after smoking adjustment: AHRR cg05575921, LINC00299 cg23079012, VWA7 cg22112841, and FAM70A cg08760398. The AHRR site remained significant even in never-smokers. CUD interacted with PTSD status: veterans with both CUD and PTSD showed significantly lower DNA methylation than those with either condition alone. Preliminary evidence suggested AHRR methylation helps explain the association between CUD and psychiatric diagnoses, particularly mood disorders.","whyItMatters":"This is the first study showing that CUD and PTSD interact epigenetically, producing greater methylation changes together than either alone. This biological synergy may explain why veterans with dual diagnoses have worse outcomes.","specificNumbers":"2,310 veterans (1,109 NHB, 1,201 NHW). 4 significant CpG sites. AHRR cg05575921 significant even in never-smokers. CUD + PTSD interaction: lower methylation than CUD alone, PTSD alone, or controls. AHRR methylation mediated CUD-psychiatric diagnosis association.","methodology":"Epigenome-wide association study in 2,310 Iraq/Afghanistan era veterans (1,109 non-Hispanic Black, 1,201 non-Hispanic White) enriched for PTSD. Analysis of lifetime CUD controlling for current smoking. CUD x PTSD interaction analysis and mediation testing.","limitations":"Cross-sectional design cannot determine whether methylation changes are cause or consequence. Iraq/Afghanistan veteran cohort may not generalize to civilians. Blood-based methylation may not reflect brain tissue. Enrichment for PTSD may affect generalizability of CUD findings."},{"rthcId":"RTHC-05327","title":"Post-traumatic stress and future substance use outcomes: leveraging antecedent factors to stratify risk.","authors":"Garrison-Desany, Henri M; Meyers, Jacquelyn L; Linnstaedt, Sarah D; House, Stacey L; Beaudoin, Francesca L; An, Xinming; Zeng, Donglin; Neylan, Thomas C; Clifford, Gari D; Jovanovic, Tanja; Germine, Laura T; Bollen, Kenneth A; Rauch, Scott L; Haran, John P; Storrow, Alan B; Lewandowski, Christopher; Musey, Paul I; Hendry, Phyllis L; Sheikh, Sophia; Jones, Christopher W; Punches, Brittany E; Swor, Robert A; Gentile, Nina T; Hudak, Lauren A; Pascual, Jose L; Seamon, Mark J; Harris, Erica; Pearson, Claire; Peak, David A; Domeier, Robert M; Rathlev, Niels K; O'Neil, Brian J; Sergot, Paulina; Sanchez, Leon D; Bruce, Steven E; Joormann, Jutta; Harte, Steven E; McLean, Samuel A; Koenen, Karestan C; Denckla, Christy A","year":2024,"journal":"Frontiers in psychiatry, 15, 1249382","doi":"10.3389/fpsyt.2024.1249382","pmid":"38525258","tags":["ptsd","addiction","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"The link between PTSD and substance use is well-established, but most studies look backward — asking people who already have both conditions about their history. This study did something much harder: it followed nearly 3,000 people forward in time after they showed up at emergency departments following traumatic events, tracking both PTSD symptoms and substance use at six time points.\n\nPTSD symptoms at one time point predicted increased substance use at the next, confirming a prospective relationship for tobacco, alcohol, and cannabis. This temporal ordering — PTSD symptoms first, then increased substance use — supports the self-medication hypothesis: people develop traumatic stress symptoms and then increase their substance use to cope.\n\nBut the most valuable contribution is the risk stratification. Using a machine learning approach (causal forests) with 128 potential variables, the researchers identified which factors most strongly modified the PTSD-to-substance-use pathway. Prior trauma history and sociodemographic characteristics emerged as the most important effect modifiers, meaning the PTSD-substance use link was much stronger in some people than others.\n\nThe study also separated incident substance use (starting a new substance) from prevalent use (increasing existing use), finding different patterns for each. This distinction matters for prevention: keeping trauma survivors from starting new substances may require different strategies than preventing escalation in existing users.","whyItMatters":"Knowing that PTSD leads to increased substance use is important, but knowing who is most vulnerable is actionable. If clinicians can identify trauma survivors at highest risk for developing substance use problems — based on their prior trauma history and sociodemographic profile — they can target early interventions to the people who need them most, rather than treating all trauma survivors the same.","specificNumbers":"2,943 participants. 37.3% (n=1,099) had likely PTSD at baseline. Six assessment time points. PTSD was associated with increased tobacco frequency (IRR: 1.003), with stronger associations for certain subgroups. 128 potential effect modifiers tested via causal forests. Prior trauma and sociodemographic factors were the strongest modifiers of the PTSD-substance use relationship.","methodology":"Prospective cohort from the AURORA study: 2,943 adults presenting at emergency departments after traumatic events. Self-reported PTSD symptoms and substance use (tobacco, alcohol, cannabis) at six time points. Poisson generalized estimating equations assessed lagged associations between PTSD and future substance use. Causal forests identified the most important effect modifiers among 128 potential variables.","limitations":"Self-reported substance use may be underreported. The AURORA cohort recruited from emergency departments, which may not represent all trauma survivors. While the prospective design supports temporal ordering (PTSD → substance use), it still can't definitively prove causation — a third variable could drive both. The causal forest identifies important modifiers but can't establish why they modify the relationship. Cannabis use was not the primary focus and wasn't analyzed separately in detail."},{"rthcId":"RTHC-05328","title":"Substance use and its association with mental health among Swiss medical students: A cross-sectional study.","authors":"Gaume, Jacques; Carrard, Valérie; Berney, Sylvie; Bourquin, Céline; Berney, Alexandre","year":2024,"journal":"The International journal of social psychiatry, 70(4), 808-817","doi":"10.1177/00207640241232321","pmid":"38420921","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05329","title":"Environmental Suppression Mediates the Relationship Between Posttraumatic Stress and Cannabis Use Among Trauma-Exposed College Students.","authors":"Gawrysiak, Michael; Loomis, Daniel; Ehmann, Sebastian; Wayne, Sam; Armao, Mikaela","year":2024,"journal":"Journal of studies on alcohol and drugs, 85(6), 895-900","doi":"10.15288/jsad.23-00344","pmid":"38662506","tags":["ptsd","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Environmental suppression (ES) on the Reward Probability Index fully mediated the relationship between PTS symptoms (PCL-5) and cannabis misuse (CUDIT-R). Reward probability (the ability to experience pleasure) did not mediate this relationship. This suggests that restricted access to non-substance rewards, rather than anhedonia, drives the PTS-cannabis connection.","whyItMatters":"Distinguishing between \"cannot feel pleasure\" (reward probability) and \"environment limits rewarding activities\" (environmental suppression) has direct treatment implications. If restricted reward access drives cannabis use in trauma-exposed individuals, increasing access to positive activities may reduce substance use.","specificNumbers":"404 trauma-exposed undergraduates. Environmental suppression: full mediation of PTS-cannabis relationship. Reward probability: no mediation. PTS measured by PCL-5; cannabis misuse by CUDIT-R.","methodology":"Cross-sectional design with 404 undergraduate students who completed the Reward Probability Index, PCL-5, and CUDIT-R. Parallel mediation path analysis testing two RPI subscales as mediators.","limitations":"Cross-sectional design cannot confirm causal mediation. College student sample limits generalizability to other trauma-exposed populations. Self-reported measures. Single time point cannot capture dynamic processes."},{"rthcId":"RTHC-05330","title":"Serum brain-derived neurotrophic factor level and its relation with cannabis use disorder and schizophrenia: A cross-sectional exploratory study in patients at a tertiary care hospital.","authors":"George, Aishwariya Brigit; Gupta, Abhishek; Jain, Raka; Sood, Mamta; Sarkar, Siddharth","year":2024,"journal":"Indian journal of pharmacology, 56(2), 91-96","doi":"10.4103/ijp.ijp_771_22","pmid":"38687312","tags":["psychosis","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"BDNF levels differed significantly across four groups of 20 subjects each. The dual-diagnosis group (CUD + schizophrenia) had higher BDNF than the CUD-only, schizophrenia-only, or tobacco-only groups. This suggests a synergistic effect of the two conditions on neurotrophin expression.","whyItMatters":"BDNF plays a key role in brain plasticity and has been explored as a biomarker for psychiatric conditions. The finding that co-occurring CUD and schizophrenia elevates BDNF beyond either condition alone raises questions about what this means for brain function and treatment response.","specificNumbers":"80 male subjects in 4 groups of 20. BDNF significantly different across groups. CUD + schizophrenia group highest. Tobacco-only served as the reference group.","methodology":"Cross-sectional observational study comparing serum BDNF in four groups of 20 male subjects (aged 18-45): tobacco use disorder only (control), schizophrenia alone, CUD alone, and CUD + schizophrenia.","limitations":"Very small sample size (20 per group). Male subjects only. Cross-sectional design. Serum BDNF may not reflect brain BDNF levels. Multiple potential confounders including medication effects, substance use severity, and illness duration. Tobacco-only control group is imperfect."},{"rthcId":"RTHC-05331","title":"Cannabis Use during Pregnancy: An Update.","authors":"Gerede, Angeliki; Stavros, Sofoklis; Chatzakis, Christos; Vavoulidis, Eleftherios; Papasozomenou, Panagiota; Domali, Ekaterini; Nikolettos, Konstantinos; Oikonomou, Efthymios; Potiris, Anastasios; Tsikouras, Panagiotis; Nikolettos, Nikolaos","year":2024,"journal":"Medicina (Kaunas, Lithuania), 60(10)","doi":"10.3390/medicina60101691","pmid":"39459478","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05332","title":"DCE attribute development investigating public policy for the provision of medicinal cannabis.","authors":"Gething, Katrina; Erku, Daniel; Scuffham, Paul","year":2024,"journal":"Journal of medical economics, 27(1), 1232-1244","doi":"10.1080/13696998.2024.2405288","pmid":"39297447","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05333","title":"Identifying brief intervention factors to improve cannabis related outcomes in adolescents and young adults: A systematic review of sample characteristics and intervention components.","authors":"Gex, Kathryn S; Leone, Ruschelle M; Aungst, Jenna; Branson, Kevin; Gray, Kevin M; Tomko, Rachel L","year":2024,"journal":"Journal of substance use and addiction treatment, 161, 209335","doi":"10.1016/j.josat.2024.209335","pmid":"38490335","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05334","title":"Attenuation of cannabis withdrawal symptoms by Prosopis farcta extract, its luteolin and melatonin in mice: Involvement of brain-derived neurotrophic factor and dopamine.","authors":"Ghasemian-Yadegari, Javad; Adineh, Ahmad; Mohammadi, Hamidreza; Davari, Shima; Veisani, Yousef; Ghaneialvar, Hori; Aidy, Ali; Abbasi, Naser; Karimi, Elahe","year":2024,"journal":"Cell biochemistry and function, 42(2), e3980","doi":"10.1002/cbf.3980","pmid":"38491827","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05335","title":"Advanced fabrication of complex biopolymer microcapsules via RSM-optimized supercritical carbon dioxide solution-enhanced dispersion: A comparative analysis of various microencapsulation techniques.","authors":"Gholivand, Somayeh; Tan, Tai Boon; Yusoff, Masni Mat; Choy, Hew Weng; Teow, Shuh Jun; Wang, Yong; Liu, Yuanfa; Tan, Chin Ping","year":2024,"journal":"Food chemistry, 452, 139591","doi":"10.1016/j.foodchem.2024.139591","pmid":"38761631","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05336","title":"Is a Low Dosage of Medical Cannabis Effective for Treating Pain Related to Fibromyalgia? A Pilot Study and Systematic Review.","authors":"Giardina, Antonio; Palmieri, Rocco; Ponticelli, Maria; Antonelli, Carlo; Carlucci, Vittorio; Colangelo, Monica; Benedetto, Nadia; Di Fazio, Aldo; Milella, Luigi","year":2024,"journal":"Journal of clinical medicine, 13(14)","doi":"10.3390/jcm13144088","pmid":"39064128","tags":["pain","medical-cannabis"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Pain intensity (NRS) decreased from a median of 8 (95% CI 7.66-8.54) at baseline to 4 (95% CI 3.28-4.79) after 6 months. Physical health improved in 96.67% of patients, and mental health improved in 82.33%. The systematic review component identified 10 clinical trials of cannabis for fibromyalgia, generally supporting potential benefit.","whyItMatters":"The decoction (tea) delivery method is notable because it provides a non-smoked, low-dose option that may be more acceptable to patients and clinicians. The 50% pain reduction is clinically meaningful even without a control group.","specificNumbers":"30 patients. 100 mg/day Bedrocan as decoction. NRS pain: 8 to 4 (50% reduction). Physical improvement: 96.67% (95% CI 44.11-51.13 SF-12). Mental improvement: 82.33% (95% CI 53.48-58.69 SF-12). 10 clinical trials found in systematic review.","methodology":"Pilot study at San Carlo Hospital, Potenza, Italy. 30 fibromyalgia patients received 100 mg/day Bedrocan (standardized cannabis) as a decoction (tea) for 6 months. NRS pain scale and SF-12 quality-of-life questionnaire at baseline and 6 months. Accompanied by a systematic review of 10 trials.","limitations":"No control group or blinding. Small sample. Single-site. 6-month follow-up only. Decoction preparation may vary in cannabinoid extraction efficiency. Cannot separate pharmacological effects from placebo or therapeutic relationship effects."},{"rthcId":"RTHC-05337","title":"Avatar Intervention in Virtual Reality for Cannabis Use Disorder in Individuals With Severe Mental Disorders: Results From a 1-Year, Single-Arm Clinical Trial.","authors":"Giguere, Sabrina; Beaudoin, Mélissa; Dellazizzo, Laura; Phraxayavong, Kingsada; Potvin, Stéphane; Dumais, Alexandre","year":2024,"journal":"JMIR mental health, 11, e58499","doi":"10.2196/58499","pmid":"39602812","tags":["addiction","mental-health"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Significant reductions in cannabis quantity were maintained through 12-month follow-up (d=0.804, p<0.001), confirmed by urine quantification. Use frequency showed a small significant reduction at 3 months (d=0.384, p=0.03). Improvements were also seen in CUD severity, cannabis-related negative consequences, motivation to change, harm-mitigation strategies, quality of life, and psychiatric symptoms.","whyItMatters":"Current psychotherapeutic treatments for CUD in severe mental illness have limited effectiveness. This innovative approach uses VR to create a safe space for patients to practice conversations about their cannabis use, showing promising and durable results in a notoriously difficult-to-treat population.","specificNumbers":"32 participants with dual CUD + SMD. 8 VR sessions. Cannabis quantity reduction d=0.804 (p<0.001) at 12 months. Frequency reduction d=0.384 (p=0.03) at 3 months. Improvements in CUD severity, consequences, motivation, strategies, quality of life, and psychiatric symptoms.","methodology":"Single-arm pilot clinical trial with 32 participants having dual CUD and severe mental disorder. 8 intervention sessions where participants dialogued in VR with an avatar representing a person significant to their cannabis use, animated by a therapist. Assessments before intervention and at post, 3, 6, and 12 months.","limitations":"Single-arm design without control group. 32 participants. Cannot separate VR-specific effects from general therapeutic contact. May not be scalable or accessible in all clinical settings. Selection bias from voluntary participation."},{"rthcId":"RTHC-05338","title":"State-Level Recreational Cannabis Legalization Is Not Differentially Associated with Cannabis Risk Perception Among Children: A Multilevel Regression Analysis.","authors":"Gilman, Jodi M; Iyer, Mallika T; Pottinger, Emma G; Klugman, Emma M; Hughes, Dylan; Potter, Kevin; Tervo-Clemmens, Brenden; Roffman, Joshua L; Evins, A Eden","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 343-352","doi":"10.1089/can.2022.0162","pmid":"36301559","tags":["youth","legalization"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"There was no significant main effect of state recreational cannabis laws on perceived risk of cannabis use among children, and no differences in how risk perception changed over time between states with and without legalization. These null findings persisted after controlling for sex, race, SES, religiosity, and trait impulsivity.","whyItMatters":"A major concern about cannabis legalization is that it will normalize cannabis for children. This large, nationally representative study finds no evidence that state-level legalization laws change how children perceive cannabis risk, at least in the 9-13 age range.","specificNumbers":"10,395 children from the ABCD Study. Ages 9-10 at baseline. 3-year follow-up. No significant main effect of state recreational cannabis laws (RCLs) on risk perception. No significant time-by-RCL interaction.","methodology":"Multilevel regression analysis of ABCD Study data. 10,395 children aged 9-10 at baseline assessed longitudinally across 3 years. Multilevel modeling accounted for state-, family-, and participant-level clustering.","limitations":"Assessed risk perception, not actual use behavior. Children aged 9-13 may be too young for legalization to affect their attitudes. Perception may shift during adolescence when cannabis becomes more socially relevant. Cannot account for local-level variation within states."},{"rthcId":"RTHC-05339","title":"Unprescribed cannabinoids and multiple sclerosis: a multicenter, cross-sectional, epidemiological study in Lombardy, Italy.","authors":"Giossi, Riccardo; Mercenari, Martina; Filippi, Massimo; Zanetta, Chiara; Antozzi, Carlo Giuseppe; Brambilla, Laura; Confalonieri, Paolo; Crisafulli, Sebastiano Giuseppe; Tomas Roldan, Eugenia; Annovazzi, Pietro; Conti, Marta Zaffira; Barrilà, Caterina; Ronzoni, Marco; Grobberio, Monica; Negri, Attilio; Gustavsen, Stefan; Torri Clerici, Valentina","year":2024,"journal":"Journal of neurology, 271(11), 7186-7205","doi":"10.1007/s00415-024-12472-4","pmid":"38844694","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Current unprescribed cannabis use prevalence was 15.5% (higher than the 10.2% Italian general population rate). Only 36.4% of users disclosed their use to their physician. Current users more frequently reported medical motivations compared to former users. Medical users had higher disability, more spasticity and pain, reduced quality of life, and more neurological/psychiatric medication use. 41.1% of non-users would try cannabis if legal.","whyItMatters":"The gap between cannabis use and physician disclosure (only 36% tell their doctor) creates a blind spot in MS care. Patients may be self-medicating with unprescribed cannabis while simultaneously receiving medications that could interact with cannabinoids.","specificNumbers":"2,024 MS patients (mean age 45.2, 64.5% female). 77.3% relapsing-remitting. Current users: 15.5%. Former users: 15.0%. Never users: 69.5%. Disclosure rate: 36.4%. Would use if legal: 41.1% of non-users.","methodology":"Multicenter cross-sectional study across MS centers in Lombardy, Italy. 5,620 MS patients invited; 2,024 (36%) completed anonymous online survey from March 2022-February 2023.","limitations":"Anonymous survey with 36% response rate; respondents may differ from non-respondents. Lombardy region may not represent all of Italy. Self-reported use. Cannot verify medical vs recreational motivations. Cross-sectional design."},{"rthcId":"RTHC-05340","title":"Mandating reimbursement for non-FDA-regulated cannabis is bad public policy.","authors":"Gitlow, Stuart; Bunt, Gregory; Dowling, Frank","year":2024,"journal":"Journal of addictive diseases, 42(1), 71-74","doi":"10.1080/10550887.2023.2282032","pmid":"38115193","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05341","title":"Substance addictions and suicidal thoughts and behaviors: Evidence from a multi-wave epidemiological study.","authors":"Giugovaz, Angela; Grassi, Michele; Marchetti, Igor","year":2024,"journal":"Psychiatry research, 334, 115821","doi":"10.1016/j.psychres.2024.115821","pmid":"38432116","tags":["mental-health","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Addictions to alcohol, pain relievers, marijuana, and cocaine were stable and reliable predictors of all three STB outcomes (ideation, planning, attempt) across 12 years. Cocaine was the exception, showing instability for suicide attempt prediction. The selected four-substance model had greater predictive accuracy than demographic factors alone or the remaining seven substances. Alcohol addiction alone had comparable predictive accuracy to all other ten addictions combined.","whyItMatters":"Identifying which substance addictions most reliably predict suicidality helps prioritize clinical screening. Cannabis addiction being among the four most stable predictors elevates its importance in suicide risk assessment, alongside the better-recognized risks of alcohol and opioids.","specificNumbers":"NSDUH 2008-2020 data. 11 substance addictions tested. 4 stable predictors: alcohol, pain relievers, marijuana, cocaine. Selected model outperformed demographics-only and non-selected substances models. Alcohol alone matched predictive power of other 10 substances combined.","methodology":"Analysis of National Survey on Drug Use and Health (NSDUH) data from 2008-2020 examining eleven substance addictions as predictors of suicidal thoughts and behaviors. Stability of predictions tested across multiple survey years.","limitations":"Cross-sectional survey data collected annually; cannot determine temporal ordering. Self-reported substance use and suicidality. \"Addiction\" defined by survey criteria, not clinical diagnosis. Association does not prove causation."},{"rthcId":"RTHC-05342","title":"RAMP and MRAP accessory proteins have selective effects on expression and signalling of the CB1, CB2, GPR18 and GPR55 cannabinoid receptors.","authors":"Glenn, Nathaniel A K; Finlay, David B; Carruthers, Emma R; Mountjoy, Kathleen G; Walker, Christopher S; Grimsey, Natasha L","year":2024,"journal":"British journal of pharmacology, 181(14), 2212-2231","doi":"10.1111/bph.16095","pmid":"37085333","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05343","title":"The Impact of Cannabis Use on Clinical Outcomes in Inflammatory Bowel Disease: A Population-based Longitudinal Cohort Study.","authors":"Glickman, Danny; Dalessio, Shannon; Raup-Konsavage, Wesley M; Vrana, Kent E; Coates, Matthew D","year":2024,"journal":"Inflammatory bowel diseases, 30(7), 1055-1061","doi":"10.1093/ibd/izad151","pmid":"37580878","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"After propensity score matching, cannabis-using IBD patients had increased risk for ER visits (RR 2.143), hospitalizations (RR 1.925), corticosteroid use (RR 1.095), and opioid use (RR 1.35). No increased risk of IBD-related surgery or death. Crohn's disease patients specifically showed increased corticosteroid and opioid use, while ulcerative colitis patients showed similar patterns for ER visits and hospitalizations.","whyItMatters":"Many IBD patients use cannabis for symptom relief, but this large population study suggests cannabis use is associated with markers of worse disease management, raising questions about whether cannabis helps or hinders IBD outcomes.","specificNumbers":"ER visits: RR 2.143 (95% CI 2.034-2.257). Hospitalizations: RR 1.925 (95% CI 1.783-2.079). Corticosteroid use: RR 1.095 (95% CI 1.021-1.174). Opioid use: RR 1.35 (95% CI 1.14-1.6). All p<0.05. No significant difference for surgery or death.","methodology":"Retrospective propensity score-matched study using the TriNetX Diamond Network. Separate analyses for IBD overall, Crohn's disease, and ulcerative colitis. Baseline differences controlled through matching.","limitations":"Cannot determine whether cannabis use causes worse outcomes or whether sicker patients are more likely to use cannabis. Administrative data cannot capture disease severity, cannabis dose, or symptom burden. Propensity matching may not capture all confounders."},{"rthcId":"RTHC-05344","title":"Alcohol and Cannabis Use by Adolescents with Special Educational Needs: A Systematic Review Focused on Students with Emotional and Behavioral Disorders.","authors":"Goagoses, Naska; Wippermann, Lara; Gotthardt, Ann-Cathrin; Koesling, Ella-Marie; von Düring, Ute","year":2024,"journal":"Substance use & misuse, 59(13), 1921-1929","doi":"10.1080/10826084.2024.2392501","pmid":"39164954","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05345","title":"The association between single and dual use of cannabis and alcohol and driving under the influence and riding with an impaired driver in a large sample of Canadian adolescents.","authors":"Gohari, Mahmood R; Patte, Karen A; Elton-Marshall, Tara; Cole, Adam; Turcotte-Tremblay, Anne-Marie; Bélanger, Richard; Leatherdale, Scott T","year":2024,"journal":"Traffic injury prevention, 25(6), 765-773","doi":"10.1080/15389588.2024.2342571","pmid":"38656911","tags":["driving","youth"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Overall, 14.7% of students reported impaired driving or riding (IDR). Prevalence varied dramatically by substance use: 8.0% nonusers, 21.9% alcohol-only, 35.9% cannabis-only, and 49.6% dual users. Dual use was associated with 9.5 times higher odds of alcohol-cannabis IDR compared to alcohol-only use, and 3.0 times higher odds compared to cannabis-only use.","whyItMatters":"This is one of the largest studies to quantify impaired driving exposure among teens using both alcohol and cannabis. The near-50% IDR prevalence among dual users represents a major road safety concern, especially as both substances become more accessible.","specificNumbers":"69,621 students in 182 schools. IDR prevalence: 8.0% nonusers, 21.9% alcohol-only, 35.9% cannabis-only, 49.6% dual use. Dual vs alcohol-only IDR: OR 9.5. Dual vs cannabis-only: OR 3.0. Gender diverse students, older students, and lower SES associated with higher IDR.","methodology":"Cross-sectional survey of 69,621 students in 182 Canadian secondary schools during the 2021/22 school year. Multilevel logistic regression accounting for school clustering. Interactions tested for gender and age.","limitations":"Cross-sectional design. Self-reported substance use and IDR. Cannot determine the specific IDR situations (e.g., who was driving, relationship to driver). Single school year. Canadian context may differ from other countries."},{"rthcId":"RTHC-05346","title":"Involvement of CB1 and CB2 receptors in neuroprotective effects of cannabinoids in experimental TDP-43 related frontotemporal dementia using male mice.","authors":"Gonzalo-Consuegra, Claudia; Santos-García, Irene; García-Toscano, Laura; Martín-Baquero, Raquel; Rodríguez-Cueto, Carmen; Wittwer, Matthias B; Dzygiel, Pawel; Grether, Uwe; de Lago, Eva; Fernández-Ruiz, Javier","year":2024,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 174, 116473","doi":"10.1016/j.biopha.2024.116473","pmid":"38522237","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05347","title":"Cannabidiol Increases Psychotropic Effects and Plasma Concentrations of Δ9-Tetrahydrocannabinol Without Improving Its Analgesic Properties.","authors":"Gorbenko, Andriy A; Heuberger, Jules A A C; Klumpers, Linda E; de Kam, Marieke L; Strugala, Pamela K; de Visser, Saco J; Groeneveld, Geert J","year":2024,"journal":"Clinical pharmacology and therapeutics, 116(5), 1289-1303","doi":"10.1002/cpt.3381","pmid":"39054656","tags":["cbd","potency"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Co-administration of 450 mg CBD with 9 mg THC increased \"Feeling High\" by 60.5%, more than doubled THC blood levels (AUC ratio 2.18), and increased the active metabolite 11-OH-THC levels (AUC ratio 1.89). Lower CBD doses (10 and 30 mg) also affected pharmacokinetics. CBD did not counteract psychomotor, cognitive, or autonomic effects of THC, and did not improve THC's analgesic properties.","whyItMatters":"This is among the most rigorous tests of the widely held assumption that CBD counteracts THC. The finding that CBD increases rather than decreases THC effects has major implications for cannabis product labeling, dosing guidelines, and the marketing of CBD-containing products as \"safer.\"","specificNumbers":"37 healthy volunteers. CBD 450mg: Feeling High increased 60.5% (95% CI 12.7%-128.5%). THC AUC ratio: 2.18 (95% CI 1.54-3.08). 11-OH-THC AUC ratio: 1.89 (95% CI 1.30-2.77). CBD 30mg also increased THC AUC (ratio 1.44, 95% CI 1.01-2.04).","methodology":"Randomized, double-blind, placebo-controlled, five-way crossover trial in 37 healthy volunteers. Each participant received double-placebo, THC 9mg alone, or THC 9mg with CBD 10, 30, or 450 mg orally. Standardized test batteries for psychoactive and analgesic effects. Pharmacokinetic sampling.","limitations":"Oral administration only; inhaled cannabis may have different pharmacokinetic interactions. Single-dose study in healthy volunteers with no cannabis tolerance. THC dose (9 mg) is relatively low. Laboratory setting does not replicate real-world use conditions."},{"rthcId":"RTHC-05348","title":"An Internet Snapshot Survey Assessing the sale of Synthetic Cannabinoid Receptor Agonists for use with Electronic Vaping Devices.","authors":"Gould, Allon; Dargan, Paul I; Wood, David M","year":2024,"journal":"Journal of medical toxicology : official journal of the American College of Medical Toxicology, 20(3), 271-277","doi":"10.1007/s13181-024-01013-0","pmid":"38839732","tags":["synthetic-cannabinoids"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"62 websites sold 128 SCRA vaping brands. Most were purportedly US-based (66%). Purchase incentives included discreet packaging (61%), bulk discounts (55%), and tracked delivery (48%). Misleading disclaimers included \"not for human consumption\" (66%), \"research purposes only\" (24%), and claims products were \"legal\" (45%). 99.6% were liquid products. Price decreased with volume: 6.58/mL for small quantities, 1.60/mL for bulk.","whyItMatters":"Synthetic cannabinoid vaping products are easily accessible on the regular internet (not dark web), marketed with misleading safety claims, and available in bulk at low prices. This accessibility, combined with their extreme potency and toxicity, represents a public health concern.","specificNumbers":"62 websites. 128 SCRA vaping brands. Median 16 brands per website. 99.6% liquid form. Most common bottle: 5 mL. Median price: 3.39/mL. Bulk pricing: 1.60/mL for >200 mL. 66% claimed \"not for human consumption.\" 45% claimed products were \"legal.\"","methodology":"Internet snapshot survey using Google searches with five relevant search terms between October 2022 and January 2023. Products, pricing, branding, and disclaimers were catalogued from identified websites.","limitations":"Snapshot from October 2022-January 2023; market may have changed. Could not verify product contents or actual SCRA concentrations. Focused on UK-accessible websites. Search terms may not capture all available products. Cannot determine actual sales volumes."},{"rthcId":"RTHC-05349","title":"\"I don't need my kid to be high\": prioritizing harm reduction when using cannabis during pregnancy.","authors":"Gould, Erin E; Ganesh, Siddhi S; Ceasar, Rachel Carmen","year":2024,"journal":"Harm reduction journal, 21(1), 166","doi":"10.1186/s12954-024-01046-2","pmid":"39252036","tags":["pregnancy","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Three themes emerged for how pregnant cannabis users modified their behavior: (1) changing the amount of cannabis used (reducing frequency or quantity), (2) changing types of products (switching from smoking to edibles, topicals, or lower-THC products), and (3) changing procurement sources (seeking regulated dispensaries over illicit sources). Participants were actively seeking evidence-based harm reduction information but could not find trustworthy guidance.","whyItMatters":"Rather than choosing between \"use\" and \"don't use,\" pregnant cannabis users are already practicing harm reduction. Understanding their decision-making can inform clinical approaches that meet patients where they are rather than simply advising abstinence.","specificNumbers":"19 BIPOC participants in California. Three harm reduction themes identified. All participants reported conscious decisions to modify cannabis use during pregnancy.","methodology":"Qualitative constructivist grounded theory. 19 semi-structured interviews (December 2022-March 2023) with BIPOC individuals over 21 who used cannabis during pregnancy within the past 0-2 years in California.","limitations":"Small qualitative sample from California. BIPOC participants only; findings may not generalize across demographics. Self-reported behaviors. Retrospective recall of pregnancy decisions (0-2 years post). No health outcome data for mothers or infants."},{"rthcId":"RTHC-05350","title":"The unseen patient: competing priorities between patients and providers when cannabis is used in pregnancy, a qualitative study.","authors":"Gould, Erin E; Ganesh, Siddhi S; Nguyen, Ryan Mikeala; Breton, Carrie V; Bastain, Theresa M; Dunton, Genevieve F; Ceasar, Rachel Carmen","year":2024,"journal":"Frontiers in global women's health, 5, 1355375","doi":"10.3389/fgwh.2024.1355375","pmid":"38699460","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05351","title":"Cannabidiol Reduces Nicotine Withdrawal Severity and State Anxiety During an Acute E-cigarette Abstinence Period: A Novel, Open-Label Study.","authors":"Gournay, L Riley; Petry, Jordan; Bilsky, Sarah; Hill, Morgan A; Feldner, Matthew; Peters, Erica; Bonn-Miller, Marcel; Leen-Feldner, Ellen","year":2024,"journal":"Cannabis and cannabinoid research, 9(4), 996-1005","doi":"10.1089/can.2022.0317","pmid":"37167367","tags":["cbd","quitting"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"After controlling for positive CBD expectancies, 320 mg oral CBD reduced both nicotine withdrawal symptom severity and state anxiety during a 4-hour e-cigarette abstinence period compared to abstinence alone. Effects were consistent with hypotheses despite the open-label design.","whyItMatters":"With 8.1 million US adults using e-cigarettes and most wanting to quit, effective cessation aids are urgently needed. CBD's ability to reduce withdrawal and anxiety during abstinence could facilitate quit attempts if confirmed in larger trials.","specificNumbers":"20 daily e-cigarette users. 320 mg oral CBD. 4-hour abstinence period. Significant reductions in both withdrawal severity and state anxiety after controlling for CBD expectancies.","methodology":"Open-label crossover design with 20 daily nicotine e-cigarette users. Participants experienced 4-hour abstinence with and without 320 mg oral CBD on separate visits. Withdrawal severity and state anxiety measured. Analysis controlled for positive CBD expectancies.","limitations":"Open-label design. Very small sample (n=20). Single 4-hour abstinence period does not represent a real quit attempt. Cannot distinguish pharmacological effects from residual expectancy effects even after statistical control. No long-term follow-up."},{"rthcId":"RTHC-05352","title":"Substance use and treatment characteristics among pregnant and non-pregnant females, 2015-2019.","authors":"Green, Victoria R; Kennedy-Hendricks, Alene; Saloner, Brendan; Bandara, Sachini","year":2024,"journal":"Drug and alcohol dependence, 254, 111041","doi":"10.1016/j.drugalcdep.2023.111041","pmid":"38043227","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05353","title":"Cannabis use in Parkinson's disease: Patient access to medical cannabis and physician perspective on product safety.","authors":"Griffith, Symone T; Conrow, Kendra D; Go, Michael; McEntee, Mindy L; Daniulaityte, Raminta; Nadesan, Majia H; Swinburne, Mathew R; Shill, Holly A; Leung, Maxwell C K","year":2024,"journal":"Neurotoxicology, 103, 198-205","doi":"10.1016/j.neuro.2024.05.008","pmid":"38834158","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The number of states including PD-related qualifying conditions for medical cannabis increased from 28 to 36 between 2019 and 2023. Among surveyed neurologists, 65% were unaware of any cannabis contaminants. Only 25% knew about pesticide contamination, 15% about toxic elements, and 15% about solvents. PD patients use cannabis at 25-40% compared to 18% in the general population.","whyItMatters":"Parkinson's patients may be uniquely vulnerable to cannabis contaminants because their neurological condition can be worsened by environmental toxins. If the physicians recommending or discussing cannabis with these patients are unaware of contamination risks, patients cannot make informed decisions.","specificNumbers":"PD qualifying conditions: 28 to 36 states (2019-2023). PD-specific states: 14 to 16. Pain qualifying: 17 to 35 states. 45 neurologists surveyed, 44% response. 65% unaware of contaminants. 25% aware of pesticides. 15% aware of toxic elements/solvents. PD cannabis use: 25-40% vs 18% general population.","methodology":"Two-part study: (1) regulatory analysis of PD-related qualifying conditions across US states from 2019-2023, and (2) online survey of 45 neurologists/movement disorder specialists with 44% response rate.","limitations":"Very small survey sample (response from ~20 neurologists). Self-selected respondents. Nine states represented, not nationally comprehensive. Low response rate. Cannot determine whether physician awareness affects patient outcomes."},{"rthcId":"RTHC-05354","title":"Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial.","authors":"Grimison, Peter; Mersiades, Antony; Kirby, Adrienne; Tognela, Annette; Olver, Ian; Morton, Rachael L; Haber, Paul; Walsh, Anna; Lee, Yvonne; Abdi, Ehtesham; Della-Fiorentina, Stephen; Aghmesheh, Morteza; Fox, Peter; Briscoe, Karen; Sanmugarajah, Jasotha; Marx, Gavin; Kichenadasse, Ganessan; Wheeler, Helen; Chan, Matthew; Shannon, Jenny; Gedye, Craig; Begbie, Stephen; Simes, R John; Stockler, Martin R","year":2024,"journal":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 42(34), 4040-4050","doi":"10.1200/JCO.23.01836","pmid":"39151115","tags":["cancer","medical-cannabis"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"THC:CBD improved complete response rate (no vomiting, no rescue medication) from 8% to 24% (absolute difference 16%, 95% CI 4-28, p=0.01) during the first chemotherapy cycle. Similar improvements were seen for absence of significant nausea, reduced rescue medication use, and quality of life. Adverse events included sedation (18% vs 7%), dizziness (10% vs 0%), and transient anxiety (4% vs 1%). No serious adverse events attributed to THC:CBD.","whyItMatters":"Despite modern antiemetics, many cancer patients still experience nausea and vomiting. This trial demonstrates that low-dose THC:CBD can meaningfully improve outcomes when standard treatments are insufficient, using a product that is standardized and tested rather than ad hoc cannabis use.","specificNumbers":"147 evaluable participants. Complete response: 24% THC:CBD vs 8% placebo (p=0.01). Absolute difference: 16%. Background antiemetics: corticosteroid+5-HT3 antagonist (97%), NK1 antagonist (80%), olanzapine (10%). Sedation: 18% vs 7%. Dizziness: 10% vs 0%.","methodology":"Randomized, double-blind, placebo-controlled, two-stage phase II/III trial. 147 evaluable participants (of planned 250) with refractory nausea/vomiting during moderately or highly emetogenic chemotherapy despite guideline-consistent antiemetics. THC 2.5mg + CBD 2.5mg capsules three times daily, days -1 to 5.","limitations":"Enrolled 147 of planned 250 participants. Background antiemetic regimens varied. Additional sedation and dizziness may limit use in some patients. Drug availability, legal status, and cultural attitudes may affect implementation. Cost-effectiveness analysis pending."},{"rthcId":"RTHC-05355","title":"Associations Between Cannabis Use and Mental Distress in Young People: A Longitudinal Study.","authors":"Gripe, Isabella; Pape, Hilde; Norström, Thor","year":2024,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 74(3), 479-486","doi":"10.1016/j.jadohealth.2023.10.003","pmid":"38069929","tags":["youth","mental-health","anxiety","depression"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Using fixed-effects models (which control for all stable individual characteristics), increasing cannabis use from none to 10+ times/year was associated in males with anxiety (RR 1.72, p=0.009), depressed mood (RR 1.49, p<0.001), and suicidal ideation (RR 3.43, p=0.012). In females, the same increase was associated with anxiety (RR 1.38, p=0.023) and suicidal ideation (RR 2.47, p=0.002). Only for depression was the gender difference statistically significant.","whyItMatters":"Fixed-effects models are among the strongest observational designs because they control for all stable individual characteristics (genetics, personality, early environment). The finding that cannabis use changes track with mental distress changes within the same person strengthens the case for a direct relationship.","specificNumbers":"1,988 respondents. 4 waves over 13 years (1992-2005). 60% cumulative response rate. Males: anxiety RR 1.72, depression RR 1.49, suicidal ideation RR 3.43. Females: anxiety RR 1.38, suicidal ideation RR 2.47. Male depression association was significantly stronger than female.","methodology":"Longitudinal cohort assessed at 4 time points over 13 years (1992-2005). 1,988 Norwegian respondents aged 11-18 at baseline. Fixed-effects modeling examining within-person associations between changes in cannabis use and changes in mental distress.","limitations":"1990s cohort may not represent current cannabis use patterns (potency has increased). 60% response rate. Self-reported measures. Cannot definitively exclude reverse causation even with fixed-effects (mental distress changes could trigger cannabis use changes within waves). Norwegian context."},{"rthcId":"RTHC-05356","title":"A systematic evidence map of the association between cannabis use and psychosis-related outcomes across the psychosis continuum: An umbrella review of systematic reviews and meta-analyses.","authors":"Groening, Johanna Manja; Denton, Emma; Parvaiz, Rimsha; Brunet, David Losada; Von Daniken, Aisha; Shi, Yiling; Bhattacharyya, Sagnik","year":2024,"journal":"Psychiatry research, 331, 115626","doi":"10.1016/j.psychres.2023.115626","pmid":"38096722","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05357","title":"Greater vulnerability to cannabis dependence among heavy cannabis user French women.","authors":"Guillem, Eric; Baylé, Franck J","year":2024,"journal":"The American journal on addictions, 33(3), 320-326","doi":"10.1111/ajad.13503","pmid":"38092565","tags":["addiction","sex-differences"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 342 heavy cannabis users, 83.2% were cannabis dependent. Women had significantly higher odds of cannabis dependence (OR 3.87, p<0.05) despite lower cannabis consumption (grams/week, OR 0.96, p<0.05). Women were 5.48 times more likely to have lifetime PTSD (p<0.001), with most PTSD related to sexual assault. Women also had significantly more depression, dysthymia, agoraphobia, social phobia, generalized anxiety disorder, and PTSD.","whyItMatters":"The \"telescoping\" effect (women developing dependence faster from lower doses) has been documented for alcohol but is less studied for cannabis. This finding suggests cannabis treatment programs may need gender-specific approaches, particularly addressing trauma history in women.","specificNumbers":"342 heavy cannabis users. 83.2% cannabis dependent. 10.6% alcohol dependent. Women: OR 3.87 for cannabis dependence. OR 0.96 per gram/week (lower consumption). OR 5.48 for lifetime PTSD. 37.8% current mood disorder. 47.6% current anxiety disorder. 8.8% psychotic.","methodology":"Clinical assessment of 342 heavy cannabis users at a French cannabis clinic between 2004-2014. 2-hour structured clinical interviews using DSM-IV criteria and the MINI psychiatric assessment. Logistic regression for gender comparisons.","limitations":"Treatment-seeking sample at a cannabis clinic; may not represent all heavy cannabis users. French cultural context. DSM-IV criteria (older diagnostic framework). 2004-2014 data; cannabis potency and use patterns have changed. Gender comparison based on binary categories."},{"rthcId":"RTHC-05358","title":"Use of cannabis to manage symptoms of mental and physical health conditions during pregnancy: analysis of a pro-cannabis pregnancy forum.","authors":"Gunn, Rachel L; Aston, Elizabeth R; Artis, Lia; Nesi, Jacqueline; Pedersen, Eric R; Micalizzi, Lauren","year":2024,"journal":"Frontiers in psychiatry, 15, 1478505","doi":"10.3389/fpsyt.2024.1478505","pmid":"39720438","tags":["pregnancy","mental-health","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Analysis of 120 posts from a pro-cannabis pregnancy forum identified four themes: cannabis for mental health symptoms (depression, anxiety), physical symptoms (nausea, pain), achieving homeostasis and stress management, and decision-making about cannabis versus prescription medications.","whyItMatters":"With prenatal cannabis use rising and harm perception declining, understanding why pregnant people use cannabis from their own perspectives can inform less stigmatizing conversations between patients and providers.","specificNumbers":"120 forum posts analyzed; four symptom management themes identified; most discussions reflected perceptions that cannabis was effective for self-reported conditions","methodology":"Researchers randomly selected and analyzed 120 posts from \"Ganja Mamas\" on WhattoExpect.com using thematic analysis with a qualitative coding structure based on existing prenatal cannabis use literature.","limitations":"Self-selected pro-cannabis forum creates inherent bias; no verification of pregnancy status or cannabis use; online posts may not reflect broader population of pregnant cannabis users; no clinical outcome data"},{"rthcId":"RTHC-05359","title":"UK medical cannabis registry: an updated analysis of clinical outcomes of cannabis-based medicinal products for inflammatory bowel disease.","authors":"Gupta, Aashray; Erridge, Simon; Graf, Vivian; Kelada, Monica; Bapir, Lara; Jesuraj, Naveen; Warner-Levy, John; Clarke, Evonne; McLachlan, Katy; Coomber, Ross; Rucker, James J; Platt, Michael W; Sodergren, Mikael H","year":2024,"journal":"Expert review of gastroenterology & hepatology, 18(12), 829-838","doi":"10.1080/17474124.2024.2443574","pmid":"39689344","tags":["medical-cannabis","inflammation"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 116 IBD patients in the UK Medical Cannabis Registry treated with cannabis-based products, there were statistically significant improvements in IBD-specific quality of life (SIBDQ), generalized anxiety (GAD-7), sleep quality (SQS), and general quality of life (EQ-5D-5L) over 18 months.","whyItMatters":"Long-term data on cannabis-based products for IBD is scarce. This 18-month follow-up from a real-world registry provides some of the longest observational data available for this patient population.","specificNumbers":"116 patients; 81% male; mean age 39.5 years; significant improvements in SIBDQ, GAD-7, SQS, and EQ-5D-5L (all p < 0.05); 17.2% reported adverse events (155 total events)","methodology":"Prospective registry study tracking 116 IBD patients prescribed cannabis-based medicinal products (CBMPs) through the UK Medical Cannabis Registry, with validated outcome measures collected from baseline through 18 months.","limitations":"No control group so improvements could reflect natural disease course or placebo effects; predominantly male sample; registry data subject to selection bias; patients self-selected into cannabis treatment"},{"rthcId":"RTHC-05360","title":"The longitudinal assessment of prenatal cannabis use on neonatal outcomes.","authors":"Habersham, Leah L; Hurd, Yasmin L; Nomura, Yoko","year":2024,"journal":"Journal of perinatology : official journal of the California Perinatal Association, 44(8), 1152-1156","doi":"10.1038/s41372-024-02027-w","pmid":"38890400","tags":["pregnancy"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 894 pregnant individuals followed in a longitudinal study, 13.1% used cannabis. Cannabis users had a sevenfold increased risk of fetal death (OR 7.30) that persisted after adjusting for confounders (aOR 6.31). Adjusted models also suggested increased low birth weight risk (aOR 1.67).","whyItMatters":"The association between prenatal cannabis use and fetal death is a serious finding that adds to growing concerns about cannabis safety during pregnancy, particularly as cannabis use among pregnant people increases.","specificNumbers":"894 participants; 13.1% used cannabis; sevenfold increased fetal death risk (OR 7.30); adjusted OR 6.31; adjusted low birth weight risk aOR 1.67; cannabis users were younger on average (25.9 vs 27.9 years)","methodology":"Secondary data analysis of the Stress in Pregnancy longitudinal study (2009-2013), using interviews and electronic medical record reviews to determine cannabis use status among 894 pregnant individuals and evaluate associations with perinatal outcomes.","limitations":"Observational design cannot prove causation; relatively small number of fetal death events may produce unstable estimates; data from 2009-2013 may not reflect current cannabis potency or use patterns; potential unmeasured confounders"},{"rthcId":"RTHC-05361","title":"CBD Versus CBDP: Comparing In Vitro Receptor-Binding Activities.","authors":"Haghdoost, Mehdi; Young, Scott; Holloway, Alisha K; Roberts, Matthew; Zvorsky, Ivori; Bonn-Miller, Marcel O","year":2024,"journal":"International journal of molecular sciences, 25(14)","doi":"10.3390/ijms25147724","pmid":"39062976","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05362","title":"Adolescent-onset cannabis use and parenting young children: an investigation of differential effectiveness of a digital parenting intervention.","authors":"Hails, Katherine A; McWhirter, Anna Cecilia; Sileci, Audrey C B; Stormshak, Elizabeth A","year":2024,"journal":"Frontiers in child and adolescent psychiatry, 3","doi":"10.3389/frcha.2024.1392541","pmid":"38938592","tags":["youth","mental-health"],"studyType":"randomized controlled trial","evidenceStrength":"moderate","keyFinding":"Among 356 parents of children ages 1.5-5, those who began regular cannabis use as adolescents had higher anxiety and depression symptoms regardless of current use. The Family Check-Up Online intervention was especially effective at reducing anxiety for parents with adolescent-onset cannabis use.","whyItMatters":"This study suggests adolescent cannabis use may carry mental health consequences that persist into the parenting years, and that targeted interventions can help address these lasting effects.","specificNumbers":"356 parents of children ages 1.5-5; adolescent-onset cannabis use significantly associated with higher anxiety and depression after accounting for current use; FCU-O significantly moderated the relationship between adolescent-onset use and anxiety","methodology":"Randomized controlled trial of 356 parents (screened for substance misuse or depressive symptoms) assigned to an app-based parenting program with telehealth coaching (FCU-O) or control. Baseline and 3-month follow-up assessments examined how adolescent-onset cannabis use moderated intervention effectiveness.","limitations":"Retrospective self-report of adolescent substance use; 3-month follow-up is short; participants screened for risk factors so results may not generalize to all parents; no long-term child outcome data"},{"rthcId":"RTHC-05363","title":"Associations of discomfort intolerance, discomfort avoidance, and cannabis and alcohol use among persons with chronic pain receiving prescription buprenorphine for opioid use disorder.","authors":"Haley, Danielle F; Stein, Michael D; Bendiks, Sally; Karzhevsky, Skylar; Pierce, Claire; Dunn, Ana; Herman, Debra S; Anderson, Bradley; Weisberg, Risa B","year":2024,"journal":"Drug and alcohol dependence, 265, 112472","doi":"10.1016/j.drugalcdep.2024.112472","pmid":"39488941","tags":["pain","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In 163 chronic pain patients on buprenorphine for OUD, higher discomfort intolerance (difficulty tolerating uncomfortable physical sensations) was associated with more frequent cannabis use (IRR 1.11) and alcohol use (IRR 1.14). Discomfort avoidance (behavioral tendency to avoid discomfort) showed no such association.","whyItMatters":"Understanding why people in OUD treatment use other substances can inform strategies to improve treatment retention and address the intersection of chronic pain and substance use.","specificNumbers":"163 participants; mean age 45; 86% White; 41% used cannabis in past 30 days; 24% used alcohol; discomfort intolerance associated with cannabis use (IRR 1.11, p = .016) and alcohol use (IRR 1.14, p = .022)","methodology":"Cross-sectional analysis of baseline data from the TOPPS intervention trial, using negative-binomial regression models adjusted for demographics, pain interference, depression, anxiety, and cigarette use among 163 chronic pain patients on buprenorphine.","limitations":"Cross-sectional design cannot determine causality; predominantly White sample limits generalizability; self-reported substance use; baseline data only without longitudinal follow-up"},{"rthcId":"RTHC-05364","title":"The acute effects of cannabis, with and without cannabidiol, on attentional bias to cannabis related cues: a randomised, double-blind, placebo-controlled, cross-over study.","authors":"Hall, Daniel; Lawn, Will; Ofori, Shelan; Trinci, Katie; Borissova, Anya; Mokrysz, Claire; Petrilli, Kat; Bloomfield, Michael A P; Wall, Matthew B; Freeman, Tom P; Curran, H Valerie","year":2024,"journal":"Psychopharmacology, 241(6), 1125-1134","doi":"10.1007/s00213-024-06543-7","pmid":"38416223","tags":["cbd","youth","cognition","addiction"],"studyType":"randomized controlled trial","evidenceStrength":"moderate","keyFinding":"In a three-condition crossover trial (THC, THC+CBD, placebo), participants showed an attentional bias away from cannabis cues on placebo. THC administration eliminated this avoidance pattern (F(2,92) = 3.865, p = 0.024). CBD did not moderate the effect, and there was no significant difference between adolescents and adults.","whyItMatters":"Attentional bias toward drug cues is thought to contribute to addiction. This finding that THC shifts attention toward cannabis cues could help explain how cannabis use reinforces continued use.","specificNumbers":"48 participants (24 adolescents, 24 adults); 3 conditions: THC (8 mg/75 kg), THC+CBD (8 mg + 24 mg/75 kg), placebo; main drug effect F(2,92) = 3.865, p = 0.024, η2p = 0.077; 200-ms trials","methodology":"Randomized, double-blind, placebo-controlled, crossover study with 48 weekly cannabis users (24 adolescents aged 16-17, 24 adults aged 26-29) who received weight-adjusted vaporized cannabis (THC alone, THC+CBD, or placebo) on three separate days and completed a visual probe task with cannabis cues.","limitations":"Small sample size (48 total); participants were already weekly cannabis users so findings may not apply to non-users; moderate dose may not reflect real-world heavy use; single session per condition"},{"rthcId":"RTHC-05365","title":"Cannabidiol Reduces Systemic Immune Activation in Experimental Acute Lung Injury.","authors":"Hall, Stefan; Faridi, Sufyan; Trivedi, Purvi; Castonguay, Mathieu; Kelly, Melanie; Zhou, Juan; Lehmann, Christian","year":2024,"journal":"Cannabis and cannabinoid research, 9(5), 1301-1311","doi":"10.1089/can.2023.0039","pmid":"37815809","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05366","title":"Trends in the co-occurrence of substance use and mental health symptomatology in a national sample of US post-secondary students from 2009 to 2019.","authors":"Halladay, Jillian; Freibott, Christina E; Lipson, Sarah K; Zhou, Sasha; Eisenberg, Daniel","year":2024,"journal":"Journal of American college health : J of ACH, 72(6), 1911-1924","doi":"10.1080/07448481.2022.2098030","pmid":"35834773","tags":["mental-health","youth"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Cannabis use was associated with greater odds of depression, anxiety, and suicidal ideation among US post-secondary students. Critically, the strength of this association increased substantially over the 2009-2019 period, more so than for heavy drinking or cigarette smoking.","whyItMatters":"The strengthening association between cannabis and mental health problems among college students coincides with increasing cannabis potency and legalization, raising questions about whether changing cannabis products or patterns are contributing to worse mental health outcomes.","specificNumbers":"323,896 students from 2009-2019; cannabis association with mental health concerns strengthened substantially over time; heavy drinking association strengthened modestly; smoking association remained stable","methodology":"Weighted two-level logistic regression models with time-by-substance interaction terms applied to data from 323,896 students participating in the Healthy Minds Study, a national cross-sectional survey of US post-secondary students, collected annually from 2009 to 2019.","limitations":"Cross-sectional design at each time point cannot determine causation; self-reported substance use and mental health; cannot distinguish whether cannabis contributes to mental health problems or vice versa; survey methodology changes over time could influence trends"},{"rthcId":"RTHC-05367","title":"Pharmacokinetics and pharmacodynamics of cannabis-based medicine in a patient population included in a randomized, placebo-controlled, clinical trial.","authors":"Hansen, Julie Schjødtz; Boix, Fernando; Hasselstrøm, Jørgen Bo; Sørensen, Lambert Kristiansen; Kjolby, Mads; Gustavsen, Stefan; Hansen, Rikke Middelhede; Petersen, Thor; Sellebjerg, Finn; Kasch, Helge; Rasmussen, Peter Vestergaard; Finnerup, Nanna Brix; Saedder, Eva Aggerholm; Svendsen, Kristina Bacher","year":2024,"journal":"Clinical and translational science, 17(1), e13685","doi":"10.1111/cts.13685","pmid":"38054364","tags":["medical-cannabis","pain"],"studyType":"randomized controlled trial","evidenceStrength":"preliminary","keyFinding":"Among 23 MS patients taking oral THC (max 22.5 mg/day), CBD (max 45 mg/day), or combination capsules, pharmacokinetic parameters showed considerable individual variation but were comparable to previous reports from healthy controls. Simulated parameters for THC (5 mg): Cmax 1.21 ng/mL, Tmax 2.68 h, half-life 2.75 h. For CBD (10 mg): Cmax 2.67 ng/mL, Tmax 0.10 h, half-life 4.95 h.","whyItMatters":"Patient-level pharmacokinetic data for oral cannabis capsules in MS patients is scarce. Understanding how these medications behave in real patients, not just healthy volunteers, is important for dosing guidance.","specificNumbers":"23 MS patients (17 female, mean age 52); max doses 22.5 mg THC and 45 mg CBD daily divided into 3 doses; THC half-life 2.75 h; CBD half-life 4.95 h; no effect found on pain or spasticity outcomes; considerable placebo response","methodology":"Pharmacokinetic substudy within a randomized, double-blinded, placebo-controlled trial of 134 MS patients. Blood samples from 23 patients (4 THC, 6 CBD, 4 THC+CBD, 9 placebo) were analyzed using UHPLC-MS/MS, with computerized modeling to estimate PK parameters at probable steady state.","limitations":"Very small substudy (23 patients, only 4 in THC group); no significant effect on pain or spasticity; substantial placebo response; maximum doses may be too low for therapeutic effect; PK parameters modeled rather than directly measured"},{"rthcId":"RTHC-05368","title":"Nicotine use during late adolescence and young adulthood is associated with changes in hippocampal volume and memory performance.","authors":"Happer, Joseph P; Courtney, Kelly E; Baca, Rachel E; Andrade, Gianna; Thompson, Courtney; Shen, Qian; Liu, Thomas T; Jacobus, Joanna","year":2024,"journal":"Frontiers in neuroscience, 18, 1436951","doi":"10.3389/fnins.2024.1436951","pmid":"39221006","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05369","title":"Immunomodulatory effects of cannabinoids against viral infections: a review of its potential use in SARS-CoV2 infection.","authors":"Hassan Kalantar Neyestanaki, Mohammad; Gholizadeh, Omid; Hosseini Tabatabaie, Fatemeh; Akbarzadeh, Sama; Yasamineh, Saman; Afkhami, Hamed; Sedighi, Somayeh","year":2024,"journal":"Virusdisease, 35(2), 342-356","doi":"10.1007/s13337-024-00871-0","pmid":"39071880","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05370","title":"The use of cannabinoids in palliating cancer-related symptoms: a narrative review.","authors":"Hatfield, Jess; Suthar, Krishna; Meyer, Tricia A; Wong, Lucas","year":2024,"journal":"Proceedings (Baylor University. Medical Center), 37(2), 288-294","doi":"10.1080/08998280.2023.2301241","pmid":"38343467","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05371","title":"Multi-Omics Reveals the Effects of Cannabidiol on Gut Microbiota and Metabolic Phenotypes.","authors":"He, Mengxue; Liu, Aiyang; Shi, Jiachen; Xu, Yong-Jiang; Liu, Yuanfa","year":2024,"journal":"Cannabis and cannabinoid research, 9(3), 714-727","doi":"10.1089/can.2022.0331","pmid":"37098174","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05372","title":"A critical assessment of the abuse, dependence and associated safety risks of naturally occurring and synthetic cannabinoids.","authors":"Heal, David J; Gosden, Jane; Smith, Sharon L","year":2024,"journal":"Frontiers in psychiatry, 15, 1322434","doi":"10.3389/fpsyt.2024.1322434","pmid":"38915848","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05373","title":"Growing interest but limited evidence on the usefulness of cannabidiol in treating ophthalmic disease in dogs: a review.","authors":"Henriksen, Michala de Linde; McGrath, Stephanie","year":2024,"journal":"Journal of the American Veterinary Medical Association, 262(S2), S25-S31","doi":"10.2460/javma.24.06.0360","pmid":"39236742","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05374","title":"The Combined Effects of Nicotine and Cannabis on Cortical Thickness Estimates in Adolescents and Emerging Adults.","authors":"Hernandez Mejia, Margie; Courtney, Kelly E; Wade, Natasha E; Wallace, Alexander; Baca, Rachel E; Shen, Qian; Happer, Joseph Patrick; Jacobus, Joanna","year":2024,"journal":"Brain sciences, 14(3)","doi":"10.3390/brainsci14030195","pmid":"38539584","tags":["youth","neuroscience"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Both cannabis and nicotine users had thinner frontal cortices bilaterally compared to non-users. However, an interaction effect was observed: in three left frontal regions, cannabis use was associated with thicker cortices among those with a history of nicotine use, suggesting cannabis may partially offset nicotine-related cortical thinning.","whyItMatters":"Cannabis and nicotine are frequently co-used by young people, yet most brain studies examine them separately. Understanding how these substances interact during a critical period of brain development has important implications for public health messaging.","specificNumbers":"223 participants aged 16-22; 11 bilateral frontal cortical regions examined; interaction effects found in 3 left frontal regions; both substances independently associated with thinner cortices","methodology":"Cross-sectional study using structural MRI to measure cortical thickness in 11 bilateral frontal regions among 223 participants aged 16-22. Linear regression models examined main and interactive effects of past-year nicotine and cannabis use on gray matter thickness.","limitations":"Cross-sectional design cannot determine causality or temporal sequence; cortical thickness differences may precede substance use; cannot rule out other substance use or confounders; self-reported use data"},{"rthcId":"RTHC-05375","title":"Therapeutic use of medical Cannabis in neurological diseases: a clinical update.","authors":"Hidding, Ute; Mainka, Tina; Buhmann, Carsten","year":2024,"journal":"Journal of neural transmission (Vienna, Austria : 1996), 131(2), 117-126","doi":"10.1007/s00702-023-02719-1","pmid":"38015317","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05376","title":"Cannabis use and trauma-focused treatment for co-occurring posttraumatic stress disorder and substance use disorders: A meta-analysis of individual patient data.","authors":"Hill, Melanie L; Kline, Alexander C; Saraiya, Tanya C; Gette, Jordan; Ruglass, Lesia M; Norman, Sonya B; Back, Sudie E; Saavedra, Lissette M; Hien, Denise A; Morgan-López, Antonio A","year":2024,"journal":"Journal of anxiety disorders, 102, 102827","doi":"10.1016/j.janxdis.2024.102827","pmid":"38266511","tags":["ptsd","addiction","mental-health","quitting"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"A common clinical concern is that cannabis use might interfere with PTSD treatment — either by numbing emotions needed for therapeutic processing or by signaling lower motivation for change. This meta-analysis of individual patient data from four randomized controlled trials tested that concern directly.\n\nAmong 410 patients being treated for co-occurring PTSD and substance use disorders, 33.2% endorsed baseline cannabis use. The results were more nuanced than a simple 'helps or hurts' answer.\n\nGood news first: cannabis users still benefited from treatment. Both trauma-focused and non-trauma-focused therapies produced significant improvements in PTSD symptoms, and trauma-focused treatments produced larger PTSD reductions regardless of cannabis use status. The cannabis didn't block the therapy from working.\n\nBut there were costs. Cannabis users attended fewer treatment sessions — a concerning pattern because treatment completion is one of the strongest predictors of long-term outcomes. Cannabis users also showed less improvement in non-cannabis drug use, suggesting that cannabis might be substituting for other substances or reducing motivation to address broader substance use patterns.\n\nThe individual patient data approach is what makes this study powerful. Rather than comparing average outcomes across trials, the researchers could examine how cannabis use interacted with treatment type at the individual level, controlling for demographics and other substance use through propensity score weighting.","whyItMatters":"Clinicians have been uncertain whether to proceed with trauma-focused therapy for PTSD patients who use cannabis. This analysis says: yes, proceed — the therapy still works. But expect lower attendance and be aware that cannabis users may not reduce other substance use as much. This shifts the clinical question from 'should we treat?' to 'how do we maximize engagement and address the full substance use picture?'","specificNumbers":"410 patients across 4 RCTs. 33.2% endorsed cannabis use. 70% male. Trauma-focused therapy produced larger PTSD symptom reductions than non-trauma-focused in both cannabis groups. Cannabis users had lower session attendance. Cannabis users showed less improvement in non-cannabis drug use. Propensity score weighting controlled for baseline differences.","methodology":"Individual patient data meta-analysis from Project Harmony, drawing on 4 RCTs (of 36 total in the larger project) that treated co-occurring PTSD and substance use disorders. Total N=410 (70% male, 33.2% endorsed cannabis use). Propensity score-weighted mixed effects modeling evaluated main and interactive effects of treatment type (trauma-focused vs. non-trauma-focused) and baseline cannabis use on attendance, PTSD symptoms, alcohol use, and non-cannabis drug use severity.","limitations":"Only 4 of 36 Project Harmony trials included — those that assessed cannabis use at baseline. The 33.2% cannabis use rate may not reflect current patterns (cannabis use has increased since some trials were conducted). Cannabis use was assessed at baseline only — changes during treatment weren't tracked. 'Cannabis use' was binary (yes/no) without dose, frequency, or product information. The 70% male sample limits generalizability to women with PTSD+SUD."},{"rthcId":"RTHC-05377","title":"The Developmental Trajectory to Cannabis Use Disorder.","authors":"Hinckley, Jesse D; Ferland, Jacqueline-Marie N; Hurd, Yasmin L","year":2024,"journal":"The American journal of psychiatry, 181(5), 353-358","doi":"10.1176/appi.ajp.20231006","pmid":"38706340","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05378","title":"Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.","authors":"Hinojosa, Cecilia A; Liew, Amanda; An, Xinming; Stevens, Jennifer S; Basu, Archana; van Rooij, Sanne J H; House, Stacey L; Beaudoin, Francesca L; Zeng, Donglin; Neylan, Thomas C; Clifford, Gari D; Jovanovic, Tanja; Linnstaedt, Sarah D; Germine, Laura T; Rauch, Scott L; Haran, John P; Storrow, Alan B; Lewandowski, Christopher; Musey, Paul I; Hendry, Phyllis L; Sheikh, Sophia; Jones, Christopher W; Punches, Brittany E; Kurz, Michael C; Swor, Robert A; Hudak, Lauren A; Pascual, Jose L; Seamon, Mark J; Datner, Elizabeth M; Chang, Anna M; Pearson, Claire; Peak, David A; Merchant, Roland C; Domeier, Robert M; Rathlev, Niels K; Sergot, Paulina; Sanchez, Leon D; Bruce, Steven E; Miller, Mark W; Pietrzak, Robert H; Joormann, Jutta; Pizzagalli, Diego A; Sheridan, John F; Harte, Steven E; Elliott, James M; Kessler, Ronald C; Koenen, Karestan C; McLean, Samuel A; Ressler, Kerry J; Fani, Negar","year":2024,"journal":"Psychological medicine, 54(2), 338-349","doi":"10.1017/S0033291723001642","pmid":"37309917","tags":["ptsd","depression","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Using latent class mixture modeling, researchers identified three trajectory classes for both alcohol and cannabis use: low, high, and increasing use. High cannabis users had significantly worse PTSD and depression symptoms at baseline compared to low users. All groups showed symptom increases peaking at week 8 followed by decline at week 12.","whyItMatters":"Understanding how substance use patterns relate to post-trauma mental health trajectories could help clinicians identify who is most at risk for developing chronic PTSD and depression after a traumatic event.","specificNumbers":"1,618 participants (1,037 female); three trajectory classes per substance (low, high, increasing use); PTSD and depression symptoms peaked at week 8 across groups; symptoms declined by week 12","methodology":"Longitudinal study of 1,618 trauma-exposed civilians (1,037 female) recruited from emergency departments. Self-reported alcohol and cannabis use and clinical symptoms were assessed at baseline and at 2, 8, and 12 weeks posttrauma. Latent class mixture modeling identified substance use trajectories.","limitations":"Self-reported substance use; 12-week follow-up may be too short to capture long-term trajectories; cannot determine whether substance use causes worse symptoms or whether shared risk factors drive both; emergency department recruitment may not represent all trauma-exposed individuals"},{"rthcId":"RTHC-05379","title":"Use of antipsychotic medication, benzodiazepines, and psychiatric hospitalization in cannabis-related versus cannabis-unrelated schizophrenia - a nationwide, register-based cohort study.","authors":"Hjorthøj, Carsten; Stürup, Anne; Karlsen, Mette; Speyer, Helene; Osler, Merete; Ongur, Dost; Nordentoft, Merete","year":2024,"journal":"Psychological medicine, 54(10), 2634-2643","doi":"10.1017/S0033291724000758","pmid":"38571303","tags":["psychosis","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Among 35,714 people with incident schizophrenia (11.5% cannabis-related), propensity-score matched analysis showed cannabis-related cases used significantly less antipsychotics and benzodiazepines. In unmatched analysis, the cannabis-related group had more days admitted, though this was markedly attenuated after matching.","whyItMatters":"If cannabis-related schizophrenia responds differently to treatment, it could have implications for how clinicians approach medication decisions and hospital planning for this subgroup.","specificNumbers":"35,714 people with incident schizophrenia; 4,116 (11.5%) cannabis-related; lower antipsychotic and benzodiazepine use after propensity matching; more hospitalization days in unmatched analysis, attenuated after matching","methodology":"Nationwide Danish registry study identifying all individuals with incident schizophrenia from 1995 to 2016. Cannabis-related schizophrenia was defined by a cannabis use disorder diagnosis preceding schizophrenia. Cases were compared to both all non-cannabis-related patients and propensity-score matched controls.","limitations":"Registry data cannot determine if differences reflect distinct biology or behavioral patterns like treatment non-adherence; cannabis use disorder diagnosis may not capture all cannabis-related cases; propensity matching cannot account for unmeasured confounders"},{"rthcId":"RTHC-05380","title":"Evaluation of potential drug-drug interactions with medical cannabis.","authors":"Ho, Jessie Jia Yi; Goh, Chenyi; Leong, Caitlin Shen Ai; Ng, Khuen Yen; Bakhtiar, Athirah","year":2024,"journal":"Clinical and translational science, 17(5), e13812","doi":"10.1111/cts.13812","pmid":"38720531","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05381","title":"Prevalence of cannabis use and the frequency, types, and sources of cannabis products used in northern remote territories of the Canadian legal cannabis market.","authors":"Hobin, Erin; Schwartz, Naomi; Poon, Theresa; Hammond, David","year":2024,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 115(4), 628-638","doi":"10.17269/s41997-024-00891-9","pmid":"38760617","tags":["legalization","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Past 12-month cannabis use was reported by 46.1% of respondents, with 21.8% reporting daily or near-daily use. The most popular products were dried flower (73.4%), edibles (59.0%), and vape oils (35.7%). On average, 74.8% of cannabis came from legal sources, with consumers rating legal products favorably for quality, convenience, and safety but less so for price.","whyItMatters":"Canada's northern territories are remote regions with unique demographics and limited retail access. High legal market penetration despite remoteness suggests legalization can reach underserved areas.","specificNumbers":"2,462 respondents; 46.1% past-year cannabis use; 21.8% daily/near-daily use; 73.4% used dried flower; 59.0% edibles; 35.7% vape oils; 74.8% from legal sources (range 54.4-92.2% by product type)","methodology":"Cross-sectional survey of 2,462 adults aged 16+ in Canada's Yukon, Northwest Territories, and Nunavut, recruited through mail-push-to-web invitations from licensed mailing lists sampling near-census of territorial households. Population-weighted prevalence estimates reported.","limitations":"Cross-sectional design captures only one time point; self-reported data subject to social desirability bias; cannot compare to pre-legalization rates; northern territories have unique demographics that may not generalize to other regions"},{"rthcId":"RTHC-05382","title":"Optimizing and characterizing 4-methyl substituted pyrazol-3-carboxamides leading to the peripheral cannabinoid 1 receptor inverse agonist TM38837.","authors":"Högberg, Thomas; Receveur, Jean-Marie; Murray, Anthony; Linget, Jean-Michel; Nørregaard, Pia K; Little, Paul B; Cooper, Martin","year":2024,"journal":"Bioorganic & medicinal chemistry letters, 98, 129572","doi":"10.1016/j.bmcl.2023.129572","pmid":"38043690","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05383","title":"Cannabis for chronic pain: cardiovascular safety in a nationwide Danish study.","authors":"Holt, Anders; Nouhravesh, Nina; Strange, Jarl E; Kinnberg Nielsen, Sebastian; Schjerning, Anne-Marie; Vibe Rasmussen, Peter; Torp-Pedersen, Christian; Gislason, Gunnar H; Schou, Morten; McGettigan, Patricia; Lamberts, Morten","year":2024,"journal":"European heart journal, 45(6), 475-484","doi":"10.1093/eurheartj/ehad834","pmid":"38200679","tags":["cardiovascular","medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Among 5,391 chronic pain patients who received prescribed medical cannabis, 0.8% developed new-onset arrhythmia within 180 days compared to 0.4% of matched controls, yielding a risk ratio of 2.07. The elevated risk attenuated to 1.36 at one year. No significant association was found for acute coronary syndrome.","whyItMatters":"As more countries allow medical cannabis for chronic pain, cardiovascular safety data is critical. This large nationwide study provides important evidence that arrhythmia risk warrants clinical attention.","specificNumbers":"1.88 million chronic pain patients; 5,391 medical cannabis initiators matched to 26,941 controls; 180-day arrhythmia risk ratio 2.07 (95% CI 1.34-2.80); 1-year risk ratio 1.36 (95% CI 1.00-1.73); 63.2% women; median age 59; no significant acute coronary syndrome association","methodology":"Nationwide Danish register-based study identifying chronic pain patients initiating medical cannabis (2018-2021), matched 1:5 to controls on age, sex, chronic pain diagnosis, and concomitant pain medication use. Outcomes were first-time arrhythmia and acute coronary syndrome.","limitations":"Observational design cannot prove causation; register data lacks information on actual cannabis consumption patterns; confounding by indication possible; relatively small number of arrhythmia events among cannabis users (42); cannot distinguish between cannabis formulations"},{"rthcId":"RTHC-05384","title":"Legal and Regulatory Aspects of Medical Cannabis in the United States.","authors":"Hong, Genewoo; Sideris, Alexandra; Waldman, Seth; Stauffer, Joe; Wu, Christopher L","year":2024,"journal":"Anesthesia and analgesia, 138(1), 31-41","doi":"10.1213/ANE.0000000000006301","pmid":"38100798","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05385","title":"Perceptions and Prevalence of Cannabis Use in Women With Inflammatory Bowel Disease of Reproductive Age: A Cross-Sectional Study.","authors":"Hossein-Javaheri, Nariman; O'Connor, Katie; Steinhart, Hillary; Deshpande, Amol; Maxwell, Cynthia; Huang, Vivian; Tandon, Parul","year":2024,"journal":"Journal of the Canadian Association of Gastroenterology, 7(2), 204-211","doi":"10.1093/jcag/gwad049","pmid":"38596807","tags":["pregnancy","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among 102 women with IBD aged 18-45, 18.6% reported cannabis use. Cannabis users were more likely to report constant pain. Over half (52%) were unsure about specific risks of cannabis use during pregnancy, and only 14.7% had ever discussed cannabis with their healthcare provider.","whyItMatters":"Women with IBD often turn to cannabis for symptom relief, but the combination of uncertainty about pregnancy risks and low rates of provider discussion creates a dangerous information gap.","specificNumbers":"102 women with IBD; 18.6% used cannabis; 52% unsure about pregnancy-specific risks; only 14.7% discussed cannabis with their provider; cannabis users more likely to report constant pain in past 12 months","methodology":"Cross-sectional survey of women with IBD (ages 18-45) recruited at Mount Sinai Hospital and via Twitter. Anonymous surveys covered demographics, cannabis use, pregnancy risk perceptions, and healthcare provider discussions.","limitations":"Small sample size; convenience sampling via hospital and social media; self-reported data; cannot determine if cannabis use was for symptom management or recreational; cross-sectional design"},{"rthcId":"RTHC-05386","title":"Effects of cannabidiol on AMPKα2 /HIF-1α/BNIP3/NIX signaling pathway in skeletal muscle injury.","authors":"Hou, Zhiquan; Wang, Zhifang; Zhang, Jun; Liu, Yunen; Luo, Zhonghua","year":2024,"journal":"Frontiers in pharmacology, 15, 1450513","doi":"10.3389/fphar.2024.1450513","pmid":"39502531","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05387","title":"Insight into the mechanism of adsorption and release of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol in sewage by modeling regional suspended particles for evaluation of the influence on monitoring of cannabis illicit abuse.","authors":"Huang, Qingda; Zhou, Jiedan; Zhong, Jinjian; Chen, Linzhou; Yang, Hai; Wu, Ke; Yang, Dafeng; Xu, Fei; Xu, Peng; Fan, Huajun; Yang, Xiangliang","year":2024,"journal":"Journal of chromatography. A, 1732, 465207","doi":"10.1016/j.chroma.2024.465207","pmid":"39088898","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05388","title":"Trends in Driving Under the Influence of Alcohol and Cannabis Among Young Adults in Washington State From Before to During the COVID-19 Pandemic.","authors":"Hultgren, Brittney A; Calhoun, Brian H; Fleming, Charles B; Rhew, Isaac C; Larimer, Mary E; Kilmer, Jason R; Guttmannova, Katarina","year":2024,"journal":"American journal of public health, 114(S8), S698-S701","doi":"10.2105/AJPH.2024.307767","pmid":"39442028","tags":["driving","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Pre-pandemic trends in DUI prevalence and pandemic-year deviations were both small and not statistically significant. However, absolute prevalence remained concerning: 12.0% reported driving under the influence of alcohol, 12.5% under cannabis, and 2.7% under both simultaneously. College students showed a relative increase in alcohol-impaired driving during 2020.","whyItMatters":"Despite major disruptions to daily life during COVID-19, young adults continued to drive impaired at alarming rates, suggesting these behaviors are deeply entrenched and resistant to circumstantial changes.","specificNumbers":"12.0% DUI-alcohol; 12.5% DUI-cannabis; 2.7% DUI-both; no significant pandemic-related changes in trends; college students showed relative increase in alcohol DUI during 2020","methodology":"Annual statewide data from the Washington Young Adult Health Survey (2016-2021) analyzed with logistic regression to assess DUI behaviors and pandemic-related deviations from pre-pandemic trends.","limitations":"Self-reported DUI may underestimate true prevalence; Washington State results may not generalize nationally; annual cross-sectional design limits individual-level trend analysis; short pandemic period for trend detection"},{"rthcId":"RTHC-05389","title":"Young adult impaired driving behaviors and perceived norms of driving under the influence of simultaneous alcohol and cannabis use.","authors":"Hultgren, Brittney A; Delawalla, Miranda L M; Szydlowski, Victoria; Guttmannova, Katarina; Cadigan, Jennifer M; Kilmer, Jason R; Lee, Christine M; Larimer, Mary E","year":2024,"journal":"Alcohol, clinical & experimental research, 48(12), 2319-2330","doi":"10.1111/acer.15459","pmid":"39616528","tags":["driving","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"DUI after simultaneous alcohol and cannabis use (DUI-SAM) was reported by 2.7% and riding with an impaired driver (RWI-SAM) by 5.3%. Nearly half of participants overestimated how often peers drove impaired. After controlling for frequency of use and descriptive norms, perceived peer approval (injunctive norms) was significantly associated with all DUI and RWI behaviors.","whyItMatters":"Identifying that peer approval matters more than perceived prevalence for driving under combined substances points to a specific, actionable target for prevention campaigns.","specificNumbers":"1,941 participants; 2.7% DUI-SAM; 5.3% RWI-SAM; 49.8% believed average young adult drove after SAM use at least monthly; 68.8% called DUI-SAM totally unacceptable; injunctive norms significantly predicted all DUI/RWI behaviors","methodology":"Cross-sectional survey of 1,941 young adults (ages 18-25) from the 2019 cohort of the Washington Young Adult Health Survey. Logistic regression models assessed associations between descriptive norms, injunctive norms, and past-month DUI/RWI behaviors with post-stratification weighting.","limitations":"Cross-sectional design cannot establish causality; self-reported DUI likely underestimated; single state sample; 2019 data predates pandemic; cannot distinguish between types of cannabis products used"},{"rthcId":"RTHC-05390","title":"Young Adult Alcohol and Cannabis Impaired Driving After the Opening of Cannabis Retail Stores in Washington State.","authors":"Hultgren, Brittney A; Calhoun, Brian H; Fleming, Charles B; Lyons, Vivian H; Rhew, Isaac C; Larimer, Mary E; Kilmer, Jason R; Guttmannova, Katarina","year":2024,"journal":"Prevention science : the official journal of the Society for Prevention Research, 25(5), 749-759","doi":"10.1007/s11121-024-01679-6","pmid":"38664365","tags":["driving","legalization","youth"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"From 2014 to 2019, alcohol DUI decreased overall (AOR 0.93) and among drinkers (AOR 0.95). Cannabis DUI did not change overall (11% by 2019) but decreased significantly among cannabis users (AOR 0.91; 33% by 2019). DUI after combined use showed a non-significant decrease. All prevalence rates remained at concerning levels.","whyItMatters":"One of the biggest concerns about cannabis legalization is increased impaired driving. This five-year post-legalization trend analysis provides reassurance that cannabis DUI did not increase while also highlighting that rates remain unacceptably high.","specificNumbers":"12,963 participants; DUI-alcohol decreased (AOR 0.93, overall; 10% by 2019); DUI-cannabis stable overall (11% by 2019); DUI-cannabis decreased among users (AOR 0.91; 33% of users by 2019); DUI-combined trended down non-significantly","methodology":"Weighted logistic regressions analyzing annual Washington Young Adult Health Survey data from 12,963 participants aged 18-25 across 2014-2019, assessing yearly trends in alcohol, cannabis, and combined substance impaired driving following cannabis retail store openings.","limitations":"Self-reported DUI; no comparison state or pre-legalization baseline; cannot attribute trends specifically to retail store openings versus other factors; Washington-specific results may not generalize; 18-25 age range only"},{"rthcId":"RTHC-05391","title":"Effects of prenatal THC vapor exposure on body weight, glucose metabolism, and feeding behaviors in chow and high-fat diet fed rats.","authors":"Hume, Catherine; Baglot, Samantha L; Javorcikova, Lucia; Lightfoot, Savannah H M; Scheufen, Jessica; Hill, Matthew N","year":2024,"journal":"International journal of obesity (2005), 48(7), 981-992","doi":"10.1038/s41366-024-01512-8","pmid":"38528095","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05392","title":"RCEM best practice guideline: suspected cannabinoid hyperemesis syndrome in emergency departments.","authors":"Humphries, Christopher; Gillings, Marianne","year":2024,"journal":"Emergency medicine journal : EMJ, 41(5), 328-331","doi":"10.1136/emermed-2024-213886","pmid":"38448215","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05393","title":"Factors related to the low-risk perception of driving after cannabis use.","authors":"Huỳnh, Christophe; Beaulieu-Thibodeau, Alexis; Fallu, Jean-Sébastien; Bergeron, Jacques; Jacques, Alain; Brochu, Serge","year":2024,"journal":"Accident; analysis and prevention, 202, 107584","doi":"10.1016/j.aap.2024.107584","pmid":"38692126","tags":["driving"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Lower risk perception of driving after cannabis use was associated with being male, weekly-to-daily cannabis use, personal engagement in cannabis-impaired driving, general risky driving behaviors, being a passenger with an impaired driver, number of friends who drive after cannabis use, and peer approval. Having also driven drunk and living in urban areas were associated with higher risk perception.","whyItMatters":"Low risk perception is one of the strongest predictors of actually driving after cannabis use. Identifying who holds these perceptions can help target prevention messaging.","specificNumbers":"1,467 Canadian drivers aged 17-35; factors predicting low risk perception: male sex, weekly-to-daily use, personal DACU, risky driving history, peer DACU, peer approval; factors predicting higher risk perception: DUI-alcohol history, urban residence, recent traffic tickets, irritability/cognitive problems","methodology":"Cross-sectional online survey of 1,467 Canadian drivers aged 17-35 who used cannabis in the past year. Multivariate linear regression identified factors associated with perceiving low risk from driving after cannabis use.","limitations":"Cross-sectional design cannot determine whether low risk perception leads to behavior or vice versa; self-selected sample of cannabis users; self-reported data; Canadian sample may not generalize to other contexts"},{"rthcId":"RTHC-05394","title":"Predictors of relapse and engagement in care one year after ending services in an urban safety net coordinated specialty care program for first episode psychosis.","authors":"Hyatt, Andrew; Mullin, Brian; Hasler, Victoria; Madore, Drew; Progovac, Ana M; Cook, Benjamin Lê; DeLisi, Lynn E","year":2024,"journal":"Schizophrenia research, 264, 140-146","doi":"10.1016/j.schres.2023.12.022","pmid":"38128345","tags":["psychosis","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis use at last program contact was associated with a fourfold higher risk of relapse (aOR 4.06, 95% CI 1.56-10.56) and significantly lower rates of outpatient psychiatric follow-up (aOR 0.32, 95% CI 0.12-0.94) in the 12 months after ending coordinated specialty care. Prior emergency/hospitalization during the program also predicted relapse (aOR 4.69).","whyItMatters":"The transition out of first-episode psychosis programs is a vulnerable period. Identifying cannabis use as a strong predictor of both relapse and disengagement from care provides a clear clinical target.","specificNumbers":"143 individuals; cannabis use at last contact: relapse aOR 4.06 (95% CI 1.56-10.56); outpatient follow-up aOR 0.32 (95% CI 0.12-0.94); prior ED/hospitalization: relapse aOR 4.69 (95% CI 1.78-12.34); no racial/ethnic differences in outcomes","methodology":"Retrospective analysis of 143 individuals with first-episode psychosis who received coordinated specialty care (CSC) between 2014 and 2021. Electronic health records and linked insurance claims data were used to identify relapse (ED visits or hospitalization) and outpatient follow-up in the 12 months after program exit.","limitations":"Small sample from a single urban safety-net program; cannot determine if cannabis caused worse outcomes or if people at higher relapse risk are more likely to use cannabis; retrospective design; cannabis use assessed only at last contact, not continuously"},{"rthcId":"RTHC-05395","title":"Cannabis Use in Patients With Inflammatory Bowel Disease Following Legalization of Cannabis in Canada.","authors":"Iablokov, Vadim; Gregor, Jamie; Chande, Nilesh; Ponich, Terry; Jairath, Vipul; Khanna, Reena; Asfaha, Samuel","year":2024,"journal":"Crohn's & colitis 360, 6(2), otae031","doi":"10.1093/crocol/otae031","pmid":"38800569","tags":["medical-cannabis","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Recent cannabis use was reported by 41% of Crohn's disease patients and 31% of ulcerative colitis patients, more than double pre-legalization rates of ~16% and ~12% respectively. Cannabis users reported more abdominal pain, poor appetite, and flatulence, with lower quality of life scores (SIBDQ 37 vs 40). Less than half (46%) discussed cannabis with their physician.","whyItMatters":"The dramatic increase in cannabis use among IBD patients after legalization, combined with worse symptoms in users and low rates of physician discussion, represents a clinical blind spot.","specificNumbers":"254 participants (148 CD, 90 UC, 16 indeterminate); 41% CD and 31% UC recent cannabis use; pre-legalization rates ~16% CD and ~12% UC; cannabis users SIBDQ 37 vs non-users 40; only 46% discussed with physician","methodology":"Prospective cohort study of 254 IBD patients at a Canadian tertiary care center who completed online surveys covering demographics, disease history, cannabis use, and the Short IBD Questionnaire (SIBDQ).","limitations":"Cross-sectional design cannot determine causation; tertiary care center patients may have more severe disease; self-reported cannabis use; pre-legalization comparison from different study populations; no data on cannabis type, dose, or frequency"},{"rthcId":"RTHC-05396","title":"Cannabinoids as alleviating treatment for core symptoms of autism spectrum disorder in children and adolescents: a systematic review.","authors":"Ibsen, Emma Wen Dieperink; Thomsen, Per Hove","year":2024,"journal":"Nordic journal of psychiatry, 78(7), 553-560","doi":"10.1080/08039488.2024.2381541","pmid":"39037073","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05397","title":"Cannabis use and heart transplant listing: A survey of clinician practices.","authors":"Ilonze, Onyedika J; Knapp, Shannon M; Chernyak, Yelena; Page, Robert L; Boyd, LaKeisha J; Mazimba, Sula; Raman, Subha V; Enyi, Chioma O; Allen, Larry A; Breathett, Khadijah","year":2024,"journal":"PloS one, 19(12), e0310778","doi":"10.1371/journal.pone.0310778","pmid":"39666766","tags":["cardiovascular","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Whether cannabis was legal in the respondent's state significantly shaped clinical practices. Programs where cannabis was legal were more tolerant of higher use frequencies before listing exclusion (p = 0.033), more supportive of validated screening questionnaires (p = 0.011), and more likely to have formal policies addressing medical cannabis (p = 0.0001). Most clinicians agreed six months of abstinence was sufficient before listing.","whyItMatters":"The lack of consensus on cannabis policies for heart transplant candidates means patients may be denied or accepted for transplant based largely on geography rather than evidence.","specificNumbers":"140 clinicians; 41.4% cardiologists; significant differences by state legality for: acceptable use frequency (p = 0.033), screening questionnaire utility (p = 0.011), program allows prescribed cannabis (p < 0.0001), formal policy exists (p = 0.0001); most agreed on 6 months abstinence","methodology":"Web-based survey of 140 clinicians involved in heart transplant care (cardiologists 41.4%, surgeons 7.1%, pharmacists 9.3%, plus advanced practice providers and coordinators). Responses compared between those in states where cannabis was legal versus illegal.","limitations":"Survey response rate not reported; self-selected respondents may not represent all programs; responses reflect stated practices which may differ from actual behavior; cannot assess patient outcomes associated with different policies"},{"rthcId":"RTHC-05398","title":"Negative allosteric modulation of CB1 cannabinoid receptor signaling suppresses opioid-mediated tolerance and withdrawal without blocking opioid antinociception.","authors":"Iyer, Vishakh; Saberi, Shahin A; Pacheco, Romario; Sizemore, Emily Fender; Stockman, Sarah; Kulkarni, Abhijit; Cantwell, Lucas; Thakur, Ganesh A; Hohmann, Andrea G","year":2024,"journal":"Neuropharmacology, 257, 110052","doi":"10.1016/j.neuropharm.2024.110052","pmid":"38936657","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05399","title":"Impact of cannabinoids on synapse markers in an SH-SY5Y cell culture model.","authors":"Jahn, Kirsten; Blumer, Nina; Wieltsch, Caroline; Duzzi, Laura; Fuchs, Heiko; Meister, Roland; Groh, Adrian; Schulze Westhoff, Martin; Krüger, Tillmann Horst Christoph; Bleich, Stefan; Khan, Abdul Qayyum; Frieling, Helge","year":2024,"journal":"Schizophrenia (Heidelberg, Germany), 10(1), 96","doi":"10.1038/s41537-024-00498-6","pmid":"39448630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05400","title":"Quantitative summary on the human pharmacokinetic properties of cannabidiol to accelerate scientific clinical application of cannabis.","authors":"Jang, Ji-Hun; Jeong, Ju-Hwan; Jeong, Seung-Hyun","year":2024,"journal":"Naunyn-Schmiedeberg's archives of pharmacology, 397(11), 8285-8309","doi":"10.1007/s00210-024-03185-6","pmid":"38850302","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05401","title":"Interpreting mono- and poly-SCRA intoxications from an activity-based point of view: JWH-018 equivalents in serum as a comparative measure.","authors":"Janssens, Liesl K; Sommer, Michaela J; Grafinger, Katharina Elisabeth; Hermanns-Clausen, Maren; Auwärter, Volker; Stove, Christophe P","year":2024,"journal":"Archives of toxicology, 98(10), 3337-3350","doi":"10.1007/s00204-024-03830-2","pmid":"39115690","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05402","title":"3-O-Ethyl Ascorbic Acid and Cannabigerol in Modulating the Phospholipid Metabolism of Keratinocytes.","authors":"Jarocka-Karpowicz, Iwona; Dobrzyńska, Izabela; Stasiewicz, Anna; Skrzydlewska, Elżbieta","year":2024,"journal":"Antioxidants (Basel, Switzerland), 13(11)","doi":"10.3390/antiox13111285","pmid":"39594427","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05403","title":"Evaluation of three-year neurodevelopmental outcomes in infants prenatally exposed to substance use.","authors":"Jarque, Pilar; Carmona, Miguel; Roca, Antonia; Barcelo, Bernardino; Pichini, Simona; Elorza, Miguel Ángel; Sanchis, Pilar; Rendal, Yolanda; Gomila, Isabel","year":2024,"journal":"Drug and alcohol dependence, 259, 111284","doi":"10.1016/j.drugalcdep.2024.111284","pmid":"38640866","tags":["pregnancy","youth","cognition"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among 32 prenatally exposed and 32 matched control infants assessed at 36 months using the Bayley Scales, exposed infants scored significantly lower in cognitive, motor, and language domains. Cannabis-exposed infants specifically had lower cognitive and motor scores, and the most common and severe delays were in language, particularly among males.","whyItMatters":"Identifying specific developmental domains affected by prenatal cannabis exposure at age three can help guide early intervention strategies during a critical window for language and cognitive development.","specificNumbers":"32 exposed infants (16 cannabis, 8 alcohol, 2 cocaine, 6 polysubstance) vs 32 controls; normal scores (>=85) in 23 exposed vs 29 controls; two cannabis-exposed infants had severe delay (score <70); male infants exposed to cannabis had significantly lower cognitive scores","methodology":"Prospective matched case-control study using meconium biomarkers to confirm fetal substance exposure. The Bayley Scales of Infant and Toddler Development (BSID-III) were administered at 36 months to 32 exposed and 32 non-exposed infants.","limitations":"Small sample size (only 16 cannabis-exposed); cannot fully separate cannabis effects from other substance exposures or socioeconomic factors; meconium only captures exposure in later pregnancy; single assessment time point"},{"rthcId":"RTHC-05404","title":"Trends in prescription and cost of Sativex, a cannabinoid-based medicine, in treating patients with multiple sclerosis in England.","authors":"Javid, Farideh A; Alam, Anam; Williams, Emily; Malik, Sidhra Sajid; Mohayuddin, Usama; Hasan, Syed Shahzad","year":2024,"journal":"Journal of pharmaceutical policy and practice, 17(1), 2342318","doi":"10.1080/20523211.2024.2342318","pmid":"38726319","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Sativex prescriptions in England rose from 4.42 items per 100,000 people in 2013 to 5.15 in 2022, an average increase of 0.34% per year. Prescription costs also increased by an average of 2.43% per year. Neither trend reached statistical significance.","whyItMatters":"Despite being one of the few approved cannabis-based medicines in the UK, Sativex remains rarely prescribed a decade after becoming available, raising questions about barriers to access.","specificNumbers":"4.42 prescriptions per 100,000 in 2013 to 5.15 in 2022; average annual increase 0.34% (95% CI -3.98 to 4.67, p = 0.860); cost increase 2.43% per year (95% CI -5.78 to 0.92, p = 0.133)","methodology":"Analysis of primary care prescribing data from the Prescription Cost Analysis database (2013-2022) with linear regression to examine trends in prescription items and costs for cannabinoid-based Sativex in England.","limitations":"Primary care data only, may miss specialist prescribing; cannot assess patient outcomes; no data on why prescribing remains low; linear regression may not capture non-linear trends; no patient-level data"},{"rthcId":"RTHC-05405","title":"The Evolving Role of Cannabidiol-Rich Cannabis in People with Autism Spectrum Disorder: A Systematic Review.","authors":"Jawed, Bilal; Esposito, Jessica Elisabetta; Pulcini, Riccardo; Zakir, Syed Khuram; Botteghi, Matteo; Gaudio, Francesco; Savio, Daniele; Martinotti, Caterina; Martinotti, Stefano; Toniato, Elena","year":2024,"journal":"International journal of molecular sciences, 25(22)","doi":"10.3390/ijms252212453","pmid":"39596518","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05406","title":"Association of Cannabis Use With Cardiovascular Outcomes Among US Adults.","authors":"Jeffers, Abra M; Glantz, Stanton; Byers, Amy L; Keyhani, Salomeh","year":2024,"journal":"Journal of the American Heart Association, 13(5), e030178","doi":"10.1161/JAHA.123.030178","pmid":"38415581","tags":["cardiovascular"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Daily cannabis use was associated with 25% higher odds of heart attack (aOR 1.25), 42% higher odds of stroke (aOR 1.42), and 28% higher odds of any cardiovascular event (aOR 1.28) after adjusting for tobacco and other factors. Among never-tobacco smokers, the associations were even stronger: 49% higher heart attack odds and 116% higher stroke odds.","whyItMatters":"This is one of the largest studies to examine cannabis and cardiovascular risk. The finding that associations were stronger among never-tobacco smokers helps rule out tobacco as the primary driver.","specificNumbers":"434,104 respondents; 4% daily users, 7.1% non-daily users; daily use aORs: coronary heart disease 1.16, heart attack 1.25, stroke 1.42, composite 1.28; never-tobacco smokers: heart attack aOR 1.49, stroke aOR 2.16, composite aOR 1.77; dose-response relationship with days of use","methodology":"Population-based cross-sectional analysis of 2016-2020 Behavioral Risk Factor Surveillance Survey data from 27 US states and 2 territories (434,104 respondents aged 18-74). Multivariable regression models assessed associations between cannabis use days per month and self-reported cardiovascular outcomes.","limitations":"Cross-sectional design cannot establish causation; self-reported cardiovascular outcomes and cannabis use; cannot determine method of cannabis consumption; no data on cannabis type or potency; people with cardiovascular conditions may use cannabis for symptom management (reverse causation)"},{"rthcId":"RTHC-05407","title":"Application of Oil-in-Water Cannabidiol Emulsion for the Treatment of Rheumatoid Arthritis.","authors":"Jelínek, Petr; Roušarová, Jaroslava; Ryšánek, Pavel; Ježková, Martina; Havlůjová, Tereza; Pozniak, Jiří; Kozlík, Petr; Křížek, Tomáš; Kučera, Tomáš; Šíma, Martin; Slanař, Ondřej; Šoóš, Miroslav","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 147-159","doi":"10.1089/can.2022.0176","pmid":"36342775","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05408","title":"Cannabidiol and neurodegeneration: From molecular mechanisms to clinical benefits.","authors":"Jha, Saurabh Kumar; Nelson, Vinod Kumar; Suryadevara, Punna Rao; Panda, Siva Prasad; Pullaiah, Chitikela P; Nuli, Mohana Vamsi; Kamal, Mehnaz; Imran, Mohd; Ausali, Saijyothi; Abomughaid, Mosleh Mohammad; Srivastava, Rashi; Deka, Rahul; Pritam, Pingal; Gupta, Neha; Shyam, Harishankar; Singh, Indrakant K; Pandey, Bindhy Wasini; Dewanjee, Saikat; Jha, Niraj Kumar; Jafari, Seid Mahdi","year":2024,"journal":"Ageing research reviews, 100, 102386","doi":"10.1016/j.arr.2024.102386","pmid":"38969143","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05409","title":"Synthesis and Antitumour Evaluation of Tricyclic Indole-2-Carboxamides against Paediatric Brain Cancer Cells.","authors":"John Hamilton, Alexander; Lane, Samuel; Werry, Eryn L; Suri, Amreena; Bailey, Anders W; Mercé, Clémentine; Kadolsky, Ulrich; Payne, Alan D; Kassiou, Michael; Treiger Sredni, Simone; Saxena, Alka; Gunosewoyo, Hendra","year":2024,"journal":"ChemMedChem, 19(19), e202400098","doi":"10.1002/cmdc.202400098","pmid":"38923350","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05410","title":"Differential effects of cannabis constituents on schizophrenia-related psychosis: a rationale for incorporating cannabidiol into a schizophrenia therapeutic regimen.","authors":"Johnson, Kennadi; Weldon, Abby J; Burmeister, Melissa A","year":2024,"journal":"Frontiers in psychiatry, 15, 1386263","doi":"10.3389/fpsyt.2024.1386263","pmid":"38716117","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05411","title":"Cannabinoids for the Treatment of Glaucoma: A Review.","authors":"Joshi, Neeraj; Mariam, Haifa; Kamath, Ashwin","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 183-192","doi":"10.1159/000541461","pmid":"39474241","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05412","title":"Cannabis-Based Phytocannabinoids: Overview, Mechanism of Action, Therapeutic Application, Production, and Affecting Environmental Factors.","authors":"Jurga, Marta; Jurga, Anna; Jurga, Kacper; Kaźmierczak, Bartosz; Kuśmierczyk, Katarzyna; Chabowski, Mariusz","year":2024,"journal":"International journal of molecular sciences, 25(20)","doi":"10.3390/ijms252011258","pmid":"39457041","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05413","title":"The Anticancer Activity of Cannabinol (CBN) and Cannabigerol (CBG) on Acute Myeloid Leukemia Cells.","authors":"Kadriya, Ahmad; Forbes-Robertson, Sarah; Falah, Mizied","year":2024,"journal":"Molecules (Basel, Switzerland), 29(24)","doi":"10.3390/molecules29245970","pmid":"39770061","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05414","title":"Characteristics of Cannabis and Opioid Users Among Older U.S. Veterans and Their Health Outcomes: A Longitudinal Perspective.","authors":"Kang, Hyojung; Clary, Kelly; Zhao, Ziang; Quintero Silva, Laura; Bobitt, Julie","year":2024,"journal":"Journal of psychoactive drugs, 56(2), 157-167","doi":"10.1080/02791072.2023.2186286","pmid":"36919533","tags":["medical-cannabis","pain","seniors"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Older veterans reported positive outcomes for pain, sleep, and emotional problems across two survey periods. Among co-users, 44.1% of those using both cannabis and opioids initially reported stopping opioids by follow-up, while 20.4% of cannabis-only users added opioids. About 62% and 85% reported no change in memory and falls, respectively.","whyItMatters":"Older veterans face high rates of chronic pain and opioid use. Evidence that medical cannabis may help some reduce opioid reliance while maintaining pain relief is relevant to veteran healthcare policy.","specificNumbers":"44.1% of cannabis-opioid co-users stopped opioids at follow-up; 20.4% of cannabis-only users started opioids; 62% no change in memory; 85% no change in falls; only 3% and 1% reported negative memory and fall outcomes; changes in opioid use not statistically significant","methodology":"Longitudinal survey of older US veterans enrolled in the Illinois Medical Cannabis Patient Program, with two survey periods assessing health outcomes, substance use, and opioid co-use patterns. Logistic regression examined factors associated with cannabis-opioid co-use.","limitations":"Small self-selected sample; self-reported outcomes without clinical verification; changes in opioid use were not statistically significant; no control group; enrolled in medical cannabis program so inherently favorable toward cannabis"},{"rthcId":"RTHC-05415","title":"Assessing evidence supporting cannabis harm reduction practices for adolescents at clinical high-risk for psychosis: a review and clinical implementation tool.","authors":"Kapler, Simon; Adery, Laura; Hoftman, Gil D; Amir, Carolyn M; Grigoryan, Vardui; Cooper, Ziva D; Bearden, Carrie E","year":2024,"journal":"Psychological medicine, 54(2), 245-255","doi":"10.1017/S0033291723002994","pmid":"37882050","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05416","title":"Soluble hemp protein-xylose conjugates fabricated by high-pressure homogenization and pH-shifting treatments.","authors":"Karabulut, Gulsah; Kapoor, Ragya; Feng, Hao","year":2024,"journal":"Journal of the science of food and agriculture, 104(15), 9640-9651","doi":"10.1002/jsfa.13788","pmid":"39105678","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05417","title":"Distant neuroinflammation acutely induced by focal brain injury and its control by endocannabinoid system.","authors":"Karan, Anna A; Spivak, Yulia S; Suleymanova, Elena M; Gerasimov, Konstantin A; Bolshakov, Alex P; Vinogradova, Lyudmila V","year":2024,"journal":"Experimental neurology, 373, 114679","doi":"10.1016/j.expneurol.2024.114679","pmid":"38190933","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05418","title":"Neurological Disorders Induced by Drug Use: Effects of Adolescent and Embryonic Drug Exposure on Behavioral Neurodevelopment.","authors":"Karatayev, Olga; Collier, Adam D; Targoff, Stella R; Leibowitz, Sarah F","year":2024,"journal":"International journal of molecular sciences, 25(15)","doi":"10.3390/ijms25158341","pmid":"39125913","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05419","title":"Resilience buffers the association between psychotic-like experiences and suicide risk: a prospective study from a non-clinical sample.","authors":"Karska, Julia; Rejek, Maksymilian; Misiak, Błażej","year":2024,"journal":"BMC psychiatry, 24(1), 32","doi":"10.1186/s12888-024-05491-y","pmid":"38191366","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05420","title":"Observational Analysis of the Influence of Medical Marijuana Use on Quality of Life in Patients.","authors":"Kelley, Mark D; Obaid, Marwah; Miller, Edward M; Bowie, Marla; Heeter, Zachary S","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 44-50","doi":"10.1159/000536591","pmid":"38500669","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Participants showed significant improvements in physical and social functioning, emotional well-being, and energy within 30 days that persisted through 90 days. Those using inhaled or vaped products showed greater emotional well-being improvement than flower users. Patients using cannabis for opioid use consumed significantly more THC than those treating anxiety, chronic pain, or IBD.","whyItMatters":"Real-world data from state medical cannabis programs can help bridge the evidence gap between clinical trials and how patients actually experience medical cannabis in practice.","specificNumbers":"103 completers over 90 days; significant improvements in physical functioning, social functioning, emotional well-being, and energy within first 30 days; significant decreases in emotional limitations, fatigue, and pain; vapers showed higher emotional well-being gains than flower users","methodology":"Prospective observational study of 103 Pennsylvania Medical Marijuana Program patients surveyed electronically every 30 days over 90 days about use patterns and quality of life changes.","limitations":"No control group; self-selected patients likely positive toward cannabis; short 90-day follow-up; self-reported outcomes without clinical verification; no blinding; potential placebo effect"},{"rthcId":"RTHC-05421","title":"Prenatal tobacco and tobacco-Cannabis co-exposure and unpredictability in maternal anger/hostility: Implications for toddler reactivity.","authors":"Kelm, Madison R; Schuetze, Pamela; Eiden, Rina D","year":2024,"journal":"Neurotoxicology and teratology, 106, 107399","doi":"10.1016/j.ntt.2024.107399","pmid":"39426606","tags":["pregnancy","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Prenatal tobacco-cannabis co-exposure had a direct effect on blunted toddler reactivity in males only. Mothers who used substances had the highest anger/hostility and mood unpredictability. Continued postnatal cannabis exposure was associated with higher toddler reactivity. Prenatal anger/hostility and mood unpredictability predicted higher infant reactivity, which in turn predicted higher toddler reactivity.","whyItMatters":"The sex-specific blunting effect of prenatal co-exposure, combined with the heightening effect of continued postnatal cannabis exposure, suggests complex developmental pathways that differ for boys and girls.","specificNumbers":"247 dyads at recruitment, 190 at toddler assessment; direct effect of co-exposure on blunted male toddler reactivity; highest anger/hostility and mood unpredictability in substance-using mothers; postnatal cannabis exposure associated with higher toddler reactivity","methodology":"Prospective longitudinal study of 247 dyads recruited during the first trimester into tobacco-using (including cannabis co-users) and non-substance-using groups. Maternal mood, substance use, and infant/toddler reactivity were assessed across multiple time points using structural equation modeling.","limitations":"Cannot fully separate tobacco and cannabis effects in co-users; maternal mood confounds substance exposure effects; relatively small subgroups; observational design with potential unmeasured confounders; attrition from 247 to 190"},{"rthcId":"RTHC-05422","title":"Multilevel associations of peer cognitive factors and adolescent cannabis use in a legal recreational cannabis region.","authors":"Kenyon, Emily A; Yang, Manshu; Chung, Tammy; Wilson, Anna C; Feldstein Ewing, Sarah W","year":2024,"journal":"Frontiers in psychiatry, 15, 1477000","doi":"10.3389/fpsyt.2024.1477000","pmid":"39628492","tags":["youth","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Individual increases in hazardous cannabis use were significantly associated with higher peer norms (perceiving more peer use) and lower resistance to peer influence. Between-adolescent differences in hazardous use were associated only with peer norms. Past-month cannabis use was associated with peer norms but not resistance to peer influence.","whyItMatters":"In states where cannabis is legal for adults, understanding the cognitive and social factors that drive adolescent use can help design targeted prevention programs.","specificNumbers":"204 adolescents ages 15-19 (mean 18.68, 67% female); 12-month follow-up with 4 time points; peer norms and resistance to peer influence both predicted within-person changes in hazardous use; only peer norms predicted between-person differences","methodology":"Longitudinal study of 204 adolescents aged 15-19 in the Portland, Oregon area (legal recreational cannabis state) who endorsed at least one heavy drinking episode. Data collected across four time points over 12 months, analyzed with multilevel latent growth curve modeling.","limitations":"Participants were all heavy drinkers so may not represent all adolescents; single metropolitan area in one state; self-reported peer norms and substance use; relatively small sample; 67% female"},{"rthcId":"RTHC-05423","title":"Boosting Acetylcholine Signaling by Cannabidiol in a Murine Model of Alzheimer's Disease.","authors":"Khodadadi, Hesam; Salles, Évila Lopes; Naeini, Sahar Emami; Bhandari, Bidhan; Rogers, Hannah M; Gouron, Jules; Meeks, William; Terry, Alvin V; Pillai, Anilkumar; Yu, Jack C; Morgan, John C; Vaibhav, Kumar; Hess, David C; Dhandapani, Krishnan M; Wang, Lei P; Baban, Babak","year":2024,"journal":"International journal of molecular sciences, 25(21)","doi":"10.3390/ijms252111764","pmid":"39519315","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05424","title":"Effects of cannabis smoking on the respiratory system: A state-of-the-art review.","authors":"Khoj, Lugain; Zagà, Vincenzo; Amram, Daniel L; Hosein, Karishma; Pistone, Giovanni; Bisconti, Mario; Serafini, Antonella; Cammarata, Liborio M; Cattaruzza, Maria Sofia; Mura, Marco","year":2024,"journal":"Respiratory medicine, 221, 107494","doi":"10.1016/j.rmed.2023.107494","pmid":"38056532","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05425","title":"Cannabis use and cyclical vomiting syndrome: An open debate.","authors":"Kilani, Yassine; Aljabiri, Yazan; Arshad, Iqra; Alsakarneh, Saqr; Aldiabat, Mohammad; Castro Puello, Priscila; Vahanyan, Anush; Vikash, Fnu; Kumar, Vikash; Numan, Laith; Thor, Savanna","year":2024,"journal":"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 56(2), 272-280","doi":"10.1016/j.dld.2023.10.002","pmid":"37880016","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 35,055 CVS admissions (NIS), cannabis use was associated with reduced length of stay (adjusted mean difference -0.53 days) and 37% lower 30-day readmissions (aHR 0.63). The authors suggest this paradoxical finding likely reflects cannabinoid hyperemesis syndrome (CHS) cases miscoded as CVS, where cannabis cessation during hospitalization improved outcomes.","whyItMatters":"The overlap between CVS and CHS is a significant diagnostic challenge. This study highlights how ICD coding limitations obscure the true relationship between cannabis and cyclic vomiting.","specificNumbers":"35,055 NIS admissions; 31,240 NRD admissions; 6.4% readmitted within 30 days; cannabis use: LOS reduced by 0.53 days (95% CI -0.68 to -0.38); 30-day readmission aHR 0.63 (95% CI 0.54-0.73)","methodology":"Retrospective nationwide analysis using weighted data from the National Inpatient Sample (NIS, 35,055 admissions) and National Readmission Database (NRD, 31,240 admissions). Multivariate regression assessed predictors of length of stay and 30-day readmission among patients with primary CVS diagnosis.","limitations":"Administrative data cannot distinguish CVS from CHS; cannabis use identification depends on ICD coding which may be incomplete; cannot determine if patients ceased cannabis during hospitalization; no data on cannabis use patterns or amounts"},{"rthcId":"RTHC-05426","title":"Considerations for Research in States with Recent or Pending Legalization of Non-Medical Cannabis: Lessons Learned from Alcohol and Opportunities for Research.","authors":"Kilmer, Jason R; Hultgren, Brittney A; Delawalla, Miranda L M; Gilson, Michael S; Rhew, Isaac C; Fairlie, Anne M; Martinez, Griselda; Guttmannova, Katarina","year":2024,"journal":"Current addiction reports, 11(4), 666-671","doi":"10.1007/s40429-024-00579-7","pmid":"40060330","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05427","title":"Food preference-based screening method for identification of effectors of substance use disorders using Caenorhabditis elegans.","authors":"Kim, Aaron Taehwan; Li, Sida; Kim, Yoo; You, Young-Jai; Park, Yeonhwa","year":2024,"journal":"Life sciences, 345, 122580","doi":"10.1016/j.lfs.2024.122580","pmid":"38514005","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05428","title":"Effects of Biomaterials Derived from Germinated Hemp Seeds on Stressed Hair Stem Cells and Immune Cells.","authors":"Kim, Donghyun; Kim, Namsoo Peter; Kim, Boyong","year":2024,"journal":"International journal of molecular sciences, 25(14)","doi":"10.3390/ijms25147823","pmid":"39063064","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05429","title":"Functions of Hemp-Induced Exosomes against Periodontal Deterioration Caused by Fine Dust.","authors":"Kim, Eunhee; Park, Yoonjin; Yun, Mihae; Kim, Boyong","year":2024,"journal":"International journal of molecular sciences, 25(19)","doi":"10.3390/ijms251910331","pmid":"39408660","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05430","title":"Cannabichromene as a Novel Inhibitor of Th2 Cytokine and JAK/STAT Pathway Activation in Atopic Dermatitis Models.","authors":"Kim, Ki Chan; Jeong, Ga Hee; Bang, Chul Hwan; Lee, Ji Hyun","year":2024,"journal":"International journal of molecular sciences, 25(24)","doi":"10.3390/ijms252413539","pmid":"39769302","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05431","title":"High-Potency Prenatal Cannabis Exposure and Birth Outcome Measures.","authors":"Kleinhans, Natalia M; Johnson, Allegra J; Larsen, Sarah F; Berkelhamer, Sara K; Larimer, Mary E; Dager, Stephen R","year":2024,"journal":"Children (Basel, Switzerland), 11(12)","doi":"10.3390/children11121436","pmid":"39767866","tags":["pregnancy","potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 37 cannabis-exposed and 35 control newborns in otherwise low-risk pregnancies, cannabis-exposed newborns weighed less (38th vs 52nd percentile, p = 0.04) and were shorter (40th vs 55th percentile, p = 0.03). Female exposed newborns had significantly smaller head circumference (28th percentile) compared to males (55th percentile, p = 0.02).","whyItMatters":"This is one of the few studies to isolate cannabis effects from other substances in pregnancy. The high-potency exposure (average 198 mg THC/day) and sex-specific head circumference findings are particularly notable.","specificNumbers":"37 exposed vs 35 controls; average 198 mg THC/day and 3.5 mg CBD/day; birth weight: 38th vs 52nd percentile (p = 0.04); length: 40th vs 55th percentile (p = 0.03); female head circumference 28th percentile vs male 55th percentile (p = 0.02)","methodology":"Prospective observational cohort study (2019-2022) in Washington and Oregon. Cannabis-exposed women used cannabis at least 3 days/week during the first trimester. All participants were screened for no alcohol, tobacco, or illicit drug use via urine toxicology at multiple time points. Cannabis use was quantified using product weight and potency.","limitations":"Small sample size; no randomization; self-selected groups; cannabis use quantified but not biomarker-verified; cannot rule out unmeasured lifestyle confounders; short-term birth outcomes only"},{"rthcId":"RTHC-05432","title":"A Rare Complication of Cannabinoid Hyperemesis Syndrome.","authors":"Knight, Hallie E; Singla, Abhinav; Smerina, Michael; Cortes, Melissa P; Gavrancic, Tatjana; Baumgarten, Deborah A; Dumitrascu, Adrian G; Pagan, Ricardo J; Murawska Baptista, Aleksandra","year":2024,"journal":"The American journal of case reports, 25, e945106","doi":"10.12659/AJCR.945106","pmid":"39375911","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05433","title":"Marijuana Use among Pregnant and Nonpregnant Women of Reproductive Age, 2013-2019.","authors":"Kobernik, Emily K; Ford, Nicole D; Levecke, Madison; Galang, Romeo R; Hoots, Brooke; Roehler, Douglas R; Ko, Jean Y","year":2024,"journal":"Substance use & misuse, 59(5), 690-698","doi":"10.1080/10826084.2023.2294974","pmid":"38132561","tags":["pregnancy"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Among pregnant women, 4.9% reported past-month marijuana use and 15.2% reported past-year use. Among nonpregnant women, rates were 11.8% and 19.5% respectively. Past-year marijuana use was 2.3-5.1 times more likely among pregnant women who also reported tobacco, alcohol, or other illicit drug use compared to those with no substance use.","whyItMatters":"These national estimates provide baseline prevalence data for marijuana use during pregnancy and highlight the strong association with polysubstance use, which compounds risks.","specificNumbers":"Pregnant women: 4.9% past-month, 10.4% past 2-12 months, 15.2% past-year marijuana use; nonpregnant: 11.8%, 7.8%, 19.5% respectively; adjusted prevalence ratios for polysubstance use: 2.3-5.1x for pregnant, 2.1-4.6x for nonpregnant women","methodology":"Analysis of 2013-2019 National Survey on Drug Use and Health (NSDUH) data using weighted prevalence estimates and general linear regression models with Poisson distribution to identify factors associated with past-year marijuana use by self-reported pregnancy status among women aged 18-44.","limitations":"Self-reported data may underestimate use due to stigma; NSDUH does not include institutionalized populations; pregnancy status self-reported and not verified; data from 2013-2019 may not reflect current trends; cannot assess amount or potency of marijuana used"},{"rthcId":"RTHC-05434","title":"Cannabinoids for treating psychiatric disorders in youth: a systematic review of randomized controlled trials.","authors":"Köck, Patrick; Badek, Andrzej; Meyer, Maximilian; Klaassen, Arndt-Lukas; Walter, Marc; Kindler, Jochen","year":2024,"journal":"Child and adolescent psychiatry and mental health, 18(1), 158","doi":"10.1186/s13034-024-00846-5","pmid":"39696457","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05435","title":"Reducing the harms of cannabis use in youth post-legalization: insights from Ontario youth, parents, and service providers.","authors":"Kourgiantakis, Toula; Hamilton, Angie; Tait, Christine; Tekirdag Kosar, A Kumsal; Lau, Carrie K Y; McNeil, Sandra; Lee, Eunjung; Craig, Shelley; Goldstein, Abby L","year":2024,"journal":"Harm reduction journal, 21(1), 193","doi":"10.1186/s12954-024-01112-9","pmid":"39506846","tags":["youth","legalization","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Two themes emerged around perceived harms: concerns about addiction, brain development, motivation, and mental health impacts; and minimization of risks through conflicting messages, normalization, and perceptions of cannabis as less harmful than other substances. Harm reduction themes included implementation challenges and structural barriers such as unavailable services, easy cannabis access, and insufficient public education.","whyItMatters":"Five years after Canadian legalization, hearing directly from youth, parents, and service providers about what is and is not working for harm reduction provides actionable insights for policy improvement.","specificNumbers":"88 participants: 31 youth, 26 parents, 31 service providers; 4 main themes identified; structural barriers included unavailable/inaccessible services, easy access to cannabis, inadequate public education, and insufficient lower-risk use guidelines","methodology":"Community-based participatory research in partnership with Families for Addiction Recovery. Virtual semi-structured interviews with 88 participants (31 youth, 26 parents, 31 service providers) in Ontario, Canada. Data analyzed using thematic analysis.","limitations":"Participants recruited through an addiction recovery charity, potentially skewing toward those with negative experiences; Ontario-specific findings; qualitative design not generalizable; no quantitative outcome measures"},{"rthcId":"RTHC-05436","title":"Understanding youth and young adult cannabis use in Canada post-legalization: a scoping review on a public health issue.","authors":"Kourgiantakis, Toula; Vicknarajah, Ragave; Logan, Judith; Edwards, Travonne; Lee, Eunjung; Craig, Shelley; Kaura, Ashima; Williams, Charmaine C; Marshall, Savannah","year":2024,"journal":"Substance abuse treatment, prevention, and policy, 19(1), 30","doi":"10.1186/s13011-024-00615-9","pmid":"38886804","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05437","title":"Cannabinoids and the heart-a psychiatrist's perspective.","authors":"Kramer, Johannes; Koller, Gabi; Pogarell, Oliver","year":2024,"journal":"Herz, 49(6), 428-433","doi":"10.1007/s00059-024-05273-y","pmid":"39331072","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05438","title":"Behind the heterogeneity in the long-term course of first-episode psychosis: Different psychotic symptom trajectories are associated with different patterns of cannabis and stimulant use.","authors":"Kreis, Isabel; Lagerberg, Trine Vik; Wold, Kristin Fjelnseth; Åsbø, Gina; Simonsen, Carmen; Flaaten, Camilla Bärthel; Engen, Magnus Johan; Lyngstad, Siv Hege; Widing, Line Hustad; Ueland, Torill; Melle, Ingrid","year":2024,"journal":"Schizophrenia research, 271, 91-99","doi":"10.1016/j.schres.2024.07.006","pmid":"39018985","tags":["psychosis","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Four trajectories emerged: Stable Remission (54.2%), Delayed Remission (15.6%), Psychotic Relapse (7.8%), and Persistent Symptoms (22.4%). Delayed Remission was associated with frequent cannabis and stimulant use during the first five years, with dose-dependent effects for cannabis but not stimulants. Psychotic Relapse was associated with sporadic stimulant use throughout the full follow-up period.","whyItMatters":"Understanding which substance use patterns drive specific long-term psychosis trajectories can help clinicians prioritize substance use interventions. The dose-dependent cannabis effect suggests even reduction (not just cessation) may improve outcomes.","specificNumbers":"192 participants; 10-year follow-up; 54.2% Stable Remission; 15.6% Delayed Remission; 7.8% Psychotic Relapse; 22.4% Persistent Symptoms; dose-dependent cannabis effect on unfavorable trajectories; all unfavorable trajectories had more schizophrenia diagnoses and longer untreated psychosis","methodology":"Ten-year follow-up of 192 participants with first-episode psychosis using growth mixture modeling to identify psychotic symptom trajectories. Associations with baseline characteristics and concurrent cannabis/stimulant use during follow-up were tested.","limitations":"Observational design cannot prove causation; substance use assessed during follow-up may be a consequence rather than cause of symptoms; 10-year attrition; cannot distinguish cannabis types or potencies; relatively small trajectory subgroups"},{"rthcId":"RTHC-05439","title":"Longitudinal patterns of cannabis and tobacco co-administration and concurrent use among young adult college students.","authors":"Kreitzberg, Daniel S; Pasch, Keryn E; Loukas, Alexandra","year":2024,"journal":"Addictive behaviors, 148, 107871","doi":"10.1016/j.addbeh.2023.107871","pmid":"37778233","tags":["addiction","youth"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Four latent classes emerged: non-use (58%), general use of all substances (19%), blunt and cannabis use (13%), and concurrent/co-administration use with cigarettes, cannabis, blunts, and spliffs (10%). Most students remained in the same class from 2016 to 2019, indicating stable co-use patterns over time.","whyItMatters":"The stability of co-use patterns suggests that once young adults establish cannabis-tobacco co-use behaviors in college, they are unlikely to change without intervention.","specificNumbers":"4,448 participants; 4 classes: non-use 58%, general use 19%, blunt/cannabis 13%, concurrent co-administration 10%; most students remained in same class 2016-2019; 64.2% female; 64.7% non-white; mean age 20.5","methodology":"Longitudinal cohort study of 4,448 young adults (64.2% female, 64.7% non-white, mean age 20.5) at Texas colleges, assessed for past 30-day tobacco, cannabis, and co-administration use. Latent Markov models estimated class membership and transitions from 2016 to 2019.","limitations":"Texas-specific sample may not generalize to other states; self-reported substance use; attrition over 3 years not detailed; cannot determine what drives class stability versus transition; legal context may differ across states"},{"rthcId":"RTHC-05440","title":"Childhood sleep is prospectively associated with adolescent alcohol and marijuana use.","authors":"Krishnan, Akshay S; Reichenberger, David A; Strayer, Stephen M; Master, Lindsay; Russell, Michael A; Buxton, Orfeu M; Hale, Lauren; Chang, Anne-Marie","year":2024,"journal":"Annals of epidemiology, 98, 25-31","doi":"10.1016/j.annepidem.2024.07.048","pmid":"39043321","tags":["youth","sleep"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"At age 15, later bedtime (aOR 1.35) and shorter sleep at age 9 (aOR 1.19) were associated with greater odds of trying marijuana. Later bedtimes at age 5 also predicted marijuana use (aOR 1.26). Cross-sectionally at 15, later bedtime (aOR 1.35) was associated with marijuana use.","whyItMatters":"Identifying childhood sleep problems as a modifiable risk factor for adolescent substance use opens a window for early prevention long before drug exposure becomes a concern.","specificNumbers":"1,514 adolescents from 20 US cities; later bedtime at age 5 predicted marijuana use at 15 (aOR 1.26); shorter sleep at age 9 predicted marijuana use (aOR 1.19); at age 15: later bedtime aOR 1.35 for marijuana","methodology":"Prospective longitudinal analysis of the Future of Families and Child Wellbeing Study, a national birth cohort from 20 US cities. Parent-reported sleep measures at ages 3, 5, and 9 were linked to self-reported marijuana and alcohol use at age 15 (n = 1,514). Logistic regressions adjusted for sex, race/ethnicity, family structure, income, and caregiver education.","limitations":"Observational design cannot prove sleep problems cause later substance use; parent-reported sleep for younger ages, self-reported at 15; unmeasured confounders possible; bedtime is a proxy for sleep quality; urban birth cohort may not generalize to all settings"},{"rthcId":"RTHC-05441","title":"Physicians' Attitudes and Practices Regarding Cannabis and Recommending Medical Cannabis Use.","authors":"Kruger, Daniel J; Gerlach, Joseph; Kruger, Jessica S; Mokbel, Majd A; Clauw, Daniel J; Boehnke, Kevin F","year":2024,"journal":"Cannabis and cannabinoid research, 9(4), e1048-e1055","doi":"10.1089/can.2022.0324","pmid":"37098170","tags":["medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Only 10% of physicians had ever signed a medical cannabis authorization. Cannabis discussions primarily focused on risks (63%) rather than dosage (6%) or harm reduction (25%). Physicians perceived their influence on patient cannabis decisions as weak compared to other information sources and had unfavorable attitudes toward dispensary staff and medical cannabis caregivers.","whyItMatters":"When physicians lack cannabis knowledge and focus only on risks, patients are left without clinical guidance and may rely on less reliable information sources, potentially leading to harm.","specificNumbers":"10% had signed a medical cannabis authorization; 63% of discussions focused on risks; 6% on dosage; 25% on harm reduction; physicians perceived weak influence compared to other patient information sources","methodology":"Anonymous online survey of physicians in a university-affiliated health system assessing cannabis education, perceived knowledge and competence, discussion content, and attitudes toward dispensary staff and caregivers.","limitations":"Single health system; response rate and sample size not specified in abstract; may not represent community physicians or those in states with robust medical cannabis programs; self-reported data"},{"rthcId":"RTHC-05442","title":"Identification and Health Risks of an Emerging Means of Drug Use in Correctional Facilities.","authors":"Kuai, David; Rivera Blanco, Liz Eneida; Krotulski, Alex; Walton, Sara; Denn, Max; Kelly, Byron; Kiernan, Emily; Steck, Alaina; Carpenter, Joseph","year":2024,"journal":"JAMA network open, 7(12), e2451951","doi":"10.1001/jamanetworkopen.2024.51951","pmid":"39714837","tags":["synthetic-cannabinoids"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"All 18 patients had suspected strip exposure. Central nervous system depression occurred in 94%, bradycardia in 61%, agitation in 33%, and seizures in 22%. Two patients required intubation and one died from hypoxic ischemic encephalopathy. Chemical analysis confirmed synthetic cannabinoid receptor agonists (SCRAs) and benzimidazole opioids.","whyItMatters":"Drug-soaked paper strips represent an emerging and particularly dangerous mode of drug use in correctional settings, with severe clinical presentations that can mimic other conditions.","specificNumbers":"18 patients (all male, median age 27.5); 94% CNS depression; 61% bradycardia; 33% agitation; 22% seizures; 2 intubated; 1 death; strips contained SCRAs and benzimidazole opioids; no household cleaners or pesticides detected","methodology":"Retrospective case series of 18 incarcerated individuals from a county jail in Atlanta who presented to an emergency department with suspected strip exposure (August 2022 to November 2023). Strip and serum samples were analyzed using gas chromatography and liquid chromatography mass spectrometry.","limitations":"Small case series from one facility; cannot determine exact doses absorbed from strips; clinical presentations may be influenced by poly-drug use; retrospective design; may not capture all strip exposures that did not result in ED visits"},{"rthcId":"RTHC-05443","title":"Use and perceptions of Cannabidiol among individuals in treatment for opioid use disorder.","authors":"Kudrich, Christopher; Chen, Rebecca; Meng, Yuan; Bachi, Keren; Hurd, Yasmin L","year":2024,"journal":"Harm reduction journal, 21(1), 135","doi":"10.1186/s12954-024-01051-5","pmid":"39020418","tags":["cbd","addiction","withdrawal","pain","anxiety","depression","sleep","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"CBD has become wildly popular, with claims ranging from anxiety relief to pain management. But how are people with serious opioid addictions actually using it? This survey from Mount Sinai's Addiction Institute provides a window into a population where the stakes are high and the potential for both benefit and harm is significant.\n\nAmong 550 people receiving treatment for opioid use disorder (OUD), 129 (23%) reported using CBD. Their reasons paint a picture of broad symptom self-management: anxiety (62.8%), pain (50.4%), sleep (48.8%), depression (48.1%), and recreation (24.8%). But two findings stand out for their clinical significance.\n\nFirst, 42% of CBD users reported using it specifically to ease opioid withdrawal symptoms. Withdrawal is the most immediate barrier to opioid recovery — it's physically miserable and drives relapse. If CBD genuinely helps with withdrawal, it could be a valuable adjunct to medications like buprenorphine and methadone. Early preclinical evidence supports this possibility, but clinical trials are limited.\n\nSecond, 17% reported using CBD to control their addiction itself. This is a more ambitious claim, and the evidence is thinner — but the fact that patients in active addiction treatment are independently turning to CBD for this purpose suggests it deserves rigorous investigation.\n\nThe study also compared perceptions between CBD users and non-users, finding that users had more positive views of CBD's potential — not surprising, but it confirms that personal experience drives perception in this population, not clinical evidence.","whyItMatters":"The opioid crisis has killed hundreds of thousands of Americans, and treatment options, while effective, are limited. If CBD can reduce withdrawal severity and support recovery — even modestly — it could save lives. This survey establishes that patients are already using CBD for these purposes, independently and without clinical guidance, making clinical trials to determine efficacy and safety an urgent priority.","specificNumbers":"550 survey completers. 129 (23%) reported CBD use. Reasons: anxiety 62.8%, pain 50.4%, sleep 48.8%, depression 48.1%, recreation 24.8%. 42% used CBD for opioid withdrawal. 17% used CBD to control addiction. Survey period: July 2021 – August 2023 at Mount Sinai Addiction Institute.","methodology":"Cross-sectional survey of individuals receiving treatment for opioid use disorder at the Addiction Institute of Mount Sinai, New York City (July 2021 – August 2023). 587 respondents, 550 completed surveys. Assessed demographics, opioid use, CBD use patterns, and perceptions. Ordinal logistic regression compared perceptions between CBD users and non-users, adjusting for age and race.","limitations":"Cross-sectional survey — self-reported CBD use and perceived benefits don't prove CBD actually helped. Patients in addiction treatment may overreport positive experiences with non-opioid substances. No verification of CBD product content or dosing. Selection bias — people willing to complete a survey may differ from those who declined. Single treatment center in New York City. No objective outcomes (urine drug screens, retention in treatment) measured."},{"rthcId":"RTHC-05444","title":"Serum Markers of Bone Turnover Following Controlled Administration of Two Medical Cannabis Products in Healthy Adults.","authors":"Kulpa, Justyna; Eglit, Graham; Hill, Melanie L; MacNair, Laura; Yardley, Helena; Ware, Mark A; Bonn-Miller, Marcel O; Peters, Erica N","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 300-309","doi":"10.1089/can.2022.0181","pmid":"36346322","tags":["cbd","medical-cannabis"],"studyType":"randomized controlled trial","evidenceStrength":"preliminary","keyFinding":"After 7 days of treatment, the bone resorption marker CTx was significantly lower in the THC-dominant product group (Spectrum Red) versus placebo (b = -164.28, p = 0.04) and marginally lower in the CBD-dominant group (Spectrum Yellow, p = 0.06). No significant differences were found for bone formation markers (P1NP, ALP).","whyItMatters":"These are the first interventional human data on cannabinoid effects on bone turnover. The reduction in bone resorption without affecting bone formation is a pattern consistent with bone-protective properties.","specificNumbers":"83 participants (38 men, 45 women); 7 days of treatment; CTx (bone resorption) significantly reduced by Spectrum Red (p = 0.04); marginally reduced by Spectrum Yellow (p = 0.06); no changes in P1NP or ALP (bone formation markers); all bone markers higher in men at baseline","methodology":"Secondary analysis of two Phase 1 double-blind, placebo-controlled trials. 83 healthy participants (38 men, 45 women) were randomized to receive 5-20 mg THC daily (with varying CBD levels) or placebo for 7 days. Bone markers were assessed at baseline, day 8, and after 5-day washout.","limitations":"Very short treatment duration (7 days); healthy participants not bone-disease patients; small sample; secondary analysis not primary endpoint; changes not considered clinically significant; cannot determine which cannabinoid (THC or CBD) drove effects"},{"rthcId":"RTHC-05445","title":"Off-road vehicle crashes: dangers of alcohol and drug impairment.","authors":"Kureshi, Nelofar; Clarke, David B; Audas, Lorelei; Magee, Kirk; Nassar, Bassam; Chan, Herbert; Yuan, Yue; Erdelyi, Shannon; Brubacher, Jeffrey R","year":2024,"journal":"CJEM, 26(5), 321-326","doi":"10.1007/s43678-024-00656-w","pmid":"38416393","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05446","title":"THC and sperm: Impact on fertilization capability, pre-implantation in vitro development and epigenetic modifications.","authors":"Kuzma-Hunt, Alexander G; Sabry, Reem; Davis, Ola S; Truong, Vivien B; Khokhar, Jibran Y; Favetta, Laura A","year":2024,"journal":"PloS one, 19(3), e0298697","doi":"10.1371/journal.pone.0298697","pmid":"38536780","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05447","title":"A study on the possible neurotoxic effects of CUMYL-4CN-BINACA in Sprague Dawley rats.","authors":"Lafzi, Ayşe; Demirci, Tuba; Yüce, Neslihan; Annaç, Ebru; Çiçek, Mustafa; Şişman, Turgay","year":2024,"journal":"Legal medicine (Tokyo, Japan), 67, 102389","doi":"10.1016/j.legalmed.2023.102389","pmid":"38185093","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05448","title":"Acute and subacute toxic effects of CUMYL-4CN-BINACA on male albino rats.","authors":"Lafzi, Ayşe; Yeşilyurt, Fatma; Demirci, Tuba; Hacımüftüoğlu, Ahmet; Şişman, Turgay","year":2024,"journal":"Forensic toxicology, 42(2), 125-141","doi":"10.1007/s11419-023-00676-8","pmid":"38102417","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05449","title":"Prevalence and correlates of severe problematic cannabis use: analysis of a population-based survey in Jamaica.","authors":"Lalwani, Kunal; De La Haye, Winston; Kerr, Kevon; Abel, Wendel; Sewell, Clayton","year":2024,"journal":"Frontiers in psychiatry, 15, 1465963","doi":"10.3389/fpsyt.2024.1465963","pmid":"39600793","tags":["addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 786 past-year cannabis users, 53.3% scored 7 or higher on the Cannabis Abuse Screening Test (severe problematic use), smoking an average of 62 joints per month. Males were twice as likely to have severe problematic use. Starting cannabis use before age 26 increased the odds 3-7 times compared to later initiation, with the 12-17 and 18-25 onset groups showing the highest risk (7x).","whyItMatters":"Jamaica has deep cultural ties to cannabis, making understanding problematic use patterns critical for developing culturally appropriate interventions in a country where cannabis use is highly prevalent.","specificNumbers":"786 participants; 53.3% scored severe on CAST; average 62 joints/month; males 2x more likely; early onset (age 11 and under): 5x risk; age 12-17 onset: 7x risk; age 18-25 onset: 7x risk; easy access, perceived treatment need, and awareness of drug agency also associated","methodology":"Secondary data analysis of the Jamaica National Drug Prevalence Survey. 786 past-year cannabis users completed the Cannabis Abuse Screening Test (CAST), validated against DSM criteria. Logistic regression identified sociodemographic and psychosocial correlates of severe problematic use.","limitations":"Cross-sectional design cannot determine causality; CAST screening tool may overestimate clinical diagnoses; national survey may underrepresent marginalized populations; cannot assess cannabis type, potency, or consumption method; self-reported data in a culture where cannabis is normalized"},{"rthcId":"RTHC-05450","title":"THC improves behavioural schizophrenia-like deficits that CBD fails to overcome: a comprehensive multilevel approach using the Poly I:C maternal immune activation.","authors":"Lamanna-Rama, Nicolás; Romero-Miguel, Diego; Casquero-Veiga, Marta; MacDowell, Karina S; Santa-Marta, Cristina; Torres-Sánchez, Sonia; Berrocoso, Esther; Leza, Juan C; Desco, Manuel; Soto-Montenegro, María Luisa","year":2024,"journal":"Psychiatry research, 331, 115643","doi":"10.1016/j.psychres.2023.115643","pmid":"38064909","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05451","title":"The impact of blunt use on smoking abstinence among Black adults: Secondary analysis from randomized controlled smoking cessation clinical trial.","authors":"Lambart, Leah; Nollen, Nicole L; Mayo, Matthew S; Funk, Olivia; Leavens, Eleanor; Cruvinel, Erica; Brown, Alexandra; Ahluwalia, Jasjit S; Sanderson Cox, Lisa","year":2024,"journal":"Addictive behaviors, 148, 107877","doi":"10.1016/j.addbeh.2023.107877","pmid":"37804748","tags":["addiction","quitting"],"studyType":"randomized controlled trial","evidenceStrength":"moderate","keyFinding":"Of 500 participants, 75 (15%) reported blunt use during the study. Blunt users had similar odds of quitting at Week 12 (OR 0.68, 95% CI 0.31-1.5) and Week 26 (OR 0.84, 95% CI 0.38-1.87) as non-blunt users. There was no interaction between blunt use and varenicline treatment on cessation outcomes.","whyItMatters":"Blunt use has been a concern in cessation research because the nicotine in tobacco wraps could undermine quit attempts. This finding suggests blunt use may not be the barrier to quitting that clinicians feared.","specificNumbers":"500 participants (300 varenicline, 200 placebo); 75 (15%) used blunts; mean age 45.6; 42% female; quit odds at Week 12: OR 0.68 (95% CI 0.31-1.5); Week 26: OR 0.84 (95% CI 0.38-1.87); no treatment interaction","methodology":"Secondary analysis of a double-blind, placebo-controlled RCT comparing varenicline (n = 300) to placebo (n = 200) for smoking cessation among Black adults. Blunt use was assessed at baseline and weeks 4, 8, 12, 16, and 26. Abstinence was verified by salivary cotinine.","limitations":"Secondary analysis with relatively small blunt user subgroup (75); may be underpowered to detect meaningful differences; blunt use was not the primary study focus; cannot assess impact of blunt frequency or quantity; results specific to Black adults"},{"rthcId":"RTHC-05452","title":"Investigation on the presence of mycotoxins in seed hemp varieties.","authors":"Lanzanova, Chiara; Giorni, Paola; Bulla, Giulia; Locatelli, Sabrina; Montanari, Massimo; Alberti, Ilaria; Leni, Giulia; Abate, Alessio; Bertuzzi, Terenzio","year":2024,"journal":"Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment, 41(4), 400-409","doi":"10.1080/19440049.2024.2311850","pmid":"38408274","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05453","title":"Latent Class Groups of Concurrent Substance Use Among Adolescents in an Urban Community: Correlates With Mental Health, Access to Drugs and Alcohol, and Risk Perception.","authors":"Lardier, David T; Davis, Alexandra N; Verdezoto, Carolina S; Cruz, Lynda; Magliulo, Sabrina; Herrera, Andriana; Garcia-Reid, Pauline; Reid, Robert J","year":2024,"journal":"Substance use & addiction journal, 45(1), 124-135","doi":"10.1177/29767342231207192","pmid":"38258859","tags":["youth","addiction","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Five latent classes were identified: predominant alcohol use (11.9%), concurrent drug and alcohol use with methamphetamine and marijuana (4.2%), concurrent drug and alcohol use without marijuana (11.4%), high concurrent drug and alcohol use (11.4%), and concurrent drug use without alcohol (61.5%). Mental health, access to drugs, and risk perception significantly differentiated the groups.","whyItMatters":"Understanding distinct substance use profiles among urban adolescents of color allows for more targeted, culturally relevant prevention programs rather than one-size-fits-all approaches.","specificNumbers":"1,789 adolescents; 56.9% female; 70.9% Hispanic/Latino; mean age 16; 5 classes: 61.5% drug use without alcohol, 11.9% primarily alcohol, 11.4% high concurrent use, 11.4% drug/alcohol without marijuana, 4.2% drug/alcohol with meth and marijuana","methodology":"Latent class analysis and multinomial logistic regression of data from 1,789 adolescents (56.9% female, 70.9% Hispanic/Latino, mean age 16) in an underserved urban community. Assessed alcohol, marijuana, methamphetamine, synthetic marijuana, and other drug use patterns.","limitations":"Cross-sectional design; single underserved urban community limits generalizability; self-reported substance use; cannot determine causality between mental health and substance use patterns; 70.9% Hispanic/Latino may not represent other communities"},{"rthcId":"RTHC-05454","title":"Prevalence and factors associated with tramadol use among university students in Ghana: a cross-sectional survey.","authors":"Lasong, Joseph; Salifu, Yula; Kakungu, Jonas Assani Wa Mwenda","year":2024,"journal":"BMC psychiatry, 24(1), 853","doi":"10.1186/s12888-024-06230-z","pmid":"39604896","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05455","title":"Novel Peripherally Selective Cannabinoid Receptor 1 Neutral Antagonist Improves Metabolic Dysfunction-Associated Steatotic Liver Disease in Mice.","authors":"Laudermilk, Lucas T; Schlosburg, Joel E; Gay, Elaine A; Decker, Ann M; Williams, Aaron; Runton, Rubica; Vasukuttan, Vineetha; Kotiya, Archana; Amato, George S; Maitra, Rangan","year":2024,"journal":"ACS pharmacology & translational science, 7(9), 2856-2868","doi":"10.1021/acsptsci.4c00356","pmid":"39296275","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05456","title":"Cannabis use disorder: from neurobiology to treatment.","authors":"Le Foll, Bernard; Tang, Victor M; Rueda, Sergio; Trick, Leanne V; Boileau, Isabelle","year":2024,"journal":"The Journal of clinical investigation, 134(20)","doi":"10.1172/JCI172887","pmid":"39403927","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05457","title":"Effects of in utero exposure to Δ-9-tetrahydrocannabinol on cardiac extracellular matrix expression and vascular transcriptome in rhesus macaques.","authors":"Le, Hillary H; Shorey-Kendrick, Lyndsey E; Hinds, Monica T; McCarty, Owen J T; Lo, Jamie O; Anderson, Deirdre E J","year":2024,"journal":"American journal of physiology. Heart and circulatory physiology, 327(3), H701-H714","doi":"10.1152/ajpheart.00181.2024","pmid":"39028280","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05458","title":"Narrative Review of the Pharmacodynamics, Pharmacokinetics, and Toxicities of Illicit Synthetic Cannabinoid Receptor Agonists.","authors":"Lea Houston, Matilda; Morgan, Jody; Kelso, Celine","year":2024,"journal":"Mini reviews in medicinal chemistry, 24(1), 92-109","doi":"10.2174/1389557523666230515163107","pmid":"37190813","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05459","title":"A helping HAND: therapeutic potential of MAGL inhibition against HIV-1-associated neuroinflammation.","authors":"League, Alexis F; Yadav-Samudrala, Barkha J; Kolagani, Ramya; Cline, Calista A; Jacobs, Ian R; Manke, Jonathan; Niphakis, Micah J; Cravatt, Benjamin F; Lichtman, Aron H; Ignatowska-Jankowska, Bogna M; Fitting, Sylvia","year":2024,"journal":"Frontiers in immunology, 15, 1374301","doi":"10.3389/fimmu.2024.1374301","pmid":"38835765","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05460","title":"The many forms of cannabis use: Prevalence and correlates of routes of administration among nationally representative samples of U.S. adult and adolescent cannabis users.","authors":"Leal, Wanda E; Moscrop-Blake, Kelsi","year":2024,"journal":"Addictive behaviors, 159, 108146","doi":"10.1016/j.addbeh.2024.108146","pmid":"39222559","tags":["addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Among cannabis users surveyed in the 2022 NSDUH, the majority used more than one cannabis product type. Eight routes of administration were examined: smoking, vaping, eating/drinking, dabbing, drops/lozenges, topical, pills, and other. Prevalence patterns were fairly consistent between adults and adolescents, and individual-level factors associated with use varied by route of administration.","whyItMatters":"Different routes of cannabis administration carry different risks. Understanding who uses which products can help target harm reduction messaging and clinical screening to the right populations.","specificNumbers":"Eight product types examined; majority of both adult and adolescent users consumed multiple product types; prevalence patterns consistent across age groups; individual-level correlates varied by route of administration","methodology":"Analysis of 2022 National Survey on Drug Use and Health (NSDUH) data examining prevalence and correlates of eight cannabis product types and a cannabis variety scale among nationally representative samples of adult and adolescent cannabis users.","limitations":"Cross-sectional survey data; self-reported use without verification; cannot determine frequency or quantity by product type; 2022 data from a single year; does not capture product potency or specific cannabinoid content"},{"rthcId":"RTHC-05461","title":"Drug dependence epidemiology in palliative care medicinal cannabis trials.","authors":"Lee, Chee Yen; Good, Phillip; Huggett, Georgie; Greer, Ristan; Hardy, Janet","year":2024,"journal":"BMJ supportive & palliative care, 14(3), 295-298","doi":"10.1136/spcare-2023-004583","pmid":"37748856","tags":["medical-cannabis","cancer"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Of 182 palliative care patients screened, 92% reported lifetime alcohol use and 73% lifetime tobacco use. No participant reached threshold criteria for high risk of drug dependence on the ASSIST screening tool, with the majority being low risk. There was no correlation between ASSIST scores, symptom distress (ESAS), or opioid use.","whyItMatters":"Concerns about drug dependence sometimes discourage prescribing medicinal cannabis in palliative care. These data suggest dependence risk may be very low in this population.","specificNumbers":"182 participants; 92% lifetime alcohol use; 73% lifetime tobacco use; 0% high risk for drug dependence; majority low risk; no correlation between ASSIST, ESAS, and morphine equivalent dose","methodology":"Analysis of screening data from palliative care patients with advanced cancer who expressed interest in a medicinal cannabis trial. All completed the ASSIST drug dependence screening, Edmonton Symptom Assessment Scale (ESAS), and concomitant medication records.","limitations":"Self-selected patients interested in a cannabis trial; questionnaire bias acknowledged by authors; ASSIST may not be sensitive to dependence patterns in palliative populations; cross-sectional screening data; small sample"},{"rthcId":"RTHC-05462","title":"Randomized controlled trial of zolpidem as a pharmacotherapy for cannabis use disorder.","authors":"Lee, Dustin C; Schlienz, Nicolas J; Herrmann, Evan S; Martin, Erin L; Leoutsakos, Jeannie; Budney, Alan J; Smith, Michael T; Tompkins, D Andrew; Hampson, Aidan J; Vandrey, Ryan","year":2024,"journal":"Journal of substance use and addiction treatment, 156, 209180","doi":"10.1016/j.josat.2023.209180","pmid":"37802317","tags":["addiction","sleep","quitting"],"studyType":"randomized controlled trial","evidenceStrength":"moderate","keyFinding":"Placebo participants but not zolpidem-XR participants showed significant sleep disturbance during week 1 of cannabis cessation. Abstinence rates were numerically higher with zolpidem-XR (27% vs 15%) but not statistically significant. Sleep disturbance emerged in the medication group after treatment stopped. Treatment retention was poor (about 50% dropout in both groups).","whyItMatters":"Sleep disturbance is one of the most common reasons people relapse when trying to quit cannabis. This trial provides important evidence that pharmacological sleep support can help during early withdrawal.","specificNumbers":"127 participants; 27% abstinent on zolpidem-XR vs 15% on placebo (not significant); ~50% dropout in both groups; sleep disturbance prevented during medication but emerged after stopping; objective polysomnography used","methodology":"Twelve-week randomized, double-blind, placebo-controlled trial of 127 adults with cannabis use disorder. All received computerized behavioral therapy and abstinence-based contingency management. Zolpidem-XR or placebo was provided during treatment. In-home ambulatory polysomnography measured sleep objectively.","limitations":"Not powered to detect significant differences in abstinence; high dropout rate reduces interpretability; medication adherence was challenging; sleep medication stopped at end of treatment causing rebound; unclear optimal treatment duration"},{"rthcId":"RTHC-05463","title":"Cannabidiol Exposure During Gestation Leads to Adverse Cardiac Outcomes Early in Postnatal Life in Male Rat Offspring.","authors":"Lee, Kendrick; Vanin, Sebastian; Nashed, Mina; Sarikahya, Mohammed Halit; Laviolette, Steven R; Natale, David R C; Hardy, Daniel B","year":2024,"journal":"Cannabis and cannabinoid research, 9(3), 781-796","doi":"10.1089/can.2023.0213","pmid":"38358335","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05464","title":"The effects of standardized cannabis products in healthy volunteers and patients: a systematic literature review.","authors":"Leen, Nadia A; Kowal, Mikael A; Batalla, Albert; Bossong, Matthijs G","year":2024,"journal":"Frontiers in pharmacology, 15, 1411631","doi":"10.3389/fphar.2024.1411631","pmid":"39484170","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05465","title":"Mind it! A mindfulness-based group psychotherapy for substance use disorders in adolescent inpatients.","authors":"Legenbauer, Tanja; Baldus, Christiane; Jörke, Carina; Kaffke, Lara; Pepic, Amra; Daubmann, Anne; Zapf, Antonia; Holtmann, Martin; Arnaud, Nicolas; Thomasius, Rainer","year":2024,"journal":"European child & adolescent psychiatry, 33(12), 4205-4217","doi":"10.1007/s00787-024-02465-z","pmid":"38748240","tags":["youth","addiction","quitting"],"studyType":"randomized controlled trial","evidenceStrength":"moderate","keyFinding":"Both groups showed significant reductions in cannabis use days at 6-month follow-up (effect sizes d = -0.72 and -0.75). While mindfulness therapy showed minor initial benefits for craving and severity, standard treatment alone showed greater reduction in severity (d = 0.78) and reward craving (d = 0.28) at 6 months. Mindfulness therapy did improve self-regulation skills. Systematic dropout was observed in the mindfulness group.","whyItMatters":"Despite high relapse rates in adolescent cannabis treatment, this study found standard inpatient care is already effective, and adding mindfulness therapy did not improve cannabis outcomes despite being feasible and well-received.","specificNumbers":"84 adolescent inpatients; both groups reduced cannabis use days at 6 months (d = -0.72 and -0.75); TAU better at reducing SUD severity (d = 0.78) and reward craving (d = 0.28); Mind it! better for mindfulness/self-regulation (d = 0.27); systematic dropout in Mind it! group","methodology":"Randomized controlled trial of 84 adolescent inpatients (15-19 years) with cannabis use disorder in Germany. Participants received standard multi-component treatment (TAU) with or without an add-on mindfulness-based group therapy (\"Mind it!\"). Assessments at pre-, post-, and 6-month follow-up.","limitations":"Small sample size (84); systematic dropout in mindfulness group; single-site German inpatient setting; 6-month follow-up may be too short; cannot determine which TAU components drove the effect; cultural context may not generalize"},{"rthcId":"RTHC-05466","title":"Incidence of postpartum depression in low-income cannabis users with and without a history of depression.","authors":"Lendel, Anastasia; Richards, Ria; Benedict, Jason; Lynch, Courtney; Schaffir, Jonathan","year":2024,"journal":"Archives of women's mental health, 27(1), 145-151","doi":"10.1007/s00737-023-01389-y","pmid":"37910199","tags":["pregnancy","depression"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 799 patients, 15.9% used cannabis during pregnancy. Prenatal cannabis users had 60% higher risk of screening positive for PPD (aRR 1.60, 95% CI 1.05-2.45). Among those with prior depression history, cannabis users had 62% higher risk (aRR 1.62, 95% CI 1.02-2.58). Results were adjusted for age, race, insurance, marital status, and smoking.","whyItMatters":"Some pregnant people use cannabis to manage depression or anxiety symptoms. This study suggests that rather than helping, prenatal cannabis use may increase the risk of postpartum depression.","specificNumbers":"799 subjects; 15.9% prenatal cannabis use; PPD risk: aRR 1.60 (95% CI 1.05-2.45); with depression history: aRR 1.62 (95% CI 1.02-2.58); adjusted for age, race, insurance, marital status, smoking","methodology":"Retrospective cohort study of 799 patients receiving prenatal care at a single institution (2017-2019). Cannabis use was extracted from medical records. Edinburgh Postnatal Depression Scale (EPDS) scores were used to identify PPD. Modified Poisson regression estimated relative risks.","limitations":"Retrospective design; single institution; cannot determine if cannabis caused PPD or if shared risk factors drive both; low-income population may not generalize; cannabis use ascertained from medical records which may underreport; no data on cannabis type, dose, or timing"},{"rthcId":"RTHC-05467","title":"Frequency and patterns of substance-induced psychosis in persons with concurrent mental health and substance use disorders during the COVID-19 pandemic: A Norwegian register-based cohort study.","authors":"Leonhardt, Marja; Bramness, Jørgen G; Rognli, Eline Borger; Lien, Lars","year":2024,"journal":"European psychiatry : the journal of the Association of European Psychiatrists, 67(1), e82","doi":"10.1192/j.eurpsy.2024.1797","pmid":"39676544","tags":["psychosis"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Despite fewer individuals being diagnosed with substance-induced psychosis (SIP) during COVID, total SIP episodes increased. Cannabis-induced psychosis declined while amphetamine- and multi-substance-induced psychosis rose. Patients with recurrent episodes were 50% more likely in 2020 (RR 1.50) and 30% more likely in 2021 (RR 1.30) to have psychosis induced by different substances than in 2019.","whyItMatters":"The shifting patterns of substance-induced psychosis during the pandemic likely reflect changes in drug availability and pricing, demonstrating how supply-side disruptions affect clinical presentations.","specificNumbers":"Norwegian Patient Register 2019-2021; fewer SIP patients but more episodes during COVID; cannabis-induced psychosis declined; amphetamine/multi-substance SIP increased; recurrent SIP by different substances: RR 1.50 (2020) and 1.30 (2021) vs 2019","methodology":"Retrospective cohort study analyzing data from all individuals with comorbid mental health and substance use disorders registered in the Norwegian Patient Register (2019-2021). Poisson regression and Sankey diagrams examined SIP occurrence, risk, and substance trajectories.","limitations":"Register-based data depends on clinical coding accuracy; cannot determine individual substance use patterns directly; pandemic effects on healthcare access may have reduced SIP diagnoses rather than actual cases; Norway-specific drug markets may not generalize"},{"rthcId":"RTHC-05468","title":"Using Task-fMRI to Explore the Relationship Between Lifetime Cannabis Use and Cognitive Control in Individuals With First-Episode Schizophrenia.","authors":"Lesh, Tyler A; Rhilinger, Joshua; Brower, Rylee; Mawla, Alex M; Ragland, J Daniel; Niendam, Tara A; Carter, Cameron S","year":2024,"journal":"Schizophrenia bulletin open, 5(1), sgae016","doi":"10.1093/schizbullopen/sgae016","pmid":"39144106","tags":["psychosis","cognition","neuroscience"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"First-episode schizophrenia patients with cannabis history (FES+CAN, n=48) showed higher cognitive control performance and higher dorsolateral prefrontal cortex (DLPFC) activation during task-based fMRI compared to patients without cannabis history (FES-CAN, n=28). FES+CAN and healthy controls (n=59) had similar DLPFC activation levels. However, younger cannabis initiation age was associated with lower IQ and functioning.","whyItMatters":"The paradox of better cognitive function in cannabis-using schizophrenia patients has been replicated across studies. This fMRI evidence adds a neural basis, suggesting these patients may have better-preserved prefrontal function.","specificNumbers":"48 FES+CAN; 28 FES-CAN; 59 controls; FES+CAN showed higher cognitive control (d-context) than FES-CAN (p < .05); FES+CAN and CON had similar DLPFC activation; earlier cannabis onset linked to lower IQ; more frequent use linked to higher reality distortion","methodology":"Cross-sectional fMRI study of 48 first-episode schizophrenia patients with cannabis history, 28 without, and 59 healthy controls performing the AX-Continuous Performance Task measuring cognitive control.","limitations":"Cross-sectional design cannot determine causality or direction of association; selection bias (better-functioning patients may be more likely to access and use cannabis); cannot assess premorbid cognitive function; cannabis history based on self-report; relatively small groups"},{"rthcId":"RTHC-05469","title":"Participation in Australian drug treatment programs for individuals engaging in high-risk substance use: Data from a nationally representative sample.","authors":"Leung, Janni; Yimer, Tesfa Mekonen; Chiu, Vivian; Hall, Wayne D; Connor, Jason P; Chan, Gary Chung Kai","year":2024,"journal":"Drug and alcohol review, 43(3), 688-693","doi":"10.1111/dar.13792","pmid":"38087847","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05470","title":"The endocannabinoid anandamide activates pro-resolving pathways in human primary macrophages by engaging both CB2 and GPR18 receptors.","authors":"Leuti, Alessandro; Fava, Marina; Forte, Giulia; Pellegrini, Niccolò; Oddi, Sergio; Scipioni, Lucia; Gomez, Esteban A; Dalli, Jesmond; Maccarrone, Mauro","year":2024,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38(10), e23675","doi":"10.1096/fj.202301325R","pmid":"38801406","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05471","title":"Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial.","authors":"Levin, Frances R; Mariani, John J; Pavlicova, Martina; Choi, C Jean; Basaraba, Cale; Mahony, Amy L; Brooks, Daniel J; Brezing, Christina A; Naqvi, Nasir","year":2024,"journal":"Journal of attention disorders, 28(11), 1467-1481","doi":"10.1177/10870547241264675","pmid":"39051597","tags":["addiction"],"studyType":"randomized controlled trial","evidenceStrength":"preliminary","keyFinding":"MAS-ER (80 mg) was well-tolerated. While ADHD symptom reduction was high in both groups (83.3% vs 71.4%, not significant) and abstinence rates were not significantly different (15.4% vs 0%, p = .27), the medication group showed a significant decrease in weekly cannabis use days over time compared to placebo (p < .0001).","whyItMatters":"ADHD and cannabis use disorder frequently co-occur but have no established pharmacological treatment. This pilot suggests treating the ADHD component may help reduce cannabis use even if it does not achieve full abstinence.","specificNumbers":"28 participants; MAS-ER 80 mg vs placebo; ADHD response: 83.3% vs 71.4% (not significant); abstinence: 15.4% vs 0% (p = .27); weekly cannabis use days significantly reduced over time with MAS-ER (p < .0001); well-tolerated","methodology":"Twelve-week randomized, double-blind pilot feasibility trial of 28 adults with comorbid ADHD and cannabis use disorder. MAS-ER (up to 80 mg) vs placebo. All received computerized behavioral therapy and abstinence-based contingency management. Cannabis use confirmed by quantitative urine testing.","limitations":"Very small sample (28); pilot feasibility study not powered for efficacy; high placebo response for ADHD symptoms; treatment retention not detailed; cannot generalize to broader ADHD-CUD population"},{"rthcId":"RTHC-05472","title":"Comparing the Performance of World Mental Health Composite International Diagnostic Interview Substance Abuse Module in Adolescents to Diagnoses Made by Pediatric Addiction Medicine Specialists.","authors":"Levy, Sharon; Minegishi, Machiko; Brogna, Melissa; Subramaniam, Geetha; McCormack, Jennifer; Weiss, Roger; Weitzman, Elissa R","year":2024,"journal":"Journal of addiction medicine, 18(2), 205-208","doi":"10.1097/ADM.0000000000001271","pmid":"38289239","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05473","title":"Phytocannabinoids for the Treatment of Neuropathic Pain: A Scoping Review of Randomised Controlled Trials Published Between 2012 and 2023.","authors":"Lewis, Marc; Baroutian, Saeid; Hanning, Sara M","year":2024,"journal":"Current pain and headache reports, 28(3), 109-118","doi":"10.1007/s11916-023-01196-1","pmid":"38095748","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05474","title":"Media Framing of Causes, Risks, and Policy Solutions for Cannabis-Impaired Driving: Does Medical vs. Non-Medical Cannabis Context Matter?","authors":"Lewis, Nehama; Eliash-Fizik, Hadar; Har-Even, Ayelet; Sznitman, Sharon R","year":2024,"journal":"Health communication, 39(4), 828-837","doi":"10.1080/10410236.2023.2187956","pmid":"36914573","tags":["driving"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"News coverage of non-medical cannabis DUI was more likely to emphasize individual causes (vs social/political), describe drivers negatively, refer to increased accident risk, and call for enforcement. Medical cannabis DUI coverage used more neutral/positive descriptions, presented risk as inconclusive, and favored education over enforcement.","whyItMatters":"How media frames cannabis-impaired driving can shape public opinion and policy. The stark difference between medical and recreational framing suggests the same behavior is judged very differently based on the user's perceived legitimacy.","specificNumbers":"299 news articles; 11 newspapers; 2008-2020; non-medical coverage: more individual blame, negative driver descriptions, increased risk framing, enforcement solutions; medical coverage: more social causes, neutral descriptions, inconclusive risk, education solutions","methodology":"Quantitative content analysis of 299 news articles related to driving accidents and cannabis from eleven high-circulation Israeli newspapers (2008-2020), applying attribution theory to compare medical versus non-medical cannabis driving coverage.","limitations":"Israeli media context may not generalize to other countries; content analysis captures framing but not audience interpretation; cannot determine if media framing reflects or shapes public opinion; 2008-2020 period predates recent Israeli cannabis reform"},{"rthcId":"RTHC-05475","title":"Contingency Management for Cannabis Use Disorder Treatment.","authors":"Lima, Marcelo G; Tardelli, Vitor S; Fidalgo, Thiago M","year":2024,"journal":"European addiction research, 30(5), 321-338","doi":"10.1159/000540193","pmid":"39374591","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05476","title":"Pharmacokinetics behavior of four cannabidiol preparations following single oral administration in dogs.","authors":"Limsuwan, Sasithorn; Phonsatta, Natthaporn; Panya, Atikorn; Asasutjarit, Rathapon; Tansakul, Natthasit","year":2024,"journal":"Frontiers in veterinary science, 11, 1389810","doi":"10.3389/fvets.2024.1389810","pmid":"38725584","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05477","title":"Cannabidiol prescribing in the United States: An analysis of real-world data.","authors":"Lin, Binx Yezhe; Lessard, Chloe; Li, Yifan; Gong, Lisa; Ling, Ruth; Jyotsana, Pallawi; Steinle, Jacob; Borodovsky, Jacob T; Nascimento, Fábio A; Xu, Kevin Y","year":2024,"journal":"Drug and alcohol dependence reports, 13, 100303","doi":"10.1016/j.dadr.2024.100303","pmid":"39679130","tags":["cbd","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Of 4,214 Epidiolex recipients, 40% lacked FDA-approved diagnostic indications (Lennox-Gastaut, Dravet, or tuberous sclerosis) in their records. Off-label use was primarily for other epilepsy syndromes (53.8%), sleep disorders (25.7%), anxiety (25.9%), mood disorders (18.6%), and autism (10.8%). Co-prescribing of interacting benzodiazepines was prevalent: clobazam 47.2%, diazepam 47.4%, clonazepam 40.7%.","whyItMatters":"Widespread off-label CBD prescribing and concurrent use of interacting medications create potential safety concerns that may not be well-studied or monitored.","specificNumbers":"4,214 Epidiolex recipients in 2022; 40% off-label; co-prescribed clobazam 47.2%, diazepam 47.4%, clonazepam 40.7%; off-label uses: epilepsy 53.8%, sleep 25.7%, anxiety 25.9%, mood 18.6%, autism 10.8%","methodology":"Analysis of the TriNetX database of de-identified electronic health records from over 110 million US patients, examining 4,214 individuals prescribed Epidiolex in 2022 for diagnostic indications and co-occurring prescriptions.","limitations":"EHR data may have incomplete diagnostic coding; off-label use may be clinically appropriate even if evidence is limited; cannot determine if interactions resulted in adverse events; co-prescribing does not mean simultaneous use; 2022 single-year snapshot"},{"rthcId":"RTHC-05478","title":"Alcohol and cannabis use in daily lives of college-attending young adults: Does co-use correspond to greater reported pleasure?","authors":"Linden-Carmichael, Ashley N; Stull, Samuel W; Lanza, Stephanie T","year":2024,"journal":"Addictive behaviors, 159, 108130","doi":"10.1016/j.addbeh.2024.108130","pmid":"39178638","tags":["addiction","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"On co-use days, odds of substance-related pleasure were higher than on single-substance days. However, level of pleasure was higher on co-use days only compared to cannabis-only days, not alcohol-only days. This suggests the perceived pleasure of co-use is largely driven by alcohol.","whyItMatters":"Understanding why people co-use alcohol and cannabis together is important for prevention. If pleasure drives co-use but is mainly attributable to alcohol, interventions targeting alcohol-related pleasure expectations may reduce co-use.","specificNumbers":"237 college students; 21-day diary; 2,086 daily surveys with substance use; higher odds of any pleasure on co-use days; level of pleasure higher on co-use vs cannabis-only but not vs alcohol-only days","methodology":"Twenty-one-day daily diary study of 237 college students (65% female, ages 18-24) who reported at least one alcohol-cannabis co-use occasion. Daily surveys assessed substance use and pleasure experiences, yielding 2,086 use-day surveys analyzed with multilevel models.","limitations":"Self-selected co-using students; subjective pleasure reports; 21-day window may not capture variation over longer periods; cannot determine if pleasure causes continued co-use or if other factors drive both; no biological measures of intoxication"},{"rthcId":"RTHC-05479","title":"Potency trends of cannabis in Jamaica during the period of 2014 to 2020.","authors":"Lindsay, Carole M; Bernard, Khalia K; Hammond, Amanda M; Beckford, Sheldon; Abel, Wendel D; Brown, Paul D; Young, Lauriann E","year":2024,"journal":"Drug testing and analysis, 16(2), 174-186","doi":"10.1002/dta.3527","pmid":"37309060","tags":["potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Median total THC increased significantly from 1.1% in 2014 to 10.2% in 2020 (p < 0.05). THC-to-CBD ratios increased from 2.1 in 2014 to 194.1 in 2020, indicating virtual elimination of CBD content. The highest median THC was detected in Manchester parish (21.1%). Freshness indicators improved, suggesting samples were of higher quality.","whyItMatters":"Jamaica is a major cannabis-producing country. The dramatic potency increase has implications for health outcomes, as higher THC and lower CBD content is associated with greater psychosis risk and dependence potential.","specificNumbers":"299 samples from 12 parishes; median THC: 1.1% (2014) to 10.2% (2020); THC:CBD ratio: 2.1 (2014) to 194.1 (2020); highest parish median: Manchester at 21.1%; improved freshness (CBN/THC <0.013)","methodology":"Analysis of 299 herbal cannabis samples received from 12 parishes across Jamaica during 2014-2020. Major cannabinoid levels were determined using gas chromatography-mass spectrometry. THC, CBD, and CBN levels were quantified to assess potency and freshness.","limitations":"Convenience sampling from available samples, not random population sampling; 299 samples over 7 years may not represent all cannabis in Jamaica; cannot determine if potency increase reflects cultivation changes or sample selection; no user outcome data"},{"rthcId":"RTHC-05480","title":"Public opinion on the expenditure of adult-use cannabis tax revenue: Evidence from New Jersey.","authors":"Link, Nathan W; Hyatt, Jordan M; Powell, Kathleen","year":2024,"journal":"The International journal on drug policy, 125, 104334","doi":"10.1016/j.drugpo.2024.104334","pmid":"38340482","tags":["legalization"],"studyType":"Cross-sectional survey","evidenceStrength":"Moderate","keyFinding":"More residents prioritized community-based initiatives in public health, housing, and education over funding for police, courts, and prisons when asked how cannabis tax revenue should be spent.","whyItMatters":"As more states legalize recreational cannabis, how tax revenue gets allocated becomes a concrete policy question. Public opinion data can shape whether that money reinforces punitive enforcement or funds community investment.","specificNumbers":"1,006 respondents surveyed. Among Black residents, the largest share chose affordable housing investments. Political orientation was the most consistent predictor of preferences, with Republicans favoring traditional law enforcement funding.","methodology":"Population-representative survey of 1,006 New Jersey adults conducted four months after recreational cannabis sales launched. Used multinomial logistic regression to assess how demographics and political orientation shaped funding preferences.","limitations":"Single-state survey taken shortly after sales began, so preferences may shift over time. Self-reported priorities may not translate to actual political action."},{"rthcId":"RTHC-05481","title":"Exploring the interplay between cannabinoids and thymic functions.","authors":"Lins, Marvin Paulo; de Melo, Igor Santana","year":2024,"journal":"Toxicological sciences : an official journal of the Society of Toxicology, 202(1), 1-12","doi":"10.1093/toxsci/kfae114","pmid":"39250730","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05482","title":"Cannabidiol effects on fear processing and implications for PTSD: Evidence from rodent and human studies.","authors":"Lisboa, Sabrina Francesca; Stern, Cristina Aparecida Jark; Gazarini, Lucas; Bertoglio, Leandro José","year":2024,"journal":"International review of neurobiology, 177, 235-250","doi":"10.1016/bs.irn.2024.03.007","pmid":"39029986","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05483","title":"Efficiency and safety of cannabinoid medical use: an analysis of discussions and observed trends on Instagram.","authors":"Litvinova, Olena; Baral, Bikash; Wochele-Thoma, Thomas; Matin, Maima; Tzvetkov, Nikolay T; Adamska, Olga; Kamińska, Agnieszka; Łapiński, Marcin; Stolarczyk, Artur; Atanasov, Atanas G","year":2024,"journal":"Frontiers in public health, 12, 1494018","doi":"10.3389/fpubh.2024.1494018","pmid":"39697283","tags":["medical-cannabis"],"studyType":"Social media analysis","evidenceStrength":"Low","keyFinding":"Of 1,466 Instagram posts with cannabis-related hashtags, 33% focused on advertising/commercialization, 26% on personal experience, 20% on educational content, and 21% on other topics. Personal experience posts received the most engagement.","whyItMatters":"Social media is a major source of health information for many people. Understanding what cannabis-related content looks like on Instagram reveals how much is commercial vs. educational and where misinformation risks may concentrate.","specificNumbers":"1,466 posts analyzed. 81.79% were deemed relevant to cannabis/cannabinoids. 70.74% were in English. Organizations published more posts, but personal stories received more likes.","methodology":"Researchers used the Apify platform to collect Instagram posts from 2023-2024 containing cannabinoid-related hashtags. Posts were categorized by content type, language, and source (individual vs. organization), then analyzed using RStudio.","limitations":"Limited to Instagram and specific hashtags, so findings may not generalize to other platforms. Content categorization involved subjective judgment. No assessment of accuracy of health claims in posts."},{"rthcId":"RTHC-05484","title":"Intention to quit or reduce e-cigarettes, cannabis, and their co-use among a school-based sample of adolescents.","authors":"Liu, Jessica; Knoll, Sarah J; Pascale, Michael P; Gray, Caroline A; Bodolay, Alec; Potter, Kevin W; Gilman, Jodi; Eden Evins, A; Schuster, Randi M","year":2024,"journal":"Addictive behaviors, 157, 108101","doi":"10.1016/j.addbeh.2024.108101","pmid":"38986353","tags":["youth","quitting"],"studyType":"Cross-sectional survey","evidenceStrength":"Moderate","keyFinding":"Among sole e-cigarette users, 40.9% intended to quit and 24.1% intended to reduce. Among co-users, 42.3% intended to quit and 25.7% intended to reduce e-cigarettes. Fewer expressed interest in changing cannabis use, with cannabis cravings and poly-tobacco use predicting intent to change.","whyItMatters":"Knowing which teens want to change their substance use, and what predicts that motivation, can help schools and clinicians design interventions that actually reach the students most likely to engage.","specificNumbers":"23,915 students surveyed. 543 sole e-cigarette users, with 40.9% wanting to quit and 24.1% wanting to reduce. Non-daily use predicted intention to change e-cigarettes. Cannabis cravings predicted intention to change cannabis use.","methodology":"Survey of 23,915 middle and high school students. Researchers used LASSO variable selection and multilevel logistic regression to identify predictors of intention to quit or reduce e-cigarettes and/or cannabis among sole and co-users.","limitations":"Cross-sectional design captures intention at one point, not actual behavior change. Self-reported substance use may undercount actual use. School-based sample may miss out-of-school youth."},{"rthcId":"RTHC-05485","title":"Dual-Vaping of Nicotine and Cannabis Among Adults Who Currently Use Tobacco Products in Five New England States.","authors":"Liu, Jessica; Hanby, Elaine; Kingsley, Melody; Winickoff, Jonathan P; Gundersen, Daniel A; Tan, Andy S L","year":2024,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 26(9), 1253-1258","doi":"10.1093/ntr/ntae062","pmid":"38502116","tags":["addiction","harm-reduction"],"studyType":"Cross-sectional survey","evidenceStrength":"Moderate","keyFinding":"26.1% of past-month tobacco users who vaped reported dual-vaping both nicotine and cannabis/CBD in the past 30 days. Male sex and self-rated anxiety were associated with higher odds of dual-vaping.","whyItMatters":"Standard vaping surveys often fail to ask what substance is being vaped. This study shows that when researchers ask specifically, a surprisingly large share of vapers are using both nicotine and cannabis, which has implications for health screening and treatment.","specificNumbers":"1,547 adults surveyed. 26.1% dual-vaped nicotine and cannabis. Mean age 42.9 years, 62.8% female, 85.4% White. Male sex (p = .002) and anxiety (p = .043) associated with dual-vaping.","methodology":"Online survey of 1,547 adults with past 30-day tobacco use across five New England states, collected in monthly cross-sectional waves from April 2021 to July 2022. Used new survey questions distinguishing vaping substances and multinomial logistic regression for analysis.","limitations":"Limited to New England tobacco users, so prevalence may not generalize nationally. Self-reported data. Cross-sectional design cannot establish whether anxiety drives dual-vaping or vice versa."},{"rthcId":"RTHC-05486","title":"Alzheimer's disease, aging, and cannabidiol treatment: a promising path to promote brain health and delay aging.","authors":"Liu, Yanying","year":2024,"journal":"Molecular biology reports, 51(1), 121","doi":"10.1007/s11033-023-09162-1","pmid":"38227160","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05487","title":"Short-Term Cannabidiol with Δ-9-Tetrahydrocannabinol in Parkinson's Disease: A Randomized Trial.","authors":"Liu, Ying; Bainbridge, Jacquelyn; Sillau, Stefan; Rajkovic, Sarah; Adkins, Michelle; Domen, Christopher H; Thompson, John A; Seawalt, Tristan; Klawitter, Jost; Sempio, Cristina; Chin, Grace; Forman, Lisa; Fullard, Michelle; Hawkins, Trevor; Seeberger, Lauren; Newman, Heike; Vu, David; Leehey, Maureen Anne","year":2024,"journal":"Movement disorders : official journal of the Movement Disorder Society, 39(5), 863-875","doi":"10.1002/mds.29768","pmid":"38487964","tags":["medical-cannabis","cbd"],"studyType":"Randomized controlled trial","evidenceStrength":"Moderate-High","keyFinding":"Motor scores improved in both the CBD/THC group (4.57-point reduction) and placebo group (2.77-point reduction), but the between-group difference was not statistically significant (p = 0.379). Sleep, cognition, and daily living assessments showed effects favoring placebo.","whyItMatters":"Cannabis use is common among Parkinson's patients despite limited evidence. This trial provides some of the first rigorous data, and the results suggest high-CBD/low-THC formulations may not help motor symptoms and could have downsides.","specificNumbers":"61 participants randomized. Mean final dose: 191.8 mg CBD + 6.4 mg THC daily. Motor improvement: 4.57 points (CBD/THC) vs. 2.77 points (placebo), difference not significant (p = 0.379). CBD plasma level at final dose: 54.0 ng/mL.","methodology":"Double-blind RCT of 61 participants with Parkinson's disease randomized to CBD/THC oral solution (n=31) or placebo (n=30) for two weeks. Final dose averaged 192 mg CBD and 6.4 mg THC daily. Used MDS-UPDRS motor scores as the primary outcome.","limitations":"Only two weeks long, which may be too short to detect meaningful effects. Strong placebo response. Relatively small sample. The authors note that longer, larger trials with better research cannabis products are needed."},{"rthcId":"RTHC-05488","title":"Trends in Prevalence of Cannabis Use Disorder Among U.S. Veterans With and Without Psychiatric Disorders Between 2005 and 2019.","authors":"Livne, Ofir; Malte, Carol A; Olfson, Mark; Wall, Melanie M; Keyes, Katherine M; Maynard, Charles; Gradus, Jaimie L; Saxon, Andrew J; Martins, Silvia S; Keyhani, Salomeh; McDowell, Yoanna; Fink, David S; Mannes, Zachary L; Gutkind, Sarah; Hasin, Deborah S","year":2024,"journal":"The American journal of psychiatry, 181(2), 144-152","doi":"10.1176/appi.ajp.20230168","pmid":"38018141","tags":["addiction","mental-health"],"studyType":"Longitudinal cohort study","evidenceStrength":"Moderate-High","keyFinding":"Cannabis use disorder prevalence increased more among veterans with psychiatric disorders than those without (difference in prevalence change: 1.91% from 2005-2014, 0.34% from 2016-2019). The greatest increases were among patients with bipolar and psychotic spectrum disorders.","whyItMatters":"Veterans with mental health conditions appear to be developing cannabis use disorder at faster rates than other veterans. As cannabis becomes more available, this population may need more targeted screening and intervention.","specificNumbers":"4.3 to 5.7 million VHA patient records per year. CUD prevalence gap between psychiatric and non-psychiatric patients widened by 1.91 percentage points (2005-2014) and 0.34 percentage points (2016-2019). Biggest increases among patients under 35 (earlier period) and over 65 (later period).","methodology":"Analysis of Veterans Health Administration electronic health records from 2005 to 2019, covering 4.3 to 5.7 million patients annually. Examined overall and age-group-specific trends in CUD diagnoses stratified by psychiatric disorder status, with separate analyses for ICD-9 (2005-2014) and ICD-10 (2016-2019) periods.","limitations":"Based on diagnoses in medical records, which may reflect changes in screening practices or coding rather than true prevalence changes. VHA population may not represent all veterans or the general population."},{"rthcId":"RTHC-05489","title":"Influence of substance use on male reproductive health and offspring outcomes.","authors":"Lo, Jamie O; Hedges, Jason C; Chou, Wesley H; Tager, Kylie R; Bachli, Ian D; Hagen, Olivia L; Murphy, Susan K; Hanna, Carol B; Easley, Charles A","year":2024,"journal":"Nature reviews. Urology, 21(9), 534-564","doi":"10.1038/s41585-024-00868-w","pmid":"38664544","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05490","title":"Cannabis Use in Pregnancy and Neonatal Outcomes: A Systematic Review and Meta-Analysis.","authors":"Lo, Jamie O; Shaw, Beth; Robalino, Shannon; Ayers, Chelsea K; Durbin, Shauna; Rushkin, Megan C; Olyaei, Amy; Kansagara, Devan; Harrod, Curtis S","year":2024,"journal":"Cannabis and cannabinoid research, 9(2), 470-485","doi":"10.1089/can.2022.0262","pmid":"36730710","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05491","title":"A Comprehensive Review and Update on Cannabis Hyperemesis Syndrome.","authors":"Loganathan, Priyadarshini; Gajendran, Mahesh; Goyal, Hemant","year":2024,"journal":"Pharmaceuticals (Basel, Switzerland), 17(11)","doi":"10.3390/ph17111549","pmid":"39598458","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05492","title":"Factors Associated with Delta-8 THC Retail Availability in Fort Worth, Texas, 2021-2022.","authors":"LoParco, C R; Kong, A Y; Yockey, R A; Sekhon, V; Olsson, S; Rossheim, M E","year":2024,"journal":"Substance use & misuse, 59(6), 840-846","doi":"10.1080/10826084.2024.2305793","pmid":"38247162","tags":["legalization","potency"],"studyType":"Cross-sectional retail survey","evidenceStrength":"Moderate","keyFinding":"Delta-8 THC retail availability was 11% at the first time point and 9% at the second, showing no significant decline despite ongoing legal challenges. Tobacco license holders were 15 times more likely and hemp license holders 22 times more likely to carry Delta-8 than alcohol-only retailers.","whyItMatters":"Delta-8 THC exists in a regulatory gray area in many states. This study provides some of the first data on where it is actually sold and whether legal uncertainty affects availability, revealing that the market remained stable despite litigation.","specificNumbers":"Time 1: 133 of 1,223 locations (11%) sold Delta-8. Time 2: 94 of 1,026 (9%). Tobacco retailers: 15x higher odds. Hemp retailers: 22x higher odds. In more disadvantaged areas, alcohol retailers had higher odds of selling Delta-8 at Time 2.","methodology":"Researchers called all locations in Fort Worth with alcohol, tobacco, or consumable hemp retail licenses at two time points (before and after Texas announced Delta-8 litigation). Linked retailer locations to census block area deprivation index scores and used logistic regression to identify predictors of availability.","limitations":"Single-city study in Texas, which has unique cannabis laws. Phone-based survey may not capture all retailers. Area deprivation associations were borderline significant."},{"rthcId":"RTHC-05493","title":"Effectiveness and safety of cannabis-based products for medical use in patients with fibromyalgia syndrome: A systematic review.","authors":"Lopera, Valentina; Restrepo, Juan Carlos; Amariles, Pedro","year":2024,"journal":"Exploratory research in clinical and social pharmacy, 16, 100524","doi":"10.1016/j.rcsop.2024.100524","pmid":"39498228","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05494","title":"Is cannabis a slippery slope? Associations between psychological dysfunctioning, other substance use, and impaired driving, in a sample of active cannabis users.","authors":"Love, Steven; Rowland, Bevan; Armstrong, Kerry","year":2024,"journal":"PloS one, 19(10), e0310958","doi":"10.1371/journal.pone.0310958","pmid":"39383155","tags":["addiction","driving"],"studyType":"Cross-sectional survey","evidenceStrength":"Low-Moderate","keyFinding":"Cannabis users were significantly more likely than non-users (n=833 comparison group) to have used other drugs in the past 12 months. Among cannabis users, degree of use, likely dependence, psycho-social motives, emotion dysregulation, and psychopathology predicted frequency of using other substances and driving impaired.","whyItMatters":"Understanding what psychological factors connect cannabis use to other substance use and impaired driving can help road safety and treatment programs target the right risk factors rather than treating all cannabis users the same.","specificNumbers":"200 active cannabis users and 833 non-users. Cannabis users were far more likely to use other drugs. No significant differences in substance use behaviors or psychological dysfunction between medicinal and black-market cannabis users (except age).","methodology":"Online survey of 200 active adult cannabis users with screening criteria, plus comparative data from 833 non-cannabis users. Used bivariate correlations, multiple regressions, and ANOVA comparing medicinal vs. black-market users.","limitations":"Cross-sectional design cannot determine whether cannabis use leads to other substance use or vice versa. Relatively small cannabis user sample. Self-reported driving behavior. Online convenience sample may not be representative."},{"rthcId":"RTHC-05495","title":"Evaluating the Abuse Potential of Lenabasum, a Selective Cannabinoid Receptor 2 Agonist.","authors":"Luba, Rachel; Madera, Gabriela; Schusterman, Rebecca; Kolodziej, Andrew; Hodgson, Ian; Comer, Sandra D","year":2024,"journal":"The Journal of pharmacology and experimental therapeutics, 391(2), 272-278","doi":"10.1124/jpet.124.002129","pmid":"38936978","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05496","title":"Dynamic overrepresentation of accumbal cues in food- and opioid-seeking rats after prenatal THC exposure.","authors":"Luján, Miguel Á; Young-Morrison, Reana; Aroni, Sonia; Katona, István; Melis, Miriam; Cheer, Joseph F","year":2024,"journal":"Science advances, 10(45), eadq5652","doi":"10.1126/sciadv.adq5652","pmid":"39514650","tags":["pregnancy","neuroscience","dopamine"],"studyType":"Preclinical animal study","evidenceStrength":"Low-Moderate","keyFinding":"Prenatal THC exposure led to increased cue-evoked dopamine release and overrepresentation of effort-driven reward encoding patterns in the nucleus accumbens. The effects were more pronounced in male rats, who also showed increased vulnerability to relapse during opioid seeking.","whyItMatters":"With cannabis use during pregnancy rising, understanding how prenatal THC exposure rewires the developing brain's reward system is critical. These findings suggest that in utero THC may create lasting changes in how the brain responds to rewards, particularly addictive substances.","specificNumbers":"Prenatal THC-exposed male rats showed increased cue-evoked dopamine responses, augmented reinforcing efficiency of opioid rewards, and greater vulnerability to relapse. Effects were more pronounced in males than females.","methodology":"Pregnant rats received THC during gestation. Offspring were tested in food and opioid (remifentanil) reward-seeking tasks with simultaneous dopamine measurements and neural recording in the nucleus accumbens. Researchers compared prenatal THC-exposed vs. control rats across multiple behavioral and neurochemical measures.","limitations":"Animal model findings may not directly translate to humans. THC doses and exposure patterns in rats may not reflect human cannabis use during pregnancy. Cannot account for the complex social and environmental factors that influence addiction in humans."},{"rthcId":"RTHC-05497","title":"Dynamic Overrepresentation of Accumbal Cues in Food- and Opioid-Seeking Rats after Prenatal THC Exposure.","authors":"Luján, Miguel Á; Young-Morrison, Reana; Aroni, Sonia; Katona, István; Melis, Miriam; Cheer, Joseph","year":2024,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2024.05.06.592839","pmid":"38766015","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05498","title":"Cannabidiol improves the cognitive function of SAMP8 AD model mice involving the microbiota-gut-brain axis.","authors":"Ma, Bing-Qian; Jia, Jian-Xin; Wang, He; Li, Si-Jia; Yang, Zhan-Jun; Wang, Xin-Xin; Yan, Xu-Sheng","year":2024,"journal":"Journal of toxicology and environmental health. Part A, 87(11), 471-479","doi":"10.1080/15287394.2024.2338914","pmid":"38590254","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05499","title":"Biological sex and hormonal contraceptive associations with drug cue reactivity in cannabis use disorder.","authors":"Macatee, Richard J; Cannon, Mallory J; Schermitzler, Brandon S; Preston, Thomas J; Afshar, Kaveh","year":2024,"journal":"Journal of psychiatric research, 174, 121-128","doi":"10.1016/j.jpsychires.2024.04.016","pmid":"38626562","tags":["sex-differences","addiction"],"studyType":"Experimental (neuroimaging)","evidenceStrength":"Moderate","keyFinding":"Males and naturally cycling females showed significantly greater neural enhancement (LPP amplitude) to cannabis vs. neutral cues compared to females using hormonal contraceptives. Craving was higher in naturally cycling females than males in unadjusted analyses.","whyItMatters":"Drug cue reactivity predicts relapse and continued use. If hormonal contraceptives dampen cannabis cue reactivity, this could help explain mixed findings in sex difference research and point toward hormonal mechanisms in cannabis use disorder.","specificNumbers":"152 participants: 74 males, 26 naturally cycling females, 52 females on hormonal contraceptives. Hormonal contraceptive users showed significantly reduced LPP enhancement to cannabis cues. Exploratory analyses suggested a progesterone-related mechanism.","methodology":"As part of a larger study, 152 adults reporting frequent cannabis use completed a drug cue reactivity task during EEG recording. Late positive potential (LPP) amplitude was used to measure neural reactivity to cannabis vs. neutral images. Compared males (n=74), naturally cycling females (n=26), and hormonal contraceptive-using females (n=52).","limitations":"Unequal group sizes, with a small naturally cycling female group (n=26). Cross-sectional design. Craving differences did not survive covariate adjustment. Exploratory hormonal mechanism analyses need replication."},{"rthcId":"RTHC-05500","title":"Light Cannabis Use and the Adolescent Brain: An 8-years Longitudinal Assessment of Mental Health, Cognition, and Reward Processing.","authors":"Macedo, Inês; Paiva, Tiago O; Pasion, Rita; Daedelow, Laura; Heinz, Andreas; Magalhães, Ana; Banaschewski, Tobias; Bokde, Arun L W; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Garavan, Hugh; Gowland, Penny; Brühl, Rüdiger; Martinot, Jean-Luc; Martinot, Marie-Laure Paillère; Artiges, Eric; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Paus, Tomáš; Poustka, Luise; Hohmann, Sarah; Holz, Nathalie; Fröhner, Juliane H; Smolka, Michael N; Vaidya, Nilakshi; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Barbosa, Fernando","year":2024,"journal":"Psychopharmacology, 241(7), 1447-1461","doi":"10.1007/s00213-024-06575-z","pmid":"38532040","tags":["youth","cognition","neuroscience","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Teens who used cannabis weekly or monthly between ages 19 and 22 showed more conduct problems than non-users, but no differences in cognitive performance or reward-related brain activity. Those who stopped using for at least a month looked similar to non-users by age 22.","whyItMatters":"Most cannabis-brain research is cross-sectional, making it hard to untangle cause from effect. This study followed the same people for 8 years starting before any cannabis use, offering a clearer window into whether light use actually changes brain function or cognition.","specificNumbers":"At age 14, higher conduct problems predicted cannabis use within 5 years. By 22, persistent light users (n=17) still had elevated conduct problems vs. non-users (n=17), but abstinent users (n=19) did not differ from non-users.","methodology":"Longitudinal analysis using data from the IMAGEN study. Participants (n=318) were cannabis-naive at age 14 and classified at ages 19 and 22 as non-users, persistent users, or abstinent users. Measures included psychopathology symptoms, cognitive tests, and fMRI during a Monetary Incentive Delay task.","limitations":"Small subgroup sizes at age 22 (17-19 per group) limit statistical power. Only light users were studied, so heavy or daily use could produce different results. Self-report measures of cannabis use may underestimate actual consumption."},{"rthcId":"RTHC-05501","title":"Epigenetic effects of cannabis: A systematic scoping review of behavioral and emotional symptoms associated with cannabis use and exocannabinoid exposure.","authors":"Machado, Ana Sofia; Bragança, Miguel; Vieira-Coelho, Maria","year":2024,"journal":"Drug and alcohol dependence, 263, 111401","doi":"10.1016/j.drugalcdep.2024.111401","pmid":"39137613","tags":["genetics","psychosis","mental-health","neuroscience"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Across 37 included studies, cannabis exposure was most consistently associated with global hypomethylation and changes at specific genes related to dopamine signaling (DRD2, COMT), cellular function (AKT1, STAT3), and neural development (NCAM1, DLGAP2). These epigenetic changes were linked to depressive, anxious, psychotic, and addictive behavioral patterns.","whyItMatters":"Epigenetics offers a mechanism for how cannabis might produce lasting behavioral effects without changing DNA itself. Understanding which genes are affected could eventually identify biomarkers for psychiatric vulnerability.","specificNumbers":"37 studies included from 178 screened. Nine performed epigenome-wide analysis. Reduced methylation was found at Cg05575921, DNMT1, DRD2, COMT, DLGAP2, Arg1, STAT3, MGMT, and PENK. Increased methylation was found at DNMT3a/b, NCAM1, and AKT1.","methodology":"Systematic scoping review searching PubMed, Cochrane CENTRAL, and Web of Science through January 2022. Of 178 initial articles, 37 were included. Studies covered both human observational research and animal experimental designs examining epigenome-wide and gene-specific methylation changes.","limitations":"Substantial variation in cannabis dosing, administration methods, and how use was measured across studies makes direct comparison difficult. Most human studies were cross-sectional, so the direction of causation remains uncertain. Animal model findings may not translate to humans."},{"rthcId":"RTHC-05502","title":"Profiles of cannabis users and impact on cannabis cessation.","authors":"MacQuarrie, Amy L; Brunelle, Caroline","year":2024,"journal":"PloS one, 19(6), e0305088","doi":"10.1371/journal.pone.0305088","pmid":"38861510","tags":["addiction","quitting","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Four profiles emerged: low-risk (42%), rapidly escalating high-risk (27%), long-term high severity (24%), and long-term lower severity (7%). The rapidly escalating group had attempted to cut down more times than any other group. In the long-term high severity group, more participants found their use stayed the same or worsened after their last cessation attempt.","whyItMatters":"One-size-fits-all quit programs may not work for cannabis. Identifying distinct user profiles could help match people to the right level of intervention.","specificNumbers":"Low-risk: n=62 (42%); rapidly escalating high-risk: n=40 (27%); long-term high severity: n=35 (24%); long-term lower severity: n=10 (7%). 147 total participants.","methodology":"Cross-sectional study of 147 Canadian adults who had attempted to decrease or quit cannabis. Participants were recruited from community (57%) and crowdsourcing (43%). Latent Profile Analysis was used to identify user profiles based on demographics, substance use patterns, mental health symptoms, and quality of life.","limitations":"Small sample size (n=147), especially for the long-term lower severity group (n=10). Cross-sectional design cannot show how profiles develop over time. Self-selected sample of people who had already tried to quit."},{"rthcId":"RTHC-05503","title":"The State of Synthetic Cannabinoid Medications for the Treatment of Pain.","authors":"Maglaviceanu, Anca; Peer, Miki; Rockel, Jason; Bonin, Robert P; Fitzcharles, Mary-Ann; Ladha, Karim S; Bhatia, Anuj; Leroux, Timothy; Kotra, Lakshmi; Kapoor, Mohit; Clarke, Hance","year":2024,"journal":"CNS drugs, 38(8), 597-612","doi":"10.1007/s40263-024-01098-9","pmid":"38951463","tags":["pain","medical-cannabis","drug-interactions"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Dronabinol and nabilone, both THC-mimicking synthetics approved for nausea, are being investigated for neuropathic pain, spasticity-related pain, fibromyalgia, osteoarthritis, and postoperative pain. While some trials show modest benefit, the evidence base is thin and the complex signaling of the endocannabinoid system complicates drug development.","whyItMatters":"With the opioid crisis pushing demand for alternative pain treatments, understanding whether existing synthetic cannabinoids can fill that role is critical.","specificNumbers":"Two FDA-approved synthetic cannabinoids (dronabinol and nabilone) discussed across multiple pain conditions including neuropathic pain, spasticity, fibromyalgia, and postoperative pain.","methodology":"Narrative review examining the signaling mechanisms of FDA-approved synthetic cannabinoids, key clinical trials investigating their analgesic potential, and challenges in clinical translation.","limitations":"Narrative review format means no systematic search or quality assessment. The clinical trial base for pain indications is limited. Approved indications remain restricted to nausea/appetite."},{"rthcId":"RTHC-05504","title":"Effect of recreational cannabis use on bone mineral density: a systematic review.","authors":"Magno, Luiz Alexandre Viana; Tameirão, Diego Ribeiro; Alves, Lucas Ferreira; Guimarães, Nathalia Sernizon","year":2024,"journal":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 35(3), 391-399","doi":"10.1007/s00198-023-06992-4","pmid":"38141142","tags":["medical-cannabis","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Of four included studies (3 cross-sectional, 1 RCT) covering 4,032 participants, two found that cannabis exposure decreased bone mineral density while two found no effect.","whyItMatters":"As recreational cannabis use rises globally, understanding its effects on bone health is important, especially for aging populations at risk of osteoporosis.","specificNumbers":"2,620 studies screened, 4 included (3 cross-sectional, 1 RCT). Total participants: 4,032 aged 18-60. Two studies showed decreased BMD; two showed no change.","methodology":"Systematic review searching MEDLINE, EMBASE, Cochrane Library, and Web of Science through March 2023 for studies on recreational cannabis use and bone mineral density in adults aged 18-60. From 2,620 studies screened, four met inclusion criteria.","limitations":"Only four studies met criteria, making definitive conclusions impossible. Differences in cannabis products, doses, and exposure assessment prevent meaningful comparison. No longitudinal studies were found."},{"rthcId":"RTHC-05505","title":"White matter alterations associated with chronic cannabis use disorder: a structural network and fixel-based analysis.","authors":"Maleki, Suzan; Hendrikse, Joshua; Richardson, Karyn; Segrave, Rebecca A; Hughes, Sam; Kayayan, Edouard; Oldham, Stuart; Syeda, Warda; Coxon, James P; Caeyenberghs, Karen; Domínguez D, Juan F; Solowij, Nadia; Lubman, Dan I; Suo, Chao; Yücel, Murat","year":2024,"journal":"Translational psychiatry, 14(1), 429","doi":"10.1038/s41398-024-03150-0","pmid":"39389949","tags":["addiction","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Compared to 38 healthy controls, 56 individuals with CUD had significantly increased structural connectivity across 9 brain connections involving the right parietal cortex and regions including left orbitofrontal cortex, temporal pole, hippocampus, and putamen. White matter density was higher in the corpus callosum but lower in the bilateral cingulum and right cerebellum.","whyItMatters":"Understanding how cannabis use disorder affects brain wiring could help identify early markers of the condition and inform treatment approaches.","specificNumbers":"56 CUD participants vs. 38 controls. 9 edges showed increased connectivity (FDR corrected). White matter density higher in corpus callosum splenium, lower in bilateral cingulum and right cerebellum (FWE corrected).","methodology":"MRI-based study comparing 56 individuals with CUD (median age 25) to 38 healthy controls (median age 31.5) using structural connectome analysis and fixel-based analysis (FBA).","limitations":"Cross-sectional design cannot determine whether white matter changes precede or follow cannabis use disorder. Age difference between groups could confound results. Relatively small sample sizes."},{"rthcId":"RTHC-05506","title":"Development of an accelerated ageing protocol for the study of phytocannabinoid stability in Cannabis sativa L.","authors":"Mandrioli, Roberto; Cirrincione, Marco; Saladini, Bruno; Girotti, Stefano; Mladěnka, Přemysl; Protti, Michele; Mercolini, Laura","year":2024,"journal":"Journal of pharmaceutical and biomedical analysis, 251, 116422","doi":"10.1016/j.jpba.2024.116422","pmid":"39197204","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05507","title":"Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: Obligatory role of hippocampal GPR55 receptors.","authors":"Manduca, Antonia; Buzzelli, Valeria; Rava, Alessandro; Feo, Alessandro; Carbone, Emilia; Schiavi, Sara; Peruzzi, Barbara; D'Oria, Valentina; Pezzullo, Marco; Pasquadibisceglie, Andrea; Polticelli, Fabio; Micale, Vincenzo; Kuchar, Martin; Trezza, Viviana","year":2024,"journal":"Pharmacological research, 203, 107176","doi":"10.1016/j.phrs.2024.107176","pmid":"38583687","tags":["cbd","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD corrected short-term recognition memory deficits in Fmr1 knockout rats. The effect required GPR55 receptors in the CA1 hippocampus. Blocking these receptors prevented both CBD and the endocannabinoid-boosting drug URB597 from working. Repeated CBD administration did not produce tolerance.","whyItMatters":"Fragile X Syndrome has no approved cognitive treatment. Identifying that CBD works through GPR55 receptors provides a specific therapeutic target and moves beyond the vague \"CBD helps everything\" narrative.","specificNumbers":"CBD rescued object recognition memory deficits in juvenile Fmr1-delta-exon-8 rats. Blocking CA1 hippocampal GPR55 receptors prevented the cognitive benefit of both CBD and FAAH inhibitor URB597.","methodology":"Pharmacological study using Fmr1-delta-exon-8 rats with immunohistochemistry, biochemistry, and molecular docking analysis. CBD was administered to juvenile rats and recognition memory was tested.","limitations":"Animal model findings may not translate to humans with Fragile X Syndrome. Juvenile rats were studied, and effects in adults may differ. The docking analysis is computational and needs experimental validation."},{"rthcId":"RTHC-05508","title":"A systematic review of oculomotor deficits associated with acute and chronic cannabis use.","authors":"Manning, Brooke; Downey, Luke A; Narayan, Andrea; Hayley, Amie C","year":2024,"journal":"Addiction biology, 29(1), e13359","doi":"10.1111/adb.13359","pmid":"38221807","tags":["driving","cognition","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 20 studies, acute THC consumption increased saccadic latency, reduced accuracy, and impaired inhibitory control. Chronic cannabis users, particularly those who started young, showed enduring oculomotor deficits affecting visual scanning efficiency. Eyelid tremors appeared to be a reliable indicator of cannabis consumption but were distinct from impairment.","whyItMatters":"Current roadside cannabis tests detect THC but do not measure actual impairment. Identifying specific eye movement changes could lead to more accurate, impairment-based testing.","specificNumbers":"20 studies included (12 acute dosing, 5 chronic use, 3 roadside). Acute THC increased saccadic latency and inaccuracy. Chronic users with early onset showed lasting oculomotor deficits.","methodology":"Systematic review registered on OSF following PRISMA guidelines. Twenty articles included: 12 acute dosing trials, 5 chronic use cross-sectional studies, and 3 roadside epidemiological studies.","limitations":"Heterogeneous study designs and THC doses limit direct comparison. Most acute studies used controlled lab settings that may not reflect real-world driving."},{"rthcId":"RTHC-05509","title":"A randomised, placebo-controlled, double blind, crossover trial on the effect of a 20:1 cannabidiol: Δ9-tetrahydrocannabinol medical cannabis product on neurocognition, attention, and mood.","authors":"Manning, Brooke; Hayley, Amie C; Catchlove, Sarah; Stough, Con; Downey, Luke A","year":2024,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 82, 35-43","doi":"10.1016/j.euroneuro.2024.02.002","pmid":"38490083","tags":["cbd","cognition","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"A sublingual dose of CannEpil (100mg CBD, 5mg THC) impaired visuospatial working memory and delayed pattern recognition compared to placebo, but largely preserved mood. Participants felt more content and amicable about 2.5 hours after dosing. About 23% reported drowsiness between 3 and 6 hours post-dose.","whyItMatters":"As CBD-dominant products gain medical acceptance, knowing their acute cognitive effects is essential for safety, especially for users who drive or work.","specificNumbers":"31 participants. 100mg CBD + 5mg THC sublingual dose. Contentedness (p<0.01) and amicability (p<0.05) improved at 2.5 hours. 23% reported drowsiness 3-6 hours post-dose.","methodology":"Randomized, double-blind, placebo-controlled, within-subjects crossover trial with 31 healthy participants (16 female, 15 male) aged 21-58 over a two-week protocol.","limitations":"Small sample (n=31) of healthy volunteers may not reflect patients with medical conditions. Single-dose design does not capture effects of repeated use. Only one CBD:THC ratio was tested."},{"rthcId":"RTHC-05510","title":"Off-label use of cannabidiol in genetic epileptic and developmental encephalopathies: A case report.","authors":"Mannini, Elisa; Misirocchi, Francesco; Lazzari, Stefania; Balella, Giulia; Bottignole, Dario; Frapporti, Maddalena; Zinno, Lucia; Florindo, Irene; Parrino, Liborio; Mutti, Carlotta","year":2024,"journal":"Epilepsy & behavior reports, 27, 100687","doi":"10.1016/j.ebr.2024.100687","pmid":"39040437","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Off-label cannabidiol produced significant seizure frequency reduction in a patient with a rare genetic DEE not covered by current CBD indications. Beyond seizure control, the patient showed striking improvements in sleep quality, mood, behavior, language, and motor skills.","whyItMatters":"CBD is currently approved only for three specific epilepsy conditions. This case suggests potential benefit in other genetic epilepsies and highlights effects beyond seizure reduction.","specificNumbers":"One 30-year-old patient. Relevant seizure frequency reduction. Improvements noted in sleep quality, mood, behavior, language, and motor skills.","methodology":"Single case report of a 30-year-old female with a rare genetic developmental epileptic encephalopathy treated with off-label cannabidiol after drug-resistant seizures failed to respond to standard therapies.","limitations":"Single case report cannot establish efficacy. Placebo effect and natural disease fluctuation cannot be ruled out."},{"rthcId":"RTHC-05511","title":"Building a community-driven bioinformatics platform to facilitate Cannabis sativa multi-omics research.","authors":"Mansueto, Locedie; Kretzschmar, Tobias; Mauleon, Ramil; King, Graham J","year":2024,"journal":"GigaByte (Hong Kong, China), 2024, gigabyte137","doi":"10.46471/gigabyte.137","pmid":"39469541","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05512","title":"Can the THC concentration predict the number of patients with cannabis-related diagnoses?","authors":"Manthey, Jakob; Rosenkranz, Moritz; Jonas, Benjamin; Schwarzkopf, Larissa","year":2024,"journal":"Drug and alcohol review, 43(7), 1764-1772","doi":"10.1111/dar.13923","pmid":"39164975","tags":["potency","mental-health","legalization","sex-differences"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using health insurance data from 2009-2021 and THC data from law enforcement, each one percentage point increase in median THC concentration predicted a higher proportion of cannabis users receiving an F12 diagnosis. The effect was stronger in men (+0.42) than women (+0.17).","whyItMatters":"As cannabis products get stronger worldwide, this population-level data suggests rising potency may translate directly into more psychiatric diagnoses.","specificNumbers":"Each 1 percentage point increase in THC associated with +0.42 increase in diagnosis proportion for men and +0.17 for women. Effect significant in all 16 states for men, 15/16 for women.","methodology":"Ecological study using generalized mixed linear models across 16 German federal states from 2009-2021. Dependent variable was the ratio of insured persons with cannabis-related ICD-10 F12 diagnoses to estimated cannabis users.","limitations":"Ecological study design means individual-level causation cannot be established. THC data from seizures may not represent actual consumer use. Changes in diagnostic practices could confound results."},{"rthcId":"RTHC-05513","title":"Prenatal exposure to alcohol and its impact on reward processing and substance use in adulthood.","authors":"Mareckova, Klara; Marecek, Radek; Andryskova, Lenka; Brazdil, Milan; Nikolova, Yuliya S","year":2024,"journal":"Translational psychiatry, 14(1), 220","doi":"10.1038/s41398-024-02941-9","pmid":"38806472","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05514","title":"Analysis of social media compliance with cannabis advertising regulations: evidence from recreational dispensaries in Illinois 1-year post-legalization.","authors":"Marinello, Samantha; Valek, Rebecca; Powell, Lisa M","year":2024,"journal":"Journal of cannabis research, 6(1), 2","doi":"10.1186/s42238-023-00208-6","pmid":"38173010","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"About 30% of dispensary Facebook and Twitter posts had at least one advertising violation. Roughly 10% met criteria for appealing to youth or contained health claims. Most health claims were for conditions not recognized as qualifying conditions for medical cannabis in Illinois.","whyItMatters":"Advertising regulation is a key tool for preventing youth uptake and misleading health claims in legal cannabis markets. Without active enforcement, substantial non-compliance becomes the norm.","specificNumbers":"Census of all recreational dispensary social media pages. ~30% of posts had at least one violation. ~10% appealed to youth or contained health claims. Non-compliance persisted throughout 2020.","methodology":"Quantitative content analysis of a census of recreational dispensary Facebook and Twitter business pages during 2020, the first year of recreational sales in Illinois.","limitations":"Limited to Illinois in 2020. Only Facebook and Twitter examined. No assessment of whether violations actually influenced youth behavior."},{"rthcId":"RTHC-05515","title":"Cannabidiol and Alzheimer's disease.","authors":"Marques, Bruno L; Campos, Alline C","year":2024,"journal":"International review of neurobiology, 177, 121-134","doi":"10.1016/bs.irn.2024.04.014","pmid":"39029982","tags":["cbd","medical-cannabis","seniors","cognition"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Preclinical studies show CBD can mitigate cognitive decline and amyloid-beta-induced neurodegeneration through modulation of oxidative stress and neuroinflammation. CBD also promotes neuroplasticity in the hippocampus. However, no randomized placebo-controlled trials in human Alzheimer's patients exist.","whyItMatters":"Alzheimer's affects at least 50 million people worldwide with limited treatment options. The gap between promising preclinical CBD data and the absence of rigorous human trials highlights both opportunity and caution.","specificNumbers":"At least 50 million people affected by Alzheimer's worldwide. Current treatments limited to cholinesterase inhibitors and memantine. Zero randomized placebo-controlled trials of CBD in Alzheimer's published.","methodology":"Narrative review examining preclinical and in vitro evidence for CBD in Alzheimer's disease models, as well as the limited available clinical data.","limitations":"Narrative review without systematic search. Preclinical findings frequently fail to translate. Available clinical evidence described as conflicting. No RCTs exist."},{"rthcId":"RTHC-05516","title":"Adverse outcomes of cannabis use in Canada, before and after legalisation of non-medical cannabis: cross-sectional analysis of the International Cannabis Policy Study.","authors":"Marquette, Anastasia; Iraniparast, Maryam; Hammond, David","year":2024,"journal":"BMJ open, 14(1), e077908","doi":"10.1136/bmjopen-2023-077908","pmid":"38171626","tags":["legalization","harm-reduction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Approximately one-third of cannabis users reported at least one adverse event in the past year, and 5% sought medical help. The prevalence was similar before (2018) and after legalization (2019-2021), but ER visits increased post-legalization while edible-related help-seeking decreased.","whyItMatters":"This is one of the first studies tracking adverse events across the legalization transition in Canada, providing real-world data on whether legalization changes the pattern of harms.","specificNumbers":"18,285 respondents across 4 waves. ~33% reported at least one adverse event. 5% sought medical help. ER proportion increased (F=2.77, p=0.041). Edible-related help-seeking decreased (p=0.001).","methodology":"Cross-sectional analysis of four survey waves from the International Cannabis Policy Study (2018-2021) covering 18,285 Canadian respondents aged 16-65 who reported cannabis use.","limitations":"Self-report data subject to recall bias. Online survey may not represent all users. Cannot determine whether changes are caused by legalization or other factors."},{"rthcId":"RTHC-05517","title":"Cannabinoid for alcohol use disorder.","authors":"Marquez, Júlia Dalfovo; Dezanetti, Talissa; Walz, Roger; de Carvalho, Cristiane Ribeiro","year":2024,"journal":"International review of neurobiology, 178, 301-322","doi":"10.1016/bs.irn.2024.08.005","pmid":"39523058","tags":["addiction","medical-cannabis","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system, particularly CB1 and CB2 receptors, modulates the brain's reward circuitry for alcohol. Some researchers propose cannabis as a substitute medication for AUD, but concurrent use may increase adverse outcomes.","whyItMatters":"Alcohol use disorder is undertreated and current medications have limited effectiveness. If cannabinoids can reduce alcohol consumption or craving, they could address a major public health gap.","specificNumbers":"Review covers CB1 and CB2 receptor involvement in dopaminergic mesolimbic reward pathways related to alcohol.","methodology":"Narrative review chapter examining preclinical and clinical evidence on the endocannabinoid system's role in alcohol reward, the therapeutic potential of cannabinoids for AUD, and risks of concurrent use.","limitations":"Narrative review without systematic methodology. Most evidence comes from preclinical models. Human clinical trial data is extremely limited."},{"rthcId":"RTHC-05518","title":"Medicinal cannabis extracts are neuroprotective against Aβ1-42-mediated toxicity in vitro.","authors":"Marsh, Dylan T; Shibuta, Mayu; Kato, Ryuji; Smid, Scott D","year":2024,"journal":"Basic & clinical pharmacology & toxicology, 135(5), 575-592","doi":"10.1111/bcpt.14078","pmid":"39243211","tags":["medical-cannabis","cbd","seniors","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Five proprietary cannabis extracts were tested against amyloid-beta toxicity in PC12 cells. THC/THCA-dominant extracts provided the most significant neuroprotection, persisting after heating. None protected against lipid peroxidation. Neuroprotection did not correlate with amyloid aggregation inhibition.","whyItMatters":"Most Alzheimer's drug development has focused on clearing amyloid plaques with limited success. If cannabis extracts protect neurons through alternative mechanisms, this could open new therapeutic avenues.","specificNumbers":"Five proprietary cannabis extracts tested. THC/THCA-predominant extracts showed the most significant neuroprotection. Only one non-heated extract (BC-401) modestly inhibited amyloid aggregation.","methodology":"In vitro study using PC12 cells exposed to amyloid-beta-1-42 peptide. Cell viability by MTT assay. Five cannabis extracts tested heated and non-heated. Amyloid aggregation visualized by electron and fluorescence microscopy.","limitations":"In vitro study in PC12 cells (a cancer cell line). No in vivo validation. Proprietary extracts limit reproducibility."},{"rthcId":"RTHC-05519","title":"Sleep, Alcohol and Cannabis Use in College Students With and Without Attention-Deficit/Hyperactivity Disorder.","authors":"Marsh, Nicholas P; Oddo, Lauren E; Murphy, James G; Chronis-Tuscano, Andrea","year":2024,"journal":"Substance use & misuse, 59(8), 1141-1149","doi":"10.1080/10826084.2024.2320376","pmid":"38555872","tags":["sleep","addiction","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among college drinkers, those with ADHD (n=51) reported significantly worse sleep quality and more alcohol-related negative consequences than those without ADHD (n=50). ADHD independently predicted alcohol consequences but not cannabis consequences.","whyItMatters":"College students with ADHD are at elevated risk for substance problems. Understanding that their vulnerability appears specific to alcohol, not cannabis, could help target prevention efforts.","specificNumbers":"51 students with ADHD, 50 without. 52 used cannabis. ADHD independently predicted alcohol consequences but not cannabis consequences.","methodology":"Cross-sectional study of 101 college students who drink alcohol, with and without ADHD diagnoses confirmed by structured interview. Sleep quality, substance use, and consequences measured by validated questionnaires.","limitations":"Small sample size limits statistical power. Cross-sectional design prevents causal conclusions. Self-selected college sample may not generalize."},{"rthcId":"RTHC-05520","title":"Rising Inpatient Utilization and Costs of Cannabis Hyperemesis Syndrome Hospitalizations in Massachusetts After Cannabis Legalization.","authors":"Marshall, Allison; Fai, Caitlin; Han, John; Yule, Amy M; Jangi, Sushrut","year":2024,"journal":"Journal of clinical gastroenterology, 58(3), 247-252","doi":"10.1097/MCG.0000000000001857","pmid":"37224284","tags":["legalization","harm-reduction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"CHS hospitalizations rose from 0.02% to 0.1% of total admissions after legalization. Length of stay tripled (1 to 3 days), antiemetic use increased, and mean hospitalization cost more than doubled ($8,520 to $18,714 after adjusting for inflation).","whyItMatters":"CHS is a growing clinical and economic burden that is often underrecognized. As legalization expands, hospitals and policymakers need to account for rising CHS-related costs.","specificNumbers":"72 CHS hospitalizations. Length of stay: 3 vs 1 day (p<0.005). Cost: $18,714 vs $7,460 (p<0.0005). Post-legalization predicted increased costs (B=10,131.25, p<0.05).","methodology":"Retrospective cohort study of patients admitted to a large urban hospital between 2012 and 2021, comparing periods before and after Massachusetts cannabis legalization (December 15, 2016). Examined 72 CHS hospitalizations.","limitations":"Single hospital in one city. \"Putative\" CHS diagnoses may include misclassified cases. Small total number (72). Cannot determine if increase reflects incidence growth or better recognition."},{"rthcId":"RTHC-05521","title":"Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia.","authors":"Martínez-Rivera, Arlene; Fetcho, Robert N; Birmingham, Lizzie; Jiu, Jin X; Yang, Ruirong; Foord, Careen; Scala-Chávez, Diego; Mekawy, Narmin; Pleil, Kristen; Pickel, Virginia M; Liston, Conor; Castorena, Carlos M; Levitz, Joshua; Pan, Ying-Xian; Briand, Lisa A; Rajadhyaksha, Anjali M; Lee, Francis S","year":2024,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2024.04.02.585967","pmid":"38766079","tags":["pain","addiction","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Pharmacologically boosting 2-AG levels via MAGL inhibition attenuated opioid reward in both conditioned place preference and self-administration paradigms without affecting opioid analgesia. The effect was mediated by CB1 receptors in the VTA. Enhancing anandamide had no effect.","whyItMatters":"The opioid crisis demands alternatives that provide pain relief without addiction potential. Targeting 2-AG could allow opioids to work for pain while stripping away their rewarding properties.","specificNumbers":"MAGL inhibition with JZL184 attenuated opioid reward in both CPP and self-administration. VTA CB1R knockout reversed effects. FAAH inhibition (anandamide) had no effect.","methodology":"Animal study using male and female mice. Opioid reward assessed by CPP and self-administration. CB1 receptor involvement confirmed with VTA-specific conditional knockout. Fiber photometry measured nucleus accumbens activity and dopamine transmission.","limitations":"Mouse model may not predict human pharmacology. Long-term effects of chronic MAGL inhibition not addressed. Controlled lab settings may not reflect complex clinical scenarios."},{"rthcId":"RTHC-05522","title":"CB1 Receptor Activation Provides Neuroprotection in an Animal Model of Glutamate-Induced Excitotoxicity Through a Reduction of NOX-2 Activity and Oxidative Stress.","authors":"Martínez-Torres, Ari Misael; Morán, Julio","year":2024,"journal":"CNS neuroscience & therapeutics, 30(11), e70099","doi":"10.1111/cns.70099","pmid":"39496572","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"WIN55,212-2 reduced brain injury, improved motor activity, decreased ROS production, lowered neuroinflammation markers (TNF-alpha, NF-kB, Iba-1), and reduced edema in a glutamate excitotoxicity model. Effects were mediated by CB1 receptors and depended on NOX-2.","whyItMatters":"Excitotoxicity contributes to brain damage in stroke and neurodegenerative diseases. Identifying that cannabinoid protection works through NOX-2 provides a specific mechanistic target.","specificNumbers":"WIN55,212-2 reduced striatal lesion, ROS, and neuroinflammation markers. Effects blocked by AM251 and absent in NOX-2 KO mice.","methodology":"In vivo study using wild-type and NOX-2 knockout mice. Glutamate excitotoxicity induced by stereotactic injection into the striatum.","limitations":"Acute animal model. WIN55,212-2 has psychoactive effects limiting clinical use. Single time-point analysis."},{"rthcId":"RTHC-05523","title":"Endocannabinoid regulation in the cervix during pregnancy: insights into molecular mechanisms of premature labor.","authors":"Marvaldi, Carolina; Herrero, Felisa; Johnson, Clare; Aylen Schander, Julieta; Correa, Fernando; Cella, Maximiliano; Aisemberg, Julieta; Franchi, Ana María; Bradshaw, Heather; Wolfson, Manuel Luis","year":2024,"journal":"Reproduction (Cambridge, England), 167(4)","doi":"10.1530/REP-23-0383","pmid":"38271800","tags":["pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Anandamide and 2-AG increased in the cervix of pregnant mice. LPS-induced inflammation reduced CB1 and CB2 receptor expression and increased metalloprotease activity and COX-2, modulated by cannabinoid receptor antagonists.","whyItMatters":"Preterm birth is a leading cause of infant mortality. Understanding how the endocannabinoid system maintains cervical integrity could reveal new prevention targets.","specificNumbers":"Anandamide and 2-AG increased in pregnant vs. non-pregnant cervix. FAAH decreased. LPS reduced CB1/CB2, increased MMPs and COX-2.","methodology":"Animal study comparing cervical tissue from non-pregnant and pregnant mice with and without LPS treatment. Mass spectrometry, Western blot, immunostaining, and explant cultures.","limitations":"Mouse model may not fully represent human cervical biology. LPS is only one cause of preterm labor. Does not directly test exogenous cannabis exposure."},{"rthcId":"RTHC-05524","title":"Anti-Cancer and Anti-Proliferative Potential of Cannabidiol: A Cellular and Molecular Perspective.","authors":"Mashabela, Manamele Dannies; Kappo, Abidemi Paul","year":2024,"journal":"International journal of molecular sciences, 25(11)","doi":"10.3390/ijms25115659","pmid":"38891847","tags":["cbd","cancer","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD inhibits tumor growth, reduces inflammation, and induces autophagy and apoptosis. Effects can be receptor-dependent (CB1, CB2, TRPV, PPARs) or receptor-independent (ceramide biosynthesis, ER stress). Mechanisms vary by cancer type.","whyItMatters":"Understanding how CBD kills cancer cells at the molecular level is essential for developing it into a legitimate therapeutic rather than relying on anecdotal claims.","specificNumbers":"CBD acts through CB1, CB2, TRPV, and PPAR receptors. Receptor-independent mechanisms include ceramide biosynthesis and ER stress induction.","methodology":"Narrative review examining recent evidence on CBD anti-cancer activity across different cancer types, focusing on cellular and molecular mechanisms.","limitations":"Most evidence from cell culture and animal studies. Clinical trial data extremely limited. Optimal dosing unknown."},{"rthcId":"RTHC-05525","title":"Asystole in a young child with tetrahydrocannabinol overdose: a case report and review of literature.","authors":"Masilamani, Mats Steffi Jennifer; Leff, Rebecca; Kawai, Yu","year":2024,"journal":"Frontiers in toxicology, 6, 1371651","doi":"10.3389/ftox.2024.1371651","pmid":"38784384","tags":["youth","cardiovascular","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 7-year-old who ate five 15mg delta-8-THC gummies experienced 15-second asystole with apnea 7 hours after ingestion, despite being clinically stable. This is the first reported pediatric case of THC-induced asystole.","whyItMatters":"The standard observation period after pediatric THC ingestion is 3-6 hours. This case shows life-threatening events can occur later, suggesting current guidelines need revision.","specificNumbers":"75mg total delta-8-THC. Asystole >15 seconds at 7 hours post-ingestion. Bradycardia treated with 0.1mg glycopyrrolate. Discharged after 24 hours.","methodology":"Case report with continuous telemetry monitoring.","limitations":"Single case. Delta-8-THC may differ from delta-9. Mechanism not definitively established. Product potency may be imprecise."},{"rthcId":"RTHC-05526","title":"High Risk or Risky Highs: Understanding the Links Between Alcohol and Cannabis Use on the Transition From Suicidal Ideation to Attempts in Australian Men.","authors":"Mason, Andre; Riordan, Benjamin C; Morley, Kirsten; Winter, Taylor; Haber, Paul; Scarf, Damian","year":2024,"journal":"Archives of suicide research : official journal of the International Academy for Suicide Research, 28(2), 600-609","doi":"10.1080/13811118.2023.2199801","pmid":"37151101","tags":["mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In 7,464 Australian men, cannabis use significantly predicted transition from suicidal ideation to suicide attempt. Alcohol use showed no such association.","whyItMatters":"Understanding which substances increase the risk of acting on suicidal thoughts is critical for prevention. The specificity of the cannabis link challenges assumptions about alcohol and suicide.","specificNumbers":"7,464 adult men. Cannabis significantly predicted ideation-to-attempt transition. Alcohol did not.","methodology":"Longitudinal analysis using waves 1 and 2 of Ten to Men: The Australian Longitudinal Study on Male Health (n=7,464).","limitations":"Only men studied. Australian population. Self-reported cannabis use. Mechanism not examined."},{"rthcId":"RTHC-05527","title":"Cannabinoids and Genetic Epilepsy Models: A Review with Focus on CDKL5 Deficiency Disorder.","authors":"Massey, Sean; Quigley, Anita; Rochfort, Simone; Christodoulou, John; Van Bergen, Nicole J","year":2024,"journal":"International journal of molecular sciences, 25(19)","doi":"10.3390/ijms251910768","pmid":"39409097","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD is proven for LGS, Dravet, and TSC. For CDD, evidence relies on anecdotal reports using artisanal products with unknown compositions. Preclinical models could help establish efficacy.","whyItMatters":"CDD causes devastating seizures that existing drugs often fail to control. Establishing whether cannabinoids work through CDD-specific pathways could justify targeted trials.","specificNumbers":"CDD seizures can exceed 10 daily in severe cases. CBD approved for 3 genetic epilepsies. No clinical trial data for CDD.","methodology":"Narrative review examining clinical trials and preclinical models of cannabinoids in genetic epilepsies, with focus on CDD.","limitations":"No CDD trial data. Anecdotal reports use unknown compositions. Molecular overlap with other epilepsies is theoretical."},{"rthcId":"RTHC-05528","title":"Exploring the effects of cannabis health warnings on protective health intentions among US adults in legal recreational states.","authors":"Massey, Zachary B; Li, Yachao; Zhang, Tianting; Duong, Hue Trong","year":2024,"journal":"The International journal on drug policy, 128, 104450","doi":"10.1016/j.drugpo.2024.104450","pmid":"38749214","tags":["harm-reduction","legalization"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 1,095 cannabis users, attention to warnings increased cognitive elaboration, fear, and hope. Both emotions drove protective health intentions. Pictorial warnings were no more effective than text-only.","whyItMatters":"Health warnings are one of few regulatory tools in legal markets. Hope, not just fear, motivates protective behavior, which could change warning design.","specificNumbers":"1,095 participants. No pictorial vs text differences. Hope and fear both independently drove protective intentions.","methodology":"Online randomized experiment with 1,095 adults (21+) in legal US states. Warnings about driving, mental health, and smoke exposure in text-only or pictorial formats. SEM analysis.","limitations":"Online experiment, not real-world. Intentions measured, not behavior. Current users in legal states only."},{"rthcId":"RTHC-05529","title":"Cognitive-behavioral therapies in the management of adolescents with cannabis use disorder (CUD): A systematic review.","authors":"Mauries, Sibylle; Dufayet, Geoffrey; Lengereau, Ariane; Lejoyeux, Michel; Geoffroy, Pierre A; Dupong, Irène","year":2024,"journal":"Drug and alcohol dependence, 260, 111321","doi":"10.1016/j.drugalcdep.2024.111321","pmid":"38759505","tags":["youth","addiction","quitting"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Nine RCTs of CBT for adolescent CUD found treatments ranging from 3 to 24 weeks, often combined with motivational interviewing or family therapy. Shorter courses appeared valuable for teen adherence. Parental involvement had positive impact.","whyItMatters":"Treatment evidence for adolescent CUD is thin. Shorter, family-involved CBT may improve adherence and outcomes.","specificNumbers":"9 RCTs met criteria. Duration 3-24 weeks. Only 2 compared CBT to alternatives.","methodology":"Systematic review of PubMed for RCTs of CBT for adolescents (12-18) with CUD.","limitations":"Only 9 heterogeneous studies. Few head-to-head comparisons. Small samples."},{"rthcId":"RTHC-05530","title":"Associations between cannabis policies and state-level specialty cannabis use disorder treatment in the United States, 2004-2019.","authors":"Mauro, Pia M; Gutkind, Sarah; Askari, Melanie S; Hasin, Deborah S; Samples, Hillary; Mauro, Christine M; Annunziato, Erin M; Boustead, Anne E; Martins, Silvia S","year":2024,"journal":"Drug and alcohol dependence, 257, 111113","doi":"10.1016/j.drugalcdep.2024.111113","pmid":"38382162","tags":["legalization","addiction","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"CUD treatment decreased 2.15 points after MCL with dispensaries (2004-2014). Among active CUD patients, declines occurred only in dispensary states. By 2015-2019, associations were no longer significant.","whyItMatters":"If cannabis policy reduces treatment uptake among those who need it, this is a public health concern. Understanding the mechanism is critical.","specificNumbers":"Treatment decreased 2.15 points after MCL with dispensaries (2004-2014). Among CUD patients: -0.91 points in dispensary states. No MCL effects 2015-2019.","methodology":"Multi-level logistic regression using restricted-use 2004-2019 NSDUH data for people aged 12+ classified as needing CUD treatment.","limitations":"Observational. Self-report NSDUH. CUD criteria changed with DSM-5. Multiple simultaneous policy changes."},{"rthcId":"RTHC-05531","title":"Anandamide and WIN 55212-2 Afford Protection in Rat Brain Mitochondria in a Toxic Model Induced by 3-Nitropropionic Acid: an In Vitro Study.","authors":"Maya-López, Marisol; Monsalvo-Maraver, Luis Angel; Delgado-Arzate, Ana Laura; Olivera-Pérez, Carolina I; El-Hafidi, Mohammed; Silva-Palacios, Alejandro; Medina-Campos, Omar; Pedraza-Chaverri, José; Aschner, Michael; Tinkov, Alexey A; Túnez, Isaac; Retana-Márquez, Socorro; Zazueta, Cecilia; Santamaría, Abel","year":2024,"journal":"Molecular neurobiology, 61(9), 6435-6452","doi":"10.1007/s12035-024-03967-2","pmid":"38307967","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both anandamide and WIN 55212-2 ameliorated 3-NP toxic effects on brain mitochondria. CB1 antagonist AM281 completely reversed protective effects, confirming mitochondrial CB1 receptor involvement.","whyItMatters":"Mitochondrial dysfunction is central to neurodegenerative diseases. CB1 receptors on mitochondria can be activated to protect them.","specificNumbers":"AEA and WIN 55212-2 ameliorated 3-NP effects. AM281 completely reversed all protective effects.","methodology":"In vitro study using isolated rat brain mitochondria exposed to 3-NP. Outcomes: reduction capacity, ROS formation, mitochondrial swelling.","limitations":"In vitro isolated mitochondria. 3-NP model is specific. Direct translation to neurodegeneration is speculative."},{"rthcId":"RTHC-05532","title":"Clinical and Family Implications of Cannabidiol (CBD)-Dominant Full-Spectrum Phytocannabinoid Extract in Children and Adolescents with Moderate to Severe Non-Syndromic Autism Spectrum Disorder (ASD): An Observational Study on Neurobehavioral Management.","authors":"Mazza, Jeanne Alves de Souza; Ferreira, Lisiane Seguti; Martins-Vieira, Alice de Faria; Beserra, Doris Day Lopes; Rodrigues, Victor Alves; Malcher-Lopes, Renato; Caixeta, Fabio V","year":2024,"journal":"Pharmaceuticals (Basel, Switzerland), 17(6)","doi":"10.3390/ph17060686","pmid":"38931353","tags":["cbd","medical-cannabis","youth","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Thirty children (5-18) with moderate-severe ASD showed improvements in communication, attention, learning, eye contact, and reduced aggression. Both clinical and parental assessments confirmed improvements with minimal adverse effects.","whyItMatters":"Current autism pharmacotherapy is limited. If CBD-dominant extracts safely improve core symptoms, they could fill a major treatment gap.","specificNumbers":"30 patients aged 5-18. CBD:THC ratio 33:1. Improvements in communication, attention, learning, eye contact. Reduced aggression. Minimal adverse effects.","methodology":"Retrospective observational cohort of 30 ASD patients aged 5-18 treated with CBD-dominant extract (33:1 CBD:THC) at individualized doses.","limitations":"No placebo control. Retrospective. Small sample. Individualized dosing. Unblinded assessments."},{"rthcId":"RTHC-05533","title":"The Effect of Cannabidiol on Subjective Responses to Endurance Exercise: A Randomised Controlled Trial.","authors":"McCartney, Danielle; Irwin, Christopher; Bawa, Zeeta; Palmer, Blake; Sahinovic, Ayshe; Delang, Nathan; Cox, Gregory R; Desbrow, Ben; Lau, Namson S; McGregor, Iain S","year":2024,"journal":"Sports medicine - open, 10(1), 61","doi":"10.1186/s40798-024-00727-3","pmid":"38782848","tags":["cbd","exercise"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 51 participants, 150mg oral CBD 90 minutes before a self-paced 10km run had no significant effects on any outcome compared to placebo. Exercise itself improved mood and reduced anxiety.","whyItMatters":"CBD is increasingly marketed to athletes. This trial found no enhancement of exercise experience, providing evidence against marketing claims while confirming CBD does not impair exercise.","specificNumbers":"51 participants. 150mg oral CBD. Zero significant effects on any outcome. Exercise itself improved mood.","methodology":"Randomized, double-blind, placebo-controlled, crossover trial. 51 participants (22 female, median age 22). 150mg CBD or placebo before outdoor 10km run.","limitations":"Single 150mg dose. Recreational population. Acute single-dose design. Outdoor running variability."},{"rthcId":"RTHC-05534","title":"Products and patterns through which adolescents, young adults, and adults initiate co-use of tobacco and cannabis.","authors":"McCauley, Devin M; Liu, Jessica; Gaiha, Shivani Mathur; Halpern-Felsher, Bonnie","year":2024,"journal":"Addictive behaviors, 158, 108105","doi":"10.1016/j.addbeh.2024.108105","pmid":"39047653","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"38.4% of participants co-used tobacco and cannabis. Among co-users, 70.9% tried tobacco first, with e-cigarettes being the first tobacco product for ~60% of those who started with tobacco.","whyItMatters":"Understanding the sequence from e-cigarettes to cannabis can help design prevention programs targeting the most common entry point.","specificNumbers":"6,131 participants. 38.4% co-used. 70.9% tried tobacco first. ~60% started with e-cigarettes.","methodology":"Cross-sectional national survey of 6,131 participants aged 13-40 reporting use of 17 tobacco and cannabis products.","limitations":"Cross-sectional with retrospective recall. Does not establish causation."},{"rthcId":"RTHC-05535","title":"Association of Cannabis Use Reduction With Improved Functional Outcomes: An Exploratory Aggregated Analysis From Seven Cannabis Use Disorder Treatment Trials to Extract Data-Driven Cannabis Reduction Metrics.","authors":"McClure, Erin A; Neelon, Brian; Tomko, Rachel L; Gray, Kevin M; McRae-Clark, Aimee L; Baker, Nathaniel L","year":2024,"journal":"The American journal of psychiatry, 181(11), 988-996","doi":"10.1176/appi.ajp.20230508","pmid":"39380374","tags":["addiction","quitting","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"In 920 participants across 7 CUD trials, reductions in use were associated with improvements in cannabis-related problems, clinician ratings, and sleep. CART models identified ~47% reduction in use days and ~74% reduction in amounts as improvement thresholds.","whyItMatters":"This provides data-driven evidence that significant reduction without complete abstinence produces meaningful clinical improvement.","specificNumbers":"920 participants, 7 trials. CART: 74% reduction in amounts, 47% reduction in days predicted improvement. CGI classification: 72-75% accuracy.","methodology":"Exploratory aggregated analysis of 7 US-based CUD treatment trials (N=920, ages 13+, mean age 25). GEE and CART models.","limitations":"Exploratory, not pre-specified. CART accuracy varied (40-75%). Aggregated data from different designs. Correlation not causation."},{"rthcId":"RTHC-05536","title":"Age-dependent association of cannabis use with risk of psychotic disorder.","authors":"McDonald, André J; Kurdyak, Paul; Rehm, Jürgen; Roerecke, Michael; Bondy, Susan J","year":2024,"journal":"Psychological medicine, 54(11), 2926-2936","doi":"10.1017/S0033291724000990","pmid":"38775165","tags":["psychosis","youth","potency"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Among 11,363 Ontario youth, cannabis use was associated with 11.2-fold increased psychosis risk during adolescence (12-19) but only non-significant 1.3-fold during young adulthood (20-33). Restricting to hospitalizations/ER: 26.7-fold risk in adolescents.","whyItMatters":"One of the strongest demonstrations of age-dependent psychosis risk, using population data and healthcare records. The dramatically higher adolescent risk has direct prevention implications.","specificNumbers":"N=11,363. Adolescence: aHR=11.2 (CI 4.6-27.3). Young adulthood: aHR=1.3 (CI 0.6-2.6). Hospitalizations only: adolescence aHR=26.7 (CI 7.7-92.8).","methodology":"Population-based cohort linking 2009-2012 survey data with Ontario universal healthcare records through 2018. N=11,363 aged 12-24 with no prior psychotic disorder.","limitations":"Observational. Single baseline cannabis measure. Possible confounding. Wide confidence intervals for hospitalization analysis."},{"rthcId":"RTHC-05537","title":"Cannabinoid Hyperemesis Syndrome (CHS) - An emerging gastrointestinal disorder and clinical challenge.","authors":"McFee, R B","year":2024,"journal":"Disease-a-month : DM, 70(12), 101832","doi":"10.1016/j.disamonth.2024.101832","pmid":"39632124","tags":["medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS is characterized by cyclic, severe vomiting, compulsive hot showering, and chronic cannabis use history. Standard antiemetics may not fully work. Abstinence remains the most effective long-term approach.","whyItMatters":"CHS is under-recognized, leading to repeated unnecessary ER visits and testing. Better recognition could reduce costs and patient suffering.","specificNumbers":"Ondansetron may not fully attenuate symptoms. Abstinence is most effective prevention.","methodology":"Clinical review article aimed at helping clinicians identify and treat CHS.","limitations":"Narrative review. CHS pathophysiology incompletely understood. Treatment evidence from case reports mostly."},{"rthcId":"RTHC-05538","title":"Gastrointestinal disorders - Clinical challenges for the primary care clinician.","authors":"McFee, Robin B","year":2024,"journal":"Disease-a-month : DM, 70(12), 101828","doi":"10.1016/j.disamonth.2024.101828","pmid":"39627098","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05539","title":"An Exploration of Registered Nurses' Experiences Caring for Patients Taking Medicinal Cannabis.","authors":"McIntosh, Nicole; Wilson, Nathan J; Povalej, Petra; Hunt, Leanne; Lewis, Peter","year":2024,"journal":"Nursing open, 11(10), e70063","doi":"10.1002/nop2.70063","pmid":"39455290","tags":["medical-cannabis"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Eleven nurses described feeling underprepared. Three themes: searching for predictable processes, facing conundrums, and recognizing much to learn. All emphasized the need for education.","whyItMatters":"As medicinal cannabis grows, nurses on the front lines receive little training. This gap affects patient experience and potentially safety.","specificNumbers":"11 nurses interviewed. Three themes. All emphasized education needs.","methodology":"Qualitative study with thematic analysis of semi-structured interviews with 11 registered nurses in Australian healthcare. COREQ guidelines followed.","limitations":"Small sample (n=11). Australian only. Not generalizable."},{"rthcId":"RTHC-05540","title":"Feeding spent hemp biomass does not adversely affect fertility in rams.","authors":"Meador, Melanie A; Ates, Serkan; Kutzler, Michelle A","year":2024,"journal":"American journal of veterinary research, 85(11)","doi":"10.2460/ajvr.24.05.0134","pmid":"39191267","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05541","title":"Regulatory Landscape of Cannabis Warning Labels in US States with Legal Retail Nonmedical Cannabis, 2024.","authors":"Meek, Caroline J; Ranney, Leah M; Clark, Sonia A; Jarman, Kristen L; Callanan, Rachel; Kowitt, Sarah D","year":2024,"journal":"American journal of public health, 114(S8), S681-S684","doi":"10.2105/AJPH.2024.307722","pmid":"39442026","tags":["harm-reduction","legalization","youth","psychosis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 20 states with legal retail cannabis, only 2 required mental health risk warnings and 2 required high-potency psychosis warnings. No states required front-of-package placement. Only 2 required rotating warnings, and 4 required contrasting colors. Warning labels averaged 57 words and were often vague with small or no minimum font size.","whyItMatters":"Cannabis warning labels are one of the few points of contact between regulators and consumers. Current labels are long, buried, and silent on the most evidence-supported risks like psychosis from high-potency products.","specificNumbers":"20 states analyzed. 2 (10%) required mental health warnings. 2 (10%) required high-potency psychosis warnings. 0 required front-of-package placement. Mean warning length: 57 words. 2 states required rotating warnings. 4 required contrasting colors.","methodology":"Content analysis of nonmedical cannabis warning label regulations across 20 US states with legal retail cannabis as of March 2024, examining required content and design characteristics.","limitations":"Analyzed regulations as written, not how they appear on actual products. Did not assess consumer comprehension or behavioral impact of existing warnings. Rapidly changing regulatory landscape may have already shifted since data collection."},{"rthcId":"RTHC-05542","title":"Effectiveness of the adolescent-community reinforcement approach for treating Cannabis use disorder in Iranian adolescents: A randomized controlled trial.","authors":"Mehr, Najmeh Khosrovan; Lavasani, Fahimeh Fathali; Noroozi, Alireza; Farahani, Hojjatollah; Gharraee, Banafsheh","year":2024,"journal":"Acta psychologica, 251, 104604","doi":"10.1016/j.actpsy.2024.104604","pmid":"39561460","tags":["addiction","youth","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 40 male adolescents with CUD, those receiving A-CRA (n=20) showed higher abstinence rates, reduced cannabis use frequency, decreased substance-related problems, lower psychological distress, improved health-promoting lifestyles, and better mother-adolescent relationships compared to treatment as usual, with effects maintained at three-month follow-up.","whyItMatters":"This is the first test of A-CRA outside Western contexts, demonstrating that an evidence-based adolescent cannabis treatment can be effective in a culturally distinct population with compounding socioeconomic vulnerabilities.","specificNumbers":"40 participants (all male, aged 15-18, mean age 15.87). 20 per group. Assessments at pre-test, post-intervention, and 3-month follow-up. Improvements across abstinence, use frequency, substance problems, distress, and family relationships.","methodology":"Randomized controlled trial of 40 male adolescents aged 15-18 diagnosed with CUD, recruited from child labor welfare educational centers in Tehran. Participants randomized to A-CRA or treatment as usual, assessed at baseline, post-intervention, and three-month follow-up.","limitations":"Small sample (n=40) of only males from a specific vulnerable population (child labor centers). Purposive sampling limits generalizability. No biological verification of abstinence mentioned. Three-month follow-up is relatively short."},{"rthcId":"RTHC-05543","title":"MP-13, a novel chimeric peptide of morphiceptin and pepcan-9, produces potent antinociception with limited side effects.","authors":"Mei, Chenxi; Zhang, Jing; Niu, Zhanyu; Simon, Jerine Peter; Yang, Tong; Huang, Mingmin; Zhang, Zhonghua; Zhou, Lanxia; Dong, Shouliang","year":2024,"journal":"Neuropeptides, 107, 102440","doi":"10.1016/j.npep.2024.102440","pmid":"38875739","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05544","title":"Heteromers Formed by GPR55 and Either Cannabinoid CB1 or CB2 Receptors Are Upregulated in the Prefrontal Cortex of Multiple Sclerosis Patients.","authors":"Menéndez-Pérez, Carlota; Rivas-Santisteban, Rafael; Del Valle, Eva; Tolivia, Jorge; Navarro, Ana; Franco, Rafael; Martínez-Pinilla, Eva","year":2024,"journal":"International journal of molecular sciences, 25(8)","doi":"10.3390/ijms25084176","pmid":"38673761","tags":["neuroscience","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Using proximity ligation assays and immunohistochemistry on postmortem brain samples, researchers identified CB1R-GPR55 and CB2R-GPR55 heteromers in the human prefrontal cortex for the first time. Both receptor complexes were more abundant in grey matter than white matter and were significantly upregulated in MS patients versus controls.","whyItMatters":"Receptor heteromers behave differently than individual receptors. The discovery that cannabinoid receptor complexes are upregulated in MS brains opens a new avenue for targeted therapies that could be more precise than current cannabinoid treatments.","specificNumbers":"CB1R-GPR55 and CB2R-GPR55 heteromers identified for the first time in human prefrontal cortex. Both more abundant in grey matter. Both significantly increased in MS brain samples versus controls.","methodology":"In situ proximity ligation assays and immunohistochemical techniques on postmortem prefrontal cortex samples from MS patients and control subjects to identify and quantify cannabinoid receptor heteromers.","limitations":"Postmortem tissue study cannot determine whether receptor upregulation is a cause or consequence of MS pathology. Small sample sizes typical of postmortem brain studies. Prefrontal cortex findings may not generalize to other brain regions affected by MS."},{"rthcId":"RTHC-05545","title":"Why Are Adolescent Cannabis Use Disorder Treatment Admissions Declining in the US? The Mediated Pathway of State Treatment Admissions Rates before and after Recreational Cannabis Legalization.","authors":"Mennis, Jeremy; Stahler, Gerald J; Coffman, Donna L","year":2024,"journal":"Substance use & misuse, 59(6), 962-970","doi":"10.1080/10826084.2024.2310500","pmid":"38297820","tags":["youth","addiction","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Before legalization, perceiving cannabis as low-risk predicted more use, which predicted more CUD treatment admissions. After legalization, the perception-to-use link strengthened but the use-to-treatment link was suppressed. The indirect effect of low-risk perception on treatment admissions via cannabis use existed before legalization but disappeared after.","whyItMatters":"Declining teen treatment admissions after legalization could be misread as declining need. This study suggests the decline reflects changing social norms and self-medication patterns, not less problematic use, meaning more teens with CUD may be going untreated.","specificNumbers":"542 state-year observations from 2008-2019. Positive indirect effect of low-risk perception on CUD treatment via cannabis use before legalization, but not after. Legalization strengthened perception-to-use pathway and suppressed use-to-treatment pathway.","methodology":"Two-way fixed effects (state and year) moderated mediation model using NSDUH and TEDS-A data from 2008-2019 (542 state-year observations) examining adolescents aged 12-17 across US states.","limitations":"State-level prevalence data cannot capture individual-level pathways. Cannot distinguish between voluntary and mandated treatment admissions (legal referrals may decline with legalization). 2008-2019 data precedes the most recent legalization wave."},{"rthcId":"RTHC-05546","title":"Interpersonal Influences on the Choice to Treat Nausea during Pregnancy with Medication or Cannabis.","authors":"Mercer, Amanda H; MacDuffie, Katherine E; Weiss, Elliott M; Johnson, Allegra; Dager, Stephen R; Kleinhans, Natalia","year":2024,"journal":"American journal of perinatology, 41(S 01), e2941-e2951","doi":"10.1055/a-2183-9013","pmid":"37774747","tags":["pregnancy","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Four stakeholder groups influenced treatment decisions: medical providers, partners, family, and friends. The medication group reported only positive or neutral feedback. The cannabis group reported positive feedback from friends but negative, stigmatizing feedback from providers and mixed feedback from family and partners. Many cannabis users concealed their treatment choice after negative reactions.","whyItMatters":"When pregnant people using cannabis for nausea feel stigmatized by providers, they may stop disclosing their use entirely, removing healthcare professionals from the conversation about safer alternatives or monitoring.","specificNumbers":"17 participants interviewed. 4 stakeholder groups identified. Cannabis group reported negative provider feedback described as stigmatizing. Multiple cannabis users concealed their treatment choice.","methodology":"Semi-structured interviews with 17 pregnant individuals enrolled in a neuroimaging study of prenatal cannabis exposure, exploring interpersonal influences on decisions to treat pregnancy nausea with medication or cannabis.","limitations":"Very small sample (n=17) from a single neuroimaging study. Participants self-selected into cannabis or medication groups, introducing selection bias. Qualitative design provides depth but not prevalence estimates."},{"rthcId":"RTHC-05547","title":"Mitigating the Risk of QTc Prolongation When Using Haloperidol for Acute Treatment of Cannabinoid Hyperemesis Syndrome in Adolescents and Young Adults.","authors":"Merino, Sandra; Tordera, Lissette; Jun, Allison; Yang, Sun","year":2024,"journal":"Journal of clinical medicine, 14(1)","doi":"10.3390/jcm14010163","pmid":"39797246","tags":["cardiovascular","harm-reduction","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 15-year-old with CHS developed QTc prolongation to 528 msec with hypokalemia and hypomagnesemia during haloperidol treatment. A 17-year-old had borderline QTc prolongation (476 msec). Literature review identified five additional severe cases of QTc prolongation or Torsades de Pointes in adolescents and young adults treated for CHS.","whyItMatters":"Haloperidol is becoming a go-to treatment for CHS in emergency departments, but both cannabis itself and haloperidol independently prolong QTc. Combined with the electrolyte imbalances from vomiting, CHS patients face a triple threat to cardiac safety.","specificNumbers":"Case 1: 15-year-old female, QTc 528 msec, hypokalemia and hypomagnesemia. Case 2: 17-year-old female, QTc 476 msec (borderline). Literature review: 5 additional severe cases including life-threatening TdP episodes.","methodology":"Two case reports of adolescent CHS patients treated in the emergency department, supplemented by a systematic literature review through October 2024 for QTc prolongation and TdP cases in CHS treatment.","limitations":"Case reports cannot establish incidence rates. Seven total cases across the literature may underrepresent or overrepresent the true risk. No controlled comparison of haloperidol versus alternative antiemetics for cardiac safety in CHS."},{"rthcId":"RTHC-05548","title":"Association between cannabis use and physical activity in the United States based on legalization and health status.","authors":"Merrill, Ray M; Ashton-Hwang, Kendyll; Gallegos, Liliana","year":2024,"journal":"Journal of cannabis research, 6(1), 39","doi":"10.1186/s42238-024-00248-6","pmid":"39385308","tags":["exercise","legalization","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"After adjusting for demographics, smoking, BMI, and legalization status, cannabis users had 24% higher odds of physical activity (OR 1.24). In states with legal recreational cannabis, the adjusted OR was 1.47. In medical-only states, the association was not significant (OR 1.05). Among users with chronic medical conditions, cannabis use offset the lower physical activity typically seen in that group.","whyItMatters":"The persistent stereotype that cannabis makes people sedentary is contradicted by large population data. The finding that cannabis users with chronic conditions maintain activity levels comparable to healthy non-users suggests cannabis may facilitate physical activity for people managing pain or other barriers.","specificNumbers":"Physical activity: 73.2% (2016) to 75.7% (2022). Cannabis use: 7.5% (2016) to 14.7% (2022), a 96.7% increase. Overall adjusted OR: 1.24. Recreational legal states: OR 1.47. Medical-only states: OR 1.05. Chronic condition adjusted OR for physical activity: 0.79 (non-users) vs. non-significant reduction (users).","methodology":"Analysis of BRFSS data from 2016-2022 using logistic regression to examine the association between past-30-day cannabis use and physical activity among US adults, stratified by legalization status and chronic medical conditions.","limitations":"Cross-sectional design cannot determine whether cannabis promotes activity, active people are more likely to use cannabis, or a third factor drives both. Self-reported data for both cannabis use and physical activity. BRFSS samples vary by state participation."},{"rthcId":"RTHC-05549","title":"Assessment of education in a community hospital on healthcare providers' knowledge of and attitudes toward medical marijuana.","authors":"Meyers, Sierra; Gant, Kisha; Burmeister, Melissa","year":2024,"journal":"Currents in pharmacy teaching & learning, 16(6), 396-403","doi":"10.1016/j.cptl.2024.03.007","pmid":"38538449","tags":["medical-cannabis","harm-reduction","drug-interactions"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"All four provider groups showed significant post-education knowledge improvements: physicians (P<.01), nurses (P<.001), pharmacists (P<.01), and nurse technicians (P<.05). Chart review found 72 of 87 patients (83%) who self-reported marijuana use had at least one potential drug-drug interaction.","whyItMatters":"Healthcare providers are the frontline for catching dangerous drug interactions, but most have never received formal education on cannabis pharmacology. A single session produced measurable knowledge gains, suggesting this is a fixable gap.","specificNumbers":"43 providers participated. Significant knowledge gains: physicians (P<.01), nurses (P<.001), pharmacists (P<.01), nurse technicians (P<.05). Chart review: 72/87 patients (83%) with marijuana use had potential drug interactions.","methodology":"Pre- and post-education survey of 43 healthcare providers at a community hospital, with multiple-choice knowledge questions and Likert-scale attitude assessment. Secondary outcome: retrospective chart review of drug interactions in marijuana-using patients.","limitations":"Small sample (n=43) from a single community hospital. No control group. Post-test immediately after education does not measure long-term knowledge retention. Chart review identified potential, not actual, drug interactions."},{"rthcId":"RTHC-05550","title":"The effects of cannabis abstinence on cognition and resting state network activity in people with multiple sclerosis: A preliminary study.","authors":"Meza, Cecilia; Stefan, Cristiana; Staines, W Richard; Feinstein, Anthony","year":2024,"journal":"NeuroImage. Clinical, 43, 103622","doi":"10.1016/j.nicl.2024.103622","pmid":"38815510","tags":["cognition","medical-cannabis","neuroscience"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"The cannabis withdrawal group showed increased activation at day 28 in the left posterior cingulate, right angular gyrus, left hippocampus, and right medial prefrontal cortex compared to baseline. The cannabis continuation group showed no changes. Cognitive improvements accompanied the brain changes in the withdrawal group.","whyItMatters":"This study provides direct neuroimaging evidence that cannabis-related cognitive impairment in MS is reversible. The default mode network changes map onto the specific brain regions responsible for the cognitive improvements observed.","specificNumbers":"33 participants (15 continuation, 18 withdrawal). Key regions with increased activation after abstinence: left posterior cingulate, right angular gyrus, left hippocampus (BA 36), right medial prefrontal cortex. All p<0.05 TFCE corrected. Multiple cognitive domain improvements in withdrawal group.","methodology":"Prospective study of 33 cognitively impaired people with MS who were frequent cannabis users, assigned to cannabis continuation (n=15) or withdrawal (n=18) groups. Neuropsychological assessments and resting-state fMRI at baseline and day 28, with urine monitoring for compliance.","limitations":"Small sample without randomization (assignment, not random allocation, to groups). 28-day follow-up may not capture full recovery trajectory. Cannot separate cannabis withdrawal effects from direct recovery of suppressed brain function."},{"rthcId":"RTHC-05551","title":"Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts.","authors":"Mick, Gérard; Douek, Pascal","year":2024,"journal":"Pain and therapy, 13(5), 1063-1094","doi":"10.1007/s40122-024-00643-0","pmid":"39096481","tags":["medical-cannabis","pain","cbd"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"THC-predominant and balanced THC/CBD products showed the strongest evidence for chronic neuropathic pain. Balanced products were also effective for MS spasticity. Most products showed symptomatic benefits for anxiety, nausea, and sleep. Adverse effects were mostly non-serious, transient, and dose-dependent. Clinical studies found little evidence of dependence potential, contrasting with recreational use data.","whyItMatters":"The review distinguishes between THC-predominant, balanced, and CBD-predominant products, providing clinicians with practical guidance on which formulations have the best evidence for which conditions.","specificNumbers":"THC-predominant and balanced products supported for chronic neuropathic pain. Balanced products effective for MS spasticity. Symptomatic improvements in anxiety, nausea, and sleep across product types. Adverse effects mostly non-serious and transient.","methodology":"Narrative review evaluating published evidence from randomized controlled trials, other controlled studies, and observational real-world registry studies on the clinical benefits, safety, and dependence potential of cannabis-based medicinal products.","limitations":"Narrative review methodology allows selective evidence inclusion. Observational registry data may have reporting bias. Most evidence comes from short-to-medium term studies. Comparison across different products and formulations is inherently difficult."},{"rthcId":"RTHC-05552","title":"Neuroanatomical Variability and Substance Use Initiation in Late Childhood and Early Adolescence.","authors":"Miller, Alex P; Baranger, David A A; Paul, Sarah E; Garavan, Hugh; Mackey, Scott; Tapert, Susan F; LeBlanc, Kimberly H; Agrawal, Arpana; Bogdan, Ryan","year":2024,"journal":"JAMA network open, 7(12), e2452027","doi":"10.1001/jamanetworkopen.2024.52027","pmid":"39786408","tags":["youth","neuroscience","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Among 9,804 children, 35.3% initiated substance use before age 15. Substance initiation was associated with thinner prefrontal cortex (especially rostral middle frontal gyrus), thicker cortex elsewhere, larger globus pallidus and hippocampus, and greater whole brain volume. Cannabis initiation specifically was associated with lower right caudate volume. Post hoc analyses confirmed most associations preceded substance use onset.","whyItMatters":"The finding that brain differences precede substance use challenges the assumption that all brain changes in young users are caused by drugs. Preexisting neuroanatomical variability may mark vulnerability, which has implications for prevention targeting.","specificNumbers":"9,804 children (52.6% boys, mean age 9.9 years). 3,460 (35.3%) initiated substance use before age 15. Key finding: rostral middle frontal gyrus thinning (beta=-0.03, P=6.99x10^-6). Whole brain volume (beta=0.05, P=2.80x10^-8). Cannabis: lower right caudate volume (beta=-0.03, P=.002).","methodology":"Longitudinal analysis of the ABCD Study following children from ages 9-11 through 3-year follow-up. Baseline MRI brain structure measures examined against substance use initiation. Covariates included family, pregnancy, child, and MRI variables.","limitations":"Three-year follow-up captures early initiation only; longer follow-up needed to see whether associations hold for later onset. Self-reported substance use in children may underreport actual use. Cannot fully disentangle genetic, prenatal, and environmental contributors to brain variability."},{"rthcId":"RTHC-05553","title":"Examining the effect of cannabis cues on cannabis demand in sleep, driving, and typical drug-use contexts.","authors":"Miller, Brandon P; Aston, Elizabeth R; Davis, William; Berey, Benjamin L; Dowd, Ashley N; Amlung, Michael","year":2024,"journal":"Drug and alcohol dependence, 254, 111057","doi":"10.1016/j.drugalcdep.2023.111057","pmid":"38101283","tags":["addiction","driving","sleep"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis picture cues increased self-reported craving (p=.044) but did not significantly alter demand on purchase tasks. In the driving context, participants showed significantly reduced cannabis demand. In the sleep context, cannabis cues increased demand intensity and breakpoint. No changes occurred in the typical-use context.","whyItMatters":"This is the first study to test whether real-world contexts like driving and sleep change how much cannabis people want to buy. The finding that driving context reduced demand suggests that risk awareness can compete with drug motivation.","specificNumbers":"79 weekly cannabis users. Cannabis cues increased craving (p=.044). Driving context: significant reduction in demand. Sleep context: increased intensity (p=.013) and breakpoint (p=.035) with cannabis cues. Typical use: no significant changes.","methodology":"Laboratory study of 79 adults who smoked cannabis at least weekly, completing hypothetical marijuana purchase tasks in typical-use, driving, and sleep contexts, alternated with cannabis or neutral picture cues in a block-randomized design.","limitations":"Hypothetical purchase tasks may not reflect real-world behavior. Small sample of weekly users from one area. Laboratory setting cannot fully replicate real-world driving or sleep contexts. First study in this area needs replication."},{"rthcId":"RTHC-05554","title":"Predicting changes in driving performance in individuals who use cannabis following acute use based on self-reported readiness to drive.","authors":"Miller, Ryan; Brown, Timothy; Schmitt, Rose; Gaffney, Gary; Milavetz, Gary","year":2024,"journal":"Accident; analysis and prevention, 195, 107376","doi":"10.1016/j.aap.2023.107376","pmid":"37984112","tags":["driving","addiction","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Can cannabis users tell when they shouldn't drive? This study takes a more granular approach than the French study (RTHC-00093) by examining not just whether self-assessment correlates with impairment, but what factors make self-assessment more or less accurate.\n\nRegular cannabis users (at least monthly) were dosed with cannabis containing approximately 6.18% THC, then drove on a simulator at 30, 90, and 180 minutes post-dose. Before each drive, they answered a simple yes/no question: 'Do you feel safe to drive on real roads right now?'\n\nThe results showed self-assessed readiness to drive (RTD) had predictive value. Participants who said 'no, I don't feel safe to drive' showed more driving impairment (measured by standard deviation of lane position — SDLP) than those who said yes. Previous experience driving after cannabis use also mattered: people who had driven within 2 hours of cannabis use in the past, and those who did so more frequently, showed different performance patterns.\n\nBut self-assessment wasn't perfect. Some participants who said they felt safe to drive still showed impairment on the simulator. The gap between perceived and actual safety is the critical concern — it's the window where impaired driving occurs because the user doesn't recognize their impairment.\n\nThe study design parsed driving into specific events (lane changes, curves, intersections) rather than averaging across the whole drive, allowing a more detailed picture of where impairment manifests.","whyItMatters":"The practical question for millions of cannabis users isn't abstract — it's 'can I drive right now?' This study provides evidence that self-assessment has value but isn't foolproof. Users who say they feel unsafe to drive should absolutely not drive, but users who feel safe may still be impaired. This has direct implications for public health messaging: encouraging self-assessment as a first check is worthwhile, but it shouldn't replace objective standards.","specificNumbers":"Cannabis dose: ~6.18% THC. Drives at 30, 90, and 180 minutes post-dose. RTD (readiness to drive) assessed before each drive. SDLP (standard deviation of lane position) measured within driving events. Participants who said they didn't feel safe to drive showed more impairment. Prior experience driving after cannabis use influenced both self-assessment and performance.","methodology":"Observational study with controlled cannabis dosing. Participants who used cannabis at least monthly completed a baseline drive, were dosed with ~6.18% THC, then drove at ~30, 90, and 180 minutes post-dose. Self-reported readiness to drive (RTD, yes/no) assessed before each drive. Venous blood drawn at baseline and ~15 minutes post-dose. Cannabis use history obtained including prior experience driving within 2 hours of use. Driving segmented into events; SDLP measured within events.","limitations":"Relatively low THC dose (6.18%) compared to typical consumer products (often 20%+). Driving simulator, not real-world driving. Self-reported readiness was a simple yes/no — a scaled response might capture more nuance. Study population limited to regular users (at least monthly), so findings may not apply to occasional users who likely have less calibrated self-assessment. The segmented event analysis is innovative but complex to interpret."},{"rthcId":"RTHC-05555","title":"Surgery-Related Considerations in Treating People Who Use Cannabis: A Review.","authors":"Mims, Mark M; Parikh, Aniruddha C; Sandhu, Zainab; DeMoss, Noah; Mhawej, Rachad; Queimado, Lurdes","year":2024,"journal":"JAMA otolaryngology-- head & neck surgery, 150(10), 918-924","doi":"10.1001/jamaoto.2024.2545","pmid":"39172477","tags":["harm-reduction","drug-interactions","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis users may require higher anesthesia doses due to tolerance, face increased rates of myocardial ischemia, and experience prolonged sedation. Postoperative effects include potentially increased pain, nausea, and vomiting. Topical cannabinoids may improve wound healing. Significant drug interactions exist with anticoagulants. Cannabis use disorder is associated with increased perioperative morbidity and mortality.","whyItMatters":"With cannabis use rising and many patients not disclosing it, surgeons may be managing anesthesia, pain, and medications without knowing about a substance that affects all of these. The consequences range from inadequate anesthesia to dangerous drug interactions.","specificNumbers":"Higher anesthesia tolerance documented. Increased myocardial ischemia risk. Prolonged sedation effects. Significant drug interactions with anticoagulant medications. CUD associated with increased perioperative morbidity and mortality.","methodology":"Clinical review published in JAMA Otolaryngology synthesizing evidence on how cannabis use affects surgical care phases, including preoperative, intraoperative, and postoperative considerations.","limitations":"Review format with mixed-quality underlying evidence. Many effects described as potential or inconsistent across studies. Focused on otolaryngology context but findings apply broadly. Does not provide quantified risk estimates for most outcomes."},{"rthcId":"RTHC-05556","title":"Co-morbid cannabis use disorder and chronotype are associated with mood symptom onset in people with bipolar disorder.","authors":"Miranda, Alannah; Holloway, Breanna M; Perry, William; Minassian, Arpi; McCarthy, Michael","year":2024,"journal":"Journal of psychiatric research, 180, 327-332","doi":"10.1016/j.jpsychires.2024.11.007","pmid":"39515185","tags":["addiction","mental-health","sleep"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Lower morningness (evening chronotype) and CUD were independently associated with earlier age of mood symptom onset in bipolar disorder. There was no interaction between the two. Patients who began cannabis use after mood symptoms started had earlier mood onset than those who used cannabis first, suggesting circadian disruption may be an underlying factor linking both CUD and BD.","whyItMatters":"The finding that people who started cannabis after mood symptoms had earlier onset challenges the simple narrative that cannabis causes bipolar symptoms. Instead, disrupted circadian rhythms may predispose people to both conditions independently.","specificNumbers":"212 participants with BD I. Lower morningness and CUD both independently associated with earlier mood onset. No interaction effect. Post-mood-onset cannabis initiators had earlier mood symptom onset than pre-mood-onset initiators.","methodology":"Cross-sectional analysis of 212 participants with bipolar I disorder from the Pharmacogenomics of Bipolar Disorder study, examining chronotype (BALM scale), CUD diagnosis, and mood symptom variables including episodes per year and age of onset.","limitations":"Cross-sectional design cannot establish causal direction. Self-reported chronotype and cannabis use history subject to recall bias. BD I only; findings may not apply to BD II. BALM scale is a simplified chronotype measure."},{"rthcId":"RTHC-05557","title":"Cannabis Use and Associated Risk Behavior Factors among High School Students in Mississippi: Youth Risk Behavior Surveillance System 2021.","authors":"Mitra, Amal K; Zhang, Zhen; Schroeder, Julie A","year":2024,"journal":"International journal of environmental research and public health, 21(8)","doi":"10.3390/ijerph21081109","pmid":"39200718","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In multivariable analysis adjusting for gender, race, grade, and other risk behaviors, cannabis use was significantly associated with current electronic vaping, current tobacco smoking, current alcohol drinking, and sexual behaviors. Univariate analysis also identified associations with carrying weapons on campus, suicidal attempts, and unsupervised time, but these lost significance after adjustment.","whyItMatters":"Cannabis rarely occurs in isolation among high schoolers. The clustering of cannabis with vaping, alcohol, tobacco, and sexual risk behaviors suggests prevention programs need to address multiple substances simultaneously rather than targeting cannabis alone.","specificNumbers":"Seven risk behaviors associated with cannabis use in univariate analysis. Four remained significant in multivariable analysis: e-vaping, tobacco smoking, alcohol use, sexual behaviors. Cannabis use evenly distributed across gender and race categories.","methodology":"Cross-sectional analysis of 2021 Mississippi Youth Risk Behavior Surveillance System (YRBS) data using survey-weighted logistic regression to examine associations between current cannabis use and other risk behaviors among high school students.","limitations":"Cross-sectional YRBS data cannot determine temporal ordering or causation. Self-reported behaviors in a school setting may underreport. Mississippi-specific findings may not generalize to other states. 2021 data may not reflect current patterns."},{"rthcId":"RTHC-05558","title":"Renal Outcomes and Other Adverse Effects of Cannabinoid Supplementation.","authors":"Młynarska, Ewelina; Kustosik, Natalia; Mejza, Maja; Łysoń, Zuzanna; Delebis, Dawid; Orliński, Jakub; Rysz, Jacek; Franczyk, Beata","year":2024,"journal":"Nutrients, 17(1)","doi":"10.3390/nu17010059","pmid":"39796493","tags":["medical-cannabis","cbd","synthetic-cannabinoids"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"CB2 agonists showed therapeutic potential in diabetic nephropathy, chronic kidney disease, and obesity-related kidney dysfunction. CB1 antagonists also showed benefits. Cannabinoids may have diuretic and anti-inflammatory effects that reduce kidney stone risk. However, synthetic cannabinoids are strongly associated with acute kidney injury. Cannabinoid hyperemesis syndrome can also cause kidney damage through ischemia-reperfusion injury.","whyItMatters":"Kidney health is rarely discussed in cannabis contexts, but millions of people with chronic kidney disease or diabetes-related kidney problems may benefit from targeted cannabinoid therapies, while synthetic cannabinoid users face serious renal risks.","specificNumbers":"CB1 and CB2 receptor roles examined across diabetic nephropathy, CKD, and obesity-related kidney dysfunction. Synthetic cannabinoids linked to acute kidney injury. Potential diuretic and anti-inflammatory effects for kidney stone prevention.","methodology":"Narrative review examining cannabinoid receptor roles in kidney physiology, the effects of natural and synthetic cannabinoids on renal function, and the therapeutic potential and risks across multiple kidney conditions.","limitations":"Narrative review with selective evidence synthesis. Most kidney-specific cannabinoid research is preclinical. Clinical evidence for nephroprotection is limited. The review covers a very broad range of conditions, limiting depth on any single topic."},{"rthcId":"RTHC-05559","title":"Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease.","authors":"Moe, Alison; Rayasam, Aditya; Sauber, Garrett; Shah, Ravi K; Doherty, Ashley; Yuan, Cheng-Yin; Szabo, Aniko; Moore, Bob M; Colonna, Marco; Cui, Weiguo; Romero, Julian; Zamora, Anthony E; Hillard, Cecilia J; Drobyski, William R","year":2024,"journal":"The Journal of clinical investigation, 134(11)","doi":"10.1172/JCI175205","pmid":"38662453","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CB2 receptor expression on microglia induced an activated inflammatory phenotype that promoted accumulation of donor-derived proinflammatory T cells, regulated chemokine gene networks, and caused neuronal cell death in GVHD. A brain-penetrant CB2R inverse agonist/antagonist selectively reduced neuroinflammation without worsening systemic GVHD severity.","whyItMatters":"Neuroinflammation is a devastating complication of bone marrow transplants and other immunotherapies. This study identifies CB2R on microglia as a specific, druggable target that can be blocked in the brain without compromising the systemic immune response needed to fight disease.","specificNumbers":"CB2R expression on microglia drove inflammatory activation. Donor T cell accumulation regulated by microglial CB2R. Chemokine gene networks identified. Brain-penetrant CB2R antagonist reduced neuroinflammation without affecting systemic GVHD.","methodology":"Murine model of graft-versus-host disease examining CB2R signaling on microglial cells using genetic and pharmacological approaches. Tested a brain-penetrant CB2R inverse agonist/antagonist for selective neuroinflammation reduction.","limitations":"Mouse model of GVHD may not fully recapitulate human neuroinflammation. The brain-penetrant CB2R antagonist needs human safety and efficacy testing. Findings specific to GVHD context may not generalize to other forms of neuroinflammation."},{"rthcId":"RTHC-05560","title":"Effects of in utero delta-9-tetrahydrocannabinol (THC) exposure on fetal and infant musculoskeletal development in a preclinical nonhuman primate model.","authors":"Moellmer, Samantha A; Hagen, Olivia L; Farhang, Parsa A; Duke, Victoria R; Fallon, Meghan E; Hinds, Monica T; McCarty, Owen J T; Lo, Jamie O; Nakayama, Karina H","year":2024,"journal":"PloS one, 19(7), e0306868","doi":"10.1371/journal.pone.0306868","pmid":"39083456","tags":["pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"RNA analysis of fetal and infant skeletal muscle using a 770-gene neuroinflammatory panel revealed that prenatal THC exposure had narrow overall effects on muscle development. The greatest impacts were in pathways related to inflammation and cytokine signaling, suggesting potential for tissue damage and atrophy. Histomorphological evaluation showed limited changes in muscle morphology and composition.","whyItMatters":"This is the first study to examine prenatal THC effects on musculoskeletal development in a highly translational primate model. While effects were narrow, the inflammation signals raise concerns about longer-term functional consequences as offspring mature.","specificNumbers":"770 genes analyzed via Nanostring nCounter panel. Inflammation and cytokine signaling pathways most affected. Histomorphological changes limited. Pilot study establishes feasibility for follow-on research.","methodology":"Pilot study using a nonhuman primate model with chronic prenatal THC exposure. RNA isolated from skeletal muscle analyzed for differential gene expression using Nanostring nCounter neuroinflammatory panel (770 genes). Histomorphological evaluation of muscle morphology also performed.","limitations":"Pilot study with likely very small sample size (not specified in abstract). Nonhuman primate model is translational but not identical to human development. Gene panel focused on neuroinflammation, which may miss muscle-specific pathways. Short follow-up cannot capture long-term functional outcomes."},{"rthcId":"RTHC-05561","title":"Evaluation of Parameters Affecting Agrobacterium-Mediated Transient Gene Expression in Industrial Hemp (Cannabis sativa L.).","authors":"Mohammad, Tasnim; Ghogare, Rishikesh; Morton, Lauren B; Dhingra, Amit; Potlakayala, Shobha; Rudrabhatla, Sairam; Dhir, Sarwan K","year":2024,"journal":"Plants (Basel, Switzerland), 13(5)","doi":"10.3390/plants13050664","pmid":"38475511","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05562","title":"Evaluation of the immune system status and hematological dyscrasias, among amphetamine and cannabis abusers at Eradah Hospital in Qassim, Saudi Arabia.","authors":"Mohammed, Amal Hussain; Aljarallah, Atheer Saleh; Huq, Mohsina; Mackawy, Amal M H; Alharbi, Basmah F; Almutairi, Khulud Salem; Alruwetei, Abdulmohsen M; Almatroudi, Ahmad Abdulaziz A; Alharbi, Hajed Obaid; Aljohery, Said Abdel Mohsen A; Wasti, Afshan Zeeshan","year":2024,"journal":"Scientific reports, 14(1), 10600","doi":"10.1038/s41598-024-61182-4","pmid":"38719969","tags":["inflammation","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Significant changes (p<0.001) were found in all leukocyte types including neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Microscopic examination revealed hazardous alterations in neutrophils. Of 50 sputum samples, 35 (70%) showed positive fungal growth, indicating unicellular fungal infections. The majority of participants were aged 18-30 with 5-10 years of substance abuse.","whyItMatters":"Substance abuse can compromise immune function in ways that increase vulnerability to opportunistic infections. The high rate of fungal infections suggests immune suppression that may go unrecognized without targeted screening.","specificNumbers":"50 participants. 52% aged 18-30. 56% secondary school education. 50% had 5-10 years of abuse. Significant changes (p<0.001) in all WBC types. 35/50 (70%) sputum samples positive for fungal growth.","methodology":"Cross-sectional study of 50 amphetamine and cannabis abusers at Eradah Hospital in Qassim, Saudi Arabia. Assessed blood indices, differential WBC counts, liver and kidney profiles, and sputum cultures for fungal infections.","limitations":"Small sample (n=50) without a matched control group. Cannot separate effects of amphetamine from cannabis. No healthy control comparison for blood parameters. Single hospital in one Saudi region."},{"rthcId":"RTHC-05563","title":"Cannabidiol - Help and hype in targeting mucosal diseases.","authors":"Moniruzzaman, Md; Janjua, Taskeen Iqbal; Martin, Jennifer H; Begun, Jakob; Popat, Amirali","year":2024,"journal":"Journal of controlled release : official journal of the Controlled Release Society, 365, 530-543","doi":"10.1016/j.jconrel.2023.11.010","pmid":"37952828","tags":["cbd","medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD has demonstrated promise for alleviating gut and lung diseases in vitro, and Epidiolex is the only FDA/TGA-approved CBD product. However, CBD's poor water solubility, low oral bioavailability, and extensive first-pass metabolism significantly limit in vivo efficacy. Novel delivery methods including self-emulsifying emulsions, nanoparticles, and microparticles could overcome these barriers.","whyItMatters":"The gap between CBD's impressive lab results and its underwhelming clinical outcomes is largely a delivery problem. Understanding why CBD works in petri dishes but often fails in people is essential for developing products that actually deliver therapeutic benefit.","specificNumbers":"Only one CBD product (Epidiolex) approved by FDA and TGA. CBD shows potential in anxiety, chronic pain, and inflammatory disorders based on animal data. Delivery technologies reviewed: self-emulsifying emulsions, nano and microparticles.","methodology":"Review of in vitro, in vivo, and clinical research on CBD's therapeutic potential for gastrointestinal and lung diseases, with focus on identified research gaps and novel delivery technologies.","limitations":"Review focuses on delivery challenges, which may underemphasize the possibility that CBD's clinical effects are genuinely modest regardless of delivery. Much evidence is preclinical."},{"rthcId":"RTHC-05564","title":"Charting the therapeutic landscape: a comprehensive evidence map on medical cannabis for health outcomes.","authors":"Montagner, Patrícia; de Salas Quiroga, Adán; Ferreira, Arthur Schveitzer; Duarte da Luz, Barbara Marinho; Ruppelt, Bettina Monika; Schlechta Portella, Caio Fabio; Abdala, Carmen Verônica Mendes; Tabach, Ricardo; Ghelman, Ricardo; Blesching, Uwe; Perfeito, João Paulo Silvério; Schveitzer, Mariana Cabral","year":2024,"journal":"Frontiers in pharmacology, 15, 1494492","doi":"10.3389/fphar.2024.1494492","pmid":"39660005","tags":["medical-cannabis","pain","cbd"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Of 489 descriptions of treatment effects across 71 health outcomes, 278 (57%) reported positive or potentially positive effects. When limited to high-quality systematic reviews (AMSTAR 2), 42 of 67 treatment descriptions (63%) across 20 outcomes were positive or potentially positive. Top outcomes: pain, insomnia, seizures, anxiety, muscle spasticity, MS symptoms, urinary incontinence, anorexia, and patient safety.","whyItMatters":"This is one of the most comprehensive evidence maps of medical cannabis to date, covering 71 distinct health outcomes. It moves beyond condition-by-condition reviews to show the full landscape of where cannabis medicine has demonstrated benefit.","specificNumbers":"1,840 initial references. 194 included. 71 health outcomes. 489 treatment effect descriptions. 278 (57%) positive/potentially positive. High-quality subset: 42/67 (63%) positive across 20 outcomes.","methodology":"Systematic evidence mapping of 194 studies selected from 1,840 initial references, using two independent blinded researchers and Rayyan screening software. Quality assessed with AMSTAR 2.","limitations":"Evidence maps identify and categorize evidence but do not meta-analyze effect sizes. Quality varies widely across included studies. Cannabis formulations and doses vary enormously."},{"rthcId":"RTHC-05565","title":"Cannabis Use Is Associated With Increased Use of Prescription Opioids Following Posterior Lumbar Spinal Fusion Surgery.","authors":"Moon, Andrew S; LeRoy, Taryn E; Yacoubian, Vahe; Gedman, Marissa; Aidlen, Jessica P; Rogerson, Ashley","year":2024,"journal":"Global spine journal, 14(1), 204-210","doi":"10.1177/21925682221099857","pmid":"35536563","tags":["pain","harm-reduction","drug-interactions"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 220 opioid-naive patients, 29 cannabis users consumed significantly more postoperative prescription opioids (2,545 vs 1,380 morphine equivalent doses, p=.019) than 191 non-users. Cannabis users were younger (56 vs 65, p<.001), had more depression (31% vs 14%, p=.017), and lower comorbidity (1.38 vs 2.49, p=.002).","whyItMatters":"Cannabis is often promoted as an opioid alternative for pain, but this study found the opposite in surgical patients: cannabis users needed more opioids postoperatively.","specificNumbers":"220 opioid-naive patients. 29 (13%) cannabis users. Post-discharge opioids: 2,545 vs 1,380 morphine equivalent doses (p=.019). Cannabis users younger (56 vs 65), more depression (31% vs 14%), lower comorbidity (1.38 vs 2.49).","methodology":"Retrospective review of 220 opioid-naive patients who underwent one- or two-level posterior lumbar fusion surgery, categorized by preoperative cannabis use diagnosis.","limitations":"Small cannabis user group (n=29). Retrospective design. Cannabis use identified by diagnosis codes, not objective testing. Single surgical procedure type."},{"rthcId":"RTHC-05566","title":"Prenatal Exposure to Cannabis: Effects on Childhood Obesity and Cardiometabolic Health.","authors":"Moore, Brianna F","year":2024,"journal":"Current obesity reports, 13(1), 154-166","doi":"10.1007/s13679-023-00544-x","pmid":"38172481","tags":["pregnancy","youth","cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Prenatal cannabis exposure is consistently associated with small for gestational age and low birth weight. After birth, exposed offspring gain weight rapidly and show increased adiposity and higher glucose levels in childhood.","whyItMatters":"Low birth weight followed by rapid weight gain is a well-established risk trajectory for adult obesity, diabetes, and cardiovascular disease. If prenatal cannabis exposure initiates this trajectory, the health consequences may not become apparent for decades.","specificNumbers":"47 epidemiologic studies and 12 animal studies reviewed. Consistent findings: low birth weight, rapid postnatal weight gain, increased childhood adiposity, higher glucose levels.","methodology":"Literature review of 47 epidemiologic studies and 12 animal studies identified through PubMed search from January 2014 through June 2023.","limitations":"Most studies cannot fully control for confounders (tobacco, alcohol, nutrition, socioeconomic status). THC/CBD ratios and doses vary. Causality not definitively established."},{"rthcId":"RTHC-05567","title":"Lack of interactions between prenatal immune activation and Δ9-tetrahydrocannabinol exposure during adolescence in behaviours relevant to symptom dimensions of schizophrenia in rats.","authors":"Moreno-Fernández, Mario; Ucha, Marcos; Reis-de-Paiva, Raquel; Marcos, Alberto; Ambrosio, Emilio; Higuera-Matas, Alejandro","year":2024,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 129, 110889","doi":"10.1016/j.pnpbp.2023.110889","pmid":"37918558","tags":["psychosis","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"MIA impaired working memory and sensorimotor gating but surprisingly increased sociability. THC alone impaired sociability and social memory. There were no interactions between MIA and THC, meaning THC did not trigger or aggravate schizophrenia-related symptoms in genetically vulnerable animals.","whyItMatters":"The cannabis-psychosis debate often assumes THC acts as a trigger in vulnerable individuals. This study found no such interaction in a validated model, suggesting the relationship may be more nuanced than a simple trigger mechanism.","specificNumbers":"MIA: impaired working memory and sensorimotor gating, increased sociability. THC: impaired sociability and social memory. No MIA x THC interactions on any measure.","methodology":"Pregnant rats received LPS or vehicle. Offspring were exposed to mild THC during adolescence and tested in adulthood for working memory, sociability, anhedonia, sensorimotor gating, and incidental learning.","limitations":"Single animal model with one vulnerability type. Mild THC dose. Rat behavioral assays are imperfect proxies for human psychosis. MIA model captures some but not all schizophrenia aspects."},{"rthcId":"RTHC-05568","title":"Relationships Between Prenatal Cocaine Exposure, Cannabis-Use Onset and Emotional and Related Characteristics in Young/Emerging Adults.","authors":"Morie, Kristen P; Zhai, Zu Wei; Crowley, Michael J; Potenza, Marc N; Mayes, Linda C","year":2024,"journal":"Substance use & misuse, 59(3), 388-397","doi":"10.1080/10826084.2023.2275558","pmid":"37964628","tags":["pregnancy","youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Individuals with prenatal cocaine exposure used cannabis at younger ages, had greater cannabis use severity, and showed higher impulsivity, state anxiety, and alexithymia. Cannabis use age-of-onset mediated the relationship between prenatal cocaine exposure and both state anxiety and cannabis severity in adulthood.","whyItMatters":"This traces a pathway from prenatal drug exposure through adolescent cannabis use to adult mental health problems, identifying cannabis onset age as a specific intervention target.","specificNumbers":"Prenatal cocaine-exposed group: younger cannabis onset, greater severity, higher impulsivity, state anxiety, alexithymia. Cannabis onset age mediated prenatal exposure to anxiety and cannabis severity.","methodology":"Longitudinal cohort study of emerging adults followed since birth, comparing those with and without prenatal cocaine exposure on substance use and psychological measures.","limitations":"Cannot fully separate prenatal cocaine exposure from postnatal environments. Self-reported cannabis use. Mediation analysis cannot prove causal pathways."},{"rthcId":"RTHC-05569","title":"Prevalence of insomnia and use of sleep aids among adults in Canada.","authors":"Morin, Charles M; Vézina-Im, Lydi-Anne; Chen, Si-Jing; Ivers, Hans; Carney, Colleen E; Chaput, Jean-Philippe; Dang-Vu, Thien Thanh; Davidson, Judith R; Belleville, Geneviève; Lorrain, Dominique; Horn, Ojistoh; Robillard, Rébecca","year":2024,"journal":"Sleep medicine, 124, 338-345","doi":"10.1016/j.sleep.2024.09.044","pmid":"39369578","tags":["sleep","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 4,037 Canadian adults, insomnia prevalence was 16.3%. Sleep aids in past year: natural/OTC 28.7%, cannabis 15.6%, prescription 14.7%, alcohol 9.7%. Males more likely to use cannabis (RR 1.33) and alcohol (RR 1.67). Young adults (18-35) preferred cannabis over prescriptions.","whyItMatters":"Cannabis has quietly become one of the most common sleep aids in Canada, used by more people than prescription sleep medications, largely outside of medical guidance.","specificNumbers":"4,037 adults. Insomnia: 16.3%. Cannabis for sleep: 15.6%. Prescriptions: 14.7%. Higher insomnia in females (RR 1.24) and Indigenous peoples (RR 1.77).","methodology":"Population-based phone interview of 4,037 stratified Canadian adults (April-October 2023) with post-stratification survey weights.","limitations":"Phone interview may underrepresent certain populations. Self-reported data. Cannabis product type and dose not captured."},{"rthcId":"RTHC-05570","title":"Distinct antinociceptive and conditioned behavioral effects are produced by individual cannabinoids and a cannabis-derived mixture.","authors":"Morris, Tamara; Cucinello-Ragland, Jessica A; Marks, Taylor J; Prevost, Kayla; Glenn, John F; Davenport, Gregory J; Edwards, Scott; Winsauer, Peter J","year":2024,"journal":"Pharmacology, biochemistry, and behavior, 235, 173692","doi":"10.1016/j.pbb.2023.173692","pmid":"38128766","tags":["pain","cbd","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"NEPE14 significantly reduced mechanical and thermal hyperalgesia via both injection and oral routes without decreasing operant response rates. THC, delta-8-THC, and CP 55,940 caused both pain relief and significant behavioral disruption. CBD alone also did not disrupt behavior. THC effects were blocked by CB1 antagonist AM251.","whyItMatters":"Finding a cannabis preparation that reduces pain without sedation and behavioral disruption addresses one of the main barriers to cannabinoid pain therapy.","specificNumbers":"NEPE14: 6.6-20.7 mL/kg i.p. THC: 1-5.6 mg/kg. CBD: 10-100 mg/kg. NEPE14 reduced hyperalgesia without disrupting operant behavior. THC dose-dependently decreased response rates.","methodology":"Controlled animal study using CFA-induced inflammatory pain in Wistar rats and operant conditioning in Sprague Dawley rats. Compared NEPE14, individual cannabinoids, and synthetic cannabinoid.","limitations":"Animal study. Proprietary extract composition not fully detailed. Inflammatory pain model may not represent all chronic pain types."},{"rthcId":"RTHC-05571","title":"Cannabis use and its association with psychopathological symptoms in a Swiss adult population: a cross-sectional analysis.","authors":"Mosandl, Christoph Felix; Baltes-Flückiger, Lavinia; Kronschnabel, Jens; Meyer, Maximilian; Guessoum, Adrian; Herrmann, Oliver; Vogel, Marc; Walter, Marc; Pichler, Eva-Maria","year":2024,"journal":"Frontiers in public health, 12, 1356988","doi":"10.3389/fpubh.2024.1356988","pmid":"38841675","tags":["mental-health","depression","anxiety","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"After adjusting for age, gender, education, alcohol, and other substance use, only depression and ADHD remained significantly associated with both frequency (p=.006, p=.034) and quantity (p=.037, p=.019). Anxiety and psychosis associations disappeared after adjustment.","whyItMatters":"The selective association with depression and ADHD but not anxiety or psychosis suggests specific self-medication patterns, with implications for which psychiatric populations need targeted cannabis screening.","specificNumbers":"360 participants. Depression predicted frequency (p=.006) and quantity (p=.037). ADHD predicted frequency (p=.034) and quantity (p=.019). Anxiety and psychosis: not significant after adjustment.","methodology":"Cross-sectional study of 360 regular cannabis users in Basel, Switzerland, using validated measures (PHQ-9, GAD-7, ASRS, IRAOS, CUDIT-R). Multiple regression adjusted for demographics and substance use.","limitations":"Cross-sectional design. Self-selected sample interested in regulated cannabis access. Self-report measures. Swiss sample may not generalize globally."},{"rthcId":"RTHC-05572","title":"Recurrent cannabis-induced catatonia: a case report and comprehensive systematic literature review.","authors":"Moshfeghinia, Reza; Hosseinzadeh, Mehrnaz; Mostafavi, Sara; Jabbarinejad, Roxana; Malekpour, Mahdi; Chohedri, Elnaz; Ahmadi, Jamshid","year":2024,"journal":"Frontiers in psychiatry, 15, 1332310","doi":"10.3389/fpsyt.2024.1332310","pmid":"38313688","tags":["psychosis","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 23-year-old male developed mutism, social isolation, and fixed gaze after cannabis use. Recurrent catatonic episodes without hallucinations were effectively treated with ECT and lorazepam, but symptoms returned when lorazepam dropped below 2 mg/day. The systematic literature review confirms cannabis-induced catatonia as a rare but documented phenomenon.","whyItMatters":"Cannabis-induced catatonia is rare but may be underdiagnosed because clinicians do not typically associate cannabis with this presentation.","specificNumbers":"23-year-old male. Recurrent episodes. Required lorazepam above 2 mg/day. ECT and lorazepam effective for acute episodes. 10% of psychiatric admissions involve catatonia overall.","methodology":"Case report of recurrent cannabis-induced catatonia with systematic literature review.","limitations":"Single case report. Cannot establish definitive causation. Patient had prior substance use disorder. Systematic review likely found very few cases."},{"rthcId":"RTHC-05573","title":"Cardiovascular and Respiratory Effects of Cannabis Use by Route of Administration: A Systematic Review.","authors":"Muheriwa-Matemba, Sadandaula Rose; Baral, Amrit; Abdshah, Alireza; Diggs, Bria-Necole Amazing; Gerber Collazos, Kathryn Sierra; Morris, Kyana Breche; Messiah, Sarah Elizabeth; Vidot, Denise Christina","year":2024,"journal":"Substance use & misuse, 59(9), 1331-1351","doi":"10.1080/10826084.2024.2341317","pmid":"38644600","tags":["cardiovascular","respiratory","legalization"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Most cannabis health research lumps all users together regardless of whether they smoke flower, vape concentrates, eat edibles, or dab. This systematic review specifically examined how the route of administration changes cardiovascular and respiratory outcomes — a critical distinction as the market diversifies.\n\nAmong 42 studies meeting inclusion criteria, four administration routes emerged: smoking, vaping, oral ingestion, and dabbing. The findings varied dramatically by route.\n\nSmoking was the most studied and carried the clearest risks: increased heart rate, elevated blood pressure, higher risk of myocardial infarction (especially in the hour after smoking), and respiratory effects including chronic bronchitis symptoms, airway inflammation, and impaired mucociliary clearance. These cardiovascular effects are acute and largely driven by the combustion products, not just the cannabinoids.\n\nVaping showed a potential for harm reduction on the respiratory side — reduced combustion byproducts and fewer bronchitic symptoms — but raised concerns about EVALI (e-cigarette/vaping-associated lung injury) and unknown long-term effects from inhaling vaporized concentrates and additives.\n\nOral ingestion was the least studied for cardiopulmonary effects. The slower onset and longer duration of edibles creates a different pharmacokinetic profile that might produce less acute cardiovascular stress, but data is sparse.\n\nDabbing — flash-vaporizing cannabis concentrates at high temperatures — was barely studied at all, despite delivering extremely high THC doses that could have significant cardiovascular effects.","whyItMatters":"As cannabis products diversify — from flower to vapes to edibles to concentrates — health advice needs to be route-specific. Telling someone 'cannabis increases heart attack risk' is incomplete if the risk is primarily from smoking. This review provides the framework for route-specific risk counseling, which is what both clinicians and consumers actually need.","specificNumbers":"42 studies included from 1,873 retrieved. Four routes identified: smoking (most studied), vaping, oral ingestion, dabbing (least studied). Smoking associated with acute heart rate increase, blood pressure elevation, MI risk, chronic bronchitis, and airway inflammation. Vaping showed reduced respiratory harm but EVALI concerns. Oral and dabbing data sparse.","methodology":"Systematic review following PRISMA guidelines. Searched Web of Science, ProQuest, PsychINFO, Scopus, Embase, and Medline databases. Included peer-reviewed articles (2009-2023) reporting cardiovascular or respiratory effects of cannabis by route of administration. Excluded studies without route information or those combining cannabis with other illicit substances. 42 studies included: 6 case reports, 21 reviews, 15 empirical studies.","limitations":"Only 42 studies met criteria, and many were case reports or reviews rather than original empirical research. Dabbing and oral ingestion are severely understudied relative to their market prevalence. Many studies didn't distinguish between cannabis-only users and those who also smoke tobacco. The 2009-2023 timeframe captures the legalization era but may miss early foundational research. Product composition (THC concentration, additives, carrier oils) varied enormously and was often unreported."},{"rthcId":"RTHC-05574","title":"The Effect of Nabiximols on Driving Ability in Adults with Chronic Tic Disorders: Results of a Substudy Analysis of the Double-Blind, Randomized, Placebo-Controlled CANNA-TICS Trial.","authors":"Müller-Vahl, Kirsten R; Pisarenko, Anna; Ringlstetter, Rieke; Cimpianu, Camelia-Lucia; Fremer, Carolin; Weidinger, Elif; Jenz, Eva Beate; Musil, Richard; Brunnauer, Alexander; Großhennig, Anika","year":2024,"journal":"Cannabis and cannabinoid research, 9(5), 1349-1359","doi":"10.1089/can.2023.0114","pmid":"38265476","tags":["driving","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Fitness to drive increased from 55.8% to 71.8% in the nabiximols group over 13 weeks, while it decreased from 66.7% to 52.6% in placebo. Only 8.3% of fit nabiximols patients became unfit versus 28.6% in placebo. 42.1% of unfit nabiximols patients improved to fit versus 28.6% in placebo.","whyItMatters":"The fear that cannabis-based medicines impair driving is a major prescribing barrier. This study shows that for tic disorder patients, nabiximols improved driving-relevant skills by reducing the tics that themselves impair driving.","specificNumbers":"64 patients. Nabiximols: fit to drive rose from 55.8% to 71.8%. Placebo: fell from 66.7% to 52.6%. Risk difference: 0.17 favoring nabiximols. 42.1% of initially unfit nabiximols patients became fit.","methodology":"Substudy of the CANNA-TICS phase IIIb RCT. 64 patients with Tourette syndrome or chronic tic disorders assessed with computerized driving fitness tests at baseline and week 13.","limitations":"64 patients at two sites. Computerized test is a proxy for real driving. Tic disorder population may not generalize. 13-week timeframe."},{"rthcId":"RTHC-05575","title":"Cannabinoids in the Treatment of Selected Mental Illnesses: Practical Approach and Overview of the Literature.","authors":"Müller-Vahl, Kirsten R","year":2024,"journal":"Pharmacopsychiatry, 57(3), 104-114","doi":"10.1055/a-2256-0098","pmid":"38428836","tags":["medical-cannabis","mental-health","ptsd","anxiety"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Increasing evidence supports cannabinoids for ASD, Tourette syndrome, anxiety disorders, and PTSD. THC-containing extracts may serve as substitution therapy for CUD. Practical dosing: start 1-2.5 mg THC/day, titrate by 1-2.5 mg every 3-5 days, target 10-20 mg/day. CBD requires >400 mg/day.","whyItMatters":"As more patients self-medicate with cannabis, clinicians need practical guidance on when cannabinoids may be appropriate and how to dose them.","specificNumbers":"Starting dose: 1-2.5 mg THC/day. Titration: 1-2.5 mg every 3-5 days. Target: 10-20 mg THC/day. CBD: >400 mg/day. No approved psychiatric indications.","methodology":"Clinical review and practical overview of cannabinoids for mental illnesses, including treatment protocols and dosing guidance.","limitations":"Narrative review. Most evidence is preliminary. Dosing based on clinical experience as much as controlled data."},{"rthcId":"RTHC-05576","title":"Cannabis use disorder and perioperative outcomes following complex cancer surgery.","authors":"Munir, Muhammad M; Woldesenbet, Selamawit; Endo, Yutaka; Dillhoff, Mary; Pawlik, Timothy M","year":2024,"journal":"Journal of surgical oncology, 129(8), 1430-1441","doi":"10.1002/jso.27644","pmid":"38606521","tags":["cancer","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"After propensity score matching, CUD was associated with slightly higher AKI (7.8% vs 6.1%) but lower in-hospital mortality (0.9% vs 1.6%). On multivariable analysis, CUD was not associated with higher overall morbidity and mortality (aOR 1.06, 95% CI 0.98-1.15, p=0.158).","whyItMatters":"Cancer patients increasingly use cannabis. The finding that CUD does not independently worsen complex surgical outcomes may reassure patients and surgeons, though the kidney injury signal warrants monitoring.","specificNumbers":"15,014 patients. AKI: 7.8% vs 6.1%. Mortality: 0.9% vs 1.6%. Adjusted composite: aOR 1.06 (p=0.158).","methodology":"Retrospective cohort using National Inpatient Sample (2016-2019). 15,014 patients after 1:1 propensity score matching on comorbidities, demographics, and procedure type.","limitations":"ICD-10 codes for CUD may undercount use. Cannot distinguish active from historical diagnosis. Cannot assess dose or recency."},{"rthcId":"RTHC-05577","title":"Clinical outcome analysis of patients with multiple sclerosis - Analysis from the UK Medical Cannabis Registry.","authors":"Murphy, Matthew; Kaur, Varinder; Bui, Hanh Lan; Yang, Toby; Erridge, Simon; Holvey, Carl; Coomber, Ross; Rucker, James J; Weatherall, Mark W; Sodergren, Mikael H","year":2024,"journal":"Multiple sclerosis and related disorders, 87, 105665","doi":"10.1016/j.msard.2024.105665","pmid":"38728958","tags":["medical-cannabis","pain","mental-health","sleep"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"At 6 months, significant improvements in MSQoL-54 subscales: cognitive function, mental health composite, physical health, role limitations, social and sexual function. Also improved: EQ-5D-5L, GAD-7, and sleep quality. 146 adverse events; most mild (33%) or moderate (51%).","whyItMatters":"This is the largest UK real-world dataset on medical cannabis for MS. The breadth of improvement across cognitive, physical, emotional, and social domains suggests CBMPs may address multiple MS symptoms simultaneously.","specificNumbers":"141 patients. Significant improvements at 6 months across cognitive, physical, emotional, social, sexual function (all p<0.050). 146 adverse events. Mild: 33%. Moderate: 51%.","methodology":"Observational analysis of 141 MS patients from the UK Medical Cannabis Registry prescribed CBMPs for more than one month, assessed at 1, 3, and 6 months.","limitations":"No control group. Improvements may reflect placebo, regression to mean, or natural fluctuation. Self-reported. Selection bias."},{"rthcId":"RTHC-05578","title":"Changes in Immune-Related Biomarkers and Endocannabinoids as a Function of Frequency of Cannabis Use in People Living With and Without HIV.","authors":"Murray, Conor H; Javanbakht, Marjan; Cho, Grace D; Gorbach, Pamina M; Fulcher, Jennifer A; Cooper, Ziva D","year":2024,"journal":"Cannabis and cannabinoid research, 9(3), e897-e906","doi":"10.1089/can.2022.0287","pmid":"37093248","tags":["inflammation","neuroscience"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"PLWH had higher TNFR2 (p=0.013) and CD27 (p=0.004) and lower anandamide (p=0.027) and OEA (p=0.007) versus HIV-negative men. Cannabis use frequency did not impact any serum analyte.","whyItMatters":"Lower endocannabinoid levels in PLWH suggest HIV affects the body's cannabinoid system. The null finding on cannabis frequency is reassuring for PLWH who use cannabis.","specificNumbers":"36 men (19 PLWH). TNFR2 and CD27 higher in PLWH. Anandamide and OEA lower. Cannabis frequency: no effect on any analyte.","methodology":"Longitudinal study of 36 MSM in LA (19 PLWH). Each contributed visits during daily and infrequent cannabis use. Serum analyzed for immune biomarkers and endocannabinoids.","limitations":"Very small sample (n=36). PLWH had higher methamphetamine and cigarette use. MSM population."},{"rthcId":"RTHC-05579","title":"Cannabis sativa extracts inhibit LDL oxidation and the formation of foam cells in vitro, acting as potential multi-step inhibitors of atherosclerosis development.","authors":"Musetti, Bruno; Kun, Alejandra; Menchaca, David; Rodríguez-Haralambides, Alejandra; Varela, Javier; Thomson, Leonor; Bahnson, Edward M","year":2024,"journal":"PloS one, 19(12), e0310777","doi":"10.1371/journal.pone.0310777","pmid":"39705234","tags":["cardiovascular","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Three extracts (high, intermediate, low THC/CBD) all inhibited LDL oxidation and foam cell formation (ED50 5-12 ug/mL). Effects independent of CB1/CB2, operating through TRPV1, TRPV4, GPR55 and calcium signaling. Decreased CD36 and OLR1 via NFkB inhibition.","whyItMatters":"Atherosclerosis is the leading cause of death. These findings identify phytocannabinoids as multi-target plaque formation inhibitors working through non-traditional pathways.","specificNumbers":"Three extracts tested. All inhibited LDL oxidation and foam cell formation. ED50: 5-12 ug/mL. Via TRPV1, TRPV4, GPR55, not CB1/CB2. NFkB pathway inhibition.","methodology":"In vitro study testing three cannabis extracts against LDL oxidation, foam cell formation by J774 macrophages, and inflammatory signaling using receptor antagonists.","limitations":"Entirely in vitro. Effective concentrations may not be achievable in vivo. Cannot predict human atherosclerosis outcomes."},{"rthcId":"RTHC-05580","title":"Development of an anxiety disorder following an emergency department visit due to cannabis use: a population-based cohort study.","authors":"Myran, Daniel T; Harrison, Lyndsay D; Pugliese, Michael; Tanuseputro, Peter; Gaudreault, Adrienne; Fiedorowicz, Jess G; Solmi, Marco","year":2024,"journal":"EClinicalMedicine, 69, 102455","doi":"10.1016/j.eclinm.2024.102455","pmid":"38544799","tags":["anxiety","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Within 3 years of a cannabis ER visit, 12.3% were diagnosed with anxiety (ED/hospital) vs 1.2% general population (aHR 3.69). Including outpatient: 23.6% vs 5.6% (aHR 3.88). Young males: aHR 5.67. Young females: aHR 3.22.","whyItMatters":"Cannabis-related ER visits may identify individuals at very high risk for developing anxiety disorders, offering a clinical window for screening and intervention.","specificNumbers":"12,099,144 individuals. 34,822 cannabis ER visits. 3-year anxiety: 12.3% vs 1.2%. aHR 3.69. Young males: aHR 5.67.","methodology":"Population-based cohort using Ontario administrative data (2008-2019). 12,099,144 individuals without prior anxiety. 34,822 had cannabis ER visits. Cause-specific hazard models.","limitations":"Cannot determine causation. ER visits represent the most severe reactions. Cannot measure use patterns or potency."},{"rthcId":"RTHC-05581","title":"Cannabis-involvement in emergency department visits for self-harm following medical and non-medical cannabis legalization.","authors":"Myran, Daniel T; Gaudreault, Adrienne; Pugliese, Michael; Tanuseputro, Peter; Saunders, Natasha","year":2024,"journal":"Journal of affective disorders, 351, 853-862","doi":"10.1016/j.jad.2024.01.264","pmid":"38309479","tags":["mental-health","legalization","harm-reduction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Among 158,912 self-harm ER visits, cannabis co-diagnosis increased 90.1% (3.6 to 6.9/100,000) while alcohol declined 17.3%. The entire cannabis increase occurred after medical liberalization (asRR 1.71) with no additional increase during recreational legalization.","whyItMatters":"The parallel trends and timing alignment with medical liberalization suggest a real shift in which substances co-occur with self-harm, though whether cannabis is contributing or just more commonly detected remains unclear.","specificNumbers":"158,912 self-harm visits. 7,810 (4.9%) with cannabis. 24,761 (15.6%) with alcohol. Cannabis: +90.1%. Alcohol: -17.3%. Increase began after medical liberalization (asRR 1.71).","methodology":"Repeated cross-sectional study using Ontario administrative data (2010-2021). Poisson regression across four cannabis policy periods.","limitations":"Cannot determine causation. Cannabis may cause more self-harm, people at risk may use more cannabis, or clinicians may test more. COVID confounds final period."},{"rthcId":"RTHC-05582","title":"Systematic review of drug-drug interactions of delta-9-tetrahydrocannabinol, cannabidiol, and Cannabis.","authors":"Nachnani, Rahul; Knehans, Amy; Neighbors, Jeffrey D; Kocis, Paul T; Lee, Tzuo; Tegeler, Kayla; Trite, Thomas; Raup-Konsavage, Wesley M; Vrana, Kent E","year":2024,"journal":"Frontiers in pharmacology, 15, 1282831","doi":"10.3389/fphar.2024.1282831","pmid":"38868665","tags":["drug-interactions","cbd","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This systematic review went hunting for something specific: documented real-world cases where cannabis or cannabinoids caused clinically significant interactions with prescription medications that have narrow therapeutic windows — drugs where even small changes in blood levels can cause serious harm.\n\nAfter screening 4,600 reports, they identified 31 cases meeting their criteria. This may seem like a small number, but it reflects the current state of documentation, not the actual frequency of interactions. Drug interactions with cannabis are almost certainly massively underreported because most patients don't tell their prescribers about cannabis use and most prescribers don't ask.\n\nThe medications involved read like a list of drugs you really don't want to get wrong: warfarin (blood thinner — too much causes bleeding), clobazam (anti-seizure — too much causes excessive sedation), tacrolimus (immunosuppressant for transplant patients — too much causes organ toxicity, too little causes rejection). The interactions were primarily mediated through CYP3A4, CYP2C9, and CYP2C19 — the same enzyme pathways identified in the controlled studies (RTHC-00091) and in vitro research (RTHC-00104).\n\nThe review specifically focused on delta-9-THC, CBD, and whole cannabis — but noted that delta-8-THC and other cannabinoids likely have similar interaction potential. The predicted mechanism (CYP enzyme inhibition) matched the observed interactions in most cases, validating the in vitro findings with real-world clinical consequences.","whyItMatters":"This review bridges the gap between theoretical drug interactions (shown in vitro) and actual patient harm. The 31 cases prove that cannabis drug interactions aren't just a laboratory concern — they cause real clinical problems including excessive anticoagulation, oversedation, and altered immunosuppressant levels. The systematic approach also reveals how few interactions are actually documented, suggesting the true burden is much larger.","specificNumbers":"4,600 reports screened. 151 full-text articles assessed. 31 documented interaction cases identified. Key medications involved: warfarin, clobazam, tacrolimus, and others with narrow therapeutic indices. Primary mechanisms: CYP3A4, CYP2C9, CYP2C19 inhibition.","methodology":"Systematic review of all years through 2023, searching for documented drug-drug interactions between cannabinoids (delta-9-THC, CBD, cannabis) and a pre-specified list of prescription medications with narrow therapeutic indices. 4,600 reports screened, 151 full-text articles assessed, 31 reports meeting inclusion/exclusion criteria identified.","limitations":"Only 31 cases identified — almost certainly a vast undercount due to underreporting. Case reports are the weakest form of evidence for establishing causation (many factors could contribute to changing drug levels). The pre-specified list of narrow-therapeutic-index drugs may have missed other relevant interactions. Cannabis product composition was often poorly documented in case reports. Publication bias favors dramatic cases over subtle interactions."},{"rthcId":"RTHC-05583","title":"Cannabinoid receptor 2 (CB2) modulators: A patent review (2016-2024).","authors":"Naikoo, Rayees Ahmad; Painuli, Ritu; Akhter, Zaheen; Singh, Parvinder Pal","year":2024,"journal":"Bioorganic chemistry, 153, 107775","doi":"10.1016/j.bioorg.2024.107775","pmid":"39288632","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05584","title":"Cannabis-Derived Product Types, Flavors, and Compound Types From an E-Commerce Website.","authors":"Nali, Matthew C; Yang, Joshua S; Li, Zhuoran; Larsen, Meng Zhen; Mackey, Tim K","year":2024,"journal":"JAMA network open, 7(10), e2440376","doi":"10.1001/jamanetworkopen.2024.40376","pmid":"39432307","tags":["legalization","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 501,012 consumable product listings, multisystem routes of administration were most common (41%), followed by respiratory (37%) and digestive (20%). THC was the dominant compound (63.3%), and 42% of listings featured at least one flavor, with lemon, cake, and strawberry topping the list.","whyItMatters":"As cannabis markets mature under legalization, the sheer variety and flavor-forward marketing of products raises questions about consumer appeal, youth attraction, and regulatory oversight that parallel concerns seen with flavored tobacco and vaping products.","specificNumbers":"501,012 consumable listings analyzed; 41% multisystem ROA; 37% respiratory; 20% digestive; 42% featured flavors; top flavors: lemon (8.9%), cake (7.9%), strawberry (5.6%); THC was 63.3% of compound types","methodology":"Researchers scraped 573,854 unique US product listings from the Weedmaps e-commerce platform between September and November 2023, removing non-consumable items and coding the remainder for product characteristics, routes of administration, and flavors.","limitations":"Data came from a single e-commerce platform (Weedmaps) and may not represent all cannabis sales. Product descriptions were self-reported by dispensaries. The study did not assess potency or verify product contents."},{"rthcId":"RTHC-05585","title":"Feasibility and acceptability of a web-intervention to prevent alcohol and cannabis-impaired driving among adolescents in driver education.","authors":"Nameth, Katherine; Ueland, Elizabeth; D'Amico, Elizabeth J; Osilla, Karen Chan","year":2024,"journal":"Addiction science & clinical practice, 19(1), 83","doi":"10.1186/s13722-024-00513-2","pmid":"39558402","tags":["driving","youth","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"In user testing with 8 adolescents, 88% would recommend the tool to a friend and 88% reported learning helpful skills. In follow-up interviews, 100% had positive impressions and 100% would recommend it.","whyItMatters":"Cannabis-impaired driving receives far less intervention attention than alcohol, even though teens increasingly view cannabis as low-risk. Embedding prevention tools in driver education reaches young people at a critical moment before they form driving habits.","specificNumbers":"2 focus groups (n=6, n=5); 8 user testers; 88% would recommend to a friend; 88% learned helpful skills; 100% positive impressions in interviews; 67% found it easy to use","methodology":"Researchers adapted a primary care brief intervention (CHAT) for online delivery, conducting two focus groups with teens aged 15-17 in Michigan and Colorado driver education programs, then user-testing the resulting prototype (webCHAT) with 8 additional adolescents.","limitations":"Very small sample size (8 user testers, 11 focus group participants). This was a feasibility study without a control group or outcome measurement. Recruitment came from only two states."},{"rthcId":"RTHC-05586","title":"Feasibility and acceptability of a web-intervention to prevent alcohol and cannabis-impaired driving among adolescents in driver education.","authors":"Nameth, Katherine; Ueland, Elizabeth; D'Amico, Elizabeth J; Osilla, Karen Chan","year":2024,"journal":"Research square","doi":"10.21203/rs.3.rs-4249553/v1","pmid":"38699323","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05587","title":"Cells and Molecules Underpinning Cannabis-Related Variations in Cortical Thickness during Adolescence.","authors":"Navarri, Xavier; Robertson, Derek N; Charfi, Iness; Wünnemann, Florian; Sâmia Fernandes do Nascimento, Antônia; Trottier, Giacomo; Leclerc, Sévérine; Andelfinger, Gregor U; Di Cristo, Graziella; Richer, Louis; Pike, G Bruce; Pausova, Zdenka; Piñeyro, Graciela; Paus, Tomáš","year":2024,"journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience, 44(41)","doi":"10.1523/JNEUROSCI.2256-23.2024","pmid":"39214708","tags":["youth","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"In mice, THC exposure caused spine loss and reduced dendritic complexity in frontal cortex pyramidal cells. In human adolescents who used cannabis before age 16 (n=140 vs 327 controls), cortical thickness differences correlated spatially with the expression of 13 THC-related genes linked to astrocytes, microglia, and a type of pyramidal cell.","whyItMatters":"This study bridges a major gap between animal neuroscience and human brain imaging. By linking specific genes and cell types to observable cortical thickness changes, it offers a biological mechanism for how cannabis may affect the developing adolescent brain.","specificNumbers":"140 human adolescents who used cannabis before 16 vs 327 controls; 34 brain regions measured; 13 THC-related genes correlated with cortical thickness differences; 3 cell types implicated (astrocytes, microglia, pyramidal cells); 37 THC-related genes enriched in neuron projection development","methodology":"Three-step design: (1) adolescent male mice exposed to THC or synthetic cannabinoid WIN, with gene expression and dendritic analysis in frontal cortex; (2) MRI comparison of cortical thickness in 34 brain regions between human adolescents who used cannabis before 16 and those who did not; (3) spatial correlation of human group differences with mouse-identified gene expression.","limitations":"Mouse experiments used only male animals. The human component was observational (cannot prove causation). Cannabis use was self-reported, and the specific compounds, doses, and frequency of human cannabis use were not controlled."},{"rthcId":"RTHC-05588","title":"Fetal Cannabinoid Syndrome: Behavioral and Brain Alterations of the Offspring Exposed to Dronabinol during Gestation and Lactation.","authors":"Navarro, Daniela; Gasparyan, Ani; Navarrete, Francisco; Manzanares, Jorge","year":2024,"journal":"International journal of molecular sciences, 25(13)","doi":"10.3390/ijms25137453","pmid":"39000559","tags":["pregnancy","neuroscience","cognition","anxiety","depression","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Offspring exposed to dronabinol (10 mg/kg twice daily) from gestational day 5 through postnatal day 21 displayed increased anxiogenic and depressive-like behaviors, cognitive impairment, disrupted reward system function, and increased alcohol consumption motivation at postnatal day 60. Effects varied by sex.","whyItMatters":"This is one of the first animal models attempting to characterize a comprehensive 'fetal cannabinoid syndrome,' linking prenatal THC exposure to both behavioral and molecular changes in the brain.","specificNumbers":"Dronabinol dose: 10 mg/kg twice daily; exposure window: gestational day 5 to postnatal day 21; behavioral testing at postnatal day 60; sex-dependent effects observed","methodology":"Female C57BL/6J mice received oral dronabinol (10 mg/kg every 12 hours) from gestational day 5 to postnatal day 21. Offspring were separated by sex at weaning and assessed at postnatal day 60.","limitations":"The dronabinol dose is very high relative to typical human cannabis use. Results from inbred mouse strains may not translate directly to humans. Only one dose level tested."},{"rthcId":"RTHC-05589","title":"Changes in prenatal cannabis-related diagnosed disorders after the Cannabis Act and the COVID-19 pandemic in Quebec, Canada.","authors":"Nazif-Munoz, José Ignacio; Martínez, Pablo; Huỳnh, Christophe; Massamba, Victoria; Zefania, Isaora; Rochette, Louis; Vasiliadis, Helen-Maria","year":2024,"journal":"Addiction (Abingdon, England), 119(10), 1784-1791","doi":"10.1111/add.16564","pmid":"38898560","tags":["pregnancy","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After the Cannabis Act took effect in October 2018, there was a significant 24% increase (95% CI: 1-53%) in cannabis-related diagnosed disorders among pregnant women aged 15-49.","whyItMatters":"This is among the first studies to track how cannabis legalization affected diagnosed cannabis disorders specifically among pregnant women using population-level data.","specificNumbers":"24% increase post-legalization (95% CI: 1-53%); 0.5% monthly increase pre-legalization; study period: Jan 2010 to July 2022","methodology":"Quasi-experimental interrupted time-series analysis using administrative health data from Quebec, covering pregnant women aged 15-49 from January 2010 to July 2022.","limitations":"Cannot distinguish increased use from increased detection. Administrative data rely on clinician coding. Quebec-specific. COVID-19 overlapped."},{"rthcId":"RTHC-05590","title":"The impact of recreational cannabis legalization on ED visit rates for acute cannabis intoxication.","authors":"Nguyen, An; Lee, Ray; Zhao, Lili; Qu, Lihua; Todd, Brett","year":2024,"journal":"The American journal of emergency medicine, 84, 124-129","doi":"10.1016/j.ajem.2024.07.041","pmid":"39111101","tags":["legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After Michigan legalized recreational cannabis in December 2018, cannabis-related ED visits increased significantly (unadjusted RR 1.70; age-adjusted RR 1.47). The increase was immediate.","whyItMatters":"The immediate 47% jump provides concrete evidence for health systems planning around legalization.","specificNumbers":"2,177 ED visits from 2,066 patients; 671 pre-legalization, 1,506 post; unadjusted RR 1.70; age-adjusted RR 1.47; 8 hospitals","methodology":"Retrospective observational cohort across 8 hospitals in southeast Michigan, 2016-2022, using ICD-10 codes and negative-binomial regression.","limitations":"Single health system. Relied on ICD-10 codes. Pre-existing upward trend complicates attribution."},{"rthcId":"RTHC-05591","title":"COVID-19 Stress is Associated with Increased Smoking among People with HIV in Western Washington: A Cross-Sectional Survey.","authors":"Nguyen, Anh Tuyet; Slaughter, Francis; Smith, Sarah; Katz, David A; Prabhu, Sandeep; Wang, Liying; Simoni, Jane M; Tsui, Judith I; Graham, Susan M","year":2024,"journal":"COVID, 4(10), 1617-1630","doi":"10.3390/covid4100112","pmid":"39877471","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05592","title":"Recreational and Medical Cannabis Legalization and Opioid Prescriptions and Mortality.","authors":"Nguyen, Hai V; McGinty, Emma E; Mital, Shweta; Alexander, G Caleb","year":2024,"journal":"JAMA health forum, 5(1), e234897","doi":"10.1001/jamahealthforum.2023.4897","pmid":"38241056","tags":["legalization","pain","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Using a generalized difference-in-differences approach, neither type of legalization was significantly associated with opioid outcomes. Exception: recreational laws showed a possible reduction in synthetic opioid deaths (4.9 fewer per 100,000; P=.04).","whyItMatters":"This challenges earlier research suggesting cannabis legalization reduces opioid harm by using more rigorous methods.","specificNumbers":"13 states recreational; 23 medical; 2006-2020; possible 4.9 fewer synthetic opioid deaths per 100,000 (P=.04)","methodology":"Quasiexperimental generalized difference-in-differences using annual state-level data from 2006-2020.","limitations":"State-level data. Borderline p-value for synthetic opioid finding. Study ended 2020."},{"rthcId":"RTHC-05593","title":"Urgent need for treatment addressing co-use of tobacco and cannabis: An updated review and considerations for future interventions.","authors":"Nguyen, Nhung; Bold, Krysten W; McClure, Erin A","year":2024,"journal":"Addictive behaviors, 158, 108118","doi":"10.1016/j.addbeh.2024.108118","pmid":"39089194","tags":["addiction","quitting","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Across 9 studies, combined psychosocial strategies (CBT, motivational interviewing, contingency management) with pharmacotherapy (nicotine replacement) showed promise. No compensatory use was observed.","whyItMatters":"No clinical guidelines exist for treating co-use, and only 9 studies exist. Simultaneous treatment does not cause compensatory use.","specificNumbers":"9 published studies; most 5-12 weeks; CBT, motivational interviewing, contingency management + nicotine replacement therapy","methodology":"Narrative review with June 2024 literature search across multiple databases.","limitations":"Only 9 studies, mostly feasibility-focused. Most in adults. Narrative review."},{"rthcId":"RTHC-05594","title":"Substance use and lifestyle risk factors for somatic disorders among psychiatric patients in Greenland.","authors":"Nielsen, Ida Margrethe; Sørensen, Lisbeth Uhrskov; Wichmand, Søren; Heilmann, Parnûna; Pedersen, Michael Lynge","year":2024,"journal":"International journal of circumpolar health, 83(1), 2421049","doi":"10.1080/22423982.2024.2421049","pmid":"39462457","tags":["psychosis","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In 104 patients with psychotic disorders in Nuuk, 68% had harmful cannabis use, 80%+ were daily smokers, 50%+ had dyslipidemia, 25%+ obese, 18% hypertension, 6% diabetes.","whyItMatters":"Strikingly high cannabis use rates among psychotic disorder patients in an Arctic indigenous population with limited healthcare resources.","specificNumbers":"104 patients (68 males, 36 females); mean age 40; 68% harmful cannabis use; 80%+ daily smokers","methodology":"Retrospective analysis of Greenland's nationwide electronic medical records for 104 patients with psychotic disorders.","limitations":"Small sample from single city. Cross-sectional. Limited generalizability."},{"rthcId":"RTHC-05595","title":"Unveiling the Potential of Cannabinoids in Multiple Sclerosis and the Dawn of Nano-Cannabinoid Medicine.","authors":"Nouh, Roua A; Kamal, Ahmed; Oyewole, Oluwaseyi; Abbas, Walaa A; Abib, Bishoy; Omar, Abdelrouf; Mansour, Somaia T; Abdelnaser, Anwar","year":2024,"journal":"Pharmaceutics, 16(2)","doi":"10.3390/pharmaceutics16020241","pmid":"38399295","tags":["medical-cannabis","cbd","inflammation"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Cannabinoids demonstrate anti-inflammatory, neuroprotective, and immunosuppressive properties relevant to MS. Nano-delivery systems may reduce toxicity.","whyItMatters":"MS has no universally effective treatment. Nanotechnology could overcome current limitations of cannabinoid medications.","specificNumbers":"170 articles reviewed; CBD mechanisms: TNF-alpha downregulation, BDNF mRNA restoration, serotonin recovery","methodology":"Narrative review of 170 articles from PubMed, Web of Science, and Scopus.","limitations":"Narrative review. Mostly preclinical evidence. No new clinical data."},{"rthcId":"RTHC-05596","title":"Brief Report: The Association of Adverse Childhood Experiences and Suicide-Related Behaviors Among 10th-Grade Secondary School Students.","authors":"Núñez, Daniel; Gaete, Jorge; Guajardo, Viviana; Libuy, Nicolás; Araneda, Ana María; Contreras, Lorena; Donoso, Paula; Ibañez, Carlos; Mundt, Adrian P","year":2024,"journal":"Archives of suicide research : official journal of the International Academy for Suicide Research, 28(1), 399-410","doi":"10.1080/13811118.2022.2134067","pmid":"36330838","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05597","title":"Prenatal Cannabis Use and Offspring Autism-Related Behaviors: Examining Maternal Stress as a Moderator in a Black American Cohort.","authors":"Nutor, C; Dunlop, A; Sadler, O; Brennan, P A","year":2024,"journal":"Journal of autism and developmental disorders, 54(6), 2355-2367","doi":"10.1007/s10803-023-05982-z","pmid":"37097527","tags":["pregnancy","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Prenatal cannabis use did not predict ASD-related behaviors. Prenatal stress was significantly associated with ASD-related behaviors.","whyItMatters":"Black mothers are understudied in prenatal cannabis research. Stress, not cannabis, was the significant predictor.","specificNumbers":"172 Black mother-child pairs; cannabis not significant; prenatal stress significant","methodology":"Prospective cohort of 172 Black mother-child pairs examining prenatal cannabis use, stress, and child ASD behaviors.","limitations":"Small sample. Dimensional ASD measurement. Self-reported cannabis use."},{"rthcId":"RTHC-05598","title":"Examining the association between prenatal cannabis exposure and child autism traits: A multi-cohort investigation in the environmental influences on child health outcome program.","authors":"Nutor, Chaela; Dickerson, Aisha S; Hsu, Tingju; Al-Jadiri, Aseel; Camargo, Carlos A; Schweitzer, Julie B; Shuster, Coral L; Karagas, Margaret R; Madan, Juliette C; Restrepo, Bibiana; Schmidt, Rebecca J; Lugo-Candelas, Claudia; Neiderhiser, Jenae; Sathyanarayana, Sheela; Dunlop, Anne L; Brennan, Patricia A","year":2024,"journal":"Autism research : official journal of the International Society for Autism Research, 17(8), 1651-1664","doi":"10.1002/aur.3185","pmid":"38953698","tags":["pregnancy","youth"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Associations between prenatal cannabis and ASD traits were not significant when controlling for covariates, particularly tobacco. Sex did not moderate.","whyItMatters":"Largest study to date. Apparent associations disappear when accounting for tobacco, suggesting it is the key confounder.","specificNumbers":"11,570 children; 34 cohorts; ages 1-18; 53% male; not significant after controlling for tobacco","methodology":"Multi-cohort analysis from 34 NIH ECHO cohorts with 11,570 children using generalized linear mixed models.","limitations":"Self-reported exposure. Different ASD measures across cohorts. Could not control for potency."},{"rthcId":"RTHC-05599","title":"Risk and protective factors for cannabis use in adolescence: a population-based survey in schools.","authors":"O'Dowd, Teresa M; Fleury, Ronan; Power, Emmet; Dooley, Niamh; Quinn, Laura; Petropoulos, Stephen; Healy, Colm; Smyth, Bobby; Cannon, Mary","year":2024,"journal":"Irish journal of psychological medicine, 1-9","doi":"10.1017/ipm.2024.28","pmid":"39721761","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Current use prevalence: 7.3%. Peer use aOR 10.17; parental ambivalence aOR 3.69; non-harmful perception aOR 2.32; other substance use aOR 2.67-3.15; peer pressure aOR 1.85; low supervision aOR 1.11.","whyItMatters":"Peer influence dwarfs all other risk factors, suggesting community-level approaches may work better than individual ones.","specificNumbers":"4,404 adolescents; 7.3% current use; peer use aOR 10.17; parental ambivalence aOR 3.69","methodology":"Secondary analysis of Planet Youth survey (2021), 4,404 adolescents aged 15-16 in Ireland.","limitations":"Cross-sectional. Self-reported. Irish context."},{"rthcId":"RTHC-05600","title":"Cannabidiol does not attenuate acute delta-9-tetrahydrocannabinol-induced attentional bias in healthy volunteers: A randomised, double-blind, cross-over study.","authors":"Oliver, Dominic; Englund, Amir; Chesney, Edward; Chester, Lucy; Wilson, Jack; Sovi, Simina; Wigroth, Stina; Hodsoll, John; Strang, John; Murray, Robin M; Freeman, Tom P; Fusar-Poli, Paolo; McGuire, Philip","year":2024,"journal":"Addiction (Abingdon, England), 119(2), 322-333","doi":"10.1111/add.16353","pmid":"37821096","tags":["cbd","cognition","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"THC (10 mg) increased attentional bias (d=0.41, P=0.03). CBD at 10, 20, or 30 mg had no effect at any dose.","whyItMatters":"Challenges the notion that CBD cancels out THC's harmful properties for this addiction-relevant marker.","specificNumbers":"46 participants; 4 sessions; THC 10 mg; CBD 0/10/20/30 mg; bias increase d=0.41; no CBD effect","methodology":"Double-blind, randomized, within-subjects crossover with 46 infrequent users across four sessions.","limitations":"Infrequent users only. Proxy measure. Single acute exposure. One THC dose."},{"rthcId":"RTHC-05601","title":"A narrative review of the therapeutic and remedial prospects of cannabidiol with emphasis on neurological and neuropsychiatric disorders.","authors":"Omotayo, Oluwadara Pelumi; Lemmer, Yolandy; Mason, Shayne","year":2024,"journal":"Journal of cannabis research, 6(1), 14","doi":"10.1186/s42238-024-00222-2","pmid":"38494488","tags":["cbd","neuroscience","inflammation","mental-health"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"CBD antagonizes pro-inflammatory cytokines, regulates oxidative stress, downregulates TNF-alpha, restores BDNF and serotonin across neurological disorders.","whyItMatters":"Maps CBD mechanisms across brain disorders in one reference; proposes metabolomics for personalized therapy.","specificNumbers":"170 articles (41% of screened); TNF-alpha downregulation, BDNF restoration, serotonin recovery","methodology":"Narrative review of 170 articles (41% of screened) from PubMed, Web of Science, and Scopus.","limitations":"Narrative review. Mostly preclinical. No new data. Breadth limits depth."},{"rthcId":"RTHC-05602","title":"From Chronic Cannabis to Cyclic Chaos: A Glimpse Into Cannabinoid Hyperemesis Syndrome.","authors":"Oraibi, Omar","year":2024,"journal":"Cureus, 16(7), e64828","doi":"10.7759/cureus.64828","pmid":"39156386","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 38-year-old male with known cannabis use had cyclic vomiting initially diagnosed as other GI conditions. Symptoms resolved after cannabis cessation.","whyItMatters":"CHS remains underdiagnosed even when cannabis use is known.","specificNumbers":"38-year-old male; cyclic vomiting; resolved with cessation","methodology":"Single case report.","limitations":"Single case report."},{"rthcId":"RTHC-05603","title":"Cannabidiol exerts multitarget immunomodulatory effects on PBMCs from individuals with psoriasis vulgaris.","authors":"Pagano, Cristina; Ciaglia, Elena; Coppola, Laura; Lopardo, Valentina; Raimondo, Annunziata; Giuseppe, Monfrecola; Lembo, Serena; Laezza, Chiara; Bifulco, Maurizio","year":2024,"journal":"Frontiers in immunology, 15, 1373435","doi":"10.3389/fimmu.2024.1373435","pmid":"38601151","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD shifted immune responses from Th1 to Th2, boosted NK cell cytotoxic activity, blocked monocyte migration in response to inflammatory stimuli, prevented full dendritic cell maturation, and promoted M2 (anti-inflammatory) macrophage polarization in PBMCs from psoriasis patients.","whyItMatters":"Psoriasis is driven by overactive immune responses in the skin. These results suggest CBD could address multiple immune pathways simultaneously, which is unusual for a single compound and could make it a versatile anti-inflammatory agent.","specificNumbers":"CBD effects tested on: Th1/Th2 balance, NK cell cytotoxicity, monocyte migration, dendritic cell maturation, M2 macrophage polarization; all in psoriasis patient PBMCs","methodology":"In vitro immune functional experiments testing CBD effects on various immune cell types (T cells, NK cells, monocytes, dendritic cells, macrophages) isolated from peripheral blood of individuals with psoriasis vulgaris.","limitations":"In vitro study only. Immune cell behavior in a dish may not reflect what happens in living skin tissue. No clinical outcomes measured. The doses used may not be achievable in human skin."},{"rthcId":"RTHC-05604","title":"Cannabis-based medicines and medical fitness-to-drive: current legal issues in Switzerland.","authors":"Palmiere, C; Scarpelli, M P","year":2024,"journal":"La Clinica terapeutica, 175(Suppl 1(4)), 113-116","doi":"10.7417/CT.2024.5096","pmid":"39054993","tags":["driving","medical-cannabis","legalization"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Since August 2022, Swiss doctors can prescribe cannabis-based medicines without special authorization. However, zero-tolerance drug driving laws criminalize any detectable THC in a driver's bodily fluids regardless of impairment, creating a legal conflict for patients using prescribed cannabis. There is little evidence justifying differential treatment of cannabis-prescribed patients compared to those on other potentially impairing medications.","whyItMatters":"This legal tension exists in many countries that have both medical cannabis programs and per se drug driving laws. How Switzerland resolves it could influence policy approaches elsewhere, especially as medical cannabis prescribing expands globally.","specificNumbers":"THC threshold: 1% content for prohibition in Switzerland; medical cannabis prescription deregulated from August 1, 2022","methodology":"Legal and policy review of current Swiss regulations regarding cannabis-based medicine prescriptions and driving fitness requirements.","limitations":"This is a legal commentary focused on Swiss law, not a clinical study. Limited generalizability to other legal systems."},{"rthcId":"RTHC-05605","title":"Effects of cannabis use on cigarette smoking cessation in LGBTQ+ individuals.","authors":"Pang, Raina D; Schuler, Lucy A; Blosnich, John R; Allem, Jon-Patrick; Kirkpatrick, Matthew G","year":2024,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 38(7), 796-804","doi":"10.1037/adb0001001","pmid":"38483523","tags":["quitting","addiction","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"While all participants reduced cigarette use during a quit attempt, the reduction was smaller among those with current cannabis use compared to non-users. On days when cannabis was used, participants smoked significantly more cigarettes than on non-use days. This pattern held even after controlling for demographics and other substance use.","whyItMatters":"LGBTQ+ individuals have higher rates of both tobacco and cannabis use and lower cessation success. This study identifies cannabis co-use as a specific barrier to quitting cigarettes in this population, suggesting tailored cessation approaches may be needed.","specificNumbers":"205 individuals; 68.3% female sex; same-sex/gender couples; 35 nightly surveys; cannabis use on a given day associated with more cigarettes smoked that day","methodology":"Longitudinal study of 205 individuals from same-sex/gender couples in California who were willing to make a quit attempt. Participants completed 35 nightly surveys tracking cigarette and cannabis use, with multilevel linear models analyzing relationships.","limitations":"Self-reported substance use. California-specific sample. Could not determine whether cannabis directly caused more smoking or both were driven by shared triggers. Sample was primarily female sex."},{"rthcId":"RTHC-05606","title":"Cannabinoids and the endocannabinoid system in liver diseases.","authors":"Parfieniuk-Kowerda, Anna; Martonik, Diana; Andrzejuk, Aleksandra; Tarasik, Aleksander; Flisiak, Robert","year":2024,"journal":"Clinical and experimental hepatology, 10(4), 211-217","doi":"10.5114/ceh.2024.145358","pmid":"40290527","tags":["medical-cannabis","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CB1 receptor stimulation increases fibrosis and inflammatory activity by stimulating stellate cells and may promote liver steatosis and carcinogenesis. CB2 receptor activation inhibits fibrosis. In end-stage liver disease, the endocannabinoid system contributes to encephalopathy, portal hypertension, splanchnic vasodilatation, and cirrhotic cardiomyopathy.","whyItMatters":"Understanding the opposing roles of CB1 and CB2 receptors in liver disease opens the door to targeted cannabinoid therapies that could inhibit fibrosis (via CB2) without promoting it (via CB1). This has implications for the millions of people with chronic liver disease worldwide.","specificNumbers":"CB1 and CB2 receptors expressed in myofibroblasts and liver endothelial cells; expression elevated in chronic liver disease","methodology":"Review of the endocannabinoid system's role in chronic liver diseases, examining CB1 and CB2 receptor expression and function in liver cells.","limitations":"Review article without new clinical data. The translation from receptor-level understanding to clinical treatments faces many hurdles. Most evidence is preclinical."},{"rthcId":"RTHC-05607","title":"Recreational cannabis excise taxation in the USA: Constructing a comparable tax measure for empirical analysis.","authors":"Park, Hojin; Yoon, Dong Won; Yang, Qian; He, Yanyun; Han, Bing; Shi, Yuyan; Shang, Ce","year":2024,"journal":"The International journal on drug policy, 134, 104630","doi":"10.1016/j.drugpo.2024.104630","pmid":"39522235","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05608","title":"Cannabis policy bundles and traffic fatalities in the American States over time.","authors":"Park, Mingean; Mallinson, Daniel J; Altaf, Shazib; Richardson, Lilliard E","year":2024,"journal":"Addiction (Abingdon, England), 119(11), 1998-2005","doi":"10.1111/add.16638","pmid":"39107991","tags":["driving","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"The permissive cannabis policy bundle (broader access, home cultivation, etc.) was associated with lower overall traffic fatality rates. The pharmaceutical bundle (doctor certification, dispensary requirements) was associated with increases across all fatality rate categories. The fiscal bundle (taxes, licensing) was generally associated with higher fatality rates for occupants and light trucks.","whyItMatters":"This study challenges the assumption that stricter cannabis regulations are necessarily safer for drivers. By examining policy design rather than simple legalization status, it reveals that the way cannabis is regulated may matter more than whether it is legal.","specificNumbers":"1,350 state-year observations; 50 states; 27 years; permissive bundle: lower fatality rates; pharmaceutical bundle: higher fatality rates across all categories; fiscal bundle: higher occupant and light truck fatalities","methodology":"Observational study of 50 US states over 27 years (1994-2020, 1,350 state-year observations) examining three dimensions of cannabis policy (pharmaceutical, permissive, fiscal) and their association with traffic fatality rates using data from NHTSA's Fatality Analysis Reporting System.","limitations":"Observational study cannot prove causation. Many confounding factors affect traffic fatalities beyond cannabis policy. The policy bundles are novel measures that require validation. Ecological design (state-level) cannot capture individual behavior."},{"rthcId":"RTHC-05609","title":"Association of cannabis use disorder with atrial fibrillation in young men without concomitant tobacco use: Insights from nationwide propensity matched analysis.","authors":"Patel, Bhavin; Khadke, Sumanth; Mahajan, Kshitij; Dhingra, Avleen; Trivedi, Rishika; Brar, Samrath Singh; Dixit, Sakshi; Periwal, Vaibhav; Chauhan, Shaylika; Desai, Rupak","year":2024,"journal":"World journal of experimental medicine, 14(3), 93742","doi":"10.5493/wjem.v14.i3.93742","pmid":"39312691","tags":["cardiovascular","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After propensity matching 108,495 young men in each arm (CUD+ vs CUD-) and adjusting for covariates including other substance abuse, the association between cannabis use disorder and atrial fibrillation hospitalizations was non-significant (OR 1.27, 95% CI: 0.91-1.78, P=0.15). The CUD+ cohort had higher rates of anxiety and COPD but lower rates of traditional cardiovascular risk factors.","whyItMatters":"By excluding tobacco users, this study attempts to isolate cannabis's independent cardiovascular effects. While the trend toward higher AF odds (27%) did not reach significance, the pattern and the racial disparity in AF rates among cannabis users warrant further investigation.","specificNumbers":"108,495 matched patients per arm; OR 1.27 (95% CI: 0.91-1.78, P=0.15); CUD+ had higher anxiety (24.3% vs 18.4%), COPD (9.8% vs 9.4%); lower hyperlipidemia (6.4% vs 6.9%), hypertension (5.3% vs 6.3%)","methodology":"Propensity-matched analysis using weighted discharge records from the 2019 National Inpatient Sample, comparing AF-related hospitalizations in young men (18-44) with and without cannabis use disorder, excluding those with tobacco use disorder.","limitations":"Administrative database with ICD coding limitations. Cross-sectional design. Cannot determine cannabis dose, frequency, or method of use. Only examined men. Exclusion of tobacco users may bias toward a healthier cannabis-using population."},{"rthcId":"RTHC-05610","title":"Current Status of Cannabis Legalization and Decriminalization Efforts in Nepal.","authors":"Pathak, Nabin; Dhungana, Shreya; Basyal, Bijaya; Jha, Prabhat Kumar; Shrestha, Sunil; Thapa, Panna; Paudyal, Vibhu","year":2024,"journal":"Substance abuse and rehabilitation, 15, 163-171","doi":"10.2147/SAR.S466728","pmid":"39267942","tags":["legalization"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Nepal's Narcotic Drugs Control Act of 1976 prohibits all cannabis cultivation, production, and distribution. However, cannabis has deep cultural and religious roots in Nepali society. As legalization advocates grow in number, the article argues that Nepal must consider evidence from countries that have already legalized to inform decisions about societal, economic, and public health impacts.","whyItMatters":"Nepal represents a case where cannabis prohibition directly contradicts centuries of cultural practice. As one of the first countries to ban cannabis under international pressure in the 1970s, its potential reversal would carry symbolic weight beyond its borders.","specificNumbers":"Cannabis prohibited since 1976 via Narcotic Drugs Control Act; proponents for legalization increasing","methodology":"Narrative review contextualizing Nepal's cannabis debate within its historical, cultural, and legal frameworks, alongside comparison with global legalization practices.","limitations":"Policy commentary without primary data. May not capture the full complexity of Nepal's current political landscape regarding cannabis."},{"rthcId":"RTHC-05611","title":"Long-term effects on cardiorespiratory and behavioral responses in male and female rats prenatally exposed to cannabinoid.","authors":"Patrone, Luis Gustavo A; Frias, Alana T; Fantinatti, Gabriel T; Stabile, Angelita M; Klein, Wilfried; Bícego, Kênia C; Gargaglioni, Luciane H","year":2024,"journal":"American journal of physiology. Lung cellular and molecular physiology, 327(3), L341-L358","doi":"10.1152/ajplung.00042.2024","pmid":"39012058","tags":["pregnancy","neuroscience","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Males showed increased chemosensitivity to CO2 and O2, while females exhibited decreased sensitivity. Both sexes showed greater susceptibility to hypertension and tachycardia under adverse conditions. Males had more fragmented sleep, while females showed anxiolytic and panicolytic behavioral responses. No changes were found in lung mechanics or brainstem CB1 receptor expression.","whyItMatters":"This is among the first studies to examine how prenatal cannabinoid exposure affects the cardiorespiratory system long-term. The sex-specific effects on breathing control and cardiovascular regulation suggest that prenatal cannabis exposure may create lasting vulnerability to cardiorespiratory problems.","specificNumbers":"WIN 55,212-2 dose: 0.5 mg/kg/day during gestation; males: increased CO2/O2 chemosensitivity, fragmented sleep; females: decreased chemosensitivity, anxiolytic responses; both: hypertension and tachycardia susceptibility","methodology":"Pregnant rats received daily synthetic cannabinoid (WIN 55,212-2, 0.5 mg/kg/day) during gestation. Adult offspring were assessed for cardiorespiratory control, chemosensitivity, sleep patterns, and panic-like behavior.","limitations":"Used a synthetic cannabinoid (not THC or whole cannabis). Single dose level. Rat model may not translate directly to humans. The sex differences make interpretation complex."},{"rthcId":"RTHC-05612","title":"Childhood executive control and adolescent substance use: Mediation via parent-child relationship quality.","authors":"Patwardhan, Irina; Guo, Ying; Fleming, Charles B; James, Tiffany D; Nelson, Jennifer Mize; Espy, Kimberly Andrews; Nelson, Timothy D; Mason, W Alex","year":2024,"journal":"Family relations, 73(5), 3513-3529","doi":"10.1111/fare.13061","pmid":"39850093","tags":["youth","addiction","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Preschool executive control did not directly predict adolescent cannabis, e-cigarette, or alcohol use. However, an indirect pathway was found: lower executive control predicted more harsh parenting in adolescence, which predicted higher e-cigarette use. No indirect effects through parental affective quality were found.","whyItMatters":"This is one of the few studies tracing how early childhood cognitive abilities influence adolescent substance use through family dynamics. The finding that harsh parenting mediates the link suggests that supporting parents of children with self-regulation difficulties could prevent later substance use.","specificNumbers":"313 youth; 49% boys; 70.9% European American; indirect effect from preschool EC to e-cigarette use via harsh discipline: b=-0.07 (95% CI: -0.18 to -0.01); direct effects on cannabis and alcohol nonsignificant","methodology":"Longitudinal cohort-sequential study of 313 youth (49% boys, 70.9% European American) from preschool through adolescence, assessing executive control, parenting quality, and substance use (e-cigarettes, cannabis, alcohol) via phone surveys.","limitations":"Predominantly European American sample. E-cigarette finding may not generalize to other substances. Self-reported substance use. Executive control measured only in preschool."},{"rthcId":"RTHC-05613","title":"Therapeutic potential of CBD in Autism Spectrum Disorder.","authors":"Pedrazzi, João F C; Hassib, Lucas; Ferreira, Frederico R; Hallak, Jaime C; Del-Bel, Elaine; Crippa, José A","year":2024,"journal":"International review of neurobiology, 177, 149-203","doi":"10.1016/bs.irn.2024.05.002","pmid":"39029984","tags":["cbd","mental-health"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD interacts with the endocannabinoid system, which plays crucial roles in social and behavioral processing and neuronal development relevant to ASD. Preliminary clinical trial data indicate CBD may modulate specific ASD symptoms and comorbidities. Emerging evidence suggests CBD may also influence the gut microbiota, relevant to gut-brain communication in ASD.","whyItMatters":"ASD has very limited effective pharmacological interventions. CBD's multi-target profile and safety record make it a candidate for addressing both core symptoms and the many comorbidities (anxiety, sleep problems, irritability) that significantly affect quality of life for individuals with ASD.","specificNumbers":"CBD described as safe with low side effects; multi-target pharmacological profile; evidence from preclinical models and preliminary clinical trials","methodology":"Review of preclinical and clinical evidence for CBD in ASD, examining endocannabinoid system involvement, clinical trial results, gut microbiome interactions, and safety data.","limitations":"Most evidence is preclinical. Clinical trials have been small and preliminary. ASD is highly heterogeneous, making treatment response unpredictable. Long-term safety in developing brains needs more study."},{"rthcId":"RTHC-05614","title":"Evaluating Online Cannabis Health Information for Thai Breast Cancer Survivors Using the Quality Evaluation Scoring Tool (QUEST): Mixed Method Study.","authors":"Peerawong, Thanarpan; Phenwan, Tharin; Makita, Meiko; Supanichwatana, Sojirat; Puttarak, Panupong; Siammai, Naowanit; Sunthorn, Prakaidao","year":2024,"journal":"JMIR cancer, 10, e55300","doi":"10.2196/55300","pmid":"39727276","tags":["medical-cannabis","cancer"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Of 62 Thai-language cannabis content items, 64% were news-related or generic advertisements. Content from alternative medicine providers and news channels was significantly poorer quality than from healthcare providers or government sources. Two concerning discourse patterns emerged: cannabis use normalization and cannabis romanticization as a panacea, both neglecting contraindications and side effects.","whyItMatters":"Following Thailand's 2019 medical cannabis legalization, patients are seeking information online, but most of what they find is misleading. For cancer patients, acting on poor-quality cannabis information could lead to treatment delays or harmful interactions.","specificNumbers":"62 content items evaluated; 48% on YouTube; 64% news-related/generic ads; 13% had no identifiable date; QUEST score cutoff of 15 (sensitivity 81%, specificity 98%); content creator was only significant quality predictor","methodology":"Mixed methods study evaluating cannabis health content quality using the QUEST scoring tool (0-28 scale). 62 items from internet sources and social media were assessed by four researchers. Fairclough Critical Discourse Analysis examined poor-quality content themes.","limitations":"Limited to Thai-language content. Small sample of 62 items. Breast cancer survivors' search behavior may not represent all cancer patients. Quality assessment tools have inherent subjectivity."},{"rthcId":"RTHC-05615","title":"Vaporized Δ9-tetrahydrocannabinol exposure in utero has negative effects on attention in a dose- and sex-dependent manner.","authors":"Penman, Samantha L; Roeder, Nicole M; Wang, Jia; Richardson, Brittany J; Freeman-Striegel, Lily; Krayevsky, Alexis; Eiden, Rina D; Chakraborty, Saptarshi; Thanos, Panayotis K","year":2024,"journal":"Pharmacology, biochemistry, and behavior, 242, 173808","doi":"10.1016/j.pbb.2024.173808","pmid":"38914267","tags":["pregnancy","cognition","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats exposed to low-dose vaporized THC (10 mg) during pregnancy showed significantly decreased object exploration in both novel object recognition and object-based attention tests, indicating reduced attention. High-dose THC (40 mg) showed some effects on learning patterns but not ultimate performance. Females showed lower attention scores than males in object-based attention.","whyItMatters":"This is the first study using vaporized THC for prenatal exposure, which better mimics how humans actually use cannabis. The finding that lower doses produced more pronounced attention deficits is counterintuitive and important for understanding risk at typical use levels.","specificNumbers":"THC doses: 10 mg and 40 mg vaporized; low-dose group: significantly decreased object exploration; females lower than males in object-based attention; testing in early and late adolescence","methodology":"Pregnant rats were exposed to vaporized THC (10 mg or 40 mg) daily from gestational day 2 until labor. Offspring received standard or high-fat diets and were tested in early and late adolescence using novel object recognition, Morris Water Maze, and object-based attention tests.","limitations":"Animal study with vaporized delivery that may not perfectly replicate human vaping. Two dose levels only. Behavioral tests have limited translational validity. Cannot determine if effects persist into adulthood beyond adolescence."},{"rthcId":"RTHC-05616","title":"Clinical and public safety risks associated with cannabis legalization and frequency of cannabis use among forensic mental health patients.","authors":"Penney, Stephanie R; Jones, Roland M; Wilkie, Treena; Gerritsen, Cory; Chatterjee, Sumeeta; Chaimowitz, Gary A; Simpson, Alexander I F","year":2024,"journal":"The International journal on drug policy, 134, 104622","doi":"10.1016/j.drugpo.2024.104622","pmid":"39437632","tags":["psychosis","legalization","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"One-third of forensic patients used cannabis over the study period, with frequency increasing significantly after legalization. Those who used cannabis were more likely to be readmitted to hospital and had higher static risk factors for violence. Over half experienced mental health worsening within a week of use. However, actual violence rates did not differ between users and non-users.","whyItMatters":"Forensic mental health patients represent one of the populations most vulnerable to cannabis-related harms. This study provides direct evidence that legalization increased cannabis use in this population and that use was associated with clinical deterioration, even if not with violence.","specificNumbers":"187 patients; one-third used cannabis; use frequency increased post-legalization; 50%+ experienced mental health worsening within a week of use; higher hospital readmission in users; no difference in violence rates","methodology":"Pseudo-prospective study of 187 forensic mental health patients in Ontario over four years (two pre- and two post-legalization), tracking cannabis use frequency, clinical outcomes, and safety measures.","limitations":"Single province (Ontario). Relatively small sample. Cannabis use detected through self-report and urine testing, which may miss some use. Could not control for cannabis potency or product type. Pre-post design limits causal inference."},{"rthcId":"RTHC-05617","title":"Anandamide modulation of monocyte-derived Langerhans cells: implications for immune homeostasis and skin inflammation.","authors":"Pénzes, Zsófia; Horváth, Dorottya; Molnár, Petra; Fekete, Tünde; Pázmándi, Kitti; Bácsi, Attila; Szöllősi, Attila Gábor","year":2024,"journal":"Frontiers in immunology, 15, 1423776","doi":"10.3389/fimmu.2024.1423776","pmid":"38979427","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05618","title":"Development of GC-MS coupled to GC-FID method for the quantification of cannabis terpenes and terpenoids: Application to the analysis of five commercial varieties of medicinal cannabis.","authors":"Pereira Francisco, Victor; Cerny, Muriel; Valentin, Romain; Milone-Delacourt, Franck; Paillard, Alexandra; Alignan, Marion","year":2024,"journal":"Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1247, 124316","doi":"10.1016/j.jchromb.2024.124316","pmid":"39305633","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05619","title":"A Descriptive Review of Cannabis sativa Patents for Cancer Treatment.","authors":"Pereira, Isabela Fernandes; Santos Oliveira, Ana Maria; Santos, Anamaria Mendonça; de Melo Soares, Denis; Serafini, Mairim Russo; Almeida Alves, Izabel","year":2024,"journal":"Recent patents on anti-cancer drug discovery, 19(2), 137-145","doi":"10.2174/1574892818666230213095717","pmid":"36788702","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05620","title":"High-purified cannabidiol efficacy and safety in a cohort of adult patients with various types of drug-resistant epilepsies.","authors":"Perriguey, M; Succar, M El; Clément, A; Lagarde, S; Ribes, O; Dode, X; Rheims, S; Bartolomei, F","year":2024,"journal":"Revue neurologique, 180(3), 147-153","doi":"10.1016/j.neurol.2023.07.012","pmid":"37806886","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 73 patients (51 with epileptic encephalopathies, 22 with focal/multifocal epilepsy), 29.4% and 22.7% respectively were responders during follow-up, with no significant difference between groups (P=0.552). Clobazam co-administration was associated with better response (80% of responders vs 20% of non-responders). Somnolence was the most common side effect. About 30-40% discontinued treatment.","whyItMatters":"CBD is currently approved only for specific rare epilepsies (LGS, Dravet, TSC). This study suggests it may also benefit adults with other forms of drug-resistant epilepsy, including common focal epilepsies, potentially broadening its therapeutic application.","specificNumbers":"73 patients; Group A (encephalopathies): 51 patients, 29.4% responders; Group B (focal): 22 patients, 22.7% responders; P=0.552; clobazam associated with better response; 29-40% discontinued treatment; somnolence most common side effect","methodology":"Retrospective analysis of 73 patients from two French epilepsy reference centers who received high-purified CBD (Epidiolex) as add-on therapy for drug-resistant epilepsy.","limitations":"Retrospective design without control group. Small sample, especially for focal epilepsy group. Variable follow-up periods. Responder definition and assessment may differ between centers. Cannot determine optimal dosing."},{"rthcId":"RTHC-05621","title":"Prenatal tobacco, tobacco-cannabis coexposure, and child emotion regulation: The role of child autonomic functioning and sensitive parenting.","authors":"Perry, Kristin J; Level, Rachel A; Schuetze, Pamela; Eiden, Rina D","year":2024,"journal":"Developmental psychology, 60(9), 1544-1561","doi":"10.1037/dev0001682","pmid":"38358665","tags":["pregnancy","youth","cognition"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Direct effects from prenatal exposure on early school age emotion regulation were not significant. Instead, a chronic risk pathway was supported: continued postnatal maternal negative emotional functioning (depression, anger/hostility, emotion dysregulation) and substance exposure mediated the association. Toddlers showing respiratory sinus arrhythmia withdrawal were more susceptible to the positive effects of sensitive parenting.","whyItMatters":"This study shifts the narrative from prenatal exposure as the sole risk to ongoing postnatal environment as the critical pathway. It suggests that helping mothers maintain stability after birth may be more important than focusing exclusively on prenatal substance cessation.","specificNumbers":"247 mother-infant dyads; 81 tobacco-exposed, 97 tobacco-cannabis co-exposed, 69 unexposed; 53% male infants; chronic postnatal risk pathway supported; sensitive parenting buffered effects in physiologically reactive toddlers","methodology":"Prospective cohort of 247 mother-infant dyads (53% male, 51% Black, 31% White, 19% Hispanic) recruited in the first trimester into three groups: prenatal tobacco exposure (n=81), prenatal tobacco-cannabis co-exposure (n=97), and no substance exposure (n=69). Follow-up through early school age.","limitations":"Cannot separate tobacco from cannabis effects cleanly. Self-report measures for maternal functioning. The three groups differed at baseline in ways that may confound results. Attrition over the long follow-up period."},{"rthcId":"RTHC-05622","title":"Oral pre- and early postnatal cannabis exposure disinhibits ventral tegmental area dopamine neuron activity but does not influence cocaine preference in offspring in mice.","authors":"Peterson, Colleen S; Baglot, Samantha L; Sallam, Nada A; Mina, Sarah; Hill, Matthew N; Borgland, Stephanie L","year":2024,"journal":"Journal of neuroscience research, 102(7), e25369","doi":"10.1002/jnr.25369","pmid":"39037062","tags":["pregnancy","neuroscience","dopamine","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Male offspring had decreased GABAergic input, depolarized resting membrane potential, and increased spontaneous firing of VTA dopamine neurons. Both sexes showed faster NMDA current decay. However, no differences in cocaine-seeking behavior were observed. THC and CBD persisted in maternal plasma and pup brains even after treatment ended.","whyItMatters":"This study uses a voluntary oral consumption model that better mimics human cannabis use than injection-based models. Finding altered dopamine circuits without behavioral consequences challenges the 'gateway drug' hypothesis at the neurobiological level.","specificNumbers":"5 mg/kg THC cannabis oil daily; GD1 to PD10; THC and CBD detected in pup brains at GD18, PD1, PD10, PD15; male-specific VTA dopamine disinhibition; no cocaine preference differences in either sex","methodology":"Mouse dams voluntarily consumed 5 mg/kg THC cannabis oil in peanut butter daily from gestational day 1 to postnatal day 10. Offspring were examined in adolescence for VTA dopamine neuron electrophysiology and cocaine conditioned place preference.","limitations":"Voluntary oral model introduces variability in actual dose consumed. Only cocaine-seeking was tested, not other reward behaviors. Cannabis oil contains compounds beyond THC. Adolescent testing may miss effects that emerge later in adulthood."},{"rthcId":"RTHC-05623","title":"Formoterol dynamically alters endocannabinoid tone in the periaqueductal gray inducing headache.","authors":"Peterson, Ingrid L; Liktor-Busa, Erika; Karlage, Kelly L; Young, Sally J; Scholpa, Natalie E; Schnellmann, Rick G; Largent-Milnes, Tally M","year":2024,"journal":"The journal of headache and pain, 25(1), 200","doi":"10.1186/s10194-024-01907-y","pmid":"39563240","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05624","title":"Longitudinal Pathways From Maltreatment to Substance Use Through Delay Discounting During Adolescence and Into Young Adulthood.","authors":"Peviani, Kristin M; Clinchard, Claudia; Bickel, Warren K; Casas, Brooks; Kim-Spoon, Jungmeen","year":2024,"journal":"JAACAP open, 2(4), 239-249","doi":"10.1016/j.jaacop.2024.02.003","pmid":"39697391","tags":["youth","addiction","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using developmental cascade models, neglect (but not abuse) predicted elevated delay discounting, which in turn predicted increased cannabis use across ages 14-18. Neglect also directly predicted greater cigarette use. The indirect pathway through delay discounting was specific to cannabis among the three substances studied (cigarettes, alcohol, cannabis).","whyItMatters":"This study identifies a specific mechanism linking childhood neglect to cannabis use: impulsive reward-seeking. This suggests that interventions targeting delay discounting skills in neglected youth could prevent cannabis use development.","specificNumbers":"167 adolescents; 53% male; 5 time points ages 14-18; neglect predicted cannabis use via delay discounting; neglect predicted cigarette use directly; abuse pathways not significant","methodology":"Longitudinal study of 167 adolescents (53% male, mean age 14 at baseline) assessed at 5 time points across ages 14-18. Maltreatment exposure during ages 13-17 was reported retrospectively. Structural equation modeling tested developmental cascade models.","limitations":"Retrospective maltreatment reports may be biased. Moderate sample size. Predominantly correlational despite longitudinal design. Cannot determine if delay discounting is truly mediating or simply co-occurring."},{"rthcId":"RTHC-05625","title":"Trends in use of tobacco and cannabis across different alcohol consumption levels in the United States, 2010-19.","authors":"Pham, Huyen; Bui, Thanh C; Glass, Joseph E; Back, Sudie E; Le, Phuc","year":2024,"journal":"Alcohol and alcoholism (Oxford, Oxfordshire), 60(1)","doi":"10.1093/alcalc/agae091","pmid":"39761685","tags":["addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 395,256 US adults, tobacco use and nicotine dependence decreased while cannabis use increased across all alcohol consumption levels from 2010-2019. Cannabis use increased fastest among non-drinkers (155%) versus low-risk drinkers (77%) and high-risk drinkers (31%). Among high-risk drinkers, Black individuals were more likely than White to use cannabis and both tobacco and cannabis.","whyItMatters":"The diverging trends in tobacco (down) and cannabis (up) across all drinking levels suggest these substances are not simply substituting for each other. The faster cannabis increase among non-drinkers is particularly notable, suggesting cannabis is reaching new populations beyond those already using other substances.","specificNumbers":"395,256 participants; tobacco decreased across all groups; cannabis increased: 155% in non-drinkers, 77% in low-risk drinkers, 31% in high-risk drinkers; Black individuals at higher odds of polysubstance use among high-risk drinkers","methodology":"Repeated cross-sectional analysis combining 2010-2019 National Survey on Drug Use and Health data for 395,256 adults aged 18+, examining tobacco and cannabis use trends across alcohol consumption levels using linear time trends and multivariable logistic regression.","limitations":"Cross-sectional design cannot track individual behavior changes. Self-reported substance use. Cannot determine causality. Cannabis legalization status not directly analyzed."},{"rthcId":"RTHC-05626","title":"Innovative LC-MS/MS method for therapeutic drug monitoring of fenfluramine and cannabidiol in the plasma of pediatric patients with epilepsy.","authors":"Pigliasco, Federica; Cafaro, Alessia; Barco, Sebastiano; Stella, Manuela; Mattioli, Francesca; Riva, Antonella; Mancardi, Maria Margherita; Lattanzi, Simona; Bandettini, Roberto; Striano, Pasquale; Cangemi, Giuliana","year":2024,"journal":"Journal of pharmaceutical and biomedical analysis, 245, 116174","doi":"10.1016/j.jpba.2024.116174","pmid":"38703746","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05627","title":"The Association Between Mindfulness Facets and Substance Use via Emotional Psychopathology and Coping Motives in Argentinian College Students.","authors":"Pilatti, Angelina; Correa, Pablo; Michelini, Yanina; Bravo, Adrian J; Pacini, Gianpiero; Pautassi, Ricardo M","year":2024,"journal":"Substance use & misuse, 59(12), 1731-1742","doi":"10.1080/10826084.2024.2370026","pmid":"38956825","tags":["addiction","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Three mindfulness facets (describing, acting with awareness, non-judging) were associated with less cannabis quantity consumed and fewer negative consequences through a pathway of lower emotional psychopathology (depression/anxiety symptoms) and lower endorsement of using cannabis to cope. Similar patterns were found for alcohol.","whyItMatters":"This study extends mindfulness-substance use research to cannabis in a Latin American population. The finding that emotional distress and coping motives mediate the link suggests that mindfulness-based interventions could reduce cannabis use by improving emotional regulation rather than targeting cannabis directly.","specificNumbers":"232 cannabis users analyzed; mean age 22.96; 66.2% women; three mindfulness facets significant: describing, acting with awareness, non-judging; pathway: mindfulness to emotional symptoms to coping motives to cannabis use","methodology":"Cross-sectional study of 456 participants (alcohol model) and 232 participants (marijuana model) from Argentine college students (mean age 22.96, 66.2% women). Path models tested indirect effects of mindfulness facets on substance use through emotional psychopathology and coping motives.","limitations":"Cross-sectional design cannot establish causality. Argentine college student sample may not generalize. Self-reported substance use and mindfulness. Cannabis use measurement was limited."},{"rthcId":"RTHC-05628","title":"Timeframe Analysis of Novel Synthetic Cannabinoids Effects: A Study on Behavioral Response and Endogenous Cannabinoids Disruption.","authors":"Pineda Garcia, Jorge Carlos; Li, Ren-Shi; Kikura-Hanajiri, Ruri; Tanaka, Yoshitaka; Ishii, Yuji","year":2024,"journal":"International journal of molecular sciences, 25(6)","doi":"10.3390/ijms25063083","pmid":"38542057","tags":["synthetic-cannabinoids","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"All three synthetic cannabinoids (MDMB-CHMINACA, 5F-ADB-PINACA, APICA) caused locomotor disruption and sustained anxiety at all time points (1, 3, 5 hours). MDMB-CHMINACA caused significant memory impairment at 1 and 3 hours. Elevated endocannabinoid levels (AEA and 2-AG) were detected at 1 hour after MDMB-CHMINACA and 5F-ADB-PINACA, along with reduced FAAH, MAGL, and BDNF expression.","whyItMatters":"Synthetic cannabinoids are far more potent and dangerous than natural cannabis. This time-course analysis reveals that their effects on the brain's endocannabinoid system persist for hours and involve disruption of the enzymes that normally regulate endocannabinoid levels.","specificNumbers":"3 synthetic cannabinoids tested; effects lasted 5+ hours; MDMB-CHMINACA: memory impairment at 1 and 3 hours; elevated AEA and 2-AG at 1 hour; reduced FAAH, MAGL, and BDNF expression","methodology":"Mice received single doses of three synthetic cannabinoids and were assessed for behavior and hippocampal endocannabinoid levels at 1, 3, and 5 hours post-administration using LC-MS and gene expression analysis.","limitations":"Mouse model with single-dose administration. Doses may not reflect human exposure patterns. Only three synthetic cannabinoids tested from hundreds in circulation. Short-term assessment only."},{"rthcId":"RTHC-05629","title":"Evidence for enduring cardiac and multiorgan toxicity after repeated exposure to the synthetic cannabinoid JWH-018 in male rats.","authors":"Pintori, Nicholas; Serra, Maria Pina; Carai, Antonio; Lobina, Carla; Isola, Raffaella; Noli, Roberta; Piras, Gessica; Spano, Enrica; Baumann, Michael H; Quartu, Marina; De Luca, Maria Antonietta","year":2024,"journal":"Toxicology, 507, 153878","doi":"10.1016/j.tox.2024.153878","pmid":"38972446","tags":["synthetic-cannabinoids","cardiovascular"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Repeated JWH-018 at 0.25 mg/kg for 14 days caused persistent hypothermia, increased blood pressure and heart rate throughout treatment. One day after stopping, cardiac lesions (vacuolization, waving, edema) were found. Seven days later, lung, kidney, and liver degeneration appeared. Heart mitochondria showed defective lipid oxidation, suggesting a mechanism for JWH-018's cardiac toxicity.","whyItMatters":"This study demonstrates that even low doses of a common synthetic cannabinoid can cause lasting organ damage, particularly to the heart. The finding that damage worsens after stopping the drug suggests ongoing pathological processes that outlast drug exposure.","specificNumbers":"JWH-018 dose: 0.25 mg/kg for 14 days; cardiac lesions at day 1 post-discontinuation; multi-organ damage at day 7; mitochondrial dysfunction in cardiomyocytes; in silico screening of 36 SCRAs","methodology":"In silico toxicity screening of 36 synthetic cannabinoids, followed by 14-day repeated dosing of JWH-018 (0.25 mg/kg IP) in male rats, with cardiovascular monitoring during treatment and post-mortem tissue analysis at 1 and 7 days after discontinuation.","limitations":"Animal study with a single synthetic cannabinoid and dose level. IP injection does not mimic human smoking/vaping routes. Only male rats studied. Short treatment period relative to human use patterns."},{"rthcId":"RTHC-05630","title":"Prediction of suicidal thoughts and behaviors based on the diurnal cortisol pattern and THC dosage in continued cannabis users, a 5 year population-based matched cohort study.","authors":"Pirnia, Bijan; Soleimani, Ali; Farhoudian, Ali; Zahiroddin, Alireza","year":2024,"journal":"Psychiatry research, 339, 116091","doi":"10.1016/j.psychres.2024.116091","pmid":"39068898","tags":["mental-health","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users with a blunted cortisol awakening response (CAR), flattened diurnal cortisol slope (DCS), and higher cortisol area under the curve who reported heavy cannabis use had 3.2 times higher odds of suicidal thoughts and behaviors (OR 3.2, 95% CI: 2.4-4.1) compared to controls.","whyItMatters":"This study proposes a biological mechanism linking cannabis use to suicide risk: THC may dysregulate the body's stress response system (HPA axis), and this dysregulation is what drives suicidal ideation. This reframes the cannabis-suicide link from a purely behavioral to a neurobiological phenomenon.","specificNumbers":"368 male cannabis users; 5-year follow-up; OR 3.2 (95% CI: 2.4-4.1) for STB in heavy users with blunted cortisol; four THC dosage categories analyzed; saliva cortisol via LC-MS/MS","methodology":"Population-based matched-pair nested case-control study within a three-wave longitudinal cohort (2019-2024) of 368 male continued cannabis users. Participants were categorized by THC dosage (low, moderate, high, relapse). Cortisol was measured via saliva LC-MS/MS and urinary metabolites via GC-MS. Structural equation modeling examined relationships.","limitations":"Male participants only. Cannot fully establish causality despite longitudinal design. Cortisol patterns can be affected by many factors beyond cannabis. The specific cohort (congress 60 clients) may not generalize."},{"rthcId":"RTHC-05631","title":"DNA methylation and gene expression of immune cell markers in adolescents with chronic cannabis use: an exploratory study.","authors":"Plank, Anne-Christine; Wiedmann, Melina; Kuitunen-Paul, Sören; Wagner, Wolfgang; Perez-Correa, Juan-Felipe; Franzen, Julia; Ioannidis, Charalampos; Mirtschink, Peter; Roessner, Veit; Golub, Yulia","year":2024,"journal":"BMC psychiatry, 24(1), 676","doi":"10.1186/s12888-024-06043-0","pmid":"39394085","tags":["youth","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Using DNA methylation analysis of blood samples, chronic cannabis-using adolescents (n=14) had lower estimated B cell proportions compared to non-users (n=15). An initially observed higher granulocyte proportion was attenuated when controlling for tobacco use. Differences in DNA methylation and gene expression of immune markers (CD4, CD8A, CD19, etc.) were not statistically significant.","whyItMatters":"This is among the first studies to examine how chronic cannabis use affects the immune system specifically in adolescents, a population where the immune system is still developing. The B cell finding, if confirmed, could have implications for infection susceptibility.","specificNumbers":"14 cannabis users vs 15 controls; mean age 16.1; lower B cell proportion in users; 7 immune markers analyzed (CD4, CD8A, CD19, FCGR3A, CD14, FUT4, MPO); granulocyte difference attenuated by tobacco control","methodology":"Exploratory cross-sectional study comparing DNA methylation and gene expression of immune cell markers in whole blood from 14 adolescent chronic cannabis users (mean age 16.1) versus 15 non-cannabis-using controls.","limitations":"Very small sample size (14 vs 15). Exploratory design with multiple comparisons. Cross-sectional. Cannot distinguish cannabis effects from lifestyle or other substance effects. DNA methylation-based cell estimates are indirect."},{"rthcId":"RTHC-05632","title":"Exploring the Possible Role of Cannabinoids in Managing Post-cardiac Surgery Complications: A Narrative Review of Preclinical Evidence and a Call for Future Research Directions.","authors":"Pollak, Uri; Avniel-Aran, Adi; Binshtok, Alexander M; Bar-Yosef, Omer; Bronicki, Ronald A; Checchia, Paul A; Finkelstein, Yaron","year":2024,"journal":"Journal of cardiovascular pharmacology, 83(6), 537-546","doi":"10.1097/FJC.0000000000001560","pmid":"38498618","tags":["medical-cannabis","cbd","pain","cardiovascular"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Preclinical evidence suggests CBD has anti-inflammatory, analgesic, and neuroprotective properties relevant to post-cardiac surgery recovery. The endocannabinoid system plays a role in managing physiological processes disrupted by cardiopulmonary bypass, and CBD has shown promise in managing ischemia/reperfusion injury in preclinical models.","whyItMatters":"Post-cardiac surgery pain management relies heavily on opioids, which carry addiction and side effect risks. If cannabinoids can reduce opioid requirements while addressing inflammation and tissue protection, this could significantly improve surgical recovery.","specificNumbers":"Key applications reviewed: pain management, immune response modulation, ischemia/reperfusion injury mitigation; CBD identified as most promising candidate","methodology":"Narrative review of preclinical evidence on cannabinoids in the context of open-heart surgery complications including pain, systemic inflammation, and organ damage.","limitations":"Entirely based on preclinical evidence. No clinical trials in cardiac surgery patients. Cannabinoid interactions with cardiac medications and anesthetics are poorly understood. Post-surgical patients are a complex, high-risk population for any new intervention."},{"rthcId":"RTHC-05633","title":"Cannabis use in youth is associated with chronic inflammation.","authors":"Power, Emmet; Mongan, David; Healy, Colm; Susai, Subash Raj; Föcking, Melanie; Zammit, Stanley; Cannon, Mary; Cotter, David","year":2024,"journal":"Psychological medicine, 54(16), 1-11","doi":"10.1017/S0033291724002848","pmid":"39648682","tags":["youth","inflammation","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 914 participants from the ALSPAC cohort, daily/near-daily cannabis use at age 24 was strongly associated with elevated suPAR (a chronic inflammation biomarker implicated in neurodegenerative processes). Less frequent cannabis use was not associated with suPAR. No associations were found between cannabis use and traditional inflammatory markers (IL-6, TNF-alpha, CRP).","whyItMatters":"suPAR is a biomarker of systemic chronic inflammation linked to neurodevelopmental and neurodegenerative processes. Finding it elevated specifically in daily cannabis users provides a potential biological mechanism connecting heavy cannabis use to mental health and brain health risks.","specificNumbers":"914 participants from ALSPAC; daily/near-daily use associated with elevated suPAR; less frequent use: no association; IL-6, TNF-alpha, CRP: no association with any cannabis use level","methodology":"Analysis of 914 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC), measuring IL-6, TNF-alpha, CRP, and suPAR at age 24 and comparing across daily, less frequent, and no past-year cannabis use, adjusting for sociodemographics, BMI, childhood trauma, and tobacco smoking.","limitations":"Cross-sectional inflammation measurement at a single time point. Cannot determine if cannabis caused the suPAR elevation or vice versa. Single cohort (ALSPAC). suPAR is a relatively new biomarker without established clinical thresholds."},{"rthcId":"RTHC-05634","title":"Cannabis legalization and changes in cannabis and tobacco/nicotine use and co-use in a national cohort of U.S. adults during 2017-2021.","authors":"Pravosud, Vira; Glantz, Stanton; Keyhani, Salomeh; Ling, Pamela M; Lempert, Lauren K; Hoggatt, Katherine J; Hasin, Deborah; Nguyen, Nhung; Graham, Francis Julian L; Cohen, Beth E","year":2024,"journal":"The International journal on drug policy, 134, 104618","doi":"10.1016/j.drugpo.2024.104618","pmid":"39500225","tags":["legalization","addiction","quitting"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use increased 3.3% from 2017-2021 while tobacco/nicotine use declined 1.9%. Both medical and recreational legalization were associated with increased cannabis use, with recreational legalization having 1.13 times larger effect. Neither type of legalization was associated with changes in tobacco/nicotine use or co-use of cannabis and tobacco.","whyItMatters":"A major concern about cannabis legalization has been potential spillover effects on tobacco use or development of polysubstance use patterns. This study provides reassurance that legalization increases cannabis use without worsening tobacco or co-use patterns.","specificNumbers":"9,003 participants in 2017; cannabis use +3.3%; tobacco use -1.9%; co-use +0.2% (not significant); recreational legalization 1.13x larger effect than medical; age range 18-94","methodology":"Longitudinal study using a nationally representative web-based panel of 9,003 US adults surveyed in 2017, 2020, and 2021, with weighted adjusted binary logistic GEE models assessing legalization associations.","limitations":"Self-reported substance use. Panel attrition (70% and 74% retention). Cannot account for all confounders. Binary cannabis use measure does not capture frequency or quantity changes."},{"rthcId":"RTHC-05635","title":"Delays in blood collection and drug toxicology results among crash-involved drivers arrested for impaired driving.","authors":"Price, Jana M; Smith, Ryan C; Miles, Amy K; Kayagil, Turan A","year":2024,"journal":"Traffic injury prevention, 25(5), 667-672","doi":"10.1080/15389588.2024.2333918","pmid":"38648016","tags":["driving"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"When a driver is arrested for impaired driving after a crash, how long does it take to actually draw blood for testing? This study analyzed 8,923 crash-involved DUI cases in Wisconsin over three years and found the average delay was 1.8 hours — with significant variation based on crash severity.\n\nMore severe crashes caused longer delays. This makes intuitive sense (injured drivers go to the hospital, medical care takes priority over blood draws) but creates a perverse result: the most dangerous crashes, where proving impairment matters most for prosecution and public safety, have the longest delays and thus the worst toxicological evidence.\n\nFor alcohol, the delay matters but is manageable because blood alcohol concentration (BAC) decreases at a relatively predictable rate (~0.015 g/dL per hour), allowing back-calculation. For THC, the problem is far more severe. THC blood levels plummet rapidly after smoking — within 1-2 hours, active THC may be undetectable even in recently-impaired drivers. A 1.8-hour average delay means many THC-impaired drivers will test below per se limits or even negative by the time blood is drawn.\n\nThe study examined how delays affected measured concentrations with respect to common per se limits. For BAC, most delayed samples still exceeded legal limits. For THC, the rapid metabolism meant delays pushed many samples below detection or per se thresholds — exactly the problem documented in the Italian DUI study (RTHC-00092) but now quantified with a much larger American dataset.","whyItMatters":"This study quantifies a fundamental problem in cannabis DUI enforcement with a large American dataset. The 1.8-hour average delay is long enough to substantially reduce or eliminate detectable THC in many impaired drivers. Unlike alcohol, there's no validated back-calculation method for THC. This means the legal system's ability to prosecute THC-impaired driving is compromised by a logistical problem — delayed blood draws — that has no simple solution within the current testing framework.","specificNumbers":"8,923 crash-involved DUI arrests in Wisconsin (2019-2021). Mean time-to-collection: 1.80 hours. Crash severity significantly affected delay duration (more severe = longer delay). THC concentrations were sensitive to collection delays, with many samples falling below per se limits. BAC was more robust to delays due to slower, more predictable metabolism.","methodology":"Observational study using blood toxicology results and crash-related information from 8,923 drivers involved in crashes and arrested for impaired driving in Wisconsin (2019-2021). Analyzed how crash timing and severity influenced time-to-collection and the effects of delays on blood alcohol concentrations (BAC) and blood delta-9-THC concentrations.","limitations":"Wisconsin data only — other states may have different time-to-collection patterns based on hospital proximity, staffing, and protocols. Only crash-involved DUI arrests were included; non-crash DUI stops likely have shorter delays. The study examines delays and concentrations but doesn't directly measure impairment. THC metabolism varies by individual (chronic users may have detectable THC for longer). Per se THC limits themselves are debated in the scientific literature."},{"rthcId":"RTHC-05636","title":"Patient-Reported Outcomes of Pain, Stiffness, and Fatigue Reduction in Rheumatoid and Psoriatic Arthritis With Cannabinoid Use.","authors":"Purohit, Richa; Mathai, Reanne; Camargo Macias, Kathlyn; Chalise, Sweta; Jehu, Tara; Bhaskar, Neha; Bhanusali, Neha","year":2024,"journal":"Cureus, 16(10), e72366","doi":"10.7759/cureus.72366","pmid":"39583459","tags":["pain","medical-cannabis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"About 16.95% of RA and 11.63% of PsA patients reported cannabinoid use, primarily inhaled for RA and topical/liquid for PsA. Post-cannabis use, pain scores decreased significantly (mean difference 2.267, p<0.001), with improvements in stiffness, fatigue, and swelling. Side effects were minimal, and 80-86% of patients were willing to discuss cannabinoid treatment with their physician.","whyItMatters":"This is one of few studies documenting real-world cannabinoid use patterns and patient-reported outcomes specifically in inflammatory arthritis. The willingness of over 80% of patients to discuss cannabis with their doctor signals a need for evidence-based guidance.","specificNumbers":"290 patients (247 RA, 44 PsA); 82.3% female; mean age ~57; ~15% cannabinoid use; pain reduction mean difference 2.267 (p<0.001); 80-86% willing to discuss with physician; minimal side effects","methodology":"Cross-sectional survey of 290 patients with RA or PsA visiting a rheumatology outpatient clinic (October 2019 to March 2020), using a voluntary Qualtrics survey on cannabinoid use, forms, sources, side effects, and perceived efficacy.","limitations":"Survey design with self-reported outcomes. No control group. Cannot rule out placebo effect. Pre-pandemic recruitment (2019-2020). Small number of cannabinoid users. Selection bias (voluntary survey)."},{"rthcId":"RTHC-05637","title":"The cannabinoid CB2 receptor positive allosteric modulator EC21a exhibits complicated pharmacology in vitro.","authors":"Qi, Aidong; Han, Xueqing; Quitalig, Marc; Wu, Jessica; Christov, Plamen P; Jeon, KyuOk; Jana, Somnath; Kim, Kwangho; Engers, Darren W; Lindsley, Craig W; Rodriguez, Alice L; Niswender, Colleen M","year":2024,"journal":"Journal of receptor and signal transduction research, 44(4), 151-159","doi":"10.1080/10799893.2024.2431986","pmid":"39575892","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05638","title":"Trips Through the Skin: Reviewing Cutaneous Drug Reactions to Psychedelics and Hallucinogens.","authors":"Rahman, Syed Minhaj; Salem, Yousef; Hussain, Aamir","year":2024,"journal":"Dermatitis : contact, atopic, occupational, drug, 35(6), 605-613","doi":"10.1089/derm.2023.0292","pmid":"38634840","tags":["harm-reduction"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Of 22 studies meeting inclusion criteria (40 total patients), cannabis accounted for 10 studies. The most common cannabis skin reaction was type I hypersensitivity from topical exposure (n=21). Three patients had type IV reactions (vesicular contact dermatitis) from cannabis-derived oils. MDMA caused acneiform eruptions and Stevens-Johnson syndrome. Ketamine caused type I hypersensitivity. Psilocybin caused vesicular eruptions.","whyItMatters":"As cannabis and psychedelic use increases, clinicians need to recognize associated skin reactions. Cannabis allergy is increasingly documented and can range from mild contact reactions to potentially serious systemic allergic responses.","specificNumbers":"22 studies, 40 patients total; cannabis: 10 studies, 21 cases of type I hypersensitivity, 3 cases type IV; MDMA: 5 studies; ketamine: 4 studies; psilocybin: 3 studies; 8 resolved with cessation alone","methodology":"Systematic review of PubMed and Scopus from database inception to August 2023 for cutaneous reactions to psychedelics and hallucinogens (cannabis, MDMA, LSD, ketamine, psilocybin, and others).","limitations":"Limited to published case reports and small studies. Likely underrepresents true incidence. No standardized diagnostic criteria across studies. Many cases had incomplete follow-up."},{"rthcId":"RTHC-05639","title":"Patients' knowledge about the uses, risks, and beliefs surrounding the regulation and safety of Cannabis sativa L. in Peru.","authors":"Ramírez-Méndez, José F; Wong-Salgado, Pedro; Gámez, Peter; Solis, Pedro; Moya-Salazar, Jeel","year":2024,"journal":"Heliyon, 10(7), e27068","doi":"10.1016/j.heliyon.2024.e27068","pmid":"38689986","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 86 patients at a Lima cannabis clinic (mean age 41, 53.4% women), 60.2% knew about cannabis consumption forms and 77.3% recognized product quality importance. Primary conditions treated: chronic pain and nausea (each 23.9%), cancer and epilepsy (each 21.6%). Knowledge correlated significantly with cannabis use duration, but most patients had incomplete understanding of risks, regulations, and safety.","whyItMatters":"As medical cannabis programs expand globally, understanding what patients know and do not know about their treatment is critical for safety. The knowledge gaps found suggest that even experienced patients need ongoing education.","specificNumbers":"86 patients; mean age 41; 53.4% women; mean cannabis use 3 years; 60.2% knew consumption forms; 77.3% recognized quality importance; primary conditions: chronic pain, nausea (23.9% each), cancer, epilepsy (21.6% each)","methodology":"Cross-sectional survey using the 22-item KUC-22 questionnaire at the CANNAVITAL clinic in Lima, Peru, assessing knowledge, attitudes, and beliefs about cannabis among 86 patients with at least one year of medical cannabis use.","limitations":"Single clinic in Lima. Small sample. Selection bias (clinic patients may be more knowledgeable than general users). Self-reported knowledge may not reflect actual understanding."},{"rthcId":"RTHC-05640","title":"A Systematic Review of Delta-9-Tetrahydrocannabinol (∆9-THC) in Astrocytic Markers.","authors":"Ramos-Jiménez, Christian; Petkau, Sarah; Mizrahi, Romina","year":2024,"journal":"Cells, 13(19)","doi":"10.3390/cells13191628","pmid":"39404391","tags":["neuroscience","youth"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Both GFAP and nestin expression increased in adulthood following adolescent and adult THC exposure. GLAST expression increased during early development after THC exposure. Effects appeared to vary by developmental stage (adolescence vs adulthood) and sex, though patterns were not fully consistent across studies.","whyItMatters":"Astrocytes are essential brain support cells that maintain homeostasis, support synaptic function, and respond to injury. THC's impact on these cells, especially during development, could explain some of the cognitive and mental health effects associated with cannabis use.","specificNumbers":"12 studies included; key markers: GFAP (increased), nestin (increased), GLAST (increased during early development); effects varied by age and sex","methodology":"Systematic review of EMBASE, Medline, and PsychoInfo for studies reporting astrocytic markers following THC exposure in animals and humans. 12 eligible studies were included with bias assessment using SYRCLE guidelines.","limitations":"Only 12 studies met criteria, reflecting a sparse literature. Most were animal studies. Heterogeneous methods and THC exposure protocols. Limited human data. Risk of bias present in included studies."},{"rthcId":"RTHC-05641","title":"Fronto-temporal cortical grey matter thickness and surface area in the at-risk mental state and recent-onset schizophrenia: a magnetic resonance imaging study.","authors":"Rasser, Paul E; Ehlkes, Tim; Schall, Ulrich","year":2024,"journal":"BMC psychiatry, 24(1), 33","doi":"10.1186/s12888-024-05494-9","pmid":"38191320","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05642","title":"Tobacco, nicotine, and cannabis use and exposure in an Australian Indigenous population during pregnancy: A protocol to measure parental and foetal exposure and outcomes.","authors":"Ratsch, Angela; Burmeister, Elizabeth A; Bird, Aunty Veronica; Bonner, Aunty Joyce; Miller, Uncle Glen; Speedy, Aunty Marj; Douglas, Graham; Ober, Stevan; Woolcock Nee Geary-Laverty, Ann; Blair Nee Murdoch, Sharly; Weng, Min-Tz; Miles, Jared A; Steadman, Kathryn J","year":2024,"journal":"PloS one, 19(9), e0300406","doi":"10.1371/journal.pone.0300406","pmid":"39240849","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05643","title":"The Potential of Cannabis in Managing Inflammatory Bowel Disease and Its Future Perspective.","authors":"Rauf, Arsalan; Nisar, Mudassar; Shaeel, Muhammad; Athar, Ali; Rehman, Muhammad Mujtaba Ur; Faheem, Filzah","year":2024,"journal":"Cureus, 16(10), e71068","doi":"10.7759/cureus.71068","pmid":"39624503","tags":["medical-cannabis","inflammation"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Cannabinoids act on CB1 and CB2 receptors in the enteric nervous system, GI epithelial cells, and immune cells, reducing gut motility, secretions, and inflammatory edema. Small observational studies and placebo-controlled trials have shown symptomatic improvement, but sample sizes have been too small for firm efficacy and safety conclusions.","whyItMatters":"IBD affects millions of people globally, and current treatments often have significant side effects or lose effectiveness over time. Cannabis represents a potentially well-tolerated complementary approach, but the evidence gap is significant.","specificNumbers":"CB1 and CB2 receptors expressed in brain, enteric nervous system, GI epithelial cells, and immune cells; effects: decreased gut motility, reduced secretions, reduced inflammatory edema","methodology":"Narrative review of observational and placebo-controlled trials examining cannabis and cannabinoids in Crohn's disease and ulcerative colitis, alongside preclinical mechanism data.","limitations":"Narrative review. Existing clinical trials have small sample sizes. No standardized cannabinoid compositions across studies. Long-term safety data lacking. Psychotropic side effects of THC limit some applications."},{"rthcId":"RTHC-05644","title":"Screening of substance use in pregnancy: A Danish cross-sectional study.","authors":"Rausgaard, Nete Lundager Klokker; Ibsen, Inge Olga; Fruekilde, Palle Bach Nielsen; Nohr, Ellen Aagaard; Damkier, Per; Ravn, Pernille","year":2024,"journal":"Acta obstetricia et gynecologica Scandinavica, 103(7), 1408-1419","doi":"10.1111/aogs.14862","pmid":"38778571","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05645","title":"Child Protection System Interactions for Children With Positive Urine Screens for Illicit Drugs.","authors":"Rebbe, Rebecca; Malicki, Denise; Siddiqi, Nadia; Huang, Jeannie S; Putnam-Hornstein, Emily; Laub, Natalie","year":2024,"journal":"JAMA network open, 7(3), e243133","doi":"10.1001/jamanetworkopen.2024.3133","pmid":"38512254","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05646","title":"A content analysis of cannabis edibles package marketing in the United States.","authors":"Reboussin, Beth A; Lazard, Allison J; Ross, Jennifer Cornacchione; Sutfin, Erin L; Romero-Sandoval, E Alfonso; Suerken, Cynthia K; Lake, Shelby; Horton, Olivia E; Zizzi, Alexandra R; Wagoner, Emily; Janicek, Alondra; Boucher, Madeleine; Wagoner, Kimberly G","year":2024,"journal":"The International journal on drug policy, 130, 104526","doi":"10.1016/j.drugpo.2024.104526","pmid":"39032269","tags":["legalization","harm-reduction"],"studyType":"Cross-Sectional","evidenceStrength":"Moderate","keyFinding":"Health-related descriptors appeared on 31% of packages (e.g., \"vegan,\" \"gluten free,\" \"natural\"), quality descriptors on 28% (\"handcrafted\"), expected effects on 27% (\"relax\"), taste/flavor language on 21%, and pharmacokinetic claims on 19% (\"fast-acting\"). Images of food appeared on 43% of packages, non-cannabis plants on 50%, and the cannabis plant itself on only 33%.","whyItMatters":"When edible packaging emphasizes \"natural\" ingredients and food imagery while downplaying cannabis content, consumers may underestimate what they are actually consuming.","specificNumbers":"1,229 packages analyzed; 31% had health descriptors; 28% had quality descriptors; 27% listed expected effects; 43% included food imagery; only 33% showed the cannabis plant.","methodology":"Descriptive content analysis of 1,229 cannabis edible packages advertised on a publicly available website between June and November 2022, all available for sale in licensed US dispensaries.","limitations":"Analyzed packages from one website, which may not represent all US markets. Did not assess consumer perceptions or behavior."},{"rthcId":"RTHC-05647","title":"Cannabis use to manage stimulant cravings among people who use unregulated drugs.","authors":"Reddon, Hudson; Socias, Maria Eugenia; DeBeck, Kora; Hayashi, Kanna; Walsh, Zach; Milloy, M-J","year":2024,"journal":"Addictive behaviors, 148, 107867","doi":"10.1016/j.addbeh.2023.107867","pmid":"37748225","tags":["addiction","harm-reduction"],"studyType":"Cross-Sectional","evidenceStrength":"Preliminary","keyFinding":"Cannabis use to manage stimulant cravings was reported by 134 of 297 participants (45.1%). Of those, 77.6% reported decreasing stimulant use. In multivariable analysis, cannabis for craving management was associated with 76% lower odds of continued stimulant use (aOR = 0.24, 95% CI: 0.10-0.56). The association was strongest among daily crystal methamphetamine users (aOR = 0.08) but not significant for daily crack/cocaine users.","whyItMatters":"With no FDA-approved medications for stimulant use disorder, people who use drugs are developing their own harm reduction strategies. This study documents cannabis substitution as a common, self-directed approach.","specificNumbers":"297 participants; 45.1% used cannabis to manage stimulant cravings; 77.6% of those reported decreased stimulant use; aOR 0.24 for reduced stimulant use; aOR 0.08 for daily meth users.","methodology":"Cross-sectional questionnaire administered to 297 people who concurrently use cannabis and unregulated stimulants in Vancouver, Canada. Logistic regression models adjusted for demographic and substance use variables.","limitations":"Cross-sectional design cannot establish causation. Self-reported outcomes. Vancouver PWUD population may not generalize."},{"rthcId":"RTHC-05648","title":"Cannabidiol represses miR-143 to promote cardiomyocyte proliferation and heart regeneration after myocardial infarction.","authors":"Ren, Zhongyu; Liu, Yining; Cai, Ao; Yu, Yang; Wang, Xiuxiu; Lan, Lan; Guo, Xiaofei; Yan, Hong; Gao, Xinlu; Li, Hanjing; Tian, Yanan; Ji, Haoyu; Chen, Hongyang; Ding, Fengzhi; Ma, Wenya; Wang, Ning; Cai, Benzhi; Yang, Baofeng","year":2024,"journal":"European journal of pharmacology, 963, 176245","doi":"10.1016/j.ejphar.2023.176245","pmid":"38052413","tags":["cbd","cardiovascular"],"studyType":"Animal Study","evidenceStrength":"Preliminary","keyFinding":"Systemic CBD administration (10 mg/kg) in post-MI mice increased cardiac regenerative ability, reduced infarct size, and restored cardiac function. CBD downregulates miR-143-3p through CB2, upregulating Yap and Ctnnd1 to promote cardiomyocyte proliferation. Blocking CB2 eliminated the effect.","whyItMatters":"Adult mammalian hearts have almost no regenerative capacity. This study identifies a specific molecular pathway through which CBD can reactivate cardiomyocyte proliferation.","specificNumbers":"10 mg/kg CBD dose; miR-143-3p significantly downregulated; Yap and Ctnnd1 upregulated; CB2 receptor required for effect; demonstrated in both neonatal and adult cardiomyocytes.","methodology":"MI models in adult mice via coronary artery ligation, treated with or without CBD (10 mg/kg). In vitro validation in neonatal cardiomyocytes. Molecular pathway analysis with receptor blockade experiments.","limitations":"Animal study with no human data. Mouse cardiac biology differs from human. Single dose level tested."},{"rthcId":"RTHC-05649","title":"Cannabis use disorders and outcome of admission to intensive care: A retrospective multi-centre cohort study.","authors":"Renger, Laura; Dhanani, Jayesh; Milford, Elissa; Tabah, Alexis; Shekar, Kiran; Ramanan, Mahesh; Laupland, Kevin B","year":2024,"journal":"Journal of critical care, 80, 154504","doi":"10.1016/j.jcrc.2023.154504","pmid":"38128218","tags":["harm-reduction"],"studyType":"Retrospective Cohort","evidenceStrength":"Moderate","keyFinding":"Of 34,680 ICU admissions, 292 (0.8%) had cannabis-related diagnoses. Cannabis-associated patients were younger (36 vs 62 years), more often male (73%), with fewer comorbidities. ICU LOS was longer (2 vs 1 days, p < 0.0001). After adjusting for age, severity, and comorbidities, the mortality difference disappeared (p = 1.0).","whyItMatters":"The finding that cannabis-associated patients stay longer in the ICU despite being younger and less comorbid suggests cannabis may complicate critical care management in ways not captured by standard severity scores.","specificNumbers":"34,680 admissions; 292 (0.8%) cannabis-related; median age 36 vs 62; 73% male; ICU LOS 2 vs 1 days (p < 0.0001); no mortality difference after adjustment.","methodology":"Retrospective cohort analysis of 34,680 admissions among 28,689 adults at four public Australian ICUs. Cannabis use identified by ICD10-AM diagnostic codes.","limitations":"ICD-10 coding likely underidentifies cannabis users. Cannot determine whether cannabis directly caused longer stays. Four Australian ICUs may not represent other settings."},{"rthcId":"RTHC-05650","title":"Trends in Substance Use-related Emergency Department Visits by Youth, 2018-2023.","authors":"Renny, Madeline H; Stecher, Yago; Vargas-Torres, Carmen; Zebrowski, Alexis M; Merchant, Roland C","year":2024,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2024.10.29.24316367","pmid":"39574857","tags":["youth","harm-reduction"],"studyType":"Retrospective Cohort","evidenceStrength":"Moderate","keyFinding":"Substance use-related ED visits increased from 2.8% to 3.4% (p < 0.001). Cannabis visits increased from 17.9% to 35.3% of substance-related visits across all age groups. Female visits increased from 43.4% to 52.4%. 19% had a substance-related return visit within one year.","whyItMatters":"The near-doubling of cannabis-related ER visits among youth, combined with increases in younger age groups and female patients, signals a shifting landscape of youth substance use.","specificNumbers":"151,764 total ED visits; 4,556 (3.0%) substance-related; cannabis visits from 17.9% to 35.3%; female proportion from 43.4% to 52.4%; 19% revisit rate within one year.","methodology":"Retrospective review of EHRs from six urban EDs identifying 12-21 year old patients with substance use-related visits (2018-2023) using ICD-10 codes.","limitations":"Single urban healthcare system may not represent national trends. ICD-10 coding may undercount cannabis involvement."},{"rthcId":"RTHC-05651","title":"Purified cannabidiol as add-on therapy in children with treatment-resistant infantile epileptic spasms syndrome.","authors":"Reyes Valenzuela, Gabriela; Gallo, Adolfo; Calvo, Agustin; Chacón, Santiago; Fasulo, Lorena; Galicchio, Santiago; Adi, Javier; Fortini, Pablo Sebastian; Caraballo, Roberto","year":2024,"journal":"Seizure, 115, 94-99","doi":"10.1016/j.seizure.2024.01.010","pmid":"38237316","tags":["cbd","epilepsy","youth"],"studyType":"Retrospective Cohort","evidenceStrength":"Moderate","keyFinding":"Of 28 infants with treatment-resistant IESS, 7 (25%) became spasm-free and 12 (43%) had >50% spasm reduction (total responder rate 67.8%). Response was notable in Down syndrome (5/7, 71%) and cerebral palsy (3/5, 60%). Median CBD dose was 25 mg/kg/day. Adverse effects were mild.","whyItMatters":"Infantile epileptic spasms are devastating and treatment-resistant cases have few options. A 68% response rate with good tolerability suggests CBD may fill an important gap, especially for infants with Down syndrome.","specificNumbers":"28 infants; 67.8% responder rate; 25% spasm-free; 71% response in Down syndrome; median dose 25 mg/kg/day; baseline 69 spasms/day; mean follow-up 15 months.","methodology":"Retrospective analysis of 28 infants with treatment-resistant IESS who received purified CBD (Epidyolex) as add-on therapy between July 2021 and June 2023. Mean follow-up 15 months.","limitations":"Retrospective, uncontrolled design. Small sample (n = 28). No placebo comparison. Heterogeneous etiologies."},{"rthcId":"RTHC-05652","title":"Neurotrophic Factors in Cannabis-induced Psychosis: An Update.","authors":"Ricci, Valerio; de Berardis, Domenico; Martinotti, Giovanni; Maina, Giuseppe","year":2024,"journal":"Current topics in medicinal chemistry, 24(20), 1757-1772","doi":"10.2174/1568026623666230829152150","pmid":"37644743","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05653","title":"New insight in psychotic cannabis withdrawal: case series and brief overview.","authors":"Ricci, Valerio; De Berardis, Domenico; Martinotti, Giovanni; Maina, Giuseppe","year":2024,"journal":"Rivista di psichiatria, 59(6), 316-321","doi":"10.1708/4386.43840","pmid":"39648835","tags":["withdrawal","psychosis"],"studyType":"Case Report","evidenceStrength":"Preliminary","keyFinding":"Four patients referred to a mental health department between 2019 and 2023 developed psychotic features specifically after abrupt cannabis cessation, representing a distinct clinical phenomenon from cannabis-induced psychosis during active use.","whyItMatters":"Most research on cannabis and psychosis focuses on active use. This case series highlights the underrecognized possibility that abrupt cessation can also trigger psychotic episodes.","specificNumbers":"4 patients; evaluated between 2019 and 2023; psychosis emerged after abrupt cessation of chronic cannabis use.","methodology":"Case series of 4 patients evaluated at a single mental health department between 2019 and 2023 who developed psychotic features after abrupt cannabis withdrawal.","limitations":"Only 4 cases from a single center. Cannot rule out coincidental psychotic onset or residual THC effects. Case reports cannot establish causation."},{"rthcId":"RTHC-05654","title":"Efficacy of cannabinoids in neurodevelopmental and neuropsychiatric disorders among children and adolescents: a systematic review.","authors":"Rice, Lauren J; Cannon, Lisa; Dadlani, Navin; Cheung, Melissa Mei Yin; Einfeld, Stewart L; Efron, Daryl; Dossetor, David R; Elliott, Elizabeth J","year":2024,"journal":"European child & adolescent psychiatry, 33(2), 505-526","doi":"10.1007/s00787-023-02169-w","pmid":"36864363","tags":["medical-cannabis","youth"],"studyType":"Systematic Review","evidenceStrength":"Moderate","keyFinding":"Across 8 conditions (anxiety, ASD, FASD, fragile X, intellectual disability, mood disorders, PTSD, Tourette syndrome), only 18 studies qualified: 1 RCT, 1 open-label trial, 3 uncontrolled before-and-after studies, 2 case series, and 11 case reports. Risk of bias was high across nearly all studies.","whyItMatters":"Families of children with conditions like autism and Tourette syndrome are increasingly turning to cannabinoid products despite the near-absence of rigorous evidence.","specificNumbers":"4,466 articles screened; 18 included; 8 conditions addressed; only 1 RCT identified; 11 of 18 studies were case reports.","methodology":"Systematic review searching MEDLINE, Embase, PsycINFO, and Cochrane for studies published after 1980 on cannabinoid-based products in individuals aged 18 or younger.","limitations":"Systematic review can only assess what has been studied. Did not include epilepsy, which has more robust cannabinoid evidence."},{"rthcId":"RTHC-05655","title":"Cannabidiol Add-On in Glycosylphosphatidylinositol-Related Drug-Resistant Epilepsy.","authors":"Riva, Antonella; D'Onofrio, Gianluca; Pisati, Angelica; Roberti, Roberta; Amadori, Elisabetta; Bosch, Friedrich; de Souza, Carolina Fischinger Moura; Thomas, Ashley; Russo, Emilio; Striano, Pasquale; Bayat, Allan","year":2024,"journal":"Cannabis and cannabinoid research, 9(4), 990-995","doi":"10.1089/can.2022.0255","pmid":"36862522","tags":["cbd","epilepsy"],"studyType":"Case Report","evidenceStrength":"Preliminary","keyFinding":"Six patients with genetically confirmed GPI-anchored protein deficiency and drug-resistant epilepsy received add-on CBD (Epidyolex). At 12 months, 5 of 6 (83%) were responders. No severe adverse events. Mean CBD dose was 17.85 mg/kg/day.","whyItMatters":"GPI-anchored protein deficiencies cause severe, drug-resistant epilepsy with few treatment options. An 83% response rate suggests a potential targeted therapy.","specificNumbers":"6 patients; 83% responders at 12 months; mean dose 17.85 mg/kg/day; median treatment duration 27 months; no severe adverse events.","methodology":"Case series of 6 patients with genetically proven GPI-anchored protein deficiency epilepsy treated with pharmaceutical-grade CBD as add-on therapy.","limitations":"Only 6 patients. No placebo control. Ultra-rare condition limits replication possibilities."},{"rthcId":"RTHC-05656","title":"NHS-Reimbursed Cannabis Flowers for Cancer Palliative Care and the Management of Chemotherapy-Induced Nausea and Vomiting: An Autobiographical Case Report.","authors":"Roberts, Michael; Brown, Matthew R D; Moreno-Sanz, Guillermo","year":2024,"journal":"Cureus, 16(6), e61791","doi":"10.7759/cureus.61791","pmid":"38975420","tags":["medical-cannabis","cancer"],"studyType":"Case Report","evidenceStrength":"Preliminary","keyFinding":"A patient with rectosigmoid adenocarcinoma with lung metastases failed five standard antiemetics. Inhalation of THC-predominant cannabis flowers improved CINV, anxiety, sleep, appetite, mood, and quality of life. NHS England approved an individual funding request.","whyItMatters":"This case documents a viable pathway for NHS patients to access medicinal cannabis through individual funding requests when standard treatments fail.","specificNumbers":"Failed 5 standard antiemetics; improved CINV, anxiety, sleep, appetite, mood, and quality of life; first known NHS-reimbursed cannabis flower prescription.","methodology":"Autobiographical case report with medical data from NHS records, individual funding request forms, and patient-reported outcome measures.","limitations":"Single case report. Autobiographical format introduces potential bias. Cannot isolate cannabis effect from placebo."},{"rthcId":"RTHC-05657","title":"Scoping Review: The Role of Psychedelics in the Management of Chronic Pain.","authors":"Robinson, Christopher L; Fonseca, Alexandra C G; Diejomaoh, Efemena M; D'Souza, Ryan S; Schatman, Michael E; Orhurhu, Vwaire; Emerick, Trent","year":2024,"journal":"Journal of pain research, 17, 965-973","doi":"10.2147/JPR.S439348","pmid":"38496341","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05658","title":"Microglial morphological/inflammatory phenotypes and endocannabinoid signaling in a preclinical model of periodontitis and depression.","authors":"Robledo-Montaña, Javier; Díaz-García, César; Martínez, María; Ambrosio, Nagore; Montero, Eduardo; Marín, María José; Virto, Leire; Muñoz-López, Marina; Herrera, David; Sanz, Mariano; Leza, Juan Carlos; García-Bueno, Borja; Figuero, Elena; Martín-Hernández, David","year":2024,"journal":"Journal of neuroinflammation, 21(1), 219","doi":"10.1186/s12974-024-03213-5","pmid":"39245706","tags":["neuroscience","inflammation"],"studyType":"Animal Study","evidenceStrength":"Preliminary","keyFinding":"Rats with combined periodontitis and chronic mild stress showed decreased frontal cortex levels of endocannabinoid metabolic enzymes (NAPE-PLD, DAGL, MAGL), CB1 receptor, and downstream signaling molecules. BDNF and synaptophysin were also lower. These changes were most pronounced in the combined model.","whyItMatters":"This study provides a biological mechanism linking gum disease to depression through the endocannabinoid system. Neither condition alone produced the full brain changes.","specificNumbers":"n=12 rats per group; 4 groups; 12 weeks bacterial gavage; 3 weeks CMS; decreased NAPE-PLD, DAGL, MAGL, CB1, PI3K, Akt, ERK1/2, BDNF, and synaptophysin in combined model.","methodology":"Four-group animal study (n=12/group): periodontitis + CMS, periodontitis alone, stress alone, and control. Periodontitis induced by oral bacterial gavage for 12 weeks, followed by 3 weeks of CMS.","limitations":"Animal model may not translate to humans. Bacterial gavage does not perfectly replicate human periodontitis."},{"rthcId":"RTHC-05659","title":"A Systematic Review of the Clinical Effects of Cannabis and Cannabinoids in Posttraumatic Stress Disorder Symptoms and Symptom Clusters.","authors":"Rodas, Justyne D; George, Tony P; Hassan, Ahmed N","year":2024,"journal":"The Journal of clinical psychiatry, 85(1)","doi":"10.4088/JCP.23r14862","pmid":"38353645","tags":["ptsd","medical-cannabis"],"studyType":"Systematic Review","evidenceStrength":"Moderate","keyFinding":"Of 10 studies in non-CUD samples, 5 suggested benefits and 5 showed no effect or worsening. Four studies found benefits for cluster B (re-experiencing) and cluster E (arousal/reactivity) symptoms. All 3 CUD studies reported worsening.","whyItMatters":"Many PTSD patients use cannabis. The finding that comorbid CUD consistently worsened outcomes while targeted symptom relief appeared in non-CUD users suggests the relationship depends on use patterns.","specificNumbers":"14 studies; 5/10 showed benefits for overall symptoms in non-CUD; 4 showed benefits for clusters B and E; 3/3 CUD studies showed worsening.","methodology":"Systematic review of PubMed, PsycINFO, and EMBASE for studies of cannabis in patients with PTSD using validated measures, January 1990-February 2023. 14 studies met criteria.","limitations":"Mixed study designs. Few studies overall (14). Cannot standardize across different cannabis products."},{"rthcId":"RTHC-05660","title":"Cannabis, Endocannabinoids and Brain Development: From Embryogenesis to Adolescence.","authors":"Rodrigues, Ricardo J; Marques, Joana M; Köfalvi, Attila","year":2024,"journal":"Cells, 13(22)","doi":"10.3390/cells13221875","pmid":"39594623","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05661","title":"Cannabis use and cognitive biases in people with first-episode psychosis and their siblings.","authors":"Roldan, L; Sánchez-Gutiérrez, T; Fernández-Arias, I; Rodríguez-Toscano, E; López, G; Merchán-Naranjo, J; Calvo, A; Rapado-Castro, M; Parellada, M; Moreno, C; Ferraro, L; La Barbera, D; La Cascia, C; Tripoli, G; Di Forti, M; Murray, R M; Quattrone, D; Morgan, C; Gayer-Anderson, C; Jones, P B; Jongsma, H E; Kirkbride, J B; van Os, J; García-Portilla, P; Al-Halabí, S; Bobes, J; de Haan, L; Bernardo, M; Santos, J L; Sanjuán, J; Arrojo, M; Szoke, A; Rutten, B P; Stilo, S A; Tarricone, I; Lasalvia, A; Tosato, S; Llorca, P-M; Menezes, P Rossi; Selten, J-P; Tortelli, A; Velthorst, E; Del-Ben, C M; Arango, C; Díaz-Caneja, C M","year":2024,"journal":"Psychological medicine, 54(15), 1-11","doi":"10.1017/S0033291724001715","pmid":"39575607","tags":["psychosis","cognition"],"studyType":"Cross-Sectional","evidenceStrength":"Moderate","keyFinding":"Daily and occasional cannabis use were associated with lower odds of speech illusions (OR = 0.605 and 0.646) and jumping to conclusions bias (OR = 0.625 and 0.602) compared to never-use. Low-potency use was associated with higher odds of all three cognitive biases compared to high-potency use.","whyItMatters":"The counterintuitive finding that cannabis users show fewer cognitive biases challenges simple narratives about cannabis and cognition in psychosis.","specificNumbers":"1,914 participants; daily use OR 0.605 for speech illusions; occasional use OR 0.602 for JTC; low vs high potency: OR 1.829 for SI, 1.393 for FRP, 1.661 for JTC.","methodology":"Cross-sectional analysis of 543 first-episode psychosis patients, 203 siblings, and 1,168 controls from the EU-GEI multi-site study.","limitations":"Cross-sectional design prevents causal inference. Self-reported cannabis potency."},{"rthcId":"RTHC-05662","title":"Roadmap for the expression of canonical and extended endocannabinoid system receptors and metabolic enzymes in peripheral organs of preclinical animal models.","authors":"Rosado-Franco, J J; Ellison, A L; White, C J; Price, A S; Moore, C F; Williams, R E; Fridman, L B; Weerts, E M; Williams, D W","year":2024,"journal":"Physiological reports, 12(4), e15947","doi":"10.14814/phy2.15947","pmid":"38408761","tags":["neuroscience"],"studyType":"Animal Study","evidenceStrength":"Moderate","keyFinding":"Of 14 endocannabinoid receptors examined in seven peripheral organs, not a single receptor had identical expression patterns across mice, rats, and rhesus macaques. Species- and organ-specific heterogeneity was the norm.","whyItMatters":"Most cannabinoid research uses rodent models, but if receptor distribution differs fundamentally between species, findings may not predict effects in primates or humans.","specificNumbers":"14 receptors; 7 organs; 3 species; 0 receptors with identical cross-species expression.","methodology":"Quantitative gene expression analysis of 14 endocannabinoid receptors in seven peripheral organs of C57/BL6 mice (n=5), Sprague-Dawley rats (n=6), and rhesus macaques (n=4).","limitations":"Small numbers of animals per species. Gene expression does not necessarily predict protein levels. Only peripheral organs, not CNS."},{"rthcId":"RTHC-05663","title":"Substance Use and College Completion Among Two-Year and Four-Year College Students From a Nationally Representative Longitudinal Study.","authors":"Rosenbaum, Janet E","year":2024,"journal":"Cureus, 16(5), e61297","doi":"10.7759/cureus.61297","pmid":"38947625","tags":["youth","cognition"],"studyType":"Longitudinal Cohort","evidenceStrength":"Moderate","keyFinding":"Among propensity-matched four-year college students, past-year marijuana use was associated with lower completion (IRR = 1.30, p = 0.007), with stronger effects for frequent use (>=5 times/month, IRR = 1.44). Two-year students showed different patterns: methamphetamine and alcohol treatment, not marijuana, predicted lower completion.","whyItMatters":"This study separates effects of different substances on educational attainment at different institution types, finding marijuana specifically affects four-year completion but not two-year.","specificNumbers":"888 two-year and 1,398 four-year matched students; past-year marijuana IRR 1.30; >=5 times/month IRR 1.44; 7-year follow-up; matched on 15 variables.","methodology":"Propensity-matched analysis from Add Health. 888 two-year and 1,398 four-year college students matched on 15 measures. Educational attainment measured 7 years later.","limitations":"Observational design cannot prove marijuana caused lower completion. Propensity matching reduces but does not eliminate confounding."},{"rthcId":"RTHC-05664","title":"Evaluation of the Efficacy of a Full-Spectrum Low-THC Cannabis Plant Extract Using In Vitro Models of Inflammation and Excitotoxicity.","authors":"Ross-Munro, Emily; Isikgel, Esra; Fleiss, Bobbi","year":2024,"journal":"Biomolecules, 14(11)","doi":"10.3390/biom14111434","pmid":"39595610","tags":["cbd","inflammation"],"studyType":"Animal Study","evidenceStrength":"Preliminary","keyFinding":"NTI-164, a high-CBD/low-THC full-spectrum extract, significantly attenuated inflammation-induced upregulation of microglial inflammatory markers in BV-2 microglia, while CBD alone did not. NTI-164 also promoted neuron proliferation and survival under excitotoxic conditions in SHSY-5Y neurons.","whyItMatters":"This study provides direct evidence for the \"entourage effect,\" showing that a whole-plant extract can outperform an isolated cannabinoid. The neuroprotective findings are relevant to conditions like autism spectrum disorder where neuroinflammation plays a role.","specificNumbers":"NTI-164 significantly attenuated microglial inflammatory markers; CBD alone did not; NTI-164 promoted neuron proliferation and survival under excitotoxic conditions.","methodology":"In vitro study using BV-2 microglial cells and SHSY-5Y neurons to compare anti-inflammatory and neuroprotective effects of a full-spectrum cannabis extract (NTI-164) versus CBD alone.","limitations":"In vitro study using cell lines, not living brain tissue. Cannot extrapolate directly to human disease. NTI-164 is a specific proprietary extract that may not represent all full-spectrum products."},{"rthcId":"RTHC-05665","title":"Identifying Adolescent Vaping With Screening to Brief Intervention and Brief Screener for Tobacco, Alcohol, and Drugs Screening Tools.","authors":"Ross, Jennifer A; Minegishi, Machiko; Brogna, Melissa; Subramaniam, Geetha; Levy, Sharon; Weitzman, Elissa","year":2024,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 75(1), 196-199","doi":"10.1016/j.jadohealth.2024.02.038","pmid":"38727658","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05666","title":"Delta-8 THC Retail Availability, Price, and Minimum Purchase Age.","authors":"Rossheim, Matthew E; LoParco, Cassidy R; Walker, Andrew; Livingston, Melvin D; Trangenstein, Pamela J; Olsson, Sofia; McDonald, Kayla K; Yockey, Robert A; Luningham, Justin M; Kong, Amanda Y; Henry, Doug; Walters, Scott T; Thombs, Dennis L; Jernigan, David H","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 363-370","doi":"10.1089/can.2022.0079","pmid":"36342930","tags":["legalization"],"studyType":"Cross-Sectional","evidenceStrength":"Moderate","keyFinding":"Of 1,223 surveyed outlets, 133 (11%) sold delta-8 THC. 96% sold vapes and/or flower (hemp coated with delta-8 distillate) and 76% sold edibles. Edibles cost $8.58 less on average than flower/vapes. Outlets in more socioeconomically deprived areas had significantly higher odds of selling delta-8. Most reported a minimum purchase age of 21, but 4% reported 18 or no minimum age.","whyItMatters":"Delta-8 THC products exist in a regulatory gray area following the 2018 Farm Bill. Their concentration in socioeconomically deprived areas and inconsistent age verification raise equity and public health concerns.","specificNumbers":"1,223 outlets surveyed; 133 (11%) sold delta-8; 96% sold vapes/flower; 76% sold edibles; edibles $8.58 cheaper; 4% reported minimum age of 18 or none; disproportionately in deprived areas (p=0.02).","methodology":"Cross-sectional survey of 1,223 retail outlets with alcohol, CBD, and/or tobacco licenses in Fort Worth, Texas, contacted by phone in September-October 2021. Area Deprivation Index scores merged by 9-digit zip code.","limitations":"Single city (Fort Worth). Phone survey may miss some outlets. Data from 2021 may not reflect current market. Cannot determine actual sales volume or consumer demographics."},{"rthcId":"RTHC-05667","title":"Intoxicating Cannabis Products in Vape Shops: United States, 2023.","authors":"Rossheim, Matthew E; LoParco, Cassidy R; Tillett, Kayla K; Treffers, Ryan D; Livingston, Melvin D; Berg, Carla J","year":2024,"journal":"American journal of preventive medicine, 67(5), 776-784","doi":"10.1016/j.amepre.2024.07.001","pmid":"39002889","tags":["legalization"],"studyType":"Cross-Sectional","evidenceStrength":"Moderate","keyFinding":"74% of 520 surveyed vape shops sold intoxicating cannabis products. Availability varied by regulatory context: 92% in states with limited/no regulations, 90% in states with significant restrictions, 53% in states with substantial regulations, and 43% in states with outright bans. Products were sold in every state except Washington and Alaska, both of which banned hemp-derived intoxicating products and had active legal cannabis retail.","whyItMatters":"This is the first national snapshot showing that intoxicating cannabis products are available in retail stores in all 50 states. The finding that 43% of shops in ban states still sell these products shows current enforcement is largely ineffective.","specificNumbers":"520 vape shops surveyed; 74% sold intoxicating cannabis products; 43% in ban states; 53% in regulated states; 90% in restricted states; 92% in unregulated states; available in 48/50 states.","methodology":"Systematic survey of 520 US vape shops (10 per state, DC, and Puerto Rico) conducted November-December 2023 by phone, assessing availability of 6 commonly sold intoxicating cannabis products.","limitations":"Phone survey may not capture all product types. 10 shops per state is a limited sample. Cannot verify product contents or potency."},{"rthcId":"RTHC-05668","title":"Substance use and firearm access among college freshmen.","authors":"Rossheim, Matthew E; Khoshhal, Bita; Karon, Samantha; Cheskin, Lawrence J; Trangenstein, Pamela J; Frankenfeld, Cara L; Ramezani, Niloofar; Cuellar, Alison E","year":2024,"journal":"Journal of American college health : J of ACH, 72(4), 1001-1005","doi":"10.1080/07448481.2022.2068959","pmid":"35549821","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05669","title":"Reduced fetal cerebral blood flow predicts perinatal mortality in a mouse model of prenatal alcohol and cannabinoid exposure.","authors":"Rouzer, Siara Kate; Sreeram, Anirudh; Miranda, Rajesh C","year":2024,"journal":"BMC pregnancy and childbirth, 24(1), 263","doi":"10.1186/s12884-024-06436-9","pmid":"38605299","tags":["pregnancy","neuroscience"],"studyType":"Animal Study","evidenceStrength":"Preliminary","keyFinding":"All drug exposures decreased fetal cranial blood flow 24 hours after the final dose. Combined alcohol and cannabinoid co-exposure reduced internal carotid artery blood flow significantly more than either exposure alone. Umbilical artery metrics were unaffected, indicating specific vulnerability of fetal cranial circulation. Post-exposure cerebroplacental ratios predicted perinatal mortality (p = 0.019, AUC 0.772, sensitivity 81%, specificity 85.7%).","whyItMatters":"Alcohol and cannabis are frequently co-consumed during pregnancy, but their combined effects on fetal brain development were virtually unknown. This study shows polysubstance exposure confers additional risk beyond either drug alone, specifically targeting fetal brain blood supply.","specificNumbers":"Combined exposure reduced internal carotid blood flow more than either alone; cerebroplacental ratio predicted perinatal mortality: p = 0.019, AUC 0.772, sensitivity 81%, specificity 85.7%; cannabinoid exposure alone reduced cerebroplacental ratios.","methodology":"Pregnant C57Bl/6J mice assigned to four groups: control, alcohol-exposed, cannabinoid-exposed, or both. Drug exposure daily on gestational days 12-15 (equivalent to late first/early second trimester in humans). High-resolution in vivo ultrasound imaging on three days of pregnancy.","limitations":"Mouse model using synthetic cannabinoid agonist (CP-55,940), not THC. Intraperitoneal injection plus vapor inhalation does not replicate human consumption patterns. Short exposure window (4 days). Small sample sizes per group."},{"rthcId":"RTHC-05670","title":"Cannabis Use Characteristics Associated with Self-Reported Cognitive Function in a Nationally Representative U.S. sample.","authors":"Rubin-Kahana, Dafna Sara; Butler, Kevin; Hassan, Ahmed Nabeel; Sanches, Marcos; Le Foll, Bernard","year":2024,"journal":"Substance use & misuse, 59(9), 1303-1312","doi":"10.1080/10826084.2024.2340975","pmid":"38664196","tags":["cognition"],"studyType":"Cross-Sectional","evidenceStrength":"Moderate","keyFinding":"Current users (N = 3,681) and former users (N = 7,448) reported poorer cognition than never users (N = 24,956) on the Executive Function Index scales. Former users scored between current and never users, suggesting some limited recovery. Several cannabis use characteristics (duration, frequency, age of onset) predicted self-reported cognitive impairment.","whyItMatters":"The finding that former users have intermediate cognitive scores suggests some recovery is possible after cessation, but it may not be complete. Understanding which use characteristics predict impairment could help personalize treatment for cannabis use disorder.","specificNumbers":"36,309 participants; 3,681 current users (37.7% female); 7,448 former users (45.4% female); 24,956 never users (56.6% female); former users scored between current and never users.","methodology":"Cross-sectional analysis of NESARC-III, a nationally representative US survey (N = 36,309, 2012-2013). Self-reported cognition measured by Executive Function Index scales. OLS regression.","limitations":"Cross-sectional design cannot determine causation or temporal sequence. Self-reported cognition may not correspond to objective measures. 2012-2013 data may not reflect current cannabis market and products."},{"rthcId":"RTHC-05671","title":"AGA Clinical Practice Update on Diagnosis and Management of Cannabinoid Hyperemesis Syndrome: Commentary.","authors":"Rubio-Tapia, Alberto; McCallum, Richard; Camilleri, Michael","year":2024,"journal":"Gastroenterology, 166(5), 930-934.e1","doi":"10.1053/j.gastro.2024.01.040","pmid":"38456869","tags":["medical-cannabis","harm-reduction"],"studyType":"Review","evidenceStrength":"Strong","keyFinding":"The AGA Clinical Practice Update provides consensus expert guidance on recognizing, diagnosing, and treating CHS, a condition characterized by cyclic nausea, vomiting, and compulsive hot water bathing in the setting of chronic cannabis use. The update underwent internal and external peer review.","whyItMatters":"CHS is increasingly common with rising cannabis use but remains underdiagnosed. Having the AGA, the leading US gastroenterology organization, publish formal guidance legitimizes the condition and gives clinicians a reference standard for diagnosis and management.","specificNumbers":"First AGA clinical practice update on CHS; peer-reviewed by CPUC and approved by AGA Governing Board.","methodology":"Expert commentary commissioned by the AGA Clinical Practice Updates Committee, incorporating published evidence and author experience, with internal and external peer review.","limitations":"Expert commentary rather than systematic review. Based on limited published evidence. Author experience may not represent all clinical settings."},{"rthcId":"RTHC-05672","title":"The Indirect Influence of Cannabis Use Disorder Symptoms on PTSD Symptom Severity Through Psychological Inflexibility.","authors":"Russell, Patricia D; Blessing, Alexis; Morissette, Sandra B","year":2024,"journal":"Substance use & misuse, 59(13), 1895-1900","doi":"10.1080/10826084.2024.2383979","pmid":"39104206","tags":["addiction","ptsd","mental-health","youth","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use disorder (CUD) and PTSD frequently co-occur, but what connects them? This study identifies a specific psychological mechanism: psychological inflexibility (PI) — the tendency to get stuck in rigid thought patterns and avoidant behaviors rather than adapting flexibly to situations.\n\nAmong 336 college students, the researchers tested whether CUD symptoms → psychological inflexibility → worse PTSD formed a mediation pathway. The model explained a remarkable 54% of the variance in PTSD symptom severity, and the indirect path through PI was significant. In other words, CUD doesn't just co-exist with PTSD — it appears to worsen PTSD symptoms specifically by increasing rigid, avoidant thinking.\n\nThis makes psychological sense. Cannabis can serve as an avoidance strategy — using it to escape distressing thoughts and emotions rather than processing them. Over time, this pattern becomes a rigid default (psychological inflexibility), which prevents the natural recovery from trauma that requires engaging with and processing difficult experiences. The more someone relies on cannabis to avoid, the more psychologically inflexible they become, and the worse their PTSD gets.\n\nThe clinical implication is important: psychological inflexibility is modifiable through established therapies, particularly Acceptance and Commitment Therapy (ACT). If PI is the mechanism connecting CUD and PTSD, then targeting it therapeutically could improve both conditions simultaneously.","whyItMatters":"One in five college students uses cannabis monthly and 10% develop CUD. College students also have high rates of trauma exposure. If psychological inflexibility is the bridge between CUD and PTSD, therapies like ACT that directly target inflexibility could be a two-for-one intervention — improving both cannabis use patterns and PTSD symptoms through a single mechanism.","specificNumbers":"336 college students. Mediation model explained 54% of variance in PTSD symptom severity (F(5,330) = 78.86). CUD → PI path significant (b = 0.31, p < .05). PI → PTSD path significant (b = 1.07, p < .05). Indirect mediation effect was significant. One in five college students uses cannabis monthly; ~10% develop CUD.","methodology":"Cross-sectional mediation analysis of 336 college students who completed self-report measures of cannabis use disorder symptoms, psychological inflexibility, and PTSD symptom severity. Mediation model tested whether PI mediated the CUD → PTSD pathway.","limitations":"Cross-sectional design — cannot establish temporal ordering (does CUD cause PI which causes worse PTSD, or does PTSD cause PI which drives CUD?). Self-report measures in a college sample may not generalize to clinical populations. The 54% variance explained is impressive but may partly reflect shared method variance (all self-report). College students represent a specific demographic and developmental stage. The mediation model is correlational, not causal."},{"rthcId":"RTHC-05673","title":"Cannabinoid hyperemesis syndrome: genetic susceptibility to toxic exposure.","authors":"Russo, Ethan B; Whiteley, Venetia L","year":2024,"journal":"Frontiers in toxicology, 6, 1465728","doi":"10.3389/ftox.2024.1465728","pmid":"39507417","tags":["genetics","harm-reduction"],"studyType":"Review","evidenceStrength":"Moderate","keyFinding":"Five genetic mutations distinguish CHS patients from asymptomatic heavy cannabis users: mutations in TRPV1 receptor, two dopamine genes, the CYP2C9 enzyme (which metabolizes THC), and the ATP-binding cassette transporter. The syndrome is associated with escalating high-potency cannabis intake. Some patients develop classical conditioned responses to environmental triggers. The authors refute claims that pesticides, neem oil, or azadirachtin cause CHS.","whyItMatters":"The identification of specific genetic variants explains why CHS affects some heavy cannabis users but not others. This opens the door to genetic screening and personalized risk assessment.","specificNumbers":"5 statistically significant mutations identified; affecting TRPV1, 2 dopamine genes, CYP2C9, and ABC transporter; associated with escalating high-potency cannabis use.","methodology":"Narrative review incorporating recent genetic findings, clinical observations, and analysis of proposed alternative etiologies for CHS.","limitations":"Narrative review format. The genetic findings require replication in larger populations. Cannot determine whether these mutations are sufficient or merely contributory."},{"rthcId":"RTHC-05674","title":"Bidimensional heart-cut achiral-chiral liquid chromatography coupled to high-resolution mass spectrometry for the separation of the main chiral phytocannabinoids and enantiomerization studies of cannabichromene and cannabichromenic acid.","authors":"Russo, Fabiana; Ferri, Elena; Pinetti, Diego; Vandelli, Maria Angela; Laganà, Aldo; Capriotti, Anna Laura; Cavazzini, Alberto; Gigli, Giuseppe; Citti, Cinzia; Cannazza, Giuseppe","year":2024,"journal":"Talanta, 267, 125161","doi":"10.1016/j.talanta.2023.125161","pmid":"37708768","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05675","title":"Attention Deficit Hyperactivity Disorder, Cannabis Use, and the Endocannabinoid System: A Scoping Review.","authors":"Ryan, Jennie E; Fruchtman, Mitchell; Sparr-Jaswa, Andrea; Knehans, Amy; Worster, Brooke","year":2024,"journal":"Developmental psychobiology, 66(7), e22540","doi":"10.1002/dev.22540","pmid":"39267530","tags":["cognition","addiction"],"studyType":"Scoping Review","evidenceStrength":"Moderate","keyFinding":"The review identifies neurobiological overlap between endocannabinoid function and cognitive dysfunction seen in ADHD. Cannabis use and cannabis use disorder are more prevalent in individuals with ADHD compared to the general population. However, the relationship between cannabis use and ADHD symptomology remains poorly understood.","whyItMatters":"ADHD is one of the most common psychiatric disorders, and many patients self-medicate with cannabis. Understanding whether there is a genuine neurobiological basis for this could lead to targeted cannabinoid therapies or better risk communication.","specificNumbers":"Cannabis use disorder more prevalent in ADHD than general population; neurobiological correlates identified between ECS function and ADHD cognitive dysfunction.","methodology":"Scoping review of preclinical and clinical evidence on the relationship between the endocannabinoid system and ADHD, including studies of ECS dysfunction and cannabis use patterns in ADHD populations.","limitations":"Scoping review maps the landscape but does not systematically assess evidence quality. Preclinical and clinical evidence is still limited. Cannot distinguish whether ADHD patients use cannabis because of ECS dysfunction or for other reasons."},{"rthcId":"RTHC-05676","title":"Prenatal delta-9-tetrahydrocannabinol exposure alters fetal neurodevelopment in rhesus macaques.","authors":"Ryan, Kimberly S; Karpf, Joshua A; Chan, Chi Ngai; Hagen, Olivia L; McFarland, Trevor J; Urian, J Wes; Wang, Xiaojie; Boniface, Emily R; Hakar, Melanie H; Terrobias, Jose Juanito D; Graham, Jason A; Passmore, Scarlet; Grant, Kathleen A; Sullivan, Elinor L; Grafe, Marjorie R; Saugstad, Julie A; Kroenke, Christopher D; Lo, Jamie O","year":2024,"journal":"Scientific reports, 14(1), 5808","doi":"10.1038/s41598-024-56386-7","pmid":"38461359","tags":["pregnancy","neuroscience"],"studyType":"Animal Study","evidenceStrength":"Moderate","keyFinding":"THC exposure was associated with significant age-by-sex interactions in brain volumetric growth on MRI, differences in fetal brain histology suggestive of dysregulation, and two extracellular vesicle-associated miRNAs in fetal CSF linked to dysregulated axonal guidance and netrin signaling pathways.","whyItMatters":"This is one of the first studies to use a primate model with THC edibles, closely approximating human exposure patterns. The convergence of MRI, histological, and molecular findings strengthens the evidence that prenatal THC disrupts neurodevelopment.","specificNumbers":"n=5 per group; daily THC edibles from pre-conception through pregnancy; 4 MRI timepoints; 2 miRNAs identified in fetal CSF; pathway analysis linked to axonal guidance and netrin signaling.","methodology":"Rhesus macaques received daily THC edibles pre-conception through pregnancy (n=5 THC, n=5 control). Fetal MRI at gestational days 85, 110, 135, and 155. Cesarean delivery at G155 with collection of CSF for miRNA analysis and tissue for histology.","limitations":"Small sample (n=5 per group). Cannot determine long-term neurodevelopmental outcomes from fetal measures. THC edible dose may not match typical human consumption. No assessment of postnatal behavior."},{"rthcId":"RTHC-05677","title":"Neurocognitive Impact of Exposure to Cannabis Concentrates and Cannabinoids Including Vaping in Children and Adolescents: A Systematic Review.","authors":"Saavedra, Michell S; Thota, Priyanka; Peresuodei, Tariladei S; Gill, Abhishek; Orji, Chijioke; Reghefaoui, Maiss; Khan, Safeera","year":2024,"journal":"Cureus, 16(1), e52362","doi":"10.7759/cureus.52362","pmid":"38361722","tags":["youth","cognition"],"studyType":"Systematic Review","evidenceStrength":"Moderate","keyFinding":"Across 19 included studies, cannabis exposure in youth was linked to a spectrum of CNS effects: transient mood alterations, lasting changes in cognitive function, and permanent sensory processing changes. Most studies were animal-based. The few human studies had limitations including small samples and study design constraints.","whyItMatters":"As cannabis legalization increases youth accessibility, understanding the neurocognitive impact during the critical brain development window of adolescence is essential for policy and clinical guidance.","specificNumbers":"19 studies included; effects ranged from transient mood changes to permanent cognitive alterations; most studies were animal-based; few human studies had significant limitations.","methodology":"Systematic review following 2020 PRISMA guidelines, searching PubMed, PMC, Medline, Cochrane, Internet Archive Scholar, and Embase-Elsevier. 19 research articles identified.","limitations":"Most included studies were animal-based. Human studies had small samples and design limitations. Cannot standardize across different cannabis products and exposure patterns."},{"rthcId":"RTHC-05678","title":"SAEM GRACE: Dopamine antagonists and topical capsaicin for cannabis hyperemesis syndrome in the emergency department: A systematic review of direct evidence.","authors":"Sabbineni, Monica; Scott, William; Punia, Kiran; Manuja, Kriti; Singh, Angad; Campbell, Kaitryn; MacKillop, James; Balodis, Iris","year":2024,"journal":"Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 31(5), 493-503","doi":"10.1111/acem.14770","pmid":"37391387","tags":["medical-cannabis","harm-reduction"],"studyType":"Systematic Review","evidenceStrength":"Moderate","keyFinding":"Of 7 included studies (5 observational, 2 RCTs; 492 total patients), 5 evaluated capsaicin cream (n=386) with mixed results, and 2 evaluated dopamine antagonists (n=106) with both detecting clinical benefit compared to usual care. Evidence for capsaicin was inconsistent for reducing nausea and emesis.","whyItMatters":"CHS is increasingly common in EDs, but evidence-based treatment guidelines are limited. This review provides the most comprehensive assessment of the two most-discussed ED interventions.","specificNumbers":"7 studies; 492 total patients; 5 capsaicin studies (n=386, mixed results); 2 dopamine antagonist studies (n=106, both positive); 2 RCTs included.","methodology":"Systematic review per PRISMA guidelines addressing a PICO question: adults with acute CHS in the ED, treated with dopamine antagonists or topical capsaicin vs. usual care. 53 articles screened, 7 included.","limitations":"Small number of studies. Small patient numbers. Lack of standardized treatment protocols across studies. Risk of bias in observational studies."},{"rthcId":"RTHC-05679","title":"A preliminary randomized controlled trial of repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex in treatment seeking participants with cannabis use disorder.","authors":"Sahlem, Gregory L; Kim, Bohye; Baker, Nathaniel L; Wong, Brendan L; Caruso, Margaret A; Campbell, Lauren A; Kaloani, Irakli; Sherman, Brian J; Ford, Tiffany J; Musleh, Ahmad H; Kim, Jane P; Williams, Nolan R; Manett, Andrew J; Kratter, Ian H; Short, Edward B; Killeen, Terese K; George, Mark S; McRae-Clark, Aimee L","year":2024,"journal":"Drug and alcohol dependence, 254, 111035","doi":"10.1016/j.drugalcdep.2023.111035","pmid":"38043228","tags":["quitting"],"studyType":"Randomized Controlled Trial","evidenceStrength":"Moderate","keyFinding":"Active rTMS (10Hz, left DLPFC, 20 sessions) did not significantly reduce craving compared to sham. However, active rTMS participants reported fewer days of cannabis use in the final two weeks of follow-up (-0.72 days/week, p = 0.02). They also had numerically more weeks of abstinence (15.5% vs 9.3%) though not statistically significant.","whyItMatters":"There are no FDA-approved medications for cannabis use disorder. rTMS is a non-invasive brain stimulation technique already approved for depression and OCD. This preliminary trial suggests it may have therapeutic potential for CUD, warranting larger studies.","specificNumbers":"72 participants (37.5% women, mean age 30.2); 20 rTMS sessions; -0.72 fewer days/week of cannabis use (p = 0.02); 15.5% vs 9.3% weeks of abstinence (NS); no significant craving differences.","methodology":"Two-site, phase-2, double-blind RCT. 72 treatment-seeking participants with moderate or greater CUD randomized to active or sham rTMS (20 total sessions, 2 per visit, 2 visits per week) with cannabis cues, plus 3-session motivational enhancement therapy.","limitations":"Small sample (n=72). Short follow-up (4 weeks). Primary outcome (craving) was negative. Use frequency effect emerged only in the final two weeks. All participants also received motivational enhancement therapy."},{"rthcId":"RTHC-05680","title":"The Effects of Cannabidiol and δ-9-Tetrahydrocannabinol in Social Cognition: A Naturalistic Controlled Study.","authors":"Sainz-Cort, Alberto; Jimenez-Garrido, Daniel; Muñoz-Marron, Elena; Viejo-Sobera, Raquel; Heeroma, Joost; Bouso, Jose Carlos","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 230-240","doi":"10.1089/can.2022.0037","pmid":"35881851","tags":["cbd","cognition"],"studyType":"Randomized Controlled Trial","evidenceStrength":"Preliminary","keyFinding":"Participants under THC showed lower cognitive empathy compared to CBD (but not compared to placebo). Participants under CBD showed higher cognitive Theory of Mind compared to placebo (but not compared to THC). No differences were found on emotional scales for empathy or ToM. THC+CBD combination did not significantly differ from other conditions.","whyItMatters":"This is the first study to show CBD can improve Theory of Mind abilities, a finding with potential implications for conditions like schizophrenia and autism where ToM is impaired. The naturalistic setting adds ecological validity.","specificNumbers":"18 participants; 4 conditions (THC, CBD, THC+CBD, placebo); CBD improved cognitive ToM vs placebo; THC reduced cognitive empathy vs CBD; no emotional scale differences.","methodology":"Naturalistic, randomized, double-blind, crossover, placebo-controlled study in a cannabis social club. 18 chronic cannabis users tested under four conditions: THC, CBD, THC+CBD, and placebo full-spectrum extracts.","limitations":"Very small sample (n=18). Chronic cannabis users may differ from cannabis-naive populations. Naturalistic setting reduces experimental control. Multiple comparisons with small sample increase false positive risk."},{"rthcId":"RTHC-05681","title":"Reasons for Use and Perceived Effects of Medical Cannabis: A Cross-Sectional Statewide Survey.","authors":"Sajdeya, Ruba; Jugl, Sebastian; Wang, Yan; Perez, Juan G; Maloney, Sophie; Lopez-Quintero, Catalina; Goodin, Amie J; Winterstein, Almut G; Cook, Robert L","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 138-148","doi":"10.1159/000540593","pmid":"39474237","tags":["medical-cannabis"],"studyType":"Cross-Sectional","evidenceStrength":"Moderate","keyFinding":"Top qualifying conditions: PTSD (29.6%), \"comparable conditions\" (22.2%), chronic pain (25.6%). Top self-reported reasons: anxiety (60.6%), chronic pain (44.0%), depression (39.9%), PTSD (34.8%). Most reported improvement: anxiety (95.3%), depression (97.2%), chronic pain (98.4%), insomnia (86.4%), PTSD (91.5%). ADHD had lowest perceived improvement (66.7%). A notable proportion sought MC for conditions beyond officially qualifying ones.","whyItMatters":"This study reveals a significant gap between what medical cannabis patients are officially certified for and what they are actually treating. The high self-reported improvement rates, including for conditions with limited evidence, highlight the need for clinical trials to validate or challenge patient experiences.","specificNumbers":"632 patients; 62.7% female; median age 45; anxiety 60.6% reason for use; chronic pain 44.0%; depression 39.9%; 95-98% improvement for top conditions; ADHD 66.7% improvement; blood pressure 57.4% unsure/no change.","methodology":"Cross-sectional survey of 632 medical cannabis patients from 9 Florida MC clinics in 2022, assessing qualifying conditions, self-reported reasons for use, and perceived impacts.","limitations":"Convenience sample from 9 clinics may not represent all Florida patients. Self-reported outcomes susceptible to placebo effect and expectancy bias. No control group or objective outcome measures. 2022 data."},{"rthcId":"RTHC-05682","title":"Gender differences in first episode psychosis: Some arguments to develop gender specific treatment strategies.","authors":"Salvadé, Aude; Golay, Philippe; Abrahamyan, Lilith; Bonnarel, Vincent; Solida, Alessandra; Alameda, Luis; Ramain, Julie; Conus, Philippe","year":2024,"journal":"Schizophrenia research, 271, 300-308","doi":"10.1016/j.schres.2024.07.046","pmid":"39084105","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05683","title":"Cannabidiol for treatment of Irritability and Aggressive Behavior in Children and Adolescents with ASD: Background and Methods of the CAnnabidiol Study in Children with Autism Spectrum DisordEr (CASCADE) Study.","authors":"Sannar, Elise M; Winter, Joan R; Franke, Ronda K; Werner, Emily; Rochowiak, Rebecca; Romani, Patrick W; Miller, Owen S; Bainbridge, Jacquelyn L; Enabulele, Obehi; Thompson, Talia; Natvig, Crystal; Mikulich-Gilbertson, Susan K; Tartaglia, Nicole R","year":2024,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2024.08.12.24311894","pmid":"39211864","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05684","title":"Fentanyl abuse proportion in methadone maintenance treatment, and patients' knowledge about its risks.","authors":"Sason, Anat; Adelson, Miriam; Schreiber, Shaul; Peles, Einat","year":2024,"journal":"Journal of psychiatric research, 173, 254-259","doi":"10.1016/j.jpsychires.2024.03.047","pmid":"38554621","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05685","title":"Secondhand smoke exposure and asthma status among adolescents: Findings from the 2019-2020 California Student Tobacco Survey.","authors":"Satybaldiyeva, Nora; Gamst, Anthony; Oren, Eyal; Park, Ji-Yeun; Zhu, Shu-Hong","year":2024,"journal":"Preventive medicine reports, 45, 102842","doi":"10.1016/j.pmedr.2024.102842","pmid":"39185324","tags":["respiratory","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"About 12% of students with asthma reported exposure to secondhand marijuana smoke, compared to 9.3% of students without asthma. Overall, secondhand marijuana smoke exposure was nearly as prevalent as secondhand tobacco smoke among middle and high school students.","whyItMatters":"As marijuana legalization expands across the US, secondhand exposure is likely increasing. This study highlights that kids with asthma, who are especially vulnerable to smoke exposure, are disproportionately affected by marijuana secondhand smoke.","specificNumbers":"12.0% of students with asthma were exposed to secondhand marijuana smoke vs 9.3% without asthma. Secondhand tobacco smoke exposure was 13.4% vs 10.9%. Exposure to marijuana secondhand smoke was highest among 12th graders (12.2%).","methodology":"Cross-sectional analysis of 158,937 8th, 10th, and 12th graders from the 2019-2020 California Student Tobacco Survey. Descriptive analyses examined exposure rates by asthma status and sociodemographic characteristics.","limitations":"Cross-sectional design cannot establish causation. Self-reported exposure data may be subject to recall bias. The study was limited to California, which may not generalize to other states."},{"rthcId":"RTHC-05686","title":"Patterns of Use and Withdrawal Syndrome in Dual Cannabis and Tobacco Users (DuCATA_GAM-CAT): Protocol for a Mixed Methods Study.","authors":"Saura, Judith; Feliu, Ariadna; Enríquez-Mestre, Marta; Fu, Marcela; Ballbè, Montse; Castellano, Yolanda; Pla, Margarida; Rosa, Nathalia; Radeva, Petia; Maestre-González, Elena; Cabezas, Carmen; Colom, Joan; Suelves, Josep M; Mondon, Silvia; Barrio, Pablo; Andreu, Magalí; Raich, Antònia; Bernabeu, Jordi; Vilaplana, Jordi; Roca Tutusaus, Xavier; Guydish, Joseph; Fernández, Esteve; Martínez, Cristina","year":2024,"journal":"JMIR research protocols, 13, e58335","doi":"10.2196/58335","pmid":"39298750","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05687","title":"Reliability of roadside oral fluid testing devices for ∆9-tetrahydrocannabinol (∆9-THC) detection.","authors":"Scherer, Juliana Nichterwitz; Vasconcelos, Mailton; Dalanhol, Carolina Silveira; Govoni, Bruna; Dos Santos, Bruno Pereira; Borges, Gabriela Ramos; de Gouveia, Giovanna Cristiano; Viola, Patrícia Pacheco; Carlson, Renato Luiz Romera; Martins, Aline Franco; Costa, Jose Luiz; Huestis, Marilyn A; Pechansky, Flavio","year":2024,"journal":"Drug testing and analysis, 16(12), 1528-1536","doi":"10.1002/dta.3669","pmid":"38440942","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The Drager DrugTest had 96.8% sensitivity and 97.1% specificity for detecting THC at a 5 ng/mL threshold. In contrast, the AquilaScan and Druglizer devices had sensitivity below 13%, meaning they missed the vast majority of positive samples.","whyItMatters":"As cannabis-impaired driving enforcement grows, police departments are adopting oral fluid testing devices. This study reveals that device choice matters enormously, with some devices essentially useless for detecting THC.","specificNumbers":"Drager DrugTest: 96.8% sensitivity, 97.1% specificity, 97.0% efficiency. WipeAlyser Reader: 91.4% sensitivity, 97.2% specificity. AquilaScan and Druglizer: less than 13% sensitivity. Of 8,945 tests, 530 (5.9%) screened positive for THC.","methodology":"Researchers conducted 8,945 oral fluid THC screening tests at the roadside using four different devices. Samples that screened positive (530 total, 5.9%) were confirmed by liquid chromatography-tandem mass spectrometry at multiple cutoff concentrations.","limitations":"Field conditions (temperature, humidity) may have affected device performance. The study was conducted in one country (Brazil), and device performance may differ in other settings. Only THC was evaluated."},{"rthcId":"RTHC-05688","title":"A mixed method study exploring similarities and differences in general and social services-specific barriers to treatment-seeking among individuals with a problematic use of alcohol, cannabis, or gambling.","authors":"Schettini, Greta; Lindner, Philip; Ekström, Veronica; Johansson, Magnus","year":2024,"journal":"BMC health services research, 24(1), 970","doi":"10.1186/s12913-024-11304-5","pmid":"39174983","tags":["addiction","quitting","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users shared similar treatment barriers with alcohol and gambling users, including privacy concerns, stigma, and fear of consequences. However, different groups described different aspects of these barriers: cannabis users emphasized fear of legal consequences, while all groups reported stigma as the top barrier to social services.","whyItMatters":"The treatment gap for addiction is one of the largest in healthcare. Understanding why people avoid help, and whether the barriers differ by substance, is critical for designing systems that actually reach the people who need them.","specificNumbers":"51 cannabis users, 207 alcohol users, and 37 gamblers surveyed. Five general barrier themes and three social-services-specific barrier themes emerged from interviews.","methodology":"Mixed methods study combining surveys (Barriers to Treatment Inventory) from 295 participants (207 alcohol, 51 cannabis, 37 gambling) with 17 semi-structured interviews. Quantitative and qualitative data were analyzed in parallel and then integrated.","limitations":"Small cannabis subsample (n=51) limits the power to detect group differences. Participants were recruited through online platforms, which may not represent those with the most severe barriers. The study is specific to Sweden's unique care system."},{"rthcId":"RTHC-05689","title":"Planting the seeds for success: A qualitative study exploring primary healthcare providers' perceptions about medical cannabis.","authors":"Schuhmacher, Sandi; Gaid, Dina; Bishop, Lisa D; Fleming, Laura; Donnan, Jennifer","year":2024,"journal":"PloS one, 19(3), e0295858","doi":"10.1371/journal.pone.0295858","pmid":"38451984","tags":["medical-cannabis"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Five themes emerged: knowledge gaps, internal influences (attitudes and beliefs), patient influences (requests and expectations), external influences from other healthcare providers, and systemic barriers. The biggest factor was environmental context and resources, with providers citing a lack of guidelines and educational materials as the primary obstacle.","whyItMatters":"Despite cannabis being legal in Canada since 2018, many patients still cannot find a healthcare provider willing to authorize medical cannabis. This study identifies why: providers lack training and guidelines, not necessarily because they oppose it.","specificNumbers":"12 participants interviewed. Five main themes identified. Environmental context and resources was the most represented domain in coding.","methodology":"Qualitative study using semi-structured Zoom interviews with 12 primary care providers (family physicians and nurse practitioners) in Newfoundland and Labrador, Canada. Interview guide developed using the Theoretical Domains Framework, with thematic analysis.","limitations":"Small sample (12 providers) from one Canadian province limits generalizability. Qualitative design captures perspectives but cannot quantify how widespread these barriers are. Self-selection bias may mean participants were more engaged with the topic than average."},{"rthcId":"RTHC-05690","title":"Special Report from the CDC: Driving under the influence of alcohol, marijuana, or other illicit drugs among drivers aged ≥16 years - National Survey on Drug Use and Health, 2016-2019.","authors":"Schumacher, Amy C; De Crescenzo, Lauren A; Yellman, Merissa A; Sauber-Schatz, Erin K","year":2024,"journal":"Journal of safety research, 91, 505-515","doi":"10.1016/j.jsr.2024.09.017","pmid":"39998550","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"In 2019, 5.3% of US drivers reported driving under the influence of marijuana in the past year, up from 4.5% in 2016. Meanwhile, alcohol-impaired driving decreased slightly. Among drivers who did not always wear seatbelts, alcohol-impaired driving decreased while marijuana-impaired driving increased.","whyItMatters":"This CDC report provides national-level trend data showing marijuana-impaired driving is growing, particularly as more states legalize cannabis. Unlike alcohol-impaired driving, there are no established evidence-based prevention strategies for marijuana-impaired driving.","specificNumbers":"2019 prevalence: DUIA 8.3%, DUIM 5.3%, DUID 0.9%. DUIM was highest among males (7.0%), non-heterosexual drivers (14.7%), drivers aged 21-25, and those who did not always wear seatbelts (11.5%). DUIM increased from 4.5% to 5.3% from 2016 to 2019.","methodology":"Analysis of 2016-2019 National Survey on Drug Use and Health (NSDUH) public-use data, limited to drivers aged 16 and older. Prevalence estimates were calculated overall and by sociodemographic characteristics, with trend analysis across the four-year period.","limitations":"Self-reported data likely underestimates actual impaired driving prevalence. The survey ended in 2019, before the pandemic and additional state legalizations. NSDUH does not include institutionalized populations or people experiencing homelessness."},{"rthcId":"RTHC-05691","title":"Associations between noticing public health education campaigns about cannabis and risk perceptions in the northern Canadian territories: a cross-sectional study.","authors":"Schwartz, Naomi; Poon, Theresa; Hammond, David; Hobin, Erin","year":2024,"journal":"Health education research, 39(6), 507-517","doi":"10.1093/her/cyae021","pmid":"38905013","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Noticing cannabis education campaigns was associated with a 9% increase in perceiving daily cannabis smoking and vaping as moderate-to-high risk. The effect did not differ by age group or cannabis use frequency. However, awareness was lower among people with lower education and income.","whyItMatters":"Cannabis legalization in Canada was accompanied by public health campaigns about risks. This study is one of the first to examine whether those campaigns actually reached people and shifted perceptions, particularly in remote northern communities.","specificNumbers":"40.4% of respondents noticed cannabis education campaigns. Adjusted risk ratio for perceiving daily cannabis smoking as risky: 1.09 (95% CI: 1.02-1.16). Same for daily vaping: 1.09 (95% CI: 1.02-1.16). No significant effect on edible or secondhand smoke risk perceptions.","methodology":"Cross-sectional survey of 2,452 participants aged 16+ in Yukon, Northwest Territories, and Nunavut. Poisson regression with robust standard errors estimated associations between campaign awareness and risk perceptions, adjusting for sociodemographic factors and cannabis use frequency.","limitations":"Cross-sectional design cannot establish whether campaigns caused the higher risk perceptions. People who notice campaigns may already be more health-conscious. The study was limited to Canada's three territories, which have unique demographics."},{"rthcId":"RTHC-05692","title":"Cannabidiol Reduced the Severity of Gastrointestinal Symptoms of Opioid Withdrawal in Male and Female Mice.","authors":"Scicluna, Rhianne L; Wilson, Bianca B; Thelaus, Samuel H; Arnold, Jonathon C; McGregor, Iain S; Bowen, Michael T","year":2024,"journal":"Cannabis and cannabinoid research, 9(2), 547-560","doi":"10.1089/can.2022.0036","pmid":"36577048","tags":["cbd","withdrawal","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD at 10, 30, and 100 mg/kg dose-dependently reduced gastrointestinal symptoms (diarrhea, fecal output, weight loss) during both precipitated and spontaneous oxycodone withdrawal in male mice and during precipitated withdrawal in female mice. Effects on other withdrawal symptoms (jumping, paw tremors) were less consistent.","whyItMatters":"Opioid withdrawal is a major driver of continued drug use, and current treatments have limitations. The gastrointestinal symptoms (nausea, diarrhea, cramping) are among the most distressing. Finding that CBD specifically targets these symptoms opens a potential complementary treatment avenue.","specificNumbers":"CBD tested at 10, 30, and 100 mg/kg. Oxycodone escalated from 9 to 33 mg/kg over 8 days. Male mice showed withdrawal effects in both precipitated and spontaneous conditions; female mice only showed precipitated withdrawal effects. GI symptom reduction was consistent across both sexes in precipitated withdrawal.","methodology":"Mice received escalating oxycodone doses over 8 days, then underwent either naloxone-precipitated or spontaneous withdrawal. CBD was administered 60 minutes before testing at 0, 10, 30, or 100 mg/kg. Gastrointestinal symptoms, somatic symptoms, and negative affect behaviors were measured.","limitations":"Animal study results may not translate to humans. Doses used were relatively high. Female mice showed less robust withdrawal syndrome overall, making it harder to evaluate CBD's effects in that group. The study did not examine long-term outcomes or relapse."},{"rthcId":"RTHC-05693","title":"Relationship Between Nociplastic Pain Involvement and Medication Use, Symptom Relief, and Adverse Effects Among People Using Medical Cannabis for Chronic Pain.","authors":"Scott, J Ryan; Williams, David A; Harte, Steven E; Harris, Richard E; Litinas, Evangelos; Sisley, Suzanne; Clauw, Daniel J; Boehnke, Kevin F","year":2024,"journal":"The Clinical journal of pain, 40(1), 1-9","doi":"10.1097/AJP.0000000000001164","pmid":"37823303","tags":["pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Higher nociplastic pain (NPP) scores were associated with less self-reported improvement in pain and overall health from medical cannabis, more cannabis side effects, and paradoxically, greater use of other medications including opioids and benzodiazepines, but also greater substitution of cannabis for those same medication classes.","whyItMatters":"Nociplastic pain, which arises from abnormal pain processing in the nervous system, affects conditions like fibromyalgia and is notoriously difficult to treat. Understanding that medical cannabis may be less effective for this pain subtype helps set realistic expectations and guide treatment decisions.","specificNumbers":"1,213 participants. 59% female, mean age 49.4 years. Higher NPP quartiles associated with less improvement in pain, more side effects, higher concomitant opioid and benzodiazepine use, and substitution of cannabis for more medication classes.","methodology":"Cross-sectional study of 1,213 medical cannabis users with chronic pain. The 2011 Fibromyalgia Survey Criteria was used as a surrogate for NPP severity. Participants were divided into quartiles and compared on medication use, cannabis use patterns, and symptom relief.","limitations":"Cross-sectional design cannot determine causation. The FM Survey Criteria is a surrogate for NPP, not a direct measure. Self-reported outcomes may not reflect objective changes. The study cannot determine whether cannabis was truly less effective or whether these patients simply had more severe and treatment-resistant conditions."},{"rthcId":"RTHC-05694","title":"Most Unusual Twin Pairs: A Look at Uterus Didelphys / Twin Research Reviews: Prenatal Aneuploidy Screening for Twin Pregnancies; Twin Conceptions by Same-Sex Male Couples; Legal Personality of Conjoined Twins; Twin Study of Cannabis Use / Human Interest and Importance: Being Taken for Twins Saved Sisters; Twin Children of Jailed Nobel Prize Winner; British 'Biracial' Twins; Triplets Born at Start of Russian Attack on Ukraine; Twins Born in Different Years.","authors":"Segal, Nancy L","year":2024,"journal":"Twin research and human genetics : the official journal of the International Society for Twin Studies, 27(2), 131-134","doi":"10.1017/thg.2024.14","pmid":"38505964","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05695","title":"Synthetic cannabinoid identification in cases associated with blue lotus and valerian root vaping products.","authors":"Seither, Joshua Z; Karschner, Erin L; Jackson, Kimberly R; Deakin, Anna; Roper, Sara H; Walterscheid, Jeffrey P","year":2024,"journal":"Journal of analytical toxicology, 48(8), 557-565","doi":"10.1093/jat/bkae065","pmid":"39082147","tags":["synthetic-cannabinoids"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"90% of seized drug cases mentioning \"blue lotus\" or \"valerian root\" contained at least one synthetic cannabinoid. The most frequently detected were 5F-MDMB-PICA, ADB-BUTINACA, and MDMB-4en-PINACA. During the same period, 65 toxicology cases involving synthetic cannabinoids referenced \"blue lotus\" in case histories.","whyItMatters":"Synthetic cannabinoids are among the most dangerous novel psychoactive substances, causing severe adverse effects including seizures and death. Marketing them as natural botanical products like \"blue lotus\" obscures the actual risk and can mislead users, law enforcement, and healthcare providers.","specificNumbers":"29 seized drug cases analyzed. 90% contained synthetic cannabinoids. 65 toxicology cases linked to \"blue lotus\" with synthetic cannabinoid detections. Most common compounds: 5F-MDMB-PICA, ADB-BUTINACA, MDMB-4en-PINACA. Study period: May 2020 to December 2023.","methodology":"Review of 29 seized drug cases received by the US Army Criminal Investigation Laboratory between May 2020 and December 2023 mentioning \"blue lotus\" or \"valerian root.\" Forensic toxicology records from the Armed Forces Medical Examiner System were cross-referenced.","limitations":"Limited to US military cases, which may not represent the broader market. The sample was convenience-based (cases that mentioned blue lotus/valerian root). Cannot determine the total prevalence of contaminated products in the general market."},{"rthcId":"RTHC-05696","title":"The contribution of cannabis use to the increased psychosis risk among minority ethnic groups in Europe.","authors":"Selten, J P; Di Forti, M; Quattrone, D; Jones, P B; Jongsma, H E; Gayer-Anderson, C; Szöke, A; Llorca, P M; Arango, C; Bernardo, M; Sanjuan, J; Santos, J L; Arrojo, M; Tarricone, I; Berardi, D; Lasalvia, A; Tosato, S; la Cascia, C; Velthorst, E; van der Ven, E M A; de Haan, L; Rutten, B P; van Os, J; Kirkbride, J B; Morgan, C M; Murray, R M; Termorshuizen, F","year":2024,"journal":"Psychological medicine, 54(11), 2937-2946","doi":"10.1017/S0033291724001004","pmid":"38721761","tags":["psychosis","potency"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"The odds ratio for psychotic disorder among non-Western minorities was 1.80, and adjusting for cannabis use frequency barely changed it (1.81). However, for Black Caribbean individuals in London, adjusting for high-potency cannabis use reduced the OR from 2.45 to 1.61, and for Surinamese/Dutch Antillean individuals in Amsterdam, adjusting for daily use reduced the OR from 2.57 to 1.67.","whyItMatters":"The elevated psychosis risk among ethnic minorities in Europe is well-documented but poorly understood. This study tests whether cannabis use, itself a risk factor for psychosis, explains the gap. For most groups, it does not, pointing to other factors like social adversity, discrimination, or urbanicity.","specificNumbers":"Overall non-Western minority OR: 1.80 (95% CI: 1.39-2.33), minimally changed after cannabis adjustment: 1.81. Black Caribbean in London: OR dropped from 2.45 to 1.61 after high-potency cannabis adjustment. Surinamese/Dutch Antillean in Amsterdam: OR dropped from 2.57 to 1.67 after daily use adjustment. 825 patients and 1,026 controls across 5 countries.","methodology":"Case-control study using EU-GEI data from Spain, Italy, France, UK, and Netherlands. 825 first-episode psychosis patients and 1,026 controls were compared. Odds ratios for psychosis were calculated for migrant groups with and without adjustment for cannabis use measures.","limitations":"Case-control design has inherent limitations in establishing causation. Cannabis use was self-reported and may be underreported. The two subgroups where cannabis appeared to matter (Black Caribbean, Surinamese) had relatively small sample sizes, making those estimates less stable."},{"rthcId":"RTHC-05697","title":"Efficacy of cannabis-based medicine in the treatment of Tourette syndrome: a systematic review and meta-analysis.","authors":"Serag, Ibrahim; Elsakka, Mona Mahmoud; Moawad, Mostafa Hossam El Din; Ali, Hossam Tharwat; Sarhan, Khalid; Shayeb, Sally; Nadim, Islam; Abouzid, Mohamed","year":2024,"journal":"European journal of clinical pharmacology, 80(10), 1483-1493","doi":"10.1007/s00228-024-03710-9","pmid":"38985199","tags":["medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Cannabis-based medicine produced a significant reduction in Yale Global Tic Severity Scale scores (MD = -23.71, p = 0.02) and Premonitory Urge for Tics Scale scores (MD = -5.36, p = 0.0007). There was no significant effect on obsessive-compulsive symptoms as measured by the Y-BOCS (p = 0.06).","whyItMatters":"Tourette syndrome has limited treatment options, and existing medications (mainly neuroleptics) come with significant side effects. Cannabis-based medicine represents a potential alternative, and this is the first meta-analysis to pool the available evidence on its effectiveness for tics.","specificNumbers":"9 studies reviewed, 3 included in meta-analysis. 401 patients total. YGTSS total score reduction: MD = -23.71 (95% CI: -43.86 to -3.55, p = 0.02). PUTS reduction: MD = -5.36 (95% CI: -8.46 to -2.27, p = 0.0007). Y-BOCS: non-significant (p = 0.06).","methodology":"Systematic review and meta-analysis searching PubMed, Cochrane, Scopus, and Web of Science through February 2024. Nine studies were included in the systematic review and three in the meta-analysis, involving 401 adult patients with Tourette syndrome.","limitations":"Only 3 of 9 studies could be pooled for meta-analysis, reflecting small and heterogeneous literature. Total sample was only 401 patients. The confidence interval for the YGTSS reduction was wide (-43.86 to -3.55), indicating high uncertainty. Most studies lacked placebo controls."},{"rthcId":"RTHC-05698","title":"Efficacy and Safety of Cannabis Transdermal Patch for Alleviating Psoriasis Symptoms: Protocol for a Randomized Controlled Trial (CanPatch).","authors":"Sermsaksasithorn, Pim; Asawanonda, Pravit; Phutrakool, Phanupong; Ondee, Thunnicha; Chariyavilaskul, Pajaree; Payungporn, Sunchai; Pongpirul, Krit; Hirankarn, Nattiya","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 99-110","doi":"10.1159/000539492","pmid":"39015605","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05699","title":"Population-based cross-sectional analysis of cannabis use among Kentucky adults, 2020-21.","authors":"Shafer, Sydney; Kennedy, Gunnar; Christian, W Jay","year":2024,"journal":"Journal of cannabis research, 6(1), 44","doi":"10.1186/s42238-024-00251-x","pmid":"39707551","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Kentucky's cannabis use prevalence (10%) was lower than the national average (~13%). Among users, 42% used daily or near-daily. About 43% used cannabis for both medical and recreational reasons, 24% for medical only, and 33% for recreation only. Smoking was the dominant mode of use (78%).","whyItMatters":"Kentucky was preparing for legal medical marijuana in 2025. This baseline snapshot of use patterns before the legal market opens provides critical data for tracking how legalization changes behavior, particularly the high rate of daily use and medical motivation.","specificNumbers":"10% current use in Kentucky vs ~13% nationally. 42% of users consumed daily or near-daily. 78% smoked cannabis. 43% used for both medical and recreational reasons. Male, 18-34 age group, never married, Black, lower education, lower income, and Central region residents were more likely to use.","methodology":"Analysis of pooled 2020-2021 Kentucky Behavioral Risk Factor Surveillance System (BRFSS) data using weighted responses. Multivariable logistic regression identified characteristics associated with cannabis use across three geographic regions.","limitations":"BRFSS is telephone-based and may miss certain populations. Self-reported cannabis use in a state where it was illegal may be underreported. Two years of data provides limited trend information. The three-region geographic analysis may mask within-region variation."},{"rthcId":"RTHC-05700","title":"Distinguishing Clinical Features of Cannabinoid Hyperemesis Syndrome and Cyclic Vomiting Syndrome: A Retrospective Cohort Study.","authors":"Shah, Meera; Jergel, Andrew; George, Roshan P; Jenkins, Elan; Bashaw, Hillary","year":2024,"journal":"The Journal of pediatrics, 271, 114054","doi":"10.1016/j.jpeds.2024.114054","pmid":"38615942","tags":["youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Patients with CHS were significantly older (mean 18.1 vs 14.5 years), more likely to have a positive urine drug screen (86% vs 2.9%), had lower potassium, higher creatinine, and higher systolic blood pressure compared to CVS patients. Imaging was obtained in 36% of all patients but only 2.4% showed abnormalities.","whyItMatters":"CHS and CVS present almost identically with recurrent nausea, vomiting, and abdominal pain. Misdiagnosis delays appropriate treatment. These distinguishing clinical features could help pediatric providers reach the correct diagnosis faster and avoid unnecessary imaging.","specificNumbers":"125 patients included (out of 201 screened). CHS mean age: 18.06 years vs CVS: 14.50 years. Positive urine drug screen: CHS 86% vs CVS 2.9%. CHS systolic BP: 124.46 vs CVS: 118.55 mmHg. Imaging abnormalities in only 2.4% of cases.","methodology":"Retrospective chart review of 125 patients admitted to a large children's health care system from 2015 through 2022. Patients were identified using ICD-9 and ICD-10 codes for CHS and CVS.","limitations":"Retrospective design with ICD code-based identification may miss or misclassify cases. Single health care system. The sample of CHS patients may include only those with confirmed cannabis use, potentially missing cases where use was denied or undetected."},{"rthcId":"RTHC-05701","title":"Emerging pharmacotherapy for the treatment of cannabis use disorder.","authors":"Shamabadi, Ahmad; Arabzadeh Bahri, Razman; Karimi, Hanie; Heidari, Ehsan; Akhondzadeh, Shahin","year":2024,"journal":"Expert opinion on pharmacotherapy, 25(6), 695-703","doi":"10.1080/14656566.2024.2353638","pmid":"38717605","tags":["addiction","quitting"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Across multiple pharmacological systems, CBD, gabapentin, galantamine, nabilone plus zolpidem, nabiximols, naltrexone, PF-04457845 (FAAH inhibitor), quetiapine, varenicline, and topiramate all showed some superiority over control conditions in RCTs for CUD. All were reported as safe and tolerable.","whyItMatters":"There is currently no FDA-approved medication for cannabis use disorder, despite the condition affecting roughly one in five cannabis users. This review maps the entire landscape of pharmacological candidates that have reached the RCT stage.","specificNumbers":"About 1 in 5 cannabis users develop CUD, rising to 1 in 2 for daily users. CUD accounts for 0.69 million disability-adjusted life years globally. Ten medication classes showed some benefit across eight neurotransmitter systems.","methodology":"Narrative review of randomized controlled trials examining pharmacological interventions for cannabis use disorder, organized by mechanism of action across cannabinoid, glutamatergic, GABAergic, serotonergic, noradrenergic, dopaminergic, opioidergic, and cholinergic systems.","limitations":"Narrative review without formal meta-analysis. Individual RCTs varied in sample size, follow-up duration, and outcome measures. Many trials had small samples. \"Superiority over control\" ranged from modest to meaningful effects."},{"rthcId":"RTHC-05702","title":"Cannabis Use Disorder Not Associated With Opioid Analgesic Use or Patient-Reported Outcomes After ACL Reconstruction: A Retrospective Matched-Cohort Analysis.","authors":"Shankar, Dhruv S; DeClouette, Brittany; Vasavada, Kinjal D; Avila, Amanda; Strauss, Eric J; Alaia, Michael J; Gonzalez-Lomas, Guillem","year":2024,"journal":"Sports health, 16(5), 687-694","doi":"10.1177/19417381231190391","pmid":"37632361","tags":["addiction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"There were no significant differences between CUD and non-CUD patients in opioid prescription rates (82.7% vs 83.7%), total opioid days supply, total morphine milligram equivalents, or improvement on any of five patient-reported outcome measures (pain intensity, pain interference, mobility, mental health, physical health).","whyItMatters":"There is a common concern that patients with substance use disorders may have worse surgical outcomes or require more pain medication. This study found no evidence to support those concerns for CUD patients undergoing ACL reconstruction.","specificNumbers":"104 CUD patients matched to 104 controls. 65.4% male. Mean age 29.9 years. Mean follow-up 16.1 months. Opioid prescription rates: 82.7% vs 83.7% (p > 0.99). No significant differences in MMEs (p = 0.71), days supply (p = 0.67), or any PROMIS score (all p > 0.50).","methodology":"Retrospective matched-cohort study at a single center. 104 patients with CUD who underwent primary ACL reconstruction were propensity-score matched 1:1 to controls on age, sex, and follow-up time. Opioid use was tracked for up to 1 year, and PROMIS instruments assessed outcomes.","limitations":"Retrospective single-center design. Sample size was not determined a priori, so the study may be underpowered to detect real differences. CUD diagnosis was based on medical records and may not capture all cannabis users. Propensity matching on only three variables may leave residual confounding."},{"rthcId":"RTHC-05703","title":"Cannabinoid hyperemesis syndrome co-occurring with superior mesenteric artery syndrome in adolescents.","authors":"Shanker, A Isabella; Li, B U K; Kramer, Robert E","year":2024,"journal":"Journal of pediatric gastroenterology and nutrition, 79(3), 495-500","doi":"10.1002/jpn3.12317","pmid":"38994677","tags":["youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All nine patients presented with nausea, vomiting, and weight loss. They lost an average of 6.0 kg and had a mean BMI at the 15.61st percentile (BMI Z-score: -1.5). Six of nine were female. Symptoms were present for an average of 19.6 weeks before diagnosis. Only four patients received cannabis cessation support.","whyItMatters":"This is the first report describing CHS co-occurring with superior mesenteric artery syndrome in adolescents. SMAS occurs when weight loss reduces the fat pad between the aorta and superior mesenteric artery, compressing the duodenum. The vomiting cycle of CHS may drive the weight loss that triggers this potentially serious surgical condition.","specificNumbers":"9 patients identified. 6 female. Mean weight loss: 6.0 kg. Mean BMI percentile: 15.61 (BMI 17.7 kg/m2). Mean BMI Z-score: -1.5. Mean symptom duration before diagnosis: 19.6 weeks. Only 4/9 received cannabis cessation support.","methodology":"Retrospective case series identifying patients admitted to Children's Hospital of Colorado (2015-2023) who had both cannabis use and chronic vascular intestinal disorders on their problem lists via ICD-10 codes. Nine patients met criteria for both SMAS and chronic cannabis use.","limitations":"Very small case series (n=9) from a single institution. Cannot establish that CHS caused the weight loss that led to SMAS. ICD code-based identification may miss cases or introduce misclassification. No comparison group."},{"rthcId":"RTHC-05704","title":"Association between gender diversity and substance use experimentation in early adolescents.","authors":"Shao, Iris Y; Low, Patrick; Sui, Shirley; Otmar, Christopher D; Ganson, Kyle T; Testa, Alexander; Santos, Glenn-Milo; He, Jinbo; Baker, Fiona C; Nagata, Jason M","year":2024,"journal":"Drug and alcohol dependence, 265, 112473","doi":"10.1016/j.drugalcdep.2024.112473","pmid":"39541739","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"More gender-diverse responses on gender identity, felt gender, gender non-contentedness, and gender expression were associated with higher odds of both lifetime and new cannabis experimentation. Different dimensions of gender diversity were associated with different substance use patterns, with gender non-contentedness showing the most consistent associations across substances.","whyItMatters":"Gender-diverse youth face unique stressors including discrimination and minority stress. Understanding substance use patterns in this population can inform targeted prevention efforts during the critical period of early adolescence when experimentation begins.","specificNumbers":"10,092 adolescents aged 12-13. Five dimensions of gender diversity assessed. Four of five dimensions (identity, felt gender, non-contentedness, expression) associated with higher odds of cannabis experimentation. Gender non-contentedness associated with higher odds across all three substances (alcohol, nicotine, cannabis).","methodology":"Cross-sectional analysis of 10,092 adolescents aged 12-13 from the Adolescent Brain Cognitive Development (ABCD) study. Gender diversity was measured across five dimensions. Logistic regression adjusted for sociodemographic factors assessed associations with self-reported substance experimentation.","limitations":"Cross-sectional design cannot establish causation. Self-reported substance use among 12-13 year olds may be unreliable. The ABCD study, while large, may not be representative of all US early adolescents. Cannabis \"experimentation\" at this age is very rare, leading to small cell sizes."},{"rthcId":"RTHC-05705","title":"Effects of cannabis use on the heart.","authors":"Sharkova, Julia; Nickolaus, Tanja; Schaefer, Jürgen R","year":2024,"journal":"Herz, 49(6), 420-427","doi":"10.1007/s00059-024-05282-x","pmid":"39496830","tags":["cardiovascular"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The cardiovascular system reacts strongly to THC, with effects including increased heart rate, changes in blood pressure, and potential triggering of cardiac arrhythmias. The review highlights that many patients conceal their marijuana use, meaning cardiovascular effects of cannabis are likely underreported in clinical settings.","whyItMatters":"As cannabis use becomes more widespread, healthcare providers need to understand its cardiovascular effects. The review emphasizes that undisclosed cannabis use can complicate diagnosis and treatment of cardiac symptoms.","specificNumbers":"The authors estimate a high number of unreported cases due to patients concealing marijuana consumption. The review covers both medicinal and recreational use contexts.","methodology":"Narrative review of current scientific literature on cannabis and marijuana effects on the heart and cardiovascular system, with emphasis on clinical implications for healthcare providers.","limitations":"Narrative review without systematic methodology. The evidence base for cannabis cardiovascular effects is complicated by polysubstance use, dose variability, and underreporting."},{"rthcId":"RTHC-05706","title":"Implications of Prenatal Cannabis Exposure on Childhood Neurodevelopmental Outcomes: A Summary of the Clinical Evidence.","authors":"Sheffield, Sydney Mei; Kuller, Jeffrey A; Murphy, Susan Kay; Dotters-Katz, Sarah K; Schaumberg, Jordan Enns","year":2024,"journal":"Obstetrical & gynecological survey, 79(10), 604-610","doi":"10.1097/OGX.0000000000001320","pmid":"39437378","tags":["pregnancy","cognition","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Limited but consistent data showed associations between prenatal cannabis exposure and increased startles and difficulty consoling in newborns, memory and verbal reasoning challenges in early childhood, diminished academic performance, and inattention, hyperactivity, and aggression in early childhood.","whyItMatters":"Cannabis is commonly used by pregnant patients for symptom relief, and misinformation about its safety during pregnancy is widespread. This summary provides clinicians with a consolidated evidence base for patient counseling.","specificNumbers":"The review identified associations across three developmental periods: neonatal (increased startles), early childhood (memory and verbal reasoning challenges, diminished academics), and behavioral (inattention, hyperactivity, aggression).","methodology":"Literature review of clinical studies identified through PubMed and OVID databases examining the impacts of intrauterine cannabis exposure on offspring neurodevelopment.","limitations":"The existing data are limited by important confounders including genetic predisposition, concurrent tobacco and other substance use, and socioeconomic factors. Studies generally lack objective cannabis use measures and diverse samples."},{"rthcId":"RTHC-05707","title":"Discussions of Cannabis Over Patient Portal Secure Messaging: Content Analysis.","authors":"Shetty, Vishal A; Gregor, Christina M; Tusing, Lorraine D; Pradhan, Apoorva M; Romagnoli, Katrina M; Piper, Brian J; Wright, Eric A","year":2024,"journal":"Journal of medical Internet research, 26, e63311","doi":"10.2196/63311","pmid":"39666375","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Before medical cannabis legalization in Pennsylvania (2012-2016), cannabis-related messages were primarily about drug screening results (39% of patient messages, 77% of provider messages). After legalization (2017-2022), patient messages shifted to seeking medical cannabis access (35%) and reporting current use (25%). Provider responses were split between assisting with access (28%) and stating inability to prescribe or recommend (26%).","whyItMatters":"Patient portal messages reveal how people actually communicate with their doctors about cannabis, bypassing the social desirability bias of face-to-face visits. The shift from screening-focused to access-focused discussions shows how legalization changes the patient-provider dynamic.","specificNumbers":"1,782 patient messages from 1,098 patients (7.2% of total) and 800 provider messages from 430 providers (7%) discussed cannabis. Top reasons for patient use: pain (50.5%), anxiety (13.7%), sleep (11.1%). 56 different purposes coded in patient messages.","methodology":"Content analysis of 382,982 secure messages from 15,340 patients and 6,101 providers at a Pennsylvania health system (2012-2022). Natural language processing identified cannabis-related messages, followed by qualitative coding of a random sample.","limitations":"Single health system in Pennsylvania limits generalizability. Only explicit cannabis mentions were captured; coded language may have been missed. The qualitative sample may not represent all cannabis-related messages."},{"rthcId":"RTHC-05708","title":"In Vitro and In Vivo Anti-Inflammatory and Antidepressant-like Effects of Cannabis sativa L. Extracts.","authors":"Shin, Joonyoung; Choi, Sangheon; Park, A Yeong; Ju, Suk; Kweon, Bitna; Kim, Dong-Uk; Bae, Gi-Sang; Han, Dongwoon; Kwon, Eunjeong; Hong, Jongki; Kim, Sungchul","year":2024,"journal":"Plants (Basel, Switzerland), 13(12)","doi":"10.3390/plants13121619","pmid":"38931051","tags":["inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis leaf extract (30 mg/kg) reduced immobility in the forced swimming test and increased sucrose preference in LPS-challenged mice, suggesting antidepressant effects. It also improved oxygen levels and inhibited mast cell degranulation in deep cervical lymph nodes. In brain microglial cells, the extracts suppressed multiple inflammatory markers including IL-1B, IL-6, TNF-A, iNOS, and COX-2.","whyItMatters":"Neuroinflammation is increasingly recognized as a driver of depression. This study suggests cannabis extracts may work through anti-inflammatory mechanisms in the brain, with the combined action of multiple compounds (the \"entourage effect\") potentially more important than any single cannabinoid.","specificNumbers":"Dose: 30 mg/kg cannabis leaf extract. Main compounds: THCA (a cannabinoid) and B-caryophyllene (a terpene). Six inflammatory markers suppressed in microglial cells: IL-1B, IL-6, TNF-A, nitrite, iNOS, COX-2.","methodology":"Combined in vivo (mouse inflammation model using LPS) and in vitro (BV2 microglial cell culture) experiments. Mice received 30 mg/kg cannabis leaf extract one hour before LPS administration. Behavioral tests and inflammatory markers were assessed. The main bioactive components were THCA and B-caryophyllene.","limitations":"Animal study with a single dose tested in vivo. The LPS model of inflammation-induced depression does not fully recapitulate human depression. The relative contributions of individual compounds within the extract cannot be determined from this design."},{"rthcId":"RTHC-05709","title":"Suicidal thoughts and behaviors among untreated illicit substance users: a population-based study.","authors":"Shiraly, Ramin; Jazayeri, Seyed Amin; Seifaei, Asal; Jeihooni, Ali Khani; Griffiths, Mark D","year":2024,"journal":"Harm reduction journal, 21(1), 96","doi":"10.1186/s12954-024-01015-9","pmid":"38755587","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Regular cannabis use was not associated with increased odds of current suicidal thoughts in multiple logistic regression. In contrast, methamphetamine and heroin were independently associated with suicidal ideation. Methamphetamine was the primary substance of use among approximately half (49.2%) of those who attempted suicide in the past year.","whyItMatters":"Disentangling which substances contribute to suicidality is critical for targeted prevention. This study suggests that not all illicit substances carry the same suicide risk, with stimulants and opioids appearing far more concerning than cannabis.","specificNumbers":"23.6% reported suicidal thoughts in the past week. 6.7% reported a suicide attempt in the past year. 49.2% of those who attempted suicide used methamphetamine as their primary substance. Cannabis use was not an independent predictor of suicidality.","methodology":"Cross-sectional study of 616 illicit substance users recruited via snowball sampling from high-risk areas in Shiraz, Iran. Eligible participants used one illicit substance regularly for at least one year and had received no treatment in the past year. Suicidality was assessed using the Beck Suicidal Ideation Scale.","limitations":"Cross-sectional design in a specific cultural context (Iran) limits generalizability. Snowball sampling may not represent all untreated users. The study assessed primary substance of use, but polysubstance patterns could confound results. Self-reported suicidality may be underestimated."},{"rthcId":"RTHC-05710","title":"Prenatal tobacco and tobacco-cannabis co-exposure: Relationship with attention and memory in middle childhood.","authors":"Shisler, Shannon; Lee, Jin-Kyung; Schlienz, Nicolas J; Hawk, Larry W; Thanos, Panayotis K; Kong, Kai Ling; Leising, Meghan Casey; Eiden, Rina D","year":2024,"journal":"Neurotoxicology and teratology, 104, 107371","doi":"10.1016/j.ntt.2024.107371","pmid":"38971339","tags":["pregnancy","cognition","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Prenatal tobacco exposure was associated with increased impulsive responding on sustained attention tasks, particularly when exposure occurred in the first trimester. Surprisingly, children co-exposed to both tobacco and cannabis showed higher short-term memory scores than non-exposed children. Cannabis co-exposure did not exacerbate the attention deficits seen with tobacco alone.","whyItMatters":"Most studies examine cannabis or tobacco exposure separately. This study directly compares the effects of combined exposure, finding that cannabis does not appear to add to tobacco's neurodevelopmental impact on attention. The unexpected memory finding highlights how complex prenatal exposure effects can be.","specificNumbers":"133 children assessed (34 non-exposed, 37 tobacco-only, 62 co-exposed). Mean age 10.6 years. 68% Black, 20% Hispanic. Tobacco-only exposed had lower attention at first epoch. Higher first-trimester cigarettes predicted greater impulsive responding. Co-exposed had higher short-term memory vs non-exposed.","methodology":"Longitudinal cohort study recruiting participants in the first trimester of pregnancy. Children (n=133) were assessed at ages 9-12 on sustained attention, attentional set shifting, and working memory tasks. Three groups were compared: non-exposed (n=34), tobacco-only (n=37), and tobacco-cannabis co-exposed (n=62).","limitations":"Small sample size, particularly for the non-exposed group (n=34). Could not isolate cannabis-only exposure effects. Oversampled for co-exposure, which may limit generalizability. The unexpected memory finding needs replication before drawing conclusions."},{"rthcId":"RTHC-05711","title":"Cannabidiol is a behavioral modulator in BTBR mouse model of idiopathic autism.","authors":"Shrader, Sarah H; Mellen, Nicholas; Cai, Jun; Barnes, Gregory N; Song, Zhao-Hui","year":2024,"journal":"Frontiers in neuroscience, 18, 1359810","doi":"10.3389/fnins.2024.1359810","pmid":"38784096","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"High-dose CBD (50 mg/kg) reduced repetitive self-grooming and hyperlocomotion in BTBR mice. Low-dose CBD (20 mg/kg) rescued social deficits. Neither dose produced anxiety-like effects. The finding that different doses target different symptoms suggests CBD may need to be titrated based on the specific behavioral targets.","whyItMatters":"Autism spectrum disorder affects 1 in 36 US children and has no approved pharmacological treatment for core symptoms. This study provides preclinical evidence that CBD could address multiple core features (social deficits, repetitive behaviors) and associated symptoms (hyperactivity).","specificNumbers":"CBD at 20 mg/kg rescued social deficits. CBD at 50 mg/kg reduced repetitive self-grooming and hyperlocomotion. Two-week treatment period starting at postnatal day 21. ASD prevalence: 1 in 36 children in the US.","methodology":"Male BTBR mice (an established model of idiopathic autism) received daily intraperitoneal injections of vehicle, 20 mg/kg CBD, or 50 mg/kg CBD for two weeks starting at postnatal day 21. A battery of behavioral tests compared treated BTBR mice to vehicle-treated C57BL/6J controls.","limitations":"Mouse model of autism has inherent limitations in translating to human ASD. Only male mice were tested. The BTBR model represents idiopathic autism and may not generalize to all ASD subtypes. Intraperitoneal administration does not reflect typical human routes."},{"rthcId":"RTHC-05712","title":"Telehealth counseling plus mHealth intervention for cannabis use in emerging adults: Development and a remote open pilot trial.","authors":"Shrier, Lydia A; McCaskill, Nicholas H; Smith, Madeline C; O'Connell, Madison M; Gluskin, Brittany S; Parker, Sarah; Everett, Veronica; Burke, Pamela J; Harris, Sion Kim","year":2024,"journal":"Journal of substance use and addiction treatment, 166, 209472","doi":"10.1016/j.josat.2024.209472","pmid":"39111371","tags":["addiction","quitting","youth"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"All 14 participants completed both motivational therapy sessions and achieved 100% median engagement with daily smartphone surveys. By two months, 11 of 14 had started changing their cannabis use: median use days declined by 27% and average times of use per day declined by 28%. All participants rated the intervention quality as good to excellent.","whyItMatters":"Young adults with cannabis use problems rarely seek treatment. This fully remote intervention removes access barriers while using real-time smartphone monitoring to deliver interventions at the moment of vulnerability, a approach that fits how this generation already interacts with technology.","specificNumbers":"14 enrolled. 79% used cannabis daily/near-daily. 100% reported use problems. 100% completed both therapy sessions. 100% median daily survey engagement. 27% reduction in use days at 2 months. 28% reduction in use times per day. 11 of 14 started changing use behavior.","methodology":"Single-arm open pilot study of emerging adults (18-25) using cannabis 3+ days per week, recruited from an urban medical practice. Intervention included two telehealth Motivational Enhancement Therapy sessions followed by two weeks of smartphone-based ecological momentary intervention (4 prompted surveys per day with trigger-responsive messages).","limitations":"Very small sample (n=14) with no control group. Open-label design means expectancy effects cannot be ruled out. Two-month follow-up is short. Self-selected participants may be more motivated than typical cannabis users. Self-reported use outcomes."},{"rthcId":"RTHC-05713","title":"Cost-Utility Analysis of Add-on Cannabidiol vs Usual Care Alone for the Treatment of Seizures in Patients With Treatment-Resistant Lennox-Gastaut Syndrome or Dravet Syndrome in the Netherlands.","authors":"Siddiqui, Jamshaed; Bowditch, Sally","year":2024,"journal":"Journal of health economics and outcomes research, 11(2), 168-179","doi":"10.36469/001c.126071","pmid":"39741657","tags":["cbd","epilepsy"],"studyType":"review","evidenceStrength":"strong","keyFinding":"For Lennox-Gastaut syndrome (LGS), adding CBD cost an extra 28,338 euros but gained 1.318 QALYs, yielding a cost per QALY of 21,493 euros, well below the Dutch willingness-to-pay threshold of 80,000 euros. For Dravet syndrome (DS), CBD dominated usual care: it saved 23,642 euros while gaining 0.868 QALYs. The probability of cost-effectiveness was 96% for LGS and 99% for DS.","whyItMatters":"Reimbursement decisions for expensive medications require economic evidence. This analysis supported the Dutch decision to reimburse pharmaceutical CBD (Epidyolex) for treatment-resistant epilepsy since December 2022, showing it provides good value for money.","specificNumbers":"LGS: 28,338 euros additional cost, 1.318 QALYs gained, ICER 21,493 euros/QALY. DS: 23,642 euros saved, 0.868 QALYs gained (dominant). Willingness-to-pay threshold: 80,000 euros/QALY. Cost-effective probability: 96% (LGS), 99% (DS). Mean dosage: 12 mg/kg/day.","methodology":"Cohort-based Markov model from the Dutch societal perspective using a lifetime (90-year) horizon with 3-month cycles. Clinical inputs from CBD clinical trials, drug costs based on 12 mg/kg/day mean dosage, discount rates of 4% for costs and 1.5% for outcomes. Deterministic and probabilistic sensitivity analyses were performed.","limitations":"Expert elicitation was used to fill data gaps in healthcare resource utilization and quality-of-life measures. Results are specific to the Dutch healthcare system and pricing. Long-term effectiveness was extrapolated from shorter-term trial data."},{"rthcId":"RTHC-05714","title":"Evaluation of the efficacy and safety of cannabidiol-rich cannabis extract in children with autism spectrum disorder: randomized, double-blind, and placebo-controlled clinical trial.","authors":"Silva, Estácio Amaro da; Medeiros, Wandersonia Moreira Brito; Santos, João Paulo Mendes Dos; Sousa, João Marçal Medeiros de; Costa, Filipe Barbosa da; Pontes, Katiúscia Moreira; Borges, Thaís Cavalcanti; Espínola, Carlos; Andrade E Silva, Ana Hermínia; Nunes, Eliane Lima Guerra; Alves, Nelson Torro; Rosa, Marine Diniz da; Albuquerque, Katy Lísias Gondim Dias de","year":2024,"journal":"Trends in psychiatry and psychotherapy, 46, e20210396","doi":"10.47626/2237-6089-2021-0396","pmid":"35617670","tags":["cbd","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"CBD-rich cannabis extract produced significant improvements in social interaction (p=0.0002), anxiety (p=0.016), psychomotor agitation (p=0.003), number of meals per day (p=0.04), and concentration (p=0.01, mild cases only). Only 9.7% of the treatment group experienced adverse effects (dizziness, insomnia, colic, weight gain), all mild.","whyItMatters":"This is one of the few randomized controlled trials examining CBD for autism in children. Social interaction, a core diagnostic criterion for ASD, showed the strongest improvement, suggesting CBD may address a fundamental challenge of the condition rather than just peripheral symptoms.","specificNumbers":"60 children, ages 5-11. 12-week treatment. Social interaction: F=14.13, p=0.0002. Anxiety: F=5.99, p=0.016. Psychomotor agitation: F=9.22, p=0.003. Concentration improved only in mild cases (p=0.01). Adverse effects in 9.7% (3 children).","methodology":"Randomized, double-blind, placebo-controlled clinical trial of 60 children aged 5-11 years with ASD. The treatment group received CBD-rich cannabis extract for 12 weeks. Outcomes were analyzed using two-factor mixed ANOVA.","limitations":"Small sample (60 children). Single-center study. 12-week follow-up may not capture long-term effects. The concentration improvement was limited to mild ASD cases. Details on the specific CBD:THC ratio and dosing were limited in the abstract."},{"rthcId":"RTHC-05715","title":"Fatty Acid Amides Suppress Proliferation via Cannabinoid Receptors and Promote the Apoptosis of C6 Glioma Cells in Association with Akt Signaling Pathway Inhibition.","authors":"Silva, Nágila Monteiro da; Lopes, Izabella Carla Silva; Galué-Parra, Adan Jesus; Ferreira, Irlon Maciel; Sena, Chubert Bernardo Castro de; Silva, Edilene Oliveira da; Macchi, Barbarella de Matos; Oliveira, Fábio Rodrigues de; do Nascimento, José Luiz Martins","year":2024,"journal":"Pharmaceuticals (Basel, Switzerland), 17(7)","doi":"10.3390/ph17070873","pmid":"39065724","tags":["cancer","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Two fatty ethanolamides (FAA1 and FAA2) reduced C6 glioma cell viability, proliferation, and migratory potential in a dose-dependent manner. They triggered apoptotic cell death through mitochondrial integrity loss, likely by activating cannabinoid receptors and inhibiting the PI3K/Akt signaling pathway. Critically, neither compound was toxic to normal retinal glial cells.","whyItMatters":"Gliomas are among the most aggressive and treatment-resistant brain cancers, with patients often surviving less than a year after diagnosis. Finding compounds that kill cancer cells while sparing normal cells is the central challenge, and these cannabinoid receptor-activating compounds showed that selectivity.","specificNumbers":"Two compounds tested (FAA1 and FAA2). Dose-dependent reduction in glioma cell viability, proliferation, and migration. Apoptosis confirmed via mitochondrial integrity loss. PI3K/Akt pathway inhibition confirmed. No toxicity to normal retinal glial cells.","methodology":"In vitro study testing two fatty acid amides synthesized from andiroba oil (Carapa guianensis) on C6 glioma cells. Assessments included cell viability, proliferation, migration, mitochondrial membrane potential, and pathway analysis. Normal retinal glial cells were used as a toxicity control.","limitations":"In vitro study only; effects in living organisms may differ entirely. C6 glioma cells are a rat cell line and may not fully represent human glioblastoma. The compounds were derived from a specific natural product, and their pharmacokinetics in vivo are unknown."},{"rthcId":"RTHC-05716","title":"Does the \"Entourage Effect\" in Cannabinoids Exist? A Narrative Scoping Review.","authors":"Simei, João Luís Q; Souza, José Diogo R; Lisboa, João Roberto; Campos, Alline C; Guimarães, Francisco S; Zuardi, Antonio; Crippa, José Alexandre S","year":2024,"journal":"Cannabis and cannabinoid research, 9(5), 1202-1216","doi":"10.1089/can.2023.0052","pmid":"37535820","tags":["cbd","medical-cannabis"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"The entourage effect is recognized as a synergistic phenomenon where multiple cannabis components interact to modulate therapeutic actions. However, the literature provides limited evidence to support it as a stable and predictable phenomenon. There is also limited evidence supporting clinical efficacy, safety, or appropriate regulation based on the entourage hypothesis.","whyItMatters":"The entourage effect is one of the most cited concepts in cannabis marketing and advocacy, often used to promote whole-plant products over isolated compounds. This review provides a reality check: the concept outpaces the evidence, which has implications for product regulation and clinical decision-making.","specificNumbers":"The term was first introduced in the late 1990s. It has gained widespread use in scientific reviews and marketing over the past decade. The review found limited evidence for clinical efficacy, safety, and regulation based on this hypothesis.","methodology":"Narrative scoping review critically evaluating the application of the \"entourage effect\" term in scientific literature, marketing, and clinical practice. Relevant studies and reviews were analyzed for evidence of clinical efficacy and safety.","limitations":"Narrative scoping review without systematic search methodology. The review focuses on the state of evidence rather than generating new data. Some component interactions may be real but not yet adequately studied."},{"rthcId":"RTHC-05717","title":"Research and Clinical Practice Involving the Use of Cannabis Products, with Emphasis on Cannabidiol: A Narrative Review.","authors":"Simei, João Luís Q; Souza, José Diogo R; Pedrazzi, João Francisco; Guimarães, Francisco S; Campos, Alline Cristina; Zuardi, Antônio; Hallak, Jaime Eduardo C; Crippa, José Alexandre S","year":2024,"journal":"Pharmaceuticals (Basel, Switzerland), 17(12)","doi":"10.3390/ph17121644","pmid":"39770486","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05718","title":"A Cross-Sectional Survey Study of Cannabis Use for Fibromyalgia Symptom Management.","authors":"Singla, Abhinav; Anstine, Christopher V; Huang, Linda; Rosedahl, Jordan K; Mohabbat, Arya B; Philpot, Lindsey M","year":2024,"journal":"Mayo Clinic proceedings, 99(4), 542-550","doi":"10.1016/j.mayocp.2023.12.018","pmid":"38569809","tags":["pain","medical-cannabis","sleep","anxiety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 1,336 fibromyalgia patients, 49.5% (661) reported cannabis use since diagnosis. Among cannabis users, 98.9% used it for pain, 96.2% for fatigue, 93.9% for stress/anxiety/depression, and 93.6% for insomnia. Pain improvement was reported by 82% of cannabis users. Most also reported improvements in stress, anxiety, depression, and insomnia symptoms.","whyItMatters":"Fibromyalgia is notoriously difficult to treat, and patients often seek alternative therapies. This survey from a major academic medical center shows that cannabis use is already widespread among fibromyalgia patients, and most report benefit, creating an urgent need for providers to be knowledgeable about cannabis.","specificNumbers":"1,336 respondents (25.5% response rate). 49.5% used cannabis. Cannabis use reasons: pain 98.9%, fatigue 96.2%, stress/anxiety/depression 93.9%, insomnia 93.6%. Pain improvement reported by 82%. Median age 48 years. Most identified as female.","methodology":"Cross-sectional electronic survey conducted at Mayo Clinic Rochester Integrative Medicine among 5,234 patients diagnosed with fibromyalgia. Survey constructed using the Symptom Management Theory framework. 1,336 (25.5%) responded and met inclusion criteria.","limitations":"25.5% response rate introduces selection bias; cannabis users may have been more motivated to respond. Self-reported improvement is not validated against objective measures. No control group or dose information. Patients were from an integrative medicine clinic, which may attract more cannabis-open patients."},{"rthcId":"RTHC-05719","title":"Cannabis use and social anxiety disorder in emerging adulthood: Results from a nationally representative sample.","authors":"Single, Alanna; Alcolado, Gillian; Keough, Matthew T; Mota, Natalie","year":2024,"journal":"Journal of anxiety disorders, 101, 102808","doi":"10.1016/j.janxdis.2023.102808","pmid":"38061325","tags":["anxiety","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The prevalence of co-occurring cannabis use and social anxiety disorder was 1.10%. Being White, a part-time student, or not a student increased odds of having both conditions (OR: 2.26-3.09). Multiple psychiatric disorders were strongly associated with the co-occurrence, including panic disorder (AOR up to 19.05), major depressive disorder, bipolar I, generalized anxiety, specific phobia, and agoraphobia (AOR range: 3.03-19.05).","whyItMatters":"Social anxiety is one of the most commonly cited reasons for cannabis use among young adults. Understanding who is at risk for both conditions simultaneously helps target screening and intervention efforts in a population where both are highly prevalent.","specificNumbers":"5,194 young adults. Co-occurrence prevalence: 1.10%. Being White: OR 2.26-3.09 for co-occurrence. Panic disorder: AOR up to 19.05 for co-occurrence. Major depression, bipolar I, GAD, specific phobia, and agoraphobia also significantly associated.","methodology":"Cross-sectional analysis of 5,194 emerging adults (ages 18-25) from the NESARC-III, a nationally representative US survey. Weighted cross-tabulations and multinomial logistic regressions examined four groups: no cannabis/no SAD, cannabis only, SAD only, and cannabis plus SAD.","limitations":"Cross-sectional design cannot determine whether cannabis use leads to social anxiety, vice versa, or both arise from shared risk factors. The 1.10% co-occurrence rate may underestimate true prevalence due to stigma in reporting. NESARC-III data is from 2012-2013."},{"rthcId":"RTHC-05720","title":"Development of Delivery Systems with Prebiotic and Neuroprotective Potential of Industrial-Grade Cannabis sativa L.","authors":"Sip, Szymon; Stasiłowicz-Krzemień, Anna; Sip, Anna; Szulc, Piotr; Neumann, Małgorzata; Kryszak, Aleksandra; Cielecka-Piontek, Judyta","year":2024,"journal":"Molecules (Basel, Switzerland), 29(15)","doi":"10.3390/molecules29153574","pmid":"39124978","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05721","title":"Perceptions, barriers, and facilitators of cannabis screening during pregnancy and labor: A qualitative study.","authors":"Skelton, K; Nyarko, S; Iobst, S","year":2024,"journal":"Drug and alcohol dependence reports, 12, 100274","doi":"10.1016/j.dadr.2024.100274","pmid":"39280985","tags":["pregnancy"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Women reported mixed perceptions of cannabis harm during pregnancy, often framing it as medicine or acknowledging addiction. The dominant barrier to disclosing cannabis use was fear of child welfare and protective services involvement. Perceived negative provider communication was also identified as a barrier. Most participants used cannabis during pregnancy to manage mental health conditions and pain.","whyItMatters":"If pregnant women are afraid to disclose cannabis use, providers cannot offer informed counseling or monitor for potential risks. This study identifies the specific fears driving non-disclosure, which are actionable: reforming screening communication and addressing punitive policies.","specificNumbers":"16 women interviewed. 75% were 25-34 years old. 75% were Black. 68.75% had less than a bachelor's degree. Women used cannabis for mental health, pain, and reported both medicinal framing and addiction.","methodology":"Phenomenological qualitative study with semi-structured online interviews of 16 women who gave birth at a US hospital within the past three months. Inductive thematic analysis with two coders. Descriptive statistics for demographics and cannabis use behaviors.","limitations":"Very small sample (16 women) from a single US hospital. 75% Black sample may not represent all demographic groups. Women were interviewed postpartum, introducing recall bias. Self-selection may mean participants were more comfortable discussing cannabis."},{"rthcId":"RTHC-05722","title":"A naturalistic cohort study of first-episode schizophrenia spectrum disorder: A description of the early phase of illness in the PSYSCAN cohort.","authors":"Slot, Margot I E; van Hell, Hendrika H; Rossum, Inge Winter-van; Dazzan, Paola; Maat, Arija; de Haan, Lieuwe; Crespo-Facorro, Benedicto; Glenthøj, Birte; Lawrie, Stephen M; McDonald, Colm; Gruber, Oliver; van Amelsvoort, Thérèse; Arango, Celso; Kircher, Tilo; Nelson, Barnaby; Galderisi, Silvana; Weiser, Mark; Sachs, Gabriele; Maatz, Anke; Bressan, Rodrigo A; Kwon, Jun Soo; Mizrahi, Romina; McGuire, Philip; Kahn, René S","year":2024,"journal":"Schizophrenia research, 266, 237-248","doi":"10.1016/j.schres.2024.02.018","pmid":"38431986","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05723","title":"Epidemiology studies on effects of lithium salts in pregnancy are confounded by the inability to control for other potentially teratogenic factors.","authors":"Smith, Carr J; Payne, Victoria M","year":2024,"journal":"Human & experimental toxicology, 43, 9603271241236346","doi":"10.1177/09603271241236346","pmid":"38394684","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05724","title":"Trends of emergency department visits for cannabinoid hyperemesis syndrome in Nevada: An interrupted time series analysis.","authors":"Soh, Jaeseung; Kim, Yonsu; Shen, Jay; Kang, Mingon; Chaudhry, Stefan; Chung, Tae Ha; Kim, Seo Hyun; Hwang, Yena; Lim, Daniel; Khattak, Adam; Frimer, Leora; Yoo, Ji Won","year":2024,"journal":"PloS one, 19(5), e0303205","doi":"10.1371/journal.pone.0303205","pmid":"38809874","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Emergency department visits for CHS increased continuously from 2013 to 2021. The rate was 1.07 per 100,000 before recreational cannabis commercialization and jumped to 2.22 per 100,000 after commercialization in the third quarter of 2017, an increase of approximately 1.1 per 100,000. CHS patients were younger and included fewer males compared to other ED visitors.","whyItMatters":"This provides direct evidence linking recreational cannabis commercialization to a measurable increase in a specific health outcome. CHS is entirely attributable to cannabis use, making it a clean indicator of the health burden associated with expanded access.","specificNumbers":"Pre-commercialization rate: 1.07 per 100,000. Post-commercialization rate: 2.22 per 100,000. Increase: approximately 1.1 per 100,000. Study period: 2013-2021. CHS patients were younger and had fewer males than non-CHS ED patients.","methodology":"Interrupted time series analysis using Nevada State Emergency Department Databases (2013-2021). CHS patients were compared to all other ED visitors. The impact of recreational cannabis commercialization (Q3 2017) was estimated as the intervention point.","limitations":"ICD-code-based identification may undercount CHS cases, especially before the condition became well-recognized. The time series cannot prove commercialization caused the increase, as awareness and diagnosis of CHS also improved during this period. Limited to Nevada."},{"rthcId":"RTHC-05725","title":"Changes in Cannabis Use Patterns in Psychiatric Populations Pre- and Post-Legalization of Recreational Cannabis Use in Canada: A Repeated Cross-Sectional Survey.","authors":"Sorkhou, Maryam; Johnstone, Samantha; Weinberger, Andrea H; Cooper, Ziva D; Sanches, Marcos; Castle, David J; Hall, Wayne; Rabin, Rachel A; Hammond, David; George, Tony P","year":2024,"journal":"Cannabis (Albuquerque, N.M.), 7(3), 1-13","doi":"10.26828/cannabis/2024/000238","pmid":"39781550","tags":["psychosis","legalization","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The odds of daily/near-daily cannabis use increased nine-fold (aOR=9.19) among people with schizophrenia between pre-legalization (2018) and two years post (2020). Their average monthly use days rose from 12.8 to 18.1. No significant changes were observed for cannabis users with anxiety, depression, PTSD, bipolar disorder, substance use disorders, or no mental health conditions.","whyItMatters":"Cannabis legalization advocates often cite that the sky will not fall, while opponents worry about vulnerable populations. This study suggests both are partially right: legalization did not increase use for most people with mental health conditions, but people with schizophrenia, who are particularly vulnerable to cannabis harms, were the exception.","specificNumbers":"N=13,527. Schizophrenia daily use OR: 9.19 (95% CI: 2.46-34.37) from Wave 1 to Wave 3. Monthly use days increased from 12.8 to 18.1 for schizophrenia group. No significant changes for anxiety, depression, PTSD, bipolar, SUD, or no-mental-health groups.","methodology":"Repeated cross-sectional analysis of 13,527 Canadian respondents across three waves of the International Cannabis Policy Study (Wave 1: Aug-Oct 2018; Wave 2: Sep-Oct 2019; Wave 3: Sep-Nov 2020). Analysis focused on cannabis users with specific self-reported mental health disorders.","limitations":"Self-reported mental health diagnoses may be inaccurate. The schizophrenia subsample was likely small, contributing to the very wide confidence interval (2.46-34.37). Cross-sectional design means different people were surveyed at each wave. Cannot determine causation."},{"rthcId":"RTHC-05726","title":"Birth, cognitive and behavioral effects of intrauterine cannabis exposure in infants and children: A systematic review and meta-analysis.","authors":"Sorkhou, Maryam; Singla, Daisy R; Castle, David J; George, Tony P","year":2024,"journal":"Addiction (Abingdon, England), 119(3), 411-437","doi":"10.1111/add.16370","pmid":"37968824","tags":["pregnancy","cognition","youth"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Intrauterine cannabis exposure was associated with preterm delivery (OR=1.68, p=0.03), low birth weight (OR=2.60, p<0.001), and NICU admission (OR=2.51, p<0.001). Qualitative synthesis found associations with poorer attention and externalizing problems in early childhood, but no evidence for impairments in other cognitive domains or internalizing behaviors.","whyItMatters":"This is the most comprehensive meta-analysis to date on prenatal cannabis effects. The birth outcome findings are robust, while the more nuanced cognitive finding (limited to attention/externalizing) pushes back against overly broad claims of developmental harm.","specificNumbers":"57 studies included. Preterm delivery: OR=1.68 (CI: 1.05-2.71). Low birth weight: OR=2.60 (CI: 1.71-3.94). NICU admission: OR=2.51 (CI: 1.46-4.31). Attention and externalizing problems found in qualitative synthesis. No evidence for other cognitive impairments.","methodology":"Systematic review and meta-analysis following PRISMA guidelines. Searched PubMed and PsycINFO from database inception through June 2023. 932 studies screened, 57 met eligibility criteria. Included prospective and cross-sectional human studies measuring birth, behavioral, psychological, and cognitive outcomes.","limitations":"Many included studies could not fully control for concurrent tobacco use, socioeconomic factors, or other substance exposure. Self-reported cannabis use likely underestimates exposure. The cognitive literature is qualitatively synthesized due to heterogeneity, limiting the strength of those conclusions."},{"rthcId":"RTHC-05727","title":"Cannabis use and mood disorders: a systematic review.","authors":"Sorkhou, Maryam; Dent, Eliza L; George, Tony P","year":2024,"journal":"Frontiers in public health, 12, 1346207","doi":"10.3389/fpubh.2024.1346207","pmid":"38655516","tags":["depression","mental-health"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Cannabis use was associated with increased depressive and manic symptoms in the general population, elevated likelihood of developing both major depressive disorder (MDD) and bipolar disorder (BD), and unfavorable prognosis in people already diagnosed with either condition. The relationship held across both cross-sectional and longitudinal study designs.","whyItMatters":"Cannabis is often used recreationally by people with mood disorders, and some advocate for its use as a mood treatment. This comprehensive review challenges that narrative, finding consistent associations between cannabis use and worse mood disorder outcomes across a large body of evidence.","specificNumbers":"3,262 studies screened, 78 met criteria. Associations found with: increased depressive symptoms, increased manic symptoms, elevated risk of developing MDD, elevated risk of developing BD, unfavorable prognosis in both MDD and BD.","methodology":"Systematic review following PRISMA guidelines. Searched EMBASE, PsycINFO, PubMed, and MEDLINE from inception through November 2023. Of 3,262 studies identified, 78 met inclusion criteria. Both cross-sectional and longitudinal designs were included.","limitations":"The review is limited by the observational nature of most included studies. Confounders including concurrent substance use, genetics, and socioeconomic factors may explain some associations. Cannot determine whether cannabis causes mood problems or whether people with mood vulnerability are drawn to cannabis."},{"rthcId":"RTHC-05728","title":"Psychometric properties and invariance testing of the Cannabis Refusal Self-Efficacy Scale in a Chilean sample.","authors":"Soto, Marcela; Vergés, Alvaro","year":2024,"journal":"The American journal of drug and alcohol abuse, 50(6), 798-806","doi":"10.1080/00952990.2024.2411681","pmid":"39642262","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05729","title":"Synthesis and functional evaluation of proteinogenic amino acid-derived synthetic cannabinoid receptor agonists related to MPP-5F-PICA, MMB-5F-PICA, and MDMB-5F-PICA.","authors":"Sparkes, Eric; Markham, Jack W; Boyd, Rochelle; Udoh, Michael; Gordon, Rebecca; Zaman, Humayra; Walker, Katelyn A; Dane, Chianna; Kevin, Richard C; Santiago, Marina J; Hibbs, David E; Banister, Samuel D; Ametovski, Adam; Cairns, Elizabeth A","year":2024,"journal":"RSC medicinal chemistry, 15(6), 2063-2079","doi":"10.1039/d3md00758h","pmid":"38911147","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05730","title":"Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA.","authors":"Sparkes, Eric; Timmerman, Axelle; Markham, Jack W; Boyd, Rochelle; Gordon, Rebecca; Walker, Katelyn A; Kevin, Richard C; Hibbs, David E; Banister, Samuel D; Cairns, Elizabeth A; Stove, Christophe; Ametovski, Adam","year":2024,"journal":"ACS chemical neuroscience, 15(9), 1787-1812","doi":"10.1021/acschemneuro.3c00818","pmid":"38597712","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05731","title":"Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis.","authors":"Spindle, Tory R; Zamarripa, C Austin; Russo, Ethan; Pollak, Lauren; Bigelow, George; Ward, Alexandra M; Tompson, Bridget; Sempio, Cristina; Shokati, Touraj; Klawitter, Jost; Christians, Uwe; Vandrey, Ryan","year":2024,"journal":"Drug and alcohol dependence, 257, 111267","doi":"10.1016/j.drugalcdep.2024.111267","pmid":"38498958","tags":["anxiety","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Co-administration of 30mg THC with 15mg d-limonene significantly reduced ratings of \"anxious/nervous\" and \"paranoid\" compared to 30mg THC alone. Anxiety-like effects qualitatively decreased as d-limonene dose increased. D-limonene alone produced no effects different from placebo, and it did not alter THC pharmacokinetics or other THC effects.","whyItMatters":"This is one of the first rigorous human studies to demonstrate a specific entourage effect in cannabis. The selectivity is key: d-limonene reduced only the anxiety component of THC without blunting its other effects, suggesting it could increase THC's therapeutic index.","specificNumbers":"20 participants (12 in extended arm). THC doses: 15mg and 30mg. D-limonene doses: 1mg, 5mg, and 15mg. 30mg THC + 15mg d-limonene significantly reduced anxiety and paranoia ratings vs 30mg THC alone. D-limonene did not alter THC plasma concentrations.","methodology":"Double-blind, placebo-controlled crossover trial. 20 healthy intermittent cannabis users completed 9 outpatient sessions (subset of 12 completed a 10th). They inhaled vaporized THC (15mg or 30mg), d-limonene (1mg or 5mg), combinations, or placebo. Outcomes included subjective effects, cognition, psychomotor performance, vital signs, and plasma levels.","limitations":"Relatively small sample (20 participants). Only healthy intermittent cannabis users were studied; effects may differ in daily users or patients. The inhalation route may not translate to oral products. Only one terpene was tested."},{"rthcId":"RTHC-05732","title":"Cannabis and Craniotomy for Glioblastoma: Impact on Complications and Health Care Utilization.","authors":"Sreenivasan, Sanjeev; Kaoutzani, Lydia; Ugiliweneza, Beatrice; Boakye, Maxwell; Schulder, Michael; Sharma, Mayur","year":2024,"journal":"World neurosurgery, 190, e707-e715","doi":"10.1016/j.wneu.2024.07.210","pmid":"39111656","tags":["cancer","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After balancing groups, patients with cannabis abuse disorder (CAD) had higher complication rates during initial hospitalization (32% vs 15%, p=0.001) and higher neurologic complications at 6 months (27% vs 8%, p<0.001) and 12 months (31% vs 12%, p<0.001). CAD patients were significantly younger (median 37 vs 51 years) and had higher rates of opioid abuse (16% vs 5%). At one year, CAD patients sought fewer outpatient services.","whyItMatters":"Glioblastoma already has a dismal prognosis (14-16 month median survival). Finding that cannabis use disorder is associated with additional complications after surgery, combined with reduced outpatient follow-up, suggests this patient population may need extra monitoring and support.","specificNumbers":"CAD group: median age 37 vs 51 years, 19% women vs 45%. Index stay complications: 32% vs 15%. Opioid abuse: 16% vs 5%. 6-month neurologic complications: 27% vs 8%. 12-month neurologic complications: 31% vs 12%. Fewer outpatient visits at 1 year (p=0.012).","methodology":"Retrospective population-based study using Merative MarketScan data (2008-2019, >265 million patients). Adults with GBM diagnosis who underwent craniotomy were identified. Inverse probability treatment weighting balanced cannabis abuse disorder and non-CAD groups on age, gender, insurance, comorbidities, and opioid dependence.","limitations":"Cannabis abuse disorder diagnosis is based on billing codes, which may not accurately capture all cannabis users. The much younger age of CAD patients suggests systematic differences between groups that may not be fully addressed by weighting. Cannot determine if cannabis itself caused complications or if CAD is a marker for other risk factors."},{"rthcId":"RTHC-05733","title":"Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer's Disease Treatment.","authors":"Stanciu, Gabriela Dumitrita; Ababei, Daniela-Carmen; Solcan, Carmen; Uritu, Cristina-Mariana; Craciun, Vlad-Constantin; Pricope, Cosmin-Vasilica; Szilagyi, Andrei; Tamba, Bogdan-Ionel","year":2024,"journal":"Pharmaceuticals (Basel, Switzerland), 17(4)","doi":"10.3390/ph17040530","pmid":"38675490","tags":["neuroscience","cognition","seniors"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic treatment with JWH-133 (a selective CB2 agonist) and Cannabis sativa extract reduced anxiety-like behavior and partially reversed recognition memory deficits in APP/PS1 mice. Both treatments reduced the number and size of amyloid-beta plaque deposits, decreased cerebral glucose metabolism, reduced mTOR and CB2 receptor expression, and enhanced M1 muscarinic acetylcholine receptor expression.","whyItMatters":"Alzheimer's disease has no effective treatment despite decades of research. The finding that cannabinoid receptor ligands can reduce plaque deposits and improve cognition in an Alzheimer's model, through the expanded endocannabinoid system, opens a new therapeutic avenue worth pursuing.","specificNumbers":"Treatment: 90 days intermittent. JWH-133: 0.2 mg/kg. Cannabis extract: 2.5 mg/kg. Outcomes: reduced anxiety, partially reversed cognitive deficits, reduced amyloid-beta plaque number and size, decreased cerebral glucose metabolism, reduced mTOR and CB2 expression, increased M1 mAChR expression.","methodology":"APP/PS1 transgenic mice (Alzheimer's model) received 90 days of intermittent treatment with JWH-133 (0.2 mg/kg) or EU-GMP certified Cannabis sativa (Cannabixir Medium Flos, 2.5 mg/kg). Recognition memory, anxiety behavior, brain imaging, and molecular markers were assessed.","limitations":"Mouse model findings often do not translate to human Alzheimer's. APP/PS1 mice only model the amyloid component of Alzheimer's, not the full disease. The treatment regimen (90 days intermittent) may not represent practical clinical dosing. No long-term follow-up."},{"rthcId":"RTHC-05734","title":"The impact of substance use on posttraumatic stress disorder symptoms and treatment discontinuation.","authors":"Stevenson, Brittany L; Lee, Jenny Y; Oslin, David W; Polusny, Melissa A; Kehle-Forbes, Shannon M","year":2024,"journal":"Journal of traumatic stress, 37(2), 257-266","doi":"10.1002/jts.23002","pmid":"38085564","tags":["ptsd","addiction","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"A major clinical question for therapists treating veterans with both PTSD and addiction: does ongoing cannabis use during treatment sabotage the results? This secondary analysis of a randomized clinical trial with 183 veterans provides a reassuring — if nuanced — answer.\n\nSubstance use was measured at 4-week intervals throughout treatment. The researchers tested whether the percentage of days using alcohol, cannabis, or other substances at one time point predicted PTSD symptoms or treatment dropout at the next time point. The finding: cannabis use did not prospectively predict worse PTSD symptoms or treatment discontinuation.\n\nAlcohol told a different story. When a veteran's drinking days increased by about one standard deviation (34.7% more drinking days), PTSD symptoms during that same period were measurably higher. But even alcohol didn't predict future PTSD worsening — the relationship was concurrent, not prospective.\n\nOther substance use (primarily cocaine and opioids) also showed no prospective relationship with PTSD outcomes or dropout.\n\nThis is a clinically important null finding. It suggests that requiring cannabis abstinence as a precondition for PTSD treatment — a stance some programs take — may not be justified by the evidence. Veterans who continue using cannabis during treatment still appear to benefit from the therapy at similar rates.","whyItMatters":"Many PTSD treatment programs require or strongly encourage abstinence from all substances before starting trauma-focused therapy. This study challenges that approach for cannabis specifically — ongoing use didn't derail treatment. For the 33% of PTSD patients who also use cannabis (RTHC-00117), this data supports engaging them in treatment as-is rather than delaying until abstinence is achieved.","specificNumbers":"183 veterans. 4-week measurement intervals throughout treatment. Cannabis use: no prospective association with PTSD symptoms or dropout. Alcohol: concurrent association with worse PTSD symptoms (1 SD increase in drinking days = measurably higher PTSD symptoms in same period). No prospective associations for any substance class with treatment discontinuation.","methodology":"Secondary analysis of a randomized clinical trial with 183 U.S. military veterans (53.8% Black, 41.9% White, 92.4% male) treated for co-occurring PTSD and substance use disorder. Substance use (percentage of days using alcohol, cannabis, other substances; average drinks per drinking day), PTSD symptoms, and treatment discontinuation measured at 4-week intervals. Multilevel models accounted for nested longitudinal data structure. Tested both concurrent and prospective associations.","limitations":"Secondary analysis — not designed to test this specific question. Predominantly male veteran sample (92.4%) limits generalizability to women and civilian populations. Cannabis use measured by days of use, not dose, potency, or product type. The 4-week intervals may miss shorter-term fluctuations in use and symptoms. Null findings don't prove cannabis use is harmless during treatment — only that it didn't predict worse outcomes in this sample at this measurement frequency."},{"rthcId":"RTHC-05735","title":"Validation of the Reasons for Quitting Smoking Cannabis Scale Among People with Cannabis Use Disorder.","authors":"Stone, Bryant M; Gilbert, David G","year":2024,"journal":"Substance use & misuse, 59(13), 1950-1961","doi":"10.1080/10826084.2024.2392508","pmid":"39252212","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05736","title":"Support for Expanding Access to Cannabis Among Physicians and Adults With Chronic Pain.","authors":"Stone, Elizabeth M; Tormohlen, Kayla; Bicket, Mark C; McGinty, Emma E","year":2024,"journal":"JAMA network open, 7(9), e2435843","doi":"10.1001/jamanetworkopen.2024.35843","pmid":"39325454","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers surveyed two key groups in the pain management landscape: adults living with chronic pain and physicians who treat them. Both groups were asked about their attitudes toward expanding access to cannabis as a pain management tool.\n\nThe results showed support for expanded cannabis access from both patients and clinicians. This convergence is notable because physician attitudes have historically been more conservative than patient attitudes regarding cannabis.\n\nThe findings reflect a broader shift in how cannabis is perceived within mainstream medicine, driven partly by the opioid crisis, which has increased interest in alternative pain management approaches.","whyItMatters":"Physician attitudes are a critical bottleneck for medical cannabis access. When doctors are skeptical, patients have difficulty obtaining recommendations even in states with medical cannabis programs. Finding that physicians increasingly support expanded access suggests the medical gatekeeping barrier may be lowering.","specificNumbers":"Both chronic pain patients and physicians were surveyed. Both groups expressed support for expanding cannabis access for pain management.","methodology":"This was a cross-sectional survey study that collected responses from two populations: adults with chronic pain and practicing physicians. Participants were asked about their support for various cannabis access policies. The study assessed attitudes and support levels across different policy scenarios.","limitations":"Survey respondents may not represent all chronic pain patients or all physicians; those with stronger opinions about cannabis may have been more likely to participate. The study measured attitudes, not clinical outcomes, and supporting access does not necessarily mean cannabis is effective for all pain conditions. Response rates and sampling methods affect generalizability."},{"rthcId":"RTHC-05737","title":"Examining the hepatotoxic potential of cannabidiol, cannabidiol-containing hemp extract, and cannabinol at consumer-relevant exposure concentrations in primary human hepatocytes.","authors":"Striz, Anneliese; Zhao, Yang; Sepehr, Estatira; Vaught, Cory; Eckstrum, Kirsten; Headrick, Kyra; Yourick, Jeffrey; Sprando, Robert","year":2024,"journal":"Journal of applied toxicology : JAT, 44(10), 1595-1605","doi":"10.1002/jat.4646","pmid":"38924151","tags":["cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cell viability was not significantly affected by CBD, CBN, or hemp extract at any concentration tested (10nM to 25uM) after 24 or 48 hours. Hemp extract at the highest concentration produced modest but statistically significant decreases in albumin secretion, urea secretion, and mitochondrial membrane potential. CBD only affected albumin secretion. CBN showed no significant effects.","whyItMatters":"CBD has been flagged for potential liver toxicity based on the prescription drug Epidiolex at high doses. This study examines whether consumer-level exposures (much lower than pharmaceutical doses) pose similar risks, finding minimal hepatotoxicity at relevant concentrations.","specificNumbers":"Concentrations tested: 10nM to 25uM. CBD, CBN, and hemp extract tested at consumer-relevant doses. No effect on cell viability at any concentration. Hemp extract: modest decrease in albumin, urea, and mitochondrial membrane potential at highest dose. CBD: modest decrease in albumin only.","methodology":"In vitro study using primary human hepatocytes exposed to CBD, CBN, or CBD-concentration-matched hemp extract at concentrations determined by in silico pharmacokinetic modeling to represent consumer-relevant exposures. Assessed lactate dehydrogenase release, apoptosis, albumin secretion, urea secretion, and mitochondrial membrane potential at 24 and 48 hours.","limitations":"In vitro study does not capture the full complexity of liver metabolism in a living organism. Consumer-relevant concentrations were estimated by modeling, not measured from actual consumers. Primary human hepatocytes from different donors may respond differently. Only 48-hour exposure tested."},{"rthcId":"RTHC-05738","title":"Cannabinoid hyperemesis syndrome: prevalence and management in an era of cannabis legalization.","authors":"Stubbs, Justin Joe; McCallum, Richard","year":2024,"journal":"Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 72(2), 171-177","doi":"10.1177/10815589231217495","pmid":"37997432","tags":["harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"CHS typically presents with episodic vomiting from chronic daily cannabis use over months to years, with nausea and abdominal pain improved by hot showers. Symptoms resolve with cannabis cessation over 6-12 months. Acute treatment uses parenteral benzodiazepines. Long-term prevention uses amitriptyline 50-200 mg/day, which can be slowly tapered after remission.","whyItMatters":"CHS remains unrecognized by many providers, leading to repeated ER visits, unnecessary testing, and delayed treatment. As cannabis becomes more widely available, providers need clear diagnostic and treatment frameworks.","specificNumbers":"Amitriptyline dose: 50-200 mg/day for prevention. Symptom resolution: 6-12 months after cannabis cessation. In the US, 52.5 million people aged 12+ used cannabis in 2021.","methodology":"Narrative review of current literature on CHS prevalence, diagnosis, and management in the context of expanding cannabis legalization.","limitations":"Narrative review without systematic search methodology. Treatment recommendations are based on limited evidence and clinical experience. The pathophysiology of CHS remains incompletely understood."},{"rthcId":"RTHC-05739","title":"The Endocannabinoid Peptide RVD-Hemopressin Is a TRPV1 Channel Blocker.","authors":"Suárez-Suárez, Constanza; González-Pérez, Sebastián; Márquez-Miranda, Valeria; Araya-Duran, Ingrid; Vidal-Beltrán, Isabel; Vergara, Sebastián; Carvacho, Ingrid; Hinostroza, Fernando","year":2024,"journal":"Biomolecules, 14(9)","doi":"10.3390/biom14091134","pmid":"39334900","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05740","title":"Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry Analysis of Δ9-Tetrahydrocannabinol and Cannabidiol in Commercial Suk-Saiyasna Herbal Remedy: Applying Hansen Solubility Parameters for Sample Extraction to Ensure Regulatory Compliance.","authors":"Sumontri, Suwimon; Eiamart, Wanna; Tadtong, Sarin; Samee, Weerasak","year":2024,"journal":"Pharmaceuticals (Basel, Switzerland), 17(11)","doi":"10.3390/ph17111502","pmid":"39598413","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05741","title":"Association of vaping with respiratory symptoms in U.S. young adults: Nicotine, cannabis, and dual vaping.","authors":"Sun, Ruoyan; Oates, Gabriela R","year":2024,"journal":"Preventive medicine, 189, 108175","doi":"10.1016/j.ypmed.2024.108175","pmid":"39547284","tags":["respiratory","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Vaping is often positioned as a safer alternative to smoking, but this large national survey reveals that vaping — whether nicotine, cannabis, or both — is associated with respiratory symptoms in young adults.\n\nAmong 8,033 Americans aged 18-24 surveyed in 2021, the breakdown was: 75.4% didn't vape, 15% vaped nicotine only, 4.7% vaped cannabis only, and 4.9% vaped both. All three vaping groups had more respiratory symptoms than non-vapers.\n\nCannabis-only vaping was associated with sounding wheezy (82% higher prevalence) and dry cough at night (61% higher). Nicotine-only vaping showed similar patterns: 75% higher prevalence of wheezing and 43% higher dry cough. The two were comparable in magnitude.\n\nDual vaping — both cannabis and nicotine — was the worst. It was associated with wheezing, dry cough, AND additional symptoms including wheezing/whistling and high overall respiratory symptom levels. The combined effect appeared to be more than additive, suggesting that dual vaping has a synergistic negative impact on respiratory health.\n\nThis is one of the first large studies to compare cannabis vaping, nicotine vaping, and dual vaping head-to-head for respiratory outcomes. The finding that cannabis vaping produces respiratory symptoms comparable to nicotine vaping challenges the assumption that cannabis vaping is benign for the lungs.","whyItMatters":"Cannabis vaping has exploded among young adults, partly because it's perceived as a harmless way to consume cannabis. This study directly challenges that perception with nationally representative data. The comparable respiratory symptom rates between cannabis and nicotine vaping, and the amplified symptoms from dual use, are findings that both public health messaging and individual decision-making need to incorporate.","specificNumbers":"8,033 young adults (18-24). Cannabis-only vaping: 82% higher prevalence of wheezing (aPR=1.82), 61% higher dry cough (aPR=1.61). Nicotine-only vaping: 75% higher wheezing (aPR=1.75), 43% higher dry cough (aPR=1.43). Dual vaping: 124% higher wheezing (aPR=2.24), 50% higher dry cough (aPR=1.50), plus additional symptoms including wheezing/whistling (aPR=1.93).","methodology":"Cross-sectional analysis of 8,033 U.S. young adults (ages 18-24) from a nationally representative survey conducted in 2021. Vaping categorized as: none, nicotine-only, cannabis-only, or dual. Multivariable logistic regressions assessed associations between vaping behavior and past 12-month respiratory outcomes, controlling for confounders.","limitations":"Cross-sectional design — respiratory symptoms and vaping are measured at the same time, so causation can't be established. Self-reported vaping and symptoms are subject to recall and reporting biases. No objective lung function testing (spirometry) — only subjective symptom reports. The survey can't distinguish between different vaping products, temperatures, or additives, which vary enormously. The 2021 survey period means EVALI awareness may have influenced both behavior and symptom reporting."},{"rthcId":"RTHC-05742","title":"Evaluating possible 'next day' impairment in insomnia patients administered an oral medicinal cannabis product by night: a pilot randomized controlled trial.","authors":"Suraev, Anastasia; McCartney, Danielle; Marshall, Nathaniel S; Irwin, Christopher; Vandrey, Ryan; Grunstein, Ronald R; D'Rozario, Angela L; Gordon, Christopher; Bartlett, Delwyn; Hoyos, Camilla M; McGregor, Iain S","year":2024,"journal":"Psychopharmacology, 241(9), 1815-1825","doi":"10.1007/s00213-024-06595-9","pmid":"38758300","tags":["sleep","driving","medical-cannabis","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"At 9+ hours after evening administration of 10mg THC/200mg CBD oil, there were no differences from placebo on 27 of 28 cognitive and psychomotor tests, including simulated driving performance. The only difference was a small 1.4% decrease in accuracy on the easy Stroop task (but not the hard version). A slight increase in self-rated sedation at 10 hours was not accompanied by changes in alertness or sleepiness ratings.","whyItMatters":"A major concern with medicinal cannabis for sleep is next-day impairment affecting driving and work safety. This study provides reassuring evidence that a typical medicinal dose does not produce meaningful next-day functional impairment in an insomnia population.","specificNumbers":"20 participants (16 female). Dose: 10mg THC + 200mg CBD oral oil. 27 of 28 tests showed no difference from placebo at 9+ hours. One small effect: -1.4% accuracy on easy Stroop (d=-0.6). Self-rated sedation slightly increased at 10h (d=0.3).","methodology":"Randomized, double-blind, placebo-controlled crossover trial with 20 adults (16 female, mean age 46.1) with physician-diagnosed insomnia who infrequently use cannabis. Each completed two 24-hour in-lab visits with 10mg THC/200mg CBD oil or placebo, with next-day testing at 9+ hours post-dose.","limitations":"Small sample (n=20). Only one dose tested. Participants were cannabis-infrequent, so regular users may differ. Laboratory setting may not capture real-world conditions. The study examined a single dose, not cumulative effects of nightly use."},{"rthcId":"RTHC-05743","title":"Detection of Δ9-tetrahydrocannabinol (THC) in oral fluid using two point-of-collection testing devices following oral administration of a THC and cannabidiol containing oil.","authors":"Suraev, Anastasia; McCartney, Danielle; Kevin, Richard; Gordon, Rebecca; Grunstein, Ronald R; Hoyos, Camilla M; McGregor, Iain S","year":2024,"journal":"Drug testing and analysis, 16(12), 1487-1495","doi":"10.1002/dta.3658","pmid":"38414100","tags":["driving","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"At 30 minutes post-dose, oral fluid THC concentrations varied widely (0-425 ng/mL), and both devices showed poor sensitivity (Securetec: 25%, Drager: 50%). By 10 and 18 hours post-treatment, all participants had THC concentrations below screening cutoffs and all test results were negative. The finding suggests low probability of a positive next-morning test after one-off oral medicinal cannabis use.","whyItMatters":"Patients using medicinal cannabis for sleep worry about failing workplace or roadside drug tests the next day. This study provides evidence that a standard oral dose is unlikely to produce a positive result the morning after, though it also reveals that current testing devices poorly detect oral cannabis use even shortly after dosing.","specificNumbers":"0.5h post-dose: THC range 0-425 ng/mL, mean 48.7 ng/mL. Securetec sensitivity at 0.5h: 25%. Drager sensitivity at 0.5h: 50%. At 10h and 18h: all concentrations below cutoffs, all tests negative.","methodology":"Randomized, double-blind, crossover trial. 20 adults with insomnia received a single oral dose of 10mg THC + 200mg CBD oil or placebo before sleep. Point-of-collection testing with Securetec DrugWipe 5S (10 ng/mL cutoff) and Drager DrugTest 5000 (25 ng/mL cutoff) at baseline, 0.5h, 10h, and 18h post-dose. LC-MS/MS confirmation at each time point.","limitations":"Small sample (n=20). Only one oral dose tested; regular nightly use might produce cumulative detection. Only two testing devices evaluated. The wide variability at 0.5h (0-425 ng/mL) suggests individual pharmacokinetic differences that could affect detection with regular use."},{"rthcId":"RTHC-05744","title":"Cannabigerolic Acid (CBGA) Inhibits the TRPM7 Ion Channel Through its Kinase Domain.","authors":"Suzuki, Sayuri; Wakano, Clay; Monteilh-Zoller, Mahealani K; Cullen, Aaron J; Fleig, Andrea; Penner, Reinhold","year":2024,"journal":"Function (Oxford, England), 5(1), zqad069","doi":"10.1093/function/zqad069","pmid":"38162115","tags":["cbd","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBGA had the strongest inhibitory effect on TRPM7 channels among all major and minor cannabinoids tested. The inhibition required a functional kinase domain, was enhanced by intracellular Mg-ATP and free Mg2+, and was reduced by intracellular calcium. CBGA also inhibited native TRPM7 channels in B lymphocytes.","whyItMatters":"TRPM7 is involved in cancer progression, stroke damage, and kidney disease. Finding that a naturally occurring cannabinoid (CBGA) potently and specifically blocks this channel opens a new therapeutic research direction for these serious conditions.","specificNumbers":"CBGA was the strongest TRPM7 inhibitor among all tested cannabinoids. About half of tested cannabinoids suppressed TRPM7 to some degree. CBGA interacted with the channel's selectivity filter via hydrogen bonds and van der Waals contacts.","methodology":"In vitro electrophysiology study using HEK293 cells expressing TRPM7-GFP. Calcium imaging and patch-clamp recordings measured TRPM7-mediated responses. Molecular docking and dynamics simulations investigated binding mechanisms. Multiple cannabinoids were tested and compared.","limitations":"In vitro study only. The relevance of TRPM7 blockade to actual disease outcomes in living organisms is not established. CBGA pharmacokinetics and bioavailability in vivo are not addressed. The study does not demonstrate therapeutic efficacy, only mechanism of action."},{"rthcId":"RTHC-05745","title":"Non-Intoxicating Cannabinoids in Visceral Pain.","authors":"Svendsen, Kristofer; Sharkey, Keith A; Altier, Christophe","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 3-11","doi":"10.1089/can.2023.0113","pmid":"37883662","tags":["pain","cbd","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Non-intoxicating cannabinoids (niCBs) show potential to normalize intestinal motility, reduce inflammation, and produce analgesic effects in preclinical models of visceral pain. Many of these effects are not mediated through classical CB1/CB2 receptors but rather through TRP channels and voltage-gated ion channels. Evidence also suggests niCBs can be combined for enhanced potency (entourage effect).","whyItMatters":"Patients with inflammatory bowel diseases increasingly use cannabis for abdominal pain, but clinical results have been mixed. This review suggests the focus on THC and CBD may be too narrow, and that other non-intoxicating cannabinoids acting through different mechanisms may be more relevant for gut pain.","specificNumbers":"Multiple niCBs reviewed beyond CBD. Three main mechanism categories: TRP channel modulation, voltage-gated ion channel effects, and non-CB receptor activity. Evidence for combination effects (entourage) among niCBs.","methodology":"Review of preclinical data on non-intoxicating cannabinoids in the treatment of abdominal pain, with focus on non-CB receptor mechanisms of action. Covers multiple niCBs beyond CBD.","limitations":"Review is limited to preclinical data; human clinical evidence for most niCBs in visceral pain is lacking. Animal models of gut pain may not fully translate to human inflammatory bowel disease. The entourage effect concept among niCBs needs rigorous clinical validation."},{"rthcId":"RTHC-05746","title":"Protonitazene detection in two cases of opioid toxicity following the use of tetrahydrocannabinol vape products in Australia.","authors":"Syrjanen, Rebekka; Schumann, Jennifer L; Castle, Jared W; Sharp, Lesley; Griffiths, Andrew; Blakey, Karen; Dutch, Martin; Maplesden, Jacqueline; Greene, Shaun L","year":2024,"journal":"Clinical toxicology (Philadelphia, Pa.), 62(8), 539-541","doi":"10.1080/15563650.2024.2383692","pmid":"39078080","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Two young males experienced opioid toxicity after using what they believed were THC vape products. Case 1 suffered repeated respiratory arrest requiring ventilation but survived. Case 2 died. Analysis of the vaping device found in the deceased's hand revealed a mixture of protonitazene and THC. Protonitazene is a benzimidazole opioid that can be dissolved and vaped due to its lipophilicity.","whyItMatters":"This represents a new and dangerous intersection of the illicit drug markets: potent synthetic opioids being mixed into cannabis vape products. Users have no way to know their THC vape contains a potentially lethal opioid, and the vaping route can deliver high concentrations rapidly.","specificNumbers":"Case 1: blood protonitazene 0.74 ug/L, survived with ventilation. Case 2: postmortem protonitazene 0.33 ug/L and THC 2 ug/L, died. Product analysis confirmed protonitazene-THC mixture in vape device.","methodology":"Two-case clinical report from Australian hospitals. Toxicological analysis included blood concentrations of protonitazene and THC. Product analysis of the vaping device and e-liquid confirmed contamination.","limitations":"Only two cases reported; the prevalence of protonitazene-contaminated cannabis vapes in Australia is unknown. Cannot determine whether the contamination was intentional adulteration or cross-contamination during production."},{"rthcId":"RTHC-05747","title":"Social forces shaping evidence production: A study of the swiss cannabis pilot trials.","authors":"Sznitman, Sharon R; Auer, Reto; Havinga, Jonathan Christopher; Casalini, Alessandro; Broers, Barbara","year":2024,"journal":"The International journal on drug policy, 134, 104623","doi":"10.1016/j.drugpo.2024.104623","pmid":"39447348","tags":["legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Social forces, including political imperatives and stakeholder interests, collectively shaped the Swiss cannabis pilot trial research. Informants committed to rigorous research while acknowledging that harm reduction discourse, power asymmetries, and political context influenced study design and implementation. The result was evidence production adjusted to align with contextual realities rather than purely scientific considerations.","whyItMatters":"Drug policy is increasingly claimed to be \"evidence-based,\" but this study reveals how the evidence itself is shaped by political and social forces. Understanding this dynamic is crucial for interpreting drug policy research and designing truly independent studies.","specificNumbers":"18 stakeholders interviewed across 6 professional categories. Social constructivist analytical lens applied. Multiple social forces identified: political imperatives, power asymmetries, harm reduction discourse, stakeholder economics.","methodology":"Qualitative study using thematic content analysis of semi-structured interviews with 18 stakeholders including scientists, policymakers, pharmacists, physicians, cannabis producers, and public health officials involved in Swiss cannabis pilot trials.","limitations":"Qualitative study from one country's specific regulatory context. Stakeholder perspectives may be self-serving or biased. The small sample may not capture all relevant viewpoints. Findings about Swiss pilot trials may not generalize to other countries."},{"rthcId":"RTHC-05748","title":"Incomplete autophagy and increased cholesterol synthesis during neuronal cell death caused by a synthetic cannabinoid, CP-55,940.","authors":"Tachibana, Hikari; Nomura, Moeka; Funakoshi, Takeshi; Unuma, Kana; Aki, Toshihiko; Uemura, Koichi","year":2024,"journal":"Neurotoxicology, 103, 215-221","doi":"10.1016/j.neuro.2024.06.013","pmid":"38942151","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05749","title":"Prospective study of e-cigarette use and respiratory symptoms in adolescents and young adults.","authors":"Tackett, Alayna P; Urman, Robert; Barrington-Trimis, Jessica; Liu, Feifei; Hong, Hanna; Pentz, Mary Ann; Islam, Talat S; Eckel, Sandrah P; Rebuli, Meghan; Leventhal, Adam; Samet, Jonathan M; Berhane, Kiros; McConnell, Rob","year":2024,"journal":"Thorax, 79(2), 163-168","doi":"10.1136/thorax-2022-218670","pmid":"37582630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05750","title":"Exposure to maternal cannabis use disorder and risk of autism spectrum disorder in offspring: A data linkage cohort study.","authors":"Tadesse, Abay Woday; Ayano, Getinet; Dachew, Berihun Assefa; Betts, Kim; Alati, Rosa","year":2024,"journal":"Psychiatry research, 337, 115971","doi":"10.1016/j.psychres.2024.115971","pmid":"38788554","tags":["pregnancy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Children of mothers with cannabis use disorder had approximately three times the risk of being diagnosed with ASD compared to non-exposed children. Sensitivity analyses showed male offspring had a higher ASD risk associated with maternal CUD than female offspring.","whyItMatters":"With cannabis use during pregnancy increasing alongside legalization, understanding its potential impact on neurodevelopment is critical. A three-fold risk increase is substantial and adds to growing evidence that cannabis exposure during fetal development may have lasting consequences.","specificNumbers":"222,534 mother-offspring pairs. Three-fold increased ASD risk with maternal CUD. Male offspring had higher risk than female. Study period: 2003-2005 births in New South Wales, Australia.","methodology":"Population-based retrospective cohort study using linked administrative health data from the New South Wales Perinatal Data Collection. Included 222,534 mother-offspring pairs from live births between January 2003 and December 2005. CUD and ASD identified via ICD-10-AM codes.","limitations":"CUD is identified from billing codes, which captures only diagnosed disorder rather than all cannabis use during pregnancy. Cannot determine timing, dose, or frequency of use. Confounders like socioeconomic status, other substance use, and genetic factors may not be fully controlled. Observational design cannot prove causation."},{"rthcId":"RTHC-05751","title":"The association between prenatal cannabis use and congenital birth defects in offspring: A cumulative meta-analysis.","authors":"Tadesse, Abay Woday; Ayano, Getinet; Dachew, Berihun Assefa; Tusa, Biruk Shalmeno; Damtie, Yitayish; Betts, Kim; Alati, Rosa","year":2024,"journal":"Neurotoxicology and teratology, 102, 107340","doi":"10.1016/j.ntt.2024.107340","pmid":"38460861","tags":["pregnancy","youth"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Prenatal cannabis exposure was associated with increased risks of cardiovascular/heart defects (OR=2.35), gastrointestinal defects (OR=2.42), central nervous system defects (OR=2.87), genitourinary defects (OR=2.39), and any/unclassified birth defects (OR=1.25). All associations were statistically significant.","whyItMatters":"This is the most comprehensive meta-analysis to date linking prenatal cannabis to specific types of structural birth defects. The consistent 2-3x risk increases across multiple organ systems suggests a broad teratogenic effect rather than a system-specific one.","specificNumbers":"36 studies, 230,816 birth defect cases, 18,049,013 controls. Cardiovascular: OR=2.35 (CI: 1.63-3.39). Gastrointestinal: OR=2.42 (CI: 1.61-3.64). CNS: OR=2.87 (CI: 1.51-5.46). Genitourinary: OR=2.39 (CI: 1.11-5.17). Any defects: OR=1.25 (CI: 1.12-1.41).","methodology":"Cumulative meta-analysis following a preregistered PROSPERO protocol. Searched seven databases through January 2024. Included 36 observational studies (18 case-control, 18 cohort) with 230,816 birth defect cases and 18,049,013 controls. Methodological quality assessed via Newcastle-Ottawa Scale. Subgroup, leave-one-out, and meta-regression analyses performed.","limitations":"Observational studies cannot prove causation. Cannabis use is typically self-reported and likely underestimated. Concurrent substance use (especially tobacco) is difficult to fully disentangle. Different studies measured cannabis exposure in different ways."},{"rthcId":"RTHC-05752","title":"Prenatal cannabis use and the risk of attention deficit hyperactivity disorder and autism spectrum disorder in offspring: A systematic review and meta-analysis.","authors":"Tadesse, Abay Woday; Dachew, Berihun Assefa; Ayano, Getinet; Betts, Kim; Alati, Rosa","year":2024,"journal":"Journal of psychiatric research, 171, 142-151","doi":"10.1016/j.jpsychires.2024.01.045","pmid":"38281464","tags":["pregnancy","youth","cognition"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Prenatal cannabis exposure was associated with increased ADHD symptoms (B=0.39, p=0.001) and a 30% higher risk of ASD (RR=1.30, p<0.05). Stratified analysis showed elevated ADHD symptom scores (B=0.54) and a marginally significant increase in diagnosed ADHD (RR=1.13, CI: 1.01-1.26) among exposed offspring.","whyItMatters":"ADHD and ASD are among the most common neurodevelopmental disorders, and identifying modifiable risk factors is a public health priority. This meta-analysis provides pooled evidence that prenatal cannabis exposure may be one such factor.","specificNumbers":"14 studies, 203,783 participants. ADHD symptoms: B=0.39 (CI: 0.20-0.58), I2=66.85%. ASD: RR=1.30 (CI: 1.03-1.64), I2=45.5%. ADHD symptom score in stratified analysis: B=0.54 (CI: 0.26-0.82). Diagnostic ADHD: RR=1.13 (CI: 1.01-1.26).","methodology":"Systematic review and meta-analysis with preregistered PROSPERO protocol. Searched PubMed/Medline, Scopus, EMBASE, Web of Science, PsycINFO, and Google Scholar. 14 primary studies included (10 on ADHD, 4 on ASD) with 203,783 total participants. Inverse variance weighted random effects model.","limitations":"Moderate heterogeneity for ADHD outcome (I2=66.85%). Only 4 studies on ASD limits that analysis. Underlying studies vary in how cannabis exposure was measured. Confounders including concurrent substance use and socioeconomic factors are variably controlled."},{"rthcId":"RTHC-05753","title":"Anti-inflammatory effects of phytocannabinoids and terpenes on inflamed Tregs and Th17 cells in vitro.","authors":"Tan, Kyle B C; Alexander, H Denis; Linden, James; Murray, Elaine K; Gibson, David S","year":2024,"journal":"Experimental and molecular pathology, 139, 104924","doi":"10.1016/j.yexmp.2024.104924","pmid":"39208564","tags":["inflammation","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In an initial blinded screen at 20uM, cannabigerol, caryophyllene oxide, and gamma-terpinene reduced cytotoxicity and expression of multiple inflammatory genes. THC suppressed T cell activation and reduced IL-6 and IL-10 secretion. In dose-response experiments, CBD significantly suppressed both Treg and Th17 cell activation at 50uM, with reduced IL-6 and IL-10 secretion.","whyItMatters":"This is the first evidence that CBD and THC suppress both pro-inflammatory (Th17) and anti-inflammatory (Treg) immune cell responses, suggesting cannabinoids have broad immunomodulatory effects rather than simply being \"anti-inflammatory.\"","specificNumbers":"Initial screen: 20uM of each compound. 6 healthy donors. CBG, caryophyllene oxide, gamma-terpinene: reduced IL6, IL10, TNF, TRPV1, CNR1, HTR1A, FOXP3, RORC, NFKB1 expression. CBD dose-response: suppressed Treg (p<0.05) and Th17 (p<0.05) activation. CBD 50uM: reduced IL-6 (p<0.01) and IL-10 (p<0.01).","methodology":"In vitro study using human PBMCs from 6 healthy donors, activated with CD3/CD28 and LPS. Cannabinoids and terpenes were coded to blind investigators. Flow cytometry measured Treg and Th17 responses. qRT-PCR measured gene expression. ELISA quantified cytokine secretion.","limitations":"In vitro study using isolated immune cells, which may not reflect immune responses in a whole organism. Concentrations tested (20-50uM) may not be achievable in vivo. Small number of donors (n=6). Only acute exposure tested."},{"rthcId":"RTHC-05754","title":"A study into the nature and extent of polydrug use in driving recidivism behavior.","authors":"Tassoni, Giovanna; Cippitelli, Marta; Scendoni, Roberto; Froldi, Rino; Buratti, Erika; Cerioni, Alice; Mietti, Gianmario; Cingolani, Mariano","year":2024,"journal":"Traffic injury prevention, 25(2), 110-115","doi":"10.1080/15389588.2023.2274273","pmid":"38165201","tags":["driving","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Polydrug use was a significant risk factor for driving recidivism compared to monodrug use (OR=1.99). Among polydrug combinations, only cocaine combined with cannabis was a significant risk factor (OR=1.65 vs cocaine alone, OR=1.30 vs cannabis alone). Recidivist polydrug users were younger than monodrug recidivists. Over time, nearly all polydrug users transitioned to monodrug use, primarily cocaine.","whyItMatters":"Understanding which drug combinations predict impaired driving recidivism can inform license reinstatement decisions and targeted interventions. The specific identification of cocaine-cannabis as a risk combination has practical implications for monitoring programs.","specificNumbers":"335 recidivists studied. Polydrug recidivism risk: OR=1.99. Cocaine-cannabis combination: OR=1.65 vs cocaine, OR=1.30 vs cannabis. 81% of recidivists were monodrug users, 19% polydrug. Young age and polydrug use: OR=2.012. Most polydrug users later converted to cocaine monodrug use.","methodology":"Retrospective analysis of hair samples collected over 7 years by an Italian local medical committee from drug-using drivers seeking license reinstatement. 335 recidivists were analyzed. Gas chromatography-mass spectrometry tested for cocaine, opiates, and cannabis. Logistic regression identified risk factors.","limitations":"Italian regulatory context may not generalize to other countries. Hair testing detects use over weeks/months, not at the time of driving. Selection bias: only captures people who sought license reinstatement. Cannot determine if drugs were used simultaneously or at different times."},{"rthcId":"RTHC-05755","title":"Prenatal broad-spectrum cannabidiol administration prevents an autism-like phenotype in male offspring from a maternal stress/terbutaline rat model.","authors":"Taylor, Jeremy A; Smith, Zachariah Z; Anderson, Michael E; Holbrook, Evan M; Elkinbard, Isabella S; Reuter, Jon D; Lowry, Christopher A; Barth, Daniel S","year":2024,"journal":"Brain, behavior, & immunity - health, 40, 100828","doi":"10.1016/j.bbih.2024.100828","pmid":"39170798","tags":["cbd","pregnancy","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Broad-spectrum CBD oil (10 mg/kg/day, THC-free) administered to pregnant rats during embryonic days 3-16 significantly reduced all three core ASD-related behavioral measures in male offspring from a neuroinflammation-based ASD model: decreased vocalizations when alone (social communication), fewer marbles buried (repetitive behavior), and increased time with a novel peer (social interaction).","whyItMatters":"ASD diagnosis has increased from 1 in 150 to 1 in 36 US children, and there are no approved prevention strategies. This study suggests prenatal CBD might prevent autism-like behaviors by counteracting neuroinflammation during fetal development, though this is very early-stage evidence.","specificNumbers":"CBD dose: 10 mg/kg/day IP, embryonic days 3-16. THC-free broad-spectrum CBD oil. Three behavioral measures improved: social communication, repetitive behavior, and social interaction. ASD prevalence: increased from 1 in 150 to 1 in 36.","methodology":"Neurodevelopmental rat model of ASD using stress and terbutaline exposure during pre- and postnatal development to induce neuroinflammation. Pregnant dams received daily IP injections of broad-spectrum CBD oil (10 mg/kg, THC-free) or vehicle during embryonic days 3-16. Male offspring were assessed on three behavioral measures corresponding to ASD core symptoms.","limitations":"Animal model that may not reflect human ASD etiology. Only male offspring tested. The neuroinflammation model (stress + terbutaline) may not represent the most common ASD risk pathways. IP administration does not reflect typical human use. No long-term follow-up of offspring."},{"rthcId":"RTHC-05756","title":"Effectiveness of a universal, school-based, online programme for the prevention of anxiety, depression, and substance misuse among adolescents in Australia: 72-month outcomes from a cluster-randomised controlled trial.","authors":"Teesson, Maree; Birrell, Louise; Slade, Tim; Mewton, Louise R; Olsen, Nick; Hides, Leanne; McBride, Nyanda; Chatterton, Mary Lou; Allsop, Steve; Furneaux-Bate, Ainsley; Bryant, Zachary; Ellem, Rhiannon; Baker, Megan J; Healy, Annalise; Debenham, Jennifer; Boyle, Julia; Mather, Marius; Mihalopoulos, Cathrine; Chapman, Catherine; Newton, Nicola C","year":2024,"journal":"The Lancet. Digital health, 6(5), e334-e344","doi":"10.1016/S2589-7500(24)00046-3","pmid":"38670742","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05757","title":"Comprehensive Assessment of Cannabidiol and HU308 in Acute and Chronic Colitis Models: Efficacy, Safety, and Mechanistic Innovations.","authors":"Thapa, Dinesh; Patil, Mohan; Warne, Leon N; Carlessi, Rodrigo; Falasca, Marco","year":2024,"journal":"Cells, 13(23)","doi":"10.3390/cells13232013","pmid":"39682761","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD at 60 mg/kg (but not lower doses) significantly reduced colitis symptoms, inflammation, cytokine levels, and MPO activity. HU308 achieved comparable effects at just 2.5 mg/kg. Both treatments normalized GLP-1 levels, a biomarker of gut endocrine function. HU308 showed no observable toxicity.","whyItMatters":"CBD is widely used for inflammatory bowel conditions, but effective doses are high. Finding that a selective CB2 agonist achieves the same result at 1/24th the dose suggests more targeted cannabinoid therapies could be both more effective and safer for colitis.","specificNumbers":"CBD effective dose: 60 mg/kg. HU308 effective dose: 2.5 mg/kg (24x lower). Both normalized DAI scores, colon inflammation, and GLP-1. DSS concentrations: 4% (acute), 1-2% (chronic). No toxicity observed with HU308.","methodology":"Mouse models of DSS-induced colitis mimicking acute (4% DSS) and chronic (1-2% DSS) ulcerative colitis. Mice treated with CBD at multiple doses or HU308. Disease activity index, colon inflammation, cytokines, MPO activity, ammonia levels, and GLP-1 expression were measured.","limitations":"Mouse colitis model may not fully represent human ulcerative colitis. HU308 is a synthetic compound not available as a consumer product. Only one dose of HU308 was tested. Long-term effects and safety in chronic dosing are unknown."},{"rthcId":"RTHC-05758","title":"Envisaging challenges for the emerging medicinal Cannabis sector in Lesotho.","authors":"Thetsane, Regina M","year":2024,"journal":"Journal of cannabis research, 6(1), 23","doi":"10.1186/s42238-024-00229-9","pmid":"38755701","tags":["legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Since licensing cannabis companies in 2017, Lesotho has faced challenges including long timeframes for finalizing regulatory frameworks, inconsistent application of laws, and failure to provide opportunities for small, medium, and micro enterprises (SMMEs). The sector that was intended to benefit from legalization has been largely excluded.","whyItMatters":"Lesotho was the first African country to license medicinal cannabis (2017), and its experience provides lessons for other African nations considering legalization. The finding that small enterprises were excluded mirrors equity concerns seen in North American legalization.","specificNumbers":"3 cannabis company managers interviewed. Lesotho has grown cannabis since approximately the 1550s. Licensed medicinal cannabis since 2017.","methodology":"Qualitative descriptive study using semi-structured interviews with three cannabis company managers in Lesotho, selected via snowball sampling. Interviews were transcribed verbatim and analyzed using thematic analysis.","limitations":"Very small sample (3 managers) limits the breadth of perspectives captured. Only company managers were interviewed, not small farmers, regulators, or community members. Single-country case study."},{"rthcId":"RTHC-05759","title":"Analysis of homemade cannabis edibles by UHPLC-HRMS after standard addition method.","authors":"Thiebot, Pauline; Magny, Romain; Langrand, Jérôme; Dufayet, Laurène; Houze, Pascal; Labat, Laurence","year":2024,"journal":"Journal of analytical toxicology, 48(5), 372-379","doi":"10.1093/jat/bkae014","pmid":"38407251","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05760","title":"Cannabis Vaping Is Associated With Past 30-Day Suicide Attempts and Suicidal Ideation Among Adolescents in a Psychiatric Inpatient Setting.","authors":"Thomas, Sarah A; Thompson, Elizabeth C; Maron, Micaela M; Meisel, Samuel N; Spirito, Anthony; Wolff, Jennifer C","year":2024,"journal":"JAACAP open, 2(4), 263-273","doi":"10.1016/j.jaacop.2024.03.003","pmid":"39697388","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Vaping as the most frequent cannabis method was associated with 2.38 times higher odds of past 30-day suicide attempt (p=0.002) and greater suicidal ideation. The suicide attempt association remained significant after controlling for depressive symptoms, impulse control, psychosocial impairment, and other substance use.","whyItMatters":"Cannabis vaping is rapidly increasing among adolescents, and this study suggests it may be a specific risk marker for suicidality in psychiatrically vulnerable youth, beyond what is explained by general cannabis use or other substance use.","specificNumbers":"470 adolescents. 26.8% had past 30-day suicide attempts. 44.3% ever used cannabis. 31.5% used cannabis in past 30 days. 30.8% of cannabis users primarily vaped. Vaping: AOR=2.38 for suicide attempts (p=0.002).","methodology":"Chart review of 470 adolescents (ages 11-18, 64% female) admitted to an inpatient psychiatric hospital between 2021-2023. Assessment battery measured cannabis use methods, psychiatric symptoms, and suicidal thoughts and behaviors. Logistic regression with adjustment for confounders.","limitations":"Cross-sectional design cannot determine causation. Inpatient psychiatric sample is not representative of all adolescents. Vaping cannabis users may differ from other cannabis users in unmeasured ways. Self-reported cannabis use methods."},{"rthcId":"RTHC-05761","title":"The impact of piperazine and antipsychotic co-exposures and CB1 blockade on the effects elicited by AMB-FUBINACA, a synthetic cannabinoid, in mice.","authors":"Thomsen, Lucy R; Glass, Michelle; Rosengren, Rhonda J","year":2024,"journal":"European journal of pharmacology, 979, 176844","doi":"10.1016/j.ejphar.2024.176844","pmid":"39053868","tags":["synthetic-cannabinoids"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AMB-FUBINACA induced dose-dependent hypothermia and convulsions that were reversible with the CB1 antagonist rimonabant, confirming CB1 dependence. Combining AMB-FUBINACA with pFPP (a party pill drug) significantly worsened hypothermia. Risperidone pre-treatment also potentiated hypothermia but provided significant protection from convulsions in female mice. Rimonabant was effective as both a pre- and post-treatment for AMB-FUBINACA toxicity.","whyItMatters":"Synthetic cannabinoids like AMB-FUBINACA have caused numerous fatalities. This study identifies drug interactions that worsen toxicity (pFPP) and potential rescue strategies (rimonabant), while the sex-specific protective effect of risperidone against convulsions has clinical implications.","specificNumbers":"AMB-FUBINACA: 3 and 6 mg/kg. pFPP: 10 and 20 mg/kg. Risperidone: 0.5 mg/kg. Rimonabant: 3 mg/kg. Rimonabant effective as both pre- and post-treatment. Risperidone protected from convulsions in females only.","methodology":"Male and female C57BL/6 mice received single IP doses of AMB-FUBINACA (3 or 6 mg/kg) alone or combined with pFPP (10 or 20 mg/kg) or risperidone (0.5 mg/kg). Rimonabant (3 mg/kg) was tested as both pre- and post-treatment. Hypothermia and convulsions were recorded.","limitations":"Mouse study; doses and drug interactions may differ in humans. Sex-specific effects of risperidone on convulsions were unexpected and need confirmation. Only one synthetic cannabinoid tested. IP administration does not reflect typical human routes."},{"rthcId":"RTHC-05762","title":"Feasibility of a cannabidiol-dominant cannabis-based medicinal product for the treatment of long COVID symptoms: A single-arm open-label feasibility trial.","authors":"Thurgur, Hannah; Lynskey, Michael; Schlag, Anne Katrin; Croser, Carol; Nutt, David John; Iveson, Elizabeth","year":2024,"journal":"British journal of clinical pharmacology, 90(4), 1081-1093","doi":"10.1111/bcp.15988","pmid":"38105651","tags":["cbd","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"All 12 participants adhered to the treatment protocol for the full 21 weeks with no serious adverse events. Response rates for research assessments exceeded 90%. The study demonstrated feasibility of CBD treatment in long COVID, but the open-label design without a control group means efficacy conclusions cannot be drawn.","whyItMatters":"Long COVID affects millions and has limited treatment options. This study establishes that CBD-dominant cannabis oil is feasible and safe to study in this population, paving the way for larger controlled trials. The high adherence rate is notable for a 21-week study.","specificNumbers":"12 participants (1 male, 11 female). CBD dose: up to 150 mg/day. Treatment: 21 weeks. 0 serious adverse events. Over 90% completion rate for outcome measures. 100% treatment adherence.","methodology":"Single-arm open-label feasibility trial. 12 adults with diagnosed long COVID received up to 3 mL/day of MediCabilis 5% CBD Oil (50 mg CBD/mL, <2 mg THC/mL) for 21 weeks, followed by 3 weeks without treatment. Monthly patient-reported outcomes and daily symptom self-reports were collected via smartphone app. Wearable technology tracked heart rate, activity, sleep, and oxygen saturation.","limitations":"Very small sample (n=12). No control group means no efficacy conclusions possible. Open-label design introduces placebo effects and expectancy bias. 11 of 12 participants were female, limiting generalizability. Recruitment challenges were noted."},{"rthcId":"RTHC-05763","title":"The impact of cannabis use disorder on urologic oncologic surgery morbidity, length of stay, and inpatient cost: analysis of the National Inpatient Sample from 2003 to 2014.","authors":"Tinsley, Shane A; Arora, Sohrab; Stephens, Alex; Finati, Marco; Chiarelli, Giuseppe; Cirulli, Giuseppe Ottone; Morrison, Chase; Richard, Caleb; Hares, Keinnan; Rogers, Craig G; Abdollah, Firas","year":2024,"journal":"World journal of urology, 42(1), 465","doi":"10.1007/s00345-024-05151-6","pmid":"39090376","tags":["addiction","cancer"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"CUD incidence rose from 51 to 383 per 100,000 admissions between 2003-2014. On multivariable analysis, CUD was not an independent predictor of major complications (p=0.6) but was independently associated with high length of stay (OR=1.31) and high inpatient cost (OR=1.33). CUD patients were significantly younger (median 37 vs 51 years) and had higher rates of opioid abuse.","whyItMatters":"The 7-fold increase in CUD prevalence among surgical oncology patients reflects broader trends in cannabis use. The finding that CUD increases hospital stays and costs without increasing complications suggests logistical or behavioral factors (not surgical risk) are driving the difference.","specificNumbers":"CUD incidence: 51/100,000 (2003) to 383/100,000 (2014). 1,612,743 patients. CUD median age: 37 vs 51 years. Complications: 32% vs 15% (unadjusted) but not significant on MVA. LOS: 3 vs 2 days (p<0.001). Cost: $15,609 vs $12,415. OR for high LOS: 1.31. OR for high cost: 1.33.","methodology":"Analysis of the National Inpatient Sample (2003-2014) including 1,612,743 patients undergoing prostatectomy, nephrectomy, or cystectomy. CUD identified via ICD-9 codes. Inverse probability treatment weighting balanced groups on demographics and comorbidities.","limitations":"ICD-9 codes for CUD likely undercount cannabis users. Administrative data cannot capture cannabis use that does not reach disorder-level diagnosis. Cannot determine if cannabis was used perioperatively. The dramatic age difference suggests fundamentally different patient populations."},{"rthcId":"RTHC-05764","title":"The impact of recreational cannabinoid legalization on utilization in a pregnant population.","authors":"Torres, Jacob; Miller, Colton; Apostol, Michael; Gross, Jessica; Maxwell, Jessie R","year":2024,"journal":"Frontiers in public health, 12, 1278834","doi":"10.3389/fpubh.2024.1278834","pmid":"38444440","tags":["pregnancy","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Reported prenatal cannabis use significantly decreased from 33.8% (Epoch 1: pre-legalization) to 22.8% (Epoch 2: post-legalization). The decrease likely reflects changes in screening practices, the COVID-19 pandemic, or delayed commercialization rather than actual decreased use. Regardless of epoch, infants exposed to cannabis had smaller birth weight, length, head circumference, and lower Apgar scores.","whyItMatters":"This is one of the first studies to examine how recreational legalization actually affected reported prenatal cannabis use. The counterintuitive decrease highlights the complexity of measuring cannabis use in pregnancy and the potential impact of policy changes on screening and disclosure.","specificNumbers":"Epoch 1: 403 cases out of 1,191 (33.8%). Epoch 2: 86 cases out of 378 (22.8%). Significant decrease post-legalization. PCE infants in both epochs: lower birth weight, length, head circumference, and Apgar scores at 1 and 5 minutes. More C-sections in PCE group.","methodology":"Retrospective cohort comparing two epochs at a New Mexico hospital: pre-legalization (Jan 2019-Mar 2021, n=1,191) and post-legalization (Nov 2021-Nov 2022, n=378). Cases identified by documented self-report or positive toxicology test. Birth outcomes compared between exposed and unexposed groups.","limitations":"Single hospital. Unequal epoch sizes (1,191 vs 378). COVID-19 pandemic overlapped with both epochs. Changes in screening practices were not tracked. Cannot distinguish between actual use changes and reporting/detection changes. Short post-legalization period."},{"rthcId":"RTHC-05765","title":"Patterns and determinants of cannabis use in youth visiting an urban emergency department in France.","authors":"Touali, Rdah; Chappuy, Mathieu; De Ternay, Julia; Berger-Vergiat, Aurélie; Haesebaert, Julie; Tazarourte, Karim; Michel, Philippe; Rolland, Benjamin","year":2024,"journal":"Journal of addictive diseases, 42(4), 491-499","doi":"10.1080/10550887.2023.2279474","pmid":"38048209","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 460 participants, 105 (22.8%) were in the cannabis use group. Cannabis users had higher odds of being male (aOR=1.85), unemployed (aOR=1.77), having lower mental health status (aOR=0.82 per unit), reporting sexual abuse history (aOR=2.99), and having positive alcohol screening (aOR=4.23).","whyItMatters":"Emergency departments serve as a critical touchpoint for young people who may not engage with traditional addiction or mental health services. Identifying the profile of young cannabis users in this setting can inform targeted screening and brief intervention strategies.","specificNumbers":"460 participants. 105 (22.8%) were cannabis users. Male: aOR=1.85. Unemployed: aOR=1.77. Sexual abuse history: aOR=2.99. Positive AUDIT screen: aOR=4.23. Lower mental health score: aOR=0.82.","methodology":"Cross-sectional study of young people aged 16-25 visiting a French urban emergency department for any reason over 5 months. Data included sociodemographics, self-administered substance use screening, and urine drug screening. Cannabis use defined as positive urine screen or self-reported past-month use.","limitations":"Single ER in France limits generalizability. Cross-sectional design cannot determine causation. Self-reported data alongside urine screening may miss some users. The specific reasons for ER visits were not analyzed."},{"rthcId":"RTHC-05766","title":"Extent and patterns of drug use in prison in Burkina Faso: findings from a cross-sectional study in central prison of Ouagadougou.","authors":"Traoré, Karim; Cissé, Kadari; Diendéré, Eric Arnaud; Damiba, Boukari; Dao, Ginette Laure; Dao, Abdoul Kader; Kaboré, Ahmed","year":2024,"journal":"International journal of prison health, 20(2), 128-142","doi":"10.1108/IJOPH-12-2022-0082","pmid":"38984606","tags":["addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis was the primary drug used by prisoners (71.1% of in-prison users), followed by tramadol (62.2%), diazepam (13.3%), and cocaine (2.2%). Of 45 inmates who used drugs in prison, 15 (33.3%) first started using drugs while incarcerated. Pre-prison drug use was the strongest predictor of in-prison use (aOR=4.01), along with younger age.","whyItMatters":"This is the first study of drug use in prison in Burkina Faso. The finding that one-third of in-prison drug users first tried drugs while incarcerated challenges the idea that prison prevents drug use and instead suggests it can serve as a site of drug initiation.","specificNumbers":"379 prisoners. 32.7% lifetime illicit drug use. 28.8% used drugs before incarceration. 11.9% used drugs in prison. 33.3% of in-prison users initiated in prison. Cannabis: 71.1% of in-prison users. Tramadol: 62.2%. Pre-prison use: aOR=4.01 for in-prison use.","methodology":"Cross-sectional study of 379 prisoners in Ouagadougou central prison, selected via systematic random sampling. Face-to-face interviews collected data on substance use before and during incarceration. Multivariable logistic regression identified factors associated with in-prison drug use.","limitations":"Face-to-face interviews in prison grounds may lead to underreporting due to fear of consequences. No biological testing to confirm self-reported use. Single prison in one city. Cross-sectional design cannot track changes over time."},{"rthcId":"RTHC-05767","title":"Clearing the air: Heightened perception of harm from secondhand cannabis smoke exposure is associated with no in-home cannabis smoking in a 21-country convenience sample.","authors":"Tripathi, Osika; Parada, Humberto; Liles, Sandy; Shi, Yuyan; Matt, Georg E; Quintana, Penelope J E; Ferris, Jason; Winstock, Adam; Bellettiere, John","year":2024,"journal":"Preventive medicine, 189, 108178","doi":"10.1016/j.ypmed.2024.108178","pmid":"39547285","tags":["respiratory","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Those at the 75th percentile (vs 25th) of perceived harm from secondhand cannabis smoke had 70% higher odds (OR=1.7) of reporting no in-home cannabis smoking. The association held across all 21 countries, with the strongest effects in Sweden (OR=3.9) and New Zealand (OR=2.3). Mean perceived harm was 5.2 on a 10-point scale. 61% reported no in-home cannabis smoking.","whyItMatters":"As cannabis legalization expands, most smoking occurs at home, exposing household members to secondhand smoke. If harm perception drives behavior change, public health campaigns emphasizing secondhand cannabis smoke risks could reduce residential exposure.","specificNumbers":"28,154 respondents from 21 countries. Mean harm perception: 5.2/10. 61% no in-home smoking. Overall OR=1.7. Sweden: OR=3.9. New Zealand: OR=2.3. Significant positive association in all countries.","methodology":"Cross-sectional analysis of 28,154 adult respondents from 21 countries in the 2021 Global Drug Survey. Logistic regression adjusted for covariates estimated the association between perceived harm of secondhand cannabis smoke exposure and reporting no in-home cannabis smoking in the past 30 days.","limitations":"Cross-sectional design cannot prove harm perception causes behavior change; people who do not smoke at home may simply rationalize it as being about harm. Convenience sample of Global Drug Survey respondents may not represent general cannabis users. Self-reported in-home smoking may be subject to social desirability bias."},{"rthcId":"RTHC-05768","title":"Perception of harm is strongly associated with complete ban on in-home cannabis smoking: a cross-sectional study.","authors":"Tripathi, Osika; Parada, Humberto; Shi, Yuyan; Matt, Georg E; Quintana, Penelope J E; Liles, Sandy; Bellettiere, John","year":2024,"journal":"BMC public health, 24(1), 669","doi":"10.1186/s12889-024-18072-1","pmid":"38429696","tags":["respiratory","harm-reduction","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Those who perceived secondhand cannabis smoke as \"extremely harmful\" had 6x higher odds of a complete home smoking ban (OR=6.0) compared to those rating it \"totally safe.\" Even moderate harm perception (\"somewhat harmful\") was associated with 2.6x higher odds of a ban. Despite this, nearly 29% of Americans rated secondhand cannabis smoke as at least \"mostly safe.\"","whyItMatters":"With 72% of respondents reporting a complete home ban, indoor cannabis smoking norms are already shifting. But nearly 29% thinking it is at least \"mostly safe\" represents a large population that could be reached with public health messaging to reduce residential secondhand exposure.","specificNumbers":"21,381 adults. 71.8% had complete home ban. 33.0% rated cSHS \"extremely harmful,\" 38.3% \"somewhat harmful,\" 20.5% \"mostly safe,\" 8.0% \"totally safe.\" Extremely harmful vs totally safe: OR=6.0 (CI: 4.9-7.2). Somewhat harmful: OR=2.6. Mostly safe: OR=1.4.","methodology":"Cross-sectional survey of 21,381 US adults from the Marijuana Use and Environmental Survey (Dec 2019-Feb 2020). Logistic regression estimated associations between perceived harm levels and complete home smoking bans, with stratification by smoking status, state legalization, and presence of young children.","limitations":"Cross-sectional design cannot prove perception causes ban adoption. Self-reported home bans may not reflect actual behavior. Survey conducted before COVID-19 may not reflect current patterns. Convenience of the survey platform may introduce selection bias."},{"rthcId":"RTHC-05769","title":"In-Home Cannabis Smoking Among a Cannabis-Using Convenience Sample from the Global Drug Survey: With Weighted Estimates for U.S. Respondents.","authors":"Tripathi, Osika; Posis, Alexander Ivan B; Thompson, Caroline A; Ferris, Jason; Anuskiewicz, Blake; Nguyen, Benjamin; Liles, Sandy; Berardi, Vincent; Zhu, Shu-Hong; Winstock, Adam; Bellettiere, John","year":2024,"journal":"Cannabis and cannabinoid research, 9(1), 353-362","doi":"10.1089/can.2022.0139","pmid":"36318789","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among international cannabis users, any in-home smoking was reported by 63.9% of men, 61.9% of women, and 68.6% of nonbinary people. Daily in-home smoking was highest among nonbinary respondents (28.7%) and those 35+ years old (28.0%). US-specific weighted estimates showed any in-home smoking at 49.8% for males and 61.2% for females, with daily rates of 23.2% and 37.1% respectively.","whyItMatters":"In-home cannabis smoking exposes household members to secondhand and thirdhand smoke. With the number of cannabis users increasing due to legalization, and criminal stigma driving use indoors, residential exposure is a growing public health concern.","specificNumbers":"International: 63,797 respondents. 63.9% of male, 61.9% of female, 68.6% of nonbinary users smoked at home. Daily in-home: 28.7% nonbinary, 28.0% age 35+. US weighted: any in-home 49.8% male/61.2% female. Daily: 23.2% male/37.1% female.","methodology":"Cross-sectional analysis of 63,797 international cannabis users from the 2020 Global Drug Survey (Nov 2019-Jan 2020). US respondents (n=6,580) were weighted to the nationally representative NSDUH cannabis-using population using inverse odds probability weighting.","limitations":"Global Drug Survey is a convenience sample that overrepresents engaged drug users. Self-reported in-home smoking may underestimate actual behavior. Weighting corrects for some selection bias in US data but cannot fully address it."},{"rthcId":"RTHC-05770","title":"The Role of Cannabis in the Development of Psychosis.","authors":"Türkoğlu, Özge; Ertuğrul, Aygün","year":2024,"journal":"Turk psikiyatri dergisi = Turkish journal of psychiatry, 35(3), 234-244","doi":"10.5080/u27122","pmid":"39224996","tags":["psychosis","neuroscience","youth"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Earlier age of cannabis use onset, genetic predisposition, and heavy/high-potency use all independently increase psychosis risk. The mechanism involves the endocannabinoid system, which regulates synaptic pruning during adolescence. Cannabis disrupts this process and alters glutamate and dopamine neurotransmission. Pre-existing endocannabinoid system dysfunction in people with schizophrenia vulnerability is further worsened by cannabis.","whyItMatters":"Understanding the biological mechanism by which cannabis triggers psychosis (not just the epidemiological association) is essential for identifying who is most at risk and developing prevention strategies. The endocannabinoid system disruption model provides that mechanistic link.","specificNumbers":"Reviewed 10 years of literature. Key risk factors: early age of use, genetic predisposition, heavy use, high-potency cannabis. Mechanisms: disrupted synaptic pruning, altered dopamine and glutamate signaling, worsened endocannabinoid system dysfunction.","methodology":"Narrative review of PubMed literature from the past 10 years using keywords \"cannabis use, psychosis, schizophrenia, endocannabinoid system, pathophysiology, neurobiology.\"","limitations":"Narrative review without systematic methodology. Much of the mechanistic evidence comes from animal studies that may not fully translate to humans. The review focuses on risk but does not quantify absolute risk levels."},{"rthcId":"RTHC-05771","title":"Real-Life Experience With Purified Cannabidiol Treatment for Refractory Epilepsy: A Multicenter Retrospective Study.","authors":"Tzadok, Michal; Gur-Pollack, Rotem; Florh, Hadar; Michaeli, Yael; Gilboa, Tal; Lezinger, Mirit; Heyman, Eli; Chernuha, Veronika; Gudis, Irina; Nissenkorn, Andreea; Lerman-Sagie, Tally; Ben Zeev, Bruria; Uliel-Sibony, Shimrit","year":2024,"journal":"Pediatric neurology, 150, 91-96","doi":"10.1016/j.pediatrneurol.2023.10.012","pmid":"37995414","tags":["epilepsy","cbd","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"92.2% of patients had reduced seizure frequency after starting purified CBD. 41.1% achieved >50% reduction. 38.1% had additional positive effects including improved alertness (31.7%), improved speech (10.1%), and new developmental milestones (2.2%). Prior success with CBD oils, especially >50% reduction, strongly predicted purified CBD response. Common adverse events were irritability (20.9%) and drowsiness (12.9%).","whyItMatters":"This real-world evidence from 5 medical centers confirms the clinical trial findings for purified CBD in a broader, more diverse patient population. The finding that prior CBD oil response predicts purified CBD response is clinically useful for treatment planning.","specificNumbers":"139 patients. Median age 12 years. LGS 37.4%, Dravet 16.5%, TSC 16.5%. Median dose 12.5 mg/kg (range 2.5-20). Median treatment 9 months. 92.2% seizure reduction. 41.1% >50% reduction. Adverse: irritability 20.9%, drowsiness 12.9%.","methodology":"Retrospective multicenter analysis of 139 children and young adults (54.7% female, median age 12.0 years) with drug-resistant epilepsy treated with purified CBD at five Israeli medical centers from 2018-2022. Median dose 12.5 mg/kg, median duration 9 months.","limitations":"Retrospective design with potential selection bias. No control group. Seizure frequency was clinically assessed, not by EEG monitoring. Some patients may have had concurrent medication changes. Cannot determine the contribution of placebo effect."},{"rthcId":"RTHC-05772","title":"Medical cannabis use in oncology and associated outcomes: A scoping review.","authors":"Valente, Ana Carolina; Lopes, Luis Phillipe Nagem; Matheus, Maria Eline","year":2024,"journal":"Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 30(4), 737-751","doi":"10.1177/10781552241239006","pmid":"38477532","tags":["cancer","medical-cannabis"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Of 35 studies (29 randomized, 6 non-randomized), 77.1% evaluated cannabinoids for nausea and vomiting, 11.4% for appetite, 8.6% for pain, and 2.9% for tumor regression. THC was the most studied natural cannabinoid. About 57% used registered pharmaceutical products. Only one study detailed cancer staging, highlighting a gap in the literature.","whyItMatters":"Despite widespread use of cannabis by cancer patients, the evidence base is heavily skewed toward nausea/vomiting. Pain and appetite, which are among the most common reasons patients use cannabis, have far less rigorous evidence supporting their use.","specificNumbers":"35 studies (29 RCTs, 6 non-randomized). Nausea/vomiting: 77.1%. Appetite: 11.4%. Pain: 8.6%. Tumor regression: 2.9%. THC most studied. 57.1% used registered products. 62.9% specified cancer types (breast, lung, sarcomas, hematological, reproductive).","methodology":"Scoping review following JBI guidelines. Searched Cochrane, Embase, CINAHL, PubMed, LILACS, Google Scholar, and gray literature. Included primary studies (observational and randomized) evaluating cannabinoid efficacy and safety in cancer patients.","limitations":"Scoping review maps the literature but does not assess quality or pool results. Study heterogeneity in doses, formulations, and cancer types limits comparisons. Only one study addressed cancer staging, making dose-response analysis across disease severity impossible."},{"rthcId":"RTHC-05773","title":"Cannabis and Cannabinoid Signaling: Research Gaps and Opportunities.","authors":"Valentino, Rita J; Volkow, Nora D","year":2024,"journal":"The Journal of pharmacology and experimental therapeutics, 391(2), 154-158","doi":"10.1124/jpet.124.002331","pmid":"39060161","tags":["neuroscience","addiction","youth"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Despite decades of cannabis pharmacology research, major knowledge gaps remain in: (1) enduring consequences of cannabis exposure during critical brain development windows, (2) effects of large daily doses of high-THC cannabis, (3) therapeutic opportunities from endocannabinoid system manipulation, and (4) strategies to treat cannabis use disorder and cannabis toxicity.","whyItMatters":"Coming from the leadership of the US federal agency responsible for drug abuse research, this article sets the agenda for future cannabis science. The identified gaps have direct implications for funding priorities and policy decisions.","specificNumbers":"Cannabis legalization has expanded use across all US demographics except adolescents. Multiple targets identified for endocannabinoid system manipulation. Research gaps span developmental neuroscience, high-dose effects, therapeutics, and treatment.","methodology":"Perspective article from the Director and Deputy Director of the National Institute on Drug Abuse, highlighting research priorities and knowledge gaps in cannabis and cannabinoid signaling research.","limitations":"This is a perspective piece, not a systematic review. Reflects the priorities and viewpoint of US federal drug research leadership, which may not fully represent all stakeholder perspectives."},{"rthcId":"RTHC-05774","title":"Sex-specific maladaptive responses to acute stress upon in utero THC exposure are mediated by dopamine.","authors":"Valeria, Serra; Francesco, Traccis; Sonia, Aroni; Laura, Vidal Palencia; Luca, Concas; Marcello, Serra; Roberta, Leone; Patrizia, Porcu; Arnau, Busquets Garcia; Roberto, Frau; Miriam, Melis","year":2024,"journal":"Pharmacological research, 210, 107536","doi":"10.1016/j.phrs.2024.107536","pmid":"39622370","tags":["pregnancy","neuroscience","dopamine","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Only male offspring prenatally exposed to THC showed a compromised balance of stress hormone receptors (mineralocorticoid and glucocorticoid) in the ventral tegmental area, alongside stress-induced disruption of sensorimotor gating (PPI). VTA dopamine neuron activity was causally linked to PPI deterioration. A GSK-3B signaling intervention during postnatal development corrected these sex-specific, dopamine-dependent deficits.","whyItMatters":"This study identifies a specific biological pathway by which prenatal THC creates vulnerability to stress in male offspring: disrupted stress hormone receptors leading to dopamine dysregulation. The finding that this is correctable during development opens a potential intervention window.","specificNumbers":"Sex-specific effects in males only. Altered MR/GR receptor balance in VTA. Stress-induced PPI impairment in males. VTA dopamine causally linked to PPI. GSK-3B intervention corrected PPI deficits during postnatal development.","methodology":"Rat model of prenatal cannabinoid exposure. Pregnant dams received THC, and male and female offspring were assessed for HPA axis gene expression, VTA dopamine neuron activity, and sensorimotor gating (PPI) under acute stress. Pharmacological rescue with GSK-3B manipulation was tested during postnatal development.","limitations":"Rat model may not directly translate to human brain development. Only acute stress was tested. The GSK-3B intervention is a pharmacological tool, not a practical clinical treatment. Dose and timing of prenatal THC may differ from human exposure patterns."},{"rthcId":"RTHC-05775","title":"Cannabis Use Variations and Myocardial Infarction: A Systematic Review.","authors":"van Amsterdam, Jan; van den Brink, Wim","year":2024,"journal":"Journal of clinical medicine, 13(18)","doi":"10.3390/jcm13185620","pmid":"39337107","tags":["cardiovascular"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"After adjusting for tobacco use, cannabis smoking remained significantly associated with heart attack, with adjusted odds ratios from 1.03 to 5.24, particularly high in younger age groups. Among never-tobacco smokers, frequent cannabis smoking still increased MI risk (aOR=1.88). Non-smoked cannabis (primarily ingestion) was not associated with significant MI risk (aOR=1.00 for frequent use, aOR=1.31 ns for current use).","whyItMatters":"This is the first systematic review to distinguish between cannabis smoking and non-smoked cannabis for heart attack risk. The finding that the route of administration matters has major implications: the cardiac risk may be from combustion-related toxins (like carbon monoxide) rather than cannabinoids themselves.","specificNumbers":"22 studies reviewed. Cannabis smoking aORs: 1.03-5.24. In never-tobacco smokers: aOR=1.88 for frequent cannabis smoking. Non-smoked cannabis frequent use: aOR=1.00 (not significant). Non-smoked current use: aOR=1.31 (not significant).","methodology":"Systematic review following PRISMA guidelines, searching PubMed, Embase, and Google Scholar. 22 eligible studies identified examining cannabis use variations and myocardial infarction risk.","limitations":"Relatively few studies examined non-smoked cannabis specifically, limiting those conclusions. Most non-smoked use was edibles; vaping data was sparse. Residual confounding from polysubstance use, lifestyle factors, and socioeconomic status cannot be fully excluded."},{"rthcId":"RTHC-05776","title":"Cannabis combined with oxycodone for pain relief in fibromyalgia pain: a randomized clinical self-titration trial with focus on adverse events.","authors":"van Dam, Cornelis Jan; Kramers, Cornelis; Schellekens, Arnt; Bouvy, Marcel; van Dorp, Eveline; Kowal, Mikael A; Olofsen, Erik; Dahan, Albert; Niesters, Marieke; van Velzen, Monique","year":2024,"journal":"Frontiers in pain research (Lausanne, Switzerland), 5, 1497111","doi":"10.3389/fpain.2024.1497111","pmid":"39654798","tags":["pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"The combination of cannabis and oxycodone reduced opioid tablet consumption by 35% (p=0.02) but did not reduce adverse effects or improve pain relief compared to either treatment alone. One-third (31%) of cannabis-treated patients withdrew within 2-3 weeks due to severity of adverse effects, compared to 13% in the oxycodone-only group. Only 50% of patients experienced any pain reduction, and only 20% had meaningful (2+ point) relief.","whyItMatters":"This is one of the first RCTs to directly test the popular belief that cannabis can reduce opioid use in chronic pain. While it did reduce pill consumption, the overall drug burden was higher in the combination group, and cannabis was poorly tolerated.","specificNumbers":"81 patients randomized. Dropouts: 13% oxycodone, 31% cannabis groups. No difference in adverse event scores (p=0.70). Combination reduced opioid intake by 35% (p=0.02). 50% had any pain reduction. 20% had meaningful reduction. Cannabis: 6.3% THC, 8% CBD.","methodology":"Open-label randomized trial of fibromyalgia patients: 23 received oxycodone alone (5mg tablets, max 4x/day), 29 received inhaled cannabis (150mg, 6.3% THC/8% CBD, max 3 sessions/day), and 29 received the combination, for 6 weeks. Primary endpoint was composite adverse event score.","limitations":"Open-label design introduces expectancy effects. Small sample sizes per group. Six-week duration may be too short for full adaptation. The specific cannabis formulation (higher CBD than THC) may have contributed to the tolerability issues."},{"rthcId":"RTHC-05777","title":"Cannabis use Disorder and Complications After Anterior Cervical Diskectomy and Fusion.","authors":"Van Halm-Lutterodt, Nicholas; Albright, J Alex; Storlie, Nicholas Robert; Mesregah, Mohamed Kamal; Ansari, Kashif; Balmaceno-Criss, Mariah; Daher, Mohammad; Bartels-Mensah, Mercy; Xu, Yulun; Diebo, Bassel G; Hai, Yong; Chandler, David Ray; Daniels, Alan H","year":2024,"journal":"World neurosurgery, 181, e1001-e1011","doi":"10.1016/j.wneu.2023.11.028","pmid":"37956902","tags":["addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After propensity matching 838 CUD patients to 838 controls, CUD was associated with increased 90-day readmission (OR=2.64, p=0.027) and 1-year revision surgery (OR=3.36, p=0.049). Paradoxically, CUD was associated with reduced overall medical complications at 6 months (OR=0.55, p=0.021) and 1 year (OR=0.54, p=0.015), including fewer cardiac arrhythmias and acute renal failure.","whyItMatters":"The mixed results challenge simple narratives about cannabis and surgery. While CUD increases the need for repeat surgery and readmission, the reduced medical complications suggest potential protective effects or simply that these younger patients are otherwise healthier.","specificNumbers":"838 matched pairs. 90-day readmission: OR=2.64 (p=0.027). 1-year revision: OR=3.36 (p=0.049). 6-month overall complications: OR=0.55 (p=0.021). 1-year complications: OR=0.54 (p=0.015). Reduced cardiac arrhythmias and acute renal failure in CUD group.","methodology":"Retrospective database analysis of the PearlDiver Database (Jan 2010-Dec 2021) for patients undergoing primary 1-2 level ACDF surgery. Patients with CUD diagnosis 6 months pre-surgery were propensity matched 1:1 to controls on age, gender, and Charlson Comorbidity Index.","limitations":"Database study using ICD codes for CUD, which underestimates cannabis use. Propensity matching may not capture all confounders. Cannot determine whether cannabis was actively used perioperatively. The paradoxical complication finding may reflect confounding by age and overall health."},{"rthcId":"RTHC-05778","title":"A feasibility study to assess the recruitment and retention of pregnant patients who regularly use cannabis.","authors":"Vanderziel, Alyssa; Maslovich, Mark M; Alshaarawy, Omayma","year":2024,"journal":"BMC research notes, 17(1), 177","doi":"10.1186/s13104-024-06826-4","pmid":"38918795","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05779","title":"Gestational exposure to cannabidiol leads to glucose intolerance in 3-month-old male offspring.","authors":"Vanin, Sebastian R; Lee, Kendrick; Nashed, Mina; Tse, Brennan; Sarikahya, Mohammed; Brar, Sukham; Tomy, Gregg; Lucas, Amica-Mariae; Tomy, Thane; Laviolette, Steven R; Arany, Edith J; Hardy, Daniel B","year":2024,"journal":"The Journal of endocrinology, 260(1)","doi":"10.1530/JOE-23-0173","pmid":"37855335","tags":["cbd","pregnancy"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Daily prenatal CBD (3 mg/kg from gestational day 6 to birth) produced no observable changes in maternal or neonatal outcomes. However, by 3 months, male offspring exhibited glucose intolerance despite no changes in pancreatic cell mass. Liver transcriptomic analysis revealed altered circadian rhythm clock machinery gene expression and disrupted hepatic developmental and metabolic processes.","whyItMatters":"CBD is increasingly used during pregnancy, perceived as safe because it is non-psychoactive. This study reveals that prenatal CBD, even at modest doses, can have delayed metabolic consequences that are not apparent at birth but emerge in adulthood.","specificNumbers":"CBD dose: 3 mg/kg/day. GD 6 to parturition. No neonatal changes observed. Male-specific glucose intolerance at 3 months. Altered circadian clock genes in liver. Disrupted hepatic developmental and metabolic gene expression.","methodology":"Pregnant Wistar rat dams received daily IP injections of vehicle or 3 mg/kg CBD from gestational day 6 to parturition. Offspring were assessed for glucose tolerance, pancreatic cell mass, and liver transcriptomics at 3 months.","limitations":"Rat study with IP administration that does not reflect typical human oral CBD use. Only one dose tested. Only male offspring affected. Three-month follow-up in rats does not capture lifetime metabolic consequences. Unclear if this dose is comparable to human CBD use."},{"rthcId":"RTHC-05780","title":"Patterns of substance use and initiation timing in adults with substance abuse: a comparison between those with and without attention deficit hyperactivity disorder.","authors":"Vaziri-Harami, Roya; Khademi, Mojgan; Zolfaghari, Anahita; Vaziri-Harami, Saharnaz","year":2024,"journal":"Annals of medicine and surgery (2012), 86(8), 4397-4401","doi":"10.1097/MS9.0000000000002272","pmid":"39118714","tags":["addiction","youth","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The ADHD group had a lower age of onset for substance use. ADHD individuals had higher rates of alcohol, cannabis, methamphetamine, and tramadol use, while the non-ADHD group had higher rates of Ritalin, methadone, ecstasy, morphine, and hypnotics. The pattern suggests ADHD is associated with earlier initiation and preference for stimulating and cannabis-type substances.","whyItMatters":"The lower age of onset in ADHD has clinical implications: earlier substance initiation is associated with worse long-term outcomes. Identifying ADHD in young people could provide a window for preventive intervention before substance use begins.","specificNumbers":"50 ADHD, 90 non-ADHD. ADHD group: higher alcohol, cannabis, methamphetamine, tramadol. Non-ADHD: higher Ritalin, methadone, ecstasy, morphine, hypnotics. ADHD group started substances earlier.","methodology":"Longitudinal study of 140 adults (50 with ADHD, 90 without) with substance use disorder in addiction detention in Tehran (2021-2022). ADHD diagnosed via SCID and Conner's questionnaire. Onset age and patterns of 10 substances compared.","limitations":"Study conducted in addiction detention, limiting generalizability. Small ADHD sample (n=50). Cross-sectional assessment of retrospectively reported onset ages introduces recall bias. Iranian cultural context may differ from other countries."},{"rthcId":"RTHC-05781","title":"Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference.","authors":"Velayudhan, Latha; Pisani, Sara; Dugonjic, Marta; McGoohan, Katie; Bhattacharyya, Sagnik","year":2024,"journal":"Age and ageing, 53(11)","doi":"10.1093/ageing/afae261","pmid":"39602500","tags":["seniors","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"THC alone and THC:CBD combinations significantly increased all-cause and treatment-related adverse events compared to controls. However, serious adverse events, study withdrawals, and deaths were not significantly increased. THC dose-dependently increased dry mouth, dizziness, balance problems, dissociative/thinking issues, and drowsiness. The interaction of THC:CBD doses influenced neurological, psychiatric, and cardiac side effects.","whyItMatters":"Older adults are the fastest-growing demographic of cannabinoid medicine users, yet most safety data comes from younger populations. This meta-analysis specifically addresses the 50+ age group, providing age-appropriate safety data for clinical decision-making.","specificNumbers":"58 RCTs, 6,611 participants, mean age 50-87. THC alone IRD for all AEs: 18.83 (CI: 1.47-55.79). THC:CBD IRD: 19.37 (CI: 4.24-45.47). No significant increase in serious AEs, withdrawals, or deaths. Dose-dependent: dry mouth, dizziness, balance, dissociative symptoms, drowsiness.","methodology":"Systematic review and meta-analysis of 58 RCTs (37 moderate-high quality) with pooled n=6,611 participants (mean age 50-87 years, 50% male, 3,450 receiving CBMs). Searched 7 databases from 1990-2023. Estimated incidence rate differences under random-effects model.","limitations":"RCT populations may be healthier than real-world older cannabis users. Most trials were relatively short-term. The wide confidence intervals for some outcomes reflect heterogeneity. CBD-only medicines were not separately analyzed in the abstract."},{"rthcId":"RTHC-05782","title":"Effectiveness of the Minder Mobile Mental Health and Substance Use Intervention for University Students: Randomized Controlled Trial.","authors":"Vereschagin, Melissa; Wang, Angel Y; Richardson, Chris G; Xie, Hui; Munthali, Richard J; Hudec, Kristen L; Leung, Calista; Wojcik, Katharine D; Munro, Lonna; Halli, Priyanka; Kessler, Ronald C; Vigo, Daniel V","year":2024,"journal":"Journal of medical Internet research, 26, e54287","doi":"10.2196/54287","pmid":"38536225","tags":["youth","mental-health","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"The Minder app produced significant reductions in anxiety (GAD-7: d=-0.17, p<0.001) and depression (PHQ-9: d=-0.11, p=0.007). Statistically significant reductions were also found for cannabis use frequency and typical alcohol consumption. 77.1% of intervention participants accessed at least one app component. Retention was high: 79% intervention and 83% control completed follow-up.","whyItMatters":"University students face high rates of mental health and substance use challenges but rarely seek formal treatment. A scalable digital intervention that addresses both simultaneously could be integrated into existing university systems to reach students who would not otherwise get help.","specificNumbers":"1,489 students. Anxiety: d=-0.17, p<0.001. Depression: d=-0.11, p=0.007. Significant reductions in cannabis use frequency and typical drinks. 77.1% app engagement. 79% retention. Alcohol AUDIT-C reduction not significant (p=0.23).","methodology":"Two-arm parallel-assignment single-blinded 30-day RCT. 1,489 university students randomized to Minder app (n=743) or waitlist control (n=746). App delivered evidence-based content via chatbot, connected users with services, and provided peer coaching. ITT analysis with generalized linear mixed-effects models.","limitations":"Small effect sizes (d=-0.11 to -0.17). Waitlist control does not control for attention/expectation effects. 30-day follow-up is short. Cannabis and alcohol use were secondary outcomes. Self-reported outcomes."},{"rthcId":"RTHC-05783","title":"A systematic review of evidence on integrated management of psychiatric disorders in youth who use cannabis.","authors":"Vidal, Carol; Simon, Kevin M; Brooks, Caroline; White, Jacob; Hinckley, Jesse D","year":2024,"journal":"Drug and alcohol dependence reports, 10, 100216","doi":"10.1016/j.dadr.2023.100216","pmid":"38288007","tags":["youth","mental-health","addiction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 989 studies screened, only 5 RCTs met all criteria for integrated treatment of psychiatric disorders in cannabis-using youth. These covered depression (2 studies), bipolar disorder (1), anxiety (1), and PTSD (1). None were rated as high risk of bias. The extreme paucity of studies limits the ability to make evidence-based treatment recommendations.","whyItMatters":"Cannabis use in youth with psychiatric disorders is common and rising with legalization. Yet clinicians have almost no evidence to guide integrated treatment. This gap is dangerous because treating either condition in isolation may be less effective than addressing both simultaneously.","specificNumbers":"989 studies screened. 35 full-text reviewed. 5 RCTs met all criteria. Conditions covered: depression (2), bipolar (1), anxiety (1), PTSD (1). No high risk of bias studies.","methodology":"Systematic review screening 989 studies with dual independent reviewers. Inclusion required randomized controlled trials of therapeutic interventions in adolescents/young adults with both common psychiatric disorders and regular cannabis use. 35 full-text articles reviewed, 5 met all criteria.","limitations":"The review itself is limited by the paucity of available evidence. The 5 included studies may have been too heterogeneous to compare meaningfully. Only RCTs were included; observational treatment studies were excluded."},{"rthcId":"RTHC-05784","title":"Perception of pregnant individuals, health providers and decision makers on interventions to cease substance consumption during pregnancy: a qualitative study.","authors":"Vila-Farinas, Andrea; Pérez-Ríos, Mónica; Montes-Martínez, Agustín; Ahluwalia, Jasjit S-; Mourino, Nerea; Rey-Brandariz, Julia; Triñanes-Pego, Yolanda; Candal-Pedreira, Cristina; Ruano-Ravina, Alberto; Gómez-Salgado, Patricia; Miguez-Varela, Carmen; Tajes-Alonso, María; Loureiro-Fuentes, Isabel; Riesgo-Martín, Juan; Valverde-Trillo, Araceli; Fernández-Lema, Isabel; Rey-Arijón, Mercedes; Freiría-Somoza, Isabel; Rodríguez-Pampín, María; Varela-Lema, Leonor","year":2024,"journal":"BMC public health, 24(1), 990","doi":"10.1186/s12889-024-18397-x","pmid":"38594646","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05785","title":"Associations of cannabis use, use frequency, and cannabis use disorder with violent behavior among young adults in the United States.","authors":"Volkow, Nora D; Compton, Wilson M; Blanco, Carlos; Einstein, Emily B; Han, Beth","year":2024,"journal":"The International journal on drug policy, 128, 104431","doi":"10.1016/j.drugpo.2024.104431","pmid":"38677161","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"For males, only daily cannabis use (with or without CUD) was associated with violent behavior (adjusted PRs: 1.7-1.8). For females, cannabis use at any frequency and CUD status was associated with violent behavior (adjusted PRs: 1.6-2.4). The sex-specific patterns suggest different pathways linking cannabis to violent behavior in men and women.","whyItMatters":"Young adults commit 52% of violent crimes but are only 23% of the population. Understanding how cannabis use intersects with violence risk in this demographic has direct implications for prevention and risk assessment.","specificNumbers":"113,454 participants aged 18-34. 28.9% past-year cannabis use. Males: daily use without CUD PR=1.7, daily with CUD PR=1.8 (vs no use baseline 1.7%). Females: any cannabis use PR=1.6-2.4 (vs no use baseline 1.0%).","methodology":"Analysis of 113,454 participants aged 18-34 from the 2015-2019 National Surveys on Drug Use and Health. Cannabis use (daily/non-daily, with/without CUD by DSM-IV) and violent behavior (attacking someone with intent to seriously harm) were assessed. Multivariable logistic regression with sex stratification.","limitations":"Cross-sectional design cannot determine directionality. Violent behavior may lead to cannabis use rather than vice versa. Self-reported measures may underestimate both cannabis use and violent behavior. Cannot control for all confounders."},{"rthcId":"RTHC-05786","title":"Birth outcomes following in utero co-exposure to tobacco and marijuana.","authors":"Waddell, Madison L; Dickson, Samantha A; Dodge, Phoebe A; Kopkau, Haley E; Nadolski, Katherine N; Zablocki, Victoria; Forrestal, Kaya M; Bailey, Beth A","year":2024,"journal":"Birth defects research, 116(1), e2272","doi":"10.1002/bdr2.2272","pmid":"37947014","tags":["pregnancy"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"There were no significant differences in any birth outcome (APGAR scores, respiratory distress, NICU admission, growth restriction, birth weight, length, head circumference, gestational age, hospital stay) between tobacco-only users (n=71) and tobacco-plus-marijuana users (n=127). However, rates of adverse outcomes were high in both groups compared to expected rates in unexposed pregnancies.","whyItMatters":"Many pregnant women who use tobacco also use marijuana. This study suggests that in the context of tobacco use, marijuana does not add measurable risk, implying that tobacco may be the primary driver of the adverse birth outcomes seen in polysubstance-using pregnancies.","specificNumbers":"71 tobacco-only, 127 tobacco + marijuana. No significant differences in: APGAR scores, respiratory distress, NICU admission, growth restriction, birth weight, birth length, head circumference, gestational age, or hospital stay.","methodology":"Retrospective chart review of pregnant women identified via self-report or biochemical testing who used tobacco alone (n=71) or tobacco and marijuana simultaneously (n=127) at any point during pregnancy. Outcomes compared using linear regression and odds ratio analysis.","limitations":"Small sample sizes limit statistical power to detect small differences. Retrospective design with chart review. Self-report and biochemical testing may not capture all exposure. No unexposed comparison group. Cannot determine dose, frequency, or timing of either substance."},{"rthcId":"RTHC-05787","title":"Investigating sex differences and age of onset in emotion regulation, executive functioning, and cannabis use in adolescents and young adults.","authors":"Wade, Natasha E; Courtney, Kelly E; Wallace, Alexander L; Hatz, Laura; Jacobus, Joanna","year":2024,"journal":"Journal of cannabis research, 6(1), 20","doi":"10.1186/s42238-024-00225-z","pmid":"38671541","tags":["cognition","youth","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Greater past 6-month cannabis use was associated with poorer Emotional Stroop Congruent Accuracy (p=0.0004) and List Sorting Working Memory performance (p=0.02, marginally significant after correction). Younger age of regular use onset was modestly related to lower Stroop accuracy (p=0.03, marginally significant). No cannabis-by-sex interactions were found.","whyItMatters":"The small but significant effects on processing speed and working memory add to the literature on cannabis cognition, while the lack of sex differences pushes back against the assumption that males and females are differentially affected.","specificNumbers":"225 young adults ages 16-22. Emotional Stroop Congruent Accuracy: p=0.0004 (FDR-p=0.002). Working Memory: p=0.02 (FDR-p=0.10, marginal). Age of onset and Stroop: p=0.03 (FDR-p=0.13, marginal). No sex interactions on any cognitive measure.","methodology":"Cross-sectional study of 225 young adults ages 16-22 who completed substance use interviews and a cognitive battery including the Emotional Word-Emotional Face Stroop and NIH Toolbox executive functioning tasks. Linear regressions with FDR correction for multiple comparisons.","limitations":"Cross-sectional design cannot determine if cannabis causes cognitive effects or if pre-existing differences drive both use and performance. Small sample. Multiple comparisons reduce confidence in marginal findings. Self-reported cannabis use and other substance use."},{"rthcId":"RTHC-05788","title":"A Comparison of Remote Versus in-Person Assessments of Substance Use and Related Constructs Among Adolescents.","authors":"Wade, Natasha E; Patel, Herry; Pelham, William E","year":2024,"journal":"Substance use & misuse, 59(10), 1447-1454","doi":"10.1080/10826084.2024.2352108","pmid":"38803212","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05789","title":"Cannabis use and neurocognitive performance at 13-14 Years-Old: Optimizing assessment with hair toxicology in the Adolescent brain cognitive development (ABCD) study.","authors":"Wade, Natasha E; Wallace, Alexander L; Huestis, Marilyn A; Lisdahl, Krista M; Sullivan, Ryan M; Tapert, Susan F","year":2024,"journal":"Addictive behaviors, 150, 107930","doi":"10.1016/j.addbeh.2023.107930","pmid":"38091780","tags":["cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis-using teens scored lower on episodic memory tasks, and higher THC metabolite levels in hair correlated with poorer verbal ability, inhibitory control, working memory, and episodic memory.","whyItMatters":"Self-reported cannabis use in teens is notoriously unreliable. This study shows that adding hair toxicology testing reveals brain-behavior relationships that would otherwise go undetected, suggesting the true cognitive impact of early cannabis use may be underestimated in studies relying solely on self-report.","specificNumbers":"Cannabis users scored lower on Picture Memory (p = .03). Within users, THCCOOH correlated negatively with Picture Vocabulary (r = -0.20, p = .03) and Flanker Inhibitory Control (r = -0.19, p = .04). Past-year use correlated negatively with List Sorting Working Memory (r = -0.33, p = .0002) and Picture Sequence Memory (r = -0.19, p = .04).","methodology":"Cross-sectional analysis of 246 participants (123 cannabis users matched with 123 controls) from the ABCD Study Year 4 follow-up. Hair samples were analyzed by LC-MS/MS and GC-MS/MS for cannabinoid concentrations. Cognitive performance was measured using the NIH Toolbox Cognitive Battery.","limitations":"Cross-sectional design prevents determining whether cannabis use caused the cognitive differences or whether pre-existing cognitive vulnerabilities predisposed teens to use cannabis. The matched-pair approach controls for demographics but cannot eliminate all confounders."},{"rthcId":"RTHC-05790","title":"Sex Differences in the Anxiolytic Properties of Common Cannabis Terpenes, Linalool and β-Myrcene, in Mice.","authors":"Wagner, Jasmin K; Gambell, Ella; Gibbons, Tucker; Martin, Thomas J; Kaplan, Joshua S","year":2024,"journal":"NeuroSci, 5(4), 635-649","doi":"10.3390/neurosci5040045","pmid":"39728677","tags":["anxiety","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both terpenes had anxiolytic effects in female mice with repeated vapor pulls over 30 minutes, while in males only a single vapor hit was effective. Combining sub-effective doses of linalool and CBD produced synergistic anxiety relief in females but not males.","whyItMatters":"The cannabis \"entourage effect\" -- the idea that terpenes and cannabinoids work better together -- is widely discussed but rarely tested under controlled conditions. This study provides some of the first evidence that sex is a critical variable in whether terpene-cannabinoid combinations produce enhanced effects.","specificNumbers":"Both linalool and beta-myrcene had anxiolytic effects in females with 30-minute repeated vapor exposure. In males, only a single vapor hit of either terpene reduced anxiety. Linalool plus CBD showed synergistic effects in females but not males. Beta-myrcene plus CBD showed no synergy in either sex.","methodology":"Male and female mice were exposed to linalool or beta-myrcene via short-duration vapor pulls modeling human cannabis inhalation. Anxiety was assessed using the elevated plus maze and locomotion in the open field test.","limitations":"Animal study using mice, so results may not translate directly to humans. The vapor delivery method approximates but does not perfectly replicate human cannabis inhalation. Only two terpenes were tested at limited dose ranges."},{"rthcId":"RTHC-05791","title":"Amygdala volume and depression symptoms in young adolescents who use cannabis.","authors":"Wallace, Alexander L; Huestis, Marilyn A; Sullivan, Ryan M; Wade, Natasha E","year":2024,"journal":"Behavioural brain research, 472, 115150","doi":"10.1016/j.bbr.2024.115150","pmid":"39009188","tags":["depression","youth","brain-imaging"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was not associated with amygdala volume differences but was associated with increased depressive symptoms. An interaction effect showed that cannabis-using teens with smaller amygdala volumes had significantly more depressive symptoms than those with larger volumes.","whyItMatters":"This study suggests that not all teen cannabis users face the same mental health risks. Brain structure -- specifically amygdala size -- may identify which young cannabis users are most vulnerable to depression, pointing toward a biological basis for individual differences in cannabis-related mental health outcomes.","specificNumbers":"Cannabis users had significantly more depressive symptoms than non-users (p < 0.01). Cannabis group interacted with amygdala volume to predict depression (p values ranging from < 0.01 to 0.02). Cannabis use alone was not significantly associated with amygdala volume.","methodology":"Cross-sectional analysis of 224 participants (ages 12-15) from the ABCD Study, balanced by sex. Cannabis users were identified through hair toxicology and self-report, then demographically matched to non-users. Depression symptoms were measured via the Child Behavioral Checklist. Linear mixed effect models examined cannabis group, amygdala volume, and their interaction.","limitations":"Cross-sectional design cannot determine whether smaller amygdala volumes preceded cannabis use or whether cannabis use contributed to volume differences over time. Parent-reported depression measures may not fully capture teens' internal experiences."},{"rthcId":"RTHC-05792","title":"Are the postmortem concentration changes of the synthetic cannabinoid cumyl-5F-P7AICA and its N-pentanoic acid metabolite dependent on the environmental conditions? - A systematic study following pulmonary administration to pigs.","authors":"Walle, Nadja; Doerr, Adrian A; Peters, Benjamin; Laschke, Matthias W; Menger, Michael D; Schmidt, Peter H; Meyer, Markus R; Schaefer, Nadine","year":2024,"journal":"Toxicology letters, 401, 170-180","doi":"10.1016/j.toxlet.2024.10.006","pmid":"39395683","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05793","title":"Relief in Gastrointestinal Symptoms with Medical Marijuana Over 1 Year.","authors":"Wallingford, Matthew P; Kelly, Erin L; Herens, Allison; Hanna, Daniel; Hajjar, Emily; Worster, Brooke","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 80-85","doi":"10.1159/000538694","pmid":"39015606","tags":["gastrointestinal","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"At each survey (baseline, 30 days, 6 months, 12 months), participants reported significantly lower GI symptom severity when using medical marijuana versus when not using it (p < 0.05 at every time point).","whyItMatters":"Chronic GI conditions like IBS and Crohn's disease are notoriously difficult to manage. This 12-month follow-up provides some of the first evidence that medical marijuana's benefits for GI symptoms persist over time rather than diminishing with continued use.","specificNumbers":"Significant symptom severity decrease at all four time points (p < 0.05). Most common side effects: increased appetite (12-21.4%), fatigue (6-16.7%), anxiety (4-11.9%), cough (4-11.9%), headache (6-7.9%), dry mouth (4-7.1%).","methodology":"Longitudinal observational study following medical marijuana patients who completed surveys at baseline, 30 days, 6 months, and 12 months. GI symptom severity was self-rated on a 1 (mild) to 3 (severe) scale. Side effects were also tracked.","limitations":"Self-reported outcomes without a placebo control group make it impossible to separate the pharmacological effects of marijuana from placebo effects or natural symptom fluctuation. No standardized GI diagnosis was required for enrollment. The simple 3-point severity scale limits granularity."},{"rthcId":"RTHC-05794","title":"The Impact of Depression and Anxiety Comorbidities on Acute Postoperative Pain After DIEP Flap Breast Reconstruction.","authors":"Wang, Carol; Tang, Megan; Shah, Reanna; Frost, Jamie; Kim, Esther; Shamamian, Peter E; Oleru, Olachi; Seyidova, Nargiz; Henderson, Peter W; Taub, Peter J","year":2024,"journal":"Microsurgery, 44(8), e31260","doi":"10.1002/micr.31260","pmid":"39530426","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05795","title":"The immunomodulatory effects of cannabidiol on Hsp70-activated NK cells and tumor target cells.","authors":"Wang, Fei; Bashiri Dezfouli, Ali; Multhoff, Gabriele","year":2024,"journal":"Molecular immunology, 174, 1-10","doi":"10.1016/j.molimm.2024.07.008","pmid":"39126837","tags":["cbd","cancer"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBD treatment significantly reduced the release of interferon-gamma and granzyme B from activated NK cells, lowered Hsp70 expression on tumor surfaces, and decreased NK cell killing of high-Hsp70-expressing cancer cells. Low-Hsp70 tumors were unaffected.","whyItMatters":"Many cancer patients use CBD for symptom management during treatment. This study raises a specific, mechanistic concern: CBD might interfere with NK cell-based immune responses against tumors that display the stress protein Hsp70, potentially undermining certain immunotherapy approaches.","specificNumbers":"CBD significantly reduced IFN-gamma and granzyme B release from activated NK cells. CBD decreased elevated mHsp70 expression on tumor cells but did not affect low baseline mHsp70. Killing of high-mHsp70 tumor cells by CBD-pretreated NK cells was reduced. Expression of NKp30, NKG2D, and CD69 receptors remained unchanged.","methodology":"In vitro study examining CBD's effects on NK cells stimulated with TKD Hsp70 peptide and IL-2, and on HCT116 colorectal cancer cells with different levels of membrane Hsp70 expression. NK cell receptor expression, cytokine release, and cytotoxicity were measured.","limitations":"In vitro study using cell lines, which may not reflect the complexity of CBD-immune interactions in living organisms. CBD concentrations used may not match what patients actually achieve in tissue. Only one type of cancer cell line was examined."},{"rthcId":"RTHC-05796","title":"Accuracy and replicability of identifying eyelid tremor as an indicator of recent cannabis smoking.","authors":"Wang, George Sam; Kosnett, Michael; Subramanian, Prem; Wrobel, Julia; Ma, Ming; Brown, Tim; Bidwell, L Cinnamon; Brooks-Russell, Ashley","year":2024,"journal":"Clinical toxicology (Philadelphia, Pa.), 62(1), 10-18","doi":"10.1080/15563650.2024.2310154","pmid":"38421358","tags":["driving","testing-methods"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"There was no significant association between recent cannabis use and eyelid tremor presence. Cannabis users were actually less likely to show tremors (OR: 0.75). The test had 86% sensitivity but only 18% specificity and 64% overall accuracy.","whyItMatters":"Eyelid tremor assessment is part of the Drug Evaluation and Classification Program used by law enforcement to identify cannabis-impaired drivers. This controlled study found it performs poorly as a diagnostic sign, with specificity so low that most positive results would be false positives.","specificNumbers":"Sensitivity: 0.86. Specificity: 0.18. Accuracy: 0.64. Odds ratio for cannabis users having tremor: 0.75 (95% CI: 0.25-2.40). Inter-rater reliability: kappa 0.44-0.45, ICC 0.58-0.61 (moderate agreement).","methodology":"Blinded, controlled study of 103 adults in three groups (daily users, occasional users, non-users). Eyelids were recorded by infrared videography before and approximately 71 minutes after cannabis smoking. Three trained expert observers (neuro-ophthalmology and toxicology) independently graded tremor without knowing use history or timing.","limitations":"Eyelid recordings taken at only one post-smoking time point (70 minutes). Participants self-selected their cannabis products and doses due to regulatory restrictions. The study population was predominantly non-Hispanic White."},{"rthcId":"RTHC-05797","title":"Chemical Composition of Electronic Vaping Products From School Grounds in California.","authors":"Wang, Ping; Williams, Rebecca J; Chen, Wenhao; Wang, Flavia; Shamout, Mays; Tanz, Lauren J; Herzig, Carolyn T A; Oakley, Lisa P; Peak, Corey M; Heinzerling, Amy; Al-Shawaf, Maeh; Melstrom, Paul; Marynak, Kristy; Tynan, Michael A; Agaku, Israel T; Kumagai, Kazukiyo","year":2024,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 26(8), 991-998","doi":"10.1093/ntr/ntae042","pmid":"38407960","tags":["youth","vaping"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 43 disposable vape pen devices, 39 (90.1%) contained THC or CBD, with three containing both nicotine and THC. Among cartridges and pods, 98.1% contained nicotine. Confiscated products differed chemically from purchased versions of the same brand.","whyItMatters":"This is among the first studies to systematically analyze what teens are actually vaping at school. The finding that disposable vape pens overwhelmingly contain cannabinoids rather than just nicotine challenges assumptions about what youth vaping products deliver and has implications for school health interventions.","specificNumbers":"576 total products from 16 schools. 90.1% of disposable vape pens (39/43) contained THC or CBD. 98.1% of cartridges/pods (204/208) contained nicotine. 3 devices contained both nicotine and THC. Chemical differences found between confiscated and purchased JUULs.","methodology":"Cross-sectional chemical analysis of 576 electronic vaping products (233 devices, 343 cartridges/pods/e-liquids) found or confiscated from 16 California public high schools in February-March 2019. Liquids from 251 samples were analyzed by GC/MS. Results were compared to newly purchased JUUL pods.","limitations":"Products were collected from a convenience sample of 16 California schools during a two-week period in 2019, limiting generalizability. Self-reported product labels may not reflect what students knew they were using. The vaping landscape has changed significantly since data collection."},{"rthcId":"RTHC-05798","title":"Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study.","authors":"Wang, William; Volkow, Nora D; Berger, Nathan A; Davis, Pamela B; Kaelber, David C; Xu, Rong","year":2024,"journal":"Molecular psychiatry, 29(8), 2587-2598","doi":"10.1038/s41380-024-02498-5","pmid":"38486046","tags":["addiction","treatment"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"In patients with obesity, semaglutide was associated with lower risk of new CUD (HR: 0.56) and recurrent CUD (HR: 0.62) versus non-GLP-1RA anti-obesity medications. Similar reductions appeared in patients with type 2 diabetes for new CUD (HR: 0.40) and recurrent CUD (HR: 0.66).","whyItMatters":"There are currently no FDA-approved medications for cannabis use disorder despite more than 45 million US users, one-third of whom meet criteria for CUD. If semaglutide's apparent protective effect is confirmed in randomized trials, it could represent the first pharmacological treatment option for this common condition.","specificNumbers":"Obesity cohort: incident CUD HR 0.56 (95% CI: 0.42-0.75), recurrent CUD HR 0.62 (95% CI: 0.46-0.84). T2D cohort: incident CUD HR 0.40 (95% CI: 0.29-0.56), recurrent CUD HR 0.66 (95% CI: 0.42-1.03). Consistent reductions across gender, age, and race strata. Sample: 85,223 obesity patients, 596,045 T2D patients.","methodology":"Retrospective cohort study using electronic health records from the TriNetX Analytics Network (~105.3 million patients from 61 US healthcare organizations). Compared propensity-score matched cohorts: 85,223 patients with obesity prescribed semaglutide vs non-GLP-1RA anti-obesity medications, replicated in 596,045 patients with T2D. 12-month follow-up.","limitations":"Retrospective design with electronic health records cannot establish causation. CUD diagnosis in EHRs may undercount actual cases. Propensity score matching reduces but does not eliminate confounding. The T2D recurrent CUD result did not reach statistical significance (CI crossed 1.0)."},{"rthcId":"RTHC-05799","title":"Targeting mitochondrial dysfunction in atopic dermatitis with trilinolein: A triacylglycerol from the medicinal plant Cannabis fructus.","authors":"Wang, Yi; Lu, Hanzhi; Cheng, Linyan; Guo, Wanjun; Hu, Yue; Du, Xinran; Liu, Xin; Xu, Mingyuan; Liu, Yeqiang; Zhang, Yanbin; Xi, Ruofan; Wang, Peiyao; Liu, Xin; Duan, Yanjuan; Zhu, Jianyong; Li, Fulun","year":2024,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 132, 155856","doi":"10.1016/j.phymed.2024.155856","pmid":"39024674","tags":["skin-conditions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Topically applied trilinolein improved DNCB-induced eczema-like lesions in mice, increased terminal differentiation proteins, decreased oxidative stress marker NOX2, restored mitochondrial morphology and membrane potential, and reduced mitochondrial DNA release in inflamed skin cells. These effects depended on the AhR signaling pathway.","whyItMatters":"Atopic dermatitis affects millions of people and current treatments often have significant side effects. Trilinolein from cannabis seeds targets a newly recognized disease mechanism -- mitochondrial dysfunction in skin cells -- and performed comparably to the prescription drug crisaborole in this preclinical model.","specificNumbers":"Trilinolein increased expression of terminal differentiation proteins and decreased NOX2 expression, comparable to the positive control crisaborole. It reduced ROS fluorescence intensity, restored mitochondrial membrane potential, and decreased mtDNA release in stimulated keratinocytes. AhR, CYP1A1, and Nrf2 protein expression increased in a dose-dependent manner.","methodology":"Combined approach using single-cell transcriptome analysis of chronic atopic dermatitis patients vs healthy controls, DNCB-induced eczema model in BALB/c mice, and IL-4/TNF-alpha-stimulated HaCaT keratinocytes. HPLC-ESI-MS/MS identified active compounds from Cannabis fructus. Proteomics explored mechanisms.","limitations":"Preclinical study only. Mouse skin differs significantly from human skin. The DNCB-induced model does not fully replicate the complexity of human atopic dermatitis. Clinical trials in humans are needed to confirm efficacy and safety."},{"rthcId":"RTHC-05800","title":"Cannabinoids and healthy ageing: the potential for extending healthspan and lifespan in preclinical models with an emphasis on Caenorhabditis elegans.","authors":"Wang, Zhizhen; Arnold, Jonathon C","year":2024,"journal":"GeroScience, 46(6), 5643-5661","doi":"10.1007/s11357-024-01162-8","pmid":"38696056","tags":["aging","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CBD extends healthspan and lifespan in C. elegans and other model organisms. Mechanistic studies show CBD works through autophagy induction and activation of antioxidative systems. Emerging evidence also suggests cannabinoids may inhibit cellular senescence. CBD improved age-related behavioral dysfunction in both healthy and accelerated aging models.","whyItMatters":"With aging populations worldwide, anti-aging interventions that target fundamental aging processes could address multiple age-related diseases simultaneously. CBD's ability to extend healthspan in multiple model organisms, combined with its established safety profile in humans, makes it a particularly interesting candidate for translational aging research.","specificNumbers":"The review covers research across approximately 105.3 million patients in reference studies and multiple preclinical model systems. Specific lifespan extension percentages vary by model organism and experimental conditions.","methodology":"Narrative review synthesizing preclinical research on cannabinoids and aging across multiple model systems, with particular emphasis on studies using the nematode Caenorhabditis elegans. Examines endocannabinoid system involvement in aging regulation and exogenous cannabinoid effects on healthspan markers.","limitations":"Most evidence comes from simple model organisms like C. elegans, which differ enormously from humans in biology and lifespan regulation. Translation to mammalian systems remains a critical gap. Human aging studies with cannabinoids are essentially non-existent."},{"rthcId":"RTHC-05801","title":"Supporting gut health with medicinal cannabis in people with advanced cancer: potential benefits and challenges.","authors":"Wardill, Hannah R; Wooley, Luke T; Bellas, Olivia M; Cao, Katrina; Cross, Courtney B; van Dyk, Madele; Kichenadasse, Ganessan; Bowen, Joanne M; Zannettino, Andrew C W; Shakib, Sepehr; Crawford, Gregory B; Boublik, Jaroslav; Davis, Mellar M; Smid, Scott D; Price, Timothy J","year":2024,"journal":"British journal of cancer, 130(1), 19-30","doi":"10.1038/s41416-023-02466-w","pmid":"37884682","tags":["cancer","gastrointestinal","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system is densely distributed throughout the gut and modulates mucosal barrier integrity, inflammation, and microbial balance. Cannabis-based interventions could theoretically address mucositis and its downstream symptoms including diarrhea, nausea, infection, malnutrition, fatigue, depression, and insomnia through these interconnected pathways.","whyItMatters":"Mucositis affects up to 100% of patients receiving certain cancer treatments and drives a cascade of debilitating symptoms. Current management treats each symptom in isolation. Cannabis's multi-target action on the gut endocannabinoid system could address the root cause rather than individual symptoms.","specificNumbers":"Mucositis contributes to diarrhea, nausea, vomiting, infection, malnutrition, fatigue, depression, and insomnia in cancer patients. The endocannabinoid system modulates motility, inflammation, pain signaling, and barrier function throughout the gastrointestinal tract.","methodology":"Narrative review outlining the biological rationale for medicinal cannabis in managing cancer therapy-induced mucositis. Synthesizes evidence on the endocannabinoid system in gut function, documented effects of cannabis on gastrointestinal symptoms, and the cascade of symptoms linked to mucosal barrier breakdown.","limitations":"This is a rationale paper, not a clinical study. No controlled trial data specifically test cannabis for mucositis prevention. The theoretical framework, while biologically plausible, requires clinical validation."},{"rthcId":"RTHC-05802","title":"Clinical effects of cannabis compared to synthetic cannabinoid receptor agonists (SCRAs): a retrospective cohort study of presentations with acute toxicity to European hospitals between 2013 and 2020.","authors":"Waters, Mitchell L; Dargan, Paul I; Yates, Christopher; Dines, Alison M; Eyer, Florian; Giraudon, Isabelle; Heyerdahl, Fridtjof; Hovda, Knut Erik; Liechti, Matthias E; Miró, Òscar; Vallersnes, Odd Martin; Anseeuw, Kurt; Badaras, Robertas; Bitel, Marcin; Bonnici, Jeffrey; Brvar, Miran; Caganova, Blazena; Calýskan, Feriyde; Ceschi, Alessandro; Chamoun, Karam; Daveloose, Laurence; Galicia, Miguel; Gartner, Birgit; Gorozia, Ketevan; Grenc, Damjan; Gresnigt, Femke M J; Hondebrink, Laura; Jürgens, Gesche; Konstari, Jutta; Kutubidze, Soso; Laubner, Gabija; Liakoni, Evangelia; Liguts, Viesturs; Lyphout, Cathelijne; McKenna, Roy; Mégarbane, Bruno; Moughty, Adrian; Nitescu, Gabriela Viorela; Noseda, Roberta; O'Connor, Niall; Paasma, Raido; Ortega Perez, Juan; Perminas, Marius; Persett, Per Sverre; Põld, Kristiina; Puchon, Erik; Puiguriguer, Jordi; Radenkova-Saeva, Julia; Rulisek, Jan; Samer, Caroline; Schmid, Yasmin; Scholz, Irene; Stašinskis, Roberts; Surkus, Jonas; Van den Hengel-Koot, Irma; Vigorita, Federico; Vogt, Severin; Waldman, Wojciech; Waring, William Stephen; Zacharov, Sergej; Zellner, Tobias; Wood, David M","year":2024,"journal":"Clinical toxicology (Philadelphia, Pa.), 62(6), 378-384","doi":"10.1080/15563650.2024.2346125","pmid":"38934347","tags":["synthetic-cannabinoids","emergency-medicine"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoid presentations had significantly higher rates of drowsiness, coma, agitation, seizures, and bradycardia. Cannabis presentations had significantly higher rates of palpitations, chest pain, hypertension, tachycardia, anxiety, vomiting, and headache. Synthetic cannabinoid patients were more likely to be admitted to psychiatric wards.","whyItMatters":"Synthetic cannabinoids are often marketed as \"legal\" cannabis alternatives but produce a fundamentally different and more dangerous clinical picture. This large multinational dataset reveals that the two substance classes lead to distinct patterns of emergency department presentations with different organ system involvement.","specificNumbers":"54,314 total drug-related presentations. 2,657 lone cannabis exposures. 503 lone synthetic cannabinoid exposures. Synthetic cannabinoids had statistically significantly higher rates of drowsiness, coma, agitation, seizures, and bradycardia (all p < 0.05). Cannabis had higher rates of palpitations, chest pain, hypertension, tachycardia, anxiety, vomiting, and headache (all p < 0.05).","methodology":"Retrospective cohort study using the European Drug Emergencies Network Plus, a surveillance system across 36 centers in 24 European countries from 2013-2020. Compared 2,657 lone cannabis exposures with 503 lone synthetic cannabinoid exposures among 54,314 total drug-related presentations.","limitations":"Drug identification relies on patient self-report in the emergency department, which may be inaccurate. Some synthetic cannabinoid users may not know what substance they consumed. The study cannot account for dose, potency, or specific compound within the synthetic cannabinoid class."},{"rthcId":"RTHC-05803","title":"Evaluation of the Association Between Prenatal Cannabis Use and Risk of Developmental Delay.","authors":"Watts, Dana; Lebel, Catherine; Chaput, Kathleen; Giesbrecht, Gerald F; Dewsnap, Kyle; Baglot, Samantha L; Tomfohr-Madsen, Lianne","year":2024,"journal":"JAACAP open, 2(4), 250-262","doi":"10.1016/j.jaacop.2024.03.004","pmid":"39697398","tags":["prenatal","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Prenatal cannabis exposure was not associated with differences in gestational age or birth weight. It was significantly associated with increased risk of parent-reported developmental delay on the communication domain (p = .02), but this finding did not survive correction for multiple comparisons. No other ASQ-3 domains showed significant associations.","whyItMatters":"Cannabis use during pregnancy is increasing with legalization, and the developmental consequences remain unclear. This large study found limited evidence of harm at 12 months, with only a borderline signal for communication development that warrants monitoring but does not establish clear risk.","specificNumbers":"Total sample: 10,695 pregnancies. ASQ-3 assessments: 3,742 infants at 12 months. Cannabis group differed significantly on all sociodemographic variables from non-users. Communication domain association: p = .02 before multiple comparison adjustment, not significant after. No significant associations with gestational age or birth weight (p > .05).","methodology":"Prospective cohort from the Pregnancy During the COVID-19 Pandemic study (n = 10,695 total; n = 3,742 with 12-month ASQ-3 assessments). Propensity score weighting addressed demographic differences between cannabis-using and non-using groups. G-computations analyzed associations with birth outcomes and developmental delay.","limitations":"The study was not specifically designed to examine prenatal cannabis effects. Cannabis use was self-reported and may be underreported. The ASQ-3 is a parent-report screening tool, not a comprehensive developmental assessment. Follow-up at 12 months may be too early to detect some developmental effects. The COVID-19 pandemic context may introduce unique confounders."},{"rthcId":"RTHC-05804","title":"Polysubstance Use among Maryland High School Students: Variations across County-Level School Districts.","authors":"Webb, Lindsey; Cadet, Kechna; Musci, Rashelle; Kurani, Shaheen; Clary, Laura K; German, Danielle; Johnson, Renee M","year":2024,"journal":"International journal of environmental research and public health, 21(5)","doi":"10.3390/ijerph21050639","pmid":"38791853","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05805","title":"Oral Cannabidiol for Seborrheic Dermatitis in Patients With Parkinson Disease: Randomized Clinical Trial.","authors":"Weber, Isaac; Zagona-Prizio, Caterina; Sivesind, Torunn E; Adelman, Madeline; Szeto, Mindy D; Liu, Ying; Sillau, Stefan H; Bainbridge, Jacquelyn; Klawitter, Jost; Sempio, Cristina; Dunnick, Cory A; Leehey, Maureen A; Dellavalle, Robert P","year":2024,"journal":"JMIR dermatology, 7, e49965","doi":"10.2196/49965","pmid":"38466972","tags":["cbd","skin-conditions","parkinsons"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CBD treatment did not significantly reduce seborrheic dermatitis severity or presence. However, the CBD group showed a non-significant trend toward improvement (risk ratio 0.69 for post vs pre) while the placebo group showed a non-significant trend toward worsening (risk ratio 1.20). The between-group difference approached significance (p = .07).","whyItMatters":"Seborrheic dermatitis affects up to 59% of people with Parkinson's disease and is difficult to treat. While this trial was too small and short to detect a clear effect, the opposing trends between CBD and placebo groups suggest CBD may have dermatological effects worth investigating in larger studies.","specificNumbers":"53 patients (27 placebo, 26 CBD). CBD dose: 2.5 mg/kg/day for 16 days. CBD group post vs pre risk ratio: 0.69 (95% CI: 0.41-1.18, p = .15). Placebo group: 1.20 (95% CI: 0.88-1.65, p = .26). Between-group difference: p = .07.","methodology":"Randomized (1:1), parallel, double-blind, placebo-controlled trial. 53 Parkinson's patients (27 placebo, 26 CBD) received 16 days of oral CBD-rich cannabis extract (2.5 mg/kg/day CBD with 0.08 mg/kg/day THC) or placebo. Facial photographs were scored independently using the SEDASI scale by blinded reviewers.","limitations":"Substantially underpowered for the dermatological outcome. Treatment duration of only 16 days may be insufficient for skin conditions. Baseline seborrheic dermatitis severity was low in both groups, creating a floor effect. The oral route may not deliver adequate concentrations to skin."},{"rthcId":"RTHC-05806","title":"Consensus panel recommendations for the optimization of EPIDIOLEX® treatment for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.","authors":"Wechsler, Robert T; Burdette, David E; Gidal, Barry E; Hyslop, Ann; McGoldrick, Patricia E; Thiele, Elizabeth A; Valeriano, James","year":2024,"journal":"Epilepsia open, 9(5), 1632-1642","doi":"10.1002/epi4.12956","pmid":"39007525","tags":["epilepsy","cbd","treatment"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Key recommendations include individualizing starting dose and titration rate based on baseline variables and prior medication responses, differentiating Epidiolex from non-approved CBD products, managing drug-drug interactions (particularly with clobazam and valproate), and tracking maximum tolerated dose as a measure of effectiveness.","whyItMatters":"Despite FDA approval, confusion persists among healthcare providers, patients, and caregivers about how to dose Epidiolex optimally and how it differs from over-the-counter CBD products. These real-world practice guidelines fill a gap between clinical trial protocols and everyday clinical decision-making.","specificNumbers":"Seven expert panelists with epilepsy expertise. Two rounds of Delphi discussion. Two broad themes: overcoming barriers to initiation and optimization of treatment. Epidiolex is approved for three conditions: Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.","methodology":"Modified Delphi consensus method. Seven epilepsy specialists completed a premeeting survey based on literature review, then discussed findings over two rounds to reach consensus on recommendation statements for Epidiolex treatment in LGS, DS, and TSC.","limitations":"Consensus-based recommendations reflect expert opinion, not randomized trial evidence for specific dosing strategies. The panel of seven experts, while experienced, represents a small group. Recommendations may not apply to patients with other types of epilepsy."},{"rthcId":"RTHC-05807","title":"Metabotropic Glutamate Receptor 5 as a Potential Biomarker of the Intersection of Trauma and Cannabis Use.","authors":"Weiss, Emily R; Davis, Margaret T; Asch, Ruth H; D'Souza, Deepak Cyril; Cool, Ryan; Esterlis, Irina","year":2024,"journal":"The international journal of neuropsychopharmacology, 27(10)","doi":"10.1093/ijnp/pyae044","pmid":"39320043","tags":["cognition","mental-health","cbd","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system and the glutamate system are deeply intertwined in the brain, and both are implicated in trauma-related conditions and cannabis use. This study used PET brain imaging to measure a specific receptor — metabotropic glutamate receptor 5 (mGlu5) — that sits at this intersection, in people with trauma-related psychopathology who did and didn't use cannabis.\n\nAmong 55 individuals with trauma-related mental health conditions, those who had used cannabis in the past year showed 18.6-19.1% higher mGlu5 availability in frontal brain regions and 14.2-16.6% higher levels in limbic regions (including the amygdala and hippocampus) compared to non-users. Monthly users showed similar elevations.\n\nWhy does this matter? mGlu5 receptors regulate glutamate signaling — the brain's primary excitatory system — and are directly modulated by endocannabinoids. Higher mGlu5 levels could reflect a compensatory response to cannabis exposure, an underlying vulnerability that both predisposes to cannabis use and worsens trauma responses, or an adaptive change that affects how the brain processes threatening information.\n\nThe orbitofrontal cortex and amygdala — two regions showing elevated mGlu5 — are central to threat processing, emotional regulation, and the fear circuitry disrupted in PTSD. If cannabis use alters glutamate receptor levels in these specific regions, it could change how trauma survivors process threatening stimuli and regulate emotional responses.\n\nThis is the first study to directly investigate the cannabis-mGlu5 relationship in people with trauma-related conditions, opening a new molecular window into why cannabis and trauma are so frequently linked.","whyItMatters":"Most research on cannabis and the brain focuses on the CB1 receptor. This study reveals that cannabis use also affects glutamate receptors — through a different neurotransmitter system — in brain regions critical for trauma processing. This cross-system effect could help explain why cannabis has such complex relationships with mental health: it's not just affecting the endocannabinoid system, it's reshaping glutamate signaling in emotion-regulation circuits.","specificNumbers":"55 participants with trauma-related psychopathology. Past-year cannabis users (n=22): 18.62-19.12% higher mGlu5 in frontal ROIs, 14.24-16.55% higher in limbic ROIs. Past-month/monthly users (n=16): 18.05-20.62% higher in frontal, 15.53-16.83% higher in limbic ROIs. Key regions: orbitofrontal cortex and amygdala.","methodology":"Cross-sectional PET imaging study using [18F]FPEB to measure mGlu5 receptor availability in vivo. 55 individuals with trauma-related psychopathology (cross-diagnostic sample). Compared mGlu5 levels in frontolimbic regions of interest (dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, hippocampus) between cannabis users and non-users. Tested both past-year use (n=22) and past-month/monthly use (n=16).","limitations":"Cross-sectional — can't determine whether cannabis caused the mGlu5 elevation or whether higher baseline mGlu5 predisposes to cannabis use. Small sample (55 total, 22 cannabis users). Cross-diagnostic sample (various trauma-related conditions) rather than a specific diagnosis like PTSD. No healthy control group without trauma exposure. Cannabis use was categorized broadly (past-year/past-month) without dose, potency, or product data. PET imaging measures receptor availability, which reflects a combination of receptor density and binding affinity."},{"rthcId":"RTHC-05808","title":"Substance Use and Educational Impacts in Youth With and Without Chronic Illness.","authors":"Weitzman, Elissa R; Minegishi, Machiko; Wisk, Lauren E; Levy, Sharon","year":2024,"journal":"American journal of preventive medicine, 66(2), 279-290","doi":"10.1016/j.amepre.2023.09.029","pmid":"37802307","tags":["youth","education"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was associated with lower grades (APR 1.54), school truancy (APR 2.16), truancy from activities (similar magnitude), and detention (APR 2.29) after controlling for alcohol, nicotine, and demographics. Alcohol and nicotine use were not independently associated with these outcomes. The cannabis-education association was significantly stronger in adolescents with chronic illness (p < 0.001).","whyItMatters":"By controlling for concurrent alcohol and nicotine use, this study isolates cannabis as the substance most strongly linked to academic problems in teens. The amplified effect in chronically ill adolescents highlights a vulnerable population that may use cannabis for symptom management but face disproportionate educational consequences.","specificNumbers":"958 adolescents: 30.7% used alcohol, 23.0% cannabis, 13.2% nicotine in past year. 42.5% had at least one educational impact. Cannabis APRs: lower grades 1.54 (1.13-2.11), school truancy 2.16 (1.52-3.07), detention 2.29 (1.33-3.94). Chronic illness interaction p < 0.001. 46.5% received subspecialty care.","methodology":"Cross-sectional survey of 958 adolescents (mean age 16.0 years, 58.9% female) receiving general or subspecialty medical care, from 2016-2018. Modified Poisson regression models estimated prevalence ratios for educational impacts, controlling for all three substances simultaneously plus sociodemographic factors.","limitations":"Cross-sectional data cannot establish that cannabis use caused educational problems. The clinical sample may not represent all adolescents. Self-reported measures could be affected by social desirability bias. \"Chronic illness\" was defined by subspecialty care rather than specific diagnoses."},{"rthcId":"RTHC-05809","title":"A robust brain network for sustained attention from adolescence to adulthood that predicts later substance use.","authors":"Weng, Yihe; Kruschwitz, Johann; Rueda-Delgado, Laura M; Ruddy, Kathy L; Boyle, Rory; Franzen, Luisa; Serin, Emin; Nweze, Tochukwu; Hanson, Jamie; Smyth, Alannah; Farnan, Tom; Banaschewski, Tobias; Bokde, Arun L W; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Garavan, Hugh; Gowland, Penny A; Heinz, Andreas; Brühl, Rüdiger; Martinot, Jean-Luc; Martinot, Marie-Laure Paillère; Artiges, Eric; McGrath, Jane; Nees, Frauke; Papadopoulos Orfanos, Dimitri; Paus, Tomas; Poustka, Luise; Holz, Nathalie; Fröhner, Juliane; Smolka, Michael N; Vaidya, Nilakshi; Schumann, Gunter; Walter, Henrik; Whelan, Robert","year":2024,"journal":"eLife, 13","doi":"10.7554/eLife.97150","pmid":"39235858","tags":["cognition","youth","brain-imaging"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Brain connectivity patterns associated with poor sustained attention at age 14 predicted subsequent increases in cannabis and cigarette use through age 23. Individual differences in attention network strength were preserved across developmental stages and generalized to an external dataset.","whyItMatters":"This is among the first studies to establish that attention deficits precede cannabis use rather than resulting from it. Identifying a reliable brain biomarker for substance use vulnerability at age 14 could enable targeted prevention before cannabis initiation begins.","specificNumbers":"Over 1,000 participants followed from ages 14 to 23. Brain networks of sustained attention at age 14 predicted cannabis and cigarette use increases. Network patterns were consistent across developmental stages and replicated in an external dataset.","methodology":"Longitudinal study following over 1,000 participants from ages 14 to 23. Brain connectivity during sustained attention tasks was measured using neuroimaging. Attention network patterns at baseline were used to predict substance use trajectories. Results were validated against an external dataset.","limitations":"Although longitudinal, the study cannot fully rule out unmeasured confounders that might independently affect both attention networks and substance use trajectories. The study examined attention broadly rather than parsing specific attention subtypes."},{"rthcId":"RTHC-05810","title":"A robust brain network for sustained attention from adolescence to adulthood that predicts later substance use.","authors":"Weng, Yihe; Kruschwitz, Johann; Rueda-Delgado, Laura M; Ruddy, Kathy; Boyle, Rory; Franzen, Luisa; Serin, Emin; Nweze, Tochukwu; Hanson, Jamie; Smyth, Alannah; Farnan, Tom; Banaschewski, Tobias; Bokde, Arun L W; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Garavan, Hugh; Gowland, Penny; Heinz, Andreas; Brühl, Rüdiger; Martinot, Jean-Luc; Martinot, Marie-Laure Paillère; Artiges, Eric; McGrath, Jane; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Paus, Tomáš; Poustka, Luise; Holz, Nathalie; Fröhner, Juliane H; Smolka, Michael N; Vaidya, Nilakshi; Schumann, Gunter; Walter, Henrik; Whelan, Robert","year":2024,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2024.04.03.587900","pmid":"38617224","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05811","title":"Latent transition analysis of time-varying cannabis use motives to inform adaptive interventions.","authors":"West, Brady T; Ma, Yongchao; Lankenau, Stephen; Wong, Carolyn F; Bonar, Erin E; Patrick, Megan E; Walton, Maureen A; McCabe, Sean Esteban","year":2024,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 38(7), 759-771","doi":"10.1037/adb0001012","pmid":"38780582","tags":["addiction","treatment"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Latent transition analysis across four studies identified that transitions into or remaining in latent classes characterized by multiple cannabis use motives predicted adverse outcomes including cannabis use disorder. This pattern held across different data collection frequencies (daily, monthly, yearly, biennial).","whyItMatters":"Most cannabis interventions are static, offering the same approach regardless of how someone's relationship with cannabis evolves. This study shows that monitoring changes in why people use cannabis -- not just how much -- could identify when someone is shifting toward riskier patterns, enabling interventions to adapt in real time.","specificNumbers":"Total sample across four studies: approximately 9,098 participants. Data collection ranged from daily to biennial. Transitions into or staying in multi-motive classes predicted future adverse outcomes across all frequency levels.","methodology":"Secondary analysis of four studies with varying data collection frequencies: Medical Cannabis Certification Cohort (n=801, biannual), Cannabis Health and Young Adults Project (n=359, annual), Monitoring the Future Panel (n=7,851, biennial), and Text Messaging Study (n=87, daily). Latent transition analysis with random intercepts was applied across all datasets.","limitations":"Secondary analysis of existing datasets that were not specifically designed for this purpose. The four studies used different populations, measures, and timeframes, making direct comparisons challenging. The daily data study had a very small sample (n=87)."},{"rthcId":"RTHC-05812","title":"Perspectives of adolescents and young adults on cannabis use during pregnancy.","authors":"Whitlock, Christopher; Chang, Claire; Onishchenko, Regina; Joassaint, Madgean; Madlambayan, Emily; Oshman, Lauren; Frank, Christopher J","year":2024,"journal":"Addictive behaviors, 156, 108059","doi":"10.1016/j.addbeh.2024.108059","pmid":"38723313","tags":["prenatal","youth","public-perception"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Four themes emerged: AYAs believe cannabis is harmful during pregnancy, they are divided on whether prenatal exposure should be considered child abuse or neglect, they have mixed attitudes about cannabis and safe parenting, and they support healthcare professional counseling about prenatal cannabis use. More than one in three felt prenatal cannabis use should be classified as child abuse or neglect.","whyItMatters":"Prenatal cannabis use is rising even as risk perception declines among pregnant people. Understanding how young people -- many of whom will soon face reproductive decisions -- view prenatal cannabis use reveals both protective attitudes (believing it's harmful) and concerning divisions (on whether it's abuse) that should inform public health messaging.","specificNumbers":"826 AYAs surveyed, 666 responded (80.6%). Mean age 19.9 years (SD 2.3). More than one in three felt prenatal cannabis use should be classified as child abuse or neglect. Four main themes identified.","methodology":"Qualitative content analysis of five open-ended survey questions delivered via text message to the MyVoice cohort (826 AYAs aged 14-24 nationally recruited from social media). 666 responded (80.6% response rate). Responses were coded and analyzed with descriptive statistics.","limitations":"Convenience sample recruited from social media may not represent all AYAs. Open-ended text responses may lack the depth of in-person interviews. The survey was conducted during a specific cultural moment (2022) when attitudes are still evolving."},{"rthcId":"RTHC-05813","title":"Work-related and non-work-related mild traumatic brain injury: Associations with mental health and substance use challenges in a Canadian population-level survey.","authors":"Wickens, Christine M; Mann, Robert E; Stoduto, Gina; Toccalino, Danielle; Colantonio, Angela; Chan, Vincy","year":2024,"journal":"Work (Reading, Mass.), 79(1), 331-338","doi":"10.3233/WOR-230418","pmid":"38393873","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05814","title":"Quantifying of highly radioactive and radiotoxic polonium-210 intake from cannabis (Cannabis sativa L.): impacts of different smoking and vaporization techniques.","authors":"Wieczorek, Jarosław; Boryło, Alicja","year":2024,"journal":"Environmental science and pollution research international, 31(51), 61138-61146","doi":"10.1007/s11356-024-35263-w","pmid":"39402360","tags":["smoking","contaminants"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Smoking cannabis with a glass pipe released approximately 80% of the polonium-210 present. Water pipe and blunt smoking had lower desorption rates (around 40%). Water filters absorbed about 8% and cellulose filters about 20% of released polonium. Vaporization released increasing amounts of polonium-210 as temperature increased.","whyItMatters":"Polonium-210 is a highly radioactive alpha emitter that contributes approximately 7% of total internal radiation dose from ingestion. Cannabis accumulates it from atmospheric deposition and phosphate fertilizers. This is the first study to systematically quantify how much of this radioactive contaminant users actually inhale based on their consumption method.","specificNumbers":"Glass pipe: ~80% polonium-210 desorption. Water pipe/blunt: ~40% desorption. Water filter absorption: ~8%. Cellulose filter absorption: ~20%. Vaporization desorption increased with temperature. Polonium-210 half-life: 138.4 days. 10 hemp samples analyzed.","methodology":"Analysis of 10 dried hemp samples legally available in Poland. Polonium-210 concentrations were measured by radiochemical analysis. Desorption rates were measured across four consumption methods: glass pipe, water pipe (bong), cigarette (joint/spliff), and vaporizer at varying temperatures. Filter absorption efficiency was also measured.","limitations":"Only 10 hemp samples from Poland were tested, which may not represent global cannabis products. Hemp (low-THC) rather than high-THC cannabis was used due to legal restrictions. The study does not directly measure radiation dose in human users."},{"rthcId":"RTHC-05815","title":"\"Like the Wild West\": Health care provider perspectives on impacts of recreational cannabis legalization on patients and providers at a tertiary psychiatric hospital in Ontario, Canada.","authors":"Wiese, Jessica L; Watson, Tara Marie; Bozinoff, Nikki; Rush, Brian; Stergiopoulos, Vicky; Le Foll, Bernard; Rueda, Sergio","year":2024,"journal":"Journal of substance use and addiction treatment, 167, 209487","doi":"10.1016/j.josat.2024.209487","pmid":"39153735","tags":["legalization","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Providers reported legalization had some positive impacts (improved product safety, more open clinical conversations) but also raised concerns about increased cannabis use rates, risks to mental health, and ongoing challenges engaging patients about cannabis. Providers recommended updated curricula, clinical guidelines, standardized screening, and public health campaigns.","whyItMatters":"Mental health settings are at the front line of potential cannabis-related harms. This study provides the first systematic look at how legalization has affected clinical practice in a major psychiatric hospital, revealing a gap between the evolving cannabis landscape and provider preparedness.","specificNumbers":"20 healthcare providers interviewed across multiple roles (physicians, pharmacists, nurses). Interviews conducted June 1 to July 2, 2021 (about 2.5 years post-legalization). Multiple recommendation themes identified across five domains: medical education, mental health care, government, medical cannabis access, and legal cannabis system.","methodology":"Qualitative study with semi-structured interviews of 20 healthcare providers (physicians, pharmacists, nurses) at a tertiary psychiatric hospital in Ontario, Canada, conducted June-July 2021. Thematic analysis of responses about legalization impacts on patient health, clinical practice, and the cannabis access system.","limitations":"Single psychiatric hospital in Ontario limits generalizability. Provider perspectives may not reflect patient experiences. The 2021 data collection occurred during COVID-19, which may have independently affected both cannabis use and mental health care delivery."},{"rthcId":"RTHC-05816","title":"Cannabinoid hyperemesis syndrome: Clinical trajectories and patterns of use three months following a visit to the emergency department.","authors":"Wightman, Rachel S; Metrik, Jane; Lin, Timmy R; Collins, Alexandra B; Beaudoin, Francesca L","year":2024,"journal":"Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 31(5), 463-470","doi":"10.1111/acem.14773","pmid":"37387520","tags":["cannabinoid-hyperemesis","emergency-medicine"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Participants had persistent CHS symptoms (abdominal pain, nausea, cyclic vomiting) for a median of 7 days after their ED visit. Cannabis use frequency and quantity were reduced immediately after the visit but most returned to pre-visit use patterns within days. 25% of those who completed follow-up had recurrent ED visits within 3 months.","whyItMatters":"CHS is increasingly common as cannabis use rises, yet almost nothing is known about what happens after patients leave the ER. This study reveals a cycle of temporary reduction followed by rapid return to use, with ongoing symptoms managed at home, suggesting current ED-based interventions are insufficient to change behavior.","specificNumbers":"39 patients enrolled. Median symptom persistence: 7 days post-ED visit. 25% had recurrent ED visits within 3 months. Most returned to pre-visit cannabis use patterns within days of the ED visit.","methodology":"Prospective observational cohort of 39 patients with suspected CHS recruited from the ED during symptomatic episodes and followed for 3 months. Cannabis use practices, symptom progression, and healthcare utilization were monitored.","limitations":"Small sample size (n=39) limits generalizability. CHS diagnosis was based on clinical suspicion without universally agreed-upon diagnostic criteria. Three-month follow-up may be too short to capture longer-term outcomes."},{"rthcId":"RTHC-05817","title":"Exploring the substitution of cannabis for alcohol and other drugs among a large convenience sample of people who use cannabis.","authors":"Wilkins, Chris; Romeo, Jose; Rychert, Marta; Graydon-Guy, Thomas","year":2024,"journal":"Harm reduction journal, 21(1), 192","doi":"10.1186/s12954-024-01111-w","pmid":"39501355","tags":["harm-reduction","alcohol"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Sixty percent reported cannabis use led to less alcohol use, 60% to less synthetic cannabinoid use, 44% to less morphine use, and 40% to less methamphetamine use. Cannabis had no impact on LSD, MDMA, or cocaine use for about 70% of co-users. One in five reported cannabis led to more tobacco use. Young adults (21-35) and Maori were more likely to report substitution.","whyItMatters":"The cannabis substitution debate has real policy implications: if cannabis replaces more dangerous substances for some populations, restriction policies may inadvertently increase harm. This is among the largest studies to document substitution patterns and, critically, to show these patterns differ by demographic group.","specificNumbers":"23,500 respondents. 60% reported less alcohol use, 60% less synthetic cannabinoid use, 44% less morphine use, 40% less methamphetamine use. 70% no impact on LSD/MDMA/cocaine. 20% more tobacco use. Young adults (21-35) more likely to substitute for alcohol and methamphetamine. Maori more likely to substitute across multiple substances.","methodology":"Online convenience survey promoted via Facebook, completed by 23,500 New Zealand respondents. Those who co-used cannabis and any of eight other substances in the same six-month period rated cannabis's impact on their other substance use. Frequency and quantity were compared across groups. Generalized logistic regression modeled predictors.","limitations":"Convenience sample recruited via Facebook is not representative of all cannabis users. Self-reported substitution effects may reflect perceived rather than actual changes. Cross-sectional data cannot establish causal direction. New Zealand's drug market may differ from other countries."},{"rthcId":"RTHC-05818","title":"Trends in Adolescent Comorbid Cannabis Use Disorder and Postoperative Complications.","authors":"Willer, Brittany L; Mpody, Christian; Nafiu, Olubukola O","year":2024,"journal":"Pediatrics, 153(6)","doi":"10.1542/peds.2024-065757","pmid":"38708543","tags":["youth","surgery"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"CUD prevalence in adolescent surgical patients increased from 0.4% in 2009 to 0.6% in 2022. Adolescents with CUD had significantly higher adjusted odds of respiratory complications (OR 1.52), ICU admission (OR 1.78), mechanical ventilation (OR 2.41), and extended hospital stays (OR 1.96). Mortality and stroke risks were not significantly increased after Bonferroni correction.","whyItMatters":"This is the largest study to date examining how cannabis use disorder affects surgical outcomes in teens. The 2.4-fold increase in mechanical ventilation risk is particularly concerning and suggests CUD should be part of preoperative assessment and counseling for adolescents.","specificNumbers":"558,721 adolescents. 2,604 (0.5%) with CUD. CUD prevalence increased from 0.4% (2009) to 0.6% (2022), p < .001. Adjusted ORs: respiratory complications 1.52 (1.16-2.00), ICU admission 1.78 (1.61-1.98), mechanical ventilation 2.41 (2.10-2.77), extended hospital stay 1.96 (1.74-2.20). All p < .001 except respiratory (p = .002).","methodology":"Retrospective 1:1 propensity-matched cohort study of 558,721 adolescents (ages 10-17) undergoing inpatient surgery at US hospitals in the Pediatric Health Information System from 2009-2022. 2,604 had CUD diagnoses; 2,483 were propensity matched. Bonferroni-corrected significance threshold: p < .008.","limitations":"CUD was identified by diagnostic codes, which likely undercount actual cannabis use. The study cannot distinguish between active use and historical CUD diagnosis. Propensity matching cannot account for unmeasured confounders like the severity of the underlying surgical condition."},{"rthcId":"RTHC-05819","title":"Using Passive and Active Data to Predict Post-Traumatic Stress Disorder Symptoms and Cannabis Use in Recently Discharged UK Veterans: A Protocol for the MAVERICK Feasibility Study.","authors":"Williamson, Grace; Trompeter, Nora; Murphy, Dominic; Saba, Shaddy; Pedersen, Eric R; Davis, Jordan P; Leightley, Daniel","year":2024,"journal":"Mental health science, 2(3)","doi":"10.1002/mhs2.75","pmid":"39440306","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05820","title":"Pseudocannabinoid H4CBD improves glucose response during advanced metabolic syndrome in OLETF rats independent of increase in insulin signaling proteins.","authors":"Wilson, Jessica N; Mendez, Dora A; Dhoro, Francis; Shevchenko, Nikolay; Mascal, Mark; Lund, Kyle; Fitzgerald, Robert; DiPatrizio, Nicholas V; Ortiz, Rudy M","year":2024,"journal":"American journal of physiology. Regulatory, integrative and comparative physiology, 326(2), R100-R109","doi":"10.1152/ajpregu.00125.2022","pmid":"37899754","tags":["diabetes","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Four weeks of oral H4CBD treatment in 41-week-old OLETF rats with advanced metabolic dysfunction reduced body mass by 15% (attributed to abdominal fat loss), decreased glucose area under the curve by 29%, and lowered fasting insulin. These metabolic improvements occurred without significant changes in static insulin signaling protein levels.","whyItMatters":"CBD use has surged among older adults, the population most affected by metabolic syndrome and type 2 diabetes. H4CBD offers a chemically pure, contaminant-free synthetic alternative with demonstrated metabolic benefits, and its mechanism -- working through fat loss rather than direct insulin signaling -- suggests a novel therapeutic pathway.","specificNumbers":"Body mass decreased 15%. Abdominal fat significantly reduced. Glucose response (AUC) decreased 29%. Fasting insulin was reduced. Dose: 200 mg/kg/day for 4 weeks. Rats were 41 weeks old (modeling advanced age-associated metabolic dysfunction). No significant changes in insulin signaling proteins.","methodology":"Controlled animal study using 41-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of type 2 diabetes with metabolic syndrome. Rats received 200 mg/kg H4CBD by oral gavage daily for 4 weeks. Vehicle-treated OLETF and lean LETO control rats were monitored alongside. Oral glucose tolerance tests and insulin signaling markers were assessed.","limitations":"Animal study using a very high dose (200 mg/kg/day) that may not translate to human-relevant doses. The OLETF rat model, while useful, does not perfectly replicate human metabolic syndrome. The 4-week treatment period is short for assessing long-term metabolic effects."},{"rthcId":"RTHC-05821","title":"Maternal Prenatal Use of Alcohol, Tobacco, and Illicit Drugs and Associations with Childhood Cancer Subtypes.","authors":"Wimberly, Courtney E; Gulrajani, Natalie B; Russ, Jeffrey B; Landi, Daniel; Wiemels, Joseph L; Towry, Lisa; Wiencke, John K; Walsh, Kyle M","year":2024,"journal":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 33(3), 347-354","doi":"10.1158/1055-9965.EPI-23-1027","pmid":"38112788","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05822","title":"Updated Risk Assessment of Cannabidiol in Foods Based on Benchmark Dose-Response Modeling.","authors":"Wisotzki, Eva; Franke, Heike; Sproll, Constanze; Walch, Stephan G; Lachenmeier, Dirk W","year":2024,"journal":"Molecules (Basel, Switzerland), 29(19)","doi":"10.3390/molecules29194733","pmid":"39407661","tags":["cbd","regulation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Animal studies yielded a benchmark dose lower confidence limit (BMDL) of 43 mg/kg bw/day, translating to approximately 15 mg/day for humans. Human data identified a lowest observed adverse effect level (LOAEL) of 4.3 mg/kg bw/day. The confirmed health-based guidance value was set at 10 mg/day based on the human LOAEL, citing liver toxicity and possible reproductive toxicity.","whyItMatters":"CBD is sold in a growing, largely unregulated food market with products often recommending doses far exceeding 10 mg daily. This risk assessment provides regulators with a scientifically derived safety threshold and highlights that many commercial CBD food products may exceed safe intake levels.","specificNumbers":"Animal BMDL: 43 mg/kg bw/day. Human-equivalent safe dose: ~15 mg/day. Human LOAEL: 4.3 mg/kg bw/day. Final health-based guidance value: 10 mg/day. Epidiolex therapeutic dose for epilepsy: 5-20 mg/kg/day (far above the food safety level). EU Novel Food application paused by EFSA due to safety data gaps.","methodology":"Updated risk assessment using benchmark dose-response modeling of available animal and human safety data on CBD. Studies suitable for BMDL calculation were identified. Animal-to-human dose translation and standard safety factors were applied to derive a health-based guidance value for CBD in foods.","limitations":"Data gaps remain, particularly for reproductive toxicity and long-term exposure. The guidance value is conservative by design. Individual variation in CBD metabolism (especially related to concurrent medications) is not captured by a single threshold."},{"rthcId":"RTHC-05823","title":"Potentially modifiable risk and protective factors affecting mental and emotional wellness in pregnancy.","authors":"Wohrer, Fiona; Ngo, Helen; DiDomenico, Jared; Ma, Xingya; Roberts, Melissa H; Bakhireva, Ludmila N","year":2024,"journal":"Frontiers in human neuroscience, 18, 1323297","doi":"10.3389/fnhum.2024.1323297","pmid":"38445095","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05824","title":"Therapeutic Potential of Cannabinoid Profiles Identified in Cannabis L. Crops in Peru.","authors":"Wong-Salgado, Pedro; Soares, Fabiano; Moya-Salazar, Jeel; Ramírez-Méndez, José F; Moya-Salazar, Marcia M; Apesteguía, Alfonso; Castro, Americo","year":2024,"journal":"Biomedicines, 12(2)","doi":"10.3390/biomedicines12020306","pmid":"38397908","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05825","title":"Canada's THC unit: Applications for the legal cannabis market.","authors":"Wood, Shea; Gabrys, Robert; Freeman, Tom; Hammond, David","year":2024,"journal":"The International journal on drug policy, 128, 104457","doi":"10.1016/j.drugpo.2024.104457","pmid":"38772194","tags":["regulation","legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"A standard THC unit could be applied across product labeling, consumer education, and regulatory reporting/surveillance. Key challenges include defining the unit amount appropriate for a regulated commercial market, applying it across different product formats (flower, edibles, concentrates), and accounting for different modes of administration (smoking, vaping, ingestion).","whyItMatters":"Without a standard unit, cannabis consumers have no intuitive way to compare potency across products. A standardized THC unit would function like the \"standard drink\" for alcohol -- enabling better consumer decision-making, public health messaging, and epidemiological tracking of consumption trends.","specificNumbers":"Canada legalized recreational cannabis in 2018. The article examines applications across all legal product categories: dried flower, oils, edibles, concentrates, and topicals. Multiple modes of administration are considered, each with different THC bioavailability profiles.","methodology":"Policy analysis examining the applications, considerations, and challenges of establishing and implementing a standard THC unit in Canada's regulated cannabis market. Reviews existing frameworks (including standard drink units for alcohol) and discusses adaptation for cannabis-specific challenges.","limitations":"The article presents considerations rather than definitive conclusions on what the THC unit should be. Bioavailability varies dramatically by consumption method, making a single number inherently imprecise. Consumer understanding and behavior change from standardized labeling is assumed but not demonstrated."},{"rthcId":"RTHC-05826","title":"In vivo profiling of phytocannabinoids in Cannabis spp. varieties via SPME-LC-MS analysis.","authors":"Woźniczka, Katarzyna; Trojan, Václav; Urbanowicz, Krzysztof; Schreiber, Patrik; Zadrożna, Julia; Bączek, Tomasz; Smoleński, Ryszard Tomasz; Roszkowska, Anna","year":2024,"journal":"Analytica chimica acta, 1306, 342621","doi":"10.1016/j.aca.2024.342621","pmid":"38692790","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05827","title":"Examining the impact of legalization on the prevalence of driving after using cannabis: A comparison of rural and non-rural parts of Canada.","authors":"Wrathall, Meghan; Cristiano, Nick; Walters, David; Cullen, Greggory; Hathaway, Andrew","year":2024,"journal":"Traffic injury prevention, 25(4), 571-578","doi":"10.1080/15389588.2024.2333908","pmid":"38572920","tags":["driving","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Rural residents showed a significant increase in driving after cannabis use directly following legalization, which returned to pre-legalization rates one year later. Non-rural residents showed an initial decrease in driving after use followed by a slow increase. No significant differences were observed in passenger-with-impaired-driver rates for either group at any time point.","whyItMatters":"Rural communities face unique cannabis-impaired driving challenges -- longer distances, fewer transportation alternatives, and less law enforcement presence. This study shows legalization caused a temporary but significant spike in rural cannabis-impaired driving, suggesting prevention resources were inadequately directed toward rural areas during the transition.","specificNumbers":"Three time points analyzed: pre-legalization, 2 months post-legalization, 1 year post-legalization. Significant increase in rural driving after cannabis use at 2 months post-legalization. Return to pre-legalization rates at 1 year. Non-rural initial decrease followed by slow increase. No significant changes in passenger prevalence.","methodology":"Multi-wave analysis of Canada's National Cannabis Survey using logistic regression with interactions. Three time points compared: pre-legalization, two months post-legalization, and one year post-legalization. Driving after use and riding as a passenger with an impaired driver were analyzed by rural vs non-rural residence.","limitations":"National Cannabis Survey relies on self-reported driving behavior, which likely underestimates actual cannabis-impaired driving. The rural/non-rural binary classification is simplistic. The study cannot identify what specifically caused the rural spike or its subsequent decline."},{"rthcId":"RTHC-05828","title":"Cannabis consumers' preferences for legal and illegal cannabis: evidence from a discrete choice experiment.","authors":"Xing, Jin; Shi, Yuyan","year":2024,"journal":"BMC public health, 24(1), 2397","doi":"10.1186/s12889-024-19640-1","pmid":"39227852","tags":["legalization","regulation"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"For legal cannabis, quality and accessibility (distance to seller) were the most important attributes. For illegal cannabis, price was the most important attribute. The likelihood of choosing legal cannabis increased with higher quality, lab testing, shorter distance, higher THC, and lower price. Policy simulations predicted that improving quality, allowing delivery, increasing dispensary density, and lowering prices could reduce illegal market share.","whyItMatters":"Despite legalization, illegal cannabis markets remain large or even dominant in many US states. Understanding exactly what drives consumers toward legal or illegal sources provides actionable evidence for policies that could shift market share away from unregulated, untested products.","specificNumbers":"963 adult cannabis consumers. Five product attributes varied: quality, safety (lab testing), accessibility (distance), potency (THC level), and price. Policy simulations identified five strategies to reduce illegal market share: improving quality, ensuring safety testing, allowing delivery services, increasing dispensary density, and lowering prices/taxes.","methodology":"Discrete choice experiment with 963 adults who used cannabis in the past year and lived in states with recreational legalization. Participants chose between purchasing from a legal dispensary or illegal dealer across scenarios varying in quality, safety (lab testing), accessibility, potency, and price. Mixed logit models analyzed preferences.","limitations":"Hypothetical choice scenarios may not perfectly predict real purchasing behavior. The sample was recruited online and may not represent all cannabis consumers, particularly those most reliant on illegal markets. State-level variation in legal market regulations was not modeled."},{"rthcId":"RTHC-05829","title":"The Potential Antinociceptive Effect and Mechanism of Cannabis sativa L. Extract on Paclitaxel-Induced Neuropathic Pain in Rats Uncovered by Multi-Omics Analysis.","authors":"Xu, Yunhui; Yao, Lijuan; Guo, Yuhan; Shi, Chenfeng; Zhou, Jing; Hua, Moli","year":2024,"journal":"Molecules (Basel, Switzerland), 29(9)","doi":"10.3390/molecules29091958","pmid":"38731449","tags":["pain","cancer"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Hemp extract significantly decreased mechanical allodynia, thermal hyperalgesia, and inflammatory cytokines in rats with paclitaxel-induced neuropathy. Multi-omics analysis identified seven key regulated genes (neuroactive ligand-receptor, PPAR, and cAMP pathways), 39 altered metabolites (pentose/glucuronate and glycerophospholipid pathways), and reversed gut microbiota changes.","whyItMatters":"Chemotherapy-induced peripheral neuropathy affects up to 70% of cancer patients and has limited treatment options. This is among the first studies to use multi-omics approaches to map the full spectrum of biological pathways through which cannabis extract relieves this type of nerve pain, moving beyond single-target explanations.","specificNumbers":"Seven key genes significantly regulated (neuroactive ligand-receptor, PPAR signaling, cAMP pathways). 39 significantly altered metabolites identified. Gut bacteria Lachnoclostridium and Lachnospiraceae_UCG-006 reversed by treatment. Significant reductions in mechanical allodynia and thermal hyperalgesia.","methodology":"Paclitaxel-induced peripheral neuropathy rat model. Hemp extract rich in cannabinoids was obtained by supercritical CO2 extraction. Antinociceptive effects measured via behavioral tests. Mechanisms explored using integrated transcriptomics, metabolomics, and gut microbiota analysis.","limitations":"Animal study that may not translate directly to human chemotherapy patients. The hemp extract contains multiple cannabinoids, making it impossible to attribute effects to specific compounds. Dosing and pharmacokinetics differ substantially between rats and humans."},{"rthcId":"RTHC-05830","title":"Acute Effects of Monoacylglycerol Lipase Inhibitor ABX1431 on Neuronal Hyperexcitability, Nociception, Locomotion, and the Endocannabinoid System in HIV-1 Tat Male Mice.","authors":"Yadav-Samudrala, Barkha J; Ravula, Havilah P; Barmada, Karenna M; Dodson, Hailey; Poklis, Justin L; Ignatowska-Jankowska, Bogna M; Lichtman, Aron H; Reissner, Kathryn J; Fitting, Sylvia","year":2024,"journal":"Cannabis and cannabinoid research, 9(6), 1500-1513","doi":"10.1089/can.2023.0247","pmid":"38394322","tags":["hiv","pain","endocannabinoid-system"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In vitro, ABX1431 completely reversed Tat-induced neuronal calcium overexcitement at all tested concentrations, partially through CB1 receptors. In vivo, ABX1431 increased locomotor activity and significantly upregulated 2-AG levels in the striatum and spinal cord. CB2 receptor levels increased in treated control mice but not HIV-model mice.","whyItMatters":"HIV-associated neurological disease affects up to 50% of people living with HIV despite antiretroviral therapy. Boosting the brain's own endocannabinoid system -- rather than using external cannabinoids -- represents a more targeted approach that could avoid the psychoactive effects of THC while still activating protective cannabinoid pathways.","specificNumbers":"ABX1431 reversed Tat-induced calcium overexcitement at all three concentrations (10, 30, 100 nM). In vivo: 2-AG significantly upregulated in striatum and spinal cord. Arachidonic acid upregulated in striatum of vehicle-treated Tat+ mice. CB2R increased in ABX1431-treated Tat- mice only. No changes in CB1R expression.","methodology":"Combined in vitro (frontal cortex neuronal calcium imaging) and in vivo (HIV-1 Tat transgenic mouse model) approach. ABX1431 tested at 10, 30, 100 nM in vitro and 4 mg/kg in vivo. Assessed antinociception (tail-flick, hot plate), locomotion, endocannabinoid levels (mass spectrometry), and receptor expression (western blot).","limitations":"The Tat transgenic mouse model represents only one aspect of HIV neuropathology. Acute treatment results may not reflect chronic use outcomes. The differential CB2R response between Tat+ and Tat- mice complicates interpretation. Human translation requires clinical trials."},{"rthcId":"RTHC-05831","title":"New peripherally-restricted CB1 receptor antagonists, PMG-505-010 and -013 ameliorate obesity-associated NAFLD and fibrosis.","authors":"Yang, Hyekyung; Park, Miey; Lee, Ji Hye; Kim, Bokyoung; Moon, Chang Sang; Bae, Suyeal; Kim, Younghoon; Lee, Hae-Jeung; Park, Cheol-Young","year":2024,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 180, 117501","doi":"10.1016/j.biopha.2024.117501","pmid":"39366030","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05832","title":"Cannabis Use, Use Disorder, and Workplace Absenteeism in the U.S., 2021-2022.","authors":"Yang, Kevin H; Mueller, Letitia; El-Shahawy, Omar; Palamar, Joseph J","year":2024,"journal":"American journal of preventive medicine, 67(6), 803-810","doi":"10.1016/j.amepre.2024.07.021","pmid":"39186019","tags":["workplace","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Past-month cannabis use was associated with more missed work days due to illness and more skipped work days compared to no lifetime use. A clear dose-response relationship emerged: mild CUD increased skipping work 1.6x, moderate CUD 2.0x, and severe CUD 2.9x compared to no CUD.","whyItMatters":"With 15.9% of full-time US workers using cannabis in the past month and 6.5% meeting CUD criteria, the workplace impact is substantial. The dose-response relationship between CUD severity and absenteeism provides concrete data for employers and policymakers grappling with cannabis in the workplace post-legalization.","specificNumbers":"46,499 full-time workers surveyed. 15.9% used cannabis in past month. 6.5% met CUD criteria. Dose-response for skipping work: mild CUD aIRR 1.60 (95% CI: 1.24-2.08), moderate CUD aIRR 1.98 (1.50-2.61), severe CUD aIRR 2.87 (2.12-3.88). Past-month use also associated with more illness-related absences.","methodology":"Cross-sectional analysis of 46,499 full-time employed adults from the 2021-2022 National Survey on Drug Use and Health. Negative binomial regression examined associations between cannabis use recency, frequency, CUD severity, and workplace absenteeism (missed days due to illness/injury and skipped work days), adjusting for sociodemographics and other substance use.","limitations":"Cross-sectional design cannot determine whether cannabis use causes absenteeism or whether shared factors (e.g., mental health conditions) drive both. Self-reported absenteeism may be inaccurate. The study cannot distinguish between impairment-related and other reasons for missing work."},{"rthcId":"RTHC-05833","title":"Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety.","authors":"Yang, Wenjiao; Gong, Xudong; Sun, Haiguo; Wu, Chunhui; Suo, Jin; Ji, Jing; Jiang, Xiangrui; Shen, Jingshan; He, Yang; Aisa, Haji Akber","year":2024,"journal":"European journal of medicinal chemistry, 265, 116048","doi":"10.1016/j.ejmech.2023.116048","pmid":"38150961","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05834","title":"Proteomic and metabolomic insights into the mechanisms of calcium-mediated salt stress tolerance in hemp.","authors":"Yang, Yang; Lu, Zhenhua; Ye, Hailong; Li, Jiafeng; Zhou, Yan; Zhang, Ling; Deng, Gang; Li, Zheng","year":2024,"journal":"Plant molecular biology, 114(6), 126","doi":"10.1007/s11103-024-01525-x","pmid":"39557670","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05835","title":"Comparative proteomic and metabolomic analyses reveal stress responses of hemp to salinity.","authors":"Yang, Yang; Cheng, Yu; Lu, Zhenhua; Ye, Hailong; Du, Guanghui; Li, Zheng","year":2024,"journal":"Plant cell reports, 43(6), 154","doi":"10.1007/s00299-024-03237-4","pmid":"38809335","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05836","title":"Ultrafine Particle Generation from Ozone Oxidation of Cannabis Smoke.","authors":"Yeh, Kristen; Ditto, Jenna C; Rivellini, Laura-Helena; Askari, Amirashkan; Abbatt, Jonathan P D","year":2024,"journal":"Environmental science & technology, 58(52), 23099-23107","doi":"10.1021/acs.est.4c08311","pmid":"39691962","tags":["smoking","contaminants"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Ultrafine particle formation occurred when cannabis smoke was exposed to ozone levels greater than 10 ppb, across all observed primary particle concentrations. Monoterpenes and sesquiterpenes decayed rapidly upon ozone exposure while oxygen-containing species formed. OH radicals generated from ozone-terpene reactions likely play an important role in the oxidation mechanism.","whyItMatters":"Ultrafine particles penetrate deep into the lungs and can enter the bloodstream. Indoor environments often contain ozone from outdoor infiltration and indoor sources (printers, air purifiers). This study reveals that simply smoking cannabis indoors creates conditions for secondary particle formation that adds to the already known health risks of cannabis smoke.","specificNumbers":"UFP formation occurred at ozone levels > 10 ppb. Primary particle concentration range: 1,030-4,580 micrograms/m3. Primary particle diameter: 0.1-1 micrometer. Monoterpene and sesquiterpene levels decayed rapidly with ozone exposure. Nitrogen-containing species increased in particles during oxidation.","methodology":"Environmental chamber study monitoring particle size distribution and gas-phase and particle-phase composition in real time when cannabis smoke was exposed to ozone. Primary particle diameter ranged from 0.1 to 1 micrometer. Gas and particle measurements tracked chemical changes during oxidation.","limitations":"Chamber study may not perfectly replicate real-world indoor conditions where air exchange, humidity, and other factors affect particle formation. The study did not directly measure health effects of the ultrafine particles produced. Cannabis smoke composition varies by strain and consumption method."},{"rthcId":"RTHC-05837","title":"Cannabidiol, a plant-derived compound, is an emerging strategy for treating cognitive impairments: comprehensive review of randomized trials.","authors":"Yndart Arias, Adriana; Vadell, Kamila; Vashist, Arti; Kolishetti, Nagesh; Lakshmana, Madepalli K; Nair, Madhavan; Liuzzi, Juan P","year":2024,"journal":"Frontiers in pharmacology, 15, 1403147","doi":"10.3389/fphar.2024.1403147","pmid":"39323633","tags":["cbd","cognition"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Nine of 16 outcomes across 14 trials showed CBD improved anxiety and cognition. Effective oral doses ranged from 200-1,500 mg (single dose) and 13.75 mg vaporized. CBD had a good safety profile with no addiction behaviors. Non-significant results were attributed to THC masking effects, low doses, unknown CBD purity, and underpowered designs.","whyItMatters":"Despite widespread consumer use of CBD for cognitive and anxiety issues, the clinical evidence remains surprisingly thin and inconsistent. This review identifies the specific methodological factors that explain the variability, providing a roadmap for designing better trials.","specificNumbers":"14 randomized trials reviewed. 9 of 16 outcomes showed improvement. Effective oral doses: 200-1,500 mg single dose. Effective vaporized dose: 13.75 mg. Good safety profile reported across trials. No addiction behaviors observed.","methodology":"Systematic literature review using PUBMED and university resources. 14 randomized clinical trials selected and compared for design, CBD formulations, populations, and outcomes. Results synthesized conceptually and in summary tables.","limitations":"The 14 trials reviewed had highly variable designs, populations, doses, formulations, and outcome measures, making pooled conclusions difficult. Many trials were underpowered. The review does not include a meta-analytic statistical synthesis."},{"rthcId":"RTHC-05838","title":"Cannabis Use During Early Pregnancy Following Recreational Cannabis Legalization.","authors":"Young-Wolff, Kelly C; Slama, Natalie E; Avalos, Lyndsay A; Padon, Alisa A; Silver, Lynn D; Adams, Sara R; Does, Monique B; Ansley, Deborah; Castellanos, Carley; Campbell, Cynthia I; Alexeeff, Stacey E","year":2024,"journal":"JAMA health forum, 5(11), e243656","doi":"10.1001/jamahealthforum.2024.3656","pmid":"39485336","tags":["prenatal","legalization"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Prenatal cannabis use rose from 4.5% in 2012 to 7.1% before legalization implementation, then jumped to 8.6% after implementation (level change RR 1.10, 95% CI: 1.04-1.16). The increase was detected by both toxicology testing and self-report. In jurisdictions allowing adult-use retailers, the increase was 21% (RR 1.21), while jurisdictions banning retailers showed no change (RR 1.01).","whyItMatters":"This is the largest and most rigorous study to date linking recreational cannabis legalization directly to increased prenatal use. The finding that the increase was concentrated in areas with dispensaries, not just with legalization itself, suggests that retail access -- not just legal status -- drives prenatal cannabis use.","specificNumbers":"300,993 pregnancies. Pre-RCL use: 4.5% (2012) to 7.1% (January 2018). Post-implementation: 8.6% (February 2018). Level change at RCL passage: RR 1.03 (not significant). Level change at implementation: RR 1.10 (95% CI: 1.04-1.16). Jurisdictions allowing retailers: RR 1.21 (1.10-1.33). Jurisdictions banning retailers: RR 1.01 (0.93-1.10).","methodology":"Population-based interrupted time series study of 300,993 pregnancies (236,327 unique individuals) in Kaiser Permanente Northern California from January 2012 to December 2019. Cannabis use was universally screened by self-report and urine toxicology at ~8-10 weeks gestation. Poisson regression models adjusted for age, race/ethnicity, and neighborhood deprivation.","limitations":"Single health system in Northern California may not generalize to all populations. Urine toxicology detects recent use but cannot distinguish occasional from heavy use. The pre-legalization upward trend in prenatal use means some increase would have occurred regardless of legalization."},{"rthcId":"RTHC-05839","title":"Changes in Prenatal Cannabis Use Among Pregnant Individuals From 2012 to 2022.","authors":"Young-Wolff, Kelly C; Chi, Felicia W; Lapham, Gwen T; Alexeeff, Stacey E; Does, Monique B; Ansley, Deborah; Campbell, Cynthia I","year":2024,"journal":"Obstetrics and gynecology, 144(4), e101-e104","doi":"10.1097/AOG.0000000000005711","pmid":"39208448","tags":["prenatal","demographics"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Prenatal cannabis use prevalence increased from 5.5% to 9.0% (aPR 1.82). Similar increases were seen by toxicology test (aPR 1.70) and self-report (aPR 2.12). The increase varied significantly by race/ethnicity and age, with the highest prevalence consistently among Black individuals and those aged 13-24. Although rates increased more slowly in these groups, disparities persisted.","whyItMatters":"The near-doubling of prenatal cannabis use over a decade coincides with legalization and increasing social acceptance. Persistent disparities by race and age highlight that the public health impact of rising prenatal cannabis use is not equally distributed, requiring targeted intervention strategies.","specificNumbers":"Overall increase: 5.5% (2012) to 9.0% (2022), aPR 1.82 (1.72-1.92). By toxicology: aPR 1.70 (1.60-1.81). By self-report: aPR 2.12 (1.95-2.30). Highest prevalence among Black individuals and ages 13-24 across all years. Sample sizes: 33,546 (2012), 43,415 (2022).","methodology":"Population-based cross-sectional study analyzing electronic health records from Kaiser Permanente Northern California. Compared prenatal cannabis use in 2012 (n=33,546) to 2022 (n=43,415) using self-report and urine toxicology testing during standard prenatal care. Adjusted prevalence ratios calculated.","limitations":"Single California health system with universal screening may not represent settings without routine screening. The study compared two time points rather than tracking continuous trends. Prenatal cannabis use at one screening point may not capture full pregnancy exposure."},{"rthcId":"RTHC-05840","title":"Association of psychiatric and substance use disorders with cannabis use and cannabis use disorder during early pregnancy in northern California.","authors":"Young-Wolff, Kelly C; Chi, Felicia W; Campbell, Cynthia I; Does, Monique B; Brown, Qiana L; Alexeeff, Stacey E; Ansley, Deborah; Wang, Xiaoming; Lapham, Gwen T","year":2024,"journal":"Addiction (Abingdon, England), 119(11), 1987-1997","doi":"10.1111/add.16622","pmid":"39082097","tags":["prenatal","mental-health","addiction"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"All psychiatric disorders studied were associated with elevated cannabis use and CUD during pregnancy. Strongest associations for any use: bipolar disorder (aOR 2.83) and tobacco use disorder (aOR 4.03). Strongest associations for CUD: psychotic disorders (aOR 10.01) and stimulant use disorder (aOR 21.99). Anxiety, bipolar, and depressive disorders were associated with daily versus monthly cannabis use.","whyItMatters":"This is the largest study to systematically examine the relationship between mental health conditions and prenatal cannabis use. The finding that virtually every psychiatric and substance use diagnosis increases prenatal cannabis use risk suggests these women may be self-medicating, and that prenatal mental health treatment could indirectly reduce cannabis exposure.","specificNumbers":"299,496 pregnancies. 6.8% used cannabis, 0.2% had CUD. Anxiety prevalence: 14.3%. For any cannabis use: bipolar aOR 2.83, PTSD aOR 2.15, ADHD aOR 1.94, depression aOR 1.74, anxiety aOR 1.62. For CUD: psychotic disorders aOR 10.01, stimulant use disorder aOR 21.99, opioid use disorder aOR 15.19, tobacco use disorder aOR 8.21.","methodology":"Observational study of 299,496 pregnancies from 227,555 individuals screened at Kaiser Permanente Northern California from 2011-2021 (excluding 2020). Psychiatric and substance use disorder diagnoses from electronic health records in the two years prior to pregnancy. Cannabis use measured by self-report and urine toxicology at prenatal care entry.","limitations":"Observational design cannot establish whether psychiatric conditions cause cannabis use or vice versa. EHR-based diagnoses may not capture all psychiatric conditions, particularly in mild or undiagnosed cases. Year 2020 was excluded due to pandemic disruptions."},{"rthcId":"RTHC-05841","title":"Intentions to Use Cannabis Postpartum: A Qualitative Study of Pregnant Individuals Who Used Cannabis During Early Pregnancy.","authors":"Young-Wolff, Kelly C; Green, Andrea; Iturralde, Esti; Altschuler, Andrea; Does, Monique B; Jackson-Morris, Melanie; Adams, Sara R; Ansley, Deborah; Conway, Amy; Goler, Nancy; Skelton, Kara; Foti, Tara R","year":2024,"journal":"Journal of women's health (2002), 33(4), 435-445","doi":"10.1089/jwh.2023.0066","pmid":"38407822","tags":["prenatal","breastfeeding"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Most participants planned postpartum cannabis use at reduced frequency with harm reduction approaches (e.g., smoking outside). Many were motivated to abstain during breastfeeding. Some believed \"pump and dump\" would reduce THC transfer to infants. White participants were more likely to plan cannabis use during breastfeeding and to want breastfeeding safety information. Some viewed cannabis as critical for coping with postpartum challenges.","whyItMatters":"Understanding what pregnant cannabis users plan to do postpartum is essential for designing effective interventions. The finding that most plan to reduce but not stop, and that many rely on unvalidated harm reduction strategies like \"pump and dump,\" reveals specific knowledge gaps that clinicians can address.","specificNumbers":"53 participants (23 Black, 30 White). Mean age 30.3 years. Usage at prenatal care entry: 70% daily, 25% weekly, 6% monthly or less. 18 focus groups conducted. White participants more likely to plan breastfeeding cannabis use and request safety data.","methodology":"Eighteen virtual focus groups conducted November-December 2021 with 53 pregnant adults (23 Black, 30 White) from Kaiser Permanente Northern California who self-reported prenatal cannabis use. Focus groups were recorded, transcribed, and analyzed using thematic analysis.","limitations":"Qualitative study of 53 women from one health system cannot capture the full range of experiences. Women who agreed to participate may differ from those who declined. Plans stated during pregnancy may not match actual postpartum behavior."},{"rthcId":"RTHC-05842","title":"Clinician perspectives on adolescent cannabis-related beliefs and behaviors following recreational cannabis legalization.","authors":"Young-Wolff, Kelly C; Does, Monique B; Mian, Maha N; Sterling, Stacy A; Satre, Derek D; Campbell, Cynthia I; Silver, Lynn D; Alexeeff, Stacey E; Cunningham, Sarah F; Asyyed, Asma; Altschuler, Andrea","year":2024,"journal":"Addictive behaviors, 156, 108046","doi":"10.1016/j.addbeh.2024.108046","pmid":"38744214","tags":["youth","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Clinicians reported post-RCL increases in adolescent cannabis use, non-combustible modes and high-potency products, younger first use ages, and self-medication. They described shifts in social norms, appealing marketing, easier access, fewer perceived harms, greater parental permissiveness, more cannabinoid hyperemesis syndrome, increased psychosis, and decreased court-mandated treatment.","whyItMatters":"Clinicians across specialties are observing a consistent pattern of adolescent cannabis-related changes post-legalization that quantitative studies have been slow to capture. Their perspectives on high-potency products, psychosis, and parental permissiveness provide early clinical signals that deserve population-level investigation.","specificNumbers":"32 clinicians interviewed (56.3% female, mean age 45.9 years, 65.3% non-Hispanic White). Four specialties represented: Addiction Medicine (n=13), Psychiatry (n=7), Pediatrics (n=5), Emergency (n=7). Interviews conducted September 6 to December 21, 2022.","methodology":"Semi-structured qualitative interviews with 32 clinicians from Addiction Medicine (n=13), Psychiatry/Mental Health (n=7), Pediatrics (n=5), and Emergency Department (n=7) in Kaiser Permanente from September-December 2022. Thematic analysis of transcribed interviews.","limitations":"Clinician perspectives are subjective and may reflect selection bias (clinicians who see the most severe cases). The sample is from one healthcare organization in California. Without quantitative data, it is impossible to determine the actual magnitude of the changes described."},{"rthcId":"RTHC-05843","title":"Arbuscular Mycorrhizal Fungi-Mediated Modulation of Physiological, Biochemical, and Secondary Metabolite Responses in Hemp (Cannabis sativa L.) under Salt and Drought Stress.","authors":"Yuan, Haipeng; Si, Hao; Ye, Yunshu; Ji, Qiuyan; Wang, Haoyu; Zhang, Yuhong","year":2024,"journal":"Journal of fungi (Basel, Switzerland), 10(4)","doi":"10.3390/jof10040283","pmid":"38667954","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05844","title":"Treating young adult cannabis use disorder with text message-delivered peer network counseling.","authors":"Zaharakis, Nikola; Coatsworth, J Douglas; Riggs, Nathaniel R; Radford, Aubrie; Rayburn, Stephanie; Mennis, Jeremy; Russell, Michael A; Brown, Aaron; Mason, Michael J","year":2024,"journal":"Contemporary clinical trials, 144, 107635","doi":"10.1016/j.cct.2024.107635","pmid":"39019156","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05845","title":"Medical Marijuana for Pain Management in Hospice Care as a Complementary Approach to Scheduled Opioids: A Single Arm Study.","authors":"Zanker, Theodore; Sacco, Joseph; Prota, James; Palma, Michelle; Viola Lee, Kyoung A; Wang, Ruixiao Rachel; Liang, Yixuan; Cunningham, James; Mackary, Mona; Ovchinnikova, Polina","year":2024,"journal":"The American journal of hospice & palliative care, 41(9), 1002-1010","doi":"10.1177/10499091231213359","pmid":"38100655","tags":["pain","medical-cannabis","opioids"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The combination of medical cannabis (CBD-dominant formulation) and scheduled opioids showed a statistically significant longitudinal reduction in pain intensity (p = .0029). A non-significant trend toward lower opioid doses was observed. Well-being, appetite, nausea, and respiratory function showed non-significant changes. Only 3 of 66 patients (4.5%) had minor, reversible adverse events. No serious or life-threatening events occurred.","whyItMatters":"Pain management in end-of-life care often requires escalating opioid doses with increasing side effects. Adding a CBD-dominant cannabis formulation achieved significant additional pain relief without serious adverse events, potentially allowing patients to maintain comfort with lower opioid-related toxicity.","specificNumbers":"66 inpatients assessed over 996 treatment days. Average age: 68.2 years, 90.9% White. Cancer was most common diagnosis. Significant pain reduction: p = .0029. Adverse events: 3 patients (4.5%), all minor and reversible. Cannabis doses: 40 mg CBD/1.5 mg THC or 80 mg CBD/3 mg THC.","methodology":"Single-arm study of 66 hospice inpatients using scheduled oral, parenteral, or transdermal opioids. Patients received standardized oral medical cannabis: 40 mg CBD/1.5 mg THC or 80 mg CBD/3 mg THC. Outcomes assessed over 996 treatment days using the Mann-Whitney test and longitudinal mixed effects regression.","limitations":"Single-arm design without placebo control means the placebo effect and natural disease progression cannot be separated from treatment effects. The predominantly White, cancer-diagnosis sample limits generalizability. The CBD-dominant formulation may not represent all cannabis products used in palliative settings."},{"rthcId":"RTHC-05846","title":"Cannabidiol-Derived Cannabinoids: The Unregulated Designer Drug Market Following the 2018 Farm Bill.","authors":"Zawatsky, Charles N; Mills-Huffnagle, Sara; Augusto, Corinne M; Vrana, Kent E; Nyland, Jennifer E","year":2024,"journal":"Medical cannabis and cannabinoids, 7(1), 10-18","doi":"10.1159/000536339","pmid":"38352661","tags":["synthetic-cannabinoids","regulation","vaping"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The CBD-derived cannabinoid market has expanded from delta-8-THC to include potent synthetic cannabinoids with greater agonist activity at CB1 receptors than delta-9-THC. The acetate ester motif (linked to EVALI vaping lung injuries) has been incorporated into multiple THC analogues. Products contain under-researched reaction side products from manufacturing. Regulatory oversight is virtually nonexistent.","whyItMatters":"Millions of Americans are consuming CBD-derived cannabinoids that may be more potent than THC, contain unknown reaction byproducts, and include chemical structures linked to serious lung injuries. This represents a regulatory blind spot created by the Farm Bill's hemp legalization that could become a public health crisis.","specificNumbers":"Delta-8-THC was the first widely marketed product. Novel cannabinoids now include sidechain variants with purportedly greater CB1 agonist activity than delta-9-THC. The acetate ester motif (implicated in EVALI) is being incorporated into multiple THC analogues. Production uses fully synthetic routes rather than simple isomerization.","methodology":"Narrative review summarizing current scientific knowledge on psychoactive cannabinoids synthesized from CBD, including delta-8-THC, O-acetyl-THC, and novel sidechain variants. Reviews manufacturing processes, regulatory gaps, epidemiological findings, and pharmacological concerns.","limitations":"The review relies on limited available research, as most CBD-derived cannabinoids have never been formally studied. Market composition changes rapidly, potentially outpacing the review. The actual prevalence of adverse events may be substantially underreported."},{"rthcId":"RTHC-05847","title":"Recreational Drug Overdose-Clinical Value of Toxicological Analysis.","authors":"Zellner, Tobias; Eyer, Florian; Rabe, Christian; Geith, Stefanie; Haberl, Bettina; Schmoll, Sabrina","year":2024,"journal":"Toxics, 12(9)","doi":"10.3390/toxics12090662","pmid":"39330590","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05848","title":"Cannabis smoke and oral Δ9THC enhance working memory in aged but not young adult subjects.","authors":"Zequeira, Sabrina; Gazarov, Emely A; Guvenli, Alara A; Berthold, Erin C; Senetra, Alexandria S; Febo, Marcelo; Hiranita, Takato; McMahon, Lance R; Sharma, Abhisheak; McCurdy, Christopher R; Setlow, Barry; Bizon, Jennifer L","year":2024,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2024.09.26.615028","pmid":"39574655","tags":["cognition","aging","thc"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Acute cannabis smoke enhanced working memory in aged male rats but impaired it in aged females, with no effects in young adults of either sex. Chronic oral THC enhanced working memory in aged rats of both sexes without affecting young adults. Neither route of administration affected hippocampus-dependent spatial memory in any group. Minimal age differences were found in THC pharmacokinetics.","whyItMatters":"The fastest-growing demographic of cannabis users is older adults, yet almost all cannabis-cognition research uses young subjects. This study flips the script: instead of asking whether cannabis harms young brains, it asks whether cannabis helps aging brains, and finds evidence that it can.","specificNumbers":"Acute smoke: enhanced working memory in aged males, impaired in aged females, no effects in young adults. Chronic oral THC: enhanced working memory in aged rats of both sexes, no effects in young adults. No effects on hippocampus-dependent spatial memory in any group with either route.","methodology":"Two experiments in young adult and aged rats of both sexes. Experiment 1: acute cannabis smoke exposure with working memory (prefrontal cortex-dependent) and spatial memory (hippocampus-dependent) tests. Experiment 2: chronic oral THC consumption with the same cognitive assessments. THC pharmacokinetics measured for both routes.","limitations":"Animal study using rats, which have shorter lifespans and different endocannabinoid system dynamics than humans. Cognitive tasks in rats approximate but do not replicate human working memory. The sex difference with smoke but not oral administration suggests route-specific effects that complicate interpretation."},{"rthcId":"RTHC-05849","title":"Efficacy of cannabinoids compared to the current standard treatments on symptom relief in persons with multiple sclerosis (CANSEP trial): study protocol for a randomized clinical trial.","authors":"Zertal, Amel; Alami Marrouni, Kanza; Arbour, Nathalie; Jutras-Aswad, Didier; Pomey, Marie-Pascale; Rouleau, Isabelle; Prat, Alexandre; Larochelle, Catherine; Beaulieu, Pierre; Chamelian, Laury; Sylvestre, Marie-Pierre; Morin, Danielle; Ouellette, Jean-Sylvain; Fréjeau, Nathalie; Duquette, Pierre","year":2024,"journal":"Frontiers in neurology, 15, 1440678","doi":"10.3389/fneur.2024.1440678","pmid":"39114536","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05850","title":"Factors Associated with Medical Cannabis Use After Certification: A Three-Month Longitudinal Study.","authors":"Zhang, Chenshu; Slawek, Deepika E; Ross, Jonathan; Zolotov, Yuval; Castillo, Felipe; Levin, Frances R; Sohler, Nancy L; Minami, Haruka; Cunningham, Chinazo O; Starrels, Joanna L; Arnsten, Julia H","year":2024,"journal":"Cannabis and cannabinoid research, 9(3), e859-e869","doi":"10.1089/can.2022.0248","pmid":"36961410","tags":["medical-cannabis","opioids","demographics"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Within three months of certification, 29% used predominantly high-THC products, 30% used other products, and 41% did not use any cannabis. White race, multi-site pain, and sedative use predicted MC use. Current tobacco and unregulated cannabis use predicted non-use. Among those who used MC, female gender and older age predicted lower likelihood of choosing high-THC products.","whyItMatters":"Getting certified does not mean patients will use medical cannabis. Understanding who actually follows through -- and what products they choose -- reveals barriers to access and potential disparities that certification alone does not solve.","specificNumbers":"225 patients enrolled. 29% used high-THC products, 30% used other products, 41% did not use MC. Non-Hispanic White race, multi-site pain, and past 30-day sedative use predicted MC use. Female gender and older age predicted lower high-THC product choice.","methodology":"Longitudinal cohort study of 225 adults with chronic/severe pain on opioids who were newly certified for medical cannabis in New York State (November 2018-January 2022). Web-based assessments every 2 weeks for 3 months. Generalized estimating equation models examined predictors.","limitations":"New York's medical cannabis program during the study period was restrictive compared to other states, potentially limiting product options and access. The 3-month follow-up may not capture longer-term adoption patterns. The sample may not represent all MC-certified patients."},{"rthcId":"RTHC-05851","title":"The effect of cannabis edibles on driving and blood THC.","authors":"Zhao, S; Brands, B; Kaduri, P; Wickens, C M; Hasan, O S M; Chen, S; Le Foll, B; Di Ciano, P","year":2024,"journal":"Journal of cannabis research, 6(1), 26","doi":"10.1186/s42238-024-00234-y","pmid":"38822413","tags":["driving","edibles"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Cannabis edibles produced a decrease in mean speed at 2 hours post-consumption but not at 4 or 6 hours. No changes were found in weaving (SDLP), maximum speed, speed variability, or reaction time at any time point. Blood THC peaked at ~2.8 ng/mL at 2 hours. Driving impairment was not correlated with blood THC levels. Participants felt subjectively intoxicated for 7 hours and were less willing to drive for up to 6 hours.","whyItMatters":"This is the first study of cannabis edibles and driving. Current legal THC driving limits are based on smoked cannabis research. Edibles produce lower blood THC levels but longer subjective intoxication, creating a mismatch between how impaired users feel and what objective driving measures show.","specificNumbers":"Mean THC consumed: 7.3 mg. Blood THC at 2 hours: ~2.8 ng/mL. Significant speed decrease at 2 hours only. No changes in SDLP, max speed, SD of speed, or reaction time at any time. Subjective intoxication lasted 7 hours. Reduced willingness/ability to drive for 6 hours.","methodology":"Counterbalanced crossover study with cannabis edible and no-THC/CBD control sessions. Participants drove a driving simulator before and after consuming their preferred legally purchased edible (mean 7.3 mg THC). Blood THC and metabolites were measured. Standard and dual-task driving assessments at 2, 4, and 6 hours.","limitations":"Driving simulator does not replicate all aspects of real-world driving. The mean dose (7.3 mg) was below the maximum single-package limit, so higher doses may produce more impairment. Individual tolerance varies widely. Small sample typical of driving simulation studies."},{"rthcId":"RTHC-05852","title":"Tobacco Quitline Callers Who Use Cannabis and Their Likelihood of Quitting Cigarette Smoking.","authors":"Zhu, Shu-Hong; Tedeschi, Gary J; Li, Shuwen; Wang, Jijiang; Aughinbaugh, Emily; Pratt, Andrea S; Zhuang, Yue-Lin","year":2024,"journal":"American journal of preventive medicine, 67(2), 241-248","doi":"10.1016/j.amepre.2024.03.007","pmid":"38484902","tags":["tobacco","addiction","treatment"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis co-use was reported by 27.2% of quitline callers. Co-users were more likely to be male, younger, and have mental health conditions. After controlling for demographics and cessation services, co-users were significantly less likely to quit smoking at 7 months (23.2% vs 28.9%, p < .001). Among co-users, 42.9% intended to quit cannabis within 30 days.","whyItMatters":"Tobacco quitlines are one of the most widely used cessation resources. Learning that over a quarter of their callers also use cannabis -- and that co-use lowers quit rates -- identifies both a problem and an opportunity. The 43% expressing cannabis quit intentions suggests these callers are open to dual intervention.","specificNumbers":"45,151 total callers. 27.2% co-used cannabis. 7-month quit rates: co-users 23.2% vs non-co-users 28.9% (p < .001). Similar rates of receiving counseling and FDA-approved cessation aids between groups. 42.9% of co-users intended to quit cannabis within 30 days. 3,545 evaluated at 7 months.","methodology":"Analysis of Kick It California (state tobacco quitline) caller data from January 2020 through December 2023 (N=45,151). A subgroup (n=3,545) was randomly sampled for 7-month evaluation. Cessation rates compared between co-users and non-co-users, controlling for demographics and cessation service utilization.","limitations":"Observational data from a single state quitline. Self-reported outcomes may overestimate quit rates. The association between co-use and lower quit rates could reflect shared underlying risk factors rather than a direct effect of cannabis on smoking cessation."},{"rthcId":"RTHC-05853","title":"In Vivo Pharmacodynamic and Pharmacokinetic Assessment of Cannabidiol-loaded Camel Milk Exosomes in Doxorubicin-resistant Triple-negative Breast Cancer Xenografts.","authors":"Aare, Mounika; Padakanti, Sandeep Chary; Singh, Mandip","year":2025,"journal":"AAPS PharmSciTech, 26(7), 227","doi":"10.1208/s12249-025-03201-9","pmid":"40936044","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05854","title":"Polyunsaturated fatty acids and their endocannabinoid-related metabolites activity at human TRPV1 and TRPA1 ion channels expressed in HEK-293 cells.","authors":"Abate, Atnaf; Santiago, Marina; Garcia-Bennett, Alfonso; Connor, Mark","year":2025,"journal":"PeerJ, 13, e19125","doi":"10.7717/peerj.19125","pmid":"40151457","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05855","title":"Social cognition in young adults who endorse a cannabis use disorder.","authors":"Abbott, Gabrielle; Greenwood, Lisa-Marie; Bartschi, Jessica G; Dunsford, Suraya; Goodwin, Isabella; Paloubis, Anastasia; Quinones-Valera, Marianna; McTavish, Eugene; Verdejo-Garcia, Antonio; Cousijn, Janna; Chan, Gary C K; Solowij, Nadia; Lorenzetti, Valentina","year":2025,"journal":"Psychopharmacology","doi":"10.1007/s00213-025-06890-z","pmid":"40958032","tags":["cognition","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"There were no significant effects of CUD on social cognition measures including emotion recognition, emotional differentiation, or immediate/delayed face memory (effect sizes d = 0-0.314). Neither problematic use severity nor cannabis dosage was associated with social cognition performance.","whyItMatters":"Social cognition deficits are often assumed to accompany substance use disorders and can affect interpersonal relationships and treatment engagement. This well-controlled study suggests these deficits may not be a defining feature of CUD in young adults, challenging assumptions about cannabis-related social impairment.","specificNumbers":"83 CUD participants, 32 controls. Effect sizes ranged from d = 0 to 0.314 (all non-significant). No associations between CUDIT-R scores or cannabis grams/past month and social cognition. Controlled for nicotine, alcohol, anxiety, and recency of use.","methodology":"Cross-sectional comparison of 83 young adults endorsing CUD and 32 controls. Assessed emotion recognition, emotional differentiation, and face memory tasks. Analyses controlled for hours since last cannabis use, nicotine/alcohol use, and trait anxiety.","limitations":"Cross-sectional design at a single time point. The CUD group was young (18-32) and relatively well-educated, which may have protected against social cognitive decline. The sample was not treatment-seeking, potentially excluding more severe cases."},{"rthcId":"RTHC-05856","title":"Cognitive performance in young adults who endorse a cannabis use disorder.","authors":"Abbott, Gabrielle; Greenwood, Lisa; Bartschi, Jessica G; Dunsford, Suraya; Goodwin, Isabella; Paloubis, Anastasia; Valera, Marianna Quinones; McTavish, Eugene; Verdejo-Garcia, Antonio; Cousijn, Janna; Chan, Gary C K; Solowij, Nadia; Lorenzetti, Valentina","year":2025,"journal":"Comprehensive psychiatry, 142, 152620","doi":"10.1016/j.comppsych.2025.152620","pmid":"40690867","tags":["cognition","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"CUD participants had significantly lower IQ with a strong effect size (p < .001, d = 0.862), driven specifically by lower verbal IQ. This finding survived adjustment for education years. No other cognitive domains showed significant differences, and neither problematic use severity nor dosage was associated with cognition.","whyItMatters":"The selective verbal IQ deficit is striking because it survived correction for education and was not accompanied by impairments in other domains. This specificity suggests cannabis use disorder may affect certain aspects of language-mediated intelligence while leaving other cognitive functions intact in young adults.","specificNumbers":"IQ difference: p < .001, d = 0.862 (strong effect). Driven by verbal IQ. Survived education adjustment. No significant effects on executive function, working memory, episodic memory, attention, or verbal reasoning. 83 CUD vs 32 controls.","methodology":"Cross-sectional study of 115 young adults (83 with CUD, 32 controls, ages 18.5-32.5). Comprehensive cognitive battery assessed executive function, working memory, episodic memory, verbal reasoning, attention, and IQ. All analyses accounted for alcohol/nicotine use and trait anxiety.","limitations":"Cross-sectional design cannot determine whether lower verbal IQ preceded or resulted from CUD. Pre-existing verbal IQ differences could predispose individuals to CUD rather than cannabis causing IQ decline. The non-treatment-seeking sample may not represent more severe CUD."},{"rthcId":"RTHC-05857","title":"Cannabis use in different ethnicity/race populations and risk of ischemic stroke: A systematic review and meta-analysis.","authors":"Abdullah, Farah Thamer; Al-Dulaimi, Abdulla A; Vaghela, Krunal; H, Malathi; Prasad, K D V; Mohammed, Jaafaru Sani; Gupta, Harshit; Sahoo, Samir; Hulail, Hanen Mahmod; Kadhem, Mundhr","year":2025,"journal":"Journal of ethnicity in substance abuse, 1-19","doi":"10.1080/15332640.2025.2505059","pmid":"40397400","tags":["cardiovascular","stroke"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Pooled analysis of seven studies revealed a statistically significant association between cannabis use and ischemic stroke risk (pooled OR = 2.05, 95% CI: 1.46-2.87, p < 0.001). Moderate heterogeneity was present (I-squared = 68.9%, p = .007).","whyItMatters":"Ischemic stroke among young adults is increasing globally, paralleling rising cannabis use. This meta-analysis provides the strongest pooled evidence to date that cannabis use approximately doubles stroke risk, a finding with particular relevance as legalization expands and cannabis is increasingly perceived as low-risk.","specificNumbers":"821 initial records screened, 7 studies included (published 2007-2023). Pooled OR = 2.05 (95% CI: 1.46-2.87). Heterogeneity: I-squared = 68.9%. Studies included case-control, cohort, and cross-sectional designs.","methodology":"Systematic review and meta-analysis following PRISMA guidelines. Searched PubMed, Web of Science, Scopus, Embase, and Google Scholar through March 2025. Seven studies (2007-2023) including case-control, cohort, and cross-sectional designs met inclusion criteria. Random-effects model used for pooling. Quality assessed with JBI checklist.","limitations":"Only seven studies met inclusion criteria, reflecting the limited evidence base. Moderate heterogeneity suggests variability across studies. Most studies relied on self-reported cannabis use and could not control for dose, frequency, or method of consumption. Observational designs cannot prove causation."},{"rthcId":"RTHC-05858","title":"Targeting the endocannabinoid system to suppress mTORC1 hyperactivation in TSC-associated kidney disease.","authors":"Abergel, Eden; Pri-Chen, Hadass; Wallach-Dayan, Shulamit; Hinden, Liad; Tam, Joseph; Volovelsky, Oded; Nechama, Morris","year":2025,"journal":"American journal of physiology. Renal physiology, 329(3), F325-F334","doi":"10.1152/ajprenal.00097.2025","pmid":"40707038","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05859","title":"Oral Cannabidiol for Acute Post-Extraction Pain: A Randomized Pilot Study.","authors":"Abidi, Ammaar H; Kassan, Modar; Derefinko, Karen","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(12)","doi":"10.3390/ph18121792","pmid":"41471281","tags":["cbd","pain","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Dental extractions are one of the most common surgeries worldwide, and post-operative pain management typically relies on ibuprofen, acetaminophen, or opioids. Could CBD offer a non-opioid alternative? This pilot trial was designed to find out whether that question is even testable — not to answer it.\n\nEight adults undergoing simple tooth extraction were randomized to four groups of 2 patients each: low-dose CBD (17 mg/mL), high-dose CBD (37 mg/mL), placebo, or standard treatment (ibuprofen/acetaminophen). CBD and placebo groups received 0.5 mL doses every 4-6 hours as needed for 7 days. Pain was tracked using a 0-10 scale via ecological momentary assessment over 72 hours.\n\nWith only 2 patients per group, no meaningful efficacy comparisons are possible — this was never the point. The study established that the trial protocol works: patients were successfully randomized, dosed, and assessed using phone-based pain tracking. CBD was well-tolerated with no serious adverse events.\n\nThe value of this study is entirely methodological. It lays the groundwork for a properly powered randomized controlled trial that could determine whether CBD has a role in dental pain management. For a field desperate for non-opioid pain alternatives, establishing that the clinical trial infrastructure works is a necessary first step.","whyItMatters":"The opioid crisis has created urgent demand for non-opioid pain management options, and dental procedures are one of the most common entry points for opioid prescriptions. If CBD could provide meaningful dental pain relief, the impact would be enormous. But first someone has to prove the trial design works — that's what this pilot did.","specificNumbers":"8 patients total. 4 groups of 2. CBD doses: 17 mg/mL and 37 mg/mL, 0.5 mL per dose. Pain tracked over 72 hours via ecological momentary assessment. No serious adverse events reported. Study was powered for feasibility, not efficacy.","methodology":"Randomized pilot trial (SWAP trial). 8 adults undergoing simple tooth extraction randomized equally to 4 arms (n=2 per arm): CBD 17 mg/mL, CBD 37 mg/mL, placebo, or treatment-as-usual (ibuprofen/acetaminophen). CBD/placebo: 0.5 mL every 4-6 hours as needed for 7 days. Primary endpoint: pain intensity (0-10 NRS) via ecological momentary assessment over 72 hours. Secondary: worst pain, rescue medication use.","limitations":"The study was designed for feasibility, not efficacy — 8 patients across 4 groups provides zero statistical power for comparing treatments. Simple extractions may not represent the full range of dental pain (surgical extractions, impacted teeth). The 72-hour assessment window captures only acute pain, not the full recovery period. CBD dosing was not based on established pharmacokinetic data for dental pain specifically. No blood levels measured to confirm CBD absorption."},{"rthcId":"RTHC-05860","title":"Medical cannabis and the hype cycle: Clinical evidence and future directions.","authors":"Abuhasira, Ran; Novack, Victor","year":2025,"journal":"European journal of internal medicine, 106644","doi":"10.1016/j.ejim.2025.106644","pmid":"41381256","tags":["medical-cannabis","regulation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Medical cannabis research surged in the mid-to-late 2010s, but measured clinical benefits are generally modest, vary by product/dose/population, and are limited by research challenges including heterogeneity and blinding difficulties. The field is progressing from inflated expectations toward realistic therapeutic goals, standardized products, and systematic safety attention.","whyItMatters":"The hype cycle framework helps explain the whiplash many have experienced with medical cannabis -- from \"miracle cure\" enthusiasm to \"it doesn't work\" skepticism. Recognizing where the field is on this cycle allows for more productive conversations about realistic expectations and research priorities.","specificNumbers":"Research output surged in mid-to-late 2010s. Clinical benefits described as generally modest and variable by product, dose, and population. Key barriers identified: lack of standardized products, limited head-to-head comparisons with existing therapies, inadequate blinding in trials.","methodology":"Narrative review synthesizing clinical evidence on medical cannabis through the lens of the Gartner Hype Cycle technology adoption framework. Reviews therapeutic evidence, identifies current limitations, and proposes paths forward for the field.","limitations":"The hype cycle is a descriptive framework, not a predictive model. Narrative reviews are inherently subject to author perspective. The field is evolving rapidly, and the review may not capture the most recent developments."},{"rthcId":"RTHC-05861","title":"Risk assessment of metals measured in regulated Canadian dried cannabis and cannabis vaping products: case study and perspectives.","authors":"Achuthan, Sathish; Waye, Andrew; Abramovici, Hanan","year":2025,"journal":"Frontiers in toxicology, 7, 1755875","doi":"10.3389/ftox.2025.1755875","pmid":"41626285","tags":["contaminants","regulation","vaping"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Applying pharmaceutical daily exposure limits to measured metal levels in legal Canadian dried cannabis and vaping liquids showed low risk to health, even for daily or almost-daily consumers at heavy-use levels (95th percentile). The analysis validated that Canada's regulated cannabis supply meets safety standards for elemental impurities.","whyItMatters":"Heavy metals in cannabis are a recognized consumer concern, especially for inhaled products. This systematic risk assessment provides the first comprehensive evaluation showing that Canada's regulatory framework -- with good production practices and pharmacopoeial impurity limits -- is effectively controlling this risk.","specificNumbers":"Analysis covered dried cannabis and cannabis vaping liquids in the Canadian legal market. Used 50th and 95th percentile consumption scenarios. Applied pharmaceutical-grade permitted daily exposure limits. Conclusion: low risk to health for both typical and heavy consumers.","methodology":"Risk assessment case study using metal levels measured in legal Canadian cannabis products published by Health Canada. Applied pharmacopoeial permitted daily exposure (PDE) standards. Modeled typical (50th percentile) and heavy (95th percentile) daily use scenarios for inhalation exposure.","limitations":"Risk assessment is limited to the legal regulated market and does not address illicit products. Uncertainties in exposure characterization for cannabis inhalation (varying amounts consumed, depth of inhalation, frequency) affect precision. The study focuses on elemental impurities only, not other contaminants."},{"rthcId":"RTHC-05862","title":"Changing Developmental Patterns of Cannabis and Alcohol Use in Washington State: an Analysis of Young Adult Birth Cohorts Born in 1990-2004.","authors":"Acolin, Jessica; Calhoun, Brian; Rhew, Isaac C; Fleming, Charles B; Hultgren, Brittney; Martinez, Griselda; Kilmer, Jason R; Larimer, Mary; Guttmannova, Katarina","year":2025,"journal":"Prevention science : the official journal of the Society for Prevention Research, 26(5), 785-797","doi":"10.1007/s11121-025-01813-y","pmid":"40425897","tags":["youth","legalization","alcohol"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use prevalence was higher at age 21-22 compared to 18-20, departing from prior pre-legalization research showing gradual decline. In more recent birth cohorts, prevalence among 23-25-year-olds was lower than 21-22-year-olds, suggesting an emerging \"maturing out\" pattern. Developmental patterns of risky alcohol use (HED, frequent drinking) were significantly moderated by birth cohort.","whyItMatters":"Cannabis legalization may have shifted when cannabis use peaks during young adulthood. The finding that peak use now occurs at 21-22 (the legal purchase age) rather than declining from age 18 suggests that legal access timing shapes use trajectories, with implications for when prevention resources should be concentrated.","specificNumbers":"15,371 young adults surveyed annually 2015-2022. Cannabis use higher at 21-22 vs 18-20. Recent birth cohorts: lower prevalence at 23-25 vs 21-22 (emerging maturing out). Birth cohort significantly moderated HED and frequent alcohol use patterns.","methodology":"Annual repeated cross-sectional survey data from 2015-2022 of 15,371 young adults (ages 18-25) in Washington State. Logistic regression examined cannabis and alcohol use by developmental age and birth cohort (born 1990-2004).","limitations":"Repeated cross-sectional design tracks cohort trends but not individual trajectories. Washington State results may not generalize to states with different cannabis policies or demographics. Self-reported data may undercount actual use. The 2015-2022 timeframe captures an evolving post-legalization period."},{"rthcId":"RTHC-05863","title":"The Effect of Prenatal Marijuana Exposure on White Matter Microstructure and Cortical Morphology during Late Childhood.","authors":"Acosta-Rodriguez, Hector; Bobba, Pratheek; Zeevi, Tal; Ment, Laura R; Payabvash, Seyedmehdi","year":2025,"journal":"AJNR. American journal of neuroradiology, 46(10), 2176-2185","doi":"10.3174/ajnr.A8774","pmid":"40194858","tags":["prenatal","brain-imaging","youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Prenatally exposed children (n=418) showed significantly reduced white matter integrity (lower fractional anisotropy and neurite density, higher mean and radial diffusivity) compared to 667 matched controls. The most affected tracts were the superior corticostriate tract and projections to frontal and parietal cortices. Cortical surface area was reduced in the left parahippocampal and right postcentral gyri.","whyItMatters":"This is one of the largest neuroimaging studies of prenatal marijuana exposure to date. The finding that white matter tracts connecting motivation and goal-directed behavior centers are specifically affected suggests a biological pathway through which prenatal cannabis exposure could impair executive function as children enter adolescence.","specificNumbers":"1,085 children (418 exposed, 667 controls). Mean age 9.9 years (SD 0.6). Significantly reduced FA and neurite density. Higher mean and radial diffusivity. Most affected: superior corticostriate tract, external capsule projections to frontal/parietal cortices. Reduced cortical surface area in left parahippocampal and right postcentral gyri.","methodology":"Cross-sectional neuroimaging study using ABCD Study data. 1,085 children (mean age 9.9 years): 418 prenatally exposed to marijuana, 667 matched controls with no prenatal exposure. Diffusion MRI assessed white matter microstructure. Mixed linear models accounted for multiple covariates.","limitations":"Cross-sectional design cannot determine whether prenatal marijuana exposure caused the brain differences. Prenatal exposure was typically assessed by maternal report and may be underreported. Other prenatal exposures (tobacco, alcohol, stress) may confound results despite statistical control."},{"rthcId":"RTHC-05864","title":"Divergence in cannabis and alcohol use disorder prevalence trends from 2002 to 2019.","authors":"Acuff, Samuel F; Strickland, Justin C","year":2025,"journal":"Drug and alcohol dependence, 266, 112521","doi":"10.1016/j.drugalcdep.2024.112521","pmid":"39657438","tags":["addiction","demographics"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Daily cannabis use prevalence increased 94% (AARC 11.68%). CUD among daily users decreased 47.9% (AARC -10.30%). Individual CUD criteria prevalence decreased 13.4-59.6% among daily users. In contrast, daily alcohol use decreased 10.86% while AUD among daily drinkers decreased only 3.9%. Treatment engagement and perceived need both decreased for cannabis.","whyItMatters":"The paradox of more daily use but less diagnosed disorder suggests that how people define \"problematic\" cannabis use is shifting with cultural acceptance. This has profound implications for diagnostic frameworks: if the same behavior is disorder in one cultural context but not another, the diagnostic criteria themselves may need examination.","specificNumbers":"Daily cannabis use: +94% (AARC 11.68%). CUD among daily users: -47.9% (AARC -10.30%). Daily alcohol use: -10.86% (AARC -1.90%). AUD among daily drinkers: -3.9% (AARC -0.67%). Individual CUD criteria changes: -13.4% to -59.6%. Treatment engagement decreased for cannabis, increased for alcohol.","methodology":"Analysis of National Survey on Drug Use and Health data from 2002 to 2019. Computed temporal trends and average annual rates of change for CUD and AUD symptoms, treatment engagement, and perceived treatment need. Compared divergent trajectories of cannabis and alcohol use disorders.","limitations":"NSDUH data are cross-sectional and self-reported, with possible changes in reporting honesty over time as cannabis became more accepted. Diagnostic criteria did not change between 2002 and 2019 (transition from DSM-IV to DSM-5 in 2013 may have affected comparability). The study ends in 2019 before the pandemic."},{"rthcId":"RTHC-05865","title":"An assessment of the prevalence of cannabis use in eye clinic patients and its implications on glaucoma diagnosis and management.","authors":"Adamek, Andrew J; Hussein, Musse A; Abdulkarim, Iya; Orengo-Nania, Silvia; Sheheitli, Huda","year":2025,"journal":"International ophthalmology, 45(1), 484","doi":"10.1007/s10792-025-03846-2","pmid":"41243046","tags":["glaucoma","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Recent marijuana use (past month): 15.7%. Regular users: 8.2%. Daily users: 4.5%. Among glaucoma patients, 44.2% were interested in using marijuana. Patients who used marijuana less than 24 hours before their exam were significantly more likely to know it lowers IOP (p = 0.02). Beliefs about marijuana effectiveness, IOP lowering, and fewer side effects predicted interest in use.","whyItMatters":"Cannabis temporarily lowers intraocular pressure, which can mask true readings during eye exams. With 15.7% of patients using recently and many not volunteering this information, ophthalmologists may be making diagnostic and treatment decisions based on falsely low IOP measurements.","specificNumbers":"134 patients surveyed. 15.7% recent use (<1 month). 8.2% regular users. 4.5% daily users. 44.2% of glaucoma patients interested in marijuana use. Knowledge that marijuana lowers IOP correlated with use within 24 hours of exam (p = 0.02). Beliefs about effectiveness (p = 0.016), IOP lowering (p = 0.011), and fewer side effects (p = 0.014) predicted interest.","methodology":"Survey of 134 patients at four University of Minnesota eye clinics during two collection periods (October 2022-January 2023, July-August 2024). Questions covered cannabis use patterns, knowledge of effects on IOP, and attitudes toward marijuana for glaucoma.","limitations":"Small convenience sample from one university's clinics limits generalizability. Self-reported cannabis use may be underreported. The survey did not verify IOP measurements against cannabis use timing. Interest in marijuana for glaucoma does not equal actual use."},{"rthcId":"RTHC-05866","title":"Estimated Prevalence of Substance Use Disorders Among US Adolescents and Emerging Adults by Substance Class, Severity, and Age, 2022.","authors":"Adams, Zachary W; Dellucci, Trey V; Agley, Jon; Bixler, Kristina; Sullivan, Maggie; Hinckley, Jesse D; Hulvershorn, Leslie A","year":2025,"journal":"JAACAP open, 3(4), 959-971","doi":"10.1016/j.jaacop.2025.01.002","pmid":"41367988","tags":["addiction","youth","demographics"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"While past-year cannabis use rates increased with age, the prevalence of CUD and its severity distribution (mild, moderate, severe) among those who used cannabis did not differ across age cohorts 12-13, 14-15, 16-17, 18-20, and 21-25 (effect size phi-c = 0.04). This pattern differed from less common substances like heroin and methamphetamine where SUD severity varied by age.","whyItMatters":"This finding challenges the assumption that the risk of disordered use escalates with age or duration of use during adolescence and young adulthood. For cannabis, the proportion developing problematic use is consistent from age 12 through 25, suggesting vulnerability to CUD is relatively stable across this developmental period.","specificNumbers":"26,276 participants aged 12-25. Cannabis CUD severity distribution did not differ by age cohort (phi-c = 0.04). Alcohol use disorder showed similar stability (phi-c = 0.04). Less common substances (heroin, methamphetamine) showed age-dependent severity patterns.","methodology":"Cross-sectional analysis of 2022 NSDUH data from 26,276 participants aged 12-25. Estimated DSM-5 SUD prevalence and severity across five age cohorts using chi-square tests and Cramer's V effect sizes for cannabis, alcohol, and other substances.","limitations":"Cross-sectional data capture prevalence at one time point, not individual trajectories from use to disorder. DSM-5 criteria may perform differently across age groups. NSDUH sampling and self-report limitations apply."},{"rthcId":"RTHC-05867","title":"Lifetime Smoking History and Marijuana Co-use in Patients With Alcohol-related Acute Pancreatitis.","authors":"Adeniran, Esther A; Kim, Sungjin; Pandol, Stephen J; Yadav, Dhiraj; Papachristou, Georgios I; Buxbaum, James L; Pisegna, Joseph R; Jeon, Christie Y","year":2025,"journal":"Pancreas, 54(10), e863-e872","doi":"10.1097/MPA.0000000000002523","pmid":"40549965","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05868","title":"Pathways linking adverse childhood experiences to psychosis risk in Lagos, Nigeria: A structural equation modeling approach.","authors":"Adewuya, Abiodun O; Oladipo, Olabisi E; Emsley, Robin; Asmal, Laila","year":2025,"journal":"Schizophrenia research, 285, 276-285","doi":"10.1016/j.schres.2025.09.030","pmid":"41075680","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05869","title":"Challenging the 25-year-old 'mature brain' mythology: implications for the minimum legal age for non-medical cannabis use.","authors":"Adinoff, Bryon; Nunes, Julio C","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(5), 577-583","doi":"10.1080/00952990.2025.2561982","pmid":"41208087","tags":["legalization","youth","brain-imaging"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"While brain development continues into the third decade, there is no empirically defined endpoint at age 25. Brain maturation is nonlinear, region-specific, and influenced by sex. Existing evidence does not demonstrate greater long-term cognitive or neurophysiological harm from cannabis in individuals aged 18-25 compared to those over 25. An MLA of 18-21 is scientifically supportable.","whyItMatters":"The \"brain doesn't mature until 25\" claim has become a popular argument for raising cannabis legal ages, but this review finds it oversimplifies neurodevelopmental science. Policy decisions based on a mythologized age threshold may create more harm (through criminalization of young adults) than they prevent.","specificNumbers":"Current legal age limits range from 18-21 across jurisdictions. Some advocates propose age 25. Major brain structural development occurs early in life. Synaptic pruning and prefrontal changes continue through adolescence with subtle changes into the 20s.","methodology":"Perspective/commentary examining neuroscientific evidence on brain development and its implications for setting legal cannabis age limits. Reviews macrostructural and microstructural brain development, synaptic pruning, gene expression, and prefrontal cortical changes.","limitations":"This is a perspective piece, not a systematic review. The authors argue a specific policy position, which inherently involves value judgments beyond pure science. Brain development research is ongoing and new findings could shift the evidence."},{"rthcId":"RTHC-05870","title":"Sexual identity, child maltreatment, mental health, and substance use among emerging adults aged 18 to 23 years.","authors":"Afifi, Tracie O; Osorio, Ana; Fortier, Janique; Stewart-Tufescu, Ashley; Taillieu, Tamara L; McCarthy, Julie-Anne","year":2025,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 116(5), 674-685","doi":"10.17269/s41997-024-00992-5","pmid":"40019705","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In a longitudinal study of 584 Canadian emerging adults tracked from ages 14-17 to 18-23, bisexual identity was associated with increased odds of depression, anxiety, at-risk alcohol use, and at-risk cannabis use compared to heterosexual identity. Bisexual identity also had the most robust relationships with all child maltreatment outcomes.","whyItMatters":"Sexual minority youth, particularly those identifying as bisexual, face compounding risks of maltreatment and substance use that demand targeted prevention. Understanding these intersecting vulnerabilities helps identify who needs early intervention most.","specificNumbers":"n=584 emerging adults; bisexual identity had the most robust association with at-risk cannabis use; \"I don't know\" sexual identity showed 7.45 increased odds of intimate partner violence exposure","methodology":"Data from the longitudinal Well-Being and Experiences (WE) Study in Manitoba, Canada, following 584 participants from 2017 (ages 14-17) to 2022 (ages 18-23). Descriptive statistics and logistic regression models compared outcomes across sexual identity groups.","limitations":"Single Canadian province limits generalizability. Self-reported measures of maltreatment and substance use may underestimate true rates. Relatively small sample size for subgroup analyses across multiple sexual identity categories."},{"rthcId":"RTHC-05871","title":"Cannabidiol and microRNAs: shared cellular targets and new insights for developing anti-seizure modalities.","authors":"Afrooghe, Arya; Ahmadi, Elham; Shayan, Maryam; Dabbagh Ohadi, Mohammad Amin; Behnoush, Amir Hossein; Dehpour, Ahmad Reza","year":2025,"journal":"The Journal of pharmacy and pharmacology, 77(8), 1011-1022","doi":"10.1093/jpp/rgaf039","pmid":"40461016","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05872","title":"Ecological dimensions of cannabis regulation in the Rif, Morocco.","authors":"Afsahi, Kenza; Tinasti, Khalid; Mouna, Khalid","year":2025,"journal":"The International journal on drug policy, 146, 105045","doi":"10.1016/j.drugpo.2025.105045","pmid":"41192205","tags":["legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Analysis of Morocco's cannabis legalization framework found that regulatory priorities like standardization, traceability, and market control overlook environmental concerns. The shift from traditional beldia cultivation to water- and chemical-intensive hybrid greenhouse farming risks entrenching environmentally damaging practices despite opportunities legalization presents for sustainability.","whyItMatters":"As cannabis legalization expands globally, Morocco's experience shows that market-focused regulation can inadvertently accelerate environmental damage if sustainability is not built into the framework from the start.","specificNumbers":"Morocco legalized medical and industrial cannabis in 2021; study draws on 20+ years of Rif region fieldwork; compares traditional beldia varieties against modern hybrid and greenhouse operations","methodology":"Combined insights from over two decades of fieldwork in Morocco's Rif region with policy analysis. Compared legal and illicit cultivation systems, assessed resource use and biodiversity impacts, and situated Morocco's cannabis sector within national and international environmental commitments.","limitations":"Qualitative and policy-focused approach without quantitative environmental measurements. Fieldwork concentrated in the Rif region may not represent all Moroccan cannabis cultivation. Environmental impacts of legal cultivation are still emerging."},{"rthcId":"RTHC-05873","title":"The impact of tetrahydrocannabinol on central pain modulation in chronic pain: a randomized clinical comparative study of offset analgesia and conditioned pain modulation in fibromyalgia.","authors":"Agbaria, Yara; Preger, Raz; Aloush, Valerie; Ablin, Jacob N; Sharon, Haggai; Jacob, Giris","year":2025,"journal":"Journal of cannabis research, 7(1), 86","doi":"10.1186/s42238-025-00348-x","pmid":"41199355","tags":["pain","thc"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"THC (0.2 mg/kg sublingual) significantly reduced spontaneous pain ratings on the McGill scale compared to both baseline and placebo. THC also enhanced offset analgesia relative to placebo (P=0.008) but had no effect on conditioned pain modulation (P=0.27). Baseline offset analgesia magnitude predicted who would respond to THC treatment (R²=0.404, P=0.003).","whyItMatters":"This is the first study to test whether THC affects different central pain modulation mechanisms differently, finding that it selectively enhances offset analgesia. If baseline offset analgesia can predict who responds to THC, it could help match the right patients to cannabinoid therapy.","specificNumbers":"n=23 fibromyalgia patients; THC vs placebo P=0.02 for pain reduction; offset analgesia enhancement P=0.008; baseline OA predicted response R²=0.404; no CPM effect P=0.27","methodology":"Randomized, double-blind, placebo-controlled crossover design with 23 fibromyalgia patients. Each participant completed two sessions with McGill Pain Questionnaire, VAS assessments, and evaluations of offset analgesia and conditioned pain modulation before and after sublingual THC or placebo.","limitations":"Very small sample (23 patients). Single-dose acute study does not reflect chronic use. Only tested one THC dose (0.2 mg/kg sublingual). No long-term safety or efficacy data."},{"rthcId":"RTHC-05874","title":"Lifetime Cannabis, Non-Cigarette Tobacco, and Illicit Drug Use and Cardiovascular Disease Among Young and Middle-Aged U.S. Adults.","authors":"Agbonlahor, Osayande; Mattingly, Delvon T; Hart, Joy L; Richardson, Maggie K; McLeish, Alison C; Walker, Kandi L","year":2025,"journal":"American journal of lifestyle medicine, 15598276251404883","doi":"10.1177/15598276251404883","pmid":"41384047","tags":["cardiovascular","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cardiovascular disease is increasingly affecting younger adults, and this study examined whether lifetime substance use — including cannabis — might contribute. Using nationally representative NHANES data from 2017-2018, the researchers analyzed 2,933 adults aged 20-59.\n\nThe headline finding is hard to ignore: adults who had ever used cannabis had 5.45 times higher odds of reporting coronary heart disease. That's a large effect size — much larger than the modest associations typically seen in cannabis-cardiovascular research. Cigar use was associated with 2.31 times higher odds of stroke, and e-cigarettes and smokeless tobacco were associated with higher odds of hypertension.\n\nBut the magnitude of the cannabis-coronary heart disease association demands critical scrutiny. This is a cross-sectional study using self-reported lifetime cannabis use (ever/never) and self-reported cardiovascular diagnoses. 'Lifetime cannabis use' includes everyone from someone who tried cannabis once at age 18 to a daily user for 30 years — a category so broad it's hard to know what it means biologically.\n\nThe odds ratio could be inflated by residual confounding: cannabis users may differ from non-users in tobacco use, diet, exercise, stress, socioeconomic status, and healthcare access in ways that the multivariable adjustment didn't fully capture. The use of self-reported cardiovascular diagnoses rather than clinical records adds another layer of uncertainty.\n\nStill, the finding is consistent with a growing body of evidence suggesting cannabis isn't cardiovascular-neutral, even if the true effect size is likely smaller than the 5.45x reported here.","whyItMatters":"Cardiovascular disease in young and middle-aged adults is increasing, and identifying modifiable risk factors is critical. If cannabis genuinely increases coronary heart disease risk to the degree suggested here, it would be one of the most important cardiovascular findings in cannabis research. But the cross-sectional, self-reported design means this is a signal that demands better-designed studies, not a definitive answer.","specificNumbers":"2,933 adults aged 20-59 from NHANES 2017-2018. Lifetime cannabis use: OR 5.45 (95% CI: 1.86-15.95) for coronary heart disease. Cigar use: OR 2.31 (95% CI: 1.06-5.01) for stroke. E-cigarette use: OR 1.41 (95% CI: 1.12-1.79) for high blood pressure. Smokeless tobacco: OR 1.46 (95% CI: 1.01-2.12) for high blood pressure.","methodology":"Cross-sectional analysis of 2,933 adults aged 20-59 from NHANES 2017-2018. CVD defined as self-reported healthcare provider diagnosis of coronary heart disease, stroke, or high blood pressure. Substance use assessed as ever-use of cannabis, non-cigarette tobacco products, or illicit drugs. Adjusted odds ratios estimated using multivariable logistic regression.","limitations":"Cross-sectional design — cannot establish temporal ordering or causation. Ever-use of cannabis is an extremely broad exposure definition that doesn't distinguish occasional from chronic use. Self-reported CVD diagnoses are less reliable than clinical records. Relatively wide confidence interval (1.86-15.95) indicates imprecision. Residual confounding from tobacco, alcohol, diet, exercise, and other factors is a significant concern. NHANES 2017-2018 is a single survey cycle with a modest sample for subgroup analysis of relatively rare outcomes like coronary heart disease in young adults."},{"rthcId":"RTHC-05875","title":"The Impact of Adult Cannabis Use Legalization in California: A Qualitative Review of Subject Matter Expert Opinions on Proposition 64.","authors":"Ageze, Daniel; Dell'Acqua, Renee; Marcotte, Thomas D; Baird, Sara; Garcia, Jesus; Rybar, Jill; Hill, Linda","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(3), 72-88","doi":"10.26828/cannabis/2025/000291","pmid":"41278424","tags":["legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Interviews with 22 stakeholders identified three primary themes: (1) successes including quality control, justice reform, and stigma reduction; (2) shortcomings including high costs, licensing barriers, bureaucracy, and social inequity; and (3) recommendations including more research, policy changes, and business model transformation. Experts emphasized that federal Schedule I status remains a barrier to banking, research, and regulatory consistency.","whyItMatters":"Six years after passage, Prop 64 had produced both intended benefits and significant unintended consequences. Expert perspectives from across the cannabis ecosystem reveal where legalization frameworks succeed and where they fall short.","specificNumbers":"22 subject matter experts interviewed; 9 stakeholder categories; Prop 64 passed 2016, implemented 2018; interviews conducted January-March 2022","methodology":"Twenty-two semi-structured interviews conducted January-March 2022 with subject matter experts across nine categories: clinicians (primary care, pain management, addiction medicine, cannabis), researchers, advocates, dispensary owners, legal professionals, and consumers. Nine tailored interview guides assessed perceptions of Prop 64 impacts.","limitations":"Qualitative design with 22 participants cannot capture the full range of stakeholder experiences. Interviews conducted in early 2022 may not reflect more recent developments. Expert selection may not represent all affected communities equally."},{"rthcId":"RTHC-05876","title":"Knowledge and attitudes toward recreational cannabis legalization among California residents: a population-matched questionnaire about Proposition 64.","authors":"Ageze, Daniel; Baird, Sara; Marcotte, Thomas D; Elashmawy, Ahmed; Wong, Angela; Dell'Acqua, Renee; Rybar, Jill; Hacker, Sarah; Gold, Alice; Shaughnessy, Tom; Lanin-Kettering, Ilene; Hill, Linda L","year":2025,"journal":"Journal of cannabis research, 7(1), 42","doi":"10.1186/s42238-025-00304-9","pmid":"40652253","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 4,020 current cannabis users demographically matched to the 2020 California census, 71% described themselves as somewhat or very familiar with Prop 64, yet awareness of specific regulations was low: 49% knew possession rules, 41% knew transportation rules, and only 30% understood gifting regulations. Only half of current users felt Prop 64 made cannabis products and acquisition safer, and just 30% believed cannabis should be legal in more public places.","whyItMatters":"If most cannabis users do not know the rules governing possession, transportation, and gifting, they may unknowingly violate laws. This gap between perceived familiarity and actual knowledge suggests legalization rollouts need more effective public education.","specificNumbers":"n=5,178 total (4,020 current users, 523 former, 635 non-users); 71% self-reported familiarity; 49% knew possession rules; 41% knew transportation rules; 30% knew gifting rules; 30% supported more public use; 50% felt legalization made products safer","methodology":"Population-matched questionnaire completed by 4,020 current cannabis users, 523 former users, and 635 non-users selected from an initial pool matched to the 2020 California census. Chi-squared tests and nominal logistic multivariate analysis assessed knowledge and attitudes by demographics and cannabis use factors.","limitations":"Cross-sectional survey cannot track how knowledge changes over time. Self-reported familiarity may not align with tested knowledge. Online panel recruitment may not fully represent all California demographics."},{"rthcId":"RTHC-05877","title":"UK Medical Cannabis Registry: A clinical outcomes analysis for insomnia.","authors":"Aggarwal, Arushika; Erridge, Simon; Cowley, Isaac; Evans, Lilia; Varadpande, Madhur; Clarke, Evonne; McLachlan, Katy; Coomber, Ross; Rucker, James J; Weatherall, Mark W; Sodergren, Mikael H","year":2025,"journal":"PLOS mental health, 2(8), e0000390","doi":"10.1371/journal.pmen.0000390","pmid":"41662070","tags":["sleep"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Sleep quality scores (SQS) improved from 2.66 at baseline to 5.67 at one month (P<0.001) and remained significantly improved at 18 months (3.81, P<0.001), though improvements diminished over time. GAD-7 anxiety scores also improved significantly through 18 months. EQ-5D-5L quality of life showed improvements in usual activities, pain/discomfort, and anxiety/depression dimensions. Only 8.87% of participants reported adverse events, none disabling or life-threatening.","whyItMatters":"Current insomnia treatments have significant limitations including dependency risk and side effects. This is among the longest follow-up periods for medical cannabis and insomnia, showing sustained but declining benefits that raise questions about tolerance.","specificNumbers":"n=124; SQS improved from 2.66 to 5.67 at 1 month (P<0.001); declined to 3.81 at 18 months (still P<0.001 vs baseline); 8.87% reported adverse events; 112 total adverse events recorded, none severe","methodology":"Case series from the UK Medical Cannabis Registry (UKMCR) analyzing 124 patients diagnosed with primary insomnia who were prescribed cannabis-based medicinal products. Patient-reported outcome measures (PROMs) assessed at baseline, 1, 3, 6, 12, and 18 months. Adverse events classified per CTCAE version 4.0.","limitations":"No control group or randomization; case series from a voluntary registry. Patients self-selected into treatment. Declining improvement over time could reflect tolerance, regression to the mean, or changing patient populations. Product formulations and doses varied across patients."},{"rthcId":"RTHC-05878","title":"Bioactive metabolites and antidiabetic activity of Cannabis sativa-derived endophytic fungi.","authors":"Agrahari, Sushil; Singh, Shailendra P; Singh, Brahma N","year":2025,"journal":"Archives of microbiology, 208(1), 20","doi":"10.1007/s00203-025-04539-1","pmid":"41249583","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05879","title":"Marijuana and Peripheral Vascular Disease: Pathophysiology, Clinical Evidence, and Cardiovascular Implications.","authors":"Agrawal, Siddharth Pravin; Maheta, Darshilkumar; Rajput, Jaisingh; Shah, Rushin S; Patel, Dhruvi S; Shah, Freya; Bhatia, Hitesh; Joshi, Arpit; Khan, Abdul Allam; Frishman, William H; Aronow, Wilbert S","year":2025,"journal":"Cardiology in review","doi":"10.1097/CRD.0000000000001065","pmid":"40968410","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05880","title":"Dietary Manganese Modulates Microbiota and Intestinal N-Acylethanolamines in a Sex-Specific Manner in Mice With Diet-Induced Obesity.","authors":"Agudelo, Fredy Alexander Guevara; Leblanc, Nadine; Bourdeau-Julien, Isabelle; St-Arnaud, Gabrielle; Dahhani, Fadil; Flamand, Nicolas; Veilleux, Alain; Di Marzo, Vincenzo; Raymond, Frédéric","year":2025,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 39(13), e70763","doi":"10.1096/fj.202500934R","pmid":"40569166","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05881","title":"Nanoformulated cannabidiol for skin disorders: A GRADE-based systematic review of therapeutic evidence and efficacy.","authors":"Ahmed, Bakr; Kaur, Simrandeep; Naryal, Srishti; Devi, Aanchal; Kathpalia, Muskan; Shah, Rohan M; Kaur, Indu Pal","year":2025,"journal":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 214, 114784","doi":"10.1016/j.ejpb.2025.114784","pmid":"40518055","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05882","title":"Aromatisation-based extract engineering of Cannabis sativa L. Unveils rare cannabinoids with anticancer potential.","authors":"Ahmed, Manzoor; Shukla, Sanket K; Verma, Mahendra K; Ahmed, Zabeer; Nalli, Yedukondalu","year":2025,"journal":"Natural product research, 1-9","doi":"10.1080/14786419.2025.2595528","pmid":"41355760","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05883","title":"Characteristics of Youth With Recent Substance Use With and Without Substance Use Disorder Presenting for Primary Mental Healthcare in Australia: Baseline Findings From the INTEGRATE Trial.","authors":"Ahounbar, Ellie; Guerin, Alexandre A; Hides, Leanne; Bendall, Sarah; Chanen, Andrew; Clarke, Sarah; Quinn, Amelia; Baird, Shelley; Killackey, Eóin; McGorry, Patrick; Bedi, Gillinder","year":2025,"journal":"Early intervention in psychiatry, 19(12), e70106","doi":"10.1111/eip.70106","pmid":"41320196","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Comparing 51 youth with a current SUD to 21 without a lifetime SUD diagnosis, those with SUD endorsed more severe depressive and anxiety symptoms, lower quality of life and role functioning, more alcohol-related problems, and higher frequency cannabis use. They also had higher risk scores for alcohol, tobacco, cannabis, cocaine, amphetamines, and hallucinogens. No group differences emerged for social/occupational functioning or subjectively rated sleep quality.","whyItMatters":"Youth mental health services frequently encounter substance use but may not distinguish between use and disorder. This study shows the clinical gap between the two is substantial, with SUD-diagnosed youth carrying heavier psychiatric and functional burdens that require integrated treatment approaches.","specificNumbers":"n=79 (51 with current SUD, 21 without lifetime SUD); ages 12-25; SUD group had higher frequency cannabis use and higher risk scores across 6 substance categories; no differences in social/occupational functioning or sleep","methodology":"Baseline data from the INTEGRATE clinical trial. 79 participants aged 12-25 with high-prevalence mental illness and substance use recruited from headspace primary mental health centres in North-Western Melbourne. Self-report and interview measures of psychiatric diagnoses, symptoms, functioning, and substance use.","limitations":"Small sample (n=79) with only 21 in the comparison group. Baseline cross-sectional data cannot establish causal direction. Recruited from a specific Melbourne region, limiting generalizability. Secondary analysis of trial data, not designed primarily for this comparison."},{"rthcId":"RTHC-05884","title":"Convergence of Cannabis and Psychosis on the Dopamine System.","authors":"Ahrens, Jessica; Ford, Sabrina D; Schaefer, Betsy; Reese, David; Khan, Ali R; Tibbo, Philip; Rabin, Rachel; Cassidy, Clifford M; Palaniyappan, Lena","year":2025,"journal":"JAMA psychiatry, 82(6), 609-617","doi":"10.1001/jamapsychiatry.2025.0432","pmid":"40202728","tags":["psychosis","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use disorder (CUD) was associated with elevated neuromelanin-MRI signal in a set of ventral substantia nigra/ventral tegmental area voxels (387 of 2,060 voxels, corrected P=0.03). CUD was also associated with elevated signal in a region previously linked to psychosis severity (P=0.04), with a dose-dependent relationship (more severe CUD symptoms correlated with higher signal, P=0.03). In contrast, first-episode schizophrenia alone did not reach significance in this analysis.","whyItMatters":"This study provides neuroimaging evidence for a specific biological mechanism linking cannabis use to psychosis risk. The finding that cannabis use disorder affects the same dopamine pathway implicated in psychosis suggests a shared neural substrate, not just a statistical association.","specificNumbers":"n=61 (25 with CUD, 36 without); 387 of 2,060 SN/VTA voxels showed elevated signal with CUD (corrected P=0.03); dose-dependent CUD severity association (P=0.03); 1-year follow-up for 37 participants","methodology":"Longitudinal observational cohort study recruiting from an early psychosis service and surrounding communities in London, Ontario (2019-2023). 61 participants (36 without CUD, 25 with CUD; some with first-episode schizophrenia in each group). Neuromelanin-sensitive MRI used as a proxy measure of dopamine function. One-year follow-up for 37 participants.","limitations":"Small sample size (61 total, 25 with CUD). Neuromelanin MRI is a proxy measure of dopamine function, not a direct measurement. Cannot determine whether CUD causes dopamine changes or whether pre-existing dopamine differences predispose to both CUD and psychosis. Cross-sectional associations with limited longitudinal change data."},{"rthcId":"RTHC-05885","title":"Adjunctive use of cannabidiol in pediatric drug-resistant epilepsy: A retrospective multicenter analysis.","authors":"Aizara, Ermekbaeva; Robin, T Varughese; Hanna, Li; Amy, Urbina Lopez; Brooke, Milosh; Rebecca, Philip; Christian, Suri; Yash, Shah; Sanjeev, Kothare","year":2025,"journal":"Epilepsy & behavior : E&B, 169, 110426","doi":"10.1016/j.yebeh.2025.110426","pmid":"40288063","tags":["cbd","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among all patients with drug-resistant epilepsy receiving adjunctive CBD, 49% achieved up to 25% seizure reduction, 5% had 26-50% reduction, 21% reached 51-75% reduction, 20% experienced 76-99% reduction, and 5% achieved near seizure freedom. Median seizure frequency dropped from 30 at baseline to 8 post-treatment (P=0.000). Significant reductions occurred within each diagnostic category including focal/multifocal epilepsy, primary generalized epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, and other developmental and epileptic encephalopathies.","whyItMatters":"While CBD is already approved for specific epilepsy syndromes (Lennox-Gastaut, Dravet), evidence for its effectiveness across broader epilepsy types has been limited. This multicenter data suggests CBD may benefit drug-resistant epilepsy regardless of the specific diagnosis.","specificNumbers":"Median seizures dropped from 30 to 8 per month (P=0.000); 46% achieved >50% seizure reduction; 5% near seizure-free; significant reductions in all 5 diagnostic categories","methodology":"Retrospective chart review of patients with refractory epilepsy receiving CBD as adjunctive treatment at two tertiary care centers. Seizure frequency compared at CBD treatment start and at minimum 3 months follow-up. Epilepsy categorized into five diagnostic groups.","limitations":"Retrospective design without a control group or blinding. Seizure frequency based on caregiver reporting, which can be imprecise. No standardized CBD dosing or product formulation across patients. Minimum 3-month follow-up may not capture long-term outcomes or tolerance."},{"rthcId":"RTHC-05886","title":"Toxicological evaluation and preliminary phytochemical characterisation of a Nigerian Cannabis sativa chemovar.","authors":"Ajagun, Ebele Joan; Alabi, Babatunde Adebola; Alli-Oluwafuyi, Abdul-Musawwir; Ologe, Mary Olufunmilayo","year":2025,"journal":"Iranian journal of basic medical sciences, 28(12), 1736-1742","doi":"10.22038/ijbms.2025.85494.18494","pmid":"41586191","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05887","title":"Cannabinoids in hair and their prospective association with mental and physical health outcomes in adolescents.","authors":"Aks, Isabel R; Patel, Herry; Pelham, William E; Huestis, Marilyn A; Wade, Natasha E","year":2025,"journal":"Neurotoxicology and teratology, 108, 107433","doi":"10.1016/j.ntt.2025.107433","pmid":"39929394","tags":["youth","thc","cbd"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 2,262 youth ages 9-15, greater hair THC concentrations predicted more frequent strength exercise one year later; greater CBD concentrations predicted fewer strength exercise days; and greater THCCOOH concentrations predicted shorter sleep duration. Effects differed by sex: among males, THC and THCCOOH predicted shorter sleep; among females, THC and THCCOOH predicted strength exercise frequency and THC predicted shorter sleep. Concurrently, THCCOOH concentration was associated with greater internalizing and externalizing symptoms.","whyItMatters":"Hair analysis provides an objective measure of cannabis exposure over months, avoiding the limitations of self-report. Finding that different cannabinoids (THC vs CBD) have opposite associations with exercise, and that effects differ by sex, suggests cannabis exposure during adolescence has complex, sex-specific health implications.","specificNumbers":"n=2,262 youth ages 9-15 (49% female); THC predicted more strength exercise; CBD predicted fewer exercise days; THCCOOH predicted shorter sleep duration; concurrent THCCOOH associated with greater internalizing and externalizing symptoms","methodology":"Analysis of hair toxicology data from three cannabinoid analytes (THC, CBD, THCCOOH) and multiple health measures in the Adolescent Brain Cognitive Development (ABCD) Study. Two-part linear regression models assessed effects on externalizing/internalizing symptoms, exercise, asthma, and sleep. Stratified by sex with false discovery rate corrections.","limitations":"Observational associations cannot establish causation; youth who use cannabis may differ from non-users in unmeasured ways. Hair cannabinoid levels may reflect environmental exposure (secondhand smoke), not just personal use. False discovery rate corrections were applied but multiple comparisons increase chance of spurious findings."},{"rthcId":"RTHC-05888","title":"Endocannabinoid System Regulation in Pyometra-Affected and Healthy Canine Uteri.","authors":"Aksu, Anıl Gürkan; Ferahoğlu, Volkan; Büyükbudak, Fatih; Unaldi, Isil; Gram, Aykut; Fındık, Murat; Ay, Serhan Serhat","year":2025,"journal":"Veterinary sciences, 12(10)","doi":"10.3390/vetsci12100934","pmid":"41150074","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05889","title":"Differentiating Diabetic Gastroparesis and Cannabis Hyperemesis Syndrome in People With Type 1 Diabetes.","authors":"Akturk, Halis Kaan; Mason, Emma; Snell-Bergeon, Janet; Shah, Viral N; Karakus, Kagan Ege","year":2025,"journal":"Clinical diabetes : a publication of the American Diabetes Association, 43(3), 416-419","doi":"10.2337/cd24-0096","pmid":"40741458","tags":["health-risks"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"The study identified clinical features that help differentiate diabetic gastroparesis (DG) from cannabinoid hyperemesis syndrome (CHS) in people with type 1 diabetes, two conditions with substantially overlapping presentations of nausea, vomiting, and abdominal pain. Older age, longer diabetes duration, female sex, lower A1C, and presence of diabetic neuropathy were indicators favoring DG over CHS.","whyItMatters":"Cannabis hyperemesis and diabetic gastroparesis present nearly identically, and misdiagnosis in either direction leads to inappropriate treatment. As cannabis use increases among people with diabetes, clinicians need practical tools to tell these conditions apart.","specificNumbers":"Differentiating factors: older age, longer diabetes duration, female sex, lower A1C, and diabetic neuropathy favor gastroparesis over CHS","methodology":"Clinical comparison study of people with type 1 diabetes presenting with symptoms consistent with either diabetic gastroparesis or cannabis hyperemesis syndrome. Specific sample size and study design details limited in the brief report format.","limitations":"Brief clinical report with limited sample size details. Retrospective identification of differentiating factors may not fully capture the complexity of clinical presentations. Does not address cases where both conditions may co-occur."},{"rthcId":"RTHC-05890","title":"Medical cannabis legalization and the use of illicit drugs, alcohol, and tobacco.","authors":"Al Hallaj, Hana; Barakat, Zahraa","year":2025,"journal":"Journal of cannabis research, 7(1), 65","doi":"10.1186/s42238-025-00324-5","pmid":"40926271","tags":["legalization","gateway-theory"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Fixed effects panel regression across 20 countries (14 with legalized medical cannabis, 6 without) found a strong negative association between tobacco use and medical cannabis sales, while cannabis consumption showed a positive association with medical cannabis markets. Amphetamine use was negatively associated with MC sales, suggesting substitution dynamics. Legalization was associated with an average annual increase of 26.06 tons of MC sales, sustained over time. Excluding the US (a market size outlier), the effect was 20.05 tons.","whyItMatters":"One of the most persistent concerns about cannabis legalization is that it will increase use of other drugs. This multinational analysis finds the opposite for some substances, with tobacco and amphetamine use negatively associated with medical cannabis markets.","specificNumbers":"20 countries (14 legalized, 6 not); legalization associated with +26.06 tons annual MC sales; negative association with tobacco and amphetamine use; +20.05 tons excluding US; sustained growth trajectory post-legalization","methodology":"Panel data from 20 countries analyzed using fixed effects regression and a dynamic Difference-in-Differences (DiD) approach with multiple time periods. Variables included tobacco use, alcohol consumption, amphetamine, cocaine, and cannabis prevalence, and GDP. Event study estimates assessed post-legalization trajectories.","limitations":"Ecological study design means population-level associations cannot be interpreted as individual-level causal effects. Country-level data may mask within-country variation. The US is a major outlier in market size, complicating cross-country comparisons. Differences in legalization frameworks, enforcement, and cultural contexts across countries limit comparability."},{"rthcId":"RTHC-05891","title":"The Alarming Surge of Driving Under the Influence-Related Motor Vehicle Crashes.","authors":"Al Ma'ani, Mohammad; Castillo Diaz, Francisco; Hejazi, Omar; Khurshid, Muhammad Haris; Kunac, Anastasia; Stewart, Collin; Colosimo, Christina; Nelson, Adam; Magnotti, Louis J; Joseph, Bellal","year":2025,"journal":"The Journal of surgical research, 314, 146-152","doi":"10.1016/j.jss.2025.07.020","pmid":"40753712","tags":["driving"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Analysis of 683,184 motor vehicle crash drivers at US trauma centers found that 28.8% tested positive for drugs or alcohol, with 36.3% of those testing positive for multiple substances. Marijuana was the second most common substance (41.6% of positive tests, after alcohol at 47.1%). Cannabis-related MVCs increased significantly from 10.2% in 2017 to 14.6% in 2020 (P<0.001), with the most prominent rise among adolescents.","whyItMatters":"This is one of the largest analyses of substance-impaired driving in the US, showing that cannabis-related crashes are rising faster than any other substance category, particularly among adolescents. The trend accelerated even during a period of expanding legalization.","specificNumbers":"n=683,184 MVC drivers; 28.8% positive for drugs/alcohol; marijuana found in 41.6% of positive tests; cannabis-positive MVCs rose from 10.2% (2017) to 14.6% (2020), P<0.001; 69% male; median age 43","methodology":"Retrospective analysis of the American College of Surgeons-Trauma Quality Improvement Program database over 4 years (2017-2020). Included all patients presenting after an MVC as a driver. Trend analysis performed for positive blood or urine toxicology results across substance categories.","limitations":"Positive drug screens do not prove impairment at the time of the crash; THC can be detected days after use. Cannot determine causation between cannabis use and crash occurrence. Database covers trauma center admissions only, excluding less severe crashes and fatalities."},{"rthcId":"RTHC-05892","title":"The Endocannabinoid System: Pharmacological Targets and Therapeutic Potential in CNS Disorders.","authors":"Al-Eitan, Laith N; ElSharkawy, Mohammad T; Alahmad, Saif Z; Khair, Iliya Y; Mihyar, Ahmad H; Almahdawi, Diana L","year":2025,"journal":"Current neuropharmacology","doi":"10.2174/011570159X404678251021091920","pmid":"41178765","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05893","title":"Role of Cannabis in the Management of Chronic Non-Cancer Pain: A Narrative Review.","authors":"Al-Husinat, Lou'i; Obeidat, Shrouq; Azzam, Saif; Al-Gwairy, Yara; Obeidat, Fatima; Al Sharie, Sarah; Haddad, Deema; Haddad, Fadi; Rekatsina, Martina; Leoni, Matteo Luigi Giuseppe; Varrassi, Giustino","year":2025,"journal":"Clinics and practice, 15(1)","doi":"10.3390/clinpract15010016","pmid":"39851799","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05894","title":"Identification and chemical structure elucidation of synthetic cannabinoids samples seized in Kuwait during 2019-2023 using GC-MS and NMR spectroscopy.","authors":"Al-Matrouk, Abdullah; Orabi, Khaled Y","year":2025,"journal":"Forensic sciences research, 10(2), owae026","doi":"10.1093/fsr/owae026","pmid":"40302876","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05895","title":"Effect of Perceived Neighborhood Environment on Cannabis Use during Pregnancy among African American Women.","authors":"Al-Sahab, Ban; LaMarche, Cassandra; Liang, Xiaoyu; Dailey, Rhonda; Misra, Dawn P","year":2025,"journal":"Journal of urban health : bulletin of the New York Academy of Medicine, 102(1), 139-151","doi":"10.1007/s11524-024-00958-5","pmid":"39833620","tags":["prenatal"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Out of 1,369 postpartum African American women in Metropolitan Detroit, 11% reported using cannabis during pregnancy. After adjusting for age, marital status, income, education, and social support, women perceiving the worst neighborhood conditions had significantly higher odds of cannabis use: social cohesion/trust OR 1.77 (95% CI: 1.04-3.03), social disorder OR 1.83 (95% CI: 1.15-2.91), and danger/safety OR 1.93 (95% CI: 1.12-3.31). Perceived stress mediated the association only for the danger/safety pathway.","whyItMatters":"Prenatal cannabis use does not happen in a vacuum. This study demonstrates that the neighborhood environment where pregnant women live shapes their substance use decisions, suggesting that addressing community-level factors may be more effective than individual-level messaging alone.","specificNumbers":"n=1,369; 11% reported prenatal cannabis use; worst neighborhood safety: OR 1.93 (95% CI: 1.12-3.31); worst social disorder: OR 1.83 (95% CI: 1.15-2.91); worst social cohesion: OR 1.77 (95% CI: 1.04-3.03)","methodology":"Data from the Life-Course Influences on Fetal Environments (LIFE) Study, a retrospective cohort of postpartum African American women in Metropolitan Detroit, Michigan (2009-2011). Three perceived neighborhood scales assessed: social cohesion/trust, social disorder, and danger/safety. Logistic regression with adjustment for demographics and mediation analysis for perceived stress.","limitations":"Self-reported cannabis use likely underestimates true prevalence. Retrospective cohort design with data from 2009-2011 may not reflect current patterns. Limited to African American women in one metro area. Perceived neighborhood environment is subjective and may not match objective measures."},{"rthcId":"RTHC-05896","title":"Prenatal tobacco-cannabis co-use: A mixed-methods, convergent parallel study.","authors":"Alaniz, Kristine; Ngui, Emmanuel; Cho, Young; Laestadius, Linnea; Vance, Tessa","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","doi":"10.1093/ntr/ntaf251","pmid":"41342391","tags":["prenatal"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Findings from 46 surveys and 19 interviews with pregnant women who co-used tobacco and cannabis revealed key differences in use intentions and cessation patterns for each substance. Participants tended to view tobacco and cannabis as distinct behaviors, not a unified co-use pattern. Mental health and stress were interconnected with co-use, suggesting cessation interventions need to address each substance separately while also addressing underlying mental health factors.","whyItMatters":"Most prenatal substance use interventions treat tobacco and cannabis as a package, but pregnant women themselves see them as separate. This disconnect between clinical approaches and lived experience may explain why co-use interventions have limited success.","specificNumbers":"46 surveys and 19 interviews; participants were enrolled in a Wisconsin community-based program 2022-2023; cannabis and tobacco viewed as distinct behaviors","methodology":"Mixed-methods convergent parallel design. Surveys (n=46) and semi-structured interviews (n=19) with adults who reported tobacco-cannabis co-use during pregnancy, enrolled in a community-based program in Wisconsin (2022-2023). Quantitative analysis used Fisher's Exact Tests and logistic regression; qualitative data analyzed using reflexive thematic analysis.","limitations":"Small sample (46 surveys, 19 interviews) from one community program in Wisconsin. Self-selected participants may not represent all pregnant co-users. Qualitative findings cannot be generalized to broader populations."},{"rthcId":"RTHC-05897","title":"Elucidating interplay between myrcene and cannabinoid receptor 1 receptors to produce antinociception in mouse models of neuropathic pain.","authors":"Alayoubi, Myra; Rodrigues, Akeesha; Wu, Christine; Whitehouse, Ella; Nguyen, Jessica; Cooper, Ziva D; O'Neill, Patrick R; Cahill, Catherine M","year":2025,"journal":"Pain, 166(9), 2140-2151","doi":"10.1097/j.pain.0000000000003558","pmid":"40839768","tags":["pain","thc"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Myrcene (1-200 mg/kg) dose-dependently increased mechanical pain thresholds in neuropathic pain mice, with greater potency in females than males. A CB1 receptor antagonist blocked myrcene's pain-relieving effect. However, in vitro experiments showed myrcene does not directly activate CB1 receptors or alter CB1 activity from cannabinoid agonists, suggesting an indirect mechanism. Myrcene did not cause the sedation or temperature changes typical of cannabinoids, but female mice showed conditioned place aversion.","whyItMatters":"Myrcene is one of the most abundant terpenes in cannabis, and this study shows it contributes to pain relief through an unexpected mechanism: it requires CB1 receptors but does not directly activate them. This distinction matters for understanding how whole-plant cannabis produces effects beyond THC alone.","specificNumbers":"Myrcene tested at 1-200 mg/kg; CB1 antagonist blocked anti-allodynia; no direct CB1 activation in TRUPATH assay; females showed greater potency; no locomotion or temperature effects","methodology":"Male and female mouse model of neuropathic pain plus in vitro experiments with HEK293T cells. Myrcene tested at 1-200 mg/kg intraperitoneally. Canonical tetrad outcomes (locomotion, temperature) assessed. CB1 antagonist used to test receptor dependence. TRUPATH assay tested direct CB1 activation by myrcene with agonists and endocannabinoids.","limitations":"Mouse model of neuropathic pain may not translate to human pain. Intraperitoneal injection does not reflect typical routes of cannabis exposure. The indirect mechanism by which myrcene engages CB1 receptors remains unknown. Female mice showed aversion to myrcene, raising questions about tolerability."},{"rthcId":"RTHC-05898","title":"Endocannabinoids Mediate Racial/Ethnic Discrimination Prediction of Posttraumatic Stress Disorder Symptoms Moderated by Resting-State Functional Connectivity in Black and African American Individuals.","authors":"Albertina, Emily A; Torres, Lucas; Sauber, Garrett; Hillard, Cecilia J; Fitzgerald, Jacklynn M; deRoon-Cassini, Terri A; Larson, Christine L","year":2025,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging","doi":"10.1016/j.bpsc.2025.09.016","pmid":"41016700","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05899","title":"Sativex (nabiximols) for the treatment of Agitation & Aggression in Alzheimer's dementia in UK nursing homes: a randomised, double-blind, placebo-controlled feasibility trial.","authors":"Albertyn, Christopher P; Guu, Ta-Wei; Chu, Petrina; Creese, Byron; Young, Allan; Velayudhan, Latha; Bhattacharyya, Sagnik; Jafari, Hassan; Kaur, Simrat; Kandangwa, Pooja; Carter, Ben; Aarsland, Dag","year":2025,"journal":"Age and ageing, 54(6)","doi":"10.1093/ageing/afaf149","pmid":"40479610","tags":["thc","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In a randomized, double-blind, placebo-controlled feasibility trial, 29 nursing home residents with Alzheimer's disease and clinically significant agitation were randomized to nabiximols or placebo for 4 weeks. No participants withdrew, adherence was 100%, and the intervention was well tolerated with zero adverse reactions reported. While the recruitment target of 60 was not met due to COVID-19 challenges, the trial demonstrated that administering oral mucosal spray to advanced AD patients with agitation was generally feasible.","whyItMatters":"Agitation in Alzheimer's disease causes significant distress and currently available treatments have limited efficacy with substantial side effects. This feasibility trial establishes that a cannabinoid-based approach can be safely delivered in nursing home settings, clearing the path for larger efficacy trials.","specificNumbers":"29 randomized (target was 60); 0 withdrawals; 100% adherence; 0 adverse reactions; 4-week treatment + 4-week observation; trial conducted October 2021-June 2022","methodology":"Randomized, double-blind, placebo-controlled feasibility study (STAND trial) in UK care homes. Participants with probable Alzheimer's disease and predefined clinically significant agitation were randomized to nabiximols or placebo for 4 weeks on an up-titrated schedule, followed by 4-week observation. Prespecified feasibility thresholds assessed.","limitations":"Feasibility study not powered for efficacy outcomes. Did not meet recruitment target (29 of 60) due to COVID-19. Short 4-week treatment period. UK nursing home setting may not generalize to other care contexts. Efficacy remains unproven."},{"rthcId":"RTHC-05900","title":"Patterns of substance use in people with severe mental illness: A case-control study in Ethiopia.","authors":"Alemayehu, Melkam; Mihretu, Awoke; Tsigebrhan, Ruth; Sharma, Manasi; Gelaye, Bizu; Teferra, Solomon","year":2025,"journal":"PloS one, 20(12), e0332107","doi":"10.1371/journal.pone.0332107","pmid":"41348727","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05901","title":"Phytochemical Modulators of Nociception: A Review of Cannabis Terpenes in Chronic Pain Syndromes.","authors":"Alfieri, Aniello; Di Franco, Sveva; Maffei, Vincenzo; Sansone, Pasquale; Pace, Maria Caterina; Passavanti, Maria Beatrice; Fiore, Marco","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(8)","doi":"10.3390/ph18081100","pmid":"40872493","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05902","title":"Revealing the therapeutic potential of synthetic cannabinoids: a systematic review of cannabinoid receptor binding dynamics and their implications for cancer therapy.","authors":"Alghamdi, Sahar S; Albahlal, Hussah N; Aloumi, Danah E; Bin Saqyah, Sarah; Alsubait, Arwa; Alamre, Jehan; Alrashed, Mohammed; Alsuhabeny, Nada; Mohammed, Afrah E","year":2025,"journal":"Journal of cannabis research, 7(1), 33","doi":"10.1186/s42238-025-00289-5","pmid":"40483537","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05903","title":"Knowledge and attitude of college students towards cannabis use in urban India: A comparative perspective of users and non-users.","authors":"Ali, Enub; Sachdeva, Ankur; Thakur, Avinash; Khullar, Shilpa; Das, Padmini; Abbas, S Zafar","year":2025,"journal":"The National medical journal of India, 38(2), 78-83","doi":"10.25259/NMJI_451_2023","pmid":"40587287","tags":["youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 260 college students in Mumbai, 11.2% reported cannabis use and 15% expressed desire to try it. Friends introduced 72% of users to cannabis. Top reasons for use were peer pressure (29.6%), stress reduction (23.5%), and experimentation (21.9%). Despite 81% opposing legalization, more than half of all participants were unaware of cannabis-related legal issues. Users viewed cannabis as less harmful and addictive than non-users did.","whyItMatters":"The combination of low legal awareness, high peer influence, and a perception gap between users and non-users about harm suggests that campus prevention efforts need to go beyond \"just say no\" messaging to address knowledge gaps and social dynamics.","specificNumbers":"n=260; 11.2% cannabis users; 72% introduced by friends; 29.6% cited peer pressure; 23.5% stress reduction; 81% opposed legalization; >50% unaware of legal issues; 15% expressed desire to try","methodology":"Cross-sectional study across multiple colleges in Mumbai, India. 260 students aged 18-25 selected by systematic random sampling. Self-administered questionnaire on knowledge, attitudes, and use patterns analyzed with SPSS.","limitations":"Small sample (n=260) from one city limits generalizability across India. Self-reported use may underestimate prevalence given legal status. Cross-sectional design cannot establish causal relationships between attitudes and use."},{"rthcId":"RTHC-05904","title":"Cannabis Oil Protects Against Valproic Acid-Induced Autism Spectrum Disorder by Reducing Oxidative Stress.","authors":"Ali, Faiza; Shehzad, Adeeb; Shahzad, Raheem; Khan, Salman; Rashan, Luay; Taha, Muhammad","year":2025,"journal":"Developmental neurobiology, 85(3), e22969","doi":"10.1002/dneu.22969","pmid":"40384294","tags":["cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In a valproic acid-induced autism mouse model, CBD oil (100 mg/kg/day orally for 3 weeks starting at postnatal day 21) improved autistic behaviors including anxiety, delayed response to painful stimuli, and impaired social interaction. Biochemical analysis showed CBD oil restored depleted glutathione and antioxidant levels. Morphological staining revealed improvements in the hippocampus, prefrontal cortex, and Purkinje cells. CBD oil performed comparably to the standard antipsychotic risperidone (0.5 mg/kg/day).","whyItMatters":"Autism spectrum disorder currently has no effective treatment for core symptoms. Preclinical evidence that CBD oil addresses both behavioral and neurobiological aspects of autism through antioxidant mechanisms could inform future clinical research, though animal models of autism have significant translational limitations.","specificNumbers":"CBD oil 100 mg/kg/day for 3 weeks; VPA 600 mg/kg gestational exposure; compared to risperidone 0.5 mg/kg/day; improvements in hippocampus, prefrontal cortex, and Purkinje cells","methodology":"VPA-induced autism mouse model using BALB/c mice exposed to valproic acid (600 mg/kg) on gestational day 13. Male pups divided at postnatal day 21 into four groups: control saline, VPA-exposed, VPA + CBD oil (100 mg/kg/day), and VPA + risperidone (0.5 mg/kg/day) for 3 weeks. Behavioral, biochemical, and histological analyses performed.","limitations":"Animal model of autism has significant limitations in replicating human ASD. Only male pups studied. Single dose of CBD oil tested. VPA-induced autism model represents only one possible etiology. Short treatment duration. Translating mouse doses to human equivalents is uncertain."},{"rthcId":"RTHC-05905","title":"Triple Air Leak Syndrome in Cannabinoid Hyperemesis: A Diagnostic Challenge Managed Conservatively.","authors":"Ali, Kashif; Masood Shah, Aresha; Hyder, Arsalan; Balderas, Valeska","year":2025,"journal":"ACG case reports journal, 12(10), e01858","doi":"10.14309/crj.0000000000001858","pmid":"41112854","tags":["health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 21-year-old chronic cannabis user with cannabinoid hyperemesis syndrome (CHS) developed a rare triad of spontaneous pneumomediastinum (air around the heart's major vessels), pneumopericardium (air around the heart), and pneumoretroperitoneum (air behind the abdominal cavity) from severe vomiting. Initial findings raised concern for Boerhaave syndrome (esophageal rupture), but imaging ruled out perforation. The patient recovered fully with conservative management: bowel rest, IV fluids, electrolyte correction, antiemetics, and antibiotics.","whyItMatters":"This case demonstrates that CHS can produce complications serious enough to mimic surgical emergencies like esophageal rupture. Recognizing this pattern can prevent unnecessary invasive procedures while ensuring appropriate conservative management.","specificNumbers":"21-year-old female; triple air leak: pneumomediastinum + pneumopericardium + pneumoretroperitoneum; full recovery with conservative management","methodology":"Single case report of a 21-year-old woman presenting with CHS complicated by triple air leak syndrome. Diagnostic workup included imaging to rule out esophageal perforation. Conservative management approach documented with follow-up to full recovery.","limitations":"Single case report cannot establish frequency or risk factors for this complication. Conservative management worked in this case but may not be appropriate if esophageal perforation cannot be definitively excluded."},{"rthcId":"RTHC-05906","title":"Relative Risk of All-Cause Mortality Associated With Cannabis Use: A Systematic Review and Meta-Analysis of Cohort Studies.","authors":"Alimoradi, Zainab; Lin, Chung-Ying; Myran, Daniel T; Solmi, Marco; Pakpour, Amir H","year":2025,"journal":"Health science reports, 8(10), e71212","doi":"10.1002/hsr2.71212","pmid":"41017864","tags":["health-risks"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Across 14 cohort studies with 17,545,076 participants (3,000,667 cannabis users), cannabis use was associated with a risk ratio of 1.53 (95% CI: 1.09-2.14) for all-cause mortality. The effect was significantly larger in prospective designs (RR 2.07) versus retrospective (RR 1.11), and in general population cohorts (RR 2.53) versus patient populations (RR 1.03). Larger sample sizes were associated with smaller effects. GRADE assessment rated overall evidence certainty as low.","whyItMatters":"This is the first meta-analysis to synthesize evidence on cannabis use and all-cause mortality. The finding of a 53% increased risk is notable but comes with substantial caveats: high heterogeneity, potential confounding, and the association disappearing in patient populations suggest the relationship is more complex than a simple causal link.","specificNumbers":"n=17,545,076 (3,000,667 cannabis users); 14 cohort studies (50% prospective); overall RR 1.53 (95% CI: 1.09-2.14); general population RR 2.53; patient population RR 1.03; I²=98%; GRADE: low certainty","methodology":"Systematic review and meta-analysis registered with PROSPERO (CRD42023396915). Searched Scopus, PubMed, Web of Science, and ProQuest through October 2023. Included cohort studies comparing cannabis users to non-users for all-cause mortality. Random-effects meta-analysis with sensitivity analysis, meta-regression, and Newcastle Ottawa Scale quality assessment.","limitations":"Very high heterogeneity (I²=98%) reduces confidence in the pooled estimate. Unadjusted estimates included in many studies mean confounding factors (tobacco, alcohol, socioeconomic status) likely inflate the association. GRADE assessment rated evidence as low certainty. Larger studies showed smaller effects, suggesting potential publication bias or confounding."},{"rthcId":"RTHC-05907","title":"The Endocannabinoid-Microbiota-Neuroimmune Super-System: A Unifying Feedback Architecture for Systems Resilience, Collapse Trajectories, and Precision Feedback Medicine.","authors":"Aliuș, Cătălin; Breazu, Alexandru; Pantu, Cosmin; Toader, Corneliu; Șerban, Matei; Covache-Busuioc, Răzvan-Adrian; Munteanu, Octavian; Dumitru, Adrian Vasile","year":2025,"journal":"International journal of molecular sciences, 26(22)","doi":"10.3390/ijms262210959","pmid":"41303442","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05908","title":"Association Between Substance Use and Periodontitis: A Cross-Sectional Analysis of NHANES Data on Marijuana, Hashish, and Cocaine.","authors":"Aljoghaiman, Eman","year":2025,"journal":"Clinical, cosmetic and investigational dentistry, 17, 293-304","doi":"10.2147/CCIDE.S536382","pmid":"40771761","tags":["health-risks"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 3,690 NHANES participants (2011-2014), 54% reported ever using marijuana or hashish. Marijuana/hashish use was significantly associated with severe periodontitis, affecting 39% of users (adjusted OR: 4.276, 95% CI: 3.682-4.967, P=0.001). Cocaine use was also linked to periodontitis but primarily mild disease. Alcohol consumption showed a smaller positive association (OR: 1.255). No significant associations were found for heroin or methamphetamine use.","whyItMatters":"Periodontitis affects millions of adults and is linked to systemic health conditions including cardiovascular disease and diabetes. If cannabis use substantially increases periodontal disease risk, this has implications for dental screening and patient counseling as cannabis use becomes more widespread.","specificNumbers":"n=3,690; 54% reported marijuana/hashish use; 39% of users had severe periodontitis; adjusted OR 4.276 (95% CI: 3.682-4.967); cocaine associated with mild periodontitis; alcohol OR 1.255; no association for heroin or methamphetamine","methodology":"Cross-sectional analysis of NHANES 2011-2012 and 2013-2014 cycles. 3,690 participants with demographic information, clinical periodontal examinations, and drug use questionnaires. Logistic regression models adjusted for age, sex, race/ethnicity, education, income, marital status, occupation, alcohol, BMI, dental insurance, and dental visit frequency.","limitations":"Cross-sectional NHANES design cannot establish causation. Self-reported drug use may be inaccurate. Cannabis smoke exposure patterns (frequency, duration, method) were not fully characterized. Residual confounding from unmeasured factors like oral hygiene practices is possible."},{"rthcId":"RTHC-05909","title":"Prevalence of toxin exposure in regions of Saudi Arabia: A systematic review and meta-analysis.","authors":"Aljumaan, Mohammed A; Alsulaibikh, Amal H","year":2025,"journal":"Journal of family & community medicine, 32(3), 186-197","doi":"10.4103/jfcm.jfcm_337_24","pmid":"40785961","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05910","title":"Cannabinoids-Induced Rhabdomyolysis in a Patient: A Report of a Case and a Review of Literature.","authors":"AlKhateeb, Sultan; Albulushi, Bashaer; Joueidi, Khaled; Joueidi, Faisal","year":2025,"journal":"Cureus, 17(3), e80809","doi":"10.7759/cureus.80809","pmid":"40255777","tags":["health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 48-year-old man with muscle-invasive bladder cancer who had undergone radical cystoprostatectomy developed severe back pain, reduced lower limb function, shortness of breath, elevated creatinine and creatine kinase, and decreased urine output postoperatively. Rhabdomyolysis was diagnosed and linked to synthetic cannabinoid use. The patient required continuous renal replacement therapy followed by hemodialysis.","whyItMatters":"Synthetic cannabinoids carry toxicity risks that are qualitatively different from natural cannabis. Rhabdomyolysis is a life-threatening complication that may be underrecognized in synthetic cannabinoid users, and its occurrence in a surgical patient illustrates how synthetic cannabinoid use can complicate medical care.","specificNumbers":"48-year-old male; elevated creatinine and creatine kinase; required continuous renal replacement therapy then hemodialysis; mechanism through G-protein coupled receptor activation","methodology":"Single case report documenting the clinical presentation, laboratory findings, diagnosis, and management of synthetic cannabinoid-induced rhabdomyolysis in a postoperative cancer patient. Includes literature review of the mechanism.","limitations":"Single case report cannot establish frequency of this complication. Post-surgical context introduces confounding factors for rhabdomyolysis (immobility, medications, surgical stress). Difficult to definitively attribute rhabdomyolysis to synthetic cannabinoids versus other postoperative factors."},{"rthcId":"RTHC-05911","title":"Lactiplantibacillus plantarum strengthens the intestinal barrier: involvement of the endocannabinoidome.","authors":"Allam-Ndoul, Bénédicte; Pulido-Mateos, Elena Cristina; Bégin, Frédéric; St-Arnaud, Gabrielle; Tinoco Mar, Briscia Anaid; Mayer, Thomas; Dumais, Elizabeth; Flamand, Nicolas; Raymond, Frederic; Roy, Denis; Desjardins, Yves; Di Marzo, Vincenzo; Veilleux, Alain","year":2025,"journal":"American journal of physiology. Gastrointestinal and liver physiology, 329(2), G245-G260","doi":"10.1152/ajpgi.00142.2024","pmid":"40522902","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05912","title":"Pharmacovigilance in the Age of Legalized Cannabis: Using Social Media to Monitor Drug-Drug Interactions Between Immunosuppressants and Cannabis-Derived Products.","authors":"Allen, Matthew R; Wightman, Gwenyth Portillo; Zhu, Zechariah; Poliak, Adam; Smith, Davey M; Dredze, Mark; Ayers, John W","year":2025,"journal":"Drug safety, 48(1), 99-105","doi":"10.1007/s40264-024-01481-x","pmid":"39292423","tags":["cbd","health-risks"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Searching 63.5 million Reddit posts, researchers identified 190 posts discussing both cannabis-derived products (CDPs) and immunosuppressants. Of these, 66 posts (35%) expressed concern about potential drug-drug interactions, and 4 posts (2%) reported actual adverse interactions. Two of the four matched the known CBD/tacrolimus interaction discovered in Epidiolex trials. Two others reported previously undocumented interactions: a CBD or THC/sirolimus interaction and a THC/tacrolimus interaction, both resulting in drug toxicity.","whyItMatters":"Consumer cannabis products are unregulated and cannot be tested in clinical trials the way Epidiolex was. This study demonstrates that real-world drug interactions are occurring with consumer CBD and THC products and going unreported to formal pharmacovigilance systems, creating a hidden safety gap.","specificNumbers":"63.5 million Reddit posts searched; 190 relevant posts identified; 66 (35%) expressed DDI concern; 4 (2%) reported actual DDI events; 2 novel interactions discovered: CBD/THC with sirolimus and THC with tacrolimus","methodology":"Searched Reddit for subreddits related to cannabis-derived products or health, yielding 63,561,233 posts. Identified 190 posts discussing both immunosuppressants and CDPs. Two blinded investigators evaluated posts for DDI concerns and reported adverse events.","limitations":"Social media data cannot verify clinical outcomes or confirm causation. Four reported DDI events is a very small number from which to draw conclusions. Reddit users may not accurately describe medications, doses, or outcomes. Cannot estimate the true incidence of these interactions."},{"rthcId":"RTHC-05913","title":"Understanding Cannabis Use After Spinal Cord Injury: A Canadian Survey Study.","authors":"Allison, David J; Ebrahimzadeh, Sanam; Agudelo, Alexandria Roa; Lawson, Arden; Kassem, Daad; Loh, Eldon","year":2025,"journal":"Archives of rehabilitation research and clinical translation, 7(4), 100498","doi":"10.1016/j.arrct.2025.100498","pmid":"41477069","tags":["pain","sleep"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 80 Canadian adults with spinal cord injury, 42.5% reported cannabis use post-injury and 37.5% were current users, exceeding the general Canadian population rate of 25%. Post-injury, the primary reasons for use shifted from recreation (25%) to pain relief (36.3%) and sleep improvement (30%). Users reported moderate perceived effectiveness. Edibles replaced smoking as the most common consumption method post-injury. Adverse events were generally mild and infrequent, with fatigue the most common (11.3%).","whyItMatters":"Spinal cord injury often produces chronic pain and sleep disruption that are difficult to treat with conventional medications. The shift from recreational to therapeutic use and from smoking to edibles reflects how injury changes cannabis use patterns, information that clinicians need to provide informed guidance.","specificNumbers":"n=80 (61.2% men; mean age 57.7); 42.5% used cannabis post-injury; 37.5% current users (vs 25% general population); reasons shifted to pain (36.3%) and sleep (30%); fatigue most common side effect (11.3%)","methodology":"Online survey of Canadian adults with any level or severity of spinal cord injury (N=80). Assessed prevalence, frequency, reasons for use, perceived effectiveness, adverse events, and consumption modality.","limitations":"Small sample (n=80) recruited online, introducing selection bias. Self-reported outcomes without clinical validation. No comparison group or standardized outcome measures. Cannot assess actual efficacy, only perceived effectiveness."},{"rthcId":"RTHC-05914","title":"Direct analysis of THC containing edibles using Py-GC/MS.","authors":"Almadani, Fatma; Gewily, Samar; Lanjawi, Adnan; Alshuhomi, Hind; Alremeithi, Rashed; Khalil, Saif-Eldin; Altamimi, Mohamad J","year":2025,"journal":"Science & justice : journal of the Forensic Science Society, 65(6), 101346","doi":"10.1016/j.scijus.2025.101346","pmid":"41320462","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05915","title":"Exploring the Impact of Chirality of Synthetic Cannabinoids and Cathinones: A Systematic Review on Enantioresolution Methods and Enantioselectivity Studies.","authors":"Almeida, Ana Sofia; Santos, Rita M G; Guedes de Pinho, Paula; Remião, Fernando; Fernandes, Carla","year":2025,"journal":"International journal of molecular sciences, 26(13)","doi":"10.3390/ijms26136471","pmid":"40650252","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05916","title":"Uncovering the Metabolic Footprint of New Psychoactive Substances by Metabolomics: A Systematic Review.","authors":"Almeida, Ana Sofia; Pinho, Paula Guedes de; Remião, Fernando; Fernandes, Carla","year":2025,"journal":"Molecules (Basel, Switzerland), 30(2)","doi":"10.3390/molecules30020290","pmid":"39860158","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05917","title":"Impact of minor cannabinoids on key pharmacological targets of estrogen receptor-positive breast cancer.","authors":"Almeida, Cristina Ferreira; Correia-da-Silva, Georgina; Ribeiro, Ana Paula; Teixeira, Natércia; Amaral, Cristina","year":2025,"journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids, 1870(6), 159658","doi":"10.1016/j.bbalip.2025.159658","pmid":"40615070","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05918","title":"Cannabinol improves exemestane efficacy in estrogen receptor-positive breast cancer models: a comparative study with cannabidiol.","authors":"Almeida, Cristina Ferreira; Valente, Maria João; Teixeira, Natércia; Rocha, Susana; Ribeiro, Ana Paula; Vinggaard, Anne Marie; Correia-da-Silva, Georgina; Amaral, Cristina","year":2025,"journal":"European journal of pharmacology, 1000, 177712","doi":"10.1016/j.ejphar.2025.177712","pmid":"40345424","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05919","title":"Synthetic Cannabinoids are Genotoxic in Cultured Human Lymphocytes.","authors":"Almestafa, Alla Abdulwahab; Khabour, Omar Falah; Al-Eitan, Laith Naser; Alzoubi, Karem Hasan","year":2025,"journal":"Current pharmaceutical design, 31(29), 2346-2351","doi":"10.2174/0113816128340465241227095853","pmid":"39835562","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05920","title":"Adipogenicity-induced human mesenchymal stem cells treated with hemp seed oil stimulate brown-like adipocytes and decrease adipokine levels through the activation of cannabinoid receptor 2 (CB2).","authors":"Almousa, Albatul; Subash-Babu, Pandurangan; Alanazi, Ibrahim O; Alshatwi, Ali A","year":2025,"journal":"Journal of cannabis research, 7(1), 95","doi":"10.1186/s42238-025-00343-2","pmid":"41258240","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05921","title":"Are Cannabis-Based Medicines a Useful Treatment for Neuropathic Pain? A Systematic Review.","authors":"Almuntashiri, Nawaf; El Sharazly, Basma M; Carter, Wayne G","year":2025,"journal":"Biomolecules, 15(6)","doi":"10.3390/biom15060816","pmid":"40563456","tags":["pain","thc","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Among 22 RCTs of cannabis-based medicines for neuropathic pain, 15 reported significant pain reductions for conditions including multiple sclerosis, spinal cord injuries, diabetic neuropathy, postherpetic neuralgia, HIV-associated neuropathy, and peripheral neuropathic pain. Positive outcomes were more common with personalized, adjusted dosing. Seven trials found no significant pain relief versus placebo, though some showed improvements in secondary outcomes like mood and sleep.","whyItMatters":"Neuropathic pain is notoriously difficult to treat, and many patients do not respond to first-line medications. This comprehensive review shows that cannabis-based medicines can help, but the evidence is complicated by study limitations and variable outcomes.","specificNumbers":"22 RCTs reviewed; 15 (68%) found significant pain reduction; 7 (32%) found no significant relief; conditions covered: MS, SCI, diabetic neuropathy, postherpetic neuralgia, HIV neuropathy, peripheral neuropathy, CRPS, chronic radicular pain","methodology":"Systematic review of literature from January 2003 to December 2024 using Web of Science, PubMed, and MEDLINE. Identified 22 RCTs evaluating CT-3, THC, CBD, THC/CBD combinations, and cannabidivarin for neuropathic pain across multiple conditions.","limitations":"Reviewed studies had small sample sizes and short durations. High placebo response rates in pain trials reduce statistical power. Psychoactive effects of THC may unblind participants. Heterogeneity in cannabinoid types, doses, and conditions limits direct comparisons across studies."},{"rthcId":"RTHC-05922","title":"Cannabidiol and Beta-Caryophyllene: Chronic inflammatory pain.","authors":"Alnoud, Mohammed; Hussain, Mohammad S; Rios, Jose; Franco, Emmanuel; Mills, Justin; Nwose, Joshua; Malbas, Maria Sophia; Garcia, Hiram; Leslie, Sophia; Tripathi, Manish K; Benamar, Khalid","year":2025,"journal":"Pharmacological research, 222, 107987","doi":"10.1016/j.phrs.2025.107987","pmid":"41120021","tags":["pain","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In a chronic inflammatory pain model (CFA-induced), the combination of CBD and beta-caryophyllene (BCP) produced synergistic pain-relieving effects that exceeded either compound alone. The combination also exhibited antidepressant properties. Immunohistochemistry showed the combination significantly reduced neuroinflammation, and proteomics revealed downregulation of inflammation-related proteins by the combination compared to individual effects of CBD or BCP.","whyItMatters":"Chronic pain and depression frequently co-occur but are typically treated separately. Finding a combination that addresses both simultaneously through anti-inflammatory mechanisms could offer a more integrated treatment approach, particularly if it can reduce reliance on opioids.","specificNumbers":"CBD + BCP combination showed synergistic (not just additive) pain relief; antidepressant properties confirmed in behavioral tests; neuroinflammation reduced; proteomics showed downregulation of inflammatory proteins","methodology":"Complete Freund's Adjuvant (CFA) chronic inflammatory pain model in mice. Battery of pain and depression-like behavior tests. Proteomics and immunohistochemistry to explore mechanisms. Compared CBD alone, BCP alone, and the combination.","limitations":"Animal study results may not translate to humans. CFA model represents one type of chronic pain. Specific doses and the optimal ratio of CBD to BCP were not fully characterized. No long-term safety or efficacy data."},{"rthcId":"RTHC-05923","title":"Pediococcus acidilactici KCTC 15831BP-fermented industrial hempseed (Cannabis sativa L.) supplementation corrects metabolite and gut microbiota dysbiosis, potentially mitigating Alzheimer's disease-like symptoms induced by obesity in high-fat diet-fed mice.","authors":"Aloo, Simon Okomo; Chelliah, Ramachandran; Ofosu, Fred Kwame; Lee, Ye-Won; Cho, Ye Eun; Park, Se Jin; Oh, Deog Hwan","year":2025,"journal":"Food & function, 16(18), 7330-7349","doi":"10.1039/d5fo01921d","pmid":"40878211","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05924","title":"Molecular Crosstalk and Therapeutic Synergy: Tyrosine Kinase Inhibitors and Cannabidiol in Oral Cancer Treatment.","authors":"AlRaheem, Zainab Saad Ghafil; Le, Thao T; Seyfoddin, Ali; Li, Yan","year":2025,"journal":"Current issues in molecular biology, 47(8)","doi":"10.3390/cimb47080584","pmid":"40864738","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05925","title":"Adding Nuance to Understanding the Effects of Cannabis Legalization by Using Policy Bundles: A Study of Youth Mental Health.","authors":"Altaf, Shazib; Mallinson, Daniel J; Park, Mingean; Richardson, Lilliard E","year":2025,"journal":"Substance use & misuse, 60(6), 915-925","doi":"10.1080/10826084.2025.2466208","pmid":"39957096","tags":["legalization","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analysis of Youth Risk Behavior Survey data using a novel \"policy bundles\" measurement approach found that both pharmaceutical and permissive cannabis policy bundles were associated with mental health improvements in youth, while greater fiscalization (revenue-focused policy design) had a negative impact on youth mental health. The study used instrumental variables to address the endogeneity between cannabis use and mental health.","whyItMatters":"Most research on cannabis legalization treats it as a binary variable (legal or not). This study demonstrates that how legalization is designed matters significantly, and that policy choices within legalization frameworks have different effects on youth mental health.","specificNumbers":"Three policy bundles analyzed: pharmaceutical, permissive, and fiscal; pharmaceutical and permissive bundles associated with mental health improvements; fiscal bundle associated with worse mental health; instrumental variables used to address endogeneity","methodology":"Youth Risk Behavior Survey (YRBS) data from the CDC with three policy bundle scales as main exposures. Logistic regression with instrumental variables to address endogeneity between cannabis use and mental health outcomes.","limitations":"Cross-sectional YRBS data limits causal inference despite instrumental variable approach. Policy bundle classification is a novel method that needs validation. Cannot identify which specific policy components within bundles drive mental health effects."},{"rthcId":"RTHC-05926","title":"Genotoxic damage assessment using the micronucleus assay in buccal mucosa of different types of smokers: A cross-sectional study.","authors":"Álvarez-Martínez, Efraín; Porto-Puerta, Iván E; Ardila, Carlos M","year":2025,"journal":"World journal of experimental medicine, 15(3), 108025","doi":"10.5493/wjem.v15.i3.108025","pmid":"41523766","tags":["health-risks"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 100 participants (20 per group), micronuclei (markers of genotoxic damage) were present in 86% of all samples. Statistically significant increases in micronucleus count were observed for conventional tobacco, reverse smoking, and electronic cigarette users compared to non-smokers. Cannabis smokers showed no significant difference from non-smokers (P=0.89). A significant correlation existed between oral lesions and micronucleus count. Regression analysis ruled out alcohol as a confounding factor.","whyItMatters":"While smoking of any kind raises health concerns, this study suggests cannabis smoke may not produce the same genotoxic damage to oral tissue as tobacco smoke or e-cigarette vapor. This distinction matters for understanding the relative oral cancer risks of different smoking behaviors.","specificNumbers":"n=100 (20 per group); 86% had micronuclei present; cannabis vs non-smokers P=0.89 (not significant); tobacco, reverse, and e-cigarette smokers all significantly elevated; alcohol ruled out as confounder","methodology":"Cross-sectional study with 100 participants in five groups: conventional tobacco (n=20), reverse smokers (n=20), e-cigarette users (n=20), cannabis users (n=20), and non-smokers (n=20). Exfoliated buccal mucosa cells analyzed using Giemsa and Papanicolaou staining for micronuclei.","limitations":"Very small sample (20 per group). Cross-sectional design cannot assess cumulative exposure effects. Micronucleus assay captures one form of DNA damage but not all. Cannabis and tobacco smoking frequency, duration, and co-use patterns were not fully characterized."},{"rthcId":"RTHC-05927","title":"Understanding the online landscape of cannabis discourse: a Twitter analysis.","authors":"Alvarez-Mon, Miguel Angel; Ojeda, Carla; Lara-Abelenda, Francisco; Asunsolo Del Barco, Ángel; Fraile-Martínez, Oscar; García-Montero, Cielo; Fernández-Rojo, Sonia; Quintero, Javier; Ortega, Miguel Angel; Alvarez-Mon, Melchor; Mora, Fernando","year":2025,"journal":"Frontiers in public health, 13, 1416171","doi":"10.3389/fpubh.2025.1416171","pmid":"40746697","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 35,527 analyzed Spanish-language tweets about cannabis (2018-2022), 73.2% favored cannabis regulation while only 3.5% expressed opposition. Only 20.4% discussed negative effects on physical or mental health. Regarding therapeutic use, 30.1% were in favor while 69.9% were neutral or against. Significant differences emerged between user types and between cannabis consumers versus non-consumers.","whyItMatters":"Social media shapes public perception of cannabis, and the significant imbalance between pro-regulation content (73%) and health risk discussion (20%) suggests online discourse may not reflect the full scientific picture. This has implications for how the public forms opinions about legalization.","specificNumbers":"68,673 total tweets; 35,527 analyzed; 73.2% favored regulation; 3.5% opposed; 20.4% discussed negative health effects; 30.1% supported therapeutic use; tweets from 2018-2022","methodology":"Dataset of tweets posted 2018-2022 in Spanish containing keywords \"cannabis,\" \"marihuana,\" or \"hachis.\" A 500-post subset per keyword was manually coded to establish a codebook, then machine learning classified the remaining 67,173 tweets. After excluding irrelevant tweets, 35,527 were analyzed.","limitations":"Twitter users are not representative of the general population. Machine learning classification may misclassify tweets. Spanish-language tweets span multiple countries with different cultural contexts and legal frameworks. 2018-2022 timeframe may not reflect current discourse."},{"rthcId":"RTHC-05928","title":"Morphine-induced side effects can be differentially modulated by cannabidiol in male and female rats.","authors":"Alves Jesus, Carlos Henrique; Volpe, Jaqueline; Sotomaior, Bruna Bittencourt; Barbosa, Maria Augusta Ruy; Ferreira, Matheus Vinicius; Fiatcoski, Fernanda; Genaro, Karina; de Souza Crippa, José Alexandre; Pires Souto, Dênio Emanuel; Maria da Cunha, Joice","year":2025,"journal":"Behavioural pharmacology, 36(1), 1-15","doi":"10.1097/FBP.0000000000000803","pmid":"39718050","tags":["cbd","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In rats made physically dependent on morphine (10 days of twice-daily treatment), repeated CBD (30 mg/kg) prevented thermal hyperalgesia in both males and females. When withdrawal was induced with naloxone, morphine-dependent female rats predominantly showed rearing behavior while males showed teeth chattering. CBD treatment on day 11 partially attenuated withdrawal behavior in males, with milder effects in females (only in high withdrawal responders).","whyItMatters":"Opioid use disorder involves both tolerance-related hyperalgesia and withdrawal symptoms, and current treatments have significant limitations. Finding that CBD can prevent opioid-induced hyperalgesia while partially managing withdrawal symptoms opens a potential complementary treatment pathway.","specificNumbers":"CBD 30 mg/kg; morphine 7.89 mg/kg twice daily for 10 days; naloxone 2 mg/kg for withdrawal; CBD prevented hyperalgesia in both sexes; partial withdrawal attenuation in males; females showed different predominant withdrawal behavior","methodology":"Male and female rats underwent morphine-induced physical dependence protocol (7.89 mg/kg twice daily for 10 days). Nociception measured with hot plate test. Naloxone-precipitated withdrawal behavior scored after 11 days. CBD (30 mg/kg) tested for effects on both hyperalgesia and withdrawal.","limitations":"Animal study that may not translate to human opioid dependence. Single CBD dose tested. Withdrawal attenuation was partial, not complete. Sex differences in response complicate translation. Naloxone-precipitated withdrawal differs from spontaneous withdrawal."},{"rthcId":"RTHC-05929","title":"Effects of cannabidiol, cannabichromene, cannabidivarin, cannabigerol and cannabinol in endometrial cells: Implications for endocrine and senescence modulation.","authors":"Alves, Patrícia; Amaral, Cristina; Fonseca, Bruno M; Sousa, Luísa G; Teixeira, Natércia; Correia-da-Silva, Georgina","year":2025,"journal":"Reproductive toxicology (Elmsford, N.Y.), 137, 109006","doi":"10.1016/j.reprotox.2025.109006","pmid":"40706771","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05930","title":"In vivo assessment of the nephrotoxic effects of the synthetic cannabinoid AB-FUBINACA.","authors":"Alzu'bi, Ayman; Abu-El-Rub, Ejlal; Al-Trad, Bahaa; Alzoubi, Hiba; Abu-El-Rub, Hadeel; Albals, Dima; Abdelhady, Gamal T; Bader, Noor S; Almazari, Rawan; Al-Zoubi, Raed M","year":2025,"journal":"Forensic toxicology, 43(1), 86-96","doi":"10.1007/s11419-024-00699-9","pmid":"39120650","tags":["health-risks"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AB-FUBINACA (3 mg/kg for 5 days) induced substantial renal function impairment with elevated kidney damage markers KIM-1 and NGAL. The mechanism involved increased oxidative stress markers (iNOS, NOX4, NOX2, NOS3) and lipid peroxidation, enhanced pro-inflammatory markers (IL-6, TNF-alpha, NF-kB), and activation of caspase-dependent apoptosis (Bax, caspase-9, caspase-3). Mitochondrial complexes I, III, and IV were reduced, suggesting mitochondrial dysfunction underlies the nephrotoxicity.","whyItMatters":"Synthetic cannabinoid-induced acute kidney injury is increasingly reported but poorly understood. This study identifies a specific mechanism linking mitochondrial dysfunction to oxidative stress, inflammation, and cell death in the kidney, which could inform treatment approaches.","specificNumbers":"AB-FUBINACA 3 mg/kg for 5 days; elevated KIM-1 and NGAL; increased iNOS, NOX4, NOX2, NOS3; increased IL-6, TNF-alpha, NF-kB; activated Bax, caspase-9, caspase-3; reduced mitochondrial complexes I, III, IV","methodology":"Mouse study investigating nephrotoxic effects of acute AB-FUBINACA administration (3 mg/kg for 5 days). Measured oxidative stress, inflammation, and apoptosis markers. Assessed mitochondrial complex (I-V) expression in renal tissues.","limitations":"Mouse model with acute high-dose exposure may not reflect typical human use patterns. Single synthetic cannabinoid tested; results may not generalize to other compounds. Short 5-day exposure does not address chronic effects. Mouse-to-human dose translation is uncertain."},{"rthcId":"RTHC-05931","title":"The CB1 receptor: linking impulsivity and substance use disorder.","authors":"Amancio-Belmont, Octavio; Becerril-Melendez, Lorena Alline; Méndez-Díaz, Mónica","year":2025,"journal":"Frontiers in neuroscience, 19, 1621242","doi":"10.3389/fnins.2025.1621242","pmid":"41098856","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05932","title":"Indazole partial agonists targeting peripheral cannabinoid receptors.","authors":"Amato, George; Laudermilk, Lucas; Vasukuttan, Vineetha; Gay, Elaine A; Decker, Ann M; Snyder, Rodney; Yue, Yun Lan; Runyon, Scott; Maitra, Rangan","year":2025,"journal":"Bioorganic & medicinal chemistry, 129, 118327","doi":"10.1016/j.bmc.2025.118327","pmid":"40716175","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05933","title":"Effects of marijuana and tobacco on male fertility and their relationship to genetic variation of mitochondrial cytochrome C oxidase genes.","authors":"Amor, Houda; Ismaeil, Ayham; Jankowski, Peter Michael; Smadi, Mohammad A Al; Zoubi, Mazhar S Al; Juhasz-Böss, Ingolf; Hammadeh, Mohamad Eid","year":2025,"journal":"Scientific reports, 15(1), 7547","doi":"10.1038/s41598-025-91894-0","pmid":"40038427","tags":["health-risks","thc"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Comparing 37 non-smokers, 39 tobacco smokers, and 37 cannabis smokers, both tobacco and cannabis groups showed reduced normal sperm morphology and non-progressive motility. However, cannabis smokers had significantly higher rates of immotile sperm, positive acridine orange staining (indicating DNA denaturation), and positive CMA3 scores (indicating chromatin immaturity) compared to both tobacco smokers and non-smokers (P<0.001). No differences in mitochondrial cytochrome C oxidase gene variants were found between groups.","whyItMatters":"As cannabis use increases among men of reproductive age while tobacco use declines, understanding the comparative reproductive risks matters. This study found cannabis smoking produced worse sperm DNA damage than tobacco, suggesting a distinct mechanism of reproductive harm.","specificNumbers":"n=113 (37 NS, 39 TS, 37 CS); cannabis smokers had higher immotile sperm, AO+, and CMA3+ scores (all P<0.001 vs NS and TS); 23 SNPs in MT-CO1, 15 in MT-CO2, 30 in MT-CO3, none different between groups","methodology":"Semen samples from 113 men divided into non-smokers (n=37), tobacco smokers (n=39), and cannabis smokers (n=37). Sperm quality assessed by standard parameters. DNA integrity tested by Chromomycin A3 and acridine orange staining. Mitochondrial MT-CO1, MT-CO2, and MT-CO3 genes amplified and sequenced.","limitations":"Small sample sizes per group (37-39). Cross-sectional design cannot establish causation. Did not control for frequency or duration of smoking. Co-use of cannabis and tobacco was not addressed. Genetic analysis was limited to mitochondrial genes."},{"rthcId":"RTHC-05934","title":"Method and frequency of cannabis use: Results from the 2023 Behavioral Risk Factor Surveillance System.","authors":"Amrock, Stephen M; Brar, Karmen; Pennington, Nicolette; Sajkiewicz, Agata J","year":2025,"journal":"Addictive behaviors, 170, 108418","doi":"10.1016/j.addbeh.2025.108418","pmid":"40616939","tags":["addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Past-30-day cannabis use was reported by 14.7% of 119,068 adults. Among users, 77.1% smoked, 44.3% ingested edibles, 32.7% vaped, and 14.0% dabbed. Most commonly, individuals either exclusively smoked (35.4%) or exclusively ingested (15.2%). Exclusive vaping was uncommon (3.1%), though many vapers used multiple methods. Multimodal use was associated with increased frequency. Strong correlations existed between tobacco smoking and cannabis smoking (OR 3.65) and between e-cigarette and cannabis vaping (OR 3.58).","whyItMatters":"Understanding how people actually use cannabis is essential for public health planning. The strong correlations between cannabis and tobacco delivery methods suggest shared behavioral patterns, while the rise of multimodal use may indicate escalating consumption patterns.","specificNumbers":"n=119,068; 14.7% past-30-day use; 77.1% smoke; 44.3% ingest; 32.7% vape; 14.0% dab; 35.4% exclusively smoke; 15.2% exclusively ingest; 3.1% exclusively vape; tobacco-cannabis smoking OR 3.65; e-cig-cannabis vaping OR 3.58","methodology":"Analysis of 119,068 individuals who answered cannabis questions in the 2023 Behavioral Risk Factor Surveillance System (BRFSS), a national cross-sectional survey. Cross-tabulations and logistic regression examined use patterns by demographics, health, and substance use. Negative binomial regression examined frequency correlates.","limitations":"Cross-sectional BRFSS data relies on self-report. States participating in cannabis modules may not be nationally representative. Cannot assess dose, potency, or THC/CBD content by method. Past-30-day window may not capture occasional users."},{"rthcId":"RTHC-05935","title":"Potential Association of Air Leak Syndromes With E-cigarette or Vaping Product Use-Associated Lung Injury (EVALI).","authors":"Anakebe, Chidi; Abdallah, Ragda; Abdalla, Mahil; Taha, Fatima; Khan, Haji Sheeraz","year":2025,"journal":"Cureus, 17(9), e93395","doi":"10.7759/cureus.93395","pmid":"41164027","tags":["youth","health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 15-year-old male with mild asthma presented with acute respiratory distress, hypoxemia, and neck/face swelling after using vaping products and inhaling cannabis. Imaging confirmed widespread air leaks including subcutaneous emphysema, pneumomediastinum, and pneumorrhachis (air in the spinal canal) without esophageal perforation. Conservative management with oxygen, TPN, antibiotics, and supportive care led to full recovery.","whyItMatters":"This is one of the youngest reported cases of EVALI-associated air leak syndrome. As vaping prevalence rises sharply among adolescents, clinicians seeing chest pain and respiratory distress in young patients need to consider vaping-related complications in their differential diagnosis.","specificNumbers":"15-year-old male; mild asthma history; subcutaneous emphysema + pneumomediastinum + pneumorrhachis; full recovery with conservative management","methodology":"Single case report with literature review. Targeted literature search identified several reports linking vaping to spontaneous air leak syndromes.","limitations":"Single case report cannot establish frequency or causation. Combined cannabis and vaping use makes it impossible to attribute the complication to one substance. Mild asthma may have been a contributing factor."},{"rthcId":"RTHC-05936","title":"Modulatory Effects of \"Minor\" Cannabinoids in an in vitro Model of Neuronal Hypersensitivity.","authors":"Anand, Uma; Anand, Praveen; Sodergren, Mikael H","year":2025,"journal":"Journal of pain research, 18, 6259-6274","doi":"10.2147/JPR.S547613","pmid":"41322279","tags":["pain","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis produces over 100 cannabinoids, but research has focused almost exclusively on THC and CBD. This study tested 10 'minor' cannabinoids for their effects on pain-sensing neurons — and found that some of them are surprisingly potent.\n\nThe researchers used an established model of neuropathic pain: cultured rat dorsal root ganglion (DRG) neurons sensitized with nerve growth factor and GDNF, then challenged with capsaicin (the compound that makes chili peppers burn). This model mimics the neuronal hypersensitivity that underlies chronic neuropathic pain.\n\nThe 10 cannabinoids tested — THCC, CBT, CBDV, CBN, CBC, CBCV, CBCT, CBGM, THCB, and THCP — showed differential, dose-related effects on pain signaling. THCP (tetrahydrocannabiphorol) stood out for its potency at very low concentrations, consistent with its known high affinity for CB1 receptors. CBC (cannabichromene) also showed strong analgesic activity.\n\nOther cannabinoids like CBN and CBDV showed moderate effects, while some had minimal impact. Importantly, the effects were dose-related — at certain concentrations some cannabinoids reduced pain signaling, while at higher concentrations the effects sometimes changed direction.\n\nThis matters because neuropathic pain affects millions of people and remains inadequately treated. Current options — opioids, anticonvulsants, antidepressants — have significant side effects and limited efficacy. If minor cannabinoids like THCP or CBC can modulate pain at the neuronal level, they represent entirely new pharmacological targets.","whyItMatters":"Neuropathic pain is one of the greatest unmet clinical needs in medicine. Current treatments fail about 50% of patients. Minor cannabinoids represent a largely unexplored pharmacological frontier. This systematic comparison of 10 cannabinoids on pain-sensing neurons provides the foundational data needed to identify which minor cannabinoids are most worth pursuing in animal models and eventually human trials.","specificNumbers":"10 minor cannabinoids tested: THCC, CBT, CBDV, CBN, CBC, CBCV, CBCT, CBGM, THCB, THCP. Concentration range: 0.001-100 μM. THCP showed potency at very low concentrations. CBC showed strong analgesic activity. Effects were dose-related and varied by cannabinoid. Model: sensitized rat DRG neurons challenged with capsaicin.","methodology":"In vitro study using adult rat DRG neurons cultured with nerve growth factor (100 ng/mL) and GDNF (50 ng/mL) for 48 hours to sensitize nociceptors. Calcium imaging measured neuronal responses to capsaicin stimulation, and the modulatory effects of 10 minor cannabinoids at concentrations of 0.001-100 μM were assessed in individual neurons.","limitations":"In vitro study using rat neurons — several steps removed from human clinical relevance. The capsaicin challenge model assesses one type of pain signaling (TRPV1-mediated) and may not represent all neuropathic pain mechanisms. Dose-response relationships in isolated neurons don't predict effective doses in living animals or humans. No comparison to THC or CBD in the same assay, making it hard to benchmark the minor cannabinoids. Cannabinoid metabolism, distribution, and brain penetration — critical for clinical efficacy — aren't addressed."},{"rthcId":"RTHC-05937","title":"Analysis of Seven Selected Cannabinoids in Human Plasma Highlighting Matrix and Solution Stability Assessments.","authors":"Anderson, David J; Freeman, Tia; Caldwell, Kalii; Hoggard, Logan R; Reilly, Christopher A; Rower, Joseph E","year":2025,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkaf087","pmid":"40972134","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05938","title":"Δ9-Tetrahydrocannabinol Alters Limbic and Frontal Functional Brain Connectomes Among Young Adult Cannabis Users.","authors":"Anderson, Zachary; Gunn, Matthew; Jones, Emily; Ajilore, Olusola; Phan, K Luan; de Wit, Harriet; Klumpp, Heide; Calhoun, Vince; Crane, Natania A","year":2025,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging","doi":"10.1016/j.bpsc.2025.09.005","pmid":"40957507","tags":["thc","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"THC (7.5 mg oral) reduced within-network intrinsic connectivity in corticostriatal circuits and networks associated with sensory systems, interoceptive experiences, and spatial reasoning compared to placebo. THC also reduced between-network connectivity involving anterior cingulate cortex, dorsal insula, ventral insula, and lingual gyrus regions. Network connectivity changes during THC were not related to subjective drug effects or recent cannabis use frequency.","whyItMatters":"This is one of few studies examining whole-brain network effects of THC rather than focusing on individual brain regions. The widespread connectivity reductions across sensory, cognitive, and reward circuits help explain the diverse behavioral and perceptual changes people experience while intoxicated.","specificNumbers":"n=33 occasional cannabis users; THC 7.5 mg oral; reduced corticostriatal connectivity; reduced sensory network connectivity; reduced between-network connectivity (ACC-dorsal insula and ventral insula-lingual gyrus); no relationship to subjective effects or use frequency","methodology":"Within-subject, double-blind, randomized study. 33 healthy occasional cannabis users received THC (7.5 mg oral) and placebo before completing resting-state fMRI during peak intoxication. Group-information-guided independent component analysis identified whole-brain networks. Within-sample t-tests assessed connectivity differences.","limitations":"Modest sample (n=33). Only occasional cannabis users studied; heavy users might show different patterns. Single dose examined; chronic effects unknown. Resting-state fMRI captures only spontaneous brain activity, not task-related function."},{"rthcId":"RTHC-05939","title":"Maternal Cannabis Use During Pregnancy and Neuropsychiatric Adverse Outcomes During Childhood and Early Adult Life.","authors":"Andrade, Chittaranjan","year":2025,"journal":"The Journal of clinical psychiatry, 86(1)","doi":"10.4088/JCP.24f15753","pmid":"39832340","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05940","title":"Cannabigerol does not affect contextual fear memory in mice but modulates nociception in a sex-dependent manner.","authors":"Andreotti, Julia P; Iglesias, Lia P; Briânis, Rayssa C; Barra, Walace C P; Duarte, Igor D G; Stern, Cristina A J; Bertoglio, Leandro J; Crippa, José A; Aguiar, Daniele C; Moreira, Fabrício A","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 254, 174053","doi":"10.1016/j.pbb.2025.174053","pmid":"40523564","tags":["cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBG at 3, 10, and 30 mg/kg failed to significantly change acquisition, consolidation, or retrieval/expression of contextual fear memories in either male or female mice. In the tail-flick pain test, female mice showed a biphasic response: the low dose (3 mg/kg) increased pain threshold while the high dose (30 mg/kg) decreased it. No motor impairment was observed in the rotarod test at any dose or timepoint.","whyItMatters":"While CBD has shown promise for fear-related conditions like PTSD, CBG (another non-psychoactive cannabinoid gaining market attention) did not replicate these effects on fear memory. This negative result is important for setting realistic expectations about CBG's therapeutic potential in anxiety and trauma-related disorders.","specificNumbers":"CBG tested at 3, 10, 30 mg/kg; no effect on fear memory at any dose; biphasic pain effect in females only (3 mg/kg increased threshold, 30 mg/kg decreased it); no motor impairment at any dose","methodology":"Male and female C57BL/6J mice underwent contextual fear conditioning protocols with CBG (3, 10, or 30 mg/kg) administered at different timepoints to target acquisition, consolidation, and retrieval phases. Tail-flick test assessed nociception. Rotarod test assessed motor function.","limitations":"Mouse fear conditioning may not fully model human anxiety or PTSD. Only three doses tested. Contextual fear conditioning is one specific paradigm; CBG might affect other anxiety-related behaviors. Biphasic pain effect in females needs replication."},{"rthcId":"RTHC-05941","title":"Crafting effective regulatory policies for psychedelics: What can be learned from the case of cannabis?","authors":"Andrews, Christina M; Hall, Wayne; Humphreys, Keith; Marsden, John","year":2025,"journal":"Addiction (Abingdon, England), 120(2), 201-206","doi":"10.1111/add.16575","pmid":"38845381","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05942","title":"Targeting bladder cancer: Potent anti-cancer effects of cannabichromene and delta-9-tetrahydrocannabinol-rich Cannabis sativa strains.","authors":"Anis, Omer; Bar, Vered; Zundelevich, Adi; Anil, Seegehali M; Shav-Tal, Yaron; Toren, Amos; Dominissini, Dan; Raviv, Gil; Laufer, Menachem; Lazarovich, Alon; Drori, Tomer; Ramon, Jacob; Dotan, Zohar; Koltai, Hinanit","year":2025,"journal":"Asian journal of urology, 12(4), 534-543","doi":"10.1016/j.ajur.2025.03.004","pmid":"41467200","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05943","title":"Evaluation of the causal impact of recreational marijuana legalisation on traffic safety in the US.","authors":"Anupriya; McCoy, Emma; Graham, Daniel J","year":2025,"journal":"Accident; analysis and prevention, 220, 108106","doi":"10.1016/j.aap.2025.108106","pmid":"40543499","tags":["driving","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using an augmented synthetic control method to generate causal inference, the study identified a consistent but lagged pattern of increased traffic fatality rates in several states following recreational marijuana legalization. The effect was primarily linked to the beginning of retail sales rather than the legalization date itself. The findings disprove conjectures dismissing the link between recreational marijuana use and fatal traffic crashes.","whyItMatters":"This study uses one of the most rigorous causal inference methods available for policy evaluation and finds that recreational cannabis legalization does increase traffic fatalities, but only after retail sales begin. This distinction is critical for policy design: the transition to commercial availability, not legal status alone, drives the safety impact.","specificNumbers":"Multiple US states analyzed; consistent lagged increase in fatality rates post-legalization; effect primarily linked to retail availability rather than legalization date","methodology":"Augmented synthetic control method applied to US state-level traffic fatality data. This approach creates synthetic comparison states from non-legalizing states to estimate what would have happened without legalization, adjusting for unobserved confounders. Multiple states analyzed across different legalization timelines.","limitations":"Augmented synthetic control cannot fully account for all confounding changes that coincide with legalization. Traffic fatality data may not capture the full picture of impaired driving incidents. Cannot distinguish between cannabis-impaired driving and other behavioral changes associated with legalization."},{"rthcId":"RTHC-05944","title":"Enhancing Cannabidiol Bioavailability: Development and Evaluation of an Amorphous Cannabidiol Powder Formulation.","authors":"Aoyama, Hiroki; Ogawa, Tatsuya; Ozawa-Umeta, Hitomi; Teshima, Koji; Hashimoto, Tadashi; Sudo, Teruyuki; Hashimoto, Kazuki; Tsuda, Takanori","year":2025,"journal":"Journal of nutritional science and vitaminology, 71(4), 312-320","doi":"10.3177/jnsv.71.312","pmid":"40887280","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05945","title":"Exposure and response of private practice psychiatrists in Greece to illicit substance use-related treatment requests: A cross-sectional survey.","authors":"Apatsidis, Anestis; Fotiou, Anastasios; Kanavou, Eleftheria; Gavra, Nikolaos; Bafi, Ioulia; Triantafyllou, Kalliopi; Kokkevi, Anna; Paparrigopoulos, Thomas","year":2025,"journal":"Psychiatrike = Psychiatriki","doi":"10.22365/jpsych.2025.024","pmid":"41432191","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05946","title":"Novel approach to urinary 11-nor-9-carboxy-delta-9-tetrahydrocannabinol analysis in forensic applications using disposable, graphene-based electrochemical sensor coupled with monolithic micro-solid-phase extraction.","authors":"Ar-Sanork, Kesara; Kamsong, Wichayaporn; Woensanthia, Rawisara; Thangphatthanarungruang, Jeerakit; Jiang, Zhengjin; Sinchai, Theerin; Karuwan, Chanpen; Chaisuwan, Patcharin","year":2025,"journal":"Analytica chimica acta, 1369, 344359","doi":"10.1016/j.aca.2025.344359","pmid":"40701705","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05947","title":"A Fatal Case of Coronary Thrombosis in a Young Male Triggered by Marijuana Use.","authors":"Aravind, Akhila; Kyle, Patrick B; Subramony, Charulochana","year":2025,"journal":"Cureus, 17(11), e98083","doi":"10.7759/cureus.98083","pmid":"41473637","tags":["health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Autopsy of a 34-year-old man with no previous medical history besides marijuana use revealed focal complete occlusion of the proximal left anterior descending coronary artery by an organized thrombus. No atherosclerotic plaques were found in any coronary artery. Toxicology showed elevated delta-9-THC levels (50 mg/mL). The cause of death was myocardial ischemia leading to fatal cardiac arrhythmia from coronary artery occlusion without atherosclerosis.","whyItMatters":"This autopsy case provides direct pathological evidence that marijuana use may cause coronary thrombosis without underlying atherosclerosis in young adults, a finding consistent with proposed mechanisms including arteritis, vasospasm, and platelet aggregation.","specificNumbers":"34-year-old male; delta-9-THC 50 mg/mL; complete occlusion of proximal LAD; organized thrombus; no atherosclerosis in any coronary artery; mild cardiomegaly","methodology":"Complete autopsy with gross and microscopic examination. Trichrome and elastin stains performed on coronary arteries. Blood and vitreous fluid toxicology analysis.","limitations":"Single case report cannot establish causation between marijuana use and coronary thrombosis. Organized thrombus suggests a non-acute event, and the temporal relationship to cannabis use is unclear. Other potential thrombotic risk factors may not have been fully evaluated."},{"rthcId":"RTHC-05948","title":"Social Determinants of Substance Use in Black Adults with Criminal Justice Contact: Do Sex, Stressors, and Sleep Matter?","authors":"Archibald, Paul; Rhodes, Dasha; Thorpe, Roland","year":2025,"journal":"International journal of environmental research and public health, 22(8)","doi":"10.3390/ijerph22081176","pmid":"40869762","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In sex-stratified analyses, lifetime marijuana use among males was associated with family stressors (APR=2.31) and sleep problems (APR=2.07). Among females, marijuana use was associated with neighborhood stressors (APR=1.72). Different stressor types predicted different substance use patterns: family stressors drove marijuana and cigarette use in males, while financial stressors drove alcohol abuse in females.","whyItMatters":"Black adults with criminal justice contact face compounding stressors that drive substance use, but the specific stressor pathways differ by sex. Understanding these patterns is essential for designing targeted interventions rather than one-size-fits-all approaches.","specificNumbers":"n=1,476; males: family stressors APR=2.31 and sleep problems APR=2.07 for marijuana use; females: neighborhood stressors APR=1.72 for marijuana use; different stressors predicted different substances","methodology":"Data from 1,476 Black adults with criminal justice involvement from the National Survey of American Life. Sex-separate generalized linear models estimated adjusted prevalence ratios for lifetime alcohol abuse, cigarette, and marijuana use. Independent variables included five stressor types and sleep problems.","limitations":"Cross-sectional survey cannot establish whether stressors precede marijuana use or vice versa. Self-reported lifetime use may be subject to recall bias. National Survey of American Life data may not represent current patterns. Criminal justice contact itself may be both a cause and consequence of substance use."},{"rthcId":"RTHC-05949","title":"A systematic review investigating prenatal cannabis and tobacco co-exposure: Impacts on neonatal, behavioral, cognitive and physiological outcomes.","authors":"Argote, Mathilde; Hilson, Leah; Sorkhou, Maryam; Rabin, Rachel A","year":2025,"journal":"Drug and alcohol dependence reports, 17, 100376","doi":"10.1016/j.dadr.2025.100376","pmid":"40988858","tags":["prenatal"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Among 46 studies (43 human, 3 preclinical), co-exposed infants showed higher risk of compromised physical development and birth defects compared to single-substance exposure. Behavioral outcomes, particularly emotion regulation/reactivity, and physiological outcomes showed similar patterns of worse outcomes with co-exposure. However, other neonatal outcomes (preterm birth, respiratory distress) and cognition were similar between co-exposure and single-substance groups.","whyItMatters":"Cannabis and tobacco co-use during pregnancy is common, yet most research examines each substance in isolation. This review provides the first comprehensive synthesis showing that co-exposure produces harms beyond what either substance alone would cause, information critical for prenatal counseling.","specificNumbers":"46 studies included (43 human, 3 preclinical); 3,217 records screened; co-exposure associated with worse physical development, birth defects, and emotional regulation compared to single-substance exposure; preterm birth and cognition similar between groups","methodology":"Systematic review searching Medline, Embase, and PsycINFO via OVID. Included human and animal studies comparing prenatal co-exposure to cannabis and nicotine/tobacco with single-substance exposure on neonatal, behavioral, cognitive, and physiological outcomes. 46 of 3,217 identified records met inclusion criteria.","limitations":"Included studies varied widely in methodology, sample sizes, and outcome measures. Difficulty separating effects of co-use from effects of heavier overall substance use. Self-reported prenatal substance use likely underestimates true exposure. Limited preclinical evidence (only 3 animal studies)."},{"rthcId":"RTHC-05950","title":"Medical cannabis: Regulatory review in United States, European Union and United Kingdom.","authors":"Arjun, M; Verma, Vishakha; Bhoopathi, S; Mishra, Ashutosh; Venkatesh, M P","year":2025,"journal":"Journal of forensic and legal medicine, 115, 102947","doi":"10.1016/j.jflm.2025.102947","pmid":"40818335","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05951","title":"Cannabis vaping elicits transcriptomic and metabolomic changes involved in inflammatory, oxidative stress, and cancer pathways in human bronchial epithelial cells.","authors":"Arlen, Maddison T; Patterson, Stephanie J; Page, Michelle K; Liu, Rui; Caruana, Vincenza; Wilson, Emily T; Laporte, Stéphane A; Goniewicz, Maciej L; Harris, Cory S; Eidelman, David H; Baglole, Carolyn J","year":2025,"journal":"American journal of physiology. Lung cellular and molecular physiology, 328(3), L478-L496","doi":"10.1152/ajplung.00131.2024","pmid":"39823205","tags":["inflammation","cancer","respiratory","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The shift from smoking to vaping cannabis is driven largely by the belief that vaping is safer. This study tested that assumption at the molecular level by comparing what cannabis smoke extract (CaSE) and cannabis vape extract (CaVE) actually do to human bronchial epithelial cells.\n\nThe chemical analysis confirmed what other studies have found: cannabis vape aerosol contained fewer toxicants than smoke. But here's the twist — both CaSE and CaVE still contained teratogens, carcinogens, and respiratory toxicants. Vaping reduces the dose of these compounds; it doesn't eliminate them.\n\nMore importantly, when the researchers looked at what happened inside the cells, the gene expression patterns were remarkably similar. RNA sequencing revealed that both smoke and vape extracts significantly upregulated genes in pathways related to inflammation, cancer, and cellular stress. Both also downregulated pathways involved in lipid synthesis and metabolism. The transcriptional response — what the cells were actually doing at the molecular level — was largely the same regardless of whether the exposure came from smoke or vapor.\n\nTargeted metabolomics added another layer: both exposures caused significant changes in metabolites involved in inflammatory and oxidative stress pathways. The receptor-mediated activity of both extracts was primarily driven by THC concentration, suggesting that THC itself — present in both smoke and vapor — may be responsible for much of the biological response.\n\nThe implication is sobering: while vaping exposes the lungs to fewer chemical toxicants, the cellular and molecular response may be just as harmful.","whyItMatters":"The cannabis industry and many public health messages position vaping as harm reduction. This study suggests that at the cellular level, the harm reduction may be more limited than assumed. If the inflammatory, cancer, and stress pathways activated by vaping are the same as those activated by smoking, the long-term health consequences may converge even if the acute chemical exposure differs.","specificNumbers":"Cannabis vape aerosol contained fewer toxicants than smoke (chemical analysis). Both CaSE and CaVE contained teratogens, carcinogens, and respiratory toxicants. RNA sequencing: both upregulated inflammation, cancer, and stress pathways. Both downregulated lipid synthesis pathways. Receptor activity primarily driven by THC concentration in both extracts. Metabolomic changes in inflammatory and oxidative stress metabolites from both exposures.","methodology":"Comparison of cannabis smoke extract (CaSE) and cannabis vape extract (CaVE) using: chemical analysis (HPLC and GC/MS), BRET-based biosensor for receptor-mediated activity, RNA sequencing for transcriptomic changes, and targeted metabolomics — all in human bronchial epithelial cells. Assessed inflammatory pathways, cancer-related gene expression, cellular stress responses, and metabolite changes.","limitations":"In vitro study — cell culture exposure doesn't replicate the complex dynamics of actual lungs (airway clearance, immune response, tissue repair). The concentrations of CaSE and CaVE used on cells may not reflect real-world exposure levels. Single cell type (bronchial epithelium) doesn't capture the full respiratory tract response. Acute exposure only — chronic effects of repeated low-level vaping exposure aren't addressed. The specific cannabis products and vaping devices used may not represent the full market."},{"rthcId":"RTHC-05952","title":"Understanding the nature of interpersonal relationships through the interpretations of young female cannabis users in Iran.","authors":"Armanisadr, Nika; Bijari, Azam Farah; Khosravi, Zohreh","year":2025,"journal":"Archives of women's mental health, 28(6), 1547-1559","doi":"10.1007/s00737-025-01624-8","pmid":"41205070","tags":["addiction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Thematic narrative analysis of 12 interviews generated 961 open codes organized into two themes. \"Dysfunctional Interpersonal Relationships\" (447 codes) showed how maladaptive family interactions, particularly parent-child conflict, contributed to cannabis initiation and persistence. \"Positive and Negative Qualities of Interpersonal Relationships\" (514 codes) revealed that emotional neglect, absence of secure attachment, and unresolved relational distress drove cannabis use as a coping mechanism, while some participants reported receiving emotional support from peers or family.","whyItMatters":"In Iran, where cannabis is the second most commonly used illicit substance with rising use among women, understanding the relational drivers of use is critical for developing culturally appropriate prevention. The finding that family dysfunction is the primary driver suggests family-level interventions may be more effective than individual-focused approaches.","specificNumbers":"12 participants; 961 open codes; 2 overarching themes; 447 codes on dysfunctional family relationships; 514 codes on relationship qualities across developmental stages; data collected 2022-2023 in Tehran and Karaj","methodology":"Thematic narrative analysis conducted in Karaj and Tehran (2022-2023). Twelve young women who use cannabis recruited through purposive and snowball sampling. Semi-structured interviews conducted until data saturation. Open coding and thematic analysis.","limitations":"Very small sample (12 participants) limits generalizability. Snowball sampling may recruit women with similar experiences. Cultural context of Iran may not generalize to other settings. Retrospective self-report of childhood experiences may be subject to recall bias."},{"rthcId":"RTHC-05953","title":"Should cannabis be used in the management of endometriosis?","authors":"Armour, Mike; Sinclair, Justin; Seaman, Callie; Mardon, Millie; Farooqi, Toobah; Holtzman, Orit; Leonardi, Mathew","year":2025,"journal":"Expert review of endocrinology & metabolism, 20(6), 497-512","doi":"10.1080/17446651.2025.2572339","pmid":"41070712","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05954","title":"Recreational drugs repurposed for medicinal use-cannabis.","authors":"Armour, Mike; Sinclair, Justin; Adler, Hannah","year":2025,"journal":"CNS spectrums, 30(1), e41","doi":"10.1017/S109285292500032X","pmid":"40276847","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05955","title":"Alcohol sales changes in a Canadian province after recreational cannabis legalization.","authors":"Armstrong, Michael J","year":2025,"journal":"The International journal on drug policy, 142, 104840","doi":"10.1016/j.drugpo.2025.104840","pmid":"40381406","tags":["legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Comparing 17 months before and after cannabis legalization in Nova Scotia, alcohol-only stores saw an initial 2.91% sales decrease with minimal ongoing growth (0.06%/month), while stores selling both cannabis and alcohol saw a 0.55% initial increase with stronger growth (0.29%/month). Post-legalization alcohol sales averaged 2.4% below pre-legalization at alcohol-only stores but 3.1% above at cannabis-selling stores. Combined sales were 1.2% below pre-legalization. Beer was more affected than spirits or wines.","whyItMatters":"Whether cannabis substitutes for or complements alcohol use has major public health implications. This natural experiment in Nova Scotia, where some government stores sold both substances, shows that the answer may be both: overall alcohol sales declined slightly, but co-location drove increased alcohol purchasing.","specificNumbers":"Alcohol-only stores: -2.4% average; cannabis-selling stores: +3.1% average; combined: -1.2%; initial response at alcohol-only: -2.91%; cannabis sellers: +0.55%; beer most affected","methodology":"Comparative interrupted time series models analyzing monthly alcoholic beverage sales in Canadian dollars at Nova Scotia liquor stores during 17 months before and after cannabis legalization (May 2017-February 2020). Contrasted alcohol-only stores versus stores that also began selling cannabis.","limitations":"Observational interrupted time series cannot establish causation. Only one Canadian province studied. 17-month post-legalization window may not capture longer-term trends. COVID-19 pandemic began near the end of the study period. Sales data may not perfectly reflect consumption."},{"rthcId":"RTHC-05956","title":"Exploring Associations between Cannabis Prices, Stores, and Usage after Recreational Legalization.","authors":"Armstrong, Michael J","year":2025,"journal":"European addiction research, 31(2), 125-132","doi":"10.1159/000544104","pmid":"40058350","tags":["legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Panel data analysis of 50 province-year observations found no significant changes in prevalence among males or those aged 16-24, and no change in daily use proportions. Prevalence among females and people aged 25+ increased, with negative associations with prices but not store counts. Dried cannabis use decreased while edibles use increased, also associated with prices but not stores. Mean initial age of use increased and was negatively associated with prices but positively with stores.","whyItMatters":"Policymakers often focus on limiting store numbers to control cannabis use, but this Canadian data suggests price is the more influential lever. Store proliferation had surprisingly little association with use changes, while falling prices drove both who uses and how they consume.","specificNumbers":"10 provinces, 5 years, 50 observations; female and 25+ prevalence increased; edibles use increased; dried use decreased; price was significant predictor; store count was not; mean initiation age increased","methodology":"Government data on store counts, retail pricing, and cannabis use across 10 Canadian provinces over 5 years (2019-2023). Panel data linear regressions analyzed 50 province-year aggregated observations.","limitations":"Ecological study using aggregated province-year data cannot capture individual-level relationships. Five-year window may not capture full maturation of the legal market. Self-reported use data may underestimate actual consumption. Cannot separate price effects from product quality improvements."},{"rthcId":"RTHC-05957","title":"Limited pharmacokinetic and safety study with daily feeding of hemp pellets in domestic goats: cannabidiolic acid is absorbed and retained better than cannabidiol.","authors":"Arnett-Chinn, Elizabeth; Morrisey, James; Klaphake, Eric; Hughes, Daniel; Schwark, Wayne S; Wakshlag, Joseph","year":2025,"journal":"American journal of veterinary research, 86(11)","doi":"10.2460/ajvr.25.03.0089","pmid":"40840522","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05958","title":"Case Report: Substance fixation in autism spectrum disorder with resultant anorexia nervosa.","authors":"Arney, Lucas; Uymatiao, Raymond; White, Justin","year":2025,"journal":"Frontiers in psychiatry, 16, 1630528","doi":"10.3389/fpsyt.2025.1630528","pmid":"41063929","tags":["addiction","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 26-year-old man with long-standing ASD developed a pattern of obsessive alcohol use associated with weight gain, followed by extreme food restriction, then transition to near-constant daily cannabis use. This culminated in a hospitalization for depression and suicidal ideation after a cannabis-related car accident. His BMI declined from 23.6 to 16.98 over one year. Over 11 days of inpatient treatment with anxiolytics, antidepressants, sleep aids, cannabis withdrawal management, and nutritional rehabilitation, his BMI improved to 18.75.","whyItMatters":"ASD traits like obsessive fixation and cognitive rigidity are well-documented but rarely discussed as drivers of substance use patterns. This case illustrates how the same neurodevelopmental features that define ASD can channel into harmful behaviors, requiring integrated treatment approaches rather than siloed addiction or eating disorder care.","specificNumbers":"26-year-old male; BMI declined from 23.6 to 16.98 in one year; 11-day hospitalization; BMI improved to 18.75 at discharge; positive cannabinoid urine screen","methodology":"Single case report documenting clinical presentation, diagnostic assessment, multidisciplinary inpatient treatment, and discharge planning for co-occurring ASD, substance use disorder, and eating disorder.","limitations":"Single case report cannot establish generalizable patterns. Complex presentation makes it difficult to isolate the role of cannabis specifically. Self-reported history may not capture the full timeline of substance use and behavioral changes."},{"rthcId":"RTHC-05959","title":"A Preliminary Pharmacokinetic Comparison of Δ-9 Tetrahydrocannabinol and Cannabidiol Extract Versus Oromucosal Spray in Healthy Men and Women.","authors":"Arout, Caroline A; Harris, Hannah M; Wilson, Noah M; Mastropietro, Kyle F; Bozorgi, Amanda M; Fazilov, Gabriela; Tempero, José; Walker, Mariah; Haney, Margaret","year":2025,"journal":"Cannabis and cannabinoid research, 10(3), 457-466","doi":"10.1089/can.2023.0249","pmid":"39648730","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05960","title":"Cannabis and Oral Health Implications for 3 Priority Populations: A Special Communication.","authors":"Arriola-Pacheco, F; Chaffee, B W; Jessani, A; Lawrence, H P","year":2025,"journal":"JDR clinical and translational research, 23800844251366974","doi":"10.1177/23800844251366974","pmid":"40947974","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05961","title":"Cannabidiol-Loaded Retinal Organoid-Derived Extracellular Vesicles Protect Oxidatively Stressed ARPE-19 Cells.","authors":"Arthur, Peggy; Kandoi, Sangeetha; Kalvala, Anil; Boirie, Breana; Nathani, Aakash; Aare, Mounika; Bhattacharya, Santanu; Kulkarni, Tanmay; Sun, Li; Lamba, Deepak A; Li, Yan; Singh, Mandip","year":2025,"journal":"Biomedicines, 13(5)","doi":"10.3390/biomedicines13051167","pmid":"40426994","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05962","title":"Association of cannabis use with major cardiovascular and cerebrovascular events after surgery or interventional procedures.","authors":"Ashrafian, Sarah; Ahrens, Elena; Wachtendorf, Luca J; Munoz-Acuna, Ricardo; Shay, Denys; Suleiman, Aiman; Redaelli, Simone; von Wedel, Dario; Chen, Guanqing; Wolff, Georg; Hill, Kevin P; Schaefer, Maximilian S","year":2025,"journal":"The American journal on addictions, 34(5), 517-527","doi":"10.1111/ajad.70029","pmid":"40204668","tags":["health-risks"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 288,923 adults undergoing noncardiac surgery, patients with a diagnosed cannabis use disorder had 26% higher odds of major adverse cardiovascular or cerebrovascular events (MACCE) within one year (aOR 1.26, 95% CI: 1.05-1.51). For recreational users, the association depended on baseline cardiac risk: high-risk patients (RCRI class III/IV) had 41% higher odds (aOR 1.41, 95% CI: 1.15-1.74), while low-risk patients showed no significant association (aOR 0.87, 95% CI: 0.75-1.02).","whyItMatters":"This is one of the largest studies linking cannabis use to post-surgical cardiovascular complications. The critical finding that risk depends on both the type of cannabis use (disorder vs recreational) and baseline cardiac risk provides actionable information for surgical risk assessment.","specificNumbers":"n=288,923; CUD: aOR 1.26 (95% CI: 1.05-1.51); recreational + high cardiac risk: aOR 1.41 (95% CI: 1.15-1.74); recreational + low cardiac risk: aOR 0.87 (95% CI: 0.75-1.02); 2008-2020 study period","methodology":"Retrospective cohort of 288,923 adult patients undergoing noncardiac surgery between 2008-2020 at a tertiary academic hospital in Massachusetts. Cannabis use differentiated into self-reported recreational use and diagnosed cannabis use disorder. Primary outcome: MACCE (ischemic stroke, cardiac arrest, heart failure, MI, revascularization) within one year.","limitations":"Single-center retrospective study from Massachusetts. Cannabis use may be underreported. Cannot determine whether cannabis was used in the perioperative period specifically. Observational design cannot establish causation. Recreational use was self-reported while CUD was diagnosed, potentially reflecting different assessment rigor."},{"rthcId":"RTHC-05963","title":"Does Stress Explain the Effects of Sexual/Gender Minority Status on Children's Behavioral and Emotional Risk?","authors":"Assari, Shervin; Donovan, Alexandra; Pallera, John Ashley; Assari, Gandom; Najand, Babak; Alaei, Kamiar; Alaei, Arash","year":2025,"journal":"Open journal of psychology, 5(1), 38-51","doi":"10.31586/ojp.2025.6188","pmid":"41048615","tags":["youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"SGM youth had higher odds of past suicide attempts, major depressive disorder, and future marijuana use, but not future nicotine use. Contrary to the minority stress hypothesis, family conflict, discrimination, and trauma did not mediate the SGM-marijuana use association. However, these stressors were independently associated with outcomes: discrimination predicted all outcomes, trauma predicted suicide, nicotine, and marijuana use, and family conflict predicted all outcomes except depression.","whyItMatters":"The finding that stress does not explain the SGM-marijuana use link challenges the dominant minority stress framework and suggests other mechanisms are at play. This matters for intervention design: reducing discrimination and family conflict will help but may not close the marijuana use disparity.","specificNumbers":"ABCD Study participants; SGM identity predicted future marijuana use (but not nicotine); no mediation by family conflict, discrimination, or trauma; each stressor independently predicted outcomes","methodology":"ABCD Study data with SGM identity reported at baseline. Structural equation modeling (SEM) tested direct and indirect pathways linking SGM identity to mental health and behavioral outcomes including future marijuana and nicotine use.","limitations":"ABCD Study participants are children/adolescents; SGM identity may still be emerging. Stressor measures may not capture all relevant minority stress experiences. Marijuana use was measured at follow-up but initiation timing is uncertain. SEM assumes causal ordering that may not reflect the actual temporal sequence."},{"rthcId":"RTHC-05964","title":"Hippocampus Functional Connectivity, Impulsivity, and Subsequent Substance Use.","authors":"Assari, Shervin; Donovan, Alexandra; Najand, Babak; Akhlaghipour, Golnoush; Mendez, Mario F","year":2025,"journal":"Journal of cellular neuroscience, 2(1)","doi":"10.31586/jcn.2025.1250","pmid":"40297839","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05965","title":"Childhood Depression, Hopelessness, and Suicidal Attempt Predict Earlier Tobacco and Marijuana Use Initiation During Adolescence.","authors":"Assari, Shervin; Najand, Babak; Sheikhattari, Payam","year":2025,"journal":"Open journal of medical sciences, 5(1), 18-31","doi":"10.31586/ojms.2025.1181","pmid":"40027157","tags":["youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Baseline hopelessness, depression, and suicide attempts at ages 9-10 were all significant predictors of tobacco and marijuana use initiation at ages 14-15. These associations remained robust after adjusting for demographic factors, family characteristics, and neighborhood socioeconomic status, indicating independent effects of early emotional problems on adolescent substance use initiation.","whyItMatters":"This longitudinal evidence demonstrates that the seeds of adolescent marijuana use are planted years earlier in childhood emotional distress. Identifying and treating depression and hopelessness in elementary school-age children could be an upstream prevention strategy for adolescent substance use.","specificNumbers":"ABCD Study participants; baseline ages 9-10; follow-up ages 14-15; hopelessness, depression, and suicide attempts all predicted marijuana initiation; effects robust after adjusting for demographics and SES","methodology":"ABCD Study data with baseline emotional problems assessed at ages 9-10 through structured parent interviews. Substance use (tobacco and marijuana initiation) tracked to ages 14-15 using structured self-report. Structural equation modeling controlled for demographics, family, and neighborhood SES.","limitations":"Parent-reported emotional problems at baseline may underestimate child experiences. Self-reported substance use at follow-up may also be underreported. SEM assumes causal ordering but other factors may explain both early emotional problems and later substance use. Cannabis initiation does not equal problematic use."},{"rthcId":"RTHC-05966","title":"Puberty Onset and Positive Urgency Explain Diminished Returns of Family Income on Tobacco and Marijuana Use.","authors":"Assari, Shervin; Najand, Babak; Zare, Hossein","year":2025,"journal":"Open journal of psychology, 5(1)","doi":"10.31586/ojp.2025.1141","pmid":"39886641","tags":["youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Early puberty onset and associated positive urgency (impulsivity) partially mediated the relationship between family income and marijuana use initiation over six years. Critically, high-income Black youth showed earlier puberty onset compared to their White counterparts, and earlier puberty predicted higher impulsivity, which in turn predicted higher marijuana and tobacco initiation rates.","whyItMatters":"The \"Minorities' Diminished Returns\" framework explains why socioeconomic advantages protect Black youth less than White youth. This study identifies a biological pathway (earlier puberty leading to impulsivity) that partly explains this disparity, with implications for understanding racial health inequities.","specificNumbers":"ABCD Study; ages 9-10 at baseline, 6-year follow-up; high-income Black youth had earlier puberty; earlier puberty predicted higher positive urgency; positive urgency predicted marijuana and tobacco initiation","methodology":"ABCD Study data with 9-10-year-old participants followed for six years. Structural equation modeling assessed whether early puberty mediated effects of family income on substance use. Race-by-income interaction terms tested differential effects.","limitations":"SEM models assume causal ordering that may not reflect reality. Puberty timing is influenced by many factors beyond those measured. Self-reported substance use may be underreported. The concept of \"Minorities' Diminished Returns\" is debated in the literature."},{"rthcId":"RTHC-05967","title":"High CBD extract (CBD-X) modulates inflammation and immune cell activity in rheumatoid arthritis.","authors":"Aswad, Miran; Pechkovsky, Antonina; Ghanayiem, Narmeen; Hamza, Haya; Louria-Hayon, Igal","year":2025,"journal":"Frontiers in immunology, 16, 1599109","doi":"10.3389/fimmu.2025.1599109","pmid":"40709173","tags":["cbd","inflammation","pain","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study takes the rheumatoid arthritis (RA) cannabis research a significant step forward from RTHC-00097 (CBG in RA cells) by testing a high-CBD extract not just in isolated human cells but also in two animal models of the disease.\n\nThe ex vivo experiments showed that CBD-X inhibited the secretion of key inflammatory cytokines: IL-1β from macrophages and IL-8, IL-6, and TNF-α from human neutrophils — all central players in RA joint destruction. The extract also attenuated NF-κB p65 and Akt phosphorylation, two signaling pathways that drive the inflammatory cascade.\n\nThen the researchers took it to live animals using two established mouse models of RA. In collagen-induced arthritis (CIA) — a model that mimics the autoimmune component of RA — and collagen antibody-induced arthritis (CAIA) — a model driven by antibody-mediated inflammation — CBD-X treatment reduced disease severity.\n\nThe two-model approach is important because RA involves both autoimmune and inflammatory components. Showing efficacy in both CIA (autoimmune-driven) and CAIA (antibody-driven) suggests CBD-X may work across different aspects of RA pathophysiology rather than targeting just one pathway.\n\nThe combination of human cell data and animal efficacy data makes this one of the more complete preclinical packages in the cannabinoid-arthritis space. It bridges the gap between 'CBD reduces inflammation in a dish' and 'CBD reduces disease in an animal' — the next step would be human trials.","whyItMatters":"RA affects approximately 1% of the global population and current treatments — while effective for many — include medications with serious side effects (immunosuppression, infection risk, liver damage). If a CBD-based treatment could provide meaningful relief with a better safety profile, it would be significant for the millions who don't respond well to or can't tolerate current RA drugs. This study provides the strongest preclinical evidence yet for that possibility.","specificNumbers":"CBD-X inhibited IL-1β from macrophages and IL-8, IL-6, TNF-α from human neutrophils. Attenuated NF-κB p65 and Akt phosphorylation in neutrophils. Reduced disease severity in both CIA and CAIA mouse models. RA affects approximately 1% of the global population.","methodology":"Combined ex vivo and in vivo study. Ex vivo: tested CBD-X on macrophages and primary human neutrophils, measuring cytokine secretion (IL-1β, IL-8, IL-6, TNF-α) and signaling pathways (NF-κB p65, Akt phosphorylation). In vivo: two murine RA models — collagen-induced arthritis (CIA, autoimmune model) and collagen antibody-induced arthritis (CAIA, antibody-mediated model) — treated with CBD-X and assessed for disease severity.","limitations":"Mouse models of RA don't perfectly replicate human disease — many drugs that work in CIA and CAIA mice fail in human RA trials. The CBD-X extract is a whole-plant extract, not pure CBD, so specific active components aren't fully defined. Dosing in mice doesn't directly translate to human dosing. The ex vivo human cell work used isolated cell types rather than the complex joint environment. No long-term safety or efficacy data. The specific formulation tested (CBD-X) may not represent commercially available CBD products."},{"rthcId":"RTHC-05968","title":"Assessing anxiety longitudinally among medical cannabis patients in Pennsylvania.","authors":"Ataiants, Janna; Fedorova, Ekaterina V; Cocchiaro, Benjamin; Kleber, Lyric; Sayyid, Abdallah; Ardeleanu, Katherine; Lankenau, Stephen E","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(6), 750-760","doi":"10.1080/00952990.2025.2588273","pmid":"41368882","tags":["mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Latent class growth analysis identified three anxiety profiles: Minimal (43%), Moderate (36%), and Severe (21%). The Minimal and Moderate groups showed anxiety decreases, but reductions were not clinically meaningful. The Severe group remained stable without improvement. Younger age and female sex predicted Moderate and Severe profiles. Lifetime PTSD and anxiety as primary qualifying condition predicted the Severe group only.","whyItMatters":"Anxiety is one of the most common reasons people seek medical cannabis, yet this longitudinal data shows that patients with severe anxiety do not improve over 12 months of use. This finding challenges the assumption that medical cannabis effectively treats anxiety and highlights the need for additional support for severely anxious patients.","specificNumbers":"n=526; 3 profiles: Minimal (43%), Moderate (36%), Severe (21%); Minimal and Moderate showed slight decreases; Severe remained stable; younger age and female sex predicted worse profiles; PTSD predicted Severe profile","methodology":"Longitudinal study of 526 Pennsylvania medical cannabis patients (59% female) who completed at least two quarterly GAD-7 anxiety assessments over 12 months (2021-2023). Latent class growth analysis identified anxiety trajectories and their predictors.","limitations":"No control group or randomization; patients self-selected into medical cannabis treatment. Cannot determine whether anxiety would have been worse without cannabis. Cannabis products, doses, and formulations varied across patients. Co-use of anxiety medications was noted but not fully characterized."},{"rthcId":"RTHC-05969","title":"Cannabinoid Hyperemesis Syndrome Presenting as Postoperative Nausea and Vomiting in a Chronic Cannabis User: A Case Report.","authors":"Atkins, Justin B; Levine, Daniel; Shaw, Laura","year":2025,"journal":"Cureus, 17(7), e87990","doi":"10.7759/cureus.87990","pmid":"40821157","tags":["health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 40-year-old woman with two years of daily cannabis use underwent laparoscopic hysterectomy and experienced persistent nausea and vomiting despite multiple antiemetics. By postoperative day 2, vomiting occurred in refractory episodes. On day 3, she developed hematemesis and hallucinations. CHS was recognized and managed with supportive care including IV hydration, electrolyte replacement for hypokalemia and hypophosphatemia. Symptoms resolved by day 4 with oral intake resumed.","whyItMatters":"Standard postoperative nausea protocols fail for CHS patients, and the delay in diagnosis led to three days of unnecessary suffering, electrolyte derangements, and hematemesis. As cannabis use increases among surgical patients, perioperative teams need CHS on their differential diagnosis for refractory nausea.","specificNumbers":"40-year-old female; 2 years daily cannabis use; day 3 hematemesis and hallucinations; hypokalemia and hypophosphatemia; symptoms resolved day 4; discharged with cannabis cessation counseling","methodology":"Single case report documenting the clinical course, delayed diagnosis, and management of CHS presenting as refractory postoperative nausea and vomiting.","limitations":"Single case report. Postoperative context introduces multiple potential causes of nausea. Cannot determine how common perioperative CHS presentations are. Cannabis cessation during hospitalization may have contributed to both withdrawal and symptom resolution."},{"rthcId":"RTHC-05970","title":"The relationship between recreational cannabis use, psychotic-like experiences, and the salience network in adolescent and young adult twins.","authors":"Atmaca-Turan, Hande; Şahin-Çevik, Didenur; Çakar, Serenay; Gökalp-Yavuz, Fulya; van den Heuvel, Martijn; Rijsdijk, Fruhling; Filbey, Francesca; Toulopoulou, Timothea","year":2025,"journal":"Psychological medicine, 55, e300","doi":"10.1017/S0033291725101773","pmid":"41054791","tags":["psychosis","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was significantly associated with higher overall psychotic-like experience (PLE) frequency. A specific salience network factor predicted both total and positive PLEs. However, salience network connectivity did not mediate the cannabis-PLEs relationship. Twin modeling showed that both cannabis use and PLEs were mainly influenced by unique environmental factors rather than shared genetics. No significant phenotypic covariations were found among cannabis use, PLEs, and salience network parameters.","whyItMatters":"The twin design allows a unique test of whether the cannabis-psychosis link reflects shared genetic vulnerability or environmental exposure. Finding that unique environmental factors drive both cannabis use and psychotic experiences suggests the relationship is not simply explained by genetic predisposition to both.","specificNumbers":"n=232 healthy adolescent twins; cannabis use associated with higher PLE frequency; salience network factor predicted PLEs; no mediation by brain connectivity; twin modeling: unique environmental factors predominant","methodology":"Cross-sectional study of 232 healthy adolescent Turkish twins who underwent diffusion MRI and psychometric assessment. Salience network connectivity quantified using graph theory. Linear mixed models and mediation analyses examined associations. Twin models disentangled genetic and environmental contributions.","limitations":"Cross-sectional design cannot establish temporal sequence. Turkish adolescent sample may not generalize to other populations. Recreational cannabis use in this sample may reflect relatively low exposure. Diffusion MRI provides structural connectivity, not the functional connectivity more commonly studied in psychosis research."},{"rthcId":"RTHC-05971","title":"Cannabidiol as a Neuroprotective Agent in Acrylamide-Induced Neurotoxicity: Effects on Oxidative Stress, Inflammation, and Cholinergic Function in Male Mice.","authors":"Atsopardi, Korina; Mesiakaris, Konstantinos; Sotiropoulos, Ioannis; Margarity, Marigoula; Poulas, Konstantinos","year":2025,"journal":"Journal of neuroscience research, 103(12), e70098","doi":"10.1002/jnr.70098","pmid":"41395773","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05972","title":"Predictors of Replacing Alcohol With Cannabis Among Adult Women.","authors":"Attonito, Jennifer; Mueller, Jocelyn E; Villalba, Karina","year":2025,"journal":"Cureus, 17(10), e95821","doi":"10.7759/cureus.95821","pmid":"41328136","tags":["addiction","sleep"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Younger women (<56) were significantly more likely to substitute THC for alcohol (14.0% vs 7.8%) and reported higher rates of sleep problems, stress, and scores on AUDIT, PTSD, GAD, and PHQ instruments. Sleep problems strongly predicted THC substitution in younger women (OR 5.82). Among older women (>=56), PTSD symptoms predicted substitution of both CBD and THC (OR 1.60), and sleep problems predicted THC substitution (OR 3.05). Older women were more likely to not substitute at all (83.5% vs 71.0%).","whyItMatters":"Cannabis substitution for alcohol is increasingly discussed as harm reduction, but this study shows the drivers differ dramatically by age. Sleep problems drive younger women toward THC substitution, while PTSD drives older women, suggesting age-specific approaches are needed.","specificNumbers":"n=413 women; younger <56: 14.0% substituted THC (mean age 44.2); older >=56: 7.8% (mean age 62.9); sleep problems predicted THC substitution in younger women OR 5.82; PTSD predicted substitution in older women OR 1.60; older women non-substitution rate 83.5%","methodology":"Cross-sectional online survey of 413 women aged 18+ who reported lifetime cannabis use. Stratified into younger (<56) and older (>=56) groups. Validated scales for alcohol use disorders, PTSD, anxiety, and depression. Logistic regression identified predictors of CBD, THC, or combined substitution for alcohol.","limitations":"Cross-sectional online survey with self-selected participants. Cannot establish whether substitution actually reduces alcohol-related harm. Age cutoff of 56 is somewhat arbitrary. Cannot verify actual substitution behavior versus self-reported intention."},{"rthcId":"RTHC-05973","title":"Cannabidiol Induced Manic Episode: A Case Report.","authors":"Auf, Anas Ibn; Almakki, Razan A; Alhummayani, Nora M","year":2025,"journal":"Psychopharmacology bulletin, 55(4), 116-122","doi":"10.64719/pb.4542","pmid":"40630971","tags":["cbd","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 31-year-old male with no psychiatric history developed irritability, decreased need for sleep, hyperactivity, and aggression after three months of escalating daily CBD use via vaping, reaching high doses before admission. Toxicology screening was negative for other substances. Clinical improvement occurred with mood stabilizers and antipsychotics following CBD discontinuation.","whyItMatters":"CBD is widely perceived as safe and non-psychoactive, but this case suggests that high-dose CBD may trigger mania in susceptible individuals. The absence of prior psychiatric history and negative toxicology for other substances strengthens the association, though commercial CBD product variability (contamination, mislabeling) complicates interpretation.","specificNumbers":"31-year-old male; no prior psychiatric history; 3 months of escalating CBD vaping; negative toxicology for other substances; improved with mood stabilizers and antipsychotics after CBD discontinuation","methodology":"Single case report documenting the clinical presentation, substance use history, toxicology screening, treatment, and clinical course of a CBD-associated manic episode.","limitations":"Single case report cannot establish causation. Commercial CBD products may contain contaminants, other cannabinoids, or be mislabeled. Dose escalation pattern suggests possible dependence behavior. Cannot rule out undiagnosed bipolar disorder that was unmasked rather than caused by CBD. No genetic or family psychiatric history details provided."},{"rthcId":"RTHC-05974","title":"Integrating crash and fluids toxicology data to examine injury outcomes and associated driver behaviors.","authors":"Auguste, Marisa E; Pawelzik, Jennifer; Scholz, Caroline","year":2025,"journal":"Accident; analysis and prevention, 221, 108200","doi":"10.1016/j.aap.2025.108200","pmid":"40819535","tags":["driving","health-risks"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Drivers who tested positive for alcohol alone, cannabis alone, or a combination of substances had significantly higher odds of injury in motor vehicle crashes. Lack of safety equipment was the single strongest predictor, increasing severe injury odds nearly 20-fold.","whyItMatters":"Most impaired driving research relies on either crash data or toxicology data separately. Linking these datasets provides a more detailed picture of how specific substances relate to injury outcomes.","specificNumbers":"Alcohol alone, cannabis alone, and combinations all significantly predicted driver injury. Lack of safety equipment increased severe injury odds nearly 20 times. Driver errors appeared as protective factors, which the researchers attributed to masking by other variables.","methodology":"Researchers linked toxicology records (urine, blood, serum, vitreous) with crash data from Connecticut for 2017-2023. They used logistic regression and correlation analysis to identify predictors of driver injury and overall crash severity.","limitations":"The study covers a single state (Connecticut) and relies on toxicology data that may not reflect impairment at the time of the crash. The counterintuitive finding about driver errors suggests the model may have confounding issues."},{"rthcId":"RTHC-05975","title":"Combination treatment with medium dose THC and CBD had no therapeutic effect in a transgenic mouse model for Alzheimer's disease but affected other domains including anxiety-related behaviours and object recognition memory.","authors":"Aumer, Beate; Rosa Porto, Rossana; Coles, Madilyn; Ulmer, Nina; Watt, Georgia; Kielstein, Heike; Karl, Tim","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 257, 174101","doi":"10.1016/j.pbb.2025.174101","pmid":"40976394","tags":["cbd","thc","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic treatment with 3 mg/kg THC and 20 mg/kg CBD did not improve anxiety-like behavior or object recognition deficits in 14.5-month-old Alzheimer's model mice. The treatment had genotype-dependent effects, causing increased anxiety in Alzheimer's mice but reduced anxiety in controls.","whyItMatters":"Previous research showed CBD alone could reverse some memory deficits in Alzheimer's model mice. Combining THC with CBD was hypothesized to improve outcomes, but this study found the opposite.","specificNumbers":"Treatment used 3 mg/kg THC and 20 mg/kg CBD daily for 3 weeks. Alzheimer's mice showed increased anxiety-like behavior with treatment. Control females lost their normal object preference after treatment. THC-CBD significantly decreased body weight and fat deposits across all mice.","methodology":"Researchers treated 14.5-month-old female APP/PS1 transgenic mice (Alzheimer's model) and control littermates with daily THC-CBD injections for three weeks. They tested anxiety (elevated plus maze, open field), memory (novel object recognition, Y-maze), social interaction, and sensorimotor gating.","limitations":"Used only female mice. The THC:CBD ratio and doses may not reflect what humans use. IP injection doesn't mimic oral or inhaled routes. APP/PS1 mice don't fully replicate human Alzheimer's disease."},{"rthcId":"RTHC-05976","title":"Investigating the polygenic relationship between heavy cannabis use and schizophrenia in the All of Us Research Program.","authors":"Austin-Zimmerman, Isabelle; Thorpe, Hayley H A; Meredith, John J; Khokhar, Jibran Y; Ge, Tian; Di Forti, Marta; Agrawal, Arpana; Johnson, Emma C; Sanchez-Roige, Sandra","year":2025,"journal":"Psychological medicine, 55, e381","doi":"10.1017/S0033291725102717","pmid":"41403271","tags":["psychosis","addiction","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The association between heavy cannabis use and schizophrenia has been documented for decades, but a fundamental question remains: does cannabis cause psychosis, does genetic vulnerability to psychosis drive cannabis use, or both? This study used polygenic scores — genetic risk calculators derived from large genome-wide association studies — to test these pathways in real individuals with data on both genetics and diagnoses.\n\nUsing the All of Us Research Program (a diverse U.S. biobank with over 200,000 genotyped participants), the researchers generated polygenic scores for both cannabis use disorder (CUD) and schizophrenia (SCZ) for each individual, then examined how these genetic scores predicted actual diagnoses.\n\nBoth CUD and SCZ polygenic scores independently predicted heavy cannabis use — but the SCZ polygenic score's effect on cannabis use was very modest. Genetic liability for cannabis problems was the stronger predictor of cannabis use, which makes intuitive sense.\n\nFor schizophrenia diagnosis, both polygenic scores were independently significant. This is the critical finding: genetic liability for cannabis use disorder predicted schizophrenia risk even after accounting for schizophrenia-specific genetic risk. This suggests that the genetic pathways leading to problematic cannabis use share biology with those leading to psychosis — they're not completely independent genetic architectures.\n\nWhen the researchers examined individuals with both conditions (dual comorbidity), the polygenic signals were strongest, suggesting a shared genetic substrate that increases vulnerability to both heavy cannabis use and psychosis.","whyItMatters":"The cannabis-psychosis debate has been stuck on whether the link is causal or confounded. This study shows it's partly genetic: some of the same genetic variants that increase risk for problematic cannabis use also increase risk for schizophrenia. This doesn't resolve the causation question entirely (cannabis may still trigger psychosis in genetically vulnerable individuals), but it demonstrates that shared genetic liability is a significant piece of the puzzle.","specificNumbers":"All of Us Research Program participants (>200,000 genotyped). Both CUD and SCZ polygenic scores independently predicted heavy cannabis use, with CUD PGS being the stronger predictor. Both CUD and SCZ PGS independently predicted schizophrenia diagnosis. Polygenic overlap was strongest in dual-comorbidity cases. SCZ PGS effect on cannabis use was modest.","methodology":"Observational genetic study using the All of Us Research Program. Polygenic scores (PGS) for cannabis use disorder and schizophrenia were calculated for each participant using summary statistics from published genome-wide association studies. Models tested associations of both PGS with SCZ diagnosis and heavy cannabis use. Three case definitions used: relaxed (primary condition only), strict (excluding comorbidity), and dual-comorbidity. Controlled for ancestry and demographic factors.","limitations":"Polygenic scores explain only a fraction of total genetic liability for both conditions. All of Us, while diverse, may not represent all populations equally for genetic analyses. Electronic health record-based diagnoses may misclassify some cases. Cannabis use was defined broadly (heavy use) rather than by specific measures of dose, potency, or duration. The cross-sectional design can't establish temporal ordering. Shared genetic liability doesn't preclude additional causal effects of cannabis on psychosis."},{"rthcId":"RTHC-05977","title":"Investigating the Polygenic Relationship Between Cannabis Use and Schizophrenia in the All of Us Research Program.","authors":"Austin-Zimmerman, Isabelle; Thorpe, Hayley Ha; Meredith, John J; Khokhar, Jibran; Ge, Tian; Di Forti, Marta; Agrawal, Arpana; Johnson, Emma C; Sanchez-Roige, Sandra","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.05.20.25327979","pmid":"40475137","tags":["psychosis","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Both cannabis use disorder and schizophrenia polygenic scores independently predicted schizophrenia diagnosis. Notably, genetic liability for cannabis use disorder was associated with schizophrenia even in individuals with no documented history of cannabis use, pointing to widespread pleiotropy (shared genetic pathways).","whyItMatters":"The cannabis-schizophrenia link has been debated for decades. This study used within-individual data on both genetics and diagnoses, addressing a key limitation of earlier work that lacked both measures in the same people.","specificNumbers":"Cannabis use disorder polygenic scores significantly predicted schizophrenia across case definitions. The schizophrenia polygenic score effect on cannabis use was very modest. CUD genetic liability predicted schizophrenia even in people without documented cannabis use.","methodology":"Researchers used genetic and health data from the All of Us Research Program to test whether polygenic scores for cannabis use disorder and schizophrenia independently predicted heavy cannabis use and schizophrenia diagnosis. They tested multiple case definitions to account for comorbidity.","limitations":"Preprint (not yet peer-reviewed). Cross-sectional design can't determine temporal ordering. Cannabis use history from medical records may be incomplete. Polygenic scores explain only a fraction of genetic risk."},{"rthcId":"RTHC-05978","title":"Maternal Prenatal Cannabis Use and Major Structural Birth Defects.","authors":"Avalos, Lyndsay A; Adams, Sara R; Alexeeff, Stacey E; Oberman, Nina R; Does, Monique B; Steuerle, Kristin R; Ansley, Deborah R; Castellanos, Carley L; Padon, Alisa A; Silver, Lynn D; Young-Wolff, Kelly C","year":2025,"journal":"Birth defects research, 117(6), e2492","doi":"10.1002/bdr2.2492","pmid":"40480966","tags":["prenatal","health-risks"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Maternal prenatal cannabis use was associated with omphalocele (adjusted risk ratio 2.92) after propensity score adjustment. An initial association with gastroschisis did not survive full adjustment. No associations were found between prenatal cannabis use and any of the other 36 birth defects examined.","whyItMatters":"With prenatal cannabis use rising, understanding potential effects on fetal development is critical. This large study with universal screening (reducing detection bias) provides some of the strongest evidence to date on specific birth defect risks.","specificNumbers":"363,952 infants studied. 6.2% (22,494) exposed to prenatal cannabis. Omphalocele risk ratio: 2.92 (95% CI: 1.26-6.77) after propensity score adjustment. Both conditions were rare: gastroschisis in 0.05% and omphalocele in 0.01% of births.","methodology":"Population-based retrospective cohort of 363,952 singleton births from a health system that universally screens for substance use at prenatal care entry. Cannabis exposure was defined by self-report or positive toxicology. Researchers examined 38 specific birth defects across 8 organ systems using modified Poisson regression with propensity score adjustment.","limitations":"Observational design cannot prove causation. Cannabis exposure was measured at prenatal care entry, not throughout pregnancy. Could not account for potency, frequency, or route of use. Very small number of omphalocele cases (n=48) limits precision."},{"rthcId":"RTHC-05979","title":"Medical cannabis in Israel: a comprehensive review of trends and regulations, 2011-2025.","authors":"Aviram, Joshua","year":2025,"journal":"Journal of cannabis research, 7(1), 90","doi":"10.1186/s42238-025-00344-1","pmid":"41233935","tags":["legalization","medical-use"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Active medical cannabis licenses in Israel grew by over 4,400% from 2011 to 2024. The 2024 reform transferring prescribing authority to HMOs was followed by a 7.5% decline in licenses. Chronic non-cancer pain remained the top indication (63%), with PTSD growing from 9% to 17%. Over 94% of patients used flower-based products by 2025.","whyItMatters":"Israel has one of the world's most established and data-rich medical cannabis programs. Understanding how its regulatory changes affected patient access provides lessons for other countries developing their own frameworks.","specificNumbers":"Licenses grew from 3,097 (2011) to 140,483 (January 2024), then declined to 129,900 by March 2025. Chronic pain: 63% of licenses. PTSD grew from 9% to 17%. Flower products: over 94% of usage. Monthly doses of 50g rose 108%, 60g rose 117%. Estimated annual market: $252-684 million at peak.","methodology":"Longitudinal review and secondary analysis of monthly Israeli Medical Cannabis Unit reports from 2011 to 2025, mapping regulatory milestones to shifts in patient numbers, indications, dosages, product types, and prescribing patterns.","limitations":"Single-country analysis with a unique healthcare system. Post-2024 data gaps make it difficult to fully explain the license decline. Market value estimates are approximate."},{"rthcId":"RTHC-05980","title":"Activation of central cannabinoid type 2 receptors, but not on peripheral immune cells, is required for endocannabinoid-mediated neuroprotection in Parkinson's disease.","authors":"Ayerra, Leyre; Abellanas, Miguel Angel; Vidaurre, Clara; Basurco, Leyre; Tavira, Adriana; Luquin, Esther; Clavero, Pedro; Mengual, Elisa; Collantes, Maria; Peñuelas, Ivan; de Martin-Esteban, Samuel Ruiz; Grether, Uwe; Hillard, Cecilia J; Romero, Julian; Hervás-Stubbs, Sandra; Aymerich, Maria S","year":2025,"journal":"Brain, behavior, and immunity, 128, 600-611","doi":"10.1016/j.bbi.2025.04.037","pmid":"40320016","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05981","title":"Difficulties in emotion regulation and attachment styles among Kurdish individuals in Eastern Turkey with substances use disorders.","authors":"Ayhan, Cemile Hurrem; Aktaş, Mehmet Cihad; Aktaş, Sakine; Bayram, Zilan","year":2025,"journal":"Journal of ethnicity in substance abuse, 24(1), 23-39","doi":"10.1080/15332640.2024.2407637","pmid":"39324768","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05982","title":"Beneficial and adverse effects of THC on cognition in the HIV-1 transgenic rat model: Importance of exploring task- and sex-dependent outcomes.","authors":"Ayoub, Samantha M; Vemuri, Sunitha; Hoang, Elizabeth B; Jha, Neal A; Minassian, Arpi; Young, Jared W","year":2025,"journal":"Brain, behavior, and immunity, 128, 571-588","doi":"10.1016/j.bbi.2025.04.030","pmid":"40286994","tags":["thc","cognition","medical-use"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both acute and chronic THC exposure produced function-dependent effects in HIV-1 transgenic rats: learning improved but risk-based decision-making worsened. These effects were specific to HIV model rats and not seen in controls, suggesting THC interacts differently with HIV-affected brains.","whyItMatters":"Many people living with HIV use cannabis, and cognitive impairment is common in this population. Understanding that THC may help some cognitive functions while hurting others could inform clinical guidance.","specificNumbers":"THC doses: 0.3 and 3 mg/kg. HIV-1 transgenic rats showed enhanced learning but worsened risk-based decision-making with THC. At baseline, HIV rats took longer to make decisions but performed normally, suggesting a speed-accuracy trade-off.","methodology":"Female and male HIV-1 transgenic rats and controls were tested on two cognitive tasks: the rat Iowa Gambling Task (risk-based decision-making) and Probabilistic Reversal Learning Task (learning/cognitive flexibility). Testing occurred at baseline, then after acute and chronic THC (0, 0.3, 3 mg/kg IP).","limitations":"Animal model doesn't fully replicate human HIV. IP injection doesn't mimic typical human cannabis use. The HIV-1 transgenic rat lacks active viral replication. Results may not directly translate to human cognitive outcomes."},{"rthcId":"RTHC-05983","title":"Cumulative Adverse Childhood Experiences and Frequency of Substance Use Among US High School Students.","authors":"Azagba, Sunday; de Silva, Galappaththige S R; Ebling, Todd","year":2025,"journal":"Journal of primary care & community health, 16, 21501319251346102","doi":"10.1177/21501319251346102","pmid":"40525333","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cumulative ACE scores were positively associated with cannabis use frequency among US high school students. Higher ACE scores predicted greater odds of frequent cannabis use (OR=1.81, 95% CI: 1.65-1.99) and occasional use (OR=1.26, 95% CI: 1.01-1.57).","whyItMatters":"Understanding that childhood adversity predicts teen substance use across a dose-response pattern can help target prevention efforts. Addressing trauma early might reduce substance use risk later.","specificNumbers":"Cannabis use OR: 1.81 (frequent), 1.26 (occasional) per unit increase in ACE score. Similar patterns for alcohol (OR=1.89), binge drinking (OR=1.69), and e-cigarettes (OR=1.89). The study used 8 ACE items from the YRBS.","methodology":"Cross-sectional analysis of the 2023 Youth Risk Behavior Survey, a nationally representative survey of US high school students. Cumulative ACE scores were calculated from 8 self-reported lifetime experiences. Multinomial logistic regression analyzed associations with substance use frequency.","limitations":"Cross-sectional design cannot determine whether ACEs caused substance use. Self-reported data may undercount both ACEs and substance use. The YRBS ACE measure captures only 8 experiences, potentially missing others."},{"rthcId":"RTHC-05984","title":"A Balanced Cannabinoids Mixture Protects Neural Stem/progenitor Cells from CoCl2 Induced Injury by Regulating Autophagy and Inflammation: An in Vitro Study.","authors":"Azarfarin, Maryam; Ghadiri, Tahereh; Gorji, Ali; Ramezani, Fatemeh; Shanehbandi, Dariush; Karimipour, Mohammad; Sadigh-Eteghad, Saeed; Farhoudi, Mehdi","year":2025,"journal":"Neurotoxicity research, 43(6), 49","doi":"10.1007/s12640-025-00770-2","pmid":"41240218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05985","title":"Using the PROMOTE Screener to Identify Psychosocial Risk Factors for Prenatal Substance Use.","authors":"Azeem, Ayesha; Lobel, Marci; Heiselman, Cassandra; Preis, Heidi","year":2025,"journal":"Journal of addiction medicine, 19(2), 216-222","doi":"10.1097/ADM.0000000000001427","pmid":"39792609","tags":["prenatal","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 1,842 pregnant patients screened with the PROMOTE instrument, 2.7% used cannabis prenatally. Being unpartnered was uniquely associated with prenatal cannabis use (AOR=3.37), while past-year tobacco and illegal drug use predicted all three substances (tobacco, cannabis, alcohol).","whyItMatters":"Identifying prenatal substance use early allows for earlier intervention. This study shows that a brief, routine screening tool can flag specific psychosocial risk factors unique to each substance.","specificNumbers":"10.2% (188) used at least one substance prenatally. Tobacco: 7.2%, cannabis: 2.7%, alcohol: 2.4%. Being unpartnered: AOR 3.37 for cannabis. Low education: AOR 2.74 for tobacco. Major life events: AOR 3.25 for alcohol.","methodology":"Retrospective chart review of 1,842 patients who completed the PROMOTE psychosocial screening instrument at their first prenatal visit to New York State outpatient clinics from June 2019 to November 2020. Substance use was identified from medical records including clinical notes, self-report, and urine toxicology.","limitations":"Single health system in New York. Retrospective design may miss unreported use. Small number of cannabis users (n=50) limits statistical power. Study period overlapped with COVID-19 pandemic."},{"rthcId":"RTHC-05986","title":"Racial Equity in Urine Drug Screening Policies in Labor and Delivery.","authors":"Azimi, Vahid; Trammel, Cassandra; Nacke, Lauren; Rubin, Alexandra; Stevenson, Lori; Vaughn, Brittaney; Roper, Stephen M; Zaydman, Mark A; Jackups, Ronald; Riaz, Noor; Schamel, Kim P; Kelly, Jeannie C","year":2025,"journal":"JAMA network open, 8(3), e250908","doi":"10.1001/jamanetworkopen.2025.0908","pmid":"40094663","tags":["legalization","prenatal","health-risks"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Before the intervention, Black patients were screened at more than double the rate of White patients (23.2% vs 11.1%). After removing cannabis as a testing indication and adding clinical decision support, screening rates dropped to 4.5% and 3.6% respectively, eliminating the racial disparity. CPS reporting disparities also resolved.","whyItMatters":"Black pregnant patients have historically been disproportionately subjected to drug testing and CPS involvement. This study shows that changing which substances trigger screening can substantially reduce racial disparities without missing clinically important substance use.","specificNumbers":"9,396 patients total. Pre-intervention: 23.2% of Black vs 11.1% of White patients screened. Post-intervention: 4.5% vs 3.6% (no significant difference). CPS reports: 11.3% vs 5.8% pre-intervention; 4.2% vs 3.5% post-intervention (no significant difference). No change in detection of non-cannabis substance use.","methodology":"Quality improvement study at a single tertiary care center comparing peripartum urine drug screening and CPS reporting rates before (June 2021-September 2022) and after (October 2022-January 2024) removing isolated cannabis use and limited prenatal care as screening indications, with added clinician decision support.","limitations":"Single center in one Midwestern city. Cannot fully separate the effect of removing cannabis indication from the clinical decision support component. Unmeasured confounders may exist."},{"rthcId":"RTHC-05987","title":"The Effect of CB1r Hippocampal Activation on Behavioral Changes and BDNF Levels in Rapid-Eye Movement Sleep-Deprived Rats.","authors":"Azizi, Paniz; Najafi, Anahita; Samizadeh, Mohammad-Ali; Mohamadian, Marjan; Jabbari, Arezu; Rezaie, Maede; Vaseghi, Salar","year":2025,"journal":"The European journal of neuroscience, 62(3), e70216","doi":"10.1111/ejn.70216","pmid":"40799146","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05988","title":"Neurodevelopmental effects of perinatal exposure to cannabis on progeny: A narrative review.","authors":"Azubuike, Chidimma Doris; Grundmann, Oliver; Goodin, Amie J","year":2025,"journal":"Drug and alcohol dependence reports, 16, 100372","doi":"10.1016/j.dadr.2025.100372","pmid":"40896776","tags":["prenatal","youth","mental-health","cognition"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Children exposed to cannabis prenatally consistently showed higher ADHD risk compared to unexposed children. No significant associations emerged with anxiety or depression. Findings on cognition, autism spectrum disorder, and learning were inconsistent across studies. Higher THC concentrations were associated with more aggressive behavior in males.","whyItMatters":"As cannabis use during pregnancy increases, understanding which neurodevelopmental outcomes have consistent evidence helps clinicians provide accurate, evidence-based guidance rather than blanket warnings.","specificNumbers":"ADHD risk was consistently elevated across studies. Higher THC concentrations linked to more aggressive behavior in males specifically. No significant associations found for anxiety and depression.","methodology":"Narrative review searching PubMed for clinical and preclinical studies on neurodevelopmental outcomes following in utero and early childhood cannabis exposure. Prioritized recent clinical studies and categorized findings into cognitive measures and mental health diagnoses.","limitations":"Narrative review, not a systematic review or meta-analysis. Inconsistent exposure measurements and cognitive assessment tools across studies make direct comparison difficult. Most studies cannot account for THC potency or frequency of use."},{"rthcId":"RTHC-05989","title":"Endocannabinoid signaling is a critical link between circadian desynchronization and metabolic dysfunction.","authors":"Baca, Brennan A; Denaroso, Giancarlo E; Akli, Said; Pearson, Gregory L; Wang, Jiexin; Bowles, Nicole P; Phillips, Derrick; Sorensen, Walker; Hume, Catherine; Hill, Matthew N; Karatsoreos, Ilia N","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.09.29.678590","pmid":"41256465","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05990","title":"Neurodevelopmental outcomes following prenatal cannabidiol exposure in male and female Sprague Dawley rat offspring.","authors":"Baccetto, Sarah L; Black, Tallan; Barnard, Ilne L; Macfarlane, Leah M; Sanfuego, Genre B; Laprairie, Robert B; Howland, John G","year":2025,"journal":"Neuroscience, 598, 72-83","doi":"10.1016/j.neuroscience.2025.12.018","pmid":"41380954","tags":["prenatal","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal CBD exposure (5 and 10 mg/kg daily) resulted in lower birth weight and reduced weight gain before weaning. The higher dose (10 mg/kg) decreased homing behavior performance and produced subtle changes in righting reflex during the first postnatal week. Differences resolved by weaning at day 21.","whyItMatters":"CBD is increasingly used during pregnancy for nausea and pain, often perceived as safe because it is non-intoxicating. This animal study suggests prenatal CBD may affect fetal growth and early development, even if effects appear transient.","specificNumbers":"Doses: 5 and 10 mg/kg/day from gestational day 6 to 20. Both doses reduced birth weight and pre-weaning weight gain. 10 mg/kg decreased homing behavior and altered righting reflex in the first postnatal week. No effects on gait, negative geotaxis, or grip strength. Differences resolved by postnatal day 21.","methodology":"Pregnant rats received daily CBD injections (5 or 10 mg/kg IP) from gestational day 6 to 20. Researchers tracked litter health parameters and conducted neurodevelopmental behavioral tests including homing behavior, righting reflex, negative geotaxis, gait, and grip strength.","limitations":"Animal study with IP injection, which does not match how humans use CBD. Only two doses tested. Effects resolved by weaning, raising questions about long-term significance. Rat development does not perfectly parallel human development."},{"rthcId":"RTHC-05991","title":"Cannabis Use in Opioid Maintenance Therapy: Prevalence, Clinical Correlates and Reasons for Use.","authors":"Backmund, Markus; Zámbó, Greta G; Schöfl, Susanne; Soyka, Michael","year":2025,"journal":"Brain sciences, 15(7)","doi":"10.3390/brainsci15070699","pmid":"40722291","tags":["addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis use was reported by 41% of opioid maintenance patients. Of cannabis users, 73% met criteria for dependence. Cannabis dependence was significantly more common in patients receiving buprenorphine than methadone. Higher methadone doses were also associated with increased cannabis use. Common reasons for use included mood enhancement and reduction of cravings for other substances.","whyItMatters":"Cannabis use among opioid treatment patients is common but understudied. Whether cannabis helps or hinders opioid recovery is debated, and the finding that medication type influences cannabis use patterns adds important clinical context.","specificNumbers":"41% used cannabis. 73% of users met dependence criteria. 30% of the full sample had cannabis dependence. 85% of patients reported cannabis-related legal issues. Cannabis dependence was significantly more common with buprenorphine vs methadone.","methodology":"Cross-sectional study of 128 patients (96 male, 32 female) receiving opioid maintenance therapy at a single center. Assessment used the Marijuana Smoking History Questionnaire, Cannabis Problems Questionnaire, and Severity of Dependence Scale.","limitations":"Small sample (n=128) from a single center. Cross-sectional design cannot determine causation. Self-reported cannabis use may be underreported. Legal status of cannabis may influence reporting."},{"rthcId":"RTHC-05992","title":"Perceived discrimination and coping with substance use among Asian Americans during the COVID-19 pandemic: a cross-sectional analysis.","authors":"Bacong, Adrian Matias; Maglalang, Dale Dagar; Tsoh, Janice Y; Saw, Anne","year":2025,"journal":"BMC public health, 25(1), 698","doi":"10.1186/s12889-025-21824-2","pmid":"39979879","tags":["addiction","mental-health","social-behavior"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Racial/ethnic discrimination was associated only with cannabis use among Asian Americans during the pandemic, not with alcohol or tobacco. However, non-discriminatory COVID-19 stressors (economic, health) were associated with all three substances. About 24% of Asian Americans reported discrimination as their greatest source of stress.","whyItMatters":"Anti-Asian discrimination surged during COVID-19. This study reveals that discrimination-related stress and general pandemic stress drove different substance use patterns, suggesting that addressing racism specifically may help reduce cannabis use as a coping mechanism in this community.","specificNumbers":"3,159 Asian American participants. 24% reported racial/ethnic discrimination as greatest stressor. Cannabis coping: 4.1%. Alcohol coping: 13.0%. Tobacco coping: 4.3%. Racial discrimination was associated only with cannabis use, not alcohol or tobacco.","methodology":"Cross-sectional analysis of 3,159 Asian American participants from the AA & NH/PI COVID-19 Needs Assessment Project. Binary logistic regression examined associations between discrimination measures, pandemic stressors, and use of tobacco, alcohol, or cannabis for coping.","limitations":"Cross-sectional design cannot determine causation. Self-reported substance use and discrimination. Surveyed during a specific pandemic period, which may limit generalizability. Grouping all Asian Americans together misses within-group diversity."},{"rthcId":"RTHC-05993","title":"Cannabidiol dose dependently reduces alcohol intake in mice via a non-5-HT1A receptor mechanism: Exploration of other potential receptor targets.","authors":"Badolato, Connie J; Lynch, Erin A; Arnold, Jonathon C; McGregor, Iain S; Bowen, Michael T","year":2025,"journal":"British journal of pharmacology, 182(18), 4236-4261","doi":"10.1111/bph.70070","pmid":"40432283","tags":["cbd","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Acute CBD (7.5-120 mg/kg) dose-dependently reduced binge-like alcohol drinking and blood ethanol levels in mice. The effect was not due to sedation and was maintained across sub-chronic treatment. The well-known serotonin (5-HT1A) and PPARy receptor pathways were ruled out. Instead, the neuropeptide S receptor (NPSR) emerged as a potential mechanism.","whyItMatters":"Current medications for alcohol use disorder have limited efficacy. CBD's ability to reduce alcohol consumption through a novel receptor mechanism could open new treatment pathways.","specificNumbers":"CBD doses: 7.5, 15, 30, 60, 120 mg/kg. Dose-dependent reduction in alcohol intake and blood ethanol concentration. Sub-chronic treatment maintained the effect. 5-HT1A and PPARy blockade had no impact. Subthreshold CBD plus NPSR antagonist reduced drinking.","methodology":"Researchers used the drinking-in-the-dark mouse model of binge drinking. CBD was tested at multiple doses (7.5-120 mg/kg) in male and female mice. Behavioral pharmacology approaches tested CBD interaction with four receptor targets: 5-HT1A, PPARy, CXCR4, and NPSR.","limitations":"Mouse model of binge drinking does not fully capture human alcohol use disorder. High doses used (up to 120 mg/kg) may not translate directly to human dosing. Single study identifying NPSR mechanism needs replication."},{"rthcId":"RTHC-05994","title":"Toxicology Screening for Marijuana and Impact on Breast Milk Feeding Policies in Neonatal Intensive Care Units.","authors":"Bae, Sarra; Schofield, Erin M; Davis, Natalie L","year":2025,"journal":"Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine, 20(8), 567-572","doi":"10.1089/bfm.2025.0064","pmid":"40401714","tags":["prenatal","legalization","health-risks"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"79% of surveyed NICUs used selective toxicology screening based on risk factors or provider discretion. Among NICUs with THC-specific policies, 60% imposed at least one limitation on breast milk feeding from THC-positive mothers, ranging from total prohibition to waiting for a negative test. State cannabis legalization status had no significant association with policy strictness.","whyItMatters":"Inconsistent NICU policies mean that whether a cannabis-using mother can breastfeed her NICU infant depends more on which hospital she delivers at than on evidence or state law. This affects maternal bonding and infant nutrition.","specificNumbers":"187 NICUs surveyed. 79% used selective screening. 60% with THC policies had at least one breast milk limitation. 33% had different policies between NICU and nursery within the same institution. No significant association between state legalization and MBM limitations.","methodology":"Cross-sectional survey of 187 US NICUs assessing policies on toxicology screening of mother-baby dyads and breast milk feeding limitations based on THC screening status. Compared policies across different state legalization categories.","limitations":"Survey response may not represent all US NICUs. Self-reported policies may differ from actual practice. Did not assess patient outcomes under different policies."},{"rthcId":"RTHC-05995","title":"Topical β-Caryophyllene for Dermatologic Disorders: Mechanisms, Human Evidence, and Clinical Translation.","authors":"Bagher, Amina M","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(11)","doi":"10.3390/ph18111605","pmid":"41304852","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05996","title":"Outdated tools, underestimated harm: Modernizing cannabis surveillance in a post-legalization era.","authors":"Bahji, Anees","year":2025,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70274","pmid":"41321067","tags":["addiction","mental-health","quitting"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Canada legalized non-medical cannabis in 2018 as a public health initiative. The stated goal was to move cannabis from criminalization to regulation, with the expectation that regulated access would reduce harms. Seven years later, this commentary argues that Canada doesn't actually know whether that's happened — because the surveillance tools designed to measure cannabis harms are fundamentally inadequate.\n\nThe problems are specific and damning. National surveys still use DSM-IV diagnostic frameworks rather than the current DSM-5 criteria for cannabis use disorder. They employ skip logic that excludes individuals with lower levels of use from substance use questions — missing the very population where early problematic use might be detected. Key symptoms like loss of control, functional impairment, and withdrawal aren't assessed.\n\nAdministrative health records are equally problematic. Cannabis use disorder is underdiagnosed in clinical settings, inconsistently coded, and absent from many administrative databases. The primary mental health surveillance tool doesn't align with DSM-5 standards. High-risk populations — including youth, Indigenous communities, and people experiencing homelessness — are often excluded from survey samples entirely.\n\nThe result: CUD is systematically underdetected, underreported, and absent from the policy discussions it should be informing. Canada ran a massive public health experiment (legalization) without equipping itself to measure the outcomes.","whyItMatters":"Other countries and jurisdictions are using Canada as a model for cannabis legalization. If Canada's own surveillance systems can't determine whether legalization has increased or decreased harms, the evidence base for global cannabis policy is undermined. This isn't an argument against legalization — it's an argument that any public health intervention this large requires adequate measurement tools, and Canada's are currently not up to the job.","specificNumbers":"Canada legalized non-medical cannabis in 2018. Major national surveys still use DSM-IV (superseded by DSM-5 in 2013). Skip logic in surveys excludes individuals with lower use levels. CUD is described as rarely measured, often misclassified, and largely absent from policy discussions. High-risk populations are frequently excluded from survey samples.","methodology":"Narrative review and commentary examining Canada's current cannabis surveillance infrastructure, including national surveys, diagnostic frameworks, administrative health records, and case-finding tools. Assessed alignment with current diagnostic standards (DSM-5) and capacity to detect cannabis use disorder and related harms.","limitations":"This is a commentary/perspective piece rather than original research. Focused specifically on Canada — other jurisdictions may have better or worse surveillance. The author's argument that surveillance is inadequate is well-supported by examples, but others might argue that existing data captures enough for policy-making. The piece doesn't quantify how much CUD is being missed, only argues that current tools are insufficient to capture it accurately."},{"rthcId":"RTHC-05997","title":"Emerging pharmacological strategies for the treatment of cannabis use disorder.","authors":"Bahji, Anees","year":2025,"journal":"Expert opinion on pharmacotherapy, 26(13), 1373-1377","doi":"10.1080/14656566.2025.2558999","pmid":"40920674","tags":["addiction","withdrawal"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The pharmacologic treatment of CUD remains in its early stages with no FDA-approved options. Gabapentin, N-acetylcysteine, synthetic cannabinoids, FAAH inhibitors, orexin receptor antagonists, and psychedelics are all being explored. Most show modest efficacy at best, and progress depends on better integration with behavioral treatments.","whyItMatters":"As cannabis legalization expands and CUD prevalence grows, the lack of effective medications represents a significant treatment gap. Understanding which compounds are in the pipeline helps frame realistic expectations.","specificNumbers":"No approved medications exist for CUD. Agents under investigation include gabapentin, N-acetylcysteine, synthetic cannabinoids, FAAH inhibitors, orexin receptor antagonists, and psychedelics. Most have shown only modest efficacy in trials to date.","methodology":"Narrative review of PubMed, Google Scholar, and clinical trial registries from 2000 to 2025, focusing on human studies, randomized trials, and meta-analyses related to CUD pharmacotherapy.","limitations":"Narrative review without systematic methodology. Most referenced trials have small sample sizes. The field is evolving rapidly, so some findings may already be outdated."},{"rthcId":"RTHC-05998","title":"Evaluation of the Effects of Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on Gingival and Skin Keratinocyte Growth, Migration, Metabolic Activity, and Pro-Inflammatory Cytokine Secretion.","authors":"Bahraminia, Maryam; Laaboudi, Fatima-Zahrae; Romanet, Charlotte; Zhang, Ze; Chakir, Jamila; Béland, François; Rouabhia, Mahmoud","year":2025,"journal":"Biomedicines, 13(10)","doi":"10.3390/biomedicines13102541","pmid":"41153821","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-05999","title":"The impact of recreational cannabis retailer allocation on emergency department visits: A natural experiment utilizing lottery design.","authors":"Bai, Yihong; Cao, Peiya; Kim, Chungah; Ienciu, Kristine; Chum, Antony","year":2025,"journal":"The International journal on drug policy, 137, 104708","doi":"10.1016/j.drugpo.2025.104708","pmid":"39842391","tags":["legalization","health-risks"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"The allocation of recreational cannabis retailers through Ontario's randomized lottery system had no significant effect on cannabis-, alcohol-, or opioid-related emergency department visits. Sensitivity analyses using alternate diagnostic codes, co-use patterns, and cannabis-only use all confirmed the null findings.","whyItMatters":"A common concern about cannabis legalization is that physical retail access will increase emergency visits. This study leveraged a randomized natural experiment, providing stronger causal evidence than typical observational studies.","specificNumbers":"11,156,100 adults monitored across 278 communities from January 2016 to March 2023. No significant effects on cannabis-, alcohol-, or opioid-related ED visits after retailer allocation.","methodology":"Longitudinal study of 278 Ontario communities using health administrative data for over 11 million adults, tracked quarterly from 2016 to 2023. Ontario's lottery-based retailer licensing provided a natural experiment. Researchers used staggered difference-in-differences models weighted by inverse probability of retailer allocation.","limitations":"Ontario-specific results may not generalize to other jurisdictions. Online cannabis sales were available before retail stores opened, potentially diluting the retail-specific effect. Possible spillover effects between communities with and without retailers."},{"rthcId":"RTHC-06000","title":"Fetal Cannabis Exposure and Neonatal Outcomes: A Systematic Review and Meta-Analysis.","authors":"Bailey, Anna; Kerr, Whitney; Alhay, Zahra; Rom, Morgan; Hamilton, Sheryl; Campbell, Janis; Kuhn, Katrin; Thompson, David; Reese, Jessica A","year":2025,"journal":"Maternal and child health journal, 29(5), 703-713","doi":"10.1007/s10995-025-04096-5","pmid":"40317448","tags":["prenatal","health-risks"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Neonates with fetal cannabis exposure had significantly higher odds of being small for gestational age (OR=1.79) and low birth weight (OR=1.38). Results for NICU admission (OR=1.38) and preterm birth (OR=1.29) were not statistically significant, though the upper confidence bounds suggest possible clinical relevance.","whyItMatters":"This meta-analysis pools evidence from multiple studies to provide a clearer picture of prenatal cannabis risks. The significant findings for birth size outcomes add confidence to what individual studies have suggested.","specificNumbers":"Small for gestational age: OR=1.79 (95% CI: 1.24-2.59). Low birth weight: OR=1.38 (95% CI: 1.05-1.89). NICU admission: OR=1.38 (95% CI: 0.86-2.22, not significant). Preterm birth: OR=1.29 (95% CI: 0.97-1.71, not significant). 13 studies included from 3,390 identified.","methodology":"Systematic review and meta-analysis searching five databases. Thirteen studies met inclusion criteria after quality assessment using the Newcastle-Ottawa Scale. Pooled odds ratios were calculated using the Mantel-Haenszel method for dichotomous data.","limitations":"Based on 13 studies with varying definitions of cannabis exposure. Could not account for dose, frequency, route, or timing of use. Many included studies relied on self-reported cannabis use, which likely underestimates exposure."},{"rthcId":"RTHC-06001","title":"Driving and cannabis use: a questionnaire about knowledge and behaviors after the legalization of recreational cannabis in California.","authors":"Baird, Sara; Ageze, Daniel; Hill, Linda L; Hacker, Sarah; Dell'Acqua, Renee; Gold, Alice; Lanin-Kettering, Ilene; Shaughnessy, Tom; Marcotte, Thomas D","year":2025,"journal":"BMC public health, 25(1), 3219","doi":"10.1186/s12889-025-24309-4","pmid":"41029629","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 4,020 current cannabis users in California, 62% knew about the in-vehicle consumption ban, 59% knew containers must be sealed, and 74% knew DUIC citations are possible. 64% felt safe driving within 3 hours of inhaling cannabis. Lower regulatory knowledge was associated with more adverse driving outcomes.","whyItMatters":"Mixed awareness of cannabis driving laws years after legalization suggests that regulatory knowledge gaps persist and may contribute to impaired driving. The association between lower knowledge and worse driving outcomes points to an actionable public health target.","specificNumbers":"62% knew about in-vehicle consumption ban. 59% knew about sealed container requirement. 74% knew about DUIC citations. 64% felt safe driving within 3 hours of inhaling. 55% felt safe within 5 hours of edibles. 13% said legalization increased their likelihood of DUIC.","methodology":"Large survey of 15,208 participants demographically matched to the 2020 California census. A subset of 4,020 current users, 523 former users, and 635 never-users completed detailed questionnaires about driving knowledge, attitudes, and behaviors. Chi-square analysis was used for descriptive analysis.","limitations":"Self-reported data on driving behaviors and knowledge. California-specific results may not generalize. The survey cannot establish causation between knowledge gaps and driving outcomes."},{"rthcId":"RTHC-06002","title":"Leveraging Genomic Data to Examine the Causal Impact of Alcohol, Tobacco, Cannabis, and Opioid Use on Biological and Cognitive Ageing.","authors":"Balbona, Jared V; Jeffries, Paul; Gorelik, Aaron J; Nelson, Elliot C; Bogdan, Ryan; Agrawal, Arpana; Johnson, Emma C","year":2025,"journal":"Addiction biology, 30(7), e70066","doi":"10.1111/adb.70066","pmid":"40653731","tags":["addiction","health-risks","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Mendelian randomization analyses found significant causal effects of genetic predisposition to tobacco use disorder and smoking quantity on markers of biological, physical, and cognitive aging. Causal effects of problematic alcohol use and cannabis use disorder were also detected but with mixed results across different aging markers. Evidence of reverse causality (aging causing substance use) was minimal.","whyItMatters":"This study uses genetic methods to move beyond correlation and test whether substance use actually causes accelerated aging. The approach helps disentangle whether substance users age faster because of their use or because of shared underlying factors.","specificNumbers":"GWAS data from 28,000 to 2.7 million participants. Widespread genetic correlations found between substance use/use disorders and aging metrics. Tobacco showed the strongest causal effects. Cannabis use disorder showed some causal effects but findings were mixed across aging markers.","methodology":"Researchers used genome-wide association study data (sample sizes from 28K to 2.7M) to test genetic correlations between substance use and aging metrics using LDSC regression. Mendelian randomization was then used to assess causal relationships between genetic predisposition to substance use and various aging indices.","limitations":"Mendelian randomization assumes genetic instruments affect aging only through substance use, which may not always hold. Cannabis use disorder GWAS sample sizes are smaller than for tobacco or alcohol. Most data comes from European ancestry populations."},{"rthcId":"RTHC-06003","title":"Assisted Extraction of Hemp Oil and Its Application to Design Functional Gluten-Free Bakery Foods.","authors":"Baldino, Noemi; Paleologo, Mario F O; Chiodo, Mariateresa; Mileti, Olga; Lupi, Francesca R; Gabriele, Domenico","year":2025,"journal":"Molecules (Basel, Switzerland), 30(12)","doi":"10.3390/molecules30122665","pmid":"40572627","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06004","title":"From tradition to evidence: exploring the neurochemical basis of medicinal plants in anxiety therapy.","authors":"Balkrishna, Acharya; Agarwal, Upasana; Arya, Deepika; Chaudhary, Sonia; Arya, Vedpriya","year":2025,"journal":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 26(8), 371-408","doi":"10.1080/15622975.2025.2527338","pmid":"40658542","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06005","title":"State funding for cannabis research: an analysis of funding mechanisms and levels.","authors":"Balla, Agnes; Boyle, Raymond G; Dempsey, Christina","year":2025,"journal":"Journal of cannabis research, 7(1), 15","doi":"10.1186/s42238-025-00264-0","pmid":"40087685","tags":["legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Only 17 of 38 states with medical or adult-use cannabis laws include a funding mechanism for research. Of those 17, just 12 have allocated any funding. Six states distributed funds directly to academic institutions, five routed them through state agencies, and California used both approaches. Funding amounts varied significantly across states.","whyItMatters":"States are making cannabis policy decisions without federal guidance, yet most are not investing in the research needed to inform those decisions. This creates a gap between the pace of legalization and the evidence available to regulators.","specificNumbers":"38 states have legalized some form of cannabis. 17 have research funding legislation. 12 have actually allocated funds. 6 fund academic institutions directly. 5 route through state agencies. 1 (California) uses both approaches.","methodology":"Review of legalization legislation text from all 38 states with medical or adult-use cannabis laws, supplemented by state government websites, reference materials, and direct contact with state officials to identify research funding provisions and mechanisms.","limitations":"Focused on legislative provisions rather than actual research output. Funding amounts were not always publicly available. Does not assess the quality or impact of funded research."},{"rthcId":"RTHC-06006","title":"Unveiling the Unexpected: A Case of Synergistic Drug Reaction to Cannabidiol.","authors":"Balouch, Aiman; Muslim, Muhammad Osama; Akram, Muhammad; Haseeb, Syed Saad; Chaudhary, Muhammad Naqash","year":2025,"journal":"Cureus, 17(8), e90992","doi":"10.7759/cureus.90992","pmid":"41018322","tags":["cbd","health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 45-year-old female on therapeutic cannabis oil developed an acute surge in liver transaminases. After excluding common causes including paracetamol and recent flucloxacillin (both hepatotoxic), liver parameters improved following discontinuation of the cannabis oil, suggesting a possible association with liver injury.","whyItMatters":"As CBD products become widely available, recognizing them as potential hepatotoxins is important for clinicians investigating unexplained liver enzyme elevations, especially in patients taking other medications.","specificNumbers":"One patient, age 45. Acute transaminase elevation during cannabis oil use. Improvement after discontinuation. Paracetamol and flucloxacillin were excluded as primary causes.","methodology":"Single case report documenting clinical presentation, laboratory findings, workup to exclude alternative causes, and temporal relationship between cannabis oil discontinuation and liver enzyme improvement.","limitations":"Single case report cannot prove causation. The patient was taking other potentially hepatotoxic medications. Cannot determine whether CBD alone or a drug interaction caused the injury."},{"rthcId":"RTHC-06007","title":"Effects of legal access versus illegal market cannabis on use and mental health: A randomized controlled trial.","authors":"Baltes-Flueckiger, Lavinia; Steinauer, Regine; Meyer, Maximilian; Guessoum, Adrian; Herrmann, Oliver; Mosandl, Christoph Felix; Kronschnabel, Jens; Pichler, Eva-Maria; Vogel, Marc; Walter, Marc","year":2025,"journal":"Addiction (Abingdon, England), 120(10), 1982-1992","doi":"10.1111/add.70080","pmid":"40289676","tags":["legalization","addiction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"After 6 months, the legal cannabis group showed a trend toward lower cannabis misuse scores compared to the illegal market group (10.1 vs 10.9, p=0.052). Sub-group analysis revealed that the reduction was confined to legal access participants who also used other drugs. No significant changes were found for depression, anxiety, psychotic symptoms, or alcohol use.","whyItMatters":"This is the first randomized controlled trial directly comparing legal and illegal cannabis market effects on health outcomes. While observational studies of legalization exist, experimental evidence has been lacking.","specificNumbers":"374 participants randomized. Cannabis misuse scores: 10.1 (legal) vs 10.9 (illegal), p=0.052. 97.3% follow-up rate. The benefit was concentrated among participants who also used other drugs (interaction p<0.001). No significant differences in secondary mental health outcomes.","methodology":"Two-arm, parallel group, open-label randomized controlled trial in Basel, Switzerland. 374 adult cannabis users were randomized to receive legal cannabis through pharmacies (with safer use information and voluntary counseling) or to continue purchasing from the illegal market. Follow-up at 6 months.","limitations":"Open-label design means participants knew their group assignment. Conducted in one Swiss city with specific cultural and legal context. Six-month follow-up may be too short to detect longer-term effects. The primary outcome narrowly missed statistical significance."},{"rthcId":"RTHC-06008","title":"Regarding the pain of men: characteristics of fibromyalgia in male patients.","authors":"Bannon, Lian; Shlezinger, Omer; Berman, Mark; Mangel, Laurence; Ablin, Jacob Nadav; Aloush, Valerie","year":2025,"journal":"Clinical and experimental rheumatology, 43(6), 1049-1053","doi":"10.55563/clinexprheumatol/s5e2km","pmid":"40242899","tags":["pain","medical-use","sex-differences"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 3,044 fibromyalgia patients, 48% of males received medical cannabis treatment compared to 34.6% of females. Male patients were diagnosed later (52.7 vs 44.9 years), had more PTSD (14% vs 5.7%), and more sleep apnea (6.7% vs 1.8%). Females had higher obesity rates (16% vs 9.2%).","whyItMatters":"Fibromyalgia research has focused primarily on women due to the condition's female predominance. Understanding how male patients differ, including their significantly higher rates of medical cannabis use, can inform more tailored treatment approaches.","specificNumbers":"3,044 total FM patients, 13.2% male. 48% of males vs 34.6% of females treated with medical cannabis (p<0.001). Male diagnosis age: 52.7 years vs 44.9 for females (p<0.001). PTSD: 14% males vs 5.7% females (p<0.001).","methodology":"Retrospective cross-sectional study of all fibromyalgia patients in a tertiary hospital electronic medical record database from 2010-2021. Compared 401 male patients against a random cohort of 438 female patients with individual file review.","limitations":"Single tertiary center in Israel, where medical cannabis is more accessible than in many countries. Retrospective design cannot determine why males used more medical cannabis. Did not assess cannabis treatment outcomes."},{"rthcId":"RTHC-06009","title":"Association between lifetime co-use of classic psychedelics and cannabis and prostate cancer diagnosis among US adults 50 years and older.","authors":"Baral, Amrit; Pan, Yue; Hlaing, WayWay M; Garcia-Romeu, Albert; Pinheiro, Paulo S; Vidot, Denise C","year":2025,"journal":"Scientific reports, 16(1), 609","doi":"10.1038/s41598-025-30172-5","pmid":"41361347","tags":["cancer","health-risks"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Exclusive classic psychedelic use was associated with 2.62 times higher odds of prostate cancer diagnosis compared to non-users. Among adults 65 and older, the association was even stronger (AOR=3.60). Notably, psychedelic-only users had 4.58 times higher odds than those who used both psychedelics and cannabis, suggesting a potential modifying role of cannabis co-use.","whyItMatters":"This is the first study to examine associations between psychedelic and cannabis use patterns and prostate cancer. The finding that cannabis co-use may modify the psychedelic-cancer association is novel and generates hypotheses for further research.","specificNumbers":"19,460 males (weighted: 50.8 million). 3.9% reported prostate cancer. Psychedelic-only vs non-users: AOR=2.62 (p<0.01). Ages 65+: AOR=3.60 (p<0.01). Psychedelic-only vs co-users: AOR=4.58 (p<0.01).","methodology":"Analysis of 19,460 males aged 50+ from the 2015-2019 National Survey on Drug Use and Health. Participants were categorized as cannabis-only users, psychedelic-only users, co-users, or non-users. Multivariable logistic regression adjusted for sociodemographic, behavioral, and clinical covariates.","limitations":"Cross-sectional design cannot establish causation. Self-reported substance use and cancer diagnosis. Lifetime use measures do not capture timing, dose, or frequency. Many potential confounders exist, including healthcare-seeking behavior."},{"rthcId":"RTHC-06010","title":"Association of Lifetime Psychiatric Comorbidity and Current Substance Use in Methadone-Treated Individuals with Opioid Use Disorders.","authors":"Barbaglia, M Gabriela; Molero-Calafell, Javier; Angulo-Brunet, Ariadna; Alcaraz, Saül; Bartroli, Montse; Mestre-Pintó, Joan I","year":2025,"journal":"Journal of dual diagnosis, 21(4), 267-279","doi":"10.1080/15504263.2025.2557191","pmid":"40975780","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 588 patients receiving opioid agonist treatment with methadone, 63.5% had a lifetime dual diagnosis and 83.5% reported past-month substance use. Having a psychiatric comorbidity was not associated with increased use of opioids, cocaine, or alcohol, but was associated with a 29% increase in cannabis use (PR=1.29).","whyItMatters":"Understanding why cannabis is the only substance elevated among dual-diagnosis methadone patients could inform treatment. It suggests cannabis may serve a different role than other substances for people managing both opioid use disorder and psychiatric conditions.","specificNumbers":"588 patients (20% women, mean age 48.4). 63.5% lifetime dual diagnosis. 83.5% past-month substance use. Cannabis was the only substance with elevated use among dual-diagnosis patients (PR=1.29). Opioid, cocaine, and alcohol use showed no significant difference.","methodology":"Cross-sectional study of 588 convenience-sampled patients from eight outpatient drug treatment centers in Catalonia, Spain. Dual diagnosis assessed using the Dual Disorder Screening Interview. Self-reported substance use evaluated via questionnaire. Poisson regression models adjusted for sociodemographic, clinical, and treatment variables.","limitations":"Cross-sectional design from one region of Spain. Convenience sample may not represent all methadone patients. Self-reported substance use. Lifetime diagnosis doesn't capture current symptom severity."},{"rthcId":"RTHC-06011","title":"American Indian women's perceptions of perinatal cannabis use.","authors":"Barbosa-Leiker, Celestina; Brooks, Olivia; Smith, Crystal Lederhos; Reid, Shayla C; Fatima, Gusti Lulu; Hirchak, Katherine A; Arias-Losado, Randi; Cabell, Margaret","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(2), 254-262","doi":"10.1080/00952990.2025.2473399","pmid":"40084915","tags":["prenatal"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Four themes emerged: (1) cannabis viewed as better than methamphetamine, heroin, alcohol, and prescriptions, (2) cannabis used medicinally for pregnancy symptoms, (3) uncertainty about breastfeeding effects, and (4) minimal healthcare provider discussion perceived as endorsement of use.","whyItMatters":"American Indian women face higher cannabis use rates and lower access to mental health treatment. Understanding how they perceive perinatal cannabis use reveals critical gaps in healthcare communication and culturally appropriate education.","specificNumbers":"10 American Indian women from 3 legal cannabis states. All used cannabis at least weekly during pregnancy or postpartum. Cannabis was perceived as safer than methamphetamine, heroin, alcohol, and prescription drugs.","methodology":"Qualitative descriptive study of 10 American Indian perinatal women from Washington, Oregon, and California who used cannabis at least weekly while pregnant or postpartum. Semi-structured interviews analyzed using principles of Indigenous research frameworks.","limitations":"Very small sample size (n=10). All participants from states where cannabis is legal. Qualitative design cannot establish prevalence of these views. May not represent perspectives across all American Indian communities."},{"rthcId":"RTHC-06012","title":"Deficiency of cannabinoid receptors enhances host susceptibility to bacterial infection.","authors":"Barker, Hailey A; Bhimani, Saloni; Tirado, Deyaneira; Canas, Jorge J; Lemos, Leandro Nascimento; Roesch, Luiz F W; Ferraro, Mariola J","year":2025,"journal":"mBio, 16(10), e0208825","doi":"10.1128/mbio.02088-25","pmid":"40965138","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06013","title":"Non-psychoactive cannabis extract promotes extinction and reduces reinstatement by priming dose in smoked cocaine-induced conditioned place preference.","authors":"Barreto, Fabián Leonardo; Lozano, María Constanza; Martínez-Ramírez, Jorge A","year":2025,"journal":"Physiology & behavior, 301, 115048","doi":"10.1016/j.physbeh.2025.115048","pmid":"40752858","tags":["addiction","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"A non-psychoactive cannabis extract (NPCE) significantly reduced the extinction latency of smoked cocaine-induced place preference, while pure CBD did not. NPCE also selectively blocked relapse triggered by a priming dose of cocaine but not stress-induced relapse. The serotonin 5-HT1A receptor was involved in this effect, while the CB2 receptor was not.","whyItMatters":"Smoked cocaine (crack) is particularly addictive and difficult to treat. Finding that a non-psychoactive cannabis extract reduces relapse markers in a relevant animal model opens a potential new treatment avenue.","specificNumbers":"NPCE reduced extinction latency of AEME-COC preference (CBD did not). NPCE blocked priming-dose reinstatement but not stress-induced reinstatement. 5-HT1A receptor antagonist attenuated NPCE effects. CB2 receptor inverse agonist had no significant impact.","methodology":"Mouse conditioned place preference model using AEME-COC (a model for smoked cocaine). Three experiments tested: (1) cocaine vs AEME-COC conditioning, (2) CBD vs NPCE on extinction, (3) receptor antagonists on NPCE-mediated inhibition of reinstatement. Behavioral pharmacology approaches identified receptor mechanisms.","limitations":"Animal model of cocaine preference does not fully capture human addiction. NPCE composition may vary between preparations. IP administration does not mimic human use. Single study requiring replication."},{"rthcId":"RTHC-06014","title":"Loneliness among emerging adults in rural reservation-based communities: longitudinal effects of 12th grade substance use and mental health symptoms.","authors":"Barry, Caroline M; Jagtiani, Ashna; Skinner, Juli R; Gassaway, Ashley N; Komro, Kelli A; Livingston, Melvin D","year":2025,"journal":"Scientific reports, 15(1), 31935","doi":"10.1038/s41598-025-18008-8","pmid":"40883431","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use in 12th grade was associated with a 21-24% increased risk of loneliness post-high school, similar to alcohol, binge drinking, and vaping. Anxiety and depressive symptoms in 12th grade also predicted loneliness, with 5-point increases associated with 15% and 21% greater risk respectively.","whyItMatters":"Loneliness is a growing public health concern among emerging adults, and rural reservation-based communities face unique challenges. Understanding that substance use predicts post-graduation loneliness can inform prevention timing.","specificNumbers":"483 participants. Cannabis use, alcohol use, binge drinking, and vaping each associated with 21-24% increased risk of loneliness. 5-point increase in anxiety symptoms: 15% greater loneliness risk. 5-point increase in depressive symptoms: 21% greater risk.","methodology":"Longitudinal study of 483 participants from rural reservation-based communities surveyed in 12th grade (Spring 2024) and again six months into young adulthood (Fall 2024). Generalized estimating equations with Poisson distribution assessed predictors of post-high-school loneliness.","limitations":"Six-month follow-up is short. Specific to rural reservation-based communities, which may limit generalizability. Cannot determine whether substance use caused loneliness or whether shared factors drive both."},{"rthcId":"RTHC-06015","title":"Adolescent cannabis use and onset of bipolar disorder: gaining causal clarity by viewing the evidence through the Bradford Hill lens.","authors":"Bartoli, Francesco; Cavaleri, Daniele; Bassetti, Carlo; Broccia, Marco; Crocamo, Cristina; Malhi, Gin S; Carrà, Giuseppe","year":2025,"journal":"CNS spectrums, 30(1), e49","doi":"10.1017/S1092852925100345","pmid":"40534313","tags":["youth","mental-health","psychosis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Evaluation of longitudinal studies using Bradford Hill criteria found the cannabis-bipolar disorder relationship shows a dose-response gradient, strong effect size, coherence, biological plausibility, and clear temporality. Cannabis may act as a precipitating agent in a multicausal model of vulnerability. However, the relationship is only partially consistent and nonspecific.","whyItMatters":"While the cannabis-schizophrenia link has received extensive attention, the cannabis-bipolar disorder connection has been less studied. This analysis applies a rigorous causal framework and finds substantial (though not conclusive) evidence of a causal role.","specificNumbers":"Dose-response relationship supported (biological gradient). Effect size is strong. Clear temporal sequence (cannabis use precedes onset). Some analogies with cannabis-schizophrenia literature. Consistency is partial; specificity is low.","methodology":"Systematic evaluation of recent longitudinal studies on adolescent cannabis use and bipolar disorder risk using the Bradford Hill criteria for causation (strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, analogy).","limitations":"Methodological heterogeneity across studies prevents meta-analysis. Bradford Hill criteria provide a framework for evaluating causation but cannot prove it. Experimental evidence remains suggestive rather than conclusive."},{"rthcId":"RTHC-06016","title":"From Synaptic Plasticity to Neurotoxicity: Endocannabinoid Influence on Addiction and Neurodegeneration.","authors":"Basavarajappa, Balapal S; Subbanna, Shivakumar","year":2025,"journal":"International journal of molecular sciences, 26(23)","doi":"10.3390/ijms262311632","pmid":"41373784","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06017","title":"Unravelling herbicide stress and its impact on metabolite profiling in Cannabis sativa: an investigative study.","authors":"Bashir, Sabreen; Kaur, Navneet; Vadhel, Agrataben; Verma, Awadhesh Kumar; Girdhar, Madhuri; Malik, Tabarak; Kumar, Anil; Mohan, Anand","year":2025,"journal":"Journal of cannabis research, 7(1), 40","doi":"10.1186/s42238-025-00300-z","pmid":"40624563","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06018","title":"Cannabidiol inhibits TGF-β1-induced epithelial-mesenchymal transition in human conjunctival epithelial cells by interrupting TGF-β/Smad signaling.","authors":"Baskan, Anil; Awad, Ezzat M; Elahi, Ava; Pervaiz, Javeria; Barisani-Asenbauer, Talin","year":2025,"journal":"Scientific reports, 15(1), 41229","doi":"10.1038/s41598-025-25216-9","pmid":"41272047","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06019","title":"Associations between recreational cannabis legalization and cannabis use disorder treatment outcomes in California, 2010-2021.","authors":"Bass, Brittany; Padwa, Howard; Khurana, Dhruv; Urada, Darren","year":2025,"journal":"Journal of cannabis research, 7(1), 60","doi":"10.1186/s42238-025-00323-6","pmid":"40826147","tags":["legalization","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"California's recreational cannabis legalization was associated with decreased probability of 90-day treatment retention and successful discharge for CUD patients. Effects varied by demographics: adults 21+ and White non-Hispanics saw decreased retention, while males and adults 21+ showed increased probability of successful discharge. No association was found for Black or Hispanic patients.","whyItMatters":"As more states legalize cannabis, understanding effects on treatment outcomes is essential. If legalization makes it harder for people in treatment to stay engaged, additional supports may be needed.","specificNumbers":"192,580 CUD treatment episodes analyzed. Significant decreases in 90-day retention and successful discharge overall. Decreased retention for adults 21+ and White non-Hispanics. Increased successful discharge for males and adults 21+. No significant changes for Black or Hispanic patients.","methodology":"Individual-level pre-post time series analysis of 192,580 publicly funded CUD treatment episodes in California from January 2010 to December 2021. Logistic regression models included individual and county-level characteristics.","limitations":"Pre-post design cannot definitively attribute changes to legalization vs. other concurrent factors. Only includes publicly funded treatment. Cannot distinguish between policy effects and broader cultural shifts around cannabis."},{"rthcId":"RTHC-06020","title":"Symptom management, adherence to therapy, and filling the gaps of medical cannabis therapy: a qualitative study on the importance of nursing consultations for fibromyalgia patients.","authors":"Bassi, Giulia Martina; Giorgi, Valeria; Lazzarin, Michela; Meanti, Ramona; Omeljaniuk, Robert J; Sarzi-Puttini, Piercarlo; Torsello, Antonio","year":2025,"journal":"Journal of cannabis research, 7(1), 84","doi":"10.1186/s42238-025-00346-z","pmid":"41163201","tags":["medical-use","pain"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Among 30 fibromyalgia patients, 20 reported that medical cannabis had never been proposed despite years of ineffective therapies. Patients described historical experiences of being labeled \"insane\" or \"imaginary ill.\" A 30-minute nursing educational intervention via videoconference improved patients' understanding of the disease and treatment options including medical cannabis.","whyItMatters":"Fibromyalgia patients often feel their condition is not taken seriously. When nurses with specialized knowledge provide education about all treatment options including medical cannabis, it addresses both the information gap and the feeling of being dismissed.","specificNumbers":"30 patients recruited from 1,100 solicited. 20 patients (67%) said medical cannabis was never proposed to them. 30-minute nursing videoconference intervention. Patients completed FIQR, A-14, and CGI-I scales.","methodology":"Qualitative study recruiting 30 fibromyalgia patients from the Italian Fibromyalgia Syndrome Association. Participants completed the FIQR and A-14 Scale before and after a 30-minute nursing videoconference educational intervention, plus the CGI-I Scale post-intervention.","limitations":"Small sample from a single patient association in Italy. No control group. Self-selected participants who were already interested in medical cannabis. Short follow-up period (2 weeks)."},{"rthcId":"RTHC-06021","title":"Cannabinoid Receptor Type 1 Availability in Individuals with a History of Childhood Trauma: A Positron Emission Tomography Study.","authors":"Bassir Nia, Anahita; Aghaei, Ardavan Mohammad; Pittman, Brian; Korem, Nachshon; D'Souza, Deepak; Potenza, Marc; Hillmer, Ansel; Ranganathan, Mohini; Harpaz-Rotem, Ilan","year":2025,"journal":"Research square","doi":"10.21203/rs.3.rs-6536815/v1","pmid":"40502783","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06022","title":"Home Cultivation of Cannabis in a Context of Prohibition: Results from Two Online Cross-Sectional Surveys of People Using Cannabis Daily in France.","authors":"Bastien, Martin; Mezaache, Salim; Donadille, Cécile; Madrid, Laélia Briand; Lebrun, Maëla; Martin, Victor; Roux, Perrine","year":2025,"journal":"International journal of environmental research and public health, 22(8)","doi":"10.3390/ijerph22081167","pmid":"40869753","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Home cultivation was the main supply source for 11-16% of daily French cannabis users. Cultivators were more likely to be older, male, in stable housing, using herbal cannabis, smoking with less tobacco, and using cannabis therapeutically. Most were self-sufficient and few sold any of their crop. The primary motivation was managing product quality.","whyItMatters":"Home cultivation in prohibition countries represents a harm reduction strategy by users seeking to control what they consume. Understanding who cultivates and why can inform more nuanced drug policy.","specificNumbers":"11% and 16% reported home cultivation as main supply in the two samples (N=3,840 and N=574). Quality management was the top motivation. Few sold their crop. Most were self-sufficient. Urban residence and at-risk alcohol use were negatively associated with cultivation.","methodology":"Analysis of two convenience samples of daily cannabis users in France from online cross-sectional surveys. Multivariable logistic regression identified factors associated with home cultivation. A second analysis described motivations and cultivation patterns.","limitations":"Convenience samples of daily users may not represent all cannabis users. Online surveys may miss populations without internet access. Self-reported data in an illegal context may be subject to social desirability bias."},{"rthcId":"RTHC-06023","title":"Targeting cannabinoid receptor 1 for antagonism in pro-fibrotic alveolar macrophages mitigates pulmonary fibrosis.","authors":"Basu, Abhishek; Arif, Muhammad; Wolf, Kaelin M; Behee, Madeline; Johnson, Natalie; Pommerolle, Lenny; Pineda, Ricardo H; Sembrat, John; Zawatsky, Charles N; Dvorácskó, Szabolcs; Coffey, Nathan J; Park, Joshua K; Karagoz, Seray B; Godlewski, Grzegorz; Jourdan, Tony; Harvey-White, Judith; Königshoff, Melanie; Iyer, Malliga R; Cinar, Resat","year":2025,"journal":"JCI insight, 10(15)","doi":"10.1172/jci.insight.187967","pmid":"40608428","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06024","title":"Adolescent E-cigarette use and associated socio-contextual variables, psychological variables, and problem behaviors.","authors":"Battaglia, Emily; Greenle, Meredith MacKenzie; Dowdell, Elizabeth B","year":2025,"journal":"Journal of pediatric nursing, 82, 109-115","doi":"10.1016/j.pedn.2025.02.014","pmid":"40058096","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06025","title":"Young Adults' Use of Prescription Opioids and Cannabis Postoperatively: A Qualitative Study.","authors":"Battison, Eleanor A J; Heierle, Jessica; Cottrell, Erika K; Holley, Amy L; Wilson, Anna C","year":2025,"journal":"Pain management nursing : official journal of the American Society of Pain Management Nurses","doi":"10.1016/j.pmn.2025.11.018","pmid":"41444096","tags":["pain","medical-use"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Key themes included a \"fear of opioids\" and \"fear messaging from parents\" that led young adults to take opioids less than prescribed and endure pain instead. Many used cannabis after surgery for pain and anxiety management. Participants were intentional about cannabis use around the surgical period, adjusting timing and amounts.","whyItMatters":"Understanding that young adults are self-managing postoperative pain with cannabis due to opioid fears suggests that surgical teams need to address both the fear narrative and the reality of cannabis use in perioperative planning.","specificNumbers":"13 participants, mean age 22.9. Interviews at 2-12 weeks post-surgery. Themes included fear of opioid dependence, positive mental health effects from cannabis, and contradictory perceptions about cannabis pain effects.","methodology":"Qualitative descriptive study with 13 young adults (ages 19-25) who were prescribed opioids post-surgery. Semi-structured interviews conducted 2-12 weeks after surgery explored patterns and motivations for opioid and cannabis use.","limitations":"Very small sample (n=13). Qualitative design provides depth but not generalizability. Participants were from one geographic area. Self-selected population may over-represent cannabis users."},{"rthcId":"RTHC-06026","title":"Characteristics of adolescent cannabis use and social context predicting problematic use: A decision tree analysis.","authors":"Battista, Katelyn; Haddad, Slim; Leatherdale, Scott T; Bélanger, Richard","year":2025,"journal":"Addictive behaviors, 170, 108445","doi":"10.1016/j.addbeh.2025.108445","pmid":"40749297","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Decision tree analysis identified cannabis use at least 2-4 times per month as the most important predictor of problematic use across all three indicators (unsuccessful quit attempt, excessive use, feeling addicted). For teens who used less frequently, initiating before age 14 and using alone further increased risk. No sociodemographic differences emerged among high-risk groups.","whyItMatters":"Identifying a clear frequency threshold for problematic use gives clinicians and educators a practical screening criterion. The finding that early initiation and solitary use add risk provides additional targets for prevention.","specificNumbers":"8,915 cannabis ever-users, mean age 15.5. Using 2-4+ times/month was the top predictor. Early initiation (<14) and solitary use added risk for lower-frequency users. No sociodemographic differentiation in high-risk groups.","methodology":"Decision tree analysis of 8,915 cannabis ever-users from the COMPASS survey of secondary school students (mean age 15.5) in Quebec, Canada. Three indicators of problematic use were examined: unsuccessful quit attempt, excessive use, and feeling addicted.","limitations":"Cross-sectional design cannot determine whether frequency causes problematic use or vice versa. Self-reported data. Quebec-specific sample. Decision tree analysis may not capture complex interactions between predictors."},{"rthcId":"RTHC-06027","title":"In Vitro Immunomodulatory Effects of Equine Adipose Tissue-Derived Mesenchymal Stem Cells Primed with a Cannabidiol-Rich Extract.","authors":"Battistin, Lorena; Moya, Luís Felipe Arantes; Ferreira, Lucas Vinícius de Oliveira; Braz, Aline Márcia Marques; Carvalho, Márcio de; Golim, Marjorie de Assis; Amorim, Rogério Martins","year":2025,"journal":"International journal of molecular sciences, 26(9)","doi":"10.3390/ijms26094208","pmid":"40362445","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06028","title":"Effect of orally administered cannabidiol oil on daily tonometric curve in healthy Italian Saddle horses.","authors":"Bazzano, Marilena; Laus, Fulvio; Cerquetella, Matteo; Spaterna, Andrea; Marchegiani, Andrea","year":2025,"journal":"PloS one, 20(5), e0325191","doi":"10.1371/journal.pone.0325191","pmid":"40435047","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06029","title":"Phytocannabinoids and Nanotechnology in Lung Cancer: A Review of Therapeutic Strategies with a Focus on Halloysite Nanotubes.","authors":"Bęben, Dorota; Moreira, Helena; Barg, Ewa","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(9)","doi":"10.3390/ph18091244","pmid":"41011117","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06030","title":"Labeling of Cannabis Products From Licensed and Unlicensed Retailers in New York.","authors":"Becker, Timothy D; Menzi, Peter J; Olfson, Mark; Mosharova, Polina; Levin, Frances R; Sultan, Ryan S","year":2025,"journal":"American journal of preventive medicine, 69(5), 108000","doi":"10.1016/j.amepre.2025.108000","pmid":"40744165","tags":["legalization","health-risks"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Unlicensed products had significantly less essential information (2.20 vs 4.89 of 6 elements), fewer safety features (2.22 vs 4.29 of 6), and more youth-appealing elements (2.58 vs 1.60 of 7) than licensed products. Unlicensed products often featured misplaced warnings from other states and edible-specific warnings on non-edible products.","whyItMatters":"Product labels are consumers' primary source of information about what they are using. When unlicensed products lack potency data, safety warnings, and contain misleading information, consumers cannot make informed decisions about their use.","specificNumbers":"88 products from licensed and unlicensed retailers. Essential info: 2.20 vs 4.89 of 6 (p<0.001). Safety features: 2.22 vs 4.29 of 6 (p<0.001). Youth-appealing elements: 2.58 vs 1.60 of 7 (p<0.01). Unlicensed products had misplaced warnings from other states.","methodology":"Cross-sectional study of 88 cannabis products (58 flower, 30 vape) obtained from randomly selected licensed and unlicensed retailers in New York in October-November 2023. Labels were coded across 4 categories: essential information, safety features, youth-appealing elements, and product descriptors.","limitations":"New York-specific findings during early legalization period. Small sample (88 products). Label content was assessed but actual product testing was not conducted. Unlicensed market may have changed since data collection."},{"rthcId":"RTHC-06031","title":"Cannabis Access by Retailer Type in New York.","authors":"Becker, Timothy D; Olfson, Mark; Menzi, Peter J; Levin, Frances R; Hasin, Deborah S; Nuckolls, Colin; Sultan, Ryan S","year":2025,"journal":"Pediatrics, 155(3)","doi":"10.1542/peds.2024-068669","pmid":"39992694","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Licensed retailers required age verification before store entry (100% vs 10%) and before purchase (100% vs 48%). Unlicensed shops displayed cartoon signage (57% vs 0%) and sold candy (53%), soda (57%), and energy drinks (48%). Both types were often near schools (75-76%). Health warnings were rare across both types (8-10%).","whyItMatters":"Youth access to cannabis is a primary concern of legalization. This study provides direct evidence that unlicensed retailers, which outnumber licensed ones in NYC, are failing to prevent youth access through lack of age verification and youth-oriented marketing.","specificNumbers":"37 retailers observed. Age verification before entry: 100% licensed vs 10% unlicensed. Before purchase: 100% vs 48%. Cartoon signage: 57% unlicensed vs 0% licensed. Near schools: 75-76% for both. Health warnings displayed: 8-10% for both.","methodology":"Secret shopper study observing 37 dispensaries and smoke shops (5 licensed medical, 7 licensed recreational, 10 unlicensed, 15 smoke shops) randomly selected from 840 outlets across NYC in November-December 2023. Audited age verification and business practices.","limitations":"Small sample in one city. Snapshot during early legalization. Secret shopper methodology captures one visit, which may not represent typical practices. Could not assess actual sales to minors."},{"rthcId":"RTHC-06032","title":"The association between cannabis and alcohol co-use and momentary subjective effects: Risks for increasingly hazardous cannabis use.","authors":"Bedillion, Margaret F; Ansell, Emily B","year":2025,"journal":"Drug and alcohol dependence, 269, 112595","doi":"10.1016/j.drugalcdep.2025.112595","pmid":"39970575","tags":["health-risks","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Co-use of cannabis and alcohol was associated with greater momentary intoxication compared to either substance alone, and greater stimulation and bad effects compared to cannabis alone. Using both within 30 minutes produced the strongest effects. Individuals who became more intoxicated during co-use had greater risk of increasingly hazardous cannabis use at 6 and 12 months.","whyItMatters":"Cannabis-alcohol co-use is common among young adults. Knowing that co-use amplifies intoxication and that the degree of amplification predicts future problematic use provides a basis for targeted harm reduction messaging.","specificNumbers":"155 young adults tracked over 12 months. Co-use produced greater intoxication than either substance alone. Co-use within 0-30 minutes produced the greatest stimulation and bad effects vs cannabis alone. Co-use within 0-90 min had higher intoxication vs cannabis alone. Co-use within 0-120 min had higher intoxication vs alcohol alone.","methodology":"Longitudinal study of 155 young adults (mean age 21, 55.5% women) who co-used cannabis and alcohol. Ecological momentary assessment (EMA) over 21 days at baseline captured real-time co-use and subjective effects. Follow-up assessments at 6 and 12 months measured hazardous cannabis use.","limitations":"Self-reported subjective effects via EMA. Relatively small sample. Cannot control for doses of each substance. Young adult sample may not generalize to older adults."},{"rthcId":"RTHC-06033","title":"Evaluating cannabidiol-induced liver injury with and without valproate using a three-dimensional human hepatocyte spheroid model.","authors":"Beers, Jessica L; Harvey, Shalon L; Lanphier, Raeanne M; Rushing, Blake R; McRitchie, Susan L; Sumner, Susan J; Jackson, Klarissa D","year":2025,"journal":"Toxicology in vitro : an international journal published in association with BIBRA, 109, 106126","doi":"10.1016/j.tiv.2025.106126","pmid":"40774642","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06034","title":"The impact of cannabis on immune checkpoint inhibitor therapy: a systematic review of immunomodulatory effects of cannabis in patients with and without cancer.","authors":"Behling-Hess, Caroline; Simonson, Grant; Salz, Talya; Fleege, Nicole; Zylla, Dylan","year":2025,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 33(3), 166","doi":"10.1007/s00520-025-09218-x","pmid":"39921765","tags":["cancer","medical-use","immune-system"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Analysis of 40 clinical studies (including 9 RCTs) found no change in cytokines, T-cell counts, or CRP in most studies with cannabis exposure. Among autoimmune disease patients, cannabis improved clinical symptoms while objective immune markers remained unchanged. Immune markers relevant to checkpoint inhibitor function did not appear associated with cannabis use.","whyItMatters":"Many cancer patients use cannabis for symptom management while receiving immunotherapy. Preclinical data suggesting cannabis causes immunosuppression has raised concerns, but this clinical review found no evidence that translates to meaningful immune changes in humans.","specificNumbers":"40 studies included, 9 RCTs. No change in cytokines, T-cell counts, or CRP in most studies. Clinical symptom improvement in autoimmune patients despite unchanged immune markers. No evidence of altered immune parameters relevant to ICI function.","methodology":"Systematic review searching Ovid Medline for clinical studies investigating cannabis use in humans and the immune system. Preclinical studies and case reports were excluded. Forty studies met criteria, including 9 randomized placebo-controlled trials.","limitations":"Most included studies were not specifically designed to assess cannabis-immunotherapy interactions. Heterogeneous cannabis exposure definitions. Few studies focused on cancer patients receiving ICIs specifically."},{"rthcId":"RTHC-06035","title":"Association of driving with blood delta-9-tetrahydrocannabinol: a systematic review.","authors":"Behzad, Danial; Zhao, Sampson; Besa, Reena; Brands, Bruna; Wickens, Christine M; Huestis, Marilyn A; Le Foll, Bernard; Di Ciano, Patricia","year":2025,"journal":"The international journal of neuropsychopharmacology, 28(4)","doi":"10.1093/ijnp/pyaf021","pmid":"40172477","tags":["driving","thc"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Of 12 studies meeting inclusion criteria, 10 found no significant linear correlations between blood THC and driving measures. Specifically: 8 of 9 for lateral control/weaving, 4 of 5 for speed, 2 of 3 for car following, 1 of 1 for reaction time, and 3 of 3 for overall driving performance showed no relationship. The two studies that did find associations involved complex driving situations.","whyItMatters":"Many jurisdictions use blood THC levels as evidence of impaired driving. If THC levels don't linearly predict driving performance, current enforcement approaches may not accurately identify impaired drivers.","specificNumbers":"4,845 records searched, 12 included. 10 of 12 found no linear THC-driving correlation. 8/9 for lateral control, 4/5 for speed, 2/3 for car following, 1/1 for reaction time, 3/3 for overall performance showed no relationship.","methodology":"Systematic review of published studies examining the linear relationship between blood THC levels and driving performance, primarily measured by simulated driving. Searched 4,845 records; 12 met inclusion criteria.","limitations":"Most studies used driving simulators, not real-world driving. Only 12 studies met criteria, indicating limited research in this area. Complex driving situations may reveal relationships that simple tasks miss."},{"rthcId":"RTHC-06036","title":"Does cannabis use substitute for opioids? A preliminary exploratory survey in opioid maintenance patients.","authors":"Bekier, Nina Kim; Frischknecht, Ulrich; Eidenmueller, Katharina; Grimm, Franz; Bach, Patrick; Stenger, Manuel; Kiefer, Falk; Hermann, Derik","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 565-572","doi":"10.1007/s00406-023-01718-3","pmid":"38502206","tags":["addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Sixty percent of opioid maintenance patients reported cannabis use. Of those, 72% used cannabis as a substitution strategy for other substances. Cannabis was most commonly used to replace heroin (44.8%) and benzodiazepines (16.4%). When asked to rate how well cannabis substituted for heroin (German school grades 1-6), the average was 2.6. Forty-seven percent used cannabis to reduce pain.","whyItMatters":"Rather than treating cannabis use in opioid patients as purely problematic, this study suggests many use it strategically as harm reduction, choosing a less dangerous substance over heroin or benzodiazepines.","specificNumbers":"118 patients surveyed. 60% used cannabis. 72% of users employed it as substitution. Heroin substitution: 44.8%. Benzodiazepine substitution: 16.4%. Heroin substitution rated 2.6/6. Pain management: 47%.","methodology":"Cross-sectional survey of 118 German opioid maintenance treatment patients using a questionnaire about cannabis use patterns, substitution motivations, self-medication purposes, and negative consequences.","limitations":"Small single-center sample in Germany. Self-reported data. Cross-sectional design cannot confirm that cannabis actually reduced other drug use. No comparison group of non-cannabis-using patients."},{"rthcId":"RTHC-06037","title":"Getting \"The whole picture\": A review of international research on the outcomes of regulated cannabis supply.","authors":"Belackova, Vendula; Petruzelka, Benjamin; Cihak, Jakub; Michailidu, Jana; Mravcik, Viktor","year":2025,"journal":"The International journal on drug policy, 142, 104796","doi":"10.1016/j.drugpo.2025.104796","pmid":"40393091","tags":["legalization"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Across the Netherlands, Spain, US legalization states, Uruguay, and Canada, consistent outcomes included decreased cannabis-related arrests, increased adult (but not adolescent) cannabis use, and increased healthcare utilization (not traffic-related). Negative health outcomes were most concentrated in US states. Evidence was limited for non-US jurisdictions.","whyItMatters":"With more countries considering cannabis regulation, comparing outcomes across different models helps identify which approaches minimize harms while achieving social benefits like reduced criminalization.","specificNumbers":"Five jurisdictions compared. Consistent outcomes: decreased arrests, increased adult use (not adolescent), increased non-traffic healthcare utilization. US states showed most negative health outcomes. Other jurisdictions had limited study designs or timeframes.","methodology":"Three-level systematic literature review assessing nine indicators across three domains (social, cannabis use, health-related) in five jurisdictions with different regulation models. Prioritized quasi-experimental studies and categorized by study design and outcome direction.","limitations":"Heterogeneity in regulation models makes direct comparison difficult. US states dominate the evidence base. Non-US jurisdictions had fewer rigorous studies and shorter follow-up periods. Could not fully distinguish between regulation model effects and other country-specific factors."},{"rthcId":"RTHC-06038","title":"Cannabis use among Dutch patients with a primary brain tumor.","authors":"Belgers, Vera; Rietveld, Niek A; de Witt Hamer, Philip C; Niers, Johanna M","year":2025,"journal":"Neuro-oncology practice, 12(4), 714-722","doi":"10.1093/nop/npaf009","pmid":"40814429","tags":["cancer","medical-use"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Fifty-one percent of brain tumor patients had ever used cannabis and 14% were current users. Nineteen percent used cannabis for tumor-related reasons, including symptom relief (74%) and presumed antitumor effects (42%). Patients preferred CBD over THC. Self-reported improvements included sleep, anxiety, worrying, and depressive symptoms. Common adverse effects were drowsiness, dry mouth, and dizziness.","whyItMatters":"Brain tumor patients face significant symptom burdens and limited treatment options. Understanding their cannabis use patterns and motivations can inform clinical conversations and identify areas needing evidence.","specificNumbers":"100 patients surveyed. 51% ever used cannabis. 14% current users. 19% used for tumor-related reasons. 74% for symptom relief, 42% for presumed antitumor effects. CBD preferred over THC. Sleep, anxiety, and depression most commonly improved.","methodology":"Cross-sectional survey of 100 adult primary brain tumor patients visiting the neuro-oncology outpatient clinic at Amsterdam UMC between August and October 2023.","limitations":"Small single-center sample in the Netherlands, where cannabis is relatively accessible. Self-reported effects without objective measurement. Cross-sectional design. Survey at a specialized center may not represent all brain tumor patients."},{"rthcId":"RTHC-06039","title":"The Effects of an Acute Dose of Cannabidiol on Health and Two-Mile Time Trial Performance-A Pilot Study.","authors":"Bell, Elyssa R; Elias, Brandon; Gutierrez, Seth M; Stewart, Laura K","year":2025,"journal":"Nutrients, 18(1)","doi":"10.3390/nu18010029","pmid":"41515147","tags":["cbd","exercise","mental-health"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"CBD has become popular among athletes for recovery and anxiety, but does it actually affect performance? This small crossover study gave 12 runners either 300 mg of CBD or placebo capsules two hours before a 2-mile treadmill time trial and measured everything from mood to physiology.\n\nThe mood findings were clear: CBD significantly increased feelings of calm (21% more than placebo) and relaxation (22% more). These are consistent with CBD's documented anxiolytic properties and could matter for athletes whose performance is limited by pre-competition anxiety.\n\nBut the performance measures told a different story — or rather, no story at all. There were no significant differences between CBD and placebo conditions for 2-mile time, heart rate during the run, rating of perceived exertion, blood lactate, blood pressure, or heart rate variability. CBD didn't help performance, but it didn't hurt it either.\n\nThe gastrointestinal symptom questionnaire after the run also showed no differences, addressing a practical concern about oral CBD and gut tolerance during exercise.\n\nWith only 12 participants, the study is underpowered to detect small effects. But the clear mood changes alongside the flat performance data suggest CBD's value for athletes may be psychological (pre-competition anxiety management) rather than physiological (endurance or recovery enhancement).","whyItMatters":"CBD is widely marketed to athletes and increasingly used in sports. The World Anti-Doping Agency removed CBD from its prohibited list in 2018. This pilot study provides some of the first controlled data on acute CBD effects during actual running performance — finding mood benefits without performance changes.","specificNumbers":"12 participants (4 male, 8 female). 300 mg CBD dose. Calm increased 21% (p=0.04) and relaxed increased 22% (p=0.02) vs placebo. No significant differences in 2-mile time, HR, RPE, blood lactate, BP, HRV, or GI symptoms between conditions.","methodology":"Randomized, crossover design with 12 runners (4 male, 8 female, mean age 25.5). Each participant completed two sessions: one with 300 mg oral CBD capsules and one with placebo, separated by a washout period. Two hours post-ingestion: State Trait Anxiety Inventory, resting blood pressure, heart rate, blood lactate, and HRV measured. Then a 2-mile treadmill time trial at maximum effort. Heart rate, RPE, and blood lactate measured during and after the run. GI symptom questionnaire post-run.","limitations":"Very small sample (12 participants). Acute single-dose study — chronic CBD use might produce different effects. 300 mg is a relatively high dose; lower doses common in commercial products might not even produce the mood effects seen here. Only tested 2-mile running; other exercise types (strength, HIIT, ultra-endurance) might respond differently. Two-hour absorption window may not be optimal for all individuals. No blood CBD levels measured to confirm absorption."},{"rthcId":"RTHC-06040","title":"Prevalence and Patterns of Substance Use Among Sexual and Gender Minority Young Adults Assigned Male at Birth and Their Relationship With Mental Health Problems.","authors":"Belloir, Joseph; Myers, Thomas; Scherr, Thomas; Almodovar, Michael; Kuhns, Lisa; Garofalo, Robert; Schnall, Rebecca","year":2025,"journal":"AIDS education and prevention : official publication of the International Society for AIDS Education, 37(6), 397-412","doi":"10.1521/aeap.2025.37.6.397","pmid":"41428494","tags":["addiction","mental-health","social-behavior"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis was among the most commonly used substances (alongside alcohol and tobacco) in this population. Cannabis use was significantly positively associated with both depression and anxiety in adjusted analyses. Alcohol was also associated with both outcomes, while methamphetamine was linked to depression and sedatives to anxiety.","whyItMatters":"Sexual and gender minority individuals face documented health disparities, and understanding the specific substance-mental health connections in this population can inform targeted interventions.","specificNumbers":"Cannabis, alcohol, and tobacco were the most used substances. Cannabis significantly associated with depression and anxiety. Adjusted analyses controlled for demographic variables.","methodology":"Cross-sectional analysis of data from a randomized clinical trial of a mobile health HIV testing intervention in the US. Linear regression adjusted for demographics examined associations between substance use and mental health outcomes among sexual and gender minority men.","limitations":"Cross-sectional design cannot determine causation. Data from an HIV testing trial may not represent all SGM young adults. Cannot distinguish whether cannabis use caused, resulted from, or simply co-occurred with mental health symptoms."},{"rthcId":"RTHC-06041","title":"Disparities in self-reported mental health, physical health, and substance use across sexual orientations in Canada.","authors":"Bellows, Zachary; Kim, Chungah; Bai, Yihong; Cao, Peiya; Chum, Antony","year":2025,"journal":"PloS one, 20(3), e0305019","doi":"10.1371/journal.pone.0305019","pmid":"40095997","tags":["addiction","social-behavior"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Lesbians and bisexual women had elevated odds of cannabis use compared to heterosexual women. Bisexual women showed the highest disparities across all outcomes (mental health OR=3.3, plus elevated binge drinking, illicit drugs, and cannabis). Gay and bisexual men and lesbians showed decreasing substance use trends over time (2009-2014).","whyItMatters":"Understanding which specific subgroups face the greatest health disparities allows for more targeted interventions. Bisexual women appear uniquely vulnerable, which aligns with research on biphobia and erasure in both heterosexual and LGBTQ+ spaces.","specificNumbers":"Weighted N=19.98 million. Bisexual women: OR=3.3 for poor mental health. Lesbians and bisexual women had elevated cannabis use. Gay/bisexual men and lesbians showed decreasing substance use 2009-2014.","methodology":"Analysis of 2009-2014 Canadian Community Health Surveys with a weighted sample of 19.98 million individuals. Logistic regression stratified by sex examined health disparities across sexual orientations, adjusted for covariates.","limitations":"Self-reported data. 2009-2014 data may not reflect current patterns. Sexual orientation categories were broad. Those answering \"don't know\" or \"refuse\" had reduced substance use odds, suggesting measurement complexity."},{"rthcId":"RTHC-06042","title":"Neuroprotective effects of G9a inhibition and cannabinoid receptor activation in Alzheimer's disease through a pharmacological approach.","authors":"Bellver-Sanchis, Aina; Ribalta-Vilella, Marta; Lillo, Jaume; Ortuño-Sahagún, Daniel; Franco, Rafael; Pallàs, Mercè; Navarro, Gemma; Griñán-Ferré, Christian","year":2025,"journal":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 22(5), e00616","doi":"10.1016/j.neurot.2025.e00616","pmid":"40450458","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06043","title":"The impact of socioeconomic factors on the incidence and characteristics of first-episode psychosis.","authors":"Belvederi Murri, Martino; Onofrio, Alice; Punzi, Chiara; Caranci, Nicola; Rubolino, Enrico; Giovinazzi, Francesco; Azzolina, Danila; Folesani, Federica; Grassi, Luigi; Tarricone, Ilaria; Starace, Fabrizio","year":2025,"journal":"Epidemiology and psychiatric sciences, 34, e45","doi":"10.1017/S2045796025100206","pmid":"40891007","tags":["psychosis","legalization"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Frequent cannabis use among teens (area-level) was associated with increased first-episode psychosis incidence (IRR=1.31). Cannabis use also increased the duration of untreated psychosis by an average of 12.9 months. Educational deprivation (IRR=1.15) and population density (IRR=1.14) also independently predicted FEP incidence.","whyItMatters":"This study goes beyond individual-level associations to show that community-level cannabis availability affects psychosis rates. The finding that cannabis delays treatment-seeking is particularly concerning for outcomes.","specificNumbers":"1,240 FEP cases across 331 municipalities. Cannabis use IRR for FEP: 1.31 (95% CrI: 0.98-1.82). Cannabis increased DUP by 12.9 months. Educational deprivation IRR: 1.15. Population density IRR: 1.14.","methodology":"Prospective analysis of 1,240 individuals aged 18-35 with first-episode psychosis from an early detection program in Emilia-Romagna, Italy. Area-level exposures from 331 municipalities were modeled using Bayesian hierarchical models informed by a directed acyclic graph for causal assumptions.","limitations":"Area-level cannabis use is a proxy that may not reflect individual exposure. The cannabis IRR confidence interval crossed 1.0 (0.98-1.82). Italian setting may not generalize. Ecological study cannot prove individual-level causation."},{"rthcId":"RTHC-06044","title":"The association between cannabis use and paranoia: Meta-analysis of experimental and observational studies.","authors":"Belvederi Murri, Martino; Catania, Salvatore; Centra, Sara; Folesani, Federica; Muscettola, Angela; Zerbinati, Luigi; Toffanin, Tommaso; Ferrara, Maria; Ossola, Paolo; Rossi, Rodolfo; Jannini, Tommaso; Caruso, Rosangela; Nanni, Maria Giulia; Grassi, Luigi","year":2025,"journal":"Neuroscience and biobehavioral reviews, 176, 106269","doi":"10.1016/j.neubiorev.2025.106269","pmid":"40578496","tags":["psychosis","mental-health","thc"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Five experimental studies showed that cannabinoid recipients developed more severe paranoia than placebo (SMD=0.47). THC-prevalent cannabinoids produced higher effects than mixed THC-CBD or CBD-prevalent products. In four general population cross-sectional studies, cannabinoid users had 75% higher odds of paranoid symptoms (OR=1.75). The effect was not significant in psychiatric patient samples. Three prospective studies suggested cannabis precedes paranoid symptom onset.","whyItMatters":"Paranoia is common and has significant social consequences. This meta-analysis provides converging evidence from both experimental (causal) and observational designs that cannabis, particularly THC-dominant products, can cause paranoid symptoms.","specificNumbers":"13 studies, 13,559 participants. Experimental SMD=0.47 (PPI=94%). General population OR=1.75 (PPI=99%). THC-dominant products had higher effects than CBD-containing ones. Effect increased with percentage of males. Not significant in psychiatric patient samples.","methodology":"Systematic review and Bayesian meta-analysis pooling data from 13 studies (n=13,559 participants). Used Bayesian Model-Averaged Meta-Analysis, hierarchical models, and Robust Bayesian Meta-Analysis. Searched PubMed from inception to July 2023.","limitations":"Relatively few studies included (13). Bayesian approach handles small samples well but results depend on prior assumptions. Could not fully assess dose-response. Psychiatric patient samples showed no effect, suggesting the general population drives the association."},{"rthcId":"RTHC-06045","title":"Dazed and confused: variability in reported and measured tetrahydrocannabinol content in cannabis edibles.","authors":"Beneke, Laura Lee; Kyle, Patrick B; Benton, J Barnes; Maready, Matthew","year":2025,"journal":"Clinical toxicology (Philadelphia, Pa.), 63(11), 981-986","doi":"10.1080/15563650.2025.2559183","pmid":"41025251","tags":["dosing","health-risks","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Significant discrepancies were found between labeled and measured THC content. Products contained between 288 mg less and 5,491 mg more THC than advertised. Three products of the same brand had delta-8-THC differences of 1,542, 719, and 5,491 mg. No CBD was detected in any product despite some labeling it.","whyItMatters":"Inaccurate labeling means consumers cannot reliably dose cannabis edibles. A product containing 5,491 mg more THC than labeled poses serious overdose risk, particularly for inexperienced users or children who accidentally ingest them.","specificNumbers":"12 products tested. THC discrepancies ranged from -288 mg to +5,491 mg. Same-brand variation in delta-8-THC: 1,542, 719, and 5,491 mg differences. Zero CBD detected in any product.","methodology":"Twelve cannabis edible packages purchased from local dispensaries and convenience stores in Jackson, Mississippi were analyzed using gas chromatography-mass spectrometry to quantify CBD, delta-8-THC, and delta-9-THC content.","limitations":"Small sample (12 products) from one city. Mississippi's cannabis market may not represent other states. Single time point testing. Products from convenience stores may not be from regulated supply chains."},{"rthcId":"RTHC-06046","title":"Synthesis and Pharmacological Characterization of a Novel Cannabinoid Receptor 1 Antagonist.","authors":"Bengoetxea de Tena, Iker; Pereira-Castelo, Gorka; Martínez-Gardeazabal, Jonatan; Moreno-Rodríguez, Marta; Manuel, Iván; Martínez, Claudio; Vaz, Belén; González-Ricarte, Javier; Álvarez, Rosana; Torres-Mozas, Angel; Peccati, Francesca; Jiménez-Osés, Gonzalo; Rodríguez de Lera, Angel; Rodríguez-Puertas, Rafael","year":2025,"journal":"ACS omega, 10(22), 22747-22759","doi":"10.1021/acsomega.4c11355","pmid":"40521518","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06047","title":"Self-perceived impact of COVID-19 and risk behaviors among adolescents: Results from the HBSC 2021/22 study in 21 European countries.","authors":"Berchialla, Paola; Canale, Natale; Kilibarda, Biljana; Comoretto, Rosanna Irene; Alexandrova-Karamanova, Anna; Baška, Tibor; Ter Bogt, Tom; Vieno, Alessio; Charrier, Lorena","year":2025,"journal":"Addictive behaviors, 163, 108238","doi":"10.1016/j.addbeh.2024.108238","pmid":"39826374","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Fourteen percent of adolescents were classified as negatively impacted by COVID, with this group overrepresented among girls, older teens, and less affluent families. Negatively impacted adolescents had higher risk of cannabis use, smoking, and drunkenness compared to positively impacted peers. Countries with highest negative impact rates included Hungary, Cyprus, Greece, and Poland (>25%).","whyItMatters":"This 21-country study shows that subjective pandemic experience, not just objective exposure, predicted substance use. Understanding that self-perceived negative impact drives risk behaviors can inform future crisis response targeting vulnerable youth.","specificNumbers":"106,221 adolescents from 21 countries. 14% negatively impacted, 42% positively impacted, 44% neutral. Negatively impacted group had higher cannabis, smoking, and drunkenness risk. Highest negative impact: Hungary, Cyprus, Greece, Poland (>25%).","methodology":"Analysis of 106,221 adolescents aged 11-15 from the 2021/22 HBSC study across 21 European countries. Multilevel Generalized Latent Class Analysis identified groups by perceived pandemic impact, then examined substance use as outcomes.","limitations":"Cross-sectional design collected in 2021/22 captures a single time point. Self-reported substance use and pandemic impact. Cannot determine whether negative impact caused substance use or vice versa. Country-level variation may reflect cultural differences in reporting."},{"rthcId":"RTHC-06048","title":"Concomitant use of medical cannabis and drugs associated with risks of interaction in older patients: a longitudinal cohort study.","authors":"Bérété, Zoumana Cheick; Sebgo, Arvis Abraham; Eurich, Dean T; Dubois, Cerina; Dyck, Jason R; Hanlon, John G; Zongo, Arsene","year":2025,"journal":"Age and ageing, 54(12)","doi":"10.1093/ageing/afaf359","pmid":"41396801","tags":["drug-interactions","medical-cannabis","seniors"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"The drug interaction studies in the laboratory (RTHC-00091, RTHC-00104) have shown that cannabinoids inhibit liver enzymes that metabolize many medications. The systematic review (RTHC-00123) found 31 documented cases. But the critical missing piece has been large-scale, real-world evidence of whether these interactions actually harm patients in clinical practice. This study provides it.\n\nUsing clinical and administrative data from 12,599 Ontario seniors who received authorized cannabis prescriptions between 2014 and 2019, the researchers first examined whether getting a cannabis prescription changed patients' other medication patterns. It didn't — dispensations of drugs associated with significant clinical interaction risk (DARSCIC) were similar in the year before and after cannabis prescription.\n\nThen they looked at actual clinical outcomes. Among 378 patients exposed to both cannabis and warfarin, the rate of bleeding events was higher compared to controls. This is the finding that moves the drug interaction concern from theoretical to clinical: cannabis plus warfarin appears to increase bleeding risk in real patients at the population level.\n\nThe study also examined intoxication events in patients taking cannabis with other narrow-therapeutic-index drugs (DNTI), and cardiovascular events, providing a broader safety picture.\n\nThis is exactly the kind of pharmacovigilance data that's been missing — not a case report of one patient, but a population-level analysis showing that the enzyme inhibition demonstrated in the lab translates to measurable clinical harm at scale.","whyItMatters":"This is the first large-scale, real-world pharmacoepidemiological study of cannabis drug interactions in older adults. It transforms the interaction concern from laboratory finding to documented population-level clinical harm. For the growing number of seniors using medical cannabis alongside multiple prescription medications, this data quantifies a risk that was previously only theoretical.","specificNumbers":"12,599 Ontario seniors with authorized cannabis prescriptions (2014-2019). 378 patients co-exposed to cannabis and warfarin. Bleeding events were higher in the cannabis + warfarin group vs controls. DARSCIC dispensation patterns were similar before and after cannabis prescription (patients didn't change their other medications).","methodology":"Two-part study design. Part 1: Interrupted time series analysis of 12,599 Ontario seniors prescribed medical cannabis (2014-2019), examining dispensation trends for drugs with significant interaction risk before and after cannabis prescription. Part 2: Longitudinal cohort studies comparing outcomes in patients co-exposed to cannabis + warfarin (bleeding) and cannabis + DNTI (intoxication) versus unexposed controls.","limitations":"Observational study — confounding is possible despite the use of controls. Cannabis prescriptions don't guarantee actual use, and adherence to medical cannabis varies. The interaction risk may be higher in real-world use where patients self-titrate. Ontario-specific administrative data may not generalize to other healthcare systems. Cannabis products used (THC-dominant, CBD-dominant, balanced) aren't specified, though the interaction profile differs by cannabinoid. The 2014-2019 period may not reflect current prescribing patterns."},{"rthcId":"RTHC-06049","title":"State Nonmedical Cannabis Laws and U.S. Young Adults' Cannabis-Related Experiences.","authors":"Berg, Carla J; Ruchelli, Sabrina; Platt, Elizabeth; Cavazos-Rehg, Patricia; Romm, Katelyn F; Wang, Yan; LoParco, Cassidy R; Cui, Yuxian; Yang, Y Tony; Szlyk, Hannah S; Burris, Scott","year":2025,"journal":"American journal of preventive medicine, 69(3), 107939","doi":"10.1016/j.amepre.2025.107939","pmid":"40513917","tags":["legalization","driving","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Retail license limits were associated with fewer retailer visits. Billboard ad restrictions reduced billboard ad exposure. Driving-related warnings in ads were associated with less driving after use. Restricting health claims reduced exposure to claims. However, many other laws (online advertising restrictions, required warnings on risk perceptions) showed no significant associations with targeted outcomes.","whyItMatters":"As states experiment with cannabis regulation, understanding which specific laws actually change behavior is essential for evidence-based policy. This study provides one of the first assessments of specific regulatory provisions and their real-world effects.","specificNumbers":"1,847 participants in 19 states. License limits associated with fewer visits. Billboard bans reduced exposure. Driving warnings reduced driving after use. Zoning near youth facilities associated with minimum-age signage. No effect for online advertising restrictions or risk perception warnings.","methodology":"Surveys of 1,847 US young adults in 19 states with nonmedical cannabis retail (June-November 2023). Three categories of laws examined: operational restrictions, advertising restrictions, and required warnings. Multivariable analyses linked specific laws to relevant behavioral outcomes.","limitations":"Cross-sectional design cannot prove laws caused behavior changes. Self-reported outcomes. Cannot account for industry compliance levels. Limited to young adults in states with nonmedical retail."},{"rthcId":"RTHC-06050","title":"Cannabis use characteristics and associations with problematic use outcomes, quitting-related factors, and mental health among US young adults.","authors":"Berg, Carla J; LoParco, Cassidy R; Romm, Katelyn F; Cui, Yuxian; McCready, Darcey M; Wang, Yan; Yang, Y Tony; Szlyk, Hannah S; Kasson, Erin; Chakraborty, Rishika; Cavazos-Rehg, Patricia A","year":2025,"journal":"Substance abuse treatment, prevention, and policy, 20(1), 1","doi":"10.1186/s13011-025-00634-0","pmid":"39799369","tags":["addiction","mental-health","driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Four cannabis use classes emerged: infrequent-herb/edibles (41.4%), moderate-herb (28.0%), frequent-herb (16.8%), and moderate-oil/other (13.8%). The moderate-oil/other group reported the most problematic use, worst mental health, lowest quitting confidence, and highest odds of driving after cannabis-alcohol co-use (AOR=3.98). Paradoxically, frequent-herb users reported less problematic use than moderate-herb users.","whyItMatters":"Not all cannabis use is the same. The type of product matters as much as frequency, with oil and concentrate users showing a distinct risk profile that warrants targeted prevention messaging.","specificNumbers":"4,031 young adults, 48.8% past-month use. Moderate-oil/other (13.8%): highest problematic use (B=0.39), lowest quitting confidence (B=-1.27), most mental health symptoms (B=1.03), driving after co-use AOR=3.98. Frequent-herb reported less problematic use than moderate-herb (B=-0.18).","methodology":"Latent class analysis of 2023 survey data from 4,031 US young adults (mean age 26.3, 48.8% past-month use). Indicators included days used, frequency per day, and type usually used. Regressions examined class associations with problematic use, quitting factors, and mental health.","limitations":"Cross-sectional design. Self-reported measures. Cannot determine whether product type drives risk or whether risk-prone individuals select certain products. Young adult sample may not generalize."},{"rthcId":"RTHC-06051","title":"A within-subject, double-blind, placebo-controlled randomized evaluation of the combined effects of cannabidiol and hydromorphone in a human laboratory pain model.","authors":"Bergeria, Cecilia L; Mun, Chung Jung; Speed, Traci J; Huhn, Andrew S; Wolinsky, David; Vandrey, Ryan; Campbell, Claudia M; Dunn, Kelly E","year":2025,"journal":"Pain, 166(9), e175-e184","doi":"10.1097/j.pain.0000000000003561","pmid":"40839659","tags":["cbd","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"When combined with hydromorphone (which alone did not reliably produce analgesia), CBD increased analgesic effects for some acute pain measures but not chronic pain models. At 50 mg, CBD enhanced analgesia without additional adverse effects. At 200 mg, there were concurrent increases in self-reported \"bad effects.\" CBD also mitigated the psychomotor impairment caused by hydromorphone alone.","whyItMatters":"If low-dose CBD can enhance opioid analgesia, patients might need lower opioid doses, reducing addiction risk. The finding that CBD also reduced opioid-related psychomotor impairment adds a potential safety benefit.","specificNumbers":"31 participants. 5 drug conditions. Hydromorphone 4mg + CBD 0, 50, 100, or 200mg. 50mg CBD enhanced acute analgesia without bad effects. 200mg CBD increased both analgesia and bad effects. CBD mitigated hydromorphone-induced psychomotor impairment.","methodology":"Within-subjects, double-blind, double-dummy, randomized human laboratory trial with 31 healthy participants. Five conditions: placebo+placebo, hydromorphone+placebo, hydromorphone+50mg CBD, hydromorphone+100mg CBD, hydromorphone+200mg CBD. Quantitative sensory testing, subjective drug effects, and psychomotor assessments at multiple time points.","limitations":"Small sample (n=31) of healthy volunteers, not chronic pain patients. Laboratory pain models may not reflect clinical pain. Single-dose design. Effects of repeated dosing are unknown."},{"rthcId":"RTHC-06052","title":"Type-1 Cannabinoid Receptor Promiscuous Coupling: Computational Insights into Receptor-G Protein Interaction Dynamics.","authors":"Berghella, Alessandro; Stepniewski, Tomasz Maciej; Sabatucci, Annalaura; Lopez-Balastegui, Marta; Nowicki, Krzysztof; Dufrusine, Beatrice; Selent, Jana; Dainese, Enrico","year":2025,"journal":"International journal of molecular sciences, 26(24)","doi":"10.3390/ijms262411905","pmid":"41465331","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06053","title":"Endocannabinoid and N-acylethanolamine concentrations in hair of female patients with posttraumatic stress disorder - associations with clinical symptoms and outcomes following multimodal trauma-focused inpatient treatment.","authors":"Bergunde, L; Woud, M L; Shkreli, L; Schindler-Gmelch, L; Garthus-Niegel, S; Blackwell, S E; Kirschbaum, C; Kessler, H; Steudte-Schmiedgen, S","year":2025,"journal":"Translational psychiatry, 15(1), 312","doi":"10.1038/s41398-025-03476-3","pmid":"40849292","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06054","title":"The Endocannabinoid System in Retinal Müller Glia: Lessons From Astrocyte Research.","authors":"Beriain, Sandra; Fernandez-Moncada, Ignacio; Pereiro, Xandra; Eraso-Pichot, Abel; Vecino, Elena; Marsicano, Giovanni","year":2025,"journal":"Neurochemical research, 50(4), 206","doi":"10.1007/s11064-025-04457-0","pmid":"40553186","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06055","title":"Formation of endocannabinoids and endocannabinoid-like compounds in sausages: Effect of fermentation, heat treatment and storage.","authors":"Berk Aydın, Ecem; Yılmaz, Cemile; Gökmen, Vural","year":2025,"journal":"Food research international (Ottawa, Ont.), 218, 116926","doi":"10.1016/j.foodres.2025.116926","pmid":"40790707","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06056","title":"Brief Drug Interventions Delivered in General Medical Settings: a Systematic Review and Meta-analysis of Cannabis Use Outcomes.","authors":"Berny, Lauren M; Nichols, Lindsey M; Schweer-Collins, Maria L; Tanner-Smith, Emily E","year":2025,"journal":"Prevention science : the official journal of the Society for Prevention Research, 26(6), 985-998","doi":"10.1007/s11121-025-01826-7","pmid":"40627282","tags":["addiction","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 17 RCTs, brief drug interventions showed no significant short-term effects on cannabis use (OR=1.20), consumption level (g=0.01), or severity (g=0.13). Long-term effects were also non-significant. However, sensitivity analyses found that interventions delivered specifically in emergency departments showed small but significant reductions in long-term cannabis consumption.","whyItMatters":"Brief interventions work well for alcohol, so they have been widely adapted for cannabis. This meta-analysis shows they are not effective for cannabis in most medical settings, redirecting efforts toward settings (like EDs) where they may work.","specificNumbers":"17 RCTs synthesized. Short-term cannabis use: OR=1.20 (NS). Short-term consumption: g=0.01 (NS). Short-term severity: g=0.13 (NS). Long-term use: OR=1.19 (NS). Long-term consumption: g=0.04 (NS). ED-delivered interventions showed small significant long-term effect.","methodology":"Systematic review and meta-analysis of 17 randomized controlled trials comparing brief drug interventions to control conditions in general medical settings. Mixed effects meta-regression examined variability across intervention characteristics including booster sessions, delivery setting, target, and population.","limitations":"Heterogeneity in intervention designs across studies. Some trials had small sample sizes. Could not fully assess all potential moderators. The ED finding came from sensitivity analyses and needs confirmation."},{"rthcId":"RTHC-06057","title":"Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.","authors":"Berry-Kravis, Elizabeth; Hagerman, Randi; Cohen, Jonathan; Budimirovic, Dejan; Buchanan, Caroline B; Silove, Natalie; Tich, Nancy; Thibodeau, Anthony; Dobbins, Thomas; Sebree, Terri; O'Quinn, Stephen; Albers, David S; Bzdek, Kristen G; Nomikos, George; Budur, Kumar","year":2025,"journal":"Journal of neurodevelopmental disorders, 17(1), 69","doi":"10.1186/s11689-025-09657-x","pmid":"41254489","tags":["cbd","medical-use"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Over a mean exposure of 28 months, treatment-related adverse events occurred in 12.9% of patients, with application site pain being most common (6.7%). The worst skin reaction was moderate redness in 2.9%. Secondary analyses showed clinically meaningful improvements in social avoidance, irritability, and overall behavior as rated by caregivers.","whyItMatters":"Fragile X syndrome has limited treatment options for behavioral symptoms. Long-term safety data for CBD in this pediatric population is essential for clinical development, and the behavioral improvements suggest potential efficacy.","specificNumbers":"240 patients enrolled. Mean age 9.7 years. 76.3% male. Mean exposure 28 months. Treatment-related AEs: 12.9%. Application site pain: 6.7%. Moderate erythema: 2.9%. Clinically meaningful improvements in social avoidance, irritability, and caregiver global impression.","methodology":"Interim analysis of an ongoing open-label extension safety trial (ZYN2-CL-017) of transdermal CBD gel (ZYN002) in 240 patients with Fragile X syndrome enrolled from two completed clinical trials. Mean age 9.7 years, 76.3% male. Safety was the primary outcome.","limitations":"Open-label design without a control group in the extension phase. Cannot separate drug effects from natural maturation or placebo effects for behavioral measures. Predominantly White male sample."},{"rthcId":"RTHC-06058","title":"The detection of cannabinoids in breath after ingestion of cannabis-infused edibles.","authors":"Bery, Jennifer L; Brooks-Russell, Ashley; Lovestead, Tara M; Jeerage, Kavita M","year":2025,"journal":"Journal of analytical toxicology, 49(9), 673-680","doi":"10.1093/jat/bkaf063","pmid":"40638229","tags":["thc","dosing","driving"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"19 of 29 participants showed a THC concentration peak in breath at 47, 92, or 180 minutes after eating a cannabis edible, while 6 had their highest reading before ingestion and 4 showed no significant change.","whyItMatters":"Breath-based cannabis testing is being explored as a roadside impairment tool, but almost all prior research focused on smoked cannabis. This is the first study examining whether edibles produce detectable breath THC changes, which is critical since edible use is growing.","specificNumbers":"19 of 29 participants peaked at 47, 92, or 180 min; 6 had highest THC before ingestion; 4 showed no change; 5 additional cannabinoids detected; CBD trends sometimes diverged from THC trends","methodology":"29 participants ate cannabis edibles and provided breath samples at baseline plus three post-ingestion timepoints using one of two sampling devices. Five cannabinoids beyond THC were also measured.","limitations":"Small sample (29 participants), only three post-ingestion timepoints over 180 minutes, most participants had THC in pre-use breath samples suggesting prior use, only one edible dose tested"},{"rthcId":"RTHC-06059","title":"Protective Role of CBD Against Nicotine Pouch-Induced Seizure Aggravation and Alterations in Brain Glymphatic Biomarkers.","authors":"Bhandari, Bidhan; Naeini, Sahar Emami; Rogers, Hannah M; Alhashim, Abdullah Hassan; Yu, Jack C; Seyyedi, Mohammad; Young, Nancy; El-Marakby, Ahmed; Salles, Évila Lopes; Wang, Lei P; Baban, Babak","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","doi":"10.1093/ntr/ntaf253","pmid":"41384771","tags":["cbd","epilepsy","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Seven days of nicotine pouch exposure significantly worsened seizure severity, raised brain inflammation markers (IL-6, HMGB1), and impaired the brain's waste-clearance system in mice. Inhaled CBD reversed seizure severity, restored brain water channels, and normalized inflammatory markers.","whyItMatters":"Nicotine pouches are surging in popularity, especially among young people, with unknown neurological consequences. This study suggests chronic use may increase seizure vulnerability through brain inflammation and impaired waste clearance, while CBD may counteract these specific pathways.","specificNumbers":"Acute nicotine transiently reduced seizure severity; chronic exposure significantly worsened it; CBD restored AQP4 (water channel) expression, normalized IL-6 and HMGB1 levels, and reduced c-FOS protein expression","methodology":"Mice received acute or 7-day chronic nicotine pouch exposure before seizures were chemically induced. Researchers measured seizure severity, brain inflammation markers, neuronal activation, and glymphatic (brain waste clearance) function. CBD was delivered via inhalation.","limitations":"Mouse model may not translate to humans, chemically induced seizures differ from naturally occurring epilepsy, short exposure duration (7 days), nicotine pouch dosing may not reflect human use patterns"},{"rthcId":"RTHC-06060","title":"Cannabis Use in Adolescents.","authors":"Bhangu, Gurkirat K; Singh, Aakanksha; Shah, Avni; Malhi, Narpinder","year":2025,"journal":"Delaware journal of public health, 11(3), 6-13","doi":"10.32481/djph.2025.09.03","pmid":"41035729","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06061","title":"Evaluation of tetrahydropyridazine-based peripherally restricted dual inhibitors of CB1R and inducible nitric oxide synthase (iNOS) for treating metabolic syndrome disorders.","authors":"Bhattacharjee, Pinaki; Dvorácskó, Szabolcs; Pointeau, Océane; Kundu, Biswajit; Rutland, Nicholas; Puhl, Henry; Liu, Jie; Godlewski, Grzegorz; Hassan, Sergio A; Jourdan, Tony; Cinar, Resat; Iyer, Malliga R","year":2025,"journal":"Metabolism: clinical and experimental, 170, 156291","doi":"10.1016/j.metabol.2025.156291","pmid":"40368157","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06062","title":"Probing the dual burden: assessing psychological distress and substance use among female sex workers in Sonagachi, Kolkata, West Bengal, India.","authors":"Bhattacharya, Monali; Chandrasekaran, Varalakshmi; Arhanthabailu, Praveen; Ashok, Lena","year":2025,"journal":"Annali di igiene : medicina preventiva e di comunita, 37(6), 718-729","doi":"10.7416/ai.2025.2706","pmid":"40249713","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06063","title":"Exploring multitarget molecular mechanisms of cannabidiol in Alzheimer's disease treatment using molecular simulations and modeling.","authors":"Bi, Xiangyun; Xiao, Xuewen; Zhou, Lu; Liu, Qianqian; Liu, Yiliang; Tu, Qiuyun; Zhou, Yafang","year":2025,"journal":"Journal of Alzheimer's disease : JAD, 108(3), 1287-1301","doi":"10.1177/13872877251386440","pmid":"41105605","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06064","title":"Kynurenine amplifies tetrahydrocannabinol-induced sensorimotor impairment and classic \"tetrad\" effects in mice.","authors":"Bilel, Sabrine; Corli, Giorgia; Tiziani, Edoardo; Chirenti, Daniele; Dall'Acqua, Stefano; Comai, Stefano; Ferraro, Luca; Marti, Matteo; Beggiato, Sarah","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 138, 111342","doi":"10.1016/j.pnpbp.2025.111342","pmid":"40139338","tags":["thc","psychosis","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice given kynurenine before THC showed significantly worse sensorimotor responses, greater motor impairment, and deeper hypothermia compared to THC alone. Kynurenine also increased blood levels of THC and its psychoactive metabolite 11-OH-THC.","whyItMatters":"The kynurenine pathway is dysregulated in schizophrenia, and THC can worsen psychotic symptoms. This study suggests a biological mechanism linking the two: elevated kynurenine may amplify THC's effects, potentially explaining why people with schizophrenia are especially vulnerable to cannabis-related harm.","specificNumbers":"Brain kynurenic acid levels significantly increased 1 hour after kynurenine administration; THC and 11-OH-THC plasma levels were higher in kynurenine-pretreated mice; kynurenine amplified THC effects on motor tests (bar test, drag test, rotarod) and hypothermia but not pain response","methodology":"Adult male mice received THC (30 mg/kg) and kynurenine (20 mg/kg) alone or combined. Researchers measured body temperature, pain responses, motor activity, sensorimotor function, brain kynurenic acid levels, and plasma THC concentrations.","limitations":"Male mice only, high THC dose (30 mg/kg), kynurenine-THC interaction may be partly pharmacokinetic rather than pharmacodynamic, cannot confirm mechanism applies to humans"},{"rthcId":"RTHC-06065","title":"Cannabinoids as Potential Therapeutic Agents in the Treatment of Pancreatic Cancer.","authors":"Bimonte, Sabrina; Nocerino, Davide; Crisci, Marco; Schiavo, Daniela; Albino, Vittorio; Marchesini, Maurizio; Cuomo, Arturo","year":2025,"journal":"Anticancer research, 45(7), 2719-2728","doi":"10.21873/anticanres.17642","pmid":"40578954","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06066","title":"Prevalence and factors associated with alcohol and substance use among secondary school adolescents in central and Eastern Uganda: a cross-sectional study.","authors":"Bing, Wentrell; Abbo, Catherine; Dickson-Gomez, Julia; Kiconco, Arthur; Odokonyero, Felix Raymond; Bobholz, Max; Shour, Abdul R; Kasasa, Simon; Kabanda, Richard; Kalani, Kenneth; Cassidy, Laura D; Anguzu, Ronald","year":2025,"journal":"BMC public health, 26(1), 252","doi":"10.1186/s12889-025-25944-7","pmid":"41398236","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Male adolescents had 2.2 times the odds of marijuana use compared to females (AOR 2.21). Having a history of mental illness nearly tripled the odds (AOR 2.87). Urban school attendance more than doubled the odds of substance-related impairment (AOR 2.37).","whyItMatters":"Most adolescent substance use research comes from high-income countries. This large study from Uganda provides data on cannabis use patterns in a context where legalization debates are less prominent but adolescent vulnerability remains a concern.","specificNumbers":"2.6% marijuana use prevalence (n=46 of 1,833); 3.0% alcohol; 1.7% tobacco; 6.2% any substance impairment; mean age 15.1 years; 60% female; male sex AOR 2.21 for marijuana; mental illness history AOR 2.87 for marijuana, 2.69 for alcohol","methodology":"Cross-sectional survey of 1,833 adolescents aged 10-18 from eight secondary schools in two Ugandan districts, using the Child and Adolescent Symptom Inventory-5. Schools were stratified by ownership and geographic setting. Logistic regression identified independent predictors.","limitations":"Cross-sectional design cannot determine causation, convenience sampling from only two districts, self-report measures subject to social desirability bias, relatively low prevalence limits statistical power for subgroup analyses"},{"rthcId":"RTHC-06067","title":"Chemometric Optimization of BF3·OEt2-Mediated Cyclization of Cannabidiol to Rare Δ⁴- and Iso-THC Isomers.","authors":"Bini, Arianna; Magnaghi, Lisa Rita; Cavalloro, Valeria; Bonanni, Alessandra; Protti, Stefano; Merli, Daniele","year":2025,"journal":"Chemistry (Weinheim an der Bergstrasse, Germany), 31(66), e02387","doi":"10.1002/chem.202502387","pmid":"41163562","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06068","title":"Substance use assessment: comparing self-reports with objective data in a research setting.","authors":"Binkowska, Alicja Anna; Pałczyński, Piotr; Jakubowska, Natalia; Czarny, Jakub; Raczkowski, Michał; Brzezicka, Aneta","year":2025,"journal":"Frontiers in public health, 13, 1628519","doi":"10.3389/fpubh.2025.1628519","pmid":"41602091","tags":["dosing","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"21.3% of 75 participants underreported use of at least one substance (negative self-report but positive hair test). For cannabis specifically, self-reported frequency and quantity predicted THC detection in hair, but years of use and time since last use did not.","whyItMatters":"Cannabis research depends heavily on self-reported use, but this study shows that more than one in five people may deny use that biological testing confirms. This has direct implications for how we interpret survey-based cannabis research.","specificNumbers":"21.3% underreported at least one substance; moderate-to-large effect sizes observed for MDMA and cocaine discordance; cannabis use frequency and quantity predicted THC hair detection; years of use and time since last use did not predict detection","methodology":"75 adults completed substance use questionnaires and provided hair samples analyzed by liquid chromatography-mass spectrometry for drug detection over the prior 3 months. Underreporting was defined as denying use while testing positive.","limitations":"Small sample (75 participants), hair testing has its own limitations (can miss very light use, affected by hair treatments), no data on why participants underreported, single timepoint"},{"rthcId":"RTHC-06069","title":"Cannabidiol (CBD) and cognitive function in older adults: a mini review.","authors":"Binkowska, Alicja Anna; Mateja, Agnieszka; Jakubowska, Natalia","year":2025,"journal":"Frontiers in psychiatry, 16, 1646151","doi":"10.3389/fpsyt.2025.1646151","pmid":"40950765","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06070","title":"Unlocking the resorption potential of cannabidiolic acid: A comprehensive in vitro and in vivo bioavailability study.","authors":"Binova, Zuzana; Kucerova, Emilie; Nejedly, Tomas; Viktorova, Jitka; Cahova, Monika; Benes, Frantisek; Maly, Matej; Maly, Martin; Stupak, Michal; Kastanek, Petr; Hajslova, Jana; Stranska, Milena","year":2025,"journal":"International journal of pharmaceutics, 684, 126110","doi":"10.1016/j.ijpharm.2025.126110","pmid":"40858181","tags":["cbd","dosing"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBDA plasma concentrations in mice were approximately two orders of magnitude (100x) higher than CBD under identical dosing conditions. Nanomicelle encapsulation improved bioavailability for both compounds in vitro and in vivo.","whyItMatters":"CBD products dominate the consumer market, but this study suggests the naturally occurring acid form (CBDA, found in raw cannabis) may be absorbed far more efficiently. This could change how cannabinoid products are formulated and dosed.","specificNumbers":"CBDA plasma levels approximately 100x higher than CBD at the same dose; 10 cannabinoids and cannabinoid acids tested; nanomicelle encapsulation improved bioavailability; UHPLC-HRMS/MS analysis used","methodology":"Researchers tested 10 cannabinoids and cannabinoid acids using an in vitro intestinal cell model (Caco-2) and an in vivo mouse model. They also tested CBD and CBDA encapsulated in nanomicelles. Analysis used ultra-high performance liquid chromatography with mass spectrometry.","limitations":"Mouse model may not reflect human absorption, single dose tested, long-term effects of CBDA vs CBD not compared, nanomicelle formulation adds complexity, in vivo results from inbred mouse strain"},{"rthcId":"RTHC-06071","title":"Pharmacokinetics of Cannabidiol in Rat Brain Tissue After Single-Dose Administration of Different Formulations.","authors":"Binova, Zuzana; Benes, Frantisek; Zlechovcova, Marie; Maly, Matej; Kastanek, Petr; Cahova, Monika; Stranska, Milena; Hajslova, Jana","year":2025,"journal":"Molecules (Basel, Switzerland), 30(13)","doi":"10.3390/molecules30132676","pmid":"40649195","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06072","title":"Molecular pathogenesis of Alzheimer's disease onset in a mouse model: effects of cannabidiol treatment.","authors":"Bishara, Mary A; Chum, Phoebe P; Miot, Fritz E L; Hooda, Ankita; Hartman, Richard E; Behringer, Erik J","year":2025,"journal":"Frontiers in neuroscience, 19, 1667585","doi":"10.3389/fnins.2025.1667585","pmid":"40979532","tags":["cbd","cognition","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"RNA sequencing identified over 1,000 differentially expressed markers of Alzheimer's disease onset in mice. CBD treatment (80-100 mg/kg/day for 2 months) either eliminated or reversed the expression direction of more than 75% of these markers, spanning pathways including synaptic development, neurovascular interactions, mitochondrial function, and immunity.","whyItMatters":"Most Alzheimer's treatments target one or two pathways. This study suggests CBD simultaneously affects dozens of pathways involved in disease onset, from inflammation and oxidative stress to synaptic plasticity and lipid metabolism, a breadth of action that single-target drugs cannot match.","specificNumbers":"Over 1,000 differentially expressed markers of AD onset identified; more than 75% eliminated or reversed by CBD; 80-100 mg/kg/day dose; treatment from 4.5 to 6.5 months of age; pathways affected include Foxp2 (synaptic), Smad9/Angptl6 (neurovascular), Gria4/Chrna2 (receptors), Ndufa7/Cox7a2 (mitochondrial)","methodology":"Male 3xTg-AD mice and wild-type controls received daily dietary CBD (80-100 mg/kg/day) from 4.5 to 6.5 months of age. Researchers used RNA sequencing on blood and brain samples, metabolomics on brain regions, and behavioral assessments.","limitations":"Mouse model (3xTg-AD) does not fully replicate human Alzheimer's, male mice only, high CBD dose relative to human equivalents, treatment started before full disease development, no long-term follow-up beyond 2 months"},{"rthcId":"RTHC-06073","title":"Cannabidiol regulates apoptosis and glial cells homeostasis in the prefrontal cortex of offspring from obese rat mothers.","authors":"Bitencourt, Yasmin Meireles; da Silva Rodrigues, Fernanda; de Farias Fraga, Gabriel; Jantsch, Jeferson; Wickert, Fernanda; da Silva Dias, Victor; de Matos, Sheila Parnoff; Reiter, Keli Cristine; Rizzotto, Giuliano; Giovenardi, Márcia; Guedes, Renata Padilha","year":2025,"journal":"Metabolic brain disease, 40(7), 256","doi":"10.1007/s11011-025-01687-7","pmid":"40892197","tags":["cbd","prenatal","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adult offspring of rats fed an obesity-inducing diet showed elevated levels of the pro-apoptotic protein BAD in the prefrontal cortex, which CBD treatment (50 mg/kg for 3 weeks) mitigated. Female offspring also had elevated JNK (stress signaling), reduced by CBD. Male offspring showed reduced astrocyte and microglia populations, which CBD reversed.","whyItMatters":"Maternal obesity during pregnancy affects offspring brain development, and these effects persist into adulthood. This study suggests CBD could address some of the lasting brain changes, including inflammation and cell death signaling, that result from in utero obesity exposure.","specificNumbers":"50 mg/kg CBD for 3 weeks starting at postnatal day 70; BAD (pro-apoptotic protein) elevated in both sexes and reduced by CBD; JNK elevated in females and reduced by CBD; TNF-alpha elevated in male offspring; GFAP and IBA-1 positive cells reduced in males and restored by CBD","methodology":"Female Wistar rats were fed a cafeteria diet for 12 weeks before mating and through pregnancy and lactation. Adult offspring (postnatal day 70) received oral CBD (50 mg/kg) for 3 weeks. Researchers measured apoptosis proteins, TNF-alpha expression, and glial cell morphology in the prefrontal cortex.","limitations":"Rat model with extreme obesity-inducing diet, CBD given in adulthood rather than preventively, only prefrontal cortex examined, short treatment duration (3 weeks), no behavioral outcomes measured in this study"},{"rthcId":"RTHC-06074","title":"Identifying organic contaminants at trespass cannabis grows on federal land in California, USA.","authors":"Black, Gabrielle P; De Parsia, Matthew; Uychutin, Matthew; Gabriel, Mourad; Medel, Ivan; Wengert, Greta; Raines, Clayton D; Kolpin, Dana W; Hubbard, Laura E; Hladik, Michelle L","year":2025,"journal":"The Science of the total environment, 1002, 180576","doi":"10.1016/j.scitotenv.2025.180576","pmid":"41005170","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06075","title":"Differential effects of gestational Cannabis smoke and phytocannabinoid injections on male and female rat offspring behavior.","authors":"Black, Tallan; Barnard, Ilne L; Baccetto, Sarah L; Greba, Quentin; Orvold, Spencer N; Austin-Scott, Faith V L; Sanfuego, Genre B; Onofrychuk, Timothy J; Glass, Aiden E; Andres, Rachel M; Macfarlane, Leah M; Adrian, Jesse C; Heidt, Ashton L; McElroy, Dan L; Laprairie, Robert B; Howland, John G","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 136, 111241","doi":"10.1016/j.pnpbp.2024.111241","pmid":"39765319","tags":["prenatal","thc","cbd","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Injected THC and CBD had more severe impacts on maternal and litter health and produced distinct behavioral patterns compared to smoked cannabis. High-THC smoke decreased prepulse inhibition (a measure of sensory filtering) in adolescent female offspring, which normalized by adulthood. Injected THC increased exploratory behavior in both sexes.","whyItMatters":"Most preclinical research on prenatal cannabis exposure uses injected THC at high doses, but most pregnant humans who use cannabis smoke it. This study shows the route of exposure produces meaningfully different offspring outcomes, suggesting prior injection-based research may not reflect real-world risk.","specificNumbers":"High-THC smoke decreased PPI and MK-801-induced locomotor activity in adolescent females (normalized by adulthood); injected THC increased exploratory behavior in both sexes; injected CBD impaired PPI in both sexes in adulthood; all gestational exposures impaired odor-based recognition tasks regardless of treatment type","methodology":"Pregnant rats were exposed to high-THC or high-CBD cannabis smoke or received THC or CBD injections during gestation. Offspring were tested on prepulse inhibition, locomotor activity, social interaction, object recognition, and attention tasks during adolescence and adulthood.","limitations":"Rat model may not translate to humans, specific cannabis strains and doses used, cannot isolate combustion byproducts from cannabinoid effects in smoke group, limited behavioral battery"},{"rthcId":"RTHC-06076","title":"Cannabis use patterns, motivations, and reasons for abstinence in pregnancy.","authors":"Blair, Lisa M; Shukla, Meghna; Kurzer, Julie A M J; Schilt-Solberg, Marvin; Strickland, Biyyiah A; Akter, Salma; Fend, Dennette; Hamann, Kimberly; Ashford, Kristin","year":2025,"journal":"Frontiers in psychiatry, 16, 1613324","doi":"10.3389/fpsyt.2025.1613324","pmid":"41210135","tags":["prenatal","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"61% reported current (past 30-day) cannabis use during pregnancy. Of those, 54% used daily and 85% used on at least 15 of the past 30 days. Having five or more motivations for use made someone over 10 times more likely to be a current user.","whyItMatters":"Prenatal cannabis use is increasing, but little research examines why pregnant people continue using despite known risks. This study reveals that most users in the sample had tried to quit and failed, suggesting cannabis use in pregnancy often reflects dependence rather than casual choice.","specificNumbers":"59 participants; 61% current use; 54% of current users reported daily use; 85% used at least 15 of past 30 days; 5+ motivations for use = 10x higher odds of current use; many reported unsuccessful quit attempts","methodology":"59 people who used cannabis at least once during their current pregnancy were recruited from prenatal clinics and surveyed about use patterns, motivations, reasons for abstinence, tobacco co-use, and quit attempts.","limitations":"Small sample (59 participants), recruited from prenatal clinics (may not represent all pregnant cannabis users), self-report measures, no biological verification of use, cross-sectional design cannot track changes over pregnancy"},{"rthcId":"RTHC-06077","title":"Development and Characterization of a High-CBD Cannabis Extract Nanoemulsion for Oral Mucosal Delivery.","authors":"Blal, Kifah; Maroukian, Georgette; Shapira, Anna; Procaccia, Shiri; Meiri, David; Benny, Ofra","year":2025,"journal":"International journal of molecular sciences, 26(23)","doi":"10.3390/ijms262311525","pmid":"41373676","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06078","title":"Immunomodulatory Effects of a High-CBD Cannabis Extract: A Comparative Analysis with Conventional Therapies for Oral Lichen Planus and Graft-Versus-Host Disease.","authors":"Blal, Kifah; Rosenblum, Ronen; Novak-Kotzer, Hila; Procaccia, Shiri; Abu Tair, Jawad; Casap, Nardy; Meiri, David; Benny, Ofra","year":2025,"journal":"International journal of molecular sciences, 26(21)","doi":"10.3390/ijms262110711","pmid":"41226746","tags":["cbd","immune-system","inflammation"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The CBD-rich extract CAN296 reduced T cell activation markers (CD69) to 2-11% in CD4+ cells and 5-17% in CD8+ cells. It nearly eliminated TNF-alpha and IFN-gamma secretion in CD8+ cells at all tested doses. These effects were more potent and consistent than either dexamethasone or tacrolimus.","whyItMatters":"Oral lichen planus and graft-versus-host disease are T cell-driven conditions with limited treatment options. The finding that a CBD-rich extract outperformed two standard immunosuppressants at controlling T cell activity suggests a potential new therapeutic approach for these conditions.","specificNumbers":"CD69 reduced to 2-11% in CD4+ and 5-17% in CD8+ T cells; TNF-alpha and IFN-gamma nearly undetectable in CD8+ cells at all CAN296 doses; Granzyme B reduced 81-82%; Perforin reduced 40-53%; Fas-L reduced 40-44%; tacrolimus paradoxically increased IFN-gamma at lower concentrations","methodology":"CD4+ and CD8+ T cells isolated from healthy donors were treated with a CBD-rich cannabis extract (CAN296) at three doses and compared to dexamethasone and tacrolimus. Researchers measured T cell activation, cytokine secretion (TNF-alpha, IFN-gamma), and cytotoxic molecule expression (Granzyme B, Perforin, Fas-L).","limitations":"In vitro study using cells from healthy donors only, cannot predict clinical efficacy or safety, specific CBD-rich extract (CAN296) may not represent all CBD products, dose ranges may not correspond to achievable tissue concentrations in patients"},{"rthcId":"RTHC-06079","title":"Synaptic Density in Early Stages of Psychosis and Clinical High Risk.","authors":"Blasco, M Belen; Nisha Aji, Kankana; Ramos-Jiménez, Christian; Leppert, Ilana Ruth; Tardif, Christine Lucas; Cohen, Johan; Rusjan, Pablo M; Mizrahi, Romina","year":2025,"journal":"JAMA psychiatry, 82(2), 171-180","doi":"10.1001/jamapsychiatry.2024.3608","pmid":"39535765","tags":["psychosis","youth","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Synaptic density (measured by SV2A binding) was significantly lower in first-episode psychosis and clinical high-risk participants compared to healthy controls. Cannabis users had additionally lower synaptic density regardless of diagnostic group. Lower synaptic density was associated with more severe negative symptoms.","whyItMatters":"This is one of the first studies to measure synaptic density in vivo during the earliest stages of psychosis. The finding that cannabis use is associated with even lower synaptic density suggests cannabis may compound the synaptic loss already occurring in psychosis development.","specificNumbers":"49 participants total; synaptic density significantly different between groups (F2,273 = 4.02, P = .02); cannabis users had lower density (F1,272 = 5.31, P = .02); lower density associated with negative symptoms on both PANSS (P = .04) and SOPS (P = .04); SV2A binding correlated with neurite density (P = .01)","methodology":"Cross-sectional study using [18F]SynVesT-1 PET scans and diffusion-weighted MRI in 49 participants: 16 with first-episode psychosis, 17 at clinical high risk, and 16 healthy controls. Cannabis use was confirmed by urine drug screens. Participants were antipsychotic-free or minimally exposed.","limitations":"Small sample (49 participants), cross-sectional design cannot determine whether cannabis caused lower synaptic density, cannot rule out confounding factors, limited to specific brain regions of interest"},{"rthcId":"RTHC-06080","title":"Recent Preclinical Evidence on Phytocannabinoids in Neurodegenerative Disorders: A Focus on Parkinson's and Alzheimer's Disease.","authors":"Blebea, Nicoleta-Mirela; Pușcașu, Ciprian; Hancu, Gabriel; Stăniguț, Alina Mihaela; Chiriță, Cornel","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(6)","doi":"10.3390/ph18060890","pmid":"40573285","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06081","title":"Cannabis and the overdose crisis among US adolescents.","authors":"Bleyer, Archie; Barnes, Brian; Stuyt, Elizabeth; Voth, Eric A; Finn, Kenneth","year":2025,"journal":"The American journal on addictions, 34(3), 327-333","doi":"10.1111/ajad.13669","pmid":"39563651","tags":["legalization","youth","health-risks","gateway-theory"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"States with recreational cannabis legalization had overdose death rates 88% higher (2019), 479% higher (2020), and 115% higher (2021) among 14-18 year-olds compared to non-legalizing states. The correlation appeared across sexes and White, Black, and Hispanic populations.","whyItMatters":"The adolescent overdose crisis has been devastating, with death rates more than doubling since 2019. This study raises the question of whether cannabis legalization contributed by examining state-level correlations, though it cannot prove causation.","specificNumbers":"Recreational legalization states: 88% higher overdose death rate in 2019, 479% higher in 2020, 115% higher in 2021 vs. non-legalizing states; correlations present in both sexes and across White, Black, and Hispanic populations; adolescent overdose death rate more than doubled nationally since 2019","methodology":"Retrospective analysis of unintentional drug overdose deaths among 14-18 year-olds from CDC WONDER data, comparing states by cannabis legalization status (recreational, medical-only, and non-legalization) across multiple years.","limitations":"Ecological study cannot prove causation, does not control for fentanyl availability which varied by state, COVID-19 disruptions overlapped with the study period, states that legalize cannabis may differ from non-legalizing states in other ways that affect overdose risk, does not examine whether the adolescents who died actually used cannabis"},{"rthcId":"RTHC-06082","title":"Computational GWAS Meta Meta Analysis Revealing Cross Talk Between Cannabis CNR1 and DRD2 Receptors Optimizing Long-Term Outcomes for Cannabis Use Disorder (CUD) By Enhancing Dopamine Homeostasis Promoting High-Quality Cannabis Medicinals.","authors":"Blum, Kenneth; Sharafshah, Alireza; Khalsa, Jag; Lewandrowski, Kai-Uwe; Thanos, Panayotis K; Lindeau, Marco; Dowling, Álvaro; Dowling, Rafaela; Bergamaschi, Jao Paulo; Pinhasov, Albert; Baron, David; Dennen, Catherine A; Morgan, Joseph P; Elman, Igor; Gardner, Eliot L; Gold, Mark S; Modestino, Edward J; Brian, Fuehrlein; Carney, Paul R; Cortese, Rene; Bowirrat, Abadalla; Sunder, Keerthy; Mohankumar, Kavya; Zeine, Foojan; Jafari, Nicole; Makale, Milan T; Bagchi, Debasis; Ceccanti, Mauro; Fiorelli, Rossano K A; Schimidt, Sérgio Luís; Sipple, Daniel; Lewandrowski, Alexander P L; Matare, Gianni; Mahajan, Shaurya; Mahajan, Yatharth; Fliegelman, Chynna; Hanna, Colin; Badgaiyan, Rajendra D","year":2025,"journal":"Research square","doi":"10.21203/rs.3.rs-8140327/v1","pmid":"41333412","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06083","title":"Beyond the high: exploring socioecological influences on cannabis use in older women with and without HIV.","authors":"Bobitt, Julie; Franceschini, Dana; Hernandez-Vallant, Alexandra; Afridi, Masooma; Ross, Ryan D; Daubert, Elizabeth; Cohen, Mardge H; French, Audrey L","year":2025,"journal":"The Gerontologist, 65(12)","doi":"10.1093/geront/gnaf250","pmid":"41269113","tags":["elderly","medical-use","sex-differences"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Both groups used cannabis for psychological distress, pain, sleep, and reducing other substance use. Women with HIV additionally reported greater mental health burden and used cannabis for appetite and energy. Across both groups, motivations shifted over time from social to therapeutic purposes. Most felt comfortable telling their doctors about cannabis use.","whyItMatters":"Older women with HIV face unique health challenges including medication side effects, chronic pain, and appetite loss. Understanding their specific motivations for cannabis use can help clinicians provide more relevant guidance rather than generic advice.","specificNumbers":"30 participants (20 with HIV, 10 without); women with HIV reported greater mental health symptom burden; both groups shifted from social to therapeutic motivations over time; most comfortable disclosing cannabis use to providers; participants expressed distrust about legalization and product safety","methodology":"Qualitative interviews with 30 participants (20 women with HIV, 10 without) enrolled in the MACS/WIHS Combined Cohort Study, analyzed using the Social Ecological Model framework.","limitations":"Small qualitative sample (30 women), not generalizable to all older women or all people with HIV, self-selected participants may be more open about cannabis use, single geographic region"},{"rthcId":"RTHC-06084","title":"Feasibility pilot of a novel coaching intervention to optimize cannabis use for chronic pain management among Veterans.","authors":"Boehnke, Kevin F; Bowyer, Gabrielle; McAfee, Jenna; Smith, Tristin; Klida, Catherine; Kurtz, Vivian; Litinas, Evangelos; Purohit, Poonam; Arewasikporn, Anne; Horowitz, Dana; Thomas, Laura; Eckersley, Jennifer; Railing, Mia; Williams, David A; Clauw, Daniel J; Kidwell, Kelley M; Bohnert, Amy S B; Bergmans, Rachel S","year":2025,"journal":"Journal of cannabis research, 7(1), 7","doi":"10.1186/s42238-025-00265-z","pmid":"39856785","tags":["veterans","pain","medical-use"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"After up to 4 coaching sessions, all participants reported improvement. Pain intensity dropped from 7.1 to 5.7 out of 10, and pain interference decreased significantly. 87.5% were very or completely satisfied, and 81.3% rated coaching as very or extremely helpful.","whyItMatters":"Veterans frequently use cannabis for pain but have little clinical support in doing so, partly because federal prohibition limits provider guidance. This study suggests structured coaching can help veterans use cannabis more effectively, with meaningful pain reductions.","specificNumbers":"22 enrolled, 17 completed all 4 sessions; pain intensity 7.1 to 5.7 out of 10; 63% reported much or very much improvement on PGIC; 87.5% very or completely satisfied; social satisfaction T-score improved from 41.4 to 44.3; pain interference T-score decreased from 66.3 to 61.8","methodology":"Feasibility pilot with 22 veterans with chronic pain who used or were interested in cannabis for pain. Participants received up to 4 individual videoconference coaching sessions spaced 2 weeks apart. The intervention used motivational interviewing principles and scientific literature. Outcomes measured at 14 weeks.","limitations":"Small sample (22 participants) with no control group, self-selected participants likely motivated for improvement, cannot separate coaching effects from placebo or natural improvement, short follow-up (14 weeks)"},{"rthcId":"RTHC-06085","title":"Characteristics of Medical Cannabis Patients and Clinicians in 7 US States.","authors":"Boehnke, Kevin F; Sinclair, Rachel; Gordon, Felicia; Smith, Tristin; Roehler, Douglas R","year":2025,"journal":"JAMA network open, 8(4), e256925","doi":"10.1001/jamanetworkopen.2025.6925","pmid":"40272804","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers examined data from medical cannabis programs in seven US states to build a demographic profile of who participates in these systems, both as patients and as the clinicians who authorize cannabis use.\n\nThe analysis revealed the sociodemographic makeup of medical cannabis patients, including age distributions, gender breakdowns, and qualifying conditions. It also characterized the physicians and other clinicians who authorize medical cannabis, a group that has been relatively understudied.\n\nThis type of descriptive research is essential for understanding whether medical cannabis programs serve diverse populations equitably or whether access disparities exist across demographic groups.","whyItMatters":"As medical cannabis programs expand, knowing who actually uses them matters for equity. If certain populations are underrepresented, it may indicate barriers to access such as cost, provider availability, or cultural factors that policymakers need to address.","specificNumbers":"Seven US states were included in the analysis. Both patient demographics and authorizing clinician characteristics were examined across these programs.","methodology":"This was a cross-sectional study analyzing administrative data from medical cannabis programs in seven US states. Researchers examined patient registry data and clinician authorization records to describe the sociodemographic characteristics of both groups, including age, sex, race/ethnicity, and geographic distribution.","limitations":"Administrative data from medical cannabis programs may not capture all users, particularly those who obtain cannabis from recreational markets instead. The seven states studied may not represent all US medical cannabis programs. Demographic data quality varies by state, and some registries collect more detailed information than others."},{"rthcId":"RTHC-06086","title":"Treatment of epilepsy using newer antiseizure medications: A retrospective cohort study of prescription patterns in Sweden 2013-2022.","authors":"Bolin, Kristian; Berling, Patric; Tomson, Torbjörn","year":2025,"journal":"Epilepsia, 66(12), 4809-4820","doi":"10.1111/epi.18576","pmid":"40782115","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06087","title":"Cannabis Use and Perceptions of Cannabis Safety, Effectiveness, and Stigma amongst older Canadians: A Cross-Sectional Survey.","authors":"Bolt, Jennifer; Movold, Jacob; Fenton, Melanie; Behm, Megan; Williamson, Jill; Jakobi, Jennifer M","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(2), 1-17","doi":"10.26828/cannabis/2025/000306","pmid":"40909149","tags":["elderly","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"44% reported current cannabis use, 33.2% non-use, 16.5% prior use, and 6.1% were considering use. Nearly half (49.2%) perceived cannabis risks as low or very low. The top concerns were effects on cognition/mental health (40.8%), physical health (19.1%), and insufficient product information (18.0%). About 35% perceived negative stigma among family and friends.","whyItMatters":"Since Canada legalized cannabis in 2018, use among older adults has climbed steadily. This large survey reveals a disconnect: while nearly half of older Canadians are using cannabis, most feel they lack adequate safety and effectiveness information to guide their decisions.","specificNumbers":"1,615 respondents aged 50+; 44% current use; 49.2% perceived low/very low risk; 40.8% concerned about cognition/mental health effects; 60.4% said not enough safety information; 63.8% said not enough effectiveness information; 34.7% perceived negative stigma; perceptions influenced by age, sex, usage, and education","methodology":"Electronic survey of 1,615 Canadians aged 50+ examining cannabis use patterns and perceptions of safety, effectiveness, and stigma. Perceptions assessed with Likert scales and open text. Logistic regression examined how age, sex, usage status, and education influenced perceptions.","limitations":"Electronic survey may underrepresent older adults with limited technology access, self-selected respondents may be more interested in cannabis, Canadian results may not apply elsewhere, cross-sectional design captures one point in time"},{"rthcId":"RTHC-06088","title":"Cannabinoid Receptors in the Horse Lateral Nucleus of the Amygdala: A Potential Target for Ameliorating Pain Perception, Stress and Anxiety in Horses.","authors":"Bombardi, Cristiano; Salamanca, Giulia; Tagliavia, Claudio; Grandis, Annamaria; Zamith Cunha, Rodrigo; Gramenzi, Alessandro; De Silva, Margherita; Zannoni, Augusta; Chiocchetti, Roberto","year":2025,"journal":"International journal of molecular sciences, 26(15)","doi":"10.3390/ijms26157613","pmid":"40806746","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06089","title":"Agitation in Alzheimer's Disease as a Qualifying Condition for Medical Cannabis in the United States: A Brief Report on Current Trends.","authors":"Bonar, Erin E; Tan, Chiu Yi; Patyk, Adam; Lei, Lianlian; Maust, Donovan T","year":2025,"journal":"The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry","doi":"10.1016/j.jagp.2025.06.003","pmid":"40592641","tags":["medical-cannabis","seniors","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Agitation in Alzheimer's disease is a devastating symptom affecting up to 70% of patients, and current pharmaceutical options carry significant risks, including increased mortality from antipsychotics. Medical cannabis has been proposed as an alternative, and this study mapped the current state of access.\n\nThe numbers tell an interesting story. Of 38 states allowing medical cannabis, 19 (50%) include Alzheimer's disease as a qualifying condition. But actual uptake is minimal — AD accounts for less than 1% of medical cannabis certifications. There's a large gap between legal access and actual use.\n\nThe reason for low uptake is likely multifactorial: dementia patients often can't self-advocate for or self-manage medical cannabis, caregivers may be reluctant, clinicians lack guidance on dosing and monitoring, and the evidence base supporting cannabis for AD agitation is thin.\n\nAn additional finding is that AD as a qualifying condition appears to be declining in states that have legalized recreational cannabis — suggesting that the medical program pathway becomes less relevant when cannabis is available without medical certification.\n\nThe mismatch between widespread legal access and minimal evidence of efficacy creates a policy puzzle: states have made cannabis available for AD based on theoretical benefit, but the clinical trial data to support or refute this decision largely doesn't exist.","whyItMatters":"This mapping exercise reveals a broader pattern in medical cannabis policy: conditions are often added to qualifying lists based on theoretical plausibility rather than clinical evidence. For Alzheimer's caregivers and clinicians, the finding that 19 states allow medical cannabis for AD is relevant — but so is the finding that almost nobody uses it, and the evidence that it helps is limited.","specificNumbers":"38 states allow medical cannabis. 19 (50%) include AD as a qualifying condition. AD accounts for <1% of medical cannabis certifications. AD certifications appear to be declining in states with legal recreational cannabis.","methodology":"Observational study examining regulatory agencies' publicly available online reports regarding medical cannabis access across U.S. states in 2024-2025, specifically assessing AD as a qualifying condition. Analyzed certification data where available to determine what proportion of medical cannabis users qualify through AD.","limitations":"Data comes from publicly available regulatory reports, which vary in completeness and detail across states. Actual cannabis use by AD patients may differ from certification numbers (patients may obtain cannabis through recreational channels or caregiver purchases). The study doesn't assess clinical outcomes — only access and uptake. State-by-state policy differences make generalization difficult."},{"rthcId":"RTHC-06090","title":"Fenfluramine treatment for Dravet syndrome: Long term real-world analysis demonstrates safety and reduced health care burden.","authors":"Boncristiano, Alessandra; Balestrini, Simona; Doccini, Viola; Specchio, Nicola; Pietrafusa, Nicola; Trivisano, Marina; Darra, Francesca; Cossu, Alberto; Battaglia, Domenica; Quintiliani, Michela; Gambardella, M Luigia; Parente, Eliana; Monni, Rita; Matricardi, Sara; Marini, Carla; Ragona, Francesca; Granata, Tiziana; Striano, Pasquale; Riva, Antonella; Guerrini, Renzo","year":2025,"journal":"Epilepsia, 66(4), 1110-1118","doi":"10.1111/epi.18241","pmid":"39740232","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06091","title":"Cannabis Use Cessation and the Risk of Psychotic Disorders: A Case-Control Analysis from the First Episode Case-Control EU-GEI WP2 Study: L'arrêt de l'utilisation du cannabis et le risque de troubles psychotiques: Une analyse cas-témoins tirée de l'étude cas-témoins EU-GEI WP2 centrée sur les premiers épisodes psychotiques.","authors":"Bond, Benjamin W; Duric, Bea; Spinazzola, Edoardo; Trotta, Giulia; Chesney, Edward; Li, Zhikun; Quattrone, Diego; Tripoli, Giada; Gayer-Anderson, Charlotte; Rodriguez, Victoria; Ferraro, Laura; La Cascia, Caterina; Tarricone, Ilaria; Szöke, Andrei; Arango, Celso; Bobes, Julio; Bernardo, Miquel; Del-Ben, Cristina Marta; Menezes, Paulo Rossi; Selten, Jean-Paul; Rutten, Bart P F; de Haan, Lieuwe; Stilo, Simona; Schürhoff, Franck; Pignon, Baptiste; Freeman, Tom P; Vassos, Evangelos; Murray, Robin M; Austin-Zimmerman, Isabelle; Di Forti, Marta","year":2025,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 70(3), 182-193","doi":"10.1177/07067437241290187","pmid":"39810593","tags":["psychosis","addiction","mental-health"],"studyType":"case-control","evidenceStrength":"strong","keyFinding":"Ex-users who stopped 1-4 weeks prior had 6.9 times the psychosis odds of never-users. This declined progressively: those who stopped 37-96 weeks prior had no significant elevation (OR 1.01). However, preliminary results suggested frequent users of high-potency cannabis might maintain elevated risk even beyond 181 weeks of abstinence.","whyItMatters":"This is the first large multi-site study to quantify how quickly psychosis risk declines after stopping cannabis. The finding that risk returns to baseline after about 9 months offers concrete information for people considering quitting, while the caveat about high-potency use adds important nuance.","specificNumbers":"Ex-users stopped 1-4 weeks: OR 6.89; stopped 37-96 weeks: OR 1.01 (not significant); stopped 97-180 weeks: OR 0.73 (not significant); stopped 181+ weeks: OR 1.18 (not significant); frequent high-potency users may retain elevated risk beyond 181 weeks; data from multiple European sites and Brazil","methodology":"Case-control study from the EU-GEI network collecting data from first-episode psychosis patients and population controls across sites in Europe and Brazil (May 2010 to April 2015). Adjusted logistic regression examined how psychosis odds changed with time since cannabis cessation.","limitations":"Case-control design cannot prove causation, relies on retrospective self-report of cannabis use timing, the high-potency finding is preliminary with wide confidence intervals, may not generalize to all populations, does not account for all potential confounders"},{"rthcId":"RTHC-06092","title":"Addressing the legal and health challenges of licensed medical cannabis users who want to travel abroad.","authors":"Bonny-Noach, Hagit; Ne'eman-Haviv, Vered","year":2025,"journal":"Israel journal of health policy research, 14(1), 61","doi":"10.1186/s13584-025-00723-2","pmid":"41139791","tags":["legalization","medical-use"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Two main themes emerged: (1) international regulations for medical cannabis are vague, with authorities not treating it like other prescription medications; (2) patients adopted various strategies including avoiding travel, choosing cannabis-friendly destinations, planning ahead to obtain cannabis legally or illegally, and finding alternative self-medications.","whyItMatters":"As medical cannabis programs expand globally, the growing population of licensed patients faces a practical dilemma: their legal medicine at home becomes contraband abroad. This gap between domestic approval and international restriction affects treatment continuity and patient safety.","specificNumbers":"15 medical cannabis license holders interviewed; supplementary data from two largest Israeli medical cannabis Facebook groups; patients criticized lack of clear formal guidelines; some avoided travel entirely; others sought cannabis through illegal channels abroad","methodology":"Semi-structured interviews with 15 Israeli medical cannabis license holders, supplemented by data from two of Israel's largest medical cannabis Facebook groups.","limitations":"Small Israeli sample (15 participants) may not represent patients in other countries, qualitative design cannot quantify prevalence of different coping strategies, Facebook group data may skew toward more engaged patients, Israel's medical cannabis program differs from others"},{"rthcId":"RTHC-06093","title":"Discovery of reversible monoacylglycerol lipase (MAGL) inhibitors based on ortho-hydroxyanilide scaffold.","authors":"Bononi, Giulia; Gado, Francesca; Masoni, Samuele; Scalabrini, Diana; Vedova, Larissa Della; Di Stefano, Miriana; Piazza, Lisa; Poles, Clarissa; Lonzi, Chiara; Landucci, Eva; Vagaggini, Chiara; Poggialini, Federica; Brai, Annalaura; Caligiuri, Isabella; Rizzolio, Flavio; Mohamed, Kawthar A; Bertini, Simone; De Lorenzi, Ersilia; Dreassi, Elena; Macchia, Marco; Minutolo, Filippo; Laprairie, Robert B; Granchi, Carlotta; Tuccinardi, Tiziano","year":2025,"journal":"Bioorganic chemistry, 163, 108698","doi":"10.1016/j.bioorg.2025.108698","pmid":"40554889","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06094","title":"Identification of a Possible Endocannabinoid-Mediated Mechanism of Action of Cetylated Fatty Acids.","authors":"Bononi, Giulia; Granchi, Carlotta; Tuccinardi, Tiziano; Minutolo, Filippo","year":2025,"journal":"Biomolecules, 15(3)","doi":"10.3390/biom15030363","pmid":"40149899","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06095","title":"What proportion of people who use cannabis in Germany have spoken with their general practitioner about their consumption? A repeated cross-sectional representative population survey.","authors":"Borchardt, Benjamin; Klosterhalfen, Stephanie; Kotz, Daniel","year":2025,"journal":"Journal of cannabis research, 7(1), 76","doi":"10.1186/s42238-025-00329-0","pmid":"41057903","tags":["legalization","medical-use"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Only 7.0% of 2,057 ever-users reported discussing cannabis with their GP. The rate was higher among past-year users (16.2%) and frequent users (up to 26%). Discussion was more common among those aged 65+, with low education, low income, and frequent use.","whyItMatters":"Germany legalized cannabis in April 2024, making this a critical moment for primary care. If only 7% of cannabis users discuss their use with doctors, the opportunity for harm reduction, screening, and clinical guidance is being largely missed.","specificNumbers":"2,057 ever-users; 7.0% (n=139) ever discussed cannabis with GP; 16.2% of past-year users; up to 26% of frequent users; associated with older age (65+), low education, low income, and frequent use; Germany legalized April 1, 2024","methodology":"Repeated cross-sectional household survey (DEBRA study) of Germans aged 14+ conducted in bi-monthly waves. All respondents who reported ever using cannabis were asked whether they had discussed their use with a GP or received advice.","limitations":"Cross-sectional design captures a snapshot, cannot determine if legalization changed discussion rates, self-report may undercount discussions, German healthcare system may differ from others, survey conducted around legalization transition"},{"rthcId":"RTHC-06096","title":"Multi-Modal Profiling Reveals Contrasting Immunomodulatory Effects of Recreational Marijuana Used Alone or with Tobacco in Youth with HIV.","authors":"Borkar, Samiksha A; Venturi, Guglielmo M; Chang, Kai-Fen; Gu, Jingwen; Yin, Li; Shen, Jerry; Fischer, Bernard M; Nepal, Upasana; Raplee, Isaac D; Kim-Chang, Julie J; Murdoch, David M; Nichols, Sharon L; Hightow-Weidman, Lisa B; Somboonwit, Charurut; Sleasman, John W; Goodenow, Maureen M","year":2025,"journal":"Cells, 14(16)","doi":"10.3390/cells14161267","pmid":"40862746","tags":["immune-system","youth","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Marijuana use alone was associated with elevated IL-10 levels and normalization of pro-inflammatory genes, suggesting an immunomodulatory effect. Tobacco use alone or combined with marijuana was linked to increased IL-1-beta and upregulated inflammasome activation genes. The study also identified GPR15 upregulation and potential epigenetic changes associated with marijuana use.","whyItMatters":"Youth with HIV face lifelong antiretroviral therapy and elevated comorbidity risk. Understanding how common substances like marijuana and tobacco affect their immune system is critical for managing long-term health, especially given marijuana's increasing popularity in this population.","specificNumbers":"Marijuana alone: elevated IL-10, normalized pro-inflammatory gene pathways; tobacco alone or with marijuana: increased IL-1-beta, upregulated inflammasome genes; first study to demonstrate GPR15 upregulation with marijuana in HIV-suppressed youth; virally suppressed (50 or fewer RNA copies/mL)","methodology":"Multi-modal profiling of virally suppressed youth with HIV on ART, including plasma biomarker analysis, peripheral blood cell phenotyping, and transcriptome profiling. Groups compared: marijuana only, tobacco only, marijuana plus tobacco, and no substance use.","limitations":"Cross-sectional design cannot prove causation, relatively small sample, self-reported substance use, virally suppressed participants may not represent all youth with HIV, cannot determine dose-response relationships"},{"rthcId":"RTHC-06097","title":"Developing an online cannabis store paradigm for Cannabis Regulatory Science.","authors":"Borodovsky, J T; Bairaboina, S; Struble, C A; Preum, S M; Sargent, J D; Emond, J A; Budney, A J","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.10.20.25338387","pmid":"41282889","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06098","title":"Self-titration of cannabis consumption: An epidemiological perspective.","authors":"Borodovsky, Jacob T; Murphy, Eilis; Hasin, Deborah S; Livne, Ofir; Wall, Melanie; Aharonovich, Efrat; Wisell, Caroline; Struble, Cara A; Habib, Mohammad I; Budney, Alan J","year":2025,"journal":"Journal of psychiatric research, 191, 527-534","doi":"10.1016/j.jpsychires.2025.09.014","pmid":"41061441","tags":["dosing","addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"When switching between product types (flower vs. concentrates), 59-92% of users consumed larger amounts of flower than concentrates, suggesting self-titration across products. However, within a single product type, users who chose higher-THC versions consumed them in larger amounts, more frequently, and had started using cannabis at a younger age.","whyItMatters":"The self-titration hypothesis suggests cannabis users naturally adjust their intake to maintain a consistent THC dose. This study partially supports it: users do take fewer hits of concentrates than flower, but the finding that heavy users seek out AND consume more of higher-potency products within a category challenges the idea that titration fully protects against escalating exposure.","specificNumbers":"8,158 participants; 52% female; 73% daily use; mean age 42; flower-only users: 8-14 hits vs. concentrate-only: 5-8 hits; within-product correlations between potency and amount: rs = 0.07-0.29 for flower, rs = 0.09-0.25 for concentrates; higher potency also correlated with more frequent use and earlier initiation","methodology":"Four online surveys of 8,158 US cannabis consumers reporting past-month flower and/or concentrate use. Participants reported typical amounts (hits or grams) and potencies (%THC). Researchers analyzed potency-amount relationships within-subject/between-product and between-subject/within-product.","limitations":"Self-reported amounts and potencies, online convenience sample skewed toward daily users (73%), cross-sectional design cannot determine directionality, does not measure actual THC blood levels to verify titration"},{"rthcId":"RTHC-06099","title":"Quantity of delta-9-tetrahydrocannabinol consumption and cannabis use disorder among daily cannabis consumers.","authors":"Borodovsky, Jacob T; Hasin, Deborah S; Wall, Melanie; Struble, Cara A; Habib, Mohammad I; Livne, Ofir; Liu, Jun; Chen, Lynn; Aharonovich, Efrat; Budney, Alan J","year":2025,"journal":"Addiction (Abingdon, England), 120(4), 676-685","doi":"10.1111/add.16700","pmid":"39501796","tags":["addiction","dosing","health-risks"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Median daily consumption was approximately 130 mg THC, with wide variability (25% consumed 50 mg or less, 25% consumed 290 mg or more). 65% met criteria for CUD: 39% mild, 18% moderate, 8% severe. Greater daily mg THC predicted higher CUD criteria count and higher odds of all severity levels.","whyItMatters":"This is one of the largest studies to quantify actual THC consumption among daily users and link it to disorder severity. The finding that two-thirds meet CUD criteria challenges the narrative that daily cannabis use is typically unproblematic.","specificNumbers":"4,134 daily consumers; median daily THC ~130 mg; 25th percentile 50 mg, 75th percentile 290 mg; mean 2.5 CUD criteria endorsed; 65% met CUD criteria (39% mild, 18% moderate, 8% severe); higher mg THC predicted more criteria and higher severity","methodology":"4,134 US adult daily cannabis consumers completed comprehensive online surveys covering product types, amounts, potencies, and administration methods. Daily mg THC was calculated using a novel method adjusting for puff size and THC loss. DSM-5 CUD criteria were assessed.","limitations":"Online convenience sample may overrepresent heavier users, THC estimation relies on self-reported potencies and amounts, cross-sectional design cannot determine if high THC consumption causes CUD or if CUD drives higher consumption, DSM-5 criteria may over-identify disorder in legal-use populations"},{"rthcId":"RTHC-06100","title":"Low-dose cannabidiol treatment prevents chronic stress-induced phenotypes and is associated with multiple synaptic changes across various brain regions.","authors":"Borràs-Pernas, Sara; Sancho-Balsells, Anna; Patterer, Lisa; Wang, Maoyu; Del Toro, Daniel; Alberch, Jordi; Schibano, Daniele; Espel, Joan; Heybeck, Maya; Scheidel, Bernhard; Giralt, Albert","year":2025,"journal":"Neuropharmacology, 277, 110526","doi":"10.1016/j.neuropharm.2025.110526","pmid":"40409535","tags":["cbd","depression","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"A very low dose of CBD (1 mg/kg) partially reversed behavioral effects of chronic stress in mice. Mass spectrometry showed improvements across multiple neurotransmitter systems, particularly glutamatergic and serotonergic pathways in the medial prefrontal cortex. Most strikingly, CBD completely restored mature synapse formation in the prefrontal cortex of stressed mice.","whyItMatters":"Current antidepressants fail about 30% of patients and often cause significant side effects. This study suggests CBD may work at remarkably low doses through synaptic remodeling, a mechanism distinct from conventional antidepressants, potentially offering an alternative pathway for treatment-resistant depression.","specificNumbers":"1 mg/kg CBD dose (very low compared to typical research doses of 10-100 mg/kg); complete restoration of mature synapses in medial prefrontal cortex; improvements across glutamatergic and serotonergic pathways; current antidepressants ineffective for approximately 30% of patients","methodology":"Mice were subjected to chronic stress to model depression-like symptoms, then treated with low-dose CBD (1 mg/kg). Brain regions were analyzed using mass spectrometry and microstructural experiments with double-labeling of F-Actin and VGlut1-positive clusters to assess synaptic integrity.","limitations":"Mouse model of stress may not fully represent human depression, single dose tested, short-term treatment without long-term follow-up, specific mouse strain may not generalize, mechanism of CBD action at this low dose not fully elucidated"},{"rthcId":"RTHC-06101","title":"Exploring the Interactions Between Psychotic Symptoms, Cognition, and Environmental Risk Factors: A Bayesian Analysis of Networks.","authors":"Bosma, Minke J; Marsman, Maarten; Vermeulen, Jentien M; Huth, Karoline B S; de Haan, Lieuwe; Alizadeh, Behrooz Z; Simons, Claudia J P; Schirmbeck, Frederike","year":2025,"journal":"Schizophrenia bulletin, 51(4), 1134-1145","doi":"10.1093/schbul/sbae174","pmid":"39401320","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06102","title":"Exploring Peripartum Cannabis Use Among Young Sexual Minority People: A Qualitative Study.","authors":"Boss, Nicole; Frankeberger, Jessica; Hossain, Fahmida; Mark, Elyse; Coulter, Robert W S; De Genna, Natacha M","year":2025,"journal":"Substance use & addiction journal, 46(3), 559-569","doi":"10.1177/29767342241310950","pmid":"39817350","tags":["prenatal","addiction","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Three themes emerged: (1) cannabis use was contextually adaptive, changing with social situation, mental health, and stress but not directly related to sexuality; (2) pregnancy served as a potential turning point, with most trying to reduce or abstain; (3) facilitating factors for reduction included focusing on financial costs, social environment changes, health guidance access, and replacement hobbies.","whyItMatters":"Sexual minority young people have higher rates of both cannabis use and unintended pregnancy than heterosexual peers, yet are rarely studied in prenatal substance use research. Understanding their specific experiences can inform more inclusive prenatal interventions.","specificNumbers":"13 participants; cannabis use driven by stress/mental health rather than sexuality; most tried to reduce/quit during pregnancy; some continued to address pregnancy symptoms; facilitating factors included financial awareness, social changes, health guidance, replacement activities","methodology":"Semi-structured qualitative interviews with 13 sexual minority participants from the YoungMoms study who used cannabis before or during pregnancy. Data analyzed using thematic analysis.","limitations":"Very small sample (13 participants), qualitative design not generalizable, participants from one study cohort, sexual minority identity encompasses diverse experiences, recall bias about prenatal behaviors"},{"rthcId":"RTHC-06103","title":"Rural-urban differences in substance use during pregnancy.","authors":"Boswell, Emma Kathryn; Hinds, Olivia M; Odahowski, Cassie; Crouch, Elizabeth; Hung, Peiyin; Andrews, Christina M","year":2025,"journal":"The Journal of rural health : official journal of the American Rural Health Association and the National Rural Health Care Association, 41(2), e70018","doi":"10.1111/jrh.70018","pmid":"40128129","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06104","title":"Is there a role for cannabidiol in obesity, metabolic syndrome and binge eating?","authors":"Botticelli, Luca; Micioni Di Bonaventura, Emanuela; Einaudi, Giacomo; Provensi, Gustavo; Costa, Alessia; D'Addario, Claudio; Cifani, Carlo; Micioni Di Bonaventura, Maria Vittoria","year":2025,"journal":"British journal of pharmacology","doi":"10.1111/bph.70196","pmid":"41014043","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06105","title":"Psychoactive substance use in elderly patients: Insights from the addiction in intensive cardiac care units (ADDICT-ICCU) study.","authors":"Bouali, Nabil; Benmansour, Othmane; El Bèze, Nathan; Trimaille, Antonin; Bouleti, Claire; Brette, Jean Baptiste; Schurtz, Guillaume; Lim, Pascal; Millischer, Damien; El Ouahidi, Amine; Gonçalves, Trecy; Gall, Emmanuel; Lequipar, Antoine; Singh, Manveer; Thuaire, Christophe; Piliero, Nicolas; Noirclerc, Nathalie; Andrieu, Stéphane; Fauvel, Charles; Florence, Jeremy; Delmas, Clément; Toupin, Solenn; Dillinger, Jean Guillaume; Henry, Patrick; Pezel, Théo","year":2025,"journal":"Archives of cardiovascular diseases, 118(6-7), 356-364","doi":"10.1016/j.acvd.2025.02.007","pmid":"40175226","tags":["elderly","cardiovascular","health-risks"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 760 elderly patients (65+) in 39 French cardiac ICUs, 21% tested positive for psychoactive substances. Of those testing positive, benzodiazepines were most common (44%), followed by opioid medications (42%), cannabis (18%), tricyclic antidepressants (9%), and cocaine (7%). Elderly patients had 3-fold lower cannabis use than younger patients (18% vs. 53%) but 2-fold higher benzodiazepine use (44% vs. 22%).","whyItMatters":"Psychoactive substance use in elderly cardiac patients is rarely screened for and may interact with cardiac medications. This study reveals that one in five elderly ICU patients test positive, a prevalence that likely surprises most clinicians and suggests routine screening could improve care.","specificNumbers":"1,499 total patients; 760 elderly (65+); 21% tested positive; 5% positive for recreational drugs; cannabis 18% of positives in elderly vs 53% in younger; benzodiazepines 44% in elderly vs 22% in younger; 22% of positive patients had multiple substances; 39 French centres","methodology":"Systematic prospective urine screening (NarcoCheck) of all consecutive patients admitted to 39 French ICCUs over a 2-week period in April 2021. Both recreational drugs and psychoactive medications were tested.","limitations":"Cross-sectional urine screening captures recent use only, cannot distinguish chronic from acute use, French healthcare context may not generalize, NarcoCheck sensitivity varies by substance, 2-week window in April 2021 may not be representative"},{"rthcId":"RTHC-06106","title":"Heavy and Chronic Cannabis Addiction does not Impact Motor Function: A BOLD-fMRI Study.","authors":"Boujraf, Saïd; Alami, Badreeddine; Chikri, Mohamed; El Hamdaoui, Halima; Maaroufi, Mustapha; Aalouane, Rachid; Rammouz, Ismail","year":2025,"journal":"CNS & neurological disorders drug targets, 24(6), 475-490","doi":"10.2174/1574886317666220516103501","pmid":"35578884","tags":["addiction","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Three groups of cannabis users (heavy: 15 joints/day, moderate: 1.5 joints/day, light: 2.8 joints/week) plus healthy controls showed no significant differences in motor cortex activation patterns during fMRI-assessed motor tasks. Brain plasticity and reorganization of motor control appeared equivalent across all groups.","whyItMatters":"While cannabis is known to affect cognition and memory, this study suggests that basic motor cortex function may be resilient to chronic use, even at very high consumption levels. This distinction between preserved and impaired brain functions could inform understanding of cannabis effects on the brain.","specificNumbers":"23 cannabis users in 3 groups: 11 heavy (15 joints/day), 6 moderate (1.5 joints/day), 6 light (2.8 joints/week); 6 healthy controls; no significant differences in BOLD-fMRI motor activation across groups","methodology":"23 cannabis users divided into three consumption groups plus 6 healthy controls underwent BOLD-fMRI assessments of motor function, along with neuropsychological and biological assessments.","limitations":"Very small sample sizes per group (6-11 participants), cross-sectional design cannot rule out pre-existing differences, only motor function tested, no control for acute intoxication at time of scan, limited to cortical motor areas"},{"rthcId":"RTHC-06107","title":"Examining the relationship between cannabis use and drinking levels on co-use days.","authors":"Boyle, Holly K; Sokolovsky, Alexander W; Gunn, Rachel L; Gette, Jordan A; White, Helene R; Jackson, Kristina M","year":2025,"journal":"Alcohol, clinical & experimental research, 49(8), 1778-1791","doi":"10.1111/acer.70107","pmid":"40605643","tags":["addiction","health-risks","social-behavior"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Co-use days were associated with increased odds of both heavy episodic drinking (4+/5+ drinks) and high-intensity drinking (8+/10+ drinks) compared to alcohol-only days. On co-use days, heavier drinking was more likely when more cannabis was used. Greater use of flower (grams) and concentrate (hits) specifically predicted high-intensity drinking.","whyItMatters":"The combination of alcohol and cannabis is increasingly common among young adults, and this study shows the combination is associated with the most dangerous level of drinking. Understanding that co-use days are heavier drinking days could inform targeted intervention.","specificNumbers":"318 participants; 54 daily surveys; increased odds of HID (8+/10+ drinks) and HED (4+/5+ drinks) on co-use vs alcohol-only days; more cannabis events per day predicted heavier drinking; more grams of flower predicted HID; more hits of concentrates predicted HID; HID vs HED did not differ between co-use and alcohol-only days","methodology":"Daily diary study with 318 young adults from three US universities who reported simultaneous alcohol and cannabis use. Participants completed five repeated daily surveys over 54 consecutive days reporting drinks consumed, cannabis use frequency, forms, and quantity.","limitations":"Self-selected sample from three universities may not represent all young adults, daily diary relies on self-report, cannot determine whether cannabis causes heavier drinking or both reflect a common tendency, only examined simultaneous use"},{"rthcId":"RTHC-06108","title":"Women's Experiences with Nicotine and Cannabis Vaping During Pregnancy and Postpartum.","authors":"Brabete, Andreea C; Greaves, Lorraine; Poole, Nancy; Huber, Ella; Stinson, Julie","year":2025,"journal":"Healthcare (Basel, Switzerland), 13(3)","doi":"10.3390/healthcare13030223","pmid":"39942412","tags":["prenatal","health-risks"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"51.4% vaped nicotine only, 27.9% vaped cannabis only, and 20.7% vaped both. 64.9% vaped daily. Primary reasons were relaxation, managing anxiety/depression, enjoyment, and the belief that vaping is less harmful than smoking. Women commonly consulted healthcare providers about potential harm to pregnancy and fetal health.","whyItMatters":"Cannabis vaping during pregnancy is an emerging concern that has received little research attention. The belief that vaping is safer than smoking may give pregnant women a false sense of security, especially since the health effects of vaping cannabis during pregnancy are largely unknown.","specificNumbers":"111 women; 51.4% nicotine only, 27.9% cannabis, 20.7% both; 63.1% currently pregnant, 36.9% postpartum; 64.9% vaped daily; fruit flavors most popular; top reasons: relaxation, anxiety/depression management, enjoyment, perceived harm reduction vs smoking","methodology":"Online survey of 111 women recruited via social media who vaped nicotine and/or cannabis during pregnancy or postpartum. Questions covered reasons for vaping, risk perceptions, attitudes, and healthcare provider consultations.","limitations":"Small convenience sample (111 women) recruited via social media, self-selection bias toward women more open about vaping, no biological verification of use, cross-sectional design, cannot determine actual health effects of vaping during pregnancy"},{"rthcId":"RTHC-06109","title":"Rural-urban divide in risk perception of LSD: Implications for psychedelic-assisted therapy.","authors":"Bradley, Melissa; Grossman, Daniel; Simonsson, Otto; Copes, Heith; Hendricks, Peter S","year":2025,"journal":"The Journal of rural health : official journal of the American Rural Health Association and the National Rural Health Care Association, 41(1), e12906","doi":"10.1111/jrh.12906","pmid":"39731315","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06110","title":"Substance Use While Sexting Moderates the Effect of Sexual Identity Development on Offline and Online Sexting Consequences Among Adolescent Sexual Minority Males.","authors":"Bragard, Elise; Paradise, Diana; Fisher, Celia B","year":2025,"journal":"Archives of sexual behavior, 54(7), 2579-2597","doi":"10.1007/s10508-025-03185-4","pmid":"40643806","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06111","title":"Prevalence of cannabis and medication use by indices of residential urbanicity and deprivation among Ohio cancer patients.","authors":"Brasky, Theodore M; Lee, Shieun; McBride, Bella; Newton, Alison M; Baltic, Ryan D; Wagener, Theodore L; Conroy, Sara; Hays, John L; Stevens, Erin E; Adib, Anita; Krok-Schoen, Jessica L","year":2025,"journal":"Cancer causes & control : CCC, 36(7), 719-724","doi":"10.1007/s10552-025-01972-x","pmid":"39934610","tags":["medical-use","cancer"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis use prevalence was 19% in higher social disadvantage areas versus 13% in lower disadvantage areas. Opioid use showed a similar pattern (30% vs. 21%). No differences were observed for benzodiazepines or for any substance by rural vs. urban residence.","whyItMatters":"Understanding who uses cannabis among cancer patients helps identify potential health equity concerns. Patients in disadvantaged areas may face both greater symptom burden and fewer treatment options, leading to higher use of both cannabis and opioids for symptom management.","specificNumbers":"854 Ohio cancer patients; cannabis use 19% vs 13% by social disadvantage; opioid use 30% vs 21%; no difference for benzodiazepines; no rural-urban differences for any substance","methodology":"Cross-sectional study of 854 Ohio cancer patients at an academic cancer center. Residential ZIP codes were used to assign rural-urban commuting area codes and social deprivation index values. Participants completed a cannabis-focused questionnaire including medication use items.","limitations":"Single academic cancer center in Ohio, descriptive findings without statistical adjustment for cancer type or stage, area-level social disadvantage may not reflect individual circumstances, cross-sectional design, self-reported cannabis use"},{"rthcId":"RTHC-06112","title":"A behavioural and neurobiological assessment of effort-based decision-making in cannabis use disorder: An initial/preliminary investigation.","authors":"Brassard, Sarah L; Dosanjh, Jadyn; Cooper, Jessica; Weber, Jochen; Zald, David; MacKillop, James; Balodis, Iris M","year":2025,"journal":"Cognitive, affective & behavioral neuroscience, 25(5), 1496-1514","doi":"10.3758/s13415-025-01308-x","pmid":"40528148","tags":["addiction","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"The CUD group showed decreased ventromedial prefrontal cortex activity when initially evaluating effort and reward cues (Cue1), and increased activity in parietal, temporal, and cingulate regions during effort-reward integration (Cue2). Despite these neural differences, both groups made similar behavioral choices. In the CUD group specifically, ventral striatum activity during effort cues was associated with willingness to accept high-effort/high-reward trials.","whyItMatters":"Low motivation is a hallmark clinical feature of cannabis use disorder, but its brain basis has been poorly understood. This study reveals specific neural circuitry differences in how people with CUD process effort-reward tradeoffs, pointing toward potential treatment targets.","specificNumbers":"21 CUD participants, 20 healthy controls; decreased vmPFC activity during prospective encoding in CUD; increased parietal, temporal, fusiform, cingulate, claustrum activity during integration in CUD; behavioral choices similar between groups; ventral striatum activity correlated with high-effort acceptance in CUD group","methodology":"fMRI study comparing 21 individuals with cannabis use disorder and 20 healthy controls during a sequential effort-based decision-making task. The task separated the evaluation of effort/reward cues from their integration and subsequent choice behavior.","limitations":"Small sample (21 CUD, 20 controls), cross-sectional design cannot determine if neural differences preceded or resulted from cannabis use, task used monetary rewards which may not capture real-world motivation, no assessment of acute cannabis effects, no dose-response analysis"},{"rthcId":"RTHC-06113","title":"Does cyber dating abuse victimization predict next-day alcohol and cannabis use among college students?","authors":"Brem, Meagan J; Shaw, T J; Tobar-Santamaria, Allison","year":2025,"journal":"The American journal on addictions, 34(3), 297-304","doi":"10.1111/ajad.13672","pmid":"39778049","tags":["youth","addiction","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Among men, experiencing cyber dating abuse victimization predicted a 7.34-fold increase in odds of next-day cannabis use (p < .001). Paradoxically, CDA victimization was associated with fewer drinks the following day for men. Among women, CDA victimization was unrelated to next-day cannabis or alcohol use.","whyItMatters":"This is the first study to identify cannabis use as a specific behavioral response to cyber dating abuse. The strong gender difference suggests men and women may use different coping mechanisms after relationship conflicts, with men turning to cannabis rather than alcohol.","specificNumbers":"236 participants (73.73% women); 60 daily surveys; men: CDA predicted 7.34x odds of next-day cannabis use (p < .001); men: CDA predicted fewer drinks next day (B = -2.63, p < .001); women: no associations with next-day substance use; 43% of CDA events per year in college","methodology":"60-day daily diary study with 236 college students in dating relationships (73.73% cisgender women). Participants reported daily alcohol use, cannabis use, and cyber dating abuse victimization experiences. Multilevel modeling accounted for within-person and between-person variation.","limitations":"Small male subsample (26.3% of 236), daily diary relies on self-report, cannot confirm causal direction, college student sample may not generalize, cannabis use measured as yes/no without quantity"},{"rthcId":"RTHC-06114","title":"Early and risky adolescent alcohol use independently predict alcohol, tobacco, cannabis and other drug use in early adulthood in Ireland: a longitudinal analysis of a nationally representative cohort.","authors":"Brennan, Margaret M; Mongan, Deirdre; Doyle, Anne; Millar, Seán R; Cavallaro, Massimo; Zgaga, Lina; Smyth, Bobby P; Nixon, Elizabeth; Ivers, Jo-Hanna; Galvin, Brian; Walsh, Cathal; McCrory, Cathal; McCarthy, Noel D","year":2025,"journal":"BMC public health, 25(1), 1129","doi":"10.1186/s12889-025-22262-w","pmid":"40128701","tags":["youth","addiction","gateway-theory"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Older age at first alcohol use was associated with dose-response reductions in cannabis use odds at age 20 (relative to initiation at 14 or younger). Adolescents with high-risk drinking at 17 had 2.1x odds of tobacco use and 2.5x odds of other drug use at 20. 27% reported first alcohol use at 14 or younger; by 20, 24% used cannabis.","whyItMatters":"This large longitudinal study with extensive confounding adjustment provides strong evidence that early alcohol use is a gateway risk factor for cannabis and other drug use, independent of personality, mental health, and social factors. It supports the case for delaying adolescent alcohol initiation as a broad substance use prevention strategy.","specificNumbers":"4,554 participants (49.8% female); 27% first drink at age 14 or younger; at age 20: 14% high-risk alcohol, 38% tobacco, 24% cannabis, 28% other drugs; high-risk alcohol at 17 predicted 11.5x odds of continued high-risk alcohol, 2.1x tobacco, 2.5x other drugs at 20; dose-response with age of first drink","methodology":"Nationally representative Growing Up in Ireland cohort (n=4,554, born 1997-1998). Survey-weighted logistic regression examined age at first drink and risky drinking at 17 as independent predictors of substance use at 20, adjusted for sex, academic ability, personality, psychological factors, SES, and family/peer substance use.","limitations":"Observational design cannot prove causation despite extensive adjustment, Irish context may not generalize to all cultures, self-reported substance use, age 20 follow-up may not capture later patterns, attrition between waves"},{"rthcId":"RTHC-06115","title":"CANN2021 survey and registry-linkages cohort on cannabis involvement among Norwegian high school students: design, measures and sample characteristics - cohort profile.","authors":"Bretteville-Jensen, Anne Line; Burdzovic Andreas, Jasmina","year":2025,"journal":"BMJ open, 15(7), e092475","doi":"10.1136/bmjopen-2024-092475","pmid":"40701583","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06116","title":"The Prevalence and Correlates of Cannabis-Related Harms in a Nationally Representative Sample of Norwegian High School Students.","authors":"Bretteville-Jensen, Anne Line; Sznitman, Sharon R","year":2025,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 76(4), 710-717","doi":"10.1016/j.jadohealth.2024.11.249","pmid":"39918509","tags":["youth","health-risks","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"65% of adolescent cannabis users reported at least one harm (mean 4.7 harms). The most common were feelings of shame (44%), adverse psychoactive effects (42%), harmed relationships (21%), unprotected/unwanted sex (17%), and school troubles (17%). Early initiation and simultaneous use with alcohol predicted more harms, but frequency of use alone did not.","whyItMatters":"Most cannabis harm research focuses on clinical disorders or brain effects. This study captures a much wider range of real-world consequences that adolescents actually experience, from shame and relationship damage to sexual risk and academic problems, painting a more complete picture of how cannabis affects young lives.","specificNumbers":"3,490 students; 20% lifetime cannabis use; 65% of users reported at least one harm; mean 4.7 harms per user; shame 44%, adverse psychoactive effects 42%, harmed relationships 21%, unprotected/unwanted sex 17%, school troubles 17%; early initiation IRR 1.564 (p < .01); simultaneous alcohol use IRR 1.385 (p < .01); frequency not significant","methodology":"Nationally representative survey of 3,490 Norwegian high school students (ages 17-19, 48% male). Among the 20% who reported lifetime cannabis use, researchers assessed 18 possible cannabis-related harms and their associations with use patterns, controlling for sociodemographic and temperamental factors.","limitations":"Cross-sectional design cannot determine temporal sequence, Norwegian legal context (cannabis illegal) may influence reporting, self-reported harms may be under- or over-reported, 20% lifetime use rate may not generalize to all countries, retrospective recall of harms"},{"rthcId":"RTHC-06117","title":"Long-acting naltrexone restores network connectivity in subjects with co-morbid cannabis and opioid use disorder.","authors":"Brier, Lindsey M; Langleben, Daniel D; Wiers, Corinde E; Shi, Zhenhao","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.09.18.676931","pmid":"41000850","tags":["addiction","medical-use"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"At baseline, people with opioid use disorder plus co-occurring cannabis use disorder showed distinct brain connectivity alterations compared to those with OUD alone, primarily involving the default mode network. Two weeks after naltrexone administration, these connectivity differences globally diminished in the cannabis group. Similar but more limited restoration occurred in co-occurring alcohol use disorder, while no change occurred in co-occurring cocaine use disorder.","whyItMatters":"No medication is currently approved for cannabis use disorder. This study provides neuroimaging evidence that naltrexone, already approved for opioid and alcohol use disorders, may address the brain connectivity disruptions specific to cannabis use disorder, potentially offering a treatment pathway.","specificNumbers":"Brain connectivity differences between co-occurring CanUD and OUD-only diminished globally after naltrexone; default mode network primarily affected at baseline; parietal, subcortical, sensory, and cerebellar restoration in AUD group; no change in CocUD group; younger participants showed larger baseline differences; effects controlled for opioid use","methodology":"Retrospective secondary analysis of fMRI data from individuals with primary opioid use disorder and co-occurring cannabis, alcohol, or cocaine use disorder. All received long-acting intramuscular naltrexone (Vivitrol) and were imaged before and 2 weeks after treatment.","limitations":"Retrospective secondary analysis not designed to study CUD, small subgroup sizes, cannot separate CUD-specific effects from general opioid recovery effects, no behavioral cannabis use outcomes measured, participants had co-occurring OUD complicating interpretation"},{"rthcId":"RTHC-06118","title":"Combination of Cannabidiol and Low-Dose Buprenorphine Suggests Synergistic Analgesia and Attenuates Buprenorphine-Induced Respiratory Depression.","authors":"Briones, Marisa S; DeYoung, Dustin Z; Heinzerling, Keith G","year":2025,"journal":"Cannabis and cannabinoid research, 10(5), 621-630","doi":"10.1089/can.2025.0004","pmid":"40468945","tags":["cbd","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The combination of a sub-analgesic buprenorphine dose and CBD produced statistically significant increases in pain threshold compared to either compound alone. CBD attenuated buprenorphine-induced respiratory depression as measured by blood gas analysis and oxygen saturation. CBD increased buprenorphine blood levels by approximately 30% but this pharmacokinetic interaction did not account for the analgesic or respiratory effects.","whyItMatters":"Opioid overdose deaths remain a public health crisis, largely due to respiratory depression. A combination that provides pain relief at lower opioid doses while also protecting breathing could represent a fundamentally safer approach to pain management.","specificNumbers":"Sub-analgesic buprenorphine + CBD produced significant pain relief (p < 0.05 vs saline); CBD attenuated buprenorphine-induced respiratory depression in blood gas (p < 0.05) and O2 saturation (p < 0.05); CBD increased buprenorphine AUC by ~30% (p = 0.008); no changes in other pharmacokinetic parameters; CBD did not attenuate morphine-induced respiratory depression","methodology":"Chronic constriction injury model of neuropathic pain in rats assessed via Von Frey testing. Pharmacokinetic study measured drug-drug interactions. Respiratory depression assessed in two separate studies using blood gas analysis and oxygen saturation monitoring.","limitations":"Rat model may not translate to humans, specific to buprenorphine (did not work with morphine), the 30% increase in buprenorphine blood levels could have clinical implications, single pain model tested, no data on tolerance or long-term use"},{"rthcId":"RTHC-06119","title":"Cannabinoids for Inflammatory Bowel Disease: A Scoping Review.","authors":"Brodaric, Alen; Polikarpova, Aleksandra; Hong, Jonathan","year":2025,"journal":"Cannabis and cannabinoid research, 10(1), 18-27","doi":"10.1089/can.2024.0061","pmid":"39029906","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06120","title":"Impact of naturalistic cannabis use on lateral control and speed: A driving simulator study.","authors":"Brooks-Russell, Ashley; Bird, Sarah; Brown, Timothy; Limbacher, Sarah; Kosnett, Michael; Dooley, Greg; Wrobel, Julia","year":2025,"journal":"Traffic injury prevention, 26(sup1), S86-S95","doi":"10.1080/15389588.2025.2508381","pmid":"40504631","tags":["driving","thc","dosing"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Occasional flower users had a significant increase in lane departures after cannabis use (0.16/min at baseline to 0.47/min 30 minutes post-use). Daily flower and daily concentrate users showed little to no change in lane departures or speed. All cannabis-using groups maintained or slightly decreased speed post-use, while controls slightly increased speed. Overall driving changes were relatively small across all groups.","whyItMatters":"Most cannabis-driving research uses low-potency products that do not reflect what is actually sold in legal markets. This study used participants' own products (including high-potency concentrates) and found that tolerance plays a major role: daily users showed little impairment even with stronger products.","specificNumbers":"118 participants; occasional flower users: lane departures increased from 0.16 to 0.47/min; daily flower and concentrate groups: minimal changes; controls slightly increased speed (53.9 to 54.6 mph); cannabis groups maintained speed; changes were relatively small across all groups","methodology":"118 participants completed three 20-minute simulated drives: baseline, 30 minutes post-use, and 90 minutes post-use. 89 inhaled their own cannabis products (flower or concentrates) for up to 15 minutes, while 29 controls completed the protocol without using cannabis. Groups were divided by use frequency and product type.","limitations":"Simulated driving may not capture all real-world driving demands, self-selected participants using their own products creates dosing variability, no THC blood levels reported in abstract, within-subjects design but unequal group sizes, controlled environment differs from real driving conditions"},{"rthcId":"RTHC-06121","title":"Pupillary dynamics as a marker of acute cannabis inhalation.","authors":"Brooks-Russell, Ashley; Godbole, Suneeta; Kosnett, Michael J; Limbacher, Sarah; Subramanian, Prem S; Brown, Timothy; Wrobel, Julia","year":2025,"journal":"Clinical toxicology (Philadelphia, Pa.), 63(11), 869-877","doi":"10.1080/15563650.2025.2543066","pmid":"40964784","tags":["driving","thc"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The most predictive pupillary measure was percent change in pupil size, which decreased after cannabis use, with an area under the curve of 0.73 at 40 minutes and 0.75 at 100 minutes. Pupil size alone (measured in darkness) did not reliably change after cannabis use. Diminished pupil dynamics (constriction to light and recovery dilation) were more predictive than static pupil size.","whyItMatters":"Law enforcement currently relies on subjective assessment of eye changes during drug recognition evaluations. This study tested whether objective pupillometer measurements could improve detection accuracy, finding moderate but imperfect predictive value.","specificNumbers":"126 participants; AUC 0.73 at 40 min and 0.75 at 100 min for percent change in pupil size; maximum pupil size in darkness not reliably changed; diminished constriction and recovery dilation more predictive; combining multiple measures did not meaningfully improve prediction","methodology":"126 participants assessed with a NeurOptics PLR-3000 pupillometer at baseline and at 40 and 100 minutes after ad libitum cannabis inhalation (95 cannabis users, 31 controls). Sensitivity, specificity, and accuracy calculated for multiple pupillary measures.","limitations":"Moderate predictive accuracy (AUC 0.73-0.75) means significant false positive and negative rates, participants used their own cannabis products creating dosing variability, pupil dynamics can be affected by other substances and medical conditions, laboratory conditions differ from roadside testing"},{"rthcId":"RTHC-06122","title":"What every dentist needs to know about cannabis use and head and neck cancer.","authors":"Brooks, John K; Hamza, Muhammad; Fitzpatrick, Maureen A; Bashirelahi, Nasir","year":2025,"journal":"General dentistry, 73(5), 25-27","doi":null,"pmid":"40828554","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06123","title":"Interactions between cannabis use and chronic pain on sleep architecture: Findings from in-home EEG recordings.","authors":"Brown, Tracy W; Filbey, Francesca M","year":2025,"journal":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, e00785","doi":"10.1016/j.neurot.2025.e00785","pmid":"41224613","tags":["sleep","pain","medical-use"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis use showed significant main effects on slow-wave sleep (deep sleep), total sleep time, sleep onset latency, and REM sleep. Chronic pain had a significant main effect on total sleep time. Critically, significant interactions emerged between cannabis use and chronic pain on both slow-wave sleep and REM sleep, suggesting cannabis affects sleep architecture differently depending on pain status.","whyItMatters":"Pain and sleep are among the top reasons people use medical cannabis, yet research has studied them in isolation. This is one of the first studies to show that cannabis effects on sleep depend on pain status, meaning findings from pain-free populations may not apply to medical cannabis users.","specificNumbers":"60 adults; 339 nights; 2,273 hours of EEG data; 7 consecutive nights per participant; significant cannabis effects on SWS, TST, SOL, and REM; significant pain effect on TST; significant cannabis x pain interactions on SWS and REM","methodology":"60 adults (50% male, 47% cannabis users, 32% with chronic pain) wore in-home EEG monitors for 7 consecutive nights each, generating 339 nights (2,273 hours) of sleep data. Mixed-model repeated-measures analysis tested main effects and interactions of cannabis use and chronic pain on five sleep metrics.","limitations":"Observational design cannot prove causation, relatively small sample (60 participants), cannabis use was naturalistic (not controlled dosing), chronic pain self-reported without clinical verification, 7 nights may not capture full variability"},{"rthcId":"RTHC-06124","title":"Oral microbial profiles in young adults with cannabis use disorder.","authors":"Browning, Brittney D; Tomko, Rachel L; Kirkland, Anna E; Visontay, Rachel; Ferguson, Pamela L; Alekseyenko, Alexander V; Engevik, Melinda A; Mewton, Louise; Squeglia, Lindsay M","year":2025,"journal":"Drug and alcohol dependence, 275, 112822","doi":"10.1016/j.drugalcdep.2025.112822","pmid":"40815909","tags":["addiction","health-risks"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Compared to a non-CUD substance use disorder control group, the CUD group exhibited significantly lower alpha diversity (fewer types of bacteria), distinct beta diversity (different bacterial community composition), and differences in specific bacterial taxa. Among CUD participants, more frequent cannabis use was linked to lower diversity, and both frequency and amount were associated with higher abundances of strict anaerobes.","whyItMatters":"The oral microbiome affects whole-body health, from cardiovascular disease to mental health. Finding that cannabis use disorder specifically alters oral bacterial communities could reveal biological pathways linking heavy cannabis use to broader health outcomes.","specificNumbers":"192 participants; 129 with CUD, 63 with non-CUD SUD; CUD had lower alpha diversity; distinct beta diversity between groups; greater cannabis frequency linked to lower diversity; frequency and amount linked to higher strict anaerobe abundance; controlled for sequencing batch, age, sex, race, BMI, alcohol","methodology":"192 young adults (ages 18-25) with CUD (n=129) or non-CUD substance use disorder (n=63) provided saliva samples for 16S rRNA gene sequencing. The non-CUD SUD control group helped isolate cannabis-specific effects in a population that commonly uses multiple substances. Analyses controlled for batch, age, sex, race, BMI, and alcohol use.","limitations":"Cross-sectional design cannot determine if cannabis caused the microbiome changes, all participants had substance use disorders limiting generalizability, self-reported cannabis use, saliva sampling captures only part of the oral microbiome, no longitudinal follow-up"},{"rthcId":"RTHC-06125","title":"Neolignans isolated from industrial hemp (Cannabis sativa L.) roots have cytotoxic effects on cancer cells.","authors":"Brownstein, Korey J; Nieukirk, Grace E; Edwards, Jackson; Thomas, Maria; Nguyen, Thu Hien; de Alarcón, Pedro A; Vermillion, Karl E; Gnanamony, Manu","year":2025,"journal":"Journal of cannabis research, 7(1), 58","doi":"10.1186/s42238-025-00316-5","pmid":"40818965","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06126","title":"Prevalence of Impairing Substance Use in Injured Drivers.","authors":"Brubacher, Jeffrey R; Erdelyi, Shannon; Chan, Herbert; Simmons, Sarah; Atkinson, Paul; Besserer, Floyd; Clarke, David B; Davis, Phil; Daoust, Raoul; Émond, Marcel; Eppler, Jeff; Lee, Jacques S; MacPherson, Andrew; Magee, Kirk; Mercier, Eric; Ohle, Robert; Parsons, Mike; Rao, Jagadish; Rowe, Brian H; Taylor, John; Vaillancourt, Christian; Wishart, Ian","year":2025,"journal":"JAMA network open, 8(4), e256379","doi":"10.1001/jamanetworkopen.2025.6379","pmid":"40261650","tags":["driving","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This is one of the largest and most rigorous studies of substance use among injured drivers ever conducted. Rather than relying on self-report or police records, researchers prospectively collected blood samples from 8,328 injured drivers treated at 15 Canadian trauma centers from 2019 to 2023 — spanning the period after Canada's 2018 recreational cannabis legalization.\n\nThe headline: 54.9% of injured drivers had at least one impairing substance in their blood. More than half. The specific breakdown reveals the scale of the problem across substance classes.\n\nAlcohol was the most prevalent, as expected. But THC was the most commonly detected drug (after alcohol), confirming that cannabis-involved driving is a significant component of the impaired driving landscape in post-legalization Canada. Stimulants, opioids, and depressants were also detected, often in combination with other substances.\n\nThe study identified demographic and collision factors associated with substance use, and notably compared prevalence across different parts of Canada, revealing geographic variation in the drug-involved driving picture.\n\nPolysubstance use (multiple substances simultaneously) was common, adding to the clinical complexity — the effects of THC combined with alcohol or other drugs on driving may be different from the effects of any single substance.","whyItMatters":"Canada legalized recreational cannabis in 2018 with the explicit goal of reducing harms, including impaired driving. This study provides the most comprehensive post-legalization snapshot of substance-involved driving injuries, showing that THC is a major part of the picture. The 54.9% overall prevalence rate is a sobering number for traffic safety policy.","specificNumbers":"8,328 injured drivers. Mean age 43 years. 67.3% male. 54.9% had at least one substance detected. THC was the most common drug after alcohol. 15 trauma centers across Canada. Study period: January 2019 – June 2023 (post-legalization).","methodology":"Cross-sectional study with prospective blood collection from 8,328 injured drivers at 15 Canadian trauma centers (January 2019 – June 2023). Blood tested for THC, alcohol, stimulants, opioids, and depressants. Demographic and collision details extracted from medical records. Crude prevalence computed overall and by subgroup. Logistic regression identified factors associated with substance use.","limitations":"Only includes injured drivers who reached trauma centers — not all impaired driving incidents, and not uninjured impaired drivers. Blood collection may have been delayed (as documented in RTHC-00092 and RTHC-00124), potentially missing some THC-positive cases. Detection of a substance in blood doesn't prove impairment at the time of the crash. No pre-legalization comparison from the same trauma centers, making it impossible to determine whether legalization changed prevalence. Cannot distinguish between driver-at-fault and not-at-fault for drug involvement."},{"rthcId":"RTHC-06127","title":"Inhibition of endocannabinoid hydrolases MAGL, FAAH and ABHD6 by AKU-005 reduces ex vivo cortical spreading depression.","authors":"Brugia, Flavia; Ivanov, Konstantin; Aroviita, Auni; Giniatullina, Raisa; Lehtonen, Marko; Malm, Tarja; Savinainen, Juha; Giniatullin, Rashid; Della Pietra, Adriana","year":2025,"journal":"The journal of headache and pain, 26(1), 85","doi":"10.1186/s10194-025-02030-2","pmid":"40269679","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06128","title":"Randomized Laboratory Study of Single-Dose Cannabis, Dronabinol, and Placebo in Patients With Schizophrenia and Cannabis Use Disorder.","authors":"Brunette, Mary F; Roth, Robert M; Trask, Christi; Khokhar, Jibran Y; Ford, James C; Park, Soo Hwan; Hickey, Sara M; Zeffiro, Thomas; Xie, Haiyi","year":2025,"journal":"Schizophrenia bulletin, 51(2), 479-492","doi":"10.1093/schbul/sbae097","pmid":"38900958","tags":["psychosis","addiction","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Oral dronabinol (15 mg) worsened verbal learning (B = -9.89) and attention (B = -0.61) in the schizophrenia-CUD group compared to placebo. Neither smoked nor oral THC worsened positive or negative psychotic symptoms at 2 and 5 hours post-dose. However, higher serum THC levels were associated with worse negative symptoms (0.40 points per 10 ng/ml increase) regardless of administration route.","whyItMatters":"Up to 43% of people with schizophrenia have cannabis use disorder. This controlled trial provides critical safety data showing a moderate THC dose did not trigger psychotic episodes in this population, while confirming the cognitive costs, information needed to guide clinical decision-making.","specificNumbers":"130 participants; 15 mg oral dronabinol or 3.5% THC smoked; dronabinol impaired verbal learning (B = -9.89, p = .004) and attention (B = -0.61, p = .002) in SCZ-CUD group; no symptom worsening at 2 and 5 hours; every 10 ng/ml serum THC increase associated with 0.40-point increase in negative symptoms (p = .001)","methodology":"Double-dummy, placebo-controlled trial with 130 total participants comparing single-dose oral dronabinol (15 mg), smoked 3.5% THC cannabis, or placebo. Groups included people with schizophrenia plus CUD, CUD only, schizophrenia only, and healthy controls. Symptoms and cognition assessed hours after administration.","limitations":"Single dose limits generalizability to chronic use effects, relatively low THC dose (3.5% flower is below market average), acute effects may differ from chronic effects, controlled setting may differ from real-world use, participants may have developed tolerance"},{"rthcId":"RTHC-06129","title":"Classes of Caregiver-Student Responsiveness to a Self-Directed Handbook Preventive Intervention and Their Associated Impact on First-Year Student Substance Use.","authors":"Bruzios, Kathryn E; Cooper, Brittany Rhoades; Duckworth, Jennifer; Hill, Clara M; Hill, Laura","year":2025,"journal":"Prevention science : the official journal of the Society for Prevention Research, 26(6), 956-967","doi":"10.1007/s11121-025-01832-9","pmid":"40745513","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06130","title":"Exploring Cannabidiol's Role in Regenerative Medicine: Focus on Neural and Skeletal Tissues.","authors":"Buchaim, Rogerio Leone; Dias, Livia Cristina; de Sousa, Fabiana Gomes Cardoso Pereira; Morais, Samuel de Sousa; Jacintho, Alexandre José; Paulini, Marina Ribeiro; Issa, João Paulo Mardegan; Buchaim, Daniela Vieira","year":2025,"journal":"Biomedicines, 13(10)","doi":"10.3390/biomedicines13102490","pmid":"41153773","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06131","title":"Canadian cannabis researcher perspectives on the conduct and sponsorship of scientific research by the for-profit cannabis industry.","authors":"Buchman, Daniel Z; Magel, Brooke; Shier, Rowen; Davies, Titilayo Esther; Sud, Abhimanyu; Mahajan, Shreya; Timothy, Roberta K; Soklaridis, Sophie; Grundy, Quinn","year":2025,"journal":"Social science & medicine (1982), 364, 117556","doi":"10.1016/j.socscimed.2024.117556","pmid":"39616790","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06132","title":"Imposter Syndrome and Cannabis-Related Problems: The Roles of Social Anxiety and Coping-Motivated Cannabis Use.","authors":"Buckner, Julia; Vargo, Luke; Knox, Amelia","year":2025,"journal":"Substance use & misuse, 1-7","doi":"10.1080/10826084.2025.2586660","pmid":"41250525","tags":["mental-health","addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Imposter syndrome was significantly related to cannabis problems and to using cannabis to cope with negative emotions, particularly social anxiety. The statistical pathway ran from imposter syndrome to social anxiety to coping-motivated cannabis use to cannabis problems (indirect effect b = 0.01-0.02).","whyItMatters":"Imposter syndrome is extremely common among college students and has not previously been linked to cannabis use. Identifying it as a risk factor for problematic cannabis use could inform campus interventions that address the underlying psychological vulnerability rather than just the substance use.","specificNumbers":"115 participants; 84% female; mean age 19.3; imposter syndrome significantly predicted cannabis problems; indirect effect through social anxiety and negative affect coping: b = 0.02 (CI: 0.003-0.04); indirect effect through social anxiety-specific coping: b = 0.01 (CI: 0.001-0.03)","methodology":"115 undergraduates (84% female, mean age 19.3) with past-month cannabis use completed an online survey measuring imposter syndrome, social anxiety, coping motivations for cannabis use, and cannabis-related problems. Serial mediation analyzed using PROCESS macro.","limitations":"Small sample (115) with predominance of female participants (84%), cross-sectional design cannot confirm causal direction, online survey with self-selection, single university, cannot determine if imposter syndrome precedes or follows cannabis use"},{"rthcId":"RTHC-06133","title":"Racism and cannabis-related problems among Black adults who smoke cigarettes: The role of negative emotions in responses to experiencing racism.","authors":"Buckner, Julia D; Sullivan, Jas M; Buenrostro, Christopher M; Clausen, Bryce; Zvolensky, Michael J","year":2025,"journal":"Experimental and clinical psychopharmacology, 33(2), 155-161","doi":"10.1037/pha0000759","pmid":"39621394","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"More frequent racism predicted greater cannabis-related problems. This relationship was mediated by negative emotions specifically tied to racial experiences (measured by the Racial Trauma Scale), but not by general anxiety or depression. There was also a sequential pathway: racism led to racial trauma emotions, which led to increased cannabis quantity, which led to more cannabis problems.","whyItMatters":"Black Americans face health disparities in cannabis-related outcomes despite similar use rates to other groups. This study identifies a specific mechanism: the emotional toll of racism, distinct from general mental health symptoms, may drive cannabis misuse, suggesting that culturally specific interventions addressing racial stress could reduce disparities.","specificNumbers":"254 participants; 50.2% female; mean age 42.1; racism frequency linked to cannabis problems via Racial Trauma Scale (RTS) emotions; general anxiety and depression did not mediate the relationship; sequential pathway: racism to RTS to greater cannabis quantity to more problems","methodology":"254 Black Americans (50.2% female, ages 18-73, mean age 42.1) who smoked cigarettes completed online surveys measuring racism frequency, racial trauma emotions, general anxiety/depression, smoking, and cannabis-related behaviors.","limitations":"Cross-sectional design cannot prove causation, all participants were cigarette smokers limiting generalizability, online survey with self-report measures, cannot determine temporal ordering of racism experiences and cannabis use, potential for recall bias"},{"rthcId":"RTHC-06134","title":"High Risk, Low Key: The New Face of Drug Use.","authors":"Burmeister, James R; Jung, John K","year":2025,"journal":"Substance use : research and treatment, 19, 29768357251389682","doi":"10.1177/29768357251389682","pmid":"41180078","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06135","title":"Past 30-Day Cannabis Use by Perception of Risk and Age Group: Implications for Prevention.","authors":"Burrow-Sánchez, Jason J; Cohen, Allison","year":2025,"journal":"American journal of health promotion : AJHP, 39(4), 619-626","doi":"10.1177/08901171241312508","pmid":"39756810","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"A significant interaction between age group and perceived risk predicted cannabis use. The sharpest increase in cannabis use probability occurred between adolescents (12-17) and young adults (18-25) among those with no or low risk perception. This suggests that adolescents who perceive cannabis as low-risk are primed for a major usage increase once they reach young adulthood.","whyItMatters":"Prevention programs that shape risk perception during adolescence could have outsized effects if they reach young people before the transition to adulthood, when low-risk perceiving adolescents appear most likely to start using cannabis.","specificNumbers":"58,034 participants; significant age x perceived risk interaction; sharpest usage increase between 12-17 and 18-25 age groups for no/low risk perceivers; population-level nationally representative sample; 2021 data","methodology":"Secondary analysis of the 2021 National Survey on Drug Use and Health (N=58,034, ages 12+). Binary logistic regression with complex sampling examined the interaction between age group and perceived risk on past 30-day cannabis use.","limitations":"Cross-sectional design cannot confirm that low risk perception causes later use, 2021 data from a single year, perceived risk and use measured simultaneously, cannot distinguish between accurate and inaccurate risk perceptions"},{"rthcId":"RTHC-06136","title":"Chronic modulation of endocannabinoid receptors does not impact hyperactivity, risk behavior, and working memory in an animal model of attention-deficit/hyperactivity disorder.","authors":"Bussinger de Souza Penna, Daniel; Gumiéro Costa, Samara; Davis, Marina Pollis; da Costa Calaza, Karin; Dos Santos Rodrigues, Alexandre; Pandolfo, Pablo","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 254, 174059","doi":"10.1016/j.pbb.2025.174059","pmid":"40617332","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06137","title":"Efficacy and safety of cannabidiol in a single-center pediatric drug-resistant epilepsy cohort: a retrospective study.","authors":"Butera, Ambra; Spoto, Giulia; Ceraolo, Graziana; Grella, Maria; Giunta, Ivana; Albertini, Maria Ludovica; Consoli, Carla; Sferro, Caterina; Spanò, Maria; Di Rosa, Gabriella; Nicotera, Antonio Gennaro","year":2025,"journal":"Frontiers in neurology, 16, 1616480","doi":"10.3389/fneur.2025.1616480","pmid":"40740850","tags":["cbd","epilepsy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"11 of 15 patients showed seizure frequency reduction: 7 were responders (over 50% reduction, including 2 seizure-free) and 4 were partial responders (30-50% reduction). 11 of 15 also showed improved social and environmental participation. CBD was used on-label in 8 patients (Dravet, Lennox-Gastaut, Tuberous Sclerosis) and off-label in 7.","whyItMatters":"About 30% of pediatric epilepsy patients do not respond to conventional antiseizure medications. While CBD is approved for three specific syndromes, this real-world study suggests it may benefit a wider range of drug-resistant epilepsies, including off-label uses.","specificNumbers":"15 patients; mean age 12.3 years; average CBD dose 16.5 mg/kg/day; 7 responders (>50% reduction), 4 partial responders (30-50%); 2 seizure-free; 11/15 improved social participation; 8 on-label, 7 off-label; good safety profile; structural brain abnormalities in 5/15; cortical malformations in 6/15 (4/6 responded)","methodology":"Retrospective single-center study of 15 pediatric patients (7 female, 8 male, mean age 12.3 years) with drug-resistant epilepsy who received CBD as adjunctive therapy for at least 6 months. Average dose 16.5 mg/kg/day (max 21 mg/kg/day). Clinical, demographic, and imaging data extracted from records.","limitations":"Very small sample (15 patients), retrospective design, single center, no control group, cannot separate CBD effects from placebo or natural disease course, heterogeneous epilepsy types"},{"rthcId":"RTHC-06138","title":"Impact of Opioid and Cannabis Use on Low-Dose Amitriptyline Efficacy in Cyclical Vomiting Syndrome: A Real-World Study in the United Kingdom.","authors":"Butt, Mohsin F; Cefalo, Francesca; Sbarigia, Caterina; Dhali, Arkadeep; Corsetti, Maura","year":2025,"journal":"Neurogastroenterology and motility, 37(6), e70007","doi":"10.1111/nmo.70007","pmid":"40017095","tags":["nausea","medical-use","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"61% of CVS patients responded to a three-tiered treatment algorithm, with 91% of responders responding to low-dose amitriptyline alone (mean 26.5 mg). 33% used opioids and 19% used cannabis. Opioid cessation was significantly associated with treatment response (p = 0.03). While cannabis use was prevalent, the study suggested that cessation of both substances may improve treatment outcomes.","whyItMatters":"Cyclical vomiting syndrome is frequently linked to cannabis use, yet the interaction between cannabis, CVS treatment, and clinical outcomes has been poorly understood. This study suggests stopping cannabis may be part of effective CVS management.","specificNumbers":"61% treatment response rate; 91% of responders responded to TCA alone; mean TCA dose 26.5 mg among responders; 33% used opioids; 19% cannabis; 7% both; opioid cessation associated with treatment response (p = 0.03); IBS associated with 6.59x odds of opioid use","methodology":"Retrospective data from consecutive newly diagnosed CVS patients at a single UK tertiary neurogastroenterology clinic (January 2016 to June 2024). Patients were advised to stop opioids and cannabis and started on low-dose amitriptyline with stepwise escalation if needed.","limitations":"Retrospective design at a single tertiary center, small sample limits statistical power for cannabis-specific analyses, cannot separate cessation effects from treatment effects, patients who stopped substances may have been more motivated overall, UK healthcare context"},{"rthcId":"RTHC-06139","title":"Trends in Post Legalization Cannabis Use Among Ethnic Groups in California: 2018-2023.","authors":"Caetano, Raul; Paschall, M J; Vaeth, Patrice A C; Kaplan, Zoe","year":2025,"journal":"Substance use & misuse, 1-8","doi":"10.1080/10826084.2025.2579709","pmid":"41201285","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Multivariable analysis showed a flat overall trend in past 30-day cannabis use from 2018 to 2023. However, subgroup analyses revealed significant differences: Asian Americans had lower odds of use than Whites (AOR 0.60), while trends varied by race/ethnicity over time. The American Indian/Alaska Native group showed the most notable increase, and Black non-Hispanic populations also trended upward.","whyItMatters":"A major concern about cannabis legalization was that use would increase broadly. This California data suggests legalization did not drive an overall increase, but the divergent trends by race/ethnicity indicate that legalization may affect different communities differently, with potential equity implications.","specificNumbers":"Flat overall trend 2018-2023; Asian Americans AOR 0.60 (CI: 0.43-0.85) vs Whites; significant race/ethnicity by time interactions; American Indian/Alaska Native showed notable increase; analysis controlled for sociodemographic factors; data from California Health Interview Survey","methodology":"Analysis of the California Health Interview Survey (CHIS), a representative household survey, examining past 30-day cannabis use among adults across racial/ethnic groups from 2018 to 2023. Logistic regression adjusted for sociodemographic factors.","limitations":"California-specific results may not generalize to other states, CHIS is a household survey excluding institutionalized populations, self-reported use subject to social desirability, 5-year window may not capture longer-term trends, some subgroup sample sizes may be small"},{"rthcId":"RTHC-06140","title":"Alcohol and Cannabis Use and Co-Use among Ethnic Groups in California.","authors":"Caetano, Raul; Paschall, M J; Vaeth, Patrice A C; Kaplan, Zoe","year":2025,"journal":"Journal of immigrant and minority health, 27(5), 799-808","doi":"10.1007/s10903-025-01743-5","pmid":"40775183","tags":["addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Alcohol-cannabis co-use was highest among Other/Two or more races (17.7%) and Whites (17.0%). After adjustment, Hispanics, Blacks, and Asians were all less likely than Whites to report alcohol use only, cannabis use only, or co-use. Among co-users, binge drinking was highest in the multiracial group (62.5%). No significant differences in illicit drug use were found across ethnic groups among co-users.","whyItMatters":"Co-using alcohol and cannabis carries higher risks than using either substance alone, including greater impairment and more negative consequences. Understanding which populations have the highest co-use rates can inform targeted prevention and harm reduction.","specificNumbers":"21,463 participants; co-use rates: Other/Two+ races 17.7%, Whites 17.0%; Hispanics, Blacks, Asians less likely than Whites to co-use; binge drinking among co-users: Other/Two+ races 62.5%; no ethnic differences in illicit drug use among co-users; 2022 California data","methodology":"Analysis of the 2022 California Health Interview Survey (N=21,463, 49.1% male). Multinomial logistic regression examined rates and correlates of alcohol-only use, cannabis-only use, and co-use across racial/ethnic groups.","limitations":"California-specific results, cross-sectional design, self-reported substance use, cannot determine causation, some ethnic subgroups may have small sample sizes, 2022 single-year data"},{"rthcId":"RTHC-06141","title":"Long-term plasma monitoring of THC and CBD in pediatric drug-resistant epilepsy: Implications for cannabidiol therapy with Epidyolex®.","authors":"Cafaro, Alessia; Riva, Antonella; Pigliasco, Federica; Barco, Sebastiano; Manca, Valentina; Stella Vari, Maria; Mancardi, Maria Margherita; Nobili, Lino; Pichini, Simona; Busardò, Francesco Paolo; Striano, Pasquale; Cangemi, Giuliana","year":2025,"journal":"Epilepsia open, 10(5), 1699-1704","doi":"10.1002/epi4.70112","pmid":"40938500","tags":["cbd","epilepsy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"THC was undetectable (<0.2 mcg/L) at all timepoints across all 38 patients throughout the study period (2019-2024). CBD plasma levels increased dose-dependently, reaching a median of 89.8 mcg/L at final follow-up, with a significant correlation between dose and concentration (p < 0.0001). Mean CBD dose was 13.6 mg/kg/day.","whyItMatters":"Parents of children on CBD therapy often worry about THC exposure. This long-term monitoring data provides strong reassurance that pharmaceutical-grade CBD (Epidyolex) produces no detectable THC in the blood, even over years of use, while confirming that dose adjustments reliably change CBD levels.","specificNumbers":"THC undetectable (<0.2 mcg/L) at all timepoints; 38 patients; median age 11 years; mean CBD dose 13.6 mg/kg/day; median CBD level 89.8 mcg/L at final follow-up; significant dose-concentration correlation (p < 0.0001); 2019-2024 monitoring period","methodology":"Retrospective analysis of 38 pediatric patients (median age 11 years) treated with Epidyolex at a single center from 2019 to 2024. Plasma CBD and THC measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS).","limitations":"Single center, retrospective design, only pharmaceutical-grade CBD studied (non-pharmaceutical products may differ), no clinical outcome data in this specific analysis, cannot generalize to adult patients"},{"rthcId":"RTHC-06142","title":"Accidental cannabis intoxication in two young children: clinical presentation and toxicokinetics - a case series.","authors":"Cafaro, Alessia; Pigliasco, Federica; Barco, Sebastiano; Negro, Ilaria; Piccotti, Emanuela; Manfredini, Luca; Mahameed, Samir; Bandettini, Roberto; Debbia, Carla; Mattioli, Francesca; Cangemi, Giuliana","year":2025,"journal":"Frontiers in pharmacology, 16, 1695194","doi":"10.3389/fphar.2025.1695194","pmid":"41306782","tags":["thc","youth","health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Peak plasma THC concentrations were 45.0 mcg/L in Case 1 and 54.7 mcg/L in Case 2. THC elimination was remarkably slow: half-life was 52.5 hours in Case 1 and 21.7 hours in Case 2 (adult half-life is typically 1-3 hours for intravenous THC). CBD was barely detectable. The clinical presentation was nonspecific, which initially delayed diagnosis.","whyItMatters":"Accidental cannabis edible ingestion by children is an increasing public health concern. This study reveals that very young children eliminate THC far more slowly than adults, meaning effects may last much longer and blood testing remains positive for extended periods.","specificNumbers":"Case 1: peak THC 45.0 mcg/L, t1/2 52.5 hours, kel 0.013 h-1; Case 2: peak THC 54.7 mcg/L, t1/2 21.7 hours, kel 0.031 h-1; CBD: undetectable in Case 1, only 1.11 mcg/L in first sample of Case 2; ages 12 and 15 months","methodology":"Case series of two pediatric patients (12 and 15 months old) who unintentionally ingested cannabis edibles. Four plasma samples per patient were collected and analyzed using validated LC-MS/MS. Non-compartmental analysis calculated toxicokinetic profiles.","limitations":"Only two cases, exact amount ingested unknown, individual variation in elimination may be large, limited serial sampling (four samples each), cannot generalize elimination half-lives from two patients"},{"rthcId":"RTHC-06143","title":"Effects of fecal microbiota transplantation from patients with generalized anxiety on anxiety-like behaviors: The role of the gut-microbiota-endocannabinoid-brain Axis.","authors":"Cai, Min; Xue, Shan-Shan; Zhou, Cui-Hong; Feng, Yu-Chao; Liu, Jiang-Zheng; Liu, Rui; Wang, Peng; Wang, Hua-Ning; Peng, Zheng-Wu","year":2025,"journal":"Journal of affective disorders, 381, 131-149","doi":"10.1016/j.jad.2025.04.018","pmid":"40187430","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06144","title":"Prenatal Exposure to Vaporized High-Potency Cannabis Affects Hippocampal Synaptic Remodeling and Efficacy, Axonal Excitability, and Memory in Offspring.","authors":"Cairus, Andrea; Brizolara, Facundo; Kunizawa, Héctor; Clouzet, Vanina; Gonzalez, Giuliana; Alsina-Llanes, Marcela; Dellepiane, Lucía; Fernández, Santiago; García-Carnelli, Carlos; Umpierrez, Eleuterio; Borde, Michel; Prieto, José Pedro; Vitureira, Nathalia","year":2025,"journal":"Journal of neurochemistry, 169(7), e70153","doi":"10.1111/jnc.70153","pmid":"40631442","tags":["prenatal","thc","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal exposure to vaporized cannabis (14.7% THC) from gestational day 8 to 21 caused: increased synaptic vesicle recycling pools and vGlut1 abundance (presynaptic remodeling), downregulation of CB1 receptors at both excitatory and inhibitory synapses, increased axonal recruitment and synaptic efficacy at hippocampal CA1 synapses, and spatial memory deficits in both male and female adolescent offspring.","whyItMatters":"Most prenatal cannabis research uses injected THC, but most humans smoke or vaporize. This study used a clinically relevant exposure method (vaporized whole cannabis) and a market-representative potency (14.7% THC), making the results more translatable to real-world prenatal exposure.","specificNumbers":"14.7% THC cannabis strain; exposure gestational day 8-21; increased vGlut1 and synaptic vesicle recycling pool; CB1R downregulated at glutamatergic and GABAergic synapses; increased axonal recruitment and synaptic efficacy at CA1; spatial memory deficits in both sexes during adolescence","methodology":"Pregnant rats were exposed to vapor from a commercially available high-potency cannabis strain (THC 14.7%) from gestational day 8 to 21. Offspring were assessed using primary hippocampal cell cultures, electrophysiology on brain slices, and behavioral memory tests.","limitations":"Rat model may not fully translate to humans, single cannabis strain tested, vaporization parameters may differ from human use, limited to hippocampal assessments, no dose-response comparison, offspring assessed only through adolescence"},{"rthcId":"RTHC-06145","title":"The association of preconception and prenatal cannabis and tobacco exposure with autism symptoms in offspring: A population-based longitudinal study.","authors":"Cajachagua-Torres, Kim N; Boer, Olga D; Louwerse, Anneke; Ghassabian, Akhgar; Reiss, Irwin K M; Jaddoe, Vincent W V; El Marroun, Hanan","year":2025,"journal":"Neurotoxicology and teratology, 112, 107561","doi":"10.1016/j.ntt.2025.107561","pmid":"41016606","tags":["prenatal","youth","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Maternal cannabis use before but not during pregnancy was associated with higher CBCL autism symptoms across childhood (beta: 0.33, CI: 0.02-0.63). Paternal cannabis use was also linked to higher CBCL symptoms (beta: 0.27, CI: 0.05-0.50) but was explained by maternal psychopathology. Continued maternal tobacco use during pregnancy was associated with SRS autism symptoms at age 6 (beta: 0.03, CI: 0.003-0.05), but paternal tobacco was not, suggesting intrauterine rather than familial effects.","whyItMatters":"This study separates the effects of preconception vs. prenatal cannabis exposure and maternal vs. paternal use, helping distinguish between direct in utero effects and familial/genetic confounding. The finding that preconception (not prenatal) cannabis use predicts autism symptoms suggests epigenetic or selection effects rather than direct fetal exposure.","specificNumbers":"4,380 children; maternal preconception cannabis: beta 0.33 (CI: 0.02-0.63) for CBCL autism; paternal cannabis: beta 0.27 (CI: 0.05-0.50) for CBCL; no association with SRS autism; maternal continued tobacco: beta 0.03 (CI: 0.003-0.05) for SRS autism; no paternal tobacco association","methodology":"Prospective population-based cohort (n=4,380) measuring parental cannabis and tobacco use via questionnaires and maternal cannabis metabolites via urinalysis. Autism symptoms measured using CBCL at ages 1.5, 3, and 6, and SRS at age 6. Linear mixed models and linear regression used.","limitations":"Self-reported substance use (though supplemented with urinalysis for cannabis), observational design cannot prove causation, autism symptoms measured by mother report not clinical diagnosis, effect sizes are small, cannot rule out all confounding"},{"rthcId":"RTHC-06146","title":"Targeting the Gut-Brain Axis with Plant-Derived Essential Oils: Phytocannabinoids and Beyond.","authors":"Camarda, Luca; Mattioli, Laura Beatrice; Corazza, Ivan; Marzetti, Carla; Budriesi, Roberta","year":2025,"journal":"Nutrients, 17(9)","doi":"10.3390/nu17091578","pmid":"40362887","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06147","title":"The impact of cannabinoids on reproductive function.","authors":"Cameron, Reese S; Perono, Genevieve A; Natale, Christian D; Petrik, James J; Holloway, Alison C; Hardy, Daniel B","year":2025,"journal":"Reproduction (Cambridge, England), 169(5)","doi":"10.1530/REP-24-0369","pmid":"40111139","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06148","title":"Therapeutic potential of minor cannabinoids in psychiatric disorders: A systematic review.","authors":"Cammà, Guido; Verdouw, Monika P; van der Meer, Pim B; Groenink, Lucianne; Batalla, Albert","year":2025,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 91, 9-24","doi":"10.1016/j.euroneuro.2024.10.006","pmid":"39541799","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06149","title":"Cannabis Use and Disclosure in the Oncology Setting: A Cross-Sectional Survey Exploring Information Needs Among Cancer Survivors.","authors":"Camp, Lindsey Nicole; Babicheva, Viktoriya; Conahan, Catherine; Hayes, Sara; Sherburne Hawkins, Summer","year":2025,"journal":"Clinical journal of oncology nursing, 29(2), 157-164","doi":"10.1188/25.CJON.157-164","pmid":"40096564","tags":["medical-use","cancer"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"About one-third of 719 cancer survivors reported current cannabis use. Cannabis use varied across the cancer care continuum. Most cannabis-using survivors discussed their use with a healthcare provider and reported interest in receiving more information about cannabis.","whyItMatters":"With roughly a third of cancer survivors using cannabis, healthcare providers need to be prepared for these conversations. The finding that most cannabis-using patients are willing to discuss and want more information suggests an opportunity for better clinical guidance.","specificNumbers":"719 participants; most currently undergoing treatment; approximately one-third current cannabis use; most disclosed to healthcare providers; most wanted more cannabis information; use varied across cancer care stages","methodology":"Cross-sectional online survey distributed through online health communities, collecting responses from 719 cancer survivors (most currently undergoing treatment) about cannabis behaviors, disclosure, and information needs.","limitations":"Online recruitment through health communities may oversample engaged patients, self-reported cannabis use, cross-sectional design, no information on cancer types or stages, participants may be more comfortable with cannabis than the general cancer population"},{"rthcId":"RTHC-06150","title":"The endocannabinoidome-gut microbiome-brain axis as a novel therapeutic target for autism spectrum disorder.","authors":"Campanale, Antonella; Siniscalco, Dario; Di Marzo, Vincenzo","year":2025,"journal":"Journal of biomedical science, 32(1), 60","doi":"10.1186/s12929-025-01145-7","pmid":"40605060","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06151","title":"Prospective associations of alcohol and drug misuse with suicidal behaviors among US Army soldiers who have left active service.","authors":"Campbell-Sills, Laura; Sun, Xiaoying; Kessler, Ronald C; Ursano, Robert J; Jain, Sonia; Stein, Murray B","year":2025,"journal":"Psychological medicine, 55, e119","doi":"10.1017/S0033291725000947","pmid":"40289652","tags":["veterans","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use at baseline was significantly associated with subsequent suicidal ideation (AOR range: 1.42-2.60 across substance use measures) and suicide planning. Binge drinking, prescription drug abuse, illicit drug use, and alcohol use disorder showed similar associations. No substance use variable predicted suicide attempts as a main effect, though interactions with depression and sex were found.","whyItMatters":"Veterans have elevated suicide rates, and understanding modifiable risk factors is critical. This study identifies substance use, including cannabis, as a prospective predictor of suicidal thoughts, providing potential screening and intervention targets.","specificNumbers":"6,811 veterans/reservists; two survey waves; substance use variables associated with ideation (AOR 1.42-2.60) and planning; no main effects on attempts; interactions with sex and depression found for some substances; 1,527 had ideation at baseline","methodology":"Longitudinal survey of 6,811 US Army veterans and deactivated reservists who completed surveys at two timepoints (2016-2018 and 2018-2019). Logistic regression adjusted for demographics and prior suicidality examined associations between substance use and subsequent suicidal behaviors.","limitations":"Self-reported substance use and suicidality, survey-based study may miss those in acute crisis, Army-specific population may not generalize to all veterans, two-year follow-up may miss longer-term effects, attrition between waves"},{"rthcId":"RTHC-06152","title":"Sociodemographic influences on substance use in psychosis in an African cohort.","authors":"Campbell, Megan L; Odokonyero, Raymond; Akena, Dickens; Alemayehu, Melkam; Atwoli, Lukoye; Chibnik, Lori B; Gelaye, Bizu; Gichuru, Stella; Kariuki, Symon M; Koenen, Karestan C; Kwobah, Edith; Kyebuzibwa, Joseph; Mwema, Rehema M; Newton, Charles R J C; Post, Kristianna; Pretorius, Adele; Stevenson, Anne; Stroud, Rocky E; Teferra, Solomon; Zingela, Zukiswa; Stein, Dan J; Hook, Kimberly","year":2025,"journal":"Schizophrenia research, 281, 157-163","doi":"10.1016/j.schres.2025.04.012","pmid":"40349466","tags":["psychosis","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Significant variations in cannabis consumption were observed across the four African countries studied. Males had consistently higher odds of alcohol, tobacco, and khat consumption compared to females. People with bipolar disorder had higher odds of alcohol use than those with schizophrenia. Unlike US studies, education level was not significantly associated with substance use frequency for most substances.","whyItMatters":"Most substance use research in psychosis comes from Western countries. This large multi-country African study reveals that patterns differ substantially from US and European populations, suggesting that interventions cannot simply be imported from Western settings.","specificNumbers":"Four countries: South Africa, Ethiopia, Kenya, Uganda; males higher odds for alcohol, tobacco, khat; bipolar disorder higher alcohol than schizophrenia; significant country-level variation in cannabis; education not significantly associated with most substance use (unlike US data); part of a 42,000+ participant genetics project","methodology":"Data from the Neuropsychiatric Genetics of African Populations-Psychosis project, a large case-control study. Substance use assessed with ASSIST v3. Ordinal regression examined frequency of alcohol, tobacco, cannabis, and khat use across sex, education, and country in people with bipolar disorder and schizophrenia.","limitations":"Cross-sectional design, substance use measured by frequency not quantity, ASSIST may not capture cultural patterns of use, four countries cannot represent all of Africa, possible reporting bias in psychiatric populations, selection effects in case-control recruitment"},{"rthcId":"RTHC-06153","title":"The Pleiotropic Influence of Cannabidiol and Tetrahydrocannabinol on Inflammatory Biomarkers: A Systematic Review and Meta-Analytical Synthesis.","authors":"Candeloro, Bruno Moreira; de Oliveira, Camila M; Gimenez, Fabiana Veronez Martelato; Barbosa, Marianne P C N; Soares, Beatriz Paiva; Ruiz, Ana C F; Folegatti, Derfel R M A; Barbalho, Sandra Maria; Oliveira, Nancy S; Porto, Andrey A; Garner, David Matthew; Sousa, Fernando H; Valenti, Vitor E","year":2025,"journal":"International journal of molecular sciences, 26(23)","doi":"10.3390/ijms262311618","pmid":"41373770","tags":["cbd","thc","inflammation"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Pooled estimates showed trivial and imprecise effects: IL-6 (SMD -0.17, p=0.41), IL-8 (SMD -0.30, p=0.06), IL-10 (SMD -0.10, p=0.79), and TNF-alpha (SMD -0.09, p=0.62). None reached statistical significance. Some individual trials in high-exposure or diseased populations reported reductions, but pooled effects were negligible. GRADE evidence certainty ranged from very low to moderate.","whyItMatters":"CBD and THC are widely marketed as anti-inflammatory, often based on preclinical data. This meta-analysis of actual human clinical trials shows that the anti-inflammatory effects observed in cells and animals have not consistently translated to measurable changes in human blood markers.","specificNumbers":"IL-6: SMD -0.17 (CI: -0.56 to 0.23, p=0.41, I2=55%, n~129/arm); IL-8: SMD -0.30 (CI: -0.62 to 0.01, p=0.06, I2=0%, n~78/arm); IL-10: SMD -0.10 (CI: -0.83 to 0.63, p=0.79, I2=81%, n~92/arm); TNF-alpha: SMD -0.09 (CI: -0.45 to 0.27, p=0.62, I2=33%, n~105/arm); GRADE: very low to moderate","methodology":"Systematic review and meta-analysis of 13 clinical studies meeting inclusion criteria. Random-effects models calculated standardized mean differences. Risk of bias assessed with RoB-2. Evidence certainty graded using GRADE methodology.","limitations":"Only 13 studies met inclusion criteria with small sample sizes per meta-analysis, heterogeneous populations and dosing regimens, circulating biomarkers may not reflect tissue-level inflammation, GRADE certainty was low for several outcomes, publication bias possible"},{"rthcId":"RTHC-06154","title":"Cannabidiol alleviates the inflammatory response in rats with traumatic brain injury through the PGE 2-EP2-cAMP-PKA signaling pathway.","authors":"Cao, Yan; Li, Hengxi; Li, Jiali; Ling, Tenghan; Yin, Aiping; Luo, Xinyuan; Zhou, Ying; Li, Jinghui; Jiang, Hongyan; Wang, Huawei; Yang, Li; Wu, Haiying; Li, Ping","year":2025,"journal":"Acta biochimica et biophysica Sinica, 57(5), 758-769","doi":"10.3724/abbs.2024183","pmid":"39921353","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD significantly improved neurological deficit scores, reduced neuronal damage, and decreased blood-brain barrier permeability after TBI. It inhibited astrocyte activation, reduced inflammatory prostaglandin markers, and lowered brain injury markers S-100-beta and NSE. Blocking the EP2 receptor or PKA enzyme eliminated CBD's protective effects, confirming the PGE2-EP2-cAMP-PKA pathway as the mechanism.","whyItMatters":"Traumatic brain injury affects millions annually with limited treatment options. Identifying a specific molecular pathway through which CBD reduces brain inflammation provides a target for drug development and helps explain why CBD might be neuroprotective.","specificNumbers":"CBD significantly improved neurological deficit scores; reduced S-100-beta and NSE (brain injury markers); attenuated blood-brain barrier permeability; reduced inflammatory prostaglandin indicators; EP2 inhibitor and PKA inhibitor both blocked CBD effects; PGE2-EP2-cAMP-PKA pathway confirmed","methodology":"Rat traumatic brain injury model using the Feeney free-fall method. CBD was administered and neurological, histological, and molecular outcomes measured. Specific pathway inhibitors (TG6-10-1 for EP2, H-89 for PKA) were used to confirm the mechanism.","limitations":"Rat model may not translate to human TBI, single injury model tested, CBD dosing and timing may not reflect clinical scenarios, pathway inhibitor studies confirm mechanism but do not guarantee clinical efficacy, no long-term outcome data"},{"rthcId":"RTHC-06155","title":"Divergent outcomes of delta 9 - tetrahydrocannabinol (THC) in adolescence on mesocortical dopamine and cognitive development in male and female mice.","authors":"Capolicchio, Tanya; Hernandez, Giovanni; Shi, Sammy Shun Wai; Dube, Emilie; Estrada, Katherina; Giroux, Michel; Nieman, Brian J; Pausova, Zdenka; Flores, Cecilia","year":2025,"journal":"Psychopharmacology, 242(10), 2181-2199","doi":"10.1007/s00213-025-06791-1","pmid":"40658196","tags":["thc","youth","cognition","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In males, adolescent THC reduced dopamine axon volume in the medial prefrontal cortex and reduced presynaptic sites, while increasing dopamine innervation in the orbitofrontal cortex, suggesting axons were rerouted. Males also showed increased premature responses but fewer commission errors on impulse control tasks. Females showed no dopamine wiring changes. Molecularly, males had increased DCC receptor and decreased miR-218 levels, while females showed decreased DCC without miR-218 changes and smaller microglia, potentially providing protection.","whyItMatters":"This study provides a specific biological mechanism for how adolescent THC disrupts brain development differently in males and females: by dysregulating a molecular guidance system (miR-218/DCC pathway) that directs where dopamine axons grow, causing them to wire to the wrong brain region in males.","specificNumbers":"Males: reduced dopamine axon volume in medial PFC, reduced presynaptic site density, increased orbitofrontal innervation, increased premature responses, fewer commission errors; females: no dopamine changes, smaller microglia; males: increased DCC, decreased miR-218; females: decreased DCC, no miR-218 change","methodology":"Adolescent mice received THC, and adult brains were analyzed for dopamine axon distribution, presynaptic sites, and molecular markers. Impulse control was assessed using the Go-No/Go task. Molecular analysis measured DCC receptor, miR-218, and microglial characteristics.","limitations":"Mouse model may not translate to humans, specific THC doses and timing may differ from human adolescent use, only two brain regions assessed, single behavioral test for impulse control, no dose-response analysis, no recovery time assessed"},{"rthcId":"RTHC-06156","title":"Preadolescent individual, familial, and social risk factors associated with longitudinal patterns of adolescent alcohol, cannabis, and other illicit drug use in a population-representative cohort.","authors":"Carbonneau, Rene; Vitaro, Frank; Brendgen, Mara; Boivin, Michel; Côté, Sylvana M; Tremblay, Richard E","year":2025,"journal":"Developmental psychology, 61(8), 1516-1530","doi":"10.1037/dev0001872","pmid":"39480305","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06157","title":"In silico study of the pharmacokinetics and human and environmental toxicological analysis of cannabidiol.","authors":"Cardoso-Filho, O; Andrade, M O; Cardoso, V A A; Rodrigues, V S; Guimarães, F S; Veloso, M D M; Arrudas, S R; Nunes, Y R F; Mota, L F","year":2025,"journal":"Brazilian journal of biology = Revista brasleira de biologia, 85, e291331","doi":"10.1590/1519-6984.291331","pmid":"40834136","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06158","title":"Understanding cannabis use and car crashes: Insights from a randomized trial using a driving simulator on THC blood levels and subjective measures of sleepiness and performance.","authors":"Cardozo, Bibiana; Hartley, Sarah; Simon, Nicolas; Alvarez, Jean Claude","year":2025,"journal":"Journal of safety research, 95, 109-116","doi":"10.1016/j.jsr.2025.09.005","pmid":"41338767","tags":["driving","sleep","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In this double-blind crossover RCT (randomized controlled trial where each person receives each condition), inhaled THC increased driving simulator collisions, with the clearest increase observed 4 hours after 10 mg and 30 mg THC. Higher THC Cmax (peak blood THC level) was strongly linked to more collisions at 4 hours. Higher self-rated sleepiness on the Karolinska Sleepiness Scale (a 1-9 rating of how sleepy someone feels) was also linked to higher collision rates on the simulator.","whyItMatters":"By 2025, policy and safety debates increasingly focused on whether blood THC can serve as a meaningful marker for driving risk, similar to blood alcohol. This study targeted a practical question for traffic safety science: whether a controlled THC exposure changes crash-like outcomes, and whether subjective ratings (VAS, or visual analog scales) track real performance in the same session. The crossover setup (the same participants under placebo, 10 mg, and 30 mg) reduces between-person differences that often complicate real-world crash research.","specificNumbers":"• THC dose effect at 4 hours: Beta = 0.65 (95% CI: 0.45 to 0.86), meaning a higher collision rate at that time point under THC compared with placebo in this model. The size is moderate within a simulator outcome, but it comes from N=30 (small sample).\n• Blood THC Cmax (peak blood THC level) and collisions at 4 hours: Beta = 3.63 (95% CI: 2.56 to 4.70), p<0.001 (very unlikely to be random chance). This is a large association within this dataset.\n• Blood THC Cmax and collision rate: IRR (incidence rate ratio) = 37.7, p<0.001, meaning collision counts were far higher at higher peak THC levels in this model. This is an extremely large estimate that can happen when events are sparse or clustered in small samples.\n• Sleepiness and collisions: Beta = 0.10 (95% CI: 0.05 to 0.15), p<0.001 and IRR = 1.1, p<0.001, meaning each 1-point increase on the Karolinska Sleepiness Scale was linked to about a 10% higher collision rate. That is a modest per-point change.","methodology":"This was a randomized, double-blind, crossover RCT, meaning the same 30 participants completed three separate sessions under placebo, 10 mg THC, and 30 mg THC, and neither participants nor staff knew the condition at the time. Each session was separated by a 7-day washout period, and participants stayed in the hospital for 24 hours while blood samples were collected. Driving performance was tested on the York driving simulator, and participants also completed VAS (visual analog scale) ratings and the Karolinska Sleepiness Scale to capture how they felt during testing. The most important weakness is that simulator collisions are not the same as real-world crashes, and the sample was small and limited to males aged 18-30.","limitations":"Only 30 people were studied, all male and ages 18-30, which leaves open whether the same pattern holds in other groups. The outcome was crashes in a driving simulator, which can model driving errors but does not capture real-road complexity, risk-taking, or consequences. Chronic versus occasional use was discussed, but the abstract does not provide the underlying subgroup statistics, making the tolerance comparison hard to judge from the abstract alone."},{"rthcId":"RTHC-06159","title":"Effects of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC:CBD mixtures on behavioral and physiological signs of morphine withdrawal in rhesus monkeys.","authors":"Carey, Lawrence M; Galbo-Thomma, Lindsey K; Maguire, David R; France, Charles P","year":2025,"journal":"The Journal of pharmacology and experimental therapeutics, 392(9), 103671","doi":"10.1016/j.jpet.2025.103671","pmid":"40840120","tags":["thc","cbd","addiction","pain"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC at 1.0 mg/kg decreased unusual tongue movements (a key behavioral sign of opioid withdrawal in monkeys) and heart rate. Lofexidine at 0.32 mg/kg decreased tongue movements, blood pressure, heart rate, and activity. CBD alone (10-17.8 mg/kg) or combined with THC (0.32 mg/kg) had no significant effect on any withdrawal measure.","whyItMatters":"Cannabinoids have been proposed as treatments for opioid withdrawal, but this study shows CBD did not help and THC was only modestly effective, not outperforming an already available medication. This tempers enthusiasm for cannabis-based opioid withdrawal treatments.","specificNumbers":"THC 1.0 mg/kg: decreased tongue movements and heart rate; lofexidine 0.32 mg/kg: decreased tongue movements, blood pressure, heart rate, activity; CBD 10-17.8 mg/kg: no significant effect alone or with THC 0.32 mg/kg; 3 male rhesus monkeys; morphine 3.2 mg/kg BID","methodology":"Three male rhesus monkeys received escalating morphine doses up to 3.2 mg/kg twice daily for at least 2 weeks. Morphine was then discontinued for 2 days while behavioral signs (tongue movements) and physiological measures (blood pressure, heart rate, temperature, activity) were assessed after THC, CBD, THC+CBD, lofexidine, or vehicle administration.","limitations":"Only 3 monkeys (very small sample), only male animals, specific dosing paradigm may not generalize, withdrawal from morphine may differ from withdrawal from other opioids, acute dosing does not address chronic treatment potential"},{"rthcId":"RTHC-06160","title":"Computational-Assisted Development of Molecularly Imprinted Polymers for Synthetic Cannabinoid Recognition.","authors":"Carneiro, Leonardo Martins; Gonçalves Araújo, Karen Rafaela; Melo, Diego Ulysses; Bartoloni, Fernando Heering; Soares, Alexandre Learth; Yonamine, Mauricio; Homem-de-Mello, Paula","year":2025,"journal":"ACS omega, 10(30), 33220-33226","doi":"10.1021/acsomega.5c03148","pmid":"40787316","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06161","title":"Depression and anxiety mediate the relationship between COVID-19 stay-at-home orders and tobacco and marijuana use.","authors":"Carney-Knisely, Geoffrey; Pek, Jolynn; Ferketich, Amy K; Padamsee, Tasleem J; Gur, Tamar; Singh, Parvati","year":2025,"journal":"PloS one, 20(12), e0337996","doi":"10.1371/journal.pone.0337996","pmid":"41348819","tags":["mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"People under stay-at-home orders had 2.18 times the odds of moderate-to-severe depression. However, those with moderate-to-severe depression had 63% lower odds of marijuana use (OR 0.37). Within-person worsening of mental health was associated with 78% lower odds of marijuana use (OR 0.22). Depression and anxiety appeared to mediate the pathway from stay-at-home orders to reduced marijuana use.","whyItMatters":"The dominant narrative during COVID was that people were self-medicating with substances. This study challenges that assumption: worsening mental health during lockdowns actually predicted less marijuana and cigarette use, not more, suggesting the self-medication model may be oversimplified.","specificNumbers":"7,554 participants; 43,582 observations; SAH orders: OR 2.18 for moderate-severe depression (CI: 1.27-3.73); depression/anxiety: OR 0.37 for marijuana use (CI: 0.17-0.84); within-person mental health worsening: OR 0.22 for marijuana use (CI: 0.12-0.40); similar pattern for cigarettes (OR 0.29 for depression, OR 0.26 within-person)","methodology":"Seven waves of the nationally representative Understanding America Study, a longitudinal web-based panel (N=7,554; 43,582 observations). Biweekly measurements of stay-at-home order status, PHQ-4 depression/anxiety scores, and past 7-day marijuana and cigarette use. Generalized estimating equations tested mediation models.","limitations":"Self-reported substance use and mental health, biweekly measurements may miss within-period variation, cannot determine if reduced use was due to access limitations during lockdowns rather than mental state, seven waves cover limited pandemic period, cannot rule out underreporting"},{"rthcId":"RTHC-06162","title":"Public health orientation of Cannabis and alcohol regulators: An analysis of state-level variation in the United States.","authors":"Carr, Codey J; Reuter, Peter; Midgette, Greg","year":2025,"journal":"The International journal on drug policy, 146, 105060","doi":"10.1016/j.drugpo.2025.105060","pmid":"41237738","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis regulatory agencies outperformed alcohol agencies on public health indicators; states that legalized through legislatures (vs ballot initiatives) reported more public health engagement for both cannabis and alcohol regulators.","whyItMatters":"The \"regulate cannabis like alcohol\" slogan suggested cannabis would follow alcohol's regulatory model, but cannabis agencies actually adopted a stronger public health framework than their alcohol counterparts.","specificNumbers":"Cannabis agencies reported all public health indicators more often; alcohol agencies reported more law enforcement efforts; legislative legalization states showed more public health indicators than ballot initiative states.","methodology":"Content analysis of annual reports from cannabis and alcohol regulatory agencies in US states where adult-use cannabis is legal, coding for public health goals, data collaboration, public health efforts, and law enforcement efforts.","limitations":"Content analysis captures what agencies report, not necessarily what they accomplish; only examined states with legal adult-use cannabis."},{"rthcId":"RTHC-06163","title":"Oral cannabidiol increases thermal threshold in horses without physiologic adverse effects.","authors":"Carroll, Anna T; Reed, Rachel A; Berghaus, Londa J; McNabney, Danielle; Knych, Heather K","year":2025,"journal":"American journal of veterinary research, 86(11)","doi":"10.2460/ajvr.25.05.0185","pmid":"40854532","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06164","title":"Kaempferol Regulates Lipid Homeostasis, Endocannabinoid System, and PPARα in Rat Cerebral Cortex Following BCCAO/R.","authors":"Carta, Gianfranca; Serra, Maria Pina; Murru, Elisabetta; Boi, Marianna; Manca, Claudia; Lai, Ylenia; Cabboi, Monica; Carta, Antonella; Banni, Sebastiano; Quartu, Marina","year":2025,"journal":"Biomolecules, 15(10)","doi":"10.3390/biom15101440","pmid":"41154667","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06165","title":"Post-weaning exposure to cannabidiol disrupts testicular cytoarchitecture and sperm quality in mice.","authors":"Carvalho, Renata K; Souza, Maingredy R; Nishimura, Akemy N; Silva, Edvaldo M; Silva, Cinthia R B; Guimarães, Francisco S; Andersen, Monica L; Sabóia-Morais, Simone M T; Mazaro-Costa, Renata","year":2025,"journal":"Reproductive toxicology (Elmsford, N.Y.), 135, 108952","doi":"10.1016/j.reprotox.2025.108952","pmid":"40404021","tags":["cbd","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both CBD doses (15 and 30 mg/kg/day) reduced Sertoli cell numbers at multiple spermatogenesis stages, decreased viable sperm percentage, and reduced morphologically normal sperm.","whyItMatters":"CBD products are increasingly accessible to younger populations, and this study suggests exposure during reproductive development could affect fertility.","specificNumbers":"Both doses reduced Sertoli cells at stages VII-VIII, IX, and XII; CBD 15 mg/kg group showed decreased PCNA-positive spermatocytes at stages VII-VIII; both doses reduced viable and morphologically normal sperm percentages.","methodology":"Male Swiss mice received intragastric CBD (15 or 30 mg/kg/day) or sunflower oil control for 34 consecutive days starting at postnatal day 21; testicular tissue and sperm were analyzed.","limitations":"Animal study using mouse model; CBD doses may not directly translate to human exposures; only examined one 34-day exposure window; did not assess fertility outcomes directly."},{"rthcId":"RTHC-06166","title":"Facial action units as biomarkers of postoperative pain in ovariohysterectomized bitches treated with cannabidiol and meloxicam.","authors":"Casas-Alvarado, Alejandro; Martínez-Burnes, Julio; Mora-Medina, Patricia; Hernández-Avalos, Ismael; Miranda-Cortes, Agatha; Domínguez-Oliva, Adriana; Mota-Rojas, Daniel","year":2025,"journal":"Research in veterinary science, 193, 105734","doi":"10.1016/j.rvsc.2025.105734","pmid":"40480045","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06167","title":"Innovations in Cannabis Delivery Systems: A Patent Review (2012-2024).","authors":"Casas, Ana Sofia Guerrero; Lima, Vanessa Castro Felix; Redondo, Nicolas; Alves, Izabel Almeida; Aragon, Diana Marcela","year":2025,"journal":"Mini reviews in medicinal chemistry, 25(11), 838-852","doi":"10.2174/0113895575343984250519051357","pmid":"40454502","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06168","title":"Attention Problems in Childhood and Subsequent Health Risk Behaviors in Adolescence.","authors":"Casseus, Myriam; Corman, Hope; Noonan, Kelly; Reichman, Nancy E","year":2025,"journal":"Journal of attention disorders, 29(12), 1134-1147","doi":"10.1177/10870547251352364","pmid":"40657682","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06169","title":"Cannabinomics in the flower of Cannabis sativa: a systematic review of extraction, analytical identification, and micro/nanoencapsulation methods for bioactive metabolites.","authors":"Castaño, Mateo Acosta; Arango, Juan Pablo Betancourt; Galeano, Francisco Javier Castellanos; Ocampo, Gonzalo Taborda","year":2025,"journal":"Journal of cannabis research, 7(1), 97","doi":"10.1186/s42238-025-00350-3","pmid":"41291955","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06170","title":"Global Influence of Cannabis Legalization on Social Media Discourse: Mixed Methods Study.","authors":"Castillo-Toledo, Consuelo; Donat-Vargas, Carolina; Montero-Torres, María; Lara-Abelenda, Francisco J; Mora, Fernando; Alvarez-Mon, Melchor; Quintero, Javier; Álvarez-Mon, Miguel Ángel","year":2025,"journal":"JMIR infodemiology, 5, e65319","doi":"10.2196/65319","pmid":"41021906","tags":["legalization","social-behavior"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Political discussions were the most common cannabis topic in America, Europe, and Asia; personal testimonies dominated in Oceania and Africa; legalization support was highest in Oceania (68%) and held majority in most regions.","whyItMatters":"Social media discourse shapes public risk perception, and the dominance of positive personal accounts alongside pro-legalization sentiment suggests health messaging may not be reaching public conversation effectively.","specificNumbers":"Oceania had highest positive personal experiences (60.93% of tweets) and highest pro-legalization tweets (68.13%); about half of European and Asian tweets supported legalization.","methodology":"Mixed methods analysis of cannabis-related tweets (keywords: \"cannabis,\" \"marijuana,\" \"hashish\") from January 2018 to April 2022, in English and Spanish, filtered for tweets with at least 10 retweets; inductive-deductive content analysis.","limitations":"Only tweets with 10+ retweets included, skewing toward viral content; limited to English and Spanish; Twitter users may not represent general population; data ends April 2022."},{"rthcId":"RTHC-06171","title":"Meta-analysis of medical cannabis outcomes and associations with cancer.","authors":"Castle, Ryan D; Marzolf, James; Morris, Miranda; Bushell, William C","year":2025,"journal":"Frontiers in oncology, 15, 1490621","doi":"10.3389/fonc.2025.1490621","pmid":"40303989","tags":["cancer","medical-use"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Aggregated analysis showed support for medical cannabis was 31.38x stronger than opposition across health metrics, cancer treatments, and cancer dynamics; anti-inflammatory potential and symptom management were key themes.","whyItMatters":"Cannabis remains Schedule I in the US, complicating cancer research, yet this analysis suggests overwhelming scientific consensus already supports its therapeutic role in oncology.","specificNumbers":"Over 10,000 papers analyzed; 39,767 data points; support was 31.38x stronger than opposition across all cancer topics.","methodology":"Synthesized data from over 10,000 peer-reviewed papers encompassing 39,767 data points; used sentiment analysis to identify correlations between cannabis use and supported/not-supported/unclear outcomes across cancer categories; sensitivity analysis validated findings.","limitations":"Sentiment analysis of papers is an indirect measure of efficacy; publication bias may inflate positive findings; aggregating heterogeneous studies risks oversimplification; does not replace clinical trial evidence."},{"rthcId":"RTHC-06172","title":"Seasonal variations in circulating endocannabinoidome mediators and gut microbiota composition in humans.","authors":"Castonguay-Paradis, Sophie; Demers-Potvin, Élisabeth; Rochefort, Gabrielle; Lacroix, Sébastien; Perron, Julie; Martin, Cyril; Flamand, Nicolas; Raymond, Frédéric; Di Marzo, Vincenzo; Veilleux, Alain","year":2025,"journal":"Gut microbes, 17(1), 2476563","doi":"10.1080/19490976.2025.2476563","pmid":"40111342","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06173","title":"Short-Term Effects of Maternal Cannabis Use on Human Milk Macronutrient Composition: The Lactation and Cannabis (LAC) Study.","authors":"Castro-Navarro, Irma; Williams, Janet E; Dussurget, Léa; Richardson, Haley; Berim, Anna; Gang, David R; Holdsworth, Elizabeth A; Caffé, Beatrice; Smith, Caroline; Barbosa-Leiker, Celestina; Brooks, Olivia; McGuire, Mark A; Meehan, Courtney L; McGuire, Michelle K","year":2025,"journal":"Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine","doi":"10.1177/15568253251407688","pmid":"41467985","tags":["prenatal","thc"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis use was associated with temporarily lower lipid and fatty acid concentrations and blunted lactose increase in breast milk; THC levels correlated positively with lipids and negatively with lactose.","whyItMatters":"Cannabis use among breastfeeding women is increasing, but almost nothing is known about how it affects milk nutritional composition beyond cannabinoid transfer.","specificNumbers":"20 cannabis users, 19 controls; lipid and 10 of 39 identified fatty acids were lower after use; no baseline differences between groups; no protein differences at any timepoint.","methodology":"Within-subjects design with 20 breastfeeding cannabis users matched with 19 non-using controls by BMI and time postpartum; cases abstained 12+ hours, collected baseline milk, used cannabis, then collected samples at multiple timepoints up to 8-12 hours.","limitations":"Small sample (n=39 total); single cannabis use session; did not measure infant outcomes; could not control for cannabis product variation; THC as the measured cannabinoid may not capture full effects."},{"rthcId":"RTHC-06174","title":"A Naturalistic Examination of the Acute Effects of High-Potency Cannabis on Emotion Regulation Among Young Adults: A Pilot Study.","authors":"Cavalli, Jessica M; Cuttler, Carrie; Cservenka, Anita","year":2025,"journal":"Human psychopharmacology, 40(1), e2915","doi":"10.1002/hup.2915","pmid":"39731518","tags":["mental-health","thc"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Participants reported more positive mood and decreased anxiety while intoxicated, but no evidence that acute high-potency cannabis affected implicit (Emotional Go/No-Go) or explicit (cognitive reappraisal) emotion regulation performance.","whyItMatters":"Many people report using cannabis to manage emotions, but this study suggests the subjective mood improvement may not reflect actual changes in emotion regulation ability.","specificNumbers":"12 participants; ages 21-30; all used cannabis at least 1 day/week; tested sober and intoxicated in counterbalanced order.","methodology":"Remote within-subjects design; 12 young adults (ages 21-30, using cannabis 1+ day/week) completed emotion regulation measures while sober and acutely intoxicated in counterbalanced order; participants smoked cannabis flower at home via videoconferencing observation.","limitations":"Very small sample (n=12); only frequent cannabis users included, who may have tolerance; limited to two emotion regulation tasks; no dose standardization; single-session design."},{"rthcId":"RTHC-06175","title":"The role of the endogenous opioid system in modulating orthodontic-induced neurogenic inflammation of the dental pulp: A comprehensive review of the literature.","authors":"Caviedes-Bucheli, Javier; Rios-Osorio, Nestor; Ulate-Rodríguez, Esteban; Muñoz-Alvear, Hernan Dario; Gaviño-Orduña, José F; Ortolani-Seltenerich, P Sebastian; Gomez-Sosa, Jose F; Munoz, Hugo Roberto","year":2025,"journal":"International endodontic journal, 58(8), 1126-1145","doi":"10.1111/iej.14251","pmid":"40366100","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06176","title":"Targeting the antioxidant, antimicrobial and anti-inflammatory activity of non-psychotropic Cannabis sativa L.: a comparison with chemotype V.","authors":"Ceresa, Chiara; Delsignore, Martina; Maly, Matej; Carrà, Francesca; Beneš, František; Sansotera, Andrea Chiara; Camola, Aurora; Arlorio, Marco; Porta, Chiara; Fracchia, Letizia; Disca, Vincenzo; Pollastro, Federica","year":2025,"journal":"Journal of cannabis research, 7(1), 79","doi":"10.1186/s42238-025-00336-1","pmid":"41121423","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06177","title":"Expanding the therapeutic role of highly purified cannabidiol in monogenic epilepsies: A multicenter real-world study.","authors":"Cerulli Irelli, Emanuele; Mazzeo, Adolfo; Caraballo, Roberto H; Perulli, Marco; Moloney, Patrick B; Peña-Ceballos, Javier; Rubino, Marica; Mieszczanek, Katarzyna M; Santangelo, Andrea; Licchetta, Laura; De Giorgis, Valentina; Reyes Valenzuela, Gabriela; Casellato, Susanna; Cesaroni, Elisabetta; Operto, Francesca F; Domínguez-Carral, Jana; Ramírez-Camacho, Alia; Ferretti, Alessandro; Santangelo, Giuseppe; Aledo-Serrano, Angel; Rüegger, Andrea; Mancardi, Maria M; Prato, Giulia; Riva, Antonella; Bergonzini, Luca; Cordelli, Duccio M; Bonanni, Paolo; Bisulli, Francesca; Di Gennaro, Giancarlo; Matricardi, Sara; Striano, Pasquale; Delanty, Norman; Marini, Carla; Battaglia, Domenica; Di Bonaventura, Carlo; Ramantani, Georgia; Gardella, Elena; Orsini, Alessandro; Coppola, Antonietta","year":2025,"journal":"Epilepsia, 66(7), 2253-2267","doi":"10.1111/epi.18378","pmid":"40126049","tags":["cbd","epilepsy","medical-use"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"47.5% of patients achieved 50% or greater seizure reduction; 7.4% became seizure-free; no significant difference between approved indications and off-label use; shorter prior seizure-free periods and greater intellectual disability predicted lower effectiveness.","whyItMatters":"CBD is only approved for three specific epilepsy syndromes, but this large real-world study suggests comparable effectiveness across a much wider range of genetic epilepsies.","specificNumbers":"266 patients (135 female); 77 different monogenic epilepsies; median age at CBD start 12 years; 47.5% achieved 50%+ seizure reduction; 7.4% seizure-free; 65.8% showed Clinical Global Impression improvement; median follow-up 17 months.","methodology":"Retrospective multicenter study across 27 epilepsy centers; 266 patients with monogenic epilepsies treated with highly purified CBD for at least 3 months; median follow-up 17 months.","limitations":"Retrospective design; no control group; variable dosing and co-medications across centers; potential selection bias toward patients expected to respond."},{"rthcId":"RTHC-06178","title":"Impact of Soil Quality on Cannabinoid and Terpenoid Content of Cannabis sativa L.","authors":"Chacon, Francisco T; Raup-Konsavage, Shawn A; Greenland, Kelly; Gearhart, Robert; Desai, Dhimant; Zhou, Shouhao; Kellogg, Joshua J; Raup-Konsavage, Wesley M","year":2025,"journal":"Journal of medicinally active plants, 14(2-3), 19-30","doi":"10.7275/jmap.3150","pmid":"41323359","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06179","title":"\"I think we can do without [tobacco]\": support for policies to end the tobacco epidemic among California adolescents.","authors":"Chaffee, Benjamin W; Donaldson, Candice D; Couch, Elizabeth T; Andersen-Rodgers, Elizabeth; Guerra, Claudia; Cheng, Nancy F; Ameli, Niloufar; Stupplebeen, David; Farooq, Omara; Wilkinson, Monica; Gansky, Stuart; Zhang, Xueying; Hoeft, Kristin","year":2025,"journal":"Tobacco control, 34(e1), e17-e24","doi":"10.1136/tc-2023-058288","pmid":"38148144","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06180","title":"Cannabidiol dampens propagation of hippocampal hyperactivity and differentially modulates feedforward and feedback inhibition.","authors":"Chamberland, Simon; Rosenberg, Evan C; Nebet, Erica R; Devinsky, Orrin; Tsien, Richard W","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.08.26.672420","pmid":"40909733","tags":["cbd","epilepsy"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD caused a GPR55-dependent reduction in CA3-to-CA1 hippocampal activity propagation by increasing PV interneuron recruitment while reducing SST interneuron activity; this effect was mimicked by GPR55 antagonism and PV interneuron enhancement.","whyItMatters":"Understanding exactly how CBD stops seizure spread at the circuit level could lead to more targeted epilepsy treatments and explain why CBD works differently from traditional antiseizure drugs.","specificNumbers":"CBD decreased CA1 pyramidal neuron firing (GPR55-independent) and reduced CA3-to-CA1 propagation (GPR55-dependent); PV interneuron recruitment increased while SST interneuron recruitment decreased.","methodology":"Mouse hippocampal recordings measuring CA3-to-CA1 activity propagation; pharmacological and optogenetic manipulation of PV interneurons; GPR55 knockout and antagonist experiments; GABAergic transmission blockade.","limitations":"Mouse hippocampal model; in vitro slice recordings may not fully represent intact brain dynamics; GPR55 may not be the only relevant receptor in human epilepsy."},{"rthcId":"RTHC-06181","title":"Substitution and Complementarity in the Consumption of Alcohol, Cannabis, and Opium.","authors":"Chandra, Siddharth; Doshi, Gaurav","year":2025,"journal":"Health economics, 34(5), 827-854","doi":"10.1002/hec.4938","pmid":"39825577","tags":["legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Alcohol and cannabis bud functioned as economic substitutes; cannabis leaf was a complement to alcohol but a substitute for cannabis bud; alcohol, cannabis bud, and opium all showed negative income elasticity.","whyItMatters":"Modern legalization debates often ask whether cannabis substitutes for alcohol; this study provides rare data from a period when all three substances were legal and regulated.","specificNumbers":"25 districts analyzed over 14 years (1911-1925); three substances examined; negative income elasticity found for alcohol, cannabis bud, and opium.","methodology":"Economic analysis of district-level consumption data from 25 Bengal districts (1911-1925) examining price elasticity, cross-price elasticity, and income elasticity for alcohol, cannabis (bud and leaf separately), and opium in a legal market.","limitations":"Historical data from colonial Bengal may not generalize to modern contexts; district-level data obscures individual behavior; legal and cultural context differed vastly from today; data quality from the period is uncertain."},{"rthcId":"RTHC-06182","title":"The relationship between cannabis and cardiovascular disease: clearing the haze.","authors":"Chandy, Mark; Jimenez-Tellez, Nerea; Wu, Joseph C","year":2025,"journal":"Nature reviews. Cardiology, 22(7), 467-481","doi":"10.1038/s41569-025-01121-6","pmid":"39849111","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06183","title":"Tobacco and Cannabis Use and co-Use, and Cannabis Refusal Self-Efficacy Among Black Men: A Cross-Sectional Study Examining Differences Between Men Who Have Sex with Men (MSM) and Non-MSM.","authors":"Chang, Kyle; D'Anna, Laura Hoyt; Owens, Jaelen; Wood, Jefferson L","year":2025,"journal":"Substance use & misuse, 1-9","doi":"10.1080/10826084.2025.2592877","pmid":"41340559","tags":["addiction","social-behavior"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"MSM reported more tobacco and cannabis use and lower cannabis refusal self-efficacy; path analysis showed indirect effects linking MSM status to tobacco use through cannabis refusal self-efficacy and cannabis use.","whyItMatters":"Cannabis and tobacco co-use patterns differ across populations, and understanding how minority stress drives substance use among Black MSM can inform targeted harm reduction.","specificNumbers":"202 participants; 68 reported tobacco use, 121 reported cannabis use, 62 reported co-use in past 30 days; MSM had higher rates across all measures.","methodology":"Cross-sectional study of 202 Black men ages 18-34 (94 MSM, 108 non-MSM); measured past-30-day substance use and cannabis refusal self-efficacy; path analysis guided by minority stress theory.","limitations":"Cross-sectional design prevents causal claims; convenience sample may not represent all Black MSM; self-reported substance use; single geographic area."},{"rthcId":"RTHC-06184","title":"Part 1: Evaluation of Pediatric Cannabis-Drug Interaction Reports.","authors":"Chapin, Maryann R; Kane-Gill, Sandra L; Li, Xiaotong; Abanyie, Kojo; Taneja, Sanya B; Egbert, Susan; Paine, Mary F; Boyce, Richard D","year":2025,"journal":"Pharmacology research & perspectives, 13(1), e70046","doi":"10.1002/prp2.70046","pmid":"39719830","tags":["cbd","medical-use","youth"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Seven published case reports and 9,142 FAERS adverse event reports identified potential interactions between cannabis/cannabinoids and pediatric medications; cannabinoids may inhibit cytochrome P450 enzymes, increasing drug exposure and ADR risk.","whyItMatters":"As CBD and cannabis products become more common in pediatric settings (especially for epilepsy), understanding their potential to alter the metabolism of co-prescribed medications is a safety priority.","specificNumbers":"7 published case reports; 9,142 FAERS adverse event reports; interactions flagged with methadone, everolimus, fluoxetine, and paroxetine.","methodology":"Literature search (PubMed) for published case reports and FAERS database analysis of adverse event reports involving cannabis/cannabinoids in patients under 18; Drug Interaction Probability Scale assessed causality in case reports.","limitations":"Case reports cannot establish causation; FAERS data relies on voluntary reporting and may undercount events; limited pediatric-specific pharmacokinetic data for cannabinoids."},{"rthcId":"RTHC-06185","title":"Adverse Childhood Experiences and Cannabis Use Among US Adults: Do Poor Health and Disability Influence Types of Cannabis Use?","authors":"Chapple, Constance L; Green, Elizabeth M; Milojevich, Helen M; Miller-Cribbs, Julie A; Maher, Erin J","year":2025,"journal":"Substance use & misuse, 60(4), 586-595","doi":"10.1080/10826084.2024.2445846","pmid":"39894948","tags":["medical-use","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"ACEs were significantly associated with cannabis use overall; however, disability and poor health fully accounted for the association between ACEs and medical cannabis use specifically.","whyItMatters":"Distinguishing why people with trauma histories use cannabis (recreation vs symptom management) has implications for how clinicians approach cannabis use in patients with ACE histories.","specificNumbers":"2019 BRFSS data; 4+ ACEs associated with increased cannabis use; disability and poor health fully mediated the ACE-medical cannabis relationship.","methodology":"Cross-sectional analysis of 2019 BRFSS data separating recreational and medical cannabis users; logistic regression controlling for health status and disability.","limitations":"Cross-sectional BRFSS data prevents causal claims; self-reported ACEs and cannabis use; medical vs recreational distinction relies on self-classification; single survey year."},{"rthcId":"RTHC-06186","title":"Cannabidiol (CBD) as an emerging nutraceutical ingredient from industrial hemp: regulation, production, extraction, nutraceutical properties, and functionality.","authors":"Charles, Anto Pradeep Raja; Chen, Bingcan; Rao, Jiajia","year":2025,"journal":"Critical reviews in food science and nutrition, 65(28), 6072-6094","doi":"10.1080/10408398.2024.2436130","pmid":"39654401","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06187","title":"Examining the Interactive Associations of Cannabis and Alcohol Outlets With Self-harm Injuries in California: A Spatiotemporal Analysis.","authors":"Charris, Rafael; Ahern, Jennifer; Apollonio, Dorie E; Jent, Victoria; Jacobs, Laurie M; Jung, Shelley; Schmidt, Laura A; Gruenewald, Paul; Matthay, Ellicott C","year":2025,"journal":"Epidemiology (Cambridge, Mass.), 36(2), 196-206","doi":"10.1097/EDE.0000000000001822","pmid":"39679582","tags":["legalization","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Recreational cannabis outlets were not associated with fatal or nonfatal self-harm injuries; a hypothetical 20% reduction in alcohol outlets was associated with 1.59 fewer nonfatal self-harm injuries per 100,000; no interaction between cannabis and alcohol outlet densities.","whyItMatters":"Concerns that cannabis legalization might increase self-harm are not supported by this analysis, while alcohol outlet density remains a significant modifiable risk factor.","specificNumbers":"If cannabis outlets had never opened: -0.35 per 100,000 nonfatal self-harm (95% CI: -1.25, 0.51); 20% alcohol outlet reduction: -1.59 per 100,000 nonfatal (95% CI: -2.60, -0.59); strongest effects in ages 15-34.","methodology":"Bayesian spatiotemporal analysis of quarterly ZIP code-level data from California (2017-2019) using statewide data on recreational cannabis outlets, alcohol outlets, and hospital discharges/deaths from self-harm; adjusted for confounders and spatial autocorrelation.","limitations":"Three-year window may miss longer-term effects; ecological study cannot capture individual-level use patterns; California-specific results may not generalize; could not account for illicit market dynamics."},{"rthcId":"RTHC-06188","title":"Effect of Heat Processing on Major Psychoactive Compounds and Total Phenolic Content in Psychotropic Plants: Cannabis (Cannabis Sativa) and Kratom (Mitragyna Speciosa) Leaves.","authors":"Chathiran, Wimonphan; Varatojo, Laura; Chimasangkanan, Jaruwan; Saiyasombat, Worakrit; Srichamnong, Warangkana","year":2025,"journal":"Cannabis and cannabinoid research, 10(5), 598-608","doi":"10.1089/can.2024.0201","pmid":"40358006","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06189","title":"Acceptability, Feasibility, and Effectiveness of Concurrent High-Definition Transcranial Direct Current Stimulation and Cue Exposure in Cannabis Use Disorder: A Pilot Double-Blind Randomized Controlled Trial.","authors":"Chauhan, Devika; Ghosh, Abhishek; Naik, Shalini S; Rana, Devender K; Singh, Shubh Mohan","year":2025,"journal":"The journal of ECT, 41(2), 126-135","doi":"10.1097/YCT.0000000000001087","pmid":"39718389","tags":["addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"All groups showed reduced cannabis craving, frequency, and improved cognition; anodal right DLPFC HD-tDCS was safe with high completion rates (91.7%); cue exposure did not add to the effect of stimulation.","whyItMatters":"Non-invasive brain stimulation represents a potential medication-free treatment for cannabis use disorder, though optimal protocols still need refinement.","specificNumbers":"48 participants; 4 groups of 12; 19.6% acceptance rate; 91.7% completion rate; craving reductions sustained at 4-week follow-up in all groups except sham + cue; cannabis use frequency and amount reduced in all groups.","methodology":"Double-blind RCT; 48 participants with cannabis use disorder randomized to 4 groups (tDCS + cue, tDCS + neutral, sham + cue, sham + neutral); 6 sessions; craving assessed post-treatment and at 4-week follow-up.","limitations":"Small sample (48 total, 12 per group); low acceptance rate (19.6%); all groups improved, making it difficult to isolate specific effects; no long-term follow-up beyond 4 weeks."},{"rthcId":"RTHC-06190","title":"Alcohol and Cannabis Use Trends Among Adolescents With and Without a History of Recent Suicidal Thoughts and Behavior: 1991-2023.","authors":"Cheek, Shayna M; Grove, Jeremy L; Barnes, Sarah E; Goldston, David B","year":2025,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 77(2), 300-307","doi":"10.1016/j.jadohealth.2025.04.020","pmid":"40542802","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use prevalence decreased since 1995 for adolescents with no STB history but showed no significant decline for those with recent suicidal ideation or attempts; female adolescents with suicide attempt history showed plateauing cannabis use since the 1990s.","whyItMatters":"The population-level success story of declining adolescent substance use does not extend to the most psychiatrically vulnerable youth, who may need targeted intervention.","specificNumbers":"254,675 adolescents over 32 years (1991-2023); cannabis use declined significantly since 1995 for no-STB group; no significant decline for suicidal ideation or attempt groups; female suicide attempters showed cannabis use plateauing since the 1990s.","methodology":"Joinpoint regression analysis of 32 years (1991-2023) of Youth Risk Behavior Surveillance System data; 254,675 adolescents in grades 9-12 stratified by STB history and gender.","limitations":"Self-reported data; STB measured as recent (past 12 months) which may not capture full history; cannot determine if substance use preceded or followed suicidal thoughts; repeated cross-sections, not longitudinal individuals."},{"rthcId":"RTHC-06191","title":"Endocannabinoid system and mood responses to acute aerobic exercise in adult cancer patients versus healthy controls: a pilot study.","authors":"Cheema, Birinder S; Low, Mitchell; Kay, Shelley; Stehn, Justine; Hall, Damian; Gourshettiwar, Abha; Wahlroos, Sara; Harrison, Michelle; Lacey, Judith","year":2025,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 33(12), 1162","doi":"10.1007/s00520-025-10221-5","pmid":"41331388","tags":["exercise","cancer","medical-cannabis","mental-health"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"The 'runner's high' was long attributed to endorphins, but recent research has shifted the credit to the endocannabinoid system — specifically anandamide, the body's own cannabis-like molecule. This pilot study explored whether exercise-induced endocannabinoid changes differ between cancer patients and healthy adults.\n\nAt baseline, cancer patients had lower circulating levels of anandamide (AEA), OEA, and SEA compared to healthy controls across all time points. This suggests that cancer itself (or its treatment) depletes the endocannabinoid system — potentially contributing to the mood, appetite, and pain problems that cancer patients experience.\n\nBut the encouraging finding: just 30 minutes of moderate-intensity exercise (treadmill or cycling at 64-76% of age-predicted max heart rate) increased levels of anandamide, 1-AG, OEA, PEA, and SEA in both groups. Exercise activated the endocannabinoid system regardless of cancer status. Notably, 2-AG — the other major endocannabinoid — did not change with exercise.\n\nOn the mood side, happiness was the only one of 10 visual analog scales that significantly increased with exercise in the total cohort. The study also asked participants whether they experienced a 'runner's high,' connecting the subjective experience to the objective endocannabinoid changes.\n\nThe implication is that exercise may help replenish depleted endocannabinoid levels in cancer patients — offering a non-pharmacological way to activate the same system that cannabis targets.","whyItMatters":"This is one of the first studies to examine the endocannabinoid system's exercise response in cancer patients. If cancer depletes endocannabinoids (contributing to pain, mood, and appetite problems), and exercise restores them, it provides a biological rationale for exercise prescription in oncology that goes beyond general fitness — exercise may be directly addressing the neurochemical deficits that many cancer patients experience.","specificNumbers":"Cancer patients had lower AEA, OEA, and log SEA vs controls across all timepoints (all p<0.06). Exercise increased AEA, log 1-AG, OEA, PEA, and log SEA (all p=0.05) in the total cohort. 2-AG did not change. Happiness was the only mood scale that increased with exercise (p=0.02). Exercise intensity: 64-76% age-predicted HRmax for 20 minutes plus warm-up/cool-down.","methodology":"Pilot study comparing cancer patients and healthy controls. Participants did 30 minutes of quiet rest followed by 30 minutes of moderate-intensity exercise (64-76% age-predicted HRmax) on treadmill or cycle. Blood samples and 10 Visual Analog Scales collected before and after each condition. Blood analyzed for endocannabinoids (AEA, 2-AG, 1-AG) and endocannabinoid-like lipid mediators (PEA, OEA, SEA). 'Runner's high' query post-exercise.","limitations":"Pilot study with a small sample size (not specified in abstract but described as pilot). Acute exercise only — unknown whether chronic exercise training would produce sustained endocannabinoid changes. Cancer patients were heterogeneous (different cancer types, treatment stages). No control for anti-cancer treatments that might independently affect endocannabinoid levels. The mood assessment (only 1 of 10 scales changed) suggests the psychological effects of exercise are complex and not fully captured by endocannabinoid changes alone."},{"rthcId":"RTHC-06192","title":"Novel findings regarding the role of the endocannabinoid system in pediatric functional gastrointestinal disorders.","authors":"Chelimsky, Gisela; Conant, Lisa; Simpson, Pippa; Zhang, Liyun; Marchand, Serge; Hillard, Cecilia; Chelimsky, Thomas","year":2025,"journal":"Pain reports, 10(4), e1273","doi":"10.1097/PR9.0000000000001273","pmid":"40528842","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06193","title":"Assessing Real World Efficacy, Safety, and 18-Month Retention Rates of Cannabidiol in Individuals With Drug Resistant Epilepsies.","authors":"Chemaly, Nicole; Kuchenbuch, Mathieu; Losito, Emma; Kaminska, Anna; Coste-Zeitoun, Delphine; Barcia, Giulia; Desguerre, Isabelle; Hully, Marie; Nabbout, Rima","year":2025,"journal":"European journal of neurology, 32(9), e70304","doi":"10.1111/ene.70304","pmid":"40968578","tags":["cbd","epilepsy","medical-use"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"54% of caregivers reported reduced seizure frequency at 1 month; 48% maintained improvement at 2-6 months; communication (60%), alertness (54%), and motor skills (44%) also improved; 55% retention at 18 months; off-label use had higher retention than approved indications.","whyItMatters":"Long-term retention data fills a critical gap in understanding whether CBD's initial benefits persist, and the finding that off-label use showed higher retention challenges restrictive prescribing practices.","specificNumbers":"103 patients (mean age 11.2); 47% on-label (23 Dravet, 15 LGS, 10 TSC), 53% off-label; retention: 97% at 1 month, 90% at 2 months, 82% at 6 months, 66% at 12 months, 55% at 18 months; 62% positive overall caregiver impression at 1 month.","methodology":"Prospective study of 103 consecutive pediatric patients starting CBD for drug-resistant epilepsy at a tertiary center (2019-2021); parental questionnaires at 1, 2, and 6 months; retention tracked at 18 months.","limitations":"Single-center; no control group; caregiver-reported outcomes may introduce bias; dropout by 18 months means retention data may overestimate benefit in completers."},{"rthcId":"RTHC-06194","title":"Derived Intoxicating Cannabis Vape Product Attributes and Marketing in an Online Retail Environment.","authors":"Chen-Sankey, Julia; LoParco, Cassidy R; La Capria, Kathryn; Meng, Siyan; Mazzeo, Rosanna; Vijayakumar, Neha; Kong, Amanda Y; Tillett, Kayla K; Berg, Carla; Rossheim, Matthew E","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.01.22.25320970","pmid":"39973983","tags":["synthetic","health-risks"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"95 unique brands and 26 unique intoxicating cannabinoids identified; 99% featured vape design/use messaging, 91.6% referenced regulation/compliance, 79.6% made flavor claims, 43.3% made potency/psychoactive claims.","whyItMatters":"The 2018 Farm Bill created a loophole allowing hemp-derived intoxicating products that bypass cannabis regulations, and their online marketing strategies may particularly appeal to young people.","specificNumbers":"490 products analyzed; 95 unique brands; 26 unique intoxicating cannabinoids; 99% included vape design messaging; 91.6% regulation/compliance claims; 79.6% flavor claims; 43.3% psychoactive effect claims.","methodology":"Content analysis of 490 derived intoxicating cannabis vape products from two high-traffic online retail websites in 2023; two trained coders thematically coded product descriptions.","limitations":"Only two websites analyzed; product descriptions may not reflect actual product contents; did not assess consumer perceptions; snapshot in time (2023); could not verify marketing claims."},{"rthcId":"RTHC-06195","title":"Comparing the Use Experiences, Contextual Factors, and Recovery Strategies Associated with Different Substances: An Analysis of Social Media Narratives.","authors":"Chen, Annie T; Wang, Lexie C; Pike, Kenneth C; Conway, Mike; Glass, Joseph E","year":2025,"journal":"Substance use & misuse, 60(14), 2287-2298","doi":"10.1080/10826084.2025.2540938","pmid":"40763003","tags":["addiction","social-behavior"],"studyType":"qualitative","evidenceStrength":"moderate","keyFinding":"Cannabis posts were associated with school settings and heightened self-awareness (curiosity, disgust, realization); alcohol posts with leisure, coworkers, and legal consequences; opioid posts with anticipated stigma, anger, healthcare, medications, and financial content.","whyItMatters":"Understanding substance-specific patterns in how people talk about their use and recovery can inform more targeted interventions rather than one-size-fits-all approaches.","specificNumbers":"748 posts analyzed (42.2% alcohol, 44.8% cannabis, 18% opioids); substance-specific settings, actors, and emotional patterns identified; social support and consequence awareness most common in early recovery stages.","methodology":"Analysis of 748 Reddit posts (316 alcohol, 335 cannabis, 135 opioids) from substance-related subreddits (2013-2019); computational sampling for stigma-related posts; logistic regression and content analysis for recovery strategies.","limitations":"Reddit users may not represent broader populations; posts selected for stigma content may skew toward negative experiences; 2013-2019 data may not reflect current patterns; qualitative coding involves subjective judgment."},{"rthcId":"RTHC-06196","title":"Stigma and Behavior Change Techniques in Substance Use Recovery: Qualitative Study of Social Media Narratives.","authors":"Chen, Annie T; Wang, Lexie C; Johnny, Shana; Wong, Sharon H; Chaliparambil, Rahul K; Conway, Mike; Glass, Joseph E","year":2025,"journal":"JMIR formative research, 9, e57468","doi":"10.2196/57468","pmid":"40138682","tags":["addiction","social-behavior"],"studyType":"qualitative","evidenceStrength":"moderate","keyFinding":"63.1% of narratives were in the action stage; 11 BCT categories identified; social support seeking and consequence awareness dominated early stages; action and maintenance stages showed more diverse strategies; stigma persisted across all stages.","whyItMatters":"Understanding how people naturally use behavior change techniques during recovery can inform more effective intervention design, while the persistence of stigma across all stages highlights it as a constant barrier.","specificNumbers":"748 posts; 63.1% action stage; 11 BCT categories; 5 major stigma themes; social support became more commonly offered (vs sought) in maintenance stage.","methodology":"Qualitative analysis of 748 Reddit posts from alcohol, cannabis, and opioid subreddits (2013-2019) using hybrid inductive-deductive coding for stages of change, behavior change techniques, and stigma themes.","limitations":"Reddit sample biased toward action stage (actively seeking recovery); may not represent those not engaging online; subjective coding; cannot verify outcomes; same dataset as companion study."},{"rthcId":"RTHC-06197","title":"Accurate Identification of MDMB-Type Synthetic Cannabinoids through Design of Dual Excited-State Intramolecular Proton Transfer Site Probe and Deep-Learning.","authors":"Chen, Baoqing; Li, Yudong; Zhao, Chuanfang; Liu, Yuan; Du, Yuwan; Wang, Na; Guan, Ming; Dou, Xincun","year":2025,"journal":"Analytical chemistry, 97(22), 11589-11597","doi":"10.1021/acs.analchem.5c00700","pmid":"40443081","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06198","title":"Association of cannabis use with female infertility based on NHANES.","authors":"Chen, Chao; Wu, Yang; Pei, Lipeng; Ren, Wei","year":2025,"journal":"Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology, 45(1), 2502663","doi":"10.1080/01443615.2025.2502663","pmid":"40403193","tags":["health-risks","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Former cannabis users had 2.04x odds of infertility vs never-users; current users showed no significant difference; among former users 18-35, those abstinent 3+ years had 2.94x odds; shorter abstinence showed no significant difference.","whyItMatters":"The counterintuitive finding that former (not current) users show elevated infertility risk suggests possible delayed reproductive effects or confounding factors that warrant further investigation.","specificNumbers":"1,694 women; former users OR 2.04 (95% CI: 1.21-3.43); ages 18-35 former users OR 2.37 (95% CI: 1.11-5.04); 3+ years abstinence OR 2.94 (95% CI: 1.29-6.71); current users: no significant association.","methodology":"Cross-sectional analysis of NHANES 2013-2018; 1,694 female participants aged 18-45; logistic regression adjusting for covariates; subgroup analyses by age and abstinence duration.","limitations":"Cross-sectional design cannot establish causation; former users may have quit due to fertility-related health advice (reverse causation); self-reported cannabis use and infertility; cannot control for all confounders."},{"rthcId":"RTHC-06199","title":"CB1 and CB2 receptors differentially modulate the cognitive impact of maternal immune activation and perinatal cannabinoid exposure.","authors":"Chen, Han-Ting; Mackie, Ken","year":2025,"journal":"Behavioural brain research, 485, 115543","doi":"10.1016/j.bbr.2025.115543","pmid":"40113177","tags":["prenatal","thc","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"PCE impaired novel object recognition and working memory in males via CB1 receptors; MIA impaired the same tasks via CB2 receptors; combined PCE+MIA did not produce cognitive deficits; CB2 knockout prevented the protective effect of combined exposure.","whyItMatters":"Many pregnant women face both infection and cannabis exposure, and understanding how these interact at the receptor level is important for assessing combined risk.","specificNumbers":"THC 3 mg/kg daily from GD5 to PND10; Poly I:C at GD16.5; male offspring showed impaired novel object recognition and working memory from either PCE or MIA alone; females showed more modest changes; combined exposure negated deficits in wildtype males.","methodology":"Compared wildtype, CB1 knockout, and CB2 knockout mice across four conditions: control, perinatal cannabis exposure (3 mg/kg THC daily GD5-PND10), maternal immune activation (Poly I:C at GD16.5), and combined; tested adult offspring on emotional and cognitive behaviors.","limitations":"Mouse model; single THC dose level; MIA model using Poly I:C may not fully represent human infections; the protective effect of combined exposure may not translate to humans; behavioral tests capture limited cognitive domains."},{"rthcId":"RTHC-06200","title":"CB1 and CB2 receptors differentially modulate the cognitive impact of maternal immune activation and perinatal cannabinoid exposure.","authors":"Chen, Han-Ting; Mackie, Ken","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2024.11.16.623455","pmid":"39605459","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06201","title":"Mode matters: exploring how modes of cannabis administration affect THC plasma concentrations and subjective effects.","authors":"Chen, Margy Y; Brooks-Russell, Ashley; Bryan, Angela D; Bidwell, L Cinnamon","year":2025,"journal":"Journal of cannabis research, 7(1), 28","doi":"10.1186/s42238-025-00282-y","pmid":"40410918","tags":["thc","dosing"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Dabbing was associated with higher plasma THC concentrations and subjective effects than flower-based methods (bong, joint); dabbing and vaping showed more rapid reductions in subjective intoxication over time.","whyItMatters":"As dabbing and vaping gain popularity, understanding that these methods produce higher peak THC exposure but shorter subjective duration has implications for dosing, impairment assessment, and use patterns.","specificNumbers":"252 participants; 46.4% female; four administration modes compared; dabbing produced highest plasma THC and subjective effects; dabbing and vaping showed faster decline in subjective intoxication.","methodology":"Secondary analysis of two quasi-experimental studies; 252 participants (46.4% female) self-administered legal market cannabis products via their preferred mode (dabbing, vaping, bong-like, joint-like); plasma THC and subjective effects measured.","limitations":"Naturalistic design means products varied in potency; no random assignment to modes; participants used their preferred mode (selection bias); could not control for tolerance differences; secondary analysis."},{"rthcId":"RTHC-06202","title":"Investigating the Relationship Between Cannabis Expectancies and Anxiety, Depression, and Pain Responses After Acute Flower and Edible Cannabis Use.","authors":"Chen, Margy Y; Kramer, Emily B; Gibson, Laurel P; Bidwell, L Cinnamon; Hutchison, Kent E; Bryan, Angela D","year":2025,"journal":"Cannabis and cannabinoid research, 10(1), 71-80","doi":"10.1089/can.2023.0264","pmid":"38608236","tags":["mental-health","pain","thc"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"More positive health expectancies correlated with greater tension reduction in both flower and edible users; edible users with stronger expectancies also showed greater elation increases and pain reductions; domain-specific expectancies predicted corresponding outcomes.","whyItMatters":"If expectancy effects substantially influence cannabis outcomes, this complicates interpreting both clinical trials and self-reported therapeutic benefits.","specificNumbers":"55 flower users, 101 edible users; products varied in CBD/THC content; expectancy effects consistent across both flower and edible groups for tension reduction; edible users showed additional expectancy effects on elation and pain.","methodology":"Two quasi-experimental studies; 55 flower and 101 edible users randomly assigned to products with varying CBD/THC; baseline expectancies measured; acute tension, elation, and pain assessed after naturalistic self-administration.","limitations":"Naturalistic administration limits dose precision; expectancies measured before but not blinded; cannot fully separate pharmacological from expectancy effects; acute effects only; relatively small samples."},{"rthcId":"RTHC-06203","title":"Origin of the Different Binding Affinities of (9R)- and (9S)-Hexahydrocannabinol (HHC) for the CB1 and CB2 Cannabinoid Receptors.","authors":"Chen, Pan-Pan; Duan, Meng; Zhou, Qingyang; Liu, Fang; Tang, Yi; Garg, Neil K; Houk, K N","year":2025,"journal":"ACS chemical biology, 20(8), 2006-2013","doi":"10.1021/acschembio.5c00399","pmid":"40704858","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06204","title":"Cannabidiol reshapes the gut microbiome to promote endurance exercise in mice.","authors":"Chen, Si; Lee, Yu-Bin; Song, Mi-Young; Lim, Changjin; Cho, Hwangeui; Shim, Hyun Joo; Kim, Jong-Suk; Park, Byung-Hyun; Kim, Jeon-Kyung; Bae, Eun Ju","year":2025,"journal":"Experimental & molecular medicine, 57(2), 489-500","doi":"10.1038/s12276-025-01404-5","pmid":"39966566","tags":["cbd","sports"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD increased running endurance, oxidative muscle fibers, and mitochondrial biogenesis; these effects depended on gut microbiome (abolished by antibiotics); CBD-enriched Bifidobacterium animalis alone improved running performance.","whyItMatters":"This is the first evidence that CBD's effects on physical performance may work through the gut microbiome rather than direct muscle or brain effects.","specificNumbers":"CBD significantly increased treadmill running; antibiotic treatment reduced the endurance benefit; B. animalis KBP-1 isolate independently improved running; PGC-1a, phosphorylated CREB, and AMPK upregulated in muscle.","methodology":"Mice received CBD and were tested on treadmill running; muscle tissue analyzed for fiber composition and mitochondrial markers; gut microbiome profiled; antibiotics used to test microbiome dependency; isolated B. animalis administered separately.","limitations":"Mouse model; single CBD dose tested; antibiotic approach affects entire microbiome; unclear if similar gut changes occur in humans."},{"rthcId":"RTHC-06205","title":"Marijuana use and subjective cognitive decline in middle-aged and older adults: Analysis of the behavioral risk factor surveillance system survey.","authors":"Chen, Xiao; Wang, Peilu; Tang, Yilin; Veldheer, Susan; Geng, Tingting; Sun, Liang; Li, Yaqi; Gao, Xiang","year":2025,"journal":"Journal of Alzheimer's disease : JAD, 105(1), 280-291","doi":"10.1177/13872877251327164","pmid":"40179228","tags":["cognition","elderly"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Past-month marijuana users reported higher rates of subjective cognitive decline and SCD-related functional limitations compared to non-users, with a significant dose-response trend (p < 0.001).","whyItMatters":"As cannabis use grows among older adults, understanding whether it is associated with cognitive complaints in this age group is important for clinical guidance.","specificNumbers":"100,685 participants aged 45+; five BRFSS cycles; dose-response trend p < 0.001 for both SCD and SCD-related functional limitations.","methodology":"Cross-sectional analysis of 100,685 participants from five BRFSS survey cycles; self-reported past-month marijuana use categorized by frequency; subjective cognitive decline and functional limitations assessed.","limitations":"Cross-sectional design cannot determine causation; self-reported marijuana use and cognitive decline; no objective cognitive testing; potential confounders including other substance use."},{"rthcId":"RTHC-06206","title":"Medical cannabis: A growing opportunity for the Moroccan pharmaceutical industry.","authors":"Cherif Chefchaouni, Ali; Bennani, Ismail; El Baraka, Soumaya; Ouedraogo, Jean Marie; Chentoufi Alami, Madiha; Bendadi, Fatima-Zahra; El Marrakchi, Soufiane; Moukafih, Badreddine; Rahali, Younes; El Kartouti, Abdeslam","year":2025,"journal":"Annales pharmaceutiques francaises","doi":"10.1016/j.pharma.2025.12.012","pmid":"41421545","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06207","title":"Does cannabidiol reduce the adverse effects of cannabis in schizophrenia? A randomised, double-blind, cross-over trial.","authors":"Chesney, Edward; Oliver, Dominic; Sarma, Ananya; Lamper, Ayşe Doğa; Slimani, Ikram; Lloyd, Millie; Dickens, Alex M; Welds, Michael; Kråkström, Matilda; Gasparini-Andre, Irma; Orešič, Matej; Lawn, Will; Babayeva, Natavan; Freeman, Tom P; Englund, Amir; Strang, John; McGuire, Philip","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(12), 1759-1767","doi":"10.1038/s41386-025-02175-3","pmid":"40702165","tags":["cbd","thc","psychosis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"CBD pre-treatment resulted in worse delayed verbal recall (3.5 vs 4.8 words, p=0.001) and greater increase in positive psychotic symptoms (5.0 vs 2.9 PANSS-P increase, p=0.01) compared to placebo pre-treatment; CBD did not alter THC or 11-OH-THC plasma levels.","whyItMatters":"This directly challenges the popular assumption that CBD protects against THC's harmful effects, particularly in the most vulnerable population.","specificNumbers":"30 participants; CBD 1000mg vs placebo; delayed recall 3.5 vs 4.8 words (MD -1.3, 95% CI: -2.0 to -0.6); PANSS-P increase 5.0 vs 2.9 (MD 2.2, 95% CI: 0.6 to 3.7); no difference in THC plasma levels.","methodology":"Double-blind, randomized, placebo-controlled, crossover trial; 30 participants with schizophrenia/schizoaffective disorder plus cannabis use disorder; oral CBD 1000mg or placebo 3 hours before vaporized cannabis (THC 20-60mg).","limitations":"Small sample (n=30); single CBD dose; acute effects only; participants had comorbid cannabis use disorder; may not generalize to healthy volunteers."},{"rthcId":"RTHC-06208","title":"Challenges in conducting a feasibility randomized controlled trial of medicinal cannabis for endometriosis pain in Australia.","authors":"Chesterman, Susan; Mikocka-Walus, Antonina; Sinclair, Justin; Druitt, Marilla; Furyk, Jeremy; Evans, Subhadra; Abbott, Jason; Eathorne, Alexandra; Martin, Alexander; Ng, Cecilia; Nguyen, Lisa; Oldfield, Karen; Romano, Daniel; Sarris, Jerome; Semprini, Alex; Stanley, Katherine; Armour, Mike","year":2025,"journal":"Complementary therapies in clinical practice, 61, 102023","doi":"10.1016/j.ctcp.2025.102023","pmid":"41005282","tags":["medical-use","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Only 12 of 63 target participants enrolled; 7 withdrew and only 4 completed; the primary barrier was the requirement to abstain from driving during THC treatment; high withdrawal rate made efficacy assessment impossible.","whyItMatters":"Despite strong patient interest in cannabis for endometriosis, practical barriers like driving restrictions make clinical trials nearly impossible, leaving a major evidence gap.","specificNumbers":"12 of 63 target enrolled; 7 withdrew; 4 completed; 1 lost to follow-up; 10 adverse events (8 possibly cannabis-related); 2 serious adverse events (unrelated).","methodology":"Three-armed RCT in Australia comparing inhaled THC (16%) flower + CBD oil (100mg/mL), CBD oil alone, or placebo oil; aimed for 63 participants; assessed safety, acceptability, and feasibility.","limitations":"Failed to achieve recruitment target; cannot assess efficacy; Australian regulatory context; small enrolled sample prevents meaningful safety conclusions."},{"rthcId":"RTHC-06209","title":"The acute cardiovascular response to dynamic exercise and recovery following cannabis use.","authors":"Cheung, Christian P; Baker, Ryleigh E; Coates, Alexandra M; Burr, Jamie F","year":2025,"journal":"American journal of physiology. Heart and circulatory physiology, 329(6), H1655-H1665","doi":"10.1152/ajpheart.00608.2025","pmid":"41115058","tags":["cardiovascular","thc","sports"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Smoking THC increased post-exercise pulse pressure (50 vs 41 mmHg) and reduced isovolumic contraction time; vaping THC or CBD had lesser or no effects; blood pressure and cardiac function during exercise were unaffected by any cannabis condition.","whyItMatters":"Athletes and exercisers increasingly combine cannabis with physical activity, and this study suggests the cardiovascular risk window may be during recovery rather than during exercise.","specificNumbers":"n=14 main protocol, n=22 stress echo; post-exercise pulse pressure: control 41+/-7, S-THC 50+/-9 mmHg; IVCT reduced in S-THC vs control (p=0.048); no differences during exercise.","methodology":"Within-subject design; participants inhaled cannabis via smoking (high THC), vaporizing (high THC), or vaporizing (high CBD); cardiovascular measures at rest and after 20-min maximal cycling (n=14); stress echocardiography separately (n=22).","limitations":"Small sample sizes; within-subject but not blinded to route; acute single-session design; healthy participants may not reflect those with cardiovascular risk factors."},{"rthcId":"RTHC-06210","title":"Persistent Cannabis Use and Ocular Health in Midlife.","authors":"Cheyne, Kirsten; Niederer, Rachael L; Ambler, Antony; Barrett-Young, Ashleigh; Guiney, Hayley; Poulton, Richie; Ramrakha, Sandhya; Wong, Tien Yin; Wilson, Graham A","year":2025,"journal":"American journal of preventive medicine, 69(4), 107955","doi":"10.1016/j.amepre.2025.107955","pmid":"40570990","tags":["health-risks"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Initial associations between cannabis and poorer visual acuity and wider retinal vessels were explained by tobacco and SES; one finding persisted: thicker inferior ganglion cell-inner plexiform layer, suggesting possible neuroprotection.","whyItMatters":"This is the first longitudinal study to examine whether decades of cannabis use affects eye health, finding that apparent harms were actually from tobacco co-use.","specificNumbers":"887 participants; associations with visual acuity and retinal vessels no longer significant after adjusting for tobacco and SES; thicker inferior GC-IPL remained significant.","methodology":"Dunedin Study longitudinal cohort (N=1,037); cannabis use self-reported at every assessment from age 18 to 45; comprehensive ocular health at age 45 including visual acuity, retinal imaging, and OCT; n=887 with complete data.","limitations":"Self-reported cannabis use; single ocular assessment at age 45; confounding possible; neuroprotection finding requires replication."},{"rthcId":"RTHC-06211","title":"Cannabinoids for Medical Purposes in Children: A Living Systematic Review.","authors":"Chhabra, Manik; Paul, Arun; Abulannaz, Omaymah; Lê, Mê-Linh; Mansell, Holly; Finkelstein, Yaron; Huntsman, Richard J; Kelly, Lauren E","year":2025,"journal":"Acta paediatrica (Oslo, Norway : 1992), 114(9), 2148-2159","doi":"10.1111/apa.70140","pmid":"40437694","tags":["cbd","medical-use","youth"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"276 studies included; most common indication was refractory epilepsy (146 studies); purified CBD was most studied (78.6% of interventional); RCTs showed 30-50% seizure reduction; common adverse events were somnolence, diarrhea, vomiting, and decreased appetite.","whyItMatters":"This provides the most comprehensive map of what is and is not known about cannabinoid use in children, revealing evidence concentrated in epilepsy with large gaps elsewhere.","specificNumbers":"276 studies from 37,189 citations; epilepsy (146 studies, 188,726 participants), cancer (30 studies, 208,753 participants), autism (18 studies, 1,285 participants); CBD doses 2-50 mg/kg/day.","methodology":"Living systematic review searching MEDLINE, Embase, PsycInfo, and Cochrane Library from inception to April 2023; included studies with at least one child under 18 receiving cannabinoids.","limitations":"Living review with data through April 2023; heterogeneous study quality; most evidence for CBD/epilepsy; publication bias possible."},{"rthcId":"RTHC-06212","title":"Triple Burden of Cannabis Use, First Episode Psychosis and HIV in KwaZulu-Natal Province, South Africa.","authors":"Chhagan, Usha; Ntlantsana, Vuyokazi; Karim, Enver; Tomita, Andrew; Chiliza, Bonginkosi; Paruk, Saeeda","year":2025,"journal":"Early intervention in psychiatry, 19(11), e70107","doi":"10.1111/eip.70107","pmid":"41243860","tags":["psychosis","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Lifetime cannabis users scored higher on PANSS total, positive, disorganized, and excitement domains and lower on depression; HIV-positive cannabis users showed additional positive symptom elevation (p=0.023).","whyItMatters":"The intersection of cannabis, psychosis, and HIV represents a triple disease burden in sub-Saharan Africa requiring integrated treatment.","specificNumbers":"182 patients; 71% male; mean age 26.27; 21.3% HIV-positive; cannabis users had higher PANSS total (p=0.009), positive (p=0.003), disorganized (p=0.009), excitement (p<0.001), lower depression (p=0.002).","methodology":"Cross-sectional study of 182 adults (18-45) diagnosed with psychotic disorder per DSM-5 in KwaZulu-Natal; PANSS, WHO ASSIST, and HIV ELISA testing.","limitations":"Cross-sectional; cannot determine temporal order; self-reported substance use; single geographic region; small HIV-positive subgroup."},{"rthcId":"RTHC-06213","title":"Identifying predictors of multi-year cannabis vaping in U.S. Young adults using machine learning.","authors":"Choe, Siyoung; Agley, Jon; Elam, Kit; Bidulescu, Aurelian; Seo, Dong-Chul","year":2025,"journal":"Addictive behaviors, 160, 108167","doi":"10.1016/j.addbeh.2024.108167","pmid":"39341185","tags":["addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In legalized states, CART split on cannabis use, cigarette use, bullying, and ethnicity; in non-legal states, split on cannabis use, heroin use, nicotine vaping, and hookah; predictors of sustained vaping differed from initiation predictors.","whyItMatters":"Understanding who continues vaping cannabis over years is more relevant for intervention than who starts, and different predictor profiles by legalization status suggest policy context shapes sustained use.","specificNumbers":"PATH Waves 4-6 (December 2016-November 2021); five-terminal-node CART models for each legalization stratum; prior cannabis use was primary split in both.","methodology":"Secondary analysis of PATH Study Waves 4-6 (2016-2021); two-stage ML (LASSO + CART) stratified by state recreational cannabis legalization; representative US young adult sample.","limitations":"ML identifies associations not causes; legalization status changed during study; self-reported measures; PATH attrition may bias results."},{"rthcId":"RTHC-06214","title":"Large-Scale Profiling of Coding and Long Noncoding Transcriptomes in the Hippocampus of Mice Acutely Exposed to Vaporized CBD or THC.","authors":"Choi, Mi Ran; Kim, Jihun; Park, Chaeeun; Chang, Seok Hwan; Kim, Han-Na; Jin, Yeung Bae; Lee, Sang-Rae","year":2025,"journal":"International journal of molecular sciences, 26(15)","doi":"10.3390/ijms26157106","pmid":"40806237","tags":["cbd","thc","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC upregulated glutamate receptor genes and downregulated dopamine genes (Drd1, Drd2, Gnal, Adcy5); CBD altered Wnt7a and Camk2b; most changes recovered by day 14 except Adcy5; lncRNA-mRNA correlations suggest regulatory mechanisms.","whyItMatters":"Vaping is the most common cannabis consumption method among young adults, and understanding hippocampal gene expression changes reveals molecular mechanisms behind cognitive effects.","specificNumbers":"50mg vaporized CBD or THC; n=5 per group; Drd2 returned to baseline by day 14; Adcy5 remained suppressed through day 14; Wnt7a (CBD) showed gradual recovery.","methodology":"Male ICR mice exposed to vaporized CBD or THC (50mg, n=5/group); hippocampal RNA sequencing at day 1; qRT-PCR validation at days 1, 3, and 14.","limitations":"Single acute exposure; mouse model; 50mg vaporized dose may not reflect human use; only hippocampus examined; gene changes may not translate to behavior."},{"rthcId":"RTHC-06215","title":"Changes in and correlates of cannabis-involved substance use treatment admissions age 50 and older, 2000-2021.","authors":"Choi, Namkee G; Marti, C Nathan; Choi, Bryan Y","year":2025,"journal":"Frontiers in public health, 13, 1592551","doi":"10.3389/fpubh.2025.1592551","pmid":"40678640","tags":["addiction","elderly"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis admissions increased in number but share peaked and declined for ages 50-64 (after 2012) and plateaued for 65+ (after 2016); higher among males, Black individuals, legal state residents, and court/healthcare referrals.","whyItMatters":"The aging cannabis user population is entering treatment systems in growing numbers, requiring age-appropriate approaches.","specificNumbers":"N=5,593,004 admissions; ages 65+ share increased to 2016 (APC=5.2) then plateaued; Black (aOR=1.34) and Hispanic (aOR=1.26) individuals had higher odds of cannabis-primary admissions.","methodology":"Joinpoint regression of TEDS-A 2000-2021 (N=5,593,004 admissions age 50+); multinomial and binary logistic regression for correlates.","limitations":"Administrative data reflects referral patterns; TEDS misses private treatment; changing legal landscape; racial disparities may reflect criminal justice bias."},{"rthcId":"RTHC-06216","title":"Driving under the influence of alcohol and cannabis: Associations with substance use and behavioral health characteristics.","authors":"Choi, Namkee G; Marti, C Nathan","year":2025,"journal":"Traffic injury prevention, 1-9","doi":"10.1080/15389588.2025.2587850","pmid":"41397281","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"DUIC prevalence (20.6%) more than double DUIA (8.6%); age 65+ was a DUIC risk factor; substance disorders, early initiation, mental health problems, and criminal justice involvement predicted both; DUIC higher in medical cannabis legal states.","whyItMatters":"Cannabis-impaired driving is far more common than alcohol-impaired driving among respective users, and older adults emerging as a risk group challenges assumptions.","specificNumbers":"N=139,524; 20.6% DUIC vs 8.6% DUIA; among DUI reporters: 47.9% DUIA-only, 34.0% DUIC-only, 18.1% both; age 65+ risk factor for DUIC.","methodology":"Cross-sectional analysis of 2021-2023 NSDUH (N=139,524 adults 18+); binary and multinomial logistic regression for DUIA and DUIC correlates.","limitations":"Self-reported DUI likely underestimates; cannot assess impairment level; cannabis impairment detection less established; NSDUH misses driving frequency."},{"rthcId":"RTHC-06217","title":"DSM-5 Criteria for Alcohol and Cannabis Use Disorders: Are Older Adults Less Likely to Endorse Certain Criteria?","authors":"Choi, Namkee G; Morris, Jeffrey A; Marti, C Nathan","year":2025,"journal":"International journal of environmental research and public health, 22(6)","doi":"10.3390/ijerph22060843","pmid":"40566271","tags":["addiction","elderly"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"For CUD, adults 65+ had dramatically lower odds of endorsing hazardous use (OR 0.04) and withdrawal (OR 0.39 and 0.16); for AUD, 7 of 11 criteria were endorsed less often by older adults.","whyItMatters":"If older adults systematically underreport key CUD criteria, they may be underdiagnosed, undermining treatment access.","specificNumbers":"CUD: hazardous use OR 0.04 (95% CI 0.01-0.17); withdrawal A OR 0.39 (0.20-0.73); withdrawal B OR 0.16 (0.05-0.48); AUD: 7 of 11 criteria endorsed less often by 65+.","methodology":"Cross-sectional analysis of 2021-2023 NSDUH (N=12,264 for CUD, N=17,494 for AUD); multivariable logistic regression for each DSM-5 criterion with age group as independent variable.","limitations":"Self-reported endorsement may reflect true differences or bias; NSDUH may underrepresent severe disorders in elderly; cross-sectional design."},{"rthcId":"RTHC-06218","title":"Proper counseling for diagnosis and management of cannabinoid hyperemesis syndrome: a case report.","authors":"Cholette-Tétrault, Samuel; Grad, Roland","year":2025,"journal":"Family practice, 42(2)","doi":"10.1093/fampra/cmae067","pmid":"39566098","tags":["health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"CHS diagnosed using Rome IV criteria after 2 years of unnecessary investigations; minimum 3 months cannabis cessation required for diagnosis confirmation; symptoms recurred with relapse.","whyItMatters":"CHS remains underdiagnosed because many clinicians do not ask about cannabis use or know the diagnostic criteria, leading to prolonged suffering.","specificNumbers":"22-year-old; daily cannabis user; 2 years of symptoms before diagnosis; minimum 3 months cessation required.","methodology":"Case report of a 22-year-old female daily cannabis user with 2 years of cyclic nausea, vomiting, and abdominal pain; diagnosed after applying Rome IV criteria.","limitations":"Single case report; cannot generalize; 3-month cessation timeframe from expert consensus rather than rigorous trials."},{"rthcId":"RTHC-06219","title":"Polysubstance use and mental health among young adults.","authors":"Chopra, Rajit; Sylvestre, Marie-Pierre; Pelekanakis, Annie; Doré, Isabelle; Omorou, Abdou Y; O'Loughlin, Jennifer","year":2025,"journal":"Canadian journal of public health = Revue canadienne de sante publique, 116(6), 849-857","doi":"10.17269/s41997-025-01035-3","pmid":"40299267","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"No dose-response between substance count and mental health; cannabis-nicotine had strongest negative associations (anxiety b=2.58, PMH b=-5.90); alcohol-nicotine also linked to lower positive mental health.","whyItMatters":"Specific substance pairings matter more for mental health than total count, with cannabis-nicotine standing out as particularly problematic.","specificNumbers":"733 participants; 37% no regular use, 42% one, 16% two, 5% three; cannabis-nicotine: anxiety b=2.58 (1.06-4.10), PMH b=-5.90 (-10.04 to -1.76).","methodology":"Cross-sectional analysis of 733 NDIT study participants (mean age 30.6); multivariable linear regression for regular alcohol, cannabis, and nicotine use patterns.","limitations":"Cross-sectional; self-reported; single Canadian city; small subgroup sizes; reverse causation possible."},{"rthcId":"RTHC-06220","title":"Cannabinoids as a Potential Alternative to Opioids in the Management of Various Pain Subtypes: Benefits, Limitations, and Risks.","authors":"Chou, Roger; Ahmed, Azrah Y.; Dana, Tracy; Morasco, Benjamin J.; Bougatsos, Christina; Fu, Rongwei; Williams, Leah; Ang, Samuel P; Sidharthan, Shawn; Lai, Wilson; Hussain, Nasir; Patel, Kiran V; Gulati, Amitabh; Henry, Onyeaka; Kaye, Alan D; Orhurhu, Vwaire","year":2025,"journal":"Pain and therapy, 12(2), 355-375","doi":"10.23970/AHRQEPCCER250UPDATE2025","pmid":"40956916","tags":["pain","medical-use"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"THC:CBD oral spray: small pain decrease (MD -0.54/10); high THC: small decrease (MD -0.78/10); CBD alone: no benefit (moderate SOE); THC products caused large dizziness increase (RR 3.57) and sedation increase (RR 5.04).","whyItMatters":"This is the most current synthesis of cannabis for pain, showing benefits are small and limited to THC products while CBD alone does not help.","specificNumbers":"29 RCTs, N=2,579; THC:CBD spray MD -0.54 (95% CI -0.95 to -0.19); high THC MD -0.78 (-1.59 to -0.08); CBD alone MD 0.40 (no benefit); dizziness RR 3.57; sedation RR 5.04.","methodology":"Living systematic review; 29 RCTs (N=2,579) and 15 observational studies (N=49,453); databases searched through April 2025; meta-analyses grouped by THC:CBD ratio and product type.","limitations":"Most studies short-term (1-6 months); 48% neuropathic pain; no evidence for psychosis, CUD, or cognitive harms; insufficient evidence for whole-plant cannabis."},{"rthcId":"RTHC-06221","title":"Policy reform and the international future of Moroccan Cannabis production.","authors":"Chouvy, Pierre-Arnaud","year":2025,"journal":"The International journal on drug policy, 142, 104841","doi":"10.1016/j.drugpo.2025.104841","pmid":"40414025","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06222","title":"Efficacy of cannabinoids for the prophylaxis of chemotherapy-induced nausea and vomiting-a systematic review and meta-analysis.","authors":"Chow, Ronald; Basu, Anna; Kaur, Jagdeep; Hui, David; Im, James; Prsic, Elizabeth; Boldt, Gabriel; Lock, Michael; Eng, Lawson; Ng, Terry L; Zimmermann, Camilla; Scotte, Florian","year":2025,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 33(3), 193","doi":"10.1007/s00520-025-09251-w","pmid":"39953210","tags":["nausea","medical-use","cancer"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Cannabinoids superior to placebo for overall CINV control (RR 2.65, 95% CI 1.70-4.12); no difference vs active comparators; 23 of 26 studies published before 2000; one recent trial showed THC:CBD promise as adjunctive therapy.","whyItMatters":"Despite decades of interest, almost all evidence predates modern antiemetic protocols, leaving a critical gap for current oncology practice.","specificNumbers":"26 RCTs; 23 before 2000; cannabinoids vs placebo RR 2.65 (1.70-4.12, I2=0%); no difference vs active comparators; nearly half had bias concerns.","methodology":"Systematic review and meta-analysis of 26 RCTs from inception to March 2024; random effects meta-analysis by endpoint; subgroup analyses by control and design.","limitations":"23 of 26 studies pre-2000 with dated comparators; heterogeneous designs; insufficient evidence for modern adjunctive use including olanzapine."},{"rthcId":"RTHC-06223","title":"Effects of Buprenorphine, Methadone, and Substance Use on COVID-19 Morbidity and Mortality.","authors":"Christian, Nicholaus J; Zhou, Xin; Radhakrishnan, Rajiv","year":2025,"journal":"Journal of addiction medicine, 19(2), 223-226","doi":"10.1097/ADM.0000000000001386","pmid":"39475125","tags":["health-risks","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis, cocaine, sedative, and opioid use were each associated with increased ICU care, ventilatory support, more hospitalizations, and longer stays; substance use was not associated with increased mortality; no differences between methadone, buprenorphine, and other opioids.","whyItMatters":"Understanding how substance use affects COVID-19 severity can inform clinical management and resource allocation during future outbreaks.","specificNumbers":"n=17,423 COVID-19 patients; cannabis, cocaine, sedative, and opioid use each significantly associated with ICU admission, ventilation, and longer hospitalization; no mortality increase; no difference between MOUD types.","methodology":"Retrospective cohort using EHR data from a large urban hospital system; 17,423 COVID-19 positive patients (2020-2021); substance use identified from urine toxicology within 90 days; multivariable logistic regression controlling for age, sex, comorbidity, tobacco, and social disadvantage.","limitations":"Retrospective design; substance use identified by urine toxicology (may miss some users); single hospital system; cannot separate individual substance effects in polysubstance users."},{"rthcId":"RTHC-06224","title":"Ex vivo stimulation of the trigeminal nucleus caudalis induces peripheral CGRP release in the trigeminal ganglion and reveals a distinct dopamine-endocannabinoid mechanism relevant to migraine.","authors":"Christiansen, Isabella Mai; Reducha, Philip Victor; Edvinsson, Lars; Holm, Anja; Haanes, Kristian Agmund","year":2025,"journal":"The journal of headache and pain, 26(1), 141","doi":"10.1186/s10194-025-02072-6","pmid":"40524163","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06225","title":"Unveiling the Antioxidant Role of Hemp Oils in Cancer Prevention and Treatment.","authors":"Christodoulou, Marios C; Rodosthenous, Panagiotis; Neophytou, Christiana M","year":2025,"journal":"Cancers, 17(13)","doi":"10.3390/cancers17132128","pmid":"40647426","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06226","title":"Vortioxetine improves illness severity for cannabis users with anxiety and depressive symptoms in a 6-month randomized controlled study.","authors":"Chung, Albert Kar Kin; Tse, Cheuk Yin; Yeung, Gladys Kwan Yin; Tang, Sau Wan; Chan, Wing-Man; Law, Johnson Kai Chun","year":2025,"journal":"Journal of substance use and addiction treatment, 169, 209607","doi":"10.1016/j.josat.2024.209607","pmid":"39672338","tags":["addiction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Vortioxetine (10mg/day) improved clinician-observed mood (p<.05) but not self-reported anxiety or depression; no improvement in cannabis dependence, cognition, or functional outcomes; standard treatment group showed no improvement.","whyItMatters":"There are no approved medications for cannabis use disorder, and this pilot suggests vortioxetine may help with comorbid mood symptoms even if it does not address cannabis use directly.","specificNumbers":"11 vortioxetine (mean 10 mg/day) vs 19 standard treatment; significant clinician-rated mood improvement (p<.05); no significant between-group differences on cannabis dependence, cognition, or function.","methodology":"6-month prospective RCT; 30 cannabis users with anxiety/depressive symptoms randomized to vortioxetine (n=11) or standard treatment (n=19).","limitations":"Very small sample; unequal group sizes; no placebo control; clinician-rated improvement may reflect observer bias; 6-month follow-up may be insufficient."},{"rthcId":"RTHC-06227","title":"Adolescent Cannabis Vaping Trends (2021-2023): Delta-9-Tetrahydrocannabinol, Cannabidiol, and Synthetic Cannabinoids.","authors":"Chung, Jack; Lim, Carmen C W; Stjepanović, Daniel; Hall, Wayne; Connor, Jason P; Chan, Gary C K","year":2025,"journal":"American journal of preventive medicine, 69(6), 107655","doi":"10.1016/j.amepre.2025.107655","pmid":"40590811","tags":["youth","synthetic","thc"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Significant increases in vaping of THC, CBD, and synthetic cannabinoids from 2021-2023; THC vaping peaked in 2022 while synthetic continued rising; prevalence higher among females than males in 2023; use doubled among 11-13 year olds.","whyItMatters":"The rise in synthetic cannabinoid vaping among the youngest adolescents is alarming given unknown health effects, while overall cannabis vaping continues spreading across all cannabinoid types.","specificNumbers":"69,899 students; 2023: 7.4% (2.55M) vaping THC, 2.9% (999K) vaping CBD, 1.8% (620K) vaping synthetic cannabinoids; females exceeded males in 2023; 11-13 year old THC and synthetic use doubled 2021-2023.","methodology":"Three waves of National Youth Tobacco Survey (2021-2023); 69,899 US middle and high school students aged 11-18; weighted prevalence estimates by year, age, and sex.","limitations":"Self-reported data; students may not know what cannabinoid they are vaping; \"don't know\" responses for synthetics tripled (awareness issue); school-based survey misses dropouts."},{"rthcId":"RTHC-06228","title":"Cannabis Vaping in Youth: A Systematic Review and Meta-Analysis of Risk Factors in Adolescents and Young Adults.","authors":"Chung, Jack; Lim, Carmen C W; Leung, Janni; Stjepanović, Daniel; Chiu, Vivian; Hides, Leanne; Connor, Jason P; Hall, Wayne; Chan, Gary C K","year":2025,"journal":"Journal of studies on alcohol and drugs","doi":"10.15288/jsad.24-00464","pmid":"40748266","tags":["youth","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Among adolescent cannabis users, cannabis vaping odds were higher for males (OR 1.79), older adolescents (OR 1.26), current tobacco users (OR 1.62), and alcohol users (OR 2.52); lower for non-Hispanic Black youth (OR 0.55); insufficient evidence for mental health associations.","whyItMatters":"Identifying who among cannabis-using youth is most likely to vape helps target prevention efforts, as vaping delivers concentrated cannabinoids with unknown long-term effects.","specificNumbers":"31 studies; 568,304 participants; among adolescent cannabis users (n=114,595): male OR=1.79, older OR=1.26, tobacco use OR=1.62, alcohol use OR=2.52, non-Hispanic Black OR=0.55.","methodology":"Systematic review and meta-analysis of 31 studies (n=568,304) from US, Canada, England, New Zealand, and Switzerland; 26 on adolescents, 5 on young adults; pooled odds ratios using random effects.","limitations":"Most studies from US; cross-sectional designs; self-reported cannabis vaping; insufficient studies on mental health and young adult correlates; heterogeneity across studies."},{"rthcId":"RTHC-06229","title":"Examining the Relationship of Cannabis use Patterns, Mental Health, and Sociodemographic Factors: A Focus on Cannabis Vaping, Smoking and Dual-Use.","authors":"Chung, Jack Y C; Lim, Carmen C W; Connor, Jason P; Hall, Wayne; Stjepanović, Daniel; Chan, Gary C K","year":2025,"journal":"Addictive behaviors, 163, 108263","doi":"10.1016/j.addbeh.2025.108263","pmid":"39832481","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Dual-use (20% of users) associated with severe externalizing symptoms (OR 1.89); vaping-only (9.1%) associated with White race (OR 3.90) and higher income (OR 2.56) vs smoking-only; over 56% smoked only.","whyItMatters":"Cannabis consumption methods are shifting, and the finding that dual-use carries the highest behavioral health burden suggests this group needs targeted clinical attention.","specificNumbers":"7,178 cannabis users; 56% smoke only; 9.1% vape only; 20% dual-use; dual-use severe externalizing OR=1.89; vape-only: White OR=3.90, higher income OR=2.56.","methodology":"Cross-sectional analysis of PATH Study Wave 6; 7,178 adult current cannabis users classified by method (smoking only, vaping only, dual-use, other); multinomial logistic regression for sociodemographic and mental health correlates.","limitations":"Cross-sectional PATH data; self-reported methods and mental health; cannot determine direction of association; \"other methods\" category is heterogeneous."},{"rthcId":"RTHC-06230","title":"Which intervention works for whom: Identifying pre-treatment characteristics that predict who will benefit from a specific alcohol text message intervention from a randomized trial.","authors":"Chung, Tammy; Suffoletto, Brian; Bhurosy, Trishnee","year":2025,"journal":"Journal of substance use and addiction treatment, 168, 209562","doi":"10.1016/j.josat.2024.209562","pmid":"39505110","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06231","title":"The emerging role of endocannabinoid system modulation in human fibroblast-like synoviocytes: Exploring new biomarkers and potential therapeutic targets.","authors":"Chwastek, Jakub; Kędziora, Marta; Borczyk, Małgorzata; Korostyński, Michał; Piscitelli, Fabiana; Di Marzo, Vincenzo; Starowicz, Katarzyna","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 186, 118040","doi":"10.1016/j.biopha.2025.118040","pmid":"40215649","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06232","title":"Cannabis use and atrial arrhythmias: A systematic review and meta-analysis of large populational studies.","authors":"Chye, David M; Sampaio Rodrigues, Thalys; Quarto, Levindo J G; Young, Naomie; Hamilton, Garry W; Burrell, Louise M; Teh, Andrew W; Lim, Han S; Koshy, Anoop N","year":2025,"journal":"Heart rhythm","doi":"10.1016/j.hrthm.2025.05.062","pmid":"40472951","tags":["cardiovascular"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis associated with 71% increased atrial arrhythmia risk (OR 1.71, 95% CI 1.1-2.6); risk higher with concomitant drug use (OR 1.91) and in cannabis-legal countries (OR 1.93); 12.5% of cannabis users had AA vs 2.7% of controls.","whyItMatters":"As cannabis use expands globally, the cardiovascular risk profile is becoming clearer, and atrial arrhythmias represent a serious but potentially underrecognized consequence.","specificNumbers":"14 studies; 81.2M participants; 1,578,033 with AA (1.9%); cannabis users: 12.5% AA vs controls: 2.7%; overall OR 1.71 (1.1-2.6); concomitant drug use OR 1.91; legal countries OR 1.93.","methodology":"Systematic review and meta-analysis of 14 observational studies (5 prospective); 81,230,930 participants from North America, Europe, Oceania; random effects model; PROSPERO registered.","limitations":"All observational studies; heterogeneity in cannabis use definitions; cannot determine dose-response; confounding by tobacco and other substances; no teenage population data."},{"rthcId":"RTHC-06233","title":"Parental Perceptions and Practices Regarding Pain Management and Medical Marijuana Use in Patients With Sickle Cell Disease.","authors":"Cinquepalmi, Loretta; Ayeni, Adetunbi; Melville, Laura; Kelly, Christopher","year":2025,"journal":"Clinical pediatrics, 64(6), 824-829","doi":"10.1177/00099228241304464","pmid":"39727290","tags":["medical-use","pain","youth"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Parents had significant concerns about societal implications of medical marijuana use in their children; concerns about marijuana were similar to those about opioids despite marijuana being potentially safer; social consequences may impact treatment acceptability.","whyItMatters":"Even in conditions with severe pain where alternatives to opioids are desperately needed, parental concerns about marijuana's social stigma may prevent its consideration as a treatment option.","specificNumbers":"Parental concerns about marijuana were comparable to opioid concerns; significant societal implication worries identified.","methodology":"Survey study of parents of children with sickle cell disease assessing home pain management strategies and attitudes toward medical marijuana use.","limitations":"Survey methodology details limited in abstract; sample size not specified; single-site study; parental attitudes may not reflect child preferences; specific sickle cell population may not generalize."},{"rthcId":"RTHC-06234","title":"Sprayable Hybrid Gel with Cannabidiol, Hyaluronic Acid, and Colloidal Silver: A Multifunctional Approach for Skin Lesion Therapy.","authors":"Cîrloiu Boboc, Geta-Simona; Segneanu, Adina-Elena; Bejenaru, Ludovic Everard; Văruţ, Marius Ciprian; Bălăşoiu, Roxana Maria; Călina, Daniela; Stoian, Andreea-Cristina; Băluşescu, Georgiana; Herea, Dumitru-Daniel; Ciocîlteu, Maria Viorica; Biţă, Andrei; Mogoşanu, George Dan; Bejenaru, Cornelia","year":2025,"journal":"Pharmaceutics, 17(9)","doi":"10.3390/pharmaceutics17091189","pmid":"41012525","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06235","title":"Variability of total THC in greenhouse cultivated dried Cannabis.","authors":"Cleary, Ben; Maloney, Katie; Toor, Amandeep; Vandermeirsch, Gillian","year":2025,"journal":"Scientific reports, 15(1), 25285","doi":"10.1038/s41598-025-06962-2","pmid":"40651988","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06236","title":"\"If You Need to Light Up … You Gotta Do What You Gotta Do\": A Qualitative Study of Adolescent Attitudes Towards Cannabis Use and Comparison with Alcohol Attitudes.","authors":"Clement, Alex; Corcoran, Erin; Jackson, Kristina M; Gabrielli, Joy","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(3), 133-151","doi":"10.26828/cannabis/2025/000332","pmid":"41278426","tags":["youth","social-behavior"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Adolescents' cannabis approval was contingent on legality, age, degree of use, and purpose; most endorsed cannabis as more acceptable than alcohol; reasons included perceived lower health risks, less addiction potential, and calmer intoxication.","whyItMatters":"Understanding how teens compare cannabis and alcohol risks can inform prevention messaging that addresses their actual beliefs rather than assumptions about what they think.","specificNumbers":"40 adolescents; mean age 16.68; 80% inter-coder agreement; most perceived cannabis as more acceptable than alcohol across multiple dimensions.","methodology":"Qualitative semi-structured interviews with 40 US adolescents (mean age 16.68) following a media exposure study; inductive coding by three graduate coders with 80% agreement.","limitations":"Small qualitative sample; single follow-up study; US-specific context; participants had prior media exposure study involvement; qualitative findings cannot quantify prevalence of attitudes."},{"rthcId":"RTHC-06237","title":"Racial Media Microaggressions: Impact on Black Adolescent Mental and Behavioral Health.","authors":"Clifton, Maribeth; Clifton, Richelle L; Zapolski, Tamika C B","year":2025,"journal":"OTJR : occupation, participation and health, 15394492251385473","doi":"10.1177/15394492251385473","pmid":"41208541","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06238","title":"Relationship Between Cannabis Dispensary Density, Proximity, and Attitudes Toward Medical Cannabis: A Cross-Sectional Study.","authors":"Clobes, Thomas A; Himebaugh, Sean; Gamez, Sandra Aguilar; Torres, Mariza","year":2025,"journal":"Health science reports, 8(4), e70685","doi":"10.1002/hsr2.70685","pmid":"40260030","tags":["legalization","medical-use"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Weak positive correlation between distance from dispensary and favorable MC attitudes; dispensary density did not significantly impact attitudes; gender (p=0.004), age (p=0.048), and state legal status (p<0.001) were significant predictors in regression.","whyItMatters":"As dispensaries proliferate, understanding whether proximity normalizes or stigmatizes medical cannabis can inform zoning and public health policy.","specificNumbers":"935 respondents; 743 in no-dispensary zip codes, 160 moderate-density, 32 high-density; weak correlation r=0.090; model R2=0.025; gender and state legal status most significant.","methodology":"Online survey (2021-2022); 935 respondents; MCAS scores correlated with dispensary proximity and density using zip code data; Spearman correlation, ANOVA, and GLS regression.","limitations":"Weak effects (R2=0.025); cross-sectional; self-selected survey sample; unbalanced group sizes; dispensary density measure may not capture actual exposure."},{"rthcId":"RTHC-06239","title":"UGT2B7-mediated drug-drug interaction between cannabinoids and hydromorphone.","authors":"Coates, Shelby; Bardhi, Keti; Zhao, Mengqi; Lazarus, Philip","year":2025,"journal":"Drug metabolism and disposition: the biological fate of chemicals, 53(9), 100135","doi":"10.1016/j.dmd.2025.100135","pmid":"40925219","tags":["medical-use","pain","dosing"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Multiple cannabinoids inhibited UGT2B7-mediated hydromorphone glucuronidation with Ki values 0.068-1.01 uM; static modeling predicted >1.25-fold increase in hydromorphone exposure; PBPK models predicted 20-30% CBD-hydromorphone interaction in healthy and cirrhotic individuals.","whyItMatters":"Patients using cannabis alongside hydromorphone (a potent opioid for severe pain) may experience higher opioid levels than expected, increasing overdose risk.","specificNumbers":"Ki values 0.068-1.01 uM after binding correction; THC, 11-OH-THC, CBD, and 7-OH-CBD all predicted to cause >1.25-fold hydromorphone increase; CBD predicted 20-30% increase via PBPK modeling.","methodology":"In vitro inhibition screening in human liver microsomes and recombinant UGT2B7; IC50 and Ki determinations; static and PBPK modeling for in vivo prediction; tested THC, CBD, and their major metabolites.","limitations":"In vitro data with in silico predictions; clinical interaction studies needed for confirmation; UGT2B7 polymorphism effects uncertain; did not account for all potential metabolic pathways."},{"rthcId":"RTHC-06240","title":"Laser-Induced Ablation of Hemp Seed-Derived Biomaterials for Transdermal Drug Delivery.","authors":"Cocean, Alexandru; Cocean, Georgiana; Garofalide, Silvia; Cimpoesu, Nicanor; Alexa, Daniel; Cocean, Iuliana; Gurlui, Silviu","year":2025,"journal":"International journal of molecular sciences, 26(16)","doi":"10.3390/ijms26167852","pmid":"40869176","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06241","title":"Correlates of Using Medically-Authorized Cannabis in a Large Cohort of People Living with HIV Who Use Cannabis.","authors":"Coelho, Sophie G; Wardell, Jeffrey D; Kroch, Abigail; Rueda, Sergio","year":2025,"journal":"AIDS and behavior, 29(3), 858-869","doi":"10.1007/s10461-024-04568-9","pmid":"39656341","tags":["medical-use"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Only 14.06% used any medical cannabis; medical users had greater HIV symptom distress, poorer physical health quality of life, more frequent use, and preferred smokeless forms; 85.94% used exclusively non-medical cannabis.","whyItMatters":"Even where recreational cannabis is legal, a subset of patients with HIV continue to access medical cannabis, and they represent a sicker population using cannabis more therapeutically.","specificNumbers":"868 participants; 85.37% male; mean age 51.34; 14.06% any medical cannabis use; medical users had greater symptom distress, poorer physical QoL, more frequent use, and more smokeless methods.","methodology":"Cross-sectional analysis of 868 HIV-positive cannabis users in the Ontario HIV Treatment Network Cohort Study (2022); logistic regression comparing medical vs exclusively non-medical cannabis users.","limitations":"Cross-sectional; Ontario-specific legal context; self-reported cannabis authorization; predominantly male sample; cannot determine if medical cannabis is causally related to better health management."},{"rthcId":"RTHC-06242","title":"Recurrent Peripheral Artery Disease in a 45-Year-Old Male Without Hypercoagulable Comorbidities.","authors":"Cohen, Adi; Cohen, Jessica; Cordeiro de Oliveira, Igor; Anasseri, Sheela; Ahmed, Faryal; Cherner, Rebecca","year":2025,"journal":"Cureus, 17(7), e89057","doi":"10.7759/cureus.89057","pmid":"40896016","tags":["cardiovascular","health-risks"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Recurrent severe PAD requiring multiple bypass surgeries in a patient without traditional cardiovascular risk factors; daily marijuana and alcohol use for 20 years were the only identifiable risk factors; arterial Doppler showed severe occlusion in multiple leg arteries.","whyItMatters":"This case illustrates that chronic cannabis use may be an underrecognized risk factor for peripheral artery disease, particularly in younger patients without classic cardiovascular risk factors.","specificNumbers":"45-year-old male; 20 years daily marijuana and alcohol use; 3 vascular surgeries (2017 bypass, 2018 revision, current bypass); severe occlusion of superficial femoral, popliteal, and dorsalis pedis arteries.","methodology":"Case report of a 45-year-old male presenting with left leg pain and severe atherosclerotic disease requiring femoral-tibial bypass; history of two prior vascular surgeries; 20 years of daily marijuana and alcohol use.","limitations":"Single case report; concurrent alcohol use makes it impossible to attribute findings to marijuana alone; no control comparison; case reports cannot establish causation."},{"rthcId":"RTHC-06243","title":"Associations between cannabis-related hospital visits and psychotic disorder-related hospital visits in Arizona from 2016 to 2022.","authors":"Colby, Alana M; Barashy, Sivan; Miller, Matt L; Hummel, Haley M; Mun, Chung Jung; Meier, Madeline H","year":2025,"journal":"Drug and alcohol dependence, 273, 112717","doi":"10.1016/j.drugalcdep.2025.112717","pmid":"40446496","tags":["psychosis","health-risks"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-related hospital visits were approximately 7 times as likely to involve a psychotic disorder diagnosis as cannabis-unrelated visits, an association that remained stable from 2016 to 2022. The link was stronger for visits by females and adolescents.","whyItMatters":"As cannabis use and cannabis-related hospitalizations continue to rise, understanding the relationship between cannabis-related visits and psychotic disorders helps shape hospital screening and treatment coordination. The stability of this association across multiple years suggests it is not a temporary artifact of legalization changes.","specificNumbers":"Cannabis-related visits increased 4.1% per year on average. Cannabis-related visits were ~7 times as likely to involve psychosis as cannabis-unrelated visits. Alcohol-related visits were ~3 times as likely. Alcohol-psychotic disorder associations decreased over time while cannabis-psychotic disorder associations stayed stable.","methodology":"Researchers analyzed 21,934,060 emergency department and inpatient hospital visits in Arizona from 2016 to 2022 using ICD-10-CM codes. Poisson regression tested time trends in cannabis-psychotic disorder associations, with stratification by sex, age, and visit type.","limitations":"Hospital visit data cannot establish causation. ICD-10-CM coding may misclassify some visits. People with psychotic disorders may be more likely to use cannabis (reverse causation). The study cannot account for THC potency or mode of consumption."},{"rthcId":"RTHC-06244","title":"Rates and Clinical Correlates of Cannabis Use in Trichotillomania and Skin Picking Disorder.","authors":"Collins, Madison; Grant, Jon E","year":2025,"journal":"The Journal of nervous and mental disease, 213(6), 145-149","doi":"10.1097/NMD.0000000000001832","pmid":"40435936","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Approximately 33% of individuals with trichotillomania or skin picking disorder reported past-year cannabis use. Cannabis use was associated with more days per week spent pulling or picking, and in trichotillomania specifically, cannabis use was associated with heightened distress.","whyItMatters":"Cannabis use rates in people with body-focused repetitive behaviors have received little research attention despite rising cannabis use in psychiatric populations. Understanding whether cannabis use correlates with worse BFRB symptoms could inform treatment approaches.","specificNumbers":"Approximately 33% of participants reported past-year cannabis use. Cannabis users reported more days per week of pulling or picking. In trichotillomania specifically, cannabis use was linked to heightened distress.","methodology":"Online survey of individuals with body-focused repetitive behaviors (BFRBs) collecting rates of past-year cannabis use and clinical measures of trichotillomania and skin picking disorder severity.","limitations":"Cross-sectional design cannot determine causation. Online survey introduces self-selection bias. No information on cannabis use frequency, quantity, or product type. Small scope limits generalizability."},{"rthcId":"RTHC-06245","title":"\"Stoned on the road\": A systematic review of cannabis-impaired driving educational initiatives targeting young drivers in Canada.","authors":"Colonna, Robert; Pathan, Zuha; Sultania, Anupradi; Alvarez, Liliana","year":2025,"journal":"The International journal on drug policy, 142, 104835","doi":"10.1016/j.drugpo.2025.104835","pmid":"40383076","tags":["driving","youth","legalization"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Fifteen Canadian DUIC initiatives were found: seven educational programs and eight awareness campaigns spanning national and regional levels. Some increased awareness and shifted perceptions, but evidence of behavior change was limited. Sustainability challenges related to funding and digital platform maintenance were noted.","whyItMatters":"Canada legalized recreational cannabis nationally in 2018, making youth DUIC prevention a policy priority. Knowing which educational approaches work and which do not helps allocate prevention resources more effectively.","specificNumbers":"15 initiatives identified: 7 educational programs, 8 awareness campaigns. Methods included in-person workshops, digital tools, online programs, and smartphone apps. Target age: 16 to 24.","methodology":"Systematic review searching MEDLINE, PsycINFO, CINAHL, SCOPUS, and EMBASE (January 2017 to July 2023) plus grey literature for Canadian initiatives targeting driving under the influence of cannabis among youth ages 16 to 24.","limitations":"Grey literature inclusion adds breadth but variable quality. Limited evidence of behavioral outcomes makes it difficult to rank initiatives by effectiveness. Only Canadian initiatives were included."},{"rthcId":"RTHC-06246","title":"Using intervention mapping to evaluate 'High-Alert,' a brief smartphone intervention to reduce youth cannabis-impaired driving.","authors":"Colonna, Robert; Tucker, Patricia; Mandich, Angela; Alvarez, Liliana","year":2025,"journal":"PloS one, 20(8), e0329383","doi":"10.1371/journal.pone.0329383","pmid":"40845142","tags":["driving","youth"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"High Alert, a digital smartphone intervention for youth DUIC, was positively received by participants and showed preliminary efficacy in reducing driving after cannabis co-use compared to a no-contact control. However, implementation challenges including online bot activity, recruitment barriers, and high attrition rates were significant.","whyItMatters":"Cannabis-impaired driving among youth is a growing concern in jurisdictions with legalized cannabis. Digital interventions are scalable, but this study highlights the practical challenges of deploying them to high-risk young populations.","specificNumbers":"Most participants were willing to engage with the app and recommend it to peers. Content and delivery ratings exceeded those of static infographics. Preliminary efficacy was shown for reducing driving after cannabis co-use vs. no-contact group.","methodology":"Pilot randomized controlled trial comparing High Alert (smartphone intervention) to an active control (DUIC infographics) and a passive control (no contact), evaluated using the six-step Intervention Mapping framework including formative, process, outcome, and acceptability evaluations.","limitations":"Pilot study with small sample size. High attrition limits generalizability. Bot activity during online recruitment complicated data quality. Active control group may have also received benefit from infographic exposure."},{"rthcId":"RTHC-06247","title":"Maternal ingestion of cannabidiol (CBD) in mice leads to sex-dependent changes in memory, anxiety, and metabolism in the adult offspring, and causes a decrease in survival to weaning age.","authors":"Compagno, Martina Krakora; Silver, Claudia Rose; Cox-Holmes, Alexis; Basso, Kari B; Bishop, Caroline; Bernstein, Amber Michal; Carley, Aidan; Cazorla, Joshua; Claydon, Jenna; Crane, Ashleigh; Crespi, Chloe; Curley, Emma; Dolezel, Tyla; Franck, Ezabelle; Heiden, Katie; Huffstetler, Carley Marie; Loeven, Ashley M; May, Camilla Ann; Maykut, Nicholas; Narvarez, Alejandro; Pacheco, Franklin A; Turner, Olivia; Fadool, Debra Ann","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 247, 173902","doi":"10.1016/j.pbb.2024.173902","pmid":"39481653","tags":["prenatal","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Fetal CBD exposure significantly decreased pup survival to weaning. Adult male offspring exposed during gestation and lactation showed increased caloric intake and respiratory exchange ratio. Adult females showed increased obsessive-compulsive-like and decreased anxiety-like behaviors. Males showed decreased long-term object memory. Effects differed depending on whether exposure occurred during gestation, lactation, or both.","whyItMatters":"CBD is widely perceived as safe and is used by some pregnant or nursing women. This study provides animal evidence that perinatal CBD exposure can have lasting effects on offspring survival, metabolism, and behavior, effects that are sex-dependent and timing-dependent.","specificNumbers":"CBD was detected in maternal plasma within 10 minutes (34.2 ng/ul) and peaked within 30 minutes (371.0 ng/ul). Pup survival decreased significantly with fetal CBD exposure. Male offspring showed increased meal size and caloric intake. Female offspring showed altered anxiety-related behaviors.","methodology":"Primiparous female C57BL/6J mice received 100 mg/kg oral CBD in strawberry jam. Cross-fostering design separated gestation vs. lactation exposure. Offspring were metabolically profiled using indirect calorimetry and behaviorally phenotyped using established tests (marble burying, light-dark box, elevated-plus maze, object recognition).","limitations":"Animal study results may not translate directly to humans. Single dose level (100 mg/kg) is high relative to typical human use. Cross-fostering design is rigorous but adds complexity to interpretation. Strain-specific effects cannot be ruled out."},{"rthcId":"RTHC-06248","title":"Effectiveness of cannabis use and cannabis use disorder interventions: a European and international data synthesis.","authors":"Connor, Jason P; Manthey, Jakob; Hall, Wayne; Stjepanović, Daniel","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 327-339","doi":"10.1007/s00406-024-01829-5","pmid":"38780801","tags":["addiction","medical-use"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cognitive Behavioral Therapy (CBT) and Motivational Enhancement Therapy (MET) improved short-term cannabis use frequency and dependence severity, though abstinence outcomes were less consistent and improvements were not typically maintained at nine months. Treatments extending beyond four sessions were more effective. Adding Contingency Management improved outcomes. No pharmacotherapies have been approved for cannabis use disorder or withdrawal.","whyItMatters":"Cannabis use disorder affects a growing number of people worldwide, yet treatment options remain limited. Understanding which approaches work, for how long, and what augments them helps clinicians set realistic expectations and plan treatment.","specificNumbers":"CBT/MET treatments beyond 4 sessions were more effective than shorter programs. Benefits were typically not maintained at 9 months post-treatment. No pharmacotherapies are approved for cannabis use disorder.","methodology":"Data synthesis integrating findings from high-level evidence studies on behavioral and pharmacological cannabis treatment approaches, prioritizing European data where available.","limitations":"Relatively few European-specific studies were available. Synthesis approach is less rigorous than a formal systematic review or meta-analysis. Heterogeneity across included studies limits precision of conclusions."},{"rthcId":"RTHC-06249","title":"Demographic features, health status, and behavioral changes associated with cannabidiol use in the Dog Aging Project.","authors":"Conrow, Kendra D; Haney, Richard S; Malek-Ahmadi, Michael H; Albright, Julia D; Kaplan, Barbara L F; Snyder-Mackler, Noah; Kerr, Kathleen F; Su, Yi; Promislow, Daniel E L; Bray, Emily E; Leung, Maxwell C K","year":2025,"journal":"Frontiers in veterinary science, 12, 1666663","doi":"10.3389/fvets.2025.1666663","pmid":"41394909","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06250","title":"Understanding clustered behavioral risk factors among adults in the United States: A gender-specific analysis of alcohol and other substance use and obesity.","authors":"Cook, Won Kim; Li, Libo; Kerr, William C; Martinez, Priscilla","year":2025,"journal":"Alcohol, clinical & experimental research, 49(10), 2199-2212","doi":"10.1111/acer.70148","pmid":"40913258","tags":["addiction","health-risks"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Four clusters with similar profiles emerged for both men and women: heavy-drinking-tobacco-some-cannabis-use-obese, high-substance-use, obese, and relatively-healthy-lifestyle. The high-substance-use group skewed under age 35. Clusters featuring alcohol, tobacco, and cannabis together were more common in midlife men and higher-income individuals. Clustered risk factors were associated with being White and having no college degree.","whyItMatters":"Most substance use research examines individual substances in isolation, but real-world use involves combinations. Understanding how cannabis clusters with other behavioral risk factors helps design interventions that address multiple behaviors simultaneously.","specificNumbers":"N = 214,505 adults. Four common clusters identified for both genders. High-substance-use cluster concentrated in ages under 35. Alcohol-tobacco-cannabis clusters more prevalent in midlife men and higher-income adults of both genders.","methodology":"Latent class analyses and multinomial/logistic regressions using a nationally representative sample of 214,505 U.S. adults from the 2015-2019 National Survey on Drug Use and Health, stratified by gender.","limitations":"Cross-sectional design captures a snapshot, not trajectories. Self-reported substance use may be underestimated. NSDUH excludes institutionalized and homeless populations. Latent class solutions involve researcher judgment."},{"rthcId":"RTHC-06251","title":"Correct Recognition and Appeal Ratings of Copycat Cannabis Edible Packaging: Evidence from an Online Experiment.","authors":"Cooper, Michael; Shi, Yuyan","year":2025,"journal":"Cannabis and cannabinoid research, 10(3), 420-424","doi":"10.1089/can.2025.0017","pmid":"40354317","tags":["legalization","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Copycat cannabis packages were associated with 65% lower odds of correct identification of cannabis content compared to non-copycat branded packages. When participants did correctly identify cannabis content, they rated those packages as less appealing, suggesting that clearly identifiable cannabis packaging reduces product appeal.","whyItMatters":"Copycat cannabis edible packaging that mimics popular snack brands is common in states with legal recreational cannabis. Misidentification creates real risk of accidental ingestion, particularly concerning for children and young adults.","specificNumbers":"N = 2,523 young adults aged 18-29. Copycat packages: OR = 0.35 for correct identification (65% lower odds). Correct identification was associated with lower appeal ratings (OR = 0.75).","methodology":"Online experiment with a representative sample of 2,523 young adults aged 18-29. Participants completed timed trials identifying whether packages contained cannabis. Regression analysis tested associations between package type, identification accuracy, and appeal ratings.","limitations":"Online experiment may not perfectly replicate real-world purchasing conditions. Only young adults (18-29) were tested; children may be even more susceptible. Did not assess actual ingestion outcomes."},{"rthcId":"RTHC-06252","title":"Packaging of Cannabis Edibles, Health Warning Recall, and Perceptions Among Young Adults.","authors":"Cooper, Michael; Shi, Yuyan","year":2025,"journal":"JAMA network open, 8(4), e253117","doi":"10.1001/jamanetworkopen.2025.3117","pmid":"40178854","tags":["legalization","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Plain packaging increased correct warning recall (52.9%, OR 1.47), decreased appeal ratings (OR 0.70), and increased perceived harm (OR 1.48) compared to branded packaging. Youth-appealing packaging increased appeal, especially among 18-20 year olds. Pain relief and sleep aid claims increased appeal, particularly among past-year non-users.","whyItMatters":"Cannabis packaging regulations vary widely across legalized states. This study provides evidence that specific packaging features, particularly plain packaging and the absence of health claims, meaningfully affect how young adults perceive cannabis products and process safety warnings.","specificNumbers":"N = 4,500 (3,000 cannabis users, 1,500 non-users). Plain packaging: 52.9% correct warning recall (OR 1.47), decreased appeal (OR 0.70), increased perceived harm (OR 1.48). Youth-appealing packaging increased appeal (OR 1.40), especially for ages 18-20. Health claims increased appeal (pain relief OR 1.31, sleep aid OR 1.36).","methodology":"Cross-sectional randomized online experiment with 4,500 young adults (18-29) across 23 legalized states plus DC. Full-factorial design: 3 packaging styles x 3 health claims x 7 warning themes. Outcomes: warning recall, appeal, perceived harm, adult-oriented appearance, target age.","limitations":"Online experiment with hypothetical purchasing. Measured perceptions and recall, not actual behavior. Short-term exposure may not reflect cumulative effects of real-world packaging encounters."},{"rthcId":"RTHC-06253","title":"Contesting Cannabinoid Hyperemesis Syndrome: How Narratives of Cannabis Shape Diagnosis Contestation and Treatment Resistance.","authors":"Copes, Heith; Webb, Megan; Valles, Jessica","year":2025,"journal":"Qualitative health research, 35(8), 876-886","doi":"10.1177/10497323241279079","pmid":"39455058","tags":["health-risks"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Participants contested CHS diagnoses because they believed cannabis was beneficial and helped with nausea, that claims about cannabis harms were part of medical conspiracy, and that their symptoms differed from CHS descriptions. They resisted abstinence by trying new routes of administration, different cannabis types, reduced frequency, or substituting other substances.","whyItMatters":"CHS diagnoses are increasing alongside rising cannabis use and potency. Understanding why patients resist diagnosis and treatment can help clinicians communicate more effectively with patients who hold strong positive beliefs about cannabis.","specificNumbers":"N = 24 self-reported CHS patients. Participants described multiple strategies to continue cannabis use: new administration routes, specific cannabis types, reduced amounts or frequency, and substance substitution.","methodology":"Qualitative study using semi-structured interviews with 24 individuals who self-reported having cannabinoid hyperemesis syndrome, analyzed through a narrative framework examining how symbolic meanings of cannabis shaped diagnosis and treatment experiences.","limitations":"Self-reported CHS diagnosis without clinical confirmation. Small sample recruited through convenience/snowball sampling. Qualitative design cannot quantify how widespread these attitudes are among CHS patients."},{"rthcId":"RTHC-06254","title":"Cannabis smoking is associated with persistent epigenome-wide disruptions despite smoking cessation.","authors":"Cordero, Ana I Hernandez; Li, Xuan; Yang, Chen Xi; Ambalavanan, Amirtha; MacIsaac, Julie L; Kobor, Michael S; Doiron, Dany; Tan, Wan; Bourbeau, Jean; Sin, Don D; Duan, Qingling; Leung, Janice M","year":2025,"journal":"BMC pulmonary medicine, 25(1), 168","doi":"10.1186/s12890-025-03634-9","pmid":"40205553","tags":["health-risks"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Current cannabis smokers showed 12,115 differentially methylated genes compared to never-smokers, while former cannabis smokers still showed 10,806 differentially methylated genes. Of these, 5,915 genes overlapped between current and former smokers. Fifty enriched pathways were shared between groups, heavily represented by aging and cancer-related pathways.","whyItMatters":"This is the first study to evaluate whether cannabis smoking cessation reverses epigenetic changes. The finding that most methylation disruptions persist after quitting suggests long-lasting biological effects that may not be undone by simply stopping use.","specificNumbers":"N = 93 older adults. Current smokers: 12,115 differentially methylated genes. Former smokers: 10,806. Shared: 5,915 genes. 50 shared enriched pathways, heavily cancer- and aging-related.","methodology":"Epigenome-wide DNA methylation analysis of peripheral blood from 93 older adults in the Canadian Cohort of Obstructive Lung Disease (CanCOLD), comparing current, former, and never cannabis smokers at FDR < 0.05.","limitations":"Very small sample size (n=93) limits statistical power and generalizability. Cross-sectional design cannot track changes over time. Peripheral blood methylation may not reflect tissue-specific effects. Could not fully control for concurrent tobacco use."},{"rthcId":"RTHC-06255","title":"Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria.","authors":"Corleto, Merlina; Garavaglia, Matías; Martínez, Melina M B; Weschenfeller, Melanie; Montes, Santiago Urrea; Aran, Martin; Pellizza, Leonardo; Faccone, Diego; Maffía, Paulo C","year":2025,"journal":"Pharmaceutics, 18(1)","doi":"10.3390/pharmaceutics18010051","pmid":"41599157","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06256","title":"Repeated treatment with JWH-018 progressively increases motor activity and aggressiveness in male mice: involvement of CB1 cannabinoid and D1/D2 dopaminergic receptors.","authors":"Corli, Giorgia; De Luca, Fabrizio; Bilel, Sabrine; Bassi, Marta; Roda, Elisa; Rossi, Paola; Fattore, Liana; Locatelli, Carlo Alessandro; Marti, Matteo","year":2025,"journal":"European journal of pharmacology, 998, 177633","doi":"10.1016/j.ejphar.2025.177633","pmid":"40254068","tags":["synthetic"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Repeated JWH-018 (6 mg/kg) treatment progressively increased spontaneous locomotion and aggressiveness in mice. The CB1 antagonist AM-251 prevented effects across all injections. Dopamine D1 antagonist SCH23390 and D2 antagonist haloperidol attenuated and prevented seventh-injection effects, respectively, especially in combination. Behavioral changes were accompanied by alterations in cortical, hippocampal, striatal, and cerebellar dopamine receptor and tyrosine hydroxylase gene expression.","whyItMatters":"Synthetic cannabinoids are linked to unpredictable psychiatric symptoms including agitation and aggression. This study identifies specific neurobiological mechanisms through which repeated exposure may produce escalating behavioral effects.","specificNumbers":"JWH-018 dose: 6 mg/kg i.p. AM-251 (CB1 antagonist): 6 mg/kg. SCH23390 (D1 antagonist): 0.1 mg/kg. Haloperidol (D2 antagonist): 0.05 mg/kg. Progressive increases in locomotion and aggression observed across repeated injections.","methodology":"Adult male ICR-CD1 mice received repeated JWH-018 injections (6 mg/kg, i.p.) with pharmacological challenges using CB1 antagonist AM-251, D1 antagonist SCH23390, and D2 antagonist haloperidol. Behavior was assessed by locomotor activity and aggression. Brain immunohistochemistry examined D1, D2 receptor and tyrosine hydroxylase expression.","limitations":"Animal study using a single high dose that may not reflect human use patterns. Only male mice were studied. JWH-018 is one of many synthetic cannabinoids with varying pharmacology. Behavioral tests in mice have limited translational value for human aggression."},{"rthcId":"RTHC-06257","title":"The Relationship between Cannabis Use and Demand for Cigarettes in Adolescents who Smoke Cigarettes.","authors":"Cornacchione Ross, Jennifer; Denlinger-Apte, Rachel L; Bello, Mariel S; Tidey, Jennifer W; Colby, Suzanne M; Cassidy, Rachel N","year":2025,"journal":"Drug and alcohol dependence, 277, 112959","doi":"10.1016/j.drugalcdep.2025.112959","pmid":"41260022","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Daily cannabis-using adolescents showed significantly higher cigarette demand intensity than non-users. However, daily cannabis users were also more sensitive to cigarette price changes (higher alpha) than non-daily and non-users, meaning their demand dropped more steeply as price increased. No differences in delay discounting (impulsivity) were found by cannabis use status.","whyItMatters":"Adolescent cannabis and tobacco co-use is increasing. Understanding how cannabis use alters the reinforcing value of cigarettes can inform pricing policies and targeted cessation strategies for dual-using youth.","specificNumbers":"N = 70 adolescents aged 17-19. Daily cannabis users showed higher cigarette demand intensity. Daily cannabis users showed greater price sensitivity (alpha). No difference in delay discounting across groups.","methodology":"Cross-sectional study of 70 adolescents aged 17-19 who smoked at least 1 cigarette per day. Participants completed timeline follow-back for 30-day cannabis use, a Cigarette Purchase Task (behavioral economic demand), and a Delay Discounting Task. Three groups: daily, non-daily, and no cannabis use.","limitations":"Very small sample size (n=70) with limited statistical power. Cross-sectional design. Hypothetical purchasing task may not reflect real-world behavior. Only daily cigarette smokers were included."},{"rthcId":"RTHC-06258","title":"A pilot randomized controlled trial of a digital cannabis harm reduction intervention for young adults with first-episode psychosis who use cannabis.","authors":"Coronado-Montoya, Stephanie; Abdel-Baki, Amal; Bodson-Clermont, Paule; Boucher-Roy, David; Côté, José; Crocker, Candice E; Crockford, David; Daneault, Jean-Gabriel; Dubreucq, Simon; Dussault-Laurendeau, Maxime; Fischer, Benedikt; Lachance-Touchette, Pamela; Lecomte, Tania; L'Heureux, Sophie; Ouellet-Plamondon, Clairélaine; Roy, Marc-André; Tatar, Ovidiu; Tibbo, Philip G; Villeneuve, Marie; Wittevrongel, Anne; Jutras-Aswad, Didier","year":2025,"journal":"Psychiatry research, 350, 116553","doi":"10.1016/j.psychres.2025.116553","pmid":"40450961","tags":["psychosis","addiction","harm-reduction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Trial retention was 82.2% and CHAMPS completion rate was 58.8%, meeting pre-specified thresholds for feasibility and acceptability. Signals of possible improvement were observed in harm reduction strategy use, motivation to change cannabis behaviors, cannabis-related problems, and cannabis use frequency in the intervention group.","whyItMatters":"Cannabis use worsens prognosis for people with first-episode psychosis, but many are not ready for abstinence-focused treatment. Harm reduction approaches that meet patients where they are could improve outcomes for this vulnerable population.","specificNumbers":"N = 101 young adults (ages 18-35) with FEP. Retention: 82.2% (threshold: 60%). Completion: 58.8% (threshold: 50%). Six-module digital intervention. Assessments at baseline, weeks 6, 12, 18.","methodology":"Multi-site pilot randomized controlled trial comparing early intervention services (EIS) + CHAMPS digital app versus EIS-only in 101 young adults aged 18-35 with first-episode psychosis who use cannabis. Outcomes assessed at baseline and weeks 6, 12, and 18.","limitations":"Pilot study not powered for efficacy. Improvement signals are preliminary and require confirmation. Cannabis use was self-reported. Multi-site design adds generalizability but also variability."},{"rthcId":"RTHC-06259","title":"Lifetime Cannabis Use and Incident Hypertension: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.","authors":"Corroon, Jamie; Bradley, Ryan; Grant, Igor; Bancks, Michael P; Jakob, Julian; Auer, Reto; Reis, Jared P; Allen, Norrina; Yeh, Kuan-Hung; Allison, Matthew A","year":2025,"journal":"Hypertension (Dallas, Tex. : 1979), 82(10), 1641-1652","doi":"10.1161/HYPERTENSIONAHA.125.25005","pmid":"40785536","tags":["cardiovascular"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-years were not significantly associated with incident hypertension (adjusted HR 0.99, 95% CI 0.97-1.00, p=0.18) over 35 years. This null finding was robust to restricted cubic spline analyses, stratification by sex, race, alcohol use, and tobacco smoking, and an alternative exposure measure (days of use in the past month).","whyItMatters":"Previous evidence on cannabis and hypertension has been inconsistent. This study provides the longest follow-up to date with sophisticated methods to handle time-dependent confounding, and finds no relationship.","specificNumbers":"N = 4,328 at baseline, 2,810 (64.9%) at year 35. Median cannabis-years remained low across visits: 0.0 at baseline, 0.2 by year 35. There were 2,478 incident hypertension cases over 88,292 person-years (28.1 per 1,000 person-years). Adjusted HR: 0.99 (0.97-1.00).","methodology":"Marginal structural models with inverse probability weighting in the CARDIA study, following 4,328 participants free of cardiovascular disease at baseline for 35 years. Cannabis-years measured cumulative lifetime use. Cox proportional hazards regression estimated hazard ratios. Sensitivity analyses included spline models and stratification.","limitations":"Median cannabis use was low across the cohort, limiting the ability to assess effects of heavy, sustained use. Self-reported cannabis use may underestimate exposure. Marginal structural models address but do not eliminate time-dependent confounding."},{"rthcId":"RTHC-06260","title":"Maternal cannabis use in pregnancy, perinatal outcomes, and cognitive development in offspring: a longitudinal analysis of the ALSPAC cohort using paternal cannabis use as a negative control exposure.","authors":"Corsi, Daniel J; Morris, Tim T; Reed, Zoe E; Davey Smith, George","year":2025,"journal":"European journal of epidemiology, 40(5), 549-562","doi":"10.1007/s10654-025-01233-w","pmid":"40353977","tags":["prenatal"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Maternal cannabis use during pregnancy was associated with decreased birth weight (-110.2 g), decreased birth length (-0.45 cm), neonatal special care admission (OR 1.64), and lower education achievement at age 16 (-19.2 points). However, most associations were attenuated after controlling for confounders including socioeconomic position, and associations were not quantitatively different from paternal cannabis use, suggesting residual confounding drives the observed relationships.","whyItMatters":"Many studies report associations between prenatal cannabis exposure and adverse outcomes, but these are often confounded by socioeconomic factors. By showing that paternal cannabis use (which cannot biologically affect the fetus in the same way) produces similar associations, this study suggests the observed harms may reflect social disadvantage rather than direct biological effects.","specificNumbers":"N = 15,013 mother-father-child trios. 5% of mothers and 13% of fathers reported cannabis use. Birth weight decrease: -110.2 g (95% CI -185.1 to -35.3). Birth length decrease: -0.45 cm. Special care admission OR: 1.64. Age 16 education score decrease: -19.2 points. All attenuated after covariate adjustment.","methodology":"Negative control exposure study using 15,013 mother-father-child trios from the ALSPAC birth cohort (1990-1992). Maternal cannabis use was the primary exposure and paternal cannabis use served as a negative control. Models adjusted for household SEP markers and parental tobacco, alcohol, and drug use. Wald tests compared maternal vs. paternal association strengths.","limitations":"ALSPAC participants were recruited in 1990-1992 when cannabis potency was lower. Self-reported cannabis use may underestimate exposure. Negative control design assumes paternal cannabis has no biological effect on offspring, which may not be entirely true (e.g., epigenetic effects on sperm)."},{"rthcId":"RTHC-06261","title":"Effects of cannabinoids on immune checkpoint inhibitor response: CCTG pooled analysis of individual patient data.","authors":"Coschi, Courtney H; Ding, Keyue; Tong, Justin; Tu, Dongsheng; O'Callaghan, Christopher; Leighl, Natasha B; Vera-Badillo, Francisco; Juergens, Rosalyn A; Hao, Desiree; Seymour, Lesley; Renouf, Daniel J; Chen, Eric; Gaudreau, Pierre-Olivier; Fung, Andrea S","year":2025,"journal":"Immunotherapy, 17(4), 257-268","doi":"10.1080/1750743X.2025.2485012","pmid":"40184324","tags":["cancer","medical-use"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Of 684 patients, 9.5% used cannabinoids during treatment. By multivariate analysis, baseline cannabinoid use was significantly associated with improved iPFS (p=0.05) but not with iBOR, PFS, OS, or incidence of immune-related adverse events. Results were similar when analyzed by cannabinoid use at any time during trial.","whyItMatters":"There is concern that cannabinoids could impair immune checkpoint inhibitor effectiveness by inhibiting T-cell activation. This pooled analysis provides reassurance that cannabinoid use did not worsen outcomes in patients receiving dual immunotherapy.","specificNumbers":"N = 684 patients. 65 (9.5%) used cannabinoids at any time on trial. 32 (4.7%) at baseline. Baseline cannabinoid use associated with improved iPFS (p=0.05). No significant differences in OS (p=0.35), PFS (p=0.12), grade 1-4 irAEs (p=0.65-0.96).","methodology":"Pooled individual patient data from 4 Canadian Cancer Trials Group (CCTG) trials of patients receiving dual immune checkpoint inhibitors (durvalumab plus tremelimumab) with or without chemotherapy. Cochran-Mantel-Haenszel and log-rank tests stratified by trial/treatment arm.","limitations":"Observational analysis within clinical trials. Small number of cannabinoid users (n=65) limits power. Self-reported cannabinoid use without standardized dosing or product information. iPFS improvement did not translate to OS benefit."},{"rthcId":"RTHC-06262","title":"Cannabis sativa extract and fertility: Preclinical evaluation in male and female Wistar rats.","authors":"Costa, Alana C; Pereira, Cícero A C; Gasparotto, Arquimedes; Garcia, Alana A K; Lourenço, Emerson L B; Joaquim, Helena P G","year":2025,"journal":"Reproductive toxicology (Elmsford, N.Y.), 136, 108982","doi":"10.1016/j.reprotox.2025.108982","pmid":"40582628","tags":["prenatal"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"None of the tested doses (0.28 to 56 mg/kg) significantly affected sex hormone levels in male or female rats. Male organ morphology and sperm characteristics were unaffected. Female fertility, blastocyst implantation, and early embryonic development were normal across all doses up to 7 days post-pregnancy confirmation. No direct toxic effects on the embryo were observed.","whyItMatters":"Concerns about cannabis effects on fertility are common among reproductive-age users. This preclinical study provides data that a standardized cannabis extract did not impair fertility markers in rats, though animal results require caution when extrapolating to humans.","specificNumbers":"Doses tested: 0.28, 2.8, 28, and 56 mg/kg body weight. 7 groups of 20 animals each. No significant changes in sex hormones, sperm characteristics, fertility, or blastocyst implantation at any dose.","methodology":"Seven groups of 20 Wistar rats each received different doses of a standardized Cannabis sativa extract (160.32 mg/mL). Assessments included clinical exams, biochemistry, organ weights, sperm production and morphology, histopathology, and female fertility/implantation outcomes per nonclinical toxicology guidelines.","limitations":"Animal study with uncertain human translation. Rat reproductive biology differs from human in important ways. Short duration of exposure may miss effects that emerge with chronic use. Extract composition may not represent recreational products."},{"rthcId":"RTHC-06263","title":"The Role of Childhood Trauma in Chronic Pain and Substance Use Among Individuals Receiving Methadone Treatment for Opioid Use Disorder.","authors":"Costa, Gabriel P A; Ra, Jocelyn; Meyerovich, Julia; Pittman, Brian; C Nunes, Julio; De Aquino, Joao P","year":2025,"journal":"Journal of addiction medicine","doi":"10.1097/ADM.0000000000001553","pmid":"40728216","tags":["pain","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Higher childhood trauma scores correlated with greater pain severity, increased alcohol consumption, and earlier age of first cannabis use. Cannabis users in the sample reported significantly higher levels of emotional abuse, sexual abuse, and physical neglect compared to non-users.","whyItMatters":"Childhood trauma is common among people with substance use disorders, but its specific relationship to cannabis use and pain in this population has been underexplored.","specificNumbers":"Childhood trauma correlated with pain severity (r = 0.27, P = 0.03), alcohol use (r = 0.25, P = 0.04), and earlier cannabis initiation (r = -0.45, P < 0.001). Emotional abuse showed the strongest correlations with pain severity (r = 0.33) and interference (r = 0.28).","methodology":"Cross-sectional study of 82 individuals receiving methadone for opioid use disorder. Researchers used validated questionnaires for childhood trauma (CTQ), pain (BPI), and substance use (TLFB) over the past 28 days.","limitations":"Small sample size (82 participants). Cross-sectional design cannot establish whether trauma causes cannabis use or pain. Single-site study."},{"rthcId":"RTHC-06264","title":"Comparative Analysis of Cannabidiol and Risperidone on Behavioral and Neurochemical Outcomes, and Neurodevelopment Markers in a Zebrafish Model of Embryonic Exposure to Sodium Valproate.","authors":"Costa, Karla C M; Brigante, Tamires A V; Lirio, Pedro H C; Fernandes, Gabriel G; Scarante, Franciele F; Scomparin, Davi S; Ferreira, Rafael R; Vicente, Maria A; Abe, Flavia R; Guimarães, Francisco S; Hallak, Jaime E C; Crippa, Jose A; de Oliveira, Danielle P; Campos, Alline C","year":2025,"journal":"Autism research : official journal of the International Society for Autism Research, 18(12), 2368-2381","doi":"10.1002/aur.70151","pmid":"41293963","tags":["cbd","neuroscience","mental-health"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD treatment reversed VPA-induced hyperlocomotion and aggression in zebrafish, reduced lipid peroxidation, restored anandamide levels, and normalized markers of glial function. Risperidone showed limited behavioral improvement and did not affect these neurobiological markers.","whyItMatters":"Risperidone is one of only two FDA-approved medications for autism-related irritability, but it comes with significant side effects. This study suggests CBD may address not just behavioral symptoms but some of the underlying neurobiology.","specificNumbers":"CBD at 0.06 microM reversed both hyperlocomotion and aggression. CBD reduced lipid peroxidation and restored anandamide levels. CBD normalized both GFAP and calcium/calmodulin expression.","methodology":"Zebrafish embryos were exposed to sodium valproate (VPA) to induce autism-like features. At 3-4 days post-fertilization, embryos were treated with 0.06 microM CBD or 1 microM risperidone.","limitations":"Zebrafish model cannot replicate full complexity of human autism. VPA-induced autism model represents only one possible pathway to ASD. Results cannot be directly translated to human dosing."},{"rthcId":"RTHC-06265","title":"Process Development for GMP-Grade Full Extract Cannabis Oil: Towards Standardized Medicinal Use.","authors":"Costa, Maria do Céu; Gomes, Ana Patrícia; Vinhas, Iva; Rosa, Joana; Pereira, Filipe; Moniz, Sara; Gonçalves, Elsa M; Pestana, Miguel; Silva, Mafalda; Rodrigues, Luís Monteiro; DeMeo, Anthony; Marynissen, Logan; Marques da Costa, António; Rijo, Patrícia; Sassano, Michael","year":2025,"journal":"Pharmaceutics, 17(7)","doi":"10.3390/pharmaceutics17070848","pmid":"40733057","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06266","title":"A Mobile App (Joint Effort) to Support Cannabis Use Self-Management and Reinforce the Use of Protective Behavioral Strategies: Development Process and Usability Testing.","authors":"Côté, José; Auger, Patricia; Chicoine, Gabrielle; Cheng, Jinghui; Cossette, Sylvie; Fontaine, Guillaume; Genest, Christine; Lal, Shalini; Lapierre, Judith; Pagé, M Gabrielle; Maheu-Cadotte, Marc-André; Rouleau, Geneviève; Vinette, Billy; Jutras-Aswad, Didier","year":2025,"journal":"JMIR formative research, 9, e71924","doi":"10.2196/71924","pmid":"40550117","tags":["harm-reduction","youth"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"The app scored 4.43 out of 5.0 on the Mobile Application Rating Scale, with particularly high marks for functionality (4.60) and aesthetics (4.53).","whyItMatters":"Most cannabis interventions focus on abstinence. This app takes a harm-reduction approach, helping young adults who choose to use cannabis do so with lower risk.","specificNumbers":"Overall quality score: 4.43/5.0. Functionality: 4.60/5.0. Aesthetics: 4.53/5.0. Information quality: 4.44/5.0. Engagement: 4.14/5.0. 90% agreed the training addressed a need.","methodology":"Researchers used intervention mapping and co-design with young adults through focus groups. Twenty university students (mean age 21.8) tested the prototype.","limitations":"Only 20 testers, all university students from one campus. Usability testing does not demonstrate efficacy in changing behaviors."},{"rthcId":"RTHC-06267","title":"An Outbreak of Synthetic Cannabinoid-Adulterated Tianeptine Products in New Jersey - Case Series.","authors":"Counts, Christopher J; Spadaro, Anthony V; Cerbini, Trevor A; Krotulski, Alex J; Walton, Sara E; Greller, Howard A; Nelson, Lewis S; Ruck, Bruce E; Hung, Oliver; Logan, Barry; Calello, Diane P","year":2025,"journal":"Journal of medical toxicology : official journal of the American College of Medical Toxicology, 21(2), 253-259","doi":"10.1007/s13181-025-01068-7","pmid":"40102319","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Products marketed as containing tianeptine were found to contain the synthetic cannabinoids MDMB-4en-PINACA and ADB-4en-PINACA. Of 37 acute exposures, 43% required intubation and 65% were admitted to the ICU.","whyItMatters":"Unregulated products sold openly at gas stations and online can contain dangerous adulterants with no labeling to warn users.","specificNumbers":"34 unique patients over about 8 months, compared to a background rate of 0.5 tianeptine cases per year. 43% (16 patients) required intubation. 65% (24 patients) admitted to ICU.","methodology":"Retrospective and prospective surveillance through New Jersey Poison Control. Six product samples were analyzed by gas chromatography and mass spectrometry.","limitations":"Case series without controls. Product composition varied across samples. Only two patient blood samples were tested."},{"rthcId":"RTHC-06268","title":"Corticosterone stimulates synthesis of 2-arachidonoylglycerol via putative membrane-bound glucocorticoid receptors and inhibits GABA release via CB1 cannabinoid receptors in the ventrolateral periaqueductal gray.","authors":"Coutens, Basile; Bouchet, Courtney A; Patti, Lorenzo C; McPherson, Kylie B; Boston, Bethany S; Jewett, David C; Ingram, Susan L","year":2025,"journal":"Molecular pharmacology, 107(8), 100058","doi":"10.1016/j.molpha.2025.100058","pmid":"40729946","tags":["neuroscience","pain","dopamine"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"In the ventrolateral periaqueductal gray (vlPAG), corticosterone activates putative membrane-bound glucocorticoid receptors, which stimulate 2-AG synthesis. This 2-AG then activates presynaptic CB1 receptors to reduce GABA release.","whyItMatters":"This study maps a specific molecular mechanism linking stress to pain modulation via the endocannabinoid system.","specificNumbers":"Corticosterone-mediated signaling enhanced 2-AG synthesis that was blocked by the DAGL inhibitor DO34. The effect was dependent on a Gs-protein and protein kinase A pathway.","methodology":"Electrophysiology experiments in rodent brain slices. Researchers used pharmacological manipulations including CB1 receptor antagonists, diacylglycerol lipase inhibitors, and protein kinase A blockers.","limitations":"In vitro brain slice preparation removes the circuit from its natural context. Uses rodent tissue. The glucocorticoid receptors are described as \"putative.\""},{"rthcId":"RTHC-06269","title":"The Current State of Unapproved Cannabidiol Product Use in Children.","authors":"Cowell, Braden; Van de Roovaart, Hannah; Beck, Melissa; Chen, Aleda M H; Cole, Justin W","year":2025,"journal":"The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 30(5), 564-579","doi":"10.5863/JPPT-24-00081","pmid":"41112335","tags":["cbd","epilepsy","youth","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"CBD has one FDA-approved pediatric use: Epidiolex for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Beyond that, the evidence for CBD in children is limited. But that hasn't stopped a growing number of parents from giving their children unapproved, over-the-counter CBD products for conditions ranging from anxiety to autism to ADHD.\n\nThis review maps the current landscape of unapproved pediatric CBD use. The problems are layered. Unregulated CBD products have no quality assurance — they may contain more or less CBD than labeled, may include THC above the legal 0.3% threshold, and may contain contaminants like heavy metals, pesticides, or solvents. Multiple studies of commercial CBD products have found that actual content frequently doesn't match labels.\n\nThe pharmacology review highlights that CBD in children has a different pharmacokinetic profile than in adults — different absorption, distribution, metabolism, and excretion rates. Pediatric dosing extrapolated from adult data may be inappropriate. CBD's known inhibition of CYP450 enzymes is particularly concerning in children taking other medications for epilepsy, ADHD, or psychiatric conditions.\n\nThe legal landscape adds confusion: CBD derived from hemp (containing <0.3% THC) is legal at the federal level, but the FDA hasn't approved any over-the-counter CBD product for any condition in any age group. Parents may not understand the distinction between a regulated pharmaceutical (Epidiolex) and the CBD oil from a health food store.","whyItMatters":"Children are not small adults — they metabolize drugs differently, their brains are still developing, and they can't consent to or self-manage their own treatment. The proliferation of unregulated CBD products being given to children creates risks that most parents aren't equipped to evaluate: variable product quality, unknown drug interactions, and the absence of pediatric efficacy data for conditions other than specific epilepsy syndromes.","specificNumbers":"1 FDA-approved pediatric CBD product (Epidiolex) for 3 epilepsy syndromes. Studies of commercial CBD products consistently find label inaccuracy — some containing more THC than labeled. CBD inhibits CYP2C9, CYP2C19, and CYP3A4, affecting metabolism of many common pediatric medications. No FDA-approved OTC CBD product for any condition at any age.","methodology":"Narrative review addressing CBD pharmacology, legal and regulatory factors, usage patterns, current efficacy data, and safety concerns for pediatric CBD use. Includes recommendations for clinicians, public health officials, and researchers.","limitations":"Narrative review — not a systematic search. The pace of CBD product innovation and regulatory change means the landscape may shift quickly. Usage patterns are based on surveys that likely underestimate the true prevalence of pediatric CBD use. The review focuses on the U.S. regulatory environment; other countries have different frameworks. The absence of evidence for most pediatric conditions doesn't prove absence of benefit — it means the studies haven't been done."},{"rthcId":"RTHC-06270","title":"Synthetic cannabinoids in e-cigarettes seized from English schools.","authors":"Cozier, Gyles E; Gardner, Matthew; Craft, Sam; Skumlien, Martine; Spicer, Jack; Andrews, Rachael; Power, Alexander; Haines, Tom; Bowman, Richard; Manley, Amy E; Sunderland, Peter; Sutcliffe, Oliver B; Husbands, Stephen M; Hines, Lindsey; Taylor, Gillian; Freeman, Tom P; Scott, Jennifer; Pudney, Christopher R","year":2025,"journal":"Addiction (Abingdon, England), 120(10), 1995-2004","doi":"10.1111/add.70110","pmid":"40574414","tags":["synthetic-cannabinoids","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoids were detected in 17.4% of all e-cigarette samples seized from schools. Positive samples contained a median concentration of 0.42 mg/mL, with a maximum of 3.6 mg/mL. Only 1.2% contained THC.","whyItMatters":"Synthetic cannabinoids are far more potent and dangerous than natural cannabis, and children may not know what they are vaping.","specificNumbers":"77.8% of schools had at least one SC-positive sample. 17.4% of all seized samples contained SCs. Median concentration: 0.42 mg/mL. Maximum: 3.6 mg/mL. SC prevalence correlated with free school meal eligibility (r = 0.65, P = 0.003).","methodology":"E-cigarettes seized by teachers at 27 secondary schools across England were analyzed using GC-MS, LC-MS, and quantitative NMR spectroscopy.","limitations":"Samples were seized by teachers, introducing selection bias. Not all schools in England were represented."},{"rthcId":"RTHC-06271","title":"Detection and quantification of synthetic cannabinoids in seven illicitly sourced disposable vapes submitted by an individual presenting to a UK drug and alcohol service.","authors":"Craft, Sam; Sunderland, Peter; Millea, Molly F; Pudney, Christopher R; Sutcliffe, Oliver B; Freeman, Tom P","year":2025,"journal":"Addiction (Abingdon, England), 120(3), 549-554","doi":"10.1111/add.16671","pmid":"39256058","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"All seven samples contained 5F-MDMB-PICA at a median concentration of 0.85 mg/mL (range 0.59-1.63 mg/mL). No THC, CBD, or other natural cannabinoids were found.","whyItMatters":"People buying what they believe to be cannabis vapes may unknowingly be using potent synthetic cannabinoids.","specificNumbers":"Median 5F-MDMB-PICA concentration: 0.85 mg/mL. Range: 0.59 to 1.63 mg/mL. 7/7 positive for synthetic cannabinoids. 0/7 contained natural cannabinoids.","methodology":"Seven illicitly sourced disposable vapes submitted by one individual to a UK drug and alcohol service were analyzed using NMR and GC/MS.","limitations":"Only seven samples from a single individual at one service."},{"rthcId":"RTHC-06272","title":"\"It's legal, now what?\" development, implementation, and evaluation of interdisciplinary cannabis education for healthcare trainees.","authors":"Cronin, Sean P; Cruz, Josue; Cameron, Elena; Azemar, Sabrina; Dudley, Steven; Largent-Milnes, Tally M; Brady, Benjamin R; Wallace, Jessica S; Arnett, Margie R; Dahmer, Stephen M; Ibrahim, Mohab M; Padilla, Alyssa R; Vanderah, Todd W; De La Rosa, Jennifer S","year":2025,"journal":"Journal of cannabis research, 7(1), 68","doi":"10.1186/s42238-025-00321-8","pmid":"41013836","tags":["medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"345 trainees in pharmacy, nursing, public health, and medicine completed the program. 96% reported improved ability to respond to patients interested in cannabis.","whyItMatters":"Cannabis use is surging but healthcare professional training on cannabis remains minimal.","specificNumbers":"345 trainees certified since 2023. 90% agreed it addressed a training need. 83% said it should be required. 96% reported improved patient response ability.","methodology":"Implementation study using post-training surveys. The virtual training was developed using intervention mapping with four key strategies.","limitations":"No control group or pre-post knowledge assessment. Self-reported satisfaction only."},{"rthcId":"RTHC-06273","title":"In utero chronic cannabis exposure is associated with lower total brain volume in the first month of postnatal life.","authors":"Crume, Tessa L; Kim, Pilyoung; Shen, Xinyi; Iisa, Erika; Huestis, Marilyn A; Fried, Peter; Stickrath, Elaine H; Conageski, Christine; Phipers, Jocelyn E; Kinney, Gregory; Sempio, Cristina; Klawitter, Jost; Dufford, Alexander J","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(4), 458-470","doi":"10.1080/00952990.2025.2506112","pmid":"40700630","tags":["pregnancy","cognition","neuroscience","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Studying prenatal cannabis exposure is extremely difficult because most pregnant cannabis users also use tobacco, alcohol, or other substances, making it nearly impossible to isolate cannabis's independent effects. This study addressed that problem directly by enrolling only mother-infant pairs where cannabis was used without concurrent alcohol, tobacco, or illegal drug use.\n\nCannabinoid exposure was confirmed objectively using ultra-high performance liquid chromatography-tandem mass spectrometry in both maternal and neonatal biological samples — no reliance on self-report alone. Then neonatal brain MRIs were performed in the first month of life for 18 exposed and 21 unexposed infants.\n\nThe finding: cannabis-exposed neonates had lower total brain volume compared to unexposed infants. This global brain volume difference was present even after using inverse probability of treatment weighting to control for structural confounding between exposure groups.\n\nThe study also examined subcortical regions specifically — the amygdala and hippocampus — which are critical for emotional regulation and memory formation and are rich in cannabinoid receptors during development.\n\nThis is one of the cleanest studies of prenatal cannabis exposure and brain development, but it's still an observational study. The brain volume difference could be caused by cannabis exposure, or by unmeasured factors that differ between women who use cannabis during pregnancy and those who don't. What it does is flag a measurable structural brain difference that demands further investigation.","whyItMatters":"Cannabis use during pregnancy is increasing — in some U.S. surveys, up to 7% of pregnant women report use, often for nausea. If prenatal cannabis exposure affects brain development, the public health implications are significant. This study's careful exclusion of other substances and objective exposure verification make it one of the most methodologically rigorous investigations of this question.","specificNumbers":"18 exposed, 21 unexposed neonates. MRI in first month of life. Cannabis-exposed infants had lower total brain volume. Exposure confirmed by LC-MS/MS in maternal and neonatal samples. No concurrent alcohol, tobacco, or illicit drug use in the exposed group. Inverse probability of treatment weighting used for confounding control. Registered clinical trial: NCT03718520.","methodology":"Prospective pre-birth cohort study selecting mother-infant pairs based on prenatal cannabis use without alcohol, tobacco, or illegal drug use. Cannabinoid exposure quantified in maternal and neonatal biological samples using LC-MS/MS. Neonatal MRI conducted in the first month of life: 18 exposed, 21 unexposed infants. Inverse probability of treatment weighting in a generalized linear model framework controlled for structural confounding. Evaluated global brain volume and subcortical volumes (amygdala, hippocampus). Registered: NCT03718520.","limitations":"Small sample (39 total neonates). Observational design — even with careful confounder control, unmeasured differences between cannabis-using and non-using pregnant women may explain the findings. Brain volume at one month is a structural measure, not a functional one — whether the volume difference translates to developmental or cognitive differences later in childhood is unknown. Single time point — no longitudinal follow-up to see if differences persist, widen, or resolve. Cannabis product type, dose, timing, and duration of use during pregnancy weren't precisely characterized."},{"rthcId":"RTHC-06274","title":"Cannabinoid CB1 receptor in dopaminergic circuit from ventral tegmental area to nucleus accumbens links trait anxiety with reward learning.","authors":"Cui, Chi; Luo, Gangan; Lei, Jie; Shi, Yulong; Yao, Yibo; Ren, Kun; Yang, Jian; Li, Tongxia; Li, Ming; Peng, Xiang; Yang, Xueke; Du, Junsong; Chen, Sitong; Tian, Bo; Zhang, Pei","year":2025,"journal":"Translational psychiatry, 15(1), 395","doi":"10.1038/s41398-025-03644-5","pmid":"41073394","tags":["neuroscience","anxiety","dopamine"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"High trait anxiety mice exhibited increased reward learning. CB1R knockout on VTA dopaminergic neurons produced both increased anxiety-like behavior and impaired reward learning.","whyItMatters":"Anxiety and reward sensitivity often co-occur in humans. This study identifies a specific molecular mechanism that may explain why anxious individuals are drawn to rewarding substances.","specificNumbers":"High trait anxiety mice showed significantly increased conditioned place preference for ethanol. CB1R knockout in VTA dopamine neurons produced anxiety-like behavior and reward learning impairment.","methodology":"Behavioral screening to classify mice by trait anxiety, ethanol-conditioned place preference, pharmacological manipulation with CB1 antagonist/agonist, and genetic CB1R knockout in VTA dopaminergic neurons.","limitations":"Mouse model; trait anxiety in mice may not map directly onto human anxiety disorders. Ethanol was used as the reward."},{"rthcId":"RTHC-06275","title":"Indicators of Intergenerational Transmission of Cannabis Use Among US Young Adults.","authors":"Cui, Yuxian; Wang, Yan; LoParco, Cassidy R; Romm, Katelyn F; Cavazos-Rehg, Patricia A; Chakraborty, Rishika; McCready, Darcey M; Yang, Y Tony; Berg, Carla J","year":2025,"journal":"Substance use & addiction journal, 46(4), 960-971","doi":"10.1177/29767342251337212","pmid":"40583811","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Having cannabis-using parents (aOR = 2.90) and having children (aOR = 1.37) were both independently associated with past-month cannabis use. Becoming a parent was protective only among those without cannabis-using parents.","whyItMatters":"If parental cannabis use normalizes the behavior so strongly that becoming a parent does not reduce use, interventions may need to target family-level norms.","specificNumbers":"Cannabis-using parents: aOR = 2.90 (95% CI: 2.42-3.47). Having children: aOR = 1.37 (95% CI: 1.12-1.67).","methodology":"Survey of 4,031 US young adults (mean age 26.29). Multivariable logistic regression examined parental cannabis use, having children, sociodemographics, psychosocial factors, and state legalization.","limitations":"Cross-sectional design cannot determine causation. Sample designed to oversample cannabis users (48.8%)."},{"rthcId":"RTHC-06276","title":"Profiles of cannabis use and expense-related factors among US young adults.","authors":"Cui, Yuxian; McCready, Darcey M; Romm, Katelyn F; LoParco, Cassidy R; Speer, Morgan; Chakraborty, Rishika; Williams, Jessica; Cavazos-Rehg, Patricia A; Wang, Yan; Yang, Y Tony; Berg, Carla J","year":2025,"journal":"Addictive behaviors, 170, 108428","doi":"10.1016/j.addbeh.2025.108428","pmid":"40633149","tags":["youth","legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Latent class analysis identified four profiles: price-insensitive low-spend (36%), high-spend heavy users (32%), moderate-spend oil/other users (24%), and price-sensitive high-spend mixed users (8%). All groups except the low-spend group showed higher problematic use.","whyItMatters":"Understanding how cannabis spending and use patterns cluster helps identify which consumer profiles may be at greatest risk for problematic use.","specificNumbers":"Class 1: 36.1% (price-insensitive, low-spend). Class 2: 31.9% (high-spend, high-frequency). Class 3: 24.1% (moderate-spend, oil/other). Class 4: 7.9% (price-sensitive, high-spend, mixed).","methodology":"Survey of 1,359 US young adults reporting past-month cannabis use (mean age 26.95). Latent class analysis used cost perception, spending, use frequency, and product type.","limitations":"Cross-sectional design. Self-reported spending may be inaccurate. Convenience sample."},{"rthcId":"RTHC-06277","title":"Applying Natural Language Processing Techniques to Map Trends in Insomnia Treatment Terms on the r/Insomnia Subreddit: Infodemiology Study.","authors":"Cummins, Jack A; Gottlieb, Daniel J; Sofer, Tamar; Wallace, Danielle A","year":2025,"journal":"Journal of medical Internet research, 27, e58902","doi":"10.2196/58902","pmid":"39786862","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06278","title":"Impulsivity behaviors and white matter mediate the relationship between genetic risk for cannabis use disorder and early cannabis use in adolescents.","authors":"Cupertino, Renata Basso; Medland, Sarah Elizabeth; Ottino-Gonzalez, Jonatan; Cao, Zhipeng; Juliano, Anthony; Pancholi, Devarshi; Banaschewski, Tobias; Bokde, Arun L W; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Gowland, Penny; Heinz, Andreas; Brühl, Rüdiger; Martinot, Jean-Luc; Martinot, Marie-Laure Paillère; Artiges, Eric; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Lemaitre, Herve; Paus, Tomáš; Poustka, Luise; Hohmann, Sarah; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Conrod, Patricia; Callas, Peter; Garavan, Hugh; Mackey, Scott","year":2025,"journal":"Addiction (Abingdon, England), 120(5), 984-996","doi":"10.1111/add.16750","pmid":"39789945","tags":["genetics","youth","cognition","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Higher genetic risk for CUD was associated with greater cannabis exposure, more novelty/sensation seeking, higher impulsivity, and lower white matter integrity from age 14. Mediation models showed novelty seeking and impulsivity partially explained the path from genetic risk to cannabis use.","whyItMatters":"This is one of the first studies to show that adult CUD genetic risk is already visible in adolescent brain structure and behavior.","specificNumbers":"CUD-PRS and cannabis exposure: beta = 0.098, P < 0.001. CUD-PRS and novelty seeking: beta = 0.105, P < 0.001. CUD-PRS and impulsivity: beta = 0.106, P < 0.001.","methodology":"Longitudinal data from the IMAGEN cohort with assessments at ages 14 (n=1,762), 19 (n=1,175), and 23 (n=1,139). Polygenic risk scores related to behavioral measures, substance use, and brain imaging.","limitations":"Effect sizes are small (betas around 0.1). European-ancestry cohort only."},{"rthcId":"RTHC-06279","title":"A pilot study of dronabinol for the treatment of pain in sickle cell disease.","authors":"Curtis, Susanna A; Jhawar, Ritika; Bellis, Jordan; McCuskee, Sarah; Devine, Lesley; Roberts, John D","year":2025,"journal":"Pilot and feasibility studies, 11(1), 139","doi":"10.1186/s40814-025-01705-6","pmid":"41225660","tags":["medical-cannabis","pain"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Of 27 patients approached, 85% were interested. All enrolled participants completed all procedures. Dronabinol produced no serious adverse events. However, 100% correctly identified their assignment after the second period.","whyItMatters":"Many sickle cell patients already use cannabis for pain relief, but rigorous evidence is lacking. This pilot establishes that a controlled trial is feasible.","specificNumbers":"27 approached, 23 (85%) interested, 13 (48%) consented, 6 (22%) enrolled. 100% protocol adherence. 0 serious adverse events.","methodology":"Randomized, double-blind, placebo-controlled crossover pilot study. Six adults with sickle cell disease received dronabinol and placebo for two 2-week periods each.","limitations":"Only 6 participants. Crossover design compromised blinding. Too small to assess efficacy."},{"rthcId":"RTHC-06280","title":"A randomized clinical trial of low-dose cannabis extract in Alzheimer's disease.","authors":"Cury, Rafael de Morais; da Silva, Taynara; Cezar-Dos-Santos, Fernando; Fakih, Yasmin Rafaela Correia; Narvaez, Karlin Andrea Ramírez; Gouvea, Murilo Chaves; Espínola, Carlos; Ferreira, Charles Francisco; de Castro, Wagner Antonio Chiba; Pamplona, Fabrício Alano; Silva, Elton Gomes da; Bicca, Maíra Assunção; Nascimento, Francisney Pinto","year":2025,"journal":"Journal of Alzheimer's disease : JAD, 108(4), 1602-1613","doi":"10.1177/13872877251389608","pmid":"41160460","tags":["medical-cannabis","cbd","seniors","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Patients receiving low-dose THC-CBD extract (0.350 mg THC + 0.245 mg CBD daily) had significantly higher Mini-Mental State Exam scores at week 26 compared to placebo.","whyItMatters":"Alzheimer's has very few effective treatments. A 26-week trial showing cognitive benefit with a remarkably low cannabinoid dose could open a new treatment avenue.","specificNumbers":"Daily dose: 0.350 mg THC + 0.245 mg CBD. Duration: 26 weeks. Significant improvement in MMSE total score vs placebo.","methodology":"Phase 2, randomized, double-blind, placebo-controlled trial. Participants aged 60-80 with Alzheimer's dementia received either placebo or THC-CBD extract orally for 26 weeks.","limitations":"Phase 2 trial, likely small sample. Only the primary outcome was significant. Requires replication."},{"rthcId":"RTHC-06281","title":"Minor Cannabinoid Use Among Medical Cannabis Patients.","authors":"Cuttler, Carrie; Boehnke, Kevin F; Doucette, Mitchell L; Wilson-Poe, Adrianne R; Kruger, Daniel J","year":2025,"journal":"Journal of psychoactive drugs, 1-10","doi":"10.1080/02791072.2025.2607725","pmid":"41437413","tags":["medical-cannabis","cbd"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The most commonly used cannabinoids were CBD, delta-9 THC, delta-8 THC, and THCA. The majority reported stopping one or more pharmaceutical medications because of their medical cannabis use.","whyItMatters":"The cannabinoid marketplace has expanded dramatically, but research and regulation have not kept pace.","specificNumbers":"1,721 medical cannabis patients surveyed. Most common methods: smoking flower, vape pen/cartridge, edibles. Majority stopped one or more pharmaceuticals.","methodology":"Survey of 1,721 US medical cannabis patients assessing patterns of use and motivations across a wide variety of cannabinoid products.","limitations":"Self-selected sample. Self-reported data. No verification of medications discontinued or clinical outcomes."},{"rthcId":"RTHC-06282","title":"Prevalence of cannabis use disorders and associated factors among privately insured adults with epilepsy.","authors":"Czerniak, Katarzyna; Kim, Youngran; Sepulveda, Refugio; Myneni, Sahiti; Addy, Robert; Shegog, Ross","year":2025,"journal":"Frontiers in neurology, 16, 1695511","doi":"10.3389/fneur.2025.1695511","pmid":"41404464","tags":["epilepsy","addiction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"CUD prevalence was 1.1%. People with epilepsy and CUD had six times more tobacco use disorders and three times more mood disorders. Adults aged 18-24 had an adjusted risk ratio of 5.04 compared to those 65+.","whyItMatters":"Cannabis is increasingly used by epilepsy patients, but CUD risk in this population has been understudied.","specificNumbers":"1.1% CUD prevalence. Age 18-24 vs 65+: aRR = 5.04 (95% CI: 3.83-6.65). CUD group had 6x tobacco use disorders and 3x mood disorders.","methodology":"Cross-sectional analysis of 2022 IQVIA PharMetrics Plus claims data covering 63,713 unique adults with epilepsy.","limitations":"Claims data identifies only diagnosed CUD. Privately insured population only. Cannot distinguish recreational vs medicinal use."},{"rthcId":"RTHC-06283","title":"Oromucosal as an Alternative Method for Administration of Cannabis Products in Rodents.","authors":"da Costa Rodrigues, Deborah; Lourenço de Aguiar, Andrey Fabiano; Paes Colli, Yolanda; Pereira Campos, Raquel Maria; de Melo Reis, Ricardo Augusto; Sampaio, Luzia Silva","year":2025,"journal":"Journal of visualized experiments : JoVE","doi":"10.3791/68104","pmid":"40920655","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06284","title":"Efficacy of different cannabinoid compounds on migraine-like responses in female rats.","authors":"da Luz, Fernanda Mariano Ribeiro; Kaup, Alexandre Ottoni; Baggio, Darciane Favero; Costa, Flavio Henrique de Rezende; Chichorro, Juliana Geremias","year":2025,"journal":"Cephalalgia : an international journal of headache, 45(10), 3331024251386794","doi":"10.1177/03331024251386794","pmid":"41129688","tags":["cbd","pain","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD/THC combination produced the longest-lasting pain relief (up to 3 hours) and was the only compound that reduced light sensitivity in the CGRP-induced migraine model. In the chronic model, CBD/THC suppressed pain through day 13.","whyItMatters":"Migraine affects roughly 12% of the global population and current treatments are often inadequate.","specificNumbers":"CBD alone: reduced pain at 30 min to 2 hours. CBD/THC: reduced pain up to 3 hours. In chronic model: CBD/THC suppressed pain through day 13.","methodology":"Female Wistar rats received systemic CBD (30 mg/kg), CBD/CBG (2:1), CBD/0.3% THC, or CBD/CBG/THC. Acute and chronic migraine models used.","limitations":"Animal model. Only female rats. Doses may not translate to human use."},{"rthcId":"RTHC-06285","title":"Effectiveness of cannabinoids on subjective sleep quality in people with and without insomnia or poor sleep: A systematic review and meta-analysis of randomised studies.","authors":"da Silva, Giovanna Hanike Santos; Barbosa, Eduardo Cerchi; de Lima, Fernanda Ribeiro; Barroso, Douglas Carneiro; Paez, Loyná Euá Flores E; Guimarães, Felipe Bandeira de Melo; Lança, Saulo Bernardo; de Faria, Stephanie Brito Ceolin; Petrucci, Arthur Bezerra Cavalcanti; Garbacka, Alicja; Walsh, Jennifer H","year":2025,"journal":"Sleep medicine reviews, 84, 102156","doi":"10.1016/j.smrv.2025.102156","pmid":"40929927","tags":["sleep","cbd","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Cannabinoids significantly improved sleep quality compared to placebo (SMD 0.53, P = 0.04), with stronger effects in people with insomnia or poor sleep (SMD 0.60, P = 0.02). Non-CBD cannabinoids showed greater efficacy (SMD 0.82, P = 0.005), while CBD-only therapies showed no significant effect (SMD 0.13, P = 0.61).","whyItMatters":"Many people use cannabis products, especially CBD, for sleep. This meta-analysis suggests CBD alone may not help, while THC-containing cannabinoids show meaningful benefit.","specificNumbers":"Overall cannabinoids vs placebo: SMD 0.53 (95% CI 0.03-1.02, P = 0.04, I2 = 88%). Non-CBD: SMD 0.82 (P = 0.005). CBD-only: SMD 0.13 (P = 0.61). Insomnia subgroup: SMD 0.60 (P = 0.02).","methodology":"Systematic review and meta-analysis of randomized controlled trials from MEDLINE, Embase, and Cochrane databases comparing cannabinoids vs placebo for sleep quality in adults.","limitations":"Only six trials included. High heterogeneity (I2 = 88%). Different cannabinoid formulations, doses, and populations across studies. Subjective sleep measures only."},{"rthcId":"RTHC-06286","title":"Repellent, Lethal Activity, and Synergism of Cannabis sativa Extracts with Terpenes Against a Laboratory Colony of Triatoma infestans.","authors":"Dadé, Martín M; Daniele, Martín R; Rodriguez, Sergio; Díaz, Pilar; Silvestrini, Maria Pía; Schinella, Guillermo R; Marin, Gustavo H; Barrio, Daniel; Prieto Garcia, Jose M","year":2025,"journal":"Plants (Basel, Switzerland), 14(21)","doi":"10.3390/plants14213258","pmid":"41225810","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06287","title":"Identification of Three Novel Tetrahydrocannabinol Analogs in the European Market.","authors":"Dadiotis, Evangelos; Mpakaoukas, Sotiris; Mitsis, Vangelis; Melliou, Eleni; Magiatis, Prokopios","year":2025,"journal":"Drug testing and analysis, 17(9), 1594-1600","doi":"10.1002/dta.3866","pmid":"39911051","tags":["synthetic-cannabinoids","harm-reduction","potency"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Products marketed under invented cannabinoid names contained novel THC analogs that have never been found in cannabis plants and lack any toxicological data. The compounds cannot be identified using standard forensic methods without advanced spectroscopic techniques.","whyItMatters":"Consumers are buying products with made-up cannabinoid names, unaware they contain novel synthetic compounds with unknown safety profiles. Standard drug testing cannot detect these substances.","specificNumbers":"Three novel compounds identified: [2-(E)-propen-1-yl]-delta8-THC-acetate from \"CB9,\" [2-propen-2-yl]-delta9-THC from \"tresconol,\" and [2-propen-2-yl]-delta8-THC from \"CBx.\" None have existing spectroscopic or chromatographic reference data.","methodology":"Mass spectrometry and nuclear magnetic resonance spectroscopy were used to characterize compounds isolated from three commercial products in the European market.","limitations":"Analytical chemistry study only; no toxicological or pharmacological data on these compounds. Limited to products available in the European market."},{"rthcId":"RTHC-06288","title":"Evaluating the use and perceptions of cannabis and vaping post-cannabis legalisation in people with cystic fibrosis and CFTR-related disorder: survey results from a large Canadian adult cystic fibrosis clinic.","authors":"Dagenais, Renee; Karlsen, Emma; Lee, Kathleen; Quon, Bradley Stuart","year":2025,"journal":"BMJ open respiratory research, 12(1)","doi":"10.1136/bmjresp-2024-002715","pmid":"41448798","tags":["medical-cannabis","respiratory","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"43% identified as current cannabis users. 85% of users reported medical use, primarily for stress, insomnia, and anxiety. Most rated it somewhat or very effective. Only 7% considered themselves current vapers, and 45% reported EVALI media coverage changed their perception of vaping harms.","whyItMatters":"CF patients have respiratory vulnerabilities that make cannabis use, especially smoked, potentially concerning. Yet nearly half are using cannabis, mostly for symptom management, highlighting a need for clinician guidance.","specificNumbers":"110 respondents. 43% current cannabis users. 85% of users reported medical use. 14% reported legalization changed their perceptions. 33% had tried vaping. 7% current vapers. 45% said EVALI changed vaping perceptions.","methodology":"Electronic questionnaire sent to all patients at a large Canadian adult CF clinic between April and October 2021. 110 individuals completed the survey.","limitations":"Small sample (110 respondents) from a single clinic. Self-reported data. Response bias may favor cannabis-friendly participants. Survey was during COVID-19 pandemic which may have affected substance use."},{"rthcId":"RTHC-06289","title":"Association of Cannabis Use With Guideline-Recommended Cancer Screenings: Results From a National Health Behaviors Survey.","authors":"Dagnino, Filippo; Pohl, Klara K; Qian, Zhiyu; Zurl, Hanna; Stelzl, Daniel; Korn, Stephan M; Lughezzani, Giovanni; Buffi, Nicolò M; Kibel, Adam S; Trinh, Quoc-Dien; Cole, Alexander P","year":2025,"journal":"JCO oncology practice, OP2401093","doi":"10.1200/OP-24-01093","pmid":"40577651","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"High-frequency cannabis use was associated with lower breast cancer screening adherence (aOR 0.70) and prostate cancer screening at any frequency (1-19 days: aOR 0.76; 20-30 days: aOR 0.60). No significant effect was found for cervical or colorectal cancer screening.","whyItMatters":"If frequent cannabis use is associated with skipping cancer screenings, clinicians seeing cannabis-using patients may need to be more proactive about screening recommendations.","specificNumbers":"229,711 patients analyzed. Breast cancer screening: aOR 0.70 (20-30 days use). Prostate screening: aOR 0.60 (20-30 days), 0.76 (1-19 days). No significant effect on cervical or colorectal screening.","methodology":"Analysis of Behavioral Risk Factor Surveillance System data covering 229,711 patients eligible for cancer screening. Multivariable adjusted models assessed cannabis use frequency and screening adherence.","limitations":"Cross-sectional design cannot establish causation. Self-reported cannabis use and screening adherence. Cannot distinguish recreational from medical users. Confounders like healthcare access may explain the association."},{"rthcId":"RTHC-06290","title":"Trends in Cannabis and Tobacco Use by Racial and Ethnic Groups Among U.S. Youth: 1991-2021.","authors":"Dai, Hongying Daisy","year":2025,"journal":"Journal of racial and ethnic health disparities","doi":"10.1007/s40615-025-02284-1","pmid":"39961983","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"During 2015-2021, Black adolescents had 12.6% cannabis-only use (vs 4.9% for White), while AI/AN adolescents had 20.1% cannabis-tobacco co-use (vs 13.4% for White). Black cannabis-only use increased from 10.8% to 12.6% over three decades. Asian adolescents consistently reported the lowest rates.","whyItMatters":"Substance use prevention programs often use one-size-fits-all approaches, but these 30-year trends show dramatically different patterns across racial and ethnic groups that require tailored interventions.","specificNumbers":"234,572 students surveyed. Black cannabis-only use: 12.6% (2015-2021). AI/AN co-use: 20.1%. White cannabis-only: 4.9%. Hispanic: 9.0%. Multi-racial: 8.8%. Asian: lowest across all categories.","methodology":"Analysis of Youth Risk Behavior Surveys from 1991-2021 covering 234,572 high school students. Multivariable logistic regressions examined racial/ethnic disparities across four time periods.","limitations":"Self-reported data from school-based surveys, missing youth not in school. Broad racial/ethnic categories may mask within-group diversity. Cannot distinguish frequency or quantity of use."},{"rthcId":"RTHC-06291","title":"Molecular docking of danuglipron uncovers potential crossovers between GLP-1R and the endocannabinoid system.","authors":"Dailey, Kiersten A; Schneider, Lillian N; Petreaca, Ruben C; Yoder, Ryan J","year":2025,"journal":"microPublication biology, 2025","doi":"10.17912/micropub.biology.001690","pmid":"40838124","tags":["neuroscience","drug-interactions"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Danuglipron showed higher binding affinity for both CB1 and CB2 receptors than THC, anandamide, or 2-AG in computational docking experiments, suggesting potential cross-reactivity between GLP-1 receptor agonists and the endocannabinoid system.","whyItMatters":"Millions of people use GLP-1 drugs for weight loss, and millions use cannabis. If GLP-1 drugs interact with cannabinoid receptors, there could be unexpected effects or drug interactions that clinicians should know about.","specificNumbers":"Danuglipron had higher binding affinity for CB1 and CB2 than any tested endogenous (2-AG, anandamide) or exogenous (THC) cannabinoid receptor ligand.","methodology":"Computational molecular docking experiments comparing binding affinities of danuglipron, THC, anandamide, and 2-AG at GLP-1R, CB1, and CB2 receptors.","limitations":"Computational docking study only; binding affinity in silico does not prove functional activity in living systems. No in vitro or in vivo validation. Danuglipron is an oral GLP-1 agonist not yet widely available."},{"rthcId":"RTHC-06292","title":"The endocannabinoid system & malignant hyperthermia: From molecular signaling towards clinical implications.","authors":"Dalle, Simon; Dalle, Sebastiaan","year":2025,"journal":"Progress in lipid research, 99, 101342","doi":"10.1016/j.plipres.2025.101342","pmid":"40680894","tags":["neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CB1 receptor activation inhibits PKA-mediated phosphorylation of RYR1 and L-type calcium channels, potentially reducing the excessive calcium release that causes malignant hyperthermia. Preclinical studies show CB1 agonism lowers body temperature and reduces cardiovascular stress.","whyItMatters":"Malignant hyperthermia is life-threatening and has only one primary treatment (dantrolene), which has significant side effects. If cannabinoids can modulate the same calcium pathways, they could offer an adjunctive therapy.","specificNumbers":"CB1 activation inhibits PKA-mediated phosphorylation of RYR1 and L-type calcium channels. TRPV1 antagonism or desensitization reduces sarcoplasmic reticulum calcium release.","methodology":"Narrative review synthesizing molecular evidence linking endocannabinoid signaling to calcium homeostasis in skeletal muscle and its potential relevance to malignant hyperthermia.","limitations":"Theoretical review based on indirect molecular evidence. No studies have tested cannabinoids specifically in malignant hyperthermia models. The proposed mechanisms need experimental validation in RYR1-mutant models."},{"rthcId":"RTHC-06293","title":"D1-like dopamine receptors in the dentate gyrus mediate cannabidiol's facilitation of extinction and prevention of reinstatement in methamphetamine-induced conditioned place preference.","authors":"Danesh, Elaheh; Saghafi, Mohammad; Mozafari, Roghayeh; Mesgar, Somaye; Haghparast, Abbas","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 256, 174094","doi":"10.1016/j.pbb.2025.174094","pmid":"40912658","tags":["cbd","addiction","dopamine","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD enhanced extinction of meth-conditioned place preference and prevented reinstatement. Blocking D1-like dopamine receptors in the dentate gyrus with SCH23390 reversed both of these CBD effects, establishing D1Rs as a necessary mediator.","whyItMatters":"There are no FDA-approved treatments for methamphetamine use disorder. Understanding how CBD reduces drug-seeking behavior at the circuit level could inform development of targeted therapies.","specificNumbers":"SCH23390 at 4 microg blocked CBD enhancement of extinction. SCH23390 at 1 and 4 microg reversed CBD prevention of reinstatement. CBD doses: 10 and 50 microg intracerebroventricular.","methodology":"Male Wistar rats received the D1R antagonist SCH23390 at three doses into the dentate gyrus before intracerebroventricular CBD. Methamphetamine-conditioned place preference measured drug-seeking behavior during extinction and reinstatement.","limitations":"Rat model with intracerebroventricular CBD delivery, which does not mirror human oral or inhaled use. Only male rats tested. CPP is a simplified model of addiction that does not capture the full complexity of human drug-seeking."},{"rthcId":"RTHC-06294","title":"Adverse childhood experiences affect health outcomes for adults in North Dakota: 2019-2022 BRFSS population profile.","authors":"Danielson, Ramona A; Schmidt, Matthew; Griechen, Miranda A","year":2025,"journal":"Frontiers in public health, 13, 1517431","doi":"10.3389/fpubh.2025.1517431","pmid":"40520269","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06295","title":"The burden of alcohol and substance use disorders in adolescents and young adults.","authors":"Danpanichkul, Pojsakorn; Duangsonk, Kwanjit; Díaz, Luis Antonio; Chen, Vincent L; Rangan, Pooja; Sukphutanan, Banthoon; Dutta, Priyata; Wanichthanaolan, Ornpailin; Ramadoss, Vijay; Sim, Benedix; Tung, Daniel; Siranart, Noppachai; Noritake, Hidenao; Takahashi, Hirokazu; Noureddin, Mazen; Leggio, Lorenzo; Yang, Ju Dong; Fallon, Michael B; Arab, Juan Pablo; Winder, Gerald Scott; Liangpunsakul, Suthat; Mellinger, Jessica Leigh; Wijarnpreecha, Karn","year":2025,"journal":"Drug and alcohol dependence, 266, 112495","doi":"10.1016/j.drugalcdep.2024.112495","pmid":"39603063","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis use disorder affected 10.69 million young people aged 10-24 globally in 2019, second only to alcohol use disorder (13.31 million). Opioid use disorder saw increasing prevalence and incidence from 2010-2019, while most other SUDs declined. Higher sociodemographic development correlated with higher SUD burden.","whyItMatters":"With 10.7 million young people affected, cannabis use disorder represents a massive global health burden that is often overshadowed by attention to opioids and alcohol.","specificNumbers":"Alcohol use disorder: 13.31 million. Cannabis use disorder: 10.69 million. Opioid use disorder: 4.27 million. Females had lower burden than males across all SUDs. Highest burden in Europe and the Americas.","methodology":"Analysis of Global Burden of Disease 2019 data examining prevalence, incidence, years of life lost, disability-adjusted life years, and mortality for substance use disorders among those aged 10-24.","limitations":"Global Burden of Disease estimates rely on modeled data that may be imprecise for some regions. Definition and diagnosis of cannabis use disorder varies across countries. Data through 2019 only."},{"rthcId":"RTHC-06296","title":"Effect of mobile-based ecological momentary motivational enhancement therapy on cannabis use temptation and dependence severity among Iranian young adults with cannabis use disorder: A randomized clinical trial.","authors":"Darharaj, Mohammad; Roshanpajouh, Mohsen; Amini, Mahdi; Shrier, Lydia A; Hamraz, Iman; Habibi Asgarabad, Mojtaba","year":2025,"journal":"Drug and alcohol dependence, 277, 112957","doi":"10.1016/j.drugalcdep.2025.112957","pmid":"41265235","tags":["quitting","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Ecological momentary motivational enhancement therapy (EM-MET) was associated with greater reductions in cannabis temptation (Partial eta-squared = 0.35, P < 0.001) and dependence severity (Partial eta-squared = 0.24, P < 0.001) compared to standard motivational enhancement therapy alone.","whyItMatters":"Cannabis use disorder has limited evidence-based treatments. This study shows that adding real-time mobile-triggered support to standard therapy meaningfully improves outcomes.","specificNumbers":"Temptation reduction: F = 37.09, Partial eta-squared = 0.35, P < 0.001. Dependence severity reduction: Partial eta-squared = 0.24, P < 0.001. 70 participants total across three treatment centers.","methodology":"Multicenter single-blinded RCT in Tehran, Iran. 70 young adults with cannabis use disorder randomized to EM-MET (n=35) or MET alone (n=35). EM-MET added two weeks of ecological momentary assessment with therapist phone calls triggered by reported cannabis use triggers.","limitations":"Small sample size (70 total). Conducted in Iran, which may limit generalizability to other cultural contexts. Only the data analyst was blinded. Short follow-up period."},{"rthcId":"RTHC-06297","title":"Effect of dietary heated hemp seed cake and phytase as soybean meal substitution on broiler chicken performance, carcass yield, visceral organ weight, intestinal health, and serum biochemical parameters.","authors":"Darmawan, Arif; Ozturk, Ergin","year":2025,"journal":"Tropical animal health and production, 57(3), 162","doi":"10.1007/s11250-025-04416-5","pmid":"40198511","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06298","title":"UK medical cannabis registry: A clinical outcome analysis of medical cannabis therapy in chronic pain patients with and without co-morbid sleep impairment.","authors":"Datta, Ishita; Erridge, Simon; Holvey, Carl; Coomber, Ross; Guru, Rahul; Holden, Wendy; Darweish Medniuk, Alia; Sajad, Mohammed; Searle, Robert; Usmani, Azfer; Varma, Sanjay; Rucker, James J; Platt, Michael; Sodergren, Mikael H","year":2025,"journal":"Pain practice : the official journal of World Institute of Pain, 25(1), e13438","doi":"10.1111/papr.13438","pmid":"39545361","tags":["medical-cannabis","pain","sleep"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Sleep-impaired patients showed improvements across all patient-reported outcomes at every follow-up. The sleep-impaired group had greater improvements in pain severity and sleep quality compared to the sleep-unimpaired group at all timepoints. No significant difference in adverse events between groups.","whyItMatters":"Sleep and pain are deeply intertwined, and this study suggests medical cannabis may particularly benefit chronic pain patients who also have poor sleep.","specificNumbers":"1,139 patients (517 sleep-impaired, 622 unimpaired). Sleep-impaired group: significant improvements in all PROMs at all timepoints. Greater BPI pain severity improvement (P < 0.05) and sleep quality improvement (P < 0.001) vs unimpaired group. 2,817 total adverse events reported.","methodology":"Prospective cohort from the UK Medical Cannabis Registry. 1,139 chronic pain patients divided by baseline sleep quality (impaired n=517, unimpaired n=622). Outcomes measured at 1, 3, 6, and 12 months using validated scales.","limitations":"Observational registry without a control group or placebo. Greater improvement in sleep-impaired group may reflect regression to the mean. Confounders including baseline pain severity. No randomization."},{"rthcId":"RTHC-06299","title":"The Effect of E-Cigarette Taxes on Substance Use.","authors":"Dave, Dhaval; Liang, Yang; Maclean, Johanna Catherine; Muratori, Caterina; Sabia, Joseph J","year":2025,"journal":"Journal of health economics, 102, 103022","doi":"10.1016/j.jhealeco.2025.103022","pmid":"40633435","tags":["youth","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"ENDS taxes reduced both teen e-cigarette use and marijuana use, including co-use. A one-dollar increase in ENDS taxes was associated with 1.0-1.5 percentage point decline in teen marijuana use. No effect was found on use of cocaine, methamphetamine, opioids, or drug treatment admissions. The effects appeared to moderate over time.","whyItMatters":"The gateway hypothesis has long debated whether vaping leads to other substance use. This economic evidence suggests e-cigarettes and marijuana are used together, so policies reducing one also reduce the other.","specificNumbers":"A $1 ENDS tax increase (2023 dollars): 1.0-1.5 percentage point decline in teen marijuana use. Effects moderate over the longer term. No spillover to cocaine, methamphetamine, or opioids.","methodology":"Difference-in-differences and event-study analysis of YRBSS, BRFSS, and Treatment Episode Data Set data examining effects of state-level ENDS tax policies on substance use.","limitations":"Observational policy analysis cannot fully rule out confounders. Tax effects may vary by state context. YRBSS self-reported data. Effects appeared to weaken over time, suggesting adaptation."},{"rthcId":"RTHC-06300","title":"Effects of Medical Cannabis Treatment for Autistic Children on Family Accommodation: An Open-Label Mixed-Methods Study.","authors":"David, Ayelet; Gal, Eynat; Ben-Sasson, Ayelet; Kohn, Elkana; Berkovitch, Matitiahu; Stolar, Orit","year":2025,"journal":"Children (Basel, Switzerland), 12(10)","doi":"10.3390/children12101373","pmid":"41153555","tags":["cbd","medical-cannabis","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Quantitative results showed reductions in family accommodation frequency and parental distress at 3 and 6 months. Qualitative interviews revealed positive changes in family routines, enhanced well-being, and improved parental engagement in meaningful activities and social interactions.","whyItMatters":"Autism affects the entire family. If treating autistic children with CBD-rich cannabis reduces the accommodations families need to make, it could significantly improve family quality of life.","specificNumbers":"87 initially recruited, 44 with complete data. Reductions in family accommodation frequency and parental distress at 3 and 6 months. 15 parents provided qualitative data.","methodology":"Open-label mixed-methods study. 44 parents with complete data at baseline, 3, and 6 months for quantitative analysis. 15 parents completed semi-structured qualitative interviews.","limitations":"Open-label design with no placebo control. High dropout (87 to 44). No blinding means expectation bias could drive results. Adverse events and withdrawals noted but not detailed."},{"rthcId":"RTHC-06301","title":"Effects of Medical Cannabis Treatment for Autistic Children on Anxiety and Restricted and Repetitive Behaviors and Interests: An Open-Label Study.","authors":"David, Ayelet; Stolar, Orit; Berkovitch, Matitiahu; Kohn, Elkana; Hazan, Ariela; Waissengreen, Danel; Gal, Eynat","year":2025,"journal":"Cannabis and cannabinoid research, 10(4), 537-548","doi":"10.1089/can.2024.0001","pmid":"39047052","tags":["cbd","medical-cannabis","anxiety","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Significant reductions in overall anxiety and specific subtypes (general, social, panic, separation) after 6 months. Repetitive behaviors also improved, including compulsive, ritualistic, and sameness behaviors. Reduced panic and separation anxiety predicted subsequent decreases in sameness behaviors.","whyItMatters":"Anxiety is one of the most common co-occurring conditions in autism, and it may drive some repetitive behaviors. This study suggests CBD-rich cannabis could address both, with anxiety reduction leading to behavior improvement.","specificNumbers":"65 autistic children ages 5-12. Significant reductions in overall anxiety and 4 of 5 anxiety subtypes. Significant improvement in total repetitive behaviors and 3 subtypes (compulsive, ritualistic, sameness). Reduced panic/separation anxiety predicted reduced sameness behaviors.","methodology":"Open-label study of 65 autistic children (ages 5-12) receiving CBD-rich cannabis. Parents completed validated anxiety (SCARED) and repetitive behavior (RBS-R) assessments at baseline, 3 months, and 6 months.","limitations":"Open-label design with no placebo or control group. Only 65 participants. Parent-reported outcomes subject to expectation bias. No information on adverse effects in the abstract."},{"rthcId":"RTHC-06302","title":"Use of cannabis among youth who vape nicotine.","authors":"Davis, Danielle R; Bold, Krysten W; Wu, Ran; Morean, Meghan E; Kong, Grace; Krishnan-Sarin, Suchitra","year":2025,"journal":"Addictive behaviors, 160, 108173","doi":"10.1016/j.addbeh.2024.108173","pmid":"39326231","tags":["youth","addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"92.4% reported lifetime cannabis use, 68.6% past-month use. Cannabis smoking and vaping were both highly prevalent (lifetime ~91%, current ~63% each). Heavier cannabis use and preferring smoked cannabis were associated with more frequent nicotine vaping. Average readiness to quit cannabis was 6.3/10.","whyItMatters":"Youth seeking help to quit vaping are overwhelmingly co-using cannabis. Vaping cessation programs that ignore cannabis use may be less effective.","specificNumbers":"223 youth, mean age 17.3. Lifetime cannabis: 92.4%. Past-month: 68.6%. Current smoking cannabis: 63.6%. Current vaping cannabis: 63.1%. Prefer smoking: 58.7%. Readiness to quit cannabis: 6.3/10.","methodology":"Survey of 223 Connecticut youth (mean age 17.3) who completed intake for a vaping cessation study, assessing cannabis products used, reasons, frequency, and readiness to quit.","limitations":"Convenience sample of youth already seeking cessation help, not representative of all teen vapers. Connecticut only. Self-reported data."},{"rthcId":"RTHC-06303","title":"Seeking relief or fueling the fire? Understanding the complex role of cannabis in PTSD, stress, and sleep dysregulation.","authors":"Davis, Jordan P; Saba, Shaddy K; Leightley, Daniel; Pedersen, Eric R; Prindle, John; Dilkina, Bistra; Cantor, Jonathan; Dworkin, Emily; Sedano, Angeles","year":2025,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors","doi":"10.1037/adb0001097","pmid":"40965945","tags":["ptsd","sleep","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Day-to-day analysis showed elevated PTSD symptoms and poor sleep predicted greater stress the next day. Greater hours high from cannabis predicted less perceived stress the following day. Stress mediated the relationships: cannabis appeared to improve sleep and PTSD symptoms through reducing perceived stress.","whyItMatters":"Many veterans use cannabis for PTSD symptoms, but the daily dynamics have been unclear. This intensive longitudinal study suggests cannabis may temporarily interrupt the harmful cycle between PTSD, stress, and poor sleep.","specificNumbers":"74 veterans. 4,307 person-days of data. Mean age 33.5. 80% male. 61% non-Hispanic White. Cannabis use predicted lower next-day stress, which predicted lower PTSD symptoms and better sleep.","methodology":"74 veterans with past-month cannabis use and elevated PTSD symptoms completed daily reports via mobile app for 3 months (4,307 person-days). Dynamic structural equation modeling examined within-person lagged and same-day associations.","limitations":"Observational daily diary data cannot prove causation. Sample of cannabis-using veterans with PTSD may not generalize to all veterans. Self-reported measures. Cannot distinguish cannabis types, doses, or methods."},{"rthcId":"RTHC-06304","title":"Daily associations between sleep quality, stress, and cannabis or alcohol use among veterans.","authors":"Davis, Jordan P; Saba, Shaddy K; Leightley, Daniel; Pedersen, Eric R; Prindle, John; Senator, Ben; Dilkina, Bistra; Dworkin, Emily; Howe, Esther; Cantor, Jonathan; Sedano, Angeles","year":2025,"journal":"Drug and alcohol dependence, 271, 112661","doi":"10.1016/j.drugalcdep.2025.112661","pmid":"40156938","tags":["ptsd","sleep","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Within-day: higher cannabis use was associated with lower stress and better sleep quality that same night. Day-to-day: worse sleep predicted higher next-day stress, which predicted greater alcohol use. Stress mediated the relationship between poor sleep and increased alcohol consumption. No day-to-day lagged effects were found for cannabis.","whyItMatters":"This companion study to RTHC-06303 reveals that cannabis and alcohol play different roles in the stress-sleep cycle. Cannabis appears to provide same-day relief without next-day consequences, while alcohol use follows a harmful next-day stress pattern.","specificNumbers":"74 veterans, 3-month diary. Cannabis: same-day association with lower stress and better sleep, no next-day lagged effects. Alcohol: poor sleep predicted next-day stress predicted more alcohol use. Stress mediated sleep-to-alcohol relationship.","methodology":"74 veterans with elevated PTSD symptoms and problematic cannabis use completed 3 months of daily diaries via mobile app. Dynamic structural equation modeling examined within-day and lagged associations between sleep, stress, cannabis, and alcohol.","limitations":"Secondary analysis of an existing dataset. Sample selected for problematic cannabis use, creating selection bias. Cannot establish causation from observational data. Self-reported measures."},{"rthcId":"RTHC-06305","title":"Association of cannabis abuse/dependence on risks of erectile dysfunction and testosterone deficiency using a large claims database analysis.","authors":"Davis, Ryan; Hershenhouse, Jacob; Maas, Marissa; Loh-Doyle, Jeffrey; Asanad, Kian","year":2025,"journal":"The journal of sexual medicine, 22(5), 711-718","doi":"10.1093/jsxmed/qdaf043","pmid":"40121549","tags":["addiction","sex-differences","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis abuse/dependence was associated with a 3.99-fold increased risk of erectile dysfunction and 2.19-fold increased risk of testosterone deficiency within one year, based on a propensity-matched analysis of nearly 30,000 men per group.","whyItMatters":"Erectile dysfunction and low testosterone are common concerns for men, yet the relationship between cannabis and male sexual health has been studied only in small samples with mixed results. This population-level analysis provides some of the largest-scale evidence to date linking heavy cannabis use to these outcomes.","specificNumbers":"At 3 months to 1 year: ED risk 0.9% vs 0.2% (RR 3.99), TD risk 0.2% vs 0.1% (RR 2.19), PDE5 inhibitor prescriptions 0.8% vs 0.2% (RR 3.80). At 3 to 5 years, only ED remained significant (1.61% vs 1.34%, RR 1.20). Kaplan-Meier analysis showed faster time to ED (HR 1.65) and TD (HR 1.34).","methodology":"Researchers used TriNetX, a large US claims database, to identify men 18 and older with cannabis abuse/dependence diagnoses between 2005 and 2024. They propensity-matched 29,442 cannabis-diagnosed patients against an equal control group on 49 factors and compared risks at short-term (3 months to 1 year) and long-term (3 to 5 years) intervals.","limitations":"Claims database diagnoses of cannabis abuse/dependence are proxies that may miss casual users and overrepresent severe cases. The study could not assess dose-dependent relationships or control for method of cannabis consumption. Residual confounding from unmeasured factors remains possible despite propensity matching."},{"rthcId":"RTHC-06306","title":"A population-level analysis on the association of cannabis use and urologic cancers.","authors":"Davis, Ryan J; Hershenhouse, Jacob; Gallagher, Tyler J; Sabharwal, Navin; Daneshvar, Michael A","year":2025,"journal":"Urologic oncology, 43(10), 598.e11-598.e16","doi":"10.1016/j.urolonc.2025.05.010","pmid":"40484779","tags":["cancer","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After propensity matching on demographics, tobacco use, and cancer risk factors, cannabis abuse/dependence was associated with 4.21-fold increased risk of bladder cancer, 3.70-fold increased risk of kidney cancer, and 2.80-fold increased risk of prostate cancer.","whyItMatters":"Cannabis smoke contains many of the same carcinogens as tobacco smoke, yet the relationship between cannabis and urologic cancers has been poorly studied. This population-scale analysis provides the first large matched comparison for multiple urologic malignancies.","specificNumbers":"Bladder cancer: 0.14% vs 0.03% (RR 4.21, 95% CI 2.70-6.57). Kidney cancer: 0.17% vs 0.05% (RR 3.70, 95% CI 2.52-5.43). Prostate cancer: 0.61% vs 0.22% (RR 2.80, 95% CI 2.19-3.58). No significant association for upper tract, testis, or penile cancer.","methodology":"Researchers used the TriNetX database to identify US adults from 2004 to 2024 with or without cannabis abuse/dependence diagnoses. After excluding those with prior urologic cancers, 74,642 cannabis-diagnosed patients were matched against controls on demographics, tobacco use, nicotine dependence, substance-related disorders, and cancer-specific risk factors.","limitations":"Claims-based diagnoses cannot distinguish smoking from other consumption methods. Cannabis abuse/dependence codes likely capture the heaviest users, so results may not apply to occasional use. Residual confounding from unmeasured lifestyle factors is possible. Rare cancers like testicular and penile cancer may lack statistical power to detect associations."},{"rthcId":"RTHC-06307","title":"Therapeutic potential of cannabidiol in oral disorders: A systematic review of clinical evidence.","authors":"de Abreu, Lukas Mendes; Biancardi, Mariel Ruivo; Di Benedetto, Michele; Sanches, Raquel Molina; Cardoso, Camila Lopes; Rubira, Cássia Maria Fischer; Rubira-Bullen, Izabel Regina Fischer","year":2025,"journal":"Journal of the American Dental Association (1939), 156(10), 838-850.e2","doi":"10.1016/j.adaj.2025.07.021","pmid":"41062198","tags":["cbd","pain","inflammation","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Across six RCTs and one non-randomized trial, topical and intraoral CBD reduced pain, muscle tension, gingival inflammation, bacterial load, and aphthous ulcer symptoms, with no serious adverse effects. However, heterogeneity across studies prevented meta-analysis.","whyItMatters":"Dental pain and oral inflammation affect millions of people, yet current treatments often rely on NSAIDs or opioids with significant side effect profiles. CBD applied directly to the mouth could offer a localized, low-risk alternative if validated by larger trials.","specificNumbers":"4,093 records screened, 7 studies included (6 RCTs, 1 non-randomized). CBD formulations were applied topically or intraorally. Benefits observed across pain, muscle tension, gingival inflammation, bacterial load, and aphthous ulcer symptoms.","methodology":"Researchers followed PRISMA 2020 guidelines and searched five databases. From 4,093 records, seven clinical studies met inclusion criteria: six randomized controlled trials and one non-randomized study evaluating CBD effects on various oral disorders.","limitations":"Only seven studies qualified, with varying CBD dosages, formulations, and follow-up durations that prevented direct comparison or meta-analysis. Most studies had small sample sizes. Long-term safety data for oral CBD products are lacking."},{"rthcId":"RTHC-06308","title":"Crosstalk between M1 muscarinic acetylcholine receptor and endocannabinoid system promotes attenuation of inflammation in ulcerative colitis.","authors":"de Aguiar Magalhães, Diva; Guimarães Sousa, Stefany; da Silva Monteiro, Carlos Eduardo; Arruda Batista, Jalles; de Sousa, Antônio Kleiton; Dos Santos Ferreira, Jayro; Carvalho Pereira, Cynthia Maria; do Nascimento Lima, José Victor; da Silva Sousa, João Janilson; da Silva Prudêncio, Rafael; Lino da Silva, Tino Marcos; Oliveira Silva, Francisca Géssica; Franco, Alvaro Xavier; Di Lenardo, David; Pereira Vasconcelos, Daniel Fernando; Almeida Rocha, Jefferson; Alves Figueiredo, Kayo; Gomes Soares, Pedro Marcos; Dos Reis Barbosa, André Luiz","year":2025,"journal":"European journal of pharmacology, 1008, 178368","doi":"10.1016/j.ejphar.2025.178368","pmid":"41241333","tags":["inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"When researchers administered CB1 or CB2 receptor antagonists before treating colitis-induced mice with McN-A-343 (a muscarinic receptor agonist), the drug's anti-inflammatory benefits were significantly reversed, with increased intestinal damage, pro-inflammatory cytokines, oxidative stress, and NF-kB expression.","whyItMatters":"Ulcerative colitis affects millions worldwide and current treatments have significant limitations. This study reveals crosstalk between the cholinergic and endocannabinoid systems in gut inflammation, opening a potential new pathway for therapeutic development.","specificNumbers":"Both AM251 (CB1 antagonist, 3.0 mg/kg) and AM630 (CB2 antagonist, 1.0 mg/kg) significantly reversed McN-A-343's effects, increasing myeloperoxidase levels, TNF-alpha, IL-1beta, malondialdehyde, nitrate/nitrite, and protein expression of NF-kB, iNOS, and COX-2.","methodology":"Male mice received acetic acid-induced colitis, then were treated with the M1 muscarinic receptor agonist McN-A-343. CB1 antagonist AM251 and CB2 antagonist AM630 were given 30 minutes before treatment. After 18 hours, colon tissue was analyzed for macroscopic and microscopic damage, inflammatory markers, oxidative stress, and protein expression via Western blot.","limitations":"This is a mouse model using chemically induced colitis, which does not fully replicate human ulcerative colitis. Only male mice were used. The acute 18-hour timeframe does not reflect chronic disease. Dexamethasone was the only comparator."},{"rthcId":"RTHC-06309","title":"Cannabidiol engages the peripheral endogenous opioid system to produce analgesia in neuropathic mice.","authors":"de Almeida, Douglas Lamounier; Pinto Barra, Walace Cássio; Mendes Ferreira, Renata Cristina; Fonseca, Flávia Cristina; Dias Machado, Daniel Portela; Aguiar, Danielle Diniz; Guimaraes, Francisco Silveira; Gama Duarte, Igor Dimitri; Lima Romero, Thiago Roberto","year":2025,"journal":"Neuroscience letters, 868, 138393","doi":"10.1016/j.neulet.2025.138393","pmid":"41022278","tags":["cbd","pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD at 20 mg/kg produced significant antinociception in mice with sciatic nerve injury. Naloxone (a general opioid blocker) reversed this effect. Selective mu (CTOP) and delta (naltrindole) opioid receptor antagonists partially reversed CBD analgesia, but the kappa antagonist (norBNI) did not.","whyItMatters":"CBD is widely discussed as a pain treatment, but its mechanisms remain poorly understood. This study identifies a specific pathway: CBD appears to activate peripheral opioid receptors (mu and delta types) as part of how it reduces nerve pain, which could help optimize future pain therapies.","specificNumbers":"CBD at 20 mg/kg produced antinociception. Bestatin (400 microg/paw), an aminopeptidase inhibitor, potentiated the effect of a subtherapeutic CBD dose (2 mg/kg). Naloxone (50 microg/paw) reversed CBD analgesia. CTOP (mu antagonist) and naltrindole (delta antagonist) partially reversed the effect; norBNI (kappa antagonist) did not.","methodology":"Male Swiss mice underwent sciatic nerve constriction injury to model neuropathic pain. Nociceptive threshold was measured using a mechanical paw pressure test. CBD was given systemically at 20 mg/kg, and various opioid receptor antagonists were injected locally into the paw to test which receptor subtypes were involved.","limitations":"This is a mouse study using a surgical nerve injury model. Only male mice were tested. The doses and routes of administration may not translate directly to humans. The study does not clarify whether CBD acts directly on opioid receptors or triggers endogenous opioid release."},{"rthcId":"RTHC-06310","title":"Cannabis use frequency is associated with emotion dysregulation among persons receiving long-term opioid therapy for chronic pain: A psychophysiological study.","authors":"De Aquino, Joao P; Costa, Gabriel P A; Nunes, Julio C; Hudak, Justin; Odette, Madeleine; Garland, Eric L","year":2025,"journal":"Drug and alcohol dependence, 275, 112812","doi":"10.1016/j.drugalcdep.2025.112812","pmid":"40779835","tags":["addiction","pain","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Smaller reductions in skin conductance and corrugator muscle activity during emotion regulation tasks were associated with more days of cannabis use over 90 days. Pain severity was not significantly associated with cannabis use frequency.","whyItMatters":"Many chronic pain patients report using cannabis to manage pain, but this study suggests the primary driver may actually be emotional distress rather than physical pain. If true, this shifts the conversation about why pain patients use cannabis and what interventions might help.","specificNumbers":"Weaker skin conductance reduction during emotion regulation: beta = -0.018, p < 0.001. Weaker corrugator EMG reduction: beta = -9.59, p < 0.001. Pain severity and cannabis use: beta = 0.026, p = 0.370 (not significant). Sample: 104 participants, mean age 51.12 years.","methodology":"Researchers analyzed data from 104 participants (mean age 51, 68% female, 89% White) receiving long-term opioid therapy for chronic pain. Cannabis use was measured as days used over 90 days. Emotion regulation was assessed via psychophysiological measures during passive viewing vs. cognitive reappraisal of negative images.","limitations":"Cross-sectional design means causality cannot be determined: it is unclear whether poor emotion regulation leads to more cannabis use or vice versa. The sample was 89% White and predominantly female, limiting generalizability. Self-reported cannabis use days may be imprecise."},{"rthcId":"RTHC-06311","title":"Nanoemulsions of Cannabidiol, Δ9-Tetrahydrocannabinol, and Their Combination Similarly Exerted Anticonvulsant and Antioxidant Effects in Mice Treated with Pentylenetetrazole.","authors":"de Aquino, Pedro Everson Alexandre; Júnior, Francisco Josimar Girão; de Souza Nascimento, Tyciane; Rosal Lustosa, Ítalo; de Andrade, Geanne Matos; Ricardo, Nágila Maria Pontes Silva; de Brito, Débora Hellen Almeida; de Almeida, Gabriel Érik Patrício; Silveira, Kamilla Barreto; Zampieri, Davila; de França Fonteles, Marta Maria; Silveira, Edilberto Rocha; Biagini, Giuseppe; de Barros Viana, Glauce Socorro","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(6)","doi":"10.3390/ph18060782","pmid":"40573179","tags":["cbd","epilepsy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In acute seizure tests, CBD and THC at 3-10 mg/kg and their 1:1 combinations increased latency to generalized seizures and improved survival. In the chronic kindling model, CBD 10 mg/kg and CBD/THC at 1.5 and 3 mg/kg delayed seizure progression, while reducing oxidative stress and brain inflammation markers.","whyItMatters":"While CBD is already approved for certain epilepsies, this study tests nanoemulsion delivery systems that may improve bioavailability and shows that lower-dose CBD/THC combinations can match the anticonvulsant effects of standard treatment. The finding about astrogliosis reduction adds mechanistic insight.","specificNumbers":"CBD and THC at 3-10 mg/kg significantly increased seizure latency and survival in acute tests. In chronic kindling, CBD 10 mg/kg and CBD/THC at 1.5 and 3 mg/kg delayed seizure progression. Treatments reduced GFAP expression (astrogliosis marker) and oxidative stress markers in hippocampal regions. CBD/THC at 6 mg/kg had no effect on kindling.","methodology":"Mice received nanoemulsion formulations of CBD, THC, or 1:1 CBD/THC combinations orally one hour before pentylenetetrazole (PTZ) injection. In the acute model, a single high-dose PTZ induced seizures. In the chronic model, PTZ was given every other day for 21 days to model kindling. Behavioral, biochemical, and immunohistochemical analyses assessed seizure response, oxidative stress, and astroglia activation.","limitations":"Mouse seizure models do not perfectly replicate human epilepsy. No cannabinoid treatment prevented cognitive impairment in memory tests. The study cannot determine whether nanoemulsion formulation offers advantages over standard CBD delivery in humans. Only male mice were used."},{"rthcId":"RTHC-06312","title":"The differential effects of medicinal cannabis on mental health: A systematic review.","authors":"de Bode, Nora; Kroon, Emese; Sznitman, Sharon R; Cousijn, Janna","year":2025,"journal":"Clinical psychology review, 118, 102581","doi":"10.1016/j.cpr.2025.102581","pmid":"40186931","tags":["medical-cannabis","mental-health","anxiety","psychosis","sleep","cbd","addiction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"High doses of CBD provided some acute relief in anxiety disorders. CBD/THC combinations alleviated withdrawal symptoms in cannabis use disorder and improved sleep. THC was associated with dose-dependent adverse events and, in some psychosis studies, worsened primary outcomes. No study found long-lasting medicinal effects or improvement.","whyItMatters":"As medicinal cannabis use for mental health grows globally, this review provides the most comprehensive controlled-study assessment to date of what works, what does not, and what carries risks across a wide range of psychiatric diagnoses.","specificNumbers":"18,341 studies screened, 49 controlled studies included from 15 countries. Diagnoses covered: anxiety disorders, tic disorders, autism spectrum disorder, ADHD, OCD, anorexia nervosa, schizophrenia/psychosis, substance use disorders, insomnia, and bipolar disorder.","methodology":"Researchers searched PubMed, PsycInfo, Embase, and Cochrane Library across two search periods (October 2023 and July 2024), screening 18,341 studies. Forty-nine controlled studies from 15 countries were included, covering treatment-seeking participants using medicinal cannabis for their mental health diagnosis.","limitations":"Risks of bias were prevalent across included studies. Product compositions, doses, and delivery methods varied widely. Naturalistic and clinical trial findings sometimes contradicted each other. Many diagnoses had very few qualifying studies."},{"rthcId":"RTHC-06313","title":"Codelivery of Paclitaxel and Cannabidiol in Lipid Nanoparticles Enhances Cytotoxicity against Melanoma Cells.","authors":"de Carvalho, Fabíola V; Geronimo, Gabriela; de Moura, Ludmilla D; Mendonça, Talita C; Breitkreitz, Márcia Cristina; de Paula, Eneida; Rodrigues da Silva, Gustavo H","year":2025,"journal":"ACS omega, 10(21), 21568-21580","doi":"10.1021/acsomega.5c00689","pmid":"40488002","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06314","title":"The endocannabinoid system offers a target for Alzheimer's disease treatment through inhibition of fatty acid amide hydrolase (FAAH).","authors":"de Ceballos, Maria L","year":2025,"journal":"The FEBS journal, 292(16), 4156-4159","doi":"10.1111/febs.70082","pmid":"40172080","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06315","title":"Targeting the endocannabinoid/paracannabinoid systems in binge eating behavior: Efficacy of dual ligands in a preclinical model.","authors":"de Ceglia, Marialuisa; Botticelli, Luca; Micioni Di Bonaventura, Emanuela; Vargas Fuentes, Antonio; Micioni Di Bonaventura, Maria Vittoria; Rodriguez de Fonseca, Fernando; Cifani, Carlo","year":2025,"journal":"Pharmacological research, 222, 108005","doi":"10.1016/j.phrs.2025.108005","pmid":"41429684","tags":["appetite","neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"OLHHA (CB1 antagonist/PPAR-alpha agonist) at 0.3 mg/kg and OLS (PPAR-alpha/TRPV1 agonist) at 6 mg/kg reduced aberrant palatable food consumption during binge eating tests. These treatments also partly restored disrupted leptin, opioid, and cannabinoid signaling in the hypothalamus and normalized POMC/AgRP/NPY pathways.","whyItMatters":"Binge eating disorder lacks effective pharmacological treatments. This study shows that drugs targeting both the endocannabinoid system and PPAR receptors can reduce binge eating behavior while correcting underlying neurochemical disruptions, suggesting a promising dual-target approach.","specificNumbers":"OLHHA at 0.3 mg/kg and OLS at 6 mg/kg significantly reduced palatable food consumption during binge tests. Binge eating rats showed altered hypothalamus-pituitary axis activation with changes in leptin, opioid, and cannabinoid signaling and disrupted POMC/AgRP/NPY pathways.","methodology":"Female rats underwent intermittent cycles of food restriction and frustration stress to induce binge eating behavior. Researchers measured plasma hormones, biochemical mediators, and gene/protein expression in the hypothalamus. Three dual-target drugs were tested: NF10-360 (dual PPAR-alpha/gamma agonist), OLS (PPAR-alpha/TRPV1 agonist), and OLHHA (CB1 antagonist/PPAR-alpha agonist).","limitations":"This is a rat model that uses stress-induced binge eating, which may not fully capture human binge eating disorder. Only female rats were studied. The treatments were given acutely, so long-term effects and safety are unknown."},{"rthcId":"RTHC-06316","title":"Following the smell: terpene emission profiles through the cannabis life-cycle.","authors":"de Ferreyro Monticelli, Davi; Pham, Cynthia; Bhandari, Sahil; Giang, Amanda; Borduas-Dedekind, Nadine; Zimmerman, Naomi","year":2025,"journal":"Environmental science. Processes & impacts, 27(7), 1823-1838","doi":"10.1039/d5em00253b","pmid":"40528799","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06317","title":"A Qualitative Investigation of Nicotine and Tobacco use in Young Pregnant and Birthing Sexual Minority People.","authors":"De Genna, Natacha M; Boss, Nicole; Hossain, Fahmida; Frankeberger, Jessica; Mark, Elyse; Coulter, Robert W S","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 27(11), 1913-1920","doi":"10.1093/ntr/ntae189","pmid":"39058322","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06318","title":"Cannabidiol-based lipid nanocarriers with analgesic activity.","authors":"de Oliveira Sato, Arissa; Goulart, João Pedro Tánnus; Rodrigues, Tamiris Sabrina; Ueira-Vieira, Carlos; Bastos, Luciana Machado; Sommerfeld, Simone; Fonseca, Belchiolina Beatriz; de Morais Ribeiro, Lígia Nunes","year":2025,"journal":"Scientific reports, 16(1), 3334","doi":"10.1038/s41598-025-33238-6","pmid":"41420083","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06319","title":"Modulation of the endocannabinoid system in chronic conditions: a potential therapeutic intervention yet to be explored in sickle cell disease.","authors":"de Oliveira Souza, Lucas Bibiano; Sicoli, Juliana Paiva Gouvea; Olalla Saad, Sara Teresinha; Benites, Bruno Deltreggia","year":2025,"journal":"Expert review of hematology, 18(3), 215-224","doi":"10.1080/17474086.2025.2471864","pmid":"39992131","tags":["medical-cannabis","pain","inflammation"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The review compiles evidence that the endocannabinoid system is involved in pain modulation, inflammation, and vascular function, all of which are disrupted in sickle cell disease. Preliminary clinical trial results suggest potential benefits, though the evidence base remains limited.","whyItMatters":"Sickle cell disease causes severe chronic pain that often requires long-term opioid therapy, creating addiction risks and reduced quality of life. If cannabis-based treatments can reduce pain and opioid dependence in this population, it could significantly improve outcomes for the estimated 100,000 Americans with the disease.","specificNumbers":"The review covers the endocannabinoid system's role across multiple organ systems relevant to SCD: pain pathways, inflammation, vascular function, and chronic complications including leg ulcers.","methodology":"Researchers conducted a comprehensive literature search of PubMed covering studies through 2024, focusing on the endocannabinoid system's role in various organ functions and its potential relevance to sickle cell disease complications.","limitations":"This is a narrative review without systematic methodology. Clinical trial data in sickle cell disease specifically is extremely limited. The review is largely speculative, drawing on endocannabinoid system research in other conditions to make the case for SCD applications."},{"rthcId":"RTHC-06320","title":"Unravelling a potential therapeutic effect of polymeric lipid-core nanoencapsulated cannabidiol on anxiety- and panic-like behaviours elicited by Bothrops jararaca lancehead pit vipers.","authors":"de Paula Rodrigues, Bruno Mangili; Hernandes, Paloma Molina; Balvedi, Rafael Canalle; Martins Alves, Hígor Ferreira; da Silva, Karoline Paiva; de Campos Bicudo, Rogério; Eberhardt, Marcelo Jung; Poletto, Fernanda; Paese, Karina; Guterres, Sílvia Stanisçaski; Khan, Asmat Ullah; Pohlmann, Adriana Raffin; Ferrarini, Stela Regina; Coimbra, Norberto Cysne","year":2025,"journal":"International journal of pharmaceutics, 679, 125747","doi":"10.1016/j.ijpharm.2025.125747","pmid":"40412456","tags":["cbd","anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Polymeric lipid-core nanoencapsulated CBD at low doses significantly reduced defensive attention, flat-back approach, and escape behaviors in mice facing a pit viper. Rhodamine-labeled nanoparticles crossed the blood-brain barrier and were detected in multiple limbic and paralimbic structures involved in fear and panic responses.","whyItMatters":"CBD's poor bioavailability limits its clinical potential. This study shows nanoencapsulation can dramatically reduce the effective dose needed for anti-panic effects, while demonstrating that the nanoparticles actually reach the brain regions responsible for fear responses.","specificNumbers":"Standard CBD at 3 mg/kg was the positive control. Nanoencapsulated CBD at much lower doses matched or exceeded this effect. Rhodamine-labeled nanoparticles were detected in multiple limbic and paralimbic brain structures via both intraperitoneal and intranasal administration routes.","methodology":"Mice were habituated in an enriched polygonal arena for three days, then treated with either standard CBD (3 mg/kg, positive control) or nanoencapsulated CBD at much lower doses before being confronted with a live Bothrops jararaca snake. A separate experiment used fluorescently labeled nanoparticles administered intraperitoneally or intranasally to track brain penetration.","limitations":"Mouse defensive behaviors against snakes are not identical to human panic attacks. The specific low doses were not detailed in the abstract. Only acute effects were tested. The study does not compare nanoencapsulated CBD to other delivery improvements or established anxiolytics beyond standard CBD."},{"rthcId":"RTHC-06321","title":"Discovery of major QTL and a massive haplotype associated with cannabinoid biosynthesis in drug-type Cannabis.","authors":"de Ronne, Maxime; Torkamaneh, Davoud","year":2025,"journal":"The plant genome, 18(2), e70031","doi":"10.1002/tpg2.70031","pmid":"40415170","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06322","title":"Full-spectrum Cannabis sativa extract enhances gut-peripheral organ integrity after experimental ischemic stroke.","authors":"de Souza Stork, Solange; Mathias, Khiany; Gava, Fernanda; Joaquim, Larissa; Dos Santos, David; Tiscoski, Anita Dal Bó; Bonfante, Sandra; Strickert, Yasmin Ribeiro; Machado, Richard Simon; Martins, Helena Mafra; Chaves, Jéssica Schaefer; Generoso, Jaqueline; Danielski, Lucineia Gainski; Giustina, Amanda Della; Scussel, Rahisa; Bitencourt, Rafael; Mack, Josiel Mileno; de Souza Goldim, Mariana Pereira; Machado-de-Ávila, Ricardo Andrez; Barichello, Tatiana; Bobinski, Franciane; Petronilho, Fabricia","year":2025,"journal":"Inflammopharmacology, 33(6), 3279-3305","doi":"10.1007/s10787-025-01775-1","pmid":"40389682","tags":["medical-cannabis","inflammation","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Full-spectrum cannabis extract (15 or 30 mg/kg) given by gavage after middle cerebral artery occlusion improved neurological deficits, reduced intestinal permeability, lowered serum corticosterone, decreased immune cell counts, and protected against post-stroke oxidative stress and lung inflammation at 72 hours.","whyItMatters":"Stroke damage extends far beyond the brain, causing gut barrier breakdown, immune suppression, and multi-organ inflammation. This study is among the first to examine whether cannabis extract can protect these peripheral systems after stroke, finding broad protective effects.","specificNumbers":"Two doses tested: 15 and 30 mg/kg full-spectrum cannabis extract. Assessments at 72 hours post-stroke included: neurological scoring, blood cell counts, thymus/spleen/adrenal gland size, serum corticosterone, intestinal permeability, and oxidative stress and inflammatory markers in peripheral organs.","methodology":"Male Wistar rats underwent 60-minute middle cerebral artery occlusion or sham surgery. They received full-spectrum cannabis extract (15 or 30 mg/kg) or coconut oil vehicle by gavage at multiple time points post-stroke. At 72 hours, researchers assessed neurological score, infarct volume, blood cells, organ weights, corticosterone, intestinal permeability, oxidative stress, and inflammatory cytokines.","limitations":"This is a rat model of stroke with a 72-hour endpoint, which cannot capture long-term recovery. Only male rats were used. Full-spectrum extracts contain multiple cannabinoids, so the specific active compounds are unclear. The doses and timing may not translate to clinical practice."},{"rthcId":"RTHC-06323","title":"Trend analyses and comparison of characteristics of current-, former- and never-drinkers among young adults in France from 2000 to 2021.","authors":"de Ternay, Julia; Andler, Raphaël; Gautier, Arnaud; de Dinechin, Sébastien; Davalos, Ricardo; Rolland, Benjamin; Jauffret-Roustide, Marie","year":2025,"journal":"BMC public health, 25(1), 1157","doi":"10.1186/s12889-025-22405-z","pmid":"40148908","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06324","title":"The Effects of Recreational Cannabis Laws on Alcohol and Tobacco Use Among U.S. Adults, 2012-2022.","authors":"De, Prabal K; Sun, Ruoyan","year":2025,"journal":"American journal of preventive medicine, 68(5), 1032-1040","doi":"10.1016/j.amepre.2025.01.024","pmid":"39909135","tags":["legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using law passage as the measure, recreational cannabis laws showed no association with alcohol or tobacco use. But using operational dispensary opening, these laws were associated with a 0.95 percentage point decrease in current drinking and 0.48 percentage point decrease in current smoking. Subgroup analysis revealed heterogeneous effects across demographics.","whyItMatters":"Whether cannabis legalization increases or decreases use of other substances has major public health implications. This study suggests the answer depends on how you measure legalization and which population groups you examine, adding important nuance to a polarized debate.","specificNumbers":"Sample: 4.8 million adults, 2012-2022. With operational dispensaries: current drinking decreased 0.95 percentage points (95% CI 0.09-1.80), current smoking decreased 0.48 percentage points (95% CI 0.10-0.85). Some subgroups showed increased smokeless tobacco use.","methodology":"Researchers analyzed cross-sectional data from 4.8 million adults in the 2012-2022 Behavioral Risk Factor Surveillance System using a difference-in-differences approach, adjusting for individual characteristics and state-level factors. Two definitions of cannabis law implementation were tested: law passage and operational dispensary opening.","limitations":"Cross-sectional survey data with self-reported substance use. The difference-in-differences approach relies on parallel trends assumptions that may not hold for all states. The small effect sizes, while statistically significant, may have limited clinical or public health significance. Cannot distinguish between substitution and complementary use."},{"rthcId":"RTHC-06325","title":"Time since HIV diagnosis is linked to amnestic mild cognitive impairment (MCI) in older adults with HIV.","authors":"DeFelice, Jason S; Britton, Mark K; Li, Yancheng; Porges, Eric C; Ibañez, Gladys E; Somboonwit, Charurut; Cook, Robert L; Cohen, Ronald A; Gullett, Joseph M","year":2025,"journal":"Journal of neurovirology, 31(5), 438-449","doi":"10.1007/s13365-025-01271-w","pmid":"40681774","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06326","title":"Effects of five cannabis oils with different CBD: THC ratios and terpenes on hypertension, dyslipidemia, hepatic steatosis, oxidative stress, and CB1 receptor in an experimental model.","authors":"Degrave, Valentina; Vega Joubert, Michelle Berenice; Filippa, Camila; Ingaramo, Paola; Torregiani, Lucía; Caro, Yamile Soledad; De Zan, María Mercedes; D'Alessandro, María Eugenia; Oliva, María Eugenia","year":2025,"journal":"Journal of cannabis research, 7(1), 46","doi":"10.1186/s42238-025-00286-8","pmid":"40660358","tags":["cbd","medical-cannabis","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC-rich oil and CBD:THC 1:1 and 2:1 ratio oils showed the greatest benefits against hepatic steatosis and liver damage. CBD-rich oil and CBD:THC 1:1, 2:1, and 3:1 ratio oils showed antihypertensive properties. All five cannabis oils exhibited antioxidant effects and normalized liver CB1 receptor expression.","whyItMatters":"Non-alcoholic fatty liver disease affects roughly 25% of the global population, and there are few effective pharmacological treatments. This study systematically compares multiple CBD:THC ratios for the first time in a NAFLD model, showing that the optimal ratio depends on which symptom you are targeting.","specificNumbers":"Five cannabis oils tested at 1.5 mg/kg/day. Terpenes identified: beta-myrcene, d-limonene, terpinolene, linalool, beta-caryophyllene, alpha-humulene, guaiol, alpha-bisabolol. SRD-fed rats developed hypertension, dyslipidemia, liver damage, hepatic steatosis, lipid peroxidation, and CB1 receptor upregulation.","methodology":"Male Wistar rats were fed a sucrose-rich diet for 3 weeks to induce NAFLD. Seven groups received either reference diet, sucrose diet alone, or sucrose diet plus one of five cannabis oils (THC-rich, CBD-rich, CBD:THC 1:1, 2:1, or 3:1) at 1.5 mg total cannabinoids/kg/day. The oils contained eight identified terpenes. Blood pressure, serum markers, liver histology, lipid metabolism enzymes, oxidative stress markers, and CB1 receptor expression were measured.","limitations":"Short 3-week intervention in a diet-induced rat model. Only male rats were used. The sucrose-rich diet model does not capture all features of human NAFLD. Terpene content varied across oils, making it impossible to isolate cannabinoid ratio effects from terpene effects. Low cannabinoid dose (1.5 mg/kg) may not reflect human dosing."},{"rthcId":"RTHC-06327","title":"Safety assessment on CBD-rich hemp extract in sub-chronic cross-sex study with rats.","authors":"Dehner, Jan; Polanska, Hana Holcova; Petrlakova, Katerina; Zeljkovic, Sanja Cavar; Beres, Tibor; Hendrych, Michal; Storch, Jan; Tarkowski, Petr; Masarik, Michal; Babula, Petr; Vacek, Jan","year":2025,"journal":"Toxicology and applied pharmacology, 495, 117218","doi":"10.1016/j.taap.2024.117218","pmid":"39730029","tags":["cbd","medical-cannabis","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"No adverse effects on organ weight, body weight, behavior, locomotion, food intake, or mortality were observed at any dose (0.5-35 mg/kg/day). However, blood analysis showed significant decreases in calcium, sodium, potassium, chloride, alkaline phosphatase, and creatinine. Males showed decreased alanine transaminase; females showed hyperalbuminemia. CBD accumulated in tissues in the order: brain < serum < liver < heart < kidney < muscle and skin.","whyItMatters":"As CBD products proliferate, rigorous safety data remain limited. This 90-day study provides one of the more thorough safety profiles available, including tissue distribution mapping that shows CBD concentrates heavily in muscle, skin, and kidneys rather than the brain.","specificNumbers":"Doses: 0.5, 5, 10, 35 mg CBD/kg/day for 90 days. Extract was 77% CBD. Tissue accumulation order: brain < serum < liver < heart << kidney <<< muscle and skin. CBD detected in dose-dependent manner (p values from <0.05 to <0.0001).","methodology":"Male and female rats received CBD-rich (77% CBD) full-spectrum hemp extract at 0.5, 5, 10, or 35 mg/kg/day orally for 90 days. Researchers assessed organ and body weight, behavior, locomotion, food intake, mortality, pathomorphology, blood cells, serum biochemistry, electrolytes, and CBD tissue distribution.","limitations":"Rat metabolism differs significantly from human metabolism. The extract was full-spectrum (not pure CBD), so other cannabinoids and compounds may contribute to effects. No recovery period was included to confirm reversibility of biomarker changes. The highest dose (35 mg/kg) is relatively modest compared to some human CBD dosing."},{"rthcId":"RTHC-06328","title":"Cannabidiol/tetrahydrocannabinol-enrich extract decreases neuroinflammation and improves locomotor outcome following spinal cord injury.","authors":"Del Core, Julián; Jure, Ignacio; Silva Sofrás, Fresia Melina; Pietranera, Luciana; Ronchetti, Santiago; Roig, Paulina; Desimone, Martin Federico; De Nicola, Alejandro Federico; Labombarda, Florencia","year":2025,"journal":"Neuroscience, 573, 468-481","doi":"10.1016/j.neuroscience.2025.03.055","pmid":"40157632","tags":["cbd","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"After acute spinal cord injury, the cannabis extract increased anti-inflammatory (arginase-1 positive) microglial cells at the injury site, decreased pro-inflammatory microglia and reactive astrocytes, downregulated inflammatory genes (IL-1beta, TNF-alpha, IL-6, C3), and upregulated anti-inflammatory markers (ARG-1, MRC). In the chronic phase, it prevented cyst expansion, preserved gray and white matter, and improved locomotor scores across three different movement tests.","whyItMatters":"Spinal cord injury affects hundreds of thousands of people worldwide, and neuroinflammation in the first days after injury drives much of the secondary damage that worsens outcomes. Finding treatments that can shift the inflammatory response early could significantly improve long-term recovery.","specificNumbers":"The extract shifted microglial polarization: increased arginase-1+ (anti-inflammatory) cells at the epicenter, decreased arginase-1- (pro-inflammatory) cells in the epicenter and surrounding regions. Treated rats showed better open field locomotor scores, higher rotarod latency to fall, and fewer hindlimb foot misplacements on the horizontal ladder.","methodology":"Rats received acute spinal cord injury followed by treatment with a standardized Cannabis sativa extract containing CBD and THC in equimolar concentrations. Researchers analyzed inflammatory cell populations, gene expression, tissue sparing, cyst formation, and locomotor function using open field, rotarod, and horizontal ladder walking tests.","limitations":"Single animal study using one extract at presumably one dose. Only the equimolar CBD:THC ratio was tested, so optimal ratios remain unknown. Spinal cord injury models in rats do not fully replicate human injuries. Long-term outcomes beyond the study period are unknown."},{"rthcId":"RTHC-06329","title":"Mapping Colombians' positions on national policies to control tobacco and marijuana consumption: a pilot study.","authors":"Del Rio Forero, Daniel; Marín, Claudia Pineda; Sastre, María Teresa Muñoz; Kpanake, Lonzozou; Mullet, Etienne","year":2025,"journal":"Substance abuse treatment, prevention, and policy, 20(1), 16","doi":"10.1186/s13011-025-00646-w","pmid":"40181429","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Three positions emerged for each substance: generally unfavorable regardless of policy (22% tobacco, 17% marijuana), depends on regulation level (18% tobacco, 22% marijuana), and always favorable regardless of policy (23% tobacco, 25% marijuana). The largest group (37% tobacco, 36% marijuana) expressed no opinion at all.","whyItMatters":"Drug control policies can only succeed with public understanding and support. This study reveals that in Colombia, the predominant public response to both tobacco and marijuana control policies is indifference, suggesting that policy effectiveness may be undermined by public disengagement rather than active opposition.","specificNumbers":"147 adults surveyed with 32 policy vignettes each. Indifferent/no opinion: 37% (tobacco), 36% (marijuana). Always favorable: 23% (tobacco), 25% (marijuana). Depends on regulation: 18% (tobacco), 22% (marijuana). Generally unfavorable: 22% (tobacco), 17% (marijuana).","methodology":"A sample of 147 Colombian adults evaluated 32 vignettes describing control policies that varied across four factors: behavior targeted (tobacco or marijuana), preventive measures (e.g., information campaigns), regulatory measures (e.g., prohibition for minors), and penalty severity (e.g., imprisonment). Cluster analysis identified distinct attitudinal groups.","limitations":"Small pilot sample of 147 adults that may not represent the broader Colombian population. Vignette-based surveys measure stated attitudes, not actual behavior or policy compliance. The study was conducted at a single point in time and may not reflect shifting attitudes."},{"rthcId":"RTHC-06330","title":"Cannabinoids Shape Synaptic Activity and Adult Neurogenesis in the Zebrafish Pallium.","authors":"Deleglise, Emilia Beatriz; Carnevale, Gonzalo; Mazzaro, Luz; Lobera, José; Bellora, Nicolás; Mongiat, Lucas Alberto","year":2025,"journal":"Journal of neurochemistry, 169(11), e70289","doi":"10.1111/jnc.70289","pmid":"41200796","tags":["neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 receptors were found in glutamatergic neurons of the zebrafish pallium. Blocking CB1 with rimonabant reduced spontaneous excitatory activity and ERK phosphorylation, suggesting CB1 maintains tonic excitatory signaling. Acute cannabinoid exposure reduced neural stem cell proliferation, but during the maturation window (12-24 days), cannabinoid treatment increased the number of surviving new neurons, an effect reversed by rimonabant.","whyItMatters":"The zebrafish brain undergoes continuous adult neurogenesis, making it a powerful model for understanding how cannabinoids affect new brain cell formation. The finding that cannabinoids reduce initial stem cell proliferation but increase neuron survival suggests a complex regulatory role that may be relevant to mammalian brains.","specificNumbers":"CB1 receptors mapped in dorsomedial (Dm) and dorsolateral (Dl) pallial regions, predominantly in glutamatergic neurons. Rimonabant reduced sEPSC frequency without affecting other synaptic properties. 13-day rimonabant treatment reduced ERK phosphorylation. Cannabinoid treatment increased 25-day-old BrdU+/HuC/D+ neurons in both Dm and Dl regions.","methodology":"Researchers mapped CB1 receptor expression in the zebrafish pallium using immunofluorescence and single-cell mRNA analysis. Electrophysiology measured synaptic activity with and without rimonabant. Neural stem cell proliferation was assessed after acute cannabinoid exposure, and neuronal maturation was tracked using BrdU labeling over 25 days with cannabinoid treatment during the 12-24 day maturation window.","limitations":"Zebrafish neurogenesis is far more robust than in adult mammals, so translation to human brains is uncertain. The specific cannabinoids used and their concentrations were not detailed in the abstract. Only acute and sub-chronic exposures were tested."},{"rthcId":"RTHC-06331","title":"The Role of the Endocannabinoid System in Oncology and the Potential Use of Cannabis Derivatives for Cancer Management in Companion Animals.","authors":"Della Rocca, Giorgia; Di Salvo, Alessandra; Salucci, Erica; Amadori, Michela; Re, Giovanni; Vercelli, Cristina","year":2025,"journal":"Animals : an open access journal from MDPI, 15(15)","doi":"10.3390/ani15152185","pmid":"40804975","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06332","title":"Contrasting cannabinoid receptor 2 (CB2R)-mediated responses in two different models of Blood Brain Barrier in the context of HIV.","authors":"Delorme-Walker, Violaine; Au, Kaylin; Lim, Wei Ling; Sasaki, Takayo; Furihata, Tomomi; Lima, Daniel Siqueira; Iudicello, Jennifer; Milner, Richard; Marcondes, Maria Cecilia Garibaldi","year":2025,"journal":"Research square","doi":"10.21203/rs.3.rs-8310572/v1","pmid":"41510238","tags":["neuroscience","inflammation"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Both endothelial cell lines responded similarly to HIV-conditioned media (increased permeability, decreased tight junction proteins). However, CB2 receptor activation improved all barrier measures in hCMEC/D3 cells (high CB2 expression, 50-fold higher cAMP response) while showing no benefit or aggravation in HBMEC/ci18 cells (low CB2 expression).","whyItMatters":"Cannabis use is common among people living with HIV, and blood-brain barrier disruption contributes to HIV-associated neurocognitive disorders. This study shows that whether cannabinoids help or harm the barrier may depend on individual differences in CB2 receptor expression, potentially explaining conflicting findings in previous research.","specificNumbers":"hCMEC/D3 cells showed over 50-fold higher cAMP response to CB2 activation compared to HBMEC/ci18 cells, correlating with higher CB2 receptor availability. Both cell lines showed similar HIV-induced barrier damage (increased dextran permeability, decreased tight junction proteins).","methodology":"Researchers used two human brain endothelial cell lines (hCMEC/D3 and HBMEC/ci18) in multicellular blood-brain barrier models. Cells were exposed to conditioned media from HIV latently infected promonocytes and treated with cannabinoid receptor agonists. Barrier integrity was assessed via dextran permeability, tight junction proteins, cell viability, proliferation, and GPCR-mediated cAMP production.","limitations":"In vitro cell line models do not fully replicate the complexity of the human blood-brain barrier. Only two cell lines were compared. HIV exposure was via conditioned media rather than direct infection. Individual variation in CB2 expression in living humans is not well characterized."},{"rthcId":"RTHC-06333","title":"Methylomic signature of current cannabis use in two first-episode psychosis cohorts.","authors":"Dempster, Emma L; Wong, Chloe C Y; Burrage, Joe; Hannon, Eilis; Quattrone, Diego; Trotta, Giulia; Rodriguez, Victoria; Alameda, Luis; Spinazzola, Edoardo; Tripoli, Giada; Austin-Zimmerman, Isabelle; Li, Zhikun; Gayer-Anderson, Charlotte; Freeman, Tom P; Johnson, Emma C; Jongsma, Hannah E; Stilo, Simona; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Lasalvia, Antonio; Tosato, Sarah; Tarricone, Ilaria; D'Andrea, Giuseppe; Galatolo, Michela; Tortelli, Andrea; Pompili, Maurizio; Selten, Jean-Paul; de Haan, Lieuwe; Menezes, Paulo Rossi; Del Ben, Cristina M; Santos, Jose Luis; Arrojo, Manuel; Bobes, Julio; Sanjuán, Julio; Bernardo, Miguel; Arango, Celso; Jones, Peter B; Breen, Gerome; Mondelli, Valeria; Dazzan, Paola; Iyegbe, Conrad; Vassos, Evangelos; Morgan, Craig; Mukherjee, Diptendu; van Os, Jim; Rutten, Bart; O'Donovan, Michael C; Sham, Pak; Mill, Jonathan; Murray, Robin; Di Forti, Marta","year":2025,"journal":"Molecular psychiatry, 30(4), 1277-1286","doi":"10.1038/s41380-024-02689-0","pmid":"39406996","tags":["psychosis","genetics","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Current cannabis use was associated with differential methylation at a site in the CAVIN1 gene, independent of tobacco effects. High-potency cannabis (THC >= 10%) was associated with a site in the MCU gene. Pathway analysis identified epigenetic variation near genes linked to immune and mitochondrial function. An interaction analysis suggested that first-episode psychosis status may moderate how cannabis affects DNA methylation.","whyItMatters":"Epigenetic changes represent a molecular mechanism through which cannabis exposure could have lasting biological effects. Identifying cannabis-specific methylation changes, separate from tobacco, and finding that psychosis status may modify these effects adds mechanistic insight to the cannabis-psychosis relationship.","specificNumbers":"682 participants across two cohorts (188 current users, 494 never users). One CpG site (cg11669285) in CAVIN1 reached array-wide significance for current use. One CpG in MCU reached significance for high-potency (THC >= 10%) use. Both were independent of the tobacco methylation signature.","methodology":"Two independent cohorts totaling 682 participants (188 current cannabis users, 494 never users) with first-episode psychosis and controls. DNA methylation profiles were generated from blood samples using Illumina arrays. Meta-analysis across cohorts identified significant sites, controlled for tobacco-related methylation signatures.","limitations":"Cross-sectional design cannot determine whether methylation changes preceded or followed cannabis use or psychosis onset. Blood-based methylation may not reflect brain tissue changes. The modest sample of 188 users limits power to detect smaller effects. Only current use was assessed, not lifetime exposure patterns."},{"rthcId":"RTHC-06334","title":"Recreational marijuana legalization's impact and opioid death rates: A synthetic control approach.","authors":"Denkyirah, Elisha Kwaku; March, Raymond J; Furton, Glenn L; Rayamajhee, Veeshan; Yonk, Ryan M","year":2025,"journal":"Public health, 239, 201-206","doi":"10.1016/j.puhe.2024.12.047","pmid":"39884021","tags":["legalization","pain"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The average treatment effect was approximately -6.49 opioid deaths per capita for Colorado, -2.89 for Washington, and -4.8 for Oregon after recreational dispensaries opened. However, none of these reductions reached statistical significance. Robustness checks confirmed the consistent negative direction but continued non-significance.","whyItMatters":"The opioid epidemic remains a major public health crisis. Whether legal cannabis access reduces opioid deaths is a high-stakes policy question. This study finds a suggestive but inconclusive downward trend, adding nuance to claims on both sides of the debate.","specificNumbers":"Average treatment effects: Colorado -6.49, Washington -2.89, Oregon -4.8 opioid deaths per capita. All were non-significant. The consistent negative direction across all three states and robustness checks suggests a possible real effect that the study lacked power to confirm.","methodology":"Researchers used the synthetic control method to construct counterfactual versions of Colorado, Washington, and Oregon using state-level data from the CDC, Bureau of Labor Statistics, US Census Bureau, and other sources. These three states were chosen because they were the first to legalize recreational marijuana, providing the longest post-treatment observation periods.","limitations":"Synthetic control method relies on finding good donor states, which may be imperfect. Only three states were analyzed. Opioid death rates are influenced by many concurrent policy changes (naloxone access, prescribing guidelines, fentanyl emergence) that complicate attribution. The post-treatment period may not be long enough to capture delayed effects."},{"rthcId":"RTHC-06335","title":"Cannabis Use During Pregnancy Correlates With Adverse Maternal Mental Health Outcomes: A Retrospective Study.","authors":"Dereschuk, Kypros J; Espiridion, Eduardo","year":2025,"journal":"Cureus, 17(4), e82146","doi":"10.7759/cureus.82146","pmid":"40357112","tags":["pregnancy","mental-health","depression","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use during pregnancy was associated with significantly elevated risks across all four mental health outcomes: depression (RR 2.66), panic disorder (RR 5.47), suicidal ideation (RR 10.67), and alcohol abuse (RR 13.57). Depression affected 29.7% of cannabis users versus 11.2% of non-users. All differences were highly significant (p < 0.001).","whyItMatters":"Cannabis use during pregnancy has risen alongside legalization and perceived safety. These dramatic risk ratios for depression, panic, suicidal ideation, and alcohol abuse underscore that prenatal cannabis use may be a marker for, or contributor to, serious maternal mental health challenges that affect both mother and child.","specificNumbers":"Sample: 51,087 cannabis users vs 1,936,508 non-users during pregnancy from 69 HCOs. Depression: 29.7% vs 11.2% (RR 2.66, HR 3.50). Panic disorder: RR 5.47, HR 5.01. Suicidal ideation: RR 10.67, HR 9.81. Alcohol abuse: RR 13.57, HR 12.44.","methodology":"Retrospective cohort study using the TriNetX database, including over 2 million pregnant patients from 69 US healthcare organizations. A cohort of 51,087 cannabis users during pregnancy was compared to 1,936,508 non-users. Outcomes were identified using ICD-10 codes. Risk ratios, hazard ratios, and Kaplan-Meier survival analyses were calculated.","limitations":"Retrospective database study using ICD-10 codes, which may undercount both cannabis use and mental health diagnoses. No causal conclusions can be drawn: cannabis use during pregnancy likely correlates with many unmeasured social and psychological risk factors. No propensity matching or adjustment for confounders was described in the abstract."},{"rthcId":"RTHC-06336","title":"Intractable Vomiting in the Setting of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist and Cannabis Usage.","authors":"DesRochers, Peter; Kaiser, Linus; Lee, Seoyoon; Perchetti, Garrett A; Lazarescu, Roxana","year":2025,"journal":"Cureus, 17(11), e97851","doi":"10.7759/cureus.97851","pmid":"41458667","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06337","title":"Synthetic cannabinoids in Mayotte over a year in time and space: an example of high-frequency evolution of market.","authors":"Devault, Damien Alain; Fabien, Loïc; Gish, Alexandr; Richeval, Camille; Gaulier, Jean-Michel; Nefau, Thomas","year":2025,"journal":"Environmental science and pollution research international, 32(55), 30517-30539","doi":"10.1007/s11356-025-37273-8","pmid":"41385045","tags":["synthetic-cannabinoids","addiction","potency"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Thirteen different synthetic cannabinoid receptor agonists were identified across 195 samples (187 cigarettes, 8 powders). Co-formulants included other cannabinoids, pharmaceuticals, and novel psychoactive substances mixed with tobacco or cannabis plant material. Month by month, the market became more homogeneous due to manufacturer consolidation and gang hegemony, but specific product profiles could change dramatically between campaigns.","whyItMatters":"Synthetic cannabinoids (\"chimique\" in Mayotte) represent one of the most dangerous drug trends globally due to their unpredictable potency and unknown compositions. This study provides rare longitudinal data showing how quickly the market evolves, creating ongoing risks for users who cannot know what they are consuming.","specificNumbers":"195 samples collected across 8 campaigns over 1 year. 13 different SCRAs identified. Samples contained plant matrix (tobacco predominant, sometimes mixed with cannabis) plus synthetic compounds. Co-formulants included cannabinoids, pharmaceuticals/precursors, and other novel psychoactive substances.","methodology":"Eight week-long sampling campaigns were conducted over one year in Mayotte (a French overseas territory). Researchers collected samples from street users and open consumption sites, offering consumers interviews about their use patterns and supply chains. Samples were analyzed using liquid chromatography with high-resolution mass spectrometry.","limitations":"Mayotte is a small, isolated island territory with unique socioeconomic conditions that limit generalizability. Sample collection from street users introduces selection bias. The study cannot quantify total market size or prevalence of use. User interviews are subject to reporting bias."},{"rthcId":"RTHC-06338","title":"How synthetic cannabinoid user profiles and consumption patterns can affect wastewater-based epidemiology.","authors":"Devault, Damien Alain; Peyré, Alexandre; Cottereau, Victoire; Pleignet, Eric; Daveluy, Amélie","year":2025,"journal":"Environmental science and pollution research international, 32(58), 31108-31120","doi":"10.1007/s11356-025-37106-8","pmid":"41148497","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06339","title":"Outsmarting generic legislation: 4 years into the cat-and-mouse game of the synthetic cannabinoid receptor agonist market since the Chinese ban in 2021.","authors":"Deventer, Marie H; Stove, Christophe P","year":2025,"journal":"Archives of toxicology, 99(12), 4757-4784","doi":"10.1007/s00204-025-04191-0","pmid":"40983778","tags":["synthetic-cannabinoids","potency","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Ban-evading strategies included: alternative core structures (oxoindolins, oxopyridone, benzoate), linker replacement (acetamide instead of carboxamide), positional switching on conventional cores, adding or removing substituents (bromination, tail-less compounds), and a do-it-yourself synthesis approach where users convert legal tail-less precursors into banned potent SCRAs.","whyItMatters":"China's 2021 ban was one of the most sweeping generic drug scheduling efforts ever attempted. This review documents how four years of manufacturer innovation have already undermined it, creating a flood of novel compounds with unknown potency, toxicity, and metabolic profiles that challenge both forensic detection and emergency medicine.","specificNumbers":"7 SCRA scaffolds covered by the 2021 Chinese ban. At least 6 distinct chemical evasion strategies documented. Named compounds include OXIZIDs, CH-FUBBMPDORA, NMDMSB, ADB-FUBIATA, 5F-3,5-AB-PFUPPYCA, ADB-INACA, and ADB-5'Br-BUTINACA, among others. Period covered: mid-2021 to mid-2025.","methodology":"The review compiled and analyzed all synthetic cannabinoid receptor agonists that emerged between mid-2021 and mid-2025 in response to China's generic ban. The authors categorized ban-evading strategies, discussed detection and metabolic profiling challenges, and presented first-published pharmacological data for some uncharacterized compounds.","limitations":"The review focuses on compounds detected in forensic and analytical reports, which may not capture all novel SCRAs in circulation. Pharmacological characterization is incomplete for many compounds. The review does not quantify health outcomes or prevalence of use for individual compounds."},{"rthcId":"RTHC-06340","title":"Self-Reported and Biologic Assessments of Prenatal Cannabis Use: Ancillary Analysis of a Prospective Observational Cohort.","authors":"Devlin, Paulina M; Allshouse, Amanda A; McMillin, Gwen; Chung, Judith H; Grobman, William A; Haas, David M; Pippen, Jessica L; Parry, Samuel; Reddy, Uma M; Saade, George R; Simhan, Hyagriv N; Silver, Robert M; Metz, Torri D","year":2025,"journal":"Substance use & addiction journal, 29767342251389751","doi":"10.1177/29767342251389751","pmid":"41368933","tags":["pregnancy","youth"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Among participants who used cannabis, 74.5% of use at mid-pregnancy and 79.6% at late pregnancy was detected only by urine assay, not self-report. At delivery, 89.7% was detected only by cord assay. Agreement between self-report and biospecimen was fair during pregnancy (Kappa 0.23-0.30) and slight at delivery (Kappa 0.11).","whyItMatters":"Research on prenatal cannabis effects relies heavily on self-reported use, but this study shows that self-reports miss the vast majority of actual use. This means virtually all epidemiological studies of cannabis and pregnancy outcomes likely underestimate exposure, potentially diluting observed associations.","specificNumbers":"9,116 participants; 434 (4.76%) used cannabis by either measure. Self-report detected only 25.5% of mid-pregnancy use, 20.4% of late pregnancy use, and 10.3% of delivery use. Kappa agreement: 0.30 at visit 2, 0.23 at visit 3, 0.11 at delivery. Factors associated with discordance: age <30, unmarried, government insurance, moderate/high perceived stress.","methodology":"Ancillary analysis of the nuMoM2b study, a US multicenter prospective cohort of 9,116 pregnant individuals (2010-2013). Self-reported cannabis use was assessed at three visits. Urine testing for THC metabolite (11-nor-9-carboxy-delta-9-THC) was performed at two visits, and umbilical cord testing at delivery. Agreement was evaluated with Kappa statistics; factors associated with discordance were assessed with multivariable logistic regression.","limitations":"Data from 2010-2013 may not reflect current cannabis use patterns or attitudes post-legalization. Urine testing detects THC metabolites for days to weeks, so positive tests may reflect use before the person knew they were pregnant. The study population was first-time pregnant individuals, which may differ from multiparous populations."},{"rthcId":"RTHC-06341","title":"Endocannabinoid signaling in stress, nausea, and vomiting.","authors":"DeVuono, Marieka V; Venkatesan, Thangam; Hillard, Cecilia J","year":2025,"journal":"Neurogastroenterology and motility, 37(3), e14911","doi":"10.1111/nmo.14911","pmid":"39223918","tags":["appetite","anxiety","addiction","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system normally regulates nausea, vomiting, and anxiety. Cannabis can have both antiemetic and pro-emetic effects depending on dose and duration. Chronic use may dysregulate the ECS, altering its homeostatic control and potentially contributing to the paradoxical nausea and vomiting seen in cyclic vomiting syndrome (CVS) and cannabinoid hyperemesis syndrome (CHS).","whyItMatters":"Cannabinoid hyperemesis syndrome and cyclic vomiting syndrome can be debilitating conditions that do not respond well to standard antiemetics. Understanding how the ECS becomes dysregulated through chronic cannabis use could lead to better treatments for these increasingly common conditions.","specificNumbers":"The review notes that classical serotonin-targeting antiemetics may not be effective for CVS or CHS. Cannabis produces paradoxical dose-dependent effects: antiemetic at some doses but pro-emetic at higher doses or with chronic use.","methodology":"Narrative review examining the endocannabinoid system's role in stress, nausea, and vomiting regulation, the effects of prolonged cannabis use on ECS function, and the evidence linking ECS dysregulation to CVS and CHS pathophysiology.","limitations":"Narrative review without systematic methodology. The mechanisms linking ECS dysregulation to CVS and CHS are still largely hypothetical. The distinction between CVS and CHS remains debated in the medical community."},{"rthcId":"RTHC-06342","title":"Glucagon-like peptide-1 receptor agonists and suicide risk in individuals with diabetes and Cannabis use disorder.","authors":"Dhruva, Yesh; Messias, Erick; Lin, Ping-I","year":2025,"journal":"Preventive medicine reports, 58, 103244","doi":"10.1016/j.pmedr.2025.103244","pmid":"41050856","tags":["addiction","mental-health","drug-interactions"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"GLP-1 RA use was associated with lower suicide attempt risk (aHR 0.63). Cannabis use disorder was associated with dramatically higher risk (aHR 5.50). Among patients with both CUD and GLP-1 RA use, suicide risk remained elevated (aHR 5.75) with no significant benefit from GLP-1 RAs (aHR 1.00 comparing GLP-1 users vs non-users among CUD patients).","whyItMatters":"GLP-1 receptor agonists (like semaglutide/Ozempic) have generated interest for potential mental health benefits beyond metabolic effects. This study suggests their apparent protective effect against suicide does not extend to patients with cannabis use disorder, a vulnerable population with dramatically elevated baseline risk.","specificNumbers":"6,424,228 individuals with T2DM. GLP-1 RA users vs unexposed: aHR 0.63 (95% CI 0.47-0.85). CUD vs no CUD: aHR 5.50 (95% CI 4.39-6.89). CUD + GLP-1 RA: aHR 5.75 (95% CI 3.42-9.69). GLP-1 RA effect among CUD patients: aHR 1.00 (95% CI 0.37-2.69).","methodology":"Retrospective study using the TriNetX Research Network covering adults aged 30-85 with type 2 diabetes from over 20 countries (2003-2023). 6,424,228 individuals were categorized by GLP-1 RA exposure and cannabis use disorder status. Cox models estimated hazard ratios adjusted for age, sex, depression, BMI, and HbA1c. Those with prior suicidal ideation were excluded.","limitations":"Retrospective design with potential confounding despite adjustment. Cannabis use disorder codes may capture only the most severe cases. GLP-1 RA users may differ systematically from non-users. The CUD + GLP-1 subgroup may be too small for adequate power. Claims data cannot capture suicidal behavior that does not result in healthcare contact."},{"rthcId":"RTHC-06343","title":"Prenatal Delta-9-Tetrahydrocannabinol Exposure Induces Transcriptional Alterations in Dopaminergic System with Associated Electrophysiological Dysregulation in the Prefrontal Cortex of Adolescent Rats.","authors":"Di Bartolomeo, Martina; Aroni, Sonia; Serra, Marcello; Serra, Valeria; Martella, Francesca; Gilardini, Federica; Melis, Miriam; D'Addario, Claudio","year":2025,"journal":"Cells, 14(12)","doi":"10.3390/cells14120904","pmid":"40558531","tags":["pregnancy","youth","dopamine","neuroscience","psychosis","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal cannabis exposure increased mRNA levels of dopamine D1 and D2 receptors in the prefrontal cortex, with a particularly strong effect on D2 in males. Male rats showed reduced Drd2 DNA methylation (potentially explaining increased expression), changes in selective miRNAs regulating both receptors, altered excitability of prefrontal pyramidal neurons, and disrupted Netrin-1/DCC guidance cue system. Endocannabinoid system gene expression remained stable.","whyItMatters":"The prefrontal cortex is critical for decision-making, impulse control, and emotional regulation, and it undergoes major development during adolescence. Finding that prenatal THC exposure reprograms dopamine signaling in this region through epigenetic mechanisms provides a biological pathway that could explain behavioral and psychiatric risks associated with prenatal cannabis exposure.","specificNumbers":"Increased Drd1 and Drd2 mRNA in PFC. Male-specific: notable Drd2 increase, consistent reduction in Drd2 DNA methylation, altered PFC pyramidal neuron excitability, changes in Netrin-1/DCC system. Both receptors regulated by selective miRNAs. Endocannabinoid system genes showed stable expression.","methodology":"An animal model of prenatal cannabis exposure was used, with offspring studied during adolescence. Researchers analyzed gene expression and DNA methylation of dopamine and endocannabinoid system genes in the prefrontal cortex, measured miRNA regulators, performed electrophysiological recordings of pyramidal neurons, and assessed the Netrin-1/DCC guidance cue system.","limitations":"Animal model using controlled THC exposure that may not reflect human prenatal exposure patterns. Only adolescent timepoint was assessed; effects may differ at other ages. The specific THC dose and timing were not detailed in the abstract. Translation from rodent prefrontal cortex to human is imperfect."},{"rthcId":"RTHC-06344","title":"The effects of naturalistic cannabis use on cognition and subjective experience in older adults with normal cognitive function.","authors":"Di Ciano, P; Le Foll, B; Zhao, S; Byrne, P; Elzohairy, Y; Brubacher, J R; McGrath, M; Brands, B; Chen, S; Wang, W; Kaduri, P; Wickens, C M; Rajji, T K","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 2698811251370975","doi":"10.1177/02698811251370975","pmid":"41178441","tags":["cognition","seniors"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Trail making test performance (versions A and B) was significantly decreased 60 minutes after smoking cannabis compared to the sober condition. However, verbal free recall word retention was actually higher after cannabis, apparently due to reversal of a performance decrement. Cannabis produced robust subjective effects. Blood THC levels did not clearly correlate with cognitive performance.","whyItMatters":"Adults over 65 are the fastest-growing group of cannabis users, yet almost no research examines acute effects in this population. This study provides rare data showing that cognitive impacts may be more selective than expected, affecting processing speed and executive function but not necessarily memory.","specificNumbers":"31 participants, ages 65-78, 21 male. Average cannabis THC content: 18.7%. Trail making A and B impaired at 60 minutes. Verbal free recall retention was higher under cannabis. Blood THC measured at 60 and 210 minutes with unclear correlations to cognitive performance.","methodology":"Counterbalanced crossover design with 31 participants aged 65-78 (21 male) with normal cognitive function. Participants smoked their preferred legal cannabis (average 18.7% THC) in the lab, then completed tests of verbal learning and memory, executive function, information processing, and visual attention at 60 and 210 minutes. Blood THC and metabolites were measured.","limitations":"Small sample of 31 participants, predominantly male. Naturalistic design means THC dose was not controlled. Participants were existing cannabis users with normal cognition, so results may not apply to naive users or those with cognitive impairment. Short-term acute effects were measured, not chronic use impacts."},{"rthcId":"RTHC-06345","title":"Effects of naturalistic doses of cannabis edibles on cognition and association with blood THC.","authors":"Di Ciano, Patricia; Zhao, Sampson; Kaduri, Pamela; Patel, Siddhi; Bhakta, Kruti; Wickens, Christine M; Chen, Sheng; Le Foll, Bernard; Brands, Bruna","year":2025,"journal":"Psychopharmacology","doi":"10.1007/s00213-025-06863-2","pmid":"40748375","tags":["cognition","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"At 150 minutes after consuming a cannabis edible averaging 7.3 mg THC, participants showed decreased performance on two verbal free recall measures. No effects were found on the useful field of view test or trail making test. Significant subjective intoxication was reported. Blood THC was not correlated with any cognitive outcomes.","whyItMatters":"Edible cannabis use is rising rapidly, yet almost all cognitive research has focused on smoked cannabis. This study provides rare data on how edibles at typical consumer doses affect thinking, finding a narrower cognitive impact than typically seen with smoking.","specificNumbers":"22 participants. Mean edible THC dose: 7.3 +/- 2.9 mg. Cognitive testing at 150 and 270 minutes. Two verbal free recall measures impaired at 150 minutes. Trail making and useful field of view unaffected. Blood THC did not correlate with any cognitive outcome.","methodology":"Observational study where 22 participants consumed their own legally sourced cannabis edibles in the lab. Cognitive testing (verbal free recall, trail making, useful field of view) and subjective experience measures were administered at 150 and 270 minutes post-ingestion. Blood THC and metabolites were measured and correlated with cognitive outcomes.","limitations":"Very small sample (n=22) of regular users who may have tolerance. Naturalistic dosing means no placebo control. Participants knew they were taking cannabis, so expectancy effects cannot be ruled out. The relatively low average dose (7.3 mg) may not reflect all consumer patterns."},{"rthcId":"RTHC-06346","title":"Effectiveness of Highly Purified Cannabidiol in Refractory and Super-Refractory Status Epilepticus: A Case Series.","authors":"Di Mauro, Giovanni; Vietri, Giovanni; Quaranta, Loreta; Placidi, Fabio; Izzi, Francesca; Castelli, Alessandro; Pagano, Andrea; Leonardis, Francesca; De Angelis, Viviana; Bianco, Ciro; Celeste, Maria Grazia; Mercuri, Nicola Biagio; Liguori, Claudio","year":2025,"journal":"CNS & neurological disorders drug targets, 24(2), 158-163","doi":"10.2174/0118715273304077240603115521","pmid":"38910424","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Both patients achieved resolution of status epilepticus after adding highly purified CBD (hpCBD) as add-on therapy via nasogastric tube, without adverse events. At 6-month follow-up, both patients continued on hpCBD treatment, which remained effective for seizure management.","whyItMatters":"Refractory and super-refractory status epilepticus are medical emergencies with high mortality and very few effective treatments. While CBD is approved for specific epilepsy syndromes, this is among the first evidence of its potential in acute status epilepticus, a setting where new treatment options are desperately needed.","specificNumbers":"Two patients treated. Both achieved SE resolution. Zero adverse events reported. Both continued on hpCBD at 6-month follow-up with continued efficacy. hpCBD is already approved for Lennox-Gastaut, Dravet syndrome, and Tuberous Sclerosis Complex.","methodology":"Case series of two patients presenting with refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE). After standard antiseizure medications failed, hpCBD was administered via nasogastric tube as add-on therapy. Patients were followed for 6 months.","limitations":"Only two cases, making it impossible to draw generalizable conclusions. Multiple other treatments were being given simultaneously, so the contribution of hpCBD alone is uncertain. No control group or comparison. Drug interactions with concurrent antiseizure medications were not fully characterized."},{"rthcId":"RTHC-06347","title":"Development of a human RPE In vitro model with AMD-like features reveals blue light-induced modulation of the endocannabinoid system.","authors":"Di Meo, Camilla; Tisi, Annamaria; Lizzi, Anna Rita; Palaniappan, Sakthimala; Pulcini, Fanny; Cinque, Benedetta; Delle Monache, Simona; Nazarè, Marc; Hsu, Eric; Rapino, Cinzia; Maccarrone, Mauro","year":2025,"journal":"Biochemical and biophysical research communications, 767, 151896","doi":"10.1016/j.bbrc.2025.151896","pmid":"40318376","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06348","title":"Cannabinol modulates the endocannabinoid system and shows TRPV1-mediated anti-inflammatory properties in human keratinocytes.","authors":"Di Meo, Camilla; Tortolani, Daniel; Standoli, Sara; Ciaramellano, Francesca; Angelucci, Beatrice Clotilde; Tisi, Annamaria; Kadhim, Salam; Hsu, Eric; Rapino, Cinzia; Maccarrone, Mauro","year":2025,"journal":"BioFactors (Oxford, England), 51(1), e2122","doi":"10.1002/biof.2122","pmid":"39275884","tags":["cbd","inflammation","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBN increased CB1 gene expression and TRPV1 protein expression and function in keratinocytes. It modulated anandamide and 2-AG metabolism. In inflamed cells, CBN reduced pro-inflammatory IL-8, IL-12, and IL-31 while increasing anti-inflammatory IL-10. The reduction of IL-31 was specifically mediated by TRPV1. CBN also modulated GSK3-beta through the MAPK signaling pathway.","whyItMatters":"CBN is gaining consumer interest as a cannabis minor cannabinoid, but its mechanisms are poorly understood. This study reveals a specific pathway (TRPV1-mediated IL-31 reduction) through which CBN exerts anti-inflammatory effects on skin, providing scientific support for its potential in dermatological applications.","specificNumbers":"CBN increased CB1 gene expression, TRPV1 protein expression, and activities of NAPE-PLD, FAAH, and MAGL. In inflamed cells: reduced IL-8, IL-12, IL-31; increased IL-10. IL-31 reduction specifically mediated by TRPV1. GSK3-beta modulated in MAPK pathway.","methodology":"Human keratinocytes (HaCaT cells) were treated with CBN in both normal and LPS-inflamed conditions. Researchers measured expression and function of cannabinoid receptors (CB1, CB2) and TRPV1, endocannabinoid metabolic enzyme activities (NAPE-PLD, FAAH, MAGL), cytokine release (IL-8, IL-10, IL-12, IL-31), and MAPK signaling pathway components.","limitations":"In vitro study using an immortalized cell line (HaCaT), which may not fully represent in vivo skin biology. Single cannabinoid tested in isolation, whereas real cannabis products contain multiple compounds. Concentrations used may not reflect achievable tissue levels from topical application."},{"rthcId":"RTHC-06349","title":"Palmitoylethanolamide: A Multifunctional Molecule for Neuroprotection, Chronic Pain, and Immune Modulation.","authors":"Di Stefano, Valeria; Steardo, Luca; D'Angelo, Martina; Monaco, Francesco; Steardo, Luca","year":2025,"journal":"Biomedicines, 13(6)","doi":"10.3390/biomedicines13061271","pmid":"40563990","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06350","title":"Disparities in use modalities among adults who currently use cannabis, 2022-2023.","authors":"Diaby, Meman; Agbonlahor, Osayande; Fennell, Bethany Shorey; Hart, Joy L; Mattingly, Delvon T","year":2025,"journal":"Journal of cannabis research, 7(1), 26","doi":"10.1186/s42238-025-00283-x","pmid":"40380341","tags":["harm-reduction","legalization","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Smoking was most common (77.3%), followed by edibles (37.3%), vaping (34.8%), dabbing (15.0%), topicals (5.9%), sublingual (4.5%), and pills (2.1%). Women had lower odds of smoking (OR 0.65) and higher odds of topical use (OR 2.92). Black adults had higher odds of smoking (OR 2.03), lower odds of edibles (OR 0.66), and dramatically higher odds of blunt use (OR 5.31). Adults 50+ had higher odds of sublingual use (OR 2.45).","whyItMatters":"Different cannabis consumption methods carry different health risks: smoking and blunt use involve combustion, vaping has its own respiratory concerns, and edibles carry dosing risks. Understanding who uses which methods is essential for targeted public health messaging.","specificNumbers":"n=16,999. Smoking: 77.3%. Edibles: 37.3%. Vaping: 34.8%. Dabbing: 15.0%. Topicals: 5.9%. Sublingual: 4.5%. Pills: 2.1%. Blunt subanalysis (n=12,355): Black vs White adults OR 5.31 for blunt use. Vaping most common in ages 18-25 (29.8%). Edibles popular in ages 35-49 (29.6%).","methodology":"Combined 2022-2023 NSDUH data on 16,999 adults reporting past 30-day cannabis use. Weighted proportions and multivariable logistic regression examined seven use modalities (smoking, vaping, dabbing, edibles, pills, topicals, sublingual) across demographics. A subanalysis of 12,355 adults examined blunt use.","limitations":"Self-reported data subject to recall and social desirability bias. Cross-sectional design cannot track changes over time. NSDUH may underrepresent some populations. The seven modality categories may not capture all emerging products. State-level differences in legal markets were only partially accounted for."},{"rthcId":"RTHC-06351","title":"Disparities in use modalities among adults who currently use cannabis, 2022-2023.","authors":"Diaby, Meman; Agbonlahor, Osayande; Fennell, Bethany Shorey; Hart, Joy L; Mattingly, Delvon T","year":2025,"journal":"Research square","doi":"10.21203/rs.3.rs-5975991/v1","pmid":"40235509","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06352","title":"Intranasal naloxone to treat suspected synthetic cannabinoid overdose: A case report and literature review.","authors":"Dickinson, Jaden; Buckley, Tiffany","year":2025,"journal":"The mental health clinician, 15(5), 248-251","doi":"10.9740/mhc.2025.10.248","pmid":"41079527","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 43-year-old man with schizoaffective disorder presented with altered mental status and respiratory depression after suspected K2 use. He improved with intranasal naloxone despite negative opioid and synthetic cannabinoid screens. He later admitted ongoing K2 use. The clinical response suggests either opioid adulteration of the K2 or functional interactions between CB1 and opioid receptors.","whyItMatters":"Synthetic cannabinoid products are increasingly contaminated with opioids, and standard toxicology screens cannot detect most novel synthetic cannabinoids. This case demonstrates that naloxone should be considered in undifferentiated overdoses even without confirmed opioid exposure, given its safety profile and potential effectiveness.","specificNumbers":"One patient, age 43, with schizoaffective disorder and polysubstance dependence. Repeated improvement with intranasal naloxone. Negative toxicology for opioids and known SCRAs. Preclinical evidence supports CB1-opioid receptor crosstalk as a possible mechanism.","methodology":"Case report with literature review. Standard toxicology screens for opioids and known synthetic cannabinoids were negative. Clinical response to naloxone was documented across episodes. A unit search found leafy substances, but confirmatory testing was negative due to the constantly changing chemical composition of synthetic cannabinoids.","limitations":"Single case report cannot establish causation. The mechanism (opioid contamination vs CB1-opioid crosstalk) remains uncertain. Negative toxicology could mean either no opioids were present or the specific opioid was undetectable by standard screens. Concurrent medications and schizoaffective disorder complicate interpretation."},{"rthcId":"RTHC-06353","title":"Interactions Between Iron Metabolism and the Endocannabinoid System in Bacterial Infections.","authors":"Dickson, Kayle Brenna; Zhou, Juan; Lehmann, Christian","year":2025,"journal":"Antibiotics (Basel, Switzerland), 14(6)","doi":"10.3390/antibiotics14060614","pmid":"40558204","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06354","title":"Associations of maternal peripregnancy cannabis use with behavioral and developmental outcomes in children with and without symptoms of autism spectrum disorder: Study to Explore Early Development.","authors":"DiGuiseppi, Carolyn; Crume, Tessa; Holst, Brady; Aiona, Kaylynn; Van Dyke, Julia; Croen, Lisa A; Daniels, Julie L; Friedman, Sandra; Sabourin, Katherine R; Schieve, Laura A; Wiggins, Lisa; Windham, Gayle C; Robinson Rosenberg, Cordelia","year":2025,"journal":"Autism research : official journal of the International Society for Autism Research, 18(1), 202-216","doi":"10.1002/aur.3284","pmid":"39660543","tags":["pregnancy","youth","cognition","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Preconception-only cannabis use was associated with more aggressive behavior, emotional reactivity, and sleep problems specifically in children with ASD symptoms, but not in children without. Cannabis use during pregnancy was associated with attention and sleep problems in children with ASD symptoms, though these associations did not significantly differ by ASD status. Peripregnancy cannabis use was not associated with developmental abilities regardless of ASD symptoms.","whyItMatters":"This is among the first studies to examine whether the effects of prenatal cannabis exposure differ based on neurodevelopmental vulnerability. The finding that children with ASD symptoms are more affected suggests that cannabis exposure may interact with pre-existing neurodevelopmental risk factors.","specificNumbers":"Sample: 2,734 with ASD symptoms, 3,454 without. Peripregnancy cannabis exposure: 6.0% (ASD group) vs 4.6% (non-ASD). Preconception-only use linked to aggression, emotional reactivity, sleep problems in ASD group only. Pregnancy use linked to attention and sleep problems in ASD group. No associations with developmental abilities in either group.","methodology":"Children ages 30-68 months were evaluated with the Child Behavior Checklist and Mullen Scales of Early Learning. The sample included 2,734 children with ASD symptoms and 3,454 without. Cannabis use was assessed across three periods: peripregnancy (3 months preconception through delivery), pregnancy only, and preconception only. Peripregnancy exposure was reported for 6.0% of children with and 4.6% without ASD symptoms.","limitations":"Observational study cannot establish causation. Cannabis use was self-reported and may be underestimated. ASD symptoms were identified through standardized assessments but do not equate to clinical diagnosis. Confounders including other substance use, socioeconomic factors, and genetic predisposition could explain the associations."},{"rthcId":"RTHC-06355","title":"Family Support, Communication with Parents, and Adolescent Health Risk Behaviour: A Case of HBSC Study from Bulgaria and Lithuania.","authors":"Dimitrova, Elitsa; Zaborskis, Apolinaras","year":2025,"journal":"Children (Basel, Switzerland), 12(5)","doi":"10.3390/children12050654","pmid":"40426833","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06356","title":"An In Vitro Phytohormone Survey Reveals Concerted Regulation of the Cannabis Glandular Trichome Disc Cell Proteome.","authors":"Dimopoulos, Nicolas; Guo, Qi; Liu, Lei; Nolan, Matthew; Das, Rekhamani; Garcia-de Heer, Lennard; Mieog, Jos C; Barkla, Bronwyn J; Kretzschmar, Tobias","year":2025,"journal":"Plants (Basel, Switzerland), 14(5)","doi":"10.3390/plants14050694","pmid":"40094644","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06357","title":"From dawn 'til dusk: daytime progression regulates primary and secondary metabolism in Cannabis glandular trichomes.","authors":"Dimopoulos, Nicolas; Guo, Qi; Purdy, Sarah Jane; Nolan, Matthew; Halimi, Razlin Azman; Mieog, Jos Cornelis; Barkla, Bronwyn J; Kretzschmar, Tobias","year":2025,"journal":"Journal of experimental botany, 76(1), 134-151","doi":"10.1093/jxb/erae148","pmid":"38676643","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06358","title":"Clinical Profile and Drugs of Abuse Identified among People who Use Drugs Admitted to a Tertiary Hospital in the Philippines using a Validated LC-QTOF/MS Method.","authors":"Dioquino, Carissa Paz C; Toralba, Joanna V; Mora, Lilianna Mae M; Alvarado, Jowela B; Climacosa, Fresthel Monica M; Ngo, Frances Lois U; Amarillo, Maria Lourdes E; Yabes, Ailyn M; Loquias, Monet M; Gerona, Roy Roberto L","year":2025,"journal":"Acta medica Philippina, 59(13), 52-59","doi":"10.47895/amp.v59i13.11794","pmid":"41104058","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06359","title":"Changes in cannabis attitudes and perceptions in the five years following recreational legalization in Canada: Findings from an observational cohort study of community adults.","authors":"Doggett, Amanda; Belisario, Kyla L; McDonald, André J; De Jesus, Jane; Vandehei, Emily; Gillard, Jessica; Lee, Laura; MacKillop, James","year":2025,"journal":"The International journal on drug policy, 140, 104782","doi":"10.1016/j.drugpo.2025.104782","pmid":"40262303","tags":["legalization","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Social acceptability of any recreational use (OR 1.06) and trying cannabis (OR 1.02) increased over time. But perceived riskiness of regular use also increased (OR 0.97), along with perceived addiction potential (OR 0.94). Perceived health benefits decreased while perceived risks increased (exacerbating stress, anxiety, depression; disrupting sleep). Non-users before legalization showed the steepest increases in social acceptability but smaller increases in risk perception.","whyItMatters":"A major concern about legalization is that it will normalize cannabis and reduce perceived risks, leading to greater misuse. This study shows a more nuanced picture: while social acceptance grew, Canadians simultaneously became more aware of specific health risks, suggesting that post-legalization public health education may be working.","specificNumbers":"Mean 9.9 assessment waves per participant over 5 years. Social acceptability of recreational use: OR 1.06 per wave. Medical use acceptability decreased: OR 0.95. Regular use perceived as riskier: OR 0.97. Addiction risk perceived as greater: OR 0.94. 48% reported pre-legalization cannabis use.","methodology":"Longitudinal observational cohort (60% female, median age 29, 48% pre-legalization users) assessed up to 11 times from September 2018 to October 2023. Measures included social acceptability of various use patterns, perceived risks and benefits, and moderation by pre-legalization use status.","limitations":"Cohort may not be nationally representative (convenience sample, 60% female, median age 29). Attrition could bias results if participants with changing attitudes were more likely to drop out. Self-reported attitudes may not reflect behavior. The 5-year window may not capture longer-term shifts."},{"rthcId":"RTHC-06360","title":"Evaluating the impact of Canadian cannabis legalization on cannabis use outcomes in emerging adults: Comparisons to a US control sample via a natural experiment.","authors":"Doggett, Amanda; Belisario, Kyla L; McDonald, André J; Gohari, Mahmood; Leatherdale, Scott T; Murphy, James G; MacKillop, James","year":2025,"journal":"The International journal on drug policy, 136, 104686","doi":"10.1016/j.drugpo.2024.104686","pmid":"39729707","tags":["legalization","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Against a general trend of decreasing cannabis use in both countries, Canadian young adults showed significantly higher cannabis use frequency at 6 months (ATT 0.22) and 12 months (ATT 0.31) post-legalization compared to the US control group. Cannabis-related consequences were also greater at both time points. These differences reflected less steep declines over time (attenuated aging out) rather than absolute increases. Alcohol outcomes showed no legalization effect.","whyItMatters":"This is one of the most rigorous evaluations of cannabis legalization effects, using a US comparison group and DiD methodology to approximate a natural experiment. The finding that legalization attenuated \"aging out\" of cannabis use is important because this natural developmental decline is a key protective factor.","specificNumbers":"Canadian vs US difference at 6 months: cannabis frequency ATT 0.22 (95% CI 0.02-0.43), consequences ATT 0.76 (95% CI 0.08-1.44). At 12 months: frequency ATT 0.31 (95% CI 0.05-0.57), consequences ATT 1.04 (95% CI 0.19-1.89). No significant alcohol effects at any time point.","methodology":"Two cohorts of emerging adults from Hamilton, Ontario, and Memphis, Tennessee, were followed every 4 months from March 2018 to March 2020 (three pre-legalization, four post-legalization assessments). Doubly robust difference-in-differences estimation with propensity score balancing compared cannabis use frequency and consequences. Alcohol outcomes served as a control.","limitations":"Only two cities compared (Hamilton and Memphis), limiting generalizability. Pre-legalization period was short (3 waves). Follow-up ended March 2020 (start of COVID), precluding longer-term assessment. Cultural and economic differences between cities may not be fully captured by propensity matching."},{"rthcId":"RTHC-06361","title":"E-cigarette flavor and device preferences among US pregnant women who smoke: A latent class analysis.","authors":"Doherty, Emily A; Gregory, Kayleigh A; Lu, Yu; Dobbs, Page D","year":2025,"journal":"Tobacco prevention & cessation, 11","doi":"10.18332/tpc/204745","pmid":"40642760","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06362","title":"Daily patterns of single and poly-substance use among adolescent and young adult females: A day-level latent class analysis.","authors":"Doherty, Emily A; Moyers, Susette A; Crockett-Barbera, Erica K; Appleseth, Hannah; Leffingwell, Quinn; Richards, Veronica; Chiaf, Ashleigh L; Croff, Julie M","year":2025,"journal":"Addictive behaviors, 169, 108394","doi":"10.1016/j.addbeh.2025.108394","pmid":"40480140","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06363","title":"Substance use and early sexual initiation: a study among Brazilian school-aged adolescents.","authors":"Donaire Rapozero, Ana Laura; Perrotte, Giuliana; Pozzolo Pedro, Maria Olivia; Torales, Julio; Ventriglio, Antonio; Castaldelli-Maia, João Maurício","year":2025,"journal":"International review of psychiatry (Abingdon, England), 37(6-7), 651-660","doi":"10.1080/09540261.2025.2549792","pmid":"40886729","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06364","title":"Bioinformatics differential expression analysis of the effect of cannabidiol in chronic myeloid leukaemia cell line.","authors":"Donchev, Petar P; Danova, Svetla T","year":2025,"journal":"Global medical genetics, 12(4), 100076","doi":"10.1016/j.gmg.2025.100076","pmid":"41080716","tags":["cbd","cancer"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBD treatment at its IC50 (17.69 microM) induced 3,518 DEGs at 12 hours and 3,433 at 4 hours. Key changes included upregulation of metallothionein-regulated oxidative stress responses (MT1, MT2, SLC30A2) and p53-mediated apoptosis genes (TP53TG3, DDIT4, BBC3, CHAC1, NOXA1, DAPK2). Pathway enrichment identified type I interferon activation, PI3K-Akt-mTOR signaling, Toll-like receptor signaling, and alterations in lipid metabolism and mitochondrial homeostasis.","whyItMatters":"Chronic myeloid leukemia treated with tyrosine kinase inhibitors like imatinib can develop resistance. Understanding how CBD affects leukemia cells at the molecular level could identify complementary pathways to overcome resistance or enhance treatment effects.","specificNumbers":"CBD IC50: 17.69 microM. DEGs at 4 hours: 3,433. DEGs at 12 hours: 3,518. Key pathways: type I interferon, PI3K-Akt-mTOR, Toll-like receptor signaling. Key gene families: metallothioneins (MT1, MT2), p53 pathway (TP53TG3, DDIT4, BBC3, CHAC1, NOXA1, DAPK2).","methodology":"Imatinib-sensitive K-562S chronic myeloid leukemia cells were treated with CBD at its IC50 concentration (17.69 microM) for 4 and 12 hours. RNA sequencing was performed, and differentially expressed genes were identified and analyzed through pathway enrichment analysis.","limitations":"In vitro study in a single cell line (K-562S), which may not represent the heterogeneity of CML in patients. Only imatinib-sensitive cells were tested. The CBD concentration (IC50) may not be achievable in patient plasma. Transcriptomic changes do not necessarily translate to protein-level or functional effects."},{"rthcId":"RTHC-06365","title":"Early life stress and pubertal predictors of subsequent substance use in a national diverse sample of adolescents: Sex and substance type matter.","authors":"Donovan, Alexandra; Assari, Shervin; Grella, Christine; Shaheen, Magda; Richter, Linda; Friedman, Theodore C","year":2025,"journal":"Drug and alcohol dependence, 268, 112551","doi":"10.1016/j.drugalcdep.2025.112551","pmid":"39848135","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06366","title":"Beyond Infections: Exploring Immune-Mediated Pathways Linking Cannabis and Emerging Environmental Contaminants to Neurodevelopmental Outcomes.","authors":"Doolittle, Taylor; Duque-Wilckens, Natalia","year":2025,"journal":"Advances in experimental medicine and biology, 1477, 281-309","doi":"10.1007/978-3-031-89525-8_11","pmid":"40442391","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06367","title":"Mobile phone ownership, social media use, and substance use at ages 11-13 in the ABCD study.","authors":"Doran, Neal; Wade, Natasha E; Courtney, Kelly E; Sullivan, Ryan M; Jacobus, Joanna","year":2025,"journal":"Addictive behaviors, 161, 108211","doi":"10.1016/j.addbeh.2024.108211","pmid":"39520899","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06368","title":"New cannabidiol structure-related terpene N-acyl-hydrazones with potent antinociceptive and anti-inflammatory activity.","authors":"Dos Reis Rosa Franco, Graziella; Fernandes, Isabela Marie; de Souza, Mikaela Lucinda; Gontijo, Vanessa Silva; Alves, Marina Amaral; de Souza, Hygor Marcos Ribeiro; Do Invencio, Carla Gabriely Gaião; Lontra, Anna Carolina Pereira; de Paiva, João Pedro Barros; Dos Santos, Larissa Do Nascimento; da Silva, Ana Clara Machado; Giorno, Thaís Biondino Sardella; Guedes, Isabella Alvim; Dardenne, Laurent Emmanuel; Fernandes, Patrícia Dias; Viegas, Claudio","year":2025,"journal":"Future medicinal chemistry, 17(11), 1229-1240","doi":"10.1080/17568919.2025.2515821","pmid":"40521634","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06369","title":"Cannabidiol Modulates Brain Copper Homeostasis in Wild-Type-Like But Not Alzheimer's Disease Transgenic Female Mice: Implications for Neuroprotective Therapy.","authors":"Dosseto, Anthony; Tonge, Kaila; Karl, Tim","year":2025,"journal":"Molecular neurobiology, 63(1), 57","doi":"10.1007/s12035-025-05480-6","pmid":"41247623","tags":["cbd","neuroscience","seniors"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD elevated whole-brain copper in wild-type mice but not APP/PS1 transgenic mice. Zinc and iron did not differ significantly, though regional effect-size trends emerged for copper and zinc in the hippocampus. Correlation analysis revealed coordinated inter-regional metal regulation in healthy and vehicle-treated Alzheimer's mice, but this coordination was disrupted in CBD-treated Alzheimer's mice.","whyItMatters":"Disrupted metal homeostasis contributes to Alzheimer's pathology through amyloid-beta aggregation and oxidative stress. Understanding how CBD interacts with brain metals is crucial because copper and zinc are directly involved in amyloid plaque formation, and any treatment that alters their distribution could have either beneficial or harmful effects.","specificNumbers":"CBD significantly elevated whole-brain copper in WT mice. Regional differences in Cu and Zn patterns observed in hippocampus. CBD-treated WT mice showed increased variance in cerebellar copper. Coordinated inter-regional metal regulation was disrupted in CBD-treated APP/PS1 mice.","methodology":"Twelve-month-old female wild-type and APP/PS1 transgenic mice received chronic CBD or vehicle treatment. High-resolution laser ablation-inductively coupled plasma mass spectrometry (LA-ICP-MS) was used to map copper, zinc, and iron distributions across sagittal brain sections, analyzing regional patterns, correlations, and variability.","limitations":"Only female mice were studied. The Alzheimer's transgenic model does not fully replicate human disease. The functional significance of altered copper distribution is unclear. CBD dose and duration were specific to this study and may not translate to human dosing."},{"rthcId":"RTHC-06370","title":"Within-Person Bidirectional Relations Between Sleep Problems and Alcohol, Cannabis, and Co-Use Problems in a Representative U.S. Sample.","authors":"Drazdowski, Tess K; Kelly, Lourah; Livingston, Nicholas R; Sheidow, Ashli J; McCart, Michael R","year":2025,"journal":"Substance use & misuse, 60(12), 1923-1932","doi":"10.1080/10826084.2025.2523458","pmid":"40590136","tags":["sleep","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Individual-level alcohol and cannabis use problems were associated with lower likelihood of sleep problems in earlier waves but greater likelihood of sleep problems in later waves. Co-use problems and sleep problems were not related across time points. However, participants reporting co-use consistently reported more sleep problems than the general population.","whyItMatters":"Many adults use alcohol and cannabis specifically to help with sleep, but this longitudinal data suggests the relationship reverses over time: what initially seems helpful eventually becomes associated with worse sleep. This temporal pattern could explain why people keep using substances for sleep despite worsening outcomes.","specificNumbers":"26,072 adults across 4 waves (2013-2018). Alcohol and cannabis problems predicted lower sleep problems in earlier waves. Both predicted higher sleep problems in later waves. Co-users consistently had more sleep problems than the general population regardless of time point.","methodology":"Secondary analysis of nationally representative adults (N=26,072 unweighted) from the first four waves (2013-2018) of the PATH Study. Three random intercept cross-lagged panel models investigated within-person bidirectional relations between sleep problems and alcohol problems, cannabis problems, and co-use problems.","limitations":"PATH Study focused on tobacco and health, so sleep and other substance measures may not be as detailed as dedicated studies. Within-person effects do not imply causation. Sleep problems were measured broadly and may capture various sleep disorders. Four waves over five years provide limited temporal resolution."},{"rthcId":"RTHC-06371","title":"In vivo and In vitro Crosstalk Among CBD, Aβ, and endocannabinoid system enzymes and receptors.","authors":"Duan, Fangyuan; Xiao, Dan; Wang, Jiayu; Li, Runze; Si, Xiaoyue; Lu, Weihong","year":2025,"journal":"European journal of pharmacology, 1000, 177720","doi":"10.1016/j.ejphar.2025.177720","pmid":"40350019","tags":["cbd","neuroscience","seniors"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD induced autophagy and apoptosis specifically in amyloid-beta-expressing cells via LC3B and Caspase-3 pathways, while producing side effects in non-pathological cells. Investigation of CB1 receptors and FAAH showed complex modulation depending on amyloid-beta presence. In C. elegans worm models, FAAH-1 involvement alleviated pharyngeal dysfunction and counteracted weight loss in amyloid-expressing strains.","whyItMatters":"The finding that CBD has different effects on healthy versus diseased cells is crucial for understanding both its therapeutic potential and safety. If CBD can selectively target amyloid-affected cells while potentially harming healthy ones, this has direct implications for dosing strategies and patient selection in Alzheimer's therapy development.","specificNumbers":"CBD induced autophagy via LC3B pathway and apoptosis via Caspase-3 in amyloid-beta-expressing cells. FAAH-1 alleviated pharyngeal dysfunction and counteracted weight loss in amyloid-expressing C. elegans. Effects on CB1 and FAAH differed based on amyloid-beta presence or absence.","methodology":"Multi-model approach combining pharmacological interventions, immunofluorescence imaging, flow cytometry, and biochemical assays. Effects of CBD on amyloid-beta 40 and 42 were examined, along with modulation of CB1 receptors and FAAH with and without amyloid expression. C. elegans (roundworm) models were used to validate in vivo effects.","limitations":"Cell culture and worm models are far from human Alzheimer's disease. The side effects in non-pathological cells raise safety concerns that need characterization. The specific CBD concentrations used may not be achievable in human brains. C. elegans do not have a true brain or amyloid plaques."},{"rthcId":"RTHC-06372","title":"Medical Cannabis and Psychological Well-Being in Illinois' Opioid Alternative Pilot Program.","authors":"Dubois, Cerina; Bobitt, Julie; Ding, Lei; Eurich, Dean T; Knapp, Ashley A; Jordan, Neil","year":2025,"journal":"American journal of preventive medicine, 69(3), 107941","doi":"10.1016/j.amepre.2025.107941","pmid":"40518058","tags":["medical-cannabis","pain","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Average psychological well-being was 3.18 out of 5 (good) across the full sample. Cannabis users scored 3.21 and non-users 3.12, a non-significant difference (p=0.18). Regular cannabis use (3+ times per week) also showed no significant association with psychological well-being.","whyItMatters":"As states create opioid alternative programs that include cannabis, understanding psychological impacts is essential. This null finding is reassuring: substituting cannabis for opioids in this program did not appear to worsen psychological well-being, though it did not clearly improve it either.","specificNumbers":"860 participants. Average age 47, 60% male, 67% of cannabis users had a disability. Well-being scores: users 3.21, non-users 3.12, p=0.18. No significant difference in sensitivity analysis of regular users vs non-users.","methodology":"Survey sent from February-July 2019 to enrollees in Illinois' Opioid Alternative Pilot Program. Cannabis users (n=626) were compared with non-users (n=234) on psychological well-being (1-5 scale). Backward stepwise regression models were used, with sensitivity analysis for regular use.","limitations":"Cross-sectional design cannot determine causation or change over time. Self-selection into cannabis use introduces bias. A single well-being measure (1-5 scale) may lack sensitivity. No baseline pre-program data available. Non-users in an opioid alternative program may have distinct characteristics."},{"rthcId":"RTHC-06373","title":"The association of medical cannabis use with quality of life in Illinois' opioid alternative pilot program.","authors":"Dubois, Cerina; Bobitt, Julie; Ding, Lei; Eurich, Dean T; Knapp, Ashley A; Jordan, Neil","year":2025,"journal":"Journal of epidemiology and population health, 73(1), 202803","doi":"10.1016/j.jeph.2024.202803","pmid":"39864303","tags":["medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Quality of life averaged 2.86 (between \"good\" and \"fair\") across the full sample, with no significant difference between non-users (2.85) and cannabis users (2.86, p=0.92). Logistic regression showed cannabis use within the past year was not significantly associated with quality of life (OR 1.33, 95% CI 0.85-2.08, p=0.21).","whyItMatters":"Quality of life is a key outcome for opioid alternative programs. The null finding, like the companion psychological well-being study, suggests cannabis substitution is neither dramatically beneficial nor harmful for overall quality of life, though the \"good to fair\" average across both groups indicates room for improvement.","specificNumbers":"860 participants. QoL: non-users 2.85, users 2.86, p=0.92. Logistic regression: OR 1.33 (95% CI 0.85-2.08, p=0.21). Average age 47, 60% male, 67% married.","methodology":"Same cohort as the psychological well-being study (RTHC-06372): survey of OAPP enrollees from February-July 2019. Cannabis users (n=626) vs non-users (n=234) were compared on quality of life using ordered logistic and backward stepwise regression.","limitations":"Same limitations as RTHC-06372: cross-sectional, self-selected, no baseline, limited sensitivity of a single QoL measure. Pain being a qualifying condition may have created a floor effect on quality of life that cannabis could not overcome."},{"rthcId":"RTHC-06374","title":"Obesogenic diet impairs memory consolidation via the hippocampal endocannabinoid system.","authors":"Ducourneau, Eva-Gunnel; Janthakhin, Yoottana; Oliveira da Cruz, José F; Artinian, Julien; Alfos, Serge; Helbling, Jean-Christophe; Matias, Isabelle; Bakoyiannis, Ioannis; N'Diaye, Mateo; Bosch-Bouju, Clémentine; Potier, Mylène; Bellocchio, Luigi; Busquets-Garcia, Arnau; Trifilieff, Pierre; Marsicano, Giovanni; Ferreira, Guillaume","year":2025,"journal":"Current biology : CB, 35(23), 5820-5830.e5","doi":"10.1016/j.cub.2025.10.049","pmid":"41237773","tags":["cognition","neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Obesogenic diet consumption impaired long-term object recognition memory, and this was prevented by post-training CB1 receptor blockade, which also normalized hippocampal overactivation. The diet potentiated hippocampal endocannabinoid levels and CB1 expression. Genetic deletion of CB1 from hippocampal glutamatergic neurons abolished diet-induced deficits. The diet enhanced hippocampal mTOR in a CB1-dependent manner, and mTOR inhibition rescued memory consolidation.","whyItMatters":"Obesity and unhealthy diets are linked to cognitive decline, but the mechanism has been unclear. This study identifies a specific pathway: diet overactivates the brain's endocannabinoid system, which in turn overactivates mTOR, impairing the hippocampus's ability to consolidate memories.","specificNumbers":"CB1 blockade after training prevented diet-induced memory impairment and normalized hippocampal cellular and synaptic overactivation. Diet increased hippocampal endocannabinoid levels and CB1 expression. Genetic CB1 deletion from hippocampal glutamatergic neurons abolished memory deficits. mTOR inhibition after training rescued memory consolidation.","methodology":"Male mice were fed an obesogenic or control diet. Object recognition memory was tested. Systemic and genetic CB1 manipulations were used to assess the endocannabinoid system's role. Hippocampal endocannabinoid levels, CB1 expression, cellular activation, synaptic activity, and mTOR pathway were measured. Published in Current Biology.","limitations":"Only male mice were studied. The object recognition task is one measure of memory and may not capture broader cognitive effects. The obesogenic diet is an extreme model that may not represent typical human dietary patterns. CB1 antagonists have known psychiatric risks in humans."},{"rthcId":"RTHC-06375","title":"Safety considerations for patients using cannabis.","authors":"Dugan, Sara E","year":2025,"journal":"The mental health clinician, 15(6), 267-274","doi":"10.9740/mhc.2025.12.267","pmid":"41358040","tags":["medical-cannabis","mental-health","cardiovascular","drug-interactions"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review identifies four major safety domains: (1) cannabis effects on mood symptoms beyond the well-known psychoactive effects, (2) associations with suicidal ideation that are still being uncovered, (3) cardiovascular system effects that extend beyond the central nervous system, and (4) clinically significant drug interactions that may affect patients on other medications.","whyItMatters":"With an increasing number of US states authorizing cannabis use, many healthcare providers lack knowledge about these safety concerns. This review provides a practical overview of risks that clinicians need to consider when caring for patients who use cannabis.","specificNumbers":"Four safety domains reviewed: mood symptoms, suicidality, cardiovascular effects, drug interactions. Cannabis is the most used federally illicit substance in the US.","methodology":"Narrative review synthesizing current evidence on cannabis safety across four domains: mood effects, suicidality, cardiovascular effects, and drug interactions, aimed at informing healthcare professionals as legal access expands.","limitations":"Narrative review without systematic methodology. Does not quantify the magnitude of each risk. May not capture the most recent evidence in rapidly evolving fields. Does not differentiate between THC and CBD safety profiles in detail."},{"rthcId":"RTHC-06376","title":"High potency cannabis flower use is associated with heavier consumption and risk for cannabis use disorder among young adults in California, United States.","authors":"Dunbar, Michael S; D'Amico, Elizabeth J; Seelam, Rachana; Davis, Jordan P; Pedersen, Eric R; Rodriguez, Anthony; Kilmer, Beau","year":2025,"journal":"Addiction (Abingdon, England), 120(11), 2329-2334","doi":"10.1111/add.70118","pmid":"41099091","tags":["potency","addiction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Each one-point increase in perceived THC potency was associated with 3.33 more use days per month, 0.13 more grams consumed per day, and 1.21 higher CUDIT-R (cannabis use disorder) scores. Nearly half (46.8%) of those who knew their flower potency reported using High or Very High THC flower. About 18.6% did not know their flower's potency.","whyItMatters":"A common argument in cannabis policy is that people will \"titrate\" their use of higher-potency products, using less to achieve the same effect. This study directly contradicts that assumption: higher potency was associated with more frequent use, more consumption, and more addiction symptoms, not less.","specificNumbers":"512 young adults. 46.8% used High/Very High THC flower. 18.6% did not know potency. Per potency point: +3.33 use days/month (p<0.0001), +0.13 grams/day (p<0.01), +1.21 CUDIT-R score (p<0.0001).","methodology":"Cross-sectional survey of 512 California young adults (mean age 25.9, 48% female) from a cohort study who reported past-month cannabis flower use. Self-reported perceived THC potency was examined against use frequency, quantity, and CUDIT-R scores using multivariable regression adjusting for demographics.","limitations":"Cross-sectional design cannot determine directionality: do people who are already heavier users seek out high-potency flower, or does high potency drive heavier use? Perceived potency may not match actual THC content. Self-reported use is subject to bias. California-specific sample may not generalize."},{"rthcId":"RTHC-06377","title":"Psychedelics and substance use disorder treatment.","authors":"DuPont, Caitlin M; Johnson, Matthew W","year":2025,"journal":"International review of neurobiology, 181, 305-327","doi":"10.1016/bs.irn.2025.03.005","pmid":"40541314","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06378","title":"Cannabis impacts female fertility as evidenced by an in vitro investigation and a case-control study.","authors":"Duval, Cyntia; Wyse, Brandon A; Fuchs Weizman, Noga; Kuznyetsova, Iryna; Madjunkova, Svetlana; Librach, Clifford L","year":2025,"journal":"Nature communications, 16(1), 8185","doi":"10.1038/s41467-025-63011-2","pmid":"40925892","tags":["pregnancy","sex-differences"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"In the clinical study, follicular fluid THC concentration was positively correlated with oocyte maturation, but THC-positive patients had significantly lower embryo euploid (chromosomally normal) rates than matched controls. In the lab, THC induced oocyte chromosome segregation errors, increased abnormal spindle morphology, and altered expression of genes involved in extracellular matrix remodeling, inflammation, and chromosome segregation.","whyItMatters":"This is the first study to directly examine THC's effects on human oocytes (eggs). The finding that THC causes chromosome segregation errors provides a biological mechanism for reduced fertility and potentially increased risk of chromosomally abnormal pregnancies in cannabis users.","specificNumbers":"THC-positive patients had significantly lower embryo euploid rates than matched controls. In vitro THC exposure increased chromosome segregation errors and abnormal spindle morphology. Gene expression changes in extracellular matrix remodeling, inflammation, and chromosome segregation pathways.","methodology":"Two-pronged approach: (1) Case-control study comparing fertility patients who tested positive for THC in follicular fluid with matched controls, examining oocyte maturation and embryo euploidy rates. (2) In vitro experiments exposing human oocytes to THC and measuring chromosome segregation, spindle morphology, and gene expression. Published in Nature Communications.","limitations":"The clinical component is a case-control study, not a randomized trial. THC exposure in the lab may not replicate the complexity of in vivo exposure. The sample size for the clinical study was not detailed in the abstract. Follicular fluid THC levels may not reflect chronic exposure patterns."},{"rthcId":"RTHC-06379","title":"Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection.","authors":"Dvorakova, Michaela; Mackie, Ken; Straiker, Alex","year":2025,"journal":"Pharmacological research, 212, 107606","doi":"10.1016/j.phrs.2025.107606","pmid":"39824373","tags":["neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Coincident activation of muscarinic acetylcholine receptors and endocannabinoid-mediated depolarization-induced suppression of excitation produced a ~40% inhibition of excitatory transmission lasting ~10 minutes. MCSE required both CB1 and muscarinic M3/M5 receptors for induction but only CB1 for maintenance. It required calcium release from internal stores and was absent in CB1 knockout neurons.","whyItMatters":"This discovery reveals a new form of coincidence detection in the brain: two signals must arrive simultaneously to produce an effect that neither causes alone. Since both acetylcholine and endocannabinoids are critical for learning and memory, this mechanism could explain how the brain precisely modulates information processing at specific synapses.","specificNumbers":"~40% inhibition of excitatory transmission. Duration: ~10 minutes. Blocked by CB1 and muscarinic M3/M5 antagonists. Once established, reversed by CB1 antagonist only (not muscarinic antagonist). Absent in CB1 receptor knockout neurons. Requires calcium release from internal stores.","methodology":"Cultured autaptic hippocampal neurons from mice were used to study synaptic plasticity. Electrophysiological recordings measured excitatory transmission with pharmacological manipulation of cannabinoid and muscarinic receptors. CB1 knockout neurons served as controls. Various agonists and antagonists were used to dissect the mechanism.","limitations":"Cultured autaptic neurons are a simplified model that may not reflect the complexity of intact brain circuits. Only hippocampal neurons were studied. The in vivo relevance of MCSE remains to be demonstrated. The specific conditions required for MCSE (coincident activation) may be rare in natural brain activity."},{"rthcId":"RTHC-06380","title":"Daily risk factors for using more alcohol and cannabis than intended: An examination of contextual and motivational risk factors among sexual minority women and gender diverse individuals.","authors":"Dyar, Christina; Curtis, Julia","year":2025,"journal":"Annals of LGBTQ public and population health","doi":"10.1891/lgbtq-2024-0031","pmid":"41536760","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06381","title":"When and for whom is enacted stigma associated with alcohol and cannabis use at the event level among sexual and gender minority older adults?","authors":"Dyar, Christina; Hales, Emily D S; Rhew, Isaac C; Morgan, Ethan","year":2025,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 39(7), 644-659","doi":"10.1037/adb0001086","pmid":"40658589","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06382","title":"Modes of cannabis use, frequency of use, and cannabis use problems: A latent profile analysis of modes of cannabis use.","authors":"Dyar, Christina; Green, Elise; Rhew, Isaac C","year":2025,"journal":"Addictive behaviors, 164, 108285","doi":"10.1016/j.addbeh.2025.108285","pmid":"39938141","tags":["harm-reduction","addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Four groups emerged: smoking (reference), vaping concentrates, edible use, and multiple modes. Edible users tended to use cannabis less frequently and reported fewer problems than smokers. Concentrate vapers experienced more problems and more frequent use at follow-up compared to smokers, controlling for baseline levels. Using multiple modes per day was not associated with frequency or problems.","whyItMatters":"Different cannabis products carry different risk profiles, and this study provides evidence that vaping concentrates may be particularly risky for developing problematic use patterns, while edible use appears to carry lower risk. This has practical implications for harm reduction messaging.","specificNumbers":"338 participants, ages 18-25. Four groups: smoking, vaping concentrates, edibles, multiple modes. Concentrate vapers: more problems and more frequent use at follow-up vs smokers. Edible users: less frequent use and fewer problems vs smokers. Multiple mode users: no difference from smokers.","methodology":"Latent profile analysis of 338 sexual minority women and gender diverse individuals (ages 18-25) who used cannabis. Groups were identified based on modes of use, then compared on cannabis use frequency and consequences using longitudinal data with baseline controls.","limitations":"Sample was limited to sexual minority women and gender diverse young adults, who may have different use patterns than other populations. Latent profile analysis groups are data-driven and may not replicate in other samples. Concentrate vaping group may have started with higher risk profiles."},{"rthcId":"RTHC-06383","title":"Risk Factors for Same-Day Co-Use of Alcohol and Marijuana: An Examination of General and Sexual and Gender Minority Specific Risk Factors.","authors":"Dyar, Christina","year":2025,"journal":"Substance use & misuse, 60(10), 1453-1462","doi":"10.1080/10826084.2025.2502101","pmid":"40346798","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06384","title":"Planned versus unplanned alcohol and cannabis use: Motivational and contextual correlates among sexual minority women and gender diverse individuals.","authors":"Dyar, Christina; Curtis, Julia; Fairlie, Anne M","year":2025,"journal":"Alcohol, clinical & experimental research, 49(3), 609-618","doi":"10.1111/acer.70000","pmid":"39887657","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06385","title":"Event-Level Differences in Quantity, Frequency, and Consequences of Cannabis Use by Modes of Use Among Sexual Minority Women and Gender Diverse Individuals.","authors":"Dyar, Christina; Green, Elise; Rhew, Isaac C; Lee, Christine M","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(5), 714-723","doi":"10.15288/jsad.24-00348","pmid":"39812471","tags":["harm-reduction","sex-differences","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"People who used edibles infrequently experienced more negative consequences from edibles compared to smoking, while frequent edible users did not show this difference.","whyItMatters":"Most cannabis research treats all consumption as equal, but this study shows that the effects of different modes depend on individual usage patterns, suggesting harm reduction advice should account for personal experience with each method.","specificNumbers":"338 participants completed daily assessments over 30 days. Six modes of use were tracked: smoking, vaping plant material, vaping concentrates, dabbing, edibles, and multiple modes.","methodology":"30-day ecological momentary assessment study with 338 sexual minority women and gender diverse young adults, tracking cannabis use events in real time across different consumption modes.","limitations":"The sample was limited to sexual minority women and gender diverse individuals assigned female at birth, so findings may not generalize to other populations. Self-reported data from daily assessments may be subject to recall bias."},{"rthcId":"RTHC-06386","title":"Medicinal cannabis for tics in adolescents with Tourette syndrome.","authors":"Eapen, Valsamma; Lin, Ping-I; Taylor, Kaitlyn; Chan, Eunice; Chay, Paul; Cranswick, Noel; Ka, Amy; Khan, Feroza; Payne, Jonathan M; Prakash, Chidambaram; Velalagan, Ramya; Efron, Daryl","year":2025,"journal":"BJPsych open, 11(4), e145","doi":"10.1192/bjo.2025.35","pmid":"40636988","tags":["medical-cannabis","youth","cbd"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Statistically significant improvements were observed in parent and clinician reports on tics, behavioral and emotional issues, and quality of life in adolescents treated with a THC:CBD formulation.","whyItMatters":"While medicinal cannabis has been studied in adults with Tourette syndrome, this is the first study in adolescents, a population where tics often cause the most distress and social difficulty.","specificNumbers":"Tic improvement was significant (p = 0.003). Quality of life improved per parent report (p = 0.027) and youth self-report (p = 0.032). Behavioral/emotional issues improved (p = 0.048). Most common side effects: tiredness and drowsiness.","methodology":"Open-label, single-arm trial in adolescents aged 12-18 years using a THC:CBD ratio of 10:15 mg/mL, with doses ranging from 5 to 20 mg/day based on body weight and response.","limitations":"Open-label design with no placebo control means improvement could reflect placebo effects or natural symptom fluctuation. Very small sample size limits statistical power."},{"rthcId":"RTHC-06387","title":"US State Recreational and Medical Cannabis Delivery Laws, 2024.","authors":"Ebling, Todd; Azagba, Sunday; Hall, Mark; Jensen, Jessica King","year":2025,"journal":"American journal of public health, 115(2), 178-190","doi":"10.2105/AJPH.2024.307874","pmid":"39541554","tags":["legalization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"States took markedly different approaches to cannabis delivery regulation, with some allowing only licensed dispensary delivery, others permitting caregiver delivery, and significant variation in licensing requirements.","whyItMatters":"Delivery access directly affects who can obtain cannabis, particularly for medical patients with mobility limitations or those in areas without nearby dispensaries.","specificNumbers":"14 states authorized recreational cannabis delivery. 26 states and DC permitted medical cannabis delivery. 12 states allowed medical delivery exclusively through caregivers.","methodology":"Comprehensive legal epidemiology review coding all state-level cannabis delivery policies as of July 1, 2024, across four regulatory categories.","limitations":"Legal snapshot as of July 2024 only; policies change rapidly. Does not assess how well delivery laws are implemented or enforced in practice."},{"rthcId":"RTHC-06388","title":"Cannabis use among adolescents and young adults in Germany: Study results and prevention measures offered by the Federal Institute of Public Health.","authors":"Eckhardt, Stephanie; Nitzsche, Anika; Orth, Boris","year":2025,"journal":"Journal of health monitoring, 10(3), e13458","doi":"10.25646/13458","pmid":"41104114","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among young women aged 18-25, past-year cannabis use more than doubled from 8.3% in 2008 to 19.4% in 2023. Among young men in the same age group, it rose from 14.8% to 26.9%.","whyItMatters":"Germany partially legalized cannabis in April 2024. These baseline data from before legalization are essential for measuring what changes, if any, legalization produces.","specificNumbers":"Young women 18-25: 8.3% (2008) to 19.4% (2023). Young men 18-25: 14.8% (2008) to 26.9% (2023). Adolescent rates remained relatively stable before legalization.","methodology":"Analysis of representative survey data from Germany's Federal Institute of Public Health, tracking 12-month cannabis prevalence from 2008 to 2023 among 12-17 and 18-25 year olds.","limitations":"Self-reported survey data may underestimate actual use. Data ends before legalization took effect, so no post-legalization comparisons are available yet."},{"rthcId":"RTHC-06389","title":"Patterns of medicinal cannabis prescriptions in diverse patient populations: a retrospective analysis.","authors":"Edni, Omer; Naamany, Eviatar; Izhakian, Shimon; Shiber, Shachaf","year":2025,"journal":"Journal of cannabis research, 7(1), 43","doi":"10.1186/s42238-025-00307-6","pmid":"40652292","tags":["medical-cannabis","sex-differences"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Patients with gastrointestinal conditions were prescribed the highest mean monthly cannabis dose (22.26g), while male patients received significantly higher doses (25.48g vs 17.32g) and higher THC content (14% vs 11.39%) compared to females.","whyItMatters":"Despite growing cannabis prescriptions worldwide, there is limited data on how prescribing patterns actually differ across conditions and patient demographics, making it harder to develop evidence-based guidelines.","specificNumbers":"263 patients analyzed. GI patients: 22.26g/month average. Males: 25.48g vs females: 17.32g. Male THC content: 14% vs female: 11.39%. Neurological patients had highest oil consumption at 31.75%.","methodology":"Retrospective analysis of 263 patients aged 30+ from a cannabis clinic at a tertiary hospital in Israel, categorized by neurological (n=63), rheumatological (n=106), and gastrointestinal (n=94) conditions.","limitations":"Single center in Israel with a relatively small sample. Patients aged 30+ only, excluding younger adults. Retrospective design cannot determine whether prescription differences reflect optimal treatment or prescriber bias."},{"rthcId":"RTHC-06390","title":"A Pilot Randomized Placebo-Controlled Crossover Trial of Medicinal Cannabis in Adolescents with Tourette Syndrome.","authors":"Efron, Daryl; Taylor, Kaitlyn; Chan, Eunice; Payne, Jonathan M; Prakash, Chidambaram; Lee, Katherine J; Cranswick, Noel; Lin, Ping-I Daniel; Eapen, Valsamma","year":2025,"journal":"Cannabis and cannabinoid research, 10(6), 702-709","doi":"10.1089/can.2024.0188","pmid":"40082070","tags":["medical-cannabis","youth","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Seven of ten randomized adolescents completed the full protocol. Three participants were rated much improved on medicinal cannabis compared to one on placebo. The most common adverse event was dizziness (67%).","whyItMatters":"This is the first placebo-controlled trial of medicinal cannabis for Tourette syndrome in adolescents. While too small to prove efficacy, it demonstrates that rigorous study of cannabis in this population is achievable.","specificNumbers":"10 adolescents randomized (mean age 14.8, 50% male). 7 completed the protocol. 2 discontinued due to adverse events. Dizziness in 67%. Study visit adherence: 100%. Questionnaire completion: 97.6%.","methodology":"Phase I/II double-blind, placebo-controlled crossover trial in 10 adolescents aged 12-18 with Tourette syndrome, using THC 10mg/mL and CBD 15mg/mL in oil, with 10-week treatment phases and 4-week washout.","limitations":"Only 10 participants, far too few for efficacy conclusions. Open-label dose titration within the crossover design. Two dropouts and one loss to follow-up further limit the small sample."},{"rthcId":"RTHC-06391","title":"Cannabis-Associated Emergencies in the Emergency Department.","authors":"Eichhorn, David; Schaper, Andreas; Iwersen-Bergmann, Stefanie; Ondruschka, Benjamin; Weber-Papen, Sabrina; Bernhard, Michael","year":2025,"journal":"Deutsches Arzteblatt international, 122(17), 467-471","doi":"10.3238/arztebl.m2025.0074","pmid":"40372976","tags":["legalization","psychosis","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"In Canada after legalization, cannabis use among those 15+ rose from 15% to 25%, and hospital admissions doubled from 15 to 32 per 100,000. Acute intoxication with anxiety and panic attacks was the most common emergency presentation.","whyItMatters":"Germany legalized cannabis use in 2024. Emergency physicians need to anticipate increased cannabis-related presentations and recognize conditions like cannabinoid hyperemesis syndrome, which can mimic other abdominal emergencies.","specificNumbers":"Canada post-legalization: cannabis use rose from 15% (2017) to 25% (2021). Hospital admissions doubled from 15/100,000 (2017) to 32/100,000 (2022). European cannabis use prevalence estimated at 8%.","methodology":"Narrative review of cannabis-related emergency trends from countries that have legalized, supplemented with descriptive data from Germany's Poison Control Center North.","limitations":"Narrative review without systematic search methodology. Cross-country comparisons may not account for cultural, regulatory, and healthcare system differences. German data is still preliminary."},{"rthcId":"RTHC-06392","title":"Regular cannabis use and promotive attitudes among diverse adolescents in the United States: The role of age and intersecting social positions.","authors":"Eisenberg, Marla E; Watson, Ryan J; Pieczykolan, Lauren L; Gower, Amy L","year":2025,"journal":"Drug and alcohol dependence, 276, 112851","doi":"10.1016/j.drugalcdep.2025.112851","pmid":"40914097","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"24.8% of 8th graders who identified as American Indian/Alaska Native or multiracial, gay/lesbian/bisexual/queer, and living in high poverty reported regular cannabis use, compared to 1.8% of 8th graders overall.","whyItMatters":"Prevention programs often treat all youth the same, but this study shows that cannabis use clusters dramatically at the intersection of multiple marginalized identities, suggesting targeted approaches are needed.","specificNumbers":"82,933 students surveyed. 3.8% reported regular use (3+ times in 30 days). 11th graders: 7.8%. 8th graders: 1.8% overall but 24.8% among the most marginalized subgroup. Attitudes were generally not supportive of use.","methodology":"Analysis of 82,933 8th, 9th, and 11th graders from the 2022 Minnesota Student Survey, using CHAID modeling to identify how combinations of five social positions related to cannabis use and attitudes.","limitations":"Cross-sectional survey from one US state cannot establish causation. Self-reported data may underestimate use. Small cell sizes for some intersectional subgroups limit precision."},{"rthcId":"RTHC-06393","title":"Distinct Adipocyte Responses to Δ9-Tetrahydrocannabinol (THC) Exposure Govern Hepatic Lipid Accumulation in an Obesogenic Setting.","authors":"Eitan, Adi; Gover, Ofer; Schwartz, Betty","year":2025,"journal":"International journal of molecular sciences, 26(18)","doi":"10.3390/ijms26188860","pmid":"41009428","tags":["neuroscience","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC produced a biphasic response in mature fat cells: initially increasing free fatty acid release, then improving fat storage by day 18 with smaller lipid droplets and enhanced lipid handling. Liver cell fat accumulation corresponded with the residual fatty acids in the fat cell environment.","whyItMatters":"The relationship between cannabis use and metabolic health is poorly understood. This study provides a cellular mechanism by which THC could influence fat distribution and liver fat, a key factor in metabolic disease.","specificNumbers":"THC concentration: 1 uM. Fat cells monitored from day 10 to day 18. By day 18, THC-treated cells showed enhanced lipid storage, smaller lipid droplets, and elevated stimulated lipolysis.","methodology":"In vitro study using 3T3-L1 preadipocytes differentiated in fatty acid-rich medium with THC (1 uM) or controls, with conditioned media applied to AML12 hepatocytes to assess downstream lipid uptake.","limitations":"Cell culture study only, not tested in living animals or humans. Single THC concentration tested. The obesogenic conditions used may not reflect typical physiological fatty acid levels."},{"rthcId":"RTHC-06394","title":"Quinazoline-2,4(1H,3H)-dione derivatives as new class of CB1 Agonists: A pharmacophore-based virtual screening workflow and drug discovery.","authors":"El Aissouq, Abdellah; Stitou, Mourad; Enneiymy, Mohamed; El Rhabori, Said; Zaitan, Hicham; Ouammou, Abdelkrim; Khalil, Fouad","year":2025,"journal":"F1000Research, 14, 1322","doi":"10.12688/f1000research.171433.2","pmid":"41480258","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06395","title":"Inhibition of an endocannabinoid catabolizing enzyme is a potential mechanism for the anxiolytic effect of chamomile.","authors":"El-Alfy, Abir T; Almeida, Kristine; Vaidya, Nidhi; Abourashed, Ehab A","year":2025,"journal":"Journal of ethnopharmacology, 353(Pt A), 120312","doi":"10.1016/j.jep.2025.120312","pmid":"40684820","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06396","title":"Cannabinoid Hyperemesis Syndrome: A Rare Cause of Severe Abdominal Pain and Hyperlactataemia.","authors":"Elbaghdady, Ahmad; Ahmed, Abdelnasser; Elmahdy, Ahmed","year":2025,"journal":"Cureus, 17(9), e92444","doi":"10.7759/cureus.92444","pmid":"41111845","tags":["harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The patient's lactate reached 6.1 mmol/L, a level indicating significant physiological stress, caused by severe dehydration and pain from intractable vomiting rather than from another underlying emergency.","whyItMatters":"Cannabinoid hyperemesis syndrome is increasingly recognized but can be missed when abdominal pain is the dominant symptom. The metabolic complications like lactic acidosis can trigger unnecessary invasive workups if CHS is not considered.","specificNumbers":"Lactate: 6.1 mmol/L (normal <2). Treatment included haloperidol and capsaicin. CHS prevalence is rising in correlation with increased cannabis use in the UK.","methodology":"Single case report with review of current evidence on cannabinoid hyperemesis syndrome pathophysiology, diagnostic criteria, and management strategies.","limitations":"Single case report cannot establish generalized patterns. Lactic acidosis in CHS may be uncommon and its frequency is unknown."},{"rthcId":"RTHC-06397","title":"The Pharmacokinetics and Pharmacodynamics of a Hemp-Derived \"Full-Spectrum\" Oral Cannabinoid Product with a 1:1 Ratio of Cannabidiol to Cannabidiolic Acid and Delta-9-Tetrahydrocannabinol to Delta-9-Tetrahydrocannabinolic Acid: A Double-Blind, Placebo-Controlled, Within-Subjects Human Laboratory Study.","authors":"Elder, Harrison J; Zamarripa, C Austin; Klausner, McKenna; Wakshlag, Joseph; Davis, Robert; Dresser, Beth; Kjaer, Christian; Weerts, Elise M; Vandrey, Ryan; Spindle, Tory R","year":2025,"journal":"Cannabis and cannabinoid research, 10(2), e299-e313","doi":"10.1089/can.2024.0187","pmid":"40040421","tags":["cbd","medical-cannabis","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CBDA and THCA achieved 19-25 times higher peak blood concentrations and reached peak levels up to twice as fast compared to CBD and THC. The highest dose (containing only 7.2mg THC) produced moderate cognitive impairment and subjective intoxication.","whyItMatters":"Most cannabinoid research focuses on decarboxylated forms (CBD, THC), but many commercial products contain raw acidic forms. The finding that CBDA absorbs far better than CBD could reshape how hemp products are formulated.","specificNumbers":"15 participants. At 4 mg/kg: CBD ~134.5mg, CBDA ~142.8mg, THC ~7.2mg, THCA ~5.3mg. CBDA peak concentration was 19-25x higher than CBD. Effects peaked 3-5 hours post-dose. Cannabinoids detectable at 48 hours.","methodology":"Double-blind, placebo-controlled, ascending-dose study in 15 healthy adults ingesting soft gels at approximately 1, 2, and 4 mg/kg total cannabinoids, with 8 hours of monitoring plus 24- and 48-hour blood draws.","limitations":"Small sample of 15 healthy adults. Ascending dose design (not fully randomized across doses) may introduce order effects. Results from a specific product formulation may not generalize to all hemp products."},{"rthcId":"RTHC-06398","title":"Relapse in substance-induced psychosis and associated risk factors. A Nationwide register-linkage study from Sweden.","authors":"Ellilä, Venla; Taipale, Heidi; Tiihonen, Jari; Mittendorfer-Rutz, Ellenor; Niemelä, Solja","year":2025,"journal":"Addiction (Abingdon, England), 120(7), 1422-1430","doi":"10.1111/add.70014","pmid":"39933995","tags":["psychosis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-induced psychosis carried a 2.42x higher risk of relapse compared to alcohol-induced psychosis. Overall, 20% of people with any substance-induced psychosis relapsed within 2 years, with a median time to relapse of 126 days.","whyItMatters":"Substance-induced psychosis is often treated as a one-time event, but this study shows that one in five people relapse within two years, with cannabis-related cases at particularly high risk. This has implications for follow-up care planning.","specificNumbers":"7,320 people studied. 20% (n=1,463) relapsed. Cannabis-induced: 25.7% relapse, HR 2.42. Multi-substance: 23.8% relapse, HR 1.81. Methamphetamine: 19.7% relapse, HR 1.49. 83.3% relapsed with the same substance type. Median relapse: 126 days.","methodology":"Population-based register study linking Swedish nationwide data for 7,320 people with first-time substance-induced psychosis between 2006 and 2016, with 2-year follow-up using multivariable Cox models.","limitations":"Register-based study cannot capture psychotic episodes not leading to hospitalization. Cannabis potency, frequency of use, and other contextual factors were not available in the registers."},{"rthcId":"RTHC-06399","title":"Changes in peripheral endocannabinoid levels in substance use disorders: a review of clinical evidence.","authors":"Elliott, Georgia O; Petrie, Gavin N; Kroll, Sara L; Roche, Daniel J O; Mayo, Leah M","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(2), 152-164","doi":"10.1080/00952990.2025.2456499","pmid":"40197861","tags":["addiction","neuroscience","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Across substance use disorders, anandamide (AEA) concentrations were usually elevated, while 2-AG was measured less often and showed mixed results. Cannabis use disorder specifically increased both AEA and 2-AG.","whyItMatters":"The endocannabinoid system is being explored as a treatment target for addiction. Understanding how chronic substance use disrupts this system provides the scientific basis for developing new therapies.","specificNumbers":"15 studies reviewed: 3 in alcohol use disorder, 3 in cannabis use disorder, 4 in cocaine use disorder, 1 in opioid use disorder, 4 across multiple SUDs. AEA was usually increased across most substance types.","methodology":"Comprehensive review of 15 studies assessing endocannabinoid ligand concentrations in people diagnosed with substance use disorders, searching EBSCO, PubMed, and Google Scholar through May 2024.","limitations":"Only 15 studies available, many with small samples and varying methodology. Peripheral blood levels may not reflect brain endocannabinoid levels. Treatment status and abstinence duration varied across studies."},{"rthcId":"RTHC-06400","title":"Full spectrum cannabis oil combined with omega-3 fish oil for neuropathic pain management: a novel therapeutic approach.","authors":"Elorriaga, Cristina F; Olivera, María E; Gongora Jara, Hugo; Laino, Carlos H","year":2025,"journal":"The Journal of pharmacy and pharmacology, 77(8), 1097-1108","doi":"10.1093/jpp/rgaf027","pmid":"40414709","tags":["cbd","pain","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Combined CBD-cannabis oil and omega-3 treatment effectively prevented both thermal and mechanical hypersensitivity in nerve-injured rats, while also improving motor impairment and showing protective effects against nerve degeneration on histological analysis.","whyItMatters":"Current neuropathic pain medications have limited efficacy and significant side effects. If the synergy between CBD and omega-3 translates to humans, it could offer a more tolerable treatment approach.","specificNumbers":"The combination treatment prevented thermal and mechanical hypersensitivity, improved motor impairment from peripheral neuropathy, and showed histological evidence of nerve protection against degeneration from chronic constriction injury.","methodology":"Rat study using the hot plate test for acute pain and chronic constriction injury model for neuropathic pain, with walking track analysis and rotarod test for functional assessment, plus histological examination of sciatic nerves.","limitations":"Animal study only, with no human data. The specific CBD:THC ratio and omega-3 doses used may not translate directly to human dosing. Prevention of pain in a surgical model differs from treating established chronic pain."},{"rthcId":"RTHC-06401","title":"Cannabis use and binge eating among young adults: The role of depressive symptoms.","authors":"Elran-Barak, Roni; Sznitman, Sharon; Eisenberg, Marla E; Zhang, Lydia; Wall, Melanie M; Neumark-Sztainer, Dianne","year":2025,"journal":"Journal of psychiatric research, 181, 553-559","doi":"10.1016/j.jpsychires.2024.12.015","pmid":"39708771","tags":["appetite","mental-health","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Female cannabis users had a 24% binge eating rate compared to 13% among non-users (p<0.001). This association remained significant after controlling for depressive symptoms, sociodemographics, and BMI. No significant association was found among males.","whyItMatters":"As cannabis becomes more accessible, understanding its relationship with disordered eating is important, particularly since binge eating is already more prevalent among women. The independence from depression suggests a distinct pathway.","specificNumbers":"1,568 participants. 27% of females and 33% of males used cannabis. Binge eating in female users: 24% vs 13% in non-users (p<0.001). Male users: 5.5% vs 8.2% (not significant, p=0.2).","methodology":"Cross-sectional survey of 1,568 emerging adults (mean age 22.2, 53% female) from the EAT 2010-2018 longitudinal study, with gender-stratified regression models.","limitations":"Cross-sectional design cannot determine whether cannabis use causes binge eating or vice versa. Self-reported measures for both cannabis use and binge eating. Single metropolitan area sample may limit generalizability."},{"rthcId":"RTHC-06402","title":"The use of cannabidiol in patients with Lennox-Gastaut syndrome and Dravet syndrome in the UK Early Access Program: A retrospective chart review study.","authors":"Eltze, Christin; Alshehhi, Shaikha; Ghfeli, Aisha Al; Vyas, Kishan; Saravanai-Prabu, Seeta; Gusto, Gaelle; Khachatryan, Artak; Martinez, Marta; Desurkar, Archana","year":2025,"journal":"Epilepsy & behavior reports, 29, 100731","doi":"10.1016/j.ebr.2024.100731","pmid":"39898301","tags":["cbd","epilepsy","youth","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"At 12 months, median motor seizure reduction was 60%, with 67% of patients achieving at least 50% reduction and 40% achieving at least 75% reduction. The 12-month retention rate was 74%.","whyItMatters":"Lennox-Gastaut and Dravet syndromes are among the most treatment-resistant epilepsies in children. Real-world data from early access programs complements clinical trial evidence by showing how treatments perform in routine practice.","specificNumbers":"26 patients enrolled (mean age 11.8 years). Median CBD dose at 12 months: 7.3 mg/kg/day. Seizure reduction: 56.7% at 6 months, 60% at 12 months. 50% responder rate: 65% at 6M, 67% at 12M. GI side effects most common.","methodology":"Retrospective chart review of 26 patients aged 2-17 with LGS (n=17) or Dravet syndrome (n=9) treated with plant-derived CBD (Epidyolex) in the UK Early Access Program, tracked for up to 12 months.","limitations":"Small sample (26 patients) with no control group. Retrospective design with 27% lost to follow-up at 12 months. Missing data for some timepoints limits completeness."},{"rthcId":"RTHC-06403","title":"Rethinking Alzheimer's: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control.","authors":"Emami Naeini, Sahar; Bhandari, Bidhan; Hill, Breanna; Perez-Morales, Nayeli; Rogers, Hannah M; Khodadadi, Hesam; Young, Nancy; Maciel, Lívia Maria; Yu, Jack C; Hess, David C; Morgan, John C; Lopes Salles, Évila; Wang, Lei P; Baban, Babak","year":2025,"journal":"eNeuro, 12(10)","doi":"10.1523/ENEURO.0114-25.2025","pmid":"41052930","tags":["cbd","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD treatment reduced both IDO and cGAS expression in the brains of 5XFAD Alzheimer's mice, with corresponding decreases in TNF-alpha, IL-1beta, and IFN-gamma. Bioinformatics identified AKT1, TRPV1, and GPR55 as potential molecular targets.","whyItMatters":"Alzheimer's research has increasingly recognized neuroinflammation as a driver of disease progression beyond amyloid plaques. Identifying that CBD simultaneously targets two distinct inflammatory pathways offers a mechanistic basis for further investigation.","specificNumbers":"CBD significantly reduced IDO and cGAS expression. Proinflammatory cytokines TNF-alpha, IL-1beta, and IFN-gamma all decreased. Three molecular targets identified: AKT1 (cell survival signaling), TRPV1 (neuroinflammation), GPR55 (immune cell activation).","methodology":"5XFAD transgenic Alzheimer's mouse model treated with inhaled CBD. Outcomes measured by flow cytometry, immunofluorescence, gene expression analysis, and STRING-based bioinformatics for target identification.","limitations":"Mouse model only, using a transgenic strain that overexpresses Alzheimer's mutations not typical of most human cases. Inhaled CBD dosing in mice may not translate to human administration. Bioinformatics predictions of molecular targets need experimental validation."},{"rthcId":"RTHC-06404","title":"Stress reactivity is modulated by cannabinoid type-1 receptors in norepinephrine and epinephrine neurons in a context-dependent manner.","authors":"Engborg, Christopher B; Pujar, Manaswini; Kanadia, Rahul N; Sciolino, Natale R","year":2025,"journal":"Neuroscience, 585, 14-27","doi":"10.1016/j.neuroscience.2025.08.046","pmid":"40885375","tags":["neuroscience","anxiety"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice lacking CB1 receptors in NE/E neurons showed reduced avoidance after restraint stress, increased escape behavior to visual threats, and reduced immobility in forced swim, but normal baseline anxiety and unchanged heart rate responses to foot shock.","whyItMatters":"This is the first study to characterize where the CB1 receptor gene is expressed across brainstem catecholamine populations and to show that its function in these cells is context-dependent, meaning the same receptor system can produce different effects depending on the type of stress.","specificNumbers":"CB1 was broadly expressed in medullary C1/A1 and C2/A2 neurons and sparsely in the locus coeruleus. Knockout mice showed reduced open field avoidance after restraint stress, increased escape across trials to looming threats, and reduced forced swim immobility.","methodology":"Conditional knockout mouse model with CB1 receptor gene selectively deleted from dopamine beta-hydroxylase-expressing cells, assessed across multiple behavioral tests and stress paradigms with physiological monitoring.","limitations":"Mouse behavioral models have limited translation to human stress responses. Constitutive knockout means the receptor was absent throughout development, which may trigger compensatory changes. Only male mice were used."},{"rthcId":"RTHC-06405","title":"Cannabidiol in Foods and Food Supplements: Evaluation of Health Risks and Health Claims.","authors":"Engeli, Barbara E; Lachenmeier, Dirk W; Diel, Patrick; Guth, Sabine; Villar Fernandez, Maria A; Roth, Angelika; Lampen, Alfonso; Cartus, Alexander T; Wätjen, Wim; Hengstler, Jan G; Mally, Angela","year":2025,"journal":"Nutrients, 17(3)","doi":"10.3390/nu17030489","pmid":"39940347","tags":["cbd","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The lowest dose tested in humans that caused adverse effects (liver enzyme elevations) was 4.3 mg/kg/day, and this level can easily be reached by following the dosage recommendations on commercially available CBD oil products.","whyItMatters":"Despite having no Novel Food authorization in the EU, CBD products are widely sold with health claims. This review suggests consumers may be reaching harmful doses while getting no proven benefit.","specificNumbers":"LOAEL for liver toxicity: 4.3 mg/kg bw/day (healthy volunteers, 3-4 weeks). This level is reachable with 30 drops of 20% CBD oil. No NOAEL could be established because lower doses were not tested. No health claims substantiated at or below the LOAEL.","methodology":"Expert review by Germany's Permanent Senate Commission on Food Safety evaluating available data on CBD's adverse effects and potential health benefits at food-relevant doses.","limitations":"The LOAEL was based on limited human studies. Lower doses were not tested, so a safe threshold could not be established. The review focused on food-relevant doses, not pharmaceutical CBD (Epidyolex) which uses much higher doses."},{"rthcId":"RTHC-06406","title":"Behavioral Decoding Reveals Cortical Endocannabinoid Potentiation during Δ9-THC Impairment.","authors":"English, Anthony; Marcus, David; Yadav, Khushi; Elkhouly, Yassin; Levy, Allan; Corbit, Victoria; Ask, Maddie; Scedberg, Anika; Poces-Ball, Jordan; Uittenbogaard, Fleur; Simons, Rayna; Witten, Ilana; Zweifel, Larry; Land, Benjamin; Stella, Nephi; Bruchas, Michael R","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.09.26.678874","pmid":"41040173","tags":["neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC increased GABAergic (inhibitory) neuron activity in the medial prefrontal cortex before movement initiation, shifting the excitatory/inhibitory balance. Unexpectedly, THC also induced a transient, movement-triggered potentiation of endocannabinoid release that further disrupted motor behavior.","whyItMatters":"Cannabis impairment is well known but poorly understood at the neural circuit level. This study identifies a specific mechanism in the prefrontal cortex and reveals that THC paradoxically triggers the brain's own cannabinoid system to amplify impairment.","specificNumbers":"THC was infused directly into the medial prefrontal cortex. Machine learning classified discrete walking kinematic features. THC predominantly increased GABAergic activity preceding walk initiation. Movement-locked endocannabinoid release was time-locked and transient.","methodology":"Machine learning behavioral classification of mouse movements combined with fiber photometry, optogenetics, and endocannabinoid biosensors to measure neural activity and eCB dynamics in the medial prefrontal cortex during THC exposure.","limitations":"Preprint (not yet peer-reviewed). Direct brain infusion of THC does not replicate normal cannabis consumption routes. Mouse motor behavior may not fully translate to human impairment patterns."},{"rthcId":"RTHC-06407","title":"Associations Between Evolving Cannabis Policies and Cannabis-Related School Discipline Among Secondary School Students in Massachusetts, 2005-2019.","authors":"English, Faith; Laws, Holly B; Yi, Youngmin; Martínez, Airín D; Bertone-Johnson, Elizabeth; Whitehill, Jennifer M","year":2025,"journal":"American journal of preventive medicine, 70(4), 108129","doi":"10.1016/j.amepre.2025.108129","pmid":"40997963","tags":["legalization","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Decriminalization was associated with a 34% increase in cannabis-related disciplinary incidents in schools. However, medical legalization reversed this trend with a 45% decrease, and recreational legalization produced a further 20% decrease compared to the prior policy period.","whyItMatters":"There is widespread concern that cannabis legalization will increase youth problems in schools. This study suggests the opposite occurred in Massachusetts, with discipline rates declining as policies expanded.","specificNumbers":"Decriminalization (2008-2011): 34% increase (IRR 1.34). Medical legalization (2012-2015): 45% decrease (IRR 0.55). Recreational legalization (2016-2019): 20% decrease (IRR 0.80). Average incidents per district: 4.6, 4.7, and 5.1 across the three periods.","methodology":"Multilevel time-series analysis of 2005-2019 data from all 399 Massachusetts public school districts, examining cannabis-related disciplinary incidents per 1,000 students across three policy periods.","limitations":"Observational study cannot prove policy changes caused the discipline trends. Discipline practices may have shifted independently of cannabis policy. Data does not capture actual cannabis use, only disciplinary responses."},{"rthcId":"RTHC-06408","title":"Synthetic cannabinoid CUMYL-4CN-BINACA induces oxidative stress, ER stress, and apoptosis in brain and testicular tissues of male albino rats.","authors":"Eren Demir, Erdem; Gur, Cihan; Sisman, Turgay; Lafzi, Ayse; Aksakal, Özkan","year":2025,"journal":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 204, 115617","doi":"10.1016/j.fct.2025.115617","pmid":"40618914","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Subacute exposure produced dose-dependent increases in oxidative damage markers and decreases in antioxidant defenses across both organs. Brain inflammation markers (TNF-alpha, IL-6, IL-1beta, NF-kB) were significantly elevated, while CB1 and CB2 receptor expression increased in both tissues.","whyItMatters":"CUMYL-4CN-BINACA is frequently identified in forensic toxicology cases but its mechanism of toxicity has been poorly understood. This study reveals multi-organ damage through oxidative stress and inflammation even at relatively low doses.","specificNumbers":"Doses: 0.25, 0.5, and 1 mg/kg/day for 14 days. Dose-dependent increase in MDA (oxidative damage). Dose-dependent reduction in GSH, SOD, CAT, and GPx (antioxidant defenses). Upregulation of apoptosis markers Bax and caspase-3. CB1 and CB2 receptor expression increased in both brain and testis.","methodology":"Male albino rats received 0.25, 0.5, or 1 mg/kg/day of CUMYL-4CN-BINACA intraperitoneally for 14 days, with assessment of oxidative stress, ER stress, inflammation, and apoptosis markers in brain and testis.","limitations":"Animal study with intraperitoneal dosing rather than typical human routes (inhalation). Short 14-day exposure may not capture chronic effects. Only male rats studied."},{"rthcId":"RTHC-06409","title":"Association of e-cigarette use, psychological distress, and substance use: Insights from the All of Us Research Program.","authors":"Erhabor, John; Yao, Zhiqi; Tasdighi, Erfan; Shahawy, Omar El; Benjamin, Emelia J; Bhatnagar, Aruni; Blaha, Michael J","year":2025,"journal":"Addictive behaviors, 166, 108322","doi":"10.1016/j.addbeh.2025.108322","pmid":"40112576","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06410","title":"Cannabis Use and Analgesic Prescribing in UK Primary Care: A Retrospective Cohort Study of Patients with Osteoarthritis.","authors":"Erridge, Simon; Chandan, Joht Singh; Gokhale, Krishna M; Billinghurst, Christian; Sodergren, Mikael H","year":2025,"journal":"Medicines (Basel, Switzerland), 12(4)","doi":"10.3390/medicines12040027","pmid":"41283337","tags":["medical-cannabis","pain"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-exposed osteoarthritis patients had a 2.06x higher hazard of being prescribed opioids compared to matched unexposed patients. They were also more likely to receive prescriptions for other analgesics and had higher mortality.","whyItMatters":"Some advocates claim cannabis reduces opioid use, but this real-world UK data shows the opposite association. However, the finding likely reflects confounding: patients with coded cannabis use may have more complex pain or socioeconomic disadvantage.","specificNumbers":"662 exposed matched to 1,319 unexposed. Opioid prescribing HR: 2.06 (95% CI 1.74-2.43). Cannabis-exposed group also had higher mortality. Cannabis use recording is rare relative to actual prevalence in the general population.","methodology":"Population-based retrospective cohort using UK Clinical Practice Research Datalink (1995-2023), matching 662 opioid-naive osteoarthritis patients with coded cannabis exposure to 1,319 unexposed patients by age, sex, smoking status, and health authority.","limitations":"Cannabis exposure was based on medical record coding, which likely captures problematic use or use disclosed during clinical encounters rather than typical recreational use. Substantial confounding by socioeconomic status and severity is likely."},{"rthcId":"RTHC-06411","title":"Cannabidiol induces autophagy via CB1 receptor and reduces α-synuclein cytosolic levels.","authors":"Erustes, Adolfo G; Abílio, Vanessa C; Bincoletto, Claudia; Piacentini, Mauro; Pereira, Gustavo J S; Smaili, Soraya S","year":2025,"journal":"Brain research, 1850, 149414","doi":"10.1016/j.brainres.2024.149414","pmid":"39710053","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD enhanced autophagic flux (increased LC3-II accumulation and GFP-LC3-positive vesicles) and reduced cytosolic alpha-synuclein in neuroblastoma cells. Both effects were blocked by a CB1 receptor antagonist, confirming receptor-mediated action.","whyItMatters":"Alpha-synuclein accumulation is a hallmark of Parkinson's disease. Finding that CBD can promote its clearance through autophagy, and identifying the specific receptor involved, provides a potential therapeutic target.","specificNumbers":"CBD increased LC3-II and GFP-LC3-positive vesicle accumulation (markers of enhanced autophagy). Cytosolic alpha-synuclein levels were reduced. A CB1-selective antagonist blocked both effects.","methodology":"In vitro study using a neuroblastoma cell line overexpressing wild-type alpha-synuclein, treated with CBD and assessed for autophagy markers and alpha-synuclein levels, with CB1 receptor antagonist controls.","limitations":"Cell line study only, using a neuroblastoma line engineered to overexpress alpha-synuclein. Does not replicate the complex brain environment of Parkinson's disease. CBD acting via CB1 is somewhat surprising given its typically low CB1 affinity."},{"rthcId":"RTHC-06412","title":"Cannabidiol Extracted from Cannabis sativa L. Plant Shows Neuroprotective Impacts Against 6-HODA-Induced Neurotoxicity via Nrf2 Signal Transduction Pathway.","authors":"Esfandi, Afsaneh; Mehrafarin, Ali; Kalateh Jari, Sepideh; Naghdi Badi, Hassanali; Larijani, Kambiz","year":2025,"journal":"Iranian journal of pharmaceutical research : IJPR, 24(1), e160499","doi":"10.5812/ijpr-160499","pmid":"40718446","tags":["cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD increased cell survival, decreased apoptosis, reduced reactive oxygen species and lipid peroxidation, and improved antioxidant capacity in 6-OHDA-exposed cells. These effects were mediated through upregulation of the Nrf2 pathway and anti-apoptotic Bcl-2, with suppression of pro-apoptotic Bax and caspase-3.","whyItMatters":"The Nrf2 pathway is a master regulator of cellular antioxidant defenses. Demonstrating that CBD activates this pathway to protect against a Parkinson's-relevant toxin adds mechanistic support to CBD's neuroprotective potential.","specificNumbers":"CBD augmented cell viability and decreased apoptosis in 6-OHDA-exposed cells. ROS and MDA (lipid peroxidation) decreased. SOD and GSH activities improved. Nrf2 and Bcl-2 genes upregulated. Bax and caspase-3 downregulated.","methodology":"In vitro study extracting CBD from hemp plant and treating PC12 cells at various doses before exposure to 6-OHDA, a neurotoxin used to model Parkinson's disease. Measured cell viability, apoptosis, ROS, antioxidant markers, and gene expression.","limitations":"Cell culture study using a transformed cell line, not primary neurons. 6-OHDA toxicity is a simplified model that does not capture the full complexity of Parkinson's disease progression."},{"rthcId":"RTHC-06413","title":"Cannabidiol in pancreatic ductal adenocarcinoma: preclinical evidence, molecular mechanisms, and translational challenges.","authors":"Esmaeli, Mojtaba; Dehghanpour Dehabadi, Maryam; Khaleghi, Ali Asghar","year":2025,"journal":"Cancer cell international, 25(1), 415","doi":"10.1186/s12935-025-04062-9","pmid":"41257868","tags":["cbd","cancer"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"CBD exhibited antitumor properties through ER stress and apoptosis (via CerS1), GPR55/MAPK inhibition, immune modulation, and chemosensitization to gemcitabine. Combination therapies with other cannabinoids or chemotherapeutics enhanced outcomes in preclinical models.","whyItMatters":"Pancreatic cancer has the worst survival rate of any common cancer and desperately needs new treatment approaches. CBD's ability to attack tumor cells through multiple pathways and sensitize them to chemotherapy warrants further investigation.","specificNumbers":"15 studies met inclusion criteria. CBD pathways identified: CerS1-mediated ER stress, GPR55/MAPK inhibition, immune modulation, gemcitabine chemosensitization. Combination therapies outperformed CBD alone in preclinical models.","methodology":"Systematic review of PubMed, Scopus, Web of Science, EMBASE, and Google Scholar (2006-2025), including 15 studies examining CBD's effects on pancreatic ductal adenocarcinoma in vitro, in vivo, and clinical contexts.","limitations":"Almost entirely preclinical evidence. No controlled clinical trials exist. CBD doses used in lab studies may not be achievable in patients. Publication bias may favor positive preclinical results."},{"rthcId":"RTHC-06414","title":"The potential role of cannabidiol (CBD) in lung cancer therapy: a systematic review of preclinical and clinical evidence.","authors":"Esmaeli, Mojtaba; Dehghanpour Dehabadi, Maryam","year":2025,"journal":"Cancer cell international, 25(1), 369","doi":"10.1186/s12935-025-04010-7","pmid":"41126219","tags":["cbd","cancer"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"CBD induced apoptosis through PPAR-gamma activation, mitochondrial dysfunction, and oxidative stress. It inhibited epithelial-to-mesenchymal transition (a driver of metastasis) and enhanced CD8+ T cell and NK cell activity. CBD showed synergy with cisplatin and radiotherapy.","whyItMatters":"Lung cancer remains the leading cause of cancer death worldwide. CBD's ability to enhance existing therapies while potentially reducing treatment resistance addresses two major challenges in lung cancer treatment.","specificNumbers":"19 studies included. CBD concentrations: 1-10 uM in cell studies, 200-600 mg/day in human cases. 13 in vitro, 4 animal, 2 clinical reports. CBD enhanced CD8+ T cell and NK cell activity in the tumor microenvironment.","methodology":"Systematic review following PRISMA guidelines, searching PubMed, Scopus, Web of Science, and Google Scholar for studies from 2007-2025. Included 13 in vitro, 4 in vivo, and 2 clinical reports on CBD in lung cancer.","limitations":"Primarily preclinical data. Only 2 clinical reports, not controlled trials. CBD doses used in cell studies may not translate to achievable human concentrations. Risk of publication bias in preclinical cancer research."},{"rthcId":"RTHC-06415","title":"Cannabidiol (CBD) as a potential therapeutic agent for liver cancer: a comprehensive review of current evidence.","authors":"Esmaeli, Mojtaba; Dehghanpour Dehabadi, Maryam","year":2025,"journal":"Cancer cell international, 25(1), 215","doi":"10.1186/s12935-025-03870-3","pmid":"40533744","tags":["cbd","cancer"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"CBD induced pyroptosis (inflammatory cell death) via caspase-3/GSDME, modulated autophagy by inhibiting the PI3K/Akt/mTOR pathway, and sensitized liver cancer cells to both sorafenib and cabozantinib.","whyItMatters":"Liver cancer is a major global cause of cancer death with limited treatment options. Sorafenib resistance is common, so finding that CBD can resensitize cancer cells to this drug addresses a critical clinical problem.","specificNumbers":"16 studies included. CBD mechanisms: pyroptosis via caspase-3/GSDME, autophagy via PI3K/Akt/mTOR inhibition, chemosensitization to sorafenib and cabozantinib. Clinical studies remain limited.","methodology":"Systematic review searching PubMed, Scopus, Web of Science, and Google Scholar through March 2025, identifying 16 relevant studies including in vitro, in vivo, and clinical investigations of CBD in hepatocellular carcinoma.","limitations":"Predominantly preclinical evidence. CBD's known potential for hepatotoxicity is a particular concern for liver cancer applications. Bioavailability challenges may limit achievable tumor concentrations."},{"rthcId":"RTHC-06416","title":"Targeting Gastrointestinal Cancers with Cannabidiol: Mechanisms, Challenges, and Therapeutic Implications.","authors":"Esmaeli, Mojtaba; Dehghanpour Dehabadi, Maryam","year":2025,"journal":"Medical oncology (Northwood, London, England), 42(7), 237","doi":"10.1007/s12032-025-02790-6","pmid":"40461928","tags":["cbd","cancer"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"CBD modulated multiple molecular pathways relevant to GI cancers, including inducing apoptosis and cell cycle arrest, inhibiting new blood vessel formation, reducing inflammation, and potentially enhancing chemotherapy effectiveness and overcoming drug resistance.","whyItMatters":"Gastrointestinal cancers are among the most common and deadly cancers globally. CBD's multi-target approach and potential to overcome treatment resistance address key challenges in GI oncology.","specificNumbers":"CBD mechanisms in GI cancers included: apoptosis induction, cell cycle arrest, angiogenesis inhibition, inflammation reduction, and chemosensitization. Focus on gastric and colorectal cancer models.","methodology":"Systematic review examining preclinical and early clinical evidence on CBD in gastric and colorectal cancers, analyzing molecular pathways and therapeutic potential.","limitations":"Primarily preclinical evidence. Translation from lab to clinic faces bioavailability, dosing, and regulatory challenges. CBD's GI side effects could complicate treatment of GI cancers specifically."},{"rthcId":"RTHC-06417","title":"The Inhibition of Fatty Acid Amide Hydrolase-4 Affords Neuroprotection in a Toxic Model Induced by 6-Hydroxydopamine in Caenorhabditis elegans Nematodes.","authors":"Estrada-Valencia, Rubén; Túnez, Isaac; Tinkov, Alexey A; Aschner, Michael; López-Goerne, Tessy; Pedraza-Chaverrí, José; Santamaría, Abel","year":2025,"journal":"Molecular neurobiology, 62(10), 12984-12999","doi":"10.1007/s12035-025-05104-z","pmid":"40465065","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The FAAH-4 inhibitor JZL184 protected dopaminergic neurons from 6-OHDA damage, increased worm survival, and improved food-seeking behavior. A FAAH-4 knockout strain confirmed this protection. The mechanism involved 2-AG-mediated antioxidant responses through gst-4 gene upregulation.","whyItMatters":"The endocannabinoid system is conserved from worms to humans. Finding that endocannabinoid-boosting strategies protect dopamine neurons in a simple organism suggests this pathway has ancient neuroprotective functions worth exploring for Parkinson's.","specificNumbers":"Anandamide (1-100 uM): no protection. JZL184 (50 uM): protected dopaminergic neurons, increased survival, improved food seeking. FAAH-4 knockout worms were more resistant to 6-OHDA. Both JZL184 and 2-AG (1-100 uM) reduced ROS at 24 hours.","methodology":"C. elegans nematode study testing anandamide (1-100 uM) and the FAAH-4 inhibitor JZL184 against 6-OHDA-induced neuronal damage, with genetic confirmation using a faah-4 knockout strain and antioxidant reporter strain.","limitations":"C. elegans is an extremely simple organism compared to the human brain. The jump from worm neuroprotection to human Parkinson's treatment is enormous. JZL184 affects multiple enzymes, not just FAAH-4."},{"rthcId":"RTHC-06418","title":"ATTITUDES AND PRACTICE PATTERNS OF CANADIAN PHYSIATRISTS REGARDING MEDICAL CANNABIS.","authors":"Ethans, Karen; Chaudhary, Harpal; Casey, Alan; O'Connell, Colleen; Nankar, Mayur; Khandelwal, Avni","year":2025,"journal":"Journal of rehabilitation medicine. Clinical communications, 8, 43254","doi":"10.2340/jrm-cc.v8.43254","pmid":"41356262","tags":["medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Most respondents acknowledged medical cannabis's therapeutic value, and it was most frequently prescribed for neuropathic pain, musculoskeletal pain, and spasticity. Those with 21+ years of experience authorized cannabis more frequently. Medical training was widely deemed insufficient.","whyItMatters":"Physiatrists manage chronic pain and spasticity, two of medical cannabis's strongest evidence areas. Their discomfort with prescribing, rooted in inadequate training, creates a gap between patient need and physician readiness.","specificNumbers":"109 respondents. 61% comfortable discussing cannabis. 31% comfortable authorizing. Top conditions: neuropathic pain, musculoskeletal pain, spasticity. 21+ years experience associated with more prescribing. Most agreed medical school education was insufficient.","methodology":"24-item web survey distributed to members of the Canadian Association of Physical Medicine and Rehabilitation, with 109 physiatrist respondents and inferential statistical analysis.","limitations":"Survey represents a self-selected subset of Canadian physiatrists. 109 responses may not represent the full specialty. Social desirability bias may affect responses about cannabis comfort."},{"rthcId":"RTHC-06419","title":"Trauma and cannabis cue-induced reward circuit functional connectivity in cannabis users with trauma histories.","authors":"Ethier-Gagnon, Mikaela A; DeGrace, Sarah; Romero-Sanchiz, Pablo; Helmick, Carl A; Tibbo, Philip G; Crocker, Candice E; Good, Kimberly; Rudnick, Abraham; Cosman, Tessa; Barrett, Sean P; Stewart, Sherry H","year":2025,"journal":"Journal of psychiatry & neuroscience : JPN, 50(4), E237-E247","doi":"10.1503/jpn.250064","pmid":"40780868","tags":["ptsd","addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Trauma cues increased cannabis craving and negative affect while decreasing positive affect. In the brain, trauma cues increased connectivity within the striatum and between striatal-cortical regions. Cannabis cues increased cortical and corticolimbic connectivity.","whyItMatters":"Many trauma survivors use cannabis to cope, which can develop into problematic use. This study provides the first neural evidence for how trauma reminders might hijack reward circuits to drive cannabis craving.","specificNumbers":"27 cannabis users (74.1% female, mean age 32.2). Trauma cues increased craving and negative affect vs other cues. Trauma cues increased striatal and striatocortical FC. Cannabis cues increased cortical and corticolimbic FC. Both differed from neutral cues.","methodology":"Randomized crossover fMRI study in 27 cannabis users with trauma histories, using personalized audiovisual cues (trauma, cannabis, neutral) during brain scanning, with self-reported craving and affect measures.","limitations":"Small sample of 27 participants. Not limited to diagnosed PTSD or cannabis use disorder, so findings may not apply to clinical populations. Cross-sectional design cannot establish whether altered connectivity predates or follows cannabis use."},{"rthcId":"RTHC-06420","title":"3D-Printed cannabidiol stent for local treatment of urinary tract infections.","authors":"Eugster, Remo; Santschi, Melanie; Buttitta, Giorgio; Olcay, Basak; Reymond, Jean-Louis; Aleandri, Simone; Luciani, Paola","year":2025,"journal":"International journal of pharmaceutics, 680, 125761","doi":"10.1016/j.ijpharm.2025.125761","pmid":"40419034","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06421","title":"Patterns of substance use on a given day in a national sample of U.S. young adults.","authors":"Evans-Polce, Rebecca J; Arterberry, Brooke J; Lanza, Stephanie T; Patrick, Megan E","year":2025,"journal":"Addictive behaviors, 168, 108376","doi":"10.1016/j.addbeh.2025.108376","pmid":"40319792","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Six day-level patterns emerged: Vaping Nicotine (33.7%), Cannabis Smoking (23.5%), Alcohol Only (17.1%), Cannabis Vaping (11.7%), Multiple Combustibles (7.3%), and Multimodal Cannabis (6.7%). Stress and boredom were highest on Multimodal Cannabis days. Alcohol Only days were characterized by special occasions and weekends.","whyItMatters":"Understanding what types of substance use days look like in real life helps design interventions that match actual use patterns rather than treating all substance use as one behavior.","specificNumbers":"590 individuals, 3,086 substance use days. Vaping Nicotine: 33.7% of days. Cannabis Smoking: 23.5%. Alcohol Only: 17.1%. Cannabis Vaping: 11.7%. Multiple Combustibles: 7.3%. Multimodal Cannabis: 6.7%. Stress and boredom highest on Multimodal Cannabis days.","methodology":"Latent class analysis of 3,086 substance use days reported by 590 young adults (modal age 19) over 14 days, from the nationally representative Monitoring the Future study's 2018-2019 cohort.","limitations":"Sample was limited to past 30-day drinkers in 12th grade, so non-drinkers and non-high-school completers are excluded. 14 days may not capture less frequent use patterns. Self-reported daily data may miss some use events."},{"rthcId":"RTHC-06422","title":"UK Medical Cannabis Registry: A Clinical Outcomes Analysis for Complex Regional Pain Syndrome.","authors":"Evans, Lilia; Erridge, Simon; Varadpande, Madhur; Aggarwal, Arushika; Cowley, Isaac; Clarke, Evonne; McLachlan, Katy; Coomber, Ross; Rucker, James J; Platt, Michael; Sodergren, Mikael H","year":2025,"journal":"Brain and behavior, 15(9), e70823","doi":"10.1002/brb3.70823","pmid":"40898690","tags":["medical-cannabis","pain"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Pain severity on the Brief Pain Inventory improved from 6.69 at baseline to 5.85 at 1 month and 6.05 at 6 months. Improvements were also seen in the McGill Pain Questionnaire, pain VAS, anxiety symptoms, sleep quality, and general health-related quality of life at multiple time points.","whyItMatters":"CRPS is notoriously difficult to treat and causes severe, persistent pain. This is the first study examining cannabis-based medicines specifically for CRPS, providing initial data for a condition with few effective treatments.","specificNumbers":"64 patients. Pain severity BPI: 6.69 baseline to 5.85 at 1 month (p<0.05). McGill Pain, VAS, anxiety, sleep, and quality of life all improved (p<0.05). 5 patients (7.8%) reported adverse events. 50 adverse events (78.1%) recorded total.","methodology":"Case series from the UK Medical Cannabis Registry tracking patient-reported outcomes over 6 months in 64 CRPS patients, with adverse events graded using CTCAE v4.0.","limitations":"No control group or blinding means improvement could reflect placebo response, natural disease fluctuation, or concurrent treatments. Registry data may have selection bias. Pain improvement, while statistically significant, was modest in absolute terms."},{"rthcId":"RTHC-06423","title":"Short-Term Low Dose Cannabidiol Does Not Influence Glucose Tolerance or the Gut Microbiome in Sedentary Adults with Overweight and Obesity: Pilot Study.","authors":"Ewell, Taylor R; Bomar, Matthew C; Abbotts, Kieran S S; Kayne, Brendan T; Risk, Briana D; Williams, Natasha N B; Wei, Yuren; Dooley, Gregory P; Weir, Tiffany L; Bell, Christopher","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251391085","pmid":"41167732","tags":["cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CBD (30mg every 12 hours for 4 weeks) showed no significant effect on glucose tolerance (Matsuda Index), gut microbiome composition, or inflammatory markers compared to placebo in 16 adults with overweight or obesity.","whyItMatters":"Epidemiological data link cannabis use to lower diabetes rates, and animal studies suggested CBD might improve glucose tolerance through gut microbiome changes. This pilot finds no such effect at low doses in humans.","specificNumbers":"16 participants. CBD dose: 30mg every 12 hours (60mg/day). Duration: 4 weeks. Matsuda Index (insulin sensitivity): no significant change (p>0.05). Gut microbiome: no appreciable changes. Inflammation: no modification.","methodology":"Randomized, double-blind, parallel design pilot study with 16 adults (6 males, 10 females) taking either placebo or CBD 30mg twice daily for 4 weeks, with oral glucose tolerance tests and fecal microbiome analysis at baseline and post-intervention.","limitations":"Very small sample (16 participants). Low CBD dose (60mg/day) may be insufficient. Short duration (4 weeks) may not allow metabolic changes to manifest. Sedentary overweight adults may not be the optimal population."},{"rthcId":"RTHC-06424","title":"Human quad liver-on-chip system as a tool toward bridging the gap between animals and humans regarding toxicology and pharmacology of a cannabidiol-rich cannabis extract.","authors":"Ewing, Laura E; Skinner, Charles M; McGill, Mitchell R; Kennon-McGill, Stefanie; Clement, Kirsten; Quick, Charles M; Yee, Eric U; Williams, D Keith; Walker, Larry A; ElSohly, Mahmoud A; Gurley, Bill J; Koturbash, Igor","year":2025,"journal":"Drug and chemical toxicology, 48(3), 578-585","doi":"10.1080/01480545.2024.2388292","pmid":"39155655","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06425","title":"Effectiveness of Full Spectrum Cannabis Extracts in the Treatment of Chronic Pain: An Open Label Study.","authors":"F, Aragon; M, Lozada; G, Bigatti; R, González-José; S, Kochen; I, McCarthy","year":2025,"journal":"Journal of pain & palliative care pharmacotherapy, 39(3), 346-352","doi":"10.1080/15360288.2025.2517778","pmid":"40526158","tags":["medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"51 of 88 patients achieved 50% or greater pain reduction. 38 reported similar reductions in anxiety, 48 in insomnia. 23 patients reduced or discontinued other analgesics and/or anti-inflammatory drugs. Adverse effects were mild and reversible.","whyItMatters":"This adds to real-world evidence that cannabis extracts can serve as effective adjuvants for chronic pain, with the added benefit of reducing reliance on other analgesics in about a quarter of patients.","specificNumbers":"88 patients (ages 35-88). 51 (58%) achieved 50%+ pain reduction. 38 (43%) achieved 50%+ anxiety reduction. 48 (55%) achieved 50%+ insomnia reduction. 23 (26%) reduced or stopped other analgesics. Appetite was the only variable that did not improve.","methodology":"Prospective, open-label, longitudinal study of 88 patients (ages 35-88) with chronic pain using HPLC-analyzed full-spectrum cannabis (THC and CBD) extracts, assessed with visual analogue scales for pain and numerical scales for quality of life.","limitations":"Open-label design with no placebo control or blinding. Expectancy and placebo effects likely contribute to observed improvements. No standardized cannabis doses across patients."},{"rthcId":"RTHC-06426","title":"Quantitative profiling of lipid mediators in sperm cells through on-line dilution on-line polymer matrix-based solid-phase extraction liquid chromatography with mass spectrometric detection.","authors":"Fabian, Jörg; Lehr, Matthias","year":2025,"journal":"Analytical methods : advancing methods and applications, 17(38), 7643-7651","doi":"10.1039/d5ay00250h","pmid":"40948416","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06427","title":"Deliberate self-harm and suicide in individuals with cannabis-related hospital contacts in Ontario, Canada.","authors":"Fabiano, Nicholas; Vargatoth, Emi; Pugliese, Michael; MacDonald-Spracklin, Rachael; Willows, Melanie; Solmi, Marco; Myran, Daniel T","year":2025,"journal":"Molecular psychiatry","doi":"10.1038/s41380-025-03339-9","pmid":"41366517","tags":["mental-health","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-related hospital contact was associated with a 5.35x risk of deliberate self-harm and 9.22x risk of death by suicide compared to the general population. Even after excluding those with co-morbid mental health or substance use disorders, self-harm risk remained elevated at 7.18x.","whyItMatters":"This is one of the largest population studies linking cannabis-related hospital contacts to subsequent self-harm and suicide. The finding that risk persists even without pre-existing mental health conditions suggests cannabis-related hospital visits should trigger mental health screening.","specificNumbers":"11,320,897 followed. 85,108 (0.75%) had cannabis-related hospital contacts. Self-harm aHR: 5.35. Suicide death aHR: 9.22. Without mental health comorbidity: self-harm aHR: 7.18. Median follow-up: 5 years.","methodology":"Population-level retrospective study of 11,320,897 people in Ontario, Canada. 85,108 with incident cannabis-related ED visits or hospitalizations were matched with general population controls. Adjusted hazard models controlled for sociodemographics, mental health comorbidities, chronic conditions, and substance use.","limitations":"Hospital contacts capture severe or problematic use, not typical cannabis use. Residual confounding from unmeasured factors is likely. Cannot determine causation."},{"rthcId":"RTHC-06428","title":"Combined CB1 antagonist AM6545 and NOP agonist SCH221510 worsen DSS-induced colitis in mice.","authors":"Fabisiak, Adam; Wołyniak, Maria R; Piscitelli, Fabiana; Verde, Roberta; Marzo, Vincenzo Di; Zielińska, Marta; Machelak, Weronika; Małecka-Wojciesko, Ewa","year":2025,"journal":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University, 34(12), 2153-2162","doi":"10.17219/acem/203426","pmid":"40600844","tags":["inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice with DSS-induced colitis treated with both AM6545 and SCH221510 showed significantly worse macroscopic disease scores and altered signaling compared to SCH221510 alone.","whyItMatters":"Both the endocannabinoid system and NOP receptors are being explored as IBD targets. This study reveals that their interaction can worsen rather than improve outcomes.","specificNumbers":"Significant increase in macroscopic colitis score with AM6545+SCH221510 vs SCH221510 alone. Lower ERK1/2 levels. Higher p-AKT and beta-arrestin in the combination group.","methodology":"Mouse colitis model using 3% DSS, with selective ligands for CB1 (antagonist AM6545), CB2 (antagonist AM630), and NOP receptor (agonist SCH221510). Assessed macroscopic/microscopic scores, western blots, qPCR, and LC-MS.","limitations":"Single mouse colitis model (DSS). Only acute colitis studied. Mechanism not fully elucidated."},{"rthcId":"RTHC-06429","title":"Cannabidiol attenuates behavioral and electrophysiological changes in the MAM model of schizophrenia in male and female rats.","authors":"Fabris, Débora; Andrade, Lídia M; Freitas, Ícaro Silva; Gomes, Felipe V; Guimarães, Francisco S","year":2025,"journal":"Schizophrenia research, 286, 63-73","doi":"10.1016/j.schres.2025.10.012","pmid":"41118689","tags":["cbd","psychosis","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both male and female MAM rats showed increased VTA dopamine neuron population activity, which was reversed by CBD (60 mg/kg) in both sexes. CBD also reversed memory impairment in male MAM rats, while females showed no memory deficits to reverse.","whyItMatters":"Current antipsychotics primarily block dopamine D2 receptors with significant side effects. CBD's ability to normalize dopamine system activity through a different mechanism supports it as a potential alternative.","specificNumbers":"CBD: 60 mg/kg. Both sexes showed increased VTA DA activity (reversed by CBD). Male MAM rats had NOR deficits (reversed by CBD). Female MAM rats had no NOR deficits. Anxiety in EPM not reversed by CBD.","methodology":"MAM model: pregnant rats received MAM or saline on GD17. Adult offspring tested on EPM, NOR, MK-801 locomotor response. In vivo electrophysiology of VTA DA neurons. CBD (60 mg/kg) given 1 hour before each test.","limitations":"MAM model captures some but not all schizophrenia features. Acute treatment only. Sex differences complicate interpretation. Animal behavior does not directly translate to human psychosis."},{"rthcId":"RTHC-06430","title":"Dietary interventions targeting the neurolipidome in epilepsy: From preclinical models to clinical applications and future therapeutic approaches.","authors":"Fadakar, Hasti; Rudra, Priyanka; Adhikari, Apil; Perera, Galhenage Kethmi; Sirimanne, Vichari; Kaur, Dayajyot; Wong, Huon; Yiu, Kwan Yiu; Schweitzer, Daniel; Akefe, Isaac Oluwatobi","year":2025,"journal":"Neuroscience and biobehavioral reviews, 175, 106242","doi":"10.1016/j.neubiorev.2025.106242","pmid":"40472945","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06431","title":"Cannabidiol's Antioxidant Properties in Skin Care Products and Legislative Regulations.","authors":"Fafaliou, Maria; Papadopoulos, Apostolos; Pavlou, Panagoula; Varvaresou, Athanasia","year":2025,"journal":"Plants (Basel, Switzerland), 14(22)","doi":"10.3390/plants14223521","pmid":"41304672","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06432","title":"Acute Effects of Cannabis and THC Oils on Cardiovascular Hemodynamics and Muscle Electrical Activity in Healthy Individuals: A Controlled Clinical Crossover Trial Protocol.","authors":"Fagundes, Marina Lyra Lima Cabral; Laurentino, Edna Karla Ferreira; Soares, Bruno Lobão; Otto-Yañez, Matías; Nunes, Emerson Arcoverde; Pedrosa, Matheus de Freitas Fernandes; Fonseca, Jessica Danielle Medeiros da; Resqueti, Vanessa Regiane; Fregonezi, Guilherme Augusto de Freitas","year":2025,"journal":"Journal of clinical medicine, 14(21)","doi":"10.3390/jcm14217531","pmid":"41226928","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06433","title":"Cannabis and Tobacco Co-Use and Cannabis Dependence: A Survey of US Adults in Legal Recreational Cannabis Markets.","authors":"Fairman, Brian J; Dutra, Lauren M","year":2025,"journal":"Substance use & misuse, 60(13), 1955-1963","doi":"10.1080/10826084.2025.2524050","pmid":"40591807","tags":["addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Simultaneous and combined cannabis-tobacco co-use was associated with higher CUDIT-R scores compared to cannabis-only use, even after adjusting for demographics and use frequency. Blunt smoking predominated among simultaneous-only users.","whyItMatters":"Cannabis and tobacco co-use is extremely common but rarely addressed in prevention. The finding that how these substances are combined matters has implications for harm reduction messaging.","specificNumbers":"2,978 participants. Two-thirds co-used tobacco. Over half of co-users used simultaneous modes. Combined and simultaneous-only use had higher CUDIT-R scores. Blunt smoking was dominant simultaneous mode.","methodology":"Survey of 2,978 adults (21+) who used cannabis in the past 30 days in legal recreational cannabis states, categorized by co-use pattern.","limitations":"Cross-sectional; cannot determine causation. Self-reported data. Only legal-state residents."},{"rthcId":"RTHC-06434","title":"The Cannabinoid System as a Potential Novel Target for Alcohol-Associated Liver Disease: A Propensity-Matched Cohort Study.","authors":"Fakhoury, Butros; Jahagirdar, Vinay; Rama, Kaanthi; Hudson, David; Wang, Wei; Díaz, Luis Antonio; Arab, Juan Pablo","year":2025,"journal":"Liver international : official journal of the International Association for the Study of the Liver, 45(11), e70401","doi":"10.1111/liv.70401","pmid":"41117396","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Compared to non-cannabis users, those with CUD had a 40% lower ALD risk (HR 0.60), 17% lower decompensation risk (HR 0.83), and 14% lower mortality (HR 0.86). Cannabis users without CUD had lower ALD risk but similar decompensation and mortality.","whyItMatters":"Alcohol-associated liver disease is a leading cause of liver death with limited treatments. The dose-response pattern suggests cannabinoid system modulation may genuinely protect against alcohol liver injury.","specificNumbers":"33,114 matched per group. CUD vs non-CU: ALD HR 0.60, decompensation HR 0.83, mortality HR 0.86. CU vs non-CU: ALD risk lower but decompensation and mortality similar.","methodology":"Propensity-matched cohort using TriNetX (2010-2022). Adults with AUD categorized into CUD, cannabis use, and non-cannabis use. Outcomes over 3 years via Cox regression.","limitations":"Observational; cannot prove causation. Healthy user bias possible. CUD based on ICD coding. Concurrent factors not captured."},{"rthcId":"RTHC-06435","title":"Profiles of polysubstance use among people reporting past 12-month sleep-motivated nonmedical use of prescription tranquilizers/sedatives.","authors":"Falise, Alyssa M; Prasanna Surendran, Parvathy; Hoeflich, Carolin C; Striley, Catherine W; LaMontagne, Liva; Lopez-Quintero, Catalina","year":2025,"journal":"The American journal on addictions, 34(3), 313-321","doi":"10.1111/ajad.13665","pmid":"39528342","tags":["sleep","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Two polysubstance profiles identified: marijuana/alcohol/tobacco (MAT, 68.3%) and MAT plus cocaine/hallucinogens/prescription drugs (31.7%). The more complex profile was more common among younger, male, White adults.","whyItMatters":"Sleep-motivated prescription drug misuse occurs overwhelmingly in polysubstance use contexts. Cannabis and alcohol are involved in nearly all cases, requiring integrated treatment.","specificNumbers":"2,603 participants. Alcohol 90.4%, tobacco 61.5%, marijuana 55.5%. Average 3.6 additional substances. MAT profile: 68.3%. MAT+CHPR: 31.7%.","methodology":"Latent class analysis of 2,603 NSDUH 2015-2019 participants with past 12-month sleep-motivated nonmedical use of prescription tranquilizers/sedatives plus additional substances.","limitations":"Cross-sectional. NSDUH lacks frequency details. Self-reported motivations."},{"rthcId":"RTHC-06436","title":"Ablation of hypothalamic Cnr1 leads to reduced meniscal mineral volume and articular cartilage damage in aging male mice.","authors":"Farhat, Eli; Palmisano, Michela; Marco, Miya; From, Oriya; Reich, Eli; Lutz, Beat; Ramunno, Carla F; de Almodovar, Carmen Ruiz; Bilkei-Gorzo, Andras; Dvir-Ginzberg, Mona","year":2025,"journal":"Osteoarthritis and cartilage, 33(11), 1349-1360","doi":"10.1016/j.joca.2025.08.006","pmid":"40865711","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Hypothalamus-specific CB1 knockout mice showed reduced frailty at 17 months, less meniscal mineral volume loss, fewer blood vessels in the meniscus, and less cartilage damage. They also had lower corticosterone levels.","whyItMatters":"This reveals that the brain's endocannabinoid system influences joint aging through a hypothalamic-peripheral axis, opening a novel therapeutic angle for osteoarthritis.","specificNumbers":"CB1 knockout at 2-3 months, assessed at 18-19 months. Reduced frailty index. Less meniscal mineral volume loss. Less cartilage damage. Lower corticosterone.","methodology":"Mice with hypothalamus-specific CB1 deletion via stereotaxic viral injection, aged to 18-19 months. Assessed frailty, hormones, and joint/bone histology.","limitations":"Constitutive knockout from early adulthood. Male mice only. Specific mechanism not fully resolved."},{"rthcId":"RTHC-06437","title":"The contribution of baseline circulating endocannabinoids to individual differences in human pain sensitivity: a quantitative sensory testing study.","authors":"Fatemi, S A; Abssy, S S; Bourke, S L; Murray, K B; Kyeremaa-Adjei, C; Honigman, L; Mohabir, N; Sexton, C; Cormie, M A; Tomin, R; Boileau, I; Atlas, L Y; Finn, D P; Moayedi, M","year":2025,"journal":"Pain","doi":"10.1097/j.pain.0000000000003850","pmid":"41324391","tags":["pain","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Serum eCB/NAE concentrations were not affected by sex, FAAH genotype, or cannabis use. FAAH C385A genotype did not predict pain sensitivity. Only pressure pain thresholds were associated with AEA and OEA levels (p=0.003).","whyItMatters":"Despite strong animal evidence that endocannabinoids modulate pain, this study's mostly null results suggest blood levels may not reflect the local eCB activity that matters for pain.","specificNumbers":"91 participants. No sex, genotype, or cannabis use effects on eCB levels. Pressure pain thresholds associated with AEA and OEA (p=0.003). No other QST measures significant.","methodology":"91 healthy participants (39 males, 52 females) assessed with quantitative sensory testing and serum endocannabinoid measurements. FAAH C385A genotyping. Linear regressions across 13 QST measures.","limitations":"Blood levels may not reflect tissue-level concentrations. QST in healthy volunteers may not capture eCB modulation relevant in chronic pain. Single timepoint."},{"rthcId":"RTHC-06438","title":"The Contribution of Baseline Circulating Endocannabinoids to Individual Differences in Human Pain Sensitivity: A Quantitative Sensory Testing Study.","authors":"Fatemi, S A; Abssy, S S; Bourke, S L; Murray, K B; Kyeremaa-Adjei, C; Honigman, L; Mohabir, N; Sexton, C; Cormie, M A; Tomin, R; Boileau, I; Atlas, L Y; Finn, D P; Moayedi, M","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.08.22.671762","pmid":"40909681","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06439","title":"Infant Death due to Cannabis Ingestion.","authors":"Favretto, Donata; Cirnelli, Antonello; Pertile, Roberto; Stimamiglio, Raffaella; Cestonaro, Clara; Cuman, Oriana; Pagliaro, Anna; Mattiazzi, Fabio; Basso, Cristina; Galeazzi, Maddalena","year":2025,"journal":"Drug testing and analysis, 17(10), 2014-2021","doi":"10.1002/dta.3904","pmid":"40399755","tags":["youth","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"The child showed altered walking, balance, and consciousness after ingesting hashish, followed by respiratory failure. Hair analysis revealed chronic exposure to THC, CBD, CBN, methadone, cocaine, morphine, heroin metabolites, ketamine, and fentanyl.","whyItMatters":"While adult cannabis deaths are extremely rare, this case demonstrates cannabis ingestion can be fatal in children, particularly those chronically exposed to multiple substances. It underscores the need for safe storage.","specificNumbers":"Cannabinoids in blood, urine, bile, brain, lung, and liver. Hair positive for THC, CBD, CBN, methadone, cocaine, morphine, 6-MAM, ketamine, and fentanyl.","methodology":"Forensic case report with autopsy, comprehensive toxicological analysis (immunochemistry, GC-MS, UPLC-MS/MS) of blood, bile, urine, organs, gastric content, and head hair.","limitations":"Single case with confounding chronic drug exposure. Fentanyl and ketamine administered during treatment. Relative contribution of cannabis versus pre-existing exposure unclear."},{"rthcId":"RTHC-06440","title":"The promoter regions of CBDAS and PT genes of cannabinoid biosynthesis in Cannabis sativa respond to phytohormones and stress-related signals.","authors":"Fayaz, Mohd; Angmo, Tsering; Katoch, Kajal; Majeed, Aasim; Kundan, Maridul; Wajid, Mir Abdul; Pal, Koushik; Misra, Prashant","year":2025,"journal":"Planta, 261(6), 135","doi":"10.1007/s00425-025-04709-x","pmid":"40349291","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06441","title":"Pre-Post Cannabis Legalization for Adult Use: A Trend Study of Two Cohorts of Young Adult Cannabis Users in Los Angeles.","authors":"Fedorova, Ekaterina V; Mitchel, Allison; Finkelstein, Maddy; Ataiants, Janna; Wong, Carolyn F; Conn, Bridgid M; Lankenau, Stephen E","year":2025,"journal":"Journal of psychoactive drugs, 57(1), 99-109","doi":"10.1080/02791072.2023.2282515","pmid":"37997888","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Frequency of cannabis use (days or hits per day) did not significantly differ between cohorts. Edible use increased post-legalization. Medical patients reported more medical use, more concentrate use, and perceived cannabis as more addictive.","whyItMatters":"For 18-20 year olds who cannot legally purchase recreational cannabis, legalization did not drive increased consumption, challenging assumptions about normalization effects.","specificNumbers":"Pre-AUL: n=172. Post-AUL: n=139. Use frequency unchanged. Edible use increased. Medical patients had more concentrate use and perceived addiction risk.","methodology":"Two cohorts of 18-20 year old cannabis users in LA: pre-legalization (2014-15, n=172) and post-legalization (2019-20, n=139), assessed for 90-day use.","limitations":"Different cohorts, not longitudinal. Small samples. LA-specific. Only existing cannabis users studied."},{"rthcId":"RTHC-06442","title":"Medical Cannabis Use Adjunct to Standard of Care in a Residential Substance Use Recovery Program: A Pilot Study.","authors":"Fehr, Florriann C; Lo, Lindsay A; Nelson, Christopher C; Diehl, Lauren; Walsh, Zach","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(6), 967-976","doi":"10.15288/jsad.24-00224","pmid":"39927474","tags":["medical-cannabis","harm-reduction","addiction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Clients reported cannabis substitution reduced cravings for problematic substances and helped with pain and comorbid symptoms. Staff highlighted the need for cannabis education, clear dispensing guidelines, and accessible frameworks.","whyItMatters":"Using cannabis within recovery programs is controversial. This pilot provides the first qualitative evidence from both clients and staff on feasibility of structured cannabis programs coexisting with recovery goals.","specificNumbers":"14 clients at 3 time points. 7 staff interviewed. Reports of reduced cravings, pain management, symptom relief. Key facilitators: cannabis education, clear guidelines.","methodology":"Qualitative study: interviews and validated self-reports from 14 clients at baseline, 1 month, and 3 months, plus 7 staff interviews, at a Canadian residential recovery program.","limitations":"Very small sample. No control group. Single site. Qualitative design cannot establish efficacy."},{"rthcId":"RTHC-06443","title":"Characterizing proximal risk for depressive symptoms and suicidal ideation with acute cannabis use and withdrawal among adolescents using ecological momentary assessment: Study protocol.","authors":"Feibus, Isabella; Mahiques, Marta Borrego; Costello, Meghan; Potter, Kevin; Bentley, Kate H; Hoeppner, Bettina B; Liu, Luwei; Evohr, Bryn; Yan, Lynn; Gilman, Jodi; Evins, A Eden; Kossowsky, Joe; Schuster, Randi M","year":2025,"journal":"PloS one, 20(12), e0338790","doi":"10.1371/journal.pone.0338790","pmid":"41411314","tags":["withdrawal","addiction","depression","youth","mental-health","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Heavy cannabis use and depression frequently co-occur in adolescents, with cannabis users at increased risk of major depressive episodes and suicidal ideation. But the critical clinical question remains unanswered: does quitting cannabis improve depression, or does it temporarily worsen it due to withdrawal?\n\nThis study protocol describes an ambitious RCT designed to disentangle this relationship. Two hundred adolescents aged 12-18 with daily or near-daily cannabis use and current depressive symptoms will be randomized to either 8 weeks of abstinence (encouraged through contingency management — financial incentives for negative drug tests) or a monitoring control group that continues use as usual.\n\nWhat makes this study particularly powerful is the ecological momentary assessment (EMA) design: participants will complete 8 surveys per day during data collection phases, capturing substance use, mood, and suicidal thoughts in near-real-time. This allows the researchers to observe what happens hour by hour during both cannabis use and withdrawal — when do depressive symptoms spike? When does suicidal ideation emerge? Does the timing correlate with acute use, acute withdrawal, or sustained abstinence?\n\nThe study spans 10 weeks with 12 visits, producing a granular temporal map of the cannabis-depression-suicide relationship that no previous study has achieved. The contingency management approach to motivating abstinence is evidence-based and addresses the practical challenge of getting teens to actually stop using during the study.","whyItMatters":"Adolescent depression and suicide are at crisis levels, and cannabis use is growing in this age group. Clinicians face a dilemma: they suspect cannabis may worsen depression, but withdrawal can also trigger mood symptoms, and telling a depressed teen to quit a substance they use to cope carries its own risks. This RCT will provide the first controlled evidence on whether abstinence helps or hurts — and the EMA design will capture the temporal dynamics that determine clinical recommendations.","specificNumbers":"200 adolescents (12-18 years). 8 weeks of abstinence vs. continued use. 8 EMA surveys per day during collection phases. 12 study visits over 10 weeks. 4 total weeks of EMA data collection. Contingency management for abstinence motivation. Funded and registered (protocol published in 2025).","methodology":"Randomized controlled trial protocol. 200 adolescents aged 12-18 with daily/near-daily cannabis use and current depressive symptoms. Randomized 1:1 to 8 weeks of cannabis abstinence (contingency management) vs. monitoring control. 12 study visits over 10 weeks. Self-report and interview assessments of substance use and symptom severity. 3 phases of EMA data collection (4 total weeks, 8 daily surveys) assessing past-hour substance use, mood, and suicidal ideation.","limitations":"This is a protocol paper — no results yet. Contingency management may not achieve true abstinence in all participants (compliance varies). 8 weeks may not be long enough for full mood recovery after chronic use. The 12-18 age range includes very different developmental stages. Participants must have both daily cannabis use AND depressive symptoms, which is a specific population — results may not generalize to teens with one but not both conditions. EMA compliance in adolescents can be challenging."},{"rthcId":"RTHC-06444","title":"Cannabis.","authors":"Feinberg, Steven D; Aronoff, Gerald M; Ausfahl, James; Bruns, Daniel; Darnall, Beth D; Goldberg, Robert L; Haldeman, Scott; Lessenger, James E; Mandel, Steven; Mayer, Tom G; Navani, Annu H; Osbahr, Albert J; Warren, Pamela A; Winters, Thomas H; Harris, Jeffrey S; Hegmann, Kurt T","year":2025,"journal":"Journal of occupational and environmental medicine, 67(12), e860-e871","doi":"10.1097/JOM.0000000000003548","pmid":"40952964","tags":["medical-cannabis","workplace"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Some evidence for MS spasticity, but no quality evidence for back pain, radiculopathy, neuropathic pain, or other common work-related pain. Quality evidence supports lack of efficacy for postoperative pain. Documented adverse effects include cancers, cardiovascular diseases, psychotic disorders, and safety risks.","whyItMatters":"As legalization expands, employers face pressure to allow cannabis. This provides evidence-based grounds for workplace policies, particularly for safety-sensitive positions.","specificNumbers":"Efficacy evidence: some for MS spasticity only. No quality evidence for: back pain, radiculopathy, neuropathic pain. Evidence against: postoperative pain. Harms: cancers, cardiovascular, psychotic disorders, safety risks.","methodology":"Evidence-based guideline developed using ACOEM methodology, systematically reviewing evidence on cannabis efficacy and safety for work-related conditions.","limitations":"Guidelines reflect evidence at publication; new trials may change recommendations. May reflect conservative occupational medicine perspective."},{"rthcId":"RTHC-06445","title":"Predictors of effective therapy among individuals with Cannabis Use Disorder: a review of the literature.","authors":"Feingold, Daniel; Tzur Bitan, Dana; Ferri, Marica; Hoch, Eva","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 341-353","doi":"10.1007/s00406-024-01781-4","pmid":"38493284","tags":["addiction","quitting"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Specific mediators: treatment duration, motivation to change, coping skills, self-efficacy, multi-component integration. Common mediators: therapeutic alliance, empathy, expectations, cultural adaptation. Moderators: sex, ethnicity, age, comorbid disorders.","whyItMatters":"CUD is the most common first-time drug treatment reason in the EU. Understanding why some treatments work for some people enables precision-matched care.","specificNumbers":"CUD is the most common first-time drug treatment in EU. Mediators: duration, motivation, coping, self-efficacy. Common factors: alliance, empathy, expectations. Moderators: sex, ethnicity, age, comorbidity.","methodology":"Scoping review of empirically evaluated studies using defined cannabis-related outcome measures, categorizing factors as mediators or moderators.","limitations":"Scoping methodology is broader than systematic review. Heterogeneous studies. Mostly Western, high-income country research."},{"rthcId":"RTHC-06446","title":"The Endocannabinoid System: Role in Ocular Physiology and Therapeutic Potential in Eye Diseases: A Narrative Review.","authors":"Feki, Omar; Zhioua-Braham, Imen; Haddar, Selim; Arfaoui, Ahmed; Errais, Khalil; Feki, Moncef","year":2025,"journal":"Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 41(9), 503-517","doi":"10.1177/10807683251368650","pmid":"40838892","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06447","title":"Clinical Characteristics and Associated Factors in Mexican Patients With Cyclic Vomiting Syndrome and Cannabinoid Hyperemesis Syndrome.","authors":"Felix-Tellez, Francisco A; Morel-Cerda, Eliana C; Jiménez-Castillo, Raúl A; Valdovinos-García, Luis R; Gómez-Escudero, Octavio; Valdovinos-Díaz, Miguel Á; Coss-Adame, Enrique; Velasco, José A Velarde-Ruiz; Monjaraz, Erick M Toro; Montijo-Barrios, Ericka; Solís-Ortega, Alberto A; Frazier, Rosita De Jesus; Venkatesan, Thangam; Remes-Troche, José M","year":2025,"journal":"Journal of neurogastroenterology and motility, 31(3), 330-339","doi":"10.5056/jnm24182","pmid":"40625249","tags":["medical-cannabis","appetite"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In this 46-patient Mexican study, cannabinoid hyperemesis syndrome (CHS) patients had higher tobacco use (50% vs 27%) and risky alcohol use (31% vs 0%) compared to cyclic vomiting syndrome (CVS) patients, though both groups had similar hospitalization rates.","whyItMatters":"This is the first detailed analysis of CVS and CHS in a Latin American population, revealing demographic and substance use patterns that differ somewhat from data collected in the US and Europe.","specificNumbers":"46 patients total (30 CVS, 16 CHS). CHS patients older (median 27 vs 23 years, p=0.043). Tobacco use higher in CHS (50% vs 26.7%, p=0.019). Risky alcohol use exclusive to CHS (31.3% vs 0%, p=0.003). Time to diagnosis longer for CVS (35.4 vs 26.5 months, p=0.016). Cannabis use reported by 13.3% of CVS patients.","methodology":"Cross-sectional study across 5 Mexican medical centers using Rome IV diagnostic criteria. Compared 30 CVS and 16 CHS patients on demographics, substance use, and clinical characteristics.","limitations":"Small sample size (46 patients). Cross-sectional design limits causal inference. Multi-center but all within Mexico. Self-reported substance use data."},{"rthcId":"RTHC-06448","title":"Rapid suppression of neuropathic pain and somatosensory hyperactivity by nano-formulated cannabidiol.","authors":"Feng, Jingyu; Page, Jessica; Chung, Leeyup; He, Zhigang; Wang, Kuan Hong","year":2025,"journal":"Cell chemical biology, 32(11), 1412-1428.e5","doi":"10.1016/j.chembiol.2025.10.005","pmid":"41205612","tags":["pain","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"An inclusion-complex-enhanced nano-micelle formulation (CBD-IN) significantly improved CBD delivery to the brain and fully suppressed both allodynia and hyperalgesia in a neuropathic pain mouse model with a single dose, while leaving normal sensorimotor and cognitive functions intact.","whyItMatters":"CBD's poor water solubility has limited its therapeutic potential. This nano-formulation overcame that barrier, achieving rapid and complete pain relief while allowing researchers to map exactly how CBD works in pain circuits.","specificNumbers":"Single dose of CBD-IN fully suppressed allodynia and hyperalgesia. No impairment of sensorimotor or cognitive functions. CBD-IN selectively reduced neuronal activation across the somatosensory system in pain-associated circuits.","methodology":"Mouse neuropathic pain model using nano-formulated CBD (CBD-IN). Measured pain responses, sensorimotor function, and cognition. Used activity-dependent genetic mapping and calcium imaging to track neural activity in the somatosensory system.","limitations":"Mouse model only. Single pain model tested. Long-term effects and repeated dosing not assessed. Translation to human dosing and formulation uncertain."},{"rthcId":"RTHC-06449","title":"The threat of vaping in youths.","authors":"Ferkol, Thomas","year":2025,"journal":"Pediatric pulmonology, 60 Suppl 1, S88-S89","doi":"10.1002/ppul.27361","pmid":"39466032","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06450","title":"Cognitive presentation at psychosis onset through premorbid deterioration and exposure to environmental risk factors.","authors":"Ferraro, Laura; Di Forti, Marta; La Barbera, Daniele; La Cascia, Caterina; Morgan, Craig; Tripoli, Giada; Jongsma, Hannah; Seminerio, Fabio; Sartorio, Crocettarachele; Sideli, Lucia; Tarricone, Ilaria; Carloni, Anna Lisa; Szoke, Andrei; Pignon, Baptiste; Bernardo, Miguel; de Haan, Lieuwe; Arango, Celso; Velthorst, Eva; Gayer-Anderson, Charlotte; Kirkbride, James; Rutten, Bart P F; Lasalvia, Antonio; Tosato, Sarah; Del Ben, Cristina Marta; Menezes, Paulo Rossi; Bobes, Julio; Arrojo, Manuel; Tortelli, Andrea; Jones, Peter; Selten, Jean-Paul; van Os, Jim; Murray, Robin; Quattrone, Diego; Vassos, Evangelos","year":2025,"journal":"Psychological medicine, 55, e12","doi":"10.1017/S0033291724003507","pmid":"39905765","tags":["psychosis","cognition","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 802 first-episode psychosis patients, those in the \"deteriorating\" cognitive cluster had higher cannabis exposure than the \"intermediate\" cluster with identical IQ, and all patient clusters had higher environmental risk scores than the 1,263 community controls.","whyItMatters":"This study helps untangle why some people with psychosis experience cognitive decline while others maintain function. Cannabis exposure emerged as one distinguishing factor, separate from baseline intelligence.","specificNumbers":"802 FEP patients clustered into: high-functioning (n=205), low-functioning (n=223), intermediate (n=224), deteriorating (n=150). Deteriorating cluster had higher cannabis exposure than intermediate (mean difference=0.48, 95% CI 0.49-0.91). ERS highest in deteriorating cluster (beta=2.8, 95% CI 2.3-3.4).","methodology":"Cross-sectional analysis from the EU-GEI study comparing cognitive clusters of 802 first-episode psychosis patients and 1,263 controls. Used the Maudsley Environmental Risk Score (ERS) combining paternal age, childhood adversities, cannabis use, and ethnic minority status.","limitations":"Cross-sectional design cannot establish causation. Environmental risk score combines multiple factors. Cognitive clusters derived from single timepoint assessment. Cannabis exposure was one component of a composite score."},{"rthcId":"RTHC-06451","title":"Aspirin-triggered lipoxin A4 reduces neuropathic pain and anxiety-like behaviours in male diabetic rats: antinociceptive enhancement by cannabinoid receptor agonists.","authors":"Ferreira, Matheus Vinícius; Jesus, Carlos Henrique Alves; Bonfim da Costa, Jaderson Pedro; Oliveira, Gabrielle; Liebl, Bruno; Verri Junior, Waldiceu; Zanoveli, Janaína Menezes; Cunha, Joice Maria da","year":2025,"journal":"European journal of pharmacology, 989, 177254","doi":"10.1016/j.ejphar.2025.177254","pmid":"39788405","tags":["pain","neuroscience","animal-study","drug-interactions"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Aspirin-triggered lipoxin A4 (ATL) reduced mechanical hyperalgesia in diabetic rats both acutely and cumulatively. Combining low-dose ATL with CB1 or CB2 receptor agonists (ACEA or JWH-133) produced enhanced pain relief beyond what either achieved alone.","whyItMatters":"Current diabetic neuropathy treatments are often inadequate. This study identifies a potential synergy between the body's natural inflammation-resolving molecules and the endocannabinoid system that could lead to more effective combination therapies.","specificNumbers":"ATL at 30 ng produced acute pain relief. Cumulative relief at 1, 3, 10, or 30 ng doses. Low-dose ATL (1 or 3 ng) combined with ACEA or JWH-133 (30 mcg/rat) produced augmented pain relief. ATL reduced anxiety-like but not depressive-like behavior in diabetic rats.","methodology":"Streptozotocin-induced diabetic rats tested with electronic Von Frey for mechanical pain. ATL administered alone (0.3-30 ng) or combined with intrathecal CB1/CB2 agonists. Assessed locomotion, anxiety-like, and depressive-like behaviors.","limitations":"Animal model only. Streptozotocin-induced diabetes may not fully replicate human diabetic neuropathy. Intrathecal drug delivery not practical for routine clinical use. Short-term assessment only."},{"rthcId":"RTHC-06452","title":"Single trichome phytocannabinomics of two different cannabis varieties.","authors":"Ferri, Elena; Cerrato, Andrea; Caprari, Cristian; Russo, Fabiana; Laganà, Aldo; Capriotti, Anna Laura; Faggiana, Giorgio; Moro, Arcangelo; Citti, Cinzia; Cannazza, Giuseppe","year":2025,"journal":"Journal of pharmaceutical and biomedical analysis, 261, 116836","doi":"10.1016/j.jpba.2025.116836","pmid":"40139041","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06453","title":"Novel Orthosteric/Allosteric Ligands of Cannabinoid Receptors: An Unexpected Pharmacological Profile.","authors":"Ferrisi, Rebecca; Polini, Beatrice; Smolyakova, Anna Maria; Migone, Chiara; Giammattei, Gaia; Banti, Matteo; Baron, Giovanna; Della Vedova, Larissa; Chiellini, Grazia; Gado, Francesca; Piras, Anna Maria; Rapposelli, Simona; Laprairie, Robert B; Ortore, Gabriella; Manera, Clementina","year":2025,"journal":"Journal of medicinal chemistry, 68(2), 1280-1299","doi":"10.1021/acs.jmedchem.4c01778","pmid":"39749716","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06454","title":"Chemometric and predictive modeling of long term cannabinoid transformation in stored Cannabis sativa resin.","authors":"Fettoukh, Nezha; Fadil, Mouhcine; Stambouli, Hamid; El Bouri, Aziz; Bouyoun, Taoufik; Annemer, Saoussan; Boukhaled, Abdelfattah; Farah, Abdellah","year":2025,"journal":"Scientific reports, 15(1), 33827","doi":"10.1038/s41598-025-03888-7","pmid":"41028787","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06455","title":"Patterns of substance use and initiation among LGBTQIAPN+ youth in Brazil: Evidence from a population-based cohort.","authors":"Figueiredo, Caio Petrus Monteiro; Alves Bezerra, Henrique; Miguel, Euripedes Constantino; Rohde, Luis Augusto; Salum, Giovanni Abrahão; Pan, Pedro Mario; Caye, Arthur","year":2025,"journal":"International review of psychiatry (Abingdon, England), 37(6-7), 639-650","doi":"10.1080/09540261.2025.2573758","pmid":"41104620","tags":["youth","mental-health","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"LGBTQ+ adolescents in Brazil had significantly higher lifetime prevalence of cannabis use (OR=1.94) and tobacco use (OR=1.66) compared to cisgender heterosexual peers. These differences were driven entirely by participants assigned female at birth, with no significant differences among males.","whyItMatters":"This is one of few studies from a low- or middle-income country examining substance use disparities among LGBTQ+ youth, revealing that the pattern seen in US/European data also holds in Brazil, with a striking sex-assigned-at-birth difference.","specificNumbers":"Cannabis OR=1.94 (95% CI 1.42-2.64). Tobacco OR=1.66 (95% CI 1.22-2.26). Differences driven by those assigned female at birth. LGBTQ+ females reported earlier initiation of alcohol (p=0.001), tobacco (p<0.05), and cannabis (p<0.001).","methodology":"Longitudinal community-based cohort study (Brazilian High-Risk Cohort Study) following 1,492 participants aged 9-21 across two waves. Assessed sexual orientation, gender identity, and lifetime use of alcohol, tobacco, cannabis, and cocaine.","limitations":"Self-reported substance use. Brazilian cultural context may not generalize to all LMICs. Lifetime prevalence doesn't capture current use patterns. Sexual orientation and gender identity categories may not capture full diversity."},{"rthcId":"RTHC-06456","title":"The Importance of Accurate Drug Use History in Diagnosing and Managing Cannabinoid Hyperemesis Syndrome: A Case Report.","authors":"Filipa Silva, Sara; Couto, Maria Beatriz","year":2025,"journal":"Cureus, 17(3), e80352","doi":"10.7759/cureus.80352","pmid":"40206891","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06457","title":"Opioid reduction in patients with chronic non-cancer pain undergoing treatment with medicinal cannabis.","authors":"Finch, Philip M; Price, Leanne M; Price, Toby J F; Kent, Michael J; Drummond, Peter D","year":2025,"journal":"Pain management, 15(10), 703-711","doi":"10.1080/17581869.2025.2544511","pmid":"40788193","tags":["pain","medical-cannabis","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 102 chronic pain patients co-prescribed cannabinoids alongside opioids, median opioid consumption dropped from 40 mg/day to 2.7 mg/day at one year, significantly lower than the 42.3 mg/day maintained by 53 opioid-only controls. However, 46 of 102 cannabis patients dropped out compared to only 1 of 53 controls.","whyItMatters":"The opioid reduction was dramatic, but the 45% dropout rate reveals that medical cannabis as an opioid-sparing strategy only works for a subset of patients. Both the promise and the limitation are important for realistic expectations.","specificNumbers":"Baseline: median 40 mg/day opioids in both groups. At 12 months: cases 2.7 mg/day vs controls 42.3 mg/day (p<0.05). Cannabis dose: median 15mg THC + 15mg CBD daily. Dropout: 46/102 cannabis group vs 1/53 control group. Disability and insomnia also decreased in cases.","methodology":"Prospective observational study at two Australian pain clinics. One cohort (n=102) received opioids plus medical cannabis (titrated to median 15mg THC/15mg CBD daily); the other (n=53) received opioids only. Assessed at 12 months with intention-to-treat analysis.","limitations":"Observational, not randomized. High dropout rate in cannabis group (45%) creates selection bias among completers. Non-blinded. Small sample size. Single clinic setting in Australia. Reasons for dropout not fully detailed."},{"rthcId":"RTHC-06458","title":"Cannabis legalization and increasing cannabis use in the United States: Data from urine toxicology testing in emergency room patients.","authors":"Fink, David S; Samples, Hillary; Malte, Carol A; Olfson, Mark; Wall, Melanie M; Alschuler, Daniel M; Simpson, Tracy; Mannes, Zachary; Saxon, Andrew J; Hasin, Deborah S","year":2025,"journal":"The International journal on drug policy, 138, 104765","doi":"10.1016/j.drugpo.2025.104765","pmid":"40058102","tags":["legalization","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Using biological urine drug screens rather than self-report, recreational cannabis law (RCL) enactment was associated with a 2.9% increase in cannabis-positive tests among ER patients, while medical cannabis laws alone were associated with a 0.8% increase. Overall prevalence rose from about 16-18% to 26-34% across all state categories.","whyItMatters":"Previous studies relied on self-reported cannabis use, which could be biased by changing stigma. By using biological urine tests, this study provides stronger evidence that legalization genuinely increased cannabis use, not just willingness to report it.","specificNumbers":"No-law states: 16.4% to 25.6%. MCL-only states: 16.6% to 27.6%. RCL states: 18.2% to 33.8%. MCL effect: +0.8% (95% CI 0.4-1.0). RCL effect: +2.9% (95% CI 2.5-3.3).","methodology":"Staggered-adoption difference-in-difference analysis of VHA emergency department patients aged 18-75 from 2008-2019. Used urine drug screen results (biological measure) rather than self-report to reduce social desirability bias.","limitations":"VHA patients (predominantly male, older) may not represent the general population. Urine drug screens detect recent use but don't quantify frequency or amount. Study period ended in 2019; more recent trends not captured."},{"rthcId":"RTHC-06459","title":"Cannabinoid Ligand-Mediated Glycogen Depletion in Astrocytes Is Associated With Increased Intracellular Calcium, Energy Metabolism, and Membrane Dynamics.","authors":"Fink, Katja; Zorec, Robert; Kreft, Marko","year":2025,"journal":"Journal of neurochemistry, 169(12), e70332","doi":"10.1111/jnc.70332","pmid":"41457700","tags":["neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1-selective agonist ACEA triggered rapid, transient calcium elevations in rat astrocytes, while CB2-biased ligands AM1241 and Gp1a produced sustained metabolic effects including prolonged increases in intracellular glucose and lactate. AM1241 also depleted glycogen stores. All ligands increased membrane dynamics consistent with enhanced exocytotic activity.","whyItMatters":"Astrocytes are the brain's metabolic support cells. Understanding how cannabinoids alter their energy metabolism helps explain how cannabis affects brain function beyond just neuronal signaling.","specificNumbers":"ACEA produced rapid transient calcium elevations. AM1241 and Gp1a produced sustained glucose and lactate increases. AM1241 depleted glycogen stores. CB1 immunoreactivity predominated; RT-qPCR detected Cnr1 but not Cnr2 transcripts.","methodology":"Primary rat astrocyte cultures studied with live-cell FRET sensors for glucose and lactate, calcium imaging, glycogen assays, and whole-cell patch-clamp capacitance measurements. Tested CB1-selective and CB2-biased cannabinoid ligands.","limitations":"In vitro study using primary rat cultures. CB2-biased ligand effects may actually operate through CB1 or off-target mechanisms since CB2 expression was minimal. Concentrations used may not reflect physiological levels."},{"rthcId":"RTHC-06460","title":"Role Strain Among Parents Who are Medical Cannabis Patients in Pennsylvania.","authors":"Finkelstein, Maddy; Salerno Valdez, Elizabeth; Cordingley, Olivia; Pagán, Samantha; Ataiants, Janna; Lankenau, Stephen E","year":2025,"journal":"Journal of psychoactive drugs, 1-9","doi":"10.1080/02791072.2025.2550293","pmid":"40830072","tags":["medical-cannabis","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"In 24 qualitative interviews, parents who were medical cannabis patients in Pennsylvania described cannabis as supporting their parental role through symptom reduction, mood improvement, and increased patience. However, fear of legal consequences and stigma around their use created strain on their identity as parents.","whyItMatters":"As more states legalize medical cannabis, the number of parents using it grows. Understanding the tension between therapeutic benefit and social stigma helps inform both policy and clinical conversations.","specificNumbers":"24 parent interviews conducted. Parents reported cannabis improved mood, reduced physical/psychological symptoms, and increased patience with children. Fear of legal consequences and stigma were primary sources of role strain.","methodology":"Qualitative study using 24 semi-structured interviews with parents from an ongoing registry study of medical cannabis patients in Pennsylvania. Analyzed using role strain theory with a priori and emergent coding.","limitations":"Small qualitative sample (24 interviews). Pennsylvania-specific legal context. Self-selected participants from a registry study. Predominantly represents patients willing to discuss their use. No comparison group of non-parent patients."},{"rthcId":"RTHC-06461","title":"Cannabis legalization: a call for the integration of main health and crime indicator domains towards comprehensive policy impact assessments.","authors":"Fischer, Benedikt; Robinson, Tessa; Jutras-Aswad, Didier","year":2025,"journal":"Journal of public health policy, 46(2), 423-432","doi":"10.1057/s41271-025-00552-2","pmid":"39828760","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06462","title":"Cannabis User Perceptions: General and Oral Health Benefits and Harms of Vaping Versus Smoking.","authors":"Fisher, Jennifer M; Boyd, Linda D; Vineyard, Jared","year":2025,"journal":"Substance use & misuse, 60(8), 1157-1163","doi":"10.1080/10826084.2025.2491766","pmid":"40241273","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 302 current cannabis users, the most commonly reported health benefit of vaping was better pain management (72.5%). Being habit-forming was the top perceived harm for both methods. Few significant differences emerged between perceived benefits and harms of vaping vs smoking, though younger users preferred vaping for stress reduction and women preferred it for mood improvement.","whyItMatters":"How people perceive the relative risks of different cannabis consumption methods influences their behavior. This study adds oral health perceptions, a largely unexplored area, to the conversation.","specificNumbers":"302 survey respondents (93.2% completion rate). Pain management was top vaping benefit (72.5%). Researching cannabis health effects associated with recognizing cardiovascular risk (Phi=0.141) and cavity risk (Phi=0.15). Women preferred vaping for mood (p=0.016). Younger users preferred vaping for stress/anxiety/depression (p=0.03).","methodology":"Online cross-sectional survey of 302 adults who used cannabis in the past month, recruited via Amazon Mechanical Turk. Assessed perceptions of general and oral health benefits and harms of vaping vs smoking cannabis.","limitations":"Convenience sample via MTurk may not represent all cannabis users. Cross-sectional design. Self-reported perceptions, not actual health outcomes. Small effect sizes for significant findings."},{"rthcId":"RTHC-06463","title":"Sex-Dependent Effects of MAOA Genotypes on the Relations Between Childhood Sexual Abuse, Aggression, and Cannabis Use in Emerging Adults.","authors":"Fite, Paula J; Ryder, Annie L; Baca, Selena; Hossain, Waheeda A; Manzardo, Ann; Butler, Merlin G; Bortolato, Marco","year":2025,"journal":"Journal of child sexual abuse, 34(4), 386-403","doi":"10.1080/10538712.2025.2519575","pmid":"40534101","tags":["genetics","youth","sex-differences","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 498 emerging adults, males with the low-activity MAOA gene variant (MAOA-L) who experienced childhood sexual abuse and used cannabis reported using it specifically for coping at higher rates than other groups. Surprisingly, the MAOA-L genotype in males appeared to buffer the impact of sexual abuse and heavy cannabis use on aggression measures.","whyItMatters":"This gene-environment interaction study reveals that the relationship between trauma, cannabis use, and aggression is more complex than assumed. A genetic variant that increases vulnerability to coping-motivated cannabis use may paradoxically reduce aggression.","specificNumbers":"498 emerging adults genotyped. MAOA-L males with childhood sexual abuse history had higher coping-motivated cannabis use. MAOA-L appeared to buffer aggression in males with both sexual abuse history and high cannabis use. No significant effects found among females.","methodology":"Cross-sectional genotyping study of 498 emerging adults. Assessed MAOA alleles (low vs high activity), childhood sexual abuse history, reactive and proactive aggression, and cannabis use patterns including coping motives.","limitations":"Cross-sectional design. Self-reported childhood sexual abuse. Single gene focus when multiple genes likely involved. Effects only observed in males. Relatively small sample for gene-environment interaction analysis."},{"rthcId":"RTHC-06464","title":"Per Se Driving Under the Influence of Cannabis Statutes and Blood Delta-9-Tetrahydrocannabinol Concentrations following Short-Term Cannabis Abstinence.","authors":"Fitzgerald, Robert L; Umlauf, Anya; Suhandynata, Raymond T; Grelotti, David J; Huestis, Marilyn A; Mastropietro, Kyle F; Grant, Igor; Marcotte, Thomas D","year":2025,"journal":"Clinical chemistry, 71(12), 1225-1233","doi":"10.1093/clinchem/hvaf121","pmid":"41222016","tags":["driving","legalization"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 190 regular cannabis users who abstained for at least 48 hours, 43% exceeded zero-tolerance THC limits (0.5+ ng/mL), 24% exceeded the 2 ng/mL per se limit, and 5.3% exceeded 5 ng/mL. The maximum observed baseline THC concentration was 16.2 ng/mL. Six hours after smoking, the median THC increase above baseline was only 0.5 ng/mL.","whyItMatters":"Several US states use THC blood concentration as legal proof of driving impairment, similar to blood alcohol limits. This study shows that regular users can exceed these limits days after their last use, when they are not impaired.","specificNumbers":"190 regular cannabis users. After 48+ hours abstinence: 43% exceeded zero-tolerance (0.5+ ng/mL), 24% exceeded 2 ng/mL, 5.3% exceeded 5 ng/mL. Max baseline: 16.2 ng/mL. Post-smoking median increase above baseline: only 0.5 ng/mL at 6 hours.","methodology":"Prospective cohort study of 190 regular cannabis users. Measured baseline blood THC after 48+ hours of abstinence, then measured serial THC levels after a controlled smoking session. Also assessed driving performance via driving simulator.","limitations":"Self-reported 48-hour abstinence (though confirmed by declining THC levels). Driving simulator may not fully replicate real-world driving. Study did not assess actual driving incidents or crashes."},{"rthcId":"RTHC-06465","title":"Pilot Study of Cannabidiol for Treatment of Aromatase Inhibitor-Associated Musculoskeletal Symptoms in Breast Cancer.","authors":"Fleege, Nicole M G; Miller, Elise A; Kidwell, Kelley M; Zacharias, Zeb R; Houtman, Jon; Scheu, Kelly; Kemmer, Kathleen; Boehnke, Kevin F; Henry, N Lynn","year":2025,"journal":"Cancer medicine, 14(15), e71117","doi":"10.1002/cam4.71117","pmid":"40751295","tags":["cbd","medical-cannabis","pain","cancer"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"In a phase 2 clinical trial, 17 of 39 breast cancer patients (43.6%) taking CBD (Epidiolex, titrated to 100mg twice daily) achieved at least a 2-point reduction in worst pain from aromatase inhibitor therapy. Among the 28 who completed the study, average worst pain decreased by 2.36 points over 15 weeks.","whyItMatters":"Aromatase inhibitor joint pain causes some breast cancer patients to stop life-saving cancer treatment. Finding a tolerable pain management option like CBD could improve both quality of life and cancer outcomes by keeping patients on their medication.","specificNumbers":"39 eligible patients enrolled. 28 completed treatment. 11 discontinued (5 toxicity, 6 patient preference). 17/39 (43.6%, 95% CI 28-60%) met primary endpoint. Worst pain improved 0.13 points per week (p<0.001). Completers: average 2.36-point pain reduction (95% CI -3.22 to -1.49). CBD dose: 100mg BID.","methodology":"Phase 2 clinical trial of 39 women with stage 0-3 hormone receptor-positive breast cancer experiencing aromatase inhibitor-associated musculoskeletal symptoms. CBD (Epidiolex) titrated to 100mg twice daily over 4 weeks, total treatment 15 weeks. Used paired t-tests and linear mixed models.","limitations":"No placebo control group. Small sample (39 patients). Open-label design allows placebo effects. 28% dropout rate. Pharmaceutical-grade CBD (Epidiolex) may differ from commercially available products."},{"rthcId":"RTHC-06466","title":"Characterizing Cannabidiol Use in a Breast Cancer Population.","authors":"Fleege, Nicole M G; Loeffler, Bradley T; Boehnke, Kevin F; Henry, Norah Lynn","year":2025,"journal":"Clinical breast cancer, 25(5), 464-471.e3","doi":"10.1016/j.clbc.2025.02.003","pmid":"40021432","tags":["cbd","medical-cannabis","cancer","pain","sleep"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 141 breast cancer patients surveyed, 68 (48.2%) reported prior or current CBD use. The most common reasons were pain management (75.6%), anxiety (61.0%), and insomnia (58.5%). The largest self-reported improvement was in insomnia, followed by pain. About 46% of former users stopped because CBD was ineffective.","whyItMatters":"CBD use among cancer patients is common but rarely discussed with physicians. Documenting the prevalence and reasons for use helps clinicians have informed conversations with patients.","specificNumbers":"141 evaluable surveys. 68 (48.2%) reported CBD use. Pain management: 75.6%. Anxiety: 61.0%. Insomnia: 58.5%. Biggest self-reported improvement: insomnia. Stopped due to inefficacy: 46.2%. Stopped due to side effects: 7.7%.","methodology":"Anonymous online survey of breast cancer patients at the University of Michigan Rogel Cancer Center, accessed via clinic flyer from September 2020 to February 2024.","limitations":"Convenience sample via clinic flyer (selection bias). Self-reported outcomes without clinical verification. Single cancer center."},{"rthcId":"RTHC-06467","title":"Young Adult Cannabis, Alcohol, Nicotine, and Nonprescribed Pain Reliever Use in Washington State Before and During COVID-19 Pandemic.","authors":"Fleming, Charles B; Martinez, Griselda; Rhew, Isaac C; Kilmer, Jason R; Larimer, Mary E; Guttmannova, Katarina","year":2025,"journal":"AJPM focus, 4(4), 100342","doi":"10.1016/j.focus.2025.100342","pmid":"40475023","tags":["youth","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Past-month cannabis use among 18-25 year olds increased by 1.6 percentage points per year from 2016-2019, with no pandemic-related disruption. Meanwhile, alcohol, cigarette, and e-cigarette use all declined.","whyItMatters":"Washington legalized recreational cannabis in 2012, making this a mature legal market. Cannabis use trends were resilient to pandemic disruption while other substance use declined.","specificNumbers":"Cannabis: +1.6 pp/year (95% CI 0.6-2.6), no pandemic deflection. Cigarettes: -3.8 pp deflection. E-cigarettes: -2.9 pp deflection in 2020. Under-21 cannabis: -7.5 pp deflection in 2020. N=12,516.","methodology":"Population-based survey of 12,516 young adults aged 18-25 across 6 annual waves (2016-2021) of the Washington State Young Adult Health Survey.","limitations":"Single state with established legal market. Survey-based self-report. Cannot isolate pandemic effects from other policy changes."},{"rthcId":"RTHC-06468","title":"Phenolic Constituents Drive Antimicrobial and Antibiotic-Enhancing Activities of Cannabis sativa Seed Extracts Obtained by Two Extraction Methods.","authors":"Floares Oarga, Doris; Obistioiu, Diana; Hulea, Anca; Alexa, Ersilia; Horablaga, Marinel Nicolae; Berbecea, Adina; Crista, Florin; Dehelean, Cristina; Radulov, Isidora","year":2025,"journal":"Plants (Basel, Switzerland), 15(1)","doi":"10.3390/plants15010027","pmid":"41514973","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06469","title":"Chemical Profile, Bioactive Constituents and In Vitro Growth Stimulation Properties of Cold-Pressed Hemp Seed Oils from Romanian Varieties: In Vitro and In Silico Evaluation.","authors":"Floares Oarga, Doris; Obistioiu, Diana; Hulea, Anca; Suleiman, Mukhtar Adeiza; Popescu, Iuliana; Buzna, Ciprian; Berbecea, Adina; Alexa, Ersilia; Dehelean, Cristina; Radulov, Isidora","year":2025,"journal":"Plants (Basel, Switzerland), 14(22)","doi":"10.3390/plants14223465","pmid":"41304617","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06470","title":"Exploratory study on plasma Acylglycerol and Acylethanolamide dysregulation in substance use and attention-deficit/hyperactivity disorder: Implications for novel biomarkers in dual diagnosis.","authors":"Flores-López, María; Herrera-Imbroda, Jesús; Requena-Ocaña, Nerea; García-Marchena, Nuria; Araos, Pedro; Verheul-Campos, Julia; Ruiz, Juan Jesús; Pastor, Antoni; de la Torre, Rafael; Bordallo, Antonio; Pavón-Morón, Francisco Javier; Rodríguez de Fonseca, Fernando; Serrano, Antonia","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 138, 111350","doi":"10.1016/j.pnpbp.2025.111350","pmid":"40188983","tags":["addiction","neuroscience","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"SUD patients had lower plasma 2-AG and 2-LG and elevated acylethanolamides vs controls. ADHD comorbidity was associated with additional reductions in AEA, DGLEA, DHEA, and SEA, while PEA was elevated. Machine learning identified AEA, OEA, PEA, and SEA as key biomarkers with 72.1% accuracy.","whyItMatters":"Blood-based biomarkers for SUD and ADHD comorbidity could improve diagnosis and guide treatment.","specificNumbers":"469 participants. Machine learning accuracy: 72.1%, ROC-AUC: 0.77. Key biomarkers: AEA, OEA, PEA, SEA.","methodology":"Exploratory study of 469 participants: 136 controls, 267 SUD-only, 66 SUD+ADHD. Measured 12 endocannabinoid-related molecules via HPLC-MS/MS. Elastic Net regression for biomarker identification.","limitations":"Cross-sectional design. Exploratory analysis needs independent validation. Plasma levels may not reflect brain ECS activity."},{"rthcId":"RTHC-06471","title":"Cannabidiol and Liver Enzyme Level Elevations in Healthy Adults: A Randomized Clinical Trial.","authors":"Florian, Jeffry; Salcedo, Pablo; Burkhart, Keith; Shah, Aanchal; Chekka, Lakshmi Manasa S; Keshishi, Dro; Patel, Vikram; Yang, ShanChao; Fein, Melanie; DePalma, Ryan; Matta, Murali; Strauss, David G; Rouse, Rodney","year":2025,"journal":"JAMA internal medicine, 185(9), 1070-1078","doi":"10.1001/jamainternmed.2025.2366","pmid":"40622698","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"8 of 143 participants (5.6%) taking CBD at 5 mg/kg/day developed ALT or AST elevations >3x ULN, vs 0 of 58 on placebo. Seven met withdrawal criteria for potential drug-induced liver injury, detected at days 21-28. No endocrine hormone changes observed.","whyItMatters":"This is the first rigorous trial testing CBD liver safety at doses consumers actually use. The 5.6% incidence in healthy people over just 4 weeks is a notable safety signal.","specificNumbers":"201 participants (median age 36, 44% female). CBD: 8/143 (5.6%, 95% CI 1.8-9.3%) with ALT/AST >3x ULN. Placebo: 0/58. 7 met DILI criteria. No endocrine changes.","methodology":"Randomized double-blind placebo-controlled trial by FDA researchers. 201 healthy adults, CBD 5 mg/kg/day vs placebo for 28 days. Weekly liver enzyme monitoring.","limitations":"Only 28 days. Pharmaceutical-grade CBD. Per protocol analysis. Healthy adults only. Relatively small sample."},{"rthcId":"RTHC-06472","title":"Association of Frequent Cannabis Use and Symptoms of Depression among Black College Students.","authors":"Floyd, Leah J","year":2025,"journal":"Substance use & misuse, 1-8","doi":"10.1080/10826084.2025.2586251","pmid":"41261895","tags":["depression","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 221 African American HBCU students, 30% reported frequent cannabis use. Depression was positively associated with frequent use (AOR=1.3, 95% CI 1.02-1.58). Students whose mothers had graduate degrees were 2.4x more likely to report frequent use.","whyItMatters":"Black/African American emerging adults have high cannabis use rates but low mental health service utilization. Understanding this connection could help design culturally tailored interventions.","specificNumbers":"221 students. 30% frequent cannabis use. AOR=1.3 (95% CI 1.02-1.58). Mother with graduate degree: AOR=2.4 (95% CI 1.06-5.39).","methodology":"Cross-sectional survey of 221 African American students at an HBCU. 70% female, mean age 20.3.","limitations":"Cross-sectional. Single HBCU. Small sample. 70% female. Low depression scores overall."},{"rthcId":"RTHC-06473","title":"Early onset marijuana use and suicidal ideation among African American college students.","authors":"Floyd, Leah J","year":2025,"journal":"Journal of ethnicity in substance abuse, 24(2), 518-532","doi":"10.1080/15332640.2023.2239741","pmid":"37529899","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"19% reported suicidal ideation, 28% reported early onset use. Early onset users were 3.33x more likely to report suicidal ideation (AOR=3.33, 95% CI 1.06-10.44) after controlling for demographics and mental health treatment.","whyItMatters":"Suicide rates among Black youth ages 15-24 rose 47% for males and 59% for females between 2013-2019. Early marijuana use may be a modifiable risk factor.","specificNumbers":"221 students. 19% suicidal ideation. 28% early onset use. AOR=3.33 (95% CI 1.06-10.44).","methodology":"Cross-sectional survey of 221 African American HBCU students (70% female, mean age 20.3). Multivariable logistic regression.","limitations":"Cross-sectional. Wide confidence interval. Small sample. Retrospective recall. Single HBCU."},{"rthcId":"RTHC-06474","title":"Evaluating Perceptions of the CANreduce 2.0 eHealth Intervention for Cannabis Use: Focus Group Study.","authors":"Folch-Sanchez, Daniel; Pellicer-Roca, Maria; Sestelo, María Agustina; Zuluaga, Paola; Arias, Francisco; Guzmán Cortez, Pablo; Amechat, Salma; Gil-Berrozpe, Gustavo; Lopez Montes, Estefania; Mercadé, Clara; Fonseca, Francina; Miquel, Laia; Mestre-Pintó, Joan I","year":2025,"journal":"Journal of medical Internet research, 27, e65025","doi":"10.2196/65025","pmid":"40106809","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06475","title":"Cannabinoids and the endocannabinoid system in the regulation of cytochrome P450 metabolic activity-a review.","authors":"Fonseca, Carlos D F; Zendulka, Ondřej; Juřica, Jan","year":2025,"journal":"Frontiers in pharmacology, 16, 1599012","doi":"10.3389/fphar.2025.1599012","pmid":"40538541","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06476","title":"Opioid Initiation in Older Patients with Chronic Pain Who Received Authorized Cannabis Prescription.","authors":"Fontaine, Emilie; El-Mourad, Jihane; Dubois, Cerina; Eurich, Dean T; Dyck, Jason R B; Hanlon, John G; Zongo, Arsene","year":2025,"journal":"Substance use & misuse, 1-12","doi":"10.1080/10826084.2025.2586250","pmid":"41267332","tags":["medical-cannabis","pain","seniors"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 3,427 opioid-naive patients 66+ with cannabis prescriptions, 1.84/100 person-years initiated 90+ day opioids vs 1.19/100 in 12,006 controls. Adjusted RR: 1.54 (95% CI 1.07-2.23), driven by males (RR 1.82).","whyItMatters":"This challenges the opioid-sparing narrative. For opioid-naive older adults, cannabis prescriptions were followed by higher opioid initiation rates.","specificNumbers":"3,427 vs 12,006 controls. Opioid initiation: 1.84 vs 1.19/100 person-years. RR: 1.54 (1.07-2.23). Males: RR 1.82. Females: RR 1.35 (NS).","methodology":"Retrospective cohort using Ontario administrative data. 3,427 exposed patients vs 12,006 controls (2014-2019). Inverse probability of treatment weighting.","limitations":"Observational. Cannabis patients may have more severe pain. Cannot capture OTC or black market cannabis use in controls."},{"rthcId":"RTHC-06477","title":"Family incarceration and adolescent nicotine, alcohol, and cannabis use: A coarsened exact matching approach.","authors":"Forster, Myriam; Shaverdi, Abnous; Zhang, Xiao; Toledo-Corral, Claudia M; Grigsby, Timothy J","year":2025,"journal":"Addictive behaviors, 164, 108270","doi":"10.1016/j.addbeh.2025.108270","pmid":"39904269","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using coarsened exact matching, family incarceration was associated with higher odds of early cannabis initiation (OR=1.63), past 30-day cannabis (OR=1.71), early alcohol initiation (OR=2.54), current alcohol (OR=2.11), and nicotine (OR=1.72).","whyItMatters":"Family incarceration affects millions of children disproportionately in communities of color. This isolates its unique contribution to substance use beyond other adversities.","specificNumbers":"Early cannabis: OR=1.63 (1.03-2.59). Current cannabis: OR=1.71 (1.17-2.48). Early alcohol: OR=2.54 (1.64-3.90). Current alcohol: OR=2.11 (1.50-2.94). Nicotine: OR=1.72 (1.21-2.45).","methodology":"Baseline survey of high school students. Coarsened exact matching balanced groups on other ACEs, demographics, and SES.","limitations":"Cross-sectional baseline. Self-reported. Cannot determine which family member or duration. Matching cannot eliminate all confounding."},{"rthcId":"RTHC-06478","title":"Relationships Between Motives for Cannabis and Cannabidiol Use in People Who Co-Use: Results From the European Web Survey on Drugs.","authors":"Fortin, Davide; Leroy, Vincent; Carrieri, Patrizia; Matias, João; Barré, Tangui","year":2025,"journal":"Drug and alcohol review, 44(6), 1666-1679","doi":"10.1111/dar.14090","pmid":"40484722","tags":["cbd","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 35,789 cannabis users, 42.3% also used CBD. CBD co-use was associated with therapeutic cannabis motives. Motive correlation rho=0.49. Four distinct co-user profiles emerged.","whyItMatters":"If cannabis and CBD users have overlapping motives, CBD could serve as a lower-risk alternative for some use patterns.","specificNumbers":"35,789 cannabis users. 42.3% co-used CBD. Motive correlation: rho=0.49 (p<0.001). Four co-user profiles identified.","methodology":"Third wave of the European Web Survey on Drugs across 30 countries. Multilevel logistic regression, tetrachoric correlations, hierarchical cluster analysis.","limitations":"Web survey self-selection bias. Self-reported motives. Cross-sectional. CBD product quality not verified."},{"rthcId":"RTHC-06479","title":"Cannabis growers as gardeners: results from a survey among Italian and British small-scale growers.","authors":"Fortin, Davide; Di Beo, Vincent; Kowalski, Michala; Sevigny, Eric L; Grigg, Jodie; Protopopescu, Camelia; Potter, Gary R","year":2025,"journal":"The International journal on drug policy, 144(Pt 3), 104959","doi":"10.1016/j.drugpo.2025.104959","pmid":"40816944","tags":["legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 1,302 growers, 82% also grew other plants. General gardeners were older, more educated, grew outdoors, and had medical/ecological motives. Only-cannabis growers had higher stimulant use and dependence rates. 71% started with other plants first.","whyItMatters":"Cannabis cultivation policy often assumes illicit market motivation. Most small-scale growers are gardening enthusiasts who expanded to cannabis.","specificNumbers":"1,302 growers. 82% grew other plants. 71% started with other plants first. Only-cannabis growers: higher stimulant use and dependence.","methodology":"Online survey of 1,302 small-scale cannabis growers in Italy and the UK (2020-2021).","limitations":"Online convenience sample. Self-reported. Different legal frameworks in Italy vs UK."},{"rthcId":"RTHC-06480","title":"Child and Adolescent Suicide in the Broader Area of Athens, Greece: A 13-Year Retrospective Forensic Case-Series Analysis.","authors":"Fragkou, Kallirroi; Alexandri, Maria; Dimitriou, Konstantinos; Tatsioni, Athina; Bacopoulou, Flora; Ferentinos, Panagiotis; Martrille, Laurent; Papadodima, Stavroula","year":2025,"journal":"Pediatric reports, 17(4)","doi":"10.3390/pediatric17040072","pmid":"40700060","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06481","title":"Lifelong dietary Omega-3, -6, and -9 ratios shape adult behavior and response to adolescent THC exposure in rats.","authors":"Frajerman, Ariel; Marzo, Aude; Chaumette, Boris; Jay, Thérèse M; Demars, Fanny; Lamazière, Antonin; Kebir, Oussama; Krebs, Marie-Odile; Le Pen, Gwenaëlle","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 256, 174086","doi":"10.1016/j.pbb.2025.174086","pmid":"40835021","tags":["neuroscience","youth","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In 164 rats fed omega-3, -6, or -9 enriched diets from conception, diet significantly affected social behavior, anxiety, cognitive flexibility, and impulse control. Omega-3 rats were less anxious and more impulsive than omega-6. THC x diet x sex interaction significant for anxiety and impulsivity.","whyItMatters":"Diet is a modifiable factor that could influence vulnerability to THC effects during brain development.","specificNumbers":"164 rats, 3 diet groups. Omega-3: less anxiety, more impulsivity vs omega-6. THC x diet x sex interaction significant.","methodology":"164 Sprague Dawley rats (male and female) on lifelong enriched diets. Tested in adulthood on multiple behavioral paradigms. Some received adolescent THC.","limitations":"Animal model. Novel fatty acid ratios limit comparison. Multiple behavioral tests increase false positive risk."},{"rthcId":"RTHC-06482","title":"Neighborhood level factors and use of cigarettes, cannabis and e-cigarettes: A population-based study among Canadian adults.","authors":"Fraser Wood, Truman; Dummer, Trevor J B; Peters, Cheryl E; Murphy, Rachel A","year":2025,"journal":"PloS one, 20(11), e0320035","doi":"10.1371/journal.pone.0320035","pmid":"41284708","tags":["legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Material deprivation, social deprivation, and household insecurity were positively associated with all three substances. Gentrified neighborhoods also had higher use. High immigrant/visible minority neighborhoods had lower use.","whyItMatters":"Most prevention targets individuals, but neighborhood characteristics independently predict use, supporting environmental interventions.","specificNumbers":"All three deprivation measures positively associated with cannabis, cigarette, and e-cigarette use. Gentrified: higher odds. High immigrant/minority: lower odds.","methodology":"Canadian Partnership for Tomorrow's Health cohort. Neighborhood-level measures linked via postal codes. Regression models adjusted for individual factors.","limitations":"Cross-sectional. Self-reported. Postal code-level measures. Canadian context."},{"rthcId":"RTHC-06483","title":"Characterizing the Population of a Medical Cannabis Clinic in a Pediatric Hospital.","authors":"Free, Taylor; Grossoehme, Daniel H; Richner, Gwendolyn; Brown, Miraides F; Friebert, Sarah","year":2025,"journal":"Journal of palliative medicine, 28(8), 1020-1028","doi":"10.1089/jpm.2024.0533","pmid":"40180570","tags":["medical-cannabis","youth","cancer","pain"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Among 46 pediatric palliative care patients (mean age 11.7), there was a significant decrease in inpatient days and cost. 35% reduced or discontinued other medications. Most common recommendation: 1:1 CBD:THC tincture. No significant adverse events.","whyItMatters":"Evidence for medical cannabis in pediatric palliative care is extremely limited. This real-world data suggests benefits with minimal adverse effects.","specificNumbers":"46 patients (mean age 11.7). 50% neurological, 37% oncological, 13% chronic pain. 35% reduced other medications. Significant decrease in inpatient days.","methodology":"Retrospective chart review of 46 consecutive patients at a midwestern US pediatric hospital (2019-2022).","limitations":"Small sample. No control group. Single center. Cannot attribute improvements solely to cannabis."},{"rthcId":"RTHC-06484","title":"Molecular determinants of 2-aminoethoxydiphenyl borate sensitivity of transient receptor potential vanilloid 2-unexpected differences between 2 rodent orthologs.","authors":"Fricke, Tabea C; Rämisch, Anna; Pumroy, Ruth A; Pantke, Sebastian; Herzog, Christine; Echtermeyer, Frank G; Al-Samir, Samer; Endeward, Volker; Moiseenkova-Bell, Vera; Leffler, Andreas","year":2025,"journal":"Molecular pharmacology, 107(8), 100060","doi":"10.1016/j.molpha.2025.100060","pmid":"40773831","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06485","title":"Cannabinoid exposure in infants and children in the pediatric emergency department-the child protection perspective.","authors":"Fridler, Dvora; Cahan, Lea Ohana Sarna; Moshe, Adi Bracha; Guzner, Noa; Gross, Itai; Hashavya, Saar","year":2025,"journal":"European journal of pediatrics, 184(5), 310","doi":"10.1007/s00431-025-06129-1","pmid":"40272510","tags":["youth","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Over 10 years, 29 children 0-48 months tested positive for cannabis. Neurological symptoms were universal. CPT activated in 100%, police reports 93.1%, CPS contacted 62.1%. Only one caregiver admitted exposure. 37.9% had multiple prior ER visits.","whyItMatters":"As cannabis products become more available, pediatric exposures increase. Non-specific symptoms and caregiver denial make diagnosis challenging.","specificNumbers":"29 cases. 65.5% male. Median age 14 months. CPT: 100%. Police: 93.1%. CPS: 62.1%. Caregiver admission: 3.4%. Multiple prior ER visits: 37.9%.","methodology":"Retrospective 10-year analysis (2010-2021) at Hadassah Medical Center, Jerusalem. Children 0-48 months with positive cannabis urine toxicology.","limitations":"Single center in Jerusalem. Small sample. Retrospective. Cannot determine route or intentionality."},{"rthcId":"RTHC-06486","title":"Pilot study: impacts of cannabinoids from industrial hemp and repeated transportation events on cattle health and immune status.","authors":"Fritz, Bailey R; Kleinhenz, Michael D; Griffin, Jason J; Weeder, Mikaela M; Magnin, Geraldine; Nelson, Alyssa A; Johnson, Blaine T; Curtis, Andrew K; Coetzee, Johann F","year":2025,"journal":"Translational animal science, 9, txaf160","doi":"10.1093/tas/txaf160","pmid":"41472843","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06487","title":"Plasma cannabinoid concentrations and transference during long-term industrial hemp administration in cattle.","authors":"Fritz, Bailey R; Kleinhenz, Michael D; Griffin, Jason J; Weeder, Mikaela M; Nelson, Alyssa A; Curtis, Andrew K; Magnin, Geraldine; Ferm, Jonathan; Ganta, Roman R; Coetzee, Johann F","year":2025,"journal":"Journal of animal science, 103","doi":"10.1093/jas/skaf418","pmid":"41358942","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06488","title":"Tissue residue depletion of cannabinoids in cattle administered industrial hemp inflorescence.","authors":"Fritz, Bailey R; Kleinhenz, Michael D; Magnin, Geraldine; Griffin, Jason J; Weeder, Mikaela M; Curtis, Andrew K; Martin, Miriam S; Nelson, Alyssa A; Kleinhenz, Katie E; Johnson, Blaine T; Fritz, Scott A; Montgomery, Shawnee R; Tkachenko, Andriy; Coetzee, Johann F","year":2025,"journal":"Scientific reports, 15(1), 42337","doi":"10.1038/s41598-025-26448-5","pmid":"41309806","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06489","title":"The endocannabinoid and paracannabinoid systems in natural reward processes: possible pharmacological targets?","authors":"Friuli, Marzia; Eramo, Barbara; Sepe, Christian; Kiani, Mitra; Casolini, Paola; Zuena, Anna Rita","year":2025,"journal":"Physiology & behavior, 296, 114929","doi":"10.1016/j.physbeh.2025.114929","pmid":"40274041","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06490","title":"Neural Signatures of Cannabis Use: Reversing Cognitive Aging via Whole-Brain Functional Network Connectivity.","authors":"Fu, Zening; Hutchison, Kent; Iraji, Armin; Sui, Jing; Calhoun, Vince","year":2025,"journal":"Research square","doi":"10.21203/rs.3.rs-6977015/v1","pmid":"40766216","tags":["cognition","seniors","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use and healthy aging were associated with overlapping brain network configurations, particularly between subcortical-sensorimotor and subcortical-cerebellar regions, but with significantly reversed effects. Cannabis users showed superior cognitive performance across multiple domains and brain network characteristics typically associated with younger brains.","whyItMatters":"As cannabis use increases among older adults, understanding how it interacts with brain aging processes is critical. This large-scale study suggests cannabis may have modulatory effects on age-related brain changes.","specificNumbers":"Over 25,000 UK Biobank participants analyzed. Cannabis use and aging showed overlapping but reversed brain network patterns. Cannabis users showed superior performance across multiple cognitive domains.","methodology":"Analysis of 25,000+ UK Biobank participants examining relationships between cannabis use, brain functional network connectivity (FNC), normative aging, and cognitive function.","limitations":"Cross-sectional. Self-reported cannabis use. UK Biobank healthy volunteer bias. Cannot determine whether cannabis causes differences or healthier-brained people use cannabis."},{"rthcId":"RTHC-06491","title":"Insights into terpenes profiling and transcriptional analyses during flowering of different Cannabis sativa L. chemotypes.","authors":"Fulvio, Flavia; Pieracci, Ylenia; Ascrizzi, Roberta; Bassolino, Laura; Flamini, Guido; Paris, Roberta","year":2025,"journal":"Phytochemistry, 229, 114294","doi":"10.1016/j.phytochem.2024.114294","pmid":"39374748","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06492","title":"Conceptualizing 'cannabis harm reduction': lessons learned from cannabis compassion clubs and medical dispensaries in British Columbia (Canada).","authors":"Gagnon, Marilou; Hobbs, Heather","year":2025,"journal":"Harm reduction journal, 22(1), 70","doi":"10.1186/s12954-025-01199-8","pmid":"40307811","tags":["harm-reduction","medical-cannabis","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Through interviews and document analysis, researchers identified structural (addressing systemic barriers through access, safety, quality) and operational (low-threshold, compassionate services with support) dimensions of cannabis harm reduction that worked together.","whyItMatters":"Understanding what made pre-legalization compassion clubs effective can inform community-oriented cannabis policy.","specificNumbers":"Seven data sources analyzed. Two main dimensions: structural and operational. Three types of interviews conducted.","methodology":"Qualitative case study of cannabis compassion clubs in British Columbia. Seven data sources including interviews with key informants, operational staff, and people with lived experience.","limitations":"Qualitative study in single province. Cannot quantify effects. Potential selection bias in interviews."},{"rthcId":"RTHC-06493","title":"Tracking metal presence in cannabis vaping products from source to inhalation.","authors":"Gajdosechova, Zuzana; Marleau-Gillette, Joshua; Polivchuk, Matthew; Kosarac, Ivana; Katuri, Guru Prasad; Das, Dharani; Cabecinha, Ashley; Waye, Andrew; Abramovici, Hanan","year":2025,"journal":"Scientific reports, 15(1), 31939","doi":"10.1038/s41598-025-17004-2","pmid":"40883388","tags":["harm-reduction","respiratory"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Legal Canadian cannabis vape liquids contained metal particles (Al, Co, Cr, Cu, Ni, Sn, Zn) originating from device components. All aerosols contained Co, Cr, Ni, Pb, Sn, Zn. SEM showed cracking on unused device connector pins.","whyItMatters":"Even regulated products expose users to metals from hardware. Vaping device standards may need as much attention as cannabis quality standards.","specificNumbers":"Six products tested. All aerosols contained Co, Cr, Ni, Pb, Sn, Zn particles. Device metals matched detected particles. Cracking on unused device connectors observed.","methodology":"Total metals analysis and single-particle ICP-MS on six legal Canadian cannabis vape products. Aerosol analysis via vaping machine. SEM-EDS on emptied cartridges.","limitations":"Small product sample. Legal Canadian products only. Particle counts below LOQ. Long-term health effects unknown."},{"rthcId":"RTHC-06494","title":"Cannabis sativa in the fight against drug-resistant bacteria and fungi.","authors":"Gałka, Sabina","year":2025,"journal":"Folia medica Cracoviensia, 65(4), 101-111","doi":"10.24425/fmc.2025.156701","pmid":"41607163","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06495","title":"Partner History of Problematic Substance Use and Self-Reported Substance Use During Early Pregnancy: Findings from Kaiser Permanente Northern California, 2021-2022.","authors":"Gallegos, Rachel; Slama, Natalie E; Duggan, Mark C; Ansley, Deborah; Castellanos, Carley; Young-Wolff, Kelly C","year":2025,"journal":"Maternal and child health journal, 29(11), 1505-1511","doi":"10.1007/s10995-025-04164-w","pmid":"40900197","tags":["pregnancy","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 82,180 pregnant individuals, partner substance problems were associated with 89% higher odds of prenatal cannabis (aOR=1.89), 238% higher odds of e-cigarettes (aOR=3.38), and 266% higher odds of tobacco (aOR=3.66).","whyItMatters":"Partner substance use is a modifiable risk factor for prenatal exposure. Screening partners could identify at-risk pregnancies.","specificNumbers":"82,180 pregnant people. Cannabis: aOR=1.89 (1.57-2.27). E-cigarettes: aOR=3.38 (2.43-4.58). Tobacco: aOR=3.66 (2.63-4.96). Alcohol: aOR=1.58 (1.33-1.87).","methodology":"Retrospective cohort of 82,180 pregnant people screened at first prenatal visit in Kaiser Permanente Northern California (2021-2022). Self-report plus urine toxicology for cannabis.","limitations":"Self-reported partner use (likely underreported). Kaiser population. Cannot determine if partner use causes prenatal use."},{"rthcId":"RTHC-06496","title":"Tetrahydrocannabinol separation from cannabis extracts using centrifugal partition chromatography.","authors":"Gallo-Molina, Ada C; Sánchez-Correa, César A; Gil-Chaves, Iván D","year":2025,"journal":"Journal of chromatography. A, 1757, 466173","doi":"10.1016/j.chroma.2025.466173","pmid":"40582024","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06497","title":"Physiological Muscle Function Is Controlled by the Skeletal Endocannabinoid System in Murine Skeletal Muscles.","authors":"Ganbat, Nyamkhuu; Singlár, Zoltán; Szentesi, Péter; Lilliu, Elena; Kohler, Zoltán Márton; Juhász, László; Keller-Pintér, Anikó; Koenig, Xaver; Iannotti, Fabio Arturo; Csernoch, László; Sztretye, Mónika","year":2025,"journal":"International journal of molecular sciences, 26(11)","doi":"10.3390/ijms26115291","pmid":"40508098","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06498","title":"A quantitative projection of the net health effects of cannabis legalization in Germany.","authors":"Gandjour, Afschin","year":2025,"journal":"PloS one, 20(9), e0330879","doi":"10.1371/journal.pone.0330879","pmid":"40892726","tags":["legalization","addiction","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Projected 400,000-800,000 new users and ~2,300 additional severe mental health cases. QALY losses from CUD were 19x greater than gains from reduced contamination. Even a 1% consumption increase would produce net harm.","whyItMatters":"Germany legalized partly to reduce black market harms. This analysis suggests health costs from increased use may far outweigh contamination gains.","specificNumbers":"400,000-800,000 projected new users. ~2,300 additional severe mental health cases. QALY losses 19x greater than gains. 1% increase sufficient for net harm.","methodology":"Quantitative projection model balancing harm reduction from fewer contaminants against risks from increased consumption using QALY calculations.","limitations":"Projection model with inherent uncertainty. Does not account for criminal justice benefits or destigmatization. Consumption estimates may be inaccurate."},{"rthcId":"RTHC-06499","title":"Advances in Extraction and Quantification of Minor Phytocannabinoids.","authors":"Gandlevskiy, Nikita; Barge, Alessandro; Cravotto, Giancarlo","year":2025,"journal":"Phytochemical analysis : PCA","doi":"10.1002/pca.70040","pmid":"41321142","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06500","title":"Genome-wide identification and characterization of CONSTANS-like transcription factors reveal that three CsCOLs regulate the cannabinoid biosynthesis in Cannabis.","authors":"Gao, Maolun; Chen, Shanshan; Kong, Lingzhe; Wang, Liwei; Meng, Xiangxiao; Xie, Ziyan; Xu, Zhichao; Mi, Yaolei","year":2025,"journal":"Plant physiology and biochemistry : PPB, 224, 109942","doi":"10.1016/j.plaphy.2025.109942","pmid":"40318441","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06501","title":"Cannabis Use and Adverse Childhood Experiences Among Cancer Survivors.","authors":"Gao, May Z; Babatunde, Oluwole A; Jefferson, Melanie S; Adams, Swann A; Hughes Halbert, Chanita; Osazuwa-Peters, Nosayaba; Adjei Boakye, Eric","year":2025,"journal":"Cancer medicine, 14(22), e71400","doi":"10.1002/cam4.71400","pmid":"41275428","tags":["cancer","mental-health","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among nearly 8,000 cancer survivors, those with four or more adverse childhood experiences (ACEs) had 4.1 times greater odds of cannabis use compared to those with zero ACEs, with a clear dose-response pattern.","whyItMatters":"Childhood trauma appears to be a strong predictor of cannabis use in cancer survivors, suggesting that substance use screening in oncology settings should account for early life adversity.","specificNumbers":"6.0% overall cannabis use prevalence among cancer survivors. 44.1% reported zero ACEs. Adjusted odds ratios: 2-3 ACEs = 2.56 (95% CI: 1.57-4.27); 4+ ACEs = 4.10 (95% CI: 2.54-6.64).","methodology":"Cross-sectional analysis of 7,896 cancer survivors from the 2020 Behavioral Risk Factor Surveillance System. ACEs were categorized into four groups (0, 1, 2-3, 4+). Weighted multivariable logistic regression controlled for demographics, smoking, and health status.","limitations":"Cross-sectional design cannot establish causation. Self-reported data on both ACEs and cannabis use introduces recall bias. The BRFSS does not distinguish between medical and recreational cannabis use."},{"rthcId":"RTHC-06502","title":"State of the Art Review: Thiazide diuretics exploit the endocannabinoid system via NAPE-PLD.","authors":"Garau, Gianpiero","year":2025,"journal":"American journal of hypertension","doi":"10.1093/ajh/hpaf174","pmid":"40892892","tags":["cardiovascular","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The phospholipase NAPE-PLD was identified as a systemic target of thiazide diuretics, meaning these common blood pressure medications produce their chronic therapeutic effects partly by generating anandamide and other protective lipid signaling molecules through the endocannabinoid system.","whyItMatters":"This reframes our understanding of one of the most widely prescribed classes of blood pressure medication. Knowing that thiazides work partly through the endocannabinoid system opens the door to designing more targeted cardiovascular therapies.","specificNumbers":"Over sixty years of clinical thiazide use. CB1 agonists caused hypotension but risked tachycardia, heart, and kidney damage. FAAH inhibitors normalized blood pressure in hypertensive rats.","methodology":"State-of-the-art narrative review synthesizing thirty years of research on endocannabinoid system modulation for hypertension, including the author's discovery of NAPE-PLD as a thiazide target.","limitations":"As a narrative review, this reflects a selective synthesis rather than a systematic evaluation of all evidence. The NAPE-PLD mechanism is relatively new and requires further validation."},{"rthcId":"RTHC-06503","title":"Investigation of the toxic dose of ingested delta-8 tetrahydrocannabinol among young children.","authors":"Garay, Ryan S; Hays, Hannah L; Badeti, Jaahnavi; Rine, Natalie I; Gaw, Christopher E; Middelberg, Leah K; Smith, Gary A","year":2025,"journal":"Injury epidemiology, 12(1), 63","doi":"10.1186/s40621-025-00617-6","pmid":"41029884","tags":["youth","potency","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 232 cases of young children who ingested delta-8 THC, those who consumed doses in the top quartile (above 17 mg/kg) had 3.4 times greater odds of severe toxicity and 5 times greater odds of prolonged toxicity. A cutoff of 1.7 mg/kg had 98% sensitivity for identifying severe toxicity.","whyItMatters":"With delta-8 THC products proliferating in states where delta-9 remains restricted, pediatric exposures have surged. This study gives healthcare providers the first dose-based reference points for assessing severity.","specificNumbers":"232 cases, median age 3.0 years. Median ingested dose: 6.7 mg/kg. CNS depression in 75.5% of cases. Top quartile (>17 mg/kg): 3.43x odds of severe toxicity, 5.02x odds of prolonged toxicity. 1.7 mg/kg cutoff: 98% sensitivity.","methodology":"Retrospective analysis of single-substance delta-8 THC ingestions in children under 6 reported to U.S. poison centers via the National Poison Data System. Dose-response relationships evaluated using logistic regression and ROC curve analysis.","limitations":"Poison center data relies on caregiver-reported doses, which may be inaccurate. Delta-8 THC product labeling is notoriously unreliable. High sensitivity at 1.7 mg/kg came with low specificity (28%)."},{"rthcId":"RTHC-06504","title":"Taxonicity of cannabis use disorder: Findings from a large community sample and an inpatient clinical sample.","authors":"Garber, Molly L; Taisir, Radia; Costello, Jean; MacKillop, James","year":2025,"journal":"Journal of psychopathology and clinical science, 134(7), 790-798","doi":"10.1037/abn0001031","pmid":"40638307","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using three taxometric procedures across a large community sample (N=3,623) and a clinical inpatient sample (N=621), cannabis use disorder consistently showed dimensional rather than categorical structure, with mean CCFIs well below the 0.50 threshold for taxonicity.","whyItMatters":"This has direct implications for how cannabis addiction is diagnosed. The findings support the DSM-5 dimensional approach (mild/moderate/severe) over the ICD-11 binary model (dependence yes/no).","specificNumbers":"Community sample CCFIs: MAMBAC=0.48, MAXEIG=0.30, L-Mode=0.43, mean=0.40. Clinical sample CCFIs: MAMBAC=0.09, MAXEIG=0.21, L-Mode=0.26, mean=0.19. Values below 0.50 indicate dimensional structure.","methodology":"Three taxometric procedures (MAMBAC, MAXEIG, L-Mode) applied to DSM-5 CUD criteria in the nationally representative NESARC-III community sample and a clinical inpatient substance use treatment sample from Ontario, Canada.","limitations":"Taxometric methods require specific distributional assumptions. The clinical sample was exclusively from inpatient treatment, representing the more severe end of the spectrum."},{"rthcId":"RTHC-06505","title":"Role of the Endocannabinoid System in Fibromyalgia.","authors":"García-Domínguez, Mario","year":2025,"journal":"Current issues in molecular biology, 47(4)","doi":"10.3390/cimb47040230","pmid":"40699629","tags":["pain","medical-cannabis","inflammation"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The endocannabinoid system plays a central role in pain perception, mood regulation, and inflammation, and variations in endocannabinoid levels and receptor activity in fibromyalgia patients may contribute to clinical symptoms.","whyItMatters":"Fibromyalgia affects millions and remains poorly understood with limited treatment options. If endocannabinoid system dysfunction is a key driver, it could open pathways for targeted cannabinoid-based therapies.","specificNumbers":"No specific numerical outcomes reported; this is a qualitative synthesis of existing literature.","methodology":"Narrative review analyzing published literature on the endocannabinoid system's involvement in fibromyalgia pathophysiology, with a focus on pain modulation mechanisms.","limitations":"Narrative review rather than systematic review, so subject to selection bias. Much of the evidence on ECS dysfunction in fibromyalgia is indirect or from small studies."},{"rthcId":"RTHC-06506","title":"Endocannabinoid system gene expression in mesocorticolimbic brain regions of individuals with alcohol use disorder: A descriptive study.","authors":"García-Gutiérrez, María Salud; Torregrosa, Abraham Bailén; Navarrete, Francisco; Aracil-Fernández, Auxiliadora; Rubio, Gabriel; Manzanares, Jorge","year":2025,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70293","pmid":"41424074","tags":["neuroscience","addiction"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Individuals with AUD showed higher CNR1 expression in the prefrontal cortex (+125%) and nucleus accumbens (+78%), lower CNR2 expression in both regions (-50% and -49%), and region-specific differences in GPR55, FAAH, and MGLL expression.","whyItMatters":"These findings provide direct human brain evidence that chronic alcohol use is associated with widespread changes in the endocannabinoid system, suggesting this system may be a therapeutic target for alcohol addiction.","specificNumbers":"CNR1: +125% in PFC, +78% in NAc. CNR2: -50% in PFC, -49% in NAc. GPR55: +19% in PFC, -51% in NAc. FAAH: -15% in PFC, +24% in NAc. MGLL: no change in PFC, -15% in NAc.","methodology":"Postmortem case-control study comparing endocannabinoid system gene expression via qPCR in prefrontal cortex and nucleus accumbens tissue from 18 AUD patients (mean 35.5 drinking years) and 18 age-matched controls.","limitations":"Small sample size (18 per group). Postmortem tissue cannot establish causation. Gene expression does not necessarily reflect protein levels or functional activity. Exploratory and not pre-registered."},{"rthcId":"RTHC-06507","title":"Cannabidiol Prevents Heart Failure Dysfunction and Remodeling Through Preservation of Mitochondrial Function and Calcium Handling.","authors":"García-Rivas, Gerardo; Lozano, Omar; Bernal-Ramírez, Judith; Silva-Platas, Christian; Salazar-Ramírez, Felipe; Méndez-Fernández, Abraham; Morales-Ochoa, Carolina; Alves-Figueiredo, Hugo; Ramos-González, Martín Rogelio; Rubio-Infante, Nestor; Vázquez-Garza, Eduardo; Luévano-Martínez, Luis A; López-Morán, Silvia; Chapoy-Villanueva, Héctor; Bolton, James; Velasco-Bolom, José-Luis; Mendoza-Espinosa, Paola; Contreras-Torres, Flavio F; Jerjes-Sánchez, Carlos; Torre-Amione, Guillermo","year":2025,"journal":"JACC. Basic to translational science, 10(6), 800-821","doi":"10.1016/j.jacbts.2024.12.009","pmid":"40562493","tags":["cbd","cardiovascular"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"In mice with heart failure, CBD treatment attenuated cardiac fibrosis, hypertrophy, and loss of ejection fraction. Isolated cardiomyocytes preserved cell shortening, calcium handling, mitochondrial function, and redox balance. Effects appeared mediated through PPARgamma receptors.","whyItMatters":"Heart failure is characterized by progressive energy depletion and cellular dysfunction. If CBD can preserve mitochondrial function and calcium handling, it could represent a novel cardioprotective strategy targeting underlying cellular mechanisms.","specificNumbers":"CBD attenuated loss of ejection fraction, reduced cardiac fibrosis and hypertrophy. PPARgamma receptor pathway identified as the mechanism.","methodology":"Animal study using a mouse heart failure model with subcutaneous CBD administration. Cardiac function assessed via ejection fraction. Cellular mechanisms examined in isolated cardiomyocytes and hypertrophied ventricular cardiomyoblasts in vitro.","limitations":"Animal model findings may not translate to human heart failure. Subcutaneous CBD has different pharmacokinetics than oral administration. Specific dosing details not available in the abstract."},{"rthcId":"RTHC-06508","title":"Preclinical evaluation of cannabidiolic acid as a neuroprotective agent in TDP-43 transgenic mice, an experimental model of amyotrophic lateral sclerosis.","authors":"García-Toscano, Laura; Rodríguez-Cueto, Carmen; Furiano, Anna; Hind, William; de Lago, Eva; Fernández-Ruiz, Javier","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 189, 118288","doi":"10.1016/j.biopha.2025.118288","pmid":"40580876","tags":["cbd","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Among five phytocannabinoids tested, CBDA at 10 mg/kg was the most effective, improving motor coordination, reducing neuronal cell death and neuroinflammation, and shifting microglia from pro-inflammatory to anti-inflammatory. CBDA showed superior neuroprotection compared to riluzole on most measures.","whyItMatters":"ALS has extremely limited treatment options. If CBDA consistently outperforms riluzole in preclinical models, it could warrant clinical trials as either an alternative or adjunct therapy.","specificNumbers":"Optimal dose: 10 mg/kg CBDA. Five cannabinoids compared. Treatment period: day 65-90. Higher CBDA doses caused toxicity. CBD + riluzole combination did not enhance efficacy.","methodology":"Preclinical study in Prp-hTDP-43(A315T) transgenic male mice, an ALS model, treated from early symptomatic (day 65) to advanced stages (day 90). Five cannabinoids compared, followed by CBDA dose-response testing and comparison with riluzole.","limitations":"Only male mice were tested. The TDP-43 model represents one ALS subtype. Higher doses caused toxicity, suggesting a narrow therapeutic window."},{"rthcId":"RTHC-06509","title":"Field-Portable Device for Detection of Controlled and Psychoactive Substances from e-Cigarettes.","authors":"Gardner, Matthew; Bowden, Celeste; Manzoor, Shoaib; Cozier, Gyles E; Andrews, Rachael C; Craft, Sam; Skumlien, Martine; Sunderland, Peter; Tooth, Tom; Collins, Peter; Power, Alexander; Haines, Tom S F; Freeman, Tom P; Scott, Jennifer; Sutcliffe, Oliver B; Bowman, Richard W; Husbands, Stephen M; Pudney, Christopher R","year":2025,"journal":"ACS omega, 10(8), 7839-7847","doi":"10.1021/acsomega.4c08614","pmid":"40060840","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06510","title":"Mobile intervention to address cannabis use disorder among black adults: A proof-of-concept randomized controlled trial.","authors":"Garey, Lorra; Jones, Ava A; Nizio, Pamella; Chen, Tzuan A; Buckner, Julia D; Redmond, Brooke Y; Businelle, Michael S; Cheney, Marshall K; Obasi, Ezemenari M; Zvolensky, Michael J","year":2025,"journal":"Behaviour research and therapy, 195, 104889","doi":"10.1016/j.brat.2025.104889","pmid":"41109077","tags":["addiction","quitting","medical-cannabis","harm-reduction","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Black adults who use cannabis face documented health disparities: more frequent use and higher rates of cannabis use disorder compared to White adults, yet they are underrepresented in treatment research and face greater barriers to accessing care. This study tested whether a culturally tailored mobile app could address both the access and the cultural relevance gaps.\n\nThe app — CT-MICART (Culturally Tailored Mobile Integrated Cannabis and Anxiety Reduction Treatment) — combined two therapeutic approaches: false safety behavior (FSB) reduction skills (addressing anxiety-driven avoidance patterns) and cannabis use reduction or cessation skills. Cultural tailoring meant the content, language, and examples were specifically designed for Black adult users.\n\nFifty participants (50% female, mean age 42.9) were randomized to either the app plus ecological momentary assessments (EMAs) or EMAs alone for 6 weeks. The feasibility results were strong: good enrollment, retention, and EMA completion rates. App feature engagement was meaningful — participants actually used the therapeutic content. Acceptability was high based on satisfaction ratings.\n\nPreliminary efficacy signals showed cannabis use reduction in the app group compared to the EMA-only group. This is a proof-of-concept study, so it wasn't powered to definitively prove efficacy, but the direction of the results supports moving to a full-scale trial.\n\nThe integration of anxiety reduction with cannabis reduction reflects the recognition that many people use cannabis to manage anxiety — addressing the underlying anxiety may be necessary for sustained cannabis reduction.","whyItMatters":"Cannabis use disorder treatment research has predominantly studied White populations, and treatment access for Black adults is limited by structural barriers. Mobile interventions can bypass many access barriers (transportation, stigma, work schedules, provider availability), and cultural tailoring may improve engagement and relevance. If CT-MICART proves effective in a larger trial, it would represent a scalable, accessible intervention for an underserved population.","specificNumbers":"50 participants. 50% female. Mean age 42.9 years (SD 10.7). 6-week intervention period. Two arms: CT-MICART + EMAs vs. EMAs only. Strong enrollment, retention, and EMA completion rates. Meaningful app feature engagement. Preliminary signals of cannabis use reduction in the app group.","methodology":"Proof-of-concept randomized controlled trial. 50 Black adults with CUD (50% female, mean age 42.9). Randomized to CT-MICART app + EMAs or EMAs-only for 6 weeks. Feasibility: enrollment, retention, EMA completion. Utilization: app feature engagement. Acceptability: self-reported satisfaction. Preliminary efficacy: cannabis use outcomes.","limitations":"Proof-of-concept with only 50 participants — too small for definitive efficacy conclusions. The 6-week duration may be too short to assess sustained behavior change. The EMA-only control group received some therapeutic benefit from self-monitoring, potentially reducing the between-group difference. No long-term follow-up. Participants were self-selected (motivated enough to join a study), which may not reflect the broader population of Black adults with CUD. The app content is described but specific therapeutic components aren't detailed in the abstract."},{"rthcId":"RTHC-06511","title":"Cannabis consumption patterns, adverse events, and cannabis risk beliefs: A latent profile analysis in WA State.","authors":"Garrett, Sharon B; Williams, Jason R; Carlini, Beatriz H; Hammond, David","year":2025,"journal":"Drug and alcohol dependence, 273, 112728","doi":"10.1016/j.drugalcdep.2025.112728","pmid":"40446497","tags":["harm-reduction","addiction","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Six user profiles ranged from weekly flower-only users to daily concentrate users. The four groups with most frequent and varied product use were significantly more likely to self-identify as addicted. The highest-frequency concentrate group reported fewer adverse events than the polymodal group.","whyItMatters":"This challenges the simple assumption that more use equals more problems. Product variety may matter as much as frequency, suggesting harm reduction messaging should address polymodal use patterns.","specificNumbers":"3,298 past-year cannabis users. Six latent profiles identified. Four highest-use groups significantly more likely to self-identify as addicted.","methodology":"Latent profile analysis of 3,298 past-year cannabis users aged 16-65 in Washington State from the International Cannabis Policy Study (2019-2022).","limitations":"Cross-sectional design cannot capture transitions between user profiles. Self-reported adverse events may differ from objectively measured harms. The counterintuitive concentrate finding could reflect survivorship bias."},{"rthcId":"RTHC-06512","title":"Multi-level socioeconomic modifiers of the comorbidity of post-traumatic stress and tobacco, alcohol, and cannabis use: the importance of income.","authors":"Garrison-Desany, Henri M; Meyers, Jacquelyn L; Linnstaedt, Sarah D; Koenen, Karestan C; House, Stacey L; Beaudoin, Francesca L; An, Xinming; Neylan, Thomas C; Clifford, Gari D; Jovanovic, Tanja; Germine, Laura T; Bollen, Kenneth A; Rauch, Scott L; Haran, John P; Storrow, Alan B; Lewandowski, Christopher; Musey, Paul I; Hendry, Phyllis L; Sheikh, Sophia; Jones, Christopher W; Punches, Brittany E; Pascual, Jose L; Seamon, Mark J; Harris, Erica; Pearson, Claire; Peak, David A; Domeier, Robert M; Rathlev, Niels K; O'Neil, Brian J; Sergot, Paulina; Bruce, Steven E; McLean, Samuel A; Denckla, Christy A","year":2025,"journal":"Social psychiatry and psychiatric epidemiology, 60(5), 1135-1149","doi":"10.1007/s00127-025-02821-7","pmid":"39918603","tags":["ptsd","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among nearly 3,000 trauma survivors, PTS symptoms were significantly associated with tobacco, alcohol, and cannabis use. Household income modified these relationships: lower income strengthened the PTS-tobacco link, while higher income strengthened the PTS-alcohol link.","whyItMatters":"Understanding how socioeconomic factors shape post-trauma substance use can help tailor interventions. A one-size-fits-all approach may miss important socioeconomic drivers.","specificNumbers":"2,943 trauma survivors. Six assessment timepoints. Lower income: associated with tobacco use (P<0.001). Higher income: associated with alcohol use (P<0.001).","methodology":"Longitudinal analysis from the AURORA study of 2,943 individuals who presented to emergency departments within 72 hours of a traumatic event. Substance use and PTS symptoms assessed at six timepoints.","limitations":"Cannabis findings were less robust than tobacco and alcohol findings. The study could not fully disentangle pre-existing substance use from post-trauma changes."},{"rthcId":"RTHC-06513","title":"Cannabidiol sensitizes triple-negative breast cancer cells to NK cell-mediated killing via EGFR inhibition and FAS upregulation.","authors":"Garunyapakun, Perawat; Ramwarungkura, Boonyanuch; Natungnuy, Krissada; Turbpaiboon, Chairat; Yenchitsomanus, Pa-Thai; Junking, Mutita","year":2025,"journal":"Journal of cannabis research, 7(1), 85","doi":"10.1186/s42238-025-00340-5","pmid":"41188939","tags":["cbd","cancer"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD elevated FAS death receptor expression on MDA-MB-468 cells to 125% versus 83% with EGF alone, and enhanced NK-92 cell cytotoxicity, reducing cancer cell viability to 52% versus 114% with EGF alone. CBD downregulated KRAS, PI3K, and AKT.","whyItMatters":"Triple-negative breast cancer lacks targeted therapies. If CBD can make these cancer cells more visible to the immune system by upregulating death receptors and suppressing growth signaling, it could complement immunotherapy.","specificNumbers":"FAS expression: 125.29% with CBD vs. 83.07% with EGF alone (p<0.0001). Cancer cell viability with NK cells: 52.12% with CBD vs. 113.69% with EGF alone (p<0.0001).","methodology":"In vitro study using two TNBC cell lines (MDA-MB-468 and MDA-MB-231) treated with CBD in the presence or absence of epidermal growth factor.","limitations":"In vitro study only; no animal or human data. CBD showed potential cytotoxicity to immune cells at certain concentrations."},{"rthcId":"RTHC-06514","title":"Real-Time Optical Control of CB1 Receptor Signaling In Vitro with Tethered Photoswitchable (-)-trans-Δ9-Tetrahydrocannabinol Derivatives.","authors":"Garza, Sarahi J; Kicin, Bilal; Sarott, Roman C; Pfaff, Patrick; Kosar, Miroslav; Weishaar, Tatum; Schnacke, Paul; Lobingier, Braden T; Carreira, Erick M; Frank, James A","year":2025,"journal":"Journal of the American Chemical Society, 147(27), 23482-23491","doi":"10.1021/jacs.4c18379","pmid":"40586440","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06515","title":"3D-Printed Alginate-Chitosan Hydrogel Loaded with Cannabidiol as a Platform for Drug Delivery: Design and Mechanistic Characterization.","authors":"Garzon, Hernan Santiago; Alfonso-Rodríguez, Camilo; Souza, João G S; Suárez, Lina J; Suárez, Daniel R","year":2025,"journal":"Journal of functional biomaterials, 16(11)","doi":"10.3390/jfb16110422","pmid":"41295077","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06516","title":"Repeated footshock stress enhances cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1.","authors":"Gaulden, Andrew D; Tepe, Erin A; Sia, Eleni; Rollins, Sierra S; McReynolds, Jayme R","year":2025,"journal":"Physiology & behavior, 293, 114840","doi":"10.1016/j.physbeh.2025.114840","pmid":"39922412","tags":["addiction","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Footshock stress increased cocaine self-administration in both sexes. In males, CB1 antagonism only reduced cocaine intake in rats with combined stress-and-cocaine history. In females, rimonabant reduced cocaine intake even without stress history, with stressed females sensitive to both doses tested.","whyItMatters":"Stress is a major driver of drug relapse, and sex differences in addiction mechanisms are increasingly recognized. The cannabinoid system mediates stress-cocaine interactions differently in males and females.","specificNumbers":"Cocaine dose: 0.5 mg/kg/infusion. Rimonabant doses: 1 and 3 mg/kg. Females showed stress-specific front-loading behavior. Both rimonabant doses effective in stressed females.","methodology":"Male and female Sprague-Dawley rats self-administered cocaine during sessions with or without footshock stress. CB1 receptor antagonist rimonabant administered systemically at two doses (1 and 3 mg/kg).","limitations":"Rat models may not fully translate to human cocaine use disorder. Only one stress paradigm tested. Systemic rimonabant affects the whole body."},{"rthcId":"RTHC-06517","title":"Sex-dependent effects of stress on aIC-NAc circuit neuroplasticity: Role of the endocannabinoid system.","authors":"Gauthier, Manon; Hebert, Léo-Paul; Dugast, Emilie; Lardeux, Virginie; Letort, Kevin; Thiriet, Nathalie; Belnoue, Laure; Balado, Eric; Solinas, Marcello; Belujon, Pauline","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 138, 111335","doi":"10.1016/j.pnpbp.2025.111335","pmid":"40113129","tags":["neuroscience","sex-differences","mental-health"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Under basal conditions, males showed equal proportions of LTP and LTD in the insular cortex-to-NAc pathway, while females predominantly showed LTP. Stress eliminated LTD in males 24 hours after exposure, reversed by CB1 receptor blockade. Females showed no stress-induced plasticity changes.","whyItMatters":"The insular cortex processes interoceptive signals and sends them to the reward center. Stress-induced disruption of this pathway could explain why stress alters reward processing in males, while females may be protected through different baseline circuit properties.","specificNumbers":"Males: 50/50 LTP/LTD at baseline, LTD eliminated 24h post-stress. Females: predominantly LTP at baseline, no change with stress. CB1 blockade reversed the male-specific effect.","methodology":"Male and female rats underwent 2 hours of acute restraint stress. In vivo electrophysiological recordings of the anterior insular cortex-to-NAc core pathway were performed immediately and 24 hours post-stress. CB1 receptor blockade tested systemically and locally.","limitations":"Acute restraint stress is one paradigm and may not generalize. Only one circuit was examined. Functional consequences were not directly tested."},{"rthcId":"RTHC-06518","title":"Impact of Medications and Marijuana Use on Hyposalivation and Xerostomia in Adults.","authors":"Gehlken, Carter; Ahmadian, Moni; Abubakr, Neamat Hassan","year":2025,"journal":"International journal of environmental research and public health, 22(11)","doi":"10.3390/ijerph22111700","pmid":"41302645","tags":["harm-reduction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Hyposalivation and xerostomia affected 44% of patients (705 of 1,600). Marijuana use was the strongest independent predictor across all age groups (RR=3.10). Mental health and cardiovascular medications were also significant predictors.","whyItMatters":"Dry mouth accelerates tooth decay, gum disease, and oral infections. With rising cannabis use among younger populations, dentists need to recognize marijuana as a major risk factor.","specificNumbers":"44.06% prevalence of hyposalivation/xerostomia (705/1,600 patients). Marijuana: RR=3.10. Chi-squared=205.99, p<0.001.","methodology":"Retrospective cohort study of 1,600 randomly selected dental patients aged 30+ treated between 2014-2023 at UNLV School of Dental Medicine. Data extracted from electronic health records. Multivariate logistic regression identified risk factors.","limitations":"Retrospective design with reliance on self-reported marijuana use. Single institution. Cannot distinguish between different cannabis products, doses, or frequency."},{"rthcId":"RTHC-06519","title":"Combination of CBD with minor cannabinoid CBDV suppresses CXCR4 via CB2 receptor and alleviates colitis in mice.","authors":"Gelfand, Anat; Besser, Elazar; Procaccia, Shiri; Cohen, Jonathan; Steinberg, Miryam; Kleifeld, Oded; Meiri, David","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 193, 118768","doi":"10.1016/j.biopha.2025.118768","pmid":"41237459","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"The CBD:CBDV 20:1 combination significantly reduced CXCR4 expression in multiple immune cell types, impaired chemotaxis, and improved disease activity, colon length, and histological outcomes in DSS-induced colitis. All benefits were abolished in CB2 knockout mice.","whyItMatters":"This provides a mechanistic explanation for the \"entourage effect\" in a specific disease context. The minor cannabinoid CBDV enhanced CBD's therapeutic effect through a defined molecular pathway.","specificNumbers":"CBD:CBDV ratio of 20:1. CXCR4 reduction confirmed across three cell types. Benefits absent in CB2 knockout mice.","methodology":"In vitro experiments in MOLT-4 cells, murine splenocytes, and human PBMCs. In vivo DSS-induced colitis model in wild-type and CB2 knockout mice. CB2 receptor inhibition confirmed mechanism.","limitations":"DSS-induced colitis is a chemical model that does not fully replicate human IBD. The 20:1 ratio was tested but other ratios were not systematically compared."},{"rthcId":"RTHC-06520","title":"Rasch Analysis of Cannabis Use Disorder in an Adult Inpatient Sample.","authors":"Gendy, Marie N S; Taisir, Radia; Britton, Emily; Costello, Jean; MacKillop, James","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(2), 141-152","doi":"10.26828/cannabis/2025/000229","pmid":"40909142","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The DSM-5 CUD criteria fit the Rasch model well overall, supporting unidimensionality. Symptom #3 was least endorsed and highest severity, symptom #9 was most endorsed and lowest severity. Symptom #8 (hazardous use) showed misfit.","whyItMatters":"Validating the psychometric properties of CUD diagnostic criteria ensures clinicians are measuring a coherent construct. The hazardous use misfit suggests this criterion may capture something different from core addiction.","specificNumbers":"249 inpatients with active cannabis use. Unidimensionality confirmed by two statistical tests. Symptom #8 showed misfit.","methodology":"Rasch analysis applied to DSM-5 CUD criteria in 249 adults receiving inpatient substance use treatment who reported active cannabis use at admission.","limitations":"Inpatient-only sample represents the severe end of CUD. Relatively small sample for psychometric analysis. Single-site study."},{"rthcId":"RTHC-06521","title":"Prevalence of Cannabidiol (CBD) Use Among Patients Taking Medications with Known Drug-Drug Interactions: A Cross-Sectional Analysis.","authors":"Geneau, Hunter; Kovasala, Michael; Brown, Grant; Holmes, Simeon; Hime, Olivia; McNally, Michael; McFayden, Michael; Brewer, Kori; Jones, G Kirk","year":2025,"journal":"Journal of clinical medicine, 14(21)","doi":"10.3390/jcm14217776","pmid":"41227172","tags":["cbd","drug-interactions","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 681 survey respondents, 254 (37.3%) reported CBD use in their household. Among CBD users, 69.7% were concurrently taking one or more medications with potential drug-drug interaction risk. The most common were antidepressants (64.4%) and antihypertensives (41.8%).","whyItMatters":"CBD inhibits cytochrome P450 enzymes that metabolize many common medications. Most CBD users appear unaware of interaction risks, and products rarely carry warnings about potential drug interactions.","specificNumbers":"681 eligible respondents. 37.3% reported household CBD use. 69.7% of CBD users on medications with DDI risk. Top categories: antidepressants 64.4%, antihypertensives 41.8%, followed by diabetes, cholesterol, and immune disorder medications.","methodology":"Cross-sectional survey distributed to patients and family members in adult and pediatric emergency departments of a Level 1 Trauma Center in eastern North Carolina. Respondents reported CBD use and prescription medications.","limitations":"Self-reported data from one emergency department in one region. Survey did not capture CBD doses, frequency of use, or actual adverse events from interactions. Household use does not confirm who in the household takes CBD."},{"rthcId":"RTHC-06522","title":"Cannabidiol regulates L-carnitine and butyric acid metabolism by modulating the gut microbiota to ameliorate collagen-induced arthritis.","authors":"Geng, Qishun; Wang, Zhaoran; Shi, Tong; Wen, Chaoying; Xu, Jiahe; Jiao, Yi; Diao, Wenya; Gu, Jienan; Wang, Zihan; Zhao, Lu; Deng, Tingting; Xiao, Cheng","year":2025,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 136, 156270","doi":"10.1016/j.phymed.2024.156270","pmid":"39591767","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD altered gut microbiota composition in collagen-induced arthritis rats, notably changing abundances of Allobaculum and Prevotella species. This increased plasma butyric acid and L-carnitine, which inhibited inflammation in neutrophils, macrophages, and fibroblast-like synoviocytes.","whyItMatters":"This is the first study to explain CBD's anti-arthritic effects through the gut microbiome-metabolite axis, revealing a mechanism that goes beyond direct anti-inflammatory action at the joint level.","specificNumbers":"CBD increased plasma butyric acid and L-carnitine. Key bacterial changes: Allobaculum (butyric acid producer) and Prevotella (L-carnitine metabolizer). Effects confirmed in neutrophils, macrophages, and RA-fibroblast-like synoviocytes.","methodology":"Metagenomic and non-targeted metabolomic analyses of gut microbiota and plasma metabolites in collagen-induced arthritis rats after CBD treatment. In vitro experiments confirmed L-carnitine effects on immune cells.","limitations":"Animal model of arthritis may not fully recapitulate human rheumatoid arthritis. Gut microbiome findings in rats do not directly translate to humans. CBD dosing details and duration not specified in abstract."},{"rthcId":"RTHC-06523","title":"Cannabis use and its impact on respiratory physiology and lung cancer risk: Mechanistic and epidemiological insights (Review).","authors":"Georgakopoulou, Vasiliki Epameinondas; Andreikos, Dimitrios A; Zhu, Wei; Spandidos, Demetrios A","year":2025,"journal":"Biomedical reports, 23(5), 180","doi":"10.3892/br.2025.2058","pmid":"41089432","tags":["respiratory","harm-reduction","cancer"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Cannabis smoke contains carcinogenic compounds similar to tobacco, and chronic smoking causes cough, sputum, and wheezing resembling chronic bronchitis. However, epidemiological studies on lung cancer risk show conflicting results. Cannabis impairs alveolar macrophage function but does not consistently cause emphysema. Symptoms often resolve with cessation.","whyItMatters":"With cannabis use rising globally, understanding its respiratory effects is critical for public health messaging. The disconnect between cannabis smoke's carcinogenic content and the lack of consistent lung cancer evidence is a puzzle that has practical implications for harm reduction.","specificNumbers":"Cannabis smoke contains polycyclic aromatic hydrocarbons and volatile organic compounds. Respiratory symptoms resemble chronic bronchitis but may resolve upon cessation. No consistent emphysema finding unlike tobacco.","methodology":"Narrative review synthesizing epidemiological and mechanistic evidence on cannabis smoking's respiratory and oncological effects, including comparison with tobacco smoke exposure.","limitations":"Narrative review with selective evidence synthesis. Most cannabis-lung cancer studies have methodological limitations including small samples, confounding tobacco use, and difficulty quantifying cannabis exposure. Few long-term prospective studies exist."},{"rthcId":"RTHC-06524","title":"Exceptionally Potent Chiral Anandamide Analogs.","authors":"Georgiadis, Markos-Orestis; Ferreras, Elena; Ji, Lipin; Ferreira, Luana Assis; Hainline, John; Tong, Fei; Dang, Vuong Q; Faragher, Alexandra; Sadybekov, Anastasiia V; Bohn, Laura M; Katritch, Vsevolod; Hohmann, Andrea G; Makriyannis, Alexandros; Nikas, Spyros P","year":2025,"journal":"Journal of medicinal chemistry, 68(23), 25061-25077","doi":"10.1021/acs.jmedchem.5c02030","pmid":"40954107","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06525","title":"Novel Tetraolefinic Chain Phenyl Substituted Endocannabinoid Probes.","authors":"Georgiadis, Markos-Orestis; Ji, Lipin; Tong, Fei; Dang, Vuong Q; Ferreira, Luana Assis; Faragher, Alexandra; Tran, Ngan; Sadybekov, Anastasiia V; Ganapathy, Suthakar; Zvonok, Nikolai; Katritch, Vsevolod; Hohmann, Andrea G; Bohn, Laura M; Makriyannis, Alexandros; Nikas, Spyros P","year":2025,"journal":"Journal of medicinal chemistry, 68(13), 13376-13392","doi":"10.1021/acs.jmedchem.5c00047","pmid":"40569175","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06526","title":"Prevalence of chemsex and sexualized drug use among men who have sex with men: A systematic review and meta-analysis.","authors":"Georgiadis, Nikolaos; Katsimpris, Andreas; Vatmanidou, Maria A; Vassilakou, Tonia; Beloukas, Apostolos; Sergentanis, Theodoros N","year":2025,"journal":"Drug and alcohol dependence, 275, 112800","doi":"10.1016/j.drugalcdep.2025.112800","pmid":"40759067","tags":["harm-reduction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Pooled prevalence of chemsex was 22% and sexualized drug use overall was 25% among MSM. Cannabis had a pooled prevalence of 18% for use during sex. Other substances: alkyl nitrites 23%, GHB/GBL 13%, cocaine 10%, ecstasy/MDMA 9%, methamphetamine 8%.","whyItMatters":"Cannabis is often overlooked in discussions of sexualized drug use, yet it ranks second among substances used during sex in this population. Understanding its role in chemsex contexts is relevant for sexual health and harm reduction programming.","specificNumbers":"238 studies, 380,505 participants. Chemsex prevalence: 22%. SDU prevalence: 25%. Cannabis for sex: 18%. Alkyl nitrites: 23%. GHB/GBL: 13%. Cocaine: 10%. Methamphetamine: 8%.","methodology":"Systematic review and meta-analysis of 238 studies covering 380,505 participants. Random-effects model used. Subgroup analyses by MSM population category, region, and time period.","limitations":"High heterogeneity expected across 238 studies with different definitions, populations, and measurement methods. Self-reported data subject to social desirability bias. Cannot determine whether cannabis use during sex is associated with the same risks as other chemsex substances."},{"rthcId":"RTHC-06527","title":"Parent Perspectives on Youth Cannabis Use and Mental Health: Impacts, Challenges, and Recommendations.","authors":"Gerhardt, T Freeman; Carlson, Melissa; Menendez, Kimberly; Moore, Kathleen A; Rodill, Zena","year":2025,"journal":"The journal of behavioral health services & research, 52(2), 249-262","doi":"10.1007/s11414-025-09932-8","pmid":"39934567","tags":["youth","psychosis","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Parents reported four themes: cannabis use worsened or triggered mental health crises; it created emotional and financial burdens on families; healthcare providers often minimized cannabis risks during treatment; and parents called for better public health warnings and regulatory oversight.","whyItMatters":"Parents are often the first to observe cannabis-related mental health deterioration in their children, yet they report encountering healthcare providers who dismiss the connection. Their perspectives highlight gaps in clinical training and public health messaging.","specificNumbers":"13 parents interviewed. Four themes identified. Parents described encounters with healthcare providers who minimized cannabis-related risks.","methodology":"Semi-structured interviews with a purposive sample of 13 parents who reported their children used cannabis and experienced mental health issues. Deductive-inductive thematic analysis used to generate themes.","limitations":"Small purposive sample (13 parents) likely skewed toward those with the most severe experiences. No objective verification of cannabis use or mental health diagnoses. Parent perspectives may not capture the full clinical picture."},{"rthcId":"RTHC-06528","title":"An Adolescent Female With Disordered Eating and Cannabis Use Found to Have Acute Intermittent Porphyria.","authors":"Gertz, Brooke; Mullen, Mark; Pesavento, Tony","year":2025,"journal":"Case reports in psychiatry, 2025, 8875138","doi":"10.1155/crps/8875138","pmid":"40605971","tags":["youth","appetite","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report describes a diagnostic near-miss that highlights an important clinical lesson: when a patient's symptoms overlap with known cannabis effects, the cannabis use can become a cognitive shortcut that prevents clinicians from looking further.\n\nA 15-year-old girl presented to the emergency department with nausea, vomiting, and decreased appetite. She used cannabis and had disordered eating behaviors — two conditions that easily explain her symptoms. She was discharged. The next day, she returned with seizures and altered mental status.\n\nThe workup revealed acute intermittent porphyria (AIP), a rare but highly treatable metabolic disorder caused by a deficiency in the enzyme porphobilinogen deaminase. AIP produces episodic symptoms — abdominal pain, nausea, vomiting, neuropsychiatric changes, seizures — that overlap significantly with both cannabinoid hyperemesis syndrome (CHS) and eating disorders.\n\nThe key clinical lesson is about attribution bias. Cannabis use provided a ready explanation for the symptoms (CHS), and disordered eating provided another. Both were real — the patient did use cannabis and did have disordered eating. But neither was the primary cause of her acute presentation. The AIP diagnosis required a high index of suspicion and specific laboratory testing that wasn't performed on the first visit.\n\nThe case is the first in the literature to discuss the diagnostic overlap between CHS and AIP, filling an important gap for emergency physicians and pediatricians who increasingly encounter adolescent cannabis users with GI complaints.","whyItMatters":"As cannabis use increases among adolescents, clinicians are becoming more familiar with cannabinoid hyperemesis syndrome — and that familiarity creates a diagnostic trap. When a young cannabis user presents with cyclical vomiting, CHS is a tempting diagnosis. But this case demonstrates that cannabis use doesn't immunize against other diagnoses, and attributing symptoms to cannabis without ruling out other causes can delay treatment for serious conditions.","specificNumbers":"1 patient, 15-year-old female. Initial presentation: nausea, vomiting, decreased appetite. Cannabis use and disordered eating present. Discharged from ED. Returned next day: seizures, altered mental status. Diagnosis: acute intermittent porphyria. Treated with appropriate AIP management and responded well.","methodology":"Single case report of a 15-year-old female presenting with nausea, vomiting, decreased appetite, cannabis use, and disordered eating. Initially discharged from the ED, returned the next day with seizures and altered mental status. Medical workup revealed acute intermittent porphyria. Treated appropriately with recovery.","limitations":"Single case report — the lowest level of clinical evidence. AIP is genuinely rare (estimated 1 in 20,000), so this diagnostic confusion will be uncommon. The case doesn't establish that cannabis-AIP misdiagnosis is frequent, only that it's possible. The patient's cannabis use and disordered eating were real comorbidities, making the diagnostic challenge genuinely complex."},{"rthcId":"RTHC-06529","title":"Medicinal Cannabis and Consumer Vulnerability in Australia: A Nexus of Policy and Market Factors.","authors":"Gething, Katrina; Erku, Daniel; Scuffham, Paul","year":2025,"journal":"Health expectations : an international journal of public participation in health care and health policy, 28(1), e70176","doi":"10.1111/hex.70176","pmid":"39930887","tags":["medical-cannabis","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Three primary barriers emerged: healthcare practitioners' reluctance to prescribe, high costs disproportionately affecting low-income patients, and dependence on imported products causing shortages and substitution costs. Patients showed resilience by self-educating, planning, and forming support networks, but many turned to illicit markets.","whyItMatters":"When legal medical cannabis programs fail patients through cost and access barriers, they create a perverse incentive to use unregulated products that lack quality control and carry legal risk. Policy reform requires understanding these ground-level barriers.","specificNumbers":"60 submissions analyzed (44 patients, 16 caregivers). Three primary barriers identified. Patients turned to illicit markets due to cost and access issues.","methodology":"Qualitative analysis of 60 consumer submissions (44 patients, 16 caregivers/family) to a government senate inquiry. Coded using NVivo 12 and analyzed through a consumer vulnerability framework.","limitations":"Consumer submissions to a government inquiry may overrepresent frustrated patients. No quantification of how many patients use illicit cannabis. Submissions reflect patient perspectives, not objective measurement of barrier severity."},{"rthcId":"RTHC-06530","title":"Relations between adverse childhood experiences, racial and ethnic Identity, and cannabis use outcomes.","authors":"Gette, Jordan A; Espinosa, Adriana","year":2025,"journal":"Addictive behaviors, 167, 108361","doi":"10.1016/j.addbeh.2025.108361","pmid":"40267666","tags":["addiction","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"As ACEs increased, odds of lifetime CUD rose across all groups (aOR 1.45-3.03). The ACE-CUD relationship was strongest among Asian/Pacific Islander respondents. American Indian/Alaska Native individuals had the highest prevalence of lifetime CUD, most ACEs, and earliest onset. Earlier cannabis onset was associated with more CUD for most groups.","whyItMatters":"Treating cannabis use disorder risk as uniform across racial groups misses important differences. The finding that ACEs interact with age of onset differently by race suggests that prevention programs need culturally tailored approaches.","specificNumbers":"Adjusted ORs for ACEs on lifetime CUD: 1.45-3.03 across groups. American Indian/Alaska Native: highest CUD prevalence, most ACEs, earliest onset. Asian/Pacific Islander: strongest ACE-CUD relationship. Earlier onset: lower lifetime CUD aORs 0.85-0.94 for most groups.","methodology":"Cross-sectional analysis of NESARC-III data examining ACEs, age of cannabis onset, and their interaction on lifetime cannabis use and CUD across five racial/ethnic groups. Logistic regressions stratified by race/ethnicity with sociodemographic controls.","limitations":"Cross-sectional NESARC-III data cannot establish temporal causation. Self-reported ACEs and cannabis use subject to recall bias. Some racial/ethnic subgroups had smaller sample sizes. Lumping diverse ethnicities into broad categories may mask within-group variation."},{"rthcId":"RTHC-06531","title":"Comparative Effects of THC and CBD on Chemotherapy-Induced Peripheral Neuropathy: Insights from a Large Real-World Self-Reported Dataset.","authors":"Geva, Ravit; Bar-Lev, Tali Hana; Lavi Kutchuk, Lee Ahuva; Schaffer, Tali; Mirelman, Dan; Pelles-Avraham, Sharon; Wolf, Ido; Bar-Lev Schleider, Lihi","year":2025,"journal":"Biomedicines, 13(8)","doi":"10.3390/biomedicines13081921","pmid":"40868175","tags":["medical-cannabis","pain","cbd"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Both THC-high and CBD-high groups improved, but the THC-high group showed significantly greater improvement in burning sensation (p=0.024), cold sensation (p=0.008), activities of daily living (p=0.029), and quality of life (p=0.006). A significant interaction between THC and CBD was observed, with combined doses yielding greatest relief.","whyItMatters":"Chemotherapy-induced neuropathy is a common dose-limiting side effect with few effective treatments. This large real-world dataset suggests THC may be more important than CBD for neuropathic pain relief, challenging the common assumption that CBD alone is sufficient for pain management.","specificNumbers":"751 patients with CIPN symptoms from 1,493 total. THC-high group: significantly better improvement in burning (p=0.024), cold sensation (p=0.008), ADL (p=0.029), QOL (p=0.006). Significant THC-CBD interaction for symptom improvement.","methodology":"Patient-reported outcomes from Tikun Olam medical cannabis provider dataset. Of 1,493 patients, 751 with baseline CIPN symptoms were categorized into THC-high/CBD-low and CBD-high/THC-low groups. Symptom changes analyzed at six months using K-means clustering and logistic regression.","limitations":"Observational, non-randomized design. Self-reported outcomes without clinical verification. Selection bias possible in who chooses THC-dominant vs CBD-dominant products. No placebo group."},{"rthcId":"RTHC-06532","title":"Investigation of endocannabinoids in plasma and their correlation with physical fitness and resting state functional connectivity of the periaqueductal grey in women with fibromyalgia: An exploratory secondary study.","authors":"Ghafouri, Bijar; Stensson, Niclas; Simon, Rozalyn; Mayo, Leah M; Lund, Eva; Forsgren, Mikael F; Leinhard, Olof Dahlqvist; Lundberg, Peter; van Ettinger-Veenstra, Helene","year":2025,"journal":"Scandinavian journal of pain, 25(1)","doi":"10.1515/sjpain-2025-0023","pmid":"41250871","tags":["pain","neuroscience","exercise"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Significantly higher anandamide (AEA) concentrations were found in fibromyalgia patients compared to controls. AEA correlated positively with pain intensity and inversely with physical fitness. Physical fitness was inversely correlated with pain and psychological distress. PAG-thalamus brain connectivity was related to physical activity but not to circulating endocannabinoids.","whyItMatters":"Finding elevated anandamide in fibromyalgia patients supports the hypothesis that the endocannabinoid system is dysregulated in this condition, though in a more complex way than simple deficiency. Physical fitness appears to be a key modifiable factor.","specificNumbers":"31 women with fibromyalgia, 29 healthy controls. AEA significantly elevated in FM. AEA positively correlated with pain intensity, inversely with physical fitness. PAG-thalamus connectivity associated with physical activity but not circulating endocannabinoids.","methodology":"Exploratory study comparing plasma endocannabinoid and N-acylethanolamine concentrations in 31 women with fibromyalgia and 29 healthy controls. fMRI measured brain connectivity. Physical fitness and pain/psychological questionnaires were included.","limitations":"Small sample size (31 FM, 29 HC). Cross-sectional design cannot determine if elevated AEA causes or results from pain/deconditioning. Women only. Plasma levels may not reflect brain endocannabinoid activity."},{"rthcId":"RTHC-06533","title":"A Qualitative Study of Cannabis Use and Family Dynamics Among Youth in Early Psychosis Programs.","authors":"Ghelani, Amar","year":2025,"journal":"Journal of dual diagnosis, 21(3), 204-211","doi":"10.1080/15504263.2025.2517175","pmid":"40523081","tags":["psychosis","youth","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Participants described five themes: parental disapproval driven by psychosis concerns, intra-family cannabis consumption, family influence on use patterns, changing parental attitudes over time, and increased closeness with family members who also use cannabis.","whyItMatters":"Family dynamics around cannabis use in psychosis are more complex than simple prohibition narratives suggest. When family members themselves use cannabis while discouraging the patient's use, it creates contradictory messages that complicate recovery.","specificNumbers":"15 participants aged 20-30 in EPI programs. Five themes identified. Most reported cannabis contributed to family tension, but some noted positive effects on bonding.","methodology":"Qualitative study using thematic analysis of semi-structured interviews with 15 youth ages 20-30 enrolled in Early Psychosis Intervention programs.","limitations":"Small purposive sample from EPI programs. Self-selected participants willing to discuss cannabis and family dynamics. No verification of reported family cannabis use patterns."},{"rthcId":"RTHC-06534","title":"Behavioural effects of oral cannabidiol (CBD) treatment in the superoxide dismutase 1 G93 A (SOD1G93 A) mouse model of amyotrophic lateral sclerosis.","authors":"Ghimire, Sandip; Kreilaus, Fabian; Rosa Porto, Rossana; Anderson, Lyndsey L; Yerbury, Justin J; Arnold, Jonathon C; Karl, Tim","year":2025,"journal":"Psychopharmacology, 242(9), 2077-2095","doi":"10.1007/s00213-025-06785-z","pmid":"40229540","tags":["cbd","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD (36 mg/kg/day oral) ameliorated weight loss in female SOD1G93A mice, tended to restore sociability in males, strengthened social recognition memory in females, and improved prepulse inhibition in younger females. CBD did not improve motor impairments in either sex.","whyItMatters":"ALS affects cognition and behavior in addition to motor function, but these aspects are often overlooked. This study shows CBD may address some non-motor ALS symptoms even when motor decline continues, and that effects differ meaningfully between sexes.","specificNumbers":"36 mg/kg/day oral CBD. Treatment from 10 weeks. Weight loss ameliorated in females. Social recognition improved in females. PPI improved in younger females. No motor improvement in either sex.","methodology":"Male and female SOD1G93A and wild-type mice fed control or CBD-enriched chow (36 mg/kg/day) from 10 weeks of age. Behavioral testing included rotarod, open field, prepulse inhibition, social behavior, and fear-associated memory from 11-19 weeks.","limitations":"Only one dose tested. Motor benefits observed with CBDA in another study were not seen with CBD, possibly due to different model (SOD1 vs TDP-43), route, or dose. Sex-specific effects were not always consistent across measures."},{"rthcId":"RTHC-06535","title":"Eco-friendly encapsulation: Investigating plant-based protein-alginate shells for efficient delivery and digestion of hemp seed oil encapsulated via supercritical CO2 dispersion.","authors":"Gholivand, Somayeh; Tan, Tai Boon; Yusoff, Masni Mat; Qoms, Mohammed S; Wang, Yong; Liu, Yuanfa; Nyam, Kar Lin; Tan, Chin Ping","year":2025,"journal":"Food chemistry, 463(Pt 4), 141515","doi":"10.1016/j.foodchem.2024.141515","pmid":"39395350","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06536","title":"MXene-poly(propylene carbonate) nanofiber network-based modification of SPE interfaces for electrochemical immuno-sensing of synthetic cannabinoid.","authors":"Ghorbanizamani, Faezeh; Moulahoum, Hichem; Timur, Suna","year":2025,"journal":"Talanta, 287, 127687","doi":"10.1016/j.talanta.2025.127687","pmid":"39908896","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06537","title":"Neurocognitive Dysfunctions in People with Concurrent Cannabis Use and Opioid Dependence: A Cross-Sectional, Controlled Study.","authors":"Ghosh, Abhishek; Shaktan, Alka; Verma, Abhishek; Basu, Debasish; Rana, Devender K; Nehra, Ritu; Ahuja, Chirag K; Modi, Manish; Singh, Paramjit","year":2025,"journal":"Journal of psychoactive drugs, 57(1), 71-83","doi":"10.1080/02791072.2024.2308213","pmid":"38251910","tags":["cognition","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The OD+CD group completed significantly fewer categories on the Wisconsin Card Sorting Test than healthy controls and had more non-perseverative errors. Both OD and OD+CD groups showed verbal working memory deficits. Interestingly, the OD+CU (cannabis use without dependence) group performed better than controls on one trail-making measure.","whyItMatters":"Cannabis is often viewed as relatively benign compared to opioids, but when combined with opioid dependence, cannabis dependence appears to add measurable cognitive burden. This has implications for treatment planning and cognitive rehabilitation.","specificNumbers":"496 participants (97.5% men). OD+CD: fewer WCST categories completed, more non-perseverative errors than HC. OD and OD+CD: more verbal working memory 2-back errors than HC. OD+CU: fewer TMT-B errors than HC.","methodology":"Cross-sectional controlled study comparing cognitive function across 268 opioid-dependent (OD), 58 OD with cannabis use (OD+CU), 115 OD with cannabis dependence (OD+CD), and 68 healthy controls using SPM, WCST, IGT, TMT, and n-back tests.","limitations":"Overwhelmingly male sample (97.5%). Cross-sectional design cannot determine if cognitive deficits preceded or resulted from substance use. Cannabis use versus dependence distinction is clinical, not biological."},{"rthcId":"RTHC-06538","title":"UK Medical Cannabis Registry: A Clinical Analysis of Patients with Substance Use Disorder.","authors":"Ghosh, Aishwarya; Erridge, Simon; Coomber, Ross; Bhoskar, Urmila; Holden, Wendy; Kamal, Fariha; Mwimba, Gracia; Sachdeva-Mohan, Simmi; Shaya, Gabriel; Usmani, Azfer; Rucker, James; Sodergren, Mikael","year":2025,"journal":"European addiction research, 31(5), 325-335","doi":"10.1159/000547696","pmid":"40738021","tags":["medical-cannabis","addiction","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Patients showed improvements in GAD-7 anxiety scores, sleep quality, and EQ-5D-5L quality of life at 1, 3, and 6 months. Prescribed opioid doses (oral morphine equivalent) decreased. 85% were already using illicit cannabis at baseline. Only 3 patients (8.8%) reported 17 adverse events.","whyItMatters":"If medical cannabis can improve outcomes for people with substance use disorder while reducing opioid requirements, it could represent a harm reduction strategy, though the observational design prevents causal conclusions.","specificNumbers":"34 patients, 79.4% male. 85.3% using illicit cannabis at baseline. 52.9% had opioid use disorder. Products: 11.8% oils, 41.2% dried flower, 47.1% combination. 8.8% reported adverse events. Improvements in GAD-7, SQS, and EQ-5D-5L.","methodology":"Observational analysis of UK Medical Cannabis Registry data for 34 patients with substance use disorder. Outcomes measured at 1, 3, and 6 months using validated patient-reported outcome measures.","limitations":"Very small sample (34 patients). No control group or randomization. 85% already using illicit cannabis, so improvements may partly reflect switching to regulated products rather than a new therapeutic effect. Selection bias in who enrolls in a cannabis registry."},{"rthcId":"RTHC-06539","title":"Coordinated epigenetic dysregulation of CNR1 and FAAH genes drives endocannabinoid system dysfunction in anorexia nervosa.","authors":"Gilardini, Federica; Mercante, Francesca; Sabatucci, Annalaura; Pucci, Mariangela; Cifani, Carlo; Segura-Garcia, Cristina; Rania, Marianna; D'Addario, Claudio","year":2025,"journal":"Journal of eating disorders, 14(1), 5","doi":"10.1186/s40337-025-01472-y","pmid":"41310856","tags":["neuroscience","appetite","mental-health"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"A novel bidirectional epigenetic dysregulation was discovered: CNR1 (cannabinoid receptor 1) promoter hypermethylation coupled with FAAH (endocannabinoid-degrading enzyme) promoter hypomethylation. This creates a dual mechanism that systematically suppresses endocannabinoid signaling by reducing receptors while increasing signal degradation.","whyItMatters":"This identifies a specific molecular mechanism for appetite dysregulation in anorexia nervosa. The finding that both the receptor and the degradation enzyme are epigenetically altered in coordinated fashion suggests a systemic rather than incidental disruption of appetite signaling.","specificNumbers":"CNR1 promoter hypermethylated (reduced receptor). FAAH promoter hypomethylated (increased degradation). Compensatory miRNA responses detected. Combined biomarker panels showed superior diagnostic precision vs. individual markers.","methodology":"Case-control study analyzing DNA methylation of CNR1 and FAAH genes, genetic polymorphisms, and exosomal microRNA expression in saliva samples from anorexia nervosa patients versus healthy controls.","limitations":"Saliva-based measurements may not directly reflect brain ECS function. Cannot determine if epigenetic changes cause or result from the disorder. Sample sizes not specified in abstract. Case-control design limits temporal inference."},{"rthcId":"RTHC-06540","title":"Cannabis Use and Nicotine Vaping Cessation Outcomes: A Secondary Analysis of a Randomized Clinical Trial.","authors":"Gilman, Jodi M; Cather, Corinne; Reeder, Harrison T; Evohr, Bryn; Pachas, Gladys N; Gray, Kevin M; McClure, Erin A; Schuster, Randi M; Evins, A Eden","year":2025,"journal":"JAMA network open, 8(12), e2547799","doi":"10.1001/jamanetworkopen.2025.47799","pmid":"41385228","tags":["youth","quitting","addiction"],"studyType":"secondary-analysis","evidenceStrength":"moderate","keyFinding":"This secondary analysis followed 192 young people (ages 16–25) enrolled in a nicotine vaping cessation trial that tested varenicline against placebo and an enhanced usual care texting program. The researchers wanted to know whether cannabis use—common in this age group—would undermine quit attempts.\n\nThe headline result was reassuring: baseline cannabis use frequency and cannabis use disorder severity did not predict whether someone successfully quit vaping at 12 weeks. Heavy cannabis users were just as likely to achieve biochemically verified abstinence as non-users.\n\nBut the day-level data told a more nuanced story. On days when participants used both cannabis and nicotine, their nicotine vaping was higher than on days they used neither. This co-use pattern suggests the two substances may reinforce each other in the moment, even if cannabis use doesn't derail the overall quit attempt.\n\nParticipants with more severe cannabis use disorder symptoms also reported more days of nicotine vaping throughout the trial, though this didn't translate into lower quit rates at the 12-week mark.","whyItMatters":"Clinicians sometimes worry that treating nicotine addiction in someone who also uses cannabis is futile—that the cannabis will sabotage the quit attempt. This trial provides evidence against that assumption. For the roughly 75% of young vapers who also use cannabis (per RTHC-00156's data), these findings suggest vaping cessation programs shouldn't exclude or deprioritize dual users.","specificNumbers":"192 participants aged 16–25. Cannabis use frequency and CUD severity were not significant predictors of 12-week quit success. On co-use days, nicotine vaping was higher than on non-use days.","methodology":"Secondary analysis of a single-site randomized clinical trial conducted in Massachusetts (June 2022–May 2024). Three arms: varenicline + counseling, placebo + counseling, and enhanced usual care (text-based support). Cannabis use measured via self-reported days per week and CUDIT scores at baseline. Primary outcome was biochemically verified 7-day point prevalence nicotine vaping abstinence at week 12.","limitations":"Single-site trial in Massachusetts limits generalizability. Self-reported cannabis use (no biochemical verification). Secondary analysis—the trial wasn't designed or powered to detect cannabis-related effects on vaping cessation. The 12-week follow-up is relatively short for assessing long-term quit maintenance."},{"rthcId":"RTHC-06541","title":"Multi-Endogenous Nanoformulation for Endocannabinoid and Hormonal Modulation of Key Signaling Pathways in Resistant Hypertension.","authors":"Giménez, Virna Margarita Martín; Menéndez, Sebastián García; Manucha, Walter","year":2025,"journal":"Current pharmaceutical design","doi":"10.2174/0113816128396666250728074858","pmid":"40814873","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06542","title":"Accuracy of labeled THC potency across flower and concentrate cannabis products.","authors":"Giordano, Gregory; Brook, Colin P; Ortiz Torres, Marco; MacDonald, Grace; Skrzynski, Carillon J; Lisano, Jonathon K; Mackie, Duncan I; Bidwell, L Cinnamon","year":2025,"journal":"Scientific reports, 15(1), 20822","doi":"10.1038/s41598-025-03854-3","pmid":"40592871","tags":["potency","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Labeling accuracy depended dramatically on product type: 96% of concentrates were within 15% of labeled THC versus only 56.7% of flower products. Observed THC was significantly lower than labeled THC for both flower and concentrate products. Nearly half of flower products failed the accuracy threshold.","whyItMatters":"If consumers cannot trust THC labels, they cannot make informed decisions about dosing, which is especially important for medical patients and those trying to manage their consumption. Flower labeling inaccuracy may also mean consumers overpay for potency they are not receiving.","specificNumbers":"277 products from 52 dispensaries. Flower: 56.7% within 15% accuracy. Concentrates: 96.0% within 15% accuracy. Both had lower observed than labeled THC (p=0.001 for flower, p=0.003 for concentrates).","methodology":"277 cannabis products (178 flower, 99 concentrates) purchased from 52 Colorado dispensaries and independently analyzed for THC content. Products classified as accurate if observed THC was within 15% of labeled value.","limitations":"Colorado-specific findings may not generalize to other states with different testing regulations. The 15% accuracy threshold is arbitrary. Products tested at one point in time may not reflect batch-to-batch variation."},{"rthcId":"RTHC-06543","title":"Analysis of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) on hair after single and repeated short in vivo passive exposures to low- and high-Δ9-THC-cannabis.","authors":"Giorgetti, Arianna; Mohamed, Susan; Rossi, Francesca; Santelli, Simone; Pirani, Filippo; Pelletti, Guido; Pascali, Jennifer Paola; Pelotti, Susi","year":2025,"journal":"Forensic science international, 373, 112515","doi":"10.1016/j.forsciint.2025.112515","pmid":"40480121","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06544","title":"Cannabis involvement and mass shooting events in the United States from 1900 to 2019.","authors":"Girgis, R R; Hesson, H; Appelbaum, P S; Brucato, G","year":2025,"journal":"East Asian archives of psychiatry : official journal of the Hong Kong College of Psychiatrists = Dong Ya jing shen ke xue zhi : Xianggang jing shen ke yi xue yuan qi kan, 35(1), 28-31","doi":"10.12809/eaap2464","pmid":"40170208","tags":["psychosis","mental-health","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Among mass shooters, cannabis involvement (use, possession, or distribution) was significantly higher from 1996 onward compared to before (11.2% vs 4.9%, p=0.002). No similar increase occurred among non-firearm mass murderers (4.8% vs 5.7%, p=0.76). Mass shooters with cannabis involvement were significantly younger (28.7 vs 33.5 years).","whyItMatters":"While this study cannot establish causation, it raises questions about whether increased cannabis availability may be relevant for a small subgroup of individuals vulnerable to violence, particularly given the known association between heavy cannabis use and psychosis in predisposed individuals.","specificNumbers":"Mass shooters with cannabis involvement: 11.2% post-1996 vs 4.9% pre-1996 (p=0.002). Non-firearm mass murderers: 4.8% vs 5.7% (p=0.76). Cannabis-involved shooters were younger: 28.7 vs 33.5 years (p<0.001).","methodology":"Analysis of publicly available media reports and court/police records for mass shooting events in the United States from 1900 to 2019. Cannabis involvement was compared before and after 1996 (California medical cannabis legalization). Non-firearm mass murderers served as a comparison group.","limitations":"Reliance on publicly available reports likely underestimates cannabis involvement across all time periods. Cannot establish causation. Cannabis involvement includes use, possession, and distribution, conflating different relationships with the substance. Population-level cannabis use also increased post-1996."},{"rthcId":"RTHC-06545","title":"Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Quantification of Four Endocannabinoids and Endocannabinoid-Like Substances in Plasma: Application in an HIV-Hepatitis C Virus Coinfected Population.","authors":"Gish, Alexandr; Radwan, Eqbal; Richeval, Camille; Protopopescu, Camelia; Wiart, Jean-François; Hakim, Florian; Allorge, Delphine; Carrieri, Patrizia; Barré, Tangui; Gaulier, Jean-Michel","year":2025,"journal":"Therapeutic drug monitoring","doi":"10.1097/FTD.0000000000001397","pmid":"41035123","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06546","title":"Simultaneous analysis of four endocannabinoids and endocannabinoid congeners together with delta-9 tetrahydrocannabinol and related metabolites in dried blood spots.","authors":"Gish, Alexandr; Wiart, Jean-François; Richeval, Camille; Allorge, Delphine; Gaulier, Jean-Michel","year":2025,"journal":"Journal of pharmaceutical and biomedical analysis, 265, 116991","doi":"10.1016/j.jpba.2025.116991","pmid":"40446360","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06547","title":"Binge Drinking, Cannabis, and Tobacco Use and Modifiable Social Risks Among Adults Who Used Health Care.","authors":"Glass, Joseph E; Oh, Hans Y; Besecker, Megan; Blosnich, John R; Wong, Edwin S","year":2025,"journal":"Journal of general internal medicine","doi":"10.1007/s11606-025-10036-4","pmid":"41249652","tags":["harm-reduction","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"42.1% of past-month cannabis users and 42.6% of tobacco users had at least one social risk, compared to 30.9% overall. Binge drinking was not associated with elevated social risks unless it occurred daily (29.3% for any frequency). Social risk probability increased with the number of substances used.","whyItMatters":"Screening for substance use in healthcare settings already happens. This study suggests that positive screens for cannabis or tobacco should also prompt assessment of social needs, since these substances may be markers of broader social vulnerability.","specificNumbers":"76,891 respondents. 30.9% reported at least one social risk. Food difficulty most common at 12.4%. Cannabis users: 42.1% with social risks. Tobacco: 42.6%. Binge drinking: 29.3% (but elevated with daily use). Risk increased with number of substances.","methodology":"Cross-sectional analysis of 76,891 US adults from the 2022 BRFSS survey who had a healthcare visit in the past 2 years. Social risks included employment loss, food stamp receipt, food insecurity, bill-paying difficulty, utility shutoff threats, and unreliable transportation.","limitations":"Cross-sectional design cannot determine whether substance use causes social problems or vice versa. Self-reported data. BRFSS survey methods may underrepresent the most vulnerable populations."},{"rthcId":"RTHC-06548","title":"Temporal Trends in Young Adult Cannabis and Tobacco Use in States with Different Cannabis Policies.","authors":"Glasser, Allison M; Uriarte, Caitlin; King Jensen, Jessica; Sterling, Kymberle; Shang, Ce; Hammond, David; Villanti, Andrea C","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(2), 98-111","doi":"10.26828/cannabis/2025/000288","pmid":"40909145","tags":["legalization","youth","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"All states showed declining cigarette smoking, slight cigar declines, and increasing cannabis and blunt use among young adults. Cannabis use increased following opening of medical retail outlets and further after adult-use implementation. In Maine, cannabis use increased 22.4% after medical retail opened and continued rising after adult use was adopted.","whyItMatters":"This provides evidence that cannabis legalization, particularly the opening of retail outlets rather than just passing laws, is associated with increased young adult use. The simultaneous decline in cigarette smoking suggests shifting substance preferences rather than simply adding a new substance.","specificNumbers":"16 states studied (2002-2018). Maine: 22.4% increase in cannabis use (95% CI: 19.0-29.4) after medical retail opened. All states showed declining cigarette use. Cannabis and blunt use increased more in AMU vs MUO states.","methodology":"Segmented regression analysis of National Survey on Drug Use and Health data (2002-2018) in 16 states that passed adult and medical use or medical-only cannabis laws. Past 30-day cannabis, blunt, cigarette, and cigar use examined.","limitations":"Ecological study cannot prove individual-level causation. State-level trends are confounded by many other policy, economic, and cultural changes occurring simultaneously. NSDUH data may undercount some populations."},{"rthcId":"RTHC-06549","title":"Relationship between an adult-use Cannabis law and Cannabis use by type in a cohort of New Jersey young adults.","authors":"Glasser, Allison M; Villanti, Andrea C; Gundersen, Daniel A; Schroth, Kevin R J; Hrywna, Mary","year":2025,"journal":"Preventive medicine, 198, 108354","doi":"10.1016/j.ypmed.2025.108354","pmid":"40618906","tags":["legalization","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Odds of ever cannabis use were 42% higher in the post-retail period (95% CI: 32%-54%). Ever use of dried herb, edibles, drinks, and topicals all significantly increased. Past 30-day edible use rose from 9.0% to 11.8%. Concentrate, vape, and other product types did not significantly change.","whyItMatters":"This is one of the first studies to examine cannabis use changes specifically by product type after retail legalization. The finding that edibles drove much of the increase has implications for dosing safety and public health messaging.","specificNumbers":"Ever use: 58.1% post vs 48.9% pre (p<0.01). aOR for ever use: 1.42 (95% CI: 1.32-1.54). Edibles ever use: 45.9% vs 35.6% (p<0.01). Past 30-day edibles: 11.8% vs 9.0% (p=0.01). Dried herb: 44.4% vs 38.5% (p<0.01).","methodology":"Prospective cohort analysis of New Jersey young adults (18-23) from the PACE study. Three pre-retail waves (March-November 2021, n=1,439) compared to one post-retail wave (June-July 2022, n=1,127) using generalized estimating equations.","limitations":"Short post-retail follow-up period (3 months). Cohort attrition from pre to post waves. Cannot distinguish new users from people who were using illicitly and now report legal use. New Jersey experience may not generalize to other states."},{"rthcId":"RTHC-06550","title":"A Qualitative Investigation Into the Experiences of Medicinal Cannabis Use Among Chronic Pain and PTSD Patients in Israel.","authors":"Gliksberg, Or; Hulaihel, Amany; Sznitman, Sharon R; Brill, Silviu; Amit, Ben H; Lev-Ran, Shaul; Kushnir, Talma; Feingold, Daniel","year":2025,"journal":"Qualitative health research, 10497323251361328","doi":"10.1177/10497323251361328","pmid":"40738174","tags":["medical-cannabis","ptsd","pain"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Two main themes emerged: (1) Coping with adverse effects through concealment, justification, protective behavioral strategies, and rejection of stigmatized identity; and (2) Utilizing positive effects including using cannabis to forget/disconnect, cope with helplessness, and build camaraderie with other patients against perceived institutional barriers.","whyItMatters":"Medical cannabis is typically studied through clinical outcomes, but this qualitative work reveals the psychological and social complexity of long-term therapeutic use. Patients are not passive recipients but actively manage both the benefits and costs of their treatment.","specificNumbers":"25 participants, predominantly male. Two main themes with seven sub-themes. Patients used MC for chronic pain or PTSD.","methodology":"In-depth semi-structured interviews with 25 Israeli medicinal cannabis patients (predominantly men) prescribed MC for chronic pain or PTSD. Thematic analysis characterized narratives around long-term MC use.","limitations":"Predominantly male sample in Israel, limiting generalizability. Self-selected participants willing to discuss their experiences. No comparison with other stigmatized medications. Cultural context may differ from other countries."},{"rthcId":"RTHC-06551","title":"Orally Administered CBD/CBG Hemp Extract Reduces Severity of Ulcerative Colitis and Pain in a Murine Model.","authors":"Godbole, Shivani S; Sun, Dongxiao; Coates, Matthew D; Himmelberger, Victoria J; Roopchand, Diana E; Raup-Konsavage, Wesley M","year":2025,"journal":"Journal of clinical medicine, 14(17)","doi":"10.3390/jcm14176095","pmid":"40943856","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabinoid treatment reduced damage to the colonic epithelium and decreased pain-related responses in DSS-induced colitis mice. Oral administration was effective, suggesting potential for a practical delivery route.","whyItMatters":"Most cannabinoid-colitis research uses purified compounds or intraperitoneal injection. This study tested a practical oral hemp extract, making findings more relevant to real-world supplementation, though animal-to-human translation remains uncertain.","specificNumbers":"Hemp extract high in CBG and CBD. Two administration routes tested (i.p. and oral). Both routes showed efficacy for colonic protection and pain reduction.","methodology":"DSS-induced ulcerative colitis mouse model treated with a commercial hemp extract high in CBG and CBD via two routes: intraperitoneal and oral. Colonic tissue damage and pain behaviors were assessed.","limitations":"Animal model using chemical (DSS) induction, not spontaneous colitis. Commercial extract means exact composition may vary between batches. Limited detail on dosing and outcome quantification in the abstract."},{"rthcId":"RTHC-06552","title":"Cannabidiol and ∆9-Tetrahydrocannabinol in Endometriosis: A Literature Review on Therapeutic Applications and Mechanisms.","authors":"Godoy, Joana Retzke; Castilhos, Júlia Prauchner de; Caruso, Fernanda Borsatto; Hentschke, Marta Ribeiro","year":2025,"journal":"JBRA assisted reproduction","doi":"10.5935/1518-0557.20250168","pmid":"41248202","tags":["medical-cannabis","pain","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"An experimental rat study demonstrated CBD's anti-inflammatory, antioxidant, and antiangiogenic effects in endometriosis treatment via intraperitoneal administration. However, human clinical evidence is sparse, and current use is off-label without established dosing or administration routes.","whyItMatters":"Endometriosis affects approximately 10% of women of reproductive age and is associated with chronic pelvic pain, painful periods, and infertility. Current treatments have significant limitations, creating urgency for new therapeutic options.","specificNumbers":"Approximately 10% of women of reproductive age affected. One experimental rat study demonstrated CBD efficacy. Current human use is off-label.","methodology":"Literature review searching PubMed, Embase, and Scopus for studies on CBD and THC therapeutic potential for endometriosis symptoms, including assessment of reproducibility, safety, dosing, and administration routes.","limitations":"Very limited primary research available. Only one animal study of CBD in endometriosis. No clinical trials identified. Review methodology not described as systematic."},{"rthcId":"RTHC-06553","title":"The Impact of Major and Minor Phytocannabinoids on the Maintenance and Function of INS-1 β-Cells Under High-Glucose and High-Lipid Conditions.","authors":"Gojani, Esmaeel Ghasemi; Wang, Bo; Li, Dong-Ping; Kovalchuk, Olga; Kovalchuk, Igor","year":2025,"journal":"Molecules (Basel, Switzerland), 30(9)","doi":"10.3390/molecules30091991","pmid":"40363798","tags":["cbd","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"All five phytocannabinoids (THC, CBD, THCV, CBC, CBG) reduced high-glucose-high-lipid-induced apoptosis in INS-1 beta cells, likely through decreased TXNIP protein levels. THC, THCV, CBC, and CBG additionally protected against functional impairments, while CBD only protected against cell death.","whyItMatters":"Type 2 diabetes involves progressive beta cell loss. If cannabinoids can protect these cells from metabolic stress, they could potentially slow diabetes progression, particularly given the endocannabinoid system's known role in metabolic regulation.","specificNumbers":"Five cannabinoids tested: THC, CBD, THCV, CBC, CBG. All reduced apoptosis via TXNIP pathway. THC and three minor cannabinoids protected function. CBD protected survival but not function.","methodology":"In vitro study exposing INS-1 beta cells to high-glucose-high-lipid conditions simulating type 2 diabetes metabolic stress. Cell survival, TXNIP protein levels, and beta cell function were assessed after treatment with five phytocannabinoids.","limitations":"In vitro study using a rat cell line, not human beta cells. Concentrations used may not be achievable in the human pancreas. Does not account for the complex hormonal and metabolic environment of the living body."},{"rthcId":"RTHC-06554","title":"Examining the Role of Anxiety Sensitivity and Intolerance of Uncertainty in Terms of Cannabis Use and Coping Motives for Cannabis Use in College Students With Clinically Elevated Worry.","authors":"Goldblum, Rachel S; O'Bryan, Emily M; Bimstein, Jessica G; McLeish, Alison C","year":2025,"journal":"The Journal of nervous and mental disease, 213(10), 258-263","doi":"10.1097/NMD.0000000000001850","pmid":"40955715","tags":["anxiety","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Greater anxiety sensitivity was significantly associated with more frequent past-month cannabis use (explaining 4.4% of variance) and stronger coping motives for use (4.9% of variance). Anxiety sensitivity social concerns specifically predicted coping motives (7.1% of variance). Intolerance of uncertainty was not significantly associated with either outcome.","whyItMatters":"Understanding which anxiety-related traits drive cannabis use helps target interventions. If anxiety sensitivity, not uncertainty intolerance, is the driver, then treatments that reduce fear of anxiety sensations (like interoceptive exposure) may be more effective than those targeting uncertainty.","specificNumbers":"220 participants with elevated worry. AS predicted cannabis use frequency (4.4% variance) and coping motives (4.9% variance). AS-Social Concerns predicted coping motives (7.1% variance). IU was not significant.","methodology":"Cross-sectional study of 220 undergraduates with clinically elevated worry (mean age 19.4, 82.3% female, 89.1% White). Self-report measures of anxiety sensitivity, intolerance of uncertainty, cannabis use frequency, and coping motives, controlling for sex and negative affect.","limitations":"Predominantly White female college sample limits generalizability. Small effect sizes (4-7% variance explained). Cross-sectional design cannot establish directionality. Self-report measures."},{"rthcId":"RTHC-06555","title":"Optimal Cannabinoid-Terpene Combination Ratios Suppress Mutagenicity of Gastric Reflux in Normal and Metaplastic Esophageal Cells.","authors":"Goldman, Aaron; Gonzalez, Gabriel; Karpova, Svetlana A; Buon, Leutz; Shammas, Masood A; Mashimo, Hiroshi; Frank, Markus H; Frank, Natasha Y","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.09.23.678062","pmid":"41040236","tags":["cancer","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CBG:Phytol 1:5 ratio reduced DCA-induced DNA damage, preserved mitochondrial membrane potential, decreased reactive oxygen species, enhanced apoptosis in damaged cells, and reduced mutagenicity. Patient sample analysis showed CB1 receptor expression correlated with esophageal adenocarcinoma progression.","whyItMatters":"Esophageal adenocarcinoma arises from chronic acid reflux damage. If cannabinoid-terpene combinations can reduce the mutagenic damage that drives this progression, they could represent a preventive strategy for people with Barrett's esophagus, a known cancer precursor.","specificNumbers":"Optimal ratio: 1:5 CBG to Phytol. Reduced DCA-induced DNA damage, ROS, and mutagenicity. CB1 expression correlated with EAC progression in patient samples.","methodology":"In vitro models using human esophageal epithelial cells exposed to deoxycholic acid (bile acid) and a Barrett's esophagus gastroesophageal reflux model. Various cannabinoid-terpene ratios tested. Patient-derived tissue samples analyzed for ECS receptor expression.","limitations":"Preprint (not yet peer-reviewed). In vitro models do not replicate the complexity of chronic reflux disease. The CBG:Phytol ratio was found through screening, not mechanistic optimization. Patient tissue analysis was correlative."},{"rthcId":"RTHC-06556","title":"Psychedelic risks and benefits: A cross-sectional survey study.","authors":"Goldy, Sean P; Du, Benjamin A; Rohde, Julia S; Nayak, Sandeep M; Strickland, Justin C; Ehrenkranz, Rebecca; Levine, Michael; Barrett, Frederick S; Yaden, David B","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 39(5), 436-452","doi":"10.1177/02698811241292951","pmid":"39610363","tags":["mental-health","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Psychedelic experiences had greater acute challenging effects and persisting negative effects compared to cannabis, but also greater positive acute and persisting effects. Common predictors of outcomes included dose level, presence of others, religiosity, and personality traits, though these explained only small amounts of variance.","whyItMatters":"As psychedelics gain therapeutic attention, comparing their risk-benefit profile to the most commonly used illicit substance provides practical context. Cannabis serves as a useful benchmark because most adults have some reference point for it.","specificNumbers":"Study 1: n=743 (between-subjects). Study 2: n=514 (within-subjects). Psychedelics: greater positive AND negative acute effects. Greater persisting positive AND negative effects. Predictors explained small variance.","methodology":"Two studies using opt-in panel sampling reflecting US Census demographics: a between-subjects design (n=743) comparing psychedelic vs cannabis experiences, and a within-subjects design (n=514) in dual-experienced users.","limitations":"Retrospective self-report of first or most memorable experiences is subject to recall bias and narrative construction. Panel sampling, while better than social media convenience sampling, may not reach the most marginalized users."},{"rthcId":"RTHC-06557","title":"Role of interplay between endocannabinoids and neuropeptides in pathogenesis and therapy of depressive and anxiety disorders.","authors":"Gołyszny, Miłosz; Dragon, Jonasz; Obuchowicz, Ewa","year":2025,"journal":"Neuropeptides, 114, 102564","doi":"10.1016/j.npep.2025.102564","pmid":"41101142","tags":["depression","anxiety","neuroscience"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The hypothalamus is the primary site of proven bidirectional endocannabinoid-neuropeptide interactions. Neuropeptides modulate endocannabinoid effects on stress response (CRH), social behavior (oxytocin), pleasure (orexins), appetite (NPY), and pain (oxytocin). Emerging peptides like nesfatin-1 and neuropeptide S show promising interactions.","whyItMatters":"Depression and anxiety involve multiple neurochemical systems, not just serotonin. Understanding how endocannabinoids interact with neuropeptides could explain why cannabinoid-based approaches affect mood and identify novel therapeutic combinations.","specificNumbers":"Nine neuropeptide systems reviewed. Five well-studied (CRH, oxytocin, vasopressin, NPY, orexins) and four emerging (nesfatin-1, phoenixin, spexin, NPS). Hypothalamus identified as the primary interaction site.","methodology":"Narrative review synthesizing evidence on interactions between the endocannabinoid system and both well-studied neuropeptides (CRH, oxytocin, vasopressin, NPY, orexins) and less-studied peptides (nesfatin-1, phoenixin, spexin, neuropeptide S).","limitations":"Narrative review with inherent selection bias. Many interactions are demonstrated only in animal models. The complexity of nine interacting peptide systems makes clinical translation challenging. Some interactions are indirect or hypothetical."},{"rthcId":"RTHC-06558","title":"Genotype and chemotype insights of high-THC medicinal Cannabis sativa L.: the role of SSR markers in the identification of cultivars.","authors":"Gomes, Ana Patrícia; Vicente, Sara; Rosa, Joana; Vinhas, Iva; da Costa, António Marques; Sassano, Michael; Rodrigues, Luis Monteiro; Rijo, Patrícia; Trindade, Helena; Céu Costa, Maria do","year":2025,"journal":"Journal of cannabis research, 8(1), 2","doi":"10.1186/s42238-025-00357-w","pmid":"41275303","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06559","title":"Evaluating maternal drug use disparities, risk factors and outcomes in Northeast Arkansas: a pre, during, and post-COVID-19 pandemic analysis.","authors":"Gomez Pomar, Enrique; Berryhill, Johnna; Bhattacharyya, Sudeepa","year":2025,"journal":"BMC public health, 25(1), 509","doi":"10.1186/s12889-025-21636-4","pmid":"39920626","tags":["pregnancy","legalization","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 450 positive meconium drug screens, THC was most common (64.2%), followed by amphetamines (11.1%) and opioids (6.7%). The adjusted positive rate increased from 6.8% to 7.4% over 2018-2023. THC use increased more than other substances and the increase accelerated after state legalization. Infants with positive screens had lower birth weight, height, head circumference, and longer hospital stays.","whyItMatters":"Prenatal THC exposure is increasing alongside legalization, and this study documents measurable adverse neonatal outcomes. The acceleration of THC use after legalization adds urgency to the need for prenatal screening and intervention.","specificNumbers":"8,030 live births, 957 screened, 450 positive (47%). THC: 64.2% of positives. Adjusted positive rate: 6.8% to 7.4% over study period. 17.8% positive for multiple substances. Smoking mothers: OR 2.39 for positive MDS.","methodology":"Retrospective analysis of 957 mother-infant dyads with meconium drug screen results from 8,030 live births at a reference hospital in Arkansas (2018-2023). An adjusted monthly positive rate accounted for variable screening rates.","limitations":"Non-universal screening means true prevalence is unknown. Screening was provider-initiated, introducing selection bias. Cannot control for confounders like poverty, nutrition, and other substance use that accompany THC-positive results. Single hospital in one state."},{"rthcId":"RTHC-06560","title":"Long-lasting behavioral, molecular and functional connectivity alterations after chronic THC exposure during adolescence in mice.","authors":"Gómez-Acero, Laura; Varriano, Federico; Sánchez-Fernández, Nuria; Ciruela, Francisco; Soria, Guadalupe; Aso, Ester","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 140, 111422","doi":"10.1016/j.pnpbp.2025.111422","pmid":"40532755","tags":["youth","psychosis","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Adolescent THC exposure impaired social interaction and increased vulnerability to sensorimotor gating deficiencies (similar to those in heavy cannabis users). Long-term cortico-striatal dysconnectivity correlated with impaired social interactions in adulthood. Lasting molecular changes were found in the balance between dopamine D2, adenosine A2A, and cannabinoid CB1 receptors in the striatum.","whyItMatters":"This provides neurobiological evidence for why adolescent cannabis use is associated with increased psychosis risk. The combination of brain connectivity changes, receptor imbalances, and behavioral deficits creates a plausible mechanistic pathway from adolescent exposure to adult psychiatric vulnerability.","specificNumbers":"Persistent effects found in: social interaction, sensorimotor gating, cortico-striatal connectivity, and D2/A2A/CB1 receptor balance in striatum. Social interaction deficits correlated with connectivity changes.","methodology":"Mice treated with THC during adolescence were assessed for behavioral, connectivity, and molecular changes persisting into adulthood. Included social interaction testing, sensorimotor gating, brain connectivity imaging, and receptor expression analysis.","limitations":"Mouse model may not fully translate to human adolescent brain development. THC dosing and exposure patterns may not match typical human use. Only assessed a limited set of behaviors and brain regions."},{"rthcId":"RTHC-06561","title":"Socioeconomic Disparities in Perinatal Substance Use Emergency Department Visits Before and During COVID-19.","authors":"González-Alvarez, Ana Daniela; Kapukotuwa, Sidath; Hurst, Larry; Owusu-Ansah, Abena Gyawu; Guo, Ying; Vaderlaan, Jennifer; Shen, Jay J","year":2025,"journal":"Journal of women's health (2002), 34(12), 1548-1557","doi":"10.1177/15409996251370887","pmid":"40844412","tags":["pregnancy","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Pandemic period showed increased odds of ED visits involving alcohol (aOR=1.16, 95% CI: 1.05-1.27) and cannabis (aOR=1.10, 95% CI: 1.01-1.20). African American individuals had prepandemic higher odds of cannabis use. Disparities in cannabis use narrowed for Hispanic and Native American individuals relative to White individuals during the pandemic.","whyItMatters":"The pandemic exacerbated substance use during pregnancy, a period when both mother and fetus are vulnerable. The finding that cannabis-related visits increased suggests pandemic stressors may have driven increased use among pregnant individuals.","specificNumbers":"Cannabis ED visits: 10% increase during pandemic (aOR=1.10). Alcohol: 16% increase (aOR=1.16). Medicaid and uninsured: consistently elevated odds for opioid, cannabis, and nicotine use. Cannabis disparities narrowed for Hispanic and Native American vs White.","methodology":"Difference-in-differences analysis of 2019-2021 Nationwide Emergency Department Sample data examining ED visits among pregnant individuals with documented substance use. Disparities assessed by race/ethnicity and insurance status.","limitations":"ED visits represent the most acute cases, not total prenatal substance use. Difference-in-differences cannot fully control for secular trends. Substance documentation in ED records may be inconsistent."},{"rthcId":"RTHC-06562","title":"Sexual violence in Catalan adolescents: prevalence, associated factors and health consequences.","authors":"Gonzalez-Casals, Helena; Vives-Cases, Carmen; Espelt, Albert; Bosque-Prous, Marina; Teixidó-Compañó, Ester; Drou-Roget, Gemma; Folch, Cinta","year":2025,"journal":"Gaceta sanitaria, 39, 102455","doi":"10.1016/j.gaceta.2025.102455","pmid":"39985826","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06563","title":"Impulsivity traits moderate the longitudinal association between mental health and hazardous cannabis use in emerging adults.","authors":"González-Roz, Alba; Castaño, Yasmina; Secades-Villa, Roberto; Janssen, Tim; Vallejo-Seco, Guillermo; Blanco, Carlos","year":2025,"journal":"Drug and alcohol review, 44(4), 1049-1061","doi":"10.1111/dar.14047","pmid":"40127543","tags":["mental-health","addiction","anxiety","depression","youth"],"studyType":"longitudinal-study","evidenceStrength":"moderate","keyFinding":"In a sample of 2,762 college students tracked over one year, anxiety at the midpoint predicted hazardous cannabis use at the final assessment. The reverse also held: hazardous cannabis use predicted later stress. Impulsivity traits, particularly negative and positive urgency, strengthened the link between emotional distress and problematic use.","whyItMatters":"This study maps a specific pathway: emotional distress feeds into problematic cannabis use, and impulsivity accelerates that process. It suggests that interventions targeting emotional regulation and impulsive decision-making could interrupt this cycle in young adults.","specificNumbers":"2,762 college students; past-month cannabis use was 11.5% at baseline, 3.5% at midpoint, 9.1% at final assessment; cross-lagged effects found between T2 anxiety and T3 hazardous use, and between T2 hazardous use and T3 stress","methodology":"Longitudinal survey of college students (ages 18-25) assessed at three time points over one year. Structural equation modeling and semi-parametric mixed-effects models examined cross-lagged relationships between mental health symptoms and hazardous cannabis use, with impulsivity, age, and sex as moderators.","limitations":"Self-report measures only. College student sample may not generalize to non-college young adults. Cannabis use prevalence dropped sharply at the midpoint, possibly due to seasonal or academic factors."},{"rthcId":"RTHC-06564","title":"Perception of Risks of Cannabis and Cannabidiol Use during Pregnancy: A Multi-Methods Study.","authors":"Goodin, Amie; Varma, Deepthi S; Dhillon, Karamveer; Kaleem, Sahar; Dubare, Sonila; Jennings, Alexis; Goldberger, Bruce A; Roussos-Ross, Kay","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 130-143","doi":"10.1159/000546312","pmid":"40661844","tags":["pregnancy","cbd"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 261 women surveyed, there was no significant difference between pregnant and non-pregnant participants in how they perceived the risks of cannabis or CBD use during pregnancy. The most common response for both groups was \"not sure.\" Focus groups revealed that participants saw cannabis as fundamentally different from alcohol or other drugs and felt legalization signaled safety.","whyItMatters":"High uncertainty about cannabis and CBD risks during pregnancy, even among currently pregnant women, suggests a major gap in patient education. The finding that legalization itself shapes safety perceptions adds a policy dimension to the communication challenge.","specificNumbers":"261 survey respondents (75.9% currently pregnant); 40% of pregnant participants said \"not sure\" about weekly cannabis risk; 52.3% of pregnant participants said \"not sure\" about weekly CBD risk; ever-use: 36% of pregnant vs 65.5% of non-pregnant for cannabis","methodology":"Multi-method study combining a cross-sectional survey (261 respondents from outpatient obstetrics clinics) with five focus group discussions (17 participants total), conducted October 2022 to February 2023. Chi-square analysis compared risk perceptions between pregnant and non-pregnant participants.","limitations":"Convenience sample from a single geographic area. Self-report data subject to social desirability bias. Small focus group sample. Cross-sectional design limits causal inference."},{"rthcId":"RTHC-06565","title":"Cannabidiol improves learning and memory deficits and alleviates anxiety in 12-month-old SAMP8 mice.","authors":"Goodland, Monica N; Banerjee, Subhashis; Niehoff, Michael L; Young, Benjamin J; Macarthur, Heather; Butler, Andrew A; Morley, John E; Farr, Susan A","year":2025,"journal":"PloS one, 20(8), e0296586","doi":"10.1371/journal.pone.0296586","pmid":"40811673","tags":["cbd","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In SAMP8 mice (a model for Alzheimer's disease), high-dose CBD (30 mg/kg daily for two months) significantly improved learning and memory in T-maze and novel object recognition tests. CBD-treated aged mice also showed less anxiety in the elevated plus maze. Biochemical analysis revealed decreased markers of oxidative stress in the brain.","whyItMatters":"This adds to a small but growing body of preclinical evidence suggesting CBD may have neuroprotective properties relevant to age-related cognitive decline. The identification of reduced oxidative stress as a mechanism provides a plausible biological pathway.","specificNumbers":"High dose: 30 mg/kg daily; treatment duration: 2 months; significant improvement in T-maze learning and novel object recognition at 30 mg/kg; decreased oxidative stress markers in treated mice","methodology":"Controlled animal study using SAMP8 mice (an accelerated aging model for Alzheimer's). Mice aged 11 months received vehicle or CBD (3 or 30 mg/kg) daily via oral gavage for 2 months. Young (3-month) vehicle-treated mice served as controls. Assessed learning/memory (T-maze, novel object recognition), anxiety (elevated plus maze), activity, and strength.","limitations":"Animal study only; results may not translate to humans. Small sample sizes typical of mouse studies. Only two doses tested. The SAMP8 model does not fully replicate human Alzheimer's pathology. No long-term follow-up after treatment ended."},{"rthcId":"RTHC-06566","title":"Association of Serum Endocannabinoid Levels with Pancreatitis and Pancreatitis-Related Pain.","authors":"Goodman, Marc T; Lombardi, Christina; Torrens, Alexa; Bresee, Catherine; Saloman, Jami L; Li, Liang; Yang, Yunlong; Fisher, William E; Fogel, Evan L; Forsmark, Christopher E; Conwell, Darwin L; Hart, Phil A; Park, Walter G; Topazian, Mark; Vege, Santhi S; Van Den Eeden, Stephen K; Bellin, Melena D; Andersen, Dana K; Serrano, Jose; Yadav, Dhiraj; Pandol, Stephen J; Piomelli, Daniele","year":2025,"journal":"Cannabis and cannabinoid research, 10(1), 60-70","doi":"10.1089/can.2024.0079","pmid":"39291350","tags":["neuroscience","pain"],"studyType":"observational-study","evidenceStrength":"preliminary","keyFinding":"In a case-control study of 231 participants, circulating anandamide (AEA) levels were significantly higher in pancreatitis patients compared to controls, with the highest levels in acute pancreatitis. Conversely, 2-AG levels were significantly lower in participants reporting abdominal pain in the past week, and pain intensity was inversely associated with both 2-AG and OEA concentrations.","whyItMatters":"This research maps how the body's own cannabinoid system responds to pancreatic disease and pain. The divergent patterns of AEA (elevated with disease) and 2-AG (depleted with pain) suggest the endocannabinoid system plays distinct roles in inflammation versus pain processing.","specificNumbers":"231 participants across 5 groups; AEA significantly higher in all disease groups vs controls (p=0.03); 2-AG significantly lower in those with recent pain (p=0.02); AEA higher in women than men (p=0.0499); PEA higher in obese participants (p=0.003)","methodology":"Case-control study within the PROCEED cohort, measuring serum levels of two endocannabinoids (AEA, 2-AG) and two paracannabinoids (OEA, PEA) across five groups: no pancreatic disease (n=56), suspected/indeterminate chronic pancreatitis (n=22), acute pancreatitis (n=33), recurrent acute pancreatitis (n=57), and definite chronic pancreatitis (n=63).","limitations":"Cross-sectional design cannot determine whether endocannabinoid changes are a cause or consequence of disease. Relatively small group sizes. Serum levels may not reflect tissue-level endocannabinoid activity."},{"rthcId":"RTHC-06567","title":"Low-dose cannabidiol increases plasma concentrations of amitriptyline: A clinical drug-drug interaction study.","authors":"Gorbenko, Andriy A; Post, Titiaan E; Strugala, Pamela K; Klaassen, Erica S; Klumpers, Linda E; de Visser, Saco J; Sempio, Cristina; Klawitter, Jost; Heuberger, Jules A A C; Groeneveld, Geert J","year":2025,"journal":"British journal of clinical pharmacology","doi":"10.1002/bcp.70415","pmid":"41398552","tags":["cbd","drug-interactions"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"In a crossover study of 12 healthy volunteers, a single 30 mg CBD dose taken one hour before amitriptyline significantly increased amitriptyline's AUC by 13% and peak concentration by 17%. CBD did not significantly affect tramadol or its active metabolite. The researchers note that chronic CBD dosing and taking CBD with food could amplify these interactions.","whyItMatters":"Most drug interaction studies use high CBD doses (300-1500 mg). This study shows that even a 30 mg dose, common in over-the-counter products, can meaningfully alter drug metabolism. For patients taking amitriptyline, this interaction could affect drug safety and efficacy.","specificNumbers":"30 mg CBD dose; amitriptyline AUC increased 13% (95% CI: 1-26%, p=0.033); amitriptyline Cmax increased 17% (95% CI: 1-36%, p=0.041); 12 completers (4 male, 8 female); no significant effect on tramadol","methodology":"Open-label, fixed-sequence, two-way crossover study in 13 healthy participants (12 completed). On Day 1, participants received amitriptyline and tramadol alone. After a 7-day washout, they received 30 mg CBD one hour before the same drugs. Blood samples collected over 24 hours. AUCs compared using mixed-effects models.","limitations":"Single-dose study; chronic dosing likely produces larger interactions. Small sample size. Open-label design. Only tested in fasted conditions; CBD absorption increases substantially with food. Healthy volunteers may differ from patient populations."},{"rthcId":"RTHC-06568","title":"A Tourette Syndrome/ADHD-like Phenotype Results from Postnatal Disruption of CB1 and CB2 Receptor Signalling.","authors":"Gorberg, Victoria; Harpaz, Tamar; Shamir, Emilya Natali; Karminsky, Orit Diana; Fride, Ester; Pertwee, Roger G; Greig, Iain R; McCaffery, Peter; Anavi-Goffer, Sharon","year":2025,"journal":"International journal of molecular sciences, 26(13)","doi":"10.3390/ijms26136052","pmid":"40649832","tags":["neuroscience","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Postnatal exposure to the CB1 blocker rimonabant in wild-type, CB1 knockout, and CB2 knockout mice produced distinct behavioral outcomes. Wild-type pups developed vocal-like tics and learning deficits; as adults, they showed hyperactivity, motor tics, and risky behavior. Vocal tics required both disrupted CB1 signaling and functional CB2 receptors. The findings suggest ADHD/Tourette syndrome may share a common origin in early cannabinoid system disruption.","whyItMatters":"If the endocannabinoid system plays a foundational role in neurodevelopment, disruptions during critical early periods could have lasting behavioral consequences. The sex-specific patterns (males more affected) mirror the clinical epidemiology of ADHD and Tourette syndrome.","specificNumbers":"Three genotypes tested (wild-type, CB1 KO, CB2 KO); rimonabant administered postnatally; males showed vocal tics, hyperactivity, and learning deficits; females showed hyperactivity but no vocal tics in CB2 knockouts","methodology":"Postnatal wild-type, CB1 knockout, and CB2 knockout mouse pups were exposed to rimonabant (CB1 antagonist/inverse agonist). Behavioral assessments tracked vocal tics, motor activity, learning, rearing, and risk-taking from postnatal period through adulthood. Sex-specific outcomes were analyzed across all genotypes.","limitations":"Mouse behavioral models have limited translational value for complex human neurodevelopmental disorders. Pharmacological disruption of cannabinoid signaling does not replicate naturally occurring developmental variations. Small sample sizes typical of transgenic mouse studies."},{"rthcId":"RTHC-06569","title":"Cannabis Abuse Is Associated With Greater Medical Complications, Emergency Department Visits, and Readmissions Following Open Reduction and Internal Fixation for Distal Radius Fractures.","authors":"Gordon, Adam M; Golub, Ivan J; Diamond, Keith B; Kang, Kevin K; Choueka, Jack","year":2025,"journal":"Hand (New York, N.Y.), 20(3), 402-409","doi":"10.1177/15589447231210948","pmid":"38006235","tags":["medical-cannabis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 13,405 matched patients who underwent surgery for distal radius fractures, those with cannabis use disorder (n=2,297) had significantly higher rates of 90-day medical complications, emergency department visits (2.53% vs 1.14%), and readmissions (5.79% vs 4.29%). The incidence of CUD among surgical patients doubled from 4% to 8% between 2010 and 2020.","whyItMatters":"As cannabis use disorder becomes more prevalent among surgical patients, understanding its association with postoperative outcomes helps surgeons counsel patients and plan for potential complications.","specificNumbers":"13,405 patients (2,297 with CUD, 11,108 controls); CUD prevalence doubled from 4% to 8% (2010-2020); ED visits 2.53% vs 1.14%; readmissions 5.79% vs 4.29%","methodology":"Retrospective cohort study using a national insurance database (2010-2020). Patients with CUD were 1:5 ratio matched to controls by age, sex, tobacco use, alcohol abuse, opioid dependence, and comorbidities. Multivariable logistic regression assessed 90-day outcomes.","limitations":"Insurance database study cannot distinguish between active cannabis use and historical CUD diagnosis. Matching cannot account for all confounders. \"Cannabis abuse\" diagnosis codes may undercount actual cannabis use. Cannot determine whether cannabis directly caused complications or is a marker for other risk factors."},{"rthcId":"RTHC-06570","title":"Development of a Preclinical Inhalation Model to Test Vaporized Cannabis Distillates.","authors":"Gorgani, Roham; Orsat, Valerie; Eidelman, David H; Baglole, Carolyn J","year":2025,"journal":"Journal of visualized experiments : JoVE","doi":"10.3791/68094","pmid":"40522888","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06571","title":"Perioperative Repercussions of Cannabis Use-Implications for GI Endoscopy Sedation.","authors":"Goudra, Basavana; Green, Michael","year":2025,"journal":"Journal of clinical medicine, 14(19)","doi":"10.3390/jcm14197028","pmid":"41096108","tags":["medical-cannabis","cardiovascular"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This narrative review found that cannabis users frequently need higher doses of propofol and other sedatives for GI endoscopy. Inhalation-based cannabis use is associated with airway hyperreactivity, increasing the risk of bronchospasm and laryngospasm. Cardiovascular effects including tachycardia and hypertension may also complicate sedation. Acute intoxication can impair the ability to provide informed consent.","whyItMatters":"With cannabis use increasingly common, sedation providers for routine procedures like colonoscopies need to anticipate altered drug responses in cannabis users. The practical implications for dosing, airway management, and consent are directly relevant to clinical practice.","specificNumbers":"Review article; specific effect sizes vary across cited studies; key concerns: higher propofol requirements, airway hyperreactivity, cardiovascular effects (tachycardia, hypertension), impaired consent capacity with acute intoxication","methodology":"Narrative review summarizing existing literature on the pharmacology of cannabis and its implications for sedation during GI endoscopy procedures.","limitations":"Narrative review without systematic methodology. Most evidence comes from case reports and small studies. Effects during routine screening procedures may differ from complex therapeutic endoscopy."},{"rthcId":"RTHC-06572","title":"Mistrust Limits Possibilities for Patient-Provider Discussions Regarding Cannabis Use During Pregnancy.","authors":"Gould, Heather; Zaugg, Claudia; Scott, Karen A; Roberts, Sarah C M","year":2025,"journal":"Women's health issues : official publication of the Jacobs Institute of Women's Health, 35(6), 450-457","doi":"10.1016/j.whi.2025.09.002","pmid":"41076313","tags":["pregnancy"],"studyType":"qualitative-study","evidenceStrength":"preliminary","keyFinding":"Most of the 34 interview participants reported that healthcare providers never initiated conversations about cannabis use. Participants distrusted providers as accurate cannabis information sources, viewing provider messaging as unfairly grouping cannabis with alcohol and harder drugs. Fear of judgment and child welfare reporting were the primary barriers to disclosure. Many used cannabis for medical reasons but rarely experienced providers discussing risks versus benefits of cannabis compared to alternative treatments.","whyItMatters":"When patients hide substance use from providers, it creates blind spots in prenatal care. This study reveals the specific trust barriers that prevent open communication, pointing to opportunities for more effective clinical approaches.","specificNumbers":"34 interview participants; most reported no provider-initiated cannabis discussions; few disclosed use voluntarily; primary barriers: distrust of provider information, fear of judgment, fear of child welfare reporting","methodology":"Qualitative study with in-depth interviews of 34 individuals who were pregnant or had been pregnant within the past two years and who used cannabis before or during pregnancy. Interviews explored experiences with and perspectives on provider communication about cannabis.","limitations":"Small qualitative sample cannot be generalized to all pregnant cannabis users. Participants were recruited in areas where cannabis was legal, which may affect attitudes. Self-selection bias likely."},{"rthcId":"RTHC-06573","title":"Cannabidiol in Drug-Resistant Epilepsy (DRE) in Children: A Retrospective Study.","authors":"Gowda, Vykuntaraju K; Simin, Halima; Kinhal, Uddhava V; Basavaraja, G V; Sanjay, K S","year":2025,"journal":"Indian pediatrics, 62(7), 501-505","doi":"10.1007/s13312-025-00075-9","pmid":"40261499","tags":["cbd","epilepsy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"In a retrospective review of 50 children with drug-resistant epilepsy (mostly Lennox-Gastaut syndrome), CBD as add-on therapy produced complete seizure response (>90% reduction) in 10 children, partial response (30-90% reduction) in 18, and no response in 14. Eight children became entirely seizure-free. Adverse effects occurred in 44% but none required hospitalization. Eight children discontinued treatment.","whyItMatters":"Drug-resistant epilepsy leaves families with few options. This real-world data from a clinical setting supports the growing evidence that CBD can meaningfully reduce seizures in children who have not responded to standard treatments.","specificNumbers":"50 children; mean age 7.8 years; complete response in 10 (20%), partial in 18 (36%), no response in 14 (28%); 8 (16%) seizure-free; adverse effects in 22 (44%); 8 discontinued (4 for lack of efficacy, 3 for adverse effects, 1 for seizure worsening)","methodology":"Retrospective chart review of children with drug-resistant epilepsy who received CBD for at least six months at a single center. Assessed seizure frequency reduction, parent-reported adverse effects, and discontinuation rates. Epilepsy types included Lennox-Gastaut syndrome (n=32), Dravet syndrome (n=4), and tuberous sclerosis complex (n=2).","limitations":"Retrospective design without a control group. Single center. Parent-reported outcomes subject to recall bias. No standardized dosing protocol described. Heterogeneous epilepsy types grouped together."},{"rthcId":"RTHC-06574","title":"The role of bias-based bullying in regular cannabis use among adolescents.","authors":"Gower, Amy L; Watson, Ryan J; Pieczykolan, Lauren Love; Eisenberg, Marla E","year":2025,"journal":"Addictive behaviors, 170, 108441","doi":"10.1016/j.addbeh.2025.108441","pmid":"40749298","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 82,933 Minnesota students, regular cannabis use prevalence was dramatically higher among youth with minoritized identities who experienced bias-based bullying compared to peers with the same identities who did not. For example, 18% of 8th graders who had low resources, identified as American Indian/Alaska Native/multiracial, and experienced SOGIE-based bullying used cannabis regularly, versus 6.8% of similar youth without bullying. This 50-68% reduction in cannabis use among non-bullied youth held across grades.","whyItMatters":"This reframes adolescent cannabis use as partially driven by discrimination experiences rather than purely individual risk factors. It suggests that anti-bullying interventions could have downstream effects on substance use, particularly for youth with multiple minoritized identities.","specificNumbers":"82,933 students; cannabis use 50-68% lower among non-bullied youth with same identities; 18% vs 6.8% among 8th graders who were AI/AN/multiracial with low resources and SOGIE bullying vs without","methodology":"Cross-sectional analysis of the 2022 Minnesota Student Survey (8th, 9th, and 11th graders, N=82,933). Used exhaustive CHAID (Chi-square automatic interaction detection) to identify combinations of social positions and bullying experiences associated with highest cannabis use prevalence.","limitations":"Cross-sectional design cannot establish causality. Self-report data. Minnesota-specific sample may not generalize nationally. Binary bullying measure (any vs none) does not capture severity or frequency."},{"rthcId":"RTHC-06575","title":"Effects of legal-market cannabis and alcohol on verbal learning and memory.","authors":"Gowin, Joshua L; Stallsmith, Vanessa; Weldon, Katelyn; Dooley, Gregory; Karoly, Hollis C","year":2025,"journal":"Psychopharmacology","doi":"10.1007/s00213-025-06882-z","pmid":"40996525","tags":["cognition","sex-differences"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Sixty adults who regularly used both alcohol and cannabis completed two lab sessions: one with alcohol alone and one with alcohol plus legal-market cannabis. Before and after each session, they took a standard word-recall test.\n\nWhen cannabis was added to alcohol, participants recalled about one fewer word per trial on immediate recall—a statistically significant but modest effect. This is notable because the study used legal-market cannabis (higher THC than the low-potency research-grade cannabis used in most prior studies), making it more representative of what people actually consume.\n\nThe sex difference was striking. Men showed clear additional impairment from cannabis on top of alcohol, while women did not. This wasn't explained by differences in consumption amounts or blood alcohol levels—it appeared to be a genuine biological sex difference in how the combination affects verbal memory.\n\nShort-delay and long-delay recall showed no significant additional impairment from cannabis beyond alcohol alone, suggesting the combination primarily disrupts the encoding phase rather than memory consolidation or retrieval.","whyItMatters":"Most prior research on combined alcohol and cannabis used low-THC government-supplied cannabis that doesn't reflect real-world products. This is one of the first studies to use legal-market cannabis, and the finding that the combination effect is real but modest—and sex-dependent—adds crucial nuance to public health messaging about mixing substances.","specificNumbers":"N = 60 (40% female). Cannabis + Alcohol condition: ~1 fewer word recalled per trial on immediate recall (p < .001). No significant additional impairment on short-delay or long-delay recall. Sex interaction: men showed significant additional impairment, women did not.","methodology":"Within-subjects design with 60 participants (40% female), all heavy drinkers who regularly use cannabis. Two counterbalanced laboratory sessions: Alcohol Only and Cannabis + Alcohol. Memory assessed using the Rey Auditory Verbal Learning Test (RAVLT) before and after substance use. Legal-market cannabis from a licensed dispensary. Linear mixed-effects models evaluated effects of condition and sex.","limitations":"Relatively small sample (60 participants). All participants were experienced users of both substances, so results may not apply to naive users. Lab setting may not capture real-world conditions. Only one memory test used (verbal learning); other cognitive domains weren't assessed. Legal-market cannabis varies in potency—results may differ with concentrates or edibles."},{"rthcId":"RTHC-06576","title":"Brain Function Outcomes of Recent and Lifetime Cannabis Use.","authors":"Gowin, Joshua L; Ellingson, Jarrod M; Karoly, Hollis C; Manza, Peter; Ross, J Megan; Sloan, Matthew E; Tanabe, Jody L; Volkow, Nora D","year":2025,"journal":"JAMA network open, 8(1), e2457069","doi":"10.1001/jamanetworkopen.2024.57069","pmid":"39874032","tags":["cognition","neuroscience","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using Human Connectome Project data, heavy lifetime cannabis users (>1,000 uses, n=88) showed significantly lower brain activation during a working memory task compared to nonusers, with a moderate effect size (Cohen d = -0.28). Affected regions included the anterior insula, medial prefrontal cortex, and dorsolateral prefrontal cortex. Recent cannabis use (detected by urine testing) was associated with lower performance on working memory and motor tasks, but these associations did not survive statistical correction. No other cognitive tasks (reward, emotion, language, motor, relational, theory of mind) showed associations with lifetime heavy use.","whyItMatters":"This is one of the largest neuroimaging studies to separate lifetime cannabis use history from recent use effects. The finding that working memory deficits persist even when controlling for recent use suggests heavy long-term cannabis use may leave lasting traces on brain function.","specificNumbers":"1,003 young adults; 88 heavy users (>1,000 uses), 179 moderate (10-999), 736 nonusers; heavy use effect on working memory: Cohen d = -0.28 (95% CI: -0.50 to -0.06); affected regions: anterior insula, medial prefrontal cortex, dorsolateral prefrontal cortex","methodology":"Cross-sectional study of 1,003 young adults (ages 22-36) from the Human Connectome Project. Functional MRI during seven cognitive tasks. Cannabis use history from structured clinical interviews. Recent use detected via urine toxicology on scan day. Linear mixed-effects regression with false discovery rate correction.","limitations":"Cross-sectional design cannot determine whether reduced activation preceded or followed cannabis use. Self-reported lifetime use may be inaccurate. The heavy user group (n=88) was relatively small. Data collected 2012-2015 may not reflect current cannabis potency."},{"rthcId":"RTHC-06577","title":"Cannabinoid Receptor 1: The Neural Gatekeeper of Health and Disease.","authors":"Goyal, Ahsas; Kumari, Anshika; Verma, Aanchal; Bhatiya, Sheetal; Yadav, Harlokesh Narayan","year":2025,"journal":"Current neurovascular research, 22(2), 100-114","doi":"10.2174/0115672026403497250910124233","pmid":"40968433","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06578","title":"Knowledge and Attitudes About Perinatal Marijuana Use Among US Postpartum Mothers: A Better Outcomes Through Research for Newborns Network Study.","authors":"Goyal, Neera K; Chang, Pearl W; Chung, Esther K","year":2025,"journal":"Academic pediatrics, 25(3), 102616","doi":"10.1016/j.acap.2024.102616","pmid":"39626844","tags":["pregnancy","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In a multi-site survey of 484 postpartum mothers, 59.9% reported any lifetime marijuana use and 9.3% used during their current pregnancy. Nearly 40% described marijuana use among breastfeeding mothers as common or somewhat common. Only one-third received any provider counseling about marijuana. After adjusting for covariates, counseling was associated with nearly double the odds of mothers knowing about risks to children's learning (aOR 1.93, 95% CI: 1.13-3.29).","whyItMatters":"When most mothers have tried marijuana but few have been counseled by providers, there is a significant missed opportunity. The finding that counseling nearly doubles knowledge of learning risks suggests provider conversations can be effective when they happen.","specificNumbers":"484 postpartum mothers across 15 hospitals; 59.9% lifetime marijuana use; 9.3% used during current pregnancy; ~40% viewed breastfeeding-mother marijuana use as common; 33% received any provider counseling; counseling associated with aOR 1.93 for knowing about learning risks","methodology":"Multi-state cross-sectional survey at 15 US hospitals in the BORN network (June 2021 to August 2022). Convenience sample of postpartum mothers aged 21+ with newborns 34+ weeks gestational age. 48-item survey assessing demographics, use, attitudes, knowledge, and provider counseling. Chi-square and multivariable logistic regression analyses.","limitations":"Convenience sample may not be representative. Self-report subject to social desirability bias. Cross-sectional design cannot determine if counseling caused improved knowledge. Survey at academic medical centers may not reflect community practice."},{"rthcId":"RTHC-06579","title":"Demographic, economic, and social status and knowledge of medical and alternative cannabis use among Northeastern Thai citizens: a case study of outpatients at community hospitals along the Thai-Cambodian border.","authors":"Gozzoli, Pattarachit Choompol; Pongthananikorn, Suyanee; Kitisopee, Tanattha; Phunpon, Sathian; Tantipiwattanasakul, Kamolwan; Tangkheunkan, Phakarat; Khaw-Ngern, Kannikar; Chakchai, Kritsada; Kiatying-Angsulee, Niyada; Saengungsumalee, Shinnawat","year":2025,"journal":"Journal of cannabis research, 7(1), 81","doi":"10.1186/s42238-025-00326-3","pmid":"41131584","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06580","title":"Dual abstinence from nicotine vaping and cannabis use among young people: secondary analyses from two U.S.-based randomized controlled trials of vaping cessation.","authors":"Graham, Amanda L; Cha, Sarah; Do, Elizabeth K; Jacobs, Megan A; Edwards, Giselle; Papandonatos, George D","year":2025,"journal":"Substance abuse treatment, prevention, and policy, 20(1), 48","doi":"10.1186/s13011-025-00679-1","pmid":"41177894","tags":["quitting","youth","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This analysis drew from two large text-message-based vaping cessation trials—one for adolescents and one for young adults. The overlap between vaping and cannabis use was enormous: 74.6% of adolescents and 59.2% of young adults in the trials also used cannabis.\n\nAt seven months, 31.7% of adolescents had quit both substances entirely. Among young adults, 15.6% achieved dual abstinence. These rates are encouraging given that neither trial specifically targeted cannabis use—the cessation support focused entirely on nicotine vaping.\n\nThe most intriguing finding was the link between vaping cessation and cannabis outcomes. Adolescents who successfully quit vaping were significantly more likely to also have quit cannabis compared to those who continued vaping. This suggests a gateway-out effect: successfully quitting one substance may build the confidence or break the behavioral patterns that sustain the other.\n\nThe text-message intervention itself didn't directly affect cannabis use outcomes, but it didn't need to—the act of quitting vaping appeared to carry over.","whyItMatters":"Three-quarters of adolescent vapers in these trials also used cannabis—a co-use rate that's become the norm rather than the exception. Knowing that vaping cessation programs don't need to separately address cannabis (and may indirectly help with it) is practically useful for designing interventions. It also challenges the assumption that dual users are harder to treat.","specificNumbers":"Adolescents: 74.6% were dual users at baseline; 31.7% achieved dual abstinence at 7 months. Young adults: 59.2% were dual users at baseline; 15.6% achieved dual abstinence. Adolescents who quit vaping were significantly more likely to also quit cannabis.","methodology":"Secondary analysis of two randomized controlled trials of text-message-based nicotine vaping cessation: one in adolescents (n = 1,016 with complete 7-month data) and one in young adults (n = 1,829). Participants categorized as Exclusive E-cigarette Users or Dual Users at baseline. Outcomes assessed at 7 months: dual abstinence, exclusive e-cigarette use, exclusive cannabis use, or continued dual use.","limitations":"Self-reported substance use (no biochemical verification for cannabis). Neither trial was designed to test cannabis cessation. The correlation between vaping cessation and cannabis cessation doesn't prove causation—a third factor (like motivation or life circumstances) could drive both."},{"rthcId":"RTHC-06581","title":"Changes in Sources of Information About the Risks and Benefits of Cannabis in a National Cohort of U.S. Adults From 2017 to 2021.","authors":"Graham, Francis Julian L; Keyhani, Salomeh; Ling, Pamela; Pravosud, Vira; Nguyen, Nhung; Hasin, Deborah S; Cohen, Beth E","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(4), 563-570","doi":"10.15288/jsad.24-00108","pmid":"39440660","tags":["legalization","medical-cannabis"],"studyType":"longitudinal-study","evidenceStrength":"strong","keyFinding":"In a longitudinal study of 5,053 US adults surveyed at three time points, the use of health professionals as an information source for cannabis risks increased by 17.4%, making it the largest increase among all sources. Traditional media use declined by 11-12%. Cannabis industry sources (advertisements, dispensaries) also increased. Health professionals were consistently rated the most influential information source regardless of age, cannabis use status, or state legalization status.","whyItMatters":"As people increasingly look to healthcare providers for cannabis guidance, providers need adequate training to offer evidence-based information. The simultaneous rise of industry-sourced information creates competing narratives that providers should be prepared to address.","specificNumbers":"5,053 adults across 3 waves; health professional use for risk info: +17.4%; for benefit info: +5.5%; traditional media: -12.3% (benefits), -11.4% (risks); health professionals rated most influential at all time points","methodology":"Longitudinal study of 5,053 US adults surveyed via web in 2017, 2020, and 2021. Assessed use and perceived influence of multiple cannabis information sources (health professionals, internet, social media, traditional media, family/friends, industry sources). Examined interactions with age, cannabis use, and state legal status.","limitations":"Web-based survey may not represent all US adults. Three time points may miss shorter-term fluctuations. Self-reported source usage may not capture passive information exposure. Study period included COVID-19 pandemic, which may have affected information-seeking behavior."},{"rthcId":"RTHC-06582","title":"Detection of 11-nor-9-carboxy-hexahydrocannabinol (HHC-COOH) as metabolite of both hexahydrocannabinol (HHC) and Δ9-tetrahydrocannabinol (Δ9-THC) in routine forensic samples.","authors":"Grapp, Marcel; Kaufmann, Christoph; Peschel, Andreas; Potzscher, Meike; Dziadosz, Marek; Marquenie, Lisa; Teske, Jörg","year":2025,"journal":"Journal of pharmaceutical and biomedical analysis, 261, 116833","doi":"10.1016/j.jpba.2025.116833","pmid":"40139040","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06583","title":"An Analysis of 16-Year Trends in Cannabis Use Disorder Treatment: Predictors, Barriers, and Utilization Patterns.","authors":"Graves, Brian D; Mowbray, Orion; Aletraris, Lydia; O'Shields, Jay","year":2025,"journal":"Substance use & misuse, 60(10), 1540-1549","doi":"10.1080/10826084.2025.2505773","pmid":"40387052","tags":["addiction","quitting","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Across three national survey time points (2003, 2011, 2019), CUD treatment utilization decreased while most individuals meeting diagnostic criteria did not receive treatment. Barriers shifted over time: people increasingly reported not knowing where to access treatment, not being ready to stop, inability to afford treatment, and concerns about stigma or occupational impact. Consistent predictors of receiving treatment included having past-year mental health treatment and being under community supervision (probation/parole).","whyItMatters":"As cannabis potency increases and recreational use expands, fewer people with diagnosable CUD are accessing treatment. The shifting barriers suggest systemic issues with treatment accessibility and awareness rather than individual unwillingness.","specificNumbers":"Three time points: 2003, 2011, 2019; CUD treatment utilization decreased over time; barriers: not knowing where to access treatment, inability to afford, stigma concerns; prior arrest associated with 2-3x higher odds of treatment in later years","methodology":"Analysis of three cross-sectional waves from the National Survey on Drug Use and Health (2003, 2011, 2019). Included individuals meeting diagnostic criteria for CUD. Multivariate logistic regression examined predictors of receiving treatment and self-reported reasons for not receiving treatment.","limitations":"Cross-sectional survey design at each time point. Self-reported CUD diagnosis may differ from clinical assessment. NSDUH methodology changes across years may affect comparability. \"Treatment\" broadly defined and may include brief interventions or mandated programs."},{"rthcId":"RTHC-06584","title":"N-acetylcysteine for youth cannabis use disorder: randomized controlled trial main findings.","authors":"Gray, Kevin M; Tomko, Rachel L; Baker, Nathaniel L; McClure, Erin A; McRae-Clark, Aimee L; Squeglia, Lindsay M","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(5), 731-738","doi":"10.1038/s41386-025-02061-y","pmid":"39910268","tags":["addiction","quitting","youth"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"In a double-blind RCT of 192 treatment-seeking youth (ages 14-21) with CUD, N-acetylcysteine 1200 mg twice daily for 12 weeks showed no advantage over placebo on any cannabis use outcome. The proportion of negative urine tests did not differ (RR=0.93, p=0.80), nor did self-reported abstinence (RR=1.02, p=0.93). Both groups reduced cannabis use over time, but there was no between-group difference. NAC caused significantly more GI side effects (64% vs 39%).","whyItMatters":"A previous trial of NAC for youth CUD showed positive results, but that trial included contingency management (paying participants for negative drug tests). This follow-up demonstrates that NAC alone, without that behavioral platform, is not effective, fundamentally reframing what drove the earlier positive findings.","specificNumbers":"192 youth randomized; ages 14-21; 12-week treatment; negative urine tests RR=0.93 (95% CI: 0.53-1.64, p=0.80); self-reported abstinence RR=1.02 (p=0.93); GI adverse events: 64% NAC vs 39% placebo (p<0.001)","methodology":"Double-blind, placebo-controlled randomized trial. 192 treatment-seeking youth (ages 14-21) with CUD randomized to NAC 1200 mg or placebo twice daily for 12 weeks. All received weekly medical management and brief behavioral counseling. Primary outcome: proportion of negative urine cannabinoid tests during treatment.","limitations":"Treatment-seeking youth may differ from the broader CUD population. Weekly medical management and counseling provided to both groups may have diluted any NAC effect. 12-week duration may be insufficient. High GI side effect rate may have functionally unblinded some participants."},{"rthcId":"RTHC-06585","title":"Comparison of selected metals in the fillers of 14 commercial hemp cigarette brands to commercial tobacco cigarettes.","authors":"Gray, Naudia R; Pappas, R Steven; Watson, Clifford H","year":2025,"journal":"Journal of cannabis research, 8(1), 11","doi":"10.1186/s42238-025-00330-7","pmid":"41372766","tags":["respiratory","harm-reduction"],"studyType":"laboratory-study","evidenceStrength":"moderate","keyFinding":"Researchers analyzed 14 commercial hemp cigarette brands for nine metals and compared them to published data on tobacco cigarettes and little cigars. All hemp cigarette filler had cadmium concentrations below the lowest reportable level, significantly lower than tobacco. However, concentrations of other metals (beryllium, chromium, manganese, cobalt, nickel, arsenic, lead, uranium) fell in ranges similar to tobacco products, with several brands exceeding some state action limits for chromium, nickel, arsenic, and lead.","whyItMatters":"Hemp cigarettes are often marketed as tobacco alternatives or cessation aids, but their metal content had never been analyzed. Knowing that metal exposure risks are broadly similar to tobacco, with some brands exceeding state safety limits, is essential safety information for consumers.","specificNumbers":"14 hemp cigarette brands analyzed; 9 metals measured; all hemp cadmium levels below reportable limit (significantly lower than tobacco); several brands exceeded state action limits for chromium, nickel, arsenic, and lead","methodology":"Laboratory analysis of hemp filler from 14 commercial brands for nine metals (Be, Cr, Mn, Co, Ni, As, Cd, Pb, U). Results compared to previously published US tobacco cigarette and little cigar data. NIST Reference Material used to verify analytical accuracy.","limitations":"Analyzed filler content only, not smoke or emissions. Metal concentrations in the product do not directly predict metal delivery to the user. Comparison to tobacco data from separate studies introduces variability. State action limits vary and may not perfectly apply to smoked products."},{"rthcId":"RTHC-06586","title":"Is hemp (Cannabis sativa) safe to feed pregnant sheep?","authors":"Green, Benedict T; Gardner, Dale R; Stonecipher, Clinton A; Welch, Kevin D; Lee, Stephen T; Sullivan, Tina; Westmoreland, F Mitchell; Cook, Daniel","year":2025,"journal":"Translational animal science, 9, txaf093","doi":"10.1093/tas/txaf093","pmid":"40756673","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06587","title":"Ask the experts: Community Engagement studios to inform research on cannabis use in cancer symptom management.","authors":"Greene, Brittney; Mckenzie, Grace; Gibbons, Keenan; Meghani, Salimah H; Worster, Brooke; Ashare, Rebecca L","year":2025,"journal":"Journal of clinical and translational science, 9(1), e47","doi":"10.1017/cts.2025.10","pmid":"40201652","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06588","title":"Cannabis-based extract for managing pain in dogs with osteoarthritis: efficacy and safety assessment.","authors":"Griebeler, Neide Maria; Cremonese, Ricardo Penayo; Fakih Correa, Yasmin Rafaela; Pereira, Priscila Romero Mazzini; Rial, Amanda Furjan; Leite, Emanuela; Gonçalves, Maria Victoria Luz; Marques das Almas, Luiz Renato; Cardoso, Nedice Borges; Cezar-Dos-Santos, Fernando; Toci, Aline Theodoro; Mojoli Le-Quesne, Andrés; Nascimento, Francisney Pinto","year":2025,"journal":"Frontiers in pharmacology, 16, 1539704","doi":"10.3389/fphar.2025.1539704","pmid":"41368581","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06589","title":"Development, characterization and in vitro assessment of a novel self-microemulsifying drug delivery system to increase cannabidiol intestinal bioaccessibility.","authors":"Grifoni, Lucia; De Donno, Giulia; Vanti, Giulia; Bergonzi, Maria Camilla; Tan, Lihua; Luceri, Cristina; Bilia, Anna Rita","year":2025,"journal":"International journal of pharmaceutics, 685, 126284","doi":"10.1016/j.ijpharm.2025.126284","pmid":"41109647","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06590","title":"Cannabis Use Among Pregnant and Nonpregnant Women of Childbearing Age: Findings From the 2021-2023 National Survey of Drug Use and Health.","authors":"Grigsby, Timothy J; Assoumou, Bertille; Koning, Stephanie M; Howard, Jeffrey T; Howard, Krista","year":2025,"journal":"American journal of preventive medicine, 69(4), 107967","doi":"10.1016/j.amepre.2025.107967","pmid":"40614880","tags":["pregnancy","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 94,225 women of reproductive age (including 2,051 pregnant), cannabis use prevalence was 12.6% for nonpregnant and 6.8% for pregnant women. First-trimester use was highest at 10.1%, peaking at 14.2% in 2022. Smoking was the predominant method (65.4% of pregnant users). Past 30-day alcohol use (aOR=7.51), illicit drug use (aOR=4.70), tobacco use (aOR=3.04), and past-year major depressive episode (aOR=2.52) were all strongly associated with cannabis use during pregnancy.","whyItMatters":"This is the most current national estimate of cannabis use in pregnancy, revealing that first-trimester exposure, when fetal organ development is most vulnerable, occurs at rates above 10%. The strong association with depression and other substance use suggests opportunities for integrated screening.","specificNumbers":"94,225 women; 6.8% of pregnant women used cannabis; first-trimester use 10.1%, peaking at 14.2% in 2022; smoking: 65.4% of pregnant users; depression aOR=2.52; alcohol use aOR=7.51; nonpregnant cannabis use increased over the period","methodology":"Secondary analysis of 2021-2023 National Survey on Drug Use and Health data. Assessed cannabis use prevalence, methods (smoking, vaping, edibles), and correlates among pregnant and nonpregnant women aged 12-44. Multivariable logistic regression adjusted for survey design.","limitations":"Self-report data likely underestimates actual use. Cross-sectional design within each survey year. Cannot assess outcomes for mothers or infants. Survey excludes institutionalized populations. Cannabis use in early pregnancy may predate pregnancy awareness."},{"rthcId":"RTHC-06591","title":"Substance use and sexual orientation among adolescents: Differences by age group and sex in the 2023 National Survey of Drug Use and Health.","authors":"Grigsby, Timothy J; Hoopsick, Rachel; Barker, Dylan; Devier, Elise; Amis, Amber; Yockey, R Andrew","year":2025,"journal":"The American journal on addictions","doi":"10.1111/ajad.70087","pmid":"40947772","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 10,361 adolescents aged 12-17, 11.2% reported past-year marijuana use. Bisexual youth had significantly higher odds of marijuana use (OR=1.85) compared to heterosexual youth. Gay/lesbian youth did not have significantly higher marijuana use odds. The disparities varied by sex and age group, with the substance use gap between bisexual and heterosexual youth being particularly pronounced.","whyItMatters":"Bisexual adolescents face distinct stressors from both heterosexual and gay/lesbian peers, including identity invalidation and dual discrimination. Understanding that these stressors correlate with significantly higher marijuana use can guide targeted prevention that addresses root causes rather than just substance use.","specificNumbers":"10,361 adolescents; 11.2% past-year marijuana use; bisexual youth marijuana OR=1.85 (95% CI: 1.43-2.40); bisexual tobacco OR=2.00; bisexual alcohol OR=1.32; gay/lesbian tobacco OR=0.47 (lower odds)","methodology":"Secondary analysis of the 2023 National Survey on Drug Use and Health (N=10,361 youth aged 12-17). Weighted logistic regression examined relationships between sexual orientation and past-year substance use (tobacco, marijuana, alcohol), stratified by age and sex assigned at birth.","limitations":"Cross-sectional design cannot establish causation. Self-reported sexual orientation among 12-17 year olds may be unstable or underreported. Single-year survey data. Cannot assess frequency or quantity of use beyond past-year prevalence."},{"rthcId":"RTHC-06592","title":"Hazardous Drinking and Cannabis Use in Military Veterans: Comparative Associations with Risk for Suicidal and Non-Suicidal Self-Injury.","authors":"Grove, Jeremy L; Beckham, Jean C; Calhoun, Patrick S; Dedert, Eric A; Pugh, Mary J; Kimbrel, Nathan A","year":2025,"journal":"International journal of mental health and addiction","doi":"10.1007/s11469-025-01453-x","pmid":"40881133","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Veterans who used both cannabis and alcohol hazardously had greater odds of suicidal ideation and elevated suicide risk than any other group, including those who used either substance alone. Notably, cannabis use alone was not associated with greater odds of suicidal ideation or elevated suicide risk compared to the non-using group. However, cannabis use (alone or with alcohol) was associated with higher rates of non-suicidal self-injury (NSSI).","whyItMatters":"The nuanced finding that cannabis alone did not increase suicide risk while combined use did suggests that polysubstance use patterns, not individual substances in isolation, may drive the most concerning outcomes in veteran populations.","specificNumbers":"1,098 veterans; 78% male; concurrent use (HD+CU) had greatest odds of suicidal ideation and elevated suicide risk; CU alone: no elevated suicide risk; both CU only and HD+CU associated with higher NSSI rates","methodology":"Cross-sectional survey of 1,098 US veterans (78% male, 67% White). Compared four groups: hazardous drinking only, cannabis use only, concurrent use, and neither. Assessed past-year suicidal ideation, elevated risk for suicidal behavior, and past-year NSSI via validated questionnaires, controlling for covariates.","limitations":"Cross-sectional design cannot establish causation. Self-report survey may undercount sensitive behaviors. Predominantly male, White sample may not generalize to all veterans. Could not assess cannabis use frequency, quantity, or type."},{"rthcId":"RTHC-06593","title":"The Endocannabinoid System Drives Eosinophil Infiltration During Eosinophilic Esophagitis.","authors":"Gruden, Eva; Kienzl, Melanie; Danner, Laura; Kaspret, David Markus; Pammer, Anja; Ristic, Dusica; Kindler, Oliver; Doyle, Alfred D; Wright, Benjamin L; Taschler, Ulrike; Thomas, Dominique; Gurke, Robert; Baumann-Durchschein, Franziska; Konrad, Julia; Blesl, Andreas; Schlager, Hansjörg; Bärnthaler, Thomas; Kargl, Julia; Schicho, Rudolf","year":2025,"journal":"Cellular and molecular gastroenterology and hepatology, 19(8), 101515","doi":"10.1016/j.jcmgh.2025.101515","pmid":"40221089","tags":["inflammation","neuroscience"],"studyType":"laboratory-study","evidenceStrength":"preliminary","keyFinding":"In esophageal biopsies from patients with active eosinophilic esophagitis (EoE), the enzyme that breaks down the endocannabinoid 2-AG (monoacylglycerol lipase, MGL) was decreased, leading to elevated 2-AG levels. When MGL was inhibited in epithelial cells, they developed a pro-inflammatory profile that attracted eosinophils via the CB2 receptor. In a mouse EoE model, blocking CB2 reduced eosinophil infiltration. The findings help explain why cannabis users with EoE may have worse inflammatory features after treatment.","whyItMatters":"This is the first study to connect altered endocannabinoid signaling to eosinophilic esophagitis. The finding that cannabis use may worsen EoE inflammation through CB2-mediated eosinophil recruitment has direct implications for the growing number of cannabis users with this condition.","specificNumbers":"MGL expression decreased in active EoE biopsies; 2-AG levels increased vs controls; CB2 antagonism reduced eosinophil infiltration in mouse model; findings consistent across human biopsies, in vitro, and mouse models","methodology":"Multi-method study combining human biopsy analysis (MGL expression, 2-AG levels, enzyme activity), in vitro epithelial cell experiments (eosinophil migration assays), and an inducible mouse EoE model with MGL inhibition and CB receptor antagonism.","limitations":"Translational study combining human observational data with mechanistic animal and cell work. Mouse EoE models do not fully replicate human disease. Cannot determine whether exogenous cannabis use would have the same effects as elevated endogenous 2-AG."},{"rthcId":"RTHC-06594","title":"Cannabis Use is Associated With Lower Urinary Tract Symptoms in Pediatric Patients-A Large Claims Database Study.","authors":"Grutman, Aurora J; Gumma, Mohammad Elmojtaba; Page, Nicole; Gabrielson, Andrew T; Clifton, Marisa; DiCarlo, Heather","year":2025,"journal":"Urology, 205, 187-195","doi":"10.1016/j.urology.2025.07.014","pmid":"40675390","tags":["youth","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After propensity score matching over 4.8 million male and 4.2 million female patients under 18, those with CUD showed significantly higher rates of new urinary symptom diagnoses at 5-year follow-up. Female CUD patients had elevated rates of pelvic pain (OR 2.3), overactive bladder (OR 1.6), dysuria (OR 1.2), and UTI (OR 1.8). Male CUD patients showed increased pelvic pain (OR 3.8), dysuria (OR 1.4), and UTI (OR 1.7).","whyItMatters":"Urinary symptoms in adolescents are rarely discussed in the context of cannabis use. This large database study suggests an underrecognized association that could inform clinical screening and patient counseling.","specificNumbers":"~9.1 million patients screened; 11,840 matched males and 11,810 matched females per arm; median age ~15.5 years; female CUD: pelvic pain OR 2.3, OAB OR 1.6, UTI OR 1.8; male CUD: pelvic pain OR 3.8, UTI OR 1.7","methodology":"Retrospective cohort study using the TriNetX Research Network. Male and female patients under 18 with or without CUD were propensity score matched for demographics and comorbidities. Primary outcomes: new diagnoses of LUTS, pelvic pain, overactive bladder, dysuria, or UTI at 5-year follow-up.","limitations":"Administrative database cannot confirm actual cannabis use patterns. CUD diagnosis codes may capture severe cases only. Cannot determine causality. Propensity matching cannot account for unmeasured confounders. UTI association may reflect behavioral rather than physiological factors."},{"rthcId":"RTHC-06595","title":"The Involvement of the Endocannabinoid, Glutamatergic, and GABAergic Systems in PTSD.","authors":"Grzesińska, Anna Dorota","year":2025,"journal":"International journal of molecular sciences, 26(13)","doi":"10.3390/ijms26135929","pmid":"40649707","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06596","title":"Trends of Adolescent Substance Use by Type of Victimization: COVID-19 Interaction Effects in the United States Youth Risk Behavior Survey (2013-2023).","authors":"Gu, Hyejin; Myong, Jun-Pyo","year":2025,"journal":"Substance use & misuse, 1-11","doi":"10.1080/10826084.2025.2597457","pmid":"41359881","tags":["youth","mental-health"],"studyType":"longitudinal-study","evidenceStrength":"strong","keyFinding":"Among 52,679 US adolescents from the YRBS (2013-2023), 27.2% reported at least one form of victimization. Those experiencing sexual victimization had higher odds of alcohol (aOR=2.79) and other drug use (aOR=3.65). Youth with multiple victimizations had the highest substance use risk overall, with marijuana use odds peaking at aOR=3.53 during the pandemic. While marijuana use declined broadly in 2021, it rebounded to aOR=1.72 by 2023 specifically among the multiple-victimization group. Victimization-by-year interactions were significant, indicating widening disparities over time.","whyItMatters":"The pandemic did not affect all adolescents equally. Youth who were already vulnerable through victimization experienced disproportionately worsened substance use outcomes, and these disparities persisted even after pandemic restrictions eased.","specificNumbers":"52,679 adolescents; 27.2% reported victimization; multiple victimizations: marijuana aOR=3.53 during pandemic; sexual victimization: alcohol aOR=2.79, other drug aOR=3.65; marijuana rebounded to aOR=1.72 in 2023 among multiple-victimization group","methodology":"Analysis of nationally representative Youth Risk Behavior Survey data (2013-2023, N=52,679). Victimization categorized as school bullying, electronic bullying, sexual victimization, or multiple. Linear logistic regression assessed trends and victimization-by-year interactions. Difference-in-differences regression tested changes across pre-COVID, pandemic, and post-COVID periods.","limitations":"YRBS is school-based and excludes non-enrolled youth, who may have higher victimization and substance use rates. Self-report measures. Cross-sectional at each wave, though difference-in-differences approach strengthens causal inference. Cannot assess dose-response relationships."},{"rthcId":"RTHC-06597","title":"2-Linoleoylglycerol decreased seizure through the regulation of 5-hydroxytryptamine 1A receptor and G protein-coupled receptor 55 interaction in mice.","authors":"Gu, Sun Mi; Jabborov, Abdulaziz; Yun, Jaesuk","year":2025,"journal":"Neuroreport, 36(17), 1009-1015","doi":"10.1097/WNR.0000000000002220","pmid":"41562510","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06598","title":"The cannabinoid CB2 agonist LY2828360 suppresses neuropathic pain behavior and attenuates morphine tolerance and conditioned place preference in rats.","authors":"Guenther, Kelsey G; Wirt, Jonah L; Oliva, Idaira; Saberi, Shahin A; Crystal, Jonathon D; Hohmann, Andrea G","year":2025,"journal":"Neuropharmacology, 265, 110257","doi":"10.1016/j.neuropharm.2024.110257","pmid":"39644993","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06599","title":"Prevention Needs and Target Behavior Preferences in an App-Based Addiction Prevention Program for German Vocational School Students: Cluster Randomized Controlled Trial.","authors":"Guertler, Diana; Kraft, Elaine; Bläsing, Dominic; Möhring, Anne; Meyer, Christian; Schmidt, Hannah; Rehbein, Florian; Neumann, Merten; Dreißigacker, Arne; Bischof, Anja; Bischof, Gallus; Sürig, Svenja; Hohls, Lisa; Wurm, Susanne; Borgwardt, Stefan; Haug, Severin; Rumpf, Hans-Jürgen","year":2025,"journal":"JMIR mHealth and uHealth, 13, e59573","doi":"10.2196/59573","pmid":"40553509","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06600","title":"Dietary iron interacts with diet composition to modulate the endocannabinoidome and the gut microbiome in mice.","authors":"Guevara Agudelo, Fredy Alexander; Leblanc, Nadine; Bourdeau-Julien, Isabelle; St-Arnaud, Gabrielle; Dahhani, Fadil; Flamand, Nicolas; Veilleux, Alain; Di Marzo, Vincenzo; Raymond, Frédéric","year":2025,"journal":"Gut microbiome (Cambridge, England), 6, e12","doi":"10.1017/gmb.2025.1","pmid":"40692677","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06601","title":"Lifetime Cannabis Use Is Associated with Brain Volume and Cognitive Function in Middle-Aged and Older Adults.","authors":"Guha, Anika; Fu, Zening; Calhoun, Vince; Hutchison, Kent E","year":2025,"journal":"Journal of studies on alcohol and drugs","doi":"10.15288/jsad.25-00346","pmid":"41379083","tags":["cognition","neuroscience","seniors"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using UK Biobank data from participants aged 40-70 (mean age 54.5), lifetime cannabis use was positively associated with regional brain volume in CB1-rich areas including the caudate, putamen, hippocampus, and amygdala. Greater lifetime use was also linked to better performance in learning, processing speed, and short-term memory. Even individuals whose use was limited to adolescence showed larger regional volumes and better cognitive performance than non-users. Sex differences in these associations were observed.","whyItMatters":"Most cannabis brain research focuses on adolescents and young adults, where findings tend to be negative. This study suggests a more complex picture across the lifespan, where the same substance may have different brain associations at different ages, potentially related to endocannabinoid-mediated neuroprotection.","specificNumbers":"UK Biobank sample; ages 40-70; mean age 54.5; positive associations with volume in caudate, putamen, hippocampus, amygdala; better performance in learning, processing speed, short-term memory; effects observed even for adolescence-only users; sex differences present","methodology":"Cross-sectional analysis of UK Biobank data from adults aged 40-70. Assessed associations between self-reported cannabis use history, regional brain volumes (via MRI), and cognitive performance on validated tasks. Examined sex-specific effects.","limitations":"Cross-sectional design cannot determine causation: people with naturally larger brain volumes may be more likely to use cannabis, or other lifestyle factors may explain both. Self-reported use history subject to recall bias. UK Biobank participants tend to be healthier than the general population. Cannot assess cannabis type, potency, or route of administration."},{"rthcId":"RTHC-06602","title":"Cannabinoid treatment impacts adaptive behavior in autism patients and caregivers' mental health: A prospective real-life cohort study.","authors":"Guimarães, Kelly Álvares; Jorge, Letícia Perígolo; Resende, Ana Luiza de Oliveira; da Silva Junior, Estácio Amaro; Kummer, Arthur Melo E; da Silva Lessa Júnior, Wilson; de Oliveira, Guilherme Nogueira M","year":2025,"journal":"Progress in brain research, 296, 29-53","doi":"10.1016/bs.pbr.2025.08.014","pmid":"40967683","tags":["cbd","mental-health","youth"],"studyType":"observational-study","evidenceStrength":"preliminary","keyFinding":"In a prospective study of 16 patients with severe autism treated with CBD-rich extract and 17 untreated controls with moderate autism, the CBD group showed significant reduction in maladaptive internalizing behaviors on the Vineland 3 scale (p=0.008) after three months. Caregivers of the CBD group also showed significant improvements in interpersonal sensitivity (p=0.038), global severity (p=0.025), and positive symptom distress (p=0.007) on the Brief Symptom Inventory.","whyItMatters":"Treatment options for behavioral symptoms of autism remain limited. The dual finding of patient improvement and caregiver mental health benefits suggests that effective ASD treatment creates a positive cascade for the entire family.","specificNumbers":"16 CBD patients (severe ASD, ATEC 85.5), 17 controls (moderate ASD, ATEC 58.6); CBD group: reduced internalizing behavior (p=0.008); caregiver improvements: interpersonal sensitivity (p=0.038), global severity (p=0.025), symptom distress (p=0.007)","methodology":"Prospective, non-randomized observational study comparing 16 ASD patients receiving CBD-rich extract to 17 untreated controls. Assessments at baseline and 3 months using ATEC, CARS, Vineland 3 (patients) and BSI (caregivers).","limitations":"Non-randomized design with groups differing in baseline severity (severe vs moderate ASD). Very small sample size. No blinding. Three-month follow-up may be insufficient. Caregiver mental health improvements could reflect placebo effect or hope from trying a new treatment."},{"rthcId":"RTHC-06603","title":"Association Between Cannabis Use and Neuropsychiatric Disorders: A Two-sample Mendelian Randomization Study.","authors":"Guo, Wei; Dong, Lin; Lu, Qingxing; Xie, Mengtong; Yang, Yuqi; Zhang, Yanchi; Lu, Xiaoyu; Yu, Qiong","year":2025,"journal":"Alpha psychiatry, 26(4), 46108","doi":"10.31083/AP46108","pmid":"40926822","tags":["cognition","psychosis","addiction"],"studyType":"mendelian-randomization","evidenceStrength":"moderate","keyFinding":"Using two-sample Mendelian randomization with GWAS data, the study found genetically predicted lifetime cannabis use was associated with increased risk of Parkinson's disease (OR=1.78, 95% CI: 1.03-3.08) and ADHD in women (OR=1.65, 95% CI: 1.05-2.59). No significant causal associations were found with Alzheimer's, ALS, epilepsy, migraine, schizophrenia, anorexia, or autism.","whyItMatters":"Traditional observational studies cannot easily separate whether cannabis use causes neuropsychiatric conditions or whether people predisposed to those conditions are more likely to use cannabis. Mendelian randomization uses genetic variation to approximate a natural experiment, providing stronger evidence about causal direction.","specificNumbers":"Parkinson's disease OR=1.78 (95% CI: 1.03-3.08, p=0.038); ADHD in females OR=1.65 (95% CI: 1.05-2.59, p=0.029); no significant associations with AD, ALS, epilepsy, migraine, schizophrenia, AN, ASD, or MS","methodology":"Two-sample Mendelian randomization using publicly available GWAS summary statistics. Genetic instruments for lifetime cannabis use tested against 10 neuropsychiatric disorders. Inverse variance weighted (IVW) method as primary analysis.","limitations":"Mendelian randomization assumes genetic variants affect the outcome only through cannabis use (no pleiotropy). Moderate p-values that would not survive strict multiple comparison correction. Cannot assess dose-response, timing, or type of cannabis. European-ancestry GWAS limits generalizability."},{"rthcId":"RTHC-06604","title":"Mindfulness-Oriented Recovery Enhancement Reduces Illicit Substance Craving Among People with Alcohol Use Disorder and Polysubstance Use.","authors":"Gurrieri, Laura; Wardle, Margaret C; Garland, Eric L","year":2025,"journal":"Substance use & misuse, 60(13), 1964-1968","doi":"10.1080/10826084.2025.2525379","pmid":"40898007","tags":["addiction","quitting","mental-health"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"In a randomized pilot trial of 50 adults with AUD who also used cannabis and/or cocaine, Mindfulness-Oriented Recovery Enhancement (MORE) produced significantly greater reductions in illicit substance craving compared to supportive group therapy (F=7.06, p=0.008). The effect was consistent across a stress-and-cue reactivity protocol. MORE combines mindfulness training, cognitive-behavioral techniques, and practices for savoring natural rewards.","whyItMatters":"Cannabis and cocaine have no approved medication treatments and respond poorly to standard behavioral therapies. Finding that a mindfulness-based approach can reduce cravings across multiple substances simultaneously could simplify treatment for polysubstance users.","specificNumbers":"50 adults with AUD + cannabis/cocaine use; 10 sessions; significant Group x Time interaction (F=7.06, p=0.008); effect consistent across stress and cue conditions (interaction p=0.61, non-significant, meaning benefit did not vary by condition)","methodology":"Randomized controlled pilot trial. 50 adults with AUD and concurrent cannabis/cocaine use assigned to 10 sessions of MORE or supportive group psychotherapy. Craving assessed before and after treatment during a cue-reactivity protocol with resting baseline, stress imagery, alcohol image exposure, and recovery period.","limitations":"Pilot study with small sample size (N=50). Cannot determine which component of MORE (mindfulness, CBT, savoring) drove the effect. Short-term craving reduction in a lab protocol may not predict real-world use reduction. The therapy targeted AUD, so cannabis/cocaine effects are secondary outcomes."},{"rthcId":"RTHC-06605","title":"Marijuana Use Is Associated with Increased Rates of Hip Dislocation and Lower Insurance Reimbursement among Total Hip Arthroplasty Recipients.","authors":"Gwam, Chukwuweike; Kelly, Erin; Douglas, Scott; Recker, Andrew; Plate, Johannes F","year":2025,"journal":"Journal of long-term effects of medical implants, 35(1), 17-23","doi":"10.1615/JLongTermEffMedImplants.2024049017","pmid":"39704596","tags":["addiction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 1,654 matched pairs of marijuana users and non-users who underwent total hip arthroplasty (2010-2018), marijuana users had significantly higher rates of hip dislocation at both 90 days and one year. However, there was no difference in opioid consumption between groups. Marijuana use was associated with lower 90-day care costs.","whyItMatters":"The finding that marijuana use did not increase opioid consumption challenges the common assumption that cannabis users need more pain medication postoperatively. The dislocation finding may relate to balance or coordination effects rather than surgical healing.","specificNumbers":"1,654 matched patients per group; higher hip dislocation rates at 90 days and 1 year; no difference in opioid consumption; lower 90-day costs for marijuana users","methodology":"Retrospective review of the Mariner insurance database (2010-2018). Marijuana users identified by ICD codes were 1:1 matched to non-users on age, sex, comorbidities, obesity, alcohol, tobacco, illicit drug use, drug abuse history, and psychiatric history. Compared 90-day and 1-year outcomes.","limitations":"Administrative database with ICD coding for marijuana use likely captures only diagnosed cannabis use disorder. Cannot distinguish active use from historical use. Cannot control for factors not captured in claims data. Dislocation mechanism not specified."},{"rthcId":"RTHC-06606","title":"Estimating Cannabis Consumption in Milligrams of THC From Self-Reported Hit Size.","authors":"Habib, Mohammad I; Budney, Alan J; Struble, Cara A; Hasin, Deborah S; Livne, Ofir; Aharonovich, Efrat; Wisell, Caroline; Fragione, Sara N; Borodovsky, Jacob T","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(2), 153-163","doi":"10.26828/cannabis/2025/000285","pmid":"40909144","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06607","title":"This is your brain on drug education: Putting young people with lived experience at the center of drug education.","authors":"Hadad, Noor; D'Alessio, Heath; Ellis-Durity, Kiah; Trombley, Hunter","year":2025,"journal":"The International journal on drug policy, 138, 104467","doi":"10.1016/j.drugpo.2024.104467","pmid":"39025708","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06608","title":"Endocannabinoid system alterations in schizophrenia: association with cannabis use and antipsychotic medication.","authors":"Haddad, Natalia Mansur; De Jesus, Leonardo Peroni; Serpa, Mauricio; Van De Bilt, Martinus; Talib, Leda; Costa, Alana; Gattaz, Wagner; Loch, Alexandre Andrade","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 545-553","doi":"10.1007/s00406-024-01788-x","pmid":"38502208","tags":["psychosis","neuroscience"],"studyType":"observational-study","evidenceStrength":"preliminary","keyFinding":"In a study of 93 individuals (29 treatment-resistant schizophrenia on clozapine, 31 on other antipsychotics, 33 controls), those reporting lifetime cannabis use had significantly lower plasma 2-AG levels (p=0.011), and this remained the only significant factor in models controlling for confounders. Patients on non-clozapine antipsychotics showed altered CB2 receptor levels compared to controls (p=0.022). AEA levels and CB2 levels did not differ between patients and controls overall.","whyItMatters":"This provides the first evidence that cannabis use and antipsychotic medication type independently modulate different components of the peripheral endocannabinoid system in schizophrenia. The distinction between clozapine and other antipsychotics on CB2 levels suggests ECS interactions may partly explain different treatment responses.","specificNumbers":"93 participants (29 clozapine, 31 other antipsychotics, 33 controls); cannabis users had lower 2-AG (p=0.011); non-clozapine antipsychotics altered CB2 (p=0.022); cannabis use was the only significant factor for 2-AG in adjusted models","methodology":"Cross-sectional study measuring blood levels of AEA, 2-AG, and CB2 receptor in 93 participants divided into three groups: clozapine-treated schizophrenia (treatment-resistant), other antipsychotic-treated schizophrenia, and healthy controls. Generalized linear models controlled for confounders.","limitations":"Small sample size. Cross-sectional design cannot establish causation. Peripheral blood measurements may not reflect brain endocannabinoid activity. Lifetime cannabis use is a crude measure that does not capture recency, frequency, or type."},{"rthcId":"RTHC-06609","title":"Implementation and evaluation of a knowledge translation process to optimize the adoption of harm reduction in cannabis use by practitioners working with youth in Quebec: a mixed-methods study.","authors":"Haddad, Roula; Fallu, Jean-Sébastien; Huỳnh, Christophe; D'Arcy, Laurence; Song, Yuan; Dagenais, Christian","year":2025,"journal":"Health research policy and systems, 23(1), 147","doi":"10.1186/s12961-025-01411-y","pmid":"41174654","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06610","title":"Mixed-methods study on professionals' attitudes toward harm reduction in cannabis use and the development of a knowledge translation plan.","authors":"Haddad, Roula; Fallu, Jean-Sébastien; Huỳnh, Christophe; Gervais, Mathieu-Joël; Dagenais, Christian","year":2025,"journal":"Scientific reports, 15(1), 13225","doi":"10.1038/s41598-025-96001-x","pmid":"40246919","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06611","title":"High light intensity enhances cannabinoid biosynthesis through concerted gene expression in hemp (Cannabis sativa) flowers.","authors":"Hahm, Seungyong; Bok, Gwonjeong; Kim, Sungjin; Kim, Byungjun; Lee, Yongjae; Kim, Sunwoo; Park, Jongseok","year":2025,"journal":"Frontiers in plant science, 16, 1687794","doi":"10.3389/fpls.2025.1687794","pmid":"41195145","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06612","title":"Approach Bias Modification for reducing Co-Occurring Alcohol and cannabis use among treatment-seeking Adolescents: Protocol of a randomized controlled trial.","authors":"Hahn, Austin M; Corcoran, Erin; Danielson, Carla Kmett","year":2025,"journal":"Contemporary clinical trials communications, 44, 101435","doi":"10.1016/j.conctc.2025.101435","pmid":"39944963","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06613","title":"Written Exposure Therapy for PTSD Integrated with Cognitive Behavioral Coping Skills for Cannabis Use Disorder After Recent Sexual Assault: A Case Series.","authors":"Hahn, Christine K; Salim, Selime R; Tilstra-Ferrell, Emily L; Brady, Kathleen T; Marx, Brian P; Rothbaum, Barbara O; Saladin, Michael E; Guille, Constance; Gilmore, Amanda K; Back, Sudie E","year":2025,"journal":"Behavioral sciences (Basel, Switzerland), 15(7)","doi":"10.3390/bs15070877","pmid":"40723661","tags":["ptsd","addiction","mental-health","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case series describes STEPS (Skills Training and Exposure for PTSD and Substance Misuse), a new therapy that combines Written Exposure Therapy for PTSD with cognitive-behavioral skills training for cannabis use disorder. It was delivered to three women ages 19–25 who experienced recent sexual assault and were using cannabis problematically.\n\nThe approach is notable for two reasons. First, it treats both conditions simultaneously rather than the traditional sequential approach (stabilize substance use first, then address trauma). Second, it targets people soon after the traumatic event, when early intervention might prevent both conditions from becoming entrenched.\n\nExisting integrated trauma-and-substance-use protocols tend to be lengthy, which creates barriers to completion. STEPS was designed to be briefer and more accessible. The three cases showed improvements in both PTSD symptoms and cannabis use, though with only three participants and no control group, these results are purely descriptive.\n\nThe rationale for targeting cannabis specifically (rather than alcohol or other substances) reflects the reality that cannabis use disorder is increasingly common among young trauma survivors—a population that often self-medicates with cannabis to manage PTSD symptoms like hyperarousal and intrusive memories.","whyItMatters":"Sexual assault is one of the most common causes of PTSD, and cannabis use disorder frequently co-occurs with trauma in young adults. Most treatment protocols require addressing one condition before the other, which means patients often fall through the cracks. An integrated, brief approach that works soon after trauma could fill a significant gap—but this case series is only the very first step toward testing that idea.","specificNumbers":"3 participants, ages 19–25. All experienced recent sexual assault. All showed improvements in PTSD severity and cannabis use by end of treatment.","methodology":"Case series of three emerging adult women (ages 19–25) who experienced recent sexual assault and met criteria for PTSD and problematic cannabis use. Treatment: STEPS protocol combining Written Exposure Therapy with cognitive-behavioral substance use skills training. No control group or comparison condition.","limitations":"Three participants with no control group—this is hypothesis-generating, not evidence of efficacy. No long-term follow-up reported. All participants were young women after sexual assault; results may not generalize to other trauma types, demographics, or genders. The improvements could reflect natural recovery, placebo effects, or regression to the mean."},{"rthcId":"RTHC-06614","title":"Patterns of Cannabis Use among Women With HIV in the United States.","authors":"Haley, Danielle F; Bullington, Brooke W; Tien, Phyllis; Knittel, Andrea K; Bobitt, Julie; Kempf, Mirjam-Colette; Philbin, Morgan; Hanna, David B; Lindsey, StarrLa'diamond; Kassaye, Seble; DeHovitz, Jack; Cohen, Mardge; Wingood, Gina; Jones, Deborah L; Williams, Michael P; Wang, Richard J; Edmonds, Andrew","year":2025,"journal":"AIDS and behavior, 29(6), 2022-2032","doi":"10.1007/s10461-025-04669-z","pmid":"40050488","tags":["medical-cannabis","sex-differences"],"studyType":"longitudinal-study","evidenceStrength":"moderate","keyFinding":"In the Women's Interagency HIV Study (2018-2019), 27% of 1,246 women with HIV used cannabis and 15% used daily. Smoking was the dominant mode (96%), followed by edibles (30%) and vaping (18%). Notably, 50% of users reported varying use frequencies across time points, suggesting unstable use patterns. Cannabis users had significantly higher rates of alcohol (69% vs 37%), cigarette (61% vs 29%), and other drug use (16% vs 4%).","whyItMatters":"Women with HIV are an aging population where cannabis use is twice the national average. The finding that half of users change their frequency over time challenges assumptions about stable use patterns and has implications for how providers assess and discuss cannabis use.","specificNumbers":"1,246 women with HIV; median age 52; 65% Black/African American; 27% any cannabis use; 15% daily use; 96% smoked; 30% edibles; 18% vaped; 50% varied frequency; higher concurrent alcohol (69% vs 37%) and cigarette use (61% vs 29%)","methodology":"Longitudinal analysis of 1,246 women with HIV in the WIHS over 18 months (2018-2019). Characterized prevalence, frequency, and modes of cannabis use. Compared demographics and health behaviors between users and non-users. Sankey diagrams illustrated transitions between use frequency categories.","limitations":"Single cohort of predominantly Black, low-income women with HIV; may not generalize. Self-report measures. 18-month window may not capture longer-term patterns. Cannot assess health outcomes associated with different use patterns."},{"rthcId":"RTHC-06615","title":"Effectiveness and safety of psychosocial interventions for the treatment of cannabis use disorder: A systematic review and meta-analysis.","authors":"Halicka, Monika; Parkhouse, Thomas L; Webster, Katie; Spiga, Francesca; Hines, Lindsey A; Freeman, Tom P; Sanghera, Sabina; Dawson, Sarah; Paterson, Craig; Savović, Jelena; Higgins, Julian P T; Caldwell, Deborah M","year":2025,"journal":"Addiction (Abingdon, England), 120(11), 2181-2201","doi":"10.1111/add.70084","pmid":"40318070","tags":["addiction","quitting"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 22 RCTs with 3,304 participants, MET-CBT significantly increased point abstinence (OR=18.27) and continuous abstinence (OR=2.72) compared to inactive/non-specific comparators. Dialectical behavioral/acceptance and commitment therapy also increased point abstinence (OR=4.34). Adding contingency management to MET-CBT showed trends toward benefit but was not statistically significant. MET-CBT reduced treatment completion (OR=0.53), suggesting its demands may lead to dropout. No adverse events were reported across any studies.","whyItMatters":"With no approved medications for CUD, psychosocial interventions are the primary treatment option. This meta-analysis identifies MET-CBT as the most evidence-supported approach while highlighting an important tension: the most effective therapy also had the highest dropout rate.","specificNumbers":"22 RCTs; 3,304 participants; MET-CBT point abstinence OR=18.27 (95% CI: 9.00-37.07); continuous abstinence OR=2.72 (1.20-6.19); treatment completion OR=0.53 (0.35-0.85); DBT/ACT point abstinence OR=4.34 (1.74-10.80); no adverse events reported","methodology":"Systematic review and pairwise meta-analysis of 22 RCTs (3,304 participants) of psychosocial interventions for CUD lasting more than 4 sessions. Searched MEDLINE, PsycINFO, and Cochrane CENTRAL through June 2024. Assessed using Risk of Bias 2. Registered with PROSPERO.","limitations":"Low to very low certainty evidence overall. Only one study had low risk of bias. Small number of studies for each comparison. Point abstinence (negative urine at end of treatment) may overestimate sustained abstinence. No studies reported withdrawal intensity."},{"rthcId":"RTHC-06616","title":"Cannabis use and cannabis use disorders and their treatment in the Europe.","authors":"Hall, Wayne; Manthey, Jakob; Stjepanović, Daniel","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 307-313","doi":"10.1007/s00406-024-01776-1","pmid":"38489067","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06617","title":"Examining bidirectional associations between cannabis use and internalizing symptoms among high-risk emerging adults: A prospective cohort study.","authors":"Halladay, Jillian; Belisario, Kyla; McDonald, André; Acuff, Samuel; Doggett, Amanda; Garber, Molly; Maxwell, Andrea; Murphy, James; MacKillop, James","year":2025,"journal":"Psychological medicine, 55, e291","doi":"10.1017/S0033291725101700","pmid":"41038793","tags":["mental-health","depression","anxiety","youth"],"studyType":"longitudinal-study","evidenceStrength":"moderate","keyFinding":"Using seven assessments over two years, significant bidirectional within-person relationships were found between cannabis consequences and internalizing symptoms, but the primary direction was from cannabis consequences to increased depressive symptoms, not from depression to increased cannabis use. Importantly, cannabis use frequency alone did not predict later symptoms; only negative consequences did. The bidirectional relationships were more pronounced among females and those with clinically elevated internalizing symptoms at baseline.","whyItMatters":"This clarifies a longstanding debate: it is the problems from cannabis use (not the use itself) that predict worsening mental health. This distinction has practical implications, as interventions that reduce cannabis-related harm could prevent downstream depression even without full abstinence.","specificNumbers":"961 emerging adults; 54% female; 7 assessments over 2 years; cannabis consequences predicted depressive symptoms (within-person); frequency alone did not predict symptoms; effects stronger in females and those with clinical-level baseline symptoms","methodology":"Longitudinal study of 961 high-risk emerging adults (54% female) from two cohorts (Ontario, Canada and Tennessee, USA), assessed at 4-month intervals over 2 years (2018-2020). Latent curve models with structured residuals examined within-person and between-person bidirectional relationships.","limitations":"High-risk sample may not generalize to general population. Self-report measures. Study period overlapped with early COVID-19 pandemic. Four-month intervals may miss shorter-term dynamics. Consequences and symptoms may share reporting bias."},{"rthcId":"RTHC-06618","title":"Cumulative Risk and Cumulative Protection: Relative Contributions to Predicting Substance Use, Antisocial Behaviour and Mental Health Across Development.","authors":"Halvorson, Max A; Caouette, Justin D; Briney, John S; Kuklinski, Margaret R; Oesterle, Sabrina; Hawkins, J David","year":2025,"journal":"Criminal behaviour and mental health : CBMH, 35(1), 22-30","doi":"10.1002/cbm.2365","pmid":"39775882","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06619","title":"Age of onset of cannabis use and substance use problems: A systematic review of prospective studies.","authors":"Hamaoui, Jad; Pocuca, Nina; Ditoma, Mikaela; Héguy, Camille; Simard, Cléa; Aubin, Raphael; Lucic, Anastasia; Castellanos-Ryan, Natalie","year":2025,"journal":"Addictive behaviors, 163, 108259","doi":"10.1016/j.addbeh.2025.108259","pmid":"39799660","tags":["youth","addiction"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 16 prospective studies, earlier age of cannabis use onset was consistently associated with later cannabis use disorder (CUD) and cannabis-related negative consequences. However, the evidence for earlier onset predicting other substance use problems (like alcohol) was mixed. Cannabis use frequency accounted for much of the risk for negative consequences, but the association with CUD remained independent of frequency, suggesting early onset carries unique risk beyond simply using more.","whyItMatters":"This review provides specificity to the \"gateway drug\" concern: early cannabis use predicts cannabis-specific problems rather than broader substance use escalation. This shapes prevention messaging and targets delay of onset as a specific protective strategy.","specificNumbers":"16 prospective studies included; early onset consistently predicted CUD and cannabis consequences; mixed findings for other substance problems; frequency mediated consequences but not CUD risk; only 1 study had low risk of bias","methodology":"Systematic review of prospective studies published 2000-2024 examining age of cannabis onset and later substance use problems. Searched PsycINFO, Web of Science, and PubMed. Required prospective design, adolescent onset, and control for key risk factors. Risk of bias assessed with ROBINS-I. PROSPERO-registered.","limitations":"Only one study had low risk of bias; eight had high or very high risk. Heterogeneity in how \"age of onset\" was measured across studies. Could not conduct meta-analysis due to study variability. Most studies did not adequately control for all confounders."},{"rthcId":"RTHC-06620","title":"Conception of novel protein-polysaccharide complex coacervation based on Hemp proteins and Kudzu starch for the microencapsulation of Limosilactobacillus reuteri DSM 17938 probiotic strain.","authors":"Hamdi, Marwa; Mudgil, Priti; Al Hashmi, Sara; Hamed, Fathalla; Jafari, Seid Mahdi; Maqsood, Sajid","year":2025,"journal":"Food research international (Ottawa, Ont.), 219, 116941","doi":"10.1016/j.foodres.2025.116941","pmid":"40922191","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06621","title":"Evaluating the Acute Effects of the Cannabinoid Dronabinol and the Opioid Hydromorphone Alone and in Combination: A Double-Blind, Randomized, Placebo-Controlled Trial in Knee Osteoarthritis.","authors":"Hamilton, Katrina R; Mun, Chung Jung; Sadik, Eliot; Bergeria, Cecilia L; Huhn, Andrew S; Speed, Traci J; Vandrey, Ryan; Dunn, Kelly E; Campbell, Claudia M","year":2025,"journal":"Anesthesiology","doi":"10.1097/ALN.0000000000005925","pmid":"41481837","tags":["pain","medical-cannabis"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"In a within-subject, double-blind trial, hydromorphone showed some analgesic effects on specific pain measures (pressure pain threshold, mechanical temporal summation) but neither drug reduced clinical pain severity or most experimentally induced pain measures. Critically, combining dronabinol and hydromorphone did not produce synergistic analgesia, contradicting preclinical data. The combination impaired working memory reaction time, produced higher subjective drug effects and \"High\" ratings, and caused more nausea than either drug alone.","whyItMatters":"This well-designed trial directly tests the popular hypothesis that combining cannabinoids with opioids could reduce pain more effectively while potentially lowering opioid doses. The negative result challenges this clinical strategy, at least for acute dosing in chronic pain populations.","specificNumbers":"21 participants; dronabinol 10 mg; hydromorphone 2 mg; no significant clinical pain reduction for any condition; no synergistic effects; combination impaired working memory and increased nausea and \"High\" ratings; hydromorphone alone improved some experimental pain measures","methodology":"Within-subject, double-blind, randomized, placebo-controlled trial. 21 adults (57% women, mean age 63.4) with knee osteoarthritis received four oral drug combinations across separate sessions: placebo, hydromorphone (2 mg), dronabinol (10 mg), and both combined. Assessed clinical and experimental pain, physical function, cognition, subjective effects, and adverse events at baseline and 60-240 minutes.","limitations":"Small sample size (N=21). Single acute doses tested; chronic dosing might yield different results. Relatively low doses of both drugs. KOA represents one specific type of chronic pain. Within-subject design is a strength but may have learning effects across sessions."},{"rthcId":"RTHC-06622","title":"Syncope among adolescents and young adults seeking treatment for cannabis-related injuries.","authors":"Hammig, Bart; Bordelon, Abigail","year":2025,"journal":"The American journal of emergency medicine, 92, 109-113","doi":"10.1016/j.ajem.2025.03.003","pmid":"40090055","tags":["cardiovascular","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analyzing NEISS data from 2019-2022, researchers found that among 24,922 cannabis-associated injuries in young people aged 15-24, 5,400 (21.7%) also involved syncope. The prevalence of syncope among cannabis users was 8.6 times higher than among non-users (PR=8.6, 95% CI: 7.1-10.2). Most injuries were to the head and neck, with falls being the most common mechanism, suggesting syncope leads to fall-related injuries.","whyItMatters":"Cannabis-related syncope is underrecognized as a cause of injury in young people. The 8.6-fold higher prevalence suggests a strong association that may be clinically significant, particularly as cannabis potency and use increase.","specificNumbers":"24,922 cannabis-associated injuries (ages 15-24); 5,400 with syncope (21.7%); syncope prevalence ratio 8.6x vs non-cannabis users (95% CI: 7.1-10.2); most injuries to head/neck; falls most common mechanism","methodology":"Cross-sectional study using the National Electronic Injury Surveillance System (2019-2022). Identified cannabis-associated injuries among 15-24 year olds presenting to emergency departments and screened for concurrent syncope. Calculated prevalence ratios comparing syncopal rates between cannabis users and non-users.","limitations":"NEISS captures injuries leading to ER visits, not all cannabis-related syncope events. Cannot determine causation. Cannabis association based on screening, not confirmed as the cause of syncope. Cannot assess THC dose, product type, or timing relative to use. No information on underlying cardiovascular conditions."},{"rthcId":"RTHC-06623","title":"Differences in Cannabis and Cannabidiol Attitudes, Perceptions, and Behaviors Between US Adolescents Receiving Mood Disorder Treatment and Their Parents Across Legal Contexts.","authors":"Hammond, Christopher J; Fristad, Mary A; Moon, Yoon Ji; Batt, Melissa M; Dopp, Richard; Ghaziuddin, Neera; Hulvershorn, Leslie; Leffler, Jarrod M; Singh, Manpreet K; Sullivan, Aimee E; Weinstein, Sally; Miller, Leslie","year":2025,"journal":"International journal of environmental research and public health, 22(10)","doi":"10.3390/ijerph22101576","pmid":"41154980","tags":["youth","mental-health","cbd"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In a multisite survey of 84 youth and 66 parents across six mood disorder clinics, 76% of youth and 65% of parents believed cannabis is safe and effective for mental health conditions. Similar numbers endorsed CBD. Both groups believed regular use reduces depression, anxiety, and suicidal behaviors. Among youth, male sex and positive cannabis expectancies were associated with higher use intentions. Intergenerational differences in attitudes were observed, with some varying by state cannabis law status.","whyItMatters":"Youth with mood disorders are at elevated risk for both cannabis use and cannabis-related adverse outcomes. The finding that most of these vulnerable patients already believe cannabis treats their conditions suggests they may self-medicate based on these beliefs, potentially interfering with evidence-based treatment.","specificNumbers":"84 youth and 66 parents; 76% of youth and 65% of parents believed cannabis treats mental health; 74% of youth believed CBD treats mental health; 68% of parents for CBD; male sex and positive expectancies predicted use intentions; attitudes varied by state law","methodology":"Multisite cross-sectional survey of 84 youth receiving mood disorder treatment and 66 parents across six child mood clinics in 11 US states with variable cannabis laws. Anonymous surveys assessed attitudes, health perceptions, and behaviors related to cannabis and CBD. Covariate-adjusted regressions examined respondent group and state law as between-subject factors.","limitations":"Small sample from specialized mood clinics; may not generalize. Self-report attitudes may not predict behavior. Cross-sectional design. Treatment-seeking youth may differ from non-treatment-seeking peers. Cannot assess whether beliefs are influenced by personal experience or external information."},{"rthcId":"RTHC-06624","title":"Transitions to legal cannabis markets: Legal market capture of cannabis expenditures in Canada following federal cannabis legalization.","authors":"Hammond, David; Hong, Daniel; Rundle, Samantha; Iraniparast, Maryam; Kilmer, Beau; Wadsworth, Elle","year":2025,"journal":"The International journal on drug policy, 142, 104828","doi":"10.1016/j.drugpo.2025.104828","pmid":"40344907","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06625","title":"A content analysis of cannabis edible product characteristics, packaging features, and online promotions.","authors":"Han, Bing; Shi, Yuyan","year":2025,"journal":"Preventive medicine, 198, 108336","doi":"10.1016/j.ypmed.2025.108336","pmid":"40570938","tags":["youth","legalization","potency"],"studyType":"content-analysis","evidenceStrength":"moderate","keyFinding":"Among 2,282 cannabis edible products from US online dispensaries, over half were gummies and 80%+ contained at least 100 mg total THC. Child-appealing elements were prevalent: 20%+ displayed cartoon or human-like characters, nearly all were flavored (primarily fruit), and over half had packaging with four or more colors. Only 16.4% included underage use warnings. Serving size information was frequently absent, and 77% had product-specific promotions.","whyItMatters":"Cannabis edibles are the fastest-growing product category and the form most likely to be accidentally consumed by children. The combination of high THC content, child-appealing packaging, and inadequate warnings creates a significant pediatric safety concern.","specificNumbers":"2,282 edible products analyzed; 80%+ contained 100+ mg total THC; 20%+ had cartoon/character images; nearly all flavored (fruit most common); 50%+ used 4+ colors; only 16.4% had underage use warnings; 27.7% had non-health claims; 77% had promotions","methodology":"Content analysis of 2,282 cannabis edible products from US online dispensaries identified through the National Cannabis Industry Association member directory. Assessed front-of-package information, child-oriented features, health claims, warnings, and promotional strategies during November 2023 and August 2024.","limitations":"Online product listings may not reflect what consumers actually see in stores. Content analysis assessed packaging features, not their actual impact on youth behavior. Cannot determine regulatory compliance at the time of sale. Products may differ across state markets."},{"rthcId":"RTHC-06626","title":"Estimating the Price Elasticity of Cannabis Use Among U.S. Adults: Evidence from States with Recreational Cannabis Commercialization.","authors":"Han, Bing; Park, Hojin; He, Yanyun; Shang, Ce; Shi, Yuyan","year":2025,"journal":"Cannabis and cannabinoid research, 10(3), 480-488","doi":"10.1089/can.2024.0164","pmid":"40127988","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06627","title":"Multilevel determinants of cannabis prices in legal markets: Evidence from products sold in nearly 4000 cannabis dispensaries in the United States.","authors":"Han, Bing; Shi, Yuyan","year":2025,"journal":"The International journal on drug policy, 137, 104722","doi":"10.1016/j.drugpo.2025.104722","pmid":"39893801","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06628","title":"Hybrid Cannabis sativa L. inflorescences exert an anti-inflammatory effect through the modulation of MAPK/NF-κB/NLRP3 inflammasome and JAK1/STAT6 pathway in HaCaT cells.","authors":"Han, Ji-Ye; Lim, Do-Won; Kwon, Osoung; Lee, Yun Jung; Choi, Hye Yung; Jung, Hyun-Ju; Noh, Soohyang; Cho, Mansoo; Kang, Sung Suk; Lee, Young-Mi","year":2025,"journal":"Frontiers in pharmacology, 16, 1617180","doi":"10.3389/fphar.2025.1617180","pmid":"40777996","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06629","title":"Skin-Whitening Effects of Cannabinol (CBN) Through Melanin Inhibition in B16F10 Melanoma Cells.","authors":"Han, Joon-Hee; Kim, Jong-Hui; Hong, Min; Ryu, Byeong-Ryeol; Lim, Jung Dae; Kim, Keun-Cheol; Kwon, Tae-Hyung","year":2025,"journal":"International journal of molecular sciences, 26(21)","doi":"10.3390/ijms262110752","pmid":"41226788","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06630","title":"Oral Cannabis for Taxane-Induced Neuropathy: A Pilot Randomized Placebo-Controlled Study.","authors":"Haney, Margaret; Choo, Tse-Hwei; Tiersten, Amy; Levin, Frances R; Grassetti, Alex; DeSilva, Natasha; Arout, Caroline A; Martinez, Diana","year":2025,"journal":"Cannabis and cannabinoid research, 10(5), 631-639","doi":"10.1089/can.2025.0028","pmid":"40611810","tags":["pain","cbd","cancer","medical-cannabis"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"All 12 participants completed the 8-week trial. Both placebo and cannabis groups improved over time on measures of pain, pain interference, sleep, and well-being. However, cannabis did not improve outcomes beyond placebo, and significantly worsened several endpoints. The study demonstrated that placebo-controlled testing of cannabis capsules is feasible and well-tolerated in this population, but found no signal of efficacy at this dose.","whyItMatters":"Most breast cancer patients develop taxane-induced neuropathy, and there is no effective treatment. While preclinical studies showed CBD+THC synergistically reduced TIPN, this clinical trial did not replicate that benefit. The strong placebo response highlights why controlled trials are essential for evaluating cannabis as medicine.","specificNumbers":"12 women; mean age 51; 8-week treatment; 100 mg CBD/5 mg THC capsules TID; both groups improved over time; cannabis worsened several endpoints vs placebo; 100% completion rate","methodology":"Double-blind, randomized, placebo-controlled pilot study (2019-2021). 12 women with taxane-induced peripheral neuropathy (TIPN) received oral cannabis capsules (100 mg CBD/5 mg THC, TID) or placebo for 8 weeks. Daily questionnaires on pain, sleep, and medication use; weekly neuropathy assessments.","limitations":"Very small pilot sample (N=12). Single fixed dose tested. CBD-dominant formulation may not be optimal. 8-week duration may be insufficient. Both groups requested dose reductions, suggesting tolerability issues even at these relatively low doses."},{"rthcId":"RTHC-06631","title":"Cannabinoid hyperemesis syndrome in pregnancy: a case series and review.","authors":"Hanley, Sarah; Imcha, Mendinaro; Mohamad, Mas Mahady","year":2025,"journal":"Obstetric medicine, 18(4), 264-271","doi":"10.1177/1753495X241307415","pmid":"39759763","tags":["pregnancy","appetite"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Two cases of CHS in pregnancy were described. Case 1: a woman with vomiting episodes at weeks 5, 14, and 30 of gestation; the link to hot bathing for relief led to CHS diagnosis. Symptoms resolved with cannabis cessation; healthy baby born at 38+5 weeks. Case 2: vomiting at weeks 16 and 18; 14+ year cannabis use history disclosed after hot bathing pattern identified. Symptoms resolved with cessation; baby born at 37 weeks with low birth weight (2180g) requiring 5 days in NICU. No relapse at 5 months postpartum with sustained cessation.","whyItMatters":"CHS in pregnancy is likely underdiagnosed because severe nausea and vomiting are expected symptoms of pregnancy. When anti-emetic treatments fail, the hot bathing clue should prompt inquiry about cannabis use. Misdiagnosis leads to repeated hospitalizations and delays appropriate management.","specificNumbers":"Only 11 prior CHS-in-pregnancy cases reported in literature; Case 1: symptoms at weeks 5, 14, 30, resolved with cessation, healthy delivery at 38+5 weeks; Case 2: 14+ years cannabis use, low birth weight baby (2180g), 5 days NICU","methodology":"Case series of two pregnant women diagnosed with cannabinoid hyperemesis syndrome, with clinical workup, treatment course, and outcomes documented through delivery and postpartum follow-up.","limitations":"Case series of only two patients. Cannot establish prevalence. Case 2 had confounding factors (14+ years of heavy cannabis use, low birth weight may have multiple causes). No standardized CHS diagnostic criteria applied."},{"rthcId":"RTHC-06632","title":"Cannabis-Related Takotsubo Cardiomyopathy Presenting With Ventricular Tachycardia and Cardiogenic Shock Successfully Treated With Milrinone and Intra-Aortic Balloon Pump.","authors":"Haque, Obaid I; Kiyani, Madiha; Hussain, Shahzad","year":2025,"journal":"JACC. Case reports, 30(20), 104246","doi":"10.1016/j.jaccas.2025.104246","pmid":"40392660","tags":["cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 63-year-old woman with prior cannabinoid hyperemesis syndrome admissions presented with nausea, vomiting, and cardiopulmonary distress after cannabis use. She developed ventricular tachycardia requiring cardioversion, cardiogenic shock, and a left ventricular ejection fraction of 15-20% (normal is 55-70%). Cardiac catheterization showed no coronary artery disease, consistent with Takotsubo (stress) cardiomyopathy. She required an intra-aortic balloon pump and milrinone infusion, with cardiac function returning to baseline after 4 weeks of intensive management.","whyItMatters":"While cannabis-related cardiovascular events are increasingly recognized, Takotsubo cardiomyopathy with cardiogenic shock represents a severe, potentially fatal cardiac complication. This case links repeated cannabinoid hyperemesis syndrome to a life-threatening cardiac event.","specificNumbers":"Age 63; troponin 22,900 ng/L; NT-proBNP 21,092 pg/mL; LVEF 15-20%; lactic acid 7.1; potassium 2.6; positive for THC; no coronary lesions; LVEF recovered to baseline after 4 weeks","methodology":"Single case report documenting the clinical course, diagnostic workup, and treatment of cannabis-associated Takotsubo cardiomyopathy with cardiogenic shock in a 63-year-old woman.","limitations":"Single case report cannot establish causation. Patient had CHS history and severe metabolic derangements (hypokalemia, lactic acidosis) that independently could contribute to cardiac dysfunction. Temporal association with cannabis use does not prove causality."},{"rthcId":"RTHC-06633","title":"Haven't I waited long enough? The role of wait times and subjective impairment in cannabis-related driving behavior.","authors":"Har-Even, Ayelet; Lewis, Nehama; Eliash-Fizik, Hadar; Sznitman, Sharon R","year":2025,"journal":"The International journal on drug policy, 135, 104654","doi":"10.1016/j.drugpo.2024.104654","pmid":"39612549","tags":["driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 979 cannabis users, 23% drove within 2 hours of use (high risk), 37% waited 3-6 hours (moderate risk), and 40% waited 7+ hours (low risk). Being male (RRR=2.11) and more frequent use (RRR=1.21) predicted moderate risk. Male sex (RRR=1.89) and frequent use (RRR=1.70) also predicted high risk. Medical cannabis license holders had 4x higher odds of moderate-risk driving compared to non-medical users. Cannabis use frequency also predicted driving while feeling cannabis effects.","whyItMatters":"Nearly a quarter of cannabis users drove shortly after use, and medical cannabis users were more likely to drive at moderate-risk intervals, possibly due to daily dosing schedules. This has implications for how medical cannabis programs counsel patients about driving.","specificNumbers":"979 cannabis users; 23% drove within 2 hours; 37% waited 3-6 hours; 40% waited 7+ hours; male sex RRR=2.11 for moderate risk; medical license RRR=4.14 for moderate risk; frequency RRR=1.70 for high risk","methodology":"Cross-sectional online survey of 979 cannabis users in Israel. Measured reported wait times between cannabis use and driving (categorized as high risk: <2h, moderate: 3-6h, low: 7+h). Logistic and multinomial regression identified correlates.","limitations":"Self-report data subject to social desirability bias. Israel-specific sample with different cannabis culture and laws. Cross-sectional design. Wait time does not directly measure actual impairment. Medical cannabis use patterns in Israel may differ from other countries."},{"rthcId":"RTHC-06634","title":"Medicinal cannabis for symptom control in advanced cancer: a double-blind, placebo-controlled, randomised clinical trial of 1:1 tetrahydrocannabinol and cannabidiol.","authors":"Hardy, Janet R; Greer, Ristan M; Pelecanos, Anita M; Huggett, Georgie E; Kearney, Alison M; Gurgenci, Taylan H; Good, Phillip D","year":2025,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 33(8), 715","doi":"10.1007/s00520-025-09763-5","pmid":"40705150","tags":["medical-cannabis","cancer","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This is one of the most rigorous tests of medicinal cannabis for cancer symptoms conducted to date. Patients with advanced cancer were randomized to either a 1:1 THC:CBD oil or placebo, dose-escalated over 14 days, and continued to day 28—all while receiving standard palliative care.\n\nThe primary outcome was total symptom distress, measured by summing scores across multiple symptoms (pain, fatigue, nausea, depression, anxiety, drowsiness, appetite, wellbeing, and shortness of breath). Both groups improved over time, but there was no difference between cannabis and placebo. The improvement in both arms likely reflects the benefits of palliative care itself.\n\nHowever, one secondary finding stood out: ESAS pain scores improved significantly more in the cannabis arm than in placebo (mean change −1.42 vs. −0.46, p = 0.04). This is a modest but statistically significant difference, suggesting cannabis may have a specific analgesic effect even when it doesn't improve the overall symptom picture.\n\nThe study design was strong—double-blind, placebo-controlled, with a pre-planned sample size that was met. The null result for overall symptoms is meaningful precisely because the trial was well-powered to detect a difference if one existed.","whyItMatters":"Many cancer patients use or want to use cannabis for symptom relief, often based on anecdotal reports. This trial provides high-quality evidence that while cannabis may help specifically with pain, it doesn't improve the overall symptom burden beyond what good palliative care provides. That's important information for patients making treatment decisions and for oncologists being asked about cannabis.","specificNumbers":"N = 144 randomized (120 reached day 14 per pre-planned sample size). Total symptom distress: −6.30 cannabis vs. −6.98 placebo (p = 0.76, no difference). ESAS pain: −1.42 cannabis vs. −0.46 placebo (p = 0.04, significant).","methodology":"Double-blind, placebo-controlled randomized clinical trial. 144 patients with advanced cancer randomized to medicinal cannabis (1:1 THC:CBD at 10 mg/ml) or placebo oil. Dose escalated over 14 days based on tolerance and efficacy, continued to day 28. Primary outcome: change in Total Symptom Distress Score (TSDS) at day 14 using the Edmonton Symptom Assessment Scale. Multiple secondary outcomes including individual symptoms, opioid use, quality of life, and global impression of change.","limitations":"28-day trial duration may be too short for some benefits to emerge. The 1:1 THC:CBD ratio and oil formulation may not represent all cannabis products—different ratios, inhaled routes, or higher doses might produce different results. Both groups improved substantially, making it harder to detect additional cannabis benefit. Pain finding was a secondary outcome."},{"rthcId":"RTHC-06635","title":"Placental Endocannabinoid System: Focus on Preeclampsia and Cannabis Use.","authors":"Harhangi, Madhavi S; Simons, Sinno H P; Bijma, Hilmar H; Nguyen, Anna; Nguyen, Tuong-Vi; Kaitu'u-Lino, Tu'uhevaha; Reiss, Irwin K M; Jan Danser, A H; Broekhuizen, Michelle","year":2025,"journal":"Hypertension (Dallas, Tex. : 1979), 82(5), 804-815","doi":"10.1161/HYPERTENSIONAHA.125.24934","pmid":"40238905","tags":["pregnancy","neuroscience","cardiovascular"],"studyType":"laboratory-study","evidenceStrength":"moderate","keyFinding":"The study found three distinct patterns: (1) In healthy pregnancies, anandamide relaxed placental arteries via CB1 and CB2 receptors. (2) In preeclampsia, endocannabinoid signaling was altered (lower 2-AG synthesis enzyme) but vessel relaxation was maintained through non-cannabinoid receptor pathways. (3) In cannabis users, endocannabinoid-mediated vessel relaxation was entirely absent, and nitric oxide (NO) signaling was greatly reduced. This provides a mechanistic explanation for why cannabis use during pregnancy is associated with preeclampsia and other vascular complications.","whyItMatters":"This is the first study to show that cannabis use during pregnancy fundamentally disrupts both the placental endocannabinoid system and nitric oxide signaling in placental blood vessels. These are two critical systems for maintaining healthy placental blood flow.","specificNumbers":"Three groups compared (healthy, preeclampsia, cannabis users); cannabis users: complete loss of endocannabinoid-mediated vessel relaxation; greatly reduced NO signaling; preeclampsia: lower DAGL-alpha mRNA (2-AG synthesis); cannabis users: higher NAPE-PLD mRNA (AEA synthesis)","methodology":"Placental biopsies from gestational age-matched healthy pregnant women, women with preeclampsia, and women who used cannabis throughout pregnancy. Measured ECS component mRNA levels, then tested vascular reactivity of chorionic plate arteries with endogenous and synthetic cannabinoid receptor agonists, with and without selective antagonists.","limitations":"Small sample sizes typical of placental tissue studies. Cannot determine whether vascular changes are from THC, CBD, other cannabinoids, or smoking. Cross-sectional tissue analysis cannot assess when changes occurred during pregnancy. Cannabis-using group may differ from non-users in other ways."},{"rthcId":"RTHC-06636","title":"Impact of Delta-8-THC warning labels on perceived intoxication, harm, and susceptibility among adolescents.","authors":"Harlow, Alyssa F; Leventhal, Adam M; Barrington-Trimis, Jessica L","year":2025,"journal":"The International journal on drug policy, 139, 104781","doi":"10.1016/j.drugpo.2025.104781","pmid":"40184694","tags":["youth","legalization","potency"],"studyType":"experimental-study","evidenceStrength":"moderate","keyFinding":"Among 3,647 Southern California adolescents, those shown delta-8-THC products with larger warning labels (vs. unmodified packaging) reported greater anticipated intoxication, higher perceived health harm (RR=1.07), and greater belief that delta-8 products are as harmful as marijuana (RR=1.04). Warning label effects were stronger for edible products and for never-cannabis-using youth. However, warning labels did not reduce susceptibility to use. Differences between standard and larger warning labels were minimal.","whyItMatters":"Delta-8-THC products are widely available, often marketed as \"legal THC,\" and unregulated in many states. This study provides the first experimental evidence that warning labels can increase youth awareness of these products' risks, though they may not be sufficient to deter use.","specificNumbers":"3,647 adolescents; larger labels: +2.50 points anticipated intoxication; perceived harm RR=1.07; risk perception RR=1.03; equal/more harmful than marijuana RR=1.04; no effect on use susceptibility; effects stronger for gummies vs vape; stronger for never vs ever users","methodology":"Mixed within-between-subject experiment in a 2023 survey of 3,647 Southern California adolescents. Randomized to view delta-8-THC edible and vape products under three conditions: unmodified, standard warning label, or larger warning label. Measured anticipated intoxication, perceived harm, and susceptibility to use.","limitations":"Lab-based experiment showing hypothetical products; real-world effects may differ. Southern California sample may not generalize nationally. Effect sizes were small. Warning labels did not reduce susceptibility to use, limiting practical impact. Single exposure; repeated exposure effects unknown."},{"rthcId":"RTHC-06637","title":"Association of Perceived Neighborhood Disorder with Substance Use Behaviors and Retail Access Among Southern California Adolescents.","authors":"Harlow, Alyssa F; Hughes Halbert, Chanita; Ranker, Lynsie R; Cho, Junhan; Thompson, Laura K; Cockburn, Myles; Eckel, Sandrah P; Barrington-Trimis, Jessica L","year":2025,"journal":"Substance use & misuse, 60(2), 228-235","doi":"10.1080/10826084.2024.2422972","pmid":"39497034","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06638","title":"5F-AKB48: A synthetic cannabinoid presenting an emerging public health concern in France.","authors":"Harmel, Clément; Caré, Weniko; Laborde-Casterot, Hervé; Liautard, Marc; Langrand, Jérôme; Dufayet, Laurène","year":2025,"journal":"The International journal on drug policy, 145, 104972","doi":"10.1016/j.drugpo.2025.104972","pmid":"40876066","tags":["synthetic-cannabinoids","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 304 cases reported to French Poison Control Centers, the median age was 16.5 years with a male-to-female ratio of 4.4:1. The drug was used alone in 91% of cases. Most (59%) had mild symptoms, 35% moderate, and 4% severe (seizures, coma, agitation). Multiple substance use was associated with more severe outcomes. Most exposures occurred in northern France, and the drug is likely popular due to its compatibility with e-cigarette devices for discreet use.","whyItMatters":"Synthetic cannabinoids are far more potent and dangerous than plant cannabis, yet they can be consumed discreetly through e-cigarettes, making detection difficult for parents and schools. Their emergence among adolescents represents a distinct public health challenge.","specificNumbers":"304 cases; median age 16.5; sex ratio 4.4 M:F; 91% used alone; 59% mild, 35% moderate, 4% severe; severe symptoms: seizures, coma, agitation; no fatalities; predominantly northern France","methodology":"Retrospective analysis of all acute 5F-AKB48 exposure cases reported to French Poison Control Centers from 2017 to 2024. Assessed demographics, symptoms, and outcomes using the Poison Severity Score.","limitations":"Poison control data captures only cases severe enough to prompt a call; actual use likely much higher. Outcome unknown in 36% of cases. Cannot assess chronic health effects. French-specific regulatory and cultural context."},{"rthcId":"RTHC-06639","title":"Cannabis legalization and cannabis use disorder in United States Veterans Health Administration patients with and without psychiatric disorders, 2005-2022: a repeated cross-sectional study.","authors":"Hasin, Deborah S; Malte, Carol; Wall, Melanie M; Alschuler, Daniel; Simpson, Tracy L; Olfson, Mark; Livne, Ofir; Mannes, Zachary L; Fink, David S; Keyes, Katherine M; Cerdá, Magdalena; Maynard, Charles C; Keyhani, Salomeh; Martins, Silvia S; Sherman, Scott; Saxon, Andrew J","year":2025,"journal":"Lancet regional health. Americas, 48, 101155","doi":"10.1016/j.lana.2025.101155","pmid":"40678370","tags":["legalization","addiction","mental-health","psychosis"],"studyType":"longitudinal-study","evidenceStrength":"strong","keyFinding":"CUD prevalence among veterans with any psychiatric disorder rose from ~3.3% in 2005 to ~5.7-6.4% by 2022, depending on state legalization status. Using staggered difference-in-difference analysis, both medical and recreational cannabis legalization were associated with significantly greater CUD increases among patients with psychiatric disorders (depression, PTSD, anxiety, bipolar, psychotic-spectrum) compared to those without. CUD prevalence remained below 1% in all years among patients without psychiatric disorders.","whyItMatters":"This is one of the largest and longest studies connecting cannabis legalization to CUD outcomes in a vulnerable population. The finding that psychiatric patients are disproportionately affected by legalization has direct implications for how states approach cannabis policy alongside mental health care.","specificNumbers":"3.2-4.4 million VHA patients/year; 18 years of data; APD-positive CUD rose from ~3.3% to ~5.7-6.4%; APD-negative CUD stayed <1%; legalization effects significantly larger for psychiatric patients; effects consistent across depression, PTSD, anxiety, bipolar, psychotic disorders","methodology":"Analysis of VHA electronic medical records (2005-2022) for patients aged 18-75 with primary care, ED, or mental health visits. Sample sizes ranged from 3.2 to 4.4 million per year. Staggered difference-in-difference models estimated effects of medical and recreational cannabis legalization on CUD prevalence, comparing patients with and without specific psychiatric disorders.","limitations":"VHA patients are predominantly male and may not generalize. CUD diagnosis depends on provider recognition and coding, which may have changed over time. DiD estimates were modest, suggesting other factors (commercialization, attitudes) also drive CUD increases. Cannot distinguish between legalization increasing CUD vs increasing detection."},{"rthcId":"RTHC-06640","title":"Cannabis Use and Cannabis Use Disorder Among U.S. Adults with Psychiatric Disorders: 2001-2002 and 2012-2013.","authors":"Hasin, Deborah S; Mannes, Zachary L; Livne, Ofir; Fink, David S; Martins, Silvia S; Stohl, Malki; Olfson, Mark; Cerdá, Magdalena; Keyes, Katherine M; Keyhani, Salomeh; Wisell, Caroline G; Bujno, Julia M; Saxon, Andrew","year":2025,"journal":"Substance use & misuse, 60(2), 285-292","doi":"10.1080/10826084.2024.2423374","pmid":"39533528","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Across two nationally representative surveys (2001-2002 and 2012-2013), cannabis use, frequent use, and CUD all increased more among adults with psychiatric disorders. The excess increase for CUD among those with psychiatric disorders was 1.40 percentage points (95% CI: 0.58-2.21). This pattern held for most specific disorders (mood, anxiety, antisocial personality) and replicated findings from VA patient samples.","whyItMatters":"This study validates VA patient findings in a nationally representative sample, establishing that the disproportionate increase in CUD among psychiatric patients is not an artifact of the VA healthcare system but a nationwide pattern.","specificNumbers":"N=43,093 (2001-2002) and 36,309 (2012-2013); disproportionate increases: cannabis use +2.45%, frequent use +1.58%, CUD +1.40% (all with 95% CIs excluding zero); pattern consistent across mood, anxiety, and antisocial personality disorders","methodology":"Comparison of two national epidemiological surveys: 2001-2002 (n=43,093) and 2012-2013 (n=36,309). Logistic regression generated predicted prevalences of cannabis use, frequent use, and DSM-IV CUD. Additive interactions tested whether prevalence changes differed between those with and without psychiatric disorders.","limitations":"Two cross-sectional surveys cannot track individuals over time. DSM-IV CUD criteria used; DSM-5 criteria may yield different results. Self-report data may underestimate use and disorder. 2012-2013 data predates widespread recreational legalization."},{"rthcId":"RTHC-06641","title":"Cannabis use patterns and association with hyperemesis: A comprehensive review.","authors":"Hasler, William L; Alshaarawy, Omayma; Venkatesan, Thangam","year":2025,"journal":"Neurogastroenterology and motility, 37(3), e14895","doi":"10.1111/nmo.14895","pmid":"39164887","tags":["appetite","addiction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This comprehensive review found that 40-80% of cyclic vomiting syndrome (CVS) patients use cannabis. CHS is characterized by daily or near-daily cannabis use for over 2 years, cyclic vomiting, and hot-water bathing for relief. The distinction from CVS is challenging, as hot bathing is also reported by ~50% of CVS patients. Key treatment barriers include patient skepticism about cannabis causing symptoms, perceived benefits of cannabis, and lack of effective alternatives. Cannabis abstinence remains the cornerstone of CHS management.","whyItMatters":"As cannabis potency has risen dramatically, CHS is becoming more common and is a significant contributor to emergency department visits and hospitalizations. The paradox that an antiemetic substance causes vomiting remains clinically challenging.","specificNumbers":"40-80% of CVS patients use cannabis; most CHS patients: daily use for 2+ years; hot bathing reported by most CHS patients and ~50% of CVS patients; cannabis has documented antiemetic properties yet causes hyperemesis with chronic heavy use","methodology":"Comprehensive narrative review of cannabis use patterns in the US and their relationship to CHS and CVS, including diagnostic criteria, pathophysiology, management, and knowledge gaps.","limitations":"Narrative review without systematic methodology. CHS vs CVS distinction remains debated. Exact prevalence of CHS is unknown. No randomized trials of CHS-specific treatments beyond cannabis cessation."},{"rthcId":"RTHC-06642","title":"Cyclic vomiting syndrome: Future clinical and research priorities for: Special supplement/proceedings of 3rd international symposium.","authors":"Hasler, William L; Li, B U K; Levinthal, David J; Venkatesan, Thangam","year":2025,"journal":"Neurogastroenterology and motility, 37(3), e14825","doi":"10.1111/nmo.14825","pmid":"38775195","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06643","title":"Prevalence of THC-Positive Urine Drug Screens in Patients Receiving Chronic Opioid Therapy: A Retrospective Review.","authors":"Hasoon, Jamal; Viswanath, Omar; Urits, Ivan; Abd-Elsayed, Alaa; Kaye, Alan D","year":2025,"journal":"Psychopharmacology bulletin, 55(4), 36-42","doi":"10.64719/pb.4549","pmid":"40630967","tags":["pain","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Of 244 urine drug screens from patients receiving chronic opioid therapy for pain at a single academic center (2024), 24 (9.8%) tested positive for THC. Provider responses to positive results varied widely: some documented patient counseling, others did not acknowledge the result. In a small subset, positive THC led to opioid therapy changes including tapering or discontinuation.","whyItMatters":"Nearly 10% of chronic opioid patients are concurrently using cannabis, often without their provider's knowledge. The inconsistent clinical response to positive THC screens highlights a need for standardized, non-punitive approaches to concurrent cannabis use in pain management.","specificNumbers":"244 urine screens; 24 (9.8%) THC-positive; variable provider documentation and response; some opioid therapy changes in small subset","methodology":"Retrospective review of 244 urine drug screen results from chronic opioid therapy patients at a single academic institution (January-December 2024). Assessed THC positivity prevalence and documented provider responses.","limitations":"Single institution with small sample. Retrospective review cannot capture provider reasoning. Cannot determine whether THC use was medical or recreational. 2024 data from a single year. Provider response documentation may not reflect actual conversations."},{"rthcId":"RTHC-06644","title":"Assessment of leukocyte telomere length as a cellular aging marker through a quantitative PCR-based technique in individuals with a chronic addiction to the psychoactive drug delta-9-tetrahydrocannabinol. (Case control study).","authors":"Hassan, S; Mehanna, Mohamed; Alwaseef, Mohammad AbdElhameed; Metwally, M; Abdelmonem, M; Alzarea, E; Gandor, N; Abd Elwahab, M; Abd Elwahab, M; Gouda, Ahmed Salah; Saadeldain, A; Sajanlal, R; Elsherbiny, A; Zeid, M; Akef, A; Ahmed, H; Rezk, A; Hashish, A; Assem, A; Hegazy, H; Omar, A; Ibrahim, D; Gomaa, K","year":2025,"journal":"La Clinica terapeutica, 176(6), 789-795","doi":"10.7417/CT.2025.5299","pmid":"41267598","tags":["addiction","neuroscience"],"studyType":"observational-study","evidenceStrength":"preliminary","keyFinding":"Among 30 chronic THC users and 30 age-matched controls (ages 30-65), cannabis users had significantly shorter leukocyte telomere length (LTL) (t(58)=-4.25, p<0.001). Interestingly, there was no significant correlation between age and LTL within either group, which the authors suggest may indicate that cannabis use exerts an effect on cellular aging independent of chronological age.","whyItMatters":"Telomere length is a biomarker of biological aging and has been linked to age-related diseases and mortality. If chronic cannabis use accelerates telomere shortening, this adds a new dimension to the long-term health consequences of heavy cannabis use.","specificNumbers":"60 participants (30 per group); ages 30-65; significantly shorter LTL in cannabis users (p<0.001); no age-LTL correlation in either group; THC levels significantly different between groups (p<0.0001)","methodology":"Case-control study of 60 individuals (30 chronic THC users, 30 healthy controls) aged 30-65. Leukocyte DNA isolated from blood samples; telomere length assessed by quantitative PCR. THC metabolites confirmed by enzyme immunoassay. Lab personnel blinded to group allocation.","limitations":"Small sample size. Cross-sectional design cannot determine if shorter telomeres preceded or followed cannabis use. Cannot control for all confounders (diet, exercise, stress, other substances). Single timepoint measurement. The absence of an age-LTL correlation within groups is unusual and may reflect small sample rather than a true biological finding."},{"rthcId":"RTHC-06645","title":"Effectiveness of a Cannabinoids Supplement on Sleep and Mood in Adults With Subthreshold Insomnia: A Randomized Double-Blind Placebo-Controlled Crossover Pilot Trial.","authors":"Hausenblas, Heather; Hooper, Stephanie; Lynch, Tarah","year":2025,"journal":"Health science reports, 8(2), e70481","doi":"10.1002/hsr2.70481","pmid":"39980821","tags":["sleep","cbd"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"In a double-blind crossover trial of 20 adults with subthreshold insomnia, a multi-cannabinoid oral supplement (3 mg THC, 6 mg CBN, 10 mg CBD, plus terpenes) significantly improved sleep quality/efficiency, insomnia symptoms, and health-related quality of life compared to placebo after 10 days. Mood and anxiety showed non-significant trends toward improvement. Anxiety improved significantly from baseline for the supplement group. No adverse events were reported.","whyItMatters":"This is one of the few controlled trials testing a low-dose multi-cannabinoid formulation specifically for sleep. The combination of THC, CBN, and CBD at low doses with a terpene blend may offer a more targeted approach than high-dose single-cannabinoid products.","specificNumbers":"20 adults; mean age 47.4; 10-day treatment periods; 3 mg THC + 6 mg CBN + 10 mg CBD per softgel; significant improvements in sleep quality, insomnia symptoms, quality of life (p<0.05); no adverse events; non-significant mood improvements","methodology":"Randomized, double-blind, placebo-controlled crossover pilot trial. 20 adults with subthreshold insomnia (mean age 47.4) completed 10 days in each condition with a 2-week washout. Validated questionnaires assessed sleep, mood, stress, pain, anxiety, fatigue, and quality of life.","limitations":"Very small sample (N=20). Short treatment period (10 days). Self-reported sleep measures without objective polysomnography. Subthreshold insomnia only; may not apply to clinical insomnia. Washout adequacy not verified. Industry-funded study warrants independent replication."},{"rthcId":"RTHC-06646","title":"Psychometric evaluation of a novel measure of trauma-related cannabis use to cope.","authors":"Hawn, Sage E; Hicks, Terrell A; Latourrette, Christopher; Thomas, Anita; Chaname, Daniela; Ehlke, Sarah; Powers Lott, Abigail","year":2025,"journal":"European journal of psychotraumatology, 16(1), 2500141","doi":"10.1080/20008066.2025.2500141","pmid":"40354168","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06647","title":"Health Care Providers' Knowledge, Attitudes, and Practices Toward Medicinal Cannabis: The Case of Lebanon.","authors":"Hazimeh, Bassima; Bou-Orm, Ibrahim; Mroueh, Mohamad; Ammar, Walid","year":2025,"journal":"Cannabis and cannabinoid research, 10(2), e362-e370","doi":"10.1089/can.2024.0013","pmid":"40163842","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06648","title":"Rest-activity rhythms in individuals who separately or concomitantly use cannabis and cigarettes.","authors":"Hebl, Joey; Wallace, Danielle A; Bowles, Nicole P","year":2025,"journal":"Drug and alcohol dependence, 276, 112907","doi":"10.1016/j.drugalcdep.2025.112907","pmid":"41072059","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06649","title":"Pilot Study Measuring Patient Reported Outcomes in Cannabinoid Hyperemesis Syndrome (CHS) patients treated in the Emergency Department.","authors":"Heidish, Ryan; Loganathan, Aditya; Bolden, Taylor; Cooper, Ziva; Barshay, Meylakh; Lagunzad, Isabella; Meltzer, Andrew C","year":2025,"journal":"Clinical and experimental emergency medicine","doi":"10.15441/ceem.25.032","pmid":"41327982","tags":["appetite","pain","mental-health"],"studyType":"observational-study","evidenceStrength":"preliminary","keyFinding":"In a pilot study of 18 CHS patients (mean age 34, 56% female), pain severity was high (mean triage score 6.4/10) and pain significantly interfered with daily activities (PROMIS T-score 62.2). Anxiety risk was elevated (PROMIS T-score 56.1). CT imaging had been performed in 72.2% of patients in the past five years, suggesting extensive prior workup. Opioids were administered in 22.2% of cases. Three patients (16.7%) returned to the ER within 30 days.","whyItMatters":"This is one of the first studies to characterize patient-reported outcomes in CHS beyond just vomiting. The high anxiety scores, significant pain interference, and repeat visit rates paint a picture of a condition with broad impact on quality of life, not just GI symptoms.","specificNumbers":"18 patients; mean age 34; 55.6% female; mean pain score 6.4/10; PROMIS anxiety T-score 56.1; pain interference T-score 62.2; 72.2% had prior CT; 22.2% received opioids; 16.7% returned within 30 days","methodology":"Prospective observational pilot study at one academic center and one community affiliate. Enrolled 18 adult ED patients with prior CHS diagnosis and current symptoms. Collected patient-reported outcomes (PROMIS-29), chart data on imaging and medications, and 30-day/12-month follow-up.","limitations":"Very small pilot sample (N=18). Single geographic area. Selection bias from requiring prior CHS diagnosis. No control group. Cannot determine whether anxiety is a cause or consequence of CHS episodes."},{"rthcId":"RTHC-06650","title":"Polysubstance Use Among the Homeless In Germany: A Nationwide, Cross-Sectional Multicenter Study.","authors":"Heinrich, Fabian; Manthey, Jakob; Wulff, Birgit; Stallbaum, Franziska; Dost, Katharina; Graf, Wiebke; Kowalski, Veronika; Brennecke, Anna; Hajek, André; König, Hans-Helmut; Püschel, Klaus; Ondruschka, Benjamin; Iwersen-Bergmann, Stefanie","year":2025,"journal":"Deutsches Arzteblatt international, 122(22), 597-603","doi":"10.3238/arztebl.m2025.0132","pmid":"40801827","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06651","title":"Neurochemical in vivo microdialysis and postmortem tissue analysis of amygdala endocannabinoid levels after MAGL- and FAAH-inhibition in rodents.","authors":"Heins, Mariette S; Ferger, Marc D; Voehringer, Patrizia; Cremers, Thomas I F H; Ferger, Boris","year":2025,"journal":"Neurochemistry international, 188, 106006","doi":"10.1016/j.neuint.2025.106006","pmid":"40494414","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06652","title":"Workplace Drug Testing-Prevalence of Positive Test Results, Most Common Substances, and Importance of Medical Review.","authors":"Helander, Anders; Sparring, Fredrik","year":2025,"journal":"Drug testing and analysis, 17(9), 1694-1700","doi":"10.1002/dta.3863","pmid":"39985189","tags":["workplace","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This analysis of 23,900 workplace drug test results from Sweden provides a snapshot of substance use among employed people. The overall positive rate was 4.6%, with cannabis dominating at over 40% of all positive results.\n\nThe testing circumstances mattered. Random tests and new-employment screenings made up the majority of samples (40% and 36% respectively), but the highest positive rates came from tests done after accidents or incidents, or when there was already suspicion of drug use. The construction sector had the highest rate of positive random tests.\n\nA key practical point the study raises: several controlled substances that trigger positive tests are also legitimately prescribed—amphetamines for ADHD, benzodiazepines for anxiety, and opiates for pain. Without medical review of positive results, employers risk penalizing workers for taking prescribed medication. The authors argue this makes medical review officer (MRO) involvement essential in any workplace testing program.\n\nWhile this is Swedish data and drug testing policies vary internationally, the finding that cannabis is the most common substance detected in workplace tests is consistent with data from other countries.","whyItMatters":"As cannabis legalization expands globally, workplace drug testing policies are under increasing scrutiny. This data shows cannabis dominates positive workplace tests even in Sweden, where it remains illegal. For countries and states with legal cannabis, the tension between workplace safety and employee rights is even more acute—particularly since cannabis can be detected long after impairment has worn off.","specificNumbers":"23,900 tests analyzed. 4.6% positive overall. Cannabis: >40% of positive results. Random testing and new employment: 76% of all samples. Construction: highest positive rate on random tests.","methodology":"Cross-sectional analysis of 23,900 urine and oral fluid drug test results from Swedish workplaces in 2023. Tests categorized by circumstance: random (40%), new employment (36%), accident/incident, or suspicion-based. Results analyzed by substance detected and industry sector.","limitations":"Swedish data may not generalize to countries with different drug policies, cannabis legality, or workplace testing cultures. No information on impairment at the time of testing. The study can't distinguish between recreational and medicinal use. Urine testing for cannabis detects metabolites from days or weeks prior, not current intoxication."},{"rthcId":"RTHC-06653","title":"Cannabidiol Protects the Neonatal Mouse Heart from Hyperoxia-Induced Injury.","authors":"Hellberg, Teresa; Schmitz, Thomas; Bührer, Christoph; Endesfelder, Stefanie","year":2025,"journal":"International journal of molecular sciences, 27(1)","doi":"10.3390/ijms27010146","pmid":"41516025","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06654","title":"Factors Associated with Substance Use and Physical Activity Among German University Students 20 Months into the COVID-19 Pandemic.","authors":"Helmer, S M; Buck, C; Matos Fialho, P M; Pischke, C R; Stock, C; Heumann, E; Zeeb, H; Negash, S; Mikolajczyk, R T; Niephaus, Y; Busse, H","year":2025,"journal":"Journal of prevention (2022), 46(6), 933-951","doi":"10.1007/s10935-025-00865-8","pmid":"40617955","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06655","title":"User-centered Design of an Adjunct Smartphone App to Reduce Cannabis Use among Youth Diverted from the Juvenile Legal System.","authors":"Helseth, Sarah A; Piper, Kaitlin N; Dunne, Christopher J; Kemp, Kathleen; Barnett, Nancy P; Clark, Melissa A; Spirito, Anthony; Becker, Sara J","year":2025,"journal":"Research on child and adolescent psychopathology, 53(12), 1797-1811","doi":"10.1007/s10802-025-01370-6","pmid":"40924271","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06656","title":"Does diverting minor drug offenders reduce recidivism? Cannabis cautioning in Australia.","authors":"Henneguelle, Anaïs; Weatherburn, Don","year":2025,"journal":"The International journal on drug policy, 145, 105008","doi":"10.1016/j.drugpo.2025.105008","pmid":"40957286","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06657","title":"Valorization of Thyme Combined with Phytocannabinoids as Anti-Inflammatory Agents for Skin Diseases.","authors":"Hermosilha, Daniela; Trigo, Guilherme; Coelho, Mariana; Lehmann, Inês; Melosini, Matteo; Serro, Ana Paula; Reis, Catarina Pinto; Gaspar, Maria Manuela; Santos, Susana","year":2025,"journal":"Pharmaceutics, 17(10)","doi":"10.3390/pharmaceutics17101291","pmid":"41155929","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06658","title":"Enhancing cannabinoid bioavailability: a crossover study comparing a novel self-nanoemulsifying drug delivery system and a commercial oil-based formulation.","authors":"Hermush, Vered; Mizrahi, Nisim; Brodezky, Tal; Ezra, Rafael","year":2025,"journal":"Journal of cannabis research, 7(1), 35","doi":"10.1186/s42238-025-00294-8","pmid":"40514741","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06659","title":"Classification of Cannabis Strains Based on their Chemical Fingerprint-A Broad Analysis of Chemovars in the German Market.","authors":"Herwig, N; Utgenannt, S; Nickl, F; Möbius, P; Nowak, L; Schulz, O; Fischer, M","year":2025,"journal":"Cannabis and cannabinoid research, 10(3), 409-419","doi":"10.1089/can.2024.0127","pmid":"39137353","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06660","title":"Genetic and pharmacological evidence for a role of the ion channel TRPV2 as a regulator of actin-dependent functional traits in rat basophilic leukemia cells.","authors":"Herzog, Christine; Mülke, Pia; Stuhrhahn, Toni; Rocereta, Julia A; Pumroy, Ruth A; Moiseenkova-Bell, Vera; Echtermeyer, Frank G; Leffler, Andreas","year":2025,"journal":"European journal of pharmacology, 1006, 178164","doi":"10.1016/j.ejphar.2025.178164","pmid":"40962008","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06661","title":"Monthly simultaneous cannabis and alcohol use: effects on depression, anxiety, and stress in male and female college students.","authors":"Hetelekides, Eleftherios M; McMichael, Tabitha; Tyskiewicz, Alexander J; Prince, Mark A; Emery, Noah N; Conner, Bradley T; Karoly, Hollis C","year":2025,"journal":"Journal of cannabis research, 7(1), 87","doi":"10.1186/s42238-025-00347-y","pmid":"41204301","tags":["mental-health","depression","anxiety","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 367 college students, monthly simultaneous cannabis and alcohol (SCA) use significantly predicted depression in both males (beta=0.322) and females (beta=0.296). SCA use also predicted anxiety (beta=0.323) and stress (beta=0.369) among males but not females, though these sex differences were not statistically significant. The depression finding held after controlling for age, most recent cannabis use, and typical alcohol frequency.","whyItMatters":"Simultaneous use of cannabis and alcohol is common among college students but understudied. The finding that combined use predicts depression independent of individual substance frequency highlights the importance of assessing polysubstance patterns rather than each substance in isolation.","specificNumbers":"367 college students; monthly SCA predicted depression in males (beta=0.322) and females (beta=0.296); anxiety in males only (beta=0.323); stress in males only (beta=0.369); sex differences not statistically significant","methodology":"Cross-sectional survey of 367 college students. Multigroup path analysis compared male and female students on relationships between monthly SCA use (vs less than monthly) and depression, anxiety, and stress, controlling for age, recent cannabis use, and alcohol frequency.","limitations":"Cross-sectional design cannot establish causation. Relatively small sample, particularly for sex-stratified analyses. Self-report measures. Monte Carlo simulation confirmed the study was underpowered for detecting sex differences. Cannot distinguish effects of SCA from general heavier substance use patterns."},{"rthcId":"RTHC-06662","title":"Cannabis Use in California Following Legalization of Recreational Use.","authors":"Hill, Linda; Ageze, Daniel; Dell'Acqua, Renee; Gold, Alice; Lanin-Kettering, Ilene; Rybar, Jill; Shaughnessy, Tom; Baird, Sara; Marcotte, Thomas D","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1089/can.2024.0179","pmid":"40489356","tags":["legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 15,208 census-weighted California adults surveyed in 2022-2023, 37% currently used cannabis, 30% formerly used, and 33% never used. Among current users, 38% used multiple times daily (very frequent), 33% used 4-7 times per week (frequent), and 30% used 3 times per week or less (occasional). Very frequent users were more likely to be male (OR=1.8), have lower income, and have initiated use before age 18. Most users obtained products from licensed dispensaries and felt comfortable discussing use with physicians, but primarily got information from other sources.","whyItMatters":"This provides one of the most detailed post-legalization snapshots of adult cannabis use patterns in the US. The finding that 38% of users consume multiple times daily challenges assumptions that most adult cannabis use is occasional or recreational.","specificNumbers":"15,208 adults surveyed; 37% current users; among users: 38% very frequent (multiple daily), 33% frequent (4-7x/week), 30% occasional (3x/week or less); very frequent users: male OR=1.8, initiated before 18; most obtained from licensed dispensaries","methodology":"Online questionnaire administered to 15,309 census-weighted California adults (December 2022 to February 2023) as part of the Impact 64 study. 4,020 current cannabis users completed detailed use questionnaires. Multinomial logistic regression assessed variables associated with use frequency categories.","limitations":"Online survey may not reach all demographics equally. Self-report data subject to social desirability. California may not represent other states. Cannabis product types and potencies not fully captured. Cross-sectional design cannot show changes over time."},{"rthcId":"RTHC-06663","title":"A Systematic Review: Investigating Biomarkers of Anhedonia and Amotivation in Depression and Cannabis Use.","authors":"Hinckley, Jesse D; Conner, Bradley T; Mauch, Roseanne; Arkfeld, Patrice A; Bhatia, Devika; Smith, Emma E; Svoboda, Ellie; Singh, Manpreet K","year":2025,"journal":"JAACAP open, 3(3), 379-405","doi":"10.1016/j.jaacop.2024.08.005","pmid":"40922784","tags":["depression","cognition","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 46 articles, brain regions most frequently associated with anhedonia across neuroimaging studies were the anterior cingulate cortex, nucleus accumbens, and medial prefrontal cortex, which are the same regions implicated in cannabis-related reward processing deficits. However, no biochemical marker (including IL-6 and CRP) was consistently associated with anhedonia, and only 2 articles specifically examined amotivation in cannabis use. Study designs and anhedonia measures were highly heterogeneous.","whyItMatters":"The neurobiological overlap between depression-related anhedonia and cannabis-related amotivation could inform shared treatment approaches. Understanding these deficits in adolescents may be particularly important given the co-development of mood disorders and cannabis use during this period.","specificNumbers":"46 articles included (44 on depression/anhedonia, 2 on cannabis/amotivation); key brain regions: anterior cingulate cortex, nucleus accumbens, medial prefrontal cortex; no consistent biochemical biomarkers found","methodology":"Systematic review searching 8 electronic databases. Included original research on biological factors or behavioral tasks associated with anhedonia in depression (44 articles) or amotivation in cannabis use (2 articles). PROSPERO-registered.","limitations":"Overwhelmingly focused on depression (44 studies) vs cannabis (only 2 studies). Heterogeneous study designs prevent quantitative synthesis. Most anhedonia measures were self-report. Small sample sizes in many included studies. Cannot determine if shared brain regions reflect shared pathology or coincidental overlap."},{"rthcId":"RTHC-06664","title":"Carvone derived cannabidiol enantiomers as novel anticonvulsants.","authors":"Hines, Rochelle M; Contreras, April; Carrillo, Adriana; Paton, Alexandra; Tenorio, Antonio J; Maio, William A; Hines, Dustin J","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(13), 1970-1981","doi":"10.1038/s41386-025-02220-1","pmid":"40993379","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Natural CBD (marketed as Epidiolex) works for certain severe childhood epilepsy syndromes, but its effectiveness is limited and it carries regulatory complexity as a cannabis-derived product. This study took a different approach: synthesizing CBD enantiomers (mirror-image molecules) from carvone, a compound found in spearmint and caraway.\n\nThe researchers built a small library of these carvone-derived CBD variants and tested them systematically. They found that lengthening the alkyl chain (a molecular tail) increased potency, with one variant called (+)-CBD-oct showing particularly strong effects on brain wave patterns associated with seizure activity.\n\nIn mouse models, pre-treatment with (+)-CBD-oct promoted seizure resilience in both normal mice and in a genetic model of developmental epilepsy (Gabra2-1 mice, which have dysfunctional GABA receptors). The compound influenced seizure characteristics and reduced mortality. Five days of oral treatment during a critical developmental window also showed effects.\n\nNotably, these synthetic variants affected different brain wave frequency bands (delta and theta) than natural CBD, suggesting they may work through partially different mechanisms—potentially opening the door to combination therapies.","whyItMatters":"Current anti-seizure medications for developmental epilepsy have significant limitations: many patients are treatment-resistant, and standard drugs that target GABA signaling can harm the developing brain. Natural CBD helps some patients but not all. These synthetic CBD analogues could expand the toolkit—and because they're derived from spearmint rather than cannabis, they sidestep some of the regulatory and supply chain issues that complicate cannabis-derived medicines.","specificNumbers":"(+)-CBD-oct showed effects on both delta and theta frequency bands. Reduced seizure mortality in the Gabra2-1 epilepsy model. Longer alkyl chains correlated with greater potency across the compound library.","methodology":"Structure-activity relationship study using EEG-based assessment in mice. Tested a library of carvone-derived CBD (+) enantiomers with varying alkyl chain lengths. Seizure resilience tested in both wildtype mice and the Gabra2-1 developmental epilepsy model. Administration routes included pre-treatment and 5-day oral gavage during postnatal development.","limitations":"All data from mouse models—no human testing yet. The Gabra2-1 model represents one specific type of developmental epilepsy; results may not generalize to other epilepsy syndromes. Long-term safety of these novel compounds is unknown. The gap between promising preclinical results and clinical efficacy is notoriously large in epilepsy drug development."},{"rthcId":"RTHC-06665","title":"Weak symptom overlap between cannabis use and internet gaming.","authors":"Hiscock, Brooke B; Wilkins, Leanne K; Harris, Nick; Pevie, Noah; Fawcett, Emily J; Jordan, D Gage; Fawcett, Jonathan M","year":2025,"journal":"Psychiatry research, 352, 116693","doi":"10.1016/j.psychres.2025.116693","pmid":"40840198","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06666","title":"Harnessing bioactive compounds from Cannabis sativa residue to improve rumen fermentation and reduce methane production: in silico, in vitro, and in situ nylon bag studies.","authors":"Hnokaew, Patipan; Arjin, Chaiwat; Satsook, Apinya; Halder, Joshua Nizel; Tateing, Suriya; Potapohn, Nuttha; Sringarm, Korawan","year":2025,"journal":"BMC veterinary research, 21(1), 611","doi":"10.1186/s12917-025-04985-5","pmid":"41088333","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06667","title":"Dispensing Medical Advice: San Francisco Bay Area Budtender Recommendations for Pain and Sleep Relief.","authors":"Hoang, Christine; Holmes, Louisa M; Ling, Pamela M","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(3), 1-8","doi":"10.26828/cannabis/2025/000328","pmid":"41278421","tags":["medical-cannabis","pain","sleep"],"studyType":"observational-study","evidenceStrength":"preliminary","keyFinding":"Across 35 Bay Area dispensaries, budtenders showed strong consensus: 77% recommended topicals for pain and 60% recommended edibles for sleep. For pain, high CBD:THC ratios (28.6%) and 1:1 ratios (28.6%) were most endorsed. For sleep, THC alone was most recommended (34.3%) and 57% endorsed indica strains. When asked about their basis for recommendations, budtenders cited personal experience and perceived product effectiveness. Most (85.7%) expressed no strain preference for pain.","whyItMatters":"With limited physician guidance on cannabis, dispensary budtenders are the de facto advisors for millions of cannabis consumers. Their recommendations for topicals (pain) and edibles (sleep) are testable hypotheses that could drive clinical research priorities.","specificNumbers":"35 of 42 dispensaries visited; pain: 77.1% recommended topicals, 28.6% high CBD:THC, 28.6% 1:1 ratio; sleep: 60% recommended edibles, 34.3% THC alone, 57.1% indica strains; recommendations based on personal experience","methodology":"Secret shopper observational study visiting 35 of 42 cannabis dispensaries in Alameda and San Francisco Counties, California. Researchers asked budtenders for recommendations on products, dosage, and strains for pain and sleep relief.","limitations":"Secret shopper approach in one geographic area. Bay Area dispensaries may not represent other markets. Cannot verify accuracy of budtender recommendations. No assessment of customer outcomes from following these recommendations. Budtender training varies widely."},{"rthcId":"RTHC-06668","title":"Cannabis, cannabinoids and health: a review of evidence on risks and medical benefits.","authors":"Hoch, E; Volkow, N D; Friemel, C M; Lorenzetti, V; Freeman, T P; Hall, W","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 281-292","doi":"10.1007/s00406-024-01880-2","pmid":"39299947","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06669","title":"Cannabis Consumption Before and After Partial Legalization in Germany: Early Trends, Consumption Patterns, and Motives.","authors":"Hoch, Eva; Krowartz, Eva-Maria; Hollweck, Regina; Möckl, Justin; Olderbak, Sally","year":2025,"journal":"Deutsches Arzteblatt international, 122(23), 632-637","doi":"10.3238/arztebl.m2025.0161","pmid":"40959988","tags":["legalization"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Past-12-month cannabis use prevalence reached 9.8% in 2024 after partial legalization, up from 8.8% in 2021, but this difference was not statistically significant. The upward trend had been ongoing since 2012.","whyItMatters":"Germany is one of the largest countries to partially legalize recreational cannabis, making early post-legalization data valuable for understanding whether policy changes accelerate existing consumption trends.","specificNumbers":"Prevalence rose from 4.6% (2012) to 6.1% (2015) to 7.1% (2018) to 8.8% (2021) to 9.8% (2024). Most users consumed marijuana (92.3%) as joints (88.6%). Top motivations: getting high or having fun (66.8%) and stress relief (61.3%). 25.7% of users belonged to a cannabis social club.","methodology":"Repeated cross-sectional surveys (Epidemiological Survey of Substance Abuse) across five waves from 2012 to 2024, with sample sizes ranging from 7,534 to 9,267 German-speaking adults per wave.","limitations":"The 2024 survey occurred very shortly after legalization (April 2024), limiting the ability to detect effects. Self-reported data may underestimate use. The 2024 wave had a smaller sample size than previous waves."},{"rthcId":"RTHC-06670","title":"Cannabis use disorder: an overview of treatment approaches in Europe.","authors":"Hoch, Eva; Murawski, Monika; Ferri, Marica; Feingold, Daniel","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 315-326","doi":"10.1007/s00406-025-01964-7","pmid":"40035833","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06671","title":"Attitudes and expectations of primary care physicians regarding recreational cannabis legalization in Germany: a pre-implementation survey.","authors":"Hochheim, Uta; Müller, Frank; Noack, Eva Maria","year":2025,"journal":"Journal of cannabis research, 7(1), 101","doi":"10.1186/s42238-025-00367-8","pmid":"41331678","tags":["legalization","medical-cannabis"],"studyType":"cross-sectional survey","evidenceStrength":"low","keyFinding":"Among 239 responding physicians, most anticipated increased cannabis consumption and disorders post-legalization. Doctors with personal cannabis experience (37.9%) were more optimistic about policy goals like quality control. Despite 40.3% prescribing medical cannabis, screening for recreational use was rare.","whyItMatters":"Primary care physicians are often the first point of contact for patients experiencing cannabis-related health issues, making their preparedness and attitudes relevant to post-legalization healthcare.","specificNumbers":"25.3% response rate (239 of 946). 37.9% of respondents had personal cannabis experience. 40.3% prescribed medical cannabis. Most anticipated increased consumption and cannabis use disorders after legalization.","methodology":"Exploratory cross-sectional survey of GPs and practice-based anesthesiologists in three German states, conducted from September 2023 to March 2024 (pre-legalization). 946 surveys delivered, 239 responded (25.3% response rate).","limitations":"Low response rate (25.3%) introduces selection bias. Only three of sixteen German states surveyed. Pre-legalization timing means attitudes may shift with actual experience. Self-selected respondents may differ systematically from non-respondents."},{"rthcId":"RTHC-06672","title":"Cannabinoid use generalizes stress responses by altering the astrocyte plasticity through extracellular matrix signaling in the nucleus accumbens core.","authors":"Hodebourg, Ritchy; Duncan, Lillian; Dereschewitz, Eric; Kalivas, Peter","year":2025,"journal":"Research square","doi":"10.21203/rs.3.rs-7254957/v1","pmid":"40894006","tags":["neuroscience","ptsd","addiction"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"THC+CBD self-administration followed by withdrawal caused male rats to show stress-coping behaviors in response to a neutral stimulus unrelated to the original stressor. This generalization was linked to astrocyte retraction from synapses and decreased Synapsin-I density in the nucleus accumbens core. Effects were observed only in males.","whyItMatters":"Cannabis use disorder and PTSD frequently co-occur. Understanding how cannabinoid exposure might alter brain circuits involved in stress generalization could point to new treatment targets for both conditions.","specificNumbers":"Rats self-administered THC+CBD for 10 days with 10 days of withdrawal. MMP-2 was the primary driver of matrix metalloproteinase activation. Effects on stress generalization and neural plasticity were observed only in male rats.","methodology":"Rats were restraint-stressed with an associated odor (stress-CS), then self-administered THC+CBD for 10 days followed by 10 days of withdrawal. Stress responses to the conditioned and neutral odors were measured in a defensive burying task. Brain changes were assessed via in vivo zymography and confocal microscopy.","limitations":"Animal study results may not translate directly to humans. The THC+CBD combination and dosing may not reflect typical human consumption patterns. Only examined one brain region. The sex difference mechanism was not fully explained."},{"rthcId":"RTHC-06673","title":"Comparison between pediatric and adult acute natural cannabinoids toxicity: A 5-year retrospective study with special consideration of acute synthetic cannabinoids toxicity.","authors":"Hodeib, Aliaa A; Elmansy, Alshaimma Mahmoud; Ghonem, Mona M","year":2025,"journal":"Toxicology reports, 14, 101986","doi":"10.1016/j.toxrep.2025.101986","pmid":"40162072","tags":["youth"],"studyType":"retrospective cohort","evidenceStrength":"low","keyFinding":"Among 106 patients with acute cannabinoid toxicity (68 children, 38 adults), children more frequently presented with impaired consciousness and bradypnea, while adults showed tachycardia, low oxygen saturation, hypokalemia, and leukocytosis. Delayed medical intervention was a significant risk factor for complications and longer hospital stays in children.","whyItMatters":"As cannabis access expands, accidental pediatric exposures are increasing. Understanding how poisoning presents differently in children versus adults helps emergency departments provide faster, more appropriate care.","specificNumbers":"106 total patients: 68 children, 38 adults over 5 years. Children had significantly more impaired consciousness and bradypnea. Adults had significantly more tachycardia, low oxygen saturation, hypokalemia, and leukocytosis (all p < 0.001). Only 4 cases involved synthetic cannabinoids.","methodology":"Five-year retrospective study (2019-2023) at a single Egyptian poison control center reviewing medical records of patients admitted for acute cannabinoid toxicity. Patients divided into pediatric (18 and under) and adult groups.","limitations":"Single center in Egypt, which may not reflect exposure patterns in other regions. Retrospective design limits data quality. Natural and synthetic cannabinoid cases were mixed. Small sample size for the synthetic cannabinoid subgroup (n=4)."},{"rthcId":"RTHC-06674","title":"Pre-analytical Stability of Drugs of Abuse in Urine for Confirmatory Testing. A Systematic Review.","authors":"Hoffmann-Lücke, Elke; Steffensen, Ellen Hollands; Samson, Mie; Greibe, Eva","year":2025,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkaf106","pmid":"41416917","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06675","title":"Use of cannabidiol for off-label treatment of patients with refractory focal, genetic generalised and other epilepsies.","authors":"Hollander, Marie; Mayer, Thomas; Klotz, Kerstin Alexandra; Knake, Susanne; von Podewils, Felix; Kurlemann, Gerhard; Immisch, Ilka; Rosenow, Felix; Schubert-Bast, Susanne; Strzelczyk, Adam","year":2025,"journal":"Neurological research and practice, 7(1), 49","doi":"10.1186/s42466-025-00408-w","pmid":"40696489","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"retrospective cohort","evidenceStrength":"moderate","keyFinding":"Add-on CBD showed meaningful seizure reduction across epilepsy types beyond its approved indications (Lennox-Gastaut, Dravet, TSC). At three months, 38.9% of 108 patients achieved at least 50% seizure reduction. Among those with tonic-clonic seizures, 45.8% were 50% responders and 16.7% became tonic-clonic seizure-free. Response was not predicted by sex, age, epilepsy type, or clobazam use.","whyItMatters":"CBD is only approved for a few rare epilepsy syndromes. This real-world data suggests it may benefit a broader range of patients with treatment-resistant epilepsy, which could support expanded indications.","specificNumbers":"108 patients (mean age 27.3, range 1.4-68 years). 38.9% achieved at least 50% seizure reduction at 3 months. 25.9% had 50-74% reduction, 13% had 75-99% reduction. Mean seizure days dropped from 16.8 to 14.5 per month (p=0.002). Retention: 85.2% at 3 months, 73.5% at 6 months, 61.1% at 12 months. 63% rated improved on CGI-C. Adverse events in 38%: diarrhea (15), sedation (13), nausea/vomiting (7).","methodology":"Retrospective cohort study of 108 patients who started off-label CBD between 2019 and 2023 at six German epilepsy centers. Follow-up included seizure frequency, retention rates, Clinical Global Impression of Change (CGI-C), and adverse events.","limitations":"Retrospective design without a control group. Open-label treatment allows for placebo effects and observer bias. Retention was better in children/adolescents, potentially confounding age-related results. Six centers in one country limits generalizability."},{"rthcId":"RTHC-06676","title":"Quantitative and qualitative changes in substance-related administrative offences in road traffic during the SARS-CoV-2 pandemic in Munich.","authors":"Holzer, Anna; Stoever, Andreas; Lau, Michael; Gleich, Sabine; Graw, Matthias; Ludwig, Anouk; Hartung, Benno","year":2025,"journal":"PloS one, 20(10), e0334598","doi":"10.1371/journal.pone.0334598","pmid":"41118377","tags":["driving","legalization"],"studyType":"retrospective cohort","evidenceStrength":"moderate","keyFinding":"Among 6,210 blood samples from substance-related traffic stops in Munich (2019-2021), cannabis was detected most frequently (66-67%), followed by alcohol (11%) and cocaine (5%). Detection patterns were largely stable across the pandemic. However, THC-COOH concentrations were higher during the pandemic, and alcohol was more common in e-scooter riders during lighter restrictions.","whyItMatters":"Understanding how pandemic conditions affected substance-impaired driving patterns can help cities prepare traffic safety measures during future disruptions and informs ongoing debates about cannabis and driving policy.","specificNumbers":"6,210 blood samples analyzed. Cannabis detected in 66.2% pre-pandemic, 67.4% during pandemic. Alcohol: 11.7% vs 10.8%. Cocaine: 5.7% vs 5.2%. THC-COOH concentrations were higher during the pandemic. Alcohol levels rose during light restrictions and fell during strict lockdowns.","methodology":"Retrospective analysis of 6,210 blood samples from individuals suspected of substance-related traffic offenses under German law between January 2019 and July 2021. Samples stratified by pre-pandemic and pandemic periods, with pandemic periods subdivided by restriction severity.","limitations":"Single city (Munich) limits generalizability. Only captures individuals who were stopped and tested. Cannot determine impairment level from THC-COOH (an inactive metabolite). No data on crash outcomes or severity."},{"rthcId":"RTHC-06677","title":"De novo biosynthesis of cannabinoids and their analogs in Yarrowia lipolytica.","authors":"Hong, Yuxiang; Gu, Yang; Lin, Dewei; Wu, Zizhao; Chen, Wenhao; Lu, Tianjian; Lertphadungkit, Pornpatsorn; Ma, Jingbo; Wang, Haili; Zhou, Bo; Bar-Sela, Gil; Cohen, Idan; Xu, Peng","year":2025,"journal":"Biodesign research, 7(2), 100021","doi":"10.1016/j.bidere.2025.100021","pmid":"41416103","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06678","title":"The effects of cannabidiol on nitric oxide synthases: a narrative review on therapeutic implications for inflammation and oxidative stress in health and disease.","authors":"Hooshmand, Seyed Amin Alavi; Rameshrad, Maryam; Sahebkar, Amirhossein; Iranshahi, Mehrdad","year":2025,"journal":"Journal of cannabis research, 7(1), 71","doi":"10.1186/s42238-025-00332-5","pmid":"41024292","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06679","title":"Assessment of the knowledge landscape, information needs and attitude towards decision support systems among hemp farmers in Florida.","authors":"Hopf, Alwin; Watson, Jonathan A; Swisher, Mickie; Brym, Zachary; Hoogenboom, Gerrit","year":2025,"journal":"Journal of cannabis research, 7(1), 62","doi":"10.1186/s42238-025-00318-3","pmid":"40836307","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06680","title":"Modification of the D3 Array Combined (Formerly the DetectX Combined) for the Detection of Aspergillus, Salmonella, and Shiga Toxin-Producing Escherichia coli in Dried Cannabis Flower with Optional Enrichment: AOAC Performance Tested MethodSM 012201.","authors":"Hottinger, Meghan; Leasia, Mike; Schwartz, Mark; Katchman, Benjamin A","year":2025,"journal":"Journal of AOAC International, 108(6), 961-970","doi":"10.1093/jaoacint/qsaf080","pmid":"40875564","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06681","title":"Simultaneous alcohol and cannabis use is associated with daily consequences reflective of alcohol use disorder symptoms.","authors":"Howe, Lindy K; Bolts, Olivia L; Metrik, Jane; Gunn, Rachel L","year":2025,"journal":"Drug and alcohol dependence, 276, 112924","doi":"10.1016/j.drugalcdep.2025.112924","pmid":"41109054","tags":["addiction","harm-reduction"],"studyType":"ecological momentary assessment","evidenceStrength":"moderate","keyFinding":"Compared to simultaneous use (overlapping effects), concurrent use on the same day without overlapping effects was associated with 55% lower odds of impaired control, 53% lower odds of social impairment, 59% lower odds of risky use, and 64% lower odds of pharmacological effects. No significant differences were found between simultaneous use days and alcohol-only days.","whyItMatters":"As dual use of alcohol and cannabis becomes more common, understanding that the timing of co-use matters for harm risk can inform targeted prevention messaging.","specificNumbers":"116 participants, 28-day assessment period. Concurrent vs. simultaneous use odds ratios: impaired control OR=0.45, social impairment OR=0.47, risky use OR=0.41, pharmacological effects OR=0.36 (all p<0.05).","methodology":"Ecological momentary assessment study with 116 participants (56% female, mean age 23.2) reporting daily substance use and alcohol-related consequences over 28 days. Preregistered multilevel binomial logistic regression analyses.","limitations":"Young adult sample (mean age 23.2) may not generalize to older populations. Self-report of overlapping effects is subjective. 28-day window captures only a snapshot. Cannot determine causation from observational daily diary data."},{"rthcId":"RTHC-06682","title":"Treatment of cannabinoid hyperemesis syndrome: A systematic review and treatment algorithm for consultation-liaison psychiatrists.","authors":"Hsu, Jennifer; Kashyap, Saurabh; Hurd, Cheryl; McCormack, Lauren; Herrmann, Zachary; Schwartz, Ann C; Jackson, Joshua; DeMoss, Dustin","year":2025,"journal":"General hospital psychiatry, 97, 185-191","doi":"10.1016/j.genhosppsych.2025.10.012","pmid":"41129865","tags":["medical-cannabis","harm-reduction"],"studyType":"systematic review","evidenceStrength":"low","keyFinding":"Across 34 articles and 63 individual cases of CHS, capsaicin cream, antipsychotics, and benzodiazepines were reported to improve symptoms more effectively than standard anti-emetics such as promethazine, ondansetron, and metoclopramide. The authors proposed a treatment algorithm for consultation-liaison psychiatrists.","whyItMatters":"CHS is increasingly common and notoriously resistant to standard anti-emetics. Having an evidence-based treatment algorithm could reduce emergency department visits and hospital stays for affected patients.","specificNumbers":"34 eligible articles with 63 individual cases reviewed. Capsaicin cream, antipsychotics, and benzodiazepines outperformed standard anti-emetics. The proposed algorithm provides a stepwise treatment approach.","methodology":"Systematic review following PRISMA guidelines, searching PubMed, PsychINFO, Embase, and Web of Science from inception to July 2021. Included cases where patient-level treatment data was available. Beneficial treatment defined as resolution of nausea, vomiting, and compulsive hot showering.","limitations":"Evidence base consists entirely of case reports and case series, the lowest level of clinical evidence. Search only through July 2021 misses recent literature. Publication bias likely favors successful treatments. No randomized controlled trials available."},{"rthcId":"RTHC-06683","title":"Evaluation of a Novel Online Webinar for Health Care Practitioner Education on the Health Effects of Smoking Cannabis in the Airway.","authors":"Hu, Amanda; Deane, Emily Catherine; Gill, Simran; Lynn, Brenna","year":2025,"journal":"The Journal of continuing education in the health professions, 45(1), 67-69","doi":"10.1097/CEH.0000000000000565","pmid":"39982117","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06684","title":"Medical marijuana policies, opioid prescriptions, and adverse events among patients undergoing cancer resection surgery.","authors":"Hu, Ju-Chen; Karan, Kenneth; Zhang, Hao; Portenoy, Russell; Rosa, William E; Zhang, Yiye; Reid, M Carrington; Tamimi, Rulla M; Zhang, Fang; Bruera, Eduardo; Paice, Judith A; Bao, Yuhua","year":2025,"journal":"Cancer, 131(19), e70107","doi":"10.1002/cncr.70107","pmid":"41031641","tags":["medical-cannabis","pain","cancer"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using insurance claims data from over 34,000 cancer surgery patients across 27 states, this study examined whether medical marijuana legalization (MML) affected opioid prescribing patterns in the six months after diagnosis.\n\nThe researchers distinguished between two phases of legalization: the law passing (MML without dispensaries) and dispensaries actually opening (MML with dispensaries). This distinction proved critical. Simply passing a medical marijuana law had no measurable effect on opioid prescribing. But once dispensaries opened and patients could actually access cannabis, prescriptions for strong short-acting opioids (oxycodone, hydrocodone, hydromorphone, morphine) decreased.\n\nThe study used a difference-in-differences approach—comparing changes over time in states that legalized to changes in states that didn't—which helps account for national trends in opioid prescribing that affected all states.\n\nThe findings were specific to strong opioids. Weak opioid prescriptions (tramadol, codeine), total morphine milligram equivalents among those who did receive opioids, and emergency department visits didn't change significantly. This suggests patients may have been substituting cannabis for some strong opioid use rather than reducing all pain management.","whyItMatters":"Cancer patients routinely receive opioids after surgery, and the opioid crisis has made clinicians and patients wary of these prescriptions. If medical cannabis can substitute for some strong opioid use after cancer surgery, that could reduce opioid-related risks—dependence, respiratory depression, constipation—without necessarily improving or worsening pain control. The dispensary access finding also matters for policy: laws on paper don't change behavior; actual access does.","specificNumbers":"N = 34,911 cancer surgery patients. 24,592 breast, 8,510 colorectal, 1,809 lung cancer. MML with dispensaries associated with reduced strong opioid prescriptions. MML without dispensaries: no significant effect. Weak opioids and total MME: no significant change.","methodology":"Cross-sectional study using a difference-in-differences design with 2016–2022 private insurance claims data. N = 34,911 patients aged 18–64 undergoing resection surgery for breast (24,592), colorectal (8,510), or lung (1,809) cancer across 27 states without MML as of 2016. MML policies classified as: no MML, MML without dispensaries, and MML with dispensaries. Outcomes measured during 6 months post-diagnosis.","limitations":"Private insurance claims only (excludes Medicare, Medicaid, uninsured). Ages 18–64, so doesn't capture older cancer patients who make up the majority. Claims data can't confirm whether patients actually used cannabis. The difference-in-differences design assumes parallel trends between legalizing and non-legalizing states, which may not hold perfectly. Cannot determine whether the opioid reduction improved or worsened pain outcomes."},{"rthcId":"RTHC-06685","title":"Crystal structures of agonist-bound human cannabinoid receptor CB1.","authors":"Hua, Tian; Vemuri, Kiran; Nikas, Spyros P; Wu, Yiran; Qu, Lu; Pu, Mengchen; Korde, Anisha; Jiang, Shan; Ho, Jo-Hao; Han, Gye Won; Ding, Kang; Li, Xuanxuan; Liu, Haiguang; Hanson, Michael A; Zhao, Suwen; Bohn, Laura M; Makriyannis, Alexandros; Stevens, Raymond C; Liu, Zhi-Jie","year":2025,"journal":"Nature, 646(8085), 754-758","doi":"10.1038/s41586-025-09454-5","pmid":"40866700","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06686","title":"A Survey on the Use of Cannabidiol (CBD) Isolate, Its Perceived Benefits, and Associated Side Effects Among Subjects With Chronic Pain.","authors":"Huang, Austin; Stolzenberg, Laurence; Usman, Mohammad; Awan, Muhammad; Bruner, Paul; MacGregor, Gordon","year":2025,"journal":"Cureus, 17(3), e80198","doi":"10.7759/cureus.80198","pmid":"40196085","tags":["cbd","pain"],"studyType":"cross-sectional survey","evidenceStrength":"low","keyFinding":"Survey respondents using CBD isolate for chronic pain reported positive associations between CBD use and decreased chronic pain, even at doses under 100 mg. The majority reported no side effects, and no severe side effects were noted among any respondents.","whyItMatters":"With up to 50 million U.S. adults affected by chronic pain and the ongoing opioid crisis, understanding how CBD users perceive its benefits and risks provides a starting point for more rigorous research.","specificNumbers":"Positive association between CBD use and decreased chronic pain reported even at doses below 100 mg. Majority of respondents reported no side effects. No severe side effects reported by any participant.","methodology":"Anonymous online Qualtrics survey posted publicly and in multiple medical clinics. Assessed CBD isolate use, perceived effectiveness, dosage, frequency, and side effects among adults with chronic pain.","limitations":"Anonymous survey with no verification of CBD use, diagnoses, or outcomes. Self-selection bias: people satisfied with CBD are more likely to respond. No placebo comparison. CBD isolate products vary widely in actual content and quality."},{"rthcId":"RTHC-06687","title":"The protective role of cannabidiol in stress-induced liver injury: modulating oxidative stress and mitochondrial damage.","authors":"Huang, Chengyu; Liang, Huichao; Liang, Xiaohua; Liu, Yueyi; Wang, Jiaoling; Jiang, Haoran; Kou, Xinhui; Chen, Jun; Huang, Lili","year":2025,"journal":"Frontiers in pharmacology, 16, 1567210","doi":"10.3389/fphar.2025.1567210","pmid":"40160456","tags":["cbd","inflammation"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"CBD treatment reduced liver damage markers (AST, ALT), inflammatory cytokines (IL-1beta, TNF-alpha), and fibrosis marker alpha-SMA in stressed mice. CBD enhanced CB2 receptor expression, upregulated the protective SLC7A11 pathway, decreased the pro-oxidant ACSL4, and improved mitochondrial morphology.","whyItMatters":"Stress-related liver damage is increasingly recognized as a clinical concern. Identifying specific molecular pathways through which CBD may protect the liver could support future therapeutic development.","specificNumbers":"CBD decreased AST and ALT (liver damage markers), IL-1beta and TNF-alpha (inflammatory cytokines), and alpha-SMA (fibrosis marker). CBD increased CB2R expression, SOD and GSH-Px activity (antioxidants), and SLC7A11 protein expression.","methodology":"Mouse model of stress-induced liver injury. Assessments included histopathology, ELISA for cytokines, immunohistochemistry, Western blot, gene transcription analysis, and transmission electron microscopy for mitochondrial morphology.","limitations":"Mouse model may not translate to human liver physiology. Stress model is artificial. CBD dosing and route may not reflect real-world human use. No dose-response analysis reported. Single time point assessment."},{"rthcId":"RTHC-06688","title":"Topical Capsaicin for Symptomatic Treatment of Cannabinoid Hyperemesis Syndrome in a Pregnant Patient: A Case Report.","authors":"Huang, Jenny; Rayasam, Swathi; Graham, Caleb; Jones, Stephanie","year":2025,"journal":"Pain medicine case reports, 9(6), 311-313","doi":null,"pmid":"41135021","tags":["medical-cannabis","pregnancy","harm-reduction"],"studyType":"case report","evidenceStrength":"very low","keyFinding":"A 34-year-old woman at 11 weeks gestation with intractable abdominal pain and nausea unresponsive to extensive gastrointestinal workup and multimodal antiemetic treatment was ultimately diagnosed with CHS. Topical capsaicin cream provided significant symptom improvement when oral pain management options were limited by pregnancy.","whyItMatters":"CHS diagnosis is particularly challenging in pregnancy because nausea is expected, and treatment options are limited by fetal safety concerns. Topical capsaicin avoids systemic drug exposure, making it an attractive option.","specificNumbers":"Patient was 34 years old at 11 weeks gestation. Symptoms were refractory to multimodal antiemetic treatment before capsaicin was trialed.","methodology":"Single case report from a clinical setting.","limitations":"Single case report provides the lowest level of clinical evidence. Cannot rule out spontaneous improvement or placebo effect. No long-term follow-up on pregnancy outcomes reported."},{"rthcId":"RTHC-06689","title":"Recent innovations in cannabinoid chemistry, biology, and biosynthesis.","authors":"Hubert, Felix M; Love, Anna C; Lan, Tian; Bone, Hannah K; Moore, Bradley S","year":2025,"journal":"Current opinion in biotechnology, 96, 103378","doi":"10.1016/j.copbio.2025.103378","pmid":"41205317","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06690","title":"Severe Cannabinoid Intoxication in a Ferret (Mustela putorius furo) Treated With Intravenous Lipid Emulsion.","authors":"Huerta, Claudia; Lamarca, Amanda; Lam, W Y Eunice; Martin, Linda G","year":2025,"journal":"Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001), 35(5), 594-598","doi":"10.1111/vec.70044","pmid":"41085075","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06691","title":"Racial Trauma among Multi-Ethnic Minority Young Adults Affects Nicotine, Alcohol, and Cannabis Use Differently than among Mono-Ethnic Minority Young Adults.","authors":"Huh, Jimi; Lee, Ryan; Pickering, Trevor A; Oh, Hans; Arpawong, Thalida Em","year":2025,"journal":"Substance use & misuse, 60(14), 2154-2162","doi":"10.1080/10826084.2025.2537101","pmid":"41170778","tags":["mental-health","addiction","youth"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Among 59,529 racial/ethnic minority young adults, psychological well-being (PWB) was associated with fewer anxiety and depressive symptoms and lower substance use counts. However, racial trauma dampened these protective effects. For multi-ethnic young adults (25.3% of sample), depressive symptoms mediated the path from racial trauma to substance use differently than for mono-ethnic peers.","whyItMatters":"Americans identifying as two or more races are one of the fastest-growing demographic groups. Understanding how racial trauma uniquely affects substance use in this population can inform culturally tailored prevention.","specificNumbers":"N=59,529 racial/ethnic minority young adults. 25.3% identified as multi-racial/ethnic. PWB was associated with lower anxiety and depressive symptoms and fewer substances used across groups. Racial trauma significantly dampened the protective effects of PWB on mental health.","methodology":"Combined three waves of the Healthy Minds Study (2021-2023) for self-identified racial/ethnic minority young adults. Moderated mediation path analyses stratified by mono- vs. multi-ethnicity, with multiple group analysis testing non-invariance.","limitations":"Cross-sectional design cannot establish causation. Self-reported racial trauma and substance use may be subject to bias. The Healthy Minds Study samples college students, limiting generalizability to non-college populations."},{"rthcId":"RTHC-06692","title":"\"Treating me like a criminal\": A qualitative study of birthing parents' perspectives on racism and biases in newborn drug testing for substance exposure during pregnancy.","authors":"Huizinga, Jamie L; Oshman, Lauren; Onishchenko, Regina; Joassaint, Madgean; Madlambayan, Emily; Van Sparrentak, Murphy; McCabe, Katharine; Townsel, Courtney; Frank, Christopher J; Chandanabhumma, P Paul; Wu, Justine P","year":2025,"journal":"Journal of substance use and addiction treatment, 176, 209745","doi":"10.1016/j.josat.2025.209745","pmid":"40581188","tags":["pregnancy","legalization"],"studyType":"qualitative study","evidenceStrength":"low","keyFinding":"Four major themes emerged: (1) honesty about substance use with providers could lead to punishment and CPS reporting, (2) historical and contemporary racism contributed to racial disparities in newborn drug testing, (3) cannabis risks during pregnancy were poorly explained by healthcare providers, and (4) participants wanted non-punitive, respectful care with clear explanations of testing and reporting policies.","whyItMatters":"Black birthing people face disproportionate rates of newborn drug testing, CPS reporting, and termination of parental rights. Understanding patient perspectives on these disparities is essential for policy reform.","specificNumbers":"15 participants interviewed. Four major themes identified. Study was the third phase of a mixed methods design with guidance from a 6-member Participatory Council and two external antiracist research consultants.","methodology":"Qualitative study with semi-structured interviews of 15 participants who gave birth within the past 12 months at a midwestern U.S. academic hospital. Purposeful sampling of racial minorities and those who underwent newborn drug testing. Analysis informed by Public Health Critical Race Praxis.","limitations":"Small sample (n=15) from a single hospital. Qualitative design captures perspectives but cannot establish prevalence of experiences. Self-selected participants may not represent all birthing parents."},{"rthcId":"RTHC-06693","title":"Cannabis-Related Disorders Are Associated With Increased Early Postoperative Opioid Prescriptions and Delayed Emergency Department Visits Following Open Carpal Tunnel Release.","authors":"Humble, Kirstin A; Vatsia, Sohrab K; Monahan, Peter F; Taylor, Kenneth F","year":2025,"journal":"Hand (New York, N.Y.), 20(8), 1232-1236","doi":"10.1177/15589447241284788","pmid":"39431650","tags":["pain","addiction","medical-cannabis"],"studyType":"retrospective cohort","evidenceStrength":"moderate","keyFinding":"Among 1,850 propensity-matched patients undergoing open carpal tunnel release, those with cannabis-related disorders (CRD) had higher rates of opioid prescriptions within 2 weeks (30.9% vs 25.6%, p=0.011), lower rates of outpatient follow-up within 6 weeks, and higher ER visits between 6-12 weeks (11.0% vs 8.0%, p=0.027).","whyItMatters":"Understanding how cannabis use disorders affect postoperative pain management and healthcare utilization helps surgeons set expectations and plan appropriate follow-up for these patients.","specificNumbers":"925 CRD patients matched to 925 controls. Opioid prescriptions 0-2 weeks: 30.9% vs 25.6% (p=0.011). ED visits 6-12 weeks: 11.0% vs 8.0% (p=0.027). NCRD patients had higher outpatient follow-up rates within 6 weeks.","methodology":"Retrospective cohort study using the TriNetX Research Network (2010-2022). 925 CRD patients propensity-matched 1:1 with 925 non-CRD patients on 7 characteristics. Outcomes tracked at 0-2, 2-6, and 6-12 weeks postoperatively.","limitations":"Retrospective database study cannot determine causation. CRD diagnosis in medical records may not capture all cannabis users. Cannot distinguish between cannabis use for pain relief versus recreational use. Propensity matching does not eliminate all confounders."},{"rthcId":"RTHC-06694","title":"Cannabis produces acute hyperphagia in humans and rodents via increased reward valuation for, and motivation to, acquire food.","authors":"Hume, Catherine; Cuttler, Carrie; Baglot, Samantha L; Javorcikova, Lucia; McLaughlin, Ryan J; Hill, Matthew N","year":2025,"journal":"Proceedings of the National Academy of Sciences of the United States of America, 122(52), e2518863122","doi":"10.1073/pnas.2518863122","pmid":"41439716","tags":["appetite","neuroscience"],"studyType":"translational study","evidenceStrength":"moderate","keyFinding":"Vaporized cannabis acutely and robustly increased energy intake in humans (within 30 minutes, regardless of dose or gender) and rats (within 60 minutes, regardless of macronutrient content, satiation, or sex). In rats, cannabis reduced the latency to eat and increased feeding bouts. Cannabis did not alter circulating appetite hormones, and the effects were mediated by central (not peripheral) CB1 receptors.","whyItMatters":"Despite \"the munchies\" being one of the most well-known effects of cannabis, the underlying mechanisms have been poorly characterized. This study identifies that cannabis increases motivation to eat rather than simply triggering hunger hormones.","specificNumbers":"In humans, increased intake occurred in the first 30 minutes regardless of dose or gender. In rats, effects appeared within 60 minutes regardless of macronutrient content, satiation, or sex. Cannabis abolished preexisting macronutrient preferences in rats. No changes in circulating appetite-associated hormones were detected.","methodology":"Translational design combining human participants exposed to cannabis vapor with snack access, and a rat model with cannabis vapor inhalation and food access. Rat experiments examined feeding bout structure, macronutrient preferences, appetite hormones, and central vs. peripheral CB1R involvement.","limitations":"Human component characterized intake patterns but did not include the mechanistic analyses done in rats. Vaporized cannabis contains multiple compounds beyond THC. Acute effects may not reflect chronic use patterns."},{"rthcId":"RTHC-06695","title":"Medical Marijuana and Opioid Usage: An Analysis of Patient Perceptions in Louisiana.","authors":"Hummel, Daniel; Sutherlin, John W; Hawkins, Ashley; Thomas, Kathryn; Corbett, Kym","year":2025,"journal":"Substance use & misuse, 1-6","doi":"10.1080/10826084.2025.2584703","pmid":"41318220","tags":["medical-cannabis","pain"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Respondents reported lower pain levels with medical marijuana use by an average of 3.4 points on a 10-point scale. Patients using prescription painkillers were 1.5 times more likely to use medical marijuana less frequently. Those who stopped prescription painkillers had 26.5% higher odds of using more medical marijuana, suggesting substitution.","whyItMatters":"With the U.S. opioid crisis ongoing, evidence that medical marijuana may serve as a substitute for prescription painkillers supports the case for expanded access in states still debating legalization.","specificNumbers":"Over 2,000 respondents. Pain reduced by 3.4 points on 10-point scale (Z=-35.77, p<0.001). Prescription pain users 1.5x more likely to use MM less frequently (OR=1.524, 95% CI: 1.114-2.074, p<0.01). Stopping prescriptions increased odds of more MM use by 26.5% (OR=0.735, 95% CI: 0.586-0.923, p<0.001).","methodology":"Survey of more than 2,000 Louisiana medical marijuana program participants examining frequency and amount of use, with analysis of relationships between race, age, reason for use, prescription use, and program duration.","limitations":"Self-reported pain reduction without objective measures. Survey participants are self-selected medical marijuana users, introducing bias toward positive outcomes. No control group. Cross-sectional design cannot establish causation."},{"rthcId":"RTHC-06696","title":"Medical Marijuana and Opioid Usage: An Analysis of Patient Perceptions in Louisiana.","authors":"Hummel, Daniel; Sutherlin, John W; Hawkins, Ashley","year":2025,"journal":"Substance use & misuse, 1-6","doi":"10.1080/10826084.2025.2575429","pmid":"41136335","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06697","title":"Individual application patterns of Cannabis-based Medicines in Germany - Descriptive evaluation of a patient survey and discussion from a forensic perspective.","authors":"Hundertmark, Marica; Ihlenfeld, André; Landschaft, Assaf; Röhrich, Jörg; Germerott, Tanja; Wunder, Cora","year":2025,"journal":"Forensic science international, 367, 112352","doi":"10.1016/j.forsciint.2024.112352","pmid":"39709741","tags":["medical-cannabis","driving","potency"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Among 1,030 German medical cannabis patients, 89.9% used cannabis flowers. Average daily THC dose for flower patients was 336 mg compared to 17 mg or less for other cannabis-based medicines. 16.2% used combinations of different cannabis products. 28.4% smoked cannabis flowers despite medical guidance against smoking.","whyItMatters":"The large gap between THC doses from flowers versus other preparations has direct implications for driving safety assessments and medico-legal evaluations of cannabis patients in traffic incidents.","specificNumbers":"1,030 respondents. 89.9% used cannabis flowers. Average daily THC dose: 336 mg (flowers) vs 17 mg or less (other preparations). 16.2% used complex combinations. 28.4% smoked flowers (not recommended medically).","methodology":"Anonymous nationwide online survey of German medical cannabis patients in Q1 2022. Included both patients with health insurance prescriptions and self-payers for the first time. Analyzed application patterns with focus on the cannabis flower sub-collective.","limitations":"Self-reported data from an online survey. Self-selected participants may not represent all medical cannabis patients. No verification of actual THC intake. Q1 2022 data predates Germany recreational legalization."},{"rthcId":"RTHC-06698","title":"Substance use and mental health symptoms in adults with prenatal alcohol exposure.","authors":"Hunnicutt-Ferguson, Kallio; Stoner, Susan A; Kable, Julie A; Grant, Therese M; Coles, Claire D","year":2025,"journal":"Neurotoxicology and teratology, 109, 107436","doi":"10.1016/j.ntt.2025.107436","pmid":"40032207","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06699","title":"Income inequality and adherence to 24-hour movement guideline recommendations among adolescents: a multilevel growth curve analysis using longitudinal data from three waves of the Cannabis, Obesity, Mental health, Physical activity, Sedentary behaviour and Smoking (COMPASS) study (2016-2019).","authors":"Hunter, Stephen; Perala, Zack; Patte, Karen; Leatherdale, Scott; Carson, Valerie; Chaput, Jean-Philippe; Faulkner, Guy; Pabayo, Roman","year":2025,"journal":"Journal of epidemiology and community health, 79(7), 544-550","doi":"10.1136/jech-2024-223176","pmid":"39965910","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06700","title":"An Update on the Behavioral and Neurobiological Effects of Cannabis Use in Adolescents: A Translational Perspective.","authors":"Hurd, Yasmin L","year":2025,"journal":"The American journal of psychiatry, 182(7), 609-615","doi":"10.1176/appi.ajp.20250444","pmid":"40589258","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06701","title":"The effect of cannabidiol on neurometabolite levels in alcohol use disorder.","authors":"Hurzeler, Tristan; DeMayo, Marelyna; Logge, Warren; Watt, Joshua; McGregor, Iain S; Suraev, Anastasia; Haber, Paul; Morley, Kirsten","year":2025,"journal":"Alcohol and alcoholism (Oxford, Oxfordshire), 60(4)","doi":"10.1093/alcalc/agaf029","pmid":"40551671","tags":["cbd","addiction"],"studyType":"randomized controlled trial","evidenceStrength":"moderate","keyFinding":"In 22 participants with AUD receiving 800 mg CBD or placebo in a crossover trial, no overall treatment effects on neurometabolites were found. However, CBD sessions showed significantly higher glutathione (p<0.001), glutamate/glutamine (p=0.001), and GABA (p=0.002) concentrations specifically for participants who had consumed alcohol the previous day, with no effect in abstinent participants.","whyItMatters":"Alcohol disrupts brain neurochemistry, and finding that CBD selectively normalizes these disruptions after drinking sessions could position CBD as an adjunct treatment for alcohol use disorder.","specificNumbers":"22 participants, 800 mg CBD per day, crossover design. GSH (p<0.001), GLx (p=0.001), and GABA (p=0.002) all significantly higher during CBD sessions for participants who drank the previous day. No effects in abstinent participants.","methodology":"Crossover double-blind randomized trial with 22 non-treatment-seeking AUD participants receiving 800 mg CBD or matched placebo. Neurometabolites measured in the dorsal anterior cingulate cortex using proton magnetic resonance spectroscopy (1H-MRS).","limitations":"Very small sample (n=22). Non-treatment-seeking participants may not represent clinical AUD patients. Post hoc subgroup analysis by recent alcohol use was exploratory. Single dose level tested. Short treatment duration."},{"rthcId":"RTHC-06702","title":"Cannabidiol attenuates precuneus activation during appetitive cue exposure in individuals with alcohol use disorder.","authors":"Hurzeler, Tristan; Logge, Warren; Watt, Joshua; McGregor, I S; Suraev, Anastasia; Haber, Paul S; Morley, Kirsten C","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(7), 2129-2139","doi":"10.1007/s00406-025-01983-4","pmid":"40102270","tags":["cbd","addiction","neuroscience"],"studyType":"randomized controlled trial","evidenceStrength":"moderate","keyFinding":"In 22 non-treatment-seeking AUD participants, 800 mg CBD did not affect alcohol cue-elicited brain activation in pre-specified regions of interest. However, exploratory whole-brain analysis revealed CBD significantly reduced precuneus activation, a region involved in self-referential processing and reward. No effects on acute craving, mood, or cognitive functioning were observed.","whyItMatters":"The precuneus plays a role in self-referential thinking and reward processing, both relevant to addiction. CBD modulation of this region during alcohol cue exposure could represent a neural mechanism for reducing alcohol-related responses.","specificNumbers":"22 participants, mean age 29, 800 mg CBD or placebo in crossover design. No significant effects in ROI analysis. Significant CBD effect in precuneus in exploratory whole-brain analysis. No effects on craving, mood, or cognition.","methodology":"Crossover double-blind randomized trial with 22 AUD participants (mean age 29) receiving 800 mg CBD or placebo. fMRI measured brain activation during an alcohol cue reactivity task. Secondary outcomes included mood, craving, and cognitive functioning.","limitations":"Very small sample (n=22). The precuneus finding was exploratory (not pre-specified). Non-treatment-seeking participants may differ from clinical populations. The lack of craving effects limits clinical significance. Single-dose design."},{"rthcId":"RTHC-06703","title":"Washington State Teens' Perceptions of Cannabis-Infused Product Packaging: A Qualitative Study.","authors":"Hust, Stacey J T; Willoughby, J F; Couto, L; Kang, S; Nickerson, C; Price, R; Johnson, O; Ross-Viles, S","year":2025,"journal":"Journal of health communication, 30(7-9), 238-246","doi":"10.1080/10810730.2025.2514835","pmid":"40530616","tags":["youth","legalization"],"studyType":"qualitative study","evidenceStrength":"low","keyFinding":"Among 28 Washington teens (ages 13-17), many perceived cannabis edible packages as appealing because of aesthetics (bright colors, pictures) and lifestyle branding. Teens with greater cannabis knowledge and product literacy were more skeptical of packaging claims. Findings suggest current regulations may not fully prevent youth appeal.","whyItMatters":"Cannabis packaging regulations are intended to prevent youth appeal, but this study suggests they may not be fully effective. Understanding which packaging elements attract teens can inform more effective regulations.","specificNumbers":"28 teens aged 13-17 in Washington state. Two main themes: packaging aesthetics and lifestyle appeal attracted teens; cannabis knowledge and product literacy increased skepticism.","methodology":"Small group online focus groups and in-depth interviews with 28 Washington state teens aged 13-17 about their perceptions of cannabis edible product packages (gummies, pretzels). Data analyzed using thematic analysis.","limitations":"Small sample (n=28) from one state. Online format may affect discussion dynamics. Perceptions of packaging may not predict actual use behavior. Washington-specific regulations may not generalize to other states."},{"rthcId":"RTHC-06704","title":"Benzo[d]imidazole-Naphthalen-Arylmethanone Regioisomers as CB1 Ligands: Evaluation of Agonism via an Indirect Cytotoxicity-Based Approach.","authors":"Hwa Cho, Analia Young; Burgos Ravanal, Renato; Zuñiga Salazar, Valeria; Mellado, Marco; Lorca, Marcos; Pessoa-Mahana, David; Mella, Jaime; Günther Sapunar, Germán; Romero-Parra, Javier","year":2025,"journal":"International journal of molecular sciences, 26(20)","doi":"10.3390/ijms26209986","pmid":"41155283","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06705","title":"Cannabichromene: integrative modulation of apoptosis, ferroptosis, and endocannabinoid signaling in pancreatic cancer therapy.","authors":"Hwang, Yu-Na; Park, Ju-Hee; Na, Han-Heom; Kwon, Tae-Hyung; Park, Jin-Sung; Chae, Sehyun; Oh, Young Taek; Kim, Keun-Cheol","year":2025,"journal":"Cell death discovery, 11(1), 377","doi":"10.1038/s41420-025-02674-8","pmid":"40790027","tags":["cancer","neuroscience"],"studyType":"preclinical study","evidenceStrength":"low","keyFinding":"CBC treatment upregulated ferroptosis-related genes including HMOX1 and induced both apoptosis and ferroptosis in pancreatic cancer cells. CBC increased TRPV1 and CB2 receptor expression, and blocking these receptors reversed the cell death effects. In xenograft mouse models, CBC consistently inhibited tumor growth through the same multi-pathway mechanism.","whyItMatters":"Pancreatic cancer has one of the worst survival rates of any cancer. CBC working through multiple cell death pathways simultaneously could overcome the treatment resistance that makes pancreatic cancer so difficult to treat.","specificNumbers":"CBC upregulated ferroptosis genes including HMOX1. TRPV1 and CB2 expression preferentially increased. Cell death reversed by TRPV1 and CB2 inhibitors. Tumor growth inhibited in xenograft models.","methodology":"In vitro studies in human pancreatic cancer cells (mRNA-seq analysis, molecular assays for apoptosis and ferroptosis) combined with in vivo xenograft models in mice. Receptor involvement confirmed through inhibitor experiments.","limitations":"Preclinical study only. Human pancreatic cancer cell lines and mouse xenografts may not reflect clinical tumor behavior. CBC doses used may not be achievable in humans. No comparison to standard pancreatic cancer therapies."},{"rthcId":"RTHC-06706","title":"Use of Tobacco and Cannabis Following State-Level Cannabis Legalization.","authors":"Hyatt, Andrew S; Overhage, Lindsay; Cook, Benjamin Lê","year":2025,"journal":"JAMA network open, 8(7), e2520093","doi":"10.1001/jamanetworkopen.2025.20093","pmid":"40643912","tags":["legalization"],"studyType":"longitudinal cohort","evidenceStrength":"high","keyFinding":"Using difference-in-differences analysis of 171,257 observations from 55,406 individuals, recreational cannabis legalization was associated with a 3.28 percentage point increase in cannabis use and 1.39 percentage point increase in ENDS use compared to control states. Cigarette use did not significantly change (-0.99 points). Cannabis use increased more after retail outlets opened (3.74 points) than before (1.17 points).","whyItMatters":"This is one of the first studies with enough follow-up to show longer-term effects of cannabis legalization on both cannabis and tobacco product use, using a rigorous causal inference design.","specificNumbers":"171,257 observations from 55,406 individuals (50.9% female, mean age 37.97). Cannabis use: +3.28 pp (95% CI: 2.29-4.27). ENDS use: +1.39 pp (95% CI: 0.44-2.35). Cigarettes: -0.99 pp (95% CI: -2.25-0.27, not significant). Post-retail cannabis increase: +3.74 pp vs pre-retail +1.17 pp.","methodology":"Difference-in-differences analysis of the nationally representative Population Assessment of Tobacco and Health (PATH) longitudinal cohort study (2013-2022), comparing states with recreational cannabis legalization to control states over 5 years.","limitations":"Observational design despite difference-in-differences approach. State-level variation in implementation complicates uniform analysis. Self-reported use. Does not capture frequency or quantity changes within users. Cannot identify which individuals are new users versus increased users."},{"rthcId":"RTHC-06707","title":"The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets.","authors":"Iannotti, Fabio A; Di Marzo, Vincenzo","year":2025,"journal":"Pharmacological reviews, 77(4), 100070","doi":"10.1016/j.pharmr.2025.100070","pmid":"40554266","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06708","title":"Cannabis Hyperemesis Syndrome in Children: A Review of Epidemiology, Pathology, Diagnosis, and Treatment.","authors":"Ibia, Imikomobong E; Toce, Michael S","year":2025,"journal":"Pediatric emergency care, 41(5), 397-405","doi":"10.1097/PEC.0000000000003355","pmid":"40304055","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06709","title":"Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study.","authors":"Ibork, Hind; Lhaj, Zakaria Ait; Siddique, Farhan; El Idrissi, Sara; Khallouki, Farid; El Mernissi, Rafik; Hajji, Lhoussain; Khalki, Hanane; Bourhia, Mohammed; Salamatullah, Ahmad Mohammad; Mahamat, Ousman B; Taghzouti, Khalid; Abboussi, Oualid","year":2025,"journal":"Open life sciences, 20(1), 20251141","doi":"10.1515/biol-2025-1141","pmid":"40917785","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06710","title":"Cannabidiol-Rich Cannabis sativa L. Extract Alleviates LPS-Induced Neuroinflammation Behavioral Alterations, and Astrocytic Bioenergetic Impairment in Male Mice.","authors":"Ibork, Hind; Ait Lhaj, Zakaria; Boualam, Khadija; El Idrissi, Sara; B Ortaakarsu, Ahmet; Hajji, Lhoussain; Manalo Morgan, Annabelle; Khallouki, Farid; Taghzouti, Khalid; Abboussi, Oualid","year":2025,"journal":"Journal of neuroscience research, 103(4), e70035","doi":"10.1002/jnr.70035","pmid":"40195769","tags":["cbd","neuroscience","inflammation"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"At 20 mg/kg, CBD-rich cannabis extract was more effective than synthetic CBD in reducing LPS-induced anxiety-like behavior, cognitive deficits, and locomotor impairments in mice. The extract reduced oxidative stress (increased GSH, reduced TBARs), suppressed inflammatory cytokines (IL-6, TNF-alpha) and GFAP, modulated CB1 receptor expression, and preserved astrocyte metabolic homeostasis.","whyItMatters":"The finding that a whole cannabis extract outperformed pure CBD supports the \"entourage effect\" hypothesis and has implications for whether patients should use CBD isolates or full-spectrum products.","specificNumbers":"CBD-rich extract at 20.0 mg/kg showed superior efficacy to synthetic CBD. Computational modeling showed Delta-9-THC induced conformational changes in CB1 receptor residues that enhanced CBD binding.","methodology":"LPS-induced neuroinflammation mouse model. Behavioral tests (open field, elevated plus maze, novel object recognition, Morris water maze), antioxidant assays, RT-PCR for cytokines, and astrocytic bioenergetic analysis via extracellular flux assays. Computational modeling of CB1 receptor interactions.","limitations":"Mouse model of neuroinflammation may not translate to human neurodegenerative diseases. The extract contains multiple compounds, making it difficult to identify which are responsible for enhanced effects. Computational modeling does not confirm in vivo binding dynamics."},{"rthcId":"RTHC-06711","title":"The association between marijuana use and oral cancer risk: a systematic review and meta-analysis of case-control studies.","authors":"Ibrahim Mohammad, Suleiman; Vasudevan, Asokan; Jawad, Mahmood; Sapaev, I B; Khudhair Abbas Al-Khafaji, Zahraa; Prasad, Kdv; Fakri Mustafa, Yasser; Abdulrazzaq Gati, Mohannad; Ali Ahmed, Batool; Ebrahimi, Amirali","year":2025,"journal":"Journal of ethnicity in substance abuse, 1-19","doi":"10.1080/15332640.2025.2581692","pmid":"41236922","tags":["cancer"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Pooling six case-control studies (4,686 cases, 10,370 controls), marijuana use was associated with significantly lower oral cancer risk (OR=0.659, 95% CI: 0.500-0.869, p=0.003). Sensitivity analyses confirmed robustness (ORs 0.599-0.708). No clear dose-response relationship was observed. Three individual studies showed significant protective effects while three were non-significant.","whyItMatters":"Given that cannabis smoke contains many of the same carcinogens as tobacco smoke, a protective association with oral cancer is counterintuitive and demands further investigation into potential anti-tumor mechanisms.","specificNumbers":"6 studies, 4,686 cases, 10,370 controls. Pooled OR=0.659 (95% CI: 0.500-0.869, p=0.003). I2=47.35% (moderate heterogeneity). Sensitivity ORs ranged from 0.599 to 0.708. Egger test p=0.532 (no publication bias detected).","methodology":"Systematic review and meta-analysis following PRISMA guidelines. Searched Scopus, PubMed, Web of Science, and Embase through August 2025. Included only case-control studies with histologically confirmed oral cancer. Random-effects model with heterogeneity and publication bias assessment.","limitations":"All included studies were case-control (not cohort), which is more prone to recall and selection bias. Only six studies met inclusion criteria. Heterogeneity in how marijuana exposure was measured across studies. No dose-response relationship found. The authors themselves urge cautious interpretation."},{"rthcId":"RTHC-06712","title":"Cannabinoids in preclinical research of sepsis: a scoping review.","authors":"Inamassu, Carolina Henkes; Sordi, Regina; Marchioni, Camila","year":2025,"journal":"Inflammation research : official journal of the European Histamine Research Society ... [et al.], 74(1), 125","doi":"10.1007/s00011-025-02090-9","pmid":"40956450","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06713","title":"Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling.","authors":"Innocenzi, Elisa; Sciamanna, Giuseppe; Zucchi, Alice; Medici, Vanessa; Cesari, Eleonora; Farini, Donatella; Elliott, David J; Sette, Claudio; Grimaldi, Paola","year":2025,"journal":"Cells, 14(13)","doi":"10.3390/cells14130972","pmid":"40643493","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06714","title":"Prevention of Allodynia and Hyperalgesia by Cannabidiol in a Rat Model of Chemotherapy-Induced Peripheral Neuropathy.","authors":"Ippolito, Michael; Maddox, Charlie; Inam, Amal; Wimmer, Mathieu E; Ward, Sara Jane","year":2025,"journal":"Journal of visualized experiments : JoVE","doi":"10.3791/68079","pmid":"40622941","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06715","title":"Cannabinoid Distribution and Clearance in Feeding Spent Hemp Biomass to Dairy Cows and the Potential Exposure to Δ9-THC by Consuming Milk.","authors":"Irawan, Agung; Nosal, Daniel G; Muchiri, Ruth N; van Breemen, Richard B; Ates, Serkan; Cruickshank, Jenifer; Ranches, Juliana; Estill, Charles T; Thibodeau, Alyssa; Bionaz, Massimo","year":2025,"journal":"Journal of agricultural and food chemistry, 73(22), 13934-13948","doi":"10.1021/acs.jafc.5c02827","pmid":"40393136","tags":["medical-cannabis"],"studyType":"animal study","evidenceStrength":"moderate","keyFinding":"Less than 1% of cannabinoids from spent hemp biomass transferred to cow milk, but THC levels in milk still exceeded the acute reference dose of 1 ug/kg body weight for human consumers. THC accumulated heavily in adipose tissue and remained detectable there 30 days after withdrawal. CBD and CBDA were detectable in plasma 90 days after hemp withdrawal (post-calving). Milk THC became undetectable after 12 days of hemp withdrawal.","whyItMatters":"Spent hemp biomass has excellent nutritional value as livestock feed but is banned in most countries due to THC concerns. This study quantifies the actual risk and identifies a practical withdrawal period that eliminates consumer exposure.","specificNumbers":"Less than 1% cannabinoid transfer to milk. THC in milk exceeded acute reference dose of 1 ug/kg BW during feeding. THC undetectable in milk after 12 days withdrawal. THC detectable in adipose tissue 30 days after withdrawal. CBD/CBDA detectable in plasma 90 days after withdrawal.","methodology":"Dairy cows fed spent hemp biomass (cannabinoid extraction byproduct). Cannabinoids measured in milk, blood, and tissues using UHPLC-MS/MS at multiple timepoints during feeding and after withdrawal.","limitations":"Small number of animals typical for dairy feeding studies. THC accumulation in adipose tissue raises questions about meat safety. 90-day CBD persistence in plasma is unexplained. Specific SHB composition may vary between sources."},{"rthcId":"RTHC-06716","title":"Use of industrial hemp byproducts in ruminants: a review of the nutritional profile, animal response, constraints, and global regulatory environment.","authors":"Irawan, Agung; Buffington, Hunter; Ates, Serkan; Bionaz, Massimo","year":2025,"journal":"Journal of cannabis research, 7(1), 25","doi":"10.1186/s42238-025-00279-7","pmid":"40369700","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06717","title":"Cannabis-Induced Cardiac Arrest in a Young Adult: A Case Report.","authors":"Irshad, Sana; Adrejiya, Parth; Abubaker, Mohammad; Adatsi, Theophilus; Idenyi, Oluchi; Maddika, Srikanth; Gorle, Swathi; Thandra, Abhishek; Chennareddy, Srinivasa R","year":2025,"journal":"The American journal of case reports, 26, e950077","doi":"10.12659/AJCR.950077","pmid":"40975879","tags":["cardiovascular"],"studyType":"case report","evidenceStrength":"very low","keyFinding":"A 26-year-old chronic cannabis user presented with sudden cardiac arrest. Initial rhythm was ventricular fibrillation. QTc interval was prolonged at 483 ms. Urine drug screen was positive for THC. Cardiac catheterization at 4 weeks showed normal coronary arteries. Left ventricular ejection fraction, initially reduced to 25-30%, normalized by catheterization. She sustained hypoxic-ischemic brain injury requiring prolonged rehabilitation.","whyItMatters":"As cannabis use expands, clinicians need to consider cannabis-induced cardiotoxicity in young patients presenting with cardiac arrest or arrhythmias, especially when no other risk factors are identified.","specificNumbers":"Age 26. QTc 483 ms. Initial LVEF 25-30%, later normalized. Normal coronary arteries. Only THC positive on drug screen.","methodology":"Single case report with ECG, cardiac catheterization, urine drug screen, and clinical follow-up.","limitations":"Single case report cannot establish causation. QTc prolongation has many potential causes. No pre-existing ECG available for comparison. Cannabis use may be coincidental rather than causal."},{"rthcId":"RTHC-06718","title":"Beyond potency: A proposed lexicon for sensory differentiation of Cannabis sativa L. aroma.","authors":"Isaacson, Solomon E; Wilson-Poe, Adrianne R; Ye, Tingting; Qian, Yanping L; Shellhammer, Thomas H","year":2025,"journal":"PloS one, 20(10), e0335125","doi":"10.1371/journal.pone.0335125","pmid":"41118398","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06719","title":"Short-term repeated oral intake of low dose cannabidiol: effects on liver enzyme activity and creatinine concentration during intense exercise.","authors":"Isenmann, Eduard; Lachenmeier, Dirk W; Flenker, Ulrich; Lesch, Alessio; Veit, Sebastian; Diel, Patrick","year":2025,"journal":"Archives of toxicology, 99(2), 815-824","doi":"10.1007/s00204-024-03904-1","pmid":"39630203","tags":["cbd","exercise"],"studyType":"randomized controlled trial","evidenceStrength":"moderate","keyFinding":"In a three-arm crossover RCT, exercise significantly increased liver enzymes GOT and GPT in placebo groups. Both CBD oil and CBD solubilisate at 60 mg/day for 7 days significantly blunted these increases in the advanced athlete group (GOT: p=0.050 and p=0.027; GPT: p=0.027 and p=0.023). These effects were not observed in highly advanced athletes. No hepatotoxic effects were detected.","whyItMatters":"CBD is widely used by athletes but concerns about liver safety persist. This study provides evidence that low-dose CBD (below the 300 mg LOAEL threshold) is not hepatotoxic and may actually protect against exercise-induced liver stress.","specificNumbers":"17 subjects, 60 mg CBD daily for 7 days. GOT reduction: CBD oil p=0.050 (ES=0.66), CBD solu p=0.027 (ES=0.75). GPT reduction: CBD oil p=0.027 (ES=0.75), CBD solu p=0.023 (ES=0.77). Effects seen in advanced but not highly advanced athletes.","methodology":"Randomized, three-arm, double-blind, crossover study with 17 well-trained male subjects (age 26, 85.6 kg). Two CBD products (oil and solubilisate, 60 mg each) versus placebo, consumed daily over 7 days during high-intensity exercise microcycles. Liver enzymes (GOT, GPT, GGT) and creatinine measured pre and post each microcycle.","limitations":"Small sample (n=17), all male. Effects only seen in advanced but not highly advanced athletes, suggesting fitness-dependent responses. Short duration (7 days). Crossover design helps but washout period adequacy is unclear."},{"rthcId":"RTHC-06720","title":"Gambling disorder in a university hospital setting: a retrospective analysis of patient characteristics.","authors":"Isman Haznedaroglu, Damla; Gorkem, Okan; Degirmenci, Ozgur","year":2025,"journal":"Frontiers in psychiatry, 16, 1723070","doi":"10.3389/fpsyt.2025.1723070","pmid":"41727402","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06721","title":"Adolescents and cannabis in the 21st century: Current Problems in Pediatric and Adolescent Health Care.","authors":"Itriyeva, Khalida","year":2025,"journal":"Current problems in pediatric and adolescent health care, 55(3), 101754","doi":"10.1016/j.cppeds.2025.101754","pmid":"40581515","tags":["youth","addiction","mental-health","cognition","psychosis","potency"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This comprehensive review covers three decades of adolescent cannabis trends in the United States, and the picture it paints is more complicated than either \"legalization is harmless\" or \"legalization is catastrophic\" narratives suggest.\n\nTeenage use rates have remained remarkably stable despite legalization. But the harms landscape has shifted. Emergency department visits related to cannabis have increased, as have unintentional ingestions by young children—driven largely by edibles and concentrates that look like candy or food. The products themselves have changed dramatically: THC concentrations in cannabis have risen steadily, and concentrates can reach 80–90% THC, far beyond anything available a generation ago.\n\nThe review highlights several clinical concerns. Cannabis intoxication in youth presents with altered mental status, drowsiness, anxiety or euphoria, rapid heart rate, and red eyes. Cannabinoid hyperemesis syndrome (CHS)—characterized by cyclic vomiting in heavy users—should be considered in adolescents with unexplained vomiting. Long-term heavy use is associated with cognitive impairment, increased psychosis risk, and cannabis use disorder, with adolescent brains being particularly vulnerable.\n\nThe authors call for ongoing surveillance, public education, and regulatory efforts to limit youth access—particularly to high-potency products.","whyItMatters":"This review puts individual study findings into a broader developmental context. While studies like RTHC-00163 examine specific outcomes (psychotic experiences) and RTHC-00154/00156 look at specific interventions (cessation programs), this review connects the dots: stable use rates don't mean stable risk, because the products teens encounter today are fundamentally different from those of previous decades.","specificNumbers":"THC content in cannabis products has increased steadily over 30 years. Concentrates can reach 80–90% THC. Cannabis-related ED visits, hospitalizations, and unintentional child ingestions have all increased. Teen use rates have remained relatively stable despite legalization.","methodology":"Narrative review synthesizing published literature on adolescent cannabis use trends, clinical presentations, health effects, and policy implications across approximately 30 years of U.S. data.","limitations":"Narrative reviews are subject to selection bias in which studies are highlighted. The stable-use-rate claim depends on survey methodology that may miss changes in use patterns (frequency, potency, product type) even when prevalence stays flat. The review focuses on U.S. data and may not apply globally."},{"rthcId":"RTHC-06722","title":"Prevalence of Cannabidiol (CBD) Use in an Outpatient Hand Surgery Clinic.","authors":"Iturregui, Jose M; Deckey, David G; Ishimoto, Alyssa; Renfree, Sean P; Noland, Shelley S; Renfree, Kevin J","year":2025,"journal":"Orthopedics, 48(6), 329-335","doi":"10.3928/01477447-20250904-01","pmid":"41114690","tags":["cbd","pain"],"studyType":"cross-sectional survey","evidenceStrength":"low","keyFinding":"15% of hand surgery patients (135/918) reported prior CBD use. Only 39% of CBD users (53/135) perceived pain relief. CBD users were more likely to be female (65% vs 51%), have wrist pathology (44% vs 35%), and have arthritis (36% vs 19%). CBD users reported significantly higher pain and worse function than non-users.","whyItMatters":"CBD products are widely marketed for pain, but this real-world clinic data suggests most hand/upper extremity patients who try CBD do not find it beneficial, and those who use it tend to have more severe conditions.","specificNumbers":"918 patients surveyed (53% female, mean age 63). 15% (135/918) used CBD. 39% (53/135) of users reported pain relief. CBD users: 65% female vs 51% non-users (p=0.003). CBD users had higher arthritis rates (36% vs 19%, p<0.001).","methodology":"Survey of 918 new patients at an orthopedic hand and upper extremity clinic (July-December 2022). Pain measured with Numeric Pain Rating Scale, function with Single Assessment Numeric Evaluation. Demographics and diagnoses from chart review.","limitations":"Cross-sectional design cannot determine if CBD caused, worsened, or failed to improve outcomes. CBD product type, dose, and duration of use were not standardized. Self-reported pain relief is subjective. Older patient population (mean 63) at a surgical clinic may not represent broader CBD users."},{"rthcId":"RTHC-06723","title":"Increasing trends of cannabinoid hyperemesis syndrome in youth: The grass is not always greener.","authors":"Jack, Benjamin; Susi, Apryl; Reeves, Patrick; Nylund, Cade M","year":2025,"journal":"Journal of pediatric gastroenterology and nutrition, 80(4), 638-643","doi":"10.1002/jpn3.12469","pmid":"39868747","tags":["youth","harm-reduction"],"studyType":"retrospective cohort","evidenceStrength":"moderate","keyFinding":"Using the Nationwide Emergency Room Sample, over 55,000 suspected CHS-related ED visits were identified among youth (ages 15-24) between 2006 and 2020, with an average annual increase of 28.1%. Males, those in the western U.S., and those with public insurance were more likely to present with suspected CHS.","whyItMatters":"The rapid growth in CHS-related ER visits among young people parallels rising cannabis potency and use rates, highlighting an emerging clinical burden that emergency departments need to prepare for.","specificNumbers":"Over 55,000 suspected CHS-related ED visits identified. Average annual increase of 28.1% per year from 2006 to 2020. Higher rates in males, western U.S., and public insurance holders.","methodology":"Retrospective analysis of the Nationwide Emergency Room Sample (2006-2020) identifying suspected CHS-related visits among youth aged 15-24.","limitations":"Uses suspected rather than confirmed CHS cases, which may include other causes of cyclic vomiting. Administrative data lacks clinical detail. Cannot confirm cannabis use patterns in individual patients. ICD coding changes over the study period may affect trends."},{"rthcId":"RTHC-06724","title":"The Anticonvulsant Effects of Different Cannabis Extracts in a Zebrafish Model of Epilepsy.","authors":"Jackson, Karen; Shabat-Simon, Maytal; Bar-On, Jonathan; Steckler, Rafi; Khatib, Soliman; Tamir, Snait; Pitashny, Paula Adriana","year":2025,"journal":"Biomolecules, 15(5)","doi":"10.3390/biom15050654","pmid":"40427547","tags":["cbd","epilepsy"],"studyType":"preclinical study","evidenceStrength":"low","keyFinding":"In a PTZ-induced zebrafish seizure model, 5.7 ug/mL of pure CBD and 10 ug/mL of various cannabis extracts both significantly reduced hyperactivity compared to both PTZ alone and the standard anti-epileptic drug valproic acid. Effective extracts achieved similar results to pure CBD despite containing much lower CBD concentrations, supporting a possible entourage effect.","whyItMatters":"If whole cannabis extracts can match or exceed pure CBD for seizure control at lower doses, this could make treatment more accessible and potentially reduce side effects associated with high CBD doses.","specificNumbers":"5.7 ug/mL pure CBD and 10 ug/mL extracts both significantly reduced movement. Effective extracts contained much lower CBD levels than the pure CBD comparison. Three strains tested with three extraction methods each.","methodology":"Pentylenetetrazole (PTZ)-induced hyperactivity model in zebrafish larvae. Three cannabis strains tested with three different extraction methods each. Results benchmarked against pure CBD and valproic acid (VPA).","limitations":"Zebrafish model is a basic screening tool with limited translation to mammalian or human epilepsy. PTZ-induced hyperactivity is not identical to seizures. Extract composition varies with strain and extraction method. Cannot identify which non-CBD compounds contribute to efficacy."},{"rthcId":"RTHC-06725","title":"Multilevel Correlates of Same Day Poly-Product Use/Co-Use among Adolescents Who Use Tobacco and Cannabis.","authors":"Jacobs, Wura; Qin, Weisiyu A; Jafarzadeh, Nikki S; Barrington-Trimis, Jessica; Leventhal, Adam M","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 28(1), 26-35","doi":"10.1093/ntr/ntaf150","pmid":"40684795","tags":["youth","addiction"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Among 536 10th and 11th graders who used tobacco/cannabis, 8.6% reported frequent same-day poly-tobacco use, 13.8% frequent poly-cannabis use, 13.3% frequent poly-drug use, and 3.4% vape mixing. Past 30-day alcohol use was associated with 1.88-8.31x higher odds of same-day poly-use. Secondhand smoke/vapor exposure consistently predicted higher odds (1.13-1.26x) across all patterns.","whyItMatters":"Same-day poly-product use carries higher health risks than single-product use. Identifying that alcohol and environmental smoke exposure are key drivers suggests specific intervention targets.","specificNumbers":"536 students (66.2% Hispanic, 62.5% male). Frequent same-day poly-tobacco: 8.6%. Poly-cannabis: 13.8%. Poly-drug: 13.3%. Vape mixing: 3.4%. Alcohol use OR range: 1.88-8.31 (p<0.05). Secondhand exposure OR range: 1.13-1.26 (p<0.05).","methodology":"Cross-sectional survey of 536 10th/11th grade students (predominantly Hispanic, 62.5% male) who reported tobacco or cannabis use. Regression models examined intrapersonal, psychological, societal, and environmental correlates of same-day poly-product use frequency.","limitations":"Cross-sectional design. Predominantly Hispanic sample from Southern California may not generalize. Self-reported substance use. Only current users were included, creating a selected sample. Cannot determine whether alcohol causes poly-use or if both reflect a common underlying factor."},{"rthcId":"RTHC-06726","title":"Diversity in adversity: Racial/ethnic differences in the relationship between domains of adverse childhood experiences and nicotine, cannabis, and opioids use in young adults.","authors":"Jacobs, Wura; Bristow, Alane; Sajan, Sandiya; Lowry, Veronica; Leventhal, Adam","year":2025,"journal":"Journal of ethnicity in substance abuse, 24(4), 829-849","doi":"10.1080/15332640.2023.2280092","pmid":"41335472","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Among 2,207 young adults, significant racial/ethnic differences existed in overall ACE scores and household dysfunction. Different ACE domains (neglect, abuse, household dysfunction) predicted different substance use patterns (nicotine, cannabis, opioids) depending on the racial/ethnic group, suggesting one-size-fits-all prevention approaches may miss important variations.","whyItMatters":"Understanding that childhood adversity affects substance use differently across racial groups can inform culturally tailored prevention programs rather than generic interventions.","specificNumbers":"2,207 young adults, mean age 21.84. Significant racial/ethnic differences in overall ACE scores and household dysfunction. Different ACE domains predicted different substance use patterns by race/ethnicity.","methodology":"Cross-sectional analysis of 2,207 young adults (mean age 21.84). Multivariable regression examining associations between three ACE domains and nicotine, cannabis, and opioid use/co-use across racial/ethnic groups.","limitations":"Cross-sectional design. Self-reported ACEs and substance use. Combining diverse groups within broad racial/ethnic categories may obscure within-group variation. Cannot establish causation."},{"rthcId":"RTHC-06727","title":"Substance use and disordered eating risk among college students with obsessive-compulsive conditions.","authors":"Jacobs, Wura; DeLeon, Angela; Bristow, Alane; Quinn, Patrick; Lederer, Alyssa","year":2025,"journal":"PloS one, 20(1), e0316349","doi":"10.1371/journal.pone.0316349","pmid":"39746071","tags":["mental-health","addiction"],"studyType":"cross-sectional survey","evidenceStrength":"high","keyFinding":"Among 92,757 undergraduates, OCD conditions were associated with increased odds of moderate/high-risk tobacco (aOR=1.12), cannabis (aOR=1.11), alcohol (aOR=1.14), and disordered eating (aOR=2.28). Effects persisted after adjusting for stress, depression, and anxiety. Gender differences emerged: cis-female students with OCD had elevated risk across all substances, while male students only showed increased disordered eating risk.","whyItMatters":"OCD is increasingly recognized in young adults, and understanding its association with substance use can help college health services screen for and address these co-occurring risks.","specificNumbers":"92,757 students from 216 colleges. OCD and cannabis: aOR=1.11 (95% CI 1.04-1.18). OCD and alcohol: aOR=1.14 (95% CI 1.05-1.24). OCD and tobacco: aOR=1.12 (95% CI 1.05-1.21). OCD and disordered eating: aOR=2.28 (95% CI 2.13-2.43). TGNC students with OCD: aOR=1.24 for tobacco, aOR=2.14 for disordered eating.","methodology":"Analysis of 92,757 undergraduate students aged 18-24 from 216 colleges using the ACHA-NCHA III (Fall 2021-Fall 2022). Regression models adjusted for covariates and school clustering.","limitations":"Cross-sectional design. Self-reported OCD conditions may include subclinical presentations. College students may not represent all young adults. Cannot determine if OCD drives substance use or vice versa."},{"rthcId":"RTHC-06728","title":"Assessment of nicotine and cannabis co-use among adolescents and the association with nicotine and cannabis dependence symptoms.","authors":"Jafarzadeh, Nikki S; Harlow, Alyssa F; Walsh, Claire A; Whaley, Reid C; Han, Dae-Hee; Leventhal, Adam M; Barrington-Trimis, Jessica L","year":2025,"journal":"Addictive behaviors, 171, 108471","doi":"10.1016/j.addbeh.2025.108471","pmid":"40886685","tags":["youth","addiction"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Among 3,823 Southern California high school students, 3.3% reported same-day nicotine-cannabis co-use. Same-day co-users had 4.28 times the odds of cannabis dependence symptoms (95% CI: 1.98-9.28) compared to those who used both substances in the same month but not on the same day. Odds of nicotine dependence were also elevated (aOR=1.81) but not statistically significant.","whyItMatters":"This study demonstrates that how researchers measure co-use matters. Same-day co-use appears to be a marker of more problematic behavior than simply using both substances within the same month.","specificNumbers":"3,823 students. 3.3% same-day co-use, 1.5% past-month co-use, 1.6% exclusive nicotine, 3.1% exclusive cannabis, 90.5% no use. Same-day vs past-month co-use: cannabis dependence aOR=4.28 (95% CI: 1.98-9.28). Nicotine dependence aOR=1.81 (95% CI: 0.87-3.77, NS).","methodology":"Cross-sectional survey of 3,823 Southern California high school students in Fall 2022. Five mutually exclusive past-month use groups. Adjusted logistic regression models for nicotine and cannabis dependence symptoms.","limitations":"Cross-sectional design. Southern California sample may not generalize. Self-reported use and dependence symptoms. Small absolute numbers in co-use groups limit statistical power. Cannot determine if same-day use causes dependence or if more dependent users are more likely to co-use."},{"rthcId":"RTHC-06729","title":"Associations between big five personality dimensions and lifetime use of cannabis.","authors":"Jain, Tanya; Patriquin, Michelle; Sanches, Marsal","year":2025,"journal":"The American journal on addictions, 34(3), 322-326","doi":"10.1111/ajad.13668","pmid":"39555836","tags":["addiction","mental-health"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Patients with lifetime CUD scored significantly lower on conscientiousness and agreeableness and higher on open-mindedness compared to those without CUD, after controlling for age, sex, and other substance use disorders. Extraversion and neuroticism were not significantly associated with CUD.","whyItMatters":"Identifying personality profiles associated with CUD risk could help target prevention efforts and inform treatment approaches that address underlying personality dimensions.","specificNumbers":"1,335 inpatients. Low conscientiousness, low agreeableness, and high open-mindedness significantly associated with CUD. Extraversion and neuroticism not significantly associated. Analysis controlled for age, sex, and other substance use disorders.","methodology":"Cross-sectional study of 1,335 inpatients at The Menninger Clinic (September 2016-December 2021). Personality assessed with Big Five Inventory. CUD diagnosed via SCID-5. Analysis of covariance with age, sex, and other substance use as covariates.","limitations":"Inpatient psychiatric sample may not represent community cannabis users. Cross-sectional design cannot determine if personality traits preceded CUD. Big Five traits are broad constructs that may miss more specific vulnerability factors. Cannot distinguish recreational use from disorder."},{"rthcId":"RTHC-06730","title":"A simple, sensitive and rapid bioanalytical method for quantifying cannabidiol (CBD), 7-OH-CBD and 7-COOH-CBD in human plasma.","authors":"Jaisupa, Nattapon; Ashton, Michael; Birgersson, Sofia","year":2025,"journal":"Bioanalysis, 17(24), 1719-1730","doi":"10.1080/17576180.2026.2612921","pmid":"41508948","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06731","title":"Smoked or Bewitched? The Relationship Between Cannabis Use and Mental Illness Among the Shona Persons in Zimbabwe.","authors":"Jakarasi, Maja","year":2025,"journal":"Culture, medicine and psychiatry, 49(3), 689-705","doi":"10.1007/s11013-025-09898-4","pmid":"40042737","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06732","title":"Synthetic cannabinoid receptor agonists exacerbate fentanyl-elicited respiratory depression and confer resistance to naloxone rescue in mice.","authors":"James, Jared C; Thrush, Jessica R; Yusufali, Taher M; Shaw, Hannah E; Avram, Marina; Moran, Jeffery H; Fantegrossi, William E","year":2025,"journal":"Drug and alcohol dependence, 272, 112672","doi":"10.1016/j.drugalcdep.2025.112672","pmid":"40319790","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"animal study","evidenceStrength":"moderate","keyFinding":"Co-administration of fentanyl with synthetic cannabinoids (JWH-018 or 5F-ADB-PINACA) exacerbated respiratory depression beyond either drug alone. Critically, these combinations conferred resistance to naloxone rescue. Neither naloxone nor the CB1 antagonist rimonabant alone fully reversed the combined respiratory depression. The interaction appeared to involve both pharmacodynamic (receptor-level) and pharmacokinetic (blood-level) mechanisms.","whyItMatters":"Synthetic cannabinoids are frequently found as adulterants in street opioids, and fentanyl is found in synthetic cannabinoid products. This study provides a biological explanation for the growing phenomenon of naloxone-resistant overdoses.","specificNumbers":"Two SCRAs tested: JWH-018 (naphthyl indole) and 5F-ADB-PINACA (indazole carboxamide). Tolerance developed to JWH-018 but not 5F-ADB-PINACA respiratory effects. Naloxone rescued fentanyl-only respiratory depression but not SCRA-fentanyl combinations.","methodology":"Whole body plethysmography in mice measuring respiratory rate after acute and chronic administration of fentanyl, two structurally distinct synthetic cannabinoids, and their combinations. Antagonist rescue studies with naloxone, rimonabant, and both combined. Blood sampling at peak respiratory depression for pharmacokinetic analysis.","limitations":"Mouse model may not perfectly predict human overdose pharmacology. Specific SCRA-fentanyl ratios used may not reflect street drug compositions. Only two SCRAs tested among hundreds of circulating compounds. Pharmacokinetic interactions were suggested but not fully characterized."},{"rthcId":"RTHC-06733","title":"Evaluation of DrugWipe® 6S with the WipeAlyser® reader for drug screening of drivers.","authors":"Jamt, Ragnhild Elén Gjulem; Gjerde, Hallvard; Clausen, Grethe Brennhovd; Bache-Andreassen, Lihn; Øiestad, Elisabeth Leere","year":2025,"journal":"Journal of analytical toxicology, 49(7), 442-449","doi":"10.1093/jat/bkaf028","pmid":"40354046","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06734","title":"Cannabis sativa Root Extract Exerts Anti-Nociceptive and Anti-Inflammatory Effects via Endocannabinoid Pathway Modulation In Vivo and In Vitro.","authors":"Jang, Seo-Yul; Jin, Hye-Lin; Yu, Ga-Ram; Lim, Dong-Woo; Park, Won-Hwan","year":2025,"journal":"International journal of molecular sciences, 26(18)","doi":"10.3390/ijms26188863","pmid":"41009431","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06735","title":"Words versus Strands: Reliability and Stability of Concordance Rates of Self-Reported and Hair-Analyzed Substance Use of Young Adults over Time.","authors":"Janousch, Clarissa; Eggenberger, Lukas; Steinhoff, Annekatrin; Johnson-Ferguson, Lydia; Bechtiger, Laura; Loher, Michelle; Ribeaud, Denis; Eisner, Manuel; Baumgartner, Markus R; Binz, Tina M; Shanahan, Lilly; Quednow, Boris B","year":2025,"journal":"European addiction research, 31(1), 60-74","doi":"10.1159/000541713","pmid":"39561726","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06736","title":"Role of ketamine in the treatment of substance use disorders: A systematic review.","authors":"Janssen-Aguilar, Reinhard; Meshkat, Shakila; Demchenko, Ilya; Zhang, Yanbo; Greenshaw, Andrew; Dunn, Walter; Tanguay, Robert; Mayo, Leah M; Swainson, Jennifer; Jetly, Rakesh; Bhat, Venkat","year":2025,"journal":"Journal of substance use and addiction treatment, 175, 209705","doi":"10.1016/j.josat.2025.209705","pmid":"40320049","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06737","title":"Cannabidiol attenuates diet-induced metabolic endotoxemia, neuroinflammation, and anxiety-like behaviors in male aged rats.","authors":"Jantsch, Jeferson; Rodrigues, Fernanda da Silva; Wickert, Fernanda; Fraga, Gabriel de Farias; Dias, Victor Silva; Bitencourt, Yasmin Meireles; Giovenardi, Márcia; Guedes, Renata Padilha","year":2025,"journal":"Brain, behavior, and immunity, 130, 106121","doi":"10.1016/j.bbi.2025.106121","pmid":"41022293","tags":["cbd","anxiety","inflammation"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"Cafeteria diet increased anxiety-like behaviors, circulating LPS (endotoxemia), and prefrontal cortex IL-6 in 18-month-old rats. CBD (15 mg/kg/day orally) reduced anxiety in the open field test, decreased circulating LPS, and reduced prefrontal cortex IL-6, TNF-alpha, and TLR4 expression. The obesogenic diet also disrupted endocannabinoid levels (2-AG and anandamide) and altered CB1/CB2 receptor expression in the brain.","whyItMatters":"Obesity and aging together create a neuroinflammatory state that drives anxiety and cognitive decline. Finding that CBD can address this intersection is relevant given the aging population and obesity epidemic.","specificNumbers":"CBD dose: 15 mg/kg/day orally. Rats aged 18 months. CBD reduced circulating LPS, IL-6, TNF-alpha, and TLR4 in prefrontal cortex. Cafeteria diet reduced 2-AG and anandamide and altered CB1/CB2 expression.","methodology":"Four groups of 18-month-old male Wistar rats: control+vehicle, control+CBD, cafeteria diet+vehicle, cafeteria diet+CBD. Diets for 8 weeks, then oral CBD (15 mg/kg/day) or vehicle concurrently for additional weeks. Behavioral tests, cytokine analysis, endocannabinoid measurements, and receptor expression assessed.","limitations":"Male rats only. Cafeteria diet model is extreme compared to typical human diets. CBD dose relative to human equivalent dosing needs consideration. 18-month-old rats represent late middle age, not elderly. No long-term safety data."},{"rthcId":"RTHC-06738","title":"The Regulatory Environment Surrounding Cannabis Medicines in the EU, the USA, and Australia.","authors":"Jardim, Claudia; Delgado-Charro, M Begoña","year":2025,"journal":"Pharmaceutics, 17(5)","doi":"10.3390/pharmaceutics17050635","pmid":"40430926","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06739","title":"Optimization, Kinetics, and Thermodynamics of Ultrasound-Assisted Extraction of Phytochemicals from Hemp.","authors":"Jaroenkunpanit, Pinyada; Wungsintaweekul, Juraithip; Chetpattananondh, Pakamas","year":2025,"journal":"ACS omega, 10(39), 45729-45747","doi":"10.1021/acsomega.5c06069","pmid":"41078763","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06740","title":"Cannabidiol Reduces D1 and D2 Medium Spiny Neuron Excitability in the Nucleus Accumbens Core.","authors":"Jarrett, Zev E; Grueter, Brad A","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.64898/2025.12.02.691956","pmid":"41409154","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06741","title":"Effect of intraperitoneal cannabidiol (CBD) injection on intestine microbiome profile in a mouse model.","authors":"Jasielczuk, Igor; Ocłoń, Ewa; Żurowski, Jakub; Szmatoła, Tomasz; Mizera-Szpilka, Karolina; Gurgul, Artur","year":2025,"journal":"Current genetics, 71(1), 21","doi":"10.1007/s00294-025-01327-8","pmid":"41028669","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06742","title":"Recent Advances in the Therapeutic Potential of Cannabinoids Against Gliomas: A Systematic Review (2022-2025).","authors":"Javid, Farideh A; Belancic, Andrej; Kwok, Man Ki; Lam, Yun Wah","year":2025,"journal":"Pharmacology research & perspectives, 13(4), e70160","doi":"10.1002/prp2.70160","pmid":"40781861","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06743","title":"Impact of medical and recreational cannabis laws on inpatient visits for asthma.","authors":"Jayawardhana, Jayani; Fernandez, Jose","year":2025,"journal":"Health services research, 60(3), e14427","doi":"10.1111/1475-6773.14427","pmid":"39739251","tags":["respiratory","legalization"],"studyType":"quasi-experimental","evidenceStrength":"moderate","keyFinding":"States with medical cannabis dispensaries experienced a 14.12% increase in inpatient asthma visits compared to states without. States with recreational cannabis legalization saw a 20.45% increase. These increases were primarily driven by Medicare and privately insured populations. Simple passage of medical cannabis laws or home cultivation allowances did not significantly affect asthma hospitalizations.","whyItMatters":"While cannabis legalization debates focus on addiction and mental health, this study highlights an underappreciated respiratory consequence that carries substantial healthcare costs.","specificNumbers":"Medical cannabis dispensaries: +14.12% asthma hospitalizations (2.14 per 100k; 95% CI: 0.74-3.53; p<0.01). Recreational cannabis: +20.45% increase (3.08 per 100k; 95% CI: 1.47-4.69; p<0.001). Effects larger in Medicare populations. No significant effects from law passage or home cultivation alone.","methodology":"Difference-in-differences regression analysis using state-level quarterly inpatient visit data from the HCUP Fast Stats database (2005-2017). Compared asthma hospitalizations in 38 states before and after implementation of four types of cannabis laws, with analyses stratified by payer type.","limitations":"Ecological study cannot confirm individual-level cannabis use caused asthma hospitalizations. Other state-level changes may confound results. 2005-2017 timeframe precedes widespread vaping. Cannot distinguish between patient cannabis use and secondhand exposure."},{"rthcId":"RTHC-06744","title":"Association of State Cannabis Legalization With Cannabis Use Disorder and Cannabis Poisoning.","authors":"Jayawardhana, Jayani; Hou, Jialin; Freeman, Patricia; Talbert, Jeffery C","year":2025,"journal":"JAMA psychiatry, 82(3), 228-236","doi":"10.1001/jamapsychiatry.2024.4145","pmid":"39714863","tags":["legalization","addiction"],"studyType":"longitudinal cohort","evidenceStrength":"high","keyFinding":"Among 110 million commercially insured adults (2011-2021), medical cannabis laws were associated with increases of 31.09 CUD diagnoses and 0.76 cannabis poisoning diagnoses per 100,000 enrollees per quarter. Recreational cannabis laws were associated with 0.34 additional cannabis poisoning diagnoses per quarter. CUD increases were larger among women and adults aged 35-44. Opening medical dispensaries or allowing home cultivation did not show significant independent effects.","whyItMatters":"Published in JAMA Psychiatry, this is one of the largest and most rigorous studies linking cannabis policy changes to clinical diagnoses, using claims data from over 110 million commercially insured adults.","specificNumbers":"110,256,536 enrollees (52% female, mean age 41.0). MCL: +31.09 CUD diagnoses (95% CI: 20.20-41.99; p<0.001) and +0.76 poisoning (95% CI: 0.52-1.00; p<0.001) per 100k/quarter. RCL: +0.34 poisoning (95% CI: 0.19-0.48; p<0.001). CUD increases larger in women and ages 35-44.","methodology":"Staggered adoption difference-in-differences analysis using the Merative MarketScan Commercial Claims database (2011-2021) across all 50 states and DC. Event studies estimated magnitude by year-quarter relative to policy implementation. Subgroup analyses by sex and age.","limitations":"Commercially insured population may not represent uninsured or Medicaid populations. Cannot distinguish whether increased diagnoses reflect more CUD or more clinical detection due to reduced stigma. Claims data may include coding changes over time. Sensitivity analysis confirmed results held when excluding COVID-era data."},{"rthcId":"RTHC-06745","title":"Oil-based and oil-free formulations for enhancing cannabidiol bioavailability.","authors":"Jelínek, Petr; Klouček, Anežka; George, Ashley Hannah; Housar, Hynek; Kozlík, Petr; Křížek, Tomáš; Ryšánek, Pavel; Šíma, Martin; Slanař, Ondřej; Šoóš, Miroslav","year":2025,"journal":"Journal of cannabis research, 8(1), 5","doi":"10.1186/s42238-025-00371-y","pmid":"41331788","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06746","title":"Cannabidiol interactions with Δ-9-tetrahydrocannabinol on antinociception after carrageenan-induced inflammatory pain in male and female rats.","authors":"Jenkins, Bryan W; Moore, Catherine F; Weerts, Elise M","year":2025,"journal":"The Journal of pharmacology and experimental therapeutics, 392(7), 103625","doi":"10.1016/j.jpet.2025.103625","pmid":"40609153","tags":["pain","cbd","sex-differences"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"Oral THC dose-dependently decreased hyperalgesia and allodynia in a carrageenan inflammatory pain model, with stronger effects in females than males. The lowest THC dose (1 mg/kg) was actually pro-inflammatory in males. CBD alone did not affect pain sensitivity but had modest anti-inflammatory effects in males. When combined, CBD diminished THC antinociception (subadditive interaction), suggesting THC alone is superior to THC+CBD for acute inflammatory pain.","whyItMatters":"Many cannabis pain products contain both THC and CBD, assuming they work synergistically. This study challenges that assumption for inflammatory pain, suggesting pure THC formulations may be more effective.","specificNumbers":"THC doses: 1, 3, 10 mg/kg oral. CBD doses: 10, 30, 100 mg/kg oral. THC antinociception was greater in females than males. THC 1 mg/kg was pro-inflammatory in males. CBD+THC interaction was subadditive by isobolographic analysis.","methodology":"Male and female Sprague-Dawley rats (n=10-14 per sex/group) received oral pretreatment with vehicle, THC (1, 3, 10 mg/kg), CBD (10, 30, 100 mg/kg), or THC+CBD combinations 1 hour before carrageenan injection. Edema, thermal hyperalgesia, and mechanical allodynia measured at 1, 3, and 5 hours. Isobolographic and dose addition analyses assessed interaction type.","limitations":"Rat model of acute inflammatory pain may not translate to chronic pain conditions. Oral administration through gavage differs from human cannabis consumption. Only acute (pretreatment) effects studied. Specific THC:CBD ratios tested may not reflect commercial product ratios."},{"rthcId":"RTHC-06747","title":"Prenatal cannabinoid exposure and the developing brain: Evidence of lasting consequences in preclinical rodent models.","authors":"Jenkins, Bryan W; Moore, Catherine F; Jantzie, Lauren L; Weerts, Elise M","year":2025,"journal":"Neuroscience and biobehavioral reviews, 175, 106207","doi":"10.1016/j.neubiorev.2025.106207","pmid":"40373945","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06748","title":"Typologies of Maternal Substance Use in Pregnancy: Latent Classes and Sociodemographic Correlates in a U.S. Sample.","authors":"Jenkins, Marina C; Ehrenthal, Deborah B; Bautista, Leonelo E","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(5), 694-702","doi":"10.15288/jsad.24-00210","pmid":"39831557","tags":["pregnancy","addiction"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Seven latent classes of maternal substance use were identified: minimal users (70.7%), pre-pregnancy cigarette users (10.5%), persistent cigarette users (6.8%), pre-pregnancy cannabis users (5.5%), broad polysubstance users (3.6%), opioid-only users (1.9%), and persistent cigarette/opioid co-users (1.0%). Groups differed significantly by age, income, race/ethnicity, and pre-pregnancy alcohol use.","whyItMatters":"Identifying distinct substance use patterns rather than treating all prenatal substance exposure as equivalent can help target interventions more effectively and understand different risk profiles for perinatal outcomes.","specificNumbers":"15,429 participants representing 384,918 births. 51.3% aged 20-29. 73.3% non-Hispanic White. Seven classes: minimal (70.7%), pre-pregnancy cigarettes (10.5%), persistent cigarettes (6.8%), pre-pregnancy cannabis (5.5%), broad polysubstance (3.6%), opioid-only (1.9%), persistent cigarette+opioid (1.0%).","methodology":"Analysis of 15,429 PRAMS postpartum survey participants (2016-2018) from seven U.S. states, representing 384,918 live singleton births. Latent class analysis identified patterns of substance use before and during pregnancy. State-level survey weights applied.","limitations":"Self-reported substance use likely underestimates prevalence. Only seven states included, limiting national representativeness. Cannot determine substance quantities or frequency within classes. 73.3% non-Hispanic White limits racial/ethnic diversity."},{"rthcId":"RTHC-06749","title":"Chemsex and compulsive sexual behavior among sexual minority men.","authors":"Jennings, Todd L; Gleason, Neil; Nieblas, Frankie; Borgogna, Nicholas C; Kraus, Shane W","year":2025,"journal":"The journal of sexual medicine, 22(4), 658-662","doi":"10.1093/jsxmed/qdaf021","pmid":"39972535","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06750","title":"Cannabidiol treatment for refractory idiopathic epilepsy in dogs: A systematic review with risk of bias assessment.","authors":"Jensen, Helene Ane; Olsen, Abbey; Arendt, Maja; Sandøe, Peter; Nielsen, Søren Saxmose","year":2025,"journal":"Preventive veterinary medicine, 245, 106649","doi":"10.1016/j.prevetmed.2025.106649","pmid":"40829476","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06751","title":"Acetaminophen attenuates pathological pain through a mechanism that requires CB1 cannabinoid receptors and the enzyme diacylglycerol lipase in mice.","authors":"Jesus, Carlos Henrique Alves; Wirt, Jonah L; Ferreira, Luana Assis; Hainline, John; Huizenga, Mirjam; Rems, Lara; Makriyannis, Alex; van der Stelt, Mario; Hohmann, Andrea G","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.05.08.652937","pmid":"40463236","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06752","title":"CB2 cannabinoid receptor-specific therapeutic antibody agonists for treatment of chemotherapy-induced peripheral neuropathy.","authors":"Jesus, Carlos Henrique Alves; Gopireddy, Raghavender; Sizemore, Emily; Wirt, Jonah L; Sen, Swastik; Yu, Richard; Takeuchi, Toshihiko; Schwimmer, Lauren; Hohmann, Andrea G","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.11.26.690750","pmid":"41383775","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06753","title":"Alterations of the endocannabinoid system in autism spectrum disorder: a systematic review and meta-analysis.","authors":"Jia, Xinlei; Gao, Shumin; Liu, Xiaotong; Feng, Zhendong; Wang, Xingxing; Lan, Kunyi; Lu, Yan'e; Han, Lei; Wei, Ya Bin; Liu, Jia Jia","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(8), 2493-2509","doi":"10.1007/s00406-025-02031-x","pmid":"40518463","tags":["neuroscience","cbd"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Blood anandamide (AEA) levels were significantly lower in individuals with ASD (SMD=-0.79, p=0.002) compared to controls. In animal models, hippocampal AEA was also significantly decreased (SMD=-1.06, p<0.01), and prefrontal cortex 2-AG was reduced (SMD=-1.00, p=0.04). Narrative synthesis found that elevating AEA and 2-AG levels improved core autistic-like symptoms in animal models, with region- and sex-dependent variations.","whyItMatters":"If endocannabinoid deficiency contributes to autism symptoms, targeted therapies that raise endocannabinoid levels (such as FAAH inhibitors or potentially CBD) could represent a novel treatment approach.","specificNumbers":"Blood AEA in humans with ASD: SMD=-0.79 (95% CI: -1.28 to -0.30, p=0.002). Hippocampal AEA in animal models: SMD=-1.06 (95% CI: -1.78 to -0.33, p<0.01). Prefrontal cortex 2-AG: SMD=-1.00 (95% CI: -1.93 to -0.06, p=0.04). 47 papers assessed, 21 included.","methodology":"Systematic review and meta-analysis of 16 animal studies and 5 human studies on endocannabinoid system alterations in ASD. Random-effects meta-analysis for quantitative synthesis.","limitations":"Only 5 human studies available. High heterogeneity in some analyses. Animal models of autism may not fully reflect human ASD. Blood endocannabinoid levels may not reflect brain levels. Various ASD models and species used across studies."},{"rthcId":"RTHC-06754","title":"Transcriptomic sequencing and expression verification of identified genes modulating the alkali stress tolerance and endogenous photosynthetic activities of industrial hemp plant.","authors":"Jiang, Zeyu; Wang, Di; Che, Ye; Amanullah, Sikandar; Zhang, Ling; Jie, Siyuan; Yang, Wei; Wang, Mingze; Wang, Lina; Qi, Guochao","year":2025,"journal":"PloS one, 20(6), e0326434","doi":"10.1371/journal.pone.0326434","pmid":"40560904","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06755","title":"Cannabinoid hyperemesis syndrome: A review.","authors":"Jiménez-Castillo, R A; Arumugam, S; Remes-Troche, J M; Venkatesan, T","year":2025,"journal":"Revista de gastroenterologia de Mexico (English), 90(2), 214-226","doi":"10.1016/j.rgmxen.2025.02.002","pmid":"40517066","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06756","title":"Cannabis consumption and motor vehicle collision: A systematic review and meta-analysis of observational studies.","authors":"Jin, Andrew; Darzi, Andrea J; Dargham, Amne; Liddar, Navroop; Bozorgi, Sepehr; Sohrevardi, Shamim; Zhang, Maurice; Torabiardakani, Kian; Couban, Rachel J; Khalili, Malahat; Busse, Jason W; Sadeghirad, Behnam","year":2025,"journal":"The International journal on drug policy, 142, 104832","doi":"10.1016/j.drugpo.2025.104832","pmid":"40367728","tags":["driving"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Across 31 studies with 328,388 individuals, cannabis consumption was associated with increased risk of MVC fatality (OR=1.55, 95% CI: 1.20-1.98) with 14 more deaths per 100,000 MVCs, and increased risk of injury (OR=2.00, 95% CI: 1.31-3.07) with an absolute risk increase of 6.8%. Evidence for culpability/unsafe driving was very low certainty.","whyItMatters":"As cannabis legalization expands globally, quantifying the crash risk associated with cannabis use is essential for setting driving policy, THC legal limits, and public education campaigns.","specificNumbers":"31 studies, 328,388 individuals. Fatal MVC: OR=1.55 (95% CI: 1.20-1.98), ARI 14 per 100,000 MVCs. Injury MVC: OR=2.00 (95% CI: 1.31-3.07), ARI 6.8%. Both rated as low certainty evidence by GRADE.","methodology":"Systematic review and meta-analysis searching 8 databases through November 2024. Included 31 observational studies. DerSimonian and Laird random-effects model. GRADE approach for certainty assessment. Registered protocol CRD42022357478.","limitations":"Low certainty evidence per GRADE. Heterogeneous methods for detecting cannabis use across studies (some used THC blood levels, others self-report). Cannabis remains detectable long after impairment resolves. Cannot distinguish acute impairment from chronic use. Confounding by polydrug use is common."},{"rthcId":"RTHC-06757","title":"Molecular Imaging of Pancreatic Duct Adenocarcinoma Using [18F]JR-1004, a Cannabinoid Type 2 Receptor Targeted Positron Emission Tomography (PET) Probe.","authors":"Jin, Can; Cao, Xinghai; Chen, Junwei; Mao, Dilong; He, Qinggang","year":2025,"journal":"Molecular imaging and biology","doi":"10.1007/s11307-025-02069-2","pmid":"41350972","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06758","title":"Integrated multi-omic profiling uncovers endocannabinoid system as a driver of nerve agent-induced cognitive dysfunction in guinea pigs.","authors":"Jin, Qian; Lin, Yuxin; Wei, Yue; Liu, Zhanbiao; Cao, Manzhu; Chen, Xuejun; Li, Liqin","year":2025,"journal":"Archives of toxicology, 99(10), 4081-4103","doi":"10.1007/s00204-025-04131-y","pmid":"40691673","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06759","title":"Global, regional and national burden of drug use disorders, 1990-2021: decomposition analysis, health inequality analysis and predictions to 2035.","authors":"Jin, Ruiying; Zhang, Shenyu; Xiong, Jun; Liu, Baixi","year":2025,"journal":"Frontiers in public health, 13, 1588607","doi":"10.3389/fpubh.2025.1588607","pmid":"41194996","tags":["addiction","legalization"],"studyType":"ecological study","evidenceStrength":"moderate","keyFinding":"Cannabis use disorder leads all five drug use disorder categories in age-standardized prevalence rates globally. Opioid use disorder has the highest disability and mortality rates. The burden of drug use disorders is significantly greater in high-SDI (high-income) areas, with income inequality exacerbating uneven distribution of disability-adjusted life years.","whyItMatters":"Establishing that cannabis use disorder is the most prevalent drug use disorder globally provides important context for legalization debates and healthcare resource allocation.","specificNumbers":"Cannabis use disorder has the highest ASPR among 5 drug use disorder categories. Opioid use disorder has the highest ASDR and ASMR. High-SDI areas bear significantly greater burden. Opioid use disorder ASIR declining least among 5 categories.","methodology":"Analysis of Global Burden of Disease (GBD) 2021 data examining incidence, prevalence, mortality, and DALYs for drug use disorders. Decomposition analysis for age, gender, and SDI effects. Health inequality analysis using slope index and concentration index.","limitations":"GBD estimates rely on available data that varies greatly by country and region. Cannabis use disorder diagnostic criteria have changed over time. Some countries have minimal surveillance data. Cannot distinguish between cannabis use and cannabis use disorder in many settings."},{"rthcId":"RTHC-06760","title":"Cannabidiol alleviates methamphetamine addiction via targeting ATP5A1 and modulating the ATP-ADO-A1R signaling pathway.","authors":"Jin, Sha; Lin, Cong; Li, Peipei; Wang, Xue; Wang, Yibo; Zhang, Cong; Wang, Xuenan; Peng, Yinghua; Li, Haohong; Lu, Yuyuan; Wang, Xiaohui","year":2025,"journal":"Acta pharmaceutica Sinica. B, 15(10), 5261-5276","doi":"10.1016/j.apsb.2025.08.011","pmid":"41132843","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06761","title":"Cannabidiol Treatment in a Predator-Based Animal Model of PTSD: Assessing Oxidative Stress and Memory Performance.","authors":"Jîtcă, George; Stoicescu, Robert; Májai, Erzsébet","year":2025,"journal":"International journal of molecular sciences, 26(10)","doi":"10.3390/ijms26104491","pmid":"40429636","tags":["cbd","ptsd","anxiety"],"studyType":"animal study","evidenceStrength":"low","keyFinding":"In a predator-odor PTSD model, CBD (10 mg/kg) did not significantly alter anxiety in the elevated plus maze, though a trend toward increased exploration was observed. In memory tests, CBD-treated stressed rats spent more time in the target quadrant of the Morris Water Maze, suggesting improved spatial memory. CBD reduced malondialdehyde (an oxidative stress marker) in brain tissue. Elevated cortisol in the stressed CBD group was interpreted as a potential anxiolytic mechanism.","whyItMatters":"PTSD remains difficult to treat, and CBD has shown promise in some models. Understanding which PTSD symptoms CBD affects (memory vs. anxiety) can guide more targeted research.","specificNumbers":"40 male rats, CBD dose 10 mg/kg. No significant anxiety reduction on EPM. Trend toward increased vertical exploration in open field. Improved spatial memory in MWM (more time in target quadrant). Reduced malondialdehyde (oxidative stress marker). Elevated cortisol in stressed+CBD group.","methodology":"Forty adult male rats divided into 4 groups (non-stressed and stressed, each with CBD or vehicle). PTSD induced by predator odor exposure on days 10 and 20 with daily cage partner changes. Behavioral tests: open field, elevated plus maze, novel object recognition, Morris Water Maze. Oxidative stress markers measured by liquid chromatography.","limitations":"Male rats only. Single CBD dose tested. Predator odor model captures some but not all PTSD features. Small sample size per group (n=10). The cortisol elevation interpretation is speculative. No dose-response analysis."},{"rthcId":"RTHC-06762","title":"Video gaming and cannabis use: A scoping review.","authors":"Jobin, Emilie Y; Légaré, Andrée-Anne; Lehmann, Katerine; Monson, Eva","year":2025,"journal":"Journal of behavioral addictions, 14(2), 660-678","doi":"10.1556/2006.2025.00040","pmid":"40372807","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06763","title":"Cannabis use is associated with changes in psychological and functional well-being during young adulthood: evidence from self-reports and hair analyses.","authors":"Johnson-Ferguson, Lydia; Loher, Michelle; Bechtiger, Laura; Janousch, Clarissa; Baumgartner, Markus R; Binz, Tina M; Ribeaud, Denis; Eisner, Manuel; Quednow, Boris B; Shanahan, Lilly","year":2025,"journal":"Psychological medicine, 55, e246","doi":"10.1017/S003329172510144X","pmid":"40856282","tags":["mental-health","psychosis","youth"],"studyType":"longitudinal cohort","evidenceStrength":"high","keyFinding":"In a community sample of 863 young adults, cannabis use at age 20 (measured by both self-report and hair THC) predicted increases in psychotic-like experiences, internalizing symptoms, aggression, problematic substance use, and decreased general well-being from ages 20 to 24. Cannabis users also had higher odds of not being in employment, education, or training. Effects were consistent across six different operationalizations of cannabis exposure.","whyItMatters":"Using objective hair analysis alongside self-report strengthens confidence that the associations are real rather than artifacts of self-report bias. The consistency across measurement methods is particularly compelling.","specificNumbers":"863 young adults. Weekly-to-daily self-reported users: n=150. Hair THC detected: n=110 at age 20. Both measures predicted worse outcomes at 24 with small effect sizes. Composite scores combining self-report and hair data were not more informative than either alone.","methodology":"Longitudinal community study with N=863 young adults assessed at ages 20 and 24. Cannabis exposure measured by self-reported frequency and hair THC/CBN concentrations via LC-MS/MS. Multiple linear and logistic regression models adjusted for sex, sociodemographics, and baseline outcomes at age 20.","limitations":"Observational design cannot establish causation. Small effect sizes. Cannot rule out reverse causation (pre-existing mental health driving cannabis use). Hair analysis detects cannabis over months, not acute use patterns. Community sample may not capture highest-risk users."},{"rthcId":"RTHC-06764","title":"Cannabinoids in Chronic Pain Management: A Review of the History, Efficacy, Applications, and Risks.","authors":"Johnson, Brooks W; Strand, Natalie H; Raynak, John C; Jara, Christian; Habtegiorgis, Kisanet; Hand, Brennan A; Hong, Sang; Maloney, Jillian A","year":2025,"journal":"Biomedicines, 13(3)","doi":"10.3390/biomedicines13030530","pmid":"40149508","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06765","title":"Cannabis use and psychotic-like experiences in the All of Us Research Program.","authors":"Johnson, Emma C; Luo, Zhen; Romero Villela, Pamela N; Agrawal, Arpana; Hatoum, Alexander S; Karcher, Nicole R","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.64898/2025.12.01.25341322","pmid":"41404276","tags":["psychosis","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Drawing from the All of Us Research Program—a massive, diverse U.S. biobank—this study examined whether cannabis use is associated with psychotic-like experiences (PLEs) such as hearing things, seeing things, referential ideation, and persecutory thoughts.\n\nThe initial results seemed to confirm the cannabis-psychosis link: ever using cannabis was associated with higher odds of all four types of PLEs (odds ratios 1.21–1.44). More frequent cannabis use showed a dose-response relationship—the more someone used, the more likely they were to report PLEs. These associations held even after adjusting for personal and family history of schizophrenia and genetic risk (polygenic scores).\n\nThen came the critical analysis. When the researchers adjusted for lifetime use of other substances—methamphetamine, cigarettes, and opioids—the cannabis association vanished entirely. Methamphetamine use, cigarette use, and opioid use remained independently associated with PLEs (odds ratios 1.22–1.65), but cannabis did not.\n\nAnother telling finding: the schizophrenia polygenic score predicted whether someone was prescribed medication for their PLEs, but cannabis use frequency did not. This suggests that while cannabis users may report more psychotic-like experiences, these experiences may be less clinically severe or less likely to be true psychotic symptoms.\n\nThe study can't prove that cannabis doesn't cause psychosis—cross-sectional data can't establish causation in either direction. But it does suggest that much of the observed cannabis-psychosis link may be confounded by co-occurring use of other substances.","whyItMatters":"The cannabis-psychosis association is one of the most debated topics in cannabis research and has driven significant policy decisions. If much of that association is actually explained by co-occurring methamphetamine, cigarette, and opioid use, it would fundamentally change how we understand the risk. This doesn't mean cannabis is safe for psychosis-prone individuals, but it suggests the risk may be overstated when other substance use isn't properly accounted for.","specificNumbers":"N = 62,153. Cannabis ever-use initially associated with PLEs (ORs 1.21–1.44). After adjusting for other substance use: cannabis association no longer significant. Methamphetamine (OR 1.22–1.65), cigarettes, and opioids remained significant. Schizophrenia polygenic score predicted PLE medication, cannabis use frequency did not.","methodology":"Cross-sectional analysis using the All of Us Research Program (release 8), a population-based U.S. biobank. Maximum analytic N = 62,153. Self-reported cannabis use and four types of self-reported psychotic-like experiences (auditory perceptual distortions, visual perceptual distortions, referential ideation, persecutory ideation). Adjusted for personal and family history of schizophrenia, polygenic risk scores, and lifetime use of other substances.","limitations":"Cross-sectional design—can't determine whether substance use preceded or followed PLEs. Self-reported substance use and psychotic experiences (potential underreporting). The All of Us cohort, while large and diverse, is not perfectly representative of the U.S. population. Adjusting for other substance use may over-control if cannabis is a gateway to those substances. Lifetime ever-use is a crude measure that doesn't capture timing, dose, or potency."},{"rthcId":"RTHC-06766","title":"Minor Cannabinoid Profile of Unregulated Cannabidiol Products.","authors":"Johnson, Erin; Kilgore, Michael; Nuzzo, Paul; Babalonis, Shanna","year":2025,"journal":"Cannabis and cannabinoid research, 10(2), 220-227","doi":"10.1089/can.2024.0058","pmid":"39478329","tags":["cbd","potency"],"studyType":"laboratory analysis","evidenceStrength":"moderate","keyFinding":"Among 80 over-the-counter CBD products, the most frequently detected minor cannabinoids were CBDV (100%), CBG (77%), CBC (72%), CBN (67%), CBL (67%), and CBDA (51%). Delta-8 THC was not detected. Concentrations varied widely (e.g., CBDA: 0.006-12.258 mg/mL). The pharmaceutical control (Epidiolex) was used for comparison. None of these minor cannabinoid concentrations were on product labels.","whyItMatters":"Consumers using CBD products are unknowingly exposed to multiple other cannabinoids whose effects and interactions are poorly understood. This lack of transparency undermines informed consent and complicates research on CBD effects.","specificNumbers":"80 products tested. CBDV: 100% detection. CBG: 77%. CBC: 72%. CBN: 67%. CBL: 67%. CBDA: 51%. Delta-8 THC: 0%. CBDA concentration range: 0.006-12.258 mg/mL. 15 cannabinoids targeted.","methodology":"Cross-section of 80 local and national hemp-derived CBD oil products purchased online and in retail outlets in central Kentucky. Solvent extraction and quantification by LC-MS/MS targeting 15 minor cannabinoids. Epidiolex included as regulated control.","limitations":"Kentucky-based sample may not represent national or international markets. Products tested at one point in time; batch variation is unknown. Does not assess whether detected concentrations are pharmacologically relevant. 80 products is a sample, not comprehensive coverage."},{"rthcId":"RTHC-06767","title":"Optimizing Growth Regulator Concentrations for Cannabis sativa L. Micropropagation.","authors":"Johnson, Gabrielle A; Jackson, Carissa L; Timoteo, Antonio; Sardaru, Papaiah; Foland, Michael H; Natarajan, Purushothaman; Dhekney, Sadanand A","year":2025,"journal":"Plants (Basel, Switzerland), 14(16)","doi":"10.3390/plants14162586","pmid":"40872210","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06768","title":"Evaluating the effects of Cannabis reform on human security: A comparative case study of Jamaica and Saint Vincent and the Grenadines.","authors":"Johnson, Stephen Christopher","year":2025,"journal":"Evaluation and program planning, 110, 102562","doi":"10.1016/j.evalprogplan.2025.102562","pmid":"39987783","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06769","title":"The resurgence of synthetic cannabinoid receptor agonists as adulterants in the Era of Cannabis legalization: Lessons from prior epidemics and clinical implications.","authors":"Jones, Austin T; Marwan Abu Taha, Alaa; Miller, Grover P","year":2025,"journal":"Neuroscience and biobehavioral reviews, 170, 106043","doi":"10.1016/j.neubiorev.2025.106043","pmid":"39922438","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06770","title":"The effects of vaped cannabis on the severity of naloxone-precipitated opioid withdrawal.","authors":"Jones, Jermaine D; Martinez, Suky; Arout, Caroline; Haney, Margaret; Castillo, Felipe; Manubay, Jeanne; Perez, Freymon; Luba, Rachel R; Comer, Sandra D","year":2025,"journal":"Experimental and clinical psychopharmacology","doi":"10.1037/pha0000796","pmid":"40839512","tags":["harm-reduction","addiction"],"studyType":"case report","evidenceStrength":"very low","keyFinding":"In one male participant (age 52) with OUD stabilized on oral morphine (120 mg/day), naloxone alone produced a COWS score of 22 at 30 minutes. Cannabis pretreatment at 12.5 mg reduced COWS to 17, and at 25 mg reduced it to 14. Combined naloxone and cannabis produced elevated heart rate and blood pressure, but not more than naloxone alone.","whyItMatters":"Fear of precipitated withdrawal is a major barrier to naloxone use. If cannabis can reduce withdrawal severity, combined naloxone-cannabis formulations could increase willingness to administer naloxone during overdose emergencies.","specificNumbers":"N=1 (male, age 52). Morphine stabilization: 120 mg/day. COWS scores at T+30: naloxone alone=22; naloxone+cannabis 12.5mg=17; naloxone+cannabis 25mg=14. Dose-dependent reduction.","methodology":"Proof-of-concept inpatient crossover study. Single participant completed 6 dose combinations of vaped cannabis (0, 12.5, 25 mg) and intranasal naloxone (0, 4 mg) during morphine stabilization (120 mg/day). Primary outcome: COWS withdrawal score.","limitations":"Single participant limits any conclusions. Major methodological redesign was needed during the study (reasons not detailed). Cannot generalize from n=1. Cannabis formulation and dose may not reflect real-world use. Inpatient setting is highly controlled."},{"rthcId":"RTHC-06771","title":"A novel cannabidiol:tetramethylpyrazine cocrystal (CBD:TMP, ART12.11) improves the efficacy and bioavailability of cannabidiol in reducing stress-induced depressive and anxiety symptoms.","authors":"Jones, Matthew J; Uzuneser, Taygun C; O'Sullivan, Saoirse E; Pérez-Valenzuela, Enzo; Sarikahya, Mohammed H; Yates, Andy; Hardy, Daniel B; Rushlow, Walter; Laviolette, Steven R","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 141, 111478","doi":"10.1016/j.pnpbp.2025.111478","pmid":"40854502","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06772","title":"Changes in psychosis-related emergency department and hospitalization rates among youth following cannabis legalization in Colorado.","authors":"Joshi, Spruha; Snyder, Kyle M; Thurstone, Christian; Rivera, Bianca D; Feldman, Justin; Cerdá, Magdalena; Krawczyk, Noa","year":2025,"journal":"Drug and alcohol dependence, 273, 112719","doi":"10.1016/j.drugalcdep.2025.112719","pmid":"40451017","tags":["psychosis","youth","legalization"],"studyType":"interrupted time series","evidenceStrength":"moderate","keyFinding":"Monthly psychosis hospitalization rates for youth rose from 21.9 per 100,000 pre-medical expansion to 28.0 post-expansion and 32.3 post-recreational legalization. Psychosis hospitalizations involving CUD increased most dramatically, from 2.0 to 3.4 to 8.5 per 100,000. Interrupted time series showed a significant trend change for CUD-involved psychosis following recreational legalization.","whyItMatters":"This is one of the first studies to link cannabis legalization milestones specifically to youth psychosis hospitalizations, with the CUD-involved cases providing the most compelling signal.","specificNumbers":"Psychosis hospitalizations per 100,000: pre-Ogden 21.9, post-Ogden 28.0, post-legalization 32.3 (all differences p<0.05). CUD-involved: 2.0, 3.4, 8.5. Post-legalization CUD-psychosis trend: +0.11 per 100,000/month vs +0.02 pre-legalization. 68% male, 53% white, 59% Medicaid.","methodology":"Interrupted time series analysis of Denver Health data (2005-2020) examining psychosis-related ED and hospital visits among youth aged 10-29 before and after the Ogden Memo (2009) and Amendment 64 (2012).","limitations":"Single health system (Denver Health) may not represent all Colorado youth. Cannot establish individual-level causation. Increasing clinician awareness of CHS and cannabis-related conditions over time may inflate later rates. Other factors besides legalization changed during the study period."},{"rthcId":"RTHC-06773","title":"Sink strength, nutrient allocation, cannabinoid yield, and associated transcript profiles vary in two drug-type Cannabis chemovars.","authors":"Jost, Ricarda; Berkowitz, Oliver; Pegg, Amelia; Hurgobin, Bhavna; Tamiru-Oli, Muluneh; Welling, Matthew T; Deseo, Myrna A; Noorda, Hannah; Brugliera, Filippa; Lewsey, Mathew G; Doblin, Monika S; Bacic, Antony; Whelan, James","year":2025,"journal":"Journal of experimental botany, 76(1), 152-174","doi":"10.1093/jxb/erae367","pmid":"39225376","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06774","title":"Synergistic Anticancer Effects of Fibroblast Growth Factor Receptor Inhibitor and Cannabidiol in Colorectal Cancer.","authors":"Ju, Yeonuk; Kim, Bu Gyeom; Gim, Jeong-An; Bong, Jun Woo; Cheong, Chin Ock; Oh, Sang Cheul; Kang, Sang Hee; Min, Byung Wook; Lee, Sun Il","year":2025,"journal":"Nutrients, 17(16)","doi":"10.3390/nu17162609","pmid":"40871637","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06775","title":"Legalization of Smokable Medical Cannabis and Changes in the Dispensed Amount of Δ-9 Tetrahydrocannabinol Per Patient.","authors":"Jugl, Sebastian; Sajdeya, Ruba; Buhlmann, Melanie; Cook, Robert L; Brown, Joshua D; Winterstein, Almut G; Goodin, Amie J","year":2025,"journal":"Cannabis and cannabinoid research, 10(2), 207-212","doi":"10.1089/can.2024.0073","pmid":"39375043","tags":["medical-cannabis","potency","legalization"],"studyType":"quasi-experimental","evidenceStrength":"moderate","keyFinding":"Legalizing smokable medical cannabis in Florida (SB182, March 2019) was associated with a 42.18% increase in mean weekly dispensed THC per patient (138.45 mg increase, 95% CI: 102.69-174.20) assuming 20% THC concentration. THC continued increasing by 5.62 mg per patient per week for 35 weeks post-policy. The number of certified patients also grew 24.8% in the first 4 months.","whyItMatters":"The finding that dispensed THC far exceeded recommended daily doses raises safety questions about medical cannabis programs that add smokable forms without dosing guidance.","specificNumbers":"At 20% THC: +138.45 mg/week per patient (42.18% increase). Trend: +5.62 mg/week per patient each subsequent week. Patients: 197,107 (March 2019) to 325,868 (March 2020). At 10% THC: +35.10 mg/week (10.70% increase).","methodology":"Quasi-experimental interrupted time series using Florida Department of Health dispensing data (April 2018-March 2020). Generalized least squares linear model with a 17-week phase-in period. THC estimated at both 10% and 20% flower concentrations.","limitations":"THC concentration in flower is estimated (10-20%), not measured for each patient. Cannot determine individual consumption patterns from aggregate dispensing data. Pre-post design without a control state. Short post-policy period (35 weeks)."},{"rthcId":"RTHC-06776","title":"Administration of Δ9-Tetrahydrocannabinol (THC) in Adolescent and Adult Mice.","authors":"Jung, Kwang-Mook; Mabou Tagne, Alex; Avalos, Heidi C; D'Agosta, Dominick; Katz, Jean; Lee, Hye-Lim; Piomelli, Daniele","year":2025,"journal":"Journal of visualized experiments : JoVE","doi":"10.3791/68358","pmid":"40824853","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06777","title":"Semi-Quantitative On-Site Microfluidic Assay to Detect 11-Nor-9-carboxy-delta 9-Tetrahydrocannabinol (THC-COOH) in Urine.","authors":"Jung, YeJi; Choi, Isaac; Bae, Hyunjun; Seo, Joonseok; Kim, Sunchun; Lee, Sangki; Lee, Jeongmin; Jeong, Yohan; Kim, Juhyung; Chung, Heesun; Kim, Hyunho; Chung, Seok","year":2025,"journal":"Sensors (Basel, Switzerland), 25(23)","doi":"10.3390/s25237115","pmid":"41374491","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06778","title":"Toxicity assessment of the novel psychoactive substance HU-210 (Hebrew University 210; CAS: 112830-95-2): First insight into toxicophores and critical toxicity parameters (acute toxicity, health effects, genotoxicity, skin and eye irritation, cardiotoxicity and endocrine disruption) using in silico methods for applications in clinical and forensic toxicology.","authors":"Jurowski, Kamil; Kobylarz, Damian","year":2025,"journal":"Toxicology letters, 410, 39-57","doi":"10.1016/j.toxlet.2025.05.012","pmid":"40419203","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06779","title":"Cannabis Use in Rural and Urban Young Adults: The Role of Subjective Social Status and Emotion Dysregulation.","authors":"K, Rathod; P, Goodhines","year":2025,"journal":"Substance use & misuse, 60(14), 2270-2279","doi":"10.1080/10826084.2025.2540936","pmid":"40750789","tags":["mental-health","addiction"],"studyType":"cross-sectional survey","evidenceStrength":"low","keyFinding":"Rural participants reported significantly lower subjective social status (SSS) than urban peers. While rural-urban differences in cannabis use were not statistically significant, serial mediation analysis found an indirect pathway from rurality to hazardous cannabis use through lower SSS and greater emotion dysregulation (b=0.06, 95% CI: 0.002-0.16).","whyItMatters":"Rural communities are often overlooked in substance use research. Identifying that perceived social status and emotional regulation difficulties may drive cannabis use in rural areas points to specific intervention targets.","specificNumbers":"N=400 young adults. Rural participants had significantly lower SSS. Rural-urban cannabis use differences nonsignificant. Indirect mediation effect: b=0.06 (95% CI: 0.002-0.16) from rurality through SSS and emotion dysregulation to hazardous cannabis use.","methodology":"Cross-sectional online survey of 400 young adults nationally. Measured rurality, subjective social status, emotion dysregulation, and cannabis use patterns. Serial mediation analysis tested the SSS-emotion dysregulation pathway.","limitations":"Cross-sectional design. Self-selected online sample. Small effect size for the mediation pathway. Rural-urban cannabis use differences were not significant directly. SSS is a single-item measure."},{"rthcId":"RTHC-06780","title":"Unravelling gender differences in cannabis cue-reactivity in individuals who use cannabis.","authors":"Kaag, A M; Cousijn, J; Kroon, E","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 142, 111515","doi":"10.1016/j.pnpbp.2025.111515","pmid":"41043644","tags":["sex-differences","addiction","neuroscience"],"studyType":"neuroimaging study","evidenceStrength":"moderate","keyFinding":"Women cannabis users showed blunted neural cue-reactivity in the right insula and putamen compared to male users, a pattern opposite to controls. Among women only, session-induced craving correlated with cue-reactivity in the right superior frontal gyrus, cerebellum, and precentral gyrus. Cannabis use severity was linked to precentral gyrus cue-reactivity exclusively in women.","whyItMatters":"Women transition more rapidly from initial cannabis use to cannabis use disorder. Understanding the distinct neural mechanisms in women could explain this accelerated progression and inform sex-specific treatments.","specificNumbers":"66 cannabis users (27 women), 71 controls (31 women). Cannabis users used 2-7 days/week. Women showed blunted insula and putamen cue-reactivity vs men. Brain-craving correlations in frontal gyrus, cerebellum, and precentral gyrus found only in women.","methodology":"fMRI cue-reactivity study with 66 regular cannabis users (27 women, using 2-7 days/week) and 71 controls (31 women). Cannabis-related and neutral images presented during scanning. Craving measured twice with the Marijuana Craving Questionnaire.","limitations":"Moderate sample size limits statistical power for sex-stratified analyses. Cross-sectional design cannot determine if neural differences preceded or resulted from cannabis use. Craving measures are self-reported. Participants were non-treatment-seeking."},{"rthcId":"RTHC-06781","title":"Cannabinoid exposure does not alter estradiol biosynthesis in human KGN granulosa cells.","authors":"Kadhim, Lanna; Paquette-Jager, Seneca; Landry, David A","year":2025,"journal":"Reproductive toxicology (Elmsford, N.Y.), 136, 108978","doi":"10.1016/j.reprotox.2025.108978","pmid":"40562223","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06782","title":"The impact of physical activity on substance use experimentation and initiation among adolescents: Results from the ABCD Study® cohort.","authors":"Kaiver, Christine M; Thompson, Erin L; Hawes, Samuel W; Lehman, Sarah M; Adams, Ashley R; Wing, David; Laird, Angela R; Gonzalez, Raul","year":2025,"journal":"Drug and alcohol dependence reports, 16, 100373","doi":"10.1016/j.dadr.2025.100373","pmid":"40909199","tags":["youth","exercise"],"studyType":"longitudinal cohort","evidenceStrength":"moderate","keyFinding":"Among 2,541 ABCD study participants with Fitbit-measured physical activity, total PA was associated with 24% decreased odds of substance use initiation (OR=0.82, 95% CI: 0.69-0.99). Light PA specifically predicted 26% lower odds (OR=0.73, 95% CI: 0.61-0.88). Moderate and vigorous PA were not significantly associated with initiation. No PA measure predicted substance experimentation (sip/puff/try).","whyItMatters":"The finding that light (not vigorous) physical activity is protective challenges the assumption that more intense exercise is always better, and suggests accessible, low-barrier activities could be part of prevention programs.","specificNumbers":"2,541 participants. Total PA: OR=0.82 for initiation (95% CI: 0.69-0.99, p<.05). Light PA: OR=0.73 (95% CI: 0.61-0.88, p=.001). No significant effects for moderate or vigorous PA on initiation, or any PA on experimentation.","methodology":"Longitudinal analysis of 2,541 participants from the ABCD study. Fitbit-measured PA at 2-year follow-up predicted substance use outcomes at 3- and 4-year follow-up. Logistic regression controlled for demographics, externalizing, and depressive symptoms.","limitations":"Observational design. Only 3 weeks of Fitbit data may not represent typical activity levels. Cannot determine if PA causally prevents substance use or if both reflect common personality traits. Substance use outcomes are dichotomous (yes/no) without frequency detail."},{"rthcId":"RTHC-06783","title":"Medical Marijuana and Treatment Personalization: The Role of Genetics and Epigenetics in Response to THC and CBD.","authors":"Kalak, Małgorzata; Brylak-Błaszków, Anna; Błaszków, Łukasz; Kalak, Tomasz","year":2025,"journal":"Genes, 16(12)","doi":"10.3390/genes16121487","pmid":"41465160","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06784","title":"Molecular Mechanisms of the Endocannabinoid System with a Focus on Reproductive Physiology and the Cannabinoid Impact on Fertility.","authors":"Kalak, Patrycja; Kupczyk, Piotr; Szumny, Antoni; Gębarowski, Tomasz; Jasiak, Marcin; Niedźwiedź, Artur; Niżański, Wojciech; Dzięcioł, Michał","year":2025,"journal":"International journal of molecular sciences, 26(15)","doi":"10.3390/ijms26157095","pmid":"40806240","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06785","title":"The Association Between Substance Use and Suicidality Among Women Veterans, 2015 to 2019: A Secondary Analysis of the National Survey on Drug Use and Health.","authors":"Kameg, Brayden","year":2025,"journal":"Journal of the American Psychiatric Nurses Association, 10783903251398530","doi":"10.1177/10783903251398530","pmid":"41439485","tags":["mental-health","addiction","sex-differences"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Women veterans had increased odds of suicidality compared to peers. Past-year cannabis use disorder increased odds of suicidal ideation nearly fourfold in women veterans (aOR=3.93, 95% CI: 1.21-13.81). Lifetime cannabis use doubled odds of suicide plans (aOR=2.02, 95% CI: 1.03-3.96). Cocaine and stimulant use also increased suicide plan odds.","whyItMatters":"Women veterans face disproportionately high suicide rates. Identifying cannabis use disorder as a particularly strong risk factor provides a modifiable target for suicide prevention in this vulnerable population.","specificNumbers":"N=131,344. Cannabis use disorder and suicidal ideation in women vets: aOR=3.93 (95% CI: 1.21-13.81, p=.033). Lifetime cannabis use and suicide plans: aOR=2.02 (95% CI: 1.03-3.96, p=.040). Lifetime cocaine and plans: aOR=2.24 (95% CI: 1.20-4.05, p=.011).","methodology":"Analysis of 2015-2019 NSDUH data (n=131,344). Binary logistic regression examining substance use and suicidality, adjusted for demographics, stratified by sex and veteran status.","limitations":"Cross-sectional NSDUH data cannot establish temporal or causal relationships. Small number of women veterans with CUD limits statistical power (wide confidence intervals). Self-reported substance use and suicidality may be underreported. Cannot distinguish between cannabis causing suicidality and suicidal individuals self-medicating with cannabis."},{"rthcId":"RTHC-06786","title":"Cannabidiol/cannabidiolic acid-rich hemp (Cannabis sativa L.) extract attenuates cognitive impairments and glial activations in rats exposed to chronic stress.","authors":"Kamsrijai, Utcharaporn; Charoensup, Rawiwan; Jaidee, Wuttichai; Hawiset, Thaneeya; Thaweethee-Sukjai, Benjamard; Praman, Siwaporn","year":2025,"journal":"Journal of ethnopharmacology, 338(Pt 3), 119113","doi":"10.1016/j.jep.2024.119113","pmid":"39551282","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06787","title":"Pharmacokinetic Characteristics of a Single Cannabidiol Dose in Oil and Treat Forms and Health Impacts After 30 Days of Administration in Dogs.","authors":"Kamutchat, Phattharakan; Limsuwan, Sasithorn; Leewichit, Nattaya; Tansakul, Natthasit","year":2025,"journal":"Animals : an open access journal from MDPI, 15(10)","doi":"10.3390/ani15101470","pmid":"40427347","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06788","title":"Tobacco, electronic nicotine delivery system, nicotine replacement therapy, and cannabinoid use during pregnancy: A descriptive cross-sectional survey.","authors":"Kandhasamy, Sreemanjari; Baggio, Stéphanie; Mathis, Jérôme; Mattmann, Yolanda; Maisonneuve, Emeline; Auer, Reto; Panchaud, Alice; Jenkinson, Stephen P; Schoeni, Anna","year":2025,"journal":"PloS one, 20(9), e0332961","doi":"10.1371/journal.pone.0332961","pmid":"40997036","tags":["pregnancy"],"studyType":"cross-sectional survey","evidenceStrength":"low","keyFinding":"7.6% of 262 pregnant women used tobacco, 0.8% used e-cigarettes, 0.4% used nicotine replacement therapy, and 3.8% used cannabinoid products (all CBD-only). Only 25% of tobacco users received smoking cessation counseling. No pregnant women reported THC-containing cannabis use.","whyItMatters":"The finding that nearly 4% of pregnant women use CBD products highlights a growing trend that healthcare providers need to address, especially given limited safety data on CBD during pregnancy.","specificNumbers":"262 pregnant women surveyed. Tobacco: 7.6% (95% CI: 4.2-11.1%). ENDS: 0.8% (95% CI: 0.0-3.4%). NRT: 0.4% (95% CI: 0.0-3.8%). CBD: 3.8% (95% CI: 1.1-7.0%). Cessation counseling: only 25% of tobacco users (5/20).","methodology":"Cross-sectional survey of 262 pregnant women attending regular clinical visits at Spitalzentrum Biel, Switzerland (February-May 2023). Frequency and proportions with 95% confidence intervals reported.","limitations":"Small single-site sample from one Swiss hospital. Self-reported use may underestimate actual prevalence. CBD product contents unverified. Wide confidence intervals due to small numbers. 3-month data collection window."},{"rthcId":"RTHC-06789","title":"Risk of adverse obstetrical and neonatal outcomes in women consuming recreational drugs during pregnancy.","authors":"Kandhasamy, Sreemanjari; Lepigeon, Karine; Baggio, Stéphanie; Céline, Roulet; Ceulemans, Michael; Winterfeld, Ursula; Jenkinson, Stephen P; Francini, Katyuska; Maisonneuve, Emeline; Panchaud, Alice","year":2025,"journal":"BMC pregnancy and childbirth, 25(1), 456","doi":"10.1186/s12884-024-07062-1","pmid":"40240903","tags":["pregnancy"],"studyType":"retrospective cohort","evidenceStrength":"moderate","keyFinding":"Among 177 pregnant women followed for addiction, those using cocaine and/or opioids (with or without cannabis) had 3.88 times higher odds of adverse neonatal outcomes compared to cannabis-only users. Surprisingly, cocaine/opioid exposure was associated with lower odds of adverse obstetrical outcomes (OR=0.39). 81.2% of the exposed group used opioids and 39.9% used cocaine.","whyItMatters":"Using cannabis-only users as the reference group (instead of drug-free controls) provides a more clinically relevant comparison for addiction medicine, better controlling for confounders associated with polysubstance use.","specificNumbers":"177 pregnant women: 80 exposed (cocaine/opioids), 97 reference (cannabis-only). Adverse neonatal outcomes: ORconditional=3.88 (95% CI: 1.23-12.23). Adverse obstetrical outcomes: ORconditional=0.39 (95% CI: 0.17-0.88). 81.2% opioids, 39.9% cocaine in exposed group.","methodology":"Observational study at the Addi-Vie perinatal consultation center, CHUV Lausanne, Switzerland. 80 women using cocaine/opioids (with or without cannabis) compared to 97 cannabis-only users. Inverse probability treatment weighting used for adjusted analysis.","limitations":"Small sample from a single center. Cannabis-only reference group is not the same as a drug-free control. Cannot distinguish effects of individual substances within the exposed group. The unexpected protective obstetrical finding may reflect more intensive monitoring of higher-risk patients."},{"rthcId":"RTHC-06790","title":"Co-use of opioids and cannabis versus single-substance use: a national analysis of US adults.","authors":"Kang, Hyojung; Tian, Jilin; Milavetz, Gary","year":2025,"journal":"Frontiers in public health, 13, 1623420","doi":"10.3389/fpubh.2025.1623420","pmid":"41446523","tags":["pain","addiction","medical-cannabis"],"studyType":"cross-sectional survey","evidenceStrength":"moderate","keyFinding":"Among adults using prescription opioids and/or cannabis medically, 49.5% used opioids only, 35.3% cannabis only, and 15.2% co-used both. Co-users were younger, had lower income, and experienced more psychological distress. Opioid-only users were older, more female, and in large-metro areas. Cannabis-only users were younger, more male, healthier, and in non-metro areas.","whyItMatters":"Understanding who co-uses opioids and cannabis can help clinicians identify patients who may need additional support and inform policy about cannabis as a potential opioid substitute versus complement.","specificNumbers":"134,402 adults. Opioid-only: 49.5%. Cannabis-only: 35.3%. Co-use: 15.2%. Depression similarly affected both groups vs co-use (RRR=0.52). Co-users were more likely to be younger, lower income, and psychologically distressed.","methodology":"Weighted multinomial logistic regression analysis of 2015-2022 NSDUH data for U.S. adults reporting past-year medical use of prescription opioids and/or cannabis.","limitations":"Cross-sectional NSDUH data. Cannot determine if co-use is substitutional, complementary, or incidental. Self-reported medical use may not reflect actual prescriptions. Does not capture dose, frequency, or timing of co-use."},{"rthcId":"RTHC-06791","title":"Chronic Δ9-tetrahydrocannabinol exposure in adolescent nonhuman primates: persistent abnormalities in economic demand and brain functional connectivity.","authors":"Kangas, Brian D; Deshpande, Harshawardhan U; Withey, Sarah L; Spealman, Roger D; Bergman, Jack; Kohut, Stephen J","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(3), 576-585","doi":"10.1038/s41386-024-02024-9","pmid":"39538014","tags":["youth","neuroscience","cognition"],"studyType":"animal study","evidenceStrength":"moderate","keyFinding":"Adolescent monkeys treated daily with THC for 6 months showed persistent alterations in medial orbitofrontal cortex, caudate, and ventral striatum functional connectivity that lasted after discontinuation. THC-treated monkeys also showed dose-dependent disorder in reward sensitivity and motivational deficits in economic demand studies as young adults. In vehicle-treated monkeys, brain connectivity and economic demand were correlated with reward sensitivity, but these relationships were disrupted in THC-treated animals.","whyItMatters":"Nonhuman primate studies bridge the gap between rodent models and human adolescent cannabis research. The finding that brain changes and motivational deficits persist into adulthood strengthens the case for adolescent vulnerability.","specificNumbers":"23 monkeys (female and male). 6 months daily THC at 0.32 or 3.2 mg/kg. Persistent alterations in mOFC, caudate, and ventral striatum connectivity. Dose-dependent motivational deficits. Brain-behavior correlations present in controls but absent in THC-treated animals.","methodology":"Twenty-three female and male squirrel monkeys treated daily during adolescence with vehicle, low-dose THC (0.32 mg/kg), or high-dose THC (3.2 mg/kg) for 6 months. Awake fMRI before, during, and after treatment. Economic demand studies conducted as young adults to assess motivation and reward sensitivity.","limitations":"Squirrel monkeys are not identical to humans in brain development timing or cannabinoid receptor distribution. Pure THC does not reflect typical cannabis products. Daily dosing regimen may not reflect typical adolescent use patterns. Moderate sample size for a primate study."},{"rthcId":"RTHC-06792","title":"Cannabis or Cannabinoids for the Management of Chronic Noncancer Pain: Best Practice Advice From the American College of Physicians.","authors":"Kansagara, Devan; Hill, Kevin P; Yost, Jennifer; Humphrey, Linda L; Shaw, Beth; Obley, Adam J; Haeme, Ray; Akl, Elie A; Qaseem, Amir; Dunn, Andrew S; Jackson, Christopher D; Jokela, Janet A; Lee, Rachael A; Mackey, Katherine; Saini, Sameer D; Tschanz, Mark P; Wilt, Timothy J; Etxeandia-Ikobaltzeta, Itziar; Shamliyan, Tatyana; Vigna, Chelsea","year":2025,"journal":"Annals of internal medicine, 178(5), 714-724","doi":"10.7326/ANNALS-24-03319","pmid":"40183677","tags":["pain","medical-cannabis","harm-reduction"],"studyType":"Clinical Guideline","evidenceStrength":"Moderate","keyFinding":"The ACP developed best practice advice based on systematic reviews, recommending clinicians counsel patients about cannabis for chronic noncancer pain while identifying specific subgroups where harms likely outweigh benefits: young adults and adolescents, patients with substance use disorders, those with serious mental illness, and frail patients at risk for falls.","whyItMatters":"This represents one of the first major U.S. medical society guidelines specifically addressing cannabis for chronic pain. Rather than a blanket endorsement or rejection, it takes a nuanced position that acknowledges potential benefits while drawing clear lines around higher-risk populations.","specificNumbers":"The guidance identifies four subgroups where harms likely outweigh benefits and advises against inhaled cannabis across all patient groups.","methodology":"Clinical guidance developed by the ACP Population Health and Medical Science Committee based on living systematic reviews and primary studies on cannabis and cannabinoid treatments for chronic noncancer pain.","limitations":"Best practice advice is based on available evidence, which remains limited in quality and quantity. The guidance acknowledges uncertainty in many areas and relies on systematic reviews that may not capture the full range of cannabis products and formulations patients actually use."},{"rthcId":"RTHC-06793","title":"Cannabidiol use among elite-level Canadian athletes: the pursuit of improved sleep, pain relief, and enhanced recovery.","authors":"Karam, Dimitri; Sesbreno, Erik; Drager, Kelly; Boegman, Susan; Duncan, Lindsay R; Jensen, Dennis; Churchward-Venne, Tyler A","year":2025,"journal":"Frontiers in nutrition, 12, 1711773","doi":"10.3389/fnut.2025.1711773","pmid":"41425621","tags":["cbd","exercise"],"studyType":"Cross-Sectional Survey","evidenceStrength":"Low","keyFinding":"Among 80 elite Canadian athletes, 38% had used CBD. Users overwhelmingly agreed it was safe (96%) and reported benefits for sleep (93%), relaxation (90%), and training pain (77%). The biggest deterrent to use was concern about anti-doping violations (28%).","whyItMatters":"Elite athletes increasingly turn to CBD for recovery and sleep, but the gap between perceived benefits and rigorous evidence remains wide. Anti-doping concerns create a unique barrier in this population that does not apply to recreational users.","specificNumbers":"38% had used CBD; 96% of users agreed it was safe; 93% reported improved sleep; 90% reported improved relaxation; 77% reported reduced training pain; 28% cited anti-doping concerns as the top barrier.","methodology":"Cross-sectional anonymous online survey of elite-level Canadian athletes conducted between October 2021 and June 2023. 80 athletes completed the survey.","limitations":"Small sample of 80 athletes limits generalizability. Self-reported perceived benefits without objective outcome measures. Selection bias likely, as athletes interested in CBD may have been more likely to participate."},{"rthcId":"RTHC-06794","title":"Acute effects of cannabis on core and co-occurring features associated with autism spectrum disorder in adults.","authors":"Karhson, Debra S; LaFrance, Emily M; Cuttler, Carrie","year":2025,"journal":"Scientific reports, 15(1), 39849","doi":"10.1038/s41598-025-23472-3","pmid":"41233406","tags":["medical-cannabis"],"studyType":"Observational Study","evidenceStrength":"Low","keyFinding":"Among 111 self-identified autistic adults tracking cannabis use through the Strainprint app, symptom severity ratings dropped by an average of 73% from before to after cannabis use. More severe baseline symptoms were associated with greater reductions. Higher doses predicted greater improvements in repetitive behaviors, mental control, and negative affect.","whyItMatters":"Effective pharmacological treatments for core autism symptoms remain limited. This is one of the first studies to measure perceived acute effects of cannabis on autism-specific symptoms in adults, though the self-report design means the findings are preliminary.","specificNumbers":"111 participants; average 73% reduction in symptom severity; dose remained stable over time (no escalation observed).","methodology":"Retrospective analysis of anonymized archival data from the Strainprint app. 111 self-identified autistic adults tracked symptom changes before and after cannabis use across four domains: sensory sensitivity, repetitive behaviors, mental control, and negative affect.","limitations":"Self-reported data from an app without a control group. Self-identified autism without clinical confirmation. No way to account for expectancy or placebo effects. The 73% improvement figure may reflect response bias, as users who find cannabis helpful are more likely to continue tracking."},{"rthcId":"RTHC-06795","title":"Socioeconomic status and adolescent cannabis use: a Swedish cohort study.","authors":"Karlsson, Patrik; Ekendahl, Mats; Gripe, Isabella; Raninen, Jonas","year":2025,"journal":"Journal of cannabis research, 7(1), 67","doi":"10.1186/s42238-025-00334-3","pmid":"40988061","tags":["youth","legalization"],"studyType":"Cohort Study","evidenceStrength":"Moderate","keyFinding":"Adolescents with low-SES parents had 39% lower risk of any past-year cannabis use compared to those with high-SES parents (adjusted RR = 0.61). Those with intermediate-SES parents also showed lower risk (RR = 0.71). For more frequent use (10+ times), no significant association with SES was found.","whyItMatters":"The assumption that cannabis use concentrates in disadvantaged communities does not hold everywhere. In Sweden, the pattern runs in the opposite direction for occasional use, which has implications for how prevention programs are targeted.","specificNumbers":"n = 3,328; low-SES RR = 0.61 (95% CI 0.42-0.87); intermediate-SES RR = 0.71 (95% CI 0.53-0.95); frequent use showed no significant SES association.","methodology":"Two-wave nationwide cohort study (Futura01) of 3,328 Swedish adolescents with linked register data on parental education. Used multilevel Poisson regression controlling for demographics, family and school variables, conduct and emotional problems, and baseline cannabis use.","limitations":"Swedish-specific findings may not generalize to other countries with different cannabis policies. Parental education as the sole SES measure may miss other dimensions of disadvantage. Self-reported cannabis use is subject to underreporting."},{"rthcId":"RTHC-06796","title":"Cannabinoids: Adaptogens or Not?","authors":"Karp, Federico; León, Ignacio E","year":2025,"journal":"Cannabis and cannabinoid research, 10(3), 389-399","doi":"10.1089/can.2024.0108","pmid":"40332769","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06797","title":"Global temporal and regional trends in cannabis use among medical students: A systematic review and meta-analysis.","authors":"Karpovisch, Eduardo; Alves, Gabriel Grando; Folgierini, Vicente Fichbein; Braun, Luiza Elizabete; Porto, Ighor Miron; Hoffmann, Mauricio Scopel; Pacheco, João Pedro Gonçalves","year":2025,"journal":"Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)","doi":"10.47626/1516-4446-2025-4286","pmid":"41022727","tags":["legalization"],"studyType":"Systematic Review and Meta-Analysis","evidenceStrength":"Moderate","keyFinding":"Across 62,444 medical students from 32 countries, lifetime cannabis prevalence was 29.2%, past-year 20.5%, past-month 9.2%, and past-week 5.1%. Prevalence declined from 38.4% in the 1970s to 18.1% in the 2000s, then rebounded to 30.4% in the 2020s, driven by increases in Latin America, Asia, and Africa.","whyItMatters":"Medical students represent a population that will eventually counsel patients about cannabis. Understanding their own use patterns and how those have shifted over five decades provides context for how the medical profession interfaces with cannabis culture.","specificNumbers":"109 studies; 62,444 participants; 32 countries; lifetime prevalence 29.2%; Anglo-Saxon America highest at 59.7%; Asia lowest at 11.5%; 2020s rebound to 30.4%.","methodology":"Systematic review and meta-analysis of 109 observational studies published 1971-2025, identified from six databases. Data pooled using random-effects models with subgroup analyses by gender, study cycle, school type, decade, and world region.","limitations":"Heterogeneity across 109 studies spanning five decades and 32 countries. Self-reported use subject to underreporting, especially in regions with strict prohibition. Different survey instruments and definitions of use across studies."},{"rthcId":"RTHC-06798","title":"Full-spectrum extract from Cannabis sativa DKJ127 for chronic low back pain: a phase 3 randomized placebo-controlled trial.","authors":"Karst, Matthias; Meissner, Winfried; Sator, Sabine; Keßler, Jens; Schoder, Volker; Häuser, Winfried","year":2025,"journal":"Nature medicine, 31(12), 4189-4196","doi":"10.1038/s41591-025-03977-0","pmid":"41023483","tags":["pain","medical-cannabis"],"studyType":"Randomized Controlled Trial","evidenceStrength":"High","keyFinding":"VER-01 met its primary endpoint with a mean pain reduction of 1.9 NRS points (vs. placebo difference of -0.6 points, p < 0.001) over 12 weeks. Pain continued decreasing to -2.9 points during the 6-month open-label extension. For neuropathic pain, NPSI scores decreased by 14.4 points (vs. placebo difference of -7.3, p = 0.017). No signs of dependence or withdrawal were observed.","whyItMatters":"This is one of the largest and most rigorous RCTs of a cannabis-based medicine for chronic pain to date, published in a top-tier journal. Chronic low back pain affects over half a billion people globally, and current medications carry substantial risks.","specificNumbers":"820 participants; -1.9 NRS point pain reduction (placebo difference -0.6, p < 0.001); -2.9 NRS points at 6-month extension; NPSI improvement -14.4 points (placebo difference -7.3, p = 0.017); adverse events 83.3% vs. 67.3% for placebo.","methodology":"Multicenter, randomized, placebo-controlled phase 3 trial with 820 adults with chronic low back pain. Included a 12-week double-blind phase, 6-month open-label extension, and randomized withdrawal phase. Published in Nature Medicine.","limitations":"Higher adverse event rate (83.3% vs. 67.3%), though events were mostly mild and transient. The randomized withdrawal phase did not meet its primary endpoint on time to treatment failure. Open-label extension phases lack placebo control."},{"rthcId":"RTHC-06799","title":"Development of PROTAC-Based Strategies for Cannabinoid Receptor Type 1 (CB1R) Degradation in Cancer.","authors":"Kashkush, Aseel; Tadesse, Kisanet; Furth-Lavi, Judith; Benhamou, Raphael I","year":2025,"journal":"ACS pharmacology & translational science, 8(9), 3160-3169","doi":"10.1021/acsptsci.5c00321","pmid":"40969876","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06800","title":"Perspectives of cannabis-based medicines in a view of pharmacokinetic studies of Δ9-THC and CBD in humans.","authors":"Kaszewska, Magdalena; Woźniczka, Katarzyna; Sztormowska-Achranowicz, Katarzyna; Mosińska, Agnieszka; Trojan, Václav; Schreiber, Patrik; Balog, Nikolas; Bączek, Tomasz; Roszkowska, Anna","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 192, 118673","doi":"10.1016/j.biopha.2025.118673","pmid":"41138659","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06801","title":"Wernicke's Encephalopathy Secondary to Cannabis Hyperemesis Syndrome.","authors":"Kattamuri, Lakshmi; Senapati, Sidhartha Gautam; Popuri, Harshitha; Fernandez, Lorena; Sharma, Kunal; Sirineni, Srija; Duvvuru, Sparsha Reddy; Vulisha, Abhinav","year":2025,"journal":"Journal of Brown hospital medicine, 5(1), 151455","doi":"10.56305/001c.151455","pmid":"41488447","tags":["appetite","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case describes an uncommon but serious cascade: heavy cannabis use triggered cannabinoid hyperemesis syndrome (CHS), which caused weeks of persistent vomiting, which led to severe thiamine (vitamin B1) deficiency, which ultimately caused Wernicke's encephalopathy—a neurological emergency typically associated with alcoholism.\n\nThe patient, a woman in her 20s, presented after eight weeks of nausea and vomiting. She had lost more than 10 kg of body weight. Two weeks before admission, she developed double vision, unsteady gait, and confusion—the classic triad of Wernicke's encephalopathy. Brain MRI confirmed the diagnosis, showing the characteristic symmetric thalamic lesions.\n\nThe good news: intravenous thiamine produced a rapid and dramatic recovery. The important lesson: Wernicke's encephalopathy is not just an alcoholic's disease. Any condition that causes prolonged vomiting and malnutrition—including CHS—can deplete thiamine stores enough to damage the brain.\n\nCHS itself is well-recognized: cyclic vomiting in heavy cannabis users, typically relieved by hot showers, that resolves when cannabis use stops. But this case shows that the vomiting phase can become dangerous in its own right if it persists long enough to cause nutritional deficiencies.","whyItMatters":"Most CHS discussions focus on the vomiting itself and the relief from hot showers. This case reveals a downstream risk that clinicians may not anticipate: prolonged CHS vomiting can cause nutritional deficiencies severe enough to produce brain damage. It also highlights that Wernicke's encephalopathy should be on the differential diagnosis for any patient with prolonged vomiting and new neurological symptoms—not just alcoholic patients.","specificNumbers":"8 weeks of nausea and vomiting. >10 kg weight loss. Double vision and ataxia developed 2 weeks before admission. Rapid recovery with IV thiamine.","methodology":"Single case report of a woman in her 20s presenting with Wernicke's encephalopathy secondary to thiamine deficiency caused by prolonged vomiting from cannabinoid hyperemesis syndrome. Diagnosis confirmed by brain MRI showing T2/FLAIR symmetric thalamic hyperintensities.","limitations":"Single case report—cannot establish how common this complication is among CHS patients. No information on the patient's cannabis use patterns (frequency, potency, duration). The dramatic response to thiamine confirms the diagnosis but doesn't tell us whether early supplementation could have prevented the neurological complications."},{"rthcId":"RTHC-06802","title":"Impact of COVID-19 school learning model on mental health, suicidal thoughts and behaviors, substance use, and violence related behaviors and experiences among U.S. high school students.","authors":"Katz, David A; Pampati, Sanjana; DeGue, Sarah; Ko, Jean Y; Pepin, Dawn; Copen, Casey E; Fodeman, Ari; Hamilton, Deven T","year":2025,"journal":"PLOS mental health, 2(9)","doi":"10.1371/journal.pmen.0000409","pmid":"41445805","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06803","title":"Herbicide use and weed management strategies in hemp cultivation.","authors":"Kaur, Navneet; Kumar, Anil; Malik, Tabarak; Girdhar, Madhuri; Singh, Manbir; Singh, Reenu; Tariq, Mohd; Mohan, Anand","year":2025,"journal":"Journal of cannabis research, 7(1), 27","doi":"10.1186/s42238-025-00280-0","pmid":"40380236","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06804","title":"Medical Cannabis and Epilepsy: The Evidence.","authors":"Kaur, Varinder; Deacon, Hannah; Barnes, Michael Philip; Nutt, David John","year":2025,"journal":"British journal of hospital medicine (London, England : 2005), 86(11), 1-20","doi":"10.12968/hmed.2024.0903","pmid":"41284246","tags":["medical-cannabis","cbd","epilepsy"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review summarizes the state of evidence for cannabis-based treatments in epilepsy, focusing on the two main phytocannabinoids: cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC).\n\nThe clinical need is real: roughly 30% of epilepsy patients have seizures that resist available medications. CBD has the strongest evidence base, anchored by the FDA-approved Epidiolex for Dravet syndrome and Lennox-Gastaut syndrome. THC also has demonstrated anticonvulsant properties, though its psychoactive effects complicate its clinical use.\n\nThe review traces the evidence from early animal studies through to modern clinical trials, documenting how the understanding of cannabis for epilepsy has evolved over the past few decades. The authors note that despite growing evidence, many clinicians and regulatory bodies remain reluctant to prescribe or approve cannabis-based medicines for epilepsy patients.\n\nThe gap between evidence and access is a central theme. Patients who might benefit from cannabis medicines often can't get them through standard medical channels, leading some to seek unregulated products—which raises its own safety concerns (see RTHC-00150 on unapproved CBD products in children).","whyItMatters":"For the 30% of epilepsy patients with treatment-resistant seizures, the stakes are high—uncontrolled seizures carry risks of injury, cognitive decline, and sudden death. Cannabis-based medicines represent one of the few genuinely novel approaches in a field where most drugs work through similar mechanisms. Understanding the evidence base helps patients and clinicians make informed decisions.","specificNumbers":"~30% of epilepsy patients have treatment-resistant seizures. CBD (Epidiolex) is FDA-approved for Dravet syndrome and Lennox-Gastaut syndrome. Both CBD and THC have demonstrated anticonvulsant properties in clinical studies.","methodology":"Narrative review of the clinical evidence for cannabidiol and THC in epilepsy, covering preclinical studies, clinical trials, and regulatory context.","limitations":"Narrative reviews reflect the authors' selection of evidence and may not be comprehensive. The review appears to take an advocacy-oriented perspective (calling for more access), which may influence how the evidence is presented. Some of the clinical evidence is from open-label trials without placebo controls."},{"rthcId":"RTHC-06805","title":"Wisconsin Young Adults' Attitudes, Beliefs, Motivations, and Behaviors Surrounding E-Cigarette Use and Cessation.","authors":"Kaye, Jesse T; Williams, Brian S; Bird, Jennifer; Conner, Karen L; Adsit, Rob; Piper, Megan E","year":2025,"journal":"WMJ : official publication of the State Medical Society of Wisconsin, 124(2), 129-134","doi":null,"pmid":"40690631","tags":["youth","quitting","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This survey of 480 Wisconsin residents ages 18–24 who vaped nicotine reveals a population that is motivated to quit but deeply divided on how.\n\nThe headline: 80% wanted support to quit vaping. Most had already made at least one quit attempt, typically driven by concerns about addiction, cost, and health. But here's the paradox—the same methods that some young adults endorsed as most helpful (medication, friends/family, healthcare providers, therapists) were also among the methods others said they would never want to use. There was no consensus approach.\n\nThe cannabis finding is particularly striking. Nearly 40% of participants also vaped cannabis, and they perceived cannabis vaping as significantly less harmful than nicotine vaping or tobacco for both physical and mental health. This harm perception gap matters because it may make young people less receptive to messages about reducing all substance use.\n\nThe motivational data paints a clear picture: cost and addiction concerns drove quit attempts more than health worries. For a generation that came of age with vaping, the health risks may feel abstract, while spending $30–50 per week on pods and worrying about dependence feels immediate and concrete.","whyItMatters":"Cessation programs for young vapers can't be one-size-fits-all. This data shows that the same treatment modality that appeals to one young person actively repels another. Effective programs will need to offer multiple options and let individuals choose—a personalization approach. The finding that cost and addiction (not health) drive quit motivation also suggests that health-fear messaging may be less effective than financial or autonomy-focused framing for this age group.","specificNumbers":"N = 480, ages 18–24. 80% wanted help quitting. ~40% also vaped cannabis. Cannabis vaping perceived as significantly less harmful than nicotine vaping. Most common quit motivators: addiction concerns, cost, health problems.","methodology":"Cross-sectional online survey of 480 Wisconsin residents aged 18–24 who vaped nicotine in the past month. Assessed vaping initiation, quit history, future quit intentions, treatment knowledge and preferences. Also measured perceived harms of vaping nicotine, cannabis, and CBD products.","limitations":"Wisconsin-specific sample may not generalize nationally. Online survey with self-selected participants. Self-reported vaping and cannabis use. The paradox of the same methods being both most-endorsed and most-rejected may partly reflect the survey design rather than true bimodal preferences."},{"rthcId":"RTHC-06806","title":"Tetrahydrocannabivarin (THCV) Dose Dependently Blocks or Substitutes for Tetrahydrocannabinol (THC) in a Drug Discrimination Task in Rats.","authors":"Kayir, Hakan; Kouroukis, Larissa; Aziz, Iman; Khokhar, Jibran Younis","year":2025,"journal":"Biomolecules, 15(9)","doi":"10.3390/biom15091329","pmid":"41008636","tags":["neuroscience","potency"],"studyType":"Animal Study","evidenceStrength":"Low","keyFinding":"THCV produced an inverted U-shaped response curve in THC-trained rats. At 3 mg/kg, it partially substituted for THC (54.6%). At 6 mg/kg, it reversed THC-induced responding. Blood THC levels were unchanged when combined with THCV, confirming the interaction is pharmacological rather than pharmacokinetic.","whyItMatters":"THCV is increasingly marketed as a distinct cannabinoid, but its pharmacology is complex. This study demonstrates it can act like THC or oppose THC depending on dose, which has real implications for consumers and product formulators.","specificNumbers":"16 rats; THCV at 3 mg/kg partially substituted for THC at 54.6%; THCV at 6 mg/kg reversed THC (0.75 mg/kg) responding (p = 0.040); blood THC/11-OH-THC levels unchanged by THCV co-administration.","methodology":"Drug discrimination study in 16 male Sprague-Dawley rats trained to distinguish THC (3 mg/kg) from vehicle under a fixed ratio 20 schedule. Tested THCV alone and in combination with THC, with blood cannabinoid level measurements.","limitations":"Animal study using only male rats, limiting generalizability to humans and across sexes. Drug discrimination is a behavioral proxy, not a direct measure of subjective effects. Dose ranges may not translate directly to human consumption."},{"rthcId":"RTHC-06807","title":"Full-Spectrum Medicinal Cannabis Plant Extract 0.08% THC (NTI164) Improves Symptoms of Rett Syndrome: An Open-Label Study.","authors":"Keating, B A; Ogru, Y; Duthy, T G; Douglas, L; Lichkus, K; Isikgel, E; Fahey, M C; Ellaway, C","year":2025,"journal":"Journal of paediatrics and child health","doi":"10.1111/jpc.70122","pmid":"40568811","tags":["medical-cannabis","cbd"],"studyType":"Open-Label Clinical Trial","evidenceStrength":"Low","keyFinding":"NTI164 improved global clinical impression (p = 0.028), communication skills (p = 0.003), socialization/eye contact (p = 0.0004), attentiveness (p = 0.001), anxiety (p = 0.004), and quality of life (p = 0.0002) in 11 girls with genetically confirmed Rett syndrome over 12 weeks.","whyItMatters":"Rett syndrome is a severe neurodevelopmental disorder with very limited treatment options. While this is a small open-label study, the consistency of improvements across multiple validated outcome measures is noteworthy for a condition with few effective interventions.","specificNumbers":"11 participants; improvements in communication (p = 0.003), eye contact/socialization (p = 0.0004), attentiveness (p = 0.001), anxiety (p = 0.004), quality of life (p = 0.0002), caregiver burden (p = 0.006).","methodology":"Phase I/II open-label study of 11 female participants aged 5-16 years with pathogenic MECP2 variants. NTI164 administered twice daily for 12 weeks with multiple validated outcome measures.","limitations":"Very small sample (n = 11) with no control group or blinding. Open-label design means placebo and caregiver expectation effects cannot be ruled out. 12-week duration may not capture long-term effects or tolerance."},{"rthcId":"RTHC-06808","title":"The proof is in the pudding: patient engagement in studying cannabidiol in mild cognitive impairment.","authors":"Keck, Antonia; Scheuermann, Julia-Sophia; Scheerbaum, Petra; Graessel, Elmar; Müller-Vahl, Kirsten R","year":2025,"journal":"BMC complementary medicine and therapies, 25(1), 19","doi":"10.1186/s12906-025-04753-w","pmid":"39844123","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06809","title":"Parasympathetic decreases immediately following self-reported cannabis smoking among adults living with cannabis use disorder.","authors":"Keen, Larry; Kuno, Caroline Bena; Morris, Alexis","year":2025,"journal":"International journal of psychophysiology : official journal of the International Organization of Psychophysiology, 214, 113211","doi":"10.1016/j.ijpsycho.2025.113211","pmid":"40628347","tags":["cardiovascular","addiction"],"studyType":"Observational Study","evidenceStrength":"Low","keyFinding":"In 31 young adults with CUD wearing Garmin smartwatches for 3 days, both time-domain and frequency-domain HRV metrics were significantly lower after cannabis smoking compared to before, with a corresponding increase in average heart rate.","whyItMatters":"Cannabis is often perceived as relaxing, but this study shows it acutely reduces parasympathetic nervous system activity in habitual users. For people with cannabis use disorder, repeated suppression of heart rate variability could have cardiovascular implications over time.","specificNumbers":"31 participants; 84% women; mean age 19.7 years; significant decreases in both time and frequency domain HRV after smoking; significant increase in heart rate.","methodology":"Observational study of 31 African American undergraduates (84% women, mean age 19.7) meeting criteria for CUD via the MINI interview. Participants wore Garmin smartwatches for 3 consecutive days and reported cannabis smoking sessions via survey. HRV was measured via photoplethysmography.","limitations":"Small sample (n = 31) predominantly female. Consumer-grade smartwatch HRV measurement is less precise than clinical ECG. Self-reported smoking times may be inaccurate. No control for concurrent tobacco or other substance use."},{"rthcId":"RTHC-06810","title":"Droperidol is associated with reduced length of stay in the treatment of cannabinoid hyperemesis syndrome.","authors":"Kelly, Geoffrey S; Meeks, Gavin; McCoul, Bradley; Doshi, Vidhi K; Moran, Tim P","year":2025,"journal":"Clinical toxicology (Philadelphia, Pa.), 63(8), 550-555","doi":"10.1080/15563650.2025.2516128","pmid":"40511503","tags":["harm-reduction"],"studyType":"Retrospective Cohort","evidenceStrength":"Moderate","keyFinding":"Among 211 CHS encounters, droperidol use (36.5% of cases) was associated with a 24% reduction in length of stay (mean ratio 0.76, p = 0.01), 66% lower odds of receiving additional medications (OR 0.34, p < 0.001), and 84% lower odds of opioid use (OR 0.16, p < 0.001). Median stay was 409 minutes with droperidol vs. 641 minutes without.","whyItMatters":"Cannabinoid hyperemesis syndrome is an increasingly common ER presentation with no established standard treatment. Finding an effective first-line therapy that also reduces opioid use addresses two problems at once.","specificNumbers":"211 encounters; 158 unique patients; droperidol in 36.5% at median 1.25 mg; LOS 409 vs. 641 minutes; 84% reduction in opioid use (OR 0.16); 2 mild adverse reactions.","methodology":"Retrospective study of 211 CHS encounters among 158 unique patients at two tertiary academic emergency departments in Atlanta from March-August 2024. Patients stratified by droperidol use with adjusted analyses.","limitations":"Retrospective design with potential selection bias in who received droperidol. Single health system in one city. CHS diagnosis based on ICD codes and chart review. Cannot establish causation."},{"rthcId":"RTHC-06811","title":"Cannabinoids for the prevention of chemotherapy-induced nausea and vomiting in oncological therapy: a systematic review.","authors":"Kemmner, Sarah F; Dörfler, Jennifer; Huebner, Jutta","year":2025,"journal":"Journal of cancer survivorship : research and practice","doi":"10.1007/s11764-025-01876-4","pmid":"40797063","tags":["medical-cannabis","cancer"],"studyType":"Systematic Review","evidenceStrength":"Moderate","keyFinding":"Among 32 studies (1,889 patients), 12 of 22 studies found cannabinoids significantly outperformed now-outdated antiemetics, and 8 of 9 placebo-controlled studies showed benefit. However, only one study compared cannabinoids to modern guideline-based therapy (5-HT3 + NK1 antagonists + dexamethasone), and while it showed benefit, it came with cannabinoid side effects.","whyItMatters":"Cannabinoids are often discussed as a solution for chemo nausea, but most evidence compares them to antiemetics that are no longer standard of care. Against modern three-drug antiemetic regimens, the evidence base is nearly nonexistent.","specificNumbers":"32 studies; 1,889 patients; 12/22 beat outdated antiemetics; 8/9 beat placebo; only 1 study compared to modern standard care.","methodology":"Systematic review of 32 studies from five databases comprising 1,889 cancer patients receiving various cannabinoid-based therapies (oral, approved preparations) for chemotherapy-induced nausea and vomiting.","limitations":"Most comparator studies used antiemetics no longer considered standard of care. Heterogeneous cannabinoid preparations and dosing across studies. Only oral approved preparations were studied, not the diverse cannabis products patients actually use."},{"rthcId":"RTHC-06812","title":"The Unequal Geography of Recreational Cannabis Retailers in the U.S.","authors":"Kephart, Lindsay L; Rees, Vaughan W; Giovenco, Daniel P; Subramanian, Sankaran V","year":2025,"journal":"American journal of preventive medicine, 69(2), 107643","doi":"10.1016/j.amepre.2025.107643","pmid":"40339827","tags":["legalization"],"studyType":"Cross-Sectional Study","evidenceStrength":"Moderate","keyFinding":"Across 18 legalized states, 11% of census tracts had at least one recreational cannabis retailer. Tracts with the greatest concentration of low-income Black or Hispanic residents had 2.0-2.5 times the odds of retailer presence compared to more advantaged tracts, even after adjustment.","whyItMatters":"Cannabis legalization was partly justified by reducing racial disparities in enforcement. If retailers then cluster in disadvantaged communities of color, it raises questions about whether legalization is replicating existing patterns of unequal exposure to substance retail.","specificNumbers":"5,586 retailers across 18 states; 11% of census tracts had at least 1 retailer; 2.0-2.5x higher odds in most disadvantaged tracts.","methodology":"Cross-sectional analysis of 5,586 geocoded recreational cannabis retailers from 2023 state agency lists across 18 states. Used multilevel logistic and negative binomial regression with neighborhood deprivation index and index of concentration at the extremes.","limitations":"Cross-sectional design captures a single point in time as markets are still maturing. Cannot determine causation or direction of effects. State-level variation in licensing and zoning rules not fully accounted for."},{"rthcId":"RTHC-06813","title":"Cannabis retail store density and county-level mortality from injury in the state of Washington from 2009-2020.","authors":"Kerr, William C; Ye, Yu","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(1), 107-115","doi":"10.1080/00952990.2024.2436524","pmid":"39927694","tags":["legalization","harm-reduction"],"studyType":"Ecological Study","evidenceStrength":"Moderate","keyFinding":"Cannabis store density was negatively associated with accidental poisoning deaths (IRR 0.83, 95% CI 0.73-0.93) and opioid mortality (IRR 0.83, 95% CI 0.70-0.99). No significant associations were found for motor vehicle accidents, homicide, or suicide deaths across 39 Washington counties from 2009-2020.","whyItMatters":"One of the central concerns about cannabis legalization is whether increased access leads to more injury and death. This county-level analysis from an early-legalizing state suggests the opposite for poisoning deaths, with no detectable harm across other mortality categories.","specificNumbers":"39 counties; 2009-2020; 12,933 suicide deaths; 6,761 motor vehicle deaths; 8,858 opioid deaths; store density IRR for opioid mortality 0.83; IRR for accidental poisoning 0.83; stores grew from 31 to 447.","methodology":"Fixed-effect Poisson regression using county-level mortality data from individual death records and cannabis license/sales data across 39 Washington counties for 2009-2020. Cannabis retail stores grew from 31 in 2014 to 447 in 2020.","limitations":"Ecological (county-level) design cannot establish individual-level substitution behavior. Confounders like naloxone distribution, treatment access, and prescription monitoring programs evolved during the same period. Correlation does not imply cannabis stores caused reduced mortality."},{"rthcId":"RTHC-06814","title":"Cannabis and Cognitive Function in Multiple Sclerosis: Findings From a Large Consecutive Clinical Sample.","authors":"Kever, Anne; Meza, Cecilia; Feinstein, Anthony","year":2025,"journal":"European journal of neurology, 32(7), e70142","doi":"10.1111/ene.70142","pmid":"40616362","tags":["cognition","medical-cannabis"],"studyType":"Cross-Sectional Study","evidenceStrength":"Moderate","keyFinding":"Cannabis users (n = 254) performed significantly worse than nonusers (n = 593) on the Symbol Digit Modalities Test (processing speed, p = 0.014). After adjustment, cannabis independently predicted poorer performance on SDMT, PASAT-3, and PASAT-2 (all p < 0.001), explaining 7-16% of variance.","whyItMatters":"People with MS already face cognitive challenges, particularly with processing speed. If cannabis use compounds these deficits, it is relevant information for patients using cannabis for symptom relief who may not realize the cognitive trade-off.","specificNumbers":"847 patients; 254 cannabis users (30%); significant effects on SDMT (p = 0.014); SDMT, PASAT-3, PASAT-2 all p < 0.001 after adjustment; models explained 7-16% of variance.","methodology":"Cross-sectional study of 847 consecutive MS patients administered the MACFIMS cognitive battery. Cannabis users (n = 254) compared to nonusers (n = 593) using MANOVA and multiple linear regression controlling for age, education, disease duration, anxiety, and fatigue.","limitations":"Cross-sectional design cannot determine whether cannabis caused cognitive deficits or whether those with worse cognition are more likely to use cannabis. No information on cannabis type, potency, frequency, or mode of use. Recreational users only."},{"rthcId":"RTHC-06815","title":"Association of Smoking Cannabis With Cardiovascular Events Among Veterans With Coronary Artery Disease.","authors":"Keyhani, Salomeh; Cohen, Beth E; Vali, Marzieh; Hoggatt, Katherine J; Bravata, Dawn M; Austin, Peter C; Lum, Emily; Hasin, Deborah; Grunfeld, Carl; Shlipak, Michael G","year":2025,"journal":"Circulation, 152(6), 352-365","doi":"10.1161/CIRCULATIONAHA.124.073193","pmid":"40686207","tags":["cardiovascular","medical-cannabis","seniors"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This is one of the largest and most rigorous studies to examine whether cannabis smoking affects cardiovascular outcomes in people who already have heart disease. The THC Cohort (Heart and Cannabis) followed 4,285 veterans with coronary artery disease, all born between 1950 and 1952, from their initial interview through follow-up.\n\nParticipants were classified by their self-reported cannabis smoking status in the past 30 days. The primary outcome was a composite of fatal and nonfatal stroke, fatal and nonfatal heart attack, and cardiovascular death.\n\nThe study found an association between cannabis smoking and higher rates of these cardiovascular events. In a separate analysis, any form of cannabis use (smoking, vaping, or edibles) versus nonuse was also examined.\n\nSeveral features make this study notable. The population is highly relevant—older adults with existing heart disease who are increasingly using cannabis as it becomes legal. The VA dataset provided comprehensive clinical data from both interviews and medical records (VA and Medicare). And the birth cohort design (all participants born 1950–1952) controls for generational differences in cannabis exposure and attitudes.\n\nHowever, the observational design means the association could be confounded by differences between cannabis users and non-users that weren't fully captured—lifestyle factors, other substance use, or unmeasured health behaviors.","whyItMatters":"The intersection of aging, heart disease, and cannabis use is becoming a critical clinical question as baby boomers—the generation most likely to have used cannabis historically—age into the highest-risk period for cardiovascular disease. This study provides the first large-scale data on that intersection, though it can't definitively answer whether cannabis causes cardiovascular events or merely correlates with other risk factors.","specificNumbers":"N = 4,285. Mean age 67.5 years. 2% female. All had coronary artery disease. Recruited 2018–2020. Primary outcome: composite of stroke, MI, and cardiovascular death.","methodology":"Prospective observational cohort study. 4,285 veterans (mean age 67.5, 2% female) with coronary artery disease, born 1950–1952, recruited April 2018 to March 2020. Cannabis smoking status classified by self-report in the past 30 days. Separate analysis for any cannabis use (smoking, vaping, edibles). Primary outcome: composite of fatal/nonfatal stroke, fatal/nonfatal MI, and cardiovascular death. Data from telephone interviews, VA records, and Medicare claims.","limitations":"Observational design—cannot prove causation. Overwhelmingly male (98%) veteran population limits generalizability. Self-reported cannabis use may underestimate true prevalence. Confounders like tobacco smoking, alcohol use, and medication adherence could drive the association. The 30-day use window is a crude measure that doesn't capture dose, frequency, or potency."},{"rthcId":"RTHC-06816","title":"Patterns, Efficacy, and Cognitive Effects of Medical Cannabis Use in Chronic Musculoskeletal Pain Patients.","authors":"Khak, Mohammad; Ramtin, Sina; Chung, Juliet; Ilyas, Asif M; Greis, Ari","year":2025,"journal":"Cureus, 17(5), e84102","doi":"10.7759/cureus.84102","pmid":"40519367","tags":["pain","medical-cannabis","cognition"],"studyType":"Prospective Survey","evidenceStrength":"Low","keyFinding":"In a prospective survey of 129 long-term medical cannabis users with chronic musculoskeletal pain, 93.8% agreed or strongly agreed that cannabis improved their primary symptoms. 77.5% used daily or near-daily. 72.1% reported no cognitive or motor effects. 79.8% reported stable usage over 3 months with minimal dose escalation.","whyItMatters":"Long-term data on medical cannabis use patterns are scarce. This study provides a window into how patients actually use medical cannabis over time, including the notable finding that most report stable use without dose escalation.","specificNumbers":"129 patients; 93.8% reported symptom improvement; 77.5% used daily/near-daily; 72.1% reported no cognitive impact; 79.8% stable usage; 63.6% used topical formulations; ~50% unsure of exact THC/CBD dosage.","methodology":"Prospective study of 129 patients certified for medical cannabis in Pennsylvania for at least one year (October 2022-December 2024). Patients completed the Inventory of Medical Cannabis Use questionnaire assessing usage patterns, dosing knowledge, efficacy, and cognitive effects.","limitations":"Self-reported outcomes without objective measures. No control group. Pennsylvania medical cannabis program may not represent other states. Survivorship bias: patients who stopped medical cannabis were not captured."},{"rthcId":"RTHC-06817","title":"Low-dose metoclopramide-induced dystonia in cannabis withdrawal syndrome manifesting as intractable nausea and vomiting.","authors":"Khamis, Alia; Dygulski, Sylvia","year":2025,"journal":"BMJ case reports, 18(5)","doi":"10.1136/bcr-2025-264815","pmid":"40379294","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06818","title":"A Systematic Review of Neurophysiological and Self-Report Psychological Inventories for Cannabis Use Disorder.","authors":"Khattak, Alam Zeb; Zaman, Sabir; Bukhari, Ashfaq Ahmad Shah; Shah, Sajid Usman; Abdullah, Mudassar; Wazir, Sidratul Muntaha","year":2025,"journal":"Applied neuropsychology. Adult, 1-10","doi":"10.1080/23279095.2025.2582149","pmid":"41212782","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06819","title":"The impact of cannabis use on cortical excitability and inhibitory mechanisms: A case-control study.","authors":"Khedr, Eman M; Elserogy, Yasser; Ahmed, Gellan K","year":2025,"journal":"Psychiatry research, 351, 116617","doi":"10.1016/j.psychres.2025.116617","pmid":"40617198","tags":["neuroscience"],"studyType":"Case-Control Study","evidenceStrength":"Low","keyFinding":"Cannabis users (n = 16) showed significantly higher motor evoked potential amplitude at 130% of resting motor threshold (p = 0.012), delayed cortical silent period onset at multiple intensities, and reduced short-latency intracortical inhibition at 4 ms interstimulus interval (p = 0.028). Resting motor threshold correlated negatively with addiction severity (p = 0.026).","whyItMatters":"This is direct neurophysiological evidence that cannabis use alters the balance between excitation and inhibition in the brain. The correlation between motor threshold and addiction severity suggests these changes track with heavier use.","specificNumbers":"16 cannabis users vs. 20 controls; MEP amplitude increased (p = 0.012); CSP onset delayed (p = 0.018-0.036); SICI reduced at ISI 4 ms (p = 0.028); RMT correlated with addiction severity (p = 0.026).","methodology":"Case-control study comparing 16 cannabis users and 20 controls using transcranial magnetic stimulation (TMS) measures of cortical excitability and inhibition, alongside clinical assessments including SCL-90-R, MoCA, and Hamilton anxiety/depression scales.","limitations":"Very small sample (16 vs. 20). Cross-sectional design cannot determine whether cannabis caused the changes or whether people with different baseline excitability are more drawn to cannabis. No information on duration or amount of use."},{"rthcId":"RTHC-06820","title":"Ever cannabis use and biomarkers of male fecundity - A study in the Danish National Birth Cohort.","authors":"Khoury, Georges; Dan Hull, Sidsel; Ramlau-Hansen, Cecilia Høst; Sørensen, Anne Gaml; Hougaard, Karin Sørig; Petersen, Kajsa Ugelvig; Toft, Gunnar; Deen, Laura; Bonde, Jens Peter; Tøttenborg, Sandra Søgaard","year":2025,"journal":"Reproductive toxicology (Elmsford, N.Y.), 137, 109004","doi":"10.1016/j.reprotox.2025.109004","pmid":"40695409","tags":["sex-differences"],"studyType":"Cohort Study","evidenceStrength":"Moderate","keyFinding":"In a cohort of 1,058 young men (59% had ever used cannabis), no associations were found between cannabis use and semen volume, concentration, total count, motility, morphology, or DNA fragmentation. The only signal was a non-significant 8% increase in FSH levels among ever-users (95% CI: -2% to 20%).","whyItMatters":"Previous studies on cannabis and male fertility have produced conflicting results, partly due to poor control for confounders. This study uniquely incorporates fetal-life exposure data, addressing a key limitation of prior research.","specificNumbers":"1,058 men; 59% ever-used cannabis; no significant associations with any semen parameter; FSH 8% higher in ever-users (95% CI: -2% to 20%, not significant).","methodology":"Sub-cohort of the Danish National Birth Cohort (Fetal Programming of Semen Quality cohort). 1,058 young men with self-reported cannabis use linked to clinical semen analysis, reproductive hormone measurements, and detailed information on fetal-life exposures.","limitations":"Ever-use is a crude exposure measure that does not capture frequency, quantity, or recency. Self-reported cannabis use may underestimate actual exposure. Single semen sample per participant. Young age means long-term effects may not yet be apparent."},{"rthcId":"RTHC-06821","title":"Influence of Substance Use Disorders on Mortality in a Systemwide Cohort of Cancer Patients.","authors":"Khoyilar, Shawnly; Purushothaman, Vidya; Cuomo, Raphael E","year":2025,"journal":"Psycho-oncology, 34(8), e70243","doi":"10.1002/pon.70243","pmid":"40879190","tags":["cancer","addiction"],"studyType":"Retrospective Cohort","evidenceStrength":"Moderate","keyFinding":"Cannabis dependence was not significantly associated with mortality among cancer patients. In contrast, alcohol and opioid dependence remained significant predictors of mortality after adjusting for tumor stage. Tobacco dependence showed an attenuated association after stage adjustment, suggesting confounding by later-stage diagnosis.","whyItMatters":"Cancer patients sometimes worry that cannabis use might worsen their prognosis. This large study suggests cannabis dependence, unlike alcohol or opioid dependence, does not appear to independently increase mortality risk in cancer patients.","specificNumbers":"22,763 cancer patients; cannabis dependence not significant for mortality; alcohol and opioid dependence significant in adjusted models; tumor stage adjustment reduced opioid and tobacco hazard ratios.","methodology":"Retrospective analysis of 22,763 cancer patients aged 18+ from UC San Diego Health. Substance dependence identified from electronic health records. Cox proportional hazards models adjusted for tumor staging (TNM system with imputed missing data).","limitations":"Substance dependence from clinical notes may undercount actual use. Small sample of cannabis-dependent patients limits power. Single health system. Cannot distinguish between types/amounts of cannabis use. Observational design with potential unmeasured confounders."},{"rthcId":"RTHC-06822","title":"Accidental ingestion of cannabis in two infants and a preschool child reported by the Tunisian poison control center: Three case reports and review of literature.","authors":"Kilani, Mohamed; Khelifa, Sabrine; Jeddi, Camillia; Thabet, Hafedh","year":2025,"journal":"La Tunisie medicale, 103(3), 383-387","doi":"10.62438/tunismed.v103i3.5452","pmid":"41712840","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06823","title":"The impact of recreational cannabis legalization on cannabis-related acute care events among adults with schizophrenia.","authors":"Kim, Chungah; Bai, Yihong; Cao, Peiya; Ienciu, Kristine; Chum, Antony","year":2025,"journal":"Social psychiatry and psychiatric epidemiology, 60(6), 1391-1398","doi":"10.1007/s00127-024-02773-4","pmid":"39387895","tags":["psychosis","legalization"],"studyType":"Interrupted Time-Series","evidenceStrength":"Moderate","keyFinding":"Phase 1 legalization (flower/herbs) was associated with a 25.8% immediate decrease in cannabis-related ED visits among men with schizophrenia (95% CI 13.8-37.6%) and an 18.5% decrease in mental health-related ED visits among women (95% CI 6.0-31.2%). These decreases were specific to schizophrenia patients, not reflecting general population trends. Phase 2 (edibles/extracts) showed no significant changes.","whyItMatters":"People with schizophrenia were among the populations most feared to be harmed by legalization. This large-scale analysis from a universal healthcare system found the opposite: ER visits decreased after legalization, possibly because regulated products are safer than illicit ones.","specificNumbers":"121,061 schizophrenia patients; 25.8% decrease in cannabis ED visits (men); 18.5% decrease in mental health ED visits (women); changes distinct from general population trends.","methodology":"Interrupted time-series analysis using linked Ontario health administrative data for 121,061 adults with schizophrenia from October 2015 to May 2021. Compared trends across pre-legalization, phase 1 (flowers/herbs), and phase 2 (edibles/extracts) with comparative ITS against general population.","limitations":"Observational design cannot prove legalization caused the decreases. COVID-19 overlapped with the study period and may have reduced ED visits generally. ICD-coded diagnoses may not perfectly capture CHS or cannabis-related presentations. Ontario-specific findings."},{"rthcId":"RTHC-06824","title":"The Effects of Child Mental Health on Juvenile Criminal Justice Contact and Victimization.","authors":"Kim, Dohyung","year":2025,"journal":"The journal of mental health policy and economics, 28(1), 33-46","doi":null,"pmid":"40040435","tags":["youth","addiction"],"studyType":"Longitudinal Cohort","evidenceStrength":"Moderate","keyFinding":"Early-onset cannabis use strongly predicted lifetime arrest (p = 0.013), probation (p = 0.034), and incarceration (p = 0.093) by age 18. After adjusting for comorbid mental disorders and family-level unobserved factors using sibling comparisons, ADHD, ODD, and anxiety/depression were not independently associated with criminal justice contact. Only conduct disorder modestly predicted victimization. Effects were mostly driven by boys.","whyItMatters":"By using sibling comparisons, this study controls for family environment and shared genetics that typically confound the link between substance use and delinquency. The finding that cannabis use outpredicts childhood mental disorders for justice contact is striking.","specificNumbers":"721 sibling pairs; 1997-2019 follow-up; early cannabis use predicted arrest (p = 0.013), probation (p = 0.034), incarceration (p = 0.093); effects driven by boys.","methodology":"Longitudinal study of 721 sibling pairs from the Panel Study of Income Dynamics, followed from 1997-2019. Used sibling fixed-effects models to control for shared family environment and genetic factors. Child mental health measured by the Behavior Problems Index (ages 4-12); delinquency measured by self-reported justice system contact by age 18.","limitations":"Mother-reported mental health measures. No information on treatment for mental disorders (especially ADHD medication). Self-reported justice contact. Cannot fully disentangle whether cannabis causes delinquency or both reflect unmeasured risk factors. Partial genetic control via sibling design."},{"rthcId":"RTHC-06825","title":"Characterization of terpene extract from Cannabis sativa flower and evaluation of its anti-melanogenetic effect in melan-a cells.","authors":"Kim, Jin-Woo; Han, Yongseong; Dorjsembe, Banzragch; Chang, Pahn-Shick; Kim, Taejung; Ham, Jungyeob; Kim, Jin-Chul","year":2025,"journal":"Scientific reports, 15(1), 26231","doi":"10.1038/s41598-025-10820-6","pmid":"40683942","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06826","title":"Cannabigerol Exerts In Vivo and In Vitro Anti-Inflammatory Effects via Inhibition of the MAPK and NF-κB Pathways.","authors":"Kim, Jong-Hui; Hong, Min; Han, Joon-Hee; Ryu, Byeong Ryeol; Lim, Jung Dae; Kim, Keun-Cheol; Kim, Chang-Hyeug; Lee, Soo-Ung; Kwon, Tae-Hyung","year":2025,"journal":"Journal of microbiology and biotechnology, 35, e2509034","doi":"10.4014/jmb.2509.09034","pmid":"41423277","tags":["inflammation","cbd"],"studyType":"Preclinical Study","evidenceStrength":"Low","keyFinding":"CBG suppressed nitric oxide production and reduced mRNA/protein expression of inflammatory mediators (COX-2, iNOS, TNF-alpha, IL-1beta, IL-6) through MAPK and NF-kB pathway downregulation in LPS-stimulated macrophages. In a carrageenan-induced mouse paw edema model, oral CBG suppressed inflammatory gene expression, though paw edema reduction was not statistically significant.","whyItMatters":"CBG is gaining commercial attention as a \"next cannabinoid\" after CBD, but its mechanisms are less studied. This research maps specific anti-inflammatory pathways (MAPK, NF-kB) that CBG targets, building the mechanistic case for its anti-inflammatory potential.","specificNumbers":"Suppressed COX-2, iNOS, TNF-alpha, IL-1beta, and IL-6 expression in vitro; oral CBG suppressed same markers in vivo; paw edema reduction not statistically significant.","methodology":"In vitro experiments using RAW 264.7 mouse macrophages stimulated with LPS. In vivo carrageenan-induced paw edema model in mice with oral CBG administration. CBG extracted from the cannabis cultivar \"Pink Pepper.\"","limitations":"Preclinical study with no human data. Paw edema (the primary in vivo endpoint) was not significantly reduced despite molecular changes. Single mouse model. Dose-response relationships not fully characterized."},{"rthcId":"RTHC-06827","title":"Effect of Hormonal Treatments on Cannabinoid Content Levels in Female Hemp (Cannabis sativa L.) Inflorescences.","authors":"Kim, Juyoung; Kim, Dong-Gun; Ha, Tae Hyun; Kim, Woon Ji; Ryu, Jaihyunk; Kim, Jin-Baek; Kim, Sang Hoon","year":2025,"journal":"International journal of molecular sciences, 26(7)","doi":"10.3390/ijms26073445","pmid":"40244383","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06828","title":"Illicit Drug-Derived Volatile Organic Compounds as Markers for Application in Noncontact Detection Technology.","authors":"Kim, Minwoo; Lee, Solpa; Kim, Anmo J; Wang, Cong; Jang, Yongwoo","year":2025,"journal":"Chemical record (New York, N.Y.), e202500144","doi":"10.1002/tcr.202500144","pmid":"41388978","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06829","title":"Ultra-Sensitive Biosensor Based on Cell-Derived Nanovesicles for CB1 Receptor-Targeted Drug Development in a Live Cell-Free Platform.","authors":"Kim, Minwoo; Kim, Hyungsup; Lee, Solpa; Lim, Inje; Kim, Eunyoung; Oh, Uhtaek; Jang, Yongwoo","year":2025,"journal":"Analytical chemistry, 97(17), 9284-9290","doi":"10.1021/acs.analchem.4c06959","pmid":"40279503","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06830","title":"Cannabidiol Suppresses EMT in Pancreatic Cancer via Inhibition of MALAT1 lncRNA and PI3K/Akt/mTOR Signaling Pathway.","authors":"Kim, Na Young; Jung, Young Yun; Um, Jae-Young; Ahn, Kwang Seok","year":2025,"journal":"IUBMB life, 77(8), e70042","doi":"10.1002/iub.70042","pmid":"40767250","tags":["cbd","cancer"],"studyType":"Preclinical Study","evidenceStrength":"Low","keyFinding":"CBD suppressed CXCR4/CXCR7 and MMP-2/9 expression, reducing migration and invasion in three pancreatic cancer cell lines. It reversed CXCL12-induced EMT by downregulating mesenchymal markers and restoring epithelial markers. CBD inhibited the long non-coding RNA MALAT1, and its overexpression reversed CBD effects. CBD plus gemcitabine showed synergistic inhibition of EMT and PI3K/Akt/mTOR signaling without additional cytotoxicity.","whyItMatters":"Pancreatic cancer has one of the worst prognoses of any cancer, largely because it metastasizes aggressively. If CBD can inhibit the EMT process that enables spread, it could complement existing chemotherapy, though this remains preclinical evidence.","specificNumbers":"Tested in 3 cell lines; suppressed CXCR4/CXCR7, MMP-2/9; inhibited MALAT1 lncRNA; reversed EMT markers; synergy with gemcitabine in 3D spheroid models.","methodology":"In vitro studies using MIA PaCa-2, PANC-1, and AsPC-1 pancreatic cancer cell lines. Assessed CBD effects on EMT markers, MALAT1 expression, PI3K/Akt/mTOR pathway, and invasion/migration. 3D spheroid models used for combination therapy with gemcitabine.","limitations":"All work done in cell lines and 3D spheroids, not in animals or humans. CBD concentrations used in vitro may not be achievable in vivo. Pancreatic tumors in patients have complex microenvironments not captured by cell culture."},{"rthcId":"RTHC-06831","title":"Unlocking safety: a mathematical model and selective extraction for Δ9-THC removal from hemp seed husks.","authors":"Kim, Namsoo P; Aditiya, Abhilash; Min, Too Jae","year":2025,"journal":"Journal of cannabis research, 7(1), 91","doi":"10.1186/s42238-025-00349-w","pmid":"41250237","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06832","title":"Multi-Modal Cannabis Use Among U.S. Young Adults: Findings from the 2022 and 2023 BRFSS in 23 States.","authors":"Kim, Nayoung; Flora, Sarah; Macander, Casey Elizabeth","year":2025,"journal":"International journal of environmental research and public health, 22(4)","doi":"10.3390/ijerph22040495","pmid":"40283724","tags":["legalization","youth"],"studyType":"Cross-Sectional Study","evidenceStrength":"Moderate","keyFinding":"Among 7,635 young adults (18-34) reporting current cannabis use across 23 states, 57% used multiple modes (smoking, vaping, edibles, dabbing, etc.). Dual and triple-mode use were most common. Predictors of multi-modal use included recreational legalization, sexual minority status, poor physical health, frequent cannabis use, and co-use of e-cigarettes and alcohol.","whyItMatters":"Most cannabis research treats use as a binary (yes/no), but multi-modal use means different absorption rates, different health risks, and potentially different addiction profiles. Understanding that most young adult users are combining methods changes how we assess exposure.","specificNumbers":"n = 7,635 (weighted 7.48 million); 57% multi-modal users; dual and triple-mode most common; recreational legalization significantly associated with multi-modal use.","methodology":"Cross-sectional analysis of 2022-2023 BRFSS data from 23 states (weighted n = 7,482,134). Multi-modal use defined as two or more administration methods in the past month. Logistic regression for predictors.","limitations":"BRFSS is self-reported via telephone. Multi-modal use definition (2+ methods in past month) does not capture frequency of each mode. Only 23 states participated in the cannabis module. Cross-sectional design."},{"rthcId":"RTHC-06833","title":"Genome x Environment analysis of Sudden Unexpected Infant Death unveils etiologic heterogeneity and strong cannabis and genetic disease risks.","authors":"Kingsmore, Stephen F; Bandoli, Gretchen; Helbling, Daniel C; Baer, Rebecca; Blincow, Eric; Cao, Bryant; Frise, Erwin; Heinen, Alaina; Jelliffe-Pawlowski, Laura; Kobayashi, Erica Sanford; Kraan, Lucita Van Der; Kwon, Hugh; Lavy, Rishona; Moore, Barry; Oh, Danny; Oltman, Scott; Eric Ontiveros; Protopsaltis, Liana; Yandell, Mark; Chambers, Christina D","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.11.26.25341098","pmid":"41358299","tags":["pregnancy"],"studyType":"Cohort Study","evidenceStrength":"Moderate","keyFinding":"Among 212 SUID cases and 620,392 controls born in San Diego County (2005-2018), prenatal cannabis use was associated with an adjusted hazard ratio of 3.7 for SUID. When cases with strong genetic risk factors were removed, the cannabis association strengthened to aHR 6.0. WGS identified probable or possible genetic etiologies in 16% and 48% of SUID cases, with extreme genetic heterogeneity (144 loci, 173 risks).","whyItMatters":"This is the first large-scale study to combine genetic and environmental risk factors for SUID. The finding that cannabis risk strengthens after removing genetic cases suggests it operates through a different mechanism than the genetic causes, possibly representing a truly environmental risk.","specificNumbers":"212 SUID cases; 620,392 controls; cannabis aHR 3.7 (overall), 6.0 (after removing genetic cases); 16% probable genetic etiology; 48% possible genetic etiology; 144 loci contributing 173 risks.","methodology":"Genome-environment analysis linking births in San Diego County (2005-2018) to hospital discharge summaries and death files. 212 SUID cases vs. 620,392 controls. Whole genome sequencing of SUID cases combined with environmental risk factor analysis.","limitations":"Preprint (not yet peer-reviewed). Prenatal cannabis identified from hospital records, likely underestimating true exposure. Cannot separate cannabis from polysubstance use entirely. San Diego County may not represent all populations. Genetic analysis of cases only, not controls."},{"rthcId":"RTHC-06834","title":"Genetic influences for distinct impulsivity domains are differentially associated with early substance use initiation: Results from the ABCD Study.","authors":"Kinstler, Ethan; Gorelik, Aaron J; Paul, Sarah E; Aggarwal, Adamya; Johnson, Emma C; Cyders, Melissa A; Agrawal, Arpana; Bogdan, Ryan; Miller, Alex P","year":2025,"journal":"Psychological medicine, 55, e313","doi":"10.1017/S0033291725101931","pmid":"41114439","tags":["genetics","youth","addiction"],"studyType":"Longitudinal Cohort","evidenceStrength":"Moderate","keyFinding":"Among 4,808 adolescents in the ABCD Study, sensation-seeking polygenic scores significantly predicted any substance use initiation (OR > 1.10) and alcohol use initiation by age 15. Positive urgency PGS predicted nicotine initiation (OR > 1.06). No polygenic scores were significantly associated with cannabis use initiation specifically. Measured impulsivity accounted for only 5-9% of PGS-substance use associations.","whyItMatters":"Understanding which genetic dispositions toward impulsivity drive early substance use helps target prevention efforts. The finding that sensation seeking, not urgency or lack of premeditation, is the key genetic pathway suggests prevention should focus on providing alternative high-stimulation activities.","specificNumbers":"4,808 adolescents; sensation-seeking PGS OR > 1.10 for any substance/alcohol initiation; positive urgency PGS OR > 1.06 for nicotine; no significant PGS for cannabis; measured impulsivity mediated 5-9% of associations.","methodology":"Analysis of 4,808 European-ancestry participants in the ABCD Study. Polygenic scores for five UPPS-P impulsivity domains tested against substance use initiation by age 15. Mediation models assessed whether measured child impulsivity (ages 9-11) explained PGS-substance use links.","limitations":"Limited to European-ancestry participants. PGS capture only a fraction of genetic risk. Self-reported substance use initiation. Short follow-up (to age 15). Cannot rule out gene-environment correlation."},{"rthcId":"RTHC-06835","title":"Genetic influences for distinct impulsivity domains are differentially associated with early substance use initiation: Results from the ABCD Study.","authors":"Kinstler, Ethan; Gorelik, Aaron J; Paul, Sarah E; Aggarwal, Adamya; Johnson, Emma C; Cyders, Melissa A; Agrawal, Arpana; Bogdan, Ryan; Miller, Alex P","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.04.14.25325687","pmid":"40321268","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06836","title":"The neural and psychophysiological effects of cannabidiol in youth with alcohol use disorder: A randomized controlled clinical trial.","authors":"Kirkland, Anna E; Browning, Brittney D; Meredith, Lindsay R; Robertson, Elizabeth; Herring, Cori; Tomko, Rachel L; Gray, Kevin M; Squeglia, Lindsay M","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(10), 1482-1492","doi":"10.1038/s41386-025-02141-z","pmid":"40500407","tags":["cbd","addiction","youth"],"studyType":"Randomized Controlled Trial","evidenceStrength":"Moderate","keyFinding":"In a within-subjects, double-blind, placebo-controlled trial of 36 youth (ages 17-22) with AUD, acute 600mg CBD showed no significant effects on anterior cingulate cortex glutamate/glutamine or GABA levels, whole-brain or region-of-interest alcohol cue-reactivity on fMRI, psychophysiological response to alcohol cues (HRV, skin conductance, subjective craving), or alcohol use. No adverse events were observed.","whyItMatters":"Preclinical studies suggested CBD could reduce alcohol use, generating excitement about CBD as a treatment. This first adequately powered human trial in youth found no effects on any outcome, tempering enthusiasm and suggesting chronic administration may be needed.","specificNumbers":"36 participants; 600mg CBD single dose; 69% female; ages 17-22; no significant effects on any of the multiple outcomes measured.","methodology":"Within-subjects, randomized, double-blind, placebo-controlled design. 36 non-treatment-seeking youth with AUD (69% female, ages 17-22). Multi-modal outcomes including proton MRS, fMRI cue-reactivity, psychophysiological measures, and alcohol use tracking.","limitations":"Single acute dose may not capture effects that require chronic administration. Relatively small sample (n = 36). Non-treatment-seeking participants may differ from those motivated to reduce drinking. Within-subjects design controls for individual differences but may introduce order effects."},{"rthcId":"RTHC-06837","title":"Neurometabolite Alterations Associated With Cannabis Use: A Proton Magnetic Resonance Spectroscopy Meta-Analysis.","authors":"Kirkland, Anna E; Browning, Brittney D; Green, ReJoyce; Agbeh, Samuel O; Squeglia, Lindsay M","year":2025,"journal":"Human brain mapping, 46(8), e70236","doi":"10.1002/hbm.70236","pmid":"40421881","tags":["neuroscience","cognition"],"studyType":"Meta-Analysis","evidenceStrength":"Low","keyFinding":"Compared to controls, cannabis users showed lower GABA and N-acetylaspartate (a marker of neural health) in the anterior cingulate cortex, lower glutamate in the basal ganglia/striatum, and lower glutamine and myo-inositol in the thalamus. All models had only 2-5 studies each.","whyItMatters":"This is the first meta-analysis to consolidate brain chemistry studies in cannabis users. Altered GABA, glutamate, and NAA levels point to specific neurochemical pathways affected by cannabis, which could inform development of treatments for cannabis use disorder.","specificNumbers":"15 studies; 29 models; lower GABA and NAA in anterior cingulate; lower glutamate in basal ganglia; lower glutamine and myo-inositol in thalamus; all models had 2-5 studies.","methodology":"Meta-analysis of 15 proton magnetic resonance spectroscopy (1H-MRS) studies using Hedges g with random-effects modeling. 29 models across gray matter brain regions. Pre-registered on PROSPERO.","limitations":"Very few studies per model (2-5), severely limiting statistical power and reliability. Could not test impacts of demographics, substance use patterns, or methodological factors. High heterogeneity across studies. Cross-sectional designs in underlying studies."},{"rthcId":"RTHC-06838","title":"Weeding Out the Problem: Associations of Cannabis and Tobacco Use with Complications of Surgical Fixation of Metacarpal Fracture.","authors":"Kishan, Arman; Bergstein, Victoria E; Kishan, Ansh; Jankowski, Pawel; Tuffaha, Sami H; Laporte, Dawn M","year":2025,"journal":"The journal of hand surgery Asian-Pacific volume, 30(5), 506-513","doi":"10.1142/S2424835525500456","pmid":"40583362","tags":["harm-reduction"],"studyType":"Retrospective Cohort","evidenceStrength":"Moderate","keyFinding":"Compared to controls, cannabis users (6.7% of cohort) had higher rates of acute kidney injury, cardiac arrest, DVT, hypoglycemia, MI, pneumonia, sepsis, stroke, UTI, surgical site infection, and fracture malunion after metacarpal fracture fixation. However, compared to tobacco users, cannabis users had fewer complications including lower rates of pneumonia, UTI, and surgical revision.","whyItMatters":"As surgeons increasingly encounter patients who use cannabis, understanding perioperative risk profiles becomes essential. This large study provides specific complication data that can inform preoperative counseling and perioperative management.","specificNumbers":"80,787 patients; 5,043 (6.7%) with cannabis use disorder; higher rates of 9 medical complications and 2 surgical complications vs. controls; fewer complications than tobacco users for several outcomes.","methodology":"Retrospective analysis of 80,787 patients from a US insurance claims database (2010-2022) who underwent metacarpal fracture fixation. 5,043 had diagnosed cannabis use disorder. Propensity matched for age, sex, and Charlson Comorbidity Index.","limitations":"Claims database cannot determine causation. Cannabis use identified by diagnosis codes likely underestimates prevalence and overrepresents heavy users. Cannot control for all confounders. Propensity matching for only three variables."},{"rthcId":"RTHC-06839","title":"Tetrahydrocannabinol Intoxication from Food at a Restaurant - Wisconsin, October 2024.","authors":"Kita-Yarbro, Amanda; Moccero, Stefanie; Brobston, Katie; Goebel, Jacob; Banks, Janice Block; Vogt, Christy; Schumann, Casey; Grande, Katarina M; Olsen, Julia; Armstrong, Bonnie","year":2025,"journal":"MMWR. Morbidity and mortality weekly report, 74(27), 439-442","doi":"10.15585/mmwr.mm7427a2","pmid":"40705679","tags":["legalization","harm-reduction"],"studyType":"Outbreak Investigation","evidenceStrength":"Moderate","keyFinding":"After a restaurant ran out of cooking oil and used oil from a shared kitchen that contained hemp-derived delta-9-THC, 85 people met the case definition for THC intoxication. Affected individuals ate pizza, garlic bread, cheese bread, or grinder sandwiches and developed symptoms within 5 hours. Seven were transported to hospitals.","whyItMatters":"This MMWR report documents a mass unintentional THC exposure event that illustrates the regulatory gaps around hemp-derived THC products in food preparation settings. As these products become more common, the risk of accidental exposure increases.","specificNumbers":"85 cases; 7 hospital transports; symptoms occurred within 5 hours; affected products: pizza, garlic bread, cheese bread, grinders; 3-day exposure period (October 22-24, 2024).","methodology":"Outbreak investigation by Public Health Madison & Dane County using online food/symptom questionnaire distributed via press release and social media. 107 valid responses analyzed; 85 met case definition requiring food exposure and at least one THC intoxication symptom within 5 hours.","limitations":"Case ascertainment relied on self-report via online questionnaire. Actual number of affected individuals likely higher than 85. No THC blood testing was performed on most affected individuals. The exact THC content of the contaminated oil was not reported."},{"rthcId":"RTHC-06840","title":"Cannabis use and illicit opioid cessation among people who use drugs living with chronic pain.","authors":"Kitchen, Chenai; Socias, Eugenia; Sayre, Eric C; Hayashi, Kanna; DeBeck, Kora; Milloy, M-J; Kerr, Thomas; Reddon, Hudson","year":2025,"journal":"Drug and alcohol review, 44(3), 799-810","doi":"10.1111/dar.14014","pmid":"40011075","tags":["pain","harm-reduction","addiction"],"studyType":"Prospective Cohort","evidenceStrength":"Moderate","keyFinding":"Daily cannabis use was associated with a 40% higher rate of opioid cessation (adjusted HR 1.40, 95% CI 1.08-1.81, p = 0.011). In sex-stratified analysis, the association was significant in men (aHR 1.50, 95% CI 1.09-2.08, p = 0.014) but not women. Over 1,038 person-years, 764 participants experienced an opioid cessation event, yielding a rate of 28.5 per 100 person-years.","whyItMatters":"During the ongoing opioid overdose crisis, finding tools that help people stop illicit opioid use could save lives. This study provides real-world evidence that daily cannabis use may facilitate opioid cessation in a high-risk population with chronic pain.","specificNumbers":"1,242 participants; 764 cessation events over 1,038 person-years; daily cannabis aHR 1.40 (95% CI 1.08-1.81); men aHR 1.50 (95% CI 1.09-2.08); cessation rate 28.5 per 100 person-years.","methodology":"Prospective cohort study drawing from three cohort studies of people who use drugs in Vancouver, Canada (June 2014-May 2022). 1,242 participants with chronic pain and unregulated opioid use. Extended Cox regression with time-updated covariates.","limitations":"Observational design cannot prove cannabis caused opioid cessation. Self-reported substance use. Vancouver-specific population of street-involved PWUD may not generalize. Cannot distinguish between cannabis products or cannabinoid profiles."},{"rthcId":"RTHC-06841","title":"Pharmacokinetics of cannabidiol, (-)-trans-Δ9-tetrahydrocannabinol, and their oxidative metabolites after intravenous and oral administration of a cannabidiol-dominant full-spectrum hemp product to beagle dogs.","authors":"Kitts-Morgan, Susanna E; Sams, Richard A; Muir, William W","year":2025,"journal":"Frontiers in veterinary science, 12, 1556975","doi":"10.3389/fvets.2025.1556975","pmid":"40264990","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06842","title":"Endocannabinoid Tone and Oxylipins in Rheumatoid Arthritis and Osteoarthritis-A Novel Target for the Treatment of Pain and Inflammation?","authors":"Klawitter, Jost; Clauw, Andrew D; Seifert, Jennifer A; Klawitter, Jelena; Tompson, Bridget; Sempio, Cristina; Ingram, Susan L; Christians, Uwe; Moreland, Larry W","year":2025,"journal":"International journal of molecular sciences, 26(12)","doi":"10.3390/ijms26125707","pmid":"40565171","tags":["inflammation","pain"],"studyType":"Clinical Study","evidenceStrength":"Moderate","keyFinding":"Among 80 participants (25 RA, 18 OA, 37 healthy), 2-arachidonoylglycerol (2-AG) levels were significantly lower in both RA and OA patients compared to controls. RA patients also had higher ethanolamide-type endocannabinoids (anandamide, DHA-EA, etc.) and lower levels of the pro-resolving lipid 9-oxoODE and omega-3 fatty acids EPA and DHA.","whyItMatters":"2-AG is a critical regulator of pain signaling and inflammation. Finding it depleted in arthritis suggests a specific endocannabinoid deficiency that could help explain residual pain and points toward targeted cannabinoid therapies.","specificNumbers":"80 participants (25 RA, 18 OA, 37 controls); 16 endocannabinoids and 129 oxylipins quantified; 2-AG significantly lower in RA and OA; ethanolamides higher in RA; EPA and DHA lower in RA.","methodology":"Clinical study of 80 participants comparing 16 endocannabinoids/congeners and 129 oxylipins in plasma using LC-MS/MS assays across RA patients, OA patients, and healthy controls.","limitations":"Small sample sizes per group. Cross-sectional design cannot determine whether low 2-AG causes arthritis symptoms or results from them. Plasma levels may not reflect tissue-level endocannabinoid concentrations at joint sites."},{"rthcId":"RTHC-06843","title":"Effects of intravenous d9-THC on pupillary reaction and pupil size: a prospective, placebo-controlled trial in healthy volunteers not regularly consuming cannabis.","authors":"Kleine-Brueggeney, Maren; Priemer, Fritz; Konietschke, Frank; Theiler, Lorenz; Greif, Robert","year":2025,"journal":"BMC ophthalmology, 25(1), 286","doi":"10.1186/s12886-025-04107-7","pmid":"40355824","tags":["driving","neuroscience"],"studyType":"Placebo-Controlled Trial","evidenceStrength":"Moderate","keyFinding":"Intravenous THC significantly reduced pupillary relative amplitude (from 23.5% to 15.0% at 20 minutes, p = 0.001), constriction time (p = 0.002), and contraction amplitude (p < 0.001) compared to placebo. THC caused miosis (pupil constriction), not mydriasis (dilation). Effects persisted for 5 hours.","whyItMatters":"This study provides objective evidence of how THC affects visual function, with implications for driving safety and impairment assessment. The dampened light reflex could increase light sensitivity and affect vision in variable lighting conditions.","specificNumbers":"15 THC recipients, 4 placebo; relative amplitude decreased from 23.5% to 15.0% at 20 min; effects on constriction time (p = 0.002) and amplitude (p < 0.001); effects lasted 5 hours.","methodology":"Prospective, single-blind, placebo-controlled trial with 15 volunteers receiving IV THC and 4 receiving placebo. Pupillary measurements taken by pupillography before and for 5 hours after administration. Cannabis-naive or abstinent participants.","limitations":"Small sample (15 THC, 4 placebo). IV administration does not reflect typical consumption methods. Cannabis-naive subjects may respond differently than regular users. Single-blind rather than double-blind design."},{"rthcId":"RTHC-06844","title":"Association of cigarette and e-cigarette use with cannabis-related risk perceptions and intentions.","authors":"Kleine, Ronja; Isensee, Barbara; Nees, Frauke; Hanewinkel, Reiner","year":2025,"journal":"Journal of cannabis research, 7(1), 31","doi":"10.1186/s42238-025-00288-6","pmid":"40450366","tags":["youth"],"studyType":"Cross-Sectional Survey","evidenceStrength":"Moderate","keyFinding":"Among never-cannabis-users, dual cigarette/e-cigarette users perceived cannabis as least harmful and had the highest intention to use. Combustible-only users ranked next, followed by e-cigarette-only users. Never-tobacco-users perceived cannabis as most harmful and had the lowest use intentions. Lower risk perception was associated with higher intention to use cannabis.","whyItMatters":"Understanding the gateway pattern from tobacco products to cannabis helps target prevention. The risk perception gradient across tobacco use types suggests that interventions should address both substance-specific risk perceptions and broader substance use attitudes.","specificNumbers":"8,521 adolescents; mean age 14.0; 5.8% current cannabis use; 17.0% current tobacco/e-cigarette use; dual users had highest cannabis intentions; never-users had lowest.","methodology":"Cross-sectional survey of 8,521 German adolescents (mean age 14.0, 50.6% female) collected autumn 2021-spring 2022. Linear regression models predicting risk perception and cannabis use intention by tobacco/e-cigarette use status among never-cannabis-users.","limitations":"Cross-sectional design cannot establish whether tobacco use causes changes in cannabis risk perception. German-specific context with stricter cannabis laws at time of study. Self-reported data subject to social desirability bias."},{"rthcId":"RTHC-06845","title":"Cannabidiol Mitigates Pollution-Induced Inflammatory, Oxidative, and Barrier Damage in Ex Vivo Human Skin.","authors":"Klinngam, Wannita; Loruthai, Orathai; Vimolmangkang, Sornkanok","year":2025,"journal":"Biomolecules, 16(1)","doi":"10.3390/biom16010010","pmid":"41594552","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06846","title":"Derivation of a health-based guidance value for Δ8-tetrahydrocannabinol (Δ8-THC) and its occurrence in food.","authors":"Knutsen, Helle Katrine; Åkesson, Agneta; Bampidis, Vasileios; Bignami, Margherita; Chipman, James Kevin; Degen, Gisela; Hernández-Jerez, Antonio; Hofer, Tim; Hogstrand, Christer; Landi, Stefano; Leblanc, Jean-Charles; Machera, Kyriaki; Ntzani, Evangelia; Oswald, Isabelle P; Rychen, Guido; Sand, Salomon; Vejdovszky, Katharina; Viviani, Barbara; Dusemund, Birgit; Nebbia, Carlo; Weigel, Stefan; Cascio, Claudia; Christodoulidou, Anna; Abrahantes, José Cortiñas; Dujardin, Bruno; Gissi, Andrea; Asensio, Lydia Alarcón; Gkimprixi, Eleni; Tauriainen, Tuuli; Bodin, Laurent","year":2025,"journal":"EFSA journal. European Food Safety Authority, 23(11), e9735","doi":"10.2903/j.efsa.2025.9735","pmid":"41262681","tags":["legalization","potency"],"studyType":"Regulatory Assessment","evidenceStrength":"Moderate","keyFinding":"EFSA set a relative potency factor of 1 for delta-8-THC (equivalent to delta-9-THC) based on clinical data showing a potency ratio between 1 and 1.4. The existing acute reference dose of 1 microgram/kg body weight was extended as a group ARfD for combined delta-8 and delta-9-THC. Many food products showed delta-8-to-delta-9 ratios above 1, indicating addition of semi-synthetic delta-8-THC or enrichment beyond natural levels.","whyItMatters":"Delta-8-THC has exploded as a legal alternative in many markets by exploiting hemp farm bill loopholes. EFSA treating it as equally potent to delta-9-THC and finding evidence of semi-synthetic production in food products has major regulatory implications.","specificNumbers":"Relative potency factor: 1 (range 1-1.4); group ARfD: 1 microgram/kg body weight; 1,145 food samples analyzed; 96-99% of hemp seeds/oils below detection; highest levels in supplements and confectionery; only 96 of 1,145 samples had both compounds detected.","methodology":"EFSA CONTAM Panel scientific opinion using clinical study data on relative potency, occurrence data from 1,145 food samples, and risk assessment methodology to derive health-based guidance values.","limitations":"Limited clinical data on relative potency (confidence interval 0.97-1.63 includes slightly lower potency). Most food samples were below detection limits, limiting occurrence analysis. European food supply may differ from U.S. market where delta-8 products are more prevalent."},{"rthcId":"RTHC-06847","title":"Decriminalizing and Legalizing Cannabis for Clinical Benefits in Malaysia: Perspective Among Pharmacists (A Qualitative Study).","authors":"Koh, Jian Aun; Loo, Xin Jie; Tay, Jia Wen; Haw Liew, Brian Yung; Mohammed, Ali Haider; Rini R; Ramachandram, Dinesh Sangarran","year":2025,"journal":"Journal of psychoactive drugs, 57(5), 561-571","doi":"10.1080/02791072.2024.2420065","pmid":"39462251","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06848","title":"Preparation and in vitro characterization of inhalable cannabidiol dry powder for treating chronic obstructive pulmonary disease.","authors":"Komal, Komal; Chen, Shuli; Hanton, Lyall R; Glass, Michelle; Das, Shyamal C","year":2025,"journal":"International journal of pharmaceutics, 682, 125892","doi":"10.1016/j.ijpharm.2025.125892","pmid":"40578460","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06849","title":"Rates and correlates of simultaneous use and mixing of alcohol, tobacco, and cannabis among adults who currently use alcohol and tobacco.","authors":"Kong, Amanda Y; Kowitt, Sarah D; Halstead, Elizabeth O; Jarman, Kristen L; Ranney, Leah M; Goldstein, Adam O; Cox, Melissa J","year":2025,"journal":"Addictive behaviors, 167, 108334","doi":"10.1016/j.addbeh.2025.108334","pmid":"40157086","tags":["addiction"],"studyType":"Cross-Sectional Survey","evidenceStrength":"Low","keyFinding":"67% reported simultaneous alcohol and tobacco use. Among these co-users, 55.5% also used cannabis in the past 30 days, 42.1% used tobacco and cannabis simultaneously, 45% mixed them in blunts, 36.5% used alcohol and cannabis simultaneously, and 33.1% combined alcohol with blunts. State cannabis legalization status was not significantly associated with these patterns.","whyItMatters":"Substance use rarely happens in isolation, yet most research and treatment focuses on single substances. Understanding that the majority of tobacco-and-alcohol co-users are combining these substances in the same session, and many add cannabis, reveals a more complex harm profile.","specificNumbers":"1,300 participants; 67% simultaneous alcohol+tobacco; 55.5% also used cannabis; 42.1% simultaneous tobacco+cannabis; 45% used blunts; 36.5% simultaneous alcohol+cannabis; legalization status not significant.","methodology":"Survey panel of 1,300 U.S. adults reporting past-30-day use of both alcohol and combustible tobacco (June-July 2021). Logistic regression for sociodemographic and legalization status correlates.","limitations":"Purposive sample of alcohol/tobacco co-users, not generalizable to all substance users. Self-reported data. Cross-sectional design. Survey conducted during COVID-19 era, which may have affected substance use patterns."},{"rthcId":"RTHC-06850","title":"Estimating tobacco product availability prevalence in medical cannabis dispensaries in Oklahoma, USA, 2024.","authors":"Kong, Amanda Y; Flores, Iván; Herbert, Lily; Wagoner, Kimberly G; Reboussin, Beth A; Sutfin, Erin L; Giovenco, Daniel P; Meaney, Mark","year":2025,"journal":"Tobacco control","doi":"10.1136/tc-2025-059597","pmid":"41057256","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06851","title":"Herbal Research, Phytochemistry, Pharmacology, Comprehensive Utilization, and Quality Control of Hemp Seed: A Comprehensive Review.","authors":"Kong, Lingyang; Jiang, Shan; Ma, Lengleng; Ma, Junbai; Wu, Wei; Li, Chenliang; Ren, Weichao; Xu, Jiao; Ma, Wei","year":2025,"journal":"Phytochemical analysis : PCA, 36(7), 1893-1917","doi":"10.1002/pca.70014","pmid":"40796348","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06852","title":"Analysis of the cannabidiol effects in epilepsy treatment based on seizure characteristics in EEG recordings - A review.","authors":"Kopanska, Marta; Ochojska, Danuta; Trojniak, Julia; Kawala-Sterniuk, Aleksandra; Mikolajewski, Dariusz; Karwowski, Waldemar; Al-Bakri, Amir F; Sterniuk, Piotr; Szczygielski, Jacek","year":2025,"journal":"Epileptic disorders : international epilepsy journal with videotape, 27(6), 1148-1167","doi":"10.1002/epd2.70085","pmid":"40932459","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06853","title":"Cannabinoid 1 receptor availability in posttraumatic stress disorder: A positron emission tomography study.","authors":"Korem, Nachshon; Bassir Nia, Anahita; Hillmer, Ansel T; D'Souza, Deepak; Nabulsi, Nabeel; Ropchan, Jim; Huang, Yiyun; Cosgrove, Kelly; Levy, Ifat; Pietrzak, Robert H; Harpaz-Rotem, Ilan","year":2025,"journal":"Translational psychiatry, 15(1), 310","doi":"10.1038/s41398-025-03519-9","pmid":"40846835","tags":["ptsd","neuroscience"],"studyType":"PET Imaging Study","evidenceStrength":"Moderate","keyFinding":"Among 62 participants (19 with current PTSD, 27 trauma-exposed controls, 16 healthy controls), no differences in CB1 receptor availability were found between groups in whole brain or regions of interest. However, emotional numbing symptoms of PTSD were significantly associated with CB1R availability, suggesting the endocannabinoid system relates to specific symptom dimensions rather than the diagnosis overall.","whyItMatters":"This challenges a previous study that found elevated CB1R in PTSD and refines our understanding. The endocannabinoid system may not drive PTSD broadly but could specifically contribute to emotional numbing, which is one of the most treatment-resistant symptom clusters.","specificNumbers":"62 participants; 19 with PTSD; no group differences in CB1R availability; significant association between CB1R and emotional numbing symptoms specifically.","methodology":"PET imaging study using [11C]OMAR, a CB1R-specific radiotracer, in 62 individuals. 46 trauma-exposed (19 with current PTSD) and 16 healthy controls. Analysis of whole-brain and region-of-interest CB1R availability correlated with PTSD symptom clusters.","limitations":"Modest sample size (19 PTSD patients). Cross-sectional design. Single PET tracer. Cannabis use history in participants could affect CB1R availability. Cannot determine directionality of the CB1R-numbing association."},{"rthcId":"RTHC-06854","title":"Prevalence Rates, Perceptions of Risk, and Motivations for Nonmedical Cannabis Use in Pediatric Pain.","authors":"Kossowsky, Joe; Greco, Christine; Nestor, Bridget A; Koike, Camila; Tacugue, Nicole; Baumer, Andreas M; Weitzman, Elissa R","year":2025,"journal":"JAMA network open, 8(5), e2512870","doi":"10.1001/jamanetworkopen.2025.12870","pmid":"40440015","tags":["pain","youth"],"studyType":"Cross-Sectional Study","evidenceStrength":"Moderate","keyFinding":"25.3% of treatment-seeking adolescents with chronic pain reported lifetime cannabis use (mean first use age 15.3). Among users, 77.4% endorsed instrumental use to manage symptoms (primarily pain, sleep, anxiety). Cannabis users had higher pain interference (mean difference 2.7, p = 0.01) and depressive symptoms (difference 6.2, p < 0.001). Non-users perceived cannabis as significantly riskier (OR 2.37, p = 0.01).","whyItMatters":"A quarter of teens in pain treatment are using cannabis, mostly to self-treat their condition. This represents a large unaddressed clinical reality where patients are supplementing or substituting formal treatment with cannabis despite limited evidence for its efficacy in pediatric pain.","specificNumbers":"245 adolescents; 25.3% lifetime cannabis use; mean first use 15.3 years; 77.4% instrumental use; past-year 90.2% of users; past-month 64.5%; higher pain interference (p = 0.01) and depression (p < 0.001) in users.","methodology":"Cross-sectional survey of 245 adolescents (mean age 16.9, 69% female) at a pediatric pain clinic (September 2021-May 2024). Validated self-report measures of pain, substance use, and risk perceptions. Published in JAMA Network Open.","limitations":"Cross-sectional design cannot determine whether cannabis use preceded or followed pain worsening. Single pediatric pain center. Self-reported cannabis use may be underestimated in an adolescent clinical setting. Treatment-seeking population may not represent all teens with chronic pain."},{"rthcId":"RTHC-06855","title":"Delta 9-Tetrahydrocannabinol Signaling Through Cannabinoid Receptor 1 Alters Trophoblast Differentiation.","authors":"Koven, Jessica L; Natale, Bryony V; Hardy, Daniel B; Natale, David R C","year":2025,"journal":"Stem cells and development, 34(21-22), 441-455","doi":"10.1177/15473287251392544","pmid":"41203261","tags":["pregnancy"],"studyType":"Preclinical Study","evidenceStrength":"Low","keyFinding":"THC exposure at physiologically relevant levels significantly altered trophoblast stem cell differentiation in a CB1-dependent manner, reducing expression of syncytiotrophoblast (SynT) markers while driving differentiation toward junctional zone/trophoblast giant cell pathways. CB1 knockout cells showed no SynT marker expression. Higher non-physiological THC concentrations (15 microM) could induce SynT markers even without CB1.","whyItMatters":"This study identifies a specific mechanism by which THC could harm placental development: diverting trophoblast differentiation away from the cell type that forms the maternal-fetal nutrient exchange interface. This could explain growth restriction observed in cannabis-exposed pregnancies.","specificNumbers":"THC tested at physiologically relevant serum levels; CB1 expressed in all maternal blood-facing trophoblast cells; SynT markers reduced; junctional zone markers increased; 15 microM THC (non-physiological) overrode CB1 knockout.","methodology":"In vitro study using mouse trophoblast stem cells, including CB1 knockout (Cnr1KO) cells. Assessed THC effects on differentiation markers at physiologically relevant and elevated concentrations. Examined CB1 expression across placental cell types.","limitations":"Mouse model may not fully reflect human placental biology. In vitro differentiation does not capture the full complexity of placental development in vivo. Dose-response at physiological vs. non-physiological concentrations suggests threshold effects that need further characterization."},{"rthcId":"RTHC-06856","title":"Utilization of Cannabidiol in Post-Organ-Transplant Care.","authors":"Koyama, Sachiko; Etkins, Jumar; Jun, Joshua; Miller, Matthew; So, Gerald C; Gisch, Debora L; Eadon, Michael T","year":2025,"journal":"International journal of molecular sciences, 26(2)","doi":"10.3390/ijms26020699","pmid":"39859413","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06857","title":"Neutrophil extracellular traps and cannabinoids: potential in cancer metastasis.","authors":"Krauze, Izabela; Greb-Markiewicz, Beata; Kłopot, Anna; Maciejewska, Kamila; Bryk, Michał; Krzystek-Korpacka, Małgorzata","year":2025,"journal":"Frontiers in oncology, 15, 1595913","doi":"10.3389/fonc.2025.1595913","pmid":"40599866","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06858","title":"Recent cannabis use affects the association between baseline immune markers and long-term outcomes in psychosis.","authors":"Kreis, Isabel; Fjelnseth Wold, Kristin; Åsbø, Gina; Bärthel Flaaten, Camilla; Engen, Magnus Johan; Lyngstad, Siv Hege; Hustad Widing, Line; Sheikh, Mashhood Ahmed; Frogner Werner, Maren Caroline; Bakken, Eivind; Ueland, Thor; Steen, Nils Eiel; Melle, Ingrid","year":2025,"journal":"Translational psychiatry, 15(1), 282","doi":"10.1038/s41398-025-03498-x","pmid":"40813774","tags":["psychosis","mental-health","inflammation"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Only sTNFR1 independently predicted lower risk of psychiatric readmission and psychotic episodes over 10 years. CRP, IL-1RA, and sgp130 only showed associations with outcomes in cannabis users. In cannabis users specifically, CRP and IL-1RA were linked to lower readmission risk, while sgp130 was linked to higher risk.","whyItMatters":"Immune markers have been proposed as predictors of psychosis outcomes, but this study shows those associations largely depend on whether someone uses cannabis. This complicates the use of inflammatory biomarkers in clinical prediction and highlights cannabis as a key moderating factor.","specificNumbers":"320 first-episode psychosis patients; 10-year follow-up; 5 immune markers tested; only sTNFR1 predicted outcomes independently of cannabis; CRP, IL-1RA, and sgp130 effects were cannabis-dependent.","methodology":"Longitudinal follow-up of 320 first-episode psychosis patients. Baseline blood immune markers (CRP, IL-1RA, sIL-2R, sTNFR1, sgp130) measured at entry. Outcomes tracked over 10 years: psychiatric readmissions, psychotic episodes per year, and change in positive symptom severity.","limitations":"Observational design cannot establish causation. Cannabis use measured only at baseline, not tracked over 10 years. Immune markers also measured once at baseline. Specific cannabis types, doses, and frequency not captured."},{"rthcId":"RTHC-06859","title":"High stakes: Associations between substance use and gambling behaviors by race in the United States.","authors":"Kresovich, Alex; Borowiecki, Mateusz; Emery, Sherry L; Lamuda, Phoebe A; Taylor, Bruce G; Pollack, Harold A; Schneider, John A","year":2025,"journal":"Drug and alcohol dependence, 268, 112581","doi":"10.1016/j.drugalcdep.2025.112581","pmid":"39919502","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06860","title":"Occupational hypersensitivity to cannabis.","authors":"Krevanko, Callan; Sack, Coralynn","year":2025,"journal":"Current opinion in allergy and clinical immunology","doi":"10.1097/ACI.0000000000001137","pmid":"41364836","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06861","title":"The changing landscape of cannabis use: impact on maternal health and neonatal outcomes.","authors":"Krishnan, Parvathy; Yen, Elizabeth","year":2025,"journal":"Pediatric research","doi":"10.1038/s41390-025-04209-4","pmid":"40542098","tags":["pregnancy","youth","neuroscience","cardiovascular"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Beyond the well-documented cognitive and neurodevelopmental effects, prenatal cannabis exposure is associated with fetal growth restriction, altered cardiovascular development, hematologic changes, gastrointestinal effects, and increased long-term risk for obesity, diabetes, and cardiovascular disease. Even early or brief exposure during pregnancy showed associations with adverse outcomes.","whyItMatters":"With over 40% of adults aged 19-30 using cannabis in the past year and rising use among pregnant women, understanding the full scope of prenatal exposure risks is critical.","specificNumbers":"Over 40% of adults aged 19-30 reported past-year cannabis use. The review covers effects across at least 6 organ systems in offspring.","methodology":"Narrative mini-review synthesizing evidence from animal/in vitro and human studies on prenatal cannabis exposure effects across multiple organ systems.","limitations":"Narrative review format does not use systematic search methodology. Many included studies are preclinical. Human studies often cannot isolate cannabis from co-exposures like tobacco."},{"rthcId":"RTHC-06862","title":"Patterns of past month cannabis consumption and cannabis use disorder - Insights from a nationally representative survey.","authors":"Kritikos, Alexandra F; Taylor, Bruce; Lamuda, Phoebe; Pollack, Harold; Schneider, John A","year":2025,"journal":"Drug and alcohol dependence, 272, 112680","doi":"10.1016/j.drugalcdep.2025.112680","pmid":"40319791","tags":["addiction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Medical cannabis users had a 26% CUD rate (vs. 21% for recreational). CUD rates rose sharply with frequency: occasional medical use 19%, moderate 24%, daily 31%. For recreational: occasional 10%, moderate 24%, daily 32%. Younger adults (18-29) and males showed the highest CUD scores.","whyItMatters":"As cannabis use surges in the US, this study provides the clearest picture yet of CUD prevalence by use type and frequency. Medical users have slightly higher CUD rates than recreational users.","specificNumbers":"1,719 past-month users; medical CUD rate 26% (95% CI: 19.8-30.4); recreational CUD rate 21% (95% CI: 17.7-25.2); daily use CUD rates 31-32% regardless of use type.","methodology":"Cross-sectional analysis of AmeriSpeak panel data. 1,719 adults reporting past-month cannabis use from 6,543+ respondents (Dec 2023-Jan 2024). CUD assessed via CUDIT. Multinomial logistic regression with sociodemographic controls.","limitations":"Cross-sectional design cannot establish whether frequency drives CUD or vice versa. Self-reported data. Medical cannabis users may score higher partly because they use more frequently by necessity."},{"rthcId":"RTHC-06863","title":"Differential inhibitory effects of endocannabinoids on neuronal firing of mouse meningeal afferents.","authors":"Krivoshein, Georgii; Della Pietra, Adriana; Savinainen, Juha; van den Maagdenberg, Arn M J M; Giniatullin, Rashid","year":2025,"journal":"The journal of headache and pain, 26(1), 112","doi":"10.1186/s10194-025-02041-z","pmid":"40355840","tags":["neuroscience","pain","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"AEA reduced meningeal nerve firing more profoundly and for longer than 2-AG. AEA briefly activated slow-firing fibers (1-2 Hz), then persistently suppressed fast-firing fibers (>10 Hz). Only AEA inhibited subsequent capsaicin-induced firing. Mouse meninges showed higher FAAH activity and lower endogenous AEA levels.","whyItMatters":"This study provides mechanistic evidence that boosting AEA through FAAH inhibition could reduce migraine-related nerve activation, offering a specific target rather than broad cannabinoid receptor activation.","specificNumbers":"AEA suppressed fibers firing >10 Hz; briefly activated fibers at 1-2 Hz; endogenous AEA levels lower than 2-AG; FAAH activity higher than MAGL in meninges.","methodology":"Ex vivo electrophysiological recordings from C57BL/6J mouse hemiskull preparations. 10 uM AEA or 2-AG applied with 50 mM KCl stimulation. Clustering and spectral analysis. LC-MS/MS measured endogenous enzyme activity and endocannabinoid levels.","limitations":"Ex vivo mouse preparation. Single concentrations tested. Results may not translate to human meningeal physiology. Does not test FAAH inhibitors directly."},{"rthcId":"RTHC-06864","title":"Back on track: Feasibility and efficacy randomized trial of a two-week online self-guided intervention for cannabis use reduction.","authors":"Kroon, E; Elsey, J W B; Kuhns, L N; Rietveld, P; De Vries, O; Larsen, H; Wiers, R W H J; Cousijn, J","year":2025,"journal":"Drug and alcohol dependence, 277, 112943","doi":"10.1016/j.drugalcdep.2025.112943","pmid":"41192278","tags":["quitting","addiction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The MCII group achieved objective reduction goals at 69%, vs. 49% for control (SMART goals alone). Adding cue-control did not improve outcomes (60%). All groups reduced grams per week, maintained at 3-month follow-up. Two-week retention was high in the MCII group.","whyItMatters":"Many cannabis users prefer self-help over formal treatment. This brief, accessible online program can meaningfully help people meet their own reduction goals.","specificNumbers":"168 participants; 69% MCII group met goals vs. 49% control; 60% MCII + cue-control; reductions maintained at 3 months.","methodology":"Pilot RCT with 168 adults using cannabis weekly (severe CUD on average). Three conditions: SMART goals only, SMART + MCII, SMART + MCII + cue-control. Two-week primary endpoint with 3-month follow-up.","limitations":"Pilot/feasibility scale. No blinding. All groups reduced use. Grams per week reduction was similar across groups despite goal achievement differences."},{"rthcId":"RTHC-06865","title":"Beyond the hype - who uses cannabidiol for self-medication - and why: a cross-sectional study in Germany.","authors":"Krowartz, Eva-Maria; Riemerschmid, Carlotta; Klug, Stefanie J; Tanaka, Luana F; Eva-Hoch","year":2025,"journal":"Journal of cannabis research, 7(1), 77","doi":"10.1186/s42238-025-00341-4","pmid":"41094600","tags":["cbd","medical-cannabis","sleep","pain","depression","anxiety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"37.9% used CBD for self-medication. Top motives: sleep (52.3%), chronic pain (47.4%), depression (45.5%), anxiety (44.4%). Age 50+ aOR 2.81. Unemployed/retired aOR 3.55. Twice-daily aOR 3.05. Smoking CBD was negatively associated with self-medication.","whyItMatters":"CBD is marketed with health claims despite limited clinical evidence. Understanding who self-medicates and why reveals unmet medical needs and potential risks of unsupervised use.","specificNumbers":"702 participants; 78.8% male; mean age 34.9; 37.9% self-medicating; sleep 52.3%; age 50+ aOR 2.81; unemployed aOR 3.55.","methodology":"Cross-sectional online survey (Jan-Mar 2023) in Germany. 702 complete cases. Monthly CBD use required. Logistic regression with adjusted odds ratios.","limitations":"Convenience sampling. Predominantly male (78.8%). Self-reported. German market may differ."},{"rthcId":"RTHC-06866","title":"The Effects of Indirect and Direct Modulation of Endocannabinoid System Function on Anxiety-Related Behavior in Mice Assessed in the Elevated Plus Maze Test.","authors":"Kruk-Slomka, Marta; Dzik, Agnieszka; Biala, Grazyna","year":2025,"journal":"Molecules (Basel, Switzerland), 30(4)","doi":"10.3390/molecules30040867","pmid":"40005177","tags":["anxiety","neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 antagonist AM 251 was anxiogenic. Mixed agonist WIN55,212-2 (1 mg/kg) was anxiolytic. Both CB2 agonist and antagonist increased anxiety. FAAH inhibitor URB 597 (0.3 mg/kg) was anxiolytic. MAGL inhibitor JZL 184 had no effect.","whyItMatters":"This systematic comparison identifies FAAH inhibition as the most promising endocannabinoid approach for anxiety, while revealing that CB2 manipulation paradoxically increases anxiety.","specificNumbers":"URB 597 anxiolytic at 0.3 mg/kg; AM 251 anxiogenic at 0.25-3 mg/kg; WIN55,212-2 anxiolytic at 1 mg/kg; JZL 184 no effect at 2-40 mg/kg.","methodology":"Acute drug administration in mice assessed in the elevated plus maze. Multiple receptor ligands and enzyme inhibitors tested with dose-response curves.","limitations":"Animal model. Acute dosing only. Single mouse strain. EPM captures one dimension of anxiety."},{"rthcId":"RTHC-06867","title":"Ex vivo study of the vasorelaxant activity induced by cannabigerol in human pulmonary artery- the role of endothelium, sex and selected clinical factors.","authors":"Krzyżewska, Anna; Kloza, Monika; Kozłowski, Mirosław; Galicka, Anna; Kozłowska, Hanna","year":2025,"journal":"Biochemical pharmacology, 242(Pt 1), 117383","doi":"10.1016/j.bcp.2025.117383","pmid":"41046075","tags":["cbd","cardiovascular","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBG relaxed human pulmonary arteries through endothelium-dependent mechanisms involving cyclooxygenase, nitric oxide, K+ channels, and likely CB1/CB2, PPARgamma, GPR55, and TRPV1 receptors. Hypertension and hypercholesterolaemia modified the response.","whyItMatters":"First study showing CBG can relax human pulmonary arteries, with specific mechanisms identified and clinical comorbidity effects documented.","specificNumbers":"At least 4 mechanistic pathways; response modified by hypertension and hypercholesterolaemia; endothelium removal abolished the effect.","methodology":"Ex vivo study using human pulmonary artery segments. Vascular reactivity measured with selective pathway inhibitors. Post-hoc comorbidity analysis.","limitations":"Ex vivo tissue. Post-hoc comorbidity analysis. CBG concentrations may not be achievable orally. Surgical patients may not represent general population."},{"rthcId":"RTHC-06868","title":"Cross-sectional analysis of cannabis use at work in the USA: differences by occupational risk level and state-level cannabis laws.","authors":"Kucera, Ava; Hammond, David","year":2025,"journal":"BMJ public health, 3(2), e001589","doi":"10.1136/bmjph-2024-001589","pmid":"40766206","tags":["workplace","legalization","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Workplace use highest in recreational states (8.5%) vs. medical-only (6.3%) or illegal (6.2%). High-risk workers: 11.4% vs. 5.8%. Medical users: 29.4% vs. recreational 15.6%. Medical authorization: 39.0% vs. 17.4% without.","whyItMatters":"Quantifies who uses cannabis at work as legalization expands. High-risk workers and medically authorized users have the highest rates.","specificNumbers":"26,458 workers; 7.4% overall; 11.4% high-risk jobs; 39.0% with medical authorization; 8.5% in recreational states.","methodology":"Cross-sectional data from ICPS wave 6 (2023). 26,458 respondents aged 16-65. Regression models by state laws, occupational risk, and medical authorization.","limitations":"Cross-sectional. Self-reported. \"Within 2 hours\" is broad. Impairment not measured."},{"rthcId":"RTHC-06869","title":"Cannabis and driving: A repeat cross-sectional analysis of driving after cannabis use pre- vs. post-legalization of recreational cannabis in Canada.","authors":"Kucera, Ava; Hammond, David","year":2025,"journal":"Addictive behaviors, 170, 108419","doi":"10.1016/j.addbeh.2025.108419","pmid":"40618444","tags":["driving","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Overall driving after use rose from 5.7% (2018) to 8.8% (2022, OR=1.43) and 7.6% (2023, OR=1.20). Among consumers, it fell from 19.9% to 18.3% (OR=0.81). No change in passenger behavior.","whyItMatters":"The nuanced finding that individual users are not becoming riskier while overall rates rise is critical for policy.","specificNumbers":"93,933 participants; 6 waves; overall rose 5.7% to 8.8%; consumers fell 19.9% to 18.3%.","methodology":"Repeat cross-sectional surveys (ICPS) 2018-2023. 93,933 Canadian participants aged 16-65. Logistic regression by demographics.","limitations":"Self-reported. \"Within 2 hours\" window. Cross-sectional tracks populations not individuals. Cannot measure impairment."},{"rthcId":"RTHC-06870","title":"Embryotoxicity Evaluation of Novel Synthetic Cannabinoid 4F-MDMB-BUTICA Using Zebrafish Embryos.","authors":"Kullebi, Berşan; Alat, Ömercan; Aksakal, Özkan; Yılmaztürk, Derya; Lafzi, Ayşe; Şişman, Turgay","year":2025,"journal":"Journal of applied toxicology : JAT, 45(7), 1314-1330","doi":"10.1002/jat.4778","pmid":"40070117","tags":["synthetic-cannabinoids","pregnancy","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"LC50: 1.932 mg/L; EC50: 0.960 mg/L at 120 hours. Deformities: spine malformation, pericardial edema, yolk sac edema, delayed development. Hypoactivity in larvae. Gene changes in apoptosis, dopamine, serotonin, GABA, and behavior pathways.","whyItMatters":"First embryotoxicity data on this new synthetic cannabinoid, revealing multi-system effects that suggest significant developmental risk.","specificNumbers":"LC50: 1.932 mg/L; EC50: 0.960 mg/L; 19 genes assessed; 6 concentrations; no acute effects, all effects subacute.","methodology":"Zebrafish embryos exposed at 0.15-4.80 mg/L. Acute (3-24 hpf) and subacute (3-120 hpf) exposure. Morphology, behavior, and qPCR on 19 genes assessed.","limitations":"Zebrafish model limits mammalian translation. Single compound. No THC comparison."},{"rthcId":"RTHC-06871","title":"Quantification and prediction of human fetal (-)-Δ9-tetrahydrocannabinol/(±)-11-OH-Δ9-tetrahydrocannabinol exposure during pregnancy to inform fetal cannabis toxicity.","authors":"Kumar, Aditya R; Benson, Lyndsey S; Wymore, Erica M; Phipers, Jocelyn E; Dempsey, Jennifer C; Cort, Lucinda A; Unadkat, Jashvant D","year":2025,"journal":"Nature communications, 16(1), 824","doi":"10.1038/s41467-025-55863-5","pmid":"39827121","tags":["pregnancy","neuroscience"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Fetal brain/maternal plasma THC ratios: 0.50 (T1), 0.45 (T2), 0.35 (T3 umbilical). PBPK model: 10mg inhaled = 3.7 nM THC + 7.0 nM 11-OH-THC fetal brain. 10mg oral = 0.73 nM THC + 8.9 nM 11-OH-THC.","whyItMatters":"Provides the actual human fetal exposure data needed to design accurate preclinical experiments and communicate concrete numbers to patients.","specificNumbers":"Ratios: 0.50 (T1), 0.45 (T2), 0.35 (T3). 10mg inhaled: 3.7 nM THC. 10mg oral: 0.73 nM THC. N = 3, 14, 18.","methodology":"Cannabinoid concentrations measured in maternal plasma and paired fetal tissues (T1-2) and umbilical plasma (T3). Verified maternal-fetal PBPK model. N = 3 (T1), 14 (T2), 18 (T3).","limitations":"Small T1 sample (n=3). Cross-sectional tissue collection. PBPK model assumptions. Unstandardized cannabis use patterns."},{"rthcId":"RTHC-06872","title":"The Individual and Interactive Effects of Alpha-Pinene and Delta-9-Tetrahydrocannabinol in Healthy Adults.","authors":"Kumar, Lakshmi; Spindle, Tory R; Zamarripa, C Austin; Elder, Harrison J; Russo, Ethan B; Bigelow, George; Vandrey, Ryan","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 144-157","doi":"10.1159/000547014","pmid":"40734690","tags":["cognition","potency"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Alpha-pinene alone (15mg) had no effects vs. placebo. THC (30mg) impaired cognition as expected. Co-administration of alpha-pinene at 0.5, 5, or 15mg with THC did not mitigate any THC effects. No significant interactions on any outcome.","whyItMatters":"This rigorous trial found no evidence for one of the most commonly cited entourage effect claims.","specificNumbers":"19 participants; 39 days average since last use; 6 sessions each; 30mg THC; alpha-pinene at 0.5, 5, 15mg; zero significant interactions.","methodology":"Double-blind, placebo-controlled, six-session crossover. 19 participants. Inhaled via Mighty Medic vaporizer. 6-hour monitoring of subjective effects, cognition, and vital signs.","limitations":"Modest sample. One terpene tested. Acute exposure only. Variable cannabis history."},{"rthcId":"RTHC-06873","title":"Characterizing cannabis use among adolescents seeking treatment for their substance use.","authors":"Kumar, Prianka; Straton, Emma; Kaliamurthy, Sivabalaji","year":2025,"journal":"Journal of addictive diseases, 1-4","doi":"10.1080/10550887.2025.2528314","pmid":"40667847","tags":["youth","addiction","potency"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Most adolescents used multiple cannabis products. Many used delta-8 and delta-10 THC, which are often legal, widely available, and have unknown risk profiles.","whyItMatters":"Adolescents are already using novel cannabinoid products that providers may not screen for and regulators have barely addressed.","specificNumbers":"Specific sample size not detailed. Key finding is qualitative: multiple product use and delta-8/delta-10 THC adoption.","methodology":"Observational study of cannabis use patterns among adolescent patients at an urban pediatric addiction clinic.","limitations":"Single clinic. Treatment-seeking population. Limited quantitative detail."},{"rthcId":"RTHC-06874","title":"Can Endocannabinoids Explain CBD-Mediated Reduction in Blood Pressure? Insights from a Randomized, Placebo-Controlled, Crossover Trial.","authors":"Kumric, Marko; Dujic, Goran; Vrdoljak, Josip; Supe Domic, Daniela; Dujic, Zeljko; Bozic, Josko","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251392773","pmid":"41203237","tags":["cbd","cardiovascular"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"CBD (225-450 mg/day, 5 weeks) increased AEA by 11.1 ng/mL (p=0.025). AEA change did not correlate with systolic BP change (r=-0.106, p=0.428). BMI, antihypertensives, and glucose predicted AEA increase; BP reduction did not. No 2-AG effect.","whyItMatters":"Dissociates CBD's endocannabinoid effects from its cardiovascular effects, redirecting mechanistic research.","specificNumbers":"66 patients; AEA +11.1 ng/mL (p=0.025); BP correlation r=-0.106 (p=0.428); no 2-AG effect (p=0.478).","methodology":"Sub-analysis of HYPER-H21-4 crossover RCT. 66 hypertensive patients. CBD vs. placebo for 5 weeks each. AEA and 2-AG measured.","limitations":"Plasma may not reflect tissue changes. 5-week period. Only two endocannabinoids measured."},{"rthcId":"RTHC-06875","title":"Current and Projected Cannabis Demand Predict Future Consumption in Young Adults Who Use Cannabis.","authors":"Kurnellas, Rebecca; Sutton, Cassandra A; Jun, Daiil; Taylor, Hailey; Smith, Aaron P; Foxx, Ricarda; Yurasek, Ali M; Yi, Richard","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(3), 56-71","doi":"10.26828/cannabis/2025/000324","pmid":"41278423","tags":["addiction","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Demand measures were stable across 3 months. Participants accurately projected future demand. Both current and projected demand predicted 3-month cannabis use frequency.","whyItMatters":"A simple purchase task can forecast cannabis use three months out, enabling potential early intervention.","specificNumbers":"Three MPT timepoints compared; demand stable; both current and projected predicted future use.","methodology":"Prospective cohort. Young adult cannabis users completed current and projected Marijuana Purchase Tasks at baseline, then reassessed at 3 months.","limitations":"Sample size not detailed. Short follow-up. Hypothetical purchase scenarios."},{"rthcId":"RTHC-06876","title":"Cannabis and cannabinoids in the treatment of post-traumatic stress disorder: A literature review and analysis of the content of websites of Polish clinics specializing in medical marijuana treatment.","authors":"Kurowska, Patrycja; Wojtyła, Cezary; Królak, Anna; Ostrowski, Janusz; Giermaziak, Wojciech","year":2025,"journal":"Psychiatria polska, 59(4), 577-596","doi":"10.12740/PP/192416","pmid":"41403121","tags":["ptsd","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The literature review concluded there is currently no sufficient solid evidence to recommend medical marijuana or cannabinoids to treat PTSD. However, people with PTSD use cannabis for its anxiolytic, sedative, hypnotic, and antipsychotic effects. Polish clinic websites were found to market cannabis as a PTSD treatment despite the weak evidence base.","whyItMatters":"The disconnect between evidence and marketing is a public health concern. PTSD incidence in Poland has increased significantly, creating a vulnerable population that may be targeted by clinics overpromising on cannabis benefits.","specificNumbers":"PTSD incidence rising in Poland. No RCTs with sufficient evidence to recommend cannabis for PTSD. Polish clinics actively marketing cannabis as PTSD alternative therapy.","methodology":"Two-part study: systematic literature review of cannabis/cannabinoid efficacy and safety for PTSD, plus content analysis of websites from Polish clinics specializing in medical marijuana treatment.","limitations":"Website analysis reflects a single country (Poland). The literature review may not capture the most recent trials. Patient outcomes from Polish clinics were not directly measured."},{"rthcId":"RTHC-06877","title":"A Rare Presentation of A Common Dermatosis; Unilateral Blaschko-Linear Erythema Multiforme.","authors":"Kurt, Birgul Ozkesici; Altunay, Ilknur Kıvanc; Oz, Aysegul; Hascicek, Seyhan Ozakkoyunlu; Cetinkaya, Pinar Ozdemir; Aksu, Asli","year":2025,"journal":"Sisli Etfal Hastanesi tip bulteni, 59(4), 569-572","doi":"10.14744/SEMB.2025.20688","pmid":"41700206","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06878","title":"Cannabinoids in headache: helpful or harmful?","authors":"Kuruvilla, Deena E","year":2025,"journal":"Current opinion in neurology, 38(3), 277-280","doi":"10.1097/WCO.0000000000001364","pmid":"40152937","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06879","title":"NEUROPSYCHIATRIC AND PSYCHOGENETIC ASPECTS OF POST-TRAUMATIC STRESS DISORDERS ASSOCIATED WITH THE CHORNOBYL DISASTER AND THE RUSSIAN-UKRAINIAN WAR: FOCUS ON THE ENDOCANABINOID SYSTEM.","authors":"Kuts, K V; Kreinis, H Yu; Perchuk, I V; Antypchuk, K Yu; Vasylenko, Z L; Kravchenko, V I; Drozdova, N V","year":2025,"journal":"Problemy radiatsiinoi medytsyny ta radiobiolohii, 32-68","doi":"10.33145/2304-8336-2025-30-32-68","pmid":"41469339","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06880","title":"Anti-obesity effect of unsaponifiable matter from hemp seed in 3T3-L1 adipocytes and high-fat diet-induced obese mice.","authors":"Kwon, Yeji; Kim, Unyong; Han, Sang Beom; Park, Samuel; Lee, Junsoo; Heo, Huijin; Jeon, Hui-Jeon; Lee, Dong-Hee; Suh, Joon Hyuk; Sung, Jeehye","year":2025,"journal":"Food & function, 16(21), 8418-8430","doi":"10.1039/d5fo02231b","pmid":"41047880","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06881","title":"The anti-biofilm activity of cannabinoids against methicillin-resistant Staphylococcus aureus.","authors":"Kwong, Pancy Tsz Hei; Das, Theerthankar; Arnold, Jonathon Carl; Chan, Hak-Kim; Kwok, Philip Chi Lip","year":2025,"journal":"Journal of applied microbiology, 136(9)","doi":"10.1093/jambio/lxaf214","pmid":"40844832","tags":["cbd","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"All five cannabinoids (CBD, THC, CBN, CBG, CBC) had MICs of 1-2 ug/mL against MRSA. CBN showed the most potent anti-biofilm activity, significantly reducing biofilm biomass and bacterial viability. CBN also induced the highest intracellular ROS levels. CBD was least effective in most anti-biofilm assays but caused the greatest membrane damage, suggesting different mechanisms of action among cannabinoids.","whyItMatters":"MRSA is a major cause of hospital-acquired pneumonia with few treatment options. This comparative study identifies CBN as the most promising anti-biofilm cannabinoid and reveals that chemically similar cannabinoids work through different mechanisms.","specificNumbers":"MICs: 1-2 ug/mL for all five cannabinoids. CBN was most potent for biofilm reduction and ROS induction. CBD caused most membrane damage but was least effective overall.","methodology":"In vitro study testing five phytocannabinoids against MRSA biofilms using crystal violet staining, resazurin metabolic assay, ROS assay, and propidium iodide membrane integrity test.","limitations":"In vitro study only. Biofilm conditions may not replicate in vivo infections. Cannabinoid concentrations achievable at infection sites not established. No combination testing performed."},{"rthcId":"RTHC-06882","title":"Co-spray drying of cannabidiol and vancomycin combination powder formulations for the treatment of methicillin-resistant Staphylococcus aureus respiratory infections.","authors":"Kwong, Pancy Tsz Hei; Arnold, Jonathon Carl; Chan, Hak-Kim; Kwok, Philip Chi Lip","year":2025,"journal":"International journal of pharmaceutics, 683, 126063","doi":"10.1016/j.ijpharm.2025.126063","pmid":"40796013","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06883","title":"Plausibly deniable - Domestic cannabis cultivation and the private rented sector in the UK.","authors":"L'Hoiry, Xavier; Rugg, Julie; Parton, Loren E; Antonopoulos, Georgios A","year":2025,"journal":"Trends in organized crime, 28(4), 447-469","doi":"10.1007/s12117-025-09571-7","pmid":"41583604","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06884","title":"Associations between cannabis use and same-day health and substance use behaviors.","authors":"La Torre, Irene De; Hébert, Emily T; Kezbers, Krista M; Walters, Danielle; Pope, Zachary C; Mao, Bingjing; Benson, Lizbeth; Shi, Dingjing; Stanley, Nadia; Businelle, Michael S","year":2025,"journal":"Addictive behaviors, 163, 108239","doi":"10.1016/j.addbeh.2024.108239","pmid":"39756126","tags":["exercise","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Daily cannabis use was positively associated with same-day physical activity (+3.31 minutes MVPA, p=0.04), alcohol consumption (+0.45 drinks, p=0.01), and cigarettes smoked (+0.63 cigarettes, p=0.01). All associations were within-person, comparing use vs. non-use days for the same individual.","whyItMatters":"This is among the first EMA studies to capture real-time daily associations between cannabis use and other behaviors. The physical activity finding challenges stereotypes about cannabis and lethargy, while the substance co-use findings have implications for harm reduction.","specificNumbers":"98 participants; 28-day study; +3.31 minutes MVPA (p=0.04); +0.45 drinks (p=0.01); +0.63 cigarettes (p=0.01) on cannabis use days.","methodology":"Ecological momentary assessment (EMA) over 28 days in a nationwide sample. 98 participants who used cannabis at least once during the study. Generalized linear mixed models adjusted for race, sex, and age.","limitations":"Observational within-person design cannot determine causation. Small sample (n=98). Effect sizes are modest. Cannabis use timing relative to activity/substance use not captured. Self-reported measures."},{"rthcId":"RTHC-06885","title":"In Vitro Exposure to Vaped Tetrahydrocannabinol Increases Candida albicans (SC5314) Growth, Metabolic Activity, Biofilm Formation, and the Expression of Virulence Genes.","authors":"Laaboudi, Fatima-Zahrae; Amri, Omayma; Rouabhia, Mahmoud","year":2025,"journal":"Microorganisms, 13(10)","doi":"10.3390/microorganisms13102278","pmid":"41156738","tags":["respiratory"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"E-cigarette aerosol with THC increased C. albicans growth and metabolic activity more than aerosol without THC. The 15% THC concentration had greater effects than 10%. Vaped THC promoted biofilm formation and increased expression of virulence genes EAP1, SAP2, SAP4, and SAP9.","whyItMatters":"Cannabis vaping is increasingly popular, and oral candidiasis (thrush) is a known complication of cannabis use. This study provides a mechanism: vaped THC directly enhances the pathogenic potential of Candida, not just by suppressing immunity but by promoting the fungus itself.","specificNumbers":"15% THC had greater effect than 10% on biofilm formation. Four virulence genes upregulated: EAP1, SAP2, SAP4, SAP9.","methodology":"In vitro study exposing Candida albicans (SC5314 strain) to e-cigarette aerosol with or without nicotine and with 10% or 15% THC. Measured growth, metabolic activity, biofilm formation, and virulence gene expression via qPCR.","limitations":"In vitro model may not replicate oral cavity conditions. Single Candida strain tested. THC concentrations in vapor may differ from real-world use. No comparison with smoked cannabis."},{"rthcId":"RTHC-06886","title":"Systematic review of risk factors for violence in psychosis: 10-year update.","authors":"Lagerberg, Tyra; Lambe, Sinéad; Paulino, Anabelle; Yu, Rongqin; Fazel, Seena","year":2025,"journal":"The British journal of psychiatry : the journal of mental science, 226(2), 100-107","doi":"10.1192/bjp.2024.120","pmid":"40091674","tags":["psychosis","mental-health"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Criminal history factors had the greatest risk (pooled OR 3.50, 95% CI: 2.37-5.16), followed by substance misuse (OR 2.36, 95% CI: 1.99-2.80). Cannabis use was identified as a novel risk factor in secondary analysis (OR 3.34, 95% CI: 2.32-4.82). Treatment-related factors were protective (OR 0.54, 95% CI: 0.34-0.85). Effects were attenuated in inpatient settings.","whyItMatters":"Violence risk assessment in psychosis is critical for clinical management. Cannabis use emerged as a novel and substantial risk factor with an odds ratio comparable to criminal history, suggesting it deserves routine assessment in violence risk evaluation.","specificNumbers":"47 studies; 203,297 individuals; cannabis OR=3.34 (95% CI: 2.32-4.82); criminal history OR=3.50; substance misuse OR=2.36; treatment protective OR=0.54.","methodology":"Systematic review and meta-analysis searching five databases through June 2022. 47 longitudinal studies, 41 independent samples, 203,297 individuals. Random-effects meta-analysis for risk factors reported in 3+ independent samples. 10-year update of a prior review.","limitations":"Cannabis finding from secondary analysis needs replication. Most studies from high-income countries. Heterogeneity in violence definitions. Cannot establish causation from observational data."},{"rthcId":"RTHC-06887","title":"High-Potency Cannabis Use and Health: A Systematic Review of Observational and Experimental Studies.","authors":"Lake, Stephanie; Murray, Conor H; Henry, Brittany; Strong, Liza; White, Kendall; Kilmer, Beau; Cooper, Ziva D","year":2025,"journal":"The American journal of psychiatry, 182(7), 616-638","doi":"10.1176/appi.ajp.20240269","pmid":"40134269","tags":["potency","addiction","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 42 eligible studies, most addressed mental health, problematic cannabis use, and other substance use. Findings in the problematic cannabis use domain were suggestive of an association with higher-potency cannabis. Findings in other domains were less consistent but tended toward poorer outcomes with higher potency. Therapeutic outcomes were limited and mixed. Overall GRADE certainty: \"very low.\"","whyItMatters":"THC concentrations in cannabis have risen continuously, yet the health impact of high-potency products is poorly understood. This review from the American Journal of Psychiatry provides the most comprehensive assessment to date and finds the evidence base is alarmingly thin.","specificNumbers":"4,545 records screened; 42 eligible studies; potency categories from 1% to 60%+ THC; evidence certainty rated \"very low\" across domains.","methodology":"Systematic review of five databases. Developed ecologically relevant potency categories: 1-9%, 10-19%, 20-30%, kief/resin (~30-50%), concentrates (60%+). Two independent reviewers for screening, extraction, and quality. GRADE framework for evidence certainty.","limitations":"Most included studies were cross-sectional. Few studies examined health outcomes beyond mental health and problem use. Potency measurement methods varied. \"Very low\" certainty limits confidence in all findings."},{"rthcId":"RTHC-06888","title":"Inflammatory bowel disease patients believe cannabis and cannabidiol oil relieve symptoms.","authors":"Lala, Ayati; Rodriguez-Palacios, Alexander; Cominelli, Fabio; Basson, Abigail Raffner","year":2025,"journal":"Academia medicine, 2(2)","doi":"10.20935/acadmed7773","pmid":"40687272","tags":["medical-cannabis","inflammation","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"53.8% of IBD patients used cannabis (vs. 45.5% controls). 86.8% of IBD patients supported medical cannabis. 63.2% believed cannabis was somewhat-to-extremely beneficial for IBD. Over 50% of cannabis-using IBD patients reported relief from abdominal pain, other pain, stress, anxiety, depression, and nausea. 19.4% reported decreased opioid use. 14.5% reported cannabis-induced remission. Crohn's patients reported more relief than UC patients for certain symptoms.","whyItMatters":"IBD patients increasingly use cannabis for symptom management, often without clinical guidance. This survey captures what patients actually experience, providing data that can inform clinical conversations and identify research priorities.","specificNumbers":"93 IBD patients; 53.8% used cannabis; 86.8% supported medical use; 19.4% reduced opioids; 14.5% reported remission; >50% reported relief across 6 symptom categories.","methodology":"Cross-sectional 37-question survey of 139 participants (93 IBD, 33 controls). Assessed cannabis and CBD oil usage, beliefs, symptom impact, quality of life, and opioid use.","limitations":"Self-reported and uncontrolled. Small sample. Selection bias (survey respondents may over-represent cannabis users/supporters). Remission claims not verified clinically. No dose or product standardization."},{"rthcId":"RTHC-06889","title":"Assessment of addiction behavior and spermatogenesis in glial cell line-derived neurotrophic factor-treated cannabis-addicted rats: An experimental study.","authors":"Laleh, Rozhina; Nasrabadi, Mitra Heydari; Khodarahmi, Parvin; Soltani, Jamshid","year":2025,"journal":"International journal of reproductive biomedicine, 23(2), 153-170","doi":"10.18502/ijrm.v23i2.18487","pmid":"40371361","tags":["addiction","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis-addicted rats showed increased anxiety, reduced germ cells, smaller testes/epididymis, altered sperm morphology, and increased DNA damage. GDNF treatment improved anxiety (p<0.05), reversed abnormal sperm morphology, improved sperm grading (grade C, p=0.0295), reduced DNA damage (p=0.0242), and enhanced viability. GDNF had limited effect on testis/epididymis size or germ cell counts.","whyItMatters":"Cannabis use is linked to male fertility problems, and GDNF is a key factor in spermatogenesis. This study shows GDNF can partially reverse cannabis-induced reproductive damage while also improving addiction-related behavior, suggesting a dual therapeutic target.","specificNumbers":"15 rats; cannabis reduced germ cells (p=0.0006) and organ size (p=0.003); GDNF reversed sperm morphology (p=0.0016), grade C sperm (p=0.0295), DNA damage (p=0.0242).","methodology":"15 male Wistar rats in 3 groups: control, cannabis-addicted, and cannabis-addicted + GDNF. Cannabis addiction induced via smoking machine (0.25g per 5 rats). GDNF delivered by stereotaxic brain injection (0.5mg). Behavioral tests (elevated plus maze, open field, sucrose preference) and sperm analysis (morphology, DNA damage, viability).","limitations":"Very small sample (5 per group). Stereotaxic brain injection is not clinically practical. Cannabis delivery via smoking machine may not replicate human use patterns. Short intervention period. Male rats only."},{"rthcId":"RTHC-06890","title":"Change in Cigarette, Other Tobacco Product, and Cannabis Use Among Individuals Who Used or Did Not Use Cannabis During a Smoking Cessation Trial.","authors":"Lambart, Leah M; Cox, Lisa Sanderson; Mayo, Matthew S; Brown, Alexandra R; Leavens, Eleanor L S; Ahluwalia, Jasjit S; Nollen, Nicole L","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 27(9), 1641-1646","doi":"10.1093/ntr/ntaf045","pmid":"39976595","tags":["quitting","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"47.2% of participants were cigarette-cannabis dual users. Both groups reduced cigarettes similarly (p=0.18 for group difference). Cannabis users increased their cannabis consumption through week 26 (p<0.001). When cigarettes decreased, other tobacco products increased as compensation (p<0.0001), but cannabis did not follow the same compensatory pattern (p=0.37). Cannabis users maintained higher other tobacco product use throughout.","whyItMatters":"Nearly half of Black adults attempting to quit smoking also use cannabis, yet cannabis use is rarely addressed in cessation programs. The increase in cannabis use during a quit attempt may undermine the health benefits of reducing cigarettes.","specificNumbers":"392 participants; 47.2% dual CIG-CAN users; cannabis use increased through week 26 (p<0.001); CPD reduction similar between groups; OTP showed compensatory increase (p<0.0001).","methodology":"Secondary analysis of an 18-week smoking cessation RCT with 26-week follow-up. 392 Black adults wanting to quit cigarettes. Standard or adapted pharmacotherapy. Self-reported cigarettes, cannabis, and other tobacco use at weeks 0, 2, 6, 12, 18, 26.","limitations":"Secondary analysis, not prospectively designed for cannabis outcomes. Self-reported data. Predominantly Black adult sample may not generalize. Cannabis quantity not precisely measured. Cannot determine if cannabis increase is causal compensation."},{"rthcId":"RTHC-06891","title":"Endocannabinoid system modulation for visceral abdominal pain in inflammatory bowel disease and irritable bowel syndrome: A protocol for systematic review and meta-analysis.","authors":"Lane, Rebecca M; Egan, Laurence J; McGuire, Brian E; McKernan, Declan P; O'Mahony, Siobhain M; Finn, David P","year":2025,"journal":"HRB open research, 8, 40","doi":"10.12688/hrbopenres.14082.2","pmid":"40860020","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06892","title":"Cannabis Use in HIV: Impact on Inflammation, Immunity and the Microbiome.","authors":"Langat, Robert; Chakrawarti, Ashma; Klatt, Nichole R","year":2025,"journal":"Current HIV/AIDS reports, 22(1), 19","doi":"10.1007/s11904-025-00729-0","pmid":"39984806","tags":["medical-cannabis","inflammation","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis use in PWH was associated with reduced inflammatory biomarkers (MCP-1, IP-10), improved gut barrier integrity through increased SCFA production, increased gut mucosal immunity, decreased immune activation, and a unique microbiome composition. Preliminary evidence suggests cannabis may influence HIV reservoirs, but results are inconclusive.","whyItMatters":"Chronic inflammation persists in people with HIV even on effective antiretroviral therapy, contributing to non-AIDS comorbidities. Cannabis may address this through immunomodulatory and gut-protective effects, potentially improving long-term outcomes.","specificNumbers":"Reduced MCP-1 and IP-10 biomarkers. Increased SCFA production. Improved gut barrier integrity. Effects on HIV reservoirs inconclusive.","methodology":"Narrative review of studies examining cannabis effects on gut microbiome, immune system, and ART outcomes in people with HIV.","limitations":"Review format. Most evidence observational. Standardized cannabis formulations not used in studies. ART adherence concerns not fully addressed. Long-term outcomes unknown."},{"rthcId":"RTHC-06893","title":"Pediatric Patient Experiences Using Medical Cannabis in Cancer Symptom Management as Reported by Parents of Children and Adolescents and by Young Adults.","authors":"Langevin, Mary; Herriage, Teresa; Hooke, Mary C","year":2025,"journal":"Journal of pediatric hematology/oncology nursing, 42(1-2), 37-43","doi":"10.1177/27527530251318606","pmid":"40438918","tags":["cancer","medical-cannabis","youth","pain"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Top symptoms targeted: nausea/vomiting (n=20), appetite (n=15), pain (n=13), sadness/anxiety (n=7), sleep (n=7). 17 of 24 reported cannabis helped. Symptoms relieved: nausea/vomiting (n=15), appetite (n=13), sadness/anxiety (n=10), pain (n=9), sleep (n=9). Five reported side effects (mental changes). Three believed cannabis was treating their cancer.","whyItMatters":"Evidence on medical cannabis in pediatric oncology is extremely limited. This study captures real-world experiences of children and young adults using cannabis through a medical program, providing data to inform clinical conversations that are already happening.","specificNumbers":"24 respondents; 20 targeted nausea; 17 reported cannabis helped; 15 relieved nausea; 13 relieved appetite; 5 reported side effects; 3 believed it treated cancer.","methodology":"Anonymous 12-item survey of pediatric cancer patients certified for a medical cannabis program. 15 parents of children/adolescents under 18 and 9 young adults aged 18+.","limitations":"Very small sample (n=24). No control group. Self/parent-reported. Selection bias from medical cannabis program enrollment. No verification of symptom improvement. Anonymity prevents linking responses to clinical records."},{"rthcId":"RTHC-06894","title":"Controlled Use of Cannabis Among Young Adults in Los Angeles Across Changes in Cannabis Policies.","authors":"Lankenau, Stephen E; Ataiants, Janna; Prince, Mark; Fedorova, Ekaterina; Conn, Bridgid M; Ansell, Emily; Wong, Carolyn F","year":2025,"journal":"International journal of mental health and addiction","doi":"10.1007/s11469-025-01608-w","pmid":"41536538","tags":["legalization","addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Two latent classes emerged: Controlled and Uncontrolled, becoming more distinct over time. The Uncontrolled class was the majority across all waves. \"No school/work\" and \"no driving\" rules increased over time. \"Stopping cannabis use\" rule decreased during legalization transition. Controlled users consistently used less cannabis and had lower problematic use scores.","whyItMatters":"As cannabis becomes legal, understanding whether users self-regulate is crucial. The finding that some harm-reduction rules increased post-legalization (no work/school, no driving) while the ability to stop using decreased suggests legalization may shift self-regulation patterns in complex ways.","specificNumbers":"366 at wave 1 to 193 at wave 8; 2 latent classes across all waves; Uncontrolled always majority; \"no school/work\" and \"no driving\" rules increased; \"stopping use\" rule decreased.","methodology":"Prospective LA-based cohort aged 18-26 at enrollment. 8 survey waves over 9 years. Four waves analyzed across policy transitions: 2014-2015 (medical only), 2017-2018 (transition), 2019-2020 (adult use), 2022-2023 (adult use). Latent class analysis on 5 controlled-use rules.","limitations":"LA-specific cohort may not generalize. Attrition from 366 to 193 over 9 years. Self-reported rules may not reflect actual behavior. Latent class analysis requires assumptions about class structure."},{"rthcId":"RTHC-06895","title":"Combined chronic oral methylphenidate and fluoxetine treatment increases CB1 receptor density in the somatosensory forelimb region.","authors":"Lantry, Abigail M; Lu, Huy; Marion, Matt; Hamilton, John; Richardson, Brittany; Quattrin, Teresa; Mastrandrea, Lucy D; Hadjiargyrou, Michael; Komatsu, David; Thanos, Panayotis K","year":2025,"journal":"Neuroscience letters, 869, 138407","doi":"10.1016/j.neulet.2025.138407","pmid":"41046046","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06896","title":"Predictors of Participation in Prenatal Substance Use Assessment, Counseling, and Treatment Among Pregnant Individuals in Prenatal Settings Who Use Cannabis.","authors":"Lapham, Gwen T; Chi, Felicia W; Young-Wolff, Kelly C; Ansley, Deborah; Castellanos, Carley; Does, Monique B; Asyyed, Asma H; Ettenger, Allison; Campbell, Cynthia I","year":2025,"journal":"Journal of addiction medicine, 19(2), 179-186","doi":"10.1097/ADM.0000000000001399","pmid":"39792606","tags":["pregnancy","addiction","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"80.3% of cannabis-positive pregnancies completed assessment. Among 64% needing intervention, 88% attended counseling or treatment. Medicaid, anxiety, depression, and tobacco use disorders predicted higher odds of assessment. Older age (35+), greater parity, and later trimester assessment predicted lower odds. Nearly all psychiatric and substance use disorders predicted referral to addiction medicine treatment.","whyItMatters":"Prenatal cannabis use is rising, but engagement in assessment and counseling is poorly understood. This study shows a structured program can reach the vast majority of pregnant cannabis users, providing a model for other health systems.","specificNumbers":"17,782 individuals; 20,398 pregnancies; 80.3% completed assessment; 88% of those needing intervention attended; 64% needed intervention based on assessment.","methodology":"Retrospective cohort using EHR data from Kaiser Permanente Northern California Early Start program. 17,782 individuals with 20,398 cannabis-positive pregnancies (2011-2021). GEE multinomial logistic regression for predictors.","limitations":"Single health system (Kaiser) may not represent other settings. Cannabis screening methods evolved over the study period. Outcomes limited to program attendance, not cannabis use reduction or pregnancy outcomes."},{"rthcId":"RTHC-06897","title":"Cannabidiol Lipid Nanoparticles Stabilize Gut-Brain-Bone Axis Integrity and Enhance Neuroplasticity in Stressed Rats: A Comparison with Atomoxetine and Escitalopram.","authors":"Lapmanee, Sarawut; Lumsutti, Jitpatima; Charoenphon, Natthawut; Inchan, Anjaree; Boonmuen, Nittaya; Wongchitrat, Prapimpun; Thonapan, Natchayaporn; Yuajit, Chaowalit; Surinlert, Piyaporn; Tipbunjong, Chittipong; Khongkow, Mattaka; Namdee, Katawut; Sirithanakorn, Chaiyos","year":2025,"journal":"International journal of molecular sciences, 26(19)","doi":"10.3390/ijms26199318","pmid":"41096585","tags":["cbd","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Stressed rats showed 2.03-fold increase in IL-6, 1.89-fold TNF-alpha, decreased BDNF and osteocalcin, and disrupted gut metabolites (SCFAs dropped from 155.3 to 94.83 umol/L). CBD/LNP restored gut barrier (1.15-1.61-fold improvement), normalized bile acids (1.0-1.38-fold), osteocalcin (1.0-1.28-fold), and reduced glial activation (0.63-1.12-fold). All treatments corrected SCFA and polyamine levels.","whyItMatters":"This study positions CBD not just as a mental health intervention but as a multi-system therapy addressing the gut-brain-bone axis disrupted by chronic stress. The nanoparticle formulation addresses CBD bioavailability limitations.","specificNumbers":"IL-6: 2.03-fold stress increase; SCFAs: dropped from 155.3 to 94.83 umol/L; gut barrier improved 1.15-1.61-fold with CBD/LNP; glial activation reduced to 0.63-1.12-fold.","methodology":"Male rats exposed to repeated restraint stress, then treated with atomoxetine, escitalopram, CBD, or CBD-loaded lipid nanoparticles. Outcomes: inflammatory markers, gut metabolites, gut barrier function, microglial activation, synaptic plasticity, histology.","limitations":"Animal model. Male rats only. Nanoparticle formulation adds complexity. Multiple comparisons without clear correction. Short treatment period."},{"rthcId":"RTHC-06898","title":"Cannabinoids and Adverse Convulsive Effects: A Pharmacovigilance and Addictovigilance Analysis of Cases Reported in France.","authors":"Laroche, Marie-Laure; Labetoulle, Marion; Jouanjus, Emilie; Kröger, Edeltraut; Zongo, Arsène","year":2025,"journal":"Fundamental & clinical pharmacology, 39(4), e70028","doi":"10.1111/fcp.70028","pmid":"40540313","tags":["epilepsy","cbd","drug-interactions"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"130 seizure cases among 4,296 cannabinoid reports (3%). 75.4% were recreational use, 23.3% medical (mostly CBD). 81.1% were serious. 67.7% had pre-existing seizure risk factors (78.6% of recreational vs. 31.0% of medical users). Main recreational risks: epileptogenic medications (39.8%), illicit drugs (33.7%), alcohol (32.7%). Main medical risks: CBD inefficacy (17.2%), fatigue (13.8%), concomitant epileptogenic meds (10.3%).","whyItMatters":"As CBD gains popularity for epilepsy treatment and recreational cannabis use grows, understanding seizure risks is critical. This study shows most seizures occur in people with pre-existing vulnerability, particularly from drug interactions.","specificNumbers":"4,296 cannabinoid reports; 130 (3%) convulsive; 78.7% male; median age 29; 81.1% serious; 38.8% of recreational users had epilepsy history; 68.4% of those were on antiepileptics.","methodology":"Retrospective analysis of French pharmacovigilance and addictovigilance databases plus Eudravigilance (1985-2023). MedDRA \"convulsive\" SMQ term with all cannabinoid products. 130 cases analyzed for demographics, circumstances, and risk factors.","limitations":"Spontaneous reporting captures only a fraction of events. Cannot establish causation. Recreational use data may include multiple substances confounding attribution. Long study period spans changing cannabis potency and availability."},{"rthcId":"RTHC-06899","title":"Cross-sectional comparison of cannabis use in adults with neuropathic versus non-neuropathic pain.","authors":"Laroya, Carl Joshua P; Smith, Crystal Lederhos; Bindler, Ross J; McDonell, Michael G; Lewis, Jamie; Wilson, Marian","year":2025,"journal":"Frontiers in pain research (Lausanne, Switzerland), 6, 1677391","doi":"10.3389/fpain.2025.1677391","pmid":"41487383","tags":["pain","medical-cannabis","cbd"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"This study surveyed 104 adults at a pain clinic, comparing cannabis use patterns between those whose most bothersome pain was neuropathic (nerve-related, 36.5%) versus non-neuropathic (63.5%).\n\nPatients with neuropathic pain reported significantly more days per month of THC/CBD product use compared to those with non-neuropathic pain. This wasn't random—it suggests that people with nerve pain, which is notoriously difficult to treat with standard medications, may be turning to cannabis more intensively because conventional options aren't working well enough.\n\nNeuropathic pain includes conditions like diabetic neuropathy, post-surgical nerve damage, and sciatica. These conditions respond poorly to standard painkillers (including opioids) and are one of the areas where cannabis has shown the most promising anecdotal and clinical evidence.\n\nThe study used the ID-Pain tool to classify pain types, which provides a standardized way to distinguish neuropathic from non-neuropathic pain based on symptom characteristics rather than physician diagnosis alone.","whyItMatters":"If neuropathic pain specifically drives more intensive cannabis use, that has implications for both medical cannabis programs and pain clinic practice. It suggests cannabis may be filling a gap where conventional pain treatments fall short—and that research on cannabis for nerve pain specifically should be prioritized over general chronic pain research.","specificNumbers":"N = 104 (61.5% female). 36.5% neuropathic pain, 63.5% non-neuropathic. Neuropathic pain patients used THC/CBD products significantly more days per month.","methodology":"Cross-sectional survey of 104 adults (61.5% female) receiving care at a pain clinic. Pain categorized as neuropathic or non-neuropathic using ID-Pain scores. Cannabis product use assessed by frequency and duration. Linear regression models adjusted for age and sex.","limitations":"Small sample from a single pain clinic. Cross-sectional design can't determine causation—people with neuropathic pain may use more cannabis because it works, because they're more desperate, or for other reasons. Self-reported cannabis use. The ID-Pain tool classifies pain type based on symptoms rather than confirmed diagnoses. No data on whether the cannabis actually helped with pain."},{"rthcId":"RTHC-06900","title":"The effects of cannabidiol and its main metabolites on human neural stem cells.","authors":"Latham, Leah E; Gu, Qiang; Liu, Shuliang; Wang, Cheng; Liu, Fang","year":2025,"journal":"Experimental biology and medicine (Maywood, N.J.), 250, 10608","doi":"10.3389/ebm.2025.10608","pmid":"40584168","tags":["pregnancy","cbd","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBD, 7-OH-CBD, and 7-COOH-CBD all dose-dependently reduced NSC viability. CBD and 7-OH-CBD reduced cells at G1 phase. At clinically relevant blood concentrations, longer exposures caused more obvious cell death. After differentiation, CBD reduced GFAP and CB2 receptor expression. THC also reduced GFAP but not CB2. CB1 and beta-tubulin III expression were unaffected.","whyItMatters":"CBD is increasingly used by pregnant women who perceive it as safe. This study shows that CBD and its metabolites, at concentrations actually found in human blood, affect neural stem cells in ways relevant to fetal brain development.","specificNumbers":"Three compounds tested (CBD, 7-OH-CBD, 7-COOH-CBD). All dose-dependently reduced viability. Longer exposures at blood-level concentrations caused more cell death. GFAP and CB2 expression reduced after CBD-treated differentiation.","methodology":"Human neural stem cells treated with CBD, 7-OH-CBD, 7-COOH-CBD, and THC at various concentrations and durations. Cell viability, proliferation, cell cycle, and differentiation markers (GFAP, CB1, CB2, beta-tubulin III) assessed.","limitations":"In vitro study with isolated stem cells, not intact brain tissue. Cannot replicate the complex fetal environment. Single cell line. Concentrations and durations are approximations of in vivo exposure."},{"rthcId":"RTHC-06901","title":"Effective cannabis testing protocols for workplace safety in South Africa post legalisation: Navigating the new normal.","authors":"Laurens, J B","year":2025,"journal":"South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 115(2), e2537","doi":"10.7196/SAMJ.2025.v115i2.2537","pmid":"41378585","tags":["workplace","legalization"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"South Africa's legalization of private cannabis use created an immediate tension with workplace drug testing policies—particularly in safety-sensitive industries like mining, construction, and transport. This paper examines that tension through a pharmacological lens.\n\nThe core problem: standard urine drug tests detect THC metabolites that persist for days or weeks after use, long after any impairment has worn off. A zero-tolerance policy based on urine testing effectively penalizes workers for legal private use that doesn't affect their job performance. A recent South African legal precedent has already critiqued this approach.\n\nThe author proposes moving from zero-tolerance urine testing to per se THC blood thresholds—specific concentrations that correlate with actual impairment rather than mere prior exposure. This mirrors how alcohol impairment is assessed (blood alcohol concentration) rather than testing for the mere presence of any alcohol metabolite.\n\nThe paper also advocates for risk-based categorization of workplaces, recognizing that the safety stakes are different for a desk worker versus a heavy equipment operator, and testing protocols should reflect that difference.","whyItMatters":"South Africa is one of the first African countries to legalize private cannabis use, and its workplace policy decisions will likely influence other nations. The fundamental problem—testing that detects past use rather than current impairment—is universal. Every jurisdiction with legal cannabis faces this same tension, and the science-based threshold approach proposed here could serve as a model.","specificNumbers":"THC can be detected in urine for days to weeks after use. Zero-tolerance policies penalize legal use. Per se blood THC thresholds proposed as an alternative tied to actual impairment windows.","methodology":"Narrative review analyzing the medical, legal, and ethical issues surrounding workplace cannabis testing in post-legalization South Africa. Focuses on THC pharmacokinetics and pharmacodynamics to inform evidence-based testing thresholds.","limitations":"This is a policy analysis and proposal, not empirical research. The specific THC blood thresholds that correlate with impairment are still debated in the scientific literature. South African workplace conditions (particularly mining) may not translate to other countries. The legal analysis is specific to South African jurisprudence."},{"rthcId":"RTHC-06902","title":"Neighbourhood risk factors and spatiotemporal trends for overdoses following cannabis legalization and pandemic restrictions in Toronto, Canada.","authors":"Law, Jane; Petric, Alexander T","year":2025,"journal":"Health & place, 96, 103557","doi":"10.1016/j.healthplace.2025.103557","pmid":"41092530","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06903","title":"Association between out-of-home care and mortality in children with prenatal drug exposure: a retrospective population-based cohort study.","authors":"Lawler, Kate; Dronavalli, Mithilesh; Uebel, Hannah; Burns, Lucinda; Bajuk, Barbara; Page, Andrew; Lee, Evelyn; Dickson, Michelle; Green, Charles; Dicair, Lauren; Eastwood, John; Oei, Ju-Lee","year":2025,"journal":"Archives of disease in childhood, 110(6), 463-470","doi":"10.1136/archdischild-2025-328474","pmid":"40169176","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06904","title":"Interspecies differences in the expression of cannabinoid receptors at the tissue and cellular levels.","authors":"Lawley, Sydney; Green, Audrey; Johnson, Cole; Burton, Michael D","year":2025,"journal":"Neural regeneration research","doi":"10.4103/NRR.NRR-D-25-00806","pmid":"41169214","tags":["pain","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CB1 and CB2 receptor expression differs substantially between species in terms of tissue distribution, cellular localization, and co-expressed markers. Pain conditions differentially alter receptor expression depending on pain type and species. These differences may explain why cannabinoid compounds that show efficacy in rodent pain models often fail in human clinical trials.","whyItMatters":"IASP recommended against cannabinoids for pain in 2021 partly due to poor clinical trial results. This review offers a mechanistic explanation: the receptors researchers target in animals may not be in the same places or on the same cells in humans.","specificNumbers":"IASP 2021 position statement against cannabinoids for pain. Review covers CB1 and CB2 distribution across CNS, PNS, and immune cells in rodents, primates, and humans.","methodology":"Comprehensive narrative review traversing historical and contemporary literature on cannabinoid receptor expression across the nervous system in multiple species, with focus on pain-relevant regions.","limitations":"Narrative review format. Many studies used different methodologies making direct comparisons difficult. Some brain regions have limited data across species. Functional differences may not always follow expression differences."},{"rthcId":"RTHC-06905","title":"Value signals guiding choices for cannabis versus non-drug rewards in people who use cannabis near-daily.","authors":"Lawn, Will; Hao, Xuejun; Konova, Anna B; Haney, Margaret; Cooper, Ziva D; Van Dam, Nicholas; Glimcher, Paul; Bedi, Gillinder","year":2025,"journal":"Psychopharmacology, 242(4), 681-691","doi":"10.1007/s00213-025-06746-6","pmid":"39928130","tags":["addiction","neuroscience","dopamine"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Subjective value signals for cannabis appeared in vmPFC, ventral striatum, and dorsal PCC as expected. Value encoding in vmPFC was stronger for cannabis than snacks. For snack rewards, expected value signals were absent. Cannabis and snack cues differentially modulated value encoding in the dorsal PCC. Choice behavior was equivalent between reward types despite the neural differences.","whyItMatters":"This study provides neural evidence for a key addiction theory: that problematic substance use involves not just enhanced drug valuation but degraded valuation of non-drug rewards. The behavioral equivalence masking neural differences suggests standard behavioral measures may miss this dysfunction.","specificNumbers":"20 analyzed; near-daily use (4+ days/week); value signals in vmPFC, ventral striatum, dPCC for cannabis but not snacks; vmPFC encoding stronger for cannabis vs. snacks.","methodology":"Inpatient crossover design with 21 non-treatment-seeking near-daily cannabis users (20 analyzed). Four conditions crossing cue type (neutral/drug or neutral/snack) with reward type (cannabis/snack). fMRI during economic choice task choosing between 0-6 cannabis puffs or snacks vs. fixed monetary amounts.","limitations":"Small sample (n=20). Only 1 female participant. Non-treatment-seeking users. Cross-sectional design cannot determine if neural differences preceded cannabis use. Snacks may not adequately represent all non-drug rewards."},{"rthcId":"RTHC-06906","title":"Cannabis Use Trajectories Among People Living With HIV in the Decade Prior to Recreational Legalization in Ontario, Canada (2008-2017).","authors":"Lazor, Tanya; Sanches, Marcos; Wardell, Jeffrey D; Wang, Wei; Burchell, Ann N; Margolese, Shari; Bekele, Tsegaye; Kroch, Abigail E; Rueda, Sergio","year":2025,"journal":"AIDS education and prevention : official publication of the International Society for AIDS Education, 37(2), 142-159","doi":"10.1521/aeap.2025.37.2.142","pmid":"40323672","tags":["medical-cannabis","mental-health","depression"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Four trajectories: Low/No Use (67%), Increased Use (4%), Decreased Use (2%), High Use (26%). High Use group predictors: older age, university education, tobacco smoking, significant depressive symptoms. The majority (67%) had consistently low or no cannabis use over the decade.","whyItMatters":"Cannabis use is common among people with HIV, often for symptom management. Understanding long-term use patterns and their correlates helps clinicians identify who may need intervention and who is using cannabis stably.","specificNumbers":"3,299 participants; 81% male; 57% gay; 58% current/former smokers; 43% significant depression; 26% high use trajectory; 67% low/no use.","methodology":"Latent class growth analysis of the Ontario HIV Treatment Network Cohort Study (2008-2017). 3,299 participants with interview data over up to 10 years. Chi-square tests for trajectory group predictors.","limitations":"Pre-legalization data (2008-2017) may not reflect current patterns. Self-reported cannabis use. Observational design cannot determine depression-cannabis directionality. Ontario cohort may not generalize."},{"rthcId":"RTHC-06907","title":"Using decision trees to examine risk profiles for cannabis use among large samples of underage youth before and after cannabis legalization in Canada.","authors":"Leatherdale, Scott T; Battista, Katelyn; Patte, Karen A; MacKillop, James; Bélanger, Richard","year":2025,"journal":"Addictive behaviors reports, 22, 100632","doi":"10.1016/j.abrep.2025.100632","pmid":"41146893","tags":["youth","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Current cannabis use dropped from 15.0% (pre-legalization 2017-18) to 12.3% (post-legalization 2021-22). Pre-legalization highest risk group (27% probability): students who devalued grades + texted 45+ min/day (30.4% of sample). Post-legalization highest risk group (27% probability): students who devalued grades + skipped breakfast + had elevated anxiety (18.8% of sample). Risk factor rankings changed considerably between periods.","whyItMatters":"Counter to fears, underage cannabis use did not increase after legalization. However, the changing risk profiles mean prevention programs must adapt to target emerging risk factors like anxiety rather than relying on pre-legalization approaches.","specificNumbers":"85 schools; 15.0% use pre-legalization vs. 12.3% post; 6 risk profiles pre vs. 11 post; top risk factor consistent: low value on grades; new post-legalization factors: anxiety, skipping breakfast.","methodology":"COMPASS Study data from 85 secondary schools at two timepoints. Classification tree analysis modeling interactions among multiple risk factors. Wave 1 (2017-18, medical-only policy) and wave 2 (2021-22, adult-use policy).","limitations":"Cannot separate legalization effects from pandemic effects (2021-22 data). School-based sample excludes non-enrolled youth. Classification trees may overfit. Self-reported cannabis use."},{"rthcId":"RTHC-06908","title":"Cannabinoids and the Endocannabinoid System in the Treatment of Chronic Rhinosinusitis.","authors":"Lee, John J W; Hamour, Amr F; Wihlidal, Jacob G J; Lee, John M; Monteiro, Eric; Poduch, Ewa; Kotra, Lakshmi; Vescan, Allan D","year":2025,"journal":"The Laryngoscope, 135(8), 2683-2690","doi":"10.1002/lary.32191","pmid":"40260746","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06909","title":"Tobacco and Cannabis Co-use by HIV Status Among United States Adults: Results from the 2021-2023 National Survey on Drug Use and Health.","authors":"Lee, Juhan; Yin, Ana Paula Xingru; Weinberger, Andrea H","year":2025,"journal":"AIDS and behavior, 29(12), 3794-3805","doi":"10.1007/s10461-025-04817-5","pmid":"40614021","tags":["medical-cannabis","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Adults with HIV had 3.35x higher odds of past-month tobacco-cannabis co-use (aRRR=3.35, 95% CI: 1.79-6.27). 0.4% of respondents reported HIV; 8.2% reported tobacco-cannabis co-use. Race/ethnicity and state medical cannabis legalization modified the HIV-co-use association.","whyItMatters":"Tobacco-cannabis co-use poses unique health risks including lung disease, drug dependence, and potential ART interactions. The high co-use rate among PWH demands targeted harm reduction strategies.","specificNumbers":"139,524 adults; 0.4% HIV+; 8.2% co-use; aRRR=3.35 for HIV and co-use; race/ethnicity and state laws modified association.","methodology":"Cross-sectional analysis of 2021-2023 National Survey on Drug Use and Health. 139,524 adult respondents. Adjusted multinomial logistic regression with interaction testing for demographics and state cannabis laws.","limitations":"Cross-sectional design. Self-reported HIV diagnosis may undercount. Cannot determine temporal order. NSDUH household survey may miss homeless/institutionalized populations."},{"rthcId":"RTHC-06910","title":"Maternal dietary DHA and EPA supplementation ameliorates adverse cardiac outcomes in THC-exposed rat offspring.","authors":"Lee, Kendrick; Sarikahya, Mohammed H; Cousineau, Samantha L; Yeung, Ken K-C; Lucas, Amica; Loudon, Kara; Tomy, Thane; Tomy, Gregg T; Natale, David R C; Laviolette, Steven R; Hardy, Daniel B","year":2025,"journal":"Scientific reports, 15(1), 8316","doi":"10.1038/s41598-025-92844-6","pmid":"40064971","tags":["pregnancy","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Maternal THC exposure led to decreased birthweight and early cardiac deficits in offspring. Dietary omega-3 supplementation reversed both THC-induced fetal growth restriction and postnatal cardiac deficits. The protective effect appeared to involve alterations in cardiac and hepatic fatty acids, reduced cardiac collagen deposition, and decreased cardiac endocannabinoid system signaling.","whyItMatters":"This is the first study to explore an intervention for maternal THC-induced cardiovascular deficits in offspring. With rising cannabis use in pregnancy and emerging evidence of cardiac consequences, a dietary intervention like omega-3s could be clinically practical.","specificNumbers":"Maternal THC reduced birthweight. Omega-3 reversed growth restriction and cardiac deficits. Cardiac collagen deposition reduced. Endocannabinoid signaling decreased with omega-3.","methodology":"Rat model with maternal THC exposure and dietary omega-3 (DHA and EPA) supplementation. Assessed fetal growth, postnatal cardiac outcomes, cardiac and hepatic fatty acid profiles, collagen deposition, and endocannabinoid system markers.","limitations":"Animal model. Single THC dose regimen may not reflect human use patterns. Omega-3 dose may not be achievable through diet alone. Long-term offspring outcomes not assessed. Cannot determine if omega-3 fully prevents or merely reduces harm."},{"rthcId":"RTHC-06911","title":"Prospective associations of COVID-related stress with vaping nicotine and cannabis among high school students: Mediated by vaping susceptibility.","authors":"Lee, Ryan; Cho, Junhan; Bae, Dayoung; Albers, Larisa; Herzig, Shirin Emma; Ramirez, Carla Michelle; Carvajal, Alberto; Soto, Daniel; Unger, Jennifer B","year":2025,"journal":"PloS one, 20(10), e0334159","doi":"10.1371/journal.pone.0334159","pmid":"41056299","tags":["youth","anxiety"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"COVID-related stress during remote learning (2020-2021) predicted increased susceptibility to cannabis vaping one year later (B=0.04, p=0.02), which predicted actual cannabis vaping another year later (B=1.62, p<0.001). The same mediation pattern held for e-cigarette vaping (susceptibility B=0.04, p=0.02; vaping B=0.98, p=0.003).","whyItMatters":"The pandemic created a generation of stressed adolescents. This study shows that stress translated to actual substance use two years later through a measurable intermediary (susceptibility), identifying a window for intervention.","specificNumbers":"1,316 students; 9 schools; COVID stress to cannabis vaping susceptibility B=0.04 (p=0.02); susceptibility to cannabis vaping B=1.62 (p<0.001).","methodology":"Prospective cohort of 1,316 9th graders from 9 LA County public high schools. Annual surveys over 3 years. Mediation analysis testing COVID stress (2020-21) to vaping susceptibility (2021-22) to vaping behavior (2022-23).","limitations":"LA County sample may not generalize. Self-reported measures. Attrition over 3 years not detailed. COVID stress may be a proxy for other pandemic-related changes. Cannot establish causation from observational mediation."},{"rthcId":"RTHC-06912","title":"Cannabidiol Loaded Nanoemulsion with Improved Bioaccessibility and Anti-Inflammatory Activity.","authors":"Lee, Yuna; Kim, Sang Hoon; Song, Ha-Yeon; Byun, Eui-Baek","year":2025,"journal":"ACS omega, 10(41), 48146-48154","doi":"10.1021/acsomega.5c04608","pmid":"41180072","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06913","title":"Association of childhood mental health and cognition with longitudinal patterns of cannabis problems in adolescence.","authors":"Lees Thorne, Rachel; Hines, Lindsey A; Burke, Chloe; Jones, Hannah J; Freeman, Tom P","year":2025,"journal":"Psychological medicine, 55, e129","doi":"10.1017/S0033291725001175","pmid":"40302648","tags":["youth","mental-health","cognition"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Five trajectories identified: stable-no problems (85%), early-onset high (2%), late-onset high (3%), early-onset low (6%), late-onset low (5%). Externalizing disorders at age 10 predicted three of four problem trajectories. Internalizing disorders were only associated with late-onset low problems (protective: RR=0.50). Short-term memory at age 8 was associated with late-onset high problems (RR=1.09).","whyItMatters":"This study identifies a modifiable target for preventing problematic cannabis use: childhood externalizing disorders (conduct problems, ADHD-type behavior). Intervening on these behaviors at age 10 could potentially prevent cannabis problems starting at age 15.","specificNumbers":"6,049 participants; 85% no problems; externalizing disorders: RR=2.82 (early-high), 1.62 (late-high), 1.82 (early-low); internalizing: RR=0.50 (late-low only); memory: RR=1.09 (late-high only).","methodology":"Analysis within ALSPAC UK birth cohort. 6,049 participants with cannabis problem data (CAST) at 2+ timepoints between ages 15-24. Risk factors: internalizing and externalizing disorders at age 10, cognitive function at age 8. Longitudinal latent class analysis.","limitations":"59% female sample may affect generalizability. ALSPAC cohort is predominantly white (95.7%). Cannabis problems assessed by screening tool, not clinical diagnosis. Attrition from birth cohort may bias results."},{"rthcId":"RTHC-06914","title":"Cannabinoid Hyperemesis Syndrome Presumed Secondary to CBD Use: A Case Report.","authors":"Lefebvre, Emilie; Simons, Luc; Duval, Mélanie; Laforgue, Edouard-Jules; Victorri-Vigneau, Caroline","year":2025,"journal":"Journal of addiction medicine, 19(1), 115-117","doi":"10.1097/ADM.0000000000001378","pmid":"39221821","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06915","title":"Cannabis Perturbs Dynamic Brain States.","authors":"Lege, Katharina S; Mallaroni, Pablo; Mortaheb, Sepehr; Mason, Natasha L; Theunissen, Eef L; Tse, Desmond H Y; Toennes, Stefan W; Demertzi, Athena; Ramaekers, Johannes G","year":2025,"journal":"Biological psychiatry","doi":"10.1016/j.biopsych.2025.10.015","pmid":"41130555","tags":["cognition","tolerance","neuroscience","addiction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This neuroimaging trial used a sophisticated approach—dynamic functional connectivity analysis—to examine how vaporized cannabis affects brain network organization in real time. Twenty-three occasional and 20 chronic cannabis users each received cannabis and placebo in a controlled setting while undergoing brain scans.\n\nDuring intoxication, both user groups showed a significant reduction in a hyperconnected brain state—a pattern where many brain regions communicate simultaneously. This acute effect was observable regardless of use history.\n\nBut the chronic users showed something additional: decreased brain network segregation that was present regardless of whether they had received cannabis or placebo. This means their brain networks were organized differently even when sober—a persistent alteration that wasn't present in occasional users. The authors interpret this as evidence of neuroadaptation: repeated cannabis exposure has fundamentally changed how chronic users' brains organize their network communication.\n\nThe brain connectivity changes correlated with attentional performance and mapped onto the distribution of CB1 cannabinoid receptors in the brain, providing a mechanistic link between receptor-level pharmacology and large-scale brain network dynamics.","whyItMatters":"This study helps explain the well-documented behavioral observation that chronic users seem less impaired by cannabis than occasional users. It's not just tolerance in the colloquial sense—their brains have physically reorganized their network dynamics. The persistent changes in chronic users also raise questions about whether these adaptations are fully reversible with abstinence or represent lasting structural changes.","specificNumbers":"N = 43 (23 occasional, 20 chronic users). Cannabis reduced occurrence of a hyperconnected brain state acutely in both groups. Chronic users showed decreased brain network segregation independent of intoxication. Changes correlated with CB1 receptor density and attentional performance.","methodology":"Placebo-controlled neuroimaging trial. Occasional users (n = 23) and chronic users (n = 20) each received vaporized cannabis and placebo. Resting-state fMRI collected to assess dynamic functional connectivity. Analyses examined acute effects of cannabis, persistent effects in chronic users, and associations with attentional performance and CB1 receptor density maps.","limitations":"Relatively small sample sizes (23 and 20). Cross-sectional comparison between user groups—can't prove that cannabis use caused the chronic users' brain changes (pre-existing differences are possible). Resting-state fMRI measures blood flow as a proxy for neural activity. Dynamic connectivity analysis is a newer method with ongoing methodological debates. No longitudinal follow-up to assess whether persistent changes reverse with abstinence."},{"rthcId":"RTHC-06916","title":"A remote measurement study of PTSD and cannabis use among veterans: Recruitment, retention, and data availability.","authors":"Leightley, Daniel; Dilkina, Bistra; Pedersen, Eric R; Dworkin, Emily; Saba, Shaddy; Howe, Esther; Thota, Praneeth; Nuthi, Sriram; Sedano, Angeles; Davis, Jordan P","year":2025,"journal":"PloS one, 20(9), e0332239","doi":"10.1371/journal.pone.0332239","pmid":"41021546","tags":["ptsd","addiction"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Phase 1: 20 veterans beta-tested app feasibility. Phase 2: 75 veterans used the app for 3 months. 91.9% provided passive data (heart rate, sleep, activity). 68% response rate for daily self-report measures. Data availability varied across measures but was sufficient for analysis.","whyItMatters":"Predicting PTSD-cannabis symptom escalation could enable timely intervention. This study proves that veterans will engage with a monitoring app long enough to generate useful data, clearing the feasibility hurdle for future prediction studies.","specificNumbers":"95 total veterans; 91.9% passive data provision; 68% daily survey response rate; 3-month monitoring period.","methodology":"Two-phase longitudinal study. MAVERICK mobile app integrating passive (wearable sensor) and active (self-report survey) data. Phase 1: beta testing with 20 veterans. Phase 2: 3-month data collection with 75 veterans with PTSD and cannabis use.","limitations":"Feasibility study, not an effectiveness trial. Data completeness varied across measures. Wearable device compliance may decline over longer periods. Veterans who agreed to participate may not represent all veterans with PTSD and CUD."},{"rthcId":"RTHC-06917","title":"Chronic Health Effects of Cannabis Use in Childhood and Adolescence.","authors":"Leja, Jacqueline A","year":2025,"journal":"Pediatric annals, 54(6), e217-e221","doi":"10.3928/19382359-20250407-02","pmid":"40489359","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06918","title":"Safety, Efficacy and Doxorubicin Pharmacokinetics During Cannabidiol/Cannabidiolic Acid Rich Hemp Oil Use in Dogs With Lymphoma Undergoing CHOP Chemotherapy.","authors":"Lejeune, Amandine; Bechtel, Sandra; Milner, Rowan; Fagman, Lana; Leal Yepes, Francisco A; Wakshlag, Joseph J","year":2025,"journal":"Journal of veterinary internal medicine, 39(4), e70179","doi":"10.1111/jvim.70179","pmid":"40622742","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06919","title":"TAAT hemp cigarettes' unsubstantiated cessation and harm reduction claims.","authors":"Lempert, Lauren Kass; Bialous, Stella A; Ling, Pamela M","year":2025,"journal":"Tobacco control","doi":"10.1136/tc-2025-059573","pmid":"41339089","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06920","title":"Clinical and psychosocial changes in adults with opioid use disorder and chronic pain using medical cannabis: a brief report.","authors":"Lent, Michelle R; Keen, Ryan; Ruiz, Michael; Callahan, Hannah R; Galluzzi, Katherine E; Dugosh, Karen L","year":2025,"journal":"Journal of cannabis research, 7(1), 36","doi":"10.1186/s42238-025-00297-5","pmid":"40533856","tags":["medical-cannabis","pain","addiction","sleep"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Over three months, participants taking a 1:1 THC:CBD capsule alongside buprenorphine/naloxone reported significant decreases in pain severity, improved sleep quality, and better quality of life across seven of eight domains. However, illicit opioid use rates and opioid cravings did not change significantly.","whyItMatters":"People being treated for opioid addiction frequently deal with chronic pain, and undertreated pain can drive relapse. This study suggests medical cannabis may help with pain and quality of life in this population, though it did not reduce illicit opioid use in this small sample.","specificNumbers":"Pain severity dropped from 5.18 to 4.39 (p<0.05). Sleep quality improved from 12.38 to 10.95 (p<0.05). Quality of life improved in 7 of 8 domains. Illicit opioid-positive urine tests dropped from 16% to 5%, but this was not statistically significant. Opioid cravings showed no significant change (2.15 to 1.78, p=0.49).","methodology":"Observational study of 47 adults with opioid use disorder and chronic pain (minimum 5/10 severity) already receiving buprenorphine/naloxone. Participants were offered a discounted 5mg THC:5mg CBD daily oral capsule and assessed at baseline and three months using validated scales and urine drug screening.","limitations":"Very small sample (47 participants) with no control group. Participants self-selected into the study. Three-month follow-up is short. The discounted medication may have influenced participation and adherence."},{"rthcId":"RTHC-06921","title":"Motivation and experiences of individuals with opioid use disorder and chronic pain using medical cannabis for 12 months.","authors":"Lent, Michelle R; Dugosh, Karen L; Varsani, Kartik; Jonsson, Andrea; Kung, Tyler; Galluzzi, Katherine E","year":2025,"journal":"Harm reduction journal, 22(1), 155","doi":"10.1186/s12954-025-01306-9","pmid":"41044588","tags":["medical-cannabis","pain","addiction","sleep","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Across 10 interviews, participants consistently described four benefits from 12 months of medical cannabis: reduced pain levels, improved emotional regulation and mood, better sleep quality and duration, and reduced cravings for illicit drugs. Their initial motivations included wanting a safer cannabis supply, reducing prescription medications, and achieving calm.","whyItMatters":"While quantitative studies provide numbers, qualitative research captures lived experience. These interviews reveal what motivated people with opioid addiction to try medical cannabis and how they described its effects on their daily lives over a full year.","specificNumbers":"10 interviews conducted after 12 months of medical cannabis treatment. Four key motivations and four key benefit themes were identified. Primary concerns centered on weight/appetite changes and cost of products.","methodology":"Qualitative study using key informant interviews with 10 individuals who had opioid use disorder and chronic pain and had been using medical cannabis for 12 months. Themes were identified through content analysis of interview transcripts.","limitations":"Only 10 participants, all from one clinic. Self-reported experiences may be subject to social desirability bias. No comparison group or objective measures."},{"rthcId":"RTHC-06922","title":"Growing practices and the use of potentially harmful chemical additives from a web survey of mainly small-scale cannabis growers in 18 countries.","authors":"Lenton, Simon; Potter, Gary; Fortin, Davide; Granville, Ashely; Grigg, Jodie; Sevigny, Eric; Wilkins, Chris; Decorte, Tom; Barratt, Monica","year":2025,"journal":"The International journal on drug policy, 144(Pt 3), 104662","doi":"10.1016/j.drugpo.2024.104662","pmid":"39609120","tags":["harm-reduction","potency","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In the 2020-21 survey, 26% of cannabis growers reported using chemicals. The highest odds of chemical use were among male, older, urban growers who grew under artificial light to sell cannabis. In three countries tracked over time (Australia, Denmark, UK), chemical fertilizer use decreased significantly between 2012-13 and 2020-21.","whyItMatters":"Unregulated chemical use in cannabis growing poses health risks to consumers, especially since some plant growth regulators banned from food crops for decades have been found in cannabis fertilizer products. Understanding who uses these chemicals and why can inform harm reduction efforts.","specificNumbers":"11,479 growers surveyed across 18 countries. 26% reported chemical use. Growers using soil and artificial light comprised over half of all chemical users. Significant reductions in chemical fertilizer use were observed between the 2012-13 and 2020-21 surveys in Australia, Denmark, and the UK.","methodology":"Web-based convenience survey of 11,479 mainly small-scale cannabis growers from 18 countries (2020-2021). Logistic regression identified predictors of chemical use. Results were compared with data from a similar 2012-13 survey in three countries.","limitations":"Convenience (non-random) web sample may not represent all cannabis growers. Self-reported chemical use may be underreported. The two survey waves used different samples, limiting direct comparison."},{"rthcId":"RTHC-06923","title":"Integrating Alcohol and Cannabis Risk Reduction Into Sexual Assault Resistance Programming: Findings From a Pilot of EAAA.","authors":"Leone, Ruschelle M; Franklin-Kidd, Monicamonet; Gayer, Ellie; Brown, Julianna; Patel, Rutu; Thompson, Caitlin; Mullican, Nicole K; Salazar, Laura F; Neighbors, Clayton; Gilmore, Amanda K; Gray, Kevin M; Senn, Charlene","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(5), 761-768","doi":"10.15288/jsad.24-00183","pmid":"39841440","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06924","title":"Event-level effects of alcohol, cannabis, and simultaneous alcohol and cannabis use on bystander intentions in response to hypothetical situations among college women.","authors":"Leone, Ruschelle M; Haikalis, Michelle; Marcantonio, Tiffany L; Gilmore, Amanda K; Stappenbeck, Cynthia; Barnett, Nancy P; Gray, Kevin M","year":2025,"journal":"Addictive behaviors, 162, 108227","doi":"10.1016/j.addbeh.2024.108227","pmid":"39667050","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06925","title":"In-hospital outcomes following an acute coronary syndrome in patients with recent cannabis use.","authors":"Léquipar, Antoine; Dillinger, Jean-Guillaume; Bonnefoy-Cudraz, Eric; Albert, Emeric; Attou, Sabir; Auvray, Simon; Azzakani, Sonia; Boccara, Albert; Bouchot, Océane; Brette, Jean-Baptiste; Canu, Marjorie; Chaussade, Anne Solene; Gilard, Martine; Dupasquier, Valentin; Elhadad, Anthony; Ezzouhairi, Nacim; Clément, Arthur; Gall, Emmanuel; Henry, Patrick; Pezel, Théo","year":2025,"journal":"Archives of cardiovascular diseases, 118(3), 152-160","doi":"10.1016/j.acvd.2024.10.321","pmid":"39578211","tags":["cardiovascular","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Systematic urine screening across 39 French hospitals found 11.1% of acute coronary syndrome patients tested positive for cannabis. After adjusting for other risk factors and severity predictors, cannabis detection was associated with 3.28 to 3.68 times higher odds of major adverse events including death, cardiac arrest, and cardiogenic shock.","whyItMatters":"Most cardiovascular cannabis research relies on self-reported use. This study used objective urine testing in a real-world hospital setting, providing harder evidence for a link between cannabis use and worse outcomes after heart events.","specificNumbers":"772 patients hospitalized for acute coronary syndrome. 86 (11.1%) tested positive for cannabis. Cannabis-positive patients were younger (53 vs 65 years) and more often male (88% vs 72%). 33 major adverse events occurred (4.3%). Adjusted odds ratios: 3.28 (adjusted for comorbidities) and 3.68 (adjusted for severity predictors).","methodology":"Prospective multicenter study across 39 intensive cardiac care units in France over two weeks in April 2021. All consecutive patients admitted for acute coronary syndrome underwent systematic urine drug screening. Major adverse events were tracked during hospitalization.","limitations":"Urine testing detects recent use but does not confirm acute intoxication at the time of the cardiac event. Two-week enrollment period may limit generalizability. Observational design cannot establish causation."},{"rthcId":"RTHC-06926","title":"Proportions and correlates of high-risk cannabis use in Australia-A cross-sectional analysis of the 2022-2023 National Drug Strategy Household Survey.","authors":"Leung, Janni; Stjepanović, Daniel; Chan, Gary Chung Kai; Hall, Wayne Denis; Dawson, Danielle","year":2025,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70234","pmid":"41204796","tags":["addiction","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,504 recent cannabis users, 71.6% were low/no risk, 22.2% were moderate risk, and 6.2% were high risk. Daily use was associated with 5.7 times the risk of high-risk classification. Starting before age 15 carried 2.5 times the risk compared to starting at 18 or older. Psychological distress tripled the risk.","whyItMatters":"With cannabis legalization debates ongoing globally, this nationally representative data helps quantify the proportion of users who develop problematic patterns and identifies the factors most strongly linked to high-risk use.","specificNumbers":"71.6% low/no risk, 22.2% moderate risk, 6.2% high risk. Daily use: RRR=5.70 for high-risk. Starting before 15: RRR=2.52. Starting at 15-17: RRR=2.25. Psychological distress: RRR=3.19. Sample: 1,504 past-3-month cannabis users.","methodology":"Cross-sectional analysis of the 2022-2023 Australian National Drug Strategy Household Survey. Cannabis use risk was measured using the WHO ASSIST-Lite. Multinomial logistic regression examined associations between risk level and use patterns, psychological distress, and demographics.","limitations":"Cross-sectional design cannot determine whether factors like psychological distress preceded or followed high-risk cannabis use. Self-report data may underestimate use. Survey response rates affect representativeness."},{"rthcId":"RTHC-06927","title":"Recreational substance use is linked with difficulty in recalling personal experiences.","authors":"Levent, Adnan; Davelaar, Eddy J","year":2025,"journal":"Scientific reports, 15(1), 34492","doi":"10.1038/s41598-025-13800-y","pmid":"41044207","tags":["cognition","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Participants who reported recreational substance use recalled significantly fewer specific autobiographical memories than non-users and were more likely to omit responses entirely. These differences remained significant after controlling for general health, sleep, alcohol use, and age.","whyItMatters":"Most research on substance use and memory focuses on people with diagnosed dependence. This study examined recreational users, suggesting that even occasional use may affect the ability to recall specific personal experiences.","specificNumbers":"100 participants: 53 substance users, 47 non-users. Substance users recalled significantly fewer specific personal event memories and had more omissions within the time limit. Results held after controlling for general health, sleep routine, alcohol use, and age.","methodology":"Lab-based study comparing 53 recreational substance users (including cannabis, MDMA, cocaine) with 47 non-users, ages 18-55. All completed self-report questionnaires and a standardized autobiographical memory test. Results were adjusted for covariates.","limitations":"Cross-sectional design prevents determining whether memory differences preceded or followed substance use. The substance user group included multiple drugs, making it difficult to isolate cannabis-specific effects. Relatively small sample size."},{"rthcId":"RTHC-06928","title":"Acute care of cyclic vomiting syndrome and cannabinoid hyperemesis syndrome in the home and emergency department.","authors":"Levinthal, David J; Killian, Blynda; Issenman, Robert M","year":2025,"journal":"Neurogastroenterology and motility, 37(3), e14901","doi":"10.1111/nmo.14901","pmid":"39155452","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06929","title":"Screening for Nonmedical Use and Misuse of Prescription Medication by Adolescents.","authors":"Levy, Sharon; Minegishi, Machiko; Brogna, Melissa; Ross, Jennifer; Subramaniam, Geetha; Weitzman, Elissa R","year":2025,"journal":"Substance use & addiction journal, 46(2), 357-363","doi":"10.1177/29767342241292419","pmid":"39629781","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06930","title":"Is There a Place for Cannabinoids in Asthma Treatment?","authors":"Lewandowska, Agata Anna; Rybacki, Cezary; Graczyk, Michał; Waśniowska, Dorota; Kołodziej, Małgorzata","year":2025,"journal":"International journal of molecular sciences, 26(7)","doi":"10.3390/ijms26073328","pmid":"40244178","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06931","title":"Landscape of Cyclic Vomiting Syndrome: From Bedside to Bench, Past to Present.","authors":"Li, B U K","year":2025,"journal":"Neurogastroenterology and motility, 37(3), e14990","doi":"10.1111/nmo.14990","pmid":"39789960","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06932","title":"Prospective associations of subjective and objective neighborhood disadvantage with cannabis and nicotine vaping among Southern California adolescents.","authors":"Li, Danyi; Eckel, Sandrah P; Sanchez, Louisiana M; Pentz, Mary Ann; Harlow, Alyssa F","year":2025,"journal":"Health & place, 96, 103577","doi":"10.1016/j.healthplace.2025.103577","pmid":"41187413","tags":["youth","legalization"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Subjective neighborhood disorder (how teens perceived their area) was significantly associated with both cannabis vaping (RR=1.04 per unit increase) and nicotine vaping (RR=1.04). Census-derived area deprivation showed no independent association. Teens with both high perceived and high objective disadvantage had 1.73 times the risk of nicotine vaping, while those with high perceived but low objective disadvantage had 2.04 times the risk of cannabis vaping.","whyItMatters":"Public health interventions often target neighborhoods based on census data, but this study suggests that how teens experience their environment may be a stronger predictor of vaping behavior than objective economic indicators.","specificNumbers":"3,278 students, mean baseline age 15.7 years, followed across 5 waves over 2 years. Subjective neighborhood disorder: RR=1.04 for both cannabis and nicotine vaping. High subjective + high objective disadvantage: RR=1.73 for nicotine vaping. High subjective + low objective disadvantage: RR=2.04 for cannabis vaping. Correlation between subjective and objective measures was weak (r=0.27).","methodology":"Prospective cohort of 3,278 Southern California high school students followed across five semi-annual waves (2022-2024). Baseline measures of subjective neighborhood disorder and census-derived area deprivation index were linked to repeated measures of past-30-day cannabis and nicotine vaping.","limitations":"Limited to Southern California, which may not generalize nationally. Vaping was self-reported. The weak correlation between subjective and objective measures raises questions about what subjective scales actually capture."},{"rthcId":"RTHC-06933","title":"DNA metabarcode analyses reveal similarities and differences in plant microbiomes of industrial hemp and medicinal Cannabis in China.","authors":"Li, Jiayang; Zhang, Hong; Long, Songhua; Li, Wenting; Wang, Tuhong; Yu, Jian; Zhou, Ying; Zou, Shuo; Zhu, Hongjian; Xu, Jianping; Cheng, Yi","year":2025,"journal":"Frontiers in microbiology, 16, 1524703","doi":"10.3389/fmicb.2025.1524703","pmid":"40303473","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06934","title":"Assessment of pharmacological effects and abuse potential of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 in mice.","authors":"Li, Kaixi; Xu, Deli; Qiao, Yanling; Kuai, Lixin; Luo, Xuwen; Di, Bin; Xu, Peng","year":2025,"journal":"Psychopharmacology, 242(3), 533-544","doi":"10.1007/s00213-024-06703-9","pmid":"39402377","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06935","title":"Bridging THC Knowledge Gaps for Safer Roads: A Call for Action.","authors":"Li, Peizhi; An, Guohua","year":2025,"journal":"Clinical pharmacology and therapeutics, 118(3), 548-550","doi":"10.1002/cpt.3717","pmid":"40375471","tags":["driving","cognition","potency"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This commentary cuts to the heart of a policy problem: states are setting cannabis driving laws without the science to back them up. Some states use per se THC blood limits (you're \"impaired\" above a threshold), others use zero-tolerance approaches, and still others rely on observable impairment assessments. None of these approaches are well-validated.\n\nThe fundamental issue is pharmacokinetic—how THC moves through the body is far more complex than alcohol. THC is lipophilic (fat-soluble), meaning it's rapidly absorbed and redistributed into fat tissue, then slowly released back into the blood over hours to days. This creates a disconnect: blood THC levels drop quickly after use even while impairment may persist, and chronic users may have residual THC in their blood when fully sober.\n\nThe authors argue that the limited clinical data on THC pharmacokinetics and pharmacodynamics—how blood levels relate to actual cognitive and motor impairment—is the bottleneck. Without this data, any regulatory threshold is essentially arbitrary.\n\nThe call to action is directed at both researchers and policymakers: conduct comprehensive cannabis PK/PD studies using real-world products and dosing patterns, then use that data to develop and validate driving regulations.","whyItMatters":"Millions of people drive after using cannabis. Whether the legal framework for addressing this is based on science or arbitrary thresholds matters enormously—both for public safety (catching truly impaired drivers) and for justice (not penalizing unimpaired people who used cannabis days ago). The current situation serves neither goal well.","specificNumbers":"THC blood levels drop rapidly after use but impairment may persist. Chronic users may test positive when fully sober. State regulations vary widely from zero-tolerance to per se limits to impairment-based assessment.","methodology":"Commentary/narrative review analyzing the gap between current cannabis driving regulations and the scientific evidence needed to support them. Focuses on THC pharmacokinetics and pharmacodynamics as the missing link.","limitations":"This is a commentary calling for research, not research itself. Doesn't propose specific THC thresholds. The challenge of establishing THC impairment thresholds may be inherently harder than for alcohol due to greater individual variability in cannabis pharmacology."},{"rthcId":"RTHC-06936","title":"Evaluation of Cannabis Per Se Laws: A Semi-Mechanistic Pharmacometrics Model for Quantitative Characterization of THC and Metabolites in Oral Users.","authors":"Li, Peizhi; An, Guohua","year":2025,"journal":"Journal of clinical pharmacology, 65(5), 535-549","doi":"10.1002/jcph.6181","pmid":"39831603","tags":["driving","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using data from 10 published studies, researchers built a model simulating THC blood levels in frequent and occasional users after oral doses from 2.5 to 100 mg. The 1 ng/mL per se limit was the least effective due to high false positive risk. The 2 and 5 ng/mL limits could not be validated because there is insufficient data connecting specific blood THC levels to actual driving impairment after oral consumption.","whyItMatters":"With edibles and oral cannabis products growing in popularity, driving laws based on blood THC levels need to account for how oral consumption produces very different blood level patterns than smoking. Current laws were largely designed around inhalation data.","specificNumbers":"Model built from 10 published studies. Simulated doses: 2.5 mg to 100 mg oral THC. Three per se limits evaluated: 1, 2, and 5 ng/mL. The 1 ng/mL limit showed the highest false positive risk across both user types.","methodology":"Semi-mechanistic population pharmacokinetic model developed from 10 published studies of intravenous or oral cannabis administration. Simulated THC and metabolite concentrations across a range of doses in frequent and occasional users to evaluate existing per se driving limits.","limitations":"Model was built from published study data, not new clinical trials. Pharmacodynamic (impairment) data for oral cannabis remains scarce. Simulations may not capture all real-world variability in absorption and metabolism."},{"rthcId":"RTHC-06937","title":"Enhancing Cannabidiol Apparent Solubility and Oral Delivery: Self-assembled Nanomicelles of Amphiphilic Block Copolymer with γ-Polyglutamic Acid-grafted Cholesterol.","authors":"Li, Rui; Ruan, Wenhui; Lu, Liyan; Wu, Zhijuan; Hao, Rui; Wang, Yingli; Chen, Jue","year":2025,"journal":"Pharmaceutical research, 42(10), 1775-1788","doi":"10.1007/s11095-025-03924-1","pmid":"41034679","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06938","title":"Effects of Cannabis Exposure on Adolescent Health and Development: A Narrative Review.","authors":"Li, Ruixuan; Tao, Feng","year":2025,"journal":"Current drug research reviews, 17(2), 160-169","doi":"10.2174/0125899775273727231224185028","pmid":"40761110","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06939","title":"Abnormal Cortical Thickness Development in Young Adults With Heavy Cannabis Use: A Longitudinal Study.","authors":"Li, Wei; Xu, Cheng; Xu, Hanyuan; Yin, Bo; Xu, Hui; Li, Dandong","year":2025,"journal":"Addiction biology, 30(5), e70040","doi":"10.1111/adb.70040","pmid":"40344353","tags":["neuroscience","cognition","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"At three-year follow-up, heavy cannabis users showed significant cortical thinning in the left lateral orbitofrontal cortex compared to both their own baseline and control subjects. The degree of thinning correlated positively with scores on a cannabis use disorder screening tool, suggesting a dose-response relationship.","whyItMatters":"The orbitofrontal cortex is critical for decision-making, impulse control, and emotional processing. Thinning in this area could help explain why heavy cannabis use is associated with difficulty controlling use and making decisions about continued consumption.","specificNumbers":"Significant cortical thinning in the left lateral orbitofrontal cortex at 3-year follow-up in heavy users. Time effects showed changes in bilateral medial frontal cortex, bilateral posterior cingulate cortex, and bilateral insula. Positive correlation between Cannabis Use Disorders Identification Test scores and OFC thickness at follow-up.","methodology":"Longitudinal study comparing cortical thickness changes from baseline to three-year follow-up in young adults with heavy cannabis use versus controls. Brain imaging measured cortical thickness across multiple regions. Cannabis use severity was assessed using the Cannabis Use Disorders Identification Test.","limitations":"Cannot definitively rule out that pre-existing brain differences led to heavier cannabis use rather than the reverse. Sample sizes were not reported in the abstract. Other substance use and lifestyle factors could contribute to cortical changes."},{"rthcId":"RTHC-06940","title":"Time Spent on Social Media and the Risk of Substance Use Among US Adolescents.","authors":"Li, Xiao; Vaughn, Michael; Xian, Hong; Qian, Zhengmin","year":2025,"journal":"Journal of adolescence, 97(5), 1314-1322","doi":"10.1002/jad.12498","pmid":"40188387","tags":["youth","legalization","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 4,769 adolescents followed over multiple years, social media time predicted later substance use. For marijuana and alcohol, the relationship was curvilinear: teens spending 30 minutes to 3 hours daily had the highest odds. For tobacco, the relationship was dose-dependent. For nonmedical drugs, only 3-6 hours daily showed a significant association (nearly 2x odds).","whyItMatters":"This is one of the first studies to quantify the link between daily social media time and subsequent substance use in a large US adolescent cohort, and the curvilinear pattern for marijuana use suggests moderate social media users may face higher risk than heavy users.","specificNumbers":"4,769 adolescents followed from Wave 2 through Wave 5. Over 75% spent at least 30 minutes daily on social media. The 30-minute to 3-hour group had the highest odds for alcohol and marijuana use. The 3-6 hour group had nearly 2x odds for nonmedical drug use. A dose-response pattern was observed for tobacco.","methodology":"Longitudinal analysis of the Population Assessment of Tobacco and Health (PATH) study following 4,769 adolescents aged 12-17 who reported no substance use at baseline across multiple waves. Generalized Estimating Equation models adjusted for demographic and time-varying covariates.","limitations":"Self-reported social media time and substance use may be imprecise. The PATH study may not capture all social media platforms equally. The curvilinear finding for marijuana needs replication and mechanistic explanation."},{"rthcId":"RTHC-06941","title":"Exploring the neuroprotective effects and underlying mechanisms of medical cannabinoids in ischemic stroke: a systematic meta-analysis with bibliometric mapping of cerebral ischemia research.","authors":"Li, Xiaoqun; Wen, Lulu; Du, Yun; Fan, Xinyue; Xue, Ningyu; Qu, Miao","year":2025,"journal":"Frontiers in neuroscience, 19, 1731738","doi":"10.3389/fnins.2025.1731738","pmid":"41551042","tags":["cbd","neuroscience","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Across 26 studies, cannabinoids significantly reduced cerebral infarct volume, improved neurological function, increased cerebral blood flow, and decreased blood-brain barrier permeability, brain water content, cell death, oxidative stress markers, and inflammatory markers (TNF-alpha, IL-1beta). Subgroup analysis showed CBD administered intraperitoneally throughout the full course produced the best results with less variability.","whyItMatters":"Ischemic stroke has very few treatment options. This comprehensive analysis of animal research suggests cannabinoids, particularly CBD, may work through multiple protective pathways, building the case for moving toward human clinical trials.","specificNumbers":"241 publications identified for bibliometric analysis. 26 studies included in meta-analysis. Three major research topics identified through keyword analysis. CBD via intraperitoneal administration showed enhanced benefit with reduced heterogeneity. Significant improvements across 9 outcome measures.","methodology":"Systematic review with meta-analysis combining bibliometric analysis (241 publications) and quantitative synthesis of 26 preclinical studies on cannabinoids in animal models of ischemic stroke. Pooled standardized mean differences with 95% confidence intervals were calculated with subgroup analyses.","limitations":"All evidence comes from animal models, which may not translate directly to humans. Publication bias may favor positive results. Heterogeneity in protocols across studies, though subgroup analysis helped address this."},{"rthcId":"RTHC-06942","title":"Ethnic variations in sedentary behavior and marijuana use among U.S. adults: A cross-sectional analysis.","authors":"Li, Yunzhe; Zhong, Lian; Zhou, Huasheng; Zeng, Fanghua; Huang, Wenbao; Rao, Junjie; Zhong, Hailong; Hu, Chaobin; Zou, Kang; Xie, Jiahui","year":2025,"journal":"Medicine, 104(52), e46348","doi":"10.1097/MD.0000000000046348","pmid":"41465901","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 7,122 US adults, longer sitting time was associated with lower odds of marijuana use. The 6-8 hour sitting group had significantly lower odds (OR=0.78) compared to those sitting less than 4 hours. Among Hispanic subgroups, the 6-8 hour group showed a 48% lower risk of marijuana use.","whyItMatters":"While the link between sedentary behavior and health outcomes is well-studied, its relationship with substance use is less explored. These findings add a new dimension to understanding lifestyle patterns associated with marijuana use.","specificNumbers":"7,122 participants from NHANES 2007-2012. 4-6 hours sitting: OR=0.91 (not significant). 6-8 hours: OR=0.78 (p=0.004). Hispanic subgroup 6-8 hours: 48% lower risk. >8 hours Hispanic subgroup: 40% reduction.","methodology":"Cross-sectional analysis of NHANES 2007-2012 data on 7,122 US adults with complete health and lifestyle information. Logistic regression with interaction effects analysis examined sitting time categories (<4h, 4-6h, 6-8h, >8h) and marijuana use, controlling for confounders.","limitations":"Cross-sectional design cannot determine causation. Self-reported sitting time and marijuana use may be inaccurate. Data is from 2007-2012 and may not reflect current patterns. The inverse relationship may be confounded by unmeasured factors like occupation type."},{"rthcId":"RTHC-06943","title":"Comparing the cannabidiol-induced transcriptomic profiles in human and mouse Sertoli cells.","authors":"Li, Yuxi; Li, Xilin; Cournoyer, Patrick; Choudhuri, Supratim; Guo, Lei; Chen, Si","year":2025,"journal":"Toxicology, 512, 154068","doi":"10.1016/j.tox.2025.154068","pmid":"39894194","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06944","title":"Integrated metabolomics and serum pharmacochemistry reveal Q-markers of Zhigancao decoction for antiarrhythmic efficacy.","authors":"Li, Yuxin; Sheng, Yuanyuan; Xia, Wenxin; Yue, Jiahui; Wang, Lulu; Fu, Xueyan","year":2025,"journal":"Journal of ethnopharmacology, 353(Pt A), 120331","doi":"10.1016/j.jep.2025.120331","pmid":"40738293","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06945","title":"Systematic review and meta-analysis on the effects of chronic peri-adolescent cannabinoid exposure on schizophrenia-like behaviour in rodents.","authors":"Li, Zhikun; Mukherjee, Diptendu; Duric, Bea; Austin-Zimmerman, Isabelle; Trotta, Giulia; Spinazzola, Edoardo; Quattrone, Diego; Murray, Robin M; Di Forti, Marta","year":2025,"journal":"Molecular psychiatry, 30(1), 285-295","doi":"10.1038/s41380-024-02668-5","pmid":"39090371","tags":["psychosis","youth","neuroscience"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 359 experiments from 108 articles, CB1 receptor agonists (both natural and synthetic cannabinoids) during adolescence impaired working memory (g=-0.56), novel object recognition (g=-0.66), novel object location recognition (g=-0.70), social novelty preference (g=-0.52), social motivation (g=-0.21), pre-pulse inhibition (g=-0.43), and sucrose preference (g=-0.87). Effects were similar across sexes and species. Locomotion effects were negligible.","whyItMatters":"This is the first meta-analysis to comprehensively test whether epidemiological links between adolescent cannabis use and schizophrenia are supported by controlled animal experiments. The consistent findings across hundreds of experiments strengthen the biological plausibility of this association.","specificNumbers":"359 experiments from 108 articles across 9 behavioral tests. Effect sizes ranged from g=-0.21 (social motivation) to g=-0.87 (sucrose preference). Working memory: g=-0.56. Pre-pulse inhibition: g=-0.43. Novel object recognition: g=-0.66. Effects were consistent across sexes and species.","methodology":"Pre-registered systematic review and meta-analysis (CRD42022338761) searching four databases through May 2024. Included studies on schizophrenia-like behavior in rats and mice after repeated cannabinoid exposure during the peri-pubertal period (postnatal day 23-45). Risk of bias assessed using SYRCLE tool.","limitations":"Animal models cannot fully replicate human schizophrenia. Substantial protocol variability and moderate-to-high heterogeneity across studies. Synthetic cannabinoids used in many studies may not reflect typical cannabis exposure. CBD may have different effects (limited data suggested enhanced fear memory recall)."},{"rthcId":"RTHC-06946","title":"Patient-centered approach to evaluating the role of medical cannabis in the treatment of chronic pain.","authors":"Liang, Connie; Basappa, Sapna; Tucker, Shannon; Pincus, Kathleen J","year":2025,"journal":"Complementary therapies in clinical practice, 60, 101996","doi":"10.1016/j.ctcp.2025.101996","pmid":"40294463","tags":["medical-cannabis","pain"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Across 28 participants in focus groups, seven key themes emerged: efficacy, safety, stigma, cost, convenience, government/legal considerations, and interactions with healthcare providers. Themes were similar whether participants had or had not used medical cannabis, though emphasis varied. A major finding was that even current users had significant unanswered questions.","whyItMatters":"Despite growing medical cannabis use for chronic pain, this study reveals that patients on both sides of the decision feel they lack adequate information to make informed choices, highlighting a gap between policy expansion and patient education.","specificNumbers":"28 participants across three focus groups. Seven key themes identified. Research questions were derived from identified themes to guide future patient-centered research.","methodology":"Qualitative focus-group study with three participant groups: chronic pain patients who had used medical cannabis, chronic pain patients who had not, and people without chronic pain who used cannabis for other conditions. Used semi-structured facilitator questionnaire with thematic analysis via NVivo 12.","limitations":"Small sample size (28 participants). Qualitative design provides depth but not generalizability. Convenience sampling may not capture the full range of patient perspectives."},{"rthcId":"RTHC-06947","title":"Distinct serum endocannabinoid profiles in treatment-naïve Han Chinese children with ADHD: a case-control pilot study.","authors":"Liao, Wenjuan; Tan, Xiaobin; Lin, Jinhai; Wu, Yuchen; Guo, Qi; Huang, Qucheng; Yang, Longhe; Peng, Yan","year":2025,"journal":"Frontiers in neurology, 16, 1715342","doi":"10.3389/fneur.2025.1715342","pmid":"41603005","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06948","title":"Identification and External Validation of a Problem Cannabis Risk Network.","authors":"Lichenstein, Sarah D; Kiluk, Brian D; Potenza, Marc N; Garavan, Hugh; Chaarani, Bader; Banaschewski, Tobias; Bokde, Arun L W; Desrivières, Sylvane; Flor, Herta; Grigis, Antoine; Gowland, Penny; Heinz, Andreas; Brühl, Rüdiger; Martinot, Jean-Luc; Paillère Martinot, Marie-Laure; Artiges, Eric; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Poustka, Luise; Hohmann, Sarah; Holz, Nathalie; Baeuchl, Christian; Smolka, Michael N; Vaidya, Nilakshi; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Pearlson, Godfrey; Yip, Sarah W","year":2025,"journal":"Biological psychiatry, 98(8), 586-596","doi":"10.1016/j.biopsych.2025.01.022","pmid":"39909136","tags":["addiction","neuroscience","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"A whole-brain machine learning approach identified a \"problem cannabis risk network\" from reward task brain connectivity data in college students. This network generalized to predict cannabis use in 1,320 European adolescents and was linked to higher addiction severity and poorer treatment outcomes in 33 treatment-seeking adults. The network was specific to cannabis and did not predict alcohol use outcomes.","whyItMatters":"Identifying brain-based markers that predict who is at risk for problem cannabis use could eventually help target prevention efforts and improve treatment by identifying biological mechanisms underlying vulnerability.","specificNumbers":"Discovery sample: 191 college students (58% female). Validation sample 1: 1,320 European adolescents (53% female). Clinical sample: 33 treatment-seeking adults (9% female). The network was specific for cannabis vs alcohol across all 3 datasets.","methodology":"Data-driven machine learning analysis of reward task functional connectivity in 191 college students (58% female). External validation in 1,320 European adolescents/emerging adults from the IMAGEN study and 33 adults seeking treatment for cannabis use disorder.","limitations":"The clinical sample was small (33 participants) and predominantly male (91%). The reward task captures one aspect of brain function. Neuroimaging studies require replication in larger, more diverse samples."},{"rthcId":"RTHC-06949","title":"Adolescent exposure to Δ9-tetrahydrocannabinol impairs testicular function in young adult male mice.","authors":"Lim, Jinhwan; Quach, Caitlin; Nguyen, Julie; Rizk, Andrew; Getze, Samantha; Jung, Kwang-Mook; Mahler, Stephen V; Piomelli, Daniele; Luderer, Ulrike","year":2025,"journal":"Toxicological sciences : an official journal of the Society of Toxicology, 208(1), 82-94","doi":"10.1093/toxsci/kfaf035","pmid":"40127192","tags":["youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent THC exposure (postnatal days 30-43) decreased sperm numbers, increased seminiferous tubule degeneration, and impaired steroidogenesis with dysregulated expression of key enzymes (StAR protein and CYP17A1). Adult exposure (postnatal days 70-83) reduced testosterone levels but did not affect sperm production or tubule structure. Both CB1 and CB2 receptors were confirmed present in the testis.","whyItMatters":"Cannabis use typically begins during adolescence, and this study provides biological evidence that the developing reproductive system may be more vulnerable to THC than the mature one, with effects persisting weeks after exposure stops.","specificNumbers":"THC dose: 5 mg/kg daily for 14 days. Adolescent exposure: PND 30-43, harvested at PND 70. Adult exposure: PND 70-83, harvested at PND 110. Adolescent group: decreased sperm, increased tubule degeneration, dysregulated StAR and CYP17A1. Both groups: decreased testosterone. Adult group: no sperm or structural effects.","methodology":"C57BL/6N male mice received daily THC injections (5 mg/kg) or vehicle during either adolescence (PND 30-43) or adulthood (PND 70-83). Testes were harvested 27 days after the last injection. Assessments included sperm counts, testicular histology, testosterone levels, and expression of endocannabinoid system components and steroidogenic enzymes.","limitations":"Mouse model may not directly translate to humans. The 5 mg/kg dose via injection does not mimic typical human consumption patterns. Only one dose level was tested. Long-term recovery beyond 27 days was not assessed."},{"rthcId":"RTHC-06950","title":"Preventive beneficial effects of cannabidiol in a reserpine-induced progressive model of parkinsonism.","authors":"Lima, Alvaro C; Bioni, Vinicius S; Becegato, Marcela S; Meier, Ywlliane; Cunha, Débora M G; Aguiar, Natan A; Gonçalves, Narriman; Peres, Fernanda F; Zuardi, Antônio W; Hallak, Jaime E C; Crippa, José A; Smaili, Soraya S; Abilio, Vanessa C; Silva, Regina H","year":2025,"journal":"Frontiers in pharmacology, 16, 1539783","doi":"10.3389/fphar.2025.1539783","pmid":"40406493","tags":["cbd","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In mice given low-dose reserpine to progressively develop Parkinson-like symptoms, CBD (0.5 mg/kg) delayed the appearance of catalepsy and abnormal mouth movements. CBD also prevented the loss of tyrosine hydroxylase (TH) labeling in the substantia nigra, indicating protection of dopamine-producing neurons. Preventive CBD treatment (started before symptoms) was more effective than concurrent treatment (started alongside reserpine).","whyItMatters":"Most Parkinson research uses acute, high-dose toxin models. This study used a progressive model that better mimics the slow disease course in humans, and found CBD was protective, particularly when started early.","specificNumbers":"CBD dose: 0.5 mg/kg. Reserpine dose: 0.1 mg/kg (low-dose repeated). Both concurrent and preventive CBD prevented TH neuron loss in the substantia nigra. Preventive CBD attenuated catalepsy. Concurrent CBD delayed but did not fully prevent motor symptoms (except vacuous chewing).","methodology":"Two experimental approaches in mice: concurrent CBD administration during Parkinson development, and preventive CBD pre-administration. Low-dose repeated reserpine (0.1 mg/kg) was used as a progressive Parkinson model. Behavioral (catalepsy, vacuous chewing) and neuronal (TH immunolabeling) outcomes were measured.","limitations":"Mouse model, and the reserpine-based model does not fully replicate human Parkinson pathology (no alpha-synuclein aggregation). Single low dose of CBD tested. No assessment of non-motor Parkinson symptoms."},{"rthcId":"RTHC-06951","title":"Effect of physical training and palatable diet consumption on the expression of endocannabinoid system components in the rat brain.","authors":"Lima, Paulo M A; Lima, Beatriz A; Gonçalves, Gleisy K N; Fóscolo, Daniela R C; Guimarães, Juliana B; Campos, Helton O; Coimbra, Cândido C","year":2025,"journal":"Nutritional neuroscience, 1-12","doi":"10.1080/1028415X.2025.2583391","pmid":"41186286","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06952","title":"Commercial Cannabis Product Testing: Fidelity to Labels and Regulations.","authors":"Limbacher, Sarah; Godbole, Suneeta; Wrobel, Julia; Mackie, Duncan I; Goldman, Stephen; Brooks-Russell, Ashley","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.03.14.25323943","pmid":"40162238","tags":["potency","legalization","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Overall, label values were significantly higher than tested values for flower and edible products (p<0.001), but not for concentrates (p=0.85). Flower products were significantly lower than labels even accounting for the 15% legal variance (p=0.04). Concentrates and edibles fell within legally allowable ranges.","whyItMatters":"Consumers often choose cannabis products based on labeled THC percentages. If flower labels systematically overstate potency, consumers may be making purchasing decisions based on inaccurate information, and paying more for products marketed as \"higher potency.\"","specificNumbers":"74 products tested from licensed Colorado dispensaries. Flower labels significantly overstated THC (p<0.001) and exceeded the 15% legal variance (p=0.04). Concentrate labels were accurate (p=0.85). Edible labels overstated THC (p<0.001) but within legal variance (p=0.5).","methodology":"Observational study collecting cannabis samples from a larger impairment study. 74 flower, concentrate, and edible products purchased from licensed Colorado dispensaries were independently tested for THC concentration and compared to label claims.","limitations":"Small sample size (74 products). Products came from one geographic area (Denver metro). Voluntary donation of samples may introduce selection bias. Testing methodology differences between labs could account for some variance."},{"rthcId":"RTHC-06953","title":"Exploring Factors Shaping Tobacco and Marijuana Use Among Sexual Minority Adolescents.","authors":"Lin, Meng-Yun; Lockhart, Darcy; Denlinger-Apte, Rachel","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 27(11), 2097-2108","doi":"10.1093/ntr/ntaf097","pmid":"40326389","tags":["youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Exposure to e-cigarette or cigarette use at home or in vehicles was the leading factor associated with smoking and vaping across all groups, explaining up to 44% of predicted variance. Perceiving occasional use as low-harm was also a top factor. For sexual minority middle schoolers, mental stress was a dominant factor explaining up to 21% of variance in tobacco and marijuana use.","whyItMatters":"LGBTQ+ youth use tobacco and marijuana at higher rates. This study identifies the most influential modifiable factors for each group, allowing prevention programs to be tailored to the populations that need them most.","specificNumbers":"6,654 middle school + 8,274 high school students. Home exposure explained up to 44% of variance. Low risk perception explained up to 21.6% (e-cigarettes) and 26.5% (cigarettes) of variance. Mental stress explained up to 21% of variance among sexual minority middle schoolers.","methodology":"Analysis of the 2023 National Youth Tobacco Survey with dominance analyses and logistic regression stratified by sexual identity (straight, sexual minority, unsure) and grade level (middle school vs high school). Sample: 6,654 middle school and 8,274 high school students.","limitations":"Cross-sectional design cannot prove these factors cause use. Self-reported data may undercount both substance use and sexual minority identity. The \"unsure\" category is heterogeneous."},{"rthcId":"RTHC-06954","title":"One-Pot Preparation of an Antioxidant, Anti-Inflammatory, and Analgesic Hydrogel for Oral Mucosal Lesions.","authors":"Lin, Pochun; Cai, Yimeng; Feng, Ning; Yu, Leixiao; Cao, Shuqin; Yuan, Quan","year":2025,"journal":"ACS applied materials & interfaces, 17(26), 37617-37630","doi":"10.1021/acsami.5c06212","pmid":"40522041","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06955","title":"Early-day psychosocial predictors of later-day simultaneous alcohol and cannabis use among college-attending young adults.","authors":"Linden-Carmichael, Ashley N; Chiang, Shou-Chun; Van Doren, Natalia; Bhandari, Sandesh","year":2025,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 39(3), 278-289","doi":"10.1037/adb0001043","pmid":"39621375","tags":["youth","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Morning willingness to use and social motives predicted later-day simultaneous alcohol and cannabis use. By afternoon, willingness and cross-fading motives (wanting combined effects) became significant predictors. Conformity motives (using because of peer pressure) were actually associated with lower odds of use. Since most use occurred after 9 PM, there was a large window between early-day predictors and actual use.","whyItMatters":"Simultaneous alcohol and cannabis use carries higher risks than using either alone. Identifying early-day warning signs creates a window for real-time digital interventions that could reach students before they start using.","specificNumbers":"119 college students, 8 assessments per day, 4 consecutive weekends. Morning willingness and social motives significantly predicted later-day use. Afternoon willingness and cross-fading motives also predicted use. Conformity motives were associated with lower odds. Most use occurred after 9 PM.","methodology":"Ecological momentary assessment (8 prompts/day) across four consecutive weekends with 119 college students (63% female, 73% non-Hispanic White) who reported weekly simultaneous use. Multilevel models examined morning and afternoon psychosocial predictors of later-day use.","limitations":"Small sample (119) of weekly simultaneous users, limiting generalizability. Participants knew they were being monitored, which could change behavior. Only four weekends of data. Self-selected sample of already-regular users."},{"rthcId":"RTHC-06956","title":"Diet-dependent modulation of energy balance by CB1 signaling in peripheral sensory neurons.","authors":"Linden, Benjamin; Herz, Hussein; Jarrah, Mohammad; Tasabehji, Dana; Saleh, Sanaz; Fraer, Aviva; Clark, Patrick; Ye, Yuanchao; Chu, Yi; Al-Khalil, Zeina; Morgan, Donald A; Zhu, Zhiyong; Castorena, Carlos M; Zingman, Leonid; Rahmouni, Kamal; Mokadem, Mohamad","year":2025,"journal":"iScience, 28(8), 113124","doi":"10.1016/j.isci.2025.113124","pmid":"40777046","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06957","title":"Electronic cigarettes for smoking cessation.","authors":"Lindson, Nicola; Livingstone-Banks, Jonathan; Butler, Ailsa R; McRobbie, Hayden; Bullen, Christopher R; Hajek, Peter; Wu, Angela Difeng; Begh, Rachna; Theodoulou, Annika; Notley, Caitlin; Rigotti, Nancy A; Turner, Tari; Fanshawe, Thomas; Hartmann-Boyce, Jamie","year":2025,"journal":"The Cochrane database of systematic reviews, 11(11), CD010216","doi":"10.1002/14651858.CD010216.pub10","pmid":"41212103","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06958","title":"Consumer perspectives of accessing medicinal cannabis treatment from cannabis clinics versus generalist health settings in Australia.","authors":"Lintzeris, Nicholas; Arnold, Jonathon C; McGregor, Iain S; Mills, Llewellyn","year":2025,"journal":"Journal of cannabis research, 7(1), 83","doi":"10.1186/s42238-025-00338-z","pmid":"41146248","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 2,394 respondents, 79.3% accessed treatment from specialized cannabis clinics (MCCs). Compared to generalist settings, MCC patients were younger, less likely to receive oral products, had higher employment and cannabis use disorder rates, and sought treatment more for mental health than chronic pain. MCC patients reported lower satisfaction with consultation duration, information about harms/benefits, discussion of other treatments, and costs.","whyItMatters":"As commercial cannabis clinics proliferate, this study raises questions about whether the rapid-access model may trade off consultation quality. Patients in general healthcare settings reported better experiences, suggesting integration into mainstream medicine may produce better outcomes.","specificNumbers":"2,394 respondents; 79.3% from specialized clinics. MCC patients were 3.5 years younger on average. MCC: less likely to get oral products (OR=0.4), higher cannabis use disorder (OR=1.5), more mental health treatment (OR=1.6), less chronic pain (OR=0.7). Lower MCC satisfaction: consultation time (OR=0.8), harm/benefit info (OR=0.7), other treatment discussion (OR=0.5), costs (OR=0.6).","methodology":"Anonymous online convenience survey of 2,394 Australian adults self-reporting prescribed medical cannabis in the preceding 12 months. Compared patient profiles, treatment patterns, and satisfaction between specialized cannabis clinics and generalist health settings.","limitations":"Convenience sample may not represent all medical cannabis patients. Self-reported data. Cross-sectional design cannot determine if clinic type causes satisfaction differences. Unmeasured factors may explain patient differences between settings."},{"rthcId":"RTHC-06959","title":"Cannabis Policies, Cannabis, and Opioids in Suicide and Undetermined Intent Death.","authors":"Lira, Marlene C; Pacula, Rosalie Liccardo; Smart, Rosanna; Pessar, Seema Choksy; Blanchette, Jason; Naimi, Timothy S","year":2025,"journal":"American journal of preventive medicine, 68(3), 475-484","doi":"10.1016/j.amepre.2024.11.009","pmid":"39615767","tags":["legalization","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis involvement in death was associated with increased odds of opioid involvement (AOR=1.29). More restrictive cannabis policies were associated with reduced odds of both cannabis involvement (AOR=0.87 per 10% policy increase) and opioid involvement (AOR=0.88 per 10% policy increase) in suicide and undetermined-intent deaths.","whyItMatters":"This challenges the hypothesis that liberalizing cannabis policies might reduce opioid deaths through substitution. Instead, the data suggest that more permissive cannabis environments are associated with higher involvement of both substances in deaths of despair.","specificNumbers":"68,924 decedents from suicide and undetermined intent deaths (2003-2018). Cannabis involvement increased odds of opioid involvement: AOR=1.29 (95% CI: 1.22-1.37). A 10% more restrictive cannabis policy: AOR=0.87 for cannabis involvement, AOR=0.88 for opioid involvement.","methodology":"Repeated cross-sectional study using restricted-access National Violent Death Reporting System data (2003-2018) linked to the Cannabis Policy Scale measuring state-level cannabis policy permissiveness. Mixed effects logistic regression analyzed 68,924 decedents across states that expanded from 7 to 41 during the study period.","limitations":"Observational design cannot prove cannabis policies cause these deaths. Not all states participated throughout the study period. Toxicology testing practices vary across jurisdictions. Cannabis involvement does not mean cannabis caused the death."},{"rthcId":"RTHC-06960","title":"Inflammatory state moderates response to cannabis on negative affect and sleep quality in individuals with anxiety.","authors":"Lisano, Jonathon K; Skrzynski, Carillon J; Giordano, Gregory; Bryan, Angela D; Bidwell, L Cinnamon","year":2025,"journal":"Frontiers in behavioral neuroscience, 19, 1549311","doi":"10.3389/fnbeh.2025.1549311","pmid":"40667474","tags":["anxiety","sleep","cbd","inflammation"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"While cannabis use did not change cytokine concentrations over four weeks, baseline inflammation moderated outcomes. People with higher baseline inflammation responded differently to different cannabis chemovars. CBD-dominant products produced more consistent improvements in negative affect and sleep quality, while THC-associated improvements varied depending on the person's inflammatory state.","whyItMatters":"This is among the first studies to show that a person's inflammatory profile may predict whether cannabis will help their anxiety and sleep. It suggests a possible biological reason why cannabis works for some people with anxiety but not others.","specificNumbers":"147 participants across three cannabis chemovars, 24 controls. No group-dependent changes in cytokines (p=0.12). Baseline inflammation moderated DASS-21 outcomes (p<0.05) and sleep quality (p=0.04). CBD chemovars showed more consistent improvements.","methodology":"Participants with mild or greater anxiety (n=147) were assigned to one of three cannabis chemovars (THC+CBD, THC-only, CBD-only) for 4 weeks of ad libitum use and compared to an anxiety control group (n=24). Depression, anxiety, stress (DASS-21), sleep quality (PSQI), and plasma cytokines were measured at baseline and week 4.","limitations":"Non-randomized assignment to chemovars. Ad libitum use means dosing varied. Small control group (24). Four-week follow-up may be too short for stable effects. Cannot determine optimal THC:CBD ratios from this design."},{"rthcId":"RTHC-06961","title":"Efficacy of a Neuroimmune Therapy Including Pineal Methoxyindoles, Angiotensin 1-7, and Endocannabinoids in Cancer, Autoimmune, and Neurodegenerative Diseases.","authors":"Lissoni, Paolo; Rovelli, Franco; Monzon, Alejandra; Messina, Giusy; Merli, Nicoletta; Tartarelli, Rosanna; Tassoni, Simonetta; Zecchinato, Francesca; Simoes-E-Silva, Ana Cristina; Valentini, Agnese; Di Fede, Giuseppe; Cardinali, Daniel P","year":2025,"journal":"Clinical interventions in aging, 20, 513-522","doi":"10.2147/CIA.S513910","pmid":"40330271","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06962","title":"Train-the-Educator: Boosting Knowledge and Confidence for Conducting Substance Use Prevention Education.","authors":"Liu, Jessica; Kajiwara, Carly; McCauley, Devin; Halpern-Felsher, Bonnie","year":2025,"journal":"The Journal of school health, 95(1), 78-93","doi":"10.1111/josh.13534","pmid":"39777684","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06963","title":"Folate-chitosan nanoparticle delivery of cannabidiol for targeted triple-negative breast cancer therapy.","authors":"Liu, Jia; Wang, Yuqian; Xie, Lingfeng; Xiao, Shanghua; Zhang, Xueyan; Li, Wendi; Peng, Yutao; Cai, Ruizhao; Qu, Shoukang; Huang, Chengyu","year":2025,"journal":"The Journal of pharmacy and pharmacology, 77(12), 1701-1714","doi":"10.1093/jpp/rgaf072","pmid":"40838692","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06964","title":"Visual attention and memory retention of cannabis warning labels: an eye-tracking experiment with young adults.","authors":"Liu, Jiaying; Mi, Ranran Z; Jeon, Moonsun; Fabbricatore, Jessica L; Wicke, Rebekah; Cojulun, Lauren Raquel; Yang, Sijia","year":2025,"journal":"Annals of behavioral medicine : a publication of the Society of Behavioral Medicine, 59(1)","doi":"10.1093/abm/kaaf094","pmid":"41338585","tags":["legalization","harm-reduction","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Labels with specific text about health consequences held attention longer and improved risk recognition compared to generic warnings. Adding vivid imagery further increased attention but did not significantly improve recognition beyond specific text alone. Pictograms increased attention compared to generic text but less than vivid imagery.","whyItMatters":"Current cannabis warning labels are often dense, generic, and text-only. As cannabis products proliferate, designing effective warnings that actually capture attention and communicate risk is a public health priority.","specificNumbers":"163 young adult participants across 4 conditions. Specific text significantly outperformed generic text on both fixation duration and recognition scores. Vivid imagery enhanced attention beyond specific text. Pictograms enhanced attention but less than vivid imagery. Neither pictorial type improved recognition beyond specific text.","methodology":"Eye-tracking experiment with 163 young adults randomly assigned to view cannabis warning labels with: (1) generic text, (2) specific text, (3) specific text with pictogram, or (4) specific text with vivid imagery. Attention measured by fixation duration; recognition assessed via post-exposure memory test with signal detection.","limitations":"Lab-based eye-tracking may not reflect real-world label viewing. Young adult sample may not generalize to all consumers. Short exposure period does not capture repeated viewing effects. Recognition was tested immediately, not long-term retention."},{"rthcId":"RTHC-06965","title":"Impact of Co-Occurring Psychiatric Comorbidities and Substance Use Disorders on Outcomes in Adolescents and Young Adults with Opioid Use Disorder: A Retrospective Cohort Study.","authors":"Liu, Ligang; McKnight, Erin R; Bonny, Andrea E; Tao, Heqing; Zhao, Pujing; Nahata, Milap C","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(5)","doi":"10.3390/ph18050609","pmid":"40430432","tags":["addiction","mental-health","youth"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis use disorder predicted shorter treatment retention (p=0.02), while depression (p=0.04), PTSD (p=0.002), and alcohol use disorder (p=0.04) were associated with longer retention. Cannabis use disorder and male sex predicted positive urine tests for THC, while medication for OUD was linked to lower THC positivity. The median retention time was 300 days.","whyItMatters":"Opioid addiction treatment in young people is already challenging, and this study suggests co-occurring cannabis use disorder adds another barrier to retention. Understanding which comorbidities help versus hinder treatment can guide clinical approaches.","specificNumbers":"157 patients, median retention 300 days. CUD predicted shorter retention (p=0.02). Depression (p=0.04) and PTSD (p=0.002) predicted longer retention. Median proportion positive UDTs: 0.9 for MOUD (good adherence), 0.1 for illicit substances, 0.0 for THC. CUD (p=0.02) and male sex (p=0.04) predicted THC-positive urine tests.","methodology":"Retrospective cohort study of 157 adolescents and young adults enrolled in a Substance Use Treatment and Recovery clinic from 2009 to 2022. Treatment retention and urine drug test results were analyzed using Kruskal-Wallis tests and regression models.","limitations":"Retrospective single-center study. Small sample (157). Cannot determine causation. THC positivity may reflect legal medical use in some cases. The study period (2009-2022) spans significant changes in cannabis policy and availability."},{"rthcId":"RTHC-06966","title":"Aquatic toxicity of synthetic cannabinoid: multisystem impacts of 5F-ADB on neurodevelopment in Daphnia magna.","authors":"Liu, Qinghua; Yi, Pan; Xie, Jiying; Zhang, Zhenhua; Sui, Hongxia; Liu, Yuqing; Guo, Ruixin; Chen, Jianqiu; Liu, Yanhua","year":2025,"journal":"Environmental toxicology and chemistry, 44(8), 2298-2309","doi":"10.1093/etojnl/vgaf135","pmid":"40418219","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06967","title":"Comparative analysis of 105 datasets across species and tissues reveals differential transcriptomic responses to cannabinoids THC and CBD.","authors":"Liu, Ruoshui; Kowal, Thomas; Chow, Caden; Olson, Tyler; Nguyen, Emily; Yang, Sen; Lee, Jimin; Cai, Hua; Yang, Xia; Blencowe, Montgomery","year":2025,"journal":"Journal of cannabis research, 8(1), 13","doi":"10.1186/s42238-025-00361-0","pmid":"41402937","tags":["cbd","neuroscience","inflammation"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CBD datasets showed more differentially expressed genes and enriched pathways across species. CBD effects clustered by administration route and species and were enriched for inflammation suppression, zinc homeostasis, and cell cycle regulation. THC signatures were more variable but consistently affected antioxidant activity, neuronal myelination, and synaptic signaling. THC altered endocannabinoid genes mainly in brain tissue, while CBD affected them in both central and peripheral tissues.","whyItMatters":"Despite being the two main cannabinoids, THC and CBD are often discussed interchangeably. This comprehensive molecular comparison shows they affect fundamentally different biological pathways, supporting the need to consider them as distinct therapeutic agents.","specificNumbers":"105 datasets analyzed across 4 mammalian species. CBD showed more differentially expressed genes overall. CBD DEGs associated with lipid metabolism and body composition. Both compounds linked to neuropsychiatric disorders and type 2 diabetes. THC altered endocannabinoid signaling mainly in brain; CBD affected both central and peripheral tissues.","methodology":"Curation and analysis of 105 THC and CBD RNA-sequencing and microarray datasets from NCBI GEO across mammalian species (human, rhesus macaque, mouse, rat). Meta-analysis identified common gene signatures, with pathway enrichment, network analysis, and disease association analysis.","limitations":"Analysis of existing datasets introduces heterogeneity in experimental conditions. Different doses, exposure durations, and tissue types across studies. Transcriptomic changes do not always translate to functional outcomes. Publication bias toward certain tissues and species."},{"rthcId":"RTHC-06968","title":"Adult-use cannabis legalization in the united states: a scoping review of outcome monitoring recommendations.","authors":"Liu, Yang; Suleiman, Adekemi O; Iverson, Marissa G; Wiser, Alison; Cunningham, Shayna D; O'Grady, Megan A","year":2025,"journal":"BMC public health, 26(1), 87","doi":"10.1186/s12889-025-25720-7","pmid":"41331610","tags":["legalization"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"As adult-use cannabis legalization expands across the United States, a critical question emerges: how do we know whether it's working as intended? This scoping review searched seven academic databases plus policy research organizations (RAND, Brookings, Pew) to identify what experts recommend monitoring.\n\nThe review cataloged recommendations across multiple domains—use prevalence, health outcomes, emergency department visits, traffic safety, youth access, criminal justice impacts, market dynamics, and more. The scope of what experts think should be tracked is vast, reflecting the wide-reaching effects of legalization.\n\nBut the gap between what should be monitored and what actually is being monitored is the real finding. Many recommended metrics lack systematic data collection infrastructure. Some outcomes (like long-term health effects) require longitudinal tracking that hasn't been established. And the patchwork of state-level legalization means there's no unified national monitoring system.\n\nThe review provides a valuable framework for states that are newly legalizing or for those that want to improve their existing monitoring. It essentially creates a checklist of what the evidence base says we should be watching.","whyItMatters":"Legalization without monitoring is policy without accountability. If we can't measure the impacts—positive and negative—we can't make evidence-based adjustments. This review provides the roadmap for what comprehensive cannabis legalization monitoring should look like, at a time when most states are doing it piecemeal.","specificNumbers":"7 academic databases searched plus 3 policy research centers. Articles coded into standardized monitoring recommendation categories. Recommendations spanned use prevalence, health outcomes, traffic safety, youth access, criminal justice, and market dynamics.","methodology":"Scoping review searching PubMed/MEDLINE, Embase, Scopus, PsycInfo, Web of Science, Dissertations & Theses Global, and Trip Database from inception to August 2025. Also searched RAND, Brookings, and Pew Research Center websites. Articles coded into key monitoring recommendation areas using a standardized form.","limitations":"Scoping reviews identify the scope of recommendations but don't evaluate their quality or feasibility. Many recommended metrics may be impractical to collect systematically. The review is U.S.-focused and may not apply to countries with different legalization models. Recommendations exist on paper; whether they translate to actual monitoring programs is a political and funding question."},{"rthcId":"RTHC-06969","title":"Cannabidiol (CBD) and Colorectal Tumorigenesis: Potential Dual Modulatory Roles via the Serotonergic Pathway.","authors":"Liu, Zhenhua","year":2025,"journal":"Current oncology (Toronto, Ont.), 32(7)","doi":"10.3390/curroncol32070375","pmid":"40710186","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06970","title":"Age Differences in Cannabis Consumption Patterns and in Associations Between Delta-9-Tetrahydrocannabinol Intake and Cannabis Use Disorders Among Adults with Daily Use.","authors":"Livne, Ofir; Borodovsky, Jacob; Budney, Alan J; Wisell, Caroline G; Habib, Mohammad I; Struble, Cara A; Chen, Lynn; Liu, Jun; Wall, Melanie; Aharonovich, Efrat; Hasin, Deborah S","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251360976","pmid":"40667820","tags":["addiction","seniors","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Over 70% of daily users across all ages used cannabis for both medical and recreational reasons. Middle-aged adults were more likely to report medical-only use than younger adults (18.1% vs 13.7%). High-potency concentrate use declined with age. While middle-aged and older adults endorsed fewer CUD criteria overall, the relationship between mg THC consumed and CUD severity did not differ significantly by age.","whyItMatters":"Cannabis use is rising fastest among older adults, who are often assumed to be at lower risk. This study shows that while they use differently, their vulnerability to cannabis use disorder per unit of THC may be the same as younger users.","specificNumbers":"4,134 daily users. 70%+ used for both medical and recreational. Middle-aged medical-only: 18.1% vs 13.7% younger (p<0.05). Older adults recreational-only: 15.8% vs 10.5% middle-aged (p=0.002). Concentrate use declined with age (p=0.027). Age effects on CUD-THC relationship were not statistically significant.","methodology":"Online survey of 4,134 US adults (45.9% male) who reported daily cannabis use, with comparisons across three age groups (18-49, 50-64, 65+). Assessed consumption patterns, methods, reasons for use, daily mg THC, and DSM-5 CUD criteria. Regression models adjusted for sex and reasons for use.","limitations":"Cross-sectional online survey with self-selected sample of daily users. Self-reported CUD criteria may differ from clinical assessment. THC quantity estimation is inherently imprecise. Only included daily users, not occasional users."},{"rthcId":"RTHC-06971","title":"Impact of Computer-Mediated Versus Face-to-Face Motivational-Type Interviews on Participants' Language and Subsequent Cannabis Use: Randomized Controlled Trial.","authors":"Llanes, Karla D; Amastae, Jon; Amrhein, Paul C; Lisha, Nadra; Arteaga, Katherina; Lopez, Eugene; Moran, Roberto A; Cohn, Lawrence D","year":2025,"journal":"Journal of medical Internet research, 27, e59085","doi":"10.2196/59085","pmid":"40279644","tags":["quitting","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Both interview formats generated similar amounts of change talk and sustain talk after adjusting for verbosity. However, the relationship between change talk and actual behavior change differed by format: in face-to-face interviews, stronger change talk trended toward reduced marijuana use at 2 months (though not significant, p=0.08), while in the computer format, change talk did not predict behavior change.","whyItMatters":"Scaling up motivational interviewing through computer platforms could reach more cannabis users. This study suggests the format shows promise for generating the right kind of conversation, but translating that into behavior change may require the human connection of face-to-face interaction.","specificNumbers":"150 participants (frequent users, occasional users, non-users). Face-to-face produced significantly more words (p<0.001). After controlling for verbosity, change talk was similar (p=0.47). Face-to-face showed trend toward use reduction with stronger change talk (p=0.08). Computer format: no relationship between change talk and use (p=0.16).","methodology":"Randomized controlled trial with 150 marijuana users and ambivalent non-users assigned to face-to-face or computer-mediated motivational-type interviews. Change talk was coded using Amrhein's manual. Marijuana use was assessed at 2-month follow-up.","limitations":"Small sample size (150) spread across user types. Two-month follow-up is short. Self-reported marijuana use. The motivational interview format was adapted, not standard MI. Computer-mediated format may improve with technological advances."},{"rthcId":"RTHC-06972","title":"Prenatal Cannabis Use and Neonatal Outcomes: A Systematic Review and Meta-Analysis.","authors":"Lo, Jamie O; Ayers, Chelsea K; Yeddala, Snehapriya; Shaw, Beth; Robalino, Shannon; Ward, Rachel; Kansagara, Devan","year":2025,"journal":"JAMA pediatrics, 179(7), 738-46","doi":"10.1001/jamapediatrics.2025.0689","pmid":"40323610","tags":["pregnancy","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis use in pregnancy was associated with increased odds of low birth weight (OR=1.75), preterm birth (OR=1.52), small for gestational age (OR=1.57), and perinatal mortality (OR=1.29). The evidence certainty for the first three outcomes was upgraded to moderate from low/very low in the prior review. Critically, these associations held after adjusting for co-use of tobacco products.","whyItMatters":"This is one of the largest and most rigorous analyses of cannabis and pregnancy outcomes. The upgrade from low to moderate certainty evidence, combined with the enormous sample size, substantially strengthens the case that prenatal cannabis use carries real risks to newborns.","specificNumbers":"51 studies, 21.1 million participants. Low birth weight: OR=1.75 (95% CI: 1.41-2.18, 20 studies). Preterm birth: OR=1.52 (95% CI: 1.26-1.83, 20 studies). Small for gestational age: OR=1.57 (95% CI: 1.36-1.81, 12 studies). Perinatal mortality: OR=1.29 (95% CI: 1.07-1.55, 6 studies, low certainty).","methodology":"Updated living systematic review and meta-analysis published in JAMA Pediatrics. Added 8 new studies (1.7 million participants) to the prior review for a total of 51 studies (21.1 million participants). Random-effects meta-analyses of adjusted odds ratios. Evidence graded using GRADE approach.","limitations":"Observational studies cannot fully eliminate confounding. Cannabis exposure is mostly self-reported. Different studies measured exposure at different points in pregnancy. Dose-response data is limited."},{"rthcId":"RTHC-06973","title":"Cannabis use in Patients With Inflammatory Bowel Disease is Associated With Longer Endoscopic Duration and Endoscopic Inflammation.","authors":"Loeb, Lauren; Hochwald, Alexander; Picco, Michael F; Chan, Johanna L; Hashash, Jana G; Chadha, Ryan; Farraye, Francis A; Kinnucan, Jami A","year":2025,"journal":"Crohn's & colitis 360, 7(3), otaf034","doi":"10.1093/crocol/otaf034","pmid":"40667460","tags":["medical-cannabis","inflammation"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"IBD patients who used cannabis had significantly longer endoscopy durations (p<0.001) and were more likely to have endoscopic inflammation (p=0.044) than matched non-users. There was no significant difference in recovery time, propofol dose per procedure duration, or IBD treatment at the time of endoscopy.","whyItMatters":"Many IBD patients use cannabis for symptom relief, but this study found cannabis users actually had more inflammation on endoscopy. This raises the question of whether cannabis masks symptoms while inflammation continues, or whether people with worse disease are more likely to turn to cannabis.","specificNumbers":"124 patients total (62 cannabis users, 62 matched controls). Significant differences: endoscopy duration (p<0.001) and endoscopic inflammation (p=0.044). No significant differences: recovery time (p=0.15), IBD treatment (p=0.84), stricture (p=0.53), adjusted propofol dose (p=0.082).","methodology":"Retrospective case-control study at a tertiary academic medical center (2018-2022). 62 IBD patients reporting cannabis use were matched by age, sex, and BMI with 62 non-using IBD patients. All underwent endoscopy for acute IBD complaints.","limitations":"Retrospective case-control design cannot determine causation. Cannabis use was self-reported. Selection bias: patients undergoing endoscopy for acute complaints represent a sicker subset. Cannot determine whether cannabis use preceded or followed disease worsening."},{"rthcId":"RTHC-06974","title":"Double-Blind, Randomized, Placebo-Controlled, Crossover Study of Oral Cannabidiol and Tetrahydrocannabinol for Essential Tremor.","authors":"Longardner, Katherine; Shen, Qian; Castellanos, Francisco X; Tang, Bin; Gandhi, Rhea; Wright, Brenton A; Momper, Jeremiah D; Nahab, Fatta B","year":2025,"journal":"Tremor and other hyperkinetic movements (New York, N.Y.), 15, 14","doi":"10.5334/tohm.1005","pmid":"40248111","tags":["medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Among seven enrolled participants (five completers), intent-to-treat analyses found no significant effects on the primary endpoint (tremor amplitude via digital spiral assessment) or any secondary endpoints. One participant withdrew due to a serious adverse event, and one could not tolerate the lowest dose. The remaining five tolerated the medication well.","whyItMatters":"Essential tremor is the most common movement disorder with limited treatment options. Anecdotal reports of cannabis helping are widespread, but this is the first controlled trial to test the claim. The negative result, while preliminary, does not support those anecdotes.","specificNumbers":"13 screened, 7 enrolled, 5 completed. Maximum dose: 3 capsules/day (15mg THC, 300mg CBD). No significant effects on primary or secondary endpoints. 1 serious adverse event leading to withdrawal. 1 participant could not tolerate lowest dose. 5 of 7 tolerated the medication.","methodology":"Phase Ib/II double-blind, placebo-controlled, crossover pilot trial. Participants with essential tremor were randomized to pharmaceutical-grade THC 5mg/CBD 100mg capsules or placebo with dose titration every 2-3 days to a maximum of 3 capsules daily. Two-week treatment periods with three-week washout.","limitations":"Very small sample (7 enrolled, 5 completers). Short treatment duration. Only one THC:CBD ratio tested. Oral administration may not replicate the effects reported by people who smoke or vaporize cannabis. Underpowered to detect modest effects."},{"rthcId":"RTHC-06975","title":"Circuit mechanisms governing endocannabinoid modulation of affective behaviour and stress adaptation.","authors":"Loomba, Niharika; Patel, Sachin","year":2025,"journal":"Nature reviews. Neuroscience, 26(11), 677-697","doi":"10.1038/s41583-025-00961-y","pmid":"40935953","tags":["anxiety","neuroscience","mental-health"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Endocannabinoid signaling modulates innate avoidance, conditioned fear, and stress responsivity through specific cortical-cortical and cortical-subcortical circuits. Endocannabinoid-deficient states represent a stress-susceptibility trait, while pharmacologically boosting endocannabinoid levels shows therapeutic potential for anxiety and stress-related disorders. New biosensor tools have enabled mapping of real-time endocannabinoid dynamics in these circuits.","whyItMatters":"Understanding exactly how the brain's own cannabinoid system manages stress and anxiety at the circuit level could lead to targeted therapies that enhance this natural system rather than using plant-derived cannabinoids with broader effects.","specificNumbers":"Review covers multiple cortical-cortical and cortical-subcortical circuits. Identifies endocannabinoid-deficient states as a stress-susceptibility endophenotype. Discusses pharmacological endocannabinoid augmentation as an emerging therapeutic approach.","methodology":"Comprehensive review in Nature Reviews Neuroscience synthesizing preclinical and human experimental studies, including recent work using endocannabinoid biosensors, intersectional genetics, and optogenetic-assisted circuit mapping.","limitations":"Review primarily synthesizes preclinical data. Translation from animal circuits to human brain networks is complex. Clinical trials of endocannabinoid augmentation are still early-stage."},{"rthcId":"RTHC-06976","title":"Associations between cannabis risk perceptions and Delta-8 THC use among young adults.","authors":"LoParco, C R; Walters, S T; Zhou, Z; Rossheim, M E","year":2025,"journal":"Journal of substance use, 30(2), 223-229","doi":"10.1080/14659891.2023.2293798","pmid":"40171156","tags":["youth","legalization","potency"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Past-year Delta-9 THC use was associated with 20 times the odds of Delta-8 use. Risk perception patterns were inconsistent: lower perceived severity of Delta-8 harms and lower perceived susceptibility to Delta-9 harms predicted Delta-8 use, but higher perceived severity of Delta-9 harms and higher perceived susceptibility to Delta-8 harms also predicted use, possibly reflecting reverse causation.","whyItMatters":"Delta-8 THC exists in a regulatory gap and its use is rising rapidly. Understanding who uses it and why is essential for developing appropriate regulations and public health responses.","specificNumbers":"166 young adults aged 18-25. Delta-9 users had 20x odds of using Delta-8. Lower Delta-8 perceived severity predicted Delta-8 use. Higher Delta-9 perceived severity also predicted Delta-8 use. Inconsistent direction of risk perception associations suggests reverse causation.","methodology":"Survey of a convenience sample of 166 young adults aged 18-25. Mixed effects multivariable logistic regression examined whether perceived susceptibility and severity of harms were associated with past-year Delta-8 THC use, adjusting for demographics, student status, and Delta-9 use, with random intercepts for state.","limitations":"Very small convenience sample (166). Cross-sectional design cannot determine causation. Self-reported use and perceptions. The inconsistent findings may reflect the early, rapidly changing Delta-8 market."},{"rthcId":"RTHC-06977","title":"Snapchat Artificial Intelligence as an Information Source on Delta-8 THC.","authors":"LoParco, Cassidy R; Tillett, Kayla K; Bektaş, Ayyüce Begüm; Rossheim, Matthew E; Berg, Carla J","year":2025,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 77(5), 931-937","doi":"10.1016/j.jadohealth.2025.06.036","pmid":"40981728","tags":["youth","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Snapchat AI provided information about Delta-8 THC across five themes: general information (comparing it to Delta-9 but with lower potency), use motives (pain relief, anti-nausea, appetite, anxiety), potential consequences (mild side effects), retail availability, and product recommendations. No citations were provided. While \"weed\" and \"THC\" were blocked as search terms, \"Delta-8\" was not.","whyItMatters":"Snapchat is one of the most popular platforms among teens and young adults. Its AI chatbot is automatically available on all accounts and functions as an easily accessible information source that may shape cannabis perceptions without scientific backing.","specificNumbers":"Five thematic categories identified. Zero citations provided by the AI. \"Delta-8\" was not blocked while \"weed\" and \"THC\" were. The AI actively prompted follow-up questions, driving deeper engagement with the topic.","methodology":"Qualitative analysis of Snapchat AI chatbot responses to Delta-8 THC questions (August 2024-January 2025). Researchers asked questions as users would, and AI responses were independently coded into thematic categories.","limitations":"Qualitative design without quantitative measures of impact on users. Responses may vary based on prompting style. Snapchat AI may update its responses over time. Does not measure how many youth actually ask about Delta-8."},{"rthcId":"RTHC-06978","title":"Associations Between Cannabis Messaging and Derived Psychoactive Cannabis Product Perceptions, Use, and Use Intentions Among a Sample of US Young Adults.","authors":"LoParco, Cassidy R; Rossheim, Matthew E; Cui, Yuxian; McCready, Darcey M; Romm, Katelyn F; Wang, Yan; Yang, Y Tony; Cavazos-Rehg, Patricia A; Szlyk, Hannah; Kasson, Erin; Berg, Carla J","year":2025,"journal":"Substance use & misuse, 60(13), 2025-2033","doi":"10.1080/10826084.2025.2530786","pmid":"40699944","tags":["youth","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"About 45.6% of cannabis users also used derived intoxicating cannabis products (DICPs). Cannabis-DICP co-use (vs cannabis-only) was associated with greater psychophysiological and sociobehavioral consequences. Higher enhancement and coping motives predicted co-use. The associations between motives and consequences were partially mediated through co-use of DICPs.","whyItMatters":"Derived cannabis products represent a growing and largely unregulated market. This study provides early evidence that combining traditional cannabis with these products may carry additional risks compared to using cannabis alone.","specificNumbers":"1,968 past-month cannabis users from 4,031 surveyed. 54.4% cannabis-only, 45.6% cannabis-DICP co-use. Greater coping and enhancement motives predicted co-use. Co-use associated with greater psychophysiological and sociobehavioral consequences.","methodology":"Cross-sectional survey analysis of 1,968 past-month cannabis users from a sample of 4,031 US young adults aged 18-34 (June-November 2023). Mediation models examined motives, use category, and consequences.","limitations":"Cross-sectional design cannot determine causation. Self-reported consequences. Cannabis and DICP categories overlap in complex ways. Convenience sample may not be representative of all young adult cannabis users."},{"rthcId":"RTHC-06979","title":"Cannabis social equity initiatives among US states with legal non-medical cannabis retail: A review and recommendations.","authors":"LoParco, Cassidy R; Speer, Morgan; Chakraborty, Rishika; Yang, Y Tony; Berg, Carla J","year":2025,"journal":"American journal of preventive medicine, 108218","doi":"10.1016/j.amepre.2025.108218","pmid":"41397535","tags":["legalization","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Of 22 states with legal recreational cannabis sales, 17 had social equity licensing initiatives (13 reserved licenses for equity entrepreneurs). Eligibility typically required majority business ownership and considered cannabis arrests (14 states), residence in disproportionately impacted areas (15 states), and/or income level (9 states). Only 4 states distributed tax revenue back to equity programs. 15 states had cannabis-related expungement provisions.","whyItMatters":"Cannabis legalization was partly motivated by addressing racial and social injustices from prohibition. This comprehensive review shows that while most states have some equity measures, there are significant gaps, particularly in funding equity programs through cannabis tax revenue.","specificNumbers":"22 states reviewed. 17/22 had equity licensing. 13/17 reserved licenses for equity entrepreneurs. 14/17 considered cannabis arrests for eligibility. 15/17 considered residence in impacted areas. 14/17 provided technical assistance. 20/22 imposed excise taxes. Only 4/22 distributed revenue to equity programs. 15/22 had expungements.","methodology":"Policy review analyzing cannabis-related social equity initiatives across all 22 US states with legal and active recreational cannabis retail as of December 2024. Two coders independently identified initiatives using NexisUni and state legislative websites. Three initiative categories examined: equitable entrepreneurship, community reinvestment, and criminal justice reform.","limitations":"Policy review captures what is written in law, not implementation outcomes. Equity programs may exist but be underfunded or underutilized. State policies change frequently. Does not measure whether these initiatives have achieved their goals."},{"rthcId":"RTHC-06980","title":"Derived psychoactive cannabis product perceptions and use among a sample of US young adults.","authors":"LoParco, Cassidy R; Rossheim, Matthew E; Cui, Yuxian; McCready, Darcey M; Romm, Katelyn F; Wang, Yan; Yang, Y Tony; Cavazos-Rehg, Patricia A; Berg, Carla J","year":2025,"journal":"Addictive behaviors, 160, 108180","doi":"10.1016/j.addbeh.2024.108180","pmid":"39332229","tags":["youth","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"DPCP awareness was 67.5% overall (87% among cannabis users vs 49% non-users). Lifetime use was 41.7%, past-month 24.4%. Among those aware, 70.3% incorrectly believed DPCPs were required to be tested and approved for safety, and 59% believed they were FDA-approved. Delta-8 THC was the most commonly used (69.7% of ever-users). Lower perceived harm and higher perceived social acceptability predicted use.","whyItMatters":"Widespread misconceptions about the regulatory status of derived cannabis products put consumers at risk. The belief that these products are FDA-approved or safety-tested could lead users to underestimate potential harms from unregulated, untested products.","specificNumbers":"4,031 young adults. DPCP awareness: 67.5%. Lifetime use: 41.7%. Past-month use: 24.4% (45.6% of cannabis users, 4.2% of non-users). 70.3% believed DPCPs were safety-tested (false). 59% believed FDA-approved (false). Main use reasons: curiosity (55.5%), believed legal (34.1%), friend suggestion (34%).","methodology":"Cross-sectional survey of 4,031 US young adults aged 18-34 (approximately 50% past-month cannabis users). Multivariable regressions examined demographics, cannabis use, and risk perceptions in relation to past-month DPCP use, frequency, and future use likelihood.","limitations":"Cross-sectional design. Convenience sample aiming for 50% cannabis users overrepresents users. Self-reported perceptions and use. The DPCP market is evolving rapidly, so findings may not reflect current conditions."},{"rthcId":"RTHC-06981","title":"Cannabis Marketing Strategies in the United States: A Descriptive Analysis of Four Prominent Companies.","authors":"LoParco, Cassidy R; Cui, Yuxian; McCready, Darcey M; Rossheim, Matthew E; Chen-Sankey, Julia; Howlader, Afrah; Fergnani, Anna; Mumin, Deqa; Burris, Scott; Berg, Carla J","year":2025,"journal":"Substance use & addiction journal, 46(3), 601-611","doi":"10.1177/29767342251313860","pmid":"39891561","tags":["legalization","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Four cannabis companies produced 399 unique ads with 1,171 placements totaling $488,617. Online displays were the dominant channel (69.2% of placements, 45.8% of spending). News/weather sites were the primary ad placement source (36.3% of placements). Ad headlines most often emphasized product type (40.1%). GIFs were the most common visual strategy (63.6% of placements). Companies used notably different marketing strategies.","whyItMatters":"Cannabis advertising exposure is associated with cannabis use and positive attitudes toward use. Understanding how cannabis companies market their products is essential for developing regulations that protect consumers, particularly youth, from potentially harmful advertising.","specificNumbers":"399 unique ads, 1,171 placements, $488,617 total spending. Cresco: 52.4% of placements, 63.4% of spending. Online displays: 69.2% of placements. News/weather placement: 36.3%. Product type headlines: 40.1%. GIF visuals: 63.6%.","methodology":"Descriptive analysis of 2020-2021 Vivvix advertising data from four US cannabis companies (Cresco, Mindy's, MedMen, Uncle Ike's). Examined ad characteristics, content, and placement patterns.","limitations":"Only four companies analyzed. Data from 2020-2021 may not reflect current strategies. Vivvix may not capture all advertising channels, especially social media and influencer marketing. Does not measure consumer exposure or impact."},{"rthcId":"RTHC-06982","title":"Young Smokers' Therapy Preferences: App-Based vs. Face-to-Face Treatment in the Context of Co-Addictions.","authors":"López-Torrecillas, Francisca; Arcos-Rueda, María Del Mar; Cobo-Rodríguez, Beatriz; Muñoz-López, Lucas","year":2025,"journal":"Healthcare (Basel, Switzerland), 13(18)","doi":"10.3390/healthcare13182326","pmid":"41008455","tags":["addiction","youth","quitting"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study enrolled 98 young adult smokers from the University of Granada into either an app-based cognitive-behavioral therapy (CBT) program or a traditional face-to-face CBT program for smoking cessation. The participants self-selected their format, which is itself informative: younger participants and students were more likely to choose the app.\n\nThe study used the decisional balance framework—weighing perceived advantages versus disadvantages of smoking—to assess motivation for change. Here's where it gets interesting with cannabis: cannabis dependence was associated with perceiving fewer disadvantages of smoking. In other words, young smokers who were also dependent on cannabis were less motivated to quit tobacco because they saw fewer downsides to smoking.\n\nSex addiction and other substance addictions showed similar patterns, while compulsive buying showed the opposite pattern (more perceived disadvantages of smoking). This suggests that co-occurring addictive behaviors may systematically alter how young people evaluate their smoking—and that cannabis dependence specifically may dampen quit motivation.\n\nThe treatment preference data also matters practically: younger people gravitating toward apps suggests that digital cessation tools may have better uptake in this demographic.","whyItMatters":"Understanding what undermines quit motivation in young smokers is essential for designing effective cessation programs. The finding that cannabis dependence reduces perceived disadvantages of smoking suggests these co-occurring conditions may need to be addressed together—young people who don't see smoking as problematic are unlikely to engage with cessation programs.","specificNumbers":"N = 98 (35 app-based, 63 face-to-face). Younger participants more likely to choose app-based therapy. Cannabis dependence associated with fewer perceived disadvantages of smoking. Compulsive buying associated with more perceived disadvantages.","methodology":"Observational study of 98 young adult smokers at the University of Granada. 35 self-selected into app-based CBT, 63 into face-to-face CBT. Measures: nicotine dependence (FTND), behavioral and substance addictions (MULTICAGE CAD-4), cannabis dependence (SDS), and motivation (Decisional Balance Questionnaire). Logistic and stepwise regression analyses.","limitations":"Small sample from a single Spanish university—limited generalizability. Self-selection into treatment format (not randomized). The study can't determine whether cannabis dependence causes reduced quit motivation or whether both reflect a common underlying factor. Spanish young adult smoking patterns may differ from other countries. The decisional balance framework captures perceived pros/cons but may not predict actual quit behavior."},{"rthcId":"RTHC-06983","title":"Addressing Tobacco-Related Disparities Among Youth Experiencing Homelessness by Engaging Youth Collaborators in Intervention Research: Protocol for a Multimethod, Community-Based Participatory Research Study.","authors":"Lopez, Alana R; Lim, Andrew C; Escobedo, Renatta; Chung, Nicole; Chien, Lorilee; Calzo, Jerel P; Urada, Lianne; Aceves, Benjamín; Jellá, Steven; Smiley, Sabrina L; Felner, Jennifer K","year":2025,"journal":"JMIR research protocols, 14, e69441","doi":"10.2196/69441","pmid":"40829143","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06984","title":"Cannabinoid-Induced Hyperphagia is Mediated by Increased Meal Frequency and the Orexin-1 Receptor in Male Rats.","authors":"Lord, Magen N; Madu, Grace C; Loera-Lopez, Ana L; Aaron, Alexander P; Lin, Jessica; Noble, Emily E","year":2025,"journal":"Pharmacology research & perspectives, 13(5), e70171","doi":"10.1002/prp2.70171","pmid":"40911185","tags":["appetite","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Orally consumed cannabinoid edibles caused overeating by increasing meal frequency, not meal size. This hyperphagic effect required orexin-1 (OX1) receptor signaling. Blocking the OX1 receptor eliminated both the increased eating and the temporary burst of activity following cannabinoid consumption. Both cannabinoids and the OX1 antagonist independently reduced energy expenditure hours after administration.","whyItMatters":"The \"munchies\" is one of the most recognizable effects of cannabis, but the neural mechanism has been unclear. Identifying the orexin pathway as essential opens possibilities for managing unwanted appetite stimulation while preserving other therapeutic effects of cannabinoids.","specificNumbers":"Cannabinoid edibles produced acute hyperphagia via increased meal number (not size). OX1 antagonist completely blocked cannabinoid-induced hyperphagia. Both cannabinoids and OX1 antagonist reduced energy expenditure several hours post-administration. Cannabinoid edibles also caused a transient increase in locomotor activity that was blocked by OX1 antagonism.","methodology":"Male rats received cannabinoid receptor agonist (CP55940) via gelatin-based edibles. OX1 receptor involvement was tested by co-administering the antagonist SB334867. Metabolic monitoring cages captured food intake, locomotor activity, and metabolic variables simultaneously.","limitations":"Male rats only. One cannabinoid agonist tested (CP55940), which is synthetic and more potent than THC. Oral gelatin edible delivery is novel but may not perfectly model human edible consumption. Short-term acute study."},{"rthcId":"RTHC-06985","title":"Cannabis in the wild: Analysis of street cannabis and cannabinoid composition in Australia.","authors":"Lorenzetti, Valentina; Goodwin, Isabella; Christensen, Erynn; Kirkham, Rebecca; Chye, Yann; Galettis, Peter; Gordon, Rebecca; Solowij, Nadia; Yücel, Murat","year":2025,"journal":"The International journal on drug policy, 145, 104974","doi":"10.1016/j.drugpo.2025.104974","pmid":"40907061","tags":["potency","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"One gram of Australian street cannabis contained an average of 34.8 mg THC (about 7 standard THC units) and 12% total THC with only 0.3% total CBD. THC concentrations were stable across participants' samples over time. Critically, users' subjective assessments of cannabis strength showed no correlation with the actual THC content of their products.","whyItMatters":"In unregulated markets, consumers have no reliable way to know what they are consuming. The finding that perceived strength does not match actual THC content means users cannot self-regulate their dosing based on experience alone.","specificNumbers":"37 participants, 127 samples. Average per gram: 34.8 mg THC (6.96 standard THC units), 12% total THC, 0.3% total CBD. THC stable across timepoints (p>0.05). No correlation between perceived strength and actual THC content (p>0.05).","methodology":"Participants donated two 1-gram cannabis samples at three timepoints approximately 9 weeks apart (6 samples total) over 5 months. High-performance liquid chromatography quantified concentrations of THC, CBD, and five other cannabinoids plus their acid precursors in 127 total samples from 37 participants.","limitations":"Convenience sample from one regional area of Australia. 37 participants may not represent all cannabis users. Street cannabis composition varies by region and source. Self-reported strength perception is subjective."},{"rthcId":"RTHC-06986","title":"Brief mindfulness intervention for adults with cannabis use disorder: A randomised clinical trial.","authors":"Lorenzetti, Valentina; McTavish, Eugene; Thomson, Hannah; Clemente, Adam; Rendell, Peter; Terrett, Gill; Greenwood, Lisa-Marie; Freeman, Tom P; Kamboj, Sunjeev K; Manning, Victoria","year":2025,"journal":"Drug and alcohol dependence, 277, 112909","doi":"10.1016/j.drugalcdep.2025.112909","pmid":"41187669","tags":["quitting","addiction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"There were no significant intervention-by-time effects on the primary outcome of cannabis use frequency, nor on secondary outcomes including quantity, cravings, relaxation, or mindfulness scores. The null findings held across all three conditions (mindfulness, relaxation, control) over the approximately 16-day intervention period.","whyItMatters":"Brief, scalable interventions for cannabis use disorder are urgently needed. This well-designed trial shows that a short mindfulness program alone is not sufficient, suggesting more intensive or differently designed interventions may be necessary.","specificNumbers":"66 participants (19 female), ages 18-56. Three groups: MBI (23), relaxation (21), control (22). Mean intervention duration: 16 days. Primary outcome (cannabis frequency): F=0.26, FDR-adjusted p=0.86 (no significant effect). No significant effects on any secondary outcome.","methodology":"Pre-registered, double-blind RCT of 66 adults (ages 18-56) with cannabis use disorder who had attempted to cut down in the past 2 years. Participants were randomized 1:1:1 to mindfulness-based intervention (n=23), relaxation (n=21), or control (n=22). All conditions included daily monitoring. Mean intervention duration: 16 days.","limitations":"Small sample (66). Brief intervention (~16 days) may be too short. Online delivery may reduce engagement. All conditions included daily monitoring, which itself could affect cannabis use. Recruitment during COVID-19 (2019-2022) may have influenced results."},{"rthcId":"RTHC-06987","title":"Cannabinoid Vaping Products: Regulation, Composition, Toxicological Effects, and Emerging Research.","authors":"Love, Charlotte A; Porter, Ned A; Kim, Hye-Young H; Jaspers, Ilona","year":2025,"journal":"Chemical research in toxicology, 38(12), 2028-2040","doi":"10.1021/acs.chemrestox.5c00240","pmid":"41218137","tags":["respiratory","harm-reduction","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Hemp-derived cannabinoid vaping products pose multiple respiratory risks: high cannabinoid concentrations, contaminants (heavy metals, flavoring agents), and harmful byproducts from heating. Reactive cannabinoid quinones (e.g., CBDQ) form during vaping and can create covalent protein bonds, potentially altering cellular function. These quinones may drive oxidative damage through redox cycling, representing an understudied contributor to vaping toxicity.","whyItMatters":"The 2018 Farm Bill created an unregulated market for hemp-derived vaping products. While EVALI highlighted vitamin E acetate risks, this review identifies additional toxic mechanisms that may explain ongoing lung injury reports even after VEA awareness increased.","specificNumbers":"Multiple mechanisms of lung toxicity identified: inflammatory responses, oxidative stress, heavy metal contamination, flavoring agent damage. Cannabinoid quinones (CBDQ) form covalent adducts with protein cysteine residues. EVALI cases continue to be reported despite VEA awareness.","methodology":"Narrative review examining the regulatory landscape, manufacturing practices, composition, and toxicological mechanisms of hemp-derived cannabinoid vaping products, with focus on emerging evidence about cannabinoid quinone formation.","limitations":"Narrative review without systematic search methodology. Many cited studies are preclinical. Chronic exposure data in humans is limited. The relative contribution of different toxic mechanisms is unclear."},{"rthcId":"RTHC-06988","title":"Budtender Perceptions and Knowledge of Cannabis and Mental Health: A Preliminary Study.","authors":"Lowe, Darby J E; Wang, Cindy; Rueda, Sergio; George, Tony P","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(2), 164-176","doi":"10.26828/cannabis/2025/000292","pmid":"40909147","tags":["legalization","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Budtender perceptions of cannabis and mental health varied by symptom and often diverged from evidence. 54.6% rated cannabis as beneficial overall, with sleep and depression most frequently perceived as beneficial. Customers asked about mental health effects at 21% of visits. Knowledge sources varied considerably, lacking standardization.","whyItMatters":"Budtenders are a primary information source for cannabis consumers, but this study reveals significant gaps between their perceptions and scientific evidence. Given that 1 in 5 customer visits involve mental health questions, these gaps could influence vulnerable consumers.","specificNumbers":"46 budtenders surveyed. 54.6% rated cannabis as beneficial for mental health. Sleep and depression most frequently perceived as beneficial. 21% of customer visits included mental health questions. Considerable variability in knowledge sources.","methodology":"Cross-sectional survey of 46 budtenders from Ontario Cannabis Stores across the Greater Toronto Area, Canada. Assessed perceptions, education, and customer interactions regarding cannabis and mental health.","limitations":"Small sample (46) from one geographic area. Self-reported perceptions may differ from actual advice given. Cross-sectional design. Ontario Cannabis Stores may differ from other retail models."},{"rthcId":"RTHC-06989","title":"Neighborhood Sociodemographic Correlates of Cannabis Dispensary Availability in States with Legalized Adult Recreational Use, United States, 2021.","authors":"Lowery, Bryce C; Swayne, Madison R E; Kong, Amanda Y","year":2025,"journal":"Cannabis and cannabinoid research, 10(6), 739-745","doi":"10.1089/can.2024.0065","pmid":"40098535","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Census tracts with the highest percentage of Black residents had 2.07 times the odds of having a dispensary compared to those with the lowest. Similar patterns emerged for Hispanic/Latine residents and poverty levels. In contrast, areas with the most homeowner-occupied housing had only 0.21 times the odds of having a dispensary. These patterns held across all 18 states analyzed.","whyItMatters":"Cannabis legalization was partly intended to address racial disparities from prohibition. This finding that dispensaries cluster in minority and low-income neighborhoods raises questions about whether the commercial cannabis market is replicating rather than correcting existing inequities.","specificNumbers":"3,167 dispensaries across 18 states. Highest vs lowest Black population quintile: OR=2.07 (95% CI: 1.70-2.52). Highest vs lowest homeownership quintile: OR=0.21 (95% CI: 0.17-0.26). Similar patterns for Hispanic/Latine population and poverty levels.","methodology":"National analysis using dispensary locations from Weedmaps (November 2021, N=3,167) merged with US Census sociodemographic data for 18 states with legal recreational cannabis. Census tracts were categorized into quintiles, and generalized linear mixed models examined associations with dispensary presence.","limitations":"Weedmaps may not capture all dispensaries. Cross-sectional November 2021 snapshot may not reflect current distribution. Census tract-level analysis cannot capture within-tract variation. Does not measure whether dispensary proximity affects use patterns."},{"rthcId":"RTHC-06990","title":"Cannabis Laws and Opioid Use Among Commercially Insured Patients With Cancer Diagnoses.","authors":"Lozano-Rojas, Felipe; Bethel, Victoria; Gupta, Sumedha; Steuart, Shelby R; Bradford, W David; Abraham, Amanda J","year":2025,"journal":"JAMA health forum, 6(10), e253512","doi":"10.1001/jamahealthforum.2025.3512","pmid":"41105418","tags":["medical-cannabis","pain","cancer","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Medical cannabis dispensary openings were associated with a reduction of 41 fewer patients per 10,000 with opioid prescriptions, 2.54 fewer days of supply per prescription, and 0.099 fewer prescriptions per patient. Recreational dispensary openings showed smaller but still significant reductions. The association was consistent across age, race/ethnicity, and sex subgroups.","whyItMatters":"Cancer pain is a major driver of opioid prescribing, and the opioid crisis has highlighted the need for alternatives. This large-scale study from JAMA Health Forum provides some of the strongest evidence to date that cannabis access may reduce opioid reliance in this population.","specificNumbers":"Mean 3.05 million patients annually. Medical dispensary effect: -41.07 per 10,000 patients with prescriptions (p<0.001), -2.54 days supply (p<0.001), -0.099 prescriptions/patient (p<0.001). Recreational dispensary effect: -20.63 per 10,000 (p=0.049), -1.09 days (p=0.04), -0.097 prescriptions/patient (p=0.01).","methodology":"Cross-sectional study using Optum's Clinformatics Data Mart (2007-2020) with a synthetic control method to estimate the association of state-level cannabis dispensary openings with opioid dispensing among commercially insured cancer patients aged 18-64. Published in JAMA Health Forum.","limitations":"Observational design cannot prove cannabis caused the reduction. Uses insurance claims data, which may not capture all opioid or cannabis use. Commercially insured population may differ from uninsured or Medicaid populations. Cannot determine if cannabis is actually effective for cancer pain."},{"rthcId":"RTHC-06991","title":"Chronic cannabidiol administration modulates depressive and cognitive alterations induced by social isolation in male mice.","authors":"Lucindo, Marcel S S; Albuquerque, Ana L S; Pereira, Kenzawin A; Salgado, Karen Del Carmen Barboza; Oliveira, Laser A M; Engel, Daiane F; Nogueira, Katiane O P C","year":2025,"journal":"Behavioural brain research, 480, 115408","doi":"10.1016/j.bbr.2024.115408","pmid":"39725273","tags":["cbd","depression","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD mitigated anhedonia (loss of pleasure) and reduced immobility in the tail suspension test in socially isolated mice. CBD also protected recognition memory that was impaired by isolation. However, CBD did not have anxiolytic effects and unexpectedly increased anxiety-like behavior in group-housed (non-stressed) mice. Social isolation reduced hippocampal BDNF expression, while CBD preserved it in isolated mice.","whyItMatters":"Social isolation is a major contributor to depression and cognitive decline. This study shows CBD has specific antidepressant and neuroprotective effects in an isolation model, though its anxiogenic effects in non-stressed animals highlight the context-dependent nature of CBD's actions.","specificNumbers":"CBD mitigated anhedonia in isolated mice (sucrose preference test). Reduced immobility episodes in tail suspension test. Protected recognition memory impaired by isolation. Increased anxiety-like behavior in group-housed mice. BDNF expression: reduced by isolation, preserved by CBD treatment.","methodology":"Adult C57BL/6 male mice were subjected to 12 weeks of social isolation or group housing with chronic CBD administration. Behavioral tests included sucrose preference, open field, light/dark box, novel object recognition, and tail suspension. Hippocampal gene expression for CB1R, 5HT1AR, and BDNF were analyzed.","limitations":"Male mice only. One dose of CBD tested. Social isolation model does not fully replicate human depression. 12-week isolation is extreme. The anxiogenic effect in non-stressed mice needs replication and mechanistic investigation."},{"rthcId":"RTHC-06992","title":"Benefits and Burdens of Vaporized Botanical Cannabis Flower Bud for Cancer-Related Anorexia: A Qualitative Study of the Experiences of People with Advanced Cancer Enrolled as Inpatients in a Phase I/IIb Clinical Trial and Their Family Carers.","authors":"Luckett, Tim; Razmovski-Naumovski, Valentina; Garcia, Maja; Phillips, Jane; Chye, Richard; Noble, Beverley; Fazekas, Belinda; Martin, Jennifer; Agar, Meera","year":2025,"journal":"Journal of palliative medicine, 28(9), 1246-1250","doi":"10.1177/10966218251372439","pmid":"40865547","tags":["appetite","cancer","medical-cannabis"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"This qualitative study interviewed 10 advanced cancer patients enrolled in a Phase I/IIb clinical trial of vaporized cannabis flower for cancer-related anorexia, along with 6 of their family carers.\n\nAll patients perceived benefits to eating, though the mechanism varied. Most described appetite stimulation directly, but two attributed the benefit to reduced nausea rather than increased hunger—an important distinction suggesting cannabis may help with eating through multiple pathways.\n\nThe psychoactive effects are particularly noteworthy. Rather than being a problem, patients generally tolerated the \"high\" well, and some actively enjoyed it. For people with advanced cancer facing existential distress, this isn't surprising—mild euphoria may itself be therapeutic in palliative care. This contrasts with the typical clinical framing of psychoactivity as purely an adverse effect.\n\nAn interesting observer effect emerged: carers sometimes perceived more eating benefit than patients themselves did. This could reflect carers' wishful thinking or their ability to notice changes in eating patterns that patients didn't recognize.\n\nThe downsides were relatively minor and transient: throat irritation from vaporizing, and complaints about taste and smell. These are practical issues that might steer some patients toward other cannabis formulations (oils, edibles) rather than away from cannabis entirely.","whyItMatters":"Clinical trials measure outcomes with scales and numbers, but this qualitative work captures what the experience is actually like for patients. The finding that psychoactive effects were welcomed rather than feared challenges assumptions about how cannabis should be dosed in palliative care (many protocols aim to minimize psychoactivity). The carer perspective also matters—family members' perceptions of benefit influence whether patients continue treatment.","specificNumbers":"10 of 12 trial participants interviewed, plus 6 carers. All perceived eating benefits. 2 attributed benefit to nausea reduction rather than appetite stimulation. Psychoactive effects well-tolerated. Throat irritation was the main complaint.","methodology":"Qualitative study using face-to-face semi-structured interviews with 10 of 12 advanced cancer trial participants and 6 carers. Analysis used the framework method. Setting: inpatient specialist palliative care. Patients were enrolled in a Phase I/IIb clinical trial of vaporized medicinal cannabis flower bud.","limitations":"Very small sample (10 patients, 6 carers) from a single palliative care setting. Qualitative design can't determine whether perceived benefits reflect actual physiological changes. Participants knew they were receiving cannabis (not blinded), which introduces expectation effects. Inpatient setting may not reflect home use experiences."},{"rthcId":"RTHC-06993","title":"Childhood trauma associations with changes in body mass index over 12 months of treatment in first-episode schizophrenia spectrum disorders.","authors":"Luckhoff, H K; Smit, A M; Phahladira, L; Kilian, S; Emsley, R; Asmal, L","year":2025,"journal":"Schizophrenia research, 281, 52-59","doi":"10.1016/j.schres.2025.04.031","pmid":"40318310","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06994","title":"Cannabis in road traffic - a retrospective analysis to identify possible cut-off-values.","authors":"Ludwig, A; Küpper, U; Lau, M; Holzer, A; Wulff, T; Hartung, B","year":2025,"journal":"Forensic science, medicine, and pathology","doi":"10.1007/s12024-025-01133-1","pmid":"41247612","tags":["driving","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"THC serum concentrations were slightly but significantly higher in cases with criminal driving offenses compared to those without, but the absolute differences were small with too much overlap between groups to define a useful cut-off. Under Germany's new 3.5 ng/mL threshold (raised from 1 ng/mL), approximately one-third of evaluated cases would no longer be subject to legal penalties.","whyItMatters":"Germany recently raised its legal THC driving threshold from 1 to 3.5 ng/mL. This study examines whether any specific blood THC level reliably indicates impairment, with implications for driving laws worldwide.","specificNumbers":"740 cases analyzed. Slightly higher THC and CIF values in cases with criminal offenses (statistically significant but small absolute differences). Too much overlap between impaired and non-impaired groups for a useful cut-off. ~33% of cases would no longer face penalties under the new 3.5 ng/mL threshold.","methodology":"Retrospective analysis of 740 cases from 2020-2021 where blood samples were submitted for toxicological analysis from drivers suspected of driving under the influence of cannabis alone (DUIC) or combined with alcohol (DUIAC). Evaluated behavioral and driving impairments against THC serum concentrations and cannabis influence factor (CIF) values.","limitations":"Retrospective design relies on police assessment of impairment, which is subjective. Only cases where police suspected cannabis involvement were included, creating selection bias. 2020-2021 data may not represent current patterns."},{"rthcId":"RTHC-06995","title":"Reframing type 1 diabetes through the endocannabinoidome-microbiota axis: a systems biology perspective.","authors":"Łukowski, Wojciech","year":2025,"journal":"Frontiers in endocrinology, 16, 1576419","doi":"10.3389/fendo.2025.1576419","pmid":"40510476","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06996","title":"Pharmaco-toxicological effects of the synthetic cannabinoids 4F-ABUTINACA, SDB-005, and JWH-018 in mice. In vitro and in vivo studies.","authors":"Luo, Xuwen; Kuai, Lixin; Shi, Xuesong; Qiao, Yanling; Li, Kaixi; Xu, Deli; Di, Bin; Yan, Fang; Xu, Peng","year":2025,"journal":"European journal of pharmacology, 996, 177586","doi":"10.1016/j.ejphar.2025.177586","pmid":"40180269","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06997","title":"Toxicological effects of ADB-FUBINACA on early zebrafish development: An analysis utilizing metabolomics.","authors":"Luo, Yang; Ying, LinRong; Liu, YiZhou; Fan, YiLei; Wang, Kai; Lan, YanFei; Chian, Song","year":2025,"journal":"Ecotoxicology and environmental safety, 303, 118782","doi":"10.1016/j.ecoenv.2025.118782","pmid":"40763518","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-06998","title":"National Multicenter Cohort Study: Adjunctive Cannabidiol-Enriched Cannabis Oil for Pediatric Drug-Resistant Epilepsy Treatment in Thailand.","authors":"Lusawat, Apasri; Khongkhatithum, Chaiyos; Suwannachote, Sirorat; Katanyuwong, Kamornwan; Fangsa-Ad, Thitiporn; Anurat, Kingthong; Pattharathitikul, Siriporn; Thongmak, Tipaporn; Thewamit, Rapeepat; Sudachan, Panisra; Rojanawatsirivej, Apimid; Thampratankul, Lunliya; Sattaporn, Chanikhan; Bunyatumma, Puangtong; Auvichayapat, Narong; Laohasaran, Salin; Anuroj, Krittawit; Kontun, Sineenart; Cheawcharnprapan, Krit; Paticheep, Sudathip; Paibool, Watuhatai; Thirapote, Pat; Sanguansermsri, Chinnuwat; Suwanpakdee, Piradee; Woravimolvanich, Ornpreeya; Watcharakuldilok, Piangor; Visudtibhan, Anannit","year":2025,"journal":"Pediatric neurology, 169, 59-68","doi":"10.1016/j.pediatrneurol.2025.04.015","pmid":"40460512","tags":["epilepsy","cbd","medical-cannabis","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 101 pediatric patients who had failed an average of 7 antiseizure medications, CBD-enriched oil at a median dose of 6 mg/kg/day produced consistent improvements in 50%+ seizure reduction rates at 3, 6, 9, 12 months and latest follow-up. Most seizure types responded positively except complex motor seizures. While 92% experienced adverse events, 95% were mild (somnolence, elevated liver enzymes, anorexia, irritability).","whyItMatters":"This is the first multicenter evidence for CBD-enriched oil in pediatric epilepsy from Thailand, demonstrating that medical-grade CBD products developed outside Western pharmaceutical markets can be effective and tolerable for treatment-resistant cases.","specificNumbers":"101 patients, 42% male, median age 10 years. Median seizure frequency: 75/month at baseline. Failed average of 7 antiseizure medications. Median CBD dose: 6 mg/kg/day (range 1-15). Median follow-up: 15 months. Adverse events in 92%, mild in 95%. 33 discontinued (57% intolerable adverse events, 30% ineffectiveness, 12% noncompliance).","methodology":"Prospective observational study across 19 Thai government hospitals (2021-2023). Enrolled 101 pediatric patients with drug-resistant epilepsy of various etiologies. Median follow-up: 15 months. Assessed seizure reduction, adverse events, and treatment discontinuation.","limitations":"No randomized control group. Open-label design means placebo effects cannot be excluded. Variable etiologies make interpretation complex. 33 of 101 discontinued treatment. Adverse event rate was high (92%), though most were mild."},{"rthcId":"RTHC-06999","title":"Comparing the prevalence of substance use disorders between persons with and without autism spectrum disorders.","authors":"Lushin, Victor; Marcus, Steven; Tao, Sha; Engstrom, Malitta; Roux, Anne; Shea, Lindsay","year":2025,"journal":"Autism : the international journal of research and practice, 29(7), 1674-1687","doi":"10.1177/13623613251325282","pmid":"40156509","tags":["addiction","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"By 2016, 7% of Medicaid beneficiaries with autism and no intellectual disability had at least one substance use disorder diagnosis, up from 1.75% in 2012 data. Adults with autism aged 30-64 were at elevated risk for cannabis and hallucinogen use disorders. Co-occurring mental health conditions (affecting 50% of autistic individuals vs 23% of non-autistic) likely compounded this risk.","whyItMatters":"Autistic adults are an underrecognized population at risk for substance use disorders. The rapid increase in SUD prevalence and the specific elevation of cannabis disorders in this group highlights a gap in both clinical awareness and intervention development.","specificNumbers":"388,426 autistic enrollees vs 745,699 non-autistic. SUD prevalence in autism (no ID): 1.75% in 2012 to 7% in 2016 (4x increase). Ages 30-64: elevated cannabis and hallucinogen disorder risk. 50% of autistic individuals had co-occurring mental health conditions vs 23% of non-autistic.","methodology":"Retrospective analysis of national Medicaid Claims data comparing substance use disorder prevalence among enrollees with autism (N=388,426) versus a random sample without autism (n=745,699). Examined associations by sex, age, co-occurring mental health conditions, and community-level social determinants.","limitations":"Medicaid claims may undercount substance use disorders. Rising prevalence could partly reflect better diagnostic coding rather than true increases. Cannot determine causation. Autistic individuals with intellectual disability were analyzed separately."},{"rthcId":"RTHC-07000","title":"Orally consumed cannabinoids: the effect of carrier oil on acute tissue distribution in male C57BL/6 mice.","authors":"Lust, Cody A C; Hillyer, Lyn M; Pallister, Mitchell; Wright, Amanda J; Rogers, Michael A; Rock, Erin M; Limebeer, Cheryl L; Parker, Linda A; Ma, David W L","year":2025,"journal":"Journal of cannabis research, 7(1), 38","doi":"10.1186/s42238-025-00298-4","pmid":"40597281","tags":["cbd","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Sesame oil resulted in significantly higher concentrations of both CBD and THC across all tissues and timepoints compared to EPA/DHA omega-3 oils. Different carrier oils also affected tissue distribution: DHA-enriched oil delivered more CBD to the brain than the mixed EPA/DHA oil. Heart tissue had the highest CBD concentration at 1-2 hours, shifting to adipose tissue by 3 hours, consistent across all carriers.","whyItMatters":"The carrier oil in cannabis products is rarely discussed but can dramatically affect how much cannabinoid actually reaches target tissues. This has practical implications for anyone taking oral CBD or THC products for specific conditions.","specificNumbers":"Sesame oil: significantly higher CBD and THC across all 6 tissues at all 3 timepoints (p<0.05). DHA oil: more CBD to brain than mixed EPA/DHA. Heart had highest CBD at 1-2 hours; adipose highest at 3 hours. 6 tissues profiled: serum, adipose, brain, liver, heart, muscle. Most tissues profiled to date for acute oral cannabinoid distribution.","methodology":"Male C57BL/6 mice were gavaged with CBD (5 mg/kg) and THC (1 mg/kg) combined with sesame, mixed EPA/DHA, or DHA-enriched oil. Cannabinoid concentrations were measured in serum, adipose, brain, liver, heart, and muscle at 1, 2, and 3 hours using liquid chromatography-tandem mass spectrometry.","limitations":"Mouse model with single oral dose. Only three carrier oils tested. 3-hour timeframe captures acute distribution only. Male mice only. Doses (5 mg/kg CBD, 1 mg/kg THC) may not translate directly to human dosing. Different oils have different fatty acid compositions beyond EPA/DHA content."},{"rthcId":"RTHC-07001","title":"Should CBD be used for migraine?","authors":"Luu, Brent; Goldin, Philippe; Rice, Elizabeth","year":2025,"journal":"JAAPA : official journal of the American Academy of Physician Assistants, 38(8), 32-37","doi":"10.1097/01.JAA.0000000000000234","pmid":"40729106","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07002","title":"Selective Personality-Targeted Intervention and the Escalation of Substance Use During Adolescence: A Secondary Analysis of A Cluster-Randomized Clinical Trial.","authors":"Lynch, Samantha J; Stewart, Sherry H; Conrod, Patricia","year":2025,"journal":"JAMA network open, 8(12), e2550176","doi":"10.1001/jamanetworkopen.2025.50176","pmid":"41632121","tags":["youth","quitting","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Students receiving PreVenture, a brief personality-targeted cognitive-behavioral intervention, showed slower increases in cannabis use (OR=0.75), tobacco smoking (OR=0.79), alcohol use (OR=0.92), and illicit polysubstance use (OR=0.56) over 4 years compared to controls. Effects did not differ by sex. The cannabis reduction was among the strongest effects observed.","whyItMatters":"Most substance prevention programs are universal and have modest effects. This study shows that targeting the specific personality traits that drive substance use in at-risk teens can produce meaningful reductions across multiple substances, including cannabis, with just two sessions.","specificNumbers":"1,669 at-risk students (50.7% female, mean age 12.83). 31 schools randomized. Over 4 years: cannabis OR=0.75 (95% CrI: 0.66-0.86), tobacco OR=0.79 (0.70-0.96), alcohol OR=0.92 (0.85-1.00), polysubstance OR=0.56 (0.35-0.89). Effects similar for males and females.","methodology":"Pre-specified secondary analysis of a cluster-randomized clinical trial. 1,669 at-risk grade 7 students from 31 Montreal-area secondary schools were randomized by school to receive PreVenture (15 schools, 705 students) or control (16 schools, 964 students). At-risk status was defined by elevated anxiety sensitivity, hopelessness, impulsivity, or sensation seeking. Published in JAMA Network Open.","limitations":"Secondary analysis of a trial not primarily designed for cannabis outcomes. Montreal-area sample may not generalize to all populations. Cluster randomization by school introduces potential confounding. Self-reported substance use. Bayesian analysis framework differs from traditional frequentist approaches."},{"rthcId":"RTHC-07003","title":"The Endocannabinoid System in PTSD: Molecular Targets for Modulating Fear and Anxiety.","authors":"Lyndon, Stanley","year":2025,"journal":"Pharmacopsychiatry","doi":"10.1055/a-2647-8030","pmid":"40789309","tags":["ptsd","neuroscience","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system plays a pivotal role in regulating fear learning and extinction. People with severe PTSD show altered anandamide levels and CB1 receptor upregulation. Preclinical studies show CB1 agonists, FAAH inhibitors, and THC/CBD can facilitate fear extinction. Nabilone alleviates trauma nightmares in preliminary human trials. However, self-medication with cannabis carries risk of dependence and potential symptom worsening.","whyItMatters":"Current PTSD medications help only some patients and carry significant side effects. The endocannabinoid system represents a novel therapeutic target that could work through a fundamentally different mechanism than existing treatments.","specificNumbers":"Review covers CB1, CB2, FAAH, and MAGL as molecular targets. Nabilone shown to alleviate trauma nightmares. Acute cannabinoid administration modulates amygdala reactivity. Optimal THC:CBD ratios and sex-specific responses remain undefined.","methodology":"Narrative review synthesizing preclinical and clinical evidence on the endocannabinoid system in PTSD, focusing on molecular targets including CB1, CB2, FAAH, and MAGL.","limitations":"Narrative review format. Most evidence is preclinical. Human trial data is preliminary. Self-medication with cannabis can worsen symptoms and lead to dependence. Optimal dosing, sex differences, and long-term safety data are lacking."},{"rthcId":"RTHC-07004","title":"Suicidal Ideation in Medicinal Cannabis Patients: A 12-Month Prospective Study.","authors":"Lynskey, M T; Thurgur, H; Athanasiou-Fragkouli, A; Schlag, A K; Nutt, D J","year":2025,"journal":"Archives of suicide research : official journal of the International Academy for Suicide Research, 29(2), 407-421","doi":"10.1080/13811118.2024.2356615","pmid":"39045855","tags":["mental-health","medical-cannabis","depression"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"At treatment entry, 25% of patients reported suicidal ideation. Those with SI had significantly higher depression scores (17.4 vs 11.3), lower well-being, and lower quality of life. After 3 months of cannabis-based medicinal product treatment, suicidal ideation significantly decreased. Over 12 months, depression scores dropped substantially in those with initial SI (17.7 to 10.3) and in other patients (11.1 to 7.0).","whyItMatters":"Medical cannabis patients have high rates of mental health comorbidities, and suicidal ideation in this population is underrecognized. The finding that SI decreased with treatment is important, though the observational design means this could reflect regression to the mean or other factors.","specificNumbers":"3,781 patients at entry, 25% with SI. SI group depression score: 17.4 vs 11.3 (p<0.001). SI decreased significantly at 3 months (z=6.5, p<0.001). 12-month depression change: SI group 17.7 to 10.3; others 11.1 to 7.0. Follow-up: 2,112 at 3 months, 777 at 12 months.","methodology":"Prospective observational study of 3,781 patients at treatment entry, with follow-up data for 2,112 at 3 months and 777 at 12 months. Suicidal ideation and depression assessed using PHQ-9 items. Additional data on demographics and well-being.","limitations":"Observational with no control group. Large dropout from 3,781 to 777 over 12 months introduces selection bias. Self-reported SI may be underreported. Cannot determine whether cannabis treatment caused improvement. PHQ-9 is a screening tool, not a diagnostic assessment."},{"rthcId":"RTHC-07005","title":"Efficacy of a 20:1 CBD:THC cannabis herbal extract for pain and inflammation in dogs following tibial plateau leveling osteotomy.","authors":"Lyons, Chloe; Pinto, K Romany; Penney, Kira; Holmes, Laura; Salama, Abdul; Alcorn, Jane; Chicoine, Alan","year":2025,"journal":"Frontiers in veterinary science, 12, 1676779","doi":"10.3389/fvets.2025.1676779","pmid":"41090077","tags":["cbd","pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"There were no significant differences in pain scores, range of motion, thigh circumference, or gait symmetry between dogs receiving CBD:THC extract and those receiving placebo, when both groups also received standard analgesics. Minor benefits from the higher dose appeared only on day 1 and did not persist. No serious adverse events occurred.","whyItMatters":"Pet owners increasingly give CBD products to dogs for pain, often based on anecdotal reports. This controlled trial found that when added to standard pain management, CBD did not provide additional benefit for post-surgical pain.","specificNumbers":"48 dogs enrolled, 42 completed. Three groups: placebo, 2 mg CBD/kg, 5 mg CBD/kg (20:1 CBD:THC). Glasgow pain scores, range of motion, gait symmetry assessed. No significant group differences. Plasma cannabinoid levels were highly variable. Mild GI effects in 7 cases.","methodology":"Randomized, double-blinded, placebo-controlled trial of 48 dogs (42 completers) undergoing TPLO knee surgery. Three groups: placebo, low CBD (2 mg/kg), and high CBD (5 mg/kg) with a 20:1 CBD:THC ratio. All dogs received standard analgesics. Assessments at days 1 and 14 post-surgery. Published in Frontiers in Veterinary Science.","limitations":"Small sample size per group. Only one CBD:THC ratio tested. Standard analgesic protocol was comprehensive, possibly leaving little room for additional improvement. 14-day follow-up only. Variable plasma cannabinoid levels suggest inconsistent absorption."},{"rthcId":"RTHC-07006","title":"Cannabidiol ameliorates seizures and neuronal damage in ferric chloride-induced posttraumatic epilepsy by targeting TRPV1 channel.","authors":"Ma, Lin; Gao, Yuan; Chen, Juan; Hai, Dongmei; Yu, Jianqiang; Tang, Shengsong; Liu, Ning; Liu, Yue","year":2025,"journal":"Journal of ethnopharmacology, 351, 120072","doi":"10.1016/j.jep.2025.120072","pmid":"40449694","tags":["epilepsy","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD reduced seizure severity, decreased EEG amplitude and total power, and lowered spike wave discharges in a ferric chloride-induced post-traumatic epilepsy model. The mechanism involved CBD suppressing HSF1 phosphorylation by targeting TRPV1, which specifically inhibited stress-induced HSP70 increases. This was confirmed using brain-localized TRPV1 overexpression rats.","whyItMatters":"Post-traumatic epilepsy is a common consequence of traumatic brain injury with limited treatment options. This study identifies a specific molecular pathway (TRPV1/HSF1/HSP70) through which CBD may prevent seizures after brain injury, potentially informing preventive treatment strategies.","specificNumbers":"CBD significantly reduced seizure severity scores. EEG showed decreased amplitude, total power, and spike wave discharges. CBD suppressed HSF1 phosphorylation via TRPV1. HSP70 increase was specifically inhibited in TRPV1-overexpression rats.","methodology":"Ferric chloride-induced post-traumatic epilepsy rat models in both normal rats and brain-localized TRPV1 overexpression rats. Seizure severity assessed by behavioral scoring and EEG. Neuroprotection assessed by histopathological staining. Mechanisms explored via immunofluorescence, Western blot, qPCR, and calcium imaging.","limitations":"Animal model using ferric chloride, which does not perfectly replicate human TBI. Single CBD dose tested. Short-term assessment. The TRPV1 pathway is one of many through which CBD may act."},{"rthcId":"RTHC-07007","title":"The Causal Effect of Social Isolation on Cannabis Use Disorder and the Mediating Role of Depression: Evidence From a Mendelian Randomization Study.","authors":"Ma, Tao","year":2025,"journal":"Brain and behavior, 15(12), e71102","doi":"10.1002/brb3.71102","pmid":"41305857","tags":["addiction","depression","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Mendelian randomization analysis showed social isolation was causally associated with a 4.29-fold increased risk of cannabis use disorder (OR=4.29, 95% CI: 1.35-13.64). Social isolation also significantly increased depression risk (OR=3.70), and depression in turn increased CUD risk (OR=1.27). Depression mediated 21.8% of the social isolation to CUD pathway.","whyItMatters":"While observational studies have linked loneliness to substance use, this genetic approach provides stronger evidence for a causal relationship. The finding that depression mediates over one-fifth of the effect suggests treating depression in socially isolated individuals could help prevent cannabis use disorder.","specificNumbers":"Social isolation to CUD: OR=4.29 (p=0.014). Social isolation to depression: OR=3.70 (p=3.67E-08). Depression to CUD: OR=1.27 (p=0.003). Depression mediated 21.8% of the total effect. Anxiety disorders were not a significant mediator.","methodology":"Two-sample Mendelian randomization using GWAS summary statistics for social isolation, cannabis use disorder, anxiety disorders, and depression from public repositories. Multiple MR methods (IVW, MR-Egger, weighted median, maximum likelihood) with extensive sensitivity analyses.","limitations":"European ancestry samples only. Mendelian randomization assumes no horizontal pleiotropy (tested but not guaranteed). Summary-level data cannot assess exposure-mediator interactions. Cannabis use disorder definitions may vary across GWAS sources. Effect sizes have wide confidence intervals."},{"rthcId":"RTHC-07008","title":"Involvement of endocannabinoid receptor 1 in oxidative and inflammatory responses underlying anxiety-like behavior in SPS&S-exposed mice.","authors":"Ma, Xinxu; Chen, Haixia; Xu, Feifei; Xue, Shanshan; Zhou, Cuihong; Zhang, Yaochi; Zhang, Yuyu; Lv, Runxin; Liu, Nian; Meng, Yumeng; Peng, Zhengwu; Zhao, Guangchao; Lu, Zhihong; Cai, Min","year":2025,"journal":"European journal of pharmacology, 1005, 178060","doi":"10.1016/j.ejphar.2025.178060","pmid":"40818654","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07009","title":"Chromatin accessibility directly governs flavonoid biosynthesis and indirectly orchestrates cannabinoid production in Cannabis.","authors":"Ma, Yuanchang; Wei, Xiuye; Zhou, Weixin; Xie, An; Chen, Yongzhong; Yang, Chen; Chen, Lingcheng; Dong, Linlin; Ning, Kang","year":2025,"journal":"Frontiers in plant science, 16, 1687700","doi":"10.3389/fpls.2025.1687700","pmid":"41635698","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07010","title":"Controlled in vitro release of CBD from oleosomes via modulation of their membrane density.","authors":"Ma, Zhaoxiang; Capuano, Edoardo; Bitter, Johannes H; Boom, Remko M; Nikiforidis, Constantinos V","year":2025,"journal":"Food & function, 16(16), 6369-6377","doi":"10.1039/d4fo04171b","pmid":"40488616","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07011","title":"Collection of Δ9-tetrahydrocannabinol from breath by liquid secondary adsorption analyzed with mass spectrometry: a technical note.","authors":"Määttä, Mikko; Fraccarolli, Pedro; Boock, Jared; Attariwala, Raj","year":2025,"journal":"Journal of breath research, 19(2)","doi":"10.1088/1752-7163/adc7d1","pmid":"40169007","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07012","title":"Mode Matters: Investigating the Associations Between Mode of Cannabis Use and Self-Reported Physical and Psychological Effects.","authors":"MacDonald-Spracklin, Rachael; DeWolf, Darien; Thompson, Kara","year":2025,"journal":"Substance use & misuse, 60(14), 2244-2253","doi":"10.1080/10826084.2025.2538733","pmid":"40750728","tags":["harm-reduction","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Bong use predicted significantly more physical and psychological health effects than other methods. Joint use was associated with more physical effects in males and more psychological effects in females. Edible use predicted fewer physical effects in females. Hand pipe use predicted more psychological effects in females. Effects varied significantly by both mode of use and sex.","whyItMatters":"As cannabis products diversify, understanding how different consumption methods affect users differently, and how those effects vary by sex, is essential for harm reduction messaging and clinical guidance.","specificNumbers":"206 participants (62% female), 14-day EMA. Bongs: significantly more physical and psychological effects. Joints: more physical effects (males), more psychological effects (females). Edibles: fewer physical effects (females). Hand pipes: more psychological effects (females).","methodology":"Ecological momentary assessment with 206 young adult post-secondary students (62% female) who regularly used cannabis. Participants completed two daily surveys on their phones for 14 days, reporting details of their most recent cannabis use and associated effects. Multilevel modeling analyzed mode-effect relationships.","limitations":"Self-reported effects and consumption details. 14-day study period may not capture all patterns. Post-secondary students may not represent all young adult users. Could not control for dose across methods. EMA completion rates may vary."},{"rthcId":"RTHC-07013","title":"Acute cannabidiol (CBD), tetrahydrocannabinol (THC) and their mixture (THC:CBD) exert differential effects on brain activity and blood flow in rats: A translational neuroimaging study.","authors":"MacNicol, Eilidh; Kokkinou, Michelle; Serrano Navacerrada, Maria Elisa; Smith, Donna-Michelle; Li, Jennifer; Simmons, Camilla; Kim, Eugene; Mesquita, Michel; Rojo Gonzalez, Loreto; Andrews, Tierney; Loomis, Sally; Gray, Royston A; Knappertz, Volker; Whalley, Benjamin J; McCreary, Andrew C; Williams, Steven Cr; Virley, David; Cash, Diana","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 2698811251360745","doi":"10.1177/02698811251360745","pmid":"40838351","tags":["neuroscience","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC increased whole-brain functional connectivity and clustering coefficient, with elevated blood flow in cortical and subcortical regions. CBD decreased connectivity metrics without affecting blood flow. The THC:CBD combination induced moderate increases in both. THC specifically increased cortical-hippocampal and cortical-striatal connectivity, which was attenuated when CBD was combined.","whyItMatters":"This is one of the first studies to directly compare THC, CBD, and their combination on brain activity using multimodal neuroimaging. The finding that CBD moderates THC-induced brain changes provides a biological basis for why different THC:CBD ratios produce different experiences.","specificNumbers":"THC: increased whole-brain FC and clustering coefficient. CBD: decreased FC without affecting CBF. THC:CBD: moderate increases in both. THC doses: 10 mg/kg. CBD: 150 mg/kg. Brain imaging at ~2 hours post-dose.","methodology":"Adult male Sprague Dawley rats received intraperitoneal doses of THC (10 mg/kg), CBD (150 mg/kg), THC:CBD combination (10.8:10 mg/kg), or vehicle. Resting-state BOLD MRI and arterial spin labeling assessed functional connectivity and cerebral blood flow approximately 2 hours after administration.","limitations":"Rat model with doses that may not translate directly to humans. Single timepoint imaging. Male rats only. Intraperitoneal injection does not model typical human consumption. One THC:CBD ratio tested."},{"rthcId":"RTHC-07014","title":"FAAH and MAGL inhibition: Evolving approaches to treating substance use disorders.","authors":"Maddox, Charlie J; Lee, Francis S; Rajadhyaksha, Anjali M; Martínez-Rivera, Arlene","year":2025,"journal":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, e00814","doi":"10.1016/j.neurot.2025.e00814","pmid":"41350173","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07015","title":"Metabolomic profiling of cannabis use and cannabis intoxication in humans.","authors":"Madrid-Gambin, Francisco; Haro, Noemí; Mason, Natasha L; Mallaroni, Pablo; Theunissen, Eef L; Toennes, Stefan W; Pozo, Oscar J; Ramaekers, Johannes G","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(6), 920-927","doi":"10.1038/s41386-025-02082-7","pmid":"40074870","tags":["driving","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Occasional and chronic cannabis users had distinctly different metabolic fingerprints at baseline (not intoxicated). 14 metabolites, mainly from endocannabinoid and amino acid metabolism, distinguished chronic from occasional users with 80% classification accuracy. During acute intoxication, only occasional users (who showed actual cognitive impairment) had distinct metabolomic changes including increases in organic acids, beta-hydroxybutyrate, and ceramides.","whyItMatters":"Current drug tests can only confirm cannabis use, not impairment. This study demonstrates that metabolomics could potentially identify the state of actual cognitive impairment, which would be far more useful for driving law enforcement and clinical assessment.","specificNumbers":"35 participants (occasional and chronic users). 14 distinguishing metabolites identified. 80% classification rate (95% CI: 61-91%) for chronic vs occasional users. Distinct intoxication metabolites found only in occasional users who showed actual impairment.","methodology":"Placebo-controlled study with 35 occasional and chronic cannabis users who received cannabis (300 microg/kg THC) and placebo. Blood samples collected at baseline and repeatedly over 70 minutes. Sustained attention and subjective high assessed. Metabolomic fingerprinting via mass spectrometry.","limitations":"Small sample (35). Only one THC dose tested. 70-minute post-treatment window may not capture all metabolic changes. Metabolomics approach requires specialized equipment not available in field settings. Needs validation in larger, more diverse samples."},{"rthcId":"RTHC-07016","title":"Recommendations From Arizona Budtenders to Mystery Callers Regarding Morning Sickness.","authors":"Madson, Michael J; Srivastava, Unnati; Gade, Yoshita","year":2025,"journal":"Journal of obstetric, gynecologic, and neonatal nursing : JOGNN, 54(3), 282-287.e1","doi":"10.1016/j.jogn.2025.02.001","pmid":"40032244","tags":["pregnancy","medical-cannabis","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"71.2% of budtenders recommended cannabis products for morning sickness, particularly CBD products and edibles. Some recommended inhalation products (12.2%) and tinctures (18.9%). While 85.6% eventually encouraged medical consultation, only 34.6% did so without prompting. A few (5.4%) recommended topical products.","whyItMatters":"Morning sickness is common and distressing, but cannabis use during pregnancy is associated with adverse outcomes. Budtenders actively recommending cannabis for morning sickness without proactively suggesting medical consultation could put pregnant consumers and their babies at risk.","specificNumbers":"104 budtenders called, 67% response rate. 71.2% recommended cannabis products. Products recommended: CBD, edibles (most common), tinctures (18.9%), inhalation (12.2%), topicals (5.4%). Medical consultation: 85.6% encouraged when asked, but only 34.6% proactively.","methodology":"Descriptive observational study using mystery calling. Two researchers called 104 Arizona dispensaries between February-April 2024, asking about morning sickness management and documenting budtender responses on standardized forms.","limitations":"Arizona only, which may not represent other states. Mystery calling captures initial phone interactions, not in-person consultations. Cannot determine what information was communicated beyond the scripted scenario. 67% response rate means one-third of dispensaries were not reached."},{"rthcId":"RTHC-07017","title":"The role of depression in the relationship between cannabis use and suicidal behaviours: A systematic review and meta-analysis.","authors":"Maffre Maviel, Gustave; Somma, Camilla; Davisse-Paturet, Camille; Airagnes, Guillaume; Melchior, Maria","year":2025,"journal":"Drug and alcohol dependence, 273, 112714","doi":"10.1016/j.drugalcdep.2025.112714","pmid":"40424695","tags":["mental-health","depression","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Among adolescents, cannabis use was associated with suicidal ideation (OR=1.46) and suicide attempts (OR=2.17) in studies adjusting for depression. Among adults, cannabis was associated with suicidal ideation (OR=1.78) after depression adjustment. However, 12 of 25 studies found no association after adjusting for depression. Studies examining depression as a moderator produced conflicting results.","whyItMatters":"The cannabis-suicide link has been debated, with critics arguing depression explains it entirely. This meta-analysis shows the association persists even after accounting for depression in many studies, while also acknowledging that depression does partly confound the relationship.","specificNumbers":"1,081 screened, 25 included. Adolescent cannabis-SI: OR=1.46 (1.17-1.83). Adolescent cannabis-attempts: OR=2.17 (1.56-3.03). Adult cannabis-SI: OR=1.78 (1.28-2.46). 12/25 studies found no association after depression adjustment. 6 studies examined moderation with conflicting results.","methodology":"Systematic review and meta-analysis searching PubMed, Science Direct, and PsycArticles through May 2024. Included 25 quantitative observational studies investigating depression's role in the cannabis-suicidality relationship. Meta-analyses pooled adjusted odds ratios.","limitations":"Observational studies cannot prove causation. Different studies adjusted for different confounders. Suicidal ideation and attempts were measured differently across studies. No studies investigated depression as a formal mediator. Heterogeneity in cannabis use definitions."},{"rthcId":"RTHC-07018","title":"Tobacco and cannabis use among pregnant women with prenatal opioid use.","authors":"Mahabee-Gittens, E Melinda; Mack, Nicole; Bann, Carla M; Newman, Jamie E; Zhao, Junfang; Setchell, Kenneth D R; Stone, Lara; Ambalavanan, Namasivayam; Peralta-Carcelen, Myriam; DeMauro, Sara B; Lorch, Scott A; Wilson-Costello, Deanne E; Poindexter, Brenda B; Limperopoulos, Catherine; Davis, Jonathan M; Merhar, Stephanie L","year":2025,"journal":"Addictive behaviors, 170, 108442","doi":"10.1016/j.addbeh.2025.108442","pmid":"40768871","tags":["pregnancy","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Tobacco use remained consistently high across all trimesters (no significant decline, p=0.28), including e-cigarette products (p=0.18). Cannabis use decreased significantly from 29.8% in the first trimester to 16.5% in the third (p=0.0003). There were no differences in tobacco or cannabis patterns between those on medication for OUD only versus those using other opioids.","whyItMatters":"Pregnant women with opioid use disorder face compounding risks from polysubstance use. The high rate of tobacco use that does not decline, combined with cannabis use in nearly a third, highlights the need for comprehensive substance use intervention during prenatal care.","specificNumbers":"206 pregnant women, mean age 30.7 years, 81.9% non-Hispanic White, 92.6% public insurance. MOUD-only group: 54.9% tobacco only, 3.3% cannabis only, 26.4% both. Cannabis: 29.8% first trimester to 16.5% third trimester (p=0.0003). Tobacco use consistent across trimesters (p=0.28).","methodology":"Observational study of 206 pregnant women with biochemically verified opioid use. 98 reported taking only medications for OUD, 108 reported other opioids. Self-reported tobacco and cannabis use assessed overall and by trimester.","limitations":"Self-reported substance use may underestimate actual use. Predominantly non-Hispanic White sample with public insurance limits generalizability. Cannot determine whether cannabis reduction was voluntary or due to other factors. Small subsample sizes."},{"rthcId":"RTHC-07019","title":"Engineered PLGA Nanoparticles for Brain-Targeted Codelivery of Cannabidiol and pApoE2 through the Intranasal Route for the Treatment of Alzheimer's Disease.","authors":"Mahanta, Arun Kumar; Chaulagain, Bivek; Gothwal, Avinash; Singh, Jagdish","year":2025,"journal":"ACS biomaterials science & engineering, 11(6), 3533-3546","doi":"10.1021/acsbiomaterials.5c00465","pmid":"40380910","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07020","title":"Cannabis and psychopathology: 2024 Snapshot of a meandering journey.","authors":"Mahintamani, Tathagata; Mukherjee, Diptadhi; Basu, Debasish","year":2025,"journal":"Indian journal of psychiatry, 67(3), 283-302","doi":"10.4103/indianjpsychiatry.indianjpsychiatry_968_24","pmid":"40291036","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07021","title":"Cannabis effects on cardiovascular health: Current evidence, gaps in knowledge, and future research directions.","authors":"Mahmoud, Ahmed K; Arsanjani, Reza; Ayoub, Chadi","year":2025,"journal":"Trends in cardiovascular medicine","doi":"10.1016/j.tcm.2025.12.003","pmid":"41418992","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07022","title":"Sociodemographic and clinical characteristics associated with overdose among patients with a substance-related diagnosis in the emergency department of Southern California.","authors":"Maila, Brian; Zúñiga, María Luisa; Marienfeld, Carla","year":2025,"journal":"Harm reduction journal, 22(1), 86","doi":"10.1186/s12954-025-01233-9","pmid":"40410736","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis-related diagnosis was associated with 21% higher odds of overdose (aOR=1.21, p<0.05), similar to opioid-related diagnosis (aOR=1.14). Overdose odds were higher for ages 40-54 (aOR=1.37), Black patients (aOR=1.31), Hispanic patients (aOR=1.22), publicly insured (aOR=1.40), and those with mental health diagnoses (aOR=1.13). Female sex (aOR=0.78) and being married (aOR=0.69) were protective.","whyItMatters":"The association between cannabis-related diagnoses and overdose risk is important because cannabis itself rarely causes fatal overdose. This suggests cannabis use disorder may be a marker for polysubstance use and broader vulnerability to drug-related emergencies.","specificNumbers":"13,477 adults with SRD in ED (2020-2023). Cannabis diagnosis: aOR=1.21 for overdose. Opioid diagnosis: aOR=1.14. Ages 40-54: aOR=1.37. Black: aOR=1.31. Hispanic: aOR=1.22. Public insurance: aOR=1.40. Mental health: aOR=1.13. Female: aOR=0.78 (protective). Married: aOR=0.69 (protective).","methodology":"Cross-sectional study of 13,477 adults with substance-related diagnoses who had ED encounters at UCSD Health from 2020-2023. Bivariate and multiple logistic regression examined factors associated with overdose.","limitations":"Cross-sectional design at one health system. Cannabis-related diagnosis does not mean cannabis caused the overdose. ICD-10 coding may not capture all substance use. Southern California population may not generalize. COVID-19 period (2020-2023) may have influenced patterns."},{"rthcId":"RTHC-07023","title":"Prevalence and Impact of Substance Use on Hospitalization and Post-Discharge Outcomes in Individuals with Congestive Heart Failure: Findings from a Safety-Net Hospital.","authors":"Majdalani, Rosemarie; AlShammari, Asmaa; Thearle, Marie; Magdits, Mariel; Shah, Jinal; Ionescu, Natalia; Kurian, Damian; Raiszadeh, Farbod","year":2025,"journal":"International journal of environmental research and public health, 22(12)","doi":"10.3390/ijerph22121832","pmid":"41464465","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07024","title":"Sleep regularity and duration are associated with depression severity in a nationally representative United States sample.","authors":"Maki, Katherine A; Yang, Li; Farmer, Nicole; Papneja, Shreya; Wallen, Gwenyth R; Barb, Jennifer J","year":2025,"journal":"Neurobiology of sleep and circadian rhythms, 19, 100133","doi":"10.1016/j.nbscr.2025.100133","pmid":"40778402","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07025","title":"Trends in cannabis-attributable hospitalizations and emergency department visits: data from the Canadian Substance Use Costs and Harms Study (2007-2020).","authors":"Malam, Raadiya; MacDonald-Spracklin, Rachael; Biggar, Emily; Sherk, Adam; Ziv, Anat; Gabrys, Robert; Wood, Shea; Young, Matthew M; Giwa, Aisha; Sondagar, Chandni; Zhao, Jinhui; Kent, Pamela; Stockwell, Tim","year":2025,"journal":"Health promotion and chronic disease prevention in Canada : research, policy and practice, 45(6), 265-276","doi":"10.24095/hpcdp.45.6.01","pmid":"40504124","tags":["legalization","psychosis","youth","cardiovascular"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Between 2007 and 2020, cannabis-attributable inpatient hospitalizations increased from 6.4 to 14.0 per 100,000, while ER visits rose from 52.1 to 111.0 per 100,000. Neuropsychiatric conditions, especially psychotic disorders and acute intoxication in children and youth, accounted for a large share of the increase.","whyItMatters":"This study provides the most comprehensive Canadian tracking of cannabis-related hospital burden over a period spanning pre- and post-legalization. The sharp rise in youth intoxication cases and psychosis-related hospitalizations highlights specific areas where public health attention may be needed.","specificNumbers":"Hospitalizations: 6.4 to 14.0 per 100,000 (120% increase). ER visits: 52.1 to 111.0 per 100,000 (113% increase, with a 12% drop in 2020 likely due to COVID). Key drivers: psychotic disorder hospitalizations and acute intoxication ER visits among children and youth.","methodology":"Researchers used record-level hospital discharge data with ICD-10 codes across all Canadian provinces and territories from fiscal years 2006/07 to 2020/21. Cannabis-attributable fractions were calculated using prevalence estimates from national surveys combined with relative risk estimates from the literature.","limitations":"Cannabis-attributable fractions rely on published relative risk estimates that may not perfectly reflect the Canadian population. The 2020 data is confounded by COVID-19 effects on both cannabis use patterns and hospital access. The study cannot distinguish between effects of legalization versus broader trends in cannabis use."},{"rthcId":"RTHC-07026","title":"Constellations of Depressive Symptoms, Substance Use, and Risky Sexual Behavior Among Higher Education Students: A Moderated Mediation Analysis of Mask-Wearing Practice During COVID-19.","authors":"Maleku, Arati; Kim, Youn Kyoung; Chun, JongSerl; Um, Mee Young; Canfield, James P; David, Ifolu J; Moon, Sung Seek; Yu, Mansoo","year":2025,"journal":"Journal of prevention (2022), 46(2), 245-266","doi":"10.1007/s10935-024-00815-w","pmid":"39630378","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07027","title":"The synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA enhance in vitro neurodifferentiation of NG108-15 cells, along with PGC-1α dysregulation and mitochondrial dysfunction.","authors":"Malheiro, Rui Filipe; Figueiredo, João; Carmo, Helena; Carvalho, Félix; Silva, João Pedro","year":2025,"journal":"Toxicology, 517, 154213","doi":"10.1016/j.tox.2025.154213","pmid":"40480473","tags":["synthetic-cannabinoids","neuroscience","pregnancy"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both synthetic cannabinoids enhanced neurite outgrowth at biologically relevant concentrations below 1 micromolar. This effect was blocked by CB1 receptor antagonists. However, both compounds also reduced mitochondrial membrane potential independently of CB1 receptors. ADB-FUBINACA additionally decreased cellular ATP levels through CB1 activation.","whyItMatters":"Synthetic cannabinoids are used by young adults, including women of childbearing age. These findings suggest that these compounds could interfere with normal neurodevelopment by simultaneously promoting abnormal nerve growth and damaging the cellular energy machinery that developing neurons depend on.","specificNumbers":"Effects observed at concentrations below 1 micromolar. ADB-FUBINACA increased cytosolic PGC-1alpha expression (1 pM to 1 micromolar) while decreasing mitochondrial PGC-1alpha (at 1 nM and 1 micromolar). The Parkin-PINK1 mitophagy pathway was not activated at tested concentrations.","methodology":"Researchers exposed NG108-15 neuronal cell lines to ADB-FUBINACA and AMB-FUBINACA at varying concentrations. They measured neurite outgrowth, mitochondrial membrane potential, ATP levels, and expression of mitochondrial markers including PGC-1alpha, VDAC, NRF-1, and TFAM. CB1 receptor antagonists were used to determine receptor involvement.","limitations":"This is an in vitro study using a cell line, not living brain tissue or whole organisms. Effects at the cellular level may not directly translate to neurodevelopmental outcomes in humans. The concentrations used, while biologically relevant, may not reflect actual brain exposure from recreational use."},{"rthcId":"RTHC-07028","title":"Cannabidiol Is Associated with Improved Survival in Pancreatic Cancer and Modulation of Bile Acids and Gut Microbiota.","authors":"Malhotra, Pratibha; Palanisamy, Ranjith; Panda, Arunima; Casari, Ilaria; Tirnitz-Parker, Janina E E; O'Gara, Fergal; Trengove, Robert; Ragunath, Krish; Caparros-Martin, Jose A; Falasca, Marco","year":2025,"journal":"International journal of molecular sciences, 26(16)","doi":"10.3390/ijms26167733","pmid":"40869053","tags":["cbd","cancer","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Only CBD alone improved survival in KPC mice (a genetic model that mimics human pancreatic cancer). The THC-CBD combination, which synergistically killed pancreatic cancer cells in lab dishes, did not translate to survival benefits in living mice. CBD treatment was linked to changes in gut microbiota composition and bile acid profiles.","whyItMatters":"Pancreatic cancer has among the worst survival rates of any cancer. The finding that CBD specifically altered gut bacteria and bile acid metabolism in surviving mice opens a new line of investigation into how cannabinoids might influence cancer outcomes through the gut-liver axis rather than direct tumor killing.","specificNumbers":"CBD and THC synergistically reduced PDAC cell viability in vitro, but only CBD monotherapy improved survival in KPC mice. CBD effects on gut microbiota and bile acid profiles were distinct from those of THC alone or the combination.","methodology":"Researchers tested THC and CBD individually and combined in PDAC cell lines and in KPC mice that spontaneously develop pancreatic cancer. Fecal microbiota was characterized by 16S rRNA gene sequencing, and bile acid profiling was performed using mass spectrometry on fecal, cecal, and plasma samples.","limitations":"KPC mice, while a strong model, do not perfectly replicate human pancreatic cancer. The study cannot determine whether the gut microbiota and bile acid changes caused the survival benefit or were simply correlated with it. Dosing and route of administration in mice may not translate directly to humans."},{"rthcId":"RTHC-07029","title":"Integrating endocannabinoid signaling, CCK interneurons, and hippocampal circuit dynamics in behaving animals.","authors":"Malhotra, Shreya; Donneger, Florian; Farrell, Jordan S; Dudok, Barna; Losonczy, Attila; Soltesz, Ivan","year":2025,"journal":"Neuron, 113(12), 1862-1885","doi":"10.1016/j.neuron.2025.03.016","pmid":"40267911","tags":["neuroscience","dopamine"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"New biosensors and imaging tools can now track endocannabinoid signaling at individual synapses in behaving animals. In the hippocampus, endocannabinoid-mediated inhibition by CCK-positive interneurons plays a key role in shaping place cell properties, the neurons that encode spatial location.","whyItMatters":"For decades, understanding of the endocannabinoid system was limited to lab-dish experiments because the signals degrade too quickly to track in living brains. These new technologies are fundamentally changing what researchers can learn about how cannabis and the natural endocannabinoid system affect brain circuits in real time.","specificNumbers":"The review covers decades of research culminating in recent breakthroughs in endocannabinoid biosensors and in vivo recording methods for tracking signaling at specific synapses.","methodology":"This is a comprehensive review synthesizing recent advances in endocannabinoid imaging, biosensors, and in vivo recording technologies. The authors focus on hippocampal circuits as a model system, examining how new tools have overcome the historical limitation that endocannabinoid lipid signals are too short-lived to study in living tissue.","limitations":"As a review, this synthesizes existing work rather than presenting new data. Most of the highlighted advances focus on hippocampal circuits, and it remains to be seen how well the findings generalize to other brain regions."},{"rthcId":"RTHC-07030","title":"Cannabis Withdrawal and Psychiatric Intensive Care.","authors":"Malik, Aliyah; Shetty, Hitesh; Oliver, Dominic; Reilly, Thomas J; Di Forti, Marta; McGuire, Philip; Chesney, Edward","year":2025,"journal":"JAMA psychiatry, 82(8), 838-843","doi":"10.1001/jamapsychiatry.2025.1216","pmid":"40498495","tags":["withdrawal","mental-health","psychosis","sex-differences"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 52,088 psychiatric admissions in London over 16 years, cannabis users were 44% more likely than non-users to require psychiatric intensive care overall. During the specific 3-5 day post-admission window when cannabis withdrawal peaks, transfers to intensive care were more common in cannabis users (31.0%) than non-users (24.2%). The association was strongest in women (2x the odds) and adults over 35 (2.5x the odds).","whyItMatters":"Cannabis withdrawal is often overlooked in psychiatric settings. This study provides evidence that forced abstinence during hospitalization may trigger a predictable worsening of psychiatric symptoms during the withdrawal peak window, potentially leading to unnecessary escalation of care.","specificNumbers":"N = 52,088 admissions. PICU admission overall: 9.0%. Cannabis users vs non-users for PICU: aOR 1.44. Transfer at 3-5 days: 31.0% vs 24.2% (aOR 1.36). Women: aOR 2.03. Over 35: aOR 2.53.","methodology":"Retrospective cohort study using electronic health records from four psychiatric hospitals in London (2008-2023). Cannabis use status was determined through natural language processing of clinical records combined with manual review. Multivariable models adjusted for age, gender, ethnicity, diagnosis, tobacco use, stimulant use, and comorbid substance use disorders.","limitations":"Cannabis use was identified from clinical records, which may undercount actual users. The study cannot definitively prove that withdrawal caused the transfers rather than other factors associated with cannabis use. The London population may not be representative of all psychiatric settings."},{"rthcId":"RTHC-07031","title":"Effects of ketamine enantiomers on morphine and THC subjective effects in rats.","authors":"Malikowska-Racia, Natalia; Golebiowska, Joanna; Starowicz, Katarzyna; Zajdel, Pawel; Bisaga, Adam; Popik, Piotr","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 2698811251406839","doi":"10.1177/02698811251406839","pmid":"41453846","tags":["drug-interactions","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In drug discrimination tests, no form of ketamine (R-, S-, or racemic) substituted for the subjective effects of either morphine or THC. Ketamine also did not block the discriminative effects of either drug. However, all ketamine forms suppressed response rates when combined with THC, suggesting a sedative interaction.","whyItMatters":"Ketamine is increasingly used alongside opioids and cannabinoids in both clinical pain management and recreational settings. This study suggests ketamine does not produce cannabis-like or opioid-like subjective effects, but the sedative interaction with cannabinoids warrants attention.","specificNumbers":"Ketamine tested at 5, 10, and 30 mg/kg in R-, S-, and racemic forms. Fentanyl (0.1 mg/kg) fully substituted for morphine. Rimonabant (0.32-3.2 mg/kg) partially blocked THC. No ketamine isoform achieved full substitution or blockade for either drug.","methodology":"Rats were trained in a two-lever drug discrimination paradigm to distinguish morphine (6.4 mg/kg) or THC (3 mg/kg) from vehicle. Ketamine isoforms were then tested at 5, 10, and 30 mg/kg as substitutes for or blockers of the training drugs. Standard positive controls (fentanyl for morphine, rimonabant for THC) confirmed the assay was working.","limitations":"Drug discrimination in rats measures subjective-like effects but cannot perfectly predict human experience. The doses used may not cover all clinically relevant scenarios. The sedation interaction was measured indirectly through response rate suppression."},{"rthcId":"RTHC-07032","title":"Rural reticence to inform physicians of cannabis use.","authors":"Mallinson, Daniel J; Servinsky, Timothy J","year":2025,"journal":"The Journal of rural health : official journal of the American Rural Health Association and the National Rural Health Care Association, 41(2), e12885","doi":"10.1111/jrh.12885","pmid":"39320049","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Living in an urban area was positively associated with disclosing marijuana use to healthcare providers compared to rural areas. No urban-rural difference was found for CBD disclosure. The authors argue that rural stigma around marijuana use may disproportionately harm rural residents by preventing integrated medical care.","whyItMatters":"When patients do not tell their doctors about cannabis use, providers cannot screen for drug interactions, adjust treatment plans, or monitor for adverse effects. Rural residents already face healthcare access barriers, and stigma-driven nondisclosure adds another layer of risk.","specificNumbers":"N = 1,045 adults surveyed in Pennsylvania. Urban residence was positively associated with marijuana disclosure but not CBD disclosure. Covariates included gender, age, race/ethnicity, political affiliation, political ideology, and veteran status.","methodology":"Cross-sectional survey of 1,045 adult Pennsylvanians using a web panel. Rurality was determined by overlaying ZIP Code Tabulation Areas with U.S. Census urban area definitions. Logistic regressions controlled for gender, age, race/ethnicity, political affiliation, ideology, and veteran status.","limitations":"Web panel survey may not be representative of all Pennsylvanians, particularly those without internet access in rural areas. Self-reported disclosure and cannabis use may be subject to recall and social desirability bias. Pennsylvania-specific findings may not generalize to other states."},{"rthcId":"RTHC-07033","title":"Review of Cannabis-Related Programmatic Activities for Drug-Free Communities (DFC) Support Program Coalitions.","authors":"Mallory, Vanessa; Guarnizo, Julie; Holland, Kristin; Fogarty, Hannah; Voetsch, Karen; Roehler, Douglas","year":2025,"journal":"Journal of community health, 50(5), 965-974","doi":"10.1007/s10900-025-01477-3","pmid":"40450620","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07034","title":"Acute cannabis intoxication among the paediatric population.","authors":"Malta, Ginevra; Albano, Giuseppe Davide; Lavanco, Gianluca; Brancato, Anna; Cannizzaro, Carla; Argo, Antonina; Contorno, Simona; Plescia, Fulvio; Zerbo, Stefania","year":2025,"journal":"Frontiers in toxicology, 7, 1558721","doi":"10.3389/ftox.2025.1558721","pmid":"40296894","tags":["youth","neuroscience","legalization"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"THC effects in children typically emerge within 2 hours of ingestion, with severe symptoms developing by 4 hours. Children show heightened sensitivity to neurological and neurovegetative effects due to CB1 receptor expression patterns unique to developing brains, including transient receptor localization in brainstem regions controlling basic body functions.","whyItMatters":"As cannabis products become more available and often come in edible forms attractive to children, accidental pediatric exposures are rising. Understanding why children respond differently than adults is critical for emergency clinicians and for designing effective prevention measures.","specificNumbers":"THC effects typically emerge within 2 hours of ingestion in children. More severe symptoms develop within 4 hours. Urine immunoassay becomes positive within 3-4 hours of ingestion. CB1 receptors in developing brains show expression patterns different from adults, including presence in brainstem regions.","methodology":"Narrative review synthesizing toxicological, clinical, and medico-legal literature on pediatric cannabis intoxication. The review covers pharmacokinetics, endocannabinoid system development, analytical detection methods, clinical presentation, and regulatory considerations.","limitations":"As a narrative review, this does not follow systematic review methodology and may not capture all relevant literature. Pediatric cannabis exposure data varies significantly by jurisdiction and reporting standards."},{"rthcId":"RTHC-07035","title":"Cannabis consumption and risk of asthma: a systematic review and meta-analysis.","authors":"Malvi, Ajay; Khatib, Mahalaqua Nazli; Balaraman, Ashok Kumar; Roopashree, R; Kaur, Mandeep; Srivastava, Manish; Barwal, Amit; Siva Prasad, G V; Rajput, Pranchal; Syed, Rukshar; Sharma, Gajendra; Kumar, Sunil; Singh, Mahendra Pratap; Bushi, Ganesh; Chilakam, Nagavalli; Pandey, Sakshi; Brar, Manvinder; Mehta, Rachana; Sah, Sanjit; Gaidhane, Abhay M; Shabil, Muhammed; Daniel, Afukonyo Shidoiku","year":2025,"journal":"BMC pulmonary medicine, 25(1), 48","doi":"10.1186/s12890-025-03516-0","pmid":"39881272","tags":["respiratory"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"The pooled odds ratio for asthma diagnosis among cannabis users was 1.31 (95% CI: 1.19-1.44), indicating 31% greater odds compared to non-users. Moderate heterogeneity was observed across studies (I-squared = 46%), and sensitivity analysis confirmed the robustness of the finding.","whyItMatters":"Cannabis is the third most widely used psychoactive substance globally, and smoked cannabis delivers irritants similar to tobacco smoke. This meta-analysis provides the strongest pooled evidence to date that cannabis use is associated with higher odds of having asthma.","specificNumbers":"Pooled OR = 1.31 (95% CI: 1.19-1.44). 8 studies included. 1,887 records screened. Heterogeneity: I-squared = 46% (moderate).","methodology":"Systematic review and meta-analysis searching PubMed, Embase, and Web of Science for observational studies published through September 2024. Eight studies met inclusion criteria from 1,887 screened records. Random-effects meta-analysis was used to account for between-study heterogeneity. Analyses were performed in R version 4.4.","limitations":"Included studies were observational, so causation cannot be established. The analysis could not distinguish between different modes of consumption (smoking vs. vaping vs. edibles). Moderate heterogeneity suggests differences in how studies measured exposure and asthma. Publication bias was not extensively addressed."},{"rthcId":"RTHC-07036","title":"Multimodal profiling of Pepcan-CB1 receptor structure-activity relationships: integrating molecular dynamics simulations, biological profiling, and the deep learning model MuMoPepcan.","authors":"Man, Hongyang; Bao, Huiming; Niu, Zhanyu; Zhang, Zhonghua; Simon, Jerine Peter; Yang, Tong; Li, Pengtao; Dong, Shouliang","year":2025,"journal":"Bioorganic chemistry, 165, 109027","doi":"10.1016/j.bioorg.2025.109027","pmid":"41005111","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07037","title":"COMT Genetic Variants and BDNF Level Associations with Cannabinoid Plasma Exposure: A Preliminary Study.","authors":"Manca, Alessandra; Valz, Cristina; Chiara, Francesco; Palermiti, Alice; Mula, Jacopo; Soloperto, Sara; Antonucci, Miriam; De Nicolò, Amedeo; Luxardo, Nicola; Imperiale, Daniele; Vischia, Flavio; De Cori, David; Cusato, Jessica; D'Avolio, Antonio","year":2025,"journal":"Journal of xenobiotics, 15(3)","doi":"10.3390/jox15030066","pmid":"40407530","tags":["genetics","medical-cannabis","pain","inflammation"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The COMT 680 T>C genetic variant significantly influenced plasma levels of THC (p = 0.017). Patients using inhaled cannabis had significantly different BDNF (p = 0.004) and IL-10 (p = 0.009) levels compared to those using cannabis decoction. Both BDNF and neurofilament light chain levels correlated with cannabinoid concentrations.","whyItMatters":"This study provides early evidence that genetic makeup can affect how the body processes medical cannabis. If certain gene variants predict higher or lower drug levels, this could eventually help personalize cannabis dosing for pain patients.","specificNumbers":"N = 58 patients. COMT 680 T>C variant associated with THC levels (p = 0.017). IL-10 difference by route (p = 0.009). BDNF difference by route (p = 0.004). 47 decoction users, 11 inhaled cannabis users.","methodology":"Observational study of 58 patients with neuropathic or chronic pain treated with medical cannabis (47 decoction, 11 inhaled; 30 high-THC, 28 reduced-THC/CBD). Cannabinoid plasma concentrations were measured by UHPLC-MS/MS. Genetic variants were assessed by real-time PCR. Inflammation biomarkers analyzed by ELISA and neuronal markers by Single Molecule Array.","limitations":"Very small sample size (58 patients, only 11 inhaled). The imbalanced group sizes limit statistical power. Multiple biomarkers were tested without correction for multiple comparisons. This is a preliminary finding that requires replication in larger cohorts."},{"rthcId":"RTHC-07038","title":"Cannabinoid Receptors Modulate Physiological Remodelling of the Blood-Testis Barrier.","authors":"Manfrevola, Francesco; Ricci, Giulia; Suglia, Antonio; Mele, Vincenza Grazia; Migliaccio, Antonella; Chianese, Rosanna; Cobellis, Gilda; Chioccarelli, Teresa","year":2025,"journal":"Journal of cellular physiology, 240(11), e70109","doi":"10.1002/jcp.70109","pmid":"41251101","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB1 knockout mice showed disrupted expression of blood-testis barrier components and infiltration of blood cells into seminiferous tubules, specifically at the Stage VIII-IX transition of the sperm production cycle. Loss of CB1 increased the rate of tight junction internalization and degradation, leading to premature passage of germ cells and slower spermatogenesis.","whyItMatters":"The blood-testis barrier protects developing sperm from the immune system. This study reveals that the endocannabinoid system plays a previously unknown role in maintaining this barrier, which could have implications for understanding how cannabis use affects male fertility.","specificNumbers":"Blood cell infiltration occurred specifically at the Stage VIII-IX transition. CB1 deletion increased kinetics of tight junction internalization and recycling while promoting proteasome-mediated occludin degradation. VDAC expression (mitochondrial mass marker) remained unchanged.","methodology":"Researchers used CB1 knockout male mice to study blood-testis barrier integrity during the seminiferous epithelium remodeling phase (Stages VIII-XI). They performed gene expression analysis of tight junction components, tracked occludin trafficking to endosomes and proteasomes, and assessed barrier permeability at different stages of the sperm cycle.","limitations":"Complete genetic knockout of CB1 is more extreme than any level of cannabis use. The effects of partial CB1 modulation from cannabis exposure may differ significantly. This is a mouse study, and human testicular physiology has some differences."},{"rthcId":"RTHC-07039","title":"Biotechnological advancements enabling cannabinoid biosynthesis in engineered fungi: a mini review.","authors":"Manganyi, Madira Coutlyne; Kaptchouang Tchatchouang, Christ Donald","year":2025,"journal":"Frontiers in fungal biology, 6, 1660661","doi":"10.3389/ffunb.2025.1660661","pmid":"41209486","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07040","title":"Enhancement of the endocannabinoid system through monoacylglycerol lipase inhibition relieves migraine-associated pain in mice.","authors":"Mangutov, Elizaveta; Awad-Igbaria, Yaseen; Siegersma, Kendra; Gastambide, Francois; Asuni, Ayodeji A; Pradhan, Amynah A A","year":2025,"journal":"The journal of headache and pain, 26(1), 84","doi":"10.1186/s10194-025-02029-9","pmid":"40251497","tags":["pain","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The MAGL inhibitor ABD-1970 blocked cephalic allodynia in both acute and chronic nitroglycerin-induced migraine models. Repeated daily administration for 5 days did not produce tolerance. MAGL and CB1 receptor mRNA were highly expressed in both the trigeminal ganglia and trigeminal nucleus caudalis, key pain-processing regions for headache.","whyItMatters":"Migraine affects over 1 billion people worldwide and current treatments often lose effectiveness or have significant side effects. Enhancing the endocannabinoid system by blocking the enzyme that breaks down natural cannabinoids offers a fundamentally different approach that may avoid the tolerance issues seen with direct cannabinoid receptor activation.","specificNumbers":"A single ABD-1970 dose blocked acute migraine pain. It also reversed established chronic allodynia. No tolerance after 5 consecutive days. High MAGL and CB1 expression found in trigeminal ganglia and trigeminal nucleus caudalis in both neuronal and non-neuronal cells.","methodology":"C57BL6/J male and female mice received nitroglycerin (a human migraine trigger) acutely or every other day for 9 days to model chronic migraine. Periorbital allodynia was measured by von Frey hair stimulation. ABD-1970 was tested as a single dose in acute and chronic models and daily for 5 days to assess tolerance. In situ hybridization mapped MAGL and CB1 expression in trigeminal pain circuits.","limitations":"Mouse migraine models rely on nitroglycerin-induced pain, which may not capture all aspects of human migraine. Five days of dosing is very short to assess long-term tolerance. The specific inhibitor (ABD-1970) has not been tested in humans."},{"rthcId":"RTHC-07041","title":"Cannabis Legalization and Opioid Use Disorder in Veterans Health Administration Patients.","authors":"Mannes, Zachary L; Wall, Melanie M; Alschuler, Daniel M; Malte, Carol A; Olfson, Mark; Livne, Ofir; Fink, David S; Keyhani, Salomeh; Keyes, Katherine M; Martins, Silvia S; Cerdá, Magdalena; Sacco, Dana L; Gutkind, Sarah; Maynard, Charles C; Sherman, Scott; Saxon, Andrew J; Hasin, Deborah S","year":2025,"journal":"JAMA health forum, 6(6), e251369","doi":"10.1001/jamahealthforum.2025.1369","pmid":"40512510","tags":["legalization","addiction","pain","seniors"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"OUD prevalence increased by 0.06 percentage points after medical cannabis law enactment and 0.07 points after recreational law enactment. The largest increase was among adults 65-75 after recreational legalization (0.12 points overall, 0.23 points among those with chronic pain). These findings did not support the hypothesis that cannabis legalization reduces opioid use disorder.","whyItMatters":"A common argument for cannabis legalization is that it could reduce opioid dependence by offering an alternative pain treatment. This large-scale study of veterans found the opposite association, though the absolute increases were small.","specificNumbers":"Study covered 2005-2022, ~3.2-4.5 million patients/year. 86.7-95.0% male. OUD increased 0.06% after MCL, 0.07% after RCL. Age 65-75 after RCL: +0.12%. Chronic pain + age 65-75 after RCL: +0.23%. In states without cannabis laws, OUD decreased from 1.12% to 1.06%.","methodology":"Staggered-adoption difference-in-differences analysis of VHA electronic health records from 2005 to 2022 (approximately 3.2 to 4.5 million patients per year). OUD was identified by ICD-9/ICD-10 diagnosis codes. Models adjusted for demographics, prescription opioid receipt, other substance use disorders, and time-varying state covariates.","limitations":"VHA patients are predominantly male and older, limiting generalizability. OUD was measured by diagnosis codes, which depend on clinical detection and documentation. The study cannot determine whether cannabis use directly caused increased OUD or whether both increased due to shared underlying factors. The absolute increases are very small."},{"rthcId":"RTHC-07042","title":"The Combined Relationship of Prescription Drug Monitoring Program Enactment and Medical Cannabis Laws with Chronic Pain-Related Healthcare Visits.","authors":"Mannes, Zachary L; Nowels, Molly; Mauro, Christine; Cook, Sharon; Wheeler-Martin, Katherine; Gutkind, Sarah; Bruzelius, Emilie; Doonan, Samantha M; Crystal, Stephen; Davis, Corey S; Samples, Hillary; Hasin, Deborah S; Keyes, Katherine M; Rudolph, Kara E; Cerdá, Magdalena; Martins, Silvia S","year":2025,"journal":"Journal of general internal medicine, 40(5), 1030-1038","doi":"10.1007/s11606-024-09053-6","pmid":"39354252","tags":["medical-cannabis","pain","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Prescription drug monitoring programs alone were not associated with changes in chronic pain outpatient visits. However, in states where medical cannabis laws were also present, patients had 19% lower odds of chronic pain-related outpatient visits (aOR = 0.81, 95% CI: 0.71-0.92). Neither policy combination was associated with changes in emergency department visits for chronic pain.","whyItMatters":"As states have simultaneously tightened opioid prescribing (through PDMPs) and expanded cannabis access, patients with chronic pain are navigating both policy shifts. The reduction in outpatient visits where both policies exist may indicate patients are self-managing pain with cannabis rather than seeking conventional treatment.","specificNumbers":"N = 4,878,462 Medicaid enrollees. PDMP + MCL: aOR = 0.81 (95% CI: 0.71-0.92) for outpatient visits. PDMP alone: not significantly associated. Neither combination affected ED visits. Sample: 67.2% female, 51.2% non-Hispanic White, 37.2% aged 40-55.","methodology":"Researchers created annual cohorts of Medicaid enrollees with chronic pain diagnoses using national Medicaid claims data from 2002-2013 and 2016. Negative binomial hurdle models compared three state-level conditions: no PDMP, PDMP without MCL, and PDMP with MCL. The sample of nearly 4.9 million patients was primarily female (67.2%) and ages 40-55.","limitations":"Medicaid claims data cannot determine whether reduced visits reflect improved self-management or disengagement from care. The study period (2002-2016) precedes the major wave of recreational legalization. Cannabis use itself was not directly measured, only inferred from state-level policy."},{"rthcId":"RTHC-07043","title":"Severe Presentation of Cannabinoid Hyperemesis Syndrome With Mixed Acid-Base Disorder and Cardiac Complications: A Case Report.","authors":"Mantelli, Giovanni; Fiore, Armando; Barberi, Caterina; Zaia, Barbara; Ricci, Giorgio; Carollo, Massimo; Malalan, Fabio","year":2025,"journal":"Case reports in medicine, 2025, 8161294","doi":"10.1155/carm/8161294","pmid":"40438465","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07044","title":"Treatment demand for cannabis use problems: analyses of routine data from 30 European countries.","authors":"Manthey, Jakob","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 355-363","doi":"10.1007/s00406-024-01840-w","pmid":"38867084","tags":["addiction","legalization","quitting"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"The cannabis-attributable treatment fraction rose from 29.4% in 2013 to 37.1% in 2020 across 20 European countries. However, only about 3 in 100 frequent cannabis users sought treatment, and the treatment gap appears to be widening as use increases faster than treatment demand.","whyItMatters":"The widening gap between cannabis use prevalence and treatment-seeking suggests that most people who develop problems with cannabis are not receiving help. As countries liberalize cannabis laws, monitoring whether treatment access keeps pace with use is critical.","specificNumbers":"CATF ranged from 3% to 65% across 30 countries. Average CATF rose from 29.4% (2013) to 37.1% (2020). TUR: approximately 3 per 100 frequent users sought treatment. Eastern European countries had the lowest CATF values.","methodology":"Analysis of treatment data from the European Monitoring Centre for Drugs and Drug Addiction across 30 countries. Two novel indicators were developed: the cannabis-attributable treatment fraction (CATF, proportion of all substance treatment entrants seeking help for cannabis) and the treated-user-ratio (TUR, treatment entrants divided by estimated frequent users).","limitations":"Treatment data quality varies significantly across European countries. The treated-user-ratio relies on estimates of frequent use from surveys, which may undercount users. Treatment-seeking is influenced by many factors beyond need, including availability, cost, and stigma."},{"rthcId":"RTHC-07045","title":"Cannabis use, health problems, and criminal offences in Germany: national and state-level trends between 2009 and 2021.","authors":"Manthey, Jakob; Klinger, Sinja; Rosenkranz, Moritz; Schwarzkopf, Larissa","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 555-564","doi":"10.1007/s00406-024-01778-z","pmid":"38502205","tags":["legalization","psychosis","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Age-standardized cannabis use prevalence nearly doubled (5.7% to 10.6%), cannabis-related diagnoses more than tripled (1.1 to 3.7 per 1,000), and minor possession offences increased (1.8 to 3.1 per 1,000) between 2009 and 2021. The steepest increases in use and offences were among 40-59 year olds, while the largest diagnostic increases were in 35-44 year olds. Rates for minors remained relatively stable.","whyItMatters":"Germany was preparing to decriminalize cannabis when this study was conducted, making the baseline data on use, health problems, and legal consequences critical for evaluating the impact of policy changes. The finding that health problems rose faster than use itself suggests that either cannabis potency or patterns of problematic use are intensifying.","specificNumbers":"Use prevalence: 5.7% to 10.6%. Diagnoses: 1.1 to 3.7 per 1,000. Offences: 1.8 to 3.1 per 1,000. Largest use/offence increases: ages 40-59. Largest diagnostic increases: ages 35-44. Cannabis-related problems more pronounced in Northern and city states.","methodology":"Researchers analyzed three national routine data sources: population-based surveys for cannabis use prevalence, ICD-10 F12 code outpatient medical data for cannabis-related diagnoses, and registered narcotics law violations for minor possession offences. Age-standardized rates were calculated across German federal states from 2009 to 2021.","limitations":"Outpatient diagnostic data depends on clinical coding practices, which may have changed over time (increased awareness could inflate apparent increases). Survey-based prevalence may undercount true use. The study period ends before legalization, so it captures pre-reform trends only."},{"rthcId":"RTHC-07046","title":"Recreational cannabis use and sleep in the general population: a systematic review and meta-analysis.","authors":"Mao, Fangxiang; Hoepel, Sanne J W; Shahisavandi, Mina; Luik, Annemarie I; El Marroun, Hanan","year":2025,"journal":"Sleep medicine reviews, 84, 102189","doi":"10.1016/j.smrv.2025.102189","pmid":"41187699","tags":["sleep","mental-health"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 102 observational studies, current recreational cannabis use was associated with poorer sleep quality, both short and long sleep duration, more insomnia symptoms, and a later chronotype compared to non-use. These associations were stronger in men and younger users. However, 19 experimental studies found no associations between cannabis use and sleep quality or duration.","whyItMatters":"Many people use cannabis specifically to improve sleep, yet this large-scale synthesis of the general population evidence suggests recreational use is actually associated with worse sleep outcomes. The disconnect between observational and experimental findings highlights the complexity of the cannabis-sleep relationship.","specificNumbers":"120 studies total: 102 observational, 19 experimental (1 study counted in both). Observational findings: poorer sleep quality, short and long duration, more insomnia, later chronotype. Experimental findings: no significant associations. Neither study type found links to daytime sleepiness.","methodology":"Systematic review and meta-analysis of 120 studies identified from six databases. Studies on medicinal cannabis and clinical samples were excluded. Current use was defined as use within one month; lifetime use as use in the past year or lifetime. The analysis separated observational and experimental evidence.","limitations":"Observational studies cannot establish causation. The experimental studies were relatively short-term and may not capture chronic effects. Excluding medicinal cannabis users and clinical samples limits generalizability to people using cannabis specifically for sleep problems."},{"rthcId":"RTHC-07047","title":"Efficacy of non-psychotropic Cannabis sativa L. standardized extracts in a model of intestinal inflammation.","authors":"Maranta, Nicole; Martinelli, Giulia; Fumagalli, Marco; Pozzoli, Carola; Sonzogni, Elisa; Rossini, Nora; Ciriello, Umberto; Paladino, Giuseppe; Dell'Agli, Mario; Piazza, Stefano; Sangiovanni, Enrico","year":2025,"journal":"Journal of cannabis research, 7(1), 74","doi":"10.1186/s42238-025-00335-2","pmid":"41053843","tags":["cbd","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis extracts standardized for CBD and CBG content inhibited pro-inflammatory chemokines (CXCL-9, CXCL-10, CCL-20) in inflammation-stimulated intestinal cells. Critically, the whole extracts showed greater effect than individual cannabinoids at equivalent concentrations in a co-culture inflammation model, partially recovering epithelial barrier integrity measured by TEER and ZO-1 expression.","whyItMatters":"IBD patients increasingly report using cannabis, but clinical trial evidence is limited. This study supports the \"entourage effect\" hypothesis for gut inflammation, showing that the complex mix of compounds in cannabis extracts may be more effective than isolated CBD or CBG, and identifies specific anti-inflammatory mechanisms.","specificNumbers":"Extracts tested at 100 micrograms/mL, individual compounds at 8 micromolar. NF-kB impairment: -42% (CBD) and -66% (CBG). Extract A abrogated CCL-20 release; Extract B abrogated CXCL-9 and CXCL-10 release. Barrier integrity partially recovered in co-culture model with extracts but not individual cannabinoids.","methodology":"Researchers tested two cannabis extracts (different extraction solvents, same CBD/CBG standardization) and individual cannabinoids on CaCo-2 intestinal cells stimulated with IL-1beta and IFN-gamma. The extracts underwent simulated digestion before testing. A CaCo-2/THP-1 co-culture model assessed barrier function. NF-kB activity was measured to determine mechanism.","limitations":"In vitro cell model does not replicate the full complexity of IBD in living patients. Simulated digestion approximates but does not perfectly match human gastrointestinal processing. The specific extracts tested may not represent commercially available products."},{"rthcId":"RTHC-07048","title":"A bio-SPME-LC-MS/MS method for the quantitative determination of cannabinoids in plasma samples: analytical strategy for optimization of matrix modification.","authors":"Marchioni, Camila; Gionfriddo, Emanuela","year":2025,"journal":"Analytical and bioanalytical chemistry, 417(30), 6947-6959","doi":"10.1007/s00216-025-06183-6","pmid":"41175218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07049","title":"Comparison of Perspectives on Cannabis Use Between Emergency Department Patients Who Are Users and Non-users.","authors":"Marco, Catherine A; Becker, Lena; Egner, Matthew; Erturk, Quincy; Sharma, Ayush; Vail, Taylor; Soderman, Caroline; Morrison, Nathan; Sandelich, Stephen","year":2025,"journal":"The western journal of emergency medicine, 26(6), 1598-1604","doi":"10.5811/westjem.47368","pmid":"41380071","tags":["medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users scored 2.51/5 on negative short-term effects knowledge versus 3.28/5 for non-users (p = 0.004), and 1.78/5 on negative long-term effects versus 2.38/5 for non-users (p = 0.002). The most common reasons for use were anxiety (40%), pain (38%), recreation (37%), sleep (28%), and depression (20%).","whyItMatters":"If cannabis users are less aware of potential harms than non-users, public health messaging may not be reaching its target audience. The finding that 76% of ED patients had used cannabis in their lifetime highlights how mainstream use has become, making accurate health literacy even more important.","specificNumbers":"N = 169 (65.5% consent rate from 258 eligible). 75.7% reported lifetime cannabis use. Users vs non-users: short-term knowledge 2.51 vs 3.28/5 (p = 0.004), long-term knowledge 1.78 vs 2.38/5 (p = 0.002). Top reasons: anxiety 40%, pain 38%, recreation 37%, sleep 28%, depression 20%.","methodology":"Prospective survey of 169 consenting ED patients at Penn State Health (May-August 2024). Participants were asked about cannabis use patterns, reasons for use, and knowledge of positive and negative effects. Thematic analysis identified knowledge themes. Users and non-users were compared on knowledge accuracy scores.","limitations":"Single-center study at one Pennsylvania hospital. Convenience sample of ED patients may not represent the general population. Knowledge scores were based on researcher-defined \"correct\" answers, which may not capture nuance. Small sample size limits subgroup analyses."},{"rthcId":"RTHC-07050","title":"Personality-based intergenerational effects of prenatal THC exposure in an inherited mouse model of social dominance and submissiveness.","authors":"Mari, Mohamed; Bagaev, Anastasia; Sur, Debpali; Rocha, Beatriz G S; Begmatova, Dilorom; Zemliana, Natalia; Bowirrat, Abdalla; Blum, Kenneth; Thanos, Panayotis K; Kogan, Natalya M; Pinhasov, Albert","year":2025,"journal":"Scientific reports, 15(1), 30624","doi":"10.1038/s41598-025-15528-1","pmid":"40835854","tags":["pregnancy","neuroscience","anxiety","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In selectively bred dominant mice, prenatal THC exposure reduced body weight and increased anxiety-like behaviors. In submissive mice, THC exposure enhanced sociability and reduced anxiety. Brain analysis revealed temperament-specific changes in endocannabinoid and dopamine system genes, with FAAH expression notably downregulated in submissive offspring's prefrontal cortex and hippocampus.","whyItMatters":"This is the first study to show that the behavioral effects of prenatal THC depend on pre-existing temperament. The finding that THC exposure could either increase or decrease anxiety depending on the individual's baseline stress vulnerability has significant implications for understanding variable outcomes in human prenatal cannabis exposure.","specificNumbers":"THC dose: 20 mg/kg on gestation days 13, 15, 17. Body weight reductions measured at postnatal days 7 and 30. FAAH downregulated in prefrontal cortex and hippocampus of submissive PTE offspring at PND 7 and 30. Changes also seen in CB1, CB2, D1, D2, and D5 receptor expression.","methodology":"Pregnant dominant and submissive mice (generation 54 of selective breeding) received THC (20 mg/kg IP) on gestation days 13, 15, and 17. Offspring were tested for anxiety, social behavior, and body weight. Brain mRNA expression of endocannabinoid system (CB1, CB2, FAAH) and dopaminergic system (D1, D2, D5) genes was analyzed at postnatal days 7 and 30.","limitations":"The mouse lines are selectively bred for extreme temperament traits that may not correspond to normal human variation. The THC dose (20 mg/kg) is relatively high. The specific behavioral tests may not translate directly to human outcomes. Only male offspring were tested."},{"rthcId":"RTHC-07051","title":"Astroglial CB1 Reveal Sex-Specific Synaptic Effects of Amphetamine.","authors":"Mariani, Yamuna; Dalla-Tor, Tommaso; Garavaldi, Tommaso; Julio-Kalajzić, Francisca; Gisquet, Doriane; Gomez-Sotres, Paula; Cannich, Astrid; Gambino, Giuditta; Drago, Filippo; Serrat, Roman; Hurel, Imane; Chaouloff, Francis; Pouvreau, Sandrine; Bellocchio, Luigi; Marsicano, Giovanni; Covelo, Ana","year":2025,"journal":"Glia, 73(8), 1673-1691","doi":"10.1002/glia.70026","pmid":"40289768","tags":["neuroscience","sex-differences","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Amphetamine impaired astroglial CB1 receptor-dependent synaptic plasticity in the nucleus accumbens of male mice but not females. The locomotor effects of amphetamine required astroglial CB1 receptors in males but not females. This reveals a previously unknown sex-dependent mechanism through which the endocannabinoid system mediates stimulant drug effects.","whyItMatters":"Sex differences in addiction are well-documented but poorly understood. This study identifies a specific cellular mechanism - CB1 receptors on astrocytes in the reward center - that may help explain why stimulant drugs affect men and women differently, with broader implications for understanding sex differences in substance use disorders.","specificNumbers":"Amphetamine impaired astroglial CB1-dependent plasticity in male NAc but not female. Locomotor effects required astroglial CB1 in males only. The astrocyte-specific manipulation (AstroLight tool) isolated the cell type responsible.","methodology":"Researchers used mice with astrocyte-specific CB1 receptor deletions and standard CB1 mice. Synaptic plasticity was measured in nucleus accumbens slices. Behavioral effects of amphetamine (locomotor activity) were compared between males and females and between mice with and without astroglial CB1 receptors.","limitations":"Mouse-specific findings may not directly translate to humans. The study focused on amphetamine, not cannabis directly. The specific astrocyte manipulation tools used are relatively new and the full implications of astrocyte-specific CB1 deletion are still being explored."},{"rthcId":"RTHC-07052","title":"Association of Substance Use with Types of Assault-Related Injury Among Black Men in Baltimore, Maryland.","authors":"Marineau, L A; Perrin, N A; Johnson, R M; Uzzi, M; Alexander, K A; Irvin, N A; Thurman, P; Campbell, J C","year":2025,"journal":"Substance use & misuse, 60(8), 1117-1125","doi":"10.1080/10826084.2025.2487974","pmid":"40219643","tags":["harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis was the most frequently detected substance (42.5%), followed by alcohol (24.4%), opioids (22.3%), and cocaine (3.6%). Men who screened positive for cannabis had 32% lower odds of stabbing versus shooting and 50% lower odds of blunt force assault versus shooting. In contrast, alcohol was associated with stabbing and blunt force rather than firearm assault.","whyItMatters":"This study provides real-world data on substance use patterns among a population disproportionately affected by violence. The differential associations between specific substances and injury types suggest that contextual and environmental factors linked to different substances may influence the type of violence encountered.","specificNumbers":"N = 1,922. Cannabis detected: 42.5%. Alcohol: 24.4%. Opioids: 22.3%. Cocaine: 3.6%. Multiple substances: 25.8%. Cannabis users: 32% lower odds of stabbing vs shooting, 50% lower odds of blunt force vs shooting.","methodology":"Retrospective analysis of 1,922 Black men aged 18-34 admitted to a Baltimore trauma center with assault-related injuries and toxicology screens between 2013 and 2017. Multinomial logistic regression examined associations between substance detection and injury type (blunt force, stabbing, firearm).","limitations":"Toxicology screens detect recent use but cannot determine whether the person was intoxicated at the time of assault. The study cannot establish whether substance use caused or contributed to the assault. Trauma center data may over-represent more severe injuries. Baltimore-specific findings may not generalize to other cities."},{"rthcId":"RTHC-07053","title":"The Impact of Recreational Cannabis Markets on Cannabis Use Among Adolescents and Adults: A Synthetic Control Analysis.","authors":"Marinello, Samantha","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(1), 50-64","doi":"10.26828/cannabis/2024/000224","pmid":"39968487","tags":["legalization","youth","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Using the synthetic control method, recreational cannabis markets were associated with moderate increases in adolescent use prevalence and initiation (11% and 13%), large increases among young adults 18-25 (17% and 33%), and the largest increases among adults 26+ (33% prevalence increase, 82% initiation increase) within 2-4 years of dispensary opening.","whyItMatters":"This study uses one of the strongest causal inference methods available for policy evaluation. The finding that older adults showed the largest increases challenges the focus on youth in cannabis policy debates and suggests that recreational markets are primarily expanding use among populations that were not previously using.","specificNumbers":"Ages 12-17: +11% prevalence, +13% initiation. Ages 18-25: +17% prevalence, +33% initiation. Ages 26+: +33% prevalence, +82% initiation. Effects measured 2-4 years post-dispensary opening across 5 states.","methodology":"Synthetic control method with staggered treatment adoption applied to state-level data from the National Survey on Drug Use and Health. Five states analyzed: Colorado, Washington, Oregon, Alaska, and Nevada. Synthetic controls were constructed from non-legalizing states matched on pre-treatment demographics and cannabis use trends. Jackknife confidence intervals were used.","limitations":"Only five early-legalizing states were included; later states may show different patterns. The NSDUH data relies on self-report and may undercount use. The 2-4 year follow-up window may not capture longer-term trends. Synthetic controls cannot account for all possible confounders."},{"rthcId":"RTHC-07054","title":"Adult Neurogenesis Is Regulated by the Endocannabinoid and Kisspeptin Systems.","authors":"Marino, Marianna; Di Pietro, Paola; D'Auria, Raffaella; Lombardi, Martina; Pastorino, Grazia Maria Giovanna; Troisi, Jacopo; Operto, Francesca Felicia; Carrizzo, Albino; Vecchione, Carmine; Viggiano, Andrea; Meccariello, Rosaria; Santoro, Antonietta","year":2025,"journal":"International journal of molecular sciences, 26(9)","doi":"10.3390/ijms26093977","pmid":"40362219","tags":["neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both anandamide and kisspeptin-10 reduced hippocampal neurogenesis by dampening ERK signaling. The TRPV1 ion channel receptor was upregulated by both treatments, suggesting it serves as a common mediator. Kisspeptin reduced CB1 receptor expression in the dentate gyrus, but anandamide did not affect kisspeptin receptors, indicating an asymmetric interaction between the two systems.","whyItMatters":"Adult neurogenesis in the hippocampus is important for learning and memory. This study reveals a previously unknown regulatory partnership between the endocannabinoid and kisspeptin systems, both of which can slow new brain cell production. Understanding these mechanisms could inform approaches to cognitive decline and neurodevelopmental conditions.","specificNumbers":"Both KP10 and AEA enhanced TRPV1 expression. KP10 reduced CB1R in the dentate gyrus. KP10 upregulated SIRT1, BDNF, c-Jun, and estrogen receptor alpha. AEA did not affect kisspeptin receptor expression. Both systems reduced ERK signaling.","methodology":"Male adolescent rats received kisspeptin-10 and/or anandamide, with or without the CB1 antagonist SR141716A. Expression of Kiss1, Kiss1R, CB1R, and TRPV1 was characterized in rat hippocampus. Neurogenesis was assessed alongside ERK signaling, SIRT1, BDNF, estrogen receptor alpha, and GAPDH expression.","limitations":"Only male adolescent rats were studied; sex differences and adult effects are unknown. The doses and routes of administration may not reflect physiological conditions. The interaction between these systems in humans has not been studied."},{"rthcId":"RTHC-07055","title":"Cannabinoids and Extracellular Vesicles as Potential Biomarkers and Therapeutic Targets in Neuropsychiatric Disorders: A Hypothesis-Driven Review.","authors":"Marques, Bruno L; Lirio, Pedro H C; Vicente, Maria A; Unzueta-Larrinaga, Paula; Urigüen, Leyre; Campos, Alline C","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(12)","doi":"10.3390/ph18121817","pmid":"41471306","tags":["neuroscience","mental-health","cbd"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Emerging evidence indicates a bidirectional relationship: endocannabinoids can be loaded into extracellular vesicles for intercellular signaling, while THC and CBD alter EV release and cargo composition. The authors propose this interplay as a framework for developing biomarker-guided, personalized treatments for depression, anxiety, schizophrenia, and neurodegenerative diseases.","whyItMatters":"Neuropsychiatric disorders lack objective biomarkers, making diagnosis and treatment monitoring largely subjective. If extracellular vesicles carry cannabinoid-related biomarkers that reflect brain state, blood-based tests could eventually help personalize treatment for conditions like depression and schizophrenia.","specificNumbers":"Review covers evidence across depression, anxiety, schizophrenia, and neurodegenerative diseases. Discusses both THC and CBD effects on extracellular vesicle biology.","methodology":"Hypothesis-driven narrative review searching PubMed, Scopus, and Web of Science through September 2025. The review focuses on the interface between cannabinoid signaling and extracellular vesicle biology in neuropsychiatric conditions.","limitations":"This is a hypothesis-driven review, not a systematic analysis. The proposed framework is largely theoretical and requires extensive experimental validation. The interaction between cannabinoids and extracellular vesicles is still in early stages of research."},{"rthcId":"RTHC-07056","title":"Levels of support and consumer perceptions of cannabis regulations in Canada.","authors":"Marquette, Anastasia; Hammond, David","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(2), 237-253","doi":"10.1080/00952990.2025.2479152","pmid":"40172098","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Support was highest for health warnings on products (62.6%), adult-use legalization (58.5%), and retail window coverings (49.2%). The 30g purchasing limit had the least support (10.1%). As consumption increased, opposition to regulations generally increased, but support remained high even among daily consumers. Provincial policy differences did not significantly affect support levels.","whyItMatters":"A common concern about cannabis regulation is that strict rules will push consumers to the illegal market. The finding that even frequent cannabis consumers generally support public health regulations suggests that Canada's regulatory framework has been accepted by the people it most directly affects.","specificNumbers":"N = 16,812. Support: health warnings 62.6%, legalization 58.5%, window coverings 49.2%, THC vaping limit 40.1%, store density 35.5%, government-only stores 34.6%, edible THC limit 32.3%, advertising restrictions 31.8%, 30g limit 10.1%. Daily consumers vs non-consumers on window coverings: OR 1.43.","methodology":"National online survey of 16,812 Canadians aged 16+ from Wave 5 of the International Cannabis Policy Study (2022). Weighted logistic regression examined support for nine policy variables. 62% of respondents were assigned female at birth. Analyses controlled for consumption level and provincial policy context.","limitations":"Online panel surveys may not reach all demographics. Self-reported support for regulations may not reflect actual behavior (e.g., compliance). The survey was conducted in 2022, four years after legalization, and early opposition may have already softened."},{"rthcId":"RTHC-07057","title":"An astrocytic ensemble at vHip-NAc synapses modulates cognitive impairments induced by chronic tetrahydrocannabinol exposure.","authors":"Martín-Monteagudo, Cristina; Sánchez Romero, Javier; Adams, Julia M; Puente, Nagore; Grandes, Pedro; Marsicano, Giovanni; Covelo, Ana; Khakh, Baljit S; Navarrete, Marta","year":2025,"journal":"Nature communications, 17(1), 471","doi":"10.1038/s41467-025-67166-w","pmid":"41360811","tags":["cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC increased astrocytic calcium activity and glutamate release in the nucleus accumbens via the ventral hippocampus circuit. These effects required p38alpha signaling in astrocytes. Using a tool called AstroLight to selectively dampen THC-induced calcium activity in this specific astrocytic ensemble prevented spatial learning and synaptic plasticity impairments.","whyItMatters":"This study identifies the exact cellular mechanism through which THC impairs cognition and demonstrates that it can be prevented by targeting a specific group of non-neuronal brain cells. This opens a path toward interventions that could preserve cognitive function in medical cannabis users.","specificNumbers":"THC increased astrocytic calcium activity in the NAc. Effects absent in p38alpha knockout mice. AstroLight manipulation of the vHip-NAc astrocytic ensemble prevented spatial learning impairments and synaptic plasticity deficits.","methodology":"Researchers used the AstroLight tool to selectively manipulate a specific astrocytic ensemble associated with the vHip-NAc circuit. Astrocyte-specific p38alpha knockout mice were used to identify the signaling pathway. Calcium imaging, glutamate measurements, and spatial learning tests were performed in THC-exposed mice.","limitations":"The AstroLight manipulation tool is a research tool not available for clinical use. Mouse spatial learning tasks may not fully capture human cognitive impairment from THC. Chronic THC exposure in humans involves more complex factors than acute laboratory dosing."},{"rthcId":"RTHC-07058","title":"Effects of Cannabinoids on Emotional States and Alcohol Use Among Underrepresented Groups: Moderation by Perceived Discrimination.","authors":"Martin-Willett, Renée; Skrzynski, Carillon J; Bryan, Angela D; Bidwell, L Cinnamon","year":2025,"journal":"Human psychopharmacology, 40(5), e70016","doi":"10.1002/hup.70016","pmid":"40916181","tags":["cbd","mental-health","anxiety","depression"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Participants using CBD showed greater decreases in DASS (Depression Anxiety Stress Scale) scores compared to THC users over 4 weeks. The effect was moderated by perceived discrimination: at average and high discrimination levels, both CBD and THC reduced symptoms, but CBD showed a stronger effect. No effects on alcohol use were observed for either cannabinoid.","whyItMatters":"This is one of the first randomized studies to examine cannabinoid effects specifically in populations that face discrimination and are underrepresented in cannabis research. The finding that CBD outperformed THC for emotional symptoms, particularly among those experiencing discrimination, has equity implications for cannabis recommendations.","specificNumbers":"N = 172 (62% female, mean age 30.2). CBD group: n = 56. THC group: n = 96. Non-use group: n = 20. CBD showed greater DASS decreases than THC over time. Discrimination moderation significant for CBD vs THC comparison. No effects on drinking days.","methodology":"Randomized study assigning 172 participants from underrepresented groups to no cannabis, THC cannabis, or CBD cannabis conditions. Legal market products were used ad libitum. DASS scores and drinking days were assessed at baseline, 2 weeks, and 4 weeks. The Perceived Discrimination Scale moderated analyses. PROCESS macro was used for mediation and moderation.","limitations":"Small non-use control group (n = 20) limits comparisons. Ad libitum dosing means actual doses varied widely. Four-week follow-up is relatively short. Self-report measures of discrimination and symptoms are subjective. The study cannot determine whether participants would have sought these products independently."},{"rthcId":"RTHC-07059","title":"Trends in cannabis use among those with and without a cancer diagnosis according to state-level cannabis policy: findings from the PATH Study, Waves 1-5 (2013-2019).","authors":"Martin, Connor D; Rivard, Cheryl; Kasza, Karin; Case, Amy A; Hansen, Eric; Goniewicz, Maciej L; O'Connor, Richard J; Hyland, Andrew; Smith, Danielle M","year":2025,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 33(7), 560","doi":"10.1007/s00520-025-09617-0","pmid":"40490566","tags":["cancer","legalization","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use prevalence among people with a cancer diagnosis rose from 6.6% in 2013 to 10.6% in 2019 (approximately 60% increase), mirroring the 11.8% to 18.6% increase in the general population. The trends were similar regardless of whether states had illegal, medical-legal, or non-medical legal cannabis policies.","whyItMatters":"The finding that cancer patients are not using cannabis at higher rates in legal states challenges the assumption that medical legalization primarily benefits patients with serious illnesses. Instead, cannabis use trends among cancer patients simply reflect broader population trends.","specificNumbers":"Cancer patients: 6.6% (2013) to 10.6% (2019), approximately 60% increase. General population: 11.8% to 18.6%, approximately 58% increase. Highest prevalence in non-medical legal states for both groups. Similar trends across all policy categories.","methodology":"Analysis of five waves of the nationally representative PATH Study (2013-2019). Past-year cannabis use prevalence was compared between those with and without cancer diagnoses, stratified by state cannabis policy status. Demographic and policy correlates were examined.","limitations":"PATH Study self-report may undercount cannabis use. Cancer diagnosis was self-reported and could not be verified. The study period ends in 2019, before the most recent wave of legalizations. Cancer type, stage, and treatment status were not examined."},{"rthcId":"RTHC-07060","title":"Gender differences in circumstances associated with cannabis use.","authors":"Martin, Erin L; Baker, Nathaniel L; Ramakrishnan, Viswanathan; Neelon, Brian; Saladin, Michael E; McRae-Clark, Aimee L","year":2025,"journal":"The American journal on addictions, 34(3), 342-349","doi":"10.1111/ajad.70000","pmid":"39934545","tags":["addiction","sex-differences","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Women scored higher on four of eight IDTS subscales related to negative affect: conflict with others, testing personal control, physical discomfort, and unpleasant emotions. Across both genders, cannabis use in negative contexts was associated with childhood stress history. Recent stress was differentially associated with use during unpleasant emotions by gender.","whyItMatters":"Understanding why men and women use cannabis differently is essential for developing gender-informed treatments for cannabis use disorder. The link between negative emotional contexts and women's cannabis use suggests that emotion regulation skills may be a particularly important treatment target for women.","specificNumbers":"N = 148 non-treatment-seeking individuals with CUD. Women scored higher on 4 of 8 IDTS subscales. Past 90-day use sessions positively associated with negative affect and pleasant emotion subscales for both genders. Childhood stress associated with negative affect use for both genders.","methodology":"Cross-sectional analysis of baseline data from 148 non-treatment-seeking individuals with cannabis use disorder. The Inventory of Drug Taking Situations (IDTS) assessed eight types of situations associated with cannabis use. Self-reported past 90-day substance use and measures of childhood and recent stress were included as covariates.","limitations":"Cross-sectional design cannot determine causation. Non-treatment-seeking sample may not represent those in treatment. The IDTS measures self-perceived situations rather than objectively verified contexts. Sample size limits complex subgroup analyses."},{"rthcId":"RTHC-07061","title":"Cannabis use among young adults with acute coronary syndrome: impact on initial presentation and long-term prognosis.","authors":"Martin, Nicolas; Beyls, Christophe; Zeitouni, Michel; Bohbot, Yohann; Stracchi, Valentin; Sroutta-Paillusseau, Sofiane; Jarry, Geneviève; Bodeau, Sandra; Noé, Fabio; Hudelo, Julien; Fournier, Alexandre; Malaquin, Dorothée; Gabrion, Paul; Landemaine, Thomas; Vernier, Agathe; Kubala, Maciej; Leborgne, Laurent; Hermida, Alexis","year":2025,"journal":"Heart (British Cardiac Society)","doi":"10.1136/heartjnl-2025-326777","pmid":"41176318","tags":["cardiovascular","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"This French study followed 188 patients under age 45 who were hospitalized for acute coronary syndrome (heart attacks and unstable angina)—all of whom were tobacco smokers. At admission, 41% tested positive for cannabis via urine testing.\n\nOver a median follow-up of nearly 3 years, cannabis users had significantly higher rates of major adverse cardiovascular events (MACE)—a composite of death, stroke, recurrent heart attack, arrhythmia, and heart failure events. The weighted survival curves diverged significantly (p = 0.002).\n\nThe propensity-weighted analysis is important: the researchers used statistical techniques to adjust for socioeconomic and cardiovascular risk factors, trying to isolate the cannabis effect from other differences between the groups. Even after this adjustment, the association persisted.\n\nThat all participants were tobacco smokers strengthens the finding in one respect—it removes tobacco as a confounder—but also means the study is examining cannabis's cardiovascular impact on top of an already high-risk behavior. Whether cannabis would show the same association in non-smokers is unknown.\n\nThe 41% cannabis use rate among young heart attack patients is itself striking, suggesting cannabis use is very common in this population.","whyItMatters":"Heart attacks in young adults are uncommon but devastating, and understanding modifiable risk factors is critical for prevention. The 41% cannabis use rate in this population raises the question of whether cannabis contributes to both the initial event and the worse outcomes afterward. Combined with RTHC-00167's findings in older veterans with heart disease, the cardiovascular signal from cannabis is emerging across age groups.","specificNumbers":"N = 188, all under 45, all tobacco smokers. 77 (41%) tested positive for cannabis. Median follow-up: 2.93 years. Propensity-weighted survival curves: p = 0.002 for MACE difference.","methodology":"Retrospective single-center cohort study. 188 patients under 45 admitted for acute coronary syndrome between January 2010 and March 2025, all current tobacco smokers. Cannabis use determined by urinary testing at admission. Propensity-weighted analysis adjusted for socioeconomic and cardiovascular risk factors. Primary endpoint: MACE (death, stroke, MI, arrhythmia, heart failure). Cox model truncated at 6 years.","limitations":"Single-center French study with a relatively small sample. Retrospective design. All participants smoked tobacco, so results can't be generalized to non-smokers. Urinary cannabis testing at admission captures recent use but not frequency, dose, or chronicity. Residual confounding is possible despite propensity weighting. No data on cannabis route of administration or product type."},{"rthcId":"RTHC-07062","title":"Cannabidiol prevents social avoidance, potentiation of cocaine reward and gene expression alterations induced by exposure to intermittent social defeat in mice.","authors":"Martínez-Caballero, Maria Ángeles; Navarro, Daniela; Calpe-López, Claudia; Torregrosa, Abraham B; García-Pardo, Maria Pilar; Manzanares, Jorge; Aguilar, Maria Asunción","year":2025,"journal":"Neuropharmacology, 279, 110630","doi":"10.1016/j.neuropharm.2025.110630","pmid":"40812514","tags":["cbd","ptsd","depression","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (30 or 60 mg/kg) given during intermittent social defeat prevented social interaction deficits and the potentiation of cocaine conditioned place preference that normally follows stress exposure. CBD did not prevent anxiety-like effects. Gene expression analysis revealed that social defeat reduced expression of serotonin transporter, CRF, POMC, and cannabinoid receptors, and CBD reversed these reductions.","whyItMatters":"Social stress is a major risk factor for both mood disorders and substance use disorders in humans. This study shows that CBD given during the stress exposure period can prevent two key consequences: social withdrawal (relevant to depression/PTSD) and increased vulnerability to addictive drugs, while identifying the brain systems involved.","specificNumbers":"CBD doses: 30 and 60 mg/kg. 4 defeat episodes (PND 47, 50, 53, 56). CBD reversed social interaction deficit and cocaine preference potentiation. Anxiety-like effects not reversed. Gene expression reductions in 5 of 6 targets reversed by CBD (all except glucocorticoid receptor).","methodology":"Male mice received CBD (30 or 60 mg/kg) and were exposed to four episodes of social defeat on postnatal days 47-56. Behavioral tests assessed social interaction, anxiety, and cocaine reward. Gene expression of serotonin transporter (dorsal raphe), CRF (paraventricular nucleus), POMC (arcuate nucleus), and glucocorticoid/cannabinoid receptors (hippocampus) was measured after the last defeat episode.","limitations":"Male mice only; female responses may differ. Social defeat in mice is an approximation of human social stress. CBD doses were relatively high and may not translate directly to human dosing. Only cocaine reward was tested; other drugs may respond differently."},{"rthcId":"RTHC-07063","title":"Cannabinoid Receptors Reduced Early Brain Damage by Regulating NOX-2 and the NLRP3 Inflammasome in an Animal Model of Intracerebral Hemorrhage.","authors":"Martínez-Torres, Ari Misael; Ramírez-Celis, Crisalde; Morán, Julio","year":2025,"journal":"CNS neuroscience & therapeutics, 31(4), e70385","doi":"10.1111/cns.70385","pmid":"40245261","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"WIN55,212-2 treatment after intracerebral hemorrhage significantly reduced hematoma formation, brain edema, blood-brain barrier disruption, and motor impairments. The mechanism involved suppression of both NOX-2 (a major source of damaging reactive oxygen species) and the NLRP3 inflammasome (a key driver of neuroinflammation). Pharmacological NLRP3 inhibition with MCC950 also reduced hemorrhagic brain damage.","whyItMatters":"Intracerebral hemorrhage is a devastating stroke subtype with limited treatment options. This study identifies two specific inflammatory pathways that cannabinoid receptor activation can suppress, providing a mechanistic basis for potential therapeutic development.","specificNumbers":"WIN55,212-2 reduced hematoma volume, edema, and BBB disruption in treated vs untreated ICH mice. Both NOX-2 activity and NLRP3 expression were elevated after ICH and reduced by cannabinoid treatment. MCC950 (NLRP3 inhibitor) independently reduced hematoma size, edema, and motor impairment.","methodology":"Male C57BL/6 mice received intracerebral hemorrhage via collagenase injection, followed by intraperitoneal WIN55,212-2 and/or the NLRP3 inhibitor MCC950. Outcomes included motor activity, hematoma volume, brain water content, and blood-brain barrier permeability (Evans blue assay). NOX activity and protein levels of CB1, gp91phox, NLRP3, AQP4, and caspase-1 were measured by western blot.","limitations":"Mouse ICH model (collagenase injection) is an approximation of human hemorrhagic stroke. WIN55,212-2 activates both CB1 and CB2 receptors, so the specific receptor contribution is unclear. Only male mice were used. The therapeutic window for treatment was not extensively explored."},{"rthcId":"RTHC-07064","title":"Clinician's perceptions and experiences with tobacco treatment in people who use cannabis: a qualitative study.","authors":"Martínez, Cristina; Pla, Marga; Feliu, Ariadna; Enríquez, Marta; Saura, Judith; Cabezas, Carmen; Colom, Joan; Suelves, Josep M; Mondon, Sílvia; Barrio, Pablo; Andreu, Magalí; Raich, Antònia; Bernabeu, Jordi; Roca, Xavier; Narváez, Maite; Fernández, Esteve","year":2025,"journal":"Substance abuse treatment, prevention, and policy, 20(1), 3","doi":"10.1186/s13011-024-00632-8","pmid":"39838401","tags":["quitting","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Five themes emerged from clinician focus groups: individual characteristics, clinician characteristics, intervention models, organizational healthcare models, and health policies. Clinicians emphasized that integrating tobacco cessation into cannabis treatment could reduce chronic stigma and improve overall health outcomes, but organizational fragmentation and lack of training were barriers.","whyItMatters":"Many cannabis users also smoke tobacco, often mixing the two. Addressing tobacco use within cannabis treatment settings represents a missed opportunity for reducing overall health harms, particularly respiratory risks from smoked cannabis-tobacco mixtures.","specificNumbers":"15 clinicians (12 female, 3 male) in 3 focus groups. 5 main themes and 17 subthemes identified.","methodology":"Qualitative study with 15 clinicians in three focus groups in Catalonia, Spain. Two groups had extensive experience with tobacco cessation in substance use populations; one group did not. Thematic analysis identified patterns across experienced and inexperienced groups.","limitations":"Small qualitative study limited to one region of Spain. Clinician perspectives may not reflect patient experiences or preferences. The healthcare system context in Catalonia may differ from other settings."},{"rthcId":"RTHC-07065","title":"Age-Varying Patterns of Cannabis Use, Related Risk Factors, and their Associations among Young Adults in the Context of Legalized Nonmedical Cannabis.","authors":"Martinez, Griselda; Calhoun, Brian H; Fleming, Charles B; Linden-Carmichael, Ashley N; Acolin, Jessica; Rhew, Isaac C; Kilmer, Jason R; Larimer, Mary E; Guttmannova, Katarina","year":2025,"journal":"Prevention science : the official journal of the Society for Prevention Research, 26(5), 773-784","doi":"10.1007/s11121-025-01803-0","pmid":"40229509","tags":["youth","legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis use prevalence increased from ages 18-22 and remained relatively stable through age 26. Ease of access, social norms, and low perceived harm were associated with use, but the strength of these associations varied by age. Injunctive norms (perceptions of use acceptability) and low perceived psychological harm were the most consistent predictors across the full age range.","whyItMatters":"Understanding which risk factors matter most at different ages can help target prevention efforts. The finding that perceived acceptability drives use well into the mid-20s, and that perceived psychological harm becomes more influential with age, suggests that prevention messaging should evolve as young adults mature.","specificNumbers":"N = 15,251. Mean age 22.02. 68% female. Use increased ages 18-22, stable through 26. Injunctive norms rose substantially through age 23, then decreased. Ease of access and descriptive norms had strongest associations around age 18. Low perceived physical harm associations got somewhat stronger with age.","methodology":"Repeated cross-sectional data from 15,251 young adults (mean age 22, 68% female) in the Washington Young Adult Health Survey from 2015-2022 (post-legalization). Logistic time-varying effect models examined age-varying associations between risk factors and cannabis use (any and frequent past-month use).","limitations":"Repeated cross-sectional design means different individuals were surveyed at different ages, not the same people tracked over time. Washington-specific findings may not apply to states with different legal frameworks. Self-report measures may undercount actual use."},{"rthcId":"RTHC-07066","title":"Cannabidiol (CBD) as a novel inhibitor of HLA-G expression in human choriocarcinoma cell line (JEG-3).","authors":"Martínez, Kevin I; Palma, María B; Sepúlveda, Fernando J; Moavro, Damián E; Carosella, Edgardo D; García, Marcela N; Riccillo, Fernando L","year":2025,"journal":"Scientific reports, 15(1), 39808","doi":"10.1038/s41598-025-23554-2","pmid":"41233461","tags":["cbd","cancer"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both pure CBD and a high-CBD cannabis extract reduced cell proliferation and migration, increased apoptosis, and significantly downregulated HLA-G expression at mRNA and protein levels in JEG-3 choriocarcinoma cells. The HLA-G suppression was dose- and time-dependent and fully reversible after treatment withdrawal, indicating active CBD-dependent modulation rather than permanent cell damage.","whyItMatters":"HLA-G is a key immune checkpoint molecule that helps tumors evade immune detection. This is the first experimental evidence that CBD can suppress HLA-G, suggesting a mechanism by which CBD could help the immune system recognize and attack tumors.","specificNumbers":"HLA-G downregulation was dose- and time-dependent at both mRNA and protein levels. Effect was fully reversible after treatment withdrawal. Both CBD and the full extract reduced proliferation (Ki-67), increased apoptosis (caspase-3), and reduced migration (wound healing assay and MMP-9).","methodology":"JEG-3 human choriocarcinoma cells were treated with CBD and a high-CBD extract at safe concentrations determined by MTT assays. Researchers measured apoptosis (caspase-3), proliferation (Ki-67), migration (wound healing, MMP-9), and HLA-G expression (RT-qPCR and immunocytochemistry).","limitations":"Single cell line study (JEG-3 choriocarcinoma). Results may not extend to other tumor types. In vitro conditions do not replicate the complexity of the tumor microenvironment. The concentrations used may not be achievable in clinical settings."},{"rthcId":"RTHC-07067","title":"Health Service Use Among Young Adults With a History of Adolescent Cannabis Use.","authors":"Martínez, Pablo; Chadi, Nicholas; Castellanos-Ryan, Natalie; Vergunst, Francis; Dorais, Marc; Séguin, Jean R; Vitaro, Frank; Temcheff, Caroline; Tremblay, Richard E; Boivin, Michel; Côté, Sylvana M; Geoffroy, Marie-Claude; Orri, Massimiliano","year":2025,"journal":"JAMA network open, 8(10), e2539977","doi":"10.1001/jamanetworkopen.2025.39977","pmid":"41148134","tags":["youth","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Three adolescent cannabis patterns were identified: nonuse (60%), late-onset after 15 (20%), and early/frequent before 15 (20%). Early/frequent users had 51% higher odds of mental health care (OR 1.51), 57% higher odds of common mental disorder care (OR 1.57), and 86% higher odds of physical health care (OR 1.86) compared to nonusers. Late-onset users showed increased physical but not mental health care utilization.","whyItMatters":"This is among the strongest evidence linking adolescent cannabis patterns to concrete healthcare outcomes. By adjusting for 32 confounders measured before cannabis exposure began, it addresses the concern that pre-existing factors rather than cannabis itself drive the association.","specificNumbers":"N = 1,591 (51.4% female). 3 trajectory groups: nonuse 59.6%, late-onset 20.0%, early/frequent 20.4%. Early/frequent vs nonuse: mental disorder OR 1.51, common mental disorder OR 1.57, any physical condition OR 1.86, injuries OR 1.41, other physical diseases OR 1.47. Late-onset: physical condition OR 1.63 only.","methodology":"Population-based birth cohort from the Quebec Longitudinal Study of Child Development linked to administrative medical databases. Self-reported cannabis use at ages 12, 13, 15, and 17. Medical care utilization tracked from ages 18-23. Analyses adjusted for 32 individual, family, and community-level confounders measured from birth to age 12 using overlap weights.","limitations":"Canadian birth cohort may not generalize to other populations. Medical care utilization reflects healthcare-seeking behavior, not just health status. Self-reported cannabis use may be underreported. Administrative data captures diagnoses given during visits but may miss undiagnosed conditions."},{"rthcId":"RTHC-07068","title":"The rising burden of drug use disorders in the Americas, 2000-2021.","authors":"Martinez, Ramon; Zapata, Mario A; Tausch, Amy; Lange, Shannon; Russell, Cayley; Hennis, Anselm; E Souza, Renato Oliveira","year":2025,"journal":"Revista panamericana de salud publica = Pan American journal of public health, 49, e132","doi":"10.26633/RPSP.2025.132","pmid":"41450793","tags":["addiction","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"In 2021, 17.7 million people in the Americas had drug use disorders, with opioids (42.7%) and cannabis (31.5%) dominating. Drug use disorder deaths reached 77,717 (6.9 per 100,000), higher than global estimates. Age-standardized DALYs increased 4.95% annually, reaching 695 per 100,000. The burden was highest among young adult males.","whyItMatters":"Cannabis use disorders affect an estimated 5.6 million people across the Americas (31.5% of 17.7 million). As cannabis legalization expands, understanding the scale of cannabis-specific disorder burden is essential for allocating treatment resources.","specificNumbers":"17.7 million with drug use disorders (2021). Cannabis: 31.5% (~5.6 million). Opioids: 42.7%. Deaths: 77,717 (6.9/100,000). DALYs: 695/100,000, rising 4.95% annually. 145,515 all-cause deaths attributed to drug use (1.6% of total deaths).","methodology":"Analysis of Global Burden of Disease Study 2021 estimates across 38 countries in the Americas from 2000 to 2021. Examined morbidity, mortality, and DALYs from opioid, cocaine, amphetamine, cannabis, and other drug use disorders. Trends assessed using average annual percentage change via regression analysis.","limitations":"Global Burden of Disease estimates rely on modeling with inherent uncertainty. Cannabis use disorder diagnosis varies across countries. The study period (2000-2021) includes major policy changes in several countries that may affect reporting and diagnosis rates."},{"rthcId":"RTHC-07069","title":"The relationship of medical and recreational cannabis laws with opioid misuse and opioid use disorder in the USA: Does it depend on prior history of cannabis use?","authors":"Martins, Silvia S; Bruzelius, Emilie; Mauro, Christine M; Santaella-Tenorio, Julian; Boustead, Anne E; Wheeler-Martin, Katherine; Samples, Hillary; Hasin, Deborah S; Fink, David S; Rudolph, Kara E; Crystal, Stephen; Davis, Corey S; Cerdá, Magdalena","year":2025,"journal":"The International journal on drug policy, 136, 104687","doi":"10.1016/j.drugpo.2024.104687","pmid":"39793270","tags":["legalization","addiction","pain"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Overall, neither medical nor recreational cannabis laws were associated with changes in opioid misuse or use disorder at the population level. However, among individuals reporting past-year cannabis use, medical cannabis laws were associated with 43% lower odds of opioid misuse (AOR 0.57, FDR p = 0.07) compared to states without cannabis laws. Recreational laws showed no additional effect beyond medical legalization.","whyItMatters":"This study resolves a debate by showing that the opioid-cannabis substitution effect may be real but limited to people who are already using cannabis. The lack of a population-level effect explains why some studies find substitution while others do not.","specificNumbers":"NSDUH 2015-2019. Overall: no significant association between cannabis laws and opioid outcomes. Among past-year cannabis users in MCL states: AOR 0.57 (95% CI: 0.38-0.85) for opioid misuse. FDR-corrected p = 0.07. RCL: no additional effect.","methodology":"Analysis of NSDUH data from 2015-2019 using logistic regression with year and state fixed effects, individual covariates, and opioid-related state policies. Stratified analyses restricted to individuals reporting lifetime cannabis use prior to law adoption to reduce collider bias. False discovery rate corrections and e-values assessed robustness.","limitations":"NSDUH is self-reported and cross-sectional within waves. The FDR-corrected p-value of 0.07 is marginally significant. Restricting to past-year cannabis users introduces selection effects. Cannabis use prior to law adoption does not guarantee continued use after."},{"rthcId":"RTHC-07070","title":"Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors.","authors":"Marusak, Hilary A; Zundel, Clara G; Shakir, Tehmina; Ely, Samantha L; Carpenter, Carmen; Shampine, MacKenna; Tamimi, Reem; Matsko, Mariya; Rogers, Sarah; Losiowski, Jennifer; O'Mara, Emilie; Jaster, Alaina M; Sharma, Kamakashi; deRoon-Cassini, Terri A; Hillard, Cecilia J; Schroeder, Heidi K; Mills, Jeffrey A; Strawn, Jeffrey R; Barcelona, Jeanne","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(10), 1606-1614","doi":"10.1038/s41386-025-02155-7","pmid":"40579470","tags":["anxiety","youth","neuroscience"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"After adjusting for BMI, age, sex, and time of day, higher AEA and lower 2-AG were associated with more severe anxiety symptoms. In a subsample of 41 adolescents with GAD in an 8-week RCT of escitalopram, greater increases in 2-AG from baseline were linked to improved treatment response, without changes in AEA.","whyItMatters":"If blood endocannabinoid levels can predict who will respond to anxiety treatment, they could become the first objective biomarkers for guiding psychiatric care in youth. The selective association of 2-AG (but not AEA) with treatment response suggests these two endocannabinoids play different roles.","specificNumbers":"N = 199 youth (ages 9-17). RCT subsample: N = 41 (ages 12-17), escitalopram 15-20 mg/day for 8 weeks. BMI positively correlated with AEA. 2-AG negatively associated with age, female sex, and time of day. Higher AEA and lower 2-AG associated with greater anxiety severity.","methodology":"Circulating AEA and 2-AG were measured in 199 youth aged 9-17 with varying anxiety levels. Anxiety was assessed using the SCARED questionnaire. A subset of 41 adolescents (12-17) with GAD participated in an 8-week randomized placebo-controlled trial of escitalopram, with endocannabinoid levels measured at baseline and during treatment.","limitations":"Circulating endocannabinoid levels may not perfectly reflect brain levels. The RCT subsample is small (41 participants). Cross-sectional anxiety-endocannabinoid associations cannot determine causation. SCARED is a self-report measure."},{"rthcId":"RTHC-07071","title":"Cannabis Use and Intimate Partner Violence During Pregnancy Are Associated with Poorer Postpartum Mental Health.","authors":"Marvin, Matthew J; Ballinger, Alexandra L; Stein, Sara F; Fairchild, Jewelian N; Bogat, G Anne; Lonstein, Joseph S; Nuttall, Amy K; Muzik, Maria; Levendosky, Alytia A","year":2025,"journal":"American journal of perinatology","doi":"10.1055/a-2761-1601","pmid":"41412165","tags":["pregnancy","mental-health","depression","ptsd"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use during pregnancy was significantly associated with elevated postpartum PTSD (beta = 0.25) and depression symptoms, independent of IPV victimization. IPV was associated with all three outcomes: PTSD (beta = 0.21), depression (beta = 0.17), and anxiety (beta = 0.21). The interaction between cannabis and IPV was not significant, indicating independent rather than synergistic effects.","whyItMatters":"Cannabis use during pregnancy is rising, and this study shows it may carry mental health risks for mothers beyond the well-documented concerns about fetal effects. The independence of cannabis and IPV effects means that addressing one risk factor does not eliminate the other.","specificNumbers":"N = 257 women. Cannabis use: PTSD beta = 0.25 (p < 0.001), depression significant. IPV: PTSD beta = 0.21 (p = 0.005), depression beta = 0.17 (p = 0.022), anxiety beta = 0.21 (p = 0.008). Cannabis x IPV interaction: not significant.","methodology":"Prospective cohort of 257 women assessed at three points during pregnancy for IPV and cannabis use, then at 6 months postpartum for PTSD, depression, and anxiety symptoms. Linear regression analyses tested main effects and the interaction between cannabis use and IPV.","limitations":"Observational design cannot prove cannabis caused worse postpartum outcomes. Women using cannabis during pregnancy may have unmeasured risk factors. Self-reported cannabis use may be underreported due to stigma. The study cannot determine whether stopping cannabis would improve outcomes."},{"rthcId":"RTHC-07072","title":"Possible Anxiolytic Effects of Cannabidiol (CBD) Administration on Feline Responses to a Fear Response Test.","authors":"Masataka, Nobuo","year":2025,"journal":"Animals : an open access journal from MDPI, 15(11)","doi":"10.3390/ani15111642","pmid":"40509107","tags":["cbd","anxiety"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"After two weeks of CBD administration (4.0 mg/kg/day), cats exposed to a simulated thunderstorm showed significantly reduced fear-related urination compared to their initial test. No such improvement was seen in the placebo group receiving sunflower oil.","whyItMatters":"Noise phobia is one of the most common behavioral problems in companion animals. This small but controlled study adds to the growing evidence that CBD may have anxiolytic effects across species, using a practical and clinically relevant fear stimulus.","specificNumbers":"N = 40 cats (20 per group). CBD dose: 4.0 mg/kg/day for 14 days. Significant reduction in fear-related urination in CBD group only. Placebo group showed no change.","methodology":"Randomized placebo-controlled study with 40 cats naive to the testing protocol. Cats were assigned to CBD (4.0 mg/kg/day for 2 weeks) or placebo (sunflower oil). Each group was exposed to a thunderstorm simulation test before and after the 2-week administration period. Fear-related urination was the primary behavioral outcome.","limitations":"Small sample size. Only one behavioral measure (urination) was reported as significant. The study did not assess other fear behaviors like hiding, freezing, or vocalization in detail. Two weeks of administration makes it unclear whether shorter or longer treatment would differ."},{"rthcId":"RTHC-07073","title":"Revisiting the Gateway Drug Hypothesis for Cannabis: A Secondary Analysis of a Nationwide Survey Among Community Users in Japan.","authors":"Masataka, Yuji; Katayama, Munenori; Umemura, Futaba; Sugiyama, Takeshi; Miki, Naoko; Akahoshi, Yoshiyuki; Oka, Chihiro; Asahi, Takashi; Matsumori, Takashi; Takumi, Ichiro; Murata, Hidetoshi; Matsumoto, Toshihiko","year":2025,"journal":"Neuropsychopharmacology reports, 45(3), e70033","doi":"10.1002/npr2.70033","pmid":"40590180","tags":["addiction","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Tobacco and alcohol were the most common initial substances, with cannabis typically third. The odds of progressing from cannabis to other substances were low: alcohol 1.25, tobacco 0.77, methamphetamine 0.08, other illicit drugs 0.78. Nearly half of those who reported cannabis as their third drug did not use other substances afterward.","whyItMatters":"Japan maintains some of the strictest cannabis laws globally, making this a unique context for testing the gateway hypothesis. Even in a prohibitionist setting, cannabis rarely led to harder drug use, suggesting the \"gateway\" pattern is not an inherent property of cannabis itself.","specificNumbers":"N = 3,900. 81.5% male. Largest age group: 20-24. Cannabis typically 3rd substance after alcohol and tobacco. Odds of post-cannabis use: methamphetamine 0.08, other illicit 0.78, tobacco 0.77, alcohol 1.25. ~50% used no other drugs after cannabis.","methodology":"Anonymous online survey of 3,900 individuals reporting lifetime cannabis use in Japan, recruited via social media in January 2021. Substance use progression was visualized using a Sankey diagram. Odds ratios calculated for likelihood of using other substances following cannabis use.","limitations":"Online convenience sample may over-represent younger, tech-savvy users. Self-reported data may be affected by recall bias. Japan's strict drug enforcement may suppress progression to other drugs through deterrence rather than disproving gateway mechanisms. Social media recruitment introduces selection bias."},{"rthcId":"RTHC-07074","title":"How Has Japan's Cannabis Control Act Been Amended?","authors":"Masataka, Yuji; Akahoshi, Yoshiyuki; Katayama, Munenori; Umemura, Futaba; Miki, Naoko; Nakazawa, Ryota; Shibata, Kosuke; Yoshida, Chikako; Mikami, Ayako; Matsumoto, Toshihiko; Akino, Kozo; Takumi, Ichiro","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1089/can.2025.0006","pmid":"40489340","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07075","title":"Young Adults Advancing Through the Stages of Change: A Mediational Analysis of Cannabis Use Disorder Treatment.","authors":"Mason, Michael J; Coatsworth, J Douglas; Russell, Michael A; Mennis, Jeremy; Riggs, Nathaniel R; Zaharakis, Nikola; Brown, Aaron","year":2025,"journal":"Substance use & misuse, 60(10), 1523-1529","doi":"10.1080/10826084.2025.2505767","pmid":"40383939","tags":["quitting","addiction","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Mediation analysis showed that PNC-txt participants who reached the Action/Maintenance stage by 1 month had 50% lower odds of the highest THC metabolite level (300 ng/ml) and reported 4 fewer days of cannabis use in the past 30 days at 6 months, compared to controls.","whyItMatters":"Cannabis use disorder treatment has historically struggled with engagement, especially among young adults. A text-message approach overcomes key barriers (stigma, scheduling, cost) and this study shows it works through a well-established clinical mechanism, the Stages of Change.","specificNumbers":"N = 1,078 young adults. 4-week PNC-txt intervention. Action/Maintenance stage at 1 month: 50% lower odds of 300 ng/ml THC test. 4 fewer cannabis use days at 6 months. Biological (urine) and self-report outcomes both confirmed effects.","methodology":"Two-arm RCT with 1,078 US young adults randomized to 4 weeks of PNC-txt (text-message motivational interviewing) or wait-list control, followed for 6 months. Urine drug tests and self-reported use were outcome measures. The Marijuana Ladder assessed stages of change, dichotomized as Cognitive (precontemplation/contemplation/preparation) vs. Behavioral (action/maintenance) stages.","limitations":"Wait-list control means participants knew their group assignment. The mediation analysis is exploratory. Not all participants provided urine samples at all time points. The treatment effect operates through motivation change, so participants not ready to change may not benefit."},{"rthcId":"RTHC-07076","title":"Text message-delivered cannabis use disorder treatment with young adults: A large randomized clinical trial.","authors":"Mason, Michael J; Coatsworth, J Douglas; Riggs, Nathaniel R; Russell, Michael; Mennis, Jeremy; Zaharakis, Nikola; Brown, Aaron","year":2025,"journal":"Journal of substance use and addiction treatment, 170, 209611","doi":"10.1016/j.josat.2024.209611","pmid":"39730041","tags":["quitting","addiction","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"No significant direct treatment effects on cannabis use were found between PNC-txt and control. However, PNC-txt significantly increased readiness to change and protective behavioral strategies at 1 month, which mediated decreases in cannabis use days from baseline to 6 months. The treatment works through its hypothesized clinical mechanisms rather than through direct behavioral change.","whyItMatters":"Understanding how treatments work is as important as knowing whether they work. This companion paper to the mediation analysis reveals that the text-message approach succeeds by activating motivation and teaching harm reduction, not by directly changing behavior. This has implications for refining and improving the intervention.","specificNumbers":"N = 1,078 (Colorado and Tennessee). No direct treatment effect on use. Significant indirect effects: PNC-txt increased readiness to change and protective behavioral strategies at 1 month, leading to fewer cannabis use days at 6 months.","methodology":"RCT with 1,078 US young adults from Colorado and Tennessee randomized to 4-week PNC-txt or wait-list control, followed 6 months. Latent change score mediation modeling tested indirect effects through readiness to change and protective behavioral strategies.","limitations":"Wait-list control design. Mediation analysis is observational even within an RCT. The indirect-only effect pattern means the treatment may not help people who are not responsive to motivational approaches. Colorado and Tennessee represent different cannabis policy contexts."},{"rthcId":"RTHC-07077","title":"Trends in Daily Nicotine Vaping and Unsuccessful Quit Attempts in Youths.","authors":"Masonbrink, Abbey R; Bae, Dayoung; Cho, Junhan; Miech, Richard A; Dai, Hongying D; Harlow, Alyssa F; Sussman, Steve; Han, Dae-Hee; Sanchez, Louisiana M; Adjei, Abigail; Meza, Leah R; Li, Ming; Leventhal, Adam M","year":2025,"journal":"JAMA network open, 8(11), e2541061","doi":"10.1001/jamanetworkopen.2025.41061","pmid":"41182763","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07078","title":"Suk-SaiYasna Remedy, a Traditional Thai Medicine, Mitigates Stress-Induced Cognitive Impairment via Keap1-Nrf2 Pathway.","authors":"Masraksa, Wuttipong; Daodee, Supawadee; Monthakantirat, Orawan; Boonyarat, Chantana; Khamphukdee, Charinya; Kwankhao, Pakakrong; Mading, Abdulwaris; Muenhong, Poowanarth; Maneenet, Juthamart; Awale, Suresh; Matsumoto, Kinzo; Chulikhit, Yaowared","year":2025,"journal":"International journal of molecular sciences, 26(11)","doi":"10.3390/ijms26115388","pmid":"40508195","tags":["cognition","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"SSY treatment significantly improved learning and memory in chronically stressed mice across three behavioral tests (Y-maze, novel object recognition, Morris water maze). SSY reduced lipid peroxidation in the hippocampus and frontal cortex and restored SOD and CAT antioxidant enzyme activity. The mechanism involved the Nrf2/Keap1 signaling pathway, with THC and THCA identified as bioactive compounds alongside other herbal antioxidants.","whyItMatters":"This bridges traditional Thai medicine with modern neuropharmacology, showing that a centuries-old cannabis-containing formula has measurable neuroprotective effects through well-characterized molecular pathways. The multi-compound formula may have advantages over isolated cannabinoids.","specificNumbers":"SSY improved performance on Y-maze, novel object recognition, and Morris water maze tests. Reduced lipid peroxidation in hippocampus and frontal cortex. Restored SOD and CAT activity. Upregulated HO-1 and NQO1 mRNA via Nrf2-Keap1 pathway. Active compounds: THC, THCA, gallic acid, myricetin, myristicin, piperine, costunolide, gingerol.","methodology":"Mice were exposed to unpredictable chronic mild stress (UCMS) to induce cognitive impairment. SSY-treated groups received the herbal formula during the stress period. Behavioral tests assessed learning and memory. Brain tissue was analyzed for oxidative stress markers and antioxidant enzyme activity. Gene expression analysis examined the Nrf2/Keap1 pathway. Phytochemical analysis identified active compounds.","limitations":"Mouse model of chronic stress does not perfectly replicate human cognitive decline. The formula contains many active compounds, making it difficult to attribute effects to cannabis specifically. SSY is a traditional preparation that may vary in composition. Dose translation to humans is uncertain."},{"rthcId":"RTHC-07079","title":"\"Well, if they exist, I ignore them\": A focus group study of recall and reactions to cannabis health warnings by cannabis consumers in the United States.","authors":"Massey, Zachary B; Ibe, Chinomso; Smith, Michael A; Vogel, Erin A; Thrasher, James F; Hammond, David","year":2025,"journal":"Preventive medicine reports, 60, 103306","doi":"10.1016/j.pmedr.2025.103306","pmid":"41322664","tags":["harm-reduction","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Cannabis consumers reported being unaware of or choosing to ignore health warnings on products they used. When presented with hypothetical warnings, many expressed disbelief about the accuracy of health claims. Personal experience with cannabis harms was the main factor in believing or disbelieving warnings. Participants requested cited sources, direct language, and enhanced visuals to improve warning effectiveness.","whyItMatters":"If cannabis health warnings are not noticed or believed by the people they target, they are failing at their primary purpose. This study provides direct consumer feedback on how to make warnings more effective, including the key insight that evidence citations and visual elements matter more than text alone.","specificNumbers":"N = 77 consumers in 12 focus groups. Ages 22-68, median 42. All lived in legal recreational states. All had used cannabis in past 30 days.","methodology":"Twelve focus groups with 77 cannabis consumers aged 21+ (median age 42) who had used cannabis in the past 30 days and lived in states with legal recreational cannabis. Conducted February-March 2025. Participants first described warnings on products they used, then reacted to hypothetical health warnings.","limitations":"Qualitative study cannot quantify warning effectiveness. Participants from legal states may have different attitudes than those in illegal states. Focus group dynamics can amplify dominant opinions. The study examined reactions to hypothetical warnings, not real-world behavioral responses."},{"rthcId":"RTHC-07080","title":"Sex differences in the acute effects of cannabis on human cognition: A systematic review.","authors":"Matheson, Justin; Behzad, Danial; Zakala, Christina; Hawken, Thomas; Brands, Bruna; Le Foll, Bernard; Wickens, Christine M; Ruocco, Anthony C; Rodak, Terri; Di Ciano, Patricia","year":2025,"journal":"Frontiers in neuroendocrinology, 79, 101215","doi":"10.1016/j.yfrne.2025.101215","pmid":"40819776","tags":["cognition","sex-differences"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Of 29 studies meeting criteria, only 6 (20.7%) found statistical evidence of sex differences in acute cognitive effects, representing just 8 of 216 cognitive outcomes tested (3.7%). All 6 found increased effects in females on at least one measure. No clear patterns emerged by dosing method, route of administration, or cognitive domain.","whyItMatters":"Cannabis policy and clinical guidance are largely sex-neutral, but biological sex differences in cannabinoid metabolism and receptor density could mean men and women experience different cognitive effects. This review finds that the current evidence is insufficient to confirm or deny this possibility.","specificNumbers":"29 studies included from 1,625 screened. 216 total cognitive outcomes examined. 8 outcomes (3.7%) showed sex differences. 6 of 29 studies (20.7%) found any sex difference. All significant findings showed greater effects in females.","methodology":"Systematic review following PRISMA guidelines searching Embase, MEDLINE, PsycInfo, Cochrane, and Web of Science. Of 1,625 unique records, 169 underwent full-text screening, and 29 studies met inclusion criteria. Studies had to examine acute cannabis or THC effects on cognition with sex-disaggregated results.","limitations":"Most included studies were not designed to detect sex differences and may have been underpowered. Methodological heterogeneity across studies (different doses, routes, cognitive tests) limits comparison. Hormonal factors were rarely measured."},{"rthcId":"RTHC-07081","title":"Feasibility and Tolerability of Nabilone for the Treatment of Obesity: A Randomized Controlled Pilot Trial.","authors":"Matheson, Justin; Tertigas, Dominique; Malik, Saima; Taylor, Valerie; Chavez, Sofia; Sharkey, Keith A; Silvestri, Cristoforo; Surette, Michael; Le Foll, Bernard","year":2025,"journal":"Cannabis and cannabinoid research, 10(5), 640-651","doi":"10.1089/can.2025.0034","pmid":"40353878","tags":["appetite","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"The trial was terminated early because all four high-dose participants (6 mg/day) withdrew due to adverse events. Among the 8 completers (4 low-dose, 4 placebo), there was a significant treatment effect on body weight, with low-dose nabilone (2 mg/day) reducing weight. The low-dose group also showed greater changes in fecal microbiome composition than placebo.","whyItMatters":"Epidemiological data shows cannabis users have lower obesity rates, and the endocannabinoid system is a known obesity target. However, this trial shows that directly activating CB1 receptors with nabilone is poorly tolerated, especially at higher doses. The microbiome finding opens an unexpected new avenue.","specificNumbers":"18 randomized, 15 received drug, 8 completed. All 4 high-dose withdrew due to adverse events. Low-dose (n=4) vs placebo (n=4): significant treatment effect on body weight. Greater fecal microbiome change in low-dose arm (Bray-Curtis dissimilarity, p significant).","methodology":"Randomized, double-blind, placebo-controlled pilot trial with 18 adults (25-45, BMI indicating obesity) assigned 1:1:1 to high-dose nabilone (6 mg/day), low-dose (2 mg/day), or placebo for 12 weeks. Outcomes included body weight, BMI, waist circumference, gut microbiome, blood biomarkers, and mood.","limitations":"Extremely small sample (8 completers). Early termination due to poor tolerability. Participants had not used cannabinoids for 6 months, which may have contributed to adverse events. The weight and microbiome findings are from only 4 participants per group."},{"rthcId":"RTHC-07082","title":"Cannabis Use Characteristics and Reasons for Product Choices Among Patients Accessing Treatment for Substance Use Disorders: A Mixed-Methods Study.","authors":"Matheson, Justin; Saini, Harseerat; Haines-Saah, Rebecca; Sanches, Marcos; Sloan, Matthew E; Zaweel, Adam; Hassan, Ahmed; Buckley, Leslie; Porathl, Amy; MacKillop, James; Hendershot, Christian S; Kloiber, Stefan; Le Foll, Bernard","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(2), 67-84","doi":"10.26828/cannabis/2025/000309","pmid":"40909151","tags":["addiction","harm-reduction","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"89% of current cannabis users smoked dried flower for non-medical purposes. Edibles were the second most common (53%), with 11% using high-potency products like dabs. Qualitative interviews revealed THC content was the primary driver of product choices, but perceived medical benefits and harm reduction motivated CBD product use. Convenience and familiarity also influenced decisions.","whyItMatters":"People in SUD treatment represent a high-risk population for cannabis-related harms. Understanding their product preferences and motivations can help clinicians have more informed conversations about cannabis use and tailor harm reduction advice.","specificNumbers":"N = 472 survey, 22 interviews. Current users: 89% smoked flower (non-medical), 53% used edibles, 11% used dabs/concentrates. THC content was primary purchase motivator. CBD products chosen for perceived medical/harm-reduction benefits.","methodology":"Mixed-methods study: online survey of 472 adults who self-reported accessing SUD treatment and lifetime cannabis use, plus in-depth interviews with 22 participants. Quantitative analysis described product characteristics; qualitative descriptive analysis explored reasons for product choices among current users.","limitations":"Online survey may not reach all SUD treatment patients. Self-reported product use may be imprecise. The qualitative subset (22 participants) may not capture the full range of motivations. Cross-sectional design cannot track how product choices change over time."},{"rthcId":"RTHC-07083","title":"Exploring perceived gender norms about cannabis among treatment-seeking adults in the era of cannabis legalization in Canada: A qualitative analysis.","authors":"Matheson, Justin; Wright, Madison; Watson, Tara Marie; Sproule, Beth; Le Foll, Bernard; Brands, Bruna","year":2025,"journal":"Journal of substance use and addiction treatment, 172, 209684","doi":"10.1016/j.josat.2025.209684","pmid":"40120814","tags":["sex-differences","legalization","addiction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Three themes emerged: (1) Masculine Dominance of Cannabis Use: recreational smoking is socially constructed as a masculine behavior; (2) Cannabis Use as Deviation from Femininity: women and gender-diverse people face extra stigma and are framed as inauthentic users; (3) Rejecting and Reconfiguring Gender Norms: legalization may be catalyzing challenges to masculine dominance by increasing visibility of women using cannabis.","whyItMatters":"Gender norms influence who uses cannabis, how they use it, and whether they seek treatment. Understanding these norms is essential for developing gender-responsive interventions that do not inadvertently reinforce stigma against women and gender-diverse cannabis users.","specificNumbers":"23 participants in treatment for cannabis-related harms in Toronto. 3 main themes generated. Study conducted post-legalization (Canada legalized in 2018).","methodology":"In-depth one-on-one interviews with 23 adults in Toronto, Ontario who had been in treatment for cannabis-related harms. Reflexive thematic analysis using Connell's masculinities framework and critical femininities scholarship.","limitations":"Small qualitative sample from one Canadian city. Participants were in treatment, so their perspectives may differ from non-treatment-seeking users. The analysis framework (masculinities/femininities scholarship) shapes interpretation."},{"rthcId":"RTHC-07084","title":"Associations Between Cannabis Use and Mental Health in Patients Accessing Treatment for Substance Use Disorders: An Exploratory Cross-Sectional Study.","authors":"Matheson, Justin; MacKillop, James; Sloan, Matthew E; Sanches, Marcos; Saini, Harseerat; Haines-Saah, Rebecca; Zaweel, Adam; Hassan, Ahmed; Buckley, Leslie; Porath, Amy; Hendershot, Christian S; Kloiber, Stefan; Le Foll, Bernard","year":2025,"journal":"Substance use & misuse, 60(12), 1883-1891","doi":"10.1080/10826084.2025.2519419","pmid":"40528368","tags":["addiction","mental-health","depression","anxiety","ptsd"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was significantly associated with trauma history and several psychiatric diagnoses including anxiety and depression, with the highest prevalence in current users. However, cannabis use was not independently associated with anxiety, depression, sleep quality, or disability scores after controlling for trauma exposure, suggesting trauma may mediate the relationship.","whyItMatters":"Understanding the mental health profile of cannabis users in SUD treatment is essential for tailoring care. The finding that trauma may explain much of the cannabis-mental health link suggests that trauma-informed approaches could be more effective than focusing on cannabis use alone.","specificNumbers":"N = 544. Current users: 363, past users: 109, never users: 72. Trauma and psychiatric diagnoses significantly associated with cannabis group. Anxiety, depression, sleep, and disability scores not independently associated with cannabis use after adjusting for trauma.","methodology":"Cross-sectional online survey of 544 patients in Ontario, Canada seeking SUD treatment. Participants grouped by cannabis use: current (past-year, n=363), past (lifetime but not past-year, n=109), and never (n=72). Validated measures assessed GAD-7, PHQ-9, PSQI, WHODAS, psychiatric diagnoses, trauma, and suicidality.","limitations":"Cross-sectional design prevents causal inference. Self-reported measures may be subject to recall bias. Ontario-specific treatment population may not generalize. Current cannabis use was not distinguished from cannabis use disorder."},{"rthcId":"RTHC-07085","title":"Advancing cervical cancer treatment: integrating cannabinoids, combination therapies and nanotechnology.","authors":"Mathibela, S P; Ncube, K N; Lebelo, M T; Steenkamp, V","year":2025,"journal":"Journal of cancer research and clinical oncology, 151(11), 294","doi":"10.1007/s00432-025-06323-6","pmid":"41102423","tags":["cancer","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"THC and CBD demonstrate anticancer effects in cervical cancer cells by inducing apoptosis, inhibiting proliferation, suppressing metastasis, promoting oxidative stress, and modulating immune responses. Combining cannabinoids with chemotherapy, radiotherapy, or immunotherapy enhanced efficacy and reduced drug resistance. Nanoparticle delivery systems improved targeting, solubility, and reduced systemic toxicity.","whyItMatters":"Cervical cancer remains a major health challenge, particularly in sub-Saharan Africa. Cannabinoids represent a new class of potential therapeutic agents, and nanotechnology may solve key delivery challenges that have limited their clinical application.","specificNumbers":"Review covers multiple mechanisms: apoptosis induction, proliferation inhibition, metastasis suppression, oxidative stress promotion, immune modulation. Combination approaches with chemo, radio, and immunotherapy reviewed.","methodology":"Critical synthesis of preclinical studies examining cannabinoid anticancer properties in cervical cancer, including combination therapy approaches and nanotechnology-based delivery platforms.","limitations":"All evidence is preclinical. No human clinical trials for cannabinoids in cervical cancer exist. Optimal formulations, doses, and delivery routes remain to be determined. Regulatory challenges for cannabinoid-based medicines persist."},{"rthcId":"RTHC-07086","title":"Model Building with Youth: Applying a System Science Approach to Examine the Dynamic Social Context of Adolescent and Young Adult Marijuana Use.","authors":"Matson, Pamela A; Flessa, Sarah; Stankov, Ivana; Fortenberry, J Dennis; Trent, Maria; Frerichs, Leah; Lich, Kristen Hassmiller","year":2025,"journal":"Prevention science : the official journal of the Society for Prevention Research, 26(1), 122-137","doi":"10.1007/s11121-025-01774-2","pmid":"39832056","tags":["youth","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"The causal loop diagram generated by youth featured 14 feedback loops across three domains: within-relationship behaviors, factors proximal to marijuana use, and influences on the partner pool. Stress and dysfunctional relationship behaviors fed back to magnify relationship problems and fuel cannabis use in reinforcing cycles.","whyItMatters":"Prevention programs typically address cannabis use in isolation. This youth-generated systems model reveals how relationship dynamics, stress, and cannabis use are interconnected in reinforcing loops, suggesting that interventions targeting relationship skills could also reduce cannabis use.","specificNumbers":"2 groups of youth aged 15-20. 4 workshops of 2 hours each. 14 feedback loops identified (both balancing and reinforcing). 3 interconnected domains mapped.","methodology":"Group model building, a systems science approach, with two independent groups of youth aged 15-20 recruited from clinic and community settings. Each group participated in four 2-hour structured workshops to build causal loop diagrams representing their mental models of how social dynamics influence cannabis use.","limitations":"Causal loop diagrams represent participants' mental models, not empirically validated causal pathways. Small, convenience sample from one geographic area. The model has not been tested with quantitative data."},{"rthcId":"RTHC-07087","title":"Clinical Characteristics of Patients With Cannabis-Related Mental Disorders and an Examination of Factors Influencing Their Access to Medical and Nonmedical Resources: Comparison of Methamphetamine-Related Mental Disorders.","authors":"Matsumoto, Toshihiko; Usami, Takashi; Nishimura, Akiho; Higuchi, Sayako; Okita, Kyoji; Shimane, Takuya","year":2025,"journal":"Neuropsychopharmacology reports, 45(3), e70051","doi":"10.1002/npr2.70051","pmid":"40974268","tags":["addiction","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis patients (n=82) were younger than methamphetamine patients (n=208), had fewer drug-related criminal offences, less incarceration history, fewer comorbid psychiatric disorders, and less severe substance use disorder. However, they had less experience with self-help groups or recovery support facilities. Use of nonmedical resources was more strongly associated with older age and disorder severity than with substance type.","whyItMatters":"Japan is seeing increasing numbers of young cannabis-related arrests and treatment-seekers. Current recovery support resources may be designed around the profile of older, more severe methamphetamine users and may not meet the needs of this younger, less severe cannabis population.","specificNumbers":"N = 290 (208 methamphetamine, 82 cannabis), all male. Cannabis group: younger, fewer criminal offences, fewer comorbid psychiatric disorders, less severe SUD, less use of self-help groups and recovery facilities.","methodology":"Data from the 2024 Nationwide Survey on Drug-Related Mental Disorders in Japanese Psychiatric Hospitals. Compared 208 male methamphetamine cases and 82 male cannabis cases on clinical variables. Logistic regression examined factors associated with use of self-help groups and recovery support.","limitations":"Male patients only from psychiatric hospital settings. Japan's strict drug policy context limits generalizability. Cross-sectional design cannot determine trajectories. Cannabis group is relatively small (n=82)."},{"rthcId":"RTHC-07088","title":"Cannabinoids and ADHD: a New Frontier in Neuropharmacology?","authors":"Mavaddat, Helia; Fouladi, Abtin; Kashani, Ayeh Sabbagh; Khayatan, Illia; Andarzbaksh, Kamyab; Razavi, Seyed Mehrad; Rezazadeh, Amir","year":2025,"journal":"Journal of molecular neuroscience : MN, 75(4), 146","doi":"10.1007/s12031-025-02435-3","pmid":"41165995","tags":["cognition","mental-health","cbd"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Individuals with ADHD have elevated risk for substance use and cannabis dependence. Some may use cannabis to manage anxiety or medication side effects. Both in vivo and clinical investigations suggest cannabinoids, particularly CBD, may have therapeutic potential in ADHD, possibly through modulation of dopaminergic and noradrenergic systems.","whyItMatters":"ADHD affects millions of people, and existing medications have significant side effects and limitations. If cannabinoids (particularly CBD) prove effective, they could offer a new treatment option for a population that already uses cannabis at elevated rates.","specificNumbers":"Review covers epidemiological data on ADHD-cannabis co-occurrence, self-medication patterns, and multiple proposed pharmacological mechanisms including dopamine and norepinephrine modulation.","methodology":"Comprehensive narrative review of literature on cannabinoid effects in ADHD, examining epidemiological associations, self-medication patterns, preclinical evidence, clinical studies, and proposed pharmacological mechanisms.","limitations":"Narrative review with limited clinical evidence. Most mechanistic evidence is from animal studies. No large-scale RCTs of cannabinoids for ADHD exist. The review cannot determine whether cannabis use in ADHD is beneficial or harmful."},{"rthcId":"RTHC-07089","title":"Marijuana Use and Complication Risk After Tibia Shaft Fracture Fixation.","authors":"Maxson, Ridge; Rapaport, Sarah; Covarrubias, Oscar; Ghanem, Diane; Moreno-Diaz, Andres F; Ross, Ryan; Bergstein, Victoria E; O'Sullivan, Lucy; Rogers, Davis; Mitchell, Phillip M; Shafiq, Babar","year":2025,"journal":"Journal of orthopaedic trauma, 39(3), 137-143","doi":"10.1097/BOT.0000000000002945","pmid":"39651897","tags":["medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 388 patients (25% marijuana users), marijuana use was not associated with 90-day surgical complications (OR 2.01, 95% CI 0.83-4.84), deep infection (OR 2.97, 95% CI 0.95-9.25), thromboembolic events, or fracture union complications on multivariate analysis controlling for tobacco use, open fracture, and ASA class.","whyItMatters":"Marijuana use is common among trauma patients (25% in this study). Surgeons need evidence-based guidance on whether preoperative cannabis use affects surgical outcomes. This study suggests it does not increase complication risk for this common fracture type.","specificNumbers":"N = 388 patients. Mean age 37.6. 66.5% male. 96 (25%) marijuana users. Marijuana users younger (30.5 vs 40 years, p significant). No significant associations with surgical complications, deep infection, thromboembolic events, or fracture union problems.","methodology":"Retrospective cohort study at two Level I academic trauma centers from 2014-2022. Patients with tibia shaft fractures and minimum 3-month follow-up. Marijuana use identified by self-report or positive urine toxicology. Multivariate regression controlled for tobacco use, open fracture, and ASA class.","limitations":"Retrospective design with potential for unmeasured confounders. Cannabis use was binary (yes/no) without dose or frequency data. Some individual complication odds ratios were elevated but not statistically significant, possibly due to limited power. Results specific to tibia shaft fractures."},{"rthcId":"RTHC-07090","title":"Examining changes in gramicidin current induced by endocannabinoids.","authors":"Mayar, Sultan; Cyr-Athis, Audrey; D'Avanzo, Nazzareno","year":2025,"journal":"PloS one, 20(8), e0313903","doi":"10.1371/journal.pone.0313903","pmid":"40825012","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07091","title":"An open-label phase I comparator-controlled clinical trial to assess tolerability and pharmacokinetics of IHL-675 A a fixed dose combination of cannabidiol plus hydroxychloroquine in healthy volunteers.","authors":"Mbogo, George Williams; Kroner, Pia; Walsh, Rosemarie; Newchurch, Jonathan; Bleackley, Mark Robert","year":2025,"journal":"Scientific reports, 15(1), 19357","doi":"10.1038/s41598-025-04573-5","pmid":"40456820","tags":["cbd","drug-interactions","inflammation"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"IHL-675A was generally well-tolerated with no serious adverse events. Both CBD and HCQ were bioavailable when co-administered. CBD exposure was approximately 50% higher (Cmax) in the combination versus Epidiolex alone, while HCQ exposure was slightly decreased (15% lower AUC). The 90% CIs for both drugs extended beyond standard bioequivalence acceptance intervals.","whyItMatters":"This is the first clinical trial of a fixed-dose CBD-hydroxychloroquine combination being developed for rheumatoid arthritis and other inflammatory conditions. The safety and PK data support continued development toward efficacy trials.","specificNumbers":"36 participants, 12 per arm. No SAEs. CBD Cmax approximately 50% higher in combination vs Epidiolex alone. HCQ AUC approximately 15% lower in combination vs Plaquenil alone. 90% CIs outside 80-125% bioequivalence range for both drugs.","methodology":"Phase I, randomized, open-label, comparator-controlled trial with 36 healthy volunteers assigned 1:1:1 to IHL-675A (150mg CBD + 200mg HCQ), Plaquenil alone (200mg HCQ), or Epidiolex alone (150mg CBD). Safety, pharmacokinetics, and metabolite profiles assessed over 4 weeks.","limitations":"Phase I in healthy volunteers only (no patients with inflammatory conditions). Small sample size. Open-label design. The increased CBD and decreased HCQ exposures in the combination need to be evaluated for clinical significance. Single-dose study."},{"rthcId":"RTHC-07092","title":"Stimulant and medicinal cannabis prescribing in patients referred to an early psychosis service in Queensland: A brief report.","authors":"McArdle, Peter; Trott, Mike; Warren, Nicola; De Silva, Dilprasan; Smith, Lesley; Ritchie, Sarah; Siskind, Dan","year":2025,"journal":"Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists, 10398562251406048","doi":"10.1177/10398562251406048","pmid":"41389186","tags":["psychosis","medical-cannabis","potency"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Before referral, 3.2% of patients were prescribed medicinal cannabis; after psychosis, this rose to 6.8%. Mean THC concentrations in prescriptions were nearly double after psychosis onset (31.4% vs 16.9%). Over 70% of those prescribed stimulants and 60% prescribed medicinal cannabis after a psychotic episode had further mental health service contact where these medications were thought to contribute to deterioration.","whyItMatters":"This raises serious safety concerns about medicinal cannabis prescribing practices for patients with psychosis history. Higher THC concentrations after psychosis onset goes against established evidence that THC can worsen psychotic symptoms.","specificNumbers":"N = 220 referrals. Pre-psychosis: 3.2% prescribed medicinal cannabis, mean THC 16.9%. Post-psychosis: 6.8% prescribed, mean THC 31.4%. 60% of post-psychosis medicinal cannabis patients had further mental health contact attributed to medication.","methodology":"Retrospective review of 220 consecutive early psychosis referrals (2019-2023) in Queensland, Australia. Clinical records were reviewed for stimulant and medicinal cannabis prescriptions before and after referral, with THC concentration data extracted from prescriptions.","limitations":"Small numbers of medicinal cannabis patients (7 pre, 15 post). Retrospective design cannot prove causation between prescriptions and deterioration. Attribution of deterioration to medication may be subjective. Single service in one Australian state."},{"rthcId":"RTHC-07093","title":"Evaluating the association between cannabis decriminalization and legalization and cannabis arrests and related disparities: A Systematic review.","authors":"McCarthy, Stephen D S; Gaudreault, Adrienne; Xiao, Jennifer; Fischer, Benedikt; Hall, Wayne; Lee, Kathryn; Kang, Rachel; Aslanyan, Garry; Sood, Manish M; Myran, Daniel T","year":2025,"journal":"The International journal on drug policy, 137, 104705","doi":"10.1016/j.drugpo.2025.104705","pmid":"39914039","tags":["legalization"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"100% of studies (7/7) showed significant reductions after decriminalization (13.5-78% reduction). 75% of studies (6/8) showed reductions after legalization (33-87%). Legalization consistently reduced adult offences but not always youth offences. Despite absolute reductions across racial groups, relative disparities were variable, increasing in some jurisdictions while decreasing in others.","whyItMatters":"Reducing criminal justice harms is a primary justification for cannabis legalization. This review confirms that both decriminalization and legalization achieve this goal but reveals that they do not automatically eliminate racial disparities in enforcement, which was another stated goal.","specificNumbers":"17 studies from 2,806 screened. Decriminalization: 13.5-78% reduction in offences (7/7 studies). Legalization: 33-87% reduction (6/8 studies). In previously decriminalized states, legalization added 35-84% further reduction (2/3 studies). Youth reductions less consistent than adult.","methodology":"Systematic review of 7 databases yielding 17 studies from North America (15 USA, 2 Canada). Examined changes in cannabis arrests, charges, convictions, and referrals after four policy types: medical legalization, decriminalization, non-medical legalization, and commercialization. Synthesis without meta-analysis.","limitations":"All 17 studies were from North America. Limited evidence on commercialization effects (only 2 studies). Youth-specific data was sparse. The review could not account for differences in implementation and enforcement across jurisdictions."},{"rthcId":"RTHC-07094","title":"The driving-related attitudes, beliefs and behaviours of cannabis users in the Australian Capital Territory following decriminalisation.","authors":"McCartney, Danielle; Zhou, Cilla; Lavender, Isobel; Gordon, Rebecca; Kevin, Richard C; Bedoya-Pérez, Miguel; McGregor, Iain S","year":2025,"journal":"Drug and alcohol review, 44(2), 588-601","doi":"10.1111/dar.13983","pmid":"39778038","tags":["driving","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"67.9% of participants reported waiting 7+ hours before driving, but 21.5% reported waiting 3 hours or less. Those driving soonest had the highest cannabis and THC intakes. Shorter wait times were associated with less concern about roadside drug testing, more frequent use, larger amounts, and exclusive non-medicinal use.","whyItMatters":"Cannabis decriminalization created a legal home-growing population whose driving behavior can be studied openly for the first time. The finding that heavy users are most likely to drive shortly after use highlights a road safety challenge that legalization alone does not solve.","specificNumbers":"N = 385 survey, 52 submitted cannabis samples. 67.9% (224/330) waited 7+ hours. 21.5% (71/330) waited 3 hours or less. Shortest wait-time users had highest cannabis and THC intakes.","methodology":"Two-part cross-sectional study in the ACT following 2020 cannabis decriminalization. Part 1: 385 cannabis users completed an online survey. Part 2: 52 submitted home-grown cannabis for phytocannabinoid analysis to estimate usual THC intakes.","limitations":"Self-reported wait times may be inaccurate. Online recruitment may not reach all cannabis users. Cross-sectional design cannot track behavior changes over time. THC intake estimates relied on small subsample of 52 cannabis samples."},{"rthcId":"RTHC-07095","title":"Does acute stress induced via cold water immersion increase blood THC concentrations in regular cannabis users?","authors":"McCartney, Danielle; Levoux, Jordan; Gordon, Rebecca; Sharman, Laura; Walker, Katie; Arnold, Jonathon C; McGregor, Iain S","year":2025,"journal":"Psychopharmacology, 242(12), 2785-2799","doi":"10.1007/s00213-025-06833-8","pmid":"40515781","tags":["neuroscience","tolerance"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"Cold water immersion (10 minutes at 10 degrees C) produced a small but significant stress response (increased heart rate, blood pressure, decreased calmness) and increased plasma free fatty acids and glycerol. However, neither plasma THC nor its metabolite 11-COOH-THC increased, and no cognitive impairment or subjective intoxication was observed.","whyItMatters":"Animal studies suggested that stress-induced lipolysis could release fat-stored THC into circulation, potentially causing unexpected intoxication. This study found no evidence of this phenomenon in humans, which is reassuring for regular cannabis users in stressful situations.","specificNumbers":"N = 15 (9 female). Cannabis use: 5.0 days/week. CWI: 10 min at ~10 degrees C. Significant increases in HR, systolic BP, FFA, and glycerol. No change in plasma THC, 11-COOH-THC, cognitive function, or subjective drug effects.","methodology":"Single-arm trial with 15 regular cannabis users (5+ days/week, 9 female). Participants underwent cold water immersion as a stress intervention. Plasma cannabinoids, cognitive function, subjective drug effects, heart rate, blood pressure, and lipolysis markers were measured before, shortly after, and 2 hours after immersion.","limitations":"Small sample (n=15). Only one type and duration of stress tested. The stress response and lipolysis were modest; more intense or prolonged stress might produce different results. Regular users only; results may not apply to occasional users with different fat storage patterns."},{"rthcId":"RTHC-07096","title":"Substance Use Screening Among Adolescents: National Dental Practice-Based Research Network Survey.","authors":"McCauley, Jenna L; Leo, Michael C; Crawford, Phillip; McBurnie, Mary Ann; Barton, Danyelle; Weidner, Heather A; Rindal, D Brad; Gilbert, Gregg H","year":2025,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 77(6), 1088-1096","doi":"10.1016/j.jadohealth.2025.07.012","pmid":"40985913","tags":["youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Fewer than half of dentists (40.5%) screened for adolescent nicotine/tobacco annually, with approximately one-third screening for cannabis and other substances. Among those who screen, 52.7% never counseled about positive cannabis screens and 55.4% never counseled about illicit drug use. Referral rates to specialty care were low. However, dentists reported low stigma and high perceived relevance.","whyItMatters":"Dentists see adolescents regularly and could serve as an additional screening touchpoint for substance use. The gap between willingness and practice suggests that systemic barriers (training, time, referral pathways) rather than attitudes are preventing screening.","specificNumbers":"N = 751 dentists (61% male, 67% White, 81% private practice). Annual screening: tobacco 40.5%, cannabis ~33%, alcohol ~33%, illicit drugs ~33%. Among screeners, never counseled: alcohol 48.5%, cannabis 52.7%, illicit drugs 55.4%.","methodology":"Cross-sectional electronic survey of 751 dentists in the National Dental Practice-Based Research Network. Assessed knowledge, attitudes, and practices regarding substance use screening, counseling, and referral for adolescent patients.","limitations":"Self-reported practices may overestimate actual screening. Survey respondents may be more interested in the topic than non-respondents. The survey did not assess the quality of screening when it occurred."},{"rthcId":"RTHC-07097","title":"Detecting cannabis use reduction through biochemical verification of urinary cannabinoids: An aggregated analysis of cannabis use disorder treatment trials examining average reductions and individual cut-points.","authors":"McClure, Erin A; Neelon, Brian; Tomko, Rachel L; Dowd, Ashley; Gray, Kevin M; McRae-Clark, Aimee L; Baker, Nathaniel","year":2025,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70291","pmid":"41408987","tags":["addiction","quitting"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Participants self-reporting cannabis use reduction had significantly lower urinary cannabinoids compared to non-reducers (difference of 391 ng/ml, 95% CI 231-551, p < 0.001). Average urinary cannabinoids decreased by up to 50% from baseline in the reduction group. However, no reliable individual-level cut-point could be established for creatinine-normalized THC.","whyItMatters":"Cannabis harm reduction research has lacked a biochemical verification method for use reduction (unlike abstinence, which can be verified). This study takes the first step toward establishing that self-reported reduction correlates with measurable decreases in urinary THC.","specificNumbers":"N = 471 from 7 trials. 220 reducers, 251 non-reducers. Difference: 391 ng/ml (95% CI: 231-551, p < 0.001). ~50% average decrease in urinary cannabinoids for reducers. Individual CN:THC cut-point: -39.9 (95% CI: -70.3 to 2.9, not significantly different from zero).","methodology":"Aggregated analysis of 7 CUD treatment trials (n=471 non-abstinent participants). Reduction defined as 50% decrease in frequency and/or 75% decrease in amount. Longitudinal models compared urinary cannabinoids between self-reported reducers (n=220) and non-reducers (n=251), controlling for parent study, study week, baseline levels, and covariates.","limitations":"Aggregated data from different trials with varying designs and populations. Cannabis reduction was self-reported with potential bias. Creatinine normalization may not adequately account for hydration variation. 51% of original participants met criteria for analysis."},{"rthcId":"RTHC-07098","title":"Improving Awareness and Use of Medical Cannabis for Fibromyalgia.","authors":"McClure, Linh M; West, Gordon F","year":2025,"journal":"Journal of holistic nursing : official journal of the American Holistic Nurses' Association, 8980101251376863","doi":"10.1177/08980101251376863","pmid":"40938880","tags":["medical-cannabis","pain"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Following an educational intervention on the benefits of medical cannabis for fibromyalgia, medical cannabis referrals increased from 4% to 17% of eligible patients (Z-score 2.3143, p = 0.0103).","whyItMatters":"Polypharmacy is a significant problem in fibromyalgia management. If medical cannabis can replace some conventional medications, provider education about this option could improve holistic patient care. The dramatic increase in referrals suggests that many providers simply were not aware of the option.","specificNumbers":"Pre-intervention: 4% referral rate. Post-intervention: 17% referral rate. Z-score: 2.3143. P-value: 0.0103.","methodology":"Quality improvement project in a single rheumatology clinic. An educational intervention on medical cannabis benefits for fibromyalgia was implemented for clinic staff. Pre- and post-intervention referral rates were compared.","limitations":"Single clinic quality improvement project. No control group. Short follow-up period. Increased referrals do not necessarily mean improved patient outcomes. The educational content may have been advocacy-oriented rather than balanced."},{"rthcId":"RTHC-07099","title":"Cannabis Use and Misuse Following Recreational Cannabis Legalization.","authors":"McDonald, André J; Doggett, Amanda; Belisario, Kyla; Gillard, Jessica; De Jesus, Jane; Vandehei, Emily; Lee, Laura; Halladay, Jillian; MacKillop, James","year":2025,"journal":"JAMA network open, 8(4), e256551","doi":"10.1001/jamanetworkopen.2025.6551","pmid":"40266618","tags":["legalization","addiction"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use frequency increased by 0.35% of days per year overall (1.75% over 5 years). CUDIT-R misuse scores decreased by 0.08 points per year (0.4 over 5 years). Critically, pre-legalization frequent consumers showed the largest decreases in both use and misuse, while occasional users and nonusers showed modest increases. Product preferences shifted from dried flower toward edibles, liquids, and vape pens.","whyItMatters":"This is among the first longitudinal studies to track the same individuals through cannabis legalization. The finding that misuse decreased even as use increased, and that frequent users improved the most, provides the most nuanced picture yet of legalization's within-person effects.","specificNumbers":"N = 1,428. 60.2% female. Mean age 34.5. 11 waves, 90% retention. Use: +0.35% of days/year. CUDIT-R: -0.08/year (scale 0-32). Frequent pre-legalization users: largest decreases. Nonusers: modest increases. Product shift: away from flower toward edibles and vape.","methodology":"Prospective cohort study with up to 11 biannual assessments from September 2018 to October 2023 in Ontario, Canada. 1,428 community-dwelling adults aged 18-65. Mean 90% retention across all waves. Linear mixed-effects modeling assessed changes in cannabis use frequency and CUDIT-R scores.","limitations":"Ontario-specific population. Self-reported use and misuse. The COVID-19 pandemic overlapped with the study period, confounding interpretation. Attrition could bias results if those worsening dropped out."},{"rthcId":"RTHC-07100","title":"Association of recreational cannabis legalization with changes in medical, illegal, and total cannabis expenditures in Canada.","authors":"McDonald, André J; Cooper, Alysha; Doggett, Amanda; Halladay, Jillian; Belisario, Kyla; MacKillop, James","year":2025,"journal":"The International journal on drug policy, 139, 104793","doi":"10.1016/j.drugpo.2025.104793","pmid":"40188703","tags":["legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Before legalization, illegal cannabis was 88.2% and medical 11.8% of the market. By 5 years post-implementation, legal recreational cannabis held 72.0%, illegal dropped to 24.3%, and medical to 3.7%. The overall market grew 75% in size. Illegal expenditures increased between passage and implementation but decreased significantly after legal sales began.","whyItMatters":"Displacing the illegal market is a primary goal of legalization. Canada has largely achieved this (illegal market down to 24%), but the 75% growth in total spending suggests legalization also expanded overall consumption, which could have public health implications.","specificNumbers":"Pre-legalization: 88.2% illegal, 11.8% medical. 5 years post: 72.0% legal recreational, 24.3% illegal, 3.7% medical. Total market grew 75%. Illegal expenditures showed significant decreasing trend post-implementation. Medical had decreasing trend from passage.","methodology":"Interrupted time series analysis of quarterly national household cannabis expenditure data from 2001 to 2023 in Canada. Examined medical, illegal, and total cannabis expenditures, adjusted for price fluctuations. Assessed changes at both legislative passage (October 2017) and implementation (October 2018).","limitations":"Illegal cannabis expenditure data is inherently uncertain. National household survey methodology may not capture all spending. Price adjustments are approximate. The growing legal market may capture previously unrecorded spending rather than representing truly new consumption."},{"rthcId":"RTHC-07101","title":"Preclinical assessment of pharmacokinetics and anticonvulsant activity of CBDTech, a novel orally administered cannabidiol (CBD) formulation for seizure and epilepsy.","authors":"McDonald, Jacob D; Zhou, Feng; Kulpa, Justyna; Kuehl, Philip J","year":2025,"journal":"Journal of cannabis research, 7(1), 73","doi":"10.1186/s42238-025-00322-7","pmid":"41029806","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"One of CBD's biggest pharmacological limitations is poor oral bioavailability—most of what you swallow gets destroyed by the liver before reaching the bloodstream (first-pass metabolism). This study tested a drug delivery technology called DehydraTECH that aims to bypass that problem.\n\nIn rats, the DehydraTECH formulation substantially improved CBD absorption compared to standard CBD in MCT oil. More importantly, it increased CBD levels in brain tissue—the target organ for seizure control. The technology uses an enhanced lipophilic composition hypothesized to shuttle CBD through absorption pathways that avoid first-pass liver metabolism.\n\nThe leading formulation, called CBDtech, was then tested in the maximal electroshock seizure (MES) model—a standard preclinical test for anticonvulsant drugs. CBDtech showed anti-seizure effects at doses between 50–100 mg/kg, comparable to or potentially better than Epidiolex at similar doses.\n\nThe practical implication: if less CBD is wasted in digestion, patients could potentially achieve therapeutic levels with lower doses, reducing side effects and cost. For epilepsy patients already taking Epidiolex (which requires high doses), a more bioavailable formulation could be meaningful.","whyItMatters":"CBD bioavailability is a real clinical problem. Epidiolex requires high doses (up to 20 mg/kg/day in children), which contributes to side effects like liver enzyme elevation, sedation, and drug interactions. A formulation that delivers more CBD to the brain with less total drug could improve the therapeutic window. This technology is still preclinical, but the pharmacokinetic data is encouraging.","specificNumbers":"25 mg/kg oral CBD compared across formulations. DehydraTECH improved absorption and brain penetration vs. MCT oil. CBDtech showed anticonvulsant effects at 50–100 mg/kg in the MES model. N = 10 rats per group for PK studies.","methodology":"Preclinical study in Sprague Dawley rats. Pharmacokinetic phase: oral administration of 25 mg/kg CBD in MCT oil vs. DehydraTECH formulations (n = 10 per group). Plasma, brain tissue, urine, and feces analyzed by LC-MS/MS. Efficacy phase: CBDtech tested in the acute maximal electroshock seizure (MES) model to determine effective dose, time of peak efficacy, and median effective dose. Compared to Epidiolex at 50–100 mg/kg.","limitations":"Rat pharmacokinetics don't directly translate to humans—species differences in drug metabolism are significant. The MES model is a basic seizure test that doesn't capture the complexity of human epilepsy syndromes. No comparison to other advanced CBD formulations beyond standard MCT oil. No long-term safety data. The technology is proprietary, which may affect access and cost."},{"rthcId":"RTHC-07102","title":"The Impact of Medical Cannabis Laws on Cannabis and Opioid Use Disorder Treatment and Overdose-Related Health Care Utilization Among Adults With Chronic Noncancer Pain.","authors":"McGinty, Emma E; Wagle, Pradhyumna; Luo, Christie Lee; Seewald, Nicholas J; Stuart, Elizabeth A; Tormohlen, Kayla N","year":2025,"journal":"The Milbank quarterly, 103(S1), 411-434","doi":"10.1111/1468-0009.70052","pmid":"40917076","tags":["legalization","pain","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Medical cannabis laws had estimated effects of less than 0.005 percentage points on CUD or OUD treatment, less than 0.009 points on new treatment initiation, and less than 0.0005 points on overdose-related care (all p > 0.05). The findings do not support the hypothesis that medical cannabis laws reduce opioid-related harms among chronic pain patients.","whyItMatters":"Medical cannabis laws are often justified partly by the potential to reduce opioid harms for pain patients. This rigorous analysis finds no evidence of this effect among Medicare beneficiaries, adding to the mixed evidence on cannabis-opioid substitution.","specificNumbers":"7 treatment states (FL, MD, MN, NH, NY, OK, PA) vs 17 comparison states. CUD/OUD treatment effect: < 0.005 percentage points. New treatment initiation: < 0.009 pp. Overdose care: < 0.0005 pp. All p > 0.05.","methodology":"Difference-in-differences and augmented synthetic control analyses comparing Medicare beneficiaries with chronic noncancer pain in 7 states implementing medical cannabis laws versus 17 comparison states without such laws. Examined CUD and OUD treatment and overdose-related healthcare utilization.","limitations":"Medicare population tends to be older and may not represent all chronic pain patients. Claims data cannot determine whether patients actually used medical cannabis. State-level policy implementation varies. The study examines treatment-seeking, not opioid use itself."},{"rthcId":"RTHC-07103","title":"Cannabis products and trends in a cohort of young adults: The VapeScan longitudinal study.","authors":"McGraw, Katlyn E; Oelsner, Elizabeth C; LoIacono, Nancy J; Gao, Siyue; Anderson, William; Sangapalaarachchi, Dona; Illievski, Vesna; Liu, Justin; Martins, Silvia; Sanchez, Tiffany R; Shimbo, Daichi; Navas-Acien, Ana","year":2025,"journal":"Tobacco induced diseases, 23","doi":"10.18332/tid/210320","pmid":"41409445","tags":["youth","potency","legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"At Visit 2, 58.9% of participants reported cannabis use. Edibles were the most common method (51.2%), followed by CBD products (31.8%), vaping (29.0%), and smoking (28.1%). Between visits, 20.9% became new cannabis vapers/smokers while only 6.3% quit vaping/smoking. This asymmetry (new users far exceeding quitters) was statistically significant (p = 0.007).","whyItMatters":"The dominance of edibles over smoking among young urban adults represents a significant shift in cannabis consumption patterns. While edibles avoid respiratory risks, they carry unique risks including delayed onset, overconsumption, and inconsistent dosing.","specificNumbers":"N = 372 (median age 26, 50.5% male). Visit 1: 33.6% dual substance use, 4% exclusive cannabis. Visit 2: 58.9% any cannabis use, 51.2% edibles, 31.8% CBD, 29.0% vape, 28.1% smoke, 3.7% topical. 20.9% new vapers/smokers, 6.3% quit (p = 0.007).","methodology":"Longitudinal cohort study (VapeScan) recruiting 372 adults aged 18-50 in NYC from 2021-2024, independently of cannabis use. Two visits with increasingly detailed cannabis questionnaires. Described product types, methods, frequency, and transitions between visits.","limitations":"NYC urban sample may not represent other populations. Small sample limits subgroup analyses. VapeScan was designed for e-cigarette research, so cannabis measures evolved between visits. Self-reported use."},{"rthcId":"RTHC-07104","title":"Cannabis in Hematology Survey Study (CHESS): A Longitudinal Investigation on Uses, Attitudes, and Outcomes of Cannabis Among Hematology Patients Undergoing Hematopoietic Stem Cell Transplant.","authors":"McLennan, Andrew I G; Booker, Reanne; Roessner, Cameron; Kerba, Marc","year":2025,"journal":"International journal of environmental research and public health, 22(7)","doi":"10.3390/ijerph22070990","pmid":"40724057","tags":["cancer","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis use decreased from 46% to 40% after transplant. Smoking as primary method dropped (38% to 18% of users), while pharmaceutical cannabinoid use increased (13% to 21%). Provider-initiated cannabis conversations increased from 10% to 37% post-transplant. Of the total sample, 63% experienced post-treatment complications and 33% developed graft-versus-host disease, 6 of whom were recent cannabis users.","whyItMatters":"This is the first study of cannabis use specifically among stem cell transplant patients. The shift toward safer consumption methods and increased provider engagement suggests that the transplant experience prompts both patients and providers to reconsider cannabis use patterns.","specificNumbers":"N = 30. Pre-HCT: 46% used cannabis, 38% smoked. Post-HCT: 40% used, 18% smoked. Pharmaceutical cannabinoids: 13% to 21%. Provider-initiated conversations: 10% to 37%. Complications: 63%. GVHD: 33% (6 of 10 were recent cannabis users).","methodology":"Longitudinal survey study of 30 eligible hematology patients assessed before and 90 days after hematopoietic stem cell transplant. Surveys covered cannabis use rate, beliefs, access to information, and physical and psychological outcomes.","limitations":"Very small sample (n=30). No control group. Cannot determine whether cannabis affected transplant outcomes. The GVHD observation is hypothesis-generating given the small numbers. Self-reported cannabis use."},{"rthcId":"RTHC-07105","title":"Parent and caregiver perceptions of cannabidiol products may put children at risk for unintentional exposure.","authors":"McNally, Michael; McFayden, Michael; Hime, Olivia; Kovasala, Michael; Brown, Grant; Geneau, Hunter; Holmes, Simeon; Brewer, Kori L; Jones, G Kirk","year":2025,"journal":"Frontiers in public health, 13, 1714993","doi":"10.3389/fpubh.2025.1714993","pmid":"41573801","tags":["cbd","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"While most parents and caregivers had heard of CBD, opinions split on whether CBD products pose safety risks to children. Many were unaware of the rising number of pediatric CBD-related poison control calls.","whyItMatters":"As CBD products proliferate in households, understanding parent awareness of pediatric exposure risks helps inform public health messaging and product safety regulations.","specificNumbers":"Survey conducted among U.S. parents/caregivers; specific sample size and percentage breakdowns available in full text.","methodology":"Cross-sectional online survey of U.S. parents and caregivers assessing knowledge, perceptions, and behaviors related to CBD products and child safety.","limitations":"Online survey with potential selection bias. Self-reported data may not reflect actual safety practices. Specific product types and formulations not differentiated."},{"rthcId":"RTHC-07106","title":"Missouri College Students' Intentions Towards Initiating or Changing Cannabis Use in a Shifting Legal Landscape.","authors":"McNamara, Ian A; Parnes, Jamie E; Stetsiv, Khrystyna; Nance, Melissa; Sauer, Jake; Greenwood, Kayleigh; Masters, Joan P; Carpenter, Ryan W","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(2), 33-50","doi":"10.26828/cannabis/2025/000286","pmid":"40909140","tags":["legalization","youth","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Following the 2022 legalization of recreational cannabis in Missouri, college students showed increased intentions to use cannabis and more favorable attitudes compared to pre-legalization baseline data.","whyItMatters":"Young adults on college campuses are a key population for understanding how legalization shifts cannabis use norms and behaviors.","specificNumbers":"Post-legalization survey of Missouri college students; specific percentages and sample sizes in full text.","methodology":"Cross-sectional survey of college students in Missouri assessing cannabis use intentions, attitudes, and behaviors after recreational legalization.","limitations":"Cross-sectional design at a single time point post-legalization. Single university sample limits generalizability. Self-reported intentions may not match actual behavior."},{"rthcId":"RTHC-07107","title":"Relation of Cannabis Use Frequency and Gambling Behavior in Individuals Who Gamble Under the Influence of Cannabis.","authors":"McPhail, Abby; Whelan, James P; Ginley, Meredith K; Pfund, Rory A","year":2025,"journal":"Journal of gambling studies, 41(2), 877-889","doi":"10.1007/s10899-025-10381-3","pmid":"40029477","tags":["addiction","mental-health","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Higher frequency of cannabis use was associated with greater gambling involvement, pointing to shared behavioral or neurobiological risk factors between the two behaviors.","whyItMatters":"Understanding the overlap between cannabis use and gambling may help identify individuals at risk for multiple addictive behaviors and inform targeted interventions.","specificNumbers":"Specific sample size and effect sizes available in full text.","methodology":"Cross-sectional analysis examining the relationship between cannabis use frequency and gambling behavior in a study population.","limitations":"Cross-sectional design cannot establish whether cannabis use drives gambling or vice versa. Confounding factors like impulsivity or socioeconomic status may explain the association."},{"rthcId":"RTHC-07108","title":"Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.","authors":"Meanti, Ramona; Bresciani, Elena; Rizzi, Laura; Molteni, Laura; Coco, Silvia; Omeljaniuk, Robert J; Torsello, Antonio","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 186, 118044","doi":"10.1016/j.biopha.2025.118044","pmid":"40209306","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07109","title":"A randomized, placebo-controlled, double-blind, pilot study of cannabis-related driving impairment assessed by driving simulator and self-report.","authors":"Meda, Shashwath A; Stevens, Michael C; Boer, Erwin R; Pittman, Brian; Gueorguieva, Ralitza; Huestis, Marilyn A; Pearlson, Godfrey D","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 39(4), 364-372","doi":"10.1177/02698811251324379","pmid":"40077985","tags":["driving","cognition","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a controlled simulator study, cannabis administration led to measurable driving impairment including lane weaving and reaction time delays, even when participants self-reported feeling capable of driving.","whyItMatters":"The disconnect between feeling capable and actually being impaired is a critical safety issue, especially as cannabis legalization expands and more people drive after using.","specificNumbers":"Randomized trial with driving simulator; specific impairment metrics and THC doses in full text.","methodology":"Randomized, controlled driving simulator study where participants received cannabis or placebo and completed standardized driving tasks while objective and subjective impairment were measured.","limitations":"Simulator driving may not perfectly replicate real-world conditions. Acute dosing in a lab does not capture the full range of cannabis use patterns. Tolerance effects in regular users may differ."},{"rthcId":"RTHC-07110","title":"Trends in Cannabis-Related Hospitalizations in Arizona From 2016 to 2021 and Associations With Mental Health-Related Hospitalizations.","authors":"Meier, Madeline H; Hummel, Haley M; Miller, Matt L","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(3), 436-445","doi":"10.15288/jsad.23-00379","pmid":"39330945","tags":["legalization","harm-reduction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-related hospitalizations in Arizona increased notably over a six-year period that included the transition from medical-only to recreational cannabis legalization.","whyItMatters":"Tracking hospitalization trends helps quantify the health system impact of cannabis legalization and informs resource planning for emergency departments and public health agencies.","specificNumbers":"Analysis covered Arizona hospital data from 2016 to 2021; specific rates and trends in full text.","methodology":"Retrospective analysis of hospital discharge data in Arizona from 2016 to 2021, tracking cannabis-related diagnoses over time.","limitations":"Hospital coding changes over time may inflate apparent trends. Cannot distinguish between increased use, increased potency, and changes in reporting. Ecological design limits individual-level inference."},{"rthcId":"RTHC-07111","title":"DNA methylation profiles of long-term cannabis users in midlife: a comprehensive evaluation of published cannabis-associated methylation markers in a representative cohort.","authors":"Meier, Madeline H; Sugden, Karen; Moffitt, Terrie E; Williams, Benjamin S; Bourassa, Kyle J; Houts, Renate; Ramrakha, Sandhya; Theodore, Reremoana; Caspi, Avshalom","year":2025,"journal":"Molecular psychiatry, 30(10), 4576-4590","doi":"10.1038/s41380-025-03042-9","pmid":"40579423","tags":["genetics","cognition","neuroscience"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Analysis of the Dunedin Multidisciplinary Health and Development Study revealed that decades of cannabis use was associated with specific DNA methylation changes, a type of epigenetic modification that can alter gene expression without changing the DNA sequence itself.","whyItMatters":"Epigenetic changes represent a biological mechanism through which cannabis exposure could have lasting effects on health, potentially affecting gene regulation in ways that persist beyond active use.","specificNumbers":"Drawn from the Dunedin Study, a birth cohort followed for decades; specific methylation sites and effect sizes in full text.","methodology":"Longitudinal birth cohort study (Dunedin Study) following participants from birth, with DNA methylation profiling conducted to compare long-term cannabis users with non-users.","limitations":"Observational design cannot confirm cannabis directly caused the methylation changes. Other lifestyle factors correlated with cannabis use could contribute. Functional significance of identified methylation changes needs further study."},{"rthcId":"RTHC-07112","title":"Global cannabis cultivation as a gendered activity: Findings from the 2020 International Cannabis Cultivation Questionnaire.","authors":"Meisel, Joshua S; Brummer, Julie E; Søgaard, Thomas Friis; Potter, Gary R; Grigg, Jodie; Jauffret-Roustide, Marie","year":2025,"journal":"The International journal on drug policy, 146, 105039","doi":"10.1016/j.drugpo.2025.105039","pmid":"41240752","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07113","title":"Trends and variations in admissions for cannabis use disorder among pregnant women in United States.","authors":"Mejia, Maria C; Sacca, Lea; Ferris, Allison H; Hennekens, Charles H; Kitsantas, Panagiota","year":2025,"journal":"Journal of perinatal medicine, 53(3), 402-406","doi":"10.1515/jpm-2024-0487","pmid":"39716832","tags":["pregnancy","addiction","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"A retrospective analysis found rising rates of hospital admissions with cannabis use disorder diagnoses among pregnant women, suggesting growing prenatal cannabis use or improved diagnostic detection.","whyItMatters":"Cannabis use during pregnancy remains controversial. Rising hospital admissions signal a growing clinical challenge that requires clearer guidelines and better prenatal screening approaches.","specificNumbers":"Trend data from hospital admission records; specific rates and time periods in full text.","methodology":"Retrospective cohort study using hospital admission records to track trends in cannabis use disorder diagnoses among pregnant women over time.","limitations":"Administrative data relies on diagnostic coding, which may undercount or overcount cases. Cannot determine whether increases reflect true prevalence changes or better detection. Does not capture outcomes for mothers or infants."},{"rthcId":"RTHC-07114","title":"The adverse public health effects of non-medical cannabis legalisation in Canada and the USA.","authors":"Mekonen Yimer, Tesfa; Hoch, Eva; Fischer, Benedikt; Dawson, Danielle; Hall, Wayne","year":2025,"journal":"The Lancet. Public health, 10(2), e148-e159","doi":"10.1016/S2468-2667(24)00299-8","pmid":"39909688","tags":["legalization","harm-reduction","mental-health"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review found that cannabis legalization has been associated with several adverse public health outcomes including increased emergency department visits, cannabis-impaired driving incidents, and accidental pediatric exposures, though effects vary by jurisdiction and policy design.","whyItMatters":"As more countries and states consider legalization, understanding the documented downsides is essential for designing policies that maximize benefits while minimizing harm.","specificNumbers":"Review synthesizes data across multiple jurisdictions; specific figures from individual studies cited in full text.","methodology":"Comprehensive review published in The Lancet synthesizing evidence from multiple jurisdictions on the adverse public health consequences of cannabis legalization.","limitations":"Reviews depend on the quality and comparability of underlying studies. Jurisdictions differ widely in regulatory frameworks, making generalization difficult. Some negative trends may reflect better surveillance rather than true increases."},{"rthcId":"RTHC-07115","title":"An in vitro evaluation of common botanical extracts on carboxylesterase 1 catalytic activity.","authors":"Melchert, Philip W; Zhang, Qingchen; Raeuscher, Josephine M; Gurley, Bill J; Markowitz, John S","year":2025,"journal":"Drug metabolism and disposition: the biological fate of chemicals, 53(9), 100129","doi":"10.1016/j.dmd.2025.100129","pmid":"40834765","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07116","title":"Cannabidiol and Alzheimer Disease: A Comprehensive Review and In Silico Insights Into Molecular Interactions.","authors":"Mello-Hortega, João V; de Oliveira, Carolina S; de Araujo, Vitoria S; Furtado-Alle, Lupe; Tureck, Luciane V; Souza, Ricardo L R","year":2025,"journal":"The European journal of neuroscience, 62(4), e70229","doi":"10.1111/ejn.70229","pmid":"40859865","tags":["cbd","neuroscience","seniors"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD has demonstrated effects on amyloid plaques, tau protein, neuroinflammation, oxidative stress, and cholinergic pathways in preclinical Alzheimer's models. In silico analysis mapped the gene network and biological pathways involved in CBD's mechanism of action.","whyItMatters":"Alzheimer's treatments remain limited and often ineffective. Identifying how CBD interacts with multiple disease pathways could open new avenues for complementary treatment research.","specificNumbers":"Review synthesizes preclinical evidence; in silico analysis mapped differential gene expression networks. Specific gene targets identified in full text.","methodology":"Comprehensive literature review combined with in silico (computer-based) analysis of gene expression data to map CBD's mechanism of action in Alzheimer's disease pathways.","limitations":"Evidence is almost entirely preclinical (animal and cell studies) and computational. No human clinical trial data for CBD in Alzheimer's was included. In silico predictions require experimental validation."},{"rthcId":"RTHC-07117","title":"Cannabinoid Hyperemesis Syndrome Is Associated With High Disease Burden: An Internet-Based Survey.","authors":"Meltzer, Andrew C; Morrison, Callen; Loganathan, Aditya; Shahamatdar, Soroush; Moon, Alice; Heidish, Ryan; Makutonin, Michael; Ma, Yan; Li, Runjia; Cooper, Ziva D","year":2025,"journal":"Annals of emergency medicine, 85(6), 521-525","doi":"10.1016/j.annemergmed.2025.01.008","pmid":"39985554","tags":["addiction","harm-reduction","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,052 self-reported CHS sufferers, the majority reported frequent cannabis use and significant healthcare utilization including emergency department visits and hospitalizations. Heavy daily use and adolescent-onset use were associated with more frequent CHS episodes.","whyItMatters":"CHS is still widely underrecognized by both users and clinicians. This large survey quantifies the real-world burden and identifies heavy use and early initiation as key risk factors.","specificNumbers":"1,052 participants surveyed. Majority reported frequent cannabis use, significant ER visits and hospitalizations. Heavy daily use and adolescent onset linked to more episodes.","methodology":"Internet-based survey of 1,052 individuals from an online CHS support group, assessing cannabis use patterns, episode frequency, and healthcare utilization.","limitations":"Self-selected online support group sample likely skews toward more severe cases. Self-reported CHS diagnosis without medical verification. Cannot establish causal direction between use patterns and CHS."},{"rthcId":"RTHC-07118","title":"The role of tetrahydrocannabivarin (THCV) in metabolic disorders: A promising cannabinoid for diabetes and weight management.","authors":"Mendoza, Scott","year":2025,"journal":"AIMS neuroscience, 12(1), 32-43","doi":"10.3934/Neuroscience.2025003","pmid":"40270953","tags":["medical-cannabis","appetite","cbd"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"THCV acts as a CB1 receptor antagonist and partial CB2 agonist, which in preclinical studies translated to appetite suppression, improved insulin sensitivity, enhanced glucose uptake, and reduced fat accumulation. Preliminary human trials showed possible appetite and blood sugar modulation.","whyItMatters":"With obesity and diabetes rates climbing globally, a non-psychoactive cannabinoid that suppresses appetite and improves metabolic function could represent a novel therapeutic avenue.","specificNumbers":"Preclinical studies showed improved insulin signaling, reduced lipid accumulation, and appetite suppression. Preliminary human data suggest glycemic control effects.","methodology":"Narrative review synthesizing preclinical (cell, animal) and preliminary human trial evidence on THCV's effects on metabolic health including obesity and type 2 diabetes.","limitations":"Most evidence is preclinical. Human trial data is preliminary with small samples. Optimal dosing, long-term safety, and drug interactions remain unknown. THCV availability in current cannabis products is limited."},{"rthcId":"RTHC-07119","title":"Antinociceptive, anti-inflammatory, and anti-dysmenorrheal activities of aerial parts of Cannabis sativa L. from the sub-middle region of the Vale do São Francisco.","authors":"Menezes, Pedro Modesto Nascimento; Rocha, João Lázaro de Oliveira; Silva, Murilo Soares; Silva, Juliane Maria Dos Santos; Araújo, Tarcísio Cícero de Lima; Deus, Deborah Lays Silva; Rolim-Neto, Pedro Jose; Matos, Luana Fernandes; Massaranduba, Ana Beatriz Rodrigues; Silva, Fabrício Souza; Rolim, Larissa Araújo","year":2025,"journal":"Frontiers in pharmacology, 16, 1677987","doi":"10.3389/fphar.2025.1677987","pmid":"41089847","tags":["pain","inflammation","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"An ethanolic extract of Cannabis sativa aerial parts demonstrated antinociceptive effects in multiple pain models (hot plate, formalin, writhing tests), anti-inflammatory activity in paw edema, and reduced uterine contractions in a dysmenorrhea model, all at doses of 1-10 mg/kg.","whyItMatters":"While individual cannabinoids are well-studied, whole-plant extract research reveals how the combined chemical profile, including cannabinoids, flavonoids, and alkaloids, contributes to therapeutic effects.","specificNumbers":"Effective at doses of 1-10 mg/kg oral. Higher doses (30-100 mg/kg) caused reduced mobility and hypothermia. Extract contained CBD, THC, CBG, flavonoids, and alkaloids.","methodology":"Preclinical pharmacological study using Swiss mice and Wistar rats across multiple validated pain, inflammation, and dysmenorrhea models with oral administration of cannabis extract.","limitations":"Animal model results do not directly translate to humans. Crude extract composition may vary between batches. No comparison with isolated cannabinoids to determine which components drive effects. Higher doses caused sedation."},{"rthcId":"RTHC-07120","title":"Smoking initiation as a mediator: investigating the causal relationship between sedentary lifestyles and cannabis use disorder through Mendelian randomization.","authors":"Meng, Deyu; Wei, Meiqi; He, Shichun; Lv, Zongnan; Zhang, Hongtu; Yang, Guang; Wang, Ziheng","year":2025,"journal":"Journal of addictive diseases, 1-11","doi":"10.1080/10550887.2025.2516290","pmid":"40629896","tags":["addiction","exercise","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using Mendelian randomization, leisure screen time was causally linked to a 43% increased risk of cannabis use disorder (OR=1.43). Smoking initiation mediated 54% of this relationship. Interestingly, sedentary work behavior showed a protective association (OR=0.61).","whyItMatters":"This study untangles the causal pathways between sedentary behavior and cannabis problems, revealing that the type of sedentary behavior matters and that tobacco smoking is a major connecting link.","specificNumbers":"Leisure screen time: OR=1.43 (95% CI 1.20-1.70, p<0.001). Sedentary work: OR=0.61 (95% CI 0.42-0.90, p=0.012). Smoking mediated 54.08% of the screen time-CUD association.","methodology":"Two-sample Mendelian randomization study using genetic variants as instruments for physical activity, sedentary behaviors, and smoking initiation, with cannabis use disorder as the outcome.","limitations":"MR assumptions may be violated if genetic instruments affect CUD through pathways other than the proposed ones. European-ancestry focused GWAS may not generalize. Cannot identify specific mechanisms beyond statistical mediation."},{"rthcId":"RTHC-07121","title":"Cannabis vape product advertising exposure is associated with cannabis vape product use and frequency among U.S. Young adults.","authors":"Meng, Siyan; Capria, Kathryn La; Stafford, Marla Royne; Yang, Cui; Padon, Alisa A; Jackson, Kristina; Chen-Sankey, Julia","year":2025,"journal":"Addictive behaviors, 171, 108475","doi":"10.1016/j.addbeh.2025.108475","pmid":"40907176","tags":["youth","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Exposure to cannabis vape product (CVP) ads, higher frequency of ad exposure, and exposure across more advertising channels were all significantly associated with both CVP use and use frequency among 2,204 young adults. Social media was the most common ad channel.","whyItMatters":"Cannabis vaping has surged among young adults, and this study identifies advertising exposure as a significant correlate of use, raising questions about advertising regulation in legal markets.","specificNumbers":"n=2,204 young adults. Ad exposure AOR=1.41 (p=0.001). Frequency of exposure AOR=1.17 per unit (p<0.001). Number of channels AOR=1.08 per channel (p<0.001). Social media was the top ad channel.","methodology":"Web-based survey of 2,204 U.S. young adults (ages 18-30) with multivariable regression analyzing associations between CVP ad exposure and use behaviors.","limitations":"Cross-sectional design cannot determine if ads cause use or if users simply notice more ads. Purposive sampling may not represent all young adults. Self-reported ad exposure is subjective."},{"rthcId":"RTHC-07122","title":"Identification and Molecular Mechanism of Novel α-Glucosidase Inhibitory Peptides from the Hydrolysate of Hemp Seed Proteins: Peptidomic Analysis, Molecular Docking, and Dynamics Simulation.","authors":"Mengyuan, Zhang; Chen, Chen; Feng, Wei; Ning, Zhao; Wanyu, Yang; Tianrong, Zhang; Guoyan, Ren; Zhijun, Qiu; Bin, Zhang","year":2025,"journal":"International journal of molecular sciences, 26(5)","doi":"10.3390/ijms26052222","pmid":"40076843","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07123","title":"In vitro pharmacological activity of twenty-eight synthetic cannabinoid receptor agonists at the type 1 and 2 cannabinoid receptors.","authors":"Mercier, Gabrielle; Mohamed, Kawthar A; Zagzoog, Ayat; Cropper, Laura; Ritchie, Brendan; Jin, Zhiyun; Patel, Mikin; Laprairie, Robert B","year":2025,"journal":"Neurochemistry international, 190, 106039","doi":"10.1016/j.neuint.2025.106039","pmid":"40876783","tags":["synthetic-cannabinoids","neuroscience","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Twenty-eight synthetic cannabinoid receptor agonists were evaluated for receptor binding and signaling. Most displayed full agonism with low nanomolar potency at both CB1 and CB2 receptors, unlike THC's partial agonism. Many showed bias toward cAMP inhibition over beta-arrestin2 recruitment, but no clear structure-activity relationship emerged.","whyItMatters":"The full agonism and high potency of synthetic cannabinoids drive their toxicity. Understanding their pharmacology is essential for predicting harm from new compounds entering illegal markets.","specificNumbers":"28 compounds tested including reference ligands CP55,940 and THC. Most showed low nanomolar potency. Many displayed signaling bias, especially at CB2R where several were inactive in beta-arrestin2 recruitment.","methodology":"In vitro pharmacological characterization using radioligand binding and two signaling assays (cAMP inhibition and beta-arrestin2 recruitment) in CHO-K1 cells expressing CB1R or CB2R.","limitations":"In vitro assays in cell lines may not reflect in vivo behavior. Only two signaling pathways were measured; other pathways may be relevant. Clinical effects depend on pharmacokinetics not captured in these assays."},{"rthcId":"RTHC-07124","title":"Concerns, Beliefs and Attitudes of Pharmacists About Medical Cannabis Use in Poland.","authors":"Merks, Piotr; Cameron, Jameason; Kazmierczak, Justyna; Białkowski, Artur; Świetlik, Dariusz; Borowska, Mariola; Wierzba, Waldemar; Bołkun-Skórnicka, Urszula; Śliż, Daniel; Blicharska, Eliza; Fedorowski, Jarosław; Vaillancourt, Regis; Religioni, Urszula","year":2025,"journal":"Healthcare (Basel, Switzerland), 13(21)","doi":"10.3390/healthcare13212657","pmid":"41228024","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Nearly half (48.9%) of Polish pharmacists believe cannabis should be used exclusively for medical purposes, while 47.6% support both medical and recreational use. Over 90% consider cannabis effective for adults, and 70% for children. However, many lack confidence in providing detailed patient guidance.","whyItMatters":"Pharmacists are often the last healthcare touchpoint before patients use medical cannabis. Their knowledge gaps and confidence levels directly affect the quality of patient care.","specificNumbers":"422 respondents. 48.9% support medical-only use. 47.6% support medical and recreational. Over 90% believe cannabis is effective for adults. ~70% acknowledge potential for children. 66%+ comfortable discussing cannabis generally.","methodology":"Cross-sectional survey of 422 pharmacists and pharmacy students in Poland using a custom questionnaire on attitudes, concerns, and experiences with medical cannabis.","limitations":"Convenience sample may not represent all Polish pharmacists. Self-reported comfort levels may not reflect actual knowledge. Survey conducted in 2021, attitudes may have shifted since."},{"rthcId":"RTHC-07125","title":"Qualitative interviews with young adults at risk for psychosis and who use Cannabis: Informing the development of a mobile intervention.","authors":"Merrill, Jennifer E; Moitra, Ethan; Giorlando, Kayla; Olsen, Elizabeth M; Leigland, Avery; Abrantes, Ana M; Whiteley, Laura","year":2025,"journal":"Addictive behaviors, 161, 108216","doi":"10.1016/j.addbeh.2024.108216","pmid":"39581126","tags":["psychosis","youth","quitting","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Five key barriers to reducing cannabis emerged: using cannabis to cope, social influences, dependence symptoms, easy access, and ambivalence about change. Four facilitators included experiencing negative consequences, focusing on personal motivation, social support, and building coping skills.","whyItMatters":"Cannabis use disorder is especially common among young people at risk for psychosis, yet few interventions are tailored to this vulnerable group. Understanding their specific barriers is essential for designing effective tools.","specificNumbers":"20 participants, 60% female, all at high risk for psychosis. Five barrier themes and four facilitator themes identified through thematic analysis.","methodology":"Qualitative study with surveys and individual interviews of 20 young adults (60% female) at clinical high risk for psychosis who use cannabis, analyzed through thematic analysis.","limitations":"Small qualitative sample limits generalizability. Self-selected participants may be more motivated to quit than the broader population. Single site study."},{"rthcId":"RTHC-07126","title":"Cognitive Difficulty Concentrating, Remembering, or Making Decisions According to Chronic Medical Conditions and Cannabis Use Among US Adults in 2022.","authors":"Merrill, Ray M","year":2025,"journal":"Innovations in clinical neuroscience, 22(7-9), 32-39","doi":null,"pmid":"41446554","tags":["cognition","mental-health","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 94,918 U.S. adults, daily cannabis use was associated with 145% higher prevalence of difficulty concentrating, remembering, or making decisions among those with chronic conditions, and 183% higher among those without. Monthly use showed 76% and 97% increases respectively.","whyItMatters":"With millions of Americans using cannabis while managing chronic conditions, understanding how cannabis interacts with existing cognitive challenges is critical for informed decision-making.","specificNumbers":"94,918 participants. Cognitive difficulty prevalence: 12.7% overall, 17.6% with chronic conditions vs 5.7% without. Daily cannabis use: 7.4%. Monthly use: 14.9%. Daily use + chronic condition: 145% higher cognitive difficulty.","methodology":"Cross-sectional analysis of the 2022 Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative telephone survey of U.S. adults aged 18+.","limitations":"Cross-sectional design cannot determine if cannabis causes cognitive difficulty or if people with cognitive problems use more cannabis. Self-reported data. Cannot account for cannabis potency, strain, or method of use."},{"rthcId":"RTHC-07127","title":"Current recommendations in the diagnosis and management of cannabinoid hyperemesis syndrome.","authors":"Meyer, Joshua; Burns, Michele M","year":2025,"journal":"Current opinion in pediatrics, 37(3), 240-243","doi":"10.1097/MOP.0000000000001464","pmid":"40172286","tags":["addiction","harm-reduction","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Beyond the traditional advice of complete THC cessation, current evidence supports using dopamine antagonists in acute CHS episodes, along with IV fluids, capsaicin cream, and standard antiemetics. Treating co-occurring anxiety, depression, and substance use disorder is now seen as critical for sustained recovery.","whyItMatters":"CHS prevalence is rising with legalization, and many clinicians still struggle with diagnosis and management. Updated treatment recommendations that go beyond \"just stop using\" could improve patient outcomes.","specificNumbers":"CHS first identified in 2004. Only known cure remains complete THC cessation. Dopamine antagonists identified as useful acute-phase treatment.","methodology":"Clinical review synthesizing current evidence on CHS pathogenesis, diagnosis, and management in both acute and chronic phases.","limitations":"Evidence base for CHS treatment remains limited. No large randomized trials guide management. Pathogenesis still poorly understood."},{"rthcId":"RTHC-07128","title":"Patterns of cannabis cultivation, cannabis and other drug use and market participation among Georgian small-scale cannabis growers: Results of online cross-sectional survey.","authors":"Mgebrishvili, Tamar; Kirtadze, Irma; Potter, Gary R; Otiashvili, David","year":2025,"journal":"The International journal on drug policy, 144(Pt 3), 104842","doi":"10.1016/j.drugpo.2025.104842","pmid":"40379485","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07129","title":"Mental health clinicians' perceptions on patient motivations and intervention engagement for prenatal cannabis use: A mixed methods study.","authors":"Mian, Maha N; Does, Monique B; Altschuler, Andrea; Green, Andrea; Ansley, Deborah R; Castellanos, Carley; Asyyed, Asma H; Satre, Derek D; Young-Wolff, Kelly C","year":2025,"journal":"Drug and alcohol dependence reports, 15, 100334","doi":"10.1016/j.dadr.2025.100334","pmid":"40384843","tags":["pregnancy","mental-health","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Among 26 perinatal mental health clinicians, nausea/morning sickness was identified as the most common motive for prenatal cannabis use. Patients primarily get cannabis information from peers rather than healthcare providers. Clinicians used motivational interviewing, harm reduction, and psychoeducation to address use.","whyItMatters":"Understanding why pregnant people use cannabis and where they get information helps shape effective clinical conversations and public health messaging during a critical developmental window.","specificNumbers":"26 clinicians surveyed (100% female, 73.1% White, mean age 48.1). 14 completed semi-structured interviews. Nausea/morning sickness ranked as top motive.","methodology":"Mixed-methods study with surveys (N=26) and semi-structured interviews (n=14) of licensed mental health clinicians in Kaiser Permanente Northern California's perinatal substance use screening program.","limitations":"Clinician perspectives may not fully reflect patient experiences. Single healthcare system limits generalizability. Small sample of predominantly White female clinicians."},{"rthcId":"RTHC-07130","title":"Substance use and mental health factors associated with self-reported higher risk cannabis use among people with HIV screened in primary care.","authors":"Mian, Maha N; Sarovar, V; Levine, T; Lea, A; Leibowitz, A; Luu, M; Flamm, J; Hare, C B; Horberg, M; Young-Wolff, K C; Phillips, K T; Silverberg, M J; Satre, D D","year":2025,"journal":"BMC public health, 25(1), 2580","doi":"10.1186/s12889-025-23735-8","pmid":"40730987","tags":["addiction","mental-health","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 973 people with HIV, 35.9% screened positive for higher risk of cannabis use disorder. In multivariable analysis, Black race (OR=1.90), anxiety (OR=1.91), and higher-risk tobacco use (OR=2.25) were independently associated with higher CUD risk.","whyItMatters":"Cannabis use is common among people with HIV, and identifying who is at highest risk for problematic use helps target screening and intervention efforts in a population already managing complex health needs.","specificNumbers":"N=973, 94.1% male, 58.5% White, median age 54.5. 35.9% at higher CUD risk. Black race OR=1.90, anxiety OR=1.91, higher-risk tobacco use OR=2.25.","methodology":"Cross-sectional analysis of TAPS screening data from 973 people with HIV across 3 primary care clinics in Kaiser Permanente Northern California.","limitations":"Cross-sectional design cannot establish causation. Predominantly male sample from one healthcare system. TAPS screening is a brief tool that may not capture the full complexity of cannabis use patterns."},{"rthcId":"RTHC-07131","title":"Clinician perspectives on barriers and facilitators to the treatment of adolescent cannabis use: A qualitative study.","authors":"Mian, Maha N; Annam, Jay; Altschuler, Andrea; Does, Monique B; Sterling, Stacy A; Satre, Derek D; Campbell, Cynthia I; Asyyed, Asma H; Silver, Lynn D; Cunningham, Sarah F; Young-Wolff, Kelly C","year":2025,"journal":"Journal of substance use and addiction treatment, 169, 209559","doi":"10.1016/j.josat.2024.209559","pmid":"39522766","tags":["youth","quitting","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Key barriers to treating adolescent cannabis use include minimization of risks by both teens and parents. Facilitators include using multiple screening tools, patient-centered approaches, and framing cannabis use within mental health context. Peer influence, virtual treatment, and parental involvement were context-dependent factors.","whyItMatters":"Clinicians across multiple specialties encounter adolescent cannabis use but face consistent barriers. Their cross-specialty insights reveal actionable strategies for improving treatment engagement.","specificNumbers":"32 clinicians interviewed (mean age 45.9, 56.3% female, 56.3% White) from four clinical settings: addiction medicine, ED, mental health, and pediatrics.","methodology":"Qualitative study interviewing 32 clinicians from addiction medicine (n=13), emergency department (n=7), mental health (n=7), and pediatrics (n=5) in an integrated healthcare system.","limitations":"Clinician perspectives from one healthcare system. No direct patient or parent input. Qualitative design limits generalizability of findings."},{"rthcId":"RTHC-07132","title":"Perinatal Cannabis Use, Depression, and the Mother-Child Dyad: Protocol for a Prospective Multimethod Study.","authors":"Micalizzi, Lauren; Howe, Lindy K; Battle, Cynthia L; Metrik, Jane; Gunn, Rachel L","year":2025,"journal":"JMIR research protocols, 14, e71302","doi":"10.2196/71302","pmid":"41379533","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07133","title":"Exploring therapeutic potential of Cannabis based therapy in autoimmune and rheumatic disorders.","authors":"Michaeli, Inbar; Lassman, Simon; Halpert, Gilad; Jacob, Giris; Amital, Howard","year":2025,"journal":"Autoimmunity reviews, 24(12), 103925","doi":"10.1016/j.autrev.2025.103925","pmid":"40907777","tags":["medical-cannabis","inflammation","pain"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis-based treatments show potential benefits across various autoimmune and rheumatic conditions, but in many cases the supporting evidence is insufficient. Social and legal barriers have hindered the rigorous clinical trials needed to validate these findings.","whyItMatters":"Autoimmune diseases affect millions and current treatments often have significant side effects. If cannabis-based therapies prove effective, they could offer a complementary or alternative approach.","specificNumbers":"Review covers multiple autoimmune and rheumatic conditions; specific outcome data from individual studies cited in full text.","methodology":"Review of updated data on cannabis-based treatments for autoimmune and rheumatic conditions including their potential therapeutic roles.","limitations":"Evidence base is largely preclinical or from small studies. Regulatory and legal barriers have prevented large-scale clinical trials. Optimal formulations, doses, and cannabinoid combinations unknown."},{"rthcId":"RTHC-07134","title":"Economic, ecological and social perspectives of industrial hemp cultivation in Germany: A qualitative analysis.","authors":"Michels, Marius; Brinkmann, Adrian; Mußhoff, Oliver","year":2025,"journal":"Journal of environmental management, 389, 126117","doi":"10.1016/j.jenvman.2025.126117","pmid":"40516259","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07135","title":"The effects of orally ingested Delta-9-Tetrahydrocannabinol on drivers' hazard perception and risk-taking behaviours: A within-subjects study of medicinal cannabis users.","authors":"Mieran, Taren; Hill, Andrew; Horswill, Mark S; Summers, Mathew J; Stefanidis, Kayla B","year":2025,"journal":"Psychopharmacology","doi":"10.1007/s00213-025-06869-w","pmid":"40742445","tags":["driving","medical-cannabis","cognition"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 41 medicinal cannabis users, oral THC did not significantly impair hazard perception skill, but participants chose slower speeds and longer following distances after consumption. Critically, they could not accurately self-assess their performance regardless of whether they had consumed THC.","whyItMatters":"Medicinal cannabis patients need practical guidance about driving. This study suggests frequent users may compensate through cautious driving, but their inability to self-assess impairment remains a safety concern.","specificNumbers":"N=41 medicinal cannabis users. No significant decline in hazard perception post-THC. Significantly slower speeds and longer following distances chosen. No correlation between perceived and actual performance.","methodology":"Within-subjects study comparing 41 medicinal cannabis users on validated video-based driving measures at baseline (no THC) and after consuming oral THC oil.","limitations":"Video-based measures, not actual driving. Moderate sample size. Participants knew they were being tested, which may have prompted extra caution. Tolerance effects from regular use likely played a role."},{"rthcId":"RTHC-07136","title":"Validation of a novel LC-MS-MS method for the separation and differentiation of Δ8- and Δ9-tetrahydrocannabinol isomers and their major metabolites in antemortem whole blood.","authors":"Mikhaltsevich, Petronela","year":2025,"journal":"Journal of analytical toxicology, 49(4), 216-223","doi":"10.1093/jat/bkaf003","pmid":"39924669","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07137","title":"Increasing Prevalence of Cannabinoid Hyperemesis Syndrome in Young Adults and Minority Populations.","authors":"Miki, Akari; Tandon, Megha; Murad, Dina; Loughman, Julia; Gilman, Jodi; Jangi, Sushrut","year":2025,"journal":"The American journal of gastroenterology, 120(12), 2954-2956","doi":"10.14309/ajg.0000000000003591","pmid":"40511929","tags":["addiction","youth","legalization"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"CHS prevalence in Massachusetts ERs increased 14-fold from 2012 to 2021 (0.729 to 10.6 per 10,000 visits). Young adults aged 18-34 saw the fastest rise. Hispanic, Black, and male individuals had the highest 10-year prevalence.","whyItMatters":"This is one of the largest population-level analyses of CHS trends, documenting a dramatic and accelerating increase that parallels cannabis legalization and rising potency.","specificNumbers":"CHS per 10,000 ED visits: 0.729 (2012) to 10.6 (2021), a 14-fold increase. Over 15 million ED visits analyzed. Highest rates in ages 18-34, Hispanic individuals, Black individuals, and men.","methodology":"Population-level analysis of over 15 million emergency department visits in Massachusetts from 2012 to 2021 using state health information data.","limitations":"Administrative data depends on correct CHS coding, which may have improved over time. Cannot determine whether increases reflect true prevalence growth or better recognition. Massachusetts-specific findings may not generalize."},{"rthcId":"RTHC-07138","title":"Chronic intermittent ethanol produces nociception through endocannabinoid-independent mechanisms in mice.","authors":"Miliano, Cristina; Dong, Yuyang; Proffit, McKenzie; Cabanas, Natalia Corvalan; Natividad, Luis A; Buczynski, Matthew W; Gregus, Ann M","year":2025,"journal":"Neuropharmacology, 277, 110502","doi":"10.1016/j.neuropharm.2025.110502","pmid":"40360036","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07139","title":"Alcohol, Tobacco, and Marijuana Use Among Individuals Receiving Prescription Opioids for Pain Management.","authors":"Miller-Matero, Lisa R; Pappas, Celeste; Altairi, Samah; Sehgal, Monica; Chrusciel, Timothy; Salas, Joanne; Secrest, Scott; Wilson, Lauren; Carpenter, Ryan W; Sullivan, Mark D; Ahmedani, Brian K; Lustman, Patrick J; Scherrer, Jeffrey F","year":2025,"journal":"The Clinical journal of pain, 41(1)","doi":"10.1097/AJP.0000000000001257","pmid":"39470110","tags":["pain","addiction","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Tobacco users had greater pain severity, more pain sites, and higher opioid misuse concern, plus higher rates of depression, anxiety, and PTSD. Cannabis users showed similar patterns with higher misuse concern and psychiatric disorders. Interestingly, alcohol use was associated with lower pain severity.","whyItMatters":"Substance use is common among pain patients on opioids. Understanding which substances are associated with poorer outcomes helps clinicians prioritize screening and intervention.","specificNumbers":"N=827. Substance use prevalence: alcohol 58.0%, marijuana 28.9%, tobacco 26.2%. Tobacco and cannabis users had more psychiatric comorbidities and opioid misuse concern. Alcohol users had lower pain scores.","methodology":"Cross-sectional survey of 827 patients with non-cancer pain receiving new opioid prescriptions from two health systems, measuring pain, substance use, and psychiatric symptoms.","limitations":"Cross-sectional design at a single time point. Cannot determine direction of causation. Self-reported substance use may undercount actual use. No information on cannabis product types or use patterns."},{"rthcId":"RTHC-07140","title":"Harmonizing cannabis and environmental policy.","authors":"Mills, Evan","year":2025,"journal":"The International journal on drug policy, 143, 104923","doi":"10.1016/j.drugpo.2025.104923","pmid":"40684614","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07141","title":"Factors associated with cannabis use disorder among Australians using prescribed and illicitly-sourced medical cannabis.","authors":"Mills, Llewellyn; Arnold, Jonathon C; Mcgregor, Iain S; Lintzeris, Nicholas","year":2025,"journal":"Drug and alcohol dependence reports, 16, 100362","doi":"10.1016/j.dadr.2025.100362","pmid":"40949606","tags":["medical-cannabis","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,796 medical cannabis users, 43% met any CUD criteria and 17% met moderate-severe CUD criteria. While illicit-source users had higher raw CUD rates (53% vs 41%), after controlling for confounders, use frequency, mental health, THC content, and proportion of recreational use were more important predictors than whether cannabis was prescribed.","whyItMatters":"As medical cannabis prescribing expands globally, this study provides the most detailed look yet at CUD prevalence among medical users and what drives risk beyond simply having a prescription.","specificNumbers":"N=1,796. 43% met any CUD criteria (>=2/11 DSM-5). 17% met moderate-severe CUD (>=4/11). Illicit users: 53% any CUD, 25% moderate-severe. Prescribed users: 41% any CUD, 15% moderate-severe.","methodology":"Online anonymous cross-sectional survey of Australians who used medical cannabis in 2022-2023, comparing prescribed versus illicitly-sourced users on DSM-5 CUD criteria using Bayesian regression.","limitations":"Online self-selected sample may over-represent heavier users. Anonymous survey cannot verify prescription status. Cross-sectional design limits causal claims. Australian regulatory context may not apply elsewhere."},{"rthcId":"RTHC-07142","title":"Pictorial warning labels reduce sharing intentions, blunt self-relevance processes elicited by social media posts promoting cannabis edibles.","authors":"Minich, Matt; Cotter, Lynne M; Kriss, Lauren A; Lu, Linqi; Yang, Sijia; Cascio, Christopher N","year":2025,"journal":"The Journal of communication, 75(5), 321-334","doi":"10.1093/joc/jqaf012","pmid":"41346345","tags":["harm-reduction","youth","legalization"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"An online experiment (N=1,776) found cannabis warning labels reduced sharing intentions. A parallel neuroimaging study (N=40) showed warning labels decreased activation in brain regions associated with self-processing compared to unlabeled cannabis posts, suggesting labels work by making content feel less personally relevant.","whyItMatters":"Social media is a primary vector for cannabis content among young people. Understanding both the behavioral and neural mechanisms of warning labels informs evidence-based content moderation strategies.","specificNumbers":"N=1,776 for behavioral experiment. N=40 for neuroimaging study. Warning labels reduced sharing intentions and decreased self-processing brain region activation compared to unlabeled cannabis posts.","methodology":"Two parallel studies: an online experiment testing warning label effects on sharing intentions (N=1,776) and a neuroimaging study examining brain activity changes (N=40), both conducted in the U.S.","limitations":"Lab-based sharing intentions may not reflect actual social media behavior. Small neuroimaging sample. Warning label designs may vary in effectiveness. Does not assess long-term habituation to labels."},{"rthcId":"RTHC-07143","title":"Understanding the Relationships between ADHD Symptoms and Cannabis-Related Consequences among Young Adults.","authors":"Minister, Claire; Hendershot, Christian S; Keough, Matthew T; Wardell, Jeffrey D","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(3), 116-132","doi":"10.26828/cannabis/2025/000312","pmid":"41278425","tags":["mental-health","addiction","youth","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In 160 young adult cannabis users, inattentive symptoms directly predicted occupational/academic problems, self-care deficits, and blackouts from cannabis, independent of consumption amount. Hyperactive/impulsive symptoms indirectly predicted dependence and impaired control through greater cannabis quantity consumed.","whyItMatters":"ADHD and cannabis problems frequently co-occur in young adults, but this study reveals the specific pathways differ by symptom type, which has direct implications for tailoring clinical interventions.","specificNumbers":"N=160, ages 19-25, 41% male. Inattentive symptoms directly linked to occupational, self-care, and blackout consequences. Hyperactive symptoms linked to dependence and impaired control through higher cannabis consumption.","methodology":"Cross-sectional study of 160 young adults (ages 19-25, 41% male) with regular cannabis use, using self-report measures, ADHD symptom scales, and 90-day timeline follow-back for cannabis consumption, plus clinical CUD interview.","limitations":"Cross-sectional design cannot establish causation. Moderate sample size. Self-reported ADHD symptoms rather than clinical diagnosis. Cannabis flower only tracked on timeline follow-back, missing concentrates and edibles."},{"rthcId":"RTHC-07144","title":"Cognitive and behavioral pathways from prenatal cocaine exposure to regular marijuana use during emerging adulthood.","authors":"Minnes, Sonia; Min, Meeyoung O; Kim, Sun Kyung; Balser, Sarah; Kim, June-Yung; Singer, Lynn T","year":2025,"journal":"Drug and alcohol dependence, 275, 112796","doi":"10.1016/j.drugalcdep.2025.112796","pmid":"40700986","tags":["pregnancy","youth","cognition","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 310 participants tracked from birth, prenatal cocaine exposure predicted poorer executive function at age 12 (beta=0.19), which predicted substance use at 15 (beta=0.21), which strongly predicted regular marijuana use at 21 (beta=0.70). Overall, 50.7% of cocaine-exposed vs 39.4% of unexposed participants used marijuana regularly.","whyItMatters":"This study maps a developmental cascade from prenatal drug exposure through childhood cognitive deficits to adolescent substance use and adult marijuana use, suggesting intervention windows at each stage.","specificNumbers":"310 participants (154 cocaine-exposed, 156 controls). Regular marijuana use at 21: 50.7% exposed vs 39.4% unexposed (p=.046). Indirect effect through executive function and early substance use: beta=0.028 (p=.032).","methodology":"Longitudinal birth cohort study following 310 participants (154 cocaine-exposed, 156 controls) from birth to age 21, using structural equation modeling to test mediation pathways.","limitations":"Cannot fully separate cocaine exposure effects from associated environmental risks. Executive function measured by caregiver report. Regular marijuana use is the outcome, which some may not consider problematic. Attrition over 21 years."},{"rthcId":"RTHC-07145","title":"Exploring the link between recreational substances and physical activity in children and adolescents: insights from the Health Behavior in School-Aged Children study (2013-2019).","authors":"Miño, Camila; Yañéz-Sepúlveda, Rodrigo; Gutiérrez-Espinoza, Héctor; Olivares-Arancibia, Jorge; Rúa-Alonso, María; Calatayud, Joaquín; López-Bueno, Rubén; López-Gil, José Francisco","year":2025,"journal":"BMC public health, 26(1), 74","doi":"10.1186/s12889-025-25448-4","pmid":"41331453","tags":["youth","exercise","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 358,391 children and adolescents across 45 countries, cannabis users did not differ significantly from non-users in physical activity levels. In contrast, tobacco use was consistently linked to about 1 fewer day per week of moderate-to-vigorous physical activity. Cannabis was linked to slightly higher activity in boys only.","whyItMatters":"The assumption that substance use universally reduces physical activity appears to be substance-specific. Understanding these differences helps target public health interventions more precisely.","specificNumbers":"358,391 participants (51% girls) from 45 countries, ages 10-17. Tobacco users had 1.09 fewer days/week of MVPA (95% CI: 1.06-1.11). Cannabis showed no significant difference overall; slightly higher MVPA in boys only (p=0.035).","methodology":"Cross-sectional analysis of the Health Behavior in School-Aged Children (HBSC) study data from 2013-2019, covering 358,391 participants aged 10-17 from 45 countries, using generalized linear mixed models.","limitations":"Cross-sectional design cannot establish causation. Self-reported substance use and physical activity may be inaccurate. Cannabis use frequency details limited. Cultural differences across 45 countries may confound results."},{"rthcId":"RTHC-07146","title":"Activation of cannabinoid receptor CB1 leads to aberrant myelination in development.","authors":"Miramontes, Tania G; Hamling, Kyla R; Doan, Ryan A; Singh, Saheli; Collins, Hannah Y; Emery, Ben; Call, Cody L; Monk, Kelly R","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.64898/2025.12.10.693544","pmid":"41415455","tags":["neuroscience","pregnancy","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"A cannabinoid agonist (WIN 55,212-2) caused oligodendrocytes to wrap myelin around neuronal cell bodies instead of only axons in developing zebrafish spinal cords. This aberrant ensheathment was CB1 receptor-dependent and occurred without disrupting normal myelin formation on axons.","whyItMatters":"Myelin is critical for brain signal transmission. Finding that cannabinoid receptor activation causes misdirected myelination during development raises concerns about how cannabis exposure during brain development could alter neural circuitry.","specificNumbers":"Increased non-axonal ensheathments in spinal cord. CB1 mutant fish were protected from the effect. Individual oligodendrocytes showed no changes in sheath number, length, or total myelin output.","methodology":"In vivo zebrafish study using pharmacological CB1/CB2 activation with longitudinal imaging to track oligodendrocyte development and myelination patterns, including CB1 mutant controls.","limitations":"Zebrafish brain development differs from mammalian development. Pharmacological agonist is not identical to THC. Functional consequences of ectopic ensheathment were not tested. Dosing may not reflect real-world human exposure."},{"rthcId":"RTHC-07147","title":"Chronic cannabis use in people with bipolar disorder is associated with comparable decision-making and functional outcome to healthy participants.","authors":"Miranda, Alannah; Roberts, Benjamin Z; Holloway, Breanna M; Peek, Elizabeth; Rosberg, Holden; Ayoub, Samantha M; Piomelli, Daniele; Jung, Kwang-Mook; Barnes, Samuel A; Rossi, Steven; Geyer, Mark A; Perry, William; Minassian, Arpi; Young, Jared W","year":2025,"journal":"Translational psychiatry, 15(1), 506","doi":"10.1038/s41398-025-03718-4","pmid":"41309543","tags":["mental-health","cognition","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among 87 participants, people with bipolar disorder who used cannabis regularly (4+ times/week) performed comparably to healthy non-users on decision-making and functional capacity measures. In contrast, healthy participants who used cannabis showed impaired decision-making. Non-using bipolar participants performed worst.","whyItMatters":"This counterintuitive finding suggests cannabis may have different cognitive effects depending on underlying brain conditions, potentially normalizing disrupted decision-making circuits in bipolar disorder.","specificNumbers":"N=87. Four groups compared. Bipolar cannabis users matched healthy non-users on Iowa Gambling Task and UPSA-2 scores. Cannabis use defined as 4+ times per week.","methodology":"Observational study comparing 87 participants across four groups (healthy cannabis users, healthy non-users, bipolar cannabis users, bipolar non-users) on the Iowa Gambling Task and UCSD Performance-based Skills Assessment.","limitations":"Small observational sample cannot establish causation. Selection bias: bipolar patients who use cannabis regularly may differ in important ways from those who do not. Cross-sectional snapshot does not capture long-term trajectories."},{"rthcId":"RTHC-07148","title":"Disparities in Treatment Outcomes for Cannabis Use Disorder Among Adolescents.","authors":"Miranda, Helena; Ostanin, Jhon; Shugar, Simon; Mejia, Maria Carmenza; Sacca, Lea; Doucette, Mitchell L; Hennekens, Charles H; Kitsantas, Panagiota","year":2025,"journal":"Pediatric reports, 17(4)","doi":"10.3390/pediatric17040074","pmid":"40700062","tags":["youth","addiction","quitting"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Of 40,054 adolescents with CUD, only 36.8% completed treatment. Black non-Hispanic adolescents had 21% lower odds of completion (OR=0.79), while Hispanic, Asian, and Native Hawaiian/Pacific Islander teens had higher completion odds. Homelessness, recent arrest, and younger age were associated with lower completion.","whyItMatters":"When nearly two-thirds of teens drop out of cannabis treatment, the system is failing them. Racial disparities in completion rates point to systemic barriers that need targeted solutions.","specificNumbers":"N=40,054 adolescents ages 12-17. Completion rate: 36.8%. Dropout: 28.4%. Transfer: 17.0%. Black non-Hispanic OR=0.79 (95% CI: 0.75-0.84). Hispanic OR=1.13, Asian OR=1.56, Native Hawaiian/PI OR=2.31.","methodology":"Analysis of the 2018-2021 Treatment Episode Data Set-Discharges (TEDS-D), a national U.S. database of substance abuse treatment episodes, using multivariable logistic regression.","limitations":"Administrative data lacks clinical detail about treatment quality or patient engagement. Cannot determine why specific groups have lower completion. Discharge coding may not capture full picture. Does not track post-discharge outcomes."},{"rthcId":"RTHC-07149","title":"Trends in urine screening positive for cannabis of emergency department admissions in Israel 2016-2024.","authors":"Miron, Oren; Zeltser, David; Schreiber, Shaul; Adelson, Miriam; Peles, Einat","year":2025,"journal":"Journal of cannabis research, 8(1), 14","doi":"10.1186/s42238-025-00379-4","pmid":"41437402","tags":["legalization","harm-reduction","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 20,022 urine toxicology tests from Israeli ER admissions (2016-2024), cannabis-positive results increased modestly from 15.4% to 17.6%. The most significant increase (16.6% to 22.4%) occurred in the 25-64 age group. Male sex, younger age, and Israeli-born status predicted positive results.","whyItMatters":"Israel has one of the world's largest medical cannabis programs. Tracking whether prescription expansion translates to increased ER presentations helps assess population-level impacts of medical access policies.","specificNumbers":"20,022 urine tests analyzed. Cannabis-positive rate: 15.4% (2016) to 17.6% (2024). Ages 25-64: 16.6% to 22.4%. Male sex OR=1.5, age <25 OR=4.1, Israeli-born OR=1.3. Co-positive for opioids OR=1.4, MDMA OR=1.8.","methodology":"Retrospective analysis of urine toxicology screening data from 20,022 emergency department admissions at a large Israeli tertiary medical center from 2016 to 2024.","limitations":"Toxicology screens were ordered based on clinical suspicion, not universally, creating selection bias. No diagnostic information about why patients were in the ER. Cannot distinguish medical from recreational cannabis use. Single-center data."},{"rthcId":"RTHC-07150","title":"Effects of cannabidiol (CBD) treatment on age-related cognitive decline in C57 mice.","authors":"Mirza Agha, Behroo; Monteith, Merrin; Earl, Jarem; Ganske, Keona; Kaloa, Tina; McDonald, Kelan J; Nixon, Abigail G; Panjwani, Maleeha; Robinson, Danika; Rusnak, Valeria; Mohajerani, Majid H; Kovalchuk, Igor; Sutherland, Robert J; Hong, Nancy S; McDonald, Robert J","year":2025,"journal":"Frontiers in aging neuroscience, 17, 1567650","doi":"10.3389/fnagi.2025.1567650","pmid":"40416734","tags":["cbd","cognition","seniors","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Fourteen-month-old mice given oral CBD for 7 months showed reduced inflammatory response in the brain and improvements in age-related cognitive decline when tested between 19-21 months of age across tasks measuring perirhinal cortex, hippocampal, amygdala, and motor function.","whyItMatters":"There are currently no approved medications for age-related cognitive decline. If CBD can reduce neuroinflammation and preserve cognition in aging brains, it could represent a widely accessible preventive approach.","specificNumbers":"CBD administered orally starting at 14 months of age. Testing at 19-21 months (equivalent to elderly in human terms). Tasks tested perirhinal cortex, hippocampus, amygdala, and motor coordination.","methodology":"Controlled animal study administering oral CBD to 14-month-old C57 mice for 7 months, followed by behavioral testing across multiple cognitive and motor tasks sensitive to different brain regions.","limitations":"Animal study with significant translational gap to humans. Specific CBD dose not stated in abstract. No dose-response comparison. Mouse aging does not perfectly model human cognitive decline. Long treatment duration may not be practical."},{"rthcId":"RTHC-07151","title":"The role of cannabinoid agonists and antagonists on folliculogenesis and evolutionary events in the mouse ovary.","authors":"Mirzaie, Vida; Eslaminejad, Touba; Sheikhbahaei, Fatemeh; Vafaei, Shayan; Nabipour, Fatemeh; Behzadi, Mina; Nematollahi-Mahani, Seyed Noureddin","year":2025,"journal":"Iranian journal of basic medical sciences, 28(9), 1171-1179","doi":"10.22038/ijbms.2025.85417.18468","pmid":"40809175","tags":["pregnancy","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CB2 receptor blocking increased primary, preantral, and antral follicles along with ovarian volume, weight, and estrogen levels. CB1 blocking increased ovarian blood vessel density. Combined agonist+antagonist treatment altered key endocannabinoid-processing enzyme expression (decreased NAPE-PLD, increased FAAH).","whyItMatters":"Understanding how the endocannabinoid system regulates ovarian function is critical as cannabis use rises among women of reproductive age. These findings suggest cannabis could meaningfully affect fertility.","specificNumbers":"80 mice in 10 groups. CB2 antagonist (AM630) increased follicle numbers across developmental stages. CB1 antagonist (AM251) increased microvascular density. 5-day treatment protocol.","methodology":"Controlled animal study using 80 female NMRI mice divided into 10 groups, receiving CB1/CB2 agonists, antagonists, or combinations for 5 days, followed by ovarian analysis including histology, gene expression, and hormone measurement.","limitations":"Mouse reproductive physiology differs from human. Short 5-day treatment may not reflect chronic cannabis use. Pharmacological agonists/antagonists are not identical to cannabis. Small sample per group."},{"rthcId":"RTHC-07152","title":"Barriers and facilitators to implementing brief motivational interventions for cannabis use disorder in routine practice: a systematic review.","authors":"Mishra, Sidharth; Mishra, Sayali; Rath, Sibanarayan","year":2025,"journal":"Journal of addictive diseases, 1-7","doi":"10.1080/10550887.2025.2573362","pmid":"41173239","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07153","title":"Cannabis: What We Use, Why It Matters, and When It Is Prescribed (Ethics, Policy, and Practice).","authors":"Mistry, Laresh N; Neelkanthan, Shreyas; More, Saudamini; Agarwal, Sumeet; Jaiswal, Himmat; Sharma, Vivek","year":2025,"journal":"Cureus, 17(7), e89073","doi":"10.7759/cureus.89073","pmid":"40896006","tags":["medical-cannabis","cbd","pain"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Cannabinoids show potential for treating orofacial pain, TMJ disorders, bruxism, and dental anxiety. However, integration into dental practice is limited by absent treatment protocols, insufficient clinical evidence, side effects like dry mouth, and unclear legal frameworks.","whyItMatters":"Dental pain management relies heavily on opioids and NSAIDs, both with significant drawbacks. If cannabinoids prove effective for dental conditions, they could offer an important alternative.","specificNumbers":"Review covers applications in orofacial neuropathic pain, TMJ disorders, myofascial pain dysfunction, bruxism, and obstructive sleep apnea. Side effects include xerostomia and periodontal disease susceptibility.","methodology":"Narrative review examining current and potential applications of cannabinoids (THC and CBD) in dentistry, including therapeutic benefits, limitations, and ethical considerations.","limitations":"Narrative review without systematic methodology. Most evidence is preclinical or from other pain conditions. No dental-specific clinical trials cited. Cannabis side effects like dry mouth could worsen dental health."},{"rthcId":"RTHC-07154","title":"The endocannabinoid system as a therapeutic target in intestinal fibrosis.","authors":"Misztal, Zofia; Kaśniewska-Kosińska, Alicja; Wołyniak, Maria; Małecka-Wojciesko, Ewa; Fabisiak, Adam","year":2025,"journal":"Frontiers in pharmacology, 16, 1669951","doi":"10.3389/fphar.2025.1669951","pmid":"41111512","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07155","title":"Legalizing Youth-Friendly Cannabis Edibles and Extracts and Adolescent Cannabis Use.","authors":"Mital, Shweta; Nguyen, Hai V","year":2025,"journal":"JAMA network open, 8(4), e255819","doi":"10.1001/jamanetworkopen.2025.5819","pmid":"40249613","tags":["legalization","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among 106,032 students in grades 7-11, provinces that legalized cannabis edibles saw a 3.8 percentage point (26%) increase in overall cannabis use and 3.4 percentage point (43%) increase in edible use compared to Quebec where youth-friendly products were banned. Cannabis smoking also increased 34%.","whyItMatters":"This is the strongest evidence yet that legalizing cannabis edibles specifically increases adolescent use. The natural experiment of Quebec banning what other provinces allowed creates a powerful policy comparison.","specificNumbers":"N=106,032 students, grades 7-11. Cannabis use: +3.8pp (26%), edibles: +3.4pp (43%), smoking: +4.4pp (34%), alcohol co-use: +2.4pp (28%). Harm perception from occasional use decreased.","methodology":"Serial cross-sectional study using nationally representative Canadian Student Tobacco Alcohol and Drugs Surveys (2018-2019 and 2021-2022) with a differences-in-differences design comparing provinces that legalized to Quebec.","limitations":"Differences-in-differences design assumes parallel trends, which may not hold perfectly. COVID-19 occurred between survey waves, potentially confounding results. Quebec differs from other provinces in ways beyond edible policy."},{"rthcId":"RTHC-07156","title":"Cannabidiol and cognitive functions/inflammatory markers in Parkinson's disease: A double-blind randomized controlled trial at Buriram Hospital (CBD-PD-BRH trial).","authors":"Mitarnun, Witoon; Kanjanarangsichai, Auempa; Junlaor, Panomporn; Kongngern, Lisa; Mitarnun, Wenika; Pangwong, Wilasinee; Nonghan, Pawarin","year":2025,"journal":"Parkinsonism & related disorders, 135, 107841","doi":"10.1016/j.parkreldis.2025.107841","pmid":"40267585","tags":["cbd","neuroscience","seniors"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 51 Parkinson's patients completing the trial, low-dose CBD (26 mg/day) was safe with no serious side effects. The only significant cognitive improvement was in MoCA naming scores. Delayed recall (primary outcome), language, inflammatory markers, and motor symptoms showed no differences between CBD and placebo groups.","whyItMatters":"This is one of the few rigorous RCTs testing CBD in Parkinson's disease. While the results are largely negative at this dose, the safety data supports exploration of higher doses in future trials.","specificNumbers":"60 randomized (27 CBD, 24 placebo completed). Mean CBD dose: 26 mg/day, THC: 1.2 mg/day. CBD detected in serum at mean 2 ng/mL. No THC detected. Only naming score improved (mean difference: 0.37, 95% CI: 0.01-0.73).","methodology":"Double-blind randomized controlled trial of 60 Parkinson's patients (51 completed) comparing 12 weeks of sublingual CBD-enriched product (101.9 mg/mL CBD, 4.8 mg/mL THC) to placebo, measuring cognitive, motor, and inflammatory outcomes.","limitations":"Very low CBD dose (26 mg/day) may be below therapeutic threshold. Small sample after dropout. 12-week duration may be too short. Blood levels suggest poor bioavailability. CBD-enriched product contained trace THC."},{"rthcId":"RTHC-07157","title":"Association of Endothelial Dysfunction With Chronic Marijuana Smoking and THC-Edible Use.","authors":"Mohammadi, Leila; Navabzadeh, Mina; Jiménez-Téllez, Nerea; Han, Daniel D; Reagan, Emma; Naughton, Jordan; Zhou, Lylybell Y; Almeida, Rahul; Castaneda, Leslie M; Abdelaal, Shadi A; Park, Kathryn S; Uyemura, Keith; Cheung, Christian P; Onder, Mehmet Nur; Goyal, Natasha; Rao, Poonam; Hellman, Judith; Cheng, Jing; Wu, Joseph C; Marcus, Gregory M; Springer, Matthew L","year":2025,"journal":"JAMA cardiology, 10(8), 851-855","doi":"10.1001/jamacardio.2025.1399","pmid":"40434782","tags":["cardiovascular","harm-reduction","potency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 55 participants, cannabis smokers had FMD of 6.0% and THC-edible users had 4.6%, both significantly lower than non-users at 10.4%. Endothelial cells exposed to cannabis smoker serum showed reduced nitric oxide production, but edible user serum did not, suggesting different vascular damage mechanisms.","whyItMatters":"This is the first study to show that THC edibles, not just smoked cannabis, impair vascular function. The JAMA Cardiology publication signals this finding is considered highly significant by the cardiology community.","specificNumbers":"N=55 (20 female, 35 male, mean age 31.3). FMD: smokers 6.0%, edible users 4.6%, non-users 10.4%. Smoker FMD inversely correlated with frequency (r=-0.7). Edible FMD inversely correlated with THC amount (r=-0.7).","methodology":"Cross-sectional CANDIDE study comparing arterial flow-mediated dilation (FMD), pulse wave velocity, and in vitro endothelial cell function across three groups: chronic cannabis smokers, THC-edible users, and non-users, all non-tobacco-users.","limitations":"Small sample size (55 total). Cross-sectional design cannot establish causation. Cannot control for all confounders. Edible users may differ from smokers in ways beyond consumption method. Functional significance of FMD differences not established."},{"rthcId":"RTHC-07158","title":"Structural changes of tubulin by interacting with Δ9-tetrahydrocannabinol: in-vitro and theoretical studies.","authors":"Mohammadkhani, Mina; Jarah, Mostafa; Gholami, Dariush; Riazi, Gholamhossein; Rezazadeh, Hadi","year":2025,"journal":"BMC neuroscience, 26(1), 47","doi":"10.1186/s12868-025-00957-5","pmid":"40739185","tags":["neuroscience","cognition"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"THC reduced microtubule polymerization in a concentration-dependent manner and caused significant changes in tubulin secondary structure as measured by circular dichroism spectroscopy. Computational modeling predicted a specific binding site for THC on beta-tubulin.","whyItMatters":"Microtubules are essential for brain cell structure, synaptic plasticity, and memory formation. Identifying a direct interaction between THC and tubulin provides a novel molecular mechanism for cannabis-related cognitive effects.","specificNumbers":"Concentration-dependent reduction in microtubule polymerization. Significant changes in tubulin secondary structure detected by CD spectroscopy. One binding site predicted on beta-tubulin by computational modeling.","methodology":"In vitro biochemical study using turbidity assays for microtubule dynamics, circular dichroism spectroscopy for protein structure, and in silico molecular docking for binding site prediction.","limitations":"In vitro study using purified tubulin, which may behave differently than tubulin inside living cells. Concentrations used may not reflect brain THC levels after cannabis use. Functional consequences (actual memory impairment) not tested."},{"rthcId":"RTHC-07159","title":"A review of cellular and molecular interactions between endocannabinoids and male fertility: Balancing beneficial and detrimental effects.","authors":"Mohammadpour-Asl, Shadi; Parvin, Ali; Akbari-Gharalari, Naeimeh; Asadi, Negar; Pooryai, Araz; Roshan-Milani, Shiva","year":2025,"journal":"Life sciences, 377, 123778","doi":"10.1016/j.lfs.2025.123778","pmid":"40449876","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07160","title":"Association of cannabinoid gene polymorphism with neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1) in type 2 diabetes mellitus with chronic kidney disease.","authors":"Mohammed, Maryam Z; Nasir, Hiba M; Al-Shakir, Nadia M M","year":2025,"journal":"Cellular and molecular biology (Noisy-le-Grand, France), 71(10), 101-110","doi":"10.14715/cmb/2025.71.10.14","pmid":"41236294","tags":["genetics"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"This study explored whether genetic variations in the cannabinoid receptor 1 (CNR1) gene—part of the endocannabinoid system—are associated with kidney damage in people with type 2 diabetes.\n\nThe researchers genotyped 120 subjects divided into three groups: 40 diabetic patients with chronic kidney disease (CKD), 40 diabetic patients without CKD, and 40 healthy controls. They looked at two specific genetic variants (SNPs) in the CNR1 gene and measured blood levels of two kidney injury biomarkers: NGAL and KIM-1.\n\nThe main finding was mixed. The heterozygous GA genotype of one variant (rs1049353) was more common in the CKD group, but the difference wasn't statistically significant. However, the study did discover multiple novel CNR1 gene variants that were submitted to the NCBI database—a contribution to the basic science of endocannabinoid genetics even if the clinical association didn't reach significance.\n\nThe theoretical basis is sound: the endocannabinoid system is involved in kidney physiology and inflammation, so genetic variations in cannabinoid receptors could plausibly influence how diabetes damages the kidneys. But this small study couldn't establish that connection definitively.","whyItMatters":"The endocannabinoid system is increasingly recognized as playing roles in metabolic disease and kidney function. If specific cannabinoid receptor gene variants predispose diabetic patients to kidney damage, that could eventually inform both genetic screening and therapeutic targeting. This study is a small first step in that direction for an Iraqi population.","specificNumbers":"N = 120 (40 T2DM + CKD, 40 T2DM only, 40 controls). GA genotype of rs1049353 more prevalent in CKD group but not statistically significant. Multiple novel CNR1 variants discovered and submitted to NCBI.","methodology":"Case-control study of 120 Iraqi subjects: 40 T2DM + CKD, 40 T2DM without CKD, 40 healthy controls. Genotyping of CNR1 SNPs rs1049353 and rs1776966256 via PCR and Sanger sequencing. Serum NGAL and KIM-1 measured by ELISA.","limitations":"Small sample size (40 per group) likely underpowered to detect modest genetic effects. Single-center Iraqi population limits generalizability. Only two SNPs examined out of many possible CNR1 variants. Cross-sectional design can't establish causation. The non-significant primary finding means the hypothesis remains unconfirmed."},{"rthcId":"RTHC-07161","title":"Investigating the Antimicrobial Efficacy of Cannabinoids and Their Derivatives Against Neisseria Gonorrhoeae by Computational Analysis.","authors":"Mohd Omeershffudin, Umairah Natasya; Zainal Abidin, Zakirah; Hein, Zaw Myo; Che Mohd Nassir, Che Mohd Nasril; Kottakal Cheriya, Ebrahim Nangarath; Kumar, Suresh; Che Ramli, Muhammad Danial","year":2025,"journal":"Biology, 14(9)","doi":"10.3390/biology14091272","pmid":"41007416","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07162","title":"Exploring the impact of drug decriminalization and legalization policies on mental health outcomes: A scoping review.","authors":"Mohebbian, Mana; Najafi, Sara; Choi, You Na; Schütz, Christian; Kassam, Rosemin; Kazanjian, Arminee; Puyat, Joseph","year":2025,"journal":"PLOS mental health, 2(10), e0000358","doi":"10.1371/journal.pmen.0000358","pmid":"41662013","tags":["mental-health","depression","psychosis","legalization"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"As drug policies liberalize worldwide, a central concern is whether this will worsen mental health outcomes. This scoping review examined 55 studies published between 2001 and 2024 that measured non-substance-use-disorder mental health outcomes (depression, anxiety, psychosis, suicidality, overall psychological wellbeing) in relation to drug decriminalization or legalization.\n\nThe headline finding: the mental health sky has not fallen. Most studies found neutral effects—drug policy liberalization didn't significantly worsen population-level mental health outcomes. For cannabis specifically, legalization showed no consistent pattern of increased depression, anxiety, or psychotic disorders at the population level.\n\nThis doesn't mean there are no individual risks. Studies examining subgroups (heavy users, adolescents, people with pre-existing vulnerabilities) sometimes found associations with worse outcomes. But at the population level—measuring aggregate mental health across entire states or countries—legalization didn't produce the mental health crisis that some predicted.\n\nThe review distinguished between decriminalization (removing criminal penalties), legalization (establishing legal access), and commercialization (allowing retail markets), noting that these represent different policy intensities that may have different effects.","whyItMatters":"Mental health impact is one of the most emotionally charged arguments in the legalization debate. This systematic mapping of the evidence provides a counterweight to both extremes—neither the claim that legalization causes a mental health crisis nor the claim that it's entirely benign is well-supported by the available evidence. The nuance matters for policy.","specificNumbers":"55 studies met inclusion criteria. Literature searched from 2001–2024 across 5 databases. Focused on non-SUD mental health outcomes: depression, anxiety, psychosis, suicidality, psychological wellbeing. Most studies found neutral population-level effects.","methodology":"Scoping review following JBI guidelines and PRISMA-ScR checklist. Searched Medline, EMBASE, CINAHL, PsycInfo, and Web of Science for studies published January 2001 to December 2024. Included studies examining non-SUD mental health outcomes related to drug decriminalization, legalization, or commercialization. 55 studies met inclusion criteria.","limitations":"Scoping reviews map the literature without assessing study quality or conducting meta-analysis. The 55 included studies varied widely in methodology, populations, and how they measured mental health. Most evidence comes from cannabis legalization in North America—less data on other drugs or other regions. Population-level null effects can mask important subgroup effects. Only English-language studies included."},{"rthcId":"RTHC-07163","title":"Effects and safety of a CBD-rich Cannabis sativa oil in knee osteoarthritis: a double-blind, randomized, placebo-controlled trial - CANOA - cannabis for osteoarthritis.","authors":"Mojoli, Andrés; Haider, Osvaldo; Fakih, Yasmin; Luz Gonçalves, Maria Victoria; Zepeda Rojas, Bruno; Xaia, Giovanna; Krefta, Emanuelly; Bicca, Maíra Assunção; Lopes de Mari, Thiago; Ferreira, Charles Francisco; Cezar-Dos-Santos, Fernando; Toci, Aline Theodoro; Nascimento, Francisney Pinto","year":2025,"journal":"Frontiers in pharmacology, 16, 1657065","doi":"10.3389/fphar.2025.1657065","pmid":"41487518","tags":["cbd","pain","inflammation","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This Brazilian trial is one of the most rigorous tests of CBD for osteoarthritis pain. Patients with knee osteoarthritis were randomized to either a full-spectrum CBD-rich cannabis oil (45 mg CBD daily) or placebo for 60 days.\n\nThe primary outcome—pain intensity measured by the WOMAC questionnaire—improved in both groups, but there was no statistically significant difference between CBD and placebo. Secondary outcomes including pain on a visual analogue scale, depression (BDI), sleep quality (PSQI), and quality of life also showed no significant between-group differences.\n\nThis is a null result, and it's an important one. The study was well-designed (double-blind, randomized, placebo-controlled), used a validated pain measure, and ran for a reasonable duration. The fact that both groups improved underscores the power of the placebo effect in pain trials—and the importance of having a control group.\n\nThe dose (45 mg CBD/day) is modest by current clinical standards, and the formulation was a full-spectrum oil (containing small amounts of other cannabinoids). Whether higher doses, different formulations, or different CBD:THC ratios would produce different results remains an open question.","whyItMatters":"Osteoarthritis is the most common form of arthritis and a leading reason people try CBD products. This trial provides rigorous evidence that at least at this dose and formulation, CBD doesn't outperform placebo for knee OA pain. Given the billions spent on CBD products marketed for joint pain, negative results from well-designed trials serve an important public health function.","specificNumbers":"60-day trial. CBD dose: 45 mg/day full-spectrum oil. No significant difference between CBD and placebo on WOMAC pain, VAS pain, depression, sleep quality, or quality of life. Both groups improved from baseline.","methodology":"Double-blind, randomized, placebo-controlled trial. Knee osteoarthritis patients randomized to CBD-rich full-spectrum cannabis oil (45 mg CBD/day) or placebo for 60 days. Primary outcome: WOMAC pain intensity. Secondary outcomes: VAS pain, Beck Depression Inventory, Pittsburgh Sleep Quality Index, SF-12 quality of life components.","limitations":"The 45 mg/day CBD dose is relatively low—some clinical protocols use 150–600 mg/day. Full-spectrum oil means other cannabinoids were present but at low, variable levels. 60-day duration may not capture longer-term effects. Single center in Brazil. The study may have been underpowered (sample size not specified in the abstract). Placebo response was substantial, as is typical in pain trials."},{"rthcId":"RTHC-07164","title":"Decriminalization of cannabis use in South Africa: The perspectives and health outcomes among medical students; A systematic qualitative review.","authors":"Mokhwelepa, L Winter; Olivia Sumbane, Gsakani","year":2025,"journal":"Journal of public health research, 14(4), 22799036251373016","doi":"10.1177/22799036251373016","pmid":"41189564","tags":["legalization","youth","mental-health"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Four themes emerged from the review: health impacts (mental and physical), attitudes toward decriminalization, educational influences, and access to support services. Medical students expressed diverse opinions about cannabis decriminalization and its health implications, with awareness gaps about cannabis effects on health and professional practice.","whyItMatters":"As future healthcare providers in a country that recently decriminalized personal cannabis use, medical students' attitudes and knowledge gaps directly affect the quality of care they will provide.","specificNumbers":"Four studies met inclusion criteria. Four key themes identified through thematic analysis. Focus on South African medical students specifically.","methodology":"Systematic qualitative review searching PubMed, Scopus, PsycINFO, and ScienceDirect for studies (2010-2024) on South African medical students and cannabis decriminalization, using thematic synthesis.","limitations":"Only four studies met inclusion criteria, indicating severe research gaps. Cannot generalize to all South African medical students or other healthcare professions. Publication bias possible."},{"rthcId":"RTHC-07165","title":"The intersection of disabilities and the risk of sexual assault victimization among female college students.","authors":"Molenaar, Michael; Santos Laanan, Frankie; Burrow-Sanchez, Jason","year":2025,"journal":"Journal of American college health : J of ACH, 1-29","doi":"10.1080/07448481.2025.2577661","pmid":"41183988","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07166","title":"Influence of recent cannabis use on altered spectral entropy modulation and connectivity strength in patients with psychosis.","authors":"Molina, Vicente; Díez, Álvaro; Fernández-Linsenbarth, Inés; Osorio-Iriarte, Emma; Beño-Ruiz de la Sierra, Rosa; Martín-Santiago, Oscar; Rodríguez-Valbuena, Claudia; Fiorini-Talavera, Juan Carlos; Arjona, Antonio","year":2025,"journal":"European archives of psychiatry and clinical neuroscience","doi":"10.1007/s00406-025-02004-0","pmid":"40550950","tags":["psychosis","neuroscience","cognition"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Both cannabis-using and non-using psychosis patients showed impaired spectral entropy modulation and elevated connectivity strength compared to 86 healthy controls. Crucially, no significant differences were found between the two patient groups on any EEG measure, suggesting cannabis was not driving the abnormalities.","whyItMatters":"If cannabis drove the brain activity abnormalities seen in psychosis, treatment strategies would differ. Finding that these are intrinsic to psychosis suggests they are vulnerability markers rather than substance-induced artifacts.","specificNumbers":"93 psychosis patients (32 recent cannabis users, 61 non-users) and 86 healthy controls. Both patient groups showed impaired SE modulation and elevated gamma/broadband connectivity. No between-patient-group differences on any measure.","methodology":"EEG study during a P300 task comparing 93 psychosis patients (32 recent cannabis users, 61 non-users) with 86 healthy controls, measuring spectral entropy modulation and connectivity strength in theta, broadband, and gamma bands.","limitations":"Cross-sectional design captures only recent cannabis use (past week). Does not address long-term or early-onset cannabis effects. Cannabis potency, frequency, and age of onset not considered. Schizophrenia and bipolar patients grouped together."},{"rthcId":"RTHC-07167","title":"The synthetic cannabinoid WIN 55,212-2 attenuates cognitive and motor deficits and reduces amyloid load in 5XFAD Alzheimer mice.","authors":"Möller, Johanna E L; Schmitt, Franziska W; Günther, Daniel; Stöver, Alicia; Bouter, Yvonne","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 247, 173944","doi":"10.1016/j.pbb.2024.173944","pmid":"39675388","tags":["neuroscience","seniors","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Aged 5XFAD Alzheimer's mice treated with WIN 55,212-2 for 42 days showed improved rotarod motor performance, rescued water maze memory deficits, and reduced amyloid plaque burden and astrogliosis in the cortex and hippocampus compared to vehicle-treated controls.","whyItMatters":"Despite recent approvals of anti-amyloid antibodies, effective Alzheimer's treatments remain elusive. This study shows a cannabinoid compound addresses multiple disease features simultaneously: cognition, motor function, plaques, and inflammation.","specificNumbers":"42 days of treatment at 0.2 mg/kg. Improved rotarod performance and water maze memory. Reduced amyloid plaques and astrogliosis in cortex and hippocampus. No effect on anxiety-like behavior.","methodology":"Controlled animal study treating 9-month-old 5XFAD mice (a well-established Alzheimer's model) with 0.2 mg/kg WIN 55,212-2 for 42 days, followed by behavioral testing and immunohistochemical brain analysis.","limitations":"Mouse Alzheimer's models do not perfectly replicate human disease. WIN 55,212-2 is a potent synthetic cannabinoid with psychoactive potential. Anxiety was not improved. Long-term safety and dose optimization not explored."},{"rthcId":"RTHC-07168","title":"Hexahydrocannabinol (HHC) use and harms in Ireland: New findings from the 2024 European Web Survey on Drugs.","authors":"Mongan, Deirdre; Killeen, Nicki; Millar, Seán R; Matias, João; Keenan, Eamon; Galvin, Brian","year":2025,"journal":"The International journal on drug policy, 145, 105011","doi":"10.1016/j.drugpo.2025.105011","pmid":"40972474","tags":["psychosis","anxiety","depression","withdrawal","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Hexahydrocannabinol (HHC)—a semi-synthetic cannabinoid marketed as a legal alternative to cannabis—was openly sold in Irish shops until it was banned in July 2025. This study, using data from the 2024 European Web Survey on Drugs, captured the scope of the problem.\n\nAmong 2,314 Irish adults who had used drugs in the previous year, 36.2% reported lifetime HHC use, 33.5% used it in the past year, and 17.8% used it in the past month. These are remarkably high prevalence figures for a substance that most people had never heard of just a few years earlier.\n\nThe primary driver was accessibility: people started using HHC because it was easily available in high street shops (62.4% obtained it from a retail store). It wasn't sought out for unique effects—it was simply there, legal, and marketed as cannabis-like.\n\nThe harm data is concerning. Among HHC users, 89.9% reported at least one negative consequence. The most common: anxiety or panic reactions (14.7%), feeling faint or dizzy (13.4%), and dissociation (11.9%). Reports of psychotic illness precipitated by HHC use had already alarmed public health officials before the ban.\n\nThis case study illustrates the whack-a-mole nature of drug regulation: when one substance is controlled, close analogues fill the legal gap, often with less safety data and potentially more harm.","whyItMatters":"HHC's rapid rise and high harm rate demonstrates what happens when synthetic cannabinoids exploit regulatory gaps. Unlike well-studied THC, HHC had minimal safety data when it hit the market. The 90% harm rate among users is far higher than reported harm rates for natural cannabis, suggesting that \"legal alternative\" does not mean \"safer alternative.\"","specificNumbers":"N = 2,314. 36.2% lifetime HHC use. 33.5% past-year use. 17.8% past-month use. 62.4% obtained from high street shops. 89.9% reported negative consequences. 14.7% anxiety/panic. 13.4% faintness/dizziness. 11.9% dissociation.","methodology":"Cross-sectional data from the 2024 European Web Survey on Drugs. 2,314 Irish adults aged 18+ who had used drugs in the previous year. Survey assessed HHC frequency, reasons for starting, sources, administration methods, and harms.","limitations":"Web survey with self-selected participants who use drugs—not representative of the general population. Self-reported harms (no clinical verification). The 90% harm rate may reflect the survey's drug-using population rather than all HHC users. Irish-specific data may not generalize to countries with different regulatory environments. Recall bias for negative experiences."},{"rthcId":"RTHC-07169","title":"Oleoylethanolamide effects on stress-induced ethanol consumption: A lipid at the crossroads between stress, reward and neuroinflammation.","authors":"Montagud-Romero, Sandra; González-Portilla, Macarena; Mellado, Susana; Grandes, Pedro; de Fonseca, Fernando Rodríguez; Pascual, María; Rodríguez-Arias, Marta","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 138, 111365","doi":"10.1016/j.pnpbp.2025.111365","pmid":"40250786","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07170","title":"Deletion of Fgf14 confers resilience to basal and stress-induced depressive-like behavior and reduces anxiety in mice.","authors":"Montarolo, Francesca; Rominto, Anita Maria; Berrino, Luna; Bertolotto, Antonio; Laezza, Fernanda; Tempia, Filippo; Hoxha, Eriola","year":2025,"journal":"Translational psychiatry, 15(1), 136","doi":"10.1038/s41398-025-03361-z","pmid":"40204701","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07171","title":"Dysregulation of the Cannabinoid System in Childhood Epilepsy: From Mechanisms to Therapy.","authors":"Montebello, Gloria; Di Giovanni, Giuseppe","year":2025,"journal":"International journal of molecular sciences, 26(13)","doi":"10.3390/ijms26136234","pmid":"40650012","tags":["epilepsy","cbd","youth","neuroscience"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The endocannabinoid system regulates neuronal excitability from early life through aging. In pediatric epilepsy, disorder-specific alterations in CB1 receptor expression and endocannabinoid levels reveal both vulnerabilities and treatment targets. CBD is FDA-approved for Dravet, Lennox-Gastaut, and Tuberous Sclerosis Complex, while newer approaches including CB1 positive allosteric modulators and FAAH/MAGL inhibitors show promise.","whyItMatters":"Over 12 million children worldwide have epilepsy, and 30% have drug-resistant forms. Understanding the endocannabinoid system offers multiple new therapeutic avenues beyond current treatments.","specificNumbers":"12+ million children with epilepsy worldwide. ~30% drug-resistant. CBD approved for 3 specific syndromes. Multiple emerging ECS-based strategies in development.","methodology":"Comprehensive molecular review of endocannabinoid system dysregulation in childhood epilepsy, covering mechanisms, current CBD-based treatments, and emerging therapeutic strategies.","limitations":"Many emerging strategies are still preclinical. Long-term effects of ECS modulation on developing brains are not fully understood. Individual variation in endocannabinoid system function complicates treatment standardization."},{"rthcId":"RTHC-07172","title":"Correlates of Recreational and Medicinal Cannabis Use Among Non-Hispanic Black and Hispanic Men with Chronic Conditions.","authors":"Montemayor, Benjamin N; Merianos, Ashley L; Bergeron, Caroline D; Sherman, Ledric D; Jacobs, Wura; Chung, Sunghyun; Hassan, Arham; Smith, Matthew Lee","year":2025,"journal":"Journal of community health, 50(6), 1127-1136","doi":"10.1007/s10900-025-01500-7","pmid":"40593365","tags":["medical-cannabis","pain","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 1,982 non-Hispanic Black and Hispanic men with chronic conditions, 21.3% reported past 30-day cannabis use. Greater pain (AOR=1.11), higher stress (AOR=1.06), and more chronic conditions (AOR=1.23) were independently associated with cannabis use. Those using both medicinally and recreationally used most frequently.","whyItMatters":"Black and Hispanic men face disproportionate chronic disease burden and are understudied in cannabis research. Understanding their use patterns is essential for equitable healthcare delivery.","specificNumbers":"N=1,982, mean age 56.6, 58.2% Black. 21.3% current cannabis use. Pain AOR=1.11 (1.07-1.16). Stress AOR=1.06 (1.01-1.10). Number of conditions AOR=1.23 (1.10-1.38). Dual users had highest frequency.","methodology":"Cross-sectional analysis of a national sample of 1,982 non-Hispanic Black and Hispanic men aged 40+ with at least one chronic condition, using logistic regression to examine cannabis use correlates.","limitations":"Cross-sectional design cannot determine if cannabis helps or worsens chronic conditions. Self-reported data subject to bias. Cannot distinguish between different cannabis products or consumption methods."},{"rthcId":"RTHC-07173","title":"Adolescent substance use in Costa Rica: findings from a national survey among secondary school students.","authors":"Montero-Zamora, Pablo; Lopez-Soto, Andrea; Cordoba, Jeancarlo; Ramirez, Esmeralda","year":2025,"journal":"Frontiers in public health, 13, 1655355","doi":"10.3389/fpubh.2025.1655355","pmid":"41041370","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07174","title":"Targeting Human Cancer Cells with Cannabidiol (CBD): Apoptotic Cytotoxicity in HeLa, MDA-MB-231, and CaCo-2 Lines.","authors":"Montes-de-Oca-Saucedo, Carlos R; Perales-Martínez, Jonathan E; Arellano-Barrientos, Juan C; Rodríguez-Tovar, Luis E; Nevárez-Garza, Alicia M; Garza-Arredondo, Aimé J; Saucedo-Cárdenas, Odila; Hernández-Vidal, Gustavo; Soto-Domínguez, Adolfo; Castillo-Velázquez, Uziel","year":2025,"journal":"International journal of molecular sciences, 26(24)","doi":"10.3390/ijms262412136","pmid":"41465562","tags":["cbd","cancer"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBD at 5-20 micromolar concentrations killed cancer cells through apoptosis with LC50 values of 9.4 (HeLa cervical), 10.3 (MDA-MB-231 breast), and 4.3 (CaCo-2 colon) micromolar at 24 hours. Non-cancerous cell lines (HaCaT skin, HUVEC endothelial) were relatively spared.","whyItMatters":"The selectivity of CBD for cancer cells over normal cells is a key finding. Many cancer treatments damage healthy tissue, so a compound that preferentially targets cancer cells has obvious therapeutic potential.","specificNumbers":"LC50 at 24h: HeLa 9.4 micromolar, MDA-MB-231 10.3 micromolar, CaCo-2 4.3 micromolar. Tested at 5, 10, and 20 micromolar for 24, 48, 72, and 96 hours. Apoptosis confirmed by flow cytometry.","methodology":"In vitro study treating three human cancer cell lines and two non-cancerous control lines with CBD at multiple concentrations (5, 10, 20 micromolar) across four time points (24-96 hours), using MTT assays, DAPI nuclear staining, and flow cytometry.","limitations":"In vitro results often do not translate to living organisms. CBD concentrations tested may not be achievable in human tumors. No comparison with standard chemotherapy drugs. Cell line experiments are simplified models of complex cancers."},{"rthcId":"RTHC-07175","title":"State adult-use cannabis policy effects on law enforcement efforts to disrupt drug markets.","authors":"Montgomery, Barrett Wallace; Athimuthu, Pranav; Richardson, Nicholas; Ray, Bradley","year":2025,"journal":"The International journal on drug policy, 140, 104802","doi":"10.1016/j.drugpo.2025.104802","pmid":"40220507","tags":["legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis legalization significantly reduced overall drug seizures, driven by large drops in cannabis seizures. The Black-white risk ratio for cannabis seizures decreased significantly, though Black individuals remained at higher risk for all drug seizure types. Non-cannabis seizures were mostly unchanged, except methamphetamine seizures increased.","whyItMatters":"Drug seizures represent the sharp end of drug enforcement policy. This study provides the first evidence on how legalization changes police behavior regarding seizures, not just arrests.","specificNumbers":"16 states analyzed, 95%+ population coverage, 2017-2022. Significant reduction in cannabis seizures. Moderate but significant decrease in Black-white cannabis seizure disparity. Methamphetamine seizures increased.","methodology":"Difference-in-differences analysis of NIBRS drug seizure data from 16 states with 95%+ population coverage (2017-2022), comparing states that legalized to those that did not.","limitations":"NIBRS data has reporting limitations. Cannot determine whether reduced seizures reflect reduced enforcement or reduced cannabis activity. Methamphetamine increase may be confounded by supply trends."},{"rthcId":"RTHC-07176","title":"Miniaturized one-step extraction for the analysis of tetrahydrocannabinol ∆9- and ∆8- isomers, phytocannabinoids, and hexahydrocannabinol in whole blood using liquid chromatography tandem mass spectrometry.","authors":"Monti, Manuela Carla; Stoll, Anna; Schlotterbeck, Götz; Duthaler, Urs","year":2025,"journal":"Journal of chromatography. A, 1760, 466276","doi":"10.1016/j.chroma.2025.466276","pmid":"40882360","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07177","title":"The Role of the Endocannabinoid System in Human Gametogenesis.","authors":"Montik, Nina; Crescenzi, Daniele; Marzocchini, Carolina; Lubinski, Irene; Grementieri, Linda; Peruzzi, Sonia; Lombó, Marta; Ciavattini, Andrea; Carnevali, Oliana","year":2025,"journal":"International journal of molecular sciences, 26(9)","doi":"10.3390/ijms26093996","pmid":"40362235","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07178","title":"Optimizing Cannabis Sample Preparation to Reduce Chloroform Usage: A Comparison of I-Optimal, D-Optimal, and A-Optimal Designs.","authors":"Monton, Chaowalit; Charoenchai, Laksana; Suksaeree, Jirapornchai; Songsak, Thanapat","year":2025,"journal":"Journal of separation science, 48(9), e70278","doi":"10.1002/jssc.70278","pmid":"40974570","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07179","title":"Changes in physicochemical, textural, and sensorial properties of pork meatballs made with the addition of hemp oil during storage.","authors":"Montowska, Magdalena; Kotecka-Majchrzak, Klaudia; Kasałka-Czarna, Natalia; Mikołajczak, Beata; Spychaj, Anita; Grygier, Anna","year":2025,"journal":"Food science and technology international = Ciencia y tecnologia de los alimentos internacional, 31(5), 405-414","doi":"10.1177/10820132231211936","pmid":"37936377","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07180","title":"Impact of prenatal exposure to delta 9-tetrahydrocannabinol and cannabidiol on birth size and postnatal growth trajectories.","authors":"Moore, Brianna F; Mueller, Noel T; Perng, Wei; Sauder, Katherine A; Hébert, Emily T; Hoyt, Adrienne T; Wymore, Erica M; Boyle, Kristen E; Su, Emily J; Shapiro, Allison L B; Kinney, Gregory; Sempio, Cristina; Klawitter, Jost; Christians, Uwe; Dabelea, Dana","year":2025,"journal":"Pediatric obesity, 20(1), e13187","doi":"10.1111/ijpo.13187","pmid":"39681476","tags":["pregnancy","youth","appetite"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 128 mother-child pairs, prenatal THC exposure (12% of children) was associated with 95g less fat mass and 2.1% lower adiposity at birth, followed by rapid postnatal growth (0.42 BMI z-score increase per square root year). Shorter breastfeeding duration amplified this pattern, with 1.1 higher BMI z-score by age 3.","whyItMatters":"The pattern of being born small then growing rapidly is associated with metabolic problems later in life. This study identifies a specific cannabinoid-driven growth trajectory that could have long-term health consequences.","specificNumbers":"128 pairs, 15 (12%) THC-exposed, 3 with concurrent CBD. THC associated with -95g fat mass (95% CI: -174 to -14), -2.1% adiposity (CI: -4.2 to -0.4). Rapid growth: +0.42 BMI z-score/sqrt year. Short breastfeeding: +1.1 BMI z-score at age 3.","methodology":"Prospective cohort following 128 mother-child pairs through 3 years, with mid-gestation urinary THC and CBD measurement, neonatal body composition assessment, and longitudinal BMI tracking.","limitations":"Small sample with only 15 THC-exposed children limits statistical power. Urinary measurement captures recent use rather than cumulative exposure. Breastfeeding may also transfer THC, complicating the protective finding. Only followed to age 3."},{"rthcId":"RTHC-07181","title":"Effects of sex and pre-exposure on Δ9-tetrahydrocannabinol (THC) vapor self-administration in rats.","authors":"Moore, Catherine F; Weerts, Elise M","year":2025,"journal":"Psychopharmacology","doi":"10.1007/s00213-025-06930-8","pmid":"41288683","tags":["addiction","sex-differences","tolerance"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Among 96 rats, both males and females voluntarily self-administered THC vapor over several months. Female rats responded more than males as the effort required increased. Prior THC vapor exposure significantly increased later self-administration, suggesting sensitization. Rats titrated their intake based on THC concentration.","whyItMatters":"This model closely mirrors human cannabis inhalation behavior and reveals important sex differences and sensitization effects that could inform understanding of why some people develop cannabis use disorder.","specificNumbers":"N=96 rats (6-12 per sex/group). Training dose: 50 mg/mL THC. Dose range tested: 50-200 mg/mL. Female rats responded more at FR4-5 schedules. THC pre-exposure increased subsequent self-administration.","methodology":"Controlled animal study with 96 Sprague Dawley rats (male and female) pre-exposed to THC or vehicle vapor, then trained to self-administer THC vapor under increasing effort requirements and varying concentrations.","limitations":"Animal models cannot fully replicate human cannabis use behavior. Propylene glycol vehicle may have its own effects. Limited to one strain of rats. Short pre-exposure period may not reflect human use patterns."},{"rthcId":"RTHC-07182","title":"Effects of sex and pre-exposure on Δ9-tetrahydrocannabinol (THC) vapor self-administration in rats.","authors":"Moore, Catherine F; Weerts, Elise M","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.08.01.668172","pmid":"40766695","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07183","title":"Cannabinoid Hyperemesis Syndrome Treated With Fosaprepitant: A Case Report.","authors":"Moore, Markus D; Alzghari, Saeed K; Soliman, Andrew N","year":2025,"journal":"Cureus, 17(8), e90477","doi":"10.7759/cureus.90477","pmid":"40979004","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07184","title":"A Narrative Review of Research on Cannabis Advertising in the United States.","authors":"Moran, Meghan Bridgid; Tharmarajah, Saraniya; Czaplicki, Lauren; Thrul, Johannes; Spindle, Tory R; Vandrey, Ryan; Pearson, Jennifer L; Zamarripa, C Austin","year":2025,"journal":"Current addiction reports, 12(1), 92","doi":"10.1007/s40429-025-00703-1","pmid":"41467048","tags":["legalization","youth","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Cannabis is marketed through price promotions, storefront signage, social media, and billboards using tactics known to increase tobacco use. Youth and adult exposure is common. Several studies found associations between cannabis marketing exposure and cannabis use, though causal evidence remains limited.","whyItMatters":"The tobacco industry spent decades perfecting marketing techniques that drive product use. Finding these same tactics in cannabis advertising is a red flag for public health, especially regarding youth.","specificNumbers":"Review covers 22 states with adult-use legalization and 16 additional with medical. Advertising channels include storefront signage, social media, billboards. Youth exposure documented across multiple studies.","methodology":"Narrative review summarizing research across three domains: content of cannabis advertising, prevalence of exposure, and effects on user perceptions and behavior in the U.S.","limitations":"Narrative review without systematic methodology. Most included studies are correlational. Cannabis advertising landscape is evolving rapidly and varies by state. Limited causal evidence."},{"rthcId":"RTHC-07185","title":"A Hidden Mark of a Troubled Past: Neuroimaging and Transcriptomic Analyses Reveal Interactive Effects of Maternal Immune Activation and Adolescent THC Exposure Suggestive of Increased Neuropsychiatric Risk.","authors":"Moreno-Fernández, Mario; Luján, Víctor; Baliyan, Shishir; Poza, Celia; Capellán, Roberto; de Las Heras-Martínez, Natalia; Morcillo, Miguel Ángel; Oteo, Marta; Ambrosio, Emilio; Ucha, Marcos; Higuera-Matas, Alejandro","year":2025,"journal":"Biological psychiatry global open science, 5(3), 100452","doi":"10.1016/j.bpsgos.2025.100452","pmid":"40115746","tags":["psychosis","pregnancy","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"While adolescent THC did not trigger visible behavioral disruptions, PET brain scans revealed alterations dependent on the combination of prenatal immune activation and THC. Gene expression analysis showed maternal immune activation affected dopamine, glutamate, and serotonin genes, with the two-hit combination shifting expression from downregulation to upregulation. Blood biomarkers of inflammatory pathway changes were identified.","whyItMatters":"This is the first study to show that the combination of prenatal immune challenge and adolescent THC leaves detectable molecular and neuroimaging marks even before behavioral symptoms emerge, suggesting a hidden vulnerability window.","specificNumbers":"Both male and female rats tested. Increasing THC doses during adolescence. PET scans at multiple time points. RNA sequencing of orbitofrontal cortex and peripheral blood mononuclear cells. Gene expression shifts identified in dopaminergic, glutamatergic, and serotonergic pathways.","methodology":"Two-hit animal model combining maternal immune activation with adolescent THC exposure in male and female rats, followed by behavioral testing, longitudinal PET neuroimaging, RNA sequencing of orbitofrontal cortex and blood cells.","limitations":"Animal model of immune activation may not fully replicate human prenatal infection. THC doses may not reflect human use patterns. Behavioral effects may emerge later than the observation window. Blood biomarkers need human validation."},{"rthcId":"RTHC-07186","title":"Cannabis-based products for medicinal use in dogs and cats: a systematic review.","authors":"Moreno-López, N; Moreno-López, C; Amariles, P","year":2025,"journal":"The Journal of small animal practice, 66(12), 855-870","doi":"10.1111/jsap.13913","pmid":"40660612","tags":["medical-cannabis","cbd","pain"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 22 studies, CBD-based formulations showed benefits for osteoarthritis pain, epilepsy, atopic dermatitis, postsurgical pain, and behavioral issues in dogs, with no serious adverse events reported. Research on cats was limited to just two studies.","whyItMatters":"Pet owners are increasingly using cannabis products for their animals, often without veterinary guidance. This systematic review provides the most comprehensive evidence assessment to date for clinical decision-making.","specificNumbers":"22 studies identified. Conditions: osteoarthritis, epilepsy, atopic dermatitis, postsurgical pain, behavioral issues. Only 2 cat studies. No serious adverse events. Long-term data limited.","methodology":"Systematic review of PubMed, LILACS, Scopus, and Google Scholar from 2014 to 2024, identifying 22 studies on cannabidiol-based products in dogs and cats.","limitations":"Most studies are small and vary in design quality. CBD product formulations differ across studies. Very limited cat data. Long-term effects unknown. Optimal dosing not established."},{"rthcId":"RTHC-07187","title":"Cannabinoid agonist WIN55,212-2 prevents scopolamine-induced impairment of spatial memory in rats.","authors":"Moreno-Rodríguez, Marta; Bengoetxea de Tena, Iker; Martínez-Gardeazabal, Jonatan; Pereira-Castelo, Gorka; Llorente-Ovejero, Alberto; Manuel, Iván; Rodríguez-Puertas, Rafael","year":2025,"journal":"European journal of pharmacology, 998, 177612","doi":"10.1016/j.ejphar.2025.177612","pmid":"40252898","tags":["neuroscience","cognition","seniors"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Subchronic low-dose WIN55,212-2 (0.5 mg/kg) prevented scopolamine-induced spatial memory impairment in Barnes maze testing. The mechanism involved increased cannabinoid and muscarinic receptor activity in motor and somatosensory cortex layers I-V, suggesting cannabinoid activation indirectly boosts the cholinergic system.","whyItMatters":"Cholinergic dysfunction is a hallmark of Alzheimer's disease and related dementias. Finding that cannabinoids can boost cholinergic tone through an indirect mechanism opens a new therapeutic pathway.","specificNumbers":"WIN55,212-2 at 0.5 mg/kg (subchronic). Scopolamine at 2 mg/kg. Protected spatial memory in Barnes maze. Increased CB and muscarinic receptor density and activity in motor/somatosensory cortex layers I-V.","methodology":"Pharmacological rat study using scopolamine (muscarinic antagonist) to model cholinergic dysfunction, with WIN55,212-2 treatment and evaluation via Barnes maze, plus autoradiographic receptor mapping.","limitations":"Acute scopolamine model produces transient cholinergic deficit, not the progressive degeneration of Alzheimer's. Effect limited to spatial memory; recognition and aversive memory were not protected. Rat results need human validation."},{"rthcId":"RTHC-07188","title":"The role of endocannabinoid signaling in the cytoskeleton functionality in migrating neurons.","authors":"Morozov, Yury M; Rakic, Pasko","year":2025,"journal":"Medical research archives, 13(10)","doi":"10.18103/mra.v13i10.7041","pmid":"41695078","tags":["neuroscience","pregnancy","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"About 40% of migrating neurons in both CB1 receptor knockout mice and wild-type mice exposed to cannabinoid agonists showed nuclear envelope ruptures or \"piercing nuclear hernias\" (PNH), a novel form of cell pathology. This shows the ECS must function within an optimal range during brain development.","whyItMatters":"This reveals a previously unknown vulnerability: developing brain cells require precisely calibrated endocannabinoid signaling. Too much or too little causes catastrophic membrane damage that could kill migrating neurons.","specificNumbers":"~40% of migrating neurons affected in both CB1 knockout and agonist-treated embryos. Novel \"piercing nuclear hernia\" (PNH) pathology described. Both nuclear and plasma membranes ruptured simultaneously.","methodology":"Developmental neuroscience study using CB1 knockout mice and cannabinoid agonist-treated wild-type mouse embryos, with ultrastructural analysis of migrating neurons in developing brain.","limitations":"Mouse embryo study with uncertain translation to human brain development. Pharmacological agonists used are not identical to THC. Functional consequences of PNH for brain development not yet established."},{"rthcId":"RTHC-07189","title":"Abnormalities of the endocannabinoid system produce piercing nuclear hernias in migrating cerebral neurons.","authors":"Morozov, Yury M; Rakic, Pasko","year":2025,"journal":"iScience, 28(8), 113188","doi":"10.1016/j.isci.2025.113188","pmid":"40799395","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07190","title":"Effect of Cannabidiol and Δ9-tetrahydrocannabinol on Anti-Inflammatory Lipid Mediator Synthesis in Humans.","authors":"Morris, Alan W J; Mueller, Raeghan L; Sempio, Cristina; Klawitter, Jost; Bryan, Angela D; Bidwell, L Cinnamon; Hutchison, Kent E","year":2025,"journal":"Cannabis and cannabinoid research, 10(4), 506-511","doi":"10.1089/can.2024.0175","pmid":"40552985","tags":["cbd","inflammation","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Using plasma data from multiple clinical studies, high-CBD cannabis use led to increased levels of anti-inflammatory eicosanoids, particularly lipoxins produced through the 15-LOX pathway. High-THC cannabis did not produce similar increases in these anti-inflammatory mediators.","whyItMatters":"This is rare human-level evidence showing how CBD produces anti-inflammatory effects at the molecular level, specifically through lipid mediator pathways, supporting its therapeutic potential for inflammatory diseases.","specificNumbers":"High-CBD cannabis increased lipoxin levels via the 15-LOX pathway. High-THC cannabis showed no similar increase. Eicosanoid levels measured across LOX, COX, and CYP450 pathways.","methodology":"Analysis of plasma samples from multiple clinical studies comparing the effects of high-CBD versus high-THC cannabis on eicosanoid levels generated through LOX, COX, and CYP450 pathways.","limitations":"Pooled data from multiple studies introduces variability. Cannot control for all differences between study populations. Specific CBD and THC doses varied. Plasma levels may not reflect tissue-level effects."},{"rthcId":"RTHC-07191","title":"A cannabinoid receptor 1 inverse agonist induces weight loss and reduces airway hyperresponsiveness in a mouse model of obese asthma.","authors":"Morris, Carolyn R; Chandrasekaran, Ravishankar; Butzirus, Isabella M; Daphtary, Nirav; Aliyeva, Minara; Manuel, Allison M; Tharp, William G; Bates, Jason H T; Anathy, Vikas; Poynter, Matthew E; Duan, Jianmin; Gaucher, Geneviève; Crater, Glenn D; Dixon, Anne E","year":2025,"journal":"American journal of physiology. Lung cellular and molecular physiology, 329(3), L327-L340","doi":"10.1152/ajplung.00049.2025","pmid":"40707031","tags":["medical-cannabis","respiratory","appetite"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CB1R inverse agonist INV-202 produced 11% weight loss in lean and 27% in obese mice. Both groups showed improved airway hyperresponsiveness, particularly reduced lung elastance. The drug also reduced inflammation markers and increased beneficial surfactant lipids in lung fluid.","whyItMatters":"Obesity is the strongest risk factor for severe asthma, and the two conditions likely share metabolic pathways. This study identifies the endocannabinoid system as a treatable link between obesity and asthma.","specificNumbers":"Weight loss: 11% (lean) and 27% (obese). 33% decrease in CCL20 in lean mice. 55% decrease in airway neutrophils. Increased phosphatidylglycerol correlated with improved lung compliance.","methodology":"Mouse model combining high-fat diet obesity and house dust mite allergic airway inflammation, with oral CB1R inverse agonist treatment and comprehensive lung function, inflammation, and lipid analysis.","limitations":"Mouse obesity and asthma models may not fully replicate human disease. First-generation CB1R antagonists (rimonabant) were withdrawn due to psychiatric side effects. Long-term safety of INV-202 not established."},{"rthcId":"RTHC-07192","title":"Cannabis use across the menstrual cycle: The impact of negative affect and cannabis use motives.","authors":"Morris, Paige E; Soto, Paul L; Buckner, Julia D","year":2025,"journal":"Addictive behaviors, 164, 108284","doi":"10.1016/j.addbeh.2025.108284","pmid":"39923384","tags":["sex-differences","pain","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among 40 normally cycling women tracked for 65 days, cannabis use was more frequent during the premenstrual phase. Physical pain motives increased during menstruation. The relationship between mood, motives, and cannabis use differed by cycle phase: higher depression drove coping-motivated use during ovulation, while lower depression drove it premenstrually.","whyItMatters":"Understanding how the menstrual cycle drives cannabis use patterns could help women make more informed choices and help clinicians provide cycle-aware guidance.","specificNumbers":"N=40 women tracked for 65 days. More frequent use in premenstrual phase. Physical motives higher in menstrual phase. Complex three-way interactions between cycle phase, mood (depression/anger), and motives.","methodology":"Daily diary study tracking 40 regularly cycling women over 65 days, measuring negative affect, cannabis use, and use motives retrospectively across menstrual cycle phases.","limitations":"Small sample of 40 women limits statistical power for complex interactions. Retrospective daily reports may have recall bias. Self-selected sample of cannabis-using women. Short 65-day window."},{"rthcId":"RTHC-07193","title":"The Role of Cannabis Policies and Perceptions of Penalties on the Association Between Adolescent Social Bonds and Cannabis Use.","authors":"Moscrop-Blake, Kelsi; Leal, Wanda E","year":2025,"journal":"Substance use & misuse, 60(12), 1913-1922","doi":"10.1080/10826084.2025.2522153","pmid":"40566853","tags":["legalization","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Medical cannabis legalization was positively associated with past-year adolescent cannabis use. Perception of serious criminal justice penalties for possession was negatively associated with use. State policy status moderated the protective effects of social bonds (attachment and involvement), weakening their influence in legalized states.","whyItMatters":"Understanding what protects teens from cannabis use in the context of changing laws helps design more effective prevention strategies, especially as more states liberalize cannabis policies.","specificNumbers":"2023 NSDUH data. Medical cannabis policies positively associated with past-year use. Perceived serious penalties negatively associated. Attachment and involvement effects moderated by state policy status.","methodology":"Cross-sectional analysis of 2023 National Survey on Drug Use and Health (NSDUH) data examining state-level cannabis policy, perceived penalties, and social bonds as predictors of adolescent cannabis use.","limitations":"Cross-sectional design cannot establish causation. State-level policies may correlate with other unmeasured factors. Perceived penalties are subjective and may not reflect actual law. Social desirability bias in reporting."},{"rthcId":"RTHC-07194","title":"Cannabidiol and low-dose γ-radiation regulate alterations consequences of hepatic-encephalopathy induced by thioacetamide: neuroprotective and anti-inflammatory role.","authors":"Mostafa, Dalia M; Hassan, Asmaa A; Aboghadeer, Ahmad R; Mansour, Somaya Z; Abdel-Hamid, Gehan R","year":2025,"journal":"Immunopharmacology and immunotoxicology, 47(5), 631-644","doi":"10.1080/08923973.2025.2542131","pmid":"40842162","tags":["cbd","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (20 mg/kg for 7 days) significantly reduced oxidative stress and inflammation in rats with liver damage-induced brain dysfunction. The treatment modulated NF-kB, ASK1, and JNK inflammatory pathways, improved NAD and serotonin levels, and enhanced cognitive performance on the Morris water maze.","whyItMatters":"Hepatic encephalopathy affects up to 40% of cirrhosis patients and has limited treatment options. CBD's neuroprotective effects in this model suggest a potential new therapeutic avenue.","specificNumbers":"CBD at 20 mg/kg for 7 days. Reduced NF-kB, ASK1, and JNK signaling. Improved NAD and serotonin levels. Enhanced Morris water maze performance. Improved brain and liver histology.","methodology":"Controlled rat study using thioacetamide-induced hepatic encephalopathy, with CBD and/or low-dose radiation treatment, measuring oxidative stress, inflammation, neurobehavior, and histopathology.","limitations":"Rat model may not fully replicate human hepatic encephalopathy. Short 7-day treatment period. Combination with radiation limits ability to isolate CBD effects. Single dose tested."},{"rthcId":"RTHC-07195","title":"Development and Characterization of Cannabidiol Self-Emulsifying Drug Delivery System: In Vitro and In Vivo Evaluation.","authors":"Mostafa, Nourhan; Taha, Iman E; Abourobe, Noha M; Ashour, Eman A","year":2025,"journal":"Biomolecules, 16(1)","doi":"10.3390/biom16010021","pmid":"41594563","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07196","title":"Population genomics of a natural Cannabis sativa L. collection from Iran identifies novel genetic loci for flowering time, morphology, sex and chemotyping.","authors":"Mostafaei Dehnavi, Mahboubeh; Damerum, Annabelle; Taheri, Sadegh; Ebadi, Ali; Panahi, Shadab; Hodgin, George; Brandley, Brian; Salami, Seyed Alireza; Taylor, Gail","year":2025,"journal":"BMC plant biology, 25(1), 80","doi":"10.1186/s12870-025-06045-4","pmid":"39838336","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07197","title":"Green light to sleep: Does cannabis work for insomnia? A case report and brief review.","authors":"Mota-Rolim, Sérgio; Melo, Pedro da Costa; Barroso, Victor Vilhena; Amaral, Eric Joel Ferreira do; Araujo, John Fontenele; Ribeiro, Sidarta","year":2025,"journal":"Progress in brain research, 296, 55-64","doi":"10.1016/bs.pbr.2025.07.005","pmid":"40967684","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07198","title":"A randomized trial on efficacy of purified cannabidiol on spasticity in multiple sclerosis patients with gait problems: first report in Iran.","authors":"Mousavi, Pegah; Emadzadeh, Maryam; Karimikhoshnoudian, Bahar; Sahraian, Mohammad Ali; Ghaffari, Mehran; Shaygannejad, Vahid; Payere, Maryam; Baghaei, Ava; Zabeti, Aram; Nahayati, Mohammadali","year":2025,"journal":"Naunyn-Schmiedeberg's archives of pharmacology, 398(12), 17435-17444","doi":"10.1007/s00210-025-04347-w","pmid":"40498097","tags":["cbd","medical-cannabis","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CBD treatment (escalating from 5 to 80 mg/day over 4 weeks) significantly improved walking speed on the T25-FW test (p=0.031) and reduced maximum pain (p=0.033) compared to placebo, but did not significantly reduce spasticity severity at 4 or 8 weeks.","whyItMatters":"MS spasticity affects millions and current treatments have significant side effects. While CBD did not reduce spasticity per se, the functional improvement in walking speed is clinically meaningful.","specificNumbers":"49 patients (24 CBD, 25 placebo). CBD escalated from 5 to 80 mg/day. T25-FW improvement: p=0.031. Maximum pain reduction: p=0.033. No significant spasticity reduction at 4 or 8 weeks.","methodology":"Double-blind randomized controlled trial of 49 MS patients with spasticity-related walking difficulties, comparing escalating-dose sublingual pure CBD to placebo over 4 weeks at Ghaem Hospital, Iran.","limitations":"Small sample size. Short 4-week treatment. Relatively low CBD doses. Single-center study in Iran. High dropout (9 of 49). Does not address long-term effects."},{"rthcId":"RTHC-07199","title":"A preliminary randomized trial of the safety, tolerability, and clinical effects of hemp-derived cannabidiol in alcohol use disorder.","authors":"Mueller, Raeghan L; Hooper, Jake F; Ellingson, Jarrod M; Olsavsky, Aviva K; Rzasa-Lynn, Rachael; Bryan, Angela D; Bidwell, L Cinnamon; Hutchison, Kent E","year":2025,"journal":"Frontiers in psychiatry, 16, 1516351","doi":"10.3389/fpsyt.2025.1516351","pmid":"40357520","tags":["cbd","addiction","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Among 44 participants with AUD randomized to full-spectrum CBD (with trace THC), broad-spectrum CBD (without THC), or placebo for 8 weeks, full-spectrum CBD reduced craving and AUD symptoms relative to both broad-spectrum CBD and placebo. Both CBD products were well tolerated with no significant differences in side effects.","whyItMatters":"Alcohol use disorder has limited treatment options. If CBD can reduce craving, especially the full-spectrum form with trace THC, it could fill a major gap in AUD pharmacotherapy.","specificNumbers":"N=44 (13 full-spectrum, 15 broad-spectrum, 16 placebo). 8-week treatment. Full-spectrum CBD reduced craving but not drinks per drinking day. No significant side effect differences across groups.","methodology":"Preliminary randomized trial of 44 adults with moderate-to-severe AUD, comparing 8 weeks of full-spectrum CBD, broad-spectrum CBD (no THC), and placebo on drinking, craving, and safety outcomes.","limitations":"Very small pilot study not powered for definitive conclusions. Cannot determine optimal CBD dose. Commercial CBD products may vary in quality. Short 8-week duration. No long-term follow-up."},{"rthcId":"RTHC-07200","title":"Comprehensive LC-MS-MS analysis of THC isomers, analogs, homologs, and metabolites in blood and urine.","authors":"Muir, Luette S; Doumit, Sarah E; Seither, Joshua Z; Knittel, Jessica L; Walterscheid, Jeffrey P; Karschner, Erin L","year":2025,"journal":"Journal of analytical toxicology, 49(5), 322-331","doi":"10.1093/jat/bkaf023","pmid":"40098275","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07201","title":"Cannabidiol as an immune modulator: A comprehensive review.","authors":"Mujahid, Khizra; Rasheed, Muhammad Shahzaib; Sabir, Azka; Nam, Jutaek; Ramzan, Talha; Ashraf, Waseem; Imran, Imran","year":2025,"journal":"Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society, 33(3), 11","doi":"10.1007/s44446-025-00005-7","pmid":"40407987","tags":["cbd","inflammation","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This comprehensive review maps how CBD interacts with the immune system, and the picture is remarkably broad. CBD doesn't have a single immune effect—it operates through multiple simultaneous mechanisms:\n\nIt regulates T cell activity, the immune cells that drive autoimmune attacks. It induces apoptosis (programmed death) in macrophages, the immune cells that fuel chronic inflammation. It suppresses pro-inflammatory cytokines—the chemical messengers that amplify inflammatory responses. And it modulates signaling pathways involved in immune homeostasis.\n\nPreclinical and clinical studies have shown these effects translate into potential therapies for autoimmune diseases: Type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. CBD has also shown promise for neuropathic pain and cancer therapy through immune-related mechanisms.\n\nThe review also covers a frontier of CBD research: nanotechnology-based delivery systems. These engineered nanoparticles improve CBD's solubility and bioavailability (addressing the same problem as RTHC-00179's DehydraTECH approach) and can target specific tissues, potentially enhancing therapeutic effects while reducing doses.\n\nThe challenge: most of this evidence is preclinical. The gap between showing immune modulation in a lab dish or mouse model and proving clinical benefit in human disease is substantial.","whyItMatters":"Autoimmune diseases affect roughly 5–8% of the population and current treatments (immunosuppressants, biologics) carry significant side effects. If CBD can modulate immune function more selectively—suppressing harmful autoimmune responses while preserving necessary immunity—it could fill an important therapeutic gap. The nanotechnology delivery advances could address CBD's poor bioavailability, which has limited its clinical efficacy to date.","specificNumbers":"CBD modulates: T cell activity, macrophage apoptosis, pro-inflammatory cytokine production, and multiple inflammatory signaling pathways. Potential applications: Type 1 diabetes, MS, rheumatoid arthritis, IBD, neuropathic pain, cancer.","methodology":"Comprehensive literature review searching PubMed, Scopus, and Web of Science for preclinical and clinical studies on CBD's immunomodulatory effects. Covers mechanisms of action, disease-specific applications, and nanotechnology delivery advances.","limitations":"Much of the evidence is preclinical (cell cultures and animal models). Doses used in preclinical studies often don't translate to achievable human doses. The review covers a very broad range of conditions, which limits depth on any single disease. Publication bias may favor positive results. Clinical trial evidence for CBD in autoimmune diseases specifically is still sparse."},{"rthcId":"RTHC-07202","title":"Field safety and efficacy study with a cannabidiol/cannabidiol acid-rich hemp paste in cats with osteoarthritic pain.","authors":"Mulder, Liza M; Deterd Oude Weme, Jeanine; Blees, Niels R; Wakshlag, Joseph J; Hughes, Daniel; Corbee, Ronald Jan","year":2025,"journal":"Journal of feline medicine and surgery, 27(10), 1098612X251367629","doi":"10.1177/1098612X251367629","pmid":"41094745","tags":["cbd","medical-cannabis","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Among 26 cats with OA, 14 completed the crossover study. CBD/CBDA paste significantly reduced pain scores on both veterinary-assessed (TRiP) and owner-assessed (DORFOP) measures after 6 weeks, with owner-reported improvements starting at 2 weeks. No changes in clinical biochemistry were observed.","whyItMatters":"This is one of the few controlled studies of CBD in cats. While the pain reduction is promising, the high dropout rate reveals a practical barrier that any feline CBD product must overcome.","specificNumbers":"26 cats enrolled, 12 dropped out (mainly refusing paste/vomiting), 14 completed. Significant reduction in TRiP and DORFOP pain scores. Owner improvements by week 2. No biochemistry changes.","methodology":"Randomized, double-blinded, placebo-controlled crossover study in 26 client-owned cats with osteoarthritis, using standardized pain assessments and blood work over 6-week treatment periods.","limitations":"Very high dropout rate (46%) limits statistical power and may bias results toward cats who tolerated the paste. Small final sample. Single formulation tested. No long-term follow-up."},{"rthcId":"RTHC-07203","title":"Cannabis use and cognition in older adults: Preliminary performance-based neuropsychological test results and directions for future research.","authors":"Mulhauser, Kyler; Sullivan, Daniel; Bair, Jessica L; Correro, Anthony N; Pal, Subhamoy; Reader, Jonathan; Hampstead, Benjamin M; Giordani, Bruno","year":2025,"journal":"Journal of the International Neuropsychological Society : JINS, 31(7-8), 518-525","doi":"10.1017/S1355617725101203","pmid":"40888078","tags":["cognition","mental-health","youth","seniors","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"As cannabis use increases among older adults, a pressing question is whether it affects cognitive function in people already at risk for or experiencing cognitive decline. This study examined 540 older adults (age 65+) from a well-characterized observational cohort, spanning the full dementia continuum: cognitively intact, mild cognitive impairment (MCI), and dementia.\n\nAbout 11% reported using cannabis in the prior six months, with the typical user consuming two to four times per month. When compared on a comprehensive neuropsychological battery covering five cognitive domains, cannabis users performed similarly to non-users across the board.\n\nThe researchers went beyond traditional statistical analysis, using propensity score matching—a technique that creates matched pairs of users and non-users who are otherwise similar—to strengthen the comparison. Even with this more rigorous approach, no cognitive differences emerged.\n\nHowever, there was a signal in the subgroup analysis: among cannabis users, those with more severe cannabis-related problems (a risk factor for cannabis use disorder) may have performed differently on cognitive tests. This suggests a dose-response or problematic-use threshold that casual use doesn't cross.\n\nThe study can't rule out that cannabis users might have been higher-functioning to begin with (selection bias), or that the 11% who reported use might differ from non-users in unmeasured ways.","whyItMatters":"The 65+ population is the fastest-growing demographic of cannabis users, and many are using it while navigating age-related cognitive concerns. Knowing that moderate cannabis use doesn't appear to worsen cognitive test performance across the dementia spectrum is relevant for clinical counseling—though the caveat about problem use severity is equally important.","specificNumbers":"N = 540, age 65+. ~11% reported past-6-month cannabis use. Median use: 2–4 times per month. No significant differences across 5 neuropsychological domains. Cannabis-related problem severity may be associated with cognitive outcomes among users.","methodology":"Cross-sectional analysis of 540 older adults (65+) from a well-characterized observational cohort spanning cognitively intact, MCI, and dementia. Cannabis use assessed by standardized questionnaire (past 6 months). Comprehensive neuropsychological assessment across 5 domains. Analysis: multivariate and univariate traditional methods plus propensity score matching. Subgroup analysis of cannabis-related problem severity among users.","limitations":"Cross-sectional design can't determine if cannabis use affects cognitive trajectories over time. Self-reported cannabis use (potential underreporting). The 11% use rate and moderate frequency mean heavy or daily users are underrepresented. Selection bias is possible—older adults who use cannabis may be healthier or more cognitively resilient to begin with. Neuropsychological tests may not capture subtle impairments in real-world functioning."},{"rthcId":"RTHC-07204","title":"Cannabis use and suicide in people with a diagnosis of schizophrenia: a systematic review and meta-analysis of longitudinal, case control, and cross-sectional studies.","authors":"Mulligan, Lee D; Varese, Filippo; Harris, Kamelia; Haddock, Gillian","year":2025,"journal":"Psychological medicine, 55, e79","doi":"10.1017/S0033291725000236","pmid":"40059733","tags":["psychosis","mental-health","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Across 29 studies (36 samples), cannabis use was associated with 40% higher odds of attempted suicide (OR=1.40, 95% CI: 1.16-1.68) and 21% higher risk of suicide death (HR=1.21, 95% CI: 1.04-1.40). Cannabis was not significantly associated with suicidal ideation alone.","whyItMatters":"Suicide is a leading cause of death in schizophrenia. Identifying cannabis use as a risk factor for suicide attempts and death provides an actionable target for clinical intervention.","specificNumbers":"29 studies, 36 samples. Attempted suicide OR=1.40 (95% CI: 1.16-1.68). Suicide death HR=1.21 (95% CI: 1.04-1.40). Suicidal ideation: not significant. Heterogeneity moderate for attempts (I2=39.6%).","methodology":"Systematic review and meta-analysis of cross-sectional, case-control, and longitudinal studies from Medline, Embase, and PsycINFO through November 2024, using random effects models.","limitations":"Cannot establish causality from meta-analysis of observational studies. Cannabis use may be a marker for severity rather than a direct cause. Some subgroup analyses lost significance. Confounding by other substance use possible."},{"rthcId":"RTHC-07205","title":"Factors associated with using disposable versus non-disposable electronic cigarettes among adults in the U.S. and Israel: a cross-sectional study with policy implications.","authors":"Mulu, Begashaw A; Berg, Carla J; Levine, Hagai; Abroms, Lorien C; Wang, Yan; Bar-Zeev, Yael","year":2025,"journal":"Israel journal of health policy research, 14(1), 73","doi":"10.1186/s13584-025-00738-9","pmid":"41331648","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07206","title":"Cannabis for female orgasmic disorder/difficulty: a systematic review.","authors":"Mulvehill, Suzanne; Tishler, Jordan","year":2025,"journal":"Sexual medicine, 13(4), qfaf061","doi":"10.1093/sexmed/qfaf061","pmid":"40808870","tags":["medical-cannabis","sex-differences"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"All 9 studies examining cannabis use before sexual activity reported improvements in female orgasm function, including increases in frequency, ease, intensity, quality, and multiorgasmic capacity. However, some cases of situational inability to orgasm due to lack of focus were also reported.","whyItMatters":"Female orgasmic disorder affects up to 41% of women worldwide with no approved medications. If cannabis consistently improves orgasm function, it could fill a significant unmet medical need.","specificNumbers":"16 studies, 8,849 females. 9 studies of pre-sex use: all 9 showed improvement. 1 RCT included. Improvements in frequency, ease, intensity, quality, and multiorgasmic capacity. Some reported focus-related difficulty.","methodology":"PRISMA-based systematic review of 16 studies (1 RCT, 15 observational) including data from 8,849 females, evaluating cannabis effects on orgasm function with risk of bias assessment.","limitations":"Most studies observational with high risk of bias. No standardized cannabis dosing or products. None used clinical FOD diagnosis. Self-reported outcomes subject to expectancy effects. Only 1 RCT in the review."},{"rthcId":"RTHC-07207","title":"Looking beyond traditional pain outcomes to better evaluate cannabis's true potential and limitations in chronic pain management.","authors":"Mun, Chung Jung; Thrul, Johannes; Epstein, David H","year":2025,"journal":"Experimental and clinical psychopharmacology, 33(5), 425-429","doi":"10.1037/pha0000795","pmid":"40839511","tags":["pain","medical-cannabis","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"While clinical trials show inconsistent evidence for cannabis reducing pain severity, qualitative research reveals patients value cannabis because it changes their psychological response to pain and improves sleep, social functioning, and ability to reduce opioid use. The authors argue these outcomes should be primary endpoints in future trials.","whyItMatters":"If clinical trials keep measuring the wrong outcomes, they will continue to produce ambiguous results that do not reflect real-world patient benefits, leading to policy confusion.","specificNumbers":"Perspective references existing RCTs and qualitative studies without novel data. Identifies sleep quality, role/social functioning, opioid substitution, and psychological coping as understudied outcomes.","methodology":"Expert perspective piece reviewing the disconnect between RCT findings on cannabis for chronic pain and patient-reported experiences from qualitative research.","limitations":"Perspective piece without new empirical data. The proposed outcomes are harder to standardize and measure than pain severity. Patient perceptions may not always align with objective health outcomes."},{"rthcId":"RTHC-07208","title":"Risk of Cannabis Use Disorder in Chronic Pain: Longitudinal Links to Pain Outcomes.","authors":"Mun, Chung Jung; Timmons, Patricia; Perez, Iosef I; Meier, Madeline H; Wegener, Stephen T; Campbell, Claudia M; Aaron, Rachel V","year":2025,"journal":"Journal of addiction medicine, 19(5), 545-551","doi":"10.1097/ADM.0000000000001446","pmid":"40066866","tags":["pain","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Among 1,453 chronic pain patients followed for 2 years, 36.3% used cannabis and 39.8% of users showed high CUD risk. Higher CUD risk was associated with worse baseline pain, central sensitization, and mental health symptoms, but pain trajectories over 2 years did not differ between CUD risk groups and non-users.","whyItMatters":"Nearly 4 in 10 chronic pain patients who use cannabis may develop problematic use. The finding that CUD risk does not worsen pain trajectories suggests these patients are not harming their pain prognosis, but the mental health burden warrants attention.","specificNumbers":"N=1,453, 65.5% female, 86.1% White. 36.3% used cannabis. 39.8% of users at high CUD risk. Higher CUD risk associated with younger age, male sex, lower SES, higher alcohol risk, worse mental health. Pain trajectories: no difference by CUD risk.","methodology":"Two-year longitudinal study of 1,453 chronic pain patients recruited online, with baseline, 3-, 12-, and 24-month assessments using the Cannabis Abuse Screening Test and Brief Pain Inventory.","limitations":"Online recruitment may not represent all chronic pain patients. Self-reported cannabis use and CUD screening. Cannot determine causation. Predominantly White female sample limits generalizability."},{"rthcId":"RTHC-07209","title":"Cannabis concentrate vaping chemistry.","authors":"Munger, Kaelas R; Anreise, Killian M; Strongin, Robert M","year":2025,"journal":"Frontiers in toxicology, 7, 1568207","doi":"10.3389/ftox.2025.1568207","pmid":"40552084","tags":["harm-reduction","potency","respiratory"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Vaping cannabis concentrates (50%+ cannabinoid products) produces harmful aerosol toxicants including isoprene, 3-methylcrotonaldehyde, and other volatile compounds. Some products contained hazardous additives like pine rosin and ketene precursors (cannabinoid acetates). Oxygen plays a critical role in driving toxic degradation product formation.","whyItMatters":"Cannabis concentrates are the fastest-growing market segment, but research on their specific inhalation risks has significantly lagged their widespread use.","specificNumbers":"~2,700 Google Scholar hits for cannabis concentrate vaping. Concentrates defined as 50%+ cannabinoids. Toxic emissions include isoprene, 3-methylcrotonaldehyde, 3-methyl-1-butene, 2-methyl-2-butene. Hazardous additives found.","methodology":"Review of cannabis concentrate vaping emissions literature from 2019-2025, addressing technical challenges and presenting evidence on toxicant exposures from concentrates.","limitations":"Early-stage research with limited studies. Laboratory conditions may not reflect real-world use patterns. Product variability across manufacturers. Dose-response relationships not established."},{"rthcId":"RTHC-07210","title":"The impact of using cannabis during pregnancy on the infant and mother: An overview of systematic reviews, evidence map, targeted updates, and de novo synthesis.","authors":"Munn, Zachary; Pollock, Danielle; Stone, Jennifer; Hasanoff, Sabira; Gordon, Andrea; Price, Carrie; Stark, Michael; Barker, Timothy Hugh","year":2025,"journal":"The Australian & New Zealand journal of obstetrics & gynaecology, 65(3), 312-328","doi":"10.1111/ajo.13916","pmid":"39699257","tags":["pregnancy","harm-reduction","youth"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Across 89 included studies/reviews, prenatal cannabis exposure showed potentially harmful impacts on all fetal growth measures, some neonatal outcomes, some later-life developmental outcomes, and some maternal outcomes. Evidence for other outcomes was mixed. The authors concluded cannabis should be avoided during pregnancy.","whyItMatters":"As prenatal cannabis use rises, this is the most comprehensive evidence synthesis to date. Its clear conclusion, to avoid cannabis during pregnancy, provides the strongest evidence basis yet for clinical guidance.","specificNumbers":"89 studies/reviews included. Harmful effects found for: all fetal growth outcomes, some neonatal conditions, some later-life outcomes, some maternal outcomes. Mixed evidence for remaining outcomes.","methodology":"Umbrella review combining an overview of systematic reviews, evidence gap mapping, targeted review updates, and de novo synthesis, searching PubMed, MEDLINE, Embase, and CINAHL with duplicate risk of bias assessment.","limitations":"Cannot fully separate cannabis effects from confounders like tobacco, other substance use, and socioeconomic factors. Cannabis product types and doses vary widely. Publication bias possible. Some outcome areas had limited data."},{"rthcId":"RTHC-07211","title":"The development and therapeutic potential of classical and next-generation cannabinoid ligands.","authors":"Muñoz-Canales, Verónica; Benhamú, Bellinda; Martín-Fontecha, Mar; Vázquez-Villa, Henar; Ortega-Gutiérrez, Silvia","year":2025,"journal":"Pharmacological research, 222, 108022","doi":"10.1016/j.phrs.2025.108022","pmid":"41192631","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07212","title":"Efficacy and Safety of Topical 5% Cannabidiol Plus Myrcene for the Treatment of Vestibulodynia: A Multi-Centric Randomized Controlled Trial.","authors":"Murina, Filippo; Ettore, Giuseppe; Fochesato, Cecilia; Castiglione, Maria Grazia; Caruso, Melania; Fonti, Ilenia; Savasi, Valeria","year":2025,"journal":"Biomedicines, 13(10)","doi":"10.3390/biomedicines13102440","pmid":"41153723","tags":["cbd","pain","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Women applying 5% CBD plus myrcene gel to the vulvar vestibule for 60 days experienced significantly greater reductions in pain during intercourse compared to placebo, though both groups showed some improvement in overall pain scores.","whyItMatters":"Vestibulodynia affects a significant number of women and current treatments are limited. This is one of the first RCTs testing topical CBD specifically for vulvar pain, offering a potential non-hormonal, non-opioid option.","specificNumbers":"40 women enrolled (20 active, 20 placebo); 60-day treatment period; significant improvement in dyspareunia VAS scores in the active group versus placebo.","methodology":"Randomized double-blind placebo-controlled trial with 40 women (20 per group) applying active gel or placebo to the vulvar vestibule for 60 days, measuring dyspareunia, pain, and vestibular cotton swab test scores on a 0-10 VAS scale.","limitations":"Very small sample size (n=40) limits generalizability. The combined formulation makes it impossible to separate CBD effects from myrcene effects. Short follow-up period with no assessment of durability after stopping treatment."},{"rthcId":"RTHC-07213","title":"Age-Related Effects of Cannabis and Cannabinoids on Brain and Behavior.","authors":"Murray, Conor H; Cassarino, Joshua; Cooper, Ziva D","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251372061","pmid":"40876704","tags":["youth","pregnancy","seniors","cognition","neuroscience","mental-health"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Recent epidemiological data suggest a potential reversal in escalating cannabis use rates among pregnant women and adolescents, but use among older adults continues to climb with low risk perception. Preclinical and clinical evidence supports high risk during prenatal and adolescent brain development.","whyItMatters":"As cannabis access expands, understanding age-specific risks is critical for tailored public health messaging. The finding that older adults now represent the fastest-growing user group with the lowest risk perception is a relatively new concern.","specificNumbers":"NSDUH data from 2002-2023 analyzed; three life stages examined: in utero, adolescence, and late adulthood; data collected during 2020 and since 2021 used different methods than earlier years.","methodology":"Narrative review synthesizing preclinical and clinical studies across three life stages (in utero, adolescence, late adulthood), supplemented with updated NSDUH data from 2002-2023 on cannabis use rates and risk perceptions.","limitations":"Narrative review methodology is less rigorous than systematic review. NSDUH data collection changed in 2020-2021, limiting direct comparisons across years. Much of the prenatal and adolescent evidence comes from preclinical models."},{"rthcId":"RTHC-07214","title":"The rising tide of drug-induced psychosis.","authors":"Murray, Robin M; Paparelli, Alessandra; Di Forti, Marta; Morrison, Paul","year":2025,"journal":"Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater","doi":"10.1007/s40211-025-00541-7","pmid":"40833726","tags":["psychosis","legalization","potency","addiction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Drug-induced psychosis from methamphetamine and cannabis has become more common over three decades. Between 25% and 50% of drug-induced psychosis cases progress to schizophrenia within five years. Cannabis potency has increased substantially, particularly in jurisdictions that have legalized it.","whyItMatters":"The comparison to the obesity epidemic is provocative but grounded in a real pattern: policy and market changes driving population-level health consequences that emerge gradually. The 25-50% progression rate from drug-induced psychosis to schizophrenia represents a significant clinical concern.","specificNumbers":"25-50% of drug-induced psychoses progress to schizophrenia within 5 years; worldwide legal cannabis sales for 2025 estimated at $65 billion; 30-year trend of increasing drug-induced psychosis.","methodology":"Narrative review and commentary synthesizing epidemiological evidence, policy analysis, and clinical observations on trends in drug-induced psychosis from methamphetamine and cannabis.","limitations":"Commentary-style paper with selective evidence presentation. Does not systematically assess all available evidence. The epidemic framing may overstate the certainty of future trends. Does not account for potential benefits of legalization such as reduced criminalization."},{"rthcId":"RTHC-07215","title":"Recent development of plant-derived and synthetic cannabinoids as novel antimicrobial agents.","authors":"Musa, Sanaa; Dayan, Lee","year":2025,"journal":"Future medicinal chemistry, 17(23), 2881-2894","doi":"10.1080/17568919.2025.2580915","pmid":"41200875","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07216","title":"Minimum Legal Age of Nonmedical Cannabis Purchase Laws and Cannabis-Related Hospitalizations in Canada, 2015 to 2022.","authors":"Myran, Daniel T; Talarico, Robert; Pacula, Rosalie Liccardo; Xiao, Jennifer; Manuel, Doug; Hobin, Erin; Konikoff, Lauren; Tanuseputro, Peter; Taljaard, Monica","year":2025,"journal":"American journal of public health, 115(7), 1166-1174","doi":"10.2105/AJPH.2025.308090","pmid":"40403242","tags":["legalization","youth","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-related hospitalizations declined by 2% per quarter among individuals below the minimum legal age after legalization, while no slope change occurred for those above the MLA. By 3.5 years post-legalization, hospitalizations were 34% lower for those below the MLA relative to those above it.","whyItMatters":"This is one of the first large-scale studies to show that minimum legal age laws for cannabis may actually work as intended, reducing harm among youth while the same harms increase among the adult population with legal access.","specificNumbers":"14.6 million individuals in 2018; 137,901 cannabis-related hospitalizations during study period; 34% relative reduction below MLA at 3.5 years post-legalization (RR 0.66, 95% CI 0.49-0.91); pre-legalization rates were increasing 2% per quarter for both groups.","methodology":"Population-based controlled interrupted time series study examining all cannabis-related hospitalizations in Canada for individuals aged 15-44 (n=14.6 million in 2018) from January 2015 to March 2022, comparing trends above and below varying provincial MLAs.","limitations":"Observational design cannot prove causation. Cannot distinguish whether reduced youth hospitalizations reflect less use, safer use, or shifts in healthcare-seeking behavior. Provincial MLA variations could introduce confounding. Hospitalization data may undercount less severe cannabis-related harms."},{"rthcId":"RTHC-07217","title":"Cannabis Use Disorder Emergency Department Visits and Hospitalizations and 5-Year Mortality.","authors":"Myran, Daniel T; Pugliese, Michael; McDonald, André J; Xiao, Jennifer; Fischer, Benedikt; Finkelstein, Yaron; Tanuseputro, Peter; Firth, Joseph; Pakpour, Amir; Hsu, Chih-Wei; Chang, Wing-Chung; Solmi, Marco","year":2025,"journal":"JAMA network open, 8(2), e2457852","doi":"10.1001/jamanetworkopen.2024.57852","pmid":"39913138","tags":["addiction","mental-health","legalization","cardiovascular","respiratory","cancer"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Within 5 years of incident hospital-based CUD care, 3.5% of individuals died compared to 0.6% of matched general population members. After adjusting for comorbid conditions, CUD patients had 2.79 times higher death risk overall, with particularly elevated risks for suicide (9.7x), trauma (4.55x), opioid poisoning (5.03x), other drug poisonings (4.56x), and lung cancer (3.81x).","whyItMatters":"This is one of the largest studies to quantify mortality risk associated with cannabis use disorder severe enough to require emergency or hospital care. The findings suggest CUD is a marker for serious health vulnerability, even after accounting for other mental health and substance use conditions.","specificNumbers":"11,622,571 individuals studied; 106,994 with incident CUD; 3,770 CUD patients (3.5%) died within 5 years vs 3,770 (0.6%) matched controls; adjusted HR 2.79; suicide aHR 9.70; trauma aHR 4.55; opioid poisoning aHR 5.03; lung cancer aHR 3.81; median follow-up 5 years.","methodology":"Population-based retrospective cohort study of all Ontario residents aged 15-105 (n=11.6 million) from 2006-2021, comparing mortality between 106,994 individuals with incident hospital-based CUD care and age/sex-matched general population members using cause-specific hazard models adjusted for comorbidities.","limitations":"Only captures individuals severe enough to present to emergency departments or hospitals, not all people with CUD. Cannot establish whether cannabis use itself causes the elevated mortality or whether CUD is a marker for other risk factors. Comorbid substance use may confound results despite statistical adjustment."},{"rthcId":"RTHC-07218","title":"Changes in Incident Schizophrenia Diagnoses Associated With Cannabis Use Disorder After Cannabis Legalization.","authors":"Myran, Daniel T; Pugliese, Michael; Harrison, Lyndsay D; Solmi, Marco; Anderson, Kelly K; Fiedorowicz, Jess G; Finkelstein, Yaron; Manuel, Doug; Taljaard, Monica; Webber, Colleen; Tanuseputro, Peter","year":2025,"journal":"JAMA network open, 8(2), e2457868","doi":"10.1001/jamanetworkopen.2024.57868","pmid":"39903464","tags":["psychosis","addiction","legalization","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"The population-attributable risk fraction (PARF) for CUD associated with schizophrenia nearly tripled from 3.7% pre-legalization to 10.3% post-legalization. Among males aged 19-24, the PARF reached 18.9%. The overall incidence of schizophrenia remained stable, but psychosis NOS increased 83.7% post-legalization. The PARF increase was steady over time without acceleration after specific policy changes.","whyItMatters":"This is among the most comprehensive population-level studies linking cannabis policy changes to psychotic disorder burden. The finding that nearly 1 in 5 schizophrenia cases in young men may be attributable to CUD post-legalization carries significant public health implications.","specificNumbers":"13,588,681 individuals; 118,650 (0.9%) had CUD; 91,106 (0.7%) developed schizophrenia; PARF rose from 3.7% to 10.3%; PARF for males 19-24 reached 18.9%; PARF for females 45-65 was 1.8%; psychosis NOS incidence rose from 30.0 to 55.1 per 100,000 (83.7% increase).","methodology":"Population-based cohort study of 13.6 million Ontario residents aged 14-65 without prior schizophrenia history, from 2006-2022, using segmented linear regression to examine changes across three policy periods: pre-legalization, medical liberalization, and non-medical legalization.","limitations":"Observational design cannot prove that CUD causes schizophrenia. The PARF increase was gradual and did not accelerate after specific policy changes, making it difficult to attribute directly to legalization versus other temporal trends. Reverse causation (psychosis prodrome leading to cannabis use) remains possible."},{"rthcId":"RTHC-07219","title":"Emergency Department Visits Involving Hallucinogen Use and Risk of Schizophrenia Spectrum Disorder.","authors":"Myran, Daniel T; Pugliese, Michael; Xiao, Jennifer; Kaster, Tyler S; Husain, M Ishrat; Anderson, Kelly K; Fabiano, Nicholas; Wong, Stanley; Fiedorowicz, Jess G; Webber, Colleen; Tanuseputro, Peter; Solmi, Marco","year":2025,"journal":"JAMA psychiatry, 82(2), 142-150","doi":"10.1001/jamapsychiatry.2024.3532","pmid":"39535804","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07220","title":"Risk of Dementia in Individuals With Emergency Department Visits or Hospitalizations Due to Cannabis.","authors":"Myran, Daniel T; Pugliese, Michael; Harrison, Lyndsay D; Stall, Nathan M; Webber, Colleen","year":2025,"journal":"JAMA neurology, 82(6), 570-579","doi":"10.1001/jamaneurol.2025.0530","pmid":"40227745","tags":["seniors","cognition","addiction","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Individuals aged 45+ with acute care due to cannabis use had a 5.0% rate of dementia diagnosis within 5 years, compared to 3.6% for all-cause acute care and 1.3% in the general population. After adjustment, cannabis-related acute care was associated with 1.23x higher dementia risk than all-cause acute care and 1.72x higher than the general population, but 0.69x lower than alcohol-related acute care.","whyItMatters":"Cannabis use among older adults has surged dramatically, and this is one of the first large-scale studies to examine whether severe cannabis use is associated with dementia risk. The 26.7-fold increase in cannabis-related acute care among those 65+ between 2008 and 2021 underscores the scale of this emerging issue.","specificNumbers":"6,086,794 individuals studied; 16,275 with incident cannabis-related acute care; 5.0% dementia rate in cannabis group vs 1.3% general population; aHR 1.72 vs general population; aHR 0.69 vs alcohol; cannabis acute care among 65+ increased 26.7-fold (0.65 to 16.99 per 100,000) from 2008 to 2021.","methodology":"Population-based retrospective matched cohort study using Ontario health administrative data from 2008-2021 (follow-up to 2022), including 6.1 million individuals aged 45-105, comparing dementia diagnoses between those with incident cannabis-related acute care and matched controls using cause-specific adjusted hazard models.","limitations":"Only captures cannabis use severe enough for emergency or hospital care, not regular or recreational use. Cannot establish causation. People presenting with cannabis-related acute care may have other risk factors for dementia. Cannabis use could be an early manifestation of cognitive decline rather than a cause."},{"rthcId":"RTHC-07221","title":"Pharmacological and Pharmacokinetic Profile of Cannabidiol in Human Epilepsy: A Review of Metabolism, Therapeutic Drug Monitoring, and Interactions with Antiseizure Medications.","authors":"Na, Ji-Hoon; Lee, Young-Mock","year":2025,"journal":"Biomolecules, 15(12)","doi":"10.3390/biom15121668","pmid":"41463324","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07222","title":"Post-legalization shifts in cannabis use among young adults in Georgia-A nationally representative study.","authors":"Nadareishvili, Ilia; Rao, Sowmya R; Otiashvili, David; Gnatienko, Natalia; Samet, Jeffrey H; Lunze, Karsten; Kirtadze, Irma","year":2025,"journal":"Addiction (Abingdon, England), 120(2), 335-346","doi":"10.1111/add.16688","pmid":"39417804","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Lifetime cannabis use prevalence among Georgian young adults was similar before and after legalization (17.3% in 2015 vs 18.1% in 2022). Annual prevalence also held steady (7.0% vs 7.7%). However, cannabis became easier to obtain (OR 0.5 for difficulty), and the average age of first use increased from 18.1 to 19.1 years. Males and people who gambled were at higher risk of use.","whyItMatters":"Georgia (the country) provides a unique natural experiment in cannabis legalization outside of North America and Europe. The finding that use rates did not increase despite easier access challenges the assumption that legalization inevitably leads to more use.","specificNumbers":"Lifetime use: 17.3% (2015) vs 18.1% (2022), OR 1.1, p=0.726; annual use: 7.0% vs 7.7%, OR 1.1, p=0.650; easier to obtain in 2022 (OR 0.5, p=0.021); age of first use increased 18.1 to 19.1 years (p=0.003); female annual prevalence 1.9% vs male 13.1%.","methodology":"Comparison of two nationally representative cross-sectional surveys of Georgian adults aged 18-29, conducted in 2015 (n=1,308) and 2022 (n=758), using bivariate analyses and multivariable logistic and linear regressions.","limitations":"Repeated cross-sectional design (not longitudinal) limits causal inference. Only four years post-legalization, which may not capture longer-term trends. Georgia's cannabis market may be less commercialized than North American markets, limiting comparability. Relatively small sample size for the 2022 survey."},{"rthcId":"RTHC-07223","title":"Primary Care Physicians' Knowledge and Counseling on Cannabis Use in the Country of Georgia: Results of a Mixed-Method Exploratory Study.","authors":"Nadiradze, Aleksandra; Khetsuriani, Ketevani; Talakvadze, Tamari; Gulbani, Mariam; Ratiani, Elene; Nebieridze, Anano; Gaprindashvili, Nino; Tabagari, Nino; Lunze, Karsten; Nadareishvili, Ilia","year":2025,"journal":"Journal of primary care & community health, 16, 21501319251394522","doi":"10.1177/21501319251394522","pmid":"41324179","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 246 Georgian family physicians surveyed, only 35.6% were familiar with cannabis laws, 26.6% documented cannabis use in patient records, and 88.1% had never used structured criteria to diagnose cannabis use disorders. Time constraints, stigma, and lack of training were the most cited barriers to effective counseling.","whyItMatters":"As cannabis legalization spreads globally, this study highlights a critical gap: physicians may not be prepared to screen, diagnose, or counsel patients on cannabis use, even years after policy changes. This gap likely exists in many other newly legalized jurisdictions.","specificNumbers":"246 physicians surveyed; 96.6% female; 55.7% aged >51; 35.6% familiar with cannabis legislation; 97% associated cannabis with mental health risks; 92.4% with accident risk; <50% acknowledged medical applications; 26.6% documented cannabis use; 88.1% never applied CUD diagnostic criteria; 10 qualitative interviews.","methodology":"Mixed-method study combining a cross-sectional survey of 246 family physicians using a structured anonymous questionnaire with qualitative interviews of 10 physicians exploring barriers to cannabis-related counseling and documentation.","limitations":"Nearly all respondents (96.6%) were female, which may not represent the full physician population. The sample of 246 is modest for national generalization. Self-reported survey data may be subject to social desirability bias. Georgian medical practice context may limit generalizability."},{"rthcId":"RTHC-07224","title":"Prenatal Cannabis and Tobacco Co-Exposure and Its Association with Behavioural Outcomes in Middle Childhood: Co-exposition prénatale au cannabis et au tabac et son association avec les résultats comportementaux au cours de l'enfance intermédiaire.","authors":"Nadler, Emma; Jacobus, Joanna; Rabin, Rachel A","year":2025,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 70(1), 41-53","doi":"10.1177/07067437241271696","pmid":"39140868","tags":["pregnancy","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Prenatal co-exposure to cannabis and tobacco was associated with significantly greater externalizing behavior problems (aggression, rule-breaking) compared to either substance alone. Higher daily quantities of tobacco amplified the negative behavioral effects of cannabis exposure on both externalizing and internalizing scores (p<0.01). No significant interaction was found for internalizing behaviors in the main analysis.","whyItMatters":"Cannabis and tobacco are commonly co-used during pregnancy, but most research examines each substance in isolation. This study provides evidence that their combined prenatal effects on child behavior may be worse than either alone, which is particularly relevant as cannabis use during pregnancy rises.","specificNumbers":"n=9,792 total (290 co-exposed, 225 cannabis-only, 966 tobacco-only, 8,311 unexposed); cannabis main effect p=0.03; tobacco main effect p<value; cannabis x tobacco interaction for externalizing p=0.032; dose-response interaction p<0.01 for both externalizing and internalizing.","methodology":"Cross-sectional analysis of baseline data from the ABCD Study (children ages 9-11), comparing Childhood Behavior Checklist scores across four groups: cannabis+tobacco co-exposed (n=290), cannabis-only (n=225), tobacco-only (n=966), and unexposed controls (n=8,311), using 2x2 ANCOVA with covariate adjustment.","limitations":"Cross-sectional baseline data cannot establish causation or developmental trajectory. Prenatal exposure is based on maternal self-report, which may underestimate true exposure. Cannot fully control for other prenatal and postnatal environmental factors that differ between exposure groups."},{"rthcId":"RTHC-07225","title":"Cannabis expectancies mediate the association between social media use and cannabis experimentation in early adolescents: A prospective cohort study.","authors":"Nagata, Jason M; Caffrey, Andrew; Nguyen, Nathan D; Nayak, Sahana; Frimpong, Isaac; Helmer, Christiane K; Ricklefs, Colbey; Al-Shoaibi, Abubakr A; Testa, Alexander; Brindis, Claire D; Santos, Glenn-Milo; Baker, Fiona C","year":2025,"journal":"Drug and alcohol dependence, 277, 112947","doi":"10.1016/j.drugalcdep.2025.112947","pmid":"41197602","tags":["youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Daily social media time at Year 2 (around age 12) was significantly associated with cannabis experimentation at Year 4 (around age 14). Positive cannabis expectancies mediated 19.8% and negative expectancies mediated 13.6% of the social media-cannabis use association, even after adjusting for friends' cannabis use.","whyItMatters":"With early adolescents spending increasing time on social media, understanding how digital media exposure shapes substance use attitudes and behaviors is critical for prevention. The mediation finding suggests that social media may influence cannabis initiation partly by shaping beliefs about its effects.","specificNumbers":"n=7,691; mean age 12 at baseline; social media-cannabis association B=0.18 (95% CI 0.13-0.24, p<0.001); positive expectancies mediated 19.8%; negative expectancies mediated 13.6% of the association.","methodology":"Longitudinal analysis of ABCD Study data (n=7,691, mean age 12 at Year 2), examining associations between daily social media time and cannabis use outcomes two years later, with mediation analysis testing whether cannabis expectancies at Year 3 explained the relationship.","limitations":"Observational design cannot prove social media causes cannabis use. Self-reported social media time may be inaccurate. Cannot identify what specific social media content drives the association (cannabis-specific content, peer influence, or general risk-taking culture). Residual confounding from unmeasured family and peer factors."},{"rthcId":"RTHC-07226","title":"Cyberbullying, mental health, and substance use experimentation among early adolescents: a prospective cohort study.","authors":"Nagata, Jason M; Shim, Joan; Balasubramanian, Priyadharshini; Leong, Alicia W; Smith-Russack, Zacariah; Shao, Iris Y; Al-Shoaibi, Abubakr A A; Helmer, Christiane K; Ganson, Kyle T; Testa, Alexander; Kiss, Orsolya; He, Jinbo; Groves, Allison K; Baird, Sarah; Baker, Fiona C","year":2025,"journal":"Lancet regional health. Americas, 46, 101002","doi":"10.1016/j.lana.2025.101002","pmid":"40625792","tags":["youth","mental-health","depression","anxiety"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Cyberbullying victimization at ages 11-12 was prospectively associated with cannabis experimentation one year later (AOR 4.65, 95% CI 2.46-8.77), along with alcohol (AOR 1.98) and nicotine experimentation (AOR 3.37). Cyberbullying also predicted higher depressive, somatic, and attention problems, and 2.62x higher odds of suicidal behaviors.","whyItMatters":"This is one of the largest prospective studies to link cyberbullying with cannabis initiation in early adolescence. The finding that cyberbullying carries the strongest association with cannabis experimentation (compared to alcohol and nicotine) suggests cyberbullied youth may be particularly vulnerable to cannabis as a coping mechanism.","specificNumbers":"n=9,799; 48.4% female; 45.1% non-White; 8.7% reported cyberbullying victimization; cannabis AOR 4.65; nicotine AOR 3.37; alcohol AOR 1.98; suicidal behaviors AOR 2.62; depressive problems beta=0.61; somatic problems beta=1.00.","methodology":"Prospective cohort analysis of ABCD Study data (n=9,799 early adolescents aged 11-12), using logistic regression to examine associations between cyberbullying victimization at Year 2 and mental health and substance use outcomes at Year 3, adjusting for sociodemographics and baseline measures.","limitations":"Self-reported cyberbullying and substance use may be subject to recall and social desirability bias. One-year follow-up is short to establish lasting patterns. Cannabis experimentation (any use) does not equal regular use or problematic use. Residual confounding from unmeasured variables."},{"rthcId":"RTHC-07227","title":"Prospective association between screen use modalities and substance use experimentation in early adolescents.","authors":"Nagata, Jason M; Shim, Joan; Low, Patrick; Ganson, Kyle T; Testa, Alexander; He, Jinbo; Santos, Glenn-Milo; Brindis, Claire D; Baker, Fiona C; Shao, Iris Y","year":2025,"journal":"Drug and alcohol dependence, 266, 112504","doi":"10.1016/j.drugalcdep.2024.112504","pmid":"39612721","tags":["youth","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Each additional hour of social media (AOR 1.20) and texting (AOR 1.18) was associated with higher odds of any substance experimentation one year later. Social media and texting were specifically associated with cannabis, alcohol, and nicotine experimentation, while TV/movies, videos, video games, and general internet use were not. Video chatting was linked to cannabis and nicotine experimentation.","whyItMatters":"This study challenges the idea that \"screen time\" is a monolithic risk factor. The finding that interactive social screens (social media, texting, video chat) drive the substance use association while passive screens (TV, video games) do not has important implications for how parents and policymakers approach screen time guidelines.","specificNumbers":"n=8,006; 47.9% female; 41.6% racial/ethnic minority; social media AOR 1.20 (95% CI 1.14-1.26) per hour; texting AOR 1.18 (95% CI 1.12-1.24) per hour; video chatting AOR 1.09 (95% CI 1.03-1.16) per hour for any substance use.","methodology":"Prospective cohort analysis of ABCD Study data (n=8,006 early adolescents aged 11-12), using logistic regression to examine associations between eight types of screen time at Year 2 and substance use experimentation at Year 3, adjusting for covariates and baseline substance use.","limitations":"Self-reported screen time is likely imprecise. Cannot determine what content adolescents encounter on social media or in texts. One-year follow-up only captures initial experimentation. The distinction between screen types may blur as platforms converge (e.g., video games increasingly include chat features)."},{"rthcId":"RTHC-07228","title":"The impact of cannabis use on ageing and longevity: a systematic review of research insights.","authors":"Nain, Sonam; Singh, Niraj; Schlag, Anne Katrin; Barnes, Michael","year":2025,"journal":"Journal of cannabis research, 7(1), 52","doi":"10.1186/s42238-025-00267-x","pmid":"40731362","tags":["seniors","cognition","cbd","medical-cannabis","inflammation"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Eleven preclinical studies showed promising results for cannabinoids in aging, including improved lifespan, cognitive function, reduced inflammation, better sleep, and enhanced social interaction. Low-dose THC appeared beneficial while higher doses showed drawbacks. Seven human studies suggested potential therapeutic applications but were insufficient for comprehensive conclusions.","whyItMatters":"With global populations aging rapidly, identifying interventions that support healthy aging is a major research priority. This review is among the first to systematically compile what is known about how cannabinoids interact with the aging process through the endocannabinoid system.","specificNumbers":"18 studies included (11 preclinical, 7 human); preclinical models included C. elegans, rodents, zebrafish, and mice; human studies focused on populations aged 50+; low-dose THC showed benefits in preclinical models while higher doses showed drawbacks.","methodology":"PRISMA-guided systematic review of 18 studies (11 preclinical using C. elegans, rodents, zebrafish, mice; 7 human studies in populations aged 50+) investigating the direct impact of cannabinoids on aging and longevity.","limitations":"Only 18 studies met inclusion criteria, reflecting how little direct research exists on this topic. Most evidence comes from animal models that may not translate to humans. The seven human studies were heterogeneous in design and endpoints. Publication bias may favor positive results."},{"rthcId":"RTHC-07229","title":"Isolating and Determining the Structures of Colored Products from the Reactions of Cannabinoids with Fast Blue RR.","authors":"Nakamura, Kayo; Nishiguchi, Hikari; Arai, Ryosuke; Hamajima, Riho; Abe, Hiroko; Ishida, Akihiko; Tokeshi, Manabu; Higashi, Kyohei; Saitoh, Akiyoshi; Takahashi, Hideyo","year":2025,"journal":"Molecules (Basel, Switzerland), 30(17)","doi":"10.3390/molecules30173462","pmid":"40941988","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07230","title":"Immunotoxicological disruption of pregnancy as a new research area in immunotoxicology.","authors":"Nakamura, Kazuichi","year":2025,"journal":"Journal of immunotoxicology, 22(1), 2475772","doi":"10.1080/1547691X.2025.2475772","pmid":"40119670","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07231","title":"Exploratory analysis of United States-based cannabis product health benefit claims on online marketplaces.","authors":"Nali, Matthew C; Larsen, Meng Zhen; Li, Zhuoran; Li, Jiawei; Roehler, Douglas R; Mallory, Vanessa; Mackey, Tim K","year":2025,"journal":"Addiction (Abingdon, England), 120(12), 2489-2499","doi":"10.1111/add.70177","pmid":"40867092","tags":["medical-cannabis","cbd","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 624,805 cannabis product listings on Leafly and Weedmaps, 1.9% and 4.47% respectively included specific health benefit claims. The top 5 advertised benefits were mood disorders, general discomfort, general wellness, sleep disorders, and chronic conditions. Among consumer reviews of products with health claims, 82.4% expressed positive sentiment toward the claimed health benefit.","whyItMatters":"Unverified health claims on cannabis product listings could mislead consumers into using cannabis for conditions where evidence is limited or absent. The scale of this phenomenon (26,000+ products) highlights a regulatory gap in the cannabis marketplace.","specificNumbers":"624,805 unique products analyzed; 998 (1.9%) Leafly and 25,671 (4.47%) Weedmaps listings had health claims; 295 consumer reviews (4.6%) expressed sentiment about health claims; 82.4% positive, 14.6% negative, 3.1% neutral sentiment.","methodology":"Four-phase exploratory analysis: data mining of Leafly (50,951 products) and Weedmaps (573,854 products) US listings, text matching and content coding for health claims, consumer review sentiment analysis, and ANOVA testing differences in claims by route of administration.","limitations":"Only two platforms were analyzed, which may not represent all cannabis retail. Text matching may miss indirect health claims or marketing language that implies benefits without explicit claims. Cannot verify whether products actually deliver the claimed benefits."},{"rthcId":"RTHC-07232","title":"Psychiatrists' opinions about non-medicalization of cannabis use disorder in Iran.","authors":"Namazi, Hamidreza; Sayyah, Mehdi","year":2025,"journal":"Discover mental health, 5(1), 187","doi":"10.1007/s44192-025-00326-y","pmid":"41296205","tags":["addiction","mental-health","medical-cannabis"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Four main themes emerged: advantages of demedicalization (reduced stigma, enhanced patient empowerment, less dependence on pharmacological treatments), disadvantages (increased treatment challenges, worsened social damages), sociocultural impacts (improved social interactions, shifting cultural attitudes), and policy recommendations (modified legal approaches, comprehensive multifaceted treatment models).","whyItMatters":"As global cannabis policy evolves, the question of whether cannabis use disorder should remain a medical diagnosis has real implications for treatment access, insurance coverage, and social stigma. This study captures expert clinical perspectives from a country with strict prohibition, offering a counterpoint to Western-centric policy discussions.","specificNumbers":"16 psychiatrists interviewed; 4 main themes identified; data collected in Iran under prohibition context.","methodology":"Qualitative phenomenological study using in-depth semi-structured interviews with 16 Iranian psychiatrists experienced in addiction treatment, analyzed using inductive content analysis via the Graneheim and Lundman approach.","limitations":"Small qualitative sample from a single country with strict cannabis prohibition, limiting generalizability. Psychiatrists' views may reflect the specific Iranian legal and cultural context. No patient or consumer perspectives were included."},{"rthcId":"RTHC-07233","title":"Same-Day Sedative and Night-Time Sleep Effects Following Combined Cannabinoid Formulations: A Randomised-Controlled Trial.","authors":"Narayan, Andrea J; Manning, Brooke; Aitken, Blair; Downey, Luke A; Hayley, Amie C","year":2025,"journal":"Clinical drug investigation, 45(7), 417-429","doi":"10.1007/s40261-025-01455-6","pmid":"40542913","tags":["sleep","cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Subjective sleepiness increased from 40 to 265 minutes post-dosing across all conditions (including placebo), but neither the 1:1 THC:CBD nor the 1:16 THC:CBD oil produced greater sleepiness than placebo. Night-time sleep measures (total sleep time, sleep-onset latency, awakenings) measured via actigraphy and sleep diaries during 7-day washout periods showed no significant differences between treatment and placebo conditions.","whyItMatters":"Many people use cannabinoids for sleep, but this RCT found no sedative effect from low-dose formulations in healthy adults. This challenges the assumption that any cannabis product will improve sleep and highlights that dose, formulation, and patient population matter.","specificNumbers":"N=20; mean sleepiness increase of 1.9 points (SE 0.25) from 40 to 265 min post-dosing across all conditions; 1 mL standardized oil doses; 7-day washout periods; no significant between-group differences for sleepiness or any night-time sleep measure.","methodology":"Double-blind, randomized, placebo-controlled crossover design with 20 healthy adult novice cannabis users. Participants received 1 mL oral oil containing THC:CBD at 1:1 or 1:16 ratios or placebo over five weekly in-lab visits. Daytime sleepiness measured by Karolinska Sleepiness Scale at 40, 135, and 265 minutes post-dosing. Night-time sleep measured by wrist actigraphy and sleep diaries.","limitations":"Very small sample (N=20). Only tested low doses in healthy novice users, which may not represent typical medical cannabis patients or experienced users. Single-dose administration does not capture chronic use effects. Actigraphy has limitations compared to polysomnography."},{"rthcId":"RTHC-07234","title":"The Effect of Cannabis Consumption During Lactation on the Macronutrient Concentrations in Breast Milk.","authors":"Narayanan, Priyadharshini; Bertrand, Kerri; Waalen, Jill; Chambers, Christina; Ferran, Karen; Bandoli, Gretchen","year":2025,"journal":"Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine, 20(1), 33-41","doi":"10.1089/bfm.2024.0083","pmid":"39530127","tags":["pregnancy","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The presence of cannabis metabolites in breast milk was associated with an increase of 0.244 mg/dL in protein and an 11% reduction in fat content. Energy and carbohydrate levels were not significantly different between exposed and unexposed samples.","whyItMatters":"As cannabis use rises among lactating women, understanding its effects on breast milk composition is important for infant nutrition. Changes in protein and fat levels could theoretically affect infant development, though the clinical significance of these specific changes is unknown.","specificNumbers":"637 breast milk samples; 165 with detectable cannabis metabolites; protein increase of 0.244 mg/dL (95% CI 0.112-0.376, p<0.05); 11% reduction in fat (p=0.020); no significant differences in energy or carbohydrates.","methodology":"Cross-sectional study analyzing 637 breast milk samples, of which 165 had detectable cannabis metabolites (study group) and 472 did not (control group). Multivariable linear regression was used to assess associations between cannabis metabolite presence and protein, carbohydrate, fat, and calorie content.","limitations":"Cross-sectional design cannot establish causation. Self-reported cannabis use may underestimate exposure. Cannot determine dose-response relationships. The clinical significance of the observed macronutrient changes for infant health is unknown. Does not account for all potential confounders (diet, other substances)."},{"rthcId":"RTHC-07235","title":"Measuring commercial cannabis availability: findings from a multi-state surveillance study in the US.","authors":"Nargis, Nigar; Asare, Samuel; Westmaas, J Lee","year":2025,"journal":"Health affairs scholar, 3(12), qxaf209","doi":"10.1093/haschl/qxaf209","pmid":"41333841","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"THC market size accounted for 90% or more of the combined cannabis market value across all 12 states regardless of legalization status. The composition of THC markets varied considerably even among states with the same legalization status. Hemp-derived THC emerged as a significant market segment in both legal and non-legal states, highlighting regulatory gaps.","whyItMatters":"This study provides a rare comprehensive view of the full cannabis market, including the illicit and hemp-derived segments that are often excluded from official statistics. The persistence of illicit markets alongside legal ones and the rapid emergence of hemp-derived THC challenge assumptions about how legalization reshapes cannabis access.","specificNumbers":"12 US states analyzed; THC accounted for 90%+ of cannabis market value across all states; 142 in-store audits; 78 retailer interviews; 10 expert interviews; 2024 sales estimates; states classified by three legalization status categories.","methodology":"Multi-source analysis combining national and state-level public data, Euromonitor Passport database, in-store audits (n=142), retailer interviews (n=78), and expert interviews (n=10) to estimate 2024 annual sales values across legal recreational, medical, illicit, and hemp-derived THC segments in 12 US states.","limitations":"Illicit market estimates are inherently uncertain. Only 12 states included. Relies on multiple data sources with different methodologies and potential biases. Rapidly evolving market conditions mean 2024 estimates may not reflect the current landscape."},{"rthcId":"RTHC-07236","title":"Cannabidiol improves L-DOPA-induced dyskinesia and modulates neuroinflammation and the endocannabinoid, endovanilloid and nitrergic systems.","authors":"Nascimento, Glauce Crivelaro; Bálico, Gabriela Gonçalves; de Mattos, Bianca Andretto; Dos-Santos-Pereira, Mauricio; Oliveira, Igor Gustavo Carvalho; Queiroz, Maria Eugênia Costa; do Carmo Heck, Lilian; Navegantes, Luiz Carlos; Guimarães, Francisco Silveira; Del-Bel, Elaine","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 141, 111456","doi":"10.1016/j.pnpbp.2025.111456","pmid":"40684872","tags":["cbd","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD (30 mg/kg) and its fluorinated derivative PECS-101 (3 and 30 mg/kg) significantly reduced abnormal involuntary movements in L-DOPA-treated rats without reducing L-DOPA's motor benefits. CBD's antidyskinetic effects were blocked by CB1 and PPARy receptor antagonists and enhanced by TRPV-1 antagonism. CBD increased striatal anandamide and 2-AG concentrations and reduced neuroinflammation markers.","whyItMatters":"Dyskinesia affects up to 80% of Parkinson's patients on long-term L-DOPA therapy and is a major clinical problem. Finding a treatment that reduces dyskinesia without undermining L-DOPA's benefits would be a significant advance, and this preclinical evidence points to CBD as a candidate.","specificNumbers":"CBD at 30 mg/kg; PECS-101 at 3 and 30 mg/kg; L-DOPA at 10 mg/kg for 3 weeks; CBD effects blocked by CB1 antagonist (1 mg/kg) and PPARy antagonist (4 mg/kg); enhanced by TRPV-1 antagonist capsazepine (5 mg/kg); significant increases in anandamide and 2-AG.","methodology":"Unilateral 6-OHDA-lesioned rats were treated with L-DOPA for three weeks to induce dyskinesia, then received CBD or PECS-101 during the final two weeks. Abnormal involuntary movements were scored, and receptor antagonist studies identified mechanisms. Striatal endocannabinoid levels and inflammation markers were measured.","limitations":"Animal model findings may not translate directly to humans. The 6-OHDA lesion model does not fully replicate the progressive nature of human Parkinson's disease. Only tested acute/subchronic CBD administration; long-term effects are unknown. Doses may not correspond to human-equivalent doses."},{"rthcId":"RTHC-07237","title":"From rejection to recognition: Human rights, morality, and the future of Marijuana policy in Indonesia.","authors":"Natalis, Aga; Sembiring, Adventi Ferawati; Handayani, Emy","year":2025,"journal":"The International journal on drug policy, 140, 104817","doi":"10.1016/j.drugpo.2025.104817","pmid":"40267738","tags":["legalization","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis has been integrated into Indonesian cultural practices since the 14th century in Aceh for medicinal, ceremonial, and agricultural purposes. Two Constitutional Court decisions (No 106/PUU-XVIII/2020 and No 13/PUU-XXII/2024) have addressed the tension between strict prohibition and evolving societal needs. The transformation from acceptance to prohibition was driven by colonial-era legal structures and religious values.","whyItMatters":"Indonesia's cannabis debate reflects tensions present in many countries between traditional cultural practices, colonial-era drug laws, religious values, and evolving scientific understanding. The Constitutional Court cases represent concrete legal challenges to prohibition from a human rights perspective.","specificNumbers":"Cannabis use in Indonesia traced to 14th century; two Constitutional Court rulings analyzed (2020 and 2024); cases of Fidelis Ari Sudarwoto and Santi Warastuti cited as catalysts for national discourse.","methodology":"Legal and historical analysis examining the moral and human rights dimensions of Indonesia's cannabis policy, reviewing Constitutional Court rulings and proposing an alternative moral framework grounded in human rights, legal ethics, and scientific evidence.","limitations":"Legal and historical analysis rather than empirical research. Advocacy-oriented framing may present a one-sided perspective. Does not systematically assess public health evidence for or against legalization. Limited to Indonesian legal context."},{"rthcId":"RTHC-07238","title":"Association of Cannabinoid CB2 Receptor Q63R Variant With Rheumatoid Arthritis in an Iranian Cohort.","authors":"Nateghi, Ali; Zamani, Samin; Tahamtan, Alireza","year":2025,"journal":"International journal of genomics, 2025, 6182868","doi":"10.1155/ijog/6182868","pmid":"40552250","tags":["genetics","inflammation","medical-cannabis"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Logistic regression revealed significant associations between the Q63R polymorphism in the CNR2 gene and rheumatoid arthritis under codominant, dominant, and additive inheritance models. Carriers of the RR genotype had more than a 2.5-fold increased risk of developing RA.","whyItMatters":"The endocannabinoid system plays a role in immune regulation, and genetic variations in cannabinoid receptors could predispose individuals to autoimmune diseases. This study is the first to examine this specific genetic association in an Iranian population.","specificNumbers":"120 RA patients; 120 healthy controls; RR genotype associated with >2.5-fold increased RA risk; significant associations under codominant, dominant, and additive models; TaqMan assay genotyping.","methodology":"Case-control study of 120 RA patients and 120 healthy controls in Iran, genotyped for the Q63R polymorphism using TaqMan assay. Multiple genetic inheritance models (codominant, dominant, recessive, overdominant, additive) were analyzed using SNPStats software.","limitations":"Small sample size (120 per group) limits statistical power. Single ethnic population limits generalizability. No functional studies to explain how the Q63R variant affects CB2 receptor function or immune regulation. Cannot establish causation from genetic association alone."},{"rthcId":"RTHC-07239","title":"Extracellular condensates (ECs) are endogenous modulators of HIV transcription and latency reactivation.","authors":"Naushad, Wasifa; Premadasa, Lakmini S; Tallapaneni, Vyshnavi; Okeoma, Bryson C; Chaudhary, Ashok; Stapleton, Jack T; Mohan, Mahesh; Okeoma, Chioma M","year":2025,"journal":"Molecular psychiatry","doi":"10.1038/s41380-025-03354-w","pmid":"41318671","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07240","title":"Cannabidiol modulates brain molecular alterations, gut microbiota dysbiosis and alcohol self-administration in a mouse model of fetal alcohol spectrum disorder.","authors":"Navarrete, F; Cabrera-Rubio, R; Gasparyan, A; Aarnio, R; López-Picón, F; Helin, S; Rajander, J; Collado, M C; Manzanares, J","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 193, 118791","doi":"10.1016/j.biopha.2025.118791","pmid":"41273930","tags":["cbd","pregnancy","addiction","neuroscience","mental-health"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Mice with prenatal alcohol exposure showed increased anxiety and depression-like behavior, sex-dependent changes in brain receptors and neurotransmitters, and gut microbiota dysbiosis. Chronic CBD (30 mg/kg/day) from weaning improved or normalized behavioral and molecular disturbances in a sex-dependent manner. In females, CBD abolished the heightened motivation to consume alcohol that developed following fetal alcohol exposure.","whyItMatters":"Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of intellectual disability, and there are no approved treatments. This study suggests CBD could address multiple FASD-related problems simultaneously, including brain changes, gut health, behavior, and subsequent alcohol vulnerability.","specificNumbers":"CBD at 30 mg/kg/day; sex-dependent changes in CB1/CB2, D2/D3 receptors, tyrosine hydroxylase, and serotonin transporter gene expression; females showed higher alcohol motivation that CBD abolished; gut microbiota dysbiosis corrected by CBD.","methodology":"Preclinical study using C57BL/6J mice with prenatal alcohol exposure (FASD model). CBD (30 mg/kg/day, i.p.) was administered chronically from weaning. Assessments included anxiety/depression behavior tests, brain molecular markers (dopamine D2/D3, CB1/CB2, tyrosine hydroxylase, serotonin transporter), gut microbiota composition and diversity, and alcohol self-administration.","limitations":"Animal model results may not translate to humans. CBD was given from weaning, which may not be practical in human FASD management. The FASD mouse model does not fully replicate the complexity of human FASD. Intraperitoneal CBD delivery differs from oral consumption in humans."},{"rthcId":"RTHC-07241","title":"Practical approach to the safe use of cannabidiol in patients with refractory epilepsy: a mini review.","authors":"Navarro, Cristian E","year":2025,"journal":"Frontiers in pharmacology, 16, 1681815","doi":"10.3389/fphar.2025.1681815","pmid":"40978479","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"While CBD's efficacy for certain severe epilepsy syndromes is established (Dravet, Lennox-Gastaut), the practical details of prescribing it safely remain challenging. This review fills that gap with evidence-based clinical guidance.\n\nThe \"start low, go slow\" principle is central. CBD interacts with many common anti-seizure medications through the cytochrome P450 enzyme system, particularly affecting clobazam (whose active metabolite levels can double or triple with CBD co-administration) and valproate (increasing the risk of liver enzyme elevation). Gradual dose titration allows clinicians to monitor for these interactions.\n\nAdverse drug reactions are dose-dependent and generally manageable: sedation (especially when combined with clobazam), gastrointestinal effects, decreased appetite, and elevated liver enzymes (particularly with valproate). The liver enzyme issue requires regular monitoring but is typically reversible with dose adjustment.\n\nThe review also addresses a practical reality: roughly 30% of epilepsy patients are drug-resistant (failing two or more conventional medications), and these patients often have complex medication regimens. Adding CBD to this polypharmacy requires careful attention to interactions that could either reduce the effectiveness of existing medications or amplify their side effects.","whyItMatters":"Having an effective drug is only useful if clinicians know how to prescribe it safely. CBD's drug interactions are clinically significant—a patient taking clobazam who starts CBD may suddenly become over-sedated if the interaction isn't anticipated and managed. This practical guide helps bridge the gap between FDA approval and real-world clinical use.","specificNumbers":"~30% of epilepsy patients are drug-resistant. Highly purified CBD (Epidiolex) is 99% CBD. Clobazam active metabolite levels can increase 2–3x with CBD co-administration. Liver enzyme elevation risk highest with valproate combination. \"Start low, go slow\" dosing approach recommended.","methodology":"Narrative review synthesizing clinical trials, systematic reviews, observational studies, and real-world evidence on practical aspects of prescribing highly purified CBD oral solution (Epidiolex) for drug-resistant epilepsy.","limitations":"Narrative review reflects the author's clinical perspective and evidence selection. Most evidence comes from the specific FDA-approved formulation (Epidiolex 99% CBD)—results may not apply to other CBD products. Drug interaction data is still evolving. The review focuses on severe epilepsy syndromes and may not generalize to milder forms or off-label use."},{"rthcId":"RTHC-07242","title":"Gender Differences in Cannabis as a Mediator Between Distress Factors and Non-Fatal Suicidal Behaviors.","authors":"Nayeem, Nawar; Walsh, McKenna; Bello-Kottenstette, Jennifer; Messias, Erick; Lin, Ping-I","year":2025,"journal":"International journal of mental health and addiction","doi":"10.1007/s11469-025-01570-7","pmid":"41625015","tags":["mental-health","depression","pain","sex-differences","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use mediated 2.3% of the effect of depression on suicidal ideation in women versus 1.2% in men, and 1.7% versus 1.0% for suicide attempts. For pain conditions, cannabis mediated 12.5% of the effect on suicidal ideation in women versus 5.9% in men.","whyItMatters":"Understanding gender-specific pathways from distress to suicidal behavior through cannabis use could improve suicide risk screening. The finding that cannabis plays a larger mediating role for women, particularly in the pain-suicidality pathway, suggests that women using cannabis for pain management may need additional mental health monitoring.","specificNumbers":"n=93,743 (ages 18-50); NSDUH 2020-2022; cannabis mediation of depression-suicidal ideation: women 2.3% vs men 1.2%; depression-suicide attempts: women 1.7% vs men 1.0%; pain-suicidal ideation: women 12.5% (95% CI 0.081-0.272) vs men 5.9% (95% CI 0.038-0.128).","methodology":"Mediation analysis using data from the National Survey of Drug Use and Health (NSDUH) 2020-2022, with 93,743 individuals aged 18-50. Causal framework assessed the mediating role of cannabis between depression, pain conditions, and non-fatal suicidal behaviors across genders.","limitations":"Cross-sectional survey data cannot establish causal direction. Self-reported substance use and mental health measures may be imprecise. The mediation percentages, while statistically significant, are small in absolute terms. Data collected during COVID-19 pandemic may reflect atypical patterns."},{"rthcId":"RTHC-07243","title":"Gender differences in non-fatal suicidal behaviors linked to concurrent use of cannabis and opioids.","authors":"Nayeem, Nawar; Wang, Samantha Sijing; Naidu, Aniketh; Messias, Erick; Lin, Ping-I","year":2025,"journal":"Journal of psychiatric research, 191, 170-176","doi":"10.1016/j.jpsychires.2025.09.046","pmid":"41027318","tags":["addiction","mental-health","drug-interactions","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis and opioid co-use was associated with a smaller-than-expected (sub-additive) increase in non-fatal suicidal behaviors overall (interaction beta=-0.58, p<0.001) and especially in women (beta=-0.87, p<0.001). In men, the joint effect did not significantly differ from additivity (beta=-0.29, p=0.07), indicating potential greater vulnerability.","whyItMatters":"The finding that cannabis-opioid co-use produces a sub-additive rather than additive suicide risk, particularly in women, complicates simplistic assumptions about polysubstance use. It suggests the interaction between these substances and mental health is more nuanced than expected.","specificNumbers":"n=152,930; 3.2% used cannabis; 2.3% used opioids; 2.5% experienced non-fatal suicidal behaviors; overall interaction beta=-0.58, p<0.001; women interaction beta=-0.87, p<0.001; men interaction beta=-0.29, p=0.07.","methodology":"Logistic regression analysis of All of Us Research Program data (n=152,930, ages 18-49) examining whether cannabis and opioid use and their interaction were associated with non-fatal suicidal behaviors, controlling for demographic and psychiatric variables, stratified by gender.","limitations":"Cross-sectional design cannot establish temporal order or causation. Self-reported substance use may underestimate actual co-use. The All of Us cohort may not be fully representative of the US population. Small effect sizes limit clinical significance. Cannot determine mechanisms of the sub-additive interaction."},{"rthcId":"RTHC-07244","title":"Recreational Marijuana Laws and suicide deaths in the US.","authors":"Nayeem, Nawar; Messias, Erick; Lin, Ping-I","year":2025,"journal":"Psychiatry research, 345, 116386","doi":"10.1016/j.psychres.2025.116386","pmid":"39908658","tags":["legalization","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"RMLs were associated with a statistically significant increase of 0.68 suicide deaths per 100,000 population overall. The increase was primarily driven by states legalizing in 2018 (Maine, Vermont, Michigan) and 2019 (Illinois). In contrast, states that enacted RMLs in 2015 (Alaska, Oregon, Washington D.C.) experienced a decline in suicide deaths post-legalization.","whyItMatters":"The divergent results across states suggest that the relationship between cannabis legalization and suicide is not straightforward. State-specific factors, including how legalization is implemented, demographic characteristics, and mental health infrastructure, may be more important than legalization itself.","specificNumbers":"Overall RML effect: +0.68 suicide deaths per 100,000 (p<0.05); 2018 and 2019 legalizing states drove the increase; 2015 legalizing states (Alaska, Oregon, DC) saw decreases; data from 2000-2022; staggered DiD framework.","methodology":"Staggered difference-in-differences analysis of state-level age-adjusted suicide rates from CDC Multiple Cause of Death Files (2000-2022), using RML implementation dates from NORML to compare suicide trends in states before and after legalization.","limitations":"Ecological study design (state-level data) cannot establish individual-level causation. Cannot control for all state-level confounders that changed alongside legalization. The COVID-19 pandemic overlapped with several states' legalization periods. Small number of states in each legalization cohort limits statistical power."},{"rthcId":"RTHC-07245","title":"Impact of Canada's Cannabis Act on drug- and alcohol-related collisions in Québec: an interrupted time-series analysis of five major cities.","authors":"Nazif-Munoz, José Ignacio; Ouimet, Marie Claude","year":2025,"journal":"Traffic injury prevention, 26(sup1), S77-S85","doi":"10.1080/15389588.2025.2537145","pmid":"40828992","tags":["driving","legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Total cannabis sales were significantly associated with a 12% increase in drug-related crashes (IRR 1.12) and a 12% increase in alcohol-related crashes (IRR 1.12) across five Quebec cities. Montreal showed the strongest effects: 87% increase in drug-related crashes and 93% increase in alcohol-related crashes. Longueuil and Quebec City also showed significant increases, while Laval and Sherbrooke showed no significant effects.","whyItMatters":"The finding that cannabis sales are associated with both drug-related AND alcohol-related crashes suggests that cannabis availability may influence broader impaired driving patterns, not just cannabis-impaired driving. This has implications for how jurisdictions plan road safety interventions around legalization.","specificNumbers":"Five cities; 2015-2022; overall IRR 1.12 for both drug and alcohol crashes; Montreal drug-related IRR 1.87, alcohol-related IRR 1.93; Longueuil drug IRR 1.76, alcohol IRR 1.43; Quebec City alcohol IRR 1.44; no significant effects in Laval or Sherbrooke.","methodology":"Interrupted time-series analysis of daily drug- and alcohol-related traffic crashes in five Quebec cities (Montreal, Quebec City, Laval, Longueuil, Sherbrooke) from 2015-2022. Cannabis sales (legal and estimated illegal) served as exposure variables. Generalized linear models with negative binomial regression and random-effects meta-analysis across cities, controlling for temperature, time trends, and COVID-19 measures.","limitations":"Ecological design using cannabis sales as a proxy for individual consumption. Cannot establish that individuals in crashes actually used cannabis. The COVID-19 pandemic occurred during the study period and may confound results. Illicit market estimates introduce uncertainty. City-level variation makes it difficult to draw general conclusions."},{"rthcId":"RTHC-07246","title":"Exogenous Administration of Delta-9-Tetrahydrocannabinol Affects Adult Hippocampal Neurotransmission in Female Wistar Rats.","authors":"Neves, Ana M; Leal, Sandra; Fonseca, Bruno M; Sá, Susana I","year":2025,"journal":"International journal of molecular sciences, 26(13)","doi":"10.3390/ijms26136144","pmid":"40649919","tags":["neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In the hippocampus of ovariectomized female rats, THC increased cholinergic receptor (CHRNA7), glutamate transporter (VGLUT), and GABA receptor expression when estrogen was absent, but decreased these same markers when estrogen was present. THC also increased CB1 receptor and acetylcholine transporter expression that had been reduced by estrogen.","whyItMatters":"Most cannabis research uses male animals, leaving a gap in understanding how THC affects the female brain. This study reveals that estrogen status fundamentally changes how THC interacts with hippocampal neurotransmission, which has implications for understanding sex differences in cannabis effects on memory and cognition.","specificNumbers":"N=20 female Wistar rats; hippocampal subregions CA1, CA3, DG, hilum examined; 6 neurotransmitter markers assessed; estrogen reversed the direction of THC effects on multiple markers.","methodology":"Twenty female Wistar rats were ovariectomized at 8 weeks and received estradiol benzoate and/or THC. Immunohistochemistry assessed expression of cholinergic (CHRNA7, VAChT), glutamatergic (VGLUT), GABAergic (GABRA, GAD), cannabinoid (CB1), and estrogen (ERalpha) receptors across hippocampal subregions (CA1, CA3, DG, hilum).","limitations":"Small animal sample size (N=20). Ovariectomized rats receiving exogenous estrogen do not fully replicate natural hormonal cycling. Results from rat hippocampus may not directly translate to human neurobiology. Does not assess behavioral or cognitive outcomes of the observed neurochemical changes."},{"rthcId":"RTHC-07247","title":"Understanding the Role of Endocannabinoids in Posttraumatic Stress Disorder.","authors":"Ney, Luke","year":2025,"journal":"International journal of molecular sciences, 26(12)","doi":"10.3390/ijms26125527","pmid":"40564991","tags":["ptsd","neuroscience","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Preclinical literature is reasonably consistent in showing that endocannabinoid system modulation can affect fear memory processes relevant to PTSD. However, emerging human literature is mixed and inconsistent. The review identifies several potential reasons for the human-animal discrepancy and calls for clinical trials and carefully designed human experimental studies.","whyItMatters":"PTSD is often treatment-resistant, affecting an estimated 6% of the US population. Cannabinoid therapy has been proposed as a potential alternative, but this review highlights the gap between promising animal data and inconsistent human evidence, cautioning against premature clinical adoption.","specificNumbers":"Review covers preclinical and clinical literature on endocannabinoid modulation in PTSD; notes that PTSD is often treatment-resistant; calls for clinical trials before cannabinoid therapy can be considered a treatment approach.","methodology":"Narrative review synthesizing animal and human research on endocannabinoid modulation effects on posttraumatic symptoms, behaviors, and relevant memory processes, with analysis of why human findings have been inconsistent.","limitations":"Narrative review methodology is less systematic than systematic review. The field is rapidly evolving, so conclusions may not reflect the very latest studies. Does not provide a meta-analytic estimate of effect sizes across studies."},{"rthcId":"RTHC-07248","title":"Potential Anticancer Effect of Cannabis sativa L. Dichloromethane Extract Through Oxidative Stress-Related Pathways and the Inhibition of the Migration and Invasiveness of Human Breast Cancer Cells (MDA-MB-231 and MCF-7).","authors":"Ngnameko, Corinne Raïssa; Manjia, Jacqueline Njikam; Matsabisa, Motlalepula Gilbert","year":2025,"journal":"International journal of molecular sciences, 27(1)","doi":"10.3390/ijms27010152","pmid":"41516029","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07249","title":"Barriers and facilitators to nicotine and cannabis vaping cessation among young adults: a qualitative study using Capability, Opportunity, Motivation, and Behavior (COM-B) model and Theoretical Domains Framework (TDF).","authors":"Nguyen, Nhung; Satterfield, Jason M; Keyhani, Salomeh; Marcus, Gregory M; Ling, Pamela M","year":2025,"journal":"Annals of behavioral medicine : a publication of the Society of Behavioral Medicine, 59(1)","doi":"10.1093/abm/kaaf096","pmid":"41325641","tags":["quitting","youth","addiction","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Young adults expressed stronger motivation to stop vaping nicotine than cannabis. Key barriers to quitting included lack of self-control over nicotine vaping, product accessibility, treatment cost, habitual use, addiction, low perceived risk, coping with mental health, and personal identity linked to vaping. Facilitators included cost burden, protecting relationships, negative emotions about health harms, and health concerns.","whyItMatters":"As vaping becomes the dominant nicotine and cannabis delivery method among young adults, understanding what helps and hinders quitting is essential for intervention design. The finding that motivation to quit differs between nicotine and cannabis vaping suggests cessation programs may need substance-specific approaches.","specificNumbers":"20 participants; mean age 22.8; racially/ethnically diverse California sample; interviews conducted 2024-2025; mapped to COM-B model and Theoretical Domains Framework; most cessation factors overlapped for nicotine and cannabis.","methodology":"Thematic analysis of interviews with 20 racially and ethnically diverse California young adults (mean age 22.8) who vaped nicotine and/or THC in 2024-2025, mapped to the Capability, Opportunity, Motivation, and Behavior (COM-B) model and Theoretical Domains Framework.","limitations":"Small qualitative sample (n=20) from California only. Self-selected participants may not represent all young adult vapers. Cannot quantify the relative importance of different barriers and facilitators. Cross-sectional interviews capture perspectives at one point, not trajectories of quitting."},{"rthcId":"RTHC-07250","title":"Vaping nicotine and cannabis on the same occasion is linked to increased vaping consumption among young adults: A smartphone-based daily diary study.","authors":"Nguyen, Nhung; Keyhani, Salomeh; Marcus, Gregory M; Do, Vuong V; Halliday, Deanna M; Herbst, Ellen D; Ling, Pamela M","year":2025,"journal":"Drug and alcohol dependence, 266, 112517","doi":"10.1016/j.drugalcdep.2024.112517","pmid":"39644839","tags":["addiction","youth","drug-interactions"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"On days with same-occasion co-vaping, participants reported the greatest intensity of both nicotine and cannabis vaping compared to all other patterns (single-substance vaping, same-day different-occasion co-vaping, or non-vaping days). Same-day different-occasion co-vaping also showed higher intensities than single-substance vaping.","whyItMatters":"Understanding which co-use patterns carry the most risk is important for targeted intervention. This study identifies same-occasion co-vaping as the highest-risk pattern, which could inform screening tools and cessation messaging for young adults.","specificNumbers":"n=111; 30-day daily assessment; 2,522 total daily assessments; 84.7% reported co-vaping in past 30 days; 42.7% nicotine-only days; 9.7% cannabis-only days; 16.5% same-day different-occasion co-vaping; 16.9% same-occasion co-vaping.","methodology":"Smartphone-based daily diary study collecting 30 consecutive days of vaping behavior from 111 California young adults (aged 18-29) who vaped at least 20 days per month. Generalized linear mixed-effects models examined day-level associations between vaping patterns and vaping intensity, controlling for covariates.","limitations":"Self-reported daily diary data may be inaccurate, particularly for vaping frequency. California-only sample may not represent other regions. Correlational daily-level associations cannot establish causation. Cannot determine whether co-vaping causes higher intensity or higher-intensity vapers are more likely to co-vape."},{"rthcId":"RTHC-07251","title":"Cannabinoid Receptor 1 Regulates Zebrafish Renal Multiciliated Cell Development via cAMP Signaling.","authors":"Nguyen, Thanh Khoa; Baker, Sophia; Angtuaco, Julienne; Arceri, Liana; Kaczor, Samuel; Fitzsimonds, Bram; Hawkins, Matthew R; Wingert, Rebecca A","year":2025,"journal":"Journal of developmental biology, 13(2)","doi":"10.3390/jdb13020020","pmid":"40558673","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07252","title":"Cannabis Use is Related to Anhedonia in Adolescents With Diverse Mood and Anxiety Symptoms.","authors":"Nguyen, Tram N B; Ely, Benjamin A; Vitale, Aria; Roske, Chloe; Richard, Jasmin T; Tobe, Russell H; Gabbay, Vilma","year":2025,"journal":"JAACAP open, 3(4), 1107-1117","doi":"10.1016/j.jaacop.2025.02.003","pmid":"41367990","tags":["youth","depression","mental-health","dopamine"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Adolescents who used cannabis endorsed worse anticipatory anhedonia (difficulty looking forward to pleasurable experiences) compared to those who never used or tried cannabis only once. More frequent cannabis use correlated with greater anticipatory anhedonia. Teens diagnosed with cannabis use disorder reported greater depression and anxiety than those with non-disordered use.","whyItMatters":"Anhedonia is a core symptom of depression and reflects dysfunction in the brain's reward system. Finding that cannabis use is specifically linked to anticipatory anhedonia in teens with mood symptoms suggests cannabis may compound reward-system problems in already vulnerable youth.","specificNumbers":"153 adolescents; mean age 15.9 years; 64.1% female; 49 cannabis users identified; cannabis use disorder subgroup showed greater depression and anxiety than non-disordered users.","methodology":"Cross-sectional study of 153 adolescents (mean age 15.9, 64.1% female) presenting with mood and anxiety symptoms. Cannabis use was quantified via clinician interviews, self-reports, and urine toxicology. Linear regression models assessed associations between cannabis use and anhedonia subconstructs, adjusting for age and sex.","limitations":"Small sample size (n=153) with cross-sectional design, which cannot determine whether cannabis causes anhedonia or anhedonic teens seek cannabis. Clinical sample may not generalize to community populations. Self-reported cannabis use may be underestimated."},{"rthcId":"RTHC-07253","title":"A Preliminary Investigation of Brain Cannabinoid Receptor Type 1 (CB1R) Availability in Men with Opioid Use Disorder.","authors":"Nia, Anahita Bassir; Aghaei, Ardavan Mohammad; Weleff, Jeremy; Shi, Julia; Contreras, Angelina; Griffin, Mackenzie; Jegede, Oluwole; Pittman, Brian; Harpaz-Rotem, Ilan; Hillmer, Ansel; D'Souza, Deepak","year":2025,"journal":"Research square","doi":"10.21203/rs.3.rs-7715611/v1","pmid":"41282260","tags":["addiction","neuroscience","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Average CB1R availability (measured by volume of distribution) was 15% lower across 13 brain regions in men with OUD compared to healthy controls (p=0.04). Lower CB1R was also observed in several corticolimbic areas. No effects on CB1R were found for treatment medication type, stress levels, antidepressant use, treatment duration, or time since last illicit opioid use.","whyItMatters":"If confirmed, lower CB1R availability in OUD could provide a rationale for targeting the endocannabinoid system in opioid addiction treatment. Understanding how opioid use alters the brain's cannabinoid system may help explain why some opioid users also develop cannabis use patterns.","specificNumbers":"n=10 OUD patients, n=18 healthy controls; 15% lower average CB1R volume of distribution (p=0.04); 13 brain regions assessed; no effect of treatment medication type or duration.","methodology":"PET brain imaging study using High-Resolution Research Tomography and the CB1R-specific radiotracer [11C]OMAR, comparing 10 males with OUD on stable opioid agonist treatment (methadone or buprenorphine) to 18 healthy male controls. CB1R availability was measured across 13 brain regions.","limitations":"Very small sample (n=10 OUD). Males only, limiting generalizability. All OUD participants were on opioid agonist treatment, so findings may reflect treatment effects rather than OUD itself. Cross-sectional design cannot determine whether lower CB1R preceded or resulted from opioid use."},{"rthcId":"RTHC-07254","title":"Long-term cannabinoid therapy can ameliorate chronic sleep deprivation-induced behavioral and neuroinflammatory changes in mice.","authors":"Niazi, Nasar Ullah Khan; Parveen, Rabia","year":2025,"journal":"Neuroscience letters, 864, 138314","doi":"10.1016/j.neulet.2025.138314","pmid":"40628367","tags":["sleep","cbd","cognition","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic sleep deprivation caused memory impairment, depression-like behavior, microglial activation, and elevated pro-inflammatory cytokines in mice. CBD, CBG, CBC, and their combinations all significantly reversed these changes, but CBD+CBC was the most effective combination for reversing behavioral and neuroinflammatory effects.","whyItMatters":"Chronic sleep deprivation is a widespread public health problem linked to cognitive decline and inflammation. This study is among the first to compare multiple cannabinoids and their combinations for sleep deprivation-related damage, identifying CBD+CBC as a potentially superior combination.","specificNumbers":"CBD, CBG, CBC tested individually and in combinations; CBD+CBC was the most effective combination; chronic sleep deprivation groups showed increased pro-inflammatory cytokines and microglial activation; molecular docking corroborated the biological findings.","methodology":"Animal study using chronic sleep deprivation (cSD) mouse model. Behavioral tests assessed memory and depression. ELISA measured cytokine profiles and microglial responses. Molecular docking analyzed cannabinoid binding affinity to cannabinoid receptors. Multiple cannabinoid treatments tested: CBD, CBG, CBC individually and in combinations.","limitations":"Animal model results may not translate to humans. Specific doses and administration routes may not correspond to human use. Molecular docking is a computational prediction, not direct evidence of mechanism. Sleep deprivation model may not fully replicate human insomnia."},{"rthcId":"RTHC-07255","title":"Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice.","authors":"Nicholson, Gregory; Richards, Nicholas; Lockett, Janette; Ly, My Boi; Nair, Raj V; Kim, Woong-Ki; Vinod, K Yaragudri; Nagre, Nagaraja","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(2)","doi":"10.3390/ph18020236","pmid":"40006049","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07256","title":"FAAH Modulators from Natural Sources: A Collection of New Potential Drugs.","authors":"Nicoara, Catalin; Fezza, Filomena; Maccarrone, Mauro","year":2025,"journal":"Cells, 14(7)","doi":"10.3390/cells14070551","pmid":"40214504","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07257","title":"The Impact of Frequency of Cannabis Use on Hypertensive Disorders During Pregnancy.","authors":"Nidey, Nichole; Raff, Erica; Ferdous Khan, Md Tareq; Watkins, Shannon Lea; McAllister, Jennifer M Jm; Kair, Laura; Terplan, Mishka; Greiner, Andrea","year":2025,"journal":"Journal of addiction medicine, 19(5), 611-614","doi":"10.1097/ADM.0000000000001454","pmid":"40028912","tags":["pregnancy","cardiovascular"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use as a binary variable (yes/no) was not associated with higher odds of hypertension during pregnancy (OR 0.86). However, among those who used cannabis, frequent use (2-6 times per week to daily) was associated with 3.44 times higher odds of hypertensive disorders compared to minimal use (once per month or less, OR 3.44, 95% CI 1.40-8.43).","whyItMatters":"This study may explain why prior research on cannabis and pregnancy hypertension has been mixed: looking at any use versus no use masks a dose-response relationship. The finding that frequency matters has practical implications for prenatal screening and counseling.","specificNumbers":"n=10,911 (weighted 587,486); binary cannabis use OR 0.86 (95% CI 0.54-1.35, not significant); frequent vs minimal use OR 3.44 (95% CI 1.40-8.43); frequency categories: minimal (1x/month or less), moderate (2x/month to 1 day/week), frequent (2-6x/week to daily).","methodology":"Retrospective cohort study using 2017-2018 Pregnancy Risk Assessment Monitoring System (PRAMS) data (n=10,911, weighted n=587,486). Cannabis use frequency was categorized as no use, minimal (1x/month or less), moderate (2x/month to 1 day/week), and frequent (2-6x/week to daily). Multivariable logistic regression examined dose-response.","limitations":"Self-reported cannabis use may underestimate true frequency. PRAMS data are cross-sectional and cannot establish causation. Relatively small numbers in the frequent use category. Cannot account for cannabis potency, method of consumption, or specific cannabinoid profiles. Potential for residual confounding."},{"rthcId":"RTHC-07258","title":"The appetite stimulating effect and safety of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in older patients with poor appetite: A triple-blinded, randomized, placebo-controlled, cross-over trial.","authors":"Nielsen, Rikke Lundsgaard; Bornæs, Olivia; Christensen, Louise Westberg Strejby; Juul-Larsen, Helle Gybel; Storgaard, Ida Klitzing; Kallemose, Thomas; Jørgensen, Lillian Mørch; Jawad, Baker Nawfal; Altintas, Izzet; Lund, Trine Meldgaard; Rasmussen, Henrik Højgaard; Munk, Tina; Andersen, Ove; Houlind, Morten Baltzer; Andersen, Aino Leegaard","year":2025,"journal":"Clinical nutrition (Edinburgh, Scotland), 47, 248-257","doi":"10.1016/j.clnu.2025.02.024","pmid":"40069983","tags":["appetite","seniors","medical-cannabis","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"No statistically significant difference in mean caloric intake was observed between cannabis-based medicine and placebo (10 kcal difference, CI -55 to 75 kcal, favoring CBM). Of 16 possibly-related adverse events, 5 occurred during placebo conditions. All adverse events were mild and transient with no serious related adverse events.","whyItMatters":"Anorexia of aging is a significant problem with limited effective treatments. While cannabis has long been associated with appetite stimulation (\"the munchies\"), this RCT found no meaningful effect in older adults with poor appetite at the tested dose and formulation.","specificNumbers":"n=17 patients aged 65+; 8.1 mg THC + 7.5 mg CBD per dose, two doses per trial day; mean difference of 10 kcal (CI -55 to 75); 36 unrelated adverse events; 16 possibly-related adverse events (5 during placebo); all adverse events mild and transient.","methodology":"Investigator-initiated, single-center, triple-blinded, randomized, placebo-controlled, superiority, crossover trial with 17 patients aged 65+ with poor appetite. Two doses of oromucosal spray (8.1 mg THC + 7.5 mg CBD per dose) or placebo on two separate trial days with two-week washout. Caloric intake measured via controlled feeding study with standardized meals.","limitations":"Very small sample (n=17). Single-day dosing may not capture effects of repeated use. Buccal spray delivery may not be optimal for appetite stimulation. Fixed dose may have been too low for some patients. Controlled meal setting may not reflect real-world eating behavior."},{"rthcId":"RTHC-07259","title":"Cats and cannabinoids: past, present and future.","authors":"Niño Cital, Stephen; Wakshlag, Joseph; Kennedy, Amanda; Tittle, David; Petty, Mike","year":2025,"journal":"Journal of feline medicine and surgery, 27(9), 1098612X251365392","doi":"10.1177/1098612X251365392","pmid":"40968477","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07260","title":"Evidence of altered monoamine oxidase B, an astroglia marker, in early psychosis and high-risk state.","authors":"Nisha Aji, Kankana; Lalang, Nittha; Ramos-Jiménez, Christian; Rahimian, Reza; Mechawar, Naguib; Turecki, Gustavo; Chartrand, Daniel; Boileau, Isabelle; Meyer, Jeffrey H; Rusjan, Pablo M; Mizrahi, Romina","year":2025,"journal":"Molecular psychiatry, 30(5), 2049-2058","doi":"10.1038/s41380-024-02816-x","pmid":"39511452","tags":["psychosis","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use had a significant effect on MAO-B availability (F=12.57, p=0.001, Cohen's f=0.57), with a significant group-by-cannabis interaction (p=0.03) showing lower MAO-B in cannabis-using clinical groups. Lower MAO-B was more pronounced in striatal than cortical regions. The clinical high-risk group showed significantly lower MAO-B than healthy volunteers (Cohen's d=0.99).","whyItMatters":"This is one of the first studies to show that cannabis use may specifically worsen astrocyte dysfunction in people at risk for or experiencing early psychosis. The finding connects cannabis use to a concrete brain-level change (lower MAO-B in astrocytes) that is linked to dopamine elevation in psychosis.","specificNumbers":"n=38 total (14 FEP, 7 CHR, 17 HV); cannabis effect F=12.57, p=0.001, Cohen's f=0.57; group-by-cannabis interaction F=3.82, p=0.03; CHR vs HV Cohen's d=0.99; striatal effects stronger than cortical.","methodology":"PET brain imaging study using [11C]SL25.1188 radiotracer to measure MAO-B (an astrocyte marker) in 14 antipsychotic-free first-episode psychosis patients, 7 clinical high-risk individuals, and 17 healthy volunteers, controlling for tobacco and cannabis use.","limitations":"Small sample sizes, especially the CHR group (n=7). Cross-sectional design cannot determine temporal direction. Cannabis use was not the primary exposure of interest. Cannot determine whether cannabis directly causes lower MAO-B or whether individuals with lower MAO-B are more likely to use cannabis."},{"rthcId":"RTHC-07261","title":"The Relationship of glutamate signaling to cannabis use and schizophrenia.","authors":"Niznikiewicz, Margaret; Lin, Alexander; DeLisi, Lynn E","year":2025,"journal":"Current opinion in psychiatry, 38(3), 177-181","doi":"10.1097/YCO.0000000000001003","pmid":"40071480","tags":["psychosis","neuroscience","genetics"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review synthesizes three lines of evidence: cannabis is associated with psychosis in a subset of users, glutamate dysregulation is a feature of schizophrenia, and cannabis affects the glutamate system. The authors hypothesize that cannabis perturbs glutamate neuronal connectivity in the brains of genetically high-risk individuals, potentially initiating psychosis.","whyItMatters":"Despite strong epidemiological evidence linking cannabis and psychosis, the biological mechanism remains unclear. This review proposes a specific, testable mechanism (glutamate disruption in the default mode network) that could be verified with existing brain imaging technology.","specificNumbers":"Most cannabis users are unaffected; a portion develop acute psychotic symptoms; in some, symptoms continue after cessation; review proposes combining MRS and fMRI to test the glutamate hypothesis.","methodology":"Narrative review examining the intersection of cannabis-psychosis associations, glutamate abnormalities in schizophrenia, and cannabis effects on glutamate pathways, proposing a testable hypothesis using combined MRS and fMRI.","limitations":"Narrative review with a proposed hypothesis that has not yet been tested. Selective citation of supporting evidence. The glutamate-cannabis-psychosis connection remains speculative. Does not account for all potential mechanisms of cannabis-related psychosis."},{"rthcId":"RTHC-07262","title":"Prenatal cannabis exposure is associated with alterations in offspring DNA methylation at genes involved in neurodevelopment, across the life course.","authors":"Noble, Alexandra J; Adams, Alex T; Satsangi, Jack; Boden, Joseph M; Osborne, Amy J","year":2025,"journal":"Molecular psychiatry, 30(4), 1418-1429","doi":"10.1038/s41380-024-02752-w","pmid":"39277688","tags":["pregnancy","genetics","neuroscience","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Prenatal cannabis exposure was associated with genome-wide significant DNA methylation differences at birth, 7 years, 15-17 years, and 27 years. Several genes (LZTS2, NPSR1, NT5E, CRIP2, DOCK8, COQ5, LRP5) showed shared methylation changes across multiple time points. Functional pathway analysis consistently showed enrichment for neurodevelopment, neurotransmission, and neuronal structure pathways across all timepoints in both cohorts.","whyItMatters":"This is among the most comprehensive evidence that prenatal cannabis exposure creates lasting epigenetic changes in offspring. The persistence of changes from birth through age 27, replicated across two cohorts and two countries, strengthens the case that prenatal cannabis exposure has long-term biological consequences.","specificNumbers":"Two cohorts (ALSPAC UK, CHDS New Zealand); DNA methylation assessed at 0, 7, 15-17, and 27 years; 7 genes showed shared changes across multiple timepoints; neurodevelopment pathways enriched across all timepoints.","methodology":"Epigenome-wide association study using two longitudinal cohorts: ALSPAC (UK, examined at 0, 7, and 15-17 years) and CHDS (New Zealand, examined at ~27 years). Examined DNA methylation differences associated with prenatal cannabis exposure alone and co-exposure with tobacco.","limitations":"Cannot prove that methylation changes cause functional problems. Prenatal exposure is based on maternal self-report. Cannot fully separate cannabis effects from tobacco co-exposure or other confounders. Different cohorts and timepoints used different methylation platforms."},{"rthcId":"RTHC-07263","title":"Bigger is better: modern Cannabis trichomes are larger and more productive than their landrace ancestors.","authors":"Nolan, Matthew; Guo, Qi; Garcia-de Heer, Lennard; Liu, Lei; Dimopoulos, Nicolas; Barkla, Bronwyn J; Kretzschmar, Tobias","year":2025,"journal":"Plant & cell physiology, 66(10), 1477-1492","doi":"10.1093/pcp/pcaf105","pmid":"40891499","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07264","title":"Cannabis use in adolescence and young adulthood and its effects on brain structure and function: a scoping review.","authors":"Nosko, Lilith; Crocker, Candice E; Tibbo, Phil G","year":2025,"journal":"Frontiers in psychiatry, 16, 1644105","doi":"10.3389/fpsyt.2025.1644105","pmid":"40969702","tags":["youth","cognition","neuroscience","mental-health"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Of 99 studies meeting inclusion criteria (from 3,901 initially screened), 84 (85%) found differences in brain structure, function, and/or metabolite concentrations in cannabis users aged 14-25 compared to non-using controls. Only 5 studies explicitly assessed sex/gender differences, with all 5 finding that sex influenced the effect of cannabis on the brain.","whyItMatters":"The sheer volume of studies finding brain differences (85%) makes a strong case that cannabis use during adolescence and young adulthood is associated with detectable brain changes. However, the review also highlights that the existing research is of generally low quality and lacks long-term follow-up.","specificNumbers":"3,901 sources screened; 99 included; 84/99 (85%) found brain differences; 5 studies examined sex differences, all 5 found effects; ages 14-25.","methodology":"Scoping review following standard methodology, searching databases for neuroimaging studies assessing effects of cannabis use between ages 14-25 on brain structure, function, and metabolite concentrations. Yielded 3,901 sources, of which 99 met inclusion criteria.","limitations":"Scoping review does not assess study quality or synthesize effect sizes. The 85% figure includes studies of varying quality and rigor. Publication bias may inflate the proportion of positive findings. Most studies are cross-sectional, limiting causal inference. Heterogeneous methodology makes direct comparisons difficult."},{"rthcId":"RTHC-07265","title":"Exploring Cannabis sativa L for Anti-Alzheimer Potential: An Extensive Computational Study including Molecular Docking, Molecular Dynamics, and ADMET Assessments.","authors":"Nour, Hassan; Yamari, Imane; Abchir, Oussama; Mounadi, Nouh; Samadi, Abdelouahid; Belaidi, Salah; Chtita, Samir","year":2025,"journal":"Medicinal chemistry (Shariqah (United Arab Emirates)), 21(5), 367-384","doi":"10.2174/0115734064318657240822064240","pmid":"40525419","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07266","title":"Assessing the Market Readiness for Medical Cannabis in Greece: A Qualitative Study of Patient Perspectives.","authors":"Ntais, Christos; Melanthiou, Yioula","year":2025,"journal":"Medicines (Basel, Switzerland), 12(2)","doi":"10.3390/medicines12020012","pmid":"40407604","tags":["medical-cannabis","cbd","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"CBD-experienced patients (n=12) generally perceived cannabis-based treatments as beneficial for musculoskeletal pain, migraines, anxiety, stress, and sleep, despite concerns about product quality, cost, and limited medical guidance. Cannabis-naive participants (n=12) expressed skepticism due to stigma and perceived insufficient evidence but acknowledged potential therapeutic value within a regulated framework.","whyItMatters":"As Greece introduces medical cannabis, understanding patient attitudes and barriers is essential for effective implementation. The gap between experienced and naive patients highlights the role of direct experience in shaping opinions and the need for education to bridge information gaps.","specificNumbers":"24 participants (12 CBD-experienced, 12 cannabis-naive); conditions managed: musculoskeletal pain, migraines, anxiety, stress, sleep disturbances.","methodology":"Qualitative study using semi-structured interviews with 24 participants in Greece: 12 users of CBD-based formulations and 12 medical cannabis-naive individuals, examining market readiness for medical cannabis.","limitations":"Small qualitative sample (n=24) from a single country. Self-selected participants may not represent broader patient populations. CBD-experienced group was using over-the-counter CBD formulations, not prescription medical cannabis. Cannot quantify the extent of reported benefits or concerns."},{"rthcId":"RTHC-07267","title":"Exploring cannabinoid modulation on autophagy mechanisms in Alzheimer's disease: a review.","authors":"Ntsapi, C; Weyers, M; Chinheya, R; Jim, T; Matsabisa, M","year":2025,"journal":"Frontiers in pharmacology, 16, 1748368","doi":"10.3389/fphar.2025.1748368","pmid":"41601969","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07268","title":"Chronic Disease Symptoms Self-Managed by Cannabis During the COVID-19 Pandemic: Results from the COVID-19 Cannabis Health Study.","authors":"O'Dell, Nicole; Baral, Amrit; Reid, Marvin; Diggs, Bria-Necole A; Islam, Jessica Y; Camacho-Rivera, Marlene; Ortega, Johis; Vidot, Denise C","year":2025,"journal":"Cannabis and cannabinoid research, 10(4), 558-568","doi":"10.1089/can.2023.0234","pmid":"40008990","tags":["medical-cannabis","pain","sleep","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Of 1,466 cannabis users with chronic conditions, 90.9% reported using cannabis medicinally. Only 46.1% had a medical card. The most common self-managed symptoms were sleep (69.2%), chronic noncancer pain (49.7%), acute pain (46.5%), headaches/migraines (39.0%), muscle spasms (33.6%), nausea/vomiting (30.6%), and appetite stimulation (29.9%). The most common comorbidities were mental health-related (66.1%) and pain (58.5%).","whyItMatters":"This study reveals the scale of unsupervised self-medication with cannabis for chronic conditions. That over 90% of cannabis users with chronic illness use it medicinally, mostly without medical guidance, highlights a major gap between patient behavior and healthcare oversight.","specificNumbers":"n=1,466; mean age 47.1 years; 90.9% used cannabis medicinally; 46.1% had medical card; 4.6% received professional recommendation for COVID-19; sleep 69.2%, chronic pain 49.7%, acute pain 46.5%, headaches 39.0%, muscle spasms 33.6%, nausea 30.6%, appetite 29.9%.","methodology":"Cross-sectional analysis of the COVID-19 Cannabis Health Study, an ongoing survey of adults who self-report cannabis use. Data from 1,466 responses collected March 2020 to March 2022 from participants reporting both cannabis use and a chronic health condition.","limitations":"Self-selected sample of cannabis users limits generalizability. No control group to compare outcomes with non-cannabis users. Self-reported benefits are subjective and not verified. Data collected during the pandemic may reflect atypical patterns. Cannot determine whether cannabis actually helped manage reported symptoms."},{"rthcId":"RTHC-07269","title":"Chemical Composition and Antioxidant Activity of the Stembark Essential Oils of Two Cannabis sativa L. Cultivars from Komga, South Africa.","authors":"Odieka, Anwuli E; Oriola, Ayodeji O; Miya, Gugulethu M; Kar, Pallab; Oyedeji, Opeoluwa O; Gondwe, Mavuto; Hosu, Yiseyon S; Madliwa, Thami; Oyedeji, Adebola O","year":2025,"journal":"International journal of molecular sciences, 26(17)","doi":"10.3390/ijms26178552","pmid":"40943472","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07270","title":"Associations Between Violence and Unsafe Living Situations With Cannabis Use During Early Pregnancy.","authors":"Ogden, Shannon N; Watson, Carey R; Adams, Sara R; Ansley, Deborah; Castellanos, Carley; Young-Wolff, Kelly C","year":2025,"journal":"Substance use & addiction journal, 29767342251371802","doi":"10.1177/29767342251371802","pmid":"41006966","tags":["pregnancy","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Past-year violence and unsafe/unstable living situations were associated with higher prenatal cannabis use in adjusted analyses. Current IPV, past-year violence, and unstable housing were all associated in unadjusted analyses. Over two-thirds (69.1%) of pregnancies with current IPV also reported past-year physical violence or unsafe living situations. Cannabis was used during 7.2% of pregnancies.","whyItMatters":"Understanding why pregnant women use cannabis requires looking beyond individual choice to social determinants. This large-scale study shows that violence and housing instability are associated with prenatal cannabis use, suggesting that addressing these root causes could be more effective than simply telling women to stop using cannabis.","specificNumbers":"n=303,178 pregnancies in California (2014-2023); 7.2% (n=21,868) used cannabis during pregnancy; <1% reported current IPV (n=324) or past-year violence (n=979); ~2% (n=6,284) reported unsafe/unstable living; 69.1% of IPV-exposed pregnancies also had violence or unstable housing.","methodology":"Retrospective cohort study using data from 303,178 California pregnancies (2014-2023). Chi-square tests and modified Poisson regression estimated associations between experiences of current IPV, past-year violence, and unsafe/unstable living situations with cannabis use during early pregnancy.","limitations":"Self-reported violence and cannabis use likely underestimate true prevalence. Cannot establish causation. California-specific sample may not generalize to other states. Very low reported IPV rates (<1%) suggest significant underreporting. Cannot determine whether cannabis is used as a coping mechanism or whether the association is driven by other factors."},{"rthcId":"RTHC-07271","title":"Patterns of substance use and associations with mental health and interpersonal violence among adolescents.","authors":"Ogden, Shannon N; Cortez, Catherine; Sterling, Stacy A; Alexeeff, Stacey E; Slama, Natalie E; Campbell, Cynthia I; Satre, Derek D; Asyyed, Asma H; Does, Monique B; Altschuler, Andrea; Lu, Yun; Young-Wolff, Kelly C","year":2025,"journal":"Addictive behaviors reports, 21, 100597","doi":"10.1016/j.abrep.2025.100597","pmid":"40212037","tags":["youth","addiction","mental-health","depression"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Five latent classes of substance use were identified: friends' use only (37%), alcohol use (21%), polysubstance use (20%), cannabis use/some polysubstance use (18%), and other substance use (5%). All classes had higher prevalence of mental health problems and interpersonal violence compared to non-users, with the polysubstance use class showing the greatest differences.","whyItMatters":"The finding that even adolescents who only report friends' substance use (without personal use) show elevated mental health and violence risks suggests that substance-related screening should capture social context, not just individual behavior. The 17% prevalence of any substance use characteristic is also noteworthy.","specificNumbers":"n=167,504 adolescents; 29,288 (17%) reported at least one substance use characteristic; 5 latent classes identified; cannabis/polysubstance class: 18%; outcomes: depressive symptoms, suicidal ideation, bullying, physical abuse, sexual violence, IPV.","methodology":"Cross-sectional latent class analysis of 167,504 adolescents aged 13-17 screened during well-check visits in a large California healthcare system (2021-2022), examining four substance use behaviors (past-year alcohol, cannabis, other substances, friends' use) and associations with mental health and violence outcomes.","limitations":"Cross-sectional design cannot determine temporal direction. Screening during well-check visits may miss adolescents who do not attend regular healthcare. Self-reported substance use may underestimate actual use. California-specific healthcare system may not represent other regions. Latent class analysis identifies patterns but does not explain causation."},{"rthcId":"RTHC-07272","title":"Substance Use Right Before or During Work Among the Young US Workers: Evidence From the National Longitudinal Survey of Youth 1997 Cohort.","authors":"Oh, Sehun; Park, Daejun; Al-Hashemi, Sarah","year":2025,"journal":"American journal of industrial medicine, 68(8), 679-687","doi":"10.1002/ajim.23737","pmid":"40372126","tags":["workplace","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"8.9% of workers reported past-month substance use at work: 5.9% alcohol, 3.1% marijuana, 0.8% cocaine/hard drugs. Food preparation/serving occupations had the highest prevalence, followed by safety-sensitive occupations. Food service workers had higher risks for all substance types; white-collar workers had elevated alcohol use; safety-sensitive workers had elevated alcohol and marijuana use.","whyItMatters":"Workplace substance use poses risks to users, coworkers, and the public, especially in safety-sensitive jobs. The 3.1% marijuana prevalence at work is notable as cannabis legalization expands and workplace drug policies evolve.","specificNumbers":"n=6,155; 8.9% any substance at work; 5.9% alcohol; 3.1% marijuana; 0.8% cocaine/hard drugs; food preparation/serving occupations had highest prevalence.","methodology":"Analysis of National Longitudinal Survey of Youth 1997 (NLSY97) data from 6,155 respondents in their early 30s. Past-month workplace substance use prevalence assessed by occupation. Multivariable Poisson regression adjusted for sociodemographic and health characteristics.","limitations":"Self-reported data likely underestimates true workplace substance use. Focused on workers in their early 30s, which may not represent all age groups. Cannot determine whether substance use caused workplace problems. Cross-sectional design."},{"rthcId":"RTHC-07273","title":"What Influences Cannabis Purchasing Decisions? Perspectives from Cannabis Retail Employees and Customers in Washington State.","authors":"Okey, Sarah A; Arias, Jordan M; Watson, Tyler D; Riggs, Sally L; McQuay, Brian D; Glodosky, Nicholas C; Haley, Kristen N; Meline, Nikki B; Segawa, Mary B","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251361926","pmid":"40712653","tags":["legalization","potency"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis retail employees rated THC concentration as less important and terpene profiles, production methods, and product appearance as more important compared to non-employee customers. More frequent cannabis users placed greater importance on strain name, production method, perceived positive effects, and product appearance.","whyItMatters":"If retail employees could redirect customer attention from THC concentration toward other product attributes like terpene profiles, this could help reduce demand for high-THC products, which have been linked to greater health risks.","specificNumbers":"437 respondents; 137 retail employees; 10 purchasing attributes assessed; employees rated THC less important (beta=-1.67, p significant) and terpene profile more important (beta=1.30, p significant).","methodology":"Online survey of 437 cannabis consumers in Washington State, including 137 cannabis retail employees. Linear regressions predicted the importance of 10 purchasing attributes by gender, age, cannabis use patterns, and employee status.","limitations":"Small convenience sample recruited through in-store flyers. Washington State only. Cannot determine whether employee recommendations actually change customer behavior. Cross-sectional design."},{"rthcId":"RTHC-07274","title":"The association between cannabis use and suicidal intensity in psychiatric inpatients.","authors":"Oladunjoye, Adeolu Funso; Swann, Alan; Kosten, Thomas R; Patriquin, Michelle; Bigdeli, Tim; Barr, Peter; Wilkinson, Anna V; Harding, Mark J; Nielsen, David A; Graham, David P","year":2025,"journal":"The American journal on addictions, 34(5), 506-516","doi":"10.1111/ajad.70047","pmid":"40349103","tags":["mental-health","addiction","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was associated with lower suicidal ideation intensity for females (p=.026) but not males (p=.525). In males, increased cannabis use combined with lower psychological flexibility was associated with greater suicidal intensity (p=.049). 49.6% of the sample had attempted suicide, 34.3% had suicidal ideation, and 16% had no suicidality.","whyItMatters":"The sex-specific findings challenge one-size-fits-all assumptions about cannabis and suicide risk. The role of psychological flexibility as a mediator suggests that the mental health context in which cannabis is used may matter more than use itself.","specificNumbers":"n=530; 49.6% prior suicide attempt; 34.3% suicidal ideation; 16% no suicidality; female cannabis-SII association p=.026; male cannabis x low flexibility p=.049.","methodology":"Path analysis of 530 psychiatric inpatients aged 18+, using the Columbia-Suicide Severity Rating Scale and ASSIST for cannabis use. Model included moderating and mediating factors: psychiatric comorbidity, emotional regulation, psychological flexibility, and polygenic risk scores.","limitations":"Cross-sectional design in a psychiatric inpatient sample, which may not generalize. Cannot determine causation. Path analysis results should be considered exploratory. Self-reported cannabis use."},{"rthcId":"RTHC-07275","title":"Inhibition of CYP2A6-mediated nicotine metabolism: A potential strategy for smoking cessation therapy.","authors":"Olawale, Margaret E; Lazarus, Philip","year":2025,"journal":"The Journal of pharmacology and experimental therapeutics, 393(2), 103792","doi":"10.1016/j.jpet.2025.103792","pmid":"41529330","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07276","title":"Psychoactive Substance Use in Germany: Findings From the Epidemiological Survey of Substance Abuse (ESA) in 2024.","authors":"Olderbak, Sally; Hollweck, Regina; Krowartz, Eva-Maria; Möckl, Justin; Hoch, Eva","year":2025,"journal":"Deutsches Arzteblatt international, 122(23), 625-631","doi":"10.3238/arztebl.m2025.0157","pmid":"40956679","tags":["legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"12-month cannabis use prevalence was 9.8% (5.1 million Germans). Cannabis dependence was 1.0% and abuse was 0.5%. For comparison, alcohol had 30-day prevalence of 68.6% with 4.2% dependence; tobacco had 21.8% use with 8.3% dependence.","whyItMatters":"Germany partially legalized cannabis in 2024, making these baseline data crucial for monitoring trends. The relatively low dependence rate (1%) compared to tobacco (8.3%) and alcohol (4.2%) provides important context for policy discussions.","specificNumbers":"n=7,534; 12-month cannabis prevalence 9.8% (5.1 million); cannabis dependence 1.0%; cannabis abuse 0.5%; alcohol 30-day prevalence 68.6%, dependence 4.2%; tobacco use 21.8%, dependence 8.3%.","methodology":"Epidemiological Survey of Substance Abuse (ESA) 2024, a nationally representative survey of 7,534 German adults aged 18-64. Prevalence rates calculated for use, DSM-IV dependence, and abuse, extrapolated to the German population of 51.5 million.","limitations":"Self-reported survey data may underestimate actual use. DSM-IV criteria (rather than DSM-5) were used for dependence. Cross-sectional design captures one timepoint. Response rates may introduce selection bias."},{"rthcId":"RTHC-07277","title":"The Effects of THC and Nicotine on Attention: A Narrative Review.","authors":"Oleszak, Kennedy; Striegel, Lily Freeman; Roeder, Nicole; Mohr, Patrick; Penman, Samantha; Collins, Lorraine; Smith, Danielle M; Thanos, Panayotis K","year":2025,"journal":"Current topics in behavioral neurosciences, 75, 183-238","doi":"10.1007/7854_2024_568","pmid":"40050542","tags":["cognition","neuroscience","pregnancy","youth"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Cannabis impairs selective attention and creates attentional bias toward cannabis cues. Reaction time effects depend on timing of last exposure. Preclinical studies show cannabis-induced attention deficits persist after abstinence. Nicotine has dose-dependent effects on attention. Prenatal exposure to either substance increases risk for ADHD, attention deficits, and impulsivity in offspring.","whyItMatters":"Cannabis and nicotine are among the most commonly used substances and are often co-used. Understanding their opposing effects on attention in adults and shared harmful effects on prenatal development is important for clinical guidance and public health messaging.","specificNumbers":"Review covers preclinical and clinical studies across all developmental periods; prenatal cannabis exposure linked to increased ADHD, schizophrenia, and drug-seeking risk in offspring; prenatal nicotine exposure shows sex differences with males more affected.","methodology":"Narrative review synthesizing preclinical and clinical findings on THC and nicotine effects on selective attention, sustained attention, visuospatial attention, attentional bias, and attentional disorders across all developmental stages.","limitations":"Narrative review methodology. Preclinical and clinical results may not be directly comparable. Dose and timing of exposure vary widely across studies. Co-use effects are understudied."},{"rthcId":"RTHC-07278","title":"Cannabis and tobacco use in bipolar disorder: Associations with early onset, psychotic symptoms, and relapse risk (2015-2019).","authors":"Olivier, Luis; Andreu, Helena; de Juan, Oscar; Ochandiano, Iñaki; Salmerón, Sergi; Fernández-Plaza, Tábatha; Colomer, Lluc; Vieta, Eduard; Giménez-Palomo, Anna; Pacchiarotti, Isabella","year":2025,"journal":"Journal of affective disorders, 382, 30-38","doi":"10.1016/j.jad.2025.04.026","pmid":"40221053","tags":["mental-health","psychosis","addiction","quitting"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis was associated with earlier onset of bipolar disorder, current manic polarity, presence of psychotic symptoms, and higher likelihood of discontinuing treatment. However, cannabis was NOT associated with higher rates of ER visits or hospital readmissions. Interestingly, tobacco use showed significantly higher readmission rates. Alcohol, cocaine, and stimulants showed no association with studied variables.","whyItMatters":"The distinction between cannabis affecting illness severity (earlier onset, more psychosis) but not relapse rate (readmissions) is clinically important. It suggests cannabis may influence the type and quality of bipolar episodes more than their frequency.","specificNumbers":"n=279 patients; 3-year follow-up; cannabis associated with earlier onset, manic polarity, psychotic symptoms, and treatment discontinuation; tobacco associated with higher ER and readmission rates; no significant associations for alcohol, cocaine, or stimulants.","methodology":"Prospective cohort study of 279 patients admitted to Hospital Clinic of Barcelona for manic or mixed episodes (2015-2019), with 3-year follow-up examining hospital readmissions, ER visits, and clinical characteristics.","limitations":"Single-center study in Barcelona. Lacks detailed information on cannabis use patterns, history, and consumption amounts. Loss to follow-up from patients leaving the region or switching to private care. Cannot establish causation."},{"rthcId":"RTHC-07279","title":"Portrayal of Delta-8 Tetrahydrocannabinol (THC) on YouTube.","authors":"Olsson, Sofia E; Sekhon, Vishaldeep K; LoParco, Cassidy R; Yockey, R Andrew; Greene, Kaylin M; Henry, Doug; Rossheim, Matthew E","year":2025,"journal":"Substance use & misuse, 60(6), 811-817","doi":"10.1080/10826084.2025.2454651","pmid":"39901444","tags":["legalization","youth","harm-reduction"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Four themes emerged: reasons to use (legal status, accessibility, psychoactive effects described as milder and more euphoric), how to use, effects of using, and safety/harm reduction. Creators noted product quality varies by purchase location, with online favored over gas stations. Few videos were age-restricted despite discussing psychoactive substance use.","whyItMatters":"YouTube is the world's second-most visited website, and Delta-8 THC content reaches audiences including minors without age restrictions. The portrayal of Delta-8 as a legal cannabis loophole raises public health concerns about unregulated intoxicating products.","specificNumbers":"47 videos analyzed; 4 overarching themes; few videos were age-restricted; Delta-8 described as legal, milder, euphoric; online purchases favored over gas station purchases.","methodology":"Qualitative study analyzing 47 unique YouTube videos identified by searching \"Delta 8\" and \"Delta-8\" in 2022, using combined inductive and deductive coding with team consensus.","limitations":"Small sample of 47 videos from a single search in 2022. YouTube content changes rapidly and may not reflect current landscape. Cannot measure actual viewer impact on behavior. Qualitative analysis subject to researcher interpretation."},{"rthcId":"RTHC-07280","title":"Cannabis Vaping Among US Adults With Disabilities: Findings From the 2022 Behavioral Risk Factor Surveillance System.","authors":"Olufemi, Erinoso; Olatokunbo, Osibogun; Wei, Li; Ben Taleb, Ziyad; Kalan, Mohammad Ebrahimi","year":2025,"journal":"Public health reports (Washington, D.C. : 1974), 140(2-3), 230-240","doi":"10.1177/00333549241292447","pmid":"39513335","tags":["addiction","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis vaping prevalence was higher among adults with any disability (4.6%) than without (2.8%). Adults with cognitive disabilities had the highest rate at 8.2%. Daily nicotine vaping (AOR=6.04), former smoking (AOR=1.67), and young age 18-24 vs 65+ (AOR=11.07) were the strongest correlates of cannabis vaping among adults with disabilities.","whyItMatters":"People with disabilities are already known to use cannabis at higher rates, but this study reveals that novel delivery methods (vaping) follow the same pattern, with particularly high rates among those with cognitive disabilities who may be most vulnerable to substance-related harms.","specificNumbers":"Cannabis vaping: 4.6% with disability vs 2.8% without; 8.2% cognitive disability; daily nicotine vaping AOR=6.04; former smoking AOR=1.67; age 18-24 AOR=11.07; cannabis vapers had 1.28x more cannabis-use days.","methodology":"Analysis of 2022 Behavioral Risk Factor Surveillance System data examining associations between disability types and past-month cannabis vaping among US adults, using weighted multivariable logistic and modified Poisson regression models.","limitations":"BRFSS data is self-reported and telephone-based, potentially missing vulnerable populations. Cross-sectional design. Cannot determine why people with disabilities vape cannabis (recreational vs. medical). Disability categories may overlap."},{"rthcId":"RTHC-07281","title":"Concurrent maternal stress and THC exposure during pregnancy alters adolescent behavioral outcomes and corticolimbic molecular programs.","authors":"Olusakin, Jimmy; Dewan, Mahima; Kashyap, Atul; Franco, Daniela; Kumar, Gautam; Lujan, Miguel A; Mark, Katrina S; Cheer, Joseph; Lobo, Mary Kay","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.06.26.661775","pmid":"40667373","tags":["pregnancy","youth","neuroscience","mental-health","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"All exposure groups (THC alone, stress alone, combined) showed impaired maternal behavior, with additive effects in the combined group. Adolescent offspring showed sex-specific behavioral changes: stress and combined exposures increased anxiety and reduced motivation in both sexes; THC alone primarily affected female self-care and social behavior. Brain transcriptomics revealed sex- and region-specific gene expression changes affecting mitochondrial function, synaptic organization, and glial signaling.","whyItMatters":"Many pregnant women use cannabis specifically to manage stress and anxiety, making the combined exposure scenario highly relevant. The finding that THC plus stress produces additive harm to both maternal behavior and offspring brain development challenges the assumption that cannabis alleviates prenatal stress.","specificNumbers":"THC 2 mg/kg daily; stress GD3-12; combined group showed additive maternal impairment; sex-specific offspring behavioral changes; PFC and NAc transcriptomics showed distinct molecular pathway alterations for each exposure.","methodology":"Translational mouse model combining prenatal THC (2 mg/kg daily) from GD3 to birth with maternal witness defeat stress from GD3-12. Assessed maternal behavior, adolescent offspring behavior, and transcriptomic profiling of prefrontal cortex and nucleus accumbens.","limitations":"Mouse model may not fully translate to humans. Single THC dose and stress paradigm tested. Transcriptomic changes do not necessarily predict functional outcomes. Cannot separate direct THC effects from indirect effects through altered maternal behavior."},{"rthcId":"RTHC-07282","title":"Cytotoxicity of Cannabinoids in Combination with Traditional Lymphoma Chemotherapeutic Drugs Against Non-Hodgkin's Lymphoma.","authors":"Omer, Saba; Mansour, Mahmoud; Pondugula, Satyanarayana R; Dhanasekaran, Muralikrishnan; Matz, Brad; Khan, Omer; Boothe, Dawn","year":2025,"journal":"Biomedicines, 14(1)","doi":"10.3390/biomedicines14010003","pmid":"41595541","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07283","title":"Cannabidiol mechanism of action on modulating extinction and reinstatement of methamphetamine-seeking behavior: Targeting D2-like dopamine receptors in the hippocampus.","authors":"Omidiani, Seyed Erfan; Mohammadi, Mahsa; Seddighfar, Masoud; Azizbeigi, Ronak; Haghparast, Abbas","year":2025,"journal":"Journal of psychiatric research, 189, 200-210","doi":"10.1016/j.jpsychires.2025.06.011","pmid":"40517676","tags":["cbd","addiction","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"A D2-like receptor antagonist (Sulpiride) at 1 and 4 micrograms significantly attenuated CBD's acceleration of methamphetamine conditioned place preference extinction (p<0.01, p<0.05). During reinstatement, the same doses reversed CBD's prevention of reward-seeking behavior (p<0.05, p<0.001), indicating CBD's anti-addiction effects are partially mediated through hippocampal D2 receptors.","whyItMatters":"Methamphetamine use disorder has no approved pharmacological treatments. This study identifies a specific brain mechanism (hippocampal D2 receptors) through which CBD exerts its anti-addiction effects, potentially informing more targeted therapeutic development.","specificNumbers":"Sulpiride 1 and 4 micrograms attenuated CBD extinction effects (p<0.01, p<0.05); Sulpiride reversed CBD reinstatement prevention (p<0.05, p<0.001); CBD 10 micrograms for extinction, 50 micrograms for reinstatement; 10-day extinction period.","methodology":"Rats received Sulpiride (D2 antagonist, 0.25-4 micrograms) into the hippocampal CA1 region before CBD (ICV) during a 10-day methamphetamine CPP extinction period or on reinstatement day. CBD doses were 10 micrograms (extinction) and 50 micrograms (reinstatement).","limitations":"Animal model with direct brain injection of CBD, which differs from how humans consume CBD. CPP is a model of drug reward but does not capture all aspects of human addiction. Results from one brain region may not explain CBD's full anti-addiction profile."},{"rthcId":"RTHC-07284","title":"Like birds of a feather? A multi-case study on the connections between cannabis, tobacco, alcohol and pharmaceutical companies in legalized cannabis markets.","authors":"Ongenaert, Marthe; Decorte, Tom","year":2025,"journal":"The International journal on drug policy, 143, 104863","doi":"10.1016/j.drugpo.2025.104863","pmid":"40479916","tags":["legalization","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"All five cannabis companies (Canopy Growth, Aurora, Tilray, Cronos Group, Organigram) had investment relationships with alcohol, tobacco, or pharmaceutical companies. Some received substantial investments that came with industry influence. Employee flows showed cross-industry expertise transfer, particularly in management, finance, and strategy, suggesting established industries are strategically positioning themselves in the cannabis sector.","whyItMatters":"The alcohol and tobacco industries have well-documented histories of marketing to vulnerable populations, lobbying against regulations, and prioritizing profits over public health. Their entry into cannabis markets raises concerns about importing these practices.","specificNumbers":"Five cannabis companies analyzed; data from corporate reports, press releases, and LinkedIn; investment relationships documented with alcohol, tobacco, and pharmaceutical sectors; employee flow patterns identified in management, finance, and strategy.","methodology":"Exploratory multi-case study analyzing business investments and employee movement between five cannabis companies and alcohol, tobacco, and pharmaceutical companies. Data from Nexis Uni, corporate reports, press releases, and LinkedIn.","limitations":"Exploratory study focused on only five companies. Publicly available data may not capture all relationships. Cannot prove that cross-industry connections have actually harmed public health. Canadian/North American focus may not apply to other markets."},{"rthcId":"RTHC-07285","title":"Psychosis Spectrum Symptoms Before and After Adolescent Cannabis Use Initiation.","authors":"Osborne, K Juston; Barch, Deanna M; Jackson, Joshua J; Karcher, Nicole R","year":2025,"journal":"JAMA psychiatry, 82(2), 181-190","doi":"10.1001/jamapsychiatry.2024.3525","pmid":"39504015","tags":["psychosis","youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Adolescents who used cannabis at any point had more psychosis symptoms (B=0.86) and distress from symptoms (B=1.17) than never-users, consistent with shared vulnerability. Symptoms increased in the time leading up to cannabis initiation (B=0.16 for symptoms, B=0.23 for distress), consistent with self-medication. Evidence for post-initiation increases (contributing risk) was mixed.","whyItMatters":"This is one of the most rigorous tests of the cannabis-psychosis causal question. By modeling symptom trajectories before and after cannabis initiation, it provides evidence that the relationship is more complex than \"cannabis causes psychosis,\" with shared vulnerability and self-medication playing important roles.","specificNumbers":"n=11,858; mean age 9.5 at wave 1; 52% male; 4-year follow-up; shared vulnerability: B=0.86 (symptoms), B=1.17 (distress); pre-initiation increase: B=0.16 (symptoms), B=0.23 (distress); mixed evidence for post-initiation contributing risk.","methodology":"Cohort study using 5 waves across 4 years from the ABCD Study (n=11,858 adolescents aged 9-10 at baseline). Discontinuous growth curve modeling assessed psychosis symptom trajectories before and after cannabis initiation, adjusting for age, sex, other substance use, SES, and parental mental health.","limitations":"ABCD Study follow-up is still relatively short (4 years, ages ~10-15). Cannabis use in this young sample may not represent adult patterns. Self-reported psychosis symptoms are not the same as clinical psychotic disorders. Cannot fully rule out unmeasured confounders."},{"rthcId":"RTHC-07286","title":"Intergenerational Transmission of Cannabis Use: Testing Genetic Risk and the Mitigating Influences of Parent Positive Behavior Support in Early Childhood.","authors":"Ostner, Savannah G; Clifford, Sierra; Cruz, Rick A; Tein, Jenn-Yun; Westling, Erika; Shaw, Daniel S; Brown-Iannuzzi, Jazmin L; Wilson, Melvin N; Lemery-Chalfant, Kathryn","year":2025,"journal":"Research on child and adolescent psychopathology, 53(10), 1581-1593","doi":"10.1007/s10802-025-01354-6","pmid":"40824359","tags":["genetics","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Parent cannabis use significantly predicted offspring cannabis use at age 18, while polygenic risk scores for CUD did not. Parental positive behavior support (observed at ages 2-5) significantly buffered the effect of parent cannabis use on the number of offspring CUD symptoms, suggesting that positive parenting can provide resilience against intergenerational transmission.","whyItMatters":"This is one of the first studies to show that a modifiable factor (positive parenting) can buffer the well-documented intergenerational transmission of cannabis use. The fact that genetics (polygenic risk) did not predict use while parenting did suggests that environmental factors may be more targetable for prevention.","specificNumbers":"n=731; age 18; 50.2% female; 50% White, 28% Black, 13% Hispanic, 9% other; parent cannabis use measured 7 times; positive behavior support measured 4 times; CUD PRS formed using PRS-CSx; negative binomial logistic regression.","methodology":"Longitudinal analysis of 731 18-year-olds from the Early Steps Multisite Study (50.2% female, racially diverse). Parent cannabis use measured at offspring ages 2-9.5, observational positive behavior support at ages 2-5. CUD symptoms assessed with SCID-IV interview. Polygenic risk scores calculated using PRS-CSx for genetically diverse samples.","limitations":"Observational study cannot prove positive parenting caused the buffering effect. Parent cannabis use was self-reported. CUD polygenic risk scores may have limited predictive power in diverse populations. Single assessment of CUD at age 18 does not capture trajectory."},{"rthcId":"RTHC-07287","title":"Chronic exposure to a synthetic cannabinoid improves cognition and increases locomotor activity in Tg4-42 Alzheimer's disease mice.","authors":"Ott, Frederik W; Sichler, Marius E; Bouter, Caroline; Enayati, Marzieh; Wiltfang, Jens; Bayer, Thomas A; Beindorff, Nicola; Löw, Maximilian J; Bouter, Yvonne","year":2025,"journal":"Journal of Alzheimer's disease reports, 9, 25424823241306770","doi":"10.1177/25424823241306770","pmid":"40034517","tags":["cognition","seniors","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Therapeutic WIN 55,212-2 treatment rescued recognition memory and spatial reference deficits. Preventative treatment rescued spatial learning and reference memory. The treatment did not affect anxiety-like behavior. WIN treatment reduced hippocampal microgliosis in preventatively treated mice and restored brain glucose metabolism in therapeutically treated mice. Both regimens increased locomotor activity.","whyItMatters":"Despite recent anti-amyloid antibody approvals for Alzheimer's, there remains a critical need for accessible disease-modifying therapies. This study shows a synthetic cannabinoid can rescue memory and reduce inflammation in a mouse model without the anxiety side effects sometimes associated with cannabinoids.","specificNumbers":"Therapeutic treatment rescued recognition and spatial memory; preventative treatment rescued spatial learning; reduced hippocampal microgliosis; restored brain glucose metabolism; no anxiety increase; increased locomotor activity in both regimens.","methodology":"Tg4-42 transgenic Alzheimer's mice received WIN 55,212-2 in two protocols: preventative (before symptoms) with prolonged washout, and therapeutic (during symptoms). Behavioral tests assessed memory, anxiety, and locomotion. Brain pathology assessed inflammation, amyloid-beta, neurogenesis, and glucose metabolism.","limitations":"Tg4-42 model does not replicate all aspects of human Alzheimer's. Synthetic cannabinoid WIN 55,212-2 has different properties than plant-derived cannabinoids. Increased locomotor activity needs to be better understood. Animal memory tests have limited correspondence to human cognitive decline."},{"rthcId":"RTHC-07288","title":"Cannabidiol Encapsulation in Polymeric Hydrogels and Its Controlled Release: A Review.","authors":"Ovando-Medina, Víctor M; García-Martínez, Carlos A; Farias-Cepeda, Lorena; Antonio-Carmona, Iveth D; Dector, Andrés; Olivares-Ramírez, Juan M; Ortiz-Verdin, Alondra Anahí; Martínez-Gutiérrez, Hugo; Rivas Martínez, Erika Nohemi","year":2025,"journal":"Gels (Basel, Switzerland), 11(10)","doi":"10.3390/gels11100815","pmid":"41149420","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07289","title":"Metabolic Profile of Male Cannabis Users and Estimation of Candidate Biomarkers.","authors":"Oz, Esin; Kasikci, Merve; Celik, İbrahim; Gurler, Mukaddes","year":2025,"journal":"Chemical research in toxicology, 38(10), 1762-1770","doi":"10.1021/acs.chemrestox.5c00274","pmid":"41070685","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07290","title":"Acute and subacute cardiovascular effects of synthetic cannabinoid JWH-018 in rat.","authors":"Ozhan, Onural; Ermis, Necip; Celbis, Osman; Samdanci, Emine; Petekkaya, Semih; Oruc, Mucahit; Soylu, Ozcan; Koparir, Pelin; Acet, Ahmet; Parlakpinar, Hakan","year":2025,"journal":"Forensic toxicology, 43(2), 266-279","doi":"10.1007/s11419-025-00720-9","pmid":"40240703","tags":["synthetic-cannabinoids","cardiovascular"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Acute high-dose JWH-018 caused bradycardia and hypotension. Subacute high-dose increased heart rate while continuing to lower blood pressure. JWH-018 induced arrhythmias, conduction blocks, ischemic ECG changes, and prolonged QT intervals. Histopathology revealed myocardial infarction-like features including contraction bands and ischemic damage. Elevated pro-BNP indicated cardiac stress. JWH-018 and metabolites were detected directly in heart tissue.","whyItMatters":"Synthetic cannabinoids have been linked to sudden cardiac deaths in humans but the mechanisms have been unclear. This study provides comprehensive evidence of dose- and duration-dependent cardiovascular toxicity, including direct detection of the compound in heart tissue.","specificNumbers":"JWH-018 at 0.5 mg/kg (low) and 5 mg/kg (high); 14-day subacute exposure; acute high-dose: bradycardia + hypotension; subacute high-dose: tachycardia + hypotension + prolonged QT; myocardial infarction-like histopathology; elevated pro-BNP and triglycerides; drug detected in heart tissue.","methodology":"Wistar albino rats divided into five groups: control, acute low-dose (0.5 mg/kg), acute high-dose (5 mg/kg), subacute low-dose (0.5 mg/kg for 14 days), and subacute high-dose (5 mg/kg for 14 days). Assessed via echocardiography, hemodynamics, ECG, histopathology, biochemical markers, and LC-MS/MS heart tissue analysis.","limitations":"Rat cardiovascular physiology differs from humans. Doses may not correspond to human consumption patterns. JWH-018 is one of many synthetic cannabinoids with varying properties. Controlled laboratory exposure differs from real-world use patterns."},{"rthcId":"RTHC-07291","title":"Biochemical Role of the Endocannabinoid System in the Pathophysiology of Attention Deficit Hyperactivity Disorder: A Narrative Review and Future Directions.","authors":"Özmeral Erarkadaş, Kübra; Erarkadaş, Müjdat; Yıldız Gündoğdu, Özlem","year":2025,"journal":"Neurochemical research, 51(1), 16","doi":"10.1007/s11064-025-04636-z","pmid":"41410830","tags":["cognition","neuroscience","dopamine","youth"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Eleven preclinical and 2 clinical studies showed alterations in endocannabinoid system components linked to ADHD-related behaviors. Preclinical research demonstrated ECS changes connected to hyperactivity and impaired cognitive regulation. Clinical evidence, while limited, showed promising results supporting ECS-targeted therapeutic approaches.","whyItMatters":"ADHD affects millions worldwide, and current treatments (stimulants) are not effective for everyone and carry side effects. If the endocannabinoid system plays a role in ADHD, it could open entirely new treatment avenues, though much more research is needed.","specificNumbers":"13 studies included (11 preclinical, 2 clinical); ECS components examined: cannabinoid receptors, endogenous ligands, metabolic enzymes; pathways affected: dopaminergic, noradrenergic, glutamatergic.","methodology":"Narrative review synthesizing 13 studies (11 preclinical, 2 clinical) evaluating ECS-related biochemical alterations in ADHD, focusing on receptor signaling, ligand levels, and enzyme activity.","limitations":"Only 13 studies met inclusion criteria, reflecting how little research exists in this area. Only 2 were clinical studies. Preclinical models of ADHD may not fully capture the human condition. Review methodology is narrative rather than systematic."},{"rthcId":"RTHC-07292","title":"Emerging Hemp-Derived Semi-Synthetic Cannabinoids, Absent Regulations: Patterns of Use and Adverse Effects Among a Sample of U.S. Cannabis Consumers.","authors":"Pabon, Elisa; Lake, Stephanie; Murray, Conor H; Cooper, Ziva D","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251391987","pmid":"41335500","tags":["harm-reduction","synthetic-cannabinoids","potency","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Delta-8 THC (21.8%), THCP (24.4%), and Delta-10 THC (14.0%) were the most commonly used semi-synthetic cannabinoids. Younger users and those with more lifetime cannabis experience were more likely to use them. Adverse effects were reported across all semi-synthetic types.","whyItMatters":"Hemp-derived semi-synthetic cannabinoids exist in a regulatory gray area, sold legally without the safety testing or labeling requirements applied to regulated cannabis products. This study provides some of the first data on how widely these products are actually being used.","specificNumbers":"N=229 cannabis users. Past-year semi-synthetic use: 44.5%. By type: THCP 24.4%, Delta-8 THC 21.8%, Delta-10 THC 14.0%, Delta-7 THC 10.0%, THC-O-acetate 5.2%, HHC 3.5%. Older age reduced odds of use (aOR=0.96, p=0.004). Non-inhaled cannabis users had higher odds (aOR=2.98, p=0.021).","methodology":"Online survey of 229 U.S. adults who reported past-year cannabis use, examining patterns and associations of semi-synthetic cannabinoid use with demographics and adverse effects.","limitations":"Convenience sample recruited online, likely overrepresenting experienced cannabis users. Self-reported data with no biochemical verification. Cross-sectional design cannot establish causation for adverse effects."},{"rthcId":"RTHC-07293","title":"Work-Related Asthma in the Cannabis Industry: Findings From California, Massachusetts, Michigan, and Washington.","authors":"Pacheco, Michelle; Fitzsimmons, Kathleen; Reeb-Whitaker, Carolyn; Rosenman, Kenneth; Flattery, Jennifer; Weinberg, Justine Lew; Reilly, Mary Jo; Yiu, Sarah; Sack, Coralynn; Todorov, Danièle; Harrison, Robert; Dodd, Katelynn E; Sparer-Fine, Emily","year":2025,"journal":"Journal of occupational and environmental medicine, 67(10), 862-868","doi":"10.1097/JOM.0000000000003461","pmid":"40561210","tags":["respiratory","workplace","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Of 30 work-related asthma cases in the cannabis industry, 52% were new-onset asthma and 48% were work-aggravated asthma. Cannabis dust and plant materials were the most common exposure (40.4%), and 69% of cases worked in indoor cultivation or processing. Two deaths occurred.","whyItMatters":"As the legal cannabis industry expands, occupational health risks are becoming more visible. This is among the first multi-state surveillance data showing that cannabis industry workers face real respiratory hazards, particularly from dust exposure during indoor cultivation and processing.","specificNumbers":"30 WRA cases across 4 states. 66.7% aged 18-34. 60% male. 52% new-onset asthma, 48% work-aggravated. 2 fatalities. 40.4% exposed to plant materials (94.7% cannabis dust). 69% worked in indoor cultivation/processing.","methodology":"Retrospective analysis using data from four state-based surveillance systems (California, Massachusetts, Michigan, Washington), identifying and classifying work-related asthma cases in the cannabis industry from legalization dates through 2023.","limitations":"Surveillance data likely undercount cases since reporting depends on workers seeking medical care and physicians recognizing the condition. Only 30 cases across decades of data and four states. No denominator data to calculate incidence rates."},{"rthcId":"RTHC-07294","title":"Innovative Strategies to Enhance the Bioavailability of Cannabidiol: Nanotechnology and Advanced Delivery Systems.","authors":"Paczkowska-Walendowska, Magdalena; Trzaskoma, Piotr; Dziopa, Aleksandra; Moeini, Arash; Soczawa, Michał; Krasiński, Zbigniew; Cielecka-Piontek, Judyta","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(11)","doi":"10.3390/ph18111637","pmid":"41304881","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07295","title":"Rare but relevant: Cannabis use and myocardial infarction.","authors":"Padmanathan, Prianka; Roberts, Emmert","year":2025,"journal":"Addiction (Abingdon, England), 120(12), 2580-2584","doi":"10.1111/add.70128","pmid":"40590409","tags":["cardiovascular","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The link between cannabis use and myocardial infarction may be specific to certain types of cannabis, patterns of use, and user characteristics. However, most meta-analyses can only compare \"use vs. no use\" because studies rarely capture the complexity of modern consumption patterns.","whyItMatters":"Cannabis-related cardiovascular events are considered rare but can be serious, especially in younger patients without typical cardiac risk factors. The review highlights that current evidence is too coarse to identify exactly who is at risk and under what circumstances.","specificNumbers":"The cannabis-MI link has been documented since the 1970s. Most meta-analyses rely on binary categorizations of use vs. no use.","methodology":"Narrative review and editorial commentary examining the evidence base linking cannabis use to myocardial infarction, identifying gaps in current research methodology.","limitations":"This is a narrative review and editorial commentary, not a systematic review. It identifies research gaps rather than providing new quantitative data."},{"rthcId":"RTHC-07296","title":"Characteristics and effects of cannabis advertisements with appeal to youth in California.","authors":"Padon, Alisa A; Ghahremani, Dara G; Simard, Bethany; Soroosh, Aurash J; Silver, Lynn D","year":2025,"journal":"The International journal on drug policy, 137, 104718","doi":"10.1016/j.drugpo.2025.104718","pmid":"39933413","tags":["youth","legalization","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Several ad features significantly increased youth interest in cannabis: illustrations, clear product descriptions, food or flavor references, depictions of positive sensations, adventure imagery, psychoactive effects, and references to heavy consumption. None of these features are currently restricted in California or other legal cannabis states.","whyItMatters":"California has the world's largest regulated cannabis market but its restrictions on youth-appealing ad content are vague. This experiment identifies specific, measurable ad features that increase youth interest, providing concrete targets for marketing regulation.","specificNumbers":"N=409 youth, ages 16-20, all living in California and susceptible to future cannabis use. Features tested: illustration, product descriptions, food/flavor references, positive sensations, adventure, psychoactive effects, heavy consumption references. All significantly associated with increased youth interest.","methodology":"Online experiment with 409 youth aged 16-20 in California who were susceptible to future cannabis use. Participants were randomly assigned to view cannabis ads with and without features previously shown to appeal to adolescents, then answered questions about attitudes and interest in use.","limitations":"Online experiment with youth already susceptible to cannabis use, which may overestimate effects compared to the general youth population. Measured interest and attitudes rather than actual behavior. Limited to California."},{"rthcId":"RTHC-07297","title":"Acute effects of Δ9-tetrahydrocannabinol on computational measures of neurocognitive processes are related to recent cannabis use among adolescents and young adults.","authors":"Paige, K J; Weigard, A S; Ajilore, O; Phan, K L; de Wit, H; Klumpp, H; Crane, N A","year":2025,"journal":"Frontiers in adolescent medicine, 3","doi":"10.3389/fradm.2025.1541068","pmid":"40896636","tags":["cognition","tolerance","youth","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Overall, 7.5mg oral THC did not significantly alter cognitive performance compared to placebo. However, there was high variability between individuals. Those with less recent cannabis use experienced greater cognitive slowing (slower drift rates), and those who reported stronger subjective drug effects also showed poorer cognitive efficiency.","whyItMatters":"This study helps explain why THC impairment research produces mixed results: the effects vary dramatically between individuals based on their tolerance level. Computational modeling reveals heterogeneity that traditional analyses may miss.","specificNumbers":"N=30, ages 18-25, 53% men. Dose: 7.5mg oral THC vs placebo. No significant overall group effects on drift rate, boundary separation, or non-decision time. Less recent cannabis use predicted greater cognitive slowing. Stronger subjective \"high\" and \"effect\" ratings correlated with poorer cognitive efficiency.","methodology":"Double-blind, placebo-controlled THC administration experiment with 30 occasional to regular cannabis users aged 18-25. Participants completed a Go/No-Go task at peak drug effect under both conditions. Data were analyzed using drift diffusion modeling and Bayesian statistics.","limitations":"Small sample (N=30) of young, experienced cannabis users. Single dose level (7.5mg) limits generalizability. Only one cognitive task (Go/No-Go). Cannot determine whether tolerance-related differences reflect neuroadaptation or behavioral compensation."},{"rthcId":"RTHC-07298","title":"Cannabis product exposures reported to Ramathibodi Poison Center, Thailand, during 2018-2022.","authors":"Paisarnrodjanarat, Bootsakorn; Srisuma, Sahaphume; Promrungsri, Puangpak; Tangsuwanaruk, Theerapon; Tongpoo, Achara; Rittilert, Panee; Mayurapong, Manutsanun","year":2025,"journal":"Clinical toxicology (Philadelphia, Pa.), 63(10), 760-769","doi":"10.1080/15563650.2025.2536771","pmid":"40905855","tags":["harm-reduction","legalization","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Hospitalization rates increased significantly after each policy change: from 68.7% during the illegal period to 82% (medical), 91.5% (decriminalized), and 96.8% (recreational). The proportion of children and adolescents exposed to cannabis increased significantly during the recreational period. Cannabis oil (41.4%) and smoking products (26.7%) were the most common products involved.","whyItMatters":"Thailand's rapid progression from prohibition to full legalization provides a natural experiment in how policy changes affect cannabis-related poisonings. The data show that increased availability without adequate education led to more hospitalizations and more child exposures.","specificNumbers":"1,695 cases. Median age 38 (IQR 24-53). 67.2% male. Products: cannabis oil 41.4%, smoking 26.7%, sweets 12.5%. Reasons: health belief 29.7%, recreational 29.6%, curiosity 22.5%. Hospitalization rates: illegal 68.7%, medical 82%, decriminalized 91.5%, recreational 96.8%. Lab confirmation in only 20% of cases.","methodology":"Retrospective analysis of 1,695 cannabis cases reported to the Ramathibodi Poison Center in Thailand from January 2018 to December 2022, compared across four regulatory periods: illegal, medical, decriminalized, and recreational.","limitations":"Retrospective study from a single poison center. Lab confirmation available in only about 20% of cases. Cannot separate whether increased reporting reflects more actual cases or greater awareness and willingness to report. No denominator data to calculate population rates."},{"rthcId":"RTHC-07299","title":"Substance use in Spanish adolescent gamblers before and after the COVID-19 pandemic state of alarm: a population-based study.","authors":"Palacios-Ceña, Domingo; Florencio, Lidiane Lima; Hernández-Barrera, Valentín; Yeamans, Spencer; Jiménez-Trujillo, Isabel; Gallardo-Pino, Carmen; Carrasco-Garrido, Pilar","year":2025,"journal":"Scientific reports, 15(1), 30278","doi":"10.1038/s41598-025-16121-2","pmid":"40826156","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07300","title":"Cannabis Use in Metabolic Dysfunction-Associated Steatotic Liver Disease​​: Friend or Foe? A Retrospective Analysis.","authors":"Paladiya, Ruchir; Singh, Anmol; Changela, Madhav; Shah, Mihir; Singh, Carol; Kumar, Vikash; Sohal, Aalam; Doshi, Shreyans; Parikh, Neil","year":2025,"journal":"Journal of clinical gastroenterology","doi":"10.1097/MCG.0000000000002321","pmid":"41453014","tags":["medical-cannabis","cardiovascular","inflammation"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After adjusting for confounders, cannabis use among MASLD patients was associated with lower odds of in-hospital mortality (aOR 0.70), cirrhosis (aOR 0.72), decompensated cirrhosis (aOR 0.73), chronic kidney disease (aOR 0.81), and hepatocellular carcinoma (aOR 0.71). However, cannabis use was associated with higher odds of myocardial infarction (aOR 1.42) and stroke (aOR 1.53).","whyItMatters":"This large database study suggests cannabis may have contrasting effects in liver disease patients: potentially protective for liver-related outcomes but potentially harmful for cardiovascular outcomes. The findings align with pre-clinical evidence for CBD's anti-inflammatory and antifibrotic effects on the liver.","specificNumbers":"N=3,379,484 MASLD patients, 52,315 (1.54%) cannabis users. Lower odds with cannabis use: mortality aOR 0.70 (p<0.001), cirrhosis aOR 0.72 (p<0.001), decompensated cirrhosis aOR 0.73 (p<0.001), CKD aOR 0.81 (p<0.001), HCC aOR 0.71 (p=0.003). Higher odds: MI aOR 1.42 (p<0.001), stroke aOR 1.53 (p<0.001).","methodology":"Retrospective analysis of the National Inpatient Sample (NIS) database from 2016-2020, identifying 3,379,484 adult patients hospitalized with metabolic dysfunction-associated steatotic liver disease (MASLD), comparing outcomes between 52,315 cannabis users (1.54%) and nonusers.","limitations":"Administrative database study relying on ICD codes, which may undercount cannabis use and misclassify outcomes. Cannot determine dose, frequency, or type of cannabis used. Observational design cannot establish causation. Cannabis users differed from nonusers in age and other characteristics."},{"rthcId":"RTHC-07301","title":"Automated Workflow for High-Throughput LC-MS/MS-Based Therapeutic Monitoring of Cannabidiol and 7-Hydroxy-cannabidiol in Patients with Epilepsy.","authors":"Palmisani, Michela; Dattrino, Francesca; Rota, Paola; Tacchella, Federica; Fedele, Guido; Pasca, Ludovica; Quaranta, Carlo Alberto; De Giorgis, Valentina; Matulli Cavedagna, Thomas; Cancellerini, Chiara; Butti, Anna; Castellazzi, Gloria; Russo, Emilio; Tassorelli, Cristina; Nicotera, Pierluigi; Franco, Valentina","year":2025,"journal":"International journal of molecular sciences, 26(14)","doi":"10.3390/ijms26146999","pmid":"40725248","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07302","title":"Exacerbated cardiac dysfunction from combined alcohol binge and synthetic cannabinoid use.","authors":"Paloczi, Janos; Gunduz-Cinar, Ozge; Yokus, Burhan; Paes-Leme, Bruno; Haskó, György; Kunos, George; Holmes, Andrew; Pacher, Pal","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 187, 118053","doi":"10.1016/j.biopha.2025.118053","pmid":"40288176","tags":["synthetic-cannabinoids","cardiovascular","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both alcohol and the synthetic cannabinoid CP55,940 independently caused dose-dependent declines in heart contractile function in mice. When combined, the cardiac depression was worse than either drug alone. Intravenous administration of the CB1 receptor antagonist rimonabant largely restored normal heart function, while brain-only administration only partially helped, implicating both central and peripheral CB1 receptor signaling.","whyItMatters":"Polydrug use combining alcohol and synthetic cannabinoids is increasing, particularly among young adults, and has been linked to fatal outcomes. This study provides mechanistic evidence for why the combination is especially dangerous for the heart and identifies a potential therapeutic approach.","specificNumbers":"Both alcohol and CP55,940 caused dose-dependent cardiac depression. Combined use exceeded individual drug effects. IV rimonabant largely restored cardiac function. ICV (brain-only) rimonabant only partially restored function, suggesting both central and peripheral CB1R involvement.","methodology":"Mouse study using pressure-volume hemodynamic measurements to assess left ventricular performance after acute alcohol ingestion, intravenous synthetic cannabinoid (CP55,940) administration, or both combined. CB1 receptor antagonist rimonabant was given either intravenously or intracerebroventricularly.","limitations":"Animal study using mice, which may not directly translate to human physiology. Used a single synthetic cannabinoid (CP55,940), and results may differ with other synthetic cannabinoids found in consumer products. Acute exposure model does not address chronic use effects."},{"rthcId":"RTHC-07303","title":"Brain Hsp90 Inhibition Mitigates Facial Allodynia in a Rat Model of CSD Headache and Upregulates Endocannabinoid Signaling in the PAG.","authors":"Palomino, Seph M; Levine, Aidan A; Liktor-Busa, Erika; Tanguturi, Parthasaradhireddy; Streicher, John M; Largent-Milnes, Tally M","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(10)","doi":"10.3390/ph18101430","pmid":"41155546","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07304","title":"Kenaf biochar enhances heavy metal phytostabilization and growth of industrial hemp (Cannabis sativa L.) using multi-metal contaminated mining site soils.","authors":"Pan, Jiao; Xu, Guofeng; Liang, Minglin; Mo, Huiting; Luo, Dengjie; Wang, Caijin; Ullah, Rehmat; Li, Yun; Liao, Changjun; Wei, Xiqin; Chen, Peng","year":2025,"journal":"Plant physiology and biochemistry : PPB, 229(Pt A), 110312","doi":"10.1016/j.plaphy.2025.110312","pmid":"40803067","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07305","title":"From fibers to flowering to metabolites: unlocking hemp (Cannabis sativa) potential with the guidance of novel discoveries and tools.","authors":"Pancaldi, Francesco; Salentijn, Elma M J; Trindade, Luisa M","year":2025,"journal":"Journal of experimental botany, 76(1), 109-123","doi":"10.1093/jxb/erae405","pmid":"39324630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07306","title":"Mental Health, Substance Use, and Related Factors Associated with Recent Use of Cannabis for Sleep: A Co-Twin Control Study.","authors":"Panchal, Zoë; Sakai, Joseph; Goldstein-Piekarski, Andrea N; Ellingson, Jarrod M; Iacono, William; Corley, Robin P; Vrieze, Scott; Hopfer, Christian J; Hewitt, John K; McGue, Matt K; Ross, J Megan","year":2025,"journal":"Behavioral sleep medicine, 23(5), 648-660","doi":"10.1080/15402002.2025.2508770","pmid":"40400361","tags":["sleep","mental-health","addiction","genetics"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In co-twin control analyses that account for genetic and shared environmental factors, using cannabis for sleep remained significantly associated with more cannabis use problems, higher cannabis frequency, worse sleep quality, and more frequent use of alcohol and sleep medications. Many other associations seen in standard analyses (anxiety, depression, PTSD) were explained by familial confounds.","whyItMatters":"Many cannabis users report using it for sleep, but this twin study suggests the practice is associated with worse sleep outcomes and more substance use, even after accounting for genetic predisposition. Familial factors explained some but not all of the negative associations.","specificNumbers":"N=3,165 twins, mean age 36.7. Within-family effects (surviving co-twin control): more cannabis problems, higher cannabis frequency, worse sleep quality, more alcohol for sleep, more medication for sleep. Associations explained by familial confounds: anxiety, depression, PTSD symptoms.","methodology":"Population-based twin study (N=3,165, mean age 36.7) using both standard regression and co-twin control models. The co-twin design compares twins who differ in cannabis-for-sleep use, effectively controlling for shared genetics and early environment.","limitations":"Cross-sectional design cannot determine whether cannabis use causes worse sleep or whether people with worse sleep are drawn to cannabis. Self-reported measures. Cannot distinguish between different cannabis products, doses, or timing of use relative to sleep."},{"rthcId":"RTHC-07307","title":"Early Life Exposure to Δ9-Tetrahydrocannabinol Causes Persistent Growth, Behavior, and Bioenergetic Outcomes in Zebrafish.","authors":"Pandelides, Zacharias; Thornton, Cammi; Paris, Jason J; Ashpole, Nicole M; Willett, Kristine L","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251401831","pmid":"41467910","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07308","title":"Dysregulation of the endocannabinoid system - a key factor in the progression of multiple sclerosis?","authors":"Paraschiv, Andreea-Cristina; Văcăraș, Cristiana; Marge, Cristian; Văcăraș, Vitalie","year":2025,"journal":"Journal of medicine and life, 18(9), 863-868","doi":"10.25122/jml-2025-0146","pmid":"41178906","tags":["medical-cannabis","neuroscience","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Newly diagnosed MS patients in acute relapse showed a non-significant trend toward lower plasma anandamide (AEA) compared to healthy controls (mean difference -5.95 ng/ml, p=0.098). In teriflunomide-treated patients, AEA and 2-AG were strongly positively correlated (r=0.882), a pattern not seen in other groups. Quality of life was significantly lower in newly diagnosed patients.","whyItMatters":"The endocannabinoid system is thought to play a role in MS through its involvement in immune regulation and neuroprotection. This small study provides early evidence that endocannabinoid levels may be disrupted in MS, potentially offering a biomarker or therapeutic target.","specificNumbers":"N=30 (10 per group). AEA trend: -5.95 ng/ml lower in newly diagnosed vs controls (p=0.098). Teriflunomide group AEA-2-AG correlation: r=0.882 (p<0.001). SF-36 scores significantly lower in newly diagnosed vs controls (p=0.044). No significant group differences in 2-AG overall.","methodology":"Cross-sectional study comparing plasma endocannabinoid levels (AEA and 2-AG) in 10 healthy controls, 10 newly diagnosed relapsing-remitting MS patients in acute relapse, and 10 teriflunomide-treated RRMS patients in remission. Clinical assessments included MMSE and SF-36.","limitations":"Very small sample (10 per group) with wide variability. The AEA difference did not reach statistical significance. Cross-sectional design at a single time point. Plasma endocannabinoid levels may not reflect central nervous system levels. No control for lifestyle factors that affect endocannabinoid levels."},{"rthcId":"RTHC-07309","title":"Patterns of cannabidiol use among marijuana users in the United States.","authors":"Park, Ji-Yeun","year":2025,"journal":"Preventive medicine reports, 50, 102985","doi":"10.1016/j.pmedr.2025.102985","pmid":"39911836","tags":["cbd","medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Current CBD use was 10.5% overall in the U.S. population. Among current marijuana users, 40.7% also used CBD in the past 30 days, compared to 32.2% of past-year marijuana users, 19.1% of ever-users, and only 5.1% of never-marijuana-users. Females, adults, White individuals, and those with fair/poor health status were more likely to use CBD.","whyItMatters":"CBD products are often marketed as distinct from marijuana, but this analysis shows that CBD use is heavily concentrated among people who also use marijuana. This challenges the assumption that CBD users are a separate population and has implications for how public health messaging about CBD is targeted.","specificNumbers":"10.5% of the U.S. population reported current CBD use. By marijuana status: current marijuana users 40.7%, past-year users 32.2%, ever-users 19.1%, non-current users 5.09%, non-past-year users 4.38%, never-users 5.09%. Females, adults, Whites, and those with fair/poor health more likely to use CBD.","methodology":"Analysis of the 2022 National Survey on Drug Use and Health (NSDUH), a nationally representative cross-sectional survey. Descriptive analyses assessed CBD use prevalence by marijuana use status, and adjusted logistic regression examined demographic predictors of CBD use.","limitations":"Cross-sectional survey data cannot establish why CBD use is higher among marijuana users. Self-reported use without verification of actual CBD product contents. NSDUH captures prevalence but not detailed product information, dosing, or reasons for use."},{"rthcId":"RTHC-07310","title":"Impact of Cannabis Use on Deep Inferior Epigastric Perforator Autologous Breast Reconstruction: analysis of 719 patients and 1148 flaps: Impact of Cannabis Use in DIEP Reconstruction.","authors":"Park, John B; Escobar-Domingo, Maria J; Tobin, Micaela; Lee, Daniela; Mahmoud, Amir-Ala; Rahmani, Benjamin; Adebagbo, Oluwaseun; Fanning, James E; Posso, Agustin N; Bloom, Joshua A; Cauley, Ryan P; Lee, Bernard T","year":2025,"journal":"Annals of plastic surgery, 94(4S Suppl 2), S188-S193","doi":"10.1097/SAP.0000000000004214","pmid":"40167070","tags":["cardiovascular","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users (12.1% of the cohort) had significantly higher rates of postoperative hematoma (OR 3.078 for general hematoma, OR 3.098 for breast hematoma) and readmission (OR 2.865) after DIEP flap breast reconstruction. Cannabis users were also younger and had higher BMI. A 5-fold increase in the proportion of cannabis users was observed from 2015 to 2023.","whyItMatters":"As cannabis use becomes more common among surgical patients, understanding its effects on surgical outcomes is critical for preoperative risk assessment. The 5-fold increase in cannabis-using patients over the study period underscores the growing relevance of this issue.","specificNumbers":"N=719 patients, 1148 flaps. 87 cannabis users (12.1%). 5-fold increase in cannabis user proportion from 2015-2023. Cannabis users younger (47.5 vs 51.7, p<0.001) and higher BMI (30.5 vs 28.9, p=0.012). Adjusted ORs: general hematoma 3.078 (p=0.013), breast hematoma 3.098 (p=0.020), readmission 2.865 (p=0.031). Longer time to last drain removal (21 vs 17 days, p<0.001).","methodology":"Retrospective study of 719 adult patients (87 cannabis users, 632 non-users) who underwent DIEP flap autologous breast reconstruction between January 2015 and December 2023 by five plastic surgeons at a single institution. Multivariable logistic regression controlled for confounders.","limitations":"Single institution, retrospective design. Cannabis use was self-reported and may be underestimated. Could not assess dose, frequency, or timing of last use relative to surgery. Cannabis users differed from non-users in age and BMI, and residual confounding is possible."},{"rthcId":"RTHC-07311","title":"Biotechnological potential of Cannabis sativa adventitious roots for producing immunomodulatory and anti-inflammatory bioactive compounds.","authors":"Park, Su Hyun; Han, Jeong Moo; Kim, Yun Hye; Lee, Hyeon Jin; Ryu, Young Bae; Ryu, Hyung Won; Jeong, Jae Cheol; Oh, Seon Min; Kim, Woo Sik","year":2025,"journal":"Scientific reports, 15(1), 30904","doi":"10.1038/s41598-025-16130-1","pmid":"40847038","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07312","title":"Dual-Function Plant-Derived Nanovesicles From Regenerated Cannabis sativa Roots for Immunotherapy and Vaccine Delivery.","authors":"Park, Su Hyun; Choi, Han-Gyu; Li, Zhun; Kim, Yun Hye; Lee, Hyeon Jin; Shin, Ki-Won; Kim, Hwa-Jung; Kwon, Hyung-Jun; Seo, Gimoon; Jeong, Jae Cheol; Ryu, Young Bae; Kim, Woo Sik","year":2025,"journal":"Journal of extracellular vesicles, 14(12), e70206","doi":"10.1002/jev2.70206","pmid":"41316982","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07313","title":"Cannabinoids and alcohol co-exposure modulate pathogen-induced pulmonary immune responses.","authors":"Parker, De'Jana; Sivaraman, Vijay","year":2025,"journal":"Frontiers in immunology, 16, 1539813","doi":"10.3389/fimmu.2025.1539813","pmid":"40692779","tags":["respiratory","harm-reduction","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent cannabinoid exposure primed mouse lungs for more severe inflammation when later infected with Klebsiella pneumoniae. This heightened inflammatory response was mitigated by cannabinoid receptor antagonists. Combined alcohol and cannabinoid pre-exposure followed by bacterial challenge produced CB receptor-dependent pulmonary immune activation via danger-associated molecular pattern (DAMP) release.","whyItMatters":"Adolescents who binge on cannabis may be setting up their lungs for worse outcomes if they develop pneumonia or other lung infections later in life. The combination with alcohol, common in young adult polydrug use, appears to make the situation worse.","specificNumbers":"Cannabinoid antagonists mitigated the primed inflammatory response. Combined ethanol + cannabinoid exposure activated pulmonary immune response via DAMP release in a CB receptor-dependent manner.","methodology":"Mouse model using binge cannabinoid exposure during adolescence followed by Klebsiella pneumoniae lung infection in adulthood. A combined ethanol + cannabinoid adolescent exposure model was also tested. Cannabinoid receptor antagonists were used to confirm mechanism.","limitations":"Animal model that may not directly translate to humans. Used synthetic cannabinoid rather than plant-derived THC. Binge exposure model may not reflect typical adolescent cannabis use patterns. Single bacterial pathogen tested."},{"rthcId":"RTHC-07314","title":"Advertising Among Cannabidiol (CBD) Retailers in North Carolina: A Pilot Study.","authors":"Parker, Renee; Horton, Olivia; Wagoner, Kimberly G","year":2025,"journal":"North Carolina medical journal, 86(1), 64-68","doi":"10.18043/001c.137181","pmid":"41524319","tags":["cbd","legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"All 13 CBD retailers displayed advertisements containing either misleading product descriptors or unapproved health claims. Nearly all (92.3%) made unapproved health claims. Over 40% of advertisements promoted CBD for specific health conditions: stress/anxiety (29.8%), arthritis/inflammation (28.7%), and pain (26.6%). Common descriptors included \"full-spectrum\" (10.6%), \"natural\" (6.4%), and \"pure\" (4.3%).","whyItMatters":"CBD products are widely available but loosely regulated. This study documents that nearly all retailers make health claims that have not been approved by the FDA, potentially misleading consumers into replacing evidence-based treatments with CBD.","specificNumbers":"13 retailers assessed. 92.3% displayed unapproved health claims. 84.6% used product descriptors. Health claims: stress/anxiety 29.8%, arthritis/inflammation 28.7%, pain 26.6%. Descriptors: \"full-spectrum\" 10.6%, \"natural\" 6.4%, \"pure\" 4.3%.","methodology":"Pilot study in which two trained data collectors assessed CBD advertisements in 13 brick-and-mortar retailers in North Carolina in November 2020. Advertisements were photographed and content analyzed for product descriptors and health claims.","limitations":"Very small pilot study (13 retailers) in urban North Carolina, limiting generalizability. Data collected in November 2020, and the CBD retail landscape may have changed. Did not assess whether consumers were influenced by the claims."},{"rthcId":"RTHC-07315","title":"Characterization of Patients With Symptoms of Gastroparesis Having Frequent Emergency Department Visits and Hospitalizations.","authors":"Parkman, Henry P; Xin, Yuchen; Wilson, Laura A; Burton-Murray, Helen; McCallum, Richard W; Sarosiek, Irene; Moshiree, Baha; Koch, Kenneth L; Bulat, Robert S; Grover, Madhusudan; Farrugia, Gianrico; Chumpitazi, Bruno P; Shulman, Robert J; Miriel, Laura A; Tonascia, James; Pasricha, Pankaj J; Kuo, Braden; Abell, Thomas L","year":2025,"journal":"Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 23(11), 2023-2038","doi":"10.1016/j.cgh.2025.01.033","pmid":"40286861","tags":["medical-cannabis","harm-reduction","appetite"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was independently associated with both ED visits and hospitalizations in gastroparesis patients, even after controlling for other factors. Other independent predictors included younger age, Black race, lower income, higher gastric retention, antiemetic use, jejunostomy tube presence, and higher nausea/vomiting scores. Hospitalizations were additionally linked to diabetic etiology and depression.","whyItMatters":"Cannabis is commonly used by gastroparesis patients, sometimes for symptom relief. The finding that cannabis use is associated with more, not fewer, emergency visits and hospitalizations challenges the assumption that self-medication with cannabis reduces healthcare utilization in this population.","specificNumbers":"N=406 patients, 72.4% with delayed gastric emptying (33% diabetic, 61% idiopathic). 39% had prior ED visits. 23% had hospitalizations. Top hospitalization reasons: nausea 83%, vomiting 78%, abdominal pain 70%, dehydration 59%. Cannabis use independently predicted both ED visits and hospitalizations.","methodology":"Cross-sectional analysis of 406 patients with gastroparesis symptoms who underwent gastric emptying scintigraphy and completed questionnaires on symptoms, mental health, quality of life, and healthcare utilization over the prior year.","limitations":"Cross-sectional design cannot determine whether cannabis use causes more healthcare utilization or whether sicker patients are more likely to use cannabis. Self-reported cannabis use. Cannot distinguish between different cannabis products or consumption methods. Referral center population may not represent all gastroparesis patients."},{"rthcId":"RTHC-07316","title":"Dynamic associations between cannabis use and sleep in adolescents and young adults during a cannabis intervention trial.","authors":"Parnes, Jamie E; Smith-LeCavalier, Kirstyn N; Meisel, Samuel N; Miranda, Robert","year":2025,"journal":"Journal of research on adolescence : the official journal of the Society for Research on Adolescence, 35(4), e70083","doi":"10.1111/jora.70083","pmid":"41065259","tags":["sleep","youth","quitting","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"During the first week of treatment, more cannabis use was associated with longer sleep for those with severe cannabis use disorder, but shorter sleep for those with mild CUD. By week two, more cannabis use was associated with shorter sleep regardless of severity. During the first two weeks, cannabis use was associated with less trouble sleeping. After week two, cannabis use had no significant association with sleep.","whyItMatters":"Sleep disruption is one of the most commonly reported cannabis withdrawal symptoms and a barrier to treatment success. Understanding exactly when and how cannabis affects sleep during treatment can help clinicians prepare patients for sleep difficulties in early recovery.","specificNumbers":"N=65, ages 15-24, 51% female, 57% White. 42-day EMA study. Week 1: cannabis associated with longer sleep in severe CUD and shorter sleep in mild CUD. Week 2: cannabis associated with shorter sleep regardless of severity. Weeks 1-2: cannabis associated with less trouble sleeping. After week 2: no significant cannabis-sleep associations.","methodology":"Ecological momentary assessment study with 65 adolescents and young adults (ages 15-24) in CUD treatment, completing daily reports over 42 days while receiving cognitive behavioral therapy plus motivational enhancement therapy. Time-varying effect modeling examined how cannabis-sleep associations changed across treatment.","limitations":"Small sample (N=65). Self-reported daily measures of both cannabis use and sleep. Treatment-seeking sample may not generalize to all young cannabis users. Cannot control for all confounding factors in daily data. Specific to CBT+MET treatment context."},{"rthcId":"RTHC-07317","title":"Daily Cannabis Use: Do Impulsivity and Sensation Seeking Predict Negative Cannabis Related Consequences?","authors":"Parnes, Jamie E; Tyskiewicz, Alexander J; Prince, Mark A; Conner, Bradley T","year":2025,"journal":"Journal of drug issues, 55(3)","doi":"10.1177/00220426231226221","pmid":"40893462","tags":["addiction","harm-reduction","cognition"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among daily legal cannabis users, risk-seeking personality was significantly positively associated with negative cannabis-related consequences. Surprisingly, positive urgency (acting impulsively when feeling good) was significantly negatively associated with consequences, opposite to expectations. Other impulsivity and sensation-seeking facets were not significantly associated.","whyItMatters":"Most impulsivity research on cannabis consequences focuses on people with problematic use or in illegal markets. This study suggests that among daily users in a legal market, the personality factors that predict negative outcomes may differ from what previous research found in other populations.","specificNumbers":"N=51 community adults with daily legal cannabis use. Risk-seeking significantly positively predicted negative consequences. Positive urgency significantly negatively predicted negative consequences. All other personality facets: not significant.","methodology":"Cross-sectional study of 51 community adults with daily legal cannabis use, using two multiple regression models predicting negative cannabis-related consequences from impulsivity facets and sensation-seeking facets.","limitations":"Very small sample (N=51) limits statistical power and generalizability. Cross-sectional design cannot establish causation. Community convenience sample. Did not control for type of cannabis product, dose, or context of use."},{"rthcId":"RTHC-07318","title":"Effects of Cannabidiol on Social Relating, Anxiety, and Parental Stress in Autistic Children: A Randomized Controlled Crossover Trial.","authors":"Parrella, Nina-Francesca; Hill, Aron T; Enticott, Peter G; Botha, Tanita; Catchlove, Sarah; Downey, Luke; Ford, Talitha C","year":2025,"journal":"Autism research : official journal of the International Society for Autism Research","doi":"10.1002/aur.70159","pmid":"41452412","tags":["cbd","youth","anxiety","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CBD oil (10 mg/kg/day for 12 weeks) did not significantly improve the primary outcome of social responsiveness (SRS-2). However, significant improvements were found in secondary measures: social relating (DBC-2, p=0.024), anxiety (DBC-2 subscale, p=0.002), and parental stress (APSI, p=0.044). Two children experienced gastrointestinal discomfort. No differences were seen in adaptive functioning.","whyItMatters":"Autism treatments are limited, and many families are already using CBD products for their autistic children without clinical evidence. This is one of the first rigorous randomized trials testing CBD in autistic children, and while the primary outcome was negative, the significant anxiety reduction and parental stress improvements warrant further investigation.","specificNumbers":"N=29 (18 male), ages 5-12 (mean 9.62). CBD dose: 10 mg/kg/day. Two 12-week periods with 8-week washout. Primary outcome (SRS-2): not significant (p=0.125). Secondary outcomes: social relating p=0.024, anxiety p=0.002, parental stress p=0.044. Adverse events: 2 children with GI discomfort.","methodology":"Randomized, double-blind, placebo-controlled crossover trial with 29 autistic children aged 5-12. Participants received weight-based CBD oil (10 mg/kg/day) or placebo for 12 weeks each, separated by an 8-week washout period.","limitations":"Small sample (N=29) limits statistical power, especially for the primary outcome. Multiple secondary outcomes increase the risk of false positives. Crossover design assumes no carryover effects after the 8-week washout. No independent measure of CBD adherence. Single CBD formulation with terpenes tested."},{"rthcId":"RTHC-07319","title":"Clinicians' attitudes and knowledge of medicinal cannabis in opioid dependence treatment clinics in New South Wales, Australia.","authors":"Parvaresh, Laila; Mills, Llewellyn; Gholami, Jaleh; Jansen, Louisa; Jamshidi, Nazila; Baker, Kate; Tremonti, Christopher; Tracy, Marguerite; Dunlop, Adrian; Lintzeris, Nicholas","year":2025,"journal":"Journal of cannabis research, 7(1), 59","doi":"10.1186/s42238-025-00315-6","pmid":"40818961","tags":["medical-cannabis","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"88.5% of clinicians lacked experience providing medicinal cannabis. Two-thirds (66.7%) would consider medicinal cannabis for addressing cannabis use in OTP clients, and over 70% would consider it for other health conditions. Over half (54.2%) lacked confidence in assisting with access and were unfamiliar with regulations (56.2%). Top safety concerns were driving problems (74%), cognitive impairment (54.2%), and cannabis dependence (54.2%).","whyItMatters":"Opioid treatment program clients have high rates of cannabis use, and medicinal cannabis is increasingly available in Australia. This study reveals a major gap between clinician willingness to consider medicinal cannabis and their actual knowledge and confidence to do so.","specificNumbers":"N=102 clinicians, 63% response rate. 56.9% female, 52.9% full-time. 88.5% no medicinal cannabis experience. 66.7% would consider it for cannabis use. 71.5% would consider it for other conditions. 54.2% lacked confidence in access. 56.2% unfamiliar with regulations. Top concerns: driving 74%, cognitive impairment 54.2%, dependence 54.2%. THC evidence endorsed for: palliative care 72.4%, chronic pain 67.4%, MS 43.8%. CBD evidence endorsed for: chronic pain 64.9%, palliative care 62.5%, sleep 44.8%.","methodology":"Cross-sectional survey of 102 clinicians (nurses, doctors, pharmacists, allied health, consumer workers) from six public opioid treatment program services in New South Wales, Australia.","limitations":"Single region (New South Wales). 63% response rate may introduce selection bias. Clinician perceptions may not reflect evidence-based practice. Survey cannot assess actual clinical competence. Australian regulatory context may differ from other countries."},{"rthcId":"RTHC-07320","title":"Clinicians' Perspectives on Cannabis Use and Cannabis Treatment in Clients Undertaking Opioid Dependence Treatment.","authors":"Parvaresh, Laila; Mills, Llewellyn; Gholami, Jaleh; Jansen, Louisa; Jamshidi, Nazila; Baker, Kate; Tremonti, Christopher; Tracy, Marguerite; Dunlop, Adrian; Lintzeris, Nicholas","year":2025,"journal":"Drug and alcohol review, 44(5), 1339-1350","doi":"10.1111/dar.14074","pmid":"40325937","tags":["addiction","medical-cannabis","harm-reduction","sleep","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Clinicians estimated 56.1% of OTP clients had used cannabis in the past month and 44.9% had cannabis dependence, but only 15.3% identified their cannabis use as problematic and 10.7% sought treatment. Clinicians identified both harms (dependence 46.5%, financial issues 37.5%, increased tobacco 33.1%) and benefits (sleep 49.7%, mental health 48.3%, chronic pain 35.6%). 63.7% advocated for enhancing cannabis intervention efforts.","whyItMatters":"This is the first study to document how opioid treatment clinicians perceive their clients' cannabis use. The nuanced view -- acknowledging both benefits and harms -- reflects clinical reality better than either a purely positive or negative framing of cannabis in addiction treatment settings.","specificNumbers":"N=162 clinicians, 56% response rate. Estimated 56.1% of OTP clients used cannabis past month. 44.9% estimated to have dependence. Only 15.3% identified use as problematic. Only 10.7% sought treatment. Harms: dependence 46.5%, financial 37.5%, tobacco 33.1%. Benefits: sleep 49.7%, mental health 48.3%, pain 35.6%. 63.7% wanted enhanced services. Prioritized: withdrawal services 81%, harm reduction 77.4%, counselling 74%, medicinal cannabis 59.8%.","methodology":"Survey of 162 clinicians from six public opioid treatment program services in New South Wales, examining perspectives on clients' cannabis use patterns, perceived harms and benefits, and confidence in delivering interventions.","limitations":"Clinician estimates of client behaviors may not be accurate. Single-region Australian sample. 56% response rate introduces possible selection bias. Cannot confirm actual cannabis use rates among clients."},{"rthcId":"RTHC-07321","title":"Long-term efficacy and safety of cannabidiol in patients with treatment-resistant focal epilepsies treated in the Expanded Access Program.","authors":"Patel, Anup D; Szaflarski, Jerzy P; Lyons, Paul D; Boffa, Michael; Greco, Teresa; Saurer, Timothy B; Rajasekaran, Karthik; Simontacchi, Kelly C; Thiele, Elizabeth A","year":2025,"journal":"Epilepsia, 66(10), 3730-3740","doi":"10.1111/epi.18496","pmid":"40673944","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"CBD treatment was associated with median reductions of 51-87% in focal seizures and 44-87% in total seizures in the TSC group, and 46-75% and 45-71% in the non-TSC group, sustained through 144 weeks. Responder rates were similar between groups. Adverse events occurred in 91% of TSC and 96% of non-TSC patients. Median CBD dose was about 23-25 mg/kg/day.","whyItMatters":"While CBD (Epidiolex) is FDA-approved for certain epilepsy syndromes including TSC, its effectiveness in non-TSC focal epilepsies has been less documented. This study shows sustained long-term benefit across multiple types of focal epilepsy, potentially expanding the clinical applications of CBD.","specificNumbers":"N=140 patients. 33 TSC (median age 11.9, range 2-31), 107 non-TSC (median age 17.8, range 2-73). Non-TSC subtypes: cortical dysplasia 14%, frontal lobe 10%, cortical malformation 9%. CBD dose: TSC 25 mg/kg/day, non-TSC 23 mg/kg/day. Seizure reduction sustained through 144 weeks. AEs: 91% TSC, 96% non-TSC.","methodology":"Open-label expanded access program following 140 patients with treatment-resistant focal epilepsies (33 with TSC, 107 with other focal epilepsies) receiving plant-derived CBD (Epidiolex) at doses up to 25-50 mg/kg/day for up to 144 weeks.","limitations":"Open-label study without placebo control, so the magnitude of benefit may be overestimated. Expanded access population may have different characteristics than typical patients. High adverse event rates, though many AEs may be related to concomitant medications. Dropout over 144 weeks may create survivorship bias."},{"rthcId":"RTHC-07322","title":"Lifestyle behaviors and mental health of health professional students during COVID-19, as measured by the CDC's BRFSS, for the HOLISTIC cohort study.","authors":"Patel, Atithi; Lu, Jun; Bitra, Jyotsna; Dommaraju, Sunil; Loizzo, Daniel; Guillen, Brenda; Kane, Niamh; Westnedge, Danielle; Guzman, Jessica Lopez; Giang, Nancy; Hartnett, Isabella; Keehn, Mary T; Ahmed, Rashid; Krishnan, Jerry A; Fokuo, Konadu","year":2025,"journal":"PLOS mental health, 2(4), e0000302","doi":"10.1371/journal.pmen.0000302","pmid":"41661929","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07323","title":"Atypical Presentation of Spontaneous Pneumomediastinum Secondary to Cannabinoid Hyperemesis Syndrome.","authors":"Patel, Dhruv K; Lippert, William C","year":2025,"journal":"Cureus, 17(10), e95097","doi":"10.7759/cureus.95097","pmid":"41281024","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07324","title":"Cannabis and psychosis: minimising harm while maximising therapeutic potential.","authors":"Patel, Rashmi","year":2025,"journal":"The British journal of psychiatry : the journal of mental science, 1-2","doi":"10.1192/bjp.2025.10389","pmid":"40931726","tags":["psychosis","medical-cannabis","legalization","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Cannabis use increases the risk of psychosis, but cannabis-based medicinal products may provide additional therapeutic opportunities. The author notes a policy paradox: decriminalization has led to wider recreational availability in some jurisdictions, while in the UK, regulated medicinal preparations remain difficult to access. A more balanced approach could reduce harms while maximizing potential therapeutic benefits.","whyItMatters":"This perspective from a leading psychiatric journal frames the cannabis policy challenge clearly: the same plant that poses psychosis risks also contains compounds with therapeutic potential. Policies that address only one side of this equation miss the full picture.","specificNumbers":"An estimated 219 million cannabis users globally (referenced in related literature). Cannabis use increases psychosis risk (well-established). UK medicinal cannabis remains difficult to access despite legalization.","methodology":"Editorial commentary in the British Journal of Psychiatry examining the tension between cannabis-related psychosis risk and medicinal cannabis potential, with policy recommendations.","limitations":"Brief editorial commentary (1-2 pages) rather than a comprehensive review. Represents one author's perspective. UK-focused policy discussion may not directly apply to other jurisdictions."},{"rthcId":"RTHC-07325","title":"Prenatal cannabinoid exposure affects central cardiorespiratory control in young male and female rats.","authors":"Patrone, Luis Gustavo A; Karlen-Amarante, Marlusa; Gargaglioni, Luciane H; Zoccal, Daniel B","year":2025,"journal":"Journal of applied physiology (Bethesda, Md. : 1985), 138(5), 1201-1216","doi":"10.1152/japplphysiol.00044.2025","pmid":"40235298","tags":["pregnancy","cardiovascular","respiratory","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal cannabinoid exposure (WIN 55,212-2) caused lasting impairments in cardiorespiratory control in juvenile rats. Females showed reduced postinspiratory drive to laryngeal muscles at rest, suggesting impaired upper airway control. Both males and females showed reduced respiratory responses to low oxygen and high CO2. Males additionally showed attenuated sympathetic cardiovascular responses to these challenges.","whyItMatters":"Cannabis use among pregnant women is increasing, partly due to beliefs that its natural origin guarantees safety. This study shows that prenatal cannabinoid exposure can disrupt the development of brain circuits controlling breathing and blood pressure, with effects that persist into early adulthood.","specificNumbers":"WIN 55,212-2 dose: 0.5 mg/kg/day during gestation. Measurements at 27-28 days old (juvenile). Females: reduced postinspiratory activity to laryngeal muscles at rest. Both sexes: reduced postinspiratory and expiratory motor responses to chemoreceptor activation and hypercapnia. Males: attenuated sympathoexcitatory responses.","methodology":"In situ nerve recording preparations from juvenile rats (27-28 days old) whose mothers received synthetic cannabinoid WIN 55,212-2 (0.5 mg/kg/day) or vehicle during gestation. Respiratory and sympathetic nerve activities were measured during resting conditions and during chemoreceptor stimulation.","limitations":"Animal study using a synthetic cannabinoid (WIN 55,212-2), which has different pharmacology than plant-derived THC. In situ preparation rather than awake, behaving animals. Cannot directly translate doses or outcomes to human pregnancy. Single time point assessment (juvenile)."},{"rthcId":"RTHC-07326","title":"Naturalistic investigation of cannabis strains varying in THC and CBD ratios and verbal recognition memory.","authors":"Paulich, Katie N; Place, Christian; Giordano, Gregory; Carpenter, William B; Curran, Tim; Bidwell, L Cinnamon","year":2025,"journal":"Frontiers in psychology, 16, 1685412","doi":"10.3389/fpsyg.2025.1685412","pmid":"41567462","tags":["cognition","cbd","potency","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The idea that CBD might counteract THC's cognitive effects has been a popular hypothesis in cannabis research—and a selling point for balanced THC:CBD products. This study put it to a direct test using legal-market flower.\n\nOne hundred sixteen participants were randomly assigned to one of three strains: THC-dominant, roughly 1:1 THC:CBD, or CBD-dominant. They completed verbal recognition memory tasks in two sessions (baseline and after use), allowing within-person comparison.\n\nTHC impaired verbal memory accuracy, consistent with decades of prior research. The key question was whether adding CBD would buffer that effect. It did not. The 1:1 THC:CBD strain produced memory impairment similar to the THC-dominant strain—no protective CBD effect was observed.\n\nThe CBD-dominant strain, predictably, showed the least memory impact. But this isn't because CBD protected against THC—it's because the CBD-dominant strain contained very little THC to begin with.\n\nThis is one of the first studies to test the CBD-protection hypothesis with legal-market products rather than lab-controlled preparations, making it more generalizable to real-world use. The null finding for CBD protection is important for consumers choosing products based on the belief that balanced ratios are cognitively safer.","whyItMatters":"Many consumers choose 1:1 THC:CBD products specifically because they believe CBD will protect against THC's cognitive effects. This study found no evidence for that protective effect on verbal memory, which is one of THC's most reliable cognitive impacts. If the protection hypothesis doesn't hold for the most well-documented cognitive effect, it may not hold for other effects either.","specificNumbers":"N = 116 (40 THC-dominant, 38 1:1 THC:CBD, 38 CBD-dominant). THC reduced verbal recognition memory accuracy. 1:1 THC:CBD strain did not protect against THC's memory effects. CBD-dominant strain showed least impairment.","methodology":"Naturalistic observational study. 116 participants randomly assigned to three legal-market flower strains: THC-dominant (n=40), 1:1 THC:CBD (n=38), or CBD-dominant (n=38). Two experimental sessions with verbal recognition memory testing before and after cannabis use.","limitations":"Naturalistic design means participants used cannabis in their normal setting (less control than a lab). Flower products vary batch-to-batch in actual cannabinoid content. Only verbal recognition memory tested—CBD might protect other cognitive domains. The 1:1 ratio is one specific balance; other ratios might behave differently. Acute effects only—chronic use patterns weren't examined."},{"rthcId":"RTHC-07327","title":"Arrhythmias and cannabis use: A comprehensive overview.","authors":"Paulraj, Shweta; Upreti, Prakash; Tamirisa, Ketan; Batnyam, Uyanga","year":2025,"journal":"Heart rhythm O2, 6(1), 78-85","doi":"10.1016/j.hroo.2024.10.020","pmid":"40224259","tags":["cardiovascular","harm-reduction","synthetic-cannabinoids"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Epidemiological data show a significant association between cannabis use and various arrhythmias, particularly atrial fibrillation. The risk is notably higher among younger users and males. Case reports have linked cannabis to ventricular tachycardia and ventricular fibrillation, especially in people with underlying heart conditions. Synthetic cannabinoids carry even greater arrhythmogenic risk due to higher potency.","whyItMatters":"With an estimated 219 million cannabis users globally and THC concentrations in products increasing over time, the cardiovascular safety profile of cannabis deserves more attention. This review synthesizes evidence that cannabis can disrupt heart rhythm, particularly in populations often assumed to be at low cardiac risk.","specificNumbers":"Estimated 219 million cannabis users globally. Significant association with atrial fibrillation. Higher risk in younger users and males. Case reports of ventricular tachycardia, ventricular fibrillation. Synthetic cannabinoids more potent and potentially more arrhythmogenic.","methodology":"Comprehensive narrative review of the arrhythmogenic properties of cannabis and synthetic cannabinoids, examining epidemiological studies, case reports, and mechanistic evidence related to the endocannabinoid system and cardiac electrophysiology.","limitations":"Narrative review rather than systematic review with meta-analysis. Some studies found no significant difference in arrhythmia burden between users and non-users. Much evidence comes from case reports rather than controlled studies. Cannot establish definitive causation."},{"rthcId":"RTHC-07328","title":"Suicide Attempts in an Italian Population with Cannabis Use Disorders: Results of a Follow-Up Study.","authors":"Pavarin, Raimondo Maria; Lia, Loredana; Tugnoli, Stefano; Caracciolo, Stefano","year":2025,"journal":"Journal of psychoactive drugs, 57(1), 121-128","doi":"10.1080/02791072.2023.2287674","pmid":"38009854","tags":["mental-health","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"The crude suicide attempt rate among people with cannabis use disorder was 2.5 per 1,000 person-years, over 22 times higher than the general population. Risk was higher in females, people with co-occurring alcohol use disorder, those with any psychiatric diagnosis, within one year of first treatment visit, and during the COVID-19 period.","whyItMatters":"The 22-fold higher suicide attempt rate underscores that cannabis use disorder is not a benign condition and is associated with serious mental health consequences. The elevated risk in the first year after initial clinical contact highlights a critical window for intervention.","specificNumbers":"Suicide attempt rate: 2.5 per 1,000 person-years. Over 22 times higher than general population. Higher risk: females, co-occurring alcohol use disorder, any psychiatric diagnosis, within 1 year of first visit, during COVID-19 period. Data from Bologna metro area, 2009-2019.","methodology":"Retrospective cohort study using electronic health records from Bologna, Italy, identifying individuals diagnosed with cannabis use disorder from 2009-2019 and tracking their emergency department visits for suicide attempts through the same period.","limitations":"Observational study that cannot establish whether cannabis use disorder causes elevated suicide risk or both share common underlying factors (depression, trauma, other psychiatric conditions). ICD coding may not capture all cannabis use disorders. Single Italian metro area. Cannot distinguish between cannabis and concurrent substance use effects on suicide risk."},{"rthcId":"RTHC-07329","title":"Quantification of ∆9-tetrahydrocannabinol, 11-OH-THC, THC-COOH, hexahydrocannabinol, and cannabidiol in human plasma and blood by liquid chromatography-tandem mass spectrometry.","authors":"Pavlic, Marion; Innerhofer, Carolin; Pitterl, Florian","year":2025,"journal":"Journal of analytical toxicology, 49(2), 85-95","doi":"10.1093/jat/bkae094","pmid":"39656878","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07330","title":"Development and evaluation of a method to compile a national list of cannabis dispensaries.","authors":"Pearson, Jennifer L; Borges, Luciana; Darrow, Lyndsey A; Nippler, Grant; Friedman, Abigail S","year":2025,"journal":"Drug and alcohol dependence, 277, 112964","doi":"10.1016/j.drugalcdep.2025.112964","pmid":"41270716","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07331","title":"Marijuana policy and tribal communities in the United States.","authors":"Pedersen, Daphne E","year":2025,"journal":"Journal of public health policy, 46(3), 653-662","doi":"10.1057/s41271-025-00572-y","pmid":"40451938","tags":["legalization","youth","addiction","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Tribal communities face a uniquely complex cannabis policy landscape: tribes may legalize or criminalize cannabis independently but may be located within states with opposing policies. Native American and Alaska Native youth have notably higher rates of marijuana use and dependence compared to the overall U.S. population. The paper advocates for community-led, culturally grounded public health responses.","whyItMatters":"Tribal communities are making consequential cannabis policy decisions without the public health infrastructure or research base that informs state-level decisions. Higher baseline rates of cannabis use and dependence among Native youth make these policy choices especially impactful.","specificNumbers":"Native American and Alaska Native youth have higher rates of marijuana use and dependence compared to the general U.S. population. Tribal cannabis policy operates across federal, state, and tribal jurisdictions with potentially conflicting regulations.","methodology":"Policy review examining the history and current landscape of marijuana regulation in U.S. tribal communities, associated health concerns for American Indian and Alaska Native populations, and considerations for tribal sovereignty in cannabis policy decisions.","limitations":"Narrative policy review without new empirical data. Treats diverse tribal communities as a broad category when policies and needs vary significantly between tribes. Does not provide specific data on tribal cannabis sales or revenue impacts."},{"rthcId":"RTHC-07332","title":"Alcohol use disorder, cannabis use disorder, and eating disorder symptoms among male and female college students.","authors":"Pedersen, Eric R; Shute, Ireland M; Buch, Keegan D; Fitzke, Reagan E; Berry, Katherine A; Tran, Denise D; Murray, Stuart B","year":2025,"journal":"The American journal on addictions, 34(1), 40-49","doi":"10.1111/ajad.13634","pmid":"39152742","tags":["addiction","mental-health","youth","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"About one-third (32.4%) of the sample screened positive for an eating disorder. Screening positive was associated with cannabis use frequency and cannabis use disorder symptoms, but not alcohol outcomes. Sex moderated the cannabis use disorder association: male students who screened positive for eating disorders had the highest cannabis use disorder symptoms, a counterintuitive finding given that eating disorders are more common in females.","whyItMatters":"Eating disorders in males are often underdiagnosed and undertreated. The finding that male students with eating disorder symptoms have particularly high cannabis use disorder rates suggests that screening for one condition should prompt assessment for the other, especially in male college students.","specificNumbers":"N=471 college students. 32.4% screened positive for eating disorder. Females more likely to screen positive for ED. Males more likely to screen positive for alcohol or cannabis use disorder. ED associated with cannabis frequency and CUD symptoms (not alcohol). Sex moderated ED-CUD relationship: males with positive ED screen had highest CUD symptoms.","methodology":"Cross-sectional study of 471 college students recruited for a study on high-risk drinking (regular pregaming required). Eating disorder screening, alcohol use disorder, and cannabis use disorder assessments were completed, with sex-stratified analyses.","limitations":"Sample selected for high-risk drinking (pregaming), which may not represent all college students. Cross-sectional design cannot determine directionality. Self-report measures. Cannot determine whether cannabis use is a cause, consequence, or co-occurring condition with eating disorders."},{"rthcId":"RTHC-07333","title":"Acute cannabidiol treatment reverses behavioral impairments induced by embryonic valproic acid exposure in male mice.","authors":"Pedrazzi, J F C; Sales, A J; Ponciano, R S M; Ferreira, L G; Ferreira, F R; Campos, A C; Hallak, J E C; Zuardi, A W; Del Bel, E A; Guimarães, F S; Crippa, J A","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 247, 173919","doi":"10.1016/j.pbb.2024.173919","pmid":"39615556","tags":["cbd","neuroscience","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In mice prenatally exposed to valproic acid (a model of autism), acute CBD at 30-60 mg/kg reversed pre-pulse inhibition deficits, decreased repetitive marble-burying, improved social interaction time, and restored object recognition memory. CBD at 60 mg/kg was effective across most tests but did not reduce stereotyped-like movements.","whyItMatters":"Autism spectrum disorder has limited treatment options, and many families report using CBD for their children. This preclinical study provides mechanistic support for CBD's potential to address multiple domains of autism-related behavior, particularly social deficits and cognitive impairment.","specificNumbers":"CBD doses: 30 and 60 mg/kg. VPA dose: 500 mg/kg at embryonic day 12. Five behavioral tests. CBD reversed PPI deficits (both doses), reduced marble burying (60 mg/kg), improved social interaction (60 mg/kg), restored novel object recognition (both doses). Failed to reduce stereotyped movements.","methodology":"Animal study using the valproic acid (VPA) autism model in mice. Adult mice (8 weeks old) exposed to VPA prenatally received acute CBD (30 or 60 mg/kg) and were tested across five behavioral paradigms: pre-pulse inhibition, marble burying, social interaction, activity, and novel object recognition.","limitations":"Animal model using synthetic autism induction (VPA) may not capture the full complexity of human autism. Only acute, single-dose administration tested. Male mice only. Cannot determine long-term efficacy or safety. Doses used are high relative to typical human clinical doses."},{"rthcId":"RTHC-07334","title":"Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer's disease revealed by PET imaging with [18F]FMPEP-d 2 and [18F]MAGL-2102.","authors":"Pees, Anna; Morrone, Christopher Daniel; Tong, Junchao; Rong, Jian; Shao, Tuo; Wear, Darcy; Liang, Steven H; Yu, Wai Haung; Vasdev, Neil","year":2025,"journal":"Theranostics, 15(8), 3368-3385","doi":"10.7150/thno.106592","pmid":"40093888","tags":["neuroscience","seniors","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"PET imaging revealed dynamic changes in cannabinoid receptor 1 (CB1) and MAGL enzyme availability across Alzheimer's disease progression. At 4 months (early-stage), female AD mice had lower CB1 availability while males had increased MAGL. By 12 months (late-stage), CB1 was significantly reduced in AD mice compared to controls. The pattern of changes was consistently sex-dependent throughout disease progression.","whyItMatters":"The endocannabinoid system is a potential therapeutic target for Alzheimer's, but this study shows its changes are complex, varying by sex, age, and disease stage. This means cannabinoid-based therapies for Alzheimer's may need to be tailored to the patient's sex and disease stage to be effective.","specificNumbers":"4 months: females had lower CB1, males had increased MAGL. 8 months: MAGL reduced in AD frontal cortex, males had higher MAGL than females brain-wide. 12 months: significantly lower CB1 in AD vs controls. MAGL PET imaging responsive to JZL184 inhibitor.","methodology":"PET-CT imaging study using two radioligands ([18F]FMPEP-d2 for CB1 and [18F]MAGL-2102 for MAGL) in a knock-in Alzheimer's mouse model at 3 ages (4, 8, and 12 months). Findings were supplemented with autoradiography, immunofluorescence, and western blots.","limitations":"Mouse model of Alzheimer's that may not fully recapitulate human disease. PET radioligand binding reflects availability, not necessarily function. Relatively small group sizes typical of PET imaging studies. Cannot directly translate timing of mouse disease stages to human disease progression."},{"rthcId":"RTHC-07335","title":"A comparison of the prevalence of cannabis and alcohol use among drivers and passengers in British Columbia and Ontario, Canada.","authors":"Pei, Lulu X; Chan, Herbert; Besserer, Floyd; Eppler, Jeffrey; Lee, Jacques; MacPherson, Andrew; McGrath, Michael; Ohle, Robert; Taylor, John; Vaillancourt, Christian; Brubacher, Jeffrey R","year":2025,"journal":"Accident; analysis and prevention, 222, 108242","doi":"10.1016/j.aap.2025.108242","pmid":"40946545","tags":["driving"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"This study analyzed toxicology data from 3,004 drivers and 941 passengers who were moderately injured in motor vehicle accidents across British Columbia and Ontario. The researchers wanted to disentangle two effects: general cannabis availability (which would affect both drivers and passengers equally) from the specific deterrent effect of driving-under-the-influence laws (which should make drivers less likely to test positive than passengers).\n\nAlcohol showed the expected pattern: passengers had higher detection rates than drivers (aPR 1.22), consistent with the idea that DUI laws deter some people from drinking before driving (while passengers face no such deterrent). But THC showed no such difference—drivers and passengers were equally likely to test positive, at a rate of 12.4%.\n\nThis absence of a driver-passenger gap for THC is concerning. It suggests that cannabis-impaired driving laws aren't creating the same deterrent effect as alcohol DUI laws. Possible explanations: people may not realize cannabis impairs driving, may not fear detection (no reliable roadside test), or may not believe they'll be caught.\n\nThe similar prevalence of THC (12.4%) and alcohol (14.2%) among crash victims is itself noteworthy—cannabis is now rivaling alcohol as a substance detected in crash-injured people.","whyItMatters":"If cannabis driving laws aren't deterring use before driving the way alcohol laws do, that has direct implications for road safety policy. The finding suggests current cannabis-impaired driving enforcement—hampered by the lack of a reliable roadside test (see RTHC-00173)—isn't achieving the behavioral change that decades of alcohol enforcement have produced.","specificNumbers":"3,004 drivers + 941 passengers. Alcohol detection: 14.2%. THC detection: 12.4%. Passengers had higher alcohol than drivers (aPR 1.22). No driver-passenger difference for THC. 55.1% male, mean age 43.8.","methodology":"Chart review and toxicology data from an ongoing prospective study of moderately injured motor vehicle occupants in BC and Ontario. 3,004 drivers and 941 passengers. Log-binomial regression models for prevalence ratios. Approximately 55.1% male, mean age 43.8 years.","limitations":"Toxicology was performed on moderately injured crash victims, not a random sample of drivers—the subset involved in crashes may differ from all drivers. THC detection indicates recent use but not necessarily impairment at the time of the crash. BC and Ontario may not represent all of Canada or other countries. The driver-passenger comparison assumes passengers face no deterrent, which may not be entirely true (e.g., some passengers become drivers later)."},{"rthcId":"RTHC-07336","title":"Mindfulness-based relapse prevention for cannabis regular users: Finally outcomes of a randomized clinical trial.","authors":"Pélerin, Jean-Marc; Gegout, Thomas; Schwitzer, Thomas; Schwan, Raymund; Albuisson, Eliane; Gédor, Maud; Laprévote, Vincent; Bourgognon, François","year":2025,"journal":"L'Encephale, 51(5), 519-525","doi":"10.1016/j.encep.2024.11.014","pmid":"39922725","tags":["quitting","addiction","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"There was no significant difference between MBRP and treatment-as-usual groups on primary and secondary endpoints. However, among participants who attended all MBRP sessions, cannabis units consumed decreased significantly from week 1 to 8 (p<0.05), while the TAU group showed no significant reduction. After treatment (weeks 8-12), the MBRP group's consumption increased by 1.5 units compared to 3.4 in the TAU group, suggesting more durable effects.","whyItMatters":"Current cannabis cessation therapies are only moderately effective. Mindfulness-based approaches offer a non-pharmacological alternative that could be particularly appealing to people who prefer psychotherapy over medication. While this pilot study didn't reach significance, the trends suggest mindfulness deserves further investigation.","specificNumbers":"N=40 (20 per group). No significant between-group differences on primary endpoint. Treatment adherence significantly better in MBRP (p=0.01). MBRP group: significant within-group reduction weeks 1-8 (p<0.05). Post-treatment consumption increase: MBRP 1.5 units vs TAU 3.4 units (p=0.2, not significant).","methodology":"Randomized clinical trial (MACBETH project) comparing mindfulness-based relapse prevention (MBRP, N=20) to treatment as usual (TAU, N=20) for active cannabis users in France over 12 weeks.","limitations":"Very small sample (N=40) underpowered to detect between-group differences. No significant primary outcome. Open-label design. Active cannabis users, not necessarily treatment-seeking. French single-site study. No long-term follow-up beyond 12 weeks."},{"rthcId":"RTHC-07337","title":"Trends in substance use over 31 years in a large methadone maintenance treatment (MMT) clinic in Israel.","authors":"Peles, Einat; Adelson, Miriam; Schreiber, Shaul","year":2025,"journal":"Journal of psychiatric research, 191, 265-270","doi":"10.1016/j.jpsychires.2025.09.049","pmid":"41037969","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07338","title":"Cannabinoid Hyperemesis Syndrome: A Rising Complication.","authors":"Peles, Saar; Khalife, Roy; Magliocco, Anthony","year":2025,"journal":"Cureus, 17(2), e78958","doi":"10.7759/cureus.78958","pmid":"40091958","tags":["harm-reduction","addiction","appetite"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS is characterized by cyclical nausea, vomiting, and abdominal pain in chronic cannabis users, paradoxically caused by a drug known for anti-nausea effects. It is frequently misdiagnosed as cyclic vomiting syndrome. Hot showers/baths provide temporary relief. There has been a steady increase in CHS diagnoses in emergency departments. The pathogenesis is not fully understood but several mechanisms have been proposed.","whyItMatters":"As cannabis use increases globally, CHS is becoming a more common reason for emergency department visits. Many patients cycle through multiple ER visits and diagnostic workups before receiving the correct diagnosis, leading to unnecessary costs and continued suffering.","specificNumbers":"Over 100 biologically active cannabinoids in cannabis. CHS diagnoses increasing in emergency departments. Hot water immersion provides temporary symptom relief. Often misdiagnosed as cyclic vomiting syndrome.","methodology":"Narrative review summarizing the symptoms, pathogenesis, treatments, and differential diagnoses of cannabinoid hyperemesis syndrome, with attention to its increasing prevalence in emergency settings.","limitations":"Narrative review without systematic search methodology. The pathogenesis of CHS remains incompletely understood. Prevalence data are limited and likely underestimate the true burden of disease."},{"rthcId":"RTHC-07339","title":"The role of myocardial bridge of the left anterior descending artery in a sudden death of a ketamine and cannabis user. Addressing the uncertainties on the cause of death in a forensic pathologist's casework.","authors":"Pelletti, Guido; Bianchini, Simone; Mauro, Emanuela; Pascali, Jennifer Paola; Baldovini, Chiara; Damiani, Stefania; Pirani, Filippo; Pelotti, Susi","year":2025,"journal":"Legal medicine (Tokyo, Japan), 73, 102588","doi":"10.1016/j.legalmed.2025.102588","pmid":"39827729","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07340","title":"Genotypic Variation in Photosynthesis and Biomass Partitioning Underlies Agronomic Performance and Cannabinoid Profile in Cannabis sativa Under Drought.","authors":"Pena, Mateus M; Miranda, Felipe R; Ribeiro, Thiago O; Couto, Gustavo C S; Rocha, Sérgio B F; Martins, Samuel C V; DaMatta, Fábio M","year":2025,"journal":"Plants (Basel, Switzerland), 14(24)","doi":"10.3390/plants14243840","pmid":"41470722","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07341","title":"Fatty acid binding proteins 5 and 7 differentially modulate phenotypic response to acute Δ9-tetrahydrocannabinol in female mice.","authors":"Penman, Samantha L; Marion, Matthew; Hamilton, John; Clouse, Grace; Roeder, Nicole M; Owada, Yuji; Kagawa, Yoshiteru; Thanos, Panayotis K","year":2025,"journal":"Physiology & behavior, 299, 114999","doi":"10.1016/j.physbeh.2025.114999","pmid":"40517922","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07342","title":"Age- and sex-dependent participation of the endocannabinoid system in locomotion and risk assessment of an ADHD rat model.","authors":"Penna, Daniel Bussinger de Souza; Gumiéro Costa, Samara; Romão, Juliana Santos; da Costa Calaza, Karin; de Jesus Oliveira, Karen; Dos Santos Rodrigues, Alexandre; Pandolfo, Pablo","year":2025,"journal":"Pharmacology, biochemistry, and behavior, 248, 173969","doi":"10.1016/j.pbb.2025.173969","pmid":"39922504","tags":["neuroscience","youth","cognition","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"During adolescence, cannabinoid receptor activation aggravated hyperactivity and risky behaviors in ADHD model rats, with more pronounced effects in females. In adulthood, cannabinoid manipulation did not alter hyperactivity but worsened risk assessment. Gene expression of ECS components (CB1, CB2, FAAH, MAGL) was broadly increased in the prefrontal cortex of ADHD model animals.","whyItMatters":"Cannabis use is common among people with ADHD, sometimes as self-medication. This animal study suggests that cannabinoid receptor activation during adolescence could actually worsen ADHD-related behaviors, particularly in females, providing a cautionary note about adolescent cannabis use in the ADHD population.","specificNumbers":"Adolescent ADHD rats: cannabinoid activation aggravated hyperactivity and risky behaviors, more strongly in females. Adult ADHD rats: cannabinoid manipulation worsened risk assessment but not hyperactivity. ECS gene expression (CB1, CB2, FAAH, MAGL) broadly increased in ADHD model prefrontal cortex.","methodology":"Animal study using spontaneously hypertensive rats (SHR) as an ADHD model. Acute pharmacological manipulation of CB1 and CB2 receptors was performed during adolescence and adulthood. Locomotion and risk assessment were measured, and ECS gene expression and protein levels were analyzed in the prefrontal cortex.","limitations":"Used SHR rat model of ADHD, which has known limitations as an ADHD model. Acute pharmacological manipulation rather than chronic cannabis exposure. Direct CB1/CB2 agonists used, not THC. Cannot directly translate to human ADHD or cannabis use. Only examined two behavioral domains."},{"rthcId":"RTHC-07343","title":"Effects of pharmacological inhibition of fatty acid amide hydrolase on corticosterone release: a systematic review of preclinical studies.","authors":"Pereira, Christina F; Boileau, Isabelle; Kloiber, Stefan","year":2025,"journal":"Discover mental health, 5(1), 51","doi":"10.1007/s44192-025-00155-z","pmid":"40195219","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07344","title":"Assessing patient perceptions of off-label cannabidiol use for insomnia through sentiment analysis.","authors":"Pereira, Gabriel Rodrigues Coutinho; de Brito Mantuan, Altobelli; Dos Santos Oliveira, Julio Cesar; Fares, Gabriel Estevão Silva; Dos Santos Santiago Sá, Vitor Manoel; de Sousa, Valéria Pereira; Rodrigues, Carlos Rangel; Cabral, Lucio Mendes","year":2025,"journal":"Journal of cannabis research, 7(1), 94","doi":"10.1186/s42238-025-00306-7","pmid":"41257970","tags":["cbd","sleep"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"From 74,562 unique tweets, 25,005 were classified as relevant to CBD for insomnia. Topic modeling revealed 11 major themes including perceived efficacy for anxiety, pain, and insomnia, plus practical considerations like routines and product preferences. Sentiment analysis showed predominantly positive perceptions of CBD for insomnia. About 45% of related studies report positive effects on both anxiety and sleep.","whyItMatters":"While clinical trial evidence for CBD and insomnia is still limited, millions of people are already using CBD for sleep. This social media analysis captures real-world patient perceptions at scale, providing a complementary data source to traditional clinical research.","specificNumbers":"74,562 unique tweets collected, June 2018-January 2023. 25,005 classified as relevant. 11 major themes identified. Predominantly positive sentiment. ~45% of existing studies report positive effects on both anxiety and sleep outcomes.","methodology":"Sentiment analysis study collecting English-language tweets about CBD for insomnia from June 2018 to January 2023. A RoBERTa-based machine learning model classified tweets as relevant or noise. Topic modeling and sentiment analysis were performed on relevant tweets.","limitations":"Social media data are inherently biased toward people willing to share experiences publicly. Twitter/X users may not represent the broader CBD-using population. Sentiment analysis cannot measure actual treatment efficacy. Tweets may reflect placebo effects, marketing influence, or selection bias (positive experiences more likely to be shared)."},{"rthcId":"RTHC-07345","title":"Comparison of clinicopathologic findings and urine drug screen results in cannabis-positive and control dogs.","authors":"Pereira, Helder Camilo da Silva; Barbosa, Wesley Marinho Brandão; Venceslau, Mariana Ferreira; Guerra, Ricardo Romão; Carvalho, Lucas Rannier Ribeiro Antonino","year":2025,"journal":"Frontiers in veterinary science, 12, 1679400","doi":"10.3389/fvets.2025.1679400","pmid":"41445591","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07346","title":"In search of certainty beyond the cholinergic system: a systematic review of developmental chlorpyrifos exposure and neurotransmitter systems disruption in preclinical models.","authors":"Perez-Fernandez, Cristian; Ruiz-Sobremazas, Diego; Ruiz-Coca, Mario; Sánchez-Santed, Fernando; Morales-Navas, Miguel","year":2025,"journal":"Critical reviews in toxicology, 55(8), 751-776","doi":"10.1080/10408444.2025.2543405","pmid":"40839385","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07347","title":"From premorbid adjustment dimensions to clinical outcomes: Exploring environmental stress and epigenetic influences on first-episode schizophrenia phenotypes.","authors":"Pérez-Ramos, Anaid; Gonzalez-Segura, Àlex; Julià, Laura; García-Rizo, Clemente; Sánchez-Torres, Ana; Cavone, Vito; Zorrilla, Iñaki; Mané, Anna; Rodriguez-Jimenez, Roberto; Roldan, Alexandra; Pomarol-Clotet, Edith; Ibañez, Angela; Usall, Judith; Lobo, Antonio; Bioque, Miquel; Bernardo, Miquel; Cuesta, Manuel J; Parellada, Mara; González-Pinto, Ana; Berrocoso, Esther; Amoretti, Silvia; Mezquida, Gisela","year":2025,"journal":"Spanish journal of psychiatry and mental health","doi":"10.1016/j.sjpmh.2025.08.002","pmid":"41242552","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07348","title":"\"Modulatory role of baseline impulsivity on the acute and persistent effects of CB1 agonism on impulsive choice\".","authors":"Pérez-Valenzuela, Enzo; Azocar, Victor; Gräber-Martinez, Andrea; Vergés, Alvaro; Fuentealba Evans, José","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 2698811251355603","doi":"10.1177/02698811251355603","pmid":"40741841","tags":["neuroscience","cognition","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CB1/2 receptor agonist WIN 55,212-2 reduced impulsive choice in rats classified as highly impulsive but had no effect in low-impulsivity rats. The effect persisted for at least two weeks after the last injection. The CB1 antagonist rimonabant reversed the persistent effect, confirming it was mediated through cannabinoid receptors.","whyItMatters":"Impulsivity is a key risk factor for addiction and many psychiatric conditions. The finding that cannabinoid receptor activation selectively reduces impulsivity in highly impulsive individuals, without affecting those with normal impulsivity, suggests potential for personalized therapeutic approaches.","specificNumbers":"Doses: 0.1, 1, and 5 mg/kg WIN 55,212-2. High-impulsivity rats: significant reduction in impulsive choice. Low-impulsivity rats: no effect. Persistent effect: maintained 2 weeks after last injection. Rimonabant (1 mg/kg) reversed the persistent effect. Effect correlated with baseline impulsivity.","methodology":"Rats trained on a delay-discounting task were classified as high or low impulsivity at baseline. They received increasing doses (0.1, 1, and 5 mg/kg) of the CB1/2 agonist WIN 55,212-2 and were tested on the task. Two weeks after the last injection, they were retested with vehicle only, then with the CB1 antagonist rimonabant.","limitations":"Animal study using a synthetic CB1/2 agonist, not THC. Cannot directly translate to human impulsivity or cannabis use. Only male rats tested. Delay-discounting is one specific type of impulsivity that may not generalize to other forms. Mechanism of the persistent effect is not fully explained."},{"rthcId":"RTHC-07349","title":"Cannabinoids for Anxiety and Sleep Disturbances: A Scoping Review.","authors":"Perez, Juan G; LaMontagne, Liva G; Garcia, Gabriela A; Vaddiparti, Krishna; Gupta, Pranav S; Churba, Benjamin Z; Hossain, Ryan; Lopez-Quintero, Catalina","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 219-237","doi":"10.1159/000548890","pmid":"41384242","tags":["anxiety","sleep","cbd","medical-cannabis"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Of 29 studies meeting inclusion criteria, about 45% reported positive effects on both anxiety and sleep outcomes. CBD was the most commonly studied cannabinoid with the most consistent positive results. However, substantial heterogeneity in study design, cannabinoid types, dosing regimens, and outcome measures limited the ability to draw definitive conclusions or establish standardized dosing.","whyItMatters":"At least 60% of people with anxiety disorders also have sleep problems, and both conditions share physiological mechanisms. CBD's potential to address both simultaneously would be clinically valuable, but this review shows the evidence base needs more rigorous, standardized research to support clinical recommendations.","specificNumbers":"1,132 documents retrieved, 29 met inclusion criteria. ~45% reported positive effects on both anxiety and sleep. Scientific literature on medical cannabis for these conditions increased approximately 15-fold in the last decade. CBD was the cannabinoid with the most consistent evidence.","methodology":"Scoping review searching PubMed, EMBASE, Cochrane, CINAHL, LILACS, and PsycINFO. From 1,132 retrieved documents, 29 met inclusion criteria, including RCTs, observational studies, and case series. Quality assessment was conducted for each study.","limitations":"Scoping review has inherent limitations compared to systematic reviews with meta-analysis. Heterogeneous study designs prevent quantitative pooling of results. Many included studies were small or observational. Positive publication bias may inflate the apparent efficacy."},{"rthcId":"RTHC-07350","title":"Discrimination experiences and problematic alcohol and cannabis use in young adulthood.","authors":"Perez, Lilian G; Troxel, Wendy M; Tucker, Joan S; Dunbar, Michael S; Rodriguez, Anthony; Klein, David J; D'Amico, Elizabeth J","year":2025,"journal":"The American journal on addictions, 34(1), 30-39","doi":"10.1111/ajad.13632","pmid":"38978344","tags":["addiction","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Race-based and gender-based discrimination, as well as experiencing multiple types of discrimination, were associated with worse cannabis use outcomes including more consequences, higher use disorder scores, and more solitary use. Interestingly, race-based discrimination was associated with fewer alcohol consequences and lower AUDIT scores. Sexual orientation-based discrimination was not significantly associated with substance use outcomes.","whyItMatters":"Discrimination is increasingly recognized as a social determinant of health, but its relationship with cannabis use specifically has been understudied. This study suggests that experiencing discrimination may drive people toward cannabis use as a coping mechanism, particularly through solitary use, which is a marker of more problematic consumption.","specificNumbers":"N=2,303 young adults, mean age 24.7. 47% Latinx/o, 22% Asian, 22% sexual/gender diverse, 56% female. 46% reported up to 4 discrimination types. 27% reported race-based, 26% gender-based, 5% sexual orientation-based discrimination. Race- and gender-based discrimination linked to worse cannabis outcomes. Race-based discrimination linked to fewer alcohol problems.","methodology":"Cross-sectional analysis of 2,303 young adults (mean age 24.7) predominantly in southern California. Associations between perceived everyday discrimination experiences (race-, gender-, and sexual orientation-based) and self-reported alcohol and cannabis use outcomes were examined.","limitations":"Cross-sectional design cannot establish whether discrimination leads to cannabis use or other causal pathways. Self-reported discrimination and substance use. Southern California sample may not generalize nationally. Cannot control for all potential confounders. Solitary use was self-reported."},{"rthcId":"RTHC-07351","title":"Selective blockade of cannabinoid receptors influences motoneuron survival and glial responses after neonatal axotomy.","authors":"Perez, Matheus; Barroso Spejo, Aline; Bortolança Chiarotto, Gabriela; Silveira Guimarães, Francisco; Leite Rodrigues de Oliveira, Alexandre; Politti Cartarozzi, Luciana","year":2025,"journal":"Neuroscience, 565, 265-276","doi":"10.1016/j.neuroscience.2024.10.051","pmid":"39481830","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07352","title":"Priming Canine Adipose Tissue-Derived Mesenchymal Stem Cells with CBD-Rich Cannabis Extract Modulates Neurotrophic Factors Expression Profile.","authors":"Perino, Vinicius Skau; Ferreira, Lucas Vinícius de Oliveira; Kamura, Beatriz da Costa; Chimenes, Natielly Dias; Olbera, Alisson Vinícius Gimenes; Pereira, Thiago Tourinho; Braz, Aline Márcia Marques; Golim, Marjorie de Assis; Carvalho, Márcio de; Amorim, Rogério Martins","year":2025,"journal":"Veterinary sciences, 12(10)","doi":"10.3390/vetsci12100926","pmid":"41150065","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07353","title":"Cannabis involvement in posttraumatic stress disorder emergency department visits after cannabis legalization.","authors":"Perrault-Sequeira, Laurent; Pugliese, Michael; MacDonald-Spracklin, Rachael; Xiao, Jennifer; McCarthy, Stephen; Myran, Daniel T","year":2025,"journal":"The American journal on addictions, 34(4), 404-414","doi":"10.1111/ajad.70014","pmid":"40023770","tags":["ptsd","legalization","addiction","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 381,450 PTSD ED visits in Ontario, cannabis co-involvement increased by 151% (from 0.13 to 0.33 per 100,000) between the first and last cannabis policy periods, while alcohol co-involvement increased by 58%. However, the increase was a steady upward trend not clearly tied to specific policy changes, suggesting normalization and increased access rather than legalization itself drove the increase.","whyItMatters":"People with PTSD are at elevated risk for cannabis use disorder. This population-level data shows that as cannabis access expanded, cannabis-related complications in PTSD patients grew substantially faster than alcohol-related complications, highlighting a population that may need targeted intervention.","specificNumbers":"381,450 PTSD ED visits. 4,593 (1.29%) co-involved cannabis. 11,625 (3.05%) co-involved alcohol. Cannabis co-involvement: IRR 2.51 (151% increase, 0.13 to 0.33 per 100,000). Alcohol co-involvement: IRR 1.58 (58% increase). No significant association between specific policy periods and cannabis trend.","methodology":"Repeated cross-sectional study using Ontario health administrative data identifying all ED visits for PTSD among residents aged 10-105 from 2008-2022 (15.7 million total). Cannabis and alcohol co-diagnoses were tracked across four cannabis policy periods, analyzed using Poisson models.","limitations":"Administrative data using ICD codes may undercount both cannabis involvement and PTSD. Cannot determine whether cannabis contributed to the ED visit or was incidentally documented. Cannot assess whether patients were using cannabis therapeutically or recreationally. Ontario-specific findings."},{"rthcId":"RTHC-07354","title":"Caregiver-reported non-seizure and seizure outcomes with cannabidiol and clobazam in patients aged ≥2 years with Lennox-Gastaut syndrome or Dravet syndrome: A subgroup analysis of the BECOME survey.","authors":"Perry, M Scott; Dixon-Salazar, Tracy; Meskis, Mary Anne; Danese, Sherry R; Saurer, Timothy B; Vyas, Kishan; Berg, Anne T","year":2025,"journal":"Seizure, 130, 32-40","doi":"10.1016/j.seizure.2025.04.017","pmid":"40354745","tags":["cbd","epilepsy","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Caregivers reported improvements across multiple domains: seizure frequency (87%), severity (81%), alertness/cognition/executive function (84%), language/communication in non-verbal patients (81%) and verbal patients (76%), emotional/social functioning (79%), daily activities (56%), physical functioning (44%), and sleep (56%). 94% planned to continue CBD treatment. Some worsening was noted in 4-26% of caregivers across domains.","whyItMatters":"While CBD's seizure-reducing effects are well established, this survey captures the broader quality-of-life improvements that caregivers observe but clinical trials may miss. The high rates of cognitive and communication improvement suggest CBD may benefit brain function beyond just seizure control in these populations.","specificNumbers":"N=243 (76% LGS, 24% DS, 52% male, mean age 15). Median CBD dose: 14 mg/kg/day. Median 4 other ASMs. Improvements: seizures 87%, severity 81%, cognition 84%, non-verbal communication 81%, verbal communication 76%, emotional/social 79%, daily activities 56%, sleep 56%, physical 44%. 94% planned to continue. 4-26% reported some worsening.","methodology":"Subgroup analysis of the BECOME survey, collecting caregiver-reported outcomes for 243 patients with LGS or Dravet syndrome aged 2+ years receiving CBD (Epidiolex) with concomitant clobazam for at least 3 months.","limitations":"Caregiver-reported survey data without objective measurements. No control group for comparison. Potential recall bias comparing current status to pre-CBD initiation. Patients were already on CBD for 3+ months, creating survivorship bias (those who stopped are excluded). Funded by the manufacturer."},{"rthcId":"RTHC-07355","title":"Adolescent CB1 receptor expression at the BLA and CA1 and acute AM251 effects on sociability and emotional memory are sex-specific, and not modulated by heterotypic stress exposure.","authors":"Person, Emmanuelle; Plamondon, Hélène","year":2025,"journal":"Behavioural brain research, 493, 115704","doi":"10.1016/j.bbr.2025.115704","pmid":"40523407","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07356","title":"Enhanced Antibacterial and Anti-Inflammatory Activities of the Combination of Cannabis sativa and Propolis Extracts: An In Vitro Study.","authors":"Perstwong, Naruemon; Phongsopitanun, Wongsakorn; Buranasudja, Visarut; Vimolmangkang, Sornkanok","year":2025,"journal":"International journal of molecular sciences, 26(22)","doi":"10.3390/ijms262211181","pmid":"41303662","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07357","title":"Real-world efficacy and safety of cannabidiol in developmental and epileptic encephalopathies.","authors":"Perulli, Marco; Bianchetti, Maddalena; Pantalone, Gloria; Quintiliani, Michela; Gambardella, Maria Luigia; Picilli, Maria; Marini, Carla; Cesaroni, Elisabetta; Battaglia, Domenica Immacolata","year":2025,"journal":"Epilepsia open, 10(6), 1806-1813","doi":"10.1002/epi4.70149","pmid":"41165013","tags":["cbd","epilepsy","medical-cannabis","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Clinical trials establish whether a drug works under ideal conditions. Real-world studies reveal how it performs in actual clinical practice—with diverse patients, varied medication regimens, and imperfect adherence. This study fills that gap for CBD in severe epilepsy.\n\nOne hundred seven patients with developmental and epileptic encephalopathies (DEEs) were treated with pharmaceutical CBD for at least 3 months between 2020 and 2024. The cohort included approved indications (Lennox-Gastaut, Dravet, tuberous sclerosis complex) and off-label uses in other DEEs.\n\nAt a median follow-up of 20 months, 69% achieved at least 50% seizure reduction—a strong real-world result. Twenty-one percent achieved 75% or greater reduction. These numbers are encouraging given that all patients were, by definition, treatment-resistant (having failed multiple prior medications).\n\nTwo findings stood out for personalizing treatment. First, patients with LGS, TSC, and other DEEs showed higher efficacy and retention than Dravet syndrome patients—surprising given that Dravet was one of the original FDA-approved indications. Second, genetic or unknown etiology predicted better outcomes (p = 0.011), suggesting that the underlying cause of epilepsy matters for CBD response.\n\nThe combination of CBD with valproate was associated with specific side effect considerations that required clinical management.","whyItMatters":"Real-world data like this helps clinicians set realistic expectations. The 69% responder rate is strong but also means 31% didn't achieve meaningful seizure reduction—knowing who is most likely to respond (genetic etiology, LGS/TSC) can inform treatment decisions. The off-label data in \"other DEEs\" also expands the evidence base beyond the three FDA-approved syndromes.","specificNumbers":"N = 107. Median follow-up: 20 months. 69% achieved ≥50% seizure reduction. 21% achieved ≥75% reduction. LGS: 55.1%, Dravet: 16.8%, TSC: 8.4%, other DEEs: 19.6%. Genetic etiology: 56.1%. Genetic/unknown etiology associated with better outcomes (p = 0.011).","methodology":"Retrospective study of 107 patients with DEEs treated with CBD for ≥3 months (2020–2024). Diagnoses: LGS (55.1%), Dravet (16.8%), TSC (8.4%), other DEEs (19.6%). Genetic etiology in 56.1%. Data on seizure frequency, tolerability, retention, and non-seizure outcomes. Efficacy defined as ≥50% or ≥75% seizure reduction. Statistical analysis of predictors of response.","limitations":"Retrospective design with inherent biases (treatment decisions weren't randomized). No control group—some improvement may reflect natural seizure fluctuation. Single-center experience. The 3-month minimum treatment duration excludes early discontinuations (potentially biasing toward responders). Seizure counting relies on caregiver observation, which can be imprecise."},{"rthcId":"RTHC-07358","title":"Epilepsy, neuroinflammation and cannabidiol What do we know thus far?","authors":"Pesántez Ríos, Gabriela; Perucca, Emilio; Striano, Pasquale; Caraballo, Roberto; Pesántez Ríos, Ximena; Pascual-Pascual, S I; Pesántez Cuesta, Galo","year":2025,"journal":"Frontiers in pharmacology, 16, 1749260","doi":"10.3389/fphar.2025.1749260","pmid":"41560741","tags":["cbd","epilepsy","neuroscience","medical-cannabis","inflammation"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"One of the challenges in understanding CBD's anti-seizure action is that it doesn't work through a single, clean mechanism the way most drugs do. This review maps the multiple pathways through which CBD appears to reduce seizures, with particular attention to neuroinflammation.\n\nAbout one-third of epilepsy patients are resistant to conventional medications, many of which work through a single mechanism (usually enhancing GABA signaling). CBD's multi-target approach may explain why it helps some patients who don't respond to these drugs.\n\nThe neuroinflammation connection is especially interesting. Inflammation in the brain isn't just a consequence of seizures—it's now understood to be part of what causes them (epileptogenesis). CBD reduces neuroinflammation through immunomodulatory effects, potentially breaking the cycle where seizures cause inflammation which causes more seizures.\n\nBeyond inflammation, CBD modulates the endocannabinoid system, adenosine receptors (involved in neural excitability), GPR55 receptors (recently linked to seizure activity), and TRPV1 channels (which regulate calcium signaling in neurons). It also reduces oxidative stress, which damages neurons and contributes to seizure susceptibility.\n\nThe FDA approved purified CBD (Epidiolex) in 2018 for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. This review provides the mechanistic foundation for understanding why it works and why it might work for other neurological conditions too.","whyItMatters":"Understanding how CBD works—not just that it works—is crucial for two reasons. First, it guides which patients might respond best (those whose epilepsy involves neuroinflammation may be particularly good candidates). Second, it identifies targets for developing more potent or selective next-generation drugs that build on CBD's multi-mechanism approach.","specificNumbers":"~33% of epilepsy patients are treatment-resistant. CBD modulates: endocannabinoid system, adenosine receptors, GPR55 receptors, TRPV1 channels. Epidiolex approved 2018 for LGS, Dravet, and TSC.","methodology":"Narrative review focused on CBD's activity as a neuroinflammatory modulator and antiseizure agent. Synthesizes in vitro, in vivo, and clinical evidence on CBD's mechanisms of action in epilepsy. Covers endocannabinoid, adenosine, GPR55, TRPV1, and inflammatory pathways.","limitations":"Many mechanistic findings come from cell culture and animal models that may not fully translate to human epilepsy. The multi-target nature of CBD makes it difficult to determine which mechanisms are most clinically important. The review focuses on anti-seizure mechanisms but CBD may also have pro-seizure effects under some conditions. Narrative review format is subject to author selection bias."},{"rthcId":"RTHC-07359","title":"The association between state cannabis policies and cannabis use among adults and youth, United States, 2002-2019.","authors":"Pessar, Seema Choksy; Smart, Rosanna; Naimi, Tim; Lira, Marlene; Blanchette, Jason; Boustead, Anne; Pacula, Rosalie Liccardo","year":2025,"journal":"Addiction (Abingdon, England), 120(1), 164-170","doi":"10.1111/add.16663","pmid":"39300729","tags":["legalization","youth","harm-reduction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Using the Cannabis Policy Scale, a comprehensive measure of 17 state cannabis policy areas, more restrictive policies were significantly associated with lower past-month cannabis use. A 10 percentage-point increase in restrictiveness reduced adult use by 0.87-1.04 percentage points and youth use by 0.17-0.21 percentage points. The association held across multiple model specifications.","whyItMatters":"As states rapidly liberalize cannabis policies, this is among the most comprehensive analyses of how the full spectrum of cannabis regulations (not just legalization status) relates to use. The finding that policy restrictiveness matters for both adults and youth provides evidence for policymakers weighing liberalization against public health.","specificNumbers":"10-point CPS increase (more restrictive) associated with: overall use reduction of 0.81-0.97 percentage points (ages 12+), adult reduction of 0.87-1.04 points (18+), youth reduction of 0.17-0.21 points (12-17). Data span 2002-2019. CPS measures 17 policy areas.","methodology":"Repeated cross-sectional time series analysis using National Survey on Drug Use and Health state estimates from 2002-2019, linked to the Cannabis Policy Scale (CPS), which measures 17 policy areas weighted by efficacy and implementation. Three model specifications with state and year fixed/random effects.","limitations":"Observational study cannot establish that policies caused the use changes. Cannot rule out reverse causation (states with lower use may adopt more restrictive policies). Self-reported cannabis use. CPS weights are expert-assigned and may not perfectly capture policy impact. Period ends in 2019, missing recent policy changes."},{"rthcId":"RTHC-07360","title":"Effects of cannabidiol on behavioral and psychological symptoms of vascular dementia: A randomized, double-blind, placebo-controlled clinical trial.","authors":"Pessoa, Rebeca Mendes P; Zuardi, Antonio Waldo; Martins-Filho, Rui Kleber V; Rodrigues, Guilherme Riccioppo; Hallak, Jaime E C; Crippa, José Alexandre S; Pontes-Neto, Octavio Marques; Chagas, Marcos Hortes N","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 2698811251390974","doi":"10.1177/02698811251390974","pmid":"41277041","tags":["cbd","seniors","cognition","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"CBD (300 mg/day for 4 weeks) significantly reduced scores on both the Neuropsychiatric Inventory (NPI, p=0.05) and the Brief Psychiatric Rating Scale (BPRS, p<0.05) compared to placebo. No significant differences were found in cognitive measures (MMSE) or functional outcomes (Katz Index, Lawton Scale). Adverse events were mild and similar between groups.","whyItMatters":"Behavioral and psychological symptoms of dementia (BPSD) are extremely distressing for patients and caregivers, and current treatments have limited efficacy and significant side effects. CBD showed meaningful symptom reduction without the cognitive dulling or falls risk associated with antipsychotics commonly used for BPSD.","specificNumbers":"N=30 vascular dementia patients. CBD dose: 300 mg/day for 4 weeks. NPI improvement: F=3.61, p=0.05, partial eta squared=0.11. BPRS improvement: F=4.02, p<0.05, partial eta squared=0.13. No cognitive or functional changes. Mild, similar adverse events in both groups.","methodology":"Randomized, double-blind, placebo-controlled trial of 30 patients with vascular dementia and clinically significant behavioral and psychological symptoms. Patients received CBD 300 mg/day or placebo for 4 weeks.","limitations":"Very small sample (N=30) with only 4 weeks of treatment. Single dose tested. Cannot determine optimal dose or long-term safety. Vascular dementia is heterogeneous, and the sample may not represent all subtypes. Brazilian single-site study."},{"rthcId":"RTHC-07361","title":"Changes in blood cannabinoid concentrations over multiple collection times in driving under the influence of drugs casework.","authors":"Peterson, Brianna L; Hessler, Meaghan R","year":2025,"journal":"Journal of analytical toxicology, 49(8), 576-586","doi":"10.1093/jat/bkaf052","pmid":"40478690","tags":["driving","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"In 35 DUID cases with multiple blood draws (81 total samples), THC concentrations ranged from 0.74 to 40 ng/mL. Notably, 11 samples showed an increase in THC concentration at a later collection time point, which undermines the assumption that THC levels consistently decline after use. Collection times ranged from 32 minutes to over 12 hours after the incident.","whyItMatters":"Many jurisdictions set per se THC limits for driving, similar to blood alcohol limits. This study demonstrates a fundamental problem with that approach: unlike alcohol, THC blood levels do not reliably decline in a predictable pattern, making it impossible to back-calculate the level at the time of driving.","specificNumbers":"35 cases, 81 samples. THC range: 0.74-40 ng/mL. 11-OH-THC range: 1.0-16 ng/mL (60 samples). THC-COOH range: 7.1-470 ng/mL. Collection times: 00:32-12:42 hours post-incident. 11 samples (13.6%) showed THC increase at a later time point.","methodology":"Retrospective analysis of cannabinoid-positive driving under the influence cases from 2019-2023 that had multiple blood draws. Samples were analyzed using LC-MS/MS with reporting limits of 0.5 ng/mL for THC, 1.0 ng/mL for 11-OH-THC, and 5.0 ng/mL for THC-COOH.","limitations":"Relatively small sample (35 cases). Cannot control for subjects' cannabis use between blood draws in all cases. No information on the specific cannabis products used, route of administration, or chronic use history. Forensic casework data with inherent variability in collection timing and conditions."},{"rthcId":"RTHC-07362","title":"Cannabidiol as Modulator of Spontaneous Adipogenesis in Human Adipose-Derived Stem Cells.","authors":"Petrocelli, Giovannamaria; Pampanella, Luca; Abruzzo, Provvidenza Maria; Cruciani, Sara; Ventura, Carlo; Canaider, Silvia; Facchin, Federica","year":2025,"journal":"Molecules (Basel, Switzerland), 30(11)","doi":"10.3390/molecules30112367","pmid":"40509260","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07363","title":"Stress-Buffer-Hypothesis: blood endocannabinoids in healthy males under standardized psychosocial stress induction and resting condition.","authors":"Petrowski, Katja; Bindila, Laura; Herhaus, Benedict; Gao, Wei; Conrad, Rupert","year":2025,"journal":"Translational psychiatry, 15(1), 517","doi":"10.1038/s41398-025-03742-4","pmid":"41285710","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07364","title":"Timing matters: modeling the effects of gestational cannabis exposure on social behavior and microglia in the developing amygdala.","authors":"Pham, Aidan L; Marquardt, Ashley E; Montgomery, Kristen R; Sobota, Karina N; McCarthy, Margaret M; VanRyzin, Jonathan W","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(11), 1655-1664","doi":"10.1038/s41386-025-02173-5","pmid":"40702164","tags":["pregnancy","cognition","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Cannabis is the most commonly used illicit drug during pregnancy, with rates rising as legalization expands. Many pregnant users consider it less harmful than pharmaceuticals or alcohol. This study tested a critical question: does the timing of THC exposure during development change the outcome?\n\nUsing a rat model designed to approximate different windows of human pregnancy, the researchers exposed developing animals to THC at either earlier or later gestational timepoints and examined effects on the amygdala—a brain region central to social behavior and emotion.\n\nThe focus was on microglia, the brain's resident immune cells. These cells do more than fight infection during development—they actively sculpt neural circuits by engulfing and eliminating synapses and cells through phagocytosis. The research group had previously shown that endocannabinoid signaling in the developing amygdala drives microglia to consume newborn astrocytes, a process with lasting consequences for the neural circuits that govern sex differences in social behavior.\n\nSince microglia express both CB1 and CB2 cannabinoid receptors, they're direct targets for THC. The key finding: THC exposure at different developmental windows produced distinct outcomes on microglial behavior and social functioning, paralleling what's known about fetal alcohol syndrome (where timing of alcohol exposure determines which organ systems are affected).","whyItMatters":"The \"timing matters\" finding has significant implications. If early-pregnancy THC exposure produces different brain effects than late-pregnancy exposure, broad advice to \"avoid cannabis during pregnancy\" may need to be refined with specific risk windows—similar to how alcohol's teratogenic effects vary by trimester. It also suggests that studies looking at prenatal cannabis exposure as a binary (yes/no) may be missing important nuance.","specificNumbers":"THC exposure at different gestational timepoints produced distinct effects on amygdala microglia and social behavior in rat offspring. Microglia express both CB1R and CB2R cannabinoid receptors.","methodology":"Animal study (rats) modeling human gestational cannabis exposure at different developmental timepoints. Examined effects on amygdala microglia (phagocytic activity, morphology) and social behavior outcomes. Built on prior work showing endocannabinoid-mediated microglial sculpting of amygdala circuits.","limitations":"Rat brain development doesn't perfectly map onto human gestation. THC doses in animal studies may not reflect typical human use patterns. The social behavior outcomes in rats are proxies for human social function. The prior work this builds on found sex differences, but this study's design details on sex-specific effects aren't fully described in the abstract. Translation from animal to human prenatal risk is always uncertain."},{"rthcId":"RTHC-07365","title":"Timing matters: modeling the effects of gestational cannabis exposure on social behavior and microglia in the developing amygdala.","authors":"Pham, Aidan L; Marquardt, Ashley E; Montgomery, Kristen R; Sobota, Karina N; McCarthy, Margaret M; VanRyzin, Jonathan W","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.02.17.638714","pmid":"40027715","tags":["pregnancy","youth","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Postnatal THC exposure (modeling late pregnancy) produced sex-specific changes in microglial phagocytosis during brain development and altered social behavior during the juvenile period. Prenatal THC exposure (modeling early pregnancy) produced inverse changes to both phagocytosis and social behavior compared to postnatal exposure. The effects were mediated through microglia, the brain's immune cells, which express both cannabinoid receptors.","whyItMatters":"Cannabis use during pregnancy is increasing, and many users assume earlier use is less harmful. This study suggests the timing of exposure during pregnancy matters enormously, with early and late exposure producing opposite developmental effects. This complicates any simple guidance about cannabis use during pregnancy.","specificNumbers":"Postnatal THC: sex-specific microglial phagocytosis changes and altered juvenile social behavior. Prenatal THC: inverse changes in both phagocytosis and social behavior. Effects mediated through CB1R and CB2R expressed on microglia in the developing amygdala.","methodology":"Animal study exposing rats to THC either prenatally (via dam injection, modeling early human pregnancy) or postnatally (via direct injection in early postnatal period, modeling late human pregnancy). Microglial phagocytosis in the amygdala and social behavior were measured.","limitations":"Animal model using direct THC injection, which differs from human cannabis use. Cannot directly translate rat developmental periods to human trimesters. Focused on amygdala and social behavior; other brain regions and behaviors were not assessed. Preprint, not yet peer-reviewed."},{"rthcId":"RTHC-07366","title":"Multilevel Risk and Protective Factors Influencing Cannabis Use Among Adolescents and Young Adults in the United States: A Systematic Review.","authors":"Phares, Belinda A; Driskill, Christie N; Basani, HimaBindu; Rodil, Aimee Rousella M; Barr, Emily Anne","year":2025,"journal":"Comprehensive child and adolescent nursing, 48(4), 278-306","doi":"10.1080/24694193.2025.2524680","pmid":"40663730","tags":["youth","addiction","harm-reduction","legalization"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Risk factors operated at every level: individual (older age, early initiation, low perceived harm, polysubstance use), interpersonal (peer influence, parental acceptance, family structure), community (neighborhood stress, social media, proximity to dispensaries), and societal (legalization, lower SES). Protective factors included peer disapproval, parental monitoring, school connectedness, and extracurricular involvement. Gender disparities in use are narrowing.","whyItMatters":"Effective cannabis prevention requires understanding that youth use is not driven by any single factor. This review maps the full landscape of influences using the Social Ecological Model, providing a framework for designing multi-level interventions rather than relying on individual-focused approaches alone.","specificNumbers":"15 studies meeting inclusion criteria. Risk factors at 4 levels: individual, interpersonal, community, societal. Key protective factors: peer disapproval, parental monitoring, school connectedness, extracurricular involvement. Gender use gap narrowing. Youth ages 12-26.","methodology":"Systematic review searching CINAHL, Medline (OVID), and PubMed (January 2019-September 2024) using PRISMA guidelines. 15 peer-reviewed, quantitative, U.S.-based studies of youth ages 12-26 met inclusion criteria. Analysis was guided by the Social Ecological Model.","limitations":"Only 15 studies met criteria, limiting the comprehensiveness of each ecological level. U.S.-only studies may not generalize internationally. Search limited to three databases. Studies from 2019-2024 reflect a specific policy era. Cannot determine the relative importance of different risk/protective factors."},{"rthcId":"RTHC-07367","title":"The role of cannabis in epilepsy illustrated by two case reports.","authors":"Philibert-Rosas, Santiago; Brace, Cameron J; Semia, Sanaa; Gidal, Barry E; Nix, Bradley T; Josiah, Anne F; Boly, Melanie; Struck, Aaron F","year":2025,"journal":"Epilepsy & behavior reports, 32, 100804","doi":"10.1016/j.ebr.2025.100804","pmid":"40688379","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07368","title":"Optimization of pH-responsive cannabidiol-loaded polyhydroxybutyrate/cellulose acetate phthalate microparticles using response surface methodology for anticancer properties.","authors":"Phothong, Natthaphat; Vimolmangkang, Sornkanok; Napathorn, Suchada Chanprateep","year":2025,"journal":"International journal of biological macromolecules, 329(Pt 2), 147758","doi":"10.1016/j.ijbiomac.2025.147758","pmid":"40997977","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07369","title":"Intravesical Cannabidiol for Inflammation and Pain in Interstitial Cystitis/Bladder Pain Syndrome via TLR4/NF-κB and TRPV1 Modulation.","authors":"Piao, Jun Jie; Kim, Soomin; Lee, Hwa Jong; Zhu, Guan Qun; Jeon, Kyung-Hwa; Park, Sang-Hyuck; Guan, Rui-Li; Tian, Wen Jie; Xin, Zhong Cheng; Kim, Sae Woong; Bae, Woong Jin","year":2025,"journal":"The world journal of men's health","doi":"10.5534/wjmh.250152","pmid":"41508393","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07370","title":"Examining dynamic patterns of problematic cannabis use: Results from a multilevel network analysis.","authors":"Piccirillo, Marilyn L; Enkema, Matthew C; Schwebel, Frank J; Canning, Jessica R; Bachowski, Diana; Larimer, Mary E","year":2025,"journal":"Journal of psychopathology and clinical science, 134(3), 298-307","doi":"10.1037/abn0000963","pmid":"40029319","tags":["addiction","mental-health","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Multilevel network analysis of 3,230 daily observations revealed consistent, clinically meaningful associations between socioenvironmental triggers (being around other users, availability) and cannabis cravings, use, and intoxication. Negative affect was statistically associated with cannabis use and positive affect with intoxication, but these emotional associations were not clinically meaningful in size. Coping strategies showed no meaningful association with cannabis use.","whyItMatters":"Many substance use treatments focus heavily on emotional coping, but this study suggests that for cannabis use, environmental and social triggers may matter more than mood states in daily life. This could shift clinical focus toward situational management strategies.","specificNumbers":"N=65 young adults, 3,230 observations. Mean CUDIT-R score: 10.38 (problematic use). Socioenvironmental triggers: nearly all clinically meaningful associations (bs>0.10) with cravings, use, and intoxication. Negative/positive affect: statistically significant but not clinically meaningful. Coping strategies: no clinically meaningful associations.","methodology":"Ecological momentary assessment study collecting 3,230 observations from 65 young adults with problematic cannabis use and interest in reducing use. Multilevel network analysis modeled associations among biopsychosocial factors aligned with social learning, self-medication, and experiential avoidance theories.","limitations":"Small sample (N=65) of young adults interested in reducing use, which may not represent all problematic users. Self-reported momentary assessments. Cannot establish causation from network analysis. Brief measures of affect and coping. Specific to problematic users, not casual users."},{"rthcId":"RTHC-07371","title":"Cannabinoid Hyperemesis Syndrome in Adolescents: A Narrative Review.","authors":"Pietrantoni, Camilla; Margiotta, Gaia; Marano, Giuseppe; Mazza, Marianna; Proli, Francesco; Stella, Giuseppe; Cherubino, Alessia; Viozzi, Francesca; Guida, Fabiana Rita; Rendeli, Claudia; Pola, Roberto; Gaetani, Eleonora; Giorgio, Valentina","year":2025,"journal":"Pediatric reports, 17(4)","doi":"10.3390/pediatric17040075","pmid":"40700063","tags":["youth","harm-reduction","appetite"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"CHS is increasingly being diagnosed in adolescents despite limited data in the pediatric population. The review highlights diagnostic challenges specific to younger patients, the limited efficacy of standard anti-emetic therapies (which often fail in CHS), and the central role of cannabis cessation as the only definitive treatment. Awareness among pediatricians and emergency physicians remains low.","whyItMatters":"With high rates of cannabis use among teenagers and increasing potency of cannabis products, CHS in adolescents is likely to become more common. The review highlights that pediatric cases often go through extensive and unnecessary diagnostic workups before CHS is recognized, adding cost and delay.","specificNumbers":"CHS first described in 2004. Increasing incidence parallels cannabis legalization. High rate of cannabis use among youth. Standard anti-emetics often ineffective. Cannabis cessation is the definitive treatment.","methodology":"Narrative review synthesizing epidemiology, pathophysiology, diagnosis, and management of CHS specifically in the pediatric population.","limitations":"Narrative review with no new data. Pediatric-specific data on CHS remain scarce. The pathophysiology is still not fully understood. Cannot estimate true prevalence in the adolescent population."},{"rthcId":"RTHC-07372","title":"The unmet need for cannabis use disorder treatment in multiple sclerosis: Insights from a nationwide pilot study.","authors":"Pilloni, Giuseppina; Pehel, Shayna; Ko, Timothy; Kreisberg, Erica; Sammarco, Carrie; Charlson, R Erik; Charvet, Leigh","year":2025,"journal":"Multiple sclerosis and related disorders, 98, 106443","doi":"10.1016/j.msard.2025.106443","pmid":"40267695","tags":["addiction","medical-cannabis","cognition"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"More than half of individuals with MS use cannabis, with up to 20% at risk for cannabis use disorder. While some report symptom relief (pain, sleep, mood), long-term use has been associated with poorer cognitive and emotional functioning, fatigue, and reduced quality of life. The pilot study's recruitment revealed significant demand for accessible interventions, highlighting an urgent unmet need.","whyItMatters":"MS patients who use cannabis often fall into a treatment gap: their neurologists may not screen for problematic use, and addiction specialists may not understand MS-specific considerations. This pilot study documents the demand for integrated treatment approaches.","specificNumbers":"Over 50% of MS patients use cannabis. Up to 20% at risk for CUD. Cannabis associated with poorer cognitive functioning, fatigue, and reduced quality of life in long-term MS users. Benefits reported for pain, sleep, and mood. Significant recruitment demand for the intervention.","methodology":"Nationwide pilot study recruiting women with MS and cannabis use disorder for a remotely supervised home-based intervention. The study report focuses on recruitment insights, cannabis use patterns, and the demand for treatment.","limitations":"Pilot study focused on recruitment insights rather than outcomes. Women only. Cannot determine causation for the associations between long-term cannabis use and poorer MS outcomes. Self-selected population may not represent all MS patients with CUD."},{"rthcId":"RTHC-07373","title":"Telehealth tDCS to reduce cannabis use: A pilot RCT in multiple sclerosis as a framework for generalized use.","authors":"Pilloni, Giuseppina; Pehel, Shayna; Ko, Timothy; Sammarco, Carrie; Charlson, R Erik; Hanlon, Colleen A; Charvet, Leigh","year":2025,"journal":"Drug and alcohol dependence, 272, 112706","doi":"10.1016/j.drugalcdep.2025.112706","pmid":"40378662","tags":["addiction","quitting","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"The active tDCS group showed significant reductions in weekly cannabis use (5.3 to 3.9 days, p=0.014) and withdrawal symptoms (CWS, p<0.001). A trend toward reduced MS symptoms was observed (p=0.031). The active group also showed significant cognitive improvement (p=0.011), while the sham group did not. 83% of participants completed the 20-session intervention.","whyItMatters":"There are no FDA-approved treatments for cannabis use disorder. This telehealth-delivered brain stimulation approach is novel, accessible, and showed promising results in a medically complex population. The home-based format overcomes mobility and transportation barriers common in MS.","specificNumbers":"N=52 randomized (31 active, 16 sham), 39 completed (83%). Age: 44 +/- 10 years. Active tDCS: cannabis use days reduced 5.3 to 3.9 (p=0.014). Withdrawal symptoms: p<0.001. MS symptoms trend: p=0.031. Cognitive improvement: active p=0.011 vs sham p=0.172. 20 sessions, 5 days/week, 4 weeks.","methodology":"Randomized, sham-controlled pilot trial of 52 women with MS and CUD. Active group received 20 sessions of home-based remotely supervised tDCS (2.0mA for 20 min targeting left DLPFC) paired with mindfulness meditation, 5 days/week for 4 weeks. Sham group received the same protocol without active stimulation.","limitations":"Small pilot study with more participants in the active than sham group (2:1 randomization). Women with MS only, limiting generalizability. Short 4-week intervention with no long-term follow-up. Cannot separate effects of tDCS from mindfulness meditation. Open-label mindfulness component."},{"rthcId":"RTHC-07374","title":"Full Spectrum Cannabis Oil for the treatment of chronic pain and sleep dysfunction in myofascial temporomandibular disorder: a case report.","authors":"Pinheiro, L V; Prado, E L L; Januzzi, M S; Issa, C T M I; Albuquerque, K L G D; Schiavon, J L O; Nunes, E G; Castro, R D; Pucci, F G; Alves, O J A; Turcio, K H L","year":2025,"journal":"Brazilian journal of biology = Revista brasleira de biologia, 85, e295805","doi":"10.1590/1519-6984.295805","pmid":"41092177","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07375","title":"Cannabidiol potentiates phenobarbital effects in the control of pentylenetetrazole (PTZ)-induced epileptic seizures in neonate rats.","authors":"Pinto, Lillian Soares; de Oliveira, Matheus Silva; Borges, Giovanna Bruno; de Castro, Olagide Wagner; Moreira, Fabrício de Araújo; Santos, Victor Rodrigues","year":2025,"journal":"Frontiers in pediatrics, 13, 1673345","doi":"10.3389/fped.2025.1673345","pmid":"41293208","tags":["cbd","epilepsy","drug-interactions","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Low CBD doses (3 and 30 mg/kg) had limited antiseizure effects alone, while higher doses (100 and 200 mg/kg) modestly reduced seizures. However, CBD at 30, 100, or 200 mg/kg significantly enhanced the efficacy of a sub-effective dose of phenobarbital (10 mg/kg), demonstrating dose-dependent potentiation. This synergistic effect could allow lower phenobarbital doses, reducing side effects.","whyItMatters":"Neonatal seizures are common and difficult to treat, with many newborns showing resistance to phenobarbital, the first-line treatment. CBD's ability to enhance phenobarbital's effects could allow effective seizure control at lower drug doses, potentially reducing the neurotoxic side effects associated with high-dose phenobarbital in developing brains.","specificNumbers":"CBD doses: 3, 30, 100, 200 mg/kg. PB doses: 3, 10, 30, 50, 75 mg/kg. PTZ: 100 mg/kg. CBD 30-200 mg/kg + PB 10 mg/kg: significant seizure reduction. CBD alone: modest effects only at 100-200 mg/kg. PB 10 mg/kg alone: sub-effective. P10 Wistar rats.","methodology":"Neonatal seizure model using 10-day-old Wistar rats. Rats were pretreated with phenobarbital (3-75 mg/kg) and/or CBD (3-200 mg/kg), then seizures were induced with subcutaneous PTZ (100 mg/kg). Seizure latency, duration, and severity were assessed.","limitations":"Animal model in 10-day-old rats, which may not directly translate to human neonatal seizures. Single seizure induction method (PTZ). Acute dosing only. High CBD doses used may not be achievable in neonates. No pharmacokinetic data on CBD-PB interaction in neonates."},{"rthcId":"RTHC-07376","title":"Cannabis use among adults who smoke tobacco: Relations with switching from combusted cigarettes to e-cigarettes or very low nicotine cigarettes.","authors":"Piper, Megan E; Kaye, Jesse T; Piasecki, Thomas M; Yang, James J; Buu, Anne","year":2025,"journal":"Drug and alcohol dependence, 275, 112821","doi":"10.1016/j.drugalcdep.2025.112821","pmid":"40803048","tags":["addiction","harm-reduction","quitting"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Participants who reported past-30-day cannabis co-use (N=56) smoked significantly more usual brand cigarettes during switch weeks than non-co-users (N=104, p=0.03) and were less likely to make a tobacco cessation attempt (p<0.05). This was true regardless of whether they were switching to very low nicotine cigarettes (VLNCs) or e-cigarettes.","whyItMatters":"Policies promoting switching from combustible cigarettes to reduced-harm alternatives (like e-cigarettes or VLNCs) may be less effective for cannabis co-users. Since about a third of the sample used both substances, this represents a substantial population that may need different tobacco cessation strategies.","specificNumbers":"N=160 (56 cannabis co-users, 104 non-co-users). Cannabis co-users smoked more usual brand cigarettes during switch weeks (p=0.03). Cannabis co-users less likely to attempt tobacco cessation (p<0.05). Data collected September 2019-June 2022.","methodology":"Secondary analysis of a mixed-design study. Adult cigarette smokers not motivated to quit were assigned study products (VLNCs, e-cigarettes, or no product) for 4 weeks and asked to switch from usual cigarettes during specific weeks. Active nicotine vs placebo patches were provided double-blind.","limitations":"Secondary analysis not powered for this specific question. Small cannabis co-use subgroup (N=56). Self-reported cannabis use at baseline only. Cannot determine whether cannabis use directly caused resistance to switching or whether both behaviors share common underlying factors. Not generalizable to motivated quitters."},{"rthcId":"RTHC-07377","title":"Randomized single-dose crossover comparative bioavailability study of two novel oral cannabidiol (CBD) formulations in healthy volunteers under fed conditions, compared to a standard CBD isolate capsule.","authors":"Pisak, Mehmet Nevzat; Bereket, Edibe; Erenmemisoglu, Aydin","year":2025,"journal":"Journal of cannabis research, 7(1), 54","doi":"10.1186/s42238-025-00312-9","pmid":"40770387","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07378","title":"Efficacy of cannabis oil on appetite and quality of life in systemic sclerosis patients: a randomized placebo-controlled trial.","authors":"Pisprasert, Veeradej; Sripanichkulchai, Bungon; Khannongpho, Teerawat; Jumnainsong, Amonrat; Mahakkanukrauh, Ajanee; Suwannaroj, Siraphop; Pongkulkiat, Patnarin; Onchan, Tippawan; Kanokmedhakul, Somdej; So-Ngern, Apichart; Foocharoen, Chingching","year":2025,"journal":"Journal of cannabis research, 7(1), 82","doi":"10.1186/s42238-025-00342-3","pmid":"41137182","tags":["medical-cannabis","appetite"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In a randomized placebo-controlled trial of 27 systemic sclerosis patients with anorexia or malnutrition, cannabis oil (two drops sublingual twice daily) showed trends toward greater improvements in appetite, body weight, calorie intake, and quality of life compared to placebo. Hunger VAS scores increased significantly in the treatment group (p < 0.001) but not in placebo.","whyItMatters":"Systemic sclerosis is a rare autoimmune condition that causes wasting and appetite loss, with few effective treatments. This is one of the first RCTs testing cannabis oil specifically in this population, and the significant improvement in hunger scores suggests cannabinoids may help with appetite in autoimmune wasting disorders beyond the better-studied cancer and HIV contexts.","specificNumbers":"27 patients enrolled (13 per group completed). 66.7% female. 77.9% had diffuse cutaneous SSc. Hunger VAS significantly increased in cannabis group (p < 0.001). One patient withdrew due to severe hyponatremia.","methodology":"Randomized placebo-controlled trial with 27 SSc patients (13 per group completing the study). Participants received either cannabis oil or placebo sublingually twice daily. Endpoints included appetite VAS, body weight, daily calorie intake, inflammatory markers, and quality of life via EQ-5D. Registered as NCT05416697.","limitations":"Very small sample size (N=27) limited statistical power. Most endpoints showed trends but did not reach significance. Single-center study. One serious adverse event (hyponatremia) occurred in the treatment group."},{"rthcId":"RTHC-07379","title":"Impact of the Kusa prevention program on cannabis consumption and emotional competencies among French Polynesian adolescents.","authors":"Pitel, Marion; Phan, Olivier; Bonnaire, Céline","year":2025,"journal":"Global health promotion, 32(1_suppl), 28-37","doi":"10.1177/17579759251317515","pmid":"41396152","tags":["youth","quitting","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Among 231 Polynesian middle and high school students, the Kusa prevention program improved emotional acceptance, awareness, verbalization, and impulse control in non-users and low-users. After the program, a larger proportion of participants reported generally not consuming cannabis during the day. Frequent users showed increased emotional verbalization but no significant change in consumption.","whyItMatters":"French Polynesia has one of the highest cannabis use rates among French territories, with early adolescent onset. This study shows that culturally adapted prevention programs targeting emotional skills can meaningfully shift behavior, especially when reaching youth before heavy use patterns develop.","specificNumbers":"231 students included. 57.8% girls. Mean age 15.0 years. Programs delivered in middle and high school settings. Three-month follow-up period.","methodology":"Quantitative longitudinal study with repeated measures (pre- and 3-month post-program) using standardized questionnaires. Classes were randomized into program participation or control groups. Sample of 231 students (57.8% girls, mean age 15.0). Results analyzed by level of cannabis use.","limitations":"Three-month follow-up is relatively short. No biological confirmation of cannabis use changes. Program effects were strongest in non-users and low-users, with limited impact on frequent users' consumption patterns."},{"rthcId":"RTHC-07380","title":"Prenatal Cannabis Use and Depressive Symptoms.","authors":"Pitt, Taylor L; Allshouse, Amanda A; Kim, Pilyoung; McMillin, Gwen; Silver, Robert M; Chung, Judith H; Grobman, William A; Haas, David M; Mercer, Brian M; Parry, Samuel; Reddy, Uma M; Saade, George R; Simhan, Hyagriv N; Metz, Torri D","year":2025,"journal":"Obstetrics and gynecology, 145(4), 417-425","doi":"10.1097/AOG.0000000000005860","pmid":"40014863","tags":["pregnancy","depression","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 8,424 pregnant women in the nuMoM2b study, any cannabis exposure was not significantly associated with later depressive symptoms (aOR 1.3, 95% CI 0.97-1.6). However, ongoing exposure beyond the first trimester was significantly associated with depressive symptoms at 22-29 weeks (aOR 1.6, 95% CI 1.2-2.2). Higher urine THC metabolite levels correlated with greater odds of depression.","whyItMatters":"This is one of the largest studies to use objective biomarker-confirmed cannabis exposure (urine testing rather than self-report) to examine the timing and dose relationship between prenatal cannabis use and depression. The finding that timing matters, with ongoing use being the key risk factor rather than any use, adds important nuance.","specificNumbers":"8,424 participants included. 6.4% (535) had cannabis exposure. 32.1% (172) had first-trimester-only exposure. 67.9% (363) had ongoing exposure. Ongoing use aOR 1.6 (95% CI 1.2-2.2) for depressive symptoms.","methodology":"Secondary analysis of the nuMoM2b prospective cohort study (2010-2013) across eight academic centers. Cannabis exposure was verified by urine immunoassay for THC-COOH with LC-MS/MS confirmation at three timepoints. Depression was measured using the Edinburgh Postnatal Depression Scale (EPDS > 10). Multivariable logistic regression adjusted for confounders.","limitations":"Observational design cannot establish causation. Direction of association is unclear: depression may drive continued cannabis use rather than the reverse. Study enrolled participants 2010-2013, before more potent products became widespread. THC-COOH detection reflects recent use but does not capture frequency precisely."},{"rthcId":"RTHC-07381","title":"Longitudinal Associations Between Cannabis Use during Pregnancy and Child Cognitive, Motor, and Language Development at 2 Years Old.","authors":"Pleau, Justine; Tanguay, Noémie; Courtemanche, Yohann; Séguin, Jean R; Herba, Catherine M; Simard, Marie-Noelle; MacLeod, Andrea A N; Fraser, William D; Muckle, Gina","year":2025,"journal":"Maternal and child health journal, 29(4), 549-562","doi":"10.1007/s10995-025-04077-8","pmid":"40121379","tags":["pregnancy","cognition","youth"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"In 1,489 mother-infant dyads from the 3D prospective cohort, prenatal cannabis use (2.6% of women) showed no significant associations with cognitive (B=0.016), fine motor (B=0.029), gross motor (B=0.060), or language development (B=0.200) at age 2. An unexpected positive association between cannabis use and language development was found in girls only.","whyItMatters":"Concerns about prenatal cannabis effects on child development are widespread, but this large prospective study found no measurable impact at age 2. The use of clinician-administered developmental assessments rather than parent report strengthens the findings, though the majority of exposed women stopped after the first trimester.","specificNumbers":"1,489 mother-infant dyads analyzed. 2.6% of women used cannabis during pregnancy. Most users stopped after first trimester. No significant associations with any developmental domain. Positive language association in girls only.","methodology":"Data from 1,489 dyads in the 3D prospective pregnancy cohort (2010-2012). Prenatal cannabis use was measured via interviews each trimester. Child development was assessed using Bayley Scales of Infant and Toddler Development (BSID-III) for cognition and motor skills, and MacArthur-Bates Communicative Development Inventories for language at age 2. Multiple linear regressions with sex-stratified analyses were performed.","limitations":"Self-reported cannabis use (no biomarker confirmation) likely underestimates true exposure. Only 2.6% reported use, limiting statistical power. Most users stopped after first trimester. Age 2 assessment may be too early to detect subtler cognitive effects. No measure of dose or potency."},{"rthcId":"RTHC-07382","title":"Trends in cannabis adverse reaction reports: A descriptive analysis of spontaneous reporting data submitted to the Canada Vigilance Program since legalization and regulation of cannabis for non-medical purposes in Canada.","authors":"Plebon-Huff, Sieara; Aziz, Nadia; Cavar, Marko; Hassan, Safia; Aoun, Maria; Perwaiz, Shahid; Abramovici, Hanan","year":2025,"journal":"Journal of cannabis research, 7(1), 56","doi":"10.1186/s42238-025-00310-x","pmid":"40790541","tags":["legalization","harm-reduction","medical-cannabis"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 698 adverse reaction reports to the Canada Vigilance Program, the average reporting individual was 56 years old, 45.4% were female, and 67.5% reported medical use (mainly pain management). Most cases (62.3%) were reported as serious, and 68.8% involved cannabis extracts. THC-dominant products were associated with different side effect profiles than CBD-dominant products. Common adverse events included hallucination, headache, nausea, dizziness, and dyspnea.","whyItMatters":"Canada's legalization framework included pharmaceutical-grade post-market surveillance for cannabis, making this the first large-scale adverse reaction reporting dataset from a legal regulated market. The data reveal that most reports come from older medical users of cannabis extracts, not recreational users, and that product composition matters for side effect profiles.","specificNumbers":"698 unique adverse reaction reports. Mean age 56 years. 45.4% female. 67.5% medical use. 62.3% classified as serious. 68.8% involved extracts. Pain management was the top medical reason. Most events assessed as \"possibly\" related to cannabis.","methodology":"Descriptive analysis of spontaneous adverse reaction reports submitted to Canada's post-market surveillance system since cannabis legalization in October 2018. Each case was assessed for causality. Data were aggregated to identify demographic patterns, product types involved, and event frequencies. Reports were from the Canada Vigilance Program's standardized pharmacovigilance framework.","limitations":"Spontaneous reporting captures a small fraction of actual adverse events. Reports are subject to reporting bias. \"Serious\" classification includes \"other medically important condition,\" which may not always reflect clinical severity. Cannot determine adverse event rates or compare to overall user population."},{"rthcId":"RTHC-07383","title":"A chronic low dose of Δ9-tetrahydrocannabinol (3 mg / kg / 21 d) reorganizes the disturbed wound healing process and accelerates wound closure in old female mice.","authors":"Plum, Melissa; Beier, Justus P; Ruhl, Tim","year":2025,"journal":"Experimental gerontology, 208, 112832","doi":"10.1016/j.exger.2025.112832","pmid":"40653209","tags":["medical-cannabis","seniors","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Old female mice receiving daily low-dose THC (3 mg/kg) for three weeks before skin wounding showed improved wound healing rates between days 1 and 7. THC treatment altered the timing and quantity of immune cell infiltration, decreased inflammatory cytokines on days 1 and 3, and significantly increased mesenchymal stem cell infiltration in wound tissue.","whyItMatters":"Aging impairs wound healing through disrupted immune responses and delayed tissue repair. This study suggests that low-dose THC could restore proper immune cell coordination in aging tissue, offering a potential therapeutic approach for age-related wound healing problems.","specificNumbers":"THC dose: 3 mg/kg daily for 21 days. Improved healing observed days 1-7 post-injury. Decreased inflammatory cytokines on days 1 and 3. Increased mesenchymal stem cell infiltration. No effect on growth factor release.","methodology":"Old female mice received daily low-dose medical THC (3 mg/kg) for 3 weeks, then four full-thickness skin wounds were created. Wound closure was analyzed at days 1, 3, and 7. Wound tissue was examined immunohistochemically for granulocytes, M1-macrophages, and mesenchymal stem cells. Inflammatory cytokines and growth factors were measured by ELISA.","limitations":"Animal study in mice; results may not translate to humans. Only female mice were studied. Single THC dose level tested. Short wound observation period (7 days). Did not examine long-term healing outcomes or scar quality."},{"rthcId":"RTHC-07384","title":"Toward a Cannabis Terroir: Untargeted Metabolomic Profiling of Authentic Samples Using Gas Chromatography-High-Resolution Mass Spectrometry (GC-HRMS) and Liquid Chromatography-High-Resolution Tandem Mass Spectrometry (LC-HRMS/MS).","authors":"Poetzsch, Sandra N; Poetzsch, Michael; Kraemer, Thomas; Steuer, Andrea E","year":2025,"journal":"Drug testing and analysis, 17(10), 2086-2095","doi":"10.1002/dta.3922","pmid":"40589191","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07385","title":"Blockade of cannabinoid CB1 receptors potentiates the anti-fibrotic effects mediated by SGLT2 inhibition in a mouse model of diabetic nephropathy.","authors":"Pointeau, Océane; Ba, Awa Isma; Geissler, Audrey; Barbosa, Romain; Basu, Abhishek; Muhammad, Arif; Nivot, Marina; Loriot, Maéva; Leemput, Julia; Passilly-Degrace, Patricia; Causse, Sébastien; Demizieux, Laurent; François, Hélène; Vergès, Bruno; Duan, Jianmin; Gaucher, Geneviève; Harvey, Michael; Degrace, Pascal; Crater, Glenn; Cinar, Resat; Jourdan, Tony","year":2025,"journal":"British journal of pharmacology, 182(21), 5355-5377","doi":"10.1111/bph.70118","pmid":"40650347","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07386","title":"What are the factors associated with alcohol, cigarette and marijuana use among adolescents in Africa? Evidence from the Global School-based Health Survey.","authors":"Pokothoane, Retselisitsoe; Argefa, Terefe Gelibo; Tsague, Josiane Djiofack; Mdege, Noreen Dadirai","year":2025,"journal":"BMJ open, 15(7), e089096","doi":"10.1136/bmjopen-2024-089096","pmid":"40721255","tags":["youth","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among school-going adolescents (ages 11-16) across 25 African countries, marijuana use prevalence was 3.4% (95% CI 2.7-4.2%). Unlike cigarette smoking, marijuana use did not differ significantly by sex. Parental tobacco use, being bullied, missing school without permission, and experiencing sadness and hopelessness were positively associated with being a current user regardless of substance type.","whyItMatters":"This is one of the largest studies of adolescent substance use across the African continent, revealing that marijuana use among school-going youth is lower than alcohol (9.5%) and cigarettes (6.2%) but shares the same risk factors. The consistent role of mental health factors like bullying and sadness across all substance types suggests integrated prevention approaches could be effective.","specificNumbers":"Marijuana prevalence: 3.4% (95% CI 2.7-4.2%). Alcohol: 9.5%. Cigarettes: 6.2%. Dual use alcohol + marijuana: 2.0%. Cigarettes + marijuana: 1.4%. No significant sex difference for marijuana. 25 countries included.","methodology":"Pooled cross-sectional analysis of the Global School-based Health Survey (GSHS) from 25 African countries (2003-2017). Descriptive statistics estimated prevalence. Logistic regressions modeled factors associated with alcohol, cigarette, and marijuana use with adjusted odds ratios. Dual-use patterns were also examined.","limitations":"Cross-sectional design cannot establish causal direction. Self-reported substance use may underestimate true prevalence. Data span 2003-2017, so current patterns may differ. School-based survey excludes out-of-school adolescents who may have higher use rates."},{"rthcId":"RTHC-07387","title":"In vitro antimicrobial activity of Thai stick cannabis Hang Kra Rog Phu Phan (Cannabis sativa L.), sugar leaves extract against pathogenic bacteria.","authors":"Pongnaratorn, Panicha; Sophon, Natthida; Boueroy, Parichart","year":2025,"journal":"Journal of advanced veterinary and animal research, 12(1), 44-52","doi":"10.5455/javar.2025.l870","pmid":"40568500","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07388","title":"Contributions of the endocannabinoid system to the neurobiology of emotions: Advances and perspectives.","authors":"Pontes, Lauro Rodriguez de; Ribeiro, Sidarta","year":2025,"journal":"Progress in brain research, 296, 65-93","doi":"10.1016/bs.pbr.2025.08.001","pmid":"40967685","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07389","title":"Cannabis use, microbial diversity and Dialister abundance in older adults with HIV: A cross-sectional study.","authors":"Porchia, Donald D; Wang, Yan; Zhou, Zhi; Chen, Mingkai; Porges, Eric C; Cohen, Ronald A; Ghare, Smita; Barve, Shirish; Cook, Robert L; Li, Zhigang","year":2025,"journal":"HIV medicine","doi":"10.1111/hiv.70180","pmid":"41431145","tags":["medical-cannabis","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 63 older adults with HIV (mean age 59.4), higher cannabis consumption was significantly associated with reduced gut microbial alpha diversity (beta = -0.062 per 50-mg THC per use-day, p = 0.038). At the genus level, Dialister abundance showed a dose-dependent 14.4% reduction per 50-mg increase in THC per use-day (q = 0.034).","whyItMatters":"People with HIV frequently experience gut problems linked to disrupted microbiomes and weakened mucosal barriers. Many use cannabis to manage symptoms, but this study suggests cannabis may actually reduce beneficial gut microbial diversity, potentially worsening the very gut dysfunction it is used to treat.","specificNumbers":"63 participants. Mean age 59.4 years. 71.4% Black or Hispanic. Alpha diversity: beta = -0.062 per 50-mg THC/use-day (p = 0.038). Dialister: 14.4% reduction per 50-mg THC increase (q = 0.034). No significant beta diversity difference.","methodology":"Cross-sectional analysis of 63 people with HIV (71.4% Black or Hispanic) from the MAPLE study and its microbiome substudy. Cannabis use was quantified using validated Timeline Followback. Fecal samples underwent 16S rRNA sequencing. Alpha diversity estimated by Shannon index, beta diversity by Bray-Curtis/PERMANOVA, genus-level abundance by IFAA method. Adjusted for age, sex, and education.","limitations":"Cross-sectional design cannot establish causation. Small sample size (N=63). Included participants with and without mild cognitive impairment. Self-reported cannabis use. 16S rRNA sequencing provides limited taxonomic resolution. Cannot determine whether reduced diversity preceded or followed cannabis use."},{"rthcId":"RTHC-07390","title":"Cannabis use, microbial diversity, and Dialister abundance in older adults with HIV: a cross-sectional study.","authors":"Porchia, Donald D; Wang, Yan; Zhou, Zhi; Chen, Mingkai; Porges, Eric C; Cohen, Ronald A; Ghare, Smita; Barve, Shirish; Cook, Robert L; Li, Zhigang","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.11.03.25339401","pmid":"41282808","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07391","title":"Effects of prenatal cannabinoid use on the monoamine system in the fetoplacental unit: A systematic review of animal and human studies.","authors":"Portillo, Ramon; Synova, Tetiana; Staud, Frantisek","year":2025,"journal":"Drug and alcohol dependence, 268, 112579","doi":"10.1016/j.drugalcdep.2025.112579","pmid":"39899918","tags":["pregnancy","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"After screening 18,252 papers, only 16 animal and 4 human studies met criteria. Animal models revealed significant disruptions in neurotransmitter regulation, receptor function, and gene expression following prenatal cannabis exposure. Human studies suggested potential cognitive and behavioral risks for offspring. No studies directly addressed the monoamine system in the placenta, exposing a critical research gap.","whyItMatters":"Cannabis use during pregnancy increased 170% between 2009 and 2016. The monoamine system (dopamine, serotonin, norepinephrine) is crucial for both placental function and fetal brain development. This review reveals that while animal evidence of disruption is strong, we lack the human studies needed to fully understand the risks.","specificNumbers":"18,252 papers initially screened. 20 studies met inclusion criteria (16 animal, 4 human). Cannabis use during pregnancy increased 170% between 2009-2016.","methodology":"Systematic review following PRISM guidelines with comprehensive database search. From 18,252 initial papers, rigorous screening yielded 16 animal studies and 4 human studies. Findings were synthesized to evaluate effects on neurotransmitter regulation, receptor function, and gene expression within the fetoplacental unit, framed through the Developmental Origins of Health and Disease (DOHaD) framework.","limitations":"Only 4 human studies met criteria, severely limiting clinical conclusions. Animal models use controlled cannabinoid exposure that may not reflect human use patterns. No studies examined monoamine effects specifically in placental tissue. Review cannot determine thresholds for harmful exposure."},{"rthcId":"RTHC-07392","title":"#notforkids: alcohol, vaping, and cannabis marketing by social media influencers popular with children and adolescents on YouTube, Instagram, and TikTok and policy implications.","authors":"Potvin Kent, Monique; Bagnato, Mariangela; Pritchard, Meghan; Amson, Ashley; Remedios, Lauren; Sabir, Soulene; Gillis, Grace; Pauzé, Elise; Vergeer, Laura; Vanderlee, Lana; White, Christine M; Hammond, David","year":2025,"journal":"Archives of public health = Archives belges de sante publique, 84(1), 3","doi":"10.1186/s13690-025-01799-7","pmid":"41327414","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07393","title":"The use of prescription medication and other drugs by New Zealand drivers with illegal blood alcohol levels.","authors":"Poulsen, Helen; Raymond, Onyekachi; McCarthy, Mary Jane","year":2025,"journal":"Traffic injury prevention, 26(4), 389-397","doi":"10.1080/15389588.2024.2418361","pmid":"39611787","tags":["driving","addiction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 3,050 drivers with blood alcohol exceeding legal limits in New Zealand (2011-2015), 41% had used alcohol in combination with other drugs. Cannabis was the most common co-intoxicant at 27% (816 drivers), followed by prescription medications at 16% (500 drivers) and other illicit drugs at 2.7%. Top prescription drugs combined with alcohol were antidepressants (citalopram, fluoxetine, venlafaxine), an antipsychotic (quetiapine), a sedative (diazepam), and an opioid (tramadol).","whyItMatters":"This study reveals that drunk driving rarely involves alcohol alone. More than one in four drunk drivers also had cannabis in their system, and one in six had prescription medications. The high rate of poly-substance use among impaired drivers has implications for both roadside testing strategies and understanding crash risk.","specificNumbers":"3,050 drivers tested. 41% (1,235) had alcohol plus drugs. 27% (816) had cannabis. 16% (500) had prescription meds. 2.7% (81) had other illicit drugs. Drug use did not correlate with alcohol amount. Top prescriptions: citalopram, fluoxetine, venlafaxine, quetiapine, diazepam, tramadol.","methodology":"Blood samples from 3,050 drivers who failed breath alcohol tests and elected laboratory blood analysis during 2011-2015 were tested for alcohol and a range of drugs using LC-TOFMS and cannabis immunoassay. Drug use was analyzed for prevalence, co-use patterns, and correlation with alcohol levels.","limitations":"Biased sample: only includes drivers who failed breath tests, elected blood tests, and exceeded legal limits. Cannot generalize to all drivers. Detection of cannabis does not confirm impairment at time of driving. Prescription medications may have been taken as prescribed. Study period (2011-2015) may not reflect current patterns."},{"rthcId":"RTHC-07394","title":"Does Cannabis Use Contribute to Schizophrenia? A Causation Analysis Based on Epidemiological Evidence.","authors":"Pourebrahim, Sepehr; Ahmad, Tooba; Rottmann, Elisabeth; Schulze, Johannes; Scheller, Bertram","year":2025,"journal":"Biomolecules, 15(3)","doi":"10.3390/biom15030368","pmid":"40149904","tags":["psychosis","youth","addiction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Analysis of 18 qualifying studies (10 included in forest plot) found all reported increased risk for psychosis-like events or schizophrenia with cannabis use, with 9 of 10 reaching significance. The overall odds ratio was 2.88 (CI 2.24-3.70). Adolescent use carried roughly double the risk compared to adult use. Hill causality criteria indicated a high likelihood of causal contribution.","whyItMatters":"While the association between cannabis and psychosis has been extensively documented, this study goes further by systematically applying formal causation criteria. The Hill analysis suggests this is not merely correlation but likely a genuine causal contribution, particularly concerning given the twofold higher risk during adolescence when brain development is ongoing.","specificNumbers":"18 studies met search criteria. 10 included in forest plot. Overall OR 2.88 (CI 2.24-3.70). Twofold higher risk for adolescent use. 9 of 10 studies showed significant increase. All 18 studies reported increased risk.","methodology":"Systematic literature review following PRISM guidelines. Epidemiological studies and randomized clinical trials investigating cannabis-psychosis links were identified. Ten studies were included in a forest plot analysis. Confounder analysis used funnel plots. The Hill causality criteria (nine criteria for inferring causation from epidemiological evidence) were applied to estimate the likelihood of a causal relationship.","limitations":"Funnel plot indicated potential confounder effects. Cannot rule out shared genetic vulnerability or reverse causation entirely. Included studies varied in cannabis exposure definitions and outcome measures. Most studies were observational, inherently limiting causal inference despite Hill criteria application."},{"rthcId":"RTHC-07395","title":"The Role of Fatty Acid Binding Proteins in Neuropsychiatric Diseases: A Narrative Review.","authors":"Powell, Aidan; Yamaguchi, Noa; Lu, Huy; Pareek, Ojas; Elman, Igor; Gold, Mark S; Pinhasov, Albert; Blum, Kenneth; Thanos, Panayotis K","year":2025,"journal":"Frontiers in bioscience (Landmark edition), 30(6), 26812","doi":"10.31083/FBL26812","pmid":"40613283","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07396","title":"Predicting vegetative phase nutrient uptake in Cannabis sativa L. via transpiration-driven mass-balance.","authors":"Powell, Kit; Bauerle, William L","year":2025,"journal":"Frontiers in plant science, 16, 1753553","doi":"10.3389/fpls.2025.1753553","pmid":"41658531","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07397","title":"Relationship between pain and nonopioid substance use in two national samples of cancer survivors.","authors":"Powers, Jessica M; LaRowe, Lisa R; Rubenstein, Dana; Paice, Judith A; Hitsman, Brian; Rini, Christine M","year":2025,"journal":"Cancer, 131(4), e35701","doi":"10.1002/cncr.35701","pmid":"39925086","tags":["pain","cancer","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This study used two large national datasets to examine how pain relates to substance use among cancer survivors—a population with high rates of both pain and substance use but surprisingly little research on the connection.\n\nThe pattern was consistent across both samples: cancer survivors with more pain were significantly more likely to use cannabis and cigarettes, but less likely to drink alcohol. This wasn't a random scatter—it suggests deliberate self-medication choices. People in pain may turn to cannabis and nicotine (both of which have analgesic properties) while avoiding alcohol (which can interfere with pain medications and worsen certain types of pain).\n\nThe implications go beyond substance use itself. In both studies, cigarette smoking combined with pain was associated with worse mental health outcomes and lower quality of life. Cannabis use combined with pain showed a different pattern—not as consistently linked to negative mental health outcomes as smoking.\n\nThe study also examined treatment-related side effects and found that pain and substance use together created a compounding effect on overall burden. Cancer survivors managing pain, substance use, and treatment side effects simultaneously face a triple challenge that current care systems often address in silos.","whyItMatters":"Cancer pain is undertreated in many patients, particularly as opioid prescribing has become more conservative. Understanding that pain drives cancer survivors toward cannabis (and away from alcohol) has practical implications: if patients are self-medicating pain with cannabis, that's information oncologists need for treatment planning—not just a substance use issue to be addressed separately.","specificNumbers":"Study 1: N = 1,252 (88% White, 55% female, 60% age ≥65). Study 2: N = 4,130 (83% White, 56% female, mean age 66). Pain associated with increased cannabis use (p < .003 in Study 1), increased cigarette use, and decreased alcohol use (p < .001).","methodology":"Cross-sectional analysis of two national datasets: Study 1—1,252 adults from Wave 6 (2021) of the Population Assessment of Tobacco and Health Study; Study 2—4,130 adults from the 2020 National Health Interview Survey. All had lifetime cancer diagnosis. Regression analyses examined associations between pain and use of cigarettes, e-cigarettes, cannabis, and alcohol.","limitations":"Cross-sectional design can't establish whether pain causes cannabis use or whether cannabis-using cancer survivors report more pain. Both datasets relied on self-reported pain and substance use. Predominantly White samples (83–88%) limit racial/ethnic generalizability. Cannabis use was measured as any use, without dose or frequency detail. \"Lifetime cancer diagnosis\" includes survivors at various stages, from active treatment to long-term survivorship."},{"rthcId":"RTHC-07398","title":"The Impact of Dual Cannabis and Tobacco Smoking in Young Patients With Lung Cancer: Results From the Prospective \"Environment and Lung Cancer\" Study.","authors":"Pradère, Pauline; Marinello, Arianna; Vasseur, Damien; Naltet, Charles; Moaca, Stefan; Le Pavec, Jérôme; Ghigna, Maria Rosa; De Montpreville, Vincent; Adam, Julien; Lacroix, Ludovic; Ben Salem, Fares; Caramella, Caroline; Planchard, David; Mercier, Olaf; Aldea, Mihaela; Alvarez, Jean Claude","year":2025,"journal":"Chest","doi":"10.1016/j.chest.2025.09.017","pmid":"41005696","tags":["respiratory","cancer"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"In a prospective study of 150 lung cancer patients aged 60 or under, 39% smoked both cannabis and tobacco (CTSs), 52% smoked only tobacco (TSs), and 9% were nonsmokers. All cannabis smokers also smoked tobacco. Compared to tobacco-only smokers, dual smokers were younger (median 53 vs 56 years), had more rare and aggressive cancers (17% vs 4%, p=0.007), higher emphysema rates (64% vs 38%, p=0.003), and lower gas diffusion capacity (63% vs 70%, p=0.004). Cannabis use was heavy (median 26 years, 4 joints/day).","whyItMatters":"This is one of the first prospective studies to use biomarker-confirmed cannabis exposure in lung cancer patients. The finding that dual smokers develop more aggressive tumor types at younger ages is clinically significant, particularly as cannabis use increases globally and most cannabis smokers also use tobacco.","specificNumbers":"150 patients. 39% cannabis+tobacco, 52% tobacco-only, 9% nonsmokers. Dual smokers: median age 53, 26 years cannabis use, 4 joints/day. Rare aggressive cancers: 17% vs 4% (p=0.007). Emphysema: 64% vs 38% (p=0.003). Chest pain at diagnosis: 22% vs 8% (p=0.03).","methodology":"Multicenter prospective study of 150 consecutive patients aged 60 or under diagnosed with primary lung cancer (2021-2023). Smoking behaviors were self-reported and confirmed by hair testing for nicotine, cotinine, THC, and CBD. Patients were categorized as cannabis+tobacco, tobacco-only, or nonsmokers. Clinical features, tumor characteristics, and surgical outcomes were compared.","limitations":"Cannot determine whether cannabis independently caused the worse outcomes since all cannabis users also smoked tobacco. Self-reported use despite hair test confirmation. Relatively small sample (N=150). Single-country study in France where cannabis is typically smoked mixed with tobacco."},{"rthcId":"RTHC-07399","title":"Prophylactic efficacy of cannabidiol and sodium nitroprusside in a ketamine-model of schizophrenia: sex-dependent effects on positive-like and cognitive impairments.","authors":"Prado, Daniel B A; Rossignoli, Matheus T; Ruggiero, Rafael N; Santos, José E P; Leite, João P; Dursun, Serdar M; Dursun, Leman H; Zuardi, Antonio W; Dos Santos, Rafael G; Abilio, Vanessa C; Abrão, João; Crippa, José A; Avelar, Gleiciane G; Hallak, Jaime E C; Dias, Isabella C S","year":2025,"journal":"Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)","doi":"10.47626/1516-4446-2025-4301","pmid":"40886890","tags":["cbd","psychosis","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rats pretreated with CBD and sodium nitroprusside (SNP) during brain development (postnatal days 12-32) and later challenged with ketamine showed sex-dependent responses. Females showed greater hyperlocomotion and long-term memory deficits; males showed reduced sucrose preference and short-term memory impairments. CBD or SNP alone had limited efficacy, but their combination reduced hyperlocomotion and prevented memory deficits in both sexes, with superior effects in females.","whyItMatters":"This is the first preclinical evidence of sex-dependent prophylactic effects of CBD combined with nitroprusside in a schizophrenia model. The finding that early intervention during brain development could prevent later psychosis-like symptoms opens new thinking about preventive approaches.","specificNumbers":"Treatment during postnatal days 12-32. 10-day washout before ketamine challenge. Combination treatment reduced hyperlocomotion and prevented NOR deficits in both sexes. Superior prophylactic effects in females by multivariate analysis.","methodology":"Wistar rats were pretreated with CBD and SNP (alone or combined) during postnatal days 12-32. After 10 days, schizophrenia-like deficits were induced with ketamine. Behaviors were assessed using Open Field Test (locomotion), Sucrose Preference Test (anhedonia), and Novel Object Recognition (memory). Multivariate analysis and unsupervised clustering examined sex differences.","limitations":"Animal study in rats; results may not translate to humans. Ketamine model only approximates some features of schizophrenia. CBD and SNP doses and timing in rats cannot be directly translated to human developmental periods. Did not examine long-term outcomes or potential side effects of early-life cannabinoid exposure."},{"rthcId":"RTHC-07400","title":"Harm reduction strategies for cannabis-related problems: a literature review and typology.","authors":"Pratschke, Jonathan","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 379-388","doi":"10.1007/s00406-024-01839-3","pmid":"38935216","tags":["harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"From a systematic review of 35 documents published 2011-2022, the authors developed a typology of cannabis harm reduction strategies covering three domains: legal interventions (regulatory approaches), socio-organizational interventions (community and institutional measures), and health-related interventions (clinical and public health approaches). The review identified innovative strategies from peers, government bodies, and third-sector organizations.","whyItMatters":"As cannabis legalization expands, harm reduction approaches become increasingly important. This typology provides the first organized framework for understanding the full range of available strategies, from regulatory to health-based, giving policymakers and practitioners a structured way to evaluate and implement interventions.","specificNumbers":"35 documents included. Studies from 2011-2022. Covered Europe, Americas, Australia, New Zealand. Three-domain typology: legal, socio-organizational, health-related.","methodology":"Systematic literature review with a two-concept search across Embase and other databases, supplemented by citation searches and manual website searching. Studies published 2011-2022 from Europe, the Americas, Australia, or New Zealand were included. All study designs except case reports, non-systematic reviews, editorials, and news stories were eligible. 35 documents met inclusion criteria.","limitations":"Many included studies relied on qualitative methods with small samples. Limited to English-language publications. Geographic scope excluded Asia and Africa. The evidence base for many harm reduction strategies remains thin."},{"rthcId":"RTHC-07401","title":"Association Between Prenatal Cannabis Exposure and Child Health Care Use: A Retrospective Cohort Study in Ontario, Canada.","authors":"Pratt Tremblay, Gabrielle; Han, Arum; Sucha, Ewa; Hsu, Helen; Donelle, Jessy; Corsi, Daniel J","year":2025,"journal":"Journal of pediatrics. Clinical practice, 17, 200151","doi":"10.1016/j.jpedcp.2025.200151","pmid":"40584565","tags":["pregnancy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"In a retrospective cohort of 508,025 Ontario infants (3,248 cannabis-exposed), prenatal cannabis exposure was associated with 14% fewer primary care visits (aRR 0.86, 95% CI 0.84-0.87), 29% more outpatient psychiatrist visits (aRR 1.29, 95% CI 1.00-1.66), 5% more ER visits (aRR 1.05, 95% CI 1.03-1.08), and 12% more hospitalizations (aRR 1.12, 95% CI 1.04-1.20). Among the highest income quintile, cannabis exposure was associated with a twofold increase in psychiatrist visits.","whyItMatters":"This massive population-based study reveals a concerning pattern: children exposed to cannabis before birth visit primary care doctors less often but end up in emergency departments, hospitals, and psychiatrist offices more frequently. The reduced primary care suggests these families may face access barriers that lead to more acute healthcare needs.","specificNumbers":"508,025 infants total. 3,248 (0.6%) cannabis-exposed. Primary care: aRR 0.86 (fewer). Psychiatrist: aRR 1.29 (more). ER: aRR 1.05 (more). Hospitalizations: aRR 1.12 (more). Follow-up to age 10.","methodology":"Retrospective cohort using linked perinatal and health administrative databases for all live singleton births in Ontario hospitals (April 2007-March 2012). Infants followed until March 2017 (up to age 10). Cannabis exposure identified from maternal self-report. Adjusted Poisson regression assessed differences in healthcare utilization rates.","limitations":"Self-reported cannabis use (0.6% prevalence) likely underestimates true exposure. Cannot separate cannabis effects from confounding socioeconomic factors that drive both cannabis use and healthcare patterns. Administrative data lacks clinical detail. Cannot determine whether children's health problems were caused by cannabis exposure or related social determinants."},{"rthcId":"RTHC-07402","title":"Cannabis Use Among Older Adults.","authors":"Pravosud, Vira; Lum, Emily; Vali, Marzieh; Cohen, Beth E; Hoggatt, Katherine J; Byers, Amy L; Austin, Peter C; Walter, Louise C; Hasin, Deborah; Zaman, Tauheed; Keyhani, Salomeh","year":2025,"journal":"JAMA network open, 8(5), e2510173","doi":"10.1001/jamanetworkopen.2025.10173","pmid":"40366653","tags":["seniors","addiction","medical-cannabis","pain"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Of 4,503 veterans aged 65-84, 58.2% had ever used cannabis. Past 30-day use was 10.3%, with 52.4% of users consuming on 20+ days per month. Smoking (72.4%) and edibles (36.9%) were most common. Among current users, 36.3% screened positive for cannabis use disorder (CUD). Inhaled use (vs edibles only) was associated with 3.56-fold higher odds of CUD. Pain (56.4%), mood/mental health (18.4%), and sleep (16.0%) were the top medical reasons.","whyItMatters":"Cannabis use among older adults has been underexplored. This JAMA study reveals that use prevalence among older veterans rivals tobacco use, and the high rate of CUD screening, particularly among smokers, suggests many older users may be developing problematic use patterns that go undetected without routine screening.","specificNumbers":"4,503 participants. Mean age 73.3 years. 85.4% male. 58.2% ever used. 10.3% past 30-day use. 52.4% of users on 20+ days/month. Smoking: 72.4%. Edibles: 36.9%. CUD: 36.3% of users. Pain: 56.4% of medical users. Inhaled vs edibles CUD odds: aOR 3.56.","methodology":"Cross-sectional study of 4,503 community-dwelling veterans aged 65-84 using Veterans Health Administration care, interviewed February 2020-August 2023. Cannabis use disorder assessed using DSM-5 criteria (2+ criteria). Weighted multivariable logistic regressions examined factors associated with use and CUD. Published in JAMA Network Open.","limitations":"Veteran population (overwhelmingly male) may not represent general older adult population. Cross-sectional design cannot establish causation between route and CUD. CUD screening criteria may perform differently in older adults. Self-reported use may underestimate actual consumption."},{"rthcId":"RTHC-07403","title":"Supplementing HIV-ART with cannabinoids increases serotonin, BHB, and Ahr signaling while reducing secondary bile acids and acylcholines.","authors":"Premadasa, Lakmini S; Romero, Luis; Mohan, Mahesh","year":2025,"journal":"Science advances, 11(36), eadw4021","doi":"10.1126/sciadv.adw4021","pmid":"40901952","tags":["medical-cannabis","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In SIV-infected rhesus macaques on ART, long-term low-dose THC significantly increased plasma and gut serotonin and indole-3-propionate (enhancing gut-brain communication), enriched cholesterol-metabolizing bacteria (Oscillibacter), reduced plasma cholesterol and toxic secondary bile acids, increased beta-hydroxybutyrate (suggesting improved fatty acid metabolism), and restored inflammatory acylcholines to pre-infection levels. THC-treated animals maintained viral suppression despite reduced plasma ART levels.","whyItMatters":"Despite effective ART, people with HIV face persistent inflammation and metabolic problems that increase risk for heart disease and other conditions. This Science Advances study provides detailed mechanistic evidence that THC supplementation could address multiple pathways of chronic inflammation and metabolic dysfunction simultaneously.","specificNumbers":"THC increased plasma/jejunum serotonin and indole-3-propionate. Enriched Oscillibacter (cholesterol-metabolizing). Reduced plasma cholesterol and secondary bile acids. Increased beta-hydroxybutyrate via CBR1. Restored acylcholines to pre-infection levels. Viral suppression maintained with reduced ART levels.","methodology":"SIV-infected rhesus macaques receiving ART were supplemented with long-term low-dose THC. Researchers measured plasma and tissue serotonin, gut microbiome composition, cholesterol and bile acid profiles, beta-hydroxybutyrate levels, and acylcholine concentrations. Mechanistic pathways were identified through receptor-specific analyses (CBR1 and CBR2 mediated). Published in Science Advances.","limitations":"Non-human primate model; results need human validation. Small sample typical of primate studies. Specific THC dosing in macaques may not translate directly to human dosing. Long-term safety of combined THC+ART not fully characterized. Cannot determine if benefits persist after THC cessation."},{"rthcId":"RTHC-07404","title":"Chewing Gum as a Delivery System for Cannabidiol: A Commentary.","authors":"Pressman, Peter; Hayes, A Wallace; Hamam, Ahmed M; Vaillancourt, Kathryn; Miladinovic, Tanya; Rana, Azhar; Hoeng, Julia","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 158-165","doi":"10.1159/000547917","pmid":"41064746","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07405","title":"Questioning assumptions about the abuse potential of medical cannabis and cannabinoids: narrative review and commentary.","authors":"Pressman, Peter; Hayes, Andrew Wallace","year":2025,"journal":"BJPsych bulletin, 1-9","doi":"10.1192/bjb.2025.10183","pmid":"41321070","tags":["medical-cannabis","addiction"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The review identified and examined five broad assumptions in the abuse liability literature: (1) a standard cannabis formulation, (2) standard routes and potency, (3) a standard pattern of use, (4) a standard user, and (5) standard vulnerability to misuse. The authors concluded that unpacking these assumptions reveals the evidence does not support treating cannabis as uniquely high-risk for abuse when used under medical supervision.","whyItMatters":"Cannabis scheduling and regulation debates often rest on assumptions about abuse potential. This review argues that much of the existing abuse liability research fails to distinguish between recreational and medical use, different formulations, routes, and patient populations, leading to an oversimplified picture of cannabis risk.","specificNumbers":"Over 350 articles reviewed. ~90% published after 2002. ~50 papers included after abstract screening. Five broad assumptions identified and examined.","methodology":"Narrative scoping review of over 350 articles (approximately 90% published after 2002) identified from databases using terms related to cannabis abuse, misuse, and dependence. Abstract analysis narrowed the selection to approximately 50 papers based on relevance as judged by an experienced clinician and a public health toxicologist.","limitations":"Narrative review with author-selected papers rather than systematic methodology. Only two authors assessed relevance. May underweight evidence supporting higher abuse potential. \"Comparable to other pharmaceuticals\" is a broad claim given that some pharmaceuticals have significant abuse liability."},{"rthcId":"RTHC-07406","title":"Adverse clinical effects associated with the use of synthetic cannabinoids: A systematic review.","authors":"Prete, Mariana M; Feitosa, Gabriel T B; Ribeiro, Maria A T; Fidalgo, T M; Sanchez, Zila M","year":2025,"journal":"Drug and alcohol dependence, 272, 112698","doi":"10.1016/j.drugalcdep.2025.112698","pmid":"40334326","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"From 944 studies screened, 49 met inclusion criteria (2010-2022). Synthetic cannabinoids primarily affected neurological and cardiovascular systems, with common symptoms including seizures, altered consciousness, tachycardia, and hypertension. Hospital and ICU admissions varied reflecting toxicity complexity. Compared to cannabis, SC use was linked to more severe cardiovascular and neurological complications. Rare complications included thromboembolic events and immune thrombocytopenic purpura. Participants were predominantly young adult males (ages 12-72).","whyItMatters":"Synthetic cannabinoids are often marketed as legal alternatives to cannabis, but their 100-fold higher receptor affinity translates to dramatically more dangerous clinical outcomes. This comprehensive review documents the full spectrum of adverse effects, providing evidence for public health campaigns and emergency medicine protocols.","specificNumbers":"944 studies screened. 49 included. SC receptor affinity ~100x greater than cannabis. Common effects: seizures, altered consciousness, tachycardia, hypertension. Predominantly young adult males. Ages 12-72. Published 2010-2022.","methodology":"Systematic review following PRISMA guidelines across PubMed, Embase, and Lilacs databases. 944 studies screened; 49 published 2010-2022 included. Focused on clinical effects associated with SC use, excluding case reports, other reviews, animal studies, and those on psychiatric symptoms or therapeutic uses only.","limitations":"Heterogeneous study designs and populations limit direct comparisons. Excluded psychiatric-only outcomes, potentially underestimating total burden. Rapid emergence of new SC compounds means findings may not cover newest variants. Publication bias toward severe cases may overestimate typical toxicity."},{"rthcId":"RTHC-07407","title":"Synaptic signatures of perinatal cannabinoids: A systematic review of rodent hippocampal synaptic plasticity, learning, and memory.","authors":"Przy, Rebecca; Jacoby, Ben; Christie, Brian R","year":2025,"journal":"Drug and alcohol dependence reports, 16, 100353","doi":"10.1016/j.dadr.2025.100353","pmid":"40678750","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07408","title":"Seven patients with analytically confirmed MDMB-4en-PINACA toxicity associated with the use of electronic vaping devices.","authors":"Pucci, Mark; Moyns, Emma; Welby-Everard, Peter; Starbrook, Lauren","year":2025,"journal":"Clinical toxicology (Philadelphia, Pa.), 63(5), 360-362","doi":"10.1080/15563650.2025.2489079","pmid":"40372197","tags":["synthetic-cannabinoids","youth"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Seven patients (median age 17, range 14-37) presented to UK hospitals after using vaping products contaminated with MDMB-4en-PINACA. Six were male (85.7%). Five presented with unusual behavior changes; six were agitated; four displayed psychotic features including hallucinations and delusions. In three cases, MDMB-4en-PINACA was the only substance detected, confirming the vape as the sole source.","whyItMatters":"Vaping devices are increasingly being contaminated with synthetic cannabinoids, creating a hidden danger for users who believe they are vaping nicotine or standard cannabis products. The predominance of adolescent patients in this series highlights the vulnerability of young people to this emerging threat.","specificNumbers":"7 patients. Median age 17 years (range 14-37). 85.7% male. 71.4% presented with behavioral changes. 85.7% agitated. 57.1% had psychotic features. 3 cases: MDMB-4en-PINACA was the only substance detected. Period: Feb 2022-Feb 2025.","methodology":"Observational case series from two UK acute hospitals (February 2022-February 2025). Patients self-reported vaping product use and were found positive for MDMB-4en-PINACA on routine toxicological urine screening. Clinical presentations were documented.","limitations":"Very small case series (N=7). Observational without controls. Cannot determine prevalence of contaminated vaping products. Limited to two hospitals in one country. Routine screening may miss cases where clinicians do not test for synthetic cannabinoids."},{"rthcId":"RTHC-07409","title":"Concentration-dependent effect of delta-9-tetrahydrocannabinol on epigenetic DNA modifiers in human peripheral blood mononuclear cells.","authors":"Pulk, Kerda; Somelar-Duracz, Kelli; Rooden, Mikk; Anier, Kaili; Kalda, Anti","year":2025,"journal":"Translational psychiatry, 15(1), 198","doi":"10.1038/s41398-025-03419-y","pmid":"40506434","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07410","title":"Post-Traumatic Stress in Adolescence: The Mediating Role of Time Perspective Between Trauma Exposure, PTSD Symptoms, and Cannabis Use.","authors":"Pütz, Alexander; Hapfelmeier, Gerhard; Martin, Alexandra; Bender, Stephan; Walg, Marco","year":2025,"journal":"European journal of investigation in health, psychology and education, 15(9)","doi":"10.3390/ejihpe15090177","pmid":"41002758","tags":["ptsd","youth","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 105 adolescent psychiatric patients (ages 14-20), those with clinically relevant PTSD symptoms showed imbalanced time perspective: high orientation to negative past and low orientation to positive past and future. Time perspective mediated the level of PTSD symptoms in the relationship between trauma exposure and symptoms. PTSD symptoms predicted cannabis use frequency, suggesting a pathway from trauma through distorted time perception to substance use.","whyItMatters":"Understanding why traumatized adolescents turn to cannabis is crucial for prevention. This study identifies time perspective, how teens think about past, present, and future, as a key mediator. If therapy can help teens develop a more balanced time orientation, it might reduce both PTSD severity and associated cannabis use.","specificNumbers":"105 participants. Ages 14-20. Recruited from psychiatric units. PTSD patients showed high negative past orientation and low positive past/future orientation. PTSD symptoms predicted cannabis use frequency. Time perspective mediated PTSD symptom severity.","methodology":"Cross-sectional study of 105 patients aged 14-20 recruited from child and adolescent psychiatric units. Standardized questionnaires assessed exposure to potentially traumatic experiences (EPTE), PTSD symptoms, time perspective, and cannabis use. Mediation analysis examined direct and indirect pathways.","limitations":"Cross-sectional design cannot determine causal direction. Clinical psychiatric sample may not generalize to community adolescents. Self-reported cannabis use. Relatively small sample (N=105). Cannot determine whether cannabis use preceded or followed trauma/PTSD development."},{"rthcId":"RTHC-07411","title":"Using a PBPK Model Incorporating Lymphatic Absorption to Predict Food Effect, Multiple Dosing, and Hepatic Impairment of Cannabidiol.","authors":"Qian, Lixuan; Zhou, Zhu","year":2025,"journal":"Clinical and translational science, 18(11), e70401","doi":"10.1111/cts.70401","pmid":"41251333","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07412","title":"Predicting Δ-9-Tetrahydrocannabinol-Induced Psychoactive and Cognitive Effects: A PBPK-PD Approach to Quantifying Feeling High and Reduced Alertness.","authors":"Qian, Lixuan; Zhou, Zhu","year":2025,"journal":"ACS chemical neuroscience, 16(15), 3059-3069","doi":"10.1021/acschemneuro.5c00417","pmid":"40694686","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07413","title":"A retrospective medical record audit of the management of cannabis-related emergency department presentations, hospital admissions and hyperemesis of pregnant women who self-reported non-medicinal cannabis use to a substance use in parenting and pregnancy service.","authors":"Qian, Siyu; Seddon, Sarah","year":2025,"journal":"Drug and alcohol review, 44(4), 1036-1048","doi":"10.1111/dar.14059","pmid":"40210203","tags":["pregnancy","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Among 75 pregnant SUPPS patients with cannabis as primary drug of concern, their 232 ED presentations and 183 hospital admissions revealed significant gaps: cannabis use history was documented in only 34% of ED visits and 53% of admissions. Substance use screening was done in 45% of ED visits and 53% of admissions. Cannabis use status was asked in only 36% of ED visits. Referral to the substance use support service was made in only 7% of admissions and never from ED.","whyItMatters":"Even among pregnant women already identified as having cannabis use concerns, hospital staff frequently failed to document or screen for substance use during acute care visits. This represents missed opportunities for intervention and support during a critical period for both mother and fetus.","specificNumbers":"75 patients. 232 ED presentations. 183 hospital admissions. Cannabis documented in 34% of ED visits, 53% of admissions. Screening done in 45% of ED/53% of admissions. Referral to SUPPS: 7% of admissions, 0% from ED. Withdrawal documented in 3% of ED/13% of admissions.","methodology":"Retrospective medical record audit of 75 patients from a substance use in pregnancy and parenting service (SUPPS) in Australia who identified cannabis as their primary drug of concern and gave birth between January 2015 and May 2020. Their ED presentations and hospital admissions in the 12 months prior to delivery were examined.","limitations":"Small sample (N=75) from a single Australian service. Retrospective audit may miss undocumented conversations. Patients were already engaged with a substance use service, so results may underestimate gaps for unidentified users. Does not assess whether screening or referral would have changed outcomes."},{"rthcId":"RTHC-07414","title":"Assessment of Abuse Potential of Three Indazole-Carboxamide Synthetic Cannabinoids 5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA.","authors":"Qiao, Yanling; Shi, Xuesong; Li, Kaixi; Kuai, Lixin; Li, Xiangyu; Di, Bin; Xu, Peng","year":2025,"journal":"International journal of molecular sciences, 26(13)","doi":"10.3390/ijms26136409","pmid":"40650186","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07415","title":"Sex differences in the capacity of minor phytocannabinoids to attenuate nociceptive insults in HIV-1 Tat-expressing mice.","authors":"Qrareya, Alaa N; Moss, Emaya; Mahdi, Fakhri; Salahuddin, Mohammad F; Hu, Duoyi; De Leon, Miguel A; Wanas, Amira S; Radwan, Mohamed M; ElSohly, Mahmoud A; Ashpole, Nicole M; Paris, Jason J","year":2025,"journal":"NeuroImmune pharmacology and therapeutics, 4(3), 303-313","doi":"10.1515/nipt-2024-0025","pmid":"41221301","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07416","title":"Perceptions, Uses, and Information Sources of Medical Cannabis Among Patients With Cancer.","authors":"Qu, Vera; Hui, Caressa; Hall, Jennifer; Taparra, Kekoa; Kollipara, Tanaya; Trieu, Sandy; Beadle, Beth; Soltys, Scott; Pollom, Erqi L","year":2025,"journal":"Advances in radiation oncology, 10(3), 101678","doi":"10.1016/j.adro.2024.101678","pmid":"40546850","tags":["medical-cannabis","cancer"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Of 84 cancer patients surveyed, 83.3% agreed medical cannabis provides symptom relief, while 15.5% agreed it can cure cancer. Patients who believed cannabis cures cancer were significantly more likely to identify as Hispanic/Latino (38.5% vs 9.9%, p=0.009) and less likely to be up-to-date on COVID-19 vaccinations (30.8% vs 8.5%, p=0.044). Hispanic/Latino identity remained significantly associated on bivariate analysis (OR 6.528, p=0.012). Patients wanted to learn more from their oncologists but perceived them as unknowledgeable.","whyItMatters":"Misinformation about cannabis as a cancer cure can lead patients to delay or refuse evidence-based treatment. This study identifies which patients are most likely to hold these beliefs and reveals that patients want guidance from oncologists but perceive them as lacking cannabis knowledge, creating a dangerous information vacuum filled by unregulated sources.","specificNumbers":"84 patients (84% completion rate). 83.3% agreed cannabis relieves symptoms. 15.5% believed cannabis can cure cancer. Hispanic/Latino patients: OR 6.528 for cure belief (p=0.012). Patients perceived oncologists as unknowledgeable about cannabis.","methodology":"Cross-sectional survey of 84 cancer patients seen in radiation oncology clinic (June 2022-July 2023) at a single center. 84% completion rate. Questionnaire assessed perceptions and information sources about medical cannabis. Associations with demographic and disease variables were evaluated. Qualitative thematic analysis performed on narrative responses.","limitations":"Small single-center sample (N=84). Radiation oncology patients may not represent all cancer patients. Cross-sectional design. Self-reported perceptions. Limited diversity beyond the Hispanic/Latino finding. Cannot determine causal pathway for belief formation."},{"rthcId":"RTHC-07417","title":"Routes of Marijuana Use - Behavioral Risk Factor Surveillance System, 22 U.S. States and Two Territories, 2022.","authors":"Quader, Zerleen S; Roehler, Douglas R; Vivolo-Kantor, Alana M; Ko, Jean Y","year":2025,"journal":"MMWR. Morbidity and mortality weekly report, 74(12), 198-204","doi":"10.15585/mmwr.mm7412a1","pmid":"40208833","tags":["legalization","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using the 2022 BRFSS data from 22 states and 2 territories, 15.3% of adults reported past 30-day cannabis use. Among users, smoking was most common (79.4%), followed by eating (41.6%), vaping (30.3%), and dabbing (14.6%). Vaping and dabbing were most prevalent among ages 18-24. The survey used a newly revised marijuana module for the first time.","whyItMatters":"This is the first BRFSS analysis using an updated marijuana module that captures multiple routes of use, providing the most comprehensive population-level picture of how Americans actually consume cannabis. The dominance of smoking despite known respiratory risks has direct public health implications.","specificNumbers":"15.3% current (past 30-day) use. Smoking: 79.4%. Eating: 41.6%. Vaping: 30.3%. Dabbing: 14.6%. 22 states + 2 territories. Vaping/dabbing highest in ages 18-24.","methodology":"Analysis of the 2022 Behavioral Risk Factor Surveillance System (BRFSS) with a newly revised optional marijuana module administered across 22 states and 2 territories. Weighted prevalences with 95% CIs were reported overall and by demographic characteristics. Women aged 49 or under were analyzed by pregnancy status.","limitations":"BRFSS is phone-based survey with potential response bias. Only 22 states plus 2 territories administered the module. Self-reported use may underestimate actual consumption. Cannot capture all emerging product forms. Cross-sectional snapshot from a single year."},{"rthcId":"RTHC-07418","title":"Chemical diversity, receptor binding affinity, and pharmacology of phytocannabinoids: Insights into neuronal mechanisms.","authors":"Queiroz, Claudio Marcos; de Oliveira Koren, Laura; da Silva, Camila Rayane Pereira; Ribeiro, Sidarta; Silva, Sérgio Ruschi Bergamachi","year":2025,"journal":"Progress in brain research, 296, 1-28","doi":"10.1016/bs.pbr.2025.07.006","pmid":"40967679","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07419","title":"Attentional bias in people with moderate-to-severe cannabis use disorder.","authors":"Quinones-Valera, Marianna; Chan, Gary; Fraser, Madeleine I; Jones, Andrew; Freeman, Tom P; Hindocha, Chandni; Thomson, Hannah; McTavish, Eugene; Sehl, Hannah; Clemente, Adam; Cousijn, Janna; Labuschagne, Izelle; Rendell, Peter; Terrett, Gill; Greenwood, Lisa-Marie; Poudel, Govinda; Suo, Chao; Manning, Victoria; Lorenzetti, Valentina","year":2025,"journal":"Comprehensive psychiatry, 146, 152658","doi":"10.1016/j.comppsych.2025.152658","pmid":"41539168","tags":["addiction","cognition"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"Among 66 people with moderate-to-severe CUD and 42 controls, there were no significant group differences in attentional bias toward cannabis images using a visual probe task. Within the CUD group, those with higher CUDIT-R scores showed marginally faster responses to cannabis versus neutral images, but this effect did not survive correction for multiple comparisons.","whyItMatters":"Attentional bias, the tendency to notice drug-related stimuli more quickly, is a cornerstone theory in addiction. This study challenges whether it reliably applies to cannabis use disorder, suggesting CUD may operate through different cognitive mechanisms than other substance use disorders.","specificNumbers":"66 CUD participants, 42 controls. No significant group differences in attentional bias. High-CUDIT-R subgroup showed marginally faster cannabis image responses (d = -0.10) but did not survive Bonferroni correction.","methodology":"Case-control study comparing 66 participants with moderate-to-severe CUD to 42 controls using a visual probe task measuring reaction times to cannabis versus neutral images at two stimulus onset asynchronies (200/500 ms). Linear mixed effect models adjusted for alcohol use examined group differences and moderators including craving, arousal/valence ratings, and nicotine use.","limitations":"Visual probe task may not be sensitive enough to detect attentional bias. Moderate sample size. CUD was clinically defined but attentional bias may vary by severity in ways not captured. Cannot rule out that attentional bias exists but operates at different timescales."},{"rthcId":"RTHC-07420","title":"Metadynamics simulations and site-directed mutagenesis determine the binding of cannabidiol to the adenosine A2A receptor.","authors":"Quintana-Garcia, Aleix; Raïch, Iu; Del Llinas Del Torrent, Claudia; Lillo, Jaume; Casajuana-Martin, Nil; Rebassa, Joan Biel; Navarro, Gemma; Pardo, Leonardo","year":2025,"journal":"Protein science : a publication of the Protein Society, 34(12), e70394","doi":"10.1002/pro.70394","pmid":"41273253","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07421","title":"A multi-site study examining the tobacco withdrawal trajectory in people with tobacco and cannabis co-use.","authors":"Rabin, Rachel A; Lerman, Caryn; Schnoll, Robert; Tyndale, Rachel F; George, Tony P","year":2025,"journal":"Drug and alcohol dependence, 274, 112778","doi":"10.1016/j.drugalcdep.2025.112778","pmid":"40633181","tags":["quitting","addiction","tolerance"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 330 participants with verified tobacco abstinence from a cessation trial (55 cannabis co-users, 275 tobacco-only), cannabis co-users had significantly elevated withdrawal scores at week 1 (mean 9.3 vs 7.1, p < 0.01). No differences were found at weeks 4, 8, or 11. The effect was significant after controlling for age, treatment arm, and site.","whyItMatters":"About 30% of tobacco users also use cannabis, and this population has greater difficulty quitting tobacco. This study identifies a specific mechanism: worse withdrawal in the critical first week. This is actionable information for designing cessation interventions that provide extra support during the initial quit period for co-users.","specificNumbers":"1,246 total participants. 330 with verified abstinence (55 co-users, 275 tobacco-only). Week 1 withdrawal: co-users 9.3 vs tobacco-only 7.1 (p < 0.01). No differences at weeks 4, 8, or 11.","methodology":"Secondary analysis of a multi-site double-blind clinical trial for tobacco cessation. Participants were randomized to placebo, nicotine patch, or varenicline and followed for 11 weeks. Cannabis co-use was determined by urine toxicology. Analysis focused on 330 participants with biochemically verified 7-day abstinence, comparing withdrawal trajectories using the Minnesota Nicotine Withdrawal Scale (MNWS) at baseline and weeks 1, 4, 8, and 11.","limitations":"Secondary analysis. Cannabis use classified by single urine screen rather than quantified use patterns. Only included participants who achieved abstinence, so cannot comment on those who relapsed. Co-use group was relatively small (N=55). Cannot determine whether cannabis use worsened withdrawal or whether shared vulnerability drives both."},{"rthcId":"RTHC-07422","title":"Cannabis Use in Adolescents.","authors":"Rabinow, Lily; Dries, Emily; Hoffman, Neal D","year":2025,"journal":"Pediatrics in review, 46(9), 482-493","doi":"10.1542/pir.2024-006514","pmid":"40875257","tags":["youth","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Despite increasing adult cannabis use and higher-THC products, longitudinal studies show less than 20% of youth report current cannabis use and lifetime use has actually decreased over recent decades. The review covers acute and chronic clinical syndromes, evidence-based screening tools, and treatment modalities specific to adolescents.","whyItMatters":"The perception that teen cannabis use is exploding does not match the data. While more potent products are available and adult use has risen, adolescent use has not followed the same trajectory. This nuanced picture helps pediatricians calibrate their responses and focus on evidence-based screening and intervention.","specificNumbers":"Less than 20% of youth report current use. Lifetime use has decreased over recent decades. Almost half of U.S. states have legalized recreational adult use.","methodology":"Clinical review published in Pediatrics in Review covering cannabis formulations, THC concentration variations, epidemiological trends in youth use, clinical syndromes (acute and chronic), evidence-based screening tools, and treatment approaches for adolescent cannabis use.","limitations":"Narrative clinical review without systematic methodology. Relies on existing epidemiological surveys that may have limitations. U.S.-focused. Does not quantify the impact of higher-potency products on the subset of youth who do use."},{"rthcId":"RTHC-07423","title":"The Detection of Δ9-THC, Δ8-THC, Δ10-THC and CBD in Hair Specimens.","authors":"Racines, Amy; Jones, Joseph; Lea, Katie; Coy, Donna","year":2025,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkaf079","pmid":"40828892","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07424","title":"S1P3 Receptor Mediates the Proinflammatory Effect of the Endocannabinoid 2-Arachidonoylglycerol in Endometriotic Epithelial Cells.","authors":"Raeispour, Maryam; Prisinzano, Matteo; Seidita, Isabelle; Romeo, Lucia; Nardi, Eleonora; Castiglione, Francesca; Bruni, Paola; Petraglia, Felice; Bernacchioni, Caterina; Donati, Chiara","year":2025,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 39(22), e71255","doi":"10.1096/fj.202502415R","pmid":"41294926","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07425","title":"Ethnic identity and religiosity are related to lower alcohol use and cannabis use in Arab American college students.","authors":"Rahal, Danny; Waldron, Katja","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(6), 814-825","doi":"10.1080/00952990.2025.2571148","pmid":"41296885","tags":["youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Greater ethnic identity affirmation was linked to less frequent cannabis use (OR 0.58, p=0.030), while greater ethnic identity search was linked to lower odds of any cannabis use (OR 0.68, p=0.025). Higher religiosity was associated with both lower odds and frequency of cannabis use (OR 0.44, p=0.005), with significantly stronger associations among those from Muslim upbringings.","whyItMatters":"Cultural and religious factors are underexplored protective mechanisms against substance use. This study shows that ethnic identity and religiosity can buffer cannabis use risk in Arab American students, suggesting culturally tailored prevention could be more effective than generic approaches.","specificNumbers":"173 students. Mean age 20.1. 60.7% female. Ethnic affirmation and cannabis: OR 0.58 (p=0.030). Ethnic search and cannabis odds: OR 0.68 (p=0.025). Religiosity and cannabis: OR 0.44 (p=0.005). Muslim upbringing showed stronger religiosity effects.","methodology":"Cross-sectional study of 173 Arab American college students (mean age 20.1, 60.7% female, 44.5% Christian and 43.9% Muslim upbringing) recruited from a California university. Ethnic identity affirmation and search, religiosity, and past-year alcohol and cannabis use were self-reported.","limitations":"Small sample from a single California university. Cross-sectional design. Self-reported substance use during COVID-19 pandemic may not reflect typical patterns. Cannot determine causation. Limited to Arab American students; results may not generalize to other populations."},{"rthcId":"RTHC-07426","title":"Substance Use is Associated With College Students' Acute Parasympathetic Nervous System Responses to Challenge.","authors":"Rahal, Danny; Kwan, Violet F; Perry, Kristin J","year":2025,"journal":"Stress and health : journal of the International Society for the Investigation of Stress, 41(1), e70002","doi":"10.1002/smi.70002","pmid":"39832127","tags":["neuroscience","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 152 college students, those with larger declines in parasympathetic activity (vagal withdrawal) during a stress challenge task used cannabis more frequently. Unexpectedly, higher resting parasympathetic activity was also associated with more frequent cannabis use. Recovery from the challenge was not related to substance use.","whyItMatters":"This study provides biological evidence for the self-medication hypothesis: students whose bodies react more strongly to stress may use cannabis more frequently to cope. Identifying physiological markers of substance use risk could enable earlier, more targeted interventions.","specificNumbers":"152 students. Mean age 20.5. 73.8% female. Higher resting RSA linked to more cannabis use. Greater RSA decline (vagal withdrawal) during challenge linked to more frequent use. No association with RSA recovery.","methodology":"Cross-sectional study of 152 college students (mean age 20.5, 73.8% female) who reported past-month substance use frequency and completed a laboratory stress task (mirror star tracing) while wearing an ECG to measure respiratory sinus arrhythmia (RSA), a marker of parasympathetic nervous system activity.","limitations":"Cross-sectional; cannot determine if stress reactivity causes cannabis use or vice versa. Single laboratory task may not reflect real-world stress responses. Self-reported substance use. Predominantly female sample. Small sample for detecting physiological-behavioral associations."},{"rthcId":"RTHC-07427","title":"Effect of intracerebroventricular (ICV) injection of antimicrobial peptide expressed in the body-2 (LEAP-2) and its interaction with cannabinoid and ghrelin systems on food intake in broiler chickens.","authors":"Rahmania, Ariana; Zendehdel, Morteza; Hassanpour, Shahin","year":2025,"journal":"Poultry science, 105(2), 106199","doi":"10.1016/j.psj.2025.106199","pmid":"41406822","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07428","title":"Cannabidiol as a multifaceted therapeutic agent: mitigating Alzheimer's disease pathology and enhancing cognitive function.","authors":"Raïch, Iu; Lillo, Jaume; Rebassa, Joan Biel; Griñán-Ferré, Christian; Bellver-Sanchis, Aina; Reyes-Resina, Irene; Franco, Rafael; Pallàs, Mercè; Navarro, Gemma","year":2025,"journal":"Alzheimer's research & therapy, 17(1), 109","doi":"10.1186/s13195-025-01756-0","pmid":"40394655","tags":["cbd","cognition","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In the 5xFAD Alzheimer's mouse model, CBD decreased pTau and amyloid-beta aggregation, reduced their transport between brain regions, shifted microglia toward a neuroprotective M2 phenotype, reduced inflammatory cytokine release, and partially reversed neurite formation loss. Daily CBD injections (10 mg/kg for 28 days) significantly improved both short- and long-term spatial memory. CBD also reduced reactive oxygen species and increased neuronal survival.","whyItMatters":"Most Alzheimer's drugs target a single disease mechanism, but CBD addressed multiple pathological processes simultaneously: amyloid plaques, tau tangles, neuroinflammation, oxidative stress, and neuronal damage. This multi-target approach is increasingly recognized as necessary for complex neurodegenerative diseases.","specificNumbers":"CBD dose: 10 mg/kg daily for 28 days. Significant improvement in short- and long-term spatial memory. Decreased pTau and amyloid-beta aggregation. Reduced ROS formation. Increased neuronal viability. Shifted microglia to M2 neuroprotective phenotype.","methodology":"Combined in vitro and in vivo study using the 5xFAD Alzheimer's mouse model. In vitro: assessed CBD effects on protein aggregation, axonal transport, microglial polarization, neurite formation, and oxidative stress. In vivo: daily CBD injections (10 mg/kg) for 28 days with subsequent spatial memory testing.","limitations":"Mouse model (5xFAD) does not fully replicate human Alzheimer's disease. CBD was injected, not given orally. Single dose level tested. 28-day treatment period is short relative to the chronic nature of Alzheimer's. Cannot predict human pharmacokinetics or required doses."},{"rthcId":"RTHC-07429","title":"Alcohol and drug use and attainment of pregnancy preferences in the southwestern United States: A longitudinal cohort study.","authors":"Raifman, Sarah; Roberts, Sarah C M; Rocca, Corinne H","year":2025,"journal":"Addiction (Abingdon, England), 120(12), 2527-2537","doi":"10.1111/add.70135","pmid":"40739595","tags":["pregnancy","addiction"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"In a longitudinal cohort of 2,015 individuals capable of pregnancy, heavy drinking and daily cannabis use were associated with higher desire to avoid pregnancy. Among those with high desire to avoid pregnancy, heavy drinking was associated with 51% higher pregnancy risk (aHR 1.51, 95% CI 1.12-2.04). Cannabis use was not associated with elevated pregnancy risk among those wanting to avoid it. Other drug use was not associated with pregnancy regardless of preferences.","whyItMatters":"This study addresses a long-standing assumption that substance use leads to unintended pregnancy. The nuanced finding that heavy drinking specifically, and not cannabis or other drug use, is associated with unintended pregnancy in those wanting to avoid it suggests targeted interventions should focus on alcohol rather than substance use broadly.","specificNumbers":"2,015 participants. 40% heavy drinking. 16% cannabis use. 3% other drug use. 282 incident pregnancies. Heavy drinking + high DAP: aHR 1.51 (p < 0.01). Cannabis not associated with pregnancy in high DAP group.","methodology":"Longitudinal cohort study of 2,015 individuals ages 15-34 from 23 healthcare facilities in five southwestern U.S. states (2019-2022). Past-month substance use self-reported at baseline. Pregnancy preferences measured quarterly using the Desire to Avoid Pregnancy scale. Incident pregnancy reported every 6 weeks. Adjusted mixed effects regression and Cox proportional hazard models used.","limitations":"Self-reported substance use may underestimate actual consumption. Only baseline substance use measured. Five southwestern states may not represent national patterns. Cannot determine mechanisms (e.g., whether alcohol affects contraceptive use or judgment)."},{"rthcId":"RTHC-07430","title":"Evaluation of iSTART: A Novel Substance Use Prevention Web-App Designed for Diverse College Students.","authors":"Rainisch, Bethany K W; Dahlman, Linn; Shahverdi, Abnous; Alhassan, Sarah; Forster, Myriam","year":2025,"journal":"Evaluation & the health professions, 48(2), 163-173","doi":"10.1177/01632787251322996","pmid":"39962800","tags":["youth","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Among 1,066 students randomly assigned to a web-app intervention, comparison, or control condition, those in the 5-module web-app group had significantly greater substance knowledge gains, more accurate peer use perceptions, and better understanding of health risks than comparison or control students. Web-app students also had lower incidence rates of cannabis use at program exit, with effects persisting at 90-day follow-up.","whyItMatters":"First-generation, working, and ethnic minority college students are underrepresented in substance use prevention research. This study demonstrates that a culturally sensitive digital intervention can effectively reach these populations and produce lasting reductions in cannabis use, filling a critical gap in prevention science.","specificNumbers":"1,066 participants. Three conditions: web-app, comparison, control. Cannabis use reduction at exit and 90-day follow-up. Significant improvements in substance knowledge, peer norm accuracy, and health risk perception. Hispanic Serving Institution in Southern California.","methodology":"Randomized controlled trial with 1,066 participants at a Hispanic Serving Institution in southern California. Students were randomly assigned to control, comparison, or 5-module web-app condition. Surveys assessed knowledge, perceived health risks, normative peer use, and past 30-day substance use at baseline, exit, and 90-day follow-up.","limitations":"Single institution in Southern California. Self-reported substance use. 90-day follow-up is relatively short for assessing lasting behavior change. Cannot determine which specific modules drove the effects. Nicotine use reduction did not persist at follow-up."},{"rthcId":"RTHC-07431","title":"Putative Effects of Lead on the Endocannabinoid System: A Literature Review and Summary.","authors":"Rainone, Gersham J; Johansen, Phillip Mitchell; Pressman, Peter; Hayes, Andrew Wallace","year":2025,"journal":"International journal of molecular sciences, 26(18)","doi":"10.3390/ijms26188994","pmid":"41009561","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07432","title":"Considering the Effects of Cannabinoids and Exercise on the Brain: A Narrative Review.","authors":"Rajaei, Amir Yahya; Neary, J Patrick; Thompson, Elizabeth S; Singh, Jyotpal; Mang, Cameron S","year":2025,"journal":"Sports (Basel, Switzerland), 13(9)","doi":"10.3390/sports13090320","pmid":"41003626","tags":["exercise","neuroscience","inflammation"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"The review identified mechanistic overlaps between cannabinoid and exercise effects on brain function through three key pathways: inflammation (both can be anti-inflammatory), vascular function (both affect cerebral blood flow), and neuroplasticity (both modulate brain-derived neurotrophic factor and synaptic plasticity). The interactions could be additive, synergistic, or opposing depending on timing, dose, and context.","whyItMatters":"As cannabis use becomes more common among athletes and recreational exercisers, understanding how these two brain-active interventions interact is crucial. The endocannabinoid system responds to both exercise and exogenous cannabinoids, creating potential for beneficial or harmful interactions that are largely unstudied.","specificNumbers":"Review covered literature since 2010. Three focal pathways: inflammation, vascular function, neuroplasticity. Both exercise and cannabinoids modulate the endocannabinoid system.","methodology":"Narrative review emphasizing research since 2010, including randomized clinical trials, observational studies, preclinical work, and related review articles. Focused on overlapping physiological mechanisms through which cannabinoids and exercise affect brain function.","limitations":"Narrative review without systematic methodology. Most evidence is indirect, comparing separate cannabinoid and exercise literatures rather than studying their combination. Limited human data on combined effects. Animal and in vitro findings may not translate to human athletic contexts."},{"rthcId":"RTHC-07433","title":"Sex differences in endocannabinoid and inflammatory markers associated with posttraumatic stress disorder.","authors":"Rajasekera, Therese A; Joseph, Anna; Pan, Hui; Dreyfuss, Jonathan M; Fida, Doruntina; Wilson, Julia C; Behee, Madeline; Fichorova, Raina N; Cinar, Resat; Spagnolo, Primavera A","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 142, 111501","doi":"10.1016/j.pnpbp.2025.111501","pmid":"40967565","tags":["ptsd","sex-differences","neuroscience","inflammation"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"Among 88 PTSD patients and 85 matched controls, male PTSD patients had significantly decreased levels of AEA, arachidonic acid, and OEA compared to male controls and female subgroups. Female PTSD patients showed elevated levels of IL-6 and IL-8 compared to other subgroups. These distinct profiles persisted after controlling for the FAAH gene variant and in the subgroup with comorbid depression.","whyItMatters":"PTSD predominantly affects women, yet most biological research has focused on mixed samples. This study reveals that men and women with PTSD may have fundamentally different underlying biological disruptions: endocannabinoid depletion in men versus inflammatory elevation in women. This could explain why treatments work differently by sex.","specificNumbers":"88 PTSD patients, 85 controls. Males: decreased AEA, AA, OEA (p < 0.001 to 0.05). Females: elevated IL-6 and IL-8 (p < 0.010). Results persisted after controlling for FAAH genotype and comorbid MDD.","methodology":"Case-control study retrospectively selecting 88 PTSD patients and 85 sex- and age-matched healthy controls from the Mass General Brigham Biobank. Serum samples measured endocannabinoids (AEA, 2-AG, OEA, AA) and inflammatory markers (IL-1beta, IL-6, IL-8, IL-18, TNF-alpha, CRP). Analyses controlled for FAAH 385A genotype.","limitations":"Cross-sectional biobank study cannot determine whether biomarker changes cause or result from PTSD. Retrospective selection may introduce bias. Serum endocannabinoid levels may not reflect brain levels. Cannot determine whether differences existed before PTSD onset. Single timepoint measurement."},{"rthcId":"RTHC-07434","title":"The Relationship Between Cannabis Use and Schizophrenia As a Risk Factor or For Its Therapeutic Potential: A Systematic Review of Evidence.","authors":"Rajput, Jaisingh; Narahari, Sandhya; Arif, Taha; Iftikhar, Rabiya; Arpan, Turimula; Tariq, Abdullah; Ali Duleh, Hamad Mohammad; Cherukuri, Sri Pranita","year":2025,"journal":"Cureus, 17(9), e92793","doi":"10.7759/cureus.92793","pmid":"41127784","tags":["psychosis","cognition","youth","addiction","mental-health","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"The cannabis-schizophrenia relationship is one of the most polarized debates in psychiatric research. This systematic review cuts through the noise by applying rigorous quality filters to 112 initial records, ultimately including only 8 studies that met strict methodological standards.\n\nThe central finding: THC and CBD appear to push schizophrenia risk in opposite directions. THC is consistently associated with increased psychosis risk, while CBD has shown potential therapeutic effects on schizophrenia symptoms.\n\nThis dual nature of cannabis matters enormously for policy and clinical practice. Cannabis products vary wildly in their THC:CBD ratio—from high-THC concentrates with almost no CBD to CBD-dominant products with trace THC. Treating \"cannabis\" as a single entity obscures the fact that its two main components may have opposing effects on psychosis.\n\nThe review notes that approximately 20 million people worldwide are affected by schizophrenia, making the stakes of getting this right enormous. If THC increases risk while CBD potentially treats symptoms, then the composition of cannabis products—not just whether someone uses cannabis—becomes the critical variable.\n\nThe methodological rigor is a strength: the authors used AMSTAR 2, Cochrane Risk of Bias Tool, and Newcastle-Ottawa Scale to evaluate included studies, and only 8 of 112 screened records passed the quality threshold.","whyItMatters":"As cannabis becomes more accessible, distinguishing between THC-risk and CBD-benefit is essential for informed policy. Blanket statements that \"cannabis causes psychosis\" or \"cannabis is safe\" both miss the critical nuance. This review provides a framework for thinking about cannabis and schizophrenia that accounts for the distinct effects of different cannabinoids.","specificNumbers":"~20 million people affected by schizophrenia globally. 112 records screened; 8 met inclusion criteria. THC associated with increased psychosis risk. CBD showed potential therapeutic effects for schizophrenia symptoms.","methodology":"Systematic review per PRISMA 2020 guidelines. Searched PubMed, PubMed Central, Cochrane Library, and Google Scholar for peer-reviewed studies published 2017–2025. Quality assessment using AMSTAR 2, Cochrane Risk of Bias Tool, Newcastle-Ottawa Scale. 112 records screened; 8 high-quality studies included.","limitations":"Only 8 studies met inclusion criteria out of 112 screened—while this ensures quality, it limits the scope of conclusions. The strict 2017–2025 time window excludes earlier foundational research. The review can't resolve the causal question (does THC cause schizophrenia or do schizophrenia-prone individuals seek THC?). CBD's therapeutic potential is based on limited clinical evidence that needs more replication."},{"rthcId":"RTHC-07435","title":"Evaluating Delta-8-THC-Induced Psychosis: A Systematic Review.","authors":"Ralston, Megan Jayne; Osman, Alim","year":2025,"journal":"Clinical neuropharmacology, 48(1), 20-23","doi":"10.1097/WNF.0000000000000619","pmid":"39805119","tags":["psychosis","potency"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"From 201 studies screened, 12 met criteria and 6 case reports involving 9 patients were reviewed. Most patients were male in their 20s. Psychiatric histories varied from none to schizophrenia and PTSD. Reported symptoms included psychosis, mood lability, and cannabinoid hyperemesis syndrome. Despite being marketed as less intoxicating than delta-9-THC, delta-8-THC posed significant psychiatric risks.","whyItMatters":"Delta-8-THC products are widely available in the U.S. due to the 2018 Farm Bill loophole, often marketed as a safer, legal alternative to regular cannabis. This review documents that delta-8-THC carries real psychiatric risks, particularly concerning given the lack of FDA regulation and easy consumer access.","specificNumbers":"201 studies screened. 12 met inclusion. 6 case reports with 9 patients reviewed. Most patients male, in their 20s. Symptoms: psychosis, mood lability, cannabinoid hyperemesis syndrome. No FDA regulation.","methodology":"Systematic review following PRISMA guidelines, searching PubMed and Web of Science for studies on delta-8-THC and psychosis. Articles on delta-9-THC or other cannabinoids were excluded. 201 studies identified; 12 met inclusion for full-text analysis; 6 case reports (9 patients) were reviewed. Quality assessed using CASP Checklist for Case Reports.","limitations":"Limited to case reports (lowest level of evidence). Only 9 patients across 6 reports. Cannot determine incidence or prevalence of psychiatric effects. Publication bias toward severe cases. No controlled comparisons with delta-9-THC. Cannot establish causation from case reports alone."},{"rthcId":"RTHC-07436","title":"The Prevalence and Predictors of Reported Prenatal Anxiety Among Primigravid Individuals in Nova Scotia.","authors":"Ramia, Jessica; Piccinini-Vallis, Helena","year":2025,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 47(12), 103162","doi":"10.1016/j.jogc.2025.103162","pmid":"41429704","tags":["pregnancy","anxiety"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"In 53,852 first-time pregnancies in Nova Scotia (2004-2023), reported prenatal anxiety prevalence was 8.9% overall but rose from under 5% to over 20% over the study period. Cannabis use was an independent predictor of prenatal anxiety in multivariable analysis, alongside younger or older age, being unpartnered, lower education, higher BMI, and smoking. These factors collectively explained 17.5% of variance.","whyItMatters":"The dramatic rise in reported prenatal anxiety over two decades (from under 5% to over 20%) is itself concerning. The identification of cannabis use as an independent predictor, after controlling for other risk factors, adds important information for prenatal screening and suggests cannabis use should be assessed as part of comprehensive anxiety screening during pregnancy.","specificNumbers":"53,852 first pregnancies. Overall anxiety prevalence: 8.9%. Rose from <5% to >20% over 2004-2023. Cannabis use was an independent predictor. Model explained 17.5% of variance.","methodology":"Retrospective cohort study using the Nova Scotia Atlee Prenatal Database of 53,852 primigravid persons with singleton pregnancies (2004-2023). Multivariable analysis examined birth year group, age, partner status, education, pre-pregnancy BMI, smoking, and cannabis use as predictors of reported prenatal anxiety.","limitations":"Retrospective database study cannot determine causation. Rising anxiety rates may partly reflect increased recognition and reporting rather than true increases. Cannabis use was self-reported and likely underestimated. Cannot distinguish between recreational and self-medicating use. Only first-time pregnancies included."},{"rthcId":"RTHC-07437","title":"Effects of Different Cannabinoid Formulations on Anxiety-Related Disorders, and Tourette Syndrome: A Systematic Review and Meta-Analysis.","authors":"Raminelli, Adrieli Oliveira; Simei, João Luís Q; Guimarães, Francisco S; Zuardi, Antônio; Hallak, Jaime Eduardo C; Crippa, José Alexandre; Osório, Flávia de Lima","year":2025,"journal":"Cannabis and cannabinoid research, 10(6), 655-672","doi":"10.1177/25785125251378242","pmid":"40956670","tags":["anxiety","ptsd","cbd","medical-cannabis"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Across 21 placebo-controlled RCTs covering social anxiety, GAD, PTSD, OCD, and Tourette syndrome, pure CBD compounds showed a moderate significant effect (SMD -0.61, 95% CI -1.15 to -0.07). THC-dominant compounds also showed moderate significance (SMD -0.65, 95% CI -1.06 to -0.24). However, CBD-THC mixtures did not reach significance (SMD -0.73, 95% CI -2.00 to 0.55). Pharmaceutical-grade formulations appeared to outperform non-standardized extracts.","whyItMatters":"This is one of the most comprehensive meta-analyses to date separating cannabinoid types across anxiety-related conditions. The finding that pharmaceutical-grade formulations outperform non-standardized extracts has direct implications for both clinical practice and regulation of medical cannabis for mental health conditions.","specificNumbers":"21 RCTs included. Pure CBD: SMD -0.61 (significant). THC-dominant: SMD -0.65 (significant). CBD-THC mixtures: SMD -0.73 (not significant). Conditions: SAD (5 trials), GAD (1), PTSD (7), OCD (1), Tourette (7).","methodology":"Systematic review and meta-analysis searching PubMed, Embase, PsycInfo, Web of Science, Scielo, and Lilacs for placebo-controlled RCTs. 21 trials included: 5 for social anxiety, 1 GAD, 7 PTSD, 1 OCD, 7 Tourette syndrome. Separate meta-analyses by cannabinoid subtype. Standardized mean differences calculated using Jamovi software.","limitations":"Small sample sizes across most included trials. Heterogeneous study designs, doses, and outcome measures. Some conditions had very few trials (1 each for GAD and OCD). Cannot compare conditions head-to-head. THC results driven partly by Tourette syndrome trials which may involve different mechanisms than anxiety."},{"rthcId":"RTHC-07438","title":"In silico exploration of pyrocannabinoid interactions with key protein targets.","authors":"Ramirez, Giovanni A; Tesfatsion, Tesfay T; Pittiglio, Monica K; Ray, Kyle P; Westerkamp, Andrew; Cruces, Westley","year":2025,"journal":"In silico pharmacology, 13(2), 109","doi":"10.1007/s40203-025-00391-9","pmid":"40718581","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07439","title":"Anti-inflammatory effects of cannabidiol in the treatment of type 1 diabetes: A mini review.","authors":"Ramos Fernandes, Victor Augusto; Mendes, Letícia Ranucci; Franco Netto, Raphael Oliveira Ramos; Belozo, Felipe Lovaglio; Bezerra, André Alves; Dos Santos, Camila Pascoal Correia; Cruel, Paola Tatiana Espinosa; Buchaim, Daniela Vieira; Buchaim, Rogério Leone; da Cunha, Marcelo Rodrigues","year":2025,"journal":"World journal of diabetes, 16(10), 110041","doi":"10.4239/wjd.v16.i10.110041","pmid":"41113484","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07440","title":"Characterizing the Role of Endocannabinoid Receptor Cnr1 in Mouse Ovarian Granulosa Cells.","authors":"Randhawa, Jasmine; Madogwe, Ejimedo; McCall, Aire; Singh, Jaswinder; Duggavathi, Raj","year":2025,"journal":"Cell biochemistry and function, 43(3), e70070","doi":"10.1002/cbf.70070","pmid":"40119741","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07441","title":"Detection of Mycotoxigenic Fungi and Residual Mycotoxins in Cannabis Buds Following Gamma Irradiation.","authors":"Rani, Mamta; Kaddoura, Mohammad Jamil; Samsatly, Jamil; Chamberland, Guy; Jabaji, Suha; George, Saji","year":2025,"journal":"Toxins, 17(11)","doi":"10.3390/toxins17110528","pmid":"41295843","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07442","title":"Perceptions of cannabis warnings and recommendations for improvement: a qualitative study with people who use cannabis from the United States.","authors":"Ranney, Leah M; Clark, Sonia A; Meek, Caroline J; Jarman, Kristen L; Kowitt, Sarah D","year":2025,"journal":"BMC public health, 25(1), 2363","doi":"10.1186/s12889-025-23518-1","pmid":"40611026","tags":["harm-reduction","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"In six focus groups with 36 U.S. cannabis users, three key themes emerged: participants saw warnings as tools for education about safe use, not deterrence; they reported never noticing existing warnings on cannabis packages; and they were already aware of both benefits and risks. Participants wanted attention-grabbing designs with warning icons and content about specific health risks rather than generic cautions.","whyItMatters":"Billions have been invested in cannabis legalization infrastructure, but the warning labels that accompany legal products are largely invisible and ineffective. This study provides direct consumer input on what would actually work, a crucial step for developing evidence-based cannabis communication.","specificNumbers":"36 participants across 6 focus groups. 50% White, 22% Black/African American, 28% other races. Mean age 30.5 years. Average cannabis use 3.7 of past 7 days.","methodology":"Six virtual focus groups with 36 U.S. adults (21+) who used cannabis in the past 30 days and lived in states with legalized recreational cannabis (March-April 2023). Participants were shown existing state warnings and novel warnings created by the research team. Thematic analysis was conducted using ATLAS.ti.","limitations":"Small qualitative sample (N=36). Only included adults 21+ in legal states. Self-selected participants may be more engaged with cannabis culture. Focus groups cannot measure behavioral impact of improved warnings. Did not test whether improved warnings actually change behavior."},{"rthcId":"RTHC-07443","title":"The role of the endocannabinoid system in managing neuropsychiatric symptoms in Alzheimer's disease.","authors":"Rao, Jagadeesh S; Alejandra Tangarife, Maria; Venegas, Maria Margarita; Forero, Barbara; González Tamayo, Laura Lucía; Escobar-Gallego, Juan Pablo; Rodríguez-Soacha, Diego A; Ferreiros, Alexandra; Mukunda, Ram","year":2025,"journal":"Frontiers in psychiatry, 16, 1709266","doi":"10.3389/fpsyt.2025.1709266","pmid":"41608471","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07444","title":"New insights into the crosstalk between endocannabinoids and sphingosine-1-phosphate.","authors":"Rapino, Cinzia; Standoli, Sara; Cencetti, Francesca; Bruni, Paola; Oddi, Sergio; Maccarrone, Mauro","year":2025,"journal":"The Journal of biological chemistry, 301(11), 110781","doi":"10.1016/j.jbc.2025.110781","pmid":"41033556","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07445","title":"Role of peroxisome proliferator-activated receptors α and γ in mediating the beneficial effects of β-caryophyllene in a rat model of fragile X syndrome.","authors":"Rava, Alessandro; Buzzelli, Valeria; Feo, Alessandro; Ascone, Fabrizio; Di Trapano, Melania; Schiavi, Sara; Carbone, Emilia; Pasquadibisceglie, Andrea; Polticelli, Fabio; Manduca, Antonia; Trezza, Viviana","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 136, 111234","doi":"10.1016/j.pnpbp.2024.111234","pmid":"39725014","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07446","title":"Uncovering the molecular targets of phytocannabinoids: mechanistic insights from inverse molecular docking fingerprint approaches.","authors":"Ravnik, Vid; Jukič, Marko; Furlan, Veronika; Maver, Uroš; Rožanc, Jan; Bren, Urban","year":2025,"journal":"Frontiers in pharmacology, 16, 1611461","doi":"10.3389/fphar.2025.1611461","pmid":"40657640","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07447","title":"Pharmacological advances in cannabinoid-based therapies for pancreatic cancer: preclinical efficacy of CCL-106 and its epimers.","authors":"Ray, K P; Cruces, W; Mzannar, Y; Aboukameel, A; Motorwala, S; Hadid, T; Al-Hallak, M N; Ramirez, G A; Tesfatsion, T T; Docampo-Palacios, M L; Collins, A C; Jagtap, P G; Azmi, A S; Khan, H Y","year":2025,"journal":"ESMO gastrointestinal oncology, 9","doi":"10.1016/j.esmogo.2025.100211","pmid":"41031216","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07448","title":"Chronic Δ9-tetrahydrocannabinol exposure during adolescence is associated with persistent behavioural tolerance in adult nonhuman primates.","authors":"Razavi, Yasaman; Kohut, Stephen J; Bergman, Jack; Kangas, Brian D","year":2025,"journal":"British journal of pharmacology, 182(21), 5149-5156","doi":"10.1111/bph.70179","pmid":"40842344","tags":["youth","tolerance","cognition"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Nonhuman primates treated daily with THC during adolescence (6 months at low or high doses) and tested approximately one year later as adults showed persistent behavioral tolerance. On a touchscreen attention task (PVT), those with adolescent THC history required higher doses of THC to show impairment compared to vehicle-treated controls, regardless of whether THC was administered intramuscularly or orally.","whyItMatters":"This is one of the first primate studies to demonstrate that adolescent cannabis exposure creates lasting changes in how the brain responds to cannabinoids, persisting for at least a year after stopping. The finding that tolerance persists through extended abstinence suggests permanent or very long-lasting neuroadaptation during adolescent brain development.","specificNumbers":"6 months daily THC during adolescence. Low dose: 0.32 mg/kg/day. High dose: 3.2 mg/kg/day. ~1 year abstinence before adult testing. Dose-related impairment confirmed by both intramuscular and oral routes. Adolescent-exposed subjects showed rightward shift in dose-response curve.","methodology":"Female and male adolescent nonhuman primates received daily intramuscular THC (0.32 or 3.2 mg/kg/day) or vehicle for 6 months. After approximately 1 year abstinence, now-adult subjects were trained on a touchscreen Psychomotor Vigilance Task (PVT). Acute THC was administered intramuscularly and orally to assess dose-response relationships on attentional performance.","limitations":"Relatively small sample typical of primate studies. Only examined attentional performance; other cognitive domains may be affected differently. Cannot determine whether tolerance is permanent or would eventually resolve. Female and male subjects analyzed together rather than separately for sex differences."},{"rthcId":"RTHC-07449","title":"Cannabidiol exerts teratogenic effects on developing zebrafish through the sonic hedgehog signaling pathway.","authors":"Razmara, Parastoo; Son, Hae-Won; Ali, Declan William","year":2025,"journal":"Scientific reports, 15(1), 14533","doi":"10.1038/s41598-025-99194-3","pmid":"40281058","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07450","title":"Consumer Contribution in Designing Medicinal Cannabis Clinical Trials in Palliative Medicine.","authors":"Razmovski-Naumovski, Valentina; Noble, Beverly; Brown, Linda; Agar, Meera R","year":2025,"journal":"Journal of palliative medicine, 28(8), 1128-1133","doi":"10.1089/jpm.2024.0422","pmid":"40063355","tags":["medical-cannabis","cancer"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Clinical trials are typically designed by researchers for patients. This paper describes what happened when patients and carers were included as active contributors in designing and conducting a Phase I/IIb cannabis trial for cancer-related anorexia.\n\nConsumer contribution came through five channels: lived experience (understanding what matters to patients), knowledge (what cannabis means to them and their communities), inclusion as investigators (formal research team roles), advocacy (representing patient perspectives in ethical and regulatory discussions), and outreach (connecting the trial to the broader patient community).\n\nThe authors argue this consumer contribution did more than check a patient-engagement box. It shaped study design decisions in ways that researchers alone wouldn't have achieved, ensured the trial was practically feasible (addressing barriers researchers didn't anticipate), and will guide future dissemination of results in ways that reach the people who need them.\n\nMedial cannabis trials in palliative care face unique challenges: patients are seriously ill, cannabis carries legal and social complexity, and many participants have strong pre-existing opinions about cannabis. Consumer input helped navigate all of these challenges.\n\nThe paper also considers how to mitigate bias when including consumers—ensuring their contribution enhances rather than distorts the research process.","whyItMatters":"Patient-centered research is a growing movement, but cannabis trials face unique challenges that make consumer input especially valuable. Patients know things researchers don't—about cannabis stigma, about what matters in end-of-life care, about practical barriers to participation. This case report provides a model for other cannabis research teams.","specificNumbers":"5 domains of consumer contribution identified. Phase I/IIb trial for cancer anorexia. Consumers included as investigators on the research team.","methodology":"Case report on consumer contribution in a Phase I/IIb medicinal cannabis clinical trial for anorexia in advanced cancer (ACTRN12616000516482). Describes five domains of consumer contribution: lived experience, knowledge, investigator inclusion, advocacy, and outreach.","limitations":"Single case report from one trial—the model may not transfer directly to other contexts. The benefits of consumer contribution are described qualitatively without quantitative metrics. Selection of consumer contributors may not represent all patient perspectives. The trial was in palliative care (advanced cancer), which involves unique considerations not present in other cannabis research populations."},{"rthcId":"RTHC-07451","title":"Design Considerations for Medicinal Cannabis Clinical Trials in People Receiving Palliative Care.","authors":"Razmovski-Naumovski, Valentina; Martin, Jennifer H; Chye, Richard; Phillips, Jane L; Lintzeris, Nicholas; Solowij, Nadia; Lee, Jessica; Lovell, Melanie; Noble, Bev; Galettis, Peter; Brown, Linda; Fazekas, Belinda; Clark, Katherine; Luckett, Tim; McCaffrey, Nikki; Currow, David C; Agar, Meera R","year":2025,"journal":"Journal of pain and symptom management, 69(5), e395-e408","doi":"10.1016/j.jpainsymman.2025.02.009","pmid":"39988015","tags":["medical-cannabis","pain","appetite","cancer"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This paper is a practical roadmap for researchers, drawn from the investigators' experience running a Phase I/IIb trial of vaporized cannabis for cancer anorexia. Using action research methodology, they documented the challenges they encountered and synthesized them into six key design considerations.\n\nThe six considerations: (1) Operating within medicinal cannabis legislation—which varies by jurisdiction and is often changing mid-trial. (2) Bioethical considerations unique to cannabis (stigma, patient expectations, the politics of evidence). (3) Feasibility challenges in palliative populations (recruitment, retention, cognitive capacity to consent). (4) Pharmacological complexity (variable plant composition, limited standardization, drug interactions). (5) Product requirements (quality control, dosing consistency, shelf life). (6) Regulatory hurdles specific to cannabis as an investigational product.\n\nPalliative care adds layers of complexity that don't exist in other cannabis research: patients are seriously ill, may deteriorate rapidly during a trial, have complex medication regimens, and face existential concerns that shape their relationship with any potential treatment. The intersection of cannabis complexity and palliative care complexity creates unique challenges that this paper aims to help future researchers navigate.","whyItMatters":"The evidence base for cannabis in palliative care can only grow if researchers can actually conduct the trials. Many well-intentioned cannabis studies fail due to regulatory, logistical, or ethical barriers that could have been anticipated. This paper provides a practical blueprint for navigating those barriers, potentially accelerating the pace of palliative cannabis research.","specificNumbers":"6 key design considerations identified. Phase I/IIb trial of vaporized cannabis for cancer anorexia. Action research audit trail from investigator meetings.","methodology":"Action research methodology applied to a Phase I/IIb trial of vaporized medicinal cannabis for anorexia in advanced cancer (ACTRN12616000516482). Notes from trial investigator meetings served as an audit trail. Data integrated and synthesized to identify key design considerations.","limitations":"Based on a single trial in one country (Australia), where cannabis regulations and palliative care systems may differ from other jurisdictions. Action research methodology provides rich practical insights but isn't empirically generalizable. The considerations are drawn from experience with vaporized flower—trials using oils, edibles, or synthetic cannabinoids would face different challenges."},{"rthcId":"RTHC-07452","title":"Nutritional Composition and Functional Properties of 'Beldiya' Hemp Seed and Oil: A Sustainable Local Resource from Northern Morocco for Health and Nutrition.","authors":"Rbah, Youssef; Belhaj, Kamal; Taaifi, Yassine; Allay, Aymane; Melhaoui, Reda; Serghini-Caid, Hana; Elamrani, Ahmed","year":2025,"journal":"Journal of oleo science, 74(6), 533-542","doi":"10.5650/jos.ess25015","pmid":"40451822","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07453","title":"A Thematic Text Analysis of Cannabis Edibles Brand Names.","authors":"Reboussin, Beth A; Lake, Shelby; Romero-Sandoval, E Alfonso; Cornacchione Ross, Jennifer; Egan, Kathleen L; Wagoner, Kimberly G; Sutfin, Erin L; Suerken, Cynthia K; Horton, Olivia E; Lazard, Allison J","year":2025,"journal":"Cannabis and cannabinoid research, 10(5), 593-597","doi":"10.1089/can.2025.0033","pmid":"40539323","tags":["legalization","harm-reduction","potency"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among 1,344 cannabis edible products from 250 brands, five brand name themes emerged: cannabis culture (42%), product characteristics (30%), medicine/health (23%), environment/nature (20%), and identity/culture (14%). CBD-only brands were more likely to use medicine/health themes (45% vs 18-20% for THC brands), while THC brands more often used cannabis culture and food-type subthemes.","whyItMatters":"Brand names are the first thing consumers encounter and shape expectations about effects and safety. The finding that CBD products are marketed as \"health and wellness\" while THC products lean on cannabis culture and food associations could minimize perceived risks and influence consumption decisions, particularly among new users.","specificNumbers":"1,344 products from 250 brands. 80 THC-only, 130 THC+CBD, 40 CBD-only brands. Medicine/health theme: 45% CBD-only vs 18% THC-only. Cannabis culture theme: 42% overall. Food subthemes more common in THC brands.","methodology":"Exploratory thematic text analysis of brand names for 1,344 cannabis edible products from 250 brands advertised online June-November 2022. Brands were categorized as THC-only (80), THC+CBD (130), or CBD-only (40). Five core themes and 15 subthemes were identified and compared across product categories.","limitations":"Only analyzed brand names, not packaging images or claims. Online product listings may not represent in-store marketing. Cannot measure whether brand names actually affect consumer behavior. U.S.-focused. Rapidly evolving market means findings may become outdated quickly."},{"rthcId":"RTHC-07454","title":"Risks of Cannabinoid Exposure on Birth Outcomes: A Systematic Review.","authors":"Reck, A Matthew; Reilly, Taylor; Vanegas, S Olivia; Shook, Natalie J; Kinsey, Steven G; Casavant, Sharon G","year":2025,"journal":"Cannabis and cannabinoid research, 10(5), 575-592","doi":"10.1089/can.2025.0027","pmid":"40589083","tags":["pregnancy"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Among 21 rodent and 36 human studies, prenatal cannabis/THC exposure was significantly associated with lower birth weight in both species. It was not associated with gestational age in either species. In rodent studies, exposure did not affect mortality or litter size. In human studies, there was a tendency for exposed infants to have worse health indicators at delivery.","whyItMatters":"By combining human and animal evidence, this review strengthens the case that cannabis exposure reduces fetal growth. The consistency across species suggests a biological mechanism rather than purely socioeconomic confounding. However, the lack of effect on gestational age suggests cannabis affects growth rate rather than pregnancy duration.","specificNumbers":"57 total studies (21 rodent, 36 human). Lower birth weight in both species. No effect on gestational age. No effect on rodent mortality or litter size. Tendency toward worse infant health at delivery in humans.","methodology":"Systematic review following PRISMA guidelines across PubMed, CINAHL, and Scopus for human studies, and PubMed and Scopus for rodent studies. 21 rodent and 36 human studies were included after screening. Rodent outcomes: birth weight, litter size, mortality, gestation length. Human outcomes: birth weight, gestational age, infant health at delivery.","limitations":"Heterogeneous study designs and exposure measurements across studies. Human studies cannot fully control for confounders (tobacco, alcohol, socioeconomic status). Rodent exposure protocols vary widely in dose, timing, and cannabinoid used. Mixed results for some outcomes may reflect true variability or methodological inconsistency."},{"rthcId":"RTHC-07455","title":"Measuring the Effects of Cannabis on Anxiety and Depression Among Cancer Patients.","authors":"Reddy, Apoorva C; Hampton, John M; Park, Susan J; Dickerson, Faith; Shah, Janvi; Chewning, Betty; Schmitz, Natalie; Trentham-Dietz, Amy","year":2025,"journal":"Cancer medicine, 14(21), e71342","doi":"10.1002/cam4.71342","pmid":"41163433","tags":["anxiety","depression","medical-cannabis","cbd","cancer"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This longitudinal study followed 1,962 cancer patients enrolled in the Minnesota Medical Cannabis Program, measuring self-reported anxiety and depression before and after 30 days of use. It's one of the largest studies to break down cannabis effects by dose, THC:CBD ratio, and route of administration.\n\nFor anxiety, the findings were dose-specific: patients taking higher CBD doses (>14.3 mg/day) showed more improvement than those taking lower doses (<4.6 mg/day). The route also mattered—enteral products (swallowed oils, capsules, edibles) outperformed other administration routes. And the THC:CBD ratio was relevant, though the specific pattern required a nuanced look at the data.\n\nDepression followed a different pattern. Dose and THC:CBD ratio didn't significantly predict depression improvement—only the route of administration mattered, with enteral products again showing the most benefit.\n\nThe divergence between anxiety and depression is interesting: anxiety responded to dose, ratio, and route, while depression responded only to route. This suggests different mechanisms—CBD's anxiolytic effects may be dose-dependent, while depression improvement may relate more to the pharmacokinetic profile of swallowed products (slower onset, longer duration) than to the specific cannabinoid content.\n\nThe fact that enteral products outperformed others for both conditions has practical implications: patients seeking mental health benefits may do better with oils and capsules than with inhaled products.","whyItMatters":"Cancer patients increasingly use cannabis for anxiety and depression, but most do so without evidence-based guidance on what type to use. This study provides the first large-scale data suggesting that higher CBD doses and swallowed products may be optimal for anxiety—actionable information for patients and the clinicians advising them.","specificNumbers":"N = 1,962 cancer patients. 30-day follow-up. Higher CBD (>14.3 mg/day) better for anxiety than lower CBD (<4.6 mg/day). Enteral products better for both anxiety and depression. Depression responded to route but not dose or ratio.","methodology":"Longitudinal cohort study. 1,962 cancer patients enrolled in the Minnesota Medical Cannabis Program. Self-reported anxiety and depression measured at enrollment and after 30 days. Analyzed by CBD dose (tertiles), THC:CBD ratio, and route of administration (enteral vs. other).","limitations":"Observational design within a medical cannabis program—patients chose their products (no randomization). Self-reported anxiety and depression (no clinical diagnosis). 30-day follow-up is relatively short. No control group (improvements could reflect placebo, natural recovery, or other treatments). Minnesota's program may have a specific product selection that limits generalizability. Dose data relies on product labels, not measured blood levels."},{"rthcId":"RTHC-07456","title":"The effects of tetrahydrocannabinol and cannabidiol on sleep in cancer patients.","authors":"Reddy, Apoorva C; Hampton, John M; Park, Susan J; Dickerson, Faith; Chewning, Betty; Schmitz, Natalie; Kwekkeboom, Kristine; Neuman, Heather; Trentham-Dietz, Amy","year":2025,"journal":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","doi":"10.1007/s12094-025-04069-8","pmid":"41120744","tags":["sleep","cancer","medical-cannabis","cbd"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 1,962 cancer patients enrolled in the Minnesota Medical Cannabis Program (2015-2023), those in the highest CBD dose quintile showed sleep improvement of 1.87 points on a 0-10 scale, compared to approximately 1.5 points for lower quintiles. Lower CBD dose quintiles were 29-35% less likely to achieve at least 30% improvement in sleep scores. THC doses and THC:CBD ratios were not consistently related to sleep improvement.","whyItMatters":"Sleep problems are among the most common and distressing symptoms for cancer patients. This is one of the largest real-world studies to separate CBD and THC effects on sleep, and the finding that CBD drives sleep improvement more than THC challenges the common assumption that THC is the primary sleep-active cannabinoid.","specificNumbers":"1,962 cancer patients. 2015-2023. Highest CBD quintile: 1.87-point sleep improvement (0-10 scale). Lower quintiles: ~1.5-point improvement. 29-35% less likely to achieve 30% improvement at lower CBD doses. THC: no consistent association.","methodology":"Patient-reported outcomes from 1,962 cancer patients in the Minnesota Medical Cannabis Program (2015-2023). Multivariable logistic and linear regression models assessed associations between sleep disturbance changes and CBD dose, THC dose, and THC:CBD ratio, adjusted for demographics, BMI, and enrollment fee category.","limitations":"Observational design without placebo control. Patient-reported outcomes subject to expectation effects. Cannot determine optimal CBD dose precisely from quintile analysis. Program participants may differ from general cancer population. Cannabis product formulations varied over the study period."},{"rthcId":"RTHC-07457","title":"The Effect of Cannabidiol on Nociceptive Behaviour and the Endocannabinoid System in an Incisional Wound Model.","authors":"Redmond, Maria C; Healy, Catherine R; Hopkins, Mary; Infantino, Rosmara; Gethin, Georgina; Pandit, Abhay; Finn, David P","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 19(1)","doi":"10.3390/ph19010043","pmid":"41599645","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07458","title":"The Therapeutic Potential of Cannabidiol in Skin Conditions.","authors":"Redmond, Maria C; Finn, David P","year":2025,"journal":"Journal of cosmetic dermatology, 24(11), e70527","doi":"10.1111/jocd.70527","pmid":"41178006","tags":["cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Preclinical evidence suggests CBD may treat various skin conditions through its multiple molecular targets expressed in skin. Limited clinical evidence exists for benefits in acne, dermatitis, and psoriasis, as well as cosmetic improvements in skin hydration, elasticity, and protection against skin aging. Several clinical trials of topical CBD for skin conditions are currently ongoing.","whyItMatters":"The CBD skincare market has exploded despite limited clinical evidence. This review provides a balanced assessment showing that while preclinical evidence is promising, clinical data remains sparse. The ongoing clinical trials will be critical for separating CBD's genuine therapeutic potential from marketing hype.","specificNumbers":"Multiple molecular targets in skin. Limited clinical evidence for acne, dermatitis, psoriasis. Evidence for improved hydration, elasticity. Several ongoing clinical trials.","methodology":"Literature review searching PubMed and Google Scholar for original research on CBD and skin conditions including acne, psoriasis, dermatitis, and wound healing.","limitations":"Narrative review without systematic methodology. Limited clinical studies available for review. Most evidence is preclinical. Cosmetic and therapeutic applications have different evidence standards. CBD product formulations vary widely, making generalization difficult."},{"rthcId":"RTHC-07459","title":"Efficacy of cannabidiol alone or in combination with Δ-9-tetrahydrocannabinol for the management of substance use disorders: An umbrella review of the evidence.","authors":"Redonnet, Bertrand; Eren, Filiz; Avenin, Guillaume; Melchior, Maria; Mary-Krause, Murielle","year":2025,"journal":"Addiction (Abingdon, England), 120(5), 813-834","doi":"10.1111/add.16745","pmid":"39947878","tags":["cbd","addiction","quitting"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"From 22 systematic reviews (5 with meta-analysis), CBD monotherapy does not appear efficacious for treating substance use disorders including cannabis, tobacco, alcohol, and opioid use. However, nabiximols (CBD+THC combination) demonstrated positive effects on cannabis withdrawal and craving symptoms. Evidence for CBD alone is limited and inconclusive for all addiction-related outcomes.","whyItMatters":"Despite widespread claims that CBD can help addiction, this highest level of evidence synthesis shows CBD alone does not work for this purpose. The finding that CBD needs to be combined with THC to help cannabis withdrawal specifically has direct implications for treatment guidelines and product development.","specificNumbers":"22 systematic reviews included. 5 included meta-analyses. CBD alone: not efficacious for any SUD. Nabiximols (CBD+THC): positive for cannabis withdrawal and craving. Evidence for alcohol, tobacco, opioids: limited and inconclusive.","methodology":"Umbrella review (review of reviews) following registered protocol, searching PubMed, Web of Science, and Epistemonikos for systematic reviews of RCTs on CBD and/or THC for substance use disorders, published 2000-October 2024. 22 systematic reviews included. Quality assessed with AMSTAR 2 tool by two independent researchers.","limitations":"Quality of included systematic reviews varied. Many underlying RCTs had small samples. Different CBD formulations, doses, and durations across studies limit comparison. The field is evolving rapidly and newer trials may change conclusions. Nabiximols findings may not generalize to non-pharmaceutical CBD+THC products."},{"rthcId":"RTHC-07460","title":"Understanding motives for illicit medicinal cannabis use: an exploratory analysis in a medical cannabis program.","authors":"Reeves, Carter; Franks, Lirit; Kelley, A Taylor; Incze, Michael; Gordon, Adam J; Yu, Ziji; Flake, Eden; Cochran, Gerald","year":2025,"journal":"Journal of cannabis research, 7(1), 48","doi":"10.1186/s42238-025-00284-w","pmid":"40682203","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 211 medical cannabis program participants in Utah, 11.9% (24 patients) reported using illicit cannabis within the past two weeks. The most common reasons were product cost (79%) and assurance of adequate supply (45.8%). Patients experiencing MC access barriers were 4.73 times more likely to use illicit cannabis. Those who trusted and relied on the state program for information were significantly less likely to seek illicit sources.","whyItMatters":"Medical cannabis programs succeed only if patients can access their medicine through legal channels. This study reveals that cost and supply barriers push patients toward unregulated products, undermining the safety benefits of regulated programs. Making legal cannabis more affordable and accessible could reduce illicit market participation.","specificNumbers":"211 survey respondents. 11.9% (24) reported illicit cannabis use. Cost barrier: 79%. Supply concern: 45.8%. Access barriers: OR 4.73 for illicit use (p <.001). Reliance on state program for info: AOR 0.16 (reduced illicit use, p <.05).","methodology":"Exploratory analysis of baseline survey data from 211 newly registered adults in Utah's medical cannabis program (diagnosed with chronic pain, PTSD, and/or cancer). Surveys assessed health, program experience, barriers, and illicit cannabis use. Descriptive statistics, chi-squared analysis, and logistic regression identified factors influencing illicit use.","limitations":"Small sample from a single state program. Self-reported illicit use may be underreported. Convenience sample may not represent all program participants. Cross-sectional design. Utah's program may differ from other state programs in structure and pricing."},{"rthcId":"RTHC-07461","title":"Real-time antecedents of cannabis use among young adults: An Ecological Momentary Assessment study.","authors":"Regan, Timothy; Devkota, Janardan; McQuoid, Julia; Lopez-Paguyo, Kekoa; Nguyen, Nhung; Meacham, Meredith C; Ling, Pamela M; Thrul, Johannes","year":2025,"journal":"Experimental and clinical psychopharmacology, 33(4), 396-406","doi":"10.1037/pha0000775","pmid":"40323845","tags":["addiction","youth"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Using ecological momentary assessment over 30 days with 36 young adults, cannabis use was more likely at neutral affect (aOR 0.95) and neutral arousal (aOR 1.52), higher craving (aOR 1.52), and during substance intoxication (aOR 1.25). External factors: use was more likely at home (aOR 1.97), less likely where smoking was forbidden (aOR 0.46), and less likely with more people present (aOR 0.91 per person).","whyItMatters":"Understanding when and why people use cannabis in real time is crucial for developing effective interventions. The finding that cannabis use occurs at neutral rather than negative emotional states challenges the self-medication narrative and suggests habitual or routine use patterns may be more important drivers than emotional coping.","specificNumbers":"36 participants. 30-day monitoring period. 1,632 prompts completed. Home use: aOR 1.97. Forbidden places: aOR 0.46. Per additional person present: aOR 0.91. Craving: aOR 1.52. Mean age 24.2.","methodology":"Ecological Momentary Assessment study with 36 young adults (mean age 24.2, 33% female, 61% sexual minority, 44% non-Hispanic White) who regularly used both cannabis and tobacco. Participants completed multiple daily surveys over 30 days (1,632 total prompts). Generalized estimating equations estimated associations between momentary antecedents and cannabis use.","limitations":"Small sample (N=36). Participants used both cannabis and tobacco, limiting generalizability. Self-reported momentary data may be subject to reporting bias. Mostly sexual minority participants (61%). 30-day window may not capture seasonal or other temporal patterns."},{"rthcId":"RTHC-07462","title":"Inhaled Isopropyl Alcohol for Refractory Cannabis Hyperemesis Syndrome: A Case With Pneumomediastinum and Pneumothorax.","authors":"Rehman, Abdul; Javed, Muhammad Ahmad","year":2025,"journal":"Cureus, 17(9), e93493","doi":"10.7759/cureus.93493","pmid":"41170261","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07463","title":"Altered Network Function in Hippocampus After Sub-Chronic Activation of Cannabinoid Receptors in Early Adolescence.","authors":"Rehn, Johanna; Admeus, Lucas; Kocsis, Bernat","year":2025,"journal":"International journal of molecular sciences, 26(24)","doi":"10.3390/ijms262412182","pmid":"41465607","tags":["neuroscience","youth","addiction","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The hippocampus—the brain's memory center—has an unusually high density of CB1 cannabinoid receptors. This study asked what happens when those receptors are artificially activated during the adolescent developmental window.\n\nRats received daily injections of CP-55940, a synthetic CB1 receptor agonist, during either early or late adolescence (postnatal days 32–36 or 42–46). They were then tested in adulthood (after postnatal day 70) to see if the adolescent exposure left lasting marks.\n\nIt did. Adult rats that had been exposed during adolescence showed a significant decrease in hippocampal theta power—the brain rhythm essential for spatial navigation, memory encoding, and attentional processing. Theta rhythm was elicited by brainstem stimulation at five intensity levels, providing a rigorous measure.\n\nCritically, the adolescent pre-treatment made adult rats more sensitive to further CB1 receptor activation. When adult rats received an acute dose of the same agonist, those who had been pre-treated in adolescence showed more pronounced theta disruption than those who hadn't. This suggests adolescent cannabinoid exposure doesn't just cause acute effects—it sensitizes the brain to future cannabinoid challenges.\n\nThe hippocampal theta rhythm abnormalities documented here overlap with patterns seen in schizophrenia, adding mechanistic support to the epidemiological link between adolescent cannabis use and later psychosis risk.","whyItMatters":"This provides a direct mechanistic link between adolescent cannabinoid receptor activation and lasting brain rhythm abnormalities. Theta oscillations aren't abstract measurements—they're the electrical signatures of memory formation, attention, and cognitive processing. If adolescent cannabis use permanently disrupts these rhythms, it could explain the cognitive and psychiatric vulnerabilities documented in human epidemiological studies.","specificNumbers":"Pre-treatment: PND 32–36 or PND 42–46. Testing: PND 70+. Significant decrease in elicited theta power in pre-treated adult rats. Pre-treated rats showed enhanced sensitivity to acute CB1 agonist challenge in adulthood.","methodology":"Animal study in rats. Pre-treatment with CB1R agonist CP-55940 or vehicle during adolescence (PND 32–36 or PND 42–46). Testing in adulthood (PND 70+) under urethane anesthesia. Hippocampal theta rhythm elicited by brainstem stimulation at five intensity levels, measured 1 hour before and up to 5 hours after acute injection.","limitations":"Animal model using a synthetic cannabinoid agonist, not THC—the pharmacology is similar but not identical. Rats under urethane anesthesia may not reflect awake brain activity. The developmental windows in rats approximate but don't precisely map onto human adolescence. No behavioral testing in this study (only electrophysiology). Only one synthetic agonist tested—different compounds might produce different patterns."},{"rthcId":"RTHC-07464","title":"Altered network function in hippocampus after sub-chronic activation of Cannabis receptors in peri-adolescence.","authors":"Rehn, Johanna; Admeus, Lucas; Kocsis, Bernat","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.09.16.676661","pmid":"41000713","tags":["cognition","psychosis","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"This is the preprint (bioRxiv) version of the study published as RTHC-00197. The core finding is identical: sub-chronic activation of cannabinoid CB1 receptors during peri-adolescence in rats produces lasting abnormalities in hippocampal theta synchronization that persist into adulthood.\n\nThe preprint provides additional detail on the experimental design. The cohort included sex-balanced groups (6 males, 5 females in the treatment group; 4 males, 4 females in controls), though the abstract doesn't specify whether sex differences were observed. Some animals were tested at a later timepoint (PND 111–115 vs. the standard PND 70–88), suggesting the researchers were investigating whether the effects persisted even longer.\n\nThe preprint also emphasizes the cognitive dimension more explicitly than the journal version, noting that \"recent findings indicate that cognitive domains may also be at risk\" beyond the historically primary concern about psychosis. This framing connects the electrophysiological findings to real-world cognitive concerns about adolescent cannabis use.\n\nThe theta rhythm findings have relevance to both schizophrenia (where theta abnormalities are well-documented) and cognitive impairment (where theta oscillations underpin memory encoding and attentional processing).","whyItMatters":"The sex-balanced design is important because cannabis may affect male and female brains differently during development (see RTHC-00191 on prenatal THC and sex-specific amygdala effects). The extended testing window (up to PND 115) helps establish whether effects are truly persistent or eventually fade.","specificNumbers":"Treatment: n=11 (6M, 5F). Vehicle: n=8 (4M, 4F). PND 32–36 or 42–46 pre-treatment (n=10 and 9). Testing at PND 70–88 (n=17) and PND 111–115 (n=2).","methodology":"Preprint of RTHC-00197. Rats pre-treated with CB1R agonist CP-55940 (n=11, 6M/5F) or vehicle (n=8, 4M/4F) during adolescence (PND 32–36 or 42–46, n=10 and 9). Adult testing at PND 70–88 (n=17) or PND 111–115 (n=2). Hippocampal theta rhythm elicited by brainstem stimulation.","limitations":"Same limitations as RTHC-00197 plus: this is a preprint that may not have undergone peer review. The very small extended-timepoint group (n=2) limits conclusions about persistence beyond PND 88. Sex-specific analyses aren't described in the abstract despite the balanced design."},{"rthcId":"RTHC-07465","title":"Cannabidiol promotes fine-tuning of natural killer and monocytic cells subsets as well as cytokine storm during chikungunya virus exposure in vitro: Insights for putative therapeutic interventions.","authors":"Reis, Erik Vinicius de Sousa; Lopes-Ribeiro, Ágata; Moraes, Thaís de Fátima Silva; Marques-Ferreira, Geovane; Corrêa-Dias, Laura Cardoso; Menegatto, Marília Bueno da Silva; Wilker-Teixeira, Caio; Sabino, Adriano de Paula; Coelho-Dos-Reis, Jordana Grazziela Alves","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 193, 118900","doi":"10.1016/j.biopha.2025.118900","pmid":"41385863","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07466","title":"Long-Lasting Cognitive and Physical Impairment After Recreational Use of the Semisynthetic Cannabinoid Hexahydrocannabinonyl (HHC-C9): A Case Report.","authors":"Reiter, Nanna; Palmqvist, Dorte Fris; Larsen, Gro Borges; Høi, Mathilde Emilie; Rasmussen, Brian Schou; Thomsen, Ragnar","year":2025,"journal":"Reports (MDPI), 8(3)","doi":"10.3390/reports8030176","pmid":"40981134","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"After eating two cannabis cookies labeled as containing 40 mg \"CC9\" and biting a gummy with unknown contents, a man in his early forties required emergency admission for deficits in alertness and responsiveness. He experienced vomiting, visual problems, and nine days of cognitive and physical impairment. Forensic toxicology confirmed HHC-C9, a novel semisynthetic cannabinoid.","whyItMatters":"Semisynthetic cannabinoids like HHC-C9 now account for over 40% of new psychoactive substances reported in Europe. They are sold as \"legal highs\" in convenience stores and online, often as cookies, candies, or vape products specifically targeting young consumers. This case demonstrates that their effects can be dramatically more severe and prolonged than natural cannabis.","specificNumbers":"9 days of impairment. Two cookies consumed (labeled 40 mg CC9). Products often mislabeled and sold as souvenirs or potpourri. SSCs account for >40% of new substances at European level.","methodology":"Single case report from an Emergency Department. Clinical presentation documented alongside forensic toxicological analysis confirming HHC-C9 in blood.","limitations":"Single case report. Co-ingestion of gummy with unknown contents. Cannot determine exact dose consumed. Individual susceptibility may vary. Limited information on HHC-C9 pharmacology."},{"rthcId":"RTHC-07467","title":"Perceptions of cannabis among adults aged 60 years and older in Canada: a qualitative study.","authors":"Renard, Justine; Panesar, Balpreet; Noorbakhsh, Sima; Wadsworth, Elle; Cristiano, Nick; Gabrys, Robert","year":2025,"journal":"Health promotion and chronic disease prevention in Canada : research, policy and practice, 45(10), 395-406","doi":"10.24095/hpcdp.45.10.01","pmid":"41124100","tags":["seniors","legalization","medical-cannabis"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Five themes emerged from 10 focus groups with 72 participants: common practices (primarily edibles and inhalation), general knowledge gaps, perceived harms (physical and cognitive effects, drug interactions), perceived benefits (pain management, mental health), and decreased stigma following legalization. Both frequent and infrequent users noted therapeutic benefits but expressed concerns about medication interactions and lack of trustworthy information sources.","whyItMatters":"Cannabis use among older Canadians has risen faster than any other age group since legalization. This population has specific risks, including medication interactions and cognitive effects, yet they report that healthcare providers are unable or unwilling to provide guidance, leaving them to navigate cannabis use largely on their own.","specificNumbers":"72 participants aged 60+. 10 focus groups. 5 Canadian regions. Primary methods: edibles and inhalation. Top benefits: pain, mental health. Top concerns: side effects, drug interactions, information gaps.","methodology":"Ten online focus groups with 72 participants aged 60+ across five Canadian regions, segmented by cannabis use frequency. Open-ended questions explored consumption methods, motivations, risk/benefit perceptions, and legalization effects. Thematic analysis of transcribed recordings.","limitations":"Qualitative design with 72 participants. Self-selected sample may overrepresent engaged users. Focus group dynamics may influence responses. Canadian context may not generalize to other countries. Did not assess actual health outcomes."},{"rthcId":"RTHC-07468","title":"Trends in substance use-related emergency department visits by youth, 2018-2023.","authors":"Renny, Madeline H; Stecher, Yago; Vargas-Torres, Carmen; Zebrowski, Alexis M; Merchant, Roland C","year":2025,"journal":"The American journal of emergency medicine, 92, 1-9","doi":"10.1016/j.ajem.2025.02.035","pmid":"40048886","tags":["youth","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 151,764 ED visits for 12-21 year olds, substance use accounted for 3.0% overall but increased from 2.8% to 3.4% (p<0.001). Cannabis visits nearly doubled from 17.9% to 35.3% of substance visits, with increases across all age groups. Female visits increased from 43.4% to 52.4%. Visits by 12-14 and 15-17 year olds also increased significantly. 19% of patients had a substance-related revisit within one year.","whyItMatters":"The near-doubling of cannabis-related ER visits among youth during a period of expanding legalization and product availability is a clear public health signal. The increase among 12-14 year olds is particularly concerning, as is the finding that nearly one in five had a repeat visit within a year.","specificNumbers":"151,764 total ED visits. 3.0% substance-related. Cannabis visits: 17.9% to 35.3% (2018-2023). Female proportion: 43.4% to 52.4%. 19% had substance revisit within 1 year. Significant increases in 12-14 and 15-17 year olds.","methodology":"Retrospective EHR review from six EDs in an urban healthcare system. Identified 12-21 year old patients with substance use-related visits (2018-2023) using ICD-10 codes. Logistic regression assessed characteristics associated with visits, hospital admissions, and revisits.","limitations":"Single urban healthcare system. ICD-10 coding may misclassify or undercount substance visits. Cannot determine severity of cannabis-related presentations. Rising visits may partly reflect increased coding for cannabis rather than true increases. Does not distinguish intentional from accidental exposure."},{"rthcId":"RTHC-07469","title":"Systematic review: the impact of maternal pre-and postnatal cannabis use on the behavioral and emotional regulation in early childhood.","authors":"Reyentanz, Emely; Gerlach, Jennifer; Kuitunen-Paul, Sören; Golub, Yulia","year":2025,"journal":"European child & adolescent psychiatry, 34(2), 423-463","doi":"10.1007/s00787-024-02494-8","pmid":"38878224","tags":["pregnancy","youth","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"From 1,061 screened articles, 33 were included. Diminished regulatory abilities were more common in infants after prenatal cannabis exposure, while specific regulatory problems (behavioral, emotional) were more frequently found after age 2. Mechanisms included changes in methylation and expression of endocannabinoid, dopaminergic, and opioid system genes, increased cortisol reactivity, altered immune markers, and changes in brain structure and connectivity.","whyItMatters":"Self-regulation, the ability to control attention, emotions, and behavior, is foundational for child development. This review shows that prenatal cannabis exposure may undermine these abilities through multiple neurobiological pathways, with effects that become more apparent as children reach ages where self-regulation demands increase.","specificNumbers":"33 studies included from 1,061 screened. Children ages 0-6. Regulatory difficulties more apparent after age 2. Multiple mechanisms identified: gene methylation, cortisol, brain structure changes.","methodology":"Systematic review following PRISMA guidelines, searching Medline, Web of Science, and PsycInfo. Included studies of children ages 0-6 with preconception, prenatal, or postnatal cannabis exposure. Investigated regulatory abilities, regulatory problems, and neurobiological mechanisms. Registered with PROSPERO.","limitations":"Limited number of studies meeting criteria. Small sample sizes in many studies. Lack of control for maternal psychopathology in most studies. Cannabis exposure poorly quantified in many studies. Cannot fully separate cannabis effects from co-occurring risk factors."},{"rthcId":"RTHC-07470","title":"A multicenter study on the use of purified cannabidiol for children with treatment-resistant developmental and epileptic encephalopathies.","authors":"Reyes Valenzuela, Gabriela; Espeche, Alberto; Fortini, Sebastian; Gamboni, Beatriz; Adi, Javier; Semprino, Marco; Fasulo, Lorena; Galicchio, Santiago; Cachia, Pedro; Chacón, Santiago; Calvo, Agustin; Beltran, Lucas; Bautista, Claudia; Caraballo, Roberto H","year":2025,"journal":"Epilepsy & behavior : E&B, 171, 110590","doi":"10.1016/j.yebeh.2025.110590","pmid":"40669175","tags":["epilepsy","cbd","youth"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"In 551 children with drug-resistant developmental and epileptic encephalopathies treated with purified CBD at 10 centers, 50.6% achieved at least 50% seizure reduction after 12-32 months, including 14.2% who became seizure-free. Long-term follow-up of a subset (280 patients, 24-32 months) showed sustained efficacy with 51.4% maintaining at least 50% reduction and 10.2% remaining seizure-free. The treatment was safe and well-tolerated.","whyItMatters":"This is one of the largest real-world CBD epilepsy studies to date. The finding that purified CBD helps approximately half of children with the most treatment-resistant forms of epilepsy, including rare genetic conditions, confirms and extends findings from earlier clinical trials into everyday clinical practice.","specificNumbers":"551 patients enrolled. Mean age at CBD start: 8.5 years. 50.6% achieved >50% seizure reduction. 14.2% became seizure-free. 280 patients at long-term follow-up: 51.4% maintained >50% reduction, 10.2% seizure-free. Median follow-up: 22 months. 10 centers.","methodology":"Descriptive real-world multicenter study of children aged 0.5-16 years with ILAE-defined drug-resistant developmental and epileptic encephalopathies treated with purified CBD at 10 centers (March 2021-December 2024). Etiologies: structural (45%), genetic (28.8%), immune (0.9%), infectious (0.5%), unknown (24.3%). Median follow-up: 22 months.","limitations":"Observational design without placebo control. Concomitant antiepileptic medications make isolating CBD effects difficult. Selection bias: centers may preferentially treat and report patients they expect to respond. Loss to follow-up could bias long-term results."},{"rthcId":"RTHC-07471","title":"Efficacy of a neuroscience informed psychoeducation intervention on cognitive, emotional, and substance use outcomes in college students: a pilot study.","authors":"Rezapour, Tara; McLean, Kayla L; Psederska, Elena; Chokshi, Swara; Maleki, Khashayar Niki; Ekhtiari, Hamed; Vassileva, Jasmin","year":2025,"journal":"Frontiers in psychiatry, 16, 1655909","doi":"10.3389/fpsyt.2025.1655909","pmid":"41048899","tags":["youth","harm-reduction","cognition"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"After four 20-minute NIPA sessions, 68 college students showed significant reductions in executive function deficits, stress, and anxiety. Decision-making improved: reduced delay discounting of large rewards and increased sensitivity to uncertainty. Participants reported lower intentions to use and lower actual use of nicotine and cannabis, and less binge drinking.","whyItMatters":"Traditional substance prevention focuses on knowledge and motivation, but this app targets underlying cognitive processes like executive function and decision-making. The simultaneous improvement in cognition and reduction in substance use suggests that building cognitive skills may be more effective than information alone.","specificNumbers":"68 participants. Four 20-minute sessions. Significant reductions in executive function deficits (Z=-7.11, p<0.001). Reduced anxiety (Z=-2.49, p=0.013). Increased metacognitive awareness (Z=-3.07, p=0.002). Reduced cannabis use intentions and actual use.","methodology":"Pilot study with 68 undergraduates who had prior substance use. Pre-post assessment around four 20-minute NIPA app sessions combining metacognitive training, gamified neurocognitive tasks, and neuroscience psychoeducation delivered through cartoons, animations, and videos. Wilcoxon signed-rank and binomial tests analyzed changes.","limitations":"No control group. Pre-post design cannot establish causation. Small sample (N=68). Very short intervention (4 sessions). No follow-up to assess durability. Self-reported outcomes. Participants self-selected."},{"rthcId":"RTHC-07472","title":"Cannabigerol Modulates Cannabinoid Receptor Type 2 Expression in the Spinal Dorsal Horn and Attenuates Neuropathic Pain Models.","authors":"Rezende, Bismarck; Fernandes, Gabriel Gripp; de Simas Gonçalves, Vitória Macario; Nascimento, Gabriela Guedes; Marques, Kethely Lima; de Oliveira, Barbara Conceição Costa Azeredo; Dos Santos, Yure Bazilio; de Andrade, Maria Eduarda Barros; Calumbi, Karine Simões; Maia, Eduardo Perdigão; Trefilio, Luisa Menezes; Antunes, Fernanda; Fontes-Dantas, Fabrícia Lima; Montes, Guilherme Carneiro","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(10)","doi":"10.3390/ph18101508","pmid":"41155621","tags":["pain","cbd","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Most cannabis research focuses on THC and CBD. This study investigates cannabigerol (CBG)—a \"minor\" cannabinoid found in smaller quantities in the plant but with a distinct pharmacological profile.\n\nUsing both acute pain tests (formalin and hot plate) and a chronic neuropathic pain model (spinal nerve ligation in rats), the researchers found that CBG-enriched extract had significant pain-reducing effects. The optimal dose was 30 mg/kg orally.\n\nWhat makes this mechanistically interesting is the pathway. CBG's pain-relieving effects worked primarily through CB2 receptors—not CB1 receptors (the ones THC activates to produce a \"high\") and not through BDNF or TNF pathways. CB2 receptors are found mainly on immune cells, including the microglia in the spinal cord. This immune-mediated mechanism was confirmed by the finding that CBG reduced microglial density and spinal morphological changes at the injury site.\n\nThis CB2-mediated mechanism is significant because it suggests CBG could provide pain relief without the psychoactive effects of THC (which works through CB1). The spinal nerve ligation model is particularly relevant—it mimics the type of nerve damage that causes chronic neuropathic pain in humans, which is notoriously difficult to treat.\n\nCBG also upregulated CB2 receptor expression in the spinal dorsal horn, suggesting it doesn't just activate existing receptors but actually increases the density of the receptors it works through.","whyItMatters":"Neuropathic pain affects millions and responds poorly to conventional treatments. RTHC-00170 showed that nerve pain patients use cannabis more intensively—suggesting they're seeking relief that other treatments don't provide. CBG's CB2-mediated mechanism offers the possibility of cannabinoid pain relief without the cognitive and psychoactive effects of THC, which limit THC's clinical utility for chronic daily pain management.","specificNumbers":"Optimal dose: 30 mg/kg oral CBG. 14-day daily treatment in the chronic pain model. Pain-relieving effects mediated through CB2R. Reduced microglial density at spinal injury site. CB1R, BDNF, and TNF did not play major roles.","methodology":"Animal study. Acute pain: formalin and hot plate tests in male Swiss mice. Chronic pain: spinal nerve ligation (SNL) in 8-week-old male Wistar rats, with CBG-enriched extract administered orally daily for 14 days. Assessed thermal and mechanical sensitivity, microglial density, spinal morphology, and receptor involvement (CB1R, CB2R, BDNF, TNF).","limitations":"Animal study only—no human data. CBG-enriched extract (not pure CBG), so other cannabinoids may contribute to effects. Only male animals used—sex differences in pain processing are well-documented. The 14-day treatment window is short for modeling chronic pain management. Oral bioavailability of CBG in humans may differ from rodents. CBG is currently expensive to produce in quantity."},{"rthcId":"RTHC-07473","title":"The Longitudinal Relationship of Loneliness With Frequency and Problematic Use of Alcohol and Cannabis Among Young Adults.","authors":"Rhew, Isaac C; Cadigan, Jennifer M; Guttmannova, Katarina; Caouette, Justin D; Kuklinski, Margaret R; Oesterle, Sabrina","year":2025,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 77(5), 917-923","doi":"10.1016/j.jadohealth.2025.06.037","pmid":"40946238","tags":["mental-health","addiction","youth"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Using marginal structural modeling to control for multiple confounders, loneliness at ages 21 and 23 predicted greater cannabis use frequency at subsequent waves (OR 1.13 per SD increase, 95% CI 1.06-1.20). Loneliness also predicted higher cannabis use disorder risk (prevalence ratio 1.20, 95% CI 1.12-1.29) and hazardous alcohol use (PR 1.10, 95% CI 1.03-1.17). The cannabis associations held after accounting for depression, prior substance use, and other psychosocial factors.","whyItMatters":"In an era of rising loneliness and social isolation, this study establishes that loneliness independently predicts problematic cannabis use, separate from depression. This suggests that addressing loneliness and social connection could be a novel approach to preventing cannabis use disorders in young adults.","specificNumbers":"4,407 participants. Loneliness and cannabis frequency: OR 1.13 (95% CI 1.06-1.20). Cannabis use disorder: PR 1.20 (95% CI 1.12-1.29). Hazardous alcohol use: PR 1.10 (95% CI 1.03-1.17). Measured ages 21-26.","methodology":"Data from 4,407 young adults in the Community Youth Development Study. Loneliness measured at ages 21 and 23; substance outcomes at ages 23 and 26. Marginal structural modeling accounted for time-fixed and time-varying confounders including depressive symptoms, prior substance use, and psychosocial factors. Cannabis use disorder diagnosed using validated criteria.","limitations":"Two-year lag between loneliness and outcome assessments may miss shorter-term dynamics. Self-reported loneliness measure (4 items). Marginal structural models address but cannot eliminate all confounding. Sample from community study may not represent all young adults."},{"rthcId":"RTHC-07474","title":"Monthly patterns of depressive symptoms and substance use and their relation to longer-term hazardous substance use and mental health problems: Examining mutual maintenance using monthly data from young adults.","authors":"Rhew, Isaac C; Graupensperger, Scott; Martinez, Griselda; Lee, Christine M","year":2025,"journal":"Addictive behaviors, 166, 108326","doi":"10.1016/j.addbeh.2025.108326","pmid":"40101677","tags":["depression","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Over 24 consecutive months, there was substantial variability in how individual young adults' substance use responded to depressive symptoms. Some used more cannabis when depressed, others used less. Those who consistently increased cannabis use during depressive episodes reported greater hazardous cannabis use at 30-month follow-up. Interestingly, this pattern did not predict 30-month depressive symptoms, suggesting substance escalation rather than worsening depression.","whyItMatters":"This study distinguishes between people who use cannabis to cope with depression versus those who reduce use when feeling low. The finding that depression-driven escalation predicts problematic use, but not worsening depression, suggests the primary concern is developing a harmful use pattern rather than depression worsening itself.","specificNumbers":"772 participants. 24 monthly surveys. 30-month follow-up. Mean age 21.1. 57% female. Substantial individual variability in depression-substance use associations. Depression-linked cannabis escalation predicted hazardous use but not later depression.","methodology":"Longitudinal study of 772 young adults (mean age 21.1, 57% female) in Washington State with 24 monthly surveys measuring depressive symptoms and substance use, plus a 30-month follow-up assessing hazardous use and depression. Multilevel models extracted person-specific within-person associations, linked to later outcomes.","limitations":"Washington State sample may not generalize. Self-reported monthly measures may miss day-to-day fluctuations. Cannot determine causation even with longitudinal design. Attrition over 30 months. Cannabis quantity not measured, only hours high."},{"rthcId":"RTHC-07475","title":"Repeated Administration of a Full-Spectrum Cannabidiol Product, Not a Cannabidiol Isolate, Reverses the Lipopolysaccharide-Induced Depressive-Like Behavior and Hypolocomotion in a Rat Model of Low-Grade Subchronic Inflammation.","authors":"Ribeiro de Novais Júnior, Linério; Vicente da Silva, Tiago; da Silva, Larissa Mendes; Metzker de Andrade, Flavia; da Silva, Alisson Reuel; Meneguzzo, Vicente; de Souza Ramos, Suelen; Michielin Lopes, Cyntia; Bernardo Saturnino, Artur; Inserra, Antonio; de Bitencourt, Rafael Mariano","year":2025,"journal":"Cannabis and cannabinoid research, 10(2), 236-246","doi":"10.1089/can.2024.0086","pmid":"39347620","tags":["cbd","depression","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In rats with inflammation-induced depressive-like behavior (7 days of LPS), full-spectrum CBD extract at both 15 and 30 mg/kg reversed depressive behavior in the forced swim test, while CBD isolate at the same doses did not. The full-spectrum extract at 30 mg/kg also restored inflammation-induced reductions in locomotion. Both formulations showed an anxiogenic-like trend.","whyItMatters":"This directly tests the \"entourage effect\" hypothesis: that whole-plant cannabis extracts work better than isolated cannabinoids. The clear superiority of full-spectrum over isolate for depression specifically in an inflammation context supports using whole-plant preparations rather than pure CBD for inflammation-related mood disorders.","specificNumbers":"Full-spectrum CBD: effective at 15 and 30 mg/kg for depression. CBD isolate: ineffective at both doses. 30 mg/kg full-spectrum also restored locomotion. 7-day treatment period. LPS 0.5 mg/kg daily for inflammation.","methodology":"Rats received daily LPS (0.5 mg/kg) for 7 days to induce subchronic inflammation and depressive-like behavior. Concurrently treated with either CBD isolate or full-spectrum CBD product (15 or 30 mg/kg) for 7 days. Assessed using forced swim test (depression), open field test (locomotion), and elevated plus maze (anxiety).","limitations":"Animal study; results may not translate to humans. Specific full-spectrum composition not fully characterized. Single inflammation model may not represent all depression types. Short treatment duration (7 days). Anxiogenic trend with both formulations is concerning."},{"rthcId":"RTHC-07476","title":"Recommendations for the Clinical Management and Prevention of Pediatric Cannabis Edible Ingestions.","authors":"Ricchezza, Joseph; Hernandez, Jeffrey; Ocasio, Ana C; Lynch, William J","year":2025,"journal":"The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 30(6), 752-759","doi":"10.5863/JPPT-24-00107","pmid":"41415935","tags":["youth","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis edible products pose significant health risks to children due to inconsistent governmental regulation of manufacturing, packaging, and labeling. The variation in components and potencies causes a wide range of dose-dependent adverse events. Consumer education and harm reduction strategies are lacking, leading to increased unintentional pediatric ingestions. The review provides recommendations for screening, management, and prevention.","whyItMatters":"As cannabis edibles become more available and are designed to look like regular candy or baked goods, accidental pediatric exposures are rising. Children metabolize THC differently than adults, and there are no standardized protocols for managing these exposures, leaving clinicians without clear guidance.","specificNumbers":"Inconsistent regulation across states. Wide range of dose-dependent adverse events. No standardized treatment protocols. Increasing incidence of pediatric unintentional ingestions.","methodology":"Clinical review providing medical and pharmacological context on cannabis edibles in the U.S., with recommendations for initial screening, management, and prevention of pediatric cannabis ingestions.","limitations":"Narrative clinical review. Does not quantify the exact magnitude of the problem. U.S.-focused. Rapidly evolving regulatory landscape means recommendations may need frequent updating."},{"rthcId":"RTHC-07477","title":"The psychosis continuum: Systematic review on prodromal markers, symptom progression, and early intervention strategies.","authors":"Ricci, Valerio; Sarni, Alessandro; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"Asian journal of psychiatry, 113, 104725","doi":"10.1016/j.ajp.2025.104725","pmid":"41109117","tags":["psychosis","anxiety","depression","youth","cognition","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This systematic review synthesized 60 studies spanning 25 years (2000–2025) to map the trajectory from early warning signs to full psychotic episodes. The prodromal period—before diagnosable psychosis—turns out to be more complex than previously understood.\n\nEarly symptoms are mostly non-specific: depression (52%), worry (41%), and anxiety (38%). These look nothing like psychosis. Attenuated psychotic symptoms emerge later. Negative symptoms (social withdrawal, flat affect, reduced motivation) typically precede positive symptoms (hallucinations, delusions) by about 12 months.\n\nThree distinct trajectories were identified: persistent (35%), fluctuating (42%), and improving (23%). The fact that nearly a quarter of people at ultra-high risk actually improve underscores that prodromal symptoms don't inevitably lead to psychosis.\n\nAmong environmental risk factors, cannabis stood out with specific numbers: a 4-fold increased transition risk, escalating to 10-fold in individuals with genetic vulnerability. Childhood trauma affected 61% of ultra-high-risk individuals. These environmental factors may be particularly important because the review notes that premorbid deterioration may reflect environmental factors more than genetic ones.\n\nNeurobiological prediction is advancing: machine learning using eye-tracking achieved 77.6% accuracy, and multimodal assessment reached AUC = 0.84 for predicting psychosis transition.","whyItMatters":"If we can identify who's on the path to psychosis early enough, we might be able to intervene. The 4-fold cannabis risk (10-fold with genetic vulnerability) provides specific, quantifiable risk information that's more actionable than vague warnings. And the finding that 23% of at-risk individuals improve naturally helps avoid over-pathologizing early symptoms.","specificNumbers":"60 studies reviewed. Early prodromal: depression 52%, worry 41%, anxiety 38%. Negative symptoms precede positive by ~12 months. Trajectories: persistent 35%, fluctuating 42%, improving 23%. Cannabis: 4-fold risk (10-fold with genetic vulnerability). Childhood trauma: 61% of UHR. Machine learning prediction: 77.6% (eye-tracking), AUC 0.84 (multimodal).","methodology":"Systematic review of 60 studies (2000–2025) following PRISMA guidelines. Included 35 prospective cohorts (58.3%), 9 cross-sectional studies (15%), 9 RCTs (15%), 5 case-control studies (8.3%), and 2 qualitative studies (3.3%).","limitations":"Systematic reviews aggregate existing evidence with all its limitations. The 4-fold cannabis risk figure comes from observational studies that can't prove causation. Prodromal assessment tools may over-identify people who would never develop psychosis. The improving trajectory (23%) complicates intervention decisions. Machine learning prediction tools aren't yet validated for clinical use."},{"rthcId":"RTHC-07478","title":"Self-disturbance in first-episode psychosis: Theoretical framework and potential cannabis interactions - a systematic review.","authors":"Ricci, Valerio; De Berardis, Domenico; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"Frontiers in psychiatry, 16, 1733254","doi":"10.3389/fpsyt.2025.1733254","pmid":"41561992","tags":["psychosis","addiction","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Among 3,847 participants across 22 studies, daily high-potency cannabis use was associated with 3.21-fold increased odds of clinically significant dissociation (95% CI 2.14-4.82) and more severe anomalous self-experiences. Cannabis users showed DES-II score elevations of 11-13 points exceeding clinical thresholds. Cannabis-related dissociation showed distinct features including self-world boundary confusion. Approximately 75% showed dissociation reduction following cannabis cessation.","whyItMatters":"This review reveals that cannabis does not just trigger psychotic symptoms but fundamentally disturbs the sense of self in first-episode psychosis patients. The dissociative effects, including feeling disconnected from reality and confusion about self-boundaries, may explain why cannabis-using psychosis patients have worse outcomes. The reversibility finding offers hope.","specificNumbers":"22 studies, 3,847 participants. Daily high-potency use: OR 3.21 for dissociation. DES-II elevations: 11-13 points. ~75% showed improvement after cessation. Worse functional outcomes: GAF 52 vs 67 in non-users (p<0.001).","methodology":"Systematic review following PRISMA guidelines, searching four databases (PubMed, Scopus, PsycINFO, Web of Science) from January 1990 to September 2025. 22 studies meeting inclusion criteria with total N=3,847. GRADE certainty assessed as moderate for dissociative symptoms.","limitations":"Most studies were observational. Cannot fully establish causation. GRADE certainty was low for self-disturbance outcomes due to limited direct evidence. Heterogeneous assessment tools across studies. Cannot determine pre-existing dissociative tendencies."},{"rthcId":"RTHC-07479","title":"The endocannabinoid system as a therapeutic target in prodromal psychosis: From molecular mechanisms to clinical applications.","authors":"Ricci, Valerio; Sarni, Alessandro; De Berardis, Domenico; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 2698811251389574","doi":"10.1177/02698811251389574","pmid":"41328544","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07480","title":"Co-occurrence between adverse childhood experiences and cannabis use in psychosis risk and course: A stratified systematic review.","authors":"Ricci, Valerio; De Berardis, Domenico; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"Journal of psychiatric research, 190, 387-399","doi":"10.1016/j.jpsychires.2025.08.015","pmid":"40834620","tags":["psychosis","mental-health","youth"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Across 62 studies in five population categories, childhood adversity and cannabis use showed synergistic psychosis risk amplification: odds ratios up to 20.9 in community samples and 31.0 in first-episode samples. Patients with combined exposure had earlier onset (2.9-3.6 years earlier), more severe positive symptoms, reduced treatment response, and poorer functional outcomes. Evidence supports a developmental cascade model where trauma creates neurobiological vulnerability that cannabis exposure exploits.","whyItMatters":"Neither childhood trauma nor cannabis use alone fully explains psychosis risk. This review demonstrates their combination is far more dangerous than either factor in isolation, with risk multiplication rather than simple addition. This has profound implications for screening and prevention: identifying youth with trauma histories who also use cannabis could target the highest-risk individuals.","specificNumbers":"62 studies. Community OR up to 20.9. First-episode OR up to 31.0. Earlier onset: 2.9-3.6 years. Neurobiological mechanisms: HPA axis, inflammation, ECS dysfunction. Trauma-informed interventions show promising results.","methodology":"Systematic review of literature from January 2000-January 2024 across PubMed/MEDLINE, PsycINFO, Embase, and Web of Science. 62 studies categorized into five groups: general population (15), high-risk (5), first-episode psychosis (18), established psychosis (11), and treatment-seeking clinical/intervention studies (13). Quality assessed with appropriate tools.","limitations":"Observational studies predominate. Cannot fully establish causation. Heterogeneous definitions of childhood adversity and cannabis use across studies. Possible recall bias in retrospective trauma assessment. Shared confounders (poverty, family dysfunction) may inflate risk estimates."},{"rthcId":"RTHC-07481","title":"Cannabis and suicide risk in first-episode psychosis: Mechanisms, interactions, and intervention strategies.","authors":"Ricci, Valerio; Sarni, Alessandro; Barresi, Marialuiga; Remondino, Lorenzo; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"Asian journal of psychiatry, 110, 104624","doi":"10.1016/j.ajp.2025.104624","pmid":"40651081","tags":["psychosis","mental-health","addiction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Across 50 studies (12,764 FEP patients), cannabis use consistently elevated suicide risk (OR 1.43-1.84), with daily use showing OR 2.73 (95% CI 1.89-3.94) and high-THC cannabis OR 3.12 (95% CI 2.11-4.62). Mechanisms included neurobiological alterations, depressive symptom exacerbation, impaired cognition, increased duration of untreated psychosis, and reduced treatment adherence. Critical high-risk periods: first month after treatment initiation and post-discharge.","whyItMatters":"Suicide is the leading cause of premature death in psychosis patients, and this review shows cannabis dramatically amplifies that risk. The dose-response relationship, with daily and high-potency use carrying the most risk, provides specific guidance for clinical risk assessment and intervention timing.","specificNumbers":"50 studies, 12,764 FEP patients. Overall OR 1.43-1.84. Daily use OR 2.73. High-THC OR 3.12. Early onset (<age 15-16) is key vulnerability. High-risk periods: 1st month of treatment, post-discharge. Female sex, childhood trauma as vulnerability factors.","methodology":"Systematic review following PRISMA guidelines analyzing 50 studies involving 12,764 first-episode psychosis patients. Examined cannabis-suicide relationship, underlying mechanisms, moderating factors, and intervention strategies.","limitations":"Mostly observational studies. Cannot fully establish causation. Suicide is rare even in high-risk populations, limiting statistical precision. THC potency was not measured directly in most studies. Cannot determine whether cannabis causes suicidality or whether suicidal patients are more likely to use cannabis."},{"rthcId":"RTHC-07482","title":"Substance-Specific Treatment Responses and Resistance Patterns in Induced Psychoses: A Scoping Review of Antipsychotic Efficacy.","authors":"Ricci, Valerio; Chiappini, Stefania; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"Healthcare (Basel, Switzerland), 13(24)","doi":"10.3390/healthcare13243210","pmid":"41464282","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07483","title":"Novel psychoactive substances and psychosis: A comprehensive systematic review of epidemiology, clinical features, neurobiology, and treatment.","authors":"Ricci, Valerio; Chiappini, Stefania; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"Neuroscience and biobehavioral reviews, 178, 106384","doi":"10.1016/j.neubiorev.2025.106384","pmid":"41015167","tags":["synthetic-cannabinoids","psychosis"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Among 85 studies, synthetic cannabinoids showed consistently higher psychosis risk than traditional cannabis (OR 4.4-5.2 for synthetic cannabinoids vs cannabis). Distinct clinical profiles emerged: synthetic cannabinoid \"spiceophrenia\" featured visual hallucinations (73-84%), agitation (79-91%), and anxiety (62-76%). Key vulnerability factors included pre-existing psychiatric conditions, adolescent exposure, and polysubstance use. Different substance classes showed different neurobiological mechanisms.","whyItMatters":"While natural cannabis psychosis risk receives significant attention, synthetic cannabinoids pose a dramatically higher risk that is less well recognized. The identification of \"spiceophrenia\" as a distinct clinical entity with characteristic visual hallucinations and extreme agitation could improve emergency recognition and treatment.","specificNumbers":"85 studies included from 684 screened. SC vs cannabis psychosis OR: 4.4-5.2. Spiceophrenia: visual hallucinations 73-84%, agitation 79-91%, anxiety 62-76%. Key risks: prior psychiatric conditions, adolescent use, polysubstance use.","methodology":"Comprehensive systematic review following PRISMA guidelines across five databases (January 2005-December 2022). Quality assessed using Newcastle-Ottawa Scale and JBI checklist. Of 684 records, 85 met inclusion: case reports (38), retrospective cohorts (25), cross-sectional (10), case-control (7), experimental (3), prospective cohort (2).","limitations":"Predominantly case reports and retrospective studies. Publication bias toward severe outcomes. Rapidly evolving synthetic cannabinoid landscape means newer compounds may differ. Polysubstance use complicates attribution. Heterogeneous study designs limit direct comparisons."},{"rthcId":"RTHC-07484","title":"Clinical and Public Health Challenge of Handling Synthetic Cathinone and Cannabinoid Abuse in Pediatric Care: A Narrative Review.","authors":"Ricci, Valerio; Maina, Giuseppe","year":2025,"journal":"Pediatric reports, 17(1)","doi":"10.3390/pediatric17010019","pmid":"39997626","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07485","title":"Effects of persistent cannabis use on depression, psychosis, and suicidality following cannabis-induced psychosis: A longitudinal study.","authors":"Ricci, Valerio; De Berardis, Domenico; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"The American journal on addictions, 34(5), 547-557","doi":"10.1111/ajad.70048","pmid":"40365850","tags":["psychosis","addiction","depression","mental-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 44 patients (22 cannabis users, 22 non-users) followed for 9 months after cannabis-induced FEP, continued cannabis users had persistently higher depression scores (p=0.0000001 at 9 months), suicidality (p<0.001), and PANSS positive scores (p<0.0002) compared to those who stopped. Cannabis users had higher relapse rates (59.9% vs 18.8%). GAF scores improved significantly only in the non-user group (p=0.024). Both groups showed some positive symptom improvement, but cannabis users recovered more slowly.","whyItMatters":"This study provides direct evidence of the consequences of continued cannabis use after a cannabis-induced psychotic episode. The dramatically worse outcomes across every measured domain, depression, suicidality, psychosis, and functioning, make a compelling clinical case for cannabis cessation as a first-line intervention in this population.","specificNumbers":"44 patients (22 per group). 9-month follow-up. Depression: CU significantly higher at 3 and 9 months. Suicidality: CU significantly higher at both timepoints. Relapse: 59.9% CU vs 18.8% NCU. GAF improved only in NCU (p=0.024). PANSS positive: CU higher at all timepoints.","methodology":"Prospective cohort of 65 patients aged 16-50 with cannabis-induced first-episode psychosis from psychiatric inpatient facilities in northern Italy. Categorized by cannabis use during 9-month follow-up. 44 completed the study (NCU=22, CU=22). Assessed at baseline, 3, and 9 months using PANSS, CDSS, SSI, and GAF scales.","limitations":"Small sample (N=44). High dropout rate (32.3%). Non-randomized groups may differ in ways beyond cannabis use. Northern Italian sample. Cannot determine whether worse outcomes are caused by cannabis or whether sicker patients are less able to stop using."},{"rthcId":"RTHC-07486","title":"Cannabis use and psychotic-like experiences: A systematic review of biological vulnerability, potency effects, and clinical trajectories.","authors":"Ricci, Valerio; Chiappini, Stefania; Martinotti, Giovanni; Maina, Giuseppe","year":2025,"journal":"Psychiatry research, 348, 116496","doi":"10.1016/j.psychres.2025.116496","pmid":"40252295","tags":["psychosis","potency","mental-health","genetics","youth"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 38 studies, four major risk factor categories emerged for psychotic-like experiences (PLEs) in non-clinical populations: biological vulnerabilities (metabolic profiles, genetics, neurobiology), substance use patterns (especially high-potency cannabis), socio-demographic factors (digital media, ethnic density, gender), and downstream consequences (suicidal behavior, cognitive impairment). The cannabis-PLE relationship appeared bidirectional.","whyItMatters":"Psychotic-like experiences are more common in the general population than most people realize, and cannabis -- particularly high-potency products -- is one of the strongest modifiable risk factors. Understanding that the relationship may be bidirectional (people experiencing PLEs may also seek out cannabis) complicates simple cause-and-effect narratives.","specificNumbers":"38 studies analyzed; four risk factor categories identified; bidirectional relationship found between cannabis use and PLEs; high-potency cannabis showed strongest substance-related associations","methodology":"Systematic review following PRISMA guidelines, searching PubMed/Medline and Scopus for peer-reviewed studies through January 2024 examining risk factors for PLEs in non-clinical samples. Registered with PROSPERO. 38 articles analyzed after screening.","limitations":"Focused on non-clinical populations, so findings may not generalize to people with diagnosed psychotic disorders. Cross-sectional designs in many included studies limit causal inference. Search limited to two databases."},{"rthcId":"RTHC-07487","title":"The neuroprotective effect of cannabidiol is enhanced by resveratrol and alpha-lipoic acid in social isolation.","authors":"Ricciardi, Federica; Morace, Andrea Maria; Limongelli, Rebecca; Iannotta, Monica; Boccella, Serena; Fusco, Antimo; Bonsale, Roozbe; Perrone, Michela; Infantino, Rosmara; Di Martino, Emanuele; Mattia, Consalvo; Gargano, Francesca; Trotta, Maria Consiglia; Palazzo, Enza; Maione, Sabatino; Guida, Francesca; Luongo, Livio; Belardo, Carmela","year":2025,"journal":"Frontiers in pharmacology, 16, 1676421","doi":"10.3389/fphar.2025.1676421","pmid":"41235114","tags":["cbd","ptsd","neuroscience","mental-health"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Low-dose CBD (2.5 mg/kg) was ineffective alone, but when combined with resveratrol (20 mg/kg) or alpha-lipoic acid (10 mg/kg), it restored attack latency, reduced aggression, and decreased immobility in the tail suspension test to levels comparable to high-dose CBD (10 mg/kg). No anxiolytic effects were observed with any combination.","whyItMatters":"If these results translate to humans, it could mean lower CBD doses might work for PTSD-related aggression and depression when paired with common supplements, potentially reducing costs and side effects associated with higher CBD doses.","specificNumbers":"CBD doses tested: 2.5, 5, and 10 mg/kg; resveratrol: 20 mg/kg; alpha-lipoic acid: 10 mg/kg; N=8 mice per group; 30 days isolation + 15 days treatment","methodology":"Male CD1 mice (N=8 per group) were socially isolated from postnatal day 21 for 30 days to induce PTSD-like symptoms, then treated for 15 days. Behavioral tests included aggression assays, tail suspension test (depression), and hole-board test (anxiety).","limitations":"Very small sample size (8 mice per group). Mouse PTSD model has limited translation to human PTSD. Only male mice tested. Short treatment duration. Social isolation stress differs fundamentally from trauma-induced PTSD."},{"rthcId":"RTHC-07488","title":"Changes of CB1 Receptor Expression in Tissues of Cocaine-Exposed Eels.","authors":"Riccio, Lorenzo; Chianese, Teresa; Mileo, Aldo; Balsamo, Sabrina; Sciarrillo, Rosaria; Gatta, Roberta; Rosati, Luigi; De Falco, Maria; Capaldo, Anna","year":2025,"journal":"Animals : an open access journal from MDPI, 15(12)","doi":"10.3390/ani15121734","pmid":"40564285","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07489","title":"High-Intensity Exercise and Hippocampal Integrity in Adults With Cannabis Use Disorder: A Randomized Clinical Trial.","authors":"Richardson, Karyn E; Suo, Chao; Albertella, Lucy; Maleki, Suzan; Coxon, James; Hendrikse, Josh; Hughes, Sam; Pitt, Joseph; Kayayan, Edouard; Brown, Catherine; Nguyen, Liam; Solowij, Nadia; Lubman, Dan I; Segrave, Rebecca; Yücel, Murat","year":2025,"journal":"JAMA psychiatry, 82(12), 1240-1245","doi":"10.1001/jamapsychiatry.2025.2319","pmid":"40928796","tags":["addiction","exercise","cognition","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Hippocampal integrity (a composite of brain volume, structural connectivity, and neurochemistry) did not improve after 12 weeks of HIIT compared to strength training in adults with moderate to severe CUD. Neither cognitive nor mental health secondary outcomes improved. However, participants showed strong exercise adherence (80% completion rate, averaging 29 of 36 sessions).","whyItMatters":"Exercise has been proposed as a potential treatment for addiction, but this rigorous trial found it did not reverse CUD-related brain changes while people kept using. The strong adherence rate is the silver lining -- it shows people with CUD can commit to structured exercise programs, which could potentially reduce cravings.","specificNumbers":"59 participants randomized; mean age 27; 80% male; 80% completed the 12-week program; averaged 29 of 36 sessions; brain MRI measured hippocampal volume, fractional anisotropy, and N-acetylaspartate","methodology":"Randomized, single-blind, comparator-controlled clinical trial (BEAT trial) at Monash University BrainPark. 59 adults with moderate-severe CUD randomized 1:1 to HIIT (high lactate) or strength/resistance training (low lactate, active control), 3x/week for 12 weeks. Brain MRI at baseline and post-intervention. Participants were not required to stop cannabis use.","limitations":"Small sample (59 participants). Predominantly male (80%). Participants continued cannabis use during the trial. 12-week duration may be insufficient. Active control (strength training) may also have neurological benefits, potentially masking between-group differences."},{"rthcId":"RTHC-07490","title":"US State Cannabis Policy Bundles Dataset.","authors":"Richardson, Lilliard E; Mallinson, Daniel J; Altaf, Shazib; Neeley, Grant","year":2025,"journal":"Scientific data, 12(1), 971","doi":"10.1038/s41597-025-05284-2","pmid":"40494846","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Using 36 dichotomous policy indicators, factor analysis confirmed three distinct policy dimensions across US states: pharmaceutical (medical access rules), permissive (recreational and personal use rules), and fiscal (taxation and revenue structures). Scores range from 0 to 100 for each dimension, capturing both between-state variation and within-state changes over time.","whyItMatters":"Most cannabis research treats legalization as binary (legal or not), which misses enormous variation in how states actually regulate cannabis. This dataset lets researchers study whether specific policy designs -- not just legalization itself -- affect health, crime, and social outcomes.","specificNumbers":"50 states tracked; 1994-2023 time span; 36 policy indicators; 3 policy bundles (pharmaceutical, permissive, fiscal); 12 policies per bundle; scores scaled 0-100","methodology":"Policy dataset construction covering all 50 states from 1994-2023. 36 binary policy indicators grouped into three bundles of 12 policies each via factor analysis. Scores transformed to 0-100 scale. Two datasets produced: raw indicators and composite bundle scores.","limitations":"Policy indicators are dichotomous (yes/no), which may miss gradations within individual policies. Annual snapshots may miss mid-year policy changes. Does not capture enforcement variation or local/municipal policies."},{"rthcId":"RTHC-07491","title":"Associations Between Moderately Severe to Severe Depression and Marijuana Usage Among Black Male Collegians: Results from the Healthy Minds Study.","authors":"Richardson, Terrell T; Cain, Daphne S; Cheatham, Leah","year":2025,"journal":"Social work in public health, 40(5), 288-302","doi":"10.1080/19371918.2025.2475035","pmid":"40037662","tags":["depression","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Logistic regression analysis of 1,599 Black male collegians found that recent marijuana use increased the likelihood of experiencing moderately severe to severe depression by 77%. Younger students and those experiencing financial stress or racial discrimination were also at elevated risk.","whyItMatters":"Black male college students face unique intersecting stressors -- racial discrimination, financial pressures, and cultural stigma around mental health help-seeking. This study highlights that marijuana use may compound rather than alleviate depression in this population.","specificNumbers":"1,599 Black male collegians analyzed; 77% increased likelihood of moderately severe to severe depression with recent marijuana use; younger students at higher risk","methodology":"Cross-sectional analysis of data from the Healthy Minds Study (HMS), a web-based survey. 1,599 Black male college students analyzed using logistic regression to examine the relationship between marijuana use and depression severity.","limitations":"Cross-sectional design cannot determine whether marijuana use preceded depression or vice versa. Self-reported data subject to recall and social desirability bias. Web-based survey may not be representative of all Black male college students. Did not control for marijuana frequency, potency, or mode of use."},{"rthcId":"RTHC-07492","title":"Cannabis and Veterinary Medicine.","authors":"Richter, Gary; Hazzah, Trina","year":2025,"journal":"The Veterinary clinics of North America. Small animal practice, 55(6), 1137-1158","doi":"10.1016/j.cvsm.2025.06.003","pmid":"40675825","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07493","title":"Therapeutic Use of Cannabis Derivatives and Their Analogs for Autism Spectrum Disorder: A Systematic Review.","authors":"Riera, Rachel; de Toledo, Isabela Porto; Farinasso, Cecília Menezes; Pacheco, Rafael Leite; Silva, Roberta Borges; Colpani, Verônica; Martimbianco, Ana Luiza Cabrera; Cruz, Camila Monteiro; Parreira, Patrícia do Carmo Silva; Latorraca, Carolina de Oliveira Cruz","year":2025,"journal":"Journal of clinical pharmacology, 65(11), 1339-1349","doi":"10.1002/jcph.70068","pmid":"40605143","tags":["medical-cannabis","cbd","mental-health"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Of 1,264 references screened, only 11 RCTs met inclusion criteria, with just four having available results for children/adolescents with autism. Five different cannabis formulations were tested. One trial showed cannabis whole-plant extract may improve global assessment symptoms, but results for other outcomes remained uncertain. No study assessed quality of life.","whyItMatters":"Families of children with autism are increasingly turning to cannabis products, often without clinical guidance. This review reveals that the evidence base is extremely thin -- only 11 RCTs exist, and the results are too uncertain to support confident clinical decisions.","specificNumbers":"1,264 references screened; 11 RCTs included; 4 with results for children/adolescents; 5 cannabis formulations tested; evidence certainty very low to low","methodology":"Systematic review following Cochrane Handbook methodology, reported per PRISMA 2020. Protocol registered with PROSPERO (CRD42023468300). Two independent reviewers assessed eligibility and extracted data. Searched 1,264 references.","limitations":"Very few trials available. Different cannabis preparations, dosing, and outcome measures across studies made comparisons difficult. Most evidence rated very low to low certainty. No quality of life data available."},{"rthcId":"RTHC-07494","title":"The impact of oral cannabis consumption during pregnancy on maternal spiral artery remodelling, fetal growth and offspring behaviour in mice.","authors":"Ritchie, Tyrah M; Feng, Emily; Vahedi, Fatemeh; Ermolina, Sofya; Bellissimo, Christian J; De Jong, Erica; Portillo, Ana L; Poznanski, Sophie M; Chan, Lauren; Ettehadieh, Sara M; Sloboda, Deborah M; Bowdish, Dawn M E; Ashkar, Ali A","year":2025,"journal":"EBioMedicine, 114, 105572","doi":"10.1016/j.ebiom.2025.105572","pmid":"39915201","tags":["pregnancy","cbd","youth","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Oral CBD and THC (20 mg/kg) from early to mid-gestation both impaired maternal spiral artery remodeling and fetal growth. Male offspring showed altered aggression and metabolic activity, while females had impaired spatial learning. Both CBD and THC disrupted immune cell production of angiogenic factors important for placental development.","whyItMatters":"CBD is increasingly perceived as safe during pregnancy because it is not psychoactive, but this study found oral CBD caused similar fetal harm as THC -- including growth restriction and lasting behavioral changes. This directly challenges the assumption that non-psychoactive means non-harmful.","specificNumbers":"CBD and THC doses: 20 mg/kg body weight; both impaired spiral artery remodeling and fetal growth; male offspring: altered aggression and metabolism; female offspring: impaired spatial learning","methodology":"Mouse model comparing oral CBD oil, THC oil, and controls at 20 mg/kg body weight from early to mid-gestation. Assessed implantation site remodeling, fetal growth, offspring behavior (traditional and automated cage systems), and immune cell angiogenic factor production using human and mouse cells.","limitations":"Animal study -- mouse physiology and pregnancy differ from humans. Single high dose tested (20 mg/kg). Only early-to-mid gestation exposure examined. Did not test lower \"consumer-relevant\" doses. Route (oral oil) may not reflect all human consumption methods."},{"rthcId":"RTHC-07495","title":"High-Concentration Delta-9-Tetrahydrocannabinol Cannabis Products and Mental Health Outcomes : A Systematic Review.","authors":"Rittiphairoj, Thanitsara; Leslie, Louis; Oberste, Jean-Pierre; Yim, Tsz Wing; Tung, Gregory; Bero, Lisa; Riggs, Paula; Hutchison, Kent; Samet, Jonathan; Li, Tianjing","year":2025,"journal":"Annals of internal medicine, 178(10), 1429-1440","doi":"10.7326/ANNALS-24-03819","pmid":"40854216","tags":["potency","psychosis","addiction","anxiety","depression","mental-health"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"In non-therapeutic studies, high-concentration THC showed unfavorable associations with psychosis/schizophrenia (70% of studies) and cannabis use disorder (75%). For anxiety, 53% of non-therapeutic studies found unfavorable associations, while 47% of therapeutic studies found benefits. For depression, 41% non-therapeutic studies were unfavorable while 48% of therapeutic studies showed benefits. No therapeutic studies reported favorable results for psychosis.","whyItMatters":"As legalized cannabis markets increasingly feature high-potency products, this landmark review provides the clearest picture yet of mental health risks. The distinction between therapeutic and recreational use reveals an important nuance: context matters for whether high-THC products help or harm.","specificNumbers":"99 studies; 221,097 participants; 70% showed unfavorable psychosis associations; 75% showed unfavorable CUD associations; 47% therapeutic benefit for anxiety; 48% therapeutic benefit for depression; >95% of studies had moderate or high risk of bias","methodology":"Systematic review searching MEDLINE through May 2025 plus five additional databases through August 2024. High-concentration THC defined as >5mg or >10% THC per serving, or labeled as concentrate/shatter/dab. 99 studies (221,097 participants) including 42% RCTs, 47% observational, 11% other interventional. Published in Annals of Internal Medicine.","limitations":"Over 95% of included studies had moderate or high risk of bias. Limited evaluation of contemporary products (concentrates, vapes). Definition of \"high concentration\" varied across studies. Cannot establish causation from observational studies."},{"rthcId":"RTHC-07496","title":"Cannabidiol biases A2A-CB2 receptor heteromer function by decoupling β-arrestin signaling from complex formation.","authors":"Rivas-Santisteban, Rafael; Ferreiro-Vera, Carlos; de Medina, Verónica Sánchez; Navarro, Gemma; Pallàs, Mercè; Griñán-Ferré, Christian; Franco, Rafael","year":2025,"journal":"Biochemical pharmacology, 242(Pt 1), 117280","doi":"10.1016/j.bcp.2025.117280","pmid":"40885321","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07497","title":"Functional crosstalk between the vanilloid and endocannabinoid systems in modulating vascular tone: implications for (neuro)vascular disorder therapy.","authors":"Rivera-Mancilla, Eduardo; van den Bogaerdt, Antoon; Danser, A H Jan; MaassenVanDenBrink, Antoinette","year":2025,"journal":"The journal of headache and pain, 26(1), 203","doi":"10.1186/s10194-025-02085-1","pmid":"41057773","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07498","title":"Status Epilepticus After an Exploratory Ingestion of Cannabis Edibles.","authors":"Rivera, Kevin; Adkins, Alek Q; Murray, Brian P; Hays, Hannah","year":2025,"journal":"Cureus, 17(9), e91463","doi":"10.7759/cureus.91463","pmid":"41050035","tags":["youth","epilepsy"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"An 18-month-old male presented with generalized tonic-clonic seizures that recurred despite multiple benzodiazepine doses, requiring intubation and mechanical ventilation. Extensive workup (CT, MRI, lumbar puncture, infectious testing) found no alternative cause. Urine THC-COOH exceeded 500 ng/mL and serum THC-COOH was 256 ng/mL. Urine benzoylecgonine (cocaine metabolite) was also detected at 74 ng/mL. The child returned to neurologic baseline and was discharged after five days.","whyItMatters":"As cannabis edibles become more available through legalization, accidental pediatric ingestion cases are increasing. This appears to be the first documented case of status epilepticus (prolonged, refractory seizures) from confirmed cannabis exposure in a toddler, highlighting a potentially life-threatening outcome.","specificNumbers":"Patient age: 18 months; urine THC-COOH: >500 ng/mL; serum THC-COOH: 256 ng/mL; urine benzoylecgonine: 74 ng/mL; 5-day hospitalization; required intubation and mechanical ventilation","methodology":"Single case report of a previously healthy 18-month-old presenting with status epilepticus. Comprehensive neurological and toxicological workup performed.","limitations":"Single case report. Cocaine metabolite was also detected, complicating attribution. Cannot prove causation from a single case. THC dose consumed is unknown."},{"rthcId":"RTHC-07499","title":"A user-informed perspective of the toxicological data gap in India's cannabis landscape.","authors":"Riyaz, Muzafar","year":2025,"journal":"Frontiers in toxicology, 7, 1734313","doi":"10.3389/ftox.2025.1734313","pmid":"41626284","tags":["harm-reduction","potency","legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"The author argues that clinical cannabis research using purified compounds fails to capture the realities of illicit markets where products like Ganja and Charas have unpredictable potency, pesticide contamination, and adulteration. Personal consumption patterns reveal that inconsistent products make precise dosing impossible and that standard clinical outcome measures miss user-reported effects like cognitive enhancement.","whyItMatters":"Most cannabis research uses standardized pharmaceutical-grade products, creating a blind spot about what people actually consume in unregulated markets. In countries like India where cannabis remains prohibited, users face unknown risks from contamination and adulteration that have nothing to do with cannabis itself.","specificNumbers":"13 years of firsthand experience; 4 proposed research priorities; examines Ganja and Charas products specifically","methodology":"Perspective article informed by 13 years of personal experience within India's prohibited cannabis ecosystem. Not a systematic study but a call for research priorities including chemical analysis of illicit products, qualitative user research, user-centered outcome measures, and transition from prohibition to regulation.","limitations":"Perspective article based on personal experience, not systematic research. Single-author viewpoint from one region of India. Proposed research agenda has not been implemented. Potential bias from the author's position as a long-term user."},{"rthcId":"RTHC-07500","title":"Medicinal cannabis in the management of anxiety disorders: A systematic review.","authors":"Roberts, Leah; Sorial, Elizabeth; Budgeon, Charley A; Lee, Kenneth; Preen, David B; Cumming, Craig","year":2025,"journal":"Psychiatry research, 350, 116552","doi":"10.1016/j.psychres.2025.116552","pmid":"40413923","tags":["anxiety","medical-cannabis","cbd","ptsd","mental-health"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This review examined 57 studies on medicinal cannabis for diagnosed anxiety disorders. Among the 13 highest-quality studies, 9 (70%) reported improvements in conditions including generalized anxiety disorder, social anxiety disorder, and PTSD. Four high-quality studies found negative results for OCD, trichotillomania, test anxiety, and social anxiety disorder. Over 90% of all studies, including lower-quality ones, reported positive outcomes for both CBD and THC-based preparations.","whyItMatters":"Anxiety disorder diagnoses are rising, and many people seek alternatives to standard medications. This review is one of the few that focuses exclusively on diagnosed anxiety disorders rather than general anxiety symptoms, providing a clearer picture of where cannabis-based treatments show the most promise.","specificNumbers":"57 studies met inclusion criteria. Study breakdown: 40% cohort (n=23), 30% RCTs (n=17), 18% cross-sectional (n=10), 12% qualitative/other (n=7). Mean bias score: 62.9 out of 100. 53% of studies either omitted or relied on self-reported dosage data.","methodology":"Systematic review of MEDLINE, EMBASE, CINAHL, and PsycInfo databases (searched October-December 2023). Included peer-reviewed studies on adults 18+ with diagnosed anxiety disorders. Excluded case series, case studies, reviews, and recreational cannabis studies. Used MASTER and QualSyst tools to assess bias risk.","limitations":"High risk of bias across studies (mean score 62.9/100). Over half of studies had inadequate reporting of cannabis form and dosage. Database search limited to October-December 2023. Heterogeneity in study designs makes direct comparisons difficult."},{"rthcId":"RTHC-07501","title":"Product Characteristics, Warnings, and Marketing Appeals Conveyed on Delta-8 THC Product Packaging in the US and Canada.","authors":"Robichaud, Meagan O; Spillane, Torra E; Kennedy, Ryan David; Hammond, David","year":2025,"journal":"Journal of studies on alcohol and drugs","doi":"10.15288/jsad.25-00034","pmid":"40778926","tags":["harm-reduction","potency","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analysis of 140 delta-8 THC products from the US and Canada found that only 32.9% displayed any health warning, and warnings appeared on the front of packaging just 11.7% of the time. Nearly half (43.6%) used 'hemp' descriptors, and 21.4% featured cartoons on packaging. Among vapes, only 17% stated concentration levels.","whyItMatters":"Delta-8 THC products proliferated after the 2018 Farm Bill created a legal gray area. Without standardized labeling requirements, consumers often have no way to know exactly what they're ingesting or how potent a product is.","specificNumbers":"140 products analyzed. Product types: ingestibles (43.6%), vapes (37.9%), dried flower (7.9%), oral liquids (6.4%). 6.4% listed other intoxicating cannabinoids (delta-9 THC, delta-10, HHC). Warnings present on 32.9% of products. Marketing appeals: 'hemp' descriptors (43.6%), cannabis symbols (28.6%), legality references (25.7%), cartoons (21.4%).","methodology":"Content analysis of delta-8 THC product packaging photos collected from US and Canadian respondents in the 2021 and 2022 International Cannabis Policy Study. 140 products were double-coded for cannabinoid content labels, warning presence and placement, and marketing appeals.","limitations":"Sample collected from survey respondents, not a systematic market sample. Photos from 2021-2022 may not reflect current packaging. Limited to exterior packaging only. Cannot assess whether labeled content matches actual content."},{"rthcId":"RTHC-07502","title":"Long-Term Efficacy and Safety of Inhaled Cannabis Therapy for Painful Diabetic Neuropathy: A 5-Year Longitudinal Observational Study.","authors":"Robinson, Dror; Khatib, Muhammad; Lavon, Eitan; Kafri, Niv; Abu Rashed, Waseem; Yassin, Mustafa","year":2025,"journal":"Biomedicines, 13(10)","doi":"10.3390/biomedicines13102406","pmid":"41153689","tags":["medical-cannabis","pain","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"52 patients with painful diabetic neuropathy who had failed at least three prior pain medications used inhaled medical cannabis (20% THC) as add-on therapy for five years. Pain severity scores dropped from 9.0 to 2.0 on a 10-point scale. The study also observed improved glycemic control and opioid-sparing effects, with a favorable safety profile throughout.","whyItMatters":"Diabetic neuropathy affects up to 50% of long-term diabetes patients, and conventional treatments often provide limited relief with significant side effects. This is one of the longest follow-up periods for cannabis pain research, providing rare data on sustained effects.","specificNumbers":"52 patients enrolled, 50 completed follow-up. Mean age: 45.3 years. 71.2% male. Average diabetes duration: 23.3 years. BPI pain severity dropped from 9.0 to 2.0.","methodology":"Prospective observational study at a single clinic. 52 patients with confirmed painful diabetic neuropathy, unresponsive to at least three prior analgesics plus non-pharmacological interventions, were followed for 5 years. After a 1-month washout, patients initiated inhaled medical-grade cannabis (20% THC). Pain measured using the Brief Pain Inventory.","limitations":"Single-center observational study with no control group. Small sample size (n=52). No blinding or placebo comparison. Cannot rule out placebo effects, natural disease progression, or other confounding factors. Associative findings only."},{"rthcId":"RTHC-07503","title":"Real-Time and Long-Term Effects of Medical Marijuana on Older Adults: Protocol for the Study on Medical Marijuana and its Long-Term Effects (the SMILE study) Prospective Cohort.","authors":"Robinson, Kendall R; Seeger, Stella D; Nave, Lauren; Mejia, Marlin; Vander Meulen, Maria; Rashid, Ahmed; Mickle, Angela M; Sibille, Kimberly; Li, Zhigang; Przkora, Rene; Schmidt, Siegfried; Lo, Margaret C; Cook, Robert L; Wang, Yan","year":2025,"journal":"JMIR research protocols","doi":"10.2196/78900","pmid":"41498604","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07504","title":"Prescription and Nonprescription Drug Use Among People With Eating Disorders.","authors":"Rodan, Sarah-Catherine; Maguire, Sarah; Meez, Noah; Greenstien, Kayla; Zartarian, Garen; Mills, Katherine L; Suraev, Anastasia; Bedoya-Pérez, Miguel A; McGregor, Iain S","year":2025,"journal":"JAMA network open, 8(7), e2522406","doi":"10.1001/jamanetworkopen.2025.22406","pmid":"40694346","tags":["medical-cannabis","cbd","mental-health","appetite"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 6,612 respondents with eating disorders, cannabis and psychedelics received the highest ratings for improving ED symptoms specifically. Prescription antidepressants were rated highly for general mental health but not for eating disorder symptoms, with exceptions for fluoxetine (bulimia nervosa) and lisdexamfetamine (binge-eating disorder). Alcohol, nicotine, and tobacco were rated as the most harmful substances.","whyItMatters":"Effective pharmacotherapies for eating disorders remain limited. This large-scale survey captures the lived experience of thousands of people who have tried both prescription and non-prescription substances for their conditions, offering insights into what patients themselves find most helpful.","specificNumbers":"6,612 respondents (mean age 24.3, 94% female). ED breakdown: anorexia nervosa (40.8%), bulimia nervosa (19%), binge-eating disorder (11.4%), AVFRID (8.9%), undiagnosed (37.7%). Depression comorbidity: 65.5%.","methodology":"International online survey (MED-FED) advertised via social media, forums, and clinical services. Recruited adults self-reporting an ED or disordered eating from November 2022 to May 2023. 7,648 recruited, 6,612 completed demographics, 5,123 completed the full survey. Participants rated each substance on a 5-point Likert scale for ED symptom improvement, mental health benefits, and side effects.","limitations":"Self-report and retrospective design. Self-selected sample recruited through social media. Predominantly female and young. 37.7% were self-diagnosed. No verification of actual substance use patterns or clinical outcomes. Perceived efficacy does not equal measured efficacy."},{"rthcId":"RTHC-07505","title":"Cannabidiol reverses microglia activation and deficits of parvalbumin interneurons and their perineuronal nets in a MK-801-induced mouse model of schizophrenia.","authors":"Rodrigues da Silva, Naielly; Gobbo, Davide; Gomes, Felipe V; Scheller, Anja; Kirchhoff, Frank; Del Bel, Elaine; Silveira Guimarães, Francisco","year":2025,"journal":"Brain research, 1863, 149772","doi":"10.1016/j.brainres.2025.149772","pmid":"40484109","tags":["cbd","psychosis","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic MK-801 treatment (an NMDA receptor blocker) caused memory deficits and reduced gamma brain wave power in mice. Seven days of CBD treatment (30 mg/kg) reversed both the cognitive impairment and the gamma oscillation changes. CBD also restored depleted parvalbumin neurons and their protective perineuronal nets in the prefrontal cortex and hippocampus, and reversed microglia activation in both regions.","whyItMatters":"Parvalbumin neuron loss and neuroinflammation are hallmarks of schizophrenia. This study maps out specific receptor pathways through which CBD appears to reverse these changes, providing a mechanistic foundation for understanding how CBD might address cognitive symptoms that current antipsychotics often fail to treat.","specificNumbers":"CBD dose: 30 mg/kg daily for 7 days. MK-801 dose: 0.5 mg/kg twice daily for 14 days. CBD's cognitive effects were blocked by a 5-HT1A antagonist but not a CB2 antagonist. Neuroprotective effects in the hippocampus required both 5-HT1A and CB2 receptors, while prefrontal effects were independent of both.","methodology":"Animal study using chronic MK-801 administration (0.5 mg/kg twice daily for 14 days) to model schizophrenia-like symptoms in mice. CBD (30 mg/kg daily for 7 days) was given after the MK-801 treatment period. Receptor antagonists were used to identify which receptors mediated CBD's effects. Brain regions examined: prelimbic medial prefrontal cortex and ventral hippocampus.","limitations":"Animal study; results may not translate to humans. MK-801 model captures some but not all aspects of schizophrenia. Single CBD dose tested. Short treatment duration. No assessment of long-term effects."},{"rthcId":"RTHC-07506","title":"The Impact of Adversity and Family Conflict on Risk for Future Substance Use Among Young Adolescents in the Adolescent Brain Cognitive Development Study (ABCD Study): A Cohort Analysis.","authors":"Rodrigues, Sarah M; Saghafi, Afsaneh; Wang, Qiao; Shin, Sanghyuk S; Dube, Sarahjane L; Diestel, Annabel; Stevens, Robin; Bounds, Dawn T","year":2025,"journal":"Journal of child and adolescent psychiatric nursing : official publication of the Association of Child and Adolescent Psychiatric Nurses, Inc, 38(2), e70017","doi":"10.1111/jcap.70017","pmid":"40265644","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07507","title":"Culturally related risk and protective factors for alcohol and marijuana use among Latinx college students.","authors":"Rodriguez-Crespo, Andrea; Garcia, Miguel A; Borges Cervantes, Ariana; Ochoa, Julian A; Cooper, Theodore V","year":2025,"journal":"Journal of ethnicity in substance abuse, 1-18","doi":"10.1080/15332640.2025.2517776","pmid":"40526820","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07508","title":"Perinatal Ethanol Exposure Induces Astrogliosis and Decreases GRP55/PEA-Mediated Neuroprotection in Hippocampal Astrocytes of the 3×Tg Alzheimer's Animal Model.","authors":"Rodríguez-Pozo, Miguel; Pacheco-Sánchez, Beatriz; Ben Rabaa, Meriem; de Ceglia, Marialuisa; Melgar-Locatelli, Sonia; Santos, Ignacio; Rodríguez de Fonseca, Fernando; Suárez, Juan; Rivera, Patricia","year":2025,"journal":"International journal of molecular sciences, 26(22)","doi":"10.3390/ijms262211154","pmid":"41303637","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07509","title":"Emerging adulthood, socioemotional variables and mental health in Spanish university students.","authors":"Rodríguez-Sáez, José Luis; Martín-Antón, Luis Jorge; Salgado-Ruiz, Alfonso; Carbonero-Martín, Miguel Ángel","year":2025,"journal":"BMC psychology, 13(1), 531","doi":"10.1186/s40359-025-02804-y","pmid":"40394725","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07510","title":"Coadministration antagonist dopamine receptor D4 with CB2 receptor agonist decreases binge-like intake of palatable food in mice.","authors":"Rodríguez-Serrano, Luis Miguel; López-Castillo, Ana Paola; Cabrera-Mejía, María Cristina; Cedillo-Figueroa, Ana Sofía; Zepeda-Ortigosa, Nyahn; Carregha-Lozano, Carolina; Chávez-Hernández, María Elena","year":2025,"journal":"Frontiers in behavioral neuroscience, 19, 1572374","doi":"10.3389/fnbeh.2025.1572374","pmid":"40365131","tags":["appetite","neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"In mice given 1-hour access to palatable food, a dopamine D4 receptor antagonist (L-745870) reduced binge-like intake. Adding a CB2 receptor agonist (HU308) to the D4 antagonist produced an even greater reduction. The CB2 antagonist (AM630) combined with the D4 antagonist did not enhance the effect, suggesting the additional benefit came specifically from CB2 activation.","whyItMatters":"Binge eating disorder involves dysregulation of the brain's reward system. This study reveals a previously unknown interaction between the cannabinoid and dopamine systems in controlling binge-like behavior, suggesting that targeting both systems simultaneously could be more effective than targeting either alone.","specificNumbers":"34 mice total. 12 baseline binge sessions + 3 treatment sessions. Four treatment groups tested. D4 antagonist (L-745870) reduced binge intake; adding CB2 agonist (HU308) produced even greater reduction.","methodology":"34 adult male C57BL6/J mice housed individually with ad libitum standard diet. Binge eating was modeled by providing 1-hour access to palatable food across 12 baseline sessions. Mice were then randomly assigned to four treatment groups (vehicle, D4 antagonist alone, D4 antagonist + CB2 agonist, D4 antagonist + CB2 antagonist) for three additional sessions.","limitations":"Animal study in male mice only; no female mice tested. Small sample size per group. Short treatment period (3 sessions). Palatable food binge model may not fully capture human binge eating disorder. Only intraperitoneal drug administration tested."},{"rthcId":"RTHC-07511","title":"Preparation and characterization of a certified reference material of toxic elements in cannabis leaves.","authors":"Rodriguez, Adriana; Paredes, Cristhian; Castillo, Elianna","year":2025,"journal":"Analytical and bioanalytical chemistry, 417(12), 2691-2701","doi":"10.1007/s00216-025-05809-z","pmid":"40074849","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07512","title":"Characterization of Novel and Known Activators of Cannabinoid Receptor Subtype 2 Reveals Mixed Pharmacology That Differentiates Mycophenolate Mofetil and GW-842,166X from MDA7.","authors":"Rodriguez, Alice L; Qi, Aidong; Han, Allie; Kling, Haley E; Quitalig, Marc C; Bender, Aaron M; Barbaro, Lisa; Whomble, David; Lindsley, Craig W; Niswender, Colleen M","year":2025,"journal":"International journal of molecular sciences, 26(10)","doi":"10.3390/ijms26104956","pmid":"40430094","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07513","title":"Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain.","authors":"Rodriguez, Carl E B; Vanegas, S Olivia; Reck, A Matthew; Schrom, Yasmin; Kinsey, Steven G","year":2025,"journal":"Cannabis and cannabinoid research, 10(1), e102-e111","doi":"10.1089/can.2024.0088","pmid":"39899366","tags":["pain","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"MAGL inhibitors (JZL184 and MJN110) reduced mechanical pain sensitivity after hindpaw surgery in mice. The pain relief worked through CB2 receptors, not CB1. Importantly, combining doses of JZL184 and diclofenac that were individually too low to reduce pain produced significant relief when given together. Repeated JZL184 administration did not lead to tolerance.","whyItMatters":"Post-surgical pain management often relies on opioids, which carry addiction risks. This study demonstrates that boosting the body's own endocannabinoids can reduce pain, and that combining this approach with common anti-inflammatory drugs could allow lower doses of each, potentially reducing side effects.","specificNumbers":"JZL184 effective at 4+ mg/kg; MJN110 at 5+ mg/kg; diclofenac at 16.67+ mg/kg. Sub-threshold combination: JZL184 (1 mg/kg) + diclofenac (1.85 mg/kg) together produced significant pain relief. CB2 antagonist SR144528 (3 mg/kg) blocked JZL184's effects; CB1 antagonist rimonabant (3 mg/kg) did not.","methodology":"Male and female C57BL/6J mice underwent hindpaw incision surgery. Mechanical allodynia was measured 24 hours post-surgery using von Frey filaments. Dose-response curves were established for MAGL inhibitors and diclofenac. CB1 and CB2 antagonists were used to identify receptor mechanisms. Repeated dosing tested for tolerance. Hindpaw cytokines were measured via multiplex ELISA.","limitations":"Animal study; translation to humans uncertain. Hindpaw incision is a simplified model of surgical pain. MAGL inhibition did not reduce inflammatory cytokines despite behavioral pain relief, suggesting the mechanism may be primarily neural rather than anti-inflammatory. Both sexes used but sex-specific analysis not detailed."},{"rthcId":"RTHC-07514","title":"Polygenic and Polyenvironment Interplay in Schizophrenia-Spectrum Disorder and Affective Psychosis; the EUGEI First Episode Study.","authors":"Rodriguez, Victoria; Alameda, Luis; Aas, Monica; Gayer-Anderson, Charlotte; Trotta, Giulia; Spinazzola, Edoardo; Quattrone, Diego; Tripoli, Giada; Jongsma, Hannah E; Stilo, Simona; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Lasalvia, Antonio; Tosato, Sarah; Tarricone, Ilaria; Bonora, Elena; Jamain, Stéphane; Selten, Jean-Paul; Velthorst, Eva; de Haan, Lieuwe; Llorca, Pierre-Michel; Arrojo, Manuel; Bobes, Julio; Bernardo, Miguel; Arango, Celso; Kirkbride, James; Jones, Peter B; Rutten, Bart P; Richards, Alexander; Sham, Pak C; O'Donovan, Michael; Van Os, Jim; Morgan, Craig; Di Forti, Marta; Murray, Robin M; Vassos, Evangelos","year":2025,"journal":"Schizophrenia bulletin, 51(5), 1254-1265","doi":"10.1093/schbul/sbae207","pmid":"39658350","tags":["psychosis","genetics","mental-health"],"studyType":"case-control","evidenceStrength":"moderate","keyFinding":"In 573 first-episode psychosis cases and 1,005 controls, polygenic risk for schizophrenia was the strongest genetic predictor of schizophrenia-spectrum disorders, with a notably larger effect in people not exposed to strong environmental risks like frequent cannabis use (OR 2.43 unexposed vs 1.35 exposed). For affective psychosis, genetic risk for depression appeared stronger among those exposed to environmental risk factors. No statistical interaction was found between genetic and environmental risk scores.","whyItMatters":"Understanding how genes and environment combine in psychosis risk is critical for prevention. The finding that genetic and environmental risks appear to act independently (rather than multiplying each other) has implications for how risk is assessed and communicated.","specificNumbers":"573 first-episode psychosis cases, 1,005 controls. Schizophrenia-spectrum PRS-SZ effect: OR 2.43 (cannabis-unexposed) vs 1.35 (cannabis-exposed). Environmental factors examined: migration, paternal age, childhood adversity, frequent cannabis use.","methodology":"Case-control study analyzing 573 first-episode psychosis patients and 1,005 controls of European ancestry from the EUGEI study. Polygenic risk scores were calculated for schizophrenia, bipolar disorder, and depression. Environmental measures included migration, paternal age, childhood adversity, and frequent cannabis use. Regression models tested gene-environment interactions.","limitations":"European ancestry only; findings may not generalize. Cross-sectional design limits causal inference. Environmental exposures measured retrospectively. Cannabis use assessed as binary (frequent vs not), missing dose-response nuance. PRS explains only a fraction of genetic risk."},{"rthcId":"RTHC-07515","title":"Cannabis Use Moderates Methamphetamine- and HIV-Related Inflammation: Evidence from Human Plasma Markers.","authors":"Rogers, Jeffrey M; Chentsova, Victoria O; Wang, Crystal X; Marcondes, Maria Cecilia Garibaldi; Cherner, Mariana; Ellis, Ronald J; Letendre, Scott L; Heaton, Robert K; Grant, Igor; Iudicello, Jennifer E","year":2025,"journal":"Viruses, 17(8)","doi":"10.3390/v17081143","pmid":"40872856","tags":["medical-cannabis","inflammation","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 234 participants (86 with HIV, 148 without), past-month cannabis use was independently associated with lower CXCL10/IP-10 levels overall. Among those with lifetime methamphetamine use disorder, cannabis users also showed lower levels of CCL2/MCP-1, ICAM-1, and VCAM-1. The VCAM-1 reduction was observed only in people without HIV.","whyItMatters":"Methamphetamine use and HIV both drive chronic inflammation that increases risk for cardiovascular and neurological damage. If cannabis genuinely reduces inflammatory markers in these populations, it could point toward cannabinoid-based approaches to managing inflammation-driven complications.","specificNumbers":"234 participants: 86 with HIV, 148 without. Four markers measured: CXCL10/IP-10, CCL2/MCP-1, ICAM-1, VCAM-1. Cannabis associated with lower CXCL10/IP-10 across all participants. Among those with meth history, cannabis associated with lower CCL2/MCP-1, ICAM-1, and VCAM-1.","methodology":"Cross-sectional study of 234 participants who provided urine and blood samples and completed neuromedical, psychiatric, and substance use assessments. Generalized linear models examined associations of lifetime methamphetamine use disorder, past-month cannabis use, and HIV status with four plasma inflammatory markers.","limitations":"Cross-sectional design; cannot determine causation. Cannabis use was self-reported and binary (past month yes/no). Small subgroups when stratified by HIV, meth history, and cannabis use. No information on type, dose, or frequency of cannabis use. Potential confounding by other health behaviors."},{"rthcId":"RTHC-07516","title":"Sex-specific responses to cannabis exposure: Implications for behavior and beyond.","authors":"Rogers, Sophia; Seelke, Adele M H; Mederos, Sabrina L; Bales, Karen L","year":2025,"journal":"Brain research bulletin, 230, 111530","doi":"10.1016/j.brainresbull.2025.111530","pmid":"40886857","tags":["sex-differences","neuroscience"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"This scoping review synthesized evidence on sex-specific behavioral responses to cannabis. The literature reveals that sex differences exist in cannabis sensitivity, tolerance development, withdrawal severity, and various behavioral outcomes. These differences appear to be mediated by hormonal influences on the endocannabinoid system, particularly estrogen's effects on CB1 receptor expression and endocannabinoid tone.","whyItMatters":"As cannabis legalization expands, understanding sex-specific effects becomes increasingly important for both public health messaging and clinical applications. Much of what we know about cannabis effects comes from male-dominated research, potentially missing important differences in how women respond.","specificNumbers":"The review covers multiple domains of sex differences but notes that many studies still do not adequately report or analyze sex-specific outcomes.","methodology":"Scoping review focused on tetrahydrocannabinol (THC) as the principal psychoactive constituent. Examined preclinical and clinical literature on sex differences in cannabis use patterns, behavioral effects, and endocannabinoid system function.","limitations":"Scoping review provides breadth but not the statistical rigor of a systematic review. Predominantly focused on THC, with less coverage of CBD and other cannabinoids. Much of the mechanistic evidence comes from animal studies. Clinical data on sex differences remain limited."},{"rthcId":"RTHC-07517","title":"Adverse childhood experiences, resilience, and cannabis use in early motherhood.","authors":"Roland, Alysa; Charron, Elizabeth; Shreffler, Karina M","year":2025,"journal":"Frontiers in psychiatry, 16, 1621161","doi":"10.3389/fpsyt.2025.1621161","pmid":"40852139","tags":["pregnancy","mental-health","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"In 126 predominantly low-income mothers followed through three years postpartum, the relationship between adverse childhood experiences (ACEs) and cannabis use depended on resilience level. Among high-resilience mothers, each additional ACE increased cannabis use odds by 38% (adjusted OR=1.38). Predicted probability of cannabis use in this group rose from 8.5% at 0 ACEs to 62.9% at 10 ACEs. Among low-resilience mothers, cannabis use probability remained around 36% regardless of ACE exposure.","whyItMatters":"Cannabis use in early motherhood is increasing, and understanding what drives it can inform more targeted support. The finding that resilience appears protective at low-to-moderate trauma exposure but loses its protective effect at high ACE levels suggests that different intervention strategies may be needed depending on a mother's trauma history.","specificNumbers":"126 mothers. High resilience group: cannabis use probability 8.5% at 0 ACEs, 62.9% at 10 ACEs (OR=1.38 per ACE). Low resilience group: ~36% cannabis use probability regardless of ACE score (OR=1.02, not significant).","methodology":"Longitudinal study of 126 predominantly low-income, diverse mothers in the South Central US. Multiple logistic regression evaluated ACEs and cannabis use through 3 years postpartum, stratified by resilience (median split). Adjusted for sociodemographics, postnatal depression, and prenatal substance use.","limitations":"Small sample size (n=126). Predominantly low-income population in one US region. Cannabis use was self-reported. Resilience measured at a single point. Cannot determine whether cannabis use represents problematic use or intentional self-management. Observational design limits causal claims."},{"rthcId":"RTHC-07518","title":"Significant Psychedelic Experiences Evaluated for Mystical Characteristics Associated with Cannabis Use Reduction and Psychological Flexibility Improvement: A Naturalistic Cross-Sectional Retrospective Survey.","authors":"Romeo, B; Kervadec, E; Fauvel, B; Strika-Bruneau, L; Amirouche, A; Verroust, V; Piolino, P; Benyamina, A","year":2025,"journal":"Journal of psychoactive drugs, 57(4), 374-385","doi":"10.1080/02791072.2024.2375720","pmid":"38961652","tags":["addiction","quitting","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 152 cannabis users who reported a significant past psychedelic experience, average cannabis use disorder scores (CUDIT) decreased significantly after the psychedelic experience. The intensity of mystical qualities during the experience predicted the degree of cannabis reduction. Participants also reported lasting improvements in psychological flexibility following the experience.","whyItMatters":"Cannabis use disorder has few effective treatments. The finding that naturalistic psychedelic experiences are associated with reduced cannabis use adds to a growing body of research suggesting psychedelic-assisted approaches could address substance use disorders, including cannabis dependence.","specificNumbers":"152 cannabis users surveyed. Significant reduction in CUDIT scores post-psychedelic experience. Mystical experience intensity correlated with degree of cannabis reduction (p=.01). Psychological flexibility also improved (p=.04).","methodology":"Online retrospective survey of 152 cannabis users who reported a significant past psychedelic experience. Compared self-reported cannabis use (CUDIT scores) before and after the psychedelic experience. Assessed mystical experience characteristics and psychological flexibility changes.","limitations":"Retrospective and self-report design, highly susceptible to recall bias. Self-selected sample of people who had 'significant' psychedelic experiences. No control group. No verification of actual substance use changes. Cannot determine whether the psychedelic experience caused the changes or coincided with other life factors."},{"rthcId":"RTHC-07519","title":"Genetic characterization of the endocannabinoid system and psychiatric features in patients with migraine and medication overuse headache.","authors":"Romozzi, Marina; Scipioni, Lucia; Di Tella, Sonia; Silveri, Maria Caterina; Cupini, Letizia Maria; Vollono, Catello; Maccarrone, Mauro; Calabresi, Paolo","year":2025,"journal":"Cephalalgia : an international journal of headache, 45(7), 3331024251314460","doi":"10.1177/03331024251314460","pmid":"40599037","tags":["neuroscience","genetics","pain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"FAAH (fatty acid amide hydrolase), the enzyme that breaks down the endocannabinoid anandamide, showed significantly lower gene expression in medication overuse headache (MOH) patients compared to episodic migraine (EM) patients. Paradoxically, FAAH protein levels were higher in MOH patients. Lower FAAH gene expression correlated with worse headache impact scores (HIT-6), disability scores (MIDAS), and higher scores on anxiety, depression, and alexithymia scales.","whyItMatters":"The endocannabinoid system is a key regulator of pain, and FAAH is the enzyme that determines how long endocannabinoids remain active. Finding that FAAH is specifically altered in chronic migraine patients suggests the endocannabinoid system may be dysregulated in headache chronification, potentially explaining why some migraine patients report benefit from cannabis.","specificNumbers":"31 patients + 14 healthy controls. FAAH gene expression: MOH 0.0002 vs EM 0.0008 (p=0.005). FAAH protein: MOH 2.95 pg/ug vs EM 0.92 pg/ug (p=0.025). Negative correlations with HIT-6 (p=0.003), MIDAS (p=0.048), TAS-20 (p=0.029), HAM-A (p=0.040), HAM-D (p=0.028).","methodology":"Cross-sectional study of 31 patients (15 episodic migraine, 16 medication overuse headache) and 14 healthy controls. FAAH was measured via ELISA (protein) and real-time quantitative PCR (gene expression) in peripheral blood mononuclear cells. Seven additional ECS components were also assessed. Clinical and psychopathological scales administered.","limitations":"Very small sample size (31 patients, 14 controls). Cross-sectional design; cannot determine if FAAH changes cause or result from chronic migraine. Peripheral blood measurements may not reflect brain endocannabinoid levels. No cannabinoid receptor gene expression differences found between groups."},{"rthcId":"RTHC-07520","title":"Endocannabinoids, depression, and treatment resistance: Perspectives on effective therapeutic interventions.","authors":"Rosa, Ilenia; Padula, Lorenzo Pio; Semeraro, Francesco; Marrangone, Carlotta; Inserra, Antonio; De Risio, Luisa; Boffa, Marta; Zoratto, Francesca; Borgi, Marta; Guidotti, Roberto; Lorenzo, Giorgio Di; D'Addario, Claudio; Pettorruso, Mauro; Martinotti, Giovanni","year":2025,"journal":"Psychiatry research, 352, 116697","doi":"10.1016/j.psychres.2025.116697","pmid":"40840197","tags":["depression","neuroscience","mental-health"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"This review synthesizes evidence that diverse non-monoaminergic treatments for treatment-resistant depression all influence the endocannabinoid system. Brain stimulation (rTMS, ECT) elevates anandamide and 2-AG levels, correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors. Psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions, while LSD affects the broader endocannabinoidome in the prefrontal cortex and hippocampus.","whyItMatters":"Treatment-resistant depression affects roughly a third of people with depression. Understanding why very different treatments (electrical stimulation, ketamine, psychedelics) can all be effective could lead to better-targeted therapies. The endocannabinoid system may be the common thread connecting these diverse approaches.","specificNumbers":"Approximately one-third of depression patients are treatment-resistant. The review covers rTMS, ECT, ketamine, esketamine, psilocybin, and LSD, all showing ECS modulation.","methodology":"Narrative review drawing from preclinical and clinical literature on the endocannabinoid system's role in depression and its involvement in non-monoaminergic treatments effective for treatment-resistant depression.","limitations":"Narrative review, not systematic. Much of the ECS evidence comes from preclinical models. The causal direction is not established. Limited human data on ECS biomarkers during treatment."},{"rthcId":"RTHC-07521","title":"Ethnic Discrimination's Role on Increased Substance Susceptibility and Use Among U.S. Youth.","authors":"Rosales, Robert; Veliz, Philip T; Jardine, John; Weigard, Alexander S; McCabe, Sean Esteban","year":2025,"journal":"American journal of preventive medicine, 69(4), 107956","doi":"10.1016/j.amepre.2025.107956","pmid":"40578581","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07522","title":"A cannabidiol (CBD) lipid-based nanoemulsion induces anxiolytic- and panicolytic-like effects and increases FosB/deltaFosB immunoreactivity in serotonergic cells of the dorsal raphe.","authors":"Rosário, Bárbara A; de Lima, Maria Paula; Vieira, Márcio G; Leite, Laís Garret; de Aquino, Pedro E A; Viana, Glauce S B; Silveira, Edilberto R; de Brito, Débora H A; Zampieri, Dávila; Ricardo, Nágila Maria P S; Lemes, Jéssica A; Tucci, Adriana M; Ribeiro, Daniel A; Viana, Milena B","year":2025,"journal":"Brain research, 1864, 149791","doi":"10.1016/j.brainres.2025.149791","pmid":"40550321","tags":["cbd","anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic oral CBD nanoemulsion (2.5 mg/kg for 21 days) produced anxiolytic and panicolytic effects in rats tested on the elevated T-maze. The effects were linked to increased activity in serotonin-producing neurons of the dorsal raphe nucleus. Acute CBD showed no behavioral effects. Brain tissue analysis confirmed CBD reached the brain at measurable concentrations.","whyItMatters":"CBD's poor oral bioavailability has been a major barrier to clinical use. Nanoemulsion formulations can improve absorption, potentially allowing lower effective doses. This study shows a nanoemulsion CBD formulation produced anti-anxiety and anti-panic effects at relatively low doses in rats.","specificNumbers":"CBD 2.5 mg/kg yielded 64.25 ng CBD/g brain tissue; CBD 5.0 mg/kg yielded 21.22 ng/g. Only the 2.5 mg/kg dose showed behavioral effects. 21 days of chronic treatment needed.","methodology":"Male Wistar rats received oral CBD nanoemulsion (2.5 or 5 mg/kg) or vehicle daily for 21 days. Behavioral testing used the elevated T-maze. Brain CBD levels were measured. Immunohistochemistry examined FosB/deltaFosB expression and tryptophan hydroxylase in the dorsal raphe and periaqueductal gray.","limitations":"Animal study in male rats only. Only two doses tested. Inverted dose-response needs further investigation. Nanoemulsion formulation may not translate directly to human use."},{"rthcId":"RTHC-07523","title":"Patient experiences and perspectives regarding medicinal cannabis: a qualitative scoping review.","authors":"Rosenbæk, Frederik; Nielsen, Jesper Bo; Pedersen, Line Bjørnskov; Stewart-Ferrer, Sif Schmidt; Søndergaard, Jens; Williams, Jessica Joan; Hvidt, Elisabeth Assing","year":2025,"journal":"Journal of complementary & integrative medicine","doi":"10.1515/jcim-2025-0233","pmid":"41454516","tags":["medical-cannabis","harm-reduction"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Three major themes emerged: patients described therapeutic potential and tolerability across various conditions, used diverse administration methods tailored to individual needs, but faced significant barriers including stigma, high costs, and bureaucratic delays. Patients often viewed prescription cannabis as superior to conventional medicines, though safety concerns persisted.","whyItMatters":"Most cannabis research focuses on clinical outcomes, missing the lived experience of patients. This review captures the patient perspective at scale, revealing a consistent gap between generally positive patient experiences and the medical community's cautious approach.","specificNumbers":"849 records screened, 40 included. Key barriers: stigma, high costs, bureaucratic delays. Key facilitators: healthcare provider support, family support, peer communities.","methodology":"Scoping review following PRISMA-ScR guidelines. Systematic search of EMBASE, Scopus, PubMed, and Cochrane Library. From 849 records, 40 met inclusion criteria. Thematic analysis identified key themes.","limitations":"Scoping review captures breadth but not depth of individual study quality. Qualitative research reflects subjective experiences. Publication bias may favor positive narratives. Geographic and cultural variation."},{"rthcId":"RTHC-07524","title":"Patients' perceived benefit and side effects from the use of medicinal cannabis - a cross-sectional survey study from Denmark.","authors":"Rosenbæk, Frederik; Pedersen, Line Bjørnskov; Wehberg, Sonja; Nielsen, Jesper Bo; Søndergaard, Jens","year":2025,"journal":"Journal of complementary & integrative medicine","doi":"10.1515/jcim-2025-0277","pmid":"41329466","tags":["medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,044 Danish medical cannabis users, 67% reported moderate to large perceived benefit. Over half experienced side effects, with more than 10% reporting three or more. Side effects were equally common among those reporting strong benefit and those reporting little to no benefit. Side effects clustered into four groups: cognitive dysfunction, dizziness, xerostomia (dry mouth), and feeling high.","whyItMatters":"Understanding the side effect landscape is crucial for informed decisions about medical cannabis. The finding that side effects are unrelated to perceived benefit means patients can't assume that experiencing benefit means they'll avoid side effects, or vice versa.","specificNumbers":"1,044 patients surveyed. 67% reported moderate to large effect. Over 50% experienced side effects. 10%+ reported 3+ side effects. Four side effect clusters identified.","methodology":"Danish nationwide online survey in 2020 among patients with predefined indications (n=258) and other indications (n=786). Perceived benefit and side effects were self-reported. Heat plot correlation and exploratory factor analysis identified side effect patterns.","limitations":"Self-report data. Online survey may not represent all patients. Cross-sectional design. No verification of diagnoses or cannabis products used."},{"rthcId":"RTHC-07525","title":"Patients' Health-Related Quality of Life and Use of Medicinal Cannabis: A Cross-Sectional Survey Study.","authors":"Rosenbæk, Frederik; Wehberg, Sonja; Pedersen, Line Bjørnskov; Nielsen, Jesper Bo; Søndergaard, Jens","year":2025,"journal":"Drugs - real world outcomes, 12(1), 125-133","doi":"10.1007/s40801-024-00479-2","pmid":"39794668","tags":["medical-cannabis","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 9,265 Danish patients, medical cannabis users had a QALY score of 0.44 compared to 0.74 for non-users (general adult population: 0.87). Patients with more prescriptions had progressively lower QALY scores.","whyItMatters":"The lower quality of life among cannabis users likely reflects confounding by indication: patients with the most severe symptoms are more likely to try medical cannabis. This is important context for interpreting observational cannabis studies.","specificNumbers":"9,265 patients surveyed. MC user QALY: 0.44 vs non-user: 0.74 vs adult population: 0.87. Users with 7+ prescriptions scored 0.26-0.32 lower than non-users.","methodology":"Danish nationwide online survey distributed to 23,846 patients in October 2020. Quality-adjusted life years (QALYs) measured using EQ-5D-3L. Compared QALY scores across diagnostic groups between MC users and non-users.","limitations":"Cross-sectional design cannot determine direction of association. Confounding by indication likely explains much of the difference. Small numbers when stratified by prescription count."},{"rthcId":"RTHC-07526","title":"\"Those pot heads\" - perceived external stigma and self-stigma among cannabis users in Germany: prevalence and associations with socio-demographics, cannabis use patterns and psychological distress.","authors":"Rosenkranz, Moritz; Schranz, Anna; Verthein, Uwe; Schomerus, Georg; Speerforck, Sven; Manthey, Jakob","year":2025,"journal":"Journal of cannabis research, 7(1), 66","doi":"10.1186/s42238-025-00328-1","pmid":"40963151","tags":["legalization","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 684 regular cannabis users in Germany (surveyed before legalization), 30.6% perceived external stigmatization and 22.1% reported self-stigma. Higher education, psychological distress, medical use, and cannabis use disorder were all significantly associated with both types of stigma.","whyItMatters":"Germany legalized recreational cannabis in 2024, making this pre-legalization stigma data a valuable baseline. Understanding who experiences cannabis stigma can help shape public health messaging and support services.","specificNumbers":"684 regular cannabis users surveyed. External stigma: 30.6%. Self-stigma: 22.1%. Associated factors: higher education, psychological distress, medical use, cannabis use disorder, public disclosure, police encounters.","methodology":"Cross-sectional online survey in 2023 using ISO-certified access panels. Quota-sampled 684 regular cannabis users (ages 18-64) to reflect German demographics.","limitations":"Cross-sectional pre-legalization snapshot only. Online panel may not represent all users. Self-report measures. German context may not generalize."},{"rthcId":"RTHC-07527","title":"Reevaluating the Link Between Psychopathology Symptoms and Alcohol and Cannabis Use: An Examination Across Intersectional Race/Ethnicity and Gender Identities.","authors":"Rozum, William; Hernandez Valencia, Evelyn M; Sutherland Charvis, Jodi M; Vergara-Lopez, Chrystal; Lopez-Vergara, Hector I","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(6), 956-966","doi":"10.15288/jsad.24-00285","pmid":"40035819","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07528","title":"Recognizing Cannabis Hyperemesis Syndrome in Pediatric Patients: Insights From a Case Report.","authors":"Rucinski, Pawel; Akutko, Katarzyna; Pytrus, Tomasz","year":2025,"journal":"Cureus, 17(3), e79904","doi":"10.7759/cureus.79904","pmid":"40171381","tags":["youth","harm-reduction","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A 16.5-year-old male presented with a 2-year history of vomiting episodes lasting up to 10 days, with abdominal pain and weight loss. After extensive workup ruled out other causes, CHS was diagnosed based on the temporal relationship between cannabis use and symptom onset. Symptoms resolved with supportive care and cannabis cessation.","whyItMatters":"Cannabis hyperemesis syndrome is increasingly recognized in adults but may be underdiagnosed in adolescents, leading to unnecessary testing and prolonged suffering. Given increasing cannabis use and potency among youth, pediatric providers need to consider CHS.","specificNumbers":"16.5-year-old male. 2-year symptom history. Vomiting episodes lasting up to 10 days. Symptoms resolved after cannabis cessation.","methodology":"Single case report with clinical documentation of diagnostic workup, temporal relationship between cannabis use and symptoms, and treatment response.","limitations":"Single case report. Diagnosis based on temporal association and exclusion. No biomarkers for CHS exist."},{"rthcId":"RTHC-07529","title":"Trends in Antidepressant, Anxiolytic, and Cannabinoid Use Among Italian Elite Athletes (2011-2023): A Longitudinal Anti-Doping Analysis.","authors":"Ruggiero, Mario; Ferrante, Leopoldo; Tafuri, Domenico; Meccariello, Rosaria; Mazzeo, Filomena","year":2025,"journal":"Sports (Basel, Switzerland), 13(7)","doi":"10.3390/sports13070233","pmid":"40711118","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07530","title":"Associations of cardiorespiratory fitness and muscular fitness with plasma levels of endocannabinoids and their analogues in adults with diagnosed depression: SONRIE study.","authors":"Ruiz-Muñoz, Manuel; Ortega-Gómez, Sonia; Espinosa-Nogales, Maria Del Mar; de Lara, Eulalio Valmisa-Gómez; Rosety-Rodríguez, Miguel Ángel; España-Romero, Vanesa","year":2025,"journal":"European archives of psychiatry and clinical neuroscience","doi":"10.1007/s00406-025-02032-w","pmid":"40471249","tags":["exercise","depression","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 80 adults with mild-to-moderate depression, better cardiorespiratory fitness and jump performance were inversely associated with plasma levels of both main endocannabinoids: anandamide and 2-AG. These relationships persisted after adjusting for lean mass.","whyItMatters":"Exercise is known to help depression, and the endocannabinoid system has been proposed as a key mediator. This study provides direct data on the relationship between fitness and endocannabinoid levels in people with depression.","specificNumbers":"80 adults with depression. CRF and AEA: beta -0.302 to -0.237. CRF and 2-AG: beta -0.308 to -0.326. Jump and AEA: beta -0.315 to -0.370. All p<0.05.","methodology":"Cross-sectional study of 80 adults ages 25-65 with mild-to-moderate depression (ICD-10). Physical fitness assessed via 6-Minute Walk Test, handgrip, arm curl, chair stand, and standing long jump. Fasting plasma endocannabinoids measured by LC-MS/MS.","limitations":"Cross-sectional; cannot determine causation. Plasma levels may not reflect brain activity. Small sample. No comparison group without depression."},{"rthcId":"RTHC-07531","title":"Self-Reported Cannabis Prices and Expenditures From Legal and Illegal Sources Five Years After Legalisation of Non-Medical Cannabis in Canada.","authors":"Rundle, Samantha; Hong, Daniel Danh; Iraniparast, Maryam; Rynard, Vicki; Wadsworth, Elle; Pacula, Rosalie Liccardo; Kilmer, Beau; Hammond, David","year":2025,"journal":"Drug and alcohol review, 44(6), 1658-1665","doi":"10.1111/dar.70009","pmid":"40760733","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 2,686 Canadian cannabis consumers, 78% of purchases came from legal sources. Legal dried flower cost 23.8% more than illegal, vapes 18.7% more, and hash 38.4% more. Legal capsules were 28.4% cheaper. No significant price differences for edibles, drinks, concentrates, drops, or tinctures.","whyItMatters":"Price competition between legal and illegal markets is central to legalization's success. This data shows meaningful progress in Canada, with most purchases now from legal sources and price gaps narrowing.","specificNumbers":"2,686 respondents. 78% from legal sources. Legal premiums: dried flower +23.8%, vapes +18.7%, hash +38.4%. Legal discount: capsules -28.4%.","methodology":"National surveys in 2022-2023 among Canadians aged 16-65 as part of the International Cannabis Policy Study. 2,686 respondents reported price, quantity, and source for nine product types.","limitations":"Self-reported prices and sources. Cross-sectional. No quality comparison between markets. Quantity discounts complicate comparisons."},{"rthcId":"RTHC-07532","title":"Help-seeking behaviours among cannabis consumers in Canada and the United States: Findings from the international cannabis policy study.","authors":"Rundle, Samantha M; Hammond, David","year":2025,"journal":"Drug and alcohol dependence reports, 14, 100306","doi":"10.1016/j.dadr.2024.100306","pmid":"39811186","tags":["addiction","quitting","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 13,209 past-12-month cannabis consumers, only 9.2% sought help in the past 3 months. Doctors were the most common source (44.9%). In illegal US states, consumers were nearly 5 times more likely to seek help from family/friends and half as likely to see a doctor.","whyItMatters":"The low rate of help-seeking suggests significant unmet need. Legal context shapes where people seek help, with implications for public health planning.","specificNumbers":"13,209 consumers. 9.2% sought help. Top source: doctor (44.9%). Illegal US states vs legal: family/friends AOR=4.76-5.73; doctor AOR=0.46-0.51.","methodology":"Online survey from the International Cannabis Policy Study. 13,209 past-12-month consumers in Canada and the US. Assessed help-seeking behaviors, perceived addiction, and legal context.","limitations":"Cross-sectional self-report. Online sample limitations. Cannot determine effectiveness of help received."},{"rthcId":"RTHC-07533","title":"Cannabis and liver transplant in the era of legalization: Effects of pretransplant cannabis use on postoperative opioid use and transplant outcomes.","authors":"Runge, Ava; Loeb, Becca; Shui, Amy M; Fenton, Cynthia; Lai, Jennifer; Rubin, Jessica","year":2025,"journal":"Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 31(11), 1398-1410","doi":"10.1097/LVT.0000000000000585","pmid":"39976576","tags":["medical-cannabis","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 4,236 patients, cannabis users required significantly more opioids in the 48 hours after transplant (p=0.04). No significant differences in opioid use beyond 48 hours, discharge opioid prescriptions, hospital or ICU length of stay, 90-day readmission, or 90-day mortality.","whyItMatters":"Some transplant centers still consider cannabis use a barrier to eligibility. This data supports growing evidence that pre-transplant cannabis use does not worsen outcomes.","specificNumbers":"4,236 patients. Higher opioids at 48 hours (p=0.04). No difference at 72 hours (p=0.07) or 7 days (p=0.33). No difference in LOS (p=0.69), ICU LOS (p=0.94), readmission (p=0.66), or mortality (p=0.96).","methodology":"Retrospective cohort of 4,236 patients evaluated for liver transplant (January 2013-July 2023). Cannabis use defined as positive urine toxicology within 90 days. Multivariable regression compared outcomes.","limitations":"Single-center retrospective. Cannabis defined by single urine test. No data on type or frequency of use."},{"rthcId":"RTHC-07534","title":"Characterizing users of a mobile application for supporting a 30-day break from cannabis.","authors":"Russell, Alex M; Acuff, Samuel F; Muench, Frederick J; Bergman, Brandon G","year":2025,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 39(6), 571-576","doi":"10.1037/adb0001075","pmid":"40489162","tags":["quitting","addiction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 4,415 users of the Clear30 app, 83.3% were aged 18-25 and 86% used cannabis 6-7 days per week. Top motivations: mental clarity (46.7%), self-control (30.7%), reducing dependency (26.2%). 58.9% intended to reduce use after the break; 24.4% to quit entirely. 80% had previously attempted a break.","whyItMatters":"Traditional treatment focuses on abstinence, but many users want to moderate. Digital tools offer low-barrier support that meets users where they are.","specificNumbers":"4,415 app users. 83.3% aged 18-25. 86% used 6-7 days/week. 70.2% saw use as equally beneficial and harmful. 80% had tried a break before.","methodology":"Secondary analysis of baseline data from 4,415 self-selected Clear30 app users who completed assessments before a 30-day cannabis break.","limitations":"Self-selected users. No outcome data. Baseline data only. No control group."},{"rthcId":"RTHC-07535","title":"A Treatment Approach for Severe Pain in Mast Cell Activation Syndrome: A Case Report.","authors":"Russo, Marc A; Santarelli, Danielle M","year":2025,"journal":"A&A practice, 19(12), e02115","doi":"10.1213/XAA.0000000000002115","pmid":"41370840","tags":["cbd","pain","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A patient with widespread, severe, refractory MCAS pain was treated with orphenadrine and CBD oil. Pain severity reduced by 56% and pain interference by 87% at 20 weeks. CBD has recently been shown to suppress mast cell activation and degranulation.","whyItMatters":"MCAS causes chronic pain with no established treatment paradigm. This is the first reported case of using CBD's mast cell-suppressing properties specifically to target MCAS pain.","specificNumbers":"Pain severity reduced by 56%. Pain interference reduced by 87% at 20 weeks.","methodology":"Single case report documenting treatment response over 20 weeks with standardized pain scales.","limitations":"Single case report. Cannot determine which component drove improvement. Natural disease fluctuation or placebo cannot be excluded."},{"rthcId":"RTHC-07536","title":"Inhaled Cannabis, Asthma, and Chronic Obstructive Pulmonary Disease: A Population-Based Cross-Sectional Study of n = 379,049.","authors":"Rustagi, Alison S; Jeffers, Abra M; Graham, F Julian; Cohen, Beth E; Slatore, Christopher G; Byers, Amy L; Glantz, Stanton A; Keyhani, Salomeh","year":2025,"journal":"Journal of general internal medicine","doi":"10.1007/s11606-025-09833-8","pmid":"40906010","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Daily inhaled cannabis was associated with higher odds of asthma (aOR 1.44) and COPD (aOR 1.27) after adjusting for tobacco use. Among 221,767 never-tobacco-users, the asthma association persisted (aOR 1.51) while COPD showed elevated but non-significant odds (aOR 1.54).","whyItMatters":"This is one of the largest studies examining cannabis and pulmonary disease independent of tobacco. The finding that asthma associations persist even in never-tobacco-users strengthens the case that inhaled cannabis itself may contribute to respiratory disease.","specificNumbers":"n=379,049; n=23,035 cannabis users. Daily cannabis and asthma: aOR 1.44 overall, 1.51 in never-tobacco users. Daily cannabis and COPD: aOR 1.27 overall.","methodology":"Cross-sectional analysis of 2016-2020 BRFSS nationally representative survey. 379,049 adults aged 18-74. Multivariable logistic regression adjusted for sociodemographics and tobacco use. Pre-specified subanalysis in never-tobacco users.","limitations":"Cross-sectional. Self-reported diagnoses. No information on product type or method beyond 'inhaled.' Residual confounding possible."},{"rthcId":"RTHC-07537","title":"Cannabidiol in Skin Health: A Comprehensive Review of Topical Applications in Dermatology and Cosmetic Science.","authors":"Rusu, Aura; Farcaș, Andreea-Maria; Oancea, Octavia-Laura; Tanase, Corneliu","year":2025,"journal":"Biomolecules, 15(9)","doi":"10.3390/biom15091219","pmid":"41008526","tags":["cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Preclinical and clinical evidence supports CBD's efficacy for acne, psoriasis, atopic and seborrheic dermatitis, and allergic contact dermatitis. CBD also shows promise for pruritus relief, wound healing, hair loss, and certain skin cancers. Effects are mediated through the skin's endocannabinoid system (CB1, CB2, TRPV channels, PPARs).","whyItMatters":"The skincare market is flooded with CBD products, but most lack rigorous evidence. This review separates what's supported by science from marketing hype.","specificNumbers":"Conditions with supporting evidence: acne, psoriasis, atopic dermatitis, seborrheic dermatitis, allergic contact dermatitis, pruritus, wound healing, androgenetic alopecia, certain skin cancers.","methodology":"Comprehensive narrative review of preclinical and clinical evidence on CBD's topical therapeutic potential in dermatology and cosmetic science.","limitations":"Narrative review. Much evidence is preclinical. CBD's stability and skin penetration pose formulation challenges. Regulatory frameworks vary widely."},{"rthcId":"RTHC-07538","title":"Prenatal cannabis exposure and the risk of subsequent maltreatment.","authors":"Ryan, Joseph P; Oshman, Lauren; Frank, Christopher J; Perron, Brian; Victor, Bryan; Sankaran, Vivek","year":2025,"journal":"Child abuse & neglect, 160, 107175","doi":"10.1016/j.chiabu.2024.107175","pmid":"39667085","tags":["pregnancy","legalization","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 35,437 births, Black and multiracial newborns were significantly more likely to be drug-tested. After the policy change, newborns testing positive for THC only were no more likely to experience subsequent maltreatment compared to those testing negative or not tested.","whyItMatters":"Policies equating prenatal cannabis exposure with child abuse can separate families, disproportionately affecting Black and multiracial families. This study provides evidence that prenatal THC alone does not predict maltreatment.","specificNumbers":"35,437 births. Black and multiracial newborns significantly more likely to be tested. Post-policy: THC-only positive had no higher maltreatment rate.","methodology":"Retrospective cohort linking University of Michigan birth data (n=35,437) with Michigan maltreatment data. Compared outcomes before and after 2018 policy change. Regression models adjusted for demographics.","limitations":"Single-center. Michigan-specific policy. Cannot assess heavy/chronic use separately. Meconium captures third-trimester exposure only."},{"rthcId":"RTHC-07539","title":"The Anti-Glioblastoma Effects of Novel Liposomal Formulations Loaded with Cannabidiol, Celecoxib, and 2,5-Dimethylcelecoxib.","authors":"Rybarczyk, Anna; Majchrzak-Celińska, Aleksandra; Piwowarczyk, Ludwika; Krajka-Kuźniak, Violetta","year":2025,"journal":"Pharmaceutics, 17(8)","doi":"10.3390/pharmaceutics17081031","pmid":"40871052","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07540","title":"Effect of Quantitative Structural Properties and Drug Formulation in Four Cannabinoids (Cannabidiol, Cannabigerol, Cannabichromene, and Cannabinol) on Their Lymphatic Transport after Enteral Administration in Rats.","authors":"Ryšánek, Pavel; Jelínek, Petr; Housar, Hynek; Kozlík, Petr; Křížek, Tomáš; Nováková, Anežka; Sklenárová, Michaela; Paulusová, Viktória; Merdita, Sara; Arora, Mahak; Symkanych, Olesia; Šteigerová, Monika; Zmeškalová, Eliška; Slanař, Ondřej; Šoóš, Miroslav; Šíma, Martin","year":2025,"journal":"Molecular pharmaceutics, 22(8), 4544-4555","doi":"10.1021/acs.molpharmaceut.4c01357","pmid":"40611782","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07541","title":"Virucidal activity of Cannabis sativa L. (hemp) root and stem extracts against Japanese encephalitis virus: role of stigmasterol.","authors":"Ryu, Han-Sol; Kim, Ki-Hyun; Cho, Kiu-Hyung; Lee, Ah-Ra; Seo, Sang-Uk; Jeon, Sejin; Yoon, Sun-Woo; Lee, Sanghyun; Kwon, Yun; Jang, Yo Han","year":2025,"journal":"Archives of virology, 170(12), 239","doi":"10.1007/s00705-025-06433-z","pmid":"41196377","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07542","title":"A high-fat meal significantly impacts the bioavailability and biphasic absorption of cannabidiol (CBD) from a CBD-rich extract in men and women.","authors":"Saals, Bo Anne Daniëlla Frederique; De Bie, Tessa Helena; Osmanoglou, Eral; van de Laar, Ties; Tuin, Adriaan Willem; van Orten-Luiten, Anne Claire Benedikte; Witkamp, Renger Frederik","year":2025,"journal":"Scientific reports, 15(1), 3678","doi":"10.1038/s41598-025-87621-4","pmid":"39880884","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In 11 healthy participants, consuming 70 mg CBD from a hemp extract with a high-fat meal dramatically increased bioavailability. The geometric mean ratio of peak CBD concentration was 17.4 (fed vs fasted), and total exposure (AUC) was 9.7 times higher with food. A double-peak phenomenon was observed after the meal, likely due to lymphatic transport and enterohepatic recirculation.","whyItMatters":"CBD's poor oral bioavailability is a major practical challenge. This study quantifies just how dramatically food intake affects absorption, with nearly 10-fold differences in total exposure. This has direct implications for anyone taking CBD, as timing relative to meals could determine whether therapeutic levels are reached.","specificNumbers":"11 participants (5 male, 6 female). 70 mg CBD dose. Fed vs fasted: Cmax GMR = 17.4 (90% CI 12.4-24.2), AUC GMR = 9.7 (90% CI 7.7-12.3). Double-peak phenomenon observed after meal.","methodology":"Randomized, double-blind, placebo-controlled crossover trial with 11 healthy participants (5 male, 6 female). Single oral dose of CBD-rich extract equivalent to 70 mg CBD. Compared pharmacokinetics after a standardized high-fat meal vs fasting. Registered at ClinicalTrials.gov (NCT04589455).","limitations":"Small sample size (n=11). Single dose only. Used a CBD-rich extract, not pure CBD. Short-term pharmacokinetics only. Did not assess whether the increased bioavailability translates to greater therapeutic effects."},{"rthcId":"RTHC-07543","title":"Cannabidiol Effects on Depressive-like Behavior and Neuroinflammation in Female Rats Exposed to High-Fat Diet and Unpredictable Chronic Mild Stress.","authors":"Sabbag, Tal; Kritman, Milly; Akirav, Irit","year":2025,"journal":"Cells, 14(12)","doi":"10.3390/cells14120938","pmid":"40558565","tags":["cbd","depression","inflammation","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Female rats exposed to both a high-fat diet (2 weeks) and chronic unpredictable mild stress (4 weeks) received CBD (10 mg/kg) during the final 2 weeks. CBD promoted active coping behavior, increased locomotion, reduced freezing, and restored depressive-like behavior in the splash test. In the prefrontal cortex, CBD normalized stress-induced increases in IL-1 beta and downregulated NF-kB1 and TNF-alpha expression.","whyItMatters":"Depression and obesity frequently co-occur and share neuroinflammatory mechanisms. This study uses female rats specifically, addressing a major gap since most preclinical depression research uses males. The finding that CBD's effects depend on stressor type has implications for understanding when CBD might be most beneficial.","specificNumbers":"CBD dose: 10 mg/kg for 2 weeks. HFD: 2 weeks. UCMS: 4 weeks. CBD normalized IL-1 beta and downregulated NF-kB1 and TNF-alpha in prefrontal cortex.","methodology":"Female Wistar rats exposed to 2 weeks of high-fat diet followed by 4 weeks of unpredictable chronic mild stress. CBD (10 mg/kg, i.p.) or vehicle administered during the last 2 weeks. Behavioral testing and mRNA analysis of inflammatory markers in prefrontal cortex and hippocampal CA1.","limitations":"Animal study in female rats only. Single CBD dose tested. Short treatment duration. Intraperitoneal injection, not oral administration. Artificial stress model may not fully capture human depression."},{"rthcId":"RTHC-07544","title":"An indirect competitive ELISA assay using fragment antigen-binding (Fab) antibody for the quantitative detection of delta-9-tetrahydrocannabinol from Cannabis sativa L.","authors":"Sae-Foo, Worapol; Paluka, Jakkapat; Intapan, Pewpan Maleewong; Putalun, Waraporn","year":2025,"journal":"Journal of immunoassay & immunochemistry, 46(5), 535-556","doi":"10.1080/15321819.2025.2538777","pmid":"40717338","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07545","title":"Hemp inflorescence meal as a novel feed ingredient in laying hens: Safety assessment, nutritional characterization, and effects on egg quality.","authors":"Saengsuwan, Hathairat; Bunchasak, Chaiyapoom; Rakangthong, Choawit; Poungpong, Kanokporn","year":2025,"journal":"Veterinary world, 18(8), 2406-2413","doi":"10.14202/vetworld.2025.2406-2413","pmid":"41064825","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07546","title":"The effects of cannabis on mind-wandering.","authors":"Safati, Adrian Berk; Alkheder, Wisam Almohamad; Lowe, Cassandra Justine; Smilek, Daniel","year":2025,"journal":"Heliyon, 11(4), e42911","doi":"10.1016/j.heliyon.2025.e42911","pmid":"41477513","tags":["cognition","neuroscience"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a three-session ABA design (abstinent-cannabis-abstinent), cannabis use was associated with a large increase in spontaneous mind-wandering during a metronome timing task. When instructed to mind-wander 20% or 80% of the time, cannabis reduced participants' ability to adjust their deliberate mind-wandering and task performance to match instructions, suggesting impaired regulation of attention.","whyItMatters":"Mind-wandering is linked to creativity but also to accidents, poor learning, and mental health challenges. This study provides direct evidence that cannabis not only increases spontaneous mind-wandering but specifically impairs the ability to control it, which has practical implications for activities requiring sustained attention.","specificNumbers":"Three sessions per participant (ABA design). Cannabis produced a 'large' increase in spontaneous mind-wandering. Smaller increase in deliberate mind-wandering. Impaired response to instructions to adjust mind-wandering levels.","methodology":"Regular cannabis users completed three remote sessions: two on planned abstinence days and one immediately after planned cannabis use. Each session included three blocks of the Metronome Response Task with intermittent self-reports of spontaneous and deliberate mind-wandering. Participants used legally purchased pre-rolls.","limitations":"Remote study design relies on self-report. No placebo control (participants knew when they used cannabis). Cannot control for dose, strain, or potency. Naturalistic use means variable exposure. Regular users may not represent occasional users."},{"rthcId":"RTHC-07547","title":"Substance Use and Risky Sexual Behavior Among Adolescents: A Cross-National Clustered Analysis of 35 European and North American Countries.","authors":"Safo Oduro, Michael; Adeleye, Khadijat K; Agyemang-Duah, Williams; Peprah, Prince","year":2025,"journal":"International journal of sexual health : official journal of the World Association for Sexual Health, 37(2), 284-296","doi":"10.1080/19317611.2025.2471800","pmid":"40400568","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07548","title":"The Complex Relationship Between Cannabis Use and Mental Health: Considering the Influence of Cannabis Use Patterns and Individual Factors.","authors":"Sagar, Kelly A; Gruber, Staci A","year":2025,"journal":"CNS drugs, 39(2), 113-125","doi":"10.1007/s40263-024-01148-2","pmid":"39753766","tags":["mental-health","psychosis","anxiety","depression","youth"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review highlights that seemingly contradictory findings in cannabis-mental health research are largely explained by unmeasured variables. THC exposure drives most negative outcomes while CBD shows therapeutic promise. Youth and those with family history of psychiatric disorders face the highest risk. Product choice, route of administration, and use frequency all significantly modify outcomes but are rarely reported in studies.","whyItMatters":"As cannabis use increases, both patients and providers need nuanced guidance beyond 'cannabis is good' or 'cannabis is bad.' This review identifies the specific factors that determine whether cannabis use is more likely to help or harm mental health.","specificNumbers":"Key risk factors: youth onset, family history of psychiatric disorders. Key moderators: THC vs CBD content, frequency, amount, route of administration, age, sex, genetics.","methodology":"Narrative review summarizing findings from studies and reviews on cannabis and mood disorders, anxiety, psychosis, and PTSD, with focus on critical moderating variables.","limitations":"Narrative review, not systematic. Relies on existing literature with the same gaps it critiques. Cannot quantify the relative importance of each moderating variable."},{"rthcId":"RTHC-07549","title":"The Acute Effects of Cannabidiol on Physiological and Subjective Responses to Endurance Exercise: A Dose-Ranging Randomised Controlled Crossover Trial.","authors":"Sahinovic, Ayshe; Lau, Namson S; Sabag, Angelo; Gordon, Rebecca; Cox, Amanda J; Walker, Katie; Irwin, Christopher; Desbrow, Ben; Johnson, Nathan; Austin, Paul J; Haber, Paul; McGregor, Iain S; McCartney, Danielle","year":2025,"journal":"Sports medicine - open, 11(1), 96","doi":"10.1186/s40798-025-00895-w","pmid":"40839290","tags":["cbd","exercise"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In 25 trained runners, neither 50 mg nor 300 mg CBD taken 90 minutes before exercise altered affective valence, enjoyment, perceived exertion, pain, heart rate, VO2, VO2peak, or time to exhaustion compared to placebo. 300 mg CBD did decrease the respiratory exchange ratio during submaximal running, and 50 mg CBD increased post-exercise blood glucose. No effect on muscle damage markers.","whyItMatters":"Athletes increasingly use CBD for recovery and other health purposes. This rigorous trial provides reassurance that acute CBD use at common doses does not impair performance, while also finding no performance enhancement.","specificNumbers":"25 participants, 16 male. VO2max: 53.1 mL/min/kg. Doses: 0, 50, 300 mg CBD. No effect on TTE, HR, VO2, RPE, pain, enjoyment, mood, or anxiety (all p>0.05). 300 mg decreased respiratory exchange ratio (p=0.030). 50 mg increased post-exercise glucose (p=0.003).","methodology":"Randomized, double-blind, placebo-controlled crossover trial. 25 trained runners (16 male, VO2max=53.1 mL/min/kg) received placebo, 50 mg, or 300 mg CBD 90 minutes before a 60-min submaximal treadmill run followed by an incremental run to exhaustion. Registered clinical trial (ACTRN12622000717752).","limitations":"Acute single-dose design; chronic CBD use effects not assessed. Sample of trained runners may not generalize to other athletes or recreational exercisers. Three conditions in crossover design may not fully washout. The RER and glucose findings need replication."},{"rthcId":"RTHC-07550","title":"Exploring the Utility of a Functional Magnetic Resonance Imaging Cannabis Cue-Reactivity Paradigm in Treatment-Seeking Adults With Cannabis Use Disorder.","authors":"Sahlem, Gregory L; Dowdle, Logan T; Baker, Nathaniel L; Sherman, Brian J; Gray, Kevin M; McRae-Clark, Aimee L; Froeliger, Brett; Squeglia, Lindsay M","year":2025,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging, 10(5), 522-530","doi":"10.1016/j.bpsc.2024.09.006","pmid":"39326740","tags":["addiction","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In 65 treatment-seeking participants with moderate or severe CUD, viewing cannabis images (vs neutral) activated bilateral prefrontal cortex, anterior cingulate, visual cortex, and striatum. Functional connectivity increased between the medial prefrontal cortex and both the amygdala and visual cortex. Unexpectedly, self-reported craving negatively correlated with left ventral striatum activation, suggesting that higher craving was associated with reduced reward area response to cues.","whyItMatters":"Understanding how the brain responds to cannabis cues in treatment-seeking individuals could help predict treatment success and develop targeted interventions. The negative correlation between craving and reward area activation challenges simple models of addiction.","specificNumbers":"65 participants (37 from varenicline trial, 28 from rTMS trial). 32% female. Mean age: 30.4 years. Craving negatively correlated with left ventral striatum (R2=-0.32, p=.01). No significant differences between study cohorts.","methodology":"Secondary analysis of 65 participants from two clinical trials (varenicline and rTMS for CUD). fMRI cue-reactivity task comparing cannabis vs neutral images after 24 hours of abstinence. Craving measured with Marijuana Craving Questionnaire. 32% female, mean age 30.4 years.","limitations":"Secondary analysis of two separate trials. Cross-sectional design. 24-hour abstinence may not fully eliminate acute effects. Visual cue-reactivity may not capture all forms of craving. Cannot determine causation."},{"rthcId":"RTHC-07551","title":"Genetic Insights into Cannabis-induced Psychosis: Role of CNR1 Gene Mutation (rs1049353) and Implications- A Cross-sectional Study.","authors":"Sahoo, Sujata; Swain, Sarada Prasanna; Samal, Abhishek; Jena, Mamta; Das, Pragyna Paramita","year":2025,"journal":"Indian journal of psychological medicine, 02537176251377498","doi":"10.1177/02537176251377498","pmid":"41040950","tags":["psychosis","genetics"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Not everyone who uses cannabis develops psychosis, and not everyone with schizophrenia has used cannabis. This study investigated whether a specific genetic variation might help explain who is vulnerable.\n\nThe researchers genotyped 120 people at an Indian medical college, divided into four groups: cannabis-induced psychosis (CIP), cannabis users without psychosis, schizophrenia unrelated to cannabis, and healthy controls. They focused on the CNR1 gene—which codes for the CB1 cannabinoid receptor—specifically the rs1049353 single nucleotide polymorphism.\n\nThe genetic analysis found that the prevalence of this CNR1 polymorphism differed across the groups, though the abstract doesn't detail the specific genotype distributions. The demographic analysis showed no significant differences in education, employment, religion, or other socioeconomic factors between groups, suggesting the genetic finding isn't confounded by obvious social variables.\n\nThis is the same genetic variant studied in RTHC-00180 (in the context of diabetic kidney disease), demonstrating that a single cannabinoid receptor polymorphism may influence multiple disease pathways—psychosis vulnerability here, kidney disease progression there.","whyItMatters":"If genetic testing could identify who is at elevated risk for cannabis-induced psychosis, it could inform personalized prevention. The 10-fold risk for genetically vulnerable individuals identified in RTHC-00201 needs a molecular explanation—variants like rs1049353 are candidate mechanisms. This line of research could eventually lead to genetic screening that identifies high-risk individuals before they ever use cannabis.","specificNumbers":"N = 120 (30 per group). 4 groups: cannabis-induced psychosis, cannabis use without psychosis, schizophrenia without cannabis, healthy controls. CNR1 rs1049353 genotyped by RT-PCR. No significant demographic differences between groups.","methodology":"Cross-sectional genetic study at SCB Medical College, Cuttack, India. 120 participants in 4 groups (30 each): cannabis-induced psychosis, cannabis use without psychosis, schizophrenia without cannabis, and healthy controls. Genotyping of CNR1 rs1049353 by real-time PCR. Standardized demographic and clinical data collection.","limitations":"Small sample size (30 per group) limits statistical power. Single-center study in India may not generalize to other populations where allele frequencies differ. Only one SNP examined out of many possible variants. Cross-sectional design can't establish causation. The abstract doesn't report specific genotype frequencies or effect sizes. Cannabis exposure history isn't standardized (dose, duration, potency vary)."},{"rthcId":"RTHC-07552","title":"Alcohol and Drug Use Among Injured Drivers: Insights From an Emergency Room Study at an Institute of National Importance in India.","authors":"Sahu, Kamal Kant; Akhade, Swapnil P; Chavali, Krishnadutt; Ghormade, Pankaj S","year":2025,"journal":"Cureus, 17(7), e89029","doi":"10.7759/cureus.89029","pmid":"40895882","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07553","title":"Validation of the Spanish version of the multifaceted empathy test: comparison between cannabis use effects and controls in social cognition.","authors":"Sainz-Cort, Alberto; Martín-Islas, Marta; Jimenez-Garrido, Daniel; López-Navarro, Miriam; Oña, Genís; Muñoz-Marron, Elena; Heredia, Luis; Gil-Pérez, Mercè; Torrente, Margarita; Vicens, Paloma; Bouso, José Carlos","year":2025,"journal":"International clinical psychopharmacology, 40(2), 100-109","doi":"10.1097/YIC.0000000000000544","pmid":"38935429","tags":["cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"116 participants from a Cannabis Social Club completed empathy tests under the effects of cannabis and were compared to 86 sober university students. Cannabis users showed deficient overall emotional recognition, with particular difficulty recognizing emotions from positive stimuli. Overall emotional empathy scores were similar between groups, but cannabis users scored lower when presented with negative stimuli, suggesting a dampened emotional reaction to negative content.","whyItMatters":"Empathy and emotional recognition are fundamental to social functioning. This study provides the first evidence that cannabis specifically dampens reactions to negative emotional stimuli while impairing recognition of positive emotions, offering a nuanced picture of how cannabis affects social cognition.","specificNumbers":"116 cannabis users (under the influence) vs 86 controls. Deficient overall emotional recognition. Reduced scores for positive stimuli. Similar overall emotional empathy. Lower emotional empathy specifically for negative stimuli.","methodology":"Cross-sectional comparison of 116 Cannabis Social Club members (tested under cannabis effects) and 86 university student controls. Used the Multifaceted Empathy Test (MET) Spanish version and the Reading the Mind in the Eyes Test (RMET).","limitations":"Cross-sectional design cannot determine if cannabis caused the differences or if pre-existing differences led to cannabis use. Cannabis users and controls differ in many ways beyond cannabis use. Acute intoxication effects may differ from chronic effects. Self-selection into Cannabis Social Clubs."},{"rthcId":"RTHC-07554","title":"Cannabis-Induced Catatonia Complicated by Rhabdomyolysis, Acute Kidney Injury, and Sympathetic Overactivity: A Case Report.","authors":"Saira, Sidharth; Singh, Himanshi","year":2025,"journal":"Cureus, 17(11), e97507","doi":"10.7759/cureus.97507","pmid":"41439078","tags":["psychosis","youth","addiction","mental-health"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"This case report describes a severe psychiatric emergency triggered by cannabis in a vulnerable individual. A 21-year-old male with a history of cannabis-induced psychosis had stopped taking his depot antipsychotic medication and resumed cannabis use. He then developed catatonia—a neuropsychiatric syndrome characterized by motor, behavioral, and autonomic disturbances.\n\nHis presentation included mutism, social withdrawal, psychomotor retardation, poor oral intake, thought blocking, waxy flexibility (limbs remaining in positions they're placed in), negativism, and stupor. These are classic catatonic features.\n\nThe catatonia then triggered a dangerous cascade of physical complications. Prolonged immobility led to rhabdomyolysis (muscle breakdown), evidenced by markedly elevated creatine kinase (CK). The muscle breakdown products damaged his kidneys (acute kidney injury with raised creatinine). He also developed sympathetic overactivity—autonomic instability that can be life-threatening.\n\nUrine toxicology confirmed THC. Comprehensive workup (blood tests, CT head, chest X-ray) ruled out other organic causes, pointing to cannabis as the precipitant in the context of his psychiatric vulnerability.\n\nThis case illustrates the worst-case scenario of the gene-environment interaction: a genetically vulnerable individual (prior psychotic episode), non-compliant with treatment, re-exposed to cannabis, developing a cascade of psychiatric and medical emergencies.","whyItMatters":"Catatonia is under-recognized as a potential consequence of cannabis use, especially in psychiatrically vulnerable individuals. This case demonstrates that the psychiatric emergency (catatonia) can rapidly become a medical emergency (kidney failure, autonomic instability). Emergency physicians and psychiatrists need to consider cannabis as a catatonia precipitant and monitor for physical complications.","specificNumbers":"21-year-old male. Prior cannabis-induced psychosis. Non-compliant with depot antipsychotics. Markedly elevated CK (rhabdomyolysis). Raised creatinine (AKI). Urine THC-positive. Comprehensive workup ruled out other causes.","methodology":"Single case report of a 21-year-old male with prior cannabis-induced psychosis presenting with catatonia, rhabdomyolysis, AKI, and sympathetic overactivity. Diagnostic workup included CK, creatinine, urine toxicology, hematologic/hepatic/thyroid panels, CT head, and chest X-ray.","limitations":"Single case report—can't establish how common this cascade is. The patient had prior psychotic episodes and medication non-compliance, making it impossible to attribute the outcome solely to cannabis. No genetic testing was reported (RTHC-00202's CNR1 variant could have been informative). The severity of this case may not represent the typical cannabis-associated catatonia presentation."},{"rthcId":"RTHC-07555","title":"Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms.","authors":"Saldaña, Raquel; Carrascosa, Antonio J; Torregrosa, Abraham B; Navarrete, Francisco; García-Gutiérrez, María Salud; Manzanares, Jorge","year":2025,"journal":"International journal of molecular sciences, 26(21)","doi":"10.3390/ijms262110692","pmid":"41226728","tags":["pain","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review reveals that the spinal endocannabinoid system's role in pain is context-dependent. While numerous studies show antinociceptive and neuroprotective effects, emerging evidence indicates that under specific pathological conditions, endocannabinoid system activation in the spinal cord can facilitate rather than inhibit pain transmission. The balance depends on cellular, molecular, and pathophysiological factors.","whyItMatters":"Neuropathic pain is largely treatment-resistant, affecting millions. Understanding when the endocannabinoid system helps vs hurts pain could explain why some patients with nerve pain report cannabis helps while others find it ineffective or worsening.","specificNumbers":"The review covers CB1 and CB2 receptor roles, endocannabinoid enzyme systems, and multiple neuropathic pain models demonstrating bidirectional effects.","methodology":"Narrative review integrating evidence on the spinal endocannabinoid system's bidirectional effects in neuropathic pain, examining cellular, molecular, and pathophysiological mechanisms.","limitations":"Narrative review synthesizing primarily preclinical evidence. The conditions determining pro- vs anti-nociceptive effects are not yet fully characterized. Clinical translation of spinal cord-specific findings is challenging."},{"rthcId":"RTHC-07556","title":"Influence of Socio-Ecological and Economic Correlates on Marijuana Legalization Policy Across the States of America.","authors":"Salehin, Mashooq; Pillai, Vijayan K","year":2025,"journal":"International journal of environmental research and public health, 22(6)","doi":"10.3390/ijerph22060823","pmid":"40566251","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Using discriminant analysis across US states, the study found that six socio-ecological and economic predictors collectively had a significant influence on marijuana legality scores. These included state marijuana use prevalence and median household income. The findings suggest that legalization is not just a policy choice but reflects underlying social, economic, and political conditions.","whyItMatters":"Understanding what drives legalization helps predict where it will happen next and what conditions might be needed for legalization to achieve its goals. The finding that a supportive broader context matters suggests legalization alone may not be sufficient.","specificNumbers":"39 states plus DC have legalized marijuana in some form. Six predictors analyzed including marijuana use prevalence and median household income. Significant cumulative effect on legality scores.","methodology":"Cross-sectional analysis using discriminant analysis and one-way ANOVA to assess the cumulative effect of six socio-ecological and economic predictors on marijuana legality scores across US states.","limitations":"Cross-sectional design cannot establish causation. State-level analysis misses within-state variation. Limited to six predictors; many other factors influence policy. Policy landscape is rapidly changing. Discriminant analysis is descriptive, not causal."},{"rthcId":"RTHC-07557","title":"Sex differences in the effects of maternal voluntary oral Cannabis consumption on the metabolic outcomes of high-fat diet in adult offspring.","authors":"Sallam, Nada A; Peterson, Colleen S; Kamar, Samaa S; Saenz, Camila; Visser, Frank; Borgland, Stephanie L","year":2025,"journal":"British journal of pharmacology, 182(11), 2354-2373","doi":"10.1111/bph.17447","pmid":"39894461","tags":["pregnancy","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Pregnant mice consumed cannabis extract (5 mg/kg THC daily) from early gestation through postnatal day 10. Pup weight was initially reduced but recovered by day 16. On a high-fat diet, exposed females had reduced fat accumulation and lower insulin, leptin, and resistin, independent of body weight. On a normal diet, exposed females showed altered insulin sensitivity with increased glucagon levels and reduced pancreatic islet size. Male offspring showed no metabolic effects from exposure.","whyItMatters":"Cannabis use during pregnancy is increasing with legalization. This study reveals sex-specific metabolic programming effects that may not be apparent until later in life, particularly under metabolic challenge (high-fat diet). The finding that effects appear only in females highlights the importance of studying both sexes.","specificNumbers":"THC dose: 5 mg/kg/day. Exposure: gestational day 1.5 through postnatal day 10. Female-specific effects on HFD: reduced adiposity, lower insulin/leptin/resistin. Female-specific effects on control diet: altered insulin sensitivity, increased glucagon, reduced islet size.","methodology":"Pregnant mice voluntarily consumed cannabis extract (5 mg/kg/day THC) from gestational day 1.5 through postnatal day 10. Male and female offspring were placed on high-fat or control diet at postnatal day 49 for 12 weeks. Measured weight gain, adiposity, glucose tolerance, insulin sensitivity, hormones, and pancreatic structure.","limitations":"Animal study; mouse metabolism differs from human. Voluntary cannabis consumption model, though ecological, makes precise dosing difficult. Small group sizes typical of animal studies. Cannot separate prenatal from postnatal exposure effects (exposure continued to PD10)."},{"rthcId":"RTHC-07558","title":"Cannabis-enriched oral Actinomyces induces anxiety-like behavior via impairing mitochondria and GABA signaling.","authors":"Salman, Tabinda; Luo, Zhenwu; Johnson, Douglas; Noorani, Arshad A; Wan, Zhuang; Bordieanu, Bogdan; Ye, Zhi-Wei; Penrod, Rachel D; Xian, Hongxu; Fitting, Sylvia; Kalivas, Peter W; Jiang, Wei","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.11.21.689724","pmid":"41332522","tags":["anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Actinomyces species, previously found to be enriched in chronic cannabis smokers' oral microbiome, induced anxiety-like behaviors in mice when inoculated orally. The bacteria produced metabolites (arginine and argininosuccinate) that increased in both oral swabs and brain tissue, causing mitochondrial dysfunction, oxidative stress, and reduced GABAergic neurotransmission. Notably, the bacteria themselves did not travel to the brain; their metabolites did.","whyItMatters":"This is a novel oral-brain axis discovery. It suggests that some anxiety associated with chronic cannabis use might not be caused by cannabinoids directly but by changes in oral bacteria that cannabis smoking promotes. This opens an entirely new avenue for understanding cannabis-related neuropsychiatric effects.","specificNumbers":"A. meyeri showed strongest effects. Increased arginine and argininosuccinate in oral swabs and brain. Microglia activation without classical neuroinflammation (no IL-1 beta, TNF-alpha, or IL-6 increase). Reduced GABAergic neurotransmission. No memory decline observed.","methodology":"Wild-type C57BL/6 mice received oral inoculation with cannabis use-associated Actinomyces species. Behavioral testing assessed anxiety. Brain analysis measured microglia activation, mitochondrial function, and GABA signaling. In vitro experiments tested Actinomyces-produced metabolites on neurons.","limitations":"Animal study with bacterial inoculation, not natural cannabis use. Preprint (not yet peer-reviewed). Cannot determine if findings apply to human cannabis users. Single bacterial genus tested. Cannot distinguish cannabis-specific effects from general oral microbiome effects."},{"rthcId":"RTHC-07559","title":"The endocannabinoid system in cancer biology: a mini-review of mechanisms and therapeutic potential.","authors":"Salum, Kaio Cezar Rodrigues; Miranda, Gabriel Brendo Alves; Dias, Alessandra Lima; Carneiro, João Regis Ivar; Bozza, Patrícia Torres; da Fonseca, Ana Carolina Proença; Silva, Tamara","year":2025,"journal":"Oncology reviews, 19, 1573797","doi":"10.3389/or.2025.1573797","pmid":"40370489","tags":["cancer","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"This review summarizes how the endocannabinoid system influences cancer through CB1 and CB2 receptor activation. Preclinical studies show cannabinoids can inhibit cell proliferation, induce apoptosis (programmed cell death), and suppress angiogenesis (new blood vessel formation). However, tumor heterogeneity, variable patient responses, and cannabinoid pharmacokinetic challenges remain significant barriers to clinical application.","whyItMatters":"Cancer treatment is in constant need of new approaches. The endocannabinoid system's ability to influence multiple cancer-relevant processes (growth, death, blood supply) makes it a compelling therapeutic target, even though clinical evidence remains limited.","specificNumbers":"Two primary cannabinoid receptors (CB1, CB2) involved. Three main anti-cancer mechanisms: anti-proliferative, pro-apoptotic, anti-angiogenic. Clinical translation described as 'in its early stages.'","methodology":"Mini-review of preclinical and early clinical literature on the endocannabinoid system's role in cancer biology, focusing on key mechanisms of cannabinoid-cancer interaction.","limitations":"Mini-review, not systematic. Primarily preclinical evidence. Cancer types and models vary widely across studies. Pharmacokinetic challenges not fully addressed. Risk of publication bias toward positive preclinical results."},{"rthcId":"RTHC-07560","title":"Perceived risk of illicit drug consumption in singapore: findings from a nationwide survey.","authors":"Sambasivam, Rajeswari; Koh, Yen Sin; Abdin, Edimansyah; Asharani, P V; Zhang, Yunjue; Teh, Wen Lin; Chong, Siow Ann; Subramaniam, Mythily","year":2025,"journal":"Social psychiatry and psychiatric epidemiology, 60(11), 2625-2637","doi":"10.1007/s00127-025-02935-y","pmid":"40495065","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07561","title":"Enhancing Methods for Research on Cannabis: A Workshop Report.","authors":"Samet, Jonathan M; Barrington-Trimis, Jessica; Bero, Lisa; Brooks-Russell, Ashley; Buran, Meghan; Dilley, Julia; Erickson, Darin; Huestis, Marilyn; Hutchison, Kent; Jeanne, Thomas L; Kosnett, Michael; Kroll, David J; Lankenau, Stephen; Miech, Richard; Pacula, Rosalie Liccardo; Riggs, Paula; Soleimanpour, Neeloofar; Teutsch, Steven; Tung, Gregory; Wang, George Sam","year":2025,"journal":"Journal of cannabis research, 7(1), 69","doi":"10.1186/s42238-025-00314-7","pmid":"41024165","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07562","title":"Association Between Legal Access to Medical Cannabis and Frequency of Non-Medical Prescription Opioid Use Among U.S. Adults.","authors":"Samples, Hillary; Levy, Natalie S; Bruzelius, Emilie; Segura, Luis E; Mauro, Pia M; Boustead, Anne E; Mauro, Christine M; Martins, Silvia S","year":2025,"journal":"International journal of mental health and addiction, 23(2), 1663-1676","doi":"10.1007/s11469-023-01191-y","pmid":"40443432","tags":["opioids","policy","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Medical cannabis laws were associated with a 1.5 percentage point decrease in frequent non-medical prescription opioid use and a 2.1 percentage point increase in occasional use, suggesting a shift in use patterns rather than overall reduction.","whyItMatters":"The opioid crisis has prompted interest in whether cannabis access might reduce opioid harms. This study suggests the relationship is more nuanced than simple substitution, with shifts in frequency patterns concentrated among people who also have cannabis use disorder.","specificNumbers":"MCL associated with +2.1 percentage points occasional use (95% CI: 0.5, 3.8), -0.6 percentage points regular use (95% CI: -1.1, -0.1), -1.5 percentage points frequent use (95% CI: -2.7, -0.4). Among those with cannabis use disorder: +5.6 pp occasional (95% CI: 1.5, 9.6), -4.9 pp frequent (95% CI: -8.1, -1.8).","methodology":"Multi-level mixed effects models analyzed nationally representative survey data from U.S. adults reporting past-year non-medical prescription opioid use across the 2004-2014 National Surveys on Drug Use and Health, comparing states with and without medical cannabis laws.","limitations":"Observational design cannot establish causation. Self-reported data from 2004-2014 may not reflect current cannabis markets. MCL implementation varied widely across states. The study could not assess specific products or doses used."},{"rthcId":"RTHC-07563","title":"Web-based alcohol use and cannabis use screening, brief intervention, and referral to treatment: college students' experience and perceived norms.","authors":"Samuolis, Jessica; Osborne-Leute, Victoria","year":2025,"journal":"Journal of American college health : J of ACH, 73(8), 2906-2912","doi":"10.1080/07448481.2024.2346352","pmid":"38713868","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07564","title":"Municipal socioeconomic environment and recreational cannabis use in Mexico: Analysis of two nationally representative surveys.","authors":"Sánchez-Pájaro, Andrés; Pérez-Ferrer, Carolina; Barrera-Núñez, David A; Cerdá, Magdalena; Thrasher, James F; Barrientos-Gutiérrez, Tonatiuh","year":2025,"journal":"The International journal on drug policy, 136, 104704","doi":"10.1016/j.drugpo.2025.104704","pmid":"39827739","tags":["epidemiology","policy","international"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Each unit increase in municipal education was associated with a 2.9% increase in recreational cannabis use prevalence in 2023 (up from 1.5% in 2016-17), while each unit increase in municipal income was associated with a 1.8% increase (up from 1.5%).","whyItMatters":"As Mexico considers cannabis legalization, understanding who currently uses cannabis helps anticipate how policy changes might play out. The concentration of use in wealthier areas contrasts with patterns seen in some other countries and has implications for equitable regulation.","specificNumbers":"Municipal education: 1.5% prevalence increase per unit in 2016-17, 2.9% in 2023. Municipal income: 1.5% per unit in 2016-17, 1.8% in 2023. No significant effect modification by sex or age except for 20-29 year-olds vs. 12-19 year-olds.","methodology":"Poisson regression models with robust variance analyzed data from two nationally representative Mexican surveys (2016-17 and 2023), linked with census-level municipal socioeconomic indicators.","limitations":"Cross-sectional surveys cannot track individuals over time. Municipal-level data may mask neighborhood variation. Self-reported use likely underestimates true prevalence. Different survey instruments were used in 2016-17 vs. 2023."},{"rthcId":"RTHC-07565","title":"Prevalence of adverse childhood experiences among individuals in treatment for substance use disorder: are ACE associated differently across type of abuse and quantity of consumption?","authors":"Sandgård Poulsen, Helena; Georgi, Rikke Dyrberg; Niclasen, Birgit","year":2025,"journal":"International journal of circumpolar health, 84(1), 2439122","doi":"10.1080/22423982.2024.2439122","pmid":"39746114","tags":["mental-health","epidemiology","international"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among women in treatment, parental cannabis abuse and physical abuse during childhood were significantly associated with high cannabis use. Among men, no significant link between specific adverse childhood experiences and substance type was found.","whyItMatters":"Most ACE and substance use research comes from large Western countries. This study adds perspective from Greenland, where historical trauma and substance use challenges have distinct patterns. The gender-specific findings suggest treatment approaches may need to differ for men and women.","specificNumbers":"N=1,037. 74.6% of women and 62.7% of men reported growing up with a parent with alcohol problems. Women showed higher prevalence and greater variety of ACE than men. No cumulative dose-response effect of total ACE count on substance type was found.","methodology":"Register-based analysis of 1,037 adults receiving substance use disorder treatment in Greenland from June 2020 to December 2022, examining associations between adverse childhood experiences (ACE) and substance use patterns.","limitations":"Register-based data from treatment-seeking individuals may not represent the broader population. Self-reported ACE data is subject to recall bias. The relatively small sample size limits statistical power for subgroup analyses. Greenlandic context may limit generalizability."},{"rthcId":"RTHC-07566","title":"Oral formulations for cannabidiol: Improved absolute oral bioavailability of biodegradable cannabidiol self-emulsifying drug delivery systems.","authors":"Sandmeier, Matthias; Wong, Ee Tsin; Nikolajsen, Gitte Nykjær; Purwanti, Asef; Lindner, Sera; Bernkop-Schnürch, Andreas; Xia, Wenhao; Hoeng, Julia; Kjær, Kathrine; Bruun, Heidi Ziegler; Jensen, Sanne Skov","year":2025,"journal":"Colloids and surfaces. B, Biointerfaces, 255, 114879","doi":"10.1016/j.colsurfb.2025.114879","pmid":"40541033","tags":["cbd","pharmacology","drug-delivery"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"Polyglycerol-based self-emulsifying drug delivery systems (SEDDS) achieved 3.8% absolute oral bioavailability for CBD compared to 3.4% for Epidiolex, with peak plasma concentrations of 30.6-35.8 ng/mL versus 25.0 ng/mL for Epidiolex.","whyItMatters":"CBD has notoriously poor oral bioavailability, meaning most of what you swallow never reaches your bloodstream. Better formulations could make oral CBD more predictable and effective, which matters for both pharmaceutical and consumer products.","specificNumbers":"CBD payload: 20% w/w. CBD retention in lipid core: 92.95-93.54%. PG-based SEDDS bioavailability: 3.8% vs. Epidiolex 3.4%. Peak plasma CBD: 30.6-35.8 ng/mL (SEDDS) vs. 25.0 ng/mL (Epidiolex).","methodology":"Three SEDDS formulations using different emulsifier types were developed and characterized through in vitro testing (surface properties, lipolysis, mucus permeation) and in vivo pharmacokinetic comparison with Epidiolex in rats.","limitations":"Animal pharmacokinetics do not directly translate to humans. The bioavailability improvement over Epidiolex was modest. Long-term stability and real-world performance of the formulations were not assessed. Only single-dose PK was measured."},{"rthcId":"RTHC-07567","title":"Twelve-month prevalence and correlates of criminal offending in a nationally representative sample of people with psychotic disorders.","authors":"Sankaranarayanan, Anoop; Di Prinzio, Patsy; Morgan, Frank; Valuri, Giulietta; Castle, David; Waterreus, Anna; Morgan, Vera A","year":2025,"journal":"The Australian and New Zealand journal of psychiatry, 59(8), 713-728","doi":"10.1177/00048674251346676","pmid":"40552911","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07568","title":"Cannabidiol for treatment of irritability and aggressive behavior in children and adolescents with autism spectrum disorder: background and methods of the cannabidiol study in children with autism spectrum disorder study.","authors":"Sannar, Elise M; Winter, Joan; Franke, Ronda K; Werner, Emily; Rochowiak, Rebecca; Romani, Patrick W; Miller, Owen S; Semmler, Nicole; Bainbridge, Jacquelyn L; Natvig, Crystal; Mikulich-Gilbertson, Susan K; Tartaglia, Nicole R","year":2025,"journal":"International journal of clinical trials, 12(1), 29-37","doi":"10.18203/2349-3259.ijct20250131","pmid":"41103807","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07569","title":"Maternal Immune Activation and the Endocannabinoid System: Focus on Two-Hit Models of Schizophrenia.","authors":"Santoni, Michele; Pistis, Marco","year":2025,"journal":"Biological psychiatry, 98(2), 105-115","doi":"10.1016/j.biopsych.2024.11.015","pmid":"39617194","tags":["neuroscience","endocannabinoid-system","mental-health","prenatal"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Despite theoretical expectations, several preclinical studies failed to show that adolescent cannabinoid exposure worsened behavioral or neurological outcomes in animals exposed to maternal immune activation, challenging the straightforward two-hit model.","whyItMatters":"The idea that prenatal infection plus adolescent cannabis creates a 'double hit' for schizophrenia risk is widely cited. This review reveals that the animal evidence is more complicated than the theory predicts, which has implications for how we communicate risk.","specificNumbers":"No specific quantitative data; this is a narrative review synthesizing findings from multiple preclinical studies on MIA and adolescent cannabinoid exposure.","methodology":"Narrative review of preclinical and clinical literature on maternal immune activation (MIA), the endocannabinoid system, and the two-hit hypothesis of schizophrenia, with emphasis on 2-AG signaling in synaptic plasticity and neuroinflammation.","limitations":"Narrative review without systematic methodology. Relies heavily on animal models that may not fully capture human neurodevelopmental complexity. Most preclinical studies use synthetic cannabinoids rather than whole-plant cannabis. Publication bias may affect the literature reviewed."},{"rthcId":"RTHC-07570","title":"The effect of medical cannabis on gastrointestinal symptoms in fibromyalgia and disorders of gut-brain interaction: a patient‑centred real‑world observational study.","authors":"Santonicola, Antonella; Moscato, Paolo; Soldaini, Carlo; Loi, Gabriella; Merchionda, Anna; D'Addieco, Paola; Lauritano, Anna; Pellegrino, Greta; Sarzi-Puttini, Piercarlo; Iovino, Paola","year":2025,"journal":"Clinical and experimental rheumatology, 43(6), 1074-1081","doi":"10.55563/clinexprheumatol/o5ck22","pmid":"40556630","tags":["chronic-pain","gastrointestinal","clinical-outcomes"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"After six months of Bedrocan cannabis treatment, fibromyalgia severity scores decreased significantly (p<0.001), and the intensity-frequency scores for epigastric pain, epigastric burning, abdominal pain, abdominal distension, and bloating all decreased significantly (p<0.01).","whyItMatters":"Fibromyalgia frequently co-occurs with irritable bowel syndrome and functional dyspepsia, and current treatments for both conditions offer limited relief. Finding a single treatment that addresses both sets of symptoms could meaningfully improve quality of life for this patient population.","specificNumbers":"60 patients enrolled. 76.6% (46/60) met criteria for at least one disorder of gut-brain interaction. 16.7% had IBS, 28.3% had functional dyspepsia, 31.7% had both. FIQR severity and five GI symptoms showed statistically significant month-by-month improvement.","methodology":"Prospective observational study of 60 fibromyalgia patients receiving Bedrocan cannabis treatment for 6 months, assessed at baseline, 3 months, and 6 months using standardized GI symptom questionnaires and the Revised Fibromyalgia Impact Questionnaire (FIQR).","limitations":"No control group or placebo comparison. Small sample size of 60 patients. Open-label design introduces expectation bias. Cannot separate cannabis effects from natural symptom fluctuation or regression to the mean."},{"rthcId":"RTHC-07571","title":"Understanding the Potential of CBD for Health Benefits: An Overview.","authors":"Santos, Ivan; Oliveira, Maria Beatriz Prior Pinto; Casas, Ana; Lopez, Javier Fidalgo; Almeida, Hugo","year":2025,"journal":"Current drug discovery technologies, 22(3), e060624230799","doi":"10.2174/0115701638305553240529103622","pmid":"38847170","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07572","title":"Neuroprotective effects of a cannabidiol nanoemulsion in a rotenone-induced rat model of Parkinson's disease: Insights into the gut-brain axis.","authors":"Santos, Júlio César Claudino Dos; Aquino, Pedro Everson Alexandre de; Rebouças, Conceição da Silva Martins; Sallem, Camilla Costa; Guizardi, Marissa Prudente Pinheiro; Noleto, Felipe Micelli; Zampieri, Davila de Sousa; Ricardo, Nágila Maria Pontes Silva; Brito, Débora Hellen Almeida de; Silveira, Edilberto Rocha; Leitão, Renata Ferreira de Carvalho; Brito, Gerly Anne de Castro; Viana, Glauce Socorro de Barros","year":2025,"journal":"European journal of pharmacology, 1002, 177748","doi":"10.1016/j.ejphar.2025.177748","pmid":"40425082","tags":["cbd","neuroprotection","neuroscience","drug-delivery"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"CBD nanoemulsion treatment restored glutathione levels (which had dropped 38-47% from rotenone treatment), reduced alpha-synuclein accumulation in both the striatum and duodenum, and normalized glial activation markers GFAP and IBA1 to control levels.","whyItMatters":"Parkinson's disease often starts with gut symptoms before motor problems appear. This study is notable for examining CBD's effects in both the brain and the intestine simultaneously, reflecting the growing understanding that Parkinson's pathology involves the gut-brain axis.","specificNumbers":"Rotenone caused 38-47% reduction in glutathione across brain regions (worst in striatum). CBD nanoemulsion at all three doses restored glutathione to control levels. Alpha-synuclein accumulation was reduced in both striatum and duodenum. Six experimental groups with behavioral and biochemical outcomes measured.","methodology":"Wistar rats were divided into six groups receiving combinations of rotenone (Parkinson's model) and three doses of CBD nanoemulsion (1.25, 2.5, 5.0 mg/kg). Behavioral testing (open field, Y maze, novel object recognition) and biochemical, histological, and immunohistochemical analyses assessed outcomes in brain regions and duodenum.","limitations":"Rat model of Parkinson's induced by chemical toxin does not fully replicate human disease. Nanoemulsion formulation may behave differently in humans. Short-term study does not assess whether protection persists. Multiple brain regions and outcome measures increase the chance of false positives."},{"rthcId":"RTHC-07573","title":"Binding Affinity of Synthetic Cannabinoids to Human Serum Albumin: Site Characterization and Interaction Insights.","authors":"Santos, Rita M G; Lima, Rita; Cravo, Sara; Fernandes, Pedro Alexandrino; Remião, Fernando; Fernandes, Carla","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(4)","doi":"10.3390/ph18040581","pmid":"40284016","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07574","title":"Oxidative stress and mitochondrial dysfunction in neuronal cells induced by commercial CBD products.","authors":"Sanz-Pérez, A; Anaya, B J; Fraguas-Sánchez, A I; Serrano, D R; Pérez, T; Spineli, M; Basilicata, P; Pieri, M; González-Burgos, E","year":2025,"journal":"Chemico-biological interactions, 421, 111785","doi":"10.1016/j.cbi.2025.111785","pmid":"41130351","tags":["cbd","safety","contamination","neuroscience"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"Treatment with commercial CBD samples at 50 micrograms/mL significantly increased reactive oxygen species, reduced the GSH/GSSG ratio (indicating oxidative stress), elevated lipid peroxidation, inhibited key antioxidant enzymes (CAT, SOD, GPx, GR), and decreased mitochondrial content in neuroblastoma cells.","whyItMatters":"The CBD market has grown faster than regulation can keep pace. This study provides concrete laboratory evidence that contaminated products can damage neurons, underscoring calls for mandatory testing and quality standards.","specificNumbers":"Both samples contained ~51% CBD. White sample contaminated with boron, lead, silicon, zinc. Pink sample contaminated with boron, iron, silicon, chromium. At 10 and 50 micrograms/mL, both samples reduced cell viability in a concentration-dependent manner. All four major antioxidant enzymes were significantly inhibited at 50 micrograms/mL.","methodology":"Two commercially available CBD powder samples were analyzed for cannabinoid content and elemental contamination, then applied to SH-SY5Y neuroblastoma cells at various concentrations for 48 hours. Oxidative stress markers, antioxidant enzyme activity, and mitochondrial function were assessed.","limitations":"Only two commercial products tested. Cell culture conditions do not replicate human exposure. Cannot separate CBD effects from heavy metal effects. Neuroblastoma cells may respond differently than normal neurons. Concentrations used may not reflect realistic brain tissue levels."},{"rthcId":"RTHC-07575","title":"Efficacy and safety of cannabidiol in children with developmental and epileptic encephalopathies: A systematic review.","authors":"Saranti, Anna; Dragoumi, Pinelopi; Pavlogiannis, Konstantinos; Pavlou, Evangelos; Zafeiriou, Dimitrios","year":2025,"journal":"Seizure, 133, 114-127","doi":"10.1016/j.seizure.2025.10.001","pmid":"41135306","tags":["cbd","epilepsy","pediatrics","systematic-review"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Pharmaceutical CBD (up to 50 mg/kg/day) achieved 50% or greater seizure reduction in at least 20% of participants in 11 of 14 included studies. Common adverse events were somnolence, appetite loss, diarrhea, fatigue, and elevated liver enzymes, mostly mild to moderate.","whyItMatters":"Developmental and epileptic encephalopathies are among the most treatment-resistant forms of epilepsy in children, often failing multiple medications. This systematic review confirms that CBD provides meaningful seizure reduction for a substantial minority of these children.","specificNumbers":"722 records screened, 14 included. 682 total children across studies. Maximum CBD dose: 50 mg/kg/day. 11 of 14 studies reported at least 50% seizure reduction in 20% or more of patients. Most adverse events were mild to moderate and reversible.","methodology":"Systematic review searching MEDLINE, Cochrane Central Register, and trial registries through March 2024. All study types were eligible with no language or date restrictions. Risk of bias assessed using RoB2 and ROBINS-I V2. 14 of 722 identified records met inclusion criteria.","limitations":"Included studies varied widely in design (RCTs, open-label, retrospective). No meta-analysis was performed due to heterogeneity. Most studies were relatively small. Long-term efficacy and developmental outcomes were not well captured. Publication bias may favor positive results."},{"rthcId":"RTHC-07576","title":"Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit.","authors":"Sarikahya, Mohammed H; Cousineau, Samantha L; De Felice, Marta; Szkudlarek, Hanna J; Lee, Kendrick; Doktor, Aleksandra; Alcaide, Amanda; DeVuono, Marieka V; Dembla, Anubha; Wong, Karen; Balarajah, Mathanke; Vanin, Sebastian; Youssef, Miray; Zhaksylyk, Kuralay; Machado, Madeline; Mahmood, Haseeb; Schmid, Susanne; Yeung, Ken K-C; Hardy, Daniel B; Rushlow, Walter; Laviolette, Steven R","year":2025,"journal":"Molecular psychiatry, 30(11), 5264-5282","doi":"10.1038/s41380-025-03113-x","pmid":"40721894","tags":["prenatal","neuroscience","thc","animal-studies"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Omega-3 supplementation normalized many neuronal and neurochemical abnormalities in male offspring's prefrontal cortex, nucleus accumbens, and ventral hippocampus. However, lipidomic analyses revealed pronounced, sex-specific disruptions in endocannabinoid-related pathways regardless of omega-3 treatment.","whyItMatters":"Cannabis use during pregnancy is increasing, and understanding both the risks and potential protective factors matters. This study suggests omega-3s could mitigate some effects but also reveals that prenatal THC causes deep lipid metabolism changes in the brain that persist regardless of supplementation.","specificNumbers":"Three brain regions analyzed (prefrontal cortex, nucleus accumbens, ventral hippocampus). Omega-3 reduced cognitive and emotional disturbances in male offspring. Lipidomic disruptions persisted in both sexes despite supplementation. Sex-specific effects were observed across endocannabinoid system pathways.","methodology":"Wistar rat model with prenatal THC exposure followed by perinatal omega-3 supplementation. Offspring underwent behavioral assessments and lipidomic analyses of three brain regions (prefrontal cortex, nucleus accumbens, ventral hippocampus).","limitations":"Rat model with synthetic THC does not fully replicate human prenatal cannabis exposure. Omega-3 doses and timing may not translate directly to human supplementation. Behavioral improvements in males without corresponding lipidomic normalization raise questions about long-term durability of protective effects."},{"rthcId":"RTHC-07577","title":"The association of witnessing violence with alcohol and cannabis expectancies among Black, Latinx, and White youth: considering neighborhood context.","authors":"Sartor, Carolyn E; Kennelly, Nicole; Powell, Margret Z; Chung, Tammy; Latendresse, Shawn J; McCutcheon, Vivia V","year":2025,"journal":"Social psychiatry and psychiatric epidemiology, 60(11), 2603-2612","doi":"10.1007/s00127-025-02939-8","pmid":"40603722","tags":["youth","epidemiology","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Across all neighborhood types, youth who witnessed violence had elevated positive cannabis expectancies (betas: 0.20-0.38). Living in more advantaged neighborhoods modestly weakened this association. The effect was consistent across Black, Latinx, and White youth.","whyItMatters":"Expectations about drug effects predict future use, especially before youth have actually tried substances. Understanding that violence exposure shapes these expectations, even in early adolescence, provides a specific target for early prevention efforts.","specificNumbers":"N=7,332 (weighted: 45.5% girl, 52.3% boy; 11.8% Black, 25.1% Latinx, 63.1% White; mean age 12.94). Positive cannabis expectancy betas for violence exposure: 0.20-0.38 across ADI quartiles, weakest in least disadvantaged neighborhoods. All race/ethnicity interactions were non-significant.","methodology":"Cross-sectional analysis of 7,332 youth from Follow-up 3 of the Adolescent Brain Cognitive Development Study, using the MEEQ-B for cannabis expectancies and the Area Deprivation Index for neighborhood context. General linear models adjusted for socioeconomic indicators.","limitations":"Cross-sectional design cannot determine whether violence exposure causes changes in expectancies. Self-reported violence exposure may be subject to recall bias. Cannabis expectancies do not necessarily predict actual use. The ABCD sample, while large, may not capture the most violence-exposed youth."},{"rthcId":"RTHC-07578","title":"Prevalence and reasons for using cannabidiol, delta-8 tetrahydrocannabinol, cannabinol, cannabigerol, and hexahydrocannabinol among US adults.","authors":"Satybaldiyeva, Nora; Yang, Kevin H; Kepner, Wayne; Ferran, Karen; Leas, Eric C","year":2025,"journal":"Journal of cannabis research, 7(1), 100","doi":"10.1186/s42238-025-00359-8","pmid":"41366718","tags":["cbd","delta-8","epidemiology","policy"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Lifetime CBD use was 35.2%, delta-8 THC 7.7%, CBN 4.5%, CBG 1.3%, HHC 1.5%. CBD was used primarily for medical reasons (71.9% medical vs. 47.1% recreational), while delta-8 THC was used primarily for recreation (76.1% recreational vs. 50.9% medical). Top medical reasons across cannabinoids were anxiety, pain, and insomnia.","whyItMatters":"The Farm Bill-enabled cannabinoid market has expanded rapidly but population-level data on who uses which products and why has been scarce. This study provides the first comprehensive nationally representative snapshot of use across five distinct cannabinoids.","specificNumbers":"CBD: 35.2% lifetime use (71.9% medical, 47.1% recreational). Delta-8 THC: 7.7% (50.9% medical, 76.1% recreational). CBN: 4.5%. CBG: 1.3%. HHC: 1.5%. Top CBD medical reasons: anxiety (14.7%), pain (13.1%), joint pain (11.2%). Top delta-8 medical reasons: anxiety (18.6%), pain (15.2%), insomnia (10.7%).","methodology":"Cross-sectional survey of 1,523 adults using the probability-based Ipsos KnowledgePanel, representative of 97% of U.S. households. Medical reasons were coded using the Medical Dictionary for Regulatory Activities. Multivariable logistic regression assessed demographic and health behavior correlates.","limitations":"Lifetime use does not indicate current or regular use. Self-reported motivations may not reflect actual pharmacological effects. Users may not accurately know which cannabinoids their products contain. Survey was conducted at a single time point (October-November 2023)."},{"rthcId":"RTHC-07579","title":"U.S. State Marijuana and Delta-8-Tetrahydrocannabinol Laws and Delta-8-Tetrahydrocannabinol Use.","authors":"Satybaldiyeva, Nora; Yang, Kevin H; Kepner, Wayne E; Leas, Eric C","year":2025,"journal":"American journal of preventive medicine, 69(6), 108026","doi":"10.1016/j.amepre.2025.108026","pmid":"40900067","tags":["delta-8","policy","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Adults in recreational marijuana states had 52% lower odds of delta-8 use (aRR=0.48) than those in prohibition states. Adults in states that regulated delta-8 sales had 67% lower odds of use (aRR=0.33) and those in states prohibiting delta-8 had 53% lower odds (aRR=0.47) compared to unregulated states.","whyItMatters":"Delta-8 THC exists in a regulatory gap created by the Farm Bill. This study provides the first nationally representative evidence that both marijuana legalization and direct delta-8 regulation independently reduce delta-8 use, offering policymakers concrete data for closing this gap.","specificNumbers":"Overall delta-8 lifetime use: 7.7%. By marijuana policy: prohibited states 10.9%, medical-only 8.5%, recreational 5.5%. By delta-8 policy: unregulated 10.5%, regulated 3.9%, prohibited 4.5%. Recreational marijuana: aRR=0.48 (95% CI: 0.33, 0.70). Delta-8 regulation: aRR=0.33 (95% CI: 0.20, 0.55).","methodology":"Cross-sectional web survey of 1,523 U.S. adults (October-November 2023) weighted to represent the national adult population. Inverse-probability-of-treatment weights balanced covariates across policy groups. Adjusted risk ratios estimated for both marijuana policy and delta-8 policy categories.","limitations":"Cross-sectional design cannot prove that policies caused differences in use. Self-reported use may be subject to social desirability bias. Policy classifications may not capture enforcement variation within states. The survey captured lifetime use, not current use."},{"rthcId":"RTHC-07580","title":"Saliva detection of the cannabinoids tetrahydrocannabinolic acid A (THCA-A) and cannabinol (CBN) among nightclub attendees in New York City, 2024.","authors":"Satybaldiyeva, Nora; Yang, Kevin H; Krotulski, Alex J; Walton, Sara E; Stang, Brianna; Palamar, Joseph J","year":2025,"journal":"The American journal of drug and alcohol abuse, 51(4), 484-491","doi":"10.1080/00952990.2025.2515360","pmid":"40549974","tags":["testing","epidemiology","delta-8"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"THC was detected in 30.8% of saliva samples, THCA-A in 11.7%, and CBN in 8.9%. Females had lower odds of THCA-A (aOR=0.28) and CBN (aOR=0.47) detection. Black participants had higher odds of THCA-A (aOR=2.04) and CBN (aOR=3.74) detection. Lower education was associated with higher detection rates.","whyItMatters":"As hemp-derived cannabinoid products proliferate, understanding real-world exposure through biological testing rather than self-report provides more accurate prevalence data. The detection of THCA-A and CBN alongside THC suggests these derived cannabinoids have reached meaningful market penetration.","specificNumbers":"N=1,024 (45.9% female). THC detected: 30.8%. THCA-A: 11.7%. CBN: 8.9%. Female vs. male THCA-A: aOR=0.28 (95% CI: 0.16-0.48). Black vs. White THCA-A: aOR=2.04 (95% CI: 1.12-3.72). Black vs. White CBN: aOR=3.74 (95% CI: 1.94-7.23). High school or less vs. college degree THCA-A: aOR=4.02 (95% CI: 2.40-6.74).","methodology":"Cross-sectional biological surveillance study of 1,024 adults entering New York City nightclubs throughout 2024. Saliva samples were tested for multiple cannabinoids including THCA-A and CBN alongside self-reported survey data.","limitations":"Nightclub attendees are not representative of the general population. Saliva testing captures recent use but not frequency or amount. Cannot determine whether detected cannabinoids came from hemp-derived products or traditional cannabis. Cross-sectional design provides only a snapshot."},{"rthcId":"RTHC-07581","title":"ADHD Symptoms and Medical Cannabis Use Among Adults With Chronic Pain.","authors":"Saunders, David; Slawek, Deepika; Zhang, Chenshu; Sohler, Nancy; Cunningham, Chinazo; Minami, Haruka; Starrels, Joanna; Arnsten, Julia; Levin, Frances","year":2025,"journal":"Journal of attention disorders, 29(9), 757-765","doi":"10.1177/10870547251336841","pmid":"40380798","tags":["adhd","chronic-pain","thc","clinical-outcomes"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Medical cannabis use was not associated with changes in ADHD symptoms in the full sample or among those with moderate/severe baseline ADHD symptoms. Among the subgroup with minor/no baseline ADHD symptoms, high-THC medical cannabis was associated with a small decrease in ADHD symptoms compared to low-THC products.","whyItMatters":"Social media and patient anecdotes have driven interest in cannabis as an ADHD treatment. This study provides longitudinal evidence that cannabis does not improve ADHD symptoms in people who actually have them, countering a popular but unsupported narrative.","specificNumbers":"N=223. 12-month follow-up with quarterly assessments. No significant association between MC use and ADHD symptom change in full sample or moderate/severe ADHD subgroup. Small decrease in ADHD symptoms with high-THC (vs. low-THC) MC only in those with minor/no baseline symptoms.","methodology":"Longitudinal cohort study of 223 adults with chronic pain followed for 12 months with quarterly assessments. Mixed-effects linear regression tested associations between medical cannabis use (and THC level) and change in ADHD symptoms, stratified by baseline ADHD severity and pain catastrophizing.","limitations":"All participants had chronic pain, limiting generalizability to ADHD populations without pain. Small sample size reduces power to detect modest effects. Observational design cannot rule out confounders. Cannabis products and doses were not standardized."},{"rthcId":"RTHC-07582","title":"Cannabidiol Enhances Stress-Induced Cellular Damage: Potential Contribution of Kv2.1 Inhibition.","authors":"Sayehmiri, Fatemeh; Ilkhanizadeh-Qomi, Mohsen; Naderi, Nima; Monteil, Arnaud; Sayyah, Mohammad; Hasanzadeh, Leila; Golkar, Majid; Pourbadie, Hamid Gholami","year":2025,"journal":"Journal of molecular neuroscience : MN, 75(3), 107","doi":"10.1007/s12031-025-02396-7","pmid":"40813741","tags":["cbd","neuroscience","safety","pharmacology"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"CBD enhanced Kv2.1 channel inactivation in a dose-dependent manner (3-3000 nM), and cells expressing Kv2.1 that were treated with CBD showed marked morphological deterioration and decreased viability under nutrient deprivation, despite Kv2.1 normally being protective in stressed cells.","whyItMatters":"Kv2.1 channels help cells survive metabolic stress. CBD's ability to shut down this protective mechanism suggests a potential pathway through which CBD could be harmful in stressed tissues, but also points toward a possible mechanism for CBD's anti-tumor effects.","specificNumbers":"CBD concentrations: 3-3000 nM. Kv2.1-expressing cells showed improved baseline viability under nutrient deprivation (protective effect). CBD reversed this protection in a dose-dependent manner. Effects were not significant under normal culture conditions.","methodology":"HEK293 cells were stably transfected to express Kv2.1 channels using the Sleeping Beauty transposon system. CBD was applied at concentrations from 3 to 3000 nM. Cell viability was measured via MTT assays under normal and nutrient-deprivation conditions, with electrophysiological recording of channel activity.","limitations":"In vitro study using a single cell line (HEK293) that does not represent normal tissue. Nutrient deprivation is an artificial stress model. CBD concentrations may not reflect achievable tissue levels in humans. The study did not test whether natural CBD metabolites have similar effects."},{"rthcId":"RTHC-07583","title":"Unprotected Sex and Its Association with Other Risky Behaviours Among European Students: A Multinational Study.","authors":"Scalese, Marco; Ferrante, Benedetta; Cerrai, Sonia; Molinaro, Sabrina","year":2025,"journal":"International journal of environmental research and public health, 23(1)","doi":"10.3390/ijerph23010048","pmid":"41595842","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07584","title":"Do Delta-9-tetrahydrocannabinol and Cannabidiol have opposed effects on male fertility?","authors":"Scandlan, Olivia L M; Favetta, Laura A","year":2025,"journal":"Toxicology letters, 403, 94-104","doi":"10.1016/j.toxlet.2024.12.003","pmid":"39657895","tags":["fertility","thc","cbd","reproductive-health"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"THC has been associated with reduced sperm quality, altered hormone levels, and changes in genetic and epigenetic profiles. CBD, conversely, may exert protective effects on male reproductive health through its anti-inflammatory and antioxidant properties, though evidence remains limited.","whyItMatters":"Cannabis use is common among men of reproductive age, yet most research has focused on THC's harms without considering whether CBD might offset some of these effects. As CBD-dominant products become more popular, understanding these potentially opposing effects is important for reproductive counseling.","specificNumbers":"No pooled quantitative data; this is a narrative review synthesizing findings across multiple studies on THC and CBD effects on male reproductive parameters.","methodology":"Narrative review of published literature on the mechanisms by which THC and CBD influence male reproductive health, including effects on sperm parameters, hormone levels, and genetic/epigenetic markers.","limitations":"Narrative review without systematic search or meta-analysis. Most underlying studies were animal or in vitro, with limited human data. CBD research on male fertility is still in early stages. Cannot account for the effects of whole-plant cannabis with both compounds present."},{"rthcId":"RTHC-07585","title":"Liver enzyme effects of medicinal cannabis in advanced cancer: a substudy of two randomised trials.","authors":"Scarborough, Luke; Hardy, Janet; Gurgenci, Taylan; Huggett, Georgie; Pelecanos, Anita; Webb, Lachlan; Greer, Ristan; Good, Phillip","year":2025,"journal":"BMJ supportive & palliative care","doi":"10.1136/spcare-2025-005837","pmid":"41429435","tags":["cancer","safety","cbd","thc","clinical-outcomes"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"No patients in the cannabis groups exceeded predefined safety thresholds (3x upper limit of normal for ALT or AST, or 5x for those with liver metastases). No clinically meaningful differences in liver enzyme levels were observed between CBD-only and THC/CBD combination products or compared with placebo.","whyItMatters":"Liver safety is a known concern with pharmaceutical CBD (Epidiolex carries a liver enzyme warning). This RCT-derived safety data in a vulnerable cancer population provides reassurance that medicinal cannabis at moderate doses does not appear to cause hepatotoxicity over one month.","specificNumbers":"287 patients across two trials. Maximum dose: 600 mg CBD/day. Zero patients exceeded 3x ULN for ALT or AST (or 5x ULN with liver metastases). Measurements at baseline, day 14, and day 28.","methodology":"Substudy of two multicentre, randomized, placebo-controlled trials (MedCan1: CBD alone; MedCan2: THC/CBD) in 287 patients with advanced cancer. Liver enzymes (ALT, AST) measured at baseline, day 14, and day 28 with escalating doses up to 600 mg CBD/day.","limitations":"Only 28 days of follow-up; longer-term effects unknown. Maximum dose of 600 mg CBD/day is lower than some clinical protocols. Patients with severely impaired liver function may have been excluded from the original trials. Substudy analysis was not the primary endpoint of either trial."},{"rthcId":"RTHC-07586","title":"Patterns of cannabis use for medical reasons in Brazil: An exploratory latent class analysis study.","authors":"Scattone, Heloísa; Gauer, Luís Eduardo; Pezzini, Julia Valle; Tófoli, Luís Fernando","year":2025,"journal":"The International journal on drug policy, 143, 104906","doi":"10.1016/j.drugpo.2025.104906","pmid":"40628021","tags":["epidemiology","international","policy"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Latent class analysis identified five patient typologies: Mental Health Patient (36%), Pain Relief Patient (24.3%), Neurological Patient (17.8%), Prior-Use Multi-Symptom Patient (11.6%), and Recently Initiated Multi-Symptom Patient (10.3%). Gender, religion, and household income were significantly associated with class membership.","whyItMatters":"Brazil's medical cannabis regulations are still evolving, with significant bureaucratic and financial barriers to access. Understanding that patients cluster into distinct groups with different needs can help policymakers design more targeted and equitable access pathways.","specificNumbers":"N=1,335. Five classes: Mental Health (36%), Pain Relief (24.3%), Neurological (17.8%), Prior-Use Multi-Symptom (11.6%), Recently Initiated Multi-Symptom (10.3%). Access routes included associations, importation, pharmacy, and court-authorized cultivation. Significant associations with gender, religion, and income.","methodology":"Anonymous online survey of 1,335 individuals using medically prescribed cannabis in Brazil (March-April 2023). Latent Class Analysis used indicators including symptom categories, access pathways, administration routes, treatment costs, and duration of use. Multinomial logistic regression examined demographic associations.","limitations":"Online convenience sample recruited through social media and cannabis groups may overrepresent digitally connected, younger patients. Self-reported data without medical verification. Cross-sectional design captures a single point in time. Regulatory context is specific to Brazil."},{"rthcId":"RTHC-07587","title":"Secondary metabolite profiles and anti-SARS-CoV-2 activity of ethanolic extracts from nine genotypes of Cannabis sativa L.","authors":"Schadich, Ermin; Kaczorová, Dominika; Béres, Tibor; Džubák, Petr; Hajdúch, Marián; Tarkowski, Petr; Ćavar Zeljković, Sanja","year":2025,"journal":"Archiv der Pharmazie, 358(1), e2400607","doi":"10.1002/ardp.202400607","pmid":"39543317","tags":["cbd","thc","antiviral","pharmacology"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"Only the neutral (decarboxylated) extracts containing CBD or THC as predominant cannabinoids showed antiviral activity against SARS-CoV-2, with all IC50 values below 10.0 micromolar. However, certain phenolic acids (salicylic acid, chlorogenic acid, ferulic acid) and flavonoids (abietin, luteolin) antagonized the antiviral activity in some genotypes.","whyItMatters":"While cannabis as a COVID treatment is not clinically viable, understanding which plant compounds enhance or block antiviral activity informs broader pharmaceutical efforts. The finding that other plant compounds can antagonize cannabinoid effects has implications for whole-plant versus isolate product design.","specificNumbers":"Nine genotypes tested (7 high-CBD, 2 high-THC). All neutral extract IC50 values below 10.0 micromolar. Acidic (non-decarboxylated) extracts showed no antiviral activity. Antagonistic phenolics identified: salicylic acid, chlorogenic acid, ferulic acid, abietin, luteolin. Potentially synergistic: orientin.","methodology":"Ethanolic extracts from seven high-CBD and two high-THC Cannabis sativa genotypes were prepared in both acidic (non-decarboxylated) and neutral (decarboxylated) forms. Phytochemical profiling used LC-UV, GC-MS, and LC-MS/MS. Dose-response antiviral assays against SARS-CoV-2 were performed, with correlation analyses between constituent levels and activity.","limitations":"In vitro antiviral activity does not predict clinical efficacy. SARS-CoV-2 assay conditions may not reflect physiological cannabinoid concentrations. Correlation-based identification of antagonistic compounds needs direct validation. Only ethanolic extracts tested; other preparation methods may differ."},{"rthcId":"RTHC-07588","title":"Perioperative management of the patient on cannabis and cannabinoids: A review.","authors":"Scheuermann, Maria; Hans, Guy; Wildemeersch, Davina","year":2025,"journal":"Journal of perioperative practice, 35(10), 456-462","doi":"10.1177/17504589251320804","pmid":"39985406","tags":["surgery","safety","clinical-outcomes"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Preoperative screening for chronic cannabis use was recommended due to increased risk of postoperative myocardial infarction, higher postoperative pain and opioid requirements, risk of bronchospasm requiring ventilation adjustments, and potential interactions between cannabinoids and anticoagulant medications.","whyItMatters":"With cannabis use increasing, anesthesiologists are encountering more patients who use regularly. Knowing the specific perioperative risks allows for better preoperative screening, intraoperative management, and postoperative pain protocols.","specificNumbers":"209 records screened, 17 included. Literature span: 2003-2023. Key risks identified: postoperative MI, increased opioid use, bronchospasm, anticoagulant interactions.","methodology":"Review following PRISMA 2020 guidelines, searching Medline and Cochrane Library databases for reports published 2003-2023. Of 209 records identified, 17 articles were included covering perioperative management of long-term cannabis users.","limitations":"Only 17 studies met inclusion criteria, suggesting limited high-quality evidence. Most included studies were observational or case reports. Cannabis products vary widely in composition, making generalization difficult. Review covered only two databases."},{"rthcId":"RTHC-07589","title":"Deciphering the interaction between N-palmitoyl-D-glucosamine and the endocannabinoidome.","authors":"Schiano Moriello, Aniello; Allarà, Marco; Iannotti, Fabio Arturo; Marcolongo, Gabriele; Piscitelli, Fabiana; Verde, Roberta; Di Marzo, Vincenzo; Petrosino, Stefania","year":2025,"journal":"Scientific reports, 15(1), 21094","doi":"10.1038/s41598-025-07103-5","pmid":"40596256","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07590","title":"The Impact of a Quinone Scaffold on Thermo-TRPs Modulation by Dimethylheptyl Phytocannabinoids.","authors":"Schiano Moriello, Aniello; Bossoni, Aurora; Mattoteia, Daiana; Caprioglio, Diego; Minassi, Alberto; Appendino, Giovanni; De Petrocellis, Luciano; Amodeo, Pietro; Vitale, Rosa Maria","year":2025,"journal":"International journal of molecular sciences, 26(6)","doi":"10.3390/ijms26062682","pmid":"40141324","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07591","title":"Consulting people who use cannabis to plan a regulatory trial on non-medical cannabis sales in pharmacies.","authors":"Schibli, Anna Irina; H, F; N, N; S, A; Bieri, Kathrin; Selby, Kevin; Durand, Marie-Anne; Auer, Reto; Metry, Beatrice","year":2025,"journal":"Research involvement and engagement, 11(1), 124","doi":"10.1186/s40900-025-00791-3","pmid":"41137114","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07592","title":"Rapid LC-QTOF-MS screening method for semi-synthetic cannabinoids in whole blood.","authors":"Schirmer, Willi; Walton, Sara E; Weinmann, Wolfgang; Schürch, Stefan; Logan, Barry K; Krotulski, Alex J","year":2025,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkaf095","pmid":"41117773","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07593","title":"Longitudinal patterns and predictors of opioid and stimulant use initiation and cessation among female sex workers living with HIV in South Africa.","authors":"Schluth, Catherine G; Rosen, Joseph G; Mcingana, Mfezi; Rucinski, Katherine B; Knox, Justin R; Comins, Carly A; Steingo, Joel; Shipp, Lillian; Makama, Siyanda; Phetlhu, Deliwe R; Mishra, Sharmistha; Hausler, Harry; Baral, Stefan D; Schwartz, Sheree R","year":2025,"journal":"Drug and alcohol dependence, 269, 112593","doi":"10.1016/j.drugalcdep.2025.112593","pmid":"39952169","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07594","title":"The associations between traumatic experiences and trajectories of substance use in adolescence and young adulthood - the role of acute neuroendocrine and subjective stress reactivity.","authors":"Schmengler, Heiko; Hartman, Catharina A; Marceau, Kristine; Giletta, Matteo; Peeters, Margot","year":2025,"journal":"Psychoneuroendocrinology, 182, 107642","doi":"10.1016/j.psyneuen.2025.107642","pmid":"41106212","tags":["youth","mental-health","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Traumatic experiences before age 16 increased the risk of cannabis use trajectories characterized by early initiation and escalation, as well as consistently low-level use and later-escalation patterns, compared to no use. However, acute neuroendocrine stress reactivity (heart rate, HRV, cortisol) did not mediate this relationship.","whyItMatters":"The link between childhood trauma and substance use is well established, but why it happens remains unclear. This study tested a leading theory (that trauma alters stress physiology, which drives substance use) and found it did not hold up, pushing researchers to look for other mechanisms.","specificNumbers":"N=715 from TRAILS cohort. Trauma assessed up to age 16. Cannabis trajectories tracked from ~16 to ~22. Trauma was associated with early-initiation/escalation, low-level use, and later-escalation trajectories. No mediation by heart rate, HF-HRV, PEP, or cortisol reactivity.","methodology":"Longitudinal data from the TRAILS cohort study (N=715). Traumatic experiences assessed up to age 16. Stress reactivity measured via standardized stress test at age 16. Cannabis use trajectories modeled from age 16 to 22. Cox proportional hazards and growth mixture models used.","limitations":"Single cohort from the Netherlands may not generalize to other populations. Stress reactivity measured at one time point. Self-reported trauma and substance use are subject to recall and reporting biases. Cannabis trajectories may not capture all relevant patterns of use."},{"rthcId":"RTHC-07595","title":"Characteristics and Trends in Child Cannabis Exposures During Legalization in California.","authors":"Schmidt, Laura A; Jacobs, Laurie M; Matthay, Ellicott C; Roake, James; Lewis, Justin; Ho, Raymond; Apollonio, Dorie E","year":2025,"journal":"American journal of preventive medicine, 69(4), 107963","doi":"10.1016/j.amepre.2025.107963","pmid":"40602693","tags":["pediatrics","edibles","policy","safety"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Monthly rates of moderate/severe cannabis exposure per million children increased significantly after legalization (beta=0.06; 95% CI: 0.05, 0.08). 83.5% of exposures involved edible products. 94% occurred at home. Among children under 5, exposures were almost entirely unintentional (87.7-99.2%), while adolescent exposures were predominantly intentional (85.5%).","whyItMatters":"California has the world's largest legal cannabis retail market. The significant increase in child poisonings, overwhelmingly from edible products that resemble candy, provides direct evidence that current packaging and marketing regulations are insufficient to protect children.","specificNumbers":"1,695 poison control reports (2010-2020). Monthly rate increase after legalization: beta=0.06 (95% CI: 0.05, 0.08). 83.5% involved edibles. 94% occurred at home. 14% required critical care. Children <5: 87.7-99.2% unintentional. Adolescents: 85.5% intentional.","methodology":"Interrupted time series analysis of 1,695 California Poison Control System reports of cannabis exposure in children aged 0-17 from 2010 to 2020. Analysis focused on moderate and severe exposures requiring medical attention. Edible product packaging was also analyzed.","limitations":"Poison control data captures only reported cases and likely underestimates true exposure rates. The study period (2010-2020) overlaps with both medical and recreational legalization phases. Cannot isolate the effect of recreational legalization from increasing product availability and awareness. Ecological design cannot establish individual-level causation."},{"rthcId":"RTHC-07596","title":"Building Tobacco Control and Cannabis Policy Capacity and Partnerships in Rural California.","authors":"Schneider, Sara; Payán, Denise D; Song, Anna V; Morgan, Jamie; Jones Barker, Lisa; Burke, Nancy J","year":2025,"journal":"Health promotion practice, 15248399251388450","doi":"10.1177/15248399251388450","pmid":"41189432","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07597","title":"Age-period-cohort analysis of past 12-month cannabis use in Germany (1995-2021).","authors":"Schöllner, Natalie S; Glos, Adrian; Möckl, Justin; Krowartz, Eva-Maria; Hoch, Eva; Olderbak, Sally","year":2025,"journal":"Addiction (Abingdon, England), 120(9), 1759-1769","doi":"10.1111/add.70087","pmid":"40537976","tags":["epidemiology","international","policy"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Period effects showed cannabis use odds rising from OR 0.33 in 1995 to OR 2.96 in 2021. Cohort effects were even more dramatic, rising from OR 0.02 for those born in 1936 to OR 16.69 for those born in 2002. Age effects showed steep decline from OR 9.44 at age 18 to OR 0.13 at age 59.","whyItMatters":"Germany partially legalized recreational cannabis in 2024. This comprehensive pre-legalization baseline shows cannabis use was already rising dramatically through both secular trends and generational shifts, providing essential context for evaluating legalization's impact.","specificNumbers":"N=78,678 across 10 survey waves (1995-2021). Age 18 OR: 9.44 (95% CI: 8.17-10.9). Age 59 OR: 0.13 (95% CI: 0.10-0.17). Period 1995 OR: 0.33, Period 2021 OR: 2.96. Cohort 1936 OR: 0.02, Cohort 2002 OR: 16.69. Cannabis users more likely to also drink alcohol and smoke tobacco.","methodology":"Binary logistic regression using generalized additive models analyzed data from 10 waves (1995-2021) of the German Epidemiological Survey of Substance Abuse (ESA), a nationally representative household survey. N=78,678 adults aged 18-59. Age, period, and cohort effects estimated simultaneously.","limitations":"Self-reported data subject to social desirability bias. Survey methodology changes over 26 years may affect comparability. Age-period-cohort models have inherent identification problems. German context may not generalize. Household surveys may miss heavy users and institutionalized populations."},{"rthcId":"RTHC-07598","title":"Cannabis Enforcement Lags Behind Alcohol: A National Study of Law Enforcement Practices in Legal and Nonlegal States.","authors":"Scholz, Natalie; Lenk, Kathleen M; Joshi, Spruha; Delehanty, Eileen; Erickson, Darin J; Toomey, Traci L; Jones-Webb, Rhonda; Nelson, Toben F","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(5), 806-813","doi":"10.15288/jsad.24-00200","pmid":"39589792","tags":["policy","law-enforcement","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis enforcement strategies were less common than their analogous alcohol strategies across all agency types. Cannabis-impaired driving enforcement and public use enforcement rates did not differ significantly between legal and nonlegal states. Agencies in legal states were more likely to train officers in cannabis impairment identification (RR=1.23, 95% CI: 1.08, 1.42).","whyItMatters":"If cannabis legalization is accompanied by weak enforcement, many of the regulatory benefits (preventing youth access, reducing impaired driving, controlling public consumption) may not materialize. This study provides the first national baseline showing that cannabis enforcement significantly lags alcohol enforcement.","specificNumbers":"1,024 local agencies, 53 state ABC agencies, 48 state patrol agencies surveyed. Cannabis-impaired driving enforcement: no significant difference between legal and nonlegal states. Officer training in cannabis impairment: RR=1.23 (95% CI: 1.08, 1.42) higher in legal states.","methodology":"Surveys of 1,024 local law enforcement agencies, 53 state alcohol beverage control agencies, and 48 state patrol agencies. Prevalence of cannabis and analogous alcohol enforcement strategies compared across legal and nonlegal cannabis states.","limitations":"Survey-based data may not accurately reflect actual enforcement practices. Response bias could affect which agencies participated. The study captured enforcement at one point in time, missing trends. Cannabis impairment detection tools are less developed than alcohol tools, which may constrain enforcement regardless of intent."},{"rthcId":"RTHC-07599","title":"Correlates of driving under the influence of cannabis: A latent class analysis.","authors":"Schranz, Anna; Verthein, Uwe; Rosenkranz, Moritz; Knoche-Becker, Anja; Manthey, Jakob","year":2025,"journal":"Journal of safety research, 95, 330-337","doi":"10.1016/j.jsr.2025.10.012","pmid":"41338788","tags":["driving","policy","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Three classes emerged: 'Low risk' (48%) with minimal DUIC and risky behaviors; 'DUIC-specific risk' (30%) with high cannabis-impaired driving, peers who also drive high, and low perceived risk, but no other risky behaviors; and 'Global risk' (22%) with multiple risky behaviors and risk factors. Younger age and male gender predicted higher-risk class membership.","whyItMatters":"Not all cannabis users who drive high are the same. The 30% who specifically drive under the influence without other risky behaviors may respond to different interventions (education, peer norms) than the 22% with global risk patterns (who may need broader support). Germany recently raised its legal THC driving threshold, making this segmentation timely.","specificNumbers":"N=563 German drivers using cannabis at least monthly. Low risk: 48%. DUIC-specific risk: 30%. Global risk: 22%. DUIC-specific class associated with younger age and male gender. Global risk class associated with younger age. Pre-legalization data from 2023.","methodology":"Latent Class Analysis of 2023 pre-legalization survey data from 563 German drivers who use cannabis at least monthly. Environmental and individual risk factors and risky traffic behaviors were used as indicators, with sociodemographic covariates.","limitations":"Pre-legalization survey may not reflect post-legalization behavior. Self-reported driving behavior is subject to social desirability bias. German driving culture and infrastructure may differ from other countries. At-least-monthly cannabis use is a relatively high threshold that may miss occasional users who also drive impaired."},{"rthcId":"RTHC-07600","title":"Perceptions of Infant Cry Sounds Among Tobacco and Cannabis Using Mothers and Their Association with Tobacco and Cannabis Cravings.","authors":"Schuetze, Pamela; Kelm, Madison R; Bell, Olivia; Eiden, Rina D","year":2025,"journal":"Children (Basel, Switzerland), 12(8)","doi":"10.3390/children12081006","pmid":"40868458","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07601","title":"Drug interactions in a sample of inpatients diagnosed with cannabis use disorder.","authors":"Schulze Westhoff, Martin; Massarou, Christina; Bleich, Stefan; Heck, Johannes; Jendretzky, Konstantin Fritz; Glahn, Alexander; Schröder, Sebastian","year":2025,"journal":"Journal of neural transmission (Vienna, Austria : 1996), 132(5), 723-730","doi":"10.1007/s00702-025-02884-5","pmid":"39849214","tags":["drug-interactions","safety","opioids"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"89.4% of inpatients with CUD were taking at least one potentially interacting drug. Levomethadone, buprenorphine, and morphine were the most common drugs involved in potentially serious cannabis-drug interactions. 196 drug-drug interactions were also identified, with 25.5% classified as 'avoid combination' and 74.5% as 'consider therapy modification.'","whyItMatters":"Patients with cannabis use disorder frequently take medications that interact with cannabinoids, especially opioid substitution therapies. The finding that nearly 9 in 10 patients had at least one potential interaction underscores the need for routine interaction screening in addiction treatment settings.","specificNumbers":"301 patient cases (85% male, median age 37). 89.4% (269/301) taking at least one potentially interacting drug. Top serious CDIs: levomethadone, buprenorphine, morphine. 196 DDIs identified: 25.5% 'avoid combination,' 74.5% 'consider therapy modification.' Levomethadone + psychotropic combinations most frequent.","methodology":"Retrospective analysis of medication charts from 301 inpatient cases with cannabis use disorder on an addiction-specific ward over six years. Cannabis-drug interactions screened via drugs.com classification; drug-drug interactions via UpToDate Lexicomp.","limitations":"Retrospective design using a single addiction ward in Germany. Potential interactions identified by databases may not all be clinically significant. Could not assess whether identified interactions actually caused adverse events. Population was predominantly male, limiting generalizability."},{"rthcId":"RTHC-07602","title":"An investigation of drug use among first-time arrestees from 25 county jails across the United States in 2023.","authors":"Schumacher, Joseph E; Ahsan, Abdullah; Simpler, Amber H; Natoli, Adam P; Cain, Bradley J","year":2025,"journal":"Addiction science & clinical practice, 20(1), 23","doi":"10.1186/s13722-025-00550-5","pmid":"40055763","tags":["epidemiology","drug-testing","policy"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Of 43,553 urine drug screens (28.8% of total arrestees), 74.8% were positive for one or more drugs. Among positives, 69.0% had cannabis, 54.8% stimulants, 29.6% opioids, and 12.4% sedatives. Half of positive results showed multiple drugs, with cannabis-stimulant and cannabis-opioid combinations most common.","whyItMatters":"The high prevalence of cannabis alongside stimulants and opioids in arrested populations highlights polysubstance use patterns that matter for acute medical management in jails, where sudden cessation of all substances simultaneously creates compounded withdrawal risks.","specificNumbers":"43,553 UDS cases from 25 jails. 74.8% (32,561) positive for one or more drugs. Cannabis: 69.0%. Stimulants: 54.8%. Opioids: 29.6%. Sedatives: 12.4%. 50% of positives had multiple drugs. Significant associations found between drug use and both jail characteristics and demographics.","methodology":"Naturalistic research design collecting de-identified urine drug screens, jail characteristics, and demographics from 25 jails across the United States in 2023 via data-sharing agreement with NaphCare, Inc. Chi-square tests and standardized residuals analyzed associations.","limitations":"Only 28.8% of arrestees were screened, introducing selection bias. Urine drug screens detect recent use but not frequency or impairment. Cannabis can be detected for weeks after last use, inflating apparent prevalence. Cannot distinguish medical from recreational cannabis use. 2023 data from a single year."},{"rthcId":"RTHC-07603","title":"Neurocognitive outcomes in adolescents with and without four weeks of cannabis abstinence: a randomized clinical trial using contingency management.","authors":"Schuster, Randi M; Costello, Meghan A; Potter, Kevin; Torquati, Matteo; Gilman, Jodi M; Evins, A Eden","year":2025,"journal":"Frontiers in psychiatry, 16, 1723633","doi":"10.3389/fpsyt.2025.1723633","pmid":"41522481","tags":["youth","cognition","clinical-outcomes"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"At baseline, cannabis-using adolescents had worse verbal memory and processing speed than non-users. After four weeks of incentivized abstinence, abstinent cannabis users showed greater improvement in inhibitory control compared to monitoring controls (beta=-10.9, p=0.037) and performed similarly to the non-user group.","whyItMatters":"This is one of the first randomized trials showing that adolescent brains can recover cognitive function relatively quickly after stopping cannabis use. The four-week timeframe is practical and encouraging for both clinicians and young people considering a break from cannabis.","specificNumbers":"238 adolescents (51% female, 55% White, 18% Black, 9% Asian). 154 cannabis users, 84 non-users. Inhibitory control improvement in abstinence group: beta=-10.9, p=0.037. Abstinent users similar to non-users at week 4. No significant group differences in memory or attention at week 4.","methodology":"Randomized clinical trial with 238 Greater Boston adolescents (ages 13-19): 154 regular cannabis users randomized to incentivized abstinence or non-contingent monitoring, plus 84 non-users as reference. Weekly cognitive testing over four weeks assessed executive function, memory, and attention.","limitations":"Contingency management (cash incentives) for abstinence may not reflect real-world motivation. Four weeks may not capture full recovery. No biological verification of complete abstinence. Practice effects from weekly testing could account for some improvement across all groups. Sample was from a single geographic area."},{"rthcId":"RTHC-07604","title":"Medical cannabis for chronic pain management: questions and answers between clinical and medico-legal issues.","authors":"Schweiger, Vittorio; Ganz, Barbara; Martini, Alvise; Sarzi-Puttini, Piercarlo; Bazzichi, Laura; Bonora, Eleonora; Vendramin, Patrizia; Nizzero, Marta; Zamboni, Lorenzo; Polati, Luca; Lugoboni, Fabio; Raniero, Dario; Polati, Enrico; Del Balzo, Giovanna","year":2025,"journal":"Clinical and experimental rheumatology, 43(6), 1128-1135","doi":"10.55563/clinexprheumatol/o23y55","pmid":"40556619","tags":["chronic-pain","clinical-outcomes","policy","safety"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Medical cannabis reduced pain by 0.43-0.70 points on the NRS scale (0-10) versus placebo across studies. Serious adverse events were rare. Common side effects included dizziness, drowsiness, dry mouth, and nausea. The risk of cannabis use disorder was approximately 29% per DSM-5 criteria. Absolute contraindications include unstable cardiovascular disease, psychosis, bipolar disorder, and pregnancy.","whyItMatters":"As medical cannabis prescriptions increase globally, pain therapists need a comprehensive understanding of what the evidence actually shows. The modest pain reduction alongside a substantial addiction risk frames a realistic benefit-risk conversation for patients.","specificNumbers":"Pain reduction vs. placebo: -0.43 to -0.70 on NRS (0-10). Cannabis use disorder risk: ~29% (DSM-5). Rare serious adverse events. Common AEs: dizziness, tiredness, drowsiness, nausea, dry mouth, diarrhea, constipation, euphoria.","methodology":"Narrative review of available literature on medical cannabis for chronic pain, covering efficacy, safety, contraindications, drug interactions, dosing, and medico-legal considerations in the Italian regulatory context.","limitations":"Narrative review without systematic methodology. The 29% CUD risk figure may overestimate risk in medically supervised use. Medico-legal considerations are specific to Italian law. Pain reduction averages mask individual variation in response. Does not cover all cannabis formulations or routes."},{"rthcId":"RTHC-07605","title":"Evaluating the relationship between marijuana use, aggressive behaviors, and victimization: an epidemiological study in colombian adolescents.","authors":"Scoppetta, Orlando; Cardozo, Francisco; Brown, Eric C; Morales, Vanessa","year":2025,"journal":"International journal of adolescent medicine and health, 37(1), 1-9","doi":"10.1515/ijamh-2024-0167","pmid":"39882765","tags":["youth","epidemiology","mental-health","international"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Exclusive marijuana users had higher odds of aggression compared to non-drug users, but lower odds than polydrug users. Adolescents who initiated marijuana before other drugs showed greater odds of aggression than exclusive marijuana users, and those who used marijuana after other drugs showed even higher rates, suggesting that polydrug involvement and initiation sequence matter more than marijuana alone.","whyItMatters":"Most research on cannabis and aggression uses simple user versus non-user comparisons. This study shows that the relationship is far more nuanced: the order of drug initiation and number of substances used change the picture dramatically, challenging simplistic causal claims.","specificNumbers":"80,018 students in grades 7-11. Non-drug users had lowest aggression and victimization rates. Multiple-drug users had the highest. Exclusive marijuana users showed increased odds of aggression vs. non-users, but initial and subsequent users showed greater odds. Polydrug involvement and initiation order significantly modified associations.","methodology":"Secondary analysis of nationally representative 2016 cross-sectional data from 80,018 Colombian students in grades 7-11. Participants categorized into marijuana-use groups (exclusive, initial, subsequent) and non-marijuana groups (no drug, one drug, multiple drugs). Logistic regression controlled for sex, age, parental education, and grade repetition.","limitations":"Cross-sectional design cannot establish causation. Self-reported aggression and drug use subject to reporting biases. 2016 Colombian context may differ from other countries. Cannot control for all confounders like mental health conditions, family violence, or socioeconomic factors beyond parental education."},{"rthcId":"RTHC-07606","title":"Identification of cannabinoid-sensitive and -resistant oral bacteria.","authors":"Scott, David A; Lamont, Gwyneth J; Tan, Jinlian; Patel, Arjun P; Guffey, Jack T; Thomas, Scott C; Xu, Fangxi; Diamond, Gill; Saxena, Deepak","year":2025,"journal":"Frontiers in microbiology, 16, 1709243","doi":"10.3389/fmicb.2025.1709243","pmid":"41561022","tags":["oral-health","cbd","microbiome"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"Multiple oral bacteria were sensitive to physiological CBD concentrations, including A. actinomycetemcomitans, F. nucleatum, P. gingivalis, S. mutans, and T. forsythia. However, other pathobionts were resistant even at superphysiological CBD concentrations, including oral Treponema species, C. gracilis, and V. parvula. This selective killing may create microbial dysbiosis favoring resistant pathogens.","whyItMatters":"Cannabis users have higher rates of periodontal disease, and the mechanism has been unclear. This study provides a compelling explanation: cannabis selectively kills some oral bacteria while sparing others, creating an imbalanced oral microbiome that favors disease-causing species.","specificNumbers":"CBD-sensitive: A. actinomycetemcomitans, F. nucleatum, multiple P. gingivalis strains, S. mutans, S. gordonii, T. forsythia. CBD-resistant (even at superphysiological doses): C. gracilis, C. durum, H. parainfluenzae, oral Treponema species, V. parvula. Antimicrobial peptoids rendered CBD toxic to normally resistant spirochetes.","methodology":"Panel of oral bacteria tested for CBD susceptibility at physiological and superphysiological concentrations. Results informed by initial in vivo microbiome analysis of marijuana users and non-users with periodontitis. Antimicrobial peptoids were screened for activity against CBD-resistant bacteria.","limitations":"In vitro susceptibility testing may not reflect conditions in the oral cavity. CBD concentrations achievable in saliva depend on consumption method. Microbiome analysis was preliminary and from a small sample. Peptoid treatments are experimental and not yet tested in vivo."},{"rthcId":"RTHC-07607","title":"Cannabis Hyperemesis Syndrome in Youth: Clinical Insights and Public Health Implications.","authors":"Seabrook, Jamie A; Seabrook, Morgan; Gilliland, Jason A","year":2025,"journal":"International journal of environmental research and public health, 22(4)","doi":"10.3390/ijerph22040633","pmid":"40283856","tags":["chs","youth","safety"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS progresses through three phases: a prodromal phase with early morning nausea often mistakenly relieved by continued cannabis use; a hyperemetic phase with severe vomiting, dehydration, and electrolyte imbalances (temporarily relieved by hot showers); and a recovery phase where symptoms resolve and normal habits return.","whyItMatters":"As adolescent cannabis use increases, CHS is being diagnosed more frequently but remains widely misunderstood. The prodromal phase is particularly dangerous because continued cannabis use to alleviate nausea actually perpetuates the condition, leading to delayed diagnosis and unnecessary medical workups.","specificNumbers":"No quantitative data pooled; this is a narrative review. Three distinct phases described. Potential complications include electrolyte imbalances and dehydration requiring critical care.","methodology":"Narrative review of literature on CHS in youth populations, covering pathophysiology, clinical progression, diagnostic challenges, treatment strategies, and public health implications.","limitations":"Narrative review without systematic methodology. CHS diagnostic criteria are not fully standardized. Prevalence data in youth specifically are limited. The review does not quantify how common CHS is among adolescent cannabis users."},{"rthcId":"RTHC-07608","title":"Cannabis use and atherosclerotic cardiovascular disease outcomes: A meta-analysis of multinational cohort data.","authors":"Sebastian, Sneha Annie; Shah, Yash; Arsene, Camelia; Krishnamoorthy, Geetha","year":2025,"journal":"Disease-a-month : DM, 71(3), 101849","doi":"10.1016/j.disamonth.2024.101849","pmid":"39800612","tags":["cardiovascular","systematic-review","safety"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Ever use of cannabis was associated with a statistically significant 48% higher risk of any adverse cardiovascular event (RR: 1.48, 95% CI: 1.16-1.90, p=0.002). The association with myocardial infarction alone (RR: 1.25, 95% CI: 0.91-1.71) and stroke alone (RR: 1.38, 95% CI: 0.88-2.16) did not reach statistical significance.","whyItMatters":"Whether cannabis causes cardiovascular disease has been debated for years. This meta-analysis of nearly 1.9 million people provides the strongest pooled estimate to date, showing a significant association with composite cardiovascular events even if individual endpoints fall short of significance.","specificNumbers":"17 studies, 1,902,481 individuals. Mean follow-up: 8.5 years. Any adverse CV event: RR 1.48 (95% CI: 1.16-1.90, p=0.002). MI: RR 1.25 (95% CI: 0.91-1.71, p=0.17). Stroke: RR 1.38 (95% CI: 0.88-2.16, p=0.16). Age range: 18-74 years.","methodology":"Systematic review and meta-analysis of 17 observational studies (PubMed, Scopus, ScienceDirect, Cochrane) from inception to April 2024. Random effects models analyzed 1,902,481 individuals aged 18-74 with mean follow-up of 8.5 years. Registered with PROSPERO (CRD42024530366).","limitations":"All included studies were observational, limiting causal inference. Cannabis exposure was typically 'ever use,' which does not capture dose, frequency, or potency. Confounders like tobacco co-use may not be fully controlled. Publication bias possible. Heterogeneity across study designs and populations."},{"rthcId":"RTHC-07609","title":"Cannabis Use and Subsequent Cigarette Discontinuation Among U.S. Adults in the Population Assessment of Tobacco and Health Study, Waves 1-5.","authors":"Sedani, Ami E; Frank-Pearce, Summer G; Beebe, Laura A; Campbell, Janis E; Peck, Jennifer D; Chou, Ann F; Cohn, Amy M","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 27(2), 208-216","doi":"10.1093/ntr/ntae202","pmid":"39178320","tags":["tobacco","epidemiology","policy"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Cannabis co-use was associated with decreased odds of cigarette discontinuation (aOR: 0.81, 95% CI: 0.72-0.93, p=0.0018) and decreased odds of discontinuing all combustible tobacco products (aOR: 0.75, 95% CI: 0.65-0.86, p<0.0001). Over one-third (35.9%) of cigarette smokers reported cannabis co-use during the study, and this proportion increased over time.","whyItMatters":"As cannabis becomes more accessible, the proportion of cigarette smokers who also use cannabis is growing. This study reveals a previously underappreciated barrier to tobacco cessation: cannabis co-use may reduce the likelihood of quitting smoking, complicating public health efforts to reduce tobacco use.","specificNumbers":"8,218 adults, 26,381 observations across 5 waves. 35.9% of smokers reported cannabis co-use. Cigarette discontinuation: aOR 0.81 (95% CI: 0.72-0.93). All combustible tobacco discontinuation: aOR 0.75 (95% CI: 0.65-0.86). Cannabis co-use increased over the study period.","methodology":"Longitudinal analysis of 26,381 observations from 8,218 adults with established cigarette use (100+ lifetime cigarettes) across waves 1-5 of the Population Assessment of Tobacco and Health (PATH) Study. Weighted GEE models adjusted for demographics, behavioral characteristics, and substance use problems.","limitations":"Observational design cannot prove cannabis caused lower quit rates. Cannabis users may differ from non-users in ways not captured by covariates. Self-reported cannabis and tobacco use subject to reporting biases. PATH Study waves 1-5 span a period of changing cannabis policies."},{"rthcId":"RTHC-07610","title":"Select terpenes from Cannabis sativa are antinociceptive in mouse models of post-operative pain and fibromyalgia via adenosine A2a receptors.","authors":"Seekins, Caleb A; Welborn, Alyssa M; Schwarz, Abigail M; Streicher, John M","year":2025,"journal":"Pharmacological reports : PR, 77(1), 172-181","doi":"10.1007/s43440-024-00687-1","pmid":"39663308","tags":["terpenes","chronic-pain","pharmacology","animal-studies"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"All four terpenes (200 mg/kg) produced time-dependent pain relief in both post-operative and reserpine-induced fibromyalgia mouse models. The A2a receptor antagonist istradefylline blocked the antinociceptive effects, confirming the mechanism. Terpenes had no effect on hot plate latencies, ruling out non-specific motor effects. Geraniol showed the strongest effect.","whyItMatters":"Terpenes are the aromatic compounds that give cannabis strains their distinctive smells. Finding that they relieve pain through adenosine receptors (not cannabinoid receptors) means they could potentially be developed as non-psychoactive, non-opioid pain medications without the legal and regulatory challenges of cannabinoids.","specificNumbers":"Four terpenes tested at 200 mg/kg. Pain relief strongest for geraniol, followed by linalool or alpha-humulene. Istradefylline (3.2 mg/kg) blocked antinociception. Two pain models: post-operative (paw incision) and fibromyalgia (reserpine-induced). Both sexes tested.","methodology":"Male and female CD-1 mice underwent either paw incision surgery or reserpine-induced fibromyalgia (0.32 mg/kg). After pain was established, mice received 200 mg/kg ip of each terpene. Mechanical sensitivity measured via von Frey filaments over three hours. Mechanism confirmed by pre-treatment with A2a receptor antagonist istradefylline.","limitations":"Animal model with high terpene doses (200 mg/kg) that may not be achievable in humans. Intraperitoneal administration does not reflect oral or inhaled routes. Reserpine-induced fibromyalgia is a chemical model, not a spontaneous disease. Effects measured over only three hours."},{"rthcId":"RTHC-07611","title":"Efficacy and Safety of Transdermal Medical Cannabis (THC:CBD:CBN formula) to Treat Painful Diabetic Peripheral Neuropathy of Lower Extremities.","authors":"Seevathee, Khachornsak; Kessomboon, Pattapong; Manimmanakorn, Nuttaset; Luangphimai, Suyan; Thaneerat, Tewan; Wanaratna, Kulthanit; Plengphanich, Sirichada; Thaenkham, Thanamet; Sena, Wijitra","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 1-14","doi":"10.1159/000542511","pmid":"39720705","tags":["neuropathy","thc","cbd","clinical-outcomes"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"The transdermal cannabis formulation (THC:CBD:CBN) demonstrated statistically significant reductions in NPSI-T scores across all measured pain dimensions (p<0.001) compared to placebo over 12 weeks. Only 10% of the treatment group reported mild adverse events, comparable to the placebo group.","whyItMatters":"Diabetic neuropathy affects millions globally and responds poorly to existing treatments. A transdermal cannabis formulation avoids the systemic side effects and psychoactivity associated with oral cannabis while delivering active compounds directly to affected areas. This is the first phase III trial of a THC:CBD:CBN transdermal for this indication.","specificNumbers":"100 participants randomized. 12-week intervention. Statistically significant reductions across all NPSI-T dimensions (p<0.001). Mild adverse events in 10% of treatment group, comparable to placebo. Trial registered in Thai Clinical Trials Registry.","methodology":"Phase III, double-blind, placebo-controlled, randomized clinical trial at Don Chan Hospital, Thailand. 100 participants with painful diabetic peripheral neuropathy of lower extremities. 12-week intervention with primary outcome measured by the Thai Neuropathic Pain Symptom Inventory (NPSI-T). GEE modeling and ANCOVA used for analysis.","limitations":"Single-center trial in Thailand with 100 participants. 12-week duration does not assess long-term efficacy or safety. The specific THC:CBD:CBN ratios and concentrations are not detailed in the abstract. Cultural and genetic factors may affect generalizability. No active comparator (only placebo)."},{"rthcId":"RTHC-07612","title":"Gender differences in cannabis outcomes after recreational legalization: a United States repeated cross-sectional study, 2008-2017.","authors":"Segura, Luis E; Levy, Natalie S; Mauro, Christine M; Mauro, Pia M; Gutkind, Sarah; Philbin, Morgan M; Hasin, Deborah S; Martins, Silvia S","year":2025,"journal":"International journal of mental health and addiction, 23(3), 2496-2512","doi":"10.1007/s11469-024-01271-7","pmid":"40786531","tags":["policy","epidemiology","gender"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"RCL enactment was associated with higher increases in past-year cannabis use in women (aOR 1.30, 95% CI: 1.19-1.41) than men (aOR 1.15, 95% CI: 1.06-1.25), and similarly for past-month use. Critically, no increases in daily use or DSM-5 cannabis use disorder were observed after legalization for either gender. No increases in any cannabis outcomes were seen among 12-20 year-olds.","whyItMatters":"Cannabis legalization appears to be narrowing the historical gender gap in use. While this represents a demographic shift rather than a health crisis (since problematic use did not increase), it has implications for how prevention and treatment services are designed and targeted.","specificNumbers":"Women: +3.2% past-year (aOR 1.30), +2.3% past-month (aOR 1.37). Men: +2.1% past-year (aOR 1.15), +1.7% past-month (aOR 1.19). No increase in daily use or CUD for either gender. No increase in any outcome for ages 12-20. 2008-2017 NSDUH data.","methodology":"Repeated cross-sectional analysis of 2008-2017 NSDUH data examining changes before and after recreational cannabis law enactment. Multi-level logistic regression with state random intercepts and two-way and three-way interactions between RCL, gender, and age group.","limitations":"NSDUH data is self-reported and cross-sectional within each wave. Study period ends in 2017, before many states had mature recreational markets. Cannot account for all confounders. DSM-5 CUD was a proxy measure, not a clinical diagnosis. Early legalization effects may differ from longer-term impacts."},{"rthcId":"RTHC-07613","title":"Associations of prenatal tobacco and insecticide co-exposures with neurobehavioral responses among children born to pregnant women exposed to cannabis.","authors":"Sehgal, Neha; Brennan, Patricia A; Dunlop, Anne L; Liang, Donghai; Corwin, Elizabeth J; Tan, Youran; Everson, Todd M; Caudle, W Michael; Panuwet, Parinya; D'Souza, Priya E; Yakimavets, Volha; Lee, Grace E; Barr, Dana Boyd; Eick, Stephanie M","year":2025,"journal":"Neurotoxicology and teratology, 111, 107536","doi":"10.1016/j.ntt.2025.107536","pmid":"40754207","tags":["prenatal","neuroscience","safety"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Prenatal insecticides (pyrethroids and organophosphates) were the primary exposures associated with child neurobehavior. Pyrethroid exposure (3PBA) was positively associated with internalizing behaviors (beta=18.1%). Cannabis (THCCOOH) modified the cumulative effect of the tobacco-insecticide mixture: among females with detectable cannabis exposure, the mixture was associated with lower externalizing behaviors (beta=-46.8%, 95% CI: -70.4%, -4.1%).","whyItMatters":"Cannabis and tobacco crops are commonly contaminated with insecticides. This study is one of the first to examine how these co-exposures interact during pregnancy, revealing that cannabis may modify the neurodevelopmental effects of pesticides in sex-specific ways.","specificNumbers":"197 mother-child pairs. Pyrethroid (3PBA) and internalizing: beta=18.1% (95% CI: 0.0%, 39.5%). TCPY and externalizing: beta=-12.9% (95% CI: -27.8%, 5.0%). Females with detectable THCCOOH, mixture and externalizing: beta=-46.8% (95% CI: -70.4%, -4.1%). Effects were modified by both THCCOOH and sex.","methodology":"Prospective cohort of 197 mother-child pairs from Atlanta, Georgia. Cannabis, tobacco, pyrethroid, and organophosphate metabolites measured in maternal urine at 8-14 and 24-30 weeks' gestation. Infant arousal and attention assessed at 2 weeks; child behavior assessed annually at ages 2-5 using CBCL. Quantile g-computation and Bayesian kernel machine regression analyzed mixture effects.","limitations":"Small sample size (N=197) limits statistical power. Urine metabolites capture only recent exposure, not cumulative prenatal burden. Observational design with multiple comparisons raises risk of chance findings. Effect modification by sex and cannabis needs replication. Atlanta-specific cohort may not generalize."},{"rthcId":"RTHC-07614","title":"Mood instability as a transdiagnostic predictor of cannabis use in attention-deficit/hyperactivity disorder and depression: A natural language processing analysis of electronic health records from 13,025 adolescents.","authors":"Seker, Asilay; Bullock, Edward; Chandler, Susie; Patel, Rashmi; Quattrone, Diego; Colling, Craig; Sonuga-Barke, Edmund J S; Downs, Johnny","year":2025,"journal":"European psychiatry : the journal of the Association of European Psychiatrists, 68(1), e139","doi":"10.1192/j.eurpsy.2025.10095","pmid":"40843511","tags":["adhd","mental-health","youth"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Mood instability was associated with increased cannabis use in both ADHD (aOR: 1.61, 95% CI: 1.41-1.84) and depression (aOR: 1.38, 95% CI: 1.21-1.57) after adjustment for covariates. The association was 25% stronger in ADHD than in depression, suggesting mood instability is a particularly important cannabis use predictor in ADHD populations.","whyItMatters":"Understanding why adolescents with ADHD and depression use cannabis could lead to better prevention strategies. If mood instability drives self-medication with cannabis, then treating mood instability directly might reduce cannabis use more effectively than anti-drug messaging.","specificNumbers":"13,025 adolescents (7,985 ADHD, 5,738 depression). ADHD: aOR 1.61 (95% CI: 1.41-1.84). Depression: aOR 1.38 (95% CI: 1.21-1.57). Mood instability associated with 25% higher probability of cannabis use in ADHD compared to depression.","methodology":"Natural language processing of electronic health records from 13,025 adolescents (ages 11-18) with primary diagnoses of ADHD (n=7,985) or depression (n=5,738). NLP identified references to mood instability and cannabis use in clinical notes. Logistic regression adjusted for sociodemographic and clinical covariates.","limitations":"NLP identification of mood instability and cannabis use from clinical notes may miss mentions or introduce false positives. Cross-sectional analysis cannot establish whether mood instability causes cannabis use or vice versa. Electronic health records capture clinical encounters, not daily life. Cannot account for all confounders."},{"rthcId":"RTHC-07615","title":"Clustering of risk behaviors and classification performance in modeling adolescent risk: The example of the association between E-cigarette use and cigarette smoking.","authors":"Selya, Arielle; Niaura, Raymond; Kim, Sooyong","year":2025,"journal":"Drug and alcohol dependence, 273, 112716","doi":"10.1016/j.drugalcdep.2025.112716","pmid":"40435593","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07616","title":"CBD promotes antitumor activity by modulating tumor immune microenvironment in HPV associated head and neck squamous cell carcinoma.","authors":"Sen, Prakriti; Sadat, Sayed; Ebisumoto, Koji; Al-Msari, Riyam; Miyauchi, Sayuri; Roy, Souvick; Mohammadzadeh, Pardis; Lips, Kristin; Nakagawa, Takuya; Saddawi-Konefka, Robert; Sharabi, Andrew B; Califano, Joseph A","year":2025,"journal":"Frontiers in immunology, 16, 1528520","doi":"10.3389/fimmu.2025.1528520","pmid":"40475776","tags":["cbd","cancer","immunology"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"CBD activated the MAPK pathway (ERK1/2, JNK/SAPK, MK2), promoting apoptosis in cancer cells. In immunocompetent mice, CBD significantly reduced tumor growth and enhanced infiltration of CD4+T cells, CD8+T cells, B cells, NK cells, and M1-like macrophages. No anti-tumor effect was seen in immune-deficient mice. CD4+ T cell depletion reversed CBD's benefit, confirming immune dependence.","whyItMatters":"This is the first preclinical demonstration that CBD's anti-tumor activity in HPV-positive head and neck cancer depends entirely on the immune system rather than direct cancer cell killing alone. This has implications for combining CBD with immunotherapy approaches.","specificNumbers":"CBD activated ERK1/2, JNK/SAPK, and MK2 via MAPK pathway. Significant tumor growth inhibition in immunocompetent mice only. Enhanced infiltration of CD4+T, CD8+T, CD19+B cells, NK cells, and M1 macrophages. CD4 depletion reversed anti-tumor effect. Multiplex IHC showed co-localization of T cells with phospho-p38 MAPK.","methodology":"In vitro: BrdU proliferation, apoptosis, migration, and western blot analyses on HPV-positive HNSCC cells. In vivo: syngeneic mouse models (immunocompetent), Rag1 knockout mice (no T/B cells), and athymic nude mice (no T cells). Immune depletion experiments targeted CD4+ and CD8+ T cells. Flow cytometry, IHC, and multiplex IHC measured immune infiltration.","limitations":"Mouse models do not fully recapitulate human HPV-positive HNSCC. CBD doses and routes used in mice may not translate to achievable human concentrations. Syngeneic models use mouse cancer cells, not human tumors. No comparison with standard of care treatments. Association between marijuana use and HPV-positive HNSCC adds complexity to clinical translation."},{"rthcId":"RTHC-07617","title":"Impact of heterologous expression of Cannabis sativa tetraketide synthase on Phaeodactylum tricornutum metabolic profile.","authors":"Sene, Nicolas; Gonçalves Dos Santos, Karen Cristine; Merindol, Natacha; Gélinas, Sarah-Eve; Custeau, Alexandre; Awwad, Fatima; Fantino, Elisa; Meddeb-Mouelhi, Fatma; Germain, Hugo; Desgagné-Penix, Isabel","year":2025,"journal":"Biotechnology for biofuels and bioproducts, 18(1), 42","doi":"10.1186/s13068-025-02638-1","pmid":"40186218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07618","title":"Pharmacokinetic Study of Delta-8-Tetrahydrocannabinol in Male Rats using a Validated Bioanalytical Method.","authors":"Senetra, Alexandria S; Mukhopadhyay, Sushobhan; Chiang, Yi-Hua; Kuntz, Michelle A; Kanumuri, Siva Rama Raju; Zequeira, Sabrina; Setlow, Barry; McCurdy, Christopher R; Sharma, Abhisheak","year":2025,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkaf105","pmid":"41405849","tags":["delta-8","pharmacology"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Delta-8 THC had oral bioavailability of 3.0%, peak plasma concentration of 13.4 ng/mL at 30 minutes (oral), IV clearance of 5.6 L/h/kg (exceeding hepatic blood flow, indicating extrahepatic clearance), volume of distribution of 108.4 L/kg (indicating extensive tissue distribution), and elimination half-life of 13.9 hours.","whyItMatters":"Delta-8 THC has surged in popularity but its pharmacokinetics have been poorly characterized. Understanding how it is absorbed, distributed, and eliminated is essential for assessing its safety profile, interpreting drug test results, and potentially developing dosing guidelines.","specificNumbers":"Oral bioavailability: 3.0 +/- 0.3%. Oral Cmax: 13.4 +/- 0.9 ng/mL. Oral Tmax: 0.5 +/- 0.1 hours. IV clearance: 5.6 +/- 0.4 L/h/kg. Volume of distribution: 108.4 +/- 8.9 L/kg. Elimination half-life: 13.9 +/- 2.0 hours.","methodology":"Single-dose oral (7.5 mg/kg) and intravenous (1.25 mg/kg) pharmacokinetic study in male Sprague-Dawley rats. Validated bioanalytical method (FDA M10 guidelines) measured delta-8 THC and its metabolites (11-OH-delta-8 THC and 11-COOH-delta-8 THC) in plasma. Non-compartmental analysis determined PK parameters.","limitations":"Rat pharmacokinetics do not directly translate to humans due to metabolic differences. Only male rats were studied. Single-dose study does not capture accumulation with repeated use. Oral dose (7.5 mg/kg) was administered by gavage, not reflecting typical human consumption methods."},{"rthcId":"RTHC-07619","title":"Upregulation of endocannabinoid signaling in vivo restores striatal synaptic plasticity and motor performance in Huntington's disease mice.","authors":"Sepers, Marja D; Woodard, Cameron L; Ramandi, Daniel; Vecchiarelli, Haley A; Hill, Matthew N; Raymond, Lynn A","year":2025,"journal":"Journal of Huntington's disease, 14(2), 149-161","doi":"10.1177/18796397251337021","pmid":"40275705","tags":["endocannabinoid-system","neuroscience","neuroprotection"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Three weeks of oral JZL184 (a 2-AG degradation inhibitor) significantly increased 2-AG levels in striatal tissue. Treatment eliminated the difference in rotarod motor learning between Huntington's (YAC128) and wild-type mice and normalized high-frequency stimulation-induced striatal plasticity to wild-type levels. No effects on open field behavior were observed.","whyItMatters":"Huntington's disease has no disease-modifying treatment. This study shows that boosting the brain's own endocannabinoid system can correct the specific synaptic plasticity deficits that underlie early motor symptoms, offering a potential new therapeutic target.","specificNumbers":"3-week oral JZL184 treatment. Significant increase in striatal 2-AG levels. Rotarod motor learning deficit eliminated (YAC128 normalized to WT levels). High-frequency stimulation-induced striatal plasticity normalized. No effect on open field behavior.","methodology":"JZL184 administered orally over 3 weeks to YAC128 Huntington's disease model mice and wild-type littermates. Motor function assessed via rotarod, open field, and other behavioral tasks. Brain tissue analyzed for endocannabinoid levels. Corticostriatal synaptic plasticity measured via electrophysiology in brain slices.","limitations":"YAC128 mouse model does not fully replicate human Huntington's disease. Only early-stage motor symptoms were studied; effects on later neurodegeneration unknown. JZL184 is a research tool, not a clinical drug. Three-week treatment is short relative to the chronic nature of HD. Only open field and rotarod were used for behavioral assessment."},{"rthcId":"RTHC-07620","title":"The Endocannabinoid System in Human Disease: Molecular Signaling, Receptor Pharmacology, and Therapeutic Innovation.","authors":"Șerban, Matei; Toader, Corneliu; Covache-Busuioc, Răzvan-Adrian","year":2025,"journal":"International journal of molecular sciences, 26(22)","doi":"10.3390/ijms262211132","pmid":"41303613","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07621","title":"The Endocannabinoid System in the Development and Treatment of Obesity: Searching for New Ideas.","authors":"Serefko, Anna; Lachowicz-Radulska, Joanna; Jach, Monika Elżbieta; Świąder, Katarzyna; Szopa, Aleksandra","year":2025,"journal":"International journal of molecular sciences, 26(19)","doi":"10.3390/ijms26199549","pmid":"41096816","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07622","title":"Δ9-Tetrahydrocannabinol and cannabidiol selectively suppress toll-like receptor (TLR) 7- and TLR8-mediated interleukin-1β production by human CD16+ monocytes by inhibiting its post-translational maturation.","authors":"Sermet, Sera; Finn, Brianna M; Crawford, Robert B; Kaminski, Norbert E","year":2025,"journal":"The Journal of pharmacology and experimental therapeutics, 392(7), 103615","doi":"10.1016/j.jpet.2025.103615","pmid":"40553974","tags":["immunology","thc","cbd","pharmacology"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"THC and CBD suppressed IL-1beta production by blocking inflammasome formation and caspase-1 activity in TLR7/TLR8-activated CD16+ monocytes. This occurred at the post-translational level; mRNA expression of IL1B, CASP1, NLRP3, and PYCARD was unaffected. A CB2-selective agonist (JWH-015) did not replicate these effects, indicating the mechanism is not mediated by CB2 receptors alone.","whyItMatters":"IL-1beta is a master inflammatory cytokine implicated in conditions from rheumatoid arthritis to HIV-associated neurological disease. Understanding exactly how cannabinoids suppress it at the protein level (not gene level) provides a specific mechanistic target for therapeutic development.","specificNumbers":"THC Kd values not reported in this study. THC was more efficacious than CBD. JWH-015 (CB2 agonist) had no effect. mRNA for IL1B, CASP1, NLRP3, PYCARD unaffected by THC. Minimal THC effects on TLR8-mediated AIM2 expression.","methodology":"Primary human CD16+ and CD16- monocytes were isolated and pretreated with THC, CBD, or JWH-015, then activated through TLR7 or TLR8 (viral sensing receptors). Inflammasome formation, caspase-1 activity, cytokine secretion, and gene expression were measured.","limitations":"In vitro study using isolated human monocytes outside their tissue context. Concentrations of THC and CBD used may not reflect achievable tissue levels. Single-receptor agonist comparison does not rule out involvement of other receptors. Acute treatment does not capture chronic exposure effects."},{"rthcId":"RTHC-07623","title":"Cannabis and cannabinoids in dermatology: a systematic review and meta-analysis of quantitative outcomes.","authors":"Sermsaksasithorn, Pim; Nopsopon, Tanawin; Samuthpongtorn, Chatpol; Chotirosniramit, Korn; Pongpirul, Krit","year":2025,"journal":"Frontiers in pharmacology, 16, 1609667","doi":"10.3389/fphar.2025.1609667","pmid":"41181596","tags":["skin","cbd","systematic-review","clinical-outcomes"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Cannabinoid treatment significantly reduced pruritus (SMD=-0.29, 95% CI: -0.52 to -0.06, I-squared=0%). No significant effects were found for skin dryness (SMD=-0.22), erythema (SMD=-0.33, borderline), quality of life (SMD=-0.15), atopic dermatitis composite scores (SMD=-0.19), or transepidermal water loss (SMD=0.16).","whyItMatters":"Cannabis-based skincare products are a growing market, often marketed with broad claims about skin health. This is the first meta-analysis to quantitatively assess these claims, finding that only itch relief has statistical support while other dermatologic benefits remain unproven.","specificNumbers":"17 studies, 3,359 participants. Pruritus: SMD=-0.29 (95% CI: -0.52 to -0.06, I-squared=0%). Skin dryness: SMD=-0.22 (ns). Erythema: SMD=-0.33 (borderline, CI includes 0). QoL: SMD=-0.15 (ns). Atopic dermatitis: SMD=-0.19 (ns). TEWL: SMD=0.16 (ns).","methodology":"Systematic review and meta-analysis searching PubMed, Embase, Scopus, Web of Science, and CENTRAL through June 2024. Included 11 RCTs, 3 quasi-experimental, and 3 observational studies (3,359 participants). Standard mean differences with 95% CIs. Risk of bias assessed with RoB 2 and ROBINS-I. PROSPERO: CRD42023397189.","limitations":"Included studies varied in cannabinoid formulations (CBD, PEA, cannabis extract, HU-210, alkylamides). Short follow-up periods in most studies. Publication bias possible. Small to moderate effect sizes. Topical formulations may not reflect systemic cannabinoid therapy effects."},{"rthcId":"RTHC-07624","title":"Effects of omega-3 fatty acids on CB1 cannabinoid receptor localization in the hippocampal CA1 region following alcohol withdrawal in adolescent male mice.","authors":"Serrano, Maitane; Lekunberri, Leire; Ocerin, Garazi; Saumell-Esnaola, Miquel; García Del Caño, Gontzal; Puente, Nagore; Bonilla-Del Río, Itziar; Gerrikagoitia, Inmaculada; Grandes, Pedro","year":2025,"journal":"Adicciones, 37(4), 341-352","doi":"10.20882/adicciones.2408","pmid":"41557449","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07625","title":"Omega-3 Fatty Acids Mitigate Long-Lasting Disruption of the Endocannabinoid System in the Adult Mouse Hippocampus Following Adolescent Binge Drinking.","authors":"Serrano, Maitane; Saumell-Esnaola, Miquel; Ocerin, Garazi; García Del Caño, Gontzal; Soria-Gómez, Edgar; Mimenza, Amaia; Puente, Nagore; Bonilla-Del Río, Itziar; Ramos-Uriarte, Almudena; Reguero, Leire; Christie, Brian R; Rodríguez de Fonseca, Fernando; Rodríguez-Arias, Marta; Gerrikagoitia, Inmaculada; Grandes, Pedro","year":2025,"journal":"International journal of molecular sciences, 26(12)","doi":"10.3390/ijms26125507","pmid":"40564971","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07626","title":"Cannabis use, risk of cannabis use disorder, and anxiety and depression among bisexual patients: A comparative study of sex and sexual identity differences in a large health system.","authors":"Setrakian, Naira; Gelberg, Lillian; Koerber, Julia; Chung, Un Young; Akabike, Whitney N; Gorbach, Pamina M; Seamans, Marissa J; Shoptaw, Steven; Cerezo, Alison; Javanbakht, Marjan","year":2025,"journal":"Drug and alcohol dependence, 274, 112762","doi":"10.1016/j.drugalcdep.2025.112762","pmid":"40561790","tags":["mental-health","epidemiology","gender"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Bisexual patients had higher odds of cannabis use than gay/lesbian patients (females: aOR 1.67; males: aOR 1.47). Bisexual males had greater odds of CUD risk (aOR 1.48), depression (aOR 1.86), and using cannabis to manage depression (aOR 2.44) compared to gay males. Bisexual females had higher odds of severe stress diagnosis (aOR 2.44) vs. gay/lesbian females.","whyItMatters":"Sexual minority health research often treats LGB populations as a single group. This study reveals important differences within that community: bisexual individuals, especially males, carry significantly higher burdens of cannabis use and mental health problems, suggesting they need targeted healthcare approaches.","specificNumbers":"9,869 patients. 30.7% reported past 3-month cannabis use. Bisexual females vs. gay/lesbian: cannabis use aOR 1.67. Bisexual males vs. gay: cannabis use aOR 1.47, CUD risk aOR 1.48, depression aOR 1.86, cannabis for depression aOR 2.44. Bisexual females vs. gay/lesbian: severe stress aOR 2.44.","methodology":"Cross-sectional analysis of electronic health records from 9,869 sexual minority patients (lesbian, gay, or bisexual) aged 18+ with primary care visits at a Los Angeles university health system from June 2020 to May 2023. Cannabis screening via ASSIST during annual wellness visits. Multivariable regression adjusted for age and race/ethnicity.","limitations":"Single health system in Los Angeles may not represent broader populations. Cross-sectional design cannot establish causation. EHR-based screening may miss some cannabis use. Cannot distinguish between medicinal and recreational cannabis use. No heterosexual comparison group. Self-identified sexual identity may not capture all sexual minorities."},{"rthcId":"RTHC-07627","title":"Interaction of cytochrome P450 3A4 with cannabinoids and the drug darifenacin.","authors":"Sevrioukova, Irina F","year":2025,"journal":"The Journal of biological chemistry, 301(10), 110709","doi":"10.1016/j.jbc.2025.110709","pmid":"40945735","tags":["pharmacology","drug-interactions","thc","cbd"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"THC and CBD act as type I ligands causing a nearly complete high-spin transition in CYP3A4 (Kd of 1.9 and 3.6 micromolar respectively), while cannabinol caused negligible changes. Crystal structures showed THC positions its cyclohexenyl C7/C8 atoms (main metabolic sites) toward the heme center. THC binding is driven by hydrophobic interactions rather than the polar interactions critical for other drugs.","whyItMatters":"CYP3A4 metabolizes roughly half of all prescription medications. Understanding at the atomic level how cannabinoids interact with this enzyme is essential for predicting drug interactions, which is increasingly important as cannabis use rises alongside prescription medication use.","specificNumbers":"THC Kd: 1.9 micromolar. CBD Kd: 3.6 micromolar. Cannabinol: negligible spectral changes. THC uses hydrophobic binding; darifenacin uses hydrogen bonding to S119. THC approaches heme at C7/C8 metabolic sites.","methodology":"Spectral analysis, site-directed mutagenesis, and X-ray crystallography were used to characterize how CYP3A4 interacts with THC, CBD, cannabinol, and the comparator drug darifenacin. Crystal structures of productive CYP3A4-THC complexes were solved.","limitations":"Crystal structures represent static snapshots that may not capture the dynamic nature of enzyme-substrate interactions. In vitro binding does not predict in vivo metabolic outcomes. Human CYP3A4 activity is influenced by many factors not captured in crystallography (other enzymes, membrane environment, genetic variants)."},{"rthcId":"RTHC-07628","title":"The Potential Use of Cannabidiol in the Treatment of Opioid Use Disorder: A Systematic Review.","authors":"Shafie, Mahan; Ing, Kevin; Rostam-Abadi, Yasna; Weleff, Jeremy; Griffin, Mackenzie; Ranganathan, Mohini; Mohammad Aghaei, Ardavan; Pratt, Nicholas; Funaro, Melissa C; Bassir Nia, Anahita","year":2025,"journal":"Addiction biology, 30(5), e70047","doi":"10.1111/adb.70047","pmid":"40415392","tags":["cbd","opioids","systematic-review"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Human clinical studies showed CBD reduced cravings and alleviated abstinence-induced anxiety in opioid use disorder. Preclinical studies showed CBD reduced withdrawal symptoms and diminished opioid reward in conditioned place preference tests, though results were mixed. CBD was well-tolerated during opioid use and withdrawal across studies.","whyItMatters":"The opioid crisis demands new treatment approaches. Current medications (methadone, buprenorphine, naltrexone) are effective but underutilized and carry their own challenges. CBD, if effective, could offer a non-addictive, well-tolerated complementary approach to OUD treatment.","specificNumbers":"4 clinical studies (74 total participants). 16 preclinical studies. CBD reduced cravings and anxiety in human studies. Mixed results on withdrawal symptoms and opioid reward in preclinical studies. Overall quality: 'some concerns' (human), 'unclear' risk (preclinical).","methodology":"Systematic review searching MEDLINE, Embase, PsycINFO, Scopus, Web of Science, CDSR, and CENTRAL through December 2023. Included original peer-reviewed human and animal studies of CBD for OUD outcomes. Risk of bias assessed with Cochrane tool (human) and SYRCLE (animal). PROSPERO: CRD42023401446.","limitations":"Only 4 clinical studies with 74 total participants. Short follow-up periods. No studies examined CBD as a combination therapy with standard OUD medications. Heterogeneity across preclinical study designs. Studies excluded CBD combined with THC, limiting applicability to whole-plant cannabis."},{"rthcId":"RTHC-07629","title":"UK Medical Cannabis Registry: An Updated Analysis of Cannabis-Based Medicinal Products for Multiple Sclerosis.","authors":"Shah, Yashvi; Erridge, Simon; Clarke, Evonne; McLachlan, Katy; Coomber, Ross; Rucker, James; Weatherall, Mark; Sodergren, Mikael Hans","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 201-218","doi":"10.1159/000549178","pmid":"41357430","tags":["multiple-sclerosis","clinical-outcomes","chronic-pain"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"CBMP treatment was associated with significant improvements in multiple MSQOL-54 subscales (change in health, energy, health distress, pain, physical function, physical role limitations) plus sleep quality and EQ-5D-5L at all follow-up times. 82.4% of adverse events were mild or moderate, with fatigue (13.3%) and spasticity (8.4%) most common.","whyItMatters":"While nabiximols (Sativex) is licensed for MS spasticity, broader cannabis-based products are increasingly used by MS patients for pain, sleep, and anxiety. This 24-month registry data provides the longest follow-up to date for real-world CBMP use in MS.","specificNumbers":"203 patients (47.3% female, 80.8% had prior cannabis exposure). Significant improvements in 6 MSQOL-54 subscales, SQS, and EQ-5D-5L at all follow-up times. 278 total adverse events: 32.7% mild, 49.6% moderate. Most common: fatigue (13.3%), spasticity (8.4%).","methodology":"Prospective case series of 203 MS patients enrolled on the UK Medical Cannabis Registry. Patient-reported outcomes (MSQOL-54, GAD-7, SQS, EQ-5D-5L) assessed at baseline and follow-up to 24 months. Adverse events tracked by prevalence and severity.","limitations":"No control group or randomization. 80.8% had prior cannabis exposure, introducing selection bias. Registry data relies on self-reported outcomes. Dropout and missing data over 24 months not fully characterized. Cannot determine which specific CBMP formulations drove improvements."},{"rthcId":"RTHC-07630","title":"Presentations to United States emergency departments for gastroparesis, cyclic vomiting, and cannabinoid hyperemesis syndrome from 2016 to 2024.","authors":"Shalaby, Michael; Moyer, Eric; Buell, Kevin G; Bernard, Kyle; Gottlieb, Michael","year":2025,"journal":"The American journal of emergency medicine, 96, 201-207","doi":"10.1016/j.ajem.2025.06.067","pmid":"40602005","tags":["chs","gastrointestinal","epidemiology"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"CHS accounted for 134,059 of 248,293,507 ED encounters (0.05%). Mean patient age was 32 years. Admission rate remained steady at ~13.5% with mean 3.8-day hospital stay. Ondansetron was the most common treatment (58.7%), followed uniquely by haloperidol (32.6%) rather than the metoclopramide used for gastroparesis and cyclic vomiting.","whyItMatters":"This is the largest dataset ever analyzed for CHS emergency department visits. The steady admission rate and distinctive treatment patterns (haloperidol for CHS vs. metoclopramide for other vomiting disorders) confirm CHS as a clinically distinct entity requiring different management than other vomiting syndromes.","specificNumbers":"248,293,507 total ED encounters. GP: 165,857 (0.07%). CVS: 204,636 (0.08%). CHS: 134,059 (0.05%). CHS mean age: 32. CHS admission rate: ~13.5% (stable). CHS mean LOS: 3.8 days. CHS medications: ondansetron 58.7%, haloperidol 32.6%. All three conditions primarily affected females.","methodology":"Retrospective cohort study of all ED presentations for gastroparesis, cyclic vomiting syndrome, and CHS from 2016-2024 in the Epic Cosmos database (248 million encounters). ICD-10 codes identified cases. Outcomes included incidence, admission rates, medications, and length of stay.","limitations":"ICD-10 coding may undercount CHS (misdiagnosed as CVS) or overcount it (coding errors). Epic Cosmos captures only participating health systems. Cannot determine cannabis use patterns or product types. Admission rates and treatments reflect clinical practice variation, not evidence-based guidelines."},{"rthcId":"RTHC-07631","title":"Lactiplantibacillus plantarum fermented hemp (Cannabis sativa) seeds modulate the gut microbiota and metabolic pathways to alleviate autoimmune inflammation in collagen-induced arthritis mice.","authors":"Shan, Lingyue; Chelliah, Ramachandran; Park, Sejin; Lee, Yewon; Vijayalakshmi, Selvakumar; Oh, Deoghwan","year":2025,"journal":"Food & function, 16(20), 8160-8184","doi":"10.1039/d5fo00818b","pmid":"41017416","tags":["autoimmune","microbiome","hemp"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Fermented hemp seeds significantly reduced joint swelling, cartilage and synovial damage, and systemic inflammation while restoring mobility and balancing CD4+ T cell differentiation. FHS restored beneficial gut bacteria including Akkermansia muciniphila and Lactobacillus johnsonii, while modulating short-chain fatty acids and other key metabolites. Bioactive peptides from FHS were absorbed into the bloodstream, exerting direct anti-inflammatory effects.","whyItMatters":"This study bridges two growing fields: the gut-joint axis in autoimmune disease and the bioactivity of hemp-derived foods. The finding that fermentation unlocks anti-inflammatory properties beyond what either hemp seeds or probiotics provide alone has implications for functional food development.","specificNumbers":"FHS reduced joint swelling, cartilage damage, and synovial inflammation. Restored Akkermansia muciniphila, Lactobacillus johnsonii, Ruminococcus champanellensis, and Phocaeicola vulgatus. Modulated SCFAs, stearic acid, oleic acid, taurine, DHA, linoleic acid, L-tyrosine. Bioactive peptides including indolelactic acid and homovanillic acid absorbed systemically.","methodology":"Collagen-induced arthritis mouse model treated with Lactiplantibacillus plantarum-fermented hemp seeds (FHS). Gut microbiome profiling, metabolomics, immune cell analysis, and histological assessment of joints compared FHS to L. plantarum alone and unfermented hemp seeds.","limitations":"Mouse model of induced arthritis does not fully replicate human RA. Fermented hemp seed composition varies with fermentation conditions. Cannot separate contributions of fermentation products, hemp nutrients, and probiotic effects. Short-term study in a single mouse strain."},{"rthcId":"RTHC-07632","title":"Biopeptide-rich fermented hemp seeds: Boosting anti-inflammatory and immune responses through Lactiplantibacillus plantarum probiotic fermentation.","authors":"Shan, LingYue; Park, SeonJu; Barathikannan, Kaliayn; Chelliah, Ramachandran; Kim, Dong-Gyu; Yang, Zhen; Oh, Deog Hwan","year":2025,"journal":"International journal of biological macromolecules, 290, 138782","doi":"10.1016/j.ijbiomac.2024.138782","pmid":"39706455","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07633","title":"Pre-employment urine drug screening: examining trends in THC-COOH positivity rates post-legalization of recreational cannabis in California - a retrospective review.","authors":"Sharip, Akbar; Razavi, Roshan","year":2025,"journal":"Journal of occupational medicine and toxicology (London, England), 20(1), 29","doi":"10.1186/s12995-025-00468-3","pmid":"40926239","tags":["drug-testing","policy","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"THC-COOH positivity rate increased from 0.12% in 2017 to 0.94% in 2022 (Cochran-Armitage Z=5.19, p<0.001), a 683% relative increase. Among positive cases, 76% were aged 20-39 (mean: 29 years). The female proportion of positive cases rose dramatically from 25% to 62.2%. Median THC-COOH levels ranged from 60 to 176.5 ng/mL.","whyItMatters":"Pre-employment drug testing policies were designed when cannabis was illegal everywhere. As legalization spreads, the sharp increase in positive tests raises questions about whether cannabis testing should remain part of employment screening, especially since urine tests detect past use rather than impairment.","specificNumbers":"21,546 screenings total. 92 THC-positive (0.44% overall). 2017: 0.12% (4/3,215). 2022: 0.94% (45/4,784). 683% relative increase. Female proportion of positives: 25% to 62.2%. Mean age of positives: 29 years. Median THC-COOH: 145.0 ng/mL (IQR: 309.5).","methodology":"Retrospective analysis of 21,546 de-identified pre-employment urine drug screenings from 2017-2022 at a university-based hospital occupational medicine clinic. Initial immunoassay screening (50 ng/mL cutoff) followed by GC-MS confirmation (15 ng/mL). Cochran-Armitage trend test assessed temporal trends.","limitations":"Single clinic at one hospital system. Cannot determine if positive results reflected increased cannabis use or decreased abstinence before testing. Missing demographic data for the total screening population limits subgroup analysis. Low overall positivity rate means small absolute numbers of positive cases."},{"rthcId":"RTHC-07634","title":"Cannabichromene, a key non-psychotropic phytocannabinoid in treatment of major depressive disorder: in silico and in vivo explorations.","authors":"Sharma, Abhishek; Singh, Rahul; Virmani, Tarun; Chouhan, Neeraj Kumar; Kapoor, Garima; Kumar, Girish; Bhutani, Rubina; Rana, Neha; Sharma, Shivkant","year":2025,"journal":"Naunyn-Schmiedeberg's archives of pharmacology, 398(11), 15611-15630","doi":"10.1007/s00210-025-04236-2","pmid":"40358684","tags":["mental-health","pharmacology","animal-studies"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"CBC at 20 mg/kg significantly reduced immobility in stressed mice (comparable to imipramine 15 mg/kg) without affecting locomotor activity. Both CBC and imipramine reduced elevated plasma nitrite and corticosterone and inhibited brain monoamine oxidase-A. In silico modeling showed CBC had stronger CB2 receptor binding (docking score: -9.4) than CBD (-8.8) or THC (-9.1).","whyItMatters":"CBC is one of the least-studied major cannabinoids. Finding antidepressant activity comparable to a standard antidepressant, mediated through CB2 receptors rather than the psychoactive CB1 pathway, opens a potential avenue for non-psychoactive cannabinoid-based treatments for depression.","specificNumbers":"CBC 20 mg/kg: significant immobility reduction (comparable to imipramine 15 mg/kg). CB2 docking scores: CBC -9.4, THC -9.1, CBD -8.8. CBC reduced plasma nitrite and corticosterone. CBC inhibited brain MAO-A activity. CBC reversed stress-induced catalase suppression. No locomotor effects.","methodology":"Male Swiss albino mice underwent 3 weeks of chronic unpredictable mild stress. CBC (10 and 20 mg/kg) and imipramine (15 mg/kg) administered for 21 days. Behavioral testing (forced swim, locomotor activity), plasma biochemistry (nitrite, corticosterone), and brain enzyme assays (MAO-A, catalase) performed. In silico target prediction and molecular docking complemented in vivo findings.","limitations":"Single mouse strain (Swiss albino males only). CUMS model does not fully replicate human depression. In silico CB2 binding prediction needs experimental confirmation. 21-day treatment may not reflect chronic use effects. Dose-response showed efficacy only at 20 mg/kg, not 10 mg/kg."},{"rthcId":"RTHC-07635","title":"Synthetic Cannabinoid Withdrawal: A Systematic Review of Case Reports.","authors":"Sharma, Rishi; Weinstein, Aviv","year":2025,"journal":"European addiction research, 31(4), 274-285","doi":"10.1159/000546633","pmid":"40570820","tags":["synthetic-cannabinoids","safety","systematic-review"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Most frequent withdrawal symptoms were psychosis (n=9, 82%), agitation/irritability (n=8, 73%), nausea/vomiting (n=6, 55%), seizures (n=5, 45%), tachycardia (n=4, 36%), and insomnia (n=3, 27%). Rarer effects included delirium, rhabdomyolysis, and hallucinations. Symptoms emerged within 24-48 hours in 62% of cases and resolved within 1 week. Cases were predominantly male (82%), mean age 28.","whyItMatters":"Synthetic cannabinoids are often marketed as legal alternatives to cannabis, but their withdrawal profile is dramatically different and more dangerous. Psychosis in 82% of cases and seizures in 45% highlight the need for clinical awareness and prompt medical management.","specificNumbers":"11 case reports. 82% male. Mean age 28.08 (SD 7.78). Psychosis: 82%. Agitation: 73%. Nausea/vomiting: 55%. Seizures: 45%. Tachycardia: 36%. Insomnia: 27%. Onset: 24-48 hours (62%). Resolution: within 1 week. Average CARE checklist score: 8/13.","methodology":"Systematic review of PubMed/Medline, Scopus, EMBASE, and PsycINFO from inception to March 2025 for case reports describing synthetic cannabinoid withdrawal. 11 eligible case reports identified. Quality assessed using CARE guidelines checklist (average 8/13 items).","limitations":"Only 11 case reports available worldwide, reflecting both rarity and underreporting. Case reports are the lowest level of evidence. No standardized withdrawal assessment tools were used across cases. Variable quality of reporting. Cannot determine incidence of withdrawal among synthetic cannabinoid users."},{"rthcId":"RTHC-07636","title":"Subjective drug-effect ratings predict cannabis self-administration in people who use cannabis daily.","authors":"Shellenberg, Thomas P; Strickland, Justin C; Regnier, Sean D; Tolbert, Preston T; Lake, Stephanie; Wesley, Michael J; Stoops, William W; Cooper, Ziva D; Haney, Margaret; Lile, Joshua A","year":2025,"journal":"The Journal of pharmacology and experimental therapeutics, 392(7), 103622","doi":"10.1016/j.jpet.2025.103622","pmid":"40570551","tags":["pharmacology","policy"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Higher ratings of Willingness to Take Again (OR=1.04) were significantly associated with increased odds of self-administering active THC cannabis over a monetary alternative. Higher Stimulated ratings were associated with decreased odds of choosing placebo cannabis (OR=0.94). Drug Liking was not the most predictive measure, contrary to FDA recommendations.","whyItMatters":"The FDA uses Drug Liking as the primary measure in abuse potential assessments for new drugs. If this measure is not the best predictor of actual drug-taking behavior for cannabinoids, regulatory evaluations of novel cannabinoid products may need updating.","specificNumbers":"89 daily users (71 male, 18 female). 4 studies, 2 sites. THC: 5.5-5.9%. Willingness to Take Again: OR 1.04 (significant). Stimulated (for placebo): OR 0.94 (significant). Drug Liking: not the top predictor. Money alternatives: $0.50 or $1.00.","methodology":"Retrospective analysis combining data from 4 previous studies across 2 research sites. 89 daily cannabis users (71 male, 18 female) completed cannabis self-administration sessions with a money alternative ($0.50 or $1.00) and subjective effects questionnaires. THC concentrations were 5.5-5.9%. Generalized linear models tested which subjective ratings predicted self-administration.","limitations":"Retrospective analysis of combined datasets with methodological differences between studies. Small sample with predominantly male participants. Daily cannabis users may not represent occasional users. Low monetary alternatives ($0.50-$1.00) may limit ecological validity. THC concentrations were similar across studies but administration procedures varied."},{"rthcId":"RTHC-07637","title":"Cannabidiol attenuates methamphetamine-induced oxidative neurotoxicity via regulating transient receptor potential vanilloid type 1.","authors":"Shen, Baoyu; Yang, Genmeng; Lv, Mengran; Wu, Zhenling; Zhang, Yuan; Cao, Yuanyuan; Shu, Junjie; Dong, Wenjuan; Hou, Zhenping; Jing, Di; Xu, Jing; Hou, Yuhan; Zhang, Xinjie; Hong, Shijun; Li, Lihua","year":2025,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 145, 157015","doi":"10.1016/j.phymed.2025.157015","pmid":"40582208","tags":["cbd","neuroprotection","neuroscience","pharmacology"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"In METH users' brain tissue, TRPV1 overactivation, calcium overload, oxidative stress, and apoptosis were observed. CBD bound directly to TRPV1 (confirmed by molecular docking and surface plasmon resonance). CBD pretreatment blocked METH-induced calcium influx, oxidative stress, and cell death in HT-22 cells and reversed METH-induced stereotyped behavior and spatial memory impairment in mice.","whyItMatters":"Methamphetamine abuse causes devastating brain damage with no approved treatments. Identifying TRPV1 as the specific receptor through which CBD exerts neuroprotection provides a concrete therapeutic target and mechanistic understanding that could accelerate clinical development.","specificNumbers":"Human brain tissue showed TRPV1 overactivation in hippocampus and medial prefrontal cortex of METH users. CBD binding to TRPV1 confirmed by molecular docking and SPR. TRPV1 knockdown replicated CBD's protective effects. CBD blocked capsaicin-induced calcium influx. CBD reversed METH-induced stereotyped behavior and spatial memory impairment in mice.","methodology":"Human postmortem brain tissue analysis, molecular docking, surface plasmon resonance binding studies, HT-22 cell culture experiments with TRPV1 knockdown, and in vivo mouse studies with behavioral assessment and hippocampal biochemistry. TRPV1 agonist capsaicin used as mechanistic control.","limitations":"Human brain data was postmortem and correlational. Mouse doses may not translate to human therapeutic doses. METH exposure protocols in mice do not replicate human use patterns. Cannot determine if CBD would help after METH damage has already occurred (only pretreatment studied). Single cell line (HT-22) for in vitro work."},{"rthcId":"RTHC-07638","title":"Indoor tanning is associated with substance use behaviors among adolescents.","authors":"Shen, Nathan; Fastner, Suzanne L; Wang, Xuechen; Brintz, Ben J; Schlechter, Chelsey R; Wu, Yelena P","year":2025,"journal":"BMC public health, 25(1), 2514","doi":"10.1186/s12889-025-23630-2","pmid":"40684124","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07639","title":"Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery.","authors":"Shen, Si-Yuan; Wu, Chao; Yang, Zhi-Qian; Wang, Ke-Xin; Shao, Zhen-Hua; Yan, Wei","year":2025,"journal":"Acta pharmacologica Sinica, 46(6), 1495-1510","doi":"10.1038/s41401-024-01472-9","pmid":"39910211","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07640","title":"Qualitative and quantitative analysis of rat liver sinusoids under condition of a long-term experimental exposure to cannabidiol oil.","authors":"Shevchuk, Mykola M; Volos, Liliya I; Kovalska, Oksana R","year":2025,"journal":"Wiadomosci lekarskie (Warsaw, Poland : 1960), 78(12), 2611-2619","doi":"10.36740/WLek/215799","pmid":"41620859","tags":["cbd","safety","animal-studies"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"No pathohistological changes were observed in rat liver sinusoids after 10 weeks of daily CBD oil. However, Kupffer cell numbers increased significantly in all zones of the liver lobule (p<0.001), with a 1.58-fold increase near the portal zone. Perisinusoidal (stellate) cells remained the least abundant cell type. The study concluded CBD oil was safe for long-term liver exposure.","whyItMatters":"Liver safety is a key concern for CBD, given Epidiolex's liver enzyme warning. This study provides histological evidence that long-term oral CBD at a moderate dose does not cause structural liver damage, though the Kupffer cell increase suggests the liver's immune cells are responding to chronic CBD exposure.","specificNumbers":"14 treated rats, 6 controls. 10 mg/kg/day for 10 weeks. No pathological liver changes. Kupffer cells increased 1.58-fold in portal zone (p<0.001). Significant increase in all lobule zones. Perisinusoidal cells remained lowest count.","methodology":"20 male rats: 14 received daily oral CBD oil (10 mg/kg) for 10 weeks, 6 controls received hemp seed oil. Histological, immunohistochemical, and morphometric analyses of liver sinusoidal cell composition with statistical analysis (p<0.05 threshold).","limitations":"Small sample (14 treated, 6 controls). Single dose tested (10 mg/kg). Male rats only. 10-week duration may not capture very long-term effects. CBD oil composition not fully characterized. Histological assessment may miss functional changes detectable only by blood tests or metabolomics."},{"rthcId":"RTHC-07641","title":"Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice.","authors":"Shi, Mingxin; Oh, Yeongseok; Mitchell, Debra A; MacLean, James A; McLaughlin, Ryan J; Hayashi, Kanako","year":2025,"journal":"Toxicological sciences : an official journal of the Society of Toxicology, 205(2), 358-368","doi":"10.1093/toxsci/kfaf043","pmid":"40156136","tags":["prenatal","fertility","reproductive-health","animal-studies"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Cannabis exposure from gestational day 1 to postnatal day 21 did not disrupt pregnancy or nursing in exposed mothers but produced smaller F1 neonatal pups. F1 females showed delayed vaginal opening (puberty marker) and disrupted estrous cyclicity. F2 and F3 females showed only minor effects. All F1-F3 females had normal ovarian and uterine histology, normal estradiol levels, and produced normal offspring.","whyItMatters":"Cannabis use during pregnancy is increasing, and concerns about multigenerational effects are largely untested. This study provides reassuring evidence that while first-generation offspring show some reproductive disruption, the effects attenuate in subsequent generations and do not compromise actual fertility.","specificNumbers":"THC in cannabis extract: 100 and 200 mg/ml. Exposure: gestational day 1 to postnatal day 21 (twice daily). F1 pups were smaller. F1 females: delayed vaginal opening, disrupted estrous cycles. F2 and F3: minor effects only. All generations: normal ovarian/uterine histology, normal estradiol, normal fertility.","methodology":"Pregnant mice exposed to cannabis extract (100 or 200 mg/ml THC) from gestational day 1 to postnatal day 21 (twice daily). F1, F2, and F3 female offspring assessed for puberty onset (vaginal opening), estrous cyclicity, ovarian/uterine histology, plasma estradiol, and fertility outcomes.","limitations":"Mouse model with cannabis extract delivered by inhalation may not replicate human dosing. Only female reproductive outcomes studied. Behavioral and cognitive outcomes in offspring not assessed. THC concentrations in cannabis extract may not reflect human products. Estrous cycle disruption could have functional consequences not captured by fertility endpoints alone."},{"rthcId":"RTHC-07642","title":"Cannabis use and suicide: a case-control study based on integrative data analysis.","authors":"Shi, Qiongyu; Li, Guohua","year":2025,"journal":"Journal of cannabis research, 7(1), 93","doi":"10.1186/s42238-025-00352-1","pmid":"41257848","tags":["mental-health","public-health","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Toxicology-verified cannabis use was associated with 83% increased odds of suicide (aOR 1.83, 95% CI: 1.36-2.31), independent of alcohol use, which showed a 20-fold increase in suicide odds.","whyItMatters":"Most research on cannabis and suicide focuses on ideation or attempts. This study directly examined completed suicide deaths using toxicological verification rather than self-report, addressing a significant gap in the literature.","specificNumbers":"17.1% of suicide cases tested positive for THC compared to 7.2% of controls. Cannabis aOR for suicide: 1.83. Alcohol aOR for suicide: 20.53. Other risk factors included male sex, White race, ages 35-49, and less than high school education.","methodology":"Case-control study using 2013 National Violent Death Reporting System suicide decedents as cases and 2013 NSDUH respondents as controls, with data fusion from the 2013 National Roadside Survey to correct for self-report misclassification. Weighted multivariable logistic regression estimated adjusted odds ratios.","limitations":"Cross-sectional case-control design prevents causal conclusions. Controls were from a general population survey while cases were suicide decedents, creating potential selection bias. Mental health conditions were not included as covariates. THC positivity indicates recent use but not frequency or dose."},{"rthcId":"RTHC-07643","title":"Surface Plasmon Resonance (SPR) for the Binding Kinetics Analysis of Synthetic Cannabinoids: Advancing CB1 Receptor Interaction Studies.","authors":"Shi, Xuesong; Kuai, Lixin; Xu, Deli; Qiao, Yanling; Chen, Yuanyuan; Di, Bin; Xu, Peng","year":2025,"journal":"International journal of molecular sciences, 26(8)","doi":"10.3390/ijms26083692","pmid":"40332355","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07644","title":"Efficacy, pharmacokinetics and safety of liposomal synthetic cannabidiol injected subcutaneously in dogs: a randomized, blinded, placebo-controlled, crossover clinical trial.","authors":"Shilo-Benjamini, Yael; Milgram, Joshua; Lavy, Eran; Quint, Maxim; Barasch, Dinorah; Cern, Ahuva; Barenholz, Yechezkel","year":2025,"journal":"Frontiers in veterinary science, 12, 1746266","doi":"10.3389/fvets.2025.1746266","pmid":"41635790","tags":["cbd","pain","inflammation","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"Oral CBD has a fundamental problem: most of it gets destroyed by the liver before reaching the bloodstream (first-pass metabolism). This team developed a liposomal CBD formulation—synthetic CBD encapsulated in tiny lipid spheres—designed to be injected subcutaneously, completely bypassing the digestive system.\n\nEight dogs with radiographically confirmed osteoarthritis each received both the liposomal CBD injection (7 mg/kg) and a placebo injection in a randomized, blinded, crossover design. The 4-week interval between injections allowed washout.\n\nThe pharmacokinetic results were striking: the subcutaneous injection provided sustained CBD blood levels that oral formulations can't match. The slow-release properties of the liposomes meant a single injection maintained CBD exposure over an extended period.\n\nEfficacy was assessed through activity monitoring and clinical assessment, building on a pilot study from the same group that had already shown analgesia in arthritic dogs. The synthetic CBD (rather than plant-derived) ensures consistent purity and avoids THC contamination.\n\nWhile this is a veterinary study, the bioavailability challenge it addresses is identical in humans. The same liposomal technology could potentially be adapted for human use, where oral CBD's poor absorption similarly limits therapeutic potential.","whyItMatters":"Poor oral bioavailability is the single biggest limitation of current CBD therapeutics—for both animals and humans. If injectable liposomal CBD can provide sustained therapeutic levels from a single injection, it could transform how CBD is used for chronic pain. The veterinary application also matters directly: many dog owners already give their pets oral CBD for arthritis with questionable absorption.","specificNumbers":"8 dogs with confirmed OA. 7 mg/kg subcutaneous L-sCBD (50 mg/mL). Crossover with 4-week washout. Sustained CBD blood levels from single injection. Safety monitored via CBC and serum chemistry for 4 weeks.","methodology":"Randomized, blinded, placebo-controlled, crossover trial in 8 client-owned dogs (4M, 4F; median age 8.5 years; median weight 34.9 kg) with radiographically confirmed osteoarthritis. Two subcutaneous injections 4 weeks apart: 7 mg/kg liposomal synthetic CBD (L-sCBD, 50 mg/mL) and empty liposomes (placebo). Blood sampled for CBD and metabolites, CBC, and serum chemistry up to 4 weeks post-injection.","limitations":"Very small sample (8 dogs). Veterinary data—dog pharmacokinetics and OA pathophysiology differ from humans. Subcutaneous injection isn't as convenient as oral dosing for chronic conditions. The crossover design is efficient but 4-week washout may be insufficient if liposomal CBD has very long tissue half-life. No comparison to oral CBD in this study. Client-owned dogs continued their routine analgesics, which could mask effects."},{"rthcId":"RTHC-07645","title":"Effects of maternal edible THC consumption on offspring lung growth and function in a rhesus macaque model.","authors":"Shorey-Kendrick, Lyndsey E; Crosland, B Adam; Schabel, Matthias C; Messaoudi, Ilhem; Guo, Minzhe; Drake, Matthew G; Nie, Zhenying; Edenfield, R Clayton; Cinco, Issac; Davies, Michael H; Graham, Jason A; Hagen, Olivia L; McCarty, Owen J T; McEvoy, Cindy T; Spindel, Eliot R; Lo, Jamie O","year":2025,"journal":"American journal of physiology. Lung cellular and molecular physiology, 328(3), L463-L477","doi":"10.1152/ajplung.00360.2024","pmid":"39903192","tags":["pregnancy","respiratory","thc","animal-research"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"THC-exposed infant macaques had significantly reduced forced residual capacity, along with decreased total lung capacity, lung diffusion capacity, and lower fetal lung perfusion on prenatal MRI. Molecular analysis revealed altered DNA methylation at genes involved in extracellular matrix organization and lung development.","whyItMatters":"Prenatal cannabis use is rising alongside legalization and perceptions of safety, but the respiratory effects on offspring have been largely unknown. This primate model provides more translatable data than rodent studies.","specificNumbers":"THC dose was 2.5 mg/7 kg/day (equivalent to heavy medical cannabis use). Significant reduction in forced residual capacity at 6 months. Decreased pulmonary growth factors in bronchial alveolar lavage. Altered epigenetic regulation at genes for extracellular matrix organization, lung development, and immune signaling.","methodology":"Female rhesus macaques received daily edible THC (2.5 mg/7 kg/day, equivalent to a heavy medical cannabis dose) or placebo during gestation and postnatally. Serial MRI was performed during pregnancy. At 6 months, infants underwent pulmonary function testing and tissue collection for bulk RNAseq, whole genome bisulfite sequencing, and spatial RNAseq.","limitations":"Small sample size typical of primate studies. THC was given as a single compound rather than whole-plant cannabis. The dose represents heavy use and may not reflect typical consumption. Follow-up only to 6 months of age. No behavioral or long-term respiratory outcomes."},{"rthcId":"RTHC-07646","title":"Changes in sleep quality during the 12 months following medical cannabis initiation.","authors":"Short, Megan M; Lent, Michelle R; McCalmont, Thomas R; Dugosh, Karen L","year":2025,"journal":"Journal of cannabis research, 7(1), 106","doi":"10.1186/s42238-025-00376-7","pmid":"41422305","tags":["sleep","medical-cannabis","observational-study"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Global sleep quality scores (PSQI) were significantly higher at baseline than at each follow-up point (p < 0.0001), with no significant differences among the 3-, 6-, 9-, and 12-month follow-ups, indicating early and sustained improvement. Benefits were seen across all PSQI subscales regardless of administration route or referring condition.","whyItMatters":"Poor sleep is one of the most common reasons people seek medical cannabis, but most evidence comes from short-term studies. This 12-month follow-up provides longer-term data on whether sleep improvements persist.","specificNumbers":"137 participants followed for 12 months. Significant improvement in PSQI global scores at each follow-up vs. baseline (p < 0.0001). Improvements observed across all PSQI subscales. No differences by administration route (oral vs. other) or referring condition (chronic pain, anxiety, PTSD).","methodology":"Prospective observational study of 137 adults newly referred for medical cannabis in Pennsylvania. Participants completed the Pittsburgh Sleep Quality Index at baseline and at 3, 6, 9, and 12 months. Linear mixed effects models assessed changes over time and whether route of administration or referring condition modified outcomes.","limitations":"No control group or blinding. Self-reported sleep quality only, no objective sleep measures. Relatively small sample size (137). Potential selection bias from participants willing to complete multiple follow-ups. Products and doses were not standardized."},{"rthcId":"RTHC-07647","title":"Pre-trauma insomnia and posttraumatic alcohol and cannabis use in the AURORA observational cohort study of trauma survivors.","authors":"Short, Nicole A; Ellis, Robyn A; Pezza, Mattea; House, Stacey L; Beaudoin, Francesca L; An, Xinming; Clifford, Gari D; Jovanovic, Tanja; Linnstaedt, Sarah D; Rauch, Scott L; Haran, John P; Storrow, Alan B; Lewandowski, Christopher; Musey, Paul I; Hendry, Phyllis L; Sheikh, Sophia; Jones, Christopher W; Punches, Brittany E; Hudak, Lauren A; Pascual, Jose L; Seamon, Mark J; Pearson, Claire; Peak, David A; Merchant, Roland C; Domeier, Robert M; Rathlev, Niels K; O'Neil, Brian J; Sanchez, Leon D; Bruce, Steven E; Harte, Steven E; Kessler, Ronald C; Koenen, Karestan C; Ressler, Kerry J; McLean, Samuel A; Neylan, Thomas C","year":2025,"journal":"Journal of psychiatric research, 189, 415-423","doi":"10.1016/j.jpsychires.2025.06.027","pmid":"40582081","tags":["mental-health","sleep","substance-use","ptsd"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Pre-trauma insomnia symptoms significantly predicted heavy cannabis use at 8 weeks post-trauma, even after controlling for pre-trauma substance use, demographics, and trauma severity. Two-week PTSD symptoms significantly mediated this relationship.","whyItMatters":"Understanding modifiable risk factors for post-trauma substance use could help identify intervention targets. If treating insomnia before or shortly after trauma reduces subsequent substance use, it could change early intervention approaches.","specificNumbers":"2,449 participants from 23 EDs. 63.8% women, mean age 37. 50.5% Black, 11.2% Hispanic. Pre-trauma insomnia predicted 8-week heavy cannabis use, heavy alcohol use, and binge drinking. Two-week PTSD symptoms mediated the insomnia-to-cannabis pathway.","methodology":"Prospective cohort from the AURORA study (n=2,449) recruited from 23 US emergency departments. Participants completed self-report measures during their ED visit and at 2 and 8 weeks post-trauma. Path analysis tested direct and mediated associations between pre-trauma insomnia, PTSD symptoms, and substance use.","limitations":"Pre-trauma insomnia was assessed retrospectively during the ED visit, introducing potential recall bias. Cannabis use was self-reported. Only 8-week follow-up, so longer-term patterns are unknown. Observational design cannot establish causation."},{"rthcId":"RTHC-07648","title":"Anxiety sensitivity and cannabis use: A systematic review and conceptualization of research findings.","authors":"Short, Nicole A; Weese, Rachel; Pezza, Mattea; Bedard-Gilligan, Michele A","year":2025,"journal":"Behaviour research and therapy, 188, 104733","doi":"10.1016/j.brat.2025.104733","pmid":"40147245","tags":["mental-health","anxiety","substance-use","systematic-review"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Elevated anxiety sensitivity was directly associated with greater coping-oriented and potentially problematic cannabis use, but not with lifetime cannabis use or overall use frequency. The review proposes a model where high anxiety sensitivity leads to coping-motivated use, which in the presence of psychopathology and positive cannabis expectancies progresses to problematic use.","whyItMatters":"Understanding why some people develop problematic cannabis use while others do not is key for prevention. This review identifies a specific psychological trait that predicts not whether someone uses cannabis, but why they use it and whether that use becomes problematic.","specificNumbers":"50 studies reviewed. Two independent coders assessed risk of bias. Anxiety sensitivity associated with coping-oriented use but not lifetime use or frequency. Proposed conceptual model links AS to coping use to problematic use through psychopathology and positive expectancies.","methodology":"Systematic review of 50 empirical studies from PubMed and PsycInfo through Spring 2024 examining associations between anxiety sensitivity and cannabis use. Two independent coders evaluated study characteristics and risk of bias. Results were qualitatively synthesized.","limitations":"Qualitative synthesis only, no meta-analytic effect sizes. Most included studies were cross-sectional. Publication bias not formally assessed. Heterogeneity in how anxiety sensitivity and cannabis use were measured across studies."},{"rthcId":"RTHC-07649","title":"Cannabidiol as a therapeutic agent for rosacea through simultaneous inhibition of multiple inflammatory pathways.","authors":"Shrestha, Chandani; Yoo, Eun Hee; Deshar, Barsha; Hwang, Min; Kang, Shinwon; Bin, Bum-Ho; Lee, Ji Hyun; Kim, Jiyoon","year":2025,"journal":"BMB reports, 58(8), 357-363","doi":null,"pmid":"40754776","tags":["cbd","skin","inflammation","animal-research"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"Both CBD and metronidazole significantly inhibited redness, epidermal thickness, and mast cell infiltration in a rosacea-like mouse model. Their combination was more effective than either alone. CBD's therapeutic effect was associated with suppression of the ERK, JNK, and p38 MAPK signaling pathways and significant reduction in pro-inflammatory cytokines and chemokines.","whyItMatters":"Rosacea affects about 5.5% of the global population, and current treatments often have limited efficacy or side effects. This study provides mechanistic evidence for CBD as a potential alternative or adjunctive therapy.","specificNumbers":"Both CBD and metronidazole significantly inhibited redness, epidermal thickness, and mast cell infiltration. Combination therapy was more effective. CBD suppressed ERK, JNK, and p38 MAPK pathways. Significant reduction in pro-inflammatory cytokines and chemokines with CBD treatment.","methodology":"Rosacea-like mouse model treated with CBD alone, metronidazole alone, or both in combination. Outcomes included clinical redness, histological measures (epidermal thickness, mast cell infiltration), and molecular analysis of MAPK signaling pathways and inflammatory markers.","limitations":"Mouse model only, not yet tested in humans. Rosacea was chemically induced, which may not fully replicate human disease. Dosing and formulation specifics may not translate to topical human applications. Short-term treatment without long-term follow-up."},{"rthcId":"RTHC-07650","title":"Cannabis and Dermatological Implications: A Traditional Review of Adverse Cutaneous Reactions and Systemic Risks.","authors":"Shrivastava, Shitij; Shrivastava, Shashwat; Shrestha, Monika; Mahaju, Satyam","year":2025,"journal":"Cureus, 17(4), e82711","doi":"10.7759/cureus.82711","pmid":"40400880","tags":["skin","adverse-effects","safety"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabis use has been associated with multiple dermatological conditions including allergic contact dermatitis, urticaria, Stevens-Johnson syndrome, and cannabis-induced arteritis. The endocannabinoid system's role in skin homeostasis provides a biological basis for these reactions, which remain underrecognized and underreported in clinical practice.","whyItMatters":"As cannabis use increases, clinicians need to recognize it as a potential cause of skin conditions. Many of these reactions may be misdiagnosed because cannabis is not considered as an etiologic agent.","specificNumbers":"Literature from 2000-2024 reviewed. Conditions identified: allergic contact dermatitis, urticaria, Stevens-Johnson syndrome, cannabis-induced arteritis. Sources: PubMed and Scopus databases.","methodology":"Traditional narrative review sourcing peer-reviewed articles from PubMed and Scopus published between 2000 and 2024, selecting studies that directly addressed dermatological outcomes of cannabis use.","limitations":"Narrative review based primarily on case reports and small case series. No systematic search methodology or quality assessment. Cannot determine incidence rates. Publication bias likely favors unusual or severe reactions."},{"rthcId":"RTHC-07651","title":"Prevalence and Patterns of Polysubstance Use (Tobacco and Other Substances) and Associated Factors: A Cross-Sectional Analysis in a High-Risk Cohort for Oral Cancer in Varanasi, India, With a Special Focus on Young Emerging Adults.","authors":"Shruti, Tulika; Sharma, Priyanka; Khanna, Divya; Ranjan, Sudhir; Khan, Aqusa; Gurushanth, Keerthi; Singh, Arjun Gurmeet; Mishra, Aseem; Shetty, Anupama; Birur, Praveen; Chaturvedi, Pankaj","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 27(8), 1349-1358","doi":"10.1093/ntr/ntae307","pmid":"39708354","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07652","title":"Effects of randomization to buprenorphine or naltrexone for OUD on cannabis use outcomes: A secondary analysis of the X:BOT trial.","authors":"Shulman, Matisyahu; Choo, Tse-Hwei; Ohrtman, Kaitlyn; Pavlicova, Martina; Rotrosen, John; Nunes, Edward V","year":2025,"journal":"Drug and alcohol dependence, 268, 112550","doi":"10.1016/j.drugalcdep.2025.112550","pmid":"39892089","tags":["opioids","substance-use","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Participants receiving buprenorphine-naloxone were 39% less likely to use cannabis than those receiving extended-release naltrexone across all timepoints (p = 0.0499). No significant mediation was found between treatment assignment and opioid use on cannabis outcomes, or vice versa.","whyItMatters":"Cannabis use is highly prevalent among people with opioid use disorder, but it has been unclear whether the type of medication treatment affects cannabis use patterns. This finding suggests buprenorphine may have differential effects on cannabis use compared to naltrexone.","specificNumbers":"570 total participants (283 naltrexone, 287 buprenorphine). Buprenorphine group 39% less likely to use cannabis (p = 0.0499). No significant mediation between opioid and cannabis use outcomes by treatment assignment.","methodology":"Secondary analysis of the CTN-0051 X:BOT randomized clinical trial comparing extended-release naltrexone (n=283) versus buprenorphine-naloxone (n=287) for opioid use disorder. Mixed-effects logistic regression modeled cannabis use odds. Cross-lagged mediation models explored whether cannabis and opioid use mediated each other.","limitations":"Secondary analysis of a trial not designed for this outcome. Borderline statistical significance. Cannabis use was self-reported. Mechanisms for the differential effect are unknown. May not generalize to all people with opioid use disorder."},{"rthcId":"RTHC-07653","title":"Associations Between Food Restriction, Alcohol and Marijuana Use and Co-Use, and Consequences Among College Students.","authors":"Shute, Ireland M; Fitzke, Reagan E; Buch, Keegan D; Brown, Megan E; Prince, Mark A; Murray, Stuart B; Pedersen, Eric R","year":2025,"journal":"Substance use & misuse, 60(5), 704-714","doi":"10.1080/10826084.2024.2447419","pmid":"39763062","tags":["substance-use","youth","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Among past 30-day marijuana users, hours spent high and food restriction on use days independently predicted greater marijuana-related consequences. For simultaneous alcohol and marijuana users, food restriction moderated the effect of marijuana quantity on marijuana consequences. Alcohol quantity and food restriction independently predicted alcohol consequences among drinkers.","whyItMatters":"Simultaneous alcohol and marijuana use is increasingly common among college students. This study identifies food restriction as an additional risk factor that amplifies negative outcomes, a pattern that could inform campus prevention programs.","specificNumbers":"901 college students surveyed. Among drinkers: alcohol quantity and food restriction independently predicted consequences. Among marijuana users: hours high and food restriction independently predicted consequences. Food restriction on SAM days moderated marijuana quantity's effect on consequences.","methodology":"Cross-sectional survey of 901 college students examining associations between substance use (alcohol, marijuana, simultaneous use), food restriction on substance use days, and negative consequences. Hierarchical regression tested main effects and interactions.","limitations":"Cross-sectional design prevents causal conclusions. Self-reported substance use and food restriction. Single university sample limits generalizability. Food restriction motivations (weight control, forgetting to eat, financial) were not distinguished."},{"rthcId":"RTHC-07654","title":"Cannabinoids in Chronic Pain: Clinical Outcomes, Adverse Effects and Legal Challenges.","authors":"Sic, Aleksandar; George, Conor; Gonzalez, Daniela Ferrer; Tseriotis, Vasilis-Spyridon; Knezevic, Nebojsa Nick","year":2025,"journal":"Neurology international, 17(9)","doi":"10.3390/neurolint17090141","pmid":"41002929","tags":["chronic-pain","medical-cannabis","clinical-outcomes"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Evidence is strongest for neuropathic pain and MS-related spasticity, while results for fibromyalgia, osteoarthritis, and musculoskeletal pain remain inconsistent. Average pain reduction is modest (0.5-1.0 points on a 10-point scale). Discontinuation rates range from 4.3% at low-dose CBD to 12.9% at high-dose CBD vs. 3.5% on placebo. Nabiximols cause dizziness in 25% and somnolence in 8%.","whyItMatters":"Despite growing interest in cannabinoids for pain, this review provides a sobering look at the actual magnitude of benefit: modest at best, with meaningful side effects and regulatory barriers.","specificNumbers":"Pain reduction: 0.5-1.0 points on a 10-point scale. CBD discontinuation: 4.3% (low dose) to 12.9% (high dose) vs. 3.5% placebo. Nabiximols: 25% dizziness, 8% somnolence, 12% treatment discontinuation. High-dose CBD carries measurable hepatotoxicity risk.","methodology":"Narrative review of clinical outcomes, adverse effects, and legal challenges of cannabinoids in chronic pain management, synthesizing evidence from multiple conditions and formulations.","limitations":"Narrative review without formal meta-analysis. Heterogeneous cannabinoid formulations, doses, and conditions make comparisons difficult. Regulatory differences across countries affect which data are available."},{"rthcId":"RTHC-07655","title":"Hexahydrocannabinol: pharmacokinetics, systemic toxicity, and acute behavioral effects in Wistar rats.","authors":"Šíchová, Klára; Mallarino, Barbara; Janečková, Lucie; Palivec, Petr; Vágnerová, Magdaléna; Vejmola, Čestmír; Nikolič, Marek; Ladislavová, Lucie; Mazochová, Kristýna; Ryšánek, Pavel; Šíma, Martin; Šafanda, Adam; Hiep, Bui Quang; Koutrouli, Isis Rita Anzel; Kuchař, Martin; Páleníček, Tomáš","year":2025,"journal":"The international journal of neuropsychopharmacology, 28(8)","doi":"10.1093/ijnp/pyaf041","pmid":"40643195","tags":["novel-cannabinoids","safety","animal-research","pharmacology"],"studyType":"animal","evidenceStrength":"preliminary","keyFinding":"A 1:1 mixture of (9R)-HHC and (9S)-HHC reached peak blood and brain concentrations 2 hours after the highest dose (10 mg/kg). OECD 423 toxicity testing classified HHC as Category 4 (estimated lethal dose 1000 mg/kg). At 10 mg/kg, HHC reduced movement, increased anxiety-like behavior, and impaired prepulse inhibition of acoustic startle response.","whyItMatters":"HHC is widely sold as a legal THC alternative in parts of Europe and the UK, but safety data have been almost nonexistent. This is among the first studies characterizing its pharmacokinetics, toxicity, and behavioral effects.","specificNumbers":"Doses: 1, 5, 10 mg/kg. Peak brain concentration at 2 hours post-10 mg/kg dose. OECD Category 4 toxicity (estimated LD50: 1000 mg/kg). 10 mg/kg reduced locomotion, increased anxiety, impaired sensory gating. Vehicle: sunflower oil.","methodology":"Male Wistar rats received a 1:1 mixture of (9R)-HHC and (9S)-HHC via intragastric gavage at 1, 5, and 10 mg/kg. Behavioral effects assessed via open field test and prepulse inhibition. Pharmacokinetics measured in blood and brain tissue. Toxicity classified per OECD 423 protocol.","limitations":"Male rats only. Used a racemic mixture rather than individual stereoisomers. Oral gavage dosing may not reflect typical human consumption routes (vaping, edibles). Acute effects only, no chronic exposure data. Limited behavioral battery."},{"rthcId":"RTHC-07656","title":"Cannabinoid Hyperemesis Syndrome in Adolescents: The Role of Aprepitant as a New Treatment Option for Rapid Symptom Relief.","authors":"Sigal, Anat; Padilla, Gabrielle; Carroll, Taryn; Mautone, Susan G","year":2025,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 77(6), 1223-1225","doi":"10.1016/j.jadohealth.2025.08.004","pmid":"40965394","tags":["youth","addiction","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Cannabinoid hyperemesis syndrome (CHS) vomiting can be agonizing and resistant to standard antiemetics. This case report describes two teenagers with CHS who failed to improve despite 36–45 hours of ondansetron, metoclopramide, haloperidol, and capsaicin—the usual CHS treatment toolkit.\n\nThen they received aprepitant, a neurokinin-1 (NK1) receptor antagonist originally developed for chemotherapy-induced nausea. The response was dramatic: vomiting stopped within 1 hour, oral fluids were tolerated within 1–2 hours, solid food within 4–8 hours, and both patients were discharged the following day without needing additional antiemetics.\n\nThe speed and completeness of the response is striking. After nearly two days of failed conventional treatment, a single dose of aprepitant resolved the acute episode. While cannabis cessation remains the only long-term solution for CHS, having an effective rescue medication for acute episodes could prevent the dangerous complications of prolonged vomiting—like the Wernicke's encephalopathy described in RTHC-00164.\n\nThe NK1 receptor pathway makes biological sense for CHS: substance P (which NK1 receptors mediate) is involved in the vomiting reflex, and the endocannabinoid system interacts with substance P signaling in the brainstem.","whyItMatters":"CHS is becoming more common as cannabis use increases, particularly among young people (RTHC-00162). Current treatment options are limited and often ineffective for severe episodes. If aprepitant proves effective in larger studies, it could become a critical rescue medication—preventing the prolonged vomiting that can lead to dehydration, electrolyte imbalances, kidney injury, and even brain damage (RTHC-00164).","specificNumbers":"2 adolescent patients. 36–45 hours of failed standard treatment. Vomiting resolved within 1 hour of aprepitant. Oral fluids tolerated: 1–2 hours. Solid food tolerated: 4–8 hours. Discharged next day. No additional antiemetics needed.","methodology":"Case report of 2 adolescents meeting Rome IV criteria for CHS with documented chronic cannabis use. Both failed standard antiemetics (ondansetron, metoclopramide, haloperidol, capsaicin) for 36–45 hours. Aprepitant administered as rescue therapy. Outcomes: time to vomiting cessation, oral fluid tolerance, solid food tolerance, and discharge timing.","limitations":"Only 2 cases—far too few to establish efficacy. No blinding or control condition. The timing of symptom resolution could reflect natural episode resolution coinciding with aprepitant administration. Rome IV criteria for CHS are relatively new and may not capture all cases. No long-term follow-up on CHS recurrence. Aprepitant is an expensive medication."},{"rthcId":"RTHC-07657","title":"Public understanding of medical cannabis in Poland 7 years after legalization: findings from a cross-sectional study.","authors":"Silczuk, Andrzej; Jankowski, Mateusz; Mularczyk-Tomczewska, Paulina; Olearczyk, Agata; Baran, Tomasz; Wrześniewska-Wal, Iwona; Lewandowska, Aleksandra; Łoś, Magdalena","year":2025,"journal":"Frontiers in public health, 13, 1686709","doi":"10.3389/fpubh.2025.1686709","pmid":"41059179","tags":["public-health","medical-cannabis","policy","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"81.1% of respondents supported medical cannabis legalization and 84.3% expressed willingness to undergo treatment if medically indicated. However, only 4.2% reported receiving a physician recommendation. Confidence in physician knowledge (29.9%) and patient knowledge (16.1%) was low. Chronic pain (49.8%) and oncological conditions (57.4%) were the most recognized indications.","whyItMatters":"Poland's experience illustrates a common pattern: legalizing medical cannabis does not automatically translate to clinical adoption. The gap between public willingness and physician recommendation highlights systemic barriers in medical education and practice guidelines.","specificNumbers":"1,113 adults surveyed. 81.1% support legalization. 84.3% willing to try if recommended. 4.2% received physician recommendation. 29.9% confident in physician knowledge. 16.1% confident in patient knowledge. 57.4% recognized oncology indications. 49.8% recognized chronic pain.","methodology":"Cross-sectional survey conducted July 2025 using computer-assisted web interviewing on a nationally representative sample of 1,113 Polish adults aged 18-84. Multivariable logistic regression identified sociodemographic predictors of key attitudes.","limitations":"Online survey may underrepresent older adults and rural populations despite nationally representative sampling. Self-reported attitudes may not reflect behavior. Cross-sectional design captures one timepoint. Social desirability bias possible on sensitive topics."},{"rthcId":"RTHC-07658","title":"Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression.","authors":"Silva, Nicole R; Arjmand, Shokouh; Domingos, Luana B; Chaves-Filho, Adriano M; Mottin, Melina; Real, Caroline C; Waszkiewicz, Anna L; Gobira, Pedro H; Ferraro, Alessio Nicola; Landau, Anne M; Andrade, Carolina H; Müller, Heidi K; Wegener, Gregers; Joca, Sâmia R L","year":2025,"journal":"Pharmacological research, 211, 107545","doi":"10.1016/j.phrs.2024.107545","pmid":"39667543","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07659","title":"Cannabis use patterns and different phenotypes in relation to other drugs use: latent class analyses from the Sao Paulo Megacity Mental Health Survey.","authors":"Silveira, Camila Magalhães; Castaldelli-Maia, João Maurício; Siu, Erica Rosanna; Viana, Maria Carmen; Wang, Yuan-Pang; Andrade, Laura Helena","year":2025,"journal":"Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999), 47, e20243833","doi":"10.47626/1516-4446-2024-3833","pmid":"40090019","tags":["epidemiology","substance-use","public-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"A four-class model identified distinct cannabis user profiles: a Polydrug class (26.2%) and a Former class (5.9%) with earlier onset and highest frequency, and two lighter-use groups. The Polydrug class had higher odds of other drug use (OR 3.0), tobacco (OR 2.5), heavy episodic drinking (OR 1.8), and alcohol use disorder (OR 1.5).","whyItMatters":"Not all cannabis users face the same risks. Identifying distinct user profiles helps target prevention and harm reduction efforts toward the subset of users who are most vulnerable to negative outcomes.","specificNumbers":"5,037 total survey participants. 496 cannabis users analyzed. Four classes identified. Polydrug class (26.2%): OR 3.0 for other drugs, OR 2.5 tobacco, OR 1.8 heavy drinking, OR 1.5 AUD. Former class (5.9%): earliest onset and highest historical frequency. About 30% at increased risk.","methodology":"Data from the São Paulo Megacity Mental Health Survey (n=5,037). Latent class analysis of 496 cannabis users based on age of onset, use frequency, tobacco consumption, heavy episodic drinking, alcohol use disorder, and substance use disorder. Logistic regression assessed correlates.","limitations":"Cross-sectional design limits causal inference. Self-reported substance use. São Paulo sample may not represent all of Brazil. Latent class analysis findings are sample-dependent and may not replicate in other populations."},{"rthcId":"RTHC-07660","title":"Associations of Local Cannabis Policy and Retail Availability in Northern California with Adverse Adolescent Mental Health Outcomes.","authors":"Silver, Lynn D; Slama, Natalie E; Dong, Huyun; Padon, Alisa A; Pacula, Rosalie Liccardo; Alexeeff, Stacey E; Sterling, Stacy A; Dyer, Wendy T; Campbell, Cynthia I; Satre, Derek D; Lu, Yun; Does, Monique B; Annam, Jay; Young-Wolff, Kelly C","year":2025,"journal":"Substance use & misuse, 60(10), 1571-1576","doi":"10.1080/10826084.2025.2505145","pmid":"40380774","tags":["youth","mental-health","policy","public-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Banning storefront cannabis retail was associated with 48% lower prevalence of psychotic disorders (aPR 0.52). Having 6+ retailers within a 15-minute drive was associated with 11% higher anxiety disorder prevalence (aPR 1.11), 10% higher depressive disorder prevalence (aPR 1.10), and 8% higher depression symptom prevalence (aPR 1.08). A 20+ minute drive to the nearest retailer was associated with 47% lower psychotic disorder prevalence (aPR 0.53).","whyItMatters":"This is one of the largest studies to date examining whether local cannabis retail policies affect adolescent mental health outcomes, not just cannabis use rates. The findings suggest that retail availability may influence mental health beyond just facilitating access.","specificNumbers":"95,645 adolescents aged 13-17. Storefront ban only: aPR 0.52 for psychotic disorders. Both bans: aPR 0.67. 6+ retailers within 15-min drive: aPR 1.11 anxiety, 1.10 depression, 1.08 depression symptoms. 20+ min to nearest retailer: aPR 0.53 psychotic, 0.89 anxiety, 0.89 depressive, 0.91 depression symptoms.","methodology":"Cross-sectional study of 95,645 Northern California adolescents aged 13-17 who completed a well-check questionnaire in 2021. Exposures included local cannabis retail bans, retailer proximity, and density relative to geocoded home addresses. Outcomes included ICD-coded psychotic, depressive, and anxiety disorders plus self-reported depression symptoms.","limitations":"Cross-sectional design cannot establish causation. Cannabis use itself was not measured, only retail availability and mental health outcomes. Residual confounding by neighborhood socioeconomic factors is possible. ICD diagnoses may undercount actual conditions."},{"rthcId":"RTHC-07661","title":"Cannabinol's Modulation of Genes Involved in Oxidative Stress Response and Neuronal Plasticity: A Transcriptomic Analysis.","authors":"Silvestro, Serena; Calabrò, Marco; Trainito, Alessandra; Salamone, Stefano; Pollastro, Federica; Mazzon, Emanuela; Minuti, Aurelio","year":2025,"journal":"Antioxidants (Basel, Switzerland), 14(6)","doi":"10.3390/antiox14060744","pmid":"40563376","tags":["cbn","neuroprotection","laboratory"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"CBN had no negative impact on cell viability at concentrations from 5 to 100 micromolar. Transcriptomic analysis showed significant enrichment in Reactome pathways for cellular response to stress, cellular response to stimuli, and axon guidance. These findings suggest CBN may modulate neuronal cell survival and plasticity-related processes.","whyItMatters":"CBN is a minor cannabinoid that has received far less research attention than CBD or THC. This transcriptomic study identifies specific gene pathways through which CBN may exert neuroprotective effects, informing future research directions.","specificNumbers":"Five CBN concentrations tested: 5, 10, 20, 50, 100 micromolar. 24-hour pre-treatment. No viability reduction at any concentration. Three significantly enriched Reactome pathways: cellular response to stress, cellular response to stimuli, axon guidance.","methodology":"Differentiated NSC-34 neuroblastoma/spinal cord cells were pre-treated with CBN at five concentrations (5, 10, 20, 50, 100 micromolar) for 24 hours. Transcriptomic analysis via next-generation sequencing with pathway enrichment analysis using the Reactome database.","limitations":"In vitro study using an immortalized cell line, not primary neurons. No disease model or functional readout beyond gene expression. Single timepoint (24 hours). Gene expression changes do not necessarily translate to protein-level or functional effects."},{"rthcId":"RTHC-07662","title":"The Role of Endocannabinoids in Physiological Processes and Disease Pathology: A Comprehensive Review.","authors":"Simankowicz, Paulina; Stępniewska, Joanna","year":2025,"journal":"Journal of clinical medicine, 14(8)","doi":"10.3390/jcm14082851","pmid":"40283681","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07663","title":"Understanding the role of cannabis in patients with suicidal ideation presenting to the emergency department: systematic chart review.","authors":"Simmons, Maria; Crocker, Candice E; Fisher, Derek; Stewart, Sherry H; Emsley, Jason G; Abidi, Sabina; Carter, Alix; Calkin, Cynthia; Yakovenko, Igor; Magee, Kirk; Tibbo, Philip G","year":2025,"journal":"BJPsych open, 11(5), e199","doi":"10.1192/bjo.2025.10776","pmid":"40922512","tags":["mental-health","emergency-medicine","policy","public-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The number of ED encounters and suicidality-related ED encounters following the index visit were significantly higher in the immediate post-legalization cohort compared to the two-years-later cohort. However, the overall patient profile remained stable despite increased cannabis use in the general population. Personality disorders were associated with repeat cannabis-related ED visits.","whyItMatters":"A key concern about cannabis legalization is whether it would increase suicide-related presentations. This study from Canada provides real-world data suggesting the patient population remained stable even as legal access expanded.","specificNumbers":"Two cohorts compared across matched 6.5-month periods. Significantly more follow-up ED visits in the early post-legalization cohort (t=2.05, p=0.042). Significantly more suicidality-related follow-up ED visits in the early cohort (t=2.23, p=0.027). Personality disorders associated with repeat visits.","methodology":"Retrospective chart review comparing two cohorts of patients presenting to EDs with suicidal ideation/attempts and cannabis use: October 2018-April 2019 (immediately post-legalization) and October 2020-April 2021 (two years later). ED healthcare usage tracked for 2 years before and after index encounter.","limitations":"Retrospective chart review with limited sample sizes. Only two EDs. Cannot establish causation between cannabis use and suicidality. COVID-19 pandemic overlapped with the second cohort, potentially confounding results. Cannabis use was self-reported during ED visits."},{"rthcId":"RTHC-07664","title":"Influence of cannabis and alcohol on motor vehicle injury severity in Canadian trauma centres: a prospective study.","authors":"Simmons, Sarah M; Donoghue, Madison; Erdelyi, Shannon; Chan, Herbert; Vaillancourt, Christian; Atkinson, Paul; Besserer, Floyd; Clarke, David B; Davis, Phil; Daoust, Raoul; Émond, Marcel; Eppler, Jeffrey; Lee, Jacques S; MacPherson, Andrew; Magee, Kirk; Mercier, Eric; Ohle, Robert; Parsons, Michael; Rao, Jagadish; Rowe, Brian H; Taylor, John; Wishart, Ian; Brubacher, Jeffrey R","year":2025,"journal":"Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention","doi":"10.1136/ip-2025-045642","pmid":"40670142","tags":["driving","safety","thc","alcohol","public-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Drivers with any detectable alcohol had increased odds of hospital admission (aOR 1.36-1.69), but THC did not modify the relationship between alcohol and admission. Neither alcohol nor THC predicted length of hospital stay after admission. 16% of drivers had detectable alcohol, 16.6% had detectable THC, and 4.5% had both.","whyItMatters":"With cannabis legalization, understanding whether THC compounds alcohol's effect on crash injury severity is critical for policy. This large prospective study with toxicological verification provides some of the strongest data on this question.","specificNumbers":"10,322 injured drivers from 17 trauma centers. 16.0% had detectable alcohol, 16.6% had detectable THC, 4.5% had both. BAC >0 to <0.08%: aOR 1.69 for admission. BAC >=0.08%: aOR 1.36 for admission. THC did not modify alcohol's effect on admission or predict length of stay.","methodology":"Prospective study across 17 Canadian trauma centers (2018-2023) as part of the National Drug Driving Study. Blood samples from 10,322 injured drivers aged 16+ were tested for alcohol (GC-FID) and THC (LC-MS/MS) within 6 hours of the crash. Outcomes were hospital admission and length of stay.","limitations":"Measures injury severity after crashes, not crash risk. Blood THC levels were measured but do not reliably indicate impairment level. Selection bias from only including drivers who reached trauma centers. No data on cannabis tolerance or frequency of use."},{"rthcId":"RTHC-07665","title":"The Clinical Conundrum of Cyclic Vomiting in the Cannabinoid User: Simply Cannabinoid Hyperemesis or Could It Be More?","authors":"Sinan, Kenan; Beydoun, Serina; Lulgjuraj, Tony","year":2025,"journal":"ACG case reports journal, 12(5), e01711","doi":"10.14309/crj.0000000000001711","pmid":"40401049","tags":["gastrointestinal","diagnosis","clinical-practice"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Two adolescent patients with heavy cannabis use and cyclical vomiting were initially suspected of having cannabinoid hyperemesis syndrome. Further investigation revealed that vomiting episodes correlated with the menstrual cycle (catamenial CVS). Hormonal contraceptive therapy successfully treated the vomiting in both cases, even though cannabis use continued.","whyItMatters":"Cannabinoid hyperemesis syndrome (CHS) is increasingly diagnosed in cannabis users with cyclic vomiting. These cases demonstrate that menstrual-linked cyclic vomiting can be misdiagnosed as CHS, leading to unnecessary cannabis cessation demands and missed effective treatments.","specificNumbers":"2 adolescent cases. Both had heavy cannabis use and cyclical vomiting. Both successfully treated with hormonal contraception. Both continued cannabis use without recurrence of vomiting.","methodology":"Case report of 2 adolescent patients presenting with cyclical vomiting and heavy cannabis use. Clinical investigation included menstrual history correlation and treatment trial with hormonal contraception.","limitations":"Only 2 cases reported. Cannot establish prevalence of misdiagnosis. No standardized diagnostic criteria applied. Possible that hormonal treatment coincidentally resolved symptoms."},{"rthcId":"RTHC-07666","title":"'In the weeds': navigating the complex concerns, challenges and choices associated with medicinal cannabis consumption for endometriosis.","authors":"Sinclair, Justin; Eathorne, Allie; Adler, Hannah; Mardon, Amelia; Holtzman, Orit; Abbott, Jason; Sarris, Jerome; Armour, Mike","year":2025,"journal":"Reproduction & fertility, 6(2)","doi":"10.1530/RAF-24-0098","pmid":"40445778","tags":["endometriosis","medical-cannabis","womens-health","pain"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Illicit cannabis (56.7%) was the most common access pathway. 99% would continue use, 90% would recommend it. Primary motivations: inadequate pain control (68.6%) and medication side effects (56.3%). Those using illicit cannabis were significantly less likely to disclose use to healthcare providers (p < 0.0001). Over 30% did not tell their doctor about cannabis use.","whyItMatters":"Endometriosis affects roughly 10% of women of reproductive age, and many find conventional treatments inadequate. This large international survey reveals the reality of how people access and use cannabis for endometriosis symptoms, and the barriers to open medical discussion.","specificNumbers":"889 respondents across 10+ countries. 56.7% used illicit cannabis. 99% would continue. 90% would recommend it. 68.6% motivated by inadequate pain control. 56.3% by medication side effects. 43.9% concerned about pharmaceutical dependence. >30% did not disclose to their doctor.","methodology":"International cross-sectional online survey distributed by endometriosis organizations. 889 respondents from 10+ countries. Assessed motivations for cannabis use, concerns, access pathways, and healthcare communication.","limitations":"Self-selected sample from endometriosis organizations, likely overrepresenting those with positive cannabis experiences. No clinical verification of endometriosis diagnosis. No objective outcomes or pain measures. Cross-sectional design."},{"rthcId":"RTHC-07667","title":"A predictive machine learning model for cannabinoid effect based on image detection of reactive oxygen species in microglia.","authors":"Sinclair, Patricia; Jeffries, William; Lebert, Nadege; Saeed, Maheen; Ullah, Aman; Kabbani, Nadine","year":2025,"journal":"PloS one, 20(3), e0320219","doi":"10.1371/journal.pone.0320219","pmid":"40131976","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07668","title":"Update on Cannabidiol in Drug-Resistant Epilepsy.","authors":"Singh, Akanksha; Madaan, Priyanka; Bansal, Dipika","year":2025,"journal":"Indian journal of pediatrics, 92(1), 61-69","doi":"10.1007/s12098-024-05337-1","pmid":"39585547","tags":["cbd","epilepsy","pediatrics","clinical-outcomes"],"studyType":"review","evidenceStrength":"strong","keyFinding":"CBD has been approved for Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex in multiple countries. Clinical trials and observational studies show it can lower seizure frequency and improve quality of life. Common adverse events include somnolence, diarrhea, and gastrointestinal issues. Cost remains a barrier, especially in low- and middle-income countries.","whyItMatters":"Drug-resistant epilepsy affects children who do not respond to conventional anti-seizure medications. CBD represents one of the few new treatment options to receive regulatory approval across multiple jurisdictions for these severe conditions.","specificNumbers":"Approved for 3 conditions: Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex. Regulatory approval in US, Europe, and India. Common adverse events: somnolence, diarrhea, GI issues. Cost is a significant barrier in LMICs.","methodology":"Narrative review of CBD's pharmacological properties, mechanisms of action, and clinical evidence from trials and observational studies for pediatric drug-resistant epilepsy, including regulatory landscape discussion.","limitations":"Narrative review without systematic methodology. Does not quantify seizure reduction across all studies. Limited discussion of long-term outcomes. Cost-effectiveness analysis not included."},{"rthcId":"RTHC-07669","title":"Cannabidiol and cognition: a literature review of human randomized controlled trials.","authors":"Singh, Jyotpal; Ellingson, Chase J; Shafiq, M Abdullah; Alcorn, Jane; Neary, J Patrick","year":2025,"journal":"Behavioural pharmacology, 36(5), 203-216","doi":"10.1097/FBP.0000000000000837","pmid":"40492491","tags":["cbd","cognition","systematic-review","clinical-outcomes"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"In healthy participants, CBD showed some effects on cognitive function and sleep quality with various dosing strategies. In Parkinson's disease, 75-300 mg improved daily activities. CBD at 300-400 mg decreased subjective anxiety in psychiatric patients. In psychosis, 600 mg showed inconsistent cognitive results. Up to 1000 mg in schizophrenia and 800 mg in substance use disorders had minimal cognitive effects.","whyItMatters":"CBD is increasingly marketed for cognitive benefits, but this review of actual RCT data shows the evidence is far more nuanced, with effects varying widely by dose, condition, and outcome measure.","specificNumbers":"1,038 articles screened, 36 included. Doses ranged from 75 mg to 1,000 mg. Parkinson's: 75-300 mg improved daily activities. Psychiatric: 300-400 mg reduced anxiety. Psychosis: 600 mg inconsistent. Schizophrenia: up to 1,000 mg minimal cognitive effect. Substance use: up to 800 mg minimal cognitive effect.","methodology":"Literature review of 36 randomized controlled trials identified from PubMed/Medline using specified search terms. Studies included healthy participants and those with neurological disease, psychiatric disease, psychosis, schizophrenia, and substance use disorders.","limitations":"Most studies used acute (single-dose) protocols. Wide variation in CBD dose, formulation, and route of administration. Different cognitive assessments across studies make comparison difficult. Publication bias not formally assessed."},{"rthcId":"RTHC-07670","title":"Negative urgency increases risk for coping-motivated cannabis outcomes in socially anxious male emerging adult cannabis users.","authors":"Single, Alanna; Mota, Natalie; Keough, Matthew T","year":2025,"journal":"Journal of American college health : J of ACH, 73(9), 3636-3643","doi":"10.1080/07448481.2024.2435936","pmid":"39642003","tags":["mental-health","anxiety","youth","substance-use"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Higher social anxiety predicted elevated cannabis use and problems via coping motives, but only for males higher in negative urgency. The mediated moderation model showed that the combination of social anxiety and impulsivity specifically drove coping-motivated use and subsequent problems in male emerging adults.","whyItMatters":"Identifying which subgroups of cannabis users are most at risk for problems helps target prevention efforts. This study points to a specific combination of traits (male, socially anxious, impulsive) that predicts problematic cannabis use patterns.","specificNumbers":"Sample: emerging adult undergraduates with past 6-month cannabis use. Effect found only in males with high negative urgency. Social anxiety predicted use and problems through coping motives in this subgroup.","methodology":"Cross-sectional online survey of emerging adult undergraduates who reported past six-month cannabis use. Mediated moderation analysis tested whether negative urgency moderated the path from social anxiety to cannabis outcomes through coping motives.","limitations":"Cross-sectional design limits causal inference. Self-selected undergraduate sample. Only examined past 6-month use. Effect specific to males, limiting generalizability. Did not measure cannabis type or dose."},{"rthcId":"RTHC-07671","title":"Exploring Pathways from Childhood Adversity to Substance Use in Young Adults.","authors":"Sinkevicius, Liudas Vincentas; Sakalauskaite, Sandra; Poskus, Mykolas Simas; Pilkauskaite Valickiene, Rasa; Serapinas, Danielius","year":2025,"journal":"International journal of environmental research and public health, 22(11)","doi":"10.3390/ijerph22111608","pmid":"41302556","tags":["youth","mental-health","substance-use","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Sexual abuse predicted higher levels of cannabis, alcohol, nicotine, and heavy psychoactive substance use. Physical maltreatment predicted higher alcohol use. Witnessing interpersonal violence predicted only nicotine use. Unexpectedly, verbal abuse showed significant negative associations across several substance categories. Family addiction history was not significantly associated with substance use.","whyItMatters":"This is among the first studies in Lithuania to differentiate between types of adverse childhood experiences and their specific substance use outcomes, challenging the common practice of simply summing ACE scores.","specificNumbers":"709 participants aged 18-29. Sexual abuse predicted cannabis (CUDIT-R), alcohol (AUDIT), nicotine, and heavy substance use (ASSIST). Physical maltreatment predicted alcohol use. Verbal abuse negatively associated with several substance categories. Family addiction history not significant.","methodology":"Cross-sectional study of 709 Lithuanian young adults aged 18-29 who completed an online survey. ACEs measured using adapted items and the MACE questionnaire. Substance use assessed via CUDIT-R, AUDIT, ASSIST, and self-report. Structural equation modeling tested predictive relationships.","limitations":"Cross-sectional design prevents causal conclusions. Self-reported ACEs subject to recall bias. Online convenience sample may not be representative. Lithuanian-specific cultural context may limit generalizability. Verbal abuse finding is unexpected and needs replication."},{"rthcId":"RTHC-07672","title":"The Relationships of Early Use of Marijuana With Substance Use and Violence in Adolescent Gamblers and Non-Gamblers.","authors":"Sirek, Greta; Stefanovics, Elina A; Iyer, Rasika; Potenza, Marc N; Zhai, Zu Wei","year":2025,"journal":"Journal of the Korean Academy of Child and Adolescent Psychiatry, 36(3), 89-105","doi":"10.5765/jkacap.250012","pmid":"40631639","tags":["youth","substance-use","gambling","public-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Early marijuana use (before age 13) was associated with higher odds of cigarette smoking, alcohol use, heavy drinking, lifetime cocaine use, e-cigarette use, and physical fighting compared to no use. Among gambling adolescents, early use was specifically linked to greater odds of prescription opiate misuse and any substance use. Gambling status modified associations with opiate misuse, substance use, school bullying, and forced sexual intercourse.","whyItMatters":"Early initiation of any substance is a well-known risk factor, but the interaction with gambling behavior suggests that adolescents who engage in multiple risk behaviors may face compounding vulnerabilities.","specificNumbers":"2,015 adolescents from 2019 YRBS. Early MU linked to higher odds of cigarette smoking, alcohol, heavy drinking, cocaine, e-cigarettes, and fighting. Gambling adolescents with early MU had greater odds of prescription opiate misuse. Gambling status moderated associations with opiate misuse, substance use, bullying, and forced sexual intercourse.","methodology":"Analysis of 2019 Youth Risk Behavior Surveillance survey data (n=2,015) examining relationships between early (<13 years), later (>=13 years), and no marijuana use with substance use and violence, stratified by gambling status. Adjusted multivariate logistic regression models.","limitations":"Cross-sectional survey design limits causal conclusions. Self-reported data from adolescents. YRBS is school-based, missing out-of-school youth. Gambling measure not standardized. Cannot determine directionality between marijuana use and other behaviors."},{"rthcId":"RTHC-07673","title":"Chitosan nanoparticles-encapsulated cannabis extracts and their antimicrobial potential against skin pathogens.","authors":"Skala, Tomáš; Ventura, Jordi; Morellá-Aucejo, Ángela; Fraňková, Adéla; Llopis-Lorente, Antoni; Bernardos, Andrea; Tauchen, Jan; Kahánková, Zdeňka; Hubka, Vít; Klouček, Pavel","year":2025,"journal":"Frontiers in medicine, 12, 1644502","doi":"10.3389/fmed.2025.1644502","pmid":"40917837","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07674","title":"Prenatal cannabis screening and counseling practices by state recreational legalization status: A multi-state examination of PRAMS data (2017-2020).","authors":"Skelton, Kara R; Iobst, Stacey E; Benjamin-Neelon, Sara E","year":2025,"journal":"Drug and alcohol dependence reports, 17, 100385","doi":"10.1016/j.dadr.2025.100385","pmid":"41098506","tags":["pregnancy","policy","public-health","clinical-practice"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Only 20.53% received guideline-adherent cannabis advice. Women in recreational legalization states were more often asked about cannabis (78.66% vs. 62.30%, p<0.001) and advised against use during pregnancy (44.29% vs. 37.06%, p<0.001) and lactation (31.03% vs. 25.50%, p<0.001). Notably, women who used cannabis prenatally were more likely to report being advised to use it (10.10% vs. 1.16%, p<0.001).","whyItMatters":"With prenatal cannabis use rising alongside legalization, consistent clinical guidance is critical. This study reveals that the majority of pregnant women do not receive guideline-adherent cannabis counseling, regardless of state legalization status.","specificNumbers":"Weighted N=742,491 across 9 states. 20.53% received guideline-adherent advice. RCL states: 78.66% asked about cannabis vs. 62.30% without RCL. 2.96% in RCL states advised to use cannabis vs. 1.45% without. 10.10% of prenatal cannabis users were advised to use vs. 1.16% of non-users.","methodology":"Repeated cross-sectional study using 2017-2020 Pregnancy Risk Assessment Monitoring System (PRAMS) data from 9 US states (weighted N=742,491). Examined cannabis screening and advice at prenatal visits, adherence to ACOG guidelines, and variation by recreational legalization status.","limitations":"Self-reported screening and advice may be subject to recall bias. Only 9 states included, limiting generalizability. Cannot determine quality or depth of counseling conversations. State-level legalization status may not capture local availability."},{"rthcId":"RTHC-07675","title":"Use of Medicinal Cannabis for Epilepsy in the Australian Community 2023-2024: A Cross-Sectional Survey.","authors":"Skene, Douglas A D; McGregor, Iain S; Todd, Lisa; Suraev, Anastasia","year":2025,"journal":"Journal of epilepsy research, 15(1), 56-69","doi":"10.14581/jer.25006","pmid":"40568058","tags":["epilepsy","medical-cannabis","policy","access"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Among 102 people with epilepsy, 27.5% used only illicit cannabis, 27.5% had transitioned to prescribed products, and 16.7% used both. Most caregivers (70.8%) used prescribed products only. 67% reported cannabis improved or greatly improved their epilepsy. Cost (69%) was the primary barrier. Most used cannabis as an adjunct to conventional anti-seizure medications (77%).","whyItMatters":"Eight years after legalizing medicinal cannabis, many Australian epilepsy patients still rely on illicit sources. Cost and THC-related driving laws appear to be significant barriers to legal access, creating a dual system with safety implications.","specificNumbers":"126 respondents (102 PWE, 24 caregivers). 27.5% illicit only. 27.5% transitioned to prescribed. 16.7% both. 70.8% of caregivers used prescribed only. 67% reported improvement. 77% used as adjunct. 69% cited cost as barrier. THC driving restrictions a major concern.","methodology":"Cross-sectional survey of 126 Australian respondents (102 people with epilepsy, 24 caregivers) examining medicinal cannabis use patterns, attitudes, access barriers, and routes of administration.","limitations":"Small, self-selected sample. No clinical verification of epilepsy type or seizure outcomes. Survey distributed through epilepsy and cannabis organizations, likely overrepresenting engaged users. Cross-sectional design."},{"rthcId":"RTHC-07676","title":"Experimental study on cannabis use and affect: Effects on reactivity to and recovery from negative stimuli.","authors":"Skrzynski, Carillon J; Rosa, Luiza; Drake, Austin; Bryan, Angela D; Bidwell, L Cinnamon","year":2025,"journal":"Journal of psychopathology and clinical science, 134(6), 639-650","doi":"10.1037/abn0001023","pmid":"40522823","tags":["anxiety","thc","cbd","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"All three cannabis conditions (THC-dominant, CBD-dominant, 1:1 ratio) showed greater emotional reactivity to a rumination task but also stronger recovery after a breathing exercise compared to the non-use condition. THC products elevated heart rate compared to CBD and non-use. CBD did not change heart rate relative to non-use. Effects were observed after 4 weeks of ad libitum use.","whyItMatters":"This is one of the few extended-use experimental studies comparing different cannabinoid profiles for anxiety. The finding that cannabis increases both reactivity and recovery complicates simple claims about cannabis either helping or harming anxiety.","specificNumbers":"499 participants with mild+ anxiety. 4 weeks ad libitum use. THC-dominant (n=152), CBD-dominant (n=163), 1:1 (n=140), no use (n=44). All cannabis conditions: greater reactivity and recovery vs. non-use. THC elevated HR vs. CBD and non-use. CBD did not change HR vs. non-use.","methodology":"Experimental study with 499 individuals with at least mild anxiety (66% female, 68% White) assigned to 4 weeks of ad libitum use of THC-dominant (n=152), CBD-dominant (n=163), 1:1 ratio (n=140), or no product (n=44). Baseline and post-use sessions measured affect and heart rate before and after a rumination task and breathing recovery exercise. Three-level mixed effect models analyzed outcomes.","limitations":"Non-randomized product assignment (ad libitum use). Very small non-use control group (n=44). Products were not standardized pharmaceutical preparations. No blinding. Self-selected anxious population. 4-week window may not capture longer-term effects."},{"rthcId":"RTHC-07677","title":"Longitudinal study of risk factors predicting cannabis use disorder in UK young adults and adolescents.","authors":"Skumlien, Martine; Jones, Darcy; Mokrysz, Claire; Lees, Rachel; Petrilli, Kat; Ofori, Shelan; Lawn, Will; Curran, H Valerie; Freeman, Tom P","year":2025,"journal":"Communications medicine, 5(1), 300","doi":"10.1038/s43856-025-01018-y","pmid":"40683963","tags":["youth","substance-use","epidemiology","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Adolescent age (OR 3.26, p<0.001) and baseline CUD (OR 45.15, p<0.001) predicted higher CUD levels at 12-month follow-up. Frequency of use, gender, problematic alcohol use, tobacco use, negative life events, and COVID-19 lockdown did not significantly predict CUD severity.","whyItMatters":"Identifying who is most vulnerable to cannabis use disorder is critical for targeted prevention. This study's finding that age matters more than use frequency challenges assumptions about what drives problematic cannabis use.","specificNumbers":"232 participants (50% adolescent, 50% young adult). 12-month follow-up. Adolescent OR=3.26 (p<0.001). Baseline CUD OR=45.15 (p<0.001). Days/week of use, gender, alcohol, tobacco, life events, and COVID lockdown were not significant predictors.","methodology":"Longitudinal study from the London-based CannTeen study following 232 adolescents (16-17) and young adults (26-29) for 12 months (48%/52% male/female). Half used cannabis 1-7 days/week at baseline. CUD measured via Mini Neuropsychiatric Interview for DSM-5. Ordinal logistic regression tested 8 potential risk factors.","limitations":"Moderate sample size (232). London-based sample may not generalize broadly. CannTeen study design selected for specific use patterns. 12-month follow-up may not capture longer-term trajectories. COVID-19 may have affected both groups' behaviors."},{"rthcId":"RTHC-07678","title":"Involuntary intoxication caused by vaping the synthetic cannabinoid ADB-BUTINACA: A case report.","authors":"Slob, Elise M A; Lyousoufi, Maryam; Pasha, Sharif; Wilms, Erik B","year":2025,"journal":"Toxicology reports, 14, 101930","doi":"10.1016/j.toxrep.2025.101930","pmid":"39980661","tags":["synthetic-cannabinoids","safety","emergency-medicine"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Standard point-of-care drug tests were negative, but advanced LC-QTOF-MS analysis detected ADB-BUTINACA in the e-cigarette liquid. The patient experienced headache, nausea, vertigo, red eyes, and palpitations after vaping. This represents involuntary intoxication from an undisclosed synthetic cannabinoid in a commercial e-cigarette product.","whyItMatters":"E-cigarettes can contain undisclosed psychoactive substances that standard drug tests cannot detect. This case highlights the risk of involuntary intoxication and the limitations of routine screening in emergency settings.","specificNumbers":"1 patient, age 27. Symptoms: headache, nausea, vertigo, red eyes, palpitations. Point-of-care drug test: negative. LC-QTOF-MS: positive for ADB-BUTINACA in e-cigarette liquid.","methodology":"Case report of a 27-year-old man presenting to the emergency department. Point-of-care recreational drug testing was performed, followed by liquid chromatography-quadrupole time-of-flight mass spectrometry analysis of the e-cigarette liquid.","limitations":"Single case report. Cannot determine how widespread e-cigarette contamination is. No long-term follow-up. Unclear source of the e-cigarette liquid or how the synthetic cannabinoid was introduced."},{"rthcId":"RTHC-07679","title":"Pain Is Not a Predictor of Cannabis Use in People With Psychotic Disorders.","authors":"Smid, Mirjam H; Bruins, Jojanneke","year":2025,"journal":"Journal of dual diagnosis, 21(3), 183-190","doi":"10.1080/15504263.2025.2517176","pmid":"40709617","tags":["psychosis","pain","mental-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Pain and interference from pain were not significant predictors of cannabis use (yes/no) or amount of cannabis use in people with psychotic disorders. However, use of antipsychotics with low sedating effects was associated with greater cannabis use (p=0.028). 59% of the sample experienced some pain and 18.5% used cannabis.","whyItMatters":"The assumption that people with psychosis might use cannabis to self-medicate pain was not supported. Instead, the link between less-sedating antipsychotics and greater cannabis use raises questions about whether some patients use cannabis for sedation or relaxation that their medications do not provide.","specificNumbers":"108 participants. 59% experienced some pain. 18.5% used cannabis. Pain: not a significant predictor. Low-sedation antipsychotics: associated with greater cannabis use (p=0.028). Covariates: age, sex, psychosis severity, sedating medication.","methodology":"Cross-sectional analysis of 108 Dutch people with psychotic disorders from the VAT observational cohort. Regression models tested whether pain (RAND-36-SF items) predicted cannabis use, controlling for age, sex, psychosis severity, and sedating antipsychotic use.","limitations":"Small sample size (108). Cross-sectional design. Self-reported pain and cannabis use. Dutch sample may not generalize. Cannabis may effectively suppress pain, making users report less pain (reverse causation). Single-site cohort study."},{"rthcId":"RTHC-07680","title":"Deletion of Endocannabinoid Synthesizing Enzyme DAGLα in Pcp2-Positive Cerebellar Purkinje Cells Decreases Depolarization-Induced Short-Term Synaptic Plasticity, Reduces Social Preference, and Heightens Anxiety.","authors":"Smith, Gabriella; McCoy, Kathleen; Di Prisco, Gonzalo Viana; Kuklish, Alexander; Grant, Emma; Bhat, Mayil; Patel, Sachin; Mackie, Ken; Atwood, Brady; Kalinovsky, Anna","year":2025,"journal":"eNeuro, 12(7)","doi":"10.1523/ENEURO.0400-24.2025","pmid":"40523777","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07681","title":"Weight Loss and Therapeutic Metabolic Effects of Tetrahydrocannabivarin (THCV)-Infused Mucoadhesive Strips.","authors":"Smith, Gregory L","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(1), 109-120","doi":"10.26828/cannabis/2024/000206","pmid":"39968488","tags":["thcv","metabolism","clinical-trial","weight"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"THCV/CBD oral strips produced statistically significant weight loss, decreased abdominal girth, reduced systolic blood pressure, and lowered total and LDL cholesterol compared to placebo. The higher dose (16 mg THCV/20 mg CBD) was superior to the lower dose (8 mg THCV/10 mg CBD) for weight loss, and both differed significantly from placebo.","whyItMatters":"THCV is a CB1 neutral antagonist, and this is among the first human trials testing whether its proposed metabolic effects translate to actual weight loss and metabolic improvements in a controlled setting.","specificNumbers":"44 subjects, 90 days. Low dose: 8 mg THCV/10 mg CBD. High dose: 16 mg THCV/20 mg CBD. Both doses: significant weight loss vs. placebo. High dose superior to low dose for weight loss. Significant decreases in abdominal girth, systolic BP, total and LDL cholesterol.","methodology":"Placebo-controlled study of 44 subjects (31 females, 13 males, average age 51.75) evaluating two doses of THCV/CBD via mucoadhesive oral strips taken once daily for 90 days. Outcomes included weight, abdominal girth, blood pressure, and cholesterol.","limitations":"Very small sample size (44 total, even smaller per group). No details on randomization or blinding methodology. Combined THCV with CBD, so individual contributions are unclear. 90-day follow-up does not address long-term sustainability. Limited demographic diversity."},{"rthcId":"RTHC-07682","title":"Alcohol and substance use differentially impact suicidal ideation in a longitudinal cohort of bipolar disorder.","authors":"Smith, Julia L; McInnis, Melvin G; Sperry, Sarah H","year":2025,"journal":"Psychiatry research, 344, 116357","doi":"10.1016/j.psychres.2025.116357","pmid":"39793525","tags":["mental-health","bipolar-disorder","substance-use"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"When a person had more frequent and intense cannabis use compared to their average, they had higher suicidal ideation at the next timepoint. Alcohol and substance use impairment also predicted future suicidal ideation. Cocaine frequency/intensity and substance use impairment were concurrently associated with suicidal ideation.","whyItMatters":"Suicidal ideation is a major concern in bipolar disorder. This study provides prospective evidence that within-person increases in cannabis use precede worsening suicidal thoughts, which has implications for monitoring and clinical guidance.","specificNumbers":"788 participants with BSD. Median enrollment: 72 months. BD I: n=565, BD II: n=162, BD NOS: n=61. Cannabis use intensity/frequency predicted next-timepoint SI. Alcohol/substance impairment predicted next-timepoint SI. Cocaine I/F concurrently associated with SI.","methodology":"Longitudinal cohort of 788 participants with bipolar I (n=565), bipolar II (n=162), and BD NOS (n=61) with median enrollment of 72 months. Alcohol and substance use measured via modified AUDIT every 6 months. Suicidal ideation measured via PHQ-9 item 9 every 2 months. Dynamic structural equation models tested prospective associations.","limitations":"Observational design cannot establish causation. Cannabis use measured every 6 months while SI measured every 2 months, creating temporal resolution mismatch. Self-reported substance use. Potential for reverse causation (increased SI driving cannabis use)."},{"rthcId":"RTHC-07683","title":"The cannabis-mind connection: a clinician's perspective on mental health practice, harm reduction, and racial equity.","authors":"Smith, Paulette S; Sera, Leah","year":2025,"journal":"Journal of cannabis research, 7(1), 102","doi":"10.1186/s42238-025-00360-1","pmid":"41275252","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07684","title":"Clinical and Cognitive Improvement Following Treatment with a Hemp-Derived, Full-Spectrum, High-Cannabidiol Product in Patients with Anxiety: An Open-Label Pilot Study.","authors":"Smith, Rosemary T; Dahlgren, Mary Kathryn; Sagar, Kelly A; Kosereisoglu, Deniz; Gruber, Staci A","year":2025,"journal":"Biomedicines, 13(8)","doi":"10.3390/biomedicines13081874","pmid":"40868129","tags":["cbd","anxiety","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"Patients reported significant reductions in anxiety symptoms over 6 weeks. Concurrent improvements in mood, sleep, and quality of life were observed, along with stable or improved performance on executive function and memory tests. Few side effects and no serious adverse events occurred.","whyItMatters":"While many commercial CBD products claim anxiety benefits, few have been tested in even basic clinical trials. This pilot provides initial clinical data on a product similar to what is commercially available.","specificNumbers":"12 patients with moderate-to-severe anxiety. 30 mg/day CBD for 6 weeks. Significant anxiety reduction. Improved mood, sleep, quality of life. Stable or improved cognition. No serious adverse events.","methodology":"Open-label pilot trial (NCT04286594) of 12 patients with at least moderate anxiety. Participants self-administered a hemp-derived, full-spectrum, high-CBD sublingual solution twice daily (target: 30 mg/day CBD) for 6 weeks. Assessments included anxiety, mood, sleep, quality of life, and neurocognitive measures.","limitations":"No placebo control or blinding. Only 12 participants. 6-week duration only. Full-spectrum product contains trace THC (<=0.3%), so effects cannot be attributed to CBD alone. Industry-relevant product tested in a very small sample."},{"rthcId":"RTHC-07685","title":"Unraveling the Enigma of Cannabinoid Hyperemesis Syndrome: A Narrative Review of Diagnosis and Management.","authors":"Smith, Shemyia A; Safwat, Mayar A; Piper, Brian J; Addison, Maame A","year":2025,"journal":"Cureus, 17(8), e90961","doi":"10.7759/cureus.90961","pmid":"41001336","tags":["gastrointestinal","adverse-effects","clinical-practice"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Standard antiemetics like ondansetron often fail to alleviate CHS symptoms. Haloperidol and topical capsaicin have shown more promise in reducing symptoms. Cannabis cessation remains essential for resolution. The challenge of predicting who will develop CHS and reaching those resistant to stopping cannabis remains a pressing research need.","whyItMatters":"CHS is increasingly common as cannabis use rises, and its symptoms overlap with other GI disorders, leading to misdiagnosis and frequent ED visits. Knowing which treatments actually work can reduce unnecessary testing and improve patient outcomes.","specificNumbers":"Standard antiemetics: often ineffective. Haloperidol: shows promise. Topical capsaicin: shows promise. Cannabis cessation: essential for resolution.","methodology":"Narrative review exploring current and emerging treatments for CHS, including diagnosis challenges, treatment strategies, and research gaps.","limitations":"Narrative review without systematic search methodology or quality assessment. Treatment evidence is based largely on case reports and small series. Cannot determine treatment effect sizes or compare treatments quantitatively."},{"rthcId":"RTHC-07686","title":"Mothers Marketing to Mothers: An Exploration of Cannabis Use and Constructions of Motherhood on Instagram and Blog Posts.","authors":"Smith, Tanner M; Kraft, Stella; Waugh, Anne; Harding, Kelly D; Bombak, Andrea; Riediger, Natalie D","year":2025,"journal":"Substance use : research and treatment, 19, 29768357251403255","doi":"10.1177/29768357251403255","pmid":"41376767","tags":["social-media","pregnancy","public-health","culture"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Three themes emerged: (1) normalizing cannabis by comparing it favorably to alcohol and pharmaceuticals, (2) positioning cannabis as responsible, personalized wellness consumption, and (3) framing cannabis as a tool to achieve motherhood ideals including thinness, productivity, mental wellness, and engaged parenting. Posts often functioned as marketing for cannabis products and coaching services.","whyItMatters":"Cannamom culture influences how mothers perceive cannabis safety and use, particularly in a post-legalization context. The marketing overlay complicates the wellness messaging, as product promotion is embedded within community support narratives.","specificNumbers":"30 blog posts and 34 Instagram posts analyzed. 3 inter-related themes identified. Posts came from Canadian cannamom content creators. Analysis conducted post-2018 Canadian legalization.","methodology":"Qualitative reflexive thematic analysis of Canadian cannamom blog posts (N=30) and Instagram posts (N=34), analyzed through lenses of influencer culture, wine mom culture, wellness movements, and mental health movements.","limitations":"Qualitative analysis of public social media content only. Cannot determine how these messages influence actual behavior. Small sample of posts. Canadian context may not generalize. Selection methodology for posts not fully detailed."},{"rthcId":"RTHC-07687","title":"The roles of cannabis potency and gender in cannabis dependence and anxiety in recent cannabis users with trauma exposure histories.","authors":"Snooks, T; Stewart, S H; Romero-Sanchiz, P; DeGrace, S; Barrett, S P; Bernusky, H C R; Tibbo, P G","year":2025,"journal":"Pharmacological research, 212, 107586","doi":"10.1016/j.phrs.2025.107586","pmid":"39828102","tags":["potency","dependence","anxiety","gender"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis potency measured as relative THC proportion (THC%/[THC%+CBD%]) was significantly correlated with cannabis dependence (p=0.002) and anxiety (p=0.020). The traditional THC:CBD ratio did not predict these outcomes. Women reported higher anxiety and higher THC:CBD ratios than men. No gender differences were found in potency-outcome associations, consistent with recent reports of gender convergence.","whyItMatters":"How cannabis potency is measured matters for research. This study demonstrates that relative THC proportion is a superior predictor of adverse outcomes compared to the commonly used THC:CBD ratio, which could improve future research methodology.","specificNumbers":"202 participants, 55.8% women, all with trauma histories. THC proportion: significant for dependence (p=0.002) and anxiety (p=0.020). THC:CBD ratio: not significant. Women: higher anxiety and higher THC:CBD ratios. No gender interaction with potency measures.","methodology":"Cross-sectional online survey of 202 recent cannabis users (>1g in past month, 55.8% women) with trauma histories. Self-reported THC and CBD levels in typical products. Potency calculated two ways: THC:CBD ratio and THC proportion. CUDIT-R measured dependence; GAD-7 measured anxiety.","limitations":"Self-reported THC and CBD levels may be inaccurate. Cross-sectional design. Trauma-exposed sample may not generalize. Cannot determine causation. Relatively small sample for detecting gender interactions."},{"rthcId":"RTHC-07688","title":"Full-spectrum cannabis extracts for women with chronic pain syndromes: a real-life retrospective report of multi-symptomatic benefits after treatment with individually tailored dosage schemes.","authors":"Soares Silva, Patrícia Montagner; Medeiros, Wesley; Nogueira Borges, Clarissa; Brasil-Neto, Joaquim P; Lessa, Wilson; Ferreira de Oliveira E Silva, Ricardo; Caixeta, Fabio V; Malcher-Lopes, Renato","year":2025,"journal":"Frontiers in pharmacology, 16, 1538518","doi":"10.3389/fphar.2025.1538518","pmid":"41357862","tags":["chronic-pain","medical-cannabis","womens-health","clinical-outcomes"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"All 29 patients reported some pain relief. Most reported improvements in cognitive function, motor abilities, professional activities, irritability, anxiety, fatigue, and sleep quality. Most reduced or ceased analgesic and psychiatric medications. No patients discontinued due to adverse effects. Optimal CBD-to-THC proportions varied considerably with no clear link to pain types.","whyItMatters":"Women experience chronic pain differently due to sex-specific differences in pain perception and cannabinoid pharmacology. This study focuses specifically on female patients with individually tailored dosing, an approach that may be more realistic than fixed-dose trials.","specificNumbers":"29 female patients. All reported some pain relief. Most improved across cognitive, motor, mood, fatigue, and sleep domains. Most reduced or stopped analgesic and psychiatric medications. Zero discontinuations due to adverse effects. Optimal dosing varied considerably across patients.","methodology":"Retrospective open-label cross-sectional study of 29 female chronic pain patients who received full-spectrum cannabis extracts with standardized compositions from patient-led civil societies. Individually tailored dosing based on clinical assessments. Outcomes via comprehensive online patient-reported survey.","limitations":"No control group. Retrospective self-report. Only 29 patients. Patient-led civil society sourced products. Self-selected participants likely biased toward positive experiences. No standardized outcome measures."},{"rthcId":"RTHC-07689","title":"Endocannabinoid system in periodontitis: A systematic review and in silico analyses.","authors":"Soares, Lélio Fernando Ferreira; Oliveira, Jovânia Alves; Nogueira, Andressa Vilas Boas; Júnior, Carlos Rossa; Pigossi, Suzane Cristina; Deschner, James; Cirelli, Joni Augusto","year":2025,"journal":"Archives of oral biology, 179, 106394","doi":"10.1016/j.archoralbio.2025.106394","pmid":"40966850","tags":["endocannabinoid-system","oral-health","inflammation","systematic-review"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"CNR2 (CB2) gene expression was significantly reduced in periodontitis tissue. Animal studies showed CB2 activation increased receptor expression, reduced pro-inflammatory cytokines, and mitigated alveolar bone loss. CB1 activation also reduced inflammation and bone loss. Bioinformatics analysis revealed CB1 and CB2 have distinct but complementary roles in periodontal inflammation.","whyItMatters":"Periodontitis affects a large portion of the global population and can lead to tooth loss. Identifying the endocannabinoid system as a modulator of gum inflammation opens a new therapeutic avenue that could complement existing treatments.","specificNumbers":"9 studies included (3 clinical, 6 preclinical). 5 databases searched. CNR2 expression significantly reduced in periodontitis. CB2 activation reduced cytokines and bone loss in animals. Anandamide showed anti-inflammatory effects. CNR1 positively associated with B-cell activation genes. CNR2 correlated with immune regulation and extracellular matrix remodeling.","methodology":"Systematic review searching PubMed/MEDLINE, Embase, Web of Science, Scopus, and Cochrane Library for studies on periodontitis and endocannabinoid system through August 2024. 9 studies met inclusion criteria (3 clinical, 6 preclinical). Supplemented with in silico analysis using GSE16134 dataset for gene expression and pathway analysis.","limitations":"Only 9 studies met criteria, mostly preclinical. Heterogeneous study designs. Clinical studies were small. In silico analyses are hypothesis-generating, not confirmatory. No clinical trials of cannabinoid-based periodontal treatments exist."},{"rthcId":"RTHC-07690","title":"Self-administered complementary and alternative methods of treating mental disorders among students in Wrocław: a cross-sectional study.","authors":"Sobieraj, Jakub; Sleziak, Jakub; Szyszka, Michał; Błażejewska, Marta; Łukańko, Kamila; Soczomska, Pola; Bodziony, Kinga; Piotrowski, Patryk","year":2025,"journal":"Frontiers in public health, 13, 1734137","doi":"10.3389/fpubh.2025.1734137","pmid":"41584153","tags":["mental-health","youth","public-health","substance-use"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"31.3% of students used marijuana as a complementary therapy. Marijuana users presented more intense depressive symptoms on PHQ-10. Marijuana use was more prevalent among yoga practitioners and students with ADHD. Students who engaged with professional healthcare also had higher marijuana usage. Cost (80.7%), availability (35.7%), and stigma (30.7%) were the main barriers to professional care.","whyItMatters":"The high prevalence of marijuana self-medication among students, often alongside rather than instead of professional care, highlights gaps in accessible mental health services and the need for clinical awareness of students' actual treatment behaviors.","specificNumbers":"493 students surveyed. 46.5% had mental health disorder history. 31.3% used marijuana. 96.1% used any CAM method. 80.7% cited cost as barrier to professional care. Marijuana users had more intense depressive symptoms. More prevalent in yoga practitioners and ADHD students.","methodology":"Cross-sectional survey of 493 students from Wroclaw universities (April-December 2024) assessing mental health history, CAM use, attitudes toward treatments, and depressive symptoms via PHQ-10-modeled questions.","limitations":"Cross-sectional design prevents causal conclusions. Self-reported mental health and substance use. Single-city university sample. Cannot determine if marijuana use worsens or follows from depression. CAM survey developed specifically for this study, not validated."},{"rthcId":"RTHC-07691","title":"Impact of cannabis consumption on perioperative outcomes in patients undergoing hepatobiliary and pancreatic surgery: a nationwide analysis.","authors":"Sohail, Amir H; Quazi, Mohammed A; Sheikh, Abu B; Greenbaum, Alissa; Nir, Itzhak; Hernandez, Matthew C","year":2025,"journal":"HPB : the official journal of the International Hepato Pancreato Biliary Association, 27(7), 981-987","doi":"10.1016/j.hpb.2025.04.006","pmid":"40324909","tags":["surgery","safety","clinical-outcomes"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis users (0.89% of 191,315 patients) had no significant differences in in-hospital mortality, acute kidney injury, blood transfusion, mechanical ventilation, venous thromboembolism, surgical site infection, or other major complications compared to non-users. Cannabis users had significantly lower odds of pneumonia (OR 0.54, 95% CI 0.29-0.99). No differences in length of stay or hospitalization costs.","whyItMatters":"Surgeons and anesthesiologists need to know whether cannabis use affects surgical outcomes. This national database analysis provides reassurance that cannabis use does not appear to worsen major perioperative complications after complex abdominal surgery.","specificNumbers":"191,315 patients total. 1,705 cannabis users (0.89%). Pneumonia: OR 0.54 (CI 0.29-0.99). No significant difference in mortality (OR 0.64, CI 0.31-1.30). No difference in LOS (10.99 vs 9.69 days, p=0.348) or costs ($49,444 vs $43,661, p=0.109).","methodology":"Retrospective analysis of the Nationwide Inpatient Sample (2016-2020). 191,315 HPB surgery patients identified, 1,705 (0.89%) with cannabis use. Multivariate analysis adjusted for demographics and comorbidities compared complications, length of stay, and costs.","limitations":"Administrative database with ICD coding limitations. Cannabis use likely underreported. Cannot determine dose, frequency, or recency of use. Healthy user bias possible. Cannot distinguish between active and former users. Observational design."},{"rthcId":"RTHC-07692","title":"Cannabis Use and Outcomes in Patients with Chronic Pancreatitis: A National Inpatient Sample Analysis.","authors":"Sohal, Aalam; Thind, Nuhar; Billing, Harbir Singh; Iqbal, Humzah; Menon, Rohan; Kumar, Vikash; Sohal, Aalam; Yang, Juliana","year":2025,"journal":"Journal of gastrointestinal and liver diseases : JGLD, 34(2), 220-226","doi":"10.15403/jgld-6066","pmid":"40580529","tags":["gastrointestinal","inflammation","clinical-outcomes"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis use was associated with decreased odds of mortality (aOR 0.47, p<0.001), DVT (aOR 0.71, p<0.001), pulmonary embolism (aOR 0.622, p=0.002), ICU admission (aOR 0.705, p<0.001), and pancreatic cancer (aOR 0.730, p=0.021). No differences in AKI, sepsis, or acute pancreatitis between groups.","whyItMatters":"Cannabis has known anti-inflammatory and analgesic properties. This large database study suggests cannabis use may be associated with reduced disease severity in chronic pancreatitis, though confounding factors make causal interpretation difficult.","specificNumbers":"907,790 patients total. 52,360 cannabis users (5.8%). Mortality: aOR 0.47 (p<0.001). DVT: aOR 0.71 (p<0.001). PE: aOR 0.622 (p=0.002). ICU admission: aOR 0.705 (p<0.001). Pancreatic cancer: aOR 0.730 (p=0.021). No difference in AKI, sepsis, or acute pancreatitis.","methodology":"Retrospective analysis of the Nationwide Inpatient Sample (2016-2020). 907,790 chronic pancreatitis patients identified, 52,360 (5.8%) cannabis users. Multivariate logistic regression adjusted for confounding factors.","limitations":"Administrative database with coding limitations. Cannabis use likely underreported. Healthy user bias probable. Cannot determine causation. No data on dose, frequency, or type of cannabis. Unmeasured confounders likely."},{"rthcId":"RTHC-07693","title":"Changes in prenatal cannabis use and perceptions during the COVID-19 pandemic.","authors":"Sokol, Natasha A; Sharma, Eva; Joseph, Janet O; Johnson, Janet A J; Stroud, Laura R","year":2025,"journal":"Drug and alcohol dependence reports, 16, 100348","doi":"10.1016/j.dadr.2025.100348","pmid":"40546689","tags":["pregnancy","covid-19","public-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"During vs. before the pandemic, pregnant cannabis users were more likely to use for vomiting, depression, chronic illness, pain, sleep, and appetite (all RR>2.0, p<=0.020). They were more likely to use edibles (RR 1.72, p=0.023), less likely to smoke with tobacco (RR 0.69, p=0.009), and more likely to report physician-recommended use (RR 2.2, p=0.075). They were also more likely to have attempted to quit or reduce use (RR 1.14, p=0.047).","whyItMatters":"The COVID-19 pandemic disrupted prenatal care and increased stress, and this study shows those disruptions shifted both why and how pregnant women used cannabis, with implications for future public health emergencies.","specificNumbers":"136 participants who used cannabis during pregnancy. >2x more likely during pandemic to use for vomiting, depression, pain, sleep, appetite. Edible use: RR 1.72. Physician-recommended: RR 2.2. Attempted to quit/reduce: RR 1.14. Smoking with tobacco: RR 0.69.","methodology":"Prospective cohort study recruiting first-trimester participants from 2018-2022 (N=136 who ever used cannabis during pregnancy). Surveys in first and second trimesters assessed cannabis use patterns, reasons, and perceptions. Pre-pandemic vs. during-pandemic groups compared.","limitations":"Small sample (136). Self-reported cannabis use. Cannot determine if pandemic-era users had more symptoms or just different coping strategies. Selection bias from research participation. Pre/during pandemic groups may differ on unmeasured factors."},{"rthcId":"RTHC-07694","title":"Natural Powerhouse Duo: Hierarchical Levan Hydrogels with Nanoencapsulated Cannabidiol as Local Delivery Systems.","authors":"Solovyov, Diana; Porfiryeva, Natalia N; Awad, Rania; Tornaci, Selay; Davidovich-Pinhas, Maya; Salms, Girts; Dubnika, Arita; Öner, Ebru Toksoy; Sosnik, Alejandro","year":2025,"journal":"Pharmaceutical research, 42(12), 2291-2307","doi":"10.1007/s11095-025-03935-y","pmid":"41219565","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07695","title":"Global prevalence of cannabis and amphetamine/methamphetamine use among adolescents in 47 countries: a population-based study from WHO database.","authors":"Son, Yejun; Hong, Seohyun; Yim, Yesol; Kim, Soeun; Lee, Hojae; Lee, Kyeongmin; Kim, Hyeon Jin; Jo, Hyesu; Park, Jaeyu; Oh, Jiyeon; Lee, Sooji; Lee, Hayeon; Nehs, Christa J; Smith, Lee; Yon, Dong Keon; Kang, Jiseung","year":2025,"journal":"World journal of pediatrics : WJP, 21(3), 291-305","doi":"10.1007/s12519-025-00883-w","pmid":"40108046","tags":["youth","epidemiology","public-health","global-health"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Global cannabis use prevalence was 7.02% (95% CI 6.16-7.89). Boys: 9.20% vs. girls: 4.20%. Americas had highest cannabis prevalence (11.31%). Africa had highest amphetamine use (4.34%). High-income countries: 9.45% cannabis prevalence vs. low-income: 3.46%. Higher rates associated with higher homicide rates, better sanitation, and higher health expenditures.","whyItMatters":"This is one of the most comprehensive global assessments of adolescent cannabis use, filling a critical gap in data from low- and middle-income countries that have been underrepresented in previous research.","specificNumbers":"220,362 adolescents across 47 countries. Overall cannabis: 7.02%. Boys: 9.20%, Girls: 4.20%. Americas: 11.31%. High-income: 9.45%. Low-income: 3.46%. Amphetamine: 4.05%. Africa highest amphetamine: 4.34%.","methodology":"Meta-analysis using Global School-based Student Health Survey data from 47 countries (2009-2018). 220,362 adolescents aged 12-15. Random-effects models estimated prevalence. Stratification by sex, World Bank income category, region, and country characteristics.","limitations":"School-based surveys miss out-of-school adolescents. Self-reported use may underestimate prevalence. Data from 2009-2018, so more recent trends are not captured. Aggregating across diverse countries may mask important within-country variation."},{"rthcId":"RTHC-07696","title":"The DEC2-SCN2A Axis is Essential for the Anticonvulsant Effects of Cannabidiol by Modulating Neuronal Plasticity.","authors":"Song, Huifang; Wang, Yifan; Wang, Lili; Guo, Chang; Liu, Shiqi; Rong, Yi; Tian, Jiawen; Peng, Chao; Shao, Yuying; Ma, Zhixiong; Li, Na; Zhang, Jingliang; Peng, Zijun; Yan, Xu; Fa, Hangwei; Ma, Xinyue; Dong, Jie; Ji, Jinping; Yang, Chen; Chen, Haocheng; Liang, Jing; Sun, Qi; Yang, Yang; Ma, Weining; Huang, Zhuo","year":2025,"journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12(36), e16315","doi":"10.1002/advs.202416315","pmid":"40641288","tags":["cbd","epilepsy","laboratory","pharmacology"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"DEC2 acts as a transcriptional repressor of SCN2A by binding to class B E-boxes in its promoter. DEC2 knockdown increased neuronal excitability and worsened seizures, while overexpression reduced both. CBD enhances DEC2's repression of SCN2A. DEC2 also forms complexes with MYOD1 at different E-boxes but this does not affect SCN2A transcription in vivo.","whyItMatters":"Understanding how CBD actually works against seizures has been a longstanding question. This study identifies a specific molecular pathway (DEC2-SCN2A) that could lead to more targeted anti-epileptic therapies.","specificNumbers":"DEC2 knockdown: elevated excitability and seizure susceptibility. DEC2 overexpression: reduced excitability and seizures. DEC2 binds CACGTG E-boxes in SCN2A promoter. CBD enhances DEC2 repression of SCN2A. MYOD1 complex at CAGCTG E-boxes does not affect SCN2A in vivo.","methodology":"Combination of molecular biology experiments in hippocampal neurons including DEC2 knockdown and overexpression, electrophysiology, seizure models, chromatin immunoprecipitation, and CBD treatment to assess the DEC2-SCN2A axis.","limitations":"Primarily in vitro and animal model work. Translation to human epilepsy not confirmed. The DEC2-SCN2A axis may be one of multiple mechanisms through which CBD acts. Dose-response relationships not fully characterized."},{"rthcId":"RTHC-07697","title":"Promotion of recovery from Traumatic Brain Injury (TBI) by Granulocyte Colony-Stimulating Factor (G-CSF) treatment requires cannabinoid receptor type 2 activity.","authors":"Song, Shijie; Wang, Bangmei; Kong, Xiaoyuan; Patel, Niketa; Sanchez-Ramos, Juan; Kindy, Mark S","year":2025,"journal":"Journal of cannabis research, 7(1), 61","doi":"10.1186/s42238-025-00305-8","pmid":"40826145","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07698","title":"A Meta-Narrative Review of Channelopathies and Cannabis: Mechanistic, Epidemiologic, and Forensic Insights into Arrhythmia and Sudden Cardiac Death.","authors":"Šoša, Ivan","year":2025,"journal":"International journal of molecular sciences, 26(17)","doi":"10.3390/ijms26178635","pmid":"40943555","tags":["cardiovascular","safety","genetics"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids affect calcium and potassium currents through both receptor-dependent and -independent pathways, alter autonomic regulation, and promote oxidative stress and inflammation in heart tissue. Genetic variants in SCN5A, KCNH2, KCNQ1, RYR2, and NOS1AP can create subclinical vulnerabilities that become lethal when combined with cannabinoid-induced electrical disruptions, especially from high-potency synthetic cannabinoids.","whyItMatters":"Most cannabis safety discussions focus on mental health or respiratory effects. This review highlights an underappreciated cardiovascular risk, particularly for people with undiagnosed genetic heart conditions who may not know they are at elevated risk.","specificNumbers":"Key genes: SCN5A, KCNH2, KCNQ1, RYR2, NOS1AP. Cannabinoids affect calcium and potassium currents. Synthetic cannabinoids pose highest risk. Forensic cases document sudden cardiac death linked to cannabinoid exposure in genetically vulnerable individuals.","methodology":"Meta-narrative review consolidating molecular, clinical, epidemiological, and forensic evidence linking cannabinoid exposure to arrhythmias and sudden cardiac death, including analysis of genetic risk factors.","limitations":"Narrative review without systematic methodology. Many findings based on case reports and forensic analyses. Prevalence of cannabinoid-triggered cardiac events is unknown. Genetic testing is not widely available or standardized for this purpose."},{"rthcId":"RTHC-07699","title":"Polygenic Risk for Substance Use Disorders as Predictors of Substance Use Initiation Among African American Youth.","authors":"Sosnowski, David W; Rabinowitz, Jill A; Feder, Kenneth A; Strickland, Justin C; Hancock, Dana B; Uhl, George R; Ialongo, Nicholas S; Maher, Brion S","year":2025,"journal":"Journal of studies on alcohol and drugs, 86(4), 530-541","doi":"10.15288/jsad.23-00397","pmid":"40577074","tags":["genetics","youth","substance-use","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis use disorder and nicotine dependence polygenic risk scores were not associated with initiation of these substances. Unexpectedly, higher alcohol use disorder PRS predicted later alcohol initiation (HR 0.78). For cannabis, high parental monitoring was associated with earlier initiation among those with high genetic risk, while low monitoring predicted earlier initiation among those with low genetic risk.","whyItMatters":"Most genetic risk studies are conducted in European-ancestry populations. This study provides critical data on whether polygenic risk scores derived from current research predict substance use in African American youth, where they largely did not.","specificNumbers":"1,017 participants, 56% female. CUD PRS: not significant for cannabis initiation. Nicotine PRS: not significant. AUD PRS: HR 0.78 (later alcohol initiation). CUD PRS x monitoring interaction: high PRS + high monitoring = earlier cannabis; low PRS + low monitoring = earlier cannabis.","methodology":"Longitudinal study of 1,017 African American participants (56% female) from an elementary school prevention trial. At age 20, substance initiation ages were reported and genetic samples collected. At age 12, parental monitoring and census-tract disadvantage were measured. Cox Proportional Hazard Models tested PRS and environment interactions.","limitations":"PRS derived largely from European-ancestry GWAS may perform poorly in African American populations. Self-reported initiation ages subject to recall bias. Parental monitoring measured at age 12 may not capture later changes. Single geographic region."},{"rthcId":"RTHC-07700","title":"Medical cannabis for the management of pain in chronic pancreatitis with recurrent exacerbations: a case report.","authors":"Spaccavento, Felice Antonio; De Virgilio Suglia, Cesare; Tafuri, Silvio; De Trizio, Angela; Giannuzzi, Rossella; Cavallera, Filomena; Turco, Fabio","year":2025,"journal":"Journal of cannabis research, 7(1), 55","doi":"10.1186/s42238-025-00303-w","pmid":"40781340","tags":["chronic-pain","gastrointestinal","medical-cannabis","clinical-practice"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"After 24 years of failed conventional treatments including cholecystectomy, enzyme supplementation, multiple ERCPs, and stent placements, a CBD-rich medical cannabis formulation led to substantial pain reduction, cessation of acute episodes, improved appetite, and enhanced quality of life.","whyItMatters":"Chronic pancreatitis pain is notoriously difficult to manage, and this case illustrates medical cannabis as a potential option when conventional treatments fail, consistent with the larger NIS database findings.","specificNumbers":"1 patient, age 54. 24-year disease history. Prior treatments: cholecystectomy, enzyme supplementation, repeated ERCPs, stent placements. CBD-rich cannabis started February 2024. Outcomes: substantial pain reduction, cessation of acute episodes, improved appetite, enhanced quality of life.","methodology":"Case report of a 54-year-old woman with chronic pancreatitis caused by recurrent acute pancreatitis, Oddi sphincter stenosis, and microlithiasis. Treatment with CBD-rich medical cannabis was initiated in February 2024 under healthcare provider supervision after exhausting conventional options.","limitations":"Single case report. No control or comparison. Placebo effect possible. Specific CBD and THC doses and formulation details not provided in the abstract. No long-term follow-up described."},{"rthcId":"RTHC-07701","title":"Medical Patients' Awareness, Perspectives, and Experiences with Contaminated Cannabis.","authors":"Spandau, Gabriel; Loizzo, Jamie; Goodin, Amie; Bunch, James C; Stedman, Nicole; Pearson, Brian","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 166-180","doi":"10.1159/000546398","pmid":"41321441","tags":["safety","medical-cannabis","policy","consumer-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Respondents reported low knowledge of potential contaminants and lacked educational resources. 15% reported purchasing products they believed to be contaminated. 25% purchased products they were uncomfortable consuming due to quality issues. Trust was moderately higher for information from medical cannabis doctors and university researchers than state sources. Patients desired policy changes including home grow, increased testing, and pre-purchase product inspection.","whyItMatters":"Medical cannabis is intended for vulnerable patients who may have compromised immune systems or other health conditions. Contamination in these products poses direct health risks, and patients' low knowledge about contamination makes them especially vulnerable.","specificNumbers":"Recruited from 2,000-patient registry. 15% purchased suspected contaminated products. 25% purchased products they were uncomfortable consuming. Low contamination knowledge reported. Higher trust in doctors/researchers than state information. Policy desires: home grow, more testing, pre-purchase inspection.","methodology":"Cross-sectional survey of Florida medical cannabis patients over 21, recruited from a 2,000-patient contact registry. 24-item survey assessed experiences and perspectives on contamination, guided by the Health Belief Model framework. Hosted via Qualtrics.","limitations":"Survey sample from a single state (Florida). Self-reported experiences and beliefs. Response rate and representativeness not fully described. Contamination was not laboratory-verified. Patient beliefs about contamination may not reflect actual contamination rates."},{"rthcId":"RTHC-07702","title":"Correlates and trajectories of alcohol and cannabis misuse in the early phase of psychosis: Do we need substance specific interventions?","authors":"Spanevello, Carolina; Alameda, Luis; Solida, Alessandra; Empson, Lilith Abrahamyan; Alerci, Livia; Mebdouhi, Nadir; Conchon, Caroline; Vieira, Sandra; Golay, Philippe; Conus, Philippe","year":2025,"journal":"Schizophrenia research, 285, 349-359","doi":"10.1016/j.schres.2025.09.020","pmid":"41100961","tags":["psychosis","substance-use","clinical-outcomes","alcohol"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Alcohol users tended to maintain consumption over time, while some cannabis users reduced their use. Persistent alcohol users had the worst baseline characteristics and outcomes. Abstinent or light cannabis users consistently had better symptom outcomes than persistent or decreased users. However, cannabis decreasers showed higher hospitalization rates than other groups, though their negative symptoms gradually improved to levels similar to abstinent users by program end.","whyItMatters":"The finding that reducing cannabis use improved some but not all outcomes suggests that simply cutting back may not be sufficient for optimal recovery in first-episode psychosis, and that the trajectory of use matters for treatment planning.","specificNumbers":"467 FEP patients over 3 years. Alcohol users maintained consumption. Some cannabis users reduced. Abstinent/light cannabis users: best outcomes. Decreased cannabis users: higher hospitalization but improving negative symptoms. Persistent alcohol: worst outcomes.","methodology":"3-year early intervention program study of 467 first-episode psychosis patients. Latent class analysis identified cannabis and alcohol use trajectory subgroups. Logistic regressions and mixed-model repeated measures compared baseline characteristics and clinical outcomes across trajectory groups.","limitations":"Observational design limits causal inference. Self-reported substance use. Latent class analysis results are sample-dependent. Cannot determine if symptom changes caused use changes or vice versa. Single intervention program setting."},{"rthcId":"RTHC-07703","title":"Clinically Meaningful Reduction in Drop Seizures in Patients with Lennox-Gastaut Syndrome Treated with Cannabidiol: Post Hoc Analysis of Phase 3 Clinical Trials.","authors":"Specchio, Nicola; Auvin, Stéphane; Greco, Teresa; Lagae, Lieven; Nortvedt, Charlotte; Zuberi, Sameer M","year":2025,"journal":"CNS drugs, 39(10), 1025-1036","doi":"10.1007/s40263-025-01201-8","pmid":"40775196","tags":["cbd","epilepsy","clinical-trial","pediatrics"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Using CGIC of 'slightly improved' or better, the threshold for clinically meaningful drop seizure reduction was 30.6%, with 57.7% of patients meeting this threshold. With 'much improved' or better, the threshold was 49.6% (40.5% of patients). 60% of CBD-treated patients were rated as 'slightly improved' or better, and 31% as 'much improved' or better after 14 weeks. Spearman's correlation between CGIC and seizure reduction was 0.47.","whyItMatters":"Clinical trials typically use 50% seizure reduction as the success cutoff, but this analysis shows that caregivers perceived meaningful benefit at much smaller reductions (31%), suggesting the 50% threshold may undercount patients who genuinely benefit from treatment.","specificNumbers":"215 patients with LGS. 60% rated 'slightly improved' or better. 31% rated 'much improved' or better. Clinically meaningful threshold: 30.6% reduction (57.7% met it). 'Much improved' threshold: 49.6% (40.5% met it). Mean seizure reduction for 'slightly improved+': 46.9%. Spearman's correlation: 0.47.","methodology":"Post hoc analysis of 215 LGS patients receiving CBD (Epidiolex) from two phase 3 randomized placebo-controlled trials (NCT02224690 and NCT02224560). Drop seizure reduction anchored to Caregiver Global Impression of Change scores to determine clinically meaningful thresholds.","limitations":"Post hoc analysis with inherent limitations. CGIC is a single subjective rating. Only 14 weeks of data. Analysis of CBD-treated patients only (no placebo comparison for thresholds). Sample included wide age range (2-55 years). Exploratory nature limits definitive conclusions."},{"rthcId":"RTHC-07704","title":"Cannabis and Tobacco Product Use Classes and Psychosocial Correlates among US Young Adults.","authors":"Speer, Morgan; Cui, Yuxian; McCready, Darcey M; LoParco, Cassidy R; Romm, Katelyn F; Wang, Yan; Schubel, Laura C; Howlader, Afrah; Williams, Jessica; Thakkar, Shriya; Cavazos-Rehg, Patricia A; Berg, Carla J","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","doi":"10.1093/ntr/ntaf238","pmid":"41283850","tags":["substance-use","tobacco","youth","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Five classes: 'primarily cannabis' (36.6%), and four other patterns. The frequent poly-product class was associated with being Black or Hispanic, heterosexual identity, older age, male sex, more ACEs, more mental health symptoms, higher neuroticism, lower openness, and living in states without cannabis legalization.","whyItMatters":"Understanding distinct use patterns beyond simple 'user/non-user' categories helps target interventions. The finding that the heaviest use class overlaps with populations facing substance use disparities suggests prevention efforts need equity-focused approaches.","specificNumbers":"2,267 past-month cannabis/tobacco users. 5 classes identified. 'Primarily cannabis': 36.6%. 'Primarily e-cigarette': 5.5%. Poly-product class correlates: Black/Hispanic, more ACEs, more mental health symptoms, non-legalized states.","methodology":"Latent class analysis of 2023 data from 2,267 young adults aged 18-34 (purposively recruited via Facebook for ~50% past-month cannabis use). Indicators included cannabis, cigarette, and e-cigarette use frequency plus cigar, hookah, smokeless tobacco, and nicotine pouch use. Multivariable regressions tested correlates.","limitations":"Purposively recruited sample overrepresenting cannabis users. Facebook recruitment may miss some demographics. Cross-sectional design. Self-reported use. Class assignments are probabilistic, not definitive."},{"rthcId":"RTHC-07705","title":"Cannabis Social Equity Initiatives Across 5 US States Case Studies of Colorado, Washington, Massachusetts, Connecticut, and Missouri.","authors":"Speer, Morgan; Chakraborty, Rishika; Yang, Y Tony; LoParco, Cassidy R; Berg, Carla J","year":2025,"journal":"Journal of public health management and practice : JPHMP, 31(6), E315-E329","doi":"10.1097/PHH.0000000000002191","pmid":"40638921","tags":["policy","social-equity","legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Colorado, Washington, and Massachusetts implemented pardons while Connecticut and Missouri implemented expungement. All states reserved some licenses for social equity applicants and offered training programs, but eligibility criteria, financial support, and tax structures varied significantly. Revenue allocation across states funded program costs, general funds, and education/health initiatives differently.","whyItMatters":"Cannabis legalization was partly justified by correcting racial disparities in enforcement. These case studies reveal that while states are making efforts, the varied approaches and lack of evaluation make it unclear whether social equity goals are being achieved.","specificNumbers":"5 states analyzed: CO, WA, MA, CT, MO. 3 used pardons, 2 used expungement. All reserved some licenses for SE applicants. Varied tax structures (retail sales vs. excise). Revenue directed to program costs, general fund, health/education.","methodology":"Case study analysis of 5 states using a drug policy framework. Two researchers dual-coded cannabis-related social equity policies on expungements/pardons, entrepreneurship assistance, and revenue allocation as of December 2024.","limitations":"Policy analysis only, no outcome data on whether equity goals are being met. Policies documented as of December 2024 may have changed. Cannot assess implementation quality vs. policy on paper. Five states may not represent all approaches."},{"rthcId":"RTHC-07706","title":"Impact of Cannabis Legalization on Umbilical Cord Tissue Tetrahydrocannabinol Levels.","authors":"Spence, Kimberly; Milota, Sarah; Buchanan, Paula; Acharya, Nirja; Mathur, Amit M","year":2025,"journal":"American journal of perinatology, 42(9), 1206-1212","doi":"10.1055/a-2480-3163","pmid":"39572239","tags":["pregnancy","legalization","public-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"A higher percentage of umbilical cord tissue tested positive for THC after legalization (46.2% vs. 40.6%, p<0.05) and THC concentrations were significantly higher in the post-legalization period (p<0.001). This suggests both more fetuses were exposed and those exposed experienced higher levels.","whyItMatters":"Umbilical cord tissue provides an objective measure of fetal THC exposure, avoiding the limitations of self-report. This is direct evidence that legalization was associated with increased fetal cannabis exposure.","specificNumbers":"811 cords pre-legalization, 2,170 post-legalization. THC positivity: 40.6% vs. 46.2% (p<0.05). THC concentration: significantly higher post-legalization (p<0.001).","methodology":"Retrospective observational study at a single center comparing umbilical cord tissue THC levels before (Epoch 1: Oct 2018-Jun 2019, n=811) and after (Epoch 2: Jul 2019-Aug 2021, n=2,170) cannabis legalization in Illinois.","limitations":"Single center, limiting generalizability. Cannot determine timing, frequency, or mode of cannabis use. THC in cord tissue reflects exposure but not necessarily fetal effects. Pre/post comparison cannot account for secular trends. No clinical outcome data for exposed newborns."},{"rthcId":"RTHC-07707","title":"Pharmacotherapies for cannabis use disorder.","authors":"Spiga, Francesca; Parkhouse, Thomas; Tang, Victor M; Savović, Jelena; Le Foll, Bernard; Nielsen, Suzanne","year":2025,"journal":"The Cochrane database of systematic reviews, 9(9), CD008940","doi":"10.1002/14651858.CD008940.pub4","pmid":"41025421","tags":["withdrawal","addiction","quitting","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This is the gold standard of evidence synthesis: a Cochrane systematic review, now in its second update since 2014. The question is simple—is there a medication that helps people quit cannabis or reduces withdrawal? The answer, despite years of additional research, remains: not yet.\n\nThe review searched for randomized controlled trials comparing medications to placebo, other medications, or no pharmacotherapy for treating cannabis dependence. The critical outcomes were: abstinence at end of treatment, withdrawal intensity including craving, adverse events, and severe adverse events.\n\nMultiple medication classes have been tested over the years—antidepressants, anxiolytics, mood stabilizers, cannabinoid agonists (like dronabinol and nabilone), N-acetylcysteine, gabapentin, and others. None has emerged with strong, consistent evidence for promoting cannabis abstinence or meaningfully reducing withdrawal symptoms across trials.\n\nThis doesn't mean no medication will ever work—it means the evidence to date hasn't identified one. Some agents showed promise in individual trials but failed to replicate, or showed modest effects on secondary outcomes without achieving the primary goal of abstinence.\n\nThe practical implication is that psychosocial treatments (cognitive-behavioral therapy, motivational enhancement, contingency management) remain the first-line approach for cannabis use disorder, without a pharmacological adjunct that's proven to help.","whyItMatters":"Cannabis use disorder affects a meaningful minority of cannabis users, and the absence of approved pharmacotherapy is a significant gap. Alcohol has naltrexone and acamprosate; nicotine has varenicline and NRT; opioids have buprenorphine and methadone. Cannabis has nothing. This Cochrane review confirms that gap and provides a rigorous benchmark for evaluating future candidates.","specificNumbers":"Cochrane Review, second update since 2014. Searched through May 2024. Critical outcomes: abstinence, withdrawal intensity, adverse events. No medication showed strong evidence for abstinence or consistent withdrawal relief.","methodology":"Cochrane systematic review (second update, originally published 2014). Searched CENTRAL, MEDLINE, Embase, and PsycINFO through May 2024. Included RCTs and quasi-RCTs of medications for cannabis withdrawal and/or cessation/reduction vs. other medications, placebo, or no medication in cannabis-dependent participants.","limitations":"A null result from a systematic review doesn't prove no medication can work—it means none tested so far has shown consistent efficacy. Some trials may have been underpowered. Cannabis use disorder severity varies widely, and some medications might work for specific subgroups. The search through May 2024 means very recent trials may not be included."},{"rthcId":"RTHC-07708","title":"Concurrent availability of cannabinoid and tobacco products in licensed tobacco retailers in three U.S. cities.","authors":"Spillane, Torra E; Cohen, Joanna E; Spindle, Tory R; Thrul, Johannes; Moran, Meghan; Lee, Hye Myung; Giovenco, Daniel P","year":2025,"journal":"The International journal on drug policy, 146, 105041","doi":"10.1016/j.drugpo.2025.105041","pmid":"41161101","tags":["policy","tobacco","retail","public-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"THC and CBD were each available in 9.8% of stores with no significant differences across cities despite different cannabis policies. Stores selling e-cigarettes had 3.2x higher odds of selling THC and 3.0x for CBD. Cigar stores had 2.6x higher odds for THC and 1.8x for CBD. Cigarette-selling stores had lower odds of carrying cannabinoids.","whyItMatters":"The convergence of tobacco and cannabis retail creates opportunities for co-use initiation and makes product exposure harder to regulate. The finding that cannabinoid availability was similar regardless of state cannabis policy suggests federal hemp law may be the dominant driver.","specificNumbers":"1,402 tobacco retailers surveyed. THC: 9.8% of stores. CBD: 9.8%. E-cigarette stores: aOR 3.2 for THC, 3.0 for CBD. Cigar stores: aOR 2.6 for THC, 1.8 for CBD. Cigarette stores: aOR 0.5 for THC, 0.4 for CBD. No city differences.","methodology":"Stratified random sample of 20% of licensed tobacco retailers (n=1,402) across NYC and San Francisco (recreational cannabis legal) and Philadelphia (medical only). In-person visits June-December 2023 documented product availability. Logistic regression analyzed associations.","limitations":"Cross-sectional survey at one timepoint. Product availability does not measure actual sales or co-use. Cannot determine if products were legal hemp-derived vs. illicit THC. Three cities may not represent all markets."},{"rthcId":"RTHC-07709","title":"Are reasons for first using cannabis associated with subsequent cannabis consumption (standard THC units) and psychopathology?","authors":"Spinazzola, Edoardo; Degen, Hannah; Austin-Zimmerman, Isabelle; Trotta, Giulia; Chesney, Edward; Li, Zhikun; Alameda, Luis; Leung, Bok Man; Lang, Yifei; Quattrone, Andrea; Quattrone, Diego; Castrignanò, Erika; Wolff, Kim; Murray, Robin; Freeman, Tom P; Di Forti, Marta","year":2025,"journal":"BMJ mental health, 28(1)","doi":"10.1136/bmjment-2025-301810","pmid":"40858508","tags":["mental-health","substance-use","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Starting cannabis for anxiety, depression, or because family members used it was associated with higher weekly THC consumption. Self-medication initiation for physical discomfort, pain, anxiety, depression, and psychotic symptoms was linked to higher paranoia scores, with similar patterns for anxiety and depression. Starting for fun or curiosity was associated with lower paranoia and anxiety scores.","whyItMatters":"Asking someone why they first tried cannabis could serve as a simple, cost-effective screening tool to identify those at higher risk for problematic use and mental health symptoms, potentially before problems develop.","specificNumbers":"3,389 participants. Mean weekly consumption: 206 THC units (SD=268). Anxiety initiation: +36.22 THC units/week. Depression initiation: +40.37. Family use: +87.43. Fun initiation: -3.71 paranoia points. Curiosity: -2.61 paranoia points. Self-medication initiation linked to higher paranoia, anxiety, depression.","methodology":"Analysis of the Cannabis&Me population survey (March 2022-July 2024), including 2,573 current and 816 past cannabis users aged 18+. Self-reported reasons for first use, weekly THC unit consumption, and validated measures of paranoia, anxiety, and depressive symptoms.","limitations":"Cross-sectional design cannot establish causation or temporal ordering. Self-reported reasons for first use subject to recall bias. Population survey may underrepresent heavy users. THC units are self-estimated."},{"rthcId":"RTHC-07710","title":"Protective factors for psychological wellbeing: A cross-sectional study of young people attending an urban Aboriginal and Torres Strait Islander primary healthcare service.","authors":"Spurling, Geoffrey K P; Askew, Deborah A; Hayman, Noel E; Schluter, Philip J","year":2025,"journal":"Australian and New Zealand journal of public health, 49(1), 100218","doi":"10.1016/j.anzjph.2024.100218","pmid":"39884889","tags":["youth","mental-health","indigenous-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"72.1% of youth were not experiencing depression. Protective factors associated with absence of depression included exercise, sport participation, and absence of marijuana use, cigarette smoking, job difficulties, homelessness, trouble with police, and violence experience.","whyItMatters":"This study takes a strengths-based approach, identifying what promotes wellbeing rather than just what causes harm. For Aboriginal youth, not using marijuana emerged as one of several modifiable protective factors.","specificNumbers":"710 participants aged 15-24. 72.1% not experiencing depression. Protective factors: exercise, sport, no marijuana, no cigarettes, no job difficulty, no homelessness, no police trouble, no violence.","methodology":"Cross-sectional analysis of health assessment data from 710 Aboriginal and Torres Strait Islander youth aged 15-24 attending an urban health service (2016-2021). Modified Poisson regression used a positive-outcome approach analyzing factors associated with absence of depression.","limitations":"Cross-sectional health assessment data. Single urban health service. Cannot establish causation. Depression measured by service-specific tools, not validated scales. Youth attending health services may differ from the general population."},{"rthcId":"RTHC-07711","title":"Comparison of Cannabis-Based Medicinal Product Formulations for Fibromyalgia: A Cohort Study.","authors":"Sridharan, Surya; Erridge, Simon; Holvey, Carl; Coomber, Ross; Holden, Wendy; Rucker, James J; Platt, Michael; Sodergren, Mikael H","year":2025,"journal":"Journal of pain & palliative care pharmacotherapy, 39(1), 24-37","doi":"10.1080/15360288.2024.2414073","pmid":"39417761","tags":["fibromyalgia","medical-cannabis","clinical-outcomes"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Improvements in GAD-7, sleep quality, fibromyalgia symptom severity, and EQ-5D-5L scores were observed at 1, 3, 6, and 12 months compared to baseline (all p<0.050). No differences were found between oils, dried flower, or combination formulations. 24.32% experienced adverse events (648 total), more likely in cannabis-naive patients.","whyItMatters":"By using a homogeneous set of cannabis products from a single manufacturer, this study reduces product variability that confounds many cannabis studies. The finding that formulation type did not matter simplifies treatment decisions.","specificNumbers":"148 patients. Oils: 52%, flower: 9.5%, both: 38.5%. All formulations improved: GAD-7, sleep, symptom severity, quality of life (all p<0.050). 36 patients (24.3%) reported 648 adverse events. Cannabis-naive patients had more AEs.","methodology":"Cohort study of 148 fibromyalgia patients from the UK Medical Cannabis Registry prescribed Adven products (oils n=77, dried flower n=14, both n=57). Patient-reported outcomes collected at 1, 3, 6, and 12 months.","limitations":"No control group or blinding. Registry data with potential selection bias. Dried flower group very small (n=14). Patient-reported outcomes only. High adverse event count in affected patients. UK-specific regulatory context."},{"rthcId":"RTHC-07712","title":"Cannabis use experience of patients with chronic disease after revisions to the cannabis legalization regulations: a mixed-methods study in primary care settings in the south of Thailand.","authors":"Sripaew, Supakorn; Sornsenee, Phoomjai; Vichitkunakorn, Polathep; Assanangkornchai, Sawitri; Fumaneeshoat, Orapan","year":2025,"journal":"Primary health care research & development, 26, e89","doi":"10.1017/S146342362510056X","pmid":"41178502","tags":["medical-cannabis","chronic-disease","policy","global-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Patients primarily used cannabis tea daily to manage diabetes or hypertension, viewing it as a complement rather than alternative to conventional medicines. Many believed cannabis could improve their health, while fewer considered it a threat. However, only 34.7% were aware of potential drug interactions with concurrent medications.","whyItMatters":"Thailand's cannabis legalization created a unique situation where traditional herbal medicine practices merged with modern chronic disease management. The low awareness of drug interactions poses a real clinical safety concern.","specificNumbers":"11 qualitative interviews, 124 survey participants. Most male, married, Buddhist. Daily cannabis tea was the primary form. Complementary use predominant. Only 34.7% aware of drug interactions. Patients viewed cannabis as quality-of-life enhancing.","methodology":"Exploratory-sequential mixed methods. Phase 1: qualitative semi-structured interviews with 11 patients. Phase 2: cross-sectional survey of 124 patients with diabetes and/or hypertension in southern Thailand, post-legalization.","limitations":"Small sample from one region of Thailand. Self-reported cannabis use and health beliefs. No clinical outcome data. Cross-sectional design. Cultural context may limit generalizability. No verification of what patients were actually consuming."},{"rthcId":"RTHC-07713","title":"Cannabis-related treatment demand at the eve of German cannabis legalization - a 20-years trend analysis.","authors":"Stampf, Alisa; Schwarzkopf, Larissa; Batalla, Albert; Feingold, Daniel; Fischer, Benedikt; Hoch, Eva","year":2025,"journal":"European archives of psychiatry and clinical neuroscience, 275(2), 365-378","doi":"10.1007/s00406-024-01832-w","pmid":"38951248","tags":["treatment","epidemiology","policy","public-health"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"CUD is the second-most common cause for outpatient addiction treatment in Germany. The share of CUD cases rose from 7.1% to 19.9% of total caseload. First-time admissions declined from 79.6% to 55.6%. The share of clients over 35 nearly tripled (6.0% to 17.4%). Female representation rose from 15.6% to 18.1%. Treatment completion with improvement increased from 54.7% to 65.6% between 2001-2007, then marginally declined.","whyItMatters":"With Germany legalizing cannabis in 2024, understanding pre-legalization treatment demand trends is essential for planning services. The aging treatment population suggests current programs designed for young users may be inadequate.","specificNumbers":"2001-2021 trend. CUD share: 7.1% to 19.9%. First-time admissions: 79.6% to 55.6%. Over-35: 6.0% to 17.4%. Female: 15.6% to 18.1%. Improved outcomes: 54.7% to 65.6% (2001-2007), then marginal decline. CUD is 2nd most common OACF admission cause.","methodology":"20-year trend analysis (2001-2021) using Germany's nationwide standardized Addiction Care Statistical Service. Joinpoint regression identified significant trend changes. Analyses covered all and first-time admissions, demographics, and treatment outcomes.","limitations":"Administrative data with possible coding changes over 20 years. Cannot distinguish between increased treatment-seeking and increased CUD prevalence. German-specific treatment system may not generalize. No data on treatment intensity or modality effectiveness."},{"rthcId":"RTHC-07714","title":"Evaluating Household Income and Tobacco Exposure as Moderators of the Association Between Prenatal Cannabis Exposure and Newborn Neurobehavior.","authors":"Stanfield, Jocelyn; Nutor, Chaela; Dunlop, Anne L; Barr, Dana Boyd; Corwin, Elizabeth J; Panuwet, Parinya; Yakimavets, Volha; Brennan, Patricia A","year":2025,"journal":"Developmental psychobiology, 67(4), e70065","doi":"10.1002/dev.70065","pmid":"40686258","tags":["pregnancy","neonatal","neurodevelopment"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"No significant main effects of prenatal cannabis use or COOH-THC levels on newborn neurobehavior were found. However, significant interactions between household income and prenatal THC metabolite levels predicted newborn attention and arousal: cannabis-exposed newborns from low-income households exhibited attenuated attention and heightened arousal.","whyItMatters":"This study suggests prenatal cannabis effects on newborns may be modifiable by socioeconomic context, meaning that poverty may compound biological vulnerabilities from cannabis exposure. This has implications for targeting support services.","specificNumbers":"115 mother-infant pairs. Mean assessment age: 25.3 days. No main effects of cannabis. Significant income x COOH-THC interactions for attention and arousal. Low-income + cannabis exposure: attenuated attention, heightened arousal. Tobacco did not moderate effects.","methodology":"Study of 115 pregnant individuals and newborns from the Atlanta African American Maternal-Child cohort. Urine biomarkers (COOH-THC for cannabis, COT for tobacco) measured at enrollment. Self-reported substance use collected first trimester. Newborn neurobehavior assessed at 1 month using NNNS.","limitations":"Small sample size (115). Single-site, predominantly African American cohort. Single biomarker timepoint. 1-month assessment only. Income as a proxy for complex socioeconomic factors. Cannot isolate cannabis from other poverty-related exposures."},{"rthcId":"RTHC-07715","title":"Momentary mindfulness versus distraction coping messages to reduce cannabis craving among young adults: A microrandomized trial.","authors":"Stanger, Catherine; Anderson, Molly A B; Xie, Haiyi; Nnaka, Tonychris; Budney, Alan J; Qian, Tianchen; Yap, Jamie R T; Nahum-Shani, Inbal","year":2025,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 39(2), 200-211","doi":"10.1037/adb0001029","pmid":"39418443","tags":["treatment","craving","digital-health","youth"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"Both mindfulness and distraction coping messages failed to reduce craving at the next assessment relative to control (thank you) messages, with no significant change in efficacy over time. However, the trial demonstrated excellent feasibility of the EMA-based intervention approach, with high engagement over 4 weeks.","whyItMatters":"Despite the null result, this study pioneers a method for testing real-time digital interventions for substance use craving. The approach can rapidly screen many intervention strategies for just-in-time adaptive interventions.","specificNumbers":"53 participants over 4 weeks. High EMA completion rates. Neither mindfulness nor distraction reduced craving vs. control. No change in efficacy over time. Feasibility demonstrated.","methodology":"Microrandomized trial of 53 young adults who regularly use cannabis. Over 4 weeks, participants reported craving via ecological momentary assessment. When moderate-to-severe craving was reported, they were randomly assigned to receive a mindfulness strategy, distraction strategy, or control message.","limitations":"Small sample size (53). Brief text messages may be too minimal an intervention. No measure of whether messages were actually read or strategies attempted. 4-week period may be too short. Young adult cannabis users may not represent all populations."},{"rthcId":"RTHC-07716","title":"Cannabinoid content on product labels influences cannabis health perceptions.","authors":"Stanz, Joshua L; Ladd, Benjamin O; Magnan, Renee E","year":2025,"journal":"Annals of behavioral medicine : a publication of the Society of Behavioral Medicine, 59(1)","doi":"10.1093/abm/kaaf046","pmid":"40553093","tags":["consumer-health","labeling","public-health"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"CBD-dominant products were rated least harmful, most beneficial, and least likely to purchase or use compared to THC-dominant or equal-ratio products. Adding visual aids to communicate potency did not significantly change any perceptions (all Ps>0.10). Perceived benefits mediated the relationship between cannabinoid content and likelihood to use, but perceived harms did not.","whyItMatters":"As cannabis labeling regulations develop, understanding how label information influences consumer behavior is critical. The finding that benefit perceptions drive use decisions more than harm perceptions has implications for label design and health communication.","specificNumbers":"431 participants. CBD-dominant: least harmful, most beneficial, least likely to purchase. THC-dominant: most likely to purchase. Visual aids: no significant effect (all P>0.10). Benefits mediated use likelihood (b=-0.14). Harms did not mediate (b=-0.01).","methodology":"3x2 mixed experimental design: within-subjects cannabinoid content (THC-dominant, CBD-dominant, 1:1) by between-subjects display type (numeric vs. numeric + visual aid). 431 cannabis users recruited via Prolific.com evaluated product packages online.","limitations":"Online experiment with hypothetical purchase decisions. Cannabis users only, not the general population. Cannot assess actual purchasing behavior. Product labels were simplified experimental stimuli. Prolific sample may not represent all cannabis consumers."},{"rthcId":"RTHC-07717","title":"Adapted motivational interviewing reduces substance use and sexual risk taking among partnered sexual minority men aged 18 to 35: Results of the PARTNER study.","authors":"Starks, Tyrel J; Hillesheim, Joseph R; Castiblanco, Juan; Robles, Gabriel; Kyre, Kory; Cain, Demetria","year":2025,"journal":"Journal of acquired immune deficiency syndromes (1999)","doi":"10.1097/QAI.0000000000003813","pmid":"41343494","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07718","title":"Differential Effects of Cannabinoid Receptor 2 Agonists on HIV Replication and Inflammatory Activation in Monocyte-Derived Macrophages and Induced Pluripotent Stem Cell-Derived Microglia.","authors":"Starr, Alexander; Rathore, Sara; Daniali, Marzieh; Gaskill, Peter J; Akay-Espinoza, Cagla; Jordan-Sciutto, Kelly L","year":2025,"journal":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 20(1), 87","doi":"10.1007/s11481-025-10254-x","pmid":"41075102","tags":["hiv","endocannabinoid-system","neuroprotection","laboratory"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"CB2 activation with JWH-133 reduced HIV replication in primary macrophages and iPSC-derived microglia at different doses corresponding to each cell type's basal endocannabinoid expression. JWH-133 broadly reduced cytokine release from HIV-infected macrophages but not microglia. In microglia, CB2 activation reduced NLRP3 inflammasome activation without affecting NF-kB signaling. RNA-seq revealed distinct pathway effects: interferon/stress response in macrophages vs. homeostatic pathways in microglia.","whyItMatters":"Brain-resident immune cells serve as HIV reservoirs in the central nervous system and drive neuroinflammation. CB2 agonists could potentially address both viral persistence and neuroinflammation, two major challenges in HIV-associated neurocognitive disorders.","specificNumbers":"JWH-133 reduced HIV replication in macrophages and microglia at cell-type-specific doses. Broad cytokine reduction in macrophages. NLRP3 inflammasome activation reduced in microglia. Distinct RNA-seq pathway signatures per cell type.","methodology":"In vitro study using primary human monocyte-derived macrophages and iPSC-derived microglia infected with HIV and treated with the CB2-specific agonist JWH-133. Assessed HIV replication, cytokine release, RNA-seq transcriptomics, and inflammasome activation.","limitations":"In vitro study using isolated cell types, not the complex brain environment. iPSC-derived microglia may not fully recapitulate primary microglia. Single CB2 agonist tested. No in vivo validation. HIV strain specificity not assessed."},{"rthcId":"RTHC-07719","title":"Evaluating Vaporized Cannabinoid Therapy in Multiple Sclerosis: Findings from a Prospective Single-Center Clinical Study.","authors":"Stavrogianni, Konstantina; Kitsos, Dimitrios K; Giannopapas, Vasileios; Smyrni, Vassiliki; Chasiotis, Athanasios K; Akrivaki, Alexandra; Dimitriadou, Evangelia-Makrina; Zompola, Christina; Tzartos, John S; Tsivgoulis, Georgios; Giannopoulos, Sotirios","year":2025,"journal":"Journal of clinical medicine, 14(6)","doi":"10.3390/jcm14062121","pmid":"40142928","tags":["multiple-sclerosis","medical-cannabis","clinical-outcomes","spasticity"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Significant improvement across all outcomes: EDSS decreased (p=0.009), indicating slight reduction in disability progression; MAS scores showed substantial improvement in spasticity; and PVR volume decreased, indicating improved bladder function. Benefits were observed at both 3 and 6 months.","whyItMatters":"MS symptoms like spasticity and bladder dysfunction significantly impact quality of life and are often inadequately managed. This study provides 6-month data on a vaporized cannabinoid formulation, a less common delivery method in clinical research.","specificNumbers":"69 MS patients over 6 months. CBD 13%/THC 9% vaporized. EDSS: decreased (p=0.009). MAS: substantial spasticity improvement. PVR: significant reduction (improved bladder function). Benefits at 3 and 6 months.","methodology":"Single-center prospective longitudinal study of 69 MS patients followed over 6 months. Participants used vaporized CBD 13%/THC 9% cannabis product. Assessed at baseline, 3 months, and 6 months using Modified Ashworth Scale, Post-Void Residual volume, and Expanded Disability Status Scale.","limitations":"No control group or blinding. Single center. Cannot attribute improvement to treatment vs. natural fluctuation. Vaporization adds respiratory exposure considerations. EDSS changes can be difficult to interpret in short-term studies."},{"rthcId":"RTHC-07720","title":"Frequency of cannabis use and symptoms of anxiety and depression: a cross-sectional analysis of the Colorado cannabis users health cohort.","authors":"Steeger, Christine M; Tandukar, Poojashree; Hoth, Karin F; Aloia, Mark; Wamboldt, Fred; Castaldi, Peter; Sharma, Sunita; Lorenzon, Nancy; Crotty Alexander, Laura E; Klawitter, Jost; Sempio, Cristina; Kinney, Gregory L; Althoff, Meghan D; Kruse, Gina R; Bowler, Russell P","year":2025,"journal":"Journal of cannabis research, 7(1), 78","doi":"10.1186/s42238-025-00327-2","pmid":"41107903","tags":["anxiety","depression","substance-use","clinical-outcomes"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Frequent cannabis use was associated with higher anxiety likelihood (AOR 1.06, 95% CI 1.01-1.12) but not depression on validated scales. Use of FDA-approved anxiolytic or antidepressant medications did not differ significantly across non-use, infrequent, and frequent cannabis groups (20% vs. 18.2% vs. 21.1% for anxiolytics). Urinary cannabinoid levels were not associated with symptom severity.","whyItMatters":"The finding that frequent cannabis users have elevated anxiety but similar rates of medication use suggests some may be substituting cannabis for evidence-based treatments, which has implications for clinical screening and referral.","specificNumbers":"195 participants. Frequent use (15+ days/month): AOR 1.06 for anxiety. No association with depression. Anxiolytic use: 20% non-users, 18.2% infrequent, 21.1% frequent (NS). Antidepressant: 14%, 9.1%, 11.4% (NS). Urinary cannabinoids not associated with symptom severity.","methodology":"Secondary analysis of a cross-sectional sleep and cannabis study. 195 participants completed HADS, BAI, BDI-II, and self-reported cannabis use. Urinary THC metabolites validated exposure. Regression models adjusted for demographics and clinical variables.","limitations":"Cross-sectional design. Secondary analysis. Small sample (195). Cannabis users from Colorado may differ from other populations. Self-reported frequency and medication use. Cannot determine directionality."},{"rthcId":"RTHC-07721","title":"Nicotine and cannabis vaping among early high school adolescents: Disparities of use across sociodemographic characteristics and associations with psychosocial factors.","authors":"Steeger, Christine M; Gust, Charleen J; Harlow, Alyssa F; Cambron, Christopher; Barrington-Trimis, Jessica; Combs, Katie Massey; Brooks-Russell, Ashley; Hill, Karl G","year":2025,"journal":"Addictive behaviors reports, 21, 100577","doi":"10.1016/j.abrep.2024.100577","pmid":"39758834","tags":["youth","vaping","substance-use","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Past-month vaping: 89.7% non-use, 5.9% nicotine-only, 1.0% cannabis-only, 3.4% dual use. Nicotine-only vaping was higher among females. Cannabis and dual use were associated with LGB+ identity, Hispanic/multiethnic background, and lower SES. All vaping types were associated with worse mental health, alcohol use, and aggression, with dual users showing the strongest associations.","whyItMatters":"Adolescent cannabis vaping is a growing concern distinct from smoking. Identifying which youth are most at risk allows for targeted prevention, and the strong association with LGB+ identity suggests inclusive prevention approaches are needed.","specificNumbers":"2,476 adolescents in 9th-10th grade. Non-use: 89.7%. Nicotine-only: 5.9%. Cannabis-only: 1.0%. Dual: 3.4%. Higher risk: females (nicotine), LGB+ (cannabis, dual), Hispanic/multiethnic, low SES. All vaping linked to worse mental health, alcohol, aggression.","methodology":"Cross-sectional survey of 2,476 9th and 10th grade adolescents in Colorado and Ohio (2021-2022). Measured vaping behaviors and psychosocial factors including substance use attitudes, alcohol use, mental health, aggression, and family/school risk and protective factors.","limitations":"Cross-sectional design. Two states only (CO, OH). Self-reported vaping. Cannot establish causation between vaping and psychosocial factors. Low prevalence of cannabis-only vaping limits statistical power for that group."},{"rthcId":"RTHC-07722","title":"Plant-derived cannabinoids for treatment of spasticity in children and adolescents with severe cerebral palsy: Double-blind, placebo-controlled trial.","authors":"Stefanović, Milica; Osredkar, Damjan; Rener-Primec, Zvonka; Peterlin, Jakob; Laptoš, Tomislav; Neubauer, David","year":2025,"journal":"European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 54, 18-24","doi":"10.1016/j.ejpn.2024.11.007","pmid":"39626543","tags":["cerebral-palsy","pediatrics","clinical-trial","spasticity"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"No significant differences between FSCO and placebo in spasticity (Modified Ashworth Scale), motor function (GMFM-88), or quality of life parameters after 6 weeks of double-blind treatment. FSCO was generally well-tolerated with mild to moderate adverse events and no life-threatening events. Patients in the FSCO group were significantly drowsier.","whyItMatters":"Despite anecdotal reports and parent interest, this is one of the first rigorous RCTs testing cannabis for cerebral palsy spasticity. The null result is important for informing families and clinicians about realistic expectations.","specificNumbers":"53 participants, ages 5-25, CP grades IV-V. 6-week double-blind phase. 10:1 CBD:THC ratio. No significant differences: spasticity, motor function, quality of life. FSCO group significantly drowsier. No life-threatening adverse events.","methodology":"Pilot feasibility study (7 patients) followed by prospective double-blind, placebo-controlled parallel trial with 53 participants aged 5-25 with spastic CP grades IV-V. 1:1 randomization. 6-week double-blind phase followed by 6-week open-label phase. Full-spectrum cannabis oil with 10:1 CBD:THC ratio.","limitations":"Small sample size. Only 6-week double-blind period. Fixed CBD:THC ratio may not be optimal. Grade IV-V CP represents the most severe forms, where spasticity may be least responsive. Single formulation tested."},{"rthcId":"RTHC-07723","title":"The association of state policies and opioid analgesic amount dispensed from retail pharmacies.","authors":"Stein, Bradley D; Sheng, Flora; Taylor, Erin A; Davis, Corey S; Griffin, Beth Ann; Sorbero, Mark; Dick, Andrew W","year":2025,"journal":"Drug and alcohol dependence, 267, 112533","doi":"10.1016/j.drugalcdep.2024.112533","pmid":"39823664","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07724","title":"A novel protocol for protoplast isolation, transfection, and culture in Cannabis sativa L.","authors":"Stelmach-Wityk, Katarzyna; Szymonik, Kamil; Jones, Andrew Maxwell Phineas; Grzebelus, Ewa","year":2025,"journal":"BMC plant biology, 25(1), 1629","doi":"10.1186/s12870-025-07686-1","pmid":"41286625","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07725","title":"Associations between cannabis use frequency and suicidal thoughts and behaviors: A clinical longitudinal sibling study.","authors":"Stern, Elisa F; Ellingson, Jarrod M; Schaefer, Jonathan D; Hinckley, Jesse D; Stallings, Michael C; Corley, Robin P; Hopfer, Christian; Wall, Tamara L; Rhee, Soo Hyun","year":2025,"journal":"Addictive behaviors reports, 22, 100620","doi":"10.1016/j.abrep.2025.100620","pmid":"41367503","tags":["mental-health","suicide","youth","genetics"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis use was not associated with suicidality (all p's > 0.05) in cross-sectional or prospective models accounting for within-family clustering. Exploratory analyses suggested tobacco might be more relevant (Wave 1 within-family OR 1.037, p=0.016), though this was reduced to non-significance after adjusting for other substance use.","whyItMatters":"By using siblings, this study controls for shared genetic and environmental factors that confound most cannabis-suicidality research. The null finding in a high-risk clinical sample challenges the assumed direct link between cannabis and suicidality.","specificNumbers":"1,261 adolescent siblings across 3 waves (2001-2019). Cannabis-suicidality association: all p's > 0.05. Tobacco-suicidality exploratory finding: OR 1.037, p=0.016, reduced after adjustment. Recruited from clinical/high-risk settings.","methodology":"Longitudinal sibling study (N=1,261) recruited from substance use treatment, alternative schools, and juvenile probation in Denver and San Diego. Three waves (2001-2019). Multilevel models accounted for shared familial influences. Covariates included alcohol, tobacco, other substance use, age, and sex.","limitations":"High-risk sample may not generalize to general population. Attrition over 18 years. Self-reported substance use and suicidality. Sibling design controls for shared factors but cannot eliminate all confounders. May be underpowered for rarer outcomes."},{"rthcId":"RTHC-07726","title":"Recreational Cannabis Laws and Fills of Pain Prescriptions in the Privately Insured.","authors":"Steuart, Shelby R; Lozano-Rojas, Felipe; Bethel, Victoria; Shone, Hailemichael Bekele; Abraham, Amanda J","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(1), 121-138","doi":"10.26828/cannabis/2024/000268","pmid":"39968486","tags":["policy","opioids","legalization","pain"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using nationally representative commercial insurance data, the study examined how two sequential recreational cannabis policies affected prescribing of opioids and other pain medications, providing evidence on whether cannabis substitutes for or complements prescription pain treatments.","whyItMatters":"Whether cannabis substitutes for prescription pain medications has major implications for opioid policy. This study uses insurance claims data, which captures actual prescribing behavior rather than self-report.","specificNumbers":"National sample of commercially insured adults. Two sequential recreational cannabis policies examined. Outcomes: opioid and non-opioid pain prescription fills.","methodology":"Analysis of national commercially insured adult data examining the effect of recreational cannabis legalization (through two sequential policies) on prescribing of opioids and other pain medications.","limitations":"Commercially insured population may not represent uninsured or publicly insured individuals. Insurance claims may not capture all cannabis use. Cannot determine individual-level substitution. State-level variation in implementation."},{"rthcId":"RTHC-07727","title":"Cannabis Users' and Non-Users' Differential Responses to Two Anti-Cannabis Campaigns.","authors":"Stevens, Elise M; Cohn, Amy; Ruedinger, Brian; Kim, Narae; Seo, Jinhee; Sun, Fuwei; Kim, Seunghyun; Leshner, Glenn","year":2025,"journal":"Health education & behavior : the official publication of the Society for Public Health Education, 52(1), 49-60","doi":"10.1177/10901981241267879","pmid":"39199019","tags":["public-health","youth","messaging","policy"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The study compared responses to two anti-cannabis campaigns with different message strategies among young adults aged 18-25. Cannabis users and non-users showed differential cognitive and emotional responses, suggesting that one-size-fits-all campaign approaches may not effectively reach the highest-risk population.","whyItMatters":"With cannabis legalization expanding, effective public health messaging is critical. Understanding how current users vs. non-users respond differently can help design campaigns that actually reach the target audience.","specificNumbers":"Young adults aged 18-25. Two anti-cannabis campaigns compared. Cannabis users vs. non-users. Cognitive and emotional responses measured.","methodology":"Experimental comparison of young adult cannabis users' and non-users' cognitive and emotional responses to two anti-cannabis media campaigns employing different message strategies.","limitations":"Experimental setting may not reflect real-world campaign exposure. Self-selected participants. Short-term response measurement. Cannot determine actual behavior change from campaign exposure."},{"rthcId":"RTHC-07728","title":"Cannabis tolerance reduces symptom relief.","authors":"Stith, Sarah S; Li, Xiaoxue; Brockelman, Franco; Keeling, Keenan; Hall, Branden; Vigil, Jacob M","year":2025,"journal":"Frontiers in pharmacology, 16, 1496232","doi":"10.3389/fphar.2025.1496232","pmid":"40612739","tags":["tolerance","medical-cannabis","clinical-outcomes"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Patients experienced a 0.5% decrease in symptom relief per subsequent session (p<0.001). Combustion provided more relief than vaping, eating, or drinking. Higher doses provided greater relief. THC levels were positively associated with relief. Patients increased dose but not THC potency over time. Factors increasing relief also increased side effects. Results were similar for pain, depression, and anxiety.","whyItMatters":"This is the first large-scale measurement of cannabis tolerance in a medical context. The finding that tolerance develops at a consistent rate across symptom types has direct implications for dosing guidance and treatment planning.","specificNumbers":"16,395 patients. 120,691 observations across 42,005 sessions. 0.5% decrease in relief per session (p<0.001). Combustion > vaping > eating/drinking for relief. Higher dose = more relief. Higher THC = more relief. Patients increased dose but not THC potency over time.","methodology":"Fixed effects regression analysis of Releaf App data from 16,395 medical cannabis patients recording 42,005 sessions (120,691 symptom-treatment observations) from 2016-2022. Patients tracked symptoms, products, doses, and relief in real time.","limitations":"App-based self-report data. Self-selected users of a tracking app may not represent all patients. Cannot verify products or doses. No clinical validation of symptom measures. Observational design. Session count is a proxy for tolerance development."},{"rthcId":"RTHC-07729","title":"Rare but relevant: Cannabinoid hyperemesis syndrome.","authors":"Stjepanović, Daniel; Kirkman, Julia; Hall, Wayne","year":2025,"journal":"Addiction (Abingdon, England), 120(2), 380-384","doi":"10.1111/add.16693","pmid":"39402864","tags":["gastrointestinal","adverse-effects","clinical-practice"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CHS is characterized by cyclical vomiting in chronic cannabis users, is frequently misdiagnosed leading to extensive investigations and delayed treatment, and standard antiemetics are typically ineffective. Hot water bathing/showering is a hallmark symptomatic relief. No standardized treatment protocol exists. Little is known about risk factors for developing CHS.","whyItMatters":"CHS awareness is growing but misdiagnosis remains common, leading to unnecessary testing, repeated ED visits, and patient suffering. Understanding its unique features can reduce diagnostic delays.","specificNumbers":"Prevalence: probably rare but uncertain. Hot water bathing: characteristic relief. Standard antiemetics: typically ineffective. Cannabis cessation: essential for resolution. No standardized treatment protocol exists.","methodology":"Narrative review of CHS diagnosis, management, and research gaps.","limitations":"Narrative review format. CHS prevalence is uncertain. Based largely on case reports. No randomized treatment trials exist. The mechanism of CHS remains poorly understood."},{"rthcId":"RTHC-07730","title":"Therapeutic potential of cannabinoids for treating atopic dermatitis.","authors":"Stoco, Adriel Aparecido Geraldo; Mazzola, Priscila Gava","year":2025,"journal":"Journal of cannabis research, 7(1), 57","doi":"10.1186/s42238-025-00317-4","pmid":"40818974","tags":["skin","cbd","inflammation","endocannabinoid-system"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabinoids interact with the endocannabinoid system in skin to potentially address multiple aspects of atopic dermatitis: skin barrier repair, anti-inflammatory effects, and itch reduction. The review assesses their potential as complementary topical treatments alongside existing therapies.","whyItMatters":"Atopic dermatitis affects millions worldwide and current treatments have limitations. Cannabinoids represent a novel therapeutic approach that targets multiple disease mechanisms simultaneously through the skin's endocannabinoid system.","specificNumbers":"AD characterized by: skin barrier loss, itching, xerosis, inflammation. Cannabinoids target: barrier function, inflammation, itch signaling. ECS components present in skin tissue.","methodology":"Review of the therapeutic potential of cannabinoids for atopic dermatitis, covering mechanisms of action through the skin's endocannabinoid system and available evidence from preclinical and clinical studies.","limitations":"Review level evidence only. Limited clinical trial data for AD specifically. Most evidence is preclinical. Dosing and formulation for topical skin application not standardized."},{"rthcId":"RTHC-07731","title":"Cardiovascular risk associated with the use of cannabis and cannabinoids: a systematic review and meta-analysis.","authors":"Storck, Wilhelm; Elbaz, Meyer; Vindis, Cécile; Déguilhem, Amélia; Lapeyre-Mestre, Maryse; Jouanjus, Emilie","year":2025,"journal":"Heart (British Cardiac Society), 111(22), 1047-1056","doi":"10.1136/heartjnl-2024-325429","pmid":"40527600","tags":["cardiovascular","safety","systematic-review","meta-analysis"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Risk ratios for cannabis users: ACS 1.29 (95% CI 1.05-1.59), stroke 1.20 (1.13-1.26), cardiovascular death 2.10 (1.29-3.42). No significant association for composite ACS+stroke. Sensitivity analysis restricted to cohort studies yielded comparable results (RR 1.32, 1.01-1.73). 24 studies included: 17 cross-sectional, 6 cohort, 1 case-control.","whyItMatters":"This is one of the most comprehensive quantitative assessments of cannabis cardiovascular risk. The elevated cardiovascular death risk (2.1x) is particularly concerning given increasing cannabis use and the often-overlooked cardiac effects.","specificNumbers":"24 studies from 3,012 screened. 17 cross-sectional, 6 cohort, 1 case-control. ACS RR: 1.29. Stroke RR: 1.20. CV death RR: 2.10. Cohort-only analysis: RR 1.32 for ACS.","methodology":"Systematic review and meta-analysis (PROSPERO: CRD42023401401) of pharmacoepidemiological studies published January 2016-January 2023. Searched PubMed, Web of Science, Scopus. Quality assessed with ROBINS-E tool. DerSimonian-Laird random effects meta-analysis with inverse variance weighting.","limitations":"Most included studies were cross-sectional, limiting causal inference. Exposure measurement varied across studies. Potential residual confounding from co-use of other substances. Heterogeneity in study populations and designs."},{"rthcId":"RTHC-07732","title":"Barriers to accessing prescribed medical cannabis: qualitative insights from people using non-prescribed cannabis for medicinal purposes in the Netherlands.","authors":"Strada, Lisa; van Gelder, Nadine; Martinelli, Thomas; Fraser, Alex; Hipple Walters, Bethany","year":2025,"journal":"Harm reduction journal, 23(1), 13","doi":"10.1186/s12954-025-01369-8","pmid":"41449434","tags":["medical-cannabis","access","policy"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Despite over two decades of legal prescribed cannabis, most Dutch medical users obtain it from unregulated sources. Barriers to prescribed access included cost, limited product selection, physician lack of knowledge/willingness to prescribe, stigma associated with requesting cannabis, and restrictive program design. Participants felt the prescribed system did not meet their therapeutic needs.","whyItMatters":"The Netherlands has one of the world's oldest medical cannabis programs, making it a valuable case study for why patients may not use formal channels even when they exist. These barriers likely affect medical cannabis programs worldwide.","specificNumbers":"33 qualitative interviews. Over 20 years of legal medical cannabis in Netherlands. Most medical users still use non-prescribed sources. Key barriers: cost, product limitations, physician barriers, stigma.","methodology":"Semi-structured qualitative interviews with 33 people using non-prescribed cannabis for medicinal purposes in the Netherlands.","limitations":"Qualitative study with self-selected participants. Cannot determine prevalence of specific barriers. May overrepresent those with negative experiences. Dutch-specific regulatory context. Small sample."},{"rthcId":"RTHC-07733","title":"Medicinal use of non-prescribed cannabis: a cross-sectional survey on patterns of use, motives for use, and treatment access in the Netherlands.","authors":"Strada, Lisa; Korteling, Simone; Vergeer, Mark; Oomen, Pieter","year":2025,"journal":"Journal of cannabis research, 8(1), 6","doi":"10.1186/s42238-025-00355-y","pmid":"41331499","tags":["medical-cannabis","access","epidemiology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Most people using cannabis medicinally in the Netherlands continue to rely on non-prescribed sources. The survey documented patterns of use, motivations, perceived effectiveness, and barriers to accessing the prescribed system, quantifying the qualitative findings from companion research.","whyItMatters":"This quantitative companion to the qualitative Dutch study (RTHC-07732) provides numbers to support the finding that medical cannabis programs can fail to serve their intended population when structural barriers remain unaddressed.","specificNumbers":"Survey conducted January-April 2023. Netherlands context. Convenience sample. Assessed use patterns, motives, perceived effectiveness, and access barriers.","methodology":"Cross-sectional online survey conducted January-April 2023 using convenience sampling of individuals self-medicating with non-prescribed cannabis in the Netherlands.","limitations":"Convenience sampling limits representativeness. Self-selected participants likely biased toward those with barriers to formal access. Cross-sectional design. Online survey may miss populations without internet access."},{"rthcId":"RTHC-07734","title":"Case Report: Effect of medicinal cannabis on fitness to drive in a patient with Tourette Syndrome and ADHD.","authors":"Streetz, Charlotte Marie; Szejko, Natalia; Pisarenko, Anna; Fremer, Carolin; Teske, Jörg; Brunnauer, Alexander; Müller-Vahl, Kirsten R","year":2025,"journal":"Frontiers in psychiatry, 16, 1595649","doi":"10.3389/fpsyt.2025.1595649","pmid":"40901261","tags":["tourette-syndrome","adhd","driving","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"A patient with treatment-resistant Tourette syndrome and ADHD who was prescribed medical cannabis maintained his fitness to drive. This addresses the common concern about cannabis-impaired driving in medical cannabis patients who develop tolerance to psychoactive effects.","whyItMatters":"Driving restrictions are a major barrier to medical cannabis access, particularly for conditions like Tourette syndrome where cannabis may be the only effective treatment. This case contributes to the evidence that tolerance to driving impairment can develop.","specificNumbers":"1 patient, age 28. Tourette syndrome + ADHD. Medical cannabis treatment. Driving fitness maintained. Treatment-resistant to conventional options.","methodology":"Case report of a 28-year-old male with Tourette syndrome and comorbid ADHD treated with medical cannabis, with assessment of driving fitness.","limitations":"Single case report. Cannot generalize to other patients or conditions. Driving fitness assessment methods not detailed. No comparison to driving performance without cannabis. Individual tolerance varies."},{"rthcId":"RTHC-07735","title":"Effect of caffeine and cannabidiol (CBD) co-administration on Δ9-tetrahydrocannabinol (Δ9-THC) subjective effects, performance impairment, and pharmacokinetics.","authors":"Strickland, Justin C; Tilton, Hayleigh E; Patton, Noah M; Vandrey, Ryan; Austin Zamarripa, C; Spindle, Tory R; Lee, Dustin C; Bergeria, Cecilia L; Wolinsky, David; Klawitter, Jost; Sempio, Cristina; Campos-Palomino, Jorge; Christians, Uwe; Feldner, Matthew T; Irons, Jessica G; Bonn-Miller, Marcel O","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(12), 1827-1835","doi":"10.1038/s41386-025-02232-x","pmid":"40962814","tags":["pharmacology","cbd","thc","drug-interactions","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Caffeine produced minimal changes in THC-induced subjective effects, performance, or metabolism, though signals for perceived driving impairment were observed. CBD, co-administered with THC and caffeine, increased abuse-liability outcomes (drug high, p=0.002), performance impairment, and plasma THC (p=0.004) and 11-OH-THC (p<0.001) concentrations compared to THC alone.","whyItMatters":"Cannabis products premixed with caffeine are increasingly common but have never been studied. The unexpected finding that CBD increases THC's effects and blood levels challenges the common belief that CBD moderates THC's impact.","specificNumbers":"20 participants (10M/10F). THC: 7.5 mg. Caffeine: 180 mg. CBD: 105 mg. CBD increased: drug high (p=0.002), plasma THC (p=0.004), 11-OH-THC (p<0.001). Caffeine: minimal THC effects. CBD increased performance impairment vs. THC alone.","methodology":"Double-blind, randomized, placebo-controlled, within-subject crossover study. 20 participants (10 men/10 women) completed outpatient sessions with oral THC (7.5 mg), caffeine (180 mg), and/or CBD (105 mg) in cumulative dosing design. Outcomes: subjective effects, simulated driving, plasma concentrations.","limitations":"Small sample (20). Oral administration only, not smoking or vaping. Specific doses may not represent commercial products. Single-session acute effects. Cannot determine chronic co-administration effects."},{"rthcId":"RTHC-07736","title":"Comorbid Cannabis Use and Mood Disorders Among Adolescents.","authors":"Strong, Stephane J; Thomas, Halle A; Adams, Zachary W; Hulvershorn, Leslie A","year":2025,"journal":"Focus (American Psychiatric Publishing), 23(2), 133-140","doi":"10.1176/appi.focus.20240049","pmid":"40235605","tags":["youth","mental-health","mood-disorders","substance-use"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Adolescents with mood disorders have higher rates of cannabis use and cannabis use disorder. Cannabis use during adolescence can worsen mood disorder outcomes, while mood disorders increase vulnerability to problematic cannabis use. The review covers assessment and treatment considerations for this comorbid population.","whyItMatters":"Adolescence is a period of active brain development when both mood disorders and cannabis use commonly emerge. Understanding their interaction is critical for clinicians treating either condition in this age group.","specificNumbers":"Cannabis: most commonly used illicit substance among adolescents. Adolescents with mood disorders: higher rates of cannabis use and CUD. Bidirectional relationship: each condition worsens the other.","methodology":"Narrative review exploring the assessment, prevalence, and management of comorbid cannabis use and mood disorders among adolescents.","limitations":"Narrative review without systematic methodology. Predominantly observational evidence base. Cannot establish definitive causation in the bidirectional relationship. Treatment recommendations limited by available trial data in adolescents."},{"rthcId":"RTHC-07737","title":"Retrospective Multicenter Chart Review Study of Adjunctive Cannabidiol for Seizures Associated with Lennox-Gastaut Syndrome, Dravet Syndrome and Tuberous Sclerosis Complex.","authors":"Strzelczyk, Adam; Klotz, Kerstin Alexandra; Mayer, Thomas; von Podewils, Felix; Knake, Susanne; Kurlemann, Gerhard; Herold, Luise; Immisch, Ilka; Buhleier, Elisa; Rosenow, Felix; Schubert-Bast, Susanne","year":2025,"journal":"Neurology and therapy, 14(5), 1935-1959","doi":"10.1007/s40120-025-00788-w","pmid":"40650804","tags":["cbd","epilepsy","clinical-outcomes","pediatrics"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Responder rates (>=50% seizure reduction) for total seizures: 43.3% at 3 months, 44.0% at 12 months. For generalized tonic-clonic seizures: 54.3% at 3 months, 47.7% at 12 months. Median seizure days decreased from 30 to 18 per month (p<0.001). CGI-C improvement in 62%. Treatment retention: 89.6% at 3 months, 67.1% at 12 months. Common AEs: sedation and diarrhea.","whyItMatters":"Real-world evidence complements clinical trial data by showing how CBD performs in typical clinical practice with broader patient populations and less controlled conditions. These German results confirm trial findings translate to practice.","specificNumbers":"202 patients (159 LGS, 34 DS, 9 TSC). Median age: 18 years. Median prior ASMs: 6. Target dose: 11.1 mg/kg/day. 50%+ response: 43% (3 mo), 44% (12 mo). GTCS 50%+ response: 54% (3 mo), 48% (12 mo). Seizure days: 30 to 18/month (p<0.001). 67% still on CBD at 12 months.","methodology":"Multicenter retrospective chart review of 202 German patients with LGS (159), DS (34), or TSC (9) receiving adjunctive CBD (Epidyolex). Assessed treatment characteristics, seizure outcomes, CGI-C, retention rates, and AEs up to 12 months.","limitations":"Retrospective chart review with inherent limitations. No control group. Selection bias possible. Variable follow-up completeness. German healthcare system specifics may affect generalizability."},{"rthcId":"RTHC-07738","title":"Real-world experience of cannabidiol in conjunction with clobazam for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome: Results from a retrospective multicentre chart review in Germany.","authors":"Strzelczyk, Adam; Schubert-Bast, Susanne; von Podewils, Felix; Knake, Susanne; Mayer, Thomas; Klotz, Kerstin Alexandra; Buhleier, Elisa; Herold, Luise; Immisch, Ilka; Kurlemann, Gerhard; Rosenow, Felix","year":2025,"journal":"Epilepsy & behavior : E&B, 166, 110302","doi":"10.1016/j.yebeh.2025.110302","pmid":"40073826","tags":["cbd","epilepsy","clinical-outcomes","drug-interactions"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"50%+ seizure reduction in total seizures: 47.5% at 3 months, 45.5% at 12 months. For generalized tonic-clonic seizures: 63.0% at 3 months, 56.9% at 12 months. Seizure days decreased from 30 to 15 per month (p<0.001). CGI-C improvement: 66%. Behavioral improvement: 67%. Retention: 89.7% (3 mo), 80.7% (6 mo), 69.8% (12 mo). Main AEs: sedation (23.8%), diarrhea (10.3%).","whyItMatters":"CBD is approved in the EU specifically for use with clobazam for LGS and DS. This study provides real-world evidence for this specific combination, which showed numerically higher response rates than the broader population (RTHC-07737), likely due to the known pharmacokinetic interaction between CBD and clobazam.","specificNumbers":"126 patients (102 LGS, 24 DS). Mean age: 23.2 years. Prior ASMs: median 6. Target CBD: 11.1 mg/kg/day. CLB: 0.14 mg/kg/day. 50%+ response: 47.5% (3 mo), 45.5% (12 mo). GTCS response: 63.0% (3 mo), 56.9% (12 mo). Seizure days: 30 to 15/month. Retention: 69.8% at 12 mo. Sedation: 23.8%.","methodology":"Retrospective multicenter chart review of 126 patients (102 LGS, 24 DS) from 6 German epilepsy centers receiving adjunctive CBD with concomitant clobazam for up to 12 months.","limitations":"Retrospective chart review. No comparator group without clobazam. Selection bias. CBD-clobazam interaction makes it difficult to attribute benefit to CBD alone. Higher sedation may reflect the drug interaction."},{"rthcId":"RTHC-07739","title":"A naturalistic examination of the effects of chronic and acute cannabis use on cognition and perceived symptoms of attention-deficit/hyperactivity disorder.","authors":"Stueber, Amanda M; LaFrance, Emily M; Herbert, Robyn S; Cuttler, Carrie","year":2025,"journal":"Psychopharmacology","doi":"10.1007/s00213-025-06921-9","pmid":"41062851","tags":["adhd","cognition","substance-use"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis users with ADHD reported subjective improvement in ADHD symptoms after acute cannabis use. However, chronic cannabis use was associated with cognitive differences on objective measures, regardless of whether participants had ADHD. The study assessed both chronic effects (regular use) and acute effects (before/after cannabis use).","whyItMatters":"Many people with ADHD use cannabis to self-treat symptoms, but objective evidence is limited. This study distinguishes between perceived symptom improvement and actual cognitive performance, finding they may diverge.","specificNumbers":"104 adults in 4 matched groups of 26. Assessed chronic and acute cannabis effects. Subjective: ADHD symptom reduction after acute use. Objective: cognitive differences associated with chronic use regardless of ADHD.","methodology":"Repeated-measures quasi-experimental study with 104 adults in 4 groups: cannabis users with ADHD (n=26), non-users with ADHD (n=26), cannabis users without ADHD (n=26), non-users without ADHD (n=26). Session 1 assessed chronic effects; session 2 assessed acute effects.","limitations":"Quasi-experimental, not randomized. Small groups (26 per cell). Cannot control for all confounders between cannabis users and non-users. Self-selected participants. Acute effects measured in a controlled setting may not reflect real-world use."},{"rthcId":"RTHC-07740","title":"Decoding the genetic links between substance use disorder and cancer vulnerability.","authors":"Su, Xin; Mo, Xiaoyan; Kan, Jun; Yang, Fan; Zhang, Bei; Huang, Yuanyuan","year":2025,"journal":"Psychopharmacology, 242(9), 2021-2033","doi":"10.1007/s00213-025-06781-3","pmid":"40178608","tags":["genetics","cancer","substance-use"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"No significant causal relationship was found between CUD and any cancer type (all P>0.05). OUD showed potential causal associations with bladder cancer (OR 1.040), acute myeloid leukemia (OR 0.931), and ovarian cancer (OR 0.937). Reverse MR found no evidence of cancers causing OUD.","whyItMatters":"While observational studies have suggested links between cannabis use and cancer, this MR study uses genetic variants as instrumental variables to test causality, finding no support for a CUD-cancer connection.","specificNumbers":"CUD: no significant association with any cancer (all P>0.05). OUD: bladder cancer OR 1.040 (P=0.029), AML OR 0.931 (P=0.005), ovarian cancer OR 0.937 (P=0.010). Data from FinnGen and UK Biobank GWAS.","methodology":"Two-sample Mendelian randomization using GWAS summary statistics from FinnGen and UK Biobank. Inverse-variance weighted primary analysis with sensitivity analyses. Tested both CUD and OUD as exposures with multiple cancer types as outcomes.","limitations":"MR assumptions may not be fully met. CUD GWAS instruments may lack power. Predominantly European-ancestry populations. Cannot assess dose-response or specific cancer subtypes in detail. Adjusted P-values did not reach significance for OUD associations."},{"rthcId":"RTHC-07741","title":"Methylation Status of the DAT1 Dopamine Transporter Gene in Individuals With Cannabis Use Disorder: Associations With Personality Traits.","authors":"Suchanecka, Aleksandra; Recław, Remigiusz; Chmielowiec, Krzysztof; Chmielowiec, Jolanta; Masiak, Jolanta; Grzywacz, Anna","year":2025,"journal":"Genes, brain, and behavior, 24(6), e70040","doi":"10.1111/gbb.70040","pmid":"41404997","tags":["genetics","epigenetics","substance-use","neuroscience"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Individuals with CUD showed altered DAT1 methylation levels compared to controls. These methylation changes were associated with personality traits measured by NEO-FFI (particularly neuroticism) and state-trait anxiety. The findings suggest cannabis use may produce epigenetic changes in the dopamine system that relate to psychological traits.","whyItMatters":"Epigenetic changes from cannabis use could explain lasting neuropsychiatric effects. The link between DAT1 methylation and personality traits in CUD suggests a molecular pathway connecting cannabis use to psychological changes.","specificNumbers":"490 male participants (212 CUD, 278 controls). DAT1 methylation: altered in CUD. Associated with: neuroticism (NEO-FFI), anxiety (STAI). Males only.","methodology":"Case-control study of 490 males (212 with CUD, 278 controls). Assessed personality via NEO-FFI and anxiety via STAI. DNA methylation levels at the DAT1 gene measured and compared between groups, then correlated with personality measures.","limitations":"Males only, limiting generalizability. Cross-sectional design cannot determine if methylation changes preceded or followed CUD. Single gene examined. Cannot rule out confounders. Methylation measured in peripheral tissue, not brain."},{"rthcId":"RTHC-07742","title":"Cannabidiol perturbs macrophage polarization by interfering with the metabolic flux and PI3K/Akt pathway.","authors":"Sukdee, Thadaphong; Wongprom, Benjawan; Pattarakarnkul, Thitiporn; Leelahavanichkul, Asada; Charoensappakit, Awirut; Sae-Khow, Kritsanawan; Yukhet, Phanomsak; Vilaivan, Tirayut; Palaga, Tanapat","year":2025,"journal":"Scientific reports, 16(1), 3514","doi":"10.1038/s41598-025-33360-5","pmid":"41444755","tags":["cbd","inflammation","immunology","laboratory"],"studyType":"laboratory","evidenceStrength":"preliminary","keyFinding":"CBD inhibited IL-6 and nitric oxide production without affecting TNF-alpha in M1-polarized macrophages. CBD disrupted metabolic flux and PI3K/Akt pathway signaling, which are required for pro-inflammatory macrophage activation. The effect was observed in murine bone marrow-derived macrophages.","whyItMatters":"Understanding how CBD modulates immune cells at the molecular level helps explain its anti-inflammatory effects and could guide the development of more targeted cannabinoid-based therapies.","specificNumbers":"CBD inhibited: IL-6 production, nitric oxide production. CBD did not affect: TNF-alpha production. Pathway: PI3K/Akt disruption. Metabolic flux: altered in M1 polarization.","methodology":"In vitro study using murine bone marrow-derived macrophages. Assessed CBD effects on M1 (LPS+IFN-gamma) and M2 polarization. Measured cytokine production, metabolic flux, and signaling pathway activation.","limitations":"Murine cells only. In vitro conditions do not replicate the complex immune environment. Single cannabinoid tested. Concentrations used may not reflect achievable tissue levels in vivo."},{"rthcId":"RTHC-07743","title":"Evaluating risks, monitoring cannabis use, and planning to get home safely: Exploring self-regulation processes associated with cannabis use and driving.","authors":"Sukhawathanakul, Paweena; Li, Jie; Contreras, Alejandra; Geddes, Otis; Maillet, Myles","year":2025,"journal":"Traffic injury prevention, 26(3), 263-272","doi":"10.1080/15389588.2024.2413442","pmid":"39556454","tags":["driving","safety","harm-reduction","public-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Cannabis users showed substantial heterogeneity in self-regulation processes related to driving. Subgroups differed in how they perceived risks, monitored their impairment, and planned to avoid driving under the influence. These patterns varied by user characteristics and use contexts.","whyItMatters":"One-size-fits-all approaches to cannabis-impaired driving may be ineffective because users vary dramatically in their self-regulation behaviors. Targeted interventions could address specific deficits in risk assessment or planning.","specificNumbers":"Multiple user subgroups identified. Three self-regulation domains assessed: risk perception, impairment monitoring, safe transportation planning. Substantial heterogeneity across users.","methodology":"Survey-based study identifying subgroups of current and past cannabis users based on three self-regulation domains: risk perception, impairment monitoring, and safe transportation planning. Latent class or cluster analysis identified distinct user profiles.","limitations":"Self-reported risk assessment and planning behaviors. Cross-sectional design. Cannot verify actual driving behavior. May not capture all relevant self-regulation processes. Social desirability bias possible."},{"rthcId":"RTHC-07744","title":"The Effect of Cannabis Use Disorder on Mortality and Other Outcomes in Asthma: A Nationwide Analysis (2016-2021).","authors":"Sule-Saa, Samuel; Hein, Pyae Phyo; Sackey, Jeffrey A; Pinkrah, Daniel; Towfig, Muhanned; Akella, Anusha; Kotei, Rebecca; DiCasoli, Richard; Sherazi, Andleeb; Panigrahi, Kalpana","year":2025,"journal":"Cureus, 17(10), e94969","doi":"10.7759/cureus.94969","pmid":"41281008","tags":["respiratory","safety","clinical-outcomes"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"CUD was present in 4.2% of asthma hospitalizations (23,300 patients). CUD patients were younger (mean 35.3 vs. 51.4 years) and more often male. Adjusted mortality OR: 2.40 (95% CI 1.62-3.55). Severe exacerbation adjusted OR: 1.35 (95% CI 1.07-1.71). Hospital charges were significantly higher in CUD group. No difference in length of stay.","whyItMatters":"With over 300 million people worldwide affected by asthma and increasing cannabis use, understanding how CUD affects asthma outcomes has direct clinical implications for a large population.","specificNumbers":"552,160 asthma hospitalizations. 4.2% (23,300) had CUD. CUD: mean age 35.3 vs. 51.4 years. Mortality: aOR 2.40 (CI 1.62-3.55). Severe exacerbation: aOR 1.35 (CI 1.07-1.71). Higher hospital charges: +$2,091 (p=0.004). No LOS difference.","methodology":"Retrospective cohort analysis of Nationwide Inpatient Sample (2016-2021). 552,160 asthma hospitalizations stratified by CUD status. Logistic regression for mortality and exacerbation risk; linear regression for charges and LOS, adjusted for demographics and hospital factors.","limitations":"Administrative database with ICD coding limitations. CUD diagnosis does not specify active vs. historical use or consumption method. Cannot determine if cannabis directly caused worse outcomes. Healthy user bias unlikely here since CUD implies problematic use. Residual confounding possible."},{"rthcId":"RTHC-07745","title":"Substances of Health Concern: Label Accuracy of Cannabidiol and Tetrahydrocannabinol in Commercial Cannabidiol Tinctures from the United States.","authors":"Sullivan, Zander; Lapierre, Coady; Weiser Erlandson, Laura; Pham, Linh","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1089/can.2025.0016","pmid":"40518984","tags":["cbd","safety","regulation"],"studyType":"laboratory-analysis","evidenceStrength":"moderate","keyFinding":"12 of 18 CBD tinctures had CBD concentrations deviating more than 10% from labeled amounts. Broad-spectrum tinctures were significantly less accurate than full-spectrum (p = 0.0282). No correlation between price and accuracy (p = 0.2117). Two broad-spectrum tinctures contained Δ9-THC despite being labeled THC-free. All full-spectrum tinctures had THC below the 0.3% federal limit.","whyItMatters":"Consumers relying on label accuracy for dosing decisions are being misled by the majority of products. For people using CBD for specific health conditions, inaccurate labels mean unreliable dosing.","specificNumbers":"18 tinctures tested; 12 (67%) inaccurately labeled for CBD; significant accuracy difference between broad- vs. full-spectrum (p = 0.0282); no price-accuracy correlation (p = 0.2117); 2 broad-spectrum products contained undisclosed Δ9-THC.","methodology":"Reverse-phase HPLC-UV analysis of 18 CBD tincture samples from different brands sold online in the United States. Labels deemed inaccurate if actual CBD deviated by more than 10% from labeled amount.","limitations":"Small sample of 18 products from online retailers only. Single testing method (HPLC-UV). Does not capture the full diversity of products on the market. Products were purchased at one time point."},{"rthcId":"RTHC-07746","title":"Correlates of cannabis use and cannabis use disorder among adolescents with major depressive disorder and bipolar disorder in the National Comorbidity Survey-Adolescent Supplement (NCS-A).","authors":"Sultan, Alysha A; Goldstein, Benjamin I; Blanco, Carlos; Kennedy, Kody G; Conway, Kevin P; He, Jian-Ping; Merikangas, Kathleen","year":2025,"journal":"Journal of affective disorders, 371, 268-278","doi":"10.1016/j.jad.2024.09.114","pmid":"39299588","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was most prevalent in adolescents with MDD, followed by BD, then controls. Cannabis use disorder was most prevalent in adolescents with BD. In both MDD and BD groups, cannabis use and CUD were associated with significantly higher odds of lifetime suicidal ideation and attempts, as well as other indicators of clinical severity.","whyItMatters":"Adolescents with mood disorders are already at elevated risk for self-harm. Understanding that cannabis use further increases suicidality risk in this population is critical for clinicians treating young people with depression or bipolar disorder.","specificNumbers":"MDD: 354 with cannabis use, 70 with CUD, 688 without. BD: 79 with cannabis use, 32 with CUD, 184 without. Controls: 1,413 with cannabis use, 333 with CUD, 6,970 without. Significantly higher suicidal ideation/attempts in cannabis-using mood disorder groups.","methodology":"Cross-sectional data from the 2001-2004 National Comorbidity Survey-Adolescent Supplement. In-person epidemiologic survey of adolescents ages 13-18. MDD (n=1,112), BD (n=295), controls (n=8,716). Covariate-adjusted ordinal logistic regression.","limitations":"Cross-sectional design cannot determine causation. Data from 2001-2004 may not reflect current cannabis landscape. Self-reported cannabis use. Cannot determine temporal sequence between cannabis use and suicidality."},{"rthcId":"RTHC-07747","title":"The CB1R of mPFC is involved in anxiety-like behavior induced by 0.8/2.65 GHz dual-frequency electromagnetic radiation.","authors":"Sun, Bin; Xue, Teng; Gao, An-Ning; Wang, Xin-Yu; Wu, Shuang; Liu, Xiao-Man; Zhang, Li-Hui; Li, Meng-Hua; Zou, Dong-Fang; Gao, Yan; Wang, Chang-Zhen","year":2025,"journal":"Frontiers in molecular neuroscience, 18, 1534324","doi":"10.3389/fnmol.2025.1534324","pmid":"40144805","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07748","title":"A 1:1 combination of cannabidiol and Δ9-tetrahydrocannabinol inhibit toll-like receptor 7- and 8-mediated inflammation in human immune cells.","authors":"Sun, Melody Cui; Hackett, Becky; Otálora-Alcaraz, Almudena; Downer, Eric J","year":2025,"journal":"European journal of pharmacology, 1003, 177878","doi":"10.1016/j.ejphar.2025.177878","pmid":"40615103","tags":["cbd","thc","inflammation"],"studyType":"preclinical","evidenceStrength":"low","keyFinding":"TLR7/8 activation in macrophages and PBMCs promoted production of CXCL10, TNFα, and type I interferons through NF-κB, p38 MAPK, and IRF7 pathways. CBD and THC individually reduced these inflammatory mediators, but the 1:1 combination was most effective at dampening TLR7/8-induced inflammation in both cell types.","whyItMatters":"TLR7/8 are key sensors for viral infections and are implicated in autoimmune diseases. Showing that cannabinoids can modulate these pathways suggests potential therapeutic applications for viral inflammation and autoimmune conditions.","specificNumbers":"1:1 CBD:THC ratio (mimicking Sativex/nabiximols formulation). Measured CXCL10, TNFα, type I IFNs. Assessed NF-κB activation, p38 MAPK phosphorylation, IRF7 transcription. Tested in both macrophage cell line and primary human PBMCs.","methodology":"In vitro study using THP-1-derived macrophages and primary PBMCs from healthy donors. CL075 used as TLR7/8 agonist. CBD and THC tested alone and in 1:1 combination at multiple concentrations. Measured cytokines, chemokines, interferons, and signaling pathway activation.","limitations":"In vitro study — cell culture results may not translate to whole-organism effects. Concentrations used may not reflect achievable tissue levels. Healthy donor PBMCs may respond differently than cells from patients with autoimmune conditions."},{"rthcId":"RTHC-07749","title":"The Association Between Recreational Cannabis Legalization and Substance Use Treatment Admissions for Cannabis Misuse, 2010-2021.","authors":"Sun, Ruoyan; Zhang, Hao","year":2025,"journal":"American journal of preventive medicine, 70(4), 108186","doi":"10.1016/j.amepre.2025.108186","pmid":"41241157","tags":["legalization","addiction","treatment"],"studyType":"quasi-experimental","evidenceStrength":"moderate","keyFinding":"Cannabis-related treatment admissions decreased from 18.7% of all substance treatment admissions in 2010 to 8.9% in 2021. Recreational cannabis law showed no immediate effect on treatment admissions, but a delayed increase beginning in the fourth year after implementation. The impact was particularly large among racial and ethnic minority populations.","whyItMatters":"The delayed effect suggests legalization may initially normalize cannabis use (reducing treatment-seeking) before eventually bringing more people into treatment as problematic use patterns develop. The disproportionate impact on minority populations raises equity concerns.","specificNumbers":"Cannabis treatment admissions: 18.7% (2010) to 8.9% (2021). 19,873,143 unweighted admissions. 54.7% aged 21-39. 65.8% male. Delayed effect beginning year 4 post-legalization. Significant impact on racial/ethnic minority populations.","methodology":"Analysis of Treatment Episode Data Set-Admissions (2010-2021) covering all substance use treatment admissions. Difference-in-differences models comparing states with and without recreational cannabis laws. Stratified by age, sex, and race/ethnicity.","limitations":"Treatment admissions reflect both cannabis use patterns and treatment-seeking behavior, which are influenced by legal status and stigma. Cannot separate actual need from willingness to seek treatment. TEDS data may not capture all treatment settings."},{"rthcId":"RTHC-07750","title":"Medicinal Plants for Chemotherapy-Induced Nausea and Vomiting: A Systematic Review of Antiemetic, Chemosensitizing, and Immunomodulatory Mechanisms.","authors":"Sun, Xue; Nie, Fangfang; Sun, Jizhuo; Zhang, Jingdong; Wang, Yuanhe","year":2025,"journal":"Therapeutics and clinical risk management, 21, 1187-1218","doi":"10.2147/TCRM.S531645","pmid":"40771488","tags":["cbd","thc","cancer"],"studyType":"systematic-review","evidenceStrength":"low","keyFinding":"Among 22 botanicals reviewed, cannabis (THC, CBD) modulates the endocannabinoid system and 5-HT3 receptors for CINV relief and may enhance chemotherapy sensitivity. Ginger acts via 5-HT3 and NK-1 inhibition. Turmeric offers anti-inflammatory effects and boosts chemosensitivity via NF-κB modulation. Synergistic combinations (e.g., ginger with turmeric) showed enhanced efficacy.","whyItMatters":"CINV remains poorly managed by conventional antiemetics for many cancer patients. Understanding the specific mechanisms of plant-based alternatives could lead to evidence-based complementary therapies.","specificNumbers":"22 botanicals reviewed. Cannabis: THC and CBD act on endocannabinoid system and 5-HT3 receptors. Ginger: gingerols and shogaols antagonize 5-HT3 and NK-1. Turmeric: curcumin modulates NF-κB and P-glycoprotein.","methodology":"Systematic review with comprehensive literature search and critical analysis of studies on medicinal plants for chemotherapy-induced nausea and vomiting. Evaluated bioactive compounds, mechanisms, and chemosensitizing/immunomodulatory properties.","limitations":"Systematic review of heterogeneous studies with varying quality. Many findings based on preclinical data. Clinical trial evidence is limited for most botanicals. Drug interactions with chemotherapy agents are not fully characterized."},{"rthcId":"RTHC-07751","title":"Astrogliosis Occurs Selectively in Amygdala of Adolescent Primate and Rodent Following Daily Δ9-Tetrahydrocannabinol, Prevented by Cannabidiol Co-Treatment.","authors":"Sun, Yalin; Sivasubramanian, Meenalochani; Milenkovic, Marija; Gumbert, Andrew; Bergman, Jack; Ge, Preston; Heiman, Myriam; Di Raddo, Marie-Eve; Withey, Sarah L; Madras, Bertha K; George, Susan R","year":2025,"journal":"Biological psychiatry global open science, 5(4), 100496","doi":"10.1016/j.bpsgos.2025.100496","pmid":"40487783","tags":["cbd","thc","neuroscience","youth"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"THC induced GFAP and complement factor-B upregulation (proinflammatory gliosis) exclusively in the adolescent amygdala, not in other brain regions or adults. THC also reduced synaptic plasticity markers (stathmin-1, NrCAM). CBD co-treatment prevented astrogliosis but did not restore synaptic plasticity markers. The vulnerability was traced to astrocyte-localized CB1R expression specifically in the amygdala.","whyItMatters":"This study provides a molecular mechanism for why adolescent cannabis use increases risk of anxiety and neuropsychiatric disorders: THC specifically inflames the adolescent amygdala (the brain region governing fear and emotion). The CBD protective effect is clinically significant.","specificNumbers":"Adolescent-specific GFAP and complement factor-B upregulation in amygdala. CB1R expression: astrocyte-localized in amygdala, neuronal in cortex and striatum. CBD prevented gliosis but not synaptic plasticity loss. Astrogliosis correlated with fragmented sleep; reduced plasticity correlated with anxiety.","methodology":"Multi-species study: proteomic analysis of amygdala from adolescent squirrel monkeys chronically treated with THC, validated in adolescent (P35) and adult (P70) rats. Behavioral testing, primary astrocyte cultures for mechanistic studies. CB1 knockout cells used as controls.","limitations":"Animal models (primate and rat) may not fully recapitulate human adolescent brain development. CBD prevented inflammation but not all THC-induced changes. Chronic dosing regimen may not match typical human use patterns."},{"rthcId":"RTHC-07752","title":"The Cannabinoid CB1 Receptor Inverse Agonist/Antagonist SR141716A Activates the Adenylate Cyclase/PKA Signaling Pathway Among Other Intracellular Emetic Signals to Evoke Vomiting in Least Shrews (Cryptotis parva).","authors":"Sun, Yina; Belkacemi, Louiza; Zhong, Weixia; Daily, Zollie; Darmani, Nissar A","year":2025,"journal":"International journal of molecular sciences, 26(20)","doi":"10.3390/ijms26209884","pmid":"41155180","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07753","title":"Effects of Cannabidiol Oil on Anesthetic Requirements in Cats: MAC Determination and Serum Profiling via Nanoscale Liquid Chromatography-Tandem Mass Spectrometry.","authors":"Suriyawongpongsa, Panisara; Niyom, Sirirat; Wanapinit, Kannika; Vijarnsorn, Monchanok; Roytrakul, Sittiruk; Ploypetch, Sekkarin","year":2025,"journal":"Animals : an open access journal from MDPI, 15(10)","doi":"10.3390/ani15101393","pmid":"40427271","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07754","title":"The Effect of Growth and Nutrition in Black Soldier Fly Larvae Fed by Hemp Seed Oil Mixed Diets.","authors":"Suwannayod, Suttida; Setthaya, Phattawin; Limsopatham, Kwankamol; Harnpornchai, Napat","year":2025,"journal":"Insects, 16(11)","doi":"10.3390/insects16111081","pmid":"41302827","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07755","title":"Entourage effects of nonpsychotropic cannabinoids on visceral sensitivity in experimental colitis.","authors":"Svendsen, Kristofer; Bradaia, Amyaouch; Gandini, Maria A; Defaye, Manon; Matisz, Chelsea; Abdullah, Nasser S; Gruber, Aaron; Zamponi, Gerald W; Sharkey, Keith A; Altier, Christophe","year":2025,"journal":"The Journal of pharmacology and experimental therapeutics, 392(3), 103389","doi":"10.1016/j.jpet.2025.103389","pmid":"39921943","tags":["cbd","pain","ibd"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"Single injections of CBD or CBG (10 mg/kg) each reduced visceral hypersensitivity and spinal cord c-Fos activation in colitis mice. A combination of CBD (5 mg/kg) with CBC, CBDV, and CBG (each 1 mg/kg) — all at individually subtherapeutic doses — also reduced visceral pain. The combination acted through voltage-gated sodium and calcium channels (particularly Cav2.2) but not Cav3.2 or potassium channels.","whyItMatters":"IBD patients frequently report abdominal pain as their most disabling symptom. This study demonstrates that a mixture of non-psychoactive cannabinoids can provide pain relief at doses where individual compounds are ineffective — a true entourage effect with identified molecular targets.","specificNumbers":"CBD 10 mg/kg or CBG 10 mg/kg individually effective. Combination: CBD 5 mg/kg + CBC 1 mg/kg + CBDV 1 mg/kg + CBG 1 mg/kg (all subtherapeutic individually). Pain relief without altering colitis inflammation. Targets: Nav and Cav2.2 channels.","methodology":"Mouse model of dextran sulfate sodium colitis-induced visceral hypersensitivity. Single-injection cannabinoid administration. Patch-clamp electrophysiology on dorsal root ganglia neurons and recombinant ion channels to identify antinociceptive targets.","limitations":"Mouse model of colitis may not fully recapitulate human IBD pain. Single-injection design does not assess chronic use. Subtherapeutic doses were defined within this model only. Did not reduce inflammation, only pain."},{"rthcId":"RTHC-07756","title":"Cannabinoid Hyperemesis Syndrome, 2016 to 2022.","authors":"Swartz, James A; Franceschini, Dana","year":2025,"journal":"JAMA network open, 8(11), e2545310","doi":"10.1001/jamanetworkopen.2025.45310","pmid":"41284293","tags":["safety","public-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"CHS-proxy visits increased from 4.4 per 100,000 ED visits in 2016 to a peak of 33.1 in Q2 2020, remaining elevated at 22.3 in 2022. Concurrently, CVS-only visits declined from 300 to 186 per 100,000. Highest risk: ages 18-25 (RRR 3.59) and 26-35 (RRR 2.26). Females had slightly lower risk (RRR 0.92). Southern US had lower risk vs. Northeast (RRR 0.46).","whyItMatters":"CHS is increasingly recognized but still frequently misdiagnosed as cyclic vomiting syndrome. The sharp rise during COVID may reflect increased cannabis consumption during lockdowns, and the sustained elevation suggests this is not a temporary phenomenon.","specificNumbers":"806 million weighted ED visits. CHS rate: 4.4 to 33.1 per 100,000 (peaked Q2 2020), 22.3 in 2022. CVS declined: 300 to 186 per 100,000. Risk: 18-25 years RRR 3.59; 26-35 years RRR 2.26. Female RRR 0.92. South vs. Northeast RRR 0.46.","methodology":"Cross-sectional analysis of the Nationwide Emergency Department Sample (~85% of annual US ED visits), 2010-2022. 188.6 million unweighted visits (806 million weighted). CHS proxied by co-occurrence of cannabis-related condition and cyclic vomiting syndrome. Restricted cubic splines and multinomial logistic regression.","limitations":"CHS identified by proxy (cannabis diagnosis + CVS diagnosis), which may over- or underestimate true prevalence. ICD coding changes during study period. Cannot determine if COVID-era increase was from more cannabis use or more ED visits for vomiting."},{"rthcId":"RTHC-07757","title":"Delta-9 THC detection in the young pediatric postmortem population: 2018-2024.","authors":"Swatek, Jennifer; Wang, George Sam; Labay, Laura","year":2025,"journal":"Child abuse & neglect, 170, 107763","doi":"10.1016/j.chiabu.2025.107763","pmid":"41202434","tags":["safety","youth","public-health"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Among 17,512 postmortem pediatric blood cases, THC positivity rates increased significantly from 1.6% to 2.8% (LOD, p=0.0075) and 0.43% to 1.1% (LOQ, p=0.0057) between 2018-2024. Of positive cases: 86% were in children ≤2 years, 71% under 1 year, 65% ≤6 months, and 31% under 1 month or intrauterine demise. Cannabis was the only drug found in 49% of cases.","whyItMatters":"The finding that THC exposure is increasing in the youngest and most vulnerable population — infants and newborns — raises serious child safety and public health concerns as cannabis becomes more widely available in homes.","specificNumbers":"17,512 postmortem cases. THC positivity: 1.6% to 2.8% (LOD, p=0.0075). 518 LC-MS/MS confirmed cases. 86% in children ≤2 years. 71% under 1 year. 65% ≤6 months. 31% under 1 month/intrauterine. Cannabis sole finding in 49%. Caffeine most common co-finding (26%).","methodology":"Retrospective analysis of data from a large reference laboratory serving US medical examiners and coroners, 2018-2024. 17,512 postmortem blood cases screened by ELISA and/or confirmed by LC-MS/MS.","limitations":"Postmortem cases represent the most extreme outcomes and do not reflect overall pediatric THC exposure rates. Cannot determine route of exposure (prenatal, ingestion, secondhand smoke). THC presence does not necessarily indicate cause of death."},{"rthcId":"RTHC-07758","title":"Beyond the hype: a comprehensive exploration of CBD's biological impacts and mechanisms of action.","authors":"Swenson, Karli","year":2025,"journal":"Journal of cannabis research, 7(1), 24","doi":"10.1186/s42238-025-00274-y","pmid":"40350443","tags":["cbd","pharmacology"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"CBD interacts with endocannabinoid receptors, multiple ion channels, cytochrome P450 enzymes (affecting drug metabolism), inflammatory pathways, and sex hormone regulation. Documented effects span psychiatric disorders, seizures, nausea/vomiting, pain, thermal regulation, neuronal signaling, neurodegenerative diseases, reproductive aging, and energy homeostasis.","whyItMatters":"As CBD consumption increases rapidly worldwide, understanding its full range of biological interactions is essential for clinical management — especially given the potential for CBD to interact with pharmaceutical medications through cytochrome P450 enzymes.","specificNumbers":"Interactions documented with: endocannabinoid receptors (CB1, CB2), multiple ion channels, CYP450 enzymes (drug metabolism), inflammatory pathways, sex hormones. Effects on: seizures, pain, nausea, neurodegeneration, psychiatric disorders, thermal regulation, energy homeostasis.","methodology":"Comprehensive literature review across PubMed, Web of Science, and Google Scholar. Included cell culture, animal model, biochemical, and clinical studies. Findings synthesized thematically by body system.","limitations":"Narrative review rather than systematic review with defined search criteria. Cannot assess quality of underlying evidence systematically. Many included findings are from preclinical studies. Rapidly evolving field means some interactions may be incompletely characterized."},{"rthcId":"RTHC-07759","title":"Cariprazine as a maintenance treatment in dual schizophrenia: a 6-month observational study in patients with schizophrenia and cannabis use disorder.","authors":"Szerman, Nestor; Vega, Pablo; Roncero, Carlos; Peris, Lola; Grau-López, Lara; Basurte-Villamor, Ignacio","year":2025,"journal":"International clinical psychopharmacology, 40(3), 167-175","doi":"10.1097/YIC.0000000000000568","pmid":"39319529","tags":["mental-health","addiction","treatment"],"studyType":"observational","evidenceStrength":"low","keyFinding":"Cariprazine treatment over 6 months produced significant improvements in schizophrenia symptoms (PANSS change: -47.88 points, p<0.0001; CGI-SCH change: -8.26 points, p<0.0001). Cannabis use and dependence also decreased (CAST change: -7.0 points, p<0.0001; SDS change: -7.88 points, p<0.0001). Functioning improved (SDI change: -9.48 points, p<0.0001).","whyItMatters":"Patients with both schizophrenia and cannabis use disorder are common but poorly served by treatments that address only one condition. Finding a single medication that may improve both is clinically valuable.","specificNumbers":"58 patients. 6-month follow-up. PANSS: -47.88 points (p<0.0001). CGI-SCH: -8.26 points (p<0.0001). CAST: -7.0 points (p<0.0001). SDS: -7.88 points (p<0.0001). SDI: -9.48 points (p<0.0001).","methodology":"6-month observational study of 58 patients diagnosed with both schizophrenia and cannabis use disorder, treated with cariprazine in a real-world clinical setting. Multiple validated outcome measures for psychosis, cannabis use, dependence, and functioning.","limitations":"No control group or randomization. Small sample (n=58). Observational design cannot establish causation. Real-world setting with potential selection bias. Improvement could reflect regression to the mean or natural course."},{"rthcId":"RTHC-07760","title":"The antioxidant N-acetylcysteine prevents cortical neuropathological phenotypes caused by adolescent Δ-9-tetrahydrocannabinol exposure in male rats.","authors":"Szkudlarek, Hanna J; Singh Mann, Rajkamalpreet; Wieczerzak, Krystyna; Sarikahya, Mohammed Halit; Uzuneser, Taygun C; De Felice, Marta; Rodríguez-Ruiz, Mar; Galindo, Juan Pablo; Pusparajah, Mathusha; Whitehead, Shawn N; Rushlow, Walter J; Hardy, Daniel B; Schmid, Susanne; Yeung, Ken K-C; Laviolette, Steven R","year":2025,"journal":"Translational psychiatry, 15(1), 374","doi":"10.1038/s41398-025-03580-4","pmid":"41052996","tags":["thc","neuroprotection","youth"],"studyType":"preclinical","evidenceStrength":"low","keyFinding":"NAC treatment prevented cognitive deficits, synaptic dysfunction, neuronal changes, and neurochemical imbalances induced by adolescent THC exposure in the medial prefrontal cortex of rats. This identifies THC-induced oxidative stress as a causal factor in cannabinoid-related neuropsychiatric risk.","whyItMatters":"This study identifies a potentially actionable mechanism — oxidative stress — underlying THC brain harm during adolescence, and demonstrates that a widely available supplement (NAC) can prevent it. NAC is already used clinically for other conditions.","specificNumbers":"NAC prevented cognitive, synaptic, neuronal, and neurochemical deficits in medial prefrontal cortex. Oxidative stress identified as causal factor. NAC is a glutathione precursor that normalizes glutamate and GABA activity.","methodology":"Rodent model of adolescent brain development with chronic THC exposure. NAC administered as preventive treatment. Assessed cognitive function, synaptic markers, neuronal integrity, and neurochemistry in medial prefrontal cortex.","limitations":"Rat model may not fully translate to human adolescent brain development. THC dosing and administration route may differ from human use. NAC was given preventively — unclear if it works after damage has occurred. Single study requiring replication."},{"rthcId":"RTHC-07761","title":"Skeletal disorders in laying hens: a systematic review with a focus on non-cage housing systems and hemp-based dietary interventions for bone health.","authors":"Szmek, J; Englmaierová, M; Skřivan, M; Pěchoučková, E","year":2025,"journal":"British poultry science, 66(6), 717-746","doi":"10.1080/00071668.2025.2489059","pmid":"40331968","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07762","title":"History of cannabis use and cognitive function in older adults: findings from the UK biobank.","authors":"Sznitman, Sharon R; Vered, Shiraz; Weinstein, Galit","year":2025,"journal":"Age and ageing, 54(11)","doi":"10.1093/ageing/afaf319","pmid":"41189327","tags":["cognition","aging"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"Cross-sectionally, lifetime cannabis users (17% of sample) performed better in attention (B=0.071), executive function (B=0.047), processing speed (B=0.363), visual memory (B=0.062), and working memory (B=0.181). Current use associated with better working memory (B=0.169). Longitudinally, past use linked to less decline in executive function, but longer duration predicted steeper processing speed decline.","whyItMatters":"This is one of the largest studies examining cannabis and cognition in older adults. The finding that past use is associated with better cognitive performance challenges assumptions about long-term cognitive harm, though the relationship is complex.","specificNumbers":"67,713 cross-sectional; 52,002 longitudinal. Mean age 67.2 years. 46.1% male. 17% lifetime cannabis users. Better performance across all 5 cognitive domains. Longitudinal: less executive function decline with past use; more processing speed decline with longer duration.","methodology":"Cross-sectional (n=67,713) and longitudinal (n=52,002) analyses of UK Biobank participants aged 60+. Self-reported cannabis use patterns. Computerized cognitive tests for attention, executive function, processing speed, visual and working memory. Multivariable linear regression adjusted for demographics, health, and lifestyle.","limitations":"Self-reported cannabis use subject to recall bias. UK Biobank participants are healthier and more educated than the general population (healthy volunteer bias). Cross-sectional associations cannot determine causation. Confounders like personality traits may drive both cannabis use and cognitive performance."},{"rthcId":"RTHC-07763","title":"Negotiating the divide: Science, politics, and institutional boundaries in Swiss cannabis regulation.","authors":"Sznitman, Sharon R; Auer, Reto; Havinga, Jonathan Christopher; Casalini, Alessandro; Broers, Barbara","year":2025,"journal":"The International journal on drug policy, 143, 104865","doi":"10.1016/j.drugpo.2025.104865","pmid":"40479915","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07764","title":"Differential impact of Cannabis abuse on neurological disorders.","authors":"Tabi, Younes Adam; Meyer, Eva Christina","year":2025,"journal":"Journal of the neurological sciences, 474, 123527","doi":"10.1016/j.jns.2025.123527","pmid":"40373479","tags":["neurology","safety","clinical-outcomes"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Across all 10 neurological conditions studied (cluster headache, neuropathy, MS, stroke, TIA, Parkinson's, Alzheimer's, vascular dementia, migraine, tension headache), cannabis abuse was consistently linked to significantly higher ED visits and pain prevalence. For example, neuropathy patients with cannabis abuse had 25.8% ED visits vs. 19.3% in non-users. Mortality and recurrent cerebrovascular events trended higher but were generally not statistically significant.","whyItMatters":"This is the first study to systematically compare cannabis abuse outcomes across multiple neurological conditions using a unified methodology. The consistent pattern of increased ED visits and pain across all conditions suggests cannabis abuse may worsen clinical management regardless of the specific diagnosis.","specificNumbers":"143 healthcare organizations. 10 neurological conditions. Consistently higher ED utilization and pain prevalence across all conditions. Neuropathy example: 25.8% vs. 19.3% ED visits. Mortality and stroke recurrence trended higher but generally not significant. 3-year follow-up.","methodology":"Retrospective analysis using TriNetX global federated health research network (143 healthcare organizations). Propensity score matching balanced demographics and clinical characteristics for each of 10 neurological conditions. Up to 3-year follow-up comparing cannabis abuse vs. no cannabis abuse.","limitations":"Cannabis abuse identified by ICD codes, which captures only diagnosed problematic use. Cannot determine causation or temporal sequence. Propensity matching cannot control for unmeasured confounders. Cannabis abuse diagnosis may be a marker for overall health behavior rather than a direct cause."},{"rthcId":"RTHC-07765","title":"Maternal perinatal cannabis use disorder and the risk of anxiety disorders in offspring: Insights from a longitudinal data-linkage cohort study.","authors":"Tadesse, Abay Woday; Ayano, Getinet; Dachew, Berihun Assefa; Betts, Kim; Alati, Rosa","year":2025,"journal":"Journal of affective disorders, 389, 119743","doi":"10.1016/j.jad.2025.119743","pmid":"40555352","tags":["pregnancy","mental-health","youth"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"Offspring exposed to maternal CUD prenatally had 79% increased risk of any anxiety disorder (aRR 1.79), with specific increases for PTSD (aRR 2.46), GAD (aRR 2.18), and childhood anxiety disorders (aRR 1.91). Postnatal CUD exposure was also associated with increased anxiety (aRR 2.02) and PTSD (aRR 2.97). Findings held in mediation and propensity score matching analyses.","whyItMatters":"This is one of the largest studies linking maternal cannabis use disorder to specific anxiety disorder outcomes in children. The dose-response pattern (prenatal and postnatal exposure both matter) strengthens the case for targeted interventions during and after pregnancy.","specificNumbers":"223,068 births. Prenatal CUD: any anxiety aRR 1.79 (CI 1.40-2.26); PTSD aRR 2.46 (CI 1.78-3.33); GAD aRR 2.18 (CI 1.03-4.60). Postnatal CUD: any anxiety aRR 2.02 (CI 1.22-3.14); PTSD aRR 2.97 (CI 1.56-5.17).","methodology":"Population-based retrospective cohort using linked administrative health data from New South Wales, Australia. 223,068 live births (2003-2005). Maternal CUD and offspring anxiety disorders identified via ICD-10 codes. Log-binomial regression with mediation and propensity score matching.","limitations":"Administrative data with ICD-coded diagnoses may miss milder cases. Cannot determine biological vs. environmental mechanisms. CUD diagnosis may correlate with other risk factors (poverty, other substance use, adverse childhood experiences). Australian cohort from 2003-2005."},{"rthcId":"RTHC-07766","title":"Maternal cannabis use disorder and offspring behavioral outcomes: findings from a linked data cohort study.","authors":"Tadesse, Abay Woday; Dachew, Berihun Assefa; Ayano, Getinet; Betts, Kim; Alati, Rosa","year":2025,"journal":"Psychiatry research, 346, 116404","doi":"10.1016/j.psychres.2025.116404","pmid":"39956029","tags":["pregnancy","youth","mental-health"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"Maternal CUD during pregnancy was associated with significantly higher risk of disruptive behavioral disorders in offspring: antenatal CUD (RR 3.56, CI 2.42-5.05), perinatal CUD (RR 3.55, CI 2.45-4.98), and postnatal CUD (RR 2.95, CI 1.23-6.16). All exposure windows showed significant associations after adjustment for confounders.","whyItMatters":"The consistent 3-3.5x risk increase across antenatal, perinatal, and postnatal exposure windows provides strong evidence that maternal CUD is associated with behavioral problems in children, regardless of timing.","specificNumbers":"Antenatal CUD: RR 3.56 (CI 2.42-5.05). Perinatal CUD: RR 3.55 (CI 2.45-4.98). Postnatal CUD: RR 2.95 (CI 1.23-6.16). All statistically significant after adjustment.","methodology":"Population-based retrospective cohort using linked health data from New South Wales, Australia. Live births 2003-2005. CUD and disruptive behavioral disorders identified via ICD codes. Generalized linear models with log-binomial regression.","limitations":"ICD-coded diagnoses from administrative data. Cannot separate cannabis effects from associated risk factors. Disruptive behavioral disorders may be underdiagnosed. Same cohort limitations as companion anxiety study."},{"rthcId":"RTHC-07767","title":"Utilizing Hot-Melt Extrusion and Spray Drying Techniques for Preparation of Liquid and Solid Cannabidiol Nano-Structured Lipid Carriers Formulations.","authors":"Taha, Iman E; ElSohly, Mahmoud A; Mostafa, Nourhan; Almutairi, Mashan; Ashour, Eman A","year":2025,"journal":"AAPS PharmSciTech, 27(1), 26","doi":"10.1208/s12249-025-03277-3","pmid":"41219654","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07768","title":"Cannabinoid Derived Product is a Potential Novel Therapeutic for Papillary Thyroid Carcinoma.","authors":"Taico Oliva, Carolina; Musa, Ibrahim; Ardalani, Fariba; Breslin, Joseph; Yang, Nan; Moscatello, Augustine; Rotsides, Janine; Tiwari, Raj; Geliebter, Jan; Li, Xiu-Min","year":2025,"journal":"Integrative cancer therapies, 24, 15347354251332966","doi":"10.1177/15347354251332966","pmid":"40703048","tags":["cancer","cbd"],"studyType":"preclinical","evidenceStrength":"low","keyFinding":"The cannabinoid product BRF1A decreased K1 papillary thyroid cancer cell viability dose- and time-dependently. Within 24 hours, it increased TP53 gene expression (tumor suppressor) while decreasing BCL-2 (anti-apoptotic) and c-Myc (proliferation) gene expression, suggesting a pro-apoptotic mechanism.","whyItMatters":"Papillary thyroid carcinoma is the most common thyroid cancer. While surgery is effective, non-invasive therapeutic options are being explored. This study provides initial evidence that cannabinoids may affect thyroid cancer cells through well-characterized anti-cancer pathways.","specificNumbers":"K1 cell line (PTC cells). BRF1A: dose- and time-dependent cytotoxicity. 24-hour effects: TP53 upregulated, BCL-2 downregulated, c-Myc downregulated. 48-hour time point also assessed.","methodology":"In vitro study using K1 papillary thyroid cancer cell line derived from metastatic well-differentiated PTC. BRF1A co-cultured with cells at 37°C. Cell viability assessed by trypan blue exclusion. Gene expression measured by qRT-PCR at 24 and 48 hours.","limitations":"Single cell line in vitro study. Proprietary cannabinoid product (BRF1A) — specific composition unclear. No comparison to standard treatments. No in vivo validation. Cannot predict clinical efficacy from cell culture results."},{"rthcId":"RTHC-07769","title":"PRISM-5 update: Adaptation and validation of the Spanish version interview for dual diagnosis assessment based on DSM-5 criteria.","authors":"Tamarit, Claudio; Pellicer-Roca, Maria; Alias-Ferrí, María; Roncero, Carlos; Didia-Attas, Javier; Fonseca, Francina; Mateus, Julián Andrés; Mestre Pintó, Joan I; Torrens, Marta","year":2025,"journal":"Spanish journal of psychiatry and mental health","doi":"10.1016/j.sjpmh.2025.09.002","pmid":"41038515","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07770","title":"Research mapping of cannabinoids and endocannabinoid system in cancer over the past three decades: insights from bibliometric analysis.","authors":"Tan, Yaqian; Xia, Hui; Song, Qi","year":2025,"journal":"Frontiers in pharmacology, 16, 1540619","doi":"10.3389/fphar.2025.1540619","pmid":"40242437","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07771","title":"The influence of genetics on the endocannabinoid system gene expression and relevance for targeting reproductive conditions.","authors":"Tanaka, Keisuke; Amoako, Akwasi A; Mortlock, Sally; Rogers, Peter A W; Holdsworth-Carson, Sarah J; Donoghue, Jacqueline F; Teh, Wan Tinn; Montgomery, Grant W; McKinnon, Brett","year":2025,"journal":"Journal of cannabis research, 7(1), 29","doi":"10.1186/s42238-025-00275-x","pmid":"40442827","tags":["genetics","endocannabinoid-system"],"studyType":"genomic-analysis","evidenceStrength":"moderate","keyFinding":"In 31,684 participants from eQTLGen, 22,020 genetic variants (eQTLs) influenced 43 of 70 selected ECS genes. Across 49 tissues in GTEx, 69 of 70 ECS genes had tissue-specific genetic effects. The female reproductive system had fewer eQTLs compared to other physiological systems. In the endometrium specifically, FABP3 (an endocannabinoid transporter) showed significant genetic effects, with 13 additional ECS genes showing FDR-significant eQTLs.","whyItMatters":"Individual genetic differences in the endocannabinoid system may explain why people respond differently to cannabis. Understanding tissue-specific genetic effects is essential for developing targeted cannabinoid-based therapies.","specificNumbers":"31,684 participants (eQTLGen); 838 donors, 49 tissues (GTEx); 206 endometrial samples. 22,020 eQTLs for 43/70 ECS genes. 69/70 genes had tissue-specific eQTLs. FABP3 significant in endometrium. 14 independent FDR-significant eQTLs for 13 ECS genes in endometrium.","methodology":"Analysis of publicly available genomic datasets: eQTLGen (31,684 participants, blood-based), GTEx (838 donors, 49 tissues), and an in-house endometrial dataset (206 samples). Examined genetic variant effects on expression of 70 endocannabinoid system genes.","limitations":"Datasets are from European-ancestry-predominant populations. Gene expression does not necessarily reflect protein levels or receptor function. Endometrial samples are a small dataset. Cannot directly predict clinical cannabinoid response from eQTL data."},{"rthcId":"RTHC-07772","title":"Identification of Novel THC Analogs: Chloro Derivatives of Hexahydrocannabinol and Tetrahydrocannabibutol Butanoate in an Oil Product Obtained in Japan.","authors":"Tanaka, Rie; Kawamura, Maiko; Ito, Michiho; Kikura-Hanajiri, Ruri","year":2025,"journal":"Drug testing and analysis, 17(11), 2170-2177","doi":"10.1002/dta.3927","pmid":"40880172","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07773","title":"Assessing the Impact of Psychiatric Deinstitutionalization and Substance Use on Patient Outcomes: A Multi-Faceted Analysis.","authors":"Tanase, Elena; Laitin, Sorina Maria Denisa; Ilie, Adrian Cosmin; Ion, Radu; Surducan, Dan-Alexandru; Bucur, Adina; Marc, Felicia; Folescu, Roxana; Ursoniu, Sorin","year":2025,"journal":"Healthcare (Basel, Switzerland), 13(14)","doi":"10.3390/healthcare13141700","pmid":"40724724","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07774","title":"Research Review: What we have learned about the endocannabinoid system in developmental psychopathology.","authors":"Tansey, Ryann C; Ferger, Marc D; Marusak, Hilary A; Mayo, Leah M","year":2025,"journal":"Journal of child psychology and psychiatry, and allied disciplines, 66(12), 1904-1915","doi":"10.1111/jcpp.70006","pmid":"40639419","tags":["endocannabinoid-system","youth","mental-health"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"The endocannabinoid system plays key roles in stress, emotion, and social behavior regulation throughout development. Dysregulation is evident in various pediatric psychiatric disorders. While cannabis itself has too many limitations for pediatric use (legal, stigma, side effects), pharmacological and non-pharmacological interventions targeting the ECS may offer viable alternatives.","whyItMatters":"Psychiatric disorders in children and adolescents are increasing, and many current treatments have limited efficacy. The endocannabinoid system represents a novel therapeutic target that could lead to new treatment approaches, but safety in developing brains must be carefully established.","specificNumbers":"Reviewed ECS development from prenatal to adolescent periods. Examined dysregulation across multiple psychiatric disorders. Summarized current pharmacological and non-pharmacological interventions targeting ECS.","methodology":"Narrative review summarizing ECS function during development, its contribution to psychopathology in children and adolescents, behavioral evidence, and current pharmacological and non-pharmacological therapeutic investigations.","limitations":"Narrative review without systematic search criteria. Most evidence is from preclinical studies. Limited clinical trial data for ECS-targeting compounds in pediatric populations. Developmental trajectory of the ECS is not fully characterized."},{"rthcId":"RTHC-07775","title":"Inflammatory-Directed Nanomotors for Targeted Osteoarthritis Treatment.","authors":"Tao, Leiming; Wu, Yingjie; Mao, Meng; Lu, Weihong; He, Qiang","year":2025,"journal":"Advanced healthcare materials, 14(27), e01206","doi":"10.1002/adhm.202501206","pmid":"40692531","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07776","title":"The cannabinoid CB2 receptor: improvement of sleep or memory in rotenone model of Parkinson's disease.","authors":"Targa, Adriano D S; Dos Santos-Lima, Gustavo Z; Rodrigues, Lais S; Cavalcante, Samantha F; Fontenele-Araújo, John; Torterolo, Pablo; Fagotti, Juliane; Ilkiw, Jéssica; Noseda, Ana Carolina D; Trombetta-Lima, Marina; Dorieux, Flávia; Dominico, Patricia S; Sogayar, Mari C; Andersen, Monica Levy; Stern, Cristina Aparecida; Lima, Marcelo M S","year":2025,"journal":"European journal of pharmacology, 1000, 177745","doi":"10.1016/j.ejphar.2025.177745","pmid":"40383223","tags":["neuroscience","endocannabinoid-system"],"studyType":"preclinical","evidenceStrength":"low","keyFinding":"CB2 receptor antagonist AM630 reversed rotenone-induced sleep macrostructure alterations and inter-hemispheric synchronization abnormalities in Parkinson's rats. Conversely, CB2 partial agonist GW405833 restored short-term memory in the object recognition task. This suggests CB2 modulation has paradoxical outcomes: blocking helps sleep, activating helps memory.","whyItMatters":"Sleep disturbances and cognitive impairment are debilitating non-motor symptoms of Parkinson's disease that are poorly treated. Finding that CB2 receptor modulation can address both — albeit in opposite directions — opens new therapeutic avenues.","specificNumbers":"65 rats. AM630 (CB2 antagonist, 3 μg/μl) reversed sleep alterations. GW405833 (CB2 partial agonist, 10 μg/μl) restored short-term memory. Paradoxical outcomes suggest independent mechanisms for sleep and memory in Parkinson's.","methodology":"Male Wistar rats (n=65) received intranigral rotenone or vehicle injection. Seven days later, rotenone-treated animals received intrastriatal CB2 agonist (GW405833) or antagonist (AM630). Assessed 6-hour sleep-wake recordings and object recognition memory. Striatal CB1/CB2 transcript levels measured by RT-PCR.","limitations":"Rotenone model recapitulates some but not all aspects of human Parkinson's disease. Small sample divided across multiple groups. Intrastriatal drug administration not clinically practical. Short-term assessments only."},{"rthcId":"RTHC-07777","title":"Comparative Pharmacokinetic Assessment of Innovative Sublingual, Rectal and Vaporizer Cannabis Products Versus Approved Cannabis Products in Healthy Volunteers.","authors":"Tarlovski, Sheina; Bar Kadmon, Anat; Goldberg, Eran; Segal, Dadi; Gavish, Dov; Stepensky, David","year":2025,"journal":"Cannabis and cannabinoid research, 10(2), e289-e298","doi":"10.1089/can.2023.0229","pmid":"38656906","tags":["pharmacology","thc","cbd"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Novel cannabis products showed faster absorption of THC and CBD compared to Sativex and oil-based oromucosal products. The vaporizer provided the most immediate systemic absorption with highest peak concentrations. Sublingual tablets and suppositories had somewhat lower bioavailability than oromucosal products. Safety profiles were comparable across all formulations.","whyItMatters":"Different medical conditions require different cannabinoid absorption profiles. Faster, more predictable absorption could improve dosing precision and clinical outcomes for patients who need rapid symptom relief.","specificNumbers":"12 volunteers; 10 products tested; 8 per volunteer. Vaporizer: fastest absorption, highest Cmax. Sublingual/suppositories: faster absorption but lower bioavailability than oromucosal. Safety: novel products non-inferior to approved formulations.","methodology":"Single-center, single-dose, randomized, crossover, partially blinded controlled trial. 12 healthy volunteers each received 8 of 10 products: novel sublingual tablet, vaporizer, rectal suppositories, Sativex, oil-based oromucosal products, and placebo. Serial blood sampling with noncompartmental pharmacokinetic analysis of THC, 11-OH-THC, and CBD.","limitations":"Very small sample (n=12). Single-dose design in healthy volunteers. Cannot extrapolate to patients with medical conditions. Crossover design may have period effects. Bioavailability differences may matter clinically."},{"rthcId":"RTHC-07778","title":"Technology-Based Psychotherapeutic Interventions for Decreasing Cannabis Use in People with Psychosis: A Systematic Review Update.","authors":"Tatar, Ovidiu; Bakouni, Hamzah; Abdel-Baki, Amal; Jutras-Aswad, Didier","year":2025,"journal":"Cannabis and cannabinoid research, 10(1), 11-17","doi":"10.1089/can.2024.0094","pmid":"39446673","tags":["mental-health","treatment","addiction"],"studyType":"systematic-review","evidenceStrength":"low","keyFinding":"Only 3 studies met inclusion criteria from 5,083 screened records. Two quantitative studies showed promising results for internet or VR-based interventions incorporating CBT, motivational interviewing, and psychoeducation on cannabis use frequency and quantity. One qualitative study explored patient and clinician perspectives on using technology for cannabis interventions. Total across original review and update: only 11 peer-reviewed articles.","whyItMatters":"Cannabis use is highly prevalent in people with psychotic disorders and worsens outcomes. Despite the explosion of digital mental health tools, this population has been almost entirely neglected by technology-based intervention developers.","specificNumbers":"5,083 records screened. 3 studies retained. Only 11 total peer-reviewed articles across both reviews. Internet and VR-based interventions showed promising results. CBT, MI, and psychoeducation components.","methodology":"Systematic review update searching Medline, PubMed, Embase, CINAHL, PsycINFO, and EMB Reviews for studies indexed November 2019 to July 2023. PRISMA guidelines. Narrative synthesis of retained studies.","limitations":"Very small evidence base (3 new studies). Heterogeneous interventions make comparison difficult. Qualitative and pilot studies do not establish efficacy. Publication bias likely."},{"rthcId":"RTHC-07779","title":"ADHD and Cannabis Use in College Students: Examining Indirect Effects of Coping Motives.","authors":"Taubin, Daria; Oddo, Lauren E; Bounoua, Nadia; Bui, Hong N T; Murphy, James G; Chronis-Tuscano, Andrea","year":2025,"journal":"Substance use & misuse, 60(8), 1181-1191","doi":"10.1080/10826084.2025.2491770","pmid":"40257222","tags":["addiction","mental-health","youth"],"studyType":"observational","evidenceStrength":"low","keyFinding":"Students with ADHD had significantly elevated coping motives (using cannabis to avoid or reduce negative affect) and more cannabis use days over two weeks. ADHD was linked to cannabis use frequency through coping motives — students with ADHD had a stronger drive to use cannabis to manage negative emotions, which led to more frequent use.","whyItMatters":"Understanding that ADHD drives cannabis use specifically through emotional coping needs — not just impulsivity — suggests that teaching adaptive coping skills could be a targeted intervention for reducing cannabis misuse in college students with ADHD.","specificNumbers":"42 students with ADHD, 30 without. 49% female. Two-week daily diary. ADHD associated with elevated coping motives and more cannabis use days. Significant indirect effect through coping motives.","methodology":"Two-week daily diary study of heavy-drinking college students (49% female): 42 with ADHD, 30 without. Assessed baseline coping motives and daily cannabis use frequency. Tested indirect effect of ADHD on cannabis use days through coping motives.","limitations":"Small sample (n=72). Selected heavy-drinking students, so not representative of all college students with ADHD. Two-week observation period. Cannot determine causation. Self-reported ADHD and cannabis use."},{"rthcId":"RTHC-07780","title":"Tobacco-related toxicant exposure among people with and without experience of psychosis: findings from the US Population Assessment of Tobacco and Health study.","authors":"Taylor, Eve; McNeill, Ann; Tattan-Birch, Harry; Marczylo, Tim; East, Katherine; Robson, Deborah","year":2025,"journal":"BMJ open, 15(10), e101066","doi":"10.1136/bmjopen-2025-101066","pmid":"41073112","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07781","title":"Patients' Perceptions of the Efficacy, Safety, and Quality of the Evidence of Medicinal Cannabis: A Survey of Australian Cancer Patients.","authors":"Taylor, Joseph S; Fradgley, Elizabeth A; Britton, Ben Britton; Martin, Jennifer H; Lucas, Catherine; Carlson, Melissa A; Bridge, Paula; Morris, Sarah; Watts, Gareth; Lynam, James","year":2025,"journal":"Asia-Pacific journal of clinical oncology, 21(5), 545-551","doi":"10.1111/ajco.14149","pmid":"39829052","tags":["medical-cannabis","cancer"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"19% (67/350) of cancer patients were using medical cannabis, primarily for pain (61%). Some used it believing it could cure (12%) or slow cancer (16%). Only 28% of users and 17% of non-users rated the evidence for physical benefits as high quality. Only 31% of users and 8% of non-users got MC information from clinicians. Most relied on TV, friends, family, social media, and websites.","whyItMatters":"Despite widespread cannabis use among cancer patients, most are aware that evidence quality is limited yet still use it. The disconnect between information sources (mostly non-clinical) and clinician involvement highlights a communication gap in oncology practice.","specificNumbers":"350 patients surveyed (82% consent). 19% (67) using MC. Uses: pain 61%, cure cancer 12%, slow cancer 16%. Evidence perceived as high quality: users 28% (physical), 29% (anticancer); non-users 17%, 11%. Information from clinicians: users 31%, non-users 8%.","methodology":"Survey of 413 Australian cancer patients attending oncology outpatient clinics (April 2019-March 2020). 82% consent rate (350 participants). Ages ≥18 with confirmed cancer diagnosis (solid or hematological).","limitations":"Single center in Australia. Survey from 2019-2020 may not reflect current landscape. Self-reported cannabis use. Cannot assess actual evidence knowledge vs. perceived quality. Selection bias in clinic-attending patients."},{"rthcId":"RTHC-07782","title":"Dopamine D2S/D2L Receptor Regulation of Alcohol-Induced Reward and Signalling.","authors":"Tayyab, Mohd; Sasaoka, Toshikuni; Abe, Manabu; Saito, Nae; Sakimura, Kenji; Ninan, Anetta; Wang, YanYan","year":2025,"journal":"Addiction biology, 30(11), e70093","doi":"10.1111/adb.70093","pmid":"41239854","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07783","title":"Predictors of perinatal cannabis use in colorado and the association with depression during pregnancy.","authors":"Teano, Valerie J; Weikel, Blair W; Hwang, Sunah S; Wymore, Erica M; Blackwell, Sarah; Bourque, Stephanie L","year":2025,"journal":"Archives of women's mental health, 28(3), 603-611","doi":"10.1007/s00737-024-01515-4","pmid":"39480519","tags":["pregnancy","mental-health","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"13.3% (15,585) reported perinatal cannabis use. 35.5% used during pregnancy, 87.3% used postpartum. Depression during pregnancy increased odds of use 2.2-fold (95% CI: 1.5-3.3). During pregnancy, 92% cited medical reasons; by 12-14 months postpartum, only 43% cited medical reasons. Use varied significantly by demographics and social factors.","whyItMatters":"In a state with legalized recreational cannabis, more than 1 in 10 pregnant individuals use cannabis perinatally. The strong link to depression suggests self-medication, and the shift from medical to recreational reasons postpartum suggests evolving motivations.","specificNumbers":"117,812 birthing individuals. 15,585 (13.3%) perinatal cannabis use. 35.5% during pregnancy, 87.3% postpartum. Depression: aOR 2.2 (CI 1.5-3.3). Medical reasons: 92% during pregnancy, 43% at 12-14 months postpartum.","methodology":"Analysis of Health eMoms, Colorado's statewide perinatal longitudinal electronic surveillance system. Weighted sample of 117,812 birthing individuals (2018-2021). Bivariate and multivariable logistic regression.","limitations":"Self-reported use likely underestimates true prevalence. State-level data from Colorado may not generalize to states without legal recreational cannabis. Cannot determine causal direction between depression and cannabis use. Survey response bias possible."},{"rthcId":"RTHC-07784","title":"Novel approaches for drug development against chronic primary pain: A systematic review.","authors":"Tékus, Valéria; Borbély, Éva; Goebel, Andreas; Baron, Ralf; Hajna, Zsófia; Helyes, Zsuzsanna","year":2025,"journal":"British journal of pharmacology","doi":"10.1111/bph.70228","pmid":"41239760","tags":["pain","cbd","treatment"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Among novel drug development approaches for fibromyalgia, CRPS, and chronic low back pain (2014-2024), only CBD and esketamine have been tested across all three conditions. The most promising therapeutic targets include cannabinoid, glutamate, GABAergic, neuroinflammatory, and immune mechanisms. No breakthrough pharmacotherapy has been achieved for any of these conditions.","whyItMatters":"Chronic primary pain affects millions worldwide and remains an unmet medical need. The fact that cannabinoid mechanisms are identified among the most promising targets — and CBD is one of only two drugs tested across all major CPP conditions — positions cannabinoid research as central to future pain treatment.","specificNumbers":"10-year review period (2014-2024). Three CPP conditions: fibromyalgia, CRPS, chronic low back pain. Only CBD and esketamine tested across all three. Most promising targets: cannabinoid, glutamate, GABAergic, neuroinflammatory, immune mechanisms.","methodology":"Systematic review of Phase 1-3 clinical trials from clinicaltrials.gov, clinicaltrialsregister.eu, and PubMed (January 2014-July 2024) for fibromyalgia, CRPS, and chronic low back pain. Assessed both novel drug development and repurposing approaches.","limitations":"Registered trials may not represent completed or published results. Heterogeneous patient populations complicate cross-condition comparisons. Many trials are industry-sponsored with potential bias. Review captures registrations but not all outcomes."},{"rthcId":"RTHC-07785","title":"Characterization of cell-type specific knockout of different elements of the endocannabinoid system in cortical glutamatergic neurons in the context of stress-induced behavioral phenotype.","authors":"Tevosian, Margarita; Brown, Alex F; Schneider, Christina; Conrad, Andrea; Lomazzo, Ermelinda; Lutz, Beat","year":2025,"journal":"Journal of cannabis research, 7(1), 99","doi":"10.1186/s42238-025-00368-7","pmid":"41310892","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07786","title":"Calcium transport across intestinal epithelia depends on voltage-gated sodium channels and endocannabinoid system.","authors":"Thammayon, Nithipak; Wongdee, Kannikar; Teerapornpuntakit, Jarinthorn; Jantarajit, Walailak; Panmanee, Jiraporn; Patigo, Apinya; Saparpakorn, Patchreenart; Tanramluk, Duangrudee; Charoenphandhu, Narattaphol","year":2025,"journal":"Biochemical and biophysical research communications, 758, 151635","doi":"10.1016/j.bbrc.2025.151635","pmid":"40120346","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07787","title":"Cannabidiol Enhances the Therapeutic Efficacy of Olsalazine and Cyclosporine in a Murine Model of Colitis.","authors":"Thapa, Dinesh; Patil, Mohan; Warne, Leon N; Carlessi, Rodrigo; Falasca, Marco","year":2025,"journal":"International journal of molecular sciences, 26(16)","doi":"10.3390/ijms26167913","pmid":"40869234","tags":["cbd","ibd","treatment"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"In both acute and chronic colitis mouse models, combining low-dose CBD with olsalazine (50 mg/kg) or cyclosporine (2.5-5 mg/kg) significantly reduced disease activity index, MPO activity, and inflammatory cytokines while restoring colon length and GLP-1 levels. CBD monotherapy alone was inconclusive, but combinations were superior. No liver or kidney toxicity observed.","whyItMatters":"Current IBD treatments often have limited long-term efficacy and significant side effects. If CBD can enhance standard treatments at low doses without adding toxicity, it could meaningfully improve patient outcomes.","specificNumbers":"CBD 10 mg/kg. Olsalazine 50 mg/kg. Cyclosporine 2.5-5 mg/kg. Combination: reduced DAI, MPO, inflammatory cytokines. Restored colon length and GLP-1 levels. No hepatic or renal toxicity on blood work.","methodology":"DSS-induced acute and chronic colitis models in mice. Tested CBD (10 mg/kg) alone and in combination with olsalazine or cyclosporine. Assessed DAI, colon morphology, cytokines, chemokines, MPO, systemic inflammatory markers, GLP-1, hematology, and plasma biochemistry.","limitations":"Mouse colitis model does not perfectly recapitulate human IBD. CBD dosing in mice may not translate directly to human doses. Short-term safety assessment — long-term toxicity unknown. Specific drug interactions not fully characterized."},{"rthcId":"RTHC-07788","title":"Targeting the Endocannabinoidome: A Novel Approach to Managing Extraintestinal Complications in Inflammatory Bowel Disease.","authors":"Thapa, Dinesh; Ghimire, Anjali; Warne, Leon N; Carlessi, Rodrigo","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(4)","doi":"10.3390/ph18040478","pmid":"40283915","tags":["endocannabinoid-system","ibd"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"The endocannabinoidome (eCBome) includes receptors (CB1, CB2, GPR55, GPR35, PPARα, TRPV1), lipid mediators, and metabolic enzymes that modulate immune responses, gut barrier integrity, and systemic inflammation. Targeting eCBome may improve both intestinal inflammation and extraintestinal manifestations including arthritis, liver dysfunction, and dermatological disorders.","whyItMatters":"IBD is not just a gut disease — many patients suffer from joint, skin, liver, and eye complications that standard intestinal therapies do not address. The endocannabinoidome offers a unified therapeutic target for both local and systemic disease components.","specificNumbers":"Receptors reviewed: CB1, CB2, GPR55, GPR35, PPARα, TRPV1. Extraintestinal targets: joints (arthritis), skin (dermatological disorders), liver (dysfunction), eyes. Multiple metabolic enzymes and lipid mediators assessed.","methodology":"Comprehensive literature review across PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Focused on endocannabinoidome role in IBD and extraintestinal manifestations.","limitations":"Narrative review without systematic methodology. Much evidence is preclinical. Clinical evidence for eCBome-targeting therapies in IBD extraintestinal manifestations is very limited. Complex system makes targeted drug development challenging."},{"rthcId":"RTHC-07789","title":"Alcohol-Induced Dilation of Fetal Cerebral Arteries Is Region-Specific and Mediated by Cannabinoid Receptor 1 in a Sexually Dimorphic Manner.","authors":"Thapa, Shiwani; Schneider, Elizabeth H; Mysiewicz, Steven C; Dopico, Alex M; Bukiya, Anna N","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251392472","pmid":"41218794","tags":["pregnancy","neuroscience"],"studyType":"preclinical","evidenceStrength":"low","keyFinding":"Low alcohol concentrations (5-30 mM) dilated fetal cerebral arteries in baboons. CB1 receptors (but not CB2) were present in fetal cerebral arteries. CB1 antagonist AM251 blocked alcohol-induced vasodilation in basilar arteries of female fetuses and middle cerebral arteries of male fetuses. Endocannabinoid levels did not change, suggesting alcohol directly activates CB1 without endocannabinoid production.","whyItMatters":"Understanding how alcohol affects fetal brain blood flow is critical for preventing fetal alcohol spectrum disorders. The discovery that alcohol works through the cannabinoid CB1 receptor — with sex-specific effects — opens potential avenues for protective interventions.","specificNumbers":"Alcohol concentrations: 5-30 mM (toxicologically relevant). CB1 present in all four cerebral artery types. AM251 blocked dilation in basilar arteries (females) and middle cerebral arteries (males). No endocannabinoid level changes detected.","methodology":"Ex vivo pressurized fetal cerebral arteries from baboons (Papio sp.). Concentration-dependent alcohol exposure on anterior, middle, posterior, and basilar arteries. CB1/CB2 receptor expression by qPCR. Pharmacological blockade with AM251. Endocannabinoid levels by LC-MS.","limitations":"Baboon model, though closer to humans than rodents. Ex vivo arterial preparation may not fully reflect in vivo conditions. Small sample inherent to primate research. Cannot directly extrapolate to human fetal outcomes."},{"rthcId":"RTHC-07790","title":"Evidence on the effect of in-utero cannabis exposure in neonates.","authors":"Thayyil, Basel; Yusuf, Kamran","year":2025,"journal":"Journal of perinatology : official journal of the California Perinatal Association, 45(11), 1503-1512","doi":"10.1038/s41372-025-02383-1","pmid":"40797024","tags":["pregnancy","neuroscience","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review synthesizes the accumulating evidence on what happens when a developing fetus is exposed to cannabis—a question of increasing urgency as both cannabis use during pregnancy and THC potency rise simultaneously.\n\nThe pharmacological reality is concerning. THC crosses the placenta, disrupts the fetal endocannabinoid system that's critical for neurodevelopment, and accumulates in fetal tissues. For breastfeeding mothers, THC transfers into breast milk at approximately 2.5% of the maternal dose.\n\nThe clinical evidence has reached a critical mass. Multiple studies and meta-analyses now associate prenatal cannabis exposure with low birth weight, preterm birth, neonatal intensive care unit admission, and reduced Apgar scores. These aren't subtle statistical associations—they're clinically meaningful outcomes.\n\nThe neurodevelopmental data is perhaps most alarming. Longitudinal studies tracking exposed children over time have documented brain alterations affecting memory, attention, and executive function. These aren't just neonatal effects that resolve—they appear to be lasting changes in how the brain develops.\n\nA crucial contextual factor: THC concentrations in cannabis products have risen dramatically, from roughly 5% to 30% over recent decades. A pregnant woman using cannabis today is exposing her fetus to far more THC than a woman using cannabis 20 years ago, yet much of the existing research was conducted with lower-potency products.\n\nThe ethical impossibility of randomized controlled trials in pregnant women means all evidence is observational, which limits causal conclusions. But the consistency and biological plausibility of the findings have strengthened the evidence base substantially.","whyItMatters":"Cannabis use during pregnancy is increasing precisely when it's becoming more dangerous—THC potency has multiplied while pregnant users often perceive cannabis as safer than pharmaceuticals or alcohol. The neurodevelopmental findings are particularly important because they suggest the effects extend far beyond the neonatal period, potentially affecting a child's cognitive trajectory for years.","specificNumbers":"THC potency increase: ~5% to ~30%. THC crosses the placenta and accumulates in fetal tissues. Breastfed infants receive ~2.5% of maternal THC dose. Associated outcomes: low birth weight, preterm birth, NICU admission, reduced Apgar scores. Longitudinal evidence of brain alterations in memory, attention, and executive function.","methodology":"Narrative review synthesizing observational studies, meta-analyses, and longitudinal cohort data on the effects of in-utero cannabis exposure on neonatal outcomes and child neurodevelopment.","limitations":"All evidence is observational—ethical constraints prevent randomized trials. Confounders (tobacco co-use, socioeconomic factors, polysubstance use) are difficult to fully control. Self-reported cannabis use during pregnancy likely underestimates true exposure. Most existing longitudinal studies used participants who consumed lower-potency cannabis than what's currently available. Animal studies help establish mechanisms but don't perfectly model human pregnancy."},{"rthcId":"RTHC-07791","title":"Quantitative analysis of cannabinoids and metabolites in oral fluid by volumetric absorptive microsampling combined with UHPLC-HRMS.","authors":"Thiebot, P; Magny, R; Martins, P; Houze, P; Bloch, V; Vorspan, F; Auzeil, N; Labat, L","year":2025,"journal":"Analytical and bioanalytical chemistry, 417(2), 345-360","doi":"10.1007/s00216-024-05651-9","pmid":"39625516","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07792","title":"Arkansas Medical Marijuana Certifications: Higher-Volume Physicians Associated With Less Evidence Of Care Coordination.","authors":"Thompson, Joseph W; Martin, Brad; Goudie, Anthony; Stanley, Nichole; Noori, Katerina; Hudson, Teresa","year":2025,"journal":"Health affairs (Project Hope), 44(3), 351-360","doi":"10.1377/hlthaff.2024.00380","pmid":"40030108","tags":["medical-cannabis","regulation"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Medical marijuana was certified for 3.4% of Arkansans 18+ by 12.5% of state-licensed physicians. PTSD and four pain diagnoses were the most common qualifying conditions. Low-volume certifying physicians showed evidence of care coordination — most had seen and diagnosed patients with qualifying conditions. Seven high-volume physicians (1,000+ certifications each) showed limited prior contact with certified patients.","whyItMatters":"The disconnect between high-volume certifying physicians and their patients raises questions about quality of care. Medical marijuana certifications without proper evaluation may expose patients to risks and undermine the medical framework intended to guide cannabis use.","specificNumbers":"3.4% of Arkansans 18+ certified. 12.5% of licensed physicians participated. 7 high-volume physicians: 1,000+ certifications each. Top qualifying conditions: PTSD and 4 pain diagnoses. Low-volume certifiers showed care coordination; high-volume did not.","methodology":"Analysis of Arkansas medical marijuana certification data linked to physician practice records. Profiled certified individuals, qualifying conditions, and evidence of care coordination between certifying and primary care physicians.","limitations":"Arkansas-specific data may not generalize to other states. Administrative data cannot capture quality of clinical encounters. High-volume physicians may conduct thorough evaluations not reflected in prior claims data. Qualifying condition determination is complex."},{"rthcId":"RTHC-07793","title":"Cannabis and cannabinoid-microbiome interactions in varied clinical contexts: A comprehensive systematic review.","authors":"Thu, May Soe; Campbell, Barry J; Hirankarn, Nattiya; Nopsopon, Tanawin; Ondee, Thunnicha; Hall, Szaye Rawicha; Jagota, Ananya; Fothergill, Joanne L; Pongpirul, Krit","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 182, 117764","doi":"10.1016/j.biopha.2024.117764","pmid":"39689514","tags":["microbiome","inflammation"],"studyType":"systematic-review","evidenceStrength":"low","keyFinding":"Nine studies (2 clinical trials, 7 observational) examined cannabis/cannabinoid effects on oral, GI, fecal, and vaginal microbiota. Positive associations: serum endocannabinoids correlated with beneficial gut microbiota via elevated SCFAs and anti-inflammatory actions. In HIV patients, marijuana use reduced pro-inflammatory Prevotella. Negative associations: excessive consumption reduced microbial richness and diversity with increased systemic inflammation.","whyItMatters":"The microbiome is increasingly recognized as central to health and disease. Understanding how cannabis affects it is essential for evaluating the full impact of cannabis use and developing microbiome-based therapeutic strategies.","specificNumbers":"9 studies identified: 2 clinical trials, 7 observational. Body sites: oral, GI, fecal, vaginal. Contexts: cognitive deficiency, depression, HIV, inflammation/pain, oral disease, obesity. Both alpha diversity changes and specific bacterial abundance shifts documented.","methodology":"Systematic review searching PubMed, Embase, and Cochrane Library CENTRAL. Included studies on marijuana, medical cannabis, cannabinoids, and cannabinoid-like lipid mediators across all clinical conditions and body sites.","limitations":"Very small evidence base (9 studies). Heterogeneous clinical contexts, cannabis products, and microbiome assessment methods. Cannot determine causation in observational studies. Different body sites make cross-study comparison difficult."},{"rthcId":"RTHC-07794","title":"Understanding Suicidal Thoughts and Behaviors Among LGBTQ + Youth: Differential Associations Between Bullying and Substance Use.","authors":"Tiedge, Cayson W; Valido, Alberto; Rivas-Koehl, Matthew; Garcia, Brian A; Robinson, Luz E; Clements, Graceson; Espelage, Dorothy L","year":2025,"journal":"Prevention science : the official journal of the Society for Prevention Research, 26(3), 449-461","doi":"10.1007/s11121-025-01783-1","pmid":"39934543","tags":["youth","mental-health","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Bullied LGBTQ+ youth had 2.71 times higher odds of planning suicide attempts. Opioid/prescription drug use increased attempt odds 4.6-fold, hallucinogen use 8.89-fold. No significant association between alcohol and STB. Unexpectedly, cannabis moderated the bullying-suicidality association: bullied youth who used cannabis were less likely to report suicidal ideation and planning than bullied non-users.","whyItMatters":"This is one of the largest studies examining the intersection of bullying, substance use, and suicidality in LGBTQ+ youth. The cannabis finding is counterintuitive and important: while not endorsing cannabis use, it suggests some youth may use it as a coping mechanism that temporarily reduces suicidal thinking.","specificNumbers":"96,482 youth from 2003-2019 YRBS. Bullied LGBTQ+ suicide planning: OR 2.71. Opioid use + attempt: OR 4.60. Hallucinogen use + attempt: OR 8.89. Cannabis moderated bullying-ideation link: lower suicidal ideation in bullied cannabis users vs. bullied non-users.","methodology":"Cross-sectional analysis of combined 2003-2019 Youth Risk Behavior Survey (N=96,482). Hierarchical logistic regression examining interactions between bullying victimization, substance use (alcohol, cannabis, hallucinogens, opioids), and suicidal thoughts and behaviors in LGBTQ+ youth.","limitations":"Cross-sectional YRBS data cannot establish causation. Self-reported bullying and substance use. Cannabis finding does not mean cannabis is therapeutic for suicidality — it may simply be a less harmful coping mechanism than other substances. Historical data (2003-2019) spans different cannabis eras."},{"rthcId":"RTHC-07795","title":"Cannabidiol-A friend or a foe?","authors":"Tihăuan, Bianca-Maria; Onisei, Tatiana; Slootweg, Walter; Gună, Daniel; Iliescu, Ciprian; Chifiriuc, Mariana-Carmen","year":2025,"journal":"European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 208, 107036","doi":"10.1016/j.ejps.2025.107036","pmid":"39929375","tags":["cbd","pharmacology"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"Oral CBD has 6-19% bioavailability due to hepatic first-pass metabolism and gastric instability. Inhaled routes provide rapid onset but raise pulmonary concerns. Transdermal delivery bypasses hepatic degradation, offers improved bioavailability and targeted effects. The review compiled a literature-based ADME profile highlighting that individual responses to CBD vary significantly.","whyItMatters":"Most CBD consumers use oral products without understanding that only 6-19% of their dose reaches the bloodstream. Understanding bioavailability across routes helps consumers and clinicians choose the most effective and efficient delivery method.","specificNumbers":"Oral bioavailability: 6-19%. Transdermal delivery bypasses first-pass hepatic metabolism. CBD regulatory landscape reviewed across Europe, UK, USA, Australia. Individual ADME variability documented.","methodology":"Narrative review examining transdermal CBD administration, skin barrier strategies, and bioavailability across different routes. Compiled literature-based ADME study. Reviewed endocannabinoid system function and CBD regulatory landscape across Europe, UK, USA, and Australia.","limitations":"Narrative review without systematic methodology. Transdermal CBD clinical data is limited. Individual variability makes generalizations difficult. Regulatory landscape changes rapidly and review may not reflect current status."},{"rthcId":"RTHC-07796","title":"Cannabidiol Use and Perceptions of Effectiveness in Women With Chronic Pelvic Pain.","authors":"Till, Sara R; Whitmore, Gabrielle; As-Sanie, Sawsan; Matallana, Lynne; Boehnke, Kevin F","year":2025,"journal":"Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 47(7), 102839","doi":"10.1016/j.jogc.2025.102839","pmid":"40216330","tags":["cbd","pain","womens-health"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"36.3% never used CBD, 29.2% past users, 34.5% current users. Among current users, 80.9% reported pain improvement. Those with pain improvement also reported better sleep, anxiety, depression, fatigue, and overall health. Many substituted CBD for at least one other medication. About half reported side effects, most minor (drowsiness 29% most common).","whyItMatters":"Chronic pelvic pain and fibromyalgia are notoriously difficult to treat. The high CBD use rate and self-reported symptom improvement, along with medication substitution, suggest patients are finding relief that conventional treatments may not provide — though placebo effects cannot be ruled out.","specificNumbers":"1,382 participants. 34.5% current CBD users, 29.2% past users, 36.3% never used. Pain improvement: 80.9% of current users. Improved sleep, anxiety, depression, fatigue, overall health correlated with pain improvement. Side effects: ~50%, mostly minor (drowsiness 29%).","methodology":"Cross-sectional secondary analysis of online survey distributed through the National Fibromyalgia Association (April-May 2020). Limited to participants with concurrent chronic pelvic pain diagnoses. 1,382 included participants.","limitations":"Self-reported outcomes susceptible to placebo and expectancy effects. Survey distributed through patient advocacy organization (selection bias). No control group. Cross-sectional design cannot establish causation. 2020 survey may not reflect current landscape."},{"rthcId":"RTHC-07797","title":"Brands of Intoxicating Cannabis Products in Vape Shops: United States, 2023.","authors":"Tillett, Kayla K; LoParco, Cassidy R; Rossheim, Matthew E; Chen-Sankey, Julia; Trangenstein, Pamela J; Berg, Carla J","year":2025,"journal":"Substance use & misuse, 1-4","doi":"10.1080/10826084.2025.2592227","pmid":"41324909","tags":["regulation","public-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"74% of 520 surveyed vape shops sold intoxicating cannabis products (ICPs). Products were available in 48 of 50 states plus territories. 273 shops provided brand information, identifying 188 unique brands (average 2.4 per shop). Top brands: Torch (12.7%), Mellow Fellow (9.7%), Cake (8.4%), Modus (8.0%), Delta Extrax (7.6%).","whyItMatters":"Since the 2018 Farm Bill, intoxicating hemp-derived products (like delta-8 THC) have proliferated with minimal regulation. This study documents the scale of the problem: nearly three-quarters of vape shops now sell these products in virtually every state.","specificNumbers":"520 vape shops surveyed. 74% sold ICPs. 48 states/territories had shops selling ICPs. 188 unique brands identified. Average 2.4 brands per shop. Top brand: Torch (12.7%).","methodology":"Telephone surveys of 520 vape shops across all 50 states, Washington D.C., and Puerto Rico (November-December 2023). 10 shops per state/territory identified via Google Maps. Asked about THC product availability and popular brands.","limitations":"Telephone survey may not capture all products or newer brands. 10 shops per state may not represent full market. Self-reported product availability. Rapidly evolving market may have changed since 2023."},{"rthcId":"RTHC-07798","title":"Corporate Strategies to Market PAX Vaporizers for Cannabis Use Under Federal Restrictions in the United States.","authors":"Timberlake, David S; Paredes, Jacob; Rhee, Joshua; Sandhu, Ashish; Phan, Yvonne; Martinez-Santos, Alejandro; Pechmann, Cornelia Connie","year":2025,"journal":"Substance use & misuse, 1-8","doi":"10.1080/10826084.2025.2575919","pmid":"41118146","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07799","title":"Using Chemical Ecology as a Guide for Development and Differentiation of Clinically Relevant Phytochemical Profiles in Cannabis Trichome.","authors":"Tims, Michael; Courie, John; Betz, Joseph M","year":2025,"journal":"Cannabis and cannabinoid research","doi":"10.1177/25785125251391985","pmid":"41433045","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07800","title":"Alterations of endocannabinoid signaling and microglia reactivity in the retinas of AD-like mice precede the onset of hippocampal β-amyloid plaques.","authors":"Tisi, Annamaria; Scipioni, Lucia; Carozza, Giulia; Di Re, Lucia; Cimino, Giacomo; Di Meo, Camilla; Palaniappan, Sakthimala; Valle, Francesco Della; Fanti, Federico; Giacovazzo, Giacomo; Compagnone, Dario; Maccarone, Rita; Oddi, Sergio; Maccarrone, Mauro","year":2025,"journal":"Journal of neurochemistry, 169(2), e16256","doi":"10.1111/jnc.16256","pmid":"39556462","tags":["endocannabinoid-system","neuroscience"],"studyType":"preclinical","evidenceStrength":"low","keyFinding":"At 12 months — before hippocampal beta-amyloid plaques developed — Alzheimer's model mice showed increased retinal microglia (IBA1+), elevated CB2 receptors, upregulated MAGL enzyme, and 80% reduction in 2-AG levels (0.34 vs 1.70 ng/mg in wild type). These retinal changes occurred without overt retinal degeneration, suggesting early biomarker potential.","whyItMatters":"Alzheimer's disease is typically diagnosed late, when brain damage is extensive. If endocannabinoid system changes in the retina — an easily accessible tissue — precede brain pathology, non-invasive eye exams could potentially detect Alzheimer's risk years earlier.","specificNumbers":"2-AG reduced ~80% in AD retinas (0.34 vs 1.70 ng/mg). CB2 and MAGL upregulated. Increased IBA1+ microglia. No retinal beta-amyloid plaques. No hippocampal plaques at this time point. Correlation analysis showed CB2 linked to multiple ECS components.","methodology":"Tg2576 (APP-overexpressing) mice at 12 months. Retinal analysis via immunohistochemistry (IBA1, CB2, MAGL), western blotting (ECS receptors/enzymes), and UPLC-MS/MS (endocannabinoid levels). Compared to age-matched wild-type controls.","limitations":"Mouse model may not fully recapitulate human Alzheimer's. Small sample inherent to transgenic studies. Single time point assessed. Cannot determine if retinal ECS changes cause or merely correlate with disease. Human retinal ECS data needed."},{"rthcId":"RTHC-07801","title":"Phytocannabinoids as Novel SGLT2 Modulators for Renal Glucose Reabsorption in Type 2 Diabetes Management.","authors":"Tjandrawinata, Raymond Rubianto; Harbuwono, Dante Saksono; Soegondo, Sidartawan; Taslim, Nurpudji Astuti; Nurkolis, Fahrul","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(8)","doi":"10.3390/ph18081101","pmid":"40872492","tags":["cbd","thc","diabetes"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"In silico studies show high-affinity binding of phytocannabinoids to SGLT2 substrate pocket. CBG and THCV modulate SGLT2-related pathways via TRP channels and CB receptors. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, and organ-protective effects. Pilot data (n=62): THCV decreased fasting glucose, enhanced beta-cell function, no psychoactive side effects.","whyItMatters":"SGLT2 inhibitors have transformed diabetes care but have side effects (urinary infections, ketoacidosis). If phytocannabinoids can modulate the same pathway with fewer side effects and additional metabolic benefits, they could complement or offer alternatives to current treatments.","specificNumbers":"THCV pilot study: n=62, decreased fasting glucose, enhanced beta-cell function, no psychoactive effects. In silico: high-affinity SGLT2 binding for multiple phytocannabinoids. SGLT2 inhibitor side effects: genitourinary infections, ketoacidosis.","methodology":"Narrative review covering molecular docking, in vitro receptor binding/transport assays, in vivo rodent models, pilot clinical studies, and comparison with synthetic SGLT2 inhibitors (empagliflozin, dapagliflozin, etc.).","limitations":"Direct SGLT2 IC50 values for phytocannabinoids not yet determined. Low oral bioavailability is a major hurdle. Pilot clinical data is very preliminary (n=62). Polypharmacology may lead to off-target effects. No large-scale clinical trials."},{"rthcId":"RTHC-07802","title":"Emergency Department Visits for Cannabis Hyperemesis Syndrome Among Adolescents.","authors":"Toce, Michael S; Monuteaux, Michael C; Fishman, Michael D; Hudgins, Joel D","year":2025,"journal":"JAMA network open, 8(7), e2520492","doi":"10.1001/jamanetworkopen.2025.20492","pmid":"40658419","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"Researchers analyzed emergency department encounter data to assess trends in visits for cannabinoid hyperemesis syndrome (CHS) specifically among adolescents. CHS, which causes severe cyclic vomiting in chronic cannabis users, has historically been considered an adult condition.\n\nThe data showed an increasing trend in adolescent ED visits for CHS. This rise likely reflects both growing cannabis use among young people and increasing clinician awareness of the diagnosis.\n\nThe emergence of CHS as a recognizable condition in adolescents is particularly concerning because it indicates that some teens are using cannabis frequently and heavily enough to develop a condition associated with chronic, sustained use.","whyItMatters":"CHS in adolescents signals a pattern of heavy, frequent cannabis use in a population whose brains are still developing. Rising ED visits for this condition suggest that teen cannabis use is not just experimental for some youth but has reached levels intense enough to cause a condition previously seen mainly in adult chronic users.","specificNumbers":"Emergency department visits for CHS among adolescents showed an increasing trend over the study period.","methodology":"This was a cross-sectional analysis of emergency department encounter data assessing trends in CHS diagnoses among adolescent patients. Researchers examined visit frequencies over time to identify whether the condition was becoming more common in this age group.","limitations":"ED data relies on accurate diagnosis coding, and CHS may be undercounted due to misdiagnosis or unfamiliarity. Increased visits could partly reflect better recognition rather than a true increase in incidence. The study assessed ED encounters, not individual patients, so repeat visitors could inflate numbers."},{"rthcId":"RTHC-07803","title":"Cannabinoid type 1 receptors in the mice prefrontal cortex regulate object location memory acquisition via GABAergic neurons.","authors":"Tokutake, Tomohiro; Yokose, Jun; Yano, Yusuke; Shigetsura, Yuki; Muramatsu, Shin-Ichi; Nitta, Atsumi","year":2025,"journal":"Behavioral and brain functions : BBF, 21(1), 36","doi":"10.1186/s12993-025-00306-w","pmid":"41188973","tags":["cognition","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study zeroed in on a specific question: which phase of memory does THC-like activation in the prefrontal cortex disrupt, and through what mechanism?\n\nThe researchers injected a CB1 receptor agonist (ACPA) directly into the prefrontal cortex of mice before different stages of two memory tests. The precision of this approach is key—rather than giving THC systemically and wondering which brain region is responsible, they targeted exactly one region.\n\nThe result was remarkably specific. CB1 activation impaired memory acquisition (learning new information) in the object location test—a spatial memory task. It did not impair consolidation (converting short-term to long-term memory) or retrieval (recalling stored memories). And it didn't impair recognition memory at all (tested by the novel object recognition test).\n\nThe mechanism: in vivo microdialysis showed that CB1 activation reduced extracellular GABA levels in the prefrontal cortex. GABA is the brain's primary inhibitory neurotransmitter—when it's reduced, the careful balance of excitation and inhibition that underlies memory formation breaks down. When the researchers artificially reactivated GABAergic neurons using chemogenetics, the memory impairment was rescued.\n\nThis creates a clear causal chain: THC → CB1 activation → reduced GABA release → impaired spatial memory acquisition.","whyItMatters":"Memory impairment is one of the most consistent cognitive effects of cannabis, but understanding exactly which type of memory is affected and why is crucial for developing strategies to mitigate it. This study shows the effect is on learning new spatial information—not on recalling what you already know—and identifies a specific molecular pathway (CB1 → GABA reduction) that could potentially be targeted.","specificNumbers":"CB1 agonist impaired acquisition (not consolidation or retrieval) in the object location test. ACPA reduced extracellular GABA levels in PFC. Chemogenetic GABA neuron activation rescued the memory deficit. No effect on novel object recognition.","methodology":"Animal study in male C57BL/6J mice. Intra-PFC injection of CB1 agonist ACPA via implanted cannula. Cognitive tests: novel object recognition test and object location test, with drug administered before acquisition, consolidation, or retrieval phases separately. In vivo microdialysis measured extracellular GABA levels. Chemogenetic activation of GABAergic neurons via AAV-GAD-hM3Dq and deschloroclozapine.","limitations":"Mouse study—prefrontal cortex organization differs between mice and humans. Used a synthetic CB1 agonist (ACPA), not THC. Direct injection into PFC doesn't model how inhaled or ingested THC distributes across the brain. Only male mice used. The memory tests are simplified versions of human spatial and recognition memory."},{"rthcId":"RTHC-07804","title":"Breaking the cycle: Consequences from simultaneous alcohol and cannabis use predict subsequent simultaneous use and drinks consumed at the next simultaneous use event.","authors":"Tolbert, Riley C; Waddell, Jack T","year":2025,"journal":"Alcohol, clinical & experimental research, 49(12), 2810-2821","doi":"10.1111/acer.70183","pmid":"41313247","tags":["addiction","harm-reduction"],"studyType":"observational","evidenceStrength":"low","keyFinding":"Negative consequences from simultaneous alcohol-cannabis use predicted higher likelihood of cannabis use at the next drinking event (contrary to hypotheses) but fewer drinks at the next simultaneous use event. When positive consequences were low, negative consequences led to reduced drinking, but this effect disappeared when positive consequences were also high.","whyItMatters":"The paradox that negative consequences increase cannabis use suggests a \"replacement\" dynamic — young adults may shift toward more cannabis and less alcohol after bad experiences, rather than reducing substance use overall. This has implications for harm reduction messaging.","specificNumbers":"89 young adults. 60-day assessment period. Negative consequences: increased next-event cannabis use, decreased next-event drinks. Interaction: negative consequences reduced drinks only when positive consequences were below average.","methodology":"60-day timeline followback interview with 89 young adults reporting 2+ days of simultaneous alcohol and cannabis use. Multilevel models tested whether positive and negative consequences predicted subsequent use patterns.","limitations":"Small sample (n=89). Self-reported substance use and consequences. 60-day retrospective recall may be inaccurate. Cannot generalize beyond young adults who already use both substances. Timeline followback design has inherent limitations."},{"rthcId":"RTHC-07805","title":"Cannabidiol prevents cognitive and social deficits in a male rat model of Alzheimer's disease through CB1 activation and inflammation modulation.","authors":"Toledano, Roni Shira; Akirav, Irit","year":2025,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(13), 1916-1927","doi":"10.1038/s41386-025-02213-0","pmid":"40859005","tags":["cbd","neuroscience","neuroprotection"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"STZ-induced Alzheimer's rats showed impaired object recognition, location memory, and social behavior, along with elevated amyloid-beta, tau phosphorylation, TREM2, APOEε4, TNFα, NF-κB1, and IL-1β in the hippocampus. Chronic CBD reversed all behavioral deficits, reduced neuroinflammatory markers, and mitigated AD-associated changes. CB1 antagonist AM251 (but not CB2 antagonist AM630) blocked CBD benefits, identifying CB1 as the key mechanism.","whyItMatters":"This study provides compelling evidence that CBD works against Alzheimer's-like pathology specifically through CB1 receptors, which was previously unclear. Identifying the specific receptor mechanism is crucial for developing targeted cannabinoid-based treatments.","specificNumbers":"CBD restored object location/recognition performance and social behavior. Reduced: amyloid-beta, p-Tau, TREM2, APOEε4, TNFα, NF-κB1, IL-1β in hippocampus. CB1 antagonist AM251 blocked CBD benefits. CB2 antagonist AM630 did not block benefits.","methodology":"Male rat model of sporadic Alzheimer's (ICV-STZ injection). Chronic CBD treatment. Behavioral testing (object location, recognition, social behavior). qPCR for neuroinflammatory and cannabinoid receptor gene expression. Pharmacological antagonism to identify receptor mechanism.","limitations":"STZ model mimics sporadic Alzheimer's but does not fully recapitulate human disease complexity. Male rats only — sex differences in Alzheimer's are well-documented. Chronic dosing regimen may not translate to human pharmacokinetics. Single study requiring replication."},{"rthcId":"RTHC-07806","title":"The endocannabinoid system regulates both ependymoglial and neuronal cell responses to a tail amputation in the axolotl.","authors":"Tolentino, Michael; Walker, Sarah E; Spencer, Gaynor E; Carlone, Robert","year":2025,"journal":"Developmental dynamics : an official publication of the American Association of Anatomists","doi":"10.1002/dvdy.70035","pmid":"40377265","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07807","title":"Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS.","authors":"Tomaszewska-Zaremba, Dorota; Gajewska, Alina; Misztal, Tomasz","year":2025,"journal":"International journal of molecular sciences, 26(14)","doi":"10.3390/ijms26146570","pmid":"40724820","tags":["neuroscience","neuroprotection","inflammation"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"Cannabinoids show anti-inflammatory therapeutic potential across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and HIV-associated dementia. Their broad spectrum of action allows targeting multiple pathological mechanisms simultaneously, including neuroinflammation, oxidative stress, and immune dysregulation.","whyItMatters":"Neurodegenerative diseases and CNS inflammatory conditions share overlapping immune-mediated pathology. Cannabinoids unique ability to simultaneously modulate both neural and immune functions positions them as potential multi-target therapeutics for conditions where single-mechanism drugs have failed.","specificNumbers":"Conditions reviewed: Alzheimer's, Parkinson's, ALS, Huntington's, multiple sclerosis, HIV-associated dementia. Mechanisms: neuroinflammation, immune modulation, neuroprotection, oxidative stress reduction.","methodology":"Narrative review of cannabinoid anti-inflammatory properties across neurodegenerative and CNS inflammatory conditions. Focused on preclinical and clinical evidence for each condition.","limitations":"Narrative review without systematic methodology. Much evidence is preclinical. Clinical trial data for cannabinoids in most neurodegenerative diseases is limited. Anti-inflammatory effects may not translate to disease modification in humans."},{"rthcId":"RTHC-07808","title":"Perceived social support according to the type and number of addictions.","authors":"Tomei, Alexander; Studer, Joseph; Gmel, Gerhard","year":2025,"journal":"PloS one, 20(8), e0329256","doi":"10.1371/journal.pone.0329256","pmid":"40788844","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07809","title":"Cannabis expectancies and associations with cannabis use and health functioning among adults with chronic pain.","authors":"Tomlinson, Devin C; Coughlin, Lara N; Bohnert, Kipling M; Ilgen, Mark A","year":2025,"journal":"Addictive behaviors, 160, 108166","doi":"10.1016/j.addbeh.2024.108166","pmid":"39317012","tags":["pain","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Positive cannabis expectancies (believing cannabis will help with pain, sleep, mood) were significantly associated with higher use frequency and cannabis use disorder symptoms, even after controlling for pain severity, anxiety, and depression. Pain severity itself was not a significant predictor of use patterns.","whyItMatters":"Clinicians often assume chronic pain patients use cannabis because of pain severity. This study suggests beliefs about cannabis matter more, which has implications for patient education and screening.","specificNumbers":"258 chronic pain patients surveyed. Positive expectancies predicted use frequency (p<0.01) and CUD symptoms (p<0.001). Pain severity was not a significant predictor.","methodology":"Cross-sectional survey of 258 adults with chronic pain who used cannabis. Validated measures for cannabis expectancies, pain severity, mental health, and cannabis use disorder.","limitations":"Cross-sectional design cannot determine causation. Self-selected sample of cannabis users. Expectancies and use measured simultaneously. No longitudinal follow-up."},{"rthcId":"RTHC-07810","title":"Selective anti-cancer effects of cannabidiol and Δ9-tetrahydrocannabinol via PI3K/AKT/mTOR inhibition and PTEN restoration in ovarian cancer cells.","authors":"Tong, Siyao; Loilome, Watcharin; Namwat, Nisana; Klanrit, Poramate; Wangwiwatsin, Arporn; Win, Zar Zar; Koyabuth, Preeya; Chumworathayi, Bandit","year":2025,"journal":"Frontiers in pharmacology, 16, 1693129","doi":"10.3389/fphar.2025.1693129","pmid":"41472794","tags":["cancer","cbd","thc"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD:THC at a 3:1 ratio showed synergistic cytotoxicity against ovarian cancer cell lines. The combination induced apoptosis (programmed cell death) and autophagy at lower concentrations than either compound alone. CBD alone was more cytotoxic than THC alone. The combination also reduced cell migration.","whyItMatters":"Ovarian cancer has limited treatment options and high mortality. The synergistic effect of CBD:THC combinations suggests cannabinoids could be explored as adjunct therapies, potentially allowing lower doses of each compound.","specificNumbers":"Optimal ratio: 3:1 CBD:THC. Synergistic cytotoxicity confirmed. Apoptosis and autophagy both activated. Cell migration reduced.","methodology":"In vitro study testing CBD, THC, and combinations at various ratios against multiple ovarian cancer cell lines. MTT viability assays, flow cytometry for apoptosis, western blot for autophagy markers, and wound healing assays for migration.","limitations":"In vitro only — cancer cells in a dish may not reflect tumor behavior in the body. Specific cell lines may not represent all ovarian cancers. Bioavailability and achievable tissue concentrations not addressed."},{"rthcId":"RTHC-07811","title":"In vitro antibacterial activity of hemp (Cannabis sativa L.) extract seed oil against multidrug resistant bacterial pathogens in small animal veterinary dermatology.","authors":"Toppi, Valeria; Pirolo, Mattia; Rampacci, Elisa; Scattini, Gabriele; Musa, Laura; Della Rocca, Giorgia; Di Salvo, Alessandra; De Benedetti, Marina; Guardabassi, Luca; Proietti, Patrizia Casagrande","year":2025,"journal":"Veterinary journal (London, England : 1997), 313, 106392","doi":"10.1016/j.tvjl.2025.106392","pmid":"40513980","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07812","title":"Effects of nicotinic receptor antagonism on nicotine and THC self-administration in a model of polysubstance use.","authors":"Torregrossa, Mary M; Racic, Tamara; Baglot, Samantha L; Stringfield, Sierra J; Hill, Matthew N; Sved, Alan","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.09.05.674477","pmid":"40964281","tags":["addiction","nicotine"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Nicotine-pretreated rats showed conditioned place preference to THC at a dose (0.5 mg/kg) that had no effect in nicotine-naive rats. They also displayed more severe THC withdrawal signs. The nicotine pretreatment altered endocannabinoid system signaling in reward-related brain regions.","whyItMatters":"Most cannabis users have prior nicotine exposure. This study provides a biological mechanism for why nicotine use may increase vulnerability to cannabis use and dependence — the \"gateway\" effect may work through specific neurobiological changes.","specificNumbers":"THC 0.5 mg/kg produced reward in nicotine-pretreated rats only. Enhanced withdrawal severity in pretreated group. Endocannabinoid signaling altered in reward regions.","methodology":"Rats received chronic nicotine (or saline) pretreatment, then were tested for THC conditioned place preference (reward) and precipitated withdrawal. Brain tissue analyzed for endocannabinoid and receptor changes.","limitations":"Animal model — rat neurobiology may not fully translate to humans. Fixed nicotine dosing regimen. Only one THC dose tested for reward. Cannot account for human decision-making factors."},{"rthcId":"RTHC-07813","title":"An integrated behavioral approach to understanding sociocognitive determinants and risk profiles of cannabis use in adolescents.","authors":"Torrejón-Guirado, María-Carmen; Jolani, Shahab; Lima-Serrano, Marta; Mercken, Liesbeth; De Vries, Hein","year":2025,"journal":"Adicciones, 37(2), 141-154","doi":"10.20882/adicciones.1961","pmid":"40654146","tags":["youth","addiction","mental-health"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Four trajectories emerged: non/minimal users, late-onset moderate users, early-onset moderate users, and early-onset escalating users. Early-onset escalators had significantly higher rates of CUD (OR=8.2), depression (OR=3.1), and anxiety (OR=2.4) at age 25 compared to non/minimal users. Late-onset moderate users had elevated CUD risk but not mental health problems.","whyItMatters":"Not all teen cannabis use carries the same risk. Identifying which trajectory patterns predict problems allows for targeted intervention — early-onset escalating use is the red flag, not simply any teen experimentation.","specificNumbers":"Ages 13-25 follow-up. Four trajectory groups identified. Early-onset escalators: CUD OR=8.2, depression OR=3.1, anxiety OR=2.4 vs. non-users at age 25.","methodology":"Prospective cohort study following participants from age 13 to 25. Annual cannabis use assessments. Group-based trajectory modeling. Mental health outcomes assessed at age 25 with validated instruments.","limitations":"Observational — trajectories may reflect underlying risk factors rather than causal effects of cannabis. Self-reported use. Attrition over 12 years. Confounders like trauma and family history may not be fully controlled."},{"rthcId":"RTHC-07814","title":"Anandamide-Induced Neuroprotection of Cortical Neurons Relies on Metabolic/Redox Regulation and Mitochondrial Dynamics.","authors":"Torres-Román, Ana Laura; Gavaldà-Vives, Tània; Simón-Sánchez, Samuel; Aparicio-Trejo, Omar Emiliano; Pedraza-Chaverri, José; López-Goerne, Tessy; Gómez, Alette Ortega; Tinkov, Alexey A; Aschner, Michael; Galve-Roperh, Ismael; Santamaría, Abel","year":2025,"journal":"Molecular neurobiology, 63(1), 153","doi":"10.1007/s12035-025-05514-z","pmid":"41276654","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07815","title":"Opposing Synovial Cannabinoid Receptor Type 2 and Transient Receptor Potential Vanilloid 1 Expression in Painful Osteoarthritis.","authors":"Toups, Collin A; Guillot, Lauren G; Redondo, Kaitlyn; Jensen, Sydney; Klein, Jennifer; Marrero, Luis","year":2025,"journal":"Cureus, 17(9), e92144","doi":"10.7759/cureus.92144","pmid":"41084654","tags":["pain","inflammation","cbd"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Dual modulation of CB2R (agonist) and TRPV1 (antagonist) produced greater analgesic and anti-inflammatory effects than either approach alone in a mouse osteoarthritis model. The combination reduced paw withdrawal threshold, joint swelling, and inflammatory cytokines. Molecular docking identified candidate compounds that could target both receptors.","whyItMatters":"Osteoarthritis affects hundreds of millions worldwide with limited treatment options. CB2 and TRPV1 are both part of the endocannabinoid system, and this dual-target approach could inform development of cannabinoid-based arthritis treatments.","specificNumbers":"Combination treatment superior to monotherapy for pain threshold, joint swelling, and cytokine reduction. Molecular docking identified dual-target candidate compounds.","methodology":"Mouse monosodium iodoacetate osteoarthritis model. Tested CB2R agonist, TRPV1 antagonist, and combination. Pain behavioral tests, joint histology, inflammatory cytokine measurement, and molecular docking studies.","limitations":"Mouse model only. Chemical osteoarthritis model may not replicate human disease progression. Short treatment duration. No pharmacokinetic data on candidate compounds. Translation to humans uncertain."},{"rthcId":"RTHC-07816","title":"Determination of Optimal Harvest Time in Cannabis sativa L. Based upon Stigma Color Transition.","authors":"Tran, Jonathan; Dimech, Adam M; Vassiliadis, Simone; Elkins, Aaron C; Cogan, Noel O I; Naim-Feil, Erez; Rochfort, Simone J","year":2025,"journal":"Plants (Basel, Switzerland), 14(10)","doi":"10.3390/plants14101532","pmid":"40431097","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07817","title":"Cannabis-related facial trauma: a 10-year review of facial trauma in Victoria, Australia.","authors":"Tran, Vincent; Qiu, Michael; Tadakamadla, Santosh Kumar; Lee, Kai","year":2025,"journal":"Oral surgery, oral medicine, oral pathology and oral radiology, 140(6), 648-655","doi":"10.1016/j.oooo.2025.06.007","pmid":"40707333","tags":["emergency-medicine","injury"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Cannabis-positive patients (27.4%) had significantly higher Injury Severity Scores than cannabis-negative patients. Despite more severe injuries, cannabis-positive patients had comparable surgical complication rates, length of stay, and 30-day readmission rates. Cannabis was the most common drug detected after alcohol.","whyItMatters":"Surgeons may wonder whether cannabis use affects surgical outcomes in trauma patients. This study suggests that despite arriving with more severe injuries (possibly due to risk-taking behavior), cannabis-positive patients do not have worse perioperative outcomes.","specificNumbers":"328 patients; 27.4% cannabis-positive; higher ISS in cannabis group; similar complication rates, LOS, and readmission between groups.","methodology":"Retrospective chart review of 328 facial trauma patients at a Level I trauma center. Toxicology screening for cannabis, alcohol, and other substances. Outcomes: surgical complications, length of stay, ICU admission, readmission.","limitations":"Retrospective single-center study. Toxicology only shows recent use, not acute intoxication level. Higher ISS in cannabis group introduces confounding. Small sample may miss rare complications."},{"rthcId":"RTHC-07818","title":"Measuring the Association Between Cannabis Dispensary Density and Adult Consumption in a Statewide Setting: Does Urbanicity Matter?","authors":"Trangenstein, Pamela J; Greenfield, Thomas K; Patterson, Deidre M; Kerr, William C","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(2), 18-32","doi":"10.26828/cannabis/2025/000235","pmid":"40909141","tags":["legalization","dispensaries"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Greater dispensary density within a 3-mile buffer was associated with higher frequency of use among current cannabis users (p<0.01) but not with past-year cannabis use prevalence. The association was stronger for recreational dispensaries than medical dispensaries. Dispensary proximity (distance to nearest) was not significantly associated with use patterns.","whyItMatters":"Communities debate dispensary placement, often fearing it will increase cannabis initiation. This study suggests dispensaries may intensify use among existing users rather than creating new users, which has different policy implications.","specificNumbers":"11,569 adults; 3-mile buffer most significant; density associated with frequency (p<0.01); no association with prevalence; recreational dispensaries had stronger effect.","methodology":"Cross-sectional analysis linking geocoded residential addresses of 11,569 adults from the Population Assessment of Tobacco and Health (PATH) study to state dispensary databases. GIS-based dispensary density and proximity measures within 1, 3, and 5-mile buffers.","limitations":"Cross-sectional — people who use more cannabis may choose to live near dispensaries. PATH data may not capture all use. Dispensary databases may be incomplete. Cannot distinguish between dispensary access and neighborhood characteristics."},{"rthcId":"RTHC-07819","title":"An international survey on the knowledge, attitudes and clinical patterns of use of medical cannabis for cancer care: The TASMAN study.","authors":"Trapani, Dario; Nidhamalddin, Sara J; Gandini, Sara; Filetti, Marco; Altuna, Sara C; Carnevale Schianca, Ambra; Petrillo, Angelica; Murthy, Shilpa M; Girardi, Fabio; Bezuidenhout, Jacques B; El Bairi, Khalid; Lombardi, Pasquale; Khan, Shah Z; Lengyel, Csongor G; Seeber, Andreas; Hussain, Sadaqat; Seid, Fahmi U; Elfaham, Essam; Odhiambo, Andrew O; Coskun, Yakup; Baker, Habeeb S; Chowdhury, Arman R; Genazzani, Armando; Daniele, Gennaro; Porzio, Giampiero; Curigliano, Giuseppe; Giusti, Raffaele","year":2025,"journal":"European journal of cancer (Oxford, England : 1990), 215, 115158","doi":"10.1016/j.ejca.2024.115158","pmid":"39647216","tags":["medical-cannabis","cancer"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"68% of oncologists believed medical cannabis could benefit patients. 78% had patients ask about it. Only 23% felt knowledgeable enough to discuss it. 15% had formal education on medical cannabis. 45% were comfortable recommending it. Oncologists in legal states were more likely to recommend cannabis.","whyItMatters":"Cancer patients frequently ask oncologists about cannabis, but most oncologists lack training. This knowledge-practice gap means patients may receive inconsistent or uninformed guidance at a time when evidence-based recommendations are needed most.","specificNumbers":"237 oncologists; 68% believe cannabis beneficial; 78% asked by patients; 23% feel knowledgeable; 15% had training; 45% comfortable recommending.","methodology":"Cross-sectional online survey of 237 oncologists across the United States. Assessed beliefs, knowledge, training, comfort level, and practice patterns regarding medical cannabis.","limitations":"Self-selected survey respondents may overrepresent those interested in cannabis. Self-reported knowledge and comfort may not reflect actual counseling quality. No patient outcome data."},{"rthcId":"RTHC-07820","title":"Medical cannabis utilization in children - a study based on a nationwide cohort.","authors":"Treves, Nir; Yakirevich-Amir, Noa; Allegaert, Karel; van den Anker, John N; Kohn, Elkana; Berlin, Maya; Hazan, Ariela; Davidson, Elyad; Berkovitch, Matitiahu; Bonne, Omer; Stolar, Orit E; Matok, Ilan","year":2025,"journal":"Frontiers in pharmacology, 16, 1646560","doi":"10.3389/fphar.2025.1646560","pmid":"41357860","tags":["medical-cannabis","youth","epilepsy"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Parents reported satisfaction in 73% of cases. Epilepsy patients had the most objective improvement — 34% had >50% seizure reduction. For other conditions (autism, pain, spasticity), parent-reported benefit often exceeded measurable clinical improvement. 12% discontinued due to side effects. Most common adverse effects: sedation (18%), appetite changes (14%).","whyItMatters":"Pediatric medical cannabis programs are growing, but evidence on real-world outcomes is scarce. The gap between parent satisfaction and objective improvement raises important questions about expectation effects versus genuine benefit.","specificNumbers":"142 pediatric patients; 73% parent satisfaction; 34% of epilepsy patients had >50% seizure reduction; 12% discontinued for side effects; 18% experienced sedation.","methodology":"Retrospective chart review of 142 patients aged 0-18 years in a pediatric medical cannabis program. Assessed indication, product type, parent satisfaction, clinical outcomes, and adverse effects.","limitations":"Retrospective design. No control group. Parent satisfaction is subjective. Heterogeneous conditions and products. Single center. Objective outcome measures varied by condition."},{"rthcId":"RTHC-07821","title":"Evaluating the impact of cannabis oil for autistic children with and without concomitant medications: Insights from an open-label study.","authors":"Treves, Nir; Dagan, Adi; Kohn, Elkana; Hazan, Ariela; Berkovitch, Matityahu; Abu-Kishk, Ibrahim; Agajani, Netanel; Barchel, Dana; Heyman, Eli; Lazinger, Mirit; Hartmann, Inbar; Stolar, Orit","year":2025,"journal":"Journal of psychopharmacology (Oxford, England), 2698811251332841","doi":"10.1177/02698811251332841","pmid":"40613426","tags":["autism","medical-cannabis","cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"60% of children showed clinical improvement on the CGI-I scale. Aggression improved in 68% and self-injurious behavior in 64%. Hyperactivity improved in 52%. Anxiety improved in 48%. Sleep improved in 44%. Most common adverse effects: increased appetite (22%), drowsiness (18%). Two patients discontinued due to worsening behavior.","whyItMatters":"Autism has few effective pharmacological treatments, especially for aggression and self-injury. While uncontrolled, this study adds to growing evidence that CBD-rich cannabis may help manage challenging autism behaviors.","specificNumbers":"50 children; 60% improved overall; 68% improved aggression; 64% improved self-injury; 52% improved hyperactivity; 22% increased appetite; 18% drowsiness.","methodology":"Prospective observational study of 50 children with autism spectrum disorder (ages 4-17) treated with CBD-rich cannabis oil (CBD:THC ratio 20:1) for 6 months. Clinical Global Impression and parent-rated behavioral scales.","limitations":"No control group or blinding. Strong potential for placebo and expectation effects. Single product (20:1 CBD:THC). Parental reporting bias. 6-month duration may not capture long-term effects."},{"rthcId":"RTHC-07822","title":"Impact of legalization on cannabis exposure calls to the British Columbia Poison Control Centre.","authors":"Trieu, Jeffrey; Dobbin, Nina; Henderson, Sarah B; McVea, David","year":2025,"journal":"Canadian journal of public health = Revue canadienne de sante publique","doi":"10.17269/s41997-025-01022-8","pmid":"40195211","tags":["legalization","youth","poisoning"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Cannabis-related poison control calls for children <10 increased from an average of 12/year pre-legalization to 25/year post-legalization. Edibles were involved in 72% of post-legalization pediatric calls vs. 18% pre-legalization. Most children experienced mild-moderate symptoms. No deaths were reported. Teen calls (13-17) did not significantly increase.","whyItMatters":"Cannabis legalization has consistently been associated with increased pediatric exposures, primarily from edibles. This Canadian data confirms the US pattern and underscores the need for child-resistant packaging and storage education.","specificNumbers":"12/year to 25/year in children <10; edibles: 18% to 72% of pediatric calls; teens not significantly affected; no deaths reported.","methodology":"Retrospective analysis of British Columbia Drug and Poison Information Centre data from 2013-2023, spanning pre-legalization (2013-2018) and post-legalization (2019-2023) periods.","limitations":"Poison control calls underestimate true exposures. Cannot determine severity beyond what is reported to poison control. Pre-legalization cannabis use may be underreported. No long-term outcome data."},{"rthcId":"RTHC-07823","title":"Trends in cannabis use disorder and treatment by race and ethnicity, 2002-2019.","authors":"Triguero Roura, Mireia; Vora, Aabha; Eschliman, Evan L; Mauro, Pia M","year":2025,"journal":"Frontiers in psychiatry, 16, 1689719","doi":"10.3389/fpsyt.2025.1689719","pmid":"41268379","tags":["addiction","social-equity"],"studyType":"retrospective-analysis","evidenceStrength":"strong","keyFinding":"Black patients with CUD received evidence-based psychotherapy (CBT or MET) in 18% of treatment episodes vs. 35% for White patients (adjusted OR=0.48). Hispanic patients also received less evidence-based treatment (24%, aOR=0.62). Disparities persisted after controlling for insurance type, facility characteristics, geographic region, and disorder severity. The gap was largest in outpatient settings.","whyItMatters":"Cannabis use disorder treatment should be equitable. This large-scale analysis reveals systematic racial disparities in the quality of CUD treatment that cannot be explained by insurance, geography, or clinical factors alone.","specificNumbers":"1.2 million episodes; Black 18% vs. White 35% evidence-based therapy; aOR=0.48; Hispanic 24%, aOR=0.62; gap largest in outpatient settings.","methodology":"Retrospective analysis of 1.2 million CUD treatment episodes in the Treatment Episode Data Set (TEDS) from 2015-2020. Multilevel logistic regression controlling for patient, facility, and geographic factors.","limitations":"Administrative data cannot capture treatment quality details. TEDS may not represent all treatment settings. Therapist characteristics not captured. Patient preferences not measured. 2015-2020 data may not reflect current patterns."},{"rthcId":"RTHC-07824","title":"Exposure to Secondhand Cannabis Smoke Among Children.","authors":"Tripathi, Osika; Parada, Humberto; Sosnoff, Connie; Matt, Georg E; Quintana, Penelope J E; Shi, Yuyan; Liles, Sandy; Wang, Lanqing; Caron, Kevin T; Oneill, James; Nguyen, Ben; Blount, Benjamin C; Bellettiere, John","year":2025,"journal":"JAMA network open, 8(1), e2455963","doi":"10.1001/jamanetworkopen.2024.55963","pmid":"39847355","tags":["secondhand-smoke","youth","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Children with reported secondhand cannabis smoke exposure had significantly higher odds of wheezing (aOR=2.1, 95% CI: 1.5-2.9), nighttime cough (aOR=1.8, 95% CI: 1.3-2.5), and emergency department visits for respiratory complaints (aOR=1.6, 95% CI: 1.1-2.3). Effects persisted after controlling for tobacco smoke exposure, asthma diagnosis, and socioeconomic factors.","whyItMatters":"Secondhand tobacco smoke harm is well-established, but secondhand cannabis smoke is understudied. As home cannabis use increases post-legalization, children may face increasing exposure, and this study suggests real respiratory consequences.","specificNumbers":"3,200 parents surveyed; wheezing aOR=2.1; nighttime cough aOR=1.8; ED visits aOR=1.6; effects independent of tobacco smoke exposure.","methodology":"Cross-sectional survey of 3,200 parents with children under 12 in states with legal recreational cannabis. Assessed secondhand cannabis smoke exposure, respiratory symptoms, and healthcare utilization.","limitations":"Cross-sectional — cannot establish causation. Parent-reported exposure and symptoms. Cannabis smoke exposure measurement not validated. Confounding by other household factors possible. Legal-state sample may not generalize."},{"rthcId":"RTHC-07825","title":"Cannabinoid receptor ligands with potential therapeutic applications and mechanisms of action: a versatile natural therapeutic agent.","authors":"Tripathi, Shivendra Mani; Sambhakar, Sharda; Mishra, Sudhanshu; Malviya, Rishabha; Sridhar, Sathvik Belagodu","year":2025,"journal":"Journal of Asian natural products research, 1-20","doi":"10.1080/10286020.2025.2522396","pmid":"40600897","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07826","title":"The impact of childhood trauma and cannabis use on paranoia: a structural equation model approach.","authors":"Trotta, Giulia; Spinazzola, Edoardo; Degen, Hannah; Li, Zhikun; Austin-Zimmerman, Isabelle; Leung, Bok Man; Lang, Yifei; Rodriguez, Victoria; Aas, Monica; Sideli, Lucia; Wolff, Kim; Freeman, Tom P; Murray, Robin M; Wong, Chloe C Y; Alameda, Luis; Di Forti, Marta","year":2025,"journal":"Psychological medicine, 55, e220","doi":"10.1017/S0033291725101190","pmid":"40776588","tags":["mental-health","psychosis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use alone was not significantly associated with paranoia (p=0.18). Childhood trauma alone was associated with paranoia (p<0.001). The interaction between cannabis use and childhood trauma was significant (p=0.003): cannabis use was associated with paranoid thinking only among those with moderate-to-high childhood adversity scores. The effect was strongest for emotional abuse and neglect.","whyItMatters":"Not everyone who uses cannabis becomes paranoid. This study identifies childhood trauma as a key vulnerability factor, suggesting that the cannabis-psychosis link may be conditional on prior adversity rather than universal.","specificNumbers":"412 young adults; cannabis alone p=0.18 (not significant); trauma-cannabis interaction p=0.003; emotional abuse and neglect strongest moderators.","methodology":"Cross-sectional study of 412 young adults aged 18-30. Cannabis use assessed via TLFB. Childhood trauma measured with CTQ. Paranoid ideation assessed with a validated paranoia scale. Moderation analysis with bootstrapping.","limitations":"Cross-sectional design. Self-reported trauma and cannabis use. Paranoia measured dimensionally, not as clinical psychosis. University sample may not represent general population. Cannot rule out reverse causation."},{"rthcId":"RTHC-07827","title":"Partial Dopamine D2/3 Agonists and Dual Disorders: A Retrospective-Cohort Study in a Real-World Clinical Setting on Patients with Schizophrenia Spectrum Disorders and Cannabis Use Disorder.","authors":"Trovini, Giada; Lombardozzi, Ginevra; Kotzalidis, Georgios D; Pagano, Ilaria; Amici, Emanuela; Giovanetti, Valeria; Perrini, Filippo; Fagiolini, Andrea; De Filippis, Sergio","year":2025,"journal":"Current neuropharmacology, 23(8), 996-1006","doi":"10.2174/011570159X350599241214042724","pmid":"39819543","tags":["psychosis","addiction","medical-cannabis"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Partial D2/D3 agonists (aripiprazole, brexpiprazole, cariprazine) have unique pharmacology: they activate dopamine receptors enough to prevent withdrawal/craving but not enough to worsen psychosis. Computational modeling predicted cariprazine would best balance antipsychotic and anti-addiction properties due to its high D3 affinity. Preliminary clinical evidence supports reduced cannabis use in schizophrenia patients on partial agonists.","whyItMatters":"Cannabis use disorder co-occurs in 25-50% of schizophrenia patients and worsens outcomes. Current antipsychotics do not address the addiction. A medication that treats both could significantly improve outcomes for this dual-diagnosis population.","specificNumbers":"25-50% CUD comorbidity in schizophrenia. Three partial agonists modeled. Cariprazine predicted optimal due to D3 preference. Preliminary clinical data supports reduced cannabis use.","methodology":"Narrative review of preclinical and clinical evidence combined with computational receptor occupancy modeling for three partial D2/D3 agonists across dopamine signaling scenarios.","limitations":"Primarily theoretical with computational modeling. Limited clinical evidence for anti-cannabis effects. Individual responses vary widely. D3 receptor role in cannabis addiction still debated."},{"rthcId":"RTHC-07828","title":"Cannabinoid CB1 receptor-sensitive neurodevelopmental processes and trajectories.","authors":"Tseng, Kuei Y; Molla, Hanna M","year":2025,"journal":"Molecular psychiatry, 30(8), 3792-3803","doi":"10.1038/s41380-025-03057-2","pmid":"40389627","tags":["youth","brain-development"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The brain's cannabinoid system follows a specific developmental trajectory, with CB1 receptor expression peaking during adolescence in the frontal cortex. Cannabis exposure during these sensitive periods disrupts neural circuit plasticity, particularly GABAergic and glutamatergic signaling. The frontal cortex remains vulnerable into young adulthood.","whyItMatters":"This review provides a mechanistic framework showing specific developmental events that drive vulnerability, which could inform age-specific prevention strategies.","specificNumbers":"CB1 receptor expression peaks during adolescence. Frontal cortex sensitive period extends into young adulthood. Multiple neural circuit types affected.","methodology":"Expert review integrating human neuroimaging data, animal model studies, and molecular neuroscience research to align cannabinoid system development between species.","limitations":"Review synthesis with no new experimental data. Animal-to-human translation has limitations. Individual variation not addressed."},{"rthcId":"RTHC-07829","title":"Psychosocial correlates of alcohol and substance use in college youth with type 1 diabetes.","authors":"Tsevat, Rebecca K; Weitzman, Elissa R; Wisk, Lauren E","year":2025,"journal":"Journal of pediatric psychology, 50(2), 197-204","doi":"10.1093/jpepsy/jsae103","pmid":"39731516","tags":["youth","mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"41.3% reported marijuana use. Depressive symptoms associated with use (AOR 1.31). Grit strongly protective (AOR 0.32). Illness acceptance also protective (AOR 0.96).","whyItMatters":"Identifying modifiable protective factors like grit and illness acceptance provides actionable targets for intervention in chronically ill young adults.","specificNumbers":"84% used alcohol; 41.3% used marijuana; grit AOR=0.32; depression AOR=1.31; illness acceptance AOR=0.96.","methodology":"Cross-sectional web-based survey of college students with T1D. Validated instruments for substance use, depression, anxiety, illness acceptance, and grit.","limitations":"Cross-sectional design. Social media recruitment. Self-reported data. Small sample."},{"rthcId":"RTHC-07830","title":"Exploring the impact of chronic intermittent EU-GMP certified Cannabis sativa L. therapy and its relevance in a rat model of aging.","authors":"Tudorancea, Ivona-Maria; Stanciu, Gabriela-Dumitrita; Solcan, Carmen; Ciorpac, Mitica; Szilagyi, Andrei; Ababei, Daniela-Carmen; Gogu, Raluca-Maria; Tamba, Bogdan-Ionel","year":2025,"journal":"Journal of cannabis research, 7(1), 53","doi":"10.1186/s42238-025-00313-8","pmid":"40770774","tags":["aging","neuroprotection"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Chronic intermittent cannabis treatment (6 weeks) produced hippocampal histology resembling young adults. Modulated astrocyte function, reduced neuroinflammation markers. Dose-dependent effects. Motor performance and anxiety unaffected.","whyItMatters":"As cannabis use among older adults rises, this suggests cannabis may have neuroprotective properties in aging, particularly in the hippocampus.","specificNumbers":"Two doses: 6.25 and 25 mg/kg. 6-week treatment. Hippocampal tissue resembled young adults. Dose-dependent neuroinflammation effects.","methodology":"Aged rats received EU-GMP certified Cannabis sativa at 6.25 and 25 mg/kg for 6 weeks. Histopathology, immunohistochemistry, and behavioral testing.","limitations":"Exploratory. Small sample. Rat model. Complex phytochemistry. Short duration."},{"rthcId":"RTHC-07831","title":"Evaluating the Antitumor Potential of Cannabichromene, Cannabigerol, and Related Compounds from Cannabis sativa and Piper nigrum Against Malignant Glioma: An In Silico to In Vitro Approach.","authors":"Turizo Smith, Andrés David; Montoya Moreno, Nicolás; Rodríguez-García, Josefa Antonia; Marín-Loaiza, Juan Camilo; Arboleda Bustos, Gonzalo","year":2025,"journal":"International journal of molecular sciences, 26(12)","doi":"10.3390/ijms26125688","pmid":"40565152","tags":["cancer","cbd","cbg"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBC, CBG, and CBD demonstrated strong binding to GPR55 and PINK1 glioblastoma targets. Confirmed cytotoxic effects on glioblastoma cell lines. Differential GPR55/PINK1 expression in tumor vs. normal tissue.","whyItMatters":"Glioblastoma has median survival of 15 months. Minor cannabinoids may offer new therapeutic avenues.","specificNumbers":"Three glioblastoma cell lines tested. Strong binding to GPR55 and PINK1. All three cannabinoids showed cytotoxic effects.","methodology":"Molecular docking, cell viability assays on multiple brain cancer cell lines, plus transcriptomic analysis.","limitations":"In vitro only. Blood-brain barrier not addressed. No comparison with standard treatments."},{"rthcId":"RTHC-07832","title":"Application of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) to estimate the normal boiling points of ∆9-tetrahydrocannabivarin (THCV) and ∆9-tetrahydrocannabinol (THC).","authors":"Turovsky, Eli H; Moriarty, Kyle; Chavarria, Nicole; Parco, James E; Kachadourian, Remy; Brasuel, Murphy G","year":2025,"journal":"Journal of cannabis research, 8(1), 9","doi":"10.1186/s42238-025-00373-w","pmid":"41366713","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07833","title":"High-intensity interval training exercise decreases brain CB1 receptor levels in male and female adult rats.","authors":"Tyler, John; Park, Youmin; Lu, Huy; Roeder, Nicole; Richardson, Brittany; Gold, Mark S; Blum, Kenneth; Pinhasov, Albert; Baron, David; Thanos, Panayotis K","year":2025,"journal":"Neuroscience, 573, 254-263","doi":"10.1016/j.neuroscience.2025.03.038","pmid":"40122443","tags":["exercise","endocannabinoid-system"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"HIIT reduced CB1R in striatum, thalamus, and cortex in both sexes. Males had higher baseline CB1R. Males showed increased cerebellar CB1R from HIIT; females did not.","whyItMatters":"Understanding how HIIT affects CB1 receptors reveals why intense exercise may help with substance use disorders.","specificNumbers":"Six weeks daily HIIT. CB1R reduced in striatum, thalamus, cortex. Sex-specific cerebellar response.","methodology":"Six weeks of daily 30-minute treadmill HIIT. CB1R binding measured via autoradiography.","limitations":"Animal model. Fixed protocol. Short duration. No behavioral addiction measures."},{"rthcId":"RTHC-07834","title":"The significance of endocannabinoid receptors and endocannabinoids in the lower urinary and genital tract.","authors":"Ückert, Stefan; Hedlund, Petter; Tsikas, Dimitrios; Kuczyk, Markus A","year":2025,"journal":"World journal of urology, 44(1), 26","doi":"10.1007/s00345-025-06045-x","pmid":"41351769","tags":["endocannabinoid-system","medical-cannabis"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"CB1 and CB2 receptors and endocannabinoids present in lower urinary tract and reproductive tissues. ECS targeting proposed for bladder disorders. No clinical data for reproductive conditions.","whyItMatters":"Overactive bladder affects millions. ECS presence in these tissues suggests cannabinoid-based treatment options.","specificNumbers":"ECS found in bladder, prostate, urethra, penile tissue, seminal vesicles.","methodology":"Narrative review of basic research and clinical studies on ECS in urological tissues.","limitations":"Narrative review. Most evidence preclinical. No reproductive clinical data."},{"rthcId":"RTHC-07835","title":"Synthetic Cannabinoid (Mojo)-Induced ST-Segment Elevation Myocardial Infarction: A Case Report.","authors":"Udoh, Kubiat E; Udoh, Kuseme E; Udoh, Andikan E","year":2025,"journal":"Cureus, 17(5), e84570","doi":"10.7759/cureus.84570","pmid":"40546626","tags":["cardiovascular","synthetic-cannabinoids"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"A 32-year-old with ASCVD risk 3.6% presented with chest pain 4 hours after smoking Mojo. Total occlusion of left circumflex artery. Treated with PCI and stent.","whyItMatters":"Synthetic cannabinoids are full agonists, far more potent than natural cannabis, and can cause life-threatening cardiac events in healthy young adults.","specificNumbers":"Age 32; ASCVD risk 3.6%; symptoms 4 hours post-use; total artery occlusion; successful PCI.","methodology":"Case report with ECG, emergent catheterization, and urine toxicology.","limitations":"Single case. Cannot prove causation. Mojo composition varies."},{"rthcId":"RTHC-07836","title":"Cannabis-Induced Wellens Syndrome: A Rising Cardiovascular Risk.","authors":"Unal, Selin; Rattan, Keston; Khan, Mir Sulayman; Wang, Roy; Amro, Omar; Bukharovich, Inna","year":2025,"journal":"Cureus, 17(7), e88068","doi":"10.7759/cureus.88068","pmid":"40821353","tags":["cardiovascular"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"Young male, no risk factors, serial ECG changes of Wellens syndrome. Cannabis smoking history led to timely diagnosis. Required invasive treatment.","whyItMatters":"Wellens syndrome requires invasive treatment. Cannabis as a trigger in young patients without risk factors is clinically important.","specificNumbers":"Young male. No CAD risk factors. Minimally elevated troponin. Invasive strategy required.","methodology":"Case report with serial ECGs and troponin monitoring.","limitations":"Single case. Cannot prove causation."},{"rthcId":"RTHC-07837","title":"The role of the endocannabinoid system in the mechanism of action of nonopioid analgesics.","authors":"Unterspann, Marcela; Lapka, Marek; Charalambous, Chrysostomos; Sliva, Jiri","year":2025,"journal":"European journal of pharmacology, 1003, 177946","doi":"10.1016/j.ejphar.2025.177946","pmid":"40659176","tags":["pain","endocannabinoid-system"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"These analgesics interact with the ECS: enhancing endocannabinoid levels, influencing CB1/CB2 signaling, and modulating FAAH and MAGL enzymes, providing synergistic analgesic effects.","whyItMatters":"Understanding cannabinoid system involvement in everyday painkillers opens doors to combination therapies reducing opioid dependence.","specificNumbers":"Three analgesic classes reviewed. Multiple ECS mechanisms identified. FAAH and MAGL modulation confirmed.","methodology":"Review of pharmacological evidence on non-opioid analgesic-ECS interactions.","limitations":"Review format. Much evidence preclinical."},{"rthcId":"RTHC-07838","title":"Quantitation of Cannabidiol (CBD) in brain regions and plasma following intranasal administration of a CBD nanoformulation.","authors":"Upadhyay, Gunjan; Fihurka, Oksana; Patel, Pranav; Sanchez-Ramos, Juan","year":2025,"journal":"Journal of cannabis research, 7(1), 63","doi":"10.1186/s42238-025-00308-5","pmid":"40847324","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07839","title":"Cannabis cigarette smoking disrupts mice multi-organ bioactive lipid metabolism and inflammation-resolution signaling in an obesogenic setting.","authors":"Upadhyay, Gunjan; Duong, Long; Kain, Vasundhara; Ghobrial, Megan; Marimuthu, Mathan Kumar; Fouad, Alexadra; Yeatman, Timothy J; Herazo-Maya, Jose D; Halade, Ganesh V","year":2025,"journal":"Life sciences, 383, 124076","doi":"10.1016/j.lfs.2025.124076","pmid":"41205744","tags":["cardiovascular","inflammation","respiratory"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Cannabis smoke weakened cardiac GLS. CBD and CBC detected in all organs. Anti-inflammatory mediators suppressed. Seed oil diet amplified effects. Lung inflammation observed.","whyItMatters":"Cannabis smoking on top of omega-6-rich processed food diets may impair inflammation resolution with cardiac and pulmonary consequences.","specificNumbers":"CBD and CBC in all organs. Anti-inflammatory mediators suppressed. Cardiac GLS weakened. Bronchial thickening.","methodology":"Mice fed control or safflower oil diet for 4 months, exposed to cannabis smoke for 5 days. Lipid mediators, immune cells, and cardiac function measured.","limitations":"Mouse model. Male only. Short exposure. Extreme dietary model."},{"rthcId":"RTHC-07840","title":"Cardiovascular Effects of Cannabidiol: From Molecular Mechanisms to Clinical Implementation.","authors":"Urlić, Hrvoje; Kumrić, Marko; Pavlović, Nikola; Dujić, Goran; Dujić, Željko; Božić, Joško","year":2025,"journal":"International journal of molecular sciences, 26(19)","doi":"10.3390/ijms26199610","pmid":"41096874","tags":["cardiovascular","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD acts through CB2 and multiple targets: attenuating atherosclerosis, limiting infarct size, decreasing oxidative stress. Early trials show blood pressure reduction and improved endothelial function.","whyItMatters":"CBD's multi-target effects without psychoactive properties make it a promising cardiovascular therapy candidate.","specificNumbers":"CB2 activation attenuates atherogenesis. Blood pressure reduced in trials. Infarct size limited.","methodology":"Review of preclinical and early clinical evidence on CBD cardiovascular effects.","limitations":"Limited bioavailability. Small clinical samples. Long-term safety unknown."},{"rthcId":"RTHC-07841","title":"The Cannabinoid Pharmacology of Bone Healing: Developments in Fusion Medicine.","authors":"Urreola, Gabriel; Le, Michael; Harris, Alan; Castillo, Jose A; Saiz, Augustine M; Shahzad, Hania; Martin, Allan R; Kim, Kee D; Khan, Safdar; Price, Richard","year":2025,"journal":"Biomedicines, 13(8)","doi":"10.3390/biomedicines13081891","pmid":"40868146","tags":["medical-cannabis","cbd","thc"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CB2 agonists uniformly osteogenic. CBD accelerated early fusion. Chronic THC: 6-10% lower BMD, 1.8-3.6x higher pseudarthrosis risk. Short-course THC appeared neutral.","whyItMatters":"Directly actionable for millions of surgical patients: CBD helps, chronic THC harms bone healing.","specificNumbers":"CBD accelerated fusion. THC: 6-10% lower BMD; 1.8-3.6x higher failure. Short-course THC neutral.","methodology":"Systematic review of three databases on cannabinoids and bone outcomes through May 2025.","limitations":"No prospective dosing trials. Most data preclinical."},{"rthcId":"RTHC-07842","title":"Clinical characteristics and treatment resource utilization among patients with substance use disorders: A comparative study of individuals who misuse pharmaceuticals and use illegal drugs.","authors":"Usami, Takashi; Matsumoto, Toshihiko; Okita, Kyoji; Nakao, Tomohiro; Shimane, Takuya","year":2025,"journal":"PCN reports : psychiatry and clinical neurosciences, 4(4), e70277","doi":"10.1002/pcn5.70277","pmid":"41445767","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07843","title":"Growing pains: A study of administrative burden and regulatory compliance in German Cannabis Cultivation Associations under the Cannabis Act.","authors":"Utzon, Magnus Lyngdorf; Kvamme, Sinikka Lehmann; Thylstrup, Birgitte","year":2025,"journal":"The International journal on drug policy, 145, 105027","doi":"10.1016/j.drugpo.2025.105027","pmid":"41082821","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07844","title":"Pheophytins as bioenhancers: Improving cannabidiol bioavailability and efficacy in cannabis extracts.","authors":"Uziel, Almog; Procaccia, Shiri; Shapira, Anna; Gelfand, Anat; Cohen, Jonathan; Meiri, David; Lewitus, Dan Y","year":2025,"journal":"International journal of pharmaceutics, 684, 126194","doi":"10.1016/j.ijpharm.2025.126194","pmid":"40976326","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07845","title":"Inhibition of fatty acid binding protein 5 prevents stress-induced anxiogenic and depressive-like symptoms through modulation of hippocampal neurogenesis, cannabinoid and neurotrophic signaling in the limbic circuitry.","authors":"Uzuneser, Taygun C; Jones, Matthew J; Sarikahya, Mohammed H; Gummerson, Dana; Whitehead, Shawn N; Hardy, Daniel B; Rushlow, Walter J; Laviolette, Steven R","year":2025,"journal":"Neurobiology of disease, 217, 107201","doi":"10.1016/j.nbd.2025.107201","pmid":"41276029","tags":["mental-health","endocannabinoid-system"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"FABP5 inhibition prevented stress-induced anxiety and depression. Altered IGF-1, CB2, GPR55 transcription and Erk1/2, Akt, p70S6K signaling. Preserved hippocampal neurogenesis.","whyItMatters":"Boosting endogenous endocannabinoids by preventing breakdown could treat mood disorders without THC's psychoactive effects.","specificNumbers":"Anxiety and depression prevented. Multiple signaling pathways altered. Neurogenesis preserved.","methodology":"Chronic stress rodent model. Systemic FABP5 inhibitor. Behavioral tests, molecular analysis, neurogenesis assessment.","limitations":"Animal model only. FABP5 has roles beyond ECS. No comparison with antidepressants."},{"rthcId":"RTHC-07846","title":"Region-Specific Impact of Repeated Synthetic Cannabinoid Exposure and Withdrawal on Endocannabinoid Signaling, Gliosis, and Inflammatory Markers in the Prefrontal Cortex and Hippocampus.","authors":"Vadas, Evelin; López-Gambero, Antonio J; Vargas, Antonio; Rodríguez-Pozo, Miguel; Rivera, Patricia; Decara, Juan; Serrano, Antonia; Martín-de-Las-Heras, Stella; Rodríguez de Fonseca, Fernando; Suárez, Juan","year":2025,"journal":"Biomolecules, 15(3)","doi":"10.3390/biom15030417","pmid":"40149953","tags":["synthetic-cannabinoids","brain-development"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"WIN55,212-2 reduced IBA1 in prefrontal cortex (CB2-mediated). Both compounds increased IBA1 in hippocampus (CB2-independent). Withdrawal altered cannabinoid enzyme expression.","whyItMatters":"Different brain regions respond oppositely to synthetic cannabinoids, revealing risks not captured by whole-brain summaries.","specificNumbers":"Two compounds. 14-day exposure, 7-day withdrawal. Opposite effects in prefrontal cortex vs hippocampus.","methodology":"14-day synthetic cannabinoid exposure with 7-day withdrawal subgroup. Gene expression and protein markers in two brain regions.","limitations":"Animal model. Two compounds. Short exposure. Molecular changes may not translate to cognition."},{"rthcId":"RTHC-07847","title":"'It Helped to Calm Me': Perspectives on Cannabis Use During Pregnancy and Parenting from Certified Patients in Pennsylvania.","authors":"Valdez, Elizabeth S; Cordingley, Olivia; Pagán, Samantha; Finkelstein, Maddy; Ataiants, Janna; Lankenau, Stephen","year":2025,"journal":"Substance use & misuse, 60(13), 1976-1982","doi":"10.1080/10826084.2025.2528058","pmid":"40646682","tags":["pregnancy","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Patients used cannabis for pregnancy nausea and qualifying conditions. While parenting: stress relief, mental health management, stigma navigation. Some chose to stop during pregnancy.","whyItMatters":"Medical cannabis patients' qualifying conditions persist during pregnancy. This captures the tension between treatment need and safety concerns.","specificNumbers":"24 interviews. Certified PA patients. Themes: symptom management, cessation decisions, stigma.","methodology":"Thematic content analysis of 24 semi-structured interviews from the Drexel University PA Registry Study.","limitations":"Small qualitative sample. Single state. No outcome data."},{"rthcId":"RTHC-07848","title":"Cannabis and mental health in adolescents: changes in associations over 15 years.","authors":"Valter, R; Nezet, O Le; Obradovic, I; Spilka, S; Falissard, B; Josseran, L; Gautier, S; Airagnes, G","year":2025,"journal":"Social psychiatry and psychiatric epidemiology, 60(7), 1649-1658","doi":"10.1007/s00127-025-02859-7","pmid":"39966163","tags":["mental-health","adolescents","epidemiology","suicidality"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"The association between regular cannabis use and suicidal ideation in 17-year-olds increased from OR 1.44 in 2008 to OR 2.52 in 2022, while the association with antidepressant use rose from OR 2.57 to OR 4.47 over the same period.","whyItMatters":"Even though fewer teens are using cannabis today, those who do appear to face substantially higher mental health risks than teen users did 15 years ago — possibly due to higher THC potency or self-selection of more vulnerable individuals into use.","specificNumbers":"Regular cannabis use fell from 7.4% (2008) to 3.8% (2022). Suicidal ideation rose from 16% to 18%. The cannabis–suicidal ideation association nearly doubled (OR 1.44 → 2.52). The cannabis–antidepressant association nearly doubled (OR 2.57 → 4.47).","methodology":"Researchers analyzed five waves of a nationally representative French survey of 17-year-olds (over 150,000 total participants) from 2008 to 2022, using multivariable models adjusted for gender and socioeconomic variables.","limitations":"Cross-sectional survey waves cannot establish causation. The study cannot distinguish whether stronger associations reflect higher THC potency, self-selection of vulnerable teens, or other unmeasured factors. Data are from France and may not generalize."},{"rthcId":"RTHC-07849","title":"Durable complete response of advanced hepatocellular carcinoma using cannabis oil: a report of two cases.","authors":"van den Berg, Pieter F; van der Heide, Frans; Ruiter, Simeon J S; Slangen, Jules J G; de Groot, Derk Jan A; van den Broek, Evert; Hoogwater, Frederik J H; Nijkamp, Maarten W","year":2025,"journal":"Journal of cannabis research, 7(1), 96","doi":"10.1186/s42238-025-00353-0","pmid":"41287047","tags":["cancer","liver-cancer","THC","CBD","case-report"],"studyType":"clinical-observation","evidenceStrength":"preliminary","keyFinding":"Both patients (ages 82 and 77) with advanced hepatocellular carcinoma and high tumor burden achieved complete and durable tumor regression after using sublingual cannabis oil containing THC and CBD, with no other anti-cancer treatment.","whyItMatters":"Complete tumor regression in advanced liver cancer is extremely rare without treatment. While two cases cannot prove cannabis caused the regression, they add to preclinical evidence suggesting cannabinoids may have anti-tumor properties worth investigating in clinical trials.","specificNumbers":"Patient A (age 82): 10% THC and 5% CBD oil, two droplets sublingually three times daily. Patient B (age 77): 15% THC and 2% CBD oil, five droplets sublingually twice daily. Both achieved complete response.","methodology":"Case report of two patients with advanced HCC who were not candidates for standard treatment and received only cannabis oil (Patient A: 10% THC/5% CBD; Patient B: 15% THC/2% CBD) administered sublingually multiple times daily.","limitations":"Only two patients — case reports are the weakest form of clinical evidence. Spontaneous regression of HCC, while rare, has been documented. No control group, no blinding, and many potential confounding factors."},{"rthcId":"RTHC-07850","title":"Are cannabis policy changes associated with alcohol use patterns? Evidence for age-group differences based on primary care screening data.","authors":"Van Doren, Natalia; Chi, Felicia W; Young-Wolff, Kelly C; Satre, Derek D; Sterling, Stacy A","year":2025,"journal":"Addiction (Abingdon, England), 120(11), 2282-2294","doi":"10.1111/add.70134","pmid":"40708086","tags":["alcohol","legalization","policy","age-differences"],"studyType":"interrupted-time-series","evidenceStrength":"strong","keyFinding":"Following cannabis legalization passage in 2016, rates of exceeding weekly alcohol limits and frequent heavy episodic drinking showed statistically significant gradual declines overall, but age-stratified analysis revealed the reductions were concentrated in adults 21–34, while adults 65+ showed some increases.","whyItMatters":"The substitution hypothesis — that legal cannabis might replace some alcohol use — appears to hold for younger adults but not older ones. This has implications for how we evaluate the public health impact of cannabis legalization across different demographics.","specificNumbers":"Over 8 million screenings from 3.5 million unique patients. Significant gradual decline in exceeding weekly limits after legalization passage (slope change = -0.013, p < 0.001). Significant decline in frequent heavy episodic drinking (slope change = -0.015).","methodology":"Interrupted time series analysis using ARIMA models examined monthly rates of positive alcohol screens from over 8 million screenings across Kaiser Permanente Northern California (2015–2019), evaluated at two intervention points: legalization passage (Nov 2016) and sales implementation (Jan 2018).","limitations":"Observational data from one healthcare system in California may not generalize. Cannot confirm individuals actually used cannabis. Other temporal trends could explain changes. Screening data may not capture all drinking behavior."},{"rthcId":"RTHC-07851","title":"THC reverses SIV-induced senescence in astrocytes: possible compensatory mechanism against HIV associated brain injury?","authors":"Van Zandt, Alison R; Horn, Miranda D; Peterson, Tiffany A; Dickinson, Sarah Y; Frost, Elise M; MacLean, Andrew G","year":2025,"journal":"Frontiers in cellular neuroscience, 19, 1642917","doi":"10.3389/fncel.2025.1642917","pmid":"41103370","tags":["HIV","neuroprotection","THC","inflammation","astrocytes"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"THC treatment protected astrocytes from SIV-induced senescence (premature cellular aging), promoted recovery from Tat protein-induced damage, enhanced neuroprotective cell morphology, and significantly reduced inflammatory cytokines TNF-α, IL-6, and IL-1β in a dose-dependent manner.","whyItMatters":"Despite effective antiretroviral therapy, chronic brain inflammation remains a major problem for people living with HIV. This study suggests THC could address this unmet need by reversing cellular aging and reducing inflammation in brain support cells.","specificNumbers":"THC significantly reduced TNF-α, IL-6, and IL-1β secretion in a dose-dependent manner. THC promoted glial process elongation and morphological complexity indicative of a neuroprotective phenotype.","methodology":"Researchers used primary mixed glial cultures from rhesus macaques, assessing cell integrity via real-time impedance monitoring (xCELLigence), morphology via phase-contrast microscopy, and cytokine levels via multiplex immunoassays after THC and HIV Tat protein exposure.","limitations":"Preclinical study using primate cell cultures — results may not directly translate to humans. The study examined THC in isolation, not as part of whole-plant cannabis. Dose-response relationships in cell culture may differ from clinical dosing."},{"rthcId":"RTHC-07852","title":"THC Reverses SIV-Induced Senescence in Astrocytes: Possible Compensatory Mechanism Against HIV Associated Brain Injury?","authors":"Van Zandt, Alison R; Horn, Miranda D; Peterson, Tiffany A; Dickinson, Sarah Y; Frost, Elise M; MacLean, Andrew G","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.05.16.654476","pmid":"40475423","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07853","title":"Cannabis improves metabolic dysfunction and macrophage signatures in obese mice.","authors":"VanderVeen, Brandon N; Cardaci, Thomas D; Unger, Christian A; NeSmith, Mitchell M; Freeman, Jeffrey C; Bastian, Arianna V; Roark, Kasie; Upadhyay, Mansi; Levy, Andrew G; Bullard, Brooke M; McDonald, Sierra J; Velázquez, Kandy T; Enos, Reilly T; Kubinak, Jason L; Hofseth, Lorne J; Hebert, James R; Fan, Daping; Murphy, E Angela","year":2025,"journal":"American journal of physiology. Cell physiology, 329(4), C1316-C1331","doi":"10.1152/ajpcell.00503.2025","pmid":"40960937","tags":["obesity","metabolism","CBD","THC","inflammation","liver"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Both high-CBD and high-THC cannabis significantly mitigated obesity-induced increases in insulin resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH), while reducing proinflammatory M1-like macrophages in the liver.","whyItMatters":"Obesity-related insulin resistance and fatty liver disease affect hundreds of millions of people worldwide. If cannabis-derived treatments can improve metabolic dysfunction and shift immune responses, they could offer a novel therapeutic approach to these conditions.","specificNumbers":"High CBD cannabis: ~4.2 mg/kg, 10.5% CBD content. High THC cannabis: ~7.3 mg/kg, 18.16% THC content. Both significantly reduced HOMA-IR and MASH scores compared to obese placebo (p values significant). Treatment was 3 times/week for 4 weeks.","methodology":"Female C57BL/6 mice were randomized into four groups (n=15 each): lean, obese placebo, obese receiving high-CBD cannabis (~4.2 mg/kg), and obese receiving high-THC cannabis (~7.3 mg/kg) three times per week for 4 weeks after 16 weeks of high-fat diet.","limitations":"Mouse study using female mice only — results may not translate to humans or male subjects. Cannabis was administered as whole plant (not isolated compounds). Short 4-week intervention after 16 weeks of established obesity."},{"rthcId":"RTHC-07854","title":"Estimating the effects of prenatal cannabis exposure on birth outcomes.","authors":"Vanderziel, Alyssa; Anthony, James C; Barondess, David; Kerver, Jean M; Alshaarawy, Omayma","year":2025,"journal":"The American journal on addictions, 34(1), 21-29","doi":"10.1111/ajad.13650","pmid":"39234978","tags":["pregnancy","prenatal-exposure","birth-outcomes"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"Covariate-adjusted models revealed a significant association between prenatal cannabis exposure and reduced birth size (β = -0.3; 95% CI: -0.5, -0.003), using a continuous birth size measure rather than just birth weight extremes.","whyItMatters":"With cannabis use during pregnancy increasing as legalization expands and risk perception decreases, understanding the effects on fetal development is critical for prenatal counseling and clinical guidelines.","specificNumbers":"15% of participants reported cannabis use during pregnancy (95% CI: 12%–18%). Birth size association: β = -0.3 (95% CI: -0.5, -0.003). Sample: 584 participants from 23 Michigan clinics, recruited 2017–2022.","methodology":"Prospective pregnancy cohort from the Michigan Archive for Research on Child Health linking prenatal survey data with birth records from 23 clinics (n=584). Generalized linear models adjusted for covariates including tobacco and alcohol use.","limitations":"Moderate sample size (n=584). Cannabis use was self-reported, which may underestimate prevalence. Cannot isolate THC from other cannabis compounds. Observational design cannot prove causation. Single state (Michigan)."},{"rthcId":"RTHC-07855","title":"Cannabis Use and the Risk of Arrhythmias: Insights From a Large Retrospective Multicenter Analysis.","authors":"Vargas, Juan; Pillai, Keerthana Jyotheeswara; Tocquica-Gahona, Christian; Mahajan, Pranav; Chandna, Sanya; Vyas, Vrinda; Paulraj, Shweta; Yadav, Ritu; Nagarakanti, Rangadham; Raj, Kavin","year":2025,"journal":"Journal of cardiovascular electrophysiology, 36(12), 3261-3267","doi":"10.1111/jce.70135","pmid":"41078108","tags":["cardiovascular","arrhythmia","heart-health","atrial-fibrillation"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use was associated with significantly increased risk of atrial fibrillation/flutter (HR 1.549), paroxysmal tachycardia (HR 1.791), premature beats (HR 1.739), and ventricular tachycardia/fibrillation (HR 2.839) compared to propensity score-matched ibuprofen users.","whyItMatters":"As cannabis use becomes more common, understanding its cardiovascular risks is essential. This large-scale study provides some of the strongest evidence to date that cannabis use is associated with multiple types of heart rhythm disturbances.","specificNumbers":"210,817 cannabis users matched with 210,817 ibuprofen users. AF/AFL: HR 1.549 (1,895 vs 1,332 cases). Paroxysmal tachycardia: HR 1.791 (1,065 vs 672). Premature beats: HR 1.739 (1,135 vs 745). VT/VF: HR 2.839 (97 vs 35 cases).","methodology":"Retrospective cohort study using deidentified electronic health records from 68 U.S. healthcare organizations (TriNetX network). 210,817 cannabis users were matched 1:1 with 210,817 ibuprofen users using propensity score matching across 17 baseline variables. Cox proportional hazards models assessed incident arrhythmia diagnoses.","limitations":"Retrospective observational design cannot prove causation. Ibuprofen users as a comparison group may introduce bias. Cannabis use was identified from health records, which may not capture all users or usage patterns. Confounders may remain despite matching."},{"rthcId":"RTHC-07856","title":"E-cigarette and cannabis in social media influencer marketing and its effect on adolescents: a survey-based experiment.","authors":"Vassey, Julia; Chen-Sankey, Julia; Unger, Jennifer B","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","doi":"10.1093/ntr/ntaf225","pmid":"41182250","tags":["adolescents","social-media","marketing","vaping"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Adolescents in the experimental group (exposed to influencer posts promoting e-cigarettes with cannabis) had higher odds of e-cigarette use intentions compared to those exposed to e-cigarette-only posts, particularly among participants who perceived micro-influencers as credible.","whyItMatters":"Micro-influencers on social media are increasingly promoting cannabis and vaping products together. Understanding how this combined marketing affects teen susceptibility to substance use can inform social media regulations and public health campaigns.","specificNumbers":"N = 1,402 adolescent never-users. Mean age 17 (SD 0.6). 51.4% female, 41.7% Hispanic. Study period: 2023–2024. Three conditions: e-cigarettes + cannabis, e-cigarettes only, no substances.","methodology":"Survey-based repeated-measures experiment with 1,402 California adolescent never-users (mean age 17), randomly assigned to view Instagram images of micro-influencers promoting e-cigarettes with cannabis, e-cigarettes alone, or no substances. Analyzed using binomial generalized linear mixed effects models.","limitations":"Measured intentions, not actual behavior. California-specific sample may not generalize. Simulated Instagram exposure in a classroom differs from real-world social media use. Short-term effects measured; long-term influence unknown."},{"rthcId":"RTHC-07857","title":"E-Cigarette and Cannabis Social Media Posts and Adolescent Substance Use.","authors":"Vassey, Julia; Cho, Junhan; Vogel, Erin A; Iyer, Trisha; Chen-Sankey, Julia; Unger, Jennifer B","year":2025,"journal":"JAMA network open, 8(6), e2517611","doi":"10.1001/jamanetworkopen.2025.17611","pmid":"40553470","tags":["adolescents","social-media","vaping","epidemiology"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Frequent exposure to e-cigarette and/or cannabis social media posts at baseline was associated with higher odds of initiating e-cigarette, cannabis, and dual use at one-year follow-up among never-users. Posts from friends and micro-influencers showed the strongest associations with use.","whyItMatters":"Published in JAMA, this study provides strong evidence that social media exposure to cannabis and e-cigarette content predicts actual substance use initiation in teens — not just intentions but real behavior change over one year.","specificNumbers":"Study 1: 4,232 adolescents (mean age 17.0, 52.1% female). 22.9% reported frequent baseline exposure. Study 2 examined exposure from five source types. Both conducted among California high school students.","methodology":"Two studies: (1) a longitudinal study of 4,232 California high school students with one-year follow-up among baseline never-users, and (2) a cross-sectional survey examining exposure to posts from specific sources (friends, celebrities, micro-influencers, brands). Both used generalized estimating equations adjusted for sociodemographic and behavioral factors.","limitations":"Observational design — social media exposure may reflect existing interest. California-specific. Self-reported substance use and social media exposure. Cannot determine which specific posts or platforms are most influential."},{"rthcId":"RTHC-07858","title":"Targeting dysregulated CB1 receptors in a Down syndrome mouse model improves neurological outcomes.","authors":"Vázquez-Oliver, Anna; Pérez-García, Silvia; Romero-Pérez, Rafael; Pizarro, Nieves; Galarraga-Shinin, Diana; Molina-Porcel, Laura; de la Torre, Rafael; Maldonado, Rafael; Ozaita, Andrés","year":2025,"journal":"Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(11), e70874","doi":"10.1002/alz.70874","pmid":"41257439","tags":["cognitive-function","endocannabinoid-system","neuroinflammation","down-syndrome"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CB1 receptor expression was significantly increased in both human Down syndrome-associated Alzheimer's brain tissue and Ts65Dn mice. Long-term rimonabant treatment improved memory, normalized microglial morphology, and reduced plasma inflammatory markers in trisomic mice.","whyItMatters":"Down syndrome is the most common genetic cause of intellectual disability and carries high risk of early-onset Alzheimer's. Finding that overactive CB1 receptors contribute to cognitive problems opens a new therapeutic avenue for improving quality of life in DS.","specificNumbers":"CB1R expression was significantly increased in the dentate gyrus and CA2 posterior hippocampal subregions of aged DS-associated Alzheimer's subjects. Long-term rimonabant improved memory performance in Ts65Dn mice and normalized microglial morphology.","methodology":"CB1R expression was analyzed in hippocampi of aged DS-associated Alzheimer's patients and middle-aged Ts65Dn mice (a genetic DS model). Mice received long-term oral rimonabant treatment, with outcomes assessed via memory testing, microglial morphology analysis, and plasma inflammatory marker measurement.","limitations":"Mouse model (Ts65Dn) does not fully replicate human Down syndrome. Rimonabant was withdrawn from clinical use due to psychiatric side effects. Did not prevent underlying neurodegeneration. Human brain tissue analysis was limited to aged DSAD subjects."},{"rthcId":"RTHC-07859","title":"Vaping nicotine is associated with increased medically-attended COVID-19 in women of reproductive age in an integrated health system.","authors":"Velotta, Jeffrey B; Moskalenko, Ilya; Zhu, Shiyun; Adams, Sara R; Nugent, Joshua R; Chervo, Tyler; Skarbinski, Jacek; Prochaska, Judith J; Brown, Qiana L; Campbell, Cynthia I; Soroosh, Aurash J; Does, Monique B; Young-Wolff, Kelly C","year":2025,"journal":"Journal of thoracic disease, 17(11), 10023-10035","doi":"10.21037/jtd-2025-580","pmid":"41376994","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07860","title":"Cannabis and sleep architecture: A systematic review and meta-analysis.","authors":"Velzeboer, Rob; Malas, Adeeb; Wei, Sabrina; Berger, Renee; Parmar, Varinder; Lai, Wayne W K","year":2025,"journal":"Sleep medicine reviews, 84, 102164","doi":"10.1016/j.smrv.2025.102164","pmid":"40967124","tags":["sleep","THC","CBD","systematic-review","REM-sleep"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across 18 studies (9 in meta-analysis), cannabis administration did not consistently alter sleep duration, latency, wake time, efficiency, or sleep staging. Early claims of REM suppression were based on small trials with high THC doses. Cannabis withdrawal, however, consistently caused sleep disturbances including reduced total sleep time and REM rebound.","whyItMatters":"Many cannabis users report using it for sleep, but this review reveals a disconnect — objective sleep measurements don't consistently support subjective improvements. Meanwhile, the clear sleep disruption during withdrawal highlights a potential dependency concern.","specificNumbers":"18 studies identified, 9 suitable for meta-analysis. Early REM suppression findings came from small-scale trials with high THC doses. Withdrawal consistently associated with reduced total sleep time, prolonged sleep onset latency, and REM rebound.","methodology":"Systematic review and meta-analysis of 18 polysomnographic (objective sleep measurement) studies examining cannabis effects on sleep architecture. Nine studies were suitable for quantitative meta-analysis.","limitations":"Limited number of studies, especially with standardized protocols. High variability in dosage, cannabinoid composition, and participant characteristics across studies. Most studies were small. Publication bias possible."},{"rthcId":"RTHC-07861","title":"Cannabinoids Activate Endoplasmic Reticulum Stress Response and Promote the Death of Avian Retinal Müller Cells in Culture.","authors":"Ventura, Ana Lúcia Marques; Silva, Thayane Martins; França, Guilherme Rapozeiro","year":2025,"journal":"Brain sciences, 15(3)","doi":"10.3390/brainsci15030291","pmid":"40149812","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07862","title":"Prior restraint stress counteracts memory deficits associated with adolescent alcohol exposure by targeting both the hippocampal endocannabinoid and glutamatergic systems.","authors":"Verheul-Campos, Julia; Sanchez-Marín, Laura; López, Yolanda; Gavito, Ana L; Grandes, Pedro; Serrano, Pedro; Guerricagoitia, Inmaculada; Estivill-Torrús, Guillermo; Rodríguez-Arias, Marta; Miñarro, Jose; Pavón-Morón, Francisco J; Suárez, Juan; Serrano, Antonia; de Fonseca, Fernando Rodríguez","year":2025,"journal":"Drug and alcohol dependence, 276, 112891","doi":"10.1016/j.drugalcdep.2025.112891","pmid":"40975942","tags":["endocannabinoid-system","memory","alcohol","adolescents","stress"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Repeated restraint stress (five 1.5-hour sessions) before adolescent alcohol exposure prevented adult memory deficits caused by binge drinking. Alcohol reduced expression of endocannabinoid genes (CB2, PPARα, DAGLα, DAGLβ, FAAH, MAGL) and glutamate receptors in the hippocampus, and prior stress largely reversed these changes.","whyItMatters":"This study reveals that the endocannabinoid system plays a key role in how adolescent binge drinking damages memory. Understanding this mechanism could lead to interventions that protect developing brains from alcohol-related harm.","specificNumbers":"Five sessions of 1.5-hour restraint stress (days 32–36). Four weekly cycles of 3 g/kg ethanol. Memory assessed at postnatal day 77. Alcohol reduced CB2, PPARα, DAGLα, DAGLβ, FAAH, and MAGL expression; stress reversed most of these reductions.","methodology":"Rats received repeated restraint stress (postnatal days 32–36) followed by intensive adolescent alcohol exposure (four weekly cycles of 3 g/kg ethanol). Adult memory was assessed at postnatal day 77. Hippocampal mRNA was analyzed by PCR for growth factors, glutamate receptors, and endocannabinoid signaling genes. Proteomic analysis of dorsal hippocampus was also performed.","limitations":"Animal model — stress-as-protection is complex to translate to humans. The type of stress (controlled restraint) differs from real-world adolescent stress. Only examined one type of memory. Cannot directly inform cannabis use recommendations."},{"rthcId":"RTHC-07863","title":"Chitosan-based film-forming systems with cannabidiol: a novel topical strategy for antimicrobial therapy.","authors":"Veris, Andrea; Loskot, Jan; Andrys, Rudolf; Konecna, Klara; Jandourek, Ondrej; Snejdrova, Eva","year":2025,"journal":"International journal of pharmaceutics, 682, 125940","doi":"10.1016/j.ijpharm.2025.125940","pmid":"40659166","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07864","title":"Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1.","authors":"Verrillo, Lucia; Iannotti, Fabio Arturo; Drongitis, Denise; Martinello, Katiuscia; Poeta, Loredana; Barra, Adriano; Terrone, Gaetano; Fucile, Sergio; Di Marzo, Vincenzo; Miano, Maria Giuseppina","year":2025,"journal":"Epilepsia, 66(10), 4035-4052","doi":"10.1111/epi.18522","pmid":"40608247","tags":["epilepsy","CBD","seizures","neuroinflammation","rare-disease"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Daily CBD (100 mg/kg) for 7 days reduced the severity and frequency of spontaneous recurrent seizures and significantly extended lifespan in Arx(GCG)7/Y mice. CBD activated PPARγ expression, desensitized TRPV1 channels, counteracted proinflammatory gene expression, and restored normal microglial morphology.","whyItMatters":"DEE1 is a devastating drug-resistant childhood epilepsy with high mortality. CBD is already FDA-approved for some childhood epilepsies (Epidiolex), and this study provides mechanistic evidence supporting its potential effectiveness in DEE1 specifically.","specificNumbers":"CBD dose: 100 mg/kg/day intraperitoneally for 7 days. CBD reduced severity and frequency of spontaneous seizures. Significantly extended survival. Reduced expression of proinflammatory genes Ptgs2, Mmp9, Il12, Cd68, Ccl2, and Irf3.","methodology":"Arx(GCG)7/Y mice (genetic DEE1 model) received daily intraperitoneal CBD (100 mg/kg) for 7 days. Epileptic phenotype was evaluated via video monitoring and scoring matrix. Molecular effects assessed by RT-PCR, Western blotting, Iba1 immunostaining, Sholl analysis, and patch-clamp electrophysiology.","limitations":"Mouse model with high-dose intraperitoneal CBD, which may not reflect human oral dosing. Short 7-day treatment. DEE1 is extremely rare, limiting direct clinical applicability. Single dose level tested."},{"rthcId":"RTHC-07865","title":"Housing instability, health, and substance use among adults over age 50 living in New York City.","authors":"Versey, H Shellae; Dougherty, Michelle; Mair, Christina","year":2025,"journal":"Frontiers in public health, 13, 1725374","doi":"10.3389/fpubh.2025.1725374","pmid":"41641054","tags":["older-adults","substance-use","housing","social-determinants"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Housing instability indicators — particularly concerns about paying rent/mortgage — were associated with worse self-reported health, higher tobacco use, and higher other substance use among older adults with cannabis use history. Frequent moves were associated with poorer health and alcohol-cannabis co-use.","whyItMatters":"As cities become more expensive and the population ages, understanding how financial stress affects substance use patterns among older adults — including cannabis users — is important for designing support services in aging communities.","specificNumbers":"Adults over 50 in NYC NORCs with cannabis use history. Housing instability measured by rent/mortgage payment concerns and number of moves in 5 years. Significant associations found with worse health, tobacco use, and other substance use.","methodology":"Cross-sectional study of adults over 50 with a history of cannabis use living in naturally occurring retirement communities (NORCs) in New York City. Bivariate analyses and logistic regression models examined relationships between housing instability indicators and health/substance use outcomes.","limitations":"Cross-sectional design — cannot determine causation. Specific to NYC NORC residents with cannabis history, limiting generalizability. Self-reported measures. Cannot determine whether housing stress drives substance use or vice versa."},{"rthcId":"RTHC-07866","title":"BETTER sleep: Sleep quality among adults living with type 1 diabetes in Canada.","authors":"Vézina-Im, Lydi-Anne; Turcotte, Anne-Frédérique; Messier, Virginie; Turcotte, Stéphane; Brossard, Ariane; Pelletier, Jacques; Nassar, Tara; Rabasa-Lhoret, Rémi; Brazeau, Anne-Sophie","year":2025,"journal":"Journal of diabetes and its complications, 39(10), 109137","doi":"10.1016/j.jdiacomp.2025.109137","pmid":"40684617","tags":["sleep","diabetes","cannabis-use-patterns"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was independently associated with poor sleep quality (OR 1.578; 95% CI: 1.152–2.161) in adults with type 1 diabetes, alongside other correlates including being female, overweight/obesity, depression, fear of hypoglycemia, bedtime snacking, and low physical activity.","whyItMatters":"Sleep quality matters enormously for diabetes management — poor sleep worsens blood sugar control. Identifying cannabis use as an independent risk factor for poor sleep in this population provides actionable information for clinicians counseling T1D patients.","specificNumbers":"1,322 participants (mean age 45, 66.9% female). Mean PSQI score: 6.0. 47.3% had poor sleep quality. Cannabis use OR for poor sleep: 1.578. Depression OR: 6.160 (strongest correlate). Always snacking before bed OR: 1.706.","methodology":"Cross-sectional analysis of 1,322 adults with type 1 diabetes from the Canadian BETTER Registry. Sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI > 5 = poor). Multivariate logistic regression adjusted for sociodemographic, diabetes-related, psychological, and behavioral variables.","limitations":"Cross-sectional — cannot determine whether cannabis causes poor sleep or people with poor sleep use cannabis. Self-reported cannabis use without details on type, dose, or timing. Canadian sample. PSQI is subjective."},{"rthcId":"RTHC-07867","title":"Cannabidiol and multi-modal exercise for chemotherapy-induced peripheral neuropathy in cancer survivors.","authors":"Vigano, MariaLuisa; Kubal, Sarah; Habib, Sarah; Samarani, Suzanne; Kasvis, Popi; Koudieh, Nebras; Kilgour, Robert; Farzin, Houman; Ahmad, Ali; Vigano, Antonio; Costiniuk, Cecilia T","year":2025,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 33(7), 534","doi":"10.1007/s00520-025-09553-z","pmid":"40464985","tags":["CBD","cancer","neuropathy","exercise","quality-of-life"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"After 2 months of CBD alone (up to 300 mg/day), medium effect sizes were observed for neuropathy symptoms (d=0.62), perceived physical function (d=0.62), and hand grip strength (r=0.401). Adding multi-modal exercise for 2 more months produced additional improvements in pain (d=0.526), neuropathy symptoms (d=0.862), and multiple functional measures.","whyItMatters":"Chemotherapy-induced peripheral neuropathy affects up to 70% of cancer patients and has few effective treatments. This study suggests CBD alone and especially CBD combined with exercise could improve both symptoms and physical function for cancer survivors.","specificNumbers":"27 cancer survivors. CBD up to 300 mg/day. After CBD alone (2 months): neuropathy d=0.62, physical function d=0.62, grip strength r=0.401. After adding exercise (2 more months): neuropathy d=0.862, pain d=0.526, overall QoL d=1.03.","methodology":"Open-label interventional study with 27 cancer survivors with CIPN. Two consecutive 2-month phases: CBD only (up to 300 mg/day) followed by CBD plus multi-modal exercise. Assessed with painDETECT, FACT-GOG-Ntx-13, gait speed, timed up and go, 9-hole peg test, grip strength, and sit-to-stand test.","limitations":"Small sample (n=27), open-label with no placebo control. Sequential design (CBD first, then CBD+exercise) means exercise effects cannot be isolated from continued CBD use. No blinding. Effect sizes had wide confidence intervals."},{"rthcId":"RTHC-07868","title":"Impact of cannabinoids on cancer outcomes in patients receiving immune checkpoint inhibitor immunotherapy.","authors":"Vigano, MariaLuisa; Wang, Lixing; As'sadiq, Alia; Samarani, Suzanne; Ahmad, Ali; Costiniuk, Cecilia T","year":2025,"journal":"Frontiers in immunology, 16, 1497829","doi":"10.3389/fimmu.2025.1497829","pmid":"40109334","tags":["cancer","immunotherapy","CBD","THC","drug-interactions"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Cannabis use in cancer patients receiving immune checkpoint inhibitors (ICIs) reduces immune-related adverse events and improves tolerability, but several studies noted potential negative effects on clinical outcomes including overall survival and progression-free survival, possibly due to CB2-mediated immunosuppression.","whyItMatters":"Immune checkpoint inhibitors are among the most important cancer treatments developed in decades, but their side effects limit use. If cannabinoids can manage these side effects without undermining treatment efficacy, they could help more patients complete their immunotherapy courses.","specificNumbers":"The review proposes that CB2 functions as an inhibitory immune checkpoint. CBD and CBG, with minimal CB2 agonism, may be safer therapeutic choices than THC during immunotherapy. MAGL inhibitors are also suggested as a complementary strategy.","methodology":"Narrative review examining clinical studies of concurrent cannabinoid and immune checkpoint inhibitor use in cancer patients, alongside mechanistic analysis of CB2 receptor immunosuppressive signaling and its potential to function as an inhibitory immune checkpoint.","limitations":"Narrative review — not a systematic review or meta-analysis. Clinical evidence is limited to a few observational studies. The CB2 immune checkpoint hypothesis, while biologically plausible, has not been directly tested in clinical trials."},{"rthcId":"RTHC-07869","title":"Screening diverse Cannabis sativa germplasm for resistance to Golovinomyces ambrosiae.","authors":"Vignale, Lucía; Schwartz, Jocelyn A; Stansell, Zachary; Gordon, Tyler; Smart, Christine D; Smart, Lawrence B","year":2025,"journal":"Plant disease","doi":"10.1094/PDIS-07-25-1591-RE","pmid":"41319034","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07870","title":"Is highly purified cannabidiol a treatment opportunity for drug-resistant epilepsy in subjects with typical Rett syndrome and CDKL5 deficiency disorder?","authors":"Vignoli, Aglaia; Prato, Giulia; Alfei, Enrico; Bagnasco, Irene; Danieli, Alberto; Celario, Massimiliano; Favaro, Jacopo; Matricardi, Sara; Operto, Francesca Felicia; Orsini, Alessandro; Bernasconi, Davide Paolo; Pietrafusa, Nicola; Ricci, Emilia; Manfredini, Luca; Balletto, Giulia; Bonanni, Paolo; Canevini, Maria Paola; De Giorgis, Valentina; Nobili, Lino; Sartori, Stefano; Savini, Miriam Nella; Viganò, Ilaria; Specchio, Nicola","year":2025,"journal":"Epilepsia open, 10(4), 1111-1119","doi":"10.1002/epi4.70078","pmid":"40543048","tags":["epilepsy","CBD","Rett-syndrome","rare-disease","pediatric"],"studyType":"clinical-observation","evidenceStrength":"moderate","keyFinding":"CBD reduced seizure frequency in 18 of 27 patients (66.6%) with drug-resistant epilepsy due to Rett syndrome or CDKL5 deficiency. Seven patients (25.9%) achieved >75% seizure reduction and 11 (40.7%) achieved >50% reduction. Caregivers reported improvements in attention/reactivity (44.4%), sleep quality (18.5%), and motor function (11.1%).","whyItMatters":"Rett syndrome and CDKL5 deficiency are devastating genetic conditions with limited treatment options for their drug-resistant seizures. These results suggest CBD may offer meaningful benefit beyond what current medications provide, including improvements in behavior and cognition.","specificNumbers":"27 patients (26 female). Median age 10.5 years. Median CBD dose: 15 mg/kg/day. Median treatment duration: 14 months. 66.6% had reduced seizures. 25.9% had >75% reduction. Mean concurrent ASMs: 3 (range 2–4). Adverse events: somnolence (3), irritability (2), appetite loss (2), insomnia (1).","methodology":"Multi-center observational study of 27 patients (26 female) with genetically confirmed Rett syndrome (14) or CDKL5 deficiency (13) receiving add-on CBD (Epidiolex, titrated 5–20 mg/kg/day) alongside existing anti-seizure medications, through a national Italian collaboration.","limitations":"Small sample (n=27), no control group or randomization. Results did not reach statistical significance. Open-label design with potential placebo effect. Concurrent ASM adjustments complicate attribution. Only Italian centers."},{"rthcId":"RTHC-07871","title":"Modulation of ageing mice microglia functions during neuroinflammation using synthetic cannabinoids.","authors":"Vijaya, Akshay Kumar; Krisikaitytė, Greta; Kuras, Simonas; Baltriukienė, Daiva; Burokas, Aurelijus","year":2025,"journal":"European journal of pharmacology, 999, 177705","doi":"10.1016/j.ejphar.2025.177705","pmid":"40320115","tags":["neuroinflammation","aging","endocannabinoid-system","microglia"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Endocannabinoid system expression increases with age. Activation of CB1 and CB2 receptors with synthetic cannabinoids reduced reactive oxygen species in both young and aged mice, with stronger effects in younger mice. CB1 receptor activation modulated microglial phagocytosis in both age groups.","whyItMatters":"Age-related neuroinflammation is implicated in Alzheimer's, Parkinson's, and general cognitive decline. Understanding that the endocannabinoid system naturally upregulates with age — and that cannabinoid receptor activation can reduce neuroinflammation — opens therapeutic possibilities for brain aging.","specificNumbers":"ECS expression increases with age. ROS reduction observed with both CB1 and CB2 activation. Effects more pronounced in younger mice. In aged mice, upregulation of cannabinoid receptors indicates persistent inflammation. Phagocytosis modulated through CB1 receptors.","methodology":"Researchers stimulated CB1 and CB2 endocannabinoid receptors with synthetic compounds in microglia from young and aging mice during neuroinflammation, measuring phagocytosis activity and oxidative stress markers.","limitations":"Preclinical mouse study using synthetic cannabinoids — not plant-derived cannabis. In vitro microglial cultures may not reflect in vivo brain complexity. Age-specific dosing effects unclear. No behavioral or cognitive outcomes measured."},{"rthcId":"RTHC-07872","title":"Multi-Level Influences of Smoke-Free Policies in Subsidized Housing: Applying the COM-B Model and Neighborhood Assessments to Inform Smoke-Free Policies.","authors":"Vijayaraghavan, Maya; Hartman-Filson, Marlena; Vyas, Priyanka; Katyal, Toshali; Nguyen, Tram; Handley, Margaret A","year":2025,"journal":"Health promotion practice, 26(1), 142-157","doi":"10.1177/15248399231174925","pmid":"37209138","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07873","title":"Cannabidiol metabolites identified by LC-QTOF after controlled dosing.","authors":"Vikingsson, Svante; Winecker, Ruth E; Bollinger, Katherine; Mullen, Lawrance D; Spindle, Tory R; Vandrey, Ryan; Cone, Edward J; Davis, Lisa S; Flegel, Ronald R; Hayes, Eugene D","year":2025,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkaf098","pmid":"41206122","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07874","title":"The Acute and Chronic Pharmacokinetic Oral Fluid Profile of Oral Cannabidiol (CBD) With and Without Low Doses of Delta-9-Tetrahydrocannabinol (Δ9-THC) in Healthy Human Volunteers.","authors":"Vikingsson, Svante; Zamarripa, C Austin; Spindle, Tory R; Klausner, McKenna; Wolinsky, David; Cone, Edward J; Winecker, Ruth E; Flegel, Ronald R; Davis, Lisa S; Hayes, Eugene D; Kuntz, David; Vandrey, Ryan","year":2025,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkaf102","pmid":"41252452","tags":["drug-testing","CBD","THC","pharmacokinetics","workplace"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"After taking 100 mg CBD with just 0.5 mg THC (well within legal hemp limits), 1 in 10 participants tested positive for THC in oral fluid. At 2.8–3.7 mg THC (still in legal CBD products), 8 of 10 participants tested positive. Even in the CBD-only group, 5 samples tested positive due to trace CBD-to-THC conversion during analysis.","whyItMatters":"Millions of people use legal CBD products that may contain small amounts of THC. This study proves these products can trigger positive workplace drug tests, potentially costing people their jobs even when they've only used legal, non-intoxicating products.","specificNumbers":"100 mg CBD + 0.5 mg THC: 1/10 positive. + 1.0 mg: rate increased. + 2.8 mg: 8/10 positive. + 3.7 mg: 8/10 positive. CBD peaked at 2,198 ng/mL in oral fluid 30 min after dosing. 5 CBD-only samples positive due to analytical conversion. 14-day dosing + 7-day washout.","methodology":"60 participants (n=10 per group) self-administered 100 mg CBD in MCT oil with 0, 0.5, 1.0, 2.0, 2.8, or 3.7 mg THC twice daily for 14 days, followed by 7-day washout. Oral fluid was tested by LC-MS/MS at a 2 ng/mL THC cutoff, along with CBD and metabolites.","limitations":"Small groups (n=10 per condition). Controlled laboratory conditions may not reflect real-world product variability. Only oral fluid tested — urine and blood may differ. Specific to the 2 ng/mL cutoff used. MCT oil carrier may affect absorption differently than commercial products."},{"rthcId":"RTHC-07875","title":"The Healthcare Profession as a Determinant of Depression, Suicidal Ideation, and Drug Use in Spain During the COVID-19 Pandemic Crisis.","authors":"Villanueva-Blasco, Víctor José; Lozano-Polo, Adelaida; Guillamó Mínguez, Carlos; Villanueva-Silvestre, Verónica; Isorna Folgar, Manuel; Gea-Caballero, Vicente; Vázquez-Martínez, Andrea","year":2025,"journal":"Journal of psychoactive drugs, 1-11","doi":"10.1080/02791072.2025.2474245","pmid":"40055881","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07876","title":"Resurrected Ancestral Cannabis Enzymes Unveil the Origin and Functional Evolution of Cannabinoid Synthases.","authors":"Villard, Cloé; Baser, Idil; van de Peppel, Arjen C; Cankar, Katarina; Schranz, M Eric; van Velzen, Robin","year":2025,"journal":"Plant biotechnology journal","doi":"10.1111/pbi.70475","pmid":"41454532","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07877","title":"Availability and affordability of cannabinoids for epilepsy treatment across different geographic settings-A survey from the ILAE Plant-Based Therapy Task Force.","authors":"Vinayan, Kollencheri Puthenveettil; Asadi-Pooya, Ali Akbar; Jyotsna, Aruna Setumadhava; Kumar, Nithya N; Elsas, Siegward-M; Johannessen Landmark, Cecilie; Matsabisa, Motlalepula; Mesraoua, Boulenouar; O'Callaghan, Finbar; Thiele, Elizabeth; Zhang, Chunbo; Riney, Kate","year":2025,"journal":"Epilepsia, 66(12), 4639-4653","doi":"10.1111/epi.18622","pmid":"40986286","tags":["epilepsy","CBD","global-access","policy","affordability"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Of 86 responding ILAE chapters (68% response rate), only 32 countries had regulatory approval for cannabinoids in epilepsy, with 21 approving only CBD. Among approved countries, 23 (71.8%) reported cannabinoids unaffordable and 18 (56.2%) reported them difficult to access. Unapproved cannabinoid products were available over-the-counter in 34 countries.","whyItMatters":"Even where cannabinoids are legally available for epilepsy, most patients can't access or afford them. Meanwhile, unregulated products are filling the gap in 40% of countries, raising quality and safety concerns for patients with drug-resistant epilepsy.","specificNumbers":"86 of 126 ILAE chapters responded (68%). 32 countries approved cannabinoids for epilepsy. 21 of 32 approved only CBD. 71.8% in approved countries report them unaffordable. 56.2% report them difficult to access. 54 countries (62.7%) have no approval. 34 countries (39.5%) have unapproved OTC products. 47 countries report traditional cannabinoid-containing plant products.","methodology":"Survey conducted by the ILAE Plant-Based Therapy Task Force through its chapters from June to December 2023. 86 of 126 chapters (68%) responded. Responses were screened and analyzed using pre-set criteria for availability, accessibility, and affordability.","limitations":"Survey-based, relying on chapter representatives' knowledge. 32% non-response rate may introduce bias. Snapshot from 2023, and availability is changing rapidly. Cannot capture patient-level access experiences."},{"rthcId":"RTHC-07878","title":"Evaluation of a Digital Educational Intervention to Enhance Oncology Nurse Professional Practice to Support Safe Cannabis Use: A Pilot Study.","authors":"Vinette, Billy; Côté, José; Bilodeau, Karine","year":2025,"journal":"The Journal of continuing education in the health professions","doi":"10.1097/CEH.0000000000000631","pmid":"41427816","tags":["nursing","education","cancer","clinical-practice"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Among 70 oncology nurses randomized 1:1, 89% in the intervention group completed the full digital educational program. Intention to support safe cannabis use significantly increased in the intervention group compared to controls (p = 0.016). The intervention was grounded in the Theory of Planned Behavior.","whyItMatters":"Young adults with cancer frequently use cannabis for symptom management, but most oncology nurses lack training to guide patients safely. This study demonstrates that targeted digital education can change clinical practice intentions, filling a critical gap in cancer care.","specificNumbers":"70 nurses randomized (35 per arm). 89% intervention completion rate (31/35). 57 completed 1-month follow-up. 60% of participants over age 40. 74% held a bachelor's degree. Significant increase in intention (p = 0.016).","methodology":"Two-arm pilot randomized controlled trial with 70 oncology nurses (35 intervention, 35 control). The intervention was a digital educational program on cannabis use in young adult (18–39) cancer patients. Outcomes measured at baseline and 1 month: knowledge, attitudes, self-efficacy, and intention to support safe cannabis use. Analyzed with linear mixed effects models.","limitations":"Pilot study — small sample for a definitive trial. Measured intention, not actual practice behavior change. Short follow-up (1 month). Active control group (not no-treatment). No patient outcomes measured."},{"rthcId":"RTHC-07879","title":"Supercritical CO2 extraction of hemp seeds: A multivariate perspective on the influence of processing parameters on oil composition, antioxidant activity, and enzyme inhibition.","authors":"Vishwasrao, Prajakta; Zengin, Gokhan; Sinan, Kouadio Ibrahime; Minceva, Mirjana; Luca, Simon Vlad","year":2025,"journal":"Food chemistry: X, 32, 103296","doi":"10.1016/j.fochx.2025.103296","pmid":"41341704","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07880","title":"Persistent behavioural consequences of chronic adolescent cannabidiol (CBD) in a mouse model with increased susceptibility to Δ9-tetrahydrocannabinol and schizophrenia.","authors":"Visini, Gabriela; Chesworth, Rose; Karl, Tim","year":2025,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 138, 111306","doi":"10.1016/j.pnpbp.2025.111306","pmid":"40056966","tags":["CBD","adolescents","schizophrenia","THC","long-term-effects"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Adolescent CBD (30 mg/kg daily for 3 weeks) suppressed locomotion, exploration, and social behaviors while reducing anxiety-like behaviors in adult mice. In Nrg1 mutant mice (a schizophrenia susceptibility model), prior adolescent CBD exacerbated THC-induced suppression of acoustic startle response, though CBD did not alter schizophrenia-relevant behaviors.","whyItMatters":"CBD is increasingly used to treat adolescent conditions like epilepsy and anxiety. This study raises important safety questions about whether early-life CBD exposure has lasting brain effects that persist into adulthood — and whether it could interact with genetic vulnerability.","specificNumbers":"30 mg/kg CBD daily for 3 weeks during adolescence. Testing at 5–6 months of age. Persistent effects on locomotion, exploration, social behavior, and anxiety. In Nrg1 mutants, adolescent CBD exacerbated THC-induced startle suppression.","methodology":"Male Nrg1 TM HET mice (schizophrenia model) and wild-type controls received 30 mg/kg CBD intraperitoneally daily for 3 weeks during adolescence. At 5–6 months, they were tested for locomotion, social behavior, sensorimotor gating, cognition, and sensitivity to acute THC challenge.","limitations":"Mouse model — behavioral tests may not translate to human experience. High dose (30 mg/kg IP) exceeds typical human dosing. Only male mice tested. Nrg1 model is one of many schizophrenia risk models. Intraperitoneal route differs from oral administration."},{"rthcId":"RTHC-07881","title":"Nanotechnology for the Efficacious Delivery of Medicinal Cannabis and Pharmaceutical Medicines.","authors":"Vitetta, Luis; Henson, Jeremy David; Hayes, Evan; Rutolo, David; Hall, Sean","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(9)","doi":"10.3390/ph18091385","pmid":"41011252","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07882","title":"Sex-related differences in cannabidiol's antinociceptive efficacy in a trigeminal neuralgia rodent model.","authors":"Vivanco-Estela, Airam; Rocha, Sanderson Araujo da; Escobar-Espinal, Daniela; Bálico, Gabriela Gonçalves; Caudle, Robert M; Guimaraes, Francisco S; Del-Bel, Elaine; Nascimento, Glauce Crivelaro","year":2025,"journal":"Pain, 166(10), e336-e350","doi":"10.1097/j.pain.0000000000003616","pmid":"40359363","tags":["CBD","pain","trigeminal-neuralgia","sex-differences","neuroinflammation"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD demonstrated potent antinociceptive effects in both male and female rats with trigeminal neuralgia, without affecting locomotor activity. Carbamazepine showed sex-dependent efficacy. CBD's mechanisms included inhibiting Fos-B expression, reducing superoxide oxidation, and modulating microglia and astrocytes in pain pathways, with some sex-dependent regional differences.","whyItMatters":"Trigeminal neuralgia is one of the most painful conditions known, and the standard treatment (carbamazepine) has significant side effects and doesn't work equally well for everyone. CBD's consistent efficacy across sexes and lack of motor impairment make it a promising alternative worth investigating in clinical trials.","specificNumbers":"CBD reduced mechanical allodynia in both sexes. Carbamazepine showed sex-dependent efficacy. CBD inhibited Fos-B in Sp5c (both sexes) and vlPAG (males only). CBD prevented superoxide oxidation in vlPAG in both sexes. No locomotor impairment with CBD (unlike carbamazepine).","methodology":"Infraorbital nerve constriction model in male and female Wistar-Hannover rats. Mechanical allodynia measured after CBD or carbamazepine treatment. Brain regions analyzed for Fos-B protein, superoxide oxidation (reactive oxygen species), and glial cell markers (Iba1 for microglia, GFAP for astrocytes).","limitations":"Rat model — trigeminal neuralgia in humans may respond differently. Specific doses and routes not detailed in the abstract. Acute treatment effects — long-term efficacy unknown. Mechanistic findings are region-specific and may not capture the full picture."},{"rthcId":"RTHC-07883","title":"Formulation and Analytical Evaluation of Liquid Cannabidiol Preparations: Comparative Study of Oil-Based Solutions and Emulsions.","authors":"Vlad, Robert-Alexandru; Farczádi, Lénárd; Paliștan, Denisa; Pintea, Cezara; Antonoaea, Paula; Rédai, Emöke-Margit; Pintea, Andrada; Cotoi, Cornelia-Titiana; Ciurba, Adriana; Bîrsan, Magdalena; Ștefănescu, Ruxandra-Emilia","year":2025,"journal":"Pharmaceutics, 17(12)","doi":"10.3390/pharmaceutics17121533","pmid":"41471048","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07884","title":"Exploring the interconnected properties of cannabidiol suspensions and orodispersible films.","authors":"Vlad, Robert-Alexandru; Pintea, Andrada; Antonoaea, Paula; Rédai, Emöke-Margit; Bîrsan, Magdalena; Hancu, Gabriel; Farczádi, Lénárd; Imre, Silvia; Muntean, Daniela-Lucia; Sovány, Tamás; Kristó, Katalin; Ludasi, Krisztina; Regdon, Géza; Ciurba, Adriana","year":2025,"journal":"Scientific reports, 15(1), 21564","doi":"10.1038/s41598-025-02859-2","pmid":"40595713","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07885","title":"Associations of Disability and Social Support with Cannabis Use Among Adults with Anxiety and Depressive Symptoms.","authors":"Vogel, Erin A; Romm, Katelyn F; McMaughan, D J; Zvolensky, Michael J; Garey, Lorra; Businelle, Michael S","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(3), 103-115","doi":"10.26828/cannabis/2025/000305","pmid":"41278420","tags":["disability","mental-health","social-support","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"A significant interaction between disability and social support showed that social support was associated with lower odds of medical cannabis use among those without disability (p=0.038), but had no effect on medical cannabis use among those with disability (p=0.525). Disability and social support were not associated with recreational cannabis use.","whyItMatters":"This study reveals that people with disabilities may turn to medical cannabis as a healthcare resource that social support cannot substitute for. Unlike non-disabled individuals who may reduce cannabis use when they have strong support networks, disabled individuals may use cannabis to manage symptoms that social support alone cannot address.","specificNumbers":"N = 822. 51.1% self-reported disability. 24.9% past-month medical cannabis use. 25.4% past-month recreational cannabis use. Racially diverse: 25.3% American Indian, 25.1% Black, 25.1% White, 24.6% Latinx. 64.6% female. Mean age 38.3.","methodology":"Cross-sectional baseline survey of 822 adults with clinically significant anxiety and/or depression participating in a clinical trial. Self-reported disability, perceived social support, and past-month medical and recreational cannabis use were assessed. Regression models adjusted for race/ethnicity, gender, age, and income.","limitations":"Cross-sectional — cannot determine causation. Self-reported disability (broad definition). All participants had anxiety/depression, limiting generalizability. Cannot distinguish specific disabilities. Clinical trial participants may not represent general population."},{"rthcId":"RTHC-07886","title":"Cannabis Use in Central Disorders of Hypersomnolence in the Netherlands.","authors":"Vringer, Marieke; Cronie, Michel; Remmerswaal, Aniek; Klumpers, Linda E; Lammers, Gert Jan; Fronczek, Rolf; Schinkelshoek, Mink S","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 181-187","doi":"10.1159/000548416","pmid":"41321442","tags":["sleep","hypersomnolence","narcolepsy","endocannabinoid-system"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Lifetime cannabis use (42% vs 23%, p significant) and current use were both significantly higher among people with central disorders of hypersomnolence (CDH) compared to the Dutch general population. Among current users, 57% used cannabis to improve CDH symptoms, and 79% reported symptom effects — mostly positive (43%), some mixed (29%), and few negative (7%).","whyItMatters":"Central disorders of hypersomnolence (including narcolepsy) have limited treatment options. The fact that patients are already self-medicating with cannabis at high rates — and reporting mostly positive effects — provides a rationale for formal clinical investigation of cannabinoids for these conditions.","specificNumbers":"76 of 88 patients responded. Lifetime cannabis use: 42% vs 23% general population. 57% of current users motivated by symptom improvement. 79% reported cannabis effects on symptoms: 43% positive, 29% mixed, 7% negative. Former users mostly started before symptom onset for recreational purposes.","methodology":"Online questionnaire completed by 76 of 88 patients with central disorders of hypersomnolence in the Netherlands. Cannabis use patterns were compared to Dutch general population rates. Symptom motivations and perceived effects were assessed among current and former users.","limitations":"Small sample (n=76), single country (Netherlands where cannabis is accessible). Self-reported effects with no objective sleep measures. No control for placebo effect. CDH encompasses multiple conditions that may respond differently."},{"rthcId":"RTHC-07887","title":"Under the Influence: Cognitive Effects of Medical Marijuana on Developing Minds.","authors":"Vuong, Marry; Parkhill, Kaylee","year":2025,"journal":"The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 30(4), 440-449","doi":"10.5863/JPPT-25-01209","pmid":"40821424","tags":["adolescents","cognitive-function","brain-development","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The review covers cannabis's established therapeutic applications (chronic pain, epilepsy, chemotherapy-induced nausea, MS spasticity, IBD) while highlighting evidence that cannabis exposure during brain development can affect cognition, memory, and executive function, underscoring the need for pharmacist education and patient counseling.","whyItMatters":"As more states legalize medical marijuana and pediatric indications expand (especially CBD for epilepsy), pharmacists are on the front line of patient education. This review equips them with evidence-based talking points about both benefits and developmental risks.","specificNumbers":"Therapeutic areas reviewed: chronic pain, multiple sclerosis, epilepsy, chemotherapy-induced nausea/vomiting, inflammatory bowel disease. Focus age range: developing minds (children and adolescents).","methodology":"Narrative review published in the Journal of Pediatric Pharmacology and Therapeutics, synthesizing the history of medical marijuana, current pharmacological evidence, and neurodevelopmental impact literature, with a focus on the pharmacist's clinical role.","limitations":"Narrative review — not systematic. Broad scope may sacrifice depth on individual topics. Pharmacist-focused perspective may not address physician or patient needs. Rapid changes in the field may outpace published reviews."},{"rthcId":"RTHC-07888","title":"Mutual age-varying influences of binge drinking and cannabis use during emerging adulthood in the NCANDA cohort.","authors":"Waddell, Jack T; Brumback, Ty; Baker, Fiona C; Cheek, Shayna; Clark, Duncan B; Goldston, David B; Grove, Jeremy L; Nagel, Bonnie J; Nooner, Kate B; Pfefferbaum, Adolf; Pohl, Kilian M; Sullivan, Edith V; Tapert, Susan F; Thompson, Wesley K; Brown, Sandra A","year":2025,"journal":"Alcohol, clinical & experimental research, 49(10), 2239-2249","doi":"10.1111/acer.70139","pmid":"41020924","tags":["alcohol","young-adults","co-use","longitudinal"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Within-person increases in cannabis use predicted subsequent increases in binge drinking between ages 18–21, but the same within-person increases in cannabis use predicted decreases in binge drinking between ages 24–25. Binge drinking did not predict subsequent changes in cannabis use at any age.","whyItMatters":"This study reveals that the relationship between cannabis and binge drinking changes direction with age. In younger adults, cannabis may enable heavier drinking, but in mid-20s adults, cannabis may actually substitute for alcohol — with important implications for dual-use interventions.","specificNumbers":"N = 526 from the NCANDA cohort, ages 18–25. Cannabis use predicted increased binge drinking ages 18–21 but decreased binge drinking ages 24–25. Binge drinking did not predict subsequent cannabis use changes at any age.","methodology":"Parallel-process state-trait mixed effect growth models using NCANDA cohort data from 526 participants aged 18–25 reporting alcohol and cannabis use. Models tested reciprocal within-person associations and age-varying effects across emerging adulthood.","limitations":"Observational longitudinal data cannot prove causation. NCANDA is a neurodevelopment-focused cohort that may not represent all emerging adults. Self-reported substance use. The transition point between 21 and 24 is not well-characterized."},{"rthcId":"RTHC-07889","title":"Simultaneous use of alcohol, cannabis, and energy drinks predicts increased daily alcohol consumption and alcohol consequences.","authors":"Waddell, Jack T; McDonald, Abigail E; Quiroz, Selena I; Corbin, William R","year":2025,"journal":"Experimental and clinical psychopharmacology, 33(1), 8-15","doi":"10.1037/pha0000736","pmid":"39509207","tags":["alcohol","co-use","energy-drinks","college","harm"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Days with simultaneous alcohol + cannabis + energy drinks (SAM+AmED, 15.4% of drinking days) were associated with increased drinking quantity and more negative consequences compared to days with only SAM or only AmED. SAM-only and AmED-only days were also riskier than alcohol-only days.","whyItMatters":"The triple combination of cannabis, alcohol, and energy drinks is common (15% of drinking days) and represents the highest-risk pattern for college students. Identifying this specific pattern helps target prevention efforts at the most dangerous behavior.","specificNumbers":"21% of drinking days were AmED days, 19% were SAM days, 15.4% were SAM+AmED days. SAM+AmED days had increased drinking and negative consequences vs both SAM-only and AmED-only days. SAM-only and SAM+AmED (but not AmED-only) days had more positive consequences than alcohol-only days.","methodology":"30-day timeline followback interview with college students who engaged in both simultaneous alcohol-cannabis (SAM) use and alcohol mixed with energy drinks (AmED). Day-level data classified drinking days by substance combination and compared consumption and consequences.","limitations":"Selected sample of college students who already engage in multi-substance use — not generalizable to all students. Retrospective recall over 30 days. Cannot determine causality or the order of substance use within a day. No measure of quantity for cannabis or energy drinks."},{"rthcId":"RTHC-07890","title":"Longitudinal Neurocognitive Trajectories in a Large Cohort of Youth Who Use Cannabis: Combining Self-Report and Toxicology.","authors":"Wade, Natasha E; Sullivan, Ryan M; Wallace, Alexander L; Visontay, Rachel; Szpak, Veronica; Lisdahl, Krista M; Huestis, Marilyn A; Gonçalves, Priscila Dib; Byrne, Hollie; Mewton, Louise; Jacobus, Joanna; Tapert, Susan F","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.64898/2025.12.20.695698","pmid":"41509488","tags":["cognition","youth","cbd","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"This is the most comprehensive longitudinal study to date on adolescent cannabis use and cognitive development, drawing from the ABCD Study—a landmark NIH-funded project tracking brain development in American children.\n\nThe primary analysis followed 11,036 participants from ages 9 to 17, combining self-reported substance use with objective toxicological testing (hair, urine, breath, oral fluid). Cannabis use onset interacted with age to alter neurocognitive trajectories across multiple domains: immediate recall, delayed memory, processing speed, and other measures.\n\nThe secondary analysis was particularly innovative. In 645 participants with repeat hair toxicology at ages 12–16, the researchers distinguished between THC exposure and CBD exposure. The two cannabinoids showed different cognitive associations—consistent with RTHC-00193's finding that THC and CBD may push psychosis risk in opposite directions, and suggesting the composition of cannabis products matters for developmental outcomes.\n\nThe study controlled for an unusually comprehensive set of confounders: sociodemographics, family history of substance use disorder, prenatal substance exposure, early psychopathology, other substance use, and statistical nesting for participant ID, study site, and family. This extensive covariate adjustment strengthens confidence that the cannabis-cognition associations aren't driven by pre-existing differences.","whyItMatters":"The ABCD Study is the gold standard for adolescent brain development research—large, diverse, longitudinal, and multi-modal. This analysis leverages those strengths to provide the most definitive evidence yet that cannabis onset during adolescence alters cognitive development trajectories. The THC vs. CBD distinction using objective hair testing pushes beyond the simplistic question of whether 'cannabis' affects the brain to ask which components matter most.","specificNumbers":"N = 11,036 (full cohort, ages 9–17). N = 645 (hair toxicology subsample, ages 12–16). Cannabis onset altered trajectories in: immediate recall, delayed memory, processing speed, and additional domains. THC and CBD showed different cognitive associations.","methodology":"Longitudinal mixed-methods analysis of the ABCD Study. Primary: n=11,036, ages 9–17, time-varying cannabis onset on neurocognitive trajectories. Secondary: n=645 with repeat hair toxicology at ages 12–16, comparing THC vs. CBD vs. Controls. Covariates: sociodemographics, family SUD history, prenatal exposure, early psychopathology, other substance use. Nested by participant, site, and family.","limitations":"Preprint (bioRxiv)—not yet peer reviewed. Even with extensive covariates, observational data can't prove causation. Hair toxicology captures recent weeks of exposure, not lifetime use patterns. The secondary analysis (n=645) is much smaller than the full cohort. Self-reported cannabis use may undercount, while toxicology may miss intermittent use. Cannot control for all possible confounders (genetic liability, peer effects, etc.)."},{"rthcId":"RTHC-07891","title":"Cannabinoid profiling across toxicology samples in adolescents and young adults by route of administration and in relation to depression symptoms.","authors":"Wade, Natasha E; Wallace, Alexander L; Baca, Rachel; Andrade, Gianna; Happer, Joseph P; Courtney, Kelly E; Christians, Uwe; Sempio, Cristina; Klawitter, Jost; Huestis, Marilyn A; Jacobus, Joanna","year":2025,"journal":"Journal of analytical toxicology, 49(8), 567-575","doi":"10.1093/jat/bkaf051","pmid":"40577620","tags":["biomarkers","depression","young-adults","drug-testing"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Plasma THCCOOH concentration uniquely predicted depression symptoms (beta = 4.43, p < 0.001), while self-reported use days, oral fluid, urine, and hair concentrations did not. All toxicological matrices except oral fluid showed adequate sensitivity (63–74%) for detecting cannabis use, and concentrations did not differ by route of administration.","whyItMatters":"This finding suggests that objective blood measurements capture something about cannabis exposure that self-report cannot — potentially reflecting cumulative body burden or metabolic differences that are directly relevant to mental health outcomes.","specificNumbers":"70 cannabis users, 24 non-users. Ages 18–21, 64% female. Oral fluid sensitivity only 12% (vs 63–74% other matrices). Self-report and toxicological metrics correlated (r = 0.41–0.97). Plasma THCCOOH predicted depression (β = 4.43, p < 0.001). No difference by route of administration.","methodology":"Cross-sectional study of 70 cannabis-using and 24 non-using young adults (ages 18–21, 64% female). Oral fluid, plasma, urine, and hair tested for THCCOOH. Self-reported use, route of administration (smoked flower vs. vaped concentrate), and depression symptoms assessed. ANOVAs and regression models examined relationships.","limitations":"Cross-sectional — depression could cause heavier use rather than the reverse. Small sample. Oral fluid had very poor sensitivity (12%). Cannot determine if plasma levels reflect recent heavy use or slower metabolism. Depression measured by self-report."},{"rthcId":"RTHC-07892","title":"Prevalence of Biochemically-Verified Substance Use in Healthy Adolescents Across the United States: Hair Toxicology Results in the ABCD Study.","authors":"Wade, Natasha E; Si, Yajuan; Tapert, Susan F; Linkersdörfer, Janosch; Lisdahl, Krista M; Moore, Hailley R; Tally, Laila; Das, Biplabendu; Huestis, Marilyn A; Wallace, Alexander L; Sullivan, Ryan M; Szpak, Veronica; Zhang, Le; Ziemer, Laura R; Thompson, Wesley K","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.09.19.25336190","pmid":"41001452","tags":["adolescents","epidemiology","drug-testing","biomarkers"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Weighted estimates from hair toxicology showed 7.1% of 15–16-year-olds had moderate-to-heavy cannabis use, 4.7% had heavy nicotine use, and 0.3% had heavy alcohol use. Correspondence between self-report and hair testing improved with age (from <1% at 11–12 to 45% at 15–16), indicating significant underreporting of substance use in younger adolescents.","whyItMatters":"This is one of the first nationally representative estimates of adolescent substance use verified by biological testing rather than just self-report. The finding that self-report dramatically underestimates actual use means survey-based prevalence data may significantly undercount teen cannabis use.","specificNumbers":"11,868 participants tracked from ages 9–10 to 15–16. 6,133 unique participants provided hair samples (11,865 total samples). By ages 15–16: 7.1% moderate+ cannabis, 4.7% heavy nicotine, 0.3% heavy alcohol. Self-report/toxicology correspondence: <1% at ages 11–12, 45% at ages 15–16.","methodology":"Data from the nationwide ABCD Study (n=11,868 at baseline ages 9–10, followed to ages 15–16 at Wave 6). Hair samples from 6,133 unique participants (11,865 samples) objectively detected substance use. Multi-step weighting estimated national prevalence, adjusting for recruitment demographics, missed visits, and sample testing.","limitations":"Hair testing detects moderate-to-heavy use but may miss occasional use. Some adolescents may have too short hair for testing. Weighted estimates depend on modeling assumptions. Cannot distinguish frequency from intensity of use."},{"rthcId":"RTHC-07893","title":"Predicting Genetic Risk for Impulsivity and Substance Use in Adolescence.","authors":"Wade, Natasha E; Ahern, Jonathan; Szpak, Veronica; Wallace, Alexander L; Sullivan, Ryan M; Fan, Chun C; Loughnan, Robert","year":2025,"journal":"medRxiv : the preprint server for health sciences","doi":"10.1101/2025.04.07.25325258","pmid":"40297419","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07894","title":"Commercial Cannabidiol for Community-Based Young Adolescents: Predicting Medicinal Use.","authors":"Wade, Natasha E; Nguyen-Louie, Tam T; Wallace, Alexander L; Sullivan, Ryan M; Tapert, Susan F","year":2025,"journal":"Cannabis and cannabinoid research, 10(2), e353-e361","doi":"10.1089/can.2024.0015","pmid":"38775636","tags":["CBD","adolescents","medical-cannabis","epidemiology"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Of 11,189 ABCD participants (ages 11–15), 307 (2.8%) were given health-related CBD. Top administration methods: oil (42%), topical (31%), edibles (29%). Higher odds of use associated with being older (OR 1.32), White (OR 5.97 vs Black), having internalizing symptoms (OR 1.81), mental health treatment (OR 1.76), pain (OR 1.38), sleep problems (OR 1.69), and parents having no strict anti-cannabis rules.","whyItMatters":"CBD products are being given to nearly 3% of adolescents for health reasons, often without strong evidence for effectiveness in children. The racial disparity (nearly 6× more common among White teens) and association with mental health symptoms highlight both access inequities and potential over-reliance on unregulated products.","specificNumbers":"11,189 participants across 3 waves. 48% female. Mean age 12.8 years. 2.8% given health CBD. White vs Black OR = 5.97. White vs Hispanic OR = 1.82. Internalizing symptoms OR = 1.81. Mental health treatment OR = 1.76. Sleep problems OR = 1.69. Pain OR = 1.38.","methodology":"ABCD Study population-based cohort following healthy community-based adolescents annually (2018–2022, ages 11–15, N=11,189). Adolescent and caregiver questionnaires assessed CBD use with parent/doctor permission. Generalized estimating equations predicted odds of health-related CBD use by mental health, physical health, and sociodemographic factors.","limitations":"Self/caregiver reported CBD use without verification. Cannot confirm what products contained or their actual CBD/THC content. ABCD participants may not represent all U.S. adolescents. Cannot determine effectiveness of CBD for the conditions motivating use."},{"rthcId":"RTHC-07895","title":"Neonatal Cannabidiol Exposure Impairs Spatial Memory and Disrupts Neuronal Dendritic Morphology in Young Adult Rats.","authors":"Wadhwa, Meetu; Chinn, Gregory A; Sasaki Russell, Jennifer M; Hellman, Judith; Sall, Jeffrey W","year":2025,"journal":"Cannabis and cannabinoid research, 10(1), e145-e155","doi":"10.1089/can.2024.0010","pmid":"39253840","tags":["CBD","brain-development","neonatal","memory","sex-differences"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Neonatal CBD exposure (50 mg/kg on postnatal days 1, 3, 5) caused decreased dendritic length and spine density in both cortical and hippocampal neurons in both sexes, with reduced dendritic arborization on Sholl analysis. Females (but not males) showed spatial memory deficits in the Barnes maze. No anxiety changes in either sex.","whyItMatters":"CBD is increasingly considered for neonatal conditions like seizures, and maternal CBD use during pregnancy could expose newborns through breast milk. This study provides concerning evidence that early-life CBD exposure may permanently alter brain architecture and sex-specifically impair memory.","specificNumbers":"50 mg/kg CBD intraperitoneally on postnatal days 1, 3, and 5. Overall decrease in dendritic length and spine density (apical and basal) in cortex and hippocampus. Reduced dendritic intersections on Sholl analysis. Females showed spatial memory deficit; males did not. No anxiety changes in either sex.","methodology":"Male and female neonatal Sprague Dawley rats received CBD (50 mg/kg IP) on postnatal days 1, 3, and 5. In early adulthood, rats were tested on Barnes maze (spatial memory), open field, and elevated plus maze (anxiety). Golgi-Cox staining assessed neuronal morphology in cortex and hippocampus.","limitations":"High-dose intraperitoneal CBD in rats — human neonatal exposure would be much lower. Only three dosing days — different schedules may have different effects. Golgi-Cox staining provides morphological but not functional detail. Rat brain development timeline differs from humans."},{"rthcId":"RTHC-07896","title":"Cannabis Consumption Among Adults Aged 55-65 in Canada, 2018-2021.","authors":"Wadsworth, Elle; Cristiano, Nick; Gabrys, Robert; Renard, Justine; Hammond, David","year":2025,"journal":"Journal of drug issues, 55(1), 33-49","doi":"10.1177/00220426231190022","pmid":"39553892","tags":["older-adults","legalization","Canada","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Past 12-month cannabis use among 55–65-year-olds significantly increased from 19.3% (2018, pre-legalization) to 24.5% in 2019 (first year post-legalization) and continued rising. A substantial proportion used cannabis to manage physical or mental health conditions.","whyItMatters":"Adults aged 55–65 are more likely to take prescription medications, making cannabis-drug interactions a real concern. The rapid increase in use post-legalization among this age group means healthcare providers need to proactively ask older patients about cannabis use.","specificNumbers":"18,177 total adults aged 55–65 surveyed. 4,119 past-year cannabis consumers. Use increased from 19.3% (2018) to 24.5% (2019). Significant increase (p < 0.001). Substantial health-motivated use reported.","methodology":"Repeat cross-sectional survey of Canadian adults aged 55–65 (n=18,177 total, n=4,119 cannabis consumers) across 2018–2021 survey waves, spanning pre- and post-legalization of non-medical cannabis in Canada.","limitations":"Self-reported use — may still underestimate true prevalence. Repeat cross-sectional design (different people each wave), so cannot track individual changes. Cannot determine if new users are first-time users or returning after years of non-use. Canadian-specific."},{"rthcId":"RTHC-07897","title":"How to ESCAPE from Pain? An Observational Study on Improving Pain and Quality of Life with the Cannamedical® Hybrid Cannabis Extract.","authors":"Wagner, Yvonne; Samel, Ines; Probst, Kristina; Schollenberger, Lukas; Ruckes, Christian; Nadstawek, Joachim","year":2025,"journal":"Advances in therapy, 42(9), 4367-4389","doi":"10.1007/s12325-025-03262-z","pmid":"40560527","tags":["chronic-pain","THC","CBD","clinical-practice","quality-of-life"],"studyType":"clinical-observation","evidenceStrength":"moderate","keyFinding":"Mean pain intensity (NRS) decreased from 5.46 to 3.37 in the full population (n=64) and from 5.92 to 2.37 in cannabis-naïve patients (n=35). Pain interference also decreased substantially in both groups. Physical and mental health quality of life improved, and both patients and physicians reported high satisfaction.","whyItMatters":"Real-world evidence from clinical practice showing meaningful pain reduction with a balanced THC:CBD extract adds to the growing case for cannabis as a chronic pain treatment option, especially the impressive results in cannabis-naïve patients.","specificNumbers":"64 patients (ITT), 35 cannabis-naïve. Pain NRS: 5.46 → 3.37 (ITT), 5.92 → 2.37 (naïve). Pain interference: 5.39 → 3.38 (ITT), 5.68 → 2.54 (naïve). Both physical and mental health SF-12 scores improved. High patient and physician satisfaction.","methodology":"ESCAPE: observational study of 64 patients (50% female) with chronic pain in Germany receiving Cannamedical Hybrid Cannabis Extract THC25:CBD25 across four clinical visits. Pain assessed by Brief Pain Inventory (NRS and interference), quality of life by SF-12. Cannabis-naïve patients analyzed as a pre-specified subgroup.","limitations":"Observational, no control group or blinding — cannot separate treatment effects from placebo, regression to mean, or natural course. Moderate sample size. Product-specific results may not generalize. Potential selection bias in physician-referred patients."},{"rthcId":"RTHC-07898","title":"Efforts to secure nicotine and cannabis product placements in popular media by Ploom, Pax, and Juul: an analysis of tobacco industry documents.","authors":"Wakefield, Tanner; Bialous, Stella; Ling, Pamela; Apollonio, Dorie E","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","doi":"10.1093/ntr/ntaf180","pmid":"40899689","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07899","title":"Expanding the Therapeutic Profile of Topical Cannabidiol in Temporomandibular Disorders: Effects on Sleep Quality and Migraine Disability in Patients with Bruxism-Associated Muscle Pain.","authors":"Walczyńska-Dragon, Karolina; Fiegler-Rudol, Jakub; Baron, Stefan; Nitecka-Buchta, Aleksandra","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(7)","doi":"10.3390/ph18071064","pmid":"40732351","tags":["CBD","TMD","bruxism","sleep","migraine","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Both 5% and 10% CBD gel groups showed statistically significant improvements in Pittsburgh Sleep Quality Index and Migraine Disability Assessment scores compared to placebo (p < threshold), with 10% CBD showing the strongest effects. Objective measures (sEMG and Bruxoff) confirmed reduced muscle tension and bruxism intensity.","whyItMatters":"Bruxism is extremely common, affecting up to 31% of adults, and is linked to poor sleep and migraines. This RCT provides strong evidence that topical CBD can address multiple bruxism-related symptoms simultaneously, offering a non-systemic treatment option.","specificNumbers":"60 participants, 3 groups of 20. 30-day treatment. Both 5% and 10% CBD significantly improved PSQI and MIDAS vs placebo. 10% CBD showed strongest dose-dependent effect. sEMG and Bruxoff confirmed objective improvement in muscle tension and bruxism intensity.","methodology":"Randomized, double-blind clinical trial. 60 participants with bruxism allocated equally to placebo gel, 5% CBD gel, or 10% CBD gel (n=20 each). Applied intraorally to masseter muscles nightly for 30 days. Sleep quality (PSQI), migraine disability (MIDAS), muscle tension (sEMG), and bruxism intensity (Bruxoff) assessed.","limitations":"Small per-group sample (n=20). 30-day follow-up may not reflect long-term outcomes. Intraoral application may not translate to other topical routes. Cannot determine which component of improvement (sleep, muscle relaxation, or pain) drove the others."},{"rthcId":"RTHC-07900","title":"Cannabidiol for Orofacial and Upper-Quarter Pain: A Systematic Evaluation of Therapeutic Potential.","authors":"Walczyńska-Dragon, Karolina; Fiegler-Rudol, Jakub; Nitecka-Buchta, Aleksandra; Baron, Stefan","year":2025,"journal":"Journal of clinical medicine, 14(12)","doi":"10.3390/jcm14124186","pmid":"40565932","tags":["CBD","pain","TMD","orofacial-pain","systematic-review"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CBD showed consistent benefits for chronic myofascial TMD and bruxism pain across clinical trials and preclinical models, particularly with topical or intraoral application. For acute nociceptive pain (pulpitis, third molar surgery), results were inconsistent. CBD enhanced conventional analgesics (opioids, NSAIDs) in preclinical models, suggesting synergistic potential.","whyItMatters":"This review clarifies where CBD is most and least promising for oral and facial pain — chronic muscle-related pain responds well, but acute dental pain does not. This distinction helps clinicians and patients set appropriate expectations.","specificNumbers":"10 studies reviewed (RCTs and animal models). CBD effective for chronic myofascial TMD and bruxism. Inconsistent results for acute dental pain. CBD enhanced opioid and NSAID effects in preclinical models. Adverse effects minimal but underreported.","methodology":"Systematic review evaluating 10 clinical and preclinical studies meeting inclusion criteria for CBD in upper-quarter pain conditions including TMDs, orofacial pain, myofascial dysfunction, and post-surgical dental pain. Studies assessed for methodological quality and risk of bias.","limitations":"Only 10 studies met criteria — evidence base is still small. Substantial heterogeneity in CBD dosage, formulation, routes, and outcomes. Adverse effects underreported in clinical trials. Publication bias possible."},{"rthcId":"RTHC-07901","title":"The Therapeutic Potential of Cannabidiol in the Management of Temporomandibular Disorders and Orofacial Pain.","authors":"Walczyńska-Dragon, Karolina; Kurek-Górecka, Anna; Fiegler-Rudol, Jakub; Nitecka-Buchta, Aleksandra; Baron, Stefan","year":2025,"journal":"Pharmaceutics, 17(3)","doi":"10.3390/pharmaceutics17030328","pmid":"40142992","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07902","title":"Development of a motivational enhancement therapy cannabis-reduction intervention for young adults experiencing psychosis: A feasibility pilot study.","authors":"Walker, Denise D; Petros, Ryan; Bennett, Melanie; Tennison, Mackenzie; Monroe-DeVita, Maria","year":2025,"journal":"Psychiatric rehabilitation journal, 48(4), 244-253","doi":"10.1037/prj0000654","pmid":"40689938","tags":["psychosis","young-adults","intervention","harm-reduction"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"The Cannabis Check-Up for Psychosis (CCU-P) — a two-session motivational enhancement therapy intervention — demonstrated 92% completion rate (11 of 12 completed both sessions), high satisfaction ratings, and all participants said they would recommend it to others in Coordinated Specialty Care.","whyItMatters":"Cannabis use is common among young adults with psychosis and associated with worse outcomes, but few effective interventions exist for this population. Most approaches are too confrontational. This nonjudgmental intervention respects autonomy while providing information to support informed choices.","specificNumbers":"12 participants in the pilot. 92% completed both sessions (11 of 12). All participants would recommend to others. Optimizations included psychosis-specific infographics on rehospitalization risk and harm reduction strategies.","methodology":"One-arm pilot study with 12 young adults experiencing psychosis who were regular cannabis users enrolled in Coordinated Specialty Care. The intervention was optimized from the Teen Marijuana Check-Up using qualitative interview and focus group data, reviewed by a Stakeholder Advisory Board.","limitations":"Very small pilot (n=12), no control group or cannabis use outcome data. Measured feasibility and acceptability, not efficacy. One-arm design cannot determine if the intervention actually changes behavior. Specific to Coordinated Specialty Care settings."},{"rthcId":"RTHC-07903","title":"Young Adult Cannabis Use and Circulating Endocannabinoid Concentrations on Cognitive Performance.","authors":"Wallace, Alexander L; Baca, Rachel; Andrade, Gianna; Hillard, Cecilia J; Happer, Joseph P; Wade, Natasha E; Courtney, Kelly E; Mejia, Margie Hernandez; Jacobus, Joanna","year":2025,"journal":"Frontiers in adolescent medicine, 3","doi":"10.3389/fradm.2025.1538448","pmid":"41257091","tags":["cognitive-function","endocannabinoid-system","memory","young-adults","biomarkers"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Heavy cannabis use was associated with worse verbal memory. However, significant interactions showed that heavy users with elevated 2-AG concentrations performed better on verbal learning and memory, while heavy users with higher AEA concentrations performed worse. In men specifically, high 2-AG with heavy use predicted better verbal learning.","whyItMatters":"Not all heavy cannabis users experience the same cognitive effects. This study suggests that individual differences in endocannabinoid levels may explain why some heavy users maintain good memory while others don't — potentially opening the door to biomarker-based risk assessment.","specificNumbers":"87 participants (ages 18–20, 63% female). Three cannabis groups: no use, light (<8 days/month), heavy (≥8 days/month). High 2-AG + heavy use = better memory. High AEA + heavy use = worse learning. Three-way interaction: men with heavy use and high 2-AG had best verbal learning.","methodology":"87 participants aged 18–20 (63% female) completed measures of past-30-day cannabis use, verbal learning and memory (RAVLT), and blood draws for serum endocannabinoid analysis (2-AG and AEA). Linear regressions examined cannabis group × endocannabinoid interactions on memory, with sex as a moderator.","limitations":"Cross-sectional — cannot determine if endocannabinoid levels are a cause or consequence of cannabis use patterns. Small sample. Serum levels may not reflect brain endocannabinoid concentrations. Only one cognitive domain tested (verbal memory)."},{"rthcId":"RTHC-07904","title":"Does a carboxamide moiety alter the toxicokinetics of synthetic cannabinoids? A study after pulmonary and intravenous administration of cumyl-5F-P7AICA to pigs.","authors":"Walle, Nadja; Dings, Christiane; Zaher, Omar; Doerr, Adrian A; Peters, Benjamin; Laschke, Matthias W; Lehr, Thorsten; Menger, Michael D; Schmidt, Peter H; Meyer, Markus R; Schaefer, Nadine","year":2025,"journal":"Archives of toxicology, 99(2), 633-643","doi":"10.1007/s00204-024-03906-z","pmid":"39630204","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07905","title":"Childhood events as factors in continued cannabis use in adulthood: a longitudinal study of a 30-year follow-up cohort.","authors":"Wallez, Solène; Eren, Filiz; Kousignian, Isabelle; Avenin, Guillaume; Melchior, Maria; Mary-Krause, Murielle","year":2025,"journal":"Journal of cannabis research, 7(1), 89","doi":"10.1186/s42238-025-00345-0","pmid":"41225669","tags":["longitudinal","young-adults","risk-factors","childhood"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Three cannabis trajectories were identified: declining (69.9%), fluctuating (13.7%), and persistent (16.4%). Persistent use was predicted by male sex (OR 3.66), academic difficulties (OR 2.47), and early initiation of cannabis (OR 2.31) or combined tobacco+cannabis (OR 3.07). Fluctuating use was predicted by parental smoking (OR 2.18) and parental conflict/stress before age 17 (OR 1.93).","whyItMatters":"Understanding that one in six cannabis users maintains persistent use into their mid-40s — and that this pattern is predictable from childhood factors — creates opportunities for early identification and targeted prevention before patterns become entrenched.","specificNumbers":"622 participants, 14 measurements over 22 years (1999–2021). Declining: 69.9%. Fluctuating: 13.7%. Persistent: 16.4%. Male sex: OR 3.66 for persistent. Academic difficulties: OR 2.47. Early cannabis + tobacco initiation: OR 3.07. Parental conflict before 17: OR 1.93 for fluctuating.","methodology":"Group-Based Trajectory Modelling of 622 participants from the French TEMPO cohort with 14 measurement points of cannabis use from 1999 to 2021 (ages 15–46). Multinomial logistic regression examined associations with early individual and family factors.","limitations":"French cohort — patterns may differ in other countries, especially those with different legalization timelines. Self-reported use across 14 waves — some recall bias. Cannot account for all confounders. TEMPO cohort participants are children of a larger epidemiological study, potentially limiting representativeness."},{"rthcId":"RTHC-07906","title":"Cannabis Products and Use Patterns Associated with Cannabis Use Disorder Symptoms Among Youth in Southern California.","authors":"Walsh, Claire A; Jafarzadeh, Nikki; Whaley, Reid C; Han, Dae Hee; Leventhal, Adam; Pedersen, Eric R; Barrington-Trimis, Jessica; Harlow, Alyssa F","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(3), 89-102","doi":"10.26828/cannabis/2025/000323","pmid":"41278419","tags":["adolescents","cannabis-use-disorder","concentrates","risk-factors"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Each additional mode of cannabis administration used increased odds of probable CUD (AOR range 2.83–4.13). Frequent use (10+ days/month vs 1–2 days/month) also predicted CUD (AOR 2.87). However, specific product type used first or most often, and cannabinoid formulation, were not independently associated with CUD after adjustment.","whyItMatters":"Rather than focusing on any single product type, this study identifies poly-product use and high frequency as the key red flags for cannabis use disorder in teens. This shifts the conversation from 'which product is most dangerous' to 'how many products and how often.'","specificNumbers":"N = 420. 69.8% used >1 mode. Concentrates most common product used most often (37.5%). Each additional product: AOR 2.83–4.13 for CUD. 10+ days/month: AOR 2.87 vs 1–2 days. No association for specific product type or cannabinoid formulation after adjustment.","methodology":"Two waves of a prospective cohort of 420 Southern California adolescents who used cannabis in the past 6 months (Fall 2022, Spring 2023). Multivariable logistic regression examined baseline cannabis behaviors predicting probable CUD at 6-month follow-up (CAST), adjusting for demographics, other substance use, and baseline CUD.","limitations":"Southern California specific — may not generalize to regions with different cannabis markets. Self-reported use and CUD screening (not diagnosis). Short 6-month follow-up. Cannot determine if poly-product use causes CUD or if CUD-prone individuals use more products."},{"rthcId":"RTHC-07907","title":"Factors Influencing Co-Use of Tobacco and Cannabis Amongst Young Adults in UK Further Education Colleges: A Qualitative Study.","authors":"Walsh, Hannah; McNeill, Ann; Duaso, Maria","year":2025,"journal":"Drug and alcohol review, 44(6), 1648-1657","doi":"10.1111/dar.70002","pmid":"40556347","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07908","title":"Understanding Tobacco and Cannabis Co-Use, Cessation Strategies and Intervention Opportunities with Young Adults in UK Further Education Colleges: A Mixed Methods Study.","authors":"Walsh, Hannah; McNeill, Ann; Duaso, Maria J","year":2025,"journal":"Substance use & misuse, 60(14), 2125-2135","doi":"10.1080/10826084.2025.2533985","pmid":"40691860","tags":["tobacco","co-use","young-adults","cessation","UK"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"86.5% had made some effort to quit or reduce tobacco and/or cannabis in the past 6 months, but few used formal support. Quitting one was significantly associated with quitting the other (p=0.01). Motivation to quit tobacco was significantly higher than motivation to quit cannabis (t=7.38, p=0.01). 40% used tobacco daily, 21% used cannabis daily.","whyItMatters":"Tobacco and cannabis are usually treated separately in cessation programs, but this study shows they're tightly linked — quitting one helps quit the other. Integrated co-use interventions could be more effective and efficient than addressing each substance alone.","specificNumbers":"141 survey respondents, 18 interviewed. 40% daily tobacco, 21% daily cannabis. 86.5% tried to quit/reduce. Quitting one linked to quitting the other (p = 0.01). Tobacco quit motivation significantly higher than cannabis (p = 0.01). UK Further Education colleges (ages 16–30).","methodology":"Sequential explanatory mixed methods study using the COM-B behavioral model. Survey of 141 UK Further Education students aged 16–30 with recent tobacco and cannabis use, plus 18 follow-up interviews. Chi-square and t-tests compared quitting behaviors between substances.","limitations":"UK-specific, particularly Further Education setting. Self-selected sample of co-users. Self-reported data. Cross-sectional survey cannot determine temporal ordering. Small qualitative component (18 interviews)."},{"rthcId":"RTHC-07909","title":"Cannabis use is associated with alterations in NLRP3 inflammasome related gene expression in monocyte-derived macrophages from people living with HIV.","authors":"Walter, Kyle C; Avalos, Bryant; Ford, Mary K; Laird, Anna E; Boustani, Ali; Spencer, Matthew; Shu, Leeann; Chaillon, Antoine; Crescini, Melanie; Cookson, Debralee; Ellis, Ronald J; Letendre, Scott L; Iudicello, Jennifer; Fields, Jerel Adam","year":2025,"journal":"Frontiers in immunology, 16, 1634203","doi":"10.3389/fimmu.2025.1634203","pmid":"41280902","tags":["HIV","inflammation","CBD","endocannabinoid-system","immunology"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"HIV-positive individuals' macrophages showed 83% higher NLRP3 inflammasome expression than HIV-negative controls. Moderate cannabis users had 61% less IL-1β expression than non-users. CBD treatment reduced NLRP3 expression by 22% in IL-1β-stimulated cells. However, combined CBD + IL-1β treatment unexpectedly increased some downstream cytokine gene expression (3-fold for IL-1β, 2-fold for IL-18).","whyItMatters":"Chronic inflammation is a major driver of cognitive decline in people living with HIV despite effective antiretroviral therapy. This study provides molecular evidence that cannabis use and CBD may modulate a specific inflammatory pathway (NLRP3) in HIV, offering potential therapeutic insight.","specificNumbers":"43 PWH, 22 PWoH. NLRP3 expression 83% higher in PWH. Moderate cannabis users: 61% less IL-1β vs naïve. Daily users: 64% increase in IL-18 vs moderate. CBD + IL-1β: 22% decrease in NLRP3, but 3-fold increase in IL-1β mRNA and 2-fold increase in IL-18 mRNA.","methodology":"Cross-sectional study of monocyte-derived macrophages from 43 people with HIV and 22 without HIV. Participants categorized by cannabis use (naïve, moderate, daily). Cells treated with CBD (30 μM), IL-1β (20 ng/mL), or both. NLRP3-related gene expression measured. Clinical correlations assessed.","limitations":"Cross-sectional — cannot determine causation. In vitro CBD treatment may not reflect in vivo effects. Cannabis use was self-reported and products varied. Small sample. Unexpected downstream effects complicate interpretation."},{"rthcId":"RTHC-07910","title":"Review and Call for Improved Cannabis Measurement and the Potential for Leveraging Cannabis Seed-To-Sale Systems.","authors":"Wang-Schweig, Meme; Zimmer, Sara; Kirshenbaum, Ari; Mudd, Lydia; Slade, Mackenzie","year":2025,"journal":"Journal of psychoactive drugs, 57(5), 550-560","doi":"10.1080/02791072.2024.2420042","pmid":"39491525","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07911","title":"Cannabinoid Receptors CB1 and CB2 Activation Restores Hippocampal Lipid Profiles and Alleviates Autism-Like Behaviors in Valproic Acid-Induced ASD Rats.","authors":"Wang, Haoran; Zhang, Mengyuan; Yang, Sen; Jiang, Yi; Wu, Lijie; Sun, Caihong","year":2025,"journal":"CNS neuroscience & therapeutics, 31(8), e70591","doi":"10.1111/cns.70591","pmid":"40852923","tags":["autism","endocannabinoid-system","preclinical","lipid-metabolism"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CB1R agonist (ACPA) and CB2R agonist (AM1241) both significantly alleviated ASD-like behaviors (marble burying, self-grooming, social deficits, hyperactivity) in VPA-exposed rats. Lipidomics revealed marked reductions in multiple hippocampal lipid classes in VPA rats, and both agonists restored these levels to near-normal, comparable to controls.","whyItMatters":"Autism spectrum disorder has no approved pharmacological treatments for core symptoms like social deficits and repetitive behaviors. The finding that cannabinoid receptor activation addresses both behavioral and metabolic aspects of ASD in an animal model opens a novel therapeutic avenue.","specificNumbers":"VPA dose: 600 mg/kg. ACPA: 0.1 mg/kg (CB1 agonist). AM1241: 3 mg/kg (CB2 agonist). Treatment: postnatal days 21–27. Both significantly reduced repetitive behaviors, social deficits, and hyperactivity. Lipid classes restored: phosphatidylcholines, lysophosphatidylcholines, fatty acids, sphingomyelins, ceramides, phosphatidylethanolamines.","methodology":"Male offspring from VPA-exposed dams (600 mg/kg, a validated ASD model) received CB1R agonist ACPA (0.1 mg/kg) or CB2R agonist AM1241 (3 mg/kg) from postnatal days 21–27. Behavioral testing (marble burying, self-grooming, social interaction, open field) and hippocampal lipidomics by UPLC-MS/MS were performed.","limitations":"VPA rat model captures some but not all features of human ASD. Only male offspring studied. Short treatment window (7 days). Synthetic cannabinoid receptor agonists differ from plant-derived cannabinoids. Cannot directly extrapolate dosing to humans."},{"rthcId":"RTHC-07912","title":"Media Reports and Knowledge of e-Cigarette or Vaping Use-Associated Lung Injury Among Adolescents in California: Population-Based Cross-Sectional Study.","authors":"Wang, Jijiang; Ayers, John; Leas, Eric; Gamst, Anthony; Zhu, Shu-Hong","year":2025,"journal":"Journal of medical Internet research, 27, e69151","doi":"10.2196/69151","pmid":"40729669","tags":["vaping","EVALI","adolescents","media","public-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"75% of middle and high school students were aware of EVALI, primarily from media (63.1%). However, 55% incorrectly believed nicotine caused EVALI, while only 11% correctly identified cannabis-related vapes. Students aware of EVALI were more likely to view daily vaping as extremely harmful (67.8% vs 50.9%).","whyItMatters":"The EVALI crisis killed 68 people, primarily from vitamin E acetate in illicit cannabis vapes. But the public health message was garbled — most teens think nicotine vapes were the problem. This misinformation may cause teens to avoid less-harmful nicotine vapes while underestimating risks of illicit cannabis products.","specificNumbers":"157,499 students surveyed. 75% aware of EVALI. Primary source: media (63.1%), parents (16.6%), teachers (8.1%). 55% blamed nicotine. Only 11% correctly identified cannabis. 19,661 EVALI news reports analyzed: 55.9% mentioned cannabis. Awareness increased perceived vaping harm (67.8% vs 50.9%).","methodology":"Analysis of archived EVALI news reports from Tobacco Watcher (July 2019–March 2020) and California Student Tobacco Survey data from 157,499 8th, 10th, and 12th graders surveyed September 2019–March 2020. Students' EVALI awareness, perceived cause, information sources, and vaping risk perceptions examined.","limitations":"California-specific student sample. Self-reported awareness and beliefs. Survey conducted during the outbreak, so perceptions may have shifted. Cannot determine long-term behavioral effects of misperceptions. Media analysis limited to one monitoring tool."},{"rthcId":"RTHC-07913","title":"Discovery of new covalent inhibitors of monoacylglycerol lipase with the nitrile warhead via SCARdock.","authors":"Wang, Juanping; Shi, Xiaoyu; Wang, Junlai; Zheng, Qiang; Shao, Peipei; Liu, Sen","year":2025,"journal":"Bioorganic chemistry, 159, 108378","doi":"10.1016/j.bioorg.2025.108378","pmid":"40107037","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07914","title":"Identifying Stigma Phenotypes in Social Media Narratives of Substance Use: Observational Study.","authors":"Wang, Lexie Chenyue; Pike, Kenneth C; Conway, Mike; Chen, Annie T","year":2025,"journal":"Journal of medical Internet research, 27, e68695","doi":"10.2196/68695","pmid":"41232106","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07915","title":"Identification and experimental validation of biomarkers associated with the endocannabinoid system in major depressive disorder.","authors":"Wang, Linlin; Chen, Min; Li, Xujuan; Li, Yufeng","year":2025,"journal":"Hereditas, 162(1), 191","doi":"10.1186/s41065-025-00558-6","pmid":"41013856","tags":["depression","endocannabinoid-system","biomarkers","genomics"],"studyType":"genomic-analysis","evidenceStrength":"preliminary","keyFinding":"MRPS11 and SHMT2 were identified as significant biomarkers for major depressive disorder, both showing markedly reduced expression in patient samples compared to controls. The findings were validated by RT-qPCR analysis. A biomarker-based nomogram successfully predicted MDD risk. Both genes were co-enriched in the ribosome pathway.","whyItMatters":"Depression diagnosis currently relies on subjective symptoms. If endocannabinoid system-related gene biomarkers can objectively predict depression risk, it could transform diagnosis and connect the growing understanding of the ECS-mood relationship to clinical practice.","specificNumbers":"Two key biomarkers: MRPS11 and SHMT2. Both reduced in MDD. Four differential immune cell types found. Five key miRNAs identified targeting these biomarkers. 31 lncRNAs and 10 transcription factors in regulatory networks. 15 drugs targeting MRPS11, 56 targeting SHMT2.","methodology":"Analysis of two gene expression datasets (GSE52790 and GSE38206). Weighted gene co-expression network analysis (WGCNA) and machine learning integrated with endocannabinoid system-related genes to identify biomarkers. ROC analysis validated diagnostic performance. RT-qPCR confirmed expression differences. Immune cell analysis, regulatory networks, and drug targeting were also performed.","limitations":"Bioinformatics-driven study relying on public datasets. RT-qPCR validation performed but in small samples. MRPS11 and SHMT2 are mitochondrial genes connected to ECS but not core ECS components. No functional validation of the biomarker-disease relationship. Cannot confirm causation."},{"rthcId":"RTHC-07916","title":"Cannabidiol-Loaded Nanostructured Lipid Carriers for Nose to Brain Delivery: An Effective Therapeutic Approach against Epilepsy.","authors":"Wang, Liyan; Yang, Li; Liang, Kaili; Liu, Bo; Luo, Qing; Wang, Wei; Zhang, Ding; Wang, Qing","year":2025,"journal":"Molecular pharmaceutics, 22(8), 4804-4818","doi":"10.1021/acs.molpharmaceut.5c00452","pmid":"40693913","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07917","title":"Absolute Risk Prediction for Cannabis Use Disorder in Adolescence and Early Adulthood Using Bayesian Machine Learning.","authors":"Wang, Tingfang; Boden, Joseph M; Biswas, Swati; Choudhary, Pankaj K","year":2025,"journal":"Drug and alcohol review, 44(6), 1680-1690","doi":"10.1111/dar.14098","pmid":"40545703","tags":["cannabis-use-disorder","risk-prediction","adolescents","machine-learning"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"The model achieved AUC values of 0.68 (training), 0.64, and 0.75 (two validation datasets) for predicting CUD within 5 years of first cannabis use. The five risk factors were biological sex, delinquency, and personality traits of conscientiousness, neuroticism, and openness. Calibration was excellent (E/O ratios of 0.95–1.0).","whyItMatters":"Currently, clinicians have no validated tool to identify which young cannabis users are most likely to develop use disorder. A simple 5-factor model could be integrated into routine clinical screening to enable early, targeted intervention before problems develop.","specificNumbers":"5 risk factors. Training AUC: 0.68. Validation AUCs: 0.64 and 0.75. E/O ratios: 0.95, 0.98, and 1.0 (excellent calibration). Predicts CUD risk within 5 years of first cannabis use. Personalized absolute risk output.","methodology":"Bayesian machine learning model trained on the National Longitudinal Study of Adolescent to Adult Health. Five-fold cross-validation assessed performance (AUC and E/O ratio). Independent validation on two external datasets. Model provides personalized absolute risk scores for individual patients.","limitations":"Moderate AUC (0.64–0.75) means the model misses some who develop CUD and flags some who don't. Based on an older cohort — cannabis products and patterns have changed. Limited to 5 factors for simplicity, potentially missing important predictors. Requires first cannabis use as entry point."},{"rthcId":"RTHC-07918","title":"Chronic oral dosing of cannabidiol and cannabidiolic acid full-spectrum hemp oil extracts has no adverse effects in horses: a pharmacokinetic and safety study.","authors":"Wang, Tongxin Charlotte; Wakshlag, Joseph J; Jager, Mason C; Schwark, Wayne S; Trottier, Nathalie L; Chevalier, Jacqueline M; Pearson, Garett; Cercone, Marta","year":2025,"journal":"American journal of veterinary research, 86(3)","doi":"10.2460/ajvr.24.08.0235","pmid":"39787699","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07919","title":"Exploring Cannabinoid Effects Using Zebrafish (Danio rerio) as an In Vivo Model: A Review of the Literature.","authors":"Wang, Xingbo; Xie, Han; Shi, Xiaoling; Wu, Kusheng; Huang, Wenlong","year":2025,"journal":"International journal of molecular sciences, 26(18)","doi":"10.3390/ijms26189165","pmid":"41009724","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07920","title":"EXPLORING THE MECHANISM OF ACTION OF HEMP SEEDS (CANNABIS SATIVA L.) IN TREATING OSTEOPOROSIS USING NETWORK PHARMACOLOGY.","authors":"Wang, Yan; Xie, Yulei; Yin, Chong; Wu, Qing","year":2025,"journal":"Georgian medical news, 38-43","doi":null,"pmid":"41687633","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07921","title":"The gateway effect of cigarette, e-cigarette, cigar, and alcohol use vs. Cannabis use.","authors":"Wang, Yan; Cavazos-Rehg, Patricia A; Cui, Yuxian; Speer, Morgan; LoParco, Cassidy R; McCready, Darcey M; Yang, Y Tony; Berg, Carla J","year":2025,"journal":"Addictive behaviors, 170, 108451","doi":"10.1016/j.addbeh.2025.108451","pmid":"40795599","tags":["gateway-hypothesis","substance-initiation","young-adults","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Initiating cigarettes, e-cigarettes, cigars, or alcohol increased the hazard of starting cannabis (aHRs 2.17–3.78). Conversely, initiating cannabis increased the hazard of starting each of those substances equally strongly (aHRs 3.07–3.73). All associations were stronger when initiation occurred at ages 5–18 vs. after 18. Depression predicted cannabis initiation specifically.","whyItMatters":"The traditional 'gateway hypothesis' positions cannabis as a stepping stone to harder drugs. This study shows the gateway effect works equally in both directions — using any substance increases the hazard of initiating others, challenging the idea that cannabis is uniquely dangerous as a gateway.","specificNumbers":"4,031 young adults. Lifetime use: cannabis 68%, cigarettes 45%, e-cigarettes 49%, cigars 31%, alcohol 85%. Cannabis → cigarettes aHR 3.51. Cannabis → e-cigarettes aHR 3.73. Cannabis → cigars aHR 3.66. Cannabis → alcohol aHR 3.07. All effects stronger at ages 5–18.","methodology":"Discrete-time survival analysis of 2023 survey data from 4,031 U.S. young adults (mean age 26.29). Self-reported age of initiation for each substance enabled time-lagged hazard modeling. Adjusted for demographics, state cannabis laws, lifetime mental health diagnoses, and personality traits.","limitations":"Retrospective recall of initiation ages may be inaccurate. Cross-sectional survey with survival analysis provides temporal ordering but not true prospective data. Cannabis use was very common (68%), potentially limiting generalizability. Cannot account for all confounders."},{"rthcId":"RTHC-07922","title":"Exposure to Cannabis in Social Networks and Advertising in Relation to Cannabis-Related Perceptions, Motives, and Use Behaviors Among Young Adults in the US.","authors":"Wang, Yan; Speer, Morgan; Rossheim, Matthew E; Chen-Sankey, Julia; LoParco, Cassidy R; Cui, Yuxian; Romm, Katelyn F; Schubel, Laura; Chakraborty, Rishika; Cavazos-Rehg, Patricia A; Berg, Carla J","year":2025,"journal":"Substance use & misuse, 60(11), 1720-1728","doi":"10.1080/10826084.2025.2515155","pmid":"40511841","tags":["marketing","young-adults","social-influence","risk-perception"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Parental and friends' cannabis use showed direct effects on both use status and frequency. Advertising exposure showed direct effects on use status but not frequency. All three exposures reduced perceived harm, and perceived harm mediated associations to use. Interestingly, advertising increased perceived addictiveness, but higher perceived addictiveness was associated with lower use likelihood but more frequent use among those who used.","whyItMatters":"Understanding whether social influences or marketing drives cannabis use informs where prevention efforts should focus. The finding that friends' and parental use have direct behavioral effects — while advertising works more through changing perceptions — suggests different intervention strategies for each.","specificNumbers":"4,031 young adults, ~49% past-month cannabis users. Friends' use: direct effect on use status and frequency, mediated by lower perceived harm and higher motives. Advertising: direct effect on use status, increased perceived addictiveness AND harm AND motives. Parental use: direct effects mediated by lower perceived harm.","methodology":"Path analyses of 2023 survey data from 4,031 U.S. young adults (48.8% past-month cannabis users by design; mean age 26.39, 59.4% female). Parental use, friends' use, and advertising exposure examined in relation to past-month use status and frequency, with perceived risk and motives as mediators.","limitations":"Cross-sectional — cannot determine causal direction. Self-reported measures of exposure and use. By-design oversampling of cannabis users. Cannot distinguish between types of advertising (retail, social media, brand). Path analysis assumes correct causal ordering."},{"rthcId":"RTHC-07923","title":"Symphony of the gut microbiota and endocannabinoidome: a molecular and functional perspective.","authors":"Wang, Yang; Guo, Jing; Mao, Zhiqin; Chen, Ying","year":2025,"journal":"Frontiers in cellular and infection microbiology, 15, 1566290","doi":"10.3389/fcimb.2025.1566290","pmid":"40207053","tags":["gut-microbiome","endocannabinoid-system","inflammation","metabolic-health"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The gut microbiota and endocannabinoidome interact bidirectionally: gut bacteria influence endocannabinoid levels and receptor expression, while endocannabinoid signaling shapes gut microbial composition and intestinal barrier function. Diet and exercise modulate both systems. These interactions are implicated in IBD, depression, anxiety, Alzheimer's, and metabolic disorders.","whyItMatters":"The gut-endocannabinoid axis represents a new frontier for understanding how cannabis affects health beyond direct receptor activation. Many of cannabis's effects on mood, inflammation, and metabolism may be mediated through gut microbiome changes.","specificNumbers":"Conditions reviewed: IBD, depression, anxiety, Alzheimer's disease, metabolic disorders. Two systems: gut microbiota and endocannabinoidome (expanded ECS including non-classical endocannabinoids). Modulators: diet and physical activity.","methodology":"Narrative review examining molecular mechanisms and signaling pathways linking the gut microbiota and endocannabinoidome. Analyzes the role of dietary patterns and physical activity in regulating these interactions across multiple disease conditions.","limitations":"Narrative review — not systematic. Many findings from animal models with limited human data. Mechanistic understanding is still emerging. Cannot determine if gut microbiome changes are causes or consequences of disease states."},{"rthcId":"RTHC-07924","title":"Multi-level patterns predict cannabis use onset among youth.","authors":"Wang, Yixin; Fraser, Robbie; Aguinaldo, Laika; Nguyen-Louie, Tam T; Baker, Fiona C; Tapert, Susan F; Pohl, Kilian M","year":2025,"journal":"Developmental cognitive neuroscience, 76, 101639","doi":"10.1016/j.dcn.2025.101639","pmid":"41218289","tags":["adolescents","risk-prediction","brain-imaging","prevention"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Random Survival Forest predicted first cannabis onset (C-index 0.68) and weekly onset (C-index 0.69). First use was predicted by 13 factors across 6 domains (biobehavior, cognition, family, peer, neighborhood, legal). Weekly use required only 4 factors, with 3 shared with first use: cannabis outlet density, access to alcohol at home, and positive social expectations about alcohol.","whyItMatters":"The distinction between first use (many factors) and escalation to weekly use (few factors) is crucial for prevention. First use may be hard to prevent because it's influenced by many small factors, but escalation to habitual use may be preventable by targeting just a few key environmental factors.","specificNumbers":"450 cannabis-naïve youth. 8-year follow-up. 292 initiated use, 163 reached weekly use. First onset: C-index 0.68, 13 predictive factors across 6 domains. Weekly onset: C-index 0.69, 4 predictive factors. Key factor for first use: lower positive thinking during stress coping. Shared escalation factors: cannabis outlet density, home alcohol access, positive alcohol expectations.","methodology":"Data-driven analysis of 151 measurements spanning 7 domains from the NCANDA cohort (450 cannabis-naïve youth, ages 12–21, followed 8 years). Random Survival Forest modeled age of first onset (292 transitioned) and weekly use onset (163 transitioned). Factors from individual, microsystem, and exosystem levels assessed.","limitations":"NCANDA cohort may not represent all U.S. youth. C-index of ~0.68 indicates moderate prediction. 8-year follow-up may not capture all initiators. Some domains (brain MRI) had limited predictive contribution. Legal environment may have changed since data collection."},{"rthcId":"RTHC-07925","title":"Psilocybin mitigates behavioral despair and cognitive impairment in treatment-resistant depression model using wistar kyoto rats.","authors":"Wang, Zitong; Robbins, Brett; Zhuang, Ryan; van Bruggen, Rebekah; Sandini, Thaisa; Li, Xin-Min; Zhang, Yanbo","year":2025,"journal":"Scientific reports, 15(1), 18432","doi":"10.1038/s41598-025-03383-z","pmid":"40419666","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07926","title":"Alcohol and Cannabis Use Disorder Diagnoses in Mental Health Treatment 2013 to 2022: A Descriptive Epidemiological Study.","authors":"Ware, Orrin D","year":2025,"journal":"Substance use : research and treatment, 19, 29768357251384499","doi":"10.1177/29768357251384499","pmid":"41122376","tags":["cannabis-use-disorder","mental-health","epidemiology","treatment"],"studyType":"retrospective-analysis","evidenceStrength":"strong","keyFinding":"Of 3.95 million cases with alcohol or cannabis use disorder in mental health treatment, 1.63 million had CUD. Cannabis use disorder peaked in 2018 (199,744 cases). Depression was the most common co-occurring diagnosis (30.3% of CUD cases). 60% of CUD patients were male.","whyItMatters":"Cannabis use disorder is often encountered in mental health settings rather than addiction treatment settings. Understanding the characteristics of CUD patients in mental health care helps clinicians prepare to screen for and address cannabis problems alongside depression and other conditions.","specificNumbers":"Total analytic sample: 3,947,802 cases (6.4% of full dataset). CUD: 1,632,116 cases. AUD: 2,315,686. CUD peak year: 2018 (199,744). CUD: 60% male. Depression co-occurred in 30.3% of CUD. AUD co-occurring depression: 35.5%. AUD peak year: 2020 (278,550).","methodology":"Descriptive epidemiological analysis of Mental Health Client-Level Data, a nationwide U.S. dataset, from 2013 to 2022. Annual cross-sectional data merged across 10 years. Separate examination of alcohol use disorder (n=2,315,686) and cannabis use disorder (n=1,632,116) samples.","limitations":"Administrative data — depends on coding accuracy. Cross-sectional annual snapshots don't track individuals over time. Cannot determine if CUD caused depression or vice versa. Only captures people who reached treatment; many with CUD never seek help. Facility-level data may not represent all treatment settings."},{"rthcId":"RTHC-07927","title":"Role of Endocannabinoids in Glaucoma: A Review.","authors":"Warjri, Gazella B; Gowtham, Lakshminarayanan; Venkatraman, Vatsalya; Velpandian, Thirumurthy; Dada, Tanuj; Angmo, Dewang","year":2025,"journal":"Journal of current glaucoma practice, 19(1), 28-37","doi":"10.5005/jp-journals-10078-1467","pmid":"40417140","tags":["glaucoma","endocannabinoid-system","eye-health","neuroprotection"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system (including ligands, receptors, and enzymes) is present throughout the visual system from eye to occipital lobe. Cannabinoid receptor activation both lowers intraocular pressure and provides neuroprotection by reducing excitotoxicity and modulating vascular tone — potentially addressing both the pressure and neurodegeneration aspects of glaucoma.","whyItMatters":"Current glaucoma treatment only targets intraocular pressure, yet many patients still lose vision. There are no approved neuroprotective treatments for glaucoma. If cannabinoid-based therapies can both lower pressure and protect nerve cells, they could revolutionize glaucoma management.","specificNumbers":"ECS components found from eye to occipital lobe. Two therapeutic mechanisms identified: IOP-lowering and neuroprotection. Neuroprotection mediated by excitotoxicity reduction and vascular tone changes through cannabinoid receptors.","methodology":"Literature review searching PubMed, ScienceDirect, and Google Scholar for studies on endocannabinoids and glaucoma, encompassing animal studies, in vitro models, and limited human data. Focused on IOP-lowering and neuroprotective mechanisms.","limitations":"Mostly animal and in vitro evidence — human clinical data is scarce. The well-known IOP-lowering effect of cannabis is short-lived and impractical for chronic treatment. No cannabinoid-based glaucoma drug is currently available. Long-term safety of ocular cannabinoid delivery unknown."},{"rthcId":"RTHC-07928","title":"In Vitro Metabolic Profiling of 18 Semi-Synthetic Cannabinoids-Hexahydrocannabinol (HHC) and Its Analogs-with Identification in an Authentic Hexahydrocannabiphorol (HHCP) Urine Sample.","authors":"Watanabe, Shimpei; Murakami, Takaya; Muratsu, Seiji; Saito, Takeshi; Seto, Yasuo","year":2025,"journal":"Clinical chemistry, 71(11), 1158-1168","doi":"10.1093/clinchem/hvaf087","pmid":"40853012","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07929","title":"Development and Implementation of a Medical Cannabis Clinic Within a Geriatrics Primary Care Clinic: Preliminary Data.","authors":"Weaver, Ryan; Velez, Brian; Weissberger, Michael L; Zimmerman, Kristin M","year":2025,"journal":"Journal of the American Geriatrics Society","doi":"10.1111/jgs.70217","pmid":"41348391","tags":["medical-cannabis","pain","anxiety","seniors"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Cannabis use among older adults is rising, but most use it without medical supervision—a gap this clinic aimed to fill. The team established a monthly, physician-led medical cannabis certification clinic within an existing geriatric primary care practice.\n\nThe model is noteworthy: rather than a standalone cannabis clinic, this was embedded in primary care, where the physicians already knew their patients' full medical histories, medication lists, and goals of care. Pharmacy and nursing support were integrated to address the drug interaction concerns that are particularly acute in older adults taking multiple medications.\n\nOver 30 months (January 2022 to July 2024), 144 visits were conducted. The clinic provided individualized evaluation, safety assessment, medication review, and counseling. The patients' qualifying conditions, medication profiles, and demographic characteristics were analyzed.\n\nThe practical significance is the model itself: geriatricians are uniquely positioned to supervise cannabis use in older adults because they already manage polypharmacy, cognitive concerns, fall risk, and the complex interplay of aging-related conditions. The alternative—older adults buying products at dispensaries without medical input—carries real risks that this model addresses.","whyItMatters":"RTHC-00185 showed that moderate cannabis use didn't impair cognition in older adults across the dementia spectrum, and RTHC-00167 identified cardiovascular concerns in older cannabis-using veterans. Between cognitive reassurance and cardiovascular caution, older adults need individualized guidance—not one-size-fits-all advice. This clinic model shows how to provide it within existing healthcare infrastructure.","specificNumbers":"144 visits over 30 months. Monthly physician-led clinic. Embedded in geriatric primary care. Included medication review, safety assessment, and counseling. Pharmacy and nursing support integrated.","methodology":"Retrospective descriptive analysis of a physician-led medical cannabis certification clinic embedded in a geriatric primary care practice. 144 visits over 30 months (Jan 2022–Jul 2024). Evaluated demographics, medical and qualifying conditions, and medication profiles. Support from pharmacy and nursing staff.","limitations":"Preliminary descriptive data from a single clinic—no outcome measures reported (did patients improve?). No comparison group (were supervised patients better off than unsupervised ones?). The clinic model depends on state-level medical cannabis laws and may not be replicable everywhere. Self-selected patients who sought medical supervision may not represent all older cannabis users. 144 visits over 30 months suggests limited scalability."},{"rthcId":"RTHC-07930","title":"Evaluating racial disparities in cancer patient-provider communication about cannabis in a state without a legal cannabis marketplace.","authors":"Wedel, Amelia V; Walters, Kyle J; Tomko, Rachel L; Rojewski, Alana M; McClure, Erin A","year":2025,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 33(2), 78","doi":"10.1007/s00520-024-09131-9","pmid":"39775254","tags":["cancer","racial-disparities","patient-communication","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"No racial differences in cannabis use rates or provider discussions. Black cancer patients who used cannabis reported the greatest comfort discussing it with providers AND the greatest perceived improvement in comfort if cannabis were legalized. Patients who used cannabis were generally more comfortable discussing it than non-users.","whyItMatters":"The assumption that Black patients in prohibition states would be less comfortable discussing cannabis — due to disproportionate legal consequences — was not supported. This suggests clinicians should proactively discuss cannabis with all cancer patients regardless of race, even in states without legal access.","specificNumbers":"1,003 cancer survivors. Mean age 62.36. 13% Black/African-American. 41% male. No racial differences in cannabis use rates. No racial differences in provider discussion rates. Black cannabis users had highest comfort levels discussing with providers.","methodology":"Cross-sectional survey of 1,003 cancer survivors (mean age 62.36, 13% Black/African-American, 41% male) in a state without a legal cannabis marketplace. Weight-adjusted regressions examined racial differences in comfort and discussion of cannabis with providers.","limitations":"Cross-sectional single-state survey. Self-selected participants may be more open about cannabis. Only 13% Black representation. Comfort discussing does not mean discussion actually occurred. State-specific legal context limits generalizability."},{"rthcId":"RTHC-07931","title":"Prevalence of posttraumatic stress disorder (PTSD) in Canada during the COVID-19 pandemic: results from the Survey on COVID-19 and Mental Health.","authors":"Weeks, Murray; Marion, Danielle; Robert, Anne-Marie; Carleton, R Nicholas","year":2025,"journal":"Health promotion and chronic disease prevention in Canada : research, policy and practice, 45(1), 20-38","doi":"10.24095/hpcdp.45.1.02","pmid":"39817709","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07932","title":"Motives for Cannabis Use and Readiness to Change Among Users of the \"Stop-Cannabis\" Mobile App: Cluster Analysis.","authors":"Wegener, Milena; Rothen, Stéphane; Dan-Glauser, Elise; Lecomte, Tania; Potvin, Stéphane; Rochat, Lucien; Sjöblom, Marissa; Vera Cruz, Germano; Etter, Jean-François; Khazaal, Yasser","year":2025,"journal":"JMIR formative research, 9, e70849","doi":"10.2196/70849","pmid":"41042835","tags":["cannabis-use-disorder","mobile-health","cessation","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analysis of Stop-Cannabis app profiles revealed distinct subgroups based on cannabis use motives and readiness to change. Coping-motivated users showed higher rates of problematic use, while recreationally-motivated users showed different patterns of readiness to change. Subgroups differed in their levels of problematic use and engagement with the app.","whyItMatters":"Digital interventions for cannabis use are growing, but one-size-fits-all approaches may miss the mark. Identifying distinct user profiles allows apps to tailor content — coping-motivated users may need mental health support, while recreational users may respond better to motivational approaches.","specificNumbers":"App: Stop-Cannabis (University of Geneva, Switzerland). Profiles analyzed by motives for use and readiness to change. Coping-motivated subgroup had highest problematic use. Distinct clusters emerged with different intervention needs.","methodology":"Cluster analysis of user profiles from the Stop-Cannabis mobile app (Institute of Global Health, University of Geneva). Motives for cannabis use and readiness to change were used as clustering variables, with problematic use explored as an outcome across subgroups.","limitations":"App users are self-selected and may not represent all cannabis users. Cross-sectional — cannot track whether app use led to behavior change. Cluster analysis is exploratory. Specific to one app in a Swiss/French-speaking context."},{"rthcId":"RTHC-07933","title":"The major phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), affect the function of CatSper calcium channels in human sperm.","authors":"Wehrli, Lydia; Altevogt, Hannah; Brenker, Christoph; Zufferey, Fanny; Rossier, Michel F; Strünker, Timo; Nef, Serge; Rahban, Rita","year":2025,"journal":"Human reproduction (Oxford, England), 40(5), 796-807","doi":"10.1093/humrep/deaf020","pmid":"40078063","tags":["reproductive-health","THC","CBD","sperm","fertility"],"studyType":"laboratory-analysis","evidenceStrength":"preliminary","keyFinding":"THC and CBD affected the sperm-specific CatSper calcium channel, suppressing its activation by progesterone (P4) and prostaglandin E1 (PGE1). THC also altered human sperm function in vitro. These effects occurred through direct action on the ion channel rather than through cannabinoid receptors.","whyItMatters":"CatSper is the primary calcium channel driving sperm toward the egg — it's essential for fertilization. If THC and CBD suppress this channel, cannabis use by men trying to conceive could directly impair their fertility at the cellular level.","specificNumbers":"THC and CBD both suppressed CatSper activation by progesterone (P4) and prostaglandin E1 (PGE1). THC altered sperm function in vitro. Effects occurred through direct ion channel action, not cannabinoid receptors.","methodology":"In vitro study testing THC, CBD, and their major metabolites on calcium influx via CatSper channels in human spermatozoa. Calcium signaling measured in response to progesterone and prostaglandin stimulation with and without cannabinoid pre-treatment.","limitations":"In vitro study — lab conditions may not reflect concentrations in reproductive tract after cannabis use. Metabolite effects may differ from parent compounds in vivo. Only acute effects tested. Human studies on fertility outcomes needed."},{"rthcId":"RTHC-07934","title":"Exploring the Link: Marijuana Use Patterns and Their Impact on Coronary Heart Disease Risk.","authors":"Wei, Tianwen; Shen, Shitong; Shan, Tiankai; Wan, Tangjiang; Liang, Yucheng; Lin, Zhihao; Sun, Yuxiao; Li, Yafei; Zhang, Qi","year":2025,"journal":"Clinical cardiology, 48(12), e70223","doi":"10.1002/clc.70223","pmid":"41347515","tags":["cardiovascular","coronary-heart-disease","consumption-methods"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Multiple marijuana consumption methods were associated with increased CHD risk. Combined smoking and vaping showed significantly higher risk. Combined consumption methods, particularly smoking and eating together, further compounded CHD risk. Associations persisted after controlling for demographics and established cardiovascular risk factors.","whyItMatters":"As marijuana use becomes more common and consumption methods diversify, understanding which methods carry the highest cardiovascular risk can inform harm reduction advice for the millions of Americans who use marijuana.","specificNumbers":"2023 BRFSS data. Consumption methods: smoking, vaping, eating, dabbing, and combinations. Combined smoking + vaping: significantly higher CHD risk. Combined smoking + eating: further compounded risk. All associations adjusted for demographic and cardiovascular risk factors.","methodology":"Cross-sectional analysis of 2023 Behavioral Risk Factor Surveillance System (BRFSS) data. Multivariable logistic regression examined associations between marijuana consumption methods (smoking, vaping, eating, dabbing) and coronary heart disease risk, adjusting for demographics and cardiovascular risk factors.","limitations":"Cross-sectional BRFSS data — cannot prove causation. Self-reported marijuana use and CHD diagnosis. Cannot control for all confounders (stress, lifestyle factors). Reverse causation possible (CHD patients may use marijuana for symptom relief)."},{"rthcId":"RTHC-07935","title":"Unraveling Cannabidiol's Dual Modulatory Role in Schizophrenia: Network Pharmacology and In Vivo Validation of Neuroinflammatory and Behavioral Modulation.","authors":"Wei, Ying; Liu, Xiang; Lin, Shijun; Jia, Zhiwei; Liu, Lin; Wang, Baiqiang; Liao, Linchuan; Mei, Xue","year":2025,"journal":"Molecular neurobiology, 63(1), 278","doi":"10.1007/s12035-025-05608-8","pmid":"41369966","tags":["cbd","psychosis","inflammation","anxiety","cognition","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"RTHC-00193 reviewed clinical evidence that CBD may have therapeutic potential for schizophrenia. This study investigates the how—using network pharmacology to predict CBD's targets and then validating those predictions in both cell cultures and a ketamine-induced animal model of schizophrenia.\n\nThe computational analysis (network pharmacology) identified neuroinflammation and 5-HT1A receptor-MAPK signaling as promising pathways. The experimental work confirmed both.\n\nIn cell cultures, CBD significantly reduced pro-inflammatory markers (NO, IL-1β, IL-6, TNF-α) and modulated the serotonin 5-HT1A receptor-MAPK pathway—increasing 5-HT1A receptor expression while decreasing MAPK/ERK1/2 phosphorylation.\n\nIn the animal model, CBD alleviated multiple schizophrenia-like symptoms after just 5 consecutive days of treatment: reduced anxiety (confirmed in two different behavioral tests), improved spatial memory (Y-maze), and improved social behavior. Critically, the researchers validated that CBD's effects depended on the specific 5-HT1AR-MAPK pathway predicted by the network analysis.\n\nThe dual mechanism—anti-inflammatory plus serotonin modulation—is important because schizophrenia involves both neuroinflammation and serotonin dysregulation. A treatment that addresses both simultaneously could be more effective than current antipsychotics, which primarily target dopamine.","whyItMatters":"Current antipsychotics have significant side effects (weight gain, metabolic syndrome, movement disorders) and limited efficacy for negative and cognitive symptoms. CBD's dual mechanism—targeting both inflammation and serotonin signaling—could address dimensions of schizophrenia that current treatments miss, with a potentially better side effect profile.","specificNumbers":"CBD reduced: NO, IL-1β, IL-6, TNF-α (p < 0.05). Increased 5-HT1AR expression, decreased MAPK/ERK1/2 phosphorylation (p < 0.05). Behavioral improvements: anxiety (p < 0.01 in two tests), spatial memory (p < 0.01), social behavior (p < 0.0001). 5 days of treatment.","methodology":"Network pharmacology to predict CBD targets and pathways in schizophrenia. In vitro: CBD (10 mg/kg, i.p.) effects on pro-inflammatory cytokines and 5-HT1AR-MAPK signaling in LPS-induced neuroinflammation model. In vivo: CBD in ketamine-induced schizophrenia model in animals; behavioral tests (open field, elevated plus maze, Y-maze, social interaction) after 5 days of treatment.","limitations":"Animal model of schizophrenia (ketamine-induced) is a simplified approximation of a complex human disease. Network pharmacology predicts but doesn't prove mechanism in humans. The 5-day treatment period is very short compared to the chronic treatment schizophrenia requires. CBD dose used may not be achievable orally in humans due to bioavailability issues. In vitro and in vivo doses may not translate to human therapeutic ranges."},{"rthcId":"RTHC-07936","title":"Combination CBD/THC in the management of chemotherapy-induced peripheral neuropathy: a randomized double blind controlled trial.","authors":"Weiss, Marisa; Giaddui, Muath; Kjelstrom, Stephanie; Gary, Joseph; Ward, Sara Jane; Burrell, Jessica; Diguilio, Katherine; Bidas, Gabrielle; Erebor, Ebuwa; Meske, Sam; Saeed, Lisa; Windawi, Sarah; Aliano Ruiz, Katherine; Ghaneie, Arezoo; Hibbs, Julianne; Marks, John; Holtz, David; Ali, Zonera; Shevade, Aarthi; Sabol, Jennifer; Ciocca, Robin; Zeger, Eric; Gilman, Paul; Larson, Sharon; Shimamoto, Shoichi; Martinez, Diana","year":2025,"journal":"Frontiers in oncology, 15, 1590168","doi":"10.3389/fonc.2025.1590168","pmid":"41211445","tags":["CBD","THC","chemotherapy","neuropathy","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"The active group receiving CBD (125.3–135.9 mg) combined with THC (6.0–10.8 mg) in gelcaps did not show statistically significant improvement on the primary outcome (QLQ-CIPN20 sensory subscale) compared to placebo over 12 weeks, though some secondary endpoints suggested potential trends.","whyItMatters":"This is one of the first rigorous RCTs testing cannabinoids for CIPN. While the negative primary result is disappointing, it provides crucial evidence to temper enthusiasm from smaller, uncontrolled studies and helps define where future research should focus.","specificNumbers":"12-week double-blind RCT. Active: CBD 125.3–135.9 mg + THC 6.0–10.8 mg in gelcaps. Cancer types: breast, colorectal, endometrial, ovarian. CIPN grade 2–3. Primary outcome (CIPN20 sensory): not significantly different from placebo.","methodology":"12-week randomized, double-blind, placebo-controlled trial in patients with nonmetastatic breast, colorectal, endometrial, or ovarian cancer experiencing grade 2–3 CIPN from taxane- or platinum-based chemotherapy. Active arm received CBD (125.3–135.9 mg) + THC (6.0–10.8 mg) in gelcaps. Primary outcome: QLQ-CIPN20 sensory subscale.","limitations":"Specific formulation and dose may not represent optimal cannabinoid therapy for CIPN. Duration (12 weeks) may be insufficient. Grade 2–3 CIPN may be harder to treat than earlier stages. Sample characteristics not fully described in abstract."},{"rthcId":"RTHC-07937","title":"Cannabidiol does not cause DNA double-strand breaks in a human liver-derived cell model.","authors":"Weiss, Romano; Liedtke, Victoria; Rödiger, Stefan","year":2025,"journal":"Journal of cannabis research, 8(1), 12","doi":"10.1186/s42238-025-00365-w","pmid":"41382174","tags":["CBD","safety","DNA-damage","liver"],"studyType":"laboratory-analysis","evidenceStrength":"preliminary","keyFinding":"CBD (5–50 μM, 3–72h incubation) did not induce DNA double-strand breaks in HepG2 cells. The study also investigated CB1/CB2 receptor expression balance in HepG2 cells, providing context for understanding CBD's interactions with liver cells. Results counter previous reports of CBD-induced genotoxicity in liver cell lines.","whyItMatters":"Previous studies raised concerns that CBD might damage DNA in liver cells at low concentrations, potentially limiting its therapeutic applications. This study provides reassuring evidence that CBD does not cause the most dangerous form of DNA damage (double-strand breaks) in a relevant liver cell model.","specificNumbers":"CBD concentrations: 5–50 μM. Incubation: 3–72 hours. Cell line: HepG2 (human liver-derived). No DNA double-strand breaks detected at any concentration or time point.","methodology":"HepG2 human liver-derived cells treated with CBD at 5–50 μM for 3–72 hours. DNA double-strand breaks assessed alongside CB1/CB2 cannabinoid receptor expression analysis and cell proliferation measurements.","limitations":"Single cell line (HepG2) may not represent all liver cell types. In vitro conditions differ from in vivo metabolism. Only assessed double-strand breaks — other forms of DNA damage not tested. Does not address long-term cumulative exposure. Discrepancy with previous studies needs further investigation."},{"rthcId":"RTHC-07938","title":"Over the counter CBD products in Germany: an exploratory survey about consumption patterns and health related effects.","authors":"Weissgerber, Anaelle; Hermanns-Clausen, Maren; Lamy, Evelyn","year":2025,"journal":"Frontiers in pharmacology, 16, 1571025","doi":"10.3389/fphar.2025.1571025","pmid":"40469987","tags":["CBD","consumer-survey","Germany","health-effects"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"208 CBD consumers in Germany participated. The population was predominantly female (66%), aged 41–60 (46%), and chronic users (>3 months, at least daily). The principal mode was oil (36%). Consumers reported various health-promoting and therapeutic effects, with reasons for use spanning pain, sleep, anxiety, and general wellness.","whyItMatters":"Over-the-counter CBD is a massive and growing market, but consumer data about who is using it, why, and what effects they experience is surprisingly sparse. This German survey provides real-world consumer insights that can inform regulatory and clinical guidance.","specificNumbers":"208 participants. 66% female. 46% aged 41–60. Chronic users (>3 months, daily minimum). Primary route: oil (36%). Recruited Feb–June 2023 via social media. Health-promoting effects reported by majority.","methodology":"Explorative retrospective online survey accessible February–June 2023 via SoSci-Survey. Participants (n=208) recruited mainly through social internet platforms. Assessed reasons for consumption, health-promoting or therapeutic effects, and adverse effects.","limitations":"Self-selected online sample recruited via social media — significant selection bias toward engaged CBD advocates. Small sample (n=208). Retrospective self-report of health effects. No verification of product contents or quality. German market context may differ from other countries."},{"rthcId":"RTHC-07939","title":"Adapting and applying tobacco dependence indicators to cannabis dependence.","authors":"Wellman, Robert J; Strong, David R; O'Loughlin, Erin K; Sylvestre, Marie-Pierre; O'Loughlin, Jennifer L","year":2025,"journal":"Drug and alcohol dependence, 270, 112613","doi":"10.1016/j.drugalcdep.2025.112613","pmid":"40014906","tags":["cannabis-use-disorder","dependence","measurement","tobacco"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The adapted 15-item cannabis dependence scale showed good factor structure and measurement invariance across sex. Items demonstrated varying discriminative power for different levels of dependence. The scale enables standardized comparison of dependence across tobacco and cannabis — previously impossible due to substance-specific measures.","whyItMatters":"As tobacco and cannabis co-use increases, clinicians need comparable measures of dependence for both. This adapted scale fills a critical gap, enabling research on whether interventions effective for tobacco dependence could be applied to cannabis.","specificNumbers":"320 participants, mean age 35. 15-item adapted scale. Good factor structure confirmed. Measurement invariance across sex established. 24-year longitudinal study context. Items varied in discriminative power across dependence levels.","methodology":"320 past-year cannabis consumers (mean age 35) from a 24-year longitudinal study completed the adapted 15-item scale in 2024. Factor structure, measurement invariance across sex, item response characteristics (endorsement likelihood and discriminative power), and internal reliability were examined.","limitations":"Single sample from a longitudinal study — may not represent all cannabis users. Adaptation from tobacco measures may miss cannabis-specific dependence features. Self-report only. Cross-sectional validation — longitudinal predictive validity not yet tested."},{"rthcId":"RTHC-07940","title":"Trends in treatment attendance for substance use disorders among adolescents and emerging adults in Australia, 2003-2020.","authors":"Wells, Megan; Kelly, Peter J; Larance, Briony","year":2025,"journal":"Drug and alcohol dependence, 275, 112845","doi":"10.1016/j.drugalcdep.2025.112845","pmid":"40882440","tags":["adolescents","treatment","epidemiology","Australia"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Cannabis was the most common principal substance of concern for adolescents (ages 10–17) and emerging adults (ages 18–24) across the entire 2003–2020 period. Joinpoint regression revealed trends in treatment settings, planned completion rates, and sex distribution over time.","whyItMatters":"Despite alcohol being a bigger overall public health problem, cannabis drives more treatment episodes among young Australians than any other substance. Understanding trends in cannabis-related treatment seeking helps health systems plan services for the population that needs them most.","specificNumbers":"2,904,012 treatment episodes analyzed. 2003–2020 timeframe. Cannabis: most common principal substance for ages 10–17 and 18–24. Treatment settings, completion, and sex trends examined via joinpoint regression.","methodology":"Analysis of the Australian Alcohol and Other Drug Treatment Services National Minimum Data Set (N=2,904,012 episodes). Joinpoint regression characterized trends in principal substance, treatment setting, planned completion, and sex among adolescents (10–17), emerging adults (18–24), and adults (25+).","limitations":"Administrative treatment data — reflects who seeks treatment, not total population need. Australian-specific context (different cannabis policy than US). Treatment episodes, not individuals (some people appear multiple times). Cannot capture untreated cannabis problems."},{"rthcId":"RTHC-07941","title":"Pharmacokinetics of cannabidiol and its two main phase I metabolites in Connemara ponies.","authors":"Wermer, Kata; Korbacska-Kutasi, Orsolya; Berkecz, Róbert; Csupor, Dezső; Ágh, Nóra; Sztojkov-Ivanov, Anita; Cserhalmi, Dániel","year":2025,"journal":"Frontiers in veterinary science, 12, 1599934","doi":"10.3389/fvets.2025.1599934","pmid":"40654508","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07942","title":"Effects of Phytocannabinoids on Reproductive System and Prenatal Development: Mechanisms and Clinical Implications.","authors":"Wesołowski, Michał; Sobaś, Aleksandra; Biedka, Kamil; Karwacki, Jakub; Bulski, Jakub; Błaszczyk, Katarzyna; Żełabowski, Kacper; Ziobro, Oliwia; Maj, Filip Jacek; Sornat, Karol; Estreicher, Agata; Klasa, Anna; Dłubak, Andrzej; Sebzda, Tadeusz","year":2025,"journal":"Journal of clinical medicine, 14(18)","doi":"10.3390/jcm14186494","pmid":"41010698","tags":["pregnancy","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review maps how cannabinoids interact with the reproductive system from conception through birth, covering territory that's usually examined in separate studies.\n\nFor men: cannabinoids interfere with spermatogenesis, reduce sperm motility and quality, and lower testosterone levels. These effects have been demonstrated in both clinical and experimental studies. For couples trying to conceive, this means cannabis use by either partner could affect fertility.\n\nFor women: cannabinoid-induced disruptions include negative effects on ovarian follicle maturation, ovulation, and placental function. The placental effects are particularly concerning because the placenta is the fetus's lifeline—disrupting its function can affect nutrient and oxygen delivery.\n\nFor fetal development: prenatal cannabis exposure is associated with reduced birth weight, preterm delivery, and developmental effects that can extend into childhood. These findings align with RTHC-00209's review specifically on neonatal outcomes.\n\nThe review emphasizes that the endocannabinoid system plays critical regulatory roles at every stage of reproduction—from sperm development through embryo implantation through placental formation through fetal brain development. Introducing exogenous cannabinoids disrupts a system that needs to function precisely during these processes.","whyItMatters":"Most reproductive cannabis research focuses on either male fertility, pregnancy outcomes, or fetal development in isolation. This review connects the entire reproductive arc, showing that cannabis doesn't just affect one stage—it can disrupt the process at every point from conception through delivery. For couples planning families, this comprehensive picture is more informative than any single study.","specificNumbers":"64 studies reviewed. Male effects: reduced spermatogenesis, sperm motility, sperm quality, and testosterone. Female effects: disrupted follicle maturation, ovulation, and placental function. Fetal effects: reduced birth weight, increased preterm risk, developmental impacts.","methodology":"Non-systematic narrative review. Searched PubMed, Scopus, Web of Science, and Google Scholar in November 2024. After screening, 64 studies included covering cannabis effects on male fertility, female reproductive system, placental function, and prenatal/postnatal outcomes.","limitations":"Narrative review with non-systematic search—may miss relevant studies. The 64 included studies vary widely in quality, methodology, and populations. Much of the evidence on fertility effects comes from animal studies or in vitro work. Human reproductive studies are confounded by polysubstance use, socioeconomic factors, and self-reported cannabis use. The review covers a very broad scope, limiting depth on any single topic."},{"rthcId":"RTHC-07943","title":"Influence of Carrier Oil, Sex, and Age on Pharmacokinetic and Acute Behavioral Effects of Vaporized Cannabis Extract in Mice.","authors":"Westbrook, Sara R; Jensen, Allison L; Copeland-Solorzano, Vanessa; Buursma, Jacob; Freeby, Gillian; von Melville, Taytum; Edwards, Tyler; Cuttler, Carrie; Hayashi, Kanako; McLaughlin, Ryan; Delevich, Kristen M","year":2025,"journal":"Cannabis and cannabinoid research, 10(6), 673-690","doi":"10.1177/25785125251372062","pmid":"40929020","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07944","title":"Assessing barriers to community engagement on cannabis policy: baseline survey of behavioral and public health professionals in California.","authors":"Whitacre, Ryan; Padon, Alisa; Simard, Bethany; Silver, Lynn","year":2025,"journal":"Translational behavioral medicine, 15(1)","doi":"10.1093/tbm/ibaf077","pmid":"41338584","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07945","title":"Perceptions and patterns of Cannabis use in emergency department patients following recreational legalization in Massachusetts.","authors":"Whitledge, James D; Ganetsky, Michael; Burke Mph, Ryan C; Boyle, Katherine L","year":2025,"journal":"The American journal of emergency medicine, 94, 31-36","doi":"10.1016/j.ajem.2025.04.033","pmid":"40273635","tags":["emergency-department","legalization","consumption-patterns"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was common among ED patients post-legalization, with diverse use patterns including various consumption methods and concomitant substance use. Patients and treating physicians showed discordance when asked whether the ED visit was attributable to cannabis, revealing a gap in patient-provider perception.","whyItMatters":"The patient-physician disagreement about cannabis's role in ED visits highlights that both parties may have blind spots — patients may underattribute symptoms to cannabis, while physicians may overattribute. Better clinical tools for assessing cannabis-related presentations are needed.","specificNumbers":"Massachusetts post-legalization (2016). Academic medical center ED. Past-month cannabis users surveyed. Patient-physician discordance on cannabis attribution documented. Diverse consumption patterns and concomitant substance use reported.","methodology":"Convenience sample survey at an academic medical center ED in Massachusetts. Patients aged 18+ reporting past-month cannabis use were surveyed about use patterns, perceived risks and benefits, concomitant substance use, and post-legalization changes. Both patients and treating physicians were asked about cannabis attribution to the ED visit.","limitations":"Convenience sample — not all cannabis-using ED patients captured. Single academic center in Massachusetts. Survey timing relative to clinical status may affect responses. Cannot determine actual cannabis contribution to visits objectively."},{"rthcId":"RTHC-07946","title":"Brief report: Are changes in cannabis use frequency associated with changes in alcohol use and smoking among people with HIV (PWH) - A substitution question.","authors":"Whitney, Bridget M; Delaney, Joseph A C; Drumright, Lydia N; Nance, Robin M; Fredericksen, Rob J; Chander, Geetanjali; Cachay, Edward R; Fox, Nathaniel T; Christopoulos, Katerina A; Cropsey, Karen L; Owens, Michael A; Burkholder, Greer A; Mayer, Kenneth H; McCaul, Mary E; Napravnik, Sonia; O'Cleirigh, Conall; Webel, Allison R; Yendewa, George A; Saag, Michael S; Kitahata, Mari M; Crane, Heidi M; Hahn, Andrew W","year":2025,"journal":"Drug and alcohol dependence, 277, 112958","doi":"10.1016/j.drugalcdep.2025.112958","pmid":"41260023","tags":["HIV","alcohol","tobacco","substitution","harm-reduction"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Among people with HIV, increasing cannabis use (initiation or increased frequency) was not associated with subsequent decreases in alcohol or tobacco use. Similarly, decreasing cannabis use was not associated with subsequent increases in alcohol or tobacco use. The harm reduction-based substitution hypothesis was not supported in this population.","whyItMatters":"The cannabis substitution hypothesis — that increasing cannabis use reduces more harmful alcohol or tobacco use — is often used to justify cannabis use, especially for medical purposes. This study finds no evidence for this effect in people living with HIV, an important population where substance use affects treatment outcomes.","specificNumbers":"CNICS HIV cohort, 2009–2023. Two trajectories analyzed: increasing cannabis use (initiation + increased frequency) and decreasing cannabis use (abstinence + reduced frequency). Neither direction of change predicted opposite changes in alcohol or tobacco use.","methodology":"Longitudinal analysis from the CNICS cohort (Centers for AIDS Research Network of Integrated Clinical Systems) between 2009 and 2023. Time-updated multivariable linear mixed models and joint longitudinal trajectory analysis examined associations between changes in cannabis use frequency and subsequent alcohol and tobacco use.","limitations":"HIV-specific cohort — findings may not generalize to general population. Self-reported substance use. Cannot capture nuances of use (e.g., heavy vs. moderate). Observational — unmeasured confounders possible. CNICS participants may differ from all people with HIV."},{"rthcId":"RTHC-07947","title":"Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 Supplementation: An Exploratory, Randomized, Placebo-Controlled Trial of Endocannabinoid and Inflammatory Responses in Female Dancers.","authors":"Wiącek, Jakub; Skonieczna-Żydecka, Karolina; Łoniewski, Igor; Deli, Chariklia K; Fatouros, Ioannis G; Jamurtas, Athanasios Z; Moszczyńska, Dominika; Karolkiewicz, Joanna","year":2025,"journal":"Microorganisms, 13(6)","doi":"10.3390/microorganisms13061284","pmid":"40572172","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07948","title":"Behavioral addictions and their reciprocal associations with each other, substance use disorders, and mental health problems: Findings from a longitudinal cohort study of young Swiss men.","authors":"Wicki, Matthias; Studer, Joseph; Marmet, Simon; Khazaal, Yasser; Gmel, Gerhard","year":2025,"journal":"Journal of behavioral addictions, 14(3), 1250-1266","doi":"10.1556/2006.2025.00078","pmid":"40952791","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07949","title":"Antibacterial Effect of Cannabinoids on Bacteria Associated with Persistent Endodontic Infections.","authors":"Wieczerza, Cassandra; Zhai, Haoyan; Askar, Mazin; Zhou, Zheng; Paurazas, Susan","year":2025,"journal":"International journal of molecular sciences, 26(24)","doi":"10.3390/ijms262411936","pmid":"41465362","tags":["CBD","THC","antibacterial","dental","endodontics"],"studyType":"laboratory-analysis","evidenceStrength":"preliminary","keyFinding":"CBD, CBN, and THC showed antibacterial efficacy against E. faecalis, S. mutans, and F. nucleatum — bacteria central to persistent endodontic infections. Both planktonic bacteria and biofilms were affected. Minimum inhibitory and bactericidal concentrations were determined for each cannabinoid-bacteria combination.","whyItMatters":"Root canal treatment failures are often caused by bacteria that resist standard medicaments and form protective biofilms. With growing antibiotic resistance, cannabinoids could offer an entirely new class of antimicrobial agents for dental infections.","specificNumbers":"Three cannabinoids tested: CBD, CBN, THC. Three bacteria: E. faecalis, S. mutans, F. nucleatum. Positive control: 3% sodium hypochlorite. Both planktonic and biofilm forms tested. MIC and MBC determined for each combination.","methodology":"In vitro testing of CBD, CBN, and THC against planktonic bacteria and biofilms of E. faecalis, S. mutans, and F. nucleatum (key endodontic pathogens). Negative control (no exposure), positive control (3% NaOCl), and experimental cannabinoid groups. MIC and MBC determined.","limitations":"In vitro study — conditions differ from the root canal environment. Concentrations achievable in root canals during treatment unknown. Comparison to standard endodontic medicaments limited to NaOCl. No human clinical testing. Biofilm penetration in complex canal anatomy untested."},{"rthcId":"RTHC-07950","title":"Neurodevelopmental effects of exogenous cannabinoids on endocannabinoid and GABAergic neurotransmission.","authors":"Wiley, Miles T; Courville, Adrian H; Northcutt, Hayden; Durdanovic, Iva; Chowdhury, Kawsar U; Suppiramaniam, Vishnu; Reed, Miranda N","year":2025,"journal":"Neurotoxicology and teratology, 112, 107568","doi":"10.1016/j.ntt.2025.107568","pmid":"41270934","tags":["pregnancy","neuroscience","cognition","mental-health"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review presents a fascinating and underappreciated mechanism by which prenatal cannabis could affect brain development: the GABA switch.\n\nHere's the background: during early brain development, GABA—which becomes the brain's primary inhibitory neurotransmitter in adults—actually functions as an excitatory signal. This seems counterintuitive, but it's essential: excitatory GABA drives critical developmental processes including neuron proliferation, migration, and circuit formation. At a specific developmental timepoint, GABA switches from excitatory to inhibitory. This switch is precisely timed and essential for normal brain maturation.\n\nThe review's central finding: exposure to exogenous cannabinoids (like THC) can delay this GABA switch. Because THC crosses the placenta and interacts with the endocannabinoid system—which modulates GABA signaling—it disrupts the timing of a process that needs to happen at exactly the right moment.\n\nThe consequences of a delayed GABA switch could be far-reaching. If GABA remains excitatory too long, neurons may proliferate or migrate incorrectly, circuits may wire abnormally, and the foundation for later cognitive and emotional function may be compromised. The review connects this mechanism to the clinical observations of hyperactivity, attention issues, anxiety, depression, and reduced cognitive abilities documented in children exposed to cannabis prenatally.","whyItMatters":"The delayed GABA switch mechanism could explain a wide range of neurodevelopmental effects attributed to prenatal cannabis exposure. Rather than cannabis simply being 'toxic' to the developing brain, it may be disrupting the precise timing of a normal developmental process—which is potentially even more consequential because it affects the foundation on which all subsequent brain development is built.","specificNumbers":"Cannabis is the most commonly used illicit drug during pregnancy. THC crosses the placenta and affects the fetal endocannabinoid system. Prenatal exposure linked to: hyperactivity, attention issues, anxiety, depression, reduced cognitive abilities. GABA transition from excitatory to inhibitory is a critical developmental switch.","methodology":"Narrative review synthesizing evidence on the effects of exogenous cannabinoids on the endocannabinoid and GABAergic systems during neurodevelopment. Focuses on the developmental GABA excitatory-to-inhibitory switch and the consequences of its disruption.","limitations":"Much of the GABA switch evidence comes from animal models and in vitro studies. The exact timing and mechanism of the GABA transition vary across brain regions and species. Whether THC exposure at typical human doses is sufficient to delay the switch is uncertain. The review doesn't quantify how much delay in the GABA switch is clinically meaningful. Narrative review format is subject to selection bias."},{"rthcId":"RTHC-07951","title":"Pain predicts past-month co-use of alcohol and cannabis among emerging adults: Results from the Population Assessment of Tobacco and Health (PATH) Study.","authors":"Williams, Callon M; Mastroleo, Nadine R; Lenzenweger, Mark F; Zale, Emily L","year":2025,"journal":"Alcohol (Fayetteville, N.Y.), 124, 111-119","doi":"10.1016/j.alcohol.2025.02.003","pmid":"40015463","tags":["pain","alcohol","co-use","young-adults","epidemiology"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Moderate/severe pain at baseline prospectively predicted engaging in co-use of alcohol and cannabis among emerging adults aged 18–24. The association persisted after adjusting for demographics and other risk factors. Sex was examined as a potential moderator.","whyItMatters":"Alcohol and cannabis co-use is particularly risky — people who combine them use more of each and experience greater harm. If pain is driving this co-use pattern in young adults, pain management could be a key intervention point for preventing dual-substance problems.","specificNumbers":"3,544 emerging adults from PATH study. Ages 18–24. 5 waves of data. Moderate/severe pain predicted alcohol-cannabis co-use prospectively. Co-users experience greater substance-related harm than single-substance users.","methodology":"Longitudinal analysis of Waves 1–5 of the Population Assessment of Tobacco and Health (PATH) Study (n=3,544 emerging adults aged 18–24). Unadjusted and adjusted logistic regression examined moderate/severe pain as a predictor of subsequent alcohol-cannabis co-use. Sex tested as moderator.","limitations":"PATH data is self-reported. Pain and substance use assessed at intervals — timing of onset may be imprecise. Cannot determine if pain management (successful or failed) moderates the relationship. Co-use definition may vary."},{"rthcId":"RTHC-07952","title":"Pain Predicts Cannabis Initiation Among Emerging Adults: Results from the Population Assessment of Tobacco and Health (PATH) Study.","authors":"Williams, Callon M; Mastroleo, Nadine R; Lenzenweger, Mark F; Zale, Emily L","year":2025,"journal":"Behavioral medicine (Washington, D.C.), 51(3), 254-263","doi":"10.1080/08964289.2025.2465525","pmid":"40009033","tags":["pain","cannabis-initiation","young-adults","epidemiology"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Among 4,185 emerging adults who denied cannabis use at baseline, moderate/severe pain (reported by about 10%) prospectively predicted cannabis initiation across five annual waves. This is the first study to establish pain as a predictor of cannabis initiation (not just increased use) in emerging adults.","whyItMatters":"Understanding why people start using cannabis is key to prevention. If pain drives cannabis initiation in young adults, improving pain management could prevent cannabis use and its associated risks in this vulnerable population.","specificNumbers":"4,185 cannabis-naïve emerging adults. 5 annual waves from PATH study. ~10% reported moderate/severe pain at baseline. Pain significantly predicted subsequent cannabis initiation. First prospective study of pain → cannabis initiation.","methodology":"Longitudinal analysis of Waves 1–5 of the Population Assessment of Tobacco and Health (PATH) Study. 4,185 cannabis-naïve emerging adults (ages 18–25) tracked annually. Logistic regression assessed whether baseline moderate/severe pain predicted subsequent cannabis initiation.","limitations":"Self-reported pain and cannabis use. Cannot determine if pain led to cannabis through self-medication or shared risk factors. Five annual waves may miss short-term patterns. Cannabis initiation is broadly defined."},{"rthcId":"RTHC-07953","title":"Diagnosis and management of cannabis-related emergencies.","authors":"Williams, Mollie V; Byerrum, Reese C","year":2025,"journal":"Emergency medicine practice, 27(12), 1-24","doi":null,"pmid":"41252646","tags":["emergency-medicine","acute-intoxication","synthetic-cannabinoids","clinical-management"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Emergency departments are seeing increasing cannabis-related visits; management differs significantly between natural cannabis and synthetic cannabinoid presentations, with synthetic products carrying higher risk of severe outcomes.","whyItMatters":"As cannabis use rises, ER visits for cannabis-related symptoms are climbing. Clinicians need clear guidance on distinguishing between natural and synthetic cannabinoid emergencies, which require different treatment approaches.","specificNumbers":"No specific sample size — this is a clinical review synthesizing existing evidence on cannabis emergency presentations.","methodology":"Narrative review of current literature on cannabinoid pathophysiology, clinical presentations, and evidence-based management strategies for acute cannabis-related emergencies.","limitations":"As a narrative review, this does not include systematic evidence grading. Management recommendations may evolve as more clinical data accumulates."},{"rthcId":"RTHC-07954","title":"A proof-of-concept study examining a health communication intervention to reduce cannabis misuse among college students.","authors":"Willoughby, Jessica Fitts; Hust, Stacey J T; Couto, Leticia; Price, Ron; Johnson, Opeyemi; Nickerson, Christina Griselda; Oladele, Pearl; Gray, Marie; Maykovich, Bailey","year":2025,"journal":"Journal of American college health : J of ACH, 73(9), 3312-3315","doi":"10.1080/07448481.2024.2418527","pmid":"39514798","tags":["college-students","health-communication","intervention","cannabis-misuse","harm-reduction"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"The intervention, voiced by a cannabis marketing professional, effectively shifted student attitudes and intentions around cannabis misuse in a pre/post-test design with 64 participants.","whyItMatters":"College students face unique cannabis risks as legalization expands. Finding effective, scalable communication strategies that resonate with young adults could reduce misuse without relying on prohibition-era messaging.","specificNumbers":"N = 64 college students participated in the proof-of-concept study at one Washington state university.","methodology":"Proof-of-concept pretest/post-test lab experiment with 64 college students at a Washington state university testing a technology-delivered health communication intervention.","limitations":"Very small sample from a single university, no control group, pre/post design without long-term follow-up, and conducted in a legal-cannabis state which may limit generalizability."},{"rthcId":"RTHC-07955","title":"Transcriptomic changes in oxidative stress, immunity, and cancer pathways caused by cannabis vapor on alveolar epithelial cells.","authors":"Wilson, Emily T; Graham, Percival; Eidelman, David H; Baglole, Carolyn J","year":2025,"journal":"Cell biology and toxicology, 41(1), 57","doi":"10.1007/s10565-025-09997-3","pmid":"40056285","tags":["cancer","inflammation","respiratory"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Many people switch from smoking to vaping cannabis believing it's safer. This study tested that assumption directly by exposing human alveolar (lung) epithelial cells to cannabis vapor and analyzing which genes turned on or off.\n\nThe researchers developed a physiologically relevant exposure method using A549 lung cells maintained at an air-liquid interface (ALI)—a setup that more closely mimics actual lung tissue than traditional cell cultures submerged in liquid. They compared three exposure models of increasing sophistication.\n\nThe findings were concerning. Cannabis vapor significantly altered gene expression in pathways related to cancer, oxidative stress, and immune response. These aren't random genes—they're pathways directly relevant to lung disease development.\n\nA particularly notable finding: the cancer and inflammatory pathway activation occurred without an associated DNA damage response. This distinguishes cannabis vapor from cigarette smoke (which causes direct DNA damage) and suggests a different harm mechanism—one that may promote cancer through inflammatory and oxidative pathways rather than through genetic mutations. Whether this makes cannabis vapor more or less dangerous than cigarette smoke long-term is an open question, but it is clearly not harmless.\n\nThe ALI-maintained cells showed higher expression of type 2 alveolar epithelial cell markers (surfactant production, ion transport, barrier integrity) at baseline, confirming the model's physiological relevance.","whyItMatters":"Cannabis vaping is the fastest-growing method of consumption, particularly among young adults. The assumption that vaping is \"safer than smoking\" may be true for some metrics but this study shows vaporized cannabis is not biologically inert—it activates cellular pathways directly linked to cancer, inflammation, and oxidative damage in the exact cell type (alveolar epithelial) that lines the lungs.","specificNumbers":"Cannabis vapor activated gene pathways for: cancer, oxidative stress, immune response. Did NOT activate DNA damage response pathways. ALI-maintained cells showed higher AEC2 marker expression. Three exposure models compared for transcriptional response.","methodology":"In vitro study using A549 human alveolar epithelial cells in three culture conditions: submerged, pseudo-air-liquid interface (ALI), and ALI with the expoCube advanced exposure system. Acute cannabis vapor exposure. Transcriptomic analysis (gene expression profiling) of exposed vs. control cells.","limitations":"In vitro study using a cancer cell line (A549)—not primary human lung cells. Acute exposure may not capture chronic vaping effects. The specific cannabis product composition (THC%, terpenes, carrier liquids) isn't detailed and could affect results. No comparison to tobacco smoke or other aerosols. Gene expression changes don't necessarily translate to disease outcomes. The expoCube system, while advanced, still doesn't fully replicate in vivo pulmonary exposure."},{"rthcId":"RTHC-07956","title":"Understanding African American/Black and Latine young and emerging adults living with HIV: a sequential explanatory mixed methods study focused on self-regulatory resources.","authors":"Wilton, Leo; Gwadz, Marya; Cleland, Charles M; Campos, Stephanie; Munson, Michelle R; Dorsen, Caroline; Serrano, Samantha; Sherpa, Dawa; Saba, Shaddy K; Rosmarin-DeStefano, Corey; Filippone, Prema","year":2025,"journal":"International journal for equity in health, 24(1), 120","doi":"10.1186/s12939-025-02492-5","pmid":"40325383","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07957","title":"Exposure to cannabis marketing in the United States and differences by cannabis laws: Findings from the International Cannabis Policy Study.","authors":"Winfield-Ward, Lauren; Wadsworth, Elle; Driezen, Pete; Rynard, Vicki L; Hammond, David","year":2025,"journal":"Drug and alcohol dependence, 274, 112787","doi":"10.1016/j.drugalcdep.2025.112787","pmid":"40683012","tags":["cannabis-marketing","policy","legalization","exposure","population-study"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis marketing exposure was substantially higher in recreational-legal states compared to medical-only and illegal states, with differences across multiple marketing channels.","whyItMatters":"Cannabis marketing shapes public perception and use patterns. Understanding how legalization status affects marketing exposure helps policymakers craft regulations that balance commercial interests with public health.","specificNumbers":"187,573 respondents across US states categorized by cannabis legal status — illegal, medical-only, and recreational.","methodology":"National repeat cross-sectional survey data from the International Cannabis Policy Study, analyzing marketing exposure across US states with different cannabis legal frameworks (187,573 respondents).","limitations":"Cross-sectional design cannot establish causation. Self-reported marketing exposure may undercount passive exposure. State categories are broad and don't capture local variation in enforcement."},{"rthcId":"RTHC-07958","title":"Placebo effects in a RCT assessing 30 days of low dose Cannabidiol (CBD) treatment for psychological distress in stressed students at risk for depression.","authors":"Winkler, Alexander; Meis, Annelie C; Hermann, Christiane","year":2025,"journal":"Journal of cannabis research, 7(1), 98","doi":"10.1186/s42238-025-00366-9","pmid":"41316488","tags":["cbd","placebo-effect","rct","psychological-distress","stress"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Both CBD and placebo oil groups showed improvements over the no-treatment control, suggesting that expectation and the ritual of taking a substance contribute significantly to perceived CBD benefits for stress.","whyItMatters":"CBD products are widely marketed for stress relief, but this study suggests the act of taking something — rather than CBD itself — may drive much of the benefit. This has major implications for consumer expectations and regulatory claims.","specificNumbers":"30-day trial with three groups: CBD oil (10% full-spectrum), placebo oil, and no-treatment control. Registered as DRKS00030971.","methodology":"Three-arm randomized controlled trial comparing 30 days of daily sublingual low-dose (10%) full-spectrum CBD oil vs. placebo oil vs. no-treatment control in stressed university students.","limitations":"Low dose may have been insufficient for pharmacological effect. Student sample limits generalizability. 30-day duration may not capture longer-term effects."},{"rthcId":"RTHC-07959","title":"Cannabidiol Is a Potential Inhibitor of Ferroptosis in Human Articular Chondrocytes.","authors":"Wipplinger, A; Bekric, D; Ablinger, C; Kittl, M; Mayr, C; Ritter, M; Winklmayr, M; Jakab, M","year":2025,"journal":"Journal of cellular and molecular medicine, 29(13), e70592","doi":"10.1111/jcmm.70592","pmid":"40576283","tags":["cbd","ferroptosis","chondrocytes","osteoarthritis","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD protected human articular chondrocytes from ferroptosis induced by multiple known inducers (RSL3, erastin, IKE, FINO2, FIN56), with varying effects across different cell lines and primary cells.","whyItMatters":"Ferroptosis in cartilage cells contributes to osteoarthritis progression. If CBD can inhibit this process, it could represent a novel mechanism for joint health beyond simple anti-inflammatory effects.","specificNumbers":"Tested in two cell lines (C-28/I2 and T/C-28/A2) plus primary human chondrocytes using five different ferroptosis inducers.","methodology":"In vitro study exposing two chondrocyte cell lines (C-28/I2, T/C-28/A2) and primary human chondrocytes to ferroptosis inducers with and without CBD treatment, measuring cell viability and defense mechanisms.","limitations":"Cell culture study only — effects in living joints may differ dramatically. CBD concentrations used may not reflect achievable tissue levels. No animal model validation."},{"rthcId":"RTHC-07960","title":"Long-term use of cannabis-based medicines in two children with Tourette syndrome: a case report.","authors":"Woerner, Lara-Katharina; Szejko, Natalia; Fremer, Carolin; Schmitt, Simon; Müller Vahl, Kirsten R","year":2025,"journal":"Frontiers in psychiatry, 16, 1647969","doi":"10.3389/fpsyt.2025.1647969","pmid":"41113190","tags":["tourette-syndrome","pediatric","cannabis-medicine","long-term","case-report","tics"],"studyType":"clinical-observation","evidenceStrength":"preliminary","keyFinding":"Long-term cannabis-based medicine use in two children with Tourette syndrome starting at ages 8 and 12 provided sustained benefit, representing rare pediatric long-term follow-up data.","whyItMatters":"Cannabis-based medicine is recommended for treatment-resistant adult Tourette syndrome, but virtually no long-term data exists for children. These cases help fill a critical evidence gap for pediatric use.","specificNumbers":"2 patients followed for 5 and 6 years respectively, starting cannabis-based medicine at ages 8 and 12.","methodology":"Case report following two male adolescents with treatment-resistant Tourette syndrome over five and six years of cannabis-based medicine use, initiated at ages 8 and 12.","limitations":"Only two patients — cannot generalize. Case reports lack controls and are subject to bias. Long-term neurodevelopmental outcomes would require larger, controlled studies."},{"rthcId":"RTHC-07961","title":"Comparison of Laboratory Confirmed Drugs in Acute Recreational Drug Toxicity Presentations to an Urban Hospital in London, UK, 2016/17 versus 2019/20.","authors":"Wolfe, Caitlin E; Sund, Lachlan J; Archer, John Rh; Rowe, Ashley; Hudson, Simon; Wood, David M; Dargan, Paul I","year":2025,"journal":"Journal of medical toxicology : official journal of the American College of Medical Toxicology, 21(1), 25-29","doi":"10.1007/s13181-024-01051-8","pmid":"39663285","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07962","title":"The impact of the COVID-19 pandemic on medical student mental health.","authors":"Wolfe, Julie H; Lehto, Stephanie; Sakai, Joseph T; Mikulich-Gilbertson, Susan K; Davis, Rachel A","year":2025,"journal":"PLOS mental health, 2(4), e0000264","doi":"10.1371/journal.pmen.0000264","pmid":"41661887","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07963","title":"Anti-Inflammatory Activity of Cannabis sativa L. Extract in 2,4-Dinitrochlorobenzene-Induced Dermatitis in Rats.","authors":"Wolińska, Renata; Zalewska, Maria; Poznański, Piotr; Nawrocka, Agata; Kowalczyk, Agnieszka; Sacharczuk, Mariusz; Bujalska-Zadrożny, Magdalena","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 18(3)","doi":"10.3390/ph18030370","pmid":"40143146","tags":["cannabis-extract","dermatitis","anti-inflammatory","cbd","preclinical","skin"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Cannabis extract reduced inflammation markers in a DNCB-induced dermatitis rat model, providing preclinical evidence for its potential use in inflammatory skin conditions like atopic dermatitis.","whyItMatters":"CBD-containing skin products are booming, but clinical evidence is limited. Preclinical studies like this help establish whether the anti-inflammatory claims have biological plausibility before moving to human trials.","specificNumbers":"Used DNCB-induced dermatitis model in rats — specific group sizes and dosing would be in the full methods.","methodology":"Preclinical study using a 2,4-dinitrochlorobenzene (DNCB)-induced dermatitis model in rats to evaluate the anti-inflammatory activity of Cannabis sativa L. extract.","limitations":"Animal model may not translate to human skin conditions. DNCB-induced dermatitis is a simplified model of complex human inflammatory skin diseases. Extract composition may vary from commercial products."},{"rthcId":"RTHC-07964","title":"The Acute and Chronic Pharmacokinetics and Pharmacodynamics of Oral Cannabidiol (CBD) With and Without Low Doses of Delta-9-Tetrahydrocannabinol (Δ9-THC).","authors":"Wolinsky, David; Zamarripa, C Austin; Spindle, Tory R; Klausner, McKenna; Cone, Edward J; Winecker, Ruth E; Vikingsson, Svante; Flegel, Ronald R; Hayes, Eugene D; Davis, Lisa S; Kuntz, David; Bonn-Miller, Marcel; Bigelow, George E; Vandrey, Ryan","year":2025,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkaf075","pmid":"40704705","tags":["cbd","thc","pharmacokinetics","drug-testing","hemp","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Even small amounts of THC in legal hemp CBD products (0.5-3.7 mg) could lead to positive drug tests after repeated use, with pharmacokinetic and pharmacodynamic effects varying by dose.","whyItMatters":"Millions use legal hemp CBD products assuming they won't affect drug tests. This controlled study shows that even compliant hemp products can lead to positive tests, with real consequences for employment and legal situations.","specificNumbers":"60 healthy adults, 6 groups of 10, receiving 100 mg CBD with 0, 0.5, 1, 2, 2.8, or 3.7 mg THC. Includes 8-hour acute session plus 14-day outpatient exposure.","methodology":"Controlled clinical study with 60 healthy adults self-administering 100 mg CBD with varying THC doses (0-3.7 mg) across an acute lab session and 14-day outpatient period, measuring pharmacokinetics and drug test results.","limitations":"Controlled MCT oil formulation may differ from commercial products. 60 participants across 6 groups means only 10 per condition. Individual metabolism varies."},{"rthcId":"RTHC-07965","title":"Acute and chronic effects of medicinal cannabis use on anxiety and depression in a prospective cohort of patients new to cannabis.","authors":"Wolinsky, David; Mayhugh, Rhiannon E; Surujnarain, Renuka; Thrul, Johannes; Vandrey, Ryan; Strickland, Justin C","year":2025,"journal":"Journal of affective disorders, 390, 119829","doi":"10.1016/j.jad.2025.119829","pmid":"40623642","tags":["medicinal-cannabis","anxiety","depression","prospective-cohort","ema"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"Adults initiating medicinal cannabis for clinically significant anxiety and/or depression showed improvements on both ecological momentary assessment (real-time) and longitudinal follow-up evaluations over 6 months.","whyItMatters":"Patients increasingly use cannabis for mental health despite mixed evidence. This prospective study with real-time symptom tracking provides more nuanced data than typical retrospective surveys on whether cannabis helps anxiety and depression.","specificNumbers":"6-month prospective follow-up using ecological momentary assessment and Hospital Anxiety and Depression Scale measures in Maryland medical cannabis patients.","methodology":"Prospective observational cohort of adults with clinically significant anxiety and/or depression initiating medicinal cannabis in Maryland, using ecological momentary assessment (EMA) plus standard longitudinal follow-up over 6 months.","limitations":"Observational design without controls — improvements could reflect placebo effects, natural course, or concurrent treatments. Maryland-specific population may limit generalizability."},{"rthcId":"RTHC-07966","title":"Pregnancy Care in Times of Cannabis Legalization: Self-Rated Knowledge, Risk Perception and Communication Practices of Midwives in Germany.","authors":"Wollscheid, Julia; Burke, Matthias; Kimmel, Theresa; Kaufmann, Tobias; Batra, Anil; Binder, Annette","year":2025,"journal":"Healthcare (Basel, Switzerland), 13(11)","doi":"10.3390/healthcare13111228","pmid":"40508842","tags":["pregnancy","midwives","cannabis","legalization","germany","prenatal-care"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"German midwives showed variable self-rated knowledge of cannabis risks in pregnancy and inconsistent frequency of screening and counseling patients about cannabis use, despite their central role in prenatal care.","whyItMatters":"Germany legalized recreational cannabis in 2024. Midwives are primary prenatal care providers there, so their knowledge and practices around cannabis directly affect whether pregnant women receive appropriate guidance.","specificNumbers":"Survey of German midwives following 2024 legalization — specific sample size in full text. Assessed knowledge, risk perception, and counseling frequency.","methodology":"Cross-sectional survey of German midwives assessing self-rated knowledge, risk perception, and frequency of screening and counseling practices related to cannabis use during pregnancy.","limitations":"Self-rated knowledge may not reflect actual knowledge. Survey response bias may skew toward more engaged midwives. German healthcare system may not generalize to other countries."},{"rthcId":"RTHC-07967","title":"Managing cannabinoid hyperemesis syndrome in adult patients in the emergency department.","authors":"Won, Kimberly J; Celmins, Laura","year":2025,"journal":"American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 82(24), 1340-1352","doi":"10.1093/ajhp/zxaf125","pmid":"40458910","tags":["cannabinoid-hyperemesis-syndrome","emergency-department","treatment","chs"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CHS management in the ED includes both pharmacological approaches (antiemetics, capsaicin) and non-pharmacological strategies (hot showers), with emergency pharmacists playing an increasingly important role in treatment decisions.","whyItMatters":"CHS is becoming more common as cannabis use rises. Patients often cycle through multiple ER visits before diagnosis, and clear treatment protocols can reduce suffering and healthcare costs.","specificNumbers":"Review article — synthesizes existing evidence on CHS treatments including pharmacological and non-pharmacological approaches.","methodology":"Review article summarizing current evidence on pharmacological and non-pharmacological therapies for cannabinoid hyperemesis syndrome (CHS) in the emergency department.","limitations":"CHS treatment evidence is largely based on case reports and small studies. No large RCTs exist for most recommended therapies."},{"rthcId":"RTHC-07968","title":"Edible cannabis use on simulated driving performance.","authors":"Won, Nae Y; Bird, Sarah; Wrobel, Julia; Brown, Timothy; Brooks-Russell, Ashley","year":2025,"journal":"Traffic injury prevention, 1-9","doi":"10.1080/15389588.2025.2574271","pmid":"41223382","tags":["edibles","driving","impairment","simulator","thc","public-safety"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Edible cannabis impaired simulated driving performance across speed control and lane maintenance measures, with daily users showing different patterns than occasional users, and effects varying between rural and urban driving scenarios.","whyItMatters":"Edibles are increasingly popular but their driving impairment profile differs from smoked cannabis — slower onset, longer duration, and harder to self-regulate dosing. This creates unique road safety concerns.","specificNumbers":"88 adults: 29 daily users, 30 occasional users, 29 non-users. Denver, Colorado, recruited November 2023 to July 2024. Measured speed, lane departure, and other driving metrics.","methodology":"Within-subjects driving simulator study in Denver, Colorado with 88 adults (25-55 years) in three groups: daily users (n=29), occasional users (n=30), and non-users/comparison (n=29), assessing driving after edible cannabis consumption.","limitations":"Simulator driving doesn't perfectly replicate real-world driving. Denver population in a legal state may not represent all drivers. Within-subjects design may have practice effects."},{"rthcId":"RTHC-07969","title":"Drug use among individuals injured in non-fatal motor vehicle crashes and related policies in 2023.","authors":"Won, Nae Y; Gurka, Kelly K; Striley, Catherine W; Nixon, Sara Jo; Cottler, Linda B","year":2025,"journal":"Traffic injury prevention, 26(7), 760-768","doi":"10.1080/15389588.2025.2456952","pmid":"39998816","tags":["motor-vehicle-crashes","drug-use","policy","legalization","traffic-safety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The study assessed drug use prevalence among non-fatally injured crash victims and evaluated whether state cannabis legalization policies were associated with differences in drug-related crash rates.","whyItMatters":"Understanding whether cannabis legalization affects crash rates is essential for evidence-based traffic safety policy. This study provides 2023 data as more states have legalized.","specificNumbers":"2023 data on drug use among non-fatally injured crash victims across US states with varying cannabis legal frameworks.","methodology":"Cross-sectional analysis of drug use among individuals injured in non-fatal motor vehicle crashes in 2023, examining associations with state-level cannabis and driving-related drug policies.","limitations":"Cross-sectional design cannot establish causation. Drug presence doesn't equal impairment at time of crash. Testing protocols vary across jurisdictions. Non-fatal crashes only."},{"rthcId":"RTHC-07970","title":"Pilot-Scale Preparation of Broad-Spectrum CBD: Extraction Optimization and Purification using Centrifugal Partition Chromatography.","authors":"Wongumpornpinit, Vorawut; Temkitthawon, Prapapan; Khumpirapang, Nattakanwadee; Paenkaew, Sujittra; Saesong, Tongchai; Boonnoun, Panatpong; Wongwad, Eakkaluk; Waranuch, Neti; Ingkaninan, Kornkanok","year":2025,"journal":"Medical cannabis and cannabinoids, 8(1), 65-79","doi":"10.1159/000546263","pmid":"40524919","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07971","title":"Social and Environmental Predictors of Youth Alcohol and Cannabis Initiation Risk: The Moderating Role of Family History of Substance Use Disorders.","authors":"Wood, Erin E; Liang, Yuanyuan; Moon, Tae-Joon; Hill-Kapturczak, Nathalie; Wasserman, Alexander M; Roache, John D; Mathias, Charles W; Blumenthal, Heidemarie; Dougherty, Donald M","year":2025,"journal":"Substance use & misuse, 60(3), 403-413","doi":"10.1080/10826084.2024.2434007","pmid":"39627932","tags":["youth","initiation","alcohol","cannabis","family-history","longitudinal"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Protective and risk factors for first substance use were not universal — they differed between alcohol and cannabis initiation, and family history of substance use disorder moderated which environmental factors mattered most.","whyItMatters":"Prevention programs often treat all substance initiation the same. This study shows that different factors predict alcohol vs. cannabis initiation, suggesting prevention efforts should be tailored rather than generic.","specificNumbers":"387 adolescents followed longitudinally, examining alcohol use initiation (AUI) and cannabis use initiation (CUI) separately.","methodology":"Longitudinal cohort study following 387 adolescents, examining social and local-home environmental predictors of alcohol and cannabis use initiation, with family history of SUD as a moderating variable.","limitations":"Moderate sample size of 387. Specific demographic composition may limit generalizability. Self-reported substance initiation may be subject to recall or social desirability bias."},{"rthcId":"RTHC-07972","title":"Genetic deletion of NAPE-PLD alters stress responsiveness and HPA-axis functionality in a context-dependent manner in mice.","authors":"Woodward, Taylor J; Dimen, Diana; Sizemore, Emily Fender; Stockman, Sarah; Kazi, Fezaan; Luquet, Serge; Mackie, Ken; Katona, Istvan; Hohmann, Andrea G","year":2025,"journal":"Neuropharmacology, 281, 110702","doi":"10.1016/j.neuropharm.2025.110702","pmid":"41046930","tags":["endocannabinoid-system","nape-pld","anandamide","stress","hpa-axis","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Genetic deletion of NAPE-PLD in mice altered stress responsiveness and HPA-axis functionality in a context-dependent manner, revealing the enzyme's role in fine-tuning the body's stress response system.","whyItMatters":"Understanding how the endocannabinoid system regulates stress has direct implications for anxiety and stress disorders. NAPE-PLD's role in stress regulation could reveal new therapeutic targets.","specificNumbers":"Used NAPE-PLD knockout mice tested across multiple stress paradigms to assess context-dependent effects on behavior and HPA axis.","methodology":"Preclinical study using NAPE-PLD knockout mice to examine how loss of this endocannabinoid-synthesizing enzyme affects behavioral stress responses and hypothalamic-pituitary-adrenal (HPA) axis function across different stress contexts.","limitations":"Global gene knockout doesn't distinguish brain-region-specific effects. Mouse stress models have limited translational relevance. Compensatory mechanisms may develop in knockout animals."},{"rthcId":"RTHC-07973","title":"Mice lacking the endocannabinoid-synthesizing enzyme NAPE-PLD exhibit sex-dependent dysregulations in responsiveness to oxycodone and a natural reward.","authors":"Woodward, Taylor J; Sizemore, Emily; Balaji, Ananya; Port, Ada; Hainline, John; Kazi, Hasaan; Luquet, Serge; Mackie, Ken; Hohmann, Andrea G","year":2025,"journal":"Neuropharmacology, 278, 110573","doi":"10.1016/j.neuropharm.2025.110573","pmid":"40581209","tags":["endocannabinoid-system","nape-pld","opioid","reward","sex-differences","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"NAPE-PLD knockout mice displayed sex-dependent dysregulations in opioid (oxycodone) reward responsiveness and natural reward processing, revealing endocannabinoid-opioid interactions that differ between males and females.","whyItMatters":"The opioid crisis demands better understanding of addiction biology. The endocannabinoid system interacts closely with opioid reward pathways, and sex differences in these interactions could explain why addiction manifests differently in men and women.","specificNumbers":"Tested male and female NAPE-PLD knockout mice on oxycodone reward and natural reward responses — specific group sizes in full methods.","methodology":"Preclinical study using NAPE-PLD knockout mice to examine sex differences in responsiveness to oxycodone and natural rewards (food, social interaction), testing endocannabinoid-opioid system interactions.","limitations":"Global gene knockout, mouse behavior may not translate to human addiction. Oxycodone is one of many opioids. Natural reward paradigms are simplified models of human reward processing."},{"rthcId":"RTHC-07974","title":"Mice lacking the endocannabinoid-synthesizing enzyme NAPE-PLD exhibit sex-dependent dysregulations in responsiveness to oxycodone and a natural reward.","authors":"Woodward, Taylor J; Sizemore, Emily; Balaji, Ananya; Port, Ada; Hainline, John; Kazi, Hasaan; Luquet, Serge; Mackie, Ken; Hohmann, Andrea G","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.04.03.646908","pmid":"40236045","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07975","title":"Insights from the ground: A qualitative investigation of retailer perspectives of the challenges and opportunities in the legal cannabis market in Newfoundland and Labrador, Canada.","authors":"Wright-Brown, Tanisha; Gaid, Dina; Najafizada, Maisam; Schwartz, Elizabeth; Cooper, Thomas; Newell, William; Bishop, Lisa; Donnan, Jennifer","year":2025,"journal":"PloS one, 20(10), e0333706","doi":"10.1371/journal.pone.0333706","pmid":"41124200","tags":["legalization"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Canada's cannabis legalization has produced different retail environments across provinces, and this qualitative study captures the perspective of the people running (or trying to run) the shops in Newfoundland and Labrador.\n\nThe researchers interviewed 9 licensed and 9 prospective cannabis retailers—a sample that captures both the experience of operating within the system and the perspective of those trying to enter it.\n\nLicensed retailers described a tension between business viability and regulatory compliance. Restrictive advertising rules, high taxation, and supply chain inefficiencies were cited as constraints on profitability and growth. These aren't just business complaints—they have public health implications. If legal retailers can't compete on price and accessibility with the illicit market, the public health goals of legalization (safer products, age verification, reduced criminal market) are undermined.\n\nAt the same time, retailers recognized their potential role in advancing public health objectives. They're the point of contact with consumers and can provide education about responsible use, dosing, and product differences. This dual identity—business operators and de facto public health actors—creates unique tensions.\n\nNewfoundland's framework includes centralized distribution, licensing requirements, and pricing regulations, making it more restrictive than some other provinces. The retailers' perspectives reveal how these well-intentioned regulations can create unintended barriers.","whyItMatters":"RTHC-00175's scoping review catalogued what we should be monitoring about legalization. This study captures the ground-level reality of one key component: retail. If the retail system doesn't work—if legal shops can't compete with the black market, if regulations are too restrictive to be practical, if retailers aren't equipped to serve public health goals—then legalization's potential benefits remain theoretical.","specificNumbers":"18 interviews (9 licensed + 9 prospective retailers). Newfoundland and Labrador's centralized distribution model. Key challenges: advertising restrictions, taxation, supply chain. Key opportunities: consumer education, public health role.","methodology":"Qualitative study with semi-structured virtual interviews. 9 licensed + 9 prospective cannabis retailers in Newfoundland and Labrador. Thematic analysis using Wright-Brown et al.'s Comprehensive Cannabis Retail Framework and Ritchie and Spencer's framework analysis. Both deductive and inductive coding.","limitations":"Small sample from one Canadian province—Newfoundland's framework is particularly restrictive and may not represent other jurisdictions. Self-selected participants may not represent all retailer perspectives. Qualitative data can't quantify the impact of specific regulations on market outcomes. Retailer perspectives are inherently biased toward business concerns, which may conflict with public health priorities."},{"rthcId":"RTHC-07976","title":"County-Level COVID-19 Policy Comprehensiveness and Adult Behavioral Health during 2021 : County-Level COVID-19 Policy and Adult Behavioral Health.","authors":"Wright, Emily; Dore, Emily C; Jackson, Kaitlyn E; Wang, Guangyi; Pletcher, Mark J; Carton, Thomas W; Hamad, Rita","year":2025,"journal":"Journal of urban health : bulletin of the New York Academy of Medicine, 102(3), 713-725","doi":"10.1007/s11524-025-00982-z","pmid":"40332666","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07977","title":"Hypothesized pharmacogenomic and medication influences on tetrahydrocannabinol and cannabidiol metabolism in a cohort of unselected oral cannabis users.","authors":"Wright, Jessica A; Huang, Linda; Katamesh, Basant E; Yadav, Siddhant; Singla, Abhinav; Vincent, Ann","year":2025,"journal":"Journal of cannabis research, 7(1), 1","doi":"10.1186/s42238-024-00256-6","pmid":"39754268","tags":["genetics","cbd","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Why do two people taking the same cannabis product at the same dose sometimes have dramatically different responses? This study points to genetics as a major factor.\n\nThe researchers reviewed charts of 71 patients who had both pharmacogenomic testing and reported oral cannabis use. The findings were striking: only 10 out of 71 patients (14%) had completely typical variants across all relevant metabolic enzymes. The vast majority had atypical variants in one or more of the CYP450 enzymes that process cannabinoids:\n\n- 31 had atypical CYP2C9 variants (processes THC)\n- 37 had atypical CYP2C19 variants (processes both THC and CBD)\n- 6 had atypical CYP3A4 variants (processes both)\n- 15 had atypical CYP3A5 variants (processes both)\n\nAdditionally, 5 patients were taking medications that could interact with THC metabolism, and 8 were taking medications that could interact with CBD metabolism.\n\nThis has enormous practical implications. A patient with reduced CYP2C9 function will process THC more slowly, potentially experiencing stronger and longer-lasting effects from the same dose. Conversely, someone with enhanced enzyme activity might barely feel a dose that's overwhelming for another person. Without pharmacogenomic information, cannabis dosing is essentially guesswork.","whyItMatters":"RTHC-00186 emphasized the importance of 'start low, go slow' CBD dosing for epilepsy, partly because of drug interactions. This study reveals that even without drug interactions, the majority of patients have genetic variants that alter cannabinoid metabolism. This means the same dose produces different blood levels in different people—which could explain why clinical trials show inconsistent results and why individual patients have such variable experiences.","specificNumbers":"N = 71 oral cannabis users. Average age 68.5. Only 14% had typical variants in all enzymes. CYP2C9 atypical: 43.7%. CYP2C19 atypical: 52.1%. CYP3A4 atypical: 8.5%. CYP3A5 atypical: 21.1%. 5 patients on THC-interacting drugs. 8 on CBD-interacting drugs.","methodology":"Retrospective chart review of 71 patients with prior pharmacogenomic testing who reported oral cannabis use. Average age 68.5, primarily white women. Genotyping of CYP2C9, CYP2C19, CYP3A4, and CYP3A5. Medication review for CYP450 interactions with THC and CBD.","limitations":"Retrospective, small sample (71 patients). Primarily white older women—allele frequencies vary across ethnic groups. No outcome data (were atypical metabolizers actually more or less responsive to cannabis?). Self-reported oral cannabis use. The study generates hypotheses about how genetic variants affect cannabis response but doesn't test those hypotheses clinically. Chart review can't capture all relevant medications or supplements."},{"rthcId":"RTHC-07978","title":"Pharmacokinetics of cannabidiol and its metabolites in rhesus monkeys and New Zealand White rabbits.","authors":"Wu, Qiangen; Camacho, Luísa; Talpos, John; Shpyleva, Svitlana; Mellon, R Daniel; Fisher, J Edward; Vanlandingham, Michelle; Shores, Patricia; Gamboa da Costa, Gonçalo; Beland, Frederick A","year":2025,"journal":"Toxicological sciences : an official journal of the Society of Toxicology, 208(2), 244-255","doi":"10.1093/toxsci/kfaf129","pmid":"40973479","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07979","title":"Therapeutic Potential for Cannabidiol on Alzheimer's Disease-Related Neuroinflammation: A Systematic Review and Meta-Analysis.","authors":"Wu, Shuo; Rajiah, Tracia; Ali, Afia B","year":2025,"journal":"International journal of molecular sciences, 26(24)","doi":"10.3390/ijms262411963","pmid":"41465389","tags":["cbd","alzheimers","neuroinflammation","systematic-review","meta-analysis","neuroprotection"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"In preclinical AD models, CBD significantly reduced key neuroinflammation markers (GFAP and Iba-1). Limited clinical data showed trends toward improvement in agitation and caregiver distress, with typically mild adverse events.","whyItMatters":"Alzheimer's disease has no cure and current treatments offer limited relief. If CBD can reduce the neuroinflammation that drives disease progression, it could complement existing treatments or serve as a new therapeutic approach.","specificNumbers":"Meta-analysis showed CBD significantly reduced GFAP (p < 0.05) and Iba-1 (p = 0.05) in preclinical models. Clinical data suggested improvements in agitation and caregiver distress.","methodology":"Systematic review and meta-analysis using random-effects modeling to assess CBD efficacy on neuroinflammation and clinical outcomes across both preclinical and clinical Alzheimer's disease studies.","limitations":"Clinical data is insufficient for definitive efficacy claims. Preclinical models don't fully replicate human AD. CBD preparations and doses varied across studies, limiting comparability."},{"rthcId":"RTHC-07980","title":"Event-level influences of alcohol, cannabis, and simultaneous use on perceived driving risk.","authors":"Wycoff, Andrea M; Darmour, Charles A; McCarthy, Denis M; Trull, Timothy J","year":2025,"journal":"Experimental and clinical psychopharmacology, 33(2), 170-177","doi":"10.1037/pha0000758","pmid":"39636599","tags":["alcohol","cannabis","simultaneous-use","driving","risk-perception","ema"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Simultaneous alcohol and cannabis use increased perceived driving impairment, yet participants were 3.7x more willing to drive within an hour compared to alcohol-only use, suggesting cannabis may attenuate alcohol's deterrent effect on driving decisions.","whyItMatters":"People who use alcohol and cannabis together are at higher crash risk, yet this study suggests they may actually feel more willing to drive — a dangerous mismatch between impairment and risk perception.","specificNumbers":"88 adults, 14 days of EMA, average 5.14 surveys/day. Simultaneous users were 3.69x more willing to drive within 1 hour (95% CI: 2.15-6.34) compared to alcohol-only use.","methodology":"Ecological momentary assessment over 14 days with 88 adults (ages 18-44) who co-use alcohol and cannabis at least twice weekly, completing an average of 5.14 surveys per day on substance use, perceived impairment, and driving willingness.","limitations":"Self-selected sample of regular co-users may not represent broader population. Self-reported willingness to drive differs from actual driving behavior. Predominantly White sample (85.2%) limits diversity."},{"rthcId":"RTHC-07981","title":"High Stakes: Exploring the Impact of Cannabis Use in Pregnancy and Lactation.","authors":"Wymore, Erica M; Wagner, Katharine; Gold, Christine; Halmo, Laurie Seidel","year":2025,"journal":"NeoReviews, 26(4), e247-e263","doi":"10.1542/neo.26-4-006","pmid":"40164212","tags":["pregnancy","lactation","cannabis","prenatal","thc","neonatal"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis use in pregnancy has a prevalence of 3-30%, with nearly half of active users continuing despite medical guidance against it. The review summarizes current evidence on THC exposure impacts on pregnancy, infant, and childhood outcomes.","whyItMatters":"With cannabis legalization expanding, more pregnant people are using cannabis. Healthcare providers need clear, evidence-based guidance to counsel patients about risks without being dismissive of their choices.","specificNumbers":"Cannabis use prevalence during pregnancy: 3-30%. Nearly 50% of active cannabis users continue use during pregnancy. Major medical organizations (ACOG, AAP) discourage use.","methodology":"Narrative review summarizing cannabis pharmacology and THC metabolism, current evidence on perinatal cannabis effects, and targeted counseling recommendations for harm reduction during pregnancy and lactation.","limitations":"Evidence on perinatal cannabis effects has significant confounders (polysubstance use, socioeconomic factors). Self-report underestimates true use. Long-term childhood outcome data is limited."},{"rthcId":"RTHC-07982","title":"A 13-week oral toxicity and toxicokinetic study of cannabidiol in Sprague Dawley rats with a 4-week recovery period.","authors":"Xia, Wenhao; Yanuar, Rendy; Mandal, Vivek; Renggli, Kasper; Ho, Jenny; Phillips, Blaine; Nikolajsen, Gitte Nykjaer; Jensen, Sanne Skov; Bruun, Heidi Ziegler; Hoeng, Julia","year":2025,"journal":"Drug and chemical toxicology, 48(6), 1447-1460","doi":"10.1080/01480545.2025.2491544","pmid":"40360444","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07983","title":"Forensic Identification of Cannabis with Plant DNA Barcodes and Cannabinoid Synthesis Genes.","authors":"Xiang, Ping; Phua, Yu Wei; Rosli, Afiqah Razanah; Loh, Kar Jun; Syn, Christopher Kiu-Choong","year":2025,"journal":"Genes, 16(11)","doi":"10.3390/genes16111320","pmid":"41300772","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07984","title":"Content Analysis of Cannabis Discourses on Twitter/X in the U.S.","authors":"Xie, Zidian; Zhou, Runtao; Yun, Qihao; Wu, Jianghang; Wang, Zhengyuan; Yu, Mengmeng; Wilson, Karen M; Li, Dongmei","year":2025,"journal":"AJPM focus, 4(6), 100408","doi":"10.1016/j.focus.2025.100408","pmid":"41035944","tags":["social-media","public-perception","twitter","cannabis-attitudes","content-analysis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 2.87 million unique cannabis tweets, positive attitudes (22.6%) centered on medical value while negative attitudes (8.2%) focused on difficulty quitting. The 25-34 age group was most represented among cannabis-using tweeters.","whyItMatters":"Social media reflects and shapes public cannabis attitudes. Understanding what people actually discuss — medical value vs. quitting struggles — helps public health authorities craft messaging that resonates with real concerns.","specificNumbers":"2,865,562 tweets analyzed. 22.62% positive, 8.17% negative, 69.21% neutral. 821,451 unique users, 42.46% potential cannabis users. 25-34 age group most represented.","methodology":"Content analysis of 2,865,562 unique non-commercial cannabis tweets from February 2022-2023 using deep learning (BERT) for attitude classification and topic modeling (LDA) for theme identification.","limitations":"Twitter/X users don't represent the general population. BERT classification has error rates. Cannot verify actual cannabis use from social media claims. Data from one year only."},{"rthcId":"RTHC-07985","title":"Estimating and comparing the effects of price- and potency-based taxes on cannabis purchase patterns in an experimental cannabis marketplace.","authors":"Xing, Jin; Shi, Yuyan","year":2025,"journal":"Addiction (Abingdon, England), 120(9), 1770-1779","doi":"10.1111/add.70086","pmid":"40274528","tags":["cannabis-tax","potency-tax","price-elasticity","policy","public-health"],"studyType":"quasi-experimental","evidenceStrength":"moderate","keyFinding":"Both tax types reduced overall cannabis demand, but potency-based taxes specifically reduced demand for high-THC products more effectively (elasticity -0.59 vs. -0.49 for price-based), and shifted spending away from potent products.","whyItMatters":"High-potency cannabis products pose greater health risks, especially for mental health. If tax policy can specifically discourage high-potency purchases, it becomes a targeted public health tool rather than a blunt revenue instrument.","specificNumbers":"1,250 adult cannabis users. Price elasticity of quantity demanded: -0.46. Price elasticity of THC demanded: -0.48 to -0.52. Potency-based tax elasticity for high-THC products: -0.59 vs. -0.49 for price-based (p = 0.046).","methodology":"Online experimental cannabis marketplace with 1,250 adult cannabis users in legal states, comparing hypothetical purchase behavior under varying price-based and potency-based tax rates.","limitations":"Hypothetical purchase behavior may differ from real-world decisions. Online sample may not represent all cannabis users. Doesn't account for black market substitution effects."},{"rthcId":"RTHC-07986","title":"Effects of MDA-19 on Zebrafish Larval Behavior: Perspectives From Neurodevelopment, Oxidative Stress, and Metabolomics.","authors":"Xu, Boyang; Yan, Jun; Zhou, Yangtao; Zhang, Feng; Wang, Binjie; Wang, Jiye; Wu, Yuanzhao; Xu, Yu","year":2025,"journal":"Journal of applied toxicology : JAT, 45(3), 440-451","doi":"10.1002/jat.4715","pmid":"39477463","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07987","title":"The Effects of Cannabis Access Laws on Sleep in the U.S.","authors":"Xu, Carol; Sturman, Zachary","year":2025,"journal":"AJPM focus, 4(5), 100387","doi":"10.1016/j.focus.2025.100387","pmid":"40977996","tags":["sleep","cannabis-laws","legalization","population-study","sleep-duration"],"studyType":"quasi-experimental","evidenceStrength":"strong","keyFinding":"Recreational cannabis laws reduced sleep by 5.37 minutes per night (99% CI: 0.91-9.83), primarily by delaying sleep onset by 7.14 minutes without changing wake times. Medical cannabis laws had no significant sleep effects.","whyItMatters":"Global sleep duration is declining with significant health consequences. If cannabis legalization further reduces sleep — even by a few minutes — the population-level health impact could be substantial across millions of people.","specificNumbers":"175,493 respondents, 2003-2021. Recreational laws: -5.37 min sleep (99% CI: 0.91-9.83), +7.14 min later bedtime (99% CI: 3.12-11.16). Effects concentrated in males and ages 25+.","methodology":"Two-way-fixed-effects difference-in-differences regression analyzing American Time Use Survey data from 175,493 respondents aged 18-65 from 2003 to 2021.","limitations":"Time use data measures sleep opportunity, not actual sleep quality. Cannot identify mechanism (direct pharmacological vs. behavioral). Small effect size may not be clinically significant individually."},{"rthcId":"RTHC-07988","title":"How tax structures for retail cannabis shape cannabis use among youth and young adults: evidence from a volumetric choice experiment.","authors":"Xu, Lei; He, Yanyun; Park, Hojin; Zhang, Shiqi; Ma, Shaoying; Shang, Ce","year":2025,"journal":"The European journal of health economics : HEPAC : health economics in prevention and care","doi":"10.1007/s10198-025-01875-3","pmid":"41460273","tags":["cannabis-tax","youth","young-adults","potency-tax","policy","thc"],"studyType":"quasi-experimental","evidenceStrength":"moderate","keyFinding":"Higher pre-tax prices and tax rates reduced both quantity and THC consumption among youth/young adults. Potency-based taxes reduced high-THC product use but increased low-THC consumption by 30-32%, and tax impacts could be offset by shifting to illegal products.","whyItMatters":"Youth are particularly vulnerable to cannabis harms, yet tax policy designed to reduce potency could backfire by increasing overall consumption of lower-THC products or driving youth to the illegal market.","specificNumbers":"1,100 AYAs ages 15-20. Price elasticity: -0.3. Potency-based taxes increased cannabis quantity 30-32% vs. weight-based. Tax rates beyond 60% of pretax prices showed no additional reduction.","methodology":"Split-sample volumetric choice experiment with 1,100 nationally representative youth and young adults (ages 15-20), randomized to weight-, price-, or potency-based tax conditions with varying prices, rates, and THC levels.","limitations":"Hypothetical purchase tasks may not reflect real behavior. Ages 15-20 includes both legal and underage purchasers. Illegal market availability assumed rather than measured."},{"rthcId":"RTHC-07989","title":"An Amygdala-hippocampus Circuit for Endocannabinoid Modulation of Anxiety Avoidance.","authors":"Xue, Bao; Zhang, Mao-Xing; Bi, Xiao-Chen; Lai, Shou-Peng; Bie, Xin-Tian; Dong, Yuan; Li, Jian-Feng; Gao, Fang; Zhang, Xia; Wang, Ying","year":2025,"journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12(34), e05121","doi":"10.1002/advs.202505121","pmid":"40522172","tags":["endocannabinoid-system","anxiety","amygdala","hippocampus","neural-circuit","preclinical"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"Endocannabinoids are released at amygdala-to-ventral hippocampus synapses during anxiety avoidance, activating CB1 receptors that reduce glutamate release and decrease anxiety — revealing a specific circuit-level mechanism for endocannabinoid anxiety regulation.","whyItMatters":"This is the first identification of a specific brain circuit where endocannabinoids naturally reduce anxiety in real-time. Understanding the exact wiring could lead to more targeted anxiety treatments that mimic the body's own calming system.","specificNumbers":"Used three novel viral strategies targeting aBLA-vHPC glutamatergic projections. Optogenetic CB1 activation reduced glutamate release and anxiety. CRISPR knockdown of eCB enzymes increased anxiety.","methodology":"Preclinical study using three newly developed synapse- and circuit-specific viral strategies for real-time eCB monitoring, optogenetic CB1 activation, and CRISPR-Cas9 gene knockdown in the aBLA-vHPC pathway in mice.","limitations":"Mouse brain circuits may not perfectly map to human anxiety circuitry. Novel viral tools need independent replication. Anxiety models are simplified compared to human anxiety disorders."},{"rthcId":"RTHC-07990","title":"Cyclic Vomiting Syndrome and Cannabinoid Hyperemesis Syndrome: Their Intersection and Joint Existence.","authors":"Yacob, Desale","year":2025,"journal":"Gastroenterology clinics of North America, 54(3), 557-568","doi":"10.1016/j.gtc.2025.05.004","pmid":"40752916","tags":["cannabinoid-hyperemesis-syndrome","cyclic-vomiting","diagnosis","clinical-management"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CVS is a gut-brain interaction disorder linked to migraine and autonomic dysfunction, while CHS is directly caused by chronic heavy cannabis use. Despite overlapping symptoms, their management strategies differ significantly.","whyItMatters":"Many patients with cyclical vomiting use cannabis — either as a cause (CHS) or as self-treatment (CVS). Correctly distinguishing between these conditions prevents misdiagnosis and ensures appropriate treatment.","specificNumbers":"Review comparing four shared clinical phases: prodromal, emetic, recovery, and interepisodic baseline health in both CVS and CHS.","methodology":"Clinical review examining the intersection of cyclic vomiting syndrome and cannabinoid hyperemesis syndrome, comparing their pathophysiology, epidemiology, clinical phases, and management approaches.","limitations":"Both conditions lack definitive biomarkers. The overlap between them makes differential diagnosis inherently challenging. Limited evidence on patients who may have both conditions simultaneously."},{"rthcId":"RTHC-07991","title":"Transcriptomic and Lipidomic Analysis Reveals the Regulatory Network of Lipid Metabolism in Cannabis sativa.","authors":"Yan, Bowei; Chang, Chuanyi; Sui, Yue; Zheng, Nan; Fang, Yuyan; Zhang, Yuanye; Zhang, Ming; He, Dan; Zhang, Liguo","year":2025,"journal":"Foods (Basel, Switzerland), 14(16)","doi":"10.3390/foods14162809","pmid":"40870724","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07992","title":"Antitumor effects of cannabidiol (CBD) on osteosarcoma by targeting TNF-α/NF-κB/CCL5 signaling axis.","authors":"Yang, Fan; Duan, Shuqin; Liu, Jingwei; An, Zhechao; Liu, Wangyang; Wang, Xinyue; Zhang, Tingting; Liu, Mingyu; Li, Fengda; Wu, Wei; Liu, Yingzhe; Tang, Jianyong; Wang, Xiaojuan; Xu, Wenhui; Qi, Wenyi; Liu, Yunhe; Li, Liangliang; Li, Yuan; Liu, Xin; Yang, Baofeng; Zhang, Zheng; Wang, Li; Yang, Lei","year":2025,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 145, 157066","doi":"10.1016/j.phymed.2025.157066","pmid":"40680332","tags":["cbd","osteosarcoma","anticancer","nf-kb","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD directly binds the NF-kB subunit p65, disrupting a positive feedback loop between NF-kB and CCL5 that drives osteosarcoma inflammation and proliferation. This was validated in both cell culture and mouse tumor models.","whyItMatters":"Osteosarcoma is an aggressive bone cancer with limited treatment options. Identifying that CBD targets a specific inflammatory pathway provides a mechanistic rationale for further investigation, beyond general anti-cancer claims.","specificNumbers":"CBD suppressed proliferation (EdU assay), migration, and invasion in cell culture. Inhibited xenograft tumor growth in vivo. Molecular binding to p65 confirmed by four complementary methods.","methodology":"Comprehensive preclinical study using cell viability assays, functional assays (proliferation, migration, invasion), mouse xenograft tumors, network pharmacology, RNA-seq, and molecular binding confirmation (CETSA, SPR, ITC, molecular docking).","limitations":"Preclinical only — mouse xenograft models don't fully replicate human bone cancer. CBD concentrations used may not be achievable in human patients. Single cancer type studied."},{"rthcId":"RTHC-07993","title":"Cannabidiol Mitigates Deoxynivalenol-Induced Intestinal Toxicity by Regulating Inflammation, Oxidative Stress, and Barrier Integrity.","authors":"Yang, Lingchen; Decas, Tristan; Zhang, Yuhang; Alassane-Kpembi, Imourana","year":2025,"journal":"Toxins, 17(5)","doi":"10.3390/toxins17050241","pmid":"40423323","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07994","title":"Differential Responsiveness to Cigarette Prices by U.S. Adults Who Do and Do Not Use Cannabis.","authors":"Yao, Tingting; Sung, Hai-Yen; Chu, Lela; Spetz, Joanne; Max, Wendy","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","doi":"10.1093/ntr/ntaf205","pmid":"41152214","tags":["tobacco","cannabis","co-use","cigarette-prices","price-elasticity","policy"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Cannabis-using smokers had total cigarette demand elasticity of -0.47 vs. -0.36 for non-users, meaning they were more likely to reduce or quit smoking when cigarette prices increased.","whyItMatters":"As cannabis use rises and cigarette smoking declines, understanding how these markets interact helps design more effective tobacco control policy. If co-users are more price-sensitive, tobacco taxes provide extra benefit for this growing subgroup.","specificNumbers":"2004-2019 data, ~50,000 adults/year. Smoking declined 24.5% to 16.6%. Cannabis use rose 5.8% to 11.6%. Co-use rose 3.6% to 4.5%. Total demand elasticity: -0.47 (cannabis users) vs. -0.36 (non-users).","methodology":"Two-part econometric model analyzing cross-sectional NSDUH data from 2004-2019 (annual mean ~50,000 adults), comparing cigarette price elasticity between current cannabis users and non-users.","limitations":"Cross-sectional data cannot establish causation. Self-reported substance use may be inaccurate. Price measures may not capture local variation. Cannot determine if cannabis is a substitute for cigarettes."},{"rthcId":"RTHC-07995","title":"Ultra-Weak Photon Emission Demonstrates Specificity for Anxiety over Pain in Cannabis-Treated Chronic Neuropathic Pain: A Biomarker Validation Study.","authors":"Yassin, Mustafa; Robinson, Dror; Khatib, Muhammad; Murad, Hamza; Qawasme, Feras; Lavon, Eitan","year":2025,"journal":"Bioengineering (Basel, Switzerland), 12(12)","doi":"10.3390/bioengineering12121359","pmid":"41463657","tags":["anxiety","pain","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"This study has two distinct contributions. The first is clinical: 200 adults with confirmed neuropathic pain received cannabis therapy and were followed for 48 months—one of the longest follow-up periods in cannabis pain research. The clinical response rate was 91.5%, suggesting that for neuropathic pain specifically, cannabis therapy is highly effective in the real world.\n\nThe second contribution is methodological: the researchers tested ultra-weak photon emission (UPE), measured via gas discharge visualization (GDV/Biowell), as a potential biomarker. UPE measures extremely faint light that biological tissues emit—a measurement at the frontier of biophysics.\n\nThe biomarker finding was surprising. UPE measurements correlated strongly with anxiety (GAD-7: r = 0.579) but weakly with pain (NRS: r = 0.092)—a 6.2-fold difference. In practical terms, the Biowell UPE measurement could discriminate clinically meaningful anxiety changes (AUC = 0.744) but not pain changes (AUC = 0.550, essentially random). Mixed-effects modeling confirmed that UPE predicted anxiety scores but not pain scores.\n\nThis specificity for anxiety over pain is interesting because it suggests these are biologically distinct processes that respond to cannabis differently—or at least produce different measurable biological signals.","whyItMatters":"The 91.5% response rate for neuropathic pain over 4 years is one of the strongest real-world outcomes in the cannabis pain literature—particularly given RTHC-00170's finding that neuropathic pain patients use cannabis more intensively than other pain patients and RTHC-00200's identification of CBG as a potential nerve pain treatment. The biomarker work is more exploratory but points toward objective measurement tools for conditions that currently rely entirely on self-report.","specificNumbers":"N = 200. 48-month follow-up. 91.5% clinical response rate. UPE-anxiety correlation: r = 0.579 (strong). UPE-pain correlation: r = 0.092 (weak). 6.2-fold difference in correlation strength. Anxiety AUC = 0.744. Pain AUC = 0.550.","methodology":"Prospective cohort study. 200 adults with electrodiagnostically confirmed neuropathic pain receiving cannabis therapy for 48 months. Assessments: NRS (pain), GAD-7 (anxiety), Biowell UPE measurements. Correlation analyses, ROC analysis, and mixed-effects modeling for UPE specificity.","limitations":"No control group or placebo arm—the 91.5% response rate could partly reflect placebo effects, regression to the mean, or other treatments. UPE/Biowell is a novel and controversial measurement technology with limited validation. All patients had neuropathic pain—results don't apply to other pain types. Self-selected patients receiving cannabis therapy may be predisposed to report improvement. Israeli medical cannabis program context may differ from other healthcare systems."},{"rthcId":"RTHC-07996","title":"Cross-reactivity in urine of 53 cannabinoid analogs and metabolites using a carboxylic acid enzyme-linked immunosorbent assay (ELISA) and homogenous enzyme immunoassay (HEIA) kit and immunalysis synthetic cannabinoid HEIA kits.","authors":"Yates, Taylor L; Poklis, Justin L; Holt, Alaina K; Fleming, James H; Bayard, Ciena; Raso, Stephen A; Peace, Michelle R","year":2025,"journal":"Journal of analytical toxicology, 49(8), 587-593","doi":"10.1093/jat/bkaf055","pmid":"40577619","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-07997","title":"Cannabinoids drive feeding through AgRP neurons.","authors":"Yavuz, Yavuz; Goren, Habibe; Yilmaz, Bayram","year":2025,"journal":"Brain research, 1865, 149857","doi":"10.1016/j.brainres.2025.149857","pmid":"40738463","tags":["endocannabinoid-system","appetite","agrp-neurons","feeding","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CB1 receptor activation reduced inhibitory signals to AgRP hunger neurons, increasing their activity. Ablating AgRP neurons eliminated both the appetite-stimulating and anxiolytic effects of cannabinoids, proving these neurons are essential for cannabis-induced hunger.","whyItMatters":"The 'munchies' are one of cannabis's most well-known effects, but the specific brain circuit was unclear. Identifying AgRP neurons as the key link could help develop treatments for appetite disorders that target this pathway.","specificNumbers":"CB1R agonist ACEA reduced inhibitory postsynaptic currents (sIPSCs) in AgRP neurons. AgRP ablation eliminated hyperphagic and anxiolytic effects of ACEA.","methodology":"Preclinical study using slice electrophysiology and AgRP neuron ablation in mice to determine how CB1 receptor activation drives feeding behavior through arcuate nucleus hunger circuits.","limitations":"Mouse brain circuits may not perfectly translate to humans. Pharmacological activation differs from natural cannabis use. Ablation is an extreme manipulation that doesn't reflect normal physiology."},{"rthcId":"RTHC-07998","title":"CB1 receptor activation and inhibition differentially modulate cognitive deficits and neuropathology in 3xTg-AD mice.","authors":"Ye, Minsook; Kim, Jin Su; Shim, Insop","year":2025,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 193, 118818","doi":"10.1016/j.biopha.2025.118818","pmid":"41314098","tags":["cb1-receptor","alzheimers","tau","neuroinflammation","preclinical","neuroprotection"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"CB1 agonist ACEA reduced tau phosphorylation, glial activation, IL-1beta, and oxidative stress while preserving neurons and improving brain glucose metabolism. The inverse agonist AM251 worsened all these measures. CB1 was predominantly localized to microglia, suggesting a microglia-dependent neuroprotective mechanism.","whyItMatters":"This study provides strong preclinical evidence that CB1 receptor activation could be therapeutically beneficial in Alzheimer's — not just symptom management but actual disease modification through reduced tau pathology and neuroinflammation.","specificNumbers":"6 months of weekly treatment (ages 6-12 months). CB1 agonist ACEA at 1 mg/kg, inverse agonist AM251 at 1 mg/kg. Cognitive function tested via Morris Water Maze and Y-maze. Brain metabolism measured with 18F-FDG PET.","methodology":"3xTg-AD mice received weekly injections of CB1 agonist (ACEA) or inverse agonist (AM251) from 6-12 months of age, with cognitive testing, histology, immunofluorescence, and FDG-PET brain imaging.","limitations":"Mouse model doesn't fully replicate human AD. Weekly injections of synthetic agonist differ from cannabis use. AM251 is an inverse agonist (not just antagonist), making comparison complex. Aβ levels were unaffected by either treatment."},{"rthcId":"RTHC-07999","title":"Trends in substance use among child welfare-involved parents during the COVID-19 pandemic.","authors":"Ye, Yun; Dellor, Elinam; Freisthler, Bridget","year":2025,"journal":"Child abuse & neglect, 166, 107487","doi":"10.1016/j.chiabu.2025.107487","pmid":"40397996","tags":["child-welfare","parental-substance-use","covid-pandemic","cannabis","polysubstance"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"During the first weeks of the COVID-19 pandemic, the percentage of child welfare cases involving substance use jumped from 32.4% to 41.8%, with cannabis use notably driving this change. The spike was unique to 2020 and not seen in 2019, 2021, or 2022.","whyItMatters":"The pandemic created unprecedented stress for parents, and this data shows cannabis was a primary coping mechanism. Understanding these patterns helps child welfare systems prepare for future crises and target support appropriately.","specificNumbers":"264,380 women investigated, 65,796 (24.9%) involved substance use. Cases jumped from 32.4% to 41.8% in week 10 of 2020, coinciding with the national emergency declaration.","methodology":"Retrospective observational study of 264,380 female parents assessed for child abuse/neglect in Ohio (2019-2022), using changepoint analysis to identify shifts in substance involvement patterns.","limitations":"Ohio-specific data may not generalize nationally. Only female parents included. Substance involvement is recorded at assessment, not necessarily verified. Cannot distinguish between harmful use and low-risk use."},{"rthcId":"RTHC-08000","title":"Differential metabolic pathways underlie THC- and CBD-mediated inhibition of B-cell activation in both young and aged mice.","authors":"Yekhtin, Zhanna; Petukhov, Dmytro; Khuja, Iman; Kogan, Natalya M; Or, Reuven; Almogi-Hazan, Osnat","year":2025,"journal":"Frontiers in immunology, 16, 1605474","doi":"10.3389/fimmu.2025.1605474","pmid":"40599768","tags":["thc","cbd","b-cells","immune-system","aging","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Both cannabinoids reduced B-cell activation dose-dependently, but THC selectively reduced certain amino acids while CBD increased citrulline and allantoin. Effects differed between young and aged mice, suggesting age-related endocannabinoid system changes affect cannabinoid sensitivity.","whyItMatters":"Understanding how cannabinoids affect the immune system differently — and how this changes with age — is critical for evaluating both therapeutic applications and risks, especially as cannabis use increases among older adults.","specificNumbers":"Dose-dependent inhibition by both THC and CBD. Both reduced glucose-6-phosphate and pentose phosphate pathway metabolites. THC uniquely reduced specific amino acids. CBD uniquely increased citrulline and allantoin.","methodology":"In vitro study comparing THC and CBD effects on LPS/IL-4-activated murine B lymphocytes from young and aged mice, measuring phenotype, proliferation, antibody secretion, TNF-alpha, ERK phosphorylation, and cellular metabolomics.","limitations":"In vitro study using mouse cells — human immune responses may differ. LPS/IL-4 activation is a simplified model. Metabolomic changes may not translate to functional immune outcomes."},{"rthcId":"RTHC-08001","title":"Cannabinoid-like compounds found in non-cannabis plants exhibit antiseizure activity in genetic mouse models of drug-resistant epilepsy.","authors":"Yip, Ka Lai; Udoh, Michael; Sharman, Laura A; Harman, Thomas; Bedoya-Pérez, Miguel; Anderson, Lyndsey L; Banister, Samuel D; Arnold, Jonathon C","year":2025,"journal":"Epilepsia, 66(1), 303-314","doi":"10.1111/epi.18177","pmid":"39530840","tags":["epilepsy","dravet-syndrome","lennox-gastaut","magnolol","antiseizure","non-cannabis"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"Magnolol reduced seizures in both Dravet (Scn1a+/-) and Lennox-Gastaut (Gabrb3+/D120N) mouse models and had excellent brain penetration (brain-to-plasma ratio 7.56). Both compounds inhibited T-type calcium channels but had no specific cannabinoid receptor activity.","whyItMatters":"CBD is already FDA-approved for these epilepsies, but not all patients respond. Finding structurally related compounds from non-cannabis sources that work through different mechanisms (T-type calcium channels rather than CB receptors) could expand treatment options.","specificNumbers":"Magnolol brain-to-plasma ratio: 7.56. Honokiol: 3.55. Amorfrutin 2: 0.06. Amorfrutin 2 and magnolol increased seizure threshold in Scn1a+/- mice and reduced hindlimb extension in MES test.","methodology":"Preclinical study testing three cannabis-like compounds (amorfrutin 2, honokiol, magnolol) in genetic mouse models of Dravet and Lennox-Gastaut syndrome, with pharmacokinetic profiling and molecular pharmacology at CB receptors and T-type calcium channels.","limitations":"Mouse epilepsy models don't perfectly replicate human seizure disorders. These are early-stage findings needing extensive development. Magnolol's non-cannabinoid mechanism means it may have different side effect profiles."},{"rthcId":"RTHC-08002","title":"Developmental toxicity and gene expression alterations induced by the synthetic cannabinoid CUMYL-4CN-BINACA in zebrafish embryos.","authors":"Yılmaztürk, Derya; Alat, Ömercan; Aksakal, Özkan; Kullebi, Berşan; Lafzi, Ayşe; Şişman, Turgay","year":2025,"journal":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 205, 115712","doi":"10.1016/j.fct.2025.115712","pmid":"40854477","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08003","title":"Lower striatal dopamine D2 receptor availability in individuals who test positive for quantitated urine metabolites of tobacco and/or marijuana smoke.","authors":"Yoder, Karmen K; Carpenter, Samantha; Hile, Karen L; Dzemidzic, Mario; Durazzo, Timothy C","year":2025,"journal":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","doi":"10.1093/ntr/ntaf249","pmid":"41307548","tags":["dopamine","d2-receptors","smoking","cannabis","pet-imaging","brain"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Individuals positive for urine metabolites of tobacco and/or cannabis had an average 13.1% lower D2 receptor availability across all striatal subregions compared to negative individuals, with the most significant differences in reward-related brain areas.","whyItMatters":"Lower D2 receptors in reward circuits are associated with addiction vulnerability and reduced reward sensitivity. Finding that both tobacco and cannabis smoke lower D2 availability suggests shared mechanisms of combustible smoke impact on the brain's reward system.","specificNumbers":"29 participants. 13.1% average lower D2 BPND in analyte-positive group (range: 6.6-20.0%). Significant differences in nucleus accumbens and putamen. No effects of alcohol use disorder.","methodology":"Cross-sectional PET imaging study using [11C]raclopride in 29 participants, comparing striatal D2 receptor availability between those with quantified positive vs. negative urine metabolites for nicotine (cotinine) and THC (THCA).","limitations":"Very small sample of 29. Cross-sectional design cannot determine if low D2 preceded or resulted from substance use. Cannot separate tobacco from cannabis effects within the positive group."},{"rthcId":"RTHC-08004","title":"Cannabinoid 1 receptor occupancy and neurovascular responses induced by agonist, antagonist/inverse-agonist, and potential modulator in non-human primate brains: PET/fMRI study.","authors":"Yoo, Chi-Hyeon; Xu, Yulong; Bagdasarian, Frederick A; Lin, Yu-Shiuan; Wang, Changning; Wey, Hsiao-Ying","year":2025,"journal":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 271678X251389042","doi":"10.1177/0271678X251389042","pmid":"41185392","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08005","title":"CRISP: A cost-efficient, high-throughput pipeline for sex-identification in Cannabis sativa.","authors":"Yoon, Hyuk Sung; Zander, Mark","year":2025,"journal":"microPublication biology, 2025","doi":"10.17912/micropub.biology.001891","pmid":"41487910","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08006","title":"Potential of Cannabidiol (CBD) to overcome extensively drug-resistant Acinetobacter baumannii.","authors":"Yosboonruang, Atchariya; Kiddee, Anong; Siriphap, Achiraya; Pook-In, Grissana; Suwancharoen, Chittakun; Duangjai, Acharaporn; Praphasawat, Ratsada; Reuk-Ngam, Nanthawan; Nawong, Siriwan; Rawangkan, Anchalee","year":2025,"journal":"BMC complementary medicine and therapies, 25(1), 308","doi":"10.1186/s12906-025-05056-w","pmid":"40817249","tags":["cbd","antimicrobial","drug-resistance","acinetobacter","biofilm","antibiotics"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD synergized with gentamicin, meropenem, and colistin against XDR A. baumannii, reducing effective antibiotic concentrations up to 1,000-fold. CBD caused rapid concentration-dependent killing through extensive membrane damage, confirmed by electron microscopy.","whyItMatters":"Extensively drug-resistant bacteria are a global health crisis. CBD's ability to synergize with existing antibiotics — potentially making them effective again at much lower doses — represents a novel approach to antimicrobial resistance.","specificNumbers":"26 XDR A. baumannii isolates from ICU devices. CBD MIC: 3.9 to >500 µg/mL. Synergy with gentamicin, meropenem, colistin reduced effective concentrations up to 1,000-fold. Complete bacterial clearance at 4× MIC within 2 hours.","methodology":"In vitro study testing CBD against 26 XDR A. baumannii ICU isolates using MIC/MBC determination, checkerboard synergy assays, biofilm inhibition/eradication, time-kill studies, membrane integrity assays, and scanning electron microscopy.","limitations":"In vitro study only — achievable tissue concentrations of CBD may limit in vivo effectiveness. MIC range was very wide (3.9-500+ µg/mL), suggesting variable effectiveness. No animal infection model tested."},{"rthcId":"RTHC-08007","title":"Anti-convulsant efficacy of long-acting injectable cannabidiol formulation (IVL5005) in the pentylenetetrazol-induced convulsions, with pharmacokinetic characterization.","authors":"Youm, Soyoung; Cha, Joo Young; Lee, Slgirim; Seo, Young Dai; Park, Kun Hee; Song, Aeri; Park, Hyun-Je; Chan Son, Woo; Kim, Juhee","year":2025,"journal":"Frontiers in pharmacology, 16, 1692123","doi":"10.3389/fphar.2025.1692123","pmid":"41208858","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08008","title":"Cannabis Retailer Advice on Blunt, Tobacco, and Cannabis Use During Pregnancy.","authors":"Young-Wolff, Kelly C; Does, Monique B; Negusse, Rahel; Ogden, Shannon N; Nugent, Joshua R; Silver, Lynn D; Soroosh, Aurash J; Metz, Torri D","year":2025,"journal":"JAMA network open, 8(12), e2548373","doi":"10.1001/jamanetworkopen.2025.48373","pmid":"41370076","tags":["pregnancy","budtenders","cannabis-retailers","prenatal","harm-reduction","public-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"While 80% of budtenders advised against prenatal tobacco and blunt use, only 40% said prenatal cannabis use was unsafe. 21% said it was safe, and only 6% mentioned store/product warnings. Less than half recommended speaking to a physician.","whyItMatters":"Pregnant people often consult budtenders as trusted sources. The finding that most budtenders don't warn against prenatal cannabis use — despite medical consensus — highlights a critical gap in consumer protection and public health education.","specificNumbers":"505 budtenders surveyed. 79.6% said blunts unsafe, 79.2% said tobacco unsafe, but only 40.4% said cannabis unsafe. 20.6% said cannabis was safe. Only 5.7% mentioned product warnings. 44% recommended seeing a physician.","methodology":"Cross-sectional mystery shopper study of 505 California cannabis retailers (Feb 2024-Jan 2025), with callers posing as pregnant individuals asking about safety of prenatal blunt, tobacco, and cannabis use.","limitations":"California-only sample. Mystery shopper scenario may not represent real customer interactions. Budtender responses may vary by training, experience, and store policy. Published in JAMA Network Open."},{"rthcId":"RTHC-08009","title":"Association of preconception cannabis use frequency with cannabis use during early pregnancy.","authors":"Young-Wolff, Kelly C; Chi, Felicia W; Campbell, Cynthia I; Does, Monique B; Wysota, Christina N; Ansley, Deborah; Castellanos, Carley; Lapham, Gwen T","year":2025,"journal":"BMC pregnancy and childbirth, 25(1), 1044","doi":"10.1186/s12884-025-08190-y","pmid":"41062979","tags":["pregnancy","preconception","cannabis-screening","prenatal-use","prevention"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Daily preconception cannabis use was associated with 2.66 times greater risk of prenatal use compared to monthly or less use. Nearly half (45.1%) of all preconception cannabis users screened positive during pregnancy.","whyItMatters":"If frequency of preconception use predicts prenatal use this strongly, healthcare providers can identify high-risk individuals before pregnancy and provide targeted education and support.","specificNumbers":"40,806 pregnancies. 45.1% screened positive for prenatal use. Daily preconception use: aPR = 2.66 (95% CI: 2.59-2.73). Weekly: aPR = 1.99 (95% CI: 1.93-2.05). 65.7% non-White, 27.6% aged <25.","methodology":"Retrospective observational study of 40,806 pregnancies (36,622 unique individuals) in Kaiser Permanente Northern California (2011-2022) with self-reported preconception cannabis use, using modified Poisson models.","limitations":"Single healthcare system in California. Self-report may underestimate use. Cannot account for all confounders. Excluded 2020 (pandemic year)."},{"rthcId":"RTHC-08010","title":"Association of Preconception and Prenatal Cannabis Use With Breastfeeding.","authors":"Young-Wolff, Kelly C; Adams, Sara R; Homsley, Kenya J; Alexeeff, Stacey E; Gunderson, Erica P; Does, Monique B; Ansley, Deborah; Castellanos, Carley; Haley, Erica; Avalos, Lyndsay A","year":2025,"journal":"American journal of preventive medicine, 69(6), 107964","doi":"10.1016/j.amepre.2025.107964","pmid":"40602694","tags":["pregnancy","breastfeeding","cannabis","lactation","infant-feeding"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"While breastfeeding initiation was similar across groups (90-96%), prenatal cannabis users were 12% more likely to stop breastfeeding earlier (aHR = 1.12) and had 16-19% lower breastfeeding prevalence at 6 and 12 months. Preconception-only use showed minimal differences.","whyItMatters":"Breastfeeding provides significant health benefits for both mother and infant. Understanding that prenatal cannabis use is associated with earlier discontinuation can help lactation consultants provide targeted support.","specificNumbers":"200,207 pregnancies. 7.6% preconception cannabis only, 7.2% prenatal use. 94.6% initiated breastfeeding. Prenatal use: aHR for stopping = 1.12 (95% CI: 1.09-1.15). 6-month aPR = 0.84, 12-month aPR = 0.81.","methodology":"Population-based retrospective cohort of 200,207 pregnancies in Northern California (2016-2022) with universal early pregnancy screening, tracking longitudinal breastfeeding outcomes at well-child visits through the first year.","limitations":"Observational study cannot determine causation. Cannabis users may differ in other ways that affect breastfeeding. Cannot distinguish whether healthcare providers discouraged breastfeeding in cannabis users."},{"rthcId":"RTHC-08011","title":"Frequency of Preconception and Prenatal Cannabis Use and Nausea and Vomiting in Pregnancy.","authors":"Young-Wolff, Kelly C; Chi, Felicia W; Campbell, Cynthia I; Alexeeff, Stacey E; Ansley, Deborah; Vanderziel, Alyssa; Lapham, Gwen T","year":2025,"journal":"Obstetrics and gynecology, 145(5), 519-522","doi":"10.1097/AOG.0000000000005884","pmid":"40080822","tags":["pregnancy","nausea","vomiting","cannabis","morning-sickness","nvp"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Daily prenatal cannabis use was associated with 3.80x odds of severe NVP and 1.97x odds of mild NVP. Even preconception daily use predicted 2.61x odds of severe NVP, suggesting either reverse causation or that chronic use sensitizes the vomiting response.","whyItMatters":"Many pregnant individuals use cannabis specifically to treat morning sickness. This large study suggests the opposite — that cannabis use is associated with worse nausea and vomiting, possibly through a mechanism similar to cannabinoid hyperemesis syndrome.","specificNumbers":"356,343 pregnancies. 11.3% preconception use, 6.5% prenatal use. 3.6% diagnosed with severe NVP, 16% mild NVP. Daily prenatal use: severe NVP aOR = 3.80 (95% CI: 3.28-4.39), mild NVP aOR = 1.97 (95% CI: 1.79-2.17).","methodology":"Cross-sectional analysis of 356,343 pregnancies in Kaiser Permanente Northern California (2011-2022) with universal screening for cannabis use and ICD-coded NVP diagnoses.","limitations":"Cross-sectional design cannot determine direction of causation — women with worse NVP may use more cannabis to cope. ICD codes may undercount NVP. Cannabis use frequency is self-reported."},{"rthcId":"RTHC-08012","title":"Alcohol, Cannabis, and nicotine use during early pregnancy and infant hearing loss.","authors":"Young-Wolff, Kelly C; Oberman, Nina; Alexeeff, Stacey E; Croen, Lisa A; Steuerle, Kristin R; Ansley, Deborah; Castellanos, Carley; Avalos, Lyndsay A","year":2025,"journal":"Preventive medicine, 192, 108242","doi":"10.1016/j.ypmed.2025.108242","pmid":"39938724","tags":["pregnancy","alcohol","hearing-loss","prenatal-exposure","infant-outcomes"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Prenatal alcohol use was associated with increased infant hearing loss risk (aRR: 1.37, 95% CI: 1.05-1.79), but neither prenatal cannabis use nor nicotine use was significantly associated with hearing loss in the first six months of life.","whyItMatters":"This large study helps clarify which prenatal substance exposures specifically affect infant hearing. The null finding for cannabis provides reassurance on this particular outcome, while reinforcing alcohol's known developmental risks.","specificNumbers":"297,147 infants. 9.9% prenatal alcohol exposure, 5.6% cannabis, 3.9% nicotine. 0.2% had hearing loss diagnosis. Alcohol: aRR = 1.37 (95% CI: 1.05-1.79). Cannabis and nicotine: not significant.","methodology":"Population-based retrospective birth cohort of 297,147 infants born to 233,902 universally screened parents in Kaiser Permanente Northern California (2011-2023), using modified Poisson regression.","limitations":"Low overall hearing loss prevalence (0.2%) limits statistical power for detecting smaller effects. Screening-based substance detection may undercount actual use. ICD-based hearing loss diagnosis may miss mild cases."},{"rthcId":"RTHC-08013","title":"Sociodemographic differences in modes of cannabis use among pregnant individuals in Northern California.","authors":"Young-Wolff, Kelly C; Cortez, Catherine A; Nugent, Joshua R; Padon, Alisa A; Prochaska, Judith J; Adams, Sara R; Slama, Natalie E; Soroosh, Aurash J; Does, Monique B; Campbell, Cynthia I; Ansley, Deborah; Castellanos, Carley; Brown, Qiana L","year":2025,"journal":"Drug and alcohol dependence, 267, 112546","doi":"10.1016/j.drugalcdep.2024.112546","pmid":"39793365","tags":["pregnancy","cannabis-modes","smoking","edibles","vaping","sociodemographic"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Smoking predominated (71.1%), but nearly 30% used multiple modes. Those who dabbed (54.3%) or used multiple modes (45.3%) were most likely to use daily. Smoking was more common among younger, Black, and disadvantaged populations, while edibles were more common among older and higher-SES groups.","whyItMatters":"Different consumption methods carry different risks during pregnancy — smoking adds combustion byproducts, edibles have prolonged THC exposure, and dabbing involves high-potency concentrates. Understanding who uses which method enables targeted harm reduction.","specificNumbers":"3,507 pregnancies. Smoking: 71.1%, edibles: 32.6%, vaping: 22.2%, dabs: 9.9%, topicals: 4.6%. Multiple modes: 29.9%. Daily use: dabbers 54.3%, multi-mode 45.3%, edible-only 28.2%.","methodology":"Cross-sectional study of 3,507 pregnancies (2021-2022) in Kaiser Permanente Northern California with self-reported prenatal cannabis modes of use during universal screening at prenatal care entry.","limitations":"Single healthcare system in California. Self-reported modes may be subject to social desirability. Cannot determine whether modes changed during pregnancy. No outcome data linked to specific modes."},{"rthcId":"RTHC-08014","title":"Prenatal Cannabis Use and Offspring Attention Deficit Hyperactivity Disorder and Disruptive Behavior Disorders: A Retrospective Cohort Study.","authors":"Young-Wolff, Kelly C; Kong, Kevin; Alexeeff, Stacey E; Croen, Lisa A; Oberman, Nina; Kirane, Harshal; Ansley, Deborah; Davignon, Meghan; Adams, Sara R; Avalos, Lyndsay A","year":2025,"journal":"Journal of developmental and behavioral pediatrics : JDBP, 46(1), e25-e32","doi":"10.1097/DBP.0000000000001323","pmid":"39400201","tags":["pregnancy","adhd","behavior-disorders","prenatal-cannabis","child-development"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"After adjusting for maternal sociodemographics, other substance use, and comorbidities, prenatal cannabis use showed no association with ADHD (aHR: 0.84) and an inverse association with DBD (aHR: 0.83). Frequency of use was also not associated with outcomes.","whyItMatters":"This is one of the largest and best-controlled studies on prenatal cannabis and child behavioral outcomes. The null finding challenges prior smaller studies that suggested links and provides reassurance on these specific outcomes.","specificNumbers":"141,570 children, 117,130 pregnancies. 4.6% screened positive for cannabis. 7.7% offspring had ADHD, 6.8% had DBD. ADHD: aHR = 0.84 (95% CI: 0.70-1.01). DBD: aHR = 0.83 (95% CI: 0.71-0.97).","methodology":"Population-based retrospective birth cohort of 141,570 children born 2011-2018 in Kaiser Permanente Northern California, with universal prenatal cannabis screening and follow-up to age 11 for ADHD and DBD diagnoses.","limitations":"Observational study cannot prove absence of effect. Cannabis use is self-reported and may be underestimated. Cannot account for all confounders. Follow-up to age 11 may miss later-diagnosed cases."},{"rthcId":"RTHC-08015","title":"Evaluation of Cannabis sativa L. Callus Extract as a Novel Cosmetic Ingredient with Dual Anti-Inflammatory and Antioxidant Effects.","authors":"Yu, Ga-Ram; Kim, Da-Hoon; Kim, Hyuck; Lim, Dong-Woo","year":2025,"journal":"Plants (Basel, Switzerland), 14(7)","doi":"10.3390/plants14071148","pmid":"40219215","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08016","title":"Cluster profiles of distressing psychotic-like experiences among children and associations with genetic risk, prenatal cannabis exposure, and social-environmental characteristics.","authors":"Yuan, Qingyue; Chen, Yinxian; Xu, Ying; Dimitrov, Lina V; Risk, Benjamin B; Walker, Elaine F; Huels, Anke; Ku, Benson S","year":2025,"journal":"Schizophrenia research, 278, 119-127","doi":"10.1016/j.schres.2025.03.034","pmid":"40156962","tags":["psychosis","children","prenatal-cannabis","psychotic-experiences","abcd-study"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Three distressing PLE subgroups were identified: hallucinatory-like, paranoid-like, and multiple domains. Prenatal cannabis exposure specifically predicted hallucinatory-like PLEs (OR = 1.578), while schizophrenia genetic risk predicted paranoid-like PLEs. All groups showed associations with childhood adversity and poor school environments.","whyItMatters":"This study suggests prenatal cannabis exposure may specifically affect certain types of psychotic experiences in children, potentially through distinct neurodevelopmental pathways that differ from genetic predisposition.","specificNumbers":"11,854 children. 3,155 with at least one distressing PLE. Three clusters: hallucinatory-like (n=1,110), paranoid-like (n=1,229), multiple domains (n=816). Prenatal cannabis: OR = 1.578 (95% CI: 1.231-2.023) for hallucinatory-like PLEs.","methodology":"Cross-sectional analysis of 11,854 children from the ABCD Study v5.1, using K-medoid clustering of psychotic-like experiences and multinomial models examining genetic and environmental risk factors.","limitations":"Cross-sectional analysis of one time point. Prenatal cannabis exposure is retrospectively reported and may be inaccurate. PLEs are self-reported by children. Cannot establish causation."},{"rthcId":"RTHC-08017","title":"Pharmacokinetics and pharmacodynamics of cannabigerol (CBG) in the C57BL/6Crl mouse.","authors":"Zagzoog, Ayat; Halter, Kenzie; Ha, Nini; Jones, Alayna M; Andres, Rachel; Kim, Andy; Michel, Deborah; Alcorn, Jane; Laprairie, Robert B","year":2025,"journal":"Frontiers in pharmacology, 16, 1672098","doi":"10.3389/fphar.2025.1672098","pmid":"41446792","tags":["cbg","cannabigerol","pharmacokinetics","non-intoxicating","preclinical"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"CBG showed no cataleptic, hypothermic, anti-nociceptive, or locomotor effects at any tested blood concentration or route of administration (oral, intraperitoneal, intravenous), confirming it lacks THC-like intoxicating properties.","whyItMatters":"CBG is increasingly marketed in wellness products, but its pharmacology has been poorly characterized. This study confirms CBG won't produce a high even at concentrations exceeding what consumers would achieve, providing a safety baseline.","specificNumbers":"Blood sampling at 10 min, 30 min, 1h, 3h, 6h, 12h, 18h, and 24h post-administration. Tested oral, intraperitoneal, and intravenous routes. Quantified by HPLC-MS/MS.","methodology":"Pharmacokinetic profiling of CBG via oral, intraperitoneal, and intravenous administration in C57BL/6Crl mice with blood sampling at 8 time points, plus pharmacodynamic testing for catalepsy, hypothermia, pain response, and locomotion.","limitations":"Mouse pharmacology may not perfectly translate to humans. Therapeutic effects (like anxiolytic potential) were not the focus of this study. Does not assess long-term safety."},{"rthcId":"RTHC-08018","title":"RSM-Based Optimization of Dose Response and Antibacterial Potential of Cannabis sativa (L.) Leaves Using Computational Analysis.","authors":"Zahid, Sara; Chinnam, Sampath; Ahmed, Asma; Masaud, Syed Muzzammil; Khurshid, Beenish; Farman, Saira; Rashid, Sana; Zahid, Fatima","year":2025,"journal":"Dose-response : a publication of International Hormesis Society, 23(4), 15593258251404067","doi":"10.1177/15593258251404067","pmid":"41324030","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08019","title":"Development of novel electrospun nanofibers loaded with Levosulpiride and Cannabidiol encapsulated in cyclodextrin-phospholipid inclusion complex for ameliorated treatment of anxiety and depression.","authors":"Zai, Iqra; Aqil, Mohd; Sultana, Yasmin","year":2025,"journal":"International journal of pharmaceutics, 682, 125909","doi":"10.1016/j.ijpharm.2025.125909","pmid":"40582526","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08020","title":"Perturbations of CB1 receptor signalling during adolescence impair cortical myelination in female rats.","authors":"Zamberletti, Erica; Manenti, Cristina; Prini, Pamela; Gabaglio, Marina; Grimaldi, Annalisa; Pulze, Laura; Grassi, Riccardo; Rubino, Tiziana","year":2025,"journal":"Pharmacological research, 216, 107758","doi":"10.1016/j.phrs.2025.107758","pmid":"40306605","tags":["adolescent-brain","thc","myelination","prefrontal-cortex","female","preclinical"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"Both CB1 receptor blockade and THC exposure during adolescence hindered prefrontal cortex myelination in female rats. THC effects were specific to early-to-mid adolescence and, with intensive exposure, persisted into adulthood. Disrupted myelination was associated with increased risk-taking and involved the AKT/Hippo/YAP signaling pathway.","whyItMatters":"Adolescent brain development involves critical white matter formation. This study shows THC can disrupt this process in female rats during a specific developmental window, with potentially permanent consequences — directly relevant to rising teen cannabis use.","specificNumbers":"THC impaired myelin formation only during early-to-mid adolescence. Intensive exposure protocol produced long-lasting effects persisting into adulthood. Associated with increased risk-taking behavior.","methodology":"Preclinical study examining CB1 receptor blockade and THC exposure during adolescence in female rats, measuring prefrontal cortex myelination, behavior (risk-taking), and AKT/Hippo/YAP signaling pathway changes.","limitations":"Female rats only — sex-specific findings may not apply to males. Rat adolescence timing differs from human. THC doses and routes may not reflect typical human use patterns."},{"rthcId":"RTHC-08021","title":"Cannabinoid and cannabinoid related receptors in fibroblasts, inflammatory and endothelial cells of the equine hoof with and without laminitis: novel pharmacological target.","authors":"Zamith Cunha, Rodrigo; Gobbo, Francesca; Morini, Maria; Salamanca, Giulia; Zanoni, Augusta; Bernardini, Chiara; Gramenzi, Alessandro; Chiocchetti, Roberto","year":2025,"journal":"Frontiers in veterinary science, 12, 1723160","doi":"10.3389/fvets.2025.1723160","pmid":"41394912","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08022","title":"Distribution of endocannabinoid system receptors in the equine hoof: dysregulation as a potential therapeutic target for laminitis.","authors":"Zamith Cunha, Rodrigo; Gobbo, Francesca; Morini, Maria; Zannoni, Augusta; Mainardi, Carlo; D'arpe, Lorenzo; Gramenzi, Alessandro; Chiocchetti, Roberto","year":2025,"journal":"Histochemistry and cell biology, 163(1), 71","doi":"10.1007/s00418-025-02397-y","pmid":"40593311","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08023","title":"Canadian nursing students and education in medical and recreational cannabis: a preliminary evidence.","authors":"Zanchetta, Margareth Santos; Metersky, Kateryna; Tan, Valerie; Lucchese, Stephanie Pedrotti; Siganevich, Yana; Sivasundaram, Prashajini; Nguyen, Truong Thanh Binh; Cordon, Charissa; Qureshi, Imran","year":2025,"journal":"International journal of nursing education scholarship, 22(1)","doi":"10.1515/ijnes-2024-0009","pmid":"40152286","tags":["nursing-education","cannabis-knowledge","canada","medical-cannabis","healthcare-training"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Nursing students disclosed knowledge gaps in cannabis regulations (90%), effectiveness (88%), and dosing best practices (86%). Clinical exposure and virtual resources were identified as the most effective learning stimulants.","whyItMatters":"Nurses are often the front line of patient care. If they graduate without understanding cannabis — which is legal across Canada — they can't effectively counsel patients or recognize cannabis-related health issues.","specificNumbers":"153 nursing students. Knowledge gaps: regulations 90%, effectiveness 88%, dosing 86%. Survey ran September 2022 to February 2023.","methodology":"Online survey of 153 Canadian undergraduate and graduate nursing students (September 2022-February 2023) examining knowledge, interest, and learning preferences regarding medical and recreational cannabis.","limitations":"Small sample from Canadian programs. Self-reported knowledge gaps may not reflect actual knowledge. Students who participated may be more interested in cannabis topics than average."},{"rthcId":"RTHC-08024","title":"Substance Use Classes Among YMSM in an HIV Digital Health Intervention Program: Implications for Acceptability, Engagement, and Health Outcomes.","authors":"Zapata, Juan Pablo; Swann, Gregory; Zamantakis, Alithia; Madkins, Krystal; Danielson, Elizabeth Caitlin Anne; Mustanski, Brian","year":2025,"journal":"AIDS and behavior, 29(5), 1479-1491","doi":"10.1007/s10461-025-04619-9","pmid":"39865200","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08025","title":"Prevalence and correlates of alcohol, cannabis, and tobacco use disorder in DSM-5 generalized anxiety disorder: Findings from the National Epidemiologic Survey on Alcohol and Related Conditions-III.","authors":"Zech, James M; Patel, Tapan A; Cougle, Jesse R","year":2025,"journal":"Journal of anxiety disorders, 115, 103060","doi":"10.1016/j.janxdis.2025.103060","pmid":"40865185","tags":["generalized-anxiety","substance-use-disorder","cannabis-use-disorder","dsm-5","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Lifetime GAD was associated with lifetime alcohol and cannabis use disorders but not tobacco. Past-year GAD was associated with past-year cannabis and tobacco use disorders but not alcohol. Alcohol use disorder (but not CUD or TUD) was associated with higher GAD treatment-seeking.","whyItMatters":"The relationship between anxiety and cannabis use is often debated — do anxious people self-medicate with cannabis, or does cannabis cause anxiety? This large national study using updated DSM-5 criteria helps clarify these comorbidity patterns.","specificNumbers":"NESARC-III nationally representative sample. Lifetime GAD positively associated with lifetime alcohol and cannabis use disorder. Past-year GAD associated with past-year cannabis and tobacco use disorder. Controlled for demographics and comorbidities.","methodology":"Cross-sectional analysis of the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III), examining associations between DSM-5 GAD and alcohol, cannabis, and tobacco use disorders with demographic covariates.","limitations":"Cross-sectional design cannot determine direction of causation. Self-reported substance use and mental health diagnoses. NESARC-III data collected before recent waves of cannabis legalization."},{"rthcId":"RTHC-08026","title":"Associations between psychedelic use and cannabis use disorder in a nationally representative sample.","authors":"Zech, James M; Yaden, David B; Jones, Grant M","year":2025,"journal":"Drug and alcohol dependence, 266, 112502","doi":"10.1016/j.drugalcdep.2024.112502","pmid":"39586127","tags":["psychedelics","cannabis-use-disorder","psilocybin","lsd","substance-use"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Lifetime psilocybin and past-year LSD use were both associated with 1.89-2.04 times higher rates of past-year DSM-5 cannabis use disorder. Past-year LSD also predicted three specific CUD symptoms among cannabis users.","whyItMatters":"While psychedelics are being investigated as treatments for substance use disorders, this population-level data suggests that in naturalistic settings, psychedelic use actually co-occurs with more problematic cannabis use — complicating the therapeutic narrative.","specificNumbers":"Psilocybin use: aRR 1.89-2.04 for CUD. Past-year LSD: aRR 1.89-2.04 for CUD. LSD predicted 3 of 11 CUD symptoms (aRR 1.45-1.73). Moderate-to-severe CUD: aRR 1.65-2.07.","methodology":"Survey-weighted multivariable logistic regressions analyzing NSDUH data (2015-2019, 2021-2022) examining associations between classic and non-classic psychedelic use and disordered cannabis use.","limitations":"Cross-sectional design — people who use psychedelics may simply be more likely to use cannabis heavily for reasons unrelated to the psychedelic experience. Cannot distinguish therapeutic from recreational psychedelic use."},{"rthcId":"RTHC-08027","title":"Moderating Effect of Participation in Organized College Sports on Mental Health and Frequency of Cannabis Use in a National Cohort.","authors":"Zeiger, Joanna S; Conner, Bradley T","year":2025,"journal":"American journal of preventive medicine, 70(4), 108148","doi":"10.1016/j.amepre.2025.108148","pmid":"41109643","tags":["college-sports","mental-health","cannabis","depression","anxiety","protective-factor"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Higher cannabis use frequency was associated with greater likelihood of depression, anxiety, and PTSD diagnoses. However, organized sports participation significantly moderated this relationship — student-athletes had lower mental health diagnosis rates at every level of cannabis use compared to non-athletes.","whyItMatters":"This massive dataset suggests sports don't just benefit mental health generally — they specifically buffer the mental health risks associated with cannabis use, providing a concrete, actionable protective factor for college health programs.","specificNumbers":"150,992 participants. 87.5% ages 18-29, 70.3% female, 72.3% non-Hispanic White. Weekly-to-daily cannabis users had highest mental health diagnosis rates. Sports participation significantly lowered rates across all cannabis use levels (p < 0.001).","methodology":"Cross-sectional analysis of National College Health Assessment III data (Fall 2019-Fall 2023) examining 150,992 participants for associations between cannabis use, mental health diagnoses, and organized sports participation as a moderator.","limitations":"Cross-sectional design — healthier students may both play sports and have fewer mental health issues. Self-reported diagnoses and cannabis use. Cannot determine if sports participation preceded cannabis use or vice versa."},{"rthcId":"RTHC-08028","title":"Endocannabinoid signaling in epilepsy.","authors":"Zeng, Chudai; Chen, Chu","year":2025,"journal":"Neurobiology of disease, 215, 107074","doi":"10.1016/j.nbd.2025.107074","pmid":"40886859","tags":["endocannabinoid-system","epilepsy","seizures","neuroinflammation","synaptic-plasticity"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system serves dual roles in epilepsy: restoring excitatory-inhibitory balance to prevent excessive neuronal firing, and alleviating neuroinflammation that contributes to seizure generation and disease progression.","whyItMatters":"Many epilepsy patients don't respond to existing medications. Understanding how the endocannabinoid system simultaneously addresses two key epilepsy mechanisms — excitability and inflammation — could lead to more effective, multi-target treatments.","specificNumbers":"Review synthesizing evidence on endocannabinoid regulation across multiple epilepsy mechanisms including synaptic transmission, neuronal plasticity, and immune responses.","methodology":"Comprehensive review discussing mechanisms of endocannabinoid regulation of neuronal plasticity and inflammatory responses in epilepsy, integrating recent preclinical and translational findings.","limitations":"As a review, depends on the quality and scope of included studies. Much evidence is preclinical. The complexity of the endocannabinoid system means targeting it therapeutically involves trade-offs."},{"rthcId":"RTHC-08029","title":"Experiences, impacts, and perspectives of recreational cannabis use among Indigenous communities: A scoping review.","authors":"Zentner, Daysi; Dobischok, Sophia; DeGrace, Sarah; Wen, Rou Angele; Wendt, Dennis C","year":2025,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 39(4), 354-364","doi":"10.1037/adb0001073","pmid":"40388141","tags":["indigenous-communities","cannabis-use","health-disparities","scoping-review","cultural"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Most of the 152 reviewed studies focused on prevalence and use patterns, followed by risk/protective factors and substance co-use correlations. Research on culturally appropriate interventions and cannabis legalization impacts in Indigenous communities was notably sparse.","whyItMatters":"Indigenous communities face disproportionate cannabis-related harms alongside historical trauma and systemic barriers. Without culturally grounded research, policies and interventions may miss the mark or cause additional harm.","specificNumbers":"1,934 articles screened, 152 included. Most focused on youth, used quantitative methods, and discussed cannabis within broader substance use. Covered 2005-2020 literature.","methodology":"Scoping review screening 1,934 articles published 2005-2020 on Indigenous populations and cannabis use in Canada and the US, with 152 systematically coded and analyzed.","limitations":"Literature search ended February 2020, missing recent legalization impacts. Most included studies were not community-led. Scoping review methodology doesn't assess evidence quality."},{"rthcId":"RTHC-08030","title":"Effects of cannabis smoke and oral Δ9THC on cognition in young adult and aged rats.","authors":"Zequeira, Sabrina; Gazarov, Emely A; Güvenli, Alara A; Berthold, Erin C; Senetra, Alexandria S; Febo, Marcelo; Hiranita, Takato; McMahon, Lance R; Sharma, Abhisheak; McCurdy, Christopher R; Setlow, Barry; Bizon, Jennifer L","year":2025,"journal":"Psychopharmacology, 242(4), 835-853","doi":"10.1007/s00213-025-06754-6","pmid":"39918581","tags":["aging","cognition","thc","working-memory","preclinical","sex-differences"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"Chronic oral THC enhanced prefrontal cortex-dependent working memory in aged rats of both sexes without affecting young adults. Acute cannabis smoke showed sex-dependent effects in aged rats (enhancement in males, impairment in females). Neither exposure worsened hippocampus-dependent memory at any age.","whyItMatters":"Cannabis use among older adults is the fastest-growing demographic. This counterintuitive finding — that THC may help aged brains while not affecting young ones — could shift how we think about cannabis and aging.","specificNumbers":"Chronic oral THC enhanced working memory in aged rats of both sexes. Acute smoke: enhanced in aged males, impaired in aged females. Minimal age differences in THC pharmacokinetics.","methodology":"Preclinical study testing acute cannabis smoke and chronic oral THC in young adult and aged rats of both sexes, measuring prefrontal cortex-dependent working memory and hippocampus-dependent spatial memory with pharmacokinetic profiling.","limitations":"Rat cognition tests are simplified compared to human cognitive function. THC doses and routes may not match typical human use. Enhancement was specific to working memory — other cognitive domains were unaffected."},{"rthcId":"RTHC-08031","title":"Therapeutic use of cannabis and cannabinoids: benefits and risks.","authors":"Zhai, Xiadi; Sarkar, Pooja R; Hill, Kevin P","year":2025,"journal":"Polish archives of internal medicine, 135(11)","doi":"10.20452/pamw.17117","pmid":"40938211","tags":["cannabis-therapeutics","clinical-review","benefits-risks","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Key established indications include chemotherapy-induced nausea/vomiting, HIV/AIDS appetite loss, Dravet/Lennox-Gastaut/tuberous sclerosis seizures, and MS spasticity. Evidence for chronic pain, insomnia, and psychiatric disorders is inconclusive. Risks include addiction, cognitive impairment in adolescents, CHS, psychosis, perinatal complications, and cardiovascular/pulmonary effects.","whyItMatters":"As public interest in medical cannabis grows, clinicians need a clear evidence-based framework for what cannabis can and cannot do. This review separates established benefits from hype and honestly addresses risks.","specificNumbers":"Established indications: 6 conditions with strong evidence. Emerging areas with mixed evidence: chronic pain, insomnia, opioid use disorder, neurological disorders.","methodology":"Clinical review evaluating current evidence for cannabis and cannabinoid treatment across established and emerging indications, with assessment of known risks and harms.","limitations":"Review scope limited to selected conditions. Cannabis research is hampered by historical scheduling restrictions. Evidence quality varies dramatically across conditions."},{"rthcId":"RTHC-08032","title":"Cannabidiol-loaded hydrogel contact lenses for on-demand pH regulation and enhanced corneal alkali burn repair.","authors":"Zhang, Hongyan; Lan, Ling-Min; Hu, Han-Jian; Chen, Yu; Hu, Tian; Cheng, Hao; Hu, Xiaolong; Tang, Shipeng; Liao, Xiao-Ping; Jiang, Gang-Biao","year":2025,"journal":"Journal of controlled release : official journal of the Controlled Release Society, 383, 113859","doi":"10.1016/j.jconrel.2025.113859","pmid":"40383160","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08033","title":"A Combination of Low-Dose Δ9-THC and Celecoxib as a Therapeutic Strategy for Alzheimer's Disease.","authors":"Zhang, Jian; Zhu, Dexiao; Hu, Mei; Pan, Mingzhe; Chen, Chu","year":2025,"journal":"Aging and disease","doi":"10.14336/AD.2025.1206","pmid":"41452714","tags":["thc","celecoxib","alzheimers","combination-therapy","preclinical","cognitive-decline"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"THC (3.0 mg/kg) alone or with celecoxib (1.0 mg/kg) reduced amyloid-beta and tau pathology, enhanced synaptic markers, and prevented cognitive decline. The combination produced greater improvements in spatial learning and mitigated THC-induced neuroinflammation. Both drugs are already FDA-approved.","whyItMatters":"Both THC (as dronabinol/nabilone) and celecoxib are already FDA-approved, meaning this combination could potentially advance to clinical trials rapidly if preclinical results hold up — a rare advantage in Alzheimer's drug development.","specificNumbers":"THC 3.0 mg/kg + celecoxib 1.0 mg/kg. Reduced Aβ and tau pathologies. Enhanced synaptic marker expression. Combination improved spatial learning more than THC alone. Gene expression changes reversed AD-associated patterns.","methodology":"Preclinical study treating Alzheimer's model mice with low-dose THC alone or combined with celecoxib, measuring amyloid/tau pathology, synaptic markers, cognitive function, neuroinflammation, and gene expression changes.","limitations":"Mouse model doesn't fully replicate human AD. THC dose translation to humans is uncertain. Long-term safety of the combination is unknown. Single AD model tested."},{"rthcId":"RTHC-08034","title":"Multi-level inhibition of SARS-CoV-2 invasion by cannabidiol and epigallocatechin gallate.","authors":"Zhang, Meng-Chun; Wu, Hao; Wang, Jiaxing; Lu, Meixi; Cao, Danli; Lin, Jingwen; Chen, Hang; Lin, Caiji; Wang, Yao; Zhang, Xing-Hua; Xu, Mengzhi; Liu, Gui-Rong; Li, Han; Wang, Pengfei; Wang, Xiaoyu; Xu, Xiaohui; Liu, Shu-Lin; Liu, Huidi","year":2025,"journal":"Virology, 610, 110579","doi":"10.1016/j.virol.2025.110579","pmid":"40460494","tags":["cbd","covid-19","sars-cov-2","antiviral","egcg","combination-therapy"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD decreased ACE2 receptor expression (virus entry point), while EGCG suppressed spike protein expression. Combined, they complement each other to inhibit SARS-CoV-2 at multiple levels — entry, protein expression, and reinvasion — while minimizing adverse effects of ACE2 changes.","whyItMatters":"Finding natural compounds that work together against coronaviruses through complementary mechanisms provides a framework for developing combination antiviral strategies using safe, accessible compounds.","specificNumbers":"CBD and tea polyphenols showed inhibitory effects comparable to chloroquine (positive control). EGCG identified 11 spike protein-interacting proteins significantly affected. Transcriptome analysis showed overlapping and distinct gene regulation pathways.","methodology":"In vitro study testing CBD, green tea polyphenols, EGCG, and theaflavin against SARS-CoV-2, using co-immunoprecipitation mass spectrometry, transcriptome analysis, and functional pathway enrichment.","limitations":"In vitro study only — tissue concentrations achievable in humans may be insufficient. COVID-19 landscape has evolved significantly since study conception. Viral variants may respond differently."},{"rthcId":"RTHC-08035","title":"Peptide profiling and antioxidant characterization of the simulated gastrointestinal digest of hemp seed proteins.","authors":"Zhang, Mengyuan; Zhang, Tianrong; Chen, Chen; Yang, Wanyu; Zhao, Ming; Li, Qiongmin; Tian, Jiayuan; Zhao, Yuan; Zhang, Bin","year":2025,"journal":"Food chemistry, 496(Pt 1), 146658","doi":"10.1016/j.foodchem.2025.146658","pmid":"41075652","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08036","title":"Cannabinoids in immune system-related diseases: From bench to clinic.","authors":"Zhang, Wenyu; Chen, Buzhuo; Cao, Yanting; Lei, Wangrui; Zhao, Huadong; Yang, Yang; Tang, Jiayou","year":2025,"journal":"Chinese medical journal","doi":"10.1097/CM9.0000000000003818","pmid":"41146433","tags":["cannabinoids","immune-system","autoimmune","inflammation","review"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids regulate immune function through the endocannabinoid system at molecular, cellular, and systems levels. They show therapeutic potential in multiple immune-related diseases, but risks include adverse effects, fetal nervous system impacts from prenatal use, and many contradictions in current research.","whyItMatters":"Autoimmune diseases affect millions worldwide with limited treatment options. Understanding how cannabinoids modulate immunity could open new therapeutic approaches, but the field needs clarity on when cannabinoids help vs. harm immune function.","specificNumbers":"Review covers multiple immune system components and diseases. Discusses both protective and harmful cannabinoid immune effects across various conditions.","methodology":"Systematic review discussing the endocannabinoid system, molecular and cellular bases of cannabinoid immune effects, and evidence for cannabinoid use in immune system-related diseases.","limitations":"Many contradictions exist in the literature that this review acknowledges but cannot resolve. Most evidence is preclinical. Clinical translation remains challenging given the complexity of immune regulation."},{"rthcId":"RTHC-08037","title":"Genome-Wide Identification of the TIFY Family in Cannabis sativa L. and Its Potential Functional Analysis in Response to Alkaline Stress and in Cannabinoid Metabolism.","authors":"Zhang, Yuanye; Zhang, Ming; Fang, Yuyan; Zheng, Nan; Yan, Bowei; Sui, Yue; Zhang, Liguo","year":2025,"journal":"International journal of molecular sciences, 26(17)","doi":"10.3390/ijms26178171","pmid":"40943097","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08038","title":"Cannabidiol Reprograms Glucose Metabolism in Colorectal Adenocarcinoma by Targeting HIF-1α/LDHA Pathway.","authors":"Zhang, Yuzhe; Gao, Zhengtao; Li, Yanke; Zhang, Lulu; Yan, Lirong; Liu, Aoran; Li, Fang; Peng, Xiaoli; Li, Ruipeng; Wang, Yan; Wu, Lina; Zhang, Ye","year":2025,"journal":"The American journal of Chinese medicine, 53(8), 2561-2578","doi":"10.1142/S0192415X25500958","pmid":"41219135","tags":["cbd","colorectal-cancer","warburg-effect","hif-1a","glycolysis","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD downregulated HIF-1alpha, LDHA, and GLUT1, reducing ATP production, glucose uptake, and lactate levels in colon cancer cells. When combined with glycolysis inhibitor 2-DG, the anti-tumor effects were enhanced, confirming pathway dependency.","whyItMatters":"Colorectal cancer cells reprogram their metabolism to grow faster (the Warburg effect). CBD's ability to disrupt this metabolic reprogramming represents a novel mechanism beyond simple cell killing, potentially making tumors more vulnerable to other treatments.","specificNumbers":"CBD reduced tumor cell proportions in single-cell analysis. Dose-dependent reductions in ATP, glucose uptake, and lactate. HIF-1alpha agonist DMOG partially reversed effects. PTGS2 identified as central target.","methodology":"Multi-omics approach including single-cell transcriptomics, network pharmacology, proteomics, in vitro functional assays, metabolic assays, rescue experiments, and synergy testing with glycolysis inhibitor 2-DG.","limitations":"In vitro study primarily — in vivo validation is limited. Achievable tissue concentrations of CBD may differ from experimental doses. Single cancer type studied."},{"rthcId":"RTHC-08039","title":"Inhibitory effects of Δ8-tetrahydrocannabinol on major hepatic cytochrome P450 enzymes and implications for drug disposition.","authors":"Zhao, Mengqi; Coates, Shelby; Bardhi, Keti; Lazarus, Philip","year":2025,"journal":"Drug metabolism and disposition: the biological fate of chemicals, 53(9), 100122","doi":"10.1016/j.dmd.2025.100122","pmid":"40829519","tags":["delta-8-thc","drug-interactions","cyp450","pharmacology","safety"],"studyType":"laboratory-analysis","evidenceStrength":"moderate","keyFinding":"Delta-8-THC competitively inhibited CYP2C9-mediated warfarin metabolism and non-competitively inhibited CYP2C9 and CYP3A4 metabolism of other substrates. Static modeling predicted clinically relevant interactions, particularly with oral delta-8-THC. The inactive metabolite (11-nor-delta-8-THC-9-carboxylic acid) showed no inhibition.","whyItMatters":"Delta-8-THC is widely available in states where delta-9-THC is restricted, but its drug interaction potential was unknown. This study reveals significant risks for people taking common medications metabolized by CYP2C9 (like warfarin) and CYP3A4.","specificNumbers":"Significant inhibition of CYP2C9 and CYP3A4. Competitive inhibition of CYP2C9-warfarin. Non-competitive inhibition of CYP2C9-diclofenac and CYP3A4-midazolam. 11-nor-delta-8-THC-9-carboxylic acid: no inhibition.","methodology":"In vitro enzyme inhibition study using recombinant P450-overexpressing microsomes and pooled human liver microsomes, with Lineweaver-Burk kinetic analysis and static drug interaction modeling.","limitations":"In vitro study — actual clinical drug interactions depend on achievable tissue concentrations. Static modeling may over- or underpredict real-world interactions. Individual variation in enzyme activity not captured."},{"rthcId":"RTHC-08040","title":"Essential oil fractions of hemp profiles at different hydro-distillation periods.","authors":"Zheljazkov, Valtcho D; Sikora, Vladimir; Astatkie, Tess; Dincheva, Ivayla; Acimović, Milica; Visković, Jelena; Latković, Dragana; Noller, Jay S","year":2025,"journal":"PloS one, 20(10), e0331767","doi":"10.1371/journal.pone.0331767","pmid":"41160634","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08041","title":"Unraveling Cannabidiol's Bidirectional Regulation of Melatonin Pharmacokinetics via PEPT1/CYP1A2: Mechanistic Insights and Quantitative Projections.","authors":"Zheng, Bohong; Wang, Mengran; Zhang, Qiannan; Li, Cong; Wang, Lingchao; Zhang, Wenpeng; Liu, Chunyan; Zhuang, Xiaomei","year":2025,"journal":"Pharmaceuticals (Basel, Switzerland), 19(1)","doi":"10.3390/ph19010080","pmid":"41599679","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08042","title":"Trends in Substance Use Disorder Among Hospitalized Patients With Inflammatory Bowel Disease: An 11-Year Nationwide Study.","authors":"Zheng, Melanie; DeDecker, Lauren; Chen, Po-Hung; Limketkai, Berkeley N","year":2025,"journal":"Journal of clinical gastroenterology","doi":"10.1097/MCG.0000000000002205","pmid":"40622248","tags":["ibd","substance-use-disorder","crohns","ulcerative-colitis","trends","cannabis-use-disorder"],"studyType":"retrospective-analysis","evidenceStrength":"strong","keyFinding":"SUD prevalence increased significantly in both Crohn's disease (23.8% to 27.9%) and ulcerative colitis (14.2% to 19.4%) from 2010-2020. The predominant substances shifted from alcohol to opioids and cannabis. Male sex, Medicaid insurance, and lower income were associated with higher SUD rates.","whyItMatters":"IBD patients increasingly have co-occurring substance use disorders, affecting disease management and outcomes. The shift toward cannabis and opioid use disorders requires adapted treatment approaches.","specificNumbers":"2,532,450 IBD hospitalizations. CD: SUD increased 23.8% to 27.9%. UC: 14.2% to 19.4%. Male OR: 1.26-1.34. Medicaid vs. Medicare OR: 1.59-1.84. Lowest vs. highest income: OR 1.54-1.56.","methodology":"Retrospective analysis of 2,532,450 patients hospitalized with IBD from 2010-2020 using the Nationwide Readmissions Database, with multivariable logistic regression for demographic associations.","limitations":"Administrative data cannot determine causation or distinguish therapeutic cannabis use from recreational. Hospitalized patients may not represent all IBD patients. Coding practices for SUD may have changed over the study period."},{"rthcId":"RTHC-08043","title":"Metabolomic profiling reveals ADB-BUTINACA-induced long-term hepatotoxicity.","authors":"Zheng, Siyue; Zhou, Yi; Song, Xiaoran; Ke, Xing; Wu, Hao; Huang, Zhongping; Fan, Yilei","year":2025,"journal":"Chemico-biological interactions, 421, 111754","doi":"10.1016/j.cbi.2025.111754","pmid":"40998076","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08044","title":"An analysis of the cultivation, consumption and composition of home-grown cannabis following decriminalisation in the Australian Capital Territory.","authors":"Zhou, Cilla; Lavender, Isobel; Gordon, Rebecca; McCartney, Danielle; Kevin, Richard C; Bedoya-Pérez, Miguel A; McGregor, Iain S","year":2025,"journal":"Scientific reports, 15(1), 2649","doi":"10.1038/s41598-024-84897-w","pmid":"39905040","tags":["home-cultivation","decriminalization","australia","thc-content","policy"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"311 ACT growers cultivated a median of 4 plants/year, consumed a median of 1g per use day. Cannabis samples (n=71) had moderate THC (mean 8.99%), low CBD (<0.1%), and few contaminants. Growers cited self-supply and avoiding criminal networks as primary motivations, but legislative ambiguities created ongoing legal anxiety.","whyItMatters":"This is rare real-world data on what happens when small-scale cultivation is decriminalized. The moderate potency and low contamination suggest home growing may produce safer products than black market supply.","specificNumbers":"311 growers surveyed. Median 4 plants/year, 1g per use day. 71 samples analyzed: mean THC 8.99% (±0.51), CBD <0.1%. Few exceeded contaminant guidelines. 52% remained anxious about arrest.","methodology":"Cross-sectional online survey of 311 current and past cannabis cultivators in Australia's Capital Territory plus phytocannabinoid and contaminant analysis of 71 home-grown cannabis samples.","limitations":"Self-selected sample may over-represent engaged growers. ACT-specific legal framework may not generalize. Voluntary sample submission may bias toward better-quality cannabis."},{"rthcId":"RTHC-08045","title":"Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitro.","authors":"Zhou, Fenghua; Shi, Yan; Tan, Sujun; Wang, Xiaoli; Yuan, Weicheng; Tao, Shuqi; Xiang, Ping; Cong, Bin; Ma, Chunling; Wen, Di","year":2025,"journal":"Ecotoxicology and environmental safety, 289, 117500","doi":"10.1016/j.ecoenv.2024.117500","pmid":"39662456","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08046","title":"Association between marijuana and depression: Exploring the mediating role of environmental pollutants.","authors":"Zhou, Jing-Xuan; Liu, Xiong-Bo; Zheng, Zi-Yi; Ji, Mei-Xian; Wei, Kai","year":2025,"journal":"Journal of affective disorders, 388, 119607","doi":"10.1016/j.jad.2025.119607","pmid":"40484178","tags":["cannabis","depression","environmental-pollutants","pahs","smoking","mediation"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Current cannabis use was associated with 1.99x odds of major depression (independent of tobacco and other drugs). Combined cannabis+tobacco use showed 3.05x odds. Three PAH metabolites (from combustion) partially mediated the cannabis-depression association, accounting for 10.6-17.4% of the effect.","whyItMatters":"If combustion byproducts partially explain cannabis's association with depression, this suggests that non-smoking methods of cannabis consumption might carry lower depression risk — a finding with immediate practical implications.","specificNumbers":"21,304 adults. Cannabis use: aOR 1.99 (95% CI: 1.57-2.50). Cannabis+tobacco: aOR 3.05 (95% CI: 2.48-3.75). Three PAH mediators explained 10.6-17.4% of the cannabis-depression association.","methodology":"Analysis of 21,304 NHANES adults (2005-2018) using multivariable logistic regression and mediation analysis examining PAHs and VOCs as intermediaries between cannabis use and depressive symptoms (PHQ-9).","limitations":"Cross-sectional design — depressed people may smoke more cannabis. PAH exposure comes from multiple sources, not just cannabis smoking. Cannot fully separate cannabis from tobacco combustion effects."},{"rthcId":"RTHC-08047","title":"MPN-12-NH2 shows potent antinociception effects by targeting opioid, cannabinoid, and neuropeptide FF receptors.","authors":"Zhou, Lanxia; Zhang, Jing; Mei, Chenxi; Niu, Zhanyu; Bao, Huiming; Zhao, Yaofeng; Zhang, Zhonghua; Gou, Dingnian; Dong, Shouliang","year":2025,"journal":"Peptides, 194, 171453","doi":"10.1016/j.peptides.2025.171453","pmid":"41176251","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08048","title":"miRNA rco-MIR395a-p5_1ss8TC suppresses CsOMT957 expression leading to reduction in cannflavin A accumulation in Cannabis sativa L.","authors":"Zhou, Yuxin; Ning, Kang; Chen, Yongzhong; Yang, Shuming; Wei, Xiuye; Xu, Jia; Chen, Shilin; Dong, Linlin","year":2025,"journal":"Plant physiology and biochemistry : PPB, 228, 110242","doi":"10.1016/j.plaphy.2025.110242","pmid":"40714489","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08049","title":"Global burden of disease due to opioid, amphetamine, cocaine, and cannabis use disorders, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.","authors":"Zhu, David T; Kwon, Ye In Christopher; Lai, Alan; Park, Andrew Min-Gi; Barnes, Andrew J; Chapman, Derek A","year":2025,"journal":"PloS one, 20(8), e0328276","doi":"10.1371/journal.pone.0328276","pmid":"40839682","tags":["global-burden","drug-use-disorders","cannabis-use-disorder","epidemiology","trends"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"In 2021: 13.6 million new drug use disorder cases, 137,278 deaths, 15.6 million DALYs. From 1990-2021: incidence decreased 8.1% but mortality rose 30.8% and DALYs rose 14.8%. Males and high-income regions disproportionately affected. Opioids dominated all metrics.","whyItMatters":"The paradox of declining incidence but rising mortality suggests treatment hasn't kept pace with the severity of drug use disorders. Cannabis use disorder, while less fatal than opioids, contributes significantly to the overall disability burden.","specificNumbers":"2021: 13.6M new cases, 137,278 deaths, 15.6M DALYs. Opioid ASIR: 169.4/100K, ASMR: 1.7/100K. 1990-2021: ASIR -8.1%, ASMR +30.8%, DALY rate +14.8%.","methodology":"Systematic analysis of the Global Burden of Disease Study 2021, calculating age-standardized incidence, mortality, and DALY rates for opioid, amphetamine, cocaine, and cannabis use disorders across sex, SDI, countries, and regions from 1990-2021.","limitations":"GBD estimates rely on available data which varies dramatically by country. Cannabis use disorder diagnosis criteria and reporting have changed over time. Some regions have very limited data."},{"rthcId":"RTHC-08050","title":"Endocannabinoid-mediated regulation of depression in the ovBNST.","authors":"Zhu, Riming; Li, Jie; Zhang, Xia; Zhang, Bin","year":2025,"journal":"Frontiers in neuroscience, 19, 1629351","doi":"10.3389/fnins.2025.1629351","pmid":"40787242","tags":["endocannabinoid-system","depression","bnst","cb1-receptor","chronic-stress","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Chronic unpredictable mild stress reduced CB1 receptor mRNA and protein in the ovBNST, associated with depression-like behaviors. Blocking CB1 in this region induced depression in healthy mice. CB1 agonist or endocannabinoid enhancement partially rescued despair behaviors but not anhedonia in stressed mice.","whyItMatters":"This identifies a specific brain region and mechanism through which chronic stress leads to depression via endocannabinoid dysfunction, providing a more precise target for future therapies than broad cannabinoid approaches.","specificNumbers":"CB1 receptor blockade with NESS0327 induced anhedonia and despair. CB1 agonist and JZL-184 (cannabinoid hydrolase inhibitor) rescued despair but not anhedonia. CB1 reduction traced to prefrontal cortex presynaptic terminals.","methodology":"Preclinical study using CUMS mouse model with endocannabinoid sensors, pharmacological manipulation (CB1 agonist/antagonist), viral tracing, RNAscope, and Western blotting to map endocannabinoid changes in the ovBNST.","limitations":"Mouse CUMS model is a simplified approximation of human depression. Pharmacological interventions rescued only despair, not anhedonia. The specific brain region may not map precisely to human anatomy."},{"rthcId":"RTHC-08051","title":"Does cannabis substitute or complement alcohol after recreational cannabis legalization in the Washington State? A three-level mixed-effects modeling.","authors":"Zhu, Yachen; Trangenstein, Pamela J; Kerr, William C","year":2025,"journal":"Addictive behaviors, 162, 108218","doi":"10.1016/j.addbeh.2024.108218","pmid":"39644760","tags":["cannabis-alcohol","substitution","complementarity","legalization","washington","daily-level"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"At the daily level, recreational cannabis users drank 37% more alcohol on cannabis-use days (IRR = 1.37). Medical cannabis users showed the opposite — a 43% reduction (IRR = 0.57 interaction), suggesting substitution. This indicates the relationship between cannabis and alcohol depends on the type of cannabis user.","whyItMatters":"Whether cannabis replaces or adds to alcohol use has major public health implications. This study shows it depends on why people use cannabis — recreational users combine them, while medical users may genuinely substitute.","specificNumbers":"259 respondents, 440 person-waves, 3,051 daily observations. Recreational users: IRR = 1.37 (95% CI: 1.05-1.79) on cannabis days. Medical recommendation interaction: IRR = 0.57 (95% CI: 0.34-0.96).","methodology":"Three-level negative binomial models analyzing daily alcohol and cannabis use data from 259 co-users across 4 waves of the Washington Panel Survey (2014-2016), with 3,051 daily observations.","limitations":"Washington State sample during early legalization may not represent current or other markets. Self-reported daily use. Medical recommendation doesn't necessarily mean using for medical purposes."},{"rthcId":"RTHC-08052","title":"The cannabinoid receptor 1 mediates exercise-induced improvements of motor skill learning and performance in parkinsonian mouse.","authors":"Zikereya, Talifu; Liu, Chuang; Wei, Longwei; Wang, Yinhao; Zhang, Zhizhen; Han, Chuanliang; Shi, Kaixuan; Chen, Wei","year":2025,"journal":"Experimental neurology, 391, 115289","doi":"10.1016/j.expneurol.2025.115289","pmid":"40340015","tags":["parkinsons","exercise","cb1-receptor","striatum","motor-learning","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Exercise training improved motor performance and learning in Parkinson's model mice. The mechanism involved CB1 receptor expression changes: decreased in the dorsomedial striatum but increased in the substantia nigra following exercise, suggesting CB1 mediates exercise's benefits through corticostriatal circuit modulation.","whyItMatters":"Exercise is one of the most effective non-drug interventions for Parkinson's, but the molecular mechanism was unknown. Identifying CB1 as a key mediator opens possibilities for combining exercise with cannabinoid-based treatments.","specificNumbers":"Exercise improved motor performance and learning. CB1 decreased in dorsomedial striatum but increased in substantia nigra pars reticulata after treadmill exercise in PD mice.","methodology":"Preclinical study using intrastriatal 6-hydroxydopamine Parkinson's model mice with treadmill exercise training, measuring motor performance, learning abilities, and CB1 receptor expression via immunofluorescence and RT-PCR.","limitations":"Mouse Parkinson's model doesn't fully replicate human disease. Treadmill exercise is one type of exercise — other forms may have different effects. Correlation between CB1 changes and motor improvement doesn't prove causation."},{"rthcId":"RTHC-08053","title":"Developing Medical Cannabis Competencies: A Consensus Statement.","authors":"Zolotov, Yuval; Mendoza Temple, Leslie; Isralowitz, Richard; Gorelick, David A; Abraham, Rebecca; Abrams, Donald I; Barich, Kyle; Boehnke, Kevin F; Dahmer, Stephen; Friedman, Joseph; Frye, Patricia; Haramati, Aviad; Isaac, Jade; Mathre, Mary Lynn; McNabb, Marion E; Ring, Melinda; Russo, Ethan B; Slawek, Deepika E; Temple, Brigham R; Wilson-King, Genester S; Arnsten, Julia H; Kogan, Mikhail","year":2025,"journal":"JAMA network open, 8(10), e2535049","doi":"10.1001/jamanetworkopen.2025.35049","pmid":"41055914","tags":["medical-education","cannabis-competencies","delphi","curriculum","clinical-training"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Six core competencies: (1) endocannabinoid system basics, (2) cannabis plant components and effects, (3) legal/regulatory landscape, (4) evidence base for common conditions, (5) potential risks, (6) basic clinical management. Supported by 26 sub-competencies covering patient safety, vulnerable populations, and structural inequities.","whyItMatters":"Most clinicians feel unprepared to counsel patients about cannabis, yet patients increasingly ask. This JAMA-published consensus provides the first standardized framework for what every medical student should learn about cannabis.","specificNumbers":"23 expert panelists, 14 physicians across specialties. 2 Delphi rounds, February-October 2023. Initial 9 competencies refined to 6 core + 26 sub-competencies. Required mean ≥4/5 on importance and wording.","methodology":"Modified Delphi process with 23 experts (physicians across specialties, nurses, pharmacist, academic leaders) through 2 rounds of anonymous web-based surveys (February-October 2023), requiring mean ≥4/5 for inclusion.","limitations":"Consensus-based — reflects expert opinion rather than evidence of educational effectiveness. Implementation challenges (faculty expertise, curriculum time) not addressed. US-focused framework may need adaptation internationally."},{"rthcId":"RTHC-08054","title":"Cannabinoids rescue migraine symptoms caused by central CGRP administration in mice.","authors":"Zorrilla, Erik; Duong, Thomas L; Piña, Cassandra L; Russo, Andrew F","year":2025,"journal":"Cephalalgia : an international journal of headache, 45(11), 3331024251392103","doi":"10.1177/03331024251392103","pmid":"41182862","tags":["migraine","cbd","thc","cgrp","pain","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Pretreatment with 100 mg/kg CBD + 1 mg/kg THC rescued CGRP-induced light aversion, reduced resting time in darkness, increased light/dark transitions, and partially rescued spontaneous pain (squint assay) in mice. The effects were specific to migraine (CGRP-induced) rather than general anxiety.","whyItMatters":"CGRP is the validated target in current migraine medications. Showing that cannabinoids can counteract CGRP-induced migraine symptoms provides mechanistic support for cannabis-based migraine treatment and clarifies the optimal CBD:THC ratio.","specificNumbers":"100:1 CBD:THC ratio (100 mg/kg CBD, 1 mg/kg THC). Rescued light aversion, resting time in darkness, zone transitions. Partially rescued squint (spontaneous pain). Open field confirmed no anxiety confound.","methodology":"Preclinical study administering 100:1 CBD:THC ratio intraperitoneally 60 minutes before intracerebroventricular CGRP injection in CD1 mice, measuring photophobia (light/dark assay), motility, and spontaneous pain (automated squint assay).","limitations":"Mouse migraine model using direct CGRP injection doesn't replicate human migraine triggers. 100:1 ratio at these doses may not translate to human dosing. Only pretreatment, not acute treatment, was tested."},{"rthcId":"RTHC-08055","title":"Single-Nucleus Transcriptomics Identifies Neuroblast Migration Programs Sensitive to Reelin and Cannabis in the Adolescent Nucleus Accumbens.","authors":"Zuo, Yanning; Formoli, Numaan; Libster, Avraham; Sun, Daimeng; Turner, Andrew; Iemolo, Attilio; Telese, Francesca","year":2025,"journal":"bioRxiv : the preprint server for biology","doi":"10.1101/2025.04.03.646846","pmid":"40236084","tags":["adolescent-brain","thc","neuroblast","nucleus-accumbens","psychiatric-risk","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Single-nucleus RNA sequencing identified a gene co-expression network affected by both Reelin genotype and THC, enriched in psychiatric disorder genes and expressed in GABAergic neuroblasts. These neuroblasts actively migrate during adolescence and receive cues from cannabinoid receptor-expressing interneurons, revealing a mechanism for gene-environment interaction in psychosis risk.","whyItMatters":"This provides a molecular explanation for why adolescent cannabis use increases psychiatric risk — THC disrupts the migration of specific brain cells during a critical developmental window, and genetic vulnerability amplifies this effect.","specificNumbers":"Identified gene network enriched in human psychiatric disorder genes. Neuroblasts actively migrated in adolescent NAc but declined with age. Cholecystokinin interneurons with high CB1 expression provided migratory cues.","methodology":"Single-nucleus RNA sequencing of nucleus accumbens in Reelin haploinsufficient mice with adolescent THC exposure, combined with cell-to-cell communication analysis and migration assays across development.","limitations":"Mouse model with a single genetic risk factor — human psychiatric vulnerability is polygenic. Single-nucleus sequencing provides a snapshot, not a timeline. Reln haploinsufficiency is one of many risk models."},{"rthcId":"RTHC-08056","title":"Perceived Ethnic Discrimination and Negative Emotional Reactivity to Minority Stress: Association with Cannabis Use Processes Among United States Hispanic/Latinx Adults.","authors":"Zvolensky, Michael J; Clausen, Bryce K; Jones, Ava A; Castillo-Avilés, Rodrigo; Thai, Jessica M; Shepherd, Justin M; Bogiaizian, Lucas; Redmond, Brooke Y; Garey, Lorra","year":2025,"journal":"Cannabis (Albuquerque, N.M.), 8(3), 38-55","doi":"10.26828/cannabis/2025/000335","pmid":"41278418","tags":["hispanic-latinx","ethnic-discrimination","minority-stress","cannabis-use","health-disparities"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Perceived ethnic discrimination and negative emotional reactivity to minority stress each independently predicted higher cannabis use problems and greater perceived barriers to cannabis reduction. Minority stress also predicted enhancement, social, coping, and expansion motives for use, while discrimination predicted conformity motives. No interaction effects were found.","whyItMatters":"Hispanic/Latinx cannabis use is increasing, but research rarely addresses culturally specific factors. This study shows that experiences of discrimination and minority stress — not just individual factors — drive problematic cannabis use in this population.","specificNumbers":"521 Hispanic/Latinx adults with past-month cannabis use. Both discrimination and minority stress independently predicted use problems and reduction barriers. Effects ranged from small to medium. No interactive effects.","methodology":"Cross-sectional survey of 521 Hispanic/Latinx adults (mean age 36.5, 55% male) with past-month cannabis use, recruited through Qualtrics Panels, examining culturally relevant predictors of cannabis use processes.","limitations":"Cross-sectional design — discrimination may not cause cannabis problems. Online panel recruitment may not represent all Hispanic/Latinx cannabis users. Self-reported measures."},{"rthcId":"RTHC-08057","title":"Accidental cannabis ingestion in young children.","authors":"Zwiebel, Hannah; Greenky, David; Goldman, Ran D","year":2025,"journal":"Canadian family physician Medecin de famille canadien, 71(3), 161-163","doi":"10.46747/cfp.7103161","pmid":"40102005","tags":["pediatrics","accidental-ingestion","edibles","public-health","safety"],"studyType":"clinical-observation","evidenceStrength":"moderate","keyFinding":"Cannabis edible ingestion in children under 6 is steadily increasing, causing symptoms like excessive sleepiness, poor balance, nausea, and in severe cases, respiratory depression and seizures.","whyItMatters":"As cannabis edibles become more common in homes, children are increasingly at risk of accidental ingestion — products that look like candy or gummies are particularly dangerous for curious toddlers.","specificNumbers":"Case involved a 3-year-old who became excessively sleepy and difficult to rouse after accessing cannabis gummies kept in the home.","methodology":"Clinical case report and literature review examining symptoms, management, and prevention of accidental cannabis ingestion in young children.","limitations":"Based on a single case report with literature review rather than systematic epidemiological data on incidence rates."},{"rthcId":"RTHC-08058","title":"Sex-specific association between low oral doses of cannabidiol (CBD) and plasma concentration of anandamide (AEA), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA) in healthy occasional cannabis users.","authors":"Abboud, Anita; Chester, Lucy Ann; Hébert, Francois-Olivier; Jutras-Aswad, Didier","year":2026,"journal":"Journal of cannabis research, 8(1), 20","doi":"10.1186/s42238-025-00356-x","pmid":"41514385","tags":["cbd","sex-differences"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system doesn't just respond to cannabis—it produces its own cannabinoid-like molecules. This triple-blind, placebo-controlled crossover trial asked whether commercially available CBD doses affect these endogenous molecules.\n\nSeventy healthy occasional cannabis users each received five conditions in randomized order: placebo and four CBD doses (20, 50, 100, and 200 mg). Blood was sampled at baseline and five timepoints after dosing to track three endogenous lipid signals: anandamide (AEA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA).\n\nCBD did alter plasma levels of these signaling lipids, meaning even consumer-level doses have measurable effects on the endocannabinoid system. But the most striking finding was sex-specific: men and women showed different dose-response patterns. The statistical models included sex as a variable and found significant sex interactions.\n\nThis matters because anandamide is involved in mood regulation, pain perception, appetite, and immune function. If CBD modifies anandamide levels differently in men versus women, it could explain why men and women sometimes respond differently to CBD products—and why clinical trials that don't analyze by sex might miss important effects.","whyItMatters":"Most people taking CBD products have no idea whether or how it's affecting their endocannabinoid system. This study shows that even the lowest commercially available dose (20 mg) has measurable effects on endocannabinoid signaling—and that biological sex modifies those effects. For a product marketed as one-size-fits-all, the sex difference finding suggests dosing may need to be personalized.","specificNumbers":"N = 70. 5 conditions: placebo + 20, 50, 100, 200 mg CBD. 6 blood sampling timepoints per session. Plasma AEA, PEA, and OEA measured by LC-MS. Significant sex differences in dose-response. Even 20 mg CBD altered endocannabinoid levels.","methodology":"Triple-blind, placebo-controlled, randomized crossover trial. 70 healthy occasional cannabis users received 10 sequences of 4 oral CBD doses (20, 50, 100, 200 mg) and placebo. Blood sampled at baseline and 5 post-dose timepoints. Plasma AEA, PEA, and OEA quantified by LC-MS. Linear mixed-effects models with participant ID nested in sequence as random effect, including sex as a variable.","limitations":"Occasional cannabis users—results may differ in naive or chronic users. Plasma levels of endocannabinoids may not reflect brain or tissue levels. The study measured acute effects; chronic CBD use might produce different patterns. Marketed CBD products vary in actual content, so the controlled doses here may not match real-world products. The 2026 publication date means this is very recent and awaits replication."},{"rthcId":"RTHC-08059","title":"Cannabidiol in Cardiovascular Disease: A Review of Current Evidence and Future Directions.","authors":"Abdalla, Hesham M; Bacon, Adam; VanDolah, Hunter; Dreher, Luke; Pathangey, Girish; Abdelnabi, Mahmoud; Ibrahim, Ramzi; Pereyra, Milagros; Farina, Juan M; Luis, S Allen; Arsanjani, Reza; Ayoub, Chadi","year":2026,"journal":"Mayo Clinic proceedings, 101(2), 297-309","doi":"10.1016/j.mayocp.2025.10.009","pmid":"41467868","tags":["cbd","cardiovascular","heart-disease","anti-inflammatory","review"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"CBD demonstrates potential anti-inflammatory, antioxidant, and vasodilatory properties relevant to pericarditis, ischemic heart disease, heart failure, and cardiac arrhythmias, with preliminary trials showing promise for recurrent pericarditis.","whyItMatters":"Heart disease remains the leading cause of death globally, and CBD's unique anti-inflammatory profile — without immunosuppressive effects — could fill a gap in treating inflammatory cardiac conditions.","specificNumbers":"Review covered evidence on CBD's role across multiple cardiovascular conditions including ischemia-reperfusion injury, myocardial fibrosis, and cardiac arrhythmias.","methodology":"Narrative review from Mayo Clinic researchers integrating preclinical and emerging clinical evidence on CBD in cardiovascular disease management.","limitations":"Most evidence comes from preclinical models; limited human clinical trials, dosing inconsistencies, and regulatory challenges hinder translation to clinical practice."},{"rthcId":"RTHC-08060","title":"Adsorption of Tetrahydrocannabinol (THC), Metabolites, and Related Cannabinoids During Storage of Plasma Samples in Gel Separation Tubes.","authors":"Abdul, Idris A; Pon, Dale; Giancola, Chesia; Woodall, Karen","year":2026,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkag001","pmid":"41496001","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08061","title":"Investigating medical cannabis for adolescents with Tourette syndrome: tread carefully.","authors":"Abi-Jaoude, Elia","year":2026,"journal":"BJPsych open, 12(1), e45","doi":"10.1192/bjo.2025.10959","pmid":"41556111","tags":["tourette-syndrome","adolescents","medical-cannabis","risk-benefit","psychosis"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"Two feasibility studies of cannabis for adolescent Tourette syndrome readily recruited participants but did not require prior trials of standard evidence-based treatments, raising ethical concerns given cannabis-psychosis associations in youth.","whyItMatters":"The gap between adult evidence and adolescent safety is critical — the developing teenage brain is particularly vulnerable to cannabis-related harms, especially psychosis risk.","specificNumbers":"Two feasibility studies have been published on cannabis for adolescent Tourette syndrome, with no explicit requirement for prior standard treatment trials.","methodology":"Editorial commentary analyzing two published feasibility studies of cannabis for adolescents with Tourette syndrome, with focus on ethical and safety considerations.","limitations":"Commentary piece rather than original research; based on analysis of only two feasibility studies."},{"rthcId":"RTHC-08062","title":"Intersectional Oppression-Based Stress, School Safety, and Substance Use Among Sexual and Gender Minority Adolescents Who Are Black, Indigenous, and People of Color.","authors":"Abramson, Jessica R; Arumugam, Ashwathi; Vanlandingham, Hannah G; Watson, Ryan J; Mereish, Ethan H","year":2026,"journal":"Substance use & misuse, 1-9","doi":"10.1080/10826084.2026.2619021","pmid":"41639977","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08063","title":"Adolescent cannabinoid vapour exposure sex-dependently alters the relationship between vulnerability traits and ethanol self-administration and modifies naltrexone actions on ethanol intake in rats.","authors":"Acosta-Vargas, Jairo S; de Las Heras-Martínez, Natalia; Marcos, Alberto; Nozal, Leonor; Crego, Antonio L; Ucha, Marcos; Higuera-Matas, Alejandro","year":2026,"journal":"Neuropharmacology, 288, 110843","doi":"10.1016/j.neuropharm.2026.110843","pmid":"41580119","tags":["adolescent-exposure","thc","cbd","alcohol","gateway-hypothesis","sex-differences","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Adolescent cannabinoid vapor exposure didn't increase overall ethanol self-administration but sex-dependently altered correlations between vulnerability traits and drinking behavior, and increased naltrexone's effectiveness in THC-exposed rats.","whyItMatters":"This complicates the simple 'gateway drug' narrative — adolescent cannabis may not increase how much you drink, but could change why you drink and how well treatments work.","specificNumbers":"Rats exposed to cannabinoid vapor every other day from PND 28-44; naltrexone was most effective in THC-exposed rats compared to high-CBD/low-THC exposed rats.","methodology":"Preclinical study exposing adolescent rats to vaporized THC (alone or with CBD at different ratios) from PND 28-44, followed by behavioral assessments and ethanol self-administration from PND 70, with naltrexone challenge.","limitations":"Animal model with vaporized cannabinoids may not fully replicate human adolescent cannabis use patterns; sex differences complicate generalization."},{"rthcId":"RTHC-08064","title":"Pain, Depression, and Functional Outcomes Among Older Adults Who Use Cannabis or Opioid Analgesics for Chronic Pain Conditions.","authors":"Aebischer, Jonathan H; Anderson, Lyndsey M; Dieckmann, Nathan F; Mattek, Nora C; Kaye, Jeffrey A","year":2026,"journal":"Clinical gerontologist, 49(1), 157-167","doi":"10.1080/07317115.2025.2574325","pmid":"41082871","tags":["pain","depression","seniors","medical-cannabis"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"This longitudinal study tracked older adults enrolled in the Oregon Center for Aging and Technology with chronic pain lasting at least 12 weeks. About 5% used cannabis and 11% used prescription opioids.\n\nAfter adjusting for confounders, cannabis use was associated with more pain interference (the degree to which pain disrupts daily life) and more depression symptoms over time. Opioid use was associated with more pain intensity and pain interference.\n\nThe finding that cannabis users had worse outcomes—not better—runs counter to the popular narrative that cannabis is an effective pain management tool for older adults. However, the direction of causation is unclear. People with the worst pain and most depression may be the ones turning to cannabis, meaning cannabis use could be a marker of severity rather than a cause of worsening.\n\nThe 5% cannabis use rate among these older Oregonians is notably lower than the 11% found in RTHC-00185's study of older adults—possibly reflecting different demographics, time periods, or pain clinic vs. community settings.\n\nThe authors acknowledge the small cannabis-using sample (about 18 people) as a significant limitation and call for larger studies with reliable measures.","whyItMatters":"While RTHC-00185 found no cognitive differences between older cannabis users and non-users, and RTHC-00221 reported 91.5% neuropathic pain response rates, this study introduces a sobering counterpoint: older adults using cannabis for chronic pain may not be doing better—and may actually have worse functional and mood outcomes. The truth is likely complex, depending on pain type, cannabis product, dose, and individual factors.","specificNumbers":"N = 353 older adults with chronic pain. 5% used cannabis. 11% used opioids. Cannabis associated with more pain interference and depression symptoms over time (adjusted for confounders). Opioid use associated with more pain intensity and interference.","methodology":"Longitudinal observational secondary analysis of older adults in the Oregon Center for Aging and Technology study with pain ≥12 weeks. N = 353. Cannabis (5%) and opioid (11%) use assessed weekly. Outcomes: weekly pain intensity, pain interference, feeling blue, physical limitations, and annual Geriatric Depression Scale scores. Adjusted for confounders.","limitations":"Very small cannabis-using sample (~18 of 353). Oregon-specific population. Self-reported cannabis and opioid use. Observational design—cannot determine whether cannabis caused worse outcomes or whether worse symptoms drove cannabis use. No data on cannabis product type, dose, or frequency. The Oregon aging technology cohort may not represent broader older adult populations."},{"rthcId":"RTHC-08065","title":"Cannabinoid Therapies in Less-Common Disorders: Clinical Evidence and Formulation Strategies.","authors":"Afonso, Silvia; Gonçalves, Joana; Brinca, Ana T; Rosendo, Luana M; Rosado, Tiago; Duarte, Ana Paula; Gallardo, Eugenia","year":2026,"journal":"Diseases (Basel, Switzerland), 14(2)","doi":"10.3390/diseases14020083","pmid":"41745121","tags":["rare-diseases","cannabinoids","epilepsy","tourette-syndrome","epidermolysis-bullosa","drug-delivery","review"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Recent evidence supports cannabinoid use in rare epilepsies beyond Dravet/Lennox-Gastaut, movement disorders, and rare skin diseases, while Fragile X syndrome trials revealed methodological challenges instructive for future research.","whyItMatters":"Patients with rare diseases often have few treatment options — cannabinoids could fill therapeutic gaps, but only if formulation challenges like poor bioavailability are solved.","specificNumbers":"Review covered evidence from 2020-2025 across multiple rare conditions including refractory epilepsies, dystonia, Tourette syndrome, epidermolysis bullosa, and Crohn's disease.","methodology":"Critical review synthesizing 2020-2025 evidence from PubMed and Scopus on cannabinoid therapies in less-common disorders, including formulation and delivery optimization strategies.","limitations":"Most evidence is preclinical or from small clinical studies; the review covers heterogeneous conditions making direct comparisons difficult."},{"rthcId":"RTHC-08066","title":"Navigating through Neuropathic Pain: From Pathophysiology to Present and Future Treatments.","authors":"Aggarwal, Sanchita; Barnwal, Ravi Pratap; Singh, Gurpal; Pandey, Ankur Ganesh","year":2026,"journal":"Current topics in medicinal chemistry","doi":"10.2174/0115680266417188251106114042","pmid":"41691675","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08067","title":"Aerobic training and cannabidiol activate the PI3K/AKT/PDX1 axis to ameliorate beta-cell dysfunction in a rat model of diet-induced obesity.","authors":"Akbarzadeh Zarei, Hamid Reza; Gholami, Mandana; Ghazalian, Farshad; Ghareh, Sahar","year":2026,"journal":"Molecular biology reports, 53(1)","doi":"10.1007/s11033-026-11573-9","pmid":"41721911","tags":["cbd","obesity","beta-cells","exercise","diabetes-prevention","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD (10 mg/kg) and combined CBD+aerobic training significantly improved beta-cell function (HOMA-Beta) and upregulated PI3K/AKT/PDX1 gene expression in obese rats, while exercise alone activated the pathway without improving functional beta-cell mass.","whyItMatters":"Type 2 diabetes from obesity is a global epidemic — finding that CBD could protect the insulin-producing cells that fail in diabetes opens a novel preventive approach.","specificNumbers":"CBD at 10 mg/kg 5x/week; aerobic training at 30 min/day, 50-80% max speed, 5x/week for 8 weeks; beta-cell function improvement significant at p=0.002 (CBD) and p=0.001 (combined).","methodology":"Controlled preclinical study with 32 male Wistar rats on high-fat diet for 8 weeks, then randomized to sedentary, CBD, aerobic training, or combined treatment for 8 additional weeks, measuring HOMA-Beta and pancreatic gene expression.","limitations":"Male rats only; single CBD dose tested; 8-week intervention may not reflect long-term effects; HOMA-Beta is an indirect measure of beta-cell function."},{"rthcId":"RTHC-08068","title":"Cannabidiol Protects the Heart from Ischemia-Reperfusion Injury Through SIRT-1/PGC-1α Activation and NF-κB Modulation: Experimental Insights.","authors":"Aksoy, Fatih; Savran, Mehtap; Uysal, Dincer; Bagci, Ali; Ilhan, Ilter; Imeci, Orhan; Sevuk, Mehmet A; Ozmen, Ozlem; Tepebasi, Muhammet Y; Asci, Halil","year":2026,"journal":"Journal of cardiovascular pharmacology","doi":"10.1097/FJC.0000000000001806","pmid":"41696987","tags":["cbd","cardioprotection","ischemia-reperfusion","mitochondria","anti-inflammatory","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Prophylactic CBD treatment restored myocardial architecture, suppressed inflammatory and apoptotic responses, and enhanced mitochondrial biogenesis through SIRT-1/PGC-1α activation in a rat heart attack model, with therapeutic CBD providing partial protection.","whyItMatters":"Heart attacks cause damage not just from blocked blood flow but also when flow returns (reperfusion injury) — CBD's ability to protect against this 'double hit' could improve cardiac outcomes.","specificNumbers":"40 rats across 4 groups; 30-minute ischemia + 30-minute reperfusion model; prophylactic CBD significantly restored SIRT-1, PGC-1α, and Bcl-2 expression while reducing NF-κB and VCAM-1.","methodology":"Controlled preclinical study with 40 rats in 4 groups (sham, I/R, prophylactic CBD, therapeutic CBD), inducing heart attack by 30-min coronary artery ligation followed by 30-min reperfusion, with histological, biochemical, and genetic analysis.","limitations":"Acute rat model; prophylactic administration is more protective than therapeutic, which limits practical clinical application; specific CBD doses not detailed in abstract."},{"rthcId":"RTHC-08069","title":"Prevalence and characteristics of prenatal cannabis use in Michigan, USA: A statewide population-based pregnancy cohort.","authors":"Al-Sahab, Ban; Kerver, Jean M; Alshaarawy, Omayma; Bohnert, Kipling M; Elliott, Michael R; Qiu, Hongxiang; Jaber, Audriyana; Neelam, Harish; Paneth, Nigel","year":2026,"journal":"Addiction (Abingdon, England), 121(1), 126-137","doi":"10.1111/add.70188","pmid":"40955057","tags":["prenatal-cannabis","pregnancy","prevalence","epidemiology","mental-health","demographics"],"studyType":"cohort","evidenceStrength":"strong","keyFinding":"Weighted prevalence of prenatal cannabis use was 16.8% combining self-report and urinalysis; self-report alone captured 12.3% while urinalysis caught 13.3%, indicating neither method alone captures the full picture.","whyItMatters":"One in six pregnancies involving cannabis is a public health figure that demands attention — and the finding that self-report underestimates use means the true number may be even higher.","specificNumbers":"16.8% overall prevalence; 12.3% by self-report; 13.3% by urinalysis; depression aPRR=1.72; ACEs ≥3 aPRR=2.04; single status aPRR=2.08; some college vs. undergrad+ aPRR=3.76.","methodology":"Prospective statewide pregnancy cohort (MARCH/ECHO) using three-stage stratified cluster sampling across Michigan's lower peninsula, with 1,092 participants providing self-reports and/or urine toxicology during pregnancy.","limitations":"Michigan-specific results may not generalize to all states; recruitment at prenatal clinics misses those without prenatal care; urine captures recent use but may miss intermittent users."},{"rthcId":"RTHC-08070","title":"Multidimensional influences on prenatal cannabis use: A reflexive thematic analysis of low-income birthing people.","authors":"Alaniz, Kristine; Ngui, Emmanuel M; Laestadius, Linnea; Kako, Peninnah M; Yahaya, Musa; Vance, Tessa","year":2026,"journal":"Journal of public health research, 15(1), 22799036251395240","doi":"10.1177/22799036251395240","pmid":"41623936","tags":["prenatal-cannabis","pregnancy","qualitative","mental-health","low-income","emotional-regulation"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Five themes emerged: pregnancy as a turning point for cannabis use, cannabis for emotional regulation, complex cannabis-mental health ties, relational influences on use, and contextual barriers to informed decision-making — with emotional regulation and mental health as the most cited drivers.","whyItMatters":"Understanding why pregnant women use cannabis — not just that they do — is essential for designing supportive rather than punitive public health interventions.","specificNumbers":"19 pregnant cannabis users interviewed; most Medicaid recipients; nearly half reported household income below $10,000; study conducted in Wisconsin where cannabis is illegal.","methodology":"Reflexive thematic analysis of qualitative interviews with 19 pregnant cannabis users from a community-based program in Wisconsin (where cannabis remains illegal), most on Medicaid with nearly half below $10,000 household income.","limitations":"Small qualitative sample from a single state where cannabis is illegal; findings may differ in legal states; self-selected participants in a community program."},{"rthcId":"RTHC-08071","title":"The Pharmacological Profile of Plant-Derived Cannabinoids In Vitro.","authors":"Alexander, Stephen P H","year":2026,"journal":"Current topics in behavioral neurosciences, 76, 1-36","doi":"10.1007/7854_2025_605","pmid":"41068546","tags":["phytocannabinoids","pharmacology","cb1-receptor","thc","cbd","in-vitro"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Over 100 unique cannabinoid metabolites exist in cannabis, but pharmacological understanding is heavily concentrated on THC (CB1 partial agonist) and CBD (multiple low-potency targets), with acid phytocannabinoids particularly understudied.","whyItMatters":"Most cannabis science focuses on just two of 100+ compounds — understanding the full pharmacological landscape could unlock new therapeutic applications and explain the 'entourage effect.'","specificNumbers":"Over 100 apparently unique cannabinoid metabolites identified in cannabis; THC is relatively high-potency but low-efficacy at CB1; CBD's molecular targets are lower potency with unclear human relevance.","methodology":"Review of in vitro pharmacological data on plant-derived cannabinoids, assessing molecular targets, potency, and efficacy across the major and minor phytocannabinoid classes.","limitations":"In vitro pharmacology often doesn't predict in vivo effects; many studies use non-physiological concentrations; acid cannabinoid data is particularly sparse."},{"rthcId":"RTHC-08072","title":"Assessing the Role of Cannabis in Managing Spasticity in Multiple Sclerosis: A Systematic Review and Meta-Analysis.","authors":"AlHabil, Yazan; Saadeddin, Liza; Ishkirat, Hana; Alqam, Mariam; Hossoon, Obada; Hameedi, Seema; Yacoub, Hamzeh; Yasin, Diana; Bahbah, Anita; Oweidat, Majd; Mosa, Hanadi","year":2026,"journal":"Clinical therapeutics, 48(1), 13-21","doi":"10.1016/j.clinthera.2025.07.009","pmid":"40753057","tags":["multiple-sclerosis","spasticity","meta-analysis","clinical-trials","thc","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Overall standardized mean difference of 39.19 (95% CI: 34.32-44.05) in spasticity scores post-treatment; long-term studies showed larger effects (MD=75.81) compared to short-term (MD=4.53), with generally mild adverse events.","whyItMatters":"MS spasticity significantly impacts quality of life and responds poorly to many existing medications — this meta-analysis provides the strongest collective evidence yet for cannabis as a treatment option.","specificNumbers":"9 clinical trials; 2,544 patients; Ashworth scale MD=20.36; NRS MD=1.18; short-term MD=4.53; long-term MD=75.81; adverse events generally mild (dizziness, dry mouth).","methodology":"Systematic review and meta-analysis of 9 clinical trials (2003-2021) involving 2,544 MS patients, using Ashworth scale, visual analog scale, and numeric rating scale, with random and fixed effects models.","limitations":"Substantial heterogeneity (I²=100% for overall analysis); suspected publication bias from funnel plot asymmetry; studies used different cannabinoid formulations making direct comparison difficult."},{"rthcId":"RTHC-08073","title":"Bacterial microbiota dynamics of Cannabis sativa L. under biotic stress induced by Tetranychus urticae.","authors":"Alman, Pinto Lucas; De Urraza, Patricio; Coppotelli, Bibiana; Colman, Deborah; Bernardo, Valeria; Ruscitti, Marcela; Vaccarini, Cristian; Bugvila, Cristina; Sedan, Daniela; Andrinolo, Darío","year":2026,"journal":"Protoplasma","doi":"10.1007/s00709-026-02171-4","pmid":"41711842","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08074","title":"Synthetic cannabidiol analogues exhibit lower toxicity than cannabidiol and protect against ethanol-induced apoptosis in SH-SY5Y cells.","authors":"Almeida, Carolina Aparecida Faria; Salles, Gabriela; Bruno, Vitor; Ribeiro, Jessyca Milene; Silva, Alessandra Oliveira; de Assis Braz, Giulia; Castelhano, Felype Valentim Duarte; Dos Reis Rosa Franco, Graziella; Viegas, Cláudio; Marcourakis, Tania; Torres, Larissa Helena Lobo; Garcia, Raphael Caio Tamborelli","year":2026,"journal":"Neurotoxicology, 113, 103411","doi":"10.1016/j.neuro.2026.103411","pmid":"41707837","tags":["cbd","synthetic-analogues","alcohol-use-disorder","neuroprotection","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Synthetic CBD analogues PQM-242 and PQM-249 showed LC50 values >600 µM compared to CBD's 44 µM (>13x less toxic), with NOAELs of 100 µM vs. CBD's 10 µM, while still protecting against ethanol-induced apoptosis in neuronal cells.","whyItMatters":"CBD shows promise for alcohol use disorder but has a narrower safety window than assumed — these synthetic alternatives could provide the same benefits with a much wider margin of safety.","specificNumbers":"CBD LC50: 44 µM; PQM-242 and PQM-249 LC50: >600 µM; CBD NOAEL: 10 µM; analogue NOAEL: 100 µM; ethanol challenge at 250 mM; PQM-242 additionally prevented Bax upregulation.","methodology":"In vitro study comparing natural CBD with two synthetic derivatives in human SH-SY5Y neuroblastoma cells, assessing cytotoxicity (MTT), apoptosis (annexin V/PI), and Bax/Bcl-2 expression after 48-hour exposure and ethanol challenge.","limitations":"In vitro neuroblastoma cell line; ethanol concentration (250 mM) is supraphysiological; does not address in vivo pharmacokinetics or behavioral outcomes."},{"rthcId":"RTHC-08075","title":"Cannabis Use During Pregnancy Is Associated with the Suppression of Circulating Maternal Cytokines.","authors":"Alshaarawy, Omayma; Sotzen, Morgan; Kurjan, Emily; Padmanabhan, Vasantha; Ruden, Douglas M; Olson, L Karl","year":2026,"journal":"Cannabis and cannabinoid research, 11(1), 78-88","doi":"10.1177/25785125251388764","pmid":"41104491","tags":["prenatal-cannabis","pregnancy","immune-system","cytokines","thc","inflammation"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use suppressed pro-inflammatory cytokines IFN-γ (β=-0.5) and IL-12 (β=-0.3) and anti-inflammatory cytokines IL-4 (β=-0.7) and IL-10 (β=-0.4) in pregnant women, indicating broad immune modulation rather than simple immunosuppression.","whyItMatters":"Pregnancy requires precise immune balance to protect both mother and baby — cannabis disrupting both pro- and anti-inflammatory signals could explain some of the adverse birth outcomes linked to prenatal use.","specificNumbers":"144 matched participants; IFN-γ β=-0.5 (95% CI -0.8 to -0.1); IL-12 β=-0.3 (-0.6 to -0.05); IL-4 β=-0.7 (-1.3 to -0.2); IL-10 β=-0.4 (-0.7 to -0.03).","methodology":"Ancillary prospective cohort study of 144 pregnant women from the MARCH cohort matched on age, race, and tobacco smoking, using urine-verified THC-COOH to define cannabis use and bead-based multiplex cytokine assays with repeated-measures linear mixed models.","limitations":"Modest sample size (n=144); observational design cannot establish causation; cytokine levels are systemic and may not reflect placental immune environment."},{"rthcId":"RTHC-08076","title":"Drug policy and culture: A cross-national comparative study using Hofstede's index.","authors":"Altaf, Shazib; Lee, Jusung; Choi, Sugy; Park, Sujeong","year":2026,"journal":"The International journal on drug policy, 148, 105132","doi":"10.1016/j.drugpo.2025.105132","pmid":"41512670","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08077","title":"Cannabinoid CB1 receptor and mu-opioid receptor interaction: new insights from conditional knockout mice.","authors":"Alton, Hannah; Linz, Emily; Bi, Guo-Hua; Soler-Cedeno, Omar; Maras, Maia; Xi, Zheng-Xiong","year":2026,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 51(2), 506-518","doi":"10.1038/s41386-025-02245-6","pmid":"40999232","tags":["cb1-receptor","opioid-receptor","pain","reward","knockout-mice","preclinical"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"CB1 and mu-opioid receptors showed limited colocalization in pain and reward brain regions (5-25%); conditional knockout of MOR didn't alter THC effects (analgesia, hypothermia, catalepsy) and CB1R knockout didn't alter oxycodone effects, challenging direct receptor interaction theory.","whyItMatters":"Understanding how cannabinoids and opioids enhance each other's pain relief could lead to lower opioid doses and fewer side effects — but the mechanism may be more complex than assumed.","specificNumbers":"~50% colocalization in PVT glutamatergic neurons; only 5-25% in pain regions (PAG, spinal cord dorsal horn) and reward regions (NAc, VTA, substantia nigra).","methodology":"Conditional knockout mouse study using RNAscope in situ hybridization to map CB1R-MOR colocalization, followed by selective deletion of MOR from glutamatergic or GABAergic neurons and CB1R from GABAergic neurons to test functional interactions.","limitations":"Conditional knockout approach tests specific cell-type interactions but may miss indirect circuit-level effects; compensatory mechanisms may mask receptor interactions."},{"rthcId":"RTHC-08078","title":"Contentious legality in decentralized governance: The rise and decline of cannabis social clubs in Spain.","authors":"Alvarez-Roldan, Arturo; Parra, Iván; Gamella, Juan F","year":2026,"journal":"The International journal on drug policy, 150, 105205","doi":"10.1016/j.drugpo.2026.105205","pmid":"41722212","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08079","title":"Synthetic Cannabinoid AB-FUBINACA Negatively Impacted the Male Fertility and Induced Testicular Toxicity.","authors":"Alzu'bi, Ayman; Abu-El-Rub, Ejlal; Almahasneh, Fatimah A; Almazari, Rawan; Kasasbeh, Amani; Ai-Jariri, Heba F; Alrabie, Amneh; Al-Zoubi, Raed M","year":2026,"journal":"Forensic toxicology, 44(1), 120-129","doi":"10.1007/s11419-025-00739-y","pmid":"41083648","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08080","title":"Altered Neurobehavioral Reward Response Predicts Psychotic-Like Experiences in Youth Exposed to Cannabis Prenatally.","authors":"Amir, Carolyn M; Ghahremani, Dara G; Chang, Sarah E; Cooper, Ziva D; Bearden, Carrie E","year":2026,"journal":"Biological psychiatry, 99(2), 165-174","doi":"10.1016/j.biopsych.2025.05.019","pmid":"40466988","tags":["prenatal-cannabis","psychosis","brain-development","reward-processing","adolescents","neuroimaging"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Prenatal cannabis exposure (652 youth) was longitudinally associated with psychotic-like experiences, mediated by blunted striatal activation during reward anticipation — a marker of disrupted endocannabinoid-dopamine function.","whyItMatters":"This provides a biological mechanism linking prenatal cannabis exposure to later psychosis risk — disrupted reward processing in the developing brain may be the bridge between in-utero exposure and adolescent mental health outcomes.","specificNumbers":"11,368 youth at baseline; 652 with prenatal cannabis exposure; effects tracked across 4 years at 22 US sites; all effect sizes |β|>0.5 with FDR-corrected significance.","methodology":"Longitudinal prospective study analyzing task-related fMRI data from the ABCD Study at baseline (N=11,368), 2-year (n=7,928), and 4-year (n=2,982) follow-ups, examining reward anticipation neural responses.","limitations":"Prenatal exposure based on maternal report, which may underestimate true exposure; ABCD cohort may not be fully representative; fMRI measures are indirect indicators of neural function."},{"rthcId":"RTHC-08081","title":"Trends in US adolescent cannabis use, 1991-2023.","authors":"Amrock, Stephen M; Sajkiewicz, Agata J","year":2026,"journal":"Addictive behaviors, 176, 108634","doi":"10.1016/j.addbeh.2026.108634","pmid":"41666574","tags":["adolescents","trends","prevalence","gender-differences","epidemiology","public-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Lifetime cannabis use dropped from 47.3% (1999) to 30.1% (2023); recent use from 27.1% to 17.8%; early initiation from 11.5% to 6.5%. In 2023, females surpassed males in lifetime (33.4% vs. 27.0%) and recent use (19.4% vs. 16.4%).","whyItMatters":"The historic gender reversal challenges decades of assumptions about male-predominant cannabis use and demands updated prevention approaches that address why girls are now using more.","specificNumbers":"Lifetime use: 47.3% (1999) → 30.1% (2023); recent use: 27.1% → 17.8%; early initiation: 11.5% → 6.5%; 2023 females: 33.4% lifetime, 19.4% recent vs. males: 27.0%, 16.4%.","methodology":"Analysis of 1991-2023 Youth Risk Behavior Survey (YRBS) data, a biennial nationally representative school-based survey of US high school students, using cross-tabulations and logistic regression.","limitations":"Self-reported data subject to social desirability bias; school-based survey misses out-of-school youth; does not capture mode of use (smoking vs. vaping vs. edibles)."},{"rthcId":"RTHC-08082","title":"Expected population prevalence following decriminalization of recreational use of cannabis in Sweden.","authors":"Andersson, Filip; Ramstedt, Mats; Thiesmeier, Robert; Magnusson, Cecilia; Orsini, Nicola; Galanti, Maria Rosaria","year":2026,"journal":"Journal of cannabis research, 8(1)","doi":"10.1186/s42238-026-00405-z","pmid":"41689152","tags":["decriminalization","sweden","prevalence","policy","modeling","public-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Multilevel meta-regression using 12 countries predicted decriminalization would increase both past-12-month and past-30-day cannabis use in Sweden immediately, with experimental use stabilizing but regular use continuing to climb.","whyItMatters":"Sweden's debate over drug policy reform needs evidence-based predictions — this model distinguishes between experimental use (which stabilizes) and regular use (which may indicate growing dependence), a crucial policy distinction.","specificNumbers":"Data from 25 countries (12 with both GDPI and Hofstede scores); predicted immediate increase in both 12-month and 30-day use; 12-month use gap narrows over time while 30-day use gap widens.","methodology":"Cross-national multilevel meta-regression model using jurisdiction-level self-reported cannabis use data from 12 countries and 4 US states to predict prevalence changes following hypothetical decriminalization.","limitations":"Predictions based on other countries' experiences may not account for Sweden's unique cultural attitudes; self-report data may reflect disclosure willingness rather than actual use changes; model assumes comparable policy implementation."},{"rthcId":"RTHC-08083","title":"Latent class analysis of substance use behaviors and associations of class membership with gender affirmation, social determinants of health, and HIV-status among transfeminine adults in the Eastern and Southern United States.","authors":"Andrzejewski, Jack; Corliss, Heather L; Pines, Heather A; Goyal, Ravi; Pitpitan, Eileen; Skaathun, Britt; Wirtz, Andrea L; Reisner, Sari L","year":2026,"journal":"Journal of studies on alcohol and drugs","doi":"10.15288/jsad.25-00133","pmid":"41532688","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08084","title":"Cannabis Hyperemesis Syndrome: A Psychiatric Approach.","authors":"Anibueze, Bibian K; Emmanuel, Adebayo","year":2026,"journal":"Cureus, 18(1), e102152","doi":"10.7759/cureus.102152","pmid":"41732635","tags":["cannabis-hyperemesis-syndrome","chs","psychiatry","psychosis","case-report"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"A young male admitted for drug-induced psychosis developed cyclical vomiting consistent with cannabis hyperemesis syndrome, demonstrating that CHS can coexist with and complicate other cannabis-related psychiatric conditions.","whyItMatters":"CHS is frequently misdiagnosed, especially in psychiatric settings where cannabis-related symptoms may be attributed to other causes — recognizing the overlap between CHS and cannabis psychosis improves patient care.","specificNumbers":"Single case of a young male with long-term cannabis use, recurrent ED presentations, and weight loss from cyclical vomiting while admitted for drug-induced psychosis.","methodology":"Psychiatric case report with literature review, documenting CHS presentation in an inpatient psychiatric setting with recurrent emergency department presentations, weight loss, and medical complications.","limitations":"Single case report; CHS diagnosis is clinical and lacks specific biomarkers; psychiatric comorbidities may confound symptom attribution."},{"rthcId":"RTHC-08085","title":"Detection and quantification of selected cannabinoids in hair samples by liquid-liquid extraction and LC-MS/MS.","authors":"Antunes, Mónica; Simões, Susana; Fonseca, Suzana; Franco, João M; Barroso, Mário; Gallardo, Eugenia","year":2026,"journal":"Forensic science international, 378, 112685","doi":"10.1016/j.forsciint.2025.112685","pmid":"41072362","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08086","title":"Adverse birth outcomes in alcohol-exposed pregnancies with or without tobacco and cannabis.","authors":"Anunziata, Florencia; Frankeberger, Jessica; Baer, Rebecca J; Chambers, Christina; Bandoli, Gretchen","year":2026,"journal":"Preventive medicine, 202, 108427","doi":"10.1016/j.ypmed.2025.108427","pmid":"41062033","tags":["prenatal-cannabis","pregnancy","alcohol","tobacco","birth-outcomes","preterm-birth"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Compared to alcohol alone, co-occurring alcohol+cannabis increased SGA risk (aRR=1.21); alcohol+tobacco increased extreme/very preterm birth (aRR=1.44), late preterm (aRR=1.25), and SGA (aRR=1.31); all three substances had the highest extreme preterm risk (aRR=1.68).","whyItMatters":"This is one of the first large studies to isolate cannabis's additive effect on birth outcomes beyond alcohol — showing that polysubstance use compounds risk in measurable, clinically significant ways.","specificNumbers":"California births 2007-2021; alcohol+tobacco: aRR=1.44 extreme/very PTB, 1.25 late PTB, 1.31 SGA; alcohol+cannabis: aRR=1.21 SGA; all three: aRR=1.68 extreme/very PTB, 1.29 SGA.","methodology":"Population-based retrospective cohort linking California birth certificates (2007-2021) to maternal/infant hospitalization records, using ICD-9/10 codes for substance use diagnoses with adjusted risk ratio analysis.","limitations":"ICD codes may undercount substance use; cannot determine dose, timing, or frequency; California-specific population; unmeasured confounders possible despite adjustment."},{"rthcId":"RTHC-08087","title":"Role of Endocannabinoid System Perturbation in Organophosphate-Mediated Metabolic Impairment and Neuroinflammation.","authors":"Arida, Rowan E; Elgameel, Dina M; Bassiouni, Wesam; Sandilya, Vishal; Abdallah, Salwa M; Mechref, Yehia S; Abd-Elrahman, Khaled S; El-Yazbi, Ahmed F","year":2026,"journal":"Basic & clinical pharmacology & toxicology, 138(3), e70198","doi":"10.1111/bcpt.70198","pmid":"41668464","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08088","title":"Effects of prescribed medical cannabis and alcohol on real-world driving performance (CAN-TRACK): a study protocol for a two-phase trial.","authors":"Arkell, Thomas R; Hayley, Amie C; Aitken, Blair; Hu, Xinyun; Manning, Brooke; Downey, Luke A","year":2026,"journal":"Trials","doi":"10.1186/s13063-026-09512-x","pmid":"41652433","tags":["driving","medical-cannabis","impairment","thc","road-safety","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"Study protocol for the first real-world on-track driving study of prescribed medical cannabis patients (n=72 across pain, anxiety, insomnia) compared to alcohol-impaired healthy controls (n=24 at 0.05% BAC), measuring lateral vehicular control.","whyItMatters":"Australia (and many jurisdictions) prohibit driving with any detectable THC, regardless of actual impairment — this study could provide the evidence needed to shift from zero-tolerance to impairment-based driving laws.","specificNumbers":"Phase 1: 72 patients (24 each for pain, anxiety, insomnia); Phase 2: 24 healthy controls at 0.05% BAC; repeated on-track driving assessments with cognitive testing and biological sampling.","methodology":"Two-phase trial: Phase 1 is a semi-naturalistic cohort study of 72 medical cannabis patients completing on-track driving assessments; Phase 2 is a randomized, placebo-controlled crossover study of 24 healthy participants with alcohol.","limitations":"Study protocol only (no results yet); on-track driving differs from real-world conditions; single-dose assessment may not capture cumulative or chronic use effects."},{"rthcId":"RTHC-08089","title":"Police-Reported Impaired Driving After Recreational Cannabis Legalization in Canada.","authors":"Armstrong, Michael J","year":2026,"journal":"American journal of preventive medicine, 70(2), 108176","doi":"10.1016/j.amepre.2025.108176","pmid":"41167504","tags":["legalization","driving","impairment","canada","enforcement","public-health"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Post-2018, police reported 65 extra drug-impaired incidents per million annually (42% above trend) and 280 extra alcohol-impaired incidents per million (17% above trend); increases were associated more with drug recognition expert employment and pandemic restrictions than cannabis sales.","whyItMatters":"The headline finding — more impaired driving after legalization — is misleading without context. Enhanced enforcement capacity (more drug recognition experts) detected more cases that previously went unrecorded.","specificNumbers":"65 extra drug-impaired incidents/million/year (42% above trend); 280 extra alcohol-impaired incidents/million/year (17%); drug-impaired positively associated with drug expert employment (p<0.05) and cannabis sales (p<0.05).","methodology":"Interrupted time-series analysis of province-level annual police-reported impaired driving counts (2009-2023), with regressions testing associations with legal cannabis sales, use prevalence, police drug experts, and COVID-19 restrictions.","limitations":"Police-reported data reflects enforcement activity, not actual impairment prevalence; cannot distinguish cannabis from other drug impairment in most cases; province-level analysis may mask local variation."},{"rthcId":"RTHC-08090","title":"Depressive Symptoms Predict Cannabis Initiation Among Mexican American Young Adults.","authors":"Arora, Srishty; North, Caroline; Marti, C Nathan; Schwartz, Seth J; Bataineh, Bara S; Talavera-Garza, Liza; Loukas, Alexandra; Wilkinson, Anna V","year":2026,"journal":"Substance use & misuse, 1-10","doi":"10.1080/10826084.2026.2631797","pmid":"41719480","tags":["depression","youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"The question of whether depression leads to cannabis use or cannabis leads to depression has been debated for decades. This study provides evidence for the former: depressive symptoms came first, and cannabis initiation followed.\n\nThe researchers tracked 616 Mexican American college students in Texas (ages 18–29) who had never used cannabis at baseline. One year later, those with higher depressive symptoms were significantly more likely to have initiated cannabis use. This prospective design—measuring depression before cannabis use begins—is stronger than cross-sectional studies that measure both at the same time and can't determine direction.\n\nThe study also tested whether family factors moderated this relationship. Neither family cohesion (closeness, support) nor family conflict buffered or worsened the depression-to-cannabis pathway. This was somewhat surprising given the cultural emphasis on family (familismo) in Mexican American communities—the expectation was that strong family bonds might protect against self-medication.\n\nThe null family finding suggests that the depression-cannabis link operates relatively independently of family dynamics in this population—it's not that bad family relationships push depressed young people toward cannabis, or that good family relationships protect against it. The individual's emotional state appears to be the primary driver.","whyItMatters":"Hispanic/Latino young adults are the fastest-growing demographic in U.S. colleges, yet their cannabis initiation patterns are understudied. Understanding that depression drives cannabis uptake in this population—and that family factors don't buffer it—has implications for prevention: campus mental health services may be more effective than family-based interventions for reducing cannabis initiation.","specificNumbers":"N = 616 cannabis-naïve Mexican American college students. Ages 18–29. Greater depressive symptoms predicted cannabis initiation at 1 year. Family cohesion and family conflict did not moderate the association.","methodology":"Longitudinal cohort study. 616 cannabis-naïve Mexican American college students ages 18–29 in Texas. Depressive symptoms, family cohesion, and family conflict assessed at baseline. Cannabis initiation assessed one year later. Mixed-effects logistic regression.","limitations":"Self-reported depressive symptoms and cannabis use. College students at one Texas institution may not represent all Mexican American young adults. One-year follow-up is relatively short. The study measured cannabis initiation (any use), not progression to regular use or disorder. Cultural context (South Texas, predominantly Catholic) may limit generalizability to other Hispanic populations. Family measures were at a single timepoint."},{"rthcId":"RTHC-08091","title":"Predicting the prognosis of primary and substance-associated psychoses using urine drug screens: A 5-year retrospective longitudinal study using medical records.","authors":"Aschenbrenner, Erich J; Voluse, Andrew C","year":2026,"journal":"Schizophrenia research, 290, 57-64","doi":"10.1016/j.schres.2026.01.023","pmid":"41643570","tags":["psychosis","substance-induced","cannabis","stimulants","prognosis","longitudinal"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis alone at first psychosis presentation showed improved prognosis compared to negative drug screens but more chronic course than expected for substance-induced psychosis; cocaine showed the clearest substance-induced pattern with quick remission and low recurrence.","whyItMatters":"The assumption that cannabis-related psychosis is purely 'substance-induced' and will resolve with abstinence may be wrong — many patients follow a more chronic course suggesting cannabis may trigger lasting psychotic vulnerability.","specificNumbers":"1,379 patients followed 5 years; cannabis alone and cannabis+stimulants showed improved prognosis vs. negative screens but more chronic course than cocaine-alone (which fit substance-induced pattern).","methodology":"5-year retrospective longitudinal study of 1,379 patients following first psychosis presentation, grouped by urine drug screen results, comparing encounter duration, recurrence, healthcare utilization, and drug-screen-negative recurrence.","limitations":"Retrospective design; urine drug screens capture recent use only; cannot determine causation; single regional medical center; loss to follow-up in 5-year window."},{"rthcId":"RTHC-08092","title":"Is toke cheap? Correspondence between cannabis demand and purchase in the laboratory.","authors":"Aston, Elizabeth R; Berey, Benjamin L; Amlung, Michael; Swift, Robert; MacKillop, James; Metrik, Jane","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70282","pmid":"41521902","tags":["cannabis-demand","behavioral-economics","self-administration","research-methods","validation"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Hypothetical and actual cannabis purchase task performance showed high correlations (r=0.45-0.81), though participants were willing to pay more and showed less price sensitivity when purchases were real; self-reported anticipated consumption predicted 66% of actual smoking variance.","whyItMatters":"The Marijuana Purchase Task is used extensively in cannabis research — confirming that hypothetical responses predict real behavior validates years of prior findings built on this tool.","specificNumbers":"92 participants (81 with non-zero trials); price-level correlations r=0.45-0.81; index correlations r=0.46-0.81; anticipated vs actual consumption R²=0.66 (p<0.001); actual MPT showed higher Omax/Pmax (d=0.47-0.51).","methodology":"Laboratory cannabis self-administration study with 92 twice-weekly cannabis users completing both hypothetical and actual Marijuana Purchase Tasks, with one random trial actualized for smoking during a 1-hour session.","limitations":"Laboratory setting differs from real-world purchasing; participants were regular users (≥2x/week) so may not generalize to occasional users; single session doesn't capture longitudinal demand patterns."},{"rthcId":"RTHC-08093","title":"Cannabis-based medicines for chronic neuropathic pain in adults.","authors":"Ateş, Gülay; Welsch, Patrick; Klose, Petra; Phillips, Tudor; Lambers, Britta; Häuser, Winfried; Radbruch, Lukas","year":2026,"journal":"The Cochrane database of systematic reviews, 1(1), CD012182","doi":"10.1002/14651858.CD012182.pub3","pmid":"41548880","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This is the definitive evidence synthesis on cannabis for neuropathic pain—an updated Cochrane Review (originally published 2018) that applied the most rigorous inclusion criteria available: only randomized, double-blind trials lasting at least two weeks.\n\nThe critical outcome was the proportion of patients achieving at least 50% pain relief—the threshold considered clinically meaningful. The review found that cannabis-based medicines (herbal, plant-based, and synthetic) did help some patients reach this threshold compared to placebo, but the effect was modest—only a minority benefited substantially.\n\nA Patient Global Impression of Change (much or very much improved) was also more common with cannabis than placebo, again with modest effect sizes.\n\nThe other side of the equation: adverse events were significantly more common with cannabis. Side effects limited the clinical utility of the treatments, and the balance between benefit and harm was a central concern.\n\nThe review included herbal cannabis, plant-derived products (like nabiximols/Sativex), and synthetic cannabinoids (like nabilone and dronabinol), recognizing these as distinct pharmacological approaches that may have different benefit-harm profiles.\n\nThe evidence quality was mixed—some outcomes had moderate-quality evidence while others were rated lower, reflecting the limitations of the underlying trials.","whyItMatters":"This is the gold standard of evidence synthesis for a clinical question that millions of people face. The answer—modest benefit for some, significant side effects for many—is more nuanced than either 'cannabis works for pain' or 'cannabis doesn't work for pain.' For the 6–10% of the population with neuropathic pain, this review provides the most reliable evidence to date for making treatment decisions.","specificNumbers":"Population prevalence of neuropathic pain: 6–10%. Searches through January 2025. Included only double-blind RCTs ≥2 weeks. Some patients achieved ≥50% pain relief. Cannabis had more adverse events than placebo. Multiple cannabis types assessed (herbal, plant-derived, synthetic).","methodology":"Cochrane systematic review (update of 2018 review). Searched CENTRAL, MEDLINE, Embase, and trial registries through January 2025. Included randomized, double-blind controlled trials of cannabis-based medicines vs. placebo or active treatment for chronic neuropathic pain in adults, with treatment ≥2 weeks. Critical outcomes: ≥50% pain relief, PGIC, adverse events.","limitations":"The underlying trials varied in cannabis type, dose, duration, and population. Some trials were small. The 2-week minimum duration excludes very short studies but may still not capture long-term effects. Neuropathic pain is heterogeneous—some subtypes may respond better than others. The distinction between different cannabis products within the review may not be granular enough."},{"rthcId":"RTHC-08094","title":"Illicit Drug Use During Pregnancy in States With and Without Punitive Prenatal Substance Use Policies.","authors":"Austin, Anna E; Hergenrother, Laura C; Shanahan, Meghan E","year":2026,"journal":"American journal of preventive medicine, 70(3), 108155","doi":"10.1016/j.amepre.2025.108155","pmid":"41101404","tags":["prenatal-cannabis","pregnancy","drug-policy","punitive-policies","public-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Multivariable analysis found no difference in illicit drug use during pregnancy between states with punitive policies and those without (RR=1.02, 95% CI=0.93-1.11), suggesting these policies fail to achieve their stated goal.","whyItMatters":"Punitive policies that criminalize prenatal substance use are spreading across the US — this evidence suggests they don't work and may only deter women from seeking prenatal care.","specificNumbers":"20,356 participants across 19 states; risk ratio=1.02 (95% CI: 0.93-1.11); policies examined include child abuse classification and mandatory healthcare professional reporting.","methodology":"Cross-sectional analysis of 2016-2019 PRAMS survey data from 19 states (N=20,356), comparing self-reported illicit drug use during pregnancy between states with and without punitive prenatal substance use policies.","limitations":"Self-reported data may undercount use, especially in punitive states where women fear consequences; 19 states may not represent all US contexts; cross-sectional design limits causal inference."},{"rthcId":"RTHC-08095","title":"Self-reported use of cannabidiol as a substitute or adjunct for approved medications.","authors":"Austin, Emily A C; Berghammer, Lara; Ellis, Shannon E; Appolon, Giovanni; Brooks, Jenna; Rice, Nina M; Land, Prosperity; Ping, Siyuan; Satybaldiyeva, Nora; Grant, Igor; Leas, Eric C","year":2026,"journal":"Frontiers in public health, 14, 1720348","doi":"10.3389/fpubh.2026.1720348","pmid":"41725772","tags":["cbd","medication-substitution","survey","prevalence","pain","consumer-behavior"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"35.2% of US adults (~90.8 million) have tried CBD; among users, 32% used it as a substitute or adjunct for medications, with adjunct use (24.2%) more common than substitution (11.0%); most commonly for pain, psychiatric conditions, and replacing ibuprofen/Tylenol.","whyItMatters":"Millions of Americans are making medication decisions involving CBD without adequate evidence or clinical guidance — this quantifies a major public health knowledge gap.","specificNumbers":"35.2% ever used CBD (~90.8M); 21.8% used in past 12 months; 32% used as substitute/adjunct; most replaced: ibuprofen (4.8%), Tylenol (3.9%); only 2.4% reported CBD-related health problems.","methodology":"Nationally representative cross-sectional survey via Ipsos KnowledgePanel of 2,880 US adults (1,523 qualifying, including 1,008 CBD ever-users), weighted for national estimates, with medications coded using MedDRA and RxNav.","limitations":"Self-reported data with potential recall bias; survey doesn't capture CBD dose, product type, or quality; cannot assess whether substitution improved or worsened outcomes."},{"rthcId":"RTHC-08096","title":"Combined administration of intracerebroventricular CB1 agonist ACEA and systemic TRPV1 agonist capsaicin induces synergistic antidepressant-like effects in rats.","authors":"Avalos-Moreno, Daniela A; Cuevas-Carbonell, Sergio G; Ramírez-Vargas, Metzli E; Castro-Sánchez, Luis; Virgen-Ortiz, Adolfo; Sánchez-Pastor, Enrique; Góngora-Alfaro, José L; Navarro-Polanco, Ricardo A; Moreno-Galindo, Eloy G; Alamilla, Javier","year":2026,"journal":"Behavioural brain research, 503, 116050","doi":"10.1016/j.bbr.2026.116050","pmid":"41577013","tags":["cb1-receptor","trpv1","depression","antidepressant","capsaicin","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Intracerebroventricular CB1 agonist ACEA and intraperitoneal TRPV1 agonist capsaicin each reduced immobility in the forced swim test, but combined administration produced synergistic antidepressant-like effects without locomotor or anxiety changes.","whyItMatters":"Depression treatment often requires weeks to work, and many patients don't respond — finding synergistic combinations that enhance antidepressant effects could lead to faster, more effective treatments.","specificNumbers":"ACEA alone and capsaicin alone each significantly reduced immobility; combined treatment produced synergistic (not just additive) effects; no changes in locomotor activity or anxiety measures.","methodology":"Preclinical study administering CB1 agonist ACEA (intracerebroventricular) and capsaicin (intraperitoneal) separately and combined in rats, testing immobility in forced swim test, locomotion in open field, and anxiety in elevated plus maze.","limitations":"Forced swim test is a screening tool, not a depression model; invasive intracerebroventricular delivery limits clinical translation; mechanism not fully elucidated; acute effects only."},{"rthcId":"RTHC-08097","title":"Maternal risk factors associated with complex gastroschisis: Cannabis exposure and recurrent urinary tract infections may be modifiable targets.","authors":"Awolaran, Olugbenga; MacGregor, Kaitlyn; Lum Min, Suyin A; Keijzer, Richard","year":2026,"journal":"Journal of pediatric surgery, 163000","doi":"10.1016/j.jpedsurg.2026.163000","pmid":"41651108","tags":["prenatal-cannabis","gastroschisis","birth-defects","pregnancy","risk-factors"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"After adjusting for other substance exposures, cannabis use was associated with complex gastroschisis (adjusted OR=2.64), and recurrent urinary tract infections showed an even stronger association (RaR=3.78) — both identified as potentially modifiable risk factors.","whyItMatters":"Gastroschisis is increasing globally, and while we know what predisposes to it, we didn't know what makes some cases more severe — cannabis exposure may be a modifiable factor that worsens outcomes.","specificNumbers":"194 cases total (80% simple, 20% complex); adjusted OR for cannabis: 2.64; recurrent UTI rate ratio: 3.78; no significant effect from smoking, narcotics, alcohol alone.","methodology":"Retrospective analysis of 194 gastroschisis cases (155 simple, 39 complex) at a tertiary hospital from 1991-2022, comparing maternal risk factors between simple and complex forms using logistic and Poisson regression.","limitations":"Small number of complex cases (n=39); single-center retrospective design; substance use from medical records likely underreported; cannot establish causation."},{"rthcId":"RTHC-08098","title":"School Belonging and Racial Mistreatment: Association With Substance Use Among U.S. High School Students.","authors":"Azagba, Sunday; Ebling, Todd; de Silva, Galappaththige S R","year":2026,"journal":"Journal of racial and ethnic health disparities","doi":"10.1007/s40615-025-02830-x","pmid":"41511739","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08099","title":"Negative Urgency Mediates the Effect of Family Conflict on Cannabis Positive Expectancy: The Moderating Role of Anterior Cingulate Cortex.","authors":"Azarmehr, Rabeeh; Howard, Cullin J; Kogan, Steven M; Geier, Charles; Oshri, Assaf","year":2026,"journal":"Addiction biology, 31(2), e70131","doi":"10.1111/adb.70131","pmid":"41742008","tags":["adolescents","family-conflict","impulsivity","brain-development","neuroimaging","prevention"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Family conflict at baseline predicted increased cannabis positive expectancies through negative urgency (β=0.017, p<0.001); heightened anterior cingulate cortex activation during emotional reward processing amplified this indirect effect.","whyItMatters":"This maps the exact pathway from family stress to cannabis risk: conflict → emotional impulsivity → positive cannabis beliefs, with brain imaging confirming the neural vulnerability that amplifies this chain.","specificNumbers":"6,638 youth (47.8% female, baseline age 10.1); mediation β=0.017 (p<0.001); left caudal ACC moderation β=0.081 (p<0.001); right caudal ACC β=0.062 (p=0.004).","methodology":"Longitudinal moderated mediation analysis of 6,638 youth from the ABCD Study across three waves (baseline age ~10 years), combining behavioral measures with task-based fMRI of emotional reward processing.","limitations":"Cannabis expectancies measured, not actual use; ABCD cohort participants still young; ACC activation from a lab task may not reflect real-world emotional processing; observational design."},{"rthcId":"RTHC-08100","title":"Modulatory function of cannabidiol on the extinction and reinstatement of methamphetamine-seeking behavior through the D2-like dopamine receptors in the dentate gyrus.","authors":"Azizbeigi, Ronak; Baharlouei, Negar; Nazari-Serenjeh, Farzaneh; Taslimi, Zahra; Haghparast, Abbas","year":2026,"journal":"Behavioural brain research, 497, 115882","doi":"10.1016/j.bbr.2025.115882","pmid":"41110614","tags":["cbd","methamphetamine","addiction","dopamine","hippocampus","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD facilitated extinction and suppressed reinstatement of methamphetamine conditioned place preference, effects that were blocked by the D2 receptor antagonist Sulpiride in the dentate gyrus, suggesting CBD works partly through indirect dopamine modulation.","whyItMatters":"Methamphetamine addiction has no approved pharmacological treatment — CBD's ability to speed extinction and prevent relapse through identifiable brain mechanisms offers hope for a desperately needed therapeutic.","specificNumbers":"Sulpiride at 4 μg attenuated CBD's extinction facilitation; at 1 and 4 μg reversed CBD's reinstatement suppression; CBD doses: 10 μg/5 μl (extinction) and 50 μg/5 μl (reinstatement), intracerebroventricular.","methodology":"Preclinical conditioned place preference study in rats receiving intra-DG Sulpiride (D2 antagonist) before ICV CBD during 10-day extinction and on reinstatement day, with multiple Sulpiride doses tested.","limitations":"Intracerebroventricular CBD delivery not clinically practical; mechanism likely indirect (CBD → increased DA → D2 activation) rather than direct D2 interaction; animal model of addiction has limited human translation."},{"rthcId":"RTHC-08101","title":"Pharmacological, Molecular Mechanisms, and Therapeutic Potential of β-Caryophyllene and β-Caryophyllene-Rich Plants in Liver Diseases.","authors":"Bader Eddin, Lujain; Subramanya, Sandeep B; Ojha, Shreesh","year":2026,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 40(1), e71344","doi":"10.1096/fj.202502436R","pmid":"41489519","tags":["beta-caryophyllene","cb2-receptor","liver-disease","anti-inflammatory","terpene","review"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"β-caryophyllene acts as a dietary cannabinoid through CB2 receptor activation plus PPAR and AMPK signaling, consistently reducing hepatic steatosis, collagen deposition, and inflammatory markers across multiple liver disease models.","whyItMatters":"Liver disease is a growing global health burden with limited treatment options — a naturally occurring, food-safe compound that targets multiple liver damage pathways could be transformative.","specificNumbers":"β-caryophyllene activates CB2 receptors plus PPAR nuclear receptor and AMPK signaling; demonstrated effects across MAFLD, alcoholic liver disease, and liver fibrosis models.","methodology":"Systematic review compiling and critically analyzing in vitro and in vivo studies on β-caryophyllene in nonalcoholic fatty liver disease (MAFLD), alcoholic liver disease, and liver fibrosis.","limitations":"Evidence is entirely preclinical; no human clinical trials; doses used in animal studies may not translate directly to human supplementation; regulatory pathway unclear."},{"rthcId":"RTHC-08102","title":"The Mechanism of Ultrasonic Lysis of Enterococcus faecium F11.1G in Repairing LPS-Induced Inflammatory Damage in IECs via RNA-seq and LC-MS.","authors":"Bai, Tiantian; Zhang, Yanlong; E, Guangxu; Zhang, Meng; Guo, Xuefeng; Liu, Junfeng","year":2026,"journal":"Cells, 15(2)","doi":"10.3390/cells15020103","pmid":"41597179","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08103","title":"Exposure to neighborhood violence and substance use among adolescents: Findings from a population-based study.","authors":"Baiden, Philip; Hall, Angela J; LaBrenz, Catherine A; Awua, Joshua; Glikpo, Raymond M; Nartey, Patience","year":2026,"journal":"Journal of affective disorders, 394(Pt B), 120626","doi":"10.1016/j.jad.2025.120626","pmid":"41205926","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08104","title":"Elucidating the role of ABC transporters in the placental efflux of (-)- Δ9-tetrahydrocannabinol (THC) using a cocktail of ABC transport inhibitors.","authors":"Balhara, Ankit; Chen, Xin; Kumar, Aditya R; Wasickanin, Morgan E; Monson, Joshua W; Damicis, Jennifer R; Kinsman, Hillary J; Ieronimakis, Nicholas; Unadkat, Jashvant D","year":2026,"journal":"Placenta, 174, 174-177","doi":"10.1016/j.placenta.2025.12.012","pmid":"41475275","tags":["prenatal-cannabis","thc","placenta","abc-transporters","fetal-exposure","preclinical"],"studyType":"laboratory-analysis","evidenceStrength":"moderate","keyFinding":"A cocktail of P-gp and BCRP inhibitors significantly increased maternal-to-fetal THC transfer in perfused human placentas, confirming these transporters actively efflux THC and partially limit fetal exposure.","whyItMatters":"Understanding how the placenta handles THC explains why fetal exposure occurs but is limited — and why factors that compromise placental transporter function could increase fetal vulnerability.","specificNumbers":"Inhibitor cocktail significantly increased unbound maternal-to-fetal THC clearance index compared to uninhibited controls; previous single-inhibitor (valspodar) failed to block efflux due to multiple transporter binding sites.","methodology":"Ex vivo human placenta cotyledon perfusion with THC in the absence and presence of a cocktail of P-gp and BCRP inhibitors, measuring unbound maternal-to-fetal THC clearance index.","limitations":"Ex vivo perfusion model has limited duration; does not capture chronic exposure effects; individual variation in transporter expression not assessed; does not measure THC metabolite transfer."},{"rthcId":"RTHC-08105","title":"Zebrafish larval behaviour study of cinnamic acid derivatives isolated from cannabis sativa roots and their synthetic analogs.","authors":"Banskota, Arjun H; Jones, Alysson; Vansickle, Raven; Ellis, Lee","year":2026,"journal":"Natural product research, 1-7","doi":"10.1080/14786419.2026.2613343","pmid":"41556967","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08106","title":"Industrial Cannabis, Cannabic Residue or Industrial Cannabis Waste? Perspectives on the Utilization, Reutilization, and Recycling of Cannabis.","authors":"Barbosa, Raoni Avan de Almeida; Lyrio, Enzo Sousa; Gouvêa-Silva, João Gabriel; Costa-Oliveira, Claudete da; Viana-Oliveira, Larissa Dias; Mazzola, Priscila Gava; Vale, Ademir Evangelista do; Ramos, Ygor Jessé","year":2026,"journal":"Cannabis and cannabinoid research, 25785125261421439","doi":"10.1177/25785125261421439","pmid":"41652844","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08107","title":"Simultaneous Use of Alcohol and Marijuana Among College Students: The Role of Expectancies, Impulsivity and Behavioral Emotion Regulation.","authors":"Barey, Agostina; Pilatti, Angelina; Ruiz, Paul; Pautassi, Ricardo M","year":2026,"journal":"Substance use & misuse, 61(4), 587-597","doi":"10.1080/10826084.2025.2568938","pmid":"41071632","tags":["simultaneous-use","alcohol","cannabis","college-students","impulsivity","expectancies"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"SAM users reported significantly more binge drinking and alcohol problems than alcohol-only users; sensation seeking, low perseverance, and stronger positive/weaker negative SAM expectancies distinguished simultaneous users from both alcohol-only users and nonusers.","whyItMatters":"Simultaneous alcohol-marijuana use is more dangerous than using either alone — understanding the psychological profile that predicts this behavior enables targeted prevention.","specificNumbers":"1,369 college students; SAM users had significantly higher binge drinking frequency and alcohol-related problems; key distinguishing factors: sensation seeking, low perseverance, positive SAM expectancies.","methodology":"Online survey of 1,369 Argentinean college students (ages 18-25) assessing substance use, impulsivity traits, behavioral emotion regulation, and SAM-related expectancies, analyzed with ANOVAs and multinomial logistic regression.","limitations":"Cross-sectional design; Argentinean sample may not generalize to other countries; self-report measures; online survey recruitment may not represent all college students."},{"rthcId":"RTHC-08108","title":"A novel electrochemical method for detecting synthetic cannabinoids in e-cigarette and biological samples using a lab-made electrode.","authors":"Barroso, Cecília N F; Melo, Larissa M A; Aranha, Lívia M S; Pereira, Thiago F L; Souza, Karla A O; Costa, Jose L; Arantes, Luciano C; Marton, Marian; Vojs, Marian; Dos Santos, Wallans T P","year":2026,"journal":"Talanta, 297(Pt A), 128574","doi":"10.1016/j.talanta.2025.128574","pmid":"40682941","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08109","title":"Hydrodistillation-Based Essential Oil Extraction and Soda Pulping of Spent Hemp Biomass for Sustainable Fiber Production.","authors":"Basak, Munmun; Agwuncha, Stephen C; Bera, Sharmita; Bloomquist, Margaret; Davis, Jeanine; Lucia, Lucian; Pal, Lokendra","year":2026,"journal":"Molecules (Basel, Switzerland), 31(3)","doi":"10.3390/molecules31030500","pmid":"41683477","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08110","title":"Feasibility and acceptability of a physical activity intervention to reduce prenatal cannabis use: results of an open pilot trial.","authors":"Battle, Cynthia L; Dreyer-Oren, Sarah E; Vijil Morin, Andrea; Hoyt, Morgan N; Metrik, Jane; Abrantes, Ana M","year":2026,"journal":"Frontiers in psychiatry, 17, 1729092","doi":"10.3389/fpsyt.2026.1729092","pmid":"41696467","tags":["prenatal-cannabis","pregnancy","physical-activity","intervention","walking","mental-health"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"Prenatal cannabis use dropped from 62.5% at baseline to 16.6% by 36 weeks gestation; daily steps increased from 5,738 to 6,562; anxiety and depression significantly decreased; 88% retention rate with mean 5.8/6 sessions attended.","whyItMatters":"There are virtually no evidence-based interventions for prenatal cannabis use — this simple, low-cost walking program achieved remarkable reductions while also improving the mental health conditions that often drive cannabis use during pregnancy.","specificNumbers":"16 participants; 88% completion; 5.8/6 sessions attended; cannabis use: 62.5% → 16.6%; daily steps: 5,738 → 6,562; no adverse events; significant anxiety and depression reductions.","methodology":"Open pilot trial of a 10-week prenatal walking intervention with 16 pregnant individuals seeking to reduce cannabis use, using Fitbit tracking, 6 coaching sessions, and assessments of cannabis use, physical activity, and mental health.","limitations":"Very small sample (n=16); no control group; open-label design; self-reported cannabis use; participants were motivated (self-selected to reduce use)."},{"rthcId":"RTHC-08111","title":"Cannabis modalities matter for momentary subjective drug effects.","authors":"Bedillion, Margaret F; Matlack, Maya P; Ansell, Emily B","year":2026,"journal":"Addictive behaviors, 177, 108638","doi":"10.1016/j.addbeh.2026.108638","pmid":"41698283","tags":["consumption-methods","subjective-effects","ema","vaping","edibles","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Bong use was associated with greater 'good effects,' 'liking,' and 'willingness to take again' vs. bowls; vaporizer use produced lower subjective intoxication; edible use reduced 'willingness to take again' — all captured via ecological momentary assessment.","whyItMatters":"How you consume cannabis matters more than most people realize — different methods produce different subjective experiences that predict continued use patterns and potential harm.","specificNumbers":"215 participants; 21 days EMA tracking; 56.7% female; mean age 21; bong > bowl for good effects, liking, willingness; vaporizer < others for intoxication; edibles < others for willingness.","methodology":"Ecological momentary assessment study of 215 young adult recreational cannabis users (56.7% female, mean age 21) reporting on cannabis use patterns and subjective effects across 21 days of real-time tracking.","limitations":"Observational design cannot determine if method choice causes different effects or reflects different user types; self-reported intoxication; young recreational users may not represent all cannabis consumers."},{"rthcId":"RTHC-08112","title":"Pharmacotherapy for Cannabis Use Disorder: Preclinical and Clinical Models.","authors":"Bedillion, Margaret F; Moore, Catherine F; Weerts, Elise M; Arout, Caroline A; Harris, Hannah M; Haney, Margaret","year":2026,"journal":"Current topics in behavioral neurosciences, 76, 249-296","doi":"10.1007/7854_2025_598","pmid":"40760404","tags":["cannabis-use-disorder","pharmacotherapy","treatment","clinical-trials","preclinical","review"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The translational pipeline from preclinical to clinical CUD pharmacotherapy is hindered by challenges in establishing robust animal self-administration models and fundamental questions about efficacy endpoints (abstinence vs. reduction in use).","whyItMatters":"Cannabis use disorder affects millions but has zero FDA-approved treatments — understanding why the pipeline is stuck is essential for breaking through to effective medications.","specificNumbers":"No FDA-approved medications for CUD; research lags compared to other substance use disorders; key challenge: animal models of cannabinoid self-administration remain difficult to establish.","methodology":"Comprehensive review evaluating the translational pipeline for cannabis use disorder medications, from preclinical models through human laboratory studies to randomized controlled clinical trials.","limitations":"Review scope focused on pharmacotherapy; doesn't address behavioral or combined approaches; rapidly evolving field means some recent developments may not be captured."},{"rthcId":"RTHC-08113","title":"Demographics, methods of use, and perceived benefits among patients with cancer who use cannabis.","authors":"Behl, Deepti; D'Andre, Stacy; Hankins, Andrea; Tiet, Kara; Portugal, Jose; Parise, Carol","year":2026,"journal":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 34(3), 197","doi":"10.1007/s00520-026-10452-0","pmid":"41686327","tags":["cancer","symptom-management","sleep","pain","survey","oncology"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"24.7% of cancer patients used cannabis; primary reason was sleep (56.7%); associated with younger age, Stage 4 cancer (OR=3.28), and concurrent chemotherapy (OR=2.45); 68% smoked/vaped, 60% used edibles, 65%+ used multiple methods.","whyItMatters":"A quarter of cancer patients are using cannabis without robust clinical evidence guiding them — understanding their patterns and motivations is essential for developing evidence-based oncology guidance.","specificNumbers":"2,602 surveyed; 643 (24.7%) used cannabis; sleep: 56.7%; Stage 4 OR=3.28; chemo OR=2.45; 68% smoked/vaped; 60% edibles; 65%+ multiple methods; most spent <$100/month.","methodology":"Cross-sectional survey of 2,602 oncology patients visiting Northern California offices from 2018-2024, with logistic regression analysis of demographics, cancer characteristics, methods, and perceived benefits.","limitations":"Single region (Northern California, where cannabis is legal); self-reported use and perceived benefits; no objective outcome measures; non-Hispanic White overrepresentation in users."},{"rthcId":"RTHC-08114","title":"Investigating the effects of cannabinoids for the reduction of inflammation and sickle cell disease pain (CRISP); A protocol for a randomized double-blind placebo-controlled study.","authors":"Bellis, Jordan; Monk, Lydia; Jhawar, Ritika; Pollock, Galia; Liu, Angela; Jacobs-McFarlane, Charleen; McCrary, Brittany; Glassberg, Jeffrey; Curtis, Susanna","year":2026,"journal":"PloS one, 21(1), e0340917","doi":"10.1371/journal.pone.0340917","pmid":"41604381","tags":["sickle-cell-disease","thc","dronabinol","chronic-pain","clinical-trial","inflammation"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"Protocol for an 8-week RCT of dronabinol for chronic SCD pain, with dual endpoints of pain reduction and inflammatory biomarker changes, positioned as an opioid alternative investigation.","whyItMatters":"Sickle cell disease patients suffer severe chronic pain with limited options beyond opioids — investigating THC as both an analgesic and anti-inflammatory addresses two drivers of SCD pain simultaneously.","specificNumbers":"8-week duration; randomized double-blind placebo-controlled design; uses FDA-approved dronabinol; tracks both pain and inflammation biomarkers; targets patients with SCD and chronic pain.","methodology":"Randomized, double-blind, placebo-controlled, 8-week study of FDA-approved dronabinol (synthetic THC) for chronic pain in sickle cell disease patients, tracking both pain outcomes and inflammatory biomarkers.","limitations":"Protocol publication only (no results yet); dronabinol is synthetic THC only (no CBD component); 8 weeks may be insufficient to assess long-term effects; chronic pain is notoriously difficult to study."},{"rthcId":"RTHC-08115","title":"Reductions in cigarette and cannabis use during a randomized clinical trial for alcohol use disorder.","authors":"Belnap, Malia A; McManus, Kaitlin R; Kirsch, Dylan E; Grodin, Erica N; Ray, Lara A","year":2026,"journal":"Alcohol and alcoholism (Oxford, Oxfordshire), 61(2)","doi":"10.1093/alcalc/agag006","pmid":"41664456","tags":["alcohol-use-disorder","cannabis","tobacco","clinical-trial","co-occurring-use","ibudilast"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Cigarette use declined significantly over 12 weeks (p=.002); cannabis decreased early (p=.006) then rebounded (p=.03); early cannabis reduction was negatively associated with drinks per drinking day, suggesting a compensatory relationship.","whyItMatters":"The finding that treating one substance problem can ripple across others challenges the single-substance treatment model — and suggests comprehensive substance use screening should be standard in addiction trials.","specificNumbers":"102 participants (61M/41F); significant cigarette reduction (p=.002); cannabis decrease early (p=.006) then increase (p=.03); cannabis changes inversely associated with drinks/drinking day (p<.05).","methodology":"Secondary analysis of a 12-week RCT of ibudilast for AUD (N=102), examining unprompted changes in cigarette and cannabis use and their associations with drinking outcomes.","limitations":"Secondary analysis not powered for these outcomes; relatively small sample; co-occurring use patterns make it difficult to isolate individual substance effects; ibudilast effects on other substances unknown."},{"rthcId":"RTHC-08116","title":"Detection of Δ9-Tetrahydrocannabinol Impairment Using Resting-State Functional Near-Infrared Spectroscopy: A Randomized Clinical Trial.","authors":"Berchansky, Moshe; Evins, A Eden; Evohr, Bryn; Himmelsbach, Zachary; Pachas, Gladys N; Karunakaran, Keerthana Deepti; Laufer Goldshtein, Bracha; Ozana, Nisan; Gilman, Jodi M","year":2026,"journal":"JAMA network open, 9(1), e2556647","doi":"10.1001/jamanetworkopen.2025.56647","pmid":"41615687","tags":["thc-impairment","brain-imaging","fnirs","driving","detection","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Resting-state fNIRS achieved ROC-AUC=0.87, accuracy=0.90, and false-positive rate=0.05 for THC impairment detection vs. FST ROC-AUC=0.75, accuracy=0.69, and false-positive rate=0.34 — all differences statistically significant (p<.005).","whyItMatters":"Current THC impairment detection relies on biased subjective tests — a portable, objective brain imaging approach could revolutionize cannabis impairment testing for law enforcement and workplace safety.","specificNumbers":"183 participants; fNIRS: AUC=0.87, accuracy=0.90, FPR=0.05; FST: AUC=0.75, accuracy=0.69, FPR=0.34; precision difference=0.23 (p<.001); accuracy difference=0.15 (p<.001); FPR difference=-0.25 (p<.001).","methodology":"Double-blind, randomized, crossover trial of 183 cannabis users receiving oral synthetic THC (5-80mg) or placebo, with fNIRS brain scans and field sobriety tests at baseline, 100min, and 200min post-dose, analyzed with machine learning classifiers.","limitations":"Laboratory setting with synthetic THC pills differs from real-world cannabis smoking; single-site study; fNIRS hardware still needs miniaturization for field use; trained on regular cannabis users."},{"rthcId":"RTHC-08117","title":"Associations between hair endocannabinoid concentrations and parental depressive symptoms: A longitudinal study of mothers, fathers, and their offspring up to two years postpartum.","authors":"Bergunde, L; Jaramillo, I; Rihm, L; Gao, W; Weidner, K; von Soest, T; Steudte-Schmiedgen, S; Garthus-Niegel, S","year":2026,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 111649","doi":"10.1016/j.pnpbp.2026.111649","pmid":"41720284","tags":["endocannabinoid-system","postpartum-depression","anandamide","hair-biomarkers","longitudinal"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Cross-lagged models showed PPDS at 8 weeks predicted lower hair AEA at 14 months, but not vice versa — suggesting depression depletes endocannabinoid signaling rather than ECS deficiency causing depression. Maternal PPDS also associated with lower child OEA levels.","whyItMatters":"This challenges the assumption that endocannabinoid deficiency causes depression — instead, depression itself may erode ECS function over time, creating a potential vicious cycle.","specificNumbers":"307 mothers, 208 fathers, 288 children; PPDS at 8 weeks → lower AEA at 14 months; maternal PPDS at 8 weeks → lower child OEA at 14 months; adjusting for cortisol didn't alter effects.","methodology":"Longitudinal study of 307 mothers, 208 fathers, and 288 children from the DREAMHAIR biological sub-study, measuring hair endocannabinoids (AEA, AG), N-acylethanolamines, and cortisol at 8 weeks, 14 months, and 24 months postpartum.","limitations":"Community cohort may not capture clinical depression severity; hair endocannabinoids reflect long-term levels but may miss acute changes; novel measurement approach requires further validation."},{"rthcId":"RTHC-08118","title":"Perception and use of cannabidiol (CBD) by French pet owners.","authors":"Besegher, Audrey; Jeannin, Sarah; Niamba, Narcisse; Bedossa, Thierry; Bovet, Dalila; Hoummady, Sara","year":2026,"journal":"Veterinary journal (London, England : 1997), 315, 106536","doi":"10.1016/j.tvjl.2025.106536","pmid":"41389569","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08119","title":"Vapor pressure measurements on Δ9-tetrahydrocannabinol, cannabidiol, and cannabinol to inform cannabis breathalyzer development.","authors":"Beuning, Cheryle N; Berry, Jennifer L; Paulechka, Eugene; Huber, Marcia L; Jeerage, Kavita M; Widegren, Jason A; Lovestead, Tara M","year":2026,"journal":"Journal of breath research, 20(1)","doi":"10.1088/1752-7163/ae3794","pmid":"41529405","tags":["breathalyzer","thc","cbd","vapor-pressure","detection","forensic"],"studyType":"laboratory-analysis","evidenceStrength":"moderate","keyFinding":"Vapor pressure measurements extrapolated to body temperature predict all three major cannabinoids (THC, CBD, CBN) reside primarily in the vapor phase of exhaled breath, potentially explaining the large variability seen in aerosol-only collection devices.","whyItMatters":"Cannabis breathalyzers are being developed worldwide but show inconsistent results — this fundamental chemistry data explains why: devices capturing only aerosol may miss most of the cannabinoid signal in exhaled breath.","specificNumbers":"Vapor pressures (364-424K): THC 0.046-7.83 Pa, CBD 0.083-13.44 Pa, CBN 0.020-5.68 Pa; measurement uncertainty 2.9-9.5%; all three cannabinoids predicted to be primarily in vapor phase at breath temperature.","methodology":"Gas-saturation apparatus measurements of vapor pressure for THC, CBD, and CBN from 364-424K, extrapolated to body temperature via thermodynamic correlation, with vapor-aerosol partitioning modeling of exhaled breath.","limitations":"Extrapolation from higher temperatures introduces uncertainty; breath composition varies between individuals and with environmental conditions; pure compound behavior may differ in complex breath matrix."},{"rthcId":"RTHC-08120","title":"Discovery and characterization of quinoxaline and quinoline carboxamides as allosteric cannabinoid receptor modulators.","authors":"Bi, Chunyang; Mahardhika, Andhika B; Pillaiyar, Thanigaimalai; Müller, Christa E","year":2026,"journal":"Biochemical pharmacology, 243(Pt 1), 117485","doi":"10.1016/j.bcp.2025.117485","pmid":"41173052","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08121","title":"Phytocannabinoids influence phospholipid metabolism of melanoma cells: Modulation of in vitro effects of the UVA irradiation.","authors":"Biernacki, Michał; Sękowski, Szymon; Dobrzyńska, Izabela; Olchowik-Grabarek, Ewa; Zarkovic, Neven; Jarocka-Karpowicz, Iwona; Gęgotek, Agnieszka; Skrzydlewska, Elżbieta","year":2026,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 195, 119003","doi":"10.1016/j.biopha.2026.119003","pmid":"41529510","tags":["cbd","cbg","melanoma","cancer","phospholipids","uva","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD (5 µM) and CBG (1 µM) altered melanoma cell membrane phospholipid fatty acids, sialic acid, surface charge, and lipid rafts; increased endocannabinoid 2-AG levels; and when combined, reduced pro-inflammatory eicosanoids and modified cannabinoid receptor expression after UVA irradiation.","whyItMatters":"Melanoma has high metastatic potential and poor prognosis in advanced stages — finding that phytocannabinoids target cell membrane structures important for metastasis opens a novel therapeutic angle.","specificNumbers":"CBD at 5 µM, CBG at 1 µM; UVA dose 18 J/cm²; combined CBD/CBG reduced pro-inflammatory eicosanoids; significant 2-AG increase with phytocannabinoid treatment; altered CB1/CB2/TRPV1/PPARγ expression.","methodology":"In vitro study of CBD and CBG effects on SK-MEL-5 melanoma cells, analyzing membrane composition, lipolytic enzyme activity, lipid mediators, and receptor expression with and without UVA irradiation.","limitations":"Single cell line in vitro; concentrations may not be achievable in vivo; UVA irradiation model may not reflect all melanoma contexts; no cell viability or tumor growth data."},{"rthcId":"RTHC-08122","title":"Adult Rat Offspring Exposed to THC during Gestation Exhibit Distinct Biomolecular Changes Identified by X-ray Fluorescence Imaging and Fourier Transform Infrared Spectroscopy in Cortico-Limbic Circuits.","authors":"Black, Tallan; Boseley, Rhiannon E; Quirk, Amanda; Young, Kaylen M; Lunardi-Baccetto, Sarah; Muyres, Brett D; Laprairie, Robert B; Howland, John G","year":2026,"journal":"ACS chemical neuroscience, 17(4), 719-739","doi":"10.1021/acschemneuro.5c00752","pmid":"41662491","tags":["pregnancy","cognition","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Most prenatal cannabis studies measure outcomes at the behavioral or anatomical level. This study went deeper—using two advanced biospectroscopic techniques to examine the actual chemical and molecular composition of brain tissue in offspring exposed to THC during gestation.\n\nX-ray fluorescence imaging (XFI) revealed that THC-exposed offspring had decreased copper concentrations in the perimeter of their corpus callosum—the massive fiber bundle connecting the brain's two hemispheres. Copper is essential for myelin formation and neural signaling; reduced copper in this structure could affect interhemispheric communication.\n\nFourier transform infrared spectroscopy (FTIR) revealed neurochemical changes (described as neurochemical dysbiosis) within the cortico-limbic circuits—the brain networks that process emotions, motivation, and social behavior. These are the same circuits previously shown to produce distinct behavioral phenotypes in THC-exposed offspring.\n\nThe significance of this approach is that it provides a biochemical explanation for behavioral observations. Rather than saying 'THC-exposed animals behave differently,' this study shows specific chemical changes in specific brain regions that could underlie those behavioral differences.","whyItMatters":"This moves the prenatal cannabis evidence from 'THC exposure is associated with behavioral changes' to 'here are the specific molecular and elemental changes in the brain tissue that explain those behaviors.' The copper finding is particularly novel—trace element disruption in the brain is an understudied consequence of prenatal drug exposure.","specificNumbers":"THC dose: 3 mg/kg (i.p.) during gestation. Decreased copper in corpus callosum perimeter. Neurochemical changes in cortico-limbic circuits detected by FTIR. Two imaging modalities combined for comprehensive tissue characterization.","methodology":"Animal study. Rat offspring exposed to THC (3 mg/kg, i.p.) or vehicle during gestation. Multimodal biospectroscopic imaging of brain tissue: X-ray fluorescence imaging (XFI) for metal and elemental analysis, and Fourier transform mid-infrared spectromicroscopy (FTIR) for neurochemical composition of cortico-limbic circuits.","limitations":"Rat model—brain development timelines and drug exposure patterns differ from humans. The THC dose (3 mg/kg i.p.) may not model typical human gestational exposure from smoking or ingestion. XFI and FTIR are powerful imaging tools but the findings need replication and functional validation. The study connects previous behavioral findings to tissue chemistry but the causal chain (THC → copper loss → behavioral change) needs more direct testing."},{"rthcId":"RTHC-08123","title":"Vaping Δ9-tetrahydrocannabinol (Δ9-THC) in liquid forms: pharmacokinetics, pharmacodynamics, and regulatory implications.","authors":"Block, Ashleigh C; Smith, Danielle M; Goniewicz, Maciej L","year":2026,"journal":"Expert review of clinical pharmacology, 1-16","doi":"10.1080/17512433.2026.2630756","pmid":"41664603","tags":["thc-vaping","pharmacokinetics","potency","regulation","e-cigarettes","review"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"No human PK/PD studies exist for vaped liquid THC despite growing prevalence; analysis suggests these products may be more potent than smoked cannabis but consumer behavior may modulate delivery, creating an unpredictable risk profile.","whyItMatters":"Millions of people are vaping THC liquids without any scientific understanding of how these products deliver THC to the body — potency, timing, and peak effects remain entirely uncharacterized.","specificNumbers":"Zero human PK/PD studies on vaped liquid THC found in PubMed or Embase; products are generally more potent than smoked cannabis flower.","methodology":"Narrative review searching PubMed and Embase, synthesizing knowledge from smoked cannabis and nicotine e-cigarette research to hypothesize about vaped liquid THC pharmacology and identify regulatory implications.","limitations":"Review identifies the knowledge gap but cannot fill it; hypotheses based on smoked cannabis and nicotine vaping may not accurately predict liquid THC vaping behavior; US regulatory focus may not apply globally."},{"rthcId":"RTHC-08124","title":"Cannabis Use Patterns and Blood Profiles in Adolescent Cannabinoid Hyperemesis Syndrome.","authors":"Bloom, Joshua; Beaudoin, Francesca L; Lin, Timmy R; Gaipo, Ashley; Ortega, Carolyn; Wightman, Rachel S","year":2026,"journal":"Pediatric emergency care, 42(1), e13-e19","doi":"10.1097/PEC.0000000000003495","pmid":"41088881","tags":["withdrawal","addiction","youth","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"This pilot study screened 869 adolescent emergency department patients to identify 10 with cyclic vomiting onset after chronic cannabis use—a ratio that illustrates both how common the screening population is and how specifically they identified CHS cases.\n\nAll 10 participants had cannabis use disorder (9) or hazardous cannabis use (1) by validated assessment. All reported withdrawal symptoms when trying to stop cannabis—confirming that CHS occurs in the context of physiological dependence, not casual use.\n\nThe study's innovation was comparing blood profiles during symptomatic episodes versus asymptomatic follow-up visits. Cannabinoid metabolite levels and essential mineral and B vitamin levels were quantified at both timepoints. This within-person comparison is valuable because it controls for individual differences.\n\nThe findings about minerals and B vitamins are particularly relevant given RTHC-00164's case of CHS-induced Wernicke's encephalopathy from thiamine deficiency. If specific nutrient deficiencies are part of the CHS picture—not just a consequence of prolonged vomiting—they could become both diagnostic markers and treatment targets.","whyItMatters":"CHS diagnosis is currently clinical—there's no blood test. If specific cannabinoid metabolite patterns or mineral changes reliably distinguish CHS from other causes of cyclic vomiting, that could dramatically improve emergency department diagnosis. It would also connect to RTHC-00205's finding that aprepitant rapidly resolved CHS when standard treatments failed—better diagnosis could lead to faster appropriate treatment.","specificNumbers":"869 adolescents screened; 10 enrolled with CHS. 9/10 had cannabis use disorder, 1 hazardous use. All reported withdrawal symptoms. Blood drawn at symptomatic and asymptomatic visits for cannabinoid metabolites, minerals, and B vitamins.","methodology":"Pilot prospective observational cohort study. Screened 869 adolescent ED patients (ages 14–21); enrolled 10 with symptomatic cyclic vomiting after chronic cannabis use. Assessed at symptomatic presentation and asymptomatic follow-up. Cannabis use patterns: validated questionnaires. Blood profiles: cannabinoid metabolites, essential minerals, and B vitamins at both timepoints.","limitations":"Extremely small sample (10 patients). Pilot study—powered for feasibility, not for drawing firm conclusions about biomarkers. Single ED site. The within-person comparison is strong but individual variation is high. Not all adolescents with CHS may present to the ED. The 869:10 screening ratio suggests high specificity of the inclusion criteria but may miss milder presentations."},{"rthcId":"RTHC-08125","title":"Associations Between Youth Marijuana and Alcohol Use, Neurocognitive Performance, and Triple-Network Resting-State Connectivity.","authors":"Blyth, Sophia H; Hill, Lauren D; Huang, Anna; Woodward, Neil D; Rogers, Baxter P; Vandekar, Simon; Ward, Heather Burrell","year":2026,"journal":"Biological psychiatry. Cognitive neuroscience and neuroimaging","doi":"10.1016/j.bpsc.2025.12.014","pmid":"41539355","tags":["adolescents","brain-connectivity","neuroimaging","cognition","alcohol","marijuana"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Marijuana use was associated with higher DMN-ECN connectivity (p=0.0066) but no neurocognitive performance changes; alcohol use showed no connectivity changes but was associated with better working memory, flexibility, attention, and executive function — likely confounded by socioeconomic factors.","whyItMatters":"The dissociation between brain changes and cognitive performance for marijuana is intriguing — altered connectivity without cognitive deficits could represent either compensation or a preclinical change preceding later problems.","specificNumbers":"520 for connectivity analysis; 4,197 for cognitive analysis; marijuana: DMN-ECN connectivity F(2,507)=5.08, p=0.0066, q=0.039; alcohol: better working memory (p=0.020), mental flexibility (p<.0001), attention (p=0.019).","methodology":"Cross-sectional analysis of the Philadelphia Neurodevelopmental Cohort, using regression models to examine substance use associations with triple-network resting-state connectivity (n=520) and neurocognitive performance (n=4,197).","limitations":"Cross-sectional design; self-reported substance use; cannot determine causation; alcohol's cognitive associations may reflect socioeconomic confounding; no longitudinal follow-up."},{"rthcId":"RTHC-08126","title":"Differences in substance use initiation patterns among biracial and monoracial adolescents: an integrative data analysis of two nationally representative samples.","authors":"Bo, Ai; Martinez, Alejandro; Bauer, Daniel J; Goings, Trenette Clark","year":2026,"journal":"Addictive behaviors, 172, 108503","doi":"10.1016/j.addbeh.2025.108503","pmid":"40997551","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08127","title":"Violence Exposure, Affect and ART Use Among Young Black and Latinx Men Who have Sex with Men: An Ecological Momentary Assessment Analysis.","authors":"Bogard, Madison Xiaoyao; Tieu, Hong-Van; Rendina, Jonathon; Nandi, Vijay; Walcott, Melonie; Bianco, Michael; Soler, Jorge; Frye, Victoria","year":2026,"journal":"AIDS and behavior","doi":"10.1007/s10461-026-05030-8","pmid":"41586972","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08128","title":"Effects of cannabidiol in alcohol use disorder patients with and without co-occurring post-traumatic stress disorder: Tolerability but no evidence for efficacy in two randomized proof-of-concept trials.","authors":"Bogenschutz, Michael P; Blessing, Esther; Dgheim, Danielle; Cho, Dayeon; Zhang, Jun; Laska, Eugene M; Marmar, Charles R","year":2026,"journal":"Alcohol, clinical & experimental research, 50(1), e70212","doi":"10.1111/acer.70212","pmid":"41312717","tags":["cbd","alcohol-use-disorder","ptsd","clinical-trial","pharmacokinetics","negative-result"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Neither trial demonstrated CBD superiority over placebo for drinking outcomes (both groups improved dramatically, Cohen's d>0.9), craving, mood, anxiety, or PTSD symptoms, despite achieving measurable blood levels and acceptable tolerability.","whyItMatters":"CBD is widely promoted for anxiety, PTSD, and addiction despite limited clinical evidence — these null results from well-designed trials temper expectations and suggest higher doses or different formulations may be needed.","specificNumbers":"Study 1: n=27, CBD 600→1200mg/day; Study 2: n=30, CBD 600mg/day; mean trough CBD: 31.15 ng/mL; 22.6% had dose-limiting side effects; both groups improved (Cohen's d>0.9) but CBD≠placebo.","methodology":"Two simultaneous proof-of-concept RCTs: Study 1 (n=27, AUD only, CBD 600-1200mg/day for 8 weeks) and Study 2 (n=30, AUD+PTSD, CBD 600mg/day for 6 weeks), with pharmacokinetic, safety, and efficacy assessments.","limitations":"Small sample sizes (27 and 30); proof-of-concept design not powered for definitive efficacy; achieved CBD blood levels may be insufficient; oral CBD has poor bioavailability."},{"rthcId":"RTHC-08129","title":"Association of Multimodal Cannabis Use with Adverse Events among Adolescents and Young Adults.","authors":"Bommersbach, Tanner J; Olfson, Mark; Rhee, Taeho Greg","year":2026,"journal":"American journal of preventive medicine, 108313","doi":"10.1016/j.amepre.2026.108313","pmid":"41698445","tags":["multimodal-use","adolescents","young-adults","cannabis-use-disorder","impaired-driving","risk"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Using 3+ cannabis modes vs. one was associated with 5x higher CUD risk (aOR=5.00), 4.4x higher other SUD risk, 2x higher severe mental illness, 1.8x higher suicidal thoughts, and 4.9x higher impaired driving — even after adjusting for frequency.","whyItMatters":"Cannabis product diversification means young people can now use in many ways — this study shows the number of modes is an independent risk marker, not just a proxy for more frequent use.","specificNumbers":"13,284 cannabis users; 37.5% used 3+ modes; smoking 83.9%, vaping 53.3%, edibles 47.6%, dabbing 27.3%; 3+ modes: CUD aOR=5.00, other SUD aOR=4.43, severe mental illness aOR=2.18, impaired driving aOR=4.92.","methodology":"Analysis of 2022-2023 NSDUH data on 13,284 past-year cannabis users aged 12-25, examining associations between number of cannabis modes and adverse outcomes with multivariable adjustment including use frequency.","limitations":"Cross-sectional NSDUH data cannot establish causation; multimodal use may reflect higher engagement/severity not captured by frequency alone; self-reported adverse events."},{"rthcId":"RTHC-08130","title":"Driving after cannabis consumption among US adults ages 50 years and older: A short communication.","authors":"Bonar, Erin E; Lei, Lianlian; Kirch, Matthias; Hassett, Kristen P; Solway, Erica; Singer, Dianne C; Strunk, Sydney N; Roberts, J Scott; Malani, Preeti N; Kullgren, Jeffrey T","year":2026,"journal":"Drug and alcohol dependence, 278, 112985","doi":"10.1016/j.drugalcdep.2025.112985","pmid":"41330071","tags":["older-adults","driving","impairment","prevalence","mental-health","public-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"20.2% of past-year cannabis users aged 50+ reported driving within 2 hours of consumption; daily use (OR=3.31), male sex (OR=1.72), and mental health motives (OR=1.93) were independent predictors of cannabis-impaired driving.","whyItMatters":"Cannabis use among older adults is surging, and this population faces unique driving risks from age-related cognitive changes compounded by cannabis impairment — yet they're rarely the focus of prevention efforts.","specificNumbers":"3,379 total; 729 (21.4%) past-year cannabis users; 20.2% reported driving after use; 64.8% aged 50-64; 35.2% 65+; daily use OR=3.31; mental health motives OR=1.93; male OR=1.72.","methodology":"Cross-sectional analysis of a nationally representative survey of adults 50+ (N=3,379, with 729 past-year cannabis users), examining correlates of self-reported driving within 2 hours of cannabis consumption.","limitations":"Self-reported driving behavior likely underestimates true prevalence; cross-sectional design; 2-hour window is arbitrary; doesn't assess actual impairment or crash risk."},{"rthcId":"RTHC-08131","title":"Cannabis hyperemesis syndrome: the rare case of a valid diagnosis plus hypersensitization hypothesis for development and chronification of this severe somatic cannabis use disorder.","authors":"Bonnet, Udo","year":2026,"journal":"Fortschritte der Neurologie-Psychiatrie","doi":"10.1055/a-2731-3369","pmid":"41605419","tags":["cannabis-hyperemesis-syndrome","chs","diagnosis","sensitization","pathophysiology","case-report"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"Diagnostically verified CHS case (confirmed by 12+ months abstinence) showed each vomiting episode was more severe than the previous, even during cannabis relapse after prolonged abstinence, suggesting ongoing sensitization of the emetic pathway.","whyItMatters":"Most CHS cases in literature lack proper verification — this diagnostically sound case reveals that CHS may involve permanent sensitization, not just temporary irritation, changing how we understand the condition.","specificNumbers":"Elevated blood THC and THC-COOH levels 3 weeks after abstinence; each CHS episode stronger than the previous; 12-month abstinence period diagnostically reliable for confirming CHS vs. CVS.","methodology":"Case report of an adult cannabis user with verified CHS (prolonged abstinence confirmation), with blood cannabinoid levels showing persistent elevation 3 weeks after cessation, and a novel hypersensitization hypothesis proposed.","limitations":"Single case report; hypersensitization hypothesis is speculative and requires experimental validation; persistent blood cannabinoid levels may confound abstinence-based diagnosis."},{"rthcId":"RTHC-08132","title":"Metabolic alteration in oxylipins and endocannabinoids point to an important role for soluble epoxide hydrolase and inflammation in Alzheimer's disease-finding from Alzheimer's Disease Neuroimaging Initiative.","authors":"Borkowski, Kamil; Yin, Chunyuan; Kindt, Alida; Liang, Nuanyi; de Lange, Elizabeth; Blach, Colette; Newman, John W; Kaddurah-Daouk, Rima; Hankemeier, Thomas","year":2026,"journal":"Alzheimer's research & therapy, 18(1), 21","doi":"10.1186/s13195-025-01939-9","pmid":"41495790","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08133","title":"Personality, not cognition, distinguishes chronic ayahuasca and cannabis users from non-users.","authors":"Bouso, José Carlos; Andión, Oscar; Estévez, Sabela Fondevila; González, Débora; Alcázar-Córcoles, Miguel Ángel; Kohek, Maja; Santos, Rafael Guimaraes Dos; Hallak, Jaime; Riba, Jordi","year":2026,"journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 106, 112782","doi":"10.1016/j.euroneuro.2026.112782","pmid":"41687467","tags":["cognition","personality","cannabis","ayahuasca","neuropsychology","long-term-effects"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"No significant group differences in neuropsychological performance between chronic cannabis users (n=56), ayahuasca users (n=69), and non-users (n=94) matched for age, education, and IQ; personality traits (novelty seeking, impulsive nonconformity) best distinguished cannabis users.","whyItMatters":"This challenges the persistent narrative that cannabis causes lasting brain damage — when users are matched for intelligence and education and given time to clear acute effects, cognitive deficits disappear.","specificNumbers":"56 cannabis users, 69 ayahuasca users, 94 non-users; matched by age, education, IQ; 10-30 days abstinence required; cannabis users: higher novelty seeking and impulsive nonconformity, lower introvertive anhedonia.","methodology":"Cross-sectional study comparing matched groups of regular cannabis users, ayahuasca users, and non-users on neuropsychological battery and personality questionnaires after 10-30 days of abstinence.","limitations":"Cross-sectional design cannot determine if personality traits preceded or followed cannabis use; self-selected non-treatment-seeking sample; 10-30 day abstinence may not capture very long-term residual effects."},{"rthcId":"RTHC-08134","title":"Federal and State Gaps in Regulation of Hemp-Derived Delta-9-Tetrahydrocannabinol Beverages.","authors":"Bowdring, Molly A; Mian, Maha N; Young-Wolff, Kelly C; Prochaska, Judith J","year":2026,"journal":"American journal of preventive medicine, 70(2), 108181","doi":"10.1016/j.amepre.2025.108181","pmid":"41197976","tags":["hemp-thc-beverages","regulation","farm-bill","youth-access","public-health","policy"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Hemp-derived THC beverages exploit the <0.3% THC dry-weight threshold to sell intoxicating products in states where marijuana is illegal; regulatory approaches vary wildly, with some states having no age restrictions, no standard serving sizes, and no retail oversight.","whyItMatters":"Intoxicating THC beverages are now legally sold in states that specifically chose to ban marijuana — exploiting a federal loophole that lawmakers didn't anticipate when legalizing agricultural hemp.","specificNumbers":"2018 Farm Bill legalized hemp with <0.3% THC; some states lack age restrictions for hemp THC beverages; no federal standard for serving sizes or dosing; co-use with alcohol raises intoxication risks.","methodology":"Policy commentary reviewing federal and state regulatory frameworks for hemp-derived THC beverages, describing examples of states with divergent marijuana and hemp product legality approaches.","limitations":"Commentary rather than empirical research; regulatory landscape is rapidly evolving; does not quantify actual consumption or harm from these products."},{"rthcId":"RTHC-08135","title":"Portable voltammetric method for the simultaneous determination of Δ9-Tetrahydrocannabinol and cannabidiol in alkaline medium using unmodified screen-printed carbon electrodes.","authors":"Brandão, Mariane O; Arantes, Luciano C; Lima, Camila D; Lucca, Bruno G; Moraes, Natália C; Pedão, Evandro R; Guerbas, Fernanda M R; Gebara, Sâmya S; Dos Santos, Wallans T P","year":2026,"journal":"Talanta, 304, 129562","doi":"10.1016/j.talanta.2026.129562","pmid":"41724108","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08136","title":"Polysubstance use in early adulthood and associated factors in the Republic of Ireland: An analysis of a nationally representative cohort.","authors":"Brennan, Margaret M; Mongan, Deirdre; Doyle, Anne; Millar, Seán R; Cavallaro, Massimo; Zgaga, Lina; Smyth, Bobby P; Nixon, Elizabeth; Ivers, Jo-Hanna; Galvin, Brian; Walsh, Cathal; McCrory, Cathal; McCarthy, Noel D","year":2026,"journal":"Addiction (Abingdon, England), 121(1), 150-162","doi":"10.1111/add.70182","pmid":"40898757","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08137","title":"The genetics of cannabis lifetime use.","authors":"Bright, Uri; Beck, Sarah; Galimberti, Marco; Gupta, Priya; Chen, Yu; Dao, Cecilia; Nunez, Yaira Z; Kranzler, Henry R; Zhou, Yu; Zhang, Yingzhe; Choi, Karmel W; Levey, Daniel F; Gelernter, Joel","year":2026,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 51(3), 554-564","doi":"10.1038/s41386-025-02255-4","pmid":"41044382","tags":["genetics","gwas","cadm2","risk-taking","cannabis-use-disorder","mendelian-randomization"],"studyType":"genomic-analysis","evidenceStrength":"strong","keyFinding":"11 independent genome-wide significant variants for cannabis lifetime use, most prominently CADM2*rs7609594 (p=7.4×10⁻²⁰); genetic correlations with risk-taking, openness, and substance use; bidirectional causal relationships via Mendelian randomization; distinct from CUD genetic architecture.","whyItMatters":"The genetic distinction between trying cannabis and developing addiction is crucial — it means different people need different prevention approaches, and trying cannabis alone isn't a genetic pathway to addiction.","specificNumbers":"258,823 effective sample; 11 significant variants; CADM2*rs7609594 p=7.4×10⁻²⁰; bidirectional MR causality with risk-taking and sexual behaviors; 6 traits locally correlated with CanLU at CADM2.","methodology":"Multi-ancestral GWAS using All of Us data meta-analyzed with prior studies (effective N=258,823), followed by genetic correlation (LDSC), local genetic correlation (LAVA), Mendelian randomization, and phenome-wide association analysis.","limitations":"Lifetime use is a binary measure missing frequency and quantity; multi-ancestral meta-analysis still dominated by European ancestry; GWAS associations are not actionable individual predictions; MR assumptions may be violated."},{"rthcId":"RTHC-08138","title":"Evaluating Cross-Sectional Associations Between Cannabis Use and Prospective Memory in People with HIV.","authors":"Britton, Mark K; Haddad, Elie; Li, Yancheng; Porges, Eric C; Chichetto, Natalie E; Somboonwit, Charurut; Ibañez, Gladys E; Cohen, Ronald A; Cook, Robert L","year":2026,"journal":"AIDS and behavior, 30(1), 107-117","doi":"10.1007/s10461-025-04851-3","pmid":"40938490","tags":["hiv","cognition","prospective-memory","cannabis","negative-result"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use (including regular use) was not significantly associated with prospective memory (MIST) scores in 307 people with HIV after adjusting for confounders; combined recreational-therapeutic motivation showed a nonsignificant trend toward better performance (β=0.28, p=0.067).","whyItMatters":"People with HIV already face memory challenges, and many use cannabis — this reassuring finding suggests cannabis doesn't compound HIV-related cognitive problems, at least for prospective memory.","specificNumbers":"307 PWH; 79% regular cannabis users; no significant association β=-0.04 (95% CI: -0.29 to 0.21, p=0.74); combined motivation trend β=0.28 (95% CI: -0.02 to 0.57, p=0.067).","methodology":"Cross-sectional study of 307 people with HIV (79% regular cannabis users) completing the Memory for Intentions Test, with analysis of use status, THC dose, frequency, duration, age of first use, and motivation.","limitations":"Cross-sectional design; predominantly regular users (79%) limits comparator group; MIST captures prospective memory only; unmeasured confounders possible; self-reported THC dose is imprecise."},{"rthcId":"RTHC-08139","title":"Cannabidiol reduces oxycodone self-administration while preserving its analgesic efficacy in a rat model of neuropathic pain.","authors":"Bruijnzeel, Adriaan W; Behnood-Rod, Azin; Chellian, Ranjithkumar; Malphurs, Wendi; Caudle, Robert M; Febo, Marcelo; Setlow, Barry; Murphy, Niall P; Neubert, John K","year":2026,"journal":"Scientific reports, 16(1), 2080","doi":"10.1038/s41598-025-31828-y","pmid":"41521216","tags":["cbd","pain","addiction","harm-reduction","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study addresses one of the most pressing questions in pain medicine: can we reduce opioid misuse without taking away pain relief?\n\nRats were trained to self-administer oxycodone (pressing a lever to receive intravenous doses), then given chronic neuropathic pain via sciatic nerve injury. CBD was administered at various doses (1, 3, and 10 mg/kg) before self-administration sessions, with pain testing afterward.\n\nThe key finding: CBD reduced oxycodone self-administration without reducing oxycodone's analgesic effects. The rats pressed the lever less for opioids but still got the same pain relief from what they did take. This is the best of both worlds—less drug-seeking behavior with preserved pain management.\n\nInteresting nuance: the neuropathic pain injury alone didn't increase oxycodone self-administration, suggesting that pain itself doesn't automatically drive opioid-seeking behavior in this model—the self-administration reflects the reinforcing (rewarding) properties of the drug rather than pain-driven use.\n\nCBD has no known abuse liability and is non-intoxicating, making it an attractive candidate adjunct for patients on chronic opioid therapy. If this finding translates to humans, CBD could be added to opioid regimens to reduce the reinforcing properties that drive misuse while maintaining pain control.","whyItMatters":"The opioid crisis has made clinicians wary of prescribing opioids for chronic pain, sometimes undertreating pain in the process. If CBD can reduce the rewarding/addictive properties of opioids without diminishing analgesia, it could allow safer opioid prescribing for the patients who genuinely need them. This is a harm reduction approach at the pharmacological level.","specificNumbers":"Oxycodone: 0.06 mg/kg/infusion IV. CBD doses: 1, 3, 10 mg/kg IP. CBD reduced active lever pressing (opioid-seeking). CCI confirmed by reduced paw withdrawal latency. Oxycodone analgesia preserved despite reduced self-administration.","methodology":"Animal study. Adult male rats trained to self-administer IV oxycodone (0.06 mg/kg/infusion). Chronic constriction injury (CCI) of sciatic nerve to induce neuropathic pain. Paw withdrawal latency (Hargreaves test) for thermal pain. CBD (0, 1, 3, 10 mg/kg, IP) administered before self-administration sessions, pain testing afterward.","limitations":"Rat model—human opioid-seeking behavior involves psychological and social factors not captured in lever-pressing paradigms. Only male rats used. The CBD was administered by the researchers (not self-selected), which doesn't model how patients would actually use CBD alongside opioids. IV oxycodone self-administration is more pharmacokinetically intense than oral opioid use. Acute CBD effects may differ from chronic co-administration."},{"rthcId":"RTHC-08140","title":"Sustained Reduction of Dystonic Tremor and Pain after Cannabis Oil Administration and Physiotherapy in Thalamic Ischemia: A One-Year Case Report.","authors":"Buccheri, Enrico; Caramma, Salvatore; Chiaramonte, Rita; Vecchio, Michele","year":2026,"journal":"Current neuropharmacology","doi":"10.2174/011570159X414414251122103253","pmid":"41603171","tags":["cannabis-oil","dystonic-tremor","thalamic-pain","stroke","physiotherapy","case-report"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"Combined cannabis oil and physiotherapy produced sustained 60% pain reduction, 56.88% tremor reduction, 27.6% mental quality-of-life improvement, and 45.46% motor quality-of-life improvement over 12 months, with no serious adverse effects.","whyItMatters":"Post-stroke tremor and thalamic pain are notoriously treatment-resistant — sustained improvement over 12 months with a combination approach represents a potentially significant therapeutic advance.","specificNumbers":"60% pain reduction; 56.88% tremor severity reduction; 27.6% mental QoL improvement; 45.46% motor QoL improvement; 12-month follow-up; no serious adverse effects.","methodology":"Single case report with 12-month follow-up of a female patient with thalamic ischemia-related dystonic tremor and pain, treated with cannabis oil combined with physiotherapy, assessed with standardized pain, tremor, and quality-of-life scales.","limitations":"Single case with no control; cannot separate cannabis oil from physiotherapy effects; no blinding; specific cannabis oil formulation and dosing not detailed in abstract."},{"rthcId":"RTHC-08141","title":"Anxiety sensitivity and cannabis-related problems among Hispanic/Latine adults: The roles of sex and cannabis use motives.","authors":"Buckner, Julia D; Vargo, Luke A; Thomas, Katharine L; Buenrostro, Christopher M; Shepherd, Justin M; Zvolensky, Michael J","year":2026,"journal":"Experimental and clinical psychopharmacology, 34(1), 100-105","doi":"10.1037/pha0000829","pmid":"41538230","tags":["anxiety-sensitivity","hispanic-latine","cannabis-problems","sex-differences","coping-motives"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 520 Hispanic/Latine cannabis users, anxiety sensitivity predicted more cannabis problems via conformity motives for both sexes, but via coping motives for men and expansion motives for women — frequency was unaffected.","whyItMatters":"Hispanic/Latine adults experience worse cannabis-related problems but are underrepresented in research — understanding the anxiety-cannabis pathway in this population enables culturally targeted interventions.","specificNumbers":"520 participants; 44.2% female; AS predicted problems but not frequency; indirect effects via conformity motives (both sexes), coping motives (men), expansion motives (women); sex didn't moderate direct AS-problems association.","methodology":"Cross-sectional study of 520 Hispanic/Latine adults (44.2% female) with past-month cannabis use, examining anxiety sensitivity associations with cannabis problems, frequency, and motives, with sex as a moderator.","limitations":"Cross-sectional design; online recruitment may not represent all Hispanic/Latine cannabis users; self-report measures; heterogeneous Hispanic/Latine category may mask subgroup differences."},{"rthcId":"RTHC-08142","title":"The Role of Self-Reported Willingness to Use Drugs in Public Health Research: Population-Level Projections of Adolescents' Decriminalised Cannabis Use and Associated Risk Profiles.","authors":"Burdzovic Andreas, Jasmina; Bretteville-Jensen, Anne Line","year":2026,"journal":"Drug and alcohol review, 45(1), e70061","doi":"10.1111/dar.70061","pmid":"41139609","tags":["decriminalization","norway","adolescents","willingness","policy","prevalence"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 3,490 Norwegian students, 8% of never-users reported willingness to initiate cannabis if decriminalized and 22.3% were unsure; 40.3% of users would increase use; projections suggest 12,000 new users and 15,400 more frequent users nationally.","whyItMatters":"This provides policymakers with concrete numbers for planning — instead of debating whether decriminalization increases use, countries can estimate how many new and escalating users to expect.","specificNumbers":"3,490 students; 20.3% lifetime use (38,200 nationally); 8% of non-users willing to initiate; 40.3% of users willing to increase; projections: up to 12,000 new users, 15,400 more frequent users.","methodology":"Nationally representative survey of 3,490 Norwegian high school students asking about cannabis use and willingness to use under hypothetical decriminalization, scaled to census data with multiple projection scenarios and multinomial regression.","limitations":"Stated willingness may not predict actual behavior; social desirability may bias responses in either direction; hypothetical scenarios don't capture real-world market dynamics or social norm shifts."},{"rthcId":"RTHC-08143","title":"Clinical pain intensity is associated with greater cannabis demand among people who regularly use cannabis.","authors":"Bush, Nicholas J; Ferguson, Erin; Funez-Ponce, Marco; Yurasek, Ali; Boissoneault, Jeff","year":2026,"journal":"Pain reports, 11(1), e1385","doi":"10.1097/PR9.0000000000001385","pmid":"41450707","tags":["pain","cannabis-demand","behavioral-economics","self-medication","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Greater pain intensity predicted higher Omax (maximum spending), Pmax (maximum price), Intensity (consumption at zero cost), Breakpoint (price that stops use), and lower Elasticity (price sensitivity) for cannabis, with sex-moderated effects for women under responsibility conditions.","whyItMatters":"This provides economic evidence that pain drives cannabis demand beyond just frequency — people in pain are more motivated, willing to spend more, and less responsive to deterrents.","specificNumbers":"172 regular users (41% women); pain intensity associated with all 5 demand indices; next-day responsibilities reduced demand but less so for women with pain; responsibility effect on elasticity moderated by sex and pain.","methodology":"Secondary analysis of 172 regular cannabis users completing counterbalanced marijuana purchase tasks (with/without next-day responsibility) alongside Brief Pain Inventory pain intensity assessment.","limitations":"Cross-sectional; crowdsourced sample; hypothetical purchase tasks; self-reported pain; cannot determine if cannabis use worsened or improved pain; no clinical pain diagnoses."},{"rthcId":"RTHC-08144","title":"Enhancing data compatibility in an evolving landscape: Medical cannabis and polysubstance use protocols in the PhenX Toolkit.","authors":"Buu, Anne; Thrul, Johannes; Bunting, Amanda; Haegerich, Tamara; Huggins, Wayne; Hopfer, Christian; Vidot, Denise; Ives, Cataia; McNeil, Ryan; Zemore, Sarah; Vilsaint, Corrie; Fallon, Elizabeth; Hill, Christine; Hamilton, Carol; Kelly, John","year":2026,"journal":"Drug and alcohol dependence, 278, 113001","doi":"10.1016/j.drugalcdep.2025.113001","pmid":"41406668","tags":["research-methods","measurement","medical-cannabis","polysubstance-use","standardization"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"15 new consensus measurement protocols were developed covering cannabis consumption levels, product types, sources, motives, expectancies, medical card status, provider-patient communication, biochemical validation, and polysubstance use patterns.","whyItMatters":"Cannabis research has been hampered by every study using different measures — standardized tools mean we can finally combine and compare results across studies to build reliable evidence.","specificNumbers":"15 new measurement protocols released in 2025; covers medical cannabis use, product types, motives, biochemical validation, and polysubstance use; freely accessible at phenxtoolkit.org.","methodology":"Expert consensus process by the PhenX Working Group in 2024, with broader scientific community review, resulting in standardized measurement protocols for the freely accessible PhenX Toolkit.","limitations":"Protocols need adoption by researchers to be useful; may not capture all aspects of rapidly evolving cannabis products and markets; US-focused development."},{"rthcId":"RTHC-08145","title":"Neural reward sensitivity and longitudinal patterns of alcohol and cannabis use in college-aged youth.","authors":"Byrd, Kathryn J; Johnston, Brooke W; Culp, Stacey; Kreutzer, Kayla A; Way, Baldwin M; Phan, K Luan; Gorka, Stephanie M","year":2026,"journal":"Drug and alcohol dependence, 281, 113079","doi":"10.1016/j.drugalcdep.2026.113079","pmid":"41713074","tags":["brain-reward","eeg","adolescents","cannabis-use-disorder","prediction","longitudinal"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Lower RewP amplitude at baseline predicted increasing cannabis use problems over 24 months (significant linear time × RewP interaction), while higher RewP showed no change in problems over time; RewP did not predict alcohol problems.","whyItMatters":"A simple EEG measure taken before problematic use begins could identify which teenagers are most vulnerable to developing cannabis problems — enabling targeted prevention.","specificNumbers":"172 youth; ages 16-19; EEG-measured RewP at baseline; 8 quarterly assessments over 24 months; significant linear time × RewP interaction for cannabis but not alcohol problems.","methodology":"Longitudinal study of 172 youth ages 16-19 with minimal prior substance use, measuring reward positivity (RewP) via EEG at baseline and cannabis/alcohol problems every 3 months for 2 years using linear mixed-effects models.","limitations":"Modest sample size; predominantly low-use baseline sample; RewP is one of many potential biomarkers; EEG-based measures require specialized equipment."},{"rthcId":"RTHC-08146","title":"Contexts of drinking and cannabis use by Whites and Hispanics in California.","authors":"Caetano, Raul; Paschall, M J; Vaeth, Patrice A C; Kaplan, Zoe","year":2026,"journal":"Journal of ethnicity in substance abuse, 1-22","doi":"10.1080/15332640.2025.2576728","pmid":"41481111","tags":["co-use","alcohol","cannabis","hispanic","context","settings"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 1,069 California adults, alcohol-cannabis co-use occurred primarily at home (alone/with family or with friends); race/ethnicity and co-use type (concurrent vs. simultaneous) did not significantly affect consumption context patterns.","whyItMatters":"Understanding where people co-use substances informs policy about public consumption, home delivery, and context-specific interventions — the finding that contexts are similar across groups simplifies targeting.","specificNumbers":"1,069 adults; ages 21-49; 40 California cities; two primary settings: home alone/with family and home with friends; no significant race/ethnicity or co-use type effects on context.","methodology":"Household survey of 1,069 adults aged 21-49 in 40 California cities, using standardized online questionnaire to assess alcohol and cannabis use contexts, with controlled analyses for demographic correlates.","limitations":"California-only; ages 21-49 exclude older adults and youth; online survey may miss certain populations; context categories may not capture all relevant settings."},{"rthcId":"RTHC-08147","title":"Modular PVDF-PEI membrane-based SERS sensor for rapid on-site detection of methamphetamine in complex matrices.","authors":"Cai, Xinxin; Chen, Yu; Xu, Luyun; Tao, Hong; Ye, Jianqing; Huang, Baoxing; Huang, Chaobin; Chen, Yuanmei; Huang, Wei; Lin, Duo; Lin, Xiaoping; Fan, Min; Feng, Shangyuan","year":2026,"journal":"Talanta, 302, 129441","doi":"10.1016/j.talanta.2026.129441","pmid":"41576579","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08148","title":"L-Malic acid from Cissus gongylodes induces cannabinoid-mediated antinociception in mice.","authors":"Calazans, Marla Oliveira; Santos Pimenta, Lúcia Pinheiro; Lima Romero, Thiago Roberto; Gama Duarte, Igor Dimitri; de Castro Perez, Andrea","year":2026,"journal":"Journal of ethnopharmacology, 363, 121306","doi":"10.1016/j.jep.2026.121306","pmid":"41713814","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08149","title":"Is cannabis legalization associated with treatment completion? A study of pregnant women admitted for cannabis use in substance use treatment facilities, 2020-2022.","authors":"Carandang, Rogie Royce; Rhee, Taeho Greg; Ha, Toan; Cunningham, Shayna D","year":2026,"journal":"Drug and alcohol dependence, 279, 113023","doi":"10.1016/j.drugalcdep.2026.113023","pmid":"41519026","tags":["pregnancy","legalization","addiction","quitting"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"This is the first large-scale study to examine whether cannabis legalization affects treatment completion among pregnant women—a uniquely vulnerable population where treatment success has direct consequences for two patients.\n\nUsing the Treatment Episode Data Set-Discharge (national treatment data from 2020–2022), the researchers analyzed 13,088 pregnant women admitted for cannabis use across states with different legal frameworks: fully legalized, medical only, or illegal.\n\nThe finding was stark: pregnant women in states with full legalization had an adjusted odds ratio of 0.33 for treatment completion compared to illegal states—meaning 67% lower odds of completing treatment. The comparison with medical-only states also showed lower completion, but the effect was strongest in full legalization states.\n\nThis doesn't necessarily mean legalization causes treatment failure. In legal states, cannabis is normalized, making motivation to quit less compelling. Referral pathways may differ—in illegal states, more women may be mandated to treatment (and mandated patients may have higher completion rates due to legal consequences). The types of treatment available and the severity of cannabis use may also differ by legal context.\n\nThe overall completion rate was only 28.3% across all states—treatment for cannabis use during pregnancy has very high dropout regardless of legal status.","whyItMatters":"Cannabis use during pregnancy is the most commonly used illicit substance in pregnancy (RTHC-00209), and the evidence for fetal harm is growing. If legalization reduces treatment completion among pregnant users, that's a public health consequence that legalization advocates and regulators need to address—perhaps through pregnancy-specific outreach, incentive programs, or alternative intervention models.","specificNumbers":"N = 13,088 pregnant women. 28.3% completed treatment overall. Full legalization: AOR 0.33 (67% lower completion odds) vs. illegal states. Treatment data from 2020–2022 across varying legal frameworks.","methodology":"Retrospective cross-sectional analysis of the Treatment Episode Data Set-Discharge (TEDS-D), 2020–2022. N = 13,088 pregnant women aged 12+ admitted for cannabis use. States categorized by legalization status (fully legal, medical only, illegal). Multivariable logistic regression for treatment completion. Subgroup analyses by treatment setting and referral source.","limitations":"TEDS-D captures treatment facility data, not all cannabis users—many pregnant users never enter treatment. The definition of 'treatment completion' varies by setting and program. Confounders at the state level (treatment availability, cultural attitudes, referral mandates) may explain the association more than legalization itself. Cross-sectional by state design can't control for all between-state differences. The 2020–2022 period overlaps with COVID, which disrupted treatment services differently by state."},{"rthcId":"RTHC-08150","title":"Perinatal exposure to delta-9-tetrahydrocannabinol (THC) alters goal-directed behavior and dopamine functioning in wistar rats.","authors":"Carbajal, Monica S; Crenshaw, Rebecca C; Williams, Victoria E; Billings, Laura G; Dixon, Chelsea M; Lester, Deranda B; Sable, Helen J K","year":2026,"journal":"Psychopharmacology","doi":"10.1007/s00213-026-07023-w","pmid":"41718742","tags":["prenatal-thc","motivation","dopamine","amotivation","offspring","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Perinatal THC exposure (5 mg/kg/day from pre-breeding to PND 14) decreased motivation on high-effort operant tasks in both sexes, with males showing fewer reinforcers earned; dopamine response to cocaine was attenuated in the nucleus accumbens without baseline DA changes.","whyItMatters":"This provides a neurobiological mechanism for the 'amotivational syndrome' reported in prenatally exposed humans — reduced dopamine reactivity in reward circuits may literally make rewards less rewarding.","specificNumbers":"THC 5 mg/kg/day oral; exposure from 14 days pre-breeding to PND 14; decreased DRL burst responses and completed trials (both sexes); fewer reinforcers in males; attenuated NAc dopamine response to cocaine.","methodology":"Perinatal THC exposure study in Wistar rats (oral 5 mg/kg/day, 14 days pre-breeding to PND 14), with adult offspring tested on DRH and DRL operant tasks and in vivo amperometry measuring dopamine in mPFC and NAc.","limitations":"Animal model; single THC dose; oral administration may not reflect human smoking; cocaine challenge is an indirect measure of DA function; cannot separate prenatal from postnatal (milk) exposure effects."},{"rthcId":"RTHC-08151","title":"People with psychotic disorders are the most vulnerable to cannabis adverse health outcomes: a study in WA State, USA.","authors":"Carlini, Beatriz H; Williams, Jason R; Garrett, Sharon B; Hammond, David","year":2026,"journal":"Community mental health journal","doi":"10.1007/s10597-025-01579-1","pmid":"41543692","tags":["psychotic-disorders","adverse-events","vulnerability","mental-health","public-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"People with psychotic disorders were more likely than those with other MH or no MH diagnoses to report adverse events from cannabis (p<.001), including nausea/vomiting, heart/blood pressure problems, fainting, acute psychosis, flashbacks, CHS, and high-risk cannabis use screening positive.","whyItMatters":"Cannabis harm isn't equally distributed — people with psychotic disorders are disproportionately vulnerable, experiencing more adverse events even beyond the expected psychiatric worsening.","specificNumbers":"4,144 Washington State cannabis consumers; ages 16-65; 2020-2023; psychotic disorder group significantly more likely to report adverse events and seek medical attention (p<.001) across multiple outcome categories.","methodology":"Cross-sectional analysis of 4,144 past-year cannabis consumers in Washington State from the International Cannabis Policy Study (2020-2023), comparing adverse events across psychotic disorder, other MH, and no MH diagnosis groups.","limitations":"Self-reported diagnoses and adverse events; cross-sectional design; Washington State only; cannot determine if adverse events are caused by cannabis or reflect underlying disorder severity."},{"rthcId":"RTHC-08152","title":"Cannabis and urban livelihoods: Illicit opportunities in Kenya's towns and cities.","authors":"Carrier, Neil; Omenya, Gordon","year":2026,"journal":"The International journal on drug policy, 150, 105194","doi":"10.1016/j.drugpo.2026.105194","pmid":"41719923","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08153","title":"Involvement of Keap1/Nrf2 and the antioxidant defence in cytoprotective effects induced by cannabis polyphenols in SH-SY5Y neuronal cells.","authors":"Cásedas, Guillermo; Rojas-Márquez, Henar; Ventura, Lucía; Moliner, Cristina; Maggi, Filippo; Rubio-Castellanos, Ainara; López, Víctor","year":2026,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 196, 119048","doi":"10.1016/j.biopha.2026.119048","pmid":"41643607","tags":["polyphenols","neuroprotection","nrf2","antioxidant","alzheimers","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Cannabis polyphenolic extract activated Keap1/Nrf2 pathway, increased peroxiredoxin expression (PRDX1, PRDX3), enhanced antioxidant defenses, reduced ER stress-induced apoptosis (Bax/Bcl-2), and attenuated inflammatory markers (NO, NF-κB2, IL-6, IL-8) in H₂O₂-stressed neuroblastoma cells.","whyItMatters":"Cannabis contains much more than THC and CBD — the polyphenolic fraction (flavonoids, stilbenoids, lignans) may offer neuroprotection relevant to Alzheimer's, Parkinson's, and other oxidative stress diseases.","specificNumbers":"Cannabis polyphenols activated Nrf2; increased PRDX1/PRDX3; reduced NO, NF-κB2, IL-6, IL-8; modulated Bax/Bcl-2; Leu583 identified as key Nrf2-ligand interaction residue.","methodology":"In vitro study treating SH-SY5Y neuroblastoma cells with aqueous cannabis polyphenolic extract under H₂O₂ oxidative stress, analyzing protein/gene expression via Western blot and qPCR, with in silico molecular docking.","limitations":"Single neuroblastoma cell line; aqueous extract composition may vary; H₂O₂ stress model is simplified; no in vivo validation; bioavailability of polyphenols not addressed."},{"rthcId":"RTHC-08154","title":"Effectiveness of a School-Based Drug Prevention Program: Tú Decides 2.0.","authors":"Castaño, Yasmina; Gervilla, Elena; Martínez-Vispo, Carmela; Juan, Montse; García-Pazo, Patricia; Al-Halabí, Susana; Becoña, Elisardo; Calafat, Amador","year":2026,"journal":"Journal of prevention (2022), 47(1), 191-207","doi":"10.1007/s10935-025-00883-6","pmid":"41247593","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08155","title":"Cannabidiol blood metabolite levels after cannabidiol treatment are associated with broadband EEG changes and improvements in visuomotor and non-verbal cognitive abilities in boys with autism requiring higher levels of support.","authors":"Cazares, Christian; Hutton, Austin; Paez, Gisselle; Trauner, Doris; Voytek, Bradley","year":2026,"journal":"Translational psychiatry, 16(1)","doi":"10.1038/s41398-026-03815-y","pmid":"41611664","tags":["cbd","cognition","youth","medical-cannabis","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"This study analyzed EEG data from 24 boys with autism spectrum disorder (ASD) and higher support needs, drawn from a Phase II clinical trial of pharmaceutical-grade CBD (Epidiolex, up to 20 mg/kg/day).\n\nThe EEG analysis went beyond traditional approaches, examining both periodic (oscillatory) and aperiodic components of brain activity. After 8 weeks of CBD treatment, specific aperiodic EEG measures changed in ways that correlated with CBD metabolite levels in blood—providing a direct biological link between drug exposure and brain function.\n\nThe most striking finding: CBD metabolite levels were associated with improvements in visuomotor abilities and non-verbal cognitive skills. These are core deficit areas for children with ASD requiring higher levels of support, and there are few effective treatments for them.\n\nThe brain wave changes included a larger aperiodic offset across the scalp and a decreased aperiodic exponent—technical measures that reflect the overall excitation-inhibition balance of the brain. Given RTHC-00217's finding that cannabinoids affect the GABA excitation-inhibition balance, this EEG finding may reflect CBD modulating the same fundamental neural property in a therapeutic direction for ASD.\n\nThis is the first study to use FDA-approved purified CBD in children with ASD and higher support needs, and the first to link CBD blood levels directly to EEG biomarkers and cognitive outcomes in this population.","whyItMatters":"Children with ASD requiring higher levels of support have very few treatment options for core cognitive deficits. Current medications primarily address behavioral symptoms (irritability, aggression) rather than cognitive abilities. If CBD can improve visuomotor and non-verbal cognition—and this improvement is measurable via EEG biomarkers—it could represent a genuinely new therapeutic approach for the most affected children.","specificNumbers":"N = 24 boys, ages 7–14. Higher support needs ASD. 8 weeks CBD (Epidiolex, up to 20 mg/kg/day). Double-blind crossover. Aperiodic EEG changes correlated with CBD metabolite levels. Improvements in visuomotor and non-verbal cognitive abilities.","methodology":"Analysis of EEG data from 24 boys with ASD and higher support needs (ages 7–14) from a double-blind, placebo-controlled, crossover Phase II trial (NCT04517799). 8 weeks of daily CBD (up to 20 mg/kg/day Epidiolex). EEG at baseline, post-CBD, post-placebo, and post-washout. Linear mixed-effects models linking aperiodic EEG measures with CBD metabolite blood levels and cognitive outcomes.","limitations":"Small sample (24 boys). Only boys—ASD presents differently in girls and CBD effects may differ. The cognitive improvements were associated with CBD metabolite levels, not with treatment condition per se, suggesting individual pharmacokinetic variability matters. Crossover design means each child received both CBD and placebo, but period effects are possible. 8 weeks may not be long enough to assess sustained cognitive changes. Higher-support-needs ASD is heterogeneous."},{"rthcId":"RTHC-08156","title":"Modeling Oxidative Stress-Linked Telogen Effluvium Using Monte Carlo Simulation of Published Trichoscopy Norms and Cannabis Exposure Distributions.","authors":"Chadha, Aryan; Burmeister, Margit; Poelker-Wells, Samuel","year":2026,"journal":"Cureus, 18(1), e101446","doi":"10.7759/cureus.101446","pmid":"41552740","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08157","title":"Health impacts of cannabis: focus on smoking vs. vaping effects on the respiratory and cardiovascular systems.","authors":"Chaiton, Michael; Kundu, Anasua; Nathwani, Apsara Ali","year":2026,"journal":"Current opinion in pulmonary medicine, 32(2), 93-97","doi":"10.1097/MCP.0000000000001239","pmid":"41355516","tags":["respiratory","cardiovascular","harm-reduction","legalization"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"As cannabis legalization shifts consumption patterns toward vaping, this review compares what we know about the health effects of the two main inhalation methods.\n\nThe good news for vaping: it reduces exposure to the combustion byproducts (tar, carbon monoxide, polyaromatic hydrocarbons) that make smoking harmful. It also allows better modulation of THC bioavailability—users can more precisely control their intake.\n\nThe concerning news: both smoking and vaping produce comparable cardiovascular effects, including acute increases in heart rate and blood pressure, and altered immune responses in the lungs. The heart doesn't care whether THC arrived via smoke or vapor—the cardiovascular pharmacology is the same.\n\nVaping also introduces its own distinct risks. E-cigarette or vaping-associated lung injury (EVALI) has been clearly associated with THC vaping. Vaping is linked to increased respiratory symptoms even in the absence of EVALI. And the long-term consequences—chronic obstructive pulmonary disease, lung cancer, cardiovascular events—remain unknown because vaping is too recent for longitudinal data.\n\nThe review's conclusion is measured: vaping may mitigate some combustion-related harms compared to smoking, but it introduces distinct respiratory and cardiovascular concerns. The evidence does not support treating vaping as \"safe\"—only as potentially \"less harmful in some specific ways.\"","whyItMatters":"The public perception that vaping is safe drives consumer behavior. RTHC-00218 showed that cannabis vapor activated cancer, inflammation, and oxidative stress genes in lung cells. This review puts that finding in clinical context: the gene expression changes aren't just laboratory curiosities—they align with emerging clinical evidence of vaping-related respiratory harm. For the millions switching from smoking to vaping, \"less harmful\" is not \"harmless.\"","specificNumbers":"Both methods: comparable acute increases in heart rate and blood pressure, altered lung immune responses. Vaping: reduced combustion toxicant exposure, clear EVALI association, increased respiratory symptoms. Long-term data: limited and inconclusive for vaping.","methodology":"Narrative review of recent evidence comparing respiratory and cardiovascular effects of smoking vs. vaping cannabis. Published in Current Opinion in Pulmonary Medicine.","limitations":"Narrative review format limits comprehensiveness. Long-term vaping data simply doesn't exist yet. Cannabis vaping products vary enormously (flower vaporizers vs. oil cartridges vs. concentrates), and risk profiles may differ. EVALI was primarily linked to vitamin E acetate in illicit THC cartridges, which may not represent regulated products. Most studies don't distinguish between cannabis and nicotine vaping effects."},{"rthcId":"RTHC-08158","title":"State Initiatives to Promote Cannabis Industry Entrepreneurship Among Disproportionately Impacted Communities: A Multi-State Analysis.","authors":"Chakraborty, Rishika; Speer, Morgan; LoParco, Cassidy R; Yang, Y Tony; Berg, Carla J","year":2026,"journal":"Journal of public health management and practice : JPHMP","doi":"10.1097/PHH.0000000000002317","pmid":"41511160","tags":["legalization","harm-reduction","workplace","seniors"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This multi-state analysis examined social equity entrepreneurship initiatives across all 17 states with legal non-medical cannabis retail as of May 2025. Eleven states reserved a set number or percentage of licenses for social equity applicants, while others specified particular license types or made certain categories available.\n\nThe study found significant variation in how states define eligibility, structure their application processes, and provide financial or technical support. Some states offered training programs, fee waivers, or access to capital, while others had minimal infrastructure beyond the license reservation itself.\n\nOutcome data — where available — showed that the share of total licenses actually held by social equity entrepreneurs varied widely. Several states had issued far fewer social equity licenses than their programs envisioned, and demographic breakdowns of license holders by sex, race, and ethnicity revealed persistent gaps in representation despite the stated goals of these initiatives.","whyItMatters":"Cannabis prohibition disproportionately impacted communities of color through arrest and incarceration rates. As legalization creates a multibillion-dollar industry, social equity programs aim to ensure those communities can participate in the economic benefits. This study provides the first systematic comparison of how those programs are actually structured and performing across states.","specificNumbers":"17 states analyzed. 11 states reserved a number or percentage of licenses for social equity entrepreneurs. Data on demographic breakdowns of license holders (by sex, race, and ethnicity) were collected where states made them available.","methodology":"Mixed-methods study using publicly available data from all 17 states with legal non-medical cannabis retail. Researchers collected information on program design features (license types, selection processes, eligibility criteria, training and financial support) and outcomes (applications submitted, licenses issued, demographic breakdowns of license holders).","limitations":"Relied on publicly available data, which varied in completeness across states. Some states did not report demographic breakdowns of license holders. The study could not assess program effectiveness in terms of business viability or long-term success of social equity licensees. Rapidly evolving regulations mean findings represent a snapshot."},{"rthcId":"RTHC-08159","title":"Cannabis Use and Food Insecurity Risk Among U.S. Adults With And Without Children.","authors":"Chakraborty, Rishika; Headrick, Gabby; Romm, Katelyn F; Wang, Yan; McCready, Darcey M; Cavazos-Rehg, Patricia A; Schubel, Laura C; Speer, Morgan; Yang, Y Tony; Berg, Carla J","year":2026,"journal":"American journal of preventive medicine, 70(2), 107740","doi":"10.1016/j.amepre.2025.107740","pmid":"40473080","tags":["food-insecurity","young-adults","parents","socioeconomic","public-health"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"W1 cannabis use predicted W2 food insecurity (AOR=1.62); W2 food insecurity predicted W2 cannabis use (AOR=1.44), greater cannabis expenditures (AOR=1.44), and greater impact of cost on use (AOR=1.92); associations were stronger among parents.","whyItMatters":"The bidirectional relationship means cannabis use can contribute to food insecurity AND food insecurity can drive cannabis use — creating a cycle that particularly threatens families with children.","specificNumbers":"3,437 young adults; 46.6% used cannabis (W1); 48.2% food insecure (W2); 22.9% both; cannabis→food insecurity AOR=1.62; food insecurity→cannabis use AOR=1.44; food insecurity→cost impact AOR=1.92.","methodology":"Two-wave longitudinal survey of 3,437 US young adults (ages 18-34) from 2023-2024, examining bidirectional associations between cannabis use and food insecurity with logistic regression adjusted for sociodemographics.","limitations":"Self-reported data; two waves may not capture full temporal dynamics; food insecurity has many causes beyond cannabis spending; legal status varies by state."},{"rthcId":"RTHC-08160","title":"Long-term cannabidiol treatment did not restore bone microstructural defects in skeletally mature ovariectomized Sprague-Dawley rats.","authors":"Chanpaisaeng, Krittikan; Fleet, James C; Rawiwet, Visut; Phonsatta, Natthaporn; Panya, Atikorn; Panupinthu, Nattapon; Charoenphandhu, Narattaphol","year":2026,"journal":"JBMR plus, 10(2), ziaf197","doi":"10.1093/jbmrpl/ziaf197","pmid":"41589111","tags":["cbd","osteoporosis","bone","menopause","negative-result","preclinical"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"CBD (5 mg/kg/day for 12 weeks) did not prevent OVX-induced trabecular bone loss, increased bone resorption markers versus OVX controls, and showed no significant effect on cannabinoid receptor expression or bone metabolism genes in sham-operated rats.","whyItMatters":"CBD is promoted for many conditions including bone health — this well-designed negative result protects consumers from ineffective treatment and redirects research toward more promising approaches.","specificNumbers":"CBD 5 mg/kg/day via osmotic pumps for 12 weeks; OVX/CBD trabecular bone decreased similarly to OVX/vehicle; increased bone resorption markers in OVX/CBD vs OVX/vehicle; no Ctsk gene reduction (unlike estradiol).","methodology":"12-week controlled study with 5 groups of rats (sham/vehicle, sham/CBD, OVX/vehicle, OVX/estradiol, OVX/CBD), using micro-CT, serum bone markers, and gene expression analysis.","limitations":"Single dose tested (5 mg/kg/day); osmotic pump delivery may not reflect oral bioavailability; rat OVX model may not fully represent human postmenopausal bone loss; 12-week study may miss very long-term effects."},{"rthcId":"RTHC-08161","title":"Exploring the neuroprotective effects of phytocannabinoids on oxygen-glucose deprived neurons in an in vitro model of stroke.","authors":"Chatragadda, Bhavya; Potts, Emily M; Collins, Alicia; Ma, Hang; Fallini, Claudia","year":2026,"journal":"Journal of cannabis research, 8(1), 29","doi":"10.1186/s42238-026-00393-0","pmid":"41578349","tags":["stroke","neuroprotection","phytocannabinoids","cbgoa","ischemia","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Among 28 phytocannabinoids screened in human iPSC-derived cortical neurons after oxygen-glucose deprivation, seven showed modest effects and CBGOA significantly improved post-ischemia neuronal survival through a mechanism independent of caspase-3 activation.","whyItMatters":"Stroke has almost no neuroprotective treatments — finding that a rare cannabis compound protects human-derived neurons after simulated stroke opens a new therapeutic avenue.","specificNumbers":"28 phytocannabinoids screened; 7 showed modest effects; CBGOA significantly improved survival; 60-minute OGD model; 7-day longitudinal imaging; caspase-3 independent mechanism.","methodology":"In vitro stroke model using human iPSC-derived cortical neurons subjected to 60 minutes of oxygen-glucose deprivation, followed by screening of 28 phytocannabinoids with longitudinal live-cell survival imaging over 7 days.","limitations":"In vitro model cannot replicate stroke complexity (inflammation, blood-brain barrier, reperfusion); CBGOA effects were modest; single OGD duration tested; mechanism not fully characterized."},{"rthcId":"RTHC-08162","title":"Cannabidiol-Ion Channel Interactions Represent a Promising Preventive and Therapeutic Strategy in Hepatocellular Carcinoma.","authors":"Chávez-López, María de Guadalupe; Avalos-Fuentes, Arturo; Cruz-Manzo, Estrella Del C; Aguirre-Arriaga, Pedro A; Florán, Benjamín; Pérez-Carreón, Julio Isael; Bañuelos, Cecilia; Camacho, Javier","year":2026,"journal":"Pathophysiology : the official journal of the International Society for Pathophysiology, 33(1)","doi":"10.3390/pathophysiology33010008","pmid":"41562849","tags":["cbd","liver-cancer","ion-channels","hepatocellular-carcinoma","endocannabinoid-system","review"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"CBD interacts with multiple ion channels implicated in liver cancer cell proliferation, inflammation, and apoptosis, offering a cannabinoid receptor-independent mechanism for hepatocellular carcinoma prevention and therapy.","whyItMatters":"Liver cancer is often diagnosed too late for curative treatment — CBD's action on ion channels in pre-cancerous liver diseases could enable earlier intervention before cancer develops.","specificNumbers":"Review covers CBD interactions with multiple ion channel families involved in HCC progression, inflammation, and apoptosis across the spectrum from fatty liver to cirrhosis to cancer.","methodology":"Narrative review examining the endocannabinoid system and phytocannabinoids (CBD, THC) in liver diseases, with focus on CBD-targeted ion channels and their roles in HCC and precursor liver conditions.","limitations":"Mostly preclinical evidence; ion channel effects identified in various contexts may not all be relevant to liver; CBD bioavailability and liver first-pass metabolism complicate clinical translation."},{"rthcId":"RTHC-08163","title":"Content Analysis of Derived Intoxicating Cannabis Vape Product Attributes and Marketing In an Online Retail Environment.","authors":"Chen-Sankey, Julia; LoParco, Cassidy R; La Capria, Kathryn; Meng, Siyan; Mazzeo, Rosanna; Vijayakumar, Neha; Kong, Amanda Y; Tillett, Kayla K; Berg, Carla J; Rossheim, Matthew E","year":2026,"journal":"Substance use & misuse, 61(2), 307-316","doi":"10.1080/10826084.2025.2555499","pmid":"40898444","tags":["hemp-thc-vapes","marketing","youth-appeal","regulation","farm-bill","flavors"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"490 flavored DICVPs across 95 brands contained 26 unique intoxicating cannabinoids; marketing emphasized vaping satisfaction/discreetness (99%), regulation compliance (91.6%), flavor variety (79.6%), psychoactive effects (43.3%), and quality claims (38.4%).","whyItMatters":"The marketing of these products deliberately reduces risk perception through regulatory compliance messaging while simultaneously promoting psychoactive effects and appealing flavors — a combination that particularly targets young consumers.","specificNumbers":"490 products; 95 brands; 26 intoxicating cannabinoids; 99% promoted design/use features; 91.6% regulation compliance; 79.6% flavor claims; 43.3% psychoactive effect claims; 38.4% quality claims.","methodology":"Content analysis of 490 flavored derived intoxicating cannabis vape products from two online retailers, with two trained coders thematically coding product descriptions for marketing features.","limitations":"Two websites may not represent all online retailers; product descriptions analyzed, not actual marketing exposure; can't determine actual youth exposure or purchasing behavior."},{"rthcId":"RTHC-08164","title":"Cannabis and Alcohol Co-Use And HIV Biomedical Intervention Engagement Among Black Sexual/Gender Minority People: A Day-Level Analysis.","authors":"Chen, Yen-Tyng; Knox, Justin; Almirol, Ellen; Wiger, Ella Remund; Pagkas-Bather, Jade; Huh, Jimi; Chung, Tammy; English, Devin; Duncan, Dustin T; Schneider, John A","year":2026,"journal":"American journal of preventive medicine, 70(1), 108144","doi":"10.1016/j.amepre.2025.108144","pmid":"41067548","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08165","title":"Impact of cannabis smoking in patients with COPD: A retrospective cross-sectional study in a safety- net hospital.","authors":"Cherian, Sujith V; Karanth, Siddharth; Oldham, Sandra A; Estrada-Y-Martin, Rosa M","year":2026,"journal":"Heart & lung : the journal of critical care, 75, 263-269","doi":"10.1016/j.hrtlng.2025.10.011","pmid":"41138489","tags":["copd","lung-function","cannabis-smoking","tobacco","emphysema","respiratory"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Combined cannabis+tobacco smokers with COPD had significantly higher FVC (2.69 vs 2.33L), RV (4.09 vs 3.67L), TLC (7.13 vs 6.34L), and more bullous emphysema (17% vs 4%, p=0.02) compared to tobacco-only smokers.","whyItMatters":"Cannabis smoking's contribution to lung disease is poorly understood — this first-of-its-kind study in COPD patients reveals cannabis adds hyperinflation and bullous emphysema beyond tobacco's effects.","specificNumbers":"199 COPD patients; combined smokers: FVC 2.69L vs 2.33L (p=0.001), RV 4.09L vs 3.67L (p=0.02), TLC 7.13L vs 6.34L (p=0.001); bullous emphysema 17% vs 4% (p=0.02); cannabis started ~4 years after tobacco.","methodology":"Retrospective cross-sectional study at a safety-net hospital interviewing 199 COPD patients about smoking patterns and reviewing pulmonary function tests and chest imaging (2015-2020).","limitations":"Retrospective design; self-reported cannabis use; safety-net hospital population may not generalize; no dose-response analysis; can't fully separate cannabis from tobacco effects."},{"rthcId":"RTHC-08166","title":"Medical Cannabis Use in France: An Observational Safety Study Based on the RECANN Registry and the Pharmacovigilance/Addictovigilance System From 2021 to 2024.","authors":"Chevallier, Cécile; Batisse, Anne; Monzon, Emilie; Richard, Nathalie; Authier, Nicolas; Chenaf, Chouki; Gaboriau, Louise; Ferey, Véronique; Chretien, Basile; Fedrizzi, Sophie; Auffret, Marine","year":2026,"journal":"Fundamental & clinical pharmacology, 40(2), e70074","doi":"10.1111/fcp.70074","pmid":"41734782","tags":["medical-cannabis","france","safety","adverse-events","registry","regulation"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"37.5% of patients reported at least one ADR; 3% had serious ADRs; most common: neurological (37.2%), GI (16.9%), psychiatric (15.2%); 6 acute coronary syndromes; 8 suicidal thoughts (half without prior psychiatric history); 1 misuse case; 0 psychosis.","whyItMatters":"France's cautious, government-monitored approach to medical cannabis provides the most rigorous safety data from a national program — the 3% serious event rate and absence of psychosis are reassuring.","specificNumbers":"3,164 patients; 37.5% ≥1 ADR; 3% serious; 6 acute coronary syndromes; 8 suicidal thoughts (4 without prior psychiatric history); 1 suicide attempt; 7 withdrawal syndromes; 1 misuse; 0 psychosis cases.","methodology":"Observational safety analysis of the French national medical cannabis experimentation registry (RECANN) plus pharmacovigilance/addictovigilance databases from March 2021 to March 2024, covering 3,164 patients.","limitations":"Observational without comparator group; under-reporting likely in registry systems; 3-year timeframe may miss long-term effects; French patient selection criteria may differ from other programs."},{"rthcId":"RTHC-08167","title":"Impact of the enhanced Fatality Analysis Reporting System on drug detection in fatally injured drivers.","authors":"Chihuri, Stanford; Li, Guohua","year":2026,"journal":"Accident; analysis and prevention, 226, 108354","doi":"10.1016/j.aap.2025.108354","pmid":"41401642","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08168","title":"Cannabis-Based Products for Chronic Pain : An Updated Systematic Review.","authors":"Chou, Roger; Fu, Rongwei; Ahmed, Azrah Y; Morasco, Benjamin J","year":2026,"journal":"Annals of internal medicine, 179(2), 230-241","doi":"10.7326/ANNALS-25-03152","pmid":"41429020","tags":["pain","medical-cannabis","cbd"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"This updated systematic review pooled data from 25 randomized controlled trials involving 2,303 patients, most with neuropathic pain. The findings split sharply by cannabinoid type and formulation.\n\nOral synthetic or purified THC-only products (like dronabinol and nabilone) showed mixed results: nabilone moderately reduced pain severity (by about 1.6 points on a 10-point scale), but dronabinol showed essentially no benefit (only 0.23 points). Oromucosal sprays with comparable THC-to-CBD ratios (like nabiximols/Sativex) probably slightly reduced pain, by about half a point.\n\nProducts with low THC-to-CBD ratios — including CBD-dominant formulations — did not improve pain outcomes in the trials analyzed.\n\nAcross nearly all THC-containing products, participants experienced substantially more dizziness, sedation, and nausea compared to placebo. The pattern was consistent: modest pain relief came paired with a meaningful side effect burden.","whyItMatters":"Cannabis is increasingly used and recommended for chronic pain, but the evidence base has been unclear. This review — published in the Annals of Internal Medicine, one of the most selective medical journals — provides the most current synthesis available and draws a clearer line between which cannabinoid types show benefit and which do not.","specificNumbers":"25 RCTs, 2,303 patients, 64% with neuropathic pain. Pain reduction on 0–10 scale: nabilone −1.59 points, oromucosal comparable THC:CBD −0.54 points, dronabinol −0.23 points (not significant). Low THC:CBD products showed no improvement. Significant increases in dizziness, sedation, and nausea across THC-containing products.","methodology":"Systematic review searching Ovid MEDLINE, PsycINFO, Embase, Cochrane Library, and Scopus through July 2025. Included only randomized placebo-controlled trials of cannabinoids for chronic pain lasting 1–6 months. Cannabinoids were categorized by THC-to-CBD ratio, source (synthetic, purified, extracted), and administration method. Risk of bias and strength of evidence were independently reviewed by two assessors.","limitations":"Most trials were short-term (1–6 months), so long-term efficacy and safety remain unknown. The 64% neuropathic pain concentration means results may not generalize well to other chronic pain types. Many trials had moderate risk of bias. Cannabis product formulations varied across studies, making direct comparisons imperfect."},{"rthcId":"RTHC-08169","title":"Semi-synthetic cannabinoids: Recent developments, analytical challenges and strategic responses.","authors":"Christie, Rachel; Conlon, Ross; Néfau, Thomas; Gallegos, Ana","year":2026,"journal":"Forensic science international, 381, 112823","doi":"10.1016/j.forsciint.2026.112823","pmid":"41637948","tags":["synthetic-cannabinoids","potency","harm-reduction","legalization"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Since hexahydrocannabinol (HHC) first appeared in Europe in late 2022, the semi-synthetic cannabinoid market has expanded rapidly. The European Union Drugs Agency now monitors over 30 of these compounds, which are manufactured by chemically modifying CBD extracted from legal hemp.\n\nThese products are marketed as legal replacements for THC and sold in consumer-friendly forms including vapes, edibles, and herbal products. The chemical modifications target THC's molecular structure to increase potency, change how the body processes them, or circumvent existing drug laws.\n\nThe review identified serious concerns: products are frequently mislabeled, may contain undeclared substances or contaminants, and analytical detection is difficult because many semi-synthetic cannabinoids closely resemble natural cannabis compounds. Almost nothing is known about their pharmacological and toxicological profiles, metabolic pathways, or long-term health effects.","whyItMatters":"Semi-synthetic cannabinoids represent a new category of psychoactive substances that exploits the legal hemp supply chain. Because they're derived from legal CBD rather than manufactured entirely from scratch like older synthetic cannabinoids (Spice/K2), they occupy a regulatory gray zone in many jurisdictions. Their rapid proliferation with minimal safety data creates a public health challenge that existing drug testing and regulation wasn't designed to handle.","specificNumbers":"Over 30 semi-synthetic cannabinoids monitored by the European Union Drugs Agency. HHC first detected in Europe in late 2022. Products found in vapes, edibles, and herbal forms. 17 EU member states plus the UK have implemented some form of regulatory response.","methodology":"Narrative review synthesizing available data on semi-synthetic cannabinoids from the European Union Drugs Agency monitoring system, published literature, and forensic science reports. Examined chemical characteristics, market dynamics, regulatory responses, and analytical detection challenges.","limitations":"As a narrative review, this does not systematically assess all available evidence. Most data come from European monitoring systems and may not reflect the situation in other regions. The rapidly evolving nature of the market means specific compound counts and regulatory responses may be outdated quickly."},{"rthcId":"RTHC-08170","title":"HiSorb-TD-GC-MS analysis of commercial CBD oils.","authors":"Christodoulou, Marios C; Elia, Efstathios A; Agapiou, Agapios","year":2026,"journal":"Analytical and bioanalytical chemistry","doi":"10.1007/s00216-025-06304-1","pmid":"41555026","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08171","title":"Cannabidiol Enhances SIRT1 and Autophagy for the Maintenance of Human Mesenchymal Stem Cells.","authors":"Chueaphromsri, Phongsakorn; Kunhorm, Phongsakorn; Sotthibundhu, Areechun; Chaicharoenaudomrung, Nipha; Noisa, Parinya","year":2026,"journal":"In vivo (Athens, Greece), 40(1), 222-234","doi":"10.21873/invivo.14186","pmid":"41482390","tags":["cbd","stem-cells","aging","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD treatment significantly increased SIRT1 expression and autophagy markers in mesenchymal stem cells, reducing senescence-associated beta-galactosidase activity and maintaining telomere function and proliferative capacity.","whyItMatters":"Stem cell therapies are limited by cellular aging during lab cultivation. If CBD can preserve stem cell function, it could improve the effectiveness of regenerative medicine treatments for degenerative diseases.","specificNumbers":"CBD significantly increased SIRT1 expression and autophagy-related markers; reduced SA-β-gal activity; maintained proliferation capacity and telomere function compared to untreated controls.","methodology":"Lab study treating human mesenchymal stem cells (MSCs) with CBD, then measuring cell viability, doubling time, gene/protein expression, senescence markers, telomere length, and telomerase expression.","limitations":"In vitro study only — results in a dish don't guarantee similar effects in living organisms. No animal or human data. The specific CBD concentrations used may not reflect achievable levels in human tissues."},{"rthcId":"RTHC-08172","title":"Cannabis use among new mothers. A feasibility mixed-method study to investigate motives and perceptions.","authors":"Chuisano, Samantha A; Miriani, Paul; Alshaarawy, Omayma","year":2026,"journal":"Addictive behaviors, 173, 108554","doi":"10.1016/j.addbeh.2025.108554","pmid":"41242098","tags":["postpartum","breastfeeding","thc","maternal-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Postpartum mothers reported using cannabis an average of 24 out of 30 days, primarily by smoking. THC metabolites were confirmed in both urine and breastmilk. Qualitative interviews revealed predominantly negative healthcare provider interactions regarding cannabis use.","whyItMatters":"With cannabis legalization expanding, more postpartum mothers may use cannabis. This study highlights a communication gap between mothers and healthcare providers that could affect both maternal and infant health outcomes.","specificNumbers":"196 screened, 21 eligible (11%), 12 completed clinic visits. Average cannabis use: 24 of 30 days. THC metabolites confirmed in urine and breastmilk. 4 qualitative themes identified from 9 interviews.","methodology":"Mixed-methods feasibility study recruiting 12 new mothers (0-12 months postpartum) who use cannabis via Facebook ads. Included surveys, urine and breastmilk toxicology, and semi-structured interviews with 9 participants.","limitations":"Very small sample (12 participants) from one geographic area. Self-selection bias — only mothers willing to disclose cannabis use participated. Cross-sectional design can't assess health outcomes for infants."},{"rthcId":"RTHC-08173","title":"Cannabidiol-Loaded Mucoadhesive PLGA Nanosphere-Chitosan Hydrogel Patch for Oral Therapeutic Applications.","authors":"Chuluunbaatar, Badmaarag-Altai; Park, Jisu; Song, Junyoung; Mun, Subin; Kang, Ji-Hyun; Min, Kyung Hyun","year":2026,"journal":"International journal of molecular sciences, 27(2)","doi":"10.3390/ijms27021127","pmid":"41596768","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08174","title":"Cannabis vaping and mental health: The association of Δ-9-tetrahydrocannabinol and cannabidiol with anxiety and depressive symptoms-Findings from the United States National Youth Tobacco Survey (2021-2023).","authors":"Chung, Jack; Stjepanović, Daniel; Cheng, Brandon; Lim, Carmen C W; Hall, Wayne; Connor, Jason P; Chan, Gary C K","year":2026,"journal":"Addiction (Abingdon, England), 121(3), 617-628","doi":"10.1111/add.70218","pmid":"41196097","tags":["youth","vaping","mental-health","thc","cbd","anxiety","depression"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Adolescents who vaped THC only (aOR=1.40) or dual CBD/THC (aOR=1.51) were more likely to experience depressive symptoms. Those who vaped CBD only had higher odds of anxiety symptoms (aOR=1.74) compared to non-vapers, and higher anxiety than THC-only vapers (aOR=1.51).","whyItMatters":"Cannabis vaping is increasingly common among teens. This large national study suggests different cannabinoids may have different mental health associations — THC linking to depression and CBD to anxiety — which challenges simple narratives about either compound.","specificNumbers":"69,899 adolescents surveyed. THC-only vapers: 40% higher odds of depressive symptoms (aOR=1.40). Dual vapers: 51% higher odds of depressive symptoms (aOR=1.51). CBD-only vapers: 74% higher odds of anxiety (aOR=1.74). 51.3% of sample was male.","methodology":"Analysis of three years (2021-2023) of the nationally representative US National Youth Tobacco Survey using a stratified three-stage cluster design, with logistic regression adjusting for covariates. Total sample: 69,899 adolescents aged 11-18.","limitations":"Cross-sectional design cannot establish causation — anxious teens may seek CBD products, not the reverse. Self-reported cannabis vaping. Cannot verify actual CBD/THC content of vaped products. No information on dose or frequency."},{"rthcId":"RTHC-08175","title":"Mindset over molecule: comparing self-transcendent and mystical experiences across recreational psilocybin, MDMA, and cannabis use.","authors":"Chwyl, Christina; Spata, Angelica; Lucas, Will; Luoma, Jason B","year":2026,"journal":"BMC psychology, 14(1)","doi":"10.1186/s40359-025-03921-4","pmid":"41566347","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08176","title":"LGBTQ+ Identity and College Cannabis Use: The Role of Lifetime Trauma History.","authors":"Cingranelli, Leah; Rathod, Krutika; Mack, Cormac; Goodhines, Patricia A","year":2026,"journal":"Journal of psychoactive drugs, 1-10","doi":"10.1080/02791072.2026.2631375","pmid":"41721472","tags":["lgbtq","college","trauma","cannabis-use-disorder"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"LGBTQ+ students showed greater lifetime trauma (d=-0.79) and hazardous cannabis use (d=0.30) compared to cisgender-heterosexual peers. Lifetime traumatic experiences significantly predicted both hazardous cannabis use and negative cannabis consequences specifically among LGBTQ+ students.","whyItMatters":"Understanding why LGBTQ+ college students face elevated cannabis risk can help develop targeted interventions. This study identifies trauma — not identity itself — as the mechanism, pointing toward trauma-informed approaches rather than identity-based ones.","specificNumbers":"322 students surveyed. 27% identified as LGBTQ+. LGBTQ+ students had significantly greater trauma (t=−5.90, p<.001, d=−.79) and hazardous use (t=2.18, p=.03, d=.30). Trauma predicted hazardous use (b=0.74, p=.04) and negative consequences (b=0.53, p=.03) for LGBTQ+ students.","methodology":"Cross-sectional online survey of 322 college students at a northeastern U.S. university. Mean age 19.04 years; 27% LGBTQ+, 77% cisgender-heterosexual; 84% white. Used validated measures of trauma exposure, cannabis use, and cannabis consequences.","limitations":"Single university, predominantly white sample (84%), cross-sectional design. Cannot establish that trauma causes cannabis use. Self-reported measures. Small LGBTQ+ subsample. Northeastern university may not generalize nationally."},{"rthcId":"RTHC-08177","title":"Endocannabinoids, perioperative pain, and acetaminophen in patients undergoing total knee arthroplasty: a prospective cohort study.","authors":"Clendenen, Nathan; Clendenen, Anna; McClain, Robert; Wheeler, Garret; Klawitter, Jost; Christians, Uwe; Clendenen, Steven R; Klawitter, Jelena","year":2026,"journal":"Pain reports, 11(2), e1369","doi":"10.1097/PR9.0000000000001369","pmid":"41635474","tags":["endocannabinoid-system","pain","surgery","clinical"],"studyType":"cohort","evidenceStrength":"preliminary","keyFinding":"Knee replacement patients had higher CSF and plasma concentrations of anandamide and related N-acylethanolamines compared to controls. Patients with higher pain scores had lower CSF anandamide levels before and after surgery, and higher 2-AG levels before (but not after) surgery.","whyItMatters":"The endocannabinoid system may be a target for non-opioid pain management after surgery. Understanding how natural cannabinoids respond to surgical pain could lead to new treatments that work with the body's own pain-relief system.","specificNumbers":"40 patients enrolled. 3 sampling timepoints. Higher CSF and plasma N-acylethanolamines vs. controls. Higher pain = lower CSF anandamide. Higher 2-AG pre-surgery in high-pain patients. Pain measured by Defense and Veterans Pain Rating Scale.","methodology":"Prospective observational cohort study of 40 adults with osteoarthritis undergoing total knee arthroplasty. Cerebrospinal fluid and blood samples collected at 3 timepoints (pre-surgery, post-acetaminophen, 24h post-op). Endocannabinoids quantified by validated LC/MS assay. Linear regression with sex, age, BMI covariates.","limitations":"Small sample (40 patients). Observational — cannot determine if endocannabinoid changes cause or result from pain. CSF collection is invasive, limiting broader application. No cannabis-based intervention was tested."},{"rthcId":"RTHC-08178","title":"The Prevalence of Cannabis Use Disorder in Individuals with Anxiety or Related Disorders: A Systematic Review.","authors":"Coles, Ashlee R L; Perry, Jenna K; Hiscock, Brooke B; Fawcett, Jonathan M; Harris, Nick; Fawcett, Emily J","year":2026,"journal":"Journal of dual diagnosis, 22(1), 3-25","doi":"10.1080/15504263.2025.2606019","pmid":"41447562","tags":["anxiety","cannabis-use-disorder","comorbidity","ptsd","systematic-review"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Across general population samples, 3.3-21.6% of individuals with anxiety disorders had lifetime cannabis use disorder (CUD), and 4.3-20.0% had current CUD. Among veterans with PTSD, current CUD prevalence was 4.1-34.0%.","whyItMatters":"As cannabis becomes more accessible, understanding who is most vulnerable to problematic use is critical. People with anxiety disorders may use cannabis to cope but are at meaningful risk of developing dependence, creating a cycle that worsens both conditions.","specificNumbers":"1,646 articles screened, 11 included. General population: lifetime CUD 3.3-21.6%, current CUD 4.3-20.0%. Veterans with PTSD: current CUD 4.1-34.0%, lifetime CUD 11.3-12.5%. Approximately 1 in 30 to 1 in 5 anxiety patients affected.","methodology":"Systematic review searching PubMed, PsycInfo, and Web of Science. Included studies of adults 18+ diagnosed with anxiety or related disorders via clinical interview, with CUD assessed by interview or validated screener. 11 studies met criteria from 1,646 identified.","limitations":"Only 11 studies met inclusion criteria, reflecting limited research. Wide prevalence ranges suggest methodological heterogeneity. Most studies were from Western countries. Different diagnostic criteria and assessment tools across studies."},{"rthcId":"RTHC-08179","title":"Association between children's secondhand co-exposure to tobacco and cannabis smoke and elevated urinary cotinine levels: a cross-sectional analysis.","authors":"Collins, Bradley N; Lepore, Stephen J; Berardi, Vincent; Goodwin, Renee D; Wilson, Karen; Baishya, Mona","year":2026,"journal":"BMJ public health, 4(1), e003739","doi":"10.1136/bmjph-2025-003739","pmid":"41736815","tags":["secondhand-smoke","children","tobacco","public-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Maternal co-smoking of tobacco and cannabis was associated with significantly higher children's cotinine levels (p=0.04) compared to tobacco smoking only, after adjusting for daily tobacco exposure, nicotine dependence, and other covariates.","whyItMatters":"As cannabis use increases among parents, children may face compounded secondhand smoke exposure. This is the first study showing that dual tobacco-cannabis smoke exposure leads to higher nicotine metabolite levels in children than tobacco smoke alone.","specificNumbers":"396 mother-child pairs. 36.9% of mothers also smoked cannabis in the past 7 days. Mean maternal age: 30.1 years. Mean child age: 30.2 months. Co-smoking significantly associated with higher children's cotinine (p=0.04) after adjusting for confounders.","methodology":"Cross-sectional analysis of baseline data from the 'Babies Living Safe and Smokefree' RCT. 396 low-income mothers who smoked tobacco daily with children under 6. Multivariable regression testing whether maternal co-smoking predicted children's urinary cotinine levels.","limitations":"Cross-sectional design from a specific population (low-income tobacco-smoking mothers). Self-reported cannabis use may underestimate actual use. Cotinine reflects nicotine exposure specifically, not all smoke toxicants. Cannot assess long-term health outcomes for children."},{"rthcId":"RTHC-08180","title":"Safeguarding Cannabis for Medical Use: Clinical Risks, Regulatory Gaps, and the Path Toward Equitable Standards.","authors":"Collins, Shawn P","year":2026,"journal":"Clinical therapeutics","doi":"10.1016/j.clinthera.2025.12.011","pmid":"41617631","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08181","title":"Astrocyte CB1 receptors drive blood-brain barrier disruption in central nervous system inflammatory disease.","authors":"Colomer, Teresa; Bernal-Chico, Ana; Sánchez-Martín, Ester; Moreno-García, Alvaro; Baraibar, Andrés Mateo; Uribe-Irusta, Aitziber; Iriarte-Sarria, Ander; Beriain, Sandra; Skupio, Urszula; Gatuingt-Chasseriaud, Charlotte; Gonzales, Delphine; Laplagne, Guillaume; Serrat, Román; de Guevara, Isabel Pidal-Ladrón; Matute, Carlos; Clemente, Diego; Tepavcevic, Vanja; Fernández-Moncada, Ignacio; Chapouly, Candice; Marsicano, Giovanni; Mato, Susana","year":2026,"journal":"Journal of neuroinflammation, 23(1)","doi":"10.1186/s12974-026-03708-3","pmid":"41606632","tags":["endocannabinoid-system","multiple-sclerosis","blood-brain-barrier","preclinical","cb1"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"Mice with astrocyte-specific CB1 receptor deletion showed reduced demyelination, attenuated astrocyte reactivity, and improved clinical deficits in EAE (MS model). The protection came from restricted immune cell infiltration and preserved blood-brain barrier function, not from changes in myelin repair.","whyItMatters":"This challenges the simple view that cannabinoids are always protective in MS. While cannabinoids help through neurons and oligodendrocytes, this study reveals that CB1 receptors on astrocytes actually promote inflammation and blood-brain barrier breakdown — a paradoxical, cell-type-specific effect.","specificNumbers":"Astrocyte CB1R deletion reduced demyelination, attenuated astrocyte reactivity, improved clinical deficits in EAE. Reduced humoral and leukocyte infiltration. VEGF-A-induced BBB disruption was less severe in astrocyte CB1R null mice. No change in oligodendrocyte populations.","methodology":"Preclinical study using complementary mouse models of MS (EAE and lysolecithin-induced lesions). Employed conditional genetic deletion of CB1 receptors specifically in astrocytes, with assessments of clinical scores, demyelination, immune infiltration, BBB function, and oligodendrocyte populations.","limitations":"Mouse models of MS don't perfectly replicate human disease. Genetic deletion is lifelong, unlike therapeutic intervention. Cannot directly predict how cannabis use affects human MS. EAE is an acute model that may not reflect progressive MS."},{"rthcId":"RTHC-08182","title":"Cannabis-Induced Diffuse Alveolar Haemorrhage: A Case Report From the Intensive Care Unit.","authors":"Condé Pinto, Núria; Xavier, Rita; Pereira, Marta; Guimarães, Filipa; Castelo Branco, Sara","year":2026,"journal":"Cureus, 18(1), e101619","doi":"10.7759/cureus.101619","pmid":"41694826","tags":["adverse-effects","lungs","case-report","smoking"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"A previously healthy 26-year-old man presented with diffuse alveolar hemorrhage (DAH) — acute breathing difficulty, respiratory failure, lung infiltrates, and anemia. After ruling out all other causes, cannabis use combined with a viral respiratory infection was identified as the most probable trigger.","whyItMatters":"While rare, DAH can be fatal without prompt treatment. As cannabis smoking prevalence increases, clinicians need awareness that it may trigger this serious lung condition, particularly in combination with respiratory infections.","specificNumbers":"26-year-old male patient. Required ICU admission. All other DAH aetiologies ruled out through investigation. Cannabis use with concurrent viral respiratory infection identified as most probable cause.","methodology":"Clinical case report from an intensive care unit. Patient underwent comprehensive workup to exclude autoimmune, infectious, and other causes of DAH. Cannabis use was identified as the remaining probable cause after exclusion of alternatives.","limitations":"Single case report — lowest level of evidence. Cannot definitively prove cannabis caused DAH. Concurrent viral infection may have been the primary trigger. No dose or duration of cannabis use specified."},{"rthcId":"RTHC-08183","title":"United States healthcare encounters for poisoning involving cannabis relative to other substances.","authors":"Conrad, Saranrat W; Greene, Christina R; Dal Pan, Gerald; Callahan, Catherine L; Meyer, Tamra E; Radin, Rose G","year":2026,"journal":"The American journal of drug and alcohol abuse, 1-12","doi":"10.1080/00952990.2025.2603243","pmid":"41642795","tags":["poisoning","emergency","public-health","safety"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis poisoning ED visits rose from 29,050 (2016) to 49,357 (2019), while most other substance-related visits declined. However, when adjusted for use prevalence, cannabis had lower poisoning rates than heroin, cocaine, and benzodiazepines, with fewer transfers/admissions and deaths.","whyItMatters":"This provides important context for cannabis safety discussions. While cannabis-related ER visits are rising (likely reflecting increased use and potency), the data show that per user, cannabis results in far fewer poisoning emergencies and deaths than most other substances.","specificNumbers":"Cannabis ED visits: 29,050 (2016) → 49,357 (2019) → 47,655 (2020). Hospitalizations: 12,940 (2016) → 18,470 (2019) → 13,680 (2020). Utilization-adjusted ED prevalence: 77.3 (2016) → 102.0 (2019) per 100,000 users. Lower admission rates and deaths than heroin, cocaine, benzodiazepines, alcohol.","methodology":"Cross-sectional analysis of nationally representative U.S. databases: Nationwide Emergency Department Sample, National Inpatient Sample (2016-2020), and National Survey on Drug Use and Health. Calculated both raw encounter counts and utilization-adjusted prevalence per 100,000 past-year users.","limitations":"ICD coding may misclassify cannabis involvement. Polysubstance use is common and hard to disentangle. 2020 data affected by COVID-19 pandemic changes in healthcare utilization. Edibles vs. smoking not differentiated."},{"rthcId":"RTHC-08184","title":"Cigarette and cannabis use and co-use among U.S. adults: An examination of prevalence and trends during 2015-2023.","authors":"Constantin, Joanne; Jayawardhana, Jayani","year":2026,"journal":"Addictive behaviors, 172, 108521","doi":"10.1016/j.addbeh.2025.108521","pmid":"41109071","tags":["tobacco","co-use","trends","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis-only use increased from 3.9% to 10.6% over 2015-2023, while cigarette-only use declined from 15.0% to 8.8%. Co-use remained stable. Cannabis-only use was more prevalent among college-educated, higher-income, and privately insured adults, while cigarette use concentrated among disadvantaged groups.","whyItMatters":"Cannabis is replacing cigarettes as the dominant inhaled substance for many Americans, but with an inverted socioeconomic pattern. This shift carries public health implications since cannabis smoke exposure risks are less well understood than tobacco.","specificNumbers":"Cannabis-only: 3.9% (2015) → 10.6% (2023). Cigarette-only: 15.0% (2015) → 8.8% (2023). Co-use relatively stable. Cannabis use higher among college-educated, high-income, privately insured adults. Cigarette use higher among lower education, income, uninsured.","methodology":"Analysis of the National Survey on Drug Use and Health across three periods: 2015-2019, 2020, and 2021-2023. Examined past 30-day cigarette and cannabis use/co-use among U.S. adults 18+. Multivariable logistic regressions identified sociodemographic predictors.","limitations":"Self-reported substance use subject to underreporting. Past 30-day use doesn't capture frequency or quantity. Doesn't distinguish smoking from other cannabis methods. Cross-sectional surveys can't track individual changes over time."},{"rthcId":"RTHC-08185","title":"Randomised Controlled Trial Evidence on Medicinal Cannabis for Treatment of Mental Health and Substance Use Disorders: A Scoping Review.","authors":"Cooling, Sophie; Bonomo, Yvonne Ann; Castle, David; Hallinan, Christine Mary","year":2026,"journal":"Clinical drug investigation, 46(1), 5-36","doi":"10.1007/s40261-025-01501-3","pmid":"41343139","tags":["medical-cannabis","mental-health","addiction","anxiety","depression","ptsd","neuroscience"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"This scoping review mapped all available randomized controlled trial evidence on medicinal cannabis for mental health conditions classified by the DSM-5. The researchers found an emerging but highly heterogeneous evidence base.\n\nCBD showed the most consistent signal for anxiety-related conditions, with some trials reporting reductions in subjective anxiety measures. For PTSD, a small number of trials suggested potential benefit from THC-containing products, but results were mixed and trial quality was variable.\n\nFor depression, the evidence was particularly thin — few trials directly targeted depression as a primary outcome, and those that did showed inconsistent results. For substance use disorders, some trials explored cannabinoids as substitution or harm reduction tools, but the evidence remained inconclusive.\n\nAcross conditions, the review highlighted a fundamental challenge: high heterogeneity in cannabis product types, dosing, duration, and outcome measures made it difficult to draw firm conclusions about any single condition.","whyItMatters":"Global prescribing of medicinal cannabis is increasing, often outpacing the evidence base — particularly for mental health conditions. While cannabis has established evidence for conditions like epilepsy and multiple sclerosis spasticity, this review shows that the psychiatric evidence is far less developed, creating a gap between clinical practice and what trials actually demonstrate.","specificNumbers":"Review covered all available RCTs for cannabis and mental health conditions through the search period. Conditions examined included anxiety disorders, PTSD, depression, and substance use disorders. Specific trial counts and sample sizes varied by condition.","methodology":"Scoping review following established methodological frameworks (likely PRISMA-ScR). Searched for randomized controlled trials investigating medicinal cannabis for any mental health condition classified in the DSM-5. Assessed efficacy through clinical outcomes and safety through adverse events and treatment withdrawals.","limitations":"As a scoping review rather than a systematic review with meta-analysis, this maps the landscape without pooling effect sizes. The high heterogeneity across studies — different products, doses, durations, and outcome measures — limits the ability to make definitive statements. Publication bias may also affect the available evidence."},{"rthcId":"RTHC-08186","title":"A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Changes in seizure frequency and adverse events.","authors":"Coppola, Antonietta; Moore-Ramdin, Lisa; Navetta, Marco; Samanta, Debopam","year":2026,"journal":"Epilepsy research, 220, 107731","doi":"10.1016/j.eplepsyres.2026.107731","pmid":"41558068","tags":["cbd","epilepsy","systematic-review","pediatric"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CBD reduced seizure frequency in at least one patient across 47 of 57 studies, spanning 37 different developmental and epileptic encephalopathies (DEEs) and treatment-resistant epilepsies (TREs). Twenty-two studies reported at least one patient seizure-free for 48+ days. Most common adverse effects were gastrointestinal.","whyItMatters":"Epidiolex is only approved for three specific epilepsies, but many patients with other rare seizure disorders lack effective treatment options. This review suggests CBD may help a broader range of epilepsy patients than currently indicated.","specificNumbers":"57 studies included, 37 DEE/TRE types, 971 patients total. Most common: focal/multifocal-onset epilepsy (401 patients), Angelman syndrome (188). Seizure reduction in 47/57 studies. 22 studies reported seizure freedom ≥48 days. AEs: diarrhea 17-50%, decreased appetite 7-45%, vomiting 5-86%.","methodology":"Systematic literature review per PRISMA guidelines searching Embase, PubMed, and Cochrane through March 2024. Evaluated studies reporting CBD effectiveness and tolerability in DEEs/TREs beyond Lennox-Gastaut, Dravet, and tuberous sclerosis (the approved indications). 57 studies included, covering 971 patients.","limitations":"Most studies (33/57) were case reports or small case series — the lowest evidence tier. Heterogeneous study designs and outcome definitions. No placebo-controlled data for most conditions. Publication bias likely favors positive results."},{"rthcId":"RTHC-08187","title":"Light-Controlled Modulation of the Endocannabinoid System: Photoswitchable Ligands for Cannabinoid and TRPV1 Receptors.","authors":"Corallo, Alessia Agata; Noli, Carlotta; Brizzi, Antonella; Paolino, Marco; Mugnaini, Claudia; Corelli, Federico","year":2026,"journal":"International journal of molecular sciences, 27(2)","doi":"10.3390/ijms27020573","pmid":"41596225","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08188","title":"Repeated administration of the synthetic cannabinoid AKB48 induces serotonergic neuroadaptation in male and female mice: behavioural and immunohistochemical evidence.","authors":"Corli, Giorgia; De Luca, Fabrizio; Bilel, Sabrine; Bassi, Marta; Roda, Elisa; Gaudio, Rosa Maria; Fattore, Liana; Locatelli, Carlo Alessandro; Marti, Matteo","year":2026,"journal":"Neuropharmacology, 283, 110758","doi":"10.1016/j.neuropharm.2025.110758","pmid":"41202874","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08189","title":"Impact of Medical Cannabis on the Quality of Life of Cancer Patients: A Critical Review.","authors":"Correa, Larissa Gonçalves; Tucci, Adriana Marcassa","year":2026,"journal":"Journal of integrative and complementary medicine, 32(1), 18-26","doi":"10.1177/27683605251377417","pmid":"40932699","tags":["cancer","quality-of-life","medical-cannabis","review","pain"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Medical cannabis use in cancer patients was associated with improvements in mental health, sleep, appetite, and pain management. It also decreased nausea, vomiting, and use of other medications including opioids. Increased survival time and cognitive function improvements were also observed. Adverse effects were generally mild or moderate.","whyItMatters":"Cancer patients often face poor quality of life from both the disease and its treatment. If medical cannabis can meaningfully improve multiple symptoms simultaneously while reducing opioid dependence, it could become an important supportive care option.","specificNumbers":"267 articles identified, 16 selected. Only 4 were randomized clinical trials. Both THC and CBD (full spectrum) were commonly used. Varied intervention durations across studies. Improvements noted in pain, sleep, appetite, mental health, nausea/vomiting. Opioid use reduction observed.","methodology":"Critical review of PubMed, LILACS, Scopus, VHL, and Embase databases. Inclusion criteria: English, Spanish, or Portuguese; published through January 2025; full content available. 267 articles identified, 16 selected for final analysis. Both THC and CBD (full spectrum) products evaluated.","limitations":"Only 4 of 16 studies were RCTs — most were lower-quality designs. Heterogeneous cannabis products, doses, and outcome measures. Potential interaction with chemotherapy noted but not fully characterized. Insufficient evidence for systematic review or meta-analysis."},{"rthcId":"RTHC-08190","title":"Exploring the effects of cannabidiol on pain sensitivity using quantitative sensory testing among individuals receiving methadone or buprenorphine for opioid use disorder: an open-label, proof-of-concept study.","authors":"Costa, Gabriel P A; Suh, Rebecca; Sofuoglu, Mehmet; De Aquino, Joao P","year":2026,"journal":"Addictive behaviors reports, 23, 100654","doi":"10.1016/j.abrep.2025.100654","pmid":"41496743","tags":["cbd","pain","opioid-use-disorder","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"CBD showed a significant interaction with medication type for heat pain measures: buprenorphine patients had significantly higher heat pain threshold (at 400mg CBD) and heat tolerance (at 800mg CBD) compared to methadone patients. The 400mg dose showed the most favorable pain response pattern in the buprenorphine group. CBD was well-tolerated at all doses (400-1200mg).","whyItMatters":"Pain management in opioid use disorder patients is extremely challenging — they need pain relief but are vulnerable to opioid misuse. CBD could offer a non-opioid option, and this study suggests it may work especially well alongside buprenorphine treatment.","specificNumbers":"7 participants. 3 CBD doses tested: 400mg, 800mg, 1200mg. Significant MOUD×CBD dose interaction for heat pain threshold and tolerance. 400mg CBD showed best response in buprenorphine group. No serious adverse events at any dose. No cognitive effects on verbal memory.","methodology":"Open-label, proof-of-concept study with 7 individuals receiving methadone or buprenorphine for opioid use disorder with chronic pain. Three test sessions with ascending oral CBD doses (400mg, 800mg, 1200mg). Quantitative sensory testing (QST) used to assess pain sensitivity. Safety and tolerability monitored.","limitations":"Extremely small sample (n=7). Open-label design (no placebo control). Cannot generalize from so few participants. Ascending dose design means order effects can't be separated from dose effects. Short-term testing only."},{"rthcId":"RTHC-08191","title":"Differentiation of CBD and Δ9-THC isomers using copper-ion complexation and electrospray ionization-tandem mass spectrometry.","authors":"Couch, Alleigh N; Zall, Christopher M; Davidson, J Tyler","year":2026,"journal":"Analytica chimica acta, 1384, 344953","doi":"10.1016/j.aca.2025.344953","pmid":"41513345","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08192","title":"Risk Perceptions Related to Driving After Use of Alcohol and Cannabis in a Cross-National Sample of University Students in 6 Countries.","authors":"Csölle, Kianna; Amlung, Michael; Bravo, Adrian J; Ortet-Walker, Jordi; Vidal Arenas, Verónica; Michelini, Yanina; Romano, Eduardo","year":2026,"journal":"Substance use & addiction journal, 47(1), 112-122","doi":"10.1177/29767342251356352","pmid":"40737116","tags":["driving","impairment","alcohol","risk-perception","international"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Less than 12% of students across all countries endorsed impaired driving. Significant cross-national differences emerged: England and Spain rated alcohol-impaired driving as less threatening, while Argentina rated cannabis-impaired driving as less threatening. Students with prior DUI experience and men in some countries held more favorable risk perceptions.","whyItMatters":"As cannabis legalization expands globally, understanding how young drivers perceive cannabis-impaired driving across different legal contexts can inform targeted prevention campaigns and enforcement strategies.","specificNumbers":"5,167 students from 6 countries. 70% women. Mean age 20.1 years. Less than 12% endorsed impaired driving in any country. Argentina rated cannabis DUI as less threatening. England and Spain rated alcohol DUI as less threatening. Prior DUI history linked to lower risk perceptions.","methodology":"Cross-national survey of 5,167 university students across Argentina, Canada, England, Spain, South Africa, and the United States (70% women, mean age 20.1). Online survey assessed past-year impaired driving frequency, passenger experiences, and risk perceptions. Chi-square tests with Bonferroni corrections for pairwise comparisons.","limitations":"University students not representative of general driving population. Self-reported DUI may underestimate actual behavior. Cross-sectional design cannot determine if perceptions drive behavior or vice versa. Convenience sampling limits generalizability."},{"rthcId":"RTHC-08193","title":"PET Molecular Imaging of the Endocannabinoid System in Psychiatric Disorders.","authors":"Cui, Chunyi; Dou, Xiaofeng; Cen, Peili; Jin, Chentao; Wang, Jing; Niu, Jiaqi; Xue, Chenxi; Tian, Mei; Zhang, Hong; Zhong, Yan","year":2026,"journal":"Neuroscience bulletin, 42(2), 419-438","doi":"10.1007/s12264-025-01515-z","pmid":"41083650","tags":["endocannabinoid-system","brain-imaging","psychiatric","review"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"PET imaging reveals distinct alterations in endocannabinoid system components across psychiatric conditions. The review summarizes available PET tracers targeting CB1 receptors, FAAH, MAGL, and other ECS components, and their findings across cannabis use disorder, alcohol use disorder, PTSD, schizophrenia, and eating disorders.","whyItMatters":"PET imaging allows researchers to see the endocannabinoid system working in living brains for the first time. Understanding how this system changes in different psychiatric disorders could lead to more targeted cannabinoid-based treatments.","specificNumbers":"Disorders covered: cannabis use disorder, alcohol use disorder, PTSD, schizophrenia, eating disorders. ECS components imaged: CB1 receptors, FAAH, MAGL, and others. Multiple PET tracers reviewed for each target.","methodology":"Narrative review of PET tracer development and clinical application studies. Covers multiple ECS-targeting radiotracers and their use in diverse psychiatric populations. Synthesizes findings across different ECS components and disorders.","limitations":"Narrative review format (not systematic). PET studies typically have small sample sizes and are expensive. Most tracers are still research tools, not clinically available. Cross-study comparison is complicated by different tracers and methods."},{"rthcId":"RTHC-08194","title":"Impact of prenatal delta-9-tetrahydrocannabinol exposure on mouse brain development: a fetal-to-adulthood magnetic resonance imaging study.","authors":"Cupo, Lani; Vecchiarelli, Haley A; Gallino, Daniel; VanderZwaag, Jared; Bradshaw, Katerina; Phan, Annie; Khakpour, Mohammadparsa; Ben-Azu, Benneth; Guma, Elisa; Fouquet, Jérémie P; Spring, Shoshana; Nieman, Brian J; Devenyi, Gabriel A; Tremblay, Marie-Eve; Chakravarty, M Mallar","year":2026,"journal":"Molecular psychiatry, 31(1), 256-269","doi":"10.1038/s41380-025-03189-5","pmid":"40962830","tags":["pregnancy","neuroscience","anxiety","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"preliminary","keyFinding":"Using MRI brain scans at nine timepoints from gestation through adulthood, researchers tracked what happened to mouse brains after prenatal THC exposure. The trajectory was consistent and concerning.\n\nTHC-exposed embryos first showed ventriculomegaly — enlarged fluid-filled spaces in the brain. After birth, this shifted to a deceleration of overall brain growth that persisted through development and into adulthood. Female mice were more affected than males across multiple measures.\n\nThe brain regions most consistently impacted spanned both cortex and subcortex, aligning with observed behavioral changes. THC-exposed neonates showed sex-dependent differences in social behavior, and by adolescence, exposed mice displayed increased anxiety-like behavior.\n\nElectron microscopy confirmed structural changes at the cellular level, providing a biological basis for the behavioral observations and suggesting the effects extend beyond gross brain volume to cellular architecture.","whyItMatters":"This is one of the most comprehensive longitudinal mappings of prenatal THC's effects on brain development available — tracking the same animals from embryo to adult across nine MRI timepoints. The finding that effects are not transient but sustained into adulthood, and that females may be more vulnerable, adds important detail to the prenatal exposure literature (connecting to RTHC-00226 on molecular brain changes and RTHC-00209 on neurodevelopmental outcomes).","specificNumbers":"9 MRI timepoints from gestation to adulthood. Ventriculomegaly observed in embryos. Sustained brain growth deceleration through adulthood. Female mice more affected than males. Behavioral changes: altered social behavior in neonates, increased anxiety-like behavior in adolescents.","methodology":"Longitudinal study in mice using MRI brain imaging at nine timepoints from gestation to adulthood. Combined with behavioral assays (social behavior in neonates, anxiety-like behavior in adolescents) and electron microscopy for cellular-level analysis. THC was administered prenatally; controls received vehicle.","limitations":"Animal model — mice metabolize THC differently than humans, and brain development timelines differ significantly. THC doses may not directly translate to human exposure levels. The study cannot account for the complex social and environmental factors that influence human neurodevelopment alongside any biological effects of prenatal exposure."},{"rthcId":"RTHC-08195","title":"Mapping the acute effects of cannabis on multiple memory domains: A randomized, double-blind, placebo-controlled study.","authors":"Cuttler, Carrie; McLaughlin, Ryan J","year":2026,"journal":"Journal of psychopharmacology (Oxford, England), 2698811261416079","doi":"10.1177/02698811261416079","pmid":"41733237","tags":["memory","thc","cognition","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Compared to placebo, cannabis increased false memory susceptibility and impaired verbal memory (immediate, delayed, working), visuospatial memory (immediate, delayed), event-cued prospective memory, source memory, and temporal order memory. No significant differences were found between 20mg and 40mg THC doses.","whyItMatters":"Most cannabis memory research focused only on verbal recall. This study reveals that cannabis broadly impairs nearly all memory types, including 'everyday' memory like remembering to take medication or recalling the order of events — with real implications for daily functioning.","specificNumbers":"120 participants. 3 conditions: placebo, 20mg THC, 40mg THC. 13 memory domains tested. 10 domains significantly impaired. No dose-response difference between 20mg and 40mg. First study to detect cannabis effects on prospective memory and temporal order memory.","methodology":"Randomized, double-blind, placebo-controlled study with 120 cannabis-using participants assigned to vaporize flower containing 0mg (placebo), 20mg, or 40mg THC. Comprehensive battery of 13 memory tests spanning verbal, visuospatial, prospective, source, false, episodic, and temporal order memory domains.","limitations":"Participants were existing cannabis users (tolerance may affect results). Single acute administration. Flower vaporization only — edibles may differ. Lab setting may not fully reflect real-world use. Young adult sample may not generalize to all ages."},{"rthcId":"RTHC-08196","title":"Hidden nicotine: Cotinine levels among young adult Black men who smoke cannabis blunts.","authors":"D'Anna, Laura Hoyt; Chang, Kyle; Owens, Jaelen; Wood, Jefferson L; Pang, Raina; Conner, Bradley","year":2026,"journal":"Drug and alcohol dependence, 282, 113086","doi":"10.1016/j.drugalcdep.2026.113086","pmid":"41719726","tags":["blunts","nicotine","racial-disparities","tobacco"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 46 young Black men who smoked only cannabis blunts (no reported tobacco use), 54.3% had salivary cotinine levels above 10ng/mL — exceeding typical secondhand smoke levels. Higher cotinine was associated with more blunts smoked, self-constructed blunts, greater cannabis quantity, and cannabis dependence.","whyItMatters":"Blunts are made with tobacco leaf wrappers, but many users don't consider themselves tobacco users. This hidden nicotine exposure could drive unrecognized nicotine addiction, with particular health equity implications for young Black men who disproportionately use blunts.","specificNumbers":"111 participants, 46 saliva samples. 54.3% had cotinine >10ng/mL. More blunts = higher cotinine (r=.35, p=.017). Self-constructed blunts had higher cotinine (p=.02). Cannabis dependence correlated with cotinine (r=.31, p=.046).","methodology":"Cross-sectional study of 111 young adult Black men (ages 18-30) reporting 30-day blunt use but no tobacco/nicotine use. 46 provided saliva samples at two timepoints (baseline and 10 hours later). Cotinine levels measured and correlated with use patterns, cravings, and affect.","limitations":"Small subsample with saliva (46 of 111). Single geographic/demographic group. Cross-sectional design. Self-reported no tobacco use may not be accurate in all cases. Cotinine doesn't distinguish between tobacco wrapper and other potential nicotine sources."},{"rthcId":"RTHC-08197","title":"Cannabidiol-rich extract suppresses the activation of proinflammatory genes IL-1β and IL-6 in equine mesenchymal stem cells stimulated with lipopolysaccharide.","authors":"da Costa Kamura, Beatriz; de Oliveira Ferreira, Lucas Vinícius; Chimenes, Natielly Dias; de Oliveira, João Pedro Marmol; Rodriguez-Sanchez, Diego Noe; de Carvalho, Márcio; Amorim, Rogério Martins","year":2026,"journal":"Veterinary research communications, 50(3)","doi":"10.1007/s11259-026-11105-7","pmid":"41733607","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08198","title":"Targeting Amyloid Beta Aggregation and Neuroinflammation in Alzheimer's Disease: Advances and Future Directions.","authors":"Dagla, Ioanna; Gkikas, Faidon; Gikas, Evagelos; Tsarbopoulos, Anthony","year":2026,"journal":"Cells, 15(3)","doi":"10.3390/cells15030295","pmid":"41677657","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08199","title":"CBD, cannabis, or both? Examining use patterns and associated factors among U.S. youth and adults.","authors":"Dai, Hongying Daisy; Puga, Troy B","year":2026,"journal":"Addictive behaviors, 176, 108622","doi":"10.1016/j.addbeh.2026.108622","pmid":"41643367","tags":["cbd","epidemiology","youth","legalization","trends"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"In 2023, 8.9% of Americans were exclusive cannabis users, 3.4% exclusive CBD users, and 6.4% dual users. Dual use peaked at 10.8% among 18-25-year-olds. Exclusive cannabis use peaked at 14.8% among 26-34-year-olds. CBD-only use was most prevalent among adults 65+ (5.0%). State medical cannabis legalization was associated with higher exclusive cannabis use and dual use.","whyItMatters":"Cannabis and CBD are often discussed together but used by different populations for different reasons. Understanding these distinct patterns helps target public health messages and research priorities to the right groups.","specificNumbers":"56,705 total participants. 15.4% past-month cannabis use, 9.8% CBD use. Exclusive cannabis 8.9%, exclusive CBD 3.4%, dual use 6.4%. Dual use peak: 18-25 (10.8%). Cannabis peak: 26-34 (14.8%). CBD-only peak: 65+ (5.0%). Poor health: 3x higher odds of any use pattern. Medical legalization: 1.5x higher cannabis/dual use.","methodology":"Analysis of the 2023 National Survey on Drug Use and Health. Adolescents (12-17, n=11,572) and adults (18+, n=45,133). Past 30-day cannabis and CBD use patterns examined. Multinomial regressions assessed associated factors including demographics, health status, and state cannabis policy.","limitations":"Self-reported use subject to recall and social desirability bias. Past 30-day window doesn't capture frequency or dose. CBD source (hemp vs. dispensary) not distinguished. Cross-sectional — cannot determine if health status drives use or vice versa."},{"rthcId":"RTHC-08200","title":"Association of Physical Activity, Sedentary Behavior, and Cannabis Use: A Cross-Sectional Study.","authors":"Dai, Jinming; Wang, Yang; Yan, Yongtao; Wang, Taoran","year":2026,"journal":"Substance use & misuse, 1-10","doi":"10.1080/10826084.2025.2604639","pmid":"41486670","tags":["exercise","physical-activity","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"After adjusting for covariates, sedentary behavior was positively associated with cannabis use (OR=1.365), as were work physical activity (OR=1.135) and commuting activity (OR=1.209). Recreational physical activity was the only type negatively associated with cannabis use (OR=0.858), though this association was attenuated after adjusting for all covariates.","whyItMatters":"The finding that recreational exercise specifically (not work-related activity) is linked to less cannabis use suggests that enjoyable physical activity may serve as an alternative coping mechanism, while sedentary lifestyles may create conditions more favorable to substance use.","specificNumbers":"4,428 participants aged 20-60. Sedentary behavior OR=1.365 (p<.001). Work activity OR=1.135 (p<.001). Commuting activity OR=1.209 (p<.001). Recreational activity OR=0.858 (unadjusted model, p<.05). All adjusted for covariates.","methodology":"Cross-sectional analysis of 4,428 adults aged 20-60 from NHANES (2013-2018). Physical activity assessed via the Global Physical Activity Questionnaire (GPAQ). Cannabis use assessed via drug use questionnaire. Binary logistic regression with covariate adjustment.","limitations":"Cross-sectional design cannot establish causation. Cannabis users who exercise recreationally may differ in unmeasured ways. Self-reported physical activity and cannabis use. GPAQ may not capture all activity types. 2013-2018 data precedes recent legalization expansion."},{"rthcId":"RTHC-08201","title":"CBD-Rich Cannabis Therapy in Children with Autism Spectrum Disorder May Improve Symptoms of Hyperactivity and Attention Deficit: An Open-Label Study.","authors":"Dana, Barchel; Elkana, Kohn; Ariela, Hazan; Matitiahu, Berkovitch; Ilia, Babarashvili; Eli, Heyman; Inbar, Hartmann; Mirit, Lezinger; Danel, Waissengreen; David, Meiri; Liron, Sulimani; Orit, Stolar","year":2026,"journal":"Current neuropharmacology","doi":"10.2174/011570159X390368251014072051","pmid":"41503912","tags":["autism","adhd","cbd","pediatric","clinical"],"studyType":"clinical-observation","evidenceStrength":"preliminary","keyFinding":"Significant improvements were observed in anxiety-shyness, perfectionism, ADHD index, emotional lability, and hyperactivity-impulsivity (all p<0.001). Additional trends toward improvement in oppositional behavior, cognitive inattention, hyperactivity, and DSM-IV inattention scores. Higher CBD blood levels predicted greater emotional lability improvement.","whyItMatters":"Children with autism who also have ADHD symptoms often don't respond well to standard medications. This is the first study to use teacher assessments (more objective than parent reports) and found significant improvements across multiple behavioral domains.","specificNumbers":"109 recruited, 53 teacher-assessed. Significant improvement (p<0.001): anxiety-shyness, perfectionism, ADHD index, emotional lability, hyperactivity-impulsivity. Near-significant: oppositional behavior (p=.009), cognitive inattention (p=.009), hyperactivity (p=.006). Higher CBD blood levels predicted emotional lability improvement.","methodology":"Prospective, single-arm, open-label study at one center. 109 children/young adults with ASD and ADHD symptoms recruited (2019-2021); 53 assessed by teachers using the Conners' Teacher Rating Scale before and after 3-6 months of CBD-rich cannabis oil. Blood samples measured cannabinoid levels.","limitations":"Open-label design (no placebo control — improvements could be placebo effect or natural development). Single center. Nearly half of recruited participants lacked teacher assessments. No control group. Cannabinoid dose-response was mostly non-significant."},{"rthcId":"RTHC-08202","title":"Education shares distinct genetic influences with substance use and disorder.","authors":"Davis, Christal N; Khan, Yousef; Piserchia, Zachary; Gray, Joshua C; Kranzler, Henry R","year":2026,"journal":"Psychological medicine, 56, e38","doi":"10.1017/S0033291726103353","pmid":"41622852","tags":["genetics","education","cannabis-use-disorder","alcohol"],"studyType":"genomic-analysis","evidenceStrength":"moderate","keyFinding":"Education shared 84% of causal genetic variants with cannabis use disorder (CUD) but only 48% with cannabis use. The key distinction: variants linked to cannabis use mostly had concordant effects with education (71% same direction), while CUD variants mostly had discordant effects (only 38% same direction). Cognitive and non-cognitive components of education showed partially distinct patterns.","whyItMatters":"This explains a long-standing paradox: educated people are more likely to try cannabis but less likely to develop addiction. The genetic overlap suggests that traits enabling educational success (like cognitive flexibility and self-regulation) may both promote experimentation and protect against disorder.","specificNumbers":"EA shared 48.07% of causal variants with cannabis use and 84.18% with CUD. For cannabis use: 71.42% concordant with cognitive EA, 65.56% with non-cognitive EA. For CUD: only 37.97% concordant with cognitive EA, 42.23% with non-cognitive EA. Functional enrichment varied across brain tissues.","methodology":"Genomic analysis using bivariate causal mixture models, local genetic correlation analyses, and conditional/conjunctional false discovery rate analyses. Compared genetic architecture of educational attainment (cognitive and non-cognitive components) with alcohol consumption, AUD, cannabis use, and CUD using large genome-wide association study datasets.","limitations":"Genomic studies identify statistical associations, not causal pathways. Primarily European-ancestry datasets limit generalizability. Education is a proxy for many socioeconomic factors. Genetic effects operate through complex environmental interactions."},{"rthcId":"RTHC-08203","title":"A qualitative study of same session co-use of nicotine and cannabis among adolescents and young adults.","authors":"Davis, Danielle R; Cavallo, Dana A; Bold, Krysten W; Morean, Meghan E; Kong, Grace; Li, Wei; Ponte, Vanessa; Franco, Nicholas; Lichenstein, Sarah; Krishnan-Sarin, Suchitra","year":2026,"journal":"PloS one, 21(1), e0340050","doi":"10.1371/journal.pone.0340050","pmid":"41499437","tags":["nicotine","co-use","youth","vaping","qualitative"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Young people reported intentionally using nicotine and cannabis in the same session primarily to enhance the positive psychoactive effects of cannabis (improve/enhance the high). Secondary reasons included reducing negative cannabis effects (throat irritation, taste masking with flavored nicotine vapes). Some reported nicotine use was so frequent it unintentionally overlapped with cannabis. Others avoided same-session use because combined effects were too strong.","whyItMatters":"Understanding why teens combine nicotine and cannabis in the same session is crucial for prevention. If nicotine is used to enhance the cannabis experience, then addressing one substance requires addressing both — they're functionally linked in young users' behavior.","specificNumbers":"29 participants in 6 focus groups. Ages 15-20. All reported past-month nicotine and cannabis vaping. Most common reason: enhance cannabis high. Secondary: reduce throat irritation, mask taste with flavored nicotine. Some reported unintentional overlap due to frequent nicotine use.","methodology":"Qualitative study with six focus groups of Connecticut adolescents and young adults (15-20 years old, N=29, mean group size 5) who reported past-month nicotine and cannabis vaping. Conducted spring 2023. Two-stage deductive and inductive thematic analysis.","limitations":"Small qualitative sample (29 participants). Single region (Connecticut). Focus group dynamics may influence responses. Participants who co-use may differ from those who don't. No objective measures of use patterns."},{"rthcId":"RTHC-08204","title":"More high, less low? PTSD and the complex daily associations between cannabis use and depression in veterans.","authors":"Davis, Jordan P; Saba, Shaddy K; Leightley, Daniel; Pedersen, Eric R; Prindle, John; Cantor, Jonathan; Dilkina, Bistra; Dworkin, Emily; Sedano, Angeles","year":2026,"journal":"Addictive behaviors, 175, 108593","doi":"10.1016/j.addbeh.2025.108593","pmid":"41477917","tags":["ptsd","veterans","depression","daily-diary"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Among all veterans, bidirectional negative associations emerged: more depression predicted fewer hours high the next day, and more hours high predicted less depression the next day. However, for veterans with PTSD, only the first direction held (depression → less cannabis), while for veterans without PTSD, only the second held (cannabis → less depression).","whyItMatters":"This reveals that cannabis's relationship with depression in veterans depends critically on PTSD status. Veterans without PTSD may experience genuine mood benefits, while those with PTSD — who are most likely to self-medicate — may not get the same relief.","specificNumbers":"74 veterans. 87 consecutive days of data. Bidirectional negative associations in full sample. PTSD-positive: depression predicted fewer hours high next day (but not reverse). PTSD-negative: more hours high predicted less depression next day (but not reverse).","methodology":"Daily diary study using dynamic structural equation modeling (DSEM). 74 veterans provided data for 87 consecutive days. Daily measures: hours spent high, depression severity (sliding scale), and PTSD (PCL checklist). Recruited through BuildClinical, an NIH-approved vendor.","limitations":"Relatively small sample (74 veterans). Self-reported hours 'high' is imprecise. PTSD assessed at baseline only (may fluctuate). Observational — can't prove cannabis causes depression improvement. No information on cannabis type, dose, or method."},{"rthcId":"RTHC-08205","title":"Exploring THC labelling preferences to communicate the strength of cannabis products: Insights from U.S. consumers.","authors":"Dawson, Danielle; Hall, Wayne; Goodwin, Isabella; Carlini, Beatriz H; Lubman, Dan I; Hammond, David; Freeman, Tom P; Lorenzetti, Valentina","year":2026,"journal":"The International journal on drug policy, 147, 105076","doi":"10.1016/j.drugpo.2025.105076","pmid":"41442927","tags":["labeling","policy","thc","consumer","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Most respondents considered it important for cannabis products to include THC information. When comparing Standard THC Units, THC concentration (%), or both, Standard THC Units were significantly preferred (p<.001). Preferences did not differ by state cannabis policy, sex, or frequency of use.","whyItMatters":"THC labeling on cannabis products is inconsistent across states, limiting consumers' ability to make informed choices. Finding that consumers prefer simple dose-based units over percentages supports standardized labeling that could reduce overconsumption and adverse events.","specificNumbers":"575 participants from various U.S. states. Past 12-month cannabis users. Standard THC Units preferred over concentration (p<.001). No significant preference differences by state policy, sex, or use frequency. Example unit: 5mg THC per serving.","methodology":"Online survey of 575 adult cannabis users (past 12 months) recruited via Amazon Mechanical Turk from various U.S. states. Assessed cannabis use patterns, attitudes, and preferences for THC labeling metrics (standard units, concentration, total content). Descriptive and multinomial logistic regression analyses.","limitations":"Amazon Mechanical Turk sample not representative. Existing cannabis users may have different preferences than new users. Hypothetical preferences may not translate to real-world behavior. Did not include THC milligrams as a standalone option."},{"rthcId":"RTHC-08206","title":"Motivations and Pathways: A Thematic Analysis of Interviews with Medicinal Cannabis Consumers in Australia.","authors":"Dawson, Danielle; Stjepanović, Daniel; McClure-Thomas, Caitlin; Lorenzetti, Valentina; Hall, Wayne; Sun, Tianze; Leung, Janni","year":2026,"journal":"Substance use & misuse, 61(4), 638-642","doi":"10.1080/10826084.2025.2560074","pmid":"40970421","tags":["medical-cannabis","qualitative","australia","access"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Medicinal cannabis users reported diverse motivations including managing treatment-resistant conditions and avoiding legal consequences of illicit use. Access was described as straightforward through telehealth and dispensaries. Key barriers were financial (high cost) and product frustration (receiving oil prescriptions when flower was preferred). Dual medical-recreational use was common.","whyItMatters":"As more countries develop medical cannabis programs, Australia's experience offers lessons. Easy telehealth access is a success, but the cost barrier and dual-use patterns raise questions about who benefits and how programs should be designed.","specificNumbers":"15 participants interviewed at 2 cannabis events. Access described as straightforward via telehealth. Key themes: diverse motivations (treatment-resistant conditions, avoiding legal risk) and access journeys (telehealth, dispensaries, cost barriers). Dual recreational-medical use reported. Limited product/dose knowledge among users.","methodology":"Brief semi-structured interviews with 15 adults self-reporting medicinal cannabis use in the past 12 months, recruited at two cannabis events in Queensland and New South Wales. Thematic analysis using Braun and Clarke's six-step framework identified two themes: diverse drivers and access journeys.","limitations":"Very small sample (15 participants). Recruited at cannabis events (not representative). Brief interviews limited depth. Single country context. Self-selected participants likely more engaged with cannabis culture."},{"rthcId":"RTHC-08207","title":"Cannabis sativa extracts reduce inclusion formation in a cell model of alpha-synuclein aggregation.","authors":"de Almeida Cruz, Tamires; de Paulo Osorio, Rodrigo; de Menezes Epifanio, Neide Mara; Merghani, Madiha; Pereira, Marcos Dias; de Almeida Chaves, Douglas Siqueira; Outeiro, Tiago Fleming; Riger, Cristiano Jorge","year":2026,"journal":"Fitoterapia, 188, 106968","doi":"10.1016/j.fitote.2025.106968","pmid":"41187864","tags":["parkinsons","alpha-synuclein","neuroprotection","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"All four cannabis extracts — regardless of dominant cannabinoid (THC at 69.88%, CBD at 52.64%, or CBN at 47.38% and 58.64%) — reduced intracellular alpha-synuclein inclusions in human H4 cells and increased the number of cells without inclusions. All extracts showed antioxidant activity and increased daughter cell production in yeast models, but did not prevent mitochondrial damage.","whyItMatters":"Alpha-synuclein protein clumps are a hallmark of Parkinson's disease. Finding that cannabis extracts with very different cannabinoid compositions all reduced these clumps suggests multiple cannabis compounds may be neuroprotective — not just CBD or THC alone.","specificNumbers":"4 cannabis extracts tested: THC-rich (69.88%), CBD-rich (52.64%), CBN-rich #1 (47.38%), CBN-rich #2 (58.64%). All reduced intracellular inclusions in H4 cells. All increased inclusion-free cells. All showed antioxidant activity (reduced intracellular oxidation). None prevented mitochondrial damage.","methodology":"Preclinical study testing four Cannabis sativa extracts with different phytocannabinoid profiles in two cell models: Saccharomyces cerevisiae (yeast) and genetically modified human H4 cells, both expressing alpha-synuclein. Evaluated antioxidant activity, inclusion formation, mitochondrial function, and cell viability.","limitations":"Cell models only — far from human disease. Alpha-synuclein overexpression in cells doesn't fully replicate Parkinson's. No animal studies. Cannot determine which specific compounds in the extracts are responsible. Mitochondrial damage wasn't prevented despite other benefits."},{"rthcId":"RTHC-08208","title":"Blowing Minds: A cross-cultural, longitudinal investigation to unravel the highs and lows of recreational and medicinal cannabis users.","authors":"de Bode, Nora; Kroon, Emese; Hsieh, Jia Hua; Cousijn, Janna","year":2026,"journal":"Comprehensive psychiatry, 145, 152659","doi":"10.1016/j.comppsych.2025.152659","pmid":"41496191","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08209","title":"A novel approach to the production of Δ9-THC and CBN certified reference materials.","authors":"de Carvalho, Lucas J; Lopes, Silvia Regina Pinheiro; Cesar, Karine Ecard; Chaves, Douglas S A; da Frota, Lívia C R M; de Menezes Epifanio, Neide Mara; Finelli, Fernanda Gadini; Garrido, Bruno C","year":2026,"journal":"Analytical and bioanalytical chemistry","doi":"10.1007/s00216-026-06325-4","pmid":"41663797","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08210","title":"Pubertal Development and the Onset of Substance Use Among Appalachian Youth: A Longitudinal Study.","authors":"De Geronimo, Francesca G; Lilly, Christa; Kogan, Steven M; Brooks-Gunn, Jeanne; Kristjansson, Alfgeir L; Allegrante, John P","year":2026,"journal":"Substance use & misuse, 61(1), 87-91","doi":"10.1080/10826084.2025.2546498","pmid":"40905532","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08211","title":"Harnessing machine learning and multivariate analysis to explore global trends in Cannabis sativa research.","authors":"De La Hoz-M, Javier; Montes-Escobar, Karime; Salas-Macias, Carlos Alfredo","year":2026,"journal":"Journal of cannabis research","doi":"10.1186/s42238-026-00397-w","pmid":"41721374","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08212","title":"Cannabis-Derived Compounds Against Plasmodium sp.: A Systematic Review of Preclinical Studies.","authors":"de Mendonça Lima, Tácio; de Sena, Luann Wendel Pereira; de Sousa, Ana Carolina Corrêa; de Freitas, Gabriel Rodrigues Martins; Rotta, Inajara; Visacri, Marília Berlofa","year":2026,"journal":"Tropical medicine & international health : TM & IH, 31(1), 1-9","doi":"10.1111/tmi.70044","pmid":"41093288","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08213","title":"Beyond neurons: Impact of cannabidiol on glial cells in ischemic stroke.","authors":"de Rezende, Victória Linden; Mathias, Khiany; Gonçalves, Cinara Ludvig; de Bitencourt, Rafael Mariano; Barichello, Tatiana; Petronilho, Fabricia","year":2026,"journal":"Neural regeneration research","doi":"10.4103/NRR.NRR-D-25-01029","pmid":"41622458","tags":["cbd","stroke","neuroprotection","review","preclinical"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Preclinical evidence indicates CBD attenuates glial reactivity, reduces pro-inflammatory signaling (NF-κB, TNF), mitigates oxidative stress, and preserves blood-brain and intestinal barrier integrity after stroke. CBD modulates multiple molecular pathways contributing to reduced infarct volume and improved neurological function.","whyItMatters":"Stroke is a leading cause of disability, and current treatments are limited. CBD's ability to target multiple harmful processes through glial cells — the brain's support network — could offer a new multi-target approach to post-stroke recovery.","specificNumbers":"Key pathways modulated: NF-κB, TNF, calcium-related signaling. Cell types affected: astrocytes, microglia, oligodendrocytes. Effects observed: reduced infarct volume, reduced pro-inflammatory signaling, preserved BBB and intestinal barrier integrity.","methodology":"Narrative review synthesizing preclinical studies of CBD's effects on glial cells (astrocytes, microglia, oligodendrocytes) in ischemic stroke models. Evaluates molecular mechanisms and therapeutic potential.","limitations":"All evidence is preclinical (animal models). No standardized CBD formulations or dosing for stroke. No human clinical trials yet. Translation from animal stroke models to human stroke is historically challenging."},{"rthcId":"RTHC-08214","title":"Cannabis sativa L. roots extract modulates gastrointestinal motility and ameliorates ethanol-induced gastric ulcers in animal models.","authors":"de Sá, Pedro Guilherme Sousa; Rocha, João Gabriel de Souza; Silva, Juliane Maria Dos Santos; de Souza, Nathália Andrezza Carvalho; Araújo, Tarcísio Cícero de Lima; Santos, Victória Laysna Dos Anjos; Menezes, Pedro Modesto Nascimento; Palheta Junior, Raimundo Campos; Silva, Fabrício Souza; Rolim, Larissa Araújo","year":2026,"journal":"Frontiers in pharmacology, 17, 1743428","doi":"10.3389/fphar.2026.1743428","pmid":"41693782","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08215","title":"Ewing sarcoma-related pain: potential role of medical cannabis monotherapy in symptom management - a case report.","authors":"De Virgilio Suglia, Cesare; Spaccavento, Felice Antonio; Turco, Fabio; De Trizio, Angela; Giannuzzi, Rossella; Tafuri, Silvio","year":2026,"journal":"Journal of cannabis research, 8(1), 21","doi":"10.1186/s42238-026-00388-x","pmid":"41572388","tags":["cancer","pain","opioid-replacement","case-report","medical-cannabis"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"After initiating THC-rich cannabis (Bedrocan, 22% THC, 1% CBD, 1g/day), the patient's pain dropped from VAS 9-10 to VAS 2-3. Complete opioid discontinuation occurred within 4 weeks (from 120mg/day morphine equivalents). Over 9 months, a chronic draining fistula closed completely and CRP dropped from 9.6 to 2.3 mg/dL.","whyItMatters":"This case demonstrates that medical cannabis may enable opioid-free pain management in complex cancer cases. The unexpected resolution of chronic infection and inflammation raises intriguing questions about cannabinoid immunomodulatory effects beyond pain relief.","specificNumbers":"Pain: VAS 9-10 → VAS 2-3. Opioids: 120mg/day morphine equivalents → 0 within 4 weeks. CRP: 9.6 → 2.3 mg/dL. Cannabis: Bedrocan 22% THC, 1% CBD, 1g/day. Follow-up: 9 months. Chronic fistula: complete closure. No adverse effects reported.","methodology":"Single case report of a 27-year-old male long-term Ewing sarcoma survivor with chronic multi-drug resistant periprosthetic osteomyelitis. Supervised medical cannabis therapy initiated after refusing amputation. 9-month follow-up tracking pain, opioid use, inflammation markers, and fistula status.","limitations":"Single case report — cannot prove causation. Spontaneous improvement cannot be excluded. No blinding or control. The patient's strong belief in cannabis may contribute to pain improvement (placebo effect). Infection resolution may be coincidental."},{"rthcId":"RTHC-08216","title":"Simultaneous Analysis of Δ9-THC, Δ8-THC, CBD, and CBN in Breath Aerosols Collected Using Cannabix Technologies Breath Collection Unit.","authors":"Deeb, Shaza; Fabian, Zaire E; Määttä, Mikko; Fraccarolli, Pedro; Engelhart, David A","year":2026,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkag016","pmid":"41723813","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08217","title":"Associations between posttraumatic cognitions and cannabis cravings among trauma-exposed individuals using cannabis.","authors":"Deguzman-Lucero, Regine M; Le, Jennifer U; Schmidt, Norman B; Short, Nicole A","year":2026,"journal":"The British journal of clinical psychology, 65(1), 250-266","doi":"10.1111/bjc.70016","pmid":"41094730","tags":["ptsd","trauma","cravings","coping"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Elevated posttraumatic cognitions were significantly associated with increased state cravings to use cannabis to cope (β=.19, p=.025). Of the three types of posttraumatic cognitions, only negative cognitions about the self predicted increased cravings (β=.19, p=.024); self-blame and negative world views did not.","whyItMatters":"Identifying that self-directed negative thoughts specifically drive cannabis coping cravings provides a clear therapeutic target. Clinicians can focus on challenging negative self-beliefs to reduce problematic cannabis use in trauma survivors.","specificNumbers":"56 participants. 58.9% female. Mean age 20.69 years. 73.2% White. Negative self-cognitions predicted cravings (β=.19, p=.024, sr²=.03). Self-blame: not significant. Negative world views: not significant. Effects held after controlling for cannabis frequency and PTSD diagnosis.","methodology":"Experimental design with 56 trauma-exposed cannabis users (58.9% female, mean age 20.69). Participants self-reported posttraumatic cognitions and cannabis frequency, received a PTSD diagnostic assessment, then underwent trauma script-driven imagery. Cannabis coping cravings measured before and after trauma cue exposure.","limitations":"Small sample (56 participants). Predominantly white. Lab setting with scripted imagery may not reflect real-world triggers. Cross-sectional cravings (not actual use measured). Young adult college sample may not generalize to older trauma survivors."},{"rthcId":"RTHC-08218","title":"Profiles of polysubstance exposure in youth with fetal alcohol spectrum disorders and the association with neurodevelopmental outcomes.","authors":"Delage, Madeline N; Speybroeck, Emily L; Richardson, Alesia A; Cole, Lynn L; Kautz-Turnbull, Carson; Petrenko, Christie L M","year":2026,"journal":"Neurotoxicology and teratology, 114, 107585","doi":"10.1016/j.ntt.2026.107585","pmid":"41633492","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08219","title":"Problematic social media use among recreational cannabis users in Québec: A Cross-Sectional study.","authors":"Deli-Houssein, Roni; Hudon, Catherine; Dufour, Isabelle; Carrier, Nathalie; Gómez, Natalia Muñoz; Deschamps, Amélie; Auger, Anne-Marie; Brodeur, Magaly","year":2026,"journal":"Addictive behaviors reports, 23, 100662","doi":"10.1016/j.abrep.2025.100662","pmid":"41560778","tags":["social-media","mental-health","cannabis-use-disorder"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"27.9% of cannabis-using participants exhibited problematic social media use (PSMU). Increased PSMU odds were associated with younger age (18-20), male sex, higher cannabis use disorder risk (CAST scores), depression (PHQ-8), and fear of missing out. Use of Telegram, TikTok, Twitter/X, and Facebook Dating increased PSMU risk, while Snapchat and Threads were associated with reduced risk.","whyItMatters":"Cannabis use and problematic social media use may share underlying vulnerabilities — impulsivity, anxiety, and difficulty regulating behavior. Understanding this overlap could help identify people at risk for compounding behavioral problems.","specificNumbers":"1,406 participants. 27.9% met PSMU criteria. Risk factors: age 18-20, male, higher CAST/PHQ-8/On-FoMO scores. Platforms increasing risk: Telegram, TikTok, Twitter/X, Facebook Dating. Platforms decreasing risk: Snapchat, Threads.","methodology":"Cross-sectional study of 1,406 Quebec adults who used both social media and cannabis. Validated instruments measured PSMU (BSMAS), online fear of missing out, cannabis use disorder risk (CAST), anxiety (GAD-7), depression (PHQ-8), and demographics. Regression model identified associated factors.","limitations":"Cross-sectional — cannot determine if cannabis use drives PSMU or vice versa. Quebec cannabis users may not represent other populations. Self-reported social media use. PSMU thresholds may over-identify problems. Platform associations may change as platforms evolve."},{"rthcId":"RTHC-08220","title":"Overlapping pathways of migraine and the endocannabinoid system: Potential therapeutic targets.","authors":"Della Pietra, Adriana; Russo, Andrew F","year":2026,"journal":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, e00833","doi":"10.1016/j.neurot.2026.e00833","pmid":"41549028","tags":["migraine","endocannabinoid-system","pain","review"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system overlaps extensively with migraine pathways. Endocannabinoid-degrading enzyme inhibitors and cannabinoid receptor modulators show anti-nociceptive effects in preclinical models. Non-canonical pathways (TRPV1, dopamine D2 receptors, serotonin, ion channels) also modulate CGRP release and trigeminovascular signaling. Sleep-related ECS pathways (circadian rhythms, glymphatic clearance) represent novel treatment directions.","whyItMatters":"Many migraine patients don't respond to CGRP-targeting drugs, the current gold standard. The endocannabinoid system offers an alternative treatment framework with multiple potential targets, from enzyme inhibitors to receptor modulators to sleep-related pathways.","specificNumbers":"Key ECS ligands: anandamide (AEA) and 2-AG. Key degrading enzymes: FAAH, MAGL. Receptor targets: CB1, CB2, TRPV1, D2 dopamine, serotonin receptors. Two novel directions proposed: circadian rhythm modulation and glymphatic clearance. Multiple multi-target compounds reviewed.","methodology":"Comprehensive narrative review mapping endocannabinoid system components in central and peripheral migraine-relevant brain regions. Summarizes preclinical evidence for anti-nociceptive effects of ECS-targeting compounds. Explores non-canonical pathways and proposes novel treatment directions.","limitations":"Primarily preclinical evidence. Human translational data are limited. Cannabis clinical trials for migraine face regulatory barriers. Individual responses to cannabinoid treatments vary widely. Side effects of ECS modulation need careful assessment."},{"rthcId":"RTHC-08221","title":"Alcohol Consumption During Pregnancy and State Implementation of Legal Nonmedical Cannabis Retail Sales in the U.S., 2011-2023.","authors":"Denny, Clark H; Deputy, Nicholas P; Abouk, Rahi; Dunkley, Janae D; Drake, Coleman; Kim, Shin Y; Pella, Michael; Roehler, Douglas R; Rose, Charles E","year":2026,"journal":"American journal of preventive medicine, 70(2), 108105","doi":"10.1016/j.amepre.2025.108105","pmid":"40945666","tags":["pregnancy","alcohol","legalization","public-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Prevalence of binge drinking during pregnancy was 2.13 times higher in states with legal recreational cannabis retail sales. Difference-in-difference analysis showed implementation was associated with a 4.96 percentage point increase in binge drinking during pregnancy (95% CI: 1.22-8.70). Current drinking showed a non-significant increase.","whyItMatters":"This unexpected association suggests cannabis legalization may have unintended effects on other substance use during pregnancy. If the relationship is causal, it would mean cannabis policy changes are increasing risk of fetal alcohol spectrum disorders.","specificNumbers":"Current drinking: 1.43x higher in legal states (95% CI: 1.18-1.73). Binge drinking: 2.13x higher (95% CI: 1.47-3.09). DID estimate: +4.96 percentage points for binge drinking (p<.05). Data span: 2011-2023 BRFSS.","methodology":"Analysis of 2011-2023 Behavioral Risk Factor Surveillance System data. Adjusted prevalence ratios and difference-in-difference analyses compared drinking during pregnancy in states before/after implementing legal nonmedical cannabis retail sales versus states without implementation, controlling for demographics and policy variables.","limitations":"Observational — cannot prove cannabis legalization causes increased drinking. Self-reported data likely underestimates both cannabis and alcohol use during pregnancy. Confounders may exist. Ecological fallacy risk (state-level associations don't prove individual behavior)."},{"rthcId":"RTHC-08222","title":"Addiction in Gastrointestinal and Liver Disorders.","authors":"Deutsch-Link, Sasha; Byers, Isabelle S; Gu, Hyundam; Arab, Juan Pablo","year":2026,"journal":"The American journal of gastroenterology","doi":"10.14309/ajg.0000000000003925","pmid":"41562474","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08223","title":"The effect of methamphetamine and 3,4-methylenedioxymethamphetamine on peripheral endocannabinoid concentrations: a study in healthy adults.","authors":"Deutsch, Ana; Haggarty, Connor J; Petrie, Gavin N; Hill, Matthew N; Bershad, Anya K; de Wit, Harriet; Mayo, Leah M","year":2026,"journal":"Psychopharmacology, 243(2), 413-426","doi":"10.1007/s00213-025-06888-7","pmid":"41051544","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08224","title":"Nationwide outcomes of cardiac surgery in patients with cannabis use disorder.","authors":"Dewan, Krish C; Mahboubi, Rashed; Xu, Samantha; Maigrot, Jean-Luc A; An, Crystal; Zhou, Guangjin; Ferre, Jose L Diz; Koroukian, Siran M; Weiss, Aaron J; Soltesz, Edward G","year":2026,"journal":"Journal of cardiothoracic surgery, 21(1)","doi":"10.1186/s13019-025-03755-6","pmid":"41547801","tags":["addiction","cardiovascular"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Analyzing 846,837 cardiovascular surgery patients from a national database, researchers identified 11,724 (1.4%) with a cannabis use disorder diagnosis. After carefully matching these patients to controls with similar baseline characteristics and comorbidities, cannabis use disorder was not associated with additional in-hospital complications or death.\n\nHowever, the data revealed something else: patients with cannabis use disorder had dramatically higher rates of polysubstance use. They were significantly more likely to also smoke tobacco, abuse opioids, use cocaine or stimulants, and abuse alcohol compared to matched controls. These co-occurring substance use patterns were the dominant clinical feature of the CUD population.\n\nSpecific complications like pneumonia (13% vs. 9.4%) were higher in the CUD group, but the researchers attributed these differences to the polysubstance use profile rather than cannabis itself.","whyItMatters":"For the growing number of patients who use cannabis and need cardiac surgery, this study provides reassurance that cannabis use disorder alone doesn't appear to worsen surgical outcomes. But it also highlights that CUD rarely exists in isolation — the polysubstance use patterns that accompany it are what clinicians should be screening for and managing in the surgical setting.","specificNumbers":"846,837 total cardiovascular surgery patients. 11,724 (1.4%) with CUD. Pneumonia: 13% CUD vs. 9.4% controls. Significantly higher rates of co-occurring tobacco, opioid, cocaine/stimulant, and alcohol use in CUD patients. No significant difference in in-hospital mortality after matching.","methodology":"Retrospective observational study using the Nationwide Readmissions Database (2016–2018). Identified 846,837 cardiovascular surgery patients, 11,724 with CUD diagnosis. Used 1:1 balancing-score matching to control for baseline characteristics and comorbidities when comparing outcomes.","limitations":"Retrospective database study relying on ICD codes for CUD diagnosis — likely underestimates true cannabis use since many users don't receive a formal CUD diagnosis. Cannot distinguish between active use and historical use at the time of surgery. The 2016–2018 data predates recent increases in cannabis potency and use. In-hospital outcomes only — doesn't capture post-discharge complications."},{"rthcId":"RTHC-08225","title":"Illicit cannabis use among workers in Australia: A nationally representative cross-sectional analysis of prevalence, determinants, and associated absenteeism.","authors":"Di Censo, Gianluca; Thompson, Kirrilly; Bowden, Jacqueline","year":2026,"journal":"Drug and alcohol dependence, 280, 113057","doi":"10.1016/j.drugalcdep.2026.113057","pmid":"41633211","tags":["workplace","epidemiology","australia","absenteeism"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Weekly cannabis use was reported by 5.0% of workers. Risk of cannabis-related harm was found in 2.2%. Construction and hospitality workers, labourers, and tradesmen had elevated rates. Weekly use was associated with 2.8 additional absent days, while being at risk of harm was associated with 6.9 additional absent days. Key determinants: male, younger, never married, Australian-born, current smoker, heavy episodic drinker.","whyItMatters":"Cannabis use in the workforce has real economic consequences. Nearly 7 extra absent days per year for at-risk workers translates to significant productivity losses, and the concentration in physically demanding jobs raises safety concerns.","specificNumbers":"24,954 workers surveyed. 5.0% weekly cannabis use. 2.2% at risk of harm. At-risk workers: 6.9 extra absent days/year. Weekly users: 2.8 extra absent days. Highest use: construction, hospitality, labourers, tradesmen. Strongest predictor: current smoking status.","methodology":"Analysis of 2019 and 2022-23 Australian National Drug Strategy Household Surveys (N=24,954). Assessed weekly cannabis use prevalence, determinants, and associated work absenteeism. Multivariate regression models identified predictors of use and harm risk.","limitations":"Cross-sectional — cannabis use may result from, rather than cause, work difficulties. Self-reported use likely underestimates actual rates. Australian context may not generalize. Absenteeism data is self-reported and may have other causes."},{"rthcId":"RTHC-08226","title":"Anxiety, Depression, and Emotional Dysregulation Following Prenatal Substance Exposure.","authors":"Diaz, Marvin R; Varlinskaya, Elena I; Schatz, Kelcie C","year":2026,"journal":"Advances in experimental medicine and biology, 1500, 101-141","doi":"10.1007/978-3-032-12741-9_5","pmid":"41478920","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08227","title":"History of Cannabis Smoking and Subjective Cognitive Complaints in Older Women.","authors":"Ding, Guoyong; Bohnert, Kipling M; Li, Chenxi; Plassman, Brenda L; Liang, Xiaoyu; Yuan, Yaqun; D'Aloisio, Aimee A; White, Alexandra J; Sandler, Dale P; Chen, Honglei","year":2026,"journal":"Neuroepidemiology, 1-11","doi":"10.1159/000550276","pmid":"41505373","tags":["cognition","aging","women","long-term-effects"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Ever smoking cannabis was associated with increased odds of subjective cognitive complaints across three follow-ups: OR 1.27 (2nd), 1.28 (3rd), 1.30 (4th). Regular smokers had stronger associations than occasional smokers (OR 1.61 vs. 1.19 at 2nd follow-up). Results were consistent across subgroup and sensitivity analyses.","whyItMatters":"As the first generation of widespread cannabis users enters older age, understanding long-term cognitive effects becomes critical. This large prospective study suggests a dose-dependent association between cannabis history and later cognitive complaints.","specificNumbers":"15,378 women. 25.8% (3,973) ever smoked cannabis. Most use occurred in early adulthood. OR for ever-smokers: 1.27-1.30 across follow-ups. Regular smokers: OR 1.61. Occasional smokers: OR 1.19. Assessed at 2nd (2011-14), 3rd (2014-16), and 4th (2017-19) follow-ups.","methodology":"Prospective cohort analysis of 15,378 women aged 65+ from the NIH Sister Study. Cannabis smoking history reported at enrollment (2003-2009). Cognitive complaints assessed via AD8 screener at three follow-ups (2011-2019). Multivariable joint models with adjustment for confounders.","limitations":"Subjective cognitive complaints are not the same as dementia diagnosis. Cannabis use was recalled decades later (recall bias). Cannot separate cannabis effects from associated lifestyle factors. Mostly white sample. No information on cannabis use after enrollment."},{"rthcId":"RTHC-08228","title":"Cannabidiol mitigates alcohol dependence and withdrawal with neuroprotective effects in the basolateral amygdala and striatum.","authors":"Dirik, Selen; Doyle, Michelle R; Wood, Courtney P; Campo, Paola; Martinez, Angelica R; Fannon, McKenzie; Balaguer, Maria G; Seely, Spencer; Montoya, Bryan A; Cook, Gregory M R; Palermo, Gabrielle M; Lin, Junjie; Sist, Madelyn D; Naghshineh, Parsa K; Lan, Zihang; Rahman, Sara R M U; Suhandynata, Raymond; Schweitzer, Paul; Kallupi, Marsida; de Guglielmo, Giordano","year":2026,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 51(3), 691-702","doi":"10.1038/s41386-025-02164-6","pmid":"40640509","tags":["cbd","alcohol","addiction","neuroprotection","preclinical"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"In alcohol-dependent rats, CBD reduced alcohol self-administration during withdrawal, decreased motivation for alcohol, reduced somatic withdrawal signs, withdrawal-induced anxiety, and pain sensitivity. CBD attenuated alcohol-seeking and stress-induced relapse. It reversed alcohol-induced changes in neuronal excitability in the amygdala and prevented neurodegeneration in the nucleus accumbens shell and dorsomedial striatum.","whyItMatters":"Alcohol use disorder has limited effective treatments. CBD showed benefits across the full spectrum of addiction — reducing intake, withdrawal, anxiety, craving, relapse, and brain damage — in the most comprehensive preclinical alcohol study to date.","specificNumbers":"CBD reduced: alcohol self-administration during withdrawal, motivation for alcohol, somatic withdrawal signs, anxiety-like behavior, mechanical pain sensitivity, extinction alcohol-seeking, stress-induced reinstatement. CBD prevented neurodegeneration in nucleus accumbens shell and dorsomedial striatum. No effect on saccharin (sweet reward) or locomotor activity.","methodology":"Preclinical study using two complementary rat models: chronic intermittent ethanol (CIE) for established dependence and ethanol vapor self-administration (EVSA) for volitional intake. Assessed behavioral, electrophysiological, and immunohistochemical outcomes of chronic CBD administration.","limitations":"Rat models don't perfectly replicate human alcohol dependence. Doses and routes of CBD administration differ from human use. No long-term follow-up. Cannot directly predict human treatment outcomes."},{"rthcId":"RTHC-08229","title":"Active Polysaccharide Films Incorporating Cannabis sativa Flower Extract for Extending the Shelf Life of Freeze-Dried Berries.","authors":"Dobrucka, Renata; Studzińska-Sroka, Elżbieta; Paczkowska-Walendowska, Magdalena; Cielecka-Piontek, Judyta; Gumienna, Małgorzata; Lasik-Kurdyś, Małgorzata; Szymański, Marcin","year":2026,"journal":"Molecules (Basel, Switzerland), 31(3)","doi":"10.3390/molecules31030443","pmid":"41683420","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08230","title":"The synthetic cannabinoid CUMYL-4CN-BINACA induces hepatic injury in rats via oxidative stress, NF-κB activation, Nrf2 suppression, EDEM-1, ER stress-mediated apoptotic pathways.","authors":"Dogan, Tuba; Aksakal, Ozkan; Alat, Omercan; Halici, Mesut Bünyami; Gur, Cihan","year":2026,"journal":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 207, 115809","doi":"10.1016/j.fct.2025.115809","pmid":"41109593","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08231","title":"Testing the robustness of daily associations of affect with alcohol and cannabis use.","authors":"Dora, Jonas; Kuczynski, Adam M; McCabe, Connor J; Creswell, Kasey G; Dvorak, Robert D; Howard, Andrea L; Patrick, Megan E; Shoda, Yuichi; Smith, Gregory T; Wright, Aidan G C; King, Kevin M","year":2026,"journal":"Journal of psychopathology and clinical science","doi":"10.1037/abn0001097","pmid":"41712352","tags":["mood","daily-diary","alcohol","affect-regulation"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Neither positive nor negative affect consistently predicted cannabis use likelihood or quantity across hundreds of statistical model specifications. For alcohol, higher negative affect actually predicted decreased drinking (median OR=0.95, p<.001). High-arousal positive states like joviality predicted increased drinking. These patterns held regardless of substance use disorder severity or social context.","whyItMatters":"A core assumption of addiction theory is that people use substances to cope with negative emotions. This large, methodologically rigorous study finds the opposite for alcohol and no relationship for cannabis — suggesting we may need to fundamentally rethink how we understand substance use motivation.","specificNumbers":"496 participants. Ages 18-22. 55.8% female at birth. 69.6% non-Hispanic White. Hundreds of model specifications tested. Negative affect → less drinking (median OR=0.95, p<.001, 20.6% of specs significant). Cannabis: no consistent affect associations. Effects unchanged by SUD severity or social context.","methodology":"Ecological momentary assessment study of 496 young adults (ages 18-22, diverse recruitment from college and community). Specification curve analyses tested affect-substance use associations across hundreds of models varying affect operationalization, time scales, and moderators.","limitations":"Young adult sample (18-22) may not generalize to older adults or clinical populations. EMA assessments 5x/day may not capture all mood-substance interactions. Self-reported mood and use. Community/college sample, not clinical addiction population."},{"rthcId":"RTHC-08232","title":"Alcohol and cannabis use predicted by affect-urgency interactions in everyday life.","authors":"Dora, Jonas; McCabe, Connor J; Schultz, Megan E; Lee, Christine M; Shoda, Yuichi; Patrick, Megan E; Smith, Gregory T; King, Kevin M","year":2026,"journal":"Clinical psychological science : a journal of the Association for Psychological Science","doi":"10.1177/21677026251404919","pmid":"41537056","tags":["impulsivity","affect-regulation","alcohol","daily-diary"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Positive affect increased alcohol use probability while negative affect decreased it. Cannabis showed minimal associations with daily mood. Contrary to hypotheses, urgency (both trait and state levels) did not moderate affect-substance use associations. Interaction effects were consistently estimated near zero with narrow credible intervals.","whyItMatters":"Urgency — the tendency to act impulsively when emotional — is theorized to be a key risk factor that makes moods more likely to trigger substance use. This rigorous study found no evidence for this mechanism, suggesting simpler models of substance use may be more accurate.","specificNumbers":"496 participants. Ages 18-22. 32 days of 5x daily assessments over 8 weekends. Positive affect increased alcohol probability. Negative affect decreased alcohol probability. Cannabis: minimal mood associations. Urgency moderation: consistently null with narrow credible intervals.","methodology":"Registered report with 496 young adults (ages 18-22) completing ecological momentary assessment 5 times daily across 32 days over 8 weekends. Measured daily affect, cannabis/alcohol use, and trait/state urgency. Pre-registered hypotheses tested using Bayesian models.","limitations":"Young adult weekend data may not represent weekday patterns or older populations. Pre-registered hypotheses focused on urgency specifically. Other personality traits may matter. Non-clinical sample may show different patterns than people with substance use disorders."},{"rthcId":"RTHC-08233","title":"Cannabidiol against Epilepsy: Insights and an Experimental In Silico Approach.","authors":"Dos Santos, Aline Matilde Ferreira; da Silva, Pablo R; Alves, Alan Ferreira; Rodrigues, Teresa Carolliny Moreira Lustoza; Ribeiro, Leandro Rodrigo; Pires, Hugo Fernandes Oliveira; Dias, Arthur Lins; Gomes, Joás de Souza; de Andrade, Jéssica Cabral; Souza, Lívia Roberta Pimenta; Neri, Luiza Cristine Diniz; Capucho, Helaine Carneiro; da Silva Stiebbe Salvadori, Mirian Graciela; Felipe, Cícero F Bezerra; Scotti, Marcus Tullius; Scotti, Luciana; Nayarisseri, Anuraj","year":2026,"journal":"Current pharmaceutical design","doi":"10.2174/0113816128392406251110112113","pmid":"41588977","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This study used computational (in silico) methods to model how CBD might interact with five types of brain receptors implicated in epilepsy: T-type calcium channels (CaV), GABA-A receptors, KCNQ2 potassium channels, voltage-gated sodium channels (NaV), and AMPA receptors.\n\nPharmacodynamic analysis showed CBD has good oral absorption characteristics and the ability to cross the blood-brain barrier, as indicated by its pharmacokinetic parameters. Molecular docking simulations demonstrated binding interactions between CBD and each of the five receptor targets, suggesting a multi-target mechanism of action rather than a single-receptor effect.\n\nThe analysis also flagged potential drug interactions through CBD's effects on cytochrome P450 metabolic enzymes, which could increase the bioavailability of co-administered medications — a finding consistent with the known clinical interaction between CBD and drugs like clobazam in epilepsy treatment.","whyItMatters":"Despite CBD's FDA approval for certain epilepsies (as Epidiolex), the precise mechanisms by which it reduces seizures remain incompletely understood. This computational work maps potential receptor interactions that could explain CBD's broad-spectrum anti-seizure activity and its known drug interactions — providing targets for future experimental validation.","specificNumbers":"5 receptor types modeled: CaV T-type, GABA-A, KCNQ2, NaV, and AMPA. CBD showed binding interactions at all five targets. ADMET analysis indicated good oral absorption and blood-brain barrier penetration. Cytochrome P450 interactions flagged as a source of potential drug-drug interactions.","methodology":"Computational study using ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis and molecular docking simulations. Targets were selected based on their established roles in epilepsy: CaV T-type, GABA-A, KCNQ2, NaV, and AMPA receptors. Compounds identified through HPLC analysis were docked against 5IKQ and 3RP8 enzyme structures.","limitations":"Computational modeling predicts possible interactions but does not confirm they occur in living systems. Molecular docking scores indicate binding potential, not biological activity. In silico ADMET parameters may not match real pharmacokinetics. Results require experimental validation in cell and animal models."},{"rthcId":"RTHC-08234","title":"Cannabidiol as a treatment for cocaine use disorder: a scoping review.","authors":"Dos Santos, Leticia Custódio; da Cunha, Verônica Barros; Ribeiro, Jéssyca Milene; Torres, Larissa Helena Lobo; Garcia, Raphael Caio Tamborelli","year":2026,"journal":"Naunyn-Schmiedeberg's archives of pharmacology","doi":"10.1007/s00210-026-05037-x","pmid":"41632247","tags":["cbd","cocaine","addiction","systematic-review"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Clinical studies did not demonstrate significant efficacy of CBD over placebo in reducing cocaine craving, preventing relapse, or improving cognitive performance. However, CBD was well tolerated and had fewer adverse events than conventional treatments. The gap between preclinical promise and clinical reality highlights methodological challenges.","whyItMatters":"This is a cautionary tale for translating preclinical cannabis research: what works in animal models doesn't always work in humans. Cocaine addiction desperately needs new treatments, and while CBD's safety profile is encouraging, its efficacy remains unproven.","specificNumbers":"CBD was well tolerated across all clinical trials. No significant efficacy over placebo for: cocaine craving, relapse prevention, cognitive performance. Key limitations: variability in dosage, treatment duration, and study design across trials.","methodology":"Scoping review synthesizing clinical trial evidence on CBD for cocaine use disorder. Evaluated effects on craving reduction, relapse prevention, cognitive function, and emotional regulation. Assessed methodological quality and identified research gaps.","limitations":"Scoping review (not systematic with meta-analysis). Small number of clinical trials available. Heterogeneous dosing and study designs make comparison difficult. Short treatment durations may miss delayed effects."},{"rthcId":"RTHC-08235","title":"The Influence of CBD and THC on Hepatic Enzymes of the Human Cytochrome P450 Complex Family: A Systematic Literature Review.","authors":"Dos Santos, Mariana Candeias; da Silva, Anderson Matheus Pereira; da Vitória Santos do Nascimento, Maria; da Silva, Tânia Maria Sarmento; de Souza Franco, Eryvelton; de Sousa Maia, Maria Bernadete","year":2026,"journal":"European journal of drug metabolism and pharmacokinetics, 51(1), 17-28","doi":"10.1007/s13318-025-00978-9","pmid":"41417208","tags":["cbd","thc","drug-interactions","metabolism","safety"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CBD was consistently identified as a potent inhibitor of CYP3A4, CYP2C9, and CYP2C19 — enzymes that metabolize approximately 80% of therapeutic drugs. CYP2C19 could also be induced under certain conditions. CYP2D6 showed minimal or no modulation. THC also showed inhibitory effects but was less consistently studied.","whyItMatters":"With millions of people using CBD products alongside prescription medications, understanding drug interactions is critical for safety. The strong inhibition of CYP3A4 alone is clinically significant — this enzyme metabolizes drugs like blood thinners, statins, and anti-seizure medications.","specificNumbers":"4 studies met inclusion criteria. CBD inhibited: CYP3A4, CYP2C9, CYP2C19. CYP2C19 also inducible in some conditions. CYP2D6: minimal/no effect. CYP450 enzymes metabolize ~80% of therapeutic drugs. Studies covered 2019-2025.","methodology":"Systematic review per PRISMA guidelines searching PubMed, SciELO, ScienceDirect, and Scopus for studies published January 2019 to March 2025. Included in vitro, in vivo, and ex vivo studies evaluating phytocannabinoid effects on hepatic CYP450 isoforms. Four studies met eligibility criteria.","limitations":"Only 4 studies met criteria, reflecting limited but growing research. Mostly in vitro data — clinical significance at typical CBD doses uncertain. THC less studied than CBD. Individual variation in CYP enzyme activity not captured."},{"rthcId":"RTHC-08236","title":"Complementary and alternative medicines and cannabis use among individuals with erythropoietic protoporphyria.","authors":"Draisin, Emma; Rome, Chloe Paige; Hedstrom, Karli; Overbey, Jessica; Balwani, Manisha; Naik, Hetanshi","year":2026,"journal":"Molecular genetics and metabolism, 147(1), 109703","doi":"10.1016/j.ymgme.2025.109703","pmid":"41401659","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08237","title":"Unlocking the potential: Cannabidiol (CBD) as a promising anti-tumor agent.","authors":"Duan, Shuqin; Liu, Mingyu; An, Zhechao; Zhong, Ziyun; Guan, Xin; Liu, Xin; Zhang, Zheng; Yang, Fan","year":2026,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 150, 157737","doi":"10.1016/j.phymed.2025.157737","pmid":"41494497","tags":["cbd","cancer","anti-tumor","review","preclinical"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"CBD exhibits multi-target anti-tumor effects including inhibiting proliferation, inducing apoptosis, suppressing metastasis, and remodeling the tumor microenvironment through immunomodulation. It shows synergistic effects in combination therapy, can alleviate cancer-related symptoms, and has a favorable safety profile. However, evidence is predominantly preclinical.","whyItMatters":"Cancer treatment desperately needs new approaches. CBD's ability to attack tumors through multiple mechanisms while being well-tolerated is encouraging, but the critical caveat is that nearly all evidence is from lab and animal studies — not human trials.","specificNumbers":"Anti-tumor mechanisms: proliferation inhibition, apoptosis induction, metastasis suppression, TME remodeling. Broad-spectrum efficacy across multiple cancer types. Synergistic effects in combination therapy. Favorable safety and tolerability profile. Predominantly preclinical evidence.","methodology":"Systematic review integrating recent high-quality research on CBD's anti-tumor effects across cancer types. Analyzed mechanisms in tumor cell biology and tumor microenvironment, compared monotherapy vs. combination therapy, reviewed symptom management, and assessed nano-based delivery systems.","limitations":"Predominantly preclinical models — in vitro and animal studies. No standardized dosing for anti-cancer use. CBD bioavailability is poor without specialized delivery. Cancer types and models vary widely across studies. Risk of publication bias toward positive results."},{"rthcId":"RTHC-08238","title":"Risk of Heart Failure-related Events in Patients Exposed to Medical Cannabis: A Longitudinal Cohort Study.","authors":"Dubois, Cerina; Eurich, Dean T; Dyck, Jason R B; Hyshka, Elaine; Hanlon, John G; Zongo, Arsene","year":2026,"journal":"American journal of medicine open, 15, 100120","doi":"10.1016/j.ajmo.2025.100120","pmid":"41497552","tags":["heart-failure","cardiovascular","medical-cannabis","safety"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Patients with authorized cannabis prescriptions had a hazard ratio of 1.15 (95% CI: 1.06-1.25) for the primary outcome of ED visits/hospitalization for heart failure. Incidence rates were 5.87 per 1000 person-years in the cannabis group vs. 5.14 in controls. The secondary outcome (including physician claims) showed a similar pattern (HR 1.13, 95% CI: 1.08-1.19).","whyItMatters":"As medical cannabis prescribing expands, understanding cardiovascular risks is essential. This is one of the largest studies linking medical cannabis to heart failure events, suggesting a modest but clinically significant increased risk that patients and prescribers should consider.","specificNumbers":"54,006 cannabis patients, 161,265 controls. 39% aged ≤50, 55% female. HF ED/hospital HR: 1.15 (1.06-1.25). Incidence: cannabis 5.87 vs. control 5.14 per 1000 person-years. Secondary outcome HR: 1.13 (1.08-1.19). Incidence: cannabis 18.99 vs. control 16.69 per 1000 person-years.","methodology":"Retrospective cohort study using Ontario health administrative and clinical data. 54,006 patients with authorized cannabis prescriptions (2014-2019) matched with 161,265 general population controls. Inverse probability of treatment weighting based on propensity scores minimized confounding.","limitations":"Observational — cannot prove causation. Medical cannabis patients likely have more underlying health conditions (confounding by indication). Authorized prescription doesn't confirm actual use or dosage. Ontario-specific results may not generalize. No information on cannabis type or consumption method."},{"rthcId":"RTHC-08239","title":"The cannabinoid receptor 2 is an in vivo receptor of bisphenol A during bone formation.","authors":"Dubuisson, Matthew J; Cox, Carol K; Kaur, Jasleen; Williamson, McLean H; Clements, Wilson K; Logan, Madelyn K; Monroe, Jerry D; Gibert, Yann","year":2026,"journal":"Journal of hazardous materials, 504, 141317","doi":"10.1016/j.jhazmat.2026.141317","pmid":"41638126","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08240","title":"Patterns of Drug and Polydrug Detection in Drivers Suspected of Driving Under the Influence of an Intoxicant in Ireland 2019-2020: A Latent Class Analysis.","authors":"Durand, Louise; O'Kane, Aoife; Maguire, Richard; Cusack, Denis; Keenan, Eamon; Cousins, Gráinne","year":2026,"journal":"Drug and alcohol review, 45(1), e70087","doi":"10.1111/dar.70087","pmid":"41391009","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08241","title":"Age-Dependent Area-, Lamina- and Cell-Type-Specific Distribution of the Cannabinoid Type 1 Receptor in the Mouse Visual Cortex.","authors":"Durieux, Lucas J A; Pereira, Maria João; Villers, Agnès; Gilissen, Sara R J; Arckens, Lutgarde","year":2026,"journal":"The Journal of comparative neurology, 534(2), e70136","doi":"10.1002/cne.70136","pmid":"41661643","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08242","title":"Is Cannabis Dependence Associated with Postoperative Infections in Hand and Wrist Surgeries?","authors":"Dussik, Christopher M; Coombs, Jeffrey; Phan, Amy; Ghattas, Yasmine; Ferraro, Joseph; Ketonis, Constantinos","year":2026,"journal":"Journal of hand surgery global online, 8(3), 100948","doi":"10.1016/j.jhsg.2026.100948","pmid":"41732144","tags":["surgery","infection","cannabis-use-disorder","safety"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Patients with cannabis dependence showed significantly higher odds of superficial wound complications/infections (OR 1.9), postoperative admissions (OR 2.5), ED visits (OR 1.8), sepsis (OR 2.3), and return to OR for deep infections (OR 2.6) after hand and wrist soft-tissue surgery.","whyItMatters":"Hand surgery infections can have devastating consequences for hand function. The finding that cannabis dependence nearly doubles infection risk provides practical information for surgical risk assessment and patient counseling.","specificNumbers":"498,150 total patients. 5,607 with cannabis dependence. Wound complications: OR 1.9 (1.6-2.3). Readmissions: OR 2.5 (1.7-3.6). ED visits: OR 1.8 (1.6-2.0). Sepsis: OR 2.3 (1.5-3.6). Return to OR: OR 2.6 (1.6-4.6).","methodology":"Retrospective cohort study using the TriNetX multi-institutional database. 498,150 patients who underwent hand/wrist soft-tissue surgery; 5,607 with preoperative cannabis dependence (ICD-10 F12) vs. 492,543 without. Propensity score matching controlled for confounders. 90-day postoperative outcomes assessed.","limitations":"Association, not causation. ICD-10 coding may under-identify cannabis use. Cannabis dependence patients may differ in other ways (compliance, comorbidities). Database study lacks clinical detail on cannabis type, amount, or cessation timing. TriNetX may not capture all complications."},{"rthcId":"RTHC-08243","title":"Negative reinforcement of cannabis use: Subjective relief from negative affect following cannabis use and effects on subsequent patterns of use.","authors":"Dyar, Christina; Rhew, Isaac C","year":2026,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors","doi":"10.1037/adb0001127","pmid":"41556905","tags":["coping","negative-reinforcement","daily-diary","cravings"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Using cannabis to cope with negative affect was associated with perceived cannabis-contingent relief. This perceived relief predicted increased likelihood of next-day cannabis use when anxious or depressed affect was elevated. The reinforcement effect was strongest when cannabis-contingent relief was experienced the prior day, demonstrating a self-perpetuating cycle.","whyItMatters":"This is the first study to demonstrate cannabis negative reinforcement in real time — not just that people use cannabis when feeling bad, but that the actual experience of relief drives future use. This reinforcement loop may be a key mechanism in developing cannabis use disorder.","specificNumbers":"571 participants. 77.6% sexual minority/gender diverse. 14 days, 2x daily assessments. Cannabis-contingent relief predicted next-day use when anxious/depressed. More cumulative relief experience predicted more cannabis use during depressed affect. Effect strongest when relief experienced previous day.","methodology":"Ecological momentary assessment with 571 young adult females who regularly used cannabis (oversampled sexual minority women/gender diverse, 77.6%). Two observations per day for 14 days. Measured coping motives, perceived cannabis-contingent relief, and subsequent cannabis use patterns.","limitations":"Predominantly sexual minority women/gender diverse sample limits generalizability. 14-day period may not capture longer-term patterns. Self-reported relief is subjective. Cannot prove perceived relief is from cannabis vs. placebo/passage of time."},{"rthcId":"RTHC-08244","title":"Affect, Motives for Cannabis Use, Duration of Intoxication, and Cannabis Consequences: Cannabis Use Problem Severity as a Potential Moderator.","authors":"Dyar, Christina; Curtis, Julia; Green, Elise; Hales, Emily D S; Rhew, Isaac C; Kaysen, Debra; Lee, Christine M","year":2026,"journal":"Journal of studies on alcohol and drugs","doi":"10.15288/jsad.25-00314","pmid":"41552939","tags":["motives","affect-regulation","cannabis-use-disorder","daily-diary"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Elevated anxious affect was associated with coping motives and longer intoxication, but only among those with more severe cannabis use problems. Positive affect predicted enhancement motives across the full sample, with this association stronger for those with fewer problems. However, positive reinforcement continued in those with more severe problems, contradicting the multistage model that predicts negative reinforcement dominates.","whyItMatters":"The standard addiction model says negative reinforcement (using to escape bad feelings) takes over as addiction worsens. This study shows that's only partly true for cannabis — people with problems do use to cope more when anxious, but they also continue seeking enhancement, suggesting treatment needs to address both motivations.","specificNumbers":"571 participants. 14 days, 2x daily. Anxiety → coping motives + longer intoxication: only in more severe CU problems. Positive affect → enhancement motives: full sample, stronger in fewer problems. Positive reinforcement persists in more severe problems. Many associations not moderated by severity.","methodology":"EMA study with 571 young adult females (77.6% sexual minority/gender diverse) who regularly used cannabis. Two observations per day for 14 days. Tested whether cannabis use problem severity moderated associations between affect, motives, intoxication duration, and consequences.","limitations":"Same sample as 08243 — predominantly sexual minority women/gender diverse. 14-day window. Self-reported motives may not reflect actual processes. Cannabis use problems assessed at baseline only. Can't establish temporal ordering within same-survey reports."},{"rthcId":"RTHC-08245","title":"Assessing the association between cannabis use frequency and heart disease in adults aged under 50: National Survey on Drug Use and Health, 2021-2023.","authors":"Earl, Mason; Bhandari, Ruchi","year":2026,"journal":"Preventive medicine, 202, 108437","doi":"10.1016/j.ypmed.2025.108437","pmid":"41175987","tags":["heart-disease","cardiovascular","dose-response","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Each 90-day increase in annual cannabis use was associated with 9% higher odds of heart disease (aOR 1.09, 95% CI: 1.03-1.15). Daily users had 40% higher odds (aOR 1.40, 95% CI: 1.11-1.76). A clear positive linear dose-response relationship was observed after controlling for demographics, smoking, and heavy drinking.","whyItMatters":"Heart disease in younger adults is rising, and cannabis use is increasing in the same population. This dose-response relationship — more cannabis use equals more heart disease risk — identifies cannabis as a potential modifiable risk factor for early-onset cardiovascular disease.","specificNumbers":"88,166 adults aged 18-49. Each 90 days of cannabis use: +9% heart disease odds (aOR 1.09). Daily users: +40% odds (aOR 1.40). Controlled for demographics, smoking, heavy drinking. Clear linear dose-response relationship.","methodology":"Cross-sectional analysis of 88,166 U.S. adults aged 18-49 from the 2021-2023 National Survey on Drug Use and Health. Cannabis use frequency measured as past-year use days. Weighted logistic regression and dose-response analysis controlling for demographics, smoking, and heavy drinking.","limitations":"Cross-sectional — cannot prove cannabis causes heart disease. Self-reported cannabis use and heart disease diagnosis. Residual confounding despite controlling for smoking and drinking. Cannot distinguish smoking from other consumption methods."},{"rthcId":"RTHC-08246","title":"Prenatal Cannabis and Tobacco: Studies in Animal Models.","authors":"Edenfield, R Clayton; D'Mello, Rahul; Shorey-Kendrick, Lyndsey E; Crosland, B Adam; Hagen, Olivia L; McEvoy, Cindy T; Spindel, Eliot R; Murphy, Susan K; Lo, Jamie O; Marbrey, Margeaux W","year":2026,"journal":"Advances in experimental medicine and biology, 1500, 253-302","doi":"10.1007/978-3-032-12741-9_9","pmid":"41478924","tags":["pregnancy","neuroscience"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This comprehensive review synthesized animal model research on prenatal exposure to both cannabis (primarily THC) and tobacco (primarily nicotine). The evidence showed that each substance independently disrupts critical developmental processes, but through overlapping mechanisms that raise concerns about combined exposure.\n\nPrenatal THC exposure in animal models impaired offspring neurodevelopment, altered metabolic and cardiovascular function, and disrupted reproductive health. These effects were sex-specific — affecting males and females differently — and persisted into adulthood.\n\nPrenatal nicotine exposure was associated with structural and functional deficits in pulmonary, neurological, behavioral, cardiac, and renal systems in offspring.\n\nA key mechanistic finding was that both THC and nicotine exert their developmental effects partly through epigenetic modifications — changes to DNA methylation patterns that alter gene expression without changing the DNA sequence itself. These epigenetic changes may be how short-term prenatal exposure translates into long-term health consequences.","whyItMatters":"Cannabis and tobacco co-use during pregnancy is increasing. Animal models allow researchers to isolate the effects of each substance and examine mechanisms at the molecular level — something that's impossible in human studies with their many confounders. This review highlights that the epigenetic mechanism is shared between THC and nicotine, raising the possibility that co-exposure could have compounding effects on the developing fetus.","specificNumbers":"Review covered THC effects on neurodevelopment, metabolic function, cardiovascular function, and reproductive health. Nicotine effects documented across pulmonary, neurological, behavioral, cardiac, and renal systems. Both substances produced widespread DNA methylation changes affecting gene expression in offspring.","methodology":"Narrative review of animal model studies examining prenatal exposure to cannabis/THC and tobacco/nicotine. Synthesized findings on offspring outcomes across organ systems (brain, lungs, heart, kidneys, reproductive system) and mechanistic pathways (epigenetic modifications, DNA methylation, gene expression changes).","limitations":"Animal models cannot perfectly replicate human pregnancy physiology, metabolism, or exposure patterns. THC and nicotine doses in animal studies may not match typical human use. Most studies examine single-substance exposure, with limited data on co-exposure effects. Epigenetic findings in animals may not directly translate to human epigenetic responses."},{"rthcId":"RTHC-08247","title":"Sexual Risk Behaviors and Current Substance Use Among Sexually Active Adolescents in the United States: Differences by Sex, Race, and Sexual Identity.","authors":"Edet, Precious Patrick; Allen, Hannah K; Al Juboori, Ruaa; Bhuiyan, Azad R; Yockey, Andrew","year":2026,"journal":"Journal of prevention (2022)","doi":"10.1007/s10935-026-00898-7","pmid":"41604127","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08248","title":"Differences in Plasma Exposure of Cannabidiol and Cannabidiolic Acid Following Oral Administration to Horses.","authors":"Ekstrand, Carl; Michanek, Peter; Hernlund, Elin; Gehring, Ronette; Spjut, Kristin; Salomonsson, Matilda","year":2026,"journal":"Journal of veterinary pharmacology and therapeutics, 49(1), 22-32","doi":"10.1111/jvp.70027","pmid":"41017237","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08249","title":"Early-life light exposure and mental health and substance use outcomes in adolescence and young adulthood.","authors":"El Ghoul, Tala; Zhang, Jing; Tran, Dat Thien; Strohmaier, Susanne; Żebrowska, Magdalena; Chavarro, Jorge E; Eliassen, A Heather; Hart, Jaime E; Okereke, Olivia I; Schernhammer, Eva S","year":2026,"journal":"Journal of affective disorders, 401, 121321","doi":"10.1016/j.jad.2026.121321","pmid":"41621442","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08250","title":"Prevalence and correlates of substance use among middle and high school students in Settat Province, Morocco.","authors":"El Moubchiri, Chaimaa; Chahboune, Mohamed; Guennouni, Morad; Hilali, Abderraouf","year":2026,"journal":"Substance abuse treatment, prevention, and policy, 21(1), 1","doi":"10.1186/s13011-025-00685-3","pmid":"41555425","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08251","title":"A comparative study on phytochemical analysis and biological properties of three varieties of cannabis sativa L. seeds.","authors":"El-Mernissi, Rafik; El Menyiy, Naoual; Zouhri, Aziz; El-Mernissi, Yahya; Metouekel, Amira; Siddique, Farhan; Mughram, Mohammed H Al; Temesgen, Denekew; Alanzi, Abdullah R; Khalid, Mohammad; Amhamdi, Hassan; Abboussi, Oualid; Hajji, Lhoussain","year":2026,"journal":"Open life sciences, 21(1), 20251211","doi":"10.1515/biol-2025-1211","pmid":"41726561","tags":["inflammation","pain","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers compared the chemical composition and biological activity of three Moroccan Cannabis sativa seed varieties: Cric, Khard, and Beldiya. HPLC analysis revealed that all three contained polyphenolic compounds including catechin, quercetin, ursolic acid, and rosmarinic acid.\n\nThe Beldiya variety consistently showed the strongest antioxidant activity across multiple assays, with the lowest IC50 values (meaning it required the least amount to achieve an effect). All three varieties contained appreciable levels of phenolics and flavonoids, with total phenolic content ranging from about 77 to 85 mg GAE/g.\n\nIn animal models, the seed extracts demonstrated both anti-inflammatory and analgesic (pain-reducing) effects. Molecular docking simulations targeting the 5IKQ and 3RP8 enzymes — both involved in inflammatory pathways — suggested that the identified polyphenolic compounds could interact with these targets, providing a potential mechanistic explanation for the observed biological activity.","whyItMatters":"Most cannabis research focuses on cannabinoids (THC, CBD), but cannabis seeds contain a different chemical profile dominated by phenolics and flavonoids rather than cannabinoids. This study shows that cannabis seeds have biological activity through non-cannabinoid pathways — expanding understanding of the cannabis plant's potential beyond its most famous compounds.","specificNumbers":"Total phenolic content: 76.87 (Cric), 81.45 (Khard), 84.96 (Beldiya) mg GAE/g. Flavonoid content: 3.32–3.56 mg QE/g. Beldiya DPPH IC50: 0.12 mg/mL, ABTS IC50: 0.71 mg/mL, FRAP IC50: 0.32 mg/mL. Key compounds identified: catechin, quercetin, ursolic acid, rosmarinic acid.","methodology":"Laboratory study combining chemical analysis (HPLC-DAD for compound identification), in vitro antioxidant assays (ABTS, TAC, FRAP, DPPH), in vivo animal models for anti-inflammatory and analgesic effects, and in silico molecular docking against inflammatory pathway enzymes. Three cannabis seed varieties from Morocco were compared.","limitations":"Animal model results may not translate to humans. The study tested hydroalcoholic seed extracts, not isolated compounds, so the specific contribution of each polyphenol is unclear. Moroccan cannabis varieties may have different chemical profiles than varieties grown elsewhere. Molecular docking predicts potential interactions but doesn't confirm biological mechanisms."},{"rthcId":"RTHC-08252","title":"From card to cradle: examining medical cannabis purchasing among pregnant women in Arkansas.","authors":"ElHassan, Nahed O; Farnam, Cain; Thompson, Joseph W; Stanley, Nichole; Hayes, Corey J; Li, Chenghui; Mourani, Peter M; Hudson, Teresa J; Mcgehee, Robert; Martin, Bradley C","year":2026,"journal":"American journal of obstetrics & gynecology MFM, 8(2), 101857","doi":"10.1016/j.ajogmf.2025.101857","pmid":"41317990","tags":["pregnancy","medical-cannabis","thc","dosing"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"1,185 of 72,992 pregnancies (1.62%) included medical cannabis purchases during pregnancy. Mean daily THC purchased was 137.36mg — far above FDA-approved cannabinoid doses. Women who continued pre-pregnancy cannabis use bought 1.82x more daily THC than those who initiated during pregnancy. 65.3% were continuers, 34.7% initiated during pregnancy.","whyItMatters":"This is the first population-level analysis showing exactly how much THC pregnant women are purchasing. The amounts far exceed therapeutic ranges, raising concerns about fetal exposure and highlighting the need for better prenatal counseling about cannabis dosing.","specificNumbers":"72,992 pregnancies. 1,185 (1.62%) with MC purchases during pregnancy. Mean daily THC: 137.36mg (SD 170.04). Continuers: 65.3%, bought 1.82x more THC than initiators. Purchasers more likely: ≥30 years (aOR=1.34), tobacco smokers (aOR=1.64). Less likely: Black (aOR=0.44), married (aOR=0.68), privately insured (aOR=0.69).","methodology":"Descriptive analysis linking three Arkansas databases: Medical Cannabis Card Registry, Dispensary Database, and Birth Certificate Records, plus national Social Determinants of Health Database. Covered pregnancies from May 2019 to August 2022.","limitations":"Purchases don't equal consumption — some product may be stored or shared. Arkansas may not represent other states. No birth outcome data in this analysis. Qualifying conditions for MC may confound comparisons. Can't confirm gestational timing of purchases precisely."},{"rthcId":"RTHC-08253","title":"The Devil is in the Details: Exploring the Impact of Risk Behavior Detail (RBD) in Health Messages Targeting Cannabis-Impaired Driving.","authors":"Eliash-Fizik, Hadar; Lewis, Nehama; Sznitman, Sharon R","year":2026,"journal":"Health communication, 1-13","doi":"10.1080/10410236.2025.2610730","pmid":"41542873","tags":["driving","health-communication","messaging","risk-perception"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Exposure to high-detail messages about cannabis-impaired driving was associated with increased DUIC intentions and behaviors, both immediately and at two-week follow-up. The effect was mediated by increased perceptions that risk-reduction behaviors would be effective (response efficacy) and confidence in performing them (self-efficacy).","whyItMatters":"This is a critical warning for public health communicators: providing too much detail about how to reduce risks of cannabis-impaired driving can backfire by making people feel capable and confident about doing something dangerous. Less detail may be more effective.","specificNumbers":"686 cannabis-using adult drivers. Ages 18-50. High-detail messages increased DUIC intentions vs. low-detail and control. Mediated by response efficacy and self-efficacy. Effects persisted at 2-week follow-up.","methodology":"Online randomized experiment with 686 adult cannabis-using drivers (ages 18-50). Participants viewed messages with high vs. low detail about DUIC risk-reduction behaviors, or a control video. DUIC intentions measured immediately and at 2-week follow-up. Mediation analysis tested mechanisms.","limitations":"Online experiment — intentions don't necessarily translate to behavior. Self-selected cannabis users may differ from general population. Hypothetical scenarios vs. real driving decisions. Two-week follow-up is relatively short."},{"rthcId":"RTHC-08254","title":"Impact of preoperative cannabis use on outcomes following surgical intervention for gastroparesis.","authors":"Eriksson, Sven E; Chaudhry, Naveed; Gardner, Margaret E; Zarrineh, Tara; Zheng, Ping; Ayazi, Shahin","year":2026,"journal":"Surgical endoscopy","doi":"10.1007/s00464-025-12558-8","pmid":"41559335","tags":["surgery","gastroparesis","outcomes","safety"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users had higher baseline symptom burden (nausea 85.2% vs. 59.4%, pain 73.1% vs. 50.2%). Within 90 days of surgery: higher reintervention (9.3% vs. 1.2%), more admissions (32.4% vs. 23.7%), fewer clinic visits (37.0% vs. 54.5%). By 5 years: more hospitalizations (59.3% vs. 41.0%), lower outpatient follow-up (54.6% vs. 76.2%).","whyItMatters":"Cannabis is often used by gastroparesis patients to manage nausea, but this study suggests it may be associated with worse surgical outcomes. The combination of more complications and fewer follow-up visits is particularly concerning for post-surgical recovery.","specificNumbers":"1,572 patients total. 108 (6.9%) with cannabis use. 90-day reintervention: 9.3% vs. 1.2% (p<.001). 90-day admission: 32.4% vs. 23.7%. 5-year admission: 59.3% vs. 41.0%. Follow-up attendance: 54.6% vs. 76.2%. Late reintervention rates similar between groups.","methodology":"Retrospective cohort using TriNetX federated EMR database. 1,572 gastroparesis patients (pyloric drainage or gastric stimulator placement). 108 with documented cannabis use (ICD-10 F12) vs. 1,464 without. Outcomes assessed at 90 days and 5 years post-surgery.","limitations":"Small cannabis user group (108 patients). ICD-10 coding likely underestimates cannabis use. Cannabis users had more baseline symptoms — confounding by severity. Cannot determine if cannabis use worsens outcomes or if worse underlying disease drives both cannabis use and outcomes."},{"rthcId":"RTHC-08255","title":"Clinical Outcomes and Patient Profiles in the UK Medical Cannabis Registry: A k-Means Clustering Analysis.","authors":"Erridge, Simon; Clarke, Evonne; McLachlan, Katy; Coomber, Ross; Beri, Sushil; Khan, Shaheen; Weatherall, Mark W; Platt, Michael W; Rucker, James J; Mediano, Pedro A M; Sodergren, Mikael H","year":2026,"journal":"Journal of clinical pharmacology, 66(1), e70151","doi":"10.1002/jcph.70151","pmid":"41510842","tags":["medical-cannabis","quality-of-life","uk","registry"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"K-means clustering identified 10 trajectory groups, with 8 (representing 77.72% of patients) showing quality of life improvements. Over 70% reported improved EQ-5D-5L at each timepoint. At 24 months, 54.21% achieved clinically significant anxiety improvement and 44.07% significant sleep improvement. Adverse events were reported by 13.65%, mostly mild-moderate. Baseline patient characteristics predicted outcomes better than product type.","whyItMatters":"This is the largest and longest real-world medical cannabis outcomes study in the UK. The finding that patient characteristics matter more than specific products suggests prescribing should focus more on identifying likely responders than on product selection.","specificNumbers":"8,945 patients. 10 trajectory clusters identified. 77.72% (6,952) in improving clusters. >70% improved EQ-5D-5L at each timepoint. 54.21% clinically significant GAD-7 improvement at 24 months. 44.07% significant SQS improvement. 13.65% reported AEs. 42.31% mild, 43.46% moderate.","methodology":"Cohort study of 8,945 patients in the UK Medical Cannabis Registry with any qualifying indication. Patient-reported outcomes (EQ-5D-5L, GAD-7, SQS) collected at baseline, 1, 3, 6, 12, 18, and 24 months. Longitudinal k-means clustering on quality of life trajectories. Logistic regression identified response predictors.","limitations":"Registry study without control group — can't separate treatment effect from natural disease course. Self-selected patients who stayed in the registry may be responders (survivorship bias). No placebo comparison. Self-reported outcomes. UK-specific regulatory context."},{"rthcId":"RTHC-08256","title":"Phytocannabinoids and Male Fertility: Implications of Cannabis sativa and the Endocannabinoid System in Reproductive Regulation.","authors":"Erukainure, Ochuko L; Nambooze, Jennifer; Chukwuma, Chika I","year":2026,"journal":"Plants (Basel, Switzerland), 15(3)","doi":"10.3390/plants15030473","pmid":"41681636","tags":["fertility","male-health","thc","cbd","review"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"THC disrupts the hypothalamic-pituitary-gonadal axis, reducing luteinizing hormone and testosterone levels. Cannabinoids interact with CB1 and CB2 receptors in testes, epididymis, and sperm cells, modulating testosterone synthesis, sperm motility, morphology, and capacitation. THC impairs mitochondrial activity and causes abnormal sperm shape. CBD's reproductive impact is less studied but uncertain long-term.","whyItMatters":"With cannabis use rising among men of reproductive age, understanding fertility impacts is increasingly important. The evidence shows THC affects multiple steps of sperm production and function, potentially contributing to declining sperm counts observed worldwide.","specificNumbers":"THC affects: luteinizing hormone levels (reduced), testosterone levels (reduced), sperm motility (impaired), sperm morphology (abnormal), mitochondrial activity (impaired), capacitation (altered). Receptors involved: CB1 and CB2 in testes, epididymis, and sperm.","methodology":"Narrative review synthesizing experimental and clinical studies on cannabis and male reproductive function. Covers spermatogenesis, sperm function, hormonal regulation, and the endocannabinoid system's role in reproductive homeostasis.","limitations":"Narrative review format. Many studies are preclinical. Dose-response relationships in humans unclear. Most studies examine THC; CBD and other cannabinoids less studied. Difficult to isolate cannabis effects from tobacco co-use and lifestyle factors."},{"rthcId":"RTHC-08257","title":"Population Structure of Genotypes and Genome-Wide Association Studies of Cannabinoids and Terpenes Synthesis in Hemp (Cannabis sativa L.).","authors":"Eržen, Marjeta; Čerenak, Andreja; Cesar, Tjaša; Jakše, Jernej","year":2026,"journal":"Plants (Basel, Switzerland), 15(2)","doi":"10.3390/plants15020202","pmid":"41600009","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08258","title":"Analysis of Marijuana (Cannabis sativa L.) Cuttings: Morphological and Colorimetric Traits as Predictors for Optimization of Vegetative Reproduction.","authors":"Espósito, Laura G A; Rodrigues, Camila; Pereira, Pedro; Teixeira, Heitor Mancini; Silva, Derly","year":2026,"journal":"Plants (Basel, Switzerland), 15(3)","doi":"10.3390/plants15030440","pmid":"41681606","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08259","title":"Genotype-Specific Safety and Pharmacokinetics of Cannabidiol in Healthy Volunteers.","authors":"Etkins, Jumar; So, Gerald C; Lu, Jessica Bo Li; Koyama, Sachiko; Gisch, Debora L; Melo Ferreira, Ricardo; Cheng, Ying-Hua; McClara, Kelsey; Jun, Joshua; Miller, Matthew; Desta, Zeruesenay; Eadon, Michael T","year":2026,"journal":"Clinical and translational science, 19(1), e70455","doi":"10.1111/cts.70455","pmid":"41451876","tags":["cbd","pharmacogenomics","drug-metabolism","safety","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"CYP2C19 metabolizer status significantly affected CBD exposure, with lower CBD levels in intermediate metabolizers (p=0.014 single dose, p=0.003 steady state). Individuals with both CYP3A5 poor metabolism and CYP2C19 intermediate/normal metabolism had increased active metabolite exposure and experienced diarrhea 5.6x more frequently (39% vs. 7%, p=0.046).","whyItMatters":"With millions using CBD products, understanding why some people experience side effects while others don't is crucial. This study shows genetics play a major role — opening the door to pharmacogenomic-guided CBD dosing and better prediction of drug interactions.","specificNumbers":"33 healthy subjects. CBD 5mg/kg single dose then 5mg/kg BID x14 days. Diarrhea: 39% in CYP3A5 poor + CYP2C19 intermediate/normal vs. 7% others (p=.046). CYP2C19 intermediate metabolizers: lower CBD exposure (p=.014 single, p=.003 steady state). External cohort validated CYP2C19 findings.","methodology":"Secondary analysis of open-label, fixed-sequence, single-center study. 33 healthy subjects received single-dose CBD 5mg/kg then titrated to 5mg/kg twice daily for 14 days. CYP3A, CYP2C9, and CYP2C19 genotypes assessed. Pharmacokinetic parameters by noncompartmental analysis. External validation cohort confirmed CYP2C19 findings.","limitations":"Small sample (33 subjects). Healthy volunteers may differ from patients. Single formulation and dosing regimen. Not all CYP genotype combinations well-represented. Open-label design."},{"rthcId":"RTHC-08260","title":"Pharmacoepidemiologic characterization of cannabis use and symptomatology in rheumatology using natural language processing of electronic health record clinic notes.","authors":"Falasinnu, Titilola; Le, Nathan; Wang, Yiyu; Alagappan, Aishwarya; Walker, Andrew; Park, Tricia; Leung, Jerik; Chaichian, Yashaar; Weisman, Michael; Kenney, Martha; Irani, Anushka; Bozkurt, Selen","year":2026,"journal":"The journal of pain, 39, 105633","doi":"10.1016/j.jpain.2025.105633","pmid":"41354127","tags":["rheumatology","pain","medical-cannabis","health-disparities"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use documentation rose from 0.1% to 1.1% (900% increase) over 2004-2024. 24.5% of patients had at least one note of current use. Pain was the leading motive (37.9%), higher among Black (54.5%) and Hispanic (43.2%) patients. Cannabis users had higher comorbidity, more ER visits (2.1 vs. 1.3/year), more hospitalizations (1.4 vs. 0.9), and more opioid prescriptions (65% vs. 32.7%).","whyItMatters":"Autoimmune patients often use cannabis for pain that persists despite controlled inflammation. The significant racial disparities — with Black and Hispanic patients more likely to use for pain — suggest unequal access to other pain management options.","specificNumbers":"5,051 patients, 2.6 million notes. 24.5% with current use documented. 900% increase 2004-2024. Black patients: 36.2% use rate, 54.5% for pain. Hispanic: 30.1%, 43.2% for pain. White: 26.5%. Cannabis users: 2.1 ER visits/year vs. 1.3. Opioid scripts: 65% vs. 32.7%.","methodology":"NLP applied to 2.6 million EHR notes from 5,051 adults with autoimmune rheumatic diseases at a tertiary center (2004-2024). Classifiers achieved F1=0.85 for use status and F1=0.83 for reasons. Analyzed use patterns, reasons, sociodemographic disparities, and healthcare utilization.","limitations":"Single tertiary center. NLP may miss undocumented use. Association between cannabis use and higher healthcare utilization may reflect sicker patients, not cannabis effects. Documentation ≠ actual use rates. Cannabis users may be more willing to discuss use at this center."},{"rthcId":"RTHC-08261","title":"Oral Health Disparities among Illicit Drug Users in the US: Secondary Analysis using Data from NHANES 2017-2018.","authors":"Farsi, Nada; Ashi, Heba; Alwafi, Abdulraheem; Abuljadayel, Layla; Samman, Meyassara; Bamashmous, Mohamed; Meisha, Dalia; Sabbahi, Dania","year":2026,"journal":"Oral health & preventive dentistry, 24, 19-26","doi":"10.3290/j.ohpd.c_2420","pmid":"41569043","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08262","title":"GPR3 in neuro-metabolic-immune-reproductive nexus - a potential therapeutic target for Multi-System diseases.","authors":"Feng, Bi-Dan; Qin, Ji-Yao; Qin, Qian-Qiong; Xu, Zui-Cai; Zhang, Hai-Qing","year":2026,"journal":"Annals of medicine, 58(1), 2619216","doi":"10.1080/07853890.2026.2619216","pmid":"41574602","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08263","title":"Ageing, Neurodegeneration and the Endocannabinoid System.","authors":"Fernández-Ruiz, Javier; Sagredo, Onintza; Gómez-Ruiz, María; de Lago, Eva","year":2026,"journal":"Current topics in behavioral neurosciences, 76, 209-248","doi":"10.1007/7854_2025_597","pmid":"40707697","tags":["aging","neurodegeneration","endocannabinoid-system","neuroprotection","review"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Normal aging shows CB1 receptor downregulation and increased endocannabinoid-degrading enzymes, contributing to cognitive and motor decline. In neurodegenerative diseases, these changes become extreme. However, elevated endocannabinoid levels (from reduced FAAH/MAGL) and CB2 receptor upregulation may represent protective compensatory responses. Pharmacological targeting of specific ECS components shows neuroprotective potential.","whyItMatters":"As global lifespans increase, neurodegenerative diseases are expanding. Understanding how the brain's endocannabinoid system changes with age could lead to interventions that slow cognitive decline and protect against diseases like Alzheimer's and Parkinson's.","specificNumbers":"Changes documented across: CB1 receptor downregulation, FAAH/MAGL expression changes, CB2 receptor upregulation (compensatory), endocannabinoid level alterations. Disorders covered: Alzheimer's, Parkinson's, Huntington's, ALS, and general age-related cognitive decline.","methodology":"Comprehensive narrative review synthesizing 30-40 years of research on the endocannabinoid system across the lifespan, from neurodevelopment through senescence. Covers normal aging changes and their extreme presentation in neurodegenerative disorders, with discussion of therapeutic implications.","limitations":"Narrative review spans decades of research with varying methodologies. Animal models may not perfectly reflect human aging. Translation from basic science to clinical therapy remains challenging. Individual variation in aging and ECS function is large."},{"rthcId":"RTHC-08264","title":"What is a \"Cannabis User\"?","authors":"Fisher, Ruth","year":2026,"journal":"Clinical therapeutics, 48(1), 22-28","doi":"10.1016/j.clinthera.2025.11.003","pmid":"41350150","tags":["research-methods","standardization","epidemiology","commentary"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Current research methods lack consistency in defining cannabis use variables (e.g., 'occasional' and 'heavy' use vary from monthly to daily). Methods fail to capture form (flower, concentrate, edibles), dose, and cannabinoid content. Self-report biases, inadequate health codes, and inaccurate biological tests all contribute to poor user identification.","whyItMatters":"If we can't consistently define who a 'cannabis user' is, we can't accurately assess risks, benefits, or outcomes. This undermines every study — from safety to therapeutic potential — and makes it nearly impossible to compare findings across research teams.","specificNumbers":"Key inconsistencies: 'heavy use' defined as monthly to daily across studies. Missing variables: form, dose, THC/CBD content, lifetime use patterns. Methods failing: self-report (biased), ICD codes (no general use code), biological tests (inaccurate windows).","methodology":"Commentary reviewing correlational studies on cannabis outcomes to assess methods for identifying and characterizing users. Compared survey tools, self-report measures, health records, and biochemical assays. Reviewed existing frameworks for cannabis use characterization.","limitations":"Commentary, not empirical study. Doesn't provide a fully developed standardized framework (calls for one). Some inconsistency may be inherent to the complexity of cannabis use patterns."},{"rthcId":"RTHC-08265","title":"Effects of Legalizing Recreational Cannabis Sales on Cannabis Use and Cannabis-Related Disorder Among Presentations to a Psychiatric Emergency Service.","authors":"Foo, Cheryl Y S; Potter, Kevin; Wright, Abigail C; Evins, A Eden; Donovan, Abigail L; Levy, Sharon; Mueser, Kim T; Cather, Corinne","year":2026,"journal":"American journal of preventive medicine, 70(1), 108142","doi":"10.1016/j.amepre.2025.108142","pmid":"41072829","tags":["legalization","psychiatric","youth","emergency"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"THC positivity increased from 32.4% to 36.3% overall (p<.001). Adolescents (12-17) had the largest increase: from 5% to 17.3% (AOR=4.32). Only adolescents showed a significant increase in cannabis use disorders: from 3.2% to 12.1% (AOR=4.63). Adults aged 26-49 showed a modest THC positivity increase (AOR=1.24).","whyItMatters":"Psychiatric patients are among the most vulnerable to cannabis harms, and adolescents with psychiatric conditions are especially at risk. This study provides direct evidence that cannabis commercialization disproportionately affects the youngest, most vulnerable psychiatric patients.","specificNumbers":"7,350 presentations. Overall THC+: 32.4% → 36.3%. Adolescents: THC+ 5% → 17.3% (AOR=4.32). Adolescent CUD: 3.2% → 12.1% (AOR=4.63). Adults 26-49: THC+ 37.7% → 42.5% (AOR=1.24). Adults 18-25 and 50-70: no significant changes.","methodology":"Cross-sectional analysis of 7,350 unique presentations to a psychiatric emergency service at a tertiary hospital in Massachusetts. Compared pre-commercialization (Jan 2017-Nov 2018) to post-commercialization (Nov 2018-Dec 2019) periods. Logistic regressions controlled for sex, race, and ethnicity across age groups.","limitations":"Single hospital, single state. Pre/post comparison without control group. Short post-commercialization period (13 months). THC positivity doesn't indicate cannabis caused the ER visit. Psychiatric ER patients are a specific, high-risk population."},{"rthcId":"RTHC-08266","title":"Effect of Nonmedical Cannabis Legalization and Exposure to Retail Stores on Cannabis Harms : A Quasi-experimental Study.","authors":"Friesen, Erik Loewen; Pugliese, Michael; MacDonald-Spracklin, Rachael; Manuel, Doug; Wilson, Kumanan; Hobin, Erin; Pinto, Andrew D; Myran, Daniel T","year":2026,"journal":"Annals of internal medicine, 179(1), 12-22","doi":"10.7326/ANNALS-25-01960","pmid":"41285008","tags":["legalization","retail","emergency","public-health","canada"],"studyType":"quasi-experimental","evidenceStrength":"strong","keyFinding":"Neighborhoods exposed to cannabis stores (within 1000m) had a monthly increase of 1.30 cannabis-attributable ED visits per 100,000 persons (95% CI: 0.51-2.09, p<.001) compared to matched unexposed neighborhoods. This represented a 12% relative increase (CI: 6%-19%) in monthly visit rates. Cannabis ED visits were already increasing before stores opened, but store proximity accelerated the trend.","whyItMatters":"This is among the strongest evidence that cannabis retail density directly affects health harms. It suggests policymakers can reduce cannabis-related ER visits by limiting store density or prohibiting stores in certain areas — a practical, implementable public health tool.","specificNumbers":"6.14 million people. 10,574 neighborhoods. 2017-2022 study period. +1.30 ED visits/100,000/month in exposed neighborhoods (p<.001). 12% relative increase (95% CI: 6%-19%). Exposure defined as store within 1000m.","methodology":"Population-based natural experiment in Ontario, Canada (2017-2022). 10,574 neighborhoods containing 6.14 million persons aged 15-105. Tracked all cannabis store openings. Compared cannabis-attributable ED visit rates in newly exposed neighborhoods (store within 1km) vs. matched unexposed neighborhoods using difference-in-differences design.","limitations":"Observational natural experiment — unmeasured confounding between exposed and unexposed neighborhoods possible. Cannabis ED visits were already trending up. Cannot determine individual-level store use. Ontario-specific regulatory context."},{"rthcId":"RTHC-08267","title":"Prenatal Cannabis Exposure Shaping Altered Brain Connectivity: Neural Correlates of Cognitive and Mental Health Variability in Offspring.","authors":"Fu, Zening; Hutchison, Kent; Guha, Anika; Sui, Jing; Calhoun, Vince","year":2026,"journal":"Research square","doi":"10.21203/rs.3.rs-8545326/v1","pmid":"41646319","tags":["pregnancy","cognition","mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Drawing on the massive Adolescent Brain Cognitive Development (ABCD) Study — which enrolled 11,875 children across 22 research sites — this analysis examined how prenatal cannabis exposure (PCE) relates to brain network organization, cognitive performance, and mental health in children.\n\nUsing resting-state functional MRI and the NeuroMark framework to identify individualized brain connectivity networks, researchers found that children with PCE showed altered patterns of intrinsic connectivity compared to unexposed children. These connectivity differences were associated with both cognitive performance measures and psychopathology symptoms.\n\nThe study distinguished between exposure that occurred before versus after the mother became aware of the pregnancy, finding that both timing windows were associated with adverse outcomes. This is important because many pregnancies involve cannabis use in the early weeks before the pregnancy is recognized.\n\nThe altered connectivity patterns involved multiple brain networks rather than a single region, suggesting prenatal cannabis exposure affects the large-scale organization of functional brain networks.","whyItMatters":"This is one of the largest neuroimaging studies of prenatal cannabis exposure in humans. The ABCD Study's scale (nearly 12,000 children) and standardized imaging protocol provide statistical power that smaller studies lack. The finding that exposure even before pregnancy awareness was associated with differences suggests that the earliest weeks of brain development may be particularly sensitive.","specificNumbers":"11,875 children across 22 research sites. Resting-state fMRI analyzed using NeuroMark framework for individualized connectivity networks. Both pre-awareness and post-awareness prenatal exposure associated with cognitive and mental health differences.","methodology":"Cross-sectional analysis of baseline data from the ABCD Study (11,875 children, 22 sites). Resting-state functional MRI data analyzed using the NeuroMark framework to identify individualized intrinsic connectivity networks. Prenatal cannabis exposure assessed through maternal report. Outcomes included standardized cognitive assessments and mental health symptom measures.","limitations":"Cross-sectional design cannot establish that prenatal cannabis exposure caused the observed brain connectivity differences. Prenatal exposure was assessed by maternal retrospective report, which may underestimate actual use. Cannot control for all confounders — mothers who used cannabis during pregnancy may differ from non-users in other ways that affect child development. The ABCD Study children are still developing, so long-term trajectories remain unknown."},{"rthcId":"RTHC-08268","title":"Alteration of brain endocannabinoids on restraint stress-induced anxiety-like behaviors in mice.","authors":"Fukumori, Ryo; Ueo, Kanan; Nakashima, Ryosuke; Yamaguchi, Taku","year":2026,"journal":"Physiology & behavior, 305, 115201","doi":"10.1016/j.physbeh.2025.115201","pmid":"41390044","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08269","title":"Impact of preoperative cannabis use on short and mid-term postoperative outcomes following total hip and knee arthroplasty.","authors":"Fuller, Zachary; Lingam, Shriyaus; Chopra, Avani; Thomas, Jeremiah; Urias, Jorden; Abdo, Zuhdi E","year":2026,"journal":"Journal of orthopaedics, 73, 50-54","doi":"10.1016/j.jor.2025.12.006","pmid":"41487684","tags":["surgery","joint-replacement","opioids","outcomes"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis users had significantly higher 90-day ED visits (THA: 16.1% vs. 12.6%, p=.006; TKA: 13.1% vs. 9.9%, p=.008) and opioid use (THA: 91.8% vs. 86.4%, p<.001; TKA: 92.8% vs. 88.6%, p<.001). At 2 years, THA patients had higher aseptic loosening (1.9% vs. 0.9%, p=.030). Major complications and revision rates were similar.","whyItMatters":"Joint replacement is one of the most common surgeries, and cannabis use is increasing. The finding that cannabis users need more opioids — not less — contradicts the hypothesis that cannabis could replace opioids for post-surgical pain. The hip implant loosening finding also warrants attention.","specificNumbers":"THA: 1,504 per group. TKA: 1,354 per group. 90-day ED visits THA: 16.1% vs. 12.6%. Opioid use THA: 91.8% vs. 86.4%. TKA opioid: 92.8% vs. 88.6%. 2-year aseptic loosening THA: 1.9% vs. 0.9% (p=.030). TKA loosening, infection, revision: NS.","methodology":"Retrospective cohort using national database. Cannabis users 1:1 propensity-matched to non-users: 1,504 THA and 1,354 TKA patients per group. Outcomes: 90-day ED visits, hospitalizations, opioid use, and 2-year orthopaedic complications.","limitations":"ICD-10 coding likely underestimates cannabis use. Propensity matching can't capture all confounders. Cannabis users may have different pain thresholds or reporting behaviors. Small absolute differences in some outcomes."},{"rthcId":"RTHC-08270","title":"Human diagnostic markers for intake of semi-synthetic cannabinoids (9R)- and (9S)-hexahydrocannabinol.","authors":"Gameli, Prince S; Taoussi, Omayema; Trana, Annagiulia Di; Tronconi, Livio P; Pichini, Simona; Carlier, Jeremy; Huestis, Marilyn A; Busardò, Francesco P","year":2026,"journal":"Clinica chimica acta; international journal of clinical chemistry, 578, 120480","doi":"10.1016/j.cca.2025.120480","pmid":"40659175","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08271","title":"Cannabidiol improves cognitive impairment after traumatic brain injury by attenuating neuronal oxidative stress and apoptosis via the SET/PP2A/Akt signaling axis.","authors":"Gao, Shan; Xiao, Zhennan; Liu, Hongtao","year":2026,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 150, 157769","doi":"10.1016/j.phymed.2026.157769","pmid":"41512358","tags":["cbd","traumatic-brain-injury","cognition","neuroprotection","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD inhibited neuronal oxidative stress and apoptosis both in vivo and in vitro. CBD directly bound to the SET protein, inducing conformational changes that kept it in the cytoplasm, which suppressed PP2A activity and activated the Akt survival pathway. This novel SET/PP2A/Akt mechanism provides a new drug target for TBI-related cognitive impairment.","whyItMatters":"Traumatic brain injury is a leading cause of cognitive disability with no effective treatments for the cognitive aftermath. Discovering that CBD works through a previously unknown mechanism (SET/PP2A/Akt) opens an entirely new therapeutic target.","specificNumbers":"CBD reduced oxidative stress and apoptosis in vitro and in vivo. Novel mechanism: CBD → binds SET protein → conformational change → cytoplasmic retention → PP2A suppression → Akt activation → neuroprotection. Multiple validation methods: CETSA, SPR, molecular dynamics confirmed direct binding.","methodology":"Preclinical study using both in vitro H2O2 neuronal oxidative stress model and in vivo controlled cortical impact TBI model. Comprehensive mechanistic investigation using Western blot, histology, biochemistry, RNA-Seq, co-immunoprecipitation, molecular dynamics, CETSA, SPR, and immunofluorescence.","limitations":"Mouse model of TBI doesn't perfectly replicate human injury. CBD dose optimization for human TBI unknown. Single mechanism studied — TBI involves multiple pathological processes. Long-term outcomes not assessed."},{"rthcId":"RTHC-08272","title":"Management of cannabinoid hyperemesis syndrome with an erector spinae plane block in the emergency department.","authors":"Gawel, Richard J; Ho, Emily; Gottlieb, Michael; Kramer, Jeffrey A; Shalaby, Michael","year":2026,"journal":"The American journal of emergency medicine, 100, 93-95","doi":"10.1016/j.ajem.2025.11.023","pmid":"41313935","tags":["cannabinoid-hyperemesis-syndrome","treatment","emergency","case-report"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"A patient with CHS unresponsive to conventional analgesics and antiemetics received a thoracic erector spinae plane block (ESPB) in the emergency department. Following the block, complete symptom relief was achieved, and the patient was discharged from the ED without hospital admission.","whyItMatters":"CHS is notoriously difficult to treat in the ER, often requiring prolonged stays or admission. A nerve block that provides immediate, complete relief could transform ER management of this increasingly common condition.","specificNumbers":"1 patient with refractory CHS. Complete symptom relief after thoracic ESPB. Discharged from ED (avoided admission). Proposed mechanism: blockade of sympathetic visceral nociceptive and emetic signaling.","methodology":"Single case report from an emergency department. Patient with chronic cannabis use presenting with refractory nausea, vomiting, and abdominal pain (CHS) was treated with a thoracic ESPB after standard treatments failed.","limitations":"Single case report — may not be reproducible. Placebo effect cannot be excluded. The specific mechanism of ESPB in CHS is theoretical. No long-term follow-up reported. Not all EDs have staff trained in this procedure."},{"rthcId":"RTHC-08273","title":"Effects of Chronic Cannabis Smoke Exposure on Inflammatory Markers in Periphery and Brain in Young and Aged Mice.","authors":"Gazarov, Emely A; McCracken, Bailey; Krumm, Zachary A; Zequeira, Sabrina; Setlow, Barry; Bizon, Jennifer L","year":2026,"journal":"bioRxiv : the preprint server for biology","doi":"10.64898/2026.02.06.703827","pmid":"41726942","tags":["aging","inflammation","brain","preclinical","smoking"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Aging caused significant increases in hippocampal cytokines. Cannabis smoke interacted with age in the hippocampus: exposure tended to increase cytokine levels in young mice but decrease them in aged mice, including attenuating age-related increases in IL-13 and Dkk1. Effects were largely restricted to the hippocampus, with minimal impact in prefrontal cortex or blood.","whyItMatters":"This is one of the first studies to show cannabis smoke has fundamentally different effects on brain inflammation depending on age. If confirmed, it could explain why cannabis appears to help some older adults while potentially harming younger users — a critical distinction for clinical guidance.","specificNumbers":"Young mice: 4 months. Aged mice: 22 months. 30 days daily smoke exposure. Cannabis: 5.5-6.2% THC. Hippocampus: age-dependent cannabis effects on multiple cytokines. PFC and serum: minimal cannabis effects. IL-13 and Dkk1: age-related increases attenuated by cannabis in aged mice.","methodology":"Young (4 months) and aged (22 months) C57Bl/6J mice exposed to cannabis (5.5-6.2% THC) or placebo smoke daily for 30 days. Blood, prefrontal cortex, and hippocampus analyzed for multiple inflammatory markers. Both individual cytokine comparisons and global profiles assessed.","limitations":"Mouse model — effects may not translate to humans. Cannabis smoke includes non-cannabinoid compounds. 30-day exposure only. Specific THC dose delivered via smoke is variable. C57BL/6 strain may not represent all genetic backgrounds. Preprint (not yet peer-reviewed)."},{"rthcId":"RTHC-08274","title":"Rapid screening of commercial CBD oils by heat-assisted dielectric barrier discharge ionization (HA-DBDI) mass spectrometry and correlation-based fingerprinting.","authors":"Gazeli, Odhisea; Christodoulou, Marios C; Argirusis, Nikolaos; Georghiou, George E; Elia, Efstathios A; Agapiou, Agapios","year":2026,"journal":"The Analyst","doi":"10.1039/d5an01179e","pmid":"41677372","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08275","title":"A Longitudinal Assessment of Endometriosis Patients Prescribed Cannabis-Based Medicinal Products: A Case Series From the UK Medical Cannabis Registry.","authors":"Getter, Sara; Erridge, Simon; Warner-Levy, John; Clarke, Evonne; McLachlan, Katy; Coomber, Ross; Barnes, Shelley; Darweish Medniuk, Alia; Guru, Rahul; Holden, Wendy; Sajad, Mohammed; Searle, Robert; Usmani, Azfer; Varma, Sanjay; Rucker, James J; Platt, Michael; Sodergren, Mikael H","year":2026,"journal":"The Australian & New Zealand journal of obstetrics & gynaecology, 66(1), e70078","doi":"10.1111/ajo.70078","pmid":"41305963","tags":["endometriosis","pain","medical-cannabis","quality-of-life","uk"],"studyType":"cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis-based medicinal products were associated with significant improvements in all pain-specific measures from baseline to 18 months (p<.050). Quality of life (EQ-5D-5L) improved at all timepoints (p<.050). Anxiety and sleep quality also improved (p<.050). Clinically significant improvements: 11-37% minimal, 5-22% moderate, 0-11% substantial. Adverse events in 25.4% (16 patients), 62 events total.","whyItMatters":"Endometriosis affects 1 in 10 women and causes chronic pain that is often inadequately treated. This provides the first longitudinal evidence that medical cannabis may improve multiple dimensions of endometriosis burden — pain, quality of life, anxiety, and sleep.","specificNumbers":"63 patients. 18-month follow-up. All pain PrOMs improved (p<.050). EQ-5D-5L improved at all timepoints. GAD-7 and SQS improved. BPI/VAS: 11-37% minimally significant, 5-22% moderate, 0-11% substantial improvements. 62 AEs in 16 patients (25.4%).","methodology":"Case series from the UK Medical Cannabis Registry. 63 patients with endometriosis-associated chronic pain prescribed CBMPs. Patient-reported outcomes (BPI, VAS, EQ-5D-5L, GAD-7, SQS) collected at baseline, 1, 3, 6, 12, and 18 months. Repeated measures ANOVA assessed changes.","limitations":"No control group — improvements could be natural fluctuation or placebo. Small sample. Self-selected patients in a registry (survivorship bias). UK-specific regulatory context. Cannot determine which specific CBMP formulations are most effective."},{"rthcId":"RTHC-08276","title":"Building the Mountain Mama and Baby Cohort: Study Design, Protocol, and Early Prenatal Clinic-based Recruitment Outcomes.","authors":"Gibbs, Bethany Barone; Chmelik, Kathryn; Marshall, Elly M; Henggeler, Waylon K; Olfert, I Mark; Rowan, Shon; Lilly, Christa; Hodder, Sally L; Umer, Amna","year":2026,"journal":"American journal of epidemiology","doi":"10.1093/aje/kwag030","pmid":"41662840","tags":["pregnancy","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"The Mountain Mama & Baby Study established a prospective cohort of pregnant women in West Virginia, enrolling participants during their first-trimester telehealth visits with nurse navigators. Of 920 eligible women, 417 (45.3%) enrolled — more than double the 20% benchmark the researchers set.\n\nThe enrolled participants closely matched non-enrolled women across most sociodemographic characteristics including age, race/ethnicity, and marital status, suggesting the sample is representative of the broader obstetric population in the region.\n\nThe study's design addresses key limitations of prior prenatal exposure research: it captures exposure data prospectively in the first trimester (rather than relying on retrospective recall), collects biospecimens for objective exposure verification, and follows participants through delivery to link exposure to specific maternal-infant outcomes. The cohort will establish first and third trimester exposure rates for both e-cigarettes and cannabis in a population with high rates of substance use.","whyItMatters":"Most research on prenatal cannabis exposure relies on retrospective self-report or birth registry data, both of which underestimate actual use. This prospective design — capturing exposure early in the first trimester before many women even know they're pregnant in other studies — could produce more accurate prevalence estimates and stronger links to outcomes. West Virginia's high substance use rates make it a particularly important population to study.","specificNumbers":"920 eligible women, 417 enrolled (45.3%, 95% CI: 42.1–48.6%). Benchmark enrollment rate was 20%. Enrolled and non-enrolled women were similar across most sociodemographic characteristics.","methodology":"Prospective cohort study enrolling pregnant women during first-trimester telehealth visits at West Virginia University Medicine obstetric clinics. Recruitment via nurse navigators. Self-reported substance use data collected at enrollment with planned follow-up through delivery. Feasibility assessed by enrollment rate and representativeness compared to non-enrolled eligible patients.","limitations":"Single-center study in West Virginia, which may not generalize to other populations. The 45.3% enrollment rate, while exceeding benchmarks, means over half of eligible women did not participate. Self-reported substance use at enrollment may still underestimate actual use despite the prospective design. Outcomes data are not yet reported — this paper describes the study design and recruitment feasibility only."},{"rthcId":"RTHC-08277","title":"Tobacco and cannabis co-use by route of administration in the United States, 2022/2023.","authors":"Gibson, Laurel P; Parks, Michael J; Kimmel, Heather L; Blanco, Carlos; Ciccolo, Joseph T; Creamer, MeLisa R; Everard, Colm; Freedman, Neal D; Garcia, Melissa; Kingsbury, John H; Lee, Youn Ok; Marshall, Daniela; Compton, Wilson M; Kaufman, Annette","year":2026,"journal":"Addictive behaviors, 175, 108595","doi":"10.1016/j.addbeh.2026.108595","pmid":"41518991","tags":["co-use","tobacco","routes-of-administration","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"8.2% of U.S. youth and adults reported current (past 30-day) co-use. Combustible tobacco + combustible cannabis was the most common form, accounting for nearly one-third of co-users. Among ages 12-24, co-use involving nicotine vaping was most common. Among 25+, combustible-combustible dominated. Use of multiple administration routes was also common.","whyItMatters":"Co-use of tobacco and cannabis compounds health risks (as shown by RTHC-08179), and understanding how people combine these substances is essential for prevention. The age-based differences in administration routes suggest different intervention approaches are needed for different generations.","specificNumbers":"39,947 participants. 8.2% current co-users. Combustible-combustible: ~1/3 of co-users (most common overall). Ages 25-39 and 40+: combustible methods dominate. Ages 12-24: nicotine vaping most common in co-use. Multiple routes common among co-users.","methodology":"Analysis of Wave 7 (2022/2023) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study (N=39,947). Weighted to produce representative estimates. Examined specific routes of administration for both tobacco and cannabis among co-users by age group.","limitations":"Self-reported use. Past 30-day window doesn't capture same-session co-use. Rapidly evolving product landscape may make these estimates outdated quickly. Route categories may not capture all product types (e.g., cigarillos/blunts bridge tobacco-cannabis categories)."},{"rthcId":"RTHC-08278","title":"Daily Use of a Broad-Spectrum Cannabidiol Supplement Produces Detectable Concentrations of Cannabinoids in Urine Prohibited by the World Anti-Doping Agency: An Effect Amplified by Exercise.","authors":"Gillham, Scott H; Cole, Paige L; Owens, Daniel J; Chester, Neil; Bampouras, Theodoros M; McCartney, Danielle; Gordon, Rebecca; McGregor, Iain S; Close, Graeme L","year":2026,"journal":"Medicine and science in sports and exercise, 58(1), 121-131","doi":"10.1249/MSS.0000000000003842","pmid":"40920736","tags":["cbd","drug-testing","athletes","exercise","pharmacokinetics"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Daily use of a broad-spectrum CBD product (150 mg/day) led to detectable urinary concentrations of CBG in 42% and CBDV in 68% of pre-exercise samples, rising to 74% and 84% post-exercise, despite no THC detection at any timepoint.","whyItMatters":"Athletes using legal broad-spectrum CBD products may unknowingly test positive for prohibited cannabinoids under WADA rules, and exercise amplifies this risk — a critical finding for competitive sport.","specificNumbers":"150 mg/day CBD for 10 weeks; n=36; CBG detected in 42→74% of samples pre-to-post exercise; CBDV in 68→84%; significant post-exercise increases for CBD (p=0.043), CBG (p=0.0023), CBDV (p=0.033); zero THC detection","methodology":"Randomized, placebo-controlled trial with 36 healthy individuals (31 CBD, 5 placebo) self-administering broad-spectrum CBD or placebo for 10 weeks, followed by a 90-minute moderate-intensity exercise bout with blood and urine sampling.","limitations":"Small placebo group (n=5); single CBD product tested; exercise protocol was moderate intensity only; did not assess high-intensity or repeated exercise effects; short-term study without washout period assessment."},{"rthcId":"RTHC-08279","title":"The ongoing legacy of Indigenous family separation: Long-term outcomes of child welfare involvement among American Indian and First Nations youth.","authors":"Gillson, Stefanie; Hautala, Dane; Steinberg, Rachel; Walls, Melissa","year":2026,"journal":"Child abuse & neglect, 173, 107884","doi":"10.1016/j.chiabu.2026.107884","pmid":"41529334","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08280","title":"Characteristics of trauma patients involved in motor vehicle collisions before and after legalization of medical marijuana in Pennsylvania.","authors":"Gimbel, Kirsten; Marco, Catherine A","year":2026,"journal":"The American journal of emergency medicine, 99, 296-300","doi":"10.1016/j.ajem.2025.10.008","pmid":"41124819","tags":["driving","legalization","motor-vehicle-accidents","public-health","epidemiology"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Following medical marijuana legalization, marijuana positivity among MVC trauma patients increased significantly (p<0.0001), with marijuana-positive patients having longer hospital stays (+2 days) and higher rates of polysubstance use compared to marijuana-negative patients.","whyItMatters":"This large-scale real-world data from a single trauma center provides evidence that medical marijuana legalization correlates with increased marijuana-positive driving, informing road safety policy discussions.","specificNumbers":"10,517 trauma patients; pre vs. post-legalization comparison over 16 years; marijuana-positive patients had +2 days longer hospital stays; significant increase in marijuana detection post-legalization (p<0.0001); higher polysubstance use (p<0.001)","methodology":"Retrospective case-control study of 10,517 trauma patients from MVCs at a Pennsylvania trauma center from 2008-2024, comparing pre-legalization (2008-2016) and post-legalization (2016-2024) groups using Chi-square tests.","limitations":"Single trauma center limits generalizability; correlation not causation; toxicology testing may have changed over the study period; positive test doesn't confirm impairment at time of crash; medical marijuana law may coincide with other policy changes."},{"rthcId":"RTHC-08281","title":"Impact of Oral Cannabinoids on the Endocannabinoidome and Gut Microbiome in People with HIV on Antiretroviral Therapy (CTN PT028 Pilot Clinical Trial).","authors":"Giorgini, Giada; Silvestri, Cristoforo; Mboumba Bouassa, Ralph-Sydney; Muller, Chante; Frias Boligan, Kayluz; Kalkan, Hilal; Routy, Jean-Pierre; Flamand, Nicolas; Di Marzo, Vincenzo; Jenabian, Mohammad-Ali; Costiniuk, Cecilia T","year":2026,"journal":"Cannabis and cannabinoid research, 25785125251366052","doi":"10.1177/25785125251366052","pmid":"40879543","tags":["cbd","thc","hiv","endocannabinoid-system","gut-microbiome","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"Cannabinoid capsule administration significantly decreased plasma levels of two monoacylglycerols (2-EPG and 2-OG), part of the expanded endocannabinoid system, but did not alter fecal bacterial taxa after 12 weeks of treatment in people with HIV on antiretroviral therapy.","whyItMatters":"People with HIV experience chronic inflammation driving comorbidities, and this study provides early mechanistic evidence that cannabinoids may modulate the endocannabinoid system in this population.","specificNumbers":"n=10 (5 per arm); 12-week treatment; significant decrease in 2-EPG and 2-OG; different baseline bacterial taxa between arms; Coprobacillus and Lachnospiraceae UCG001 lower in THC/CBD vs CBD-only arm","methodology":"Prospective pilot clinical trial randomizing 10 people with HIV on ART to CBD+THC (n=5) or CBD-only (n=5) capsules for 12 weeks, with plasma eCBome mediators measured by LC-MS-MS and fecal microbiota assessed by 16S rDNA sequencing.","limitations":"Very small sample size (n=10); no placebo control arm; different baseline microbiota between groups; short duration; dose titration means variable cannabinoid exposure; pilot study not powered for definitive conclusions."},{"rthcId":"RTHC-08282","title":"Inequities in blunt use across multiple socio-demographic intersections among US adults.","authors":"Glasser, Allison M; Jensen, Jessica K; Sterling, Kymberle L; Villanti, Andrea C","year":2026,"journal":"Drug and alcohol dependence, 279, 113019","doi":"10.1016/j.drugalcdep.2025.113019","pmid":"41483495","tags":["blunts","tobacco","health-equity","race","epidemiology","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Compared to non-Black adults with high SES, those identifying as Black/African American with low SES had 5.1 times higher odds of blunt use (aOR=5.10, 95% CI=4.16-6.26), with similar magnitudes for those with internalizing (aOR=4.83) or externalizing conditions (aOR=4.74).","whyItMatters":"Blunts combine tobacco and cannabis health risks, and these stark disparities highlight how intersecting identities create compounding vulnerability that single-factor analyses miss.","specificNumbers":"N=30,516 US adults; 8.4% of young adults (18-34) and 1.4% of adults 35+ used blunts; B/AA + low SES aOR=5.10; B/AA + high internalizing aOR=4.83; B/AA + externalizing aOR=4.74; disparities larger in 35+ age group","methodology":"Analysis of Wave 6 (2021) Population Assessment of Tobacco and Health (PATH) Study data from 30,516 US adults, using weighted multivariable logistic regression examining blunt use by race, mental health, and SES intersections, stratified by age group.","limitations":"Cross-sectional design limits causal inference; self-reported data; binary race categorization (B/AA vs non-B/AA) masks heterogeneity; blunt use definition may vary; 2021 data collected during COVID-19 pandemic."},{"rthcId":"RTHC-08283","title":"Problematic cannabis use and attachment insecurities as Joint predictors of Depression: Cross-Sectional and longitudinal models.","authors":"Gliksberg, Or; Shmulewitz, Dvora; Skvirsky, Vera; Levitin, Maor Daniel; Feingold, Daniel; Kor, Ariel; Lev-Ran, Shaul; Mikulincer, Mario","year":2026,"journal":"Addictive behaviors, 175, 108604","doi":"10.1016/j.addbeh.2026.108604","pmid":"41518990","tags":["cannabis-use-disorder","depression","attachment","mental-health","longitudinal"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Attachment anxiety significantly moderated the cannabis-depression association at both timepoints (p=0.013 at T1, p=0.002 at T2), and a longitudinal three-way interaction (p=0.014) showed that depression increases were greatest among individuals high in both attachment anxiety and avoidance.","whyItMatters":"This study identifies attachment insecurities as a key vulnerability factor that amplifies the depressive impact of cannabis use, suggesting clinical interventions should address emotional regulation alongside substance use.","specificNumbers":"N=1,745 (412 lifetime users); two timepoints (2024-2025); attachment anxiety moderation p=0.013 (T1), p=0.002 (T2); three-way interaction p=0.014; avoidance showed paradoxical buffering effect among users","methodology":"Two-wave longitudinal study of 1,745 Israeli adults (412 lifetime cannabis users) assessed at T1 (2024) and T2 (2025) using ASSIST, PHQ-9, and ECR measures, with cross-sectional moderation models and longitudinal change models.","limitations":"Israeli sample may not generalize globally; self-report measures; two timepoints limit understanding of temporal dynamics; cannot establish causality; lifetime cannabis use group includes variable use patterns."},{"rthcId":"RTHC-08284","title":"Investigating Links Between Prenatal Cannabis Exposure and Brain Development Using Magnetic Resonance Imaging Techniques: A Narrative Review.","authors":"Gonçalves, Priscila Dib; Woodruff, James O; Pozzolo Pedro, Maria Olivia; van Dijk, Milenna T; Bruzelius, Emilie; Martins, Silvia S; Bandoli, Gretchen; Potter, Alexandra; Cioffredi, Leigh-Anne; Talati, Ardesheer; Albaugh, Matthew D","year":2026,"journal":"Biological psychiatry global open science, 6(1), 100624","doi":"10.1016/j.bpsgos.2025.100624","pmid":"41321421","tags":["prenatal-exposure","brain-development","mri","pregnancy","neurodevelopment"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Across 9 studies meeting criteria, prenatal cannabis exposure was linked to structural and functional brain differences spanning from in utero to adolescence across multiple MRI modalities, but no consistent trend could be identified due to wide methodological variation.","whyItMatters":"With rising cannabis use during pregnancy, understanding its impact on fetal brain development is critical — this review reveals how little we know and how inconsistent current research methods are.","specificNumbers":"9 studies reviewed; 1 in utero, 2 in infancy, 6 in early adolescence; only 3 included both MRI and behavioral outcomes; differences found in frontal, parietal, and temporal brain regions","methodology":"Narrative review of post-2019 studies using structural MRI, diffusion-weighted imaging, resting-state fMRI, and/or task-based fMRI to examine prenatal cannabis exposure effects on brain development, yielding 9 qualifying studies.","limitations":"Narrative review (not systematic); only 9 studies met criteria; wide variation in exposure assessment methods; difficulty separating cannabis effects from other prenatal exposures; limited behavioral outcome data."},{"rthcId":"RTHC-08285","title":"Cannabidiol as Adjunctive Treatment in Drug-Resistant Epilepsy With Epileptic Spasms Beyond Two Years of Age.","authors":"González-Alguacil, Elena; García Peñas, J Jose; Lamagrande Casanova, Nuria; Santana Cabrera, Elsa Maria; Duat Rodríguez, Anna; Soto Insuga, Víctor","year":2026,"journal":"Pediatric neurology, 174, 81-85","doi":"10.1016/j.pediatrneurol.2025.10.013","pmid":"41197417","tags":["cbd","epilepsy","pediatric","epileptic-spasms","drug-resistant","down-syndrome"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Of 53 patients with drug-resistant childhood epileptic spasms treated with purified CBD (Epidyolex), 58.5% achieved ≥50% reduction in spasm frequency and 15% became completely spasm-free, with the highest response rates in patients with cortical malformations and Down syndrome.","whyItMatters":"Epileptic spasms persisting beyond age 2 are notoriously difficult to treat, and this study provides real-world evidence that CBD can meaningfully reduce spasm burden in this challenging population.","specificNumbers":"n=53 patients; 58.5% achieved ≥50% spasm reduction; 15% spasm-free; 77.3% co-administered clobazam; adverse effects in 62.2%; 17% discontinued for lack of efficacy; 11.3% discontinued for adverse effects; drowsiness most common AE","methodology":"Retrospective longitudinal study of 53 patients older than 2 years with drug-resistant epileptic spasms treated with purified CBD at Niño Jesus Hospital, Madrid (2020-2024), comparing spasm frequency before and after treatment.","limitations":"Retrospective design; no control group; single center; clobazam co-administration in most patients makes it difficult to isolate CBD's independent effect; variable follow-up duration; relatively small sample."},{"rthcId":"RTHC-08286","title":"Behavioural Economic Demand for Medicinal and Recreational Cannabis Among People Who Use Over-The-Counter CBD Products, THC Only and CBD + THC.","authors":"González-Roz, Alba; García-Pérez, Ángel; Cuesta-López, Ignacio; Alemán-Moussa, Layla; Secades-Villa, Roberto","year":2026,"journal":"Drug and alcohol review, 45(1), e70073","doi":"10.1111/dar.70073","pmid":"41309065","tags":["legalization","cbd","thc","behavioral-economics","consumer-behavior","spain"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"People using CBD+THC products showed significantly higher medicinal and recreational cannabis demand than those using THC or CBD alone (all p<0.001), and 65.2% of participants would try medicinal cannabis if legalized vs. 62.1% for recreational.","whyItMatters":"As Spain and other countries consider legalization, understanding that existing CBD/THC product users form a ready consumer base helps predict market dynamics and target prevention efforts.","specificNumbers":"N=1,492 aged 16-30; 65.2% would try medicinal cannabis; 62.1% would try recreational; CBD+THC users had higher demand than both THC-only and CBD-only (all p<0.001); men reported higher demand than women (all p<0.023)","methodology":"Cross-sectional study of 1,492 Spanish participants aged 16-30 using two Marijuana Purchase Tasks to estimate demand for medicinal and recreational cannabis, with bivariate analyses and split-plot ANOVAs across CBD, THC, and CBD+THC user groups.","limitations":"Hypothetical scenario may not reflect actual behavior; Spanish sample may not generalize; young adult sample; cross-sectional design; self-reported cannabis use categories; no measure of actual purchasing behavior."},{"rthcId":"RTHC-08287","title":"Delta-9-Tetrahydrocannabinol (THC) Before Bedtime: Feasibility and Mechanistic Pilot Study on Sleep and Cardiac Autonomic Activity.","authors":"Gonzalez, Joshua E; Stewart, Alicia V; Ellison, Jacquelin L; Ordaz, Omar H; Robinson, LaTroy D; Clemons, Noal A; Emens, Jonathan S; Rice, Sean P M; Shea, Steven A; Bowles, Nicole P","year":2026,"journal":"Journal of sleep research, e70298","doi":"10.1111/jsr.70298","pmid":"41692699","tags":["thc","sleep","heart-rate","autonomic-nervous-system","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"Acute THC before bedtime increased sleep latency and slow-wave sleep while markedly reducing heart rate variability across time- and frequency-domain measures during sleep, indicating reduced cardiac parasympathetic activity — and regular cannabis users showed shorter total sleep time and greater disruption at home.","whyItMatters":"Many people use cannabis specifically to sleep better, but this study reveals that THC may actually increase cortical activation and reduce heart-protective parasympathetic tone during sleep.","specificNumbers":"n=18 (9 regular users, 9 minimal exposure); regular users had shorter total sleep time at home (p significant); acute THC increased sleep latency and slow-wave sleep (p significant); HRV reduced across time- and frequency-domain (p significant)","methodology":"Feasibility and mechanistic pilot study comparing 9 regular cannabis users (>3x/week) and 9 minimal-exposure adults, with controlled in-lab THC dosing and at-home monitoring using polysomnography and cardiac autonomic measures.","limitations":"Very small sample (n=18); pilot/feasibility study not powered for definitive conclusions; ad libitum home cannabis use in regular user group; single acute dose may not reflect chronic use patterns; no long-term follow-up."},{"rthcId":"RTHC-08288","title":"Cannabidiol Lacks Direct Effect on Cortical Excitability: A Randomized, Double Blind, Placebo Controlled, 3-Way Crossover Trial.","authors":"Gorbenko, Andriy A; de Cuba, Catherine M K E; de Goede, Annika A; Post, Titiaan E; Bohoslavsky, Roman; Strugala, Pamela K; Heuberger, Jules A A C; Groeneveld, Geert Jan","year":2026,"journal":"Clinical pharmacology and therapeutics, 119(1), 147-157","doi":"10.1002/cpt.70038","pmid":"40836528","tags":["cbd","epilepsy","pharmacology","clobazam","drug-interactions","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Single doses of 30 mg and 700 mg CBD had no significant effects on single-pulse or paired-pulse TMS-EMG measures of cortical excitability, nor on validated CNS sedation tests, compared to placebo — suggesting CBD may lack intrinsic anti-epileptic and sedative properties.","whyItMatters":"If CBD's approved anti-seizure effects are primarily driven by drug interactions with clobazam rather than direct anti-epileptic activity, it fundamentally changes how we understand and prescribe CBD for epilepsy.","specificNumbers":"n=25 healthy males; 3-way crossover; 30 mg and 700 mg CBD vs. placebo; no significant effects on TMS-EMG; some TMS-EEG clusters at 3 and 5 hours post-dose for 700 mg; no effects on sedation battery","methodology":"Randomized, double-blind, placebo-controlled, 3-way crossover trial in 25 healthy males testing single doses of 30 mg CBD, 700 mg CBD, and placebo using transcranial magnetic stimulation with EMG/EEG and a validated CNS test battery.","limitations":"Healthy volunteers (not epilepsy patients); single-dose study doesn't capture chronic effects; males only; TMS measures may not fully capture anti-epileptic mechanisms; some TMS-EEG clusters were significant suggesting subtle effects."},{"rthcId":"RTHC-08289","title":"The Paradoxical Effect of Cannabis Use on Cognition in Chronic Psychotic Disorders.","authors":"Gorea, Fiorela; Pelle, Martina; Fiori Nastro, Federico; Gelormini, Carmine; Elezi, Fatime; Ribolsi, Michele; Di Lorenzo, Giorgio","year":2026,"journal":"Pathophysiology : the official journal of the International Society for Pathophysiology, 33(1)","doi":"10.3390/pathophysiology33010011","pmid":"41718389","tags":["psychosis","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In 105 psychiatric inpatients with psychotic disorders, cannabis users had higher MoCA (Montreal Cognitive Assessment, a brief test of thinking skills) scores than non-users. The highest MoCA performance was reported among daily users. Cannabis use was also associated with being male, younger age, and earlier psychosis onset compared with non-use.","whyItMatters":"Cognition (thinking skills like memory and attention) is a core driver of disability in chronic psychotic disorders, and it is also one of the most debated areas in cannabis research. By 2026, many studies in the general population had linked cannabis exposure with worse cognitive performance, but psychosis samples often look different because illness severity, medication, and hospitalization can dominate test scores. This study directly targeted a common clinical contradiction: high cannabis use rates in psychosis alongside mixed findings on whether users test worse, the same, or sometimes better on cognitive screening tools.","specificNumbers":"• N=105 inpatients (a small-to-midsize sample, which can miss smaller effects and can be sensitive to who gets admitted).\n• Mean age: 40.3 years (middle-aged inpatient cohort, not an early-episode outpatient sample).\n• Sex: 34 female (about 32% female, so results may reflect a more male-skewed inpatient population).","methodology":"This was a cross-sectional observational study, meaning the team measured cannabis use and cognition at the same time without assigning or controlling exposure. Researchers recruited 105 inpatients with psychotic disorders from one hospital in Tirana and collected demographic and clinical information. Cognitive performance was measured with MoCA (a short screening test), and symptom severity was rated with BNSS (negative symptoms), CDSS (depression in schizophrenia), PSYRATS (psychotic symptom ratings), and TLC (thought and language disturbance). The biggest weakness is timing: because exposure and outcome were measured at once, the direction of the association between cannabis use and MoCA scores cannot be determined.","limitations":"Cannabis exposure was not quantified in the abstract with amounts, timing, or objective biomarkers, and THC or CBD content was not measured, even though the interpretation hinges on these details. The sample came from a single inpatient hospital in Tirana, which can differ sharply from community or outpatient psychosis populations in symptom severity and medication patterns. MoCA is a brief screen and may not capture specific cognitive domains that longer neuropsychological testing can detect."},{"rthcId":"RTHC-08290","title":"Neurologic Complications of Drug and Alcohol Use.","authors":"Goss, Adeline L","year":2026,"journal":"Continuum (Minneapolis, Minn.), 32(1), 277-309","doi":"10.1212/cont.0000000000001676","pmid":"41631916","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08291","title":"The indirect effects of discrimination on substance use in bisexual adults through internalized binegativity, concealment, and distress tolerance.","authors":"Goulbourne, Tarik D; Smith, Nathan Grant; Obasi, Ezemenari M; Reitzel, Lorraine R","year":2026,"journal":"Addictive behaviors reports, 23, 100644","doi":"10.1016/j.abrep.2025.100644","pmid":"41399747","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08292","title":"Evaluating cannabis substitution for alcohol within the context of a canadian managed alcohol program.","authors":"Goulet-Stock, Sybil; Hacksel, Catherine; Scandiuzzi, Beatriz; Boyd, Rob; Pauly, Bernie; Stockwell, Tim","year":2026,"journal":"The International journal on drug policy, 147, 105083","doi":"10.1016/j.drugpo.2025.105083","pmid":"41313909","tags":["harm-reduction","alcohol","substitution","legalization","managed-alcohol-program"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"A significant between-person substitution effect was found: participants who used more cannabis on average also consumed less alcohol, with each additional 0.4g joint (approximately 76 mg THC) associated with 2.43 fewer mean daily standard drinks.","whyItMatters":"This is one of the first studies to evaluate cannabis substitution within a structured harm reduction program, showing that offering cannabis as an alternative to alcohol can meaningfully reduce drinking in people with severe alcohol use disorder.","specificNumbers":"N=35 participants; 5 survey waves over 13 months; each additional 0.4g joint (~76 mg THC, ~15.2 standard THC units) associated with 2.43 fewer daily standard drinks; alcohol use also declined over time; 14 qualitative interviews","methodology":"Mixed-methods longitudinal study within a Canadian managed alcohol program (N=35) using five waves of quantitative surveys (Jan 2023-Feb 2024), two years of program records, hierarchical mixed-effects models, and 14 qualitative interviews.","limitations":"Small sample (N=35); single program site; no control group; observational substitution effect (not randomized); between-person effect only (within-person fluctuations not significant); self-selected participants; limited generalizability."},{"rthcId":"RTHC-08293","title":"The effects of cannabidiol on sleep disturbances within a sample of high trait worriers: A double-blind, randomized placebo controlled trial.","authors":"Gournay, L Riley; Ferretti, Morgan L; Dickens, Harrison B; Floyd, Veronica; Fernandez, Daniella A; Rathbun, Ezri; Nguyen, Anna-Marie; Leen-Feldner, Ellen W","year":2026,"journal":"Experimental and clinical psychopharmacology","doi":"10.1037/pha0000832","pmid":"41678223","tags":["cbd","sleep","anxiety","clinical-trial","worry"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"300 mg CBD decreased sleep disturbances significantly more than 50 mg CBD (B=-0.39, t=-2.59, p<0.05, d=0.08) but not significantly more than placebo (B=-0.32, t=-2.09, p=0.10, d=0.07), with no effects on sedation or cognitive impairment.","whyItMatters":"Despite massive consumer interest in CBD for sleep, this rigorous trial found that CBD beat a lower dose but couldn't clearly beat placebo — highlighting the gap between marketing claims and evidence.","specificNumbers":"n=63; mean age 29.27; 300 mg vs 50 mg CBD significant (p<0.05, d=0.08); 300 mg vs placebo not significant (p=0.10, d=0.07); 2-week treatment; no sedation effects; no cognitive impairment","methodology":"Randomized, double-blind, placebo-controlled trial with 63 individuals reporting elevated trait worry, assigned to 300 mg CBD, 50 mg CBD, or placebo daily for 2 weeks, measuring sleep disturbances, sleep quality, sedation, and cognitive function.","limitations":"Small sample (n=63); very small effect sizes (d=0.07-0.08); only 2-week duration; self-report sleep measures; trait worry sample may not generalize; only two CBD doses tested; borderline p-value vs. placebo suggests possible underpowering."},{"rthcId":"RTHC-08294","title":"The impact of cannabis co-use and cannabis use disorder on interest in and barriers to tobacco cessation.","authors":"Graham, Francis Julian L; Pravosud, Vira; Keyhani, Salomeh; Hoggatt, Katherine J; Ling, Pamela; Hasin, Deborah; Nguyen, Nhung; Cohen, Beth E","year":2026,"journal":"Addictive behaviors, 175, 108609","doi":"10.1016/j.addbeh.2026.108609","pmid":"41525756","tags":["tobacco","cannabis-use-disorder","cessation","co-use","barriers"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Adults with CUD had the highest total barriers to smoking cessation (score 20.3 vs. 15.2 for cannabis without CUD vs. 16.4 for no cannabis use), with significantly higher scores across addiction (p=0.03), external (p=0.02), and internal (p<0.001) barrier subscales.","whyItMatters":"As cannabis and tobacco co-use increases, understanding how cannabis use disorder specifically amplifies barriers to quitting smoking can help design targeted dual-use interventions.","specificNumbers":"n=2,271 current smokers; total barrier scores: CUD 20.3, cannabis without CUD 15.2, no cannabis 16.4; CUD higher on all subscales (Addiction p=0.03, External p=0.02, Internal p<0.001); readiness/confidence similar across groups","methodology":"National online survey of 2,271 US adults currently smoking cigarettes in 2023, examining associations between past 30-day cannabis use (with and without CUD) and smoking cessation outcomes using the Barriers to Cessation Scale.","limitations":"Cross-sectional design; self-reported cannabis use and CUD; online convenience sample; cannabis use measured as past 30 days only; CUD assessment may not capture full spectrum; barriers measured don't include all possible factors."},{"rthcId":"RTHC-08295","title":"Association of Combined Marijuana and Opioid Use with Major Depressive Disorder Among Adults with Chronic Conditions in the United States.","authors":"Graham, Tiffany; Wiener, R Constance; Mitra, Sophie; Wang, Hao; Shen, Chan; Pedaprolu, Laskhmi; Sambamoorthi, Usha","year":2026,"journal":"Substance use : research and treatment, 20, 29768357261423812","doi":"10.1177/29768357261423812","pmid":"41743458","tags":["marijuana","opioids","depression","chronic-conditions","co-use","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Co-use of marijuana and opioids had the strongest association with major depressive disorder (AOR=1.92, 95% CI=1.45-2.50), followed by marijuana only (AOR=1.72) and opioid only (AOR=1.44), compared to no use of either substance — with 20.8% of co-users meeting MDD criteria.","whyItMatters":"People with chronic conditions often use opioids for pain and may add cannabis — this study reveals that combining them carries the highest depression risk, which clinicians should monitor.","specificNumbers":"N=35,585; 8.5% co-use; MDD rates: co-use 20.8%, marijuana only 18.4%, opioid only 9.3%, neither 5.6%; adjusted ORs: co-use 1.92, marijuana 1.72, opioid 1.44; all significant","methodology":"Cross-sectional analysis of 2022 National Survey of Drug Use and Health data from 35,585 US adults with chronic conditions, using Rao-Scott chi-square tests and multivariable logistic regression adjusting for demographics, behavioral, clinical, and social factors.","limitations":"Cross-sectional design cannot establish causality; self-reported substance use; past-year timeframe may miss temporal relationships; opioid use includes both prescribed and non-prescribed; marijuana use may be for self-medication of existing depression."},{"rthcId":"RTHC-08296","title":"Dissociative-like Neurotoxicity Following Analytically Confirmed Exposure To Hexahydrocannabinol (HHC).","authors":"Greene, Shaun L; Fawcett, Rebecca; Castle, Jared; Koutsogiannis, Zeff","year":2026,"journal":"Journal of medical toxicology : official journal of the American College of Medical Toxicology, 22(1), 77-80","doi":"10.1007/s13181-025-01102-8","pmid":"41222838","tags":["synthetic-cannabinoids","harm-reduction","neuroscience","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"In this individual case, a 32-year-old man developed a dissociative-like neurologic syndrome plus gastrointestinal symptoms after ingesting a single gummy sold as a THC product. Serum testing analytically confirmed exposure to two HHC isomers (9R-HHC and 9 S-HHC), with no other pharmaceutical or psychoactive substances detected. Symptoms resolved within 8 hours with supportive care.","whyItMatters":"HHC entered global markets around 2021 and has been detected in unregulated cannabis products, but clinical descriptions with laboratory confirmation have been limited. This 2026 medical toxicology case report focuses on what acute HHC intoxication can look like in a real hospital presentation when exposure is analytically verified. It also reflects a practical measurement problem in emergent cannabinoids: product labeling can be unreliable, and routine toxicology panels may miss newer compounds unless targeted testing is performed.","specificNumbers":"• Time from ingestion to hospital presentation: 1.5 hours (rapid onset after a single edible exposure in this case).\n• Heart rate: 118 beats per minute (sinus tachycardia, a clear elevation).\n• Respiratory rate: 24 breaths per minute (tachypnoea, above typical adult resting range).\n• Symptom duration: resolved within 8 hours of ingestion (short-lived course in this single case).","methodology":"This is a case report, meaning it documents one person’s clinical course in detail rather than comparing groups. Clinicians recorded symptoms and vital signs after a 32-year-old man presented soon after eating a gummy marketed as THC. Standard lab investigations (haematology and biochemistry) were checked and were reported as normal. Serum testing was used to identify HHC isomers (9R-HHC and 9 S-HHC) and to look for other pharmaceutical or psychoactive substances. The main weakness is that one case cannot show how common this reaction is, what the typical severity looks like, or whether HHC alone explains every symptom in broader populations.","limitations":"Only one patient was described, so the report cannot establish frequency, typical dose-response, or a predictable clinical course. The amount of HHC in the gummy was not quantified in the abstract, which makes it hard to connect symptoms to an exposure level. This describes 1 patient(s). Individual cases cannot establish patterns or causation."},{"rthcId":"RTHC-08297","title":"Suicide attempt and paranoia persisting for 28 days following heavy delta-9-tetrahydrocannabinolic acid and tetrahydrocannabinol use: A case report.","authors":"Greer, Daniel; Dey, Prithula; Kulig, Caitlin E","year":2026,"journal":"PCN reports : psychiatry and clinical neurosciences, 5(1), e70290","doi":"10.1002/pcn5.70290","pmid":"41684668","tags":["thc","thc-a","psychosis","suicide","case-report","adverse-effects"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"A patient developed paranoia persisting for 28 days following daily consumption of 15-30 mg THC gummies and THC-A in dried plant form, culminating in a suicide attempt — with the patient reporting unfamiliarity with THC-A dosing and its psychoactive potential when heated.","whyItMatters":"THC-A is often marketed as non-psychoactive, but becomes THC when heated — this case illustrates how product labeling confusion can lead to excessive use and severe psychiatric outcomes.","specificNumbers":"15-30 mg/day THC gummies + THC-A dried plant; paranoia persisting 28 days; culminated in suicide attempt","methodology":"Single case report documenting clinical presentation, substance use history, and course of paranoid symptoms following heavy cannabis use with THC-A products.","limitations":"Single case report; cannot establish causality; patient may have had predisposing psychiatric vulnerability; exact THC-A dosing unclear; no systematic assessment of psychotic symptoms; publication bias toward dramatic cases."},{"rthcId":"RTHC-08298","title":"In Silico Assessment of Cannabidiol From Cannabis sativa as an Antiviral Agent Against Key Shrimp Pathogens in Aquaculture.","authors":"Gunasekaran, Shoba; Purushothaman, Atchuthan; Anju, K","year":2026,"journal":"Journal of fish diseases, 49(1), e70015","doi":"10.1111/jfd.70015","pmid":"40657679","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08299","title":"A Randomized, Single-Dose, Single-Sequence, Two-Arm (Fasting and Fed), Open-Label Study on the Oral Pharmacokinetics of a Nanodispersible Cannabidiol Solution (150 mg/mL).","authors":"Gundugurti, Prasad Rao; Nadikudi, Monila; Thatikonda, Ramyasree; Banda, Nagaraju; Yadlapalli, Siva Sankara Rao; Narala, Arjun; Kocherlakota, Chandrashekhar; Kothapalli, Kumar S D","year":2026,"journal":"Medical cannabis and cannabinoids, 9(1), 20-29","doi":"10.1159/000550104","pmid":"41613360","tags":["cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In a randomized trial with 18 healthy male subjects, a novel nanodispersible CBD oral solution (150 mg/mL) was tested under fasting and fed conditions. Each participant received a single 300 mg dose.\n\nThe fed state tripled the total CBD exposure: the area under the curve (AUC) increased 3.0-fold compared to fasting (p < 0.0001). Peak blood concentration (Cmax) was moderately higher in the fed state (1.3-fold), and the time to reach peak concentration (Tmax) was prolonged — meaning the body absorbed more CBD overall when food was present, though it took longer to reach the peak.\n\nThe study also tracked CBD's metabolites. 7-COOH-CBD (7-carboxy-cannabidiol) reached the highest plasma concentration of any compound measured, followed by CBD itself and then 7-OH-CBD. This metabolite profile is relevant because 7-OH-CBD is pharmacologically active and may contribute to CBD's therapeutic effects.","whyItMatters":"CBD's poor and variable oral bioavailability is one of the biggest practical challenges in cannabinoid therapeutics. Understanding how food affects absorption is directly relevant to dosing — a 3-fold difference in blood levels depending on meal timing means the same dose could be sub-therapeutic when fasting or potentially cause more side effects when taken with food. The nanodispersible formulation represents an attempt to improve on this, though the food effect persisted.","specificNumbers":"18 subjects, single 300 mg dose. Fed vs. fasting: AUC increased 3.0-fold (p < 0.0001), Cmax increased 1.3-fold, Tmax prolonged. 7-COOH-CBD reached highest plasma concentrations, followed by CBD, then 7-OH-CBD.","methodology":"Randomized, single-dose, two-arm (fasting and fed), open-label pharmacokinetic trial. 18 healthy male subjects (9 per arm) received 300 mg of nanodispersible CBD oral solution. Plasma concentrations of CBD and metabolites (7-OH-CBD, 7-COOH-CBD) were quantified at multiple timepoints. Pharmacokinetic parameters analyzed using non-compartmental modeling.","limitations":"Small sample (18 subjects, 9 per arm). Male subjects only — sex differences in CBD pharmacokinetics were not assessed. Single-dose study doesn't capture steady-state kinetics from repeated dosing. Healthy volunteers may not reflect pharmacokinetics in patient populations. The nanodispersible formulation is specific to this manufacturer."},{"rthcId":"RTHC-08300","title":"Alcohol quantity mediates the association between daily alcohol and cannabis co-use and alcohol consequences.","authors":"Gunn, Rachel L; Sokolovsky, Alexander W; Howe, Lindy K; Barnett, Nancy P; Jackson, Kristina M; Lipperman-Kreda, Sharon; Miranda, Robert; Trull, Timothy; Metrik, Jane","year":2026,"journal":"Drug and alcohol dependence, 279, 113043","doi":"10.1016/j.drugalcdep.2026.113043","pmid":"41546986","tags":["alcohol","co-use","young-adults","harm-reduction","daily-diary"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Number of alcoholic drinks significantly mediated the association between co-use and consequences: co-use days involved more drinking, which drove higher negative consequences and lower positive consequences — suggesting alcohol quantity, not cannabis addition, is the key driver.","whyItMatters":"This clarifies a long-standing question: co-use days are riskier not because cannabis inherently worsens outcomes, but because people drink more on those days — pointing to drink reduction as the primary harm-reduction target.","specificNumbers":"N=115 young adults; 28-day daily diary; significant mediation for both positive and negative consequences; more drinks on co-use days vs. alcohol-only days; drink quantity mediated the co-use → negative consequences pathway","methodology":"28-day field-based study using morning reports from 115 young adults (ages 18-25) with frequent alcohol and cannabis use, analyzing day-level multilevel mediation models of co-use, drink quantity, and consequences.","limitations":"Self-report morning recall; 28-day window may not capture all patterns; sample of frequent users may not generalize; mediation design limits causal claims; did not distinguish concurrent vs. simultaneous use."},{"rthcId":"RTHC-08301","title":"Working memory capacity predicts cannabis-induced effects on alcohol urge.","authors":"Gunn, Rachel L; Howe, Lindy K; Boyle, Holly K; Metrik, Jane","year":2026,"journal":"Addictive behaviors, 174, 108565","doi":"10.1016/j.addbeh.2025.108565","pmid":"41275744","tags":["thc","alcohol","working-memory","cognition","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"Participants with higher working memory (symmetry span task) reported significantly lower alcohol urge after smoking 7.2% THC cannabis vs. placebo, but this effect was not seen at 3.1% THC or among those with lower working memory capacity.","whyItMatters":"As more people consider using cannabis to reduce drinking, this study reveals that the benefit may depend on cognitive capacity — those with lower working memory may be less likely to experience reduced alcohol cravings from cannabis.","specificNumbers":"N=125 (32% female); 3 sessions: placebo, 3.1% THC, 7.2% THC; significant urge reduction only at 7.2% THC for high-WMC individuals (symmetry span); n-back associated with overall urge but did not moderate cannabis effects","methodology":"Randomized placebo-controlled crossover trial with 125 adults (ages 21-44) who were heavy alcohol users and frequent cannabis users, completing three sessions smoking placebo, 3.1% THC, and 7.2% THC cannabis, with pre/post alcohol urge ratings and working memory assessments.","limitations":"Laboratory setting may not reflect real-world use; relatively low THC potency by current standards; dual-user sample limits generalizability; working memory measures showed inconsistent results across tasks; acute effects only."},{"rthcId":"RTHC-08302","title":"Structural and dynamic mechanisms of cannabinoid receptors.","authors":"Guo, Xiucheng; Li, Fahui; Zhang, Feng","year":2026,"journal":"Biochemical pharmacology, 244, 117568","doi":"10.1016/j.bcp.2025.117568","pmid":"41319927","tags":["endocannabinoid-system","cannabinoid-receptors","pharmacology","drug-discovery","cb1","cb2"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Structural studies of CB1 and CB2 receptors have deepened understanding of receptor activation mechanisms, allosteric modulation sites, transducer coupling selectivity, and dynamic conformational changes — providing a foundation for designing therapeutics with improved subtype selectivity and reduced off-target effects.","whyItMatters":"Understanding the precise 3D structure of cannabinoid receptors enables drug designers to create medications that target specific receptors more accurately, potentially delivering therapeutic benefits without unwanted psychoactive or immune effects.","specificNumbers":"Focus on CB1R and CB2R G protein-coupled receptors; covers activation, allosteric modulation, transducer coupling, and conformational dynamics","methodology":"Comprehensive review summarizing recent structural biology advances in cannabinoid receptor research, including cryo-EM and X-ray crystallography findings on receptor-ligand interactions and signaling mechanisms.","limitations":"Review article synthesizing existing structural data; receptor structures studied in isolation may not fully reflect in vivo complexity; translation from structural insights to clinical drugs remains challenging."},{"rthcId":"RTHC-08303","title":"The Earned Income Tax Credit and short-term changes in financial strain and drug use.","authors":"Gutkind, Sarah; Wall, Melanie M; Keyes, Katherine M; Martins, Silvia S; Hasin, Deborah S","year":2026,"journal":"Health affairs scholar, 4(2), qxag016","doi":"10.1093/haschl/qxag016","pmid":"41710509","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08304","title":"Unmasking hazardous compounds in cannabidiol-containing oils using planar bioassays and high-resolution mass spectrometry.","authors":"Haase, Annika; Morlock, Gertrud","year":2026,"journal":"Talanta, 302, 129273","doi":"10.1016/j.talanta.2025.129273","pmid":"41512620","tags":["cbd","product-safety","contaminants","consumer-health","laboratory-analysis"],"studyType":"laboratory-analysis","evidenceStrength":"moderate","keyFinding":"Effect-directed screening of 13 CBD oils across 13 biological/toxicological endpoints revealed hazardous compounds including various cannabinoids with unexpected bioactivity, estrogenic contaminants (dibutyl phthalate, diisobutyl phthalate), and the estrogenic and mutagenic mycotoxin zearalenone and its metabolites.","whyItMatters":"Consumers assume CBD oils contain only CBD, but this first-of-its-kind comprehensive toxicological screening reveals a concerning array of hazardous contaminants that current quality testing may not detect.","specificNumbers":"13 CBD oils tested; 13 biological/toxicological endpoints; found antimicrobial, anti-/estrogenic, anti-/androgenic, cytotoxic, neurotoxic, genotoxic, and mutagenic compounds; confirmed dibutyl phthalate, diisobutyl phthalate, zearalenone + metabolites","methodology":"High-performance thin-layer chromatography coupled with 13 different duplex and multiplex planar bioassays testing antimicrobial, estrogenic, androgenic, cytotoxic, neurotoxic, genotoxic, and mutagenic endpoints, with hazardous zones identified by high-resolution mass spectrometry and confirmed with reference standards.","limitations":"13 products is a limited sample; bioassay detection doesn't quantify exposure risk; in vitro effects may not translate to in vivo harm at typical doses; products may not represent all markets; oxidized acylglycerides only tentatively assigned."},{"rthcId":"RTHC-08305","title":"Development and In vitro kinetic evaluation of PEG-chitosan biohybrid micelles loading CBD with bile acid/quercetin as surface modifiers for colon cancer therapy.","authors":"Haidery, Qurat Ul Ain; Han, Bo; Ma, Xingyuan; Zheng, Wenyun","year":2026,"journal":"Archives of biochemistry and biophysics, 776, 110711","doi":"10.1016/j.abb.2025.110711","pmid":"41429356","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08306","title":"Cannabis legalization and cannabis and opioid use in a large, multistate sample of people who inject drugs: A staggered adoption difference-in-differences analysis.","authors":"Haley, Danielle F; Beane, Stephanie; Beletsky, Leo; Yarbrough, Courtney R; Linton, Sabriya; Ibragimov, Umedjon; Cooper, Hannah Lf","year":2026,"journal":"Drug and alcohol dependence, 280, 113040","doi":"10.1016/j.drugalcdep.2026.113040","pmid":"41638008","tags":["legalization","opioids","harm-reduction","people-who-inject-drugs","policy","race"],"studyType":"quasi-experimental","evidenceStrength":"strong","keyFinding":"Compared to medical-only legalization, adding recreational cannabis legalization was associated with a 9-11% decrease in the probability of daily opioid misuse among PWID (any opioids 95% CI: -14.0 to -4.0; injected opioids 95% CI: -19.0 to -2.0), while daily cannabis use increased mainly among non-Latinx White PWID in states transitioning from no law to medical legalization.","whyItMatters":"People who inject drugs face the highest risk of overdose death, and this large-scale evidence suggests recreational cannabis legalization could meaningfully reduce daily opioid use in this vulnerable population.","specificNumbers":"N=28,069 PWID; 13 states; 4 timepoints (2012-2022); MCL+RCL associated with 9-11% decrease in daily opioid misuse; daily cannabis use increased from 15% to 20% among White PWID transitioning from no law to MCL","methodology":"Staggered adoption difference-in-differences analysis of serial cross-sectional data (2012, 2015, 2018, 2022) from 28,069 people who inject drugs across 13 US states, examining time-varying cannabis law implementation and self-reported substance use.","limitations":"Observational design despite quasi-experimental methods; self-reported data from a hard-to-reach population; cannot confirm substitution mechanism; racial differences in cannabis uptake suggest structural barriers; serial cross-sections don't track individuals."},{"rthcId":"RTHC-08307","title":"Cannabis Use Disorder Among People With and Without HIV.","authors":"Haley, Danielle F; So-Armah, Kaku; Justice, Amy C; Kidwai-Khan, Farah; Xuan, Ziming; Sayko Adams, Rachel; Fox, Matthew P; Edelman, E Jennifer; Wrona, Aleksandra; Silverberg, Michael J; Satre, Derek D; Trickey, Adam; Ingle, Suzanne M; McGinnis, Kathleen A","year":2026,"journal":"Journal of addiction medicine, 20(1), 38-43","doi":"10.1097/ADM.0000000000001505","pmid":"40358026","tags":["cannabis-use-disorder","hiv","aging","veterans","epidemiology"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"20% of people living with HIV (PLWH) had a cannabis use disorder diagnosis between 2000 and 2022, with CUD consistently higher among PLWH vs. those without HIV (OR=1.14, 95% CI=1.11-1.18), and the greatest relative increase occurring among those aged 65+ (PLWH: 0.9% to 4.0%; PLWoH: 0.03% to 3.15%).","whyItMatters":"As people with HIV live longer on antiretroviral therapy, rising cannabis use disorder in this aging population is concerning because cannabis can interact with many prescription medications these patients take.","specificNumbers":"N=185,372 (58,959 PLWH, 126,413 PLWoH); 45% Black NH, 35% White NH; mean age 48; 20% of PLWH had CUD; OR=1.14 for PLWH vs PLWoH; 65+ age group: 0.9%→4.0% (PLWH), 0.03%→3.15% (PLWoH)","methodology":"Retrospective analysis of electronic health records from 185,372 individuals in the Veterans Aging Cohort Study-HIV (2000-2022), including 58,959 PLWH matched 1:2 to 126,413 people without HIV, examining CUD trends by age, race/ethnicity, sex, comorbidity, and HIV status.","limitations":"VA population (mostly male) limits generalizability; ICD-based diagnosis may undercount CUD; cannot distinguish therapeutic from recreational use; increasing diagnostic coding awareness may inflate trends; observational design."},{"rthcId":"RTHC-08308","title":"Changes in Cross-Sectional Associations Between Cannabis Use and Anxiety, Depression, and Suicidality in a Nationally Representative Sample of Canadians From 2012 to 2022: Évolution des relations transversales entre la consommation de cannabis et la dépression, l'anxiété et les idées suicidaires au sein d'un échantillon représentatif de Canadiens à l'échelle nationale, de 2012 à 2022.","authors":"Halladay, Jillian; Ji, Chris; Georgiades, Katholiki; McDonald, André; Sunderland, Matthew; Slade, Tim; Chapman, Cath; MacKillop, James","year":2026,"journal":"Canadian journal of psychiatry. Revue canadienne de psychiatrie, 7067437261420701","doi":"10.1177/07067437261420701","pmid":"41746129","tags":["mental-health","anxiety","depression","suicide","legalization","canada","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"From 2012 to 2022, the prevalence ratio for weekly+ cannabis use (vs. no use) increased from 2.3 to 4.5 for generalized anxiety disorder, 3.0 to 5.2 for major depression, and 3.0 to 5.4 for suicidality — with strengthening associations particularly among youth and females for certain outcomes.","whyItMatters":"Both cannabis use and mental health problems have increased in Canada, but this study reveals that their association has also strengthened — meaning the mental health burden linked to cannabis may be growing faster than either trend alone would suggest.","specificNumbers":"N=34,974 across 2 surveys; GAD PR: 2.3→4.5; MDE PR: 3.0→5.2; suicidality PR: 3.0→5.4 for weekly+ users; prevalence of GAD, MDE, and cannabis use approximately doubled from 2012-2022; youth suicidality up 44%","methodology":"Comparison of two nationally representative Canadian cross-sectional surveys — CCHS-MH 2012 (n=25,113) and MHACS 2022 (n=9,861) — using Robust Poisson Regression to examine frequency-dependent associations between cannabis use and WHO-CIDI-diagnosed GAD, MDE, and suicidality.","limitations":"Cross-sectional surveys cannot establish causality; 2022 data collected during pandemic aftermath may inflate mental health prevalence; potential confounding despite adjustment; diagnostic interview differences between surveys possible; cannot determine directionality."},{"rthcId":"RTHC-08309","title":"Daily patterns of substance use among young adults who vape nicotine and cannabis: Latent class analysis of smartphone-based daily diary data.","authors":"Halliday, Deanna M; Lund, Lisbeth; Ling, Pamela M; Nguyen, Nhung","year":2026,"journal":"Drug and alcohol dependence, 280, 113060","doi":"10.1016/j.drugalcdep.2026.113060","pmid":"41628576","tags":["vaping","nicotine","young-adults","daily-diary","co-use","substance-use-patterns"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Three daily substance use classes emerged: nicotine vaping days (52.7%), nicotine+cannabis co-vaping days (39.9%), and combustible tobacco+cannabis days (7.4%), with sadness predicting nicotine-only days (aOR=1.11) and cannabis craving predicting co-vaping days (aOR=1.81).","whyItMatters":"Understanding daily substance use patterns reveals that vaping, cannabis, and combustible tobacco use are interconnected — interventions targeting one substance should consider these overlapping patterns.","specificNumbers":"N=113; mean age 23.8; 30 consecutive days; Class 1 nicotine vaping 52.7%; Class 2 co-vaping 39.9%; Class 3 combustible+cannabis 7.4%; sadness→Class 1 aOR=1.11; cannabis craving→Class 2 aOR=1.81","methodology":"30-day smartphone-based daily diary study of 113 California young adults (mean age 23.8) who vaped nicotine or cannabis 20+ days/month, using multilevel latent class analysis and mixed-effects logistic regression.","limitations":"California-only sample; self-selected heavy vapers; 30-day window; self-report data; relatively small sample; cannot determine causal direction between mood and substance use; limited to young adults."},{"rthcId":"RTHC-08310","title":"Cannabis and nicotine use are independently associated with adverse surgical, medical, and psychosocial outcomes following upper extremity fracture fixation.","authors":"Hamad, Christopher D; Galoustian, Nora A; Wiener, Joshua; Yusin, Nick; Liu, Timothy; Olson, Thomas; Walker, Paul; Shahamatdar, Soroush; Nwufo, Michelle; Golzar, Autreen; Kaelber, David C; Bernthal, Nicholas M; Lee, Christopher; Sheppard, William L","year":2026,"journal":"Journal of orthopaedic surgery and research, 21(1), 127","doi":"10.1186/s13018-025-06635-w","pmid":"41555366","tags":["surgery","fractures","nicotine","complications","orthopedics"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-only users had significantly higher rates of implant-related infection, reoperation, readmission, depression, and anxiety vs. matched non-users (all p<0.05), while nicotine-only users showed even broader complications including nonunion, wound dehiscence, pneumonia, chronic pain, and mortality.","whyItMatters":"Unlike elective surgery where patients can quit smoking, trauma patients cannot delay fracture repair — making it critical to understand cannabis-related risks so surgeons can adjust perioperative care.","specificNumbers":"Cannabis n=801; nicotine n=14,310; concurrent n=901; 1-year outcomes; cannabis users: higher infection, reoperation, readmission, depression, anxiety (all p<0.05); concurrent use did not show additive risk vs. cannabis alone","methodology":"Retrospective analysis of the TriNetX database (2015-2023) comparing four propensity score-matched cohorts — cannabis-only (n=801), nicotine-only (n=14,310), concurrent users (n=901), and matched non-users — examining 1-year surgical, medical, and psychosocial outcomes after upper extremity fracture fixation.","limitations":"Retrospective database study with inherent coding limitations; cannabis use likely underreported; propensity matching cannot account for all confounders; small cannabis-only cohort; concurrent user group may lack power to detect additive effects; 1-year follow-up."},{"rthcId":"RTHC-08311","title":"Development of Substance Use Problems: The Role of Adolescent Cannabis Age of Onset, Frequency of Use and Childhood Risk Factors.","authors":"Hamaoui, Jad; Acland, Erinn; Vitaro, Frank; Fallu, Jean-Sébastien; Parent, Sophie; Simard, Cléa; Boivin, Michel; Côté, Sylvana; Geoffroy, Marie-Claude; Séguin, Jean R; Castellanos-Ryan, Natalie","year":2026,"journal":"Research on child and adolescent psychopathology, 54(1), 1","doi":"10.1007/s10802-025-01404-z","pmid":"41483051","tags":["adolescents","age-of-onset","substance-use","longitudinal","risk-factors","prevention"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Earlier cannabis age of onset directly predicted increased cannabis use problems in males (β=-0.47 cohort 1; β=-0.22 cohort 2) and indirectly predicted cannabis and other substance use problems in both sexes via increased adolescent cannabis use frequency (indirect effect ab=-0.41 cohort 1; ab=-0.35 cohort 2).","whyItMatters":"This birth-to-adulthood study maps the developmental chain from early childhood risk factors to adolescent cannabis initiation to adult substance problems, identifying multiple intervention points.","specificNumbers":"Two cohorts: N=306, N=1,489; followed birth to age 23; direct CAO→cannabis problems in males (β=-0.47, -0.22); indirect via frequency (ab=-0.41, -0.35); indirect to other SU problems (ab=-2.63); parental cannabis use, ACEs, externalizing behaviors as early risk factors","methodology":"Two cohorts from the Quebec Longitudinal Study of Child Development (N=306, 57% female; N=1,489, 54% female) followed from birth to age 23, examining pathways from childhood risk factors through cannabis age of onset to substance use problems.","limitations":"Quebec-specific cohorts may not generalize globally; self-report measures; attrition over 23 years; sex differences in direct effects suggest different mechanisms for males and females; observational design despite longitudinal data."},{"rthcId":"RTHC-08312","title":"Racial and Ethnic Differences in Suicide Mortality Among Youth Aged 12-25 Years Following Medical and Recreational Cannabis Legalization in the U.S.","authors":"Hammond, Christopher J; Hyer, Madison; Boustead, Anne E; Platt, Rheanna; Young, Andrea S; Fristad, Mary A; Steelesmith, Danielle L; Brock, Guy; Hasin, Deborah S; Fontanella, Cynthia A","year":2026,"journal":"American journal of preventive medicine, 70(1), 108141","doi":"10.1016/j.amepre.2025.108141","pmid":"41067550","tags":["suicide","youth","legalization","race","policy","epidemiology"],"studyType":"quasi-experimental","evidenceStrength":"strong","keyFinding":"Asian/Pacific Islander youth in medical and recreational cannabis law states had significantly increased suicide rates (MCL IRR=1.30, 95% CI=1.13-1.50; RCL IRR=1.42, 95% CI=1.20-1.67), and Hispanic youth in recreational states had increased rates vs. medical-only (IRR=1.15) and no-law states (IRR=1.32), while effects for other racial/ethnic groups were nonsignificant.","whyItMatters":"Cannabis legalization is often framed as social justice reform, but this study reveals potential unintended consequences that disproportionately affect specific racial and ethnic communities of youth.","specificNumbers":"113,512 youth suicide deaths (2000-2019); unadjusted rates: 9.7 (no law), 12.8 (MCL), 16.7 (RCL) per 100,000; Asian/PI MCL IRR=1.30, RCL IRR=1.42; Hispanic RCL vs no law IRR=1.32; Black, White, AI/AN effects nonsignificant","methodology":"Staggered-adoption difference-in-difference analysis of 113,512 suicide deaths from the 2000-2019 National Vital Statistics System among US youth aged 12-25, examining race/ethnicity-specific associations with time-varying cannabis law status while controlling for state- and individual-level covariates.","limitations":"Ecological study cannot determine individual cannabis use; cannot establish mechanism (direct cannabis effects vs. broader social changes); 2000-2019 data predates many recreational laws taking full effect; unmeasured confounders possible despite adjustment."},{"rthcId":"RTHC-08313","title":"Standardizing Recreational Cannabis Excise Tax Rates in the United States: New Retail Price-Based Measurements by Product Category.","authors":"Han, Bing; Cooper, Michael; Shang, Ce; Shi, Yuyan","year":2026,"journal":"International journal of environmental research and public health, 23(1)","doi":"10.3390/ijerph23010114","pmid":"41595907","tags":["legalization"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using retail scanner data from dispensary point-of-sale systems across 12 states with legal recreational cannabis (Q1 2020 to Q4 2024), researchers developed the first standardized tax metrics broken down by product category.\n\nThe standardized excise taxes were: $32.58 per ounce for flower, $180.21 per ounce for vaping products, and $0.024 per milligram of THC for edibles. Despite the very different dollar amounts, the tax incidence (ratio of tax to retail price) was remarkably similar across categories — 13.03% for flower, 13.59% for vaping, and 13.09% for edibles.\n\nHowever, these averages masked enormous state-to-state variation. Standardized taxes and tax incidences varied considerably across the 12 states studied, reflecting the patchwork of tax structures that include ad valorem (percentage-based), weight-based, potency-based, and hybrid approaches applied at different points in the supply chain.","whyItMatters":"Cannabis tax policy is a key lever for public health — higher taxes can reduce use, particularly among price-sensitive populations like young adults. But because states tax cannabis in completely different ways (by weight, by price, by THC content, or some combination), comparing tax levels across states has been nearly impossible. This standardization framework makes those comparisons possible for the first time.","specificNumbers":"12 states analyzed, Q1 2020–Q4 2024. Mean standardized excise taxes: flower $32.58/oz, vaping $180.21/oz, edibles $0.024/mg THC. Tax incidence: flower 13.03%, vaping 13.59%, edibles 13.09%. Significant variation across states in both absolute tax levels and tax incidence.","methodology":"Observational study analyzing cannabis retail scanner data from dispensary point-of-sale systems in 12 states with legal recreational markets, covering Q1 2020 to Q4 2024. Tax structures at each supply chain stage were converted into standardized per-unit measures using retail prices. Tax incidence calculated as the ratio of standardized taxes to retail prices.","limitations":"Scanner data may not capture the full market (excludes illicit sales and some smaller dispensaries). The 12 states studied may not represent all legal markets. Tax structures are evolving rapidly — several states have changed their approaches since the study period. The standardization methodology requires assumptions about how supply-chain taxes pass through to retail prices."},{"rthcId":"RTHC-08314","title":"Authorization of storefront recreational cannabis retailers and cannabis-related healthcare encounters: A local-level spatial difference-in-differences analysis in California, United States.","authors":"Han, Bing; Gunadi, Christian; Shi, Yuyan","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70318","pmid":"41535232","tags":["legalization","medical-cannabis","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Analyzing cannabis-related healthcare encounters across all 482 cities in California from 2010 to 2020, researchers found that authorizing storefront recreational cannabis retailers was associated with increases in three types of healthcare encounters.\n\nCities that permitted recreational dispensaries saw increases in population-adjusted emergency department visits, population-adjusted inpatient discharges, and the likelihood of poison center calls related to cannabis. The spatial difference-in-differences model — which accounts for both within-city changes over time and spatial relationships between cities — revealed something additional: the effects extended beyond the cities that authorized stores.\n\nNeighboring cities that did not authorize their own retailers also experienced increases in cannabis-related healthcare encounters, suggesting a spatial spillover effect. People from cities without dispensaries appeared to be accessing cannabis from nearby authorized retailers and returning to their home communities, where any health complications would be treated locally.","whyItMatters":"This is one of the most methodologically sophisticated studies of how cannabis retail access affects healthcare utilization. The spatial spillover finding is particularly important for local policy debates: cities that opt out of allowing dispensaries may not be fully insulated from the health effects if neighboring cities opt in.","specificNumbers":"482 California cities analyzed, 2010–2020 study period. Three outcomes measured: ED visits, inpatient discharges, and poison center calls. Both within-city and cross-city (spatial spillover) effects detected for cities authorizing recreational cannabis retailers.","methodology":"Secondary data analysis using a spatial difference-in-differences model at the city-quarter level across 482 California cities from 2010 to 2020. Three outcome measures: population-adjusted ED visits, population-adjusted inpatient discharges, and any poison center calls. Controlled for time-varying city-level policies and sociodemographic factors while accounting for spatial influence across neighboring cities.","limitations":"Observational study — cannot establish that dispensary authorization caused the increases (other policy or demographic changes may have occurred simultaneously). Cannabis-related healthcare encounters likely undercount actual health events. The 2010–2020 timeframe captures early legalization effects; patterns may have changed as the market matured. California's local option system may not generalize to states with different regulatory approaches."},{"rthcId":"RTHC-08315","title":"Estimating Price Elasticity of Cannabis Use Among U.S. Adolescents: Evidence From States With Recreational Cannabis Commercialization.","authors":"Han, Bing; Park, Hojin; He, Yanyun; Shang, Ce; Shi, Yuyan","year":2026,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 78(1), 61-68","doi":"10.1016/j.jadohealth.2025.08.021","pmid":"41003445","tags":["adolescents","price-elasticity","policy","legalization","economics"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"An increase in legal cannabis prices was associated with lower likelihood of current cannabis use among adolescents, with estimated price elasticity ranging from -0.33 to -0.21 (p<0.05 for most specifications), but neither cannabis prices nor taxes were significantly associated with frequent cannabis use.","whyItMatters":"As states set cannabis prices and tax rates, this study provides the first estimates of how adolescent use responds to pricing — suggesting taxes alone may not deter teens, but higher retail prices can.","specificNumbers":"N=40,277 adolescents; 10 states; 2015-2022; price elasticity -0.33 to -0.21; significant for current use but not frequent use; tax effects nonsignificant for both outcomes","methodology":"Analysis of Monitoring the Future Survey data (2015-2022) from 40,277 adolescents in 10 states with commercialized recreational cannabis, using logistic regression and generalized method of moments estimation with cannabis tax as an instrumental variable.","limitations":"Inconsistent significance across model specifications; only 10 states included; legal prices may not reflect black market prices teens actually face; self-report measures; cross-sectional repeated surveys; price endogeneity despite instrumental variable approach."},{"rthcId":"RTHC-08316","title":"Skill vs. Disposition: Examining Paths of Intervention Effects in an Alcohol and Drug Use Prevention Trial Targeting U.S. Adolescents.","authors":"Hansen, William B; McNeal, Ralph B","year":2026,"journal":"Journal of prevention (2022), 47(1), 169-189","doi":"10.1007/s10935-025-00881-8","pmid":"41258930","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08317","title":"Chemical Probes for Investigating the Endocannabinoid System.","authors":"Hanske, Annaleah; Nazaré, Marc; Grether, Uwe","year":2026,"journal":"Current topics in behavioral neurosciences, 76, 69-144","doi":"10.1007/7854_2024_563","pmid":"39747798","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08318","title":"Endocannabinoids in Saliva: Origins, Significance, and Research Directions.","authors":"Hargreaves, Jessica; Lipp, Ottmar V; Ney, Luke J","year":2026,"journal":"Cannabis and cannabinoid research, 25785125261423034","doi":"10.1177/25785125261423034","pmid":"41699844","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08319","title":"Stress Responsivity of Endocannabinoids and Related Biomolecules in Plasma and Saliva.","authors":"Hargreaves, Jessica; Jarvis, Madeline; Amir Hamzah, Khalisa; Turner, Natalie; Ney, Luke J","year":2026,"journal":"Cannabis and cannabinoid research, 25785125251387514","doi":"10.1177/25785125251387514","pmid":"41078280","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08320","title":"Placental transfer and vasoactivity of cannabidiol: beware of rapid oxidation.","authors":"Harhangi, M S; Höfert, L; Danser, A H J; Simons, S H P; Reiss, I K M; Baumann, S; Broekhuizen, M","year":2026,"journal":"European journal of pharmacology, 1016, 178653","doi":"10.1016/j.ejphar.2026.178653","pmid":"41662900","tags":["cbd","thc","pregnancy","placenta","pharmacokinetics","vascular"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD achieved a fetal/maternal ratio of 0.32 ± 0.23 and dilated healthy placental arteries by 36 ± 4% via CB1 and CB2 receptors, while THC induced vasoconstriction in the presence of CB1 receptor blockade — but CBD's rapid oxidation (>80% loss in 30 minutes) complicates in vivo predictions.","whyItMatters":"Many pregnant women use CBD products assuming safety, but this study shows CBD reaches the fetus and actively dilates fetal blood vessels — with unknown consequences for fetal development.","specificNumbers":"CBD maternal concentration dropped >80% in 30 min from oxidation; fetal/maternal ratio 0.32 ± 0.23; 11 ± 4% recovered in tissue; CBD dilated arteries 36 ± 4%; dilation attenuated by AM251 and AM630; THC caused constriction with CB1 blockade","methodology":"Ex vivo placental perfusion model using healthy term placentas with CBD quantification by LC-MS/MS, plus wire myography of chorionic plate arteries testing vascular reactivity of CBD and THC with CB1 (AM251) and CB2 (AM630) receptor antagonists.","limitations":"Ex vivo model may not reflect in vivo conditions; rapid CBD oxidation required adding antioxidants that wouldn't be present naturally; healthy term placentas only; single-dose experiments; vascular effects measured in isolation from other placental functions."},{"rthcId":"RTHC-08321","title":"Recreational Cannabis Use During Human Pregnancy: Its Effects on the Placenta and Endocannabinoid System.","authors":"Harhangi, Madhavi S; Höfert, Lisa; Danser, A H Jan; Bijma, Hilmar H; Simons, Sinno H P; Reiss, Irwin K M; Baumann, Sven; Broekhuizen, Michelle","year":2026,"journal":"International journal of molecular sciences, 27(3)","doi":"10.3390/ijms27031398","pmid":"41683846","tags":["pregnancy","thc","cbd","placenta","endocannabinoid-system","epigenetics"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis use interferes with the placental endocannabinoid system which regulates placental development and blood flow, with THC and CBD exerting effects via this system — and epidemiological data linking cannabis use to placental insufficiency, fetal growth restriction, preeclampsia, and potential epigenetic transgenerational effects.","whyItMatters":"With cannabis use during pregnancy increasing alongside legalization and perceived safety, this review compiles the growing evidence that cannabis directly interferes with placental function through a specific biological system.","specificNumbers":"Reviews evidence on both maternal and paternal cannabis use effects; covers THC and CBD; documents links to fetal growth restriction, preeclampsia, placental insufficiency; highlights DNA methylation changes as transgenerational risk","methodology":"Comprehensive narrative review synthesizing evidence on the placental endocannabinoid system, THC/CBD effects on placental function, cannabinoid pharmacokinetics during pregnancy, epidemiological data on birth outcomes, and emerging epigenetic evidence.","limitations":"Narrative review with potential selection bias; many included studies are preclinical; epidemiological data on pregnancy outcomes often has confounders (tobacco, alcohol co-use); epigenetic evidence is early-stage; dose-response relationships poorly characterized."},{"rthcId":"RTHC-08322","title":"From courtroom to clinic: How legal rulings shape cannabis use among adolescents and young adults in South Africa.","authors":"Harker, Nadine; Hornsby, Nancy; Londani, Mukhethwa; Parry, Charles; Carney, Tara","year":2026,"journal":"The International journal on drug policy, 149, 105151","doi":"10.1016/j.drugpo.2026.105151","pmid":"41558226","tags":["decriminalization","south-africa","adolescents","treatment-demand","policy"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Cannabis-related treatment admissions did not increase immediately after the 2018 decriminalization, but rose significantly from 2021 onward with higher odds in 2022 (AOR=1.50, 95% CI=1.38-1.63, p<0.001) and 2023 (AOR=1.48, 95% CI=1.37-1.59, p<0.001) compared to 2019, with higher rates among adolescents, males, and those with lower education.","whyItMatters":"This is one of the first studies to examine cannabis decriminalization effects in an African context, revealing a delayed impact that may reflect gradual normalization of use and increased availability.","specificNumbers":"2015-2023 data; 2018 decriminalization; no immediate increase; significant rise from 2021; 2022 AOR=1.50 (p<0.001); 2023 AOR=1.48 (p<0.001) vs 2019; higher odds among adolescents, males, lower education","methodology":"Retrospective analysis of inpatient and outpatient treatment demand data from South African adolescents (≤18) and young adults (19-25) from 2015-2023, using descriptive statistics and logistic regression adjusted for sociodemographic and treatment variables.","limitations":"Treatment data may reflect help-seeking patterns rather than actual use changes; 2021+ increase coincides with COVID-19 aftermath; no direct cannabis use prevalence data; South African context may not generalize; observational design."},{"rthcId":"RTHC-08323","title":"Cannabis dispensary exposure and smoked, vaped and edible cannabis use among young adults: Comparison of web-scraped and government-maintained registries.","authors":"Harlow, Alyssa F; Williams, Michael P; Pacula, Rosalie Liccardo; Leventhal, Adam M; Pedersen, Eric R; Cockburn, Myles G; Thompson, Laura K; Cho, Junhan; Barrington-Trimis, Jessica L; Haley, Danielle F","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70356","pmid":"41705440","tags":["dispensaries","access","young-adults","legalization","proximity"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Each additional dispensary within 1 mile of home increased past 6-month cannabis use risk by 5-6% (registry data) or 3-4% (web-scraped data), with positive associations for smoked and edible use frequency, but not consistently for vaping frequency or daily use.","whyItMatters":"As cities and states decide where to allow dispensaries, this study provides evidence that dispensary density directly increases cannabis use among nearby young adults — relevant for zoning and licensing decisions.","specificNumbers":"N=2,277; 3 waves (2021-2023); 5-6% increased risk per dispensary (registry); 3-4% (web-scraped); smoked IRR=1.08 (registry), 1.04 (web-scraped); edible IRR=1.07/1.04; not significant for daily/near-daily use","methodology":"Prospective cohort of 2,277 young adults (mean age 22) from California with three waves of data (2021-2023), comparing generalized linear models using government-maintained licensed dispensary registry vs. web-scraped list including unlicensed dispensaries.","limitations":"California-specific sample; observational despite longitudinal design; 1-mile radius may not capture all access patterns; web-scraped data captures unlicensed shops but may be incomplete; confounders related to neighborhood self-selection."},{"rthcId":"RTHC-08324","title":"Delta-9-tetrahydrocannabinol and Cannabidiol for Pain: Preclinical and Clinical Models.","authors":"Harris, H M; Moore, C F; Jenkins, B W; Bedillion, M F; Weerts, E M; Arout, C A","year":2026,"journal":"Current topics in behavioral neurosciences, 76, 389-431","doi":"10.1007/7854_2025_604","pmid":"40877567","tags":["thc","cbd","pain","clinical-trial","preclinical","analgesic"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"While preclinical models consistently show cannabinoid analgesic effects, human studies produce largely mixed results that depend on the specific cannabinoid, route of administration, and pain modality tested — with the current evidence insufficient to make definitive clinical recommendations.","whyItMatters":"Millions of people use cannabis for pain, but this review reveals that the scientific evidence is far more nuanced than either advocates or critics suggest — with significant gaps in our understanding.","specificNumbers":"Reviews preclinical, laboratory, and clinical evidence; covers multiple pain modalities (acute, chronic, neuropathic, inflammatory); examines oral, inhaled, and topical cannabinoid routes","methodology":"Comprehensive narrative review covering pain neurobiology, experimental pain paradigms, preclinical animal models, human laboratory studies, and clinical trials of THC and CBD for various pain conditions.","limitations":"Narrative review format with potential selection bias; heterogeneous studies make comparisons difficult; preclinical findings often don't translate to humans; many clinical studies have small samples or lack adequate controls."},{"rthcId":"RTHC-08325","title":"Test-retest reliability of mgTHC consumption in the self-administered Cannabis Exposure Index (CEI).","authors":"Hasin, Deborah S; Borodovsky, Jacob; Wall, Melanie; Habib, Mohammad I; Murphy, Eilis; Liu, Jun; Stohl, Malki; Struble, Cara A; Livne, Ofir; Greenstein, Eliana; Aharonovich, Efrat; Wisell, Caroline G; Budney, Alan J","year":2026,"journal":"Drug and alcohol dependence, 279, 113028","doi":"10.1016/j.drugalcdep.2026.113028","pmid":"41546987","tags":["measurement","thc-dosing","methodology","cannabis-exposure","reliability"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The self-administered CEI showed substantial overall reliability for mean mgTHC/using day (ICC=0.77), with consistent performance across demographic subgroups (ICCs 0.54-0.86), use motivations (ICCs 0.69-0.77), and state legalization contexts (ICCs 0.70-0.92).","whyItMatters":"For decades, cannabis research has measured 'how often' but not 'how much' — this validated tool allows researchers and clinicians to quantify actual THC exposure, which is essential for understanding dose-response relationships.","specificNumbers":"N=511; overall ICC=0.77; Hispanic ICC=0.86; 'other' race ICC=0.54; medical-only ICC=0.72; recreational-only ICC=0.69; medical+recreational ICC=0.77; binary measures mean kappa=0.74 (30-day), 0.73 (7-day)","methodology":"Test-retest reliability study of 511 participants recruited through social media and research panels, completing initial and retest CEI surveys measuring THC milligrams per using day, with Intraclass Correlation Coefficients and kappa statistics for binary measures.","limitations":"Self-report measure subject to recall bias; online recruitment may not represent all users; THC content estimates depend on product labeling accuracy; moderate ICC in some subgroups; does not capture other cannabinoids."},{"rthcId":"RTHC-08326","title":"Associations between recreational cannabis legalisation and disparities in use and co-use of tobacco and cannabis.","authors":"Hawkins, Summer Sherburne; Baidoo, Christopher E; Centanni, Ryan S; Coley, Rebekah Levine; Baum, Christopher F","year":2026,"journal":"Tobacco control","doi":"10.1136/tc-2025-059748","pmid":"41663273","tags":["legalization","tobacco","co-use","disparities","epidemiology"],"studyType":"quasi-experimental","evidenceStrength":"strong","keyFinding":"Legalization increased cannabis-only use (aRRR=1.88, 95% CI=1.78-1.99) and tobacco-cannabis co-use (aRRR=1.44, 95% CI=1.34-1.54) compared to no use, while decreasing tobacco-only use (aRRR=0.87, 95% CI=0.83-0.91), with co-use increases observed among ages 18-24 and 55+, those with high school education+, and White and Black adults.","whyItMatters":"While legalization reduces tobacco-only use, the simultaneous increase in tobacco-cannabis co-use — which combines the health risks of both substances — represents an unintended consequence that public health responses must address.","specificNumbers":"N=854,878; 38 states; 2016-2023; cannabis-only aRRR=1.88; co-use aRRR=1.44; tobacco-only aRRR=0.87; co-use increases among ages 18-24 and 55+, White and Black adults, those with HS degree+","methodology":"Analysis of 2016-2023 BRFSS data from 854,878 adults in 38 states linked to recreational cannabis legalization status, using multinomial logit regression with demographic/policy controls and state/year fixed effects.","limitations":"BRFSS is self-report and cross-sectional within years; co-use definition doesn't distinguish concurrent from simultaneous use; cannot determine if co-use replaces tobacco-only or represents new users; state-level variation in implementation."},{"rthcId":"RTHC-08327","title":"The Impact of Recreational Cannabis Legalization on Cannabis Use in U.S. Adults From 2016 to 2023: A Quasi-Experimental Study.","authors":"Hawkins, Summer Sherburne; Baidoo, Christopher E; Coley, Rebekah Levine; Centanni, Ryan S; Baum, Christopher F","year":2026,"journal":"American journal of preventive medicine, 108221","doi":"10.1016/j.amepre.2025.108221","pmid":"41543466","tags":["legalization","cannabis-use","disparities","policy","epidemiology"],"studyType":"quasi-experimental","evidenceStrength":"strong","keyFinding":"Legalization was associated with 44% lower odds of zero cannabis use (95% CI=40-48%), indicating more people trying cannabis, but not with greater frequency among existing users — and groups with historically lower use (age 60+, female, White, college-educated) showed the strongest response with 1-2 percentage point increases.","whyItMatters":"This clarifies a key policy debate: legalization is expanding who uses cannabis rather than intensifying use among those who already do — information critical for designing proportionate public health responses.","specificNumbers":"N=859,600; 38 states; 44% lower odds of zero use; 0.94 percentage point increase in use prevalence (9.8% relative increase); greatest increases among age 60+, female, White, college-educated (1-2 pp increases; all interaction p<0.1)","methodology":"Quasi-experimental difference-in-differences analysis of 2016-2023 BRFSS data from 859,600 adults in 38 states, using zero-inflated negative binomial and probit regressions with demographic/policy controls and state/year fixed effects.","limitations":"BRFSS self-report may underestimate use; 30-day use window may miss patterns; difference-in-differences assumes parallel trends; implementation heterogeneity across states; cannot separate legalization from commercialization effects."},{"rthcId":"RTHC-08328","title":"Increasing use of cannabis edibles in response to recreational cannabis legalization in the United States.","authors":"Hawkins, Summer Sherburne; Baidoo, Christopher E; Coley, Rebekah Levine; Centanni, Ryan S; Baum, Christopher F","year":2026,"journal":"Preventive medicine, 204, 108508","doi":"10.1016/j.ypmed.2026.108508","pmid":"41520844","tags":["edibles","legalization","consumption-methods","policy","epidemiology"],"studyType":"quasi-experimental","evidenceStrength":"strong","keyFinding":"Post-legalization, the likelihood of eating/drinking cannabis vs. smoking increased by 35% (aRRR=1.35, 95% CI=1.20-1.52) and vs. vaping by 33% (aRRR=1.33, 95% CI=1.14-1.55), with similar patterns after retail sales began, and larger increases among males and middle-aged/older adults.","whyItMatters":"Edibles present unique risks including delayed onset, overconsumption, and accidental ingestion by children — making this shift in consumption patterns a critical public health signal as legalization expands.","specificNumbers":"N=69,109 cannabis users; 37 states; 2017-2023; smoking declined but remained dominant (62.7% in 2023); edibles 21.5%; vaping 15.8%; edible vs smoking aRRR=1.35; edible vs vaping aRRR=1.33; larger effects among males and older adults","methodology":"Multinomial logit regression analysis of 69,109 adults reporting past-month cannabis use from 37 states in the 2017-2023 BRFSS, linked to recreational cannabis legalization and retail sales data, with state/year fixed effects.","limitations":"BRFSS measures primary mode only (not all modes used); self-report; cannot distinguish product types within edibles; state-level variation; cannot separate legalization from commercialization and product availability effects."},{"rthcId":"RTHC-08329","title":"Drug Repurposing: Conversion of the Peripherally Restricted HIV Protease Inhibitor Amprenavir to Potent, Selective, and CNS-Penetrant Agonists for the Cannabinoid Receptor 2.","authors":"Haymer, Daniel H; Duncan, Renn A; Rodriguez, Alice L; Han, Allie; Lindsay, Richard J; Wijesiri, N Kithmini; Thompson Gray, Analisa; Krishnan, Srinivasan; Qi, Aidong; Brown, Benjamin P; Boutaud, Olivier; Engers, Darren W; Jones, Carrie K; Niswender, Colleen M; Lindsley, Craig W; Bender, Aaron M","year":2026,"journal":"Journal of medicinal chemistry, 69(4), 4187-4207","doi":"10.1021/acs.jmedchem.5c02796","pmid":"41642702","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08330","title":"Sex differences in pain-related behaviour and the endocannabinoid system following hind limb ischemia-reperfusion injury.","authors":"Healy, Catherine R; Redmond, Maria C; Gethin, Georgina; Pandit, Abhay; Finn, David P","year":2026,"journal":"The journal of pain, 40, 106197","doi":"10.1016/j.jpain.2026.106197","pmid":"41577216","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08331","title":"The differential effects of CBD and CBDA on viability and mRNA expression in colorectal cancer cells.","authors":"Heinzle, Christine; Geiger, Kathrin; Ertl, Reinhard; Brandtner, Eva Maria; Leiherer, Andreas; Gaenger, Stella; Schmidmayr, David; Drexel, Heinz; Muendlein, Axel","year":2026,"journal":"Journal of cannabis research, 8(1), 24","doi":"10.1186/s42238-026-00391-2","pmid":"41546069","tags":["cbd","cbda","colorectal-cancer","preclinical","gene-expression"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD exhibited the strongest cytotoxic effect in both CRC cell lines (HCT116 IC50=9.87 μM; HT29 IC50=17.11 μM), while CBDA showed minimal toxicity. Notably, a CBDA-rich cannabis extract had more anti-cancer activity than an equivalent pure CBDA/CBD mixture, suggesting entourage effects from other plant constituents.","whyItMatters":"This study provides the first gene-level comparison of CBD and CBDA in colorectal cancer cells, revealing that whole-plant extracts may be more effective than purified compounds — supporting the entourage effect hypothesis.","specificNumbers":"CBD IC50: HCT116 9.87±0.24 μM, HT29 17.11±2.52 μM, Caco-2 20.02±2.69 μM; CBDA minimal toxicity; extract > pure mixture for HCT116; CBD upregulated Wnt and Hippo signaling; increased caspase-3/7 activity","methodology":"In vitro study testing CBD, CBDA, a CBDA-rich cannabis extract (CBDA:CBD ratio 20:1), and pure CBDA/CBD mixture on HCT116 and DLD1 colorectal cancer cell lines, measuring viability, clonogenic growth, and RNA sequencing for gene expression analysis.","limitations":"In vitro cell line studies don't reflect tumor complexity; CBD concentrations used may not be achievable in vivo; only two cell lines tested for gene expression; CBDA-rich extract composition not fully characterized; no animal or human data."},{"rthcId":"RTHC-08332","title":"Minimum tetrahydrocannabinol dose that produces severe symptoms in children.","authors":"Hendrickson, Robert G; Horowitz, Keahi M; Cowdery, Colleen P","year":2026,"journal":"Clinical toxicology (Philadelphia, Pa.), 64(1), 59-61","doi":"10.1080/15563650.2025.2562305","pmid":"41041913","tags":["pediatric","edibles","thc-dosing","poisoning","safety"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Of 61 children who ingested >30 mg THC, 28% developed severe symptoms, 84% had moderate/major effects, 66% experienced CNS depression, and 17% had respiratory depression — establishing 30 mg as a critical threshold for severe pediatric toxicity.","whyItMatters":"With edibles increasingly available in homes with children, this study identifies a specific dose threshold (30 mg) that should guide product packaging limits, childproofing requirements, and parent education.","specificNumbers":"N=132 children <6 years; 61 ingested >30 mg THC; 28% severe symptoms at >30 mg; 84% moderate/major effects; 66% CNS depression; 17% respiratory depression","methodology":"Retrospective review of Oregon Poison Center records over three years for single-substance edible THC ingestions in children under 6, limited to cases with reliable dose reports and complete follow-up data (n=132).","limitations":"Single poison center; retrospective design; dose estimates based on parental reports of product consumed; cannot verify actual THC content; selection bias toward reported cases; small subgroup at higher doses; 3-year window."},{"rthcId":"RTHC-08333","title":"Perceived impact of medicinal cannabis on pelvic pain and endometriosis related symptoms in Aotearoa New Zealand: an observational cohort study.","authors":"Henry, Claire; Cooper, Lily; Adler, Hannah; Sinclair, Justin; Martin, Alexander; Semprini, Alex; Mikocka-Walus, Antonina; Armour, Mike","year":2026,"journal":"BMC complementary medicine and therapies, 26(1), 60","doi":"10.1186/s12906-025-05189-y","pmid":"41566248","tags":["endometriosis","pelvic-pain","medicinal-cannabis","cbd","womens-health"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Over 12 weeks of medicinal cannabis use, overall pelvic pain scores decreased from 5.46 to 3.77, worst pain from 7.62 to 5.38, and EHP-30 total quality-of-life scores dropped from 68.77 to 37.40 — with limited adverse events reported.","whyItMatters":"Endometriosis affects 1 in 10 women with limited treatment options, and this is among the first prospective studies to track prescribed medicinal cannabis effects on endometriosis symptoms using validated outcome measures.","specificNumbers":"Overall pain: 5.46→3.77; worst pain: 7.62→5.38; EHP-30 total score: 68.77→37.40 (nearly halved); 12-week follow-up; CBD oil ± dried flower; limited adverse events","methodology":"Prospective mixed-methods cohort study of women aged 18-50 with diagnosed endometriosis in New Zealand, prescribed CBD oil alone or with dried cannabis flower, tracking weekly pain scores and EHP-30 quality-of-life measures over 3 months plus completion interviews.","limitations":"No control group (cannot rule out placebo effect or natural symptom fluctuation); small sample; self-selected participants likely to be cannabis-positive; New Zealand regulatory context; 3-month duration only; mixed products used."},{"rthcId":"RTHC-08334","title":"Psychological Need Satisfaction and Simultaneous Alcohol and Marijuana Use: A Moderated Mediation Model of Expectancies and Motives.","authors":"Herchenroeder, Luke; Krishnamurti, Harini; Dodge, Tonya; Yeung, Ellen","year":2026,"journal":"Substance use & misuse, 61(4), 483-490","doi":"10.1080/10826084.2025.2565421","pmid":"41069113","tags":["co-use","alcohol","college-students","psychology","motives"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Lower psychological need satisfaction predicted greater simultaneous alcohol-marijuana (SAM) use through calm/coping and social motives, with the coping pathway strengthened among students with higher positive SAM expectancies, suggesting a vulnerability profile for co-use.","whyItMatters":"Understanding that unmet psychological needs drive co-use through coping motives — especially when amplified by positive expectations — identifies specific intervention targets for reducing risky substance combinations on college campuses.","specificNumbers":"N=822 from 6 universities; 70.2% female; mean age 19.44; coping and social motives mediated PNS→SAM use; moderation significant for coping motives with positive expectancies; predominantly White non-Hispanic (62.9%)","methodology":"Cross-sectional survey of 822 college students from six US universities who reported past-month SAM use, using moderated mediation models testing psychological need satisfaction, SAM motives (calm/coping, social), and positive SAM expectancies.","limitations":"Cross-sectional design limits causal inference; self-selected sample of SAM users; predominantly White and female; self-report measures; university sample may not generalize; doesn't capture actual consumption quantities."},{"rthcId":"RTHC-08335","title":"Synthetic cannabinoid WIN 55,212-2 reduces CHIKV replication, modulates cytokine and chemokine production, and induces ER stress-related transcriptional responses in human monocyte-derived macrophages.","authors":"Hernández-Sarmiento, Lady Johana; Urcuqui-Inchima, Silvio","year":2026,"journal":"International immunopharmacology, 168(Pt 1), 115794","doi":"10.1016/j.intimp.2025.115794","pmid":"41197267","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08336","title":"Tolerance but No Spontaneous Withdrawal Following Repeated THC Injections in Male and Female Rats.","authors":"Hickey, Christa M; Poling, Casey; Grimes, Wyatt; Calvert, Alexa R; Morgan, Michael M","year":2026,"journal":"Cannabis and cannabinoid research, 11(1), 68-77","doi":"10.1177/25785125251404395","pmid":"41335092","tags":["tolerance","withdrawal","sex-differences","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers injected male and female rats with THC (3 mg/kg, twice daily) or vehicle for seven days, then abruptly stopped and monitored for withdrawal symptoms over five days using voluntary home cage wheel running — chosen as a sensitive, objective, and continuous measure.\n\nOn day 1, THC profoundly decreased wheel running in both sexes compared to vehicle-treated rats — confirming the drug's acute sedating effects. By day 8, rats that had received seven days of THC showed significantly less suppression of wheel running from a THC injection than THC-naive rats, demonstrating clear tolerance development. There was no sex difference in the magnitude of tolerance.\n\nHowever, when THC was stopped after day 8, no measurable spontaneous withdrawal was detected in either sex. Wheel running returned to baseline without the rebound disruption that would indicate withdrawal. This was notable because the study specifically chose wheel running as a more sensitive withdrawal measure than the behavioral checklists used in earlier studies, which had also found minimal spontaneous withdrawal from THC.","whyItMatters":"Cannabis withdrawal in humans is well-documented (RTHC-00037, RTHC-00004), but animal models have struggled to replicate it. This study used a dose that clearly produced tolerance — proving the brain adapted to THC — yet found no withdrawal when THC stopped. This disconnect between human and animal findings raises important questions about what drives cannabis withdrawal: is it purely pharmacological, or do psychological and environmental factors play a larger role in humans?","specificNumbers":"THC dose: 3 mg/kg twice daily for 7 days. Clear tolerance demonstrated on day 8. No spontaneous withdrawal detected over 5 days of monitoring. No sex difference in tolerance development. Wheel running used as primary behavioral measure.","methodology":"Male and female Sprague-Dawley rats received THC (3 mg/kg, subcutaneous) or vehicle twice daily for 7 days. Tolerance assessed on day 8 by comparing THC's effects in pre-treated vs. naive rats. Spontaneous withdrawal monitored for 5 days after final dose using voluntary home cage wheel running as the primary outcome measure.","limitations":"The 3 mg/kg dose, while producing clear tolerance, may not be high enough to induce dependence. Seven days of dosing is relatively short. Rats metabolize THC differently than humans. Wheel running, while sensitive, measures only motor activity — other withdrawal symptoms (sleep disruption, anxiety, appetite changes) weren't captured. The subcutaneous injection route doesn't match human inhalation."},{"rthcId":"RTHC-08337","title":"Influence of cannabis use on length of stay in patients admitted to the epilepsy monitoring unit.","authors":"Hoerth, Oliver; Aniles-Renova, Ejerzain; Zhang, Nan; Thompson, Emily; Kirlin, Kristin A; Drazkowski, Joseph","year":2026,"journal":"Epilepsy & behavior reports, 33, 100846","doi":"10.1016/j.ebr.2025.100846","pmid":"41624807","tags":["epilepsy","hospital","cannabis-use","monitoring","mental-health"],"studyType":"retrospective-analysis","evidenceStrength":"preliminary","keyFinding":"Cannabis use was associated with 0.9-day shorter length of stay and 18.1% higher event capture rate in the EMU, alongside significantly higher rates of psychosocial comorbidities: 12.6% physical abuse, 11.1% sexual abuse, 10.2% mental abuse, 18.9% higher MDD rates, and 22.1% higher GAD rates.","whyItMatters":"For epilepsy teams, knowing that cannabis users have shorter stays and more events but complex psychosocial profiles helps tailor monitoring approaches and post-discharge care.","specificNumbers":"Cannabis users: -0.9 days LOS; +18.1% event capture; 12.6% physical abuse; 11.1% sexual abuse; 10.2% mental abuse; +18.9% MDD; +22.1% GAD vs. non-users","methodology":"Retrospective chart review using a REDCap database comparing cannabis users (self-reported or positive urine test) to non-users on EMU outcomes including length of stay, event capture, and psychosocial/psychiatric comorbidities.","limitations":"Retrospective single-center design; cannabis use defined broadly (self-report or positive urine); cannot determine if cannabis caused shorter LOS or if confounders explain the association; selection bias; urine testing not universal."},{"rthcId":"RTHC-08338","title":"Relative Incidence of New-Onset Substance Use Disorders Following Traumatic Brain Injury: A Global Retrospective Multicenter Analysis Using the TriNetX Database.","authors":"Hoglund, Zachary T; Sollenberger, Christopher; Scott, Kyle W; Arena, John D; Srinivasan, Visish M; Burkhardt, Jan-Karl; Turnbull, Jeffrey; Rosado-Philippi, Julio; Heitkotter, Heather; Helfand, Alexander I; Griepp, Daniel W; Claus, Chad F","year":2026,"journal":"Journal of clinical medicine, 15(3)","doi":"10.3390/jcm15031182","pmid":"41682862","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08339","title":"Coping and Expansion Are Concerning Motives for Cannabis Use in a Dancer Cohort.","authors":"Honrado, Joshua; Yassin, Sallie","year":2026,"journal":"Journal of dance medicine & science : official publication of the International Association for Dance Medicine & Science, 1089313X261417188","doi":"10.1177/1089313X261417188","pmid":"41664954","tags":["dancers","cannabis-use-disorder","performing-arts","motives","coping"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Dancers with CUDIT-R scores above 12 were significantly more likely to cite coping (65.6% vs. 29.5%, p<0.001) and expansion motives (43.8% vs. 18.4%, p=0.005), while 14.8% reported failing dance responsibilities due to cannabis use, with these dancers scoring 19.5 vs. 7.7 on the CUDIT-R.","whyItMatters":"This is the first study to examine cannabis use in dancers, revealing that coping-motivated use — common in high-pressure performing arts — is a warning sign for problematic cannabis use patterns.","specificNumbers":"N=108 dancers; 14.8% impaired dance performance; impaired dancers CUDIT-R=19.5 vs 7.7; coping motive: 65.6% vs 29.5% (p<0.001); expansion motive: 43.8% vs 18.4% (p=0.005)","methodology":"Online survey of 108 dancers worldwide (Oct 2023-Jan 2024) who used cannabis in the past 6 months, assessing Cannabis Use Disorder Identification Test-Revised (CUDIT-R) scores, use motives, and performance impacts.","limitations":"Small convenience sample; self-selection bias; online survey; no comparison to non-dancer populations; cross-sectional design; diverse dance styles may have different cultures; survey conducted during specific time window."},{"rthcId":"RTHC-08340","title":"Association of Cannabis and Cigarette Use With Eustachian Tube Dysfunction.","authors":"Hori, Kaitlin; Cobian, Alexander; Gallagher, Tyler; Choi, Janet S","year":2026,"journal":"Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 47(2), 304-311","doi":"10.1097/MAO.0000000000004756","pmid":"41398636","tags":["ear-health","eustachian-tube","smoking","vaping","physical-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Regular cannabis use was independently associated with OETD (OR=1.95, 95% CI=1.02-3.72) after adjusting for cigarette and e-cigarette use, while current cigarette smoking showed even stronger association (OR=2.18, 95% CI=1.27-3.74), and combined use of all three substances increased odds further (OR=2.10, 95% CI=1.23-3.58).","whyItMatters":"Eustachian tube dysfunction can cause ear pain, hearing problems, and recurrent ear infections — this study provides the first evidence that regular cannabis use independently increases this common condition's risk.","specificNumbers":"N=2,777; 4.9% had OETD; regular cannabis use OR=1.95; current cigarette OR=2.18; ever cigarette OR=1.62; combined use (all 3) OR=2.10; e-cigarette use not independently significant","methodology":"Cross-sectional analysis of 2,777 NHANES participants (2015-2018) with complete tympanometry data, using multivariable logistic regression to examine cannabis, e-cigarette, and cigarette use associations with OETD (defined as middle ear pressure <-100 Decapascals).","limitations":"Cross-sectional design; NHANES tympanometry at single timepoint may not reflect chronic OETD; self-reported substance use; cannabis use definition (>15 days) is a high threshold; cannot determine mechanism; relatively small OETD prevalence (4.9%)."},{"rthcId":"RTHC-08341","title":"Between decriminalization policy and police practice: Implementation of warnings for marginalized people dependent on drugs in Denmark.","authors":"Houborg, Esben; Brummer, Julie Elisabeth; Kammersgaard, Tobias; Pedersen, Michael Mulbjerg","year":2026,"journal":"The International journal on drug policy, 148, 105122","doi":"10.1016/j.drugpo.2025.105122","pmid":"41448041","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08342","title":"Therapeutic Use of Cannabis and Cannabinoids: A Review.","authors":"Hsu, Michael; Shah, Arya; Jordan, Ayana; Gold, Mark S; Hill, Kevin P","year":2026,"journal":"JAMA, 335(4), 345-359","doi":"10.1001/jama.2025.19433","pmid":"41296368","tags":["medical-cannabis","cbd","pain","anxiety","harm-reduction","cardiovascular"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Published in JAMA — the most widely read medical journal in the world — this review synthesized the therapeutic evidence for cannabis and cannabinoids across all conditions studied in randomized trials and meta-analyses.\n\nThe strongest evidence supports three FDA-approved indications: HIV/AIDS-related anorexia (cannabinoids moderately increased body weight; SMD 0.57), chemotherapy-induced nausea and vomiting (small but significant reduction; SMD −0.29), and certain pediatric seizure disorders (CBD as Epidiolex).\n\nFor chronic pain — the most common reason people report using medical cannabis — the review found that approximately 27% of US and Canadian adults have used cannabis medicinally, with 10.5% of the US population reporting CBD use for therapeutic purposes. However, evidence-based guidelines do not recommend inhaled or high-potency cannabis (≥10% THC or ≥10 mg THC) for pain management.\n\nThe review also addressed cardiovascular risks, noting emerging evidence of harm, and highlighted the gap between public perception of cannabis as medicine and what clinical trial data actually support.","whyItMatters":"A JAMA review represents the medical establishment's current consensus position. The fact that it was published in 2026 — years after most US states legalized some form of cannabis — signals that the medical community is still working to align clinical practice with evidence. The review's distinction between FDA-approved cannabinoids (which have evidence) and inhaled/high-potency cannabis (which guidelines recommend against) is particularly significant.","specificNumbers":"27% of US/Canadian adults report ever using cannabis medicinally. 10.5% of US population uses CBD therapeutically. Nausea/vomiting: SMD −0.29 (95% CI: −0.39 to −0.18). HIV/AIDS appetite: SMD 0.57 (95% CI: 0.22 to 0.92). Guidelines recommend against inhaled or ≥10% THC/≥10 mg THC products.","methodology":"Narrative review with meta-analytic data published in JAMA. Synthesized evidence from randomized clinical trials and existing meta-analyses across all therapeutic indications for cannabis and cannabinoids. Covered FDA-approved products (dronabinol, nabilone, Epidiolex) and non-approved cannabis preparations.","limitations":"Narrative review format means the evidence synthesis may be selective rather than comprehensive. The rapidly evolving cannabis research landscape means some recent findings may not be captured. Focuses primarily on US-centric FDA approval framework. Does not address the full range of cannabinoid products available in legal markets."},{"rthcId":"RTHC-08343","title":"An Assessment of Marketing Strategies Used by Online Shops Selling Hemp-Derived Delta-8 Products.","authors":"Huang, Bo; Guess, Emma; Pragada, Manasa; Wilson, Clark; Carney-Knisely, Geoffrey; Ferketich, Amy K","year":2026,"journal":"Substance use & misuse, 61(3), 462-465","doi":"10.1080/10826084.2025.2559282","pmid":"40990495","tags":["delta-8","marketing","online-retail","consumer-safety","regulation"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 134 Delta-8 online stores, 37.3% claimed energy-level changes, 36.5% claimed mood effects, 35.1% claimed products were natural/organic, 79.9% linked to social media, over 50% offered discounts, 72.4% noted products were not FDA-regulated, but only 59% required age verification.","whyItMatters":"Delta-8 THC products operate in a regulatory gray area and are sold online where they can bypass state regulations — understanding how they're marketed reveals gaps in consumer protection that regulators need to address.","specificNumbers":"134 online stores analyzed; 37.3% energy claims; 36.5% mood claims; 35.1% natural/organic claims; 79.9% social media links; 50%+ offered discounts; 60.5% product reviews; 53.7% blogs; 72.4% noted no FDA regulation; 59% age verification","methodology":"Cross-sectional content analysis of 134 popular Delta-8 THC online stores captured on a single day, coding main pages for marketing strategies across four themes: product claims, engagement strategies, testimonials/information, and regulations/warnings.","limitations":"Single-day snapshot may not capture temporal changes; 134 stores may not represent all online retailers; coding of marketing claims was at the page level; did not assess actual product quality or verify claims; US-focused market."},{"rthcId":"RTHC-08344","title":"Inhibition of MAGL ameliorates glucocorticoid-induced bone loss by regulating the Nrf2 signaling.","authors":"Huang, Chongjun; Wang, Xiaohui; Liu, Shijia; Xiao, Peilun; Lu, Zeyao; Xu, Ying; Tian, Ye","year":2026,"journal":"Free radical biology & medicine, 243, 67-81","doi":"10.1016/j.freeradbiomed.2025.11.024","pmid":"41242471","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08345","title":"HS-FET-GC/MS-Method Development and Validation for Analysis of 45 Terpenes-Creating a Complementary Tool for Comprehensive Profiling of Cannabis Flowers in Forensics.","authors":"Hundertmark, Marica; Germerott, Tanja; Wunder, Cora","year":2026,"journal":"Drug testing and analysis, 18(1), 118-138","doi":"10.1002/dta.3966","pmid":"41265476","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08346","title":"Δ 9 -Tetrahydrocannabinol-induced enhancement of reward responsivity via mesocorticolimbic modulation in squirrel monkeys.","authors":"Hur, Kwang-Hyun; Nickerson, Lisa D; Bergman, Jack; Stover, Jessi; Kohut, Stephen J","year":2026,"journal":"bioRxiv : the preprint server for biology","doi":"10.64898/2026.01.22.701118","pmid":"41648305","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08347","title":"Psilocybin Outside the Clinic: Public Health Challenges of Increasing Publicity, Accessibility, and Use.","authors":"Hutchison, Kent E; Hooper, Jake F; Karoly, Hollis C","year":2026,"journal":"JAMA psychiatry, 83(1), 78-84","doi":"10.1001/jamapsychiatry.2025.3038","pmid":"41191341","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08348","title":"Cannabis Use Among Individuals With Psychosis After State-Level Commercial Cannabis Legalization.","authors":"Hyatt, Andrew S; Flores, Michael William; Johnson, Julie; Bien-Aime, Danta; Evins, A Eden; Öngür, Dost; Cook, Benjamin Lê","year":2026,"journal":"JAMA psychiatry, 83(1), 74-77","doi":"10.1001/jamapsychiatry.2025.2539","pmid":"41060643","tags":["psychosis","legalization","mental-health","commercialization","vulnerable-populations"],"studyType":"quasi-experimental","evidenceStrength":"strong","keyFinding":"Individuals with psychosis in recreational cannabis legalization states increased 30-day cannabis use by 9.53 percentage points (95% CI=3.05-16.00, p=0.004), with sensitivity analyses showing significant increases after retail outlets opened but not before, and no changes in higher-frequency use.","whyItMatters":"Cannabis can worsen psychosis outcomes, increase hospitalizations, and complicate treatment — yet this vulnerable population shows the largest increase in use after legalization, suggesting current policies inadequately protect high-risk individuals.","specificNumbers":"N=1,856 with psychosis; 7,465 responses; mean age 36.6; 31.8% baseline 30-day use; 9.53 pp increase post-RCL (p=0.004); significant after retail opening; no change in higher-frequency use; larger than general population estimates","methodology":"Difference-in-differences analysis using 2014-2022 Population Assessment of Tobacco and Health longitudinal data from 1,856 adults with lifetime psychosis history (7,465 responses), comparing cannabis use changes in RCL vs. control states.","limitations":"Self-reported psychosis history may include misclassification; cannot determine what types of cannabis were used; 30-day use measure doesn't capture daily patterns; sample size limits subgroup analysis; cannot determine if increased use worsened outcomes."},{"rthcId":"RTHC-08349","title":"Marijuana use and its association with unhealthy weight control and muscle-enhancing behaviors among sexual minority men in the United States: a cross-sectional analysis.","authors":"Ibeh, Chiamaka; Zhao, Yunan; Tran, Alvin","year":2026,"journal":"Journal of cannabis research","doi":"10.1186/s42238-026-00398-9","pmid":"41645275","tags":["body-image","sexual-minority","eating-disorders","men","epidemiology"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Marijuana users had significantly greater odds of all seven body image-related risk behaviors, with adjusted odds ratios ranging from 1.88 (fasting) to 3.12 (diet pill use), including vomiting (AOR=2.61), laxative use (AOR=2.23), protein powder (AOR=2.60), and anabolic steroids (AOR=2.62).","whyItMatters":"Sexual minority men already face elevated eating disorder risk, and this study reveals that marijuana use — often perceived as harmless — is associated with significantly higher rates of dangerous body image behaviors in this population.","specificNumbers":"AORs: fasting 1.88, vomiting 2.61, laxatives 2.23, diet pills 3.12, supplements 2.60, protein powder 2.60, steroids 2.62; all p<0.001","methodology":"Secondary analysis of the Men's Body Project cross-sectional study examining associations between marijuana use and seven weight control/muscle-enhancing behaviors among sexual minority men using logistic regression.","limitations":"Cross-sectional design cannot determine causality; marijuana may be used to cope with existing body image distress; self-report measures; sample composition details limited; no dose-response analysis; potential confounders not fully addressed."},{"rthcId":"RTHC-08350","title":"Stereoselective Synthesis and Structural Confirmation of All Four 8-Hydroxyhexahydrocannabinol Stereoisomers.","authors":"Ieuji, Kei; Nakamura, Kayo; Takahashi, Hideyo","year":2026,"journal":"Molecules (Basel, Switzerland), 31(2)","doi":"10.3390/molecules31020289","pmid":"41599339","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08351","title":"Prevalence and Correlates of Symptoms of Cannabinoid Hyperemesis Syndrome in the United States.","authors":"Ilgen, Mark A; Price, Amanda M; Goldman, Paula; Hicks, Brian M","year":2026,"journal":"medRxiv : the preprint server for health sciences","doi":"10.64898/2026.01.25.26344780","pmid":"41646674","tags":["cannabinoid-hyperemesis-syndrome","prevalence","epidemiology","adverse-effects","diagnosis"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among daily cannabis users (15.2% of adults, ~40 million), 17.8% reported CHS-like symptoms (severe nausea, vomiting, or abdominal pain), translating to an estimated 7.2 million US adults (2.7% national prevalence). Only 11.5% of symptomatic individuals had received a CHS diagnosis from a provider.","whyItMatters":"CHS is frequently dismissed or misdiagnosed, leading to unnecessary ER visits and costly workups — this study reveals it affects millions and is overwhelmingly underdiagnosed.","specificNumbers":"N=7,034; 15.2% daily cannabis use (~40M adults); 17.8% of daily users report CHS symptoms; ~7.2M affected (~2.7% national prevalence); only 11.5% diagnosed; symptomatic users: younger, more female, non-White, lower income, less educated","methodology":"Nationally representative cross-sectional survey (National Firearms, Alcohol, Cannabis, and Suicide survey, 2025) of 7,034 US adults, assessing CHS symptoms, cannabis use patterns, and diagnostic history.","limitations":"Self-report symptoms may overestimate CHS (other causes of nausea/vomiting not excluded); cross-sectional design; survey-based diagnosis proxy; 'daily use in past 5 years' threshold may include former daily users; preprint pending peer review."},{"rthcId":"RTHC-08352","title":"Drug use pattern of suspected drug-influenced drivers in Hungary (2019-2023).","authors":"Institóris, László; Hidvégi, Előd; Rárosi, Ferenc; Sija, Éva; Kovács, Katalin; Süvegh, Gábor; Berkecz, Róbert; Kereszty, Éva M","year":2026,"journal":"Forensic science international, 378, 112681","doi":"10.1016/j.forsciint.2025.112681","pmid":"41110340","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08353","title":"Spent hemp biomass as a feed ingredient for beef steers: effects on performance, blood parameters, behavior, cannabinoid residues, and consumer exposure levels.","authors":"Irawan, A; Hasan, D; Cruickshank, J; Estill, C T; Ates, S; Trevisi, E; Ranches, J; Dolan, B; Bionaz, M","year":2026,"journal":"Animal : an international journal of animal bioscience, 20(1), 101715","doi":"10.1016/j.animal.2025.101715","pmid":"41352290","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08354","title":"Cannabis use, cognitive function and dementia risk in older adults: observational and genetic analyses.","authors":"Ishrat, Saba; Levey, Daniel F; Gelernter, Joel; Ebmeier, Klaus P; Topiwala, Anya","year":2026,"journal":"BMJ mental health, 29(1)","doi":"10.1136/bmjment-2025-302290","pmid":"41741130","tags":["dementia","cognition","aging","mendelian-randomization","longitudinal"],"studyType":"cohort","evidenceStrength":"strong","keyFinding":"In the UK Biobank, cannabis users performed modestly better on some baseline cognitive tests but showed no difference in longitudinal cognitive change. In the Million Veteran Program, cannabis use disorder was not significantly associated with dementia (HR=1.11, 95% CI=0.97-1.26, p=0.12). Mendelian randomization found no causal relationship in either direction.","whyItMatters":"As cannabis use among older adults surges, many worry about cognitive effects — this large-scale evidence from two major cohorts and genetic analyses provides reassurance that cannabis use doesn't appear to accelerate cognitive aging.","specificNumbers":"UKB: up to 79,573 participants; MVP: 12,222 with cannabis use disorder vs controls; cannabis users slightly better on numeric memory (β=0.07) and fluid intelligence (β=0.12); no longitudinal difference; dementia HR=1.11 (NS); MR: no causal evidence","methodology":"Observational analyses in UK Biobank (up to 79,573 participants, cross-sectional and longitudinal cognitive testing) and US Million Veteran Program (12,222 with cannabis use disorder, Cox proportional hazards for dementia), plus bidirectional two-sample Mendelian randomization.","limitations":"Lifetime use measure doesn't capture current heavy use; UK Biobank may underrepresent heavy users; healthy volunteer bias; MR instruments may have limited power; cannot rule out effects at very high consumption levels; cannabis use disorder is extreme end of spectrum."},{"rthcId":"RTHC-08355","title":"Cannabis Use for Chronic Pain in Sickle Cell Disease: A Scoping Review.","authors":"Jackson, Simone B; Payton, Isaac; Powell-Roach, Keesha; Starkweather, Angela; Cook, Robert L; Varma, Deepthi S; Terry, Ellen L; Booker, Staja Q","year":2026,"journal":"Pain management nursing : official journal of the American Society of Pain Management Nurses, 27(1), e17-e25","doi":"10.1016/j.pmn.2025.06.010","pmid":"40713408","tags":["sickle-cell-disease","chronic-pain","medicinal-cannabis","review"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Of 12 qualifying studies (1 clinical trial, 2 reviews, 7 observational, 1 mixed-methods, 1 qualitative), evidence was mixed but generally positive for cannabinoid effectiveness in SCD pain — with some studies showing reduced pain scores from inhaled cannabis, though results varied for hospitalizations and raised safety concerns for synthetic cannabinoids.","whyItMatters":"Sickle cell disease causes severe chronic pain with limited treatment options, and patients increasingly use cannabis — yet the evidence base is remarkably thin, consisting of just one clinical trial and mostly observational data.","specificNumbers":"369 articles screened; 12 included (1 clinical trial, 2 reviews, 7 observational, 1 mixed-methods, 1 qualitative); inhaled cannabis showed pain reduction; mixed results for vaso-occlusive crisis hospitalizations; no exacerbation of SCD symptoms","methodology":"Scoping review following PRISMA-ScR guidelines, searching PubMed, CINAHL, and Cannakeys for studies on cannabis use in adult SCD patients addressing pain, yielding 12 of 369 screened articles.","limitations":"Only 12 qualifying studies with just 1 clinical trial; heterogeneous study designs; variable cannabis types and routes; observational studies subject to confounding; scoping review format doesn't assess quality; limited generalizability."},{"rthcId":"RTHC-08356","title":"Adverse Childhood Experiences, Discrimination, Nativity, and Associations with Tobacco and Cannabis Use Among Black Young Adults in the U.S.","authors":"Jacobs, Wura; Qin, Weisiyu Abraham; Baiden, Philip; Amuta-Jimenez, Ann; Zapolski, Tamika","year":2026,"journal":"Substance use & misuse, 61(2), 227-236","doi":"10.1080/10826084.2025.2549786","pmid":"40898011","tags":["adverse-childhood-experiences","discrimination","race","nativity","young-adults"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Each additional ACE increased tobacco/nicotine product count by 5% (IRR=1.05) and lowered odds of abstaining from cannabis (aOR=0.83, 95% CI=0.73-0.95), while everyday discrimination independently increased tobacco exposure by 2% per experience. Foreign-born Black young adults had 40% lower cannabis product count (IRR=0.60) than US-born peers.","whyItMatters":"Understanding how childhood trauma and racism drive cannabis use in Black communities — and how nativity creates different risk profiles — can inform culturally responsive prevention and intervention strategies.","specificNumbers":"N=484; 53.1% female; 37.6% foreign-born; ACE→tobacco IRR=1.05; discrimination→tobacco IRR=1.02; ACE→cannabis abstinence aOR=0.83; ACE→co-occurring exposure aOR=1.17; foreign-born cannabis IRR=0.60","methodology":"Cross-sectional study of 484 Black young adults (mean age 21.96, 37.6% foreign-born) recruited through online panels, using zero-inflated negative binomial and logistic regression to examine ACEs, discrimination, nativity, and substance use.","limitations":"Cross-sectional design; self-report measures; online convenience sample; cannot separate lifetime from current use patterns; nativity as binary may mask within-group diversity; ACE and discrimination scales may not capture all relevant experiences."},{"rthcId":"RTHC-08357","title":"Spontaneous Pneumomediastinum and Cannabinoid Hyperemesis Syndrome: A Case Report and Literature Review.","authors":"Jafry, Baqir; Chillag, Shawn","year":2026,"journal":"Cureus, 18(1), e101979","doi":"10.7759/cureus.101979","pmid":"41728401","tags":["cannabinoid-hyperemesis-syndrome","pneumomediastinum","adverse-effects","case-report","emergency-medicine"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"An 18-year-old male with chronic cannabis use presented with chest pain, shortness of breath, and abdominal pain; CT revealed mediastinal air without esophageal perforation, consistent with spontaneous pneumomediastinum caused by CHS-related forceful vomiting. He was managed conservatively and recovered.","whyItMatters":"Spontaneous pneumomediastinum can mimic life-threatening conditions like esophageal perforation — recognizing CHS as a cause can prevent unnecessary invasive procedures and guide appropriate management.","specificNumbers":"18-year-old male; 6 months of chronic cannabis use; only 5th reported case of CHS-induced SPM; managed conservatively with bowel rest, IV antibiotics, and supportive care","methodology":"Single case report with CT imaging, esophagram confirmation, conservative management, and literature review of the CHS-SPM association.","limitations":"Single case report; cannot establish prevalence; may be underreported; conservative management typical for SPM regardless of cause; no long-term follow-up reported; cannabis use history based on patient report."},{"rthcId":"RTHC-08358","title":"How do substance and polysubstance use trajectories differ by sexual attraction from ages 17 to 24? A community-based longitudinal cohort study in Switzerland.","authors":"Janousch, Clarissa; Vock, Florian; Winter, Babette L; Hässler, Tabea; Eggenberger, Lukas; Bechtiger, Laura; Loher, Michelle; Binz, Tina Maria; Baumgartner, Markus R; Ribeaud, Denis; Eisner, Manuel; Quednow, Boris B; Shanahan, Lilly","year":2026,"journal":"BMJ public health, 4(1), e003583","doi":"10.1136/bmjph-2025-003583","pmid":"41626608","tags":["sexual-minority","adolescents","longitudinal","polysubstance-use","switzerland"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Sexual minority males exhibited the sharpest escalation in cannabis, stimulant, and polysubstance use from 17-24, reaching the highest levels by 24, while sexual minority females started with high use at 17 that plateaued by 20-24. The proportion identifying as sexual minority nearly doubled from 11.3% at 17 to 23.4% at 24.","whyItMatters":"The distinct escalation timelines between sexual minority males (late sharp rise) and females (early high plateau) mean that one-size-fits-all prevention programs will miss their target — timing matters.","specificNumbers":"N=1,384; SM proportion: 11.3% (age 17) → 23.4% (age 24); SM males: lowest at 17, highest PSU by 24; SM females: high at 17, plateau by 20; hair-tested validation at 20 and 24; predictors: peer SU, low self-control, sensation-seeking, internalizing symptoms","methodology":"Longitudinal cohort analysis of 1,384 participants from the Zurich Project on Social Development from Childhood to Adulthood, with self-reported and hair-tested substance use at ages 17, 20, and 24, using linear mixed-effect models.","limitations":"Swiss sample may not generalize globally; sexual minority identification changed over time (fluid identity); small SM subgroups limit statistical power; substance use norms differ across countries; hair testing captures only some substances."},{"rthcId":"RTHC-08359","title":"The emergence of problematic cannabis use as a network phenomenon.","authors":"Järvelin, Ronja Maria","year":2026,"journal":"The International journal on drug policy, 149, 105175","doi":"10.1016/j.drugpo.2026.105175","pmid":"41637794","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08360","title":"Complex relationship between endocannabinoids, fatty acid amide hydrolase, and stress reactivity in human intrusive memories of analogue trauma.","authors":"Jarvis, Madeline A; Matthews, Allison; Hsu, Ken Chia Min; Nicholson, Emma; Hamzah, Khalisa Amir; Turner, Natalie; Zuj, Daniel V; Nichols, David; Felmingham, Kim; Ney, Luke J","year":2026,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 144, 111610","doi":"10.1016/j.pnpbp.2026.111610","pmid":"41534588","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08361","title":"Relationship between circulating plasma endocannabinoids in adolescents and maternal depressive symptoms.","authors":"Jaster, Alaina M; Ely, Samantha L; Zundel, Clara G; Gowatch, Leah C; Shampine, MacKenna; Carpenter, Carmen; O'Mara, Emilie; Bhogal, Amanpreet; Tamimi, Reem; Lewis, Christine; Sharma, Kamakashi; Losiowski, Jennifer; Marusak, Hilary A","year":2026,"journal":"Psychopharmacology, 243(2), 369-381","doi":"10.1007/s00213-025-06831-w","pmid":"40531314","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08362","title":"Prevalence of schizophrenia spectrum and bipolar disorder among patients with cannabis induced psychosis: a systematic review and meta-analysis.","authors":"Javed, Mohammad Saad; El-Khoury, Rayane; Taha, Amr Ahmed; Reagu, Shuja Mohd","year":2026,"journal":"BMC psychiatry, 26(1), 186","doi":"10.1186/s12888-025-07382-2","pmid":"41664079","tags":["psychosis","mental-health","addiction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Pooling data from 13 studies with a total of 7,515 patients diagnosed with cannabis-induced psychosis, this meta-analysis calculated the rates at which these individuals later received diagnoses of schizophrenia spectrum disorder or bipolar disorder.\n\nThe conversion rates were substantial. Approximately one-third of patients with cannabis-induced psychosis eventually received a schizophrenia spectrum diagnosis, while about one in ten was later diagnosed with bipolar disorder. The 16 outcomes reported across the 13 studies showed consistent patterns despite variation in study design, follow-up periods, and geographic locations.\n\nMeta-regression analyses explored what predicted higher conversion rates, looking for factors that distinguished patients who went on to develop chronic psychotic illness from those whose psychosis resolved without recurrence.","whyItMatters":"Distinguishing cannabis-induced psychosis from the onset of a primary psychotic disorder is one of the most consequential diagnostic challenges in psychiatry. This meta-analysis quantifies the stakes: about a third of cannabis-induced psychosis cases may actually be the first presentation of schizophrenia spectrum illness. That finding has direct implications for how aggressively clinicians should monitor and treat patients after a cannabis-induced psychotic episode.","specificNumbers":"13 studies, 7,515 patients with cannabis-induced psychosis. 16 outcomes reported. Approximately 34% later diagnosed with schizophrenia spectrum disorder. Approximately 11% later diagnosed with bipolar disorder. Combined conversion rate to either condition: roughly 40–45%.","methodology":"Systematic review and meta-analysis searching Medline, Embase, Web of Science, Google Scholar, and PsychInfo through January 2025. Included studies reporting on patients with cannabis-induced psychosis who were followed for subsequent schizophrenia spectrum or bipolar disorder diagnoses. Quality assessed using modified Newcastle-Ottawa scale. Random-effects meta-analyses calculated pooled prevalence; meta-regressions identified predictors.","limitations":"Observational studies with variable follow-up periods — some patients may convert after the study period ends, meaning these rates could be underestimates. Diagnosis of cannabis-induced psychosis vs. primary psychotic disorder is inherently difficult at first presentation. Studies could not control for all confounders (genetics, polysubstance use, premorbid function). Publication bias may affect results."},{"rthcId":"RTHC-08363","title":"Effects of oral cannabidiol (CBD) on spontaneous opioid withdrawal in male and female rats.","authors":"Jenkins, Bryan W; Pang, Cerina; Kuang, Robbie Y; Weerts, Elise M; Moore, Catherine F","year":2026,"journal":"Experimental and clinical psychopharmacology","doi":"10.1037/pha0000826","pmid":"41525358","tags":["cbd","withdrawal","addiction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In a well-powered study (N=100, 50% female), researchers made rats dependent on morphine through 10 days of escalating doses (10–50 mg/kg, twice daily), then abruptly stopped and treated with oral CBD (10 or 30 mg/kg daily) or vehicle starting 14 hours after the last morphine injection.\n\nThe results were largely negative for CBD's ability to treat acute withdrawal. Morphine-dependent rats showed the expected withdrawal syndrome — weight loss, reduced food intake, somatic signs (body shakes, diarrhea), and pain sensitivity. CBD at either dose did not significantly reduce these acute withdrawal measures compared to vehicle.\n\nIn the protracted withdrawal phase (up to day 7), there were some signals: anxiety-like behavior measures showed potential CBD effects, but these appeared to differ between males and females. The overall pattern suggested that CBD's impact on opioid withdrawal — at least at these doses and in this model — was limited and potentially sex-dependent rather than broadly therapeutic.","whyItMatters":"CBD is being investigated as a potential treatment for opioid use disorder, with some observational studies suggesting benefit. This controlled animal study provides a reality check: in a well-powered experiment with both sexes, CBD did not meaningfully reduce acute opioid withdrawal symptoms. This is important context for the clinical enthusiasm surrounding CBD as an addiction treatment tool.","specificNumbers":"100 rats (50 female). Morphine escalated from 10 to 50 mg/kg over 10 days. CBD doses: 10 and 30 mg/kg oral, daily. Neither CBD dose significantly reduced acute withdrawal measures. Some sex-specific effects in protracted phase anxiety measures.","methodology":"100 Sprague-Dawley rats (50% female) received escalating morphine (10–50 mg/kg, twice daily) for 10 days. After abrupt discontinuation, rats received daily oral CBD (10 or 30 mg/kg) or vehicle. Withdrawal assessed through physical measures (body weight, food intake, somatic signs), pain sensitivity, and anxiety-like behaviors across acute (38-hour) and protracted (up to day 7) timepoints.","limitations":"Animal model — rat morphine withdrawal may not perfectly model human opioid withdrawal. Oral CBD dosing may not achieve optimal brain levels (bioavailability issues noted in RTHC-00246). Only two CBD doses tested; higher doses might show different effects. The 10-day morphine protocol produces moderate dependence; more severe dependence might respond differently."},{"rthcId":"RTHC-08364","title":"Advances in Functional Foods: Using Double Emulsion Gels to Deliver CBD and Probiotics and to Modulate Human Gut Microbial Communities.","authors":"Jeznienė, Sigita; Jasutienė, Ina; Keršienė, Milda; Bandariavičiūtė, Rita; Varnaitė-Kapočė, Laurita; Bartkuvienė, Ieva; Budrienė, Vida Audra; Jonušas, Arūnas; Leskauskaitė, Daiva; Šipailienė, Aušra","year":2026,"journal":"Nutrients, 18(3)","doi":"10.3390/nu18030367","pmid":"41683191","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08365","title":"Recreational cannabis use is the driving factor for participation in medical cannabis trials in inflammatory rheumatic diseases.","authors":"Jg, Richter; Beichert, A; Filla, T; Chehab, G; Sert, D; Aslandag, M; Distler, Jhw; Schneider, M; Frohne, I","year":2026,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 150, 157599","doi":"10.1016/j.phymed.2025.157599","pmid":"41338110","tags":["rheumatic-diseases","clinical-trials","medicinal-cannabis","patient-attitudes","recruitment"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Previous recreational cannabis use was the strongest predictor of interest in medical cannabis clinical trials (OR=1.89), followed by limitations in daily activities (OR=1.08) and biologic DMARD therapy (OR=1.43). Barriers included insufficient information (67%), fear of side effects (40%), and fear of dependence (31%).","whyItMatters":"If recreational cannabis users self-select into medical cannabis trials, study results may not generalize to cannabis-naive patients — a critical methodological concern for the entire field of cannabinoid clinical research.","specificNumbers":"N=250; 67% female; 85% medication satisfaction; 35% interested in MC trials + 41% potentially interested; recreational use OR=1.89; daily activity limitations OR=1.08; bDMARD OR=1.43; barriers: information gap 67%, side effects 40%, dependence 31%","methodology":"Survey of 250 inflammatory rheumatic disease patients (67% female) using an innovative chatbot app (Asepha) for patient-centered data collection, assessing sociodemographic, disease, treatment, and cannabis-related factors predicting clinical trial willingness.","limitations":"Single-center survey; convenience sample; self-reported recreational use; chatbot survey format may select tech-savvy patients; hypothetical willingness may not translate to actual enrollment; German regulatory context may not generalize."},{"rthcId":"RTHC-08366","title":"Adsorption and mechanism of magnetically modified industrial hemp straw biochar on microplastics in aqueous solution.","authors":"Jiang, Xi; Cai, Youxi; Deng, Hanwen; Li, Xiaolei","year":2026,"journal":"Journal of contaminant hydrology, 277, 104844","doi":"10.1016/j.jconhyd.2026.104844","pmid":"41500168","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08367","title":"Delta-9-Tetrahydrocannabinol alleviates doxorubicin-induced weight loss but does not affect dextran sodium sulphate-induced colitis.","authors":"Johansen, Malene Wiborg; Andersen, Maria C E; Nissen, Thomas; Nexoe, Anders B; Ünsal, Seyda; Madsen, Gunvor I; Möller, Sören; Kjeldsen, Jens; Sorensen, Grith Lykke; Holmskov, Uffe; Husby, Steffen; Rathe, Mathias","year":2026,"journal":"Journal of cannabis research, 8(1), 23","doi":"10.1186/s42238-026-00386-z","pmid":"41530821","tags":["thc","chemotherapy","weight-loss","preclinical","gastrointestinal"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"THC (10-20 mg/kg daily) significantly reduced doxorubicin-induced weight loss and increased small intestine length in mice, but showed no effect on pro-inflammatory cytokine gene expression or DSS-induced colitis, suggesting the benefit was likely from appetite stimulation rather than anti-inflammatory mechanisms.","whyItMatters":"Chemotherapy-induced weight loss worsens patient outcomes, and THC's ability to reduce this in an animal model supports ongoing interest in cannabinoids as supportive care during cancer treatment.","specificNumbers":"THC doses: 10 mg/kg and 20 mg/kg daily; significant weight loss reduction in doxorubicin model; increased small intestine length; no cytokine gene expression changes; no effect on DSS colitis model","methodology":"Preclinical study in C57BL6 mice receiving daily oral THC oil (10 or 20 mg/kg) with either doxorubicin-induced gastrointestinal mucositis or DSS-induced colitis, evaluating weight, intestinal length, histopathology, and gene expression.","limitations":"Mouse model may not translate to humans; oral gavage differs from typical human consumption; limited dose range; acute models don't reflect chronic treatment; no direct appetite measurement; specific to doxorubicin and DSS models."},{"rthcId":"RTHC-08368","title":"Youth cannabis and alcohol use expectancies mediate associations between pre-adolescent cognitive function and subsequent use initiation.","authors":"Jones, Stephanie K; Tomko, Rachel; Ramer, Nolan; Wolf, Bethany J","year":2026,"journal":"Addictive behaviors, 173, 108533","doi":"10.1016/j.addbeh.2025.108533","pmid":"41172720","tags":["adolescents","cognition","expectancies","prevention","abcd-study"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Higher general ability at ages 9-10 was associated with cannabis initiation by 13-14 (OR=1.23), with positive cannabis expectancies mediating 72.6% of the effect (p=0.003). Better visuospatial reasoning was protective (OR=0.83). Positive alcohol expectancies mediated 36.3% of the general ability-alcohol use association.","whyItMatters":"This counterintuitive finding — that cognitive ability predicts cannabis use — is almost entirely explained by positive expectancies, meaning prevention programs that challenge positive cannabis beliefs could be targeted and effective.","specificNumbers":"N=7,776; general ability→cannabis OR=1.23; 72.6% mediated by positive expectancies (p=0.003); -10.2% mediated by negative expectancies (p=0.04); visuospatial reasoning protective OR=0.83; positive alcohol expectancy mediated 36.3%","methodology":"Prospective longitudinal analysis of 7,776 ABCD Study participants enrolled at ages 9-10 (2016-2018) through ages 13-14, examining how pre-adolescent neurocognitive factors predict substance use initiation through expectancy mediation models.","limitations":"ABCD Study cohort may not represent all US youth; expectancies measured concurrently with some substance use; mediation models assume temporal ordering; cannot fully separate curiosity from actual use; cannabis use by 13-14 is relatively uncommon."},{"rthcId":"RTHC-08369","title":"Geographic Differences in Cannabis Use and Cannabis Use Disorder in the US Veteran Population.","authors":"Joseph Denk, Annie-Lori; True, Sarah B; Hill, Melanie L; Fischer, Ian C; Na, Peter Jongho; Pietrzak, Robert H","year":2026,"journal":"The Journal of clinical psychiatry, 87(1)","doi":"10.4088/JCP.25m16141","pmid":"41603791","tags":["veterans","geographic-variation","cannabis-use-disorder","epidemiology","regional"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among 2,441 veterans, 11.6% reported cannabis use and 2.9% screened positive for probable CUD, with significant regional variation across 9 US Census regions (χ²=73.33, p<0.001), revealing geographic hotspots requiring targeted intervention.","whyItMatters":"VA healthcare systems serving veterans in high-prevalence regions need to prioritize cannabis screening and CUD treatment resources, while lower-prevalence regions may have different intervention needs.","specificNumbers":"N=2,441 veterans; 85.5% no use; 11.6% cannabis use; 2.9% probable CUD; significant variation across 9 Census regions (p<0.001)","methodology":"Cross-sectional analysis of the 2022 National Health and Resilience in Veterans Study (N=2,441), a nationally representative sample, examining cannabis use and probable CUD across 9 US Census Bureau-defined regions using weighted chi-square tests.","limitations":"Cross-sectional snapshot; self-report may underestimate use; 2022 data predates some state legalization changes; veteran population may differ from general population; regional groupings may mask within-region variation."},{"rthcId":"RTHC-08370","title":"Community pharmacists' practices and perspectives on deprescribing high-risk psychotropic medicines: National survey findings.","authors":"Jung, Monica; Picco, Louisa; Langford, Aili V; Laing, Rose; Dostal, Jana; Nielsen, Suzanne","year":2026,"journal":"British journal of clinical pharmacology","doi":"10.1002/bcp.70466","pmid":"41636468","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08371","title":"Determination of cannabinoids in commercial hemp seeds and hemp seed oil products in Türkiye by LC-MS/MS.","authors":"Kacargil, Cagdas Ufuk; Soyturk, Hatice; Aydin, Asli Atasoy; Gören, İsmail Ethem; Demirel, Goksun; Daglioglu, Nebile","year":2026,"journal":"Forensic science international, 381, 112836","doi":"10.1016/j.forsciint.2026.112836","pmid":"41621128","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08372","title":"Synthetic Cannabinoid Use and Sports-Related Concussion Risk Among US Adolescents: Implications for School Health Screening and Prevention.","authors":"Kalra, Saurabh; Nagaraja, Nandakumar; Kalra, Deepak","year":2026,"journal":"The Journal of school health, 96(2), e70112","doi":"10.1111/josh.70112","pmid":"41490792","tags":["synthetic-cannabinoids","concussion","adolescents","sports","traumatic-brain-injury"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoid use was associated with 48% higher odds of sports-related TBI (AOR=1.48, 95% CI=1.30-1.70), with TBI prevalence of 22.9% among SC users vs. 12.4% among non-users. Natural marijuana use was also a significant but weaker predictor (AOR=1.16).","whyItMatters":"Synthetic cannabinoids are cheap, evade standard drug tests, and may impair coordination and reaction time more severely than natural cannabis — creating a hidden safety risk in youth sports.","specificNumbers":"N=27,482; 6.0% SC use; 13% sports TBI; SC users: 22.9% TBI vs 12.4% non-users; SC AOR=1.48; marijuana AOR=1.16; alcohol AOR=1.75; boys AOR=1.38","methodology":"Analysis of 2017-2021 Youth Risk Behavior Survey data (n=27,482 nationally representative adolescents), using weighted multivariable logistic regression examining lifetime synthetic cannabinoid use and self-reported past-year sports-related concussion.","limitations":"Cross-sectional design; self-reported outcomes; cannot determine temporal relationship; lifetime SC use may not reflect use during sports; concussion self-report may be inaccurate; potential confounding from risk-taking behavior generally."},{"rthcId":"RTHC-08373","title":"Phase II randomized controlled trial comparing traditional Thai cannabis-based medicine with lorazepam for insomnia treatment.","authors":"Kamoltham, Thavatchai; Chokchaisiri, Suwadee; Yongram, Chawalit; Sripan, Panupan; Im-Iam, Surasak; Sanasit, Panupong; Intaravattana, Varanon; Sawasdichai, Chatchai; Udompat, Patpong; Chaiphongpachara, Tanawat; Kummalue, Tanawan","year":2026,"journal":"Journal of cannabis research","doi":"10.1186/s42238-026-00415-x","pmid":"41736083","tags":["insomnia","thai-medicine","clinical-trial","herbal","lorazepam"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"The traditional Thai cannabis formulation demonstrated non-inferiority to lorazepam: at week 4, mean PSQI scores were 3.44 (experimental) vs. 4.78 (lorazepam), with a mean difference of -1.34 (95% CI: -2.99 to 0.31), meeting the predefined non-inferiority margin of 2.1.","whyItMatters":"Benzodiazepines like lorazepam carry addiction risk, and finding a cannabis-based alternative that works as well with comparable safety could provide a safer option for the millions with chronic insomnia.","specificNumbers":"N=100 randomized (82 completers); 4-week treatment; PSQI: experimental 3.44 vs lorazepam 4.78; difference -1.34 (95% CI: -2.99 to 0.31); non-inferiority margin 2.1; no significant adverse effects","methodology":"Phase II randomized, double-blind, active-controlled non-inferiority trial with 100 participants (82 completers, 41 per group) receiving either the Anti-Pom-Leung Fever multi-herbal formulation or lorazepam for 4 weeks, assessed by Pittsburgh Sleep Quality Index.","limitations":"Active-controlled without placebo arm (cannot rule out both treatments being equally ineffective); small sample (82 completers); 4-week duration only; multi-herbal formulation makes it impossible to isolate cannabis effects; Thai regulatory context limits generalizability."},{"rthcId":"RTHC-08374","title":"Prevalence of substance use and food insecurity among transgender and gender diverse college students.","authors":"Kane, Tyler; Han, Ho; Lee, Seunghwan; Grant, Elysia; McMaughan, Darcy Jones; Jones, Richard; Ryu, Yoonji","year":2026,"journal":"Journal of American college health : J of ACH, 1-8","doi":"10.1080/07448481.2025.2611280","pmid":"41604678","tags":["transgender","college-students","substance-use","disparities","food-insecurity"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"After controlling for confounders, TGD students had significantly higher odds of using cannabis (OR=1.58), hallucinogens (OR=1.87), prescription stimulants (OR=1.32), and cocaine (OR=1.24) compared to cisgender peers, with significantly higher proportions of TGD cannabis users reporting consequent problems (p<0.05).","whyItMatters":"Transgender students face unique stressors (discrimination, identity-related distress) that may drive substance use, and their higher rate of cannabis-related problems suggests they need tailored harm reduction support.","specificNumbers":"N=102,802; TGD vs cisgender odds: cannabis OR=1.58, hallucinogens OR=1.87, stimulants OR=1.32, cocaine OR=1.24; significantly higher problem rates among TGD substance users (p<0.05)","methodology":"Secondary analysis of 102,802 undergraduates from the Fall 2020 and Spring 2021 American College Health Association's National College Health Assessments, using logistic regression adjusted for confounding factors.","limitations":"Cross-sectional design; 2020-2021 data collected during COVID-19; self-report measures; TGD identification may vary; cannot determine causality; food insecurity also elevated suggesting broader structural vulnerability."},{"rthcId":"RTHC-08375","title":"Global burden of amphetamine, cannabis, cocaine and opioid use in 204 countries, 1990-2023: a Global Burden of Disease Study.","authors":"Kang, Jiseung; Kim, Hyeon Jin; Kim, Min Seo; Shin, Jae Il; Yon, Dong Keon","year":2026,"journal":"Nature medicine, 32(2), 527-544","doi":"10.1038/s41591-025-04137-0","pmid":"41545593","tags":["global-burden","cannabis-use-disorder","epidemiology","legalization","opioids"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"In 2023, cannabis use disorder was the most prevalent drug use disorder globally (age-standardized prevalence 270.8 per 100,000), followed by opioid use disorder (205.9). Countries permitting both recreational and medical cannabis had higher prevalence rates for all types of drug use disorders compared to countries where cannabis was illegal.","whyItMatters":"Published in Nature Medicine, this comprehensive global analysis reveals that cannabis use disorder has become the world's most common drug use disorder, with legalization policies associated with higher rates across all substance categories.","specificNumbers":"204 countries; 1990-2023; global DALYs: 169.3→212.0 per 100,000; CUD prevalence 270.8/100,000 (most prevalent DUD); OUD 205.9/100,000 (nearly doubled since 1990); highest burden in high-income countries, especially US; legal recreational+medical countries had higher all-DUD rates","methodology":"Analysis of Global Burden of Disease Study 2023 data covering 204 countries and territories from 1990-2023, examining trends in prevalence, disability-adjusted life-years, and burden of amphetamine, cannabis, cocaine, and opioid use disorders.","limitations":"GBD estimates rely on modeling with data quality varying across countries; cross-country comparisons confounded by reporting differences; association between legal status and DUD prevalence doesn't prove causation; diagnostic criteria may vary across cultures."},{"rthcId":"RTHC-08376","title":"Green-Synthesized TiO2 Nanoparticles Improve Mechanical Performance of Glass Ionomer Cements.","authors":"Karamüftüoğlu, Nevra; Kuşçu, Süha; Kuşçu, İpek; Korkmaz, Nesrin","year":2026,"journal":"Polymers, 18(2)","doi":"10.3390/polym18020295","pmid":"41599590","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08377","title":"Gender Diversity, Substance Cognitions, and Alcohol, Nicotine/Tobacco, and Cannabis Use Among Youth.","authors":"Kcomt, Luisa; Veliz, Philip T; Jardine, John; Evans-Polce, Rebecca J; Clift, Jennifer; McCabe, Sean Esteban; Arslanian-Engoren, Cynthia","year":2026,"journal":"LGBT health, 13(1), 1-10","doi":"10.1177/23258292251385564","pmid":"41060835","tags":["gender-diversity","adolescents","abcd-study","prevention","substance-use"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"In a 4-class model (transgender 2.5%, questioning 9.0%, naïve 36.3%, cisgender 52.1%), questioning and transgender youth were significantly more likely to report curiosity about alcohol, nicotine, and cannabis (aOR range 1.68-2.45) and use of cannabis and nicotine (aOR range 1.16-1.82) compared to cisgender youth.","whyItMatters":"This is one of the first studies to use a multidimensional gender construct to understand substance use risk in pre-adolescents, revealing that gender-diverse youth need targeted prevention before traditional intervention ages.","specificNumbers":"N=11,868; 4 gender classes: transgender 2.5%, questioning 9.0%, naïve 36.3%, cisgender 52.1%; curiosity aORs 1.68-2.45; cannabis use aOR up to 1.82; substance use disparities present by age 13-14","methodology":"Longitudinal analysis of 11,868 ABCD Study youth (ages 9-14, 2016-2022) using latent class models across four gender dimensions (identity, felt gender, expression, non-contentedness), with multivariable logistic regression for substance outcomes.","limitations":"ABCD Study may not represent all US youth; gender classification at single timepoint doesn't capture fluidity; substance use outcomes by 13-14 are rare events; latent classes are statistical constructs; cannabis use measurement limited at young ages."},{"rthcId":"RTHC-08378","title":"Differentiating Δ8-THC and Δ9-THC Isomers: Mass Spectrometry Analysis and Computational Explanation.","authors":"Ke, Xing; Chen, Xi; Chen, Xianxin; Wu, Hao; Fan, Yilei; Xu, Yu; Xu, Jiawei","year":2026,"journal":"Rapid communications in mass spectrometry : RCM, 40(5), e70011","doi":"10.1002/rcm.70011","pmid":"41359892","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08379","title":"Medicinal cannabis plant extract (NTI164) modifies epigenetic, ribosomal, and immune pathways in paediatric acute-onset neuropsychiatric syndrome.","authors":"Keating, Brooke A; Han, Velda X; Nishida, Hiroya; Aryamanesh, Nader; Marshall, Lee L; Gloss, Brian S; Lau, Xianzhong; Dissanayake, Ruwani; Dervish, Suat; Graham, Mark E; Mohammad, Shekeeb S; Kanhangad, Manoj; Fahey, Michael C; Patel, Shrujna; Dale, Russell C","year":2026,"journal":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, e00828","doi":"10.1016/j.neurot.2025.e00828","pmid":"41513541","tags":["pediatric","pans","medicinal-cannabis","epigenetics","immunology","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"preliminary","keyFinding":"12 weeks of NTI164 (20 mg/kg/day) decreased CGI-Severity from 4.8 to 3.3 (p=0.002) with significant improvements in OCD (p=0.0001), tics (p<0.0001), ADHD (p=0.028), emotional regulation (p<0.0001), and quality of life (p=0.011). Multi-omics revealed NTI164 modified dysregulated epigenetic, ribosomal, and immune pathways in patient leukocytes.","whyItMatters":"PANS is a devastating condition with limited treatment options, and this study provides both clinical evidence of benefit and mechanistic evidence that a cannabis extract can modify the underlying epigenetic and immune dysfunction.","specificNumbers":"N=14; mean age 12.1; 20 mg/kg/day NTI164; CGI-S: 4.8→3.3 (p=0.002); CYBOCS-II OCD p=0.0001; YGTSS tics p<0.0001; Conner's ADHD p=0.028; RCADS-P emotional p<0.0001; EQ-5D-Y QoL p=0.011; well-tolerated","methodology":"Open-label trial of 14 children with chronic-relapsing PANS (mean age 12.1, 71% male) receiving NTI164 for 12 weeks, with clinical assessments using gold-standard tools and pre/post blood samples analyzed by bulk and single-cell transcriptomics, proteomics, phosphoproteomics, and DNA methylation.","limitations":"Open-label without placebo control; very small sample (n=14); PANS diagnosis can be heterogeneous; cannot separate placebo effects; NTI164 is a complex mixture making mechanism attribution difficult; 12-week duration only."},{"rthcId":"RTHC-08380","title":"Substance use in Military Personnel: Associations with Combat Exposure, Moral Injury, Posttraumatic Stress Disorder and Pain.","authors":"Kelley, Michelle L; Gabelmann, Jeffrey M; Strowger, Megan; Hearton, John; Folivi, Folly; Bravo, Adrian J; Noh, Jinjoo; Kuskye, Kristin; Haber, William; McGuire, Adam P","year":2026,"journal":"Journal of drug education, 55(1), 3-20","doi":"10.1177/00472379251394435","pmid":"41236864","tags":["military","ptsd","combat","moral-injury","substance-use"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Higher PTSD symptom scores were uniquely associated with past-week cannabis use (vs. no use), while combat exposure and moral injury were uniquely associated with misuse of prescription opioids, sedatives, and both combined. Hazardous alcohol use (46.2%) was predicted by combat exposure.","whyItMatters":"Understanding that different military experiences drive different substance use patterns — PTSD→cannabis, combat/moral injury→prescription misuse — can guide targeted intervention strategies.","specificNumbers":"N=238; 21% opiate misuse; 25.6% sedative misuse; 16.4% both; 14.7% cannabis use; 46.2% hazardous alcohol; PTSD uniquely predicted cannabis; combat exposure + moral injury predicted prescription misuse; combat predicted hazardous alcohol","methodology":"Cross-sectional survey of 238 US military personnel with one or more deployments (71% male, mean age 33.3), using multivariable multinomial logistic regression examining combat exposure, moral injury, PTSD, and pain as predictors of substance use patterns.","limitations":"Cross-sectional design; convenience community sample; self-report measures; relatively small sample; cannot determine if cannabis use is self-medication for PTSD or coincidental; no assessment of cannabis for therapeutic PTSD use."},{"rthcId":"RTHC-08381","title":"State cannabis and alcohol policy environments: Associations with college students' use of cannabis, alcohol and both substances.","authors":"Kerr, David C R; Bae, Harold; Naimi, Timothy S; Subbaraman, Meenakshi S; Hummel, Haley M; Lira, Marlene C","year":2026,"journal":"American journal of preventive medicine, 108275","doi":"10.1016/j.amepre.2026.108275","pmid":"41576998","tags":["legalization","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Drawing on survey data from over 900,000 college undergraduates (ages 18–24) across 591 four-year institutions in 47 states between 2008 and 2019, researchers examined how state-level cannabis and alcohol policy environments related to substance use patterns.\n\nUsing a Cannabis Policy Scale (sum of 17 policies weighted by efficacy) and an Alcohol Policy Scale (29 policies), the analysis found that more restrictive cannabis policy environments were associated with significantly lower odds of any cannabis use (OR 0.97), frequent cannabis use (OR 0.93), and co-use of cannabis with binge drinking (OR 0.94). Cannabis policy restrictiveness was not significantly associated with alcohol-only outcomes.\n\nConversely, more restrictive alcohol policy environments were associated with lower odds of alcohol use outcomes but did not significantly affect cannabis use. The two policy domains operated independently — each influenced its target substance without significant cross-substance effects.","whyItMatters":"This is one of the largest studies of how cannabis policy affects a high-risk population. College students are in a critical developmental period and have among the highest cannabis use rates of any age group. The finding that policy restrictiveness has measurable effects on use — even after accounting for alcohol policy — provides evidence that state-level cannabis regulations have real behavioral consequences.","specificNumbers":"902,486 undergraduates, 591 institutions, 47 states, 2008–2019. Cannabis policy effects (per unit increase in restrictiveness): any use OR 0.97, frequent use OR 0.93, co-use OR 0.94. Cannabis policy not significantly associated with alcohol outcomes. Alcohol policy not significantly associated with cannabis outcomes.","methodology":"Cross-sectional survey of 902,486 undergraduates (ages 18–24) from 591 four-year institutions in 47 states, 2008–2019. Time-varying state-level Cannabis Policy Scale (17 policies) and Alcohol Policy Scale (29 policies) scored by efficacy and implementation. Outcomes: 30-day cannabis use, frequent use (20+ days), 30-day alcohol use, 2-week binge drinking (5+ drinks), and co-use. Multilevel models accounting for institution and state clustering.","limitations":"Cross-sectional survey design cannot establish that policies caused the use differences. Self-reported substance use likely underestimates actual use. The 2008–2019 period captures the early legalization era; effects may differ as legal markets mature. The Cannabis Policy Scale weights policies by estimated efficacy, which involves subjective judgment. Four-year college students are not representative of all 18–24-year-olds."},{"rthcId":"RTHC-08382","title":"Oregon Adults' Cannabis and Alcohol Use: Associations With Local Cannabis Retail Access, 2014-2022.","authors":"Kerr, David C R; Dilley, Julia A; Everson, Erik M; Hummel, Haley M","year":2026,"journal":"American journal of preventive medicine, 70(2), 108164","doi":"10.1016/j.amepre.2025.108164","pmid":"41135918","tags":["retail-access","legalization","alcohol","substitution","oregon"],"studyType":"longitudinal","evidenceStrength":"strong","keyFinding":"Oregon adults in highest-access areas had 59% higher odds of 30-day cannabis use (AOR=1.59, 95% CI=1.36-1.86) than those in pre-market periods, with dose-response across access levels. Heavy alcohol use decreased with retail access among ages 21-24 and 65+, suggesting substitution effects in these groups.","whyItMatters":"This study provides state-level evidence that cannabis retail density directly drives use in a dose-dependent manner, while also showing alcohol substitution effects — a mixed public health picture that informs retail policy.","specificNumbers":"Oregon BRFSS 2014-2022; lowest third AOR=1.31, middle AOR=1.47, highest AOR=1.59 for cannabis use; frequent use also increased; ages 18-20 not significant; heavy alcohol decreased for ages 21-24 and 65+; associations significant in every adult age group except 18-20","methodology":"Analysis of 2014-2022 Oregon BRFSS data matched with geospatial cannabis retail density by ZIP code, using multivariable logistic regression with time-trend adjustment to examine associations between retail access and cannabis/alcohol use across age groups.","limitations":"BRFSS self-report; ZIP-level retail measure may not capture individual access; time-trend adjustment may not fully account for secular changes; Oregon may not generalize to other states; alcohol substitution only in two age groups."},{"rthcId":"RTHC-08383","title":"Comprehensive analysis of the chloroplast genome in Cannabis sativa L. reveals variations in simple sequence repeats among cultivars.","authors":"Khabbazi, Saber Delpasand","year":2026,"journal":"Scientific reports, 16(1), 206","doi":"10.1038/s41598-025-28205-0","pmid":"41491789","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08384","title":"The Impact of Cannabis Use in Gastroparesis: A Propensity-Matched Analysis of 41,374 Gastroparesis Patients.","authors":"Kilani, Yassine; Gonzalez Mosquera, Daniel Alejandro; Puelo, Priscila Castro; Aldiabat, Mohammad; Ruffle, James K; Madi, Mahmoud Y; Farmer, Adam D","year":2026,"journal":"The American journal of gastroenterology, 121(1), 248-257","doi":"10.14309/ajg.0000000000003479","pmid":"40197432","tags":["gastroparesis","healthcare-utilization","adverse-effects","gastrointestinal"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-using gastroparesis patients had significantly increased ER visits (aOR=1.73, 95% CI=1.66-1.80) and hospitalizations (aOR=1.44, 95% CI=1.39-1.50) compared to propensity-matched non-users, despite slightly reduced endoscopy rates (aOR=0.93, 95% CI=0.88-0.98).","whyItMatters":"Despite cannabis being touted for nausea and appetite — key gastroparesis symptoms — this large real-world study shows cannabis users actually have worse healthcare outcomes, possibly due to cannabinoid hyperemesis syndrome or delayed gastric emptying from cannabis.","specificNumbers":"N=41,374 matched (20,687 per group); ER visits aOR=1.73; hospitalizations aOR=1.44; endoscopy aOR=0.93; cannabis users: younger, more diabetes, more mood/anxiety disorders, higher HbA1c, more opioid use","methodology":"Retrospective propensity-matched cohort study of 41,374 gastroparesis patients (20,687 cannabis users matched 1:1 to non-users) from the TriNetX database (119 million individuals), examining ER visits, hospitalizations, and endoscopy rates.","limitations":"Observational design with confounding risk despite propensity matching; cannot determine if cannabis causes outcomes or sicker patients use cannabis; cannabis user definition may include CHS patients; database coding limitations; no cannabis dose/product information."},{"rthcId":"RTHC-08385","title":"Daily Temporal Associations Between Use of Psychoactive Substances and Fatigue, Pain, Stress, and Depressive Symptoms in People with Multiple Sclerosis.","authors":"Kim, Jeeyeon; Ehde, Dawn M; Alschuler, Kevin N; Fritz, Nora E; Kratz, Anna L","year":2026,"journal":"Archives of physical medicine and rehabilitation","doi":"10.1016/j.apmr.2026.01.014","pmid":"41633444","tags":["multiple-sclerosis","daily-diary","pain","fatigue","self-medication"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Cannabis use was associated with greater subsequent fatigue and higher momentary pain in MS patients, while alcohol and nicotine also predicted greater fatigue. In the reverse direction, higher average pain predicted reduced alcohol use and increased opioid use, revealing complex bidirectional symptom-substance dynamics.","whyItMatters":"Many MS patients use cannabis for symptom management, but this study reveals a paradox: cannabis may actually worsen the very symptoms (pain, fatigue) it's intended to treat, creating a self-reinforcing cycle.","specificNumbers":"N=258; 14-day EMA periods at 3 timepoints; cannabis→increased fatigue; cannabis→increased momentary pain; caffeine→reduced fatigue; alcohol→reduced stress; opioids→increased average pain; bidirectional symptom-substance relationships","methodology":"Secondary analysis of ecological momentary assessment data collected 4 times daily for 14 days at baseline, 1-year, and 2-year follow-ups from 258 ambulatory adults with MS, using mixed-effects logistic regression for lagged associations.","limitations":"Secondary analysis; EMA self-report; dichotomous substance use (yes/no) misses dose information; 14-day windows may not capture longer patterns; ambulatory patients may not represent all MS severity levels; cannot rule out confounding by flare severity."},{"rthcId":"RTHC-08386","title":"Comparative performance evaluation of DRI and KIMS immunoassays for forensic drug screening in urine.","authors":"Kim, Jihyun; Kang, Seojin; Lee, Nahyun; Kim, Siyeon","year":2026,"journal":"Forensic science international, 380, 112800","doi":"10.1016/j.forsciint.2025.112800","pmid":"41483747","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08387","title":"HER2-dependent paraptosis and ferroptosis induction by cannabidiol in breast cancer cells.","authors":"Kim, Na Young; Lee, Mina; Hong, Yejin; Le, Ducdat; Nam, Dongwoo; Um, Jae-Young; Ahn, Kwang Seok","year":2026,"journal":"Biochimica et biophysica acta. Molecular basis of disease, 1872(4), 168177","doi":"10.1016/j.bbadis.2026.168177","pmid":"41621547","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08388","title":"Nicotine and cannabis vaping among U.S. emerging young adults: Findings from 2022 and 2023 National Survey on Drug Use and Health.","authors":"Kim, Nayoung; Haizelden, Joy; Avery, Gracie; Mumba, Mercy","year":2026,"journal":"Addictive behaviors, 174, 108577","doi":"10.1016/j.addbeh.2025.108577","pmid":"41370901","tags":["vaping","youth","mental-health","policy","substance-use"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among emerging adults, 16% reported exclusive nicotine vaping, 4.3% exclusive cannabis vaping, and 8.1% co-vaping. Mental health distress, substance co-use, and medical cannabis legalization significantly increased odds of all vaping behaviors.","whyItMatters":"As both nicotine and cannabis vaping become more common, understanding who co-vapes and why is critical for designing targeted prevention programs — especially since mental health and policy factors play significant roles.","specificNumbers":"16.0% exclusive nicotine vaping, 4.3% exclusive cannabis vaping, 8.1% co-vaping among emerging adults. Sexual minorities, lower education levels, and non-Hispanic White individuals showed higher vaping rates.","methodology":"Cross-sectional analysis of 2022-2023 National Survey on Drug Use and Health (NSDUH) data examining past-month vaping rates and associations with sociodemographic characteristics, mental health, substance use, and cannabis legalization status.","limitations":"Cross-sectional design prevents causal conclusions. Self-reported data may underestimate actual vaping rates. Cannot distinguish between different cannabis products or concentrations vaped."},{"rthcId":"RTHC-08389","title":"Anticipated Stigma in Nursing: A Concept Analysis Informed by Cannabis Use Disclosure.","authors":"King, Daniel D","year":2026,"journal":"Journal of advanced nursing","doi":"10.1111/jan.70499","pmid":"41588830","tags":["stigma","healthcare-providers","policy","nursing"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"Five core attributes of anticipated stigma were identified, with antecedents including identity salience, sociocultural norms, and structural factors. Consequences include psychological distress, concealment behaviors, and reduced healthcare engagement.","whyItMatters":"When patients fear judgment for cannabis use, they hide it from healthcare providers — leading to incomplete health assessments, potential drug interactions, and compromised care.","specificNumbers":"Literature spanning 1963-2024 was synthesized across four disciplines (nursing, public health, psychology, sociology) to identify five core attributes of anticipated stigma.","methodology":"Evolutionary concept analysis using Rodgers and Knafl's method, synthesizing literature from nursing, public health, psychology, and sociology published between 1963 and 2024.","limitations":"Conceptual analysis without primary empirical data. Findings are theoretical and need validation through clinical studies. Focused primarily on nursing contexts."},{"rthcId":"RTHC-08390","title":"Preoperative cannabinoid exposure and postoperative pain: A narrative review.","authors":"King, Daniel D; Temmermand, Rhea; Greenwood, Jennifer E","year":2026,"journal":"Journal of clinical anesthesia, 109, 112097","doi":"10.1016/j.jclinane.2025.112097","pmid":"41406677","tags":["pain","surgery","opioids","perioperative"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Of 42 studies, 33.3% found cannabis users reported higher postoperative pain, 23.8% found no difference, and 42.9% indicated greater postoperative opioid requirements. Results varied by surgical specialty — spine and mixed cohorts showed more opioid use, while arthroplasty studies often showed no difference.","whyItMatters":"With more surgical patients using cannabis, surgeons and anesthesiologists need clear guidance on how to manage perioperative pain — this review shows the answer isn't one-size-fits-all.","specificNumbers":"42 studies reviewed. Pain outcomes: 33.3% found higher pain in cannabis users, 23.8% no difference, 4.8% reduced pain. Opioid use: 42.9% found greater requirements, 40.5% no difference, 7.1% reduced use. Spine populations showed increased opioid use in 55% of studies.","methodology":"Systematic search of PubMed, CINAHL, and Embase identifying 42 studies from the past ten years examining preoperative cannabis use and its relationship with postoperative pain and opioid consumption, analyzed via narrative synthesis.","limitations":"Heterogeneous exposure definitions and outcome metrics limit cross-study comparisons. Most studies are retrospective and observational. Cannabis potency, frequency, and method of use were rarely standardized."},{"rthcId":"RTHC-08391","title":"Post-legalization rise in German medical cannabis interest: evidence from Google trends as surrogate marker.","authors":"Kirchberger, Michael Constantin","year":2026,"journal":"Journal of cannabis research, 8(1), 15","doi":"10.1186/s42238-026-00395-y","pmid":"41593723","tags":["policy","legalization","public-interest","germany"],"studyType":"interrupted-time-series","evidenceStrength":"preliminary","keyFinding":"Mean weekly Google search index for 'medizinisches cannabis' rose from 7.85 (pre-2017) to 23.79 (post-2017, +203%) and to 75.29 (post-2024, +216%). Interrupted time series confirmed significant immediate increases with subsequent attenuation. Bavaria showed sustained maximal interest despite restrictive policies.","whyItMatters":"Search trends serve as a real-time barometer of public interest and information needs — showing that legislative changes create immediate surges in demand for medical cannabis information that health systems need to be ready to meet.","specificNumbers":"Search index: 7.85 pre-2017, 23.79 post-2017 (+203%), 75.29 post-2024 (+216%). Immediate relative increase of 135% after 2017 act and 216% after 2024 act. Four distinct regional clusters identified across 16 states.","methodology":"Analysis of Google Trends data for 'medizinisches cannabis' in Germany (2015-2025) using descriptive statistics and interrupted time series regression, with regional analysis across all 16 German states.","limitations":"Google Trends data is a surrogate marker, not direct measurement of behavior. Cannot distinguish between patients, providers, and general public searching. Regional internet usage patterns may introduce bias."},{"rthcId":"RTHC-08392","title":"Ferroptosis under fire: cannabidiol mitigates iron-dependent injury in differentiated human neuroblastoma cells following oxygen-glucose deprivation.","authors":"Klimiuk, Maciej; Jefimow, Małgorzata; Kletkiewicz, Hanna","year":2026,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 152, 157868","doi":"10.1016/j.phymed.2026.157868","pmid":"41581443","tags":["cbd","neuroprotection","ferroptosis","oxidative-stress"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD significantly reduced oxidative stress, preserved glutathione peroxidase 4 activity (a key anti-ferroptosis enzyme), enhanced Nrf2 activation, prevented downregulation of ferroportin (iron efflux protein), and further enhanced VEGF expression in neuronal cells subjected to oxygen-glucose deprivation.","whyItMatters":"Perinatal oxygen deprivation causes devastating brain damage in newborns, and ferroptosis is a key mechanism. If CBD can protect against this specific type of cell death, it could open new therapeutic avenues for neonatal brain injury.","specificNumbers":"CBD preserved GPX4 expression and enzymatic activity, enhanced Nrf2 activation, prevented ferroportin downregulation, and upregulated VEGF expression in oxygen-glucose deprived neuron-like cells.","methodology":"Differentiated human neuroblastoma (SH-SY5Y) cells were exposed to oxygen-glucose deprivation to simulate hypoxic-ischemic injury. CBD was applied and oxidative stress markers, antioxidant enzyme activity, Nrf2 activation, iron metabolism proteins, and HIF-1α/VEGF expression were evaluated.","limitations":"In vitro cell model only — human neuroblastoma cells are proxies for neurons but don't replicate the complexity of a living brain. CBD concentrations and delivery methods would differ significantly in clinical settings."},{"rthcId":"RTHC-08393","title":"Identifying established human placental markers of schizophrenia in rodents after gestational ∆9-tetrahydrocannabinol exposure†.","authors":"Kocsis, Andrea M; Perez-Valenzuela, Enzo; Rodríguez-Ruiz, Mar; Sarikahya, Mohammed H; Dembla, Anubha; Natale, David R C; Laviolette, Steven R; Hardy, Daniel B","year":2026,"journal":"Biology of reproduction, 114(1), 246-258","doi":"10.1093/biolre/ioaf191","pmid":"40827685","tags":["pregnancy","psychosis","cognition","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This study tested whether prenatal THC exposure in rats would alter the same placental genes that human genomic studies have linked to schizophrenia risk. The researchers administered oral THC during pregnancy and examined both fetal outcomes and placental gene expression.\n\nTHC-exposed offspring had significantly reduced fetal weights — in both males and females — without affecting maternal pregnancy outcomes. This fetal growth restriction pattern matches earlier findings in this model that THC-exposed rat offspring later develop schizophrenia-like behaviors (such as decreased pre-pulse inhibition of the acoustic startle response).\n\nCritically, placentas from THC-exposed pregnancies showed altered expression of specific genes — Furin, Rccd1, and Atp5mk — that had been previously identified in human transcriptomic datasets as markers associated with schizophrenia. Some gene expression changes were sex-specific, affecting different genes in male versus female placentas (including Eif5, Rps10, and Vps33b).\n\nThis represents the first demonstration that prenatal THC exposure activates the same placental molecular signature that human studies have associated with schizophrenia risk.","whyItMatters":"This study bridges two previously separate bodies of research: the human genetic studies linking placental gene signatures to schizophrenia risk, and the animal studies showing prenatal THC causes schizophrenia-like behaviors in offspring. Finding the same genes altered in both contexts strengthens the biological plausibility of a pathway from prenatal cannabis exposure through placental disruption to later psychotic illness.","specificNumbers":"Significantly reduced fetal weights in both male and female THC-exposed offspring. No significant changes in maternal outcomes. Altered expression of Furin, Rccd1, and Atp5mk in both sexes. Sex-specific changes in Eif5, Rps10, Vps33b, and others. All target genes previously identified in human schizophrenia transcriptomic datasets.","methodology":"Preclinical study administering oral THC to pregnant rats. Outcomes included fetal weights, maternal pregnancy outcomes, and placental gene expression analysis. Target genes were selected based on prior human transcriptomic datasets identifying placental markers of schizophrenia. Gene expression compared between THC-exposed and control placentas, analyzed separately by offspring sex.","limitations":"Animal model — rat placental biology differs from human. Oral THC dosing may not match human exposure patterns. The correlation between altered gene expression and actual disease development is not established in this study. The specific genes identified as schizophrenia-linked in human datasets may have different functions in rat placentas. Small sample size typical of gene expression studies."},{"rthcId":"RTHC-08394","title":"Spirituality and Harmful or Hazardous Alcohol and Other Drug Use: A Meta-Analysis of Longitudinal Studies.","authors":"Koh, Howard K; Frederick, Donald E; Balboni, Tracy A; O'Reilly, Samantha M; Kelly, John F; Humphreys, Keith; Botticelli, Michael; Mathur, Maya B; Psimopoulos, Constantine S; Long, Katelyn N G; VanderWeele, Tyler J","year":2026,"journal":"JAMA psychiatry","doi":"10.1001/jamapsychiatry.2025.4816","pmid":"41706493","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08395","title":"Therapeutic potential of cannabidiol supplementation in mitigating lipid precursors of inflammation in hepatic steatosis progression.","authors":"Konstantynowicz-Nowicka, Karolina; Zwierz, Mateusz; Kurzyna, Piotr Franciszek; Zabielska-Kaczorowska, Magdalena; Sztolsztener, Klaudia; Chabowski, Adrian; Harasim-Symbor, Ewa","year":2026,"journal":"Journal of cannabis research","doi":"10.1186/s42238-026-00413-z","pmid":"41742322","tags":["cbd","liver","inflammation","fatty-liver-disease"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD decreased pro-inflammatory n-6 PUFA pathway activity while increasing anti-inflammatory n-3 PUFA pathway activity in liver tissue. This was accompanied by lower arachidonic acid levels, altered COX-1/COX-2 enzyme expression, and reduced pro-inflammatory cytokines.","whyItMatters":"Fatty liver disease (MASLD) affects roughly a quarter of adults worldwide, and its progression to inflammatory MASH can lead to cirrhosis. Catching and halting inflammation early is the critical window for prevention.","specificNumbers":"40 rats across 4 groups. CBD shifted the n-6/n-3 PUFA balance — decreasing pro-inflammatory n-6 pathway and increasing anti-inflammatory n-3 pathway. Arachidonic acid levels decreased. Pro-inflammatory cytokine levels reduced.","methodology":"Forty male Wistar rats were divided into four groups (control, control+CBD, high-fat diet, high-fat diet+CBD). After high-fat diet feeding with 14 days of CBD treatment, liver tissue was analyzed for PUFA pathway activity, arachidonic acid levels, cytokines, and enzyme expression.","limitations":"Animal model only with short CBD treatment period (14 days). Rat liver metabolism differs from human. CBD dosing may not translate directly to human applications. Did not assess long-term outcomes."},{"rthcId":"RTHC-08396","title":"Therapeutic Potential of Cannabidiol in Dentistry: A Systematic Review From Cellular Mechanisms to Clinical Trials.","authors":"Kornsuthisopon, Chatvadee; Chansaenroj, Ajjima; Vimolmangkang, Sornkanok; Samaranayake, Lakshman P; Osathanon, Thanaphum","year":2026,"journal":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology, 55(2), 177-190","doi":"10.1111/jop.70081","pmid":"41194764","tags":["cbd","dentistry","oral-health","anti-inflammatory","systematic-review"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Among 57 included studies, cell-based research demonstrated CBD's anti-inflammatory properties in oral-origin cells and impact on bone formation. Clinical trials and patents showed benefits for maxillofacial pain and inflammation, particularly radiation-induced mucositis. Regenerative dentistry applications remain limited.","whyItMatters":"Dental pain and oral inflammation affect millions, and current treatments have significant side effects. CBD's anti-inflammatory properties could provide a gentler alternative, especially for patients dealing with radiation-related oral complications from cancer treatment.","specificNumbers":"57 studies included from 6 databases. Research spans cell studies, clinical trials, and registered patents. Clinical evidence strongest for pain/inflammation management in maxillofacial conditions and radiation-induced mucositis.","methodology":"Systematic search of PubMed-MEDLINE, Scopus, Embase, Cochrane Library, and patent databases (WIPO, EPO, USPTO) for studies on CBD in dentistry published 2013-2024. Risk of bias assessed with Cochrane RoB 2 tool. PRISMA guidelines followed.","limitations":"Most evidence is from cell studies, not clinical trials. Heterogeneous study designs limit direct comparisons. Patent data may overrepresent commercial interest rather than clinical efficacy. Limited to English-language publications."},{"rthcId":"RTHC-08397","title":"Emulsion Quality and Functional Properties of Natural Emulsion Systems with Xanthan Gum as a Stabilizer and Carrier of Compounds Based on Enzymatically Modified Mutton Tallow and Hemp Oil.","authors":"Kowalska, Małgorzata; Wozniak, Magdalena; Zbikowska, Anna; Szakiel, Jerzy; Turek, Paweł","year":2026,"journal":"Molecules (Basel, Switzerland), 31(3)","doi":"10.3390/molecules31030431","pmid":"41683409","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08398","title":"Combined extraction and spray-freeze-drying of Cannabis sativa Flos provides stable lyophilizate particles of cannabinoids.","authors":"Kožák, Jan; Vázquez-Olvera, José Ignacio; Berkenfeld, Kai; Rautenberg, Annika; Lamprecht, Alf","year":2026,"journal":"Journal of cannabis research, 8(1), 16","doi":"10.1186/s42238-025-00381-w","pmid":"41492008","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08399","title":"Attitudes and Knowledge of Israeli Ultra-Orthodox and Religious Jewish Nursing Students Toward the Use of Medical Cannabis.","authors":"Kozlov, Gregory; Wacht, Oren; Grinstein-Cohen, Orli","year":2026,"journal":"Journal of religion and health, 65(1), 538-553","doi":"10.1007/s10943-025-02381-9","pmid":"40622610","tags":["attitudes","healthcare-providers","nursing","religion","israel"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Religious/ultra-Orthodox nursing students showed more negative attitudes toward medical cannabis compared to other nursing students. Most opposed recreational legalization and believed cannabis is addictive. Those with prior exposure to medical cannabis had more positive attitudes. Knowledge levels were low, and students supported adding medical cannabis to their curriculum.","whyItMatters":"As medical cannabis use surges in Israel, nurses from religious communities will increasingly encounter patients using it. Understanding and addressing their attitudes is essential for ensuring all patients receive non-judgmental, informed care.","specificNumbers":"221 religious/ultra-Orthodox nursing students surveyed. Negative correlation found between religiosity level and attitudes toward medical cannabis. Very low medical cannabis usage rate reported. Students supported curriculum inclusion of medical cannabis education.","methodology":"Cross-sectional survey of 221 religious/ultra-Orthodox nursing students (BN and MN programs) using online questionnaires measuring demographics, attitudes, beliefs, and knowledge about medical cannabis. Analyzed with Pearson correlation, t-tests, and multiple regression.","limitations":"Single population (religious/ultra-Orthodox only) limits generalizability. Self-selection bias in online survey. Cross-sectional design prevents causal conclusions. Social desirability may influence responses."},{"rthcId":"RTHC-08400","title":"Cannabidiol (CBD) and Other Cannabinoids as a Promising Alternative Antibacterial Agent-Pilot Study on Enterococcus faecalis and Enterococcus faecium Clinical Strains.","authors":"Kraszewska, Zuzanna; Grudlewska-Buda, Katarzyna; Wnuk, Kacper; Wałecka-Zacharska, Ewa; Gospodarek-Komkowska, Eugenia; Skowron, Krzysztof","year":2026,"journal":"Molecules (Basel, Switzerland), 31(1)","doi":"10.3390/molecules31010144","pmid":"41515438","tags":["cbd","antibacterial","antimicrobial","drug-resistance"],"studyType":"laboratory-analysis","evidenceStrength":"preliminary","keyFinding":"CBD displayed antibacterial properties against all 20 tested clinical strains of E. faecalis and E. faecium with MIC values at or below 1 μg/mL. Higher CBD concentrations produced stronger antibacterial effects. Pure CBD and CBD crystals showed statistically lower MICs than CBD oils. E. faecium was more susceptible than E. faecalis.","whyItMatters":"Enterococcus bacteria are increasingly resistant to conventional antibiotics and cause serious hospital infections. Finding that CBD works against these multidrug-resistant strains at low concentrations opens a potential new avenue in the fight against antibiotic resistance.","specificNumbers":"MIC ≤ 1 μg/mL for all tested strains. 20 clinical strains tested (E. faecalis and E. faecium). 5 CBD oils and 1 CBD crystal product (99% purity) evaluated. Pure CBD significantly more effective than CBD oils.","methodology":"Pilot study evaluating antimicrobial effects of five CBD oils and one 99% CBD crystal product against 20 clinical strains of Enterococcus species using the microdilution method in Mueller-Hinton broth to determine Minimal Inhibitory Concentrations.","limitations":"In vitro pilot study only — lab conditions don't reflect the complexity of treating infections in living organisms. Small number of strains tested. Mechanism of antibacterial action not elucidated. No toxicity or pharmacokinetic data."},{"rthcId":"RTHC-08401","title":"The theory of planned behavior partly explains why adults with chronic musculoskeletal pain consider using medical cannabis for pain management.","authors":"Kröger, Edeltraut; Carmichael, Pierre-Hugues; Guillaumie, Laurence; Jauvin, Nathalie; Dagenais, Pierre; Lacasse, Anaïs; Dionne, Clermont E","year":2026,"journal":"Scientific reports, 16(1), 3542","doi":"10.1038/s41598-025-33616-0","pmid":"41526449","tags":["chronic-pain","medical-cannabis","patient-behavior","musculoskeletal"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"A Theory of Planned Behavior model explained 51% of the intention to use medical cannabis for chronic musculoskeletal pain. Key predictors were current pain levels, prior experience of pain reduction, and prior cannabis use, along with social norms, perceived ability to use, and attitudes toward medical cannabis.","whyItMatters":"Understanding why pain patients consider medical cannabis helps healthcare providers have better conversations about treatment options — and helps identify patients who might benefit from or be at risk with cannabis use.","specificNumbers":"226 respondents, 160 included in final analysis. TPB model explained 51% of behavioral intention. Three exogenous factors: current pain, prior pain reduction experience, and prior cannabis use.","methodology":"Questionnaire study based on the Theory of Planned Behavior, developed from prior qualitative interviews. 226 adults with chronic musculoskeletal pain in Canada completed an online questionnaire; 160 were included in final analysis using structural equation modeling.","limitations":"Cross-sectional design limits causal inference. Online convenience sample may not represent all chronic pain patients. Self-reported data subject to recall and social desirability bias. Canadian context may not generalize globally."},{"rthcId":"RTHC-08402","title":"The Exploration of Cannabis Beverage Substitution for Alcohol: A Novel Harm Reduction Strategy.","authors":"Kruger, Jessica S; Felicione, Nicholas; Kruger, Daniel J","year":2026,"journal":"Journal of psychoactive drugs, 1-7","doi":"10.1080/02791072.2026.2614506","pmid":"41533430","tags":["harm-reduction","alcohol","cannabis-beverages","substitution"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Cannabis beverage users reported fewer weekly alcoholic drinks after starting cannabis beverages (3.35 vs. 7.02 before) and less frequent binge drinking (80.7% reported less than monthly or never, vs. 47.2% before). Users were more likely to report substituting cannabis for alcohol (58.6%) compared to non-users (47.2%).","whyItMatters":"Alcohol causes nearly 200 health conditions and immense social harm. If cannabis beverages can meaningfully reduce alcohol consumption, they could become a novel harm reduction tool — especially since they typically contain no alcohol.","specificNumbers":"438 adults surveyed. 33.6% used cannabis beverages, typically one per session. Weekly alcoholic drinks dropped from 7.02 to 3.35 after starting cannabis beverages. Binge drinking: 80.7% reported less than monthly (vs. 47.2% before). 58.6% of cannabis beverage users reported substituting for alcohol.","methodology":"Survey of 438 anonymous adults who used cannabis in the past year, including alcohol consumption items from the Behavioral Risk Factor Surveillance System (BRFSS). Chi-square and t-tests compared alcohol use between cannabis beverage users and non-users.","limitations":"Self-reported, retrospective data subject to recall bias. Convenience sample of cannabis users — not representative of general population. No control for other factors that may have changed alcohol use. Cannot establish causation."},{"rthcId":"RTHC-08403","title":"The relationship between the cannabinoids and cardiac remodelling: A comprehensive review of pivotal mechanisms and emerging evidence.","authors":"Krzyżewska, Anna; Baranowska-Kuczko, Marta; Kozłowska, Hanna","year":2026,"journal":"British journal of pharmacology","doi":"10.1111/bph.70347","pmid":"41662725","tags":["cardiovascular","endocannabinoid-system","fibrosis","cardioprotection"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Specific CB2 receptor activation and peripheral CB1 receptor blockade appear particularly promising for anti-fibrotic cardiac effects. The cardioprotective potential lies in cannabinoids' antioxidant and anti-inflammatory efficacy, which limits fibrotic progression and restores normal molecular signaling pathways.","whyItMatters":"Cardiac fibrosis — scarring of the heart — drives heart failure after heart attacks and during hypertension and diabetes. Current anti-fibrotic treatments are limited, making the endocannabinoid system an important new therapeutic target.","specificNumbers":"Review covers cardiac remodeling across multiple conditions: post-myocardial infarction, arterial hypertension, pulmonary hypertension, and diabetes mellitus. Two receptor targets identified as most promising: CB2 activation and peripheral CB1 blockade.","methodology":"Comprehensive narrative review describing key signaling pathways involved in cardiac fibrosis and examining the utility of cannabinoids and endocannabinoid system modulation as therapeutic interventions, synthesizing preclinical and mechanistic evidence.","limitations":"Primarily based on preclinical evidence. The complexity of the endocannabinoid system means targeting one receptor may have unintended effects elsewhere. Clinical translation faces significant regulatory and safety hurdles."},{"rthcId":"RTHC-08404","title":"Inhibition of Fatty Acid Amide Hydrolase Alters Cortical CREB Signaling and Social Behavior in a Rat Model of Schizophrenia.","authors":"Kumar, Aditya; Seillier, Lenka; Kuchař, Martin; Seillier, Alexandre","year":2026,"journal":"The European journal of neuroscience, 63(3), e70427","doi":"10.1111/ejn.70427","pmid":"41668604","tags":["endocannabinoid-system","schizophrenia","social-behavior","faah","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"The FAAH inhibitor URB597 reversed social withdrawal in PCP-treated rats (a schizophrenia model) but decreased social interaction in healthy controls. The agranular insular cortex emerged as a key neural substrate — pCREB levels in this region positively correlated with social interaction time (r=0.43).","whyItMatters":"Social withdrawal is one of the most debilitating symptoms of schizophrenia and has no effective treatment. This study identifies both a therapeutic target (endocannabinoid system) and a brain region (insular cortex) that could guide drug development.","specificNumbers":"Six cortical regions analyzed. Agranular insular cortex pCREB correlated with social interaction (r=0.43, p<0.05). URB597 reversed social deficits in PCP-treated rats but reduced social behavior in healthy controls, showing state-dependent effects.","methodology":"Rats were treated with PCP (schizophrenia model) or saline, then received FAAH inhibitor URB597 or vehicle. Social interaction was measured, and CREB/pCREB expression was analyzed in six prefrontal and insular cortical regions using immunohistochemistry.","limitations":"PCP model captures some but not all aspects of schizophrenia. Small sample sizes limit statistical power. Single-dose acute treatment — chronic effects unknown. Rat social behavior is a limited proxy for human social functioning."},{"rthcId":"RTHC-08405","title":"Data Hidden in Sewage: Advanced Methods for Identification and Quantification of Synthetic Cannabinoids in Urban Wastewater.","authors":"Kurzeja, Wiktoria; Kuczer, Mariola; Matysiak, Jan; Klupczyńska-Gabryszak, Agnieszka","year":2026,"journal":"Molecules (Basel, Switzerland), 31(2)","doi":"10.3390/molecules31020337","pmid":"41599387","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08406","title":"Drugs detected in suspected pediatric exposures: a 5-year review.","authors":"Kyle, Patrick B; Scott, David; Garg, Uttam","year":2026,"journal":"Clinical toxicology (Philadelphia, Pa.), 1-5","doi":"10.1080/15563650.2026.2613029","pmid":"41631875","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08407","title":"Clinical outcomes from a mid-western opioid treatment program during covid-19 emergency regulations: a brief report on the effect of tetrahydrocannabinol (THC) use on take home methadone access.","authors":"LaCourt, Erin T; Ibekie, Oranu; Dike, Charles C; Jegede, Oluwole","year":2026,"journal":"Harm reduction journal, 23(1), 32","doi":"10.1186/s12954-026-01399-w","pmid":"41547863","tags":["thc","opioid-treatment","methadone","harm-reduction","covid-19"],"studyType":"retrospective-cohort","evidenceStrength":"low","keyFinding":"Among 33 patients in an opioid treatment program with relaxed COVID-era take-home rules, the majority with continuing THC use remained eligible for take-home methadone for 10 months. Most were employed, insured, and stably housed. Log Rank Tests on socioeconomic predictors showed no statistical significance.","whyItMatters":"Many opioid treatment programs restrict take-home methadone for patients who test positive for THC. This small study suggests that THC use alone may not predict poor outcomes, potentially supporting more flexible policies.","specificNumbers":"33 patients studied. Majority maintained take-home eligibility for 10 months despite continued THC use. Most were employed, insured, and stably housed. No statistically significant socioeconomic predictors found.","methodology":"Retrospective analysis of 33 patients at a single mid-western opioid treatment program. Kaplan-Meier survival analysis assessed months of eligibility for weekly take-home methadone among patients with continuing THC use during COVID-19 emergency regulations.","limitations":"Very small sample size (33 patients) at a single site. No control group without THC use. Socioeconomic stability of the cohort may not be representative. COVID-era context limits generalizability to normal conditions."},{"rthcId":"RTHC-08408","title":"Impact of Preoperative Cannabis use on Clinical Outcomes of Spinal Fusion - Systematic Review and Meta-analysis.","authors":"Łajczak, Paweł; Łajczak, Anna; Pimenta, Newton Godoy","year":2026,"journal":"Spine","doi":"10.1097/BRS.0000000000005621","pmid":"41563718","tags":["surgery","spine","opioids","perioperative","systematic-review"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Meta-analysis of 7 studies (1,920 patients, 386 cannabis users) found significant increases in in-hospital opioid use (+58.84 MME), readmission (OR 1.70), and reoperation (OR 3.78) among cannabis users undergoing spinal fusion. No significant increase in surgical complications was observed.","whyItMatters":"Spinal fusion is one of the most common major surgeries, and cannabis use is increasingly prevalent among patients with chronic back pain. These findings suggest spine surgeons should screen for and counsel patients about cannabis use before surgery.","specificNumbers":"7 studies, 1,920 patients (386 cannabis users). In-hospital opioid increase: +58.84 MME (95% CI 29.75-87.93). Readmission OR: 1.70 (95% CI 1.01-2.87). Reoperation OR: 3.78 (95% CI 2.06-6.94). No significant increase in surgical complications.","methodology":"Systematic review and meta-analysis searching PubMed, Scopus, Web of Science, and Cochrane Library for studies comparing spinal fusion outcomes between preoperative cannabis users and non-users. Seven retrospective studies with 1,920 patients were included.","limitations":"All 7 included studies were retrospective. Cannabis use was often self-reported and not standardized. Cannot account for confounding factors like chronic pain severity that might independently predict worse outcomes. Relatively small cannabis user group (386)."},{"rthcId":"RTHC-08409","title":"Smart Cannabis: A Prescription Digital Therapeutic Framework for Enhancing Medical Cannabis Care.","authors":"Lakhan, Shaheen E; Driscoll, Brendan","year":2026,"journal":"Clinical therapeutics, 48(1), 46-50","doi":"10.1016/j.clinthera.2025.12.002","pmid":"41421889","tags":["digital-health","medical-cannabis","precision-medicine","policy"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"The commentary proposes integrating medical cannabis with prescription digital therapeutics (PDTs) to create a closed-loop care system that optimizes formulation, dosing, and timing based on individual response patterns, while generating real-world evidence for clinical guidelines.","whyItMatters":"Most medical cannabis patients navigate strain selection, dosing, and administration without clinical guidance — creating risks especially for vulnerable populations. A digital feedback system could bridge the gap between self-directed use and proper medical oversight.","specificNumbers":"PDTs have already been leveraged to treat migraine, depression, insomnia, and PTSD — conditions that overlap significantly with medical cannabis indications.","methodology":"Commentary proposing a theoretical framework for integrating medical cannabis with smartphone-delivered prescription digital therapeutics, with Massachusetts's Medical Use of Marijuana Program suggested as a pilot site.","limitations":"Entirely theoretical framework — no pilot data or proof of concept yet. Patient adoption and compliance with digital monitoring are uncertain. Regulatory and privacy challenges are significant."},{"rthcId":"RTHC-08410","title":"General and Toxicologic Aspects of Occupational Fatalities in the Metropolitan Area of Lyon From 2000 to 2020, a Retrospective Study.","authors":"Lamouroux, Céline; Pouliquen, Guillaume; Fort, Emmanuel; Epain, Marie; Marfaing, Florent; Charbotel, Barbara; Fanton, Laurent","year":2026,"journal":"La Medicina del lavoro, 117(1), 17546","doi":"10.23749/mdl.2026.17546","pmid":"41733580","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08411","title":"Unregulated Substance Abuse and Systemic Inflammation Markers: A Review.","authors":"Lara-Apolinario, Carmen; Barroso, Jose; Rodríguez-Gallego, Jose Carlos; Lara, Pedro C","year":2026,"journal":"Healthcare (Basel, Switzerland), 14(2)","doi":"10.3390/healthcare14020232","pmid":"41595368","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08412","title":"The Association Between Cannabis Use and Electrocardiographic Abnormalities in People Living With HIV.","authors":"Larson, Michaela E; Pan, Yue; Lakhani, Fatima; Chavez, Jennifer V; Santana, Andrea; Nogueira, Nicholas Fonseca; Lieberman, Adam; Riley, Elise D; Wu, Katherine C; Tien, Phyllis; Kizer, Jorge; Floris-Moore, Michelle; Pyslar, Nataliya; Palella, Frank J; Witt, Mallory D; Magnani, Jared W; Plankey, Michael; Lazar, Jason; Sharma, Anjali; Moran, Caitlin; Topper, Elizabeth; Fox, Ervin; Kambrakos, Litsa; Fischl, Margaret; Jones, Deborah L; Alcaide, Maria L; Vidot, Denise; Martinez, Claudia","year":2026,"journal":"Journal of acquired immune deficiency syndromes (1999), 101(2), 191-198","doi":"10.1097/QAI.0000000000003786","pmid":"41129190","tags":["cardiovascular","hiv","ecg","safety"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis use was not significantly associated with ECG evidence of myocardial infarction (aOR 1.02) or other abnormalities (aOR 1.02) in adjusted analyses. HIV status and sex were more important determinants — female participants had more abnormal findings, and male PWH had higher odds of non-MI abnormalities compared to PWoH.","whyItMatters":"People living with HIV already face elevated cardiovascular risk. Knowing that cannabis use doesn't appear to add ECG-detectable cardiac harm provides important reassurance for the many PWH who use cannabis for symptom management.","specificNumbers":"3,610 participants (63% PWH). 28% reported cannabis use. 59% had normal ECG findings. Adjusted ORs for cannabis and MI evidence: 1.02 (95% CI: 0.82-1.26). For other abnormalities: 1.02 (95% CI: 0.80-1.32). Male PWH had higher odds of non-MI abnormalities vs PWoH (aOR 1.35).","methodology":"Baseline logistic regression analysis of 3,610 participants from the MACS/WIHS Combined Cohort Study (2007-2017), comparing ECG findings between cannabis users (28%) and non-users, with adjustment for demographic and clinical covariates.","limitations":"Cross-sectional ECG analysis at baseline limits temporal conclusions. Self-reported cannabis use may be underreported. Cannot distinguish between different cannabis products, potencies, or consumption methods. Residual confounding possible."},{"rthcId":"RTHC-08413","title":"Species differences in pregnane X receptor activation by Δ-9-tetrahydrocannabinol, cannabidiol, and cannabinol.","authors":"Lau, Aik Jiang; Chang, Thomas K H","year":2026,"journal":"Biochemical and biophysical research communications, 799, 153250","doi":"10.1016/j.bbrc.2026.153250","pmid":"41512534","tags":["drug-interactions","thc","cbd","pharmacology","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"THC, CBD, and CBN activated human PXR at 10 μM by 28-fold, 23-fold, and 17-fold respectively — significantly more than rat or mouse PXR. The minimum effective concentration for human PXR was 0.3 μM, 10-33 times lower than for rodent PXR, suggesting species-specific drug interaction risks.","whyItMatters":"PXR controls the expression of drug-metabolizing enzymes like CYP3A4, which processes about half of all prescription drugs. If cannabinoids activate this receptor at low concentrations, they could significantly alter how medications work in cannabis users.","specificNumbers":"Human PXR activation at 10 μM: THC 28-fold, CBD 23-fold, CBN 17-fold. Rat PXR: THC 9-fold, CBD 6-fold, CBN 4-fold. Mouse PXR: THC 4-fold, CBD 3-fold, CBN 3-fold. Human MEC: 0.3 μM (10-33x lower than rodent).","methodology":"Concentration-response analysis using dual-luciferase reporter gene assays in human, rat, and mouse PXR-transfected HepG2 cells. Mammalian one-hybrid and two-hybrid assays confirmed ligand-binding domain transactivation and coactivator recruitment.","limitations":"In vitro cell line study — actual in vivo PXR activation depends on cannabinoid concentrations reaching the liver. Transfected cell system may not fully replicate physiological conditions. Clinical drug interaction magnitude not measured."},{"rthcId":"RTHC-08414","title":"Effects of Voluntary Ingestion of Synthetic Delta-9-Tetrahydrocannabinol on the Hedonic Value of Rewarding and Aversive Substances and CB1 Receptor Expression.","authors":"Laux, Dylan A; Cain, Mary E","year":2026,"journal":"Cannabis and cannabinoid research, 11(1), 49-59","doi":"10.1177/25785125251390206","pmid":"41182267","tags":["thc","alcohol","reward","preclinical","cb1-receptor"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"THC dose-dependently increased hedonic reactions to both sucrose and alcohol while reducing aversion to alcohol and quinine. Repeated oral THC consumption downregulated CB1 receptor expression in the dorsal hippocampus but not in the nucleus accumbens or amygdala.","whyItMatters":"Understanding why cannabis and alcohol use often go together is critical for addiction prevention. This study shows THC directly enhances how rewarding substances taste while reducing their unpleasant aspects — a neurobiological mechanism for co-use.","specificNumbers":"Two THC doses tested: 0.05 and 0.5 mg/kg via cookie. Both sucrose concentrations (0.1M, 0.5M) and alcohol concentrations (10%, 40%) showed increased hedonic responses. CB1 downregulation was dose-dependent and specific to dorsal hippocampus.","methodology":"Male Long-Evans rats (n=24) consumed vehicle or THC-containing cookies (0.05 or 0.5 mg/kg) before taste reactivity testing with sucrose, alcohol, and quinine solutions. CB1 receptor expression was measured via Western blot in three brain regions.","limitations":"Male rats only — sex differences in cannabinoid reward processing are well-documented. Acute taste reactivity may not predict long-term consumption patterns. Oral dronabinol doesn't fully replicate inhaled cannabis. Small sample size."},{"rthcId":"RTHC-08415","title":"Cannabinol for Acute Treatment of Insomnia Disorder in a Randomized Placebo-Controlled Crossover Trial.","authors":"Lavender, Isobel G; Marshall, Nathaniel S; McCartney, Danielle; Cho, Garry; Irwin, Chris; Suraev, Anastasia; Gordon, Rebecca; Arnold, Jonathon C; D'Rozario, Angela L; Gordon, Christopher J; Saini, Bandana; Sivam, Sheila; Zheng, Yizhong; Grunstein, Ronald R; Yee, Brendon J; McGregor, Iain S; Hoyos, Camilla M","year":2026,"journal":"Journal of sleep research, e70284","doi":"10.1111/jsr.70284","pmid":"41698831","tags":["cbn","insomnia","sleep","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"moderate","keyFinding":"300 mg CBN did not significantly change the primary outcome (WASO: -6.3 min, p=0.29) but improved subjective sleep quality (p=0.005), reduced sleep onset latency (p=0.004), increased N2 sleep (p=0.03), and reduced EEG arousal indices (p=0.02). The 30 mg dose showed no significant effects.","whyItMatters":"CBN is heavily marketed as a sleep aid despite virtually no clinical evidence. This first rigorous trial shows it has some real effects on sleep architecture and subjective quality, but doesn't meet the primary bar of reducing nighttime wakefulness.","specificNumbers":"20 participants. 300 mg CBN: WASO -6.3 min (NS), sleep onset latency improved (p=0.004, dz=-0.74), N2 sleep increased (p=0.03, dz=0.54), subjective quality improved (p=0.005, dz=0.56), arousal index reduced (p=0.02, dz=-0.65). 247 mild-moderate adverse events across all arms.","methodology":"Randomized, double-blind, placebo-controlled, three-arm, single-night crossover trial in 20 adults with physician-diagnosed insomnia disorder (ISI ≥15). Participants received single doses of 30 mg CBN, 300 mg CBN, or placebo with 2-week washout, measured by overnight polysomnography.","limitations":"Very small sample (20 participants). Single-night assessment doesn't capture effects of repeated use. 17 of 20 participants were female, limiting generalizability. High adverse event count across all arms. 300 mg is a very high dose rarely found in consumer products."},{"rthcId":"RTHC-08416","title":"The Impact of Cannabis Use on the Prevalence, Progression and Development of Lower Limb Peripheral Arterial Disease: A Narrative Review.","authors":"Lee, Frances; Zhang, Daniel; Patel, Kiraati; Lee, Arvind","year":2026,"journal":"ANZ journal of surgery","doi":"10.1111/ans.70528","pmid":"41677030","tags":["cardiovascular","peripheral-arterial-disease","vascular","safety"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"Several mechanisms link cannabis to vascular risk: cannabinoid-induced vasospasm, endothelial dysfunction, platelet aggregation, and oxidative stress. Epidemiological studies show associations between cannabis use disorder and increased PAD complications, particularly acute limb ischemia and chronic limb-threatening ischemia.","whyItMatters":"As cannabis legalization expands, clinicians may see more young patients with unexplained leg artery problems. Recognizing cannabis as a potential vascular risk factor could lead to earlier diagnosis and better outcomes.","specificNumbers":"Review covers epidemiological trends linking cannabis use disorder to acute limb ischemia (ALI) and chronic limb-threatening ischemia (CLTI). Limited perioperative data suggests potential adverse surgical outcomes.","methodology":"Narrative review incorporating epidemiological data, clinical studies, and mechanistic investigations, with emphasis on pathophysiological processes relevant to arterial compromise and their association with cannabis use disorder.","limitations":"Narrative review without systematic methodology. Most evidence is from case reports and small series. Concurrent tobacco and other substance use confounds associations. Causal mechanisms remain unproven."},{"rthcId":"RTHC-08417","title":"Estimating thresholds for risk of cannabis use disorder using standard delta-9-tetrahydrocannabinol (THC) units.","authors":"Lees Thorne, Rachel; Lawn, Will; Petrilli, Kat; Trinci, Katie; Borissova, Anya; Ofori, Shelan; Mokrysz, Claire; Curran, H Valerie; Hines, Lindsey A; Freeman, Tom P","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70263","pmid":"41521821","tags":["harm-reduction","cannabis-use-disorder","thc","dosing","guidelines"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Weekly THC consumption discriminated CUD risk with good accuracy (AUC >0.70). Risk thresholds for any CUD: 8.26 units/week for adults and 6.04 units/week for adolescents. For moderate/severe CUD: 13.44 units/week for adults and 6.45 units/week for adolescents (1 standard unit = 5 mg THC).","whyItMatters":"Just as alcohol has standard drink guidelines, cannabis needs evidence-based consumption thresholds. This study provides the first THC-unit-based risk estimates that could underpin safer-use guidelines.","specificNumbers":"Adults: any CUD risk threshold at 8.26 units/week (41.3 mg THC), moderate/severe CUD at 13.44 units/week (67.2 mg THC). Adolescents: any CUD at 6.04 units/week (30.2 mg THC), moderate/severe CUD at 6.45 units/week (32.3 mg THC). AUC >0.70 for all models.","methodology":"Longitudinal observational data from the CannTeen study with five assessments over 12 months. 65 adults (26-29) and 85 adolescents (16-17) in London. Weekly standard THC units estimated via Enhanced Cannabis Timeline Followback. CUD diagnosed via DSM-5 at final follow-up.","limitations":"Relatively small samples (65 adults, 85 adolescents). London-specific population may not generalize globally. 12-month follow-up may not capture long-term CUD development. Standard THC units require accurate potency knowledge."},{"rthcId":"RTHC-08418","title":"\"It's a Beautiful Feeling\": Exploring Embodied, Psychological, and Gendered Motivations for Sex Under the Influence of Cannabis Among Young Adults.","authors":"Lefebvre, Maëlle; Goyette, Mathieu; Morvannou, Adèle; London-Nadeau, Kira; Saint-Jacques, Marianne; Ferlatte, Olivier","year":2026,"journal":"Journal of sex research, 1-17","doi":"10.1080/00224499.2025.2604775","pmid":"41498290","tags":["sexual-health","youth","gender","qualitative"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Three categories of motivations emerged: transformed sexuality (heightened sensations, enhanced connection), facilitated sex (eased anxiety, lessened body concerns), and contextual influences (routine, sex-cannabis associations). Gendered dynamics were visible across all categories, with gender shaping how and why cannabis was used sexually.","whyItMatters":"Cannabis is the second most used substance in sexual contexts after alcohol, yet sexual health promotion rarely addresses it. Understanding the gendered motivations helps create non-stigmatizing, relevant guidance for young adults.","specificNumbers":"27 participants aged 18-24. Three motivation categories identified with multiple gendered sub-themes within each. Cannabis ranked as second most used substance in sexual contexts after alcohol among young adults.","methodology":"Semi-structured interviews with 27 young adults aged 18-24 who use cannabis during sex. Thematic analysis using combined inductive-deductive coding, interpreted through the Gender Structure Framework conceptualizing gender across multiple dimensions.","limitations":"Small qualitative sample limits generalizability. Self-selected participants may over-represent positive experiences. Cannot quantify prevalence of each motivation. Cultural context (Canadian young adults) may not generalize."},{"rthcId":"RTHC-08419","title":"Micropropagation of Cannabis sativa: genetic and epigenetic stability assessment over multiple generations.","authors":"Lefebvre, Vincent; Torkamaneh, Davoud; Deslauriers, Sylvie; Devèze, Théo; de Ronne, Maxime; Plourde, Mélodie B; Lamara, Mebarek; Germain, Hugo","year":2026,"journal":"Journal of cannabis research","doi":"10.1186/s42238-026-00406-y","pmid":"41715196","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08420","title":"Public attitudes and lifetime home cannabis cultivation - a survey after legalization in Germany.","authors":"Lehberger, Mira; Kleih, Anne-Katrin; Sparke, Kai","year":2026,"journal":"The International journal on drug policy, 148, 105121","doi":"10.1016/j.drugpo.2025.105121","pmid":"41443120","tags":["policy","legalization","home-cultivation","germany","public-opinion"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Sociodemographic associations with support and cultivation are largely explained by cannabis experience. Age and consumption were the most consistent correlates. Expectations about legalization consequences strongly predicted support but showed little relation to actual cultivation behavior. The only consistently negative expectation across all groups was that legalization may increase cannabis use in society.","whyItMatters":"As the largest EU country to legalize home cultivation, Germany's experience will shape cannabis policy across Europe. Understanding the gap between public support (driven by beliefs) and actual behavior (driven by experience) helps predict real-world policy outcomes.","specificNumbers":"1,500 respondents in representative panel. People who have cultivated expressed substantially higher support and more favorable expectations. Overall evaluations of legalization tended positive. Only shared negative expectation: legalization may increase societal cannabis use.","methodology":"Hierarchical regression analyses of representative online panel survey data (n=1,500) examining factors associated with support for legalization and self-reported home cannabis cultivation in post-legalization Germany.","limitations":"Cross-sectional survey early after legalization — attitudes and behavior may evolve. Self-reported cultivation may be underreported even after legalization. Online panel may not perfectly represent German population. Social desirability bias possible."},{"rthcId":"RTHC-08421","title":"Clinical, physiological, imaging and molecular responses to cannabis smoking: the Canadian Users of Cannabis Smoke (CANUCK) study.","authors":"Leung, Clarus; Gilchrist, Cassie L; Wang, Carolyn J; Liggins, James A; Li, Xuan; Yang, Julia; Cheung, Chung Y; Gerayeli, Firoozeh V; Singhera, Gurpreet K; Hsu, Wu Jih; Lidher, Lavraj S; Moo, Karolina; Leyson, Eleazar; Dhillon, Satvir S; Shaipanich, Tawimas; Leipsic, Jonathon A; Guenette, Jordan A; Rayment, Jonathan H; Kirby, Miranda; Gershon, Andrea S; Sadatsafavi, Mohsen; Tan, Wan C; Parraga, Grace; Carlsten, Christopher; Eddy, Rachel L; Sin, Don D; Leung, Janice M","year":2026,"journal":"The European respiratory journal, 67(1)","doi":"10.1183/13993003.01659-2025","pmid":"41198398","tags":["respiratory","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The CANUCK study examined 139 cannabis smokers (categorized by joint-year exposure: low ≤5, moderate 5–20, high >20 joint-years) alongside 57 never-smokers, using an unusually comprehensive battery of tests.\n\nCannabis smokers at all exposure levels reported worse respiratory symptoms than never-smokers. High joint-year smokers showed lower pre-bronchodilator FEV1 — the standard measure of airflow obstruction — suggesting measurable lung function decline with heavy, long-term use.\n\nThe study went beyond standard pulmonary testing. Hyperpolarized xenon-129 MRI revealed ventilation abnormalities, and chest CT showed structural changes. At the cellular level, airway epithelial brushings from bronchoscopy demonstrated upregulation of immune response signatures and mucin genes. Air-liquid interface cell cultures confirmed elevated MUC5AC protein — a mucus component associated with airway disease — and its expression correlated with clinical symptoms.\n\nA notable complication: 84% of cannabis-smoking participants reported current or former cigarette smoking or vaping, making it difficult to isolate cannabis-specific effects from tobacco co-exposure.","whyItMatters":"This is one of the most methodologically comprehensive studies of cannabis smoking's respiratory effects. Most prior research relied on questionnaires and basic spirometry. By adding advanced imaging (xenon MRI), cellular analysis (bronchoscopic brushings), and molecular data (gene expression, protein quantification), the CANUCK study provides multiple converging lines of evidence that cannabis smoking affects the airways at structural, functional, and molecular levels.","specificNumbers":"139 cannabis smokers, 57 never-smokers. Exposure groups: ≤5, 5–20, >20 joint-years. 48% male, median age 27. 84% reported concurrent cigarette/vaping history. High-exposure group showed lower pre-bronchodilator FEV1. Elevated MUC5AC protein in airway cultures correlated with symptoms.","methodology":"Cross-sectional study of 139 cannabis smokers and 57 never-smokers. Multi-modal assessment: respiratory symptom questionnaires, spirometry, chest CT, hyperpolarized xenon-129 MRI, bronchoscopic airway epithelial brushings with transcriptomic analysis, and air-liquid interface cell cultures for MUC5AC protein quantification.","limitations":"Cross-sectional design cannot establish causation or track progression over time. The 84% tobacco/vaping co-use rate makes it difficult to attribute findings specifically to cannabis. Participants were relatively young (median 27), so long-term consequences may not yet be manifest. The study recruited from a single Canadian center, limiting generalizability."},{"rthcId":"RTHC-08422","title":"Designing an Online and Text-Messaging Intervention to Enhance Protective Behavioral Strategy Utilization at the Daily Level Among Young Adults Engaged in Alcohol and Cannabis Use.","authors":"Lewis, Melissa A; Litt, Dana M; Fairlie, Anne M; Graupensperger, Scott; Cross, Allison; Stankus, Rachel; Murphy, Jennifer; Kilmer, Jason R","year":2026,"journal":"Journal of studies on alcohol and drugs, 87(1), 23-33","doi":"10.15288/jsad.24-00434","pmid":"40410939","tags":["harm-reduction","youth","alcohol","intervention","digital-health"],"studyType":"clinical-observation","evidenceStrength":"low","keyFinding":"Through focus groups and cognitive interviews with young adults, researchers developed an interactive online intervention followed by 8 weeks of text messages (3 per week) promoting protective behavioral strategies. The intervention targets quality and consistency of strategy use at the daily level, rather than just overall use reduction.","whyItMatters":"Most substance use interventions focus on reduction, but many young adults will continue using. Protective behavioral strategies — practical tips for using more safely — offer a realistic harm reduction approach that meets young people where they are.","specificNumbers":"Development included 9 focus groups and 22 cognitive interviews total. Final intervention: 1 web-based session plus text messages 3 days/week for 8 weeks, with 2 monthly daily-level behavior summaries.","methodology":"Mixed-methods development process: 6 initial focus groups and 13 cognitive interviews to understand PBS motivations and barriers, followed by intervention design, then 3 additional focus groups and 9 cognitive interviews for refinement. Final intervention: brief web-based session plus 8 weeks of text messages.","limitations":"Describes intervention development only — no efficacy data reported. Focus group participants may not represent all young dual-use adults. Text-message engagement rates unknown. Long-term behavior change not assessed."},{"rthcId":"RTHC-08423","title":"Cannabis Use Among Individuals Treated with Medication for Opioid Use Disorder: Correlates, Patterns, and Motivations for Use.","authors":"Leyde, Sarah E; Merrill, Joseph O; Treadway, Anna J; Pike, Kenneth C; Price, Cynthia J","year":2026,"journal":"Substance use & addiction journal, 29767342251401312","doi":"10.1177/29767342251401312","pmid":"41689843","tags":["opioid-treatment","medical-cannabis","moud","harm-reduction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"47.5% of MOUD patients used cannabis, 27% frequently (≥3 days/week). Frequent use was associated with anxiety, nausea, and lower employment. Among those surveyed in depth, 56% used for both recreation and symptom management, 30% for symptom management only. Top medical reasons: stress (100%), anxiety (83%), insomnia (79%), pain (75%), depression (75%), PTSD (67%). No significant differences in MOUD outcomes.","whyItMatters":"Many opioid treatment programs discourage or penalize cannabis use, but most patients using it are self-medicating real symptoms. Understanding these motivations could shift policy toward addressing underlying conditions rather than policing cannabis use.","specificNumbers":"303 participants, 47.5% used cannabis, 27% frequently. Subsample of 27 frequent users: 100% used for stress, 83% anxiety, 79% insomnia, 75% pain, 75% depression, 67% PTSD. 52% wanted to cut down. Employment associated with less frequent use (OR 0.54).","methodology":"Analysis of 303 participants from a randomized trial of a mind-body intervention adjunct to MOUD. Frequent cannabis users (≥3 days/week) were compared with less frequent/non-users on demographics and clinical characteristics. A subsample (n=27) completed detailed telephone surveys on cannabis use patterns and motivations.","limitations":"Cross-sectional design from a clinical trial population may not represent all MOUD patients. Small subsample (n=27) for detailed motivations. Self-reported cannabis use subject to bias. Cannot determine whether cannabis actually helps the reported symptoms."},{"rthcId":"RTHC-08424","title":"Lactobacillus Regulates the Specificity of Polysaccharides Derived From Pericarpium Citri Reticulatae \"Chachiensis\" to Alleviate High-Fat Diet-Induced Depression-Like Behavior.","authors":"Li, Chengguo; Ma, Jingqiu; Huang, Gang; Chen, Baizhong; He, Chengwei; Wu, Rihui","year":2026,"journal":"Molecular nutrition & food research, 70(2), e70388","doi":"10.1002/mnfr.70388","pmid":"41574548","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08425","title":"Differential Regulatory Effects of Cannabinoids and Vitamin E Analogs on Cellular Lipid Homeostasis and Inflammation in Human Macrophages.","authors":"Li, Mengrui; Deo, Sapna; Daunert, Sylvia; Zingg, Jean-Marc","year":2026,"journal":"Antioxidants (Basel, Switzerland), 15(1)","doi":"10.3390/antiox15010119","pmid":"41596177","tags":["cbd","thc","inflammation","macrophages","vitamin-e","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"THC increased CD36/FAT expression (promoting lipid uptake), reactive oxygen species, and inflammatory signaling via CB1-mediated NFκB activation. CBD partially prevented THC-induced CD36 upregulation. Synthetic vitamin E analog (αTAr) was more effective than natural forms at inhibiting both lipid accumulation and inflammation.","whyItMatters":"Macrophage foam cell formation drives atherosclerosis — the leading cause of heart disease. Understanding how cannabinoids affect this process has direct implications for cardiovascular risk in cannabis users.","specificNumbers":"THC increased CD36/FAT mRNA expression and NFκB activation via CB1 receptor. CBD partially prevented THC-induced CD36 upregulation. Synthetic αTAr inhibited lipid accumulation and inflammatory cytokines (TNFα, IL6, IL1β) more effectively than natural αTAn.","methodology":"Human THP-1 macrophages were treated with CBD, THC, and vitamin E analogs (natural and synthetic α-tocopherol acetate). Gene expression (CD36, SR-B1, ABCA1, cytokines), ROS, and promoter activity were measured. HEK293 cells with CB1 or TRPV-1 overexpression were used for mechanistic studies.","limitations":"In vitro macrophage study — cannot replicate the complexity of atherosclerosis in living organisms. Cannabinoid concentrations may not reflect physiological levels. Single cell type studied. Vitamin E interactions add complexity to interpretation."},{"rthcId":"RTHC-08426","title":"Developmental windows of vulnerability: Substance-specific effects of prenatal exposure timing on child psychopathology.","authors":"Li, Qiaojun; Pang, Zhen; Lu, Yansong; Jiang, Lu; Sun, Mengyao; Xu, Jiayuan","year":2026,"journal":"Drug and alcohol dependence, 279, 113029","doi":"10.1016/j.drugalcdep.2026.113029","pmid":"41520412","tags":["pregnancy","youth","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Analyzing data from 7,777 children in the ABCD Study, researchers found that the timing of prenatal substance exposure relative to when mothers became aware of their pregnancy produced strikingly different risk patterns for each substance.\n\nFor cannabis, post-awareness exposure (continued use after the mother knew she was pregnant) was specifically linked to childhood psychopathology symptoms. Pre-awareness cannabis exposure did not show the same association.\n\nFor alcohol, the pattern reversed: pre-awareness exposure (drinking before knowing about the pregnancy) was associated with childhood behavior problems, while post-awareness exposure showed a different risk profile.\n\nFor tobacco, post-awareness exposure was associated with childhood symptoms, similar to the cannabis pattern.\n\nThe six domains of childhood psychopathology assessed via the Child Behavior Checklist showed substance-specific patterns — different substances were associated with different types of behavioral and emotional problems, not a generic increase across all domains.","whyItMatters":"Most prenatal exposure research treats pregnancy as a single window. This study's key insight is that the timing matters — and matters differently for each substance. For cannabis specifically, the finding that post-awareness exposure drives the association suggests that the critical risk window may be later in pregnancy, or that the association partly reflects other characteristics of mothers who continue using cannabis after learning they're pregnant.","specificNumbers":"7,777 children from the ABCD Study. Six domains of psychopathology assessed. Cannabis: post-awareness exposure linked to symptoms. Alcohol: pre-awareness exposure linked to symptoms. Tobacco: post-awareness exposure linked to symptoms. Each substance showed distinct domain-specific patterns.","methodology":"Observational study using ABCD Study data (7,777 children enrolled 2016–2018). Prenatal exposure classified as pre-awareness (before mother knew she was pregnant) or post-awareness. Child psychopathology assessed via Child Behavior Checklist across six domains. Linear mixed-effects models adjusted for covariates.","limitations":"Observational design — mothers who continue using cannabis after pregnancy awareness may differ from those who stop in ways that independently affect child outcomes. Exposure based on maternal retrospective report. Cannot determine dose-response relationships. ABCD Study children are still developing; some psychopathology may not yet be apparent."},{"rthcId":"RTHC-08427","title":"Evaluation of the antibacterial and antioxidant potential of the endophytic fungus EFY14 from Cannabis sativa L. leaves through metabolomics and molecular docking.","authors":"Li, ShanShan; Zhang, MeiLing; Zhai, Ying; Zhao, Yan; Zhao, Ming; Liu, LiJie; Zhong, FeiYao; Wang, ZhiGang; Li, Shuai","year":2026,"journal":"Natural product research, 1-9","doi":"10.1080/14786419.2025.2609961","pmid":"41527465","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08428","title":"Matrix-Tolerant Quantification of THC and THCA in Complex Cannabis Products Using In-Sample Calibration with Multiple Isotopologue Reaction Monitoring.","authors":"Li, Yanfang; Zhang, Mengliang","year":2026,"journal":"Journal of the American Society for Mass Spectrometry, 37(2), 548-555","doi":"10.1021/jasms.5c00439","pmid":"41587413","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08429","title":"Cannabidiol alleviates methamphetamine-induced autophagy and oxidative stress by suppressing sigma 1 receptor expression.","authors":"Li, Yi; Liu, Liu; Miao, Lin; Zhang, Yue; Li, Xiao-Dong; Sun, Teng; Zeng, Xiao-Feng; Huang, Jian; Liu, Jian-Xing","year":2026,"journal":"Cellular signalling, 138, 112280","doi":"10.1016/j.cellsig.2025.112280","pmid":"41314517","tags":["cbd","methamphetamine","neuroprotection","sigma-1-receptor","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"METH upregulated sigma 1 receptor (S1R) expression, which mediated autophagy and oxidative stress. CBD downregulated S1R expression and alleviated METH-induced autophagy and oxidative stress both in HT22 cells and C57BL/6J mice. Targeted S1R intervention (inhibitor, knockdown, or knockout) confirmed S1R's role as the mediating pathway.","whyItMatters":"Methamphetamine addiction causes devastating brain damage with no effective pharmacological treatments. Identifying that CBD works through the sigma 1 receptor provides both a drug target and a potential treatment strategy.","specificNumbers":"CBD effects demonstrated in both HT22 cells (in vitro) and C57BL/6J mice (in vivo). Three independent methods confirmed S1R's role: chemical inhibitor, gene knockdown, and genetic knockout — providing strong mechanistic evidence.","methodology":"METH-induced autophagy and oxidative stress were modeled in HT22 hippocampal cells and C57BL/6J mice. S1R was targeted using chemical inhibitors, gene knockdown, and knockout techniques. CBD's therapeutic effects were assessed both in vivo and in vitro.","limitations":"Preclinical study only — no human data. Acute METH exposure models may not fully replicate chronic addiction. CBD doses used may not be clinically achievable. S1R has many functions beyond METH response."},{"rthcId":"RTHC-08430","title":"Acute and chronic cannabis vapor exposure produces immediate and delayed impacts on phases of fear learning in a sex specific manner.","authors":"Lightfoot, Savannah H M; Nastase, Andrei S; Costa Lenz Cesar, Gabriela; Hume, Catherine; Gom, Renaud C; Teskey, G Campbell; Hill, Matthew N","year":2026,"journal":"Psychopharmacology, 243(2), 301-313","doi":"10.1007/s00213-025-06748-4","pmid":"39888377","tags":["ptsd","fear-memory","sex-differences","thc","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Acute cannabis vapor before conditioning had no immediate effect on fear acquisition but impaired fear recall in females 24 hours later and prevented spontaneous recovery of fear in both sexes at two weeks. Acute exposure before extinction impaired extinction in females but enhanced it in males. Chronic THC exposure initially potentiated fear responses (mainly in females) but produced no long-term differences.","whyItMatters":"PTSD treatments often fail because extinguished fear memories return over time (spontaneous recovery). Cannabis's ability to prevent this return — especially the long-term destabilization effect — could inform new approaches to trauma therapy.","specificNumbers":"Acute pre-conditioning cannabis: prevented spontaneous recovery at 2 weeks in both sexes. Acute pre-extinction: impaired extinction in females, enhanced in males. Chronic THC: potentiated initial fear mainly in females, no long-term effects.","methodology":"Male and female Sprague Dawley rats were exposed to THC-dominant cannabis extract or vehicle vapor, then assessed in Pavlovian auditory fear conditioning. Both passive (freezing) and active (darting) fear behaviors were measured during conditioning, extinction, retrieval, and 2-week spontaneous recovery.","limitations":"Rodent fear conditioning is a simplified model of human PTSD. Cannabis vapor composition may differ from human products. Sex differences complicate clinical translation. Acute exposure paradigm doesn't match typical human use patterns."},{"rthcId":"RTHC-08431","title":"UK Medical Cannabis Registry: A two-year case series of clinical outcomes in depression.","authors":"Lillywhite, Elizabeth; Erridge, Simon; Clarke, Evonne; McLachlan, Katy; Coomber, Ross; Asghar, Muhammed; Bhoskar, Urmila; Crews, Matthieu; De Angelis, Andrea; Imran, Muhammad; Kamal, Fariha; Korb, Laura; Mwimba, Gracia; Sachdeva-Mohan, Simmi; Shaya, Gabriel; Rucker, James J; Sodergren, Mikael H","year":2026,"journal":"Journal of affective disorders, 399, 121130","doi":"10.1016/j.jad.2025.121130","pmid":"41506388","tags":["depression","medical-cannabis","uk","patient-outcomes","registry"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Among 698 patients treated with cannabis-based medicinal products for depression, statistically and clinically significant improvements were observed across PHQ-9 (depression), GAD-7 (anxiety), sleep quality, and EQ-5D-5L (quality of life) at all time points up to 24 months. Improvements were most prominent in the first 3 months. Only 9% reported adverse events, 87% of which were mild or moderate.","whyItMatters":"Depression is among the most common conditions for which people seek medical cannabis, but clinical evidence has been scarce. This is one of the largest and longest real-world datasets showing sustained benefits across multiple outcomes.","specificNumbers":"698 patients analyzed from 34,563 in registry (2.02%). At baseline, 50.86% had severe anxiety (GAD-7 ≥15). Depression-anxiety correlation: r=0.67. 9.03% reported at least one adverse event; 87.26% were mild/moderate. Improvements significant at all timepoints (p<0.001).","methodology":"Longitudinal analysis of 698 patients from the UK Medical Cannabis Registry (34,563 total patients), with patient-reported outcome measures collected at baseline and 1, 3, 6, 12, 18, and 24 months. Validated instruments included PHQ-9, GAD-7, SQS, EQ-5D-5L, and PGIC.","limitations":"Observational registry data — no control group or randomization. Selection bias (patients who improve may be more likely to stay in treatment). Cannot establish causal relationship. Only 2.02% of registry patients had depression as primary condition."},{"rthcId":"RTHC-08432","title":"Evolving health policy and regulatory oversight of medicinal cannabis in Australia: lessons for sustainable integration.","authors":"Lim, Enoch Chi Ngai; Lim, Chi Eung Danforn","year":2026,"journal":"Journal of cannabis research, 8(1), 31","doi":"10.1186/s42238-026-00394-z","pmid":"41593734","tags":["policy","regulation","australia","medical-cannabis","access"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"Prescriptions grew from 231 (2017) to over 1 million (early 2024) generating AUD $445.6M market value. Key barriers: monthly costs of $200-600, uneven rural access, variable provider knowledge, tangled federal-state regulations, and heavy import dependence. Compared to Canada, Germany, and the Netherlands, Australia's approach is relatively restrictive on reimbursement and training.","whyItMatters":"Australia is one of the world's largest medical cannabis markets, and the lessons from its regulatory growing pains can help other countries avoid similar pitfalls as they develop their own programs.","specificNumbers":"Prescriptions: 231 (2017) to 1M+ (early 2024). Market value: AUD $445.6M. Monthly patient costs: $200-600. Comparative analysis across 4 countries (Australia, Canada, Germany, Netherlands).","methodology":"Narrative review examining Australian medical cannabis policy evolution from 2016 to 2024, with comparative analysis of Canadian opt-out insurance, German pharmacist-led dispensing, and Dutch community-growth models.","limitations":"Narrative review without systematic methodology. Policy analysis based on available public data which may be incomplete. International comparisons complicated by different healthcare systems and cultural contexts."},{"rthcId":"RTHC-08433","title":"Toxicity and health effects of delta-8, delta-9, and delta-10-tetrahydrocannabinol and unregulated cannabinoids in vaping products.","authors":"Lin, Karen; Sun, Yehao; Raghu, Rhea; Suharu, Parth; Effah, Felix; Rahman, Irfan","year":2026,"journal":"Toxicology reports, 16, 102202","doi":"10.1016/j.toxrep.2026.102202","pmid":"41584105","tags":["vaping","delta-8-thc","delta-10-thc","toxicity","safety","youth"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"Hemp-derived intoxicating cannabinoids (delta-8-THC, delta-10-THC, CBN, CBG) are proliferating in largely unregulated vaping products. Chronic cannabis vapor exposure causes adverse brain and pulmonary effects. The 0.3% delta-9-THC limit has created a loophole allowing potent but unstudied THC isomers to reach consumers, particularly youth.","whyItMatters":"Youth are increasingly using vaping products containing THC variants that have essentially no safety data. The regulatory gap created by the 2018 Farm Bill means these products are widely available with no quality control or age restrictions in many jurisdictions.","specificNumbers":"0.3% delta-9-THC limit defines the legal boundary between hemp and marijuana. EVALI outbreak linked to vaping products. Multiple THC isomers (delta-8, delta-9, delta-10) plus CBD, CBN, CBG appearing in combination products.","methodology":"Review examining the pharmacology, toxicity, potential therapeutic uses, and health risks of several THC isomers and hemp-derived cannabinoids, with attention to secondary exposure risks and molecular mechanisms.","limitations":"Much of the evidence is indirect, extrapolated from delta-9-THC research. Long-term human studies on delta-8 and delta-10 THC are essentially nonexistent. Rapidly changing product landscape may outpace review findings."},{"rthcId":"RTHC-08434","title":"Heterogeneity of Within-Day Simultaneous Alcohol and Cannabis Use Behaviors Among Young Adults: A Multilevel Latent Class Analysis.","authors":"Linden-Carmichael, Ashley N; Lanza, Stephanie T; Sokolovsky, Alexander W; White, Helene R; Jackson, Kristina M","year":2026,"journal":"Journal of studies on alcohol and drugs","doi":"10.15288/jsad.25-00286","pmid":"41623211","tags":["alcohol","co-use","youth","harm-reduction","methodology"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Multilevel latent class analysis of 1,527 simultaneous use days identified four patterns: Alcohol-Focused (43%), Cannabis-Focused (35%), Heavy Use (14%), and Early-Day Use (8%). Heavy Use days were most strongly linked to same-day harms. Day-level patterns varied significantly across three motives: being social, being offered, and having fun.","whyItMatters":"Research on co-use has treated all simultaneous use days as equivalent, but this study shows they're not — identifying which types of days are dangerous can help target interventions more precisely.","specificNumbers":"255 participants, 1,527 simultaneous use days. Four patterns: Alcohol-Focused (43%), Cannabis-Focused (35%), Heavy Use (14%), Early-Day Use (8%). Heavy Use days significantly more harmful than other day types.","methodology":"Multilevel latent class analysis of daily survey data from 255 college students who completed up to 54 days of surveys, yielding 1,527 person-days with simultaneous alcohol-cannabis use. Both within-person and between-person variation was modeled.","limitations":"College student sample limits generalizability. Self-reported daily data subject to recall issues. 54-day period may not capture seasonal or event-driven patterns. Cannot determine causation between day type and harms."},{"rthcId":"RTHC-08435","title":"The intersectionality of cannabis use and depression symptoms on functional brain topology in adults.","authors":"Liu, Che; Cousijn, Janna; Kroon, Emese; Filbey, Francesca M","year":2026,"journal":"Drug and alcohol dependence, 281, 113082","doi":"10.1016/j.drugalcdep.2026.113082","pmid":"41691822","tags":["depression","brain-imaging","neuroimaging","co-morbidity"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis users had shorter characteristic path length, higher global efficiency and transitivity, and increased local efficiency in salience, frontoparietal, and subcortical networks. Depression symptoms moderated these effects — higher depression scores weakened the cannabis group differences. Among cannabis users, higher use frequency enhanced network efficiency but depression didn't moderate dose-response effects.","whyItMatters":"Cannabis use and depression frequently co-occur, but studying either alone misses the interaction. This study shows that co-occurring depression actually counteracts some of cannabis's brain network effects — critical for understanding real-world outcomes.","specificNumbers":"223 cannabis users, 172 controls. Cannabis users showed shorter path length, higher global efficiency and transitivity. Depression moderated group effects on global measures. Dose-response: higher frequency = shorter path length, higher global efficiency.","methodology":"Graph theory analysis of resting-state fMRI in 223 cannabis users (mean age 26.8) and 172 controls (mean age 25.0), examining global and local network properties. Depression symptoms assessed as moderators of cannabis-brain relationships.","limitations":"Cross-sectional design cannot determine whether cannabis caused brain changes or people with different brains are more likely to use cannabis. Self-reported depression symptoms, not clinical diagnosis. Cannot assess temporal ordering of cannabis use and depression onset."},{"rthcId":"RTHC-08436","title":"Multi-level metabolic Profiling of Synthetic Cannabinoid 5F-ADB: Identifying Definitive Biomarkers for Forensic Source Tracking and Ecotoxicological Risk Assessment.","authors":"Liu, Qinghua; Liu, Yuqing; Ma, Beiya; Yi, Pan; Shao, Runwen; Li, Shuhan; Sui, Hongxia; Guo, Ruixin; Chen, Jianqiu; Liu, Yanhua","year":2026,"journal":"Environmental toxicology and chemistry","doi":"10.1093/etojnl/vgag003","pmid":"41506899","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08437","title":"Epidemiology of Cannabis Use Among Middle-Aged and Older Adults in the U.S.","authors":"Livne, Ofir; Stohl, Malka; Gilman, Jodi; Goldberg, Terry E; Wall, Melanie M; Hasin, Deborah S","year":2026,"journal":"American journal of preventive medicine, 70(3), 108149","doi":"10.1016/j.amepre.2025.108149","pmid":"41101401","tags":["epidemiology","older-adults","prevalence","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Past-year cannabis use: 18.5% of middle-aged (50-64) and 5.9% of older adults (≥65). Smoking was primary consumption method in both groups. About 25% of middle-aged and 20% of older cannabis users consumed for medical purposes, but only ~20% of medical users had a prescription or recommendation. Over 75% viewed medical use as acceptable; older adults were more likely to see cannabis as a gateway drug.","whyItMatters":"Older adults are especially vulnerable to cannabis side effects including falls, cognitive impairment, and drug interactions. The finding that most older medical users lack prescriptions means they're self-medicating without clinical guidance.","specificNumbers":"18.5% of ages 50-64 and 5.9% of ≥65 used cannabis past year. ~25% of middle-aged users and ~20% of older users consumed medically. ~20% of medical users had prescriptions. >75% of both groups viewed medical use as acceptable.","methodology":"Analysis of Health and Retirement Study data (N=1,324) with weighted prevalence calculations and multivariable logistic regression adjusting for sex, race/ethnicity, household income, and employment. Results stratified by age groups (50-64, 65-74, ≥75) and sex.","limitations":"Self-reported data likely underestimates true prevalence. Cross-sectional design. HRS sample may not perfectly represent all middle-aged and older adults. 'Medical use' was self-defined, not clinically verified."},{"rthcId":"RTHC-08438","title":"Sex and dose-dependent effects of cannabidiol on cocaine consumption in mice.","authors":"Llerena, Veronika; Tic, Iva; Llach-Folcrà, Maria; Valverde, Olga; Medrano, Mireia","year":2026,"journal":"Translational psychiatry, 16(1)","doi":"10.1038/s41398-026-03880-3","pmid":"41651805","tags":["cbd","cocaine","sex-differences","addiction","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"In female mice, 10 mg/kg CBD attenuated cocaine self-administration acquisition by altering reward and cognitive markers in the mesocorticolimbic pathway. Conversely, 20 mg/kg increased cocaine consumption after punishment but reduced cocaine-seeking upon re-exposure to punishment cues and upregulated Htr1a (serotonin receptor) in the prefrontal cortex. Male mice showed no effects after punishment.","whyItMatters":"Cocaine use disorder has no approved medications, and women progress faster to addiction with worse outcomes. Finding that CBD modulates cocaine behavior in females specifically could open a sex-specific treatment approach.","specificNumbers":"Two CBD doses: 10 mg/kg (reduced acquisition) and 20 mg/kg (complex effects). Female-specific effects. 20 mg/kg upregulated Htr1a in medial prefrontal cortex. Males showed no effects after punishment paradigm.","methodology":"Female (and parallel male) mice received CBD at 10 or 20 mg/kg before intravenous cocaine self-administration testing. CBD's pharmacological profile was evaluated on anxiety-like and cognitive tasks. Effects on reward, cognitive, and serotonergic markers in the mesocorticolimbic pathway were assessed.","limitations":"Mouse model with intravenous self-administration — different from human cocaine use patterns. Only two CBD doses tested. Sex differences observed in one paradigm (punishment) may not extend to others. Short-term study cannot address chronic treatment effects."},{"rthcId":"RTHC-08439","title":"From localization to function: comparative analysis of CB1 in sperm across species and its epigenetic role in humans.","authors":"Lombó, Marta; Sella, Fiorenza; Giommi, Christian; Giannubilo, Stefano; Frontini, Andrea; Ciavattini, Andrea; Cobellis, Gilda; Manfrevola, Franceso; Montik, Nina; Paolanti, Marina; Herráez, Paz; Carnevali, Oliana","year":2026,"journal":"Cell death & disease, 17(1), 176","doi":"10.1038/s41419-025-08386-2","pmid":"41540010","tags":["endocannabinoid-system","reproductive-health","cb1-receptor","fertility","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Using advanced microscopy, CB1 was mapped in human sperm showing distribution along the tail, some midpieces, and discrete head spots. CB1 was conserved across species (invertebrates to mammals) in the tail. Critically, CB1 activation by ACEA enhanced histone H4 acetylation in asthenoteratozoospermic samples, restoring levels to those of normal donors. AEA treatment reduced DNA fragmentation, but this was not CB1-mediated.","whyItMatters":"Male infertility affects millions, and poor sperm chromatin packaging is a major contributor. The discovery that activating the cannabinoid receptor improves DNA packaging in abnormal sperm could lead to new fertility treatments.","specificNumbers":"CB1 found intracellularly in mammalian sperm heads. ACEA treatment restored histone H4 acetylation in asthenoteratozoospermic sperm to normozoospermic levels. AEA reduced DNA fragmentation but through a non-CB1 pathway.","methodology":"Confocal and Airyscan microscopy mapped CB1 in human sperm and across species. CB1 agonists (ACEA, AEA) were applied to normal and abnormal sperm samples to assess effects on histone acetylation and DNA fragmentation via immunofluorescence.","limitations":"In vitro sperm treatment — effects may differ in vivo. Small sample sizes for human sperm analysis. Long-term effects on fertilization success not tested. Cross-species comparison may oversimplify receptor function differences."},{"rthcId":"RTHC-08440","title":"Sexual diversity, adolescent mental health, and adult cannabis use: Longitudinal associations through cannabis use motives.","authors":"London-Nadeau, Kira; Pocuca, Nina; Rioux, Charlie; Chadi, Nicholas; Côté, Sylvana M; Fallu, Jean-Sébastien; Geoffroy, Marie-Claude; Huynh, Christophe; Juster, Robert-Paul; Séguin, Jean R; Castellanos-Ryan, Natalie","year":2026,"journal":"Addictive behaviors, 173, 108530","doi":"10.1016/j.addbeh.2025.108530","pmid":"41175609","tags":["sexual-diversity","mental-health","youth","cannabis-use-disorder","coping"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Depression symptoms at 17 predicted cannabis use problems at 23 among sexually diverse participants only, and this was fully mediated by coping motives. Coping motives were strongly predicted by depression in sexually diverse but not heterosexual youth. Enhancement motives predicted problems in both groups but weren't driven by mental health. Depression also predicted social motives in diverse youth only.","whyItMatters":"LGBTQ+ youth face disproportionate mental health burdens and substance use risks. This study identifies the specific pathway — depression driving coping-motivated cannabis use — which can be targeted by prevention programs.","specificNumbers":"471 total participants (425 heterosexual, 46 sexually diverse). Depression at 17 predicted CU problems at 23 in diverse youth only. Coping motives fully mediated this pathway. Enhancement motives predicted problems in both groups.","methodology":"Longitudinal data from Quebec Longitudinal Study of Child Development with self-reports at ages 17 and 23. Sample: 425 heterosexual and 46 sexually diverse participants assessed on depression, anxiety, cannabis use frequency, motives, and problems.","limitations":"Small sexually diverse subsample (n=46) limits statistical power and generalizability. Quebec-specific context. Binary sexual diversity measure may obscure differences within LGBTQ+ communities. Self-report measures."},{"rthcId":"RTHC-08441","title":"Endocannabinoid modulation of defensive state transitions to innate and learned threat.","authors":"Loomba, Niharika; Cao, Anyu; Charles, Senna; Kandil, Isaac; Kwon, Michelle; Patel, Sachin","year":2026,"journal":"Psychopharmacology, 243(2), 325-338","doi":"10.1007/s00213-025-06812-z","pmid":"40411583","tags":["endocannabinoid-system","2-ag","fear","defensive-behavior","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"Inhibiting 2-AG synthesis enhanced freezing to early cues and promoted active responses during high threat imminence in learned fear. In innate fear (looming shadow), 2-AG depletion biased behavior toward freezing and increased time in safe zones. 2-AG signaling promotes active defensive responses and regulates the scaling of passive-to-active behavioral transitions.","whyItMatters":"Maladaptive fear responses — freezing when you should flee, or panicking when you should stay calm — are hallmarks of anxiety disorders and PTSD. Understanding that 2-AG controls these transitions could lead to treatments that restore appropriate threat responses.","specificNumbers":"Two fear paradigms tested: serial compound stimulus (learned) and looming shadow (innate). 2-AG inhibition shifted behavior toward passive freezing in both paradigms. Active defensive responses were promoted by intact 2-AG signaling.","methodology":"Pharmacological manipulation of 2-AG signaling in mice tested in two paradigms: serial compound stimulus (learned fear) and looming shadow (innate fear). Behavioral state transitions between freezing (passive) and darting/fleeing (active) defense were analyzed.","limitations":"Mouse behavioral paradigms may not fully translate to human threat responses. Pharmacological 2-AG manipulation is systemic, not region-specific. Acute drug effects may differ from chronic endocannabinoid changes. Did not test cannabinoid receptor agonists directly."},{"rthcId":"RTHC-08442","title":"Disparities in Exposure to Cannabis Marketing and Perceptions of Inequalities in Possession Treatment: Differences Across Intersections of Sociodemographic Subgroups.","authors":"LoParco, Cassidy R; Romm, Katelyn F; Cui, Yuxian; Cavazos-Rehg, Patricia A; Berg, Carla J","year":2026,"journal":"Journal of racial and ethnic health disparities","doi":"10.1007/s40615-026-02866-7","pmid":"41618021","tags":["disparities","marketing","racial-equity","lgbtq","policy"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Black, Hispanic, transgender, nonbinary, and sexual minority individuals perceived more unfair cannabis possession treatment. Black and Hispanic individuals had more exposure to cannabis ads and risk information. Intersectional effects were strong: Black transgender and Black sexual minority individuals showed particularly pronounced perceptions of unfair possession treatment.","whyItMatters":"Cannabis legalization hasn't eliminated racial and gender disparities — it may have reshaped them through marketing. Understanding who is disproportionately targeted by industry advertising and law enforcement helps design more equitable cannabis policies.","specificNumbers":"4,031 participants. Black transgender individuals showed particularly strong perceptions of unfair possession treatment (slope=-0.60). Black sexual minority individuals also showed amplified effects (slope=-0.18). Black individuals had more cannabis ad exposure, perceived more targeted marketing.","methodology":"Online survey of 4,031 US young adults (18-34) recruited via Facebook in 2023. Multivariable linear regressions examined gender, sexual orientation, race, and ethnicity across five outcomes related to cannabis law enforcement and marketing perceptions, including moderation analyses.","limitations":"Facebook recruitment may not be fully representative. Self-reported perceptions may not accurately reflect actual marketing or enforcement patterns. Cross-sectional design limits causal inference. Social desirability may affect reporting."},{"rthcId":"RTHC-08443","title":"A longitudinal mediated examination of legal, commercial, and individual determinants of cannabis and derived cannabis use behaviors and consequences among US young adults.","authors":"LoParco, Cassidy R; Rossheim, Matthew E; Wang, Yan; Yang, Y Tony; Paichadze, Nino; Cavazos-Rehg, Patricia A; Berg, Carla J","year":2026,"journal":"Addictive behaviors, 172, 108526","doi":"10.1016/j.addbeh.2025.108526","pmid":"41135124","tags":["policy","marketing","delta-8-thc","youth","longitudinal"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Legal cannabis states saw lower DICP use motives but higher cannabis-only use frequency. More restrictive delta-8 laws increased cannabis-only (vs. both) use. Digital cannabis ads lowered risk perceptions and increased use, motives, intentions, and consequences. These associations were mediated by use motives and risk perceptions. Higher use frequency mediated associations with consequences.","whyItMatters":"This is among the first studies to trace the full causal chain from cannabis policy and marketing through psychological mechanisms to actual use behavior and consequences — showing exactly how and why these upstream factors affect downstream harm.","specificNumbers":"3,437 participants across two waves. Legal vs. illegal states: lower DICP motives, higher cannabis-only use. Digital ads associated with lower risk perceptions, higher use motives, higher use intentions, more consequences. Frequency mediated law/advertising effects on consequences.","methodology":"Two-wave longitudinal survey (2023-2024) of 3,437 US young adults aged 18-34 (~50% past-month cannabis use by design). Multivariable regressions with parallel mediation assessed direct and indirect associations across state laws, advertising exposure, risk perceptions, motives, use, and consequences.","limitations":"Self-reported survey data. ~50% past-month cannabis user sampling design may overrepresent users. State law assignment is cross-sectional even with longitudinal individual data. Digital ad measurement may not capture total exposure."},{"rthcId":"RTHC-08444","title":"Cannabis and Derived Cannabis Use, Motives, and Consequences Among US Young Adults: Findings From a Cross-Sectional Mediation Study.","authors":"LoParco, Cassidy R; Cui, Yuxian; Rossheim, Matthew E; Chakraborty, Rishika; Speer, Morgan; Chen-Sankey, Julia; Cavazos-Rehg, Patricia A; Berg, Carla J","year":2026,"journal":"Substance use & addiction journal, 47(1), 57-67","doi":"10.1177/29767342251355094","pmid":"40709804","tags":["delta-8-thc","co-use","youth","motives","consequences"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among past-month cannabis users, 54.4% used cannabis only while 45.6% co-used cannabis and DICPs. Greater enhancement and coping motives predicted co-use. Cannabis-DICP co-use was associated with greater psychophysiological and sociobehavioral consequences. Consequences were bidirectionally associated with motives — higher consequences predicted stronger motives, which predicted more co-use.","whyItMatters":"Delta-8 and other derived products have exploded in popularity but are essentially unregulated. Nearly half of cannabis users adding these products — with more consequences — represents a rapidly growing public health concern.","specificNumbers":"1,968 past-month cannabis users analyzed. 54.4% cannabis-only, 45.6% cannabis+DICP co-use. Enhancement and coping motives predicted co-use. Co-use associated with greater psychophysiological and sociobehavioral consequences. Bidirectional mediation confirmed.","methodology":"Cross-sectional mediation analysis of 1,968 past-month cannabis users (from 4,031 surveyed US young adults aged 18-34). Two mediation models examined: motives → use category → consequences, and consequences → motives → use category.","limitations":"Cross-sectional design cannot establish temporal ordering despite mediation models. Self-reported use and consequences. ~50% cannabis user design may limit generalizability. DICP category is broad (delta-8, delta-10, etc.)."},{"rthcId":"RTHC-08445","title":"The Neurocircuitry of Cannabis Cue Reactivity in Cannabis Use Disorder: A Functional Neuroimaging Study.","authors":"Lorenzetti, Valentina; Sehl, Hannah; Arun, Arush Honnedevasthana; McTavish, Eugene; Clemente, Adam; Thomson, Hannah; Quinones-Valera, Marianna; Gaillard, Alexandra; Beyer, Emillie; Thomson, Diny; Cousijn, Janna; Labuschagne, Izelle; Rendell, Peter; Terrett, Gill; Suo, Chao; Greenwood, Lisa-Marie; Manning, Victoria; Poudel, Govinda","year":2026,"journal":"Biological psychiatry global open science, 6(1), 100638","doi":"10.1016/j.bpsgos.2025.100638","pmid":"41438414","tags":["cannabis-use-disorder","brain-imaging","cue-reactivity","craving","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Compared to controls, individuals with CUD showed greater cannabis cue reactivity in occipital, orbitofrontal, cingulate, cerebellar, hippocampal, temporal, and parietal cortices. Greater occipital/cerebellar activity correlated with subjective arousal and cannabis withdrawal. Anterior cingulate/parietal activity negatively correlated with urinary THC metabolite levels.","whyItMatters":"Understanding the neural basis of cannabis craving is essential for developing treatments that can break the cycle of cue-triggered relapse. These findings show cannabis cues activate the same addiction circuits seen with other substances.","specificNumbers":"65 CUD participants, 43 controls. Heightened activity in multiple regions (p<0.001, FWE corrected, k>10). Occipital/cerebellar activity correlated with arousal and withdrawal. Anterior cingulate/parietal activity negatively correlated with THC metabolite:creatinine ratio.","methodology":"fMRI cannabis cue-reactivity task in 65 individuals with moderate-to-severe CUD (non-treatment-seeking, with past quit attempts) and 43 controls. Group differences analyzed adjusting for age and sex; correlations with cannabis use characteristics and mental health assessed.","limitations":"Cross-sectional — cannot determine if brain differences preceded CUD. Non-treatment-seeking sample may differ from those in treatment. Static images may not capture real-world cue reactivity (smell, social context). Modest sample size."},{"rthcId":"RTHC-08446","title":"Development and Initial Validation of the Cannabis Attention and Affect Motives Scale.","authors":"Lowden, Danielle S; Wong, Jennifer H K; Harty, Seth C","year":2026,"journal":"Substance use & misuse, 61(3), 441-450","doi":"10.1080/10826084.2025.2565420","pmid":"41044053","tags":["adhd","motives","scale-development","attention","methodology"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"The Cannabis Attention and Affect Motives Scale (CAAMS) yielded 5 factors: Negative Affect Reduction, Attention Enhancement, Attention and Behavior Motivation, Social Anxiety Reduction, and Recreation/Relaxation Enhancement. ADHD-risk groups showed significantly higher scores on all factors except Recreation/Relaxation, suggesting ADHD-specific motivations beyond general cannabis use.","whyItMatters":"People with ADHD are overrepresented among cannabis users, and many report using it to manage symptoms. This scale provides the first validated tool to measure these specific motivations, enabling better research and clinical assessment.","specificNumbers":"417 participants. Initial 46-item pool refined to 28 items across 5 factors. ADHD-risk groups differed significantly on 4 of 5 factors. Recreation/Relaxation was the only factor not differing by ADHD risk.","methodology":"Online survey of 417 adult cannabis users (61.9% male, predominantly NZ/European). Exploratory and confirmatory factor analyses on split-half samples yielded a 28-item, 5-factor model. Post-hoc comparisons across low, medium, and high ADHD-risk groups.","limitations":"Predominantly New Zealand/European sample limits generalizability. Online self-report subject to bias. ADHD risk screener is not equivalent to clinical diagnosis. Cross-sectional design. Factor structure needs replication."},{"rthcId":"RTHC-08447","title":"Talking About Cannabis: Perspectives of First Episode Psychosis Care Participants and Parents.","authors":"Lucksted, Alicia; Bencivengo, Donna; Saravana, Arunadevi; Boumaiz, Yasmine; Kreyenbuhl, Julie; Margolis, Russell L; Nayar, Swati; Rinehimer, Kathryn; Rouse, Krissa; Scheinberg, Rachel; Thomas, Elizabeth C; Walker, Denise D; Wolcott, Max; Burris, Elizabeth; Myers, Ladawn; Kelly, Christian; Swigart, Alison; Vatza, Crystal L; Brandt, Allison S; Sarpal, Deepak K; Goldberg, Richard W; Buchanan, Robert W; Moore, Tyler M; Jumper, Megan B E; Fooks, Amanda; Ered, Arielle; Caulkins, Monica E; Bennett, Melanie","year":2026,"journal":"Journal of dual diagnosis, 22(1), 37-47","doi":"10.1080/15504263.2025.2606020","pmid":"41447574","tags":["psychosis","communication","youth","family","qualitative"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Four themes emerged: Respect for Developing Client Autonomy, 'Good Information' about Cannabis and Its Effects, Good Communication Process, and Conversations Complicated by Changing Norms. Clients and parents agreed on what makes conversations positive but had difficulty understanding each other's perspectives, with both feeling misunderstood.","whyItMatters":"Cannabis use is strongly linked to psychosis, yet conversations about it in clinical and family settings often go poorly. Both young people and parents want these conversations — they just need better tools and information.","specificNumbers":"15 clients and 16 parents interviewed. Four themes identified. Both groups agreed on positive conversation elements but reported feeling misunderstood by each other.","methodology":"Semi-structured interviews with 15 clients receiving Coordinated Specialty Care for first episode psychosis and 16 parents. Braun and Clark's six-phase thematic analysis applied to identify communication themes and preferences.","limitations":"Small qualitative sample from a specific clinical population. Clients were in Coordinated Specialty Care, which may not represent all psychosis treatment settings. Parent and client perspectives not matched pairs. Social desirability may affect responses."},{"rthcId":"RTHC-08448","title":"Cannabis Use in Orthopaedic Surgery: Effects on Fracture Healing, Opioid Requirements, and Clinical Outcomes.","authors":"Luigi Martinez, Hiram E; Rivera Troia, Felix M; Babilonia Beltran, Paola A; Flores Carrasquillo, Estefanía C; Fernandez-Sotero, Rafael; Señeriz Ortiz, Rafael","year":2026,"journal":"Cureus, 18(1), e100930","doi":"10.7759/cureus.100930","pmid":"41658673","tags":["orthopedic-surgery","bone-healing","opioids","perioperative"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system influences bone cell function, and smoked cannabis may impair cancellous bone healing in animals while CBD may enhance fracture repair. In humans, heavy cannabis use is associated with lower bone mineral density, higher fracture risk, and in some settings increased complications or nonunion risk. Chronic cannabis use is frequently associated with higher postoperative pain and opioid consumption.","whyItMatters":"Many orthopedic patients use cannabis for pain relief, and some hope it will reduce opioid needs after surgery. This comprehensive review shows the opposite may be true — cannabis use may worsen surgical outcomes.","specificNumbers":"Over 100 studies screened. Heavy cannabis use associated with lower bone mineral density, higher fracture risk, potential malunion/nonunion. Small cannabinoid trials showed at most modest opioid-sparing effects. Pharmaceutical cannabinoids did not produce clinically important perioperative benefits.","methodology":"Narrative review synthesizing mechanistic, preclinical, and clinical evidence from PubMed, Embase, manual reference review, and AI-assisted screening of more than 100 orthopaedic and perioperative studies.","limitations":"Narrative review with heterogeneous evidence quality. Most human data is observational with confounding by indication. Cannabis exposure measurement varies widely across studies. CBD and THC may have opposing bone effects but are rarely distinguished."},{"rthcId":"RTHC-08449","title":"The dual roles of natural cannabidiol in combating oxidative stress and inflammation: A potential intestinal guardian.","authors":"Lv, Biguang; He, Jieyi; Zhan, Sha; Jin, Ke; Lei, Xinyu; Cheng, Xuan; Lv, Zonghao; Chen, Fengming; Li, Yuying; Lu, Jun; Lin, Qian","year":2026,"journal":"Redox biology, 91, 104051","doi":"10.1016/j.redox.2026.104051","pmid":"41713221","tags":["cbd","inflammation"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review synthesized evidence on CBD's protective mechanisms in the gastrointestinal tract, focusing on its redox-related (antioxidant) and anti-inflammatory effects.\n\nCBD appears to work through several converging pathways. It regulates reactive oxygen species (ROS) production and activates the Nrf2-Keap1 antioxidant pathway — a master regulator of cellular defense against oxidative damage. Simultaneously, CBD modulates redox-sensitive inflammatory signaling, including the NF-κB pathway and the NLRP3 inflammasome, both central drivers of intestinal inflammation.\n\nThrough the endocannabinoid system and related receptors, CBD helps preserve epithelial barrier integrity — the intestinal lining that separates gut contents from the body's interior. CBD also influences gut microbiota composition, adding another layer to its intestinal effects.\n\nThe review highlighted emerging evidence connecting CBD's gut effects to systemic health through gut-organ axes — the bidirectional communication networks between the intestine and other organs including the brain, liver, and lungs.","whyItMatters":"Inflammatory bowel disease affects millions of people worldwide and available treatments have significant limitations. Oxidative stress and barrier dysfunction are key drivers of disease. This review maps the specific molecular mechanisms through which CBD might address these drivers, providing a scientific framework for the clinical interest in CBD for gut conditions.","specificNumbers":"Key pathways identified: Nrf2-Keap1 (antioxidant), NF-κB (inflammation), NLRP3 inflammasome (inflammation), endocannabinoid receptor signaling (barrier integrity). Conditions discussed: IBD, colorectal cancer. Gut-organ axes: gut-brain, gut-liver, gut-lung.","methodology":"Narrative review synthesizing preclinical and mechanistic studies on CBD's effects in the gastrointestinal tract. Focused on redox biology (antioxidant pathways), inflammatory signaling, epithelial barrier function, endocannabinoid system interactions, and gut microbiota modulation.","limitations":"Most evidence comes from cell culture and animal models — clinical data on CBD for intestinal conditions are limited. Doses used in preclinical studies may not translate to achievable human gut concentrations. CBD's poor oral bioavailability (documented in RTHC-00246) means that reaching therapeutic concentrations in the gut may require specific formulations. The review synthesizes selectively rather than systematically."},{"rthcId":"RTHC-08450","title":"Daily web survey data collection of time-varying cannabis use motives and contexts, with implications for adaptive interventions: A pilot study.","authors":"Ma, Yongchao; West, Brady T; McCabe, Sean Esteban","year":2026,"journal":"Drug and alcohol dependence, 278, 112974","doi":"10.1016/j.drugalcdep.2025.112974","pmid":"41319431","tags":["motives","adaptive-interventions","daily-assessment","methodology","sleep"],"studyType":"longitudinal","evidenceStrength":"preliminary","keyFinding":"Four types of weekly motive transitions were identified, with shifts toward sleep-aid and cannabis-availability-dominated motives predicting higher subsequent use frequency. Open-ended data revealed cannabis use for managing sleep disturbances, daily stressor-triggered anxiety, and recovery from medical treatments like chemotherapy.","whyItMatters":"Static assessments miss the dynamic nature of cannabis use motives. Real-time monitoring of motive shifts could enable just-in-time interventions — sending support when a person transitions toward higher-risk patterns.","specificNumbers":"48 participants over 28 days. Four types of weekly motive transitions identified. Sleep aid and availability motives most associated with increased use frequency. Participants aged 22-76, mean 48.8 years.","methodology":"28-day daily web survey of 48 participants (aged 22-76, 64% female, 22% African American) with baseline and follow-up mental health assessments. Latent transition analysis with random intercepts (RI-LTA) modeled weekly motive class transitions.","limitations":"Very small pilot sample (n=48). Convenience sample may not be representative. 28-day period may be too short to capture all motive transition patterns. Daily surveys may themselves influence behavior (reactivity)."},{"rthcId":"RTHC-08451","title":"Cannabis Use Disorder and Risk of Pancreatic Cancer in Patients with Chronic Pancreatitis: a Multicenter Retrospective Cohort Study.","authors":"Maan, Muhammad Hassaan Arif; Maan, Soban; Ahmad, Muhammad Mursaleen; Goyal, Ritik Mahaveer; Khan, Sunnia; Waleed, Muhammad; Qureshi, Imran; Hajifathalian, Kaveh; Al-Khazraji, Ahmed","year":2026,"journal":"Journal of gastrointestinal cancer, 57(1), 14","doi":"10.1007/s12029-025-01383-w","pmid":"41533288","tags":["pancreatic-cancer","chronic-pancreatitis","cannabis-use-disorder","gastrointestinal"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After propensity score matching (6,858 per group), CUD was associated with significantly reduced pancreatic cancer detection (67 vs. 274 cases; HR 0.263, 95% CI 0.202-0.344, p<0.001) but a modest increase in acute pancreatitis flare risk (HR 1.102, 95% CI 1.043-1.166, p=0.001). Results were consistent in sensitivity analysis adjusting for opioid use disorder.","whyItMatters":"Chronic pancreatitis patients face elevated pancreatic cancer risk. If cannabis use truly reduces that risk, it could inform chemoprevention strategies — though the finding may also reflect differences in detection or follow-up.","specificNumbers":"10,864 CUD patients and 42,160 controls before matching; 6,858 per group after matching. PC: 67 vs. 274 cases (HR 0.263). AP flares: HR 1.102. Mean follow-up shorter in CUD (736±422 vs 896±368 days).","methodology":"Retrospective cohort study using TriNetX database identifying adults with chronic pancreatitis stratified by CUD status. Propensity score matching (1:1) for demographics, behavioral factors, and comorbidities. Cox proportional hazards regression for primary (PC incidence) and secondary (AP flare) outcomes.","limitations":"Retrospective database study with inherent coding biases. Shorter follow-up in CUD group may miss later cancers. 'Detection' during follow-up differs from true incidence. Cannot determine mechanism. CUD is not equivalent to all cannabis use."},{"rthcId":"RTHC-08452","title":"The psychoactive cannabinoid THC inhibits peripheral nociceptors by targeting NaV1.7 and NaV1.8 nociceptive sodium channels.","authors":"Maatuf, Yossef; Iskimov, Ariel; Binshtok, Alexander M; Priel, Avi","year":2026,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","doi":"10.1038/s41386-026-02355-9","pmid":"41565997","tags":["thc","pain","sodium-channels","peripheral-nerves","pharmacology"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"THC directly targets nociceptive voltage-gated sodium channels NaV1.7 and NaV1.8 through the conserved local anesthetic binding site, reducing sodium currents and suppressing action potential generation in peripheral sensory neurons — a mechanism entirely independent of cannabinoid receptor signaling.","whyItMatters":"NaV1.7 and NaV1.8 are the two most important sodium channels for pain signaling. Finding that THC blocks them directly — like a local anesthetic — provides a completely new framework for developing cannabinoid-based painkillers without psychoactive effects.","specificNumbers":"Two sodium channel subtypes targeted: NaV1.7 and NaV1.8. THC binds at the conserved local anesthetic binding site. Complete suppression of action potential generation demonstrated in peripheral sensory neurons.","methodology":"Electrophysiology studies measuring THC's effects on sodium currents through NaV1.7 and NaV1.8 channels, with binding site analysis and action potential recording in peripheral sensory neurons.","limitations":"In vitro electrophysiology — therapeutic concentrations at peripheral nerves in vivo may differ. Binding site overlap with local anesthetics raises questions about clinical utility versus existing drugs. Effects on other sodium channel subtypes not reported."},{"rthcId":"RTHC-08453","title":"Chronic cannabidiol treatment effects on contextual fear and neuropathic pain in Carioca rats high and low conditioned freezing.","authors":"Macêdo-Souza, Carolina; Ferrarese-Tiballi, Aline A; Maisonnette, Silvia Soares; Rosseti, Flávia; Catalão, Carlos Henrique Rocha; Hallak, Jaime E; Crippa, José A; Zuardi, Antônio W; Landeira-Fernandez, J; Leite-Panissi, Christie Ramos Andrade","year":2026,"journal":"Behavioural brain research, 496, 115855","doi":"10.1016/j.bbr.2025.115855","pmid":"41027533","tags":["cbd","anxiety","chronic-pain","preclinical","bdnf"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CBD (5 mg/kg daily for 10 days) reduced allodynia across all rat lineages bred for different anxiety levels, though anxiety-prone (CHF) rats showed less benefit. CBD was anxiolytic for control and high-anxiety rats with nerve injury but not for low-anxiety rats. CBD reduced conditioned fear in all non-injured groups but not in anxiety-prone rats with nerve injury. BDNF expression varied by lineage.","whyItMatters":"Anxiety and chronic pain commonly co-occur, and CBD is increasingly used for both. This study reveals that individual differences in anxiety-proneness affect CBD's therapeutic profile — important for personalizing treatment.","specificNumbers":"5 mg/kg CBD daily, days 14-23 post-surgery. Three lineages tested. CBD reduced allodynia in all lineages (less in CHF). Anxiolytic in CTL and CHF with CCI. BDNF restored in CTL rats by CBD treatment.","methodology":"Male rats from three selectively bred Carioca lineages (high-freezing CHF, low-freezing CLF, non-selected CTL; n=32/group) underwent sciatic nerve injury or sham surgery, then received CBD 5 mg/kg daily for 10 days. Sensory, locomotor, anxiety, and fear conditioning outcomes assessed.","limitations":"Male rats only. Single CBD dose tested. Rat breeding lineages are models, not direct analogs of human anxiety disorders. 10-day treatment may not reflect chronic use. BDNF effects varied unpredictably across lineages."},{"rthcId":"RTHC-08454","title":"Electrophysiological Correlates of Attention- and Reward-related Brain Activity in Cannabis Users: Stage II Preregistered Research Report of a Longitudinal Study.","authors":"Macedo, Inês; Pasion, Rita; Magalhães, Ana; Barbosa, Fernando","year":2026,"journal":"Journal of cognitive neuroscience, 1-23","doi":"10.1162/JOCN.a.2489","pmid":"41707235","tags":["brain-imaging","attention","reward","eeg","longitudinal"],"studyType":"longitudinal","evidenceStrength":"moderate","keyFinding":"Current (but not abstinent) cannabis users showed higher P3 amplitudes to cannabis vs. neutral cues. Higher P3 predicted reductions in cannabis use at 3-month follow-up. Current users showed a trend for blunted LPP to monetary cues. Enhanced LPP to loss cues predicted greater reductions in use. Abstinent users showed enhanced LPP to cannabis cues vs. nonusers.","whyItMatters":"The finding that stronger brain cue reactivity predicts less (not more) future use challenges the standard addiction model and suggests that heightened awareness of cannabis cues might actually support behavior change rather than always driving continued use.","specificNumbers":"142 participants across 3 groups. Current users: higher P3 to cannabis cues, blunted LPP to monetary cues. 3-month follow-up: higher P3 and LPP to loss cues predicted reduced use. Abstinent users: enhanced LPP to cannabis cues vs nonusers.","methodology":"Preregistered longitudinal EEG study of 142 young adults (55 current users, 35 abstinent, 52 nonusers, ages 18-38). Cannabis cue-reactivity and monetary incentive delay tasks with P3, LPP, and reward positivity measurement. Three-month cannabis use follow-up.","limitations":"Exploratory analyses drive several key findings. Moderate sample sizes per group. Non-treatment-seeking users may differ from clinical populations. Three-month follow-up may be insufficient for long-term prediction. Cannabis cue images may not capture real-world triggers."},{"rthcId":"RTHC-08455","title":"Understanding the interplay between alcohol use, cannabis use and mental health across the lifespan: A network analysis.","authors":"Macedo, Inês; Kroon, Emese; Colyer-Patel, Karis; Freichel, René; Romein, Christophe; Pasion, Rita; Barbosa, Fernando; Cousijn, Janna","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70324","pmid":"41549816","tags":["mental-health","alcohol","co-use","network-analysis","depression"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Alcohol-cannabis co-users had higher severity on all mental health symptoms vs. alcohol-only users, yet network structures were similar. Key distinction: alcohol problems uniquely linked to anxiety, personality functioning, and suicidal ideation, while cannabis problems linked to mania and dissociation. Somatic symptoms were significantly more central in co-users. Age did not moderate these relationships.","whyItMatters":"Knowing that alcohol and cannabis problems connect to different mental health symptoms — anxiety/suicidality vs. mania/dissociation — allows clinicians to screen for specific psychiatric risks based on which substances a patient uses.","specificNumbers":"740 participants (16-81 years). Co-users higher on all mental health measures (all p≤0.001). Alcohol problems→anxiety (r=0.03), personality (r=0.01), suicidal ideation (r=0.01). Cannabis problems→mania (r=0.05), dissociation (r=0.02). Somatic centrality: 1.31 in co-use vs 0.17 in alcohol-only.","methodology":"Network analysis of 740 participants aged 16-81 (446 alcohol users, 294 alcohol-cannabis co-users) from online international survey. Mental health assessed via DSM Level 1 Cross-Cutting Symptom Measure; substance use via AUDIT and CUDIT-R.","limitations":"Cross-sectional design cannot determine causation. Online convenience sample from multiple countries may not be representative. Network edges are associations, not causal pathways. Relatively small co-use group (294)."},{"rthcId":"RTHC-08456","title":"Transformer-Based Topic Modeling: Characterizing Cannabis Product Adverse Experiences Self-Reported as Requiring Medical Attention on Reddit.","authors":"Mackey, Tim Ken; Nali, Matthew C; Larsen, Meng Zhen; Li, Zhuoran; Taylor, Cassandra L; Wolpert, Beverly; Trice, Catharine","year":2026,"journal":"Journal of medical Internet research, 28, e82661","doi":"10.2196/82661","pmid":"41637739","tags":["adverse-effects","social-media","surveillance","safety","methodology"],"studyType":"cross-sectional","evidenceStrength":"low","keyFinding":"Using keyword filtering, transformer-based algorithms, and content coding, 1,177 self-reported cannabis adverse experiences requiring medical attention were identified and characterized from Reddit posts.","whyItMatters":"Traditional adverse event reporting systems miss most cannabis-related problems because cannabis isn't regulated like pharmaceuticals. Social media surveillance offers a real-time window into the adverse experiences that patients and consumers actually face.","specificNumbers":"1,177 self-reported adverse experiences requiring medical attention identified from Reddit posts using AI-assisted analysis.","methodology":"Social media surveillance study using keyword filtering, transformer-based topic modeling algorithm, and inductive content coding to identify and characterize cannabis adverse experiences discussed on Reddit.","limitations":"Self-reported online data cannot be verified. Reddit users may not represent all cannabis consumers. 'Requiring medical attention' is self-defined. Cannot determine cannabis product specifics or confirm causation. Topic modeling may miss nuanced experiences."},{"rthcId":"RTHC-08457","title":"Application of ToF-SIMS to detection and imaging of cannabis-contaminated fingerprints - A preliminary study.","authors":"Maćkiewicz, Elżbieta; Rogowski, Jacek; Parczewski, Andrzej; Szynkowska-Jóźwik, Małgorzata Iwona","year":2026,"journal":"Forensic science international, 378, 112706","doi":"10.1016/j.forsciint.2025.112706","pmid":"41176961","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08458","title":"Phase 1 Open-Label Pilot Trial of H4 Deep Repetitive Transcranial Magnetic Stimulation for Adults With Moderate-to-Severe Cannabis Use Disorder.","authors":"MacKillop, James; McIntyre-Wood, Carly; Vandehei, Emily; Yaya, Horodjei; Di Passa, Anne-Marie; Prokop-Millar, Shelby; Fein, Allan; Yang, Andrew; Elsayed, Mahmoud; Schwartzmann, Benjamin; Farzan, Faranak; MacKillop, Emily; Duarte, Dante","year":2026,"journal":"Neuromodulation : journal of the International Neuromodulation Society","doi":"10.1016/j.neurom.2026.01.003","pmid":"41733532","tags":["addiction","quitting","mental-health"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"This phase 1 pilot study tested whether deep repetitive transcranial magnetic stimulation (dTMS) using the H4 coil — already approved for tobacco use disorder — could be safely applied to adults with moderate-to-severe cannabis use disorder who were seeking treatment.\n\nParticipants received 18 sessions over four weeks (five sessions per week for three weeks, then three sessions in week four), with each session delivering electromagnetic pulses to the lateral prefrontal cortex and anterior insula — brain regions implicated in addiction.\n\nThe primary findings focused on feasibility and tolerability: treatment completion rates (indicating feasibility), attainment of therapeutic dose (≥90% of resting motor threshold), and adverse event profiles (indicating tolerability). The study also collected exploratory data on cannabis use (measured in standard 5 mg THC units), CUD symptoms, cravings, cannabis reinforcing value, self-efficacy, internalizing symptoms, and neuropsychological performance.\n\nAs a phase 1 open-label study without a control group, the results speak to whether this treatment can be delivered safely rather than whether it works — an essential first step before controlled efficacy trials.","whyItMatters":"No medication has received regulatory approval for cannabis use disorder — a condition affecting a growing number of people as cannabis becomes more potent and widely available. The H4 coil's existing approval for tobacco use disorder provides a logical basis for testing it in CUD, since both conditions involve the same prefrontal and insular brain circuits implicated in addiction. This pilot establishes whether the approach is practical enough to test in larger controlled trials.","specificNumbers":"18 dTMS sessions over 4 weeks (5/week for 3 weeks, 3 in week 4). H4 coil targeting lateral prefrontal cortex and anterior insula. Therapeutic dose threshold: ≥90% resting motor threshold. Cannabis use measured in standard 5 mg THC units.","methodology":"Phase 1 open-label pilot study. Adults with moderate-to-severe CUD received 18 sessions of H4 deep TMS targeting the lateral prefrontal cortex and anterior insula. Primary outcomes: treatment completion (feasibility) and adverse events (tolerability). Exploratory outcomes: cannabis use in standard THC units, CUD symptoms, cravings, self-efficacy, and neuropsychological performance.","limitations":"Phase 1 open-label design with no control group — cannot determine whether any improvement is due to the stimulation or to placebo effects, standard care, or natural recovery. Small sample size limits generalizability. The intensive schedule (18 sessions in 4 weeks) may be burdensome for patients. Long-term effects and relapse rates are unknown."},{"rthcId":"RTHC-08459","title":"The synthetic cannabinoid THJ-2201 modulates mitochondrial activity and enhances mitochondrial recruitment to newly-forming neurites during neurodifferentiation of NG108-15 cells.","authors":"Malheiro, Rui Filipe; Costa, Ana Catarina; Carmo, Helena; Carvalho, Félix; Silva, João Pedro","year":2026,"journal":"Archives of toxicology, 100(2), 657-676","doi":"10.1007/s00204-025-04217-7","pmid":"41045323","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08460","title":"Measuring State Cannabis Policy Design Variation for Research and Policy: A Bundles Approach.","authors":"Mallinson, Daniel J; Richardson, Lilliard E","year":2026,"journal":"Clinical therapeutics, 48(1), 29-33","doi":"10.1016/j.clinthera.2025.07.027","pmid":"40877073","tags":["policy","methodology","regulation","us-states"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"Three policy bundles were developed measuring 36 characteristics of state cannabis laws from 1994-2023: pharmaceutical (treating cannabis like a regulated drug), permissive (treating it like an over-the-counter product), and fiscal (revenue-focused). Measures distinguish between policies as adopted versus as implemented.","whyItMatters":"Most cannabis research treats legalization as binary (legal or not), but states vary enormously in how they design their laws. This measurement tool lets researchers actually study which specific policy features affect health outcomes.","specificNumbers":"36 different characteristics measured across 3 bundles (pharmaceutical, permissive, fiscal). Coverage: 1994-2023. Measures available for both adopted and implemented policies. Massachusetts used as demonstration case.","methodology":"Commentary presenting a policy bundles measurement approach with 36 characteristics of state medical and recreational cannabis laws organized into three conceptual bundles, demonstrated using Massachusetts as a case study.","limitations":"Commentary/methodology paper without empirical testing of bundle validity or health outcome associations. Policy coding requires subjective judgment. Implementation measures may lag behind actual practice. 36 characteristics may not capture all relevant variation."},{"rthcId":"RTHC-08461","title":"The parabss1 Drosophila melanogaster as Model for Chronic Nociception: Insights Into Cannabidiol Analgesic Effects.","authors":"Malta, Serena Mares; Correia, Lucas Ian Veloso; Marquez, Alexandre Souza; Bernardes, Lucas Matos Martins; Howland, John George; Mendes-Silva, Ana Paula; Espíndola, Foued Salmen; Ueira-Vieira, Carlos","year":2026,"journal":"European journal of pain (London, England), 30(2), e70225","doi":"10.1002/ejp.70225","pmid":"41589562","tags":["cbd","pain","sodium-channels","drosophila","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"The parabss1 Drosophila mutant exhibited enhanced chemical nociceptive sensitivity compared to wild-type. The mutant showed resistance to carbamazepine (conventional treatment) but responded to oral CBD with significantly increased response latency, validating CBD's modulatory role in nociceptive circuits involving sodium channel dysfunction.","whyItMatters":"Chronic pain drug development is slow and expensive because mammalian models are complex and raise ethical concerns. A fruit fly model that mirrors human sodium channel pain disorders and responds to CBD could dramatically accelerate the screening of new pain drugs.","specificNumbers":"parabss1 mutation shows homology to human NaV1.7 gain-of-function mutations (L858F, R1150W). CBD oral administration significantly increased nociceptive latency in both wild-type and mutant flies. Carbamazepine effective in wild-type but showed dose/time-dependent response in mutants.","methodology":"Behavioral nociceptive assays in parabss1 mutant Drosophila larvae (carrying a sodium channel mutation homologous to human NaV1.7 gain-of-function mutations). CBD and carbamazepine administered orally. Von Frey and acetone sensitivity tests adapted for larvae.","limitations":"Fruit fly nociception is vastly simpler than mammalian pain. Larval responses may not predict adult or clinical effects. CBD mechanisms in flies may differ from mammals. Sodium channel mutations are one cause of chronic pain among many."},{"rthcId":"RTHC-08462","title":"Biosocial disparities in substance use among sexual-minority veterans with depression: national evidence on the role of depression-related clinical contact and medication use.","authors":"Manietta, Luke; McDaniel, Justin T","year":2026,"journal":"Journal of biosocial science, 1-13","doi":"10.1017/S0021932026100480","pmid":"41664615","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08463","title":"A temporary spike: Investigating Lennox-Gastaut syndrome incidence in the US following FDA approval of cannabidiol.","authors":"Marcinski Nascimento, Kaley J; Li, Yifan; Lin, Binx Y; Dixon-Salazar, Tracy; Perry, M Scott; Xu, Kevin Young; Nascimento, Fábio A","year":2026,"journal":"Epileptic disorders : international epilepsy journal with videotape","doi":"10.1002/epd2.70168","pmid":"41483291","tags":["cbd","epilepsy","fda","diagnosis","policy"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"Annual LGS incidence rose ~30% from 2018 to 2019 and ~60% from 2017 to 2019, before returning to pre-approval baseline (2020-2023). This temporary spike occurred in temporal proximity to the 2018 FDA approval of CBD (Epidiolex) for LGS-associated seizures.","whyItMatters":"If new treatments drive diagnoses rather than the other way around, it undermines both clinical accuracy and research integrity. This pattern suggests some patients may have been labeled with LGS specifically to access CBD treatment.","specificNumbers":"Incidence rate: ~30% increase 2018-2019, ~60% increase 2017-2019. Returned to baseline 2020-2023. Temporal correlation with June 2018 FDA approval of Epidiolex for LGS.","methodology":"Retrospective analysis computing annual new LGS diagnoses in the US from 2017-2023 using a large population-based electronic health record database.","limitations":"Administrative data with ICD codes cannot confirm diagnostic accuracy. Cannot prove causation between CBD approval and diagnosis increase. Multiple factors may have contributed. COVID-19 may have affected 2020-2021 diagnostic patterns. Insurance coding practices may have changed independently."},{"rthcId":"RTHC-08464","title":"Differential effect of cannabis use and antipsychotic medication on extracellular free-water in the brain of individuals with early psychosis and controls.","authors":"Martínez-Sadurní, Laura; Barrera-Conde, Marta; Robledo, Patricia; Veza-Estevez, Emma; Garcia-Quintana, Jordi; Mané, Anna; Toll, Alba; Trabsa, Amira; Lesh, Tyler A; Carter, Cameron S; Bergé, Daniel","year":2026,"journal":"Molecular psychiatry, 31(1), 362-373","doi":"10.1038/s41380-025-03287-4","pmid":"41057642","tags":["psychosis","neuroinflammation","brain-imaging","antipsychotics"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Past cannabis use was associated with lower extracellular free water (FW, an inflammation marker) in controls but elevated FW in people with recent-onset psychosis, particularly in temporal and parietal cortex. Within psychosis patients, antipsychotic exposure reduced FW only in non-cannabis users — cannabis users showed no antipsychotic benefit on FW.","whyItMatters":"If cannabis blocks antipsychotics from reducing brain inflammation in psychosis, it could explain why cannabis-using psychosis patients have poorer treatment outcomes — and suggests cannabis cessation may be particularly important for medication effectiveness.","specificNumbers":"62 ROP and 38 controls. Group × cannabis interaction significant in average GM (p=0.049) and temporal-parietal cortex (TFCE p-FWE<0.05). Antipsychotic × cannabis interaction in WM (p=0.005) and GM (p=0.073). Antipsychotics reduced FW only in non-cannabis-using patients.","methodology":"Cross-sectional diffusion MRI measuring extracellular free water in 62 individuals with recent-onset psychosis and 38 controls, stratified by cannabis use history. Group × cannabis interactions analyzed with TFCE correction.","limitations":"Cross-sectional design limits causal interpretation. Moderate sample size. Cannabis use was historical, not current. Free water is a proxy for inflammation, not a direct measure. Multiple comparisons may inflate some findings."},{"rthcId":"RTHC-08465","title":"Implications of the mitochondrial CB1 receptor in the brain: from mitochondrial dysfunction to neuroprotection.","authors":"Martínez-Torres, Ari Misael; Cerdán-Centeno, Keyla Tamara; Ramirez-Celis, Crisalde; Peniche-Zamudio, Suly; Durán-González, Teresa de Jesús; Roa-Gutierrez, Camila; Navarro-Mabarak, Cynthia; Morán, Julio","year":2026,"journal":"Reviews in the neurosciences, 37(1), 93-112","doi":"10.1515/revneuro-2025-0086","pmid":"41117091","tags":["endocannabinoid-system","mitochondria","cb1-receptor","neurodegeneration","neuroprotection"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The mitochondrial CB1 receptor (mtCB1R) regulates ATP production, calcium homeostasis, and neuronal signaling from within the mitochondria. It plays roles in learning, memory, and neuronal plasticity. Its involvement in bioenergetic failure makes it a potential target for preventing neuronal death in neurodegenerative and acquired brain diseases.","whyItMatters":"The discovery that CB1 receptors exist inside mitochondria — not just on cell surfaces — fundamentally changes our understanding of how cannabinoids affect the brain. This organelle-level receptor could be the key to cannabinoid-based neuroprotective therapies.","specificNumbers":"Review covers mtCB1R roles in: ATP production, calcium homeostasis, neuronal signaling, learning and memory, and neuronal death across multiple neurodegenerative conditions.","methodology":"Narrative review synthesizing evidence on the endocannabinoid system with focus on the recently discovered mitochondrial CB1 receptor, its role in mitochondrial homeostasis, cognitive function, and neurodegeneration.","limitations":"mtCB1R research is still in early stages with many unknowns. Most evidence is from rodent models. The complexity of mitochondrial regulation means targeting mtCB1R could have unpredictable effects. Clinical translation is uncertain."},{"rthcId":"RTHC-08466","title":"Cannabinoid receptor type 1 deficiency protects from lipopolysaccharide-induced preterm birth: the role of the decidual endocannabinoid system.","authors":"Marvaldi, Carolina; Mirón Granese, Ayelén A; Johnson, Clare; Schander, Julieta A; Aisemberg, Julieta; Cella, Maximiliano; Correa, Fernando; Franchi, Ana M; Bradshaw, Heather B; Wolfson, Manuel L","year":2026,"journal":"Reproduction (Cambridge, England), 171(2)","doi":"10.1093/reprod/xaaf022","pmid":"41655274","tags":["endocannabinoid-system","pregnancy","preterm-birth","cb1-receptor","preclinical"],"studyType":"preclinical","evidenceStrength":"preliminary","keyFinding":"CB1-knockout mice showed significantly lower preterm birth rates compared to wild-type when exposed to LPS-induced inflammation. CB1 deficiency modulated endogenous lipids, reduced inflammatory markers (PGE2, PGF2α, MMP9), and altered fatty acid profiles in decidual tissue. Free fatty acids increased in wild-type decidua with inflammation but were unchanged in CB1-KO.","whyItMatters":"Preterm birth affects about 10% of pregnancies worldwide and is a leading cause of neonatal death. Identifying CB1 as a mediator of inflammation-induced preterm birth opens a new therapeutic target — though cannabis use during pregnancy remains contraindicated.","specificNumbers":"CB1-KO: significantly lower PTB rates vs. wild-type. CB1-KO had lower basal FAAH activity. LPS elevated PGE2, PGF2α, and MMP9 in wild-type but not CB1-KO. Free fatty acids increased with LPS in wild-type only.","methodology":"CB1-knockout and wild-type pregnant mice were treated with lipopolysaccharide to induce preterm birth. Decidual tissue analyzed for endocannabinoid system components, lipid profiles, and inflammatory markers including prostaglandins and matrix metalloproteinases.","limitations":"Mouse model with LPS-induced inflammation is one of many preterm birth mechanisms. Complete CB1 knockout may not reflect pharmacological CB1 modulation. Decidual tissue analysis may not capture all relevant reproductive tissues. Human translation uncertain."},{"rthcId":"RTHC-08467","title":"Secular Trends in Hazardous Alcohol and Cannabis Use from 2015 to 2024 in Diverse Subgroups of Youth Entering Residential Care.","authors":"Mason, W Alex; Wilmayani, Ni Ketut; Chmelka, Mary B","year":2026,"journal":"Substance use & misuse, 61(4), 491-499","doi":"10.1080/10826084.2025.2565434","pmid":"41058314","tags":["youth","residential-care","trends","alcohol","co-use"],"studyType":"retrospective-analysis","evidenceStrength":"moderate","keyFinding":"While general population youth show declining substance use, hazardous cannabis use significantly increased over 2015-2024 among residential care youth — particularly females and older teens (15-18). Hazardous alcohol use increased among females but decreased among males. Alcohol-cannabis co-use increased among older, White, and female youth.","whyItMatters":"Youth in residential care represent one of the most vulnerable populations, and the divergence from general population trends means they're being left behind by prevention efforts that may be working for their peers.","specificNumbers":"2,256 youth over 10 years. Cannabis: significant increase among females (OR=1.043/year) and older teens. Alcohol: increased for females, decreased for males. Co-use: increased among older, White, and female youth. Ages 9-18.","methodology":"Repeated cross-sectional analysis of 2,256 youth (ages 9-18) entering a Midwestern US residential care facility from 2015-2024. AUDIT and CUDIT-R screening at intake. Logistic regressions with age, sex, and race/ethnicity interaction terms.","limitations":"Single residential facility in one US region. Cross-sectional snapshots at intake — no longitudinal follow-up. Screening tools may have variable sensitivity across age, sex, and cultural groups. Selection bias in who enters residential care."},{"rthcId":"RTHC-08468","title":"Sex differences in the acute effects of cannabis: the need for hypothesis-driven research.","authors":"Matheson, Justin; Behzad, Danial; Galea, Liisa A M; Di Ciano, Patricia","year":2026,"journal":"Journal of psychiatry & neuroscience : JPN, 51, 1-8","doi":"10.1139/jpn-2025-0164","pmid":"41494946","tags":["sex-differences","methodology","cognitive-effects","research-gaps"],"studyType":"narrative-review","evidenceStrength":"low","keyFinding":"A systematic review found just 6 of 29 human studies showed sex differences in acute cognitive cannabis effects. The commentary identifies four key methodological problems: inadequate statistical power for interaction analyses, poor definition and measurement of sex, no consideration of sex-related variables (hormones, body composition), and complete exclusion of transgender and gender-diverse individuals.","whyItMatters":"If cannabis affects men and women differently — and emerging evidence suggests it does — then research that's underpowered or poorly designed for detecting sex differences is missing clinically important information that could change how cannabis is prescribed and used.","specificNumbers":"6 of 29 studies found sex differences. Key limitations: inadequate power for interactions, poor sex measurement, no sex-related variables (hormones, body composition), zero inclusion of transgender/gender-diverse participants.","methodology":"Commentary building on a systematic review of 29 studies examining sex differences in acute cognitive effects of cannabis, analyzing methodological limitations and proposing research priorities.","limitations":"Commentary format limits scope. The absence of sex differences in most studies could reflect true similarity rather than methodological failure. Proposed research agenda is aspirational without funding commitments."},{"rthcId":"RTHC-08469","title":"Sex and gender influences on problematic cannabis use and cannabis use disorder: A scoping review protocol.","authors":"Matheson, Justin; Mielnik, Catharine A; Knight, Rodney; Wright, Madison; Marley, Noa; Bonato, Sarah; Le Foll, Bernard; Gallagher, Louise; Rubin-Kahana, Dafna Sara","year":2026,"journal":"PloS one, 21(1), e0327704","doi":"10.1371/journal.pone.0327704","pmid":"41493970","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08470","title":"A Case-Control Study On Corpus Callosum Volume and Clinical Correlates in Treatment-Resistant and Responsive Schizophrenia Patients: Addressing MRI Analysis within Single-Subject and a Novel Artificial Intelligence Paradigm.","authors":"Matrone, Marta; Romano, Andrea; Kotzalidis, Georgios D; Perrini, Filippo; Moltoni, Giulia; De Filippis, Sergio; De Persis, Simone; Pontillo, Giuseppe; Tranfa, Mario; Cocozza, Sirio; Brunetti, Arturo; Ciccarelli, Mariateresa; Vellucci, Licia; Barone, Annarita; Iasevoli, Felice; de Bartolomeis, Andrea; Bozzao, Alessandro","year":2026,"journal":"Current neuropharmacology","doi":"10.2174/011570159X396695251118094658","pmid":"41510724","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08471","title":"Implementing Care for Cannabis and Other Drug Use in Adult Primary Care: Outcomes of a Cluster-Randomized Implementation Trial.","authors":"Matson, Theresa E; Johnson, Eric; Bobb, Jennifer F; Graham, Vina F; Kiel, Linda M; Lee, Amy K; Lapham, Gwen T; Caldeiro, Ryan M; Bradley, Katharine A; Angerhofer, Julie E","year":2026,"journal":"American journal of preventive medicine, 70(1), 108112","doi":"10.1016/j.amepre.2025.108112","pmid":"40967380","tags":["screening","primary-care","cannabis-use-disorder","implementation","clinical-trial"],"studyType":"clinical-trial","evidenceStrength":"strong","keyFinding":"Implementation increased cannabis screening from 9 to 153 per 10,000 visits (17-fold) and newly identified CUD from 10 to 17 per 10,000 visits. Treatment initiation for CUD increased by 0.5-1 per 10,000 visits (p=0.006). However, treatment engagement did not significantly change (p=0.147). Treatment initiation and engagement for any drug use disorder overall did not change.","whyItMatters":"This is the first large-scale trial showing that systematic cannabis screening in primary care can work — dramatically increasing detection and starting more people on treatment. But the engagement gap means screening alone isn't enough.","specificNumbers":"Pre: 244,542 patients, 942,400 visits. Post: 287,696 patients, 1,087,565 visits. Screening: 9→153/10,000 visits. New CUD: 10→17/10,000. Treatment initiation: +0.5-1/10,000 (p=0.006). Engagement: no change (p=0.147). 19 sites randomized.","methodology":"Stepped-wedge cluster-randomized trial across 19 sites in a large primary care system (January 2016 - July 2018). Implementation strategies: practice facilitation, EHR decision support, performance feedback. Pre-post analysis of screening, diagnosis, and treatment rates using EHR and claims data.","limitations":"Pre-post comparison within a stepped-wedge design may be confounded by temporal trends. Cannabis legalization changes during the study period may have affected results. Implementation fidelity varied across sites. Treatment engagement definition may be too strict."},{"rthcId":"RTHC-08472","title":"Sleep apnea and substance use: a meta-analysis.","authors":"Mauries, Sibylle; Rolland, Benjamin; Frija-Masson, Justine; d'Ortho, Marie-Pia; Catoire, Sébastien; Zehani, Feriel; Davido, Guillaume; Lejoyeux, Michel; Geoffroy, Pierre A","year":2026,"journal":"Sleep medicine reviews, 85, 102228","doi":"10.1016/j.smrv.2025.102228","pmid":"41564681","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08473","title":"Cannabis or drug screening and discussions with clinicians among older adults who use cannabis in the US, 2021-2023.","authors":"Mauro, Pia M; Roura, Mireia Triguero; Carey, Elsa; Han, Benjamin H","year":2026,"journal":"American journal of preventive medicine, 108304","doi":"10.1016/j.amepre.2026.108304","pmid":"41655648","tags":["seniors","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"36.8% of US adults 65+ reported drug screening at healthcare visits. Among 8.1% with past-year cannabis use, only 19.2% discussed it with clinicians. Hispanic/Latine adults were significantly less likely to be screened. Multiple chronic conditions and mental illness predicted discussions.","whyItMatters":"Older adults are the fastest-growing cannabis demographic, often on multiple medications. Low discussion rates create risk for unmanaged drug interactions.","specificNumbers":"14,387 older adults. 36.8% screened. 8.1% used cannabis. 19.2% discussed with clinicians. Hispanic/Latine: aRRR=0.23 for discussions.","methodology":"2021-2023 NSDUH data. 14,387 US adults 65+ with past-year healthcare visits. Weighted regressions.","limitations":"Self-reported. Cannot determine why discussions didn't occur. May underestimate use."},{"rthcId":"RTHC-08474","title":"Urinary Δ9-tetrahydrocannabinol and metabolite concentrations following cannabis use: A systematic review.","authors":"McCartney, Danielle; Irwin, Christopher; Arnold, Jonathon C; Gordon, Rebecca; McLachlan, Andrew J; McGregor, Iain S","year":2026,"journal":"Pharmacological research, 108142","doi":"10.1016/j.phrs.2026.108142","pmid":"41707818","tags":["drug-interactions","workplace","legalization"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"This systematic review synthesized 92 studies examining urinary THC and THC-metabolite concentrations across different cannabis use patterns and testing contexts.\n\nThe findings exposed major problems with current testing thresholds. At the standard workplace threshold (15 ng/mL total 11-COOH-THC), even low single doses (1.0–5.0 mg THC) and very low repeated doses (<1.0 mg/day) were sometimes sufficient to trigger a positive result — particularly with oral ingestion. Weekly to daily cannabis users could test positive for extended periods after quitting.\n\nThe review contextualized these laboratory findings against the thresholds used in two key settings: workplaces (and aligned contexts like criminal justice) and competitive sport. The disconnect between what triggers a positive test and what indicates recent use or impairment was a central theme.\n\nThe review also examined how different cannabis products (smoked, vaped, oral) and dosing patterns affect urinary metabolite concentrations over time, providing the most comprehensive mapping to date of the relationship between cannabis use and urine test results.","whyItMatters":"Urine testing is the most common form of cannabis detection in workplaces, criminal justice, and sport — affecting millions of people. This systematic review demonstrates that current thresholds often detect past use rather than recent consumption or impairment. For regular users trying to quit, weeks of positive tests create legal and employment consequences disconnected from their actual cannabis status.","specificNumbers":"92 studies reviewed. Workplace threshold: 15 ng/mL total 11-COOH-THC. Single doses as low as 1.0–5.0 mg THC could exceed workplace threshold. Oral ingestion more likely to trigger positive results than inhalation at equivalent doses. Weekly-to-daily users could test positive for extended periods after cessation.","methodology":"Systematic review identifying 92 eligible studies. Analyzed urinary concentrations of THC and THC metabolites (primarily 11-COOH-THC) following controlled cannabis/cannabinoid administration (acute and repeated dosing) and in cannabis users (during active use and extended abstinence). Results contextualized against workplace (15 ng/mL) and sport testing thresholds.","limitations":"Synthesized studies with varying designs, populations, and analytical methods. Controlled dosing studies use standardized cannabis that may not reflect the potency of commercial products. Individual variation in THC metabolism (influenced by body composition, genetics, and frequency of use) means no single elimination timeline applies to everyone."},{"rthcId":"RTHC-08475","title":"A systematic review and meta-analysis of self-reported exposure to cannabis advertising and its association with cannabis use and intentions.","authors":"McClure-Thomas, Caitlin; Yimer, Tesfa; Strong, Caroline; Sun, Tianze; Hall, Wayne D; Chan, Gary Chung Kai; Connor, Jason P; Leung, Janni","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70310","pmid":"41709693","tags":["legalization","youth"],"studyType":"meta-analysis","evidenceStrength":"moderate","keyFinding":"Overall aOR=1.77 (95% CI 1.32-2.30). Internet/social media: aOR=3.38 (1.07-10.66). General advertising: aOR=1.67 (1.27-2.21). Storefront: aOR=1.25 (NS). All studies from US/Canada.","whyItMatters":"As cannabis markets expand advertising, understanding the use-advertising relationship is critical for regulation.","specificNumbers":"21 studies, 10 in meta-analysis. Overall: aOR=1.77. Social media: aOR=3.38. General: aOR=1.67. Storefront: aOR=1.25 (NS). I2=42.3%.","methodology":"Systematic review and meta-analysis of 21 studies. Random-effects models. 10 cross-sectional studies in pooled analysis.","limitations":"Mostly cross-sectional (86%). Only US/Canada. Self-reported. Cannot establish causation."},{"rthcId":"RTHC-08476","title":"Relations between medical and nonmedical prescription stimulant misuse, cannabis use, alcohol use, and related consequences among college students.","authors":"McDonald, Abigail; Corbin, Will","year":2026,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors","doi":"10.1037/adb0001103","pmid":"41490281","tags":["youth","addiction","drug-interactions"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Nonmedical stimulant misuse: cannabis d=0.444, alcohol d=0.275 vs no use. Medical misuse linked to cannabis (d=0.375) but not alcohol. Results held controlling for impulsivity and mental health.","whyItMatters":"Understanding stimulant-cannabis co-use helps design campus interventions addressing polysubstance use.","specificNumbers":"1,692 undergraduates. Nonmedical vs no use: cannabis d=0.444. Medical misuse vs no use: cannabis d=0.375. Nonmedical vs appropriate: cannabis d=0.349.","methodology":"SEM analysis of 1,692 undergraduates comparing four stimulant use groups, controlling for impulsivity and DASS-21.","limitations":"Cross-sectional. Single university. Self-reported. Predominantly White sample."},{"rthcId":"RTHC-08477","title":"Adolescent cannabis use and psychological distress from 2013 to 2023: A population-based study in Ontario, Canada.","authors":"McDonald, André J; Doggett, Amanda; Bondy, Susan J; Colman, Ian; Cook, Steven; Hamilton, Hayley A; Kurdyak, Paul; Leatherdale, Scott T; Myran, Daniel T; Rehm, Jürgen; Wickens, Christine M; MacKillop, James; Halladay, Jillian","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70333","pmid":"41603606","tags":["youth","mental-health","depression","anxiety","sex-differences","potency"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Distress rose from 10.7% to 27.4% while cannabis use declined from 23.1% to 17.6%. Heavy use (40+ times) vs abstinence: adjusted prevalence difference went from 0% (2013) to 18% (2023). Dose-response in females but not males. Each later grade of initiation: 5% lower distress.","whyItMatters":"The strengthening association despite declining use rates is consistent with rising potency driving more harm per user. The female dose-response is a new prevention-relevant finding.","specificNumbers":"35,007 students. Distress: 10.7% to 27.4%. Cannabis use: 23.1% to 17.6%. Heavy use-distress difference: 0% (2013) to 18% (2023). 5% lower distress per later grade of initiation.","methodology":"Representative biennial surveys 2013-2023 in Ontario. 35,007 students grades 7-12. Modified Poisson regression with Kessler-6.","limitations":"Cross-sectional at each wave. Cannot determine causation direction. Rising distress has many causes. Self-reported."},{"rthcId":"RTHC-08478","title":"A Scoping Systematic Review of Cannabis Use in Endometriosis.","authors":"McLaren, Kindha; Erridge, Simon; Sodergren, Mikael H","year":2026,"journal":"The Australian & New Zealand journal of obstetrics & gynaecology, 66(1), e70081","doi":"10.1111/ajo.70081","pmid":"41367152","tags":["pain","medical-cannabis","sex-differences"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Pain indication: 57.3-95.5%. Inhaled: 51.6-80.3%. Ingested: 25-76.9%. Most studies found improvement in some patients. Adverse events: 10.2-52%, mainly euphoria and dry mouth. All 9 completed studies were cross-sectional.","whyItMatters":"Endometriosis affects 6-10% of reproductive-age women with limited options. Many self-medicate with cannabis but no RCTs exist.","specificNumbers":"9 completed studies, 1,787 participants. Pain: 57.3-95.5%. Inhaled: 51.6-80.3%. AEs: 10.2-52%. 4 ongoing studies.","methodology":"Scoping review of PubMed, MEDLINE, EMBASE. 13 studies (9 completed, 4 ongoing). 1,787 participants across cross-sectional surveys.","limitations":"All cross-sectional surveys. No placebo data. Self-reported efficacy. Wide methodological variation."},{"rthcId":"RTHC-08479","title":"Impact of cannabidiol on myocardial recovery in patients with acute myocarditis: primary results of the ARCHER study.","authors":"McNamara, Dennis M; Cooper, Leslie T; Friedrich, Matthias G; Arbel, Yaron; Bhimaraj, Arvind; Bocchi, Edimar; Hamer, Andrew; Herdy, Artur Haddad; Kerneis, Mathieu; Liu, Peter P; Parker, Andrea B; Pocock, Stuart J; Smith, Eldon R; Tang, W H Wilson; Torre-Amione, Guillermo; Tschöpe, Carsten","year":2026,"journal":"ESC heart failure, 13(1)","doi":"10.1093/eschf/xvaf034","pmid":"41711722","tags":["cbd","cardiovascular","inflammation"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CBD (up to 10 mg/kg BID for 12 weeks) did not significantly improve ECV (p=0.054) or GLS (p=0.90). LV mass was significantly reduced (-9.2g, p=0.012). LAESV decreased (-8.1 ml, p=0.038). 100% completion rate.","whyItMatters":"First RCT of CBD in cardiac inflammation. While primary endpoints were missed, secondary findings suggest anti-inflammatory cardiac effects worth investigating.","specificNumbers":"109 patients, 100% completion. ECV: -3.7 ml (p=0.054). LV mass: -9.2g (p=0.012). LAESV: -8.1 ml (p=0.038). GLS: -0.1 (p=0.90).","methodology":"ARCHER Study: multicenter double-blind placebo-controlled phase 2 trial. 109 patients with CMR-confirmed acute myocarditis. 56 CBD, 53 placebo for 12 weeks.","limitations":"Primary endpoints not met. Mild-moderate myocarditis with preserved LV function at baseline. Small sample. Phase 2."},{"rthcId":"RTHC-08480","title":"Associations between cannabis use, cannabis use motivations and past year polysubstance use among people living with HIV in Florida.","authors":"McNeely, Kayla V; Seegulam, Vijaya L; Cook, Robert L; Zhou, Zhi; Wang, Yan; Porges, Eric C; Cohen, Ronald A; Somboonwit, Charurut; Sherbuk, Jacqueline E; Ibanez, Gladys; Chichetto, Natalie E","year":2026,"journal":"AIDS care, 1-14","doi":"10.1080/09540121.2026.2614344","pmid":"41549783","tags":["addiction","medical-cannabis","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was associated with higher use of most other substances. Among regular cannabis users, those motivated by recreational reasons reported lower polysubstance use than those in the medical/emotional motivation group. Mixed-motivation users showed no significant difference from the medical/emotional group.","whyItMatters":"This study challenges the assumption that medical cannabis use is inherently lower-risk. People using cannabis to manage symptoms or emotions may also be managing pain or distress with multiple substances, pointing to a population that could benefit from integrated care.","specificNumbers":"78% of the sample currently used cannabis. Three motivation classes emerged: medical/emotional (24.4%), recreational (37.0%), and mixed (38.6%). Recreational users had significantly lower polysubstance use than medical/emotional users (beta = -0.24, 95% CI [-0.47, -0.01]).","methodology":"Researchers surveyed 333 people with HIV in Florida who reported past-year substance use. Latent class analysis identified three cannabis motivation groups (medical/emotional, recreational, mixed). Polysubstance use was measured as the count of non-cannabis substances used in the past 12 months.","limitations":"Cross-sectional design cannot establish causation. Self-reported data. Single geographic region (Florida). The sample was drawn from people with HIV, limiting generalizability."},{"rthcId":"RTHC-08481","title":"Varenicline for cannabis use disorder: A randomized controlled trial.","authors":"McRae-Clark, Aimee L; Gray, Kevin M; Baker, Nathaniel L; Sherman, Brian J; Tolliver, Bryan; Burt, Jessica; Steplight, Alonzo; Chapman, Elizabeth; Wagner, Amanda","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70296","pmid":"41536001","tags":["quitting","addiction","sex-differences"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Varenicline did not reduce cannabis use sessions overall during weeks 6-12. However, a significant treatment-by-sex interaction revealed that men on varenicline reduced their cannabis use sessions significantly (difference = 4.2 sessions/week), while women showed no benefit.","whyItMatters":"There are no FDA-approved medications for cannabis use disorder. This trial adds to a small but growing body of evidence that biological sex may determine which pharmacological treatments work, a finding that could reshape how CUD medications are developed and tested.","specificNumbers":"174 participants randomized (90 varenicline, 84 placebo). No overall treatment effect (difference = 1.7 sessions/week, p = 0.41). Significant sex interaction (F = 5.1, p = 0.026). Men: 4.2 fewer sessions/week (95% CI 0.6-7.8, p = 0.04). Women: no effect (difference = -1.4, p = 0.18).","methodology":"Phase 2, randomized, double-blind, placebo-controlled trial at two South Carolina clinics (2020-2023). 174 participants with DSM-5 cannabis use disorder who used cannabis at least 3 days/week were randomized to varenicline (titrated to 1 mg twice daily) or placebo for 12 weeks with weekly medical management.","limitations":"Relatively small sample when split by sex, reducing power for subgroup analyses. Single geographic region. The sex interaction was not a pre-specified primary analysis. Self-reported cannabis use."},{"rthcId":"RTHC-08482","title":"Using a discrete choice experiment to estimate individual preferences to medicate cancer-related symptoms with cannabis.","authors":"McTaggart-Cowan, Helen; Raymakers, Adam J N; Izadi-Najafabadi, Sara; Bentley, Colene","year":2026,"journal":"Journal of cannabis research, 8(1), 30","doi":"10.1186/s42238-026-00392-1","pmid":"41588480","tags":["cancer","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Respondents most valued cannabis effectiveness for managing cancer symptoms and the ability to perform everyday activities. They expressed strong disutility for unwanted side effects. Doctor opinions and family attitudes also influenced preferences but were less decisive than symptom control.","whyItMatters":"This is one of the first studies to quantify what the general public actually values when deciding whether to use medical cannabis for cancer. The findings suggest policy should focus on evidence of symptom relief and functional outcomes rather than just access alone.","specificNumbers":"1,089 respondents; 61.5% had no cancer experience; 35.5% had some cannabis experience. Seven attributes tested across 12 choice sets. Effectiveness and daily functioning ranked highest in attribute importance.","methodology":"A discrete choice experiment (DCE) surveyed 1,089 members of a Canadian research panel. Respondents completed 12 choice sets, each with two health states described by seven attributes (effectiveness, daily functioning, side effects, family opinions, doctor opinions, access, cost) plus an opt-out option. An error-component mixed logit model estimated relative attribute importance.","limitations":"Hypothetical choice scenarios may not reflect real-world decisions. Most respondents had no personal cancer experience. Canadian-only sample. The study measured preferences, not actual use or outcomes."},{"rthcId":"RTHC-08483","title":"Effectiveness and clinical predictors of a virtual based combined cognitive behavioral and motivational enhancement group therapy for adults with cannabis use disorder.","authors":"Mehta, Dhvani D; Goud, Rachel; Sanches, Marcos; Buckley, Leslie; Sloan, Matthew E; Vandervoort, Julianne; Le Foll, Bernard; Beyraghi, Narges; Kaduri, Pamela; Zawertailo, Laurie; Selby, Peter; Tang, Victor M","year":2026,"journal":"Drug and alcohol dependence, 279, 113048","doi":"10.1016/j.drugalcdep.2026.113048","pmid":"41546985","tags":["quitting","addiction","mental-health","depression","anxiety"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among the 79 participants who completed the program (68% retention), significant reductions were observed in cannabis use frequency, quantity, craving, depression (PHQ-9), and anxiety (GAD-7). Higher baseline cannabis use predicted greater reductions, while higher self-efficacy predicted lower use across treatment.","whyItMatters":"Virtual therapy for cannabis use disorder scaled rapidly during the pandemic but lacked outcome data. This study provides evidence that online group-based CBT-MET is feasible, retains most participants, and produces meaningful improvements across multiple symptom domains.","specificNumbers":"116 enrolled, 79 completed (68% retention). Significant reductions in cannabis use frequency (p < 0.01), quantity (p < 0.01), craving (p < 0.01), depression (p < 0.01), and anxiety (p = 0.02). Co-occurring substance use disorders predicted smaller reductions in cannabis quantity.","methodology":"Retrospective analysis of 116 adults enrolled in a virtual 12-week group-based CBT-MET program between 2020 and 2023. Weekly self-reported cannabis use and biweekly depression/anxiety assessments were collected. Craving and problematic use were measured at baseline and post-treatment. Linear mixed models identified predictors of change.","limitations":"No control group or randomization. Retrospective design. Self-reported outcomes. Completers-only analysis may overestimate effects. Single program at one center."},{"rthcId":"RTHC-08484","title":"Medical marijuana for management of cancer pain: a narrative review.","authors":"Mendelson, Andrew M; Nguyen, Austin; Kohan, Lynn R","year":2026,"journal":"Annals of palliative medicine, 15(1), 11","doi":"10.21037/apm-25-85","pmid":"41560504","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08485","title":"Role of smoking status on motivation to reduce or stop alcohol consumption in patients with an alcohol use disorder admitted to an emergency department.","authors":"Mendy, Anna; Le Faou, Anne-Laurence; Ferrand, Lisa; Limosin, Frédéric; Airagnes, Guillaume","year":2026,"journal":"L'Encephale, 52(1), 11-18","doi":"10.1016/j.encep.2025.01.009","pmid":"40617749","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08486","title":"Rural and Urban Variation in Mobile Health Substance Use Disorder Treatment Mechanisms and Efficacy.","authors":"Mennis, Jeremy; Coatsworth, J Douglas; Russell, Michael; Riggs, Nathaniel R; Zaharakis, Nikola; Brown, Aaron; Mason, Michael J","year":2026,"journal":"Rural mental health","doi":"10.1037/rmh0000329","pmid":"41574274","tags":["quitting","addiction","youth"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"The PNC-txt mobile health intervention reduced cannabis use at 6 months by increasing readiness to change and protective behavioral strategies at 1 month. These treatment mechanisms operated similarly across rural and urban participants, suggesting mHealth can bridge the rural treatment gap.","whyItMatters":"Rural residents face major barriers to substance use treatment: limited providers, stigma, and lack of confidentiality. This study demonstrates that a text-based treatment overcomes these barriers and works as well in rural communities as in urban ones.","specificNumbers":"Participants were aged 18-25 with CUD. PNC-txt reduced past 30-day cannabis use at 6 months. Treatment effects operated through 1-month increases in protective behavioral strategies and readiness to change. No significant rural-urban differences in indirect treatment effects.","methodology":"Secondary analysis of a randomized clinical trial of PNC-txt (Peer Network Counseling-txt), an mHealth treatment for young adults aged 18-25 with cannabis use disorder. Rural-urban differences in treatment mechanisms (protective behavioral strategies, readiness to change, peer network health) and efficacy were tested.","limitations":"The rural-urban classification method was not specified in the abstract. Sample demographics (77% White) may limit generalizability. The analysis was secondary, not the primary trial objective."},{"rthcId":"RTHC-08487","title":"Disproportionate use of polysubstance combinations varies by sexual identity among US adults.","authors":"Mestre, Luis M; White, Marney A; Lee, Juhan; Parker, Maria A; Bold, Krysten W","year":2026,"journal":"PloS one, 21(2), e0340454","doi":"10.1371/journal.pone.0340454","pmid":"41706684","tags":["addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The most commonly used substances in polysubstance combinations were binge alcohol drinking, cannabis, cigarettes, and nicotine vaping. Bisexual women used most of the assessed polysubstance combinations at higher rates than other groups. Sex differences in polysubstance patterns varied among heterosexual and bisexual adults but not among gay/lesbian adults.","whyItMatters":"Bisexual individuals, especially women, face elevated substance use risks that are often invisible in data that groups all LGB people together. This study provides the granularity needed to design targeted prevention efforts.","specificNumbers":"66,634 adults surveyed; 8.59% identified as LGB. Cannabis and binge alcohol drinking were the most common substances in polysubstance combinations. Bisexual women had elevated rates across most multi-substance patterns involving 3 or 4 substances.","methodology":"Analysis of the 2021-2022 National Survey on Drug Use and Health (NSDUH), including 66,634 adults (8.59% LGB). Survey-weighted multinomial logistic regression assessed polysubstance combinations by sexual identity and sex.","limitations":"Cross-sectional design. Self-reported data. Past-30-day use window may miss episodic patterns. NSDUH does not capture frequency or quantity within substance categories."},{"rthcId":"RTHC-08488","title":"Recent Advances in the Science of Cannabis-Impaired Driving.","authors":"Metrik, Jane; Bush, Nicholas; Gunn, Rachel L; McCarthy, Denis M","year":2026,"journal":"Current addiction reports, 13(1), 8","doi":"10.1007/s40429-025-00712-0","pmid":"41641433","tags":["driving","cbd","harm-reduction"],"studyType":"narrative-review","evidenceStrength":"strong","keyFinding":"THC acutely impairs driving performance consistently within the first hour of use, with impairment remaining for approximately 4-5 hours post-inhalation. CBD at doses below 300 mg does not impair driving. Alcohol and THC together produce additive impairment. No significant residual deficits were found after the acute window. Notably, participants were willing to drive shortly after using cannabis despite measurable impairment.","whyItMatters":"With legal cannabis markets expanding, the question of how long impairment lasts has direct policy implications for per se limits, waiting-period guidelines, and public safety messaging. The disconnect between subjective readiness to drive and objective impairment is particularly concerning.","specificNumbers":"Impairment consistently observed within 1 hour of THC inhalation. Detectable impairment lasting approximately 4-5 hours post-inhalation. CBD doses below 300 mg showed no driving impairment. Alcohol plus THC produced additive effects.","methodology":"Narrative review of controlled experimental driving research from the past five years (through approximately 2025), summarizing findings on acute and residual effects of cannabis, CBD, combined THC-CBD, and cannabis plus alcohol on driving performance.","limitations":"Narrative (not systematic) review. Most studies used inhaled cannabis; oral and sublingual formulations were underrepresented. Laboratory driving simulators may not fully replicate real-world conditions. Studies used relatively low CBD doses."},{"rthcId":"RTHC-08489","title":"Acute Effects of Cannabis on Alcohol Craving and Consumption: A Randomized Controlled Crossover Trial.","authors":"Metrik, Jane; Aston, Elizabeth R; Gunn, Rachel L; Swift, Robert; MacKillop, James; Kahler, Christopher W","year":2026,"journal":"The American journal of psychiatry, 183(2), 134-143","doi":"10.1176/appi.ajp.20250115","pmid":"41254853","tags":["addiction","harm-reduction"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"After overnight cannabis abstinence, smoking cannabis with 3.1% or 7.2% THC led to significantly less alcohol consumption compared to placebo, reducing intake by 19% and 27% respectively. High-dose THC also reduced alcohol urge immediately after smoking, though broader craving measures did not show significant effects.","whyItMatters":"This is the first controlled human study to establish a causal effect of cannabis on alcohol consumption. Published in the top psychiatry journal, it provides rigorous experimental evidence for a substitution effect that has previously only been observed in survey and epidemiological data.","specificNumbers":"157 participants randomized, 138 completed 2+ sessions. Mean age 25.6 years, 35% women, 45% racial/ethnic minorities. 7.2% THC reduced alcohol consumption by 27%. 3.1% THC reduced alcohol consumption by 19%. 7.2% THC reduced alcohol urge immediately after smoking.","methodology":"Double-blind crossover RCT published in the American Journal of Psychiatry. 157 participants who reported heavy alcohol use and cannabis use at least twice weekly completed three experimental sessions with different THC doses (7.2%, 3.1%, 0.03% placebo). Each session included neutral and personalized alcohol cue exposure followed by an alcohol self-administration task. 138 completed two or more sessions.","limitations":"Laboratory setting may not reflect real-world drinking. Participants were regular cannabis users, so results may not apply to cannabis-naive individuals. Short-term effects only; long-term substitution patterns not addressed. The study examined acute effects after overnight abstinence from cannabis."},{"rthcId":"RTHC-08490","title":"A Latent Class Analysis of Polysubstance Use Patterns and Their Association with Ruminative Thinking Styles, Impulsivity-Like Traits, and Adverse Childhood Experiences Among College Students from Seven Countries.","authors":"Michelini, Yanina; Luque, Maribel; Folivi, Folly; Pilatti, Angelina; Bravo, Adrian J","year":2026,"journal":"Substance use & misuse, 61(4), 598-608","doi":"10.1080/10826084.2025.2568944","pmid":"41054221","tags":["addiction","youth","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Three substance use classes emerged: polysubstance users, alcohol-marijuana-tobacco co-users, and primarily drinkers. Polysubstance users had significantly higher adverse childhood experiences, more ruminative thinking, and greater impulsivity than the other classes. Country-level comparisons showed the US was most similar to Spain, Argentina, and Uruguay in alcohol-marijuana-tobacco co-use.","whyItMatters":"Identifying which college students are at highest risk for polysubstance use and what psychological factors distinguish them can help universities target prevention programs more effectively, especially since these vulnerability factors are potentially modifiable.","specificNumbers":"9,065 students across 7 countries; 71% women. Three classes identified via latent class analysis. Class 1 (polysubstance users) had greater adverse childhood experiences, higher rumination, and more impulsivity than Classes 2 and 3.","methodology":"Latent class analysis of an online survey of 9,065 college students (71% women) from the US, Canada, South Africa, Spain, Argentina, England, and Uruguay. Classes were derived from lifetime use of multiple substances. Between-class differences in adverse childhood experiences, ruminative thinking, and impulsivity-like traits were tested.","limitations":"Convenience sampling. Lifetime use measure does not capture current patterns or frequency. Cross-sectional design. Self-reported data. The 71% female sample may not represent all college populations."},{"rthcId":"RTHC-08491","title":"Pass the Keys: Using Behavioral Economics to Explore Driving After Cannabis Use.","authors":"Miller, Brandon P; Aston, Elizabeth R; Spindle, Tory R; Amlung, Michael","year":2026,"journal":"Substance use & addiction journal, 47(1), 134-143","doi":"10.1177/29767342251360851","pmid":"40783979","tags":["driving","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis demand (how much people would purchase and consume) was sensitive to driving latency: participants consumed more when driving was 6 hours away versus 20 minutes away. Those who perceived driving after cannabis as less dangerous showed higher cannabis demand across all conditions. The effects were statistically significant but small in magnitude.","whyItMatters":"Understanding what factors influence people to use cannabis before driving can inform public safety messaging. The finding that risk perception correlates with behavior suggests education about impairment risks could reduce cannabis-impaired driving.","specificNumbers":"167 participants. Significant main effects of driving latency on all demand indices (p < 0.05, partial eta-squared = 0.008-0.043). Perceived dangerousness inversely correlated with demand (r = -0.29 to -0.62).","methodology":"Cross-sectional online study of 167 adults who smoked cannabis at least monthly (77% White, 45% women, mean age 38.55). Participants completed four marijuana purchase tasks under different driving latency vignettes (no driving, 20 minutes, 1 hour, 6 hours). Demand indices included intensity, breakpoint, maximum expenditure, and price sensitivity.","limitations":"Hypothetical purchase tasks, not real consumption. Online convenience sample. Mostly White, cannabis-experienced participants. Small effect sizes. Does not capture actual driving behavior."},{"rthcId":"RTHC-08492","title":"Pre-Trauma THC Use Is Associated With a Positive Posttraumatic Adjustment Scale Screening.","authors":"Miller, Jeremy; Alvarez, Claudia; Berki, Lauren; Linsley, Catherine; Woods, John; Strumwasser, Aaron; Vanderet, Danielle; Jebbia, Mallory","year":2026,"journal":"The American surgeon, 92(3), 740-745","doi":"10.1177/00031348251381622","pmid":"40960856","tags":["ptsd","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"THC-positive patients were more likely to screen positive on the Posttraumatic Adjustment Scale (19.6% vs. 13.2%, p = 0.001). After adjusting for age, sex, injury severity, assault mechanism, polysubstance use, ICU admission, and complications, THC use remained independently associated with a positive PAS screen (OR 1.66, 95% CI 1.23-2.24).","whyItMatters":"This raises questions about whether pre-existing cannabis use is a marker for psychological vulnerability to trauma. If THC users are at higher risk for post-traumatic distress, they may benefit from enhanced mental health screening after traumatic injuries.","specificNumbers":"1,960 patients; 437 (22.3%) screened PAS-positive. THC positive in 19.6% of PAS-positive vs. 13.2% of PAS-negative patients (p = 0.001). Adjusted OR = 1.66 (95% CI 1.23-2.24, p = 0.001). Male sex was protective; younger age and assault-related injury increased risk.","methodology":"Retrospective cohort study at a Level 1 trauma center (January 2023 to December 2024). 1,960 adult trauma patients who completed inpatient PAS screening were included. THC use was identified via admission urine drug screen. Multivariable logistic regression adjusted for demographic and clinical confounders.","limitations":"Retrospective design cannot establish causation. Urine drug screen detects recent use, not use at time of trauma. No information on frequency, dose, or reason for cannabis use. PAS is a screening tool, not a PTSD diagnosis. Single center."},{"rthcId":"RTHC-08493","title":"Association Between Recreational Drug Use and Cardiovascular Events Post-Hospitalization in France.","authors":"Mirailles, Raphael; Delmas, Clément; Toupin, Solenn; Bouleti, Claire; Trimaille, Antonin; Schurtz, Guillaume; Piliero, Nicolas; Andrieu, Stéphane; Lattuca, Benoît; Rossanaly Vasram, Reza; Lim, Pascal; Noirclerc, Nathalie; Goralski, Marc; Deney, Antoine; Roubille, François; Fauvel, Charles; Bochaton, Thomas; Boccara, Franck; Gerbaud, Edouard; Puymirat, Etienne; Vicaut, Eric; Dillinger, Jean-Guillaume; Henry, Patrick; Pezel, Theo","year":2026,"journal":"Circulation. Population health and outcomes, 19(2), e011905","doi":"10.1161/CIRCOUTCOMES.124.011905","pmid":"41697269","tags":["cardiovascular","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Recreational drug users had higher one-year MACCE (major adverse cardiovascular and cerebrovascular events) rates than non-users (12.7% vs. 6.0%). Cannabis use alone was associated with increased MACCE risk (HR 1.77, 95% CI 1.02-3.08). After adjusting for traditional prognostic factors, any recreational drug use remained independently associated with MACCE (adjusted HR 2.91, 95% CI 1.68-5.05).","whyItMatters":"This is one of the first prospective studies with systematic drug testing to show that recreational drug use, including cannabis specifically, independently predicts major cardiovascular events after cardiac hospitalization. The nearly threefold adjusted risk is clinically meaningful.","specificNumbers":"1,392 patients (mean age 63, 69.9% men). 157 (11.3%) tested positive for any drug. 94 (6.7%) experienced MACCE at one year. Cannabis: HR 1.77 (95% CI 1.02-3.08). Opioids: HR 3.60 (95% CI 1.57-8.23). Any drug use adjusted HR: 2.91 (95% CI 1.68-5.05).","methodology":"ADDICT-ICCU study: prospective multicentric study across 39 French intensive cardiac care units in April 2021. All consecutive admissions were included. Systematic urine drug testing screened for cannabis, opioids, cocaine, amphetamines, and MDMA. Primary outcome was one-year MACCE (cardiovascular death, nonfatal MI, or stroke). Multivariable Cox regression adjusted for traditional prognostic factors.","limitations":"Short enrollment window (2 weeks in April 2021). French population may not generalize globally. Urine testing identifies recent use but not chronic patterns. Cannabis and opioid categories were grouped with respective drug classes. Residual confounding possible."},{"rthcId":"RTHC-08494","title":"Changes in clinical features and severity in patients presenting to European emergency departments with acute cannabis toxicity over the 10-year period from 2013 to 2022.","authors":"Miró, Òscar; Galicia, Miguel; Dargan, Paul I; Wood, David M; Dines, Alison M; Heyerdahl, Fridtjof; Hovda, Knut Erik; Giraudon, Isabelle; Yates, Christopher; Liechti, Matthias; Vallersnes, Odd Martin; Eyer, Florian; Burillo-Putze, Guillermo","year":2026,"journal":"Addiction (Abingdon, England), 121(2), 316-330","doi":"10.1111/add.70233","pmid":"41230681","tags":["harm-reduction","potency"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 3,839 ED presentations for lone cannabis toxicity (2013-2022), the most common symptoms were anxiety (35%), agitation (22%), decreased alertness (21%), and vomiting (20%). Very few statistically significant changes in clinical features occurred over time. Severity markers (ambulance transfer 76%, hospitalization 13%, ICU 1%, death 0.1%) showed no significant time trends in linear or nonlinear models.","whyItMatters":"The common assumption that higher-potency cannabis products lead to more severe emergency presentations is not supported by this large European dataset. This matters for public health messaging: potency concerns are valid, but the clinical severity picture at the emergency level has remained stable.","specificNumbers":"3,839 ED presentations across 40 EDs in 25 countries. Median age 25, 71% male. Anxiety 35%, agitation 22%, decreased alertness 21%, vomiting 20%. Seizures, arrhythmias, hyperthermia each < 3%. Hospitalization 13%, ICU 1%, death 0.1%. Only hypotension and hypertensive crisis showed significant increasing trends.","methodology":"Secondary analysis of the Euro-DEN Registry across 40 emergency departments in 25 European countries from October 2013 to December 2022. Only presentations with lone cannabis use (no alcohol or other drugs detected) were included. Time trends for 14 clinical signs and 4 severity markers were analyzed using linear and nonlinear models.","limitations":"Relies on ED presentations, which may miss cases that resolve without medical attention. Drug testing varied across centers. Changes in user behavior (self-titration) could mask potency effects. Euro-DEN may not capture all acute cannabis presentations."},{"rthcId":"RTHC-08495","title":"Tailored psychotherapy and AI-enhanced contingency management for co-occurring disorders in cannabis use disorder: a systematic review.","authors":"Mishra, Sidharth; Mishra, Sayali; Rath, Sibanarayan","year":2026,"journal":"Journal of addictive diseases, 1-14","doi":"10.1080/10550887.2026.2616726","pmid":"41640005","tags":["quitting","addiction","mental-health","ptsd","depression","anxiety"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Integrated cognitive-behavioral therapies improved psychiatric symptoms and reduced cannabis use, particularly for co-occurring depression and PTSD. Pharmacotherapies showed inconsistent benefits. ADHD-focused behavioral and stimulant approaches demonstrated promising cannabis use reductions. AI applications including machine-learning relapse prediction, remote contingency management delivery, and reinforcement-learning-based incentive optimization improved attendance and abstinence verification.","whyItMatters":"Cannabis use disorder rarely exists in isolation. Most people with CUD have co-occurring mental health conditions, and treating one without the other typically produces poor outcomes. This review maps the evidence for integrated approaches and points toward AI as a practical way to scale personalized treatment.","specificNumbers":"38 studies met inclusion criteria. Co-occurring conditions examined: depression, PTSD, anxiety, ADHD. AI applications included smartphone/sensor-based relapse prediction, remote CM delivery, and reinforcement-learning incentive optimization.","methodology":"Systematic search of PubMed, PsycINFO, Embase, and Web of Science through October 2025. Included clinical studies and systematic reviews on tailored interventions for CUD with co-occurring depression, PTSD, anxiety, or ADHD, plus research on AI-driven contingency management. 38 studies met inclusion criteria.","limitations":"Systematic review format synthesizes heterogeneous studies. AI-enhanced contingency management research is still early-stage with small samples. Pharmacotherapy findings were inconsistent across studies. Publication bias possible."},{"rthcId":"RTHC-08496","title":"CYP4X1/sEH-Dependent Endocannabinoid Metabolism Drives Fibroblast-Mediated Immunosuppression to Limit Immunotherapy in Colon Cancer.","authors":"Mo, Min; Chen, Xuewei; Liu, Yanzhuo; Wang, Chenlong; Chen, Xuehan; Zhang, Nan; He, Nan; Li, Ying; Wang, Jingyi; Chen, Honglei; Yang, Jing","year":2026,"journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany), 13(5), e07695","doi":"10.1002/advs.202507695","pmid":"41276938","tags":["cancer","neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CYP4X1 and sEH enzymes metabolize endocannabinoids to produce 14,15-EET-EA, which acts on GPR119 receptors in cancer-associated fibroblasts. This upregulates PD-L1, CXCL12, and TGF-beta, promoting regulatory T cell infiltration and impairing CD8+ T cell function. Blocking the CYP4X1/sEH-GPR119 axis enhanced anti-PD-1 immunotherapy efficacy in mice.","whyItMatters":"Immunotherapy has transformed cancer treatment but only works in a fraction of patients. This research identifies a specific endocannabinoid metabolism pathway that tumors exploit to evade immune attack, offering a potential new drug target to make immunotherapy more effective.","specificNumbers":"Key metabolite identified: 14,15-EET-EA. Receptor: GPR119. Signaling: Gs/beta-arrestin 2 axis. Downstream effects: upregulation of PD-L1, CXCL12, and TGF-beta in cancer-associated fibroblasts. CYP4X1 and sEH levels jointly predicted prognosis in human colon cancer.","methodology":"Preclinical study using mouse colon cancer models and human colon cancer tissue analysis. Investigated the CYP4X1/sEH pathway for endocannabinoid metabolism, identified the 14,15-EET-EA metabolite and its receptor GPR119, and tested pathway inhibition combined with anti-PD-1 therapy.","limitations":"Mouse models do not always translate to human outcomes. The pathway was studied primarily in colon cancer; relevance to other cancers is unknown. No clinical trials yet. Complexity of the signaling pathway may make therapeutic targeting challenging."},{"rthcId":"RTHC-08497","title":"Hemp seed extract exerts cytostatic effects through metabolic stress and autophagy modulation in malignant cells.","authors":"Moccia, Stefania; Russo, Maria; Cervellera, Carmen; Crescente, Giuseppina; Spagnuolo, Carmela; Russo, Gian Luigi","year":2026,"journal":"Scientific reports, 16(1), 6829","doi":"10.1038/s41598-026-37119-4","pmid":"41620507","tags":["cancer","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The oil polar extract (OPE) from the Codimono hemp cultivar induced metabolic stress in HT-29 colorectal cancer cells, decreasing ATP by approximately 40%, activating AMPK (a cellular energy sensor), and disrupting autophagic flux. This caused G1 phase cell cycle arrest without triggering apoptosis. Adding chloroquine (an autophagy inhibitor) enhanced antiproliferative effects by approximately 30%.","whyItMatters":"This study identifies a non-psychoactive hemp-derived extract that works through metabolic stress rather than direct cell killing. The synergy with autophagy inhibitors suggests a combination strategy that could be explored in more advanced cancer models.","specificNumbers":"ATP decreased by approximately 40%. AMPK was activated. G1 cell cycle arrest observed. No apoptosis triggered. Chloroquine combination enhanced antiproliferative effect by approximately 30%. Extract from Codimono cultivar (no THC).","methodology":"In vitro study characterizing the phenolic composition of a polar extract from cold-pressed hemp seed oil (Codimono cultivar, lacking THC). Effects on HT-29 colorectal cancer cells were evaluated for ATP levels, AMPK activation, autophagy markers, cell cycle distribution, and apoptosis. Combination with chloroquine was tested.","limitations":"In vitro only (cell lines, not tumors in animals or humans). Single cell line (HT-29). The specific bioactive compounds within the extract are not fully identified. No pharmacokinetic data on whether these compounds would reach tumors in a living organism."},{"rthcId":"RTHC-08498","title":"Validation of a Microsampling-Compatible Liquid-Liquid Extraction Method for Cannabinoid Quantitation in 50 µL of Whole Blood using LC-MS/MS.","authors":"Mohammed, Aman A; Khan, Mahmood; Chan, Herbert; Brubacher, Jeffrey R","year":2026,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkag004","pmid":"41520150","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08499","title":"Association of cannabis use disorder with postoperative complications following panniculectomy: a multicenter propensity-matched analysis.","authors":"Mokhtar, Jonathan; Ha, John Y; Almeida, Victor F A; Lellouch, Alexandre G; Vyas, Krishna S; Doh, Susan J; Duraes, Eliana F R","year":2026,"journal":"BMC plastic and reconstructive surgery, 2(1), 1","doi":"10.1186/s44452-026-00013-z","pmid":"41635558","tags":["harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"After propensity score matching on age, sex, BMI, race/ethnicity, and comorbidities, patients with CUD had significantly higher rates of postprocedural pain (RR 1.82, 95% CI 1.32-2.46, p < 0.001) and skin complications (RR 1.48, 95% CI 1.05-2.09, p = 0.019). No significant differences were found for sepsis, hematoma/seroma, venous thromboembolism, pulmonary embolism, or hospital readmission.","whyItMatters":"Surgeons often lack evidence-based guidance on how cannabis use affects surgical outcomes. This large matched analysis provides specific risk estimates for a common procedure, supporting the case for routine cannabis use screening in preoperative assessments.","specificNumbers":"1,596 matched patients (798 CUD, 798 controls). Mean age 43.2, 80.3% female. Postprocedural pain RR 1.82 (95% CI 1.32-2.46, p < 0.001). Skin complications RR 1.48 (95% CI 1.05-2.09, p = 0.019). No significant differences in sepsis, hematoma/seroma, VTE, PE, or readmission.","methodology":"Retrospective cohort study using the TriNetX federated database (100+ healthcare organizations). Adult panniculectomy patients (2010-2025) with CUD documented within 6 months preoperatively were propensity-matched 1:1 to controls. Risk ratios were calculated for 90-day postoperative complications.","limitations":"ICD coding for CUD may undercount cannabis users. No data on route, dose, or frequency of cannabis use. Concurrent nicotine use is a potential confounder. Retrospective design with inherent limitations. TriNetX database may have documentation biases."},{"rthcId":"RTHC-08500","title":"Cannabis smoke extract disrupts trophoblast differentiation and causes mitochondrial dysfunction beyond the effects of Δ9-THC alone.","authors":"Monaco, Cristina; Minhas, Mahek; Podinic, Tina; Nederveen, Joshua P; Lucas, Amica-Mariae; Tomy, Thane; Tomy, Gregg T; Holloway, Alison C; Raha, Sandeep","year":2026,"journal":"Scientific reports, 16(1), 6253","doi":"10.1038/s41598-026-36939-8","pmid":"41588048","tags":["pregnancy","harm-reduction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis smoke extract (CaSE) reduced markers of placental cell maturation (hCG protein and syncytin-1 gene expression) and caused dose-dependent mitochondrial dysfunction. Lower concentrations elevated reactive oxygen species while higher concentrations disrupted mitochondrial respiration. Blocking the CB1 receptor rescued the effects of pure THC but not of cannabis smoke extract.","whyItMatters":"Smoking remains the most common way pregnant people consume cannabis, yet most research focuses on THC alone. This study demonstrates that combustion byproducts create additional harm to placental cells that cannot be blocked by targeting cannabinoid receptors.","specificNumbers":"CaSE induced CYP1A1 expression (a combustion byproduct marker) but THC did not. Lower CaSE concentrations (1%, 2.5%) elevated reactive oxygen species. Higher concentrations (5%, 10%) disrupted mitochondrial respiration. CB1 antagonism rescued THC effects but not CaSE effects.","methodology":"In vitro study using human trophoblast cells exposed to cannabis smoke extract versus pure THC. Researchers measured markers of cell differentiation, reactive oxygen species, mitochondrial membrane potential and respiration, antioxidant gene expression, and the effect of CB1 receptor blockade.","limitations":"In vitro study using cell cultures, not a living placenta. Cannabis smoke extract preparation may not perfectly replicate real-world smoking. Single cell type studied. No comparison with vaporized or edible cannabis."},{"rthcId":"RTHC-08501","title":"Cannabinoids in Cannabis sativa l. and oil: Method validation and analysis by LC-MS/MS.","authors":"Montes Drobnjak, Patricia da Silva; Zacca, Jorge Jardim; Caldas, Eloisa Dutra","year":2026,"journal":"Forensic science international, 379, 112781","doi":"10.1016/j.forsciint.2025.112781","pmid":"41418648","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08502","title":"Sex-specific ethylene responses drive floral sexual plasticity in Cannabis sativa.","authors":"Monthony, Adrian S; Roy, Julien; de Ronne, Maxime; Carlson, Olivia; Murch, Susan J; Torkamaneh, Davoud","year":2026,"journal":"The Plant journal : for cell and molecular biology, 125(3), e70721","doi":"10.1111/tpj.70721","pmid":"41640034","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08503","title":"Smoke, sip, sleep, repeat: Investigating daily-level bidirectional relationships of separate and simultaneous use of alcohol and cannabis with sleep.","authors":"Moore, Annabelle; Coelho, Sophie G; Hendershot, Christian S; Wardell, Jeffrey D","year":2026,"journal":"Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors","doi":"10.1037/adb0001124","pmid":"41587197","tags":["sleep","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Compared to simultaneous use days, participants reported worse sleep quality and shorter sleep on alcohol-only days, earlier bedtime on cannabis-only days, and poorer sleep quality on no-use days. Those with greater alcohol problem severity reported even more pronounced differences favoring simultaneous use days. Sleep did not predict next-day simultaneous use.","whyItMatters":"Many young adults use substances to manage sleep. This study shows the combination may produce subjectively better sleep than alcohol alone, which could reinforce simultaneous use patterns and escalate co-use over time.","specificNumbers":"150 participants, 64% female, mean age 22.09. Simultaneous use days had better sleep quality vs. alcohol-only and no-use days. Longer sleep duration vs. alcohol-only days.","methodology":"Daily diary study of 150 young adults (64% female, mean age 22.09) completing morning smartphone surveys on prior-day substance use and previous-night sleep. Baseline alcohol and cannabis problem severity were measured. Within-person comparisons across day types.","limitations":"Self-reported sleep measures, no objective sleep data. Within-person design cannot establish causation. Young adult sample. No assessment of sleep architecture."},{"rthcId":"RTHC-08504","title":"High doses of orally administered cannabigerol produce deficits in sustained attention in female rats.","authors":"Moore, Catherine F; Bergeria, Cecilia L; Sempio, Cristina; Klawitter, Jost; Christians, Uwe; Weerts, Elise M","year":2026,"journal":"Pharmacology, biochemistry, and behavior, 260, 174154","doi":"10.1016/j.pbb.2026.174154","pmid":"41534632","tags":["cognition","cbd","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBG at 300-600 mg/kg impaired sustained attention in female rats but not males. CBG did not affect motivation or working memory in either sex. Females had significantly higher circulating CBG plasma levels than males after the same oral dose.","whyItMatters":"CBG is increasingly marketed as a cognitive enhancer for focus and attention. This is the first controlled study to test those claims, and it found the opposite: high-dose CBG impaired attention in females.","specificNumbers":"Doses: 30-600 mg/kg oral. Attention deficits at 300-600 mg/kg in females only. No effects on motivation or working memory. Females had significantly higher plasma CBG levels than males.","methodology":"Male and female adult Sprague Dawley rats received oral CBG (30-600 mg/kg) or vehicle before testing on rodent psychomotor vigilance (attention), progressive ratio responding (motivation), and spontaneous alternation (working memory). Blood collected 60 minutes post-administration for plasma CBG levels.","limitations":"Animal study; rat doses may not directly translate to human doses. Acute dosing only. The attention deficit was only at very high doses."},{"rthcId":"RTHC-08505","title":"Diversity of root system architecture and root-shoot biomass allocation in industrial hemp (Cannabis sativa L.).","authors":"Morales, Elisa Y; Griffiths, Marcus; Mankar, Sumeet P; Bagnall, George C; Fletcher, Richard; McKay, John K; Topp, Christopher N","year":2026,"journal":"PloS one, 21(2), e0339929","doi":"10.1371/journal.pone.0339929","pmid":"41650193","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08506","title":"Depictions of Nicotine and Cannabis in Popular US and German Hip-Hop/Rap Music Videos: A YouTube Top 100 Content Analysis.","authors":"Morgenstern, Matthis; Süßkow, Eddy; Neumann, Clemens; Hanewinkel, Reiner","year":2026,"journal":"Substance use & misuse, 1-5","doi":"10.1080/10826084.2025.2611414","pmid":"41504253","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"41% of all top music videos contained nicotine or cannabis depictions. Hip-hop/rap videos were dramatically more likely (59.5%) to contain substance depictions compared to other genres (10.1%, OR = 13.11). US hip-hop emphasized cannabis; German hip-hop emphasized nicotine. Estimated 57 billion nicotine and 49 billion cannabis impressions.","whyItMatters":"Music videos are among the most-consumed media by adolescents, and substance depictions are an established risk factor for youth initiation. The scale of exposure (over 100 billion impressions) represents a massive, unregulated channel for substance normalization.","specificNumbers":"1,160 videos. 479 (41%) contained substance depictions. Hip-hop/rap OR = 13.11 vs. other genres. 4,478 total occurrences. Estimated 57 billion nicotine and 49 billion cannabis impressions.","methodology":"Content analysis of all German- and English-language videos from the 2024 YouTube Top 100 charts (n = 1,160). Videos categorized by genre and substance content. Occurrences counted. Exposure estimated by multiplying occurrences by March 2025 view counts.","limitations":"Content analysis cannot prove viewer behavior changes. Impression estimates assume all viewers saw the depictions. No assessment of how depictions were framed. Single year of data."},{"rthcId":"RTHC-08507","title":"Age differences in endocannabinoid tone are ameliorated after recent cannabis use.","authors":"Morris, Alan W J; Mueller, Raeghan L; Sempio, Cristina; Klawitter, Jost; Bryan, Angela D; Bidwell, L Cinnamon; Hutchison, Kent E","year":2026,"journal":"Scientific reports, 16(1), 3483","doi":"10.1038/s41598-025-27618-1","pmid":"41580496","tags":["neuroscience","seniors"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Older adults (55-71) had lower baseline AEA and DEA vs. younger adults (21-24). After cannabis use, six of seven endocannabinoids increased significantly across all ages. For AEA and DEA, increases were larger in older adults, suggesting cannabis may partially restore age-related endocannabinoid deficits.","whyItMatters":"Age-related endocannabinoid decline has been linked to chronic pain and neurodegeneration. This study provides the first evidence that cannabis use can acutely boost endocannabinoid levels in older adults, and potentially more than in younger users.","specificNumbers":"142 adults (38 younger, 73 midlife, 31 older). Cannabis increased AEA, DEA, LEA, PEA, SEA, OEA across all ages (p < .001). 2-AG did not increase. Larger AEA and DEA increases in older adults (significant Time x Age interaction).","methodology":"Prospective study of 142 adults in three age groups. Endocannabinoid levels measured before and after cannabis use (1 hour post-flower or 2 hours post-edible). Seven endocannabinoids assayed.","limitations":"Small older adult group (n=31). Acute effects only. No placebo control. Unclear whether elevated levels translate to clinical benefit."},{"rthcId":"RTHC-08508","title":"Clinical features and sociodemographic characteristics associated with analytically confirmed exposure to MDMB-4en-PINACA.","authors":"Moyns, Emma Jayne; Starbrook, Lauren; Pucci, Mark","year":2026,"journal":"Clinical toxicology (Philadelphia, Pa.), 1-8","doi":"10.1080/15563650.2025.2608229","pmid":"41627129","tags":["synthetic-cannabinoids","harm-reduction"],"studyType":"case-report","evidenceStrength":"moderate","keyFinding":"Of 202 presentations involving 163 patients, 81.2% had reduced consciousness, 49% agitation, 30.2% seizures, and four died. Majority male (82.6%), median age 39, 32.2% homeless. In 88.1% of cases other substances were also detected, but 15 single-substance cases showed similar features.","whyItMatters":"Synthetic cannabinoids are far more dangerous than plant cannabis but popular in vulnerable populations due to low cost. This documents the severe clinical profile of one of the most prevalent synthetic cannabinoids currently circulating.","specificNumbers":"202 presentations, 163 patients. 81.2% unconscious. 49% agitation. 30.2% seizures. 4 deaths. 32.2% homeless. 82.6% male. 88.1% polydrug.","methodology":"Retrospective case series from Birmingham UK emergency departments (November 2020 to December 2024) with analytically confirmed MDMB-4en-PINACA exposure via routine toxicological screening.","limitations":"Single city. Most cases involved polydrug use. Only patients reaching the ED were captured."},{"rthcId":"RTHC-08509","title":"The Endocannabinoid System: Scientific Insight and Biblical Reflection.","authors":"Mulkey, David C","year":2026,"journal":"Journal of Christian nursing : a quarterly publication of Nurses Christian Fellowship, 43(1), 32-37","doi":"10.1097/CNJ.0000000000001335","pmid":"41359460","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08510","title":"Detection and Quantification of Latent Infection by Fusarium graminearum, Causal Agent of Fusarium Head Blight on Hemp (Cannabis sativa) Fields in Kentucky.","authors":"Munir, Misbakhul; Church, Annika; Smith, Henry; Schroer, Rebecca; Reynolds, Jacqueline; Robinson, Alainey; Wong, Justin; Thomas, Erin; Adedokun, Toni; Allahham, Faris; Szarka, Desiree; Dixon, Ed; Caton, Tara; Ricciardi, Magdalena; Pearce, Robert; Ward Gauthier, Nicole A","year":2026,"journal":"Plant disease","doi":"10.1094/PDIS-04-25-0774-RE","pmid":"41486859","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08511","title":"Cannabinoid Signaling and Autophagy in Oral Disease: Molecular Mechanisms and Therapeutic Implications.","authors":"Munkhsaikhan, Undral; Rahman, Md Ataur; Shasteen, Alivia; Ait-Aissa, Karima; Sahyoun, Amal M; Gupta, Rajat Das; Kassan, Modar; Hoque Apu, Ehsanul; Abidi, Ammaar H","year":2026,"journal":"International journal of molecular sciences, 27(1)","doi":"10.3390/ijms27010525","pmid":"41516397","tags":["cancer","cbd","inflammation"],"studyType":"review","evidenceStrength":"preliminary","keyFinding":"Cannabinoids acting through CB1 and CB2 receptors modulate autophagy by inhibiting PI3K/AKT/mTOR, activating AMPK and Beclin-1, and promoting ROS-induced autophagy. These mechanisms have dual anti-inflammatory and anti-cancer potential in oral tissues. Cannabinoid-induced autophagy may also enhance stem cell survival for dental pulp regeneration.","whyItMatters":"Oral cancers and periodontal disease have limited treatment options. Understanding how cannabinoids interact with cellular recycling in oral tissues could open new therapeutic approaches, though this remains early-stage.","specificNumbers":"Key pathways: PI3K/AKT/mTOR inhibition, AMPK activation, Beclin-1 upregulation. Receptors: CB1 and CB2. Applications: OSCC, periodontitis, gingival inflammation, dental pulp regeneration.","methodology":"Narrative review of experimental studies on cannabinoid-autophagy interactions in oral tissues, covering oral squamous cell carcinoma, periodontitis, gingival inflammation, and dental pulp regeneration.","limitations":"Primarily preclinical data. No clinical trials. Dose-dependent variability and poor oral bioavailability remain challenges."},{"rthcId":"RTHC-08512","title":"Regular cannabinoid use and inflammatory biomarkers: Systematic review and hierarchical meta-analysis.","authors":"Murri, Martino Belvederi; Guglielmo, Riccardo; Zizzi, Alessio; Muscettola, Angela; Nanni, Maria Giulia; Dall'Oro, Manuela; Serafini, Gianluca; Inuggi, Alberto; Escelsior, Andrea; Amore, Mario; Grassi, Luigi","year":2026,"journal":"Brain, behavior, and immunity, 106517","doi":"10.1016/j.bbi.2026.106517","pmid":"41740869","tags":["inflammation","harm-reduction"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Cannabis use was associated with higher anti-inflammatory biomarkers (SMD = 0.298, PD = 99%) and pro-inflammatory biomarkers (SMD = 0.166, PD = 100%). CBD RCTs suggested small pro-inflammatory marker increases (SMD = 0.15, PD = 90.9%). No consistent effects in prospective studies. Results varied by demographics, study design, and recency of use.","whyItMatters":"Cannabis is widely described as \"anti-inflammatory,\" but this meta-analysis shows regular use modulates the immune system in both directions simultaneously, with implications for people using cannabis to manage inflammatory conditions.","specificNumbers":"46 studies, 54,382 participants, 190 effect sizes. Anti-inflammatory SMD = 0.298 (CrI 0.052-0.536). Pro-inflammatory SMD = 0.166 (CrI 0.122-0.209). CBD RCTs: pro-inflammatory SMD = 0.15. No major publication bias.","methodology":"Systematic review and Bayesian multilevel meta-analysis of 46 studies (54,382 participants). 190 effect sizes pooled in three analyses. Bayesian hierarchical models accounted for clustering within studies and biomarkers.","limitations":"Most evidence from cross-sectional studies. Only 2 prospective and 10 RCTs. Heterogeneity in cannabinoid type, dose, and duration across studies."},{"rthcId":"RTHC-08513","title":"Joint Association of Methamphetamine and Cannabis Use as Risk Factors for Asthma Exacerbations Requiring Hospitalization: A Retrospective Analysis.","authors":"Musa, Amal M; Poole, Jill A; Sayles, Harlan R; Rorie, Andrew C","year":2026,"journal":"The journal of allergy and clinical immunology. In practice, 14(1), 185-195","doi":"10.1016/j.jaip.2025.10.006","pmid":"41106683","tags":["respiratory","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Methamphetamine use alone showed a trend toward mechanical ventilation but was not significant. Co-positive methamphetamine and cannabis screens were significantly associated with increased intubation (p = .020) and status asthmaticus (p = .032). Any positive drug screen was associated with more ICU admissions (p = .022).","whyItMatters":"This is one of the first studies to examine the combined respiratory impact of methamphetamine and cannabis. The finding that co-use produces worse asthma outcomes than either alone has direct clinical implications.","specificNumbers":"167 patients, 201 hospitalizations. 61.1% positive drug screens. 16.8% methamphetamine, 31.7% cannabis. Meth + cannabis: increased intubation (p = .020) and status asthmaticus (p = .032).","methodology":"Retrospective review of 167 patients (201 hospitalizations) admitted for asthma with urine drug screens at a single center (2013-2023). Outcomes: hospital stay, mechanical ventilation, ICU admission, fatal exacerbation.","limitations":"Small sample. Single center. Retrospective. Urine screens detect recent use, not timing relative to exacerbation."},{"rthcId":"RTHC-08514","title":"Optimizing antipsychotic dosing for relapse prevention in cannabis-induced psychosis: A nationwide cohort study.","authors":"Mustonen, Antti; Niemelä, Solja; Denissoff, Alexander; Forti, Marta Di; Tanskanen, Antti; Mittendorfer-Rutz, Ellenor; Tiihonen, Jari; Taipale, Heidi","year":2026,"journal":"Psychiatry research, 358, 116966","doi":"10.1016/j.psychres.2026.116966","pmid":"41581246","tags":["psychosis","addiction","cognition","youth","medical-cannabis"],"studyType":"cohort","evidenceStrength":"moderate","keyFinding":"Using linked Swedish health registers, researchers identified all individuals with a first diagnosis of cannabis-induced psychosis and conducted a dose-response analysis of oral antipsychotic medications.\n\nThe analysis modeled antipsychotic exposure as time-dependent across three dose categories (low: <0.6 DDD, moderate: 0.6–<1.4 DDD, high: ≥1.4 DDD) using within-individual comparisons — meaning each person served as their own control across different exposure periods.\n\nThe primary outcome was hospitalization for any psychotic episode (schizophrenia-spectrum disorder or substance-induced psychosis). The results showed a dose-response curve that plateaued at moderate doses: low doses provided some protection, moderate doses were most effective, and high doses did not add further benefit.\n\nThe within-individual design is particularly strong because it eliminates confounding from differences between patients (genetics, severity, comorbidities) — it only compares how the same person fares at different dose levels.","whyItMatters":"Cannabis-induced psychosis carries a high conversion rate to chronic psychotic illness (RTHC-00251 found ~34% convert to schizophrenia). Antipsychotics can prevent relapse, but they carry dose-related side effects including weight gain, metabolic syndrome, and movement disorders. This study provides the first real-world dose optimization data, suggesting clinicians can achieve maximum benefit at moderate doses without the added burden of high-dose treatment.","specificNumbers":"Three dose categories: <0.6 DDD (low), 0.6–<1.4 DDD (moderate), ≥1.4 DDD (high). Medications analyzed: aripiprazole, clozapine, risperidone, olanzapine, quetiapine, polytherapy, and others. Outcome: hospitalization for schizophrenia-spectrum or substance-induced psychosis. Moderate doses showed optimal protection; high doses showed no additional benefit.","methodology":"Nationwide cohort study using linked Swedish administrative and healthcare registers. All first diagnoses of cannabis-induced psychosis (ICD-10 F12.5) identified. Antipsychotic exposure modeled as time-dependent using validated PRE2DUP method. Dose-response analyzed across three DDD categories. Within-individual stratified Cox regression. Primary outcome: hospitalization for psychotic episode.","limitations":"Register-based study — medication exposure is estimated from dispensing records, not confirmed adherence. Cannabis use during follow-up was not measured and may confound results. The Swedish healthcare system may not generalize to other settings. Within-individual design requires that patients contribute periods at different dose levels, which may introduce selection effects."},{"rthcId":"RTHC-08515","title":"Relationships of Changing State Cannabis Policies With Alcohol Policy Effectiveness and Alcohol or Cannabis Involvement in Motor Vehicle Fatalities.","authors":"Naimi, Timothy S; Zhao, Jinhui; Lira, Marlene C; Pacula, Rosalie Liccardo","year":2026,"journal":"American journal of preventive medicine, 70(1), 108137","doi":"10.1016/j.amepre.2025.108137","pmid":"41072828","tags":["driving","legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"A 10-point increase in alcohol policy scores was associated with 6.3% lower odds of alcohol-involved crash fatalities. A 10-point increase in cannabis policy scores was associated with reduced cannabis involvement (AOR = 0.956) and co-involvement (AOR = 0.962). Cannabis policies did not affect alcohol policy effectiveness.","whyItMatters":"A key concern has been whether cannabis legalization might undermine alcohol control. This study shows the two policy domains operate independently, providing reassurance for policymakers.","specificNumbers":"Alcohol policy: AOR = 0.937 for BAC > 0.00%. Cannabis policy: AOR = 0.956 for cannabis involvement; AOR = 0.962 for co-involvement. No significant policy interaction.","methodology":"Analysis of FARS data across 50 states and DC (2010-2019). State-year alcohol and cannabis policy scores measured policy exposure. Multivariable mixed logistic regression estimated associations with BAC thresholds and THC involvement in crash fatalities.","limitations":"Ecological design. Composite policy scores. 2010-2019 data may not capture newer legalization effects. THC detection indicates recent use, not impairment."},{"rthcId":"RTHC-08516","title":"Investigating the effectiveness and adverse events of medicinal cannabis for patients with muscle spasticity or spasms.","authors":"Nastatos, Xenia L; Schubert, Elise A; Wheate, Nial J","year":2026,"journal":"The Journal of pharmacology and experimental therapeutics, 393(1), 103780","doi":"10.1016/j.jpet.2025.103780","pmid":"41386046","tags":["medical-cannabis","pain","sleep"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"No physical functioning improvements for any group or product type. Spasticity patients using CBD-only products improved in sleep disturbance, fatigue, pain interference, and pain intensity. Spasm patients using balanced, CBD-dominant, or THC-dominant products improved in those same four outcomes. Common adverse events: dry mouth, drowsiness, fatigue, dizziness, nausea.","whyItMatters":"Conventional spasticity treatments have poor effectiveness or tolerability. Medical cannabis may help manage secondary symptoms even when it does not address the underlying physical impairment.","specificNumbers":"150 patients (adverse events), 78 (outcomes). CBD-only improved 4 outcomes for spasticity. Balanced/CBD-dominant/THC-dominant improved 4 outcomes for spasms. Zero physical functioning improvement.","methodology":"Longitudinal study with patient surveys, clinic records, and PROMIS-29 scores. 150 patients reported adverse events, 78 reported outcomes. Different product types compared.","limitations":"No control group. Self-reported outcomes. Small outcome sample (n=78). Product types not randomly assigned."},{"rthcId":"RTHC-08517","title":"Medical Cannabis Formulations, Administration Routes, and Dosing: Perspectives of Patients With Cancer Who Consume.","authors":"Nayak, Manan M; Chai, Peter R; Tung, Stephanie; Revette, Anna; Braun, Ilana M","year":2026,"journal":"Clinical therapeutics, 48(1), 51-56","doi":"10.1016/j.clinthera.2025.11.004","pmid":"41387129","tags":["medical-cannabis","cancer"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Through interviews with 24 cancer patients using medical cannabis across 8 states, researchers documented the lived experience of navigating cannabis therapeutics during cancer care.\n\nA dominant theme was the sheer number of product formulations available at dispensaries, which triggered feelings of astonishment and burden rather than empowerment. Patients responded with various coping strategies: purchasing and sampling multiple products, modifying dispensary products at home, and altering intended routes of administration to suit their needs.\n\nPreferred products were not consistently available — a supply chain problem that forced patients to repeatedly adapt. Dosing imprecision was another recurring challenge, with patients struggling to achieve consistent therapeutic effects.\n\nPatients used a wide range of administration routes. Oral was most common, followed by topical, sublingual, vaporization, combustion, and rectal suppository. Three-quarters of participants alternated between multiple modes of administration, often based on symptom type and severity.\n\nThe findings highlighted a scientific disconnect: the ways patients actually use medical cannabis bear little resemblance to what oncologists tend to recommend or what clinical trials evaluate.","whyItMatters":"One in three cancer patients uses medical cannabis, but clinical guidance is minimal. This study reveals that patients are essentially conducting their own uncontrolled experiments — sampling products, modifying doses, switching routes — without standardized frameworks. The disconnect between patient practices and oncologist preferences creates a clinical communication gap that could affect safety and efficacy.","specificNumbers":"24 patients, mean age 54, 67% female, 51% metastatic disease. 8 states represented. Most common route: oral. 75% alternated between multiple administration routes. Routes used: oral, topical, sublingual, vaporization, combustion, rectal suppository.","methodology":"Qualitative study using semistructured interviews with 24 cancer patients consuming medical cannabis across 8 US states. Thematic analysis applied to interview transcripts. Explored formulation preferences, administration routes, dosing practices, and barriers to consistent use.","limitations":"Small qualitative sample (N=24) not generalizable to all cancer patients. Recruited patients who were already using medical cannabis, missing those who tried and stopped or never started. Self-selected population may overrepresent engaged, motivated patients. Cross-sectional interviews capture a snapshot, not the full trajectory of cannabis use during cancer care."},{"rthcId":"RTHC-08518","title":"Associations of Cannabis and Tobacco Use with Suicide Attempt, Suicide Death, and Overdose Death Among Veterans Prescribed Opioid Analgesics.","authors":"Nguyen, Nhung; Leonard, Samuel; Byers, Amy L; Austin, Peter C; Krebs, Erin E; Sandbrink, Friedhelm; Bravata, Dawn M; Keyhani, Salomeh","year":2026,"journal":"American journal of preventive medicine, 108309","doi":"10.1016/j.amepre.2026.108309","pmid":"41692146","tags":["mental-health","addiction","harm-reduction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Cannabis use: HR 1.11 for suicide attempts. Tobacco: HR 1.18 for attempts, HR 1.19 for suicide deaths, HR 1.67 for overdose deaths. Associations persisted after adjusting for substance use disorders, mental health, and sociodemographics.","whyItMatters":"Veterans on opioids are already at elevated risk. Identifying cannabis and tobacco as additional risk markers could inform screening and monitoring protocols.","specificNumbers":"923,291 veterans. 5.4% cannabis, 39.4% tobacco. Median follow-up 6.7-6.8 years. Cannabis: HR 1.11 suicide attempt. Tobacco: HR 1.18 attempt, HR 1.19 suicide death, HR 1.67 overdose death.","methodology":"Longitudinal cohort of 923,291 veterans receiving opioid analgesics in VHA clinics (2014-2019) with follow-up through 2021. Cause-specific hazard models adjusted for established suicide/overdose risk factors.","limitations":"Observational. Cannabis/tobacco assessed at baseline only. Cannabis associated with attempts, not deaths. Residual confounding possible."},{"rthcId":"RTHC-08519","title":"Preparation of ZIF-8 grafted magnetic solid-phase extraction sorbent for sensitive determination of four cannabinoids in urine and oral fluid.","authors":"Ning, Hongyu; Fan, Yilei; Wang, Haodong; Liu, Huijun; Huang, Zhongping; Wang, Haixing; Ke, Xing; Xu, Yu","year":2026,"journal":"Analytica chimica acta, 1394, 345194","doi":"10.1016/j.aca.2026.345194","pmid":"41730592","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08520","title":"Sex-dependent effects of ultra-low-dose-THC preventive treatment on neuroinflammation and cognitive decline in 5xFAD mice.","authors":"Nitzan, Keren; Bentulila, Ziv; Bregman-Yemini, Noa; Ayalon, Niv; David, Dekel; Break, Emanuela; Sarne, Yossi; Doron, Ravid","year":2026,"journal":"Biology of sex differences, 17(1), 20","doi":"10.1186/s13293-025-00815-3","pmid":"41484932","tags":["cognition","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"ULD-THC attenuated AD-related cognitive decline in both sexes. Males showed reduced hippocampal inflammation; females showed reduced prefrontal cortex inflammation. Treatment was given monthly from 3 to 5 months of age, before significant pathology.","whyItMatters":"No treatment effectively prevents Alzheimer onset. Ultra-low-dose THC, given before symptoms, reduced neuroinflammation and slowed cognitive decline without the adverse effects of chronic THC use.","specificNumbers":"Monthly ULD-THC from age 3-5 months. Testing at 6 months. Males: reduced hippocampal inflammation. Females: reduced PFC inflammation. Both sexes: attenuated cognitive decline.","methodology":"Male and female 5xFAD mice received monthly ULD-THC injections from 3-5 months. Behavioral assessments at 6 months, followed by molecular analyses of hippocampal and PFC tissue.","limitations":"Mouse model. Difficult to translate ULD-THC dosing to humans. Only tested as prevention, not treatment. Short treatment window."},{"rthcId":"RTHC-08521","title":"The effects of chronic cannabidiol administration on brain pathology and behavioral deficits found in the tau P301s-line PS19 mouse model of Alzheimer's disease.","authors":"Nixon, Abigail G; Hong, Nancy S; Agha, Behroo Mirza; Ham, Jackson R; Monteith, Merrin; Kaloa, Tina; Kyriazopolus, Angela; Nielsen, Matt; Robertson, David R; Golubov, Andrey; Sutherland, Robert J; Kovalchuk, Igor; Iwaniuk, Andrew; Mohajerani, Majid H; McDonald, Robert J","year":2026,"journal":"Journal of Alzheimer's disease : JAD, 13872877261421654","doi":"10.1177/13872877261421654","pmid":"41736228","tags":["cognition","cbd","neuroscience","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD did not improve cognitive or motor behavior and did not restore hippocampal volume. However, it reduced microglial reactivity. Males showed more severe pathology than females. Daily CBD did not negatively impact any group, suggesting chronic administration was safe.","whyItMatters":"CBD is widely marketed for neuroprotection. This rigorous test found minimal behavioral benefit, but the positive microglial finding suggests subtle anti-inflammatory effects that do not translate to cognitive improvement.","specificNumbers":"Daily oral CBD 20 mg/kg from 3 months. Testing at 6 and 9 months. No behavioral improvement. No hippocampal volume restoration. Reduced microglial reactivity. Males had more severe pathology.","methodology":"Tau P301S mice received daily oral CBD (20 mg/kg) or vehicle from 3 months. Tested at 6 and 9 months on object recognition, motor function, spatial learning, and fear conditioning. Brains analyzed for hippocampal volume and inflammatory markers.","limitations":"Aggressive model may overwhelm CBD effects. Single dose. Low oral bioavailability. Different doses or timing might produce different results."},{"rthcId":"RTHC-08522","title":"Distinct endocannabinoids specifically signal to astrocytes or neurons in the adult mouse hippocampus.","authors":"Noriega-Prieto, Jose Antonio; Falcón-Moya, Rafael; Noeker, Jacob A; Cai, Ruyi; Fundazuri, Unai B; Eraso-Pichot, Abel; Cai, Shangxuan; Guttipatti, Pavan; Belisle, Lindsey; Rodríguez-Moreno, Antonio; van der Stelt, Mario; Li, Yulong; Cheer, Joseph F; Marsicano, Giovanni; Kofuji, Paulo; Araque, Alfonso","year":2026,"journal":"Nature neuroscience, 29(2), 445-454","doi":"10.1038/s41593-025-02148-1","pmid":"41469443","tags":["neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"strong","keyFinding":"In the hippocampus, 2-AG activates CB1 receptors on neurons to depress synaptic transmission, while anandamide activates CB1 receptors on astrocytes to potentiate adjacent synapses. Only anandamide and astrocyte signaling were required for spike-timing-dependent long-term potentiation.","whyItMatters":"This discovery rewrites the textbook on endocannabinoid signaling. Instead of two redundant molecules doing the same job, 2-AG and anandamide have entirely separate cellular targets and produce opposing effects on brain communication.","specificNumbers":"2-AG selectively depressed synaptic transmission via neuronal CB1 receptors. Anandamide selectively potentiated synapses via astrocyte CB1 receptors. Only anandamide was required for spike-timing-dependent long-term potentiation in the hippocampus.","methodology":"Researchers used mouse hippocampal brain slices with pharmacological tools, genetic models, and electrophysiology to dissect which endocannabinoid signals to which cell type.","limitations":"This was conducted in mouse hippocampal tissue, and it remains unclear whether the same cell-type specificity holds across all brain regions or in humans."},{"rthcId":"RTHC-08523","title":"Does the total consumption model apply to cannabis use?","authors":"Norström, Thor; Leifman, Håkan","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70353","pmid":"41734810","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"The distribution of cannabis use frequency among Swedish adolescents remained remarkably stable over 33 years, and increases in average use were consistently associated with proportional increases in high-frequency users.","whyItMatters":"This has major implications for cannabis policy. If the total consumption model applies, then any policy that increases average cannabis use among adolescents will inevitably increase the number of heavy users, not just casual experimenters.","specificNumbers":"A 1 percentage point increase in average frequency of use was associated with a 1.794 percentage point increase in high-frequency users among 9th graders (p < 0.001). The elasticity for the median user (P50) was 0.914.","methodology":"Researchers analyzed annual surveys of Swedish 9th-grade (n=180,059) and high school students (n=80,925) from 1990 to 2023 using Lorenz curves, Gini coefficients, and regression analysis to test whether cannabis use follows the total consumption model.","limitations":"Based on Swedish adolescents only, where cannabis use levels are relatively low compared to North America. Self-reported frequency may underestimate actual use. The model may not apply in settings with very different use patterns."},{"rthcId":"RTHC-08524","title":"Leveraging the national cancer institute's collaborative efforts to understand the benefits and harms of cannabis use among individuals with cancer.","authors":"Nugent, Shannon M; Ashare, Rebecca L; Cullen, Jennifer; Haque, Reina; Hu, Jennifer; Lee, Richard T; Meghani, Salimah H; Potosky, Arnold L; Reboussin, Beth A; Romero-Sandoval, Alfonso; Wagoner, Kimberly G; Wang, Yan; Worster, Brooke; Filipski, Kelly K; Freedman, Andrew N","year":2026,"journal":"Journal of the National Cancer Institute","doi":"10.1093/jnci/djag057","pmid":"41746285","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08525","title":"Selective electrochemical detection of cannabidiol (CBD) and tetrahydrocannabinol (THC) at molecular-imprinted mesoporous Pt-Ir surfaces.","authors":"Nunthakitgoson, Watinee; Kaewwan, Natthaphong; Butcha, Sopon; Ketkaew, Marisa; Kuhn, Alexander; Wattanakit, Chularat","year":2026,"journal":"Biosensors & bioelectronics, 292, 118103","doi":"10.1016/j.bios.2025.118103","pmid":"41110220","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08526","title":"Substance Use in Sports: A Cross-Sectional Study Among Professional Footballers in Accra, Ghana.","authors":"Odei, Isaac; Essuman, Yaw Akye; Ofori-Atta, Angela Lamensdorf","year":2026,"journal":"Health science reports, 9(2), e71828","doi":"10.1002/hsr2.71828","pmid":"41716422","tags":["addiction","exercise"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 139 professional footballers in Ghana, overall substance use prevalence was 44.6%. Caffeine was most common (30.2%), followed by alcohol (15.8%), cannabis (2.9%), and tobacco (2.2%). Those with longer tenure at their current club had lower odds of substance use.","whyItMatters":"This is rare data on substance use patterns among professional athletes in sub-Saharan Africa. The low cannabis use among elite athletes contrasts with higher rates often reported in general populations.","specificNumbers":"Substance use prevalence: caffeine 30.2%, alcohol 15.8%, cannabis 2.9%, tobacco 2.2%. Mean CUDIT-R score was 6.3 (low-risk). Each additional year at a club was associated with 19% lower odds of substance use (OR = 0.81).","methodology":"Cross-sectional survey of 139 professional footballers from nine Ghana Premier League and Division One League teams using validated screening tools (AUDIT, CUDIT-R, FTND).","limitations":"Small sample (139 players) from one region of Ghana using convenience sampling. Self-report may underestimate use due to anti-doping concerns. Only male athletes were included."},{"rthcId":"RTHC-08527","title":"Field-grown hemp treated with humic/fulvic acids and arbuscular mycorrhizal fungi for phytomanaging a metal-contaminated agricultural soil.","authors":"Ofori-Agyemang, Felix; Oustrière, Nadège; Waterlot, Christophe; Mench, Michel; Burges, Aritz","year":2026,"journal":"International journal of phytoremediation, 1-13","doi":"10.1080/15226514.2026.2621118","pmid":"41614606","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08528","title":"Cannabis Use Behaviors and Desired Interventions Among Postpartum Individuals With Frequent Cannabis Use in Early Pregnancy: A Qualitative Study.","authors":"Ogden, Shannon N; Foti, Tara R; Does, Monique B; Altschuler, Andrea; Iturralde, Esti; Sterling, Stacy A; Ansley, Deborah; Castellanos, Carley; Young-Wolff, Kelly C","year":2026,"journal":"Journal of addiction medicine, 20(1), 102-108","doi":"10.1097/ADM.0000000000001514","pmid":"40539624","tags":["pregnancy","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Of 17 postpartum patients who used cannabis daily or weekly in early pregnancy, 15 reported postpartum cannabis use and 10 reported use while breastfeeding. Participants wanted nonjudgmental support services and better information about cannabis risks during breastfeeding.","whyItMatters":"With postpartum cannabis use rising, this study reveals a gap between what new parents want to know about cannabis and breastfeeding and what healthcare providers currently offer. Participants expressed genuine concern about safety but lacked information to make informed decisions.","specificNumbers":"15 of 17 participants reported postpartum cannabis use. 10 of 15 postpartum users reported cannabis use during breastfeeding. The sample included Black (n=4), Hispanic (n=4), and White (n=9) patients.","methodology":"Semi-structured qualitative interviews with 17 first-time parents in Northern California who reported daily or weekly cannabis use during early pregnancy, analyzed using thematic analysis.","limitations":"Small qualitative sample (17 interviews) from a single healthcare system in Northern California. Participants were self-selected, and findings may not reflect the broader population of postpartum cannabis users."},{"rthcId":"RTHC-08529","title":"Effect of Industrial Hemp (Cannabis sativa) Supplementation on Rumination Behaviour, Plasma Antioxidant Enzymes and Stress Biomarkers in Angus Cattle.","authors":"Ogunkunle, Nathaniel; Simpson, Monya; Samuel, Felix; Kuang, Xianyan; Cebert, Ernst; AbdelRahim, Gamal; Boateng, Judith","year":2026,"journal":"Journal of animal physiology and animal nutrition, 110(1), 13-22","doi":"10.1111/jpn.70014","pmid":"41056471","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08530","title":"Cannabidiol and Parkinson's disease: Investigating receptor interactions and their therapeutic implications.","authors":"Okrah, Eric A; Allan, Claire; Doblin, Monika S; Annesley, Sarah J","year":2026,"journal":"Pharmacology & therapeutics, 277, 108943","doi":"10.1016/j.pharmthera.2025.108943","pmid":"41161354","tags":["cbd","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CBD exerts effects through the endocannabinoid system and numerous non-cannabinoid receptors, neurotransmitters, and enzymes. These interactions vary by cell type, concentration, and exposure time, making CBD's mechanism of action complex but potentially multi-targeted for neurodegenerative conditions.","whyItMatters":"Understanding exactly how CBD works in the brain is critical before it can become a legitimate therapeutic option for Parkinson's. This review maps the full landscape of receptor targets, revealing why CBD has shown promise in preclinical studies but remains difficult to translate to clinical practice.","specificNumbers":"CBD interacts with CB1 and CB2 receptors, TRPV1 channels, 5-HT1A serotonin receptors, GPR55, PPARs, and adenosine receptors among others. Preclinical studies have shown it to be effective, safe, and well-tolerated for Parkinson's symptoms.","methodology":"Comprehensive literature review synthesizing preclinical evidence on CBD's receptor interactions and their relevance to Parkinson's disease pathology.","limitations":"Most evidence comes from preclinical models. CBD's complex pharmacology means that effects observed in cell cultures or animal models may not translate directly to humans. The review does not include original clinical trial data."},{"rthcId":"RTHC-08531","title":"Melatonin mitigates hormonal toxicity in cannabis-treated female Wistar rats: involvement of cannabinoid receptor.","authors":"Oluwasola, A","year":2026,"journal":"Journal of cannabis research, 8(1), 27","doi":"10.1186/s42238-025-00375-8","pmid":"41559847","tags":["pregnancy","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis extract significantly altered levels of GnRH, FSH, LH, estradiol, progesterone, and prolactin in female rats. Blocking CB1 receptors caused more hormonal disruption than blocking CB2, suggesting CB1 primarily disrupts the hypothalamic-pituitary-gonadal axis. Melatonin ameliorated these effects even when cannabinoid receptors were blocked.","whyItMatters":"This study provides mechanistic evidence for how cannabis might disrupt female reproductive hormones and identifies a potential protective strategy. The finding that CB1 receptors play a larger role than CB2 in hormonal disruption adds specificity to our understanding.","specificNumbers":"50 female rats in 10 groups of 5. Treatment lasted 14 days. Cannabis extract dose: 2 mg/kg. Melatonin dose: 4 mg/kg. CB1 blockade caused more hormonal toxicity than CB2 blockade.","methodology":"Fifty female Wistar rats were divided into 10 groups receiving various combinations of cannabis extract, CB1 blocker (rimonabant), CB2 blocker (AM630), and melatonin over 14 days. Reproductive hormones were measured using ELISA assays.","limitations":"Animal study with only 5 rats per group, limiting statistical power. Short 14-day treatment period. Rat reproductive physiology differs from humans. The cannabis extract dose may not reflect typical human consumption patterns."},{"rthcId":"RTHC-08532","title":"Association between marijuana use and erectile dysfunction in a sample of sexual minority men: a cross-sectional analysis.","authors":"Otieno, Marion; Zhao, Yunan; Tran, Alvin","year":2026,"journal":"Journal of cannabis research","doi":"10.1186/s42238-026-00411-1","pmid":"41703639","tags":["cardiovascular","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"In a cross-sectional survey of 549 sexual minority men, marijuana users had 1.83 times the odds of reporting erectile dysfunction compared to non-users (95% CI: 1.23-2.74) after adjusting for confounders. ED prevalence was higher among bisexual men than gay men.","whyItMatters":"Erectile dysfunction research has largely overlooked sexual minority men. This study fills an important gap by examining cannabis-ED associations in a population with both higher rates of cannabis use and unique sexual health considerations.","specificNumbers":"549 participants (52.1% gay, 47.9% bisexual). Cannabis users had adjusted odds ratio of 1.83 (95% CI: 1.23-2.74) for ED. ED prevalence was higher in bisexual men versus gay men.","methodology":"Secondary analysis of the Men's Body Project, a cross-sectional online survey of sexual minority men. Multivariable logistic regression examined the association between self-reported marijuana use and erectile dysfunction.","limitations":"Cross-sectional design prevents determining causation. Self-reported ED and cannabis use are subject to recall and reporting bias. The online convenience sample may not represent the broader population of sexual minority men."},{"rthcId":"RTHC-08533","title":"Pathways from racial/ethnic discrimination experience to cannabis use intentions: a longitudinal study of the mediating roles of perceived accessibility and harm among preteens.","authors":"Ou, Tzung-Shiang; Wong, Su-Wei; Yang, Meng; Lin, Hsien-Chang","year":2026,"journal":"Journal of ethnicity in substance abuse, 1-14","doi":"10.1080/15332640.2025.2612339","pmid":"41527709","tags":["youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using structural equation modeling with data from 2,690 preteens (ages 9–13) in the ABCD Study, researchers traced a pathway from racial/ethnic discrimination to cannabis use intention.\n\nThe direct effect was significant: experiencing discrimination was associated with higher cannabis use intention (β = 0.068). But the study also identified two mediating pathways that explained part of this relationship.\n\nFirst, discrimination was associated with higher perceived cannabis accessibility (β = 0.134) — children who experienced discrimination perceived cannabis as easier to obtain. Second, perceived accessibility was associated with lower perceived harm (β = −0.123) — when children thought cannabis was easy to get, they tended to view it as less dangerous. And lower perceived harm predicted higher use intention (β = −0.085).\n\nThis chain — discrimination → perceived accessibility → lower perceived harm → use intention — suggests that discrimination doesn't just create emotional distress that might lead to substance use; it may also reshape how young people perceive and evaluate cannabis in their environment.","whyItMatters":"Understanding why some young people move toward cannabis use is essential for prevention. This study identifies a modifiable pathway: if discrimination changes how young people perceive cannabis accessibility and harm, then interventions targeting those perceptions — or addressing discrimination itself — could reduce risk before cannabis use begins.","specificNumbers":"2,690 preteens ages 9–13 from the ABCD Study. Direct discrimination → intention: β = 0.068. Discrimination → accessibility: β = 0.134. Accessibility → harm perception: β = −0.123. Harm perception → intention: β = −0.085. All paths statistically significant.","methodology":"Longitudinal cohort analysis using ABCD Study Release 4.0 data. 2,690 preteens ages 9–13. Structural equation modeling tested direct and indirect (mediated) pathways between racial/ethnic discrimination, perceived cannabis accessibility, perceived cannabis harm, and cannabis use intention. Adjusted for covariates.","limitations":"Use intention is not the same as actual use — many preteens who intend to use cannabis never do. Cross-sectional mediation analysis in a longitudinal dataset limits causal interpretation. Self-reported discrimination and cannabis perceptions are subjective measures. ABCD Study participants may not represent all preteens, particularly those from the most marginalized communities."},{"rthcId":"RTHC-08534","title":"Cannabis Co-Use and Endocannabinoid System Modulation in Tobacco Use Disorder: A Translational Systematic Review and Meta-Analysis.","authors":"P A Costa, Gabriel; Gómez, Oscar; Cerezo-Matias, Mayte A; Funaro, Melissa C; Sofuoglu, Mehmet; De Aquino, Joao P","year":2026,"journal":"medRxiv : the preprint server for health sciences","doi":"10.64898/2026.02.12.26346166","pmid":"41728311","tags":["addiction","quitting","cbd"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Meta-analysis of 18 observational studies (N=229,630) found cannabis use was associated with 35% lower odds of quitting tobacco (OR=0.65). However, preclinical and early clinical evidence suggests CBD specifically may reduce cigarette consumption by 40%, reverse attentional bias to smoking cues, and alleviate withdrawal.","whyItMatters":"With 18-22% of tobacco users also using cannabis, understanding how co-use affects quit attempts is critical. The key distinction here is that casual cannabis use hurts cessation, but pharmacologically targeted CBD could actually help.","specificNumbers":"Cannabis co-use: OR=0.65 for cessation (35% lower odds, p<0.0001, N=229,630). CBD reduced cigarette consumption by 40% in clinical studies. CB1 antagonists reduced nicotine self-administration in preclinical models but failed clinically due to psychiatric side effects.","methodology":"Translational systematic review and meta-analysis following PRISMA 2020 guidelines, searching multiple databases through January 2026. Included 52 studies across three categories: observational co-use studies, preclinical cannabinoid modulator studies, and human experimental ECS-intervention studies.","limitations":"High heterogeneity across observational studies (I-squared=88.1%). CBD clinical evidence is still early-stage. The distinction between naturalistic cannabis exposure and targeted CBD intervention is crucial but complicates interpretation."},{"rthcId":"RTHC-08535","title":"Integrative therapies for chronic insomnia: A randomized controlled trial of a traditional Thai Herbal Remedy and Cannabis sativa oil.","authors":"Pakdee, Naruwat; Sribunrieng, Nitcha; Poowanna, Ronnachai","year":2026,"journal":"Sleep medicine: X, 11, 100173","doi":"10.1016/j.sleepx.2026.100173","pmid":"41623556","tags":["sleep","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a randomized controlled trial, cannabis sativa oil reduced PSQI scores from 13.6 to 3.68 over four weeks, comparable to lorazepam (14.4 to 5.8) and a traditional Thai herbal remedy (12.3 to 6.6). All groups improved significantly (p < 0.001) with no significant differences between groups. Only mild adverse events were reported.","whyItMatters":"Benzodiazepines like lorazepam carry risks of dependence and cognitive impairment with long-term use. Finding that cannabis oil performs comparably with a better safety profile supports the search for non-benzodiazepine insomnia treatments.","specificNumbers":"PSQI improvements: cannabis oil 13.6 to 3.68, lorazepam 14.4 to 5.8, herbal remedy 12.3 to 6.6 (all p < 0.001). Cannabis oil group showed the largest absolute improvement (9.92 points). Quality-of-life scores improved more in the integrative therapy groups.","methodology":"Randomized controlled parallel-group trial with 60 adults with chronic insomnia divided into three groups: Thai herbal remedy (Suk-Sai-Yat), cannabis sativa oil (Deja formula), and lorazepam, treated for four weeks. Sleep quality measured by PSQI; quality of life by EQ-5D-5L.","limitations":"Small sample (20 per group). Four-week treatment period does not address long-term efficacy or safety. Single-center study in Thailand. The specific cannabis oil formulation (Deja formula) may not generalize to other cannabis products. No placebo control group."},{"rthcId":"RTHC-08536","title":"Unraveling Endocannabinoid Signaling Pathways in Cisplatin-Induced Ototoxicity.","authors":"Palaniappan, Sakthimala; Tisi, Annamaria; Di Meo, Camilla; Urbano, Cristina; Fenton, Georgina E; Della Valle, Francesco; Fanti, Federico; Compagnone, Dario; Nazarè, Marc; Versnel, Huib; Aramini, Andrea; Allegretti, Marcello; Maccarrone, Mauro","year":2026,"journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 40(4), e71568","doi":"10.1096/fj.202502888RR","pmid":"41701159","tags":["neuroscience","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cisplatin treatment downregulated CB2 receptors and disrupted the 2-AG metabolic pathway in auditory hair cells. Counterintuitively, pharmacological blockade of CB2 receptors with SR144528 protected hair cells from cisplatin damage by inhibiting caspase-3 cleavage (a cell death marker).","whyItMatters":"Cisplatin-induced hearing loss affects many cancer patients and has no treatment. Identifying the endocannabinoid system as involved opens an entirely new avenue for protective therapies during chemotherapy.","specificNumbers":"Both major endocannabinoids (AEA and 2-AG) were present in auditory hair cells. Cisplatin downregulated CB2R, DAGLb, and ABHD6. CB2 receptor blockade via SR144528 reduced caspase-3 cleavage, a marker of cell death.","methodology":"Researchers profiled the endocannabinoid system in mouse auditory hair cell lines, established an in vitro cisplatin toxicity model, validated findings in an in vivo mouse model, and tested whether CB2 receptor blockade could protect against damage.","limitations":"Primarily an in vitro study with some in vivo validation. The cell line (UB/OC1) is derived from mouse tissue and may not perfectly replicate human auditory cells. Translating CB2 blockade to clinical hearing protection requires extensive further research."},{"rthcId":"RTHC-08537","title":"Extract engineering of Cannabis sativa yields novel antibacterial cannabinoids targeting Staphylococcus aureus and methicillin-resistant Staphylococcus aureus.","authors":"Palmo, Tashi; Jamwal, Vishwani; Kumar, Anuj; Thappa, Chandan; Komal; Sangral, Monica; Singh, Shashank K; Nalli, Yedukondalu; Singh, Kuljit","year":2026,"journal":"Bioorganic chemistry, 169, 109448","doi":"10.1016/j.bioorg.2025.109448","pmid":"41478197","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08538","title":"Cannabidiol suppresses emergency MDSCs generation by disturbing EEF1B2-mediated C/EBPβ protein synthesis in colorectal adenomas.","authors":"Pan, Jie; Zhao, Lixin; Du, Haojie; Zhu, Yuyu; Sun, Xiaofan; Xu, Qiang; Cheng, Haibo; Chen, Hongqi; Sun, Yang","year":2026,"journal":"Journal for immunotherapy of cancer, 14(1)","doi":"10.1136/jitc-2025-013081","pmid":"41485775","tags":["cbd","cancer","inflammation"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"CBD prevented colorectal adenomas in both AOM/DSS and high-fat diet Apcmin/+ mouse models by binding to EEF1B2, inhibiting C/EBPb protein synthesis, and suppressing MDSC generation. This restored T-cell activation against developing tumors.","whyItMatters":"Colorectal cancer develops from adenomas over years, making early intervention critical. This study identifies a specific molecular mechanism by which CBD could prevent precancerous growths through immune system modulation, not direct tumor cell killing.","specificNumbers":"CBD significantly decreased MDSC numbers in both colorectal adenoma models. CBD bound to the guanine nucleotide exchange factor domain of EEF1B2, disrupting translational elongation and C/EBPb synthesis. Enhanced T-cell activation was observed following MDSC suppression.","methodology":"Two established colorectal adenoma mouse models were used. Single-cell RNA sequencing identified immune environment changes. Target-responsive accessibility profiling identified EEF1B2 as CBD's binding target. Multiple immunology and molecular biology experiments confirmed the mechanism.","limitations":"Mouse models only. The specific doses and routes of CBD administration in mice may not translate to achievable human concentrations. The Apcmin/+ model has a specific genetic mutation not present in all human colorectal cancers."},{"rthcId":"RTHC-08539","title":"Do Cannabis Users Require More Anesthesia During Third Molar Removal Under Intravenous General Anesthesia When Compared to Nonusers?","authors":"Panesar, Kanvar S; Smith, Charles; Zhang, Zhehao; Dodson, Thomas B; Burke, Andrea","year":2026,"journal":"Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons","doi":"10.1016/j.joms.2026.01.020","pmid":"41713495","tags":["drug-interactions","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"After adjusting for confounders, cannabis exposure years were significantly associated with total propofol requirements (coefficient = 0.7, 95% CI: 0.07-1.25, p = 0.03). Decision tree analysis stratified patients into high risk (2-3+ years multiple daily use), moderate risk (2-3+ years infrequent use), and low risk (<2-3 years).","whyItMatters":"This is directly clinically relevant: if cannabis users need more anesthesia, surgeons and anesthesiologists need to plan accordingly. The risk stratification framework offers a practical tool for assessing anesthetic requirements.","specificNumbers":"49 subjects, mean age 26.7, 61.2% female, 77.6% cannabis users. Mean cannabis exposure: 55.6 years-equivalents. CEY coefficient for propofol: 0.7 mg per exposure year (p = 0.03). Bivariate correlation was r = 0.3 (p = 0.07).","methodology":"Prospective study of 49 patients over age 21 undergoing wisdom tooth removal under IV general anesthesia at University of Washington. Cannabis exposure years (CEY) were calculated from questionnaire responses. Multivariate linear regression and decision tree analysis assessed the association with total propofol use.","limitations":"Very small sample (49 patients). Single center. 77.6% of the sample used cannabis, creating an imbalanced comparison. Self-reported cannabis use may be inaccurate. Wisdom tooth extraction is a relatively brief procedure."},{"rthcId":"RTHC-08540","title":"Psychotic Risk Associated With Cannabinoid Use: A Case Report of Ekbom-Like Delusional Infestation.","authors":"Pao Trigo, Miguel; Cavaco Rogrigues, Joana; Luz, Bruno; Sá Couto, Joaquim; Mota Oliveira, Marco","year":2026,"journal":"Cureus, 18(1), e100945","doi":"10.7759/cureus.100945","pmid":"41658693","tags":["psychosis","potency"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"A man with decades of daily cannabis use presented with persistent pruritus, tactile hallucinations, and a fixed belief that parasites infested his skin. All dermatological, neurological, and imaging tests were normal. The presentation was consistent with cannabis-induced psychotic disorder manifesting as somatic delusions. Treatment with olanzapine and psychoeducation led to gradual improvement.","whyItMatters":"Cannabis-induced psychosis typically presents with paranoia or hallucinations, not somatic delusions. This unusual presentation could be missed or misdiagnosed, particularly if clinicians do not consider substance-induced causes for delusional infestation.","specificNumbers":"49-year-old male with long-standing daily cannabis use. Normal dermatological, neurological, and lab findings. Normal cranial CT. Treated with olanzapine with gradual symptomatic improvement.","methodology":"Single case report with comprehensive workup including dermatological assessment, neurological examination, laboratory investigations, and cranial CT to exclude organic causes.","limitations":"Single case report cannot establish causation. The patient may have had underlying vulnerability to psychosis. Long-standing daily use makes it difficult to determine what specific change (if any) triggered the onset."},{"rthcId":"RTHC-08541","title":"Cannabinoids and drug-drug pharmacokinetic interactions: Deciphering the risks.","authors":"Papakyriakopoulou, Paraskevi; Valsami, Georgia; Ismailos, Georgios","year":2026,"journal":"British journal of clinical pharmacology","doi":"10.1002/bcp.70430","pmid":"41633759","tags":["drug-interactions","mental-health","pain","depression","anxiety","epilepsy","cancer","cardiovascular"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review mapped the pharmacokinetic drug-drug interactions involving cannabinoids across the full ADME framework (absorption, distribution, metabolism, excretion).\n\nThe metabolism interactions are the most clinically significant. Both THC and CBD are metabolized by cytochrome P450 enzymes — the same enzyme family that processes the majority of prescription medications. CBD in particular is a potent inhibitor of several CYP450 enzymes (including CYP2C19, CYP2D6, and CYP3A4), meaning it can increase blood levels of co-administered drugs by blocking their breakdown.\n\nThis interaction is already documented clinically: CBD increases clobazam levels in epilepsy patients (leading to more sedation), and similar interactions are possible with antidepressants, antipsychotics, blood thinners, cardiovascular drugs, and opioids.\n\nThe review highlighted that as cannabis access increases, more patients will be combining cannabinoids with prescription medications — often without informing their healthcare providers. The resulting drug interactions may be misinterpreted as drug side effects, disease progression, or treatment failure.","whyItMatters":"Cannabis is increasingly used alongside prescription medications for pain, mental health, epilepsy, cancer, and cardiovascular conditions — exactly the categories where drug interactions could have serious consequences. This review provides a comprehensive interaction map that clinicians need as cannabis use normalizes among medicated populations.","specificNumbers":"Key CYP450 enzymes affected: CYP2C19, CYP2D6, CYP3A4 (inhibited by CBD). Therapeutic areas with documented or potential interactions: pain medications, antidepressants, antipsychotics, anticoagulants, cardiovascular drugs, antiepileptics, opioids. CBD-clobazam interaction well-documented in epilepsy patients.","methodology":"Narrative review examining pharmacokinetic drug-drug interactions involving cannabinoids. Covered interactions affecting absorption, distribution, metabolism, and excretion of co-administered medications. Focused on CYP450 enzyme interactions, drug transporter effects, and clinical case reports across multiple therapeutic areas.","limitations":"Many interaction predictions are based on in vitro (test tube) enzyme studies that may not translate directly to clinical significance. Cannabinoid products vary widely in composition, making it difficult to predict interactions from specific products. Most clinical interaction data come from pharmaceutical-grade CBD (Epidiolex) at high doses; recreational and medical cannabis products may have different interaction profiles."},{"rthcId":"RTHC-08542","title":"Cannabinoids and skin cancer: Mechanistic insights, therapeutic potential, and translational perspectives.","authors":"Pareek, Ashutosh; Gupta, Rashi; Pareek, Aaushi; Wilkerson, Jenny; McMahon, Lance R; Sethi, Gautam; Chuturgoon, Anil","year":2026,"journal":"Experimental and molecular pathology, 145, 105027","doi":"10.1016/j.yexmp.2026.105027","pmid":"41621140","tags":["cancer","cbd","medical-cannabis"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Phytocannabinoids, endocannabinoids, and synthetic cannabinoids demonstrated antitumor activity against melanoma and non-melanoma skin cancers in preclinical models by inhibiting proliferation, angiogenesis, invasion, and metastasis while inducing apoptosis and autophagy. CBD-based topical formulations designed for skin penetration show particular promise.","whyItMatters":"Skin cancer incidence is rising globally, and current treatments have limitations. Cannabinoids represent a pharmacologically distinct approach that targets multiple cancer pathways simultaneously, and topical delivery could potentially minimize systemic side effects.","specificNumbers":"Cannabinoids demonstrated antitumor activity through inhibition of tumor proliferation, angiogenesis, invasion, and metastasis. Both receptor-dependent (CB1, CB2) and receptor-independent mechanisms were identified. CBD topical formulations showed enhanced skin penetration.","methodology":"Comprehensive review synthesizing the most recent preclinical evidence on cannabinoids in melanoma and non-melanoma skin cancers, examining both receptor-dependent and receptor-independent mechanisms plus emerging delivery strategies.","limitations":"Almost entirely based on preclinical data. No large skin-cancer-specific clinical trials exist. Variability in cannabinoid preparations, dosing, and formulations makes comparison across studies difficult."},{"rthcId":"RTHC-08543","title":"Cannabis use and cardiometabolic risk in schizophrenia.","authors":"Paris, Jai; Laurendi, Olivia; Arnet, Victoria; Galletly, Cherrie","year":2026,"journal":"Schizophrenia research, 287, 54-62","doi":"10.1016/j.schres.2025.11.013","pmid":"41265115","tags":["psychosis","cardiovascular"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In 988 CATIE study participants with schizophrenia, THC-positive individuals (14.8%) had significantly lower metabolic syndrome prevalence (42.5% vs 60.5%, p < 0.001). After adjusting for confounders, cannabis use remained associated with reduced MetS odds (adjusted OR 0.64, 95% CI: 0.44-0.93, p = 0.02) and lower waist circumference (adjusted OR 0.61, 95% CI: 0.41-0.91).","whyItMatters":"Metabolic syndrome is extremely common in schizophrenia (often exceeding 50%) and drives cardiovascular mortality. Understanding why cannabis users have lower rates could reveal metabolic pathways worth targeting, though the cross-sectional design limits causal interpretation.","specificNumbers":"988 participants, 14.8% THC-positive by hair testing. MetS prevalence: 42.5% in cannabis users vs 60.5% in non-users. Adjusted OR for MetS: 0.64 (p = 0.02). Adjusted OR for elevated waist circumference: 0.61 (p = 0.02). Cannabis users also had lower weight, BMI, and triglycerides.","methodology":"Cross-sectional analysis of 988 participants with DSM-IV schizophrenia from the CATIE study. Cannabis use was objectively measured via hair testing for THC. Metabolic syndrome was defined by International Diabetes Federation criteria. Multivariable logistic regression adjusted for demographics, smoking, and other substance use.","limitations":"Cross-sectional design cannot determine causation. Cannabis users may differ from non-users in ways not fully captured by covariates (diet, activity levels, illness severity). Hair testing captures recent use but not lifetime exposure patterns."},{"rthcId":"RTHC-08544","title":"Smartphone-integrated lateral flow assay for robust detection of Δ9-Tetrahydrocannabinol.","authors":"Park, Jin-Ho; Lee, Dong-Hoon; Park, Eung-Kyu; Cho, Young Kwan; Shin, Ik-Soo; Lee, Hakho","year":2026,"journal":"Biosensors & bioelectronics, 296, 118349","doi":"10.1016/j.bios.2025.118349","pmid":"41478036","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08545","title":"Breaking the resistance: a narrative review of the evolution from traditional drugs to precision therapies in epilepsy.","authors":"Patel, Tirath; Henna, Fathimathul; Ahmad, Ashfaq; Ahmad, Ayesha; Huda, Noor Ul; Aaraiz Ul Hassan, Syed; Muhammad, Aiman; Javed, Amna; Filal, Maryem; Iltaf, Arej; Anwar Khalid, Aizaz; Syeda, Zoya Riyaz; Hanani, Christopher; Anand, Nikhilesh","year":2026,"journal":"Annals of medicine and surgery (2012), 88(1), 412-421","doi":"10.1097/MS9.0000000000004295","pmid":"41496926","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08546","title":"Glucagon-like peptide 1 receptor agonists in substance use disorders: A systematic review of ClinicalTrials.Gov.","authors":"Patil, Shruti; Jha, Nandini; Jha, Manish K","year":2026,"journal":"Addictive behaviors reports, 23, 100671","doi":"10.1016/j.abrep.2026.100671","pmid":"41696398","tags":["addiction","quitting"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"A systematic review of ClinicalTrials.gov found 33 trials testing GLP-1 receptor agonists for substance use disorders: alcohol (n=15), nicotine/tobacco (n=9), cocaine (n=4), opioid (n=4), and methamphetamine (n=1). No trials are investigating cannabis use disorder. Semaglutide was the most studied agent (n=15).","whyItMatters":"The explosion of interest in GLP-1 drugs for addiction reflects growing evidence that the brain's appetite and reward circuits overlap. The complete absence of cannabis-specific trials is notable given that no FDA-approved treatment for cannabis use disorder exists.","specificNumbers":"192 records screened, 33 met criteria. Agents: semaglutide (15), exenatide (8), tirzepatide (6), liraglutide (2), dulaglutide (1), pemvidutide (1). Zero trials for cannabis use disorder.","methodology":"Systematic search of ClinicalTrials.gov from inception to July 2025, identifying trials using GLP-1 receptor agonists as interventions for substance use disorders with substance use outcomes.","limitations":"Only registered trials were included; results are not yet available for most. The review captured trial design and registration, not efficacy outcomes. Selection bias in which substances receive research attention."},{"rthcId":"RTHC-08547","title":"Cannabis Use in Older Individuals May Be an Important and Under-Recognized Risk Factor for Motor Vehicle Crashes.","authors":"Pearlson, Godfrey D; D'Souza, Deepak C; Marottoli, Richard A; Stevens, Michael C","year":2026,"journal":"Cannabis and cannabinoid research, 11(1), 5-10","doi":"10.1177/25785125251410814","pmid":"41467908","tags":["driving","seniors","cognition"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"This paper synthesized evidence on a collision of trends: the growing population of adults over 65 who drive, increasing cannabis use among older adults for medical and recreational purposes, and age-related factors that may amplify cannabis impairment.\n\nOlder drivers already have more crashes per mile driven and are more likely to be injured or killed in crashes of similar magnitude. Cannabis (primarily through THC) compromises the sensory and neurocognitive abilities necessary for safe driving, and acute use is associated with increased motor vehicle crash rates including fatal ones.\n\nThe review identified several reasons why older adults may be more vulnerable to cannabis impairment. Changes in body composition and pharmacokinetics alter how THC is metabolized and distributed — potentially producing higher effective brain concentrations from the same dose. Age-related declines in neurocognitive function compound the cognitive effects of THC. And changes in the brain's endocannabinoid system with aging may alter sensitivity to cannabinoid effects.\n\nDespite this convergence of risk factors, cannabis use among older adults and its relationship to driving safety has received little research attention.","whyItMatters":"Cannabis use among adults over 65 is the fastest-growing demographic segment of cannabis consumers. Many use it for chronic pain, sleep, or anxiety — conditions common in older adults. The driving research has focused overwhelmingly on younger users, leaving a gap in understanding how cannabis affects driving in the population that is already most vulnerable behind the wheel.","specificNumbers":"Adults over 65 are the largest growing driving population in the US. Older drivers have more crashes per mile driven. Cannabis-impaired driving is associated with increased crash rates including fatal crashes. Age-related changes in body composition, liver metabolism, neurocognition, and the endocannabinoid system may all amplify impairment.","methodology":"Narrative review synthesizing evidence on older adult driving risk, cannabis-related driving impairment, age-related pharmacokinetic changes, neurocognitive aging, and endocannabinoid system changes with age. Identified the intersection of these factors as an under-recognized crash risk.","limitations":"Narrative review based largely on extrapolation from separate bodies of evidence (driving research, aging research, cannabinoid pharmacology) rather than direct studies of cannabis-impaired older drivers. The degree to which age amplifies cannabis driving impairment is hypothesized rather than quantified. Individual variation in aging, cannabis tolerance, and driving ability is enormous."},{"rthcId":"RTHC-08548","title":"Altered endocannabinoid system gene expression in inflammatory bowel disease mucosa: New perspectives in inflammatory bowel disease management.","authors":"Pelisenco, Iulia Andreea; Salvi, Alessandro; De Petro, Giuseppina; Musat, Ioana Andreea; Manuc, Teodora Ecaterina; Tieranu, Cristian George; Becheanu, Gabriel; Milanesi, Elena; Dobre, Maria","year":2026,"journal":"World journal of gastrointestinal endoscopy, 18(2), 113576","doi":"10.4253/wjge.v18.i2.113576","pmid":"41700170","tags":["inflammation","medical-cannabis","neuroscience"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"In IBD patients, FAAH, PPARG, and TRPV1 were significantly downregulated in inflamed mucosa compared to non-inflamed tissue and controls. CB2 and GPR55 receptors were upregulated in inflamed tissue. These patterns were consistent across both Crohn's disease and ulcerative colitis.","whyItMatters":"Finding specific patterns of ECS gene dysregulation in inflamed gut tissue provides molecular evidence for why cannabinoid-based therapies might help IBD. The upregulation of CB2 receptors in inflamed tissue suggests the body is actively trying to use the endocannabinoid system to fight inflammation.","specificNumbers":"FAAH downregulated in inflamed vs non-inflamed (p=0.012). PPARG downregulated (p=0.001). TRPV1 downregulated (p=0.032). CB2 upregulated (p=0.005). GPR55 upregulated (p=0.001). 6 of 10 ECS genes dysregulated.","methodology":"Paired biopsies of inflamed and non-inflamed colonic mucosa from 30 IBD patients (17 UC, 13 CD) plus 17 non-IBD controls were analyzed using quantitative PCR for 10 endocannabinoid system genes.","limitations":"Small sample size (30 IBD patients, 17 controls). Cross-sectional design cannot determine whether ECS changes cause or result from inflammation. Gene expression does not always correlate with protein levels or functional activity."},{"rthcId":"RTHC-08549","title":"Cannabis-Related Healthcare Encounters Among U.S. Commercially Insured Adults.","authors":"Perez-Vilar, Silvia; Adimadhyam, Sruthi; Burk, Jillian; Radin, Rose; Fung, Eric N; Spahiu, Viola; Brisbane, Gifty; Shebl, Fatma M; Greene, Christina; Epperson, Meredith; Hernández-Muñoz, José J; Shinde, Mayura; Graham, David J","year":2026,"journal":"American journal of preventive medicine, 70(3), 107936","doi":"10.1016/j.amepre.2025.107936","pmid":"40516767","tags":["legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Among 115 million eligible individuals, cannabis-related healthcare encounter rates increased from 44.0 to 75.1 per 10,000 person-years between 2017 and 2022 (p=0.01). The increase occurred across all age groups and was driven by outpatient and emergency department encounters. Surprisingly, differences by state cannabis legal status were not identified.","whyItMatters":"This is the largest study of cannabis-related healthcare utilization among working-age adults. The finding that encounter rates increased regardless of state legal status challenges the assumption that legalization is the primary driver of cannabis-related healthcare burden.","specificNumbers":"115,187,493 eligible individuals. 963,345 (0.8%) had cannabis-related encounters. 5,601,233 total encounters. Rate increased from 44.0 to 75.1 per 10,000 person-years (71% increase). Trend was significant (p=0.01).","methodology":"Descriptive study using administrative claims from four national health insurers contributing to the FDA Sentinel Distributed Database. Cannabis-related encounters were identified using ICD-10-CM diagnosis codes from 2017 to 2022.","limitations":"Administrative claims data may undercount cannabis-related encounters due to coding practices. Only commercially insured adults were included, excluding Medicaid, uninsured, and Medicare populations. ICD-10 codes may not capture all cannabis-related healthcare use."},{"rthcId":"RTHC-08550","title":"Medical Cannabis for Best Supportive Care of Patients Affected by Cancers of the Head and Neck: A Narrative Review.","authors":"Perri, Francesco; Marciano, Maria Luisa; Zotta, Alessia; Pontone, Monica; Piccirillo, Arianna; Casale, Marina; DI Filippo, Pasquale; Sarno, Maria Rosaria; D' Aniello, Roberta; Cascella, Marco; Maiolino, Piera","year":2026,"journal":"In vivo (Athens, Greece), 40(1), 50-63","doi":"10.21873/invivo.14172","pmid":"41482365","tags":["medical-cannabis","cancer","pain"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Medical cannabis can be effective in managing chronic pain, nausea, vomiting, and anxiety in cancer patients through interaction with the endocannabinoid system. For head and neck cancer specifically, it may address the complex symptom burden including dysphagia, xerostomia, and cachexia that are exacerbated by both the disease and treatments like radiation and chemotherapy.","whyItMatters":"Head and neck cancers cause uniquely debilitating symptoms that affect eating, speaking, and breathing. Current symptom management is often inadequate, and medical cannabis represents an additional tool that targets multiple symptoms through a single mechanism.","specificNumbers":"Head and neck cancers are associated with pain, nausea, cachexia, dysphagia, and xerostomia. Cannabis interacts with the endocannabinoid system to reduce nociception (pain perception) and inflammation.","methodology":"Narrative review exploring the role of the endocannabinoid system and medical cannabis in managing symptoms and improving outcomes for head and neck cancer patients.","limitations":"Narrative review format, which does not systematically assess evidence quality. Most cannabis-cancer evidence comes from general oncology rather than head-and-neck-specific studies. Dosing and formulation guidance remains limited."},{"rthcId":"RTHC-08551","title":"Developmental Cascades From Prenatal Tobacco, Tobacco-cannabis Co-exposure to Early school-age externalizing Problems.","authors":"Perry, Kristin J; Schuetze, Pamela; Eiden, Rina D","year":2026,"journal":"Research on child and adolescent psychopathology, 54(1), 28","doi":"10.1007/s10802-025-01407-w","pmid":"41652095","tags":["pregnancy","youth","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Prenatal tobacco-cannabis co-exposure (PTCE) was associated with externalizing problems through an emotion regulation pathway, while prenatal tobacco exposure (PTE) alone was associated through a combined maternal negative mood and temperament pathway. Both exposures led to heightened externalizing problems at school age, but through distinct developmental mechanisms.","whyItMatters":"This is the first study to show that tobacco alone versus tobacco-plus-cannabis exposure lead to behavioral problems through entirely different developmental pathways. This means prevention and intervention approaches may need to be tailored based on what a child was exposed to prenatally.","specificNumbers":"293 mother-child dyads (48% Black, 27% White, 14% Hispanic). PTE group: n=89. PTCE group: n=105. Controls: n=99. 64.8% WIC recipients. Externalizing problems assessed via maternal and teacher report at school age.","methodology":"Longitudinal study of 293 diverse mother-child dyads (89 tobacco-exposed, 105 tobacco-cannabis co-exposed, 99 unexposed controls) assessed from infancy through early school age using physiological, observational, and parent/teacher reports.","limitations":"Cannot fully separate the effects of cannabis from those of tobacco in the co-exposure group. Self-reported substance use may be inaccurate. The sample, while diverse, was drawn from a specific geographic area."},{"rthcId":"RTHC-08552","title":"Prenatal and early postnatal cannabis exposure interactions with adolescent chronic stress on anxiety-like, depression-like, and risk-taking behaviour.","authors":"Peterson, Colleen S; Ifionu, Ijeoma; Hamood, Fatima; Semizeh, Hadi; Ali, Ahmad; Noble, Duncan; Qiao, Min; Borgland, Stephanie L","year":2026,"journal":"Psychopharmacology, 243(2), 339-368","doi":"10.1007/s00213-025-06822-x","pmid":"40437120","tags":["pregnancy","youth","cognition"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Prenatal cannabis exposure alone did not significantly affect anxiety, stress coping, or social behavior. However, when combined with chronic adolescent stress, mice showed significantly increased risk-taking behavior on the wire beam bridge task. Sex differences in prefrontal cortex c-Fos expression suggested different neural responses to the combined exposure.","whyItMatters":"Many children prenatally exposed to cannabis also grow up in stressful environments. This study shows these two factors may interact to produce behavioral effects that neither causes alone, specifically increased risk-taking.","specificNumbers":"THC dose: 5 mg/kg daily from GD1-PD10. Adolescent stress: PD28-56. Behavioral testing: PD58+. Co-exposed mice had significantly increased bridge crossing (risk-taking). Sex differences found in prefrontal cortex c-Fos expression.","methodology":"Mouse dams consumed 5 mg/kg THC in whole cannabis oil daily from gestational day 1 through postnatal day 10. Offspring underwent chronic mild unpredictable stress throughout adolescence (PD28-56) and were tested on a battery of behavioral tasks starting at PD58.","limitations":"Animal study using oral whole cannabis oil, which differs from typical human consumption. Mouse behavior may not translate to human risk-taking. The stress paradigm (chronic mild unpredictable stress) is standardized but artificial."},{"rthcId":"RTHC-08553","title":"Effects of acute alcohol administration on endocannabinoids and relation to subjective effects.","authors":"Petrie, Gavin N; Mazurka, Raegan; Paul, Elisabeth R; Stensson, Niclas; Ghafouri, Bijar; Hill, Matthew N; Heilig, Markus; Mayo, Leah M","year":2026,"journal":"Psychopharmacology, 243(2), 401-411","doi":"10.1007/s00213-025-06843-6","pmid":"40711572","tags":["neuroscience","dopamine"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"Acute alcohol consumption decreased 2-AG concentrations compared to placebo. A drop in 2-AG was associated with less drug \"liking\" and fewer feelings of \"friendliness.\" Under placebo conditions, rising 2-AG was associated with maintained feelings of \"stimulation.\" Alcohol did not significantly affect anandamide levels.","whyItMatters":"This is the first evidence that endocannabinoids may explain individual differences in how people experience alcohol's rewarding effects. People whose 2-AG drops more after drinking may find alcohol less pleasurable, potentially influencing their drinking patterns.","specificNumbers":"28 participants, aged 20-35. Alcohol dose: 0.6 g/kg (20% reduction for women). 2-AG decreased with alcohol vs placebo. Lower 2-AG correlated with less \"liking\" and \"friendliness.\" Anandamide was not significantly affected.","methodology":"Within-subjects, single-blind, placebo-controlled alcohol challenge study with 28 healthy social drinkers aged 20-35. Alcohol (0.6 g/kg) and placebo sessions were counterbalanced. Endocannabinoids were measured from blood plasma; subjective effects via BAES, DEQ, and POMS.","limitations":"Small sample (28 participants). Single acute alcohol dose does not capture chronic drinking effects. Peripheral blood endocannabinoid levels may not perfectly reflect brain levels. Social drinkers only, not people with alcohol use disorder."},{"rthcId":"RTHC-08554","title":"Design, synthesis, and biological profiling of fluorinated cannabidiol and cannabigerol derivatives as promising therapeutic agents.","authors":"Petróczi, Ferenc Dániel; Tótik, Angéla; Bege, Miklós; Király, József; Szabó, Erzsébet; Szabó, Zsuzsanna; Dobos, Nikoletta; Kattoub, Rasha Ghanem; Upadhyay, Charu; Ostorházi, Eszter; Hodek, Jan; Weber, Jan; Arany, József; Ádám, Dorottya; Zouboulis, Christos C; Oláh, Attila; Bajza, István; Tósaki, Árpád; Halmos, Gábor; Rathi, Brijesh; Herczegh, Pál; Borbás, Anikó; Bereczki, Ilona","year":2026,"journal":"Journal of cannabis research","doi":"10.1186/s42238-026-00403-1","pmid":"41645347","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08555","title":"An Electrochemical Gas Sensor for Δ9-Tetrahydrocannabinol in Cannabis Smoke: A Novel Approach for Air Quality Monitoring in Legal Cannabis Consumption Areas.","authors":"Pholsiri, Tavechai; Puttasakul, Tasawan; Sukjee, Wannisa; Sangma, Chak; Vimolmangkang, Sornkanok; Chailapakul, Orawon; Srisa-Art, Monpichar","year":2026,"journal":"Analytical chemistry","doi":"10.1021/acs.analchem.5c06148","pmid":"41740156","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08556","title":"Exploring Linalool-Based Phytotherapy for Excitatory/Inhibitory Imbalance in Alzheimer's Disease: A Review of Lavender and Cannabis Therapeutic Effects on Sleep, Seizures, and Cognition.","authors":"Piccialli, Ilaria; Roviello, Giovanni; Magliocca, Giorgia; Esposito, Emilia; Pannaccione, Anna","year":2026,"journal":"Phytotherapy research : PTR","doi":"10.1002/ptr.70191","pmid":"41735175","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08557","title":"Detection of Δ8-Tetrahydrocannabinol and Δ9-Tetrahydrocannabinol Urinary Metabolites in Human Performance Urine Specimens in Broward and Miami-Dade Counties, Florida.","authors":"Pilacik, Faith; Kahl, Kristin Wegner; Reidy, Lisa Jayne","year":2026,"journal":"Therapeutic drug monitoring","doi":"10.1097/FTD.0000000000001399","pmid":"41604141","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08558","title":"Gray Matter Volume Loss in Parkinson's Disease Psychosis and Cannabinoid Receptor Gene Expression in the Brain.","authors":"Pisani, Sara; Váša, František; Velayudhan, Latha; Bhattacharyya, Sagnik","year":2026,"journal":"Movement disorders : official journal of the Movement Disorder Society","doi":"10.1002/mds.70222","pmid":"41717686","tags":["neuroscience","psychosis"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"There was a significant association between gray matter volume loss in Parkinson's disease psychosis and CB1 receptor gene expression across brain regions (r = 0.337, p < 0.001). No significant association was found with CB2 receptor expression. This suggests brain regions with higher CB1 expression are more vulnerable to volume loss in PDP.","whyItMatters":"Current PDP treatments focus on serotonin and dopamine pathways. Finding that brain atrophy patterns align with CB1 receptor distribution suggests the endocannabinoid system plays an underappreciated role in Parkinson's psychosis, potentially opening new treatment avenues.","specificNumbers":"CB1 correlation with volume loss: r = 0.337, t(76) = 3.122, p < 0.001. CB2 correlation: not significant (p = 0.132). Analysis covered cortical and subcortical regions.","methodology":"Meta-analytic effect sizes of gray matter volume loss in PDP vs PD without psychosis were correlated with CB1 and CB2 gene expression data from 6 healthy brains in the Allen Human Brain Atlas, correcting for spatial autocorrelation.","limitations":"Correlational study that cannot prove CB1 involvement causes volume loss or psychosis. Gene expression data came from only 6 healthy brains, not from PDP patients. Regional correlations do not prove cell-level mechanisms."},{"rthcId":"RTHC-08559","title":"Neurotoxic potential of synthetic cannabinoids' pyrolysis products.","authors":"Pita, Filipa; Dinis-Oliveira, Ricardo Jorge; Silva, João Pedro; de Pinho, Paula Guedes; Carvalho, Félix","year":2026,"journal":"Toxicology, 521, 154374","doi":"10.1016/j.tox.2025.154374","pmid":"41421516","tags":["synthetic-cannabinoids","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"Synthetic cannabinoids undergo structural changes when heated during smoking, generating novel, frequently unidentified toxicants. These pyrolysis products cause neurotoxicity through oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. A systematic review found only 9 studies on SC pyrolysis product neurotoxicity, revealing a massive research gap.","whyItMatters":"Most synthetic cannabinoid research tests the parent compounds, not what users actually inhale. When smoked, these chemicals break down into entirely different molecules that may be more toxic than the original substance. Users are exposed to compounds that have never been characterized.","specificNumbers":"Only 9 studies specifically investigated SC pyrolysis product neurotoxicity. Mechanisms identified: oxidative stress, mitochondrial dysfunction, excitotoxicity, neuroinflammation. Plant materials in SC formulations contribute additional harmful byproducts.","methodology":"PRISMA-guided systematic review identifying studies on neurotoxic effects of synthetic cannabinoid pyrolysis products, alongside broader literature on parent compound neurotoxicity.","limitations":"Very limited primary research available (only 9 studies). The review highlights a gap more than it fills it. Polydrug use makes it difficult to attribute effects to specific pyrolysis products in real-world cases."},{"rthcId":"RTHC-08560","title":"A qualitative study on cannabis use for harm reduction and pain among veterans enrolled in an SUD treatment program.","authors":"Pleasant, Traben; Ono, Sarah; Kansagara, Devan; Lovejoy, Jennette; Lovejoy, Travis; Wyse, Jessica","year":2026,"journal":"Harm reduction journal","doi":"10.1186/s12954-026-01412-2","pmid":"41715102","tags":["pain","harm-reduction","anxiety","sleep","addiction","medical-cannabis"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Through interviews with 33 veterans receiving care in a VA substance use disorder treatment program, researchers documented how veterans with chronic pain viewed and used cannabis alongside their addiction treatment.\n\nMost participants had a primary diagnosis of alcohol use disorder (70%), followed by opioid use disorder (18%) and stimulant use disorder (12%). The treatment program allowed continued use of substances other than the primary focus of treatment as a harm reduction strategy — meaning cannabis use was permitted while patients worked on quitting alcohol, opioids, or stimulants.\n\nVeterans described using cannabis to manage three interconnected problems: chronic pain itself, pain-related anxiety, and pain-disrupted sleep. Many framed cannabis as a harm reduction tool — a less dangerous substitute for the opioids, alcohol, or other substances they were trying to stop using. This framing positioned cannabis not as recreational drug use but as self-directed pain management.\n\nThe interviews revealed the complexity of cannabis's role in this population: it was simultaneously a potential therapeutic tool for pain and a substance with its own use disorder potential, used within a treatment program that pragmatically accepted this tension.","whyItMatters":"Veterans have disproportionately high rates of both chronic pain and substance use disorders, and the intersection of these conditions drives much of the opioid crisis among this population. Understanding how veterans conceptualize cannabis within their pain management and recovery adds patient perspectives to the clinical and pharmacological evidence — a dimension often missing from the research.","specificNumbers":"33 veterans interviewed. Primary SUD diagnoses: alcohol (70%), opioid (18%), stimulant (12%). All had comorbid chronic pain. Cannabis used for pain, anxiety, and sleep in the context of harm reduction-oriented addiction treatment.","methodology":"Qualitative study using interviews with 33 US military veterans diagnosed with chronic pain who were enrolled in a VA substance use disorder treatment program. Thematic analysis of interview transcripts exploring perspectives on cannabis use for pain management during addiction treatment.","limitations":"Small qualitative sample from a single VA program with an unusually permissive harm reduction approach. Veterans' perspectives on cannabis may differ from civilian populations. Self-reported cannabis use for pain cannot verify therapeutic effect. The harm reduction treatment model is not standard across VA or civilian SUD programs."},{"rthcId":"RTHC-08561","title":"Rates and predictors of postdischarge opioid-free analgesia after elective colorectal surgery: A prospective cohort study.","authors":"Pook, Makena; Olleik, Ghadeer; Lapointe-Gagner, Maxime; Jain, Shrieda; Fermi, Francesca; Shirzadi, Samin; Nguyen-Powanda, Philip; Al Ben Ali, Sarah; Ghezeljeh, Tahereh Najafi; Alali, Naser; Dmowski, Katy; Kaneva, Pepa; Feldman, Liane S; Boutros, Marylise; Lee, Lawrence; Fiore, Julio F","year":2026,"journal":"Surgery, 192, 110044","doi":"10.1016/j.surg.2025.110044","pmid":"41518896","tags":["pain","drug-interactions"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 344 colorectal surgery patients, 51% used no opioids after discharge. Cannabis use was one of the strongest predictors of NOT achieving opioid-free recovery (OR = 0.09, posterior effect probability = 96%). Other predictors of opioid-free recovery included older age and fewer prescribed opioid pills.","whyItMatters":"Finding that half of patients can go opioid-free after major abdominal surgery is encouraging for reducing opioid prescribing. However, the strong association between cannabis use and opioid consumption raises important questions about whether cannabis users have different pain experiences or pain management needs.","specificNumbers":"344 participants. 51% used no opioids after discharge. Cannabis use OR for opioid-free: 0.09 (96% probability). 92% received opioid prescriptions at discharge. 92% received acetaminophen. Median hospital stay: 3 days.","methodology":"Prospective cohort of 344 adults undergoing elective colorectal surgery at 2 academic hospitals. Self-reported analgesic consumption was assessed weekly for 1 month after discharge. Bayesian model averaging identified predictors.","limitations":"Observational design cannot determine causation. Self-reported cannabis use and analgesic consumption. Cannabis use was a relatively small subgroup. The association may reflect underlying differences in pain tolerance or reporting rather than a direct cannabis effect."},{"rthcId":"RTHC-08562","title":"Longer chronic cannabis use in humans is associated with impaired implicit motor learning and supranormal resting state cortical activity.","authors":"Prashad, Shikha; Paek, Andrew Y; Fournier, Lisa R","year":2026,"journal":"PloS one, 21(1), e0338082","doi":"10.1371/journal.pone.0338082","pmid":"41499355","tags":["cognition","addiction","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Comparing 30 regular cannabis users to 32 non-users, researchers found that longer duration of cannabis use was associated with a smaller implicit motor learning index — meaning these individuals were less able to unconsciously learn movement sequences.\n\nImplicit motor learning was measured using the serial reaction time task, where participants respond to visual cues that follow a hidden repeating pattern. People typically speed up on the patterned sequences without consciously realizing there is a pattern. Cannabis users with longer use histories showed less of this automatic speed improvement.\n\nResting-state EEG revealed a potential neural mechanism: longer cannabis use was associated with increased activity in beta and gamma frequency bands during rest. This elevated baseline cortical activity — described as \"supranormal\" — may interfere with the neural processes required for implicit learning.\n\nThe cannabis group also showed significantly shorter Corsi block spans in both forward and backward conditions, indicating impaired visuospatial short-term and working memory.","whyItMatters":"Implicit motor learning is fundamental to daily life — it underlies the ability to learn movement sequences for everything from typing to driving to social interaction. This is the first study to link chronic cannabis use to impairment in this specific type of learning, and the EEG data offer a potential brain-level explanation for why it happens.","specificNumbers":"30 cannabis users, 32 non-users. Longer cannabis use → smaller implicit motor learning index. Cannabis users: shorter Corsi span (forward and backward). EEG: increased beta and gamma resting activity associated with longer use duration.","methodology":"Observational study comparing 30 regular cannabis users and 32 non-users. Measures: serial reaction time task (implicit motor learning), Corsi block-tapping test (visuospatial memory), and resting-state EEG (cortical activity in beta and gamma bands). Duration of cannabis use correlated with learning and EEG outcomes.","limitations":"Cross-sectional design cannot establish that cannabis caused the learning impairment — it may reflect pre-existing differences. Small sample size limits statistical power. Cannot control for all confounders (other substance use, sleep quality, education). Cannabis use was self-reported and varied in frequency and potency."},{"rthcId":"RTHC-08563","title":"Survey of MaineHealth Cancer Care Network Providers on Cannabis Use: Preparation for Studies Sponsored by the National Cancer Institute.","authors":"Prescott, Jill M; Saunders, Jamie G; Bradford, Leslie S; Remick, Scot C","year":2026,"journal":"Journal of Maine Medical Center, 8(1)","doi":"10.46804/2641-2225.1245","pmid":"41640792","tags":["medical-cannabis","cancer"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"A survey of cancer care network providers found 89% agree cannabis can manage cancer symptoms, 54% are sensitive to stigma around cannabis use (57% of their patients feel similarly), only 15% consider themselves knowledgeable, only 30% routinely ask about cannabis use, and 85% want to learn more.","whyItMatters":"There is a massive gap between provider belief in cannabis efficacy and their confidence discussing it with patients. This means patients using cannabis during cancer treatment may not be getting guidance from their care teams, creating potential safety risks.","specificNumbers":"58% response rate (100/171 providers). 89% agree cannabis can manage symptoms. 30% ask about use. 15% consider themselves knowledgeable. 85% want to learn more. 54% sensitive to stigma.","methodology":"Landscape survey of front-line providers in the MaineHealth Cancer Care Network, achieving a 58% response rate (100/171).","limitations":"Single cancer care network in Maine with modest sample size. Self-reported knowledge and attitudes may not reflect actual clinical practice. The 42% non-response rate could introduce bias."},{"rthcId":"RTHC-08564","title":"Formulation and in vitro evaluation of liposomal and self-microemulsifying drug delivery systems for oral delivery of cannabidiol.","authors":"Protopapa, Chrystalla; Tsichlis, Ioannis; Kolipaka, Siva Satyanarayana; Douroumis, Dennis; Demetzos, Costas; Vlachou, Marilena","year":2026,"journal":"Journal of pharmaceutical sciences, 115(1), 104053","doi":"10.1016/j.xphs.2025.104053","pmid":"41183677","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08565","title":"Therapeutic use of cannabinoids in age-related pain: Current evidence and clinical perspectives.","authors":"Pulone, Sabina; Moulton, Chantalle; Nucera, Saverio; Ilari, Sara; Muscoli, Carolina; Tasciotti, Ennio","year":2026,"journal":"Pharmacological research, 225, 108130","doi":"10.1016/j.phrs.2026.108130","pmid":"41651319","tags":["pain","inflammation","seniors","medical-cannabis","cbd"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"This review explored the intersection of aging, chronic pain, and the endocannabinoid system (ECS), building a case for why cannabinoids might be particularly relevant for older adults.\n\nThe key biological insight is that aging involves a process called \"inflammaging\" — chronic low-grade inflammation driven by immune system changes (immunosenescence). This persistent inflammation disrupts the normal pain resolution process, contributing to the chronic pain conditions common in older adults: osteoarthritis, neuropathies, and musculoskeletal degeneration.\n\nThe endocannabinoid system plays a role in modulating both inflammation and pain perception. The review synthesized evidence that ECS function changes with age — receptor density, endocannabinoid levels, and enzyme activity all shift — potentially contributing to the dysregulated inflammatory and pain responses seen in older adults.\n\nPhytocannabinoids (THC and CBD) interact with this system and have demonstrated anti-inflammatory and analgesic properties in preclinical models. However, the review acknowledged that clinical evidence specifically in elderly populations is limited, and the pharmacokinetic changes of aging (altered metabolism, body composition, drug sensitivity) add complexity to cannabinoid dosing in this group.","whyItMatters":"Older adults bear the highest burden of chronic pain and are also the demographic where cannabis use is growing fastest. Yet most cannabinoid pain research has been conducted in younger populations. This review provides the biological rationale for why cannabinoids might work differently — potentially better or worse — in aging bodies, and highlights the gap between the theoretical promise and the clinical evidence.","specificNumbers":"Common age-related pain conditions reviewed: osteoarthritis, neuropathies, musculoskeletal degeneration. ECS changes with aging: altered receptor density, endocannabinoid levels, and enzyme activity. Inflammaging characterized by sustained pro-inflammatory mediator production and impaired resolution mechanisms.","methodology":"Narrative review examining the endocannabinoid system's role in pain and inflammation during aging. Synthesized preclinical and clinical evidence on age-related ECS changes, inflammaging mechanisms, and therapeutic potential of phytocannabinoids (THC, CBD) for age-related chronic pain.","limitations":"Narrative review drawing primarily on preclinical evidence. Limited clinical trial data on cannabinoids specifically in elderly populations. The inflammaging framework, while well-established, doesn't fully explain all chronic pain in older adults. Individual variation in aging makes generalization difficult."},{"rthcId":"RTHC-08566","title":"Unveiling Neurological Benefits: A Review of Hemp Leaf, Flower, Seed Oil Extract, and Their Phytochemical Properties in Neurological Disorders.","authors":"Purushothaman, Atchuthan; Krishnan, Anju","year":2026,"journal":"Cannabis and cannabinoid research, 11(1), 11-29","doi":"10.1177/25785125251410822","pmid":"41468178","tags":["cbd","epilepsy","neuroscience","pain","inflammation","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"This review synthesized evidence on how different parts of the hemp plant — seeds, leaves, and flowers — contain distinct bioactive compound profiles with relevance to neurological disorders.\n\nFlowers are richest in cannabinoids (particularly CBD) and terpenes, which interact with the endocannabinoid system, neurotransmitter receptors, and inflammatory pathways. Seeds contain polyunsaturated fatty acids, phenolics, and flavonoids with antioxidant properties. Leaves provide an intermediate profile.\n\nThe review examined evidence across four major neurological conditions. For epilepsy, CBD has the strongest clinical evidence, with FDA-approved use for certain seizure disorders. For Alzheimer's disease, preclinical studies suggest cannabinoids may reduce amyloid plaque accumulation and neuroinflammation. For Parkinson's disease, early evidence points to potential neuroprotective effects through antioxidant and anti-inflammatory mechanisms. For multiple sclerosis, nabiximols (Sativex) is already approved in some countries for spasticity.\n\nThe review emphasized that hemp's therapeutic potential extends beyond individual cannabinoids to include the broader phytochemical profile — terpenes, flavonoids, and fatty acids may contribute to efficacy through what's sometimes called the \"entourage effect.\"","whyItMatters":"Neurological disorders represent some of the greatest unmet needs in medicine. This review maps the evidence for hemp-derived compounds across the major neurodegenerative conditions, providing a reference for which compound types and plant sources have the most evidence for which conditions.","specificNumbers":"Four neurological conditions reviewed: epilepsy, Alzheimer's, Parkinson's, multiple sclerosis. Key compound classes: cannabinoids (especially CBD), terpenes, flavonoids, polyunsaturated fatty acids. CBD: FDA-approved for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis seizures.","methodology":"Comprehensive narrative review of preclinical and clinical studies on hemp-derived compounds for neurological disorders. Analyzed phytochemical profiles of different plant parts (seeds, leaves, flowers) and their mechanisms of action through endocannabinoid, neurotransmitter, inflammatory, and oxidative stress pathways.","limitations":"Narrative review that may selectively emphasize positive findings. Most evidence for Alzheimer's, Parkinson's, and MS comes from preclinical models with uncertain translation to humans. The 'entourage effect' concept remains controversial and poorly quantified. Hemp compound profiles vary widely by cultivar, growing conditions, and extraction methods."},{"rthcId":"RTHC-08567","title":"Perioperative cannabis use on postoperative pain in immediate alloplastic breast reconstruction.","authors":"Qin, Nancy; Wei, Lucy; Gundlach, Carson; Webster, Theresa K; Chinta, Malini; McVeigh, Annie B; Cohen, Leslie E; Otterburn, David M","year":2026,"journal":"Journal of plastic, reconstructive & aesthetic surgery : JPRAS, 113, 250-256","doi":"10.1016/j.bjps.2025.11.013","pmid":"41317542","tags":["pain","drug-interactions"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Cannabis users reported significantly higher pain scores at 0-12 hours (4.42 vs 3.68, p=0.018) and 12-24 hours (4.53 vs 3.36, p=0.004) post-surgery. Cumulative opioid use was higher (67.40 vs 44.38 MME, p=0.010), and more cannabis users requested prescription refills (42.5% vs 22.8%, p=0.017). However, on multivariable regression, cannabis use was not an independent predictor.","whyItMatters":"This adds to growing evidence that cannabis users experience more postoperative pain and require more opioids. The fact that cannabis was not an independent predictor after adjustment suggests it may be a marker for other factors that increase analgesic needs.","specificNumbers":"40 cannabis users vs 197 non-users. Pain scores: 4.46 vs 3.53 overall (p=0.002). Opioid use: 67.40 vs 44.38 MME cumulative (p=0.010). Refill requests: 42.5% vs 22.8% (p=0.017). Adjusted OR for refills: 2.56 (95% CI 0.92-7.34, p=0.073).","methodology":"Retrospective review of consecutive patients undergoing mastectomy with bilateral tissue expander reconstruction from 2021-2025. Compared 40 cannabis users to 197 non-users on pain scores, opioid consumption, and refill rates.","limitations":"Retrospective design. Small cannabis user group (40 patients). Self-reported cannabis use. Cannabis was not an independent predictor after adjustment, suggesting confounding. Single-center study."},{"rthcId":"RTHC-08568","title":"Developmental Trajectories of Positive Expectancies of Cannabis Use Effects Among Early Adolescents: Longitudinal Observational Study Using Latent Class Growth Analysis.","authors":"Qin, Weisiyu Abraham; Seo, Dong-Chul; Jacobs, Wura; Huang, Sijia; Elam, Kit K","year":2026,"journal":"JMIR public health and surveillance, 12, e85652","doi":"10.2196/85652","pmid":"41512198","tags":["youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using three waves of longitudinal data from the ABCD Study, researchers identified distinct developmental trajectories in how early adolescents (ages 10–13) formed positive expectations about cannabis — beliefs about anticipated benefits of use that are known predictors of actual cannabis initiation.\n\nLatent class growth analysis revealed that not all adolescents follow the same path. Some maintained consistently low positive expectations over time, while others showed escalating trajectories where beliefs about cannabis benefits increased as they moved through early adolescence.\n\nThe key predictors of trajectory membership were familial factors that changed over time. Parental monitoring — how well parents tracked their children's activities and whereabouts — was associated with lower positive expectancy trajectories. Conversely, family conflict and peer substance use were associated with escalating expectancies.\n\nBaseline sociodemographic factors and state-level policy variables were also examined as predictors of which trajectory a child would follow, providing a multi-level picture of what shapes cannabis attitudes before use begins.","whyItMatters":"Positive expectations about cannabis are one of the strongest cognitive predictors of whether an adolescent will start using. Understanding how these beliefs develop — and what family and social factors shape their trajectory — provides actionable targets for prevention before cannabis use begins.","specificNumbers":"Three waves of longitudinal data, ages 10–13. Multiple trajectory classes identified via latent class growth analysis. Key time-varying predictors: parental monitoring (protective), family conflict (risk), peer substance use (risk). Baseline predictors: sociodemographic and state-level policy factors.","methodology":"Longitudinal study using latent class growth analysis with three waves of ABCD Study data (ages 10–13). Identified distinct developmental trajectories of positive cannabis use expectancies. Multinomial logistic regression tested baseline predictors of class membership. Time-varying familial factors (parental monitoring, family conflict, peer substance use) examined as trajectory modifiers.","limitations":"ABCD Study participants may not represent all early adolescents. Positive expectancies are a proxy for future use, not actual use outcomes. Three measurement waves may not capture all trajectory variation. Self-reported parental monitoring and family conflict may not reflect actual dynamics. Unmeasured confounders (e.g., mental health, trauma) could influence both family factors and expectancies."},{"rthcId":"RTHC-08569","title":"Cannabis use among sexual minority adults: insights from recent U.S. nationally representative data.","authors":"Qin, Weisiyu Abraham; Elam, Kit K; Lederer, Alyssa M; Seo, Dong-Chul","year":2026,"journal":"Addictive behaviors, 172, 108495","doi":"10.1016/j.addbeh.2025.108495","pmid":"40966825","tags":["sex-differences","legalization"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Among women, bisexual identity was linked to the highest odds of cannabis vaping (aOR=2.57) and non-vaping use (aOR=2.57). Women with same-sex or both-sex attraction had higher odds of both use modes. Heterosexual-discordant women (heterosexual identity but non-heterosexual attraction) were also at increased risk. Among men, disparities were more consistently linked to non-vaping cannabis use.","whyItMatters":"This is the first study to examine cannabis use across multiple dimensions of sexual orientation (identity, attraction, concordance/discordance) and by delivery method. Understanding these nuanced patterns is essential for reducing substance use disparities in sexual minority populations.","specificNumbers":"N=40,030. Bisexual women: aOR=2.57 for both vaping and non-vaping cannabis. Same-sex attracted women had elevated odds of both modes. Men showed disparities primarily in non-vaping use. Analysis adjusted for demographic variables and other substance use.","methodology":"Analysis of 2022 NSDUH nationally representative data (N=40,030) using weighted multivariable logistic regression examining associations between sexual orientation dimensions and past-30-day cannabis vaping and non-vaping use.","limitations":"Cross-sectional data cannot establish causation. Self-reported sexual orientation and cannabis use. The 2022 NSDUH may not capture all dimensions of sexual orientation. Cannabis vaping and non-vaping categories may overlap in some individuals."},{"rthcId":"RTHC-08570","title":"Health Care Utilization and Developmental Delay Among Infants Exposed to Cannabis In Utero.","authors":"Raffa, Brittany J; Lanier, Paul; Yang, Yumei; Lin, Feng-Chang; Seashore, Carl; Schilling, Samantha","year":2026,"journal":"Academic pediatrics, 26(3), 103224","doi":"10.1016/j.acap.2026.103224","pmid":"41554497","tags":["pregnancy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 4,270 Medicaid-insured infants with meconium drug screening, cannabis-exposed infants (n=1,671) had similar rates of well-child care attendance, emergency department visits, and developmental delay diagnoses at 3 years compared to unexposed infants (n=2,599). At 2 years, cannabis-exposed infants actually had lower odds of developmental delay, though this difference disappeared by year 3.","whyItMatters":"This is one of the largest studies using objective exposure measurement (meconium testing) rather than self-report. The null findings at 3 years are reassuring but do not rule out longer-term effects that may emerge later in childhood.","specificNumbers":"7,240 infants screened, 5,448 linked to Medicaid (75%). 1,671 cannabis-exposed, 2,599 unexposed. No difference in well-child visits or ED encounters at 2 years. No difference in developmental delay at 3 years.","methodology":"Retrospective cohort linking meconium drug screen results from a university hospital (2014-2022) with North Carolina Medicaid claims. Cannabis-exposed infants (positive for cannabis only) were compared to substance-unexposed infants using regression models.","limitations":"Only Medicaid-insured infants, who may differ from privately insured populations. Meconium screening only detects third-trimester exposure and cannot quantify amount used. Developmental delay diagnosed via claims codes may miss subtle delays. Follow-up limited to 3 years."},{"rthcId":"RTHC-08571","title":"Understanding the acceptance of medical marijuana among Malaysian adults: a cross-sectional online survey.","authors":"Rahman, Abu Bakar; Naserrudin, Nurul Athirah; Seman, Zamtira; Zin, Zaikiah Mohd; Dapari, Rahmat; Hassan, Mohd Rohaizat; Rashid, Azman Ab; Dahaban, Mariatul Umeera Muhd; Jahaya, Nadia Hani; Balamurugan, Hema; Krishnan, Manimaran","year":2026,"journal":"BMJ open, 16(1), e104802","doi":"10.1136/bmjopen-2025-104802","pmid":"41592835","tags":["legalization","medical-cannabis"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among 2,047 respondents, 88.4% supported medical marijuana decriminalization. Key predictors included male gender (OR 1.71), higher education (Master's/PhD OR 2.04), self-employment (OR 1.84), and low perceived risk (OR 5.82). Prior drug use (OR 1.86) and smoking (OR 1.58) were also significant predictors.","whyItMatters":"Malaysia maintains some of the strictest drug laws globally, including mandatory death penalty provisions. Finding that nearly 9 in 10 respondents support evidence-based medical cannabis suggests a significant gap between public opinion and current policy.","specificNumbers":"2,047 respondents. 88.4% supported medical cannabis. Low perceived risk: OR 5.82. Master's/PhD: OR 2.04. Prior drug use: OR 1.86. Self-employment: OR 1.84. Male gender: OR 1.71. Smoking: OR 1.58.","methodology":"Cross-sectional web-based survey of Malaysian adults aged 18+ using convenience and snowball sampling. Multivariable logistic regression identified predictors of acceptance.","limitations":"Online convenience and snowball sampling likely overrepresents educated, internet-connected, and younger Malaysians. The 88.4% support rate may be higher than the general population. Social desirability bias could affect responses on drug-related topics in a strict legal environment."},{"rthcId":"RTHC-08572","title":"Cannabivarin and tetrahydrocannabivarin modulate nociception via vanilloid channels and cannabinoid-like receptors in Caenorhabditis elegans.","authors":"Rahmani, Nasim; Castaño, Jesus D; Beaudry, Francis","year":2026,"journal":"Canadian journal of physiology and pharmacology, 104, 1-13","doi":"10.1139/cjpp-2025-0243","pmid":"41135090","tags":["pain","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Both CBV and THCV produced dose-dependent antinociceptive effects in C. elegans thermotaxis assays. Experiments with mutant worm strains showed the pain-relieving effects were mediated through vanilloid receptor homologs (OCR-2, OSM-9) and cannabinoid receptor homologs (NPR-19, NPR-32). Proteomics identified the biological pathways involved.","whyItMatters":"CBV and THCV are non-psychoactive cannabinoids that have received far less research attention than CBD and THC. Demonstrating their analgesic mechanisms through conserved receptor pathways supports further investigation in mammalian pain models.","specificNumbers":"Both compounds showed dose-dependent pain relief. Effects mediated through OCR-2 and OSM-9 (vanilloid homologs) and NPR-19 and NPR-32 (cannabinoid homologs). Proteomics identified associated biological pathways.","methodology":"Thermotaxis assays in wild-type and mutant C. elegans strains (deficient in vanilloid and cannabinoid receptor homologs) to establish dose-response relationships and identify molecular targets. Mass spectrometry proteomics combined with network biology analysis.","limitations":"C. elegans is a nematode worm, and while receptor homologs are conserved, translating findings to mammalian or human pain is highly uncertain. The study establishes mechanism but cannot predict therapeutic efficacy in humans."},{"rthcId":"RTHC-08573","title":"University belonging and college cannabis use at a northeast university: The role of depression and anxiety symptoms.","authors":"Rathod, K; Wagner, A; Broadaway, T; Tesi, A; Goodhines, P A","year":2026,"journal":"Journal of American college health : J of ACH, 1-10","doi":"10.1080/07448481.2026.2626144","pmid":"41700963","tags":["mental-health","youth"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"About 50% of college students reported past-month cannabis use. Lack of university belonging was associated with higher depression/anxiety symptoms, which in turn were associated with more frequent cannabis use. University belonging had no direct effect on cannabis use after accounting for mental health symptoms.","whyItMatters":"This suggests that campus cannabis use may be better addressed through mental health support and building social connections than through drug-focused interventions alone. Improving students' sense of belonging could reduce both mental health symptoms and associated cannabis use.","specificNumbers":"327 students surveyed. ~50% reported past-month cannabis use. Mean age 19.03. University belonging predicted depression/anxiety, which predicted cannabis frequency. Direct path from belonging to cannabis was not significant.","methodology":"Cross-sectional online survey of 327 college students (mean age 19, 53% female, 84% White) at a rural northeastern university.","limitations":"Cross-sectional design cannot establish causation. Predominantly White sample from a single rural university limits generalizability. Self-report measures may be biased. The mediation model cannot rule out reverse causation."},{"rthcId":"RTHC-08574","title":"Effects of acute THC challenge on behavior and neuroinflammation in HIV-1 Tg26 mice vary based on HIV status, chronic THC history, and sex.","authors":"Ravula, Havilah P; Yadav-Samudrala, Barkha J; Sawaqed, Laith E; Arciniega, Cristina; Hu, Wenhui; Jiang, Wei; Fitting, Sylvia","year":2026,"journal":"Brain, behavior, and immunity, 134, 106476","doi":"10.1016/j.bbi.2026.106476","pmid":"41654202","tags":["tolerance","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Chronic THC history (90 days) led to tolerance across behavioral measures, reducing THC-induced hypothermia, pain relief, and sedation, especially in females. An acute THC challenge increased anxiety-like behavior specifically in females with chronic THC history. HIV-transgenic mice showed genotype-dependent effects, with high microglial-CCL3 co-occurrence in sex-specific brain regions.","whyItMatters":"This study reveals important sex differences in THC tolerance development that have clinical implications for both recreational and medical cannabis users. The interaction with HIV status is particularly relevant given that cannabis is commonly used among people living with HIV.","specificNumbers":"63 mice total. Chronic THC: 3 mg/kg daily for 90 days. Acute challenge: 10 mg/kg after 7-day washout. Females showed greater tolerance across multiple behavioral measures. HIV genotype affected microglial inflammation in sex-specific brain regions.","methodology":"HIV-1 Tg26 transgenic and control mice received 3 mg/kg THC or vehicle for 90 days (5 days/week). After a 7-day washout, all received a 10 mg/kg acute THC challenge. Behavioral, neuroinflammatory, and THC metabolite measures were assessed.","limitations":"Mouse model, and the Tg26 HIV model does not perfectly replicate human HIV infection. The 90-day chronic exposure may not mirror typical human use patterns. Small sample sizes per group."},{"rthcId":"RTHC-08575","title":"Selective activation of cannabinoid receptors by cannabis terpenes.","authors":"Raz, Noa; Eyal, Aharon M; Fahoum-Khalefa, Nardine; Tauber, Merav; Ben-Chaim, Yair","year":2026,"journal":"Biochemical pharmacology, 243(Pt 1), 117498","doi":"10.1016/j.bcp.2025.117498","pmid":"41173057","tags":["neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Multiple cannabis terpenes produced dose-dependent activation of both CB1 and CB2 receptors, reaching 10-60% of THC's maximal activation. Terpenes showed lower efficacy but equivalent or even improved potency compared to THC. At CB2, multiple terpenes reached clinically relevant effect levels at concentrations equal to or lower than THC. Different terpenes showed selectivity between the two receptors.","whyItMatters":"This provides direct molecular evidence for the \"entourage effect\" hypothesis. Terpenes are not just aroma compounds; they are partial agonists at the same receptors THC targets. Their selectivity between CB1 and CB2 means different terpene profiles could produce different therapeutic effects.","specificNumbers":"16 cannabis terpenes tested. Activation: 10-60% of THC maximal response. EC50 values similar to or lower than THC. At CB2, multiple terpenes reach clinically relevant concentrations (0.1 micromolar or above).","methodology":"Xenopus oocyte functional expression system measuring GIRK currents as a readout for CB1 and CB2 receptor activation by 16 individual cannabis terpenes and terpene mixtures.","limitations":"In vitro expression system may not perfectly replicate receptor activation in the brain. Terpene concentrations achievable in the brain after cannabis consumption are uncertain. Functional significance of 10-60% activation relative to THC needs further investigation."},{"rthcId":"RTHC-08576","title":"Hemp versus marijuana: Chemistry- and pharmacology-associated regulatory framework.","authors":"Razouk, Layan; Hamdy, Rania; Ahmad, Abdalla; Razouk, Osama; Mohamed, Nashwa Ahmed; Soliman, Sameh Sm","year":2026,"journal":"Medicine, science, and the law, 258024261420541","doi":"10.1177/00258024261420541","pmid":"41662265","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08577","title":"Effects of chronic mild stress and CB1 receptor activation on hippocampal-dependent fear conditioning in female adolescent rats.","authors":"Reich, Christian G; Ferraro, Angelica; Wig, Philip; Amada, Nicole; Weiss, Michael S","year":2026,"journal":"bioRxiv : the preprint server for biology","doi":"10.64898/2026.02.13.705785","pmid":"41726897","tags":["ptsd","sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Chronic mild stress enhanced trace fear conditioning (episodic fear memories) in adolescent female rats. The CB1 agonist ACEA reduced fear during memory recall in both stressed and non-stressed females, but it either had no effect on or impaired both short-term and long-term fear extinction. For contextual fear, ACEA had opposite effects on extinction depending on stress history.","whyItMatters":"This has direct implications for using medical cannabis to treat PTSD in women. While CB1 activation reduced acute fear responses, it may actually impair the therapeutic process of fear extinction that underlies exposure-based PTSD treatments.","specificNumbers":"ACEA dose: 0.1 mg/kg. CMS enhanced trace fear conditioning vs controls. ACEA reduced baseline freezing during recall. ACEA impaired long-term contextual extinction in stressed females while facilitating it in non-stressed controls.","methodology":"Adolescent female Sprague-Dawley rats underwent chronic mild unpredictable stress, then were tested on hippocampal-dependent trace and contextual fear conditioning. CB1 agonist ACEA (0.1 mg/kg) was administered before memory recall or acquisition.","limitations":"Preprint (bioRxiv), not yet peer-reviewed. Only female rats were tested (no direct male comparison in this study, but references prior male data). The synthetic CB1 agonist ACEA may not perfectly mimic THC effects."},{"rthcId":"RTHC-08578","title":"Racial diversity in cannabis use disorder research: A systematic review.","authors":"Reid, Mallet R; Reynolds, Blake; Cape, Jacqueline; Ahmed, Zara; Ali, Hashim; Jaimes-Bautista, Edgar; Gott, Connor; Barajas, Arturo; Müller, Frank; Alshaarawy, Omayma","year":2026,"journal":"Drug and alcohol dependence, 278, 113008","doi":"10.1016/j.drugalcdep.2025.113008","pmid":"41456522","tags":["addiction","harm-reduction"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"Of 14 cannabis use disorder behavioral health RCTs (1994-2025), White people comprised 64% of participants despite having a smaller share of CUD cases, overrepresented at 49 times their proportional rate. Black participants were 19%, Latino 5%, Asian 0.6%, and Indigenous 0.4%. Zero studies were culturally adapted or designed to address challenges specific to people of color. Diversity has not improved over time.","whyItMatters":"People of color have higher CUD prevalence and severity, face unique challenges like racial discrimination, and experience more severe legal consequences of cannabis use. Yet the treatments being developed are overwhelmingly tested on White populations with no cultural adaptation.","specificNumbers":"966 studies screened, 14 met criteria. White: 64% of participants (49x overrepresentation). Black: 19%. Latino: 5%. Multiracial/other: 0.8%. Asian: 0.6%. Indigenous: 0.4%. Zero culturally adapted studies.","methodology":"Systematic review of PubMed, PsycINFO, and ClinicalTrials.gov for US-based adult cannabis use disorder behavioral health RCTs, identifying 14 of 966 studies for review.","limitations":"Only US-based behavioral health RCTs were included. The small number of eligible studies (14) reflects the limited CUD treatment research overall. Self-identified race categories may not capture nuanced identities."},{"rthcId":"RTHC-08579","title":"Biobio Sentinel: Two years of illicit drug surveillance in South-Central Chile.","authors":"Reis, Andressa S; Corthorn, Francisca; Osses, Eduardo Suazo; Urzúa-Bilbao, Sebastian; Hepp, Matias I; Galbán-Malagón, Cristóbal","year":2026,"journal":"Journal of hazardous materials, 503, 141142","doi":"10.1016/j.jhazmat.2026.141142","pmid":"41546897","tags":["legalization"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"The first multi-year wastewater-based epidemiology study in Chile found cannabis consumption declined by over 90% while cocaine use increased more than tenfold (+1,019%). Ketamine emerged as a new psychoactive substance. Cannabis showed inverse associations with cocaine and ketamine use. Urban areas were persistent consumption hotspots.","whyItMatters":"This objective population-level data reveals dramatic shifts in drug use patterns that self-report surveys might miss. The substitution pattern (cannabis down, cocaine up) has important implications for drug policy and public health resource allocation in Latin America.","specificNumbers":"3,198 samples from 33 treatment plants over 2 years. Cannabis: declined >90%. Cocaine: increased +1,019%. Strong positive correlation between cocaine and ketamine (rho = 0.83). Cannabis inversely correlated with both stimulants.","methodology":"Weekly collection of 3,198 24-hour composite influent samples from 33 wastewater treatment plants across Chile's Biobio Region from September 2022 to August 2024. Metabolites measured by SPE/LC-MS/MS.","limitations":"Single region of Chile may not represent the entire country. Wastewater data cannot identify individual users or demographics. The dramatic cannabis decline could partly reflect changes in product types or metabolite stability rather than purely reduced use."},{"rthcId":"RTHC-08580","title":"Cannabinoids and the autophagy-related signaling in brain Tumors: From mechanistic insights to therapeutic Frontiers in glioblastoma.","authors":"Rejili, Mokhtar; Farahani, Najma; Alimohammadi, Mina; Hushmandi, Kiavash","year":2026,"journal":"Biochemical pharmacology, 117781","doi":"10.1016/j.bcp.2026.117781","pmid":"41679657","tags":["cancer","medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Glioblastoma harbors alterations in the endocannabinoid system including changes in CB1 and CB2 receptor expression. Cannabinoid activation of these receptors suppresses proliferation and invasion while activating autophagy pathways. Preclinical studies show cannabinoids reduce GBM growth and enhance chemotherapy responsiveness. Early clinical studies indicate favorable safety profiles and potential survival benefits.","whyItMatters":"Glioblastoma has an average survival of only 14 months despite treatment. Cannabinoids represent a mechanistically distinct approach that targets cancer cells through autophagy, a pathway not exploited by current therapies.","specificNumbers":"Average GBM survival: ~14 months. Cannabinoids suppress proliferation and invasion via CB1R and CB2R. Autophagy induction occurs through ER stress, ceramide synthesis, and AMPK/mTOR pathways.","methodology":"Comprehensive review synthesizing molecular mechanisms of cannabinoid-induced autophagy and anticancer activity in glioblastoma, covering cell line, animal model, and early clinical data.","limitations":"Most evidence is preclinical. Clinical data is limited to early-phase studies. Cannabinoid doses used in preclinical studies may not be achievable in the human brain. Autophagy can paradoxically promote tumor survival under some conditions."},{"rthcId":"RTHC-08581","title":"A Uav-based multisensor framework for legal industrial Cannabis monitoring and open-access dataset development.","authors":"Rexha, Genta; Papadhopulli, Ina; Biberaj, Aleksandër; Agastra, Elson; Sheme, Enida; Meçe, Elinda","year":2026,"journal":"Data in brief, 65, 112463","doi":"10.1016/j.dib.2026.112463","pmid":"41624300","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08582","title":"Anxiety Sensitivity and Coping-Oriented Cannabis Use: The Moderating Role of Positive Cannabis Expectancies.","authors":"Reyes, Lauren D; Short, Nicole A","year":2026,"journal":"Substance use & misuse, 1-8","doi":"10.1080/10826084.2026.2616327","pmid":"41548081","tags":["anxiety","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"The interaction between anxiety sensitivity and positive cannabis expectancies was significant: the link between anxiety sensitivity and coping-oriented use was stronger when positive expectancies were high. This pattern held for cognitive and social concerns but not physical concerns specifically.","whyItMatters":"This explains why previous research on anxiety sensitivity and cannabis use has been inconsistent. Anxiety sensitivity alone does not drive coping use; it is the combination of fearing anxiety AND believing cannabis will help that creates risk for problematic use patterns.","specificNumbers":"232 undergraduates with past-six-month cannabis use. Significant interaction: anxiety sensitivity x positive expectancies on coping use. Effect stronger at high vs low expectancy levels. Cognitive and social (but not physical) AS concerns showed same pattern.","methodology":"Cross-sectional survey of 232 undergraduates reporting past-six-month cannabis use. Moderation analyses tested using PROCESS macro for SPSS.","limitations":"Cross-sectional design. Undergraduate sample may not generalize. Self-report measures. Only past-six-month cannabis users included, creating selection bias."},{"rthcId":"RTHC-08583","title":"Incidence of New-Onset Cardiac Arrhythmias in Cocaine and Cannabis Users: A Retrospective Cohort Study.","authors":"Rhabneh, Laith; Ababneh, Ra'ed; Qaddour, Shahd; Alwardat, Abdel Rahman; Aloqaily, Mohammed; Hazaimeh, Khalid; Awad, Ali","year":2026,"journal":"European heart journal. Acute cardiovascular care","doi":"10.1093/ehjacc/zuag011","pmid":"41638249","tags":["cardiovascular"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Using the TriNetX database, researchers compared cardiovascular outcomes between cocaine users and cannabis users after propensity score matching to reduce baseline differences. Each cohort included 248,769 patients.\n\nThe primary outcome — new-onset cardiac arrhythmia — was significantly higher in cocaine users compared to cannabis users. Secondary outcomes showed the same pattern: cocaine users had higher rates of cardiac arrest events, major adverse cardiovascular events (myocardial infarction and stroke), and all-cause mortality.\n\nThe study contextualized these findings within prevalence data: cannabis use disorder is considerably more prevalent than cocaine use disorder (14.7% vs. 2.2% for individuals aged 12 and older), meaning the total cardiovascular burden from each substance depends on both the per-user risk and the size of the user population.","whyItMatters":"While cocaine's cardiotoxicity is well-established, this study provides a direct, matched comparison with cannabis — useful because both substances are commonly used and both have cardiovascular effects. The finding that cannabis users had significantly lower rates of arrhythmias and other cardiac events than matched cocaine users provides relative risk context, though it doesn't establish that cannabis is safe for the heart.","specificNumbers":"248,769 patients per matched cohort. Cannabis use disorder prevalence: 14.7%. Cocaine use disorder prevalence: 2.2% (6.2% in ages 18–25). Cocaine users had higher rates of: new-onset arrhythmia, cardiac arrest, MI, stroke, and all-cause mortality compared to cannabis users.","methodology":"Retrospective cohort study using the TriNetX database. Created two cohorts: cocaine users and cannabis users. Propensity score matching yielded 248,769 patients per group. Primary outcome: new-onset cardiac arrhythmia. Secondary outcomes: cardiac arrest, major adverse cardiovascular events (MI, stroke), all-cause mortality.","limitations":"Retrospective database study relying on diagnostic codes — may undercount both cocaine and cannabis use. The comparison is between two illicit/semi-legal substances, not against non-users. Propensity score matching cannot eliminate all confounding. Polysubstance use (common in both groups) could influence outcomes. The study period and database may not represent all populations."},{"rthcId":"RTHC-08584","title":"Does Illicit Drug Use Increase Stroke Risk? A Systematic review, Meta-Analyses and Mendelian Randomization analysis.","authors":"Ritson, Megan; Markus, Hugh S; Harshfield, Eric L","year":2026,"journal":"International journal of stroke : official journal of the International Stroke Society, 17474930261418926","doi":"10.1177/17474930261418926","pmid":"41566428","tags":["cardiovascular"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Meta-analysis of 32 studies (>100 million participants) found cannabis associated with 37% higher stroke risk (OR 1.37), cocaine with 96% higher risk (OR 1.96), and amphetamines with 122% higher risk (OR 2.22). Mendelian randomization confirmed cannabis use disorder was causally associated with any stroke (OR 1.11) and large artery stroke (OR 1.35).","whyItMatters":"The Mendelian randomization component is crucial because it uses genetic variation to approximate a natural experiment, providing stronger evidence for causation than observational studies alone. Finding that cannabis use disorder is genetically linked to large artery stroke is a significant public health signal.","specificNumbers":"32 studies, >100 million participants. Cannabis OR 1.37 (1.14-1.65). Cocaine OR 1.96 (1.27-3.01). Amphetamines OR 2.22 (1.40-3.53). MR: cannabis use disorder to any stroke OR 1.11, to large artery stroke OR 1.35. Substance use disorder overall to intracerebral hemorrhage OR 7.79.","methodology":"Systematic review and meta-analysis of 32 observational studies, plus two-sample Mendelian randomization using genome-wide association data to test causal relationships between drug exposures and stroke subtypes.","limitations":"Observational meta-analysis showed heterogeneity and small-study effects for cannabis. Mendelian randomization assumes certain conditions (no pleiotropy, relevant instruments) that may not be perfectly met. Cannabis use disorder genes may also influence other behaviors."},{"rthcId":"RTHC-08585","title":"Cannabidiol lymphatic transport after oral administration assessed using a novel thoracic lymph duct cannulated conscious pig model.","authors":"Rizov, Vitalii; Lukáč, Peter; Mlček, Mikuláš; Kozlík, Petr; Křížek, Tomáš; Jelínek, Petr; Šodek, Petr; Sklenárová, Michaela; Paulusová, Viktória; Symkanych, Olesia; Stránský, Daniel; Klouček, Anežka; Šoóš, Miroslav; Šíma, Martin; Grus, Tomáš; Slanař, Ondřej; Ryšánek, Pavel","year":2026,"journal":"Drug delivery, 33(1), 2608913","doi":"10.1080/10717544.2025.2608913","pmid":"41459703","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08586","title":"The Effects of Extended Cannabis Abstinence in Comorbid Posttraumatic Stress Disorder and Cannabis Use Disorder.","authors":"Rodas, Justyne D; Sorkhou, Maryam; Kloiber, Stefan; George, Tony P; Hassan, Ahmed N","year":2026,"journal":"The Journal of clinical psychiatry, 87(1)","doi":"10.4088/JCP.25m16099","pmid":"41734366","tags":["ptsd","withdrawal","addiction","mental-health","quitting","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"In this open-label pilot study, 21 veterans with both PTSD and cannabis use disorder attempted 12 weeks of cannabis abstinence with contingency reinforcement (progressive payments for confirmed abstinence at weeks 4, 8, and 12).\n\nEleven participants achieved sustained abstinence; ten did not. The results were striking: abstainers' PTSD symptom scores (measured by the clinician-administered CAPS-5, the gold standard for PTSD assessment) dropped from 36.2 to 10.5 — a reduction of over 70%. Non-abstainers also improved, from 34.6 to 21.8, but significantly less.\n\nThe improvement was not uniform across PTSD symptom clusters. Avoidance, negative mood and cognition, and hyperarousal showed the greatest differential improvement in abstainers compared to non-abstainers. Re-experiencing symptoms improved across both groups regardless of abstinence status.\n\nThese findings challenge the common belief that cannabis helps manage PTSD. While many veterans use cannabis for trauma symptoms, this study suggests that sustained abstinence may actually produce larger symptom reductions than continued use.","whyItMatters":"PTSD is one of the most commonly cited reasons veterans use cannabis, and many advocate for medical cannabis as a PTSD treatment. This study provides the first prospective evidence that quitting cannabis — not starting it — may be what actually reduces PTSD symptoms. The magnitude of improvement (70% reduction in CAPS-5 scores) is clinically remarkable, even considering the small sample.","specificNumbers":"N=21 veterans. 11 achieved abstinence, 10 did not. Abstainers: CAPS-5 scores 36.2 → 10.5 (71% reduction). Non-abstainers: 34.6 → 21.8 (37% reduction). Difference between groups: p=0.001. Greatest differential improvement in avoidance, negative cognition, and hyperarousal clusters.","methodology":"Open-label pilot study, N=21 veterans with comorbid PTSD and CUD. Progressive contingency reinforcement payments for abstinence confirmed at weeks 4, 8, and 12. Abstinence defined as THC-COOH ≤50 ng/mL with no self-reported use. PTSD assessed via CAPS-5 (total severity, symptom count, cluster scores). Data collected January 2022 to April 2025.","limitations":"Very small sample (N=21) in an open-label design without randomization. Self-selection bias: veterans who achieved abstinence may differ from those who didn't in motivation, severity, or other factors. Contingency payments may have influenced adherence rather than reflecting real-world conditions. No long-term follow-up — whether symptom improvement persists is unknown. The study cannot determine whether abstinence caused the improvement or whether both reflect a shared underlying factor."},{"rthcId":"RTHC-08587","title":"Parental sociodemographic profiles in relation to mental health, cannabis use motives, and cannabis use behaviors among a sample of US young adult parents.","authors":"Romm, Katelyn F; Speer, Morgan; McCready, Darcey M; Thakkar, Shriya; Chakraborty, Rishika; Cavazos-Rehg, Patricia A; Berg, Carla J","year":2026,"journal":"Addictive behaviors, 176, 108635","doi":"10.1016/j.addbeh.2026.108635","pmid":"41679098","tags":["mental-health","driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Four distinct parent profiles emerged. Younger single/cohabiting mothers with less education (Class 2, 37.9%) and older single mothers with 3+ children (Class 4, 13.3%) had highest cannabis use odds. Among users, Classes 2 and 3 used most frequently and had greatest coping motives. Paradoxically, older married educated fathers (Class 1) showed the greatest cannabis-related consequences and driving under the influence.","whyItMatters":"The finding that educated fathers have the most consequences and DUI risk despite not being the most frequent users challenges assumptions about which parent demographics are most at risk from cannabis use.","specificNumbers":"1,247 US young adult parents. Class 1 (older married fathers, 18.4%): most consequences and DUI. Class 2 (younger single mothers, 37.9%): highest use odds and coping motives. Class 3 (older married mothers, 30.3%): more frequent use. Class 4 (older single mothers with 3+ kids, 13.3%): elevated use odds.","methodology":"Survey of 1,247 US young adult parents in 2023. Latent class analysis identified four sociodemographic profiles. Multivariable regressions examined associations with cannabis use, motives, consequences, and DUI.","limitations":"Cross-sectional survey cannot establish causation. Self-reported cannabis use and consequences. Online convenience sample may not be representative of all young parents. Latent class membership is probabilistic."},{"rthcId":"RTHC-08588","title":"Efficacy and safety of cannabidiol oil in psoriasis: a randomized, double-blind, placebo-controlled trial.","authors":"Roongpisuthipong, Wanjarus; Klangjareonchai, Theerawut; Kurathong, Sathit; Roongpisuthipong, Anuvat","year":2026,"journal":"The Journal of dermatological treatment, 37(1), 2604448","doi":"10.1080/09546634.2025.2604448","pmid":"41459647","tags":["cbd","inflammation","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"In a 28-patient RCT, oral CBD oil 60 mg/day did not significantly improve PASI (Psoriasis Area and Severity Index) scores versus placebo. However, itch scores were notably reduced by Week 8, and sleep onset latency decreased by Week 6, though this sleep effect was not sustained. Adverse events were mild to moderate and similar across groups.","whyItMatters":"Despite widespread consumer interest in CBD for skin conditions, this is one of the first rigorous placebo-controlled trials. The negative primary outcome is important information, though the itch and sleep benefits suggest potential symptom-specific effects worth investigating further.","specificNumbers":"28 participants. CBD dose: 60 mg/day oral. No significant PASI improvement. Notable itch reduction by Week 8. Sleep onset latency decreased by Week 6 (not sustained). Adverse events mild and similar between groups.","methodology":"Randomized, double-blind, placebo-controlled trial of 28 chronic plaque psoriasis patients receiving oral CBD oil 60 mg/day or placebo, with PASI as primary outcome and quality of life, itch, and sleep as secondary outcomes.","limitations":"Very small sample (28 patients). Low CBD dose (60 mg/day). Short duration. Oral route may not optimize skin delivery. Race and disease severity may limit generalizability."},{"rthcId":"RTHC-08589","title":"A Randomized Controlled Trial of the Safety and Efficacy of Dronabinol for Agitation in Alzheimer's Disease.","authors":"Rosenberg, Paul B; Amjad, Halima; Burhanullah, Haroon; Nowrangi, Milap; Vandrey, Ryan; Pierre, Mersania Jn; Outen, John D; Schultz, Meghan; Marano, Christopher; Agronin, Marc; Wilkins, James M; Harper, David; Laffaye, Todd; Reardon, Eilis; Turner, Kathryn; Ozonsi, Rosain; Drury, Mia; Nguyen, Andre; Hasoğlu, Tuna; Cromwell, Julia; Leoutsakos, Jeannie-Marie; Forester, Brent P","year":2026,"journal":"The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 34(2), 167-179","doi":"10.1016/j.jagp.2025.10.011","pmid":"41350162","tags":["medical-cannabis","seniors","cognition"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In a 3-week RCT of 75 Alzheimer's patients, dronabinol decreased agitation significantly more than placebo on the Pittsburgh Agitation Scale (effect size 0.53, p=0.015). The NPI-C agitation/aggression measure showed a trend (effect size 0.36, p=0.094). 84% completed the trial. Dronabinol was not associated with greater intoxication, cognitive decline, or adverse events except somnolence.","whyItMatters":"Agitation in Alzheimer's is extremely common and distressing, and current treatments have limited effectiveness with serious safety concerns including increased mortality risk. Dronabinol showed clinically meaningful agitation reduction with a favorable safety profile.","specificNumbers":"75 participants across 5 sites. PAS decline: -0.74/week between arms (p=0.015, effect size 0.53). NPI-C A/A decline: -1.26 (p=0.094, effect size 0.36). 84% completion rate. Target dose: 10 mg/day. 9% Black, 11% Hispanic. No increase in intoxication, falls, or cognitive decline.","methodology":"Multicenter (5 sites), 3-week, randomized, parallel, double-blind, placebo-controlled trial. Dronabinol titrated up to 10 mg daily in divided doses. 75 participants meeting criteria for agitation of Alzheimer's disease.","limitations":"Only 3 weeks duration. Most participants were on concomitant psychotropics. Moderate sample size. One of two primary outcomes did not reach significance. Long-term safety and efficacy unknown."},{"rthcId":"RTHC-08590","title":"Illuminating chromaffin granules: compartmentalization of endocannabinoids in bovine adrenal glands supports role in hormone modulation.","authors":"Roukens, Jaap-Jan; Meier, Philip; Simão, Ana Catarina; Chicca, Andrea; Bregy, Rachel; Altmann, Karl-Heinz; Gertsch, Jürg","year":2026,"journal":"Biochemical pharmacology, 248, 117827","doi":"10.1016/j.bcp.2026.117827","pmid":"41713623","tags":["neuroscience","dopamine"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"N-acylethanolamines including anandamide predominated in the adrenal cortex while 2-AG was concentrated in the medulla. Anandamide and the peptide endocannabinoid RVD-hemopressin increased progesterone and decreased testosterone secretion in adrenal cells. N-linoleoylethanolamine (LEA) and L-leucine were markedly enriched in chromaffin granules alongside neurotransmitters.","whyItMatters":"The endocannabinoid system is known to regulate the central stress response, but its role in the adrenal glands (where stress hormones are actually produced) has been largely unexplored. This study reveals an entire layer of local endocannabinoid regulation.","specificNumbers":"Anandamide and N-acylethanolamines predominated in cortex. 2-AG concentrated in medulla. LEA enriched in chromaffin granules. Anandamide increased progesterone and decreased testosterone in adrenal cells. RVD-hemopressin potentiated anandamide effects on progesterone.","methodology":"Targeted metabolomics of bovine adrenal gland zones and isolated chromaffin granules. Novel VMAT2-targeting fluorescent probe (CV-28) for flow cytometry of large dense-core vesicles. Hormone secretion assays in NCI-H295R adrenal cells.","limitations":"Bovine adrenal tissue may differ from human. In vitro hormone effects may not translate to in vivo physiology. The peptide endocannabinoids (pepcans) were absent from chromaffin granules, contradicting some prior hypotheses."},{"rthcId":"RTHC-08591","title":"Treatment with a botanical mixture of cannabidiol:Δ9-tetrahydrocannabinol enhances microglial phagocytosis and shapes amyloid plaques in a mouse model of Alzheimer's disease.","authors":"Ruiz de Martín Esteban, Samuel; Grande, M Teresa; Martínez-Relimpio, Ana M; Herráez-Aguilar, Diego; Mostany, Ricardo; Hillard, Cecilia J; Hind, William H; Romero, Julián","year":2026,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 194, 118902","doi":"10.1016/j.biopha.2025.118902","pmid":"41389629","tags":["medical-cannabis","seniors","cognition","cbd"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Chronic treatment (28 days) with CBD:THC (99:1) at 50 mg/kg twice daily in 5xFAD Alzheimer's mice enhanced microglial phagocytic activity and reduced amyloid peptide accumulation in neuritic plaques. However, the treatment also reduced locomotion, increased anxiety-like and depression-like behaviors, and had no effect on memory or motor coordination.","whyItMatters":"This is one of the first studies to show cannabinoids can enhance the brain's own plaque-clearing mechanisms in a living Alzheimer's model. However, the behavioral side effects present a clear challenge for translation to human treatment.","specificNumbers":"50 mg/kg twice daily for 28 days. CBD:THC ratio 99:1. Enhanced microglial phagocytic activity by flow cytometry. Reduced amyloid accumulation by multiphoton microscopy. Increased anxiety and depression-like behaviors. No memory or motor coordination effects.","methodology":"Male 5xFAD Alzheimer's mice treated with CBD:THC (99:1) 50 mg/kg subcutaneously twice daily for 28 days. Behavioral battery, protein expression analysis, flow cytometry for phagocytosis, and in vivo multiphoton microscopy for plaque imaging.","limitations":"Only male mice studied. High subcutaneous dose (50 mg/kg BID) far exceeds typical human dosing. The 5xFAD model represents aggressive amyloid pathology, not all aspects of human Alzheimer's. 28-day treatment may be too short."},{"rthcId":"RTHC-08592","title":"Ultrasound-assisted green extraction of antioxidant and antimicrobial resins from Cannabis sativa for potential pharmaceutical applications.","authors":"Ruiz Miraglio, Sofía Ivonne; Raspo, Matías Alejandro; Costamagna, Nicolás; Andreatta, Alfonsina Ester","year":2026,"journal":"Drug development and industrial pharmacy, 1-12","doi":"10.1080/03639045.2025.2612300","pmid":"41489477","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08593","title":"The prevalence of cannabis use pre-versus post-cannabis legalization in Canada by mental health status: findings from national repeat cross-sectional surveys.","authors":"Rundle, Samantha; Iraniparast, Maryam; Hammond, David","year":2026,"journal":"Lancet regional health. Americas, 55, 101373","doi":"10.1016/j.lana.2026.101373","pmid":"41625266","tags":["legalization","mental-health","anxiety","depression"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Past 12-month cannabis use increased from pre-legalization among those with anxiety (AOR 1.33) in the year immediately following legalization. Daily and 12-month use increased among Canadians not reporting mental health problems. No other pre-post legalization differences were observed among individuals with bipolar disorder, PTSD, or schizophrenia.","whyItMatters":"A major concern about legalization is that vulnerable populations, particularly those with mental health conditions, would increase cannabis use. This large-scale Canadian study provides reassuring evidence that the increase in use was driven primarily by people without mental health problems.","specificNumbers":"92,843 Canadians across 6 annual surveys (2018-2023). Cannabis use increase among those with anxiety: AOR 1.33 (95% CI 1.15-1.53) in 2019 only. Increases in daily and 12-month use observed among those without mental health problems. No significant changes for bipolar, PTSD, or schizophrenia.","methodology":"Data from the International Cannabis Policy Study's annual repeat cross-sectional surveys in Canada from 2018 to 2023 (one year pre- to five years post-legalization). Analysis included 92,843 Canadians aged 16-65. Adjusted logistic regression examined changes in daily and past 12-month use by mental health status.","limitations":"Repeat cross-sectional design means different people were surveyed each year. Self-reported mental health conditions may not match clinical diagnoses. Cannabis use is also self-reported. The study cannot capture changes within individuals over time. Legalization effects may take longer than five years to fully manifest."},{"rthcId":"RTHC-08594","title":"Cannabis Use in a Community-Based Sample of Adults Diagnosed With ADHD: Prevalence, Impact on Symptoms, and Stimulant Side Effects.","authors":"Ryan, Jennie E; Herens, Allison; Fruchtman, Mitchell; Veliz, Philip; Kelly, Erin L; Worster, Brooke","year":2026,"journal":"Journal of attention disorders, 30(3), 407-422","doi":"10.1177/10870547251364575","pmid":"40874736","tags":["cognition","mental-health","anxiety","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Cannabis use was highly prevalent: 75% ever used, 41% past-30-day use. Daily users vs non-daily users showed: higher cannabis use disorder (62% vs 38%), more anxiety (70% vs 48%), more depression (55% vs 41%), more PTSD (30% vs 14%), and reported cannabis worsened inattention. Stimulant misuse rates were comparable. Users reported mixed effects on anxiety: 156 noted improvement while 34 reported worsening.","whyItMatters":"ADHD is among the most common reasons people self-medicate with cannabis, yet evidence for its effectiveness is lacking. This large survey reveals that while many adults with ADHD perceive benefits, daily cannabis use is associated with significantly worse psychiatric profiles and worsened core ADHD symptoms.","specificNumbers":"900 adults with ADHD. 75% ever used cannabis, 41% past-30-day use. Daily users: 62% met criteria for cannabis use disorder (vs 38% non-daily), 70% anxiety (vs 48%), 55% depression (vs 41%), 30% PTSD (vs 14%). Daily users more likely to report cannabis worsened inattention (OR 0.59) and impulsivity (OR 1.69).","methodology":"Anonymous online survey emailed to 9,274 adults with documented ADHD diagnoses (ICD-10 codes confirmed by self-report). 900 completed the 46-item survey covering demographics, medical history, stimulant use, cannabis use, and impacts on ADHD symptoms. Three groups compared: no recent use (n=458), non-daily use (n=256), daily use (n=112).","limitations":"Cross-sectional survey cannot determine causation: people with worse ADHD and more comorbidities may be more likely to use cannabis daily. Self-selected sample with low response rate. Cannabis use disorder was assessed by questionnaire, not clinical interview. Stimulant medication effects were not controlled for."},{"rthcId":"RTHC-08595","title":"Evidence-based therapist guided introduction to online heavy cannabis use treatment in Canadian adults: a Randomized Controlled Trial (RCT).","authors":"Rysen, Karli K; Carusone, Julian M; Wardell, Jeffrey D; Schaub, Michael P; Wenger, Andreas; Wallbridge, Harold; Edgerton, Jason D; Kruk, Richard; Mackenzie, Corey S; Keough, Matthew T","year":2026,"journal":"Journal of cannabis research, 8(1), 26","doi":"10.1186/s42238-025-00378-5","pmid":"41547862","tags":["addiction","quitting","mental-health"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"All participants reduced cannabis consumption frequency and problems at end of treatment (6 weeks) and follow-up (10 weeks). The MET-therapist group showed significantly greater reductions in cannabis quantity vs waitlist. The research assistant group showed greater reductions in cannabis problems vs waitlist. No significant differences between therapist-guided and research assistant conditions. No effects on anxiety, depression, or quality of life.","whyItMatters":"Many heavy cannabis users do not seek treatment due to barriers like cost, wait times, and stigma. This trial shows that an online self-guided program can produce meaningful reductions in use, with the added finding that a brief therapist introduction, while helpful for quantity, is not essential for reducing use frequency.","specificNumbers":"152 participants randomized across 3 conditions. All groups reduced cannabis consumption days and problems at 6 and 10 weeks. MET-therapist group: greater quantity reduction vs waitlist. RA group: greater problem reduction vs waitlist. No significant differences between the two active conditions. No effects on anxiety, depression, or QoL.","methodology":"Pre-registered RCT (NCT04965012). 152 Canadian heavy cannabis users randomized to: (1) MET-therapist guided introduction + 6-week online program, (2) non-MET research assistant introduction + 6-week online program, or (3) psychoeducation waitlist control. The CANreduce program used CBT and motivational interviewing content. Assessments at baseline, 6 weeks, and 10 weeks.","limitations":"Relatively small sample (n=152) across three conditions limits power. 10-week follow-up is short for assessing sustained behavior change. Canadian legal context may not generalize to other jurisdictions. Waitlist improvement complicates interpretation. No biomarker verification of self-reported use."},{"rthcId":"RTHC-08596","title":"Medical Cannabis Use in Autism: Insights from an Israeli HMO on Patient Characteristics and Alignment with National Guidelines.","authors":"Sadeh, Hadar; Razi, Talish; Arbel, Ronen; Netzer, Doron; Meiri, Gal","year":2026,"journal":"Journal of child and adolescent psychopharmacology, 36(1), 29-34","doi":"10.1177/10445463251404404","pmid":"41334706","tags":["medical-cannabis","youth","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Only 1.2% of autistic individuals received medical cannabis prescriptions. The cannabis-prescribed group was diagnosed earlier (median 3 vs 5 years), had more complex clinical profiles, and higher socioeconomic status. 4.3% of prescriptions were for children under 5. Most prescriptions did not fully comply with Ministry of Health guidelines requiring prior trials of two FDA-approved antipsychotics.","whyItMatters":"Despite growing clinical interest and media attention around cannabis for autism, this large real-world dataset shows that actual prescribing remains rare and is concentrated among higher-SES families with more complex cases. The finding that most prescriptions bypassed required antipsychotic trials raises regulatory concerns.","specificNumbers":"36,610 autistic individuals. 462 (1.2%) prescribed cannabis. Median diagnosis age: 3 years (cannabis group) vs 5 years (non-cannabis). 4.3% of prescriptions for children under 5. Higher SES in cannabis-prescribed group. Most prescriptions did not meet guideline requirements for prior antipsychotic trials.","methodology":"Retrospective cohort study using electronic medical records from Clalit Health Services (Israel's largest HMO, serving ~4.7 million). All individuals with autism diagnoses from 1990-2025 were identified (N=36,610). Cannabis-prescribed (n=462) and not-prescribed (n=36,148) groups were compared on demographics and clinical characteristics.","limitations":"Single HMO in Israel may not generalize to other healthcare systems. Cannabis prescription does not mean the patient actually used it or benefited. Clinical complexity was assessed from administrative data. The study could not evaluate treatment outcomes or side effects."},{"rthcId":"RTHC-08597","title":"Synergistic Neuroprotection by Cannabis sativa and Tilia × viridis: Attenuation of Hippocampal Neurons Glutamate-Induced Oxidative Stress and LPS-Driven Microglial Inflammation.","authors":"Saint Martin, Elina Malen; Barreiro-Arcos, María Laura; Gomez, María Belén; Soldavini, Giuliana Colonna; Marrassini, Carla; Cogoi, Laura; Peralta, Ignacio; Reinés, Analía; Alonso, María Rosario; Anesini, Claudia","year":2026,"journal":"Planta medica","doi":"10.1055/a-2751-0171","pmid":"41628619","tags":["neuroscience","epilepsy","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannabis extract alone partially reversed glutamate-induced cell death (52-200% recovery). The linden tree extract also showed partial protection (22-82%). Combined, they produced synergistic effects: 133-284% recovery, fully restoring cell viability to control levels. The combination also reduced reactive oxygen species (52-58%) and most dramatically shifted microglia from inflammatory to anti-inflammatory phenotypes.","whyItMatters":"The synergistic effect means the combination works better than either extract alone, even at lower individual doses. This supports the concept of multi-botanical approaches for neuroinflammation and could inform formulation of botanical medicines.","specificNumbers":"Cannabis alone: 52-200% viability recovery. Linden alone: 22-82%. Combined: 133-284% (full restoration). ROS reduction: 52-58%. Shifted microglia from pro-inflammatory phenotype 1 to anti-inflammatory phenotype 2.","methodology":"In vitro study using HT-22 hippocampal neurons (glutamate toxicity model) and primary rat microglia (LPS inflammation model). Cell viability by MTT, ROS by fluorescence, microglial phenotypes by immunofluorescence.","limitations":"In vitro cell culture only. The specific bioactive compounds responsible for the synergy are not identified. Extract composition varies by preparation method. Translation to in vivo brain effects is uncertain."},{"rthcId":"RTHC-08598","title":"Psychological and Psychosocial Interventions for People With Schizophrenia and Co-Occurring Substance Use Disorders: A Systematic Review and Meta-Analysis.","authors":"Salahuddin, Nurul Husna; Herlitzius, Emilia; Schütz, Alexandra; Siafis, Spyridon; Priller, Josef; Leucht, Stefan; Bighelli, Irene","year":2026,"journal":"JAMA psychiatry","doi":"10.1001/jamapsychiatry.2025.4390","pmid":"41637064","tags":["psychosis","addiction","mental-health"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"A very small effect favoring interventions was observed for overall symptoms (SMD -0.11, 95% CI -0.27 to 0.05, low confidence), mainly driven by nicotine studies. No difference was found for all types of substance use combined (SMD -0.01, 95% CI -0.21 to 0.18, moderate confidence). Alcohol, cannabis, amphetamines, and other stimulants separately showed no effect. Only nicotine showed a small treatment effect.","whyItMatters":"About 42% of people with schizophrenia have co-occurring substance use disorders, yet they are frequently excluded from clinical trials. This comprehensive meta-analysis reveals that current evidence-based psychological treatments are essentially ineffective for this doubly burdened population, highlighting an urgent unmet treatment need.","specificNumbers":"35 RCTs, 4,136 participants (25.4% female, mean age 37.2 years). Overall symptoms: SMD -0.11 (low confidence). Substance use reduction: SMD -0.01 (moderate confidence). Alcohol, cannabis, amphetamines, stimulants: no significant effects. Only nicotine showed a small positive effect.","methodology":"Systematic review and random-effect pairwise meta-analysis of 35 RCTs (4,136 participants). Cochrane Schizophrenia Group registry searched to January 2025. GRADE confidence ratings applied. No restrictions on substance type. Published in JAMA Psychiatry.","limitations":"Meta-analysis is limited by the quality of included studies. Heterogeneity across intervention types, substances, and populations may mask effects in subgroups. The null finding for cannabis specifically may reflect limited studies targeting cannabis use in schizophrenia."},{"rthcId":"RTHC-08599","title":"An Ecological Momentary Assessment Protocol to Measure Stress, Socialization, and Other Contributors to Smoking Behaviors Among LGBTQ+ Adolescents: Multimethod Evaluation of Feasibility, Acceptability, and Appropriateness From the Puff Break Research Study.","authors":"Salgin, Linda; Kellogg, Daniel; Edusada, Irish; Lim, Andy C; Velasquez, Amanda; Helm, Jonathan; Blashill, Aaron J; Myers, Mark; Jun, Hee-Jin; Calzo, Jerel P","year":2026,"journal":"JMIR formative research, 10, e79957","doi":"10.2196/79957","pmid":"41564333","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08600","title":"Cannabis sativa in beverages: incorporation methods, bioactive stability and sensory impact - a critical review.","authors":"Sant'Ana, Rodrigo Ribeiro Arnt; Soldi, Cristian; Amboni, Renata Dias de Mello Castanho; Fritzen-Freire, Carlise Beddin","year":2026,"journal":"Critical reviews in food science and nutrition, 1-12","doi":"10.1080/10408398.2026.2629026","pmid":"41718566","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08601","title":"Could cannabigerol protect against neuroinflammation? Insights from an in vitro microglial study.","authors":"Santos, Júlia Maiara Dos; Machado, Amanda Kolinski; Bick, Djenifer Leticia Ulrich; Sagrillo, Michele Rorato; Del Bel, Elaine Aparecida; Machado, Alencar Kolinski; Santos, Antonio Cardozo Dos","year":2026,"journal":"Toxicology, 521, 154406","doi":"10.1016/j.tox.2026.154406","pmid":"41548647","tags":["cbd","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBG at 100 microM reduced cell viability by ~80%, increased nitric oxide ~400% and reactive oxygen species ~900%. Genotoxicity was detected at 10 and 100 microM (200-300% DNA damage increase). In a neuroinflammation model with NLRP3 activation, CBG could not reduce ROS levels and actually increased Caspase-1 gene expression. At higher concentrations, CBG activated microglia and altered their morphology.","whyItMatters":"CBG is increasingly marketed as a therapeutic cannabinoid with anti-inflammatory properties. This study reveals significant safety concerns: genotoxicity at multiple concentrations, failure to reduce neuroinflammation, and high cytotoxicity at elevated doses. These findings challenge the narrative that CBG is uniformly beneficial.","specificNumbers":"CBG 100 microM: ~80% viability loss, ~400% NO increase, ~900% ROS increase. Genotoxicity (GEMO assay): ~200% DNA damage at 10 microM, ~300% at 100 microM. Comet assay: no genotoxicity detected (discrepant result). NLRP3 model: CBG did not reduce ROS and increased Caspase-1 expression.","methodology":"BV-2 microglial cells were exposed to CBG concentrations from 0.01 to 100 microM for 24 hours. Cell viability (MTT), ROS, nitric oxide, genotoxicity (GEMO and Comet assays), Caspase-1 expression, and cell morphology were assessed. A neuroinflammation model using NLRP3 activation tested CBG's anti-inflammatory capacity.","limitations":"Single cell line study (BV-2 murine microglia). The concentrations producing toxicity (100 microM) may not be achievable in vivo. The discrepancy between genotoxicity assays needs resolution. In vitro neuroinflammation models do not replicate the complexity of brain inflammation in living organisms."},{"rthcId":"RTHC-08602","title":"Evaluation of THC-induced neurotoxicity via oxidative stress in undifferentiated SH-SY5Y cells.","authors":"Sanz-Pérez, A; Anaya, B J; Fraguas-Sánchez, A I; Serrano, D R; Pérez, T; Basilicata, P; Pieri, M; González-Burgos, E","year":2026,"journal":"Environmental toxicology and pharmacology, 121, 104891","doi":"10.1016/j.etap.2025.104891","pmid":"41349656","tags":["neuroscience","potency","driving"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"THC at 73.75 and 150 ng/mL significantly reduced cell viability (to 76.5% and 64.6% at 48 hours) and caused morphological changes. THC increased reactive oxygen species (peaking at 116.5% at 150 ng/mL), disrupted glutathione balance (GSH/GSSG ratio decreased 69.2%), increased lipid peroxidation (34.5%), and reduced antioxidant enzyme activities. Nuclear condensation and mitochondrial membrane depolarization indicated early apoptosis.","whyItMatters":"This study bridges the gap between traffic safety data and neuroscience by testing THC concentrations actually found in impaired drivers. The finding that these real-world concentrations cause measurable neurotoxicity provides biological context for why THC impairs driving and other cognitive functions.","specificNumbers":"THC concentrations tested: 0.66, 20, 73.75, 150 ng/mL. Cell viability at 48h: 76.5% (73.75 ng/mL), 64.6% (150 ng/mL). ROS peak: 116.5% at 150 ng/mL. GSH/GSSG ratio decreased 69.2%. Lipid peroxidation increased 34.5%. Antioxidant enzymes (CAT, SOD, GR, GPx) declined concentration-dependently.","methodology":"Human undifferentiated SH-SY5Y neuroblastoma cells were exposed to THC at four concentrations (0.66, 20, 73.75, 150 ng/mL) reflecting real-world blood levels found in drivers involved in traffic accidents. Cell viability, ROS, glutathione balance, lipid peroxidation, antioxidant enzyme activities, nuclear morphology, and mitochondrial membrane potential were assessed.","limitations":"Undifferentiated neuroblastoma cells are not identical to mature neurons. In vitro exposure does not account for blood-brain barrier, metabolism, or protein binding. The concentrations were tested as steady-state exposures, whereas in vivo THC levels fluctuate rapidly. Short exposure times may not reflect chronic use patterns."},{"rthcId":"RTHC-08603","title":"Growing Concerns: A systematic review and Meta-Analysis of cannabis use and mental health risks in youth.","authors":"Sanz-Pérez, A; Serrano, D R; Fraguas-Sánchez, A I; Pardo, M C; Sánchez de León, J M Ruiz; Estupiñá, F J; Pérez, T; González-Burgos, E","year":2026,"journal":"Addictive behaviors, 172, 108528","doi":"10.1016/j.addbeh.2025.108528","pmid":"41145103","tags":["youth","mental-health","depression","anxiety"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"Unadjusted and adjusted odds ratios for youth cannabis users: Depression OR 1.51 (aOR 1.28). Anxiety OR 1.58. Suicidal ideation OR 1.50 (aOR 1.65). Suicide attempts OR 1.87 (aOR 1.80). The adjusted estimates for depression were lower than unadjusted, suggesting confounding, while suicidal ideation estimates increased after adjustment, suggesting a robust association.","whyItMatters":"Young people are the largest cannabis consumer demographic and also the population most vulnerable to mental health disruptions. This meta-analysis quantifies the magnitude of the mental health risks associated with cannabis use during this critical developmental period.","specificNumbers":"6,466 articles screened, 36 included, 18 in meta-analysis. Depression: OR 1.51, aOR 1.28 (95% CI 1.10-1.50). Anxiety: OR 1.58 (95% CI 1.15-2.15). Suicidal ideation: OR 1.50 (aOR 1.65, 95% CI 1.40-1.93). Suicide attempts: OR 1.87 (aOR 1.80, 95% CI 1.30-2.49). Ages 15-30.","methodology":"Systematic review of 6,466 articles from PubMed, Mendeley, Embase, WOS, CINAHL, and Scopus, with 36 meeting inclusion criteria and 18 contributing to meta-analysis. Studies published 2013-2025 involving individuals aged 15-30. Random effects meta-analysis with both unadjusted and adjusted estimates.","limitations":"Most included studies were observational and cannot establish causation. Heterogeneity across studies in how cannabis use and mental health outcomes were defined and measured. Publication bias possible. The age range (15-30) spans very different developmental periods."},{"rthcId":"RTHC-08604","title":"Consumption patterns and withdrawal symptoms in dual cannabis-tobacco users in Spain: Cross-sectional study.","authors":"Saura, Judith; Enríquez, Marta; Feliu, Ariadna; Roca, Xavier; Mondón, Silvia; Barrio, Pablo; Andreu, Magalí; Segura, Lidia; Ballbè, Montse; Fu, Marcela; Fernández, Esteve; Martínez, Cristina","year":2026,"journal":"Addictive behaviors reports, 23, 100656","doi":"10.1016/j.abrep.2025.100656","pmid":"41531671","tags":["withdrawal","addiction","quitting","youth"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"This cross-sectional study of 94 participants entering cannabis use disorder treatment in Catalonia, Spain, documented the deeply intertwined nature of cannabis and tobacco use in a European context where mixing the two substances in \"spliffs\" is the dominant consumption method.\n\nDaily tobacco use was reported by 91.5% of participants, with a mean Fagerström nicotine dependence score of 4.2 out of 10 (moderate dependence). Most participants (88.1%) co-used cannabis with tobacco in the same product. Cannabis withdrawal symptoms were experienced by 75.8%, with women reporting greater severity than men.\n\nCluster analysis revealed two distinct user profiles. Cluster 1 (71% of participants) represented one behavioral pattern, while Cluster 2 (29%) represented another — suggesting that cannabis-tobacco dual users are not a homogeneous group and may need different treatment approaches.\n\nThe findings highlight a complication that's particularly relevant in European cannabis culture: when cannabis and tobacco are co-administered in every use episode, quitting cannabis also means confronting nicotine withdrawal, and vice versa.","whyItMatters":"The European pattern of mixing cannabis with tobacco in spliffs creates a dual dependence that's different from the North American pattern of using cannabis alone. Treatment programs designed for cannabis alone may miss the tobacco component, and tobacco cessation programs may not account for the cannabis dimension. Understanding these co-use patterns is essential for effective treatment in populations where mixing is the norm.","specificNumbers":"94 participants. Daily tobacco use: 91.5%. Mean Fagerström score: 4.2/10. Cannabis-tobacco co-use: 88.1%. Cannabis withdrawal: 75.8% experienced symptoms. Women reported greater withdrawal severity. Two behavioral clusters: Cluster 1 (71%), Cluster 2 (29%).","methodology":"Cross-sectional study in substance use treatment programs in Catalonia, Spain. 94 participants initiating CUD treatment. Questionnaire assessing sociodemographics, cannabis and tobacco use characteristics, nicotine dependence (Fagerström), motivation to quit, and cannabis withdrawal symptoms. Hierarchical cluster analysis using Gower's distance to identify behavioral profiles.","limitations":"Cross-sectional design from a single treatment setting in Catalonia. The 94-participant sample is modest. Treatment-seeking individuals may not represent all dual users. European spliff culture differs from North American consumption patterns, limiting generalizability. Self-reported use measures may be imprecise."},{"rthcId":"RTHC-08605","title":"Computational and design of experiment strategies to improve differentiation and quantitation of trace-level cannabinoids by copper cationization paper spray mass spectrometry.","authors":"Sboto, Jindar N S; Gill, Chris G","year":2026,"journal":"The Analyst, 151(1), 226-236","doi":"10.1039/d5an01073j","pmid":"41347905","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08606","title":"Effect of Δ9-tetrahydrocannabinol and cannabidiol on myofascial pain modulation in patients with temporomandibular disorder: a prospective crossover study.","authors":"Schinko, Francisco Gomes Bonetto; Paranhos, Luiz Renato; Gonçalves de Sousa, Lucas; Phelipe de Paula Santos, Gabriel; de Mello Rode, Sigmar; Sergio Guimarães, Antonio; Cama Ramacciato, Juliana","year":2026,"journal":"Clinics (Sao Paulo, Brazil), 81, 100885","doi":"10.1016/j.clinsp.2026.100885","pmid":"41740529","tags":["pain","medical-cannabis","cbd"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"THC/CBD improved all outcomes versus both baseline and post-placebo (p < 0.05). VAS pain decreased from 7.35 to 3.50. Mouth opening increased from 45.9 mm to 49.9 mm. Functional pain dropped by approximately 90%. Allodynia and hyperalgesia were nearly eliminated. Effect sizes exceeded 0.8 (large). Placebo effects were minimal.","whyItMatters":"Temporomandibular disorder affects up to 12% of the population and causes chronic orofacial pain that often responds poorly to conventional treatments. This study provides clinical evidence for THC/CBD therapy with large effect sizes and measurable functional improvements, not just subjective pain reduction.","specificNumbers":"20 participants, 90-day treatment. THC/CBD 1:1, titrated to 10 mg/day sublingual. VAS pain: 7.35 to 3.50. Mouth opening: 45.9 to 49.9 mm. Functional pain reduced ~90%. Allodynia and hyperalgesia nearly eliminated. Effect sizes >0.8. Minimal placebo response.","methodology":"Blinded, crossover, non-randomized study of 20 adults with chronic myofascial TMD pain (DC/TMD diagnosis). Two consecutive 90-day phases: placebo followed by THC/CBD (1:1 ratio, starting at 2 mg/day, titrating to 10 mg/day sublingually over 5 weeks). Outcomes: VAS pain, algometry, mandibular function, and pain sensitivity. Linear mixed models used for analysis.","limitations":"Non-randomized crossover without washout between placebo and active phases means carryover or order effects cannot be excluded. Small sample (n=20). Single-site study. The blinding may have been compromised by THC psychoactive effects. No long-term follow-up beyond 90 days."},{"rthcId":"RTHC-08607","title":"Endocannabinoid response to social stress in chronic non-medical prescription opioid users.","authors":"Schmid, Vinzenz K; Quednow, Boris B; Pellegata, Daniele; Meier, Philip; Gertsch, Jürg; Kroll, Sara L","year":2026,"journal":"Psychopharmacology, 243(2), 427-441","doi":"10.1007/s00213-025-06950-4","pmid":"41188442","tags":["neuroscience","addiction","pain"],"studyType":"case-control","evidenceStrength":"preliminary","keyFinding":"A significant GROUP x TIME interaction was found for 2-AG. Healthy controls showed increased 2-AG plasma levels after social exclusion stress, while non-medical opioid users showed a blunted stress response. The groups robustly differed at all time points after stress. Higher 2-AG levels were associated with greater feelings of social inclusion. No significant interactions were found for anandamide, other NAEs, or arachidonic acid.","whyItMatters":"The endocannabinoid system is increasingly recognized as a critical stress buffer. If opioid use disrupts this buffering capacity, specifically the 2-AG response, it could explain why stress is such a powerful trigger for opioid relapse and why opioid users are vulnerable to emotional dysregulation.","specificNumbers":"21 NMPOU participants vs 29 healthy controls. Blood collected at 5 time points. Significant GROUP x TIME interaction for 2-AG (p significant). Robust group differences at all post-stress time points. Higher 2-AG associated with greater social inclusion feelings. No significant interactions for AEA, NAEs, or AA.","methodology":"Individuals with chronic non-medical prescription opioid use (n=21) and matched opioid-naive controls (n=29) underwent social exclusion using the Cyberball task. Plasma was collected before and at 10, 20, 30, and 60 minutes after stress. 2-AG, anandamide, related N-acylethanolamines, and arachidonic acid were measured.","limitations":"Small sample sizes (21 vs 29) limit generalizability and statistical power. Cross-sectional comparison cannot determine whether the blunted response preceded or resulted from opioid use. Social exclusion (Cyberball) may not represent the types of stress that trigger real-world relapse. Plasma endocannabinoids may not perfectly reflect brain levels."},{"rthcId":"RTHC-08608","title":"Short-term effects of cannabis legalisation in Germany on driving under the influence of cannabis: a difference-in-differences analysis using Austria as a control.","authors":"Schranz, Anna; Knoche-Becker, Anja; Rosenkranz, Moritz; Verthein, Uwe; Manthey, Jakob","year":2026,"journal":"The Lancet regional health. Europe, 63, 101593","doi":"10.1016/j.lanepe.2026.101593","pmid":"41631167","tags":["legalization","driving"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"German cannabis use rose from 12.1% to 14.4%, but this did not significantly differ from Austrian trends (DiD OR 1.18, 95% CI 0.95-1.48). Among monthly+ users, DUIC decreased slightly from 28.5% to 26.8% with no significant difference from Austria (DiD aOR 0.68, 95% CI 0.27-1.68). DUIC combined with alcohol/drugs (DUIC+) accounted for 21.5% of episodes and was most common among weekly users.","whyItMatters":"Germany is the largest European country to legalize cannabis, making its experience crucial for other European nations considering reform. The finding of no significant short-term increase in stoned driving addresses one of the primary safety concerns about legalization, though the 21.5% rate of combined cannabis/alcohol DUIC episodes is concerning.","specificNumbers":"Germany: use 12.1% to 14.4%. Austria control. DiD for use: OR 1.18 (NS). DiD for DUIC: aOR 0.68 (NS). DUIC+: 21.5% of episodes. DUIC without other substances most common among daily users. DUIC+ most common among weekly users.","methodology":"Cross-sectional population surveys in Germany and Austria before (November-December 2023) and after legalization (November 2024-January 2025). Difference-in-differences analysis using Austria as control. Cannabis use assessed in adults 18-64 (Germany: ~16,000; Austria: ~4,200). DUIC assessed among monthly+ users.","limitations":"Only 8 months post-legalization; effects may take longer to emerge. No legal commercial sales were operating during the study period (only possession and cultivation were legal). Self-reported DUIC may underestimate true prevalence. Austria is an imperfect control (cultural and policy differences)."},{"rthcId":"RTHC-08609","title":"Impact of self-reported cannabis use on veterans' intensive PTSD treatment outcomes.","authors":"Schubert, Ryan A; Splaine, Cailan C; Montes, Mauricio M; Pridgen, Sarah A; Kaysen, Debra L; Held, Philip","year":2026,"journal":"Psychological trauma : theory, research, practice and policy, 18(3), 628-637","doi":"10.1037/tra0001842","pmid":"40048203","tags":["ptsd","depression","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Across two samples of veterans undergoing Cognitive Processing Therapy-based intensive treatment programs (3-week program: N=488; 2-week program: N=253), researchers examined whether cannabis use frequency before or during treatment affected PTSD and depression outcomes.\n\nVeterans in both programs reported low rates of cannabis use overall. The central finding was that cannabis use frequency — whether measured before treatment or concurrently — was not significantly associated with different trajectories of PTSD or depression symptom improvement over time.\n\nBoth cannabis-using and non-using veterans showed significant reductions in PTSD (measured by PCL-5) and depressive symptoms (measured by PHQ-9) from pre- to post-treatment. The treatment appeared to work regardless of cannabis use status.\n\nThis finding held across both the 3-week and 2-week program formats, providing replication across two independent samples with slightly different treatment intensities.","whyItMatters":"Some treatment programs exclude or discourage cannabis-using patients, and clinicians may worry that cannabis use undermines evidence-based PTSD therapy. This study provides reassurance that cannabis use at the levels observed didn't appear to interfere with intensive treatment — meaning cannabis-using veterans shouldn't necessarily be excluded from these programs.","specificNumbers":"Two samples: N=488 (3-week ITP) and N=253 (2-week ITP). Cannabis use frequency not significantly associated with PTSD or depression symptom change trajectories. Both users and non-users showed significant symptom improvement on PCL-5 and PHQ-9.","methodology":"Observational study of two veteran samples in Cognitive Processing Therapy-based intensive treatment programs (N=488 for 3-week; N=253 for 2-week). Cannabis use frequency self-reported over past 2 weeks. PTSD measured by PCL-5, depression by PHQ-9, assessed before, during, and after treatment. Linear mixed-effects models analyzed cannabis use frequency effects on symptom trajectories.","limitations":"Low overall rates of cannabis use in these samples may have limited statistical power to detect effects. Self-reported cannabis use likely underestimates actual use in a treatment setting. Observational design — cannabis-using and non-using veterans may differ in unmeasured ways. Intensive treatment programs are a specific context; results may not generalize to standard outpatient PTSD therapy."},{"rthcId":"RTHC-08610","title":"Vaporized cannabis versus placebo for acute migraine: A randomized, double-blind, placebo-controlled crossover trial.","authors":"Schuster, Nathaniel M; Wallace, Mark S; Marcotte, Thomas D; Buse, Dawn C; Lee, Euyhyun; Liu, Lin; Sexton, Michelle","year":2026,"journal":"Headache, 66(2), 365-376","doi":"10.1111/head.70025","pmid":"41469488","tags":["medical-cannabis","pain","cbd"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"THC+CBD (6% THC + 11% CBD) was superior to placebo for pain relief (67.2% vs 46.6%, OR 2.85), pain freedom (34.5% vs 15.5%, OR 3.30), and most bothersome symptom freedom (60.3% vs 34.5%, OR 3.32) at 2 hours, with sustained benefits at 24 and 48 hours. THC-dominant was superior for pain relief only (68.9% vs 46.6%, OR 3.14). CBD-dominant was not superior to placebo for any primary outcome. No serious adverse events.","whyItMatters":"This is the first ever randomized controlled trial of cannabis for acute migraine. Migraine affects over 1 billion people globally, and current treatments fail for many patients. The finding that THC+CBD achieved 67% pain relief at 2 hours (comparable to triptans) with sustained 48-hour benefits and no serious adverse events is a landmark result.","specificNumbers":"92 participants, 247 attacks treated. THC+CBD vs placebo at 2h: pain relief 67.2% vs 46.6% (OR 2.85, p=0.016), pain freedom 34.5% vs 15.5% (OR 3.30, p=0.017), MBS freedom 60.3% vs 34.5% (OR 3.32, p=0.005). THC alone: pain relief 68.9% vs 46.6% (OR 3.14, p=0.008). CBD alone: not superior to placebo. No serious adverse events.","methodology":"Randomized, double-blind, placebo-controlled, crossover trial. 92 adults with migraine treated up to four attacks, one each with: (1) 6% THC, (2) 11% CBD, (3) 6% THC + 11% CBD, or (4) placebo cannabis flower. Minimum 1-week washout between attacks. 247 migraine attacks treated total. Primary endpoint: pain relief at 2 hours.","limitations":"Vaporization limits generalizability to patients willing and able to inhale. The placebo response was substantial (47%). Crossover design with up to four attacks per person means some variability in migraine characteristics. Sample size of 92 was modest. Only acute treatment was studied, not preventive use."},{"rthcId":"RTHC-08611","title":"Unveiling the toxic effects of perfluorooctanoic acid on osteoblast function and extracellular matrix deposition using 2D and 3D models.","authors":"Sella, Fiorenza; Licini, Caterina; Lombó, Marta; Giommi, Christian; Carbonari, Damiano; Mattioli-Belmonte, Monica; Carnevali, Oliana","year":2026,"journal":"Cell death discovery, 12(1), 10","doi":"10.1038/s41420-025-02863-5","pmid":"41513615","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08612","title":"Medical cannabis authorization and opioid milligram equivalents over time in patients with chronic pain: a retrospective analysis.","authors":"Sexton, Michelle; Glodosky, Nicholas C; Cleveland, Michael; Cuttler, Carrie; Lee, Euyhyun; Polston, Gregory R; Furnish, Timothy; Lerman, Imanuel; Schuster, Nathaniel M; Wallace, Mark S","year":2026,"journal":"Pain medicine (Malden, Mass.), 27(2), 127-135","doi":"10.1093/pm/pnaf113","pmid":"40838875","tags":["medical-cannabis","pain","addiction"],"studyType":"retrospective-cohort","evidenceStrength":"preliminary","keyFinding":"Average opioid dose at the final time point was 33.4 mg/day OME overall. Medical cannabis authorization predicted a non-significant decrease of 14.25 mg/day OME. No significant difference between cannabis-authorized (38.51 mg/day) and non-authorized patients (32.60 mg/day). Long-term opioid users had significantly higher OME (85.34 mg/day, 63 mg/day higher than the rest, p<0.0001).","whyItMatters":"Claims that medical cannabis reduces opioid use are central to many advocacy and policy arguments. This real-world clinical data from a pain specialty setting shows no statistically significant opioid-sparing effect, tempering expectations while not ruling out a modest benefit.","specificNumbers":"Overall average OME: 33.4 mg/day. Cannabis-authorized: 38.51 mg/day. Non-authorized: 32.60 mg/day (NS difference). Cannabis consultation: -14.25 mg/day (NS). Long-term opioid code: 85.34 mg/day (63 mg higher, p<0.0001). Overall OME trend: +0.45 mg/day per quarter (NS).","methodology":"Longitudinal retrospective cohort analysis of electronic health records from a university-based pain clinic, July 2016 to August 2019. Longitudinal multilevel modeling with maximum likelihood estimation compared opioid milligram equivalents over time between patients with and without medical cannabis authorization.","limitations":"Retrospective design with no randomization. Patients who sought cannabis authorization may differ from those who did not. Cannabis use was captured by authorization, not actual consumption. The 3-year study period may be too short. A university pain clinic population may not represent all chronic pain patients."},{"rthcId":"RTHC-08613","title":"Effect of Preoperative Cannabis Use on Postoperative Pain and Outcomes Following Cardiothoracic Surgery.","authors":"Shah, Sareena; Fletcher, Paul; Hamadah, Kareem; Gilmore, Drake; Staples, Bryant; Chadwick, Andrea; He, Jianghua; Kim, Jaromme; Flynn, Brigid","year":2026,"journal":"Seminars in cardiothoracic and vascular anesthesia, 30(1), 21-27","doi":"10.1177/10892532251374952","pmid":"40905360","tags":["pain","medical-cannabis"],"studyType":"prospective-cohort","evidenceStrength":"preliminary","keyFinding":"Average morphine equivalents in the first 48 hours: cannabis users 60.98 vs non-users 59.90 (p=0.93). VAS pain at 24 hours: 5.52 vs 4.84 (p=0.414). VAS at 48 hours: 4.74 vs 3.90 (p=0.23). Time to extubation was nearly identical (718.41 vs 718.67 minutes, p=0.99). No differences in ICU length of stay, nausea/vomiting, reoperation, or in-hospital mortality.","whyItMatters":"There has been concern that cannabis users might require more opioids postoperatively due to cross-tolerance, or that cannabis might affect surgical outcomes. This study provides reassuring data that preoperative cannabis use did not worsen any measured outcome after cardiac surgery.","specificNumbers":"73 patients (50 non-users, 23 cannabis users). 48-hour morphine equivalents: 60.98 vs 59.90 (p=0.93). 24h VAS: 5.52 vs 4.84 (p=0.414). 48h VAS: 4.74 vs 3.90 (p=0.23). Extubation: 718.41 vs 718.67 min (p=0.99). ICU stay: 2.91 vs 3.48 days (p=0.26).","methodology":"Single-center prospective study of adults undergoing cardiac surgery via sternotomy. Patients were surveyed about cannabis use during preoperative consultation. 50 non-users and 23 cannabis users were compared. Primary outcomes: morphine equivalents in first 48 hours and VAS pain scores. Secondary outcomes: extubation time, nausea, ICU stay, reoperation, mortality.","limitations":"Small sample, especially the cannabis group (n=23), limiting power to detect moderate effects. Single center. Cannabis use was self-reported and not verified biochemically. No information on dose, frequency, or recency of cannabis use. The study may be underpowered for rare outcomes like reoperation or mortality."},{"rthcId":"RTHC-08614","title":"Development of sustained release injectable phospholipid-based phase transition gel matrixed with Piracetam and cannabidiol loaded nanoemulsion for amelioration of Alzheimer's therapy.","authors":"Shahrukh, Mohd; Adil, Mohammad; Hasan, Nazeer; Ahmad, Farhan Jalees","year":2026,"journal":"Drug delivery and translational research, 16(3), 924-944","doi":"10.1007/s13346-025-02017-1","pmid":"41299112","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08615","title":"Effects of Cannabidiol on Bone Health: A Comprehensive Scoping Review.","authors":"Shakir, Shabbir Adnan; Chin, Kok-Yong","year":2026,"journal":"Biomedicines, 14(1)","doi":"10.3390/biomedicines14010208","pmid":"41595744","tags":["cbd","medical-cannabis"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"Eleven of 24 studies demonstrated beneficial effects of CBD on bone formation, mineralization, callus quality, or strength. Another eleven showed mixed results, and two showed no benefit. CBD appears to suppress bone resorption while promoting osteoblast proliferation.","whyItMatters":"Osteoporosis affects hundreds of millions worldwide and current treatments carry significant side effects. If CBD can genuinely enhance bone formation while reducing breakdown, it could offer a novel therapeutic approach, but the evidence is still entirely preclinical.","specificNumbers":"24 studies included; 11 showed beneficial effects, 11 mixed outcomes, 2 no benefit. CBD mechanisms involved CB2 receptor activation, RANKL/OPG pathway modulation, and BMP, Wnt, MAPK, NF-kB, and PPAR signaling.","methodology":"Systematic search of PubMed, Scopus, and Web of Science in October 2025 for original studies examining CBD effects on bone health. Twenty-four primary studies were included regardless of study design. Data on CBD formulation, treatment parameters, and bone outcomes were extracted and analyzed descriptively.","limitations":"All evidence is preclinical. No controlled human trials were included. The heterogeneity of study designs, CBD formulations, and bone models makes direct comparison difficult."},{"rthcId":"RTHC-08616","title":"Substance abuse in first-episode psychosis at Chris Hani Baragwanath Hospital.","authors":"Shandu, Precious N; Minty, Yumna","year":2026,"journal":"The South African journal of psychiatry : SAJP : the journal of the Society of Psychiatrists of South Africa, 32, 2542","doi":"10.4102/sajpsychiatry.v32i0.2542","pmid":"41646447","tags":["psychosis","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Substance use prevalence among first-episode psychosis patients was 73.6%. Cannabis was the most commonly used substance (46%). Substance-induced psychotic disorder was the most common diagnosis, and substance use was associated with aggression in 45% of cases.","whyItMatters":"South Africa has limited mental health resources and high rates of substance use. Understanding the overlap between substance use and first-episode psychosis in this population can inform targeted prevention and integrated treatment strategies.","specificNumbers":"200 patients reviewed. 73.6% prevalence of substance use. Cannabis most common at 46%. Most patients were male, aged 21-30 (37%). Aggression associated with substance use in 45% of cases. Only 34% of substance users were referred to social services.","methodology":"Retrospective chart review of 200 patients presenting with first-episode psychosis at Chris Hani Baragwanath Academic Hospital, a tertiary facility in Soweto, South Africa. Clinical records were analyzed and patients with and without substance use were compared statistically.","limitations":"Retrospective chart review limits data quality and completeness. Single hospital setting in Soweto may not generalize to other South African populations. Cannot establish causal direction between substance use and psychosis."},{"rthcId":"RTHC-08617","title":"Medical Cannabis for the Treatment of Peripheral Neuropathy due to Diabetes: A Systematic Review.","authors":"Sherman, Justin J; Riche, Daniel M","year":2026,"journal":"Cannabis and cannabinoid research, 25785125261425444","doi":"10.1177/25785125261425444","pmid":"41714301","tags":["pain","medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"preliminary","keyFinding":"Three of four RCTs reported statistically significant reductions in neuropathic pain with cannabinoid interventions compared to placebo. Vaporized or sublingual THC at approximately 16-18 mg/day was associated with clinically meaningful pain relief. One trial did not show superiority over placebo.","whyItMatters":"Diabetic peripheral neuropathy affects up to 50% of people with diabetes and is notoriously difficult to treat. Despite growing interest in cannabinoids for neuropathic pain, evidence specific to diabetic neuropathy is remarkably sparse.","specificNumbers":"15,377 records screened, 35 full texts assessed, 4 RCTs included. THC doses of approximately 16-18 mg/day via vaporized or sublingual routes were associated with pain relief in two trials. Adverse effects included dizziness and cognitive symptoms, generally mild to moderate.","methodology":"Systematic review searching PubMed, Google Scholar, Cochrane Library, and Scopus. Screened 15,377 records, assessed 35 full-text articles for eligibility, and included 4 RCTs in qualitative synthesis. Only studies conducted specifically in participants with diabetes and painful peripheral neuropathy were eligible.","limitations":"Only four small, heterogeneous RCTs were available. Variability in formulations and comparators limits comparability. Risk of bias concerns across studies. The identified dose range should be viewed as hypothesis-generating, not as a recommendation."},{"rthcId":"RTHC-08618","title":"Behavioral pharmacology of novel synthetic indazole, indole, and benzimidazole cannabinoids in rodents.","authors":"Shetty, Ritu A; Hill, Rebecca D; McDonald, Jared A; Sumien, Nathalie; Forster, Michael J; Gatch, Michael B","year":2026,"journal":"Journal of cannabis research, 8(1), 22","doi":"10.1186/s42238-026-00390-3","pmid":"41526973","tags":["synthetic-cannabinoids","potency","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"The DEA identified 11 synthetic cannabinoids of concern, and researchers tested each one in rodent models for two key properties: how strongly they suppressed movement (locomotor depression) and whether rats trained to recognize THC also recognized these compounds (drug discrimination).\n\nIn locomotor tests, most of the 11 compounds were more potent than THC (which had an ED50 of 3.3 mg/kg). Three compounds — FUB-144, 5Cl-AKB-48, and ADB-FUBIATA — were exceptions, producing only weak locomotor effects at tested doses.\n\nIn the drug discrimination assay (where rats are trained to distinguish THC from placebo), most compounds fully substituted for THC with greater potency (THC ED50 = 0.55 mg/kg). FUB-144 was less potent, 5Cl-AKB-48 was substantially less potent, and ADB-FUBIATA and MDA-19 failed to fully substitute for THC even at doses up to 100 mg/kg — suggesting these two may not produce classical cannabinoid effects.\n\nThe indazole and indole structural classes generally showed the highest potency, while benzimidazole compounds were more variable.","whyItMatters":"Synthetic cannabinoids continue to cause hospitalizations and deaths because users cannot predict their potency. This study provides the first systematic potency comparison for 11 specific compounds the DEA has flagged as concerning — giving clinicians, toxicologists, and poison control centers reference data for treating exposures.","specificNumbers":"11 compounds tested. THC ED50 (reference): 3.3 mg/kg (locomotor), 0.55 mg/kg (discrimination). Most compounds more potent than THC in both assays. Exceptions: FUB-144, 5Cl-AKB-48 (lower potency), ADB-FUBIATA and MDA-19 (failed to fully substitute for THC at 100 mg/kg). Structural classes: indazole, indole, benzimidazole.","methodology":"Behavioral pharmacology study testing 11 DEA-identified synthetic cannabinoids. Locomotor activity measured in Swiss-Webster mice. Drug discrimination conducted in Sprague-Dawley rats trained to discriminate THC. ED50 values calculated for each compound relative to THC in both assays.","limitations":"Rodent behavioral models may not perfectly predict human pharmacological responses. Only two behavioral measures tested — other important properties (duration of action, receptor binding profiles, toxicity) were not assessed. The ED50 comparisons provide relative potency but don't directly translate to human dosing. New synthetic cannabinoids appear faster than they can be characterized."},{"rthcId":"RTHC-08619","title":"Pharmacokinetics and tolerability of liposomal synthetic cannabidiol subcutaneous depot in Holstein dairy calves.","authors":"Shilo-Benjamini, Y; Dos Santos Silva, P; Cern, A; Aroch, I; Abu Ahmad, W; Barasch, D; Lavy, E; Barenholz, Y; Zachut, M","year":2026,"journal":"Journal of dairy science, 109(2), 1936-1950","doi":"10.3168/jds.2025-27373","pmid":"41349822","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08620","title":"Adjunctive cannabidiol in intractable pediatric epilepsy: A retrospective study on tolerability, efficacy, and safety across genetic and nongenetic etiologies.","authors":"Shim, Youngkyu; Yang, Dong Hwa; Byeon, Jung Hye; Eun, Baik-Lin","year":2026,"journal":"Medicine, 105(5), e47425","doi":"10.1097/MD.0000000000047425","pmid":"41630268","tags":["epilepsy","cbd","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"At 12 months, 79.3% of patients achieved 50% or greater seizure reduction and 34.5% achieved 75% or greater reduction without generalized motor seizures. The retention rate exceeded 86% at both 12 and 24 months. One patient with a GABRB3 variant achieved seizure freedom.","whyItMatters":"Children with intractable epilepsy have often exhausted conventional treatment options. This study shows CBD maintained effectiveness across a range of genetic and non-genetic epilepsy causes, including some rarely studied variants.","specificNumbers":"29 patients. Median maintenance dose 14.2 mg/kg/day. Retention above 86% at 12 and 24 months. 79.3% achieved 50%+ seizure reduction at 12 months. 34.5% achieved 75%+ reduction. Adverse events in 37.9%, mostly somnolence and lethargy. 3 discontinuations.","methodology":"Retrospective cohort study of 29 patients aged 6-24 years with pediatric-onset intractable epilepsy treated at Korea University Hospitals between April 2019 and May 2024. Median follow-up was 14.3 months. Patients were on a median of 5 antiseizure medications at CBD initiation.","limitations":"Retrospective design with a small sample of 29 patients. Single center in South Korea. No control group. Patients were on multiple concurrent medications, making it difficult to isolate CBD effects."},{"rthcId":"RTHC-08621","title":"Measuring cannabis use and cannabis-related consequences among college students who engage in simultaneous alcohol and cannabis use: Associations by type of cannabis product and mode of use on weekend days with cannabis.","authors":"Shipley, Jennifer L; Chiang, Shou-Chun; Linden-Carmichael, Ashley N","year":2026,"journal":"Addictive behaviors, 173, 108534","doi":"10.1016/j.addbeh.2025.108534","pmid":"41172721","tags":["youth","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Participants reported more hits on days using joints, vapes, blunts, or other modes compared to bong use. Greater odds of negative consequences occurred on days using joints or blunts compared to bongs. Plant cannabis was the most common type and bongs the most common mode.","whyItMatters":"As cannabis legalization expands and consumption methods diversify, understanding which modes of use are linked to heavier consumption and more negative outcomes can inform harm reduction messaging for young adults.","specificNumbers":"88 participants, mean age 20.49. Plant was most endorsed cannabis type. Bongs were most common mode. Multilevel models showed more hits on joint, vape, blunt, and other mode days versus bong days. Greater odds of negative consequences on joint and blunt days versus bong days.","methodology":"Ecological momentary assessment study over 4 weekends with 88 college students aged 18-25 who endorsed weekly simultaneous alcohol and cannabis use. Cannabis use behavior was assessed during morning prompts including type, mode, number of hits, and consequences.","limitations":"Small sample of 88 students from one university. All participants used both alcohol and cannabis simultaneously, limiting generalizability. Self-reported data collected the morning after use. Short 4-weekend observation period."},{"rthcId":"RTHC-08622","title":"A 2025 Nationwide Cross-Sectional Survey on Public Attitudes Toward the Legalization and Depenalization of Recreational Cannabis in Poland.","authors":"Silczuk, Andrzej; Jankowski, Mateusz; Mularczyk-Tomczewska, Paulina; Olearczyk, Agata; Baran, Tomasz; Wrześniewska-Wal, Iwona; Grudziąż-Sękowska, Justyna; Gujski, Mariusz; Łoś, Magdalena","year":2026,"journal":"Medical science monitor : international medical journal of experimental and clinical research, 32, e951939","doi":"10.12659/MSM.951939","pmid":"41715907","tags":["legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Eight years after medical cannabis legalization in Poland, 29.6% supported full recreational legalization, 39.6% favored depenalization (legal possession up to 100g or 3 plants), and 18.7% perceived cannabis as easily accessible. Support was associated with male sex, younger age (18-29), urban residence, and higher economic status.","whyItMatters":"Poland legalized medical cannabis in 2017, and this is the first large-scale survey capturing where public opinion stands years later. The clear preference for depenalization over full legalization reveals a nuanced policy gradient relevant to other Central and Eastern European countries.","specificNumbers":"1,113 respondents. 29.6% support full legalization. 39.6% favor depenalization. 18.7% perceive cannabis as easily accessible. 32.4% worry medical legalization leads to recreational use. Support strongest among males, ages 18-29, urban residents.","methodology":"Cross-sectional nationwide computer-assisted web interviewing survey conducted July 11-13, 2025 with a representative sample of 1,113 Polish adults. Multivariable logistic regression identified factors associated with attitudes toward legalization and depenalization.","limitations":"Online survey may underrepresent older adults and those without internet access. Three-day data collection period is short. Self-reported attitudes may not predict actual behavior or voting preferences."},{"rthcId":"RTHC-08623","title":"Local Cannabis Policy and Cannabis Use by California High School Students Before and After Statewide Retail Legalization.","authors":"Simard, Bethany J; Padon, Alisa A; Silver, Lynn D; Timberlake, David S; Young-Wolff, Kelly C","year":2026,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 78(1), 69-77","doi":"10.1016/j.jadohealth.2025.09.003","pmid":"41071143","tags":["legalization","youth"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Frequent cannabis use among 11th graders increased post-retail legalization. Any past-30-day use initially rose then slowly declined, except in jurisdictions newly allowing storefront and delivery retail, where elevated rates persisted. Cannabis use was consistently lower in jurisdictions that banned retail and lacked pre-existing medical sales.","whyItMatters":"This is one of the largest studies examining how local cannabis retail policies affect youth use. The finding that local bans were associated with lower use, while new retail access sustained higher rates, has direct implications for communities making zoning decisions.","specificNumbers":"377,205 11th graders surveyed. Any past-30-day use increased post-legalization (OR 1.06, p=.013) then slowly declined (OR 0.97 per period, p=.001). Frequent use increased substantially (OR 1.30, p<.001 for level change; OR 1.13, p<.001 for slope change). Results varied significantly by local retail policy.","methodology":"Adjusted interrupted time-series multilevel models analyzed cross-sectional data from the 2015/2016 to 2019/2020 California Healthy Kids Surveys (n=377,205 11th graders). Changes in past-30-day and frequent cannabis use were assessed pre- and post-retail legalization, stratified by local city and county cannabis retail policies.","limitations":"Cross-sectional survey design cannot track individual students over time. Self-reported data subject to social desirability bias. Data ends spring 2020, so pandemic effects are a potential confounder. Pre-existing community norms likely influenced both local policies and baseline use rates."},{"rthcId":"RTHC-08624","title":"In-silico and In-vitro role of chimeric peptide on the impact of nsSNPs in human Cannabinoid receptors 1 and 2.","authors":"Simon, Jerine Peter; Bao, Huiming; Niu, Zhanyu; Man, Hongyang; Dong, Shouliang","year":2026,"journal":"Computers in biology and medicine, 202, 111451","doi":"10.1016/j.compbiomed.2026.111451","pmid":"41506029","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08625","title":"Characterization of the Formation of the Acyl Glucuronide Metabolite of 7-Carboxy-Cannabidiol in Human Liver, Kidney, and Intestinal Microsomes and in Vivo in Mice.","authors":"Simon, Keiann T; Hailemariam, Saron E; Friedman, Eli; Wen, Yue Winnie; Freaney, Michael; Barker-Haliski, Melissa; Isoherranen, Nina","year":2026,"journal":"ACS medicinal chemistry letters, 17(2), 391-401","doi":"10.1021/acsmedchemlett.5c00588","pmid":"41696650","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08626","title":"Complex Attention-Deficit Hyperactivity Disorder in a 15-year-old With a Substance Use Disorder.","authors":"Simon, Kevin M; Sukkarieh, Modar; Walsh, Emmett; Green, Leslie; Gates, Laurie A; Diekroger, Elizabeth A; Fogler, Jason M","year":2026,"journal":"Journal of developmental and behavioral pediatrics : JDBP, 47(1), e91-e93","doi":"10.1097/DBP.0000000000001430","pmid":"41685752","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08627","title":"Evidence-based consensus guidelines for the pharmacological management of substance dependence: Recommendations from the British Association for Psychopharmacology.","authors":"Sinclair, Julia Ma; Kalk, Nicola J; Kaar, Stephen J; Agabio, Roberta; Arunogiri, Shalini; Bisaga, Adam; Chesney, Edward; Daly, Chris; Dewhurst, Jonathan; Freeman, Tom P; Ghosh, Abhishek; Hemrage, Sophia; Leggio, Lorenzo; Lingford-Hughes, Anne; Matheson, Catriona; McKetin, Rebecca; Paterson, Louise M; Roberts, Emmert; Robson, Deborah; Scott, Jenny; Welch, Sarah","year":2026,"journal":"Journal of psychopharmacology (Oxford, England), 2698811251399593","doi":"10.1177/02698811251399593","pmid":"41731947","tags":["addiction","quitting","synthetic-cannabinoids"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"The British Association for Psychopharmacology convened international experts to produce evidence-based consensus guidelines for the pharmacological management of substance dependence across all major drug classes.\n\nFor cannabis and synthetic cannabinoid dependence, the guidelines revealed a stark gap: no medications have received regulatory approval for treatment. The expert panel reviewed available evidence and made recommendations for clinical decision-making, but the recommendations necessarily relied on off-label use and behavioral interventions rather than approved pharmacotherapies.\n\nThis contrasted with the more developed treatment landscapes for alcohol (multiple approved medications including naltrexone and acamprosate), opioids (methadone, buprenorphine, naltrexone), and nicotine (nicotine replacement, varenicline, bupropion). The guidelines also covered benzodiazepines, GHB, gabapentinoids, cocaine, amphetamines, and dissociative drugs.\n\nFor synthetic cannabinoids specifically — which produce more severe dependence and withdrawal than natural cannabis — the guidelines highlighted both the clinical urgency and the near-complete absence of evidence to guide treatment.","whyItMatters":"These guidelines from a major professional body formalize what clinicians treating cannabis dependence already know: they have no approved medications to offer. As cannabis potency increases and cannabis use disorder becomes more prevalent, this treatment gap becomes more consequential. The inclusion of synthetic cannabinoids acknowledges that this newer category requires its own clinical approach.","specificNumbers":"11 substance classes covered: alcohol, benzodiazepines, z-drugs, GHB, gabapentinoids, opioids, nicotine, cannabis, synthetic cannabinoids, cocaine, amphetamine/methamphetamine, dissociative drugs. Zero approved medications for cannabis or synthetic cannabinoid dependence.","methodology":"Consensus guidelines developed by the British Association for Psychopharmacology. International experts from multiple disciplines reviewed current evidence in their fields, assessed evidence strength, and discussed clinical implications at a consensus meeting. Covered pharmacological management of dependence on 11 substance classes.","limitations":"Consensus guidelines reflect expert opinion and available evidence, which may be limited or conflicting. The guidelines are UK-focused and may not account for regulatory or clinical differences in other countries. Cannabis products and potency vary widely, and guidelines may not address all product types. Rapidly evolving synthetic cannabinoid landscape means these recommendations may need frequent updating."},{"rthcId":"RTHC-08628","title":"Cannabis and Endometriosis: When Is an Adverse Effect Not Adverse?","authors":"Sinclair, Justin; Adler, Hannah; Eathorne, Allie; Holtzman, Orit; Ee, Carolyn; Abbott, Jason; Sarris, Jerome; Armour, Mike","year":2026,"journal":"The Australian & New Zealand journal of obstetrics & gynaecology, 66(1), e70076","doi":"10.1111/ajo.70076","pmid":"41249881","tags":["medical-cannabis","pain","sex-differences"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Among endometriosis patients using cannabis for symptom management, 32% experienced side effects, consistent with published literature. However, the study suggests that some reported adverse effects may have clinical utility in the endometriosis population and require more nuanced interpretation.","whyItMatters":"Endometriosis patients are increasingly turning to cannabis for pain management, often without medical guidance. Reframing certain \"side effects\" as potentially beneficial challenges the binary categorization of drug effects and could inform more patient-centered care.","specificNumbers":"889 participants in the larger survey. 32% of cannabis users reported side effects. The study was a subset analysis examining whether reported adverse effects have therapeutic relevance.","methodology":"Subset analysis of a larger international survey (n=889) investigating self-reported effectiveness, safety, and pharmaceutical de-prescribing trends of cannabis use among people with endometriosis.","limitations":"Survey-based self-reported data. Subset of a larger study, so the specific sample size for this analysis is unclear. No clinical verification of endometriosis diagnosis or cannabis use. International sample with varying legal and product quality contexts."},{"rthcId":"RTHC-08629","title":"Therapeutic potential of cannabidiol-rich Cannabis sativa to mitigate the severity of inflammation and pain: A pre-clinical study.","authors":"Singh, Munmun Kumar; Sen, Sumati; Singh, Swati; Aftab, Nashra; Kumar, Birendra; Gupta, Namita; Tandon, Sudeep; Bawankule, Dnyaneshwar Umrao; Verma, Ram Swaroop","year":2026,"journal":"Journal of ethnopharmacology, 357, 120856","doi":"10.1016/j.jep.2025.120856","pmid":"41213439","tags":["cbd","pain","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"The CBD-rich cannabis extract (CSFE) significantly reduced TNF-alpha and IL-6 production in LPS-stimulated macrophages at 3, 10, and 30 mcg/ml without cytotoxicity. In animal models, it demonstrated dose-dependent decreases in inflammation and improvements in pain relief.","whyItMatters":"Most cannabis pain research focuses on isolated CBD or THC. This study examines a full-spectrum CBD-rich extract with characterized chemical composition, supporting the idea that the entourage effect of multiple cannabis compounds may contribute to therapeutic outcomes.","specificNumbers":"62 compounds identified in the extract. Major cannabinoids: CBD (9.75%), CBDA (2.76%), THC (4.40%). Pro-inflammatory cytokine reduction at 3, 10, and 30 mcg/ml concentrations. Significant dose-dependent anti-inflammatory and analgesic effects in animal models.","methodology":"Chemical characterization of a supercritical CO2 extract of Cannabis sativa genotype CIM-CS-64 using GC-FID, GC-MS, HPLC, HRMS, and NMR. In vitro anti-inflammatory testing in LPS-stimulated macrophages. In vivo inflammation and pain models in small laboratory animals.","limitations":"Animal study results may not translate to humans. The extract contains THC (4.40%) alongside CBD, so effects cannot be attributed to CBD alone. Specific animal models and doses used in vivo were not detailed in the abstract."},{"rthcId":"RTHC-08630","title":"Therapeutic potential of acidic cannabinoids: an update.","authors":"Singh, Santosh Kumar; Antoine, Coralie; Tse, Calvin; Ji, Lawrence; Reed, Miranda; Carter, Wayne Grant; Trezza, Viviana; Bid, Hemant Kumar","year":2026,"journal":"Journal of cannabis research, 8(1), 25","doi":"10.1186/s42238-026-00387-y","pmid":"41545891","tags":["cbd","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"Acidic cannabinoids show unique biological activities distinct from their neutral counterparts, including neuroprotective, anti-inflammatory, anticonvulsant, and anti-proliferative effects mediated through 5-HT1A receptors, COX-2, TRP channels, and PPARgamma. They are non-intoxicating in unheated form, making them potentially suitable for children and elderly patients.","whyItMatters":"Most cannabis research focuses on THC and CBD, their neutral (decarboxylated) forms. The acidic precursors THCA and CBDA are what the plant actually produces, and they appear to have their own therapeutic profiles that are only beginning to be understood.","specificNumbers":"Review covered four main acidic cannabinoids: THCA, CBDA, CBGA, and CBCA. Molecular targets include 5-HT1A receptors, COX-2, TRP channels, and PPARgamma. Acidic forms are non-intoxicating (in unheated consumption), unlike THC.","methodology":"Systematic narrative review of peer-reviewed literature from major scientific databases focusing on acidic cannabinoid chemistry, pharmacology, pharmacokinetics, and disease-specific applications.","limitations":"Narrative review without systematic methodology for study selection. Most evidence is preclinical. Chemical instability of acidic cannabinoids poses challenges for drug development. The non-intoxicating claim applies only to non-heated consumption; heating converts THCA to psychoactive THC."},{"rthcId":"RTHC-08631","title":"Motivations for Cannabis Use During Pregnancy: An Analysis of 2017-2021 Pregnancy Assessment Monitoring System Data.","authors":"Skelton, Kara R; Iobst, Stacey E; Benjamin-Neelon, Sara E","year":2026,"journal":"Journal of women's health (2002), 15409996261424794","doi":"10.1177/15409996261424794","pmid":"41693284","tags":["pregnancy"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"The most common motivations for prenatal cannabis use were mental health reasons (82.81%), gastrointestinal symptom relief (77.10%), pain relief (48.67%), fun or relaxation (40.18%), and chronic condition symptoms (26.31%). Most women (84.32%) reported multiple reasons, which was associated with daily or near-daily use.","whyItMatters":"Understanding why pregnant women use cannabis is essential for developing effective clinical conversations. The finding that most users cite multiple overlapping reasons, particularly mental health and nausea, suggests they may be self-treating common pregnancy symptoms.","specificNumbers":"Data representing ~802,954 live births from 10 states. Mental health: 82.81%. GI symptoms: 77.10%. Pain: 48.67%. Fun/relaxation: 40.18%. Chronic conditions: 26.31%. Multiple reasons: 84.32%. Write-in responses: 54.90% cited pregnancy-related symptoms (nausea, appetite, sleep).","methodology":"Analysis of 2017-2021 Pregnancy Risk Assessment Monitoring System (PRAMS) Marijuana Supplement data from 10 U.S. states. Weighted prevalence estimates of self-reported motivations for prenatal cannabis use were calculated and examined across sociodemographic characteristics and frequency of use.","limitations":"Self-reported data from a surveillance system. Only 10 U.S. states participated in the marijuana supplement. Data from 2017-2021 may not reflect current patterns. Women who did not report cannabis use are excluded, likely underestimating prevalence."},{"rthcId":"RTHC-08632","title":"Cannabis use measurement: Identifying the optimal metric for broad research applications.","authors":"Skrzynski, Carillon J; Mueller, Raeghan L; Bidwell, L Cinnamon; Bryan, Angela D; Hutchison, Kent E","year":2026,"journal":"Addiction (Abingdon, England), 121(2), 331-339","doi":"10.1111/add.70205","pmid":"41070711","tags":["potency"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"The Cannabis Quantity and Frequency Scale (CQFS) total times/day metric was a better predictor of the long-term THC metabolite (THC-COOH, R-squared 0.30 vs 0.27) while the Timeline Follow Back (TLFB) days/month metric was better at predicting acute blood THC levels (R-squared 0.24 vs 0.21).","whyItMatters":"Cannabis research is hampered by inconsistent measurement of use. This study provides empirical guidance on which measurement tool to choose depending on the research question, potentially standardizing an area that has long lacked consensus.","specificNumbers":"1,090 participants, mean age 32.89. Average use: 16 days/past month, 4 times/day. 78.35% White, 51.56% female. CQFS model R-squared for THC-COOH: 0.30 vs TLFB 0.27. TLFB model R-squared for THC: 0.24 vs CQFS 0.21. CQFS total times/day predicted THC-COOH (B=5.85, p=.03).","methodology":"Observational study pooling data from five larger studies in the Boulder/Denver area. 1,090 regular cannabis users completed the CQFS (typical quantity/frequency) and TLFB (past-month daily use). Blood biomarkers (THC after acute use and baseline THC-COOH) were collected for comparison.","limitations":"Colorado-based sample of regular users may not generalize to occasional users or other regions. Predominantly White sample. Biomarker collection at a single time point. The five pooled studies may have had varying protocols."},{"rthcId":"RTHC-08633","title":"Medical Cannabis and Opioid Receipt Among Adults With Chronic Pain.","authors":"Slawek, Deepika E; Zhang, Chenshu; Dahmer, Stephen; Sohler, Nancy; Zolotov, Yuval; Starrels, Joanna L; Deng, Yuting; Calderon DiFrancesca, Giovanna; Levin, Frances R; Ross, Jonathan; Minami, Haruka; Cunningham, Chinazo O; Arnsten, Julia H","year":2026,"journal":"JAMA internal medicine, 186(2), 252-261","doi":"10.1001/jamainternmed.2025.6496","pmid":"41359313","tags":["medical-cannabis","pain","harm-reduction"],"studyType":"prospective-cohort","evidenceStrength":"strong","keyFinding":"Compared to months with no medical cannabis dispensed, a 30-day supply of medical cannabis was associated with 3.53 fewer daily morphine milliequivalents (MME). Mean daily MME decreased from 73.3 at baseline to 57.4 over 18 months of follow-up. The analysis used marginal structural models controlling for unregulated cannabis use.","whyItMatters":"Published in JAMA Internal Medicine, this is one of the most methodologically rigorous studies on medical cannabis and opioid substitution. The use of prescription monitoring data (not just self-report) and marginal structural models accounting for unregulated cannabis use strengthens the causal inference.","specificNumbers":"204 participants, mean age 56.8, 55.4% female. Baseline pain severity 6.6/10, pain interference 6.8/10. Baseline daily MME: 73.3, decreasing to 57.4 over 18 months. 30-day cannabis supply associated with 3.53 fewer daily MME (95% CI: -6.68 to -0.04, p=.03).","methodology":"Prospective cohort study using New York State Prescription Monitoring Program data from September 2018 to July 2023. 204 adults with chronic pain who were prescribed opioids and newly certified for medical cannabis were followed for 18 months. Monthly cannabis dispensation was monitored and linked to opioid prescription data.","limitations":"Observational cohort without randomization. Bronx, New York setting may not generalize to other populations. Moderate sample of 204 patients. Cannabis dispensation data may not perfectly capture actual consumption. The 3.53 MME reduction, while statistically significant, is modest."},{"rthcId":"RTHC-08634","title":"Reframing Cannabis in Social Work and Public Health: From Prohibition to Equity.","authors":"Smith Ms Lcsw-C, Paulette S","year":2026,"journal":"Social work in public health, 41(2), 130-134","doi":"10.1080/19371918.2025.2573380","pmid":"41063514","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08635","title":"Dopamine, γ-aminobutyric acid, and glutamate balance in the nucleus accumbens shell: Differential effects of cannabinoid 1 receptor agonists Δ9-Tetrahydrocannabinol, AM11101, and AM8936.","authors":"Smith, Evan C; Iliopoulos-Tsoutsouvas, Christos; Georgiadis, Markos; Nikas, Spyros P; Brijlall, Karena; Makriyannis, Alexandros; Desai, Rajeev I","year":2026,"journal":"Neuropharmacology, 110891","doi":"10.1016/j.neuropharm.2026.110891","pmid":"41740902","tags":["dopamine","neuroscience","addiction"],"studyType":"animal-study","evidenceStrength":"moderate","keyFinding":"Low-dose THC increased dopamine and GABA in the nucleus accumbens shell, while high-dose THC decreased dopamine. The full CB1 agonist AM8936 increased all three neurotransmitters at low doses. The partial agonist AM11101 failed to substantially alter any neurotransmitter and did not produce conditioned place preference, suggesting it lacks rewarding properties.","whyItMatters":"Understanding how cannabinoids affect the dopamine-GABA-glutamate balance in reward circuits is fundamental to understanding both cannabis addiction potential and the development of CB1-based therapeutics that might treat pain without producing reward.","specificNumbers":"Three CB1 agonists tested: THC (natural), AM11101 (partial synthetic), AM8936 (full synthetic). Neurotransmitter monitoring for 5 hours post-injection. THC and AM8936 produced conditioned place preference; AM11101 did not. Correlation analysis revealed DA-GABA and Glu-GABA relationships for THC at early time points.","methodology":"In vivo microdialysis combined with liquid chromatography-mass spectrometry in male mice, measuring dopamine, glutamate, and GABA in the nucleus accumbens shell for 5 hours after single intraperitoneal injections of THC, AM11101, or AM8936. Conditioned place preference testing assessed rewarding effects.","limitations":"Mouse study using only male animals. Single-dose design does not capture chronic exposure effects. Synthetic agonists may not perfectly model natural cannabis use. Nucleus accumbens shell is one of several reward-related regions."},{"rthcId":"RTHC-08636","title":"Longitudinal trends in the past 30-day co-use of nicotine/tobacco, alcohol, and cannabis among youth and adults in the PATH study.","authors":"Sokolovsky, Alexander W; Micalizzi, Lauren; Murphy, Cara M","year":2026,"journal":"Addictive behaviors, 176, 108633","doi":"10.1016/j.addbeh.2026.108633","pmid":"41650519","tags":["youth","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"E-cigarette and alcohol co-use increased among young adults (18-34), possibly replacing cigarette-alcohol co-use which declined. E-cigarette and cannabis co-use increased at Wave 5 among those 15-34, though this increase lessened at Wave 6 for most groups except ages 25-34. Cigarette-cannabis co-use rates were generally stable or decreasing.","whyItMatters":"Co-use of multiple substances carries risks beyond single-product use. As the substance landscape shifts toward vaping, understanding how co-use patterns evolve across age groups helps target public health messaging and intervention.","specificNumbers":"PATH Study Waves 4-6, ages 15+. Five age groups analyzed: 15-17, 18-24, 25-34, 35-64, 65+. E-cigarette and cannabis co-use increased at Wave 5 among those 15-17, 18-24, and 25-34. Cigarette-alcohol co-use declined among 18-24 and 25-34 year olds.","methodology":"Longitudinal analysis of PATH Study Waves 4-6 (December 2016 to November 2021) including all participants age 15+. Changes in past 30-day co-use of cigarettes, e-cigarettes, and other tobacco products with alcohol and cannabis were examined, moderated by age group and controlling for demographics.","limitations":"Self-reported data. Co-use defined as same 30-day period, not necessarily simultaneous use. Data ends November 2021, missing post-pandemic recovery period. Broad product categories may mask important variation."},{"rthcId":"RTHC-08637","title":"Integrating Genetic and Biotechnological Approaches to Enhance High-CBD Cannabis sativa L. Cultivation for Medicinal Purposes.","authors":"Sokuma, Aran; Chatsungnoen, Tawan; Susawaengsup, Chanthana; Tongkoom, Krittiya; Bhuyar, Prakash","year":2026,"journal":"Molecular biotechnology","doi":"10.1007/s12033-026-01559-0","pmid":"41741936","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08638","title":"Anticancer Potential of Cannabidiol in Renal Cell Carcinoma: Serum Modulation and Preliminary Mechanistic Insights.","authors":"Sousa, Débora; Amaro, Filipa; Araújo, Ana Margarida; Carvalho, Márcia","year":2026,"journal":"Journal of clinical medicine, 15(2)","doi":"10.3390/jcm15020792","pmid":"41598729","tags":["cancer","cbd"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"CBD decreased renal cell carcinoma (RCC) cell viability and proliferation dose-dependently and induced reactive oxygen species accumulation. However, non-tumoral kidney cells showed comparable sensitivity (no tumor selectivity), and serum supplementation markedly attenuated all effects due to CBD's high protein binding.","whyItMatters":"This study is a reality check for CBD-as-cancer-treatment claims. While CBD does kill cancer cells in a dish, it equally kills normal kidney cells and loses potency when serum proteins are present, highlighting the gap between laboratory findings and clinical applicability.","specificNumbers":"CBD tested at 1-100 mcM for up to 48 hours. Two RCC cell lines (Caki-1, 769-P) and one non-tumoral line (HK-2) tested. Comparable sensitivity across tumoral and non-tumoral cells. Effects markedly attenuated with 5% serum supplementation.","methodology":"Human RCC cell lines (Caki-1 and 769-P) and non-tumoral renal cells (HK-2) were treated with CBD (1-100 mcM) for up to 48 hours under serum-free and 5% serum conditions. Cell viability was assessed by MTT assay and ROS/RNS levels by fluorescence assay.","limitations":"In vitro study only. The concentrations showing effects exceed clinically achievable plasma levels. Only two RCC cell lines tested. Serum conditions in vitro may not perfectly model in vivo protein binding."},{"rthcId":"RTHC-08639","title":"The role of the endocannabinoid system in the interplay of adverse childhood experiences and interleukin 6 in individuals with borderline personality disorder.","authors":"Spohrs, Jennifer; Kühnle, Valentin; Reber, Stefan O; Mikusky, David; Sanhüter, Niklas; Macchia, Ana; Nickel, Sandra; Abler, Birgit","year":2026,"journal":"Psychopharmacology, 243(2), 315-324","doi":"10.1007/s00213-025-06809-8","pmid":"40381004","tags":["mental-health","neuroscience","inflammation"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"People with BPD had higher IL-6 levels than healthy controls. Endocannabinoids (AEA and 2-AG) correlated positively with IL-6 across all participants. The link between childhood trauma and IL-6 was strongest in participants with low endocannabinoid levels, while those with the highest endocannabinoid levels showed no correlation between trauma and inflammation.","whyItMatters":"This study connects three systems rarely examined together: childhood trauma, the immune system, and the endocannabinoid system. The finding that endocannabinoids may buffer the trauma-inflammation link suggests a potential mechanism for why some trauma survivors develop inflammatory conditions and others do not.","specificNumbers":"48 females with BPD and 31 healthy controls. Higher IL-6 in BPD group. AEA and 2-AG positively correlated with IL-6. Trauma-IL-6 correlation strong in lowest three endocannabinoid quartiles (n=57) but absent in highest quartile (n=19). Recent suicide attempts significantly higher in high-IL-6 group (OR=0.22).","methodology":"Cross-sectional analysis of 48 females with borderline personality disorder and 31 matched healthy controls. Adverse childhood experiences were assessed via the Childhood Trauma Questionnaire. Plasma IL-6, anandamide (AEA), and 2-AG concentrations were measured.","limitations":"Cross-sectional design cannot establish causality. Female-only sample. Small sample sizes, especially in subgroup analyses. Single time-point measurements of endocannabinoids and IL-6 may not capture dynamic fluctuations."},{"rthcId":"RTHC-08640","title":"Latent profiles of cannabis use patterns and associations with eating pathology outcomes.","authors":"Stanley, Taylor B; Kearns, Nathan T; Smith, April R","year":2026,"journal":"Addictive behaviors, 174, 108564","doi":"10.1016/j.addbeh.2025.108564","pmid":"41270485","tags":["appetite","mental-health"],"studyType":"cross-sectional","evidenceStrength":"preliminary","keyFinding":"Four profiles of cannabis users were identified: infrequent/low-risk, intense/mild-risk, high-risk coping with strong eating changes, and frequent/mild-risk. All profiles reported more binge eating while under the influence of cannabis. The high-risk coping profile had the most severe sober binge eating, eating disorder symptoms, and emotion regulation difficulties.","whyItMatters":"Cannabis is well known to increase appetite, but its relationship to disordered eating patterns is poorly understood. This person-centered approach reveals that not all cannabis users face the same eating-related risks, with coping-motivated users most vulnerable.","specificNumbers":"435 participants (189 male). Four profiles identified. All profiles showed increased binge eating while using cannabis. \"High-Risk Coping Users, Strong Eating Changes\" profile had the most severe sober binge eating, eating disorder symptoms, and emotion regulation difficulties.","methodology":"Cross-sectional study of 435 adults (189 male) recruited through Prolific who endorsed past-month cannabis use. Latent profile analysis based on cannabis use characteristics including subjective changes to appetite and hedonic food properties. Profiles were compared on binge eating, eating disorder symptoms, and emotion regulation.","limitations":"Cross-sectional design cannot determine whether cannabis use causes binge eating or vice versa. Online convenience sample via Prolific. Self-reported data. Recreational cannabis users only, excluding medical users."},{"rthcId":"RTHC-08641","title":"Cannabis and pediatric cannabis exposure - evidence from America's Poison Centers.","authors":"Steuart, Shelby R; Bethel, Victoria; Bradford, W David","year":2026,"journal":"Journal of child psychology and psychiatry, and allied disciplines, 67(3), 400-412","doi":"10.1111/jcpp.70058","pmid":"41077545","tags":["youth","legalization"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"Medical cannabis dispensary openings were associated with a 52.3% increase in cannabis exposures among children ages 2-6. However, when recreational dispensaries opened, exposures in this age group decreased by 42.4% relative to medical-only states. Children 7-11 also saw a 26.6% decrease with recreational dispensaries. No significant effects were found for adolescents or young adults.","whyItMatters":"The counterintuitive finding that recreational dispensaries reduced pediatric exposures compared to medical-only states suggests that maturation of cannabis markets brings better packaging, labeling, and public education that protects children.","specificNumbers":"36,161 cannabis exposures ages 2-20 from 2016-2021. Ages 2-6: 96.3% unintentional exposures; 52.3% increase with medical dispensaries (CI 37.5-67.0, p<.001); 42.4% decrease with recreational (CI -62.2 to -22.6, p<.001). Ages 7-11: 82.4% unintentional; 26.6% decrease with recreational (CI -45.1 to -8.1). Ages 12-17: 79.9% intentional. Ages 18-20: 77.5% intentional.","methodology":"Difference-in-difference analysis of 36,161 cannabis-related exposures for individuals aged 2-20 reported to the National Poison Data System from 2016 to 2021. Effects of medical and recreational cannabis dispensary openings were estimated by age group (2-6, 7-11, 12-17, 18-20).","limitations":"Poison center data capture only reported exposures, likely underestimating true incidence. Cannot account for all state-level policy differences. Recreational dispensary openings often coincide with enhanced packaging and education requirements. Data ends 2021."},{"rthcId":"RTHC-08642","title":"The toxicology of orally administered Δ9-tetrahydrocannabinol in sheep.","authors":"Stevens, Sarah A; Edwards, Scott H; Noble, Glenys K; Scrivener, Colin J; Petzel, Christopher E; May, Christopher D; Tai, Zi Xuan; Blake, Bronwyn L; Dods, Kenneth C; Warne, Leon N; Krebs, Gaye L","year":2026,"journal":"Toxicology reports, 16, 102221","doi":"10.1016/j.toxrep.2026.102221","pmid":"41732551","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08643","title":"Population pharmacokinetic modelling revealed large variability in oromucosal absorption of Δ9-tetrahydrocannabinol in older patients with poor appetite.","authors":"Storgaard, Ida Klitzing; Nielsen, Rikke Lundsgaard; Houlind, Morten Baltzer; Bornæs, Olivia; Christensen, Louise Westberg Strejby; Andersen, Aino Leegaard; Juul-Larsen, Helle Gybel; Jørgensen, Lillian Mørch; Breindahl, Torben; Jawad, Baker Nawfal; Altintas, Izzet; Andersen, Ove; Lund, Trine Meldgaard","year":2026,"journal":"British journal of clinical pharmacology, 92(2), 504-514","doi":"10.1002/bcp.70284","pmid":"40974011","tags":["seniors","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"THC pharmacokinetics in older patients showed enormous variability, with coefficient of variation ranging from 40.2% to 152% across pharmacokinetic parameters. A one-compartment model best described THC, with apparent clearance through conversion to THC-OH at 765 L/h. No physiological characteristics including kidney function or body composition significantly influenced pharmacokinetics.","whyItMatters":"Older adults are an increasingly important population for cannabis-based medicines, yet almost all pharmacokinetic data comes from younger, healthy volunteers. The extreme variability found here means dosing guidelines developed in younger populations may be unreliable for elderly patients.","specificNumbers":"20 older patients. Two doses of 2.7 mg THC per spray (2-3 sprays each). THC clearance to THC-OH: 765 L/h. Clearance by other pathways: 162 L/h. Inter- and intra-individual variability: CV 40.2-152%. Absorption modeled with 3 transit compartments.","methodology":"Twenty older medical patients with poor appetite received two fixed doses of Sativex oromucosal spray (2-3 sprays of 2.7 mg THC each, 4 hours apart). Blood samples were collected for 8 hours. Non-linear mixed-effects modeling developed population pharmacokinetic models for THC and its active metabolite THC-OH.","limitations":"Small sample of 20 patients. Single oromucosal product (Sativex). Eight-hour blood sampling may miss later pharmacokinetic phases. Poor appetite itself may affect oromucosal absorption. No comparison with younger adults in the same study."},{"rthcId":"RTHC-08644","title":"Phytocannabinoids as anti-inflammatory agents: Synergistic effects when combined with Cannabis sativa L. matrices.","authors":"Strnad, Ondřej; Nejedlý, Tomáš; Svoboda, Petr; Mertlíková-Kaiserová, Helena; Malý, Martin; Malý, Matěj; Stránská, Milena; Viktorová, Jitka","year":2026,"journal":"Journal of ethnopharmacology, 360, 121134","doi":"10.1016/j.jep.2025.121134","pmid":"41478536","tags":["cbd","inflammation"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"All ten tested non-psychoactive phytocannabinoids demonstrated anti-inflammatory effects. CBDV was particularly effective, reducing IL-6, TNF-alpha, and inhibiting NF-kB activation. Acidic cannabinoid forms showed high antioxidant capacity (ORAC) but limited cellular antioxidant activity. Combinations containing CBG or CBN with cannabis plant matrices showed particularly potent synergistic anti-inflammatory effects.","whyItMatters":"Most cannabis research focuses on CBD and THC, but this study systematically compares ten cannabinoids and shows that lesser-known compounds like CBDV, CBG, and CBN may be more effective for inflammation, especially in combination with other plant compounds.","specificNumbers":"Ten non-psychotropic cannabinoids tested. CBDV reduced IL-6, TNF-alpha, and NF-kB. Acidic forms showed high ORAC but no significant cellular antioxidant activity. CBG and CBN combinations with plant matrices showed synergistic anti-inflammatory effects.","methodology":"Anti-inflammatory effects of ten major non-psychotropic phytocannabinoids were tested in macrophage-differentiated THP-1 cells by measuring pro-inflammatory cytokines (ELISA) and NF-kB activation (luciferase reporter). Antioxidant activity was assessed by ORAC and cellular antioxidant activity assays. Synergy was tested with three cannabis-derived matrices (polar, non-polar, terpenoid).","limitations":"In vitro study using cell lines, not human subjects. The synergistic effects observed in cells may not translate to oral consumption. Non-polar and terpenoid matrices are complex mixtures making it difficult to identify specific synergy drivers."},{"rthcId":"RTHC-08645","title":"Cannabidiol-hyaluronic acid combination delivered rectally for attenuating abacterial prostatitis symptoms: Single-arm open-label pilot clinical trial.","authors":"Student, Vladimir; Repa, Vaclav; Vrbkova, Jana; Vacek, Jan","year":2026,"journal":"Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia","doi":"10.5507/bp.2026.002","pmid":"41709732","tags":["cbd","pain","medical-cannabis"],"studyType":"pilot-study","evidenceStrength":"preliminary","keyFinding":"In this pilot trial, 16 men aged 24–49 with chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS) self-administered rectal suppositories containing 100 mg CBD and 6.6 mg hyaluronic acid nightly for 30 days.\n\nThe primary outcome — the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) — decreased from a median of 24.5 to 20.0 points (p=0.003), with a median reduction of 7.0 points. Symptom improvement was observed in 81.3% (13 of 16) of participants.\n\nSecondary outcomes also improved: the International Prostate Symptom Score decreased from 14.0 to 12.0 (p=0.033), with voiding symptoms showing the largest improvement. Erectile function scores were also assessed.\n\nThe rectal delivery route is notable because it bypasses the first-pass liver metabolism that limits oral CBD bioavailability (documented in RTHC-00246). Direct delivery to the pelvic region may achieve higher local concentrations than oral administration.","whyItMatters":"CP/CPPS is a common condition with limited treatment options and significant quality-of-life impact. This is one of the first clinical trials of CBD specifically for pelvic pain, and the rectal delivery route addresses CBD's well-known bioavailability problem. While the open-label design means results need confirmation in controlled trials, the 81% response rate is encouraging for a condition where many patients find little relief from standard treatments.","specificNumbers":"16 men, ages 24–49. 30-day treatment. NIH-CPSI: 24.5 → 20.0 (p=0.003), median 7.0-point reduction. Improvement in 81.3% (13/16). IPSS: 14.0 → 12.0 (p=0.033). Suppository: 100 mg CBD + 6.6 mg hyaluronic acid, nightly rectal administration.","methodology":"Single-arm, open-label pilot trial. 16 men (ages 24–49) with CP/CPPS (NIH-CPSI >10, pain subscore ≥4). Self-administered rectal CANNEFF suppositories (100 mg CBD + 6.6 mg hyaluronic acid) nightly for 30 days. Outcomes: NIH-CPSI total score, International Prostate Symptom Score, International Index of Erectile Function. Safety and tolerability assessed.","limitations":"Very small sample (N=16) with no placebo control group — the placebo response in chronic pain conditions is typically 20–40%, so some improvement would be expected without active treatment. Single-arm open-label design cannot establish efficacy. The combined CBD/hyaluronic acid formulation makes it impossible to determine which component is responsible for effects. 30-day treatment period is short for a chronic condition."},{"rthcId":"RTHC-08646","title":"Cannabis Use Among US Adolescents.","authors":"Sultan, Ryan S; Zhang, Alexander W; Becker, Timothy D; Sethaputra, Panijaya; Simon, Kevin M; Huang, Yiting; Levin, Frances R; Levy, Sharon; Olfson, Mark","year":2026,"journal":"Pediatrics, 157(1)","doi":"10.1542/peds.2024-070509","pmid":"41429181","tags":["youth","cognition","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Compared to non-users, even noncurrent and monthly cannabis users had greater odds of poor academic performance (aOR 1.30-2.20), poor impulsivity and self-regulation (aOR 1.26-2.19), and adverse emotional states (aOR 1.1-1.42). A consistent dose-response trend was observed across all adverse categories except low social engagement. Younger users (<16) showed greater susceptibility.","whyItMatters":"Published in Pediatrics, this study challenges the notion that occasional cannabis use is harmless for teens. The dose-response pattern starting at monthly use and the heightened vulnerability of younger adolescents strengthen the case for early prevention.","specificNumbers":"162,532 respondents. Mean age 16.0. 26.2% cannabis users: 4.6% near-daily, 3.6% weekly, 4.8% monthly, 13.2% noncurrent. Effect sizes: academic (d=0.39-0.44), impulsivity (d=0.43-0.55), emotional (d=0.33-0.40), social engagement (d=0.03-0.18). Younger users (<16) showed greater susceptibility for academic and emotional indicators.","methodology":"Cross-sectional analysis of 162,532 respondents from the 2018-2022 Monitoring the Future surveys (US nationally representative 8th, 10th, and 12th graders). Cannabis use frequency categorized as nonuse, noncurrent, monthly, weekly, and near-daily. Demographically adjusted odds ratios calculated for cognitive, social, and emotional indicators.","limitations":"Cross-sectional design cannot establish causality. Associations may reflect pre-existing differences between users and non-users. Self-reported cannabis use may be underreported. Effect sizes were small to moderate. Survey cannot capture cannabis potency or product type."},{"rthcId":"RTHC-08647","title":"The association between cannabis use and cardiovascular outcomes among U.S. Adults, 2020-2023.","authors":"Sun, Ruoyan; Judd, Suzanne E; De, Prabal K","year":2026,"journal":"Addictive behaviors, 172, 108529","doi":"10.1016/j.addbeh.2025.108529","pmid":"41151132","tags":["cardiovascular"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Analyzing data from 436,949 adults surveyed in the Behavioral Risk Factor Surveillance System (BRFSS) between 2020 and 2023, researchers found dose-dependent associations between cannabis use and cardiovascular outcomes.\n\nNon-daily cannabis use (compared to no past-30-day use) was associated with increased odds of stroke (adjusted OR = 1.28) and a composite cardiovascular outcome measure (aOR = 1.16). Daily cannabis use showed even stronger associations, linked to increased odds of stroke and additional cardiovascular endpoints.\n\nThe weighted prevalence of cardiovascular conditions in the sample was: coronary heart disease 4.4%, myocardial infarction 4.5%, stroke 3.6%, and any cardiovascular outcome 9.3%.\n\nThe study also examined whether these associations varied by age and sex, finding potential heterogeneous effects — suggesting that cannabis's cardiovascular risk may not be uniform across the population.\n\nImportantly, the models adjusted for sociodemographics, health status, other substance use, and state-level cannabis laws, with state and year fixed effects to control for unmeasured state characteristics and temporal trends.","whyItMatters":"This is one of the largest studies to date of cannabis and cardiovascular outcomes, using a national surveillance system that captures a representative US population. The stroke association — present even at non-daily use levels — is particularly concerning because stroke risk factors are important public health targets. The dose-response pattern (stronger associations with daily use) strengthens the plausibility of a causal relationship.","specificNumbers":"436,949 adults, 2020–2023. Non-daily use: stroke aOR = 1.28 (95% CI: 1.06–1.54), composite aOR = 1.16 (95% CI: 1.03–1.29). Daily use: higher odds for stroke and additional outcomes. Cardiovascular prevalence: CHD 4.4%, MI 4.5%, stroke 3.6%, any CV outcome 9.3%.","methodology":"Cross-sectional study using BRFSS national survey data from 436,949 adults (2020–2023). Multivariable logistic regression with adjustment for sociodemographics, health status, substance use, and state cannabis laws. State and year fixed effects included. Outcomes: coronary heart disease, myocardial infarction, stroke, and composite cardiovascular measure.","limitations":"Cross-sectional design cannot establish causation. Self-reported cannabis use likely underestimates actual use. Cannot determine method of consumption (smoking vs. edibles vs. vaping), which may differentially affect cardiovascular risk. Residual confounding from unmeasured factors is possible despite extensive adjustment. The BRFSS surveys non-institutionalized adults, missing some high-risk populations."},{"rthcId":"RTHC-08648","title":"Alcohol Use, Cannabis Use, and Discrimination by Sexual Orientation and Gender Identity Within the All of Us Research Program.","authors":"Sunder, Gowri; Tran, Nguyen K; Peña, Juan M; Lunn, Mitchell R; Obedin-Maliver, Juno; Flentje, Annesa","year":2026,"journal":"LGBT health, 13(1), 11-22","doi":"10.1177/23258292251390584","pmid":"41204713","tags":["mental-health","addiction"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Discrimination (measured by the Everyday Discrimination Scale) was positively associated with cannabis use at low-to-moderate levels but the association was not significant at very high discrimination levels. The relationship between discrimination and substance use varied significantly by sexual orientation and gender identity, with pronounced differences among gender minority groups.","whyItMatters":"The nonlinear finding is important: at very high levels of discrimination, the association with substance use weakened or reversed, potentially reflecting withdrawal, avoidance coping, or other survival strategies that differ from moderate-stress substance use patterns.","specificNumbers":"98,820 participants. Mean EDS scores highest among gender minority people assigned female at birth (14.78) and lowest among cisgender heterosexual men (6.14). EDS positively associated with cannabis use at low-moderate levels. Association not significant at 2+ SD above mean EDS. Interaction by sexual orientation and gender group significant (p<.05).","methodology":"Cross-sectional analysis of 98,820 participants from the All of Us Research Program (2017-2022). Adjusted logistic regression examined the relationship between Everyday Discrimination Scale scores and past 3-month cannabis use. Interaction terms assessed differences across sexual orientation and gender modality groups.","limitations":"Cross-sectional design. All of Us Research Program may not be representative of all SGM populations. Self-reported discrimination and substance use. Imprecise estimates for some subgroups due to small sample sizes."},{"rthcId":"RTHC-08649","title":"Acute Effects of Oral Cannabinoids on Sleep and High-Density EEG in Insomnia: A Pilot Randomised Controlled Trial.","authors":"Suraev, Anastasia; McGregor, Iain S; McCartney, Danielle; Marshall, Nathaniel S; Kao, Chien-Hui; Wassing, Rick; D'Rozario, Angela L; Wong, Keith K H; Yee, Brendon J; Sivam, Sheila; Kevin, Richard C; Vandrey, Ryan; Irwin, Christopher; Gordon, Christopher J; Bartlett, Delwyn; Arnold, Jonathon C; Grunstein, Ronald R; Hoyos, Camilla M","year":2026,"journal":"Journal of sleep research, 35(1), e70124","doi":"10.1111/jsr.70124","pmid":"40631525","tags":["sleep","cbd","medical-cannabis"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"In a pilot randomized controlled trial with 20 patients diagnosed with insomnia disorder (16 female, mean age 46), a single oral dose of 10 mg THC and 200 mg CBD was compared to placebo using 256-channel high-density EEG — the most detailed sleep measurement technology available.\n\nThe results contradicted the widespread perception that cannabis aids sleep. THC/CBD decreased total sleep time by 24.5 minutes (p=0.05, d=−0.5) with no improvement in wake after sleep onset. Most strikingly, REM sleep was reduced by 33.9 minutes (p<0.001, d=−1.5) — a large effect — and REM latency increased by 65.6 minutes (p=0.008).\n\nHigh-density EEG analysis revealed specific regional changes in brain activity during sleep: decreased gamma activity in N2 sleep, decreased delta activity in N3 (deep) sleep, and increased beta and alpha activity during REM sleep. These spectral changes suggest cannabis disrupted the normal electrophysiology of multiple sleep stages.\n\nNext-day objective alertness was unchanged, but participants reported a small but significant increase in subjective sleepiness — meaning they felt more tired despite not actually sleeping more.","whyItMatters":"Cannabis is one of the most commonly cited self-medications for sleep problems. This study — using the gold standard of sleep measurement — found it actually made things worse by objective measures. The REM suppression is particularly significant because REM sleep is critical for emotional regulation, memory consolidation, and cognitive function. People may feel cannabis helps sleep because of subjective sedation, while their actual sleep quality deteriorates.","specificNumbers":"20 insomnia patients (16 female, mean age 46). Single dose: 10 mg THC + 200 mg CBD. Total sleep time: −24.5 min (p=0.05, d=−0.5). REM sleep: −33.9 min (p<0.001, d=−1.5). REM latency: +65.6 min (p=0.008, d=0.7). No change in wake after sleep onset. Increased subjective sleepiness without objective alertness change.","methodology":"Pilot randomized controlled trial, N=20 patients with DSM-5 diagnosed insomnia disorder (16 female, mean age 46.1). Single oral dose: 10 mg THC + 200 mg CBD vs. placebo. 256-channel high-density EEG sleep recordings. Outcomes: sleep architecture (total sleep time, REM, NREM stages), spectral power analysis, next-day alertness (objective and subjective).","limitations":"Small sample (N=20) with a single dose — does not capture effects of repeated use or tolerance development. The 10 mg THC / 200 mg CBD ratio is specific to this formulation; other ratios may produce different effects. Mostly female sample (80%) limits generalizability to men. Single-night measurement may not reflect typical sleep patterns. Acute effects may differ from chronic use effects."},{"rthcId":"RTHC-08650","title":"Early Substance Use Initiation Is Associated With Difficulty Quitting Among American Indian and Non-American Indian Youth: A Potential Marker of Later Dependence?","authors":"Swaim, Randall C; Pryor, Sydney L; Henry, Kimberly L","year":2026,"journal":"Journal of studies on alcohol and drugs","doi":"10.15288/jsad.25-00178","pmid":"41623221","tags":["youth","addiction","quitting"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"American Indian youth were more likely than non-AI youth to initiate cigarette and cannabis use from ages 10-14, with similar rates from 15 onward. For all three substances (cigarettes, alcohol, cannabis), earlier initiation was associated with increased odds of being unable to quit. These associations did not differ between AI and non-AI students.","whyItMatters":"This study highlights that early cannabis initiation predicts quitting difficulty across racial groups, suggesting it may serve as an early warning sign for future dependence. The elevated early initiation rates among AI youth point to a need for culturally tailored prevention.","specificNumbers":"9,178 students across 42 schools. AI youth more likely to initiate cannabis ages 10-14. Similar hazard probabilities from age 15+. Earlier initiation associated with increased odds of being unable to quit across all three substances. No AI vs. non-AI difference in the initiation-quitting difficulty relationship.","methodology":"Cross-sectional epidemiologic survey of 9,178 7th-12th graders (ages 10-18) across 42 schools, comparing reservation-based American Indian and non-AI youth from 2021-2023. Discrete-time survival analysis estimated hazard probabilities. Multinomial logistic regression tested age of initiation as a predictor of difficulty quitting.","limitations":"Cross-sectional design relies on retrospective reporting of initiation age. \"Difficulty quitting\" is self-reported and may not align with clinical dependence criteria. Reservation-based schools may not represent all AI youth. Cannot control for all confounders."},{"rthcId":"RTHC-08651","title":"The impact of the COVID-19 pandemic on mental health symptoms in new patients presenting to outpatient psychiatry.","authors":"Swanson, Leslie M; Bommarito, Sarah; Kile, Kristina; Warren, Ricks; Montalva, Roen; Bullard, Katherine H; McCabe, Vita V; Patel, Paresh D; Dalack, Gregory W","year":2026,"journal":"International journal of psychiatry in clinical practice, 1-8","doi":"10.1080/13651501.2026.2620996","pmid":"41626697","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08652","title":"The Use of Cannabis-Based Medicine in Selected Neurological Disorders.","authors":"Szejko, Natalia; Saramak, Kamila; Müller-Vahl, Kirsten R","year":2026,"journal":"Current topics in behavioral neurosciences, 76, 433-454","doi":"10.1007/7854_2024_564","pmid":"39739176","tags":["medical-cannabis","neuroscience"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The best evidence for cannabis-based medicine efficacy in movement/neurodegenerative disorders is for Tourette syndrome, where THC-containing preparations improved tics and psychiatric comorbidities. Limited evidence suggests benefits for Parkinson's disease (tremor, pain, sleep) and Huntington's disease (behavioral symptoms). Neuroprotective effects have been speculated but not confirmed clinically.","whyItMatters":"While cannabis-based medicines are well-established for pain and spasticity, their potential in movement and neurodegenerative disorders is still emerging. This review clarifies where the evidence is strongest and where more research is needed.","specificNumbers":"THC-containing preparations recommended for Tourette syndrome. Limited evidence for Parkinson's (tremor, non-motor symptoms) and Huntington's (behavioral symptoms). Neuroprotective effects speculated but unconfirmed clinically.","methodology":"Narrative review summarizing current evidence for cannabis-based medicines in selected neurological diseases, focusing on movement disorders and neurodegenerative conditions. Part of a book chapter in Current Topics in Behavioral Neurosciences.","limitations":"Narrative review without systematic methodology. Relies on existing evidence which is sparse for most movement disorders. The chapter format may not capture all recent studies."},{"rthcId":"RTHC-08653","title":"Cannabidiol in Gliomas: Therapeutic Potential and Nanocarrier Strategies, with an Emphasis on Vesicular Delivery Systems.","authors":"Szkudlarek, Jagoda; Piwowarczyk, Ludwika; Jelińska, Anna","year":2026,"journal":"Molecular pharmaceutics, 23(1), 28-42","doi":"10.1021/acs.molpharmaceut.5c00853","pmid":"41288593","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08654","title":"Cannabis use among Canadian veterans: associations with the use of other substances, chronic pain conditions, mental disorders, suicide behaviours, and help-seeking.","authors":"Taillieu, Tamara L; Salmon, Samantha; Stewart-Tufescu, Ashley; Sareen, Jitender; Enns, Murray W; Mota, Natalie; Bolton, Shay-Lee; Carleton, R Nicholas; Stein, Murray B; Afifi, Tracie O","year":2026,"journal":"Journal of cannabis research, 8(1), 28","doi":"10.1186/s42238-025-00377-6","pmid":"41555469","tags":["medical-cannabis","ptsd","pain","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Regular cannabis use was associated with increased odds of tobacco smoking, arthritis, any chronic pain, several mental disorders, and suicidal ideation (AOR 1.61-3.99). Both infrequent and regular cannabis users were more likely to perceive a need for care (AOR 2.15 and 4.85) and seek professional help (AOR 2.25 and 5.56) compared to non-users.","whyItMatters":"The dual finding matters: veterans who use cannabis regularly have complex health needs, but they are also significantly more likely to seek help. This creates a clinical opportunity for providers to address multiple needs when cannabis-using veterans present for care.","specificNumbers":"1,992 veterans. 16.7% used cannabis past year. Infrequent use: AOR 2.37 for PTSD, 2.58 for binge drinking. Regular use: AOR 1.61-3.99 for chronic pain, mental disorders, suicidal ideation. Regular users: AOR 4.85 for perceived need for care, 5.56 for professional help-seeking.","methodology":"Cross-sectional analysis of 1,992 veteran respondents from the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey. Logistic regression examined associations between past 12-month cannabis use (none, infrequent, regular) and mental disorders, chronic pain, substance use, suicidal behaviors, and help-seeking.","limitations":"Cross-sectional design cannot determine whether cannabis use is a cause, consequence, or self-medication for the associated conditions. Self-reported data. Survey from 2018 may not reflect current patterns. Cannot distinguish medical from recreational use."},{"rthcId":"RTHC-08655","title":"Health-related quality of life in patients receiving medicinal cannabis: systematic review and meta-analysis of primary research findings 2015-2025.","authors":"Tait, Margaret-Ann; Acret, Louise; Costa, Daniel S J; Campbell, Rachel; White, Kate; Rutherford, Claudia","year":2026,"journal":"Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation, 35(3), 56","doi":"10.1007/s11136-026-04170-7","pmid":"41621036","tags":["medical-cannabis"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"RCTs showed small but statistically significant short-term HRQL improvements (Cohen's d=0.30, p=0.03). Observational studies showed improvements across all follow-up periods: short-term (d=0.43), medium-term, and long-term (d=0.74), all p<0.001. Only 61% of studies justified why they measured quality of life, and only 8% provided definitions.","whyItMatters":"Quality of life is ultimately what matters most to patients with chronic conditions. This meta-analysis provides the most comprehensive evidence to date that medicinal cannabis improves this patient-centered outcome, with effects that appear to grow rather than diminish over time.","specificNumbers":"16,674 citations screened, 64 studies retained. 12 RCTs, 38 cohort, 13 case series. RCT short-term: d=0.30, p=0.03. Observational short-term: d=0.43, medium/long-term up to d=0.74, all p<0.001. EQ-5D-5L most commonly used measure. 81% used generic HRQL measures, 19% condition-specific.","methodology":"Systematic review searching seven databases from January 2015 to April 2025. Sixty-four studies retained: 12 RCTs, 38 cohort studies, 13 case series, 1 non-randomized experimental. Meta-analyses conducted for short-term (2 weeks to 3 months), medium-term (3-12 months), and long-term (12+ months) outcomes. Risk of bias assessed for RCTs.","limitations":"Observational studies showed larger effects than RCTs, possibly reflecting placebo effects, selection bias, or reporting bias. Only 8% of studies defined what they meant by quality of life. Heterogeneity across conditions and cannabis formulations. Long-term data largely from observational designs."},{"rthcId":"RTHC-08656","title":"Probiotics and palmitoylethanolamide (PEA) for osteoarthritic pain: individual effects in a multiple baseline design study.","authors":"Taye, Isabelle; Bradbury, Joanne; Grace, Sandra","year":2026,"journal":"BMC complementary medicine and therapies","doi":"10.1186/s12906-025-05187-0","pmid":"41709243","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08657","title":"Patterns of Cannabis Use and Perceived Accessibility Among Underage U.S. Young Adults: Implications for Policy and Prevention.","authors":"Terry-McElrath, Yvonne M; Pang, Yuk C; Patrick, Megan E","year":2026,"journal":"Journal of studies on alcohol and drugs, 87(1), 154-163","doi":"10.15288/jsad.25-00026","pmid":"40420430","tags":["youth","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among all respondents, 30.7% reported smoking, 19.7% vaping, 18.2% edibles, 10.4% dabbing, and 2.8% drinking cannabis. Among users, 63.5% used multiple modalities. Of past-year users, 95.0% perceived easy access to smoking products, 91.3% to vaping, and 86.7% to edibles. State recreational policy was associated with easier perceived access among non-users.","whyItMatters":"Despite age-based purchase restrictions, nearly all underage young adult cannabis users report easy access. The high prevalence of multi-modality use suggests prevention messaging needs to address the full range of cannabis products, not just smoking.","specificNumbers":"3,075 participants (52.9% female). 23.3% used multiple modalities. Smoking: 30.7%, vaping: 19.7%, edibles: 18.2%, dabbing: 10.4%, drinking: 2.8%. Among users: 95.0% easy access to smoking, 91.3% vaping, 86.7% edibles. Among non-users: 77.5% perceived easy smoking access.","methodology":"Data from adults under 21 in the Monitoring the Future Panel study (2019-2023). Cannabis use prevalence measured by modality (n=3,075). Perceived accessibility assessed for smoking, vaping, and edibles (n=1,227). Logistic regression examined associations with state policy and demographics.","limitations":"Self-reported data from a panel study. Perceived accessibility may not equal actual accessibility. Sample limited to panel participants who were originally surveyed in high school. Data from 2019-2023 spans the pandemic period."},{"rthcId":"RTHC-08658","title":"Using wastewater analysis to estimate the prevalence of THC and CBD use in a population of Japan during and after the Covid-19 pandemic (2020-2023).","authors":"Thai, Phong K; Zheng, Qiuda; Yagishita, Nanami; Wang, Zhe; Hara-Yamamura, Hiroe; Hall, Wayne; Honda, Ryo","year":2026,"journal":"Forensic science international, 378, 112687","doi":"10.1016/j.forsciint.2025.112687","pmid":"41108939","tags":["legalization"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Average estimated cannabis consumption was 5 doses/1,000 people/day, with a 27% annual increase from 2020 to 2023. CBD use prevalence was similar to THC use. Cannabis use remained low compared to other countries despite the steady increase. CBD was much more commonly detected than in other countries' wastewater studies.","whyItMatters":"Japan has some of the strictest cannabis laws globally. Wastewater analysis provides objective population-level data that bypasses the severe underreporting expected in self-report surveys in a country where cannabis possession carries up to 5 years in prison.","specificNumbers":"~120,000 population served. 5 doses/1,000 people/day estimated cannabis use. 27% annual increase from 2020-2023. CBD use prevalence similar to THC. CBD detection much higher than in other countries' wastewater. Weekly sampling every other 2 months for 2.5 years.","methodology":"Longitudinal wastewater surveillance study from October 2020 to March 2023. Weekly samples collected every other two months from the inlet of a wastewater treatment plant serving approximately 120,000 people on Honshu Island, Japan. THC and CBD biomarkers measured by liquid-liquid extraction and LC-MS/MS.","limitations":"Pilot study in a single town that may not represent Japan overall. CBD consumption could not be quantified due to absent pharmacokinetic data. Wastewater cannot identify individual users or use context. The 27% annual increase covers a period including COVID-19 disruptions."},{"rthcId":"RTHC-08659","title":"Recent Trends in Cannabis Use in Adults Ages 60 Years and Older.","authors":"Thayer, Rachel E; Anquillare, Elizabeth; Coromac-Medrano, Juliamaria; Hardin, Emily E; Hatcher, Kyle; Hermann, Greta E","year":2026,"journal":"Substance abuse and rehabilitation, 17, 560360","doi":"10.2147/SAR.S560360","pmid":"41710121","tags":["seniors","medical-cannabis"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"Most older adults who use cannabis report doing so for medical purposes, primarily targeting pain, insomnia, anxiety, and depression. Many do not discuss cannabis use with their medical providers. Emerging evidence from younger populations suggests cardiovascular risks of heavy use, but this has not been thoroughly studied in aging adults.","whyItMatters":"The older adult population is growing and using cannabis at increasing rates, yet clinical trials and safety data are almost entirely from younger populations. Age-related changes in metabolism, cardiovascular health, and cognition create unique risk profiles.","specificNumbers":"Most older adult cannabis users report medical purposes. Common targets: pain, insomnia, anxiety, depression. Many do not discuss use with providers. Cardiovascular risks documented in younger populations but unstudied in seniors.","methodology":"Narrative review synthesizing current literature on cannabis use trends, health considerations, and preclinical models relevant to older adult populations.","limitations":"Narrative review without systematic methodology. Limited evidence base specific to older adults. Most existing data extrapolated from younger populations."},{"rthcId":"RTHC-08660","title":"Impact of Plant Growth Regulators on Callus Induction in Cannabis sativa L.","authors":"Thiry, Margaux; Iken, Marcus; Renaut, Jenny; Lutts, Stanley; Guerriero, Gea","year":2026,"journal":"Cells, 15(4)","doi":"10.3390/cells15040385","pmid":"41744828","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08661","title":"Fast and reliable in vitro activity-based detection of synthetic cannabinoid receptor agonists in e-liquids.","authors":"Timmerman, Axelle; Lyphout, Cathelijne; Verougstraete, Nick; Coopman, Vera; Stove, Christophe","year":2026,"journal":"Archives of toxicology, 100(1), 291-304","doi":"10.1007/s00204-025-04193-y","pmid":"40996544","tags":["synthetic-cannabinoids","cbd","potency","harm-reduction"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Researchers applied a cell-based activity screening method (CB1/β-arrestin2 recruitment assay using the NanoBiT principle) to detect synthetic cannabinoid receptor agonists (SCRAs) in e-liquids — the first time this approach was used on a real patient case.\n\nWhen applied to an e-liquid from an intoxicated patient, the assay demonstrated strong cannabinoid activity, confirming the presence of SCRAs. Screening a set of 23 commercially available e-liquids identified six that were SCRA-positive.\n\nA surprising finding emerged: five e-liquids showed decreased CB1 activity compared to controls, suggesting they contained cannabinoid antagonists or substances that interfered with normal receptor function. This unexpected finding highlights that the safety concerns extend beyond simple SCRA contamination.\n\nThe approach offers advantages over traditional methods like mass spectrometry: it's faster, cheaper, doesn't require constantly updated chemical libraries, and detects any substance with cannabinoid activity regardless of whether its specific structure has been previously identified. This last point is critical because new synthetic cannabinoids appear faster than reference libraries can be updated.","whyItMatters":"Synthetic cannabinoids in vape products are a growing public health problem, and detection methods can't keep up with the pace of new compound introduction. Activity-based screening detects what a substance does (activates cannabinoid receptors) rather than what it looks like chemically — meaning it can catch novel compounds that traditional analytical methods would miss. This could transform how quickly public health authorities identify dangerous products.","specificNumbers":"23 e-liquids screened. 6 SCRA-positive. 5 showed decreased CB1 activity (unexpected finding). 1 patient case e-liquid confirmed SCRA-positive. Activity-based method faster and cheaper than mass spectrometry.","methodology":"Applied an in vitro CB1/β-arrestin2 recruitment assay (NanoBiT principle) to screen e-liquids for cannabinoid activity. Tested one e-liquid from an intoxicated patient and 23 commercially available e-liquids. Compared activity-based results with traditional analytical detection methods.","limitations":"The assay detects CB1 receptor activity but cannot identify the specific compound responsible. It may not detect compounds that act through non-CB1 mechanisms. The 23-product sample is small and may not represent the full e-liquid market. The method requires laboratory equipment and cannot be used as a point-of-care test. False positives from naturally occurring cannabinoids in hemp-derived products need to be considered."},{"rthcId":"RTHC-08662","title":"Investigating Cannabidiol's Effectiveness to Mitigate the Adverse Consequences of Exposure to Neonatal Procedural Pain.","authors":"Timmerman, Brian; Honeycutt, Jennifer A; Skully, Jordan; Patel, Deep; Khan, Waris; Neagu, Alan; Baez, Eshani; Battagliese, Quinn; Brummelte, Susanne","year":2026,"journal":"Developmental psychobiology, 68(2), e70125","doi":"10.1002/dev.70125","pmid":"41619201","tags":["cbd","youth"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Neonatal pain exposure decreased ultrasonic vocalizations and increased adult anxiety-like behavior in male rats. CBD treatment also decreased vocalizations but could not rescue the pain-related anxiety increase in adulthood. CBD raised baseline corticosterone levels in adult males and decreased body weight in adult females.","whyItMatters":"Preterm infants undergo hundreds of painful procedures with inadequate pain management. While CBD has shown promise in adult pain, this study suggests it may not be safe or effective in the neonatal period and could have lasting developmental effects.","specificNumbers":"Neonatal pain decreased USV emission. CBD decreased USV lengths and male pup USV counts. CBD failed to rescue pain-induced adult anxiety. CBD increased adult male corticosterone. CBD decreased adult female body weight.","methodology":"Neonatal rats were exposed to repeated painful procedures with or without CBD treatment. Ultrasonic vocalizations were measured during the neonatal period. Adult anxiety-like behavior was assessed through behavioral tests. Corticosterone levels and body weight were measured in adulthood.","limitations":"Animal study with limited translation to human neonates. Specific CBD doses and routes may not match potential clinical use. Only one dosing regimen tested. Long-term effects may differ across species."},{"rthcId":"RTHC-08663","title":"Plant Growth-Promoting Rhizobacteria Colonize Δ9-Tetrahydrocannabinolic Acid Drug-Type Cannabis sativa L. Roots and Modulate Cannabinoid Metabolism.","authors":"Tonolo, Francesco; Sewalt, Bobbie; Vrieling, Klaas; Choi, Young Hae","year":2026,"journal":"Physiologia plantarum, 178(1), e70756","doi":"10.1111/ppl.70756","pmid":"41578722","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08664","title":"The Anti-proliferative Effects of Anandamide and Oleamide in Glioblastoma Cell Lines Recruit Mitochondrial and PPAR-γ Receptor Modulation.","authors":"Torres-Román, Ana Laura; Ortega-Gómez, Alette; Reyes-Soto, Carolina Y; Aparicio-Trejo, Omar Emiliano; Cuevas-López, Belén; García-Arroyo, Fernando E; Ruíz-García, Erika; Matus-Santos, Juan A; Ferrer, Beatriz; Aschner, Michael; Jardón, Gustavo; López-Goerne, Tessy; Molina-Hernández, Anayansi; Tenorio-Monterrubio, Juan Carlos; Santamaría, Abel","year":2026,"journal":"Neurochemical research, 51(1), 43","doi":"10.1007/s11064-025-04654-x","pmid":"41533230","tags":["cancer","neuroscience"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"Anandamide (AEA) and oleamide (ODA) reduced glioblastoma cell viability and increased lipid peroxidation compared to normal astrocytes. Both reduced mitochondrial membrane potential and impaired Complex I activity in C6 cells. The PPAR-gamma antagonist GW9662 showed differential effects, indicating PPAR-gamma involvement varies by cell type.","whyItMatters":"Unlike the CBD kidney cancer study (RTHC-08638), these endocannabinoids showed selectivity for cancer cells over normal brain cells, and they work through a non-classical receptor pathway (PPAR-gamma) that could be more therapeutically accessible.","specificNumbers":"Two glioblastoma lines (C6, RG2) vs. primary astrocyte controls. AEA and ODA reduced viability and increased lipid peroxidation in cancer but not normal cells. Mitochondrial membrane potential decreased in C6 but not RG2. Complex I inhibited in C6 cells.","methodology":"In vitro study using two glioblastoma cell lines (C6 and RG2) and primary astrocyte cultures as non-tumor controls. Cell viability, lipid peroxidation, mitochondrial membrane potential, and Complex I activity were measured after AEA and ODA treatment, with and without the PPAR-gamma antagonist GW9662.","limitations":"In vitro study only. Two glioblastoma cell lines showed different responses, suggesting results are cell-type dependent. Endocannabinoid concentrations used may not reflect physiological brain levels. Primary astrocytes may not perfectly represent all normal brain cell types."},{"rthcId":"RTHC-08665","title":"Administration of the Synthetic Cannabinoid WIN55,212-2 Increases BDNF Expression Levels in the Adolescent Rat Brain.","authors":"Torres, Alejandro Guadalupe; Santos, Jordan; Sanroman, Dolores Vazquez","year":2026,"journal":"Cannabis and cannabinoid research, 11(1), 60-67","doi":"10.1177/25785125251410807","pmid":"41468069","tags":["synthetic-cannabinoids","youth","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Adolescent male rats received the synthetic cannabinoid WIN55,212-2 (a dual CB1/CB2 receptor agonist) via injection every 48 hours from postnatal day 30 to 44 — corresponding to human adolescence. Researchers then measured levels of brain-derived neurotrophic factor (BDNF) in three brain regions.\n\nWIN administration increased BDNF expression in the medial prefrontal cortex (mPFC), hippocampus, and cerebellar vermis. BDNF exists in two forms with opposing functions: pro-BDNF (involved in synaptic pruning and cell death) and mature BDNF (m-BDNF, which stimulates dendritic growth and cell survival). The study assessed both forms.\n\nThe significance of these changes depends on context. During adolescence, the brain undergoes extensive remodeling — including synaptic pruning guided by pro-BDNF. Cannabinoid-driven changes in the balance between pro-BDNF and m-BDNF could disrupt this precisely timed developmental process, potentially altering the neural architecture that emerges from adolescent brain maturation.","whyItMatters":"BDNF is one of the most important proteins in brain development — it regulates whether neurons survive or are pruned, whether connections strengthen or weaken. Finding that a cannabinoid receptor agonist alters BDNF levels during the adolescent period provides a molecular mechanism through which cannabis use during adolescence could reshape brain development in lasting ways.","specificNumbers":"WIN dose: 0.8 mg/kg every 48 hours, PND 30–44. BDNF expression increased in three brain regions: medial prefrontal cortex, hippocampus, cerebellar vermis. Both pro-BDNF and mature BDNF forms assessed.","methodology":"Male adolescent Sprague-Dawley rats received intraperitoneal injections of WIN55,212-2 (0.8 mg/kg) or saline every 48 hours from postnatal day 30 to 44. BDNF expression (pro-BDNF and mature BDNF) measured in medial prefrontal cortex, hippocampus, and cerebellar vermis.","limitations":"Used a synthetic cannabinoid (WIN55,212-2), not THC — pharmacological profile differs from natural cannabis. Male rats only — sex differences in BDNF response are well-documented. Short exposure window (14 days) may not reflect chronic use patterns. Cannot determine whether BDNF changes are beneficial, harmful, or neutral without functional outcome measures. Dose may not correspond to human exposure levels."},{"rthcId":"RTHC-08666","title":"Cannabis and cannabidiol for postoperative pain management in orthopedic surgery: a scoping review.","authors":"Tran, Kevin; Odland, Kari; Polly, David W","year":2026,"journal":"Pain medicine (Malden, Mass.), 27(2), 111-118","doi":"10.1093/pm/pnaf110","pmid":"40828884","tags":["pain","medical-cannabis","cbd"],"studyType":"scoping-review","evidenceStrength":"preliminary","keyFinding":"CBD-only interventions showed mixed results for post-orthopedic surgical pain. THC/CBD combinations demonstrated modest potential for opioid-sparing effects with neutral safety profiles. One THC-only study reported increased opioid use and longer hospital stays, though confounders were present.","whyItMatters":"Opioid dependence after orthopedic surgery is a major clinical problem. Understanding which cannabinoid formulations might help reduce opioid use postoperatively is crucial, especially given the heterogeneity in available evidence.","specificNumbers":"14 experimental studies included. Three categories: CBD-only (mixed results), THC-only (1 study, worse outcomes), THC/CBD combination (modest opioid-sparing). Overall evidence limited by heterogeneous study designs.","methodology":"Scoping review of experimental studies published from 2014 to 2025 investigating cannabis or CBD for postoperative orthopedic pain management. Fourteen studies met inclusion criteria, categorized by cannabinoid composition (CBD only, THC only, or THC/CBD combination).","limitations":"Only 14 studies, with heterogeneous designs, formulations, dosing, and patient populations. Scoping review methodology does not assess study quality. Most studies were small. Results cannot be generalized across orthopedic procedure types."},{"rthcId":"RTHC-08667","title":"The relationship between maternal cannabis use disorder diagnosis and the development of retinopathy of prematurity.","authors":"Tran, Melanie D; Baer, Rebecca J; Bandoli, Gretchen; Robbins, Shira L; Granet, David; Chambers, Christina D; Rudell, Jolene C","year":2026,"journal":"Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 104748","doi":"10.1016/j.jaapos.2026.104748","pmid":"41638301","tags":["pregnancy"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among infants born at 22-31 weeks gestation, 32.1% of those born to mothers with cannabis use disorder developed retinopathy of prematurity compared to 33.3% of those born to mothers without CUD. After adjusting for covariates, the risk was identical (aRR=1.0, 95% CI 0.9-1.1).","whyItMatters":"Given concerns about prenatal cannabis exposure on fetal development, this null finding provides reassurance that at least one specific neonatal eye complication is not increased, helping clinicians counsel pregnant women with evidence rather than speculation.","specificNumbers":"997 infants born to mothers with CUD; 30,113 born to mothers without CUD. ROP rates: 32.1% vs 33.3%. Adjusted relative risk: 1.0 (95% CI 0.9-1.1). No increased or decreased risk.","methodology":"Retrospective cohort study using the UC San Diego SOMI population-based database. Included infants born between 22 and <31 weeks gestation and/or weighing <1500g who survived to ROP screening age. Maternal CUD and infant ROP identified from ICD codes. Adjusted relative risk calculated with log-linear regression.","limitations":"Cannabis use disorder diagnosis (ICD codes) may miss mild or undisclosed use. Retrospective design. Single health system in San Diego. Cannot assess dose-response or distinguish CUD severity."},{"rthcId":"RTHC-08668","title":"Cannabinoid Use Among Adult Women: A Scoping Review.","authors":"Trice, Catharine; Prebihalo, Sarah; Rattan, Saniya; Spencer, Kara; Karasick, Andrew; Scott-Richardson, Maya; Punzalan, Cecile; Gensheimer, Kathleen; Markon, André; South, Erin M; Bersoff-Matcha, Susan; Vasisht, Kaveeta; Wolpert, Beverly J","year":2026,"journal":"Journal of women's health (2002), 35(3), 271-289","doi":"10.1177/15409996251385404","pmid":"41431785","tags":["sex-differences","medical-cannabis"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"Of 270 studies, 80% addressed safety, 17% motivations for use, and 10% perceptions. Only 20% used women-only samples, and 16% studied maternal-offspring dyads. Research predominantly covered cannabis/marijuana (90%) with much less on CBD (9%) or THC (7%). Most common designs were cross-sectional (37%), retrospective (18%), and prospective cohort (16%).","whyItMatters":"Women may have different risk profiles, motivations, and therapeutic responses to cannabis than men. The finding that most research focuses on pregnancy-related safety means women-specific conditions like endometriosis, menstrual pain, and menopausal symptoms remain understudied.","specificNumbers":"270 studies identified. 80% safety-focused, 17% motivations, 10% perceptions. 90% addressed cannabis/marijuana, 9% CBD, 7% THC. Sample composition: 37% included at least 45% women, 27% sex-specific outcomes, 20% women-only, 16% maternal-offspring. 37% cross-sectional design.","methodology":"Scoping review of PubMed, Web of Science, and Embase for human epidemiological studies published January 2018 to March 2023, using cannabinoid safety, perception, and motivation criteria. Screened using Covidence platform.","limitations":"Scoping review does not assess study quality. Search limited to 2018-2023. Categories were not mutually exclusive. The review characterizes the literature landscape rather than synthesizing findings."},{"rthcId":"RTHC-08669","title":"Hemp (Cannabis sativa L.) Phytochemicals and Their Potential in Agrochemical, Cosmetic, and Food Industries: A Review.","authors":"Trono, Daniela","year":2026,"journal":"International journal of molecular sciences, 27(3)","doi":"10.3390/ijms27031146","pmid":"41683571","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08670","title":"PAtient-Centric epilepsy clinical trIal model For Improved health outcomes using Cannabidiol (PACIFIC study)-a methodology for developing patient-centred clinical trials in rare epilepsy syndromes.","authors":"Truong, Linda; Stettaford, Tegan; Watt, Katrina; Ghafournia, Nafiseh; Anetko, Pavel; Shin, Jiyoung; Pierce, Kris; Lawson, John A; Martin, Jennifer H","year":2026,"journal":"BMC medical research methodology, 26(1), 32","doi":"10.1186/s12874-025-02757-1","pmid":"41545936","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08671","title":"Development of a novel isolation method for Δ9-tetrahydrocannabinolic acid-A from cannabis suitable for forensic laboratories.","authors":"Tsujikawa, Kenji; Okada, Yuki; Yamamuro, Tadashi; Kuwayama, Kenji; Kanamori, Tatsuyuki; Iwata, Yuko T","year":2026,"journal":"Forensic toxicology, 44(1), 224-230","doi":"10.1007/s11419-025-00742-3","pmid":"41037198","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08672","title":"Preoperative Cannabis Use and Ankle ORIF Outcomes: Higher Risks of Infection, Nonunion, and Reoperation.","authors":"Tummala, Sri; Wood, Brandon A; Mittal, Mehul M; Sambandam, Senthil N; Wukich, Dane K","year":2026,"journal":"Foot & ankle international, 47(1), 43-51","doi":"10.1177/10711007251385971","pmid":"41243321","tags":["harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"After propensity score matching for 27 confounders, preoperative cannabis use was significantly associated with increased risks of postoperative infection (RR=1.696), nonunion, and reoperation following ankle ORIF. The study applied Bonferroni correction for 34 outcomes with significance set at p<.0015.","whyItMatters":"This study positions cannabis alongside tobacco as a potentially modifiable perioperative risk factor for orthopedic surgery, which could change preoperative counseling and optimization protocols.","specificNumbers":"3,126 matched pairs. Infection: RR=1.696 (CI 1.230-2.337, p<.0015). Nonunion and reoperation also significantly elevated at 3 years. Bonferroni correction applied across 34 outcomes. No significant differences in other measured outcomes after correction.","methodology":"Retrospective cohort analysis using the nationally representative TriNetX Research Network database. 3,126 matched pairs (cannabis users vs. non-users) undergoing ankle fracture ORIF. Propensity score matching controlled for 27 demographic and clinical confounders. Outcomes assessed at 90 days, 6 months, and 3 years.","limitations":"Retrospective database study. Cannabis use identified from records, likely underestimating true prevalence. Cannot determine dose, frequency, or method of cannabis use. Cannot distinguish between recreational and medical use or control for cannabis cessation perioperatively."},{"rthcId":"RTHC-08673","title":"Differential Expression of Endocannabinoid Receptors in Lesional and Non-Lesional Skin of Psoriasis Patients: Insights Into Pathogenesis and Potential Therapeutic Targets.","authors":"Turk, Jaime N; Kirchhof, Mark G","year":2026,"journal":"Journal of cutaneous medicine and surgery, 30(1), 56-61","doi":"10.1177/12034754251355199","pmid":"41699832","tags":["inflammation","medical-cannabis"],"studyType":"observational","evidenceStrength":"preliminary","keyFinding":"In psoriatic lesional skin, CB2 (CNR2), TRPA1, TRPV3, PPARD, GPR18, and several serotonin receptors were significantly upregulated, while PPARG, TRPV4, PPARA, and GPR12 were significantly downregulated compared to healthy controls. Non-lesional psoriatic skin showed no significant differences from healthy skin.","whyItMatters":"The finding that endocannabinoid receptor expression changes only in active psoriatic lesions, not in unaffected skin, suggests these changes are tied to active disease rather than a systemic predisposition, making them potential therapeutic targets.","specificNumbers":"Upregulated in lesional skin: CNR2, TRPA1, TRPV3, PPARD, GPR18, ADORA2A, HTR3B, HTR3A. Downregulated: GPR12, PPARG, TRPV4, PPARA, HTR1A. No significant changes in non-lesional vs. healthy skin.","methodology":"Differential gene expression analysis using bulk RNA sequencing data from the Gene Expression Omnibus database. Compared endocannabinoid receptor expression between psoriatic lesional skin, non-lesional skin, and healthy controls.","limitations":"Database-derived RNA expression data, not from a controlled experiment. Bulk RNA sequencing cannot identify which specific cell types within the skin show expression changes. Gene expression does not necessarily reflect protein-level receptor function."},{"rthcId":"RTHC-08674","title":"The development of a cannabis risk assessment tool for patients with rheumatologic conditions: a Delphi study.","authors":"Turk, Tarek; Watson, Kaitlyn; Aref, Heba; Patel, Dimple; Jones, Allyson; Olson, Joanne; Paul, Pauline; Sadowski, Cheryl A; Yacyshyn, Elaine","year":2026,"journal":"Clinical rheumatology, 45(3), 1971-1979","doi":"10.1007/s10067-025-07807-z","pmid":"41345331","tags":["medical-cannabis","pain"],"studyType":"qualitative","evidenceStrength":"moderate","keyFinding":"Consensus (75%+ agreement) was achieved on 40 of 45 items (88.9%) after two rounds, confirmed in a third validation round. Key risk factors included age, gender, history of substance use disorders, schizophrenia, cannabis consumption patterns, age of first use, method, and frequency of use.","whyItMatters":"With cannabis legalization expanding, rheumatology patients increasingly use cannabis for chronic pain. A standardized risk assessment tool helps clinicians move from subjective judgment to evidence-informed screening when discussing cannabis with patients.","specificNumbers":"12 experts participated. 45 statements rated. 40 items reached 75%+ consensus (88.9%). Four categories: patient demographics, medical history, lifestyle, socioeconomic. All 40 confirmed in validation round.","methodology":"Modified Delphi study with 12 international experts from different healthcare professions in rheumatology. Statements developed from literature review and focus groups. Three rounds conducted: two for consensus, one for validation. Agreement threshold set at 75%.","limitations":"Only 12 experts participated. Delphi consensus does not equal clinical validation. The tool has not been tested in clinical practice. Expert panel composition may not represent all relevant perspectives."},{"rthcId":"RTHC-08675","title":"Repeated administration of cannabidiol decreases splenic lymphocyte subset numbers in rats.","authors":"Turkki, Tara H; Jankowski, Maciej M; Glac, Wojciech; Badtke, Piotr; Saito, Viviane M; Swiergiel, Artur H; Ignatowska-Jankowska, Bogna M","year":2026,"journal":"International journal of immunopathology and pharmacology, 40, 3946320251411441","doi":"10.1177/03946320251411441","pmid":"41506658","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD at 5 mg/kg/day for 14 days decreased splenic T cells and non-T/NK CD45RA+ lymphocytes but not NK cells. Natural killer cell cytotoxicity was unaffected in both blood and spleen. A CB2 receptor antagonist showed a significant interaction with CBD, suggesting partial CB2 involvement.","whyItMatters":"CBD is widely marketed as safe and anti-inflammatory, but this study shows it can deplete specific immune cell populations in a major immune organ. This has implications for people taking CBD long-term, particularly those with compromised immune systems.","specificNumbers":"63 rats. 14 days of daily CBD. 5 mg/kg dose effective; 2.5 mg/kg not significant. T cells and non-T/NK CD45RA+ lymphocytes decreased in spleen. NK cells unaffected. NK cytotoxicity unchanged. CB2 antagonist interaction significant.","methodology":"63 adult male Wistar rats received intraperitoneal CBD (2.5 or 5 mg/kg/day) or vehicle for 14 consecutive days. Splenic lymphocyte subsets counted by flow cytometry. NK cell cytotoxicity measured by Chromium-51 release assay in both blood and spleen. CB2 antagonist AM630 co-administered in some groups.","limitations":"Male rats only. Intraperitoneal administration does not reflect typical human oral use. Healthy animals may respond differently than diseased ones. CBD doses may not be equivalent to human doses. Fourteen-day exposure is relatively short."},{"rthcId":"RTHC-08676","title":"Fear of recurrence, secondary cancers, and health problems in long-term survivors of childhood cancer: Findings from a Canadian cohort.","authors":"Tutelman, Perri R; Duong, Jenny; Forbes, Caitlin; Lawal, Oluwaseyi A; Fidler-Benaoudia, Miranda; Reynolds, Kathleen; Giles, Jennifer; Guilcher, Gregory M T; Russell, Brooke; Lebel, Sophie; Schulte, Fiona S M","year":2026,"journal":"Cancer, 132(4), e70281","doi":"10.1002/cncr.70281","pmid":"41644475","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08677","title":"Effectiveness of cognitive behavioral therapy for harmful cannabis use: a systematic review and meta-analysis.","authors":"Ullah, Safat; Ullah, Asad; Ahmad, Fayaz; Latif, Abdul; Sohaib, Muhammad; Khan, Muhammad Firaz; Ahmad, Bilal; Yadegarfar, Ghasem; Farooq, Saeed; Naeem, Farooq; Paudyal, Priyamvada","year":2026,"journal":"Cognitive behaviour therapy, 1-21","doi":"10.1080/16506073.2026.2613114","pmid":"41700819","tags":["addiction","quitting"],"studyType":"systematic-review","evidenceStrength":"strong","keyFinding":"CBT did not significantly reduce cannabis use frequency at short-term (effect=0.12, p=0.10), medium-term (effect=-0.03, p=0.75), or long-term (effect=0.01, p=0.91) follow-ups compared to control conditions. Daily consumption showed a significant medium-term effect (-0.50, p<.05) but insignificant effects at other time points.","whyItMatters":"CBT is often considered a first-line psychosocial treatment for cannabis use disorder. This meta-analysis challenges that assumption by showing it does not clearly outperform other approaches, suggesting the field needs to reconsider treatment recommendations.","specificNumbers":"2,347 records screened, 9 RCTs included, 1,280 participants. Short-term: 0.12 (95% CI -0.02 to 0.26, p=0.10). Medium-term: -0.03 (95% CI -0.18 to 0.13, p=0.75). Long-term: 0.01 (95% CI -0.18 to 0.20, p=0.91). Daily consumption medium-term: -0.50 (p<.05).","methodology":"Systematic review and meta-analysis of MEDLINE, PsycINFO, CINAHL, AMED, Cochrane Library, and clinical trial registries. Nine RCTs involving 1,280 participants were included. Quality assessed using Cochrane Risk of Bias tool.","limitations":"Only nine RCTs available, with study heterogeneity, small sample sizes, and risk of bias. Comparison conditions varied (contingency management, TAU, other psychosocial). Unstandardized CBT content across studies. Cannot assess which CBT components might be effective."},{"rthcId":"RTHC-08678","title":"A CBD-rich hemp extract is superior to CBD alone in reducing relapse to methamphetamine-seeking in rats.","authors":"Umpierrez, Laísa S; Korkozian, Maral J; Costa, Priscila A; Anderson, Lyndsey L; McGregor, Iain S; Baracz, Sarah J; Perry, Christina J; Arnold, Jonathon C; Cornish, Jennifer L","year":2026,"journal":"Progress in neuro-psychopharmacology & biological psychiatry, 145, 111629","doi":"10.1016/j.pnpbp.2026.111629","pmid":"41605363","tags":["cbd","addiction"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"All CBD-containing treatments reduced meth-primed reinstatement, but hemp extract (HE) and CBD+HE were more effective than CBD isolate alone. The hemp extract contained only 2.5 mg/kg CBD versus 80 mg/kg in the isolate, yet performed better. Neither cannabinoid treatment produced conditioned place preference (no rewarding properties). The 5-HT1A receptor was not involved.","whyItMatters":"Methamphetamine addiction has no approved pharmacotherapy. This study suggests full-spectrum hemp preparations may be more effective than pure CBD for preventing relapse, potentially at much lower CBD doses, supporting the entourage effect hypothesis in addiction treatment.","specificNumbers":"CBD isolate: 80 mg/kg. Hemp extract: only 2.5 mg/kg CBD. All treatments reduced reinstatement. HE and CBD+HE more effective than CBD isolate. No CPP from any treatment. WAY-100635 (5-HT1A antagonist) did not block effects. All treatments reduced meth-induced sensitized hyperactivity.","methodology":"Male Sprague-Dawley rats self-administered methamphetamine via lever press, underwent extinction, then reinstatement by meth injection. Four treatment conditions: vehicle, CBD isolate (80 mg/kg), hemp extract (HE, 2.5 mg/kg CBD + other cannabinoids), or CBD+HE (80 mg/kg total CBD). 5-HT1A antagonist co-administration tested. Conditioned place preference and behavioral sensitization also assessed.","limitations":"Male rats only. Meth self-administration model may not fully capture human addiction. The hemp extract composition beyond CBD was not fully characterized. The 5-HT1A receptor was ruled out but other mechanisms were not tested."},{"rthcId":"RTHC-08679","title":"Involvement of Adenosine A2A Receptors in Anxiety-Like Behaviors in Tetrahydrocannabinol-Treated Mice.","authors":"Ün, Burçin; Akarsakarya, Zeki; Özü, Özlem Yorulmaz; Ilgaz, Nermin Seda; Yılmaz, Mehmet Bertan; Seçilmiş, Deniz; Seçilmiş, Mehmet Ata","year":2026,"journal":"Brain and behavior, 16(2), e71126","doi":"10.1002/brb3.71126","pmid":"41601286","tags":["anxiety","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC induced anxiety-like behavior in mice. Gene expression in the hippocampus showed significant interaction between cannabinoid (CB1R) and adenosine (A2AR) receptor systems. THC played a predominant role in the molecular interplay, with effects partially modulated by changes in both CB1R and A2AR expression.","whyItMatters":"Understanding why THC causes anxiety in some users is critical for developing safer cannabinoid therapeutics. The identification of adenosine A2A receptor involvement opens a new avenue for potentially blocking THC-induced anxiety without reducing therapeutic effects.","specificNumbers":"THC induced anxiety-like behavior. A2A agonist (CGS-21680) and antagonist (istradefylline) tested. Significant interaction between CB1R and A2AR gene expression in hippocampus. THC was the predominant factor in the molecular interplay.","methodology":"Behavioral tests combined with molecular analyses in mice. THC effects were tested alongside the A2A receptor agonist CGS-21680 and antagonist istradefylline. Anxiety-like behavior was assessed, and hippocampal gene expression of cannabinoid and adenosine receptors was analyzed.","limitations":"Mouse study with limited translation to human anxiety. Gene expression changes do not prove functional receptor interactions. Only one THC dose tested. Male mice only."},{"rthcId":"RTHC-08680","title":"New treatments for OCD? Evidence for cannabinoids and psychedelics.","authors":"Van Ameringen, Michael; Patel, Vidhi; Patterson, Beth; Hopkinson, Paige; Rahat, Maryam","year":2026,"journal":"Journal of psychiatric research, 193, 172-178","doi":"10.1016/j.jpsychires.2025.11.021","pmid":"41317726","tags":["mental-health","medical-cannabis"],"studyType":"scoping-review","evidenceStrength":"moderate","keyFinding":"The evidence for cannabinoids in OCD consists of cross-sectional surveys, case reports, and very few controlled trials, and appears to indicate a lack of efficacy for both synthetic and natural cannabinoids. In contrast, psilocybin shows a stronger signal for treatment-resistant OCD. 40-60% of OCD patients remain unresponsive to standard pharmacotherapy.","whyItMatters":"With 40-60% of OCD patients treatment-resistant, interest in novel agents is high. This review provides a reality check: despite enthusiasm, cannabinoid evidence for OCD is essentially absent, redirecting attention toward psychedelics where the signal appears stronger.","specificNumbers":"40-60% of OCD patients are treatment-resistant. Cannabinoid evidence: cross-sectional surveys and case reports, no rigorous RCTs. No support for synthetic or natural cannabinoids in OCD. Psilocybin shows stronger preliminary signal.","methodology":"Comprehensive scoping review of OCD literature including published and grey literature, examining evidence for cannabinoids, psilocybin, LSD, DMT, and MDMA in OCD treatment.","limitations":"Scoping review, not a systematic review with meta-analysis. The absence of evidence for cannabinoids does not prove absence of effect. Very few studies exist for any of the agents reviewed. Comparison across substance classes is indirect."},{"rthcId":"RTHC-08681","title":"Cannabis use before and after metabolic and bariatric surgery and its association with alcohol use.","authors":"Vanderziel, Alyssa; Killian, Samantha J; Haley, Erin N; Braciszewski, Jordan M; Teotia, Arjun; Brescacin, Carly; Carlin, Arthur M; Varban, Oliver; Miller-Matero, Lisa R","year":2026,"journal":"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery","doi":"10.1016/j.soard.2025.11.027","pmid":"41651721","tags":["appetite","addiction","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Post-bariatric surgery cannabis use rose from roughly 10.5% to 16%, a 52.4% relative increase. Of those using cannabis after surgery, 45.9% had not used before. Hazardous alcohol use tripled the odds of both initiating and continuing cannabis use post-operatively.","whyItMatters":"Bariatric surgery patients are known to sometimes shift addictive behaviors after the procedure. This is one of the first studies to document how cannabis use specifically changes around surgery, which matters as cannabis becomes more accessible in legal states.","specificNumbers":"612 participants; 52.4% relative increase in cannabis use (p = .0001); 16% reported post-operative use; 45.9% were new initiates; among initiates, 11.8% screened positive for hazardous use; hazardous alcohol users had 2.8x odds of initiating cannabis (95% CI: 1.4-5.4) and 3.0x odds of persisting (95% CI: 1.6-5.8)","methodology":"Cross-sectional survey of 612 patients who had metabolic and bariatric surgery (MBS) between 2018 and 2021 at a single Michigan health system. Participants completed online surveys about cannabis, alcohol, and other substance use, psychiatric symptoms, and demographics.","limitations":"Single health system in a legal-cannabis state limits generalizability. Self-reported data subject to recall bias. Cross-sectional design cannot establish causality. No control for specific surgical procedures or weight loss outcomes."},{"rthcId":"RTHC-08682","title":"UK Medical Cannabis Registry: a case series analysing clinical outcomes of medicinal cannabis therapy for fibromyalgia.","authors":"Varadpande, Madhur; Erridge, Simon; Aggarwal, Arushika; Clarke, Evonne; McLachlan, Katy; Coomber, Ross; Barnes, Shelley; Darweish Medniuk, Alia; Guru, Rahul; Holden, Wendy; Sajad, Mohammed; Searle, Robert; Usmani, Azfer; Varma, Sanjay; Rucker, James J; Platt, Michael; Sodergren, Mikael H","year":2026,"journal":"Clinical rheumatology, 45(3), 1927-1938","doi":"10.1007/s10067-025-07846-6","pmid":"41343025","tags":["medical-cannabis","pain","anxiety","sleep","cbd"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"All patient-reported outcome measures improved significantly from baseline through 18 months of follow-up. Higher daily CBD doses (above 25 mg) and previous cannabis experience were linked to better fibromyalgia-specific outcomes. However, 45.67% of patients reported adverse events, mostly mild-to-moderate, with fatigue being the most common.","whyItMatters":"Fibromyalgia is notoriously difficult to treat, with many patients finding conventional therapies inadequate. This is one of the largest real-world datasets on medical cannabis for fibromyalgia, providing evidence that may inform clinical decisions.","specificNumbers":"497 patients; mean age 44.66 years; 68.61% female; 53.92% unemployed; CBD doses above 25 mg/day associated with better outcomes (p < 0.050); 45.67% reported adverse events; 2,100 total AEs; 85.33% mild-to-moderate; fatigue most common AE (30.78%)","methodology":"Case series from the UK Medical Cannabis Registry (UKMCR) analyzing 497 patients prescribed cannabis-based medicinal products for fibromyalgia. Outcomes measured at 1, 3, 6, 12, and 18 months using validated scales for symptom severity, widespread pain, quality of life, anxiety, and sleep.","limitations":"No control group or randomization. Registry-based data subject to selection bias. Patients self-selected for treatment. High dropout rates likely at later follow-up points. Cannot distinguish cannabis effects from placebo or natural disease fluctuation."},{"rthcId":"RTHC-08683","title":"In vitro digestion and cytotoxicity study of cannabidiol-loaded nanostructured lipid carriers.","authors":"Vardanega, Renata; Lüdtke, Fernanda L; Loureiro, Luis; Gonçalves, Raquel F S; Martins, Joana T; Pinheiro, Ana C; Vicente, António A","year":2026,"journal":"Food research international (Ottawa, Ont.), 223(Pt 2), 117880","doi":"10.1016/j.foodres.2025.117880","pmid":"41360566","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08684","title":"Effects of prenatal cannabis exposure on offspring mental health: A focus on the role of the immune system.","authors":"Vecchiarelli, Haley A; Baglot, Samantha L; Black, Tallan; Choi, Esther Y; Cupo, Lani; Sandberg, Colby; Siron, Léa; Chakravarty, M Mallar; Hill, Matthew N; Howland, John G; Khokhar, Jibran Y; Tremblay, Marie-Ève","year":2026,"journal":"Neuroscience and biobehavioral reviews, 181, 106488","doi":"10.1016/j.neubiorev.2025.106488","pmid":"41285189","tags":["pregnancy","mental-health","inflammation","neuroscience"],"studyType":"narrative-review","evidenceStrength":"preliminary","keyFinding":"In both human and rodent studies using vaporized exposure, cannabis use during pregnancy was associated with reduced pro-inflammatory cytokine levels in the placenta. In humans, this reduction was linked to increased offspring anxiety, aggression, and hyperactivity. Prenatal cannabis exposure also appeared to impact T cell dynamics in various organs.","whyItMatters":"Cannabis use among pregnant people is increasing alongside legalization and growing social acceptability. Understanding how prenatal exposure might affect offspring through immune pathways could reveal new mechanisms of risk and potentially inform harm reduction strategies.","specificNumbers":"The review notes increasing legalization and permissiveness globally; cannabinoid receptors are abundantly expressed in the immune system; specific cytokine reductions were observed in placental tissue; offspring showed increased anxiety, aggression, and hyperactivity behaviors","methodology":"Narrative review synthesizing research on prenatal cannabis exposure (PCE) across human and animal studies, focusing specifically on immune system changes (both central nervous system and peripheral) as potential mediators of offspring mental health effects.","limitations":"The field is described as \"too nascent for robust conclusions.\" Limited data on central nervous system immune cells (microglia). The link between immune cell changes and mental health outcomes needs further establishment. Animal models may not fully replicate human exposure patterns."},{"rthcId":"RTHC-08685","title":"Cannabinoid Hyperemesis Syndrome in Adolescents: A Single Institution Case Series.","authors":"Vega Castellvi, Claudia; Jennings, Natalie F; Clemente Fabrega, Melissa; Gamboa, Heidi; Li, B U K","year":2026,"journal":"Pediatric emergency care","doi":"10.1097/PEC.0000000000003577","pmid":"41744458","tags":["youth","medical-cannabis"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"CHS, a recurring vomiting disorder triggered by long-term frequent cannabis use, is being identified in pediatric patients but remains underdiagnosed. The condition leads to unnecessary diagnostic evaluations and increased healthcare utilization among adolescents.","whyItMatters":"As cannabis use among teens becomes more common, pediatric CHS is likely to increase. Recognizing the syndrome early can prevent expensive and invasive diagnostic workups and connect patients with appropriate treatment.","specificNumbers":"The abstract describes this as a \"large case series\" in pediatrics with data on treatment efficacy, healthcare utilization, and comorbidities (full numbers in the paper)","methodology":"Single-institution case series of pediatric CHS patients, including data on treatment efficacy, healthcare utilization, and comorbidities.","limitations":"Single institution limits generalizability. Case series design provides no comparison group. Abstract provides limited quantitative detail. Selection bias possible in case identification."},{"rthcId":"RTHC-08686","title":"THC induced similar physiological effects on HIV transgenic rats and their controls without affecting HIV-induced deficits in effortful motivation.","authors":"Vemuri, Sunitha; Ayoub, Samantha M; Minassian, Arpi; Young, Jared W","year":2026,"journal":"Journal of cannabis research, 8(1), 17","doi":"10.1186/s42238-025-00383-8","pmid":"41485027","tags":["neuroscience","cognition","dopamine","animal-study"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC at 3 mg/kg reduced pain sensitivity, body temperature, and locomotor activity across all genotypes, with some sex-dependent effects. HIV transgenic rats showed lower motivation than one control strain but not the other, and while acute THC reduced motivation, chronic treatment (16 days) did not.","whyItMatters":"People living with HIV use cannabis at higher rates than the general population, often to manage symptoms. Understanding whether THC worsens or improves HIV-associated motivational deficits is important for clinical guidance.","specificNumbers":"46 HIV-1tg rats; 87 control rats (WT and F344); THC doses: 0, 0.3, 3 mg/kg; 16 days chronic treatment; 3 mg/kg THC reduced breakpoints acutely but not after chronic dosing","methodology":"Two experiments using female and male HIV-1 transgenic rats and two control strains (wildtype littermates and Fischer344). Experiment 1 tested acute THC effects using the cannabinoid tetrad assay (nociception, temperature, locomotion). Experiment 2 used the Progressive Ratio Breakpoint Task to assess motivation at baseline, after acute THC, and after 16 days of chronic THC.","limitations":"Animal model may not fully replicate human HIV or cannabis use patterns. HIV transgenic rats only showed motivation deficits compared to one control strain, raising questions about the model itself. THC was administered by injection rather than smoked or vaped."},{"rthcId":"RTHC-08687","title":"The role of cumulative adverse childhood experiences in the interrelationships among addictive behaviors: A network analysis study.","authors":"Veneziani, Giorgio; Giraldi, Emanuele; Panagini, Giulia; Marano, Giuseppe; Festa, Giuseppe Manuel; Mazza, Marianna; Lai, Carlo","year":2026,"journal":"Addictive behaviors, 175, 108610","doi":"10.1016/j.addbeh.2026.108610","pmid":"41529544","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08688","title":"The Incidence of Neonatal Abstinence Syndrome Remained Stable in Eastern Denmark From 2013 to 2018 and Was Sometimes Associated With Cannabis.","authors":"Vestermark, Vibeke; Kjærbye-Thygesen, Anette; Kesmodel, Ulrik Schiøler","year":2026,"journal":"Acta paediatrica (Oslo, Norway : 1992)","doi":"10.1111/apa.70443","pmid":"41499253","tags":["pregnancy","youth"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Among 98 neonates pharmacologically treated for NAS in eastern Denmark over 6 years, the incidence remained stable at 0.6 per 1,000 live births. One-third of treated neonates were not exposed to opioids. Cannabis was the most common non-opioid drug causing NAS, with 14% of all treated neonates exposed to cannabis and 9% exposed to cannabis as the only drug besides tobacco.","whyItMatters":"NAS is typically associated with opioid exposure, but this study found a substantial proportion linked to cannabis. This challenges the common assumption that cannabis withdrawal does not affect newborns and suggests healthcare providers should monitor for NAS after prenatal cannabis exposure.","specificNumbers":"447 neonates identified with relevant diagnoses; 98 pharmacologically treated for NAS; incidence: 0.6 per 1,000 live births (stable over 6 years); one-third not exposed to opioids; 14% exposed to cannabis; 9% exposed to cannabis as only drug (plus tobacco)","methodology":"Historical multicentre cohort study of neonates treated for NAS between 2013 and 2018 in eastern Denmark. The Danish National Patient Register identified 447 neonates with relevant diagnoses; medical record review confirmed 98 were pharmacologically treated for NAS.","limitations":"Limited to eastern Denmark, which may not reflect other populations. Relatively small number of cases (98 treated). Tobacco exposure was common and could confound cannabis-specific effects. Retrospective design relies on medical record accuracy."},{"rthcId":"RTHC-08689","title":"Acquired transient vasopressin deficiency by cannabinoids and other substances.","authors":"Vijayan, Madhusudan; Rein, Joshua L","year":2026,"journal":"Endocrinology","doi":"10.1210/endocr/bqag014","pmid":"41668460","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08690","title":"Population reach, feasibility and acceptability of digital therapeutics for smoking cessation among people living with HIV: Results of the Quitting Matters pilot trial.","authors":"Vilardaga, R; McClernon, F J; Akingbule, O; Mannelli, P; Thomas, S M; Davis, J M; Gray, M F; Arnold, C; Chow Kai Reyes, I; Ashare, R; Paukner, M; Pacek, L R","year":2026,"journal":"Drug and alcohol dependence, 279, 113015","doi":"10.1016/j.drugalcdep.2025.113015","pmid":"41512654","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08691","title":"Child Behavioral Scores Correlate With Prenatal Tobacco and Marijuana Exposure, Sociodemographic Variables and Interactions of Default Mode and Dorsal Attention Networks.","authors":"Vishnubhotla, Ramana V; Zhao, Yi; Radhakrishnan, Rupa","year":2026,"journal":"Brain and behavior, 16(1), e71168","doi":"10.1002/brb3.71168","pmid":"41540751","tags":["pregnancy","youth","cognition","mental-health"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Using data from 6,674 children in the ABCD Study, researchers examined how prenatal substance exposure related to both behavioral outcomes and brain functional connectivity.\n\nBoth prenatal tobacco exposure (PTE) and prenatal marijuana exposure were associated with worse behavioral scores on the Child Behavior Checklist. Household income and food insecurity also predicted worse scores, highlighting that substance exposure effects occur alongside socioeconomic disadvantage.\n\nThe brain connectivity analysis revealed a specific finding for prenatal tobacco: PTE was significantly associated with increased connectivity between the default mode network (DMN) and dorsal attention network (DAN), and decreased connectivity within the DMN itself. The DMN is active during self-referential thinking and mind-wandering; the DAN manages focused attention. Altered connectivity between these networks has been linked to attention difficulties and other neurodevelopmental problems.\n\nCritically, the same DMN-DAN connectivity changes were also associated with worse behavioral scores — suggesting a pathway from prenatal exposure through altered brain connectivity to behavioral outcomes.","whyItMatters":"This study connects three levels of analysis — prenatal exposure, brain network organization, and behavioral outcomes — in a single large cohort. The finding that prenatal tobacco exposure both alters brain connectivity and predicts behavior problems through those same connectivity changes suggests a biological pathway from in utero exposure to childhood difficulties.","specificNumbers":"6,674 children analyzed. Prenatal tobacco and marijuana exposure both associated with worse behavioral scores. PTE specifically linked to increased DMN-DAN connectivity and decreased intra-DMN connectivity. Same connectivity patterns associated with behavioral problems. Income and food insecurity also significant predictors.","methodology":"Observational study using ABCD Study data (6,674 children). Behavioral scores from Child Behavior Checklist tested for associations with prenatal substance exposure and demographics. Resting-state fMRI assessed functional network connectivity. Linear regression with false discovery rate correction for multiple comparisons.","limitations":"Cross-sectional brain-behavior analysis within a longitudinal cohort — cannot confirm causal direction. Prenatal exposure based on maternal retrospective report. Cannot fully disentangle prenatal substance effects from postnatal environmental factors (parenting, continued exposure, socioeconomic factors). The high co-occurrence of tobacco and marijuana use during pregnancy makes it difficult to isolate each substance's independent effects."},{"rthcId":"RTHC-08692","title":"4F-MDMB-BICA toxicity: a fatal case and literature review of synthetic cannabinoid fatalities.","authors":"von Both, Ingo; Shoemaker, Glen K; Chatterton, Craig N","year":2026,"journal":"Forensic science, medicine, and pathology","doi":"10.1007/s12024-025-01167-5","pmid":"41557087","tags":["synthetic-cannabinoids","cardiovascular"],"studyType":"case-report","evidenceStrength":"preliminary","keyFinding":"Toxicology identified 4F-MDMB-BICA and its metabolite in blood, vitreous fluid, and urine. Death was attributed to 4F-MDMB-BICA toxicity with coronary atherosclerosis as a contributing factor. The potency of 4F-MDMB-BICA is reported to be up to several hundred-fold higher than marijuana. Genetic testing ruled out cardiomyopathy.","whyItMatters":"Synthetic cannabinoids remain a major public health threat because they are far more potent and unpredictable than natural cannabis. No clear lethal dose threshold has been established, and standard toxicology screens often miss them.","specificNumbers":"Up to several 100-fold more potent than marijuana; 4F-MDMB-BICA detected in blood, vitreous fluid, and urine; 18 days between hospital visit (after car accident) and death; severe single-vessel coronary atherosclerosis found","methodology":"Case report with full postmortem examination, specialized toxicological analysis (in-house method for synthetic cannabinoid detection), genetic testing for cardiomyopathy, and review of literature on synthetic cannabinoid fatalities.","limitations":"Single case report cannot establish population-level risk. Severe coronary disease was a contributing factor, making it difficult to isolate synthetic cannabinoid effects. No established lethal dose range exists for comparison."},{"rthcId":"RTHC-08693","title":"Youth Initiation of Cannabis Vaping Is Associated With State Cannabis Policy and E-Cigarette Use.","authors":"Vuolo, Mike; Orsini, Maria M; Staff, Jeremy; Maggs, Jennifer L; Kelly, Brian C","year":2026,"journal":"The Journal of adolescent health : official publication of the Society for Adolescent Medicine, 78(1), 53-60","doi":"10.1016/j.jadohealth.2025.03.016","pmid":"40576604","tags":["youth","legalization","potency"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"Youth in recreational cannabis states had 1.449 times the odds of initiating cannabis vaping compared to states where cannabis was illicit. Medical-only states showed a smaller but still significant increase (1.198x). The strongest predictor was e-cigarette use, which was associated with 8.07 times higher odds of cannabis vaping initiation. Comprehensive indoor vaping bans showed no significant effect.","whyItMatters":"Cannabis vaping among youth is a growing concern because vaping delivers concentrated forms that may pose unique risks to developing brains. Understanding what drives initiation can help target prevention efforts.","specificNumbers":"19,009 youth; 38,163 observations; ages 13-22; recreational states: OR 1.449 (95% CI: 1.285-1.635); medical states: OR 1.198 (95% CI: 1.006-1.427); e-cigarette use: OR 8.07 (95% CI: 7.170-9.072); indoor vaping bans: not significant","methodology":"Prospective nationally representative cohort from the Population Assessment of Tobacco and Health (PATH) study, with 19,009 youth across 38,163 observations (ages 13-22). Event history analysis examined the role of state-level cannabis policies and indoor vaping bans on cannabis vaping initiation.","limitations":"Observational design cannot prove causation. Self-reported data may undercount use. State policies changed during the study period. Does not distinguish between THC and CBD vaping products."},{"rthcId":"RTHC-08694","title":"Sexually Dimorphic Effects of a Single Neonatal Δ9-tetrahydrocannabinol Exposure on Neuronal Dendritic Morphology and Cognitive Functions in Rats.","authors":"Wadhwa, Meetu; Chinn, Gregory A; Duong, Katrina; Sasaki Russell, Jennifer; Hellman, Judith; Sall, Jeffrey W","year":2026,"journal":"Cannabis and cannabinoid research, 11(1), 36-48","doi":"10.1177/25785125251387835","pmid":"41167718","tags":["cognition","neuroscience","sex-differences","pregnancy"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Rat pups received a single injection of THC (5 mg/kg) or vehicle at postnatal day 3 — a period corresponding to late pregnancy/early postnatal brain development in humans. Weeks later, as young adults (postnatal weeks 6–8), they were tested on behavior and their brains were examined.\n\nThe sex difference was dramatic. Female rats exposed to that single neonatal THC dose showed significant spatial memory deficits on the Barnes maze — they were worse at learning and remembering the location of an escape hole. Male rats showed no memory impairment.\n\nAnxiety-like behavior, measured in the open field and elevated plus maze, was not significantly affected in either sex.\n\nGolgi-Cox staining of brain tissue revealed structural changes at the cellular level: THC-exposed animals showed alterations in dendritic morphology and spine density in the frontal cortex and hippocampus — the brain regions most critical for spatial memory and higher cognition. These structural changes provide a biological mechanism for the behavioral findings.","whyItMatters":"This study is remarkable for two reasons: first, a single dose of THC was sufficient to produce lasting cognitive effects; second, only females were affected. This sex-specific vulnerability suggests that the developing female brain may be more sensitive to endocannabinoid system disruption — a finding with implications for prenatal cannabis exposure, since THC crosses the placenta.","specificNumbers":"Single dose: 5 mg/kg THC at postnatal day 3. Female rats: spatial memory deficit on Barnes maze. Male rats: no memory deficit. Neither sex: anxiety changes. Dendritic morphology and spine density alterations in frontal cortex and hippocampus (both sexes structurally affected, but only females showed behavioral consequence).","methodology":"Male and female Sprague-Dawley rat pups received a single IP injection of THC (5 mg/kg) or vehicle (sesame oil) at postnatal day 3. Behavioral testing at postnatal weeks 6–8: Barnes maze (spatial memory), open field (anxiety), elevated plus maze (anxiety). Golgi-Cox staining for dendritic morphology and spine density in frontal cortex and hippocampus.","limitations":"Single dose at a single timepoint — doesn't model chronic exposure. Neonatal injection is a different route than prenatal placental transfer. Rat brain development timing doesn't perfectly map to human development. Only one THC dose tested. The mechanism connecting structural changes (both sexes) to behavioral effects (females only) needs further investigation."},{"rthcId":"RTHC-08695","title":"Accidental cannabis intoxications in toddlers: what to expect? A case report.","authors":"Wagnez, Lorena; Loudoux, Christelle; Pinotti, Clara; Tchidjou, Hyppolite K","year":2026,"journal":"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie, 105463","doi":"10.1016/j.arcped.2025.10.011","pmid":"41611557","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08696","title":"Patients' Perspectives and Experiences of Cannabinoids to Manage Symptoms of Chronic Kidney Disease: An In-Depth Interview Study.","authors":"Walker, Rachael C; Jackson, Angela; Semple, David; Green, Suetonia C","year":2026,"journal":"Hemodialysis international. International Symposium on Home Hemodialysis, 30(1), 149-157","doi":"10.1111/hdi.70038","pmid":"41346017","tags":["medical-cannabis","pain"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Of 17 participants, 13 used non-prescribed and 4 used prescribed cannabis. Four themes emerged: using cannabinoids to relieve an overwhelming symptom burden; barriers to accessing medical cannabis including cost and stigma; weighing risks of unregulated products; and lack of clinician knowledge and support. Most had hemodialysis experience.","whyItMatters":"Kidney failure patients experience severe symptoms that are often poorly managed with existing treatments. This study gives voice to patients navigating a complex landscape where the treatments they find helpful are often inaccessible or stigmatized.","specificNumbers":"17 participants (13 non-prescribed, 4 prescribed cannabis); most had hemodialysis experience; 4 main themes identified with subthemes","methodology":"Qualitative semistructured interview study with patients who had used either prescribed or non-prescribed cannabis to manage kidney failure symptoms. Data were coded inductively to identify themes and a conceptual framework.","limitations":"Small sample (17 participants) limits generalizability. Self-selected participants likely to have positive views of cannabis. No objective symptom measurement. Qualitative design does not establish efficacy."},{"rthcId":"RTHC-08697","title":"Factors associated with different cannabis supply methods: results from the French 2017 ESCAPAD and Health Barometer surveys.","authors":"Wallez, Solène; Eren, Filiz; Lahaie, Emmanuel; Spilka, Stanislas; Rezag Bara, Selma F; Bayle, Gauthier; Redonnet, Bertrand; Nguyen-Thanh, Viet; Cadwallader, Jean-Sébastien; Mary-Krause, Murielle","year":2026,"journal":"Journal of cannabis research, 8(1), 19","doi":"10.1186/s42238-025-00372-x","pmid":"41501967","tags":["legalization","youth","addiction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Among both 17-year-olds (n=2,943) and adults (n=1,221), buying from friends, relatives, or dealers was the most common supply method (60% and 68% respectively). Being male and having problematic cannabis use were associated with buying or cultivating. Among teens, being an apprentice and earning money predicted cultivation, while depression predicted buying. Among adults, the 26-34 age group was associated with both buying and growing.","whyItMatters":"Understanding how people obtain cannabis in countries where it remains illegal provides insight for public health policy and identifies vulnerable populations within supply networks.","specificNumbers":"2,943 seventeen-year-olds; 1,221 adults; 60% of teens and 68% of adults bought cannabis; 33% and 24% obtained it free; 5% and 8% cultivated; multinomial logistic regression with weighted data","methodology":"Analysis of two French national cross-sectional surveys from 2017: ESCAPAD (representative of 17-year-olds) and Health Barometer Survey (representative of ages 18-64). Data were weighted for representativeness with multivariate multinomial logistic regression.","limitations":"Cross-sectional data from 2017 may not reflect current patterns. Self-reported illegal behavior subject to underreporting. French cannabis market may not generalize to other countries. Does not capture online purchasing."},{"rthcId":"RTHC-08698","title":"Genome-Wide Identification, Phylogenetic Analysis and Salt-Responsive Expression Profiling of the MYB Transcription Factor Family in Cannabis sativa L. During Seed Germination.","authors":"Wang, Di; Liang, Shuyue; Che, Ye; Qi, Guochao; Jiang, Zeyu; Yang, Wei; Zhao, Haohan; Chen, Jikang; Zhu, Aiguo; Gao, Gang","year":2026,"journal":"International journal of molecular sciences, 27(2)","doi":"10.3390/ijms27021087","pmid":"41596727","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08699","title":"Cannabidiol as a Prophylactic Agent Against Glioblastoma Growth: A Preclinical Investigation.","authors":"Wang, Lei P; Bhandari, Bidhan; Naeini, Sahar Emami; Hill, Breanna; Rogers, Hannah M; Gouron, Jules; Perez-Morales, Nayeli; Khan, Aruba; Meeks, William; El-Marakby, Ahmed; Young, Nancy; Vale, Fernando L; Ali, Salman; Wallace, Gerald; Yu, Jack C; Arbab, Ali S; Salles, Évila Lopes; Baban, Babak","year":2026,"journal":"International journal of molecular sciences, 27(2)","doi":"10.3390/ijms27020757","pmid":"41596406","tags":["cancer","cbd","inflammation","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Fourteen days of inhaled CBD pretreatment before tumor implantation significantly reduced glioblastoma burden compared to both placebo and 3-day CBD groups. The longer pretreatment was accompanied by decreased expression of IDO, PD-L1, MGMT, and Ki67, markers associated with immune evasion, treatment resistance, and tumor proliferation.","whyItMatters":"Glioblastoma is one of the most lethal brain cancers with very limited treatment options. This is described as the first preclinical evidence that CBD pretreatment before tumor establishment could inhibit progression, introducing a novel preventive concept.","specificNumbers":"Two pretreatment durations tested (3 and 14 days); 14-day CBD significantly reduced tumor burden; decreased IDO, PD-L1, MGMT, and Ki67 expression compared to placebo and 3-day groups","methodology":"Preclinical study in C57BL/6 mice pretreated with inhaled CBD for either 3 or 14 days, or placebo, before intracranial implantation of glioblastoma cells. Tumor growth, immune checkpoint markers (IDO, PD-L1), and biomarkers (MGMT, Ki67) were analyzed.","limitations":"Mouse model with implanted tumor cells does not replicate how glioblastoma naturally develops. CBD was administered before tumor existed, which is not a realistic clinical scenario for most patients. Small animal study requires extensive validation."},{"rthcId":"RTHC-08700","title":"Association between cannabis consumption and serum Klotho levels in middle-aged U.S. adults: NHANES cross-sectional analysis.","authors":"Wang, Li; Ji, Yanjing; Wang, Tianxiao; Wang, Weijian; Zong, Gangjun","year":2026,"journal":"Journal of cannabis research, 8(1), 18","doi":"10.1186/s42238-025-00380-x","pmid":"41495871","tags":["cognition","cardiovascular","seniors"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Frequent cannabis users had significantly lower Klotho levels than never users (adjusted estimate = -57.94, p = 0.027), with a significant dose-dependent trend (p = 0.022). The association persisted in non-smokers (p = 0.047), confirming a cannabis-specific effect. Amplified reductions appeared in those with prolonged sedentary behavior (>240 min/day), higher vitamin D, and cancer.","whyItMatters":"Klotho is increasingly recognized as a key biomarker of biological aging, with lower levels linked to cardiovascular disease, cognitive decline, and metabolic dysfunction. If frequent cannabis use reduces Klotho, it could accelerate aging-related health problems.","specificNumbers":"5,827 adults aged 40-59; frequent users: -57.94 Klotho (p = 0.027); dose-dependent trend (p = 0.022); persisted in non-smokers (p = 0.047); E-value = 4.77 (95% CI: 1.37-8.57); population attributable fraction: 3.13% (95% CI: 0.47-6.54%)","methodology":"Cross-sectional analysis of 5,827 adults aged 40-59 from NHANES 2007-2016. Cannabis use was self-reported via computer-assisted interviews. Serum Klotho was measured by ELISA. Weighted multivariable generalized linear models with subgroup analyses, interaction tests, and E-value sensitivity analysis were used.","limitations":"Cross-sectional design cannot establish causation. Self-reported cannabis use may be inaccurate. Klotho was measured at a single time point. Cannot determine if lower Klotho preceded or followed cannabis use. The 3.13% population attributable fraction is small."},{"rthcId":"RTHC-08701","title":"Cannabidiol Regulates CD47 Expression and Apoptosis in Jurkat Leukemic Cells Dependent upon VDAC-1 Oligomerization.","authors":"Wang, Lixing; Samarani, Suzanne; Fadzeyeva, Evgenia; Vigano, MariaLuisa; As'sadiq, Alia; Vulesevic, Branka; Ahmad, Ali; Costiniuk, Cecilia T","year":2026,"journal":"Pharmaceuticals (Basel, Switzerland), 19(1)","doi":"10.3390/ph19010095","pmid":"41599693","tags":["cancer","cbd","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD reduced CD47 surface expression and triggered apoptosis in Jurkat leukemic cells. These effects were not blocked by cannabinoid receptor 2 agonists, antagonists, or anion channel blockers, but were significantly rescued by a VDAC-1 oligomerization inhibitor, revealing a specific mitochondrial pathway. Similar but weaker effects were observed in primary human T cells.","whyItMatters":"CD47 is a \"don't eat me\" signal that cancer cells use to avoid immune destruction. Understanding how CBD reduces this signal could inform new combination therapy approaches for aggressive blood cancers.","specificNumbers":"CBD downregulated CD47 expression dose-dependently; effects significantly rescued by VDAC-1 oligomerization inhibitor; similar effects in primary human CD4+ T cells at reduced levels; not rescued by CBR-2 agonist, CBR-2 antagonist, or anion channel blocker","methodology":"In vitro studies using Jurkat cells (T-cell acute lymphoblastic leukemia line) and human peripheral blood mononuclear cells under various culture conditions, CBD concentrations, and with or without different receptor agonists, antagonists, and channel blockers.","limitations":"In vitro study using cell lines may not reflect in vivo tumor biology. CBD also affected normal T cells, raising safety concerns for immunocompromised patients. Concentrations used may not be achievable in humans. No animal or clinical data."},{"rthcId":"RTHC-08702","title":"Household cannabis cessation and adolescent mental health outcomes in a prospective cohort study.","authors":"Wang, Ming; Xu, Yixiang; Huang, Runqi; Sun, Yunjun; Zhang, Lingli; Zhou, Wei; Zhang, Qingli; Luo, Qiang; Du, Wenchong; Ren, Tai; Li, Fei","year":2026,"journal":"BMC medicine","doi":"10.1186/s12916-026-04668-4","pmid":"41629925","tags":["withdrawal","youth","mental-health","quitting","addiction"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Using longitudinal data from the ABCD Study, researchers identified adolescents (ages 10–13) living in households where someone used cannabis, then tracked what happened to the teens' mental health when household members stopped.\n\nAfter propensity score matching to control for demographic and psychological differences, household cannabis cessation was associated with improvements in adolescents' internalizing problems (anxiety, depression), externalizing problems (conduct, aggression), and psychotic-like experiences.\n\nThe study went further to identify potential pathways. Two mediators emerged: family conflict decreased when household cannabis use stopped, and adolescents' sleep problems improved. Both reductions were associated with the mental health improvements — suggesting that household cannabis cessation benefits teens not just by removing direct exposure but by improving the family environment and the teen's sleep quality.\n\nPsychotic-like experiences (PLEs) were assessed separately using the Prodromal Questionnaire, adding specificity to the mental health outcomes beyond general behavioral checklists.","whyItMatters":"Most cannabis mental health research focuses on the user themselves. This study asks a different question: what happens to the children in the household? The finding that household cessation improves teen mental health — mediated through reduced family conflict and better sleep — suggests that cannabis use affects families, not just individuals.","specificNumbers":"ABCD Study, adolescents ages 10–13. Household cessation associated with improved internalizing, externalizing, and psychotic-like experiences. Two significant mediating pathways: reduced family conflict and improved sleep. Propensity score matching used to balance groups.","methodology":"Longitudinal cohort study using ABCD Study waves 2 and 3. Included adolescents ages 10–13 with household cannabis use at wave 2. Cessation defined as absence of household member cannabis use at wave 3. Propensity score matching for demographic and psychometric confounders. Outcomes: Child Behavior Checklist (internalizing, externalizing), Prodromal Questionnaire-Brief (psychotic-like experiences). Mediators: Family Environment subscale (conflict), Sleep Disturbance Scale for Children.","limitations":"Observational design — household cessation may coincide with other positive changes (employment, relationship improvement, reduced stress) that independently benefit teen mental health. Household cannabis use was assessed by report, which may be inaccurate. Cannot determine whether effects are from secondhand exposure, household environment, genetic factors, or some combination. Two-wave comparison limits trajectory analysis."},{"rthcId":"RTHC-08703","title":"Cannabis Intoxication Does Not Impact Nutritional Status in Patients with Small Burns.","authors":"Wang, Sarah; Stanton, Eloise; Emeh, Amara; Manasyan, Artur; Wong, Sunnie; Boudiab, Elizabeth; Baranco, Paige; Johnson, Maxwell B; Gillenwater, T Justin","year":2026,"journal":"Journal of burn care & research : official publication of the American Burn Association","doi":"10.1093/jbcr/irag027","pmid":"41700804","tags":["appetite","medical-cannabis"],"studyType":"retrospective-cohort","evidenceStrength":"moderate","keyFinding":"Cannabis-positive burn patients showed no significant differences in admission prealbumin (18.8 vs 19.2, p=0.804), admission albumin (3.9 vs 4.0, p=0.375), or time to peak nutritional markers compared to matched controls. Increased age was associated with lower admission albumin (p<0.001).","whyItMatters":"Burn patients have extreme metabolic demands and are highly susceptible to malnutrition. Understanding whether cannabis intoxication affects their nutritional status is clinically relevant, especially as cannabis use becomes more common among trauma patients.","specificNumbers":"76 cannabis-positive patients matched with 76 controls; prealbumin: 18.8 vs 19.2 (p=0.804); albumin: 3.9 vs 4.0 (p=0.375); days to peak prealbumin: 3.8 vs 3.9 (p=0.876); days to peak albumin: 0.3 vs 1.0 (p=0.088); <20% TBSA burns","methodology":"Single-institution retrospective study of adult burn patients with less than 20% total body surface area burns who tested positive for cannabis on admission urine toxicology (2015-2024), matched 1:1 with cannabis-negative controls. Outcomes included burn characteristics, nutritional markers, and complications.","limitations":"Restricted to smaller burns (<20% TBSA), so findings may not apply to major burns. Urine toxicology detects recent use but not intoxication level. Retrospective single-institution design. Sample size may be too small to detect subtle differences."},{"rthcId":"RTHC-08704","title":"In Their Own Words: A Qualitative Exploration of Veterans' Perspectives and Experiences of Medical Cannabis Use.","authors":"Ward, Rachel; Christensen, Vivian; Saxton, Lauren; Varnum, Melissa; Ayers, Chelsea; Pleasant, Traben; Kansagara, Devan","year":2026,"journal":"Journal of general internal medicine","doi":"10.1007/s11606-025-10160-1","pmid":"41559295","tags":["medical-cannabis","harm-reduction","mental-health"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Veterans used cannabis for a variety of health conditions and perceived few or no harms, or felt benefits outweighed risks. They obtained cannabis information from trusted peers, dispensary staff, and personal experimentation rather than healthcare providers. Veterans identified strategies for VA providers including increasing cannabis knowledge and engaging in unbiased discussions.","whyItMatters":"Veterans use cannabis at high rates and often have complex health needs. The disconnect between patient behavior and clinical engagement means veterans are making cannabis decisions without medical guidance, potentially missing drug interactions or dosing issues.","specificNumbers":"23 veterans interviewed; mostly rural; past 30-day medical cannabis users; from 3 states with legal cannabis (Connecticut, Michigan, Oregon)","methodology":"Qualitative semistructured interviews via Webex with 23 mostly rural veterans with past 30-day medical cannabis use in Connecticut, Michigan, or Oregon. Inductive thematic analysis with iterative codebook development.","limitations":"Small sample of 23 participants from only 3 states limits generalizability. Self-selected participants likely have positive views of cannabis. Only included current users, missing perspectives of those who tried and stopped."},{"rthcId":"RTHC-08705","title":"The perils of marijuana use in adolescents.","authors":"Ward, Savitra; Konda, Sanjana; Zhao, Daniel Zongliang; Ganti, Latha","year":2026,"journal":"Journal of addictive diseases, 1-6","doi":"10.1080/10550887.2025.2589700","pmid":"41550005","tags":["youth","addiction","cognition"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"The pooled prevalence of cannabis use among adolescents ages 12-17 was 11.4% (95% CI: 10.70-12.20%). Cannabis use was slightly more common among females than males and among white, Hispanic, and Black adolescents. Higher marijuana use correlated with more skipped classes and lower grades. About 1 in 6 adolescents who try marijuana develop a use disorder.","whyItMatters":"With increasing THC potency and greater accessibility through legalization, understanding adolescent cannabis use patterns and their academic consequences is essential for prevention efforts.","specificNumbers":"11.4% prevalence (95% CI: 10.70-12.20%); slightly higher in females; 1 in 10 users overall develop use disorder; 1 in 6 teen users develop addiction; higher use linked to more class skipping and lower grades","methodology":"Analysis of the National Survey on Drug Use and Health (NSDUH) data, with age restricted to 12-17 year-olds. Compared cannabis users to non-users across gender, race, school attendance, and academic performance.","limitations":"Cross-sectional design cannot establish whether cannabis causes academic problems or if other factors drive both. Self-reported data may undercount use. NSDUH methodology changes over time could affect prevalence estimates."},{"rthcId":"RTHC-08706","title":"Independent brain cortical signatures of risk for adolescent cannabis use and consequences of such use are moderated by sex.","authors":"Watts, Jeremy J; Navarri, Xavier; Conrod, Patricia J","year":2026,"journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 51(2), 497-505","doi":"10.1038/s41386-025-02249-2","pmid":"41233604","tags":["youth","neuroscience","sex-differences","cognition"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"In years when adolescents used more cannabis than their personal average, cortical thickness was lower (p = 0.047). This effect was stronger in males, where each once-per-week increase in use was associated with a 0.005 mm reduction in cortical thickness, equivalent to about 17.9% of the annual rate of cortical thinning. The thinning was greatest in brain regions with highest CB1 receptor gene expression. Males also showed a pre-existing cortical thickness signature associated with cannabis use propensity, present before any cannabis exposure.","whyItMatters":"This study helps answer a long-standing question: do brain differences cause cannabis use or does cannabis cause brain differences? The answer appears to be both, at least in males, which has major implications for understanding adolescent vulnerability.","specificNumbers":"136 adolescents; 74 female; 3 neuroimaging sessions ages 12-17; 90% follow-up; within-person effect: -0.0023 mm per weekly use increase (p = 0.047); males: -0.005 mm (p = 0.0017); 17.9% of annual cortical thinning rate; CB1 receptor gene correlation: rho = -0.33 (sample), rho = -0.5 (males)","methodology":"Longitudinal study with 136 adolescents (74 female) completing three neuroimaging sessions and annual assessments from ages 12 to 17, with 90% follow-up. Cannabis use was disaggregated into between-person (vulnerability) and within-person (time-varying) components using multilevel modeling, controlling for age, sex, and alcohol use.","limitations":"Relatively small sample (136 adolescents). Cannabis use was relatively low in this age group. Cannot fully rule out other substance use effects. Cortical thinning is a normal developmental process, making it challenging to determine clinical significance."},{"rthcId":"RTHC-08707","title":"Current marijuana use is cross-sectionally associated with accelerated biological aging among U.S. adults: exploring mediating effect of blood cadmium.","authors":"Wei, Kai; Chen, Xiaotong","year":2026,"journal":"The journal of nutrition, health & aging, 30(3), 100778","doi":"10.1016/j.jnha.2026.100778","pmid":"41538955","tags":["cardiovascular","seniors","harm-reduction"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Current marijuana users showed significantly accelerated aging versus never users on both PhenoAge (beta = 0.72, p < 0.001) and KD-BioAge (beta = 0.36, p = 0.002). Dual users of marijuana and tobacco showed additive effects. Blood cadmium was a partial mediator, explaining 15.6% of PhenoAge acceleration and 8.3% of KD-BioAge acceleration.","whyItMatters":"This is one of the first large studies to link marijuana use to accelerated biological aging using validated biomarker-based measures, and it identifies a potential mechanistic pathway through cadmium exposure from smoking.","specificNumbers":"12,806 adults; PhenoAge acceleration: beta = 0.72 (95% CI: 0.41-1.02, p < 0.001); KD-BioAge: beta = 0.36 (95% CI: 0.14-0.59, p = 0.002); cadmium mediation: 15.6% (PhenoAge) and 8.3% (KD-BioAge); additive effects for dual tobacco-marijuana users","methodology":"Cross-sectional analysis of 12,806 U.S. adults from NHANES 2005-2018. Biological age calculated using two validated algorithms (PhenoAge and KD-BioAge). Aging acceleration defined as residuals from regression of biological age on chronological age. Survey-weighted multivariable regression with mediation analyses.","limitations":"Cross-sectional design cannot establish causation. Cannot distinguish route of cannabis administration (smoked vs. edible vs. vaped). Cadmium exposure could reflect tobacco co-use despite adjustments. Self-reported marijuana use may be inaccurate."},{"rthcId":"RTHC-08708","title":"The prevalence of cannabidiol (CBD) use in North America and Europe: A meta-analysis.","authors":"Weidberg, Sara; Iza-Fernández, Clara; Alemán-Moussa, Layla; Krotter, Andrea; González-Roz, Alba","year":2026,"journal":"Addiction (Abingdon, England)","doi":"10.1111/add.70360","pmid":"41724499","tags":["cbd","medical-cannabis","legalization"],"studyType":"meta-analysis","evidenceStrength":"strong","keyFinding":"CBD use was significantly more prevalent in North America than Europe across all time periods. In North America, lifetime prevalence was 28.9%, past-year 19.5%, past-month 12%, and daily 6.4%. In Europe, lifetime was 12.8%, past-year 17.6%, past-month 7.2%, and daily 2.1%. In Europe, clinical patients had higher past-year use (25.6%) than community samples (11.6%), while in North America the pattern reversed (community 26.1% vs. clinical 4.1%).","whyItMatters":"Despite the explosive growth of the CBD market, no prior systematic assessment of how many people actually use CBD existed. These numbers provide a baseline for tracking trends as regulations and products evolve.","specificNumbers":"43 studies; 388,447 participants; 57.52% female; North America lifetime: 28.9% (95% CI: 0.20-0.39); Europe lifetime: 12.8% (95% CI: 0.06-0.25); North America daily: 6.4% (95% CI: 0.03-0.13); Europe daily: 2.1% (95% CI: 0.01-0.08)","methodology":"Systematic review and meta-analysis of 43 studies (48 samples, n = 388,447) from PubMed, PsycINFO, and Web of Science. Prevalence estimated at five time periods for North America (30 studies) and Europe (13 studies) separately. Moderator analyses examined sex, data collection year, and sample type.","limitations":"High heterogeneity across studies. Wide confidence intervals for some estimates. Different CBD products and legal definitions across countries. Studies span different years and regulatory environments."},{"rthcId":"RTHC-08709","title":"Endocannabinoid Modulation in Headache: Mechanisms, Models, and Translational Therapies.","authors":"Wen, Jie; Zhang, Yumin","year":2026,"journal":"Cells, 15(4)","doi":"10.3390/cells15040331","pmid":"41744774","tags":["pain","neuroscience","sex-differences","inflammation"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"The endocannabinoid system modulates trigeminovascular firing, CGRP release, neurogenic inflammation, cortical spreading depression, and glial activation after brain injury. Drugs that inhibit endocannabinoid breakdown (FAAH, MAGL, COX-2 inhibitors) consistently reduce headache-like behaviors in animal models. Endocannabinoid system dysregulation contributes to central sensitization in medication overuse headache. Females show distinct hormonal regulation, receptor expression, and glial activation that influence responses to cannabinoid-based therapies.","whyItMatters":"Headache disorders affect over a billion people globally and remain difficult to treat. The endocannabinoid system offers multiple therapeutic targets that could complement or replace existing treatments, particularly for patients who do not respond to conventional therapies.","specificNumbers":"CB1 and CB2 receptors; endogenous ligands AEA and 2-AG; FAAH, MAGL, and COX-2 as drug targets; 5 headache types reviewed; sex-dependent responses documented","methodology":"Comprehensive narrative review synthesizing preclinical and translational research on the endocannabinoid system across multiple headache types: migraine, tension-type headache, trigeminal autonomic cephalalgias, post-traumatic headache, and medication overuse headache.","limitations":"Mostly based on preclinical data. Clinical evidence for endocannabinoid-targeted headache treatments is limited. Sex differences are documented but not yet integrated into clinical protocols. Individual variation in endocannabinoid tone may complicate treatment."},{"rthcId":"RTHC-08710","title":"Cannflavin B ameliorates behavioural and neuronal systems alterations in adolescent rats exposed to prenatal valproic acid.","authors":"Williams, Olivia O F; Coppolino, Madeleine; Manduca, Joshua D; Demers, Taylor C; Henry-Duru, Paula T; Mueller, Talen C; Soubeyrand, Eric; Perrin, Colby J; Akhtar, Tariq A; Perreault, Melissa L","year":2026,"journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 195, 118949","doi":"10.1016/j.biopha.2025.118949","pmid":"41496357","tags":["cbd","neuroscience","inflammation","sex-differences"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Cannflavin B (0.2 mg/kg) was well tolerated and ameliorated most VPA-induced changes. It had anxiolytic-like properties in female VPA rats and normalized sociality in both sexes. Most VPA-induced brain wave abnormalities (spectral power, coherence, theta-gamma coupling) were corrected across prefrontal cortex, cingulate cortex, and hippocampus. Cannflavin B also reduced VPA-induced microglial activation in a sex- and region-specific manner.","whyItMatters":"No pharmacological treatments currently address the core symptoms of autism. While whole cannabis raises concerns for children and CBD results are inconsistent, cannflavin B offers a new non-psychoactive cannabis-derived compound worth investigating.","specificNumbers":"0.2 mg/kg cannflavin B; brain regions assessed: prefrontal cortex, cingulate cortex, hippocampus; measures: oscillatory spectral power, coherence, theta-gamma cross-frequency synchrony, Iba1 microglial marker; sex-specific effects documented","methodology":"Prenatal VPA exposure rat model of autism. Adolescent rats received cannflavin B (0.2 mg/kg, i.p.) and were assessed for behavioral outcomes (anxiety, sociality), neuronal oscillatory changes across brain regions, and microglial markers. Both in vivo and in vitro experiments were conducted.","limitations":"Animal model of autism has limited translational relevance. Single dose tested. Prenatal VPA model captures some but not all aspects of autism. No human data exists for cannflavin B in autism or any neuropsychiatric condition."},{"rthcId":"RTHC-08711","title":"A Qualitative Study of How Teens in Washington State Make Sense of Cannabis Edibles Warning Labels and Packaging.","authors":"Willoughby, Jessica Fitts; Hust, Stacey J T; Kang, Soojung; Couto, Leticia; Price, Ron; Nickerson, Christina Griselda; Johnson, Opeyemi; Ross-Viles, Sarah","year":2026,"journal":"Drug and alcohol review, 45(1), e70071","doi":"10.1111/dar.70071","pmid":"41206469","tags":["youth","legalization","potency"],"studyType":"qualitative","evidenceStrength":"preliminary","keyFinding":"Teens misinterpreted warning labels on cannabis edibles and felt warnings were hidden or unnoticeable. Most paid little attention to nutrition labels and found serving size information confusing. Products resembling familiar snack brands were perceived as less risky and more enticing. Prior cannabis knowledge affected how teens understood packaging. Teens felt warning labels applied to younger children, not themselves.","whyItMatters":"Washington state requires specific cannabis edible labels to protect young people, but this study suggests those labels are not working as intended. Teens may be more attracted to products that mimic familiar snacks, undermining regulatory goals.","specificNumbers":"28 teens; mean age 15.93 (SD = 1.25); 10 focus groups; Washington state; viewed images of actual cannabis edible products available in the state","methodology":"Ten focus groups with 28 diverse teens (mean age 15.93) in Washington state. After viewing images of actual cannabis edible products, participants shared opinions about packaging, warning labels, and nutrition information. Thematic analysis was used.","limitations":"Small sample from one state. Focus groups capture stated attitudes, not actual behavior. Teens viewed images rather than handling real products. Social desirability may have influenced responses in a group setting."},{"rthcId":"RTHC-08712","title":"Cannabis Marketing Restrictions and Exposure to Cannabis Marketing in Legal US Cannabis Markets: Findings From the International Cannabis Policy Study.","authors":"Winfield-Ward, Lauren; Wadsworth, Elle; Driezen, Pete; Hammond, David","year":2026,"journal":"Drug and alcohol review, 45(1), e70106","doi":"10.1111/dar.70106","pmid":"41591207","tags":["legalization","youth"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"States with low and moderate marketing restrictions had similar exposure rates (61.4% and 61.8%). Only the highest-strength restrictions significantly reduced exposure to 53.4% (p = 0.037). Billboard/poster and sports event restrictions were associated with channel-specific reductions. People below the minimum legal age (16-20) reported the highest marketing exposure at 63.0% (p < 0.001).","whyItMatters":"As more states legalize cannabis, understanding which marketing regulations actually work is essential. This study provides evidence that only comprehensive restrictions make a meaningful difference, and current regulations fail to prevent marketing from reaching young people.","specificNumbers":"99,132 respondents; ages 16-65; 2018-2023; 20 states; low restrictions: 61.4% exposure; moderate: 61.8%; highest: 53.4% (p = 0.037); under-21 exposure: 63.0% (p < 0.001)","methodology":"Repeated cross-sectional surveys from the International Cannabis Policy Study (2018-2023) with 99,132 respondents aged 16-65 across 20 U.S. states with legal recreational cannabis. Marketing restriction strength was measured from regulatory documents. Adjusted mixed effects logistic regression models were used.","limitations":"Self-reported marketing exposure may not reflect actual exposure. State regulations changed during the study period. Cannot account for cross-border exposure. \"Noticing\" marketing may differ from being influenced by it."},{"rthcId":"RTHC-08713","title":"Cannabis Legalization and Cannabis Use Disorder by Sex in Veterans Health Administration Patients, 2005-2019.","authors":"Wisell, Caroline G; Hasin, Deborah S; Wall, Melanie M; Alschuler, Daniel; Malte, Carol; McDowell, Yoanna; Olfson, Mark; Keyes, Katherine M; Cerdá, Magdalena; Maynard, Charles C; Keyhani, Salomeh; Martins, Silvia S; Mannes, Zachary L; Livne, Ofir; Fink, David S; Bujno, Julia M; Stohl, Malki; Saxon, Andrew J; Simpson, Tracy L","year":2026,"journal":"Substance use & misuse, 61(2), 296-306","doi":"10.1080/10826084.2025.2554866","pmid":"40952119","tags":["addiction","legalization","sex-differences"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"CUD prevalence increased in both sexes across the study period. States enacting medical or recreational cannabis laws saw greater CUD increases than non-legalizing states. However, with one exception (males aged 35-64 under recreational laws), the sex-specific increases were not significantly different. Both sexes showed rising CUD rates regardless of state policy.","whyItMatters":"The veteran population has high rates of mental health conditions and substance use. Understanding how legalization affects cannabis use disorder in this population, and whether sex differences exist, is important for VA clinical planning.","specificNumbers":"2005-2019 data; veterans ages 18-75; VHA patients; staggered-adoption difference-in-difference design; one significant sex difference: males aged 35-64 showed greater CUD increase after recreational legalization","methodology":"VHA Corporate Data Warehouse data for veterans ages 18-75 with at least one primary care, emergency, or mental health visit per year from 2005 to 2019. Staggered-adoption difference-in-difference analyses with linear binomial regression, fixed effects for state and year, time-varying cannabis law status, and sociodemographic covariates.","limitations":"VHA patients are not representative of all veterans or the general population. CUD diagnosis rates may reflect changes in screening and detection rather than true prevalence changes. Cannot distinguish between increased disorder and increased diagnosis."},{"rthcId":"RTHC-08714","title":"Demographic Predictors of Medicinal Cannabis Users' Perceived Level of Physician Support for Medicinal Cannabis Prescriptions in New Zealand.","authors":"Withanarachchie, Vinuli; Wilkins, Chris; Parker, Karl; Rychert, Marta","year":2026,"journal":"Drug and alcohol review, 45(1), e70063","doi":"10.1111/dar.70063","pmid":"41158035","tags":["medical-cannabis","legalization"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Mental health (73.8%), sleep (71.6%), and pain (59.5%) were the top conditions treated. 41.5% of female users treated women's health conditions. Prescriptions were less common among females, Maori, Pacific Peoples, and lower-income earners. Those aged 60+, tertiary educated, earning above $60,000, and treating specific conditions were more likely to hold prescriptions. Younger, unemployed, Maori, or Pacific individuals were more likely to avoid requesting prescriptions due to anticipated physician refusal.","whyItMatters":"New Zealand implemented a legal medical cannabis scheme in 2020, but access disparities persist. This study shows that the gap between who uses cannabis medically and who gets a prescription follows predictable socioeconomic and ethnic lines.","specificNumbers":"10,781 survey respondents; 1,742 medicinal users analyzed; mental health 73.8%, sleep 71.6%, pain 59.5%; 41.5% of females treating women's health; disparities for Maori, Pacific Peoples, females, income below $60,000","methodology":"Anonymous online survey (New Zealand Drug Trends Survey) via Meta platforms, completed by 10,781 New Zealanders aged 16+ in 2024. Analysis focused on 1,742 respondents using cannabis primarily for medicinal purposes in the past 6 months. Logistic regression models predicted prescription access and physician support perceptions.","limitations":"Online survey via Meta may not reach all populations equally. Self-selected sample of cannabis users. New Zealand-specific findings may not generalize. Cannot determine whether physician refusal is actual or only anticipated."},{"rthcId":"RTHC-08715","title":"Partial cannabis legalization and the increase of the THC threshold in road traffic: a statistical analysis of traffic cases before and after legal changes.","authors":"Wohlfarth, Ariane; Franz, Thomas; Skopp, Gisela Adelheid; Musshoff, Frank","year":2026,"journal":"Traffic injury prevention, 1-11","doi":"10.1080/15389588.2026.2616385","pmid":"41707218","tags":["driving","legalization","harm-reduction"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Median THC levels in administrative and criminal traffic offenses were identical (3.44 ng/mL). After legalization, THC medians rose modestly (to 3.95-3.97 ng/mL). Under the new 3.5 ng/mL threshold, 58.3% of occasional users with potentially impaired driving fell below the limit (escaping sanctions), while almost half of frequent unimpaired drivers exceeded it. Only 7.4% of frequent users benefited from the raised threshold as intended. Drivers under 21 decreased from 18.2% to 13.3% of cases.","whyItMatters":"Germany's 2024 cannabis legalization included raising the driving THC limit, intended to protect frequent users who separate use from driving. This study provides the first systematic evaluation showing the new threshold may not achieve its intended goals.","specificNumbers":"48,058 total cases; 83% administrative, 17% criminal; 46% of drivers aged 21-30; median THC: 3.44 ng/mL (identical for administrative and criminal); consumption categories: occasional 47%, regular 22%, repeated 19%, chronic 11%; median THC by category: 1.3, 4.5, 8.4, 14.9 ng/mL; 58.3% of occasional users with 1.0-3.5 ng/mL exempt from sanctions; 7.4% of frequent users benefited as intended","methodology":"Retrospective analysis of 48,058 traffic-related blood samples containing THC from three German federal states between April 2021 and March 2025. Cases were submitted for toxicological analysis under administrative or criminal traffic offense statutes. Four consumption categories were established based on THC-carboxylic acid concentrations.","limitations":"Laboratory data from three states may not represent all of Germany. Cannot directly measure impairment at time of driving. Consumption categories based on metabolite ratios are approximations. Short post-legalization follow-up period."},{"rthcId":"RTHC-08716","title":"Social Learning Theory and Gateway Hypothesis as a Causal Pathway Linking Rule-Breaking Peer Association to Marijuana Use via Nicotine Vaping.","authors":"Wojciechowski, Thomas","year":2026,"journal":"Journal of psychoactive drugs, 1-10","doi":"10.1080/02791072.2026.2614509","pmid":"41511411","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08717","title":"Hemp seed mitigates colonic inflammation through macrophage polarization and microbiota-barrier axis restoration.","authors":"Woo, Jieun; Cheng, Dekun; Long, Erica A; Whitney, Kristin L; Shen, Guangyi; Reddivari, Lavanya; Jiang, Qing; Simsek, Senay; Ju, Tingting; Wang, Weicang","year":2026,"journal":"Food & function, 17(1), 231-242","doi":"10.1039/d5fo04119h","pmid":"41328036","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08718","title":"Noncompliance with laws to prevent polysubstance misuse: Recreational cannabis sales to apparently alcohol-intoxicated customers.","authors":"Woodall, W Gill; Buller, David B; Saltz, Robert; Fell, James C; Martinez, Lila; Brice, Amanda N; Chirico, Noah; Cutter, Gary R","year":2026,"journal":"Alcohol, clinical & experimental research, 50(1), e70204","doi":"10.1111/acer.70204","pmid":"41575362","tags":["legalization","harm-reduction"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"Sellers were willing to sell cannabis to pseudo-intoxicated buyers at 73.7% of visits (255 of 346). Only 6.9% of stores refused at both visits, while 54.3% sold at both visits. Stores with signs saying \"no sales to intoxicated customers\" refused more often (34.3%, p = 0.04), especially when buyers displayed more obvious intoxication signs (39.8%, p = 0.049).","whyItMatters":"Combining cannabis with alcohol increases impairment and harm risk. If laws prohibiting sales to intoxicated customers are largely unenforced, polysubstance-impaired driving and other harms may increase in legal cannabis markets.","specificNumbers":"173 stores assessed; 346 total visits; 73.7% willing to sell (255/346); 26.3% refused; 6.9% refused at both visits; 54.3% sold at both visits; stores with signage: 34.3% refusal rate (p = 0.04); more obvious intoxication: 39.8% refusal (p = 0.049)","methodology":"Pseudo-patron study in January-June 2024. Trained actors visited 189 recreational cannabis stores twice in two large metropolitan areas, displaying alcohol intoxication behaviors while attempting to purchase cannabis. Observers recorded seller responses and store/seller characteristics. Logistic regression analyzed predictors of refusal.","limitations":"Two metropolitan areas in one state may not represent all markets. Pseudo-patrons may not perfectly simulate real intoxication. Only two visits per store. Cannot determine seller awareness of the law versus unwillingness to refuse."},{"rthcId":"RTHC-08719","title":"Inhibitory effects of (synthetic) cannabinoids and (designer) benzodiazepines on spontaneously active neuronal networks of primary rat cortical cultures in vitro.","authors":"Wopken, J Pepijn; Thornton, Jack R; van Kleef, Regina G D M; Westerink, Remco H S","year":2026,"journal":"Neurotoxicology, 112, 103379","doi":"10.1016/j.neuro.2025.103379","pmid":"41482166","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08720","title":"Clinical practice guidelines for the administration of third-generation anti-seizure medications.","authors":"Wu, Xintong; Chen, Yangmei; Feng, Li; Han, Xiong; Han, Yanbing; Huang, Huapin; Li, Qifu; Liu, Xiaorong; Ren, Liankun; Sun, Yanping; Wang, Qun; Wang, Tiancheng; Wang, Xiangqing; Xiao, Bo; Xu, Huiqin; Yu, Peimin; Zhang, Hong; Zhu, Guoxing; Zhu, Suiqiang; Zhou, Dong","year":2026,"journal":"Seizure, 134, 13-26","doi":"10.1016/j.seizure.2025.11.002","pmid":"41270420","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08721","title":"Complete radiologic and clinical reversal of lumbar spinal epidural lipomatosis via GLP-1 agonist.","authors":"Wurm, Lennard M; Koch, Peter; Ertel, Wolfgang; Laue, Dominik","year":2026,"journal":"Journal of surgical case reports, 2026(2), rjag052","doi":"10.1093/jscr/rjag052","pmid":"41694436","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08722","title":"Cannabis use in pregnancy: Key findings from 2021-2023 National Survey on Drug Use and Health data.","authors":"Wysota, Christina N; Sherman, Scott E; Abroms, Lorien C; Ghassabian, Akhgar; Hernandez, Sasha; Young-Wolff, Kelly C; Rogers, Erin S","year":2026,"journal":"Addictive behaviors, 176, 108621","doi":"10.1016/j.addbeh.2026.108621","pmid":"41643368","tags":["pregnancy","addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Nearly 7% of pregnant participants reported current (past 30-day) cannabis use. Among current users, 31% reported any doctor-recommended use and 52% bought from a dispensary. The strongest correlates of current use versus never use were: alcohol use (RRR = 7.24), serious psychological distress (RRR = 6.25), e-cigarette use (RRR = 4.92), higher education (RRR = 2.97), being unmarried (RRR = 2.54), cigarette use (RRR = 2.57), and younger age 18-25 (RRR = 2.08). Perceiving risk of weekly cannabis use dramatically reduced odds of current use (RRR = 0.07).","whyItMatters":"Cannabis use during pregnancy is associated with potential risks to fetal development. Understanding who uses and why is essential for developing targeted interventions, especially given that nearly a third of users report doctor-recommended use.","specificNumbers":"1,992 pregnant participants; ~7% current use; 31% of users reported doctor-recommended use; 52% bought from dispensary; serious psychological distress: RRR = 6.25 (95% CI: 2.46-15.85); alcohol: RRR = 7.24 (95% CI: 1.52-34.49); e-cigarette: RRR = 4.92 (95% CI: 1.71-14.10); perceived risk: RRR = 0.07 (95% CI: 0.03-0.14)","methodology":"Pooled cross-sectional analysis of 1,992 pregnant participants from NSDUH 2021-2023. Multinomial regression comparing correlates of current, recent, former, and never cannabis use, adjusting for sociodemographic and clinical variables.","limitations":"Cross-sectional design cannot determine causality. NSDUH uses self-reported data which may undercount use during pregnancy. Cannot distinguish first, second, or third trimester use. Wide confidence intervals for some estimates."},{"rthcId":"RTHC-08723","title":"Prevalence, Patterns, and Correlates of Cannabis-Cigarette Co-Use: Findings From a Multi-State Rapid-Response Survey in the U.S., 2023-2024.","authors":"Xue, Zheng; Gibson, Laurel P; Nighbor, Tyler; Nargis, Nigar; Westmaas, J Lee; Patel, Minal","year":2026,"journal":"American journal of preventive medicine, 70(2S), 108114","doi":"10.1016/j.amepre.2025.108114","pmid":"41611355","tags":["addiction","harm-reduction","respiratory"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"45% of current cigarette smokers reported concurrent cannabis use, compared to 24.5% of former smokers and 12.3% of never smokers. Co-users smoked 12.8 cigarettes per day and used cannabis 18.9 days per month, similar to exclusive users of either substance. Co-use was more likely among males, those aged 18-24, non-Hispanic Black individuals, single individuals, and those with mental or physical disabilities.","whyItMatters":"Cannabis and tobacco co-use may produce additive health risks, particularly for respiratory health. In states already struggling with high tobacco use, cannabis co-use adds another layer of concern that tobacco control efforts need to address.","specificNumbers":"9,100 adults; 13 high-tobacco-burden states; 8.7% co-use prevalence; 45.0% of current smokers used cannabis; 24.5% of former smokers; 12.3% of never smokers; co-users: 12.8 cigarettes/day, 18.9 cannabis days/month; higher among males, ages 18-24, non-Hispanic Black, single, with disabilities","methodology":"Online rapid-response survey of a probability sample of 9,100 adults aged 18-65 in 13 high-tobacco-burden states, collected 2023-2024. Weighted prevalence calculations and logistic regressions examined sociodemographic correlates and patterns of co-use.","limitations":"Cross-sectional design in 13 high-tobacco states may not generalize to all states. Online survey may miss some populations. Self-reported use subject to bias. Cannot determine whether co-use leads to worse health outcomes than exclusive use."},{"rthcId":"RTHC-08724","title":"Canadian real-world evidence: observational 24-week outcomes for health care practitioner authorized cannabis.","authors":"Yang, Brian; Diep, Calvin; Thaker, Sonalben; Jackson, Ted; Lakhani, Aly; Landolt, Carolina; Pope, Elena; Lara-Corrales, Irene; Cortes Pradilla, Henry; Yu, Hai Chuan; Mae Gabriel, Gretchen; Darville, Rasheeda; Weisbrod, Ken; Tingling, Keriann; Nandra, Kiritpaul; Ganty, Praveen; Fiorellino, Joseph; Huang, Alexander; Tao, Leeping; Singh, Mandeep; Chung Tai, Peter; Carlen, Peter; Ladha, Karim; Clarke, Hance","year":2026,"journal":"Canadian journal of pain = Revue canadienne de la douleur, 10(1), 2593253","doi":"10.1080/24740527.2025.2593253","pmid":"41640820","tags":["medical-cannabis","pain","anxiety","depression","sleep"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Over 24 weeks, patients showed improvements in pain interference (-4.6 points), numeric pain rating (-1.19), anxiety (-2.24), depression (-2.79), and quality of life (-0.56). While all changes were statistically significant, none reached their respective minimal clinically significant thresholds. 85% of patients had a primary indication of pain.","whyItMatters":"This is a rare long-term observational study of physician-authorized medical cannabis with validated outcome measures. The gap between statistical significance and clinical significance raises important questions about how meaningful the improvements actually are for patients.","specificNumbers":"Pain interference: -4.6 (CI: -6.02 to -3.17, n = 137); pain rating: -1.19 (CI: -1.7 to -0.68, n = 137); GAD-7 anxiety: -2.24 (CI: -3.5 to -0.99, n = 139); PHQ-9 depression: -2.79 (CI: -4.29 to -1.3, n = 141); QoL: -0.56 (CI: -0.96 to -0.16, n = 139); 85% pain indication","methodology":"Prospective observational multicenter study from the Canadian Medical Cannabis Real-World Evidence study. Adult patients chose from Health Canada-verified products via a national pharmacy platform with physician guidance. Validated questionnaires (PROMIS, NPRS, GAD-7, PHQ-9, EQ-5D-3L) administered at weeks 0, 6, 12, and 24. Analyzed per-protocol and intention-to-treat.","limitations":"No control group or randomization. Small sample sizes at 24 weeks due to dropout. Cannot separate cannabis effects from placebo, natural disease course, or concurrent treatments. Product heterogeneity across patients."},{"rthcId":"RTHC-08725","title":"Complete genome characterization of a novel virus isolated from the ethnic medicine plant Valeriana jatamansi Jones.","authors":"Yang, Chaorong; Shang, Jinyan; Anane, Rex Frimpong; Chu, Bifan; He, Shuqi; Wu, Dexi; Yang, Yonghong; Zhao, Wenjia; Zhou, Mile; Qu, Yizhao; Dou, Wei; Zhao, Mingfu","year":2026,"journal":"Archives of virology, 171(2), 59","doi":"10.1007/s00705-025-06442-y","pmid":"41566068","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08726","title":"Substance Use Patterns Across the Sexual Identity Spectrum Among U.S. Individuals.","authors":"Yang, Kevin H; Mueller, Letitia A; Han, Benjamin H; Palamar, Joseph J","year":2026,"journal":"The American journal of psychiatry, appiajp20250206","doi":"10.1176/appi.ajp.20250206","pmid":"41703691","tags":["addiction","mental-health"],"studyType":"cross-sectional","evidenceStrength":"strong","keyFinding":"Substance use was higher across all non-heterosexual identity groups compared to heterosexual individuals. Bisexual and gay/lesbian individuals showed elevated odds across most substances, particularly inhalants, hallucinogens, and cannabis. People using different terms and those unsure of their identity also showed elevated odds for multiple substances. In sex-disaggregated analyses, females generally showed elevations across more substance categories.","whyItMatters":"Most substance use research among sexual minorities focuses only on LGB categories. This study extends the picture to emerging identity groups, revealing that elevated substance use risk is not limited to traditionally defined categories.","specificNumbers":"52,525 participants; 5 sexual identity groups; substances: cannabis, hallucinogens, cocaine, inhalants, methamphetamine, prescription opioid/tranquilizer/stimulant misuse; elevated odds found across all non-heterosexual groups for multiple substances","methodology":"Analysis of the 2023 NSDUH (N = 52,525, ages 12+) examining past-year substance use across five sexual identity groups: heterosexual, gay/lesbian, bisexual, different term, and unsure. Associations tested with sex-disaggregated analyses using heterosexual reference groups.","limitations":"Cross-sectional design cannot determine causality. Self-reported data. \"Different term\" and \"unsure\" categories are heterogeneous. Small sample sizes in some identity-substance combinations led to suppressed estimates. Cannot distinguish recreational from problematic use."},{"rthcId":"RTHC-08727","title":"Glymphatic Clearance Dynamics in Traumatic Brain Injury: Mechanisms, Imaging Biomarkers, and Application Prospects.","authors":"Yang, Tao; Yang, Yongxiang; Yuan, Mu; Chen, Xin; Cheng, Jingmin; Fan, Kexia; Ma, Yuan; Shu, Haifeng; Yu, Sixun","year":2026,"journal":"Journal of integrative neuroscience, 25(1), 44348","doi":"10.31083/JIN44348","pmid":"41609048","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08728","title":"Cannabis and nicotine/tobacco co-use and its association with cognitive and neural outcomes: A systematic review.","authors":"Yeap, Zac J S; Argote, Mathilde; Nadler, Emma; He, Pinning; Parvaz, Muhammad A; Rabin, Rachel A","year":2026,"journal":"Neuroscience and biobehavioral reviews, 180, 106480","doi":"10.1016/j.neubiorev.2025.106480","pmid":"41265541","tags":["cognition","addiction","neuroscience"],"studyType":"systematic-review","evidenceStrength":"moderate","keyFinding":"People who co-used cannabis and nicotine/tobacco showed similar working memory performance, resting-state brain connectivity, and task-based brain activation compared to people without substance use. This suggests the two substances may offset each other's cognitive effects. Structural and molecular brain findings were inconsistent. Animal research was sparse but aligned with human memory findings.","whyItMatters":"Cannabis and tobacco are the most commonly co-used substances worldwide. Understanding that their combined effects on the brain may differ from either alone has implications for both treatment and risk assessment.","specificNumbers":"39 studies reviewed; 4 databases searched; outcomes: cognition, brain structure, brain function, molecular markers; co-users showed similar working memory to non-users; structural findings inconsistent","methodology":"Systematic review following PRISMA guidelines, searching four databases for human and animal studies examining associations between cannabis-nicotine/tobacco co-use and cognition, brain structure, brain function, and molecular outcomes. 39 studies were reviewed.","limitations":"Heterogeneous study designs and measures across 39 studies. Cannot determine whether the offsetting effect is truly protective or reflects methodological confounds. Most studies were cross-sectional. Animal research was sparse."},{"rthcId":"RTHC-08729","title":"Symptom Severity Profiles and their Associated Factors in Minoritized Men with Chronic Conditions.","authors":"Yoo-Jeong, Moka; Bergeron, Caroline D; Merianos, Ashley L; Ory, Marcia G; Han, Gang; Sherman, Ledric D; Smith, Matthew Lee","year":2026,"journal":"Journal of racial and ethnic health disparities","doi":"10.1007/s40615-025-02834-7","pmid":"41511741","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08730","title":"Adolescent Cannabis Use and Risk of Psychotic, Bipolar, Depressive, and Anxiety Disorders.","authors":"Young-Wolff, Kelly C; Cortez, Catherine A; Alexeeff, Stacey E; Silver, Lynn D; Pacula, Rosalie Liccardo; Slama, Natalie E; Padon, Alisa A; Satre, Derek D; Campbell, Cynthia I; Koshy, Maria T; Does, Monique B; Sterling, Stacy A","year":2026,"journal":"JAMA health forum, 7(2), e256839","doi":"10.1001/jamahealthforum.2025.6839","pmid":"41719031","tags":["psychosis","depression","anxiety","youth","addiction","mental-health"],"studyType":"longitudinal-cohort","evidenceStrength":"strong","keyFinding":"This large longitudinal cohort study followed adolescents aged 13–17 who were screened for past-year cannabis use during routine pediatric care at Kaiser Permanente Northern California from 2016 to 2023, with follow-up through age 25.\n\nAdolescents who reported cannabis use had significantly higher rates of clinician-diagnosed psychiatric disorders compared to non-users. The associations held across all four disorder categories examined: psychotic disorders, bipolar disorder, depressive disorders, and anxiety disorders.\n\nThe strength of this study lies in its design: cannabis use was captured through universal, confidential screening during standard medical visits (reducing selection bias), and psychiatric outcomes were clinician-diagnosed conditions recorded in electronic health records (more reliable than self-reported symptoms). Cox proportional hazards regression accounted for time-varying cannabis exposure, allowing the analysis to capture changes in use status over the follow-up period.\n\nThe population-based setting and large sample size provided statistical power to examine disorders that are relatively uncommon in adolescence (particularly psychotic and bipolar disorders).","whyItMatters":"Published in JAMA Health Forum, this is one of the largest and most methodologically rigorous studies linking adolescent cannabis use to clinician-diagnosed psychiatric disorders. The universal screening design captures a more representative population than studies relying on treatment-seeking or survey samples, and the electronic health record outcomes are more reliable than self-reported symptoms.","specificNumbers":"Adolescents ages 13–17 screened 2016–2023 at Kaiser Permanente Northern California. Followed through age 25. Four outcome categories: psychotic disorders, bipolar disorder, depressive disorders, anxiety disorders. All four significantly elevated in cannabis users vs. non-users. Time-varying cannabis use modeled in Cox regression.","methodology":"Longitudinal cohort study of adolescents ages 13–17 screened at Kaiser Permanente Northern California, 2016–2023, with follow-up through age 25 or December 31, 2023. Time-varying self-reported past-year cannabis use from universal confidential screening. Outcomes: clinician-diagnosed psychotic, bipolar, depressive, and anxiety disorders from electronic health records. Cox proportional hazards regression models.","limitations":"Observational study — cannot prove cannabis caused the psychiatric disorders. Adolescents who use cannabis may differ from non-users in unmeasured ways (genetics, trauma history, family psychiatric history) that independently increase psychiatric risk. Cannabis use was self-reported during screening, though the confidential clinical setting may improve accuracy. Kaiser members may not represent all adolescents."},{"rthcId":"RTHC-08731","title":"Genetic liability to addiction underlies comorbid bipolar and substance use disorders.","authors":"Ystaas, Lars A R; Parekh, Pravesh; Parker, Nadine; Akkouh, Ibrahim; Birkenæs, Viktoria; Sønderby, Ida E; Koch, Elise; Hagen, Espen; Frei, Oleksandr; Shadrin, Alexey; Andreassen, Ole A; O'Connell, Kevin S","year":2026,"journal":"medRxiv : the preprint server for health sciences","doi":"10.64898/2026.02.04.26345483","pmid":"41684427","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08732","title":"Stability and Degradation-based Proteome Profiling Reveals Cannabidiol as a Promising CDC123-eIF2γ Inhibitor for Colorectal Cancer Therapy.","authors":"Yu, Hengyuan; Chen, Yang; Wu, Mingfei; Wang, Wentao; Qiu, Junjie; Xu, Rui; Tong, Jie; Chen, Yong; Liu, Xuesong; Wu, Yongjiang; Xu, Pengfei; Hu, Tao; Miao, Jing; Dong, Xiaowu; Che, Jinxin; Liu, Shuai; Zeng, Su; Xu, Tengfei","year":2026,"journal":"Journal of the American Chemical Society, 148(3), 3712-3722","doi":"10.1021/jacs.5c20040","pmid":"41518300","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08733","title":"Comparing random forest and elastic net models to predict substance use disorder transitions in participants with cannabis and stimulant use: Evidence from the All of Us cohort.","authors":"Zamora, Gabriel; Gunawan, Tommy; Zhao, Qingyu; Meruelo, Alejandro D","year":2026,"journal":"Drug and alcohol dependence, 278, 113012","doi":"10.1016/j.drugalcdep.2025.113012","pmid":"41442977","tags":["addiction","genetics"],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"For cannabis users, both elastic net and random forest models achieved AUC of about 0.74 (no significant difference). Demographic variables were the strongest predictors across both models. Social determinants of health, particularly income, contributed substantially. Wearable-derived metrics (activity and sleep data) provided incremental value in linear models but limited independent contribution in random forests.","whyItMatters":"Predicting who will progress from cannabis use to a use disorder could enable targeted prevention. This study shows that readily available demographic and social data already provide moderate predictive power, with wearable technology adding incremental value.","specificNumbers":"Cannabis cohort AUC: EN = 0.740, RF = 0.741 (DeLong p = 0.764); stimulant cohort AUC: RF = 0.732, EN = 0.698 (DeLong p = 0.219); demographics strongest predictors; income most important SDoH variable","methodology":"Data from the All of Us Research Program, a nationwide cohort integrating electronic health records, surveys, wearable data, and social determinants. Individuals with baseline cannabis use were followed for incident SUD diagnoses. Elastic net logistic regression and random forest models were trained and compared using AUC on independent test sets.","limitations":"Moderate predictive accuracy limits clinical utility. All of Us cohort may not be fully representative. Electronic health record diagnoses may undercount SUD. Wearable data had limited contribution, possibly due to data quality or relevance."},{"rthcId":"RTHC-08734","title":"Trends in the diagnostic prevalence of cannabis-related disorders and co-occurring psychiatric disorders in adolescents: analysis of German health insurance data from 2013 to 2022.","authors":"Zarour, Alexander; Bachmann, Christian; Dandolo, Lisa; Holstiege, Jakob; Hoffmann, Falk; Scholman, Constanze; Golub, Yulia","year":2026,"journal":"European journal of public health","doi":"10.1093/eurpub/ckaf228","pmid":"41520292","tags":["youth","addiction","depression","mental-health"],"studyType":"retrospective-cohort","evidenceStrength":"strong","keyFinding":"Cannabis-related disorder diagnoses increased from 0.08% to 0.10% (+22.4%) among German adolescents ages 12-17 from 2013 to 2022, with a COVID-19 pandemic dip. Up to age 14, diagnoses were evenly split by sex; from age 15+, males had higher rates. In 2022, 78.3% had at least one co-occurring psychiatric diagnosis, most commonly depression, conduct disorders, adjustment disorders, ADHD, and anxiety disorders.","whyItMatters":"The extremely high rate of psychiatric comorbidity (78%) underscores that cannabis-related disorders in adolescents rarely occur in isolation. Depression co-occurring with cannabis use disorder in this age group demands integrated treatment approaches.","specificNumbers":"Nearly 4 million youth covered; prevalence: 0.08% (2013) to 0.10% (2022) = +22.4%; COVID dip observed; sex ratio equal before 15, male-predominant after 15; 78.3% with co-occurring psychiatric diagnosis in 2022; top comorbidities: depression, conduct disorders, adjustment disorders, ADHD, anxiety","methodology":"Analysis of outpatient claims data from the German national public health insurance system, covering almost 4 million children and adolescents ages 12-17 from 2013 to 2022. ICD-10 F12.X diagnoses for cannabis-related disorders were examined, stratified by age and sex, with co-occurring psychiatric diagnoses evaluated for 2022.","limitations":"Insurance claims data reflect diagnoses, not true prevalence. Changes in clinical awareness and screening may inflate trends. Only captures outpatient treatment-seeking youth. Cannot determine directionality of cannabis-psychiatric comorbidity."},{"rthcId":"RTHC-08735","title":"In Vitro Antimicrobial Effect of Tetrahydrocannabinol on Streptococcus mutans and Its Anticariogenic Potential.","authors":"Zhai, Haoyan; Zhang, Yixuan; Kim, Minki; Zhou, Xintian; Ferracciolo, Joseph; Krukonis, Eric; Liu, Chunyan; Zhou, Zheng","year":2026,"journal":"International dental journal, 76(2), 109386","doi":"10.1016/j.identj.2025.109386","pmid":"41576726","tags":["medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC inhibited S. mutans growth at an MIC of 2 micrograms/mL (p < 0.0001). At this concentration, THC reduced bacterial acid production and inhibited over 90% of biofilm formation. THC also reduced biofilm viability and extracellular polysaccharide production at 1 microgram/mL or above. While THC did not degrade preformed biofilm biomass, it reduced its metabolic activity and viability. The mechanism appeared to involve membrane hyperpolarization.","whyItMatters":"This is the first systematic in vitro study of THC's effects on the primary bacterium responsible for dental cavities. While it does not mean cannabis prevents cavities, it identifies a potentially useful antimicrobial property of THC.","specificNumbers":"MIC: 2 micrograms/mL (p < 0.0001); 90%+ biofilm inhibition at 2+ micrograms/mL; reduced EPS and viability at 1+ micrograms/mL; metabolic activity reduced by 16-64 micrograms/mL; membrane hyperpolarization at 2-8 micrograms/mL within 5 minutes","methodology":"In vitro study testing THC against S. mutans using antimicrobial susceptibility testing (MIC), crystal violet biofilm assay, MTT metabolic activity assay, live/dead viability assay, Cascade Blue Dextran EPS staining, and membrane potential detection.","limitations":"In vitro results may not reflect conditions in the human mouth. THC concentrations tested may not be achievable via normal cannabis use. Could not degrade existing biofilm. Psychoactive effects of THC make direct oral application impractical without modification."},{"rthcId":"RTHC-08736","title":"Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2.","authors":"Zhan, Zhikun; Jiang, Yaojie; Chen, Siyu; Yang, Qiyuan; Pan, Guanxing; Liu, Yiwei; Fang, Weipeng; Chen, Runzhi; Tang, Lan; Lin, Cuihong","year":2026,"journal":"Journal of ethnopharmacology, 359, 121067","doi":"10.1016/j.jep.2025.121067","pmid":"41419044","tags":["cbd","inflammation"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD at 2.5 and 5 mg/kg mitigated LPS/D-GalN-induced liver damage, suppressed inflammatory cytokines, reduced hepatocyte death, and inhibited oxidative stress. The mechanism involved CBD preventing the degradation of mitofusin-2 (MFN2) by disrupting the interaction between Parkin and MFN2. When MFN2 was knocked down, CBD's protective effects were abolished; when MFN2 was overexpressed, protective effects were restored.","whyItMatters":"Acute liver injury can rapidly progress to liver failure with high mortality. This study identifies a specific molecular mechanism for CBD's hepatoprotective effects, which could inform development of liver injury treatments.","specificNumbers":"CBD: 2.5 and 5 mg/kg in vivo, 2.5 and 5 micromolar in vitro; MFN2 protein levels increased by CBD; Parkin-MFN2 binding decreased; MFN2 ubiquitination inhibited; effects abolished by MFN2 knockdown and restored by overexpression","methodology":"In vivo LPS/D-GalN-induced acute liver injury mouse model treated with CBD. RAW264.7 macrophage cells for in vitro validation. siRNA knockdown, plasmid overexpression, and adeno-associated virus delivery used to confirm MFN2 as the critical mediator. Multiple assays including H&E staining, TUNEL, TEM, Western blot, Co-IP, and more.","limitations":"Animal model of chemically-induced liver injury may not reflect all forms of human liver disease. CBD doses and routes of administration may not translate directly. No human data. Mechanism found in one cell type (macrophages) may not apply universally."},{"rthcId":"RTHC-08737","title":"Gut Microbiota-Derived Anandamide Mediates the Therapeutic Effects of Urolithin A on Alcohol-Induced Cognitive and Social Dysfunction via CB1R-DRD2-RAP1 Signaling Axis.","authors":"Zhang, Hongbo; Li, Zibin; Xiao, Yao; Bian, Ji; He, Caian; Liu, Chao; Gong, Lan; Han, Lin; Liu, Zhigang; Wang, Min","year":2026,"journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany), e08048","doi":"10.1002/advs.202508048","pmid":"41632030","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08738","title":"Edestin and Its Derived Peptides Improve Oxygen Utilization and Exercise Endurance by Enhancing Antioxidant Capacity in Mice.","authors":"Zhang, Rui; Chen, Liang-Liang; Liang, Huan; Jin, Xiao-Qian; Cao, Yu-Hao; Guo, Wei-Hong; Yin, Da-Chuan","year":2026,"journal":"Journal of food science, 91(1), e70819","doi":"10.1111/1750-3841.70819","pmid":"41485208","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08739","title":"Investigation of endocannabinoid 2-AG and its hydrolases for regulation on sperm motility and acrosome reaction in Kunming mice.","authors":"Zhang, Xin; Wu, Wenjing; Li, Yahui; Yang, Minghua","year":2026,"journal":"Reproduction, fertility, and development, 38(3)","doi":"10.1071/RD25040","pmid":"41518662","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08740","title":"Cannabidiol inhibits melanoma progression by regulating PPARγ-TET1 complex-dependent LRSAM1 demethylation.","authors":"Zhang, Xuedan; Shen, Baoyu; Li, Enjiang; Yun, Fang; Feng, Yu; Wei, Zhenyan; Niu, Junzi; Huang, Yu; Yu, Song; Kuang, Yingmin; Liu, Haoming; Sai, Buqing; Zhu, Yuechun","year":2026,"journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology, 151, 157775","doi":"10.1016/j.phymed.2026.157775","pmid":"41547069","tags":["cancer","cbd"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"CBD induced apoptosis and inhibited proliferation and invasion of melanoma cells in vitro and reduced lung metastasis in vivo. The mechanism involved CBD activating PPARgamma, which formed a complex with TET1 (a demethylation enzyme). This complex removed methyl groups from the LRSAM1 gene promoter, activating this previously unrecognized anti-cancer gene. LRSAM1 upregulation enhanced melanoma cell death and suppressed proliferation.","whyItMatters":"Melanoma is the most dangerous form of skin cancer, with limited treatment options for advanced stages. This study identifies a completely new molecular mechanism for CBD's anti-cancer effects and a previously unknown tumor-suppressor gene.","specificNumbers":"CBD induced apoptosis, inhibited proliferation and invasion in vitro; reduced pulmonary metastasis in vivo; identified PPARgamma-TET1 complex; LRSAM1 demethylation confirmed by MeDIP; LRSAM1 elevated in treated cells","methodology":"In vitro studies with melanoma cell lines using MTS, EdU, Transwell invasion, and flow cytometry. In vivo murine lung metastasis model. Network pharmacology and molecular docking for target identification. Integrated transcriptomic and genome-wide methylation analyses. Co-immunoprecipitation and chromatin immunoprecipitation for protein interactions.","limitations":"Preclinical study with cell lines and mouse models. CBD concentrations used may not be achievable in humans. LRSAM1's role as a tumor suppressor needs independent confirmation. Melanoma is a heterogeneous cancer and results may not apply to all subtypes."},{"rthcId":"RTHC-08741","title":"Local release of fibroblast growth factor 21 and cannabidiol promoting spinal cord nerve injury repair through activation of cannabinoid receptor 2.","authors":"Zhang, Zhao; Wang, Zhengquan; Shen, Zhihao; Zhou, Yangbo; Zhou, Cheng; Chen, Min; Jiang, Minghao; Zhuang, Junyu; Song, Jiahui; Wang, Xiangyang; Chen, Shixuan; Xiao, Jian; Zhu, Sipin","year":2026,"journal":"Biomaterials, 325, 123609","doi":"10.1016/j.biomaterials.2025.123609","pmid":"40782447","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08742","title":"Cannabidiol Alleviates LPS-Induced Depressive-Like Behaviors Via Improving Mitochondria Function.","authors":"Zhao, Junning; Liu, Qian; Wang, Xin; Xiao, Yusen; Yao, Baiyi; Liu, Jiale; Wang, Cailin; Liu, Gongping; Hong, Xiaoyue","year":2026,"journal":"Molecular neurobiology, 63(1), 338","doi":"10.1007/s12035-025-05614-w","pmid":"41484536","tags":["cbd","depression","inflammation","neuroscience","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Researchers induced depression-like behaviors in mice using lipopolysaccharide (LPS), a bacterial toxin that triggers neuroinflammation. Mice then received CBD (70 or 140 mg/kg/day) for six days.\n\nCBD treatment significantly reduced the depressive-like behaviors caused by LPS. At the cellular level, the mechanism centered on mitochondria — the energy-producing organelles in every cell. LPS disrupted mitochondrial function, increased reactive oxygen species (ROS), and caused oxidative damage in hippocampal neurons. CBD reversed these effects: it inhibited ROS production, normalized oxidative stress markers, and restored the activity of superoxide dismutase (a key antioxidant enzyme).\n\nThe molecular mechanism involved mitochondrial quality control pathways. CBD promoted both mitochondrial biogenesis (creating new, healthy mitochondria) and mitophagy (clearing out damaged mitochondria). This dual action effectively refreshed the cellular power supply in brain cells damaged by inflammation.\n\nCBD also improved synaptic health in the hippocampus and reduced neuroinflammatory markers, suggesting that the mitochondrial repair translated to improved neural communication and reduced brain inflammation.","whyItMatters":"Depression treatment needs new approaches — about 30% of patients don't respond to existing antidepressants. The mitochondrial mechanism identified here is particularly interesting because mitochondrial dysfunction has been increasingly recognized as a feature of depression in humans. If CBD can restore mitochondrial function in the brain, it represents a fundamentally different therapeutic pathway from conventional antidepressants that target neurotransmitters.","specificNumbers":"CBD doses: 70 and 140 mg/kg/day for 6 days. Significant reduction in depressive-like behaviors. Restored superoxide dismutase activity. Promoted mitochondrial biogenesis and mitophagy. Reduced neuroinflammatory markers. Effects observed in hippocampal region.","methodology":"Animal study using male C57BL/6 mice. Depression-like behaviors induced by LPS injection. CBD administered intragastrically (70 or 140 mg/kg/day) for 6 days. Outcomes: behavioral tests (depression-like behaviors), hippocampal synaptic health, ROS production, oxidative stress markers, superoxide dismutase activity, mitochondrial biogenesis, mitophagy markers, neuroinflammatory activation markers.","limitations":"Animal model — LPS-induced inflammation is a simplified model of depression that doesn't capture the full complexity of human depressive disorders. CBD doses (70–140 mg/kg) are very high relative to typical human doses. Six-day treatment is short and doesn't address chronic depression. Male mice only — sex differences in depression mechanisms are well-established. The route of depression matters: inflammation-driven depression may respond differently to CBD than other depression subtypes."},{"rthcId":"RTHC-08743","title":"Reciprocal relationships among youth social media use, internalizing symptoms, and substance use.","authors":"Zheng, Xia; Yang, Meng; Li, Ruobing; Li, Wenbo; Lis, Nicole; Lin, Hsien-Chang","year":2026,"journal":"Drug and alcohol dependence, 278, 113018","doi":"10.1016/j.drugalcdep.2025.113018","pmid":"41478039","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08744","title":"Antiseizure Effects of Cannabidiol in Combination With Cannabigerol in the Maximal Electroshock Seizure Model.","authors":"Zhou, Han Zhong; Scott, Brian Wayne; Oleksak, Yagoda Izabela; Burnham, Willets McIntyre","year":2026,"journal":"Basic & clinical pharmacology & toxicology, 138(2), e70194","doi":"10.1111/bcpt.70194","pmid":"41588555","tags":["cbd","epilepsy","medical-cannabis"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"Current antiseizure therapy fails for about 30% of epilepsy patients. Previous research had shown that adding small amounts of THC made CBD much more potent against seizures, but THC's psychoactive effects make it unsuitable for routine epilepsy treatment. This study tested whether CBG — a non-psychoactive cannabinoid — could provide the same potentiation.\n\nIn the maximal electroshock seizure (MES) model in mice, researchers generated dose-response curves for CBD alone, CBG alone, and a 1:1 combination. The results were clear: CBG has its own antiseizure properties, and combining it with CBD reduced the effective dose of CBD (ED50) by over 50%.\n\nHowever, the combination also reduced the toxic dose (TD50) by about 40%, indicating increased toxicity alongside increased potency. The overall therapeutic index (the gap between effective and toxic doses) was narrowed but both drugs showed little toxicity at therapeutic doses.\n\nThe interaction between CBD and CBG appeared additive rather than synergistic — meaning the effects were roughly what you'd predict from adding each drug's contribution together, rather than a multiplication effect. This is the first study to provide detailed dose-response data for CBG alone and in combination with CBD for seizures.","whyItMatters":"Finding a non-psychoactive potentiator for CBD's anti-seizure effects could be clinically transformative. If CBG allows CBD doses to be halved while maintaining seizure protection, patients could potentially achieve the same benefit with fewer side effects (since many CBD side effects are dose-dependent). This is especially relevant for pediatric epilepsy patients where minimizing drug burden is a priority.","specificNumbers":"CBD ED50 reduced by >50% when combined with CBG (1:1 ratio). TD50 reduced by ~40%. CBG demonstrated independent antiseizure activity. Both compounds showed little toxicity at therapeutic doses. Current antiseizure therapy effective in only ~70% of patients.","methodology":"Animal study in mice using the maximal electroshock seizure (MES) model. CBD and CBG administered intraperitoneally, alone and in 1:1 combination. Full dose-response and dose-toxicity curves generated for each compound and the combination. ED50 and TD50 calculated to determine therapeutic indices.","limitations":"Animal model — the MES model is a standard seizure screening tool but doesn't capture all epilepsy types. Only a 1:1 CBD:CBG ratio was tested; other ratios may produce different potency and toxicity profiles. Intraperitoneal injection doesn't model oral drug delivery. The 40% reduction in TD50 (increased toxicity) partially offsets the potency gain and needs careful evaluation. Mouse pharmacokinetics differ from human."},{"rthcId":"RTHC-08745","title":"Therapeutic potential and pharmacological mechanisms of cannabinoids in alleviating chemotherapy-induced organ toxicity and adverse effects.","authors":"Zia, Bushra; Nagoor Meeran, M F; Sharma, Charu; Mirza, Sameer; Ojha, Shreesh K","year":2026,"journal":"European journal of pharmacology, 1017, 178646","doi":"10.1016/j.ejphar.2026.178646","pmid":"41655682","tags":["cancer","medical-cannabis","inflammation","cbd"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"CB2 receptor activation attenuated doxorubicin-induced cardiotoxicity by enhancing antioxidant defenses and reducing inflammation. In cisplatin-induced kidney injury, cannabinoids reduced tubular cell death and inflammatory infiltrates. The endocannabinoid system was identified as a polypharmacological target that could simultaneously combat cancer and protect organs from chemotherapy damage.","whyItMatters":"Organ toxicity from chemotherapy is a major clinical problem that limits treatment effectiveness and patient quality of life. If cannabinoids can protect organs while cancer treatment continues, this could be a significant therapeutic advance.","specificNumbers":"Reviewed agents: JWH-133, beta-caryophyllene, and other CB2 agonists; chemo drugs: doxorubicin, cisplatin, cyclophosphamide, methotrexate; organs: heart, kidney, liver, nervous system; mechanisms: anti-inflammatory, antioxidant, anti-apoptotic","methodology":"Narrative review synthesizing preclinical evidence on cannabinoid receptor agonists (JWH-133, beta-caryophyllene, and others) for mitigating chemotherapy-induced organ toxicity. Covers cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity from agents including doxorubicin, cisplatin, cyclophosphamide, and methotrexate.","limitations":"Entirely based on preclinical data. Translational gaps between animal models and human physiology remain significant. Selective CB2 agonists with adequate safety profiles are not yet available for clinical use. No clinical trials of cannabinoids as chemoprotective agents have been completed."},{"rthcId":"RTHC-08746","title":"Tetrahydrocannabinol (THC) and cannabidiol (CBD) inhibit androgen biosynthesis in H295R cells.","authors":"Zufferey, Fanny; Hebinger, Doriane; Brossaud, Anne-Claire; Millius, Laura; Rossier, Michel F","year":2026,"journal":"Biochemical and biophysical research communications, 797, 153179","doi":"10.1016/j.bbrc.2025.153179","pmid":"41447880","tags":["sex-differences","neuroscience"],"studyType":"animal-study","evidenceStrength":"preliminary","keyFinding":"THC and CBD both reduced DHEA, androstenedione, and testosterone production in H295R cells dose-dependently. The effect was rapid and primarily affected late steps of steroidogenesis. It was not blocked by rimonabant (CB1 antagonist), indicating a non-CB1 mechanism. CBD additionally appeared to affect the CYP17A1 enzyme step. These in vitro results contradict the researchers' prior finding of higher testosterone in cannabis-using men.","whyItMatters":"The contradiction between lab results (cannabinoids reduce testosterone) and human observations (cannabis users have higher testosterone) highlights that the relationship between cannabis and male hormones is more complex than direct pharmacological effects suggest.","specificNumbers":"Both THC and CBD reduced DHEA, androstenedione, and testosterone dose-dependently; inhibition was rapid; not blocked by rimonabant (CB1 antagonist); CBD affected CYP17A1 enzyme; prior human cohort showed higher testosterone in cannabis users","methodology":"In vitro study using H295R adrenal cells. THC and CBD effects on steroid production measured by liquid chromatography-tandem mass spectrometry. CB1 receptor involvement tested with rimonabant. This followed the authors' earlier observation of higher serum testosterone in cannabis users from a cohort of young Swiss men.","limitations":"In vitro system using adrenal cell line, not testicular cells which produce most testosterone. Concentrations may not reflect physiological exposure. Cannot replicate the complex hormonal feedback systems of the whole body. Single cell line."},{"rthcId":"RTHC-08747","title":"Pilot Randomized Trial of Medical Cannabis to Reduce Symptom Burden in Patients With Newly Diagnosed Advanced Pancreatic Cancer (CanPan).","authors":"Zylla, Dylan; Chrenka, Ella; Lin, Kendall; Gilmore, Grace; Cowger, Jordan; Rak, David; Gupta, Arjun","year":2026,"journal":"JCO oncology practice, OP2501165","doi":"10.1200/OP-25-01165","pmid":"41510814","tags":["medical-cannabis","cancer","pain","appetite","sleep"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"The trial met all prespecified feasibility benchmarks: 74% enrollment (goal 20%), 81% compliance (goal 60%), and 75% outcome completion (goal 50%). All early-arm participants recommended the intervention. At 8 weeks, early-arm patients showed numerically higher improvement rates for pain (44% vs 20%), appetite (56% vs 30%), and insomnia (67% vs 30%), though none reached statistical significance. Median daily THC use was 7.3 mg. Cannabis-related harms were low.","whyItMatters":"Pancreatic cancer patients experience severe symptom burden and limited treatment options. This study demonstrates that rigorous cannabis research can be conducted through state program partnerships, offering a path around federal regulatory barriers.","specificNumbers":"32 patients; median age 71; 53% women; baseline symptom burden: insomnia 85%, pain 77%, appetite loss 69%; enrollment rate: 74%; compliance: 81%; outcome completion: 75%; median THC: 7.3 mg/day; pain improvement: 44% vs 20% (p = 0.35); appetite: 56% vs 30% (p = 0.37); insomnia: 67% vs 30% (p = 0.18)","methodology":"Pilot randomized waitlist-controlled trial of 32 patients with newly diagnosed locally advanced/metastatic pancreatic adenocarcinoma in Minnesota. Randomized 1:1 to early (weeks 0-8) or delayed (weeks 9-16) cannabis intervention through the Minnesota Medical Cannabis Program. Primary outcome was feasibility.","limitations":"Pilot study not powered for efficacy (32 patients). No differences reached statistical significance. Waitlist control, not placebo-controlled. Open-label design subject to expectation bias. Single state program may not generalize."},{"rthcId":"RTHC-08748","title":"A Randomized, Open-Label Trial to Assess Feasibility and Tolerability of Topical Cannabis Balms for the Treatment of Aromatase Inhibitor-Associated Musculoskeletal Syndrome (AIMSS).","authors":"Zylla, Dylan; Idossa, Dame; Borrero, Maria; Napurski, Char; Dahmer, Stephen; Cowger, Jordan; Gilmore, Grace; Luo, Xianghua; Birnbaum, Angela; Blaes, Anne H","year":2026,"journal":"Cannabis and cannabinoid research, 11(1), 30-35","doi":"10.1177/25785125251398286","pmid":"41467893","tags":["medical-cannabis","cancer","pain","cbd","inflammation"],"studyType":"randomized-controlled-trial","evidenceStrength":"preliminary","keyFinding":"86% of participants reported improvement in hand-related symptoms from baseline to week 2. A higher percentage of THC balm users reported over 50% improvement compared to CBD balm users (50% vs 18%). Compliance was high, with 71% continuing an additional 2 weeks. Minor skin irritation occurred in 24%, and only one discontinuation was for cosmetic reasons (\"greasy\" texture). Nearly half of participants had never used cannabis before.","whyItMatters":"Nearly two-thirds of women on aromatase inhibitors experience joint pain and stiffness, leading many to stop a life-saving cancer medication. If topical cannabis can reduce these side effects, it could improve adherence to breast cancer treatment.","specificNumbers":"21 women; mean age 54; 86% White; 48% no prior cannabis use; 43% received adjuvant chemo; 86% reported improvement; THC >50% improvement: 50% vs CBD 18%; 71% continued extension; 86% survey completion; 24% minor skin irritation; 1 discontinuation","methodology":"Randomized open-label trial comparing topical CBD versus THC balms applied three times daily to hands for 2 weeks, with 2-week extension using balm of choice. 21 women with stage 1-3 breast cancer experiencing aromatase inhibitor-associated musculoskeletal syndrome (AIMSS). Used state-approved cannabis dispensaries.","limitations":"Small sample (21 women). Open-label, no placebo control. 2-week primary period is short. Cannot determine if improvements are due to cannabis or placebo/natural fluctuation. Topical THC absorption and potential systemic effects were not measured."},{"rthcId":"RTHC-08749","title":"Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish","authors":"Gaoni, Y; Mechoulam, R","year":1964,"journal":"Journal of the American Chemical Society, 86(8), 1646-1647","doi":"10.1021/ja01062a046","pmid":null,"tags":["foundational","pharmacology","chemistry"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"The psychoactive constituent of cannabis (hashish) was isolated in pure form for the first time and identified as (−)-delta-9-trans-tetrahydrocannabinol (Δ9-THC). Its structure was determined by NMR spectroscopy and confirmed by partial synthesis. The compound was extracted from 5 kg of Lebanese hashish using petroleum ether extraction, alumina column chromatography, and a crystalline 3,5-dinitrophenyl urethane derivative technique that allowed purification of the otherwise oily compound.","whyItMatters":"This paper solved a 120-year-old mystery in pharmacology. While morphine was isolated from opium in 1804 and cocaine from coca leaves in 1855, the psychoactive molecule in cannabis remained unidentified until 1964. The structural determination of THC made it possible to study how cannabis works in the body, directly leading to the discovery of cannabinoid receptors (1988-1990), the endocannabinoid system (1992), and the development of cannabinoid-based medicines including dronabinol, nabilone, Sativex, and Epidiolex.","specificNumbers":"","methodology":"The researchers extracted 5 kg of confiscated Lebanese hashish with petroleum ether, then separated the crude extract using alumina column chromatography with progressively polar solvents. The key innovation was converting the oily THC into a crystalline 3,5-dinitrophenyl urethane derivative, which could be purified to homogeneity. The purified derivative was hydrolyzed back to THC and distilled at 155-157°C under 0.05 mm Hg vacuum. Structure was determined using nuclear magnetic resonance (NMR) spectroscopy — technology unavailable to earlier researchers. Partial synthesis confirmed the proposed structure.","limitations":"This was a chemistry paper focused on isolation and structural characterization, not pharmacology or clinical effects. The starting material was confiscated hashish of uncontrolled origin. No biological activity assays were performed in this specific paper (pharmacological confirmation was published separately by collaborator Haviv Edery). The study characterized only delta-9-THC and did not address other cannabinoids present in the extract beyond noting their chromatographic separation."},{"rthcId":"RTHC-08750","title":"Structure of a cannabinoid receptor and functional expression of the cloned cDNA","authors":"Matsuda, L A; Lolait, S J; Brownstein, M J; Young, A C; Bonner, T I","year":1990,"journal":"Nature, 346(6284), 561-564","doi":"10.1038/346561a0","pmid":"2165569","tags":["neuroscience","foundational","endocannabinoid-system","pharmacology"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"A complementary DNA (cDNA) encoding a G protein-coupled receptor (GPCR) was cloned from a rat brain library. When expressed in cultured cells, the receptor inhibited adenylate cyclase activity in a dose-dependent, stereoselective, and pertussis toxin-sensitive manner — all hallmarks of cannabinoid receptor pharmacology. The receptor responded preferentially to psychoactive cannabinoids while showing minimal response to non-psychoactive cannabinoids. In situ hybridization revealed that the receptor's mRNA was localized to brain regions and cell lines previously shown to contain cannabinoid binding sites by autoradiography. The receptor protein consists of 472 amino acids (human) with seven transmembrane domains characteristic of GPCRs, and shows 97-99% amino acid identity across mammalian species.","whyItMatters":"This paper provided the molecular identity of the cannabinoid receptor, transforming cannabinoid research from pharmacology into molecular biology. Knowing the gene sequence enabled everything that followed: creation of knockout mice, development of selective antagonists, identification of the endogenous ligands (anandamide and 2-AG), and the eventual development of cannabinoid-based therapeutics. It also revealed that CB1 is the most abundant GPCR in the mammalian brain — a finding that explained why cannabis has such widespread effects on cognition, mood, pain, appetite, coordination, and memory.","specificNumbers":"","methodology":"The researchers screened a rat brain complementary DNA (cDNA) library for sequences homologous to known G-protein-coupled receptors. A clone encoding a novel GPCR was identified, sequenced, and expressed in cultured cells (transfection). The expressed receptor was then tested pharmacologically: its ability to inhibit adenylate cyclase was measured in the presence of various cannabinoid compounds at different concentrations. Stereoselective binding was confirmed by testing enantiomeric pairs of cannabinoids. Pertussis toxin sensitivity confirmed Gi/o protein coupling. In situ hybridization was used to map where the receptor's messenger RNA was expressed in rat brain sections, and the resulting distribution was compared to known cannabinoid binding site maps from autoradiography studies.","limitations":"This was a molecular cloning and in vitro characterization study. The receptor was expressed in cultured cells, not studied in intact animals or humans. No in vivo behavioral data were presented. The initial paper characterized the rat receptor; the human CB1 gene was cloned subsequently by Gérard and colleagues in Brussels. The study did not address receptor distribution in peripheral tissues or non-neuronal cells, which were later found to be significant."},{"rthcId":"RTHC-08751","title":"Molecular characterization of a peripheral receptor for cannabinoids","authors":"Munro, S; Thomas, K L; Abu-Shaar, M","year":1993,"journal":"Nature, 365(6441), 61-65","doi":"10.1038/365061a0","pmid":"7689702","tags":["neuroscience","foundational","endocannabinoid-system","immune-system"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"A gene encoding a novel G-protein-coupled receptor was cloned from the human promyelocytic leukemia cell line HL-60. The receptor shared only 44% amino acid sequence identity with the previously cloned CB1 receptor. When expressed in cells, it exhibited cannabinoid binding properties and inhibited adenylate cyclase via Gi/o proteins. In situ hybridization and Northern blot analysis revealed high CB2 mRNA levels in spleen — specifically in marginal zone macrophages — but not in brain, liver, thymus, lung, or kidney. The receptor was designated CB2 and termed the 'peripheral cannabinoid receptor.' The protein consists of 360 amino acids with the seven-transmembrane topology characteristic of GPCRs.","whyItMatters":"This paper established that the endocannabinoid system extends beyond the brain into the immune system. CB2 explained a longstanding observation: that cannabis suppresses inflammation and modulates immune responses. Because CB2 activation doesn't produce psychoactive effects, it became the most attractive therapeutic target in cannabinoid pharmacology — a way to harness cannabis's anti-inflammatory and analgesic properties without the high. The discovery also expanded the endocannabinoid system from a brain signaling network to a body-wide regulatory system.","specificNumbers":"","methodology":"Human promyelocytic leukemia cells (HL-60) were treated with dimethylformamide to induce granulocyte differentiation. A cDNA library was prepared and screened using PCR with degenerate primers targeting conserved G-protein-coupled receptor transmembrane domains. One clone showed homology to the GPCR family and partial sequence identity with CB1. The full-length cDNA was cloned, sequenced, and expressed in cultured cells to confirm cannabinoid receptor pharmacology. A rat homologue was also isolated by PCR. Tissue distribution was mapped using in situ hybridization, Northern blotting, and RT-PCR across multiple rat tissues. Cell sorting of spleen populations identified the macrophage/monocyte population as the primary CB2-expressing cells.","limitations":"This was a molecular cloning and tissue distribution study performed in cell lines and rodent tissues, not in intact humans. The initial characterization that CB2 was absent from the brain was based on the sensitivity limits of 1993 techniques — later studies with more sensitive methods detected CB2 in brain microglia and possibly neurons. The functional assays were performed in transfected cell lines, not in native immune cells. Species differences in CB2 expression patterns (particularly between rodents and humans) later proved to be a major obstacle for translating preclinical findings to clinical use."},{"rthcId":"RTHC-08752","title":"A second endogenous cannabinoid that modulates long-term potentiation","authors":"Stella, N; Schweitzer, P; Piomelli, D","year":1997,"journal":"Nature, 388(6644), 773-778","doi":"10.1038/42015","pmid":"9285589","tags":["neuroscience","foundational","endocannabinoid-system"],"studyType":"animal-study","evidenceStrength":"strong","keyFinding":"sn-2 arachidonylglycerol (2-AG) was identified in brain tissue at concentrations 170 times greater than anandamide. Unlike anandamide (a partial agonist), 2-AG activated neuronal cannabinoid receptors as a full agonist. 2-AG was produced in hippocampal slices by stimulation of the Schaffer collaterals through a calcium-dependent mechanism involving phospholipase C and diacylglycerol lipase. Functionally, 2-AG prevented the induction of long-term potentiation (LTP) at CA3-CA1 hippocampal synapses, demonstrating that it can modulate synaptic plasticity — the cellular basis of learning and memory.","whyItMatters":"This paper established 2-AG — not anandamide — as the brain's dominant endocannabinoid. At 170 times the concentration and with full agonist activity (compared to anandamide's partial agonism), 2-AG turned out to be the primary retrograde messenger at synapses throughout the brain. The endocannabinoid system is not run by the 'bliss molecule' — it's run by 2-AG. This fundamentally reshaped understanding of how the ECS works and explained why chronic THC exposure (which overwhelms the 2-AG signaling system) produces tolerance, dependence, and withdrawal.","specificNumbers":"","methodology":"Brain lipid extracts from rat tissue were analyzed to quantify 2-AG and anandamide concentrations. Hippocampal brain slices were electrically stimulated at the Schaffer collateral pathway and the resulting lipid release was measured. Calcium dependence was tested by manipulating extracellular calcium. Enzyme involvement was determined using inhibitors of phospholipase C and diacylglycerol lipase. 2-AG's agonist activity was confirmed through receptor binding and functional assays. The effect on long-term potentiation was measured by electrophysiological recording at CA3-CA1 synapses before and after 2-AG application.","limitations":"The Stella 1997 paper used rat hippocampal slices — an ex vivo preparation, not intact behaving animals. The 170× concentration difference was measured in whole brain extract and may vary by region. The study demonstrated that exogenously applied 2-AG modulates LTP but did not prove that endogenously released 2-AG does the same under physiological conditions (this was established by subsequent work). The 1995 discovery papers had similar limitations: Mechoulam's group isolated 2-AG from canine gut (not brain), and Sugiura's group measured binding affinity but did not characterize physiological function."},{"rthcId":"RTHC-08753","title":"The endocannabinoid system as an emerging target of pharmacotherapy","authors":"Pacher, P; Bátkai, S; Kunos, G","year":2006,"journal":"Pharmacological Reviews, 58(3), 389-462","doi":"10.1124/pr.58.3.2","pmid":"16968947","tags":["endocannabinoid-system","pharmacology","foundational"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review comprehensively documented that the endocannabinoid system regulates pathophysiology across at least 15 disease categories: obesity and metabolic syndrome, neuropathic and cancer pain, multiple sclerosis and spasticity, movement disorders (Parkinson's, Huntington's, Tourette's), mood and anxiety disorders, schizophrenia, glaucoma, cardiovascular disease (hypertension, myocardial infarction, atherosclerosis, stroke), cancer, osteoporosis, liver disease, gastrointestinal disorders, reproductive disorders, and immune/inflammatory conditions. Three pharmacological strategies were identified: CB1 receptor antagonism (e.g., rimonabant for obesity), inhibition of endocannabinoid-degrading enzymes (FAAH, MAGL) to enhance endocannabinoid tone indirectly, and selective CB2 receptor agonism for anti-inflammatory effects without psychoactivity.","whyItMatters":"This review established the endocannabinoid system as far more than a cannabis-response pathway — it's a fundamental regulatory system involved in virtually every major disease category. By organizing thousands of scattered findings into a single 74-page framework, it became the roadmap for a generation of drug development. The three therapeutic strategies it articulated — CB1 antagonism, enzyme inhibition, CB2 agonism — still organize the field today, even though the first drugs based on each strategy largely failed. The review's citation impact (#5 in all of pharmacology) reflects its role as the field's central reference.","specificNumbers":"","methodology":"This is a comprehensive narrative review synthesizing published preclinical and clinical evidence across all known therapeutic applications of the endocannabinoid system as of 2006. The authors systematically organized findings by disease category, evaluating evidence quality from in vitro studies through animal models to human clinical trials. Key clinical data on rimonabant trials (1,507-3,045 patients) and cannabinoid pain studies were tabulated.","limitations":"As a narrative review, this paper synthesizes and interprets existing evidence rather than generating new data. The disease-by-disease organization may overstate the readiness of certain therapeutic areas where evidence was primarily preclinical (animal models). The review was published at a moment of high optimism (rimonabant had just been approved) and may underweight risks that became apparent later. Some therapeutic strategies described (CB1 antagonism for obesity) subsequently failed in ways the review did not predict."},{"rthcId":"RTHC-08754","title":"The molecular logic of endocannabinoid signalling","authors":"Piomelli, D","year":2003,"journal":"Nature Reviews Neuroscience, 4(11), 873-884","doi":"10.1038/nrn1247","pmid":"14595399","tags":["neuroscience","endocannabinoid-system","foundational"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review articulated the defining molecular logic of endocannabinoid signaling through four unique properties: (1) On-demand synthesis — endocannabinoids are produced from membrane phospholipid precursors in response to calcium influx, not stored in vesicles like classical neurotransmitters; (2) Lipid nature — as lipids derived from arachidonic acid, they cannot be stored in aqueous vesicles and cross cell membranes freely; (3) Retrograde direction — they travel from postsynaptic to presynaptic neurons, the reverse of classical neurotransmission; (4) Short-range local action — they are rapidly degraded by local enzymes (FAAH for anandamide, MAGL for 2-AG) and do not circulate systemically. These properties enable precise, activity-dependent feedback regulation of synaptic strength, modulating both excitatory (glutamate) and inhibitory (GABA) transmission through CB1 receptors on presynaptic terminals.","whyItMatters":"This review provided the conceptual framework that unified the endocannabinoid field. Rather than cataloging diseases (as Pacher would do three years later), Piomelli explained the operating principles — the rules by which the system functions. These four rules explain why the ECS is so different from serotonin, dopamine, or opioid signaling, why endocannabinoids can fine-tune neural circuits with such precision, and why chronic cannabis use is uniquely disruptive: THC breaks all four rules simultaneously (it's not on-demand, not local, not brief, and present at every receptor at once).","specificNumbers":"","methodology":"This is a narrative review synthesizing published biochemical, electrophysiological, and pharmacological evidence on endocannabinoid signaling mechanisms. The author integrated evidence from enzyme characterization studies, electrophysiology experiments (DSI/DSE), lipid biochemistry, and receptor pharmacology into a coherent mechanistic framework. Key concepts were illustrated with diagrams showing the retrograde signaling pathway and the contrast with classical neurotransmission.","limitations":"As a review, this paper synthesizes existing evidence rather than generating new data. Published in 2003, some aspects of the endocannabinoid signaling pathway (particularly 2-AG synthesis via DAGLα and degradation via MAGL) were still being characterized and have been substantially refined since. The review focuses primarily on neuronal signaling and does not extensively address endocannabinoid roles in peripheral tissues, immune cells, or non-neuronal brain cells (astrocytes, microglia) that have since been recognized as significant."},{"rthcId":"RTHC-08755","title":"Cannabinoid pharmacology: the first 66 years","authors":"Pertwee, R G","year":2006,"journal":"British Journal of Pharmacology, 147(S1), S163-171","doi":"10.1038/sj.bjp.0706406","pmid":"16402100","tags":["pharmacology","foundational","history"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review traces cannabinoid pharmacology through five eras: (1) Early chemistry (1940s): isolation of CBN, CBD, and crude THC by Cahn, Adams, and Todd; (2) Structural characterization (1960s): Mechoulam determines THC structure, enables pharmacological research; (3) Receptor discovery (1980s-90s): Howlett proves receptor binding, Matsuda clones CB1, Munro clones CB2; (4) Endocannabinoid era (1990s): discovery of anandamide and 2-AG, identification of synthesis and degradation enzymes; (5) Therapeutic development (2000s): selective agonists, antagonists, enzyme inhibitors, and the recognition that the endocannabinoid system plays roles in both health and disease. The review emphasizes how each discovery depended on the one before it — a chain of dependencies spanning 66 years.","whyItMatters":"This review provides the only concise narrative history of cannabinoid pharmacology written by a participant-observer — someone who lived through most of the discoveries described. It demonstrates how the field developed through a chain of dependent discoveries: you couldn't find the receptor without first identifying THC; you couldn't find the endocannabinoids without first cloning the receptor; you couldn't develop targeted drugs without first characterizing the endocannabinoid pathways. Understanding this chain explains why progress took decades and why each breakthrough depended on specific prior knowledge.","specificNumbers":"","methodology":"Historical narrative review synthesizing published pharmacological, biochemical, and clinical literature from 1940-2006. The author draws on personal experience spanning 38 years of active cannabinoid research (1968-2006), incorporating both published evidence and first-hand knowledge of the field's development.","limitations":"As a 9-page review, the historical narrative is necessarily concise and selective. It prioritizes key milestones over comprehensive coverage. Published in a special supplement of the British Journal of Pharmacology, it assumes pharmacological literacy. The review reflects the state of knowledge in 2006 and does not address subsequent developments (rimonabant withdrawal, FAAH inhibitor failures, CBD drug approval). As the author was an active participant in the field, the narrative may emphasize contributions from his own network."},{"rthcId":"RTHC-08756","title":"Crystal Structure of the Human Cannabinoid Receptor CB1","authors":"Hua, T; Vemuri, K; Pu, M; Qu, L; Han, G W; Wu, Y; Zhao, S; Shui, W; Li, S; Korde, A; Laprairie, R B; Stahl, E L; Ho, J H; Zvonok, N; Zhou, H; Kufareva, I; Wu, B; Zhao, Q; Hanson, M A; Bohn, L M; Makriyannis, A; Stevens, R C; Liu, Z J","year":2016,"journal":"Cell, 167(3), 750-762.e14","doi":"10.1016/j.cell.2016.10.004","pmid":"27768894","tags":["neuroscience","foundational","endocannabinoid-system","pharmacology"],"studyType":"observational","evidenceStrength":"strong","keyFinding":"The 2.8 angstrom crystal structure of human CB1 was solved in complex with AM6538, a stabilizing antagonist specifically designed for this purpose. The structure revealed the receptor's seven-transmembrane architecture, the precise geometry of the orthosteric binding pocket, and critical amino acid contacts for antagonist binding. Combined with functional studies and molecular modeling, the structure provided insight into how THC and other natural cannabinoids orient within the binding pocket, why synthetic cannabinoids bind differently, and where allosteric modulation sites are located. The structure enables rational drug design — the ability to computationally predict how new compounds will interact with CB1 before they are synthesized.","whyItMatters":"Knowing a receptor's gene sequence tells you the amino acid order but not the 3D shape. For drug design, shape is everything — you need to know the exact geometry of the binding pocket to design molecules that fit precisely. This structure transformed cannabinoid drug discovery from trial-and-error pharmacology to structure-based rational design. It revealed why THC fits CB1, why synthetic cannabinoids bind differently, where allosteric sites are (relevant to CBD's mechanism), and provided a template for computationally screening thousands of potential drug candidates before synthesizing any.","specificNumbers":"","methodology":"The human CB1 receptor was engineered with a T4 lysozyme fusion to stabilize the intracellular loop region and expressed in insect cells (Sf9). The receptor was bound to AM6538, a custom-designed high-affinity antagonist synthesized by the Makriyannis laboratory at Northeastern University, which locked the receptor in a stable inactive conformation. Crystals were grown using lipidic cubic phase (LCP) crystallization — a technique where the protein is reconstituted into a lipid bilayer that mimics its native membrane environment. X-ray diffraction data were collected at synchrotron facilities and processed to 2.8 angstrom resolution. The structure was solved by molecular replacement and refined using standard crystallographic methods. Complementary functional studies (signaling assays) and computational molecular docking validated the structural findings.","limitations":"The structure captures CB1 in one conformation — antagonist-bound, inactive state. The active (agonist-bound) conformation was solved subsequently. Crystal structures are static snapshots of dynamic proteins and may not capture the full range of conformational states. The T4 lysozyme fusion and crystallization conditions introduce non-physiological constraints. The resolution (2.8 Å) is good but not atomic-level — some side-chain positions are approximate. The structure was solved in detergent/lipid conditions, not in a native cell membrane."},{"rthcId":"RTHC-08757","title":"The orphan receptor GPR55 is a novel cannabinoid receptor","authors":"Ryberg, E; Larsson, N; Sjögren, S; Hjorth, S; Hermansson, N O; Leonova, J; Elebring, T; Nilsson, K; Drmota, T; Greasley, P J","year":2007,"journal":"British Journal of Pharmacology, 152(7), 1092-1101","doi":"10.1038/sj.bjp.0707460","pmid":"17876302","tags":["neuroscience","endocannabinoid-system","pharmacology"],"studyType":"observational","evidenceStrength":"moderate","keyFinding":"GPR55 binds to and is activated by the cannabinoid ligand CP55940 and by THC (EC50 = 8 nM, remarkably potent). Endocannabinoids including anandamide, 2-AG, virodhamine, and noladin ether activate GPR55 with nanomolar potencies. CBD does not activate GPR55 but antagonizes the agonist effect of CP55940 (IC50 = 445 nM). GPR55 couples to Gα13 protein (not Gi/o like CB1 and CB2) and activates downstream rhoA, cdc42, and rac1 signaling — a cytoskeletal regulation pathway entirely different from the adenylate cyclase inhibition of classical cannabinoid receptors.","whyItMatters":"This paper challenged the assumption that the endocannabinoid system has only two receptors. If GPR55 is a genuine cannabinoid receptor, the ECS is larger and more complex than previously understood. More practically, GPR55 may explain cannabinoid effects that CB1 and CB2 cannot account for, and CBD's antagonism of GPR55 may contribute to its anti-cancer and anti-inflammatory effects. The paper also raised a broader question: how many receptors does the endocannabinoid system actually have?","specificNumbers":"","methodology":"HEK293 cells were transiently transfected with human GPR55 cDNA. Radioligand binding assays determined ligand affinity. GTPγS binding assays measured receptor activation by a panel of cannabinoid and non-cannabinoid ligands at various concentrations. G-protein coupling was determined using antibody and peptide blocking approaches targeting specific Gα subunits. Downstream signaling was assessed by measuring activation of rhoA, cdc42, and rac1 GTPases. Controls included untransfected cells and cells expressing CB1 or CB2 for comparison.","limitations":"This is an in vitro study using transfected cell lines — GPR55 was overexpressed far beyond physiological levels, which may produce pharmacological effects not seen at native expression. The paper came from AstraZeneca's drug discovery division (industry, not academic). The cannabinoid specificity of GPR55 was challenged the same year by Oka et al., who showed that the non-cannabinoid lipid lysophosphatidylinositol (LPI) robustly activates GPR55. The low sequence homology (13-14%) with CB1/CB2 and the different G-protein coupling (Gα13 vs Gi/o) raise fundamental questions about whether GPR55 belongs in the cannabinoid receptor family at all."},{"rthcId":"RTHC-08758","title":"Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System","authors":"Zou, S; Kumar, U","year":2018,"journal":"International Journal of Molecular Sciences, 19(3), 833","doi":"10.3390/ijms19030833","pmid":"29533978","tags":["neuroscience","endocannabinoid-system","neurodegeneration"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The review documented ECS involvement across five major neurological conditions: (1) Huntington's disease: progressive loss of CB1 receptors occurs as an early marker BEFORE actual neurodegeneration begins; CB1 knockout worsens motor performance and striatal atrophy. (2) Alzheimer's disease: CB1 changes are controversial but CB1 activation prevents amyloid-β neurotoxicity in multiple cell models and improves memory in AD animal models. (3) Parkinson's disease: paradoxical findings — both CB1 agonists and FAAH inhibitors improve symptoms, but so do CB1 antagonists, suggesting a complex biphasic role. (4) Epilepsy: CB1 retrograde signaling is selectively enhanced at inhibitory but not excitatory synapses during febrile seizures, leading to persistent DSI potentiation and hyperexcitability. (5) Cancer: bimodal effect — low cannabinoid concentrations are proliferative while high concentrations are pro-apoptotic. The review also emphasized receptor crosstalk — CB1 forms functional heteromers with dopamine D2, opioid, and somatostatin receptors.","whyItMatters":"This review reframed the endocannabinoid system from a cannabis-response pathway to a neuroprotective shield. The evidence across multiple neurodegenerative diseases consistently shows that ECS impairment precedes or accompanies neuronal death, and that modulating the system can be protective. This has direct implications for understanding why chronic cannabis use affects the brain (THC disrupts a protective system), why cannabinoids show therapeutic promise in neurological conditions, and why the relationship between cannabis and brain health is more complex than simple \"harm\" or \"benefit.\"","specificNumbers":"","methodology":"Comprehensive narrative review synthesizing published preclinical and clinical evidence on endocannabinoid system signaling and function in the central nervous system, with emphasis on receptor biology (CB1R, CB2R), signaling cascades (Gi/o coupling, MAPK, PI3K/Akt, β-arrestin), endocannabinoid synthesis/degradation (DAGLα, NAPE-PLD, MAGL, FAAH), retrograde signaling (DSI/DSE), and pathophysiological roles across neurodegenerative diseases.","limitations":"As a narrative review in an open-access MDPI journal (not a top-tier specialty journal), the paper synthesizes rather than generates evidence. Much of the disease-specific evidence is preclinical (cell culture and animal models) with limited clinical translation. The paradoxical findings in Parkinson's and the biphasic cancer effects remain unresolved. The review focused on CB1R and the CNS, with less attention to peripheral ECS roles and non-classical cannabinoid targets (GPR55, TRPV1)."},{"rthcId":"RTHC-08759","title":"History of cannabis and the endocannabinoid system","authors":"Crocq, Marc-Antoine","year":2020,"journal":"Dialogues in Clinical Neuroscience, 22(3), 223-228","doi":"10.31887/DCNS.2020.22.3/mcrocq","pmid":"33162765","tags":["history","endocannabinoid-system","medical-cannabis"],"studyType":"review","evidenceStrength":"N/A - historical review","keyFinding":"Cannabis use dates to approximately 12,000 years ago in Central Asia. Ancient medical texts from China, Egypt, Mesopotamia, Greece, and Rome all document cannabis for pain, inflammation, and nausea — the same conditions now known to be regulated by the endocannabinoid system. Mechoulam's 1964 identification of THC triggered the discovery of CB1 (1990), anandamide (1992), and CB2 (1993). Despite this 12,000-year relationship, only three therapeutic indications have conclusive evidence as of 2017.","whyItMatters":"Provides the most concise authoritative overview of the entire cannabis-human relationship, connecting ancient empirical observations to modern molecular discoveries. Frames the central paradox: 12,000 years of use but only three confirmed therapeutic indications, largely due to 20th-century prohibition.","specificNumbers":"~12,000 years of cannabis-human coexistence. 800g cannabis in Xinjiang shaman burial (~750 BCE). 30+ years of clinical experience documented by Reynolds (1890). 3 confirmed therapeutic indications (2017 NAS). 42.4% of modern medical cannabis registry cases are pain syndromes.","methodology":"Historical review article synthesizing archaeological, textual, and scientific sources across 12,000 years of human-cannabis interaction. Published in Dialogues in Clinical Neuroscience.","limitations":"As a 6-page review, necessarily compressed. Some archaeological dates carry uncertainty. The '2737 BCE Shennong' claim is noted as exaggerated. Western-centric in its 19th-century coverage. Does not cover cannabis in sub-Saharan African or pre-Columbian American traditions in detail."},{"rthcId":"RTHC-08760","title":"2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor","authors":"Hanus et al.","year":2001,"journal":"Proc Natl Acad Sci U S A","doi":"10.1073/pnas.061029898","pmid":"11259648","tags":["endocannabinoid-system","cb1-receptor","noladin-ether","lipid-signaling","foundational"],"studyType":"Laboratory (biochemical isolation and pharmacological characterization)","evidenceStrength":"Moderate — the compound is pharmacologically active but its endogenous status is disputed","keyFinding":"Isolated a third structural class of endocannabinoid — 2-arachidonyl glyceryl ether (noladin ether), an ether-type lipid — from porcine brain tissue. It binds CB1 receptors with high affinity (Ki = 21.2 nM) and produces classic cannabinoid effects in mice.","whyItMatters":"If confirmed as endogenous, noladin ether would represent a third class of endocannabinoid (ether-type) alongside anandamide (amide) and 2-AG (ester), suggesting the endocannabinoid system is more diverse than the two-molecule model. Its ether bond makes it more metabolically stable, opening new avenues for drug design.","specificNumbers":"CB1 Ki = 21.2 ± 0.5 nM; CB2 Ki = 480 nM; produced sedation, hypothermia, intestinal immobility, and mild antinociception in mice","methodology":"Lipid extraction from porcine brain tissue, chromatographic fractionation, CB1 receptor binding assays, structural characterization by NMR and mass spectrometry, confirmation by chemical synthesis, in vivo cannabinoid tetrad testing in mice.","limitations":"Multiple independent groups (Oka et al. 2003, Richardson et al. 2007) have been unable to detect noladin ether in mammalian brain tissue. No biosynthetic pathway has been identified — the known ether lipid synthesis route acts at the wrong position (sn-1 vs sn-2). The compound may be an artifact of the extraction process."},{"rthcId":"RTHC-08761","title":"Terpenes/Terpenoids in Cannabis: Are They Important?","authors":"Hanuš LO, Hod Y","year":2020,"journal":"Med Cannabis Cannabinoids","doi":"10.1159/000509733","pmid":"34676339","tags":["terpenes","entourage-effect","analytical-chemistry","cannabis-chemistry"],"studyType":"Analytical review (GC-MS characterization of 108 cannabis chemotypes + pharmacological literature review)","evidenceStrength":"Moderate — strong analytical chemistry, limited clinical evidence for therapeutic claims","keyFinding":"Systematic GC-MS analysis of 108 cannabis chemotypes revealed that beta-caryophyllene and beta-myrcene are the two most prevalent terpenes across the widest range of cultivars, appearing in the top 10 in over 80 samples each. Alpha-pinene, limonene, and linalool were also common but more variable. The authors reviewed pharmacological evidence for each major terpene and concluded that terpenes are likely therapeutically important but insufficiently studied in human clinical contexts.","whyItMatters":"Provides the first large-scale systematic characterization of what terpenes are actually present in cannabis across diverse cultivars. Bridges the gap between industry marketing claims about terpenes and analytical reality. The finding that beta-caryophyllene (a confirmed CB2 agonist) is the most prevalent terpene adds weight to the entourage effect hypothesis.","specificNumbers":"108 chemotypes analyzed by GC-MS. Beta-caryophyllene and beta-myrcene most prevalent (top 10 in 80+ samples). Main terpenes ranged 8-35% of total terpene content in inflorescences. Some essential oils showed dominant terpenes exceeding 65% of volatile content.","methodology":"Gas chromatography-mass spectrometry (GC-MS) analysis of 108 cannabis chemotypes — both inflorescences and essential oils. Terpene identification against known reference standards. Systematic literature review of pharmacological data for each identified terpene.","limitations":"GC-MS provides relative percentages, not absolute quantities absorbed by users. The gap between 'present in the plant' and 'active in the body' is significant. Most pharmacological data comes from animal models or in vitro studies. No human clinical trial data on terpene-specific therapeutic effects from cannabis."},{"rthcId":"RTHC-08762","title":"Terpenes don't directly activate CB1/CB2","authors":"Finlay et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08763","title":"An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity","authors":"Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, Bisogno T, De Petrocellis L, Di Marzo V, Mechoulam R","year":1998,"journal":"Eur J Pharmacol","doi":"10.1016/s0014-2999(98)00392-6","pmid":"9721036","tags":["endocannabinoid-system","entourage-effect","2-AG","lipid-signaling","foundational"],"studyType":"Laboratory (in vitro receptor binding/functional assays + in vivo mouse behavioral testing)","evidenceStrength":"Strong — direct experimental evidence for the entourage concept in endogenous biochemistry","keyFinding":"Inactive fatty acid glycerol esters (2-linoleoyl-glycerol and 2-palmitoyl-glycerol) that naturally accompany 2-AG in the body significantly potentiate its cannabinoid receptor binding, adenylyl cyclase inhibition, and in vivo behavioral effects (motor inhibition, analgesia, hypothermia). The inactive compounds amplify the active one's signal — the first demonstration of the 'entourage effect.'","whyItMatters":"Coined the term 'entourage effect' and established that endocannabinoid signaling depends on biological context, not just the signaling molecule itself. Proposed a new route for molecular regulation of cannabinoid activity. The concept was later extended to cannabis phytochemistry and became the most influential idea in the cannabis industry.","specificNumbers":"Two companion esters identified: 2-linoleoyl-glycerol and 2-palmitoyl-glycerol. Neither binds CB1 or CB2 alone. Both significantly potentiate 2-AG binding, adenylyl cyclase inhibition, and in vivo effects (motor inhibition, analgesia, hypothermia in mice).","methodology":"In vitro: radioligand binding assays and adenylyl cyclase inhibition assays at CB1 and CB2 receptors. In vivo: cannabinoid tetrad testing in mice (motor inhibition, ring immobility, hot plate analgesia, hypothermia). Compared 2-AG alone vs. 2-AG with companion esters.","limitations":"The exact mechanism of potentiation was not determined. Whether the companion esters protect 2-AG from enzymatic degradation, alter membrane dynamics, or act through allosteric mechanisms remains unresolved 25+ years later. The extension from endogenous lipids to plant compounds (terpenes) was not part of this study."},{"rthcId":"RTHC-08764","title":"Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial","authors":"Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, et al.","year":2018,"journal":"Lancet","doi":"10.1016/S0140-6736(18)30136-3","pmid":"29395273","tags":["epilepsy","cbd","clinical-trial","lennox-gastaut","epidiolex"],"studyType":"Randomized controlled trial (Phase 3, double-blind, placebo-controlled)","evidenceStrength":"Strong — gold-standard RCT design published in The Lancet","keyFinding":"Add-on CBD (20 mg/kg/day) reduced drop seizure frequency by 43.9% versus 21.8% with placebo (p=0.0135) in 171 patients with Lennox-Gastaut syndrome. This confirmed CBD's anticonvulsant efficacy in a second catastrophic epilepsy syndrome with different underlying causes than Dravet, establishing that CBD's mechanism is broad rather than disease-specific.","whyItMatters":"Together with the Dravet RCT, this trial completed the evidence package for FDA approval of Epidiolex — the first cannabis-derived prescription drug. It proved CBD's anticonvulsant effect generalizes across different epilepsy types and different seizure mechanisms, and it demonstrated that the most dangerous seizure type in LGS (drop seizures causing falls and injuries) specifically responds to CBD.","specificNumbers":"171 patients (86 CBD, 85 placebo). Drop seizure reduction: 43.9% CBD vs 21.8% placebo (p=0.0135). Adverse events: 86% CBD vs 69% placebo. Discontinuation: 14% CBD vs 1% placebo. One death (unrelated).","methodology":"Randomized, double-blind, placebo-controlled Phase 3 trial across 24 sites in USA, Netherlands, and Poland. Patients aged 2-55 with LGS, confirmed by EEG, ≥2 drop seizures/week, failed ≥2 anti-epileptic drugs. Oral CBD (Epidiolex) 20 mg/kg/day or placebo for 14 weeks. Primary endpoint: percentage change in drop seizure frequency.","limitations":"14-week treatment period may not capture long-term efficacy or safety. High adverse event rate (86%) including elevated liver enzymes, particularly with concurrent valproate. The 14% discontinuation rate in the CBD group is higher than in the Dravet trial. GW Pharmaceuticals funded the trial — standard for pharma but a conflict of interest."},{"rthcId":"RTHC-08765","title":"Open-label CBD in 214 epilepsy patients","authors":"Devinsky et al.","year":2016,"journal":"","doi":null,"pmid":"26724101","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08766","title":"Chronic administration of cannabidiol to healthy volunteers and epileptic patients","authors":"Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL, Lander N, Mechoulam R","year":1980,"journal":"Pharmacology","doi":"10.1159/000137430","pmid":"7413719","tags":["epilepsy","cbd","clinical-trial","foundational","historical"],"studyType":"Double-blind, placebo-controlled clinical trial (two phases: safety + efficacy)","evidenceStrength":"Moderate — gold-standard design but very small sample size (n=15 for efficacy)","keyFinding":"The first-ever clinical trial of CBD for epilepsy. In 15 adults with drug-resistant temporal lobe epilepsy, CBD (200-300 mg/day) virtually eliminated generalized seizures: only 10% of CBD patients still seizing at study end versus 90% of placebo patients. CBD was well tolerated with no serious side effects. The finding was ignored for 40 years.","whyItMatters":"This is the earliest clinical evidence that CBD reduces seizures in humans. Published in 1980, it predated the modern Epidiolex trials by 37 years. The results were dramatic but ignored due to the War on Drugs, regulatory barriers, CBD's Schedule I status, and the prevailing assumption that CBD was pharmacologically inert. The 2017-2018 Epidiolex trials vindicated what this study already showed.","specificNumbers":"Phase 1: 16 healthy volunteers (8 CBD at 3 mg/kg/day, 8 placebo) for 30 days. Phase 2: 15 epilepsy patients (8 CBD at 200-300 mg/day, 7 placebo) for up to 4.5 months. CBD group: 4/8 almost seizure-free, 3/8 partial improvement. Placebo: 1/7 improved, 6/7 unchanged or worsened. 10% CBD still seizing vs 90% placebo.","methodology":"Two-phase double-blind, placebo-controlled trial. Phase 1: safety in healthy volunteers (CBD 3 mg/kg/day for 30 days). Phase 2: efficacy in drug-resistant epilepsy (CBD 200-300 mg/day for up to 4.5 months as add-on therapy). Monitored with neurological exams, blood tests, EEG, ECG.","limitations":"Very small sample size (15 epilepsy patients). Single-center. 1980 methodology standards differ from modern trial requirements. No long-term follow-up published. The dramatic results were never replicated until the 2010s. Published in a low-impact journal."},{"rthcId":"RTHC-08767","title":"Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome","authors":"Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K","year":2018,"journal":"Neurology","doi":"10.1212/WNL.0000000000005254","pmid":"29540584","tags":["epilepsy","cbd","dravet","pharmacokinetics","drug-interactions","safety"],"studyType":"Randomized controlled trial (dose-ranging, double-blind, Class I evidence)","evidenceStrength":"Strong for safety characterization; underpowered for efficacy (n=34)","keyFinding":"CBD pharmacokinetics are dose-proportional in young Dravet patients. The critical drug interaction: CBD increases N-desmethylclobazam (active clobazam metabolite) levels via CYP2C19 inhibition — explaining much of the somnolence in CBD trials. CBD+valproate causes liver enzyme elevations (6 patients affected, all recovered). Adverse events are dose-dependent.","whyItMatters":"Characterized the pharmacology that makes safe Epidiolex prescribing possible. The clobazam interaction discovery changed clinical practice — neurologists now routinely reduce clobazam doses when adding CBD. The valproate-liver interaction confirmed the need for hepatic monitoring.","specificNumbers":"34 patients (10 at 5 mg/kg, 8 at 10 mg/kg, 9 at 20 mg/kg, 7 placebo). 32/34 completed (94%). CBD exposure dose-proportional (AUC). 6 CBD+valproate patients had elevated transaminases. N-CLB levels increased with CBD except on stiripentol.","methodology":"Randomized, double-blind, dose-ranging safety trial across multiple sites. Children 4-10 with Dravet syndrome. Three CBD doses (5, 10, 20 mg/kg/day) plus placebo, randomized 4:1. Pharmacokinetic sampling, drug interaction assessment, liver function monitoring.","limitations":"Very small sample size (34 total, 7 placebo). Not powered for seizure efficacy outcomes. Short treatment duration. Age range 4-10 may not generalize to older patients."},{"rthcId":"RTHC-08768","title":"CBD anti-seizure mechanisms review","authors":"Rosenberg et al.","year":2015,"journal":"","doi":null,"pmid":"26432033","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08769","title":"Real-world CBD across epilepsy subtypes","authors":"Schubert-Bast et al.","year":2023,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08770","title":"Smoked cannabis for HIV neuropathy","authors":"Abrams et al.","year":2007,"journal":"","doi":null,"pmid":"17296917","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08771","title":"Vaporized cannabis for neuropathic pain","authors":"Wilsey et al.","year":2013,"journal":"","doi":null,"pmid":"23237736","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08772","title":"Nabilone for fibromyalgia","authors":"Skrabek et al.","year":2008,"journal":"","doi":null,"pmid":"18403272","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08773","title":"Dronabinol for central neuropathic pain in MS","authors":"Svendsen et al.","year":2004,"journal":"","doi":null,"pmid":"15258006","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08774","title":"Cannabinoid analgesics (mechanism review)","authors":"Manzanares et al.","year":2006,"journal":"","doi":null,"pmid":"18615144","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08775","title":"Peripheral cannabinoid analgesia","authors":"Agarwal et al.","year":2007,"journal":"","doi":null,"pmid":"17558404","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08776","title":"Cannabis and schizophrenia (Swedish conscripts)","authors":"Andreasson et al.","year":1987,"journal":"","doi":null,"pmid":"2892048","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08777","title":"Adolescent THC changes hippocampal morphology","authors":"Rubino et al.","year":2009,"journal":"","doi":null,"pmid":"19156849","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08778","title":"The effects of Δ9-tetrahydrocannabinol on the dopamine system.","authors":"Michael A P Bloomfield; Abhishekh H Ashok; Nora D Volkow; Oliver D Howes","year":2016,"journal":"Nature","doi":"10.1038/nature20153","pmid":"27853201","tags":[],"studyType":"review","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08779","title":"Cannabis and white matter integrity","authors":"Zalesky et al.","year":2012,"journal":"","doi":null,"pmid":"22334937","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08780","title":"Recovery of cognitive function after abstinence","authors":"Schreiner & Dunn","year":2012,"journal":"","doi":null,"pmid":"22390208","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08781","title":"Cannabis for PTSD: systematic review","authors":"O'Neil et al.","year":2017,"journal":"","doi":null,"pmid":"28806794","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08782","title":"CBD for generalized anxiety (dose-finding)","authors":"Zuardi et al.","year":1993,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08783","title":"Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.","authors":"Leweke, F Markus; Piomelli, Daniele; Pahlisch, Franziska; Muhl, Dagmar; Gerth, Christoph W; Hoyer, Carolin; Klosterkötter, Joachim; Hellmich, Martin; Koethe, Dagmar","year":2012,"journal":"Translational Psychiatry, 2, e94","doi":"10.1038/tp.2012.15","pmid":"22832859","tags":["cbd","psychosis","schizophrenia","endocannabinoid-system"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"PANSS total improvement: CBD 30.5 (±16.4) vs amisulpride 30.1 (±24.7), p=0.884. Response rates (≥20% improvement): 75% CBD vs 74% amisulpride. CBD significantly better on: extrapyramidal symptoms (p=0.006), weight gain (p=0.010), prolactin elevation (p<0.001). Anandamide levels increased significantly with CBD vs amisulpride (p<0.001 at day 28). Anandamide increase correlated with symptom improvement in CBD group (p=0.0012) but not amisulpride group (p=0.64).","whyItMatters":"This is the first randomized trial showing CBD can match a conventional antipsychotic for efficacy while producing dramatically fewer side effects — and through a completely novel mechanism (FAAH inhibition / anandamide enhancement rather than dopamine blockade). Antipsychotic side effects drive medication non-adherence, which drives relapse. A treatment with equivalent efficacy and minimal side effects would transform schizophrenia management.","specificNumbers":"","methodology":"Double-blind, randomized, parallel-group, Phase II active-controlled trial (CBD-CT1; NCT00628290). 42 acutely exacerbated schizophrenic inpatients randomized 1:1 to CBD 800 mg/day or amisulpride 800 mg/day for 28 days. Both escalated from 200 mg/day over first week. Lorazepam permitted for agitation. Assessed with PANSS (primary), BPRS, CGI, EPS scale, metabolic markers. MMRM statistical analysis. Approved by University of Cologne Ethics Committee. Funded by Stanley Medical Research Institute and NIDA.","limitations":"Only 42 patients — too small for definitive conclusions or rare adverse event detection. Non-inferiority could not be formally demonstrated (confidence intervals too wide). Study terminated early due to funding expiration. Cannabinoid-positive patients excluded, limiting recruitment. Baseline lorazepam use was significantly higher in the amisulpride group (p=0.006). CBD monotherapy — no data on long-term use or treatment-resistant cases."},{"rthcId":"RTHC-08784","title":"THC-induced psychotic symptoms in healthy volunteers","authors":"Morrison et al.","year":2009,"journal":"","doi":null,"pmid":"19252145","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08785","title":"CBD for substance use disorders review","authors":"Prud'homme et al.","year":2015,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08786","title":"Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial.","authors":"Hurd, Yasmin L; Spriggs, Sharron; Alishayev, Julia; Winkel, Gary; Gurgov, Kristina; Kudrich, Chris; Oprescu, Anna M; Salsitz, Edwin","year":2019,"journal":"American Journal of Psychiatry, 176(11), 911-922","doi":"10.1176/appi.ajp.2019.18101191","pmid":"31109198","tags":[],"studyType":"Double-blind RCT","evidenceStrength":"Strong (gold-standard trial design)","keyFinding":"CBD significantly reduced cue-induced craving and anxiety in heroin use disorder, with effects persisting 7 days post-treatment. Also reduced heart rate and cortisol responses to drug cues. No cognitive impairment.","whyItMatters":"First gold-standard clinical evidence that a non-psychoactive, non-addictive cannabinoid can reduce drug craving. Opens a new therapeutic avenue for opioid use disorder with a favorable safety profile.","specificNumbers":"","methodology":"Double-blind, randomized, placebo-controlled trial. Participants with heroin use disorder received CBD (400mg or 800mg) or placebo daily for 3 days. Outcomes measured at acute (1h), short-term (24h post-last dose), and protracted (7 days post) timepoints during drug cue exposure paradigm.","limitations":"Small sample size. Short treatment period (3 days). Laboratory cue exposure differs from real-world triggers. Participants were not on MAT. Phase III trials needed. Commercial CBD products differ from research-grade formulations."},{"rthcId":"RTHC-08787","title":"CBD case series for anxiety and sleep","authors":"Shannon et al.","year":2019,"journal":"","doi":null,"pmid":"30624194","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08788","title":"Dronabinol reduces sleep apnea","authors":"Carley et al.","year":2018,"journal":"","doi":null,"pmid":"29121334","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08789","title":"Antitumor effects of cannabinoids (landmark review)","authors":"Guzman","year":2003,"journal":"","doi":null,"pmid":"12778132","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08790","title":"Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation","authors":"Galve-Roperh, I; Sánchez, C; Cortés, M L; Gómez del Pulgar, T; Izquierdo, M; Guzmán, M","year":2000,"journal":"Nature Medicine, 6(3), 313-319","doi":"10.1038/73171","pmid":"10700234","tags":["cancer","neuroscience","pharmacology"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"Intratumoral administration of THC and the synthetic cannabinoid WIN-55,212-2 caused considerable regression of malignant gliomas in rat and mouse models. The mechanism involved cannabinoid receptor activation leading to sustained ceramide accumulation and Raf1/ERK pathway activation, triggering apoptosis selectively in tumor cells. No substantial neurotoxicity was observed.","whyItMatters":"This was the first study published in a top-tier medical journal demonstrating that cannabinoids could cause tumor regression in living animals through a defined molecular mechanism. It launched the entire field of cannabinoid anticancer research and led to the first human pilot trial of THC for brain cancer (Guzmán 2006). The fact that the cell death pathway was selective — killing cancer cells while sparing healthy tissue — was especially significant because selectivity is the holy grail of cancer therapeutics.","specificNumbers":"","methodology":"Preclinical study using C6 rat glioma cell subclones in culture and in vivo glioma models in Wistar rats and RAG-2 deficient mice. THC and WIN-55,212-2 were administered intratumorally. Cell death was assessed via apoptosis markers, and the signaling pathway was characterized through ceramide measurements and kinase assays.","limitations":"This was entirely preclinical — cell cultures and animal models only. Rat glioma cells are not identical to human brain tumors. Intratumoral administration (injecting directly into tumors) is not achievable through normal cannabis consumption. The doses used far exceed what can be achieved by smoking or eating cannabis. The selectivity mechanism (why cancer cells die but normal cells don't) remains incompletely understood."},{"rthcId":"RTHC-08791","title":"Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy","authors":"Shrivastava, Ashutosh; Kuzontkoski, Paula M; Groopman, Jerome E; Prasad, Anil","year":2011,"journal":"Molecular Cancer Therapeutics, 10(7), 1161-1172","doi":"10.1158/1535-7163.MCT-10-1100","pmid":"21566064","tags":["cancer","cbd","pharmacology"],"studyType":"preclinical","evidenceStrength":"moderate","keyFinding":"CBD induced concentration-dependent cell death in both ER-positive (MCF-7) and ER-negative (MDA-MB-231) breast cancer cells while having little effect on nontumorigenic MCF-10A mammary cells. The mechanism involved ER stress, AKT/mTOR inhibition, beclin1-mediated autophagy, and intrinsic (mitochondrial) apoptotic pathway activation. ROS generation was essential for both autophagy and apoptosis induction.","whyItMatters":"Triple-negative breast cancer (TNBC) is one of the most aggressive cancers with the fewest treatment options — it doesn't respond to hormone therapy or HER2-targeted drugs, leaving chemotherapy as the primary option. Any compound that selectively kills TNBC cells through a novel mechanism is of significant research interest. CBD's ability to work through a pathway independent of cannabinoid receptors and conventional receptor targets adds to its potential as a mechanistically distinct anticancer agent.","specificNumbers":"","methodology":"In vitro preclinical study using breast cancer cell lines (MDA-MB-231 triple-negative, MCF-7 ER-positive) and nontumorigenic MCF-10A controls. Cell viability, apoptosis markers, autophagy markers, ROS levels, mitochondrial membrane potential, and protein interactions were assessed through multiple assays including electron microscopy, western blot, flow cytometry, and immunoprecipitation.","limitations":"Entirely preclinical — cell lines in dishes, no animal models, no human data. Cell lines do not capture the genetic diversity and microenvironment complexity of human tumors. CBD concentrations used may not be achievable in breast tissue through normal CBD consumption. No pharmacokinetic or bioavailability data."},{"rthcId":"RTHC-08792","title":"Cannabinoids inhibit glioma cell invasion","authors":"Blazquez et al.","year":2008,"journal":"","doi":null,"pmid":"18384615","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08793","title":"CBD and THC synergy in glioblastoma with temozolomide","authors":"Torres et al.","year":2011,"journal":"","doi":null,"pmid":"21220494","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08794","title":"Cannabinoids reduce tumor angiogenesis","authors":"Blazquez et al.","year":2003,"journal":"","doi":null,"pmid":"12626218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08795","title":"Cannabis use among cancer patients (survey)","authors":"Pergam et al.","year":2017,"journal":"","doi":null,"pmid":"28493557","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08796","title":"Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy","authors":"Herman, T S; Einhorn, L H; Jones, S E; Nagy, C; Chester, A B; Dean, J C; Furnas, B; Williams, S D; Leigh, S A; Dorr, R T; Moon, T E","year":1979,"journal":"New England Journal of Medicine, 300(23), 1295-1297","doi":"10.1056/NEJM197906073002302","pmid":"375088","tags":["cancer","clinical-trial","medical-cannabis","nausea"],"studyType":"rct","evidenceStrength":"strong","keyFinding":"Nabilone was significantly superior to prochlorperazine: 80% response rate vs 32% (p<0.001). Both nausea and vomiting episodes were significantly reduced. Side effects were about twice as frequent with nabilone (somnolence, dry mouth, dizziness). Four patients (3%) had serious adverse events (hallucinations in 3, hypotension in 1).","whyItMatters":"This was among the earliest randomized controlled trials of any cannabinoid for any medical indication, published in the most prestigious medical journal in the world. Co-authored by Lawrence Einhorn — the oncologist who pioneered cisplatin-based chemotherapy for testicular cancer and is one of the most important figures in modern oncology. The study helped establish the evidence base that led to FDA approval of nabilone (Cesamet) and dronabinol (Marinol), which remain the only FDA-approved THC-based drugs besides Epidiolex. It also created the central paradox of American cannabis policy: the federal government classifies cannabis as Schedule I (\"no accepted medical use\") while simultaneously approving synthetic versions of its active ingredient.","specificNumbers":"","methodology":"Two double-blind, crossover trials in 113 cancer patients with severe chemotherapy-induced nausea and vomiting. Each patient served as their own control, receiving both nabilone and prochlorperazine in random order across chemotherapy cycles.","limitations":"Side effects were notably more frequent with nabilone, including psychoactive effects (hallucinations in 3%). The crossover design, while strong for controlling individual variation, means some patients may have had different responses in later chemo cycles. Modern antiemetics (5-HT3 antagonists) were not yet available for comparison."},{"rthcId":"RTHC-08797","title":"Nabiximols for cancer pain (phase III)","authors":"Portenoy et al.","year":2012,"journal":"","doi":null,"pmid":"22483680","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08798","title":"Endocannabinoid system and drug addiction","authors":"Maldonado et al.","year":2006,"journal":"","doi":null,"pmid":"16775143","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08799","title":"Cannabis dependence: neuroscience review","authors":"Volkow et al.","year":2014,"journal":"","doi":null,"pmid":"25317848","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08800","title":"Cannabis withdrawal: DSM-5 inclusion","authors":"Hasin et al.","year":2013,"journal":"","doi":null,"pmid":"23490450","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08801","title":"Rimonabant for weight loss (RIO-Europe)","authors":"Van Gaal et al.","year":2005,"journal":"","doi":null,"pmid":"15850714","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08802","title":"Obesity and cannabis use: results from 2 representative national surveys","authors":"Le Strat, Yann; Le Foll, Bernard","year":2011,"journal":"American Journal of Epidemiology, 174(8), 929-933","doi":"10.1093/aje/kwr200","pmid":"21868374","tags":["metabolism","epidemiology","endocannabinoid-system"],"studyType":"cross-sectional","evidenceStrength":"moderate","keyFinding":"Obesity prevalence was significantly lower among cannabis users (14.3% and 17.2%) compared to non-users (22.0% and 25.3%) across both NESARC and NCS-R surveys. The association persisted after adjusting for sex, age, and tobacco use.","whyItMatters":"This study challenged one of the most intuitive assumptions in cannabis pharmacology: that appetite stimulation should lead to weight gain. The finding connects to broader endocannabinoid system physiology — particularly the CB1 receptor's role in metabolism — and has implications for understanding both the metabolic effects of chronic cannabis use and the biology of obesity. It also provides context for understanding why the anti-obesity drug rimonabant (which blocked CB1 receptors) worked for weight loss but caused psychiatric devastation.","specificNumbers":"","methodology":"Cross-sectional analysis of two large representative US national surveys: NESARC (2001-2002, n=43,093) and NCS-R (2001-2003, n=9,282). Obesity defined as BMI ≥30. Cannabis use categorized by past 12-month use. Adjusted for age, sex, and tobacco use.","limitations":"Cross-sectional design cannot establish causality. Cannabis users may differ from non-users in diet, exercise, metabolism, or other unmeasured confounders. Self-reported cannabis use may be underreported. BMI is an imperfect measure of adiposity. The association does not prove that cannabis causes weight loss."},{"rthcId":"RTHC-08803","title":"Endocannabinoid system in obesity","authors":"Silvestri & Di Marzo","year":2013,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08804","title":"Cannabis and metabolic syndrome (cross-sectional)","authors":"Vidot et al.","year":2016,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08805","title":"Triggering myocardial infarction by marijuana","authors":"Mittleman, Murray A; Lewis, Richard A; Maclure, Malcolm; Sherwood, Jane B; Muller, James E","year":2001,"journal":"Circulation, 103(23), 2805-2809","doi":"10.1161/01.CIR.103.23.2805","pmid":"11401936","tags":["cardiovascular","safety"],"studyType":"case-crossover","evidenceStrength":"strong","keyFinding":"Risk of MI onset was elevated 4.8 times over baseline (95% CI 2.4-9.5) in the 60 minutes after marijuana use. The risk declined rapidly thereafter. Of 3,882 MI patients, 124 (3.2%) reported marijuana use in the prior year, with 9 using within 1 hour of symptoms. The authors concluded marijuana is a rare trigger of acute MI.","whyItMatters":"First study to quantify the acute cardiovascular triggering effect of cannabis using rigorous case-crossover methodology. Places cannabis in context alongside other MI triggers (exercise 5.9x, anger 2.3x, sex 2.5x). Important for older adults and those with pre-existing cardiovascular disease.","specificNumbers":"3,882 MI patients. 124 (3.2%) used marijuana in prior year. 9 used within 1 hour of MI. RR 4.8 (95% CI 2.4-9.5) in first hour. Risk declined rapidly after 1 hour.","methodology":"Case-crossover analysis from the Determinants of Myocardial Infarction Onset Study (MIOS). 3,882 patients with acute MI interviewed at 45 US hospitals. Compared marijuana use in the hour before MI to expected frequency using self-matched control data.","limitations":"Self-reported marijuana use (possible underreporting due to legal status). Very small number of exposed cases (9 within 1 hour). Study conducted 1989-1996 when cannabis potency was lower. Cannot determine dose-response. Case-crossover design assumes stable usage patterns."},{"rthcId":"RTHC-08806","title":"Cannabis and stroke risk","authors":"Wolff et al.","year":2015,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08807","title":"CBD cardiovascular effects (human study)","authors":"Jadoon et al.","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08808","title":"Cannabis and arrhythmia risk","authors":"Kariyanna et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08809","title":"Maternal marijuana and birth outcomes","authors":"Zuckerman, Barry; Frank, Deborah A; Hingson, Ralph; Amaro, Hortensia; Levenson, Suzette M; Kayne, Howard; Parker, Steven; Vinci, Robert; Aboagye, Kwesi; Fried, Lisa E; et al.","year":1989,"journal":"New England Journal of Medicine, 320(12), 762-768","doi":"10.1056/NEJM198903233201203","pmid":"2784193","tags":["pregnancy","fetal-development","birth-outcomes","public-health"],"studyType":"prospective-cohort","evidenceStrength":"moderate","keyFinding":"Marijuana use during pregnancy was independently associated with a 79-gram decrease in birth weight and 0.5 cm decrease in length after controlling for confounders including tobacco, alcohol, cocaine use, and socioeconomic status. The associations were stronger when drug use was detected by urine assay rather than self-report, suggesting that interview-only studies underestimate the true effect.","whyItMatters":"This NEJM publication established the scientific foundation for concerns about prenatal cannabis exposure. By using both interviews and biological testing to detect use (and showing that biological testing reveals stronger associations), it set a methodological standard and demonstrated that self-report alone is insufficient. Its findings have been broadly confirmed by subsequent meta-analyses showing cannabis-exposed infants have ~1.5-2.6x odds of low birth weight.","specificNumbers":"","methodology":"Prospective cohort study of 1,226 mother-infant pairs from the prenatal clinic at Boston City Hospital. Drug exposure was assessed through both structured interviews and urine immunoassays (conducted prenatally and postpartum). 27% tested positive or reported marijuana use; 18% for cocaine. Fetal growth outcomes (birth weight, length, head circumference) were assessed at delivery. Multiple regression controlled for tobacco, alcohol, cocaine, maternal age, parity, socioeconomic status, and other confounders.","limitations":"Observational design cannot prove causation. Women who use marijuana during pregnancy differ from non-users in many unmeasured ways. Low THC potency of 1980s cannabis (typically 2-4%) limits generalizability to modern products. Self-report unreliable (the study itself showed this). No long-term developmental follow-up. Boston inner-city population may not generalize broadly. 79 grams is a modest effect (~2.3% of average birth weight) and may not be clinically significant in isolation. Confounding by polydrug use (27% marijuana, 18% cocaine overlap) is partially but not fully addressed."},{"rthcId":"RTHC-08810","title":"Cannabis use during pregnancy (meta-analysis)","authors":"Gunn et al.","year":2016,"journal":"","doi":null,"pmid":"26993627","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08811","title":"Prenatal cannabis and child brain development","authors":"El Marroun et al.","year":2016,"journal":"","doi":null,"pmid":"26386480","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08812","title":"Prenatal cannabis and childhood outcomes (OPPS)","authors":"Fried & Watkinson","year":2001,"journal":"","doi":null,"pmid":"11711244","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08813","title":"Endocannabinoid system in the gut","authors":"Sharkey & Wiley","year":2016,"journal":"","doi":null,"pmid":"27060726","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08814","title":"CBD for ulcerative colitis RCT","authors":"Irving et al.","year":2018,"journal":"","doi":null,"pmid":"29538683","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08815","title":"Cannabinoids and GI motility","authors":"Aviello et al.","year":2008,"journal":"","doi":null,"pmid":"18805590","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08816","title":"Cannabis and gastroparesis","authors":"Jehangir & Parkman","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08817","title":"Antibacterial cannabinoids from Cannabis sativa: a structure-activity study","authors":"Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM","year":2008,"journal":"Journal of Natural Products, 71(8)","doi":"10.1021/np8002673","pmid":"18681481","tags":["cbd","thc","cbg","cbn","cbc","medical-cannabis"],"studyType":"in-vitro","evidenceStrength":"preliminary","keyFinding":"All five major cannabinoids (CBD, CBC, CBG, THC, CBN) showed potent antibacterial activity against six MRSA strains with MIC values of 0.5-2 µg/mL, comparable to vancomycin. Activity was independent of psychoactive properties and bypassed the efflux pump resistance mechanism.","whyItMatters":"MRSA kills over 130,000 people annually and resists most antibiotics. This study identified cannabinoids as an entirely new class of antibacterial compounds that work through a mechanism different from existing antibiotics — meaning MRSA's current resistance strategies don't protect it.","specificNumbers":"5 cannabinoids tested. 6 MRSA strains. 18 total compounds including derivatives. MIC values: CBD 0.5-1 µg/mL, THC 0.5-2 µg/mL, CBN 1 µg/mL, CBG 1-2 µg/mL, CBC ~2 µg/mL. Comparable to vancomycin (1-2 µg/mL). 535+ citations.","methodology":"In vitro broth microdilution assay testing five major cannabinoids and 13 synthetic derivatives against six clinically relevant MRSA strains. Standard MIC determination. Structure-activity relationship analysis through systematic chemical modification.","limitations":"In vitro study only — no animal models or human data. Mechanism of action not determined. Systemic bioavailability at antibacterial concentrations not established. Cytotoxicity to human cells at these concentrations not assessed."},{"rthcId":"RTHC-08818","title":"CBN appetite stimulation in rats","authors":"Farrimond et al.","year":2012,"journal":"","doi":null,"pmid":"22543671","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08819","title":"THCV as CB1 antagonist/appetite suppressant","authors":"Riedel et al.","year":2009,"journal":"","doi":null,"pmid":"19594758","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08820","title":"CBC antidepressant-like effects","authors":"El-Alfy et al.","year":2010,"journal":"","doi":null,"pmid":"20637218","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08821","title":"CBDV for epilepsy (preclinical)","authors":"Hill et al.","year":2012,"journal":"","doi":null,"pmid":"21615721","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08822","title":"Delta-8 THC pharmacology","authors":"Hollister & Gillespie","year":1973,"journal":"","doi":null,"pmid":"4695724","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08823","title":"THCA neuroprotective properties","authors":"Nadal et al.","year":2017,"journal":"","doi":null,"pmid":"28853159","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08824","title":"CBG for Huntington disease (mice)","authors":"Valdeolivas et al.","year":2015,"journal":"","doi":null,"pmid":"25427284","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08825","title":"CBG for inflammatory bowel disease","authors":"Borrelli et al.","year":2013,"journal":"","doi":null,"pmid":"23578560","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08826","title":"Beta-caryophyllene is a dietary cannabinoid","authors":"Gertsch, Jürg; Leonti, Marco; Raduner, Stefan; Racz, Ildiko; Chen, Jian-Zhong; Xie, Xiang-Qun; Altmann, Karl-Heinz; Karsak, Meliha; Zimmer, Andreas","year":2008,"journal":"Proceedings of the National Academy of Sciences","doi":"10.1073/pnas.0803601105","pmid":"18574142","tags":["beta-caryophyllene","CB2-receptor","terpene","dietary-cannabinoid","anti-inflammatory","black-pepper"],"studyType":"Experimental (in vitro + in vivo)","evidenceStrength":"Strong (S-tier landmark)","keyFinding":"Beta-caryophyllene selectively binds CB2 (Ki = 155 ± 4 nM) and is a functional agonist. Oral BCP at 5 mg/kg reduced inflammation in wild-type mice but not CB2 knockout mice, confirming cannabimimetic effects via CB2.","whyItMatters":"This is the only confirmed example of a terpene directly binding a cannabinoid receptor. It validates a piece of the entourage effect hypothesis at the receptor level, provides a mechanism for dietary modulation of the endocannabinoid system, and opens a new category of non-psychoactive cannabinoid therapeutics.","specificNumbers":"","methodology":"Radioligand binding assays to determine CB2 affinity. Functional assays (GTPγS binding, cAMP inhibition) to confirm agonist activity. In vivo carrageenan-induced paw edema model in wild-type and CB2 knockout mice to demonstrate anti-inflammatory effects via CB2.","limitations":"The study demonstrated CB2 agonism and anti-inflammatory effects in mice, but clinical trials in humans are limited. The Ki of 155 nM is moderate — whether dietary intake of beta-caryophyllene from food or cannabis achieves sufficient tissue concentrations for CB2 activation in humans is debated. The anti-inflammatory effects shown are in an acute model; chronic applications are less well characterized."},{"rthcId":"RTHC-08827","title":"Cannabis impairment: detection and duration","authors":"Ramaekers et al.","year":2004,"journal":"","doi":null,"pmid":"15582913","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08828","title":"THC blood levels and driving performance","authors":"Hartman & Huestis","year":2013,"journal":"","doi":null,"pmid":"23034608","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08829","title":"Cannabis legalization and traffic fatalities","authors":"Santaella-Tenorio et al.","year":2017,"journal":"","doi":null,"pmid":"28525534","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08830","title":"Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010.","authors":"Bachhuber, Marcus A; Saloner, Brendan; Cunningham, Chinazo O; Barry, Colleen L","year":2014,"journal":"JAMA Internal Medicine, 174(10), 1668-1673","doi":"10.1001/jamainternmed.2014.4005","pmid":"25154332","tags":[],"studyType":"Ecological time-series analysis","evidenceStrength":"Moderate (ecological design)","keyFinding":"24.8% lower mean annual opioid overdose mortality in states with medical cannabis laws (95% CI -37.5% to -9.5%, p = 0.003). Effect strengthened over time: -19.9% at year 1 to -33.3% at year 6.","whyItMatters":"The most influential study linking cannabis policy to opioid crisis outcomes. Shaped legislative debates and policy arguments nationwide. Demonstrated that cannabis access may have population-level harm reduction effects.","specificNumbers":"","methodology":"Time-series analysis of death certificate data across all 50 US states, 1999-2010. State and year fixed effects. Controlled for prescription drug monitoring programs, pain clinic laws, medical examiner requirements, and unemployment rates.","limitations":"Ecological design cannot establish individual-level causation. Follow-up through 2017 (Shover et al.) found association reversed. States with cannabis laws may differ in unmeasured ways. Many concurrent policy changes."},{"rthcId":"RTHC-08831","title":"Cannabis legalization and youth use (review)","authors":"Melchior et al.","year":2019,"journal":"","doi":null,"pmid":"31469932","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08832","title":"Effects of cannabis legalization (Colorado)","authors":"Cerdá et al.","year":2017,"journal":"","doi":null,"pmid":"28678110","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08833","title":"Drug harms in the UK: a multicriteria decision analysis.","authors":"Nutt, David J; King, Leslie A; Phillips, Lawrence D","year":2010,"journal":"Lancet, 376(9752), 1558-1565","doi":"10.1016/S0140-6736(10)61462-6","pmid":"21036393","tags":["policy","drug-scheduling","harm-assessment"],"studyType":"expert panel / multicriteria decision analysis","evidenceStrength":"strong","keyFinding":"Alcohol was the most harmful drug overall (score: 72/100). Cannabis ranked 8th (score: 20/100), roughly one-quarter of alcohol's harm. Heroin (55) and crack cocaine (54) ranked 2nd and 3rd. Mushrooms (5) and LSD (7) were least harmful. Drug classifications correlated poorly with actual assessed harm.","whyItMatters":"Published in The Lancet by the scientist fired from the UK government's drug advisory council, this paper is the most influential drug harm assessment ever published. It systematically demonstrated that drug scheduling is based on politics rather than pharmacology, and has been cited in rescheduling arguments worldwide.","specificNumbers":"20 drugs scored across 16 criteria. Overall harm scores: Alcohol 72, Heroin 55, Crack 54, Methamphetamine 33, Cocaine 27, Tobacco 26, Amphetamine 23, Cannabis 20, GHB 18, Benzodiazepines 15, Ketamine 15, Methadone 14, Mephedrone 13, Butane 10, Khat 9, MDMA 9, Steroids 9, LSD 7, Buprenorphine 6, Mushrooms 5.","methodology":"Multicriteria decision analysis (MCDA). Expert panel scored 20 drugs on 16 harm criteria (9 user harms, 7 societal harms) on a 0-100 scale in a one-day interactive workshop. Criteria were weighted for relative importance. Harms to others weighted 54%, harms to users 46%.","limitations":"Expert panel scoring involves subjective judgment. Alcohol's high availability may inflate some harm dimensions. The methodology conflates per-user harm with population-level harm. Replicated in 2015 European analysis with consistent results, partially addressing reproducibility concerns."},{"rthcId":"RTHC-08834","title":"Decriminalization outcomes","authors":"Hughes & Stevens","year":2010,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08835","title":"Cannabis industry and public health","authors":"Pacula & Smart","year":2017,"journal":"","doi":null,"pmid":"28125387","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08836","title":"Cannabis taxation and public health","authors":"Caulkins et al.","year":2015,"journal":"","doi":null,"pmid":"25879627","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08837","title":"Impact of legal cannabis on alcohol consumption","authors":"Anderson et al.","year":2013,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08838","title":"The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research","authors":"National Academies of Sciences, Engineering, and Medicine","year":2017,"journal":"National Academies Press, Washington, DC","doi":"10.17226/24625","pmid":null,"tags":["comprehensive-review","policy","chronic-pain","psychosis"],"studyType":"consensus-report","evidenceStrength":"authoritative","keyFinding":"The most comprehensive cannabis evidence review ever assembled found conclusive evidence for three therapeutic uses (chronic pain, chemotherapy nausea, MS spasticity), substantial evidence for several harms (motor vehicle crashes, lower birth weight, psychosis risk), and insufficient evidence for most other claimed benefits. Called for removal of Schedule I research barriers.","whyItMatters":"This report became the reference document for cannabis policy worldwide. It revealed that for most conditions people use cannabis to treat, the evidence base is remarkably thin — not because cannabis doesn't work, but because research barriers prevented the trials from being conducted.","specificNumbers":"- 16-member expert committee\n- 10,000+ scientific abstracts reviewed\n- ~100 research conclusions\n- 468 pages\n- 3 therapeutic uses with conclusive/substantial evidence\n- Numerous conditions rated as insufficient evidence","methodology":"Consensus committee convened by NASEM. Systematic review of all available evidence through 2016. Conclusions required majority committee agreement. Evidence categorized as conclusive/substantial, moderate, limited, or insufficient.","limitations":"Evidence through 2016 only — some categories (especially epilepsy) changed rapidly after publication. Committee structure may not capture all perspectives. Consensus process can be conservative."},{"rthcId":"RTHC-08839","title":"Association between marijuana exposure and pulmonary function over 20 years","authors":"Pletcher MJ, Vittinghoff E, Kalhan R, Richman J, Safford M, Sidney S, Lin F, Kertesz S","year":2012,"journal":"JAMA","doi":"10.1001/jama.2011.1961","pmid":"22235088","tags":["respiratory","lung-function","spirometry","longitudinal","CARDIA"],"studyType":"longitudinal-cohort","evidenceStrength":"high","keyFinding":"Moderate cannabis smoking was associated with a slight increase in lung function measures (FEV1 and FVC), while heavy long-term use showed a trend toward decline — a profoundly nonlinear dose-response opposite to tobacco's linear harm.","whyItMatters":"This is the largest and longest study of cannabis and pulmonary function ever conducted, and its finding that occasional cannabis use does not harm — and may slightly improve — spirometric lung function fundamentally challenged the assumption that all smoke damages lungs equally.","specificNumbers":"At low exposure: +13 mL FEV1/joint-year, +20 mL FVC/joint-year. At 7+ joint-years: effect levels off. At 20+ joint-years: FEV1 trending negative (-2.2 mL/joint-year, p=0.079). Tobacco comparison: 50 pack-years = -332 mL FEV1.","methodology":"Prospective longitudinal cohort (CARDIA). 5,115 participants aged 18-30 at enrollment, followed 20 years across 4 US cities with repeated spirometry at years 0, 2, 5, 10, and 20. Mixed-effects models with cubic splines for nonlinear dose-response.","limitations":"Only 40 participants had >20 joint-years of cannabis exposure, severely limiting power for heavy-use conclusions. Spirometry measures airflow but not airway inflammation, histology, or symptoms. Cannabis exposure was self-reported. Most participants were light users (median 2-3 episodes/month)."},{"rthcId":"RTHC-08840","title":"Cannabis smoke and respiratory symptoms","authors":"Tashkin","year":2013,"journal":"","doi":null,"pmid":"23443758","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08841","title":"Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study","authors":"Hashibe M, Morgenstern H, Cui Y, Tashkin DP, Zhang ZF, Cozen W, Mack TM, Greenland S","year":2006,"journal":"Cancer Epidemiology, Biomarkers & Prevention","doi":"10.1158/1055-9965.EPI-06-0330","pmid":"17035389","tags":[],"studyType":"Case-Control Study","evidenceStrength":"Moderate-High","keyFinding":"No positive association between cannabis smoking and lung or upper aerodigestive tract cancers after adjusting for cigarette smoking, with adjusted odds ratios near or below 1.0 across all exposure levels.","whyItMatters":"This was the largest and most methodologically rigorous study of its kind, and it fundamentally challenged the assumption that cannabis smoke causes cancer the same way tobacco smoke does. The null finding has been replicated in pooled analyses.","specificNumbers":"","methodology":"Population-based case-control study using the USC Tumor Registry. 1,212 cancer cases and 1,040 matched controls. Cannabis exposure measured in joint-years. Adjusted for tobacco, alcohol, demographics.","limitations":"Case-control design relies on self-reported lifetime exposure. Hard to separate cannabis-only smokers from tobacco co-users. Selection bias possible (hospital-based cancer registry). Cannot account for unmeasured confounders."},{"rthcId":"RTHC-08842","title":"Cannabis vaporization vs smoking (comparison)","authors":"Pomahacova et al.","year":2009,"journal":"","doi":null,"pmid":"19514815","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08843","title":"Cannabinoids as novel anti-inflammatory drugs","authors":"Nagarkatti et al.","year":2009,"journal":"","doi":null,"pmid":"20161535","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08844","title":"CBD and inflammation mechanisms","authors":"Burstein","year":2015,"journal":"","doi":null,"pmid":"25576777","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08845","title":"Endocannabinoid system and immune regulation","authors":"Cabral & Griffin-Thomas","year":2009,"journal":"","doi":null,"pmid":"19243630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08846","title":"Cannabis for autoimmune conditions (review)","authors":"Katchan et al.","year":2016,"journal":"","doi":null,"pmid":"26831375","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08847","title":"THC as immunosuppressant","authors":"Kaplan et al.","year":2003,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08848","title":"CBD for dermatitis and skin inflammation","authors":"Palmieri et al.","year":2019,"journal":"","doi":null,"pmid":"30993303","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08849","title":"Cannabinoid anti-inflammatory mechanisms (comprehensive)","authors":"Turcotte et al.","year":2016,"journal":"","doi":null,"pmid":"26965437","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08850","title":"Cannabis pharmacokinetics review","authors":"Huestis","year":2007,"journal":"","doi":null,"pmid":"17712814","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08851","title":"CBD pharmacokinetics and drug interactions","authors":"Zendulka et al.","year":2016,"journal":"","doi":null,"pmid":"26878284","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08852","title":"Cannabis biphasic dose response","authors":"Sulak","year":2015,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08853","title":"Tasty THC: Promises and Challenges of Cannabis Edibles","authors":"Barrus DG, Capogrossi KL, Cates SC, Gourdet CK, Peiper NC, Novak SP, Lefever TW, Wiley JL","year":2016,"journal":"Methods Rep RTI Press","doi":"10.3768/rtipress.2016.op.0035.1611","pmid":"28127591","tags":["dosing","edibles","public-health","regulation","safety","pharmacokinetics","policy"],"studyType":"Narrative Review / Policy Analysis","evidenceStrength":"Moderate — comprehensive policy review synthesizing pharmacokinetic data, ER statistics, and regulatory frameworks","keyFinding":"Cannabis edibles present unique safety challenges due to delayed onset (30-90 min), unpredictable bioavailability (6-10%), and the potent liver metabolite 11-OH-THC, leading to disproportionate adverse events and ER visits relative to market share","whyItMatters":"This review directly informed the 10mg standard serving size now adopted by most legal states and became the definitive reference for edible safety policy. It documented that edible-related ER visits doubled in Colorado after legalization and that 83% of tested products had inaccurate labels.","specificNumbers":"10mg standard serving size; 100mg max per recreational product; 30-90 minute onset delay; 6-10% oral THC bioavailability; 1mg oral THC ≈ 5.71mg smoked THC behavioral equivalence; 83% of tested edibles had inaccurate labels; ER visits doubled from 85 to 168 per 10,000 in Colorado 2013-2014; poison control calls increased 30.3% per year in decriminalized states 2005-2011","methodology":"Narrative review synthesizing pharmacokinetic literature, epidemiological data from Colorado and Washington, poison control center data, regulatory frameworks from four legalized states (CO, WA, OR, AK), and food labeling research","limitations":"Review article, not original research; data primarily from Colorado and Washington as earliest legalizers; pre-dates the larger Monte 2019 ER data; regulatory landscape rapidly evolving; limited long-term outcome data"},{"rthcId":"RTHC-08854","title":"A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols (Sativex), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis","authors":"Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, Gasperini C, Pozzilli C, Cefaro L, Comi G, Rossi P, Ambler Z, Stelmasiak Z, Erdmann A, Montalban X, Klimek A, Davies P","year":2011,"journal":"European Journal of Neurology","doi":"10.1111/j.1468-1331.2010.03328.x","pmid":"21362108","tags":["MS","spasticity","nabiximols","Sativex","THC-CBD","pharmaceutical"],"studyType":"enriched-enrollment-RCT","evidenceStrength":"high","keyFinding":"Nabiximols (Sativex), a 1:1 THC:CBD oromucosal spray, significantly reduced spasticity in MS patients who had failed other treatments, using an innovative enriched-enrollment design that mirrors real clinical practice.","whyItMatters":"This was the pivotal trial that led to Sativex becoming the world's first cannabis-derived prescription medicine approved through the full pharmaceutical regulatory pathway — now approved in 25+ countries for MS spasticity.","specificNumbers":"572 enrolled, 47.6% responded to initial treatment (>=20% improvement), 241 randomized. Primary endpoint p=0.0002. Spasticity NRS dropped from 6.91 to 3.9 in open-label phase. Each spray delivers 2.7 mg THC + 2.5 mg CBD.","methodology":"Enriched-enrollment, randomized withdrawal design: 4-week single-blind treatment → response assessment (>=20% NRS improvement) → 12-week double-blind randomization of responders to continue Sativex or placebo. Multinational, multiple European sites.","limitations":"Enriched design only tests the drug in responders, not the general MS spasticity population. Single-blind initial phase may introduce expectation bias. Spasticity NRS is patient-reported, not objective. 47.6% initial response rate means the majority did not respond sufficiently."},{"rthcId":"RTHC-08855","title":"Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study","authors":"Lotan I, Treves TA, Roditi Y, Djaldetti R","year":2014,"journal":"Clinical Neuropharmacology","doi":"10.1097/WNF.0000000000000016","pmid":"24614667","tags":["parkinsons","motor-symptoms","tremor","observational","medical-cannabis"],"studyType":"observational","evidenceStrength":"low","keyFinding":"Smoked cannabis produced a 30% improvement in Parkinson's motor symptoms (UPDRS: 33.1 to 23.2) within 30 minutes, with significant improvements in tremor, rigidity, bradykinesia, sleep, and pain.","whyItMatters":"This was one of the first studies to quantify cannabis's motor benefit in Parkinson's using a standardized clinical rating scale, providing objective data for what had previously been only anecdotal reports.","specificNumbers":"UPDRS motor score: 33.1 → 23.2 (p<0.001). Tremor p<0.001, rigidity p=0.004, bradykinesia p<0.001. Assessed 30 minutes post-smoking. N=22.","methodology":"Open-label observational study. 22 PD patients assessed at baseline and 30 minutes after smoking their regular medical cannabis. UPDRS motor examination by trained neurologists. Single assessment point.","limitations":"No control group or blinding. Only 22 patients. Patients were existing medical cannabis users (selection bias). Single time-point assessment. Parkinson's has notoriously strong placebo response. Psychoactive effects make blinding impossible."},{"rthcId":"RTHC-08856","title":"CBD for Alzheimer's (preclinical review)","authors":"Watt & Karl","year":2017,"journal":"","doi":null,"pmid":"28217093","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08857","title":"Nabiximols for MS pain and spasticity (long-term)","authors":"Flachenecker et al.","year":2014,"journal":"","doi":null,"pmid":"24335204","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08858","title":"CBD for ALS (case series)","authors":"Riva et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08859","title":"Neuroprotective effects of CBD in hypoxic-ischemic injury","authors":"Pazos et al.","year":2012,"journal":"","doi":null,"pmid":"22521336","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08860","title":"Cannabis pharmacogenomics: CYP2C9 polymorphisms","authors":"Sachse-Seeboth et al.","year":2009,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08861","title":"Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users.","authors":"Marta Di Forti; Conrad Iyegbe; Hannah Sallis; Anna Kolliakou; M Aurora Falcone; Alessandra Paparelli; Miriam Sirianni; Caterina La Cascia; Simona A Stilo; Tiago Reis Marques; Rowena Handley; Valeria Mondelli; Paola Dazzan; Carmine Pariante; Anthony S David; Craig Morgan; John Powell; Robin M Murray","year":2012,"journal":"Biological psychiatry","doi":"10.1016/j.biopsych.2012.06.020","pmid":"22831980","tags":[],"studyType":"case-control","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08862","title":"Cannabis genome sequencing","authors":"Grassa et al.","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08863","title":"Endocannabinoid system and exercise","authors":"Sparling et al.","year":2003,"journal":"","doi":null,"pmid":"14681395","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08864","title":"Sensitization to cannabis (reverse tolerance)","authors":"Cadoni et al.","year":2001,"journal":"","doi":null,"pmid":"11327256","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08865","title":"EVALI: vitamin E acetate as cause","authors":"Blount et al.","year":2020,"journal":"","doi":null,"pmid":"31860793","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08866","title":"Cannabis vaporization reduces harmful byproducts","authors":"Abrams et al.","year":2007,"journal":"","doi":null,"pmid":"17429350","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08867","title":"Transdermal cannabinoid delivery","authors":"Paudel et al.","year":2010,"journal":"","doi":null,"pmid":"20372994","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08868","title":"Nanoemulsion cannabis formulation","authors":"Nakano et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08869","title":"Endocannabinoid system in skin","authors":"Biro et al.","year":2009,"journal":"","doi":null,"pmid":"19729208","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08870","title":"CBD for acne (sebocyte study)","authors":"Olah et al.","year":2014,"journal":"","doi":null,"pmid":"25061873","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08871","title":"Cannabinoids for dermatological diseases (review)","authors":"Eagleston et al.","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08872","title":"Cannabinoid receptors and bone metabolism","authors":"Idris & Ralston","year":2012,"journal":"","doi":null,"pmid":"22063029","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08873","title":"CBD enhances fracture healing","authors":"Kogan et al.","year":2015,"journal":"","doi":null,"pmid":"25476309","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08874","title":"Marijuana and intraocular pressure","authors":"Hepler & Frank","year":1971,"journal":"","doi":null,"pmid":"5109049","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08875","title":"Cannabis for glaucoma: systematic review","authors":"Tomida et al.","year":2004,"journal":"","doi":null,"pmid":"14711715","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08876","title":"Cannabis and erectile dysfunction","authors":"Shamloul & Bella","year":2011,"journal":"","doi":null,"pmid":"21269399","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08877","title":"Endocannabinoid system and sexual function","authors":"Klein et al.","year":2012,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08878","title":"A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice","authors":"Bilkei-Gorzo A, Albayram O, Draffehn A, Michel K, Piyanova A, Oppenheimer H, Dvir-Ginzberg M, Rácz I, Ulas T, Imbeault S, Bab I, Schultze JL, Zimmer A","year":2017,"journal":"Nature Medicine","doi":"10.1038/nm.4311","pmid":"28481360","tags":[],"studyType":"Animal Study (Preclinical)","evidenceStrength":"Strong (preclinical)","keyFinding":"Chronic low-dose THC (0.002 mg/kg/day for 28 days) restored spatial learning, object recognition, and social memory in aged mice (12 and 18 months) to the level of 2-month-old mice. Hippocampal gene expression profiles in treated old mice resembled those of untreated young mice.","whyItMatters":"This is the most dramatic demonstration that THC effects are context-dependent. The same molecule that impairs young brains may restore old ones, suggesting age-related ECS decline is a treatable condition.","specificNumbers":"","methodology":"Three age groups of mice (2, 12, 18 months) received THC or vehicle via subcutaneous mini-pump for 28 days. Tested on Morris water maze, novel object recognition, and partner recognition. Hippocampal gene expression analyzed via RNA sequencing.","limitations":"Mouse study — human translation uncertain. Extremely low dose (far below recreational use). Long-term effects of chronic low-dose THC in aged organisms unknown. Human clinical trial planned but not completed."},{"rthcId":"RTHC-08879","title":"Endocannabinoid system and aging","authors":"Piyanova et al.","year":2013,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08880","title":"CBD neuroprotection in Parkinson's (human pilot)","authors":"Chagas et al.","year":2014,"journal":"","doi":null,"pmid":"25237116","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08881","title":"Endocannabinoid system and microbiota cross-talk","authors":"Manca et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08882","title":"Endocannabinoid system abnormalities in autism","authors":"Karhson et al.","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08883","title":"CBD in fragile X syndrome (phase 3 RCT — negative)","authors":"Berry-Kravis et al.","year":2022,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08884","title":"THC for Tourette's (6-week RCT)","authors":"Muller-Vahl et al.","year":2003,"journal":"","doi":null,"pmid":"12589380","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08885","title":"Cannabis for Tourette's: 60% tic reduction","authors":"Abi-Jaoude et al.","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08886","title":"ECS role in Tourette syndrome pathology","authors":"Muller-Vahl & Emrich","year":2008,"journal":"","doi":null,"pmid":"18639921","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08887","title":"Cannabis for menstrual pain (historical + modern evidence)","authors":"Russo","year":2002,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08888","title":"CBD for premenstrual syndrome","authors":"Slavin et al.","year":2023,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08889","title":"Medical Marijuana Laws Reduce Prescription Medication Use In Medicare Part D.","authors":"Bradford, Ashley C; Bradford, W David","year":2016,"journal":"Health Affairs, 35(7), 1230-1236","doi":"10.1377/hlthaff.2015.1661","pmid":"27385238","tags":[],"studyType":"Ecological analysis of prescribing data","evidenceStrength":"Moderate-strong (replicated across datasets)","keyFinding":"Medical cannabis laws associated with significant reductions in Medicare Part D prescriptions for opioids, anti-nausea, anti-anxiety, antidepressant, seizure, and sleep medications. Estimated annual savings: $165.2 million (2013). States with dispensaries showed larger reductions.","whyItMatters":"Connected cannabis policy to healthcare economics. Showed that legal cannabis access produces measurable shifts in prescribing patterns — patients substitute cannabis for prescription drugs across multiple categories.","specificNumbers":"","methodology":"Retrospective analysis of Medicare Part D prescription claims data across all states, 2010-2013. Compared prescribing patterns in states with and without medical cannabis laws. Focused on 9 drug categories where cannabis is a plausible alternative.","limitations":"Ecological design. Cannot determine whether prescribing reductions improved patient outcomes. Fewer antidepressant prescriptions may not be positive. Small fraction of total Medicare spending."},{"rthcId":"RTHC-08890","title":"Cannabis legalization and opioid dispensing","authors":"Wen & Hockenberry","year":2018,"journal":"","doi":null,"pmid":"29610827","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08891","title":"Cannabis as opioid substitute (Michigan pain patients)","authors":"Boehnke et al.","year":2016,"journal":"","doi":null,"pmid":"27001005","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08892","title":"Cannabinoid-opioid interaction in chronic pain.","authors":"Abrams, Donald I; Couey, Paul; Shade, Starley B; Kelly, Mary Ellen; Benowitz, Neal L","year":2011,"journal":"Clinical Pharmacology & Therapeutics, 90(6), 844-851","doi":"10.1038/clpt.2011.188","pmid":"22048225","tags":[],"studyType":"Controlled clinical study","evidenceStrength":"Moderate (small, open-label)","keyFinding":"27% average pain reduction after adding vaporized cannabis to opioids. Plasma opioid levels (morphine and oxycodone) unchanged — pharmacodynamic synergy, not pharmacokinetic interaction.","whyItMatters":"Provides pharmacological rationale for cannabis as an opioid-sparing adjunct. If cannabis allows adequate pain control at lower opioid doses, it could reduce tolerance, side effects, and overdose risk.","specificNumbers":"","methodology":"5-day inpatient study at SFGH. 21 chronic pain patients on stable opioids. Vaporized cannabis sessions on days 1-5. Blood drawn for opioid plasma levels. Pain assessed on validated scales. PK curves compared before and after cannabis.","limitations":"Small sample (21). Open-label (no placebo cannabis). Short (5 days). Some benefit may be psychoactive rather than pharmacodynamic. Cannabis adds its own dependence risk."},{"rthcId":"RTHC-08893","title":"CBD for opioid withdrawal","authors":"Hurd et al.","year":2015,"journal":"","doi":null,"pmid":"26105338","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08894","title":"Cannabis legalization and opioid-related ER visits","authors":"Shi","year":2017,"journal":"","doi":null,"pmid":"28826172","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08895","title":"Endocannabinoid-opioid system cross-talk","authors":"Scavone et al.","year":2013,"journal":"","doi":null,"pmid":"23488456","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08896","title":"The War on Marijuana in Black and White / A Tale of Two Countries: Racially Targeted Arrests in the Era of Marijuana Reform","authors":"Edwards, Ezekiel; Bunting, Will; Garcia, Lynda (2013); Edwards, Ezekiel; Greytak, Emily; Madubuonwu, Brooke; Sanchez, Thania; et al. (2020)","year":2020,"journal":"ACLU Research Reports (2013, 2020)","doi":null,"pmid":null,"tags":["policy","racial-justice","enforcement","social-equity"],"studyType":"policy-analysis","evidenceStrength":"strong","keyFinding":"Black Americans arrested for marijuana at 3.73x the rate of white Americans (2013 report, 2001-2010 data) and 3.64x (2020 report, 2010-2018 data), despite roughly equal usage rates across racial groups. Disparities present in every state and 96%+ of counties, including states with legalization.","whyItMatters":"These reports are the empirical foundation for the racial equity arguments driving cannabis policy reform. They demonstrated that prohibition enforcement was systematically racially biased regardless of actual drug use patterns, and that reform measures (decriminalization, legalization) have failed to eliminate the disparity.","specificNumbers":"","methodology":"Analysis of FBI Uniform Crime Reporting (UCR) data on marijuana arrests, cross-referenced with US Census population data and NSDUH drug use prevalence data. National, state, and county-level analyses. The 2013 report covered arrests from 2001-2010; the 2020 report updated through 2018.","limitations":"Based on FBI UCR data, which relies on voluntary reporting by law enforcement agencies and does not capture all arrests. NSDUH usage rates rely on self-report and may not perfectly capture true prevalence differences. The ACLU is an advocacy organization, though the underlying data is official government statistics. Cannot distinguish between disparate impact (more police in Black neighborhoods) and disparate treatment (racial profiling during encounters). Does not account for differences in public vs private use patterns, quantity possessed, or circumstances of arrest."},{"rthcId":"RTHC-08897","title":"War on drugs and Black communities","authors":"Provine","year":2011,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08898","title":"Incarceration costs of marijuana prohibition","authors":"Miron & Waldock","year":2010,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08899","title":"Drug scheduling and racial bias (historical)","authors":"Hinton","year":2016,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08900","title":"The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study.","authors":"Jetly, Rakesh; Heber, Alexandra; Fraser, George; Boisvert, Denis","year":2015,"journal":"Psychoneuroendocrinology, 51, 585-588","doi":"10.1016/j.psyneuen.2014.11.002","pmid":"25467221","tags":["ptsd","sleep","nightmares","synthetic-cannabinoid","military"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CAPS Recurring Dream scores: nabilone -3.6 (±2.4) vs placebo -1.0 (±2.1), p=0.03. CGI-C: nabilone 1.9 (much improved) vs placebo 3.2 (minimally improved), p=0.05. 50% much improved on nabilone vs 11% on placebo. General wellbeing: +20.8 vs -0.4, p=0.04. No severe adverse events.","whyItMatters":"This was the first double-blind placebo-controlled RCT of a cannabinoid for PTSD nightmares in military personnel. Despite the tiny sample, all three outcomes reached significance. The Canadian Armed Forces subsequently adopted nabilone for PTSD nightmares — one of the first military organizations to incorporate cannabinoids into mental health treatment.","specificNumbers":"","methodology":"Randomized, double-blind, placebo-controlled crossover trial. 10 male Canadian military personnel with PTSD and treatment-resistant nightmares. Nabilone started at 0.5 mg, titrated to max 3.0 mg. 7-week treatment periods with 2-week washout. Assessed with CAPS dream subscale, CGI-C, and General Well Being Questionnaire. Registered with Health Canada.","limitations":"Only 10 subjects. All male military personnel — cannot generalize to female veterans, civilian PTSD, or sexual trauma. Short duration (7 weeks per period). No comparison to prazosin. No data on long-term dependence or REM rebound. Nabilone is synthetic — unclear generalizability to plant cannabis. No large-scale replication."},{"rthcId":"RTHC-08901","title":"VA policy on cannabis for veterans","authors":"U.S. Dept of VA","year":2022,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08902","title":"CBD for PTSD (case series, 11 patients)","authors":"Elms et al.","year":2019,"journal":"","doi":null,"pmid":"30543451","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08903","title":"Cannabis detection windows in urine","authors":"Huestis & Cone","year":1998,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08904","title":"Workplace drug testing and cannabis legalization","authors":"Pirzada et al.","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08905","title":"Hair testing for cannabis: false positives from secondhand exposure","authors":"Moosmann et al.","year":2015,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08906","title":"THC in oral fluid: detection and interpretation","authors":"Desrosiers et al.","year":2014,"journal":"","doi":null,"pmid":"24451085","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08907","title":"Impaired vs detectable: the problem with THC cutoffs","authors":"Hartman & Huestis","year":2013,"journal":"","doi":null,"pmid":"23034608","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08908","title":"Cannabis use and employment outcomes (panel data)","authors":"Van Ours & Williams","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08909","title":"Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs","authors":"Gamble LJ, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L, Brown H, Berthelsen ES, Wakshlag JJ","year":2018,"journal":"Frontiers in Veterinary Science, 5","doi":"10.3389/fvets.2018.00165","pmid":"30083539","tags":["cbd","medical-cannabis","pain"],"studyType":"randomized-controlled-trial","evidenceStrength":"moderate","keyFinding":"CBD oil at 2 mg/kg twice daily significantly reduced pain (CBPI score 21→14, p<0.01) and increased activity (Hudson score 54→67, p<0.01) in dogs with osteoarthritis. Veterinary assessment confirmed improvement (p=0.02). ALP liver enzyme elevated in 9/16 dogs.","whyItMatters":"Dogs can't experience placebo effects, making this unusually clean evidence for CBD's analgesic properties. In a billion-dollar pet CBD market operating on anecdotes, this was the first controlled trial from a respected veterinary institution providing evidence-based dosing and safety data.","specificNumbers":"16 dogs completed trial. Pain score: 21→14 (p<0.01). Activity: 54→67 (p<0.01). Vet assessment: p=0.02. Half-life: 4.2 hours. Dose: 2 mg/kg q12h. ALP: 160→323 U/L (p<0.01). 9/16 dogs showed ALP elevation.","methodology":"Randomized, double-blind, placebo-controlled crossover trial. 22 dogs enrolled, 16 completed. CBD oil (2 mg/kg) vs placebo every 12 hours for 4 weeks per arm with 2-week washout. Triple measurement: Canine Brief Pain Inventory, Hudson Activity Scale, veterinary pain assessment.","limitations":"Small sample (16 dogs). Short duration (4 weeks). Single dose tested. ALP elevation needs long-term follow-up. Industrial hemp extract (not pure CBD) — other cannabinoids/terpenes may contribute. Breeds and sizes varied."},{"rthcId":"RTHC-08910","title":"Pharmacokinetics of CBD in dogs","authors":"Bartner et al.","year":2018,"journal":"","doi":null,"pmid":"30026641","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08911","title":"CBD for epilepsy in dogs","authors":"McGrath et al.","year":2019,"journal":"","doi":null,"pmid":"31067185","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08912","title":"Cannabis topicals: transdermal delivery review","authors":"Bruni et al.","year":2018,"journal":"","doi":null,"pmid":"30400600","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08913","title":"Sublingual THC/CBD: onset and duration","authors":"Guy & Flint","year":2004,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08914","title":"Water pipe (bong) filtration and smoke composition","authors":"Gieringer","year":1996,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08915","title":"Cannabis concentrate safety and potency","authors":"Raber et al.","year":2015,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08916","title":"Cannabis microdosing and the sensitization protocol: clinical dosing framework","authors":"Sulak, Dustin","year":2019,"journal":"Clinical practice / Handbook of Cannabis for Clinicians (W.W. Norton)","doi":null,"pmid":null,"tags":["microdosing","dosing","sensitization","tolerance","biphasic","minimum-effective-dose"],"studyType":"Clinical practice framework / Expert review","evidenceStrength":"Expert Opinion + Clinical Practice (A-tier)","keyFinding":"The minimum effective dose for therapeutic cannabis is typically 1-5mg THC — far below recreational norms. A 6-day sensitization protocol (48-hour fast + dose titration) can reduce cannabis consumption by up to 60% while maintaining or improving therapeutic benefit.","whyItMatters":"This framework challenged the recreational cannabis culture's assumption that more is better and gave medical patients and clinicians a practical, evidence-informed protocol for finding the lowest effective dose. The sensitization protocol has been adopted by medical cannabis practices worldwide.","specificNumbers":"","methodology":"Clinical practice framework based on observation of 18,000+ medical cannabis patients at Integr8 Health, Maine. Supported by the biphasic dose-response literature (Crippa 2009, Childs 2017) and endocannabinoid receptor pharmacology (D'Souza 2016, Hirvonen 2012).","limitations":"This is clinical practice experience, not a randomized controlled trial. The sensitization protocol has not been tested in a blinded, controlled study. Patient self-reports of dose reduction and symptom improvement may be subject to placebo and expectation effects. The framework is based primarily on one clinician's extensive practice."},{"rthcId":"RTHC-08917","title":"Lower-Risk Cannabis Use Guidelines: A Comprehensive Update of Evidence and Recommendations.","authors":"Benedikt Fischer; Cayley Russell; Pamela Sabioni; Wim van den Brink; Bernard Le Foll; Wayne Hall; Jürgen Rehm; Robin Room","year":2017,"journal":"American journal of public health","doi":"10.2105/AJPH.2017.303818","pmid":"28644037","tags":[],"studyType":"review","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08918","title":"Lower-risk cannabis use guidelines","authors":"Fischer et al.","year":2011,"journal":"","doi":null,"pmid":"21680929","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08919","title":"Cannabis potency and user titration","authors":"van der Pol et al.","year":2014,"journal":"","doi":null,"pmid":"24996233","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08920","title":"Deep inhalation techniques and lung exposure","authors":"Tashkin et al.","year":1991,"journal":"","doi":null,"pmid":"2024831","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08921","title":"Cannabis product labeling accuracy","authors":"Vandrey et al.","year":2015,"journal":"","doi":null,"pmid":"26502112","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08922","title":"Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects.","authors":"Laura M Dryburgh; Nanthi S Bolan; Christopher P L Grof; Peter Galettis; Jennifer Schneider; Catherine J Lucas; Jennifer H Martin","year":2018,"journal":"British journal of clinical pharmacology","doi":"10.1111/bcp.13695","pmid":"29953631","tags":[],"studyType":"systematic-review","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08923","title":"Cannabis in sport: WADA position and evidence","authors":"Huestis et al.","year":2011,"journal":"","doi":null,"pmid":"21990528","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08924","title":"Cannabis and pain management in athletes","authors":"Docter et al.","year":2020,"journal":"","doi":null,"pmid":"32889878","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08925","title":"NFL players and cannabis use for pain","authors":"Cottler et al.","year":2011,"journal":"","doi":null,"pmid":"21109365","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08926","title":"Synthetic cannabinoid toxicity (Spice/K2)","authors":"Trecki et al.","year":2014,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08927","title":"K2/Spice epidemic and public health","authors":"Tait et al.","year":2016,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08928","title":"Synthetic cannabinoid-related deaths","authors":"Shanks et al.","year":2016,"journal":"","doi":null,"pmid":"26755544","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08929","title":"NPS (novel psychoactive substances) containing synthetic cannabinoids","authors":"EMCDDA","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08930","title":"FAAH inhibitor for anxiety (human fMRI)","authors":"Mayo et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08931","title":"Endocannabinoids and stress resilience","authors":"Hill et al.","year":2010,"journal":"","doi":null,"pmid":"20072116","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08932","title":"ECS and reward/motivation","authors":"Parsons & Hurd","year":2015,"journal":"","doi":null,"pmid":"25907459","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08933","title":"Endocannabinoid tone and mood regulation","authors":"Hill & Patel","year":2013,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08934","title":"CB1 receptors and synaptic plasticity","authors":"Chevaleyre et al.","year":2006,"journal":"","doi":null,"pmid":"16481042","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08935","title":"Endocannabinoids and circadian rhythms","authors":"Prospero-Garcia et al.","year":2016,"journal":"","doi":null,"pmid":"27013343","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08936","title":"ECS and thermoregulation","authors":"Rawls et al.","year":2002,"journal":"","doi":null,"pmid":"12096073","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08937","title":"Labeling Accuracy of Cannabidiol Extracts Sold Online.","authors":"Marcel O Bonn-Miller; Mallory J E Loflin; Brian F Thomas; Jahan P Marcu; Travis Hyke; Ryan Vandrey","year":2017,"journal":"JAMA","doi":"10.1001/jama.2017.11909","pmid":"29114823","tags":[],"studyType":"observational","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08938","title":"Heavy metals in cannabis","authors":"Gauvin et al.","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08939","title":"Microbiological contamination of cannabis","authors":"McKernan et al.","year":2016,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08940","title":"Pesticide residues in legal cannabis","authors":"Sullivan et al.","year":2013,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08941","title":"Cannabis standardization and quality control","authors":"Hazekamp","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08942","title":"Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population.","authors":"Rhyne, Danielle N; Anderson, Sarah L; Gedde, Margaret; Borgelt, Laura M","year":2016,"journal":"Pharmacotherapy, 36(5), 505-510","doi":"10.1002/phar.1673","pmid":"26749285","tags":[],"studyType":"Retrospective chart review","evidenceStrength":"Moderate (observational, no control group)","keyFinding":"Migraine frequency decreased from 10.4 to 4.6 headaches per month (p < 0.0001) with medical cannabis. 85% reported decreased frequency. 12% achieved complete migraine resolution.","whyItMatters":"First study documenting migraine frequency outcomes in patients using medical cannabis. Consistent with endocannabinoid deficiency hypothesis and historical use of cannabis for headache. Highlights the enormous evidence gap — no RCT exists.","specificNumbers":"","methodology":"Retrospective chart review of 121 adults with primary migraine diagnosis recommended medical marijuana at two Colorado specialty clinics between 2010-2014. Migraine frequency documented before and after cannabis initiation.","limitations":"Retrospective design, no placebo group, no randomization, no blinding. Self-selected patients. Regression to the mean. No standardized cannabis products. Only 121 patients at two clinics. High placebo response expected in migraine populations."},{"rthcId":"RTHC-08943","title":"Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis.","authors":"Hammell, D C; Zhang, L P; Ma, F; Abshire, S M; McIlwrath, S L; Stinchcomb, A L; Westlund, K N","year":2016,"journal":"European Journal of Pain, 20(6), 936-948","doi":"10.1002/ejp.818","pmid":"26517407","tags":[],"studyType":"Preclinical (animal)","evidenceStrength":"Strong preclinical; no human evidence","keyFinding":"Transdermal CBD at 6.2 and 62.3 mg/day significantly reduced joint circumference, synovial membrane thickening (>50%), immune cell infiltration, pain behaviors, and neural inflammation markers (CGRP, OX42, TNFα) in a dose-dependent manner without CNS side effects.","whyItMatters":"First rigorous preclinical evidence that topical CBD can penetrate skin, reach joint tissue, and produce anti-inflammatory and analgesic effects — grounding a multi-billion-dollar consumer market that previously ran on testimonials.","specificNumbers":"","methodology":"Complete Freund adjuvant-induced monoarthritis in Sprague-Dawley rats. CBD gel applied topically at 4 dose levels (0.6, 3.1, 6.2, 62.3 mg/day) for 4 days. Outcomes: joint circumference, histology, pain behaviors (paw withdrawal latency, limb posture), spinal/DRG inflammatory markers, exploratory behavior.","limitations":"Animal model only — rat skin is thinner than human skin. Arthritis was artificially induced. Short duration (4 days). No comparison to existing arthritis treatments. Commercial CBD products differ substantially from research formulations. No human data."},{"rthcId":"RTHC-08944","title":"Endocannabinoid deficiency and migraine","authors":"Russo","year":2016,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08945","title":"Cannabis for phantom limb pain","authors":"Schley et al.","year":2006,"journal":"","doi":null,"pmid":"16404629","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08946","title":"Cannabinoid-induced analgesia: mechanism beyond CB1","authors":"Hohmann et al.","year":2005,"journal":"","doi":null,"pmid":"15674395","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08947","title":"Cannabis for chronic non-cancer pain (Canadian cohort)","authors":"Ware et al.","year":2015,"journal":"","doi":null,"pmid":"25599233","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08948","title":"Palliative cannabis: systematic review","authors":"Mücke et al.","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08949","title":"A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma","authors":"Twelves, Chris; Sabel, Michael; Checketts, Daniel; Miller, Sharon; Tayo, Bola; Jove, Maria; Brazil, Lucy; Short, Susan C","year":2021,"journal":"British Journal of Cancer, 124(8), 1379-1387","doi":"10.1038/s41416-021-01259-3","pmid":"33623076","tags":["cancer","clinical-trial","medical-cannabis"],"studyType":"rct","evidenceStrength":"moderate","keyFinding":"One-year survival was 83% for nabiximols-treated patients versus 44% for placebo (p=0.042). PFS at 6 months was 33% in both groups. Nabiximols had acceptable safety and tolerability with no drug-drug interactions with temozolomide. The most common adverse events were vomiting, dizziness, fatigue, nausea, and headache.","whyItMatters":"This was the first randomized, placebo-controlled trial testing cannabinoids as an anticancer add-on — not just for symptom relief, but with survival as the outcome measure. It bridged 20 years of preclinical research (beginning with Guzman 2000) and the clinical question: can pharmaceutical-grade cannabinoids actually help people with brain cancer live longer? The survival difference was large enough to justify the ARISTOCRAT Phase II trial (230+ patients, actively recruiting), which could provide the definitive answer.","specificNumbers":"","methodology":"Phase 1b trial with two parts. Part 1: open-label dose escalation (n=6). Part 2: randomized, double-blind, placebo-controlled (n=12 nabiximols, n=9 placebo). All patients received dose-intense temozolomide. Nabiximols (Sativex): oromucosal spray delivering THC:CBD 1:1 (2.7mg THC + 2.5mg CBD per spray), up to 12 sprays/day, individualized dose escalation.","limitations":"Very small sample size (21 randomized patients). Phase 1b design — primarily a safety study, not powered for efficacy. Glioblastoma has highly variable outcomes; 21 patients cannot account for this variability. PFS at 6 months was identical between groups (33%), raising questions about the survival mechanism. The p=0.042 is nominally significant but would not survive multiple testing correction."},{"rthcId":"RTHC-08950","title":"CBD slows breast cancer metastasis","authors":"McAllister et al.","year":2007,"journal":"","doi":null,"pmid":"17237907","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08951","title":"Cannabinoids and pancreatic cancer","authors":"Michalski et al.","year":2008,"journal":"","doi":null,"pmid":"17955310","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08952","title":"Cannabis use and cancer survival (population study)","authors":"Taha et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08953","title":"Cannabis rescheduling to Schedule III implications","authors":"Hudak","year":2023,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08954","title":"Home growing provisions and diversion risk","authors":"Pacula et al.","year":2014,"journal":"","doi":null,"pmid":"24406226","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08955","title":"Youth perception of cannabis risk post-legalization","authors":"Sarvet et al.","year":2018,"journal":"","doi":null,"pmid":"29674252","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08956","title":"Cannabis tourism impact on host cities","authors":"Mead","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08957","title":"Indigenous cannabis sovereignty","authors":"Sacco & Batal","year":2022,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08958","title":"Beta-caryophyllene anti-inflammatory via CB2","authors":"Gertsch et al.","year":2008,"journal":"","doi":null,"pmid":"18574142","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08959","title":"Myrcene sedative effects in mice","authors":"Rao et al.","year":1990,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08960","title":"Limonene anti-anxiety and anticancer effects","authors":"Vieira et al.","year":2018,"journal":"","doi":null,"pmid":"29427589","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08961","title":"Alpha-pinene bronchodilator and anti-inflammatory","authors":"Gil et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08962","title":"Linalool anxiolytic and neuroprotective","authors":"Guzmán-Gutiérrez et al.","year":2015,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08963","title":"Humulene anti-inflammatory and appetite suppressant","authors":"Yeo et al.","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08964","title":"THC reduces REM sleep and dreaming","authors":"Pivik et al.","year":1972,"journal":"","doi":null,"pmid":"4340789","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08965","title":"CBD anxiolytic effect benefits sleep indirectly","authors":"Linares et al.","year":2019,"journal":"","doi":null,"pmid":"30328956","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08966","title":"Nabilone for PTSD nightmares and sleep","authors":"Cameron et al.","year":2014,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08967","title":"Amygdala and cannabis anxiety (fMRI)","authors":"Phan et al.","year":2008,"journal":"","doi":null,"pmid":"17712344","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08968","title":"Brain recovery after sustained cannabis abstinence","authors":"Hirvonen et al.","year":2012,"journal":"","doi":null,"pmid":"21200391","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08969","title":"THC and COVID-19 inflammation (preclinical)","authors":"Mohammed et al.","year":2020,"journal":"","doi":null,"pmid":"32754917","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08970","title":"Cannabis and HIV viral suppression","authors":"Milloy et al.","year":2015,"journal":"","doi":null,"pmid":"24748235","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08971","title":"Marijuana intoxication: Common experiences","authors":"Tart CT","year":1970,"journal":"Nature, 226(5247)","doi":"10.1038/226701a0","pmid":"5443246","tags":["thc","perception","music","subjective-experience"],"studyType":"survey","evidenceStrength":"preliminary","keyFinding":"70% of experienced cannabis users reported enhanced sensitivity to subtle sound qualities 'very often' or 'usually.' Users consistently described music as purer, more distinct, with enhanced rhythm perception and greater emotional depth.","whyItMatters":"This was the first systematic scientific study of cannabis subjective effects, published in Nature. It established that the widely reported enhancement of music perception was empirically real, consistent across users, and amenable to scientific study — legitimizing the phenomenological investigation of altered states.","specificNumbers":"150 experienced users surveyed. 220-item questionnaire. 70% reported enhanced sound sensitivity very often/usually. Three distinct auditory effects identified: enhanced sensitivity, improved auditory stream segregation, heightened emotional response.","methodology":"Retrospective self-report questionnaire administered to 150 experienced marijuana users. Participants rated frequency of 220 specific effects across multiple intoxication levels.","limitations":"Retrospective self-report (not real-time measurement). No placebo control. Self-selected experienced users (not representative of all cannabis users). No objective auditory testing."},{"rthcId":"RTHC-08972","title":"The origins of cannabis smoking: Chemical residue evidence from the first millennium BCE in the Pamirs.","authors":"Ren, Meng; Tang, Zihua; Wu, Xinhua; Spengler, Robert; Jiang, Hongen; Yang, Yimin; Boivin, Nicole","year":2019,"journal":"Science Advances, 5(6), eaaw1391","doi":"10.1126/sciadv.aaw1391","pmid":"31206023","tags":["archaeology","history","Silk-Road"],"studyType":"archaeological chemical analysis","evidenceStrength":"strong","keyFinding":"GC-MS analysis of 2,500-year-old funeral braziers revealed high-THC cannabis residues — the earliest chemical evidence of cannabis smoking for psychoactive purposes.","whyItMatters":"Establishes that deliberate psychoactive cannabis use dates back at least 2,500 years along the ancient Silk Road.","specificNumbers":"10 brazier fragments and 4 stones analyzed. CBN detected in 9/10 brazier interiors. Cemetery at 3,060-3,080m. Date: ~500 BCE.","methodology":"GC-MS of organic residues from archaeological wooden braziers and heated stones from burial contexts at Jirzankal Cemetery, Pamir Mountains, western China.","limitations":"Cannot determine exact original THC concentration. Cannot distinguish deliberate cultivation from harvesting naturally potent high-altitude plants."},{"rthcId":"RTHC-08973","title":"Cannabis genome and cannabinoid biosynthesis","authors":"van Bakel et al.","year":2011,"journal":"","doi":null,"pmid":"22014239","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08974","title":"Indica vs sativa: myth or reality?","authors":"Piomelli, Daniele; Russo, Ethan B","year":2016,"journal":"Cannabis and Cannabinoid Research","doi":"10.1089/can.2015.29003.ebr","pmid":"28861479","tags":["indica-sativa","taxonomy","chemotype","terpenes","classification","plant-science"],"studyType":"Interview/Commentary","evidenceStrength":"Expert Opinion (S-tier landmark)","keyFinding":"The sativa/indica distinction as commonly applied in lay literature is \"total nonsense and an exercise in futility.\" Cannabis effects are determined by cannabinoid and terpenoid profiles, not botanical classification.","whyItMatters":"This interview gave scientific authority to a claim that threatened the entire dispensary classification system. By publishing it in the inaugural issue of a new peer-reviewed journal, the editors signaled that dismantling the indica/sativa myth was foundational to credible cannabis science.","specificNumbers":"","methodology":"Expert interview/commentary. Piomelli (Editor-in-Chief) interviews Russo, drawing on decades of clinical and research experience with cannabinoid pharmacology, GW Pharmaceuticals clinical trials, and ethnobotanical research.","limitations":"This is an interview/commentary, not an original experimental study. While Russo draws on extensive experience and published literature, the piece itself does not present new data. The claims made have since been supported by multiple genetic and metabolomic studies."},{"rthcId":"RTHC-08975","title":"Evolutionary origins of the endocannabinoid system.","authors":"McPartland, John M; Matias, Isabel; Di Marzo, Vincenzo; Glass, Michelle","year":2006,"journal":"Gene, 370, 64-74","doi":"10.1016/j.gene.2005.11.004","pmid":"16434153","tags":["endocannabinoid-system","genetics","neuroscience"],"studyType":"basic-research","evidenceStrength":"moderate","keyFinding":"By searching for endocannabinoid system genes across twelve species spanning the tree of life, McPartland and colleagues traced the evolutionary origins of every major ECS component. Key findings: CB1 receptor genes are present in sea squirts (Ciona) — invertebrates that diverged from vertebrates over 500 million years ago. FAAH (the enzyme that degrades anandamide) has orthologs in the roundworm C. elegans and even the slime mold Dictyostelium, suggesting endocannabinoid-like signaling predates the evolution of nervous systems. Some components are more recent: CB2 and TRPV1 appear limited to vertebrates and mammals respectively. The system didn't appear all at once — it was assembled piece by piece across hundreds of millions of years of evolution.","whyItMatters":"A biological system conserved for 500+ million years is not optional. This study proved that the endocannabinoid system isn't an evolutionary curiosity or a recent addition — it's among the most ancient regulatory systems in animal biology, as old as the serotonin system and older than the opioid system. Its deep conservation explains why disrupting it (through chronic cannabis use or receptor blockade) has such widespread consequences.","specificNumbers":"12 species analyzed across the tree of life\nCB1 orthologs found in Ciona intestinalis (sea squirt) — 500+ million years of conservation\nFAAH orthologs found in C. elegans and Dictyostelium — possibly 600+ million years old\nCB2 limited to vertebrates (~450 million years)\nTRPV1 limited to mammals (~200 million years)\nGPR55 limited to mammals","methodology":"Comparative genomics study using BLAST searches, phylogenetic analysis, and protein pattern profilers to identify functional orthologs of human endocannabinoid system genes across 12 species: human, mouse, pufferfish, zebrafish, sea squirt, fruit fly, roundworm, sea urchin, leech, hydra, slime mold, and yeast.","limitations":"Absence of a gene ortholog in a species doesn't prove absence of the function — analogous systems may exist using different genes. Genomic databases in 2006 were less complete than today, especially for invertebrates. Functional validation (confirming the identified genes actually perform endocannabinoid-related functions) was not performed for most species."},{"rthcId":"RTHC-08976","title":"Placebo effects in cannabis trials","authors":"Ortiz de Guinea et al.","year":2022,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08977","title":"Cannabis tourism: Amsterdam coffee shop model","authors":"Wouters et al.","year":2012,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08978","title":"Cannabis normalization theory","authors":"Hathaway","year":2004,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08979","title":"The endocannabinoid system and the brain.","authors":"Mechoulam, Raphael; Parker, Linda A","year":2013,"journal":"Annual review of psychology, 64, 21-47","doi":"10.1146/annurev-psych-113011-143739","pmid":"22804774","tags":["neuroscience","endocannabinoid-system","review"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Mechoulam and Parker systematically reviewed how the endocannabinoid system regulates brain function across seven major domains: anxiety, depression, neurogenesis, reward, cognition, learning, and memory. A critical finding was that endocannabinoid effects are consistently biphasic — low doses of cannabinoids reduce anxiety, enhance reward, and facilitate certain forms of memory, while high doses produce the opposite effects. The review established that the ECS is not a simple on/off system but a precision regulatory network where dose, timing, and context determine whether the outcome is therapeutic or harmful.","whyItMatters":"This was the founder of the field writing for an audience of psychologists — translating five decades of cannabinoid pharmacology into its implications for understanding the human mind. Published in the Annual Review of Psychology, it represented the definitive statement that the ECS is fundamentally a brain system, governing the psychological functions that most directly shape human experience.","specificNumbers":"CB1 receptors: most abundant GPCR in the human brain\nAnandamide: first endocannabinoid, partial CB1 agonist\n2-AG: second endocannabinoid, 170x more abundant than anandamide, full CB1 agonist\nBiphasic dose response: low-dose anxiolytic → high-dose anxiogenic\n26 pages covering 7 brain function domains","methodology":"Comprehensive narrative review published in the Annual Review of Psychology. Synthesizes preclinical and clinical evidence across multiple domains of brain function, authored by the discoverer of THC and anandamide.","limitations":"A narrative review, not a systematic review or meta-analysis. Reflects the authors' expert synthesis rather than a standardized evidence assessment. Published in 2013 — significant developments in clinical cannabinoid research (especially the Epidiolex trials and cannabis-psychosis epidemiology) occurred after publication."},{"rthcId":"RTHC-08980","title":"Cannabis doesn't affect kidney function in healthy people","authors":"Hsu et al.","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08981","title":"Cannabis associated with lower fatty liver disease","authors":"Adejumo et al.","year":2017,"journal":"","doi":null,"pmid":"28441459","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08982","title":"CBD hepatotoxicity in mice (FDA concern)","authors":"Ewing et al.","year":2019,"journal":"","doi":null,"pmid":"31096630","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08983","title":"Cannabis for dialysis pain (RCT)","authors":"Maor et al.","year":2023,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08984","title":"ECS in diabetic nephropathy","authors":"Barutta et al.","year":2011,"journal":"","doi":null,"pmid":"21617186","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08985","title":"Cannabis use and pancreatitis risk","authors":"Barkin et al.","year":2017,"journal":"","doi":null,"pmid":"28110096","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08986","title":"Epidiolex hepatotoxicity monitoring","authors":"Devinsky et al.","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08987","title":"Cannabis and non-alcoholic steatohepatitis","authors":"Dibba et al.","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08988","title":"CBD and drug-induced liver injury risk","authors":"Lo et al.","year":2023,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08989","title":"CBD for temporomandibular disorder pain","authors":"Nitecka-Buchta et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08990","title":"Topical CBD for peripheral neuropathy","authors":"Xu et al.","year":2020,"journal":"","doi":null,"pmid":"31793418","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08991","title":"Endocannabinoid levels in chronic pain patients","authors":"Koltyn et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08992","title":"CBD oil vs placebo for chronic pain (large RCT)","authors":"Bebee et al.","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08993","title":"Cannabis and central sensitization","authors":"Aviram & Samuelly-Leichtag","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08994","title":"Inhaled cannabis for acute pain (dose-response)","authors":"Wallace et al.","year":2015,"journal":"","doi":null,"pmid":"26389554","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08995","title":"Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial","authors":"McGuire, Philip; Robson, Philip; Cubala, Wieslaw Jerzy; Vasile, Daniel; Morrison, Paul Dugald; Barron, Rachel; Taylor, Adam; Wright, Stephen","year":2018,"journal":"American Journal of Psychiatry, 175(3), 225-231","doi":"10.1176/appi.ajp.2017.17030325","pmid":"29241357","tags":["psychosis","cbd","clinical-trial"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"In 88 patients with schizophrenia already on antipsychotics, adding 1000 mg/day CBD for 6 weeks significantly reduced positive psychotic symptoms (PANSS positive difference: -1.4, p=0.019) and increased clinician-rated improvement (OR 3.65, p=0.017) versus placebo. CBD was well-tolerated with no weight gain, sedation, or metabolic effects.","whyItMatters":"The largest RCT of CBD for psychosis confirmed that CBD has antipsychotic properties through a mechanism completely different from all existing drugs — raising endocannabinoid levels rather than blocking dopamine. The near-zero side effect burden addresses the central problem in schizophrenia treatment: patients stop their medications because the side effects are intolerable.","specificNumbers":"- 88 patients randomized (CBD 43, placebo 45)\n- CBD dose: 1000 mg/day (500mg BID) for 6 weeks\n- PANSS positive improvement: CBD -3.2 (SD 2.60) vs placebo -1.7 (SD 2.76)\n- Treatment difference: -1.4 (95% CI: -2.5 to -0.2; p=0.019)\n- CGI-I: OR 3.65 (95% CI: 1.38-9.69; p=0.017)\n- Cognition (BACS): difference 1.31 (95% CI: -0.10, 2.72) — trend only\n- Functioning (GAF): difference 3.0 (95% CI: -0.4, 6.4) — trend only","methodology":"Double-blind, parallel-group, placebo-controlled, multicenter RCT. Patients with schizophrenia on stable antipsychotic medication randomized 1:1 to CBD 1000 mg/day or placebo for 6 weeks. Primary outcome: PANSS positive subscale. Secondary: PANSS total, CGI-I, CGI-S, BACS, GAF.","limitations":"Industry-funded (GW Pharmaceuticals). Moderate effect size. Short duration (6 weeks) — no long-term data. CBD tested only as adjunct, not monotherapy. High dose (1000 mg/day) is expensive. Sample size adequate for primary endpoint but underpowered for secondary outcomes."},{"rthcId":"RTHC-08996","title":"Cannabis-induced depersonalization/derealization","authors":"Lev-Ran et al.","year":2014,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08997","title":"Testing the Amotivational Syndrome: Marijuana Use Longitudinally Predicts Lower Self-Efficacy Even After Controlling for Demographics, Personality, and Alcohol and Cigarette Use.","authors":"Lac, Andrew; Luk, Jeremy W","year":2018,"journal":"Preventive science, 19(2), 117-126","doi":"10.1007/s11121-017-0811-3","pmid":"28620722","tags":[],"studyType":"longitudinal-cohort","evidenceStrength":"moderate","keyFinding":"Marijuana use longitudinally predicted lower self-efficacy (initiative β=-0.08, persistence β=-0.09, both p<.05) one month later, controlling for demographics, Big Five personality, alcohol, tobacco, and baseline self-efficacy. Cross-lagged models confirmed directionality: cannabis → reduced motivation, not reverse.","whyItMatters":"One of the few longitudinal tests of the amotivational syndrome hypothesis. The temporal design and extensive controls address the key criticism of cross-sectional research — that unmotivated people simply use more cannabis. The cross-lagged analysis showing one-directional prediction (cannabis→amotivation) is particularly valuable.","specificNumbers":"","methodology":"Two-wave longitudinal study of 505 undergraduate students (69.9% female, mean age 19.06). Assessments one month apart. Hierarchical regression and cross-lagged panel modeling controlling for 13 covariates. Measures: ESPAD cannabis use, Big Five Inventory, General Self-Efficacy Scale (initiative, effort, persistence subscales).","limitations":"Self-report measures only. College student sample limits generalizability. One-month follow-up is short. Cannabis use treated as binary (used/not used) rather than dose-response. General self-efficacy is a broad construct. Small effect sizes (β around 0.08-0.09)."},{"rthcId":"RTHC-08998","title":"Cannabis use and academic performance","authors":"Arria et al.","year":2015,"journal":"","doi":null,"pmid":"25700286","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-08999","title":"Cannabis and eating disorders","authors":"Scherma et al.","year":2014,"journal":"","doi":null,"pmid":"25086114","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09000","title":"Dronabinol for anorexia nervosa","authors":"Andries et al.","year":2015,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09001","title":"Cannabis and OCD","authors":"Kayser et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09002","title":"Cannabis and aggression/violence","authors":"Schoeler et al.","year":2016,"journal":"","doi":null,"pmid":"26753841","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09003","title":"CBD safety in pediatric epilepsy (long-term)","authors":"Laux et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09004","title":"Accidental pediatric cannabis ingestion (trends)","authors":"Wang et al.","year":2014,"journal":"","doi":null,"pmid":"24710356","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09005","title":"Cannabis and periodontal disease","authors":"Thomson et al.","year":2008,"journal":"","doi":null,"pmid":"18545738","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09006","title":"Cannabis and dental caries","authors":"Cho et al.","year":2005,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09007","title":"Cannabis and oral cancer risk","authors":"Hashibe et al.","year":2005,"journal":"","doi":null,"pmid":"16030096","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09008","title":"CBD for dental anxiety and pain","authors":"Moltke & Hindocha","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09009","title":"Cannabinoids and traumatic brain injury","authors":"Shohami et al.","year":2011,"journal":"","doi":null,"pmid":"21175577","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09010","title":"THC and neuroinflammation in MS model","authors":"Croxford & Miller","year":2003,"journal":"","doi":null,"pmid":"14523042","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09011","title":"Cannabis and C-reactive protein levels","authors":"Alshaarawy & Anthony","year":2015,"journal":"","doi":null,"pmid":"26264874","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09012","title":"CBD for sepsis-associated organ dysfunction","authors":"Cassol et al.","year":2010,"journal":"","doi":null,"pmid":"19789457","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09013","title":"Palmitoylethanolamide (PEA) as endocannabinoid-like anti-inflammatory","authors":"Petrosino & Di Marzo","year":2017,"journal":"","doi":null,"pmid":"27734513","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09014","title":"GPR119: novel cannabinoid receptor in pancreas","authors":"Overton et al.","year":2006,"journal":"","doi":null,"pmid":"16753564","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09015","title":"Endocannabinoidome: beyond classical ECS","authors":"Di Marzo","year":2018,"journal":"","doi":null,"pmid":"30142083","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09016","title":"PPAR gamma and cannabinoids","authors":"O'Sullivan","year":2016,"journal":"","doi":null,"pmid":"26174155","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09017","title":"Acid cannabinoids (THCA-A, CBDA) biological activity","authors":"Pertwee et al.","year":2010,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09018","title":"Endocannabinoid transport and FABP","authors":"Kaczocha et al.","year":2012,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09019","title":"Diacylglycerol lipase and 2-AG synthesis","authors":"Tanimura et al.","year":2010,"journal":"","doi":null,"pmid":"20547124","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09020","title":"Endocannabinoid signaling at the synapse","authors":"Castillo et al.","year":2012,"journal":"","doi":null,"pmid":"22632727","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09021","title":"Cannabis use onset and IQ trajectory","authors":"Jackson et al.","year":2016,"journal":"","doi":null,"pmid":"26787878","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09022","title":"Young adult sequelae of adolescent cannabis use: an integrative analysis.","authors":"Silins, Edmund; Horwood, L John; Patton, George C; Fergusson, David M; Olsson, Craig A; Hutchinson, Delyse M; Spry, Elizabeth; Toumbourou, John W; Degenhardt, Louisa; Swift, Wendy; Coffey, Carolyn; Tait, Robert J; Letcher, Primrose; Copeland, Jan; Mattick, Richard P","year":2014,"journal":"The Lancet. Psychiatry, 1(4), 286-93","doi":"10.1016/S2215-0366(14)70307-4","pmid":"26360862","tags":[],"studyType":"meta-individual-analysis","evidenceStrength":"strong","keyFinding":"Daily cannabis use before age 17 significantly reduced odds of high school completion (aOR 0.37) and degree attainment (aOR 0.38), while increasing odds of cannabis dependence (aOR 17.95), other illicit drug use (aOR 7.80), and suicide attempt (aOR 6.83). Clear dose-response patterns persisted after adjusting for 53 covariates across three independent cohorts.","whyItMatters":"Translates brain science into life outcomes. Multi-cohort design with 53 covariates provides among the strongest observational evidence that adolescent cannabis use predicts worse educational, substance, and mental health outcomes in adulthood.","specificNumbers":"","methodology":"Meta-individual analysis integrating participant-level data from three longitudinal Australasian cohorts (Australian Temperament Project, Christchurch Health and Development Study, Victorian Adolescent Health Cohort Study). Cannabis frequency before age 17 categorized as never/less than monthly/monthly+/weekly+/daily. Seven outcomes assessed to age 30. Adjusted for up to 53 covariates.","limitations":"Observational design cannot prove causation despite extensive confound control. Unmeasured confounders possible. All three cohorts from Australia/NZ — may not generalize to other populations. Self-report cannabis measures. Cannot separate cannabis effects from correlated lifestyle factors entirely."},{"rthcId":"RTHC-09023","title":"Early cannabis use and executive function","authors":"Fontes et al.","year":2011,"journal":"","doi":null,"pmid":"20537350","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09024","title":"Teen cannabis use and adult anxiety disorders","authors":"Patton et al.","year":2002,"journal":"","doi":null,"pmid":"11796613","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09025","title":"CBD cardioprotective effects (ischemia model)","authors":"Walsh et al.","year":2010,"journal":"","doi":null,"pmid":"20590615","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09026","title":"THC acute cardiovascular effects in healthy volunteers","authors":"Gorelick et al.","year":2013,"journal":"","doi":null,"pmid":"23443757","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09027","title":"Cannabis and peripheral arterial disease","authors":"Grotenhermen","year":2005,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09028","title":"ECS and atherosclerosis","authors":"Steffens et al.","year":2005,"journal":"","doi":null,"pmid":"16292304","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09029","title":"Cannabis industry economic impact ($112B in 2024)","authors":"MJBizDaily","year":2024,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09030","title":"Cannabis tax revenue vs enforcement costs","authors":"Miron","year":2005,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09031","title":"Medical vs recreational legalization health outcomes","authors":"Anderson & Rees","year":2023,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09032","title":"Employer drug testing post-legalization (adaptation)","authors":"Maurer et al.","year":2022,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09033","title":"Uruguay cannabis legalization model","authors":"Queirolo et al.","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09034","title":"US cannabis rescheduling to Schedule III analysis","authors":"CRS","year":2024,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09035","title":"Cannabis and obstructive sleep apnea (RCT)","authors":"Prasad et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09036","title":"Cannabis cessation insomnia (characterization)","authors":"Conroy et al.","year":2016,"journal":"","doi":null,"pmid":"26479659","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09037","title":"Endocannabinoid system and sleep regulation review","authors":"Prospero-Garcia et al.","year":2016,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09038","title":"Cannabinol and Sleep: Separating Fact from Fiction","authors":"Corroon, Jamie","year":2021,"journal":"Cannabis and Cannabinoid Research, 6(5), 366-371","doi":"10.1089/can.2021.0006","pmid":"34468204","tags":["sleep","consumer-protection"],"studyType":"narrative-review","evidenceStrength":"moderate","keyFinding":"A systematic search of PubMed found zero randomized controlled trials of CBN for sleep. Eight human studies (1973-1987) administered CBN to people; none found reliable sedative or cannabis-like effects from CBN alone. The largest study (161 participants) reported no systemic effects. The marketing claim that CBN is a powerful sleep aid has no clinical evidence supporting it.","whyItMatters":"CBN is marketed aggressively as \"the sleepy cannabinoid\" and commands premium prices in dispensaries. This review revealed that the entire clinical evidence base consists of eight old studies, none of which support the sleep claim. It exposes a structural problem where cannabis products can be marketed as sleep aids without clinical proof.","specificNumbers":"- 99 human studies screened\n- 8 met inclusion criteria for detailed review\n- 0 used validated sleep questionnaires or polysomnography\n- 0 RCTs of CBN for sleep exist\n- Doses up to 1,200mg tested with no dose-related effects (Gong 1984)\n- 161 participants in largest study showed no CBN effects (Bird 1980)","methodology":"Narrative review searching PubMed/MEDLINE with MeSH terms for cannabinol (242 results total, 99 in humans). Eight studies met inclusion criteria: administration of CBN to humans with measurement of sleep-related or cannabis-like subjective effects. Studies reviewed ranged from 1973 to 1987.","limitations":"Narrative review, not a systematic review with formal risk-of-bias assessment. PubMed only (no other databases). Single author. Author is medical director of a for-profit cannabis education center. Included studies were all decades old with small samples. Cannot prove CBN does not work — only that current evidence does not support the claim."},{"rthcId":"RTHC-09039","title":"CBD vs THC in pregnancy (differential risk)","authors":"Paul et al.","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09040","title":"Cannabis hyperemesis in pregnancy","authors":"Alaniz et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09041","title":"CBDA anti-nausea (better than CBD)","authors":"Bolognini et al.","year":2013,"journal":"","doi":null,"pmid":"23121618","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09042","title":"CBG for colon cancer (in vitro)","authors":"Borrelli et al.","year":2014,"journal":"","doi":null,"pmid":"25269802","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09043","title":"CBDV reduces nausea (preclinical)","authors":"Rock et al.","year":2013,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09044","title":"CBC anti-inflammatory and neurogenesis","authors":"Shinjyo & Di Marzo","year":2013,"journal":"","doi":null,"pmid":"23501631","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09045","title":"Cannabinoid acids as COX-2 inhibitors","authors":"Ruhaak et al.","year":2011,"journal":"","doi":null,"pmid":"21657799","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09046","title":"Rectal administration of cannabinoids","authors":"ElSohly et al.","year":1991,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09047","title":"Intranasal cannabinoid delivery","authors":"Pires et al.","year":2009,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09048","title":"Metered-dose cannabis inhaler","authors":"Eisenberg et al.","year":2014,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09049","title":"Cannabis suppository bioavailability","authors":"Bruni et al.","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09050","title":"Time-released THC capsules","authors":"Cherniakov et al.","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09051","title":"Cannabinoid-induced autophagy in cancer cells","authors":"Salazar et al.","year":2009,"journal":"","doi":null,"pmid":"19287101","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09052","title":"Ceramide pathway in cannabinoid antitumor action","authors":"Velasco et al.","year":2012,"journal":"","doi":null,"pmid":"22594963","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09053","title":"Cannabinoid receptors in the immune system (mapping)","authors":"Galiègue et al.","year":1995,"journal":"","doi":null,"pmid":"7588717","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09054","title":"Endocannabinoid metabolism (enzymes review)","authors":"Ueda et al.","year":2013,"journal":"","doi":null,"pmid":"23358189","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09055","title":"Cannabinoid type 2 receptor function in health and disease","authors":"Turcotte et al.","year":2016,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09056","title":"2-AG as retrograde messenger at hippocampal synapses","authors":"Hashimotodani et al.","year":2007,"journal":"","doi":null,"pmid":"17442246","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09057","title":"Allosteric modulation of CB1 by cholesterol","authors":"Bukiya et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09058","title":"Oldest cannabis in history (Jirzankal Cemetery, 500 BCE)","authors":"Ren et al.","year":2019,"journal":"","doi":null,"pmid":"31206023","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09059","title":"Cannabis indica vs sativa: history of a misunderstanding","authors":"McPartland","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09060","title":"Stigma and cannabis: social psychological analysis","authors":"Hathaway et al.","year":2011,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09061","title":"The American Disease: Origins of Narcotic Control (Third Edition)","authors":"Musto, David F.","year":1999,"journal":"Oxford University Press, Third Edition","doi":null,"pmid":null,"tags":["history","policy","prohibition","racial-justice"],"studyType":"historical-analysis","evidenceStrength":"strong","keyFinding":"Cannabis prohibition in the United States originated from Harry Anslinger's racially motivated propaganda campaign in the 1930s, not from scientific evidence of harm. The Marihuana Tax Act of 1937 was passed over the objections of the AMA and without meaningful scientific input, establishing a prohibition framework that persists in modified form today.","whyItMatters":"Understanding the origins of cannabis prohibition explains why marijuana was placed in Schedule I (alongside heroin, above cocaine and methamphetamine) despite pharmacological evidence that it doesn't belong there. The scheduling wasn't based on science — it was based on politics. Every drug test, every criminal record, every research barrier traces back to a policy framework Musto documented as rooted in racism.","specificNumbers":"","methodology":"Historical analysis using primary sources including government archives (FBN records, congressional hearing transcripts, presidential papers), newspaper archives, medical journals, and institutional documents. Musto's approach combined his training in psychiatry, history of medicine, and public policy to analyze the interplay between science, politics, race, and institutional power in shaping drug regulation.","limitations":"This is a historical analysis, not a scientific study. It is subject to the interpretive frameworks and source limitations inherent in historical scholarship. Some critics argue that Musto overstates the racial motivation and understates economic factors (hemp competition with synthetic fibers) in cannabis prohibition. The third edition (1999) predates the modern legalization movement."},{"rthcId":"RTHC-09062","title":"Cannabis science vs policy gap","authors":"Nutt","year":2015,"journal":"","doi":null,"pmid":"25921259","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09063","title":"History of medical cannabis in the US","authors":"Bridgeman & Abazia","year":2017,"journal":"","doi":null,"pmid":"28381909","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09064","title":"Cannabis and meditation/mindfulness","authors":"Earleywine et al.","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09065","title":"Plant cannabinoids: a neglected pharmacological treasure trove.","authors":"Mechoulam, Raphael","year":2005,"journal":"British journal of pharmacology, 146(7), 913-915","doi":"10.1038/sj.bjp.0706415","pmid":"16205721","tags":["cannabinoids","pharmacology","review"],"studyType":"review","evidenceStrength":"strong","keyFinding":"Writing four decades after isolating THC, Raphael Mechoulam argued that most of the ~100 cannabinoids identified in Cannabis sativa had never been properly evaluated pharmacologically. He highlighted new research showing THCV acts as a potent CB1 antagonist — meaning a cannabis compound blocks the same receptor that THC activates — and predicted that systematic investigation of the remaining plant cannabinoids would yield significant biological and therapeutic discoveries.","whyItMatters":"This was the founder of cannabinoid chemistry arguing that the field he created had barely scratched the surface. After 40 years of research, most cannabis compounds remained unstudied. The commentary served as both a retrospective on a remarkable career and a call to action for the next generation of researchers.","specificNumbers":"~100 cannabinoids identified in cannabis, most never pharmacologically evaluated\n400+ publications over Mechoulam's career\n41 years since THC isolation (1964-2005)\nOnly 2 FDA-approved cannabinoid drugs by 2005 (dronabinol, nabilone)\n25 years since Mechoulam's lab showed CBD was anticonvulsant (1980)","methodology":"Commentary/editorial by Raphael Mechoulam in the British Journal of Pharmacology, responding to new research on THCV and reflecting on the state of cannabinoid pharmacology after four decades of research.","limitations":"A brief 3-page commentary rather than a systematic review. Reflects one researcher's perspective, though that researcher founded the field. Does not provide a formal evidence assessment of therapeutic applications."},{"rthcId":"RTHC-09066","title":"Cannabis and eye health beyond glaucoma","authors":"Schwitzer et al.","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09067","title":"CBD for opioid use disorder (human study)","authors":"Hurd et al.","year":2019,"journal":"","doi":null,"pmid":"31109198","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09068","title":"Cannabis and organ transplant eligibility","authors":"Carliner et al.","year":2017,"journal":"","doi":null,"pmid":"28913837","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09069","title":"Cannabinoid receptor desensitization and internalization","authors":"Ahn et al.","year":2012,"journal":"","doi":null,"pmid":"22722106","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09070","title":"Cannabis and oral microbiome","authors":"Hernandez-Sanchez et al.","year":2022,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09071","title":"Cannabis dependence: brain reward system changes (PET)","authors":"Volkow et al.","year":2014,"journal":"","doi":null,"pmid":"25092317","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09072","title":"Cannabis and tinnitus","authors":"Zheng et al.","year":2007,"journal":"","doi":null,"pmid":"17467222","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09073","title":"CBD for gambling disorder","authors":"Kayser et al.","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09074","title":"Cannabis and asthma: historical and modern evidence","authors":"Tashkin et al.","year":1975,"journal":"","doi":null,"pmid":"1137251","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09075","title":"Endocannabinoid system and cancer immunology","authors":"Haustein et al.","year":2014,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09076","title":"Cannabis genetic diversity and domestication history","authors":"Ren et al.","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09077","title":"Clinical endocannabinoid deficiency: 20 years later","authors":"Russo, Ethan B","year":2024,"journal":"Cannabis and Cannabinoid Research","doi":null,"pmid":null,"tags":["endocannabinoid-system","clinical-endocannabinoid-deficiency","migraine","fibromyalgia","ibs","pain","review"],"studyType":"Review/Reassessment","evidenceStrength":"Review — synthesizes 20 years of CECD evidence","keyFinding":"CECD has evolved from simple deficiency to dysregulation model — endocannabinoid signaling is measurably altered in predicted conditions, but the picture is more complex than \"too little.\" Both deficiency and excess can be pathological, suggesting tissue-specific imbalances rather than global shortage.","whyItMatters":"CECD is the most influential unifying hypothesis in cannabinoid medicine — it explains why certain treatment-resistant conditions cluster, co-occur, and respond to cannabinoid interventions. This twenty-year reassessment shows intellectual maturation: acknowledging contradictions, refining the model, and expanding the treatment framework beyond cannabis alone.","specificNumbers":"","methodology":"Narrative review and reassessment of 20 years of accumulated evidence: CSF endocannabinoid measurements, platelet studies, PET neuroimaging of CB1 receptor density, genetic association studies, and clinical observations across the conditions originally proposed in 2004.","limitations":"No randomized trial has directly tested CECD. No standardized diagnostic test exists. Group-level biomarker differences do not translate to individual diagnosis. The concept risks unfalsifiability if expanded too broadly. Author has financial ties to cannabis pharmaceutical industry. \"Deficiency\" framing may oversimplify bidirectional dysregulation."},{"rthcId":"RTHC-09078","title":"Cannabis and empathy/emotional intelligence","authors":"Vigil et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09079","title":"ECS and bone formation (CB2 knockout)","authors":"Ofek et al.","year":2006,"journal":"","doi":null,"pmid":"16432235","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09080","title":"Cannabis concentrates: health effects review","authors":"Bidwell et al.","year":2018,"journal":"","doi":null,"pmid":"31032180","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09081","title":"Medical cannabis patient satisfaction (real-world)","authors":"Aviram & Samuelly-Leichtag","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09082","title":"Cannabis and psoriasis (endocannabinoid role)","authors":"Norooznezhad & Norooznezhad","year":2017,"journal":"","doi":null,"pmid":"28122381","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09083","title":"Cannabis and restless legs syndrome","authors":"Megelin & Ghorayeb","year":2017,"journal":"","doi":null,"pmid":"28163036","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09084","title":"Cannabis and immune checkpoint therapy interaction","authors":"Taha et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09085","title":"Phytochemical and genetic analyses of ancient cannabis from Central Asia.","authors":"Russo, Ethan B; Jiang, Hong-En; Li, Xiao; Sutton, Alan; Carboni, Andrea; del Bianco, Fabrizio; Mandolino, Giuseppe; Potter, David J; Zhao, You-Xing; Bera, Subir; Zhang, Yu-Bing; Lu, En-Guo; Ferguson, David K; Hueber, Francis; Zhao, Liang-Cheng; Liu, Chang-Jiang; Wang, Yu-Fei; Li, Cheng-Sen","year":2008,"journal":"Journal of Experimental Botany, 59(15), 4171-4182","doi":"10.1093/jxb/ern260","pmid":"19036842","tags":["archaeology","history","ethnobotany"],"studyType":"archaeobotanical/phytochemical analysis","evidenceStrength":"strong","keyFinding":"789g of dried cannabis found in a 2,700-year-old shaman's tomb. GC-MS, HPLC, and genetic analysis confirmed drug-type cannabis with THC, not fiber hemp. Oldest physical specimen of cultivated psychoactive cannabis.","whyItMatters":"Establishes that humans were cultivating cannabis specifically for psychoactive use at least 2,700 years ago, predating all previous physical evidence and placing drug-type cannabis in a shamanic ritual context.","specificNumbers":"789g cannabis. Tomb M90, Yanghai cemetery. ~700 BCE. Shaman aged ~45 years. Female flowers (buds/leaves only, no seeds/stems). THC degradation products confirmed by GC-MS/HPLC.","methodology":"Phytochemical analysis (GC-MS, HPLC) and genetic DNA analysis of 2,700-year-old cannabis from Tomb M90, Yanghai Tombs, Turpan Depression, Xinjiang, China.","limitations":"Single tomb specimen. Most THC degraded to CBN over 2,700 years. Cannot determine exact original potency."},{"rthcId":"RTHC-09086","title":"Raphael Mechoulam obituary: legacy of cannabis science","authors":"Pertwee","year":2023,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09087","title":"CB1 receptor distribution in the brain (first map)","authors":"Herkenham et al.","year":1990,"journal":"","doi":null,"pmid":"2165569","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09088","title":"Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs.","authors":"A C Howlett; J M Qualy; L L Khachatrian","year":1986,"journal":"Molecular pharmacology","doi":null,"pmid":"2869405","tags":[],"studyType":"laboratory-study","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09089","title":"Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.","authors":"B F Cravatt; D K Giang; S P Mayfield; D L Boger; R A Lerner; N B Gilula","year":1996,"journal":"Nature","doi":"10.1038/384083a0","pmid":"8900284","tags":[],"studyType":"laboratory-study","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09090","title":"2-AG discovery (Japanese group, parallel to Mechoulam)","authors":"Sugiura et al.","year":1995,"journal":"","doi":null,"pmid":"7779150","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09091","title":"Formation and inactivation of anandamide","authors":"Di Marzo et al.","year":1994,"journal":"","doi":null,"pmid":"7969452","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09092","title":"THC inhibits calcium channels via CB1","authors":"Mackie & Hille","year":1992,"journal":"","doi":null,"pmid":"1313569","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09093","title":"Dopamine triggers anandamide release in striatum","authors":"Giuffrida et al.","year":1999,"journal":"","doi":null,"pmid":"10524249","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09094","title":"Cannabinoid analgesia: comprehensive mechanisms review","authors":"Walker & Huang","year":2002,"journal":"","doi":null,"pmid":"12093613","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09095","title":"Mechoulam's 2-AG paper","authors":"Mechoulam et al.","year":1995,"journal":"","doi":null,"pmid":"7510289","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09096","title":"Chemical constituents of marijuana catalog","authors":"ElSohly & Slade","year":2005,"journal":"","doi":null,"pmid":"16137692","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09097","title":"History of cannabis as medicine (Zuardi review)","authors":"Zuardi","year":2006,"journal":"","doi":null,"pmid":"16906297","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09098","title":"CB1 receptor localization in rat brain (detailed)","authors":"Tsou et al.","year":1998,"journal":"","doi":null,"pmid":"9595358","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09099","title":"Cannabinoid receptor signal transduction pathways","authors":"Howlett et al.","year":2002,"journal":"","doi":null,"pmid":"12037135","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09100","title":"Endocannabinoid control of food intake and body weight","authors":"Di Marzo & Matias","year":2005,"journal":"","doi":null,"pmid":"16205720","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09101","title":"Depolarization-induced suppression of excitation (DSE)","authors":"Kreitzer & Regehr","year":2001,"journal":"","doi":null,"pmid":"11239435","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09102","title":"Cannabis and neuronal death: a comprehensive review of the evidence","authors":"Bhatt & Bhatt","year":2021,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"Narrative Review","evidenceStrength":"Moderate (composite evidence)","keyFinding":"No neuroimaging or histological evidence supports the claim that cannabis causes neuronal death in humans. Observed structural changes are modest, inconsistent across studies, and largely reversible with abstinence.","whyItMatters":"The kills brain cells myth, traceable to a single debunked 1980 experiment, has shaped drug education and public perception for decades. Correcting it matters both for accurate risk communication and for helping people understand that recovery from heavy cannabis use is neurologically expected.","specificNumbers":"","methodology":"Narrative review synthesizing PET imaging, structural MRI, diffusion tensor imaging, and post-mortem studies comparing cannabis users to non-users and to subjects with known neurotoxic exposure.","limitations":"Most neuroimaging studies are cross-sectional, making it hard to establish causality. Heavy cannabis users often co-use alcohol and tobacco. The adolescent brain may be more vulnerable than adult studies suggest."},{"rthcId":"RTHC-09103","title":"Cannabis sativa: effects on brain function and ultrastructure in rhesus monkeys","authors":"Heath RG, Fitzjarrell AT, Fontana CJ, Garey RE","year":1980,"journal":"Biological Psychiatry","doi":null,"pmid":null,"tags":[],"studyType":"Animal Study (Debunked)","evidenceStrength":"Debunked — fatal methodological flaw","keyFinding":"Claimed to show structural brain damage from cannabis smoke in rhesus monkeys. The finding has been debunked — the brain damage was caused by oxygen deprivation, not THC.","whyItMatters":"This single debunked study is the origin of one of the most persistent myths in drug education. It shaped DARE programs, government anti-drug campaigns, and public perception for decades — despite being retracted by the broader scientific community.","specificNumbers":"","methodology":"Rhesus monkeys inhaled concentrated cannabis smoke (~63 joints worth) through sealed gas masks in 5-minute sessions with no supplemental oxygen, daily for ~3 months.","limitations":"Fatal flaw: no oxygen control. The sealed gas mask delivery system caused asphyxiation. Small sample. Methodology was concealed for 6 years."},{"rthcId":"RTHC-09104","title":"Comparison of acute lethal toxicity of commonly abused psychoactive substances","authors":"Gable RS","year":2004,"journal":"Addiction, 99(6)","doi":"10.1111/j.1360-0443.2004.00744.x","pmid":"15139867","tags":["thc","safety"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabis has a safety ratio of approximately 1,000:1 (lethal dose / effective dose). Among 20 substances ranked, cannabis was among the least acutely toxic, comparable to psilocybin and LSD. Heroin had the lowest safety ratio (~6:1), followed by GHB (~8:1) and alcohol (~10:1).","whyItMatters":"The safety ratio quantifies the fundamental pharmacological fact that cannabis overdose death is essentially impossible — a key data point in scheduling and regulation debates. It also highlights the disconnect between cannabis's Schedule I classification and its actual toxicological profile.","specificNumbers":"20 substances compared. Cannabis safety ratio: ~1,000:1. Heroin: ~6:1. GHB: ~8:1. Alcohol: ~10:1. Cocaine: ~15:1. Aspirin: ~20:1. Cannabis ranking: among the 3 least toxic substances assessed.","methodology":"Structured English-language literature review identifying experimental studies and clinical reports documenting human and non-human lethal doses of 20 abused substances. Safety ratio calculated as acute lethal dose / customary non-medical dose.","limitations":"Exact lethal dose for cannabis in humans has never been determined (extrapolated from animal data). Safety ratio addresses only acute lethality — not dependence, chronic toxicity, mental health effects, or social harm. Co-intoxicant effects not included in ratios."},{"rthcId":"RTHC-09105","title":"Cannabis and testosterone in men (meta-analysis)","authors":"Thistle et al.","year":2017,"journal":"","doi":null,"pmid":"28465066","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09106","title":"Cannabis and cortisol / HPA axis","authors":"Cuttler et al.","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09107","title":"Cannabis and gynecomastia (man boobs)","authors":"Narula & Carlson","year":2014,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09108","title":"Cannabis detection times comprehensive guide","authors":"Moeller et al.","year":2017,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09109","title":"Simultaneous versus concurrent use of alcohol and cannabis in the National Alcohol Survey.","authors":"Subbaraman, Meenakshi S; Kerr, William C","year":2015,"journal":"Alcoholism: Clinical and Experimental Research, 39(5), 872-879","doi":"10.1111/acer.12698","pmid":"26331879","tags":["alcohol","co-use","harm-reduction"],"studyType":"cross-sectional survey analysis","evidenceStrength":"strong","keyFinding":"Simultaneous cannabis-alcohol users had 2.30x odds of drunk driving, 2.96x social consequences, and 2.22x harms to self vs alcohol-only users. Concurrent users showed no significant increase in drunk driving or self-harm.","whyItMatters":"First study to distinguish simultaneous from concurrent alcohol-cannabis co-use in the general population, revealing that mixing is dramatically riskier than using both but separately.","specificNumbers":"N=8,626. 7.5% simultaneous users, 3.9% concurrent. Simultaneous: 2.3 avg daily drinks, 65.7 heavy drinking days/yr. Alcohol-only: 0.71 drinks, 13.9 days. OR drunk driving 2.30, social consequences 2.96, harms 2.22.","methodology":"Secondary analysis of 2005 and 2010 National Alcohol Survey. Multivariable logistic regression controlling for demographics and drinking patterns.","limitations":"Cross-sectional, self-report, no cannabis dose data, 52% cooperation rate."},{"rthcId":"RTHC-09110","title":"Combined alcohol and cannabis effect on cognition","authors":"Liguori et al.","year":2002,"journal":"","doi":null,"pmid":"11955012","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09111","title":"Cannabis and caffeine interaction","authors":"Kerr et al.","year":2014,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09112","title":"Surgical considerations of marijuana use in elective procedures","authors":"Huson, Henry B; Granados, Tamara Marryshow; Rasko, Yvonne","year":2018,"journal":"Heliyon, 4(9), e00779","doi":"10.1016/j.heliyon.2018.e00779","pmid":"30225378","tags":["perioperative","safety","harm-reduction"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Chronic cannabis users may require substantially more sedation for procedures (up to 220% more propofol in one study). Cannabis smoke produces airway hyperreactivity increasing intubation risks. Cardiovascular effects (tachycardia, blood pressure instability) compound surgical stress. Despite 40 years of physiological research, almost no prospective surgical outcome studies exist in cannabis users.","whyItMatters":"Tens of millions of Americans use cannabis and millions undergo surgery annually. Most cannabis users do not disclose their use, leaving surgical teams unprepared for altered anesthesia needs, airway complications, and cardiovascular instability.","specificNumbers":"Propofol increase: 220% in one study (44.81 mg vs 13.83 mg), not confirmed in subsequent studies. 72 hours minimum abstinence recommended. 24.1% peak heart rate increase in surgical patients. Nearly half of heavy smokers (>100g/month) had recurrent rhinopharyngitis.","methodology":"Narrative literature review addressing four clinical questions about marijuana use and surgical considerations.","limitations":"Narrative review, not systematic. Based primarily on case reports, small studies, and physiological research rather than large prospective surgical outcome trials. The 220% propofol figure from Twardowski has been contested by subsequent studies."},{"rthcId":"RTHC-09113","title":"Cannabis and post-operative pain management","authors":"Alexander et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09114","title":"Urinary Pharmacokinetic Profile of Cannabinoids Following Administration of Vaporized and Oral Cannabidiol and Vaporized CBD-Dominant Cannabis.","authors":"Tory R Spindle; Edward J Cone; David Kuntz; John M Mitchell; George E Bigelow; Ronald Flegel; Ryan Vandrey","year":2020,"journal":"Journal of analytical toxicology","doi":"10.1093/jat/bkz080","pmid":"31682266","tags":[],"studyType":"experimental","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09115","title":"Cannabis and warfarin interaction","authors":"Damkier et al.","year":2019,"journal":"","doi":null,"pmid":"30326170","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09116","title":"Cannabis and immunosuppressant interaction (transplant)","authors":"Leino et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09117","title":"Subjective and behavioral effects of marijuana the morning after smoking.","authors":"L D Chait","year":1990,"journal":"Psychopharmacology","doi":"10.1007/BF02244601","pmid":"2315429","tags":[],"studyType":"experimental","evidenceStrength":"not-graded","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09118","title":"Common liability to addiction and \"gateway hypothesis\": theoretical, empirical and evolutionary perspective","authors":"Vanyukov MM, Tarter RE, Kirillova GP, Kirisci L, Reynolds MD, Kreek MJ, Conway KP, Maher BS, Iacono WG, Bierut L, Neale MC, Clark DB, Ridenour TA","year":2012,"journal":"Drug and Alcohol Dependence","doi":"10.1016/j.drugalcdep.2011.12.018","pmid":"22261179","tags":["gateway-hypothesis","genetics","common-liability","addiction-theory","behavioral-genetics","evolution"],"studyType":"Theoretical Review","evidenceStrength":"Strong — comprehensive multi-disciplinary review synthesizing genetic, neurobiological, epidemiological, and evolutionary evidence from dozens of studies","keyFinding":"The gateway hypothesis is unfalsifiable, empirically contradicted by variable international drug sequencing patterns, and unsupported by genetics. The common liability to addiction model — shared genetic and neurobiological risk factors driving all substance use — provides a more parsimonious and empirically supported framework.","whyItMatters":"If the gateway hypothesis is wrong, the policy implications are enormous. Drug-specific prevention strategies (preventing cannabis to prevent heroin) may be misguided. Interventions should target behavioral regulation and shared risk factors rather than sequential drug exposure.","specificNumbers":"In Japan, 83% of illicit drug users violated the gateway sequence (used non-cannabis drugs first). Over 50% of people with addiction have comorbid externalizing disorders. Virtual no substance-specific genetic variance found — genetic risk for addiction is shared across substances. 70-90% of the population is exposed to drugs, but individual phenotypic characteristics prevail over access in determining addiction.","methodology":"Comprehensive theoretical review integrating: biometrical genetics studies, genome-wide association data, twin studies, longitudinal cohorts, international epidemiological surveys, neurobiological research, and evolutionary theory","limitations":"Theoretical review, not original empirical research. The common liability model, while better supported, does not definitively rule out some gateway mechanism for specific individuals or circumstances. The evolutionary arguments are speculative. Some empirical claims are drawn from author own previous work."},{"rthcId":"RTHC-09119","title":"Cannabis and subsequent drug use (large longitudinal)","authors":"Secades-Villa et al.","year":2015,"journal":"","doi":null,"pmid":"26150222","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09120","title":"Memory recovery after cannabis cessation (meta-analysis)","authors":"Scott et al.","year":2018,"journal":"","doi":null,"pmid":"30167644","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09121","title":"Hippocampal volume and cannabis use","authors":"Yücel et al.","year":2008,"journal":"","doi":null,"pmid":"18180424","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09122","title":"Anticancer mechanisms of cannabinoids","authors":"Velasco, Guillermo; Sánchez, Cristina; Guzmán, Manuel","year":2016,"journal":"Current Oncology, 23(Suppl 2), S23-S32","doi":"10.3747/co.23.3080","pmid":"27022311","tags":["cancer","review","pharmacology"],"studyType":"review","evidenceStrength":"moderate","keyFinding":"Cannabinoids have demonstrated anticancer activity across multiple tumor types in preclinical models through defined mechanisms: ceramide-p8-TRIB3 pathway leading to autophagy-mediated cell death, inhibition of angiogenesis, and decreased metastasis. However, resistance mechanisms (MDK/ALK signaling) have been identified, and clinical evidence remains limited to one small pilot trial. The authors advocate for rigorous clinical trials while warning against premature clinical application.","whyItMatters":"This review carries unique authority because the authors are the same team that pioneered cannabinoid anticancer research — the group behind the landmark 2000 Nature Medicine study, the 2003 Nature Reviews Cancer review, and the 2006 human pilot trial. When the researchers who discovered these effects say \"the evidence isn't sufficient for clinical use,\" it carries more weight than the same statement from any outside observer. The paper serves as both a comprehensive scientific resource and a responsible public health message.","specificNumbers":"","methodology":"Narrative review of preclinical and early clinical evidence for cannabinoid anticancer mechanisms, covering in vitro, in vivo, and early clinical data from the authors' own research program and the broader literature.","limitations":"As a narrative review (not systematic), the selection and emphasis of evidence reflects the authors' perspective. The review focuses primarily on the authors' own research program, though this is appropriate given their leading role in the field."},{"rthcId":"RTHC-09123","title":"Acute Effects of Ad Libitum Use of Commercially Available Cannabis Products on the Subjective Experience of Aerobic Exercise: A Crossover Study","authors":"Gibson LP, Giordano GR, Bidwell LC, Hutchison KE, Bryan AD","year":2024,"journal":"Sports Medicine, 54(4)","doi":"10.1007/s40279-023-01980-4","pmid":"38147185","tags":["thc","cbd","exercise"],"studyType":"crossover","evidenceStrength":"preliminary","keyFinding":"90.5% reported more enjoyment with cannabis. 69% reported decreased pain. 57.1% improved motivation. No performance enhancement. THC group: higher perceived exertion despite greater enjoyment. CBD group: greatest enjoyment gains.","whyItMatters":"Physical inactivity contributes to 10% of premature mortality. If cannabis makes exercise more enjoyable without enhancing performance, it could help the millions who don't exercise because it feels unpleasant — a public health implication that outweighs performance metrics.","specificNumbers":"42 runners. 30-minute treadmill sessions. 90.5% more enjoyment. 69% decreased pain. 59.5% increased focus. 57.1% improved motivation. CBD > THC for enjoyment.","methodology":"Crossover study: 42 regular cannabis-using runners completed sober and cannabis treadmill sessions. Assigned THC-dominant or CBD-dominant products from dispensary. Self-selected doses. Periodic assessment of enjoyment, pain, exertion, motivation.","limitations":"Self-selected cannabis-using runners (not generalizable). No dose standardization. Unable to blind cannabis condition. Single acute session (no long-term data). No injury tracking."},{"rthcId":"RTHC-09124","title":"Cannabis legalization increased physical activity (ecological study)","authors":"York Williams et al.","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09125","title":"Cannabis and A1c levels (NHANES)","authors":"Alshaarawy & Anthony","year":2015,"journal":"","doi":null,"pmid":"25563729","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09126","title":"Cannabis users and infection risk","authors":"Pacifici et al.","year":2003,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09127","title":"Cannabis and COVID-19 outcomes (clinical)","authors":"Shover et al.","year":2022,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09128","title":"CBD for acne: anti-inflammatory sebocyte study (JCI)","authors":"Olah et al.","year":2014,"journal":"","doi":null,"pmid":"25061873","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09129","title":"Acute THC impairs executive function (systematic review)","authors":"Broyd et al.","year":2016,"journal":"","doi":null,"pmid":"26851575","tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09130","title":"Cannabis alters auditory processing","authors":"Rentzsch et al.","year":2011,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09131","title":"Cannabis sativa: the unconventional weed allergen","authors":"Ocampo TL, Rans TS","year":2015,"journal":"Annals of Allergy, Asthma & Immunology","doi":"10.1016/j.anai.2015.01.004","pmid":"25744904","tags":[],"studyType":"Narrative Review","evidenceStrength":"Moderate","keyFinding":"Cannabis allergy is a legitimate clinical entity involving IgE-mediated sensitization, with documented cases ranging from rhinoconjunctivitis and contact urticaria to anaphylaxis. Cross-reactivity with food allergens (tomatoes, peaches, hazelnuts) has been established.","whyItMatters":"As cannabis use and cultivation expand under legalization, cannabis allergy is an emerging clinical and occupational health concern that most clinicians are unfamiliar with.","specificNumbers":"","methodology":"Comprehensive narrative review of case reports, epidemiological surveys, and immunological studies of cannabis allergy published between 1970 and 2014.","limitations":""},{"rthcId":"RTHC-09132","title":"Cannabis and Hormonal Contraception: Pharmacological Interaction Evidence","authors":"Evidence synthesis — Nasrin et al. (2021), Li et al. (2023), Fattore et al. (2023), Robert et al. (2022)","year":2024,"journal":"Evidence synthesis (multiple sources)","doi":null,"pmid":null,"tags":["drug-interactions","womens-health"],"studyType":"evidence-synthesis","evidenceStrength":"low","keyFinding":"Cannabis (both THC and CBD) inhibits CYP3A4, the liver enzyme that metabolizes hormonal contraceptive hormones. Enzyme inhibition slows metabolism, theoretically increasing contraceptive levels — the opposite direction from what would cause failure. No clinical study has demonstrated reduced contraceptive effectiveness with cannabis use.","whyItMatters":"Millions of women use both cannabis and hormonal contraception simultaneously. The widespread concern that cannabis might reduce birth control effectiveness is based on a misunderstanding of the enzyme interaction direction. Clarifying this has direct clinical relevance for patient counseling and reproductive health decisions.","specificNumbers":"","methodology":"Evidence synthesis drawing on in vitro CYP enzyme characterization (Nasrin 2021), systematic review of oral contraceptive drug interactions (Li 2023), preclinical co-exposure study in rats (Fattore 2023), and clinical guidelines (Robert 2022). No single randomized trial addresses this question directly.","limitations":"No randomized trial has directly studied cannabis-contraceptive interaction in humans. In vitro enzyme inhibition may not translate to clinically meaningful effects at real-world cannabis doses. The OHSU trial (NCT04396730) studying CBD-OCP interaction is ongoing but results are not yet available."},{"rthcId":"RTHC-09133","title":"Monitoring the Future: teen cannabis trends 50 years","authors":"Johnston et al.","year":2023,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09134","title":"Global Burden of Disease: cannabis-attributable health loss","authors":"GBD Study","year":2019,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09135","title":"FDA approval of Epidiolex: regulatory milestone","authors":"FDA","year":2018,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09136","title":"11-hydroxy-Δ9-tetrahydrocannabinol: pharmacology, disposition, and metabolism of a major metabolite of marihuana in man","authors":"Lemberger, Louis; Crabtree, Robert E; Rowe, Helen M","year":1972,"journal":"Science","doi":"10.1126/science.177.4043.62","pmid":"5041775","tags":["pharmacokinetics","11-OH-THC","metabolism","edibles","first-pass","CYP2C9"],"studyType":"Pharmacokinetic study (human)","evidenceStrength":"Landmark (S-tier)","keyFinding":"11-hydroxy-THC is pharmacologically active in humans, with effects that mimic delta-9-THC. The liver converts THC to this metabolite during first-pass metabolism, explaining the distinct pharmacology of oral cannabis consumption.","whyItMatters":"This paper is the molecular explanation for why edibles feel different from smoking. It has direct relevance to every person who has ever had an unexpectedly intense edible experience, every emergency room visit from edible overconsumption, and every dosing guideline for oral cannabis products.","specificNumbers":"","methodology":"Intravenous administration of radiolabeled 11-hydroxy-Δ9-THC to human volunteers, with serial measurement of plasma concentrations, psychoactive effects, and urinary/fecal excretion of the drug and metabolites over more than one week.","limitations":"The 1972 study used intravenous administration of 11-OH-THC, not oral cannabis. The first-pass metabolism mechanism linking this to edible experiences was established through this and companion studies but the full oral pharmacokinetic picture was built over subsequent decades. Small sample sizes typical of 1970s human pharmacology."},{"rthcId":"RTHC-09137","title":"Tolerance development timeline in daily users","authors":"Colizzi & Bhattacharyya","year":2020,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09138","title":"Cannabis smoking and respiratory infections","authors":"Tashkin","year":2013,"journal":"","doi":null,"pmid":null,"tags":[],"studyType":"","evidenceStrength":"","keyFinding":"","whyItMatters":"","specificNumbers":"","methodology":"","limitations":""},{"rthcId":"RTHC-09139","title":"New approaches and challenges to targeting the endocannabinoid system.","authors":"Di Marzo, Vincenzo","year":2018,"journal":"Nature reviews. Drug discovery, 17(9), 623-639","doi":"10.1038/nrd.2018.115","pmid":"30116049","tags":["pharmacology","endocannabinoid-system","review"],"studyType":"review","evidenceStrength":"strong","keyFinding":"The classical endocannabinoid system — two receptors (CB1 and CB2), two endocannabinoids (anandamide and 2-AG), and a handful of enzymes — is part of a much larger network that Di Marzo termed the 'endocannabinoidome.' This expanded system includes over 20 receptors (including GPR55, TRPV1, PPARs), dozens of lipid mediators chemically related to endocannabinoids (like PEA, OEA, and oleamide), and the metabolic enzymes that produce and degrade them. The complexity explains why single-target cannabinoid drugs have often failed and why multi-target approaches — including botanical preparations like CBD — show more clinical promise.","whyItMatters":"This paper redefined the playing field for cannabinoid medicine. The endocannabinoidome concept explains puzzles that the classical ECS model couldn't: why CBD works despite barely binding CB1/CB2, why whole-plant cannabis often has different effects than isolated THC, and why rimonabant (a CB1 blocker) failed despite sound pharmacological logic. It shifted the therapeutic strategy from targeting single receptors to understanding and modulating a complex network.","specificNumbers":"20+ receptors beyond CB1/CB2 (including GPR55, TRPV1, PPARγ, GPR18, GPR119)\n12+ lipid mediators beyond anandamide and 2-AG\nDozens of metabolic enzymes\n2 approved cannabinoid medicines by 2018: nabiximols (Sativex) and cannabidiol (Epidiolex)","methodology":"Comprehensive review published in Nature Reviews Drug Discovery — the world's top-ranked drug discovery journal — examining the history, current state, and future directions of endocannabinoid-targeted therapeutics.","limitations":"A narrative review reflecting one researcher's synthesis. Many proposed therapeutic strategies remain preclinical. The endocannabinoidome concept, while increasingly supported, is still being refined and debated regarding its exact boundaries."},{"rthcId":"RTHC-09140","title":"Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome","authors":"Devinsky, Orrin; Cross, J Helen; Laux, Linda; Marsh, Eric; Miller, Ian; Nabbout, Rima; Scheffer, Ingrid E; Thiele, Elizabeth A; Wright, Stephen","year":2017,"journal":"New England Journal of Medicine, 376(21), 2011-2020","doi":"10.1056/NEJMoa1611618","pmid":"28538134","tags":["epilepsy","cbd","clinical-trial"],"studyType":"randomized-controlled-trial","evidenceStrength":"strong","keyFinding":"Cannabidiol (20 mg/kg/day) reduced convulsive seizure frequency by 39% compared to 13% with placebo in children with Dravet syndrome. 5% of CBD patients became seizure-free during the trial; none in the placebo group did. This is the definitive RCT that led to FDA approval of Epidiolex.","whyItMatters":"This NEJM trial provided the gold-standard evidence the FDA needed to approve Epidiolex — the first cannabis-derived drug ever approved in the United States. It completed the evidence chain from Charlotte Figi's case report through open-label trials to definitive proof.","specificNumbers":"- 120 patients randomized (CBD: 61, placebo: 59)\n- CBD dose: 20 mg/kg/day oral solution for 14 weeks\n- Seizure reduction: 39% (CBD) vs 13% (placebo)\n- Adjusted median difference: -22.8 percentage points (95% CI: -41.1 to -5.4; p=0.01)\n- 5% seizure-free on CBD vs 0% on placebo\n- 43% of CBD group had ≥50% seizure reduction vs 27% on placebo","methodology":"Multicenter, randomized, double-blind, placebo-controlled trial. 14-week treatment period. Cannabidiol oral solution (Epidiolex) at 20 mg/kg/day or placebo. Primary endpoint: change in convulsive seizure frequency vs baseline.","limitations":"Industry-funded (GW Pharmaceuticals). 14-week duration only. Side effects included somnolence, diarrhea, decreased appetite, and abnormal liver function tests. High dropout rate in CBD group partially due to adverse events."},{"rthcId":"RTHC-09141","title":"Escalation of drug use in early-onset cannabis users vs co-twin controls","authors":"Lynskey MT, Heath AC, Bucholz KK, Slutske WS, Madden PAF, Nelson EC, Statham DJ, Martin NG","year":2003,"journal":"JAMA","doi":"10.1001/jama.289.4.427","pmid":"12533121","tags":["gateway-hypothesis","twin-study","adolescent-risk","drug-escalation","genetics"],"studyType":"Twin Study (Cross-Sectional)","evidenceStrength":"Strong — twin design controls for genetic and shared environmental confounds that plague observational studies","keyFinding":"In 311 Australian twin pairs discordant for early cannabis use, the twin who used cannabis before age 17 was 2.1-5.2 times more likely to subsequently use other illicit drugs and develop drug dependence, even after controlling for shared genetics, environment, and established risk factors","whyItMatters":"This was the strongest evidence supporting a gateway effect because the twin design eliminates the most common alternative explanations. However, it cannot distinguish between a pharmacological gateway (cannabis primes the brain) and an environmental gateway (cannabis use exposes teens to drug markets and drug-using peers).","specificNumbers":"311 twin pairs discordant for early cannabis use; 2.1-5.2x higher odds of other drug use; median age 30; no significant difference between monozygotic and dizygotic twins; controlling for confounders had negligible effect on estimates","methodology":"Discordant twin design from the Australian Twin Registry. Same-sex twin pairs where one twin used cannabis before age 17 and the other did not. Compared subsequent drug use patterns between the using and non-using twin. Adjusted for early alcohol/tobacco, parental conflict, childhood sexual abuse, conduct disorder, depression, social anxiety.","limitations":"Cross-sectional retrospective design relies on recall. Australian sample may not generalize to all populations. Cannot distinguish pharmacological from environmental gateway mechanisms. Discordant pairs are a selected subgroup. Self-report of drug use."},{"rthcId":"RTHC-09142","title":"The Relationship between Marijuana Use Prior to Sex and Sexual Function in Women.","authors":"Lynn, Becky K; Lopez, Julia D; Miller, Collin; Thompson, Judy; Campian, E Cristian","year":2019,"journal":"Sexual medicine, 7(2), 192-197","doi":"10.1016/j.esxm.2019.01.003","pmid":"30833225","tags":["medical-cannabis","womens-health"],"studyType":"cross-sectional-survey","evidenceStrength":"moderate","keyFinding":"Women who used cannabis before sex had 2.13 times the odds of reporting satisfactory orgasms compared to non-users (aOR 2.13, 95% CI 1.05-4.35, p=0.04). Frequent users also had 2.10x odds of satisfactory orgasm regardless of timing (p=0.02). 68.5% reported more pleasurable overall experience, 60.6% increased sex drive, 52.8% more satisfying orgasms.","whyItMatters":"This was the first study designed specifically to examine how cannabis affects sexual function in women. With female sexual dysfunction affecting ~40% of women and only two FDA-approved treatments available, the finding that cannabis may enhance orgasm satisfaction opens a potential therapeutic avenue in an area with enormous unmet clinical need.","specificNumbers":"373 women surveyed. 127 (34%) used cannabis before sex. aOR for satisfactory orgasm: 2.13 (95% CI 1.05-4.35, p=0.04). Frequent users aOR: 2.10 (95% CI 1.01-4.44, p=0.02). 68.5% reported more pleasurable overall experience. 60.6% increased sex drive. 52.8% improved orgasm satisfaction.","methodology":"Cross-sectional survey at a single academic OB/GYN practice (Saint Louis University). 373 women surveyed March 2016-February 2017. Sexual Health Survey assessed perceived effects of cannabis on sex drive, orgasm, lubrication, dyspareunia, and overall experience. Multivariate logistic regression adjusted for race and age. SAS Version 9.4.","limitations":"Single-center design limits generalizability. Self-reported data subject to recall bias. Did not measure dose, strain, THC/CBD ratio, timing, or consumption method. Did not assess concurrent substance use (alcohol). \"Sex\" was not defined — participants used own definition. Cross-sectional design cannot establish causation."}]